PMID- 30394820 TI - Expanding the Indications of Robotic Partial Nephrectomy for Highly Complex Renal Tumors: Urologists' Perception of the Impact of Hyperaccuracy Three-Dimensional Reconstruction. AB - OBJECTIVES: To assess the role of three-dimensional (3D) reconstruction in aiding preoperative planning for highly complex renal tumors amenable to robotic partial nephrectomy (RPN). MATERIALS AND METHODS: Computed tomography (CT) scans and respective 3D reconstructions of 20 highly complex renal tumors were displayed to the attendees/urologists of the 6th Techno-Urology Meeting ( www.technourologymeeting.com ). These 20 cases had already undergone RPN performed by a single experienced surgeon. The attendees were asked to watch the videos of the CT scans first, and then the respective 3D reconstructions of 5 of the 20 cases who were randomly selected. A purpose-built questionnaire collected responders' surgical experience and surgical indication (RPN versus nephrectomy) after viewing the CT scan and the respective 3D reconstructions. RESULTS: Twenty expert urologists, 27 young urologists, and 61 residents (total = 108) participated in the study. Five hundred forty-two views of the cases were obtained. Based on CT scans, RPN was indicated in 256 cases (47.2%). After viewing the respective 3D reconstructions, in 148 cases the responders changed their idea: indication to RPN raised in 404 cases (74.5%) (P < .001). The opinions changed regardless of the surgical experience. CONCLUSIONS: The findings of this study are encouraging, and they might represent a significant step toward the validation of the use of 3D reconstruction for surgical planning in patients undergoing robotic kidney surgery. The use of this technology might translate into a larger adoption of nephron-sparing approach. Further investigation in this area is warranted to corroborate these findings. PMID- 30394821 TI - Assessing the Impact of a Novel Integrated Palliative Care and Medical Oncology Inpatient Service on Health Care Utilization before Hospice Enrollment. AB - BACKGROUND: Evidence increasingly supports the integration of specialist palliative care (PC) into routine cancer care. A novel, fully integrated PC and medical oncology inpatient service was developed at Duke University Hospital in 2011. OBJECTIVE: To assess the impact of PC integration on health care utilization among hospitalized cancer patients before hospice enrollment. METHODS: Retrospective cohort study. Patients in the solid tumor inpatient unit who were discharged to hospice between September 1, 2009, and June 30, 2010 (pre PC integration), and September 1, 2011, to June 30, 2012 (postintegration). Cohorts were compared on the following outcomes from their final hospitalization before hospice enrollment: intensive care unit days, invasive procedures, subspecialty consultations, radiographic studies, hospital length of stay, and use of chemotherapy or radiation. Cohort differences were examined with descriptive statistics and nonparametric tests. RESULTS: Two hundred ninety-six patients were included in the analysis (133 pre-PC integration; 163 post-PC integration). Patient characteristics were similar between cohorts. Health care utilization was relatively low in both groups, although 26% and 24% were receiving chemotherapy at the time of admission or during hospitalization in the pre- and post-PC integration cohorts, respectively, and 6.8% in each cohort spent time in an intensive care unit. We found no significant differences in utilization between cohorts. DISCUSSION: PC integration into an inpatient solid tumor service may not impact health care utilization during the final hospitalization before discharge to hospice. This likely reflects the greater benefits of integrating PC farther upstream from the terminal hospitalization, if one hopes to meaningfully impact utilization near the end of life. PMID- 30394822 TI - A Call to Action From the APNA Council for Safe Environments: Defining Violence and Aggression for Research and Practice Improvement Purposes. PMID- 30394823 TI - Opinions on a Firearm Prohibition Policy That Targets Intimate Partner Violence. AB - Firearms and intimate partner violence form a nexus of dangerousness and lethality. But, some policies aim to separate the two phenomena. The present study aims to fill a gap in the literature focusing on opinions toward a firearm prohibition for persons with injunctions for protection in effect against them by analyzing data from a convenience sample of 290 undergraduate students at a large research university in Florida, United States. Overall, any agreement with the policy was high. Multivariate analyses indicated that females/women and gender identity minorities, together, tended to express more agreement with firearm prohibition than males/men. Multivariate analysis also showed that participants who experienced sexual violence also displayed more agreement with the prohibition when compared to individuals who did not experience sexual violence victimization. "Lower" severity sexual violence victimization had the strongest relationship with policy opinions. Possible explanations for the gender difference in opinions include the implications of hegemonic masculinity and power differentials among genders. A possible explanation for the relationship between sexual violence victimization and policy opinions includes empathy. Policy implications and directions for future research include investigating the potential relationship gap in firearm prohibitions within Florida, engaging college men to change the conceptions around firearms through educational intervention, harnessing the tech-savvy power that college students have to generate awareness of policies, and considering interconnections among opinions, polyvictimization, and firearm policies. PMID- 30394824 TI - Developing Age-Appropriate Supportive Facilities, Resources, and Activities for Adolescents and Young Adults with Cancer Across Departments and Diagnoses: A Single-Center Experience. AB - In 2015, a support initiative for adolescents and young adults with cancer, Kraeftvaerket, was created at Rigshospitalet, Copenhagen University Hospital in Denmark. The primary objective of Kraeftvaerket is to provide youth-friendly support, care, and treatment practices. As Kraeftvaerket provides services to both pediatric and adult departments, a network between patients who would otherwise not interact has been created. The initiative is managed by a Youth Coordinator, and specifically trained health professional Youth Ambassadors. Dedicated staff, including Youth Coordinator and the Youth Ambassadors, are essential in maintaining focus on current initiatives for this patient group. PMID- 30394826 TI - Telemedicine and Child Neurology. AB - Over the past 2 decades, various telehealth technologies, in particular synchronous video teleconferencing between provider and patient, have been incorporated into the practice of neurology. The practice of child neurology is now starting to take advantage of these rapidly evolving resources. This review describes the evolution of tele-neurology, starting with adult tele-stroke services and expanding to the management of both adults and children with a variety of chronic neurologic disorders including epilepsy, headache, movement disorders, and neurodevelopmental disabilities. Resources required for the development and sustainment of a child neurology telemedicine program are discussed together with requirements for licensure, and credentialing, and the importance of educating current and future neurology practitioners in how to provide this clinical service. PMID- 30394825 TI - Prenatal hypocalvaria after prolonged intrauterine exposure to angiotensin II receptor antagonists. AB - We report a case of prenatal exposure to angiotensin II receptor antagonists (ARA II) from the beginning of pregnancy in a patient with a hypokinetic dilated cardiomyopathy. This case report emphasizes the fetal renal impact of prolonged intrauterine exposure to renin-angiotensin system (RAS) blockers, and highlights that this exposure can cause severe prenatal hypocalvaria. This delayed ossification can be reversible after birth, but the presence of anhydramnios indicates an early and irreversible block of RAS blockers in the fetus that is responsible for fetal kidney development abnormalities. This association carries a high risk of neonatal death. Prolonged exposure to ARA II or other RAS blockers remains prohibited throughout pregnancy. PMID- 30394827 TI - A new dynamic model for in vitro evaluation of intravascular devices. AB - INTRODUCTION:: A dynamic model to evaluate thrombus formation on intravascular catheters in vitro is presented. The model enables fluid infusion, variation in the catheter orientation, and variable flow conditions. It was applied on a catheter used to shunt cerebrospinal fluid to a vein, a dural venous sinus, for the treatment of hydrocephalus. METHODS:: Fresh human blood-filled circuits were circulated in a non-occlusive roller pump. A catheter infused either with cerebrospinal fluid, Ringer's lactate, or no fluid (control) was inserted through each circuit's wall. Sixteen circuits (six cerebrospinal fluid, six Ringer's lactate, four control) ran for 60 min. Qualitative assessment was performed by measuring viscoelastic properties of blood at the start and end of the experiment; quantitative evaluation of clot formation by scanning electron microscope. RESULTS:: Average blood velocity was 79 mm/s, with a pressure wave between 5 and 15 mm Hg. At the experiment's end, the infused fluid represented 5.88% of the blood/infusion volume in the circuit. The control circuits showed no statistical difference between the start and end for viscoelastic testing, whereas both Ringer's lactate and cerebrospinal fluid enhanced coagulation, most pronounced for the latter. Most thrombus material was observed on catheters in the cerebrospinal fluid group. Clot formation was less pronounced on the surface of the catheter facing the blood flow. DISCUSSION:: A dynamic model for intravascular catheter testing mimics better clinical conditions when evaluating blood-material interaction. Catheter position, blood flow around the catheter, and infusion fluid all have a potential impact on the hemocompatibility of a given catheter. PMID- 30394828 TI - The Nordic countries on top of the world - what next? PMID- 30394829 TI - miR-191 secreted by platelet-derived microvesicles induced apoptosis of renal tubular epithelial cells and participated in renal ischemia-reperfusion injury via inhibiting CBS. AB - OBJECTIVE: To reveal the role of miR-191 in apoptosis of renal tubular epithelial cells and in the involvement of renal ischemia-reperfusion injury. MATERIALS AND METHODS: Renal transplantation rat model was established. miR-191 and Cystathionine-beta-synthase (CBS) were measured by qRT-PCR and Western blot. The regulation of miR-191 on CBS was detected by luciferase reporter assay. RESULTS: miR-191 expression in platelets and platelet microvesicles (P-MVs) of patients and model rats was significantly upregulated than that of health and normal rats. Also, mRNA and protein levels of CBS in renal tissues of patients were significantly downregulated than that of health and normal rats. We also found that P-MVs could transfer miR-191 to HK-2 cells. Luciferase reporter assay showed that CBS was a direct target of miR-191. In addition, we proved that P-MVs secreted miR-191 inhibited CBS expression in HK-2 cells, and P-MVs-secreted miR 191 promoted HK-2 cell apoptosis via CBS. Finally, we verified the trends of CBS expressions, HK-2 cell apoptosis and apoptosis-related proteins in vivo were similar as the trends in vitro. CONCLUSION: CBS was a direct target of miR-191, and miR-191 could transfer to HK-2 cells via P-MVs to decrease the expression of CBS, thus to promote cell apoptosis and renal IR injury. PMID- 30394830 TI - Prospective evaluation of preoperative and postoperative sleep quality in carpal tunnel release. AB - Sleep disturbance is a frequent symptom of carpal tunnel syndrome. The aim of this study was to investigate the effect of median nerve decompression on sleep quality of patients with this condition. The study sample consisted of 41 patients with severe carpal tunnel syndrome who were admitted to our clinic and treated with open median nerve decompression. Sensation and functional recovery of the patients were followed using the Boston Function Questionnaire, the Semmes Weinstein monofilament test and the two-point discrimination test. Symptomatic recovery of the patients was followed by the Boston Symptom Questionnaire. The tests were used before surgery and at three and six months afterwards. Sensory, functional and symptomatic recovery from the third month to the sixth month following surgery also affected sleep parameters and improved the sleep quality of patients with carpal tunnel syndrome. Level of evidence: IV. PMID- 30394831 TI - Does End-of-Life Care Differ for Anglophones and Francophones? A Retrospective Cohort Study of Decedents in Ontario, Canada. AB - BACKGROUND: Approximately half of decedents in Ontario, Canada, receive some palliative care, but little is known about the influence of language on the nature of these services. OBJECTIVE: To examine differences between English- and French-speaking residents of Ontario in end-of-life care and outcomes (e.g., health care costs and location of death). DESIGN: A retrospective cohort study using multiple linked databases. SETTING/SUBJECTS: A population-based cohort of decedents in Ontario (2010-2013) who were living in long-term care institutions (i.e., nursing homes) or receiving home care before death (N = 25,759). Data from two regions with higher representations of Francophones were examined, with the final distribution by primary language being 75% Anglophone, 18% Francophone, and 7% other languages. RESULTS: Compared with Anglophones, Francophones were more frequent users of long-term care (47.6% vs. 37.1%) and less frequent users of home care (71.3% vs. 76.3%). In adjusted models, the number of days spent in hospital in the last 90 days of life was similar between Anglophones and Francophones, although the odds of dying in hospital were significantly higher among the latter. The mean total health care cost in the last year of life was slightly lower among French ($62,085) compared with English ($63,814) speakers. CONCLUSIONS: There are statistically significant differences in end-of-life outcomes between linguistic groups in Ontario, namely more institutionalization in long-term care, less home care use and more deaths in-hospital among Francophones (adjusted). Future research is needed to examine the cause of these differences. Strategies to ensure equitable access to quality end-of-life care are required. PMID- 30394832 TI - Rottlerin inhibits cell growth and invasion via down-regulation of EZH2 in prostate cancer. AB - Rottlerin as a natural agent, which is isolated from Mallotus philippinensis, has been identified to play a critical role in tumor inhibition. However, the molecular mechanism of rottlerin-mediated anti-tumor activity is still ambiguous. It has been reported that EZH2 exhibits oncogenic functions in a variety of human cancers. Therefore, inhibition of EZH2 could be a promising strategy for the treatment of human cancers. In this study, we aim to explore whether rottlerin could inhibit tumorigenesis via suppression of EZH2 in prostate cancer cells. Multiple approaches such as FACS, Transwell invasion assay, RT-PCR, Western blotting, and transfection were performed to determine our aim. We found that rottlerin treatment led to inhibition of cell growth, migration and invasion, but induction of apoptosis in prostate cancer cells. Importantly, we defined that rottlerin decreased the expression of EZH2 and H3K27me3 in prostate cancer cells. Moreover, overexpression of EZH2 abrogated the rottlerin-induced inhibition of cell growth, migration, and invasion in prostate cancer cells. Consistently, down regulation of EZH2 enhanced rottlerin-triggered anti-tumor function. Collectively, our work demonstrated that rottlerin exerted its tumor suppressive function via inhibition of EZH2 expression in prostate cancer cells. Our findings indicated that rottlerin might be a potential therapeutic compound for treating patients with prostate cancer. PMID- 30394833 TI - Intrathecal formation of anticardiolipin antibodies in a patient with SLE-related relapsing longitudinal myelitis: a possible pathogenic connection. AB - BACKGROUND: Nontraumatic acute transverse myelitis (ATM) can occur in response to infectious, inflammatory and vascular triggers; 1% of patients with systemic lupus erythematosus (SLE) develop ATM, but the mechanism remains unknown. OBJECTIVE: The objective of this case report is to describe a case of intrathecal formation of anticardiolipin antibodies (aCL) during SLE-related ATM. METHODS: A single patient analysis was conducted. RESULTS: A 26-year-old housewife was diagnosed with SLE at age 19. Circulating aCL antibodies were positive at diagnosis. At age 21, she developed an episode of severe sepsis. At 23 years of age she developed an episode of ATM that left her paraplegic with a D10 sensory level, from which she recovered partially. Three years later, she developed a clinical relapse of ATM. During that second episode, serum levels of aCL were within normal limits, while cerebrospinal fluid levels were increased, suggesting intrathecal production of aCL. CONCLUSION: Here, we present a case of a woman who developed relapsing SLE-related longitudinally extensive ATM in whom intrathecal formation of aCL was demonstrated, suggesting that local production and cross recognition of nervous tissue by those autoantibodies may be myelopathic. PMID- 30394834 TI - Effectiveness of renoprotective approaches for persistent proteinuria in lupus nephritis: more than just immunosuppression. AB - OBJECTIVE: The objective of this study is to evaluate the efficacy of a tightly controlled renoprotective protocol in systemic lupus erythematosus (SLE) patients with persistent proteinuria. METHODS: Thirteen SLE patients with nephritis and persistent proteinuria (>1 g/24 hours) were included. The protocol consisted of regular clinical evaluations every two weeks to assess blood pressure (BP, target <130/80 mmHg), adherence to therapy, diet and smoking. No change in immunosuppressive drugs was allowed but reduction of glucocorticoid dose was permitted if indicated. Clinical, laboratory and treatment evaluations were performed at baseline and at the end of the study (after three months). RESULTS: SLE patients had a mean age of 37.85 +/- 7.68 years and disease duration of 9.85 +/- 7.29 years. At baseline, patients had a mean duration of maintenance therapy of 10.38 +/- 7.56 months, 12 with mycophenolate mofetil (92.3%) and one with azathioprine (7.7%). At least one dose optimization of antihypertensive regimen was required in all patients during the study. Seven patients (53.8%) had BP>130/80mmHg at baseline. At the end, 11 patients (84.6%) achieved stable BP target; 92.3% were using an angiotensin-converting enzyme inhibitor, 53.9% an angiotensin receptor blocker, and 46.2% were using combined therapy. All patients had a significant reduction in proteinuria levels (2.26 +/- 1.09 vs 0.88 +/- 0.54 g/24 hours, p < 0.001) and 61.5% achieved proteinuria <1 g/24 hours. A significant decrease in mean prednisone dose was observed (10.96 +/- 6.73 vs 5.38 +/- 3.36 mg/day, p = 0.013) as well as mean Systemic Lupus Erythematosus Disease Activity Index score (4.38 +/- 0.72 vs 3.08 +/- 1.86, p = 0.043). No significant changes were identified in serum creatinine, albumin, potassium, complement 3 and complement 4 levels ( p > 0.05). CONCLUSION: This study provides evidence that a tightly controlled renoprotective protocol is effective in reducing persistent proteinuria in lupus nephritis. The concomitant reduction of prednisone without any change in immunosuppression reinforces the importance of strategies beyond the treatment of nephritis activity. PMID- 30394835 TI - Changes in the blood level, efficacy, and safety of tacrolimus in pregnancy and the lactation period in patients with systemic lupus erythematosus. AB - OBJECTIVES: We investigated the efficacy and safety of tacrolimus (TAC) by monitoring its serum concentration for mothers and infants in pregnant patients with systemic lupus erythematosus (SLE). METHODS: We measured trough concentrations of TAC in 25 pregnant patients with SLE to assess influence of TAC on the disease activity. Additionally, we measured the concentrations of TAC in umbilical arterial blood, breast milk, and breastfed infants to investigate the safety of TAC for the mothers and infants. RESULTS: The trough concentrations of TAC in the mothers significantly decreased in the second trimester as compared with those before pregnancy. However, the decrease in the trough concentrations of TAC did not lead to the deterioration of SLE. When examined, the doses of TAC were significantly lower in the second trimester and postpartum in the deteriorating group than those in the non-deteriorating group. There were no adverse events by TAC in mothers and fetuses. The concentrations of TAC in the umbilical cord blood were lower than those in the maternal blood. The relative infant dose in breastfed infants of TAC was < 1%. The level of TAC in infant bloods was below detectable limits. CONCLUSION: These findings suggest that TAC is one of the most effective and safest immunosuppressive drugs for use in pregnant patients with SLE. PMID- 30394836 TI - Persistent hypoglossal artery aneurysm: Case report and qualitative systematic review. AB - A persistent hypoglossal artery was first described in 1889 and is one of the more common anatomical variations arising from aberration in normal development. Endovascular coiling has been recognised as a robust treatment for acutely ruptured intracranial arterial aneurysms, although specific data regarding an aneurysm arising from a persistent hypoglossal artery is lacking due to the low incidence. Here we report both the oldest patient reported to be treated with a persistent hypoglossal artery-associated aneurysm and also explicitly report endovascular treatment of a persistent hypoglossal artery aneurysm arising at the posterior inferior communicating artery origin. Qualitative systematic review of the available medical literature demonstrates limited evidence regarding treatment of persistent hypoglossal artery-associated aneurysms with the majority being carried out via open surgery. Ruptured posterior inferior communicating artery aneurysm arising from a persistent hypoglossal artery can be successfully and safely treated by endovascular therapy via the persistent hypoglossal artery. Randomised study of this situation is unlikely to be feasible; however, qualitative review of the literature reveals six such aneurysms that have been treated surgically, and this case appears to be the first via an endovascular means. PMID- 30394837 TI - A case of tandem stenoses at the proximal common and internal carotid arteries treated with transbrachial stenting: a case report. AB - The transfemoral approach is a common technique for carotid artery stenting. However, it has the risk of distal embolism when stenting for a stenosis of the proximal common carotid artery because of poor stability of the guiding catheter resulting in difficulty in setting the embolic protection device prior to stenting. We present a novel therapeutic approach and technique for the treatment of tandem carotid stenoses including the proximal common carotid artery. A 63 year-old man presented with double stenoses at the common carotid artery and internal carotid artery. We used a transbrachial sheath guide that had a 6 Fr (2.24 mm, 0.088 inch) internal diameter and was 90 cm long, and was specifically designed for direct cannulation to the common carotid artery, like a modified Simmons catheter. Because the sheath guide positioned in the aortic arch made it possible to introduce safely the embolic protection device distal to the internal carotid artery stenosis without touching the plaque at the stenosis with no use of any coaxial catheters or guidewires, carotid artery stenting for tandem stenoses could be successfully carried out. The postoperative course was uneventful. In carotid artery stenting, especially for stenosis of the proximal common carotid artery, the sheath guide designed for transbrachial carotid cannulation was useful in stenting the tandem carotid stenoses. PMID- 30394838 TI - Very delayed discontinuation of telescoped Pipeline embolization devices: a case report. AB - BACKGROUND: Flow diversion with the Pipeline embolization device (PED) is a widely accepted treatment modality for aneurysm occlusion. Previous reports have shown no recanalization of aneurysms on long-term follow-up once total occlusion has been achieved. CASE DESCRIPTION: We report on a 63-year-old male who had a large internal carotid artery cavernous segment aneurysm. Treatment with PED resulted in complete occlusion of the aneurysm. However, follow-up angiography at four years revealed recurrence of the aneurysm due to disconnection of the two PEDs placed in telescoping fashion. CONCLUSION: Herein, we present the clinico radiological features and discuss the possible mechanisms resulting in the recanalization of aneurysms treated with flow diversion. PMID- 30394839 TI - Acute administration of tirofiban versus aspirin in emergent carotid artery stenting. AB - BACKGROUND: Carotid artery stenting requires antiplatelet therapy for prevention of in-stent thrombosis. Patients suffering from acute ischemic stroke undergoing intravenous thrombolysis and emergent carotid artery stenting (eCAS) are at high risk for intracranial bleeding. We assessed efficacy and safety of acute administration of intravenous tirofiban versus aspirin in these patients. METHODS: A retrospective, single center, cohort study was carried out of 32 patients who underwent eCAS (18 received tirofiban, 14 received aspirin) at our comprehensive stroke center (2008-2016). RESULTS: Of our 32 consecutive eCAS patients, favorable clinical outcomes (modified Rankin scale <= 2) were achieved in eight (47%) tirofiban patients and six (46%) aspirin patients ( p = 0.96). Overall rates were similar for symptomatic intracranial bleeding (tirofiban 22%, aspirin 29%, p = 0.68) and mortality (tirofiban 18%, aspirin 23%, p = 0.71). CONCLUSIONS: Tirofiban and aspirin demonstrated similar efficacy and safety in thrombolyzed stroke patients who underwent eCAS in our cohort. Intravenous tirofiban with its short half-life might represent an alternative to aspirin in select patients. PMID- 30394840 TI - Delayed intracranial aneurysm formation after cardiac myxoma resection: Report of two cases and review of the literature. AB - Myxomas are slowly growing benign neoplasms and represent the most common tumor of the heart. Embolism from cardiac myxoma occurs in 30-45% of patients and in at least half of the cases cerebral arteries are affected leading mainly to embolic ischemic strokes and rarely to delayed intracranial aneurysm formation. We present two cases with delayed intracranial aneurysmal formation 14 years and 18 years after cardiac myxoma resection. To the best of our knowledge these two cases represent the longest time interval between aneurysm detection after complete cardiac myxoma resection with no recurrence confirmed by transesophageal echocardiogram. Our study also provides the longest clinical and radiological follow-up on this type of lesion. PMID- 30394841 TI - Transnasal devascularisation of a sinonasal hypervascular tumour (glomangiopericytoma) with direct injection of liquid polymer agent (Squid(r)). AB - The technique of direct intratumoral injection of permanent liquid agents has evolved significantly over the past few decades. The percutaneous direct puncture technique is being utilised more and more for embolisation of head and neck hypervascular lesions. We describe a case treated via the direct percutaneous transnasal (TN) puncture technique for embolisation of a sinonasal hypervascular tumour, performed in a 21-year-old male patient. Due to extensive vascularisation of the tumour, preoperative embolisation was requested by our otolaryngologist team in order to minimise intraoperative bleeding and reduce surgical morbidity. A primary attempt at trans-arterial embolisation through selective ophthalmic artery catheterisation was unsuccessful due to unfavourable anatomy. An extensive devascularisation of the nasal fossa lesion was obtained using a single injection of low-density polymeric embolic agent (SQUID(r)). Post-operative eradication was uneventful. Final histopathology exam revealed vascular tumour consistent with a rare sinonasal glomangiopericytoma. To our knowledge, this is the first reported case of a rare sinonasal glomangiopericytoma treated by direct TN injection, utilising the liquid polymer agent SQUID(r). PMID- 30394842 TI - Surgical options in experimental porcine model for endovascular training in complex vascular lesions. AB - We describe a new, elegant, two-phase, microsurgical method that minimizes the surgical preparation time for different complex vascular lesions in a swine model. In the first phase, the model is prepared microsurgically in the experimental laboratory using arterial or/and venous grafts. In the second phase, the model is implanted in the experimental animal. This two-fold method allows for increasing the complexity and accuracy of the model while reducing preparation time on the day of the training session. PMID- 30394843 TI - Intravenous versus intra-arterial digital subtraction angiography: Occlusion rate and complication assessment of experimental aneurysms after flow diverter treatment in rabbits. AB - PURPOSE: Conventional intra-arterial digital subtraction angiography, which requires surgical exposure and ligation of the femoral or carotid artery, is a limited method of evaluating elastase-induced aneurysms in New Zealand white rabbits. The purpose of this study was to assess aneurysm morphology, occlusion rates and complications after flow diverter treatment comparing intravenous and intra-arterial digital subtraction angiography. METHODS: We previously published a preclinical study in which we evaluated the occlusion rates of elastase-induced aneurysms after treatment with a prototype flow diverter, by using intra-arterial digital subtraction angiography at three months ( n = 9) and six months ( n = 9). In addition to that intravenous digital subtraction angiography before treatment, after one month (early follow-up group) and after three months (late follow-up group) was performed. Occlusion rates were compared within the two groups by means of residual contrast filling. RESULTS: Baseline aneurysm characteristics revealed no significant differences between intra-arterial digital subtraction angiography and intravenous digital subtraction angiography. Aneurysm occlusion rates in both follow-up groups using intravenous digital subtraction angiography were significantly higher compared to intra-arterial digital subtraction angiography (early follow-up group: intravenous digital subtraction angiography (one month) versus intra-arterial digital subtraction angiography (three months); p = 0.03 and late follow-up group: intravenous digital subtraction angiography (three months) versus intra-arterial digital subtraction angiography (six months); p = 0.04). Intravenous digital subtraction angiography is feasible to detect and reproduce device occlusions, in-stent stenosis and post-stent stenosis. CONCLUSION: Intravenous digital subtraction angiography can not give a sufficient statement on the aneurysm occlusion process compared to intra-arterial digital subtraction angiography and is therefore not recommended for imaging follow-up after flow diverter treatment in rabbits. Regarding untreated aneurysms and complications like device occlusions, in-stent stenosis and post-stent stenosis intravenous digital subtraction angiography proofed to be a good alternative to intra-arterial digital subtraction angiography in our study. PMID- 30394844 TI - Initiatives to reduce postoperative surgical site infections of the head and neck cancer surgery with a special emphasis on developing countries. AB - INTRODUCTION: Surgery in patients with head and neck cancers is frequently complicated by multiple stages of procedure that includes significant surgical removal of all or part of an organ with cancer, tissue reconstruction, and extensive neck dissection. Postoperative wound infections, termed 'surgical site infections' (SSIs) are a significant impediment to head-and-neck cancer surgery and recovery, and need to be addressed. Areas covered: Approximately 10-45% of patients undergoing head-and-neck cancers surgery develop SSIs. SSIs can lead to delayed wound healing, increased morbidity and mortality as well as costs. Consequently, SSIs need to be avoided where possible, as even the surgery itself impacts on patients' subsequent activities and their quality of life, which is exacerbated by SSIs. Several risk factors for SSIs need to be considered to reduce future rates, and care is also needed in the selection and duration of antibiotic prophylaxis. Expert commentary: Head and neck surgeons should give personalized care especially to patients at high risk of SSIs. Such patients include those who have had chemoradiotherapy and need reconstructive surgery, and patients from lower and middle-income countries and from poorer communities in high income countries, who often have high levels of co-morbidity because of resource constraints. PMID- 30394845 TI - MiR-130a-5p prevents angiotensin II-induced podocyte apoptosis by modulating M type phospholipase A2 receptor. AB - Podocyte apoptosis is considered as the important element that promotes the development and progress of membranous nephropathy (MN). Unfortunately, the underlying mechanism of podocytes apoptosis in MN remains elusive. We compared the renal expressions of miR-130a-5p and M-type phospholipase A2 receptor (PLA2R) between MN patients (n = 30) and 30 controls by qRT-PCR and western blot, respectively. The podocyte damage model in vitro was established by angiotensin II (Ang II, 100 nmol/L) exposure for 24 h. Interaction between miR-130a-5p and PLA2R was determined using dual-luciferase reporter gene assay. MN mice were induced by intravenous injection of cBSA. In this study, miR-130a-5p expression was significantly decreased both in the renal biopsy specimens from MN patients and podocyte cell line AB8/13 following stimulation of Ang II. Overexpressed miR 130a-5p in AB8/13 cells significantly attenuated the Ang II induced-apoptosis in vitro. In contrast, down-regulated miR-130a-5p induced podocyte apoptosis. PLA2R was identified as the target of miR-130a-5p in AB8/13 cells. And up-regulated or down-regulated PLA2R could obviously attenuate the effect of miR-130a-5p overexpression or knockdown on the apoptosis of AB8/13 cells. Furthermore, it was also observed that overexpressed miR-130a-5p by miR-130a-5p agomir could obviously alleviate renal injury in MN mice. In conclusion, decreased miR-130a-5p was contributed to the pathological mechanism of MN through increasing PLA2R expression, which induced podocyte apoptosis. PMID- 30394846 TI - Prevalence and Mechanisms of Carbapenem Resistance Among Acinetobacter baumannii Clinical Isolates in Egypt. AB - The increasing number of carbapenem-resistant Acinetobacter baumannii clinical isolates is a major concern, which restricts therapeutic options for treatment of serious infections caused by this emerging pathogen. The aim of this work is to assess the antimicrobial resistance profile and identify the molecular mechanisms involved in carbapenem resistance in A. baumannii isolated from different clinical sources in Mansoura University Hospitals, Egypt. Antimicrobial susceptibility testing has shown that resistance to carbapenem has dramatically increased (98%) with concomitant elevated levels of resistance to quinolones, trimethoprim/sulfamethoxazole, and aminoglycosides. Polymyxin B and colistin are considered the last resort. Random amplified polymorphic DNA (RAPD) typing method revealed great diversity among A. baumannii isolates. Coexistence of diverse intrinsic and acquired carbapenem-hydrolyzing beta-lactamases has been detected in the tested isolates: Ambler class A: blaKPC (56%) and blaGES (48%), and Ambler class B: blaNDM (30%), blaSIM (28%), blaVIM (20%), and blaIMP (10%). Most isolates (94%) carried blaOXA-23-like and blaOXA-51-like simultaneously. blaOXA 23-like was preceded by ISAba1 providing a potent promoter activity for its expression. Sequencing analysis revealed that ISAba1 has been also inserted in carbapenem resistance-associated outer membrane protein (OMP) (carO) gene in three isolates, two of which were clonal based on RAPD typing, leading to interruption of its expression as confirmed by SDS-PAGE analysis of OMP fractions. Carbapenem resistance genes are widely distributed among A. baumannii clinical isolates from different clinical sources. Therefore, enhanced infection control measures, effective barriers, and rational use of antimicrobials should be enforced in hospitals for minimizing the widespread resistance to carbapenems and all other antibiotics. PMID- 30394847 TI - Aortic valve replacement with or without myocardial revascularization in octogenarians. Can minimally invasive extracorporeal circuits improve the outcome? AB - OBJECTIVE:: The positive impact of minimally invasive extracorporeal circuits (MiECC) on patient outcome is expected to be most evident in patients with limited physiologic reserves. Nevertheless, most studies have limited their use to low-risk patients undergoing myocardial revascularization. As such, there is little evidence to their benefit outside this patient population. We, therefore, set out to explore their potential benefit in octogenarians undergoing aortic valve replacement (AVR) with or without concomitant myocardial revascularization. METHODS:: Based on the type of the utilized ECC, we performed a retrospective propensity score-matched comparison among all octogenarians (n = 218) who received a primary AVR with or without concomitant coronary artery bypass grafting in our institution between 2003 and 2010. RESULTS:: A MiECC was utilized in 32% of the patients. The propensity score matching yielded 52 matched pairs. The 30-day postoperative mortality (2% vs. 10%; p=0.2), the incidence of low cardiac output (0% vs. 6%; p=0.2) and the Intensive Care Unit (ICU) stay (2.5 +/- 2.6 vs. 3.8 +/- 4.7 days; p=0.06) were all in favour of the MiECC group, but failed to reach statistical significance while the 90-day postoperative mortality did (2% vs. 16%; p=0.02). CONCLUSION:: MiECCs have a positive influence on the outcome of octogenarians undergoing AVR with or without concomitant coronary artery bypass grafting. Their use should, therefore, be extended beyond isolated coronary artery bypass graft (CABG) surgery. PMID- 30394848 TI - Response to "Commentary on pelvic venous reflux in males with varicose veins and recurrent varicose veins". PMID- 30394849 TI - Development of a fluid-structure interaction model to simulate mitral valve malcoaptation. AB - OBJECT:: Mitral regurgitation (MR) is a condition in which the mitral valve does not prevent the reversal of blood flow from the left ventricle into the left atrium. This study aimed at numerically developing a model to mimic MR and poor leaflet coaptation and also comparing the performance of a normal mitral valve to that of the MR conditions at different gap junctions of 1, 3 and 5 mm between the anterior and posterior leaflets. RESULTS:: The results revealed no blood flow to the left ventricle when a gap between the leaflets was 0 mm. However, MR increased this blood flow, with increases in the velocity and pressure within the atrium. However, the pressure within the aorta did not vary meaningfully (ranging from 22 kPa for a 'healthy' model to 25 kPa for severe MR). CONCLUSIONS:: The findings from this study have implications not only for understanding the changes in pressure and velocity as a result of MR in the ventricle, atrium or aorta, but also for the development of a computational model suitable for clinical translation when diagnosing and determining treatment for MR. PMID- 30394850 TI - The effectiveness of narrative writing on the moral distress of intensive care nurses. AB - BACKGROUND:: Nursing is a profession that has always been accompanied with common ethical concerns. There are some evidences which indicate that narrative writing on traumatic experiences may improve an individual's emotional health. OBJECTIVE:: This study aimed to determine the effectiveness of narrative writing on moral distress of nurses working in intensive care unit. RESEARCH DESIGN:: This study was a clinical trial with pre- and post-test design. The frequency and intensity of moral distress was measured by a valid and reliable questionnaire (Corely) at baseline and after 8 weeks. The intervention group was asked to write about their deepest emotions and stressful experiences in the intensive care unit for 8 weeks. PARTICIPANTS AND RESEARCH CONTEXT:: Using consensus sampling, 120 nurses of intensive care unit and neonatal intensive care unit of the teaching hospitals (in Iran) were invited to and were randomly allocated into the intervention and control groups. ETHICAL CONSIDERATIONS:: Participation was voluntary, data were anonymized, and the confidentiality of the participating nurses and their institutions maintained. The ethical approval was obtained from an IRB or research ethics committee. FINDINGS:: In total, 106 nurses completed the trial consisting of 87.75% females. The mean work experience of nurses in the intervention and control groups was 7.21 +/- 4.96 and 8.28 +/- 5.45 years, respectively. Independent t-test showed no statistical difference neither in the intensity of moral distress ( P = 0.8), nor in its frequency ( P = 0.5) between the two groups. DISCUSSION:: As nurses constantly face ethical tensions, moral distress is a phenomenon that results from the different situations of critical care units. Their concern about receiving negative feedback from the managerial level may have influenced the outcome of the intervention. CONCLUSION:: Narratives writing by the nurses showed no effect on reducing the intensity and frequency of moral distress. It seems that due to the intensity of moral distress in clinical settings, we need to test variety solutions to reduce the problem. PMID- 30394851 TI - Using Telepsychiatry to Enrich Existing Integrated Primary Care. AB - BACKGROUND: Integrated care is characterized by evolving heterogeneity in models. Using telepsychiatry to enhance these models can increase access, quality, and efficiencies in care. INTRODUCTION: The purpose of this report is to describe the process and outcomes of adapting telepsychiatry into an existing integrated care service. MATERIALS AND METHODS: Telepsychiatry was implemented into an existing integrated care model in a high-volume, urban, primary care clinic in Colorado serving patients with complex physical and behavioral needs. Consultative, direct care, educational/training encounters, provider-to-provider communication, process changes, and patient-level descriptive measures were tracked as part of ongoing quality improvement. RESULTS: Telepsychiatry was adapted into the existing behavioral health services using an iterative team meeting process within a stepped care model. Over 35% of the requests for psychiatry services were medication related-and medication changes (type/dose) were the most frequent referral outcome of psychiatric consultation. Forty percent of patients in the service had multiple behavioral health diagnoses, in addition to physical health diagnoses. DISCUSSION: Telehealth will become an increasingly necessary component in building hybrid/blended integrated care teams. Examples of flexible model implementation will support clinics in tailoring effective applications for their unique patient panels. CONCLUSIONS: An adapted integrated care model leveraging telepsychiatry is successfully serving the complex deep end of a primary care patient population in Colorado. Lessons learned in implementing this model include the importance of team attitudes. PMID- 30394852 TI - Inferior vena cava stenosis after heart transplant: a rare cause of venoarterial extracorporeal membrane oxygenation weaning failure. AB - INTRODUCTION:: The discontinuation of venoarterial extracorporeal membrane oxygenation (VA ECMO) is a critical step in patient recovery. To reduce risks, weaning trials must be performed to buttress this important decision. However, a successful weaning trial does not preclude the possibility of complications. CASE REPORT:: Here, we report a case of sudden multiple organ failure in a heart transplant patient, occurring after a successful ECMO weaning trial. We finally diagnosed a rare post-surgical complication of bicaval orthotopic heart transplantation, a severe stenosis of the inferior vena cava (IVC) that had been masked by the post-operative ECMO. DISCUSSION AND CONCLUSION:: Our case report should serve as a cautionary tale: it may be of interest to add a search for complications at the vascular anastomoses to the weaning trial procedure and to keep an eye out for them in the following days. PMID- 30394853 TI - The Use of Telemedicine to Address Disparities in Access to Specialist Care for Neonates. AB - INTRODUCTION: Outcomes for premature and critically ill neonates are improved with care provided by neonatologists in a neonatal intensive care unit (NICU). For smaller hospitals, maintaining the personnel and equipment necessary for the delivery and care of unexpectedly high-risk neonates is a significant challenge. To address this disparity in access, telemedicine has been increasingly used to support providers, patients, and their families in community newborn nurseries and NICUs. The purpose of this review is to present the current state of the use of telemedicine by regional NICUs to support community newborn nurseries, NICUs, and families. METHODS: A literature review was conducted by two independent reviewers. Articles were selected for inclusion if they described the use of telemedicine with neonates or in the NICU. Two reviewers assessed the quality of the articles using the National Heart, Lung, and Blood Institute Study Quality Assessment Tools. RESULTS: Fourteen articles were identified. After consensus discussion, eight of the articles were rated good and six were rated fair by the two reviewers. Many of the articles suggested improvements in quality of care, family satisfaction, and reductions in the cost of care. Unfortunately, a majority of the studies to date have had small sample sizes or were performed in a single institution and lacked robust evaluations of patient- and family centered outcomes and provider decision making. CONCLUSIONS: While these early studies are promising, more robust studies involving more patients and more institutions are needed to identify opportunities where telemedicine can impact health outcomes, patient-centeredness, or costs of care of neonates. PMID- 30394855 TI - Urethral pull-up operation for distal and mid-penile hypospadias: a new safe method. AB - This case series of 51 patients (age range = 11-17 years; 30-month follow-up) describes a new modified approach to treatment of distal and mid-penile hypospadias that has fewer complications. The meatal locations were sub-coronal (51%), coronal (45%) and mid-penile (4%). Forty patients had chordee. Urethra with the corpus spongiosum was dissected off the corpus cavernosum up to the peno scrotal junction. The distal 5 mm stenotic and avascular part of the urethral tube was excised. The elastic urethra was then stretched and sutured to form a neo-meatus. The urethra was anchored to the Buck's fascia at the glandular, sub coronal and mid-penile levels. Meatal regression in one patient (2%), subcutaneous hematomas in two patients (4%) and wound dehiscence in two patients (4%) were the complications in the immediate postoperative period. None developed fistula, meatal stenosis or residual chordee in the 30-month follow-up. PMID- 30394854 TI - Development and Characterization of an 18F-labeled Ghrelin Peptidomimetic for Imaging the Cardiac Growth Hormone Secretagogue Receptor. AB - One-third of patients with heart disease develop heart failure, which is diagnosed through imaging and detection of circulating biomarkers. Imaging strategies reveal morphologic and functional changes but fall short of detecting molecular abnormalities that can lead to heart failure, and circulating biomarkers are not cardiac specific. Thus, there is critical need for biomarkers that are endogenous to myocardial tissues. The cardiac growth hormone secretagogue receptor 1a (GHSR1a), which binds the hormone ghrelin, is a potential biomarker for heart failure. We have synthesized and characterized a novel ghrelin peptidomimetic tracer, an 18F-labeled analogue of G-7039, for positron emission tomography (PET) imaging of cardiac GHSR1a. In vitro analysis showed enhanced serum stability compared to natural ghrelin and significantly increased cellular uptake in GHSR1a-expressing OVCAR cells. Biodistribution studies in mice showed that tissue uptake of the tracer was independent of circulating ghrelin levels, and there was negligible cardiac uptake and high uptake in the liver, intestines, and kidneys. Specificity of tracer uptake was assessed using ghsr -/- mice; both static and dynamic PET imaging revealed no difference in cardiac uptake, and there was no significant correlation between cardiac standardized uptake values and GHSR1a expression. Our study lays the groundwork for further refinement of peptidomimetic PET tracers targeting cardiac GHSR1a. PMID- 30394856 TI - Low-cost laparoscopy for rural areas: the flexible video laparoscope. AB - Diagnostic laparoscopies are a very useful diagnostic tool especially in rural areas. However, the very high costs of the current diagnostic equipment make them unavailable to most of the rural centres. We describe a low-cost laparoscope that does away with the telescope and rod lens system and offers very good quality pictures for diagnostic laparoscopy at small fraction of the cost of current laparoscopic surgical instruments. PMID- 30394857 TI - Scrotal abscess consequent on syphilitic epididymo-orchitis. AB - Syphilis is notorious and a great imitator of all diseases. It is a chronic bacterial infection, caused by the sexually transmitted spirochete, Treponema pallidum. Though it has drastically reduced in prevalence, its recent resurgence (especially with HIV disease) is worrying. Without treatment, the disease can progress over years through a series of clinical stages and lead to irreversible neurological or cardiovascular complications. The disease may occur in any organ, including the testis, and is commonly mistaken for malignancy. We report a case of scrotal abscess consequent on epididymo-orchitis, confirmed by histopathological examination to be syphilitic in origin, in an immunocompromised HIV-positive patient. PMID- 30394858 TI - Cultural Collectivism and Tightness Moderate Responses to Norm Violators: Effects on Power Perception, Moral Emotions, and Leader Support. AB - Responses to norm violators are poorly understood. On one hand, norm violators are perceived as powerful, which may help them to get ahead. On the other hand, norm violators evoke moral outrage, which may frustrate their upward social mobility. We addressed this paradox by considering the role of culture. Collectivistic cultures value group harmony and tight cultures value social order. We therefore hypothesized that collectivism and tightness moderate reactions to norm violators. We presented 2,369 participants in 19 countries with a norm violation or a norm adherence scenario. In individualistic cultures, norm violators were considered more powerful than norm abiders and evoked less moral outrage, whereas in collectivistic cultures, norm violators were considered less powerful and evoked more moral outrage. Moreover, respondents in tighter cultures expressed a stronger preference for norm followers as leaders. Cultural values thus influence responses to norm violators, which may have downstream consequences for violators' hierarchical positions. PMID- 30394859 TI - Older Patients' Perspectives of Online Health Approaches in Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a complex, chronic condition. Patients commonly have limited access to face-to-face support due to decreased mobility, symptom burden, and availability of services. Online health care approaches provide the potential for increased access to self-management education and support. This study sought to understand older patients with COPD's perspectives of online approaches to health care. MATERIALS AND METHODS: Participants older than 65 years were recruited from a respiratory service at an academic medical center. Qualitative, focus groups were used and recorded, transcribed verbatim, and analyzed using thematic analysis to identify key and repeated emergent themes. RESULTS: Focus groups were undertaken between January and May 2014. Thematic analysis resulted in five overall themes: (1) concern over risks in the online environment; (2) multimedia and technology use as part of everyday life; (3) online resources as an opportunity for revision of forgotten knowledge; (5) potential for facilitation of decision-making support across geographical and physical barriers; and (4) perceived benefits of online peer support for people with COPD. CONCLUSIONS: Overall, these older participants with COPD had positive views of online health information, but did raise the need for guidance to ensure valid and reliable online sources. The capacity for online sources to increase access to decision support and up-to-date information was viewed positively, as was the ability to interact with peers who had similar experiences. Telecommunication tools and approaches are already being utilized in health care interactions. Further research is required into the most appropriate, feasible, and sustainable online health approaches to support patients with chronic illnesses such as COPD. PMID- 30394860 TI - Covariates of the Severity of Aggression in Sexual Crimes: Psychopathy and Borderline Characteristics. AB - Whereas risk assessment literature on sexual offending has primarily focused on prediction of subsequent sexual crimes, and not the severity of those crimes, the first aim of the present study was to identify variables that predict the amount of damage to victims in sexual crimes compared with those that predict general aggressiveness. The second aim was to ascertain whether adding emotional instability measurements, as in borderline personality disorder (BPD), would add incremental variance to that captured by the facets of the Psychopathy Checklist Revised (PCL-R). Trained raters assessed on the PCL-R, BPD, and measures of severity of sexual and nonsexual violence 302 adults who had sexually offended. PCL-R's Antisociality and two externalizing BPD factors (one from the standard and one from the alternative criteria) were significant predictors of violence both in sexual and nonsexual crimes. In contrast, deficits in the PCL-R's Affective facet (2) predicted victim damage in sexual contexts only, whereas the Lifestyle Impulsivity facet (3) of the PCL-R predicted violence in nonsexual contexts only. These findings suggest that adding measures of emotional dysregulation to commonly used instruments like the PCL-R, which assesses callousness and antisociality, may be beneficial for predicting violence. PMID- 30394861 TI - Probiotics in Prevention of Surgical Site Infections. AB - Despite significant improvements in peri-operative care, surgical site infections (SSIs) remain an important contributor to morbidity, cost, and death. The human gastrointestinal tract is a complex microenvironment linking host cells and the indigenous microflora or "microbiome," creating a "super-organism" that engages in macro-nutrient and micro-nutrient extraction for the host while serving as a barrier to toxins and other detrimental bacterial end-products. Maintaining a healthy microbiome in the peri-operative period may enable control of multi-drug resistance (MDR) organisms, whereas use of antibiotics simply resets the dysbiotic relation by eliminating multiple strains of bacteria. Such loss of microbial diversity or abundance can slow wound healing. Use of pro-biotics to prevent infection has been evaluated in several studies, but their utility is not yet clear. There is a clear need for randomized trials to draw firm conclusions about their efficacy and to make clinical recommendations. PMID- 30394862 TI - Inverse Association Between Antiviral Immunity and Lupus Disease Activity. AB - This longitudinal study focused on the relationship between lupus activity and the levels of intracellular proteins, phosphorylated interferon regulatory factor 7 (pIRF7), caspase-9 and -10, and mitochondrial antiviral signaling protein (MAVS) and melanoma differentiation-associated protein 5 (MDA5). Ten patients with systemic lupus erythematosus (SLE) were followed at clinics, and their disease activity indexes (SLEDAIs) were determined. Correlation analysis was used to test the influence of changes in intracellular markers on changes in SLEDAI score at two time points. All the patients were women with a median age of 43.5 years. Time to disease condition change varied from 30 to 283 days in this study (188.5 +/- 74.31 days). The intracellular protein levels increased after regular follow-up and oral medication. Although there was a decreasing trend in SLEDAI scores in patients after regular follow-up and oral medication, the changes were not statistically significant. The statistical results were as follows: pIRF7 (r = -0.58, p = 0.04), MAVS (r = -0.587, p = 0.04), MDA5 (r = -0.914, p < 0.001), and caspase-10 (44 kDa) (r = 0.593, p = 0.04). The disease activity of SLE was inversely associated with levels of antiviral immunity. The antiviral immunity was represented with MDA5, MAVS, and pIRF7. PMID- 30394864 TI - Midwest Nursing Research Society News. PMID- 30394863 TI - Prediction of Insulin Resistance with Anthropometric and Clinical Laboratory Measures in Nondiabetic Teenagers. AB - BACKGROUND: Adolescent obesity is an important risk factor for cardiovascular disease in part due to its relationship to type 2 diabetes. Therefore, screening for type 2 diabetes is recommended. However, since insulin resistance (IR) is an early precursor of diabetes, it would be beneficial if IR predictors from routine assessments could identify those at greatest metabolic risk before diabetes has developed. METHODS: Adolescents aged 14-18 years with normal fasting plasma glucose (n = 252) were selected from the National Health and Nutrition Examination Survey 2013-2014. IR was estimated with homeostatic model assessment (HOMA). Multivariable linear/logistic regressions with demographic covariates assessed HOMA Index (HI)-determined IR associations with common clinical measurements. RESULTS: The constellation of body mass index (BMI) percentile (P < 0.0001), diastolic blood pressure (DBP, P = 0.0056), and serum alanine aminotransferase (ALT, P = 0.0295) predicted log-transformed HI; cholesterol, triglycerides, and high- and low-density lipoprotein cholesterol were not predictive. Secondary gender analyses indicated significant associations in males (BMI percentile, P = 0.0008; DBP, P = 0.0003; ALT, P = 0.0436), but only BMI percentile in females (P = 0.0001). After stratifying predictors at clinical thresholds, logistic regressions had increased specificity at HI's 85th percentile compared with its 75th [85th: area under curve (AUC) = 0.87, 75th: AUC = 0.80]. At the 85th HI percentile, IR was associated with these components [BMI percentile: adjusted odds ratio (aOR) = 34.31, 95% confidence interval (CI): 8.5 139.3; ALT: aOR = 11.36, 95% CI: 3.0-43.7; DBP: aOR = 7.73, 95% CI: 2.4-24.6]. In males, IR was associated with elevated BMI percentile (aOR 24.0) and ALT (aOR 23.9) and in females with elevated BMI percentile (aOR 45.8) and DBP (aOR 17.9). CONCLUSIONS: Three routine clinical assessments, BMI percentile, DBP, and ALT, predicted IR at HI's 75th and 85th percentiles in nondiabetic adolescents. Prospective validation may yield simple gender-specific screening identifying nondiabetic adolescents at greatest need of treatment intervention. PMID- 30394865 TI - Mesosutterella multiformis gen. nov., sp. nov., a member of the family Sutterellaceae and Sutterella megalosphaeroides sp. nov., isolated from human faeces. AB - Two novel, obligately anaerobic, Gram-stain-negative, rod or coccoid-shaped bacteria, designated strains 4NBBH2T and 6FBBBH3T, were isolated from faecal samples of a healthy Japanese woman and man. The 16S rRNA gene sequence analysis showed that these strains represent a distinct lineage within the family Sutterellaceae. Strain 4NBBH2T formed a monophyletic branch between the genera Parasutterella and Sutterella, with sequence similarity to Sutterella stercoricanis CCUG 47620T (92.6 %), followed by Sutterella wadsworthensis WAL 7877 (92.4 %), Sutterella parvirubra YIT 11816T (92.1 %) and Parasutterella secunda YIT 12071T (91.8 %). Strain 6FBBBH3T was affiliated to the genus Sutterella, with highest similarity to S. stercoricanis CCUG 47620T (97.1 %), followed by S. parvirubra YIT 11816T (96.6 %) and S. wadsworthensis WAL 7877 (95.2 %). Strains 4NBBH2T and 6FBBBH3T were asaccharolytic. Analysis of fatty acids revealed that strain 4NBBH2T could be differentiated from Sutterella species (including strain 6FBBBH3T) by the presence of a low concentration of C16 : 1omega7c. The major respiratory quinones of strain 4NBBH2T were menaquinone (MK)-6 and methylmenaquinone (MMK)-6, whereas those of strain 6FBBBH3T were MK-5 and MMK-5. The G+C content of the genomic DNA of strains 4NBBH2T and 6FBBBH3T were 56.9 and 62.8 mol%, respectively. On the basis of the collected data, strain 4NBBH2T represents a novel species in a novel genus of the family Sutterellaceae, for which the name Mesosutterella multiformis gen. nov., sp. nov. is proposed. The type strain is 4NBBH2T (=JCM 32464T=DSM 106860T). We also propose a novel Sutterella species, Sutterellamegalosphaeroides sp. nov., for strain 6FBBBH3T (=JCM 32470T=DSM 106861T). PMID- 30394866 TI - Sphingopyxis lindanitolerans sp. nov. strain WS5A3pT enriched from a pesticide disposal site. AB - An aerobic, Gram-stain-negative, rod-shaped, non-motile, mesophilic soil bacterium, strain WS5A3pT, was isolated from a pesticide burial site in north west Poland. The strain grew at 12-37 degrees C, at pH 8-9 and with 0-2 % (w/v) NaCl. The main fatty acids detected in WS5A3pT were summed feature 3, summed feature 8 and C16 : 0. The major respiratory quinone was Q-10 and major polar lipids were phosphatidylethanolamine, sphingoglycolipid and phosphatidylglycerol. The G+C content of the genome was 65.1 mol%. Phylogenetic pairwise distance analysis of the 16S rRNA gene placed this strain within the genus Sphingopyxis, with the highest similarity to Sphingopyxis witflariensis W-50T (98.8 %), Sphingopyxis bauzanensis BZ30T and Sphingopyxis ginsengisoli Gsoil 250T (98.3 %) and Sphingopyxis granuli NBRC 100800T (98.09 %). Genomic similarity analyses using ANIb and dDDH algorithms indicated levels of similarity of 81.44, 80.84 and 81.16 % between WS5A3pT and S. witflariensis, S. bauzanensisand S. granuli, respectively for average nucleotide identity and 25.90, 25.00 and 26.10 % for digital DNA-DNA hybridization. Based on the phylogenetic and phenotypic data, strain WS5A3pT should be considered as a representative of a novel Sphingopyxis species. The name Sphingopyxis lindanitolerans sp. nov. is proposed with the type strain WS5A3pT (=DSM 106274T=PCM 2932T). PMID- 30394867 TI - Detection, infection dynamics and small RNA response against Culex Y virus in mosquito-derived cells. AB - Many insect cell lines are persistently infected with insect-specific viruses (ISV) often unrecognized by the scientific community. Considering recent findings showing the possibility of interference between arbovirus and ISV infections, it is important to pay attention to ISV-infected cell lines. One example is the Entomobirnavirus, Culex Y virus (CYV). Here we describe the detection of CYV using a combination of small RNA sequencing, electron microscopy and PCR in mosquito cell lines Aag2, U4.4 and C7-10. We found CYV-specific small RNAs in all three cell lines. Interestingly, the magnitude of the detected viral RNA genome is variable among cell passages and leads to irregular detection via electron microscopy. Gaining insights into the presence of persistent ISV infection in commonly used mosquito cells and their interactions with the host immune system is beneficial for evaluating the outcome of co-infections with arboviruses of public health concern. PMID- 30394868 TI - Analysis of the multifunctionality of Marburg virus VP40. AB - The Marburg virus (MARV) matrix protein, VP40, is a multifunctional protein that is essential for the assembly and release of viral particles, inhibition of the interferon response and viral transcription/replication. VP40 is assumed to be present as soluble monomers and membrane-bound higher-order oligomers. To investigate the functional relevance of oligomerization and lipid binding of VP40 we constructed mutants with impaired VP40-VP40 or VP40-lipid interactions and tested their capacity to bind the plasma membrane, to form virus-like particles (VLPs) and to inhibit viral RNA synthesis. All of the analysed VP40 mutants formed perinuclear aggregates and were defective in their delivery to the plasma membrane and in VLP production. The VP40 mutants that were competent for oligomerization but lacked VP40-lipid interactions formed fibril-like structures, influenced MARV inclusion body formation and inhibited viral transcription/replication more strongly than the VP40 wild-type. Altogether, mutations that interfere with VP40's transition from monomer to higher-order oligomers and/or lipid interactions destroy the protein's multifunctionality. PMID- 30394869 TI - Dynamic changes in lysine acetylation and succinylation of the elongation factor Tu in Bacillus subtilis. AB - Nepsilon-lysine acetylation and succinylation are ubiquitous post-translational modifications in eukaryotes and bacteria. In the present study, we showed a dynamic change in acetylation and succinylation of TufA, the translation elongation factor Tu, from Bacillus subtilis. Increased acetylation of TufA was observed during the exponential growth phase in LB and minimal glucose conditions, and its acetylation level decreased upon entering the stationary phase, while its succinylation increased during the late stationary phase. TufA was also succinylated during vegetative growth under minimal citrate or succinate conditions. Mutational analysis showed that triple succinylation mimic mutations at Lys306, Lys308 and Lys316 in domain-3 of TufA had a negative effect on B. subtilis growth, whereas the non-acylation mimic mutations at these three lysine residues did not. Consistent with the growth phenotypes, the triple succinylation mimic mutant showed 67 % decreased translation activity in vitro, suggesting a possibility that succinylation at the lysine residues in domain-3 decreases the translation activity. TufA, including Lys308, was non-enzymatically succinylated by physiological concentrations of succinyl-CoA. Lys42 in the G-domain was identified as the most frequently modified acetylation site, though its acetylation was likely dispensable for TufA translation activity and growth. Determination of the intracellular levels of acetylating substrates and TufA acetylation revealed that acetyl phosphate was responsible for acetylation at several lysine sites of TufA, but not for Lys42 acetylation. It was speculated that acetyl-CoA was likely responsible for Lys42 acetylation, though AcuA acetyltransferase was not involved. Zn2+-dependent AcuC and NAD+-dependent SrtN deacetylases were responsible for deacetylation of TufA, including Lys42. These findings suggest the potential regulatory roles of acetylation and succinylation in controlling TufA function and translation in response to nutrient environments in B. subtilis. PMID- 30394870 TI - Influenza virus RNA polymerase may be activated inside the virion. AB - Influenza A and B virions are packaged with their polymerases to catalyse RNA dependent RNA polymerase activity. Since there is no evidence to rule in or out the permissiveness of influenza virions to triphosphate ribonucleotides, we functionally evaluated this. We found the means to stimulate influenza A and B RNA polymerase activity inside the virion, called natural endogenous RNA polymerase (NERP) activity. Stimulation of NERP activity increased up to 3 log10 viral RNA content, allowing the detection of influenza virus in otherwise undetectable clinical samples. NERP activation also improved our capacity to sequence misidentified regions of the influenza genome from clinical samples. By treating the samples with the ribavirin triphosphate we inhibited NERP activity, which confirms our hypothesis and highlights that this assay could be used to screen antiviral drugs. Altogether, our data show that NERP activity could be explored to increase molecular diagnostic sensitivity and/or to develop antiviral screening assays. PMID- 30394871 TI - Arcobacter lacus sp. nov. and Arcobacter caeni sp. nov., two novel species isolated from reclaimed water. AB - Two strains (RW43-9T and RW17-10T) recovered from secondary treated wastewater from the Wastewater Treatment Plant (WWTP) in Reus (Spain) were characterized by a polyphasic taxonomic study, showing evidence that they represented two novel Arcobacter species. Based on the 16S rRNA gene for strain RW43-9T, the closest relative was Arcobacter butzleri LMG 10828T (99.9 % similarity), while for strain RW17-10T it was Arcobacter venerupis CECT 7836T (99.4 %). Additionally, multilocus phylogenetic analysis of five concatenated housekeeping genes (atpA, gyrA, gyrB, hsp60 and rpoB) showed that the two strains formed separate branches that are different from known Arcobacter species. Whole genome sequences of the two strains (RW43-9T and RW17-10T) were obtained and they were compared with those of the type strains of their nearest species. Using average nucleotide identity and in silico DNA-DNA hybridization gave values that were below 96 and 70 %, respectively. These results clearly confirm that they represent novel species. Additionally, the phenotypic characterization of the strains allowed their differentiation from other species. Therefore, the strains are proposed as representing two novel species with the names Arcobacter lacus sp. nov. (type strain RW43-9T=CECT 8994T=LMG 29062T) and Arcobacter caeni sp. nov. (type strain RW17-10T=CECT 9140T=LMG 29151T). PMID- 30394872 TI - Next-generation sequencing analysis of new genotypes appearing during antiviral treatment of chronic hepatitis C reveals that these are selected from pre existing minor strains. AB - Coinfection with more than one hepatitis C virus (HCV) genotype is common, but its dynamics, particularly during antiviral treatment, remain largely unknown. We employed next-generation sequencing (NGS) to analyse sequential serum and peripheral blood mononuclear cell (PBMC) samples in seven patients with transient presence or permanent genotype change during antiviral treatment with interferon and ribavirin. Specimens were collected right before the therapy initiation and at 2, 4, 6, 8, 12, 20, 24, 36, 44 and 48 weeks during treatment and 6 months after treatment ceased. A mixture of two different genotypes was detected in the pretreatment samples from five patients and the minor genotype constituted 0.02 to 38 %. A transient or permanent change of the predominant genotype was observed in six patients. In three cases genotype 3 was replaced as the predominant genotype by genotype 4, in two cases genotype 3 was replaced by genotype 1, and in one subject genotype 1 was replaced by genotype 4. The PBMC- and serum-derived sequences were frequently discordant with respect to genotype and/or genotype proportions. In conclusion, pre-existing minor HCV genotypes can be selected rapidly during antiviral treatment and become transiently or permanently predominant. In coinfections involving genotype 3, genotype 3 was eliminated first from both the serum and PBMC compartments. The PBMC- and serum-derived HCV sequences were frequently discordant with respect to genotype and/or genotype proportions, suggesting that they constitute separate compartments with their own dynamics. PMID- 30394873 TI - Current and future goals are represented in opposite patterns in object-selective cortex. AB - Adaptive behavior requires the separation of current from future goals in working memory. We used fMRI of object-selective cortex to determine the representational (dis)similarities of memory representations serving current and prospective perceptual tasks. Participants remembered an object drawn from three possible categories as the target for one of two consecutive visual search tasks. A cue indicated whether the target object should be looked for first (currently relevant), second (prospectively relevant), or if it could be forgotten (irrelevant). Prior to the first search, representations of current, prospective and irrelevant objects were similar, with strongest decoding for current representations compared to prospective (Experiment 1) and irrelevant (Experiment 2). Remarkably, during the first search, prospective representations could also be decoded, but revealed anti-correlated voxel patterns compared to currently relevant representations of the same category. We propose that the brain separates current from prospective memories within the same neuronal ensembles through opposite representational patterns. PMID- 30394874 TI - Value-based attentional capture affects multi-alternative decision making. AB - Humans and other animals often violate economic principles when choosing between multiple alternatives, but the underlying neurocognitive mechanisms remain elusive. A robust finding is that adding a third option can alter the relative preference for the original alternatives, but studies disagree on whether the third option's value decreases or increases accuracy. To shed light on this controversy, we used and extended the paradigm of one study reporting a positive effect. However, our four experiments with 147 human participants and a reanalysis of the original data revealed that the positive effect is neither replicable nor reproducible. In contrast, our behavioral and eye-tracking results are best explained by assuming that the third option's value captures attention and thereby impedes accuracy. We propose a computational model that accounts for the complex interplay of value, attention, and choice. Our theory explains how choice sets and environments influence the neurocognitive processes of multi alternative decision making. PMID- 30394876 TI - Inferring Physical Function from Wearable Activity Monitors: Analysis of Free Living Activity Data from Patients with Knee Osteoarthritis. AB - BACKGROUND: Clinical assessments for physical function do not objectively quantify routine daily activities. Wearable activity monitors enable objective measurement of daily activities, but it is unclear how these map to clinically measured physical function measures. OBJECTIVE: The objective of our study was to derive a representation of physical function from daily measurements of free living activity obtained via a wearable activity monitor. We also evaluated our derived measure against objectively measured function using an ordinal classification setup. METHODS: We defined function profiles representing average time spent in a set of pattern classes over consecutive days. We constructed a function profile using minute-level activity data from a wearable activity monitor available from the Osteoarthritis Initiative (OAI). Using the function profile as input, we trained statistical models that classified subjects into quartiles of objective measurements of physical function as measured via the 400m walk test, the 20m walk test and 5 times sit-stand test. We evaluated model performance on held-out data. RESULTS: The function profile derived from minute level activity data can accurately predict physical performance as measured via clinical assessments. Using held-out data, the Goodman-Kruskal Gamma statistic obtained in classifying performance values in the 1st quartile, inter-quartile range and the 4th quartile was 0.62, 0.53 and 0.51, for the 400m walk, the 20m walk and 5 times sit-stand tests respectively. CONCLUSIONS: Function profiles accurately represent physical function, as demonstrated by the relationship between the profiles and clinically measured physical performance. Estimation of physical performance via function profiles derived from free-living activity data may enable remote functional monitoring of patients. PMID- 30394875 TI - A novel mechanism of gland formation in zebrafish involving transdifferentiation of renal epithelial cells and live cell extrusion. AB - Transdifferentiation is the poorly understood phenomenon whereby a terminally differentiated cell acquires a completely new identity. Here, we describe a rare example of a naturally occurring transdifferentiation event in zebrafish in which kidney distal tubule epithelial cells are converted into an endocrine gland known as the Corpuscles of Stannius (CS). We find that this process requires Notch signalling and is associated with the cytoplasmic sequestration of the Hnf1b transcription factor, a master-regulator of renal tubule fate. A deficiency in the Irx3b transcription factor results in ectopic transdifferentiation of distal tubule cells to a CS identity but in a Notch-dependent fashion. Using live-cell imaging we show that CS cells undergo apical constriction en masse and are then extruded from the tubule to form a distinct organ. This system provides a valuable new model to understand the molecular and morphological basis of transdifferentiation and will advance efforts to exploit this rare phenomenon therapeutically. PMID- 30394877 TI - Posterolateral Versus Transforaminal Interbody L4/5 Fusion: Correlation With Subsequent Surgery. AB - STUDY DESIGN: This is a retrospective cohort study. OBJECTIVE: To compare posterolateral versus transforaminal interbody fusion (PLF vs. PLF+TLIF) of the L4/5 segment regarding rates of subsequent surgery, clinical and radiographic parameters, and patient satisfaction. SUMMARY OF BACKGROUND DATA: Surgical treatment of lumbar stenosis, decompression with or without fusion, is an efficacious treatment in select patients. Reoperation is thought to be a problem after lumbar fusion. Despite multiple studies, the fusion method that minimizes the need for subsequent surgery has yet to be determined. MATERIALS AND METHODS: A retrospective cohort study was conducted on 89 patients who had an isolated L4/5 decompression and fusion, from January 2006 to 2012. All patients had stenosis and degenerative spondylolisthesis at the L4/5 level. All surgeries were performed at a single center, using either PLF (31 patients) or PLF+TLIF (58 patients) techniques. Preoperative and postoperative patient-reported outcome measures (Oswestry disability index, visual analog scale back pain, visual analog scale leg pain) and radiographic parameters (L4/5 lordosis and overall lumbar lordosis) were measured. Patient satisfaction was acquired via a questionnaire. Chart reviews and patient questionnaires were used to determine the incidence of subsequent lumbar surgery over a minimum follow-up of 5 years. RESULTS: At an average of 8.7 years follow-up, 2 of 31 patients in the PLF group had subsequent lumbar surgery, compared with 16 of 58 patients in the PLF+TLIF group (6% vs. 28%; P=0.02). There were no significant differences between groups with respect to sex, age, body mass index, tobacco, perioperative measures, patient-reported outcomes, or radiographic parameters (P>0.05). CONCLUSIONS: Both PLF and PLF+TLIF are effective fusion methods for L4/5 stenosis and spondylolisthesis. In this study, patients treated with PLF were less likely to undergo a subsequent lumbar surgery. More research is needed to determine which factors influence whether PLF or PLF+TLIF should be used in these patients. LEVEL OF EVIDENCE: Level III. PMID- 30394878 TI - Percutaneous Vertebroplasty Does Not Increase the Incidence of New Fractures in Adjacent and Nonadjacent Vertebral Bodies. AB - STUDY DESIGN: This was a clinical retrospective study. OBJECTIVES: This retrospective study aimed to investigate the incidence of new vertebral compression fractures (NVCFs) and analyze the risk factors that influence the secondary fractures in adjacent and nonadjacent levels after percutaneous vertebroplasty (PVP) and conservative treatment (CT). SUMMARY OF BACKGROUND DATA: PVP is an effective procedure to alleviate the pain caused by osteoporotic vertebral compression fractures. NVCFs have been noted as a potential late sequela of the procedure. However, it remains unclear whether NVCFs are due to this augmentation or simply are the result of the natural progression of osteoporosis. METHODS: A total of 290 patients who had undergone PVP and 270 patients who had undergone CT during the last 4 years were examined. They were followed-up on a monthly basis by telephone for >2 years. They were divided into 2 groups: NVCFs and non-NVCFs. The groups were statistically compared in terms of age, sex, body mass index, initial fracture levels, bone mineral density (BMD) score of the spine, original fracture levels, and new fracture levels. RESULTS: After a mean follow-up of at least 24 months (range, 24-78 mo), 42 NVCFs occurred in 37 of 290 patients after PVP and 33 NVCFs in 30 of 270 patients after CT. Only BMD was significantly different between the groups. Lower BMD was a significant predictive factor for NVCFs. CONCLUSIONS: PVP did not increase the incidence of NVCFs, especially those adjacent to the treated vertebrae, following augmentation with PVP compared with CT. The most important risk factor for NVCFs was osteoporosis.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc nd/4.0/. PMID- 30394879 TI - Usability Evaluation of a Dashboard for Home Care Nurses. AB - The introduction of electronic health records has produced many challenges for clinicians. These include integrating technology into clinical workflow and fragmentation of relevant information across systems. Dashboards, which use visualized data to summarize key patient information, have the potential to address these issues. In this article, we outline a usability evaluation of a dashboard designed for home care nurses. An iterative design process was used, which consisted of (1) contextual inquiry (observation and interviews) with two home care nurses; (2) rapid feedback on paper prototypes of the dashboard (10 nurses); and (3) usability evaluation of the final dashboard prototype (20 nurses). Usability methods and assessments included observation of nurses interacting with the dashboard, the system usability scale, and the Questionnaire for User Interaction Satisfaction short form. The dashboard prototype was deemed to have high usability (mean system usability scale, 73.2 [SD, 18.8]) and was positively evaluated by nurse users. It is important to ensure that technology solutions such as the one proposed in this article are designed with clinical users in mind, to meet their information needs. The design elements of the dashboard outlined in this article could be translated to other electronic health records used in home care settings. PMID- 30394880 TI - A Case Report of Paravertebral Block: A Safe Alternative for Microdiscectomy in a Pregnant Patient. AB - Nonobstetric surgery during pregnancy is common. Administration of safe anesthesia to a pregnant patient, while minimizing its side effects on the fetus, is a major challenge for the anesthesiologist. Both general anesthesia and central neuraxial block are associated with risks during early pregnancy. Regional nerve blocks are being explored as possible alternatives whenever feasible. This report emphasizes the usefulness of ultrasound-guided, modified bilateral paravertebral block in a first-trimester pregnant patient undergoing microdiscectomy for cauda equina syndrome. PMID- 30394881 TI - An Evaluation of the Eighth Edition of the American Joint Committee on Cancer (AJCC) Staging System for Retroperitoneal Sarcomas Using the National Cancer Data Base (NCDB): Does Size Matter? AB - OBJECTIVES: Retroperitoneal sarcomas (RPS) are often large at diagnosis calling into question the seventh edition AJCC size classification of <5 cm (T1) or >=5 cm (T2). The eighth edition expands T stage into 4 categories (T1: <=5 cm, T2: 515 cm). We evaluated the prognostic ability of the eighth edition using the National Cancer Database (NCDB). METHODS: Patients with RPS treated between 1998 and 2011 were identified from the NCDB; overall survival (OS) was compared. RESULTS: Of the 6427 patients identified, 9% had tumors <=5 cm (n=580), 19.4% 515 cm (n=3045). With the eighth edition, stage II patients (G2/3 <=5 cm) have a similar OS to stage IIIA patients (G2/3 5 cm10 cm) show a decrease in OS. Tumor size as a continuous variable had a modest effect on survival (HR, 1.004; P=0.04). On multivariate analysis, higher T-stage was associated with decreased OS (T4 HR, 1.3; P<0.001) but high grade and incomplete resection (R2) were stronger prognostic factors. The c-index for both editions were similar (80.13 eighth vs. 80.08 seventh). CONCLUSIONS: The eighth edition AJCC staging system for retroperitoneal sarcoma incorporates larger tumor size parameters that better characterize most patients, but tumor size alone is only a modest predictor of outcome. PMID- 30394882 TI - Monoaminergic modulation of decision-making under risk of punishment in a rat model. AB - The ability to decide advantageously among options that vary in both their risks and rewards is critical for survival and well-being. Previous work shows that some forms of risky decision-making are robustly modulated by monoamine signaling, but it is less clear how monoamine signaling modulates decision-making under risk of explicit punishment. The goal of these experiments was to determine how this form of decision-making is modulated by dopamine, serotonin, and norepinephrine signaling, using a task in which rats choose between a small, 'safe' food reward and a large food reward associated with variable risks of punishment. Preference for the large, risky reward (risk-taking) was reduced by administration of a D2/3 dopamine receptor agonist (bromocriptine) and a selective D2 agonist (sumanirole). The selective D3 agonist PD128907 appeared to attenuate reward discrimination abilities but did not affect risk-taking per se. In contrast, drugs targeting serotonergic and noradrenergic signaling had few if any effects on choice behavior. These data suggest that in contrast to other forms of risky decision-making, decision-making under risk of punishment is selectively modulated by dopamine signaling, predominantly through D2 receptors. PMID- 30394883 TI - Plasma miR-181a-5p Downregulation Predicts Response and Improved Survival After FOLFIRINOX in Pancreatic Ductal Adenocarcinoma. AB - OBJECTIVE: The aim of the study was to identify plasma microRNA (miRNA) biomarkers for stratifying and monitoring patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) treated with FOLFIRINOX, and to investigate their functional roles. SUMMARY BACKGROUND DATA: FOLFIRINOX has become a standard therapy for patients with advanced PDAC and can be used to potentially downstage disease. However, only a subset of patients respond, and biomarkers to guide decision-making are urgently needed. METHODS: We used microarray-based profiling to discover deregulated miRNAs in pre- and postchemotherapy plasma samples from patients based on their progression-free survival (PFS) after FOLFIRINOX. Nine candidate plasma miRNAs were validated in an independent cohort (n = 43). The most discriminative plasma miRNA was correlated with clinicopathological factors and survival, and also investigated in an additional cohort treated with gemcitabine plus nab-paclitaxel. Expression patterns were further evaluated in matched tumor tissues. In vitro studies explored its function, key downstream gene-targets, and interaction with 5 fluorouracil, irinotecan, and oxaliplatin. RESULTS: Plasma miR-181a-5p was significantly downregulated in non-progressive patients after FOLFIRINOX. In multivariate analysis, this decline correlated with improved PFS and overall survival, especially when combined with CA19-9 decline [hazard ratio (HR) = 0.153, 95% confidence interval (CI), 0.067-0.347 and HR = 0.201, 95% CI, 0.070 0.576, respectively]. This combination did not correlate with survival in patients treated with gemcitabine plus nab-paclitaxel. Tissue expression of miR 181a-5p reflected plasma levels. Inhibition of miR-181a-5p coupled with oxaliplatin exposure in pancreatic cell lines decreased cell viability. CONCLUSIONS: Plasma miR-181a-5p is a specific biomarker for monitoring FOLFIRINOX response. Decline in plasma miR-181a-5p and CA19-9 levels is associated with better prognosis after FOLFIRINOX and may be useful for guiding therapeutic choices and surgical exploration.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0. PMID- 30394884 TI - Assessment of Bleeding Risk and Cerebrovascular Events in Bipolar Disorder Patients With Atrial Fibrillation on Warfarin Versus Rivaroxaban. PMID- 30394885 TI - Lung Biopsy in Patients with Acute Respiratory Distress Syndrome Supported on Extracorporeal Membrane Oxygenation: A 2 Year Experience. PMID- 30394886 TI - Surgical Techniques for Implanting the EVAHEART 2 Double Cuff Tipless Inflow Cannula. AB - The EVAHEART 2 (Sun Medical Technology Research Corporation, Nagano, Japan) is an investigational centrifugal ventricular assist device in the United States, introduced a new type inflow, named "double cuff tipless" inflow cannula intended to mitigate the risks of cannula malposition and subsequent ischemic stroke events associated with thrombi around the inflow cannula. To achieve these performance benefits of the "tipless" design, however, it is crucial to adhere to the recommended surgical procedure. We introduced a polymer-based patient model that mimics a dilated cardiomyopathy apex for inflow cannula implantation training. Here, we used the model to simulate appropriate and inappropriate techniques for inflow suturing. With the appropriate technique, the inflow ostium is aligned on the endocardial plane, and the cut myocardial surface is not exposed to the bloodstream. By contrast, with the inappropriate technique, which is represented as a worst-case suturing scenario, the inflow ostium is misaligned, thus exposing the cut myocardial cross-section to the bloodstream. This misalignment can predispose to platelet deposition, thrombus formation, and pannus formation with long-term support. Repeated training with this human apex model is important to confirm the inflow position and intraventricular finish before moving on to human cases. Along with rigorous preclinical training, technical adherence will help to ensure better clinical outcomes. PMID- 30394887 TI - Usefulness of Glycemic Control Using an Artificial Pancreas Apparatus for Cardiovascular Surgery. AB - Blood glucose management is important for cardiovascular surgery using cardiopulmonary bypass. The usefulness of an artificial pancreas apparatus (STG 55) to control blood glucose in patients undergoing cardiopulmonary bypass was investigated. Subjects comprised 44 patients using the artificial pancreas during cardiopulmonary bypass between June 2016 and March 2017; 55 were initially enrolled, but 11 were excluded because of blood removal failure. Patients were divided into a monitoring group in which blood glucose levels were only monitored using the artificial pancreas (11 patients: six people with diabetes and 5 people without diabetes) and a management group with glycemic control by automatic insulin administration using the artificial pancreas (33 patients: people with diabetes and 21 people without diabetes). Mean maximum blood glucose levels and variation ranges significantly differed between the monitoring and management groups (p = 0.02). The variation range significantly differed between people with and without diabetes in the monitoring group (p = 0.008), but not in the management group. The artificial pancreas apparatus continuously and accurately reflected glycemic variations, facilitating strict and favorable control. PMID- 30394888 TI - The Author Reply: The efficacy of bedside respiratory muscle training in patients with stroke: A randomized controlled trial. PMID- 30394889 TI - Respiratory Muscle Training in Patients with Stroke. PMID- 30394890 TI - Altered functional connectivity of amygdala with the fronto-limbic-striatal circuit in temporal lobe lesion as a proposed mechanism for post-stroke depression. AB - OBJECTIVE: Post-stroke depression (PSD) is an important complication that affects stroke rehabilitation. Abnormal cortical-subcortical connectivity may be associated with the development of PSD. However, few studies have focused on the emotional network of PSD in the temporal lobe lesions. This study was to investigate amygdala-cortical functional connectivity (FC) in the temporal lobe in individuals with and without PSD. DESIGN: Twenty-three patients with PSD and 21 stroke patients without depression were recruited to undergo functional magnetic imaging scanning. RESULTS: In stroke patients with depression, the left amygdala had increased FC with the bilateral precuneus and right orbital frontal lobe but decreased FC with the right putamen. The right amygdala had increased FC with the right temporal pole, right rectus gyrus, and left orbital frontal lobe but decreased FC with the right primary sensory area (S1). Correlative analyses revealed that the amygdala's FC with the right orbital frontal lobe, right insular cortex, and right cingulate cortex were correlated with the Hamilton Depression Rating Scale (HAMD) score. CONCLUSION: The current study identified mood affected through the fronto-limbic-striatal circuit in PSD. Hyperconnectivity between the amygdala, default mode network, and salience network might be related to depressive symptoms, which may provide novel insight into the underlying neuropathological mechanisms of PSD in temporal lobe lesions. PMID- 30394891 TI - Clozapine-Associated Myocarditis: Is It Time to Start Monitoring? PMID- 30394892 TI - Editorial: From old to new: roles of protein sources and individual amino acids in clinical nutrition. PMID- 30394893 TI - Diabetes and frailty. AB - PURPOSE OF REVIEW: Disability and its preceding condition, frailty, are outstanding issues for achieving healthy aging. Diabetes is a very prevalent chronic disease among older patients that favours frailty status. This review will analyse the relationship between diabetes and frailty in the elderly and summarize the current strategies to improve physical function in diabetic older patients. RECENT FINDINGS: We have analyzed the current knowledge providing insight on the relationship between frailty and diabetes in older people. Epidemiological evidences and potential mechanisms connecting diabetes with frailty in the aging process have been examined. Finally, the strategies to reduce frailty in aged population with diabetes were discussed. SUMMARY: Current evidence reveals the high prevalence of diabetes in frail older patients, producing an additional impairment of physical performance in this population. Insulin resistance seems to contribute to this clinical manifestation which is related to the impact of diabetes on skeletal muscle function, on vascular function, and on the hormonal milieu. Exercise, nutritional and educational interventions, and less strict glycaemic control appear as the most effective strategies to reduce frailty in diabetic older people. PMID- 30394894 TI - New insights into the anorexia of ageing: from prevention to treatment. AB - PURPOSE OF REVIEW: Undernutrition in older adults is associated with frailty, functional decline, and mortality. The 'anorexia of ageing' is the age-related appetite and weight loss underpinning such undernutrition. This review examines the latest evidence for its prevention and treatment. RECENT FINDINGS: Existing nutritional therapies for the anorexia of ageing include supporting nutritional intake with fortified food or supplements, including protein, omega-3 fatty acids, multivitamins, and vitamin D. The Mediterranean diet provides high fat intake and nutrient density in a moderate volume of colourful and flavoursome food and is strengthening in evidence for healthy ageing. Studies of the gut microbiome, which potentially regulates normal appetite by acting on the brain gut communication axis, are pertinent. Utilisation of the genetic profile of individuals to determine nutritional needs is an exciting advancement of the past decade and may become common practice. SUMMARY: Prevention or early treatment of the anorexia of ageing in older adults is critical. Latest evidence suggests that once significant weight loss has occurred, aggressive nutritional support may not result in improved outcomes. PMID- 30394895 TI - The diversity of healthy diets for older persons across the world. AB - PURPOSE OF REVIEW: To examine eating patterns, and with a particular focus on the different healthy diets followed by older persons across the world and the factors that can limit accessibility to healthy foods. RECENT FINDINGS: Recent evidence has demonstrated that older people are, generally speaking, following less healthy diets with respect to the past. The only exception seems to be China, but the quality of the food there appears to be less than optimal. Socioeconomic status and, in particular, the price of food seems to be the most important factors linked to diet quality. SUMMARY: Although healthy diets are associated with lower risk of several chronic disabling diseases, elderly people tend to follow less healthy diets with respect to the past. Public health strategies can and should promote healthy eating patterns in this population. PMID- 30394896 TI - Pre-Cardiogenic Shock: A New Clinical Entity. AB - The pathogenesis of cardiogenic shock has evolved from an acute event due to a large myocardial infarction to a semi-acute event due to rapid hemodynamic deterioration on a background of preexisting left ventricular systolic dysfunction. Pre-cardiogenic shock refers to the period of rapid hemodynamic deterioration that precedes overt cardiogenic shock with hypotension, inflammatory response and end-organ failure. Mortality remains extremely high in cardiogenic shock and has not improved over the past decades. Pre-cardiogenic shock offers a unique opportunity to initiate early treatment that may result in better clinical outcomes. The present review addresses the definition, recognition and management of pre-cardiogenic shock with pharmacologic or mechanical support of the failing left ventricle. PMID- 30394897 TI - Will precision medicine be available for all patients in the near future? AB - PURPOSE OF REVIEW: Evidence-based medicine and guidelines directing the diagnosis and treatment of patients are changing. General recommendations are moving towards an individual focus, where technology evolution allows identification of specific patterns and where 'one size fits all' no longer has a place. RECENT FINDINGS: Emerging innovations on health technology include useful tools for individualizing patients' specific conditions and follow-up. There are several preventive initiatives that aim to reduce allergic disease development, but they have no generalizable and definitive results as yet. Both omics and molecular diagnosis have provided the basis for differentiating clusters of patients, both allowing prediction of severity and also indicating appropriate management. Here we discuss examples contributing to some specific conditions we are now facing. SUMMARY: Precision medicine encompasses a personalized care of the patient, the prediction of a successful treatment, the potential prevention of a disease and its progression when present and the important active participation of the patient in the planning and guidance of the approach and management. Technology and medical innovations like omics and molecular diagnosis help for discriminating specific phenotypes/endotypes and the correct individualized interventions. The great challenge for implementing precision medicine will be the possibility of providing those advances to everyone at affordable costs. CONCLUSION: Technology and innovations in medicine are aimed to help all patients globally, providing evidence for particular conditions that need to be personally considered, involving the patient's decision while treating, predicting and preventing disease. Our aim should be to have precision medicine available everywhere at any time. PMID- 30394898 TI - Comparison of the 2010 and 2017 Infectious Diseases Society of America guidelines on the diagnosis and treatment of Clostridium difficile infection. AB - PURPOSE OF REVIEW: To highlights the key changes in the updated Infectious Diseases Society of America and Society for Healthcare Epidemiology of America guidelines with respect to the diagnosis and treatment of Clostridium difficile infection (CDI). RECENT FINDINGS: CDI continues as a major threat to healthcare institutions and as a community-associated infection related primarily to antibiotic exposure. Infectious Diseases Society of America/Society for Healthcare Epidemiology of America produced extensive CDI guidelines in 2010; in 2018, updated guidance has been published. The new guidelines include key changes with respect to the treatment and diagnosis of CDI. SUMMARY: Updated, evidence guidelines allow optimization of the diagnosis of CDI and the use of therapeutic interventions, in particular to reduce the risk of recurrent infection. PMID- 30394899 TI - Growth hormone and chronic kidney disease. AB - PURPOSE OF REVIEW: Elevated circulating levels of growth hormone (GH) and/or increased expression of the GH receptor in the kidney are associated with the development of nephropathy in type1 diabetes and acromegaly. Conditions of GH excess are characterized by hyperfiltration, glomerular hypertrophy, glomerulosclerosis and albuminuria, whereas states of decreased GH secretion or action are protected against glomerulopathy. The direct role of GH's action on glomerular cells, particularly podocytes, has been the focus of recent studies. In this review, the emerging role of GH on the biological function of podocytes and its implications in the pathogenesis of diabetic and chronic kidney disease will be discussed. RECENT FINDINGS: Elevated GH levels impair glomerular permselectivity by altering the expression of podocyte slit-diaphragm proteins. GH stimulates the epithelial-mesenchymal transition of podocytes and decreases podocyte count. GH also induces the expression of prosclerotic molecules transforming growth factor beta, and TGFBIp. SUMMARY: Our understanding of the cellular and molecular effects of GH in the pathogenesis of renal complications of diabetes and acromegaly has significantly progressed in recent years. These observations open up new possibilities in the prevention and treatment of diabetic nephropathy. PMID- 30394900 TI - The clinical consequences of neutrophil priming. AB - PURPOSE OF REVIEW: Neutrophils priming has been long studied in vitro. Recent studies describe it in vivo. In pathophysiological conditions, complex, heterogeneous characteristics of priming are described in the last few years. RECENT FINDINGS: Priming can occur systemically when insults such as sepsis or trauma result in an array of circulating mediators and circulating primed neutrophils seem to exert detrimental effects either directly, or indirectly by interacting with other cells, thereby contributing to the development of organ dysfunction. Local priming of neutrophils augments their ability to clear infection, but may also lead to local bystander tissue injury, for example, in the inflamed joint. The complexity, heterogeneity and dynamic nature of inflammatory responses and the accessibility of cells from local sites make neutrophil priming challenging to study in human disease; however, recent advances have made significant progress to this field. SUMMARY: Herein, we summarize the literature regarding neutrophil priming in selected conditions. In some diseases and in the setting of specific genetic influences, the priming repertoire seems to be restricted, with only some neutrophil functions upregulated. A greater understanding of the nature of neutrophil priming and its role in human disease is required before this process becomes tractable to therapeutic intervention. PMID- 30394901 TI - Obesity and adult asthma: diagnostic and management challenges. AB - PURPOSE OF REVIEW: Despite advances in our understanding of the obese asthma phenotype, heterogeneity and large gaps in knowledge have hindered significant advances in directed interventions. RECENT FINDINGS: Obesity is associated with poorer asthma-related outcomes and increased risk of progression to severe asthma. Obese asthma is associated with variability in the expression of inflammatory markers, lung function impairments, and response to conventional and biologic therapies. In addition, traditional asthma biomarkers are not as reliable in obese patients. Several mechanistic pathways that uniquely impact asthma in obesity have been identified. Pathways involving innate lymphoid cells (ILC) type 2 (ILC-2) cells, surfactant protein-A, cell division control protein (CDC)42, interleukin (IL)-6, IL-17, and IL-33 are likely causal inflammatory pathways. Obesity also confounds lung function parameters making accurate diagnosis more challenging. As such, personalized asthma therapies directed towards obese asthma endotypes remain elusive. SUMMARY: Obesity confounds traditional asthma biomarkers and lung function measurements, thus defining obese asthma endotypes remains challenging. Novel pathways are being identified and hold promise for future targeted therapies. However, we are in dire need of updated guidelines regarding asthma diagnosis in obese patients and the development of biomarkers that more accurately identify specific endotypes. PMID- 30394902 TI - Role of microRNAs and exosomes in asthma. AB - PURPOSE OF REVIEW: Numerous signaling pathways and inflammatory responses in cells and tissues are under microRNA (miRNA) control. In the present review, the role of miRNAs and exosomes in the pathogenesis of asthma will be discussed. RECENT FINDINGS: MiRNAs differentially expressed with asthma, for example, miRNA 34/449, let-7, miRNA-19, miRNA-21, and miRNA-455, were identified in various cell types and tissues including epithelial cells, T cells, type 2 innate lymphoid cells, lung tissues, and smooth muscles. Current data suggest the involvement of these miRNAs in epithelial differentiation, mucus production, airway remodeling, inflammation, etc. However, it is often difficult to predict which genes are targeted by a specific miRNA. We recently combined genome-wide miRNA analyses together with transcriptome in bronchial biopsies, in relation to chronic mucus hypersecretion, then performed a genome-wide miRNA-mRNA network analysis and identified the key miRNA regulators for chronic mucus hypersecretion. SUMMARY: There is now growing evidence suggesting that miRNAs play critically important roles in asthma. Several asthma-associated miRNAs have already been identified. Although miRNAs are attractive targets for therapeutic intervention, a safe and effective delivery to target tissues and cells in humans remains a challenge. PMID- 30394903 TI - How do psychedelics work? AB - PURPOSE OF REVIEW: Psychedelics are reawakening interest from psychiatry, cognitive neuroscience and the general public with impressive outcomes in small scale clinical trials, intriguing human brain imaging work and high-impact journalism. RECENT FINDINGS: This brief opinion piece offers a perspective on how psychedelics work in the brain that may help contextualize these developments. It attempts to link various scales of action, from the molecular (serotonin 2A receptor agonism) through to the anatomical and functional (heightened plasticity) and up to the dynamic (increased brain entropy), systems level (network disintegration and desegregation) and experiential. SUMMARY: It is proposed that psychedelics initiate a cascade of neurobiological changes that manifest at multiple scales and ultimately culminate in the relaxation of high level beliefs. The purpose of psychedelic therapy is to harness the opportunity afforded by this belief-relaxation to achieve a healthy revision of pathological beliefs. PMID- 30394904 TI - Recent developments in understanding the relationship between 22q11.2 deletion syndrome and psychosis. AB - PURPOSE OF REVIEW: Individuals with 22q11.2 deletion syndrome have high rates of comorbid mental illness, particularly psychosis and schizophrenia. The purpose of this review is to summarize recent research in the area of 22q11.2 deletion syndrome and psychosis. RECENT FINDINGS: Research over the past year has identified negative symptoms, functional impairment, dysphoric mood and a childhood diagnosis of attention deficit hyperactivity disorder as important clinical predictors of psychosis risk in 22q11.2 deletion syndrome. As previously reported in nondeleted schizophrenia, recent studies have implicated neuroinflammation as a possible neurobiological mechanism for psychosis in 22q11.2 deletion syndrome. Recent neuroimaging findings suggest that the cortex is significantly thinner in those with 22q11.2 deletion syndrome and psychosis compared to those without psychosis, replicating similar findings in nondeleted schizophrenia. Further data from the International 22q11.2 Deletion Syndrome Brain and Behavior Consortium have suggested that chromosomal microdeletions are significantly more likely to involve protein-coding genes and several rare copy number variants are associated with the presence of psychosis in deleted individuals. SUMMARY: There have been several significant recent advances to further characterize the high rates of psychosis in 22q11.2 deletion syndrome, to identify additional clinical predictors of psychosis and to increase our understanding of the neural substrate and genetic cause of psychosis in 22q11.2 deletion syndrome. PMID- 30394905 TI - A personalized approach to long QT syndrome. AB - PURPOSE OF REVIEW: Our purpose is to provide an update on the new clinical and genetic aspects of long QT syndrome (LQTS). LQTS is the most common channelopathy and a cause of syncope and sudden death in the young. Although there are 17 types of LQTS, most patients have types 1 or 2 which are due to mutations in KCNQ1 and KCNH2 (encoding for the cardiac potassium channels), and type 3 which is due to a mutation in SCN5A (encoding for the sodium channel). LQTS is characterized by incomplete penetrance and variable expressivity. Significant data exist concerning the common types of LQTS and include mutational location, biophysical function, gene-specific triggers, and disease modifiers that are known and help characterize the disease. RECENT FINDINGS: Recent studies support the use of beta blockers in LQTS. Nadolol and propranolol are superior likely because of their sodium channel blocking effects. There are recent data supporting the use of beta blockers in LQTS type 3 in which their use was once discouraged. There are increasing data that left cardiac sympathetic denervation is effective in LQTS and should be considered before an implantable cardioverter defibrillator is implanted. SUMMARY: LQTS is a model for effective collaboration between clinicians and basic scientists and between cardiologists and geneticists. Recent advances in the derivation of induced pluripotent stem cells from LQTS patients and creation of genetically engineered human models using clusters of regularly interspaced palindromic repeats (CRISPR/Cas9) will advance translational arrhythmia research and move us toward the goal of personalized medicine. PMID- 30394906 TI - Advances in medical therapy for pulmonary arterial hypertension. AB - PURPOSE OF REVIEW: The purpose of this review is to demonstrate advances in the medical treatment of pulmonary arterial hypertension (PAH). Reviewed will be the evidence that favors the use of risk assessment in the treatment of PAH. Optimization of combination therapy depending on the risk or worsening will be reviewed. Finally, recent advances in new treatment strategies will be mentioned. RECENT FINDINGS: The use of therapies in sequence or in combination for the treatment of PAH has been shown to decrease morbidity and mortality. Tailoring these treatment strategies to a risk of worsening has been shown to decrease mortality and time to clinical worsening because of PAH. In addition, there have been several advances in the development of other medications separate from the three known pathogenic pathways in PAH. SUMMARY: In the last 15 years, 12 specific therapies have been approved for PAH. These therapies target three separate pathogenic pathways [the endothelin (ET), nitric oxide (NO) and prostacyclin (PGI2)]. As a result, treatment guidelines have tailored the treatment of PAH with these medications either as single drug therapy or in combination. Recently, other treatment pathways have been explored as new strategies for the treatment of PAH. PMID- 30394907 TI - Management strategies for the preemie ductus. AB - PURPOSE OF REVIEW: Patent ductus arteriosus (PDA) remains the most common cardiovascular condition afflicting neonates. Despite 5 decades of scientific inquiry pediatric cardiologists and neonatologists still cannot answer the simple question of which PDAs should be treated. RECENT FINDINGS: Although the volume of the shunt is difficult to calculate, echocardiography, biochemical markers, and clinical exam can provide clues to the magnitude and physiologic consequences of the shunt. Epidemiologic data exists showing a positive relationship between a PDA and numerous morbidities. As a result, for most of the 20th and early 21st century, nearly all PDAs where indiscriminately considered to be hemodynamically significant and attempts to close it where initiated shortly after birth. However, no randomized trials of PDA closure have been able to show significant differences between affected and unaffected groups. In fact, surgical ligation has repeatedly been associated with increased morbidities and worse long-term neurodevelopmental outcomes. As a result, most clinicians favor a strategy of watchful waiting. SUMMARY: In this review, we aim to summarize the scientific literature, along with some of the contemporary biases, that exist with regards to the pathophysiology, genetics, and treatment strategies for the neonatal PDA. PMID- 30394908 TI - The importance of genetics and genetic counselors in the evaluation of patients with bicuspid aortic valve and aortopathy. AB - PURPOSE OF REVIEW: Bicuspid aortic valve (BAV) is a common congenital heart defect, with an estimated frequency of 1-2% in the general population. BAV may occur as an isolated finding or as a feature of certain syndromes. This article discusses potential genetic causes of BAV, includes a list of current known and candidate genes associated with BAV, provides a hypothetical case demonstrating the importance of genetic testing and cascade screening, and highlights the value of genetic counselors specializing in cardiovascular genetics. RECENT FINDINGS: Individuals with BAV are at significantly increased risk of progressive aortic valve disease and aortic root aneurysms. There is high heritability associated with BAV, and several specific genes have recently been associated with BAV. There is wide phenotypic variability among BAV malformations, including which cusps are involved and the degree of aortic root involvement. Genotype-phenotype correlations exist that impact treatment recommendations. Genetic testing can reduce morbidity and mortality by guiding management strategies and identifying asymptomatic relatives before significant complications occur. SUMMARY: Identifying cases of BAV with an identifiable genetic cause can significantly impact patients and family members. The list of associated genes is constantly growing. Genetic counselors have an important role in the evaluation of families at risk of BAV. PMID- 30394909 TI - Erratum. PMID- 30394910 TI - Contemporary Management of Appendicular Skeletal Metastasis by Primary Tumor Type. AB - Skeletal metastases exert a profound effect on patients and society, and will be encountered by most orthopedic surgeons. Once a primary malignancy is diagnosed, multidisciplinary management should focus on maximizing the quality of life while minimizing disease- and treatment-related morbidity. This may be best achieved with discerning attention to the unique characteristics of primary cancer types, including pathologic fracture healing rates, longevity, and efficacy of adjuvant therapies. Some lesions may respond well to nonsurgical measures, whereas others may require surgery. A single surgical intervention should allow immediate unrestricted activity and outlive the patient. In certain scenarios, a therapeutic benefit may be provided by excision with a curative intent. In these scenarios, or when endoprosthetic reconstruction is necessary, patients may be best referred to an orthopedic oncologist. PMID- 30394911 TI - External Fixation in the Emergency Department for Pilon and Unstable Ankle Fractures. AB - INTRODUCTION: Pilon and unstable ankle fractures are often treated initially with an external fixator (ex-fix). Ex-fix application in the emergency department (ED) has been described but not compared with that placed in the operating room (OR). METHODS: Retrospective, case-cohort study was performed at a level-1 trauma center. Using CPT codes, we identified patients who had surgical fixation of pilon or ankle fractures with an initial ex-fix application (in the ED or the OR). Postoperative outcomes and hospital logistical data were compared between the two groups. RESULTS: Ninety-six patients met the inclusion criteria. The average age of patients was 47 years, and 54 (56%) of the patients were men. Thirty-three patients had the ex-fix placed in the OR, whereas 63 patients had the ex-fix placed in the ED. Postsurgical complications (prominent implant, nonunion, deep infection, deep vein thrombosis, loss of reduction) were seen in 6 of 33 patients in the ED ex-fix group and in 8 of 63 patients in the OR ex-fix group (P = 0.51). Deep infections occurred in 2 of 33 patients in the OR ex-fix group and in 5 of 63 patients in the ED ex-fix group (P = 0.71). Revision ex-fix for loss of reduction was performed in 4 of 33 patients in the OR ex-fix group and in 10 of 63 patients in the ED ex-fix group (P = 0.59). Mean length of stay was 14 days for the OR ex-fix group and 13 days for the ED ex-fix group (P = 0.35). CONCLUSION: No statistically significant differences were found in postsurgical complications (surgical or infectious) or ex-fix revision rates for the ED ex-fix group and the OR ex-fix group. Results indicate that uniplanar ex fix may be safely applied in the ED. LEVEL OF EVIDENCE: Level III, therapeutic. PMID- 30394912 TI - Ocular and Genetic Characteristics Observed in Two Cases of Fish-Eye Disease. AB - PURPOSE: To present ocular findings and anterior segment-optical coherence tomography (AS-OCT) imaging findings of 2 cases of fish-eye disease (FED) involving 2 novel genetic variants of the lecithin-cholesterol acyltransferase (LCAT) gene. METHODS: A case report. RESULTS: A 46-year-old woman and 63-year-old man presented with blurred vision, burning sensation, and whitening of both eyes for 2 and 3 years, respectively. Ophthalmologic examination revealed slightly decreased visual acuity, yellowish-white diffuse corneal opacities causing corneal clouding, and dry eye disease bilaterally in both patients. AS-OCT imaging demonstrated diffuse hyperreflective corneal opacities predominantly located in the anterior stroma. On systemic examination, both patients had very low plasma high-density lipoprotein cholesterol levels. However, they did not have any systemic associations with familial LCAT deficiency or Tangier disease, which are differential diagnoses for corneal clouding and low plasma high-density lipoprotein cholesterol. Both patients were diagnosed with FED based on clinical findings. Furthermore, genetic analysis, in which novel variants of c.86A>G (p.Asn29Ser) in the first exon and c.1052A>G (p.Tyr351Cys) in the sixth exon on the LCAT gene were detected, confirmed the diagnosis. CONCLUSIONS: Although it is a rare genetic disorder, FED should be considered in the differential diagnosis of corneal clouding. Corneal lipid deposits, visible on AS-OCT are suggestive of FED, and genetic analysis can be used to confirm the clinical diagnosis. Finally, there may be a relationship between dry eye disease and LCAT enzyme deficiency disorders, which should be investigated in further studies. PMID- 30394913 TI - The Use of Ultrasonography for Verifying Gastric Tube Placement in Newborns. AB - BACKGROUND: The use of gastric tubes in newborns admitted to a neonatal intensive care unit is fairly high, and there is a risk of serious complications related to this procedure. PURPOSE: Considering the need to find a method that does not involve the patient's exposure to radiation, this study aimed to evaluate the diagnostic accuracy of ultrasonography for verifying gastric tube placement in newborns. METHODS: This was a prospective, double-blind, observational study performed in a neonatal intensive care unit, in which 159 infants had gastric intubation using ultrasound examination and radiological imaging, to verify positioning. Results were analyzed in terms of diagnostic accuracy. RESULTS: The tubes were correctly positioned in 157 cases (98.7%), according to radiological images, and in 156 cases (98.1%), according to ultrasound. The sensitivity analysis was 0.98 and the positive predictive value was 0.99. It was not possible to perform a specificity analysis, as there were not enough negative cases in the sample. IMPLICATIONS FOR PRACTICE: The use of ultrasonography to identify correct positioning of gastric tubes in infants and newborns shows good sensitivity. IMPLICATIONS FOR RESEARCH: It was not possible to evaluate the ultrasonography specificity; further studies with greater samples are probably necessary, so that this objective can be achieved.Video Abstract available at https://journals.lww.com/advancesinneonatalcare/Pages/videogallery.aspx?videoId=2 &autoPlay=true. PMID- 30394914 TI - Implementation of a Central Line Maintenance Bundle for Dislodgement and Infection Prevention in the NICU. AB - BACKGROUND: Infants in the newborn intensive care unit (NICU) often receive medications or nutritional support for extended periods. Due to the fragility of veins, central lines are often used. Adverse outcomes from central lines such as infections and line dislodgements, where the line terminates in a peripheral vessel rather than centrally, can drastically increase infant morbidity and mortality. Although evidence exists addressing the specialized needs of premature or smaller infants, there is far less evidence regarding infants that are larger, more physiologically complex, and have longer stays. PURPOSE: Using evidence based practice strategies, we examined the literature for central line maintenance practices specific to the NICU population and created a care maintenance bundle to reduce infection and line dislodgement rates. Furthermore, we examined implementation of this bundle. METHODS/SEARCH STRATEGY: A systematic search of PubMed, Cochrane Library, and CINAHL provided evidence for a practice change for central line maintenance for our nontunneled central lines. During project implementation, infection and dislodgement rates for both tunneled and nontunneled lines were examined in order have a control and intervention group. FINDINGS/RESULTS: Prior to central line maintenance bundle implementation, there were 19 total incidences of central line dislodgements and 5 central line infections (14 dislodgements and 4 infections were from nontunneled lines, 5 dislodgements and 1 infection from a tunneled line). Postintervention there were 1 total dislodgement and 4 central line infections (the dislodgement was from a nontunneled line and all infections were from tunneled lines). IMPLICATIONS FOR PRACTICE: Although research has shown frequent, scheduled dressing changes using the chlorhexidine patch decreases infection rates, the risk of dislodgement and skin breakdown for NICU infants outweighs the potential benefit of decreased infection. IMPLICATIONS FOR RESEARCH: Further research is needed to determine whether this central line maintenance bundle would be beneficial for tunneled central lines. PMID- 30394915 TI - The Best Interests of Infants and Families During Palliative Care at the End of Life: A Review of the Literature. AB - BACKGROUND: Palliative care is an integral element of care provision in neonatal intensive care units (NICUs). Healthcare providers working in NICUs are likely to provide palliative care at some point in their career. PURPOSE: This article examines what neonatal palliative care entails, how parents perceive healthcare providers' actions, what they potentially need at the end of their infant's life, and what bereavement interventions are most supportive for parents. SEARCH STRATEGY: We conducted a search of full-text articles published in English in PubMed and CINAHL using the following key words: "NICU bereavement care," "end-of life care," "infant loss," and "palliative care." FINDINGS: Healthcare providers should consider alleviation of the infant's pain and suffering when discussing whether to provide or continue aggressive medical interventions. The timing of these discussions is important. Parents appear to be most comforted by compassionate, caring healthcare providers who show competence and knowledge in the provision of medical/nursing and palliative care. IMPLICATIONS FOR PRACTICE: Healthcare providers working in NICUs require specific training in bereavement/palliative care for infants. Families facing the death of their infant must receive support from qualified providers both during and after that death. Furthermore, the infant's quality of life must be considered when discussing withholding or withdrawing care. IMPLICATIONS FOR RESEARCH: There is a need for further research investigating the specific types of training required by healthcare providers in NICU settings who are providing bereavement/palliative care to neonates, in order to best support the families' needs in these situations. PMID- 30394916 TI - Low Low-Density Lipoprotein Levels Are Associated With, But Do Not Causally Contribute to, Increased Mortality in Sepsis. AB - OBJECTIVES: Low low-density lipoprotein levels are associated with increased mortality in sepsis. Whether low low-density lipoprotein levels contribute causally to adverse sepsis outcome is unknown. DESIGN: Retrospective analysis of two sepsis patient cohorts using a Mendelian Randomization strategy. SETTING: Sepsis patients enrolled into clinical research cohorts at tertiary care teaching hospitals. PATIENTS: The first cohort included 200 sepsis patients enrolled in an observational study in a hospital Emergency Department. The second cohort included genotyped patients enrolled in the Vasopressin and Septic Shock Trial. INTERVENTIONS: Retrospective analysis of these patient datasets. In 632 patients enrolled in Vasopressin and Septic Shock Trial, Proprotein Convertase Subtilisin/Kexin type 9, and 3-Hydroxy-3-Methylglutaryl-CoA Reductase single nucleotide polymorphisms known to be associated with low-density lipoprotein levels were genotyped, and a genetic score related to low-density lipoprotein levels was calculated. MEASUREMENTS AND MAIN RESULTS: In the first cohort, we replicated the finding that low low-density lipoprotein levels are associated with increased 28-day mortality. In genotyped patients in the Vasopressin and Septic Shock Trial trial, we found that the 3-Hydroxy-3-Methylglutaryl-CoA Reductase genetic score, known to be directly related to low low-density lipoprotein levels, was not associated with increased mortality. Surprisingly the Proprotein Convertase Subtilisin/Kexin type 9 genetic score, known to be directly related to low low-density lipoprotein levels, was associated with decreased (not increased) mortality. CONCLUSIONS: Both 3-Hydroxy-3-Methylglutaryl-CoA Reductase and Proprotein Convertase Subtilisin/Kexin type 9 genetic scores should have been associated with increased mortality if low low-density lipoprotein levels contributed causally to sepsis mortality. But this was not the case, and the opposite was observed for the Proprotein Convertase Subtilisin/Kexin type 9 genetic score. This suggests that low-density lipoprotein levels, per se, do not contribute causally to adverse sepsis outcomes. The Proprotein Convertase Subtilisin/Kexin type 9 genetic score finding raises the possibility that increased low-density lipoprotein clearance (the effect of these Proprotein Convertase Subtilisin/Kexin type 9 genotypes) may contribute to improved sepsis outcomes. PMID- 30394917 TI - Comparison of Methods for Identification of Pediatric Severe Sepsis and Septic Shock in the Virtual Pediatric Systems Database. AB - OBJECTIVES: To compare the performance of three methods of identifying children with severe sepsis and septic shock from the Virtual Pediatric Systems database to prospective screening using consensus criteria. DESIGN: Observational cohort study. SETTING: Single-center PICU. PATIENTS: Children admitted to the PICU in the period between March 1, 2012, and March 31, 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During the study period, all PICU patients were prospectively screened daily for sepsis, and those meeting consensus criteria for severe sepsis or septic shock on manual chart review were entered into the sepsis registry. Of 7,459 patients admitted to the PICU during the study period, 401 met consensus criteria for severe sepsis or septic shock (reference standard cohort). Within Virtual Pediatric Systems, patients identified using "Martin" (n = 970; kappa = 0.43; positive predictive value = 34%; F1 = 0.48) and "Angus" International Classification of Diseases, 9th Edition, Clinical Modification codes (n = 1387; kappa = 0.28; positive predictive value = 22%; F1 = 0.34) showed limited agreement with the reference standard cohort. By comparison, explicit International Classification of Diseases, 9th Edition, Clinical Modification codes for severe sepsis (995.92) and septic shock (785.52) identified a smaller, more accurate cohort of children (n = 515; kappa = 0.61; positive predictive value = 57%; F1 = 0.64). PICU mortality was 8% in the reference standard cohort and the cohort identified by explicit codes; age, illness severity scores, and resource utilization did not differ between groups. Analysis of discrepancies between the reference standard and Virtual Pediatric Systems explicit codes revealed that prospective screening missed 66 patients with severe sepsis or septic shock. After including these patients in the reference standard cohort as an exploratory analysis, agreement between the cohort of patients identified by Virtual Pediatric Systems explicit codes and the reference standard cohort improved (kappa = 0.73; positive predictive value = 70%; F1 = 0.75). CONCLUSIONS: Children with severe sepsis and septic shock are best identified in the Virtual Pediatric Systems database using explicit diagnosis codes for severe sepsis and septic shock. The accuracy of these codes and level of clinical detail available in the Virtual Pediatric Systems database allow for sophisticated epidemiologic studies of pediatric severe sepsis and septic shock in this large, multicenter database. PMID- 30394918 TI - The Effect of Propofol and Dexmedetomidine Sedation on Norepinephrine Requirements in Septic Shock Patients: A Crossover Trial. AB - OBJECTIVES: Propofol-based sedation may increase hemodynamic instability by decreasing vascular tone and venous return. Incremental exogenous catecholamines doses may be required to counteract such effects, aggravating the deleterious effects of sympathetic overstimulation. alpha-2 adrenergic agonists have been reported to decrease norepinephrine requirements in experimental septic shock. The aim of the present study is to test the hypothesis that switching from sedation with propofol to the alpha-2 agonist dexmedetomidine may decrease norepinephrine doses in septic shock. DESIGN: Prospective open-label crossover study. SETTINGS: University hospital, ICU. PATIENTS: Thirty-eight septic shock patients requiring norepinephrine to maintain adequate mean arterial pressure and needing deep sedation with propofol and remifentanil to maintain a Richmond Agitation-Sedation Scale score between -3 and -4. INTERVENTIONS: An initial set of measurements including hemodynamics, norepinephrine doses, and depth of sedation were obtained during sedation with propofol. Propofol was then replaced by dexmedetomidine and a second set of data was obtained after 4 hours of dexmedetomidine infusion. Sedation was switched back to propofol, and a final set of measurements was obtained after 8 hours. A Richmond Agitation-Sedation Scale score between -3 and -4 was maintained during the study period. MEASUREMENTS AND MAIN RESULTS: Norepinephrine requirements decreased from 0.69 +/- 0.72 MUg/kg/min before dexmedetomidine to 0.30 +/- 0.25 MUg/kg/min 4 hours after dexmedetomidine infusion, increasing again to 0.42 +/- 0.36 MUg/kg/min while on propofol 8 hours after stopping dexmedetomidine (p < 0.005). Dexmedetomidine dosage was 0.7 +/- 0.2 MUg/kg/hr. Before and after dexmedetomidine infusion, sedative doses remained unchanged (propofol 2.6 +/- 1.2 vs 2.6 +/- 1.2 mg/kg/hr; p = 0.23 and remifentanil 1.27 +/- 0.17 vs 1.27 +/- 0.16 MUg/kg/hr; p = 0.52, respectively). Richmond Agitation-Sedation Scale was -4 (-4 to -3) before, -4 (-4 to -3) during, and -4 (-4 to -4) after dexmedetomidine (p = 0.07). CONCLUSIONS: For a comparable level of sedation, switching from propofol to dexmedetomidine resulted in a reduction of catecholamine requirements in septic shock patients. PMID- 30394919 TI - A Pilot Study Evaluating the Effect of Cooler Dialysate Temperature on Hemodynamic Stability During Prolonged Intermittent Renal Replacement Therapy in Acute Kidney Injury. AB - OBJECTIVES: Acute kidney injury requiring renal replacement therapy is associated with high morbidity and mortality. Complications of renal replacement therapy include hemodynamic instability with ensuing shortened treatments, inadequate ultrafiltration, and delay in renal recovery. Studies have shown that lowering dialysate temperature in patients with end-stage renal disease is associated with a decrease in the frequency of intradialytic hypotension. However, data regarding mitigation of hypotension by lowering dialysate temperature in patients with acute kidney injury are scarce. We conducted a prospective, randomized, cross over pilot study to evaluate the effect of lower dialysate temperature on hemodynamic status of critically ill patients with acute kidney injury during prolonged intermittent renal replacement therapy. DESIGN: Single-center prospective, randomized, cross-over study. SETTING: ICUs and a step down unit in a tertiary referral center. PATIENTS: Acute kidney injury patients undergoing prolonged intermittent renal replacement therapy. INTERVENTIONS: Participants were randomized to start prolonged intermittent renal replacement therapy with dialysate temperature of 35 degrees C or dialysate temperature of 37 degrees C. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the number of hypotensive events, as defined by any of the following: decrease in systolic blood pressure greater than or equal to 20 mm Hg, decrease in mean arterial pressure greater than or equal to 10 mm Hg, decrease in ultrafiltration, or increase in vasopressor requirements. The number of events was analyzed by Poisson regression and other outcomes with repeated-measures analysis of variance. Twenty-one patients underwent a total of 78 prolonged intermittent renal replacement therapy sessions, 39 in each arm. The number of hypotensive events was twice as high during treatments with dialysate temperature of 37 degrees C, compared with treatments with the cooler dialysate (1.49 +/- 1.12 vs 0.72 +/- 0.69; incidence rate ratio, 2.06; p <= 0.0001). Treatment sessions with cooler dialysate were more likely to reach prescribed ultrafiltration targets. CONCLUSIONS: Patients with acute kidney injury undergoing prolonged intermittent renal replacement therapy with cooler dialysate experienced significantly less hypotension during treatment. Prevention of hemodynamic instability during renal replacement therapy helped to achieve ultrafiltration goals and may help to prevent volume overload in critically ill patients. PMID- 30394920 TI - The Fragility and Reliability of Conclusions of Anesthesia and Critical Care Randomized Trials With Statistically Significant Findings: A Systematic Review. AB - OBJECTIVES: The Fragility Index, which represents the number of patients responsible for a statistically significant finding, has been suggested as an aid for interpreting the robustness of results from clinical trials. A small Fragility Index indicates that the statistical significance of a trial depends on only a few events. Our objectives were to calculate the Fragility Index of statistically significant results from randomized controlled trials of anesthesia and critical care interventions and to determine the frequency of distorted presentation of results or "spin". DATA SOURCES: We systematically searched MEDLINE from January 01, 2007, to February 22, 2017, to identify randomized controlled trials exploring the effect of critical care medicine or anesthesia interventions. STUDY SELECTION: Studies were included if they randomized patients 1:1 into two parallel arms and reported at least one statistically significant (p < 0.05) binary outcome (primary or secondary). DATA EXTRACTION: Two reviewers independently assessed eligibility and extracted data. The Fragility Index was determined for the chosen outcome. We assessed the level of spin in negative trials and the presence of recommendations for clinical practice in positive trials. DATA SYNTHESIS: We identified 166 eligible randomized controlled trials with a median sample size of 207 patients (interquartile range, 109-497). The median Fragility Index was 3 (interquartile range, 1-7), which means that adding three events to one of the trials treatment arms eliminated its statistical significance. High spin was identified in 42% (n = 30) of negative randomized controlled trials, whereas 21% (n = 20) of positive randomized controlled trials provided recommendations. Lower levels of spin and recommendations were associated with publication in journals with high impact factors (p < 0.001 for both). CONCLUSIONS: Statistically significant results in anesthesia and critical care randomized controlled trials are often fragile, and study conclusions are frequently affected by spin. Routine calculation of the Fragility Index in medical literature may allow for better understanding of trials and therefore enhance the quality of reporting. PMID- 30394921 TI - Effects of Fluid Bolus Therapy on Renal Perfusion, Oxygenation, and Function in Early Experimental Septic Kidney Injury. AB - OBJECTIVES: To examine the effects of fluid bolus therapy on systemic hemodynamics, renal blood flow, intrarenal perfusion and oxygenation, PO2, renal function, and fluid balance in experimental early septic acute kidney injury. DESIGN: Interventional study. SETTING: Research institute. SUBJECTS: Adult Merino ewes. INTERVENTIONS: Implantation of flow probes on the pulmonary and renal arteries and laser Doppler oxygen-sensing probes in the renal cortex, medulla, and within a bladder catheter in sheep. Infusion of Escherichia coli to induce septic acute kidney injury (n = 8). After 24, 25, and 26 hours of sepsis, fluid bolus therapy (500 mL of Hartmann's solution over 15 min) was administered. MEASUREMENTS AND MAIN RESULTS: In conscious sheep, infusion of Escherichia coli decreased creatinine clearance and increased plasma creatinine, renal blood flow (+46% +/- 6%) and cortical perfusion (+25% +/- 4%), but medullary perfusion (-48% +/- 5%), medullary PO2 (-56% +/- 4%), and urinary PO2 (-54% +/- 3%) decreased (p < 0.01). The first fluid bolus therapy increased blood pressure (+6% +/- 1%), central venous pressure (+245% +/- 65%), cardiac output (+11% +/- 2%), medullary PO2 (+280% +/- 90%), urinary PO2 (+164% +/- 80%), and creatinine clearance (+120% +/- 65%) at 30 minutes. The following two boluses had no beneficial effects on creatinine clearance. The improvement in medullary oxygenation dissipated following the third fluid bolus therapy. Study animals retained 69% of the total volume and 80% of sodium infused. Throughout the study, urinary PO2 correlated significantly with medullary PO2. CONCLUSIONS: In early experimental septic acute kidney injury, fluid bolus therapy transiently improved renal function and medullary PO2, as also reflected by increased urinary PO2. These initial effects of fluid bolus therapy dissipated within 4 hours, despite two additional fluid boluses, and resulted in significant volume retention. PMID- 30394922 TI - Practical Method for Calculation of Graft Index in Renal Transplant Scintigraphy: A Technical Note. AB - Some quantitative indices have been described for renal transplant scintigraphy in evaluating graft dysfunction, some medical complications, and in predicting early and delayed graft function and long-term graft prognosis. Graft index is very useful and more accurate than many other indices in the prediction of delayed graft function and long-term prognosis. In this technical note, the method of calculation of graft index is shown in detail for the authors who want to use this index in further studies or in clinical practice. PMID- 30394923 TI - Complete Remission After Single Radioiodine Therapy in Malignant Struma Ovarii With Bone and Lymph Node Metastases. AB - A 67-year-old woman presented with malignant struma ovarii after radical bilateral salpingo-oophorectomy. The surgery revealed a 4.4 cm papillary thyroid carcinoma (follicular variant) within a right-sided ovarian teratoma. I sodium iodide positron emission tomography / computed tomography and cervical ultrasound showed 2 slightly hyperfunctional thyroid nodules and several metastases, including bone metastases with intense iodine uptake. Thyroidectomy was necessary in preparation for radioiodine therapy and proofed the thyroid nodules to be benign. Complete remission was achieved by single radioiodine therapy (30 months of follow-up). PMID- 30394925 TI - Trapping of 18F-Fluciclovine (FACBC) in Superior Sagittal Sinus. AB - As F-fluciclovine (FACBC) becomes more popular, new incidental findings are discovered. We present here a case of a 71-year-old man with prostate cancer in whom an FACBC PET/CT showed uptake in the superior sagittal sinus, which was found to be simply due to a dilated superior sagittal sinus on subsequent MRI. Accumulation in the superior sagittal sinus is a variant that interpreters of FACBC PET/CT should be aware of. PMID- 30394924 TI - Predicting Response to Neoadjuvant Chemotherapy in Patients With Breast Cancer: Combined Statistical Modeling Using Clinicopathological Factors and FDG PET/CT Texture Parameters. AB - PURPOSE: The aim of this study was to develop a combined statistical model using both clinicopathological factors and texture parameters from F-FDG PET/CT to predict responses to neoadjuvant chemotherapy in patients with breast cancer. MATERIALS AND METHODS: A total of 435 patients with breast cancer were retrospectively enrolled. Clinical and pathological data were obtained from electronic medical records. Texture parameters were extracted from pretreatment FDG PET/CT images. The end point was pathological complete response, defined as the absence of residual disease or the presence of residual ductal carcinoma in situ without residual lymph node metastasis. Multivariable logistic regression modeling was performed using clinicopathological factors and texture parameters as covariates. RESULTS: In the multivariable logistic regression model, various factors and parameters, including HER2, histological grade or Ki-67, gradient skewness, gradient kurtosis, contrast, difference variance, angular second moment, and inverse difference moment, were selected as significant prognostic variables. The predictive power of the multivariable logistic regression model incorporating both clinicopathological factors and texture parameters was significantly higher than that of a model with only clinicopathological factors (P = 0.0067). In subgroup analysis, texture parameters, including gradient skewness and gradient kurtosis, were selected as independent prognostic factors in the HER2-negative group. CONCLUSIONS: A combined statistical model was successfully generated using both clinicopathological factors and texture parameters to predict the response to neoadjuvant chemotherapy. Results suggest that addition of texture parameters from FDG PET/CT can provide more information regarding treatment response prediction compared with clinicopathological factors alone. PMID- 30394926 TI - Peritoneal Deciduoid Malignant Mesothelioma on 67Ga SPECT/CT. AB - Malignant mesotheliomas may be classified into epithelioid (60%), sarcomatoid (20%), or mixed (20%) type microscopically. Malignant deciduoid mesothelioma, a rare phenotype of epithelioid mesothelioma, arises more commonly from the peritoneum of young women, but is also from the pleura of elderly people. In the current report, the authors describe an unusual case of peritoneal malignant epithelioid mesothelioma with rare deciduoid phenotype demonstrated with Ga SPECT/CT. PMID- 30394927 TI - Management of Primary Lymph Nodal Gastrinoma With Liver Metastases Resulting in Zollinger-Ellison Syndrome. AB - Primary lymph node gastrinoma has been defined as gastrin-producing tumor present in lymph nodes and predominantly found in well-defined anatomical region known as gastrinoma triangle. They are usually localized preoperatively with imaging, and their surgical resection results in long-term relief. The authors report a case of unresectable primary lymph nodal gastrinoma with liver metastases in a 14-year old adolescent boy with proven histopathology detected on Ga-DOTANOC whole-body PET/CT scan followed by preoperative multiple Lu-DOTATATE cycles for cytoreduction. Subsequent surgical resection of residual mass resulted in complete response with a follow-up of around 4 years in this unusual case of Zollinger-Ellison syndrome. PMID- 30394928 TI - Sorafenib Reduced Significantly Heptopulmonary Shunt in a Large Hepatocelullar Carcinoma. AB - An 81-year-old man with a large hepatocellular carcinoma was referred in our institution for Y radioembolization (RE). The preliminary arteriography using Tc macroaggregate albumin demonstrated an important hepatopulmonary shunt. It was an exclusion criterion for RE due to high risks of lung radiations. Then, the patient was treated with sorafenib during 4 months, stopped because of grade 3 toxicity. A second liver arteriography was performed, and Tc-macroaggregate albumin imaging showed an important reduction of the lung shunt. Transient therapy with sorafenib permitted to close the lung shunt and was a bridge for RE. PMID- 30394929 TI - 18F-FDG PET/CT Imaging in an Adolescent Patient With Primary Prostatic Stromal Sarcoma. AB - Primary prostatic stromal sarcoma is an extremely rare disease that predominantly occurs in adults, accounting for only 0.1% of all prostate cancers. Prostatic stromal sarcoma is quite aggressive and can spread to lung, liver, bone, and other organs. Metastasis is one of the most important predictors for prognosis. Here, we reported a case of a 17-year-old adolescent boy diagnosed with primary prostatic stromal sarcoma through prostate biopsy, and stage was confirmed by F FDG PET/CT. PMID- 30394930 TI - Intertumoral Heterogeneity of 18F-FDG and 68Ga-PSMA Uptake in Prostate Cancer Pulmonary Metastases. AB - We present a case of a 61-year-old man with history of prostate cancer and rising PSA levels referred for restaging. Ga-PSMA-11 PET/CT identified 2 lung nodules with low and moderate PSMA uptake. Subsequent F-FDG PET/CT showed high hypermetabolism in the nodule with low PSMA uptake, and low hypermetabolism in the nodule with moderate PSMA uptake. The isolated pulmonary findings and metabolic appearance is an atypical presentation of prostate cancer metastases and raised concern for a second primary malignancy. Fine-needle aspiration of the F-FDG active lung nodule confirmed metastatic prostatic adenocarcinoma that subsequently responded to androgen deprivation therapy and abiraterone acetate. PMID- 30394931 TI - Primary Hepatic Neuroendocrine Tumor: Pretherapy and Posttherapy FDG PET/CT Finding. AB - A 53-year-old man with tentative diagnosis of likely hepatocellular carcinoma underwent FDG PET/CT, which showed intense activity in both right lobe and caudate lobe of the liver. However, pathology examination from biopsy showed neuroendocrine tumor. He received transarterial chemoembolization and systemic chemotherapy. Posttherapy follow-up FDG PET/CT revealed no abnormal FDG activity in the liver. PMID- 30394932 TI - Ectopic Papillary Thyroid Carcinoma Mimicking Esophageal Cancer in FDG PET: A Case Report. AB - Ectopic papillary thyroid carcinoma (PTC) usually occurs along the cervical midline and was barely reported in FDG PET studies. We present a rare case of ectopic PTC within the esophagus with focal FDG activity on FDG PET in a 43-year old woman who was previously diagnosed as having esophageal cancer based on the endoscopy and PET findings. Surgical pathology revealed the presence of PTC lesion within the muscular layer of the esophagus. Combining this with the negative imaging and laboratory results suggesting a normal thyroid gland led to a diagnosis of primary ectopic PTC. PMID- 30394933 TI - ACR Practice Parameter for the Performance of Gallium-68 DOTATATE PET/CT for Neuroendocrine Tumors. AB - Radiopharmaceuticals targeting cell surface expression of somatostatin receptors (SSTRs) are particularly useful in the evaluation of neuroendocrine tumors. Gallium-68 DOTA-Tyr-octreotatate (Ga-DOTATATE) primarily binds to SSTR type 2 receptors. Ga DOTATATE PET/CT is proven to have high impact on the management of neuroendocrine patients compared to traditional anatomical imaging as well as provides additional information over that of conventional nuclear medicine studies (indium-III DTPA-octreotide). It can result in change in management of approximately 75% of patients with neuroendocrine tumors. Ga DOTATATE and F FDG PET/CT imaging are complementary, with the degree of uptake varying depending on the degree of differentiation of the tumor. Well-differentiated tumors maintain their SSTRs and are positive on Ga DOTATATE PET/CT scan, while dedifferentiated tumors are less likely to demonstrate uptake of Ga DOTATATE but will demonstrate uptake with F FDG PET/CT. In addition, Ga DOTATATE PET/CT identifies patients with SSTR expression in their tumors, who have progressed on somatostatin analog therapy, for treatment with Lu DOTATATE. PMID- 30394934 TI - Update 2018: 18F-FDG PET/CT and PET/MRI in Head and Neck Cancer. AB - There are recent advances, namely, a standardized method for reporting therapy response (Hopkins criteria), a multicenter prospective cohort study with excellent negative predictive value of F-FDG PET/CT for N0 clinical neck, a phase III multicenter randomized controlled study establishing the value of a negative posttherapy F-FDG PET/CT for patient management, a phase II randomized controlled study demonstrating radiation dose reduction strategies for human papilloma virus related disease, and Food and Drug Administration approval of nivolumab for treatment of recurrent head and neck squamous cell carcinoma. PMID- 30394935 TI - Systematic analysis of breast atypical hyperplasia-associated hub genes and pathways based on text mining. AB - The purpose of this study was to describe breast atypical hyperplasia (BAH) related gene expression and to systematically analyze the functions, pathways, and networks of BAH-related hub genes. On the basis of natural language processing, gene data for BAH were extracted from the PubMed database using text mining. The enriched Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways were obtained using DAVID (http://david.abcc.ncifcrf.gov/). A protein-protein interaction network was constructed using the STRING database. Hub genes were identified as genes that interact with at least 10 other genes within the BAH-related gene network. In total, 138 BAH-associated genes were identified as significant (P<0.05), and 133 pathways were identified as significant (P<0.05, false discovery rate<0.05). A BAH-related protein network that included 81 interactions was constructed. Twenty genes were determined to interact with at least 10 others (P<0.05, false discovery rate<0.05) and were identified as the BAH-related hub genes of this protein-protein interaction network. These 20 genes are TP53, PIK3CA, JUN, MYC, EGFR, CCND1, AKT1, ERBB2, CTNN1B, ESR1, IGF-1, VEGFA, HRAS, CDKN1B, CDKN1A,PCNA, HGF, HIF1A, RB1, and STAT5A. This study may help to disclose the molecular mechanisms of BAH development and provide implications for BAH-targeted therapy or even breast cancer prevention. Nevertheless, connections between certain genes and BAH require further exploration.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc nd/4.0/. PMID- 30394936 TI - Bridging Continuing Medical Education and Quality Improvement Efforts: A Qualitative Study on a Health Care System in the Kingdom of Saudi Arabia. AB - INTRODUCTION: There have been initial efforts to link continuing medical education (CME), quality improvement (QI), and patient safety in North America. However, limited empirical research has been performed to characterize the relationship and integration between CME and QI/patient safety in the Kingdom of Saudi Arabia (KSA). To explore health care leaders' perceptions and experiences of collaboration between the CME department (CME-D) and the quality management administration (QMA), we conducted an exploratory qualitative study at a large governmental health care center named [blinded for peer review] in [blinded for peer review], KSA. METHODS: The health care managers at [blinded for peer review] were asked to identify their perception on the state of collaboration between the CME-D and QMA. Data collection, in the form of one-to-one semistructured interviews, was directed by an interview guide. Interviews were transcribed verbatim, and the participants' perspectives were analyzed thematically using a theoretical framework. RESULTS: Fifteen participants were recruited: one top manager of the CME-D, three top managers from the QMA, seven representatives from the medical board, and four representatives from the executive board. Key findings of the interviews were the presence of some shared ad hoc goals between the CME-D and QMA. However, insufficiency of other collaborative factors reflected a "potential collaboration" (level 1) based on D'Amour's model of collaboration. DISCUSSION: This is the first qualitative study to explore the perceptions and experiences of CME and QI health care managers on their collaboration at one of the largest health centers in the KSA. Further research should investigate the feasibility of implementing interventions to intensify collaboration between CME and QI. PMID- 30394937 TI - Physicians as Teachers and Lifelong Learners. AB - INTRODUCTION: Lifelong learning requires sustained motivation for learning. Employing a motivational theory framework, we investigated the relationships of psychological need satisfaction, clinical teaching involvement, and lifelong learning of physicians at different career stages and in various medical specialties. We also examined the associations of physician lifelong learning with stress, burnout, teaching enjoyment, and life satisfaction, all of which are essential for physician well-being and, ultimately, for the provision of quality patient care. METHODS: This was a cross-sectional study. Using survey methodology, quantitative data were collected from 202 practicing physicians in Canada. The questionnaire contained validated scales of physician lifelong learning and psychological need satisfaction, measures of clinical teaching (involvement and enjoyment), stress level, burnout frequency, and life satisfaction. Analysis of covariance and correlational analysis were performed. RESULTS: On average, participants reported moderate to moderately high levels of lifelong learning, psychological need satisfaction, teaching enjoyment, and life satisfaction. Irrespective of career stage and specialty, physicians' psychological need satisfaction and involvement in clinical teaching were significant in relation to lifelong learning. That is, physicians who experienced greater psychological need satisfaction at work and those who were involved in clinical teaching had, on average, higher lifelong learning scores. Physician lifelong learning had significant associations with life satisfaction and teaching enjoyment but not with stress level and burnout frequency. DISCUSSION: Fulfilling physicians' basic psychological needs at work and supporting them in their teaching roles is likely to enhance physician lifelong learning and, ultimately, quality of patient care. PMID- 30394938 TI - Osteoarthritis following meniscus and ligament injury: insights from translational studies and animal models. AB - PURPOSE OF REVIEW: The interaction between joint injuries and posttraumatic osteoarthritis (PTOA) is generally thought to be mechanical in nature, however, surgical intervention has little effect on the development of PTOA. Little is known about the biological underpinning of how meniscus and anterior cruciate ligament (ACL) tears lead to cartilage degeneration. This review summarizes the latest findings regarding biological factors that influence how the knee responds to meniscus and ligament injuries, how meniscus and/or ACL tears turn the joint in the direction of PTOA and whether patient risk for PTOA after meniscus/ACL injury can be predicted. RECENT FINDINGS: Literature indicates that numerous intrinsic and extrinsic factors are associated with the biological response of the knee to injuries associated with PTOA. Gene/protein biomarkers provide insight into the biologic response of the knee to meniscus/ACL tears and the relationship to osteoarthritis in at-risk patients. Animal studies detail the time-course of disease pathogenesis and inform about the molecules that potentially alter the course of disease. SUMMARY: The molecular metabolic state of the meniscus/ACL after injury is associated with several biological factors. The limited studies to date provide initial evidence on the early molecular manifestations of injury, suggesting possible mechanisms for further study. PMID- 30394939 TI - An update on the nomenclature for cutaneous vasculitis. AB - PURPOSE OF REVIEW: Cutaneous vasculitis reflects a spectrum ranging from skin limited to severe systemic forms. To date, there is still no generally acknowledged nomenclature for cutaneous vasculitis. This review aims to summarize the recent advances in the nomenclature of cutaneous vasculitis. RECENT FINDINGS: The most widely adopted vasculitis classification system is the one of 2012 Revised Chapel Hill Consensus Conference (CHCC) which represent not such a classification but a nomenclature system that name vasculitis on the basis of the size of the vessel affected. The CHCC 2012 did not deal with the special features of cutaneous vasculitis and did not explicitly discuss the presence of skin limited or skin-dominant forms of vasculitis. Therefore, a consensus group was formed to propose an Addendum to CHCC 2012, focusing on cutaneous vasculitis. The Addendum better clarify the main aspects of some single-organ vasculitis, including IgM/IgG vasculitis, nodular vasculitis, erythema elevatum et diutinum and recurrent macular vasculitis in hypergammaglobulinemia. Moreover, it differentiated normocomplementemic from hypocomplementemic urticarial vasculitis. Finally, it recognized cutaneous polyarteritis nodosa as a distinct subtype of polyarteritis nodosa. SUMMARY: Classification criteria are useful tools to standardize names and definitions for cutaneous vasculitis; however, they do not represent diagnostic criteria. Collaborative efforts are still needed to get a shared classification and valid diagnostic criteria for cutaneous vasculitis. PMID- 30394940 TI - Sex bias in autoimmunity. AB - PURPOSE OF REVIEW: To give an overview of recently published articles addressing the mechanisms underlying sex bias in autoimmune disease. RECENT FINDINGS: Recent studies investigating the origins of sex bias in autoimmune disease have revealed an extensive and interconnected network of genetic, hormonal, microbial, and environmental influences. Investigation of sex hormones has moved beyond profiling the effects of hormones on activity and prevalence of immune cell types to defining the specific immunity-related genes driving these changes. Deeper examination of the genetic content of the X and Y chromosomes and genetic escapees of X chromosome inactivation has revealed some key drivers of female biased autoimmunity. Animal studies are offering further insights into the connections among microbiota, particularly that of the gut, and the immune system. SUMMARY: Sex bias in autoimmune disease is the manifestation of a complex interplay of the sex chromosomes, sex hormones, the microbiota, and additional environmental and sociological factors. PMID- 30394941 TI - Treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer: update and perspectives. AB - PURPOSE OF REVIEW: We describe recent developments in the rapidly evolving field of anaplastic lymphoma kinase-targeting agents. RECENT FINDINGS: Five targeted drugs are currently available in the clinic via regular approval or named patient programs, including crizotinib, ceritinib, alectinib, brigatinib and lorlatinib. Further drugs are tested in clinical trials. This review summarizes published data, together with drug-specific information on dosing and toxicity. Moreover, we discuss different clinical scenarios and potential treatment options in patients with tumor progression, based on current literature and our own experience. SUMMARY: Patients with metastatic, anaplastic lymphoma kinase rearranged nonsmall cell lung cancer should be managed by interdisciplinary expert teams. New drugs with enhanced brain activity are available, and some patients may benefit from local therapies. PMID- 30394942 TI - Does Ki-67 Have a Role in the Diagnosis of Placental Molar Disease? AB - The use of p57 immunohistochemistry (IHC) can distinguish complete mole (CM) from partial mole (PM) and nonmolar abortus (NMA). Molecular genotyping (MG) is the gold standard method for the definitive diagnosis of PM and NMA. However, MG is expensive and not always available. Some data suggest Ki-67 IHC may be helpful in distinguishing NMAs from PMs and could be a substitute for MG. In this study, we examined the utility of p57 and Ki-67 IHC stains in the diagnosis of placental molar disease. The study cohort consisted of 60 cases of products of conception (20 CMs, 20 PMs, and 20 NMAs). All CM cases showed absent (<10%) p57 IHC in chorionic villi. All PM and NMA cases had been subjected to MG and showed diandric triploid or biparental inheritance, respectively. Ki-67 and p57 IHC staining was done on formalin-fixed paraffin-embedded sections from all 60 cases. Both IHC stains were interpreted blinded to the diagnosis. On rereview, we recorded the percentage of cells with nuclear p57 staining in villous cytotrophoblast and stromal cells. Ki-67 proliferative index (%) was determined by manual count of at least 500 villous cytotrophoblastic cells in areas with highest Ki-67 reactivity. Any intensity of nuclear staining was considered positive. The utility of p57 IHC is mainly to exclude or confirm CM. Although there is a significantly higher Ki-67 expression in CMs in comparison to PMs and NMAs, this did not add diagnostic utility. PMs tend to have higher Ki-67 expression than NMAs; however, the difference is not statistically significant. Our data suggest that the use of p57 and Ki-67 IHC cannot reliably distinguish PM from NMAs. PMID- 30394943 TI - Gastrointestinal recall questionnaires compare poorly with prospective patient diaries for gastrointestinal symptoms: data from population and primary health centre samples. AB - BACKGROUND: Clinical understanding of gastrointestinal symptoms is commonly based on patient reports of symptom experience. For diagnosis and treatment choices to be appropriate, symptom reports need to be accurate. We examined the agreement between questionnaire recall and prospective diary enumeration of symptoms relevant to the irritable bowel syndrome. PATIENTS AND METHODS: Data are reported from a randomly selected general population sample (n=238) and also a primary healthcare centre (PHC) sample (n=503, 10 PHCs). All the patients completed the questionnaires, which included Rome III-qualifying irritable bowel syndrome items and a stool and symptom diary over either 7 or 14 days. Agreement between retrospective questionnaire reports and prospective diaries was evaluated. RESULTS: Concordance between questionnaires and diaries was highest for the simple construct of the occurrence of abdominal pain, although after adjusting for possible chance, agreement was only moderate in the general population sample. More complex constructs, such as pain relieved by defecation, yielded poorer concordance. In general, concordance was stronger among PHC respondents than in the general population sample. CONCLUSION: Concordance between questionnaires and diaries was generally poor and related to the complexity of the symptom construct and the type of respondent. The information used to classify individuals based on patient self-report may be unreliable, and therefore, more effort is needed to develop data collection instruments. PMID- 30394944 TI - The efficacy and safety of endoscopic ultrasound-guided ablation of pancreatic cysts with alcohol and paclitaxel: a systematic review. AB - Endoscopic ultrasound (EUS)-guided pancreatic cyst ablation with alcohol lavage or paclitaxel-based regimens are investigative modalities. To evaluate the safety and efficacy of EUS-guided pancreatic cyst ablation with alcohol lavage or paclitaxel-based regimens. A systematic review of computerized bibliographic databases was carried out for studies of EUS-guided pancreatic cyst ablation with alcohol lavage or paclitaxel-based regimens from January 1980 to February 2018. EUS-guided cyst ablation-related outcomes (cyst resolution) and complications. Data were extracted from six studies (N=207 patients) for EUS-guided cyst ablation with alcohol lavage and eight studies (N=347 patients) for EUS-guided cyst ablation with paclitaxel-based regimens. The pooled proportion of patients with complete cyst resolution was 68/207 (32.8%) for EUS-guided cyst ablation with alcohol lavage and 221/347 (63.6%) for EUS-guided cyst ablation with paclitaxel. Postablation adverse events with EUS-guided ablation with alcohol lavage were 44/207 (21.7%), and those with EUS-guided ablation with paclitaxel based regimens were 52/347 (15%). Limitations of this study are because of the variability in study design and regimens tested, paucity of randomized trials, and differences in pancreatic cyst types receiving treatment. EUS-guided cyst ablation appears to be effective and safe. The effect on pancreatic cancer incidence is unknown; EUS-guided pancreatic cyst ablation modalities require further improvement and validation to determine their role in the treatment of patients with pancreatic cystic lesions. PMID- 30394945 TI - Comprehensive training in robotic surgery. AB - PURPOSE OF REVIEW: Robotic training in urology can be poorly structured, lack a basic skills foundation, and may not include teaching in important nontechnical human factor skills vital to the safe delivery of robotic care. Assessment of acquired skills is not routine. There is a need for structured and standardized curricular to deliver validated training and final assessment. The present reviews the current literature on training methods for robotic surgery, and examines the evidence for their effect on performance, where available. RECENT FINDINGS: There is good evidence for the beneficial effect of dry lab simulators on robotic skills acquisition, but less for cadaveric and animal models. Two urological authorities have developed comprehensive curricula for robotic training that take a novice robotic surgeon through the full stages of robotic skills acquisition. These are in the early stages of development and validation but have stimulated the development of curricula in other specialties. SUMMARY: The future landscape for robotic urology training is likely to include structured, mandated, and centralized training, possibly administered by urological organizations. There will be roles for telementoring, advanced education for robotic trainers, and regular revalidation of expert robotic surgeons. PMID- 30394946 TI - Electroclinical Features of Generalized Paroxysmal Fast Activity in Typical Absence Seizures. AB - PURPOSE: Generalized paroxysmal fast activity (GPFA) is a diffuse, paroxysmal, frontal predominant activity described in patients with generalized epilepsies. Studies specifically focusing on electroclinical features of typical absence seizures in children have not reported any GPFA-like features. We sought to identify GPFA in children with typical absence seizures, study its incidence, characteristic electroclinical features, and effect on their epilepsy. METHODS: We performed a retrospective review of electroencephalograms of children with diagnosis of absence epilepsy. A total of 173 subjects were identified. In subjects with GPFA on their electroencephalograms, GPFA characteristics were collected (i.e., predominant location, duration, amplitude, frequency, provocation factors, and if GPFA was followed by spike-wave discharges). In GPFA positive subjects, further data sets were collected examining their demographics, duration of epilepsy, and pharmacoresponsiveness to epilepsy. RESULTS: Generalized paroxysmal fast activity was identified in 10 subjects (5.78%) with female to male ratio of 9:1. Median age of subjects was 17 years, and median duration of illness was 9.5 years. Mean maximum GPFA amplitude was 88.3 MUV with posterior predominance in 9/10 subjects. Generalized paroxysmal fast activity frequency ranged between 11 and 20 Hz with duration of 1 to 4 seconds. Generalized paroxysmal fast activity was provoked with eye closure, hyperventilation, and photic stimulation. Antiseizure medications had no effect on GPFA, and epilepsy was well controlled in most subjects. CONCLUSIONS: Generalized paroxysmal fast activity is uncommon in children with typical absence seizures and has medium voltage, posterior predominance, and marked female preponderance. Generalized paroxysmal fast activity is seen during both pharmacoresponsive and drug-resistant epilepsy, and is not affected by antiseizure medications. It may serve as an independent marker of lifelong epilepsy. PMID- 30394947 TI - Differentiated service delivery: navigating the path to scale. AB - PURPOSE OF REVIEW: Differentiated service delivery (DSD) has emerged as an approach for HIV programs seeking to better serve the needs of people living with HIV, reduce unnecessary burdens on the health system, and improve client outcomes. We reviewed recent evidence that addresses the challenge of DSD scale up. RECENT FINDINGS: Most current evidence focuses on treatment of clinically stable adult clients in high HIV prevalence settings. Nonetheless, a growing body of research is emerging on how the concept of differentiation is being applied to HIV testing, linkage, and initiation; service delivery to specific demographic groups including key populations - MSM, people who inject drugs, people in prisons, sex workers, and transgender people; service delivery to adolescents and pregnant women; and impact on related medical conditions like advanced HIV. There is also an increasing emphasis on measuring client experience. Key barriers to scale-up include the capacity of monitoring and evaluation systems, access to viral load monitoring and funding for community-led demand generation efforts. Another barrier is the lack of sufficient data to evaluate the various manifestations of the DSD model. SUMMARY: Emerging evidence is providing welcome nuance to the discourse on the concept of DSD for HIV. The challenge will be taking evolving DSD concepts from pilot to scale. Countries must review their particular context, define the expected needs of their clients in different settings, introduce appropriate models - and be willing to adjust programming based on quantitative and qualitative outcomes. PMID- 30394948 TI - Creating demand for long-acting formulations for the treatment and prevention of HIV, tuberculosis, and viral hepatitis. AB - PURPOSE OF REVIEW: Long-acting parenteral drug delivery is an established and widely accepted solution to the problem of poor adherence when daily oral medications are used to treat or prevent chronic medical conditions. Poor adherence to oral formulations remains a major barrier to successfully treating or preventing HIV, tuberculosis (TB), and viral hepatitis. The uptake of long acting formulations developed for these infections is uncertain, despite their promise. This review addresses the current state of development of long-acting and extended-release approaches to HIV, TB, and viral hepatitis in the context of creating market demand for such products. RECENT FINDINGS: Two nanoformulated long-acting injectable antiretroviral compounds, cabotegravir and rilpivirine, recently completed Phase 2 clinical trials demonstrating safety, tolerability, and antiretroviral activity, and should be available in high income countries following completion of ongoing Phase 3 trials. Long-acting polymer implants of the antiretroviral nucleosides tenofovir alafenamide and 4'-ethynyl-2-fluoro-2' deoxyadenosine are being tested in animals and should soon enter human studies; tenofovir alafenamide also has activity against hepatitis B virus. Long-acting versions of several broadly neutralizing monoclonal antibodies are in advanced clinical trials for HIV prevention and treatment. Long-acting formulations for TB are in preclinical development. There is no evidence that comparable formulations for viral hepatitis are being developed at present. SUMMARY: Long-acting and extended release formulations are promising approaches to the treatment and prevention of common infectious diseases, but their availability is limited at this time. These products hold great promise for the global control of important human infections. Based on experience with other diseases, it is likely that their use will become more widespread if they are cost competitive with generic oral formulations. PMID- 30394949 TI - Innovations and challenges in early infant diagnosis of HIV. AB - PURPOSE OF REVIEW: This article aims at examining the key recent advances in the field of EID, as well as at discussing approaches for resolving the major bottlenecks faced by health systems in the identification and linkage to care of HIV-infected infants. RECENT FINDINGS: Programmatic experience in South Africa and research in other high-burden countries showed that birth HIV testing is accurate, feasible and has the potential to decrease infant mortality. Substantial evidence has mounted on the accuracy of point-of-care testing for EID, including for birth testing. Importantly, it has now been demonstrated that point-of-care EID improves the rate of results return to patients and has significant positive effect on ART initiation rates. Finally, there are good examples of how EID fits into more comprehensive and integrated packages of services covering the antenatal, birth and postpartum periods. SUMMARY: Point-of care testing for EID, including for birth testing, should be widely implemented to complement laboratory-based testing in high-burden countries. Most of the current barriers for timely EID testing and ART initiation in infants are related to weaknesses in the health system, and will require the implementation of comprehensive approaches aiming at scaling-up these interventions within strengthened primary healthcare services. PMID- 30394950 TI - Prophylactic Fixation Can Be Cost-effective in Preventing a Contralateral Bisphosphonate-associated Femur Fracture. AB - BACKGROUND: Bisphosphonates reduce the risk of fractures associated with osteoporosis but increase the risk of atypical subtrochanteric femur fractures. After unilateral atypical femur fracture, there is risk of contralateral fracture, but the indications for prophylactic fixation are controversial. QUESTIONS/PURPOSES: The purpose of this study is to use Markov modeling to determine whether contralateral prophylactic femur fracture fixation is cost effective after a bisphosphonate-associated atypical femur fracture and, if so, what patient-related factors may influence that determination. METHODS: Markov modeling was used to determine the cost-effectiveness of contralateral prophylactic fixation after an initial atypical femur fracture. Simulated patients aged 60 to 90 years were included and separated into standard and high fracture risk cohorts. Patients with standard fracture risk were defined as those presenting with one atypical femur fracture but without symptoms or findings in the contralateral femur, whereas patients with high fracture risk were typified as those with more than one risk factor, including Asian ethnicity, prodromal pain, femoral geometry changes, or radiographic findings in the contralateral femur. Outcome probabilities and utilities were derived from studies matching to patient characteristics, and fragility fracture literature was used when atypical femur fracture data were not available. Associated costs were largely derived from Medicare 2015 reimbursement rates. Sensitivity analysis was performed on all model parameters within defined ranges. RESULTS: Prophylactic fixation for a 70 year-old patient with standard risk for fracture costs USD 131,300/quality adjusted life-year (QALY) and for high-risk patients costs USD 22,400/QALY. Sensitivity analysis revealed that prophylaxis for high-risk patients is cost effective at USD 100,000/QALY when the cost of prophylaxis was less than USD 29,400, the probability of prophylaxis complications was less than 21%, or if the patient was younger than 89 years old. The parameters to which the model was most sensitive were the cost of prophylaxis, patient age, and probability of prophylaxis-related complications. CONCLUSIONS: Prophylactic fixation of the contralateral side after unilateral atypical femur fracture is not cost-effective for standard-risk patients but is cost-effective among high-risk patients between 60 and 89 years of age with a high risk for an atypical femur fracture defined by patients with more than one risk factor such as Asian ethnicity, prodromal pain, varus proximal femur geometry, femoral bowing, or radiographic changes such as periosteal beaking and a transverse radiolucent line. However, our findings are based on several key assumptions for modeling such as the probability of fractures and complications, the costs associated for each health state, and the risks of surgical treatment. Future research should prospectively evaluate the degree of risk contributed by known radiographic and demographic parameters to guide management of the contralateral femur after a patient presents with an atypical femur fracture. LEVEL OF EVIDENCE: Level III, economic and decision analyses. PMID- 30394951 TI - To Improve Your Surgical Drilling Skills, Make Use of Your Index Fingers. AB - BACKGROUND: Surgery has greatly benefited from various technologic advancements over the past decades. Surgery remains, however, mostly manual labor performed by well-trained surgeons. Little research has focused on improving osseous drilling techniques. The objective of this study was to compare the accuracy and precision of different orthopaedic drilling techniques involving the use of both index fingers. QUESTIONS/PURPOSES: (1) Does the shooting grip technique and aiming at the contralateral index finger improve accuracy and precision in drilling? (2) Is the effect of drilling technique on accuracy and precision affected by the experience level of the performer? METHODS: This study included 36 participants from two Dutch training hospitals who were subdivided into three groups (N = 12 per group) based on their surgical experience (that is, no experience, residents, and surgeons). The participants had no further experience with drilling outside the hospital nor were there other potential confounding variables that could influence the test outcomes. Participants were instructed to drill toward a target exit point on a synthetic bone model. There were four conditions: (1) clenched grip without aiming; (2) shooting grip without aiming; (3) clenched grip with aiming at the contralateral index finger; and (4) shooting grip aiming at the contralateral index finger. Participants were only used to a clenched grip without aiming in clinical practice. Each participant had to drill five times per technique per test, and the test was repeated after 4 weeks. Accuracy was defined as the systematic error of all measurements and was calculated as the mean of the five distances between the five exit points and the target exit point, whereas precision was defined as the random error of all measurements and calculated as the SD of those five distances. Accuracy and precision were analyzed using mixed design analyses of variance. RESULTS: Accuracy was highest when using a clenched grip with aiming at the index finger (mean 4.0 mm, SD 1.1) compared with a clenched grip without aiming (mean 5.0 mm, SD 1.2, p = 0.004) and a shooting grip without aiming (mean 4.9 mm, SD 1.4, p = 0.015). The shooting grip with aiming at the index finger (mean 4.1 mm, SD 1.2) was also more accurate than a clenched grip without aiming (p = 0.006) and a shooting grip without aiming (p = 0.014). Shooting grip with aiming at the opposite index finger (median 2.0 mm, interquartile range [IQR] 1.2) showed the best precision and outperformed a clenched grip without aiming (median 2.9 mm, IQR 1.1, p = 0.016), but was not different than the shooting grip without aiming (median 2.2 mm, IQR 1.4) or the clenched grip with aiming (median 2.4 mm, IQR 1.3). The accuracy of surgeons (mean 4.1 mm, SD 1.1) was higher than the inexperienced group (mean 5.0 mm, SD 1.1, p = 0.012). The same applied for precision (median 2.2 mm, IQR 1.0 versus median 2.8 mm, IQR 1.4, p = 0.008). CONCLUSIONS: A shooting grip combined with aiming toward the index finger of the opposite hand had better accuracy and precision compared with a clenched grip alone. Based on this study, experience does matter, because the orthopaedic surgeons outperformed the less experienced participants. Based on our study, we advise surgeons to aim at the index finger of the opposite hand when possible and to align the ipsilateral index finger to the drill bit. LEVEL OF EVIDENCE: Level II, therapeutic study. PMID- 30394952 TI - ArtiFacts: Private John Reardon's Right Arm. PMID- 30394953 TI - Right Mini-thoracotomy Mitral Valve Surgery: The Art and Science of the Tailoring Approach. PMID- 30394954 TI - Titanium Fastener Utilization During HeartMate 3 Left Ventricular Assist Device Implantation. AB - OBJECTIVE: The objective of this study was to investigate the feasibility of using titanium fasteners for securement of the inflow sewing ring during HeartMate 3 implantation. The secondary objective was to compare cardiopulmonary bypass and total operative times between the titanium fastener and hand-tied knot groups. METHODS: Clearance between the sewing ring and the HeartMate 3 device was assessed in vitro. Thirty-one patients undergoing HeartMate 3 implantation via median sternotomy at a single center from April 2017 to February 2018 were reviewed. The sewing ring was secured with hand-tied knots (n = 18) or titanium fasteners (n = 13). Cannulation strategy and implantation technique were otherwise identical between groups. Central arterial and venous cannulation was performed for cardiopulmonary bypass. The left ventricular apex was cored, and the sewing ring was attached with hand-tied knots or titanium fasteners. RESULTS: There was adequate clearance for the titanium fastener to secure the inflow sewing ring and then connect to the HeartMate 3 in vitro. The inflow sewing ring was successfully secured during HeartMate 3 implantation in the titanium fastener group. Cardiopulmonary bypass time was 75 and 92 minutes for the titanium fastener and hand-tied groups, respectively (P < 0.03). Total operative time was 177 and 193 minutes for the titanium fastener and hand-tied groups, respectively (P = 0.513). CONCLUSIONS: The inflow sewing ring of the HeartMate 3 was efficiently secured using titanium fasteners. Titanium fasteners resulted in shorter cardiopulmonary bypass times compared with the hand-tied group. There was no difference in total operative time. PMID- 30394955 TI - Totally Endoscopic Surgical Repair of Partial Atrioventricular Septal Defect in Children: Two Cases. AB - There have been few reports on the application of totally endoscopic surgery for repairing partial atrioventricular septal defect. In this report, we present two children who were successfully repaired partial atrioventricular septal defect by using totally endoscopic surgery without robotic assistance. PMID- 30394956 TI - Minimally Invasive Ozaki Procedure in Aortic Valve Disease: The Preliminary Results. AB - OBJECTIVE: The Ozaki procedure for aortic valve reconstruction was reported in 2014 with low mortality, a highly reproducible rate and a good midterm result. However, the procedure still requires conventional sternotomy to be accomplished. The aim of the study was to start an initial evaluation for the feasibility of the minimally invasive approach in combination with the Ozaki technique. METHODS: From January 06, 2017, to January 12, 2017, nine patients with severe aortic valve diseases underwent minimally invasive Ozaki procedure through an upper ministernotomy. The pericardium was harvested endoscopically using three trocars in different intercostal spaces. Then, a ministernotomy was performed and the Ozaki procedure was accomplished in a similar manner to the conventional technique. We analyzed the in-hospital mortality and complications of this group. RESULTS: The mean age was 47.4 years and 55.6% patients were female. The predominant pathology was chronic rheumatic valve disease (66.7%) and other patients were diagnosed with a bicuspid aortic valve. The mean aortic cross-clamp time was 106.8 minutes, the mean cardiopulmonary bypass time was 153.6 minutes, the mean ventilation time was 8.4 hours, and the mean intensive care unit time was 1.6 days. No mortality was recorded in our series, no conversion to full sternotomy was required, one patient experienced right hemothorax requiring drainage, and one patient required valve replacement. Intraoperative transesophageal echocardiography and predischarge transthoracic echocardiography showed five competent valves and three valves with trivial regurgitation, and no stenosis was detected. CONCLUSIONS: Ministernotomy combined with Ozaki procedure might be feasible, as well as an alternative to conventional sternotomy. This approach is associated with low mortality and morbidity and may be beneficial in younger populations. PMID- 30394957 TI - Evaluation of Conduction Disorders After Aortic Valve Replacement With Rapid Deployment Bioprostheses. AB - OBJECTIVE: The aim of this retrospective, single-center study was to evaluate the occurrence of conduction disorders after rapid deployment aortic bioprosthesis implantation. METHODS: Electrocardiograms of patients undergoing INTUITY (Edwards Lifesciences, Irvine, CA USA) bioprosthesis implantation were collected at admission, during postoperative course, and at discharge. Primary end point was the occurrence of new-onset conduction disorders, defined as complete left bundle branch block, complete right bundle branch block, permanent pacemaker implantation, and worsening of pre-existing rhythm abnormalities. Secondary end points were the assessment of preoperative and postoperative QRS duration and the identification of transitory conduction disorders. RESULTS: Forty-four patients (July 2015-December 2016) were included in the analysis. Preoperatively, patients with normal conduction and with already existing disorders were 25 (56.8%) and 19 (43.2%), respectively. Primary end point occurred in 14 patients (31.8%). Two patients (4.5%) received pacemaker implantation. In patients with normal preoperative conduction, new abnormalities were found in eight cases (32%): all left bundle branch blocks with one pacemaker implantation. Worsening of pre existing conduction disorders was found in six patients (31.6%) with one pacemaker implantation. QRS duration increased in 20 patients (45.4%), and average increase was 37 milliseconds. Overall, we observed a significant increase of QRS (96 +/- 21 milliseconds vs. 111 +/- 28 milliseconds, P < 0.001). Three patients experienced a new-onset temporary left bundle branch block. CONCLUSIONS: New-onset conduction disorders or worsening of pre-existing rhythm abnormalities occur in one third of patients after rapid deployment aortic bioprosthesis implantation. Although the incidence of postoperative pacemaker implantation before discharge is low, strict follow-up is mandatory to identify a potential need for pacemaker implantation in a timely manner. PMID- 30394958 TI - Robotic Versus Video-Assisted Thoracoscopic Surgery Pulmonary Segmentectomy: A Cost Analysis. AB - OBJECTIVE: Pulmonary segmentectomy using robotic assistance is often perceived as being more expensive than segmentectomy using video-assisted thoracic surgery. The robotic technique allows for meticulous dissection during segmentectomy, potentially leading to fewer parenchymal injuries, fewer air leaks, and shorter length of stay. This study compared pulmonary segmentectomy costs using video assisted thoracic surgery versus robotic with manual staplers versus robotic with robotic staplers. METHODS: Retrospective analyses were performed evaluating our early experience with robotic pulmonary segmentectomy for 30 months compared with the video-assisted thoracic surgery approach. All 50 anatomical segmentectomies performed since introduction of robotic technique in the practice were included. Twenty-eight procedures were robotic-assisted and 22 were video-assisted thoracic surgery. Procedure-specific evaluation of direct costs was performed, including cost of robotic instruments, staplers, and average length of stay in the hospital. RESULTS: The mean +/- SD age was 70 +/- 10 years (range = 43-91 years). There were 12 males in the robotic group and eight in the video-assisted thoracic surgery group (P = 0.642). The mean age was 69 years in the robotic group and 71 years in the video-assisted thoracic surgery group (P = 0.367). The median length of stay was 2 (2-4) days in the robotic group (range = 1-9) and 4 (2-5) days in the video-assisted thoracic surgery group (range = 1-20, P = 0.089). The cost of robotic segmentectomy with manual staplers was less than that with robotic staplers. Both robotic techniques cost less than video-assisted thoracic surgery. CONCLUSIONS: In this small series, cost and outcomes in our early experience with robotic-assisted segmentectomy were comparable with our video-assisted thoracic surgery approach with trends toward shorter length of stay and fewer complications. Larger series are needed to validate these results. PMID- 30394959 TI - Program. PMID- 30394960 TI - Home care for heart failure: can caregiver education prevent hospital admissions? A randomized trial in primary care. AB - AIM: To assess the feasibility and effectiveness of a low-complexity, low-cost model of caregiver education in primary care, targeted to reduce hospitalizations of heart failure patients. METHODS: A cluster-randomized, controlled, open trial was proposed to general practitioners, who were invited to identify patients with heart failure, exclusively managed at home and continuously attended by a caregiver. Participating general practitioners were then randomized to: usual treatment; caregiver education (educational session for recognizing early symptoms/signs of heart failure, with recording in a diary of a series of patient parameters, including body weight, blood pressure, heart rate). The patients were observed at baseline and during a 12-month follow-up. RESULTS: Three hundred and thirteen patients were enrolled (163 in the intervention, 150 in the usual care group), 63% women, mean age 85.3 +/- 7.7 years. At the end of the 12-month follow up, a trend towards a lower incidence of hospitalizations was observed in the intervention group (hazard ratio 0.73; 95% CI 0.53-1.01 P = 0.061). Subgroup analysis showed that for patients with persistent/permanent atrial fibrillation, age less than 90 years or Barthel score equal to or greater than 50 a significant lower hospital admission rate occurred in the intervention group (hazard ratio 0.63; 95% CI 0.39-0.99; P = 0.048, hazard ratio 0.66; 95% CI 0.45-0.97; P = 0.036 and hazard ratio 0.61; 95% CI 0.41-0.89; P = 0.011, respectively). CONCLUSION: Caregivers training for early recognition of symptoms/signs of worsening heart failure may be effective in reducing hospitalizations, although the benefit was evident only in specific patient subgroups (with persistent/permanent atrial fibrillation, age <90 years or Barthel score >= 50), with only a positive trend in the whole cohort. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03389841. PMID- 30394961 TI - Safety and efficacy of a cardiologist-only approach to deep sedation for electrical cardioversion. AB - AIMS: Electrical cardioversion is still the preferred method to restore sinus rhythm in patients with atrial fibrillation. The main disadvantage is that electrical cardioversion requires deep sedation, generally administered by anaesthesiologists, for safety concern. An exclusively cardiologic management of deep sedation should have the advantage to reduce resources and time consumed. METHODS: All consecutive patients admitted to our division with persistent atrial fibrillation or atrial flutter to undergo elective electrical cardioversion from June 2002 to December 2016 were included. The sedation protocol was managed only by cardiologists and involved the administration of a 5-mg bolus of midazolam, followed by increasing doses of propofol to achieve the desired sedation level. Exclusion criteria were strictly observed. Complications were recorded. A retrospective analysis on a deidentified database has been performed. RESULTS: A total of 1188 electrical cardioversions were scheduled in our centre. A total of 1195 patients were scheduled in our centre, of whom 1188 met inclusion criteria. Electrical cardioversion was performed in 1073 cases (90.3%). Electrical cardioversion was successful in restoring sinus rhythm in 1030 (96.0%) patients. Immediate recurrence of atrial fibrillation occurred in 89 patients (8.3%). 99/1073 (9.22%) patients underwent trans-oesophagel echocardiography before cardioversion. Deep sedation, according to our protocol, was effective in 100% of cases. Midazolam was administered at a dosage of 5 mg to all patients, while propofol was administered at a dosage ranging from 20 to 80 mg (25.1 +/- 11.0 mg SD). No anaesthesia-related complications were observed, neither significant respiratory depression requiring intubation nor anaesthesiologist support. CONCLUSION: The exclusively cardiological procedure of deep sedation seems to be safe and effective. PMID- 30394962 TI - T2 Mapping in Prostate Cancer. AB - OBJECTIVES: The aim of the study was to determine the quantitative T2 values in prostate tissue and evaluate them for detection and grading of prostate cancer. MATERIALS AND METHODS: After approval from the local ethics committee, morphological T2-weighted (T2w) images, apparent diffusion coefficient (ADC) maps from diffusion-weighted images, quantitative T2 maps, and calculated T2w images from 75 men (median age, 66.3 years; median PSA, 8.2 ng/mL) were acquired at 3 T magnetic resonance imaging (MRI). Data were retrospectively evaluated for their distinction between prostate pathologies. Eight hundred fifty-seven areas of normal gland (n = 378), prostate cancer (54x Gleason score 6, 98x Gleason score 7, 25x Gleason score 8), benign prostatic hyperplasia (BPH) nodes (n = 150), prostatitis (n = 119), and precancerous lesions (n = 33) were determined on calculated and morphological T2w images. Histological criterion standards were whole gland sections (16 patients), MRI-guided in-bore biopsies (32 patients), MRI/transrectal ultrasound-fusion biopsies (15 patients), and systematic 12-core transrectal ultrasound-guided biopsies (12 patients). Significance was assumed to be P < 0.05. RESULTS: The quantitative T2 values vary significantly between prostate cancer and normal gland tissue (area under the curve [AUC], 0.871), cancer and BPH nodes (AUC = 0.827), and Gleason score 6 and 7 or higher (AUC, 0.742). The quantitative T2 values decrease with increasing Gleason scores and correlate significantly with the ADC values (r = 0.806). The detection accuracy of prostate cancer on calculated (AUC = 0.682) and morphological T2w images (AUC = 0.658) is not significantly different. CONCLUSIONS: Quantitative T2 values seem to be suitable for distinguishing between prostate cancer and normal gland tissue or BPH nodes. Similar to the ADC values, they offer an indication of the aggressiveness of the prostate cancer. PMID- 30394963 TI - The Impact of Different Magnetic Resonance Imaging Equipment and Scanning Parameters on Signal Intensity Ratio Measurements in Phantoms and Healthy Volunteers: Implications for Interpreting Gadolinium Signal Changes Within the Brain. AB - OBJECTIVES: The aim of this study was to examine the variation in signal intensity ratio (SIR) values in Eurospin gel phantoms and healthy volunteer (HV) brain images in response to different magnetic resonance imaging hardware and software settings. MATERIALS AND METHODS: Gel phantoms with T1 relaxation times similar to the dentate nucleus (DN), pons (P), globus palladus (GP), and thalamus (Th) were scanned using a T1-weighted 2-dimensional spin-echo sequence on 2 magnetic resonance imaging scanners (3 T and 1.5 T). Imaging was performed by sequentially altering selected magnetic resonance (MR) parameters relative to a default pulse sequence, and the protocol was implemented repeatedly over 3 months. The experiment was also repeated on a cohort of 15 young HVs. Calculations of DN/P and GP/Th SIR values were derived for the images of the gels (GelDN/P and GelGP/Th) and the HVs (HVDN/P and HVGP/Th). RESULTS: For the default sequence, the mean SIR values of GelDN/P and GelGP/Th varied by +/-2.20% and +/ 0.75%, respectively, when measured over multiple imaging sessions (3 T). Within a single imaging session, these variations were smaller (+/-0.17% for GelDN/P and +/-0.15% for GelGP/Th). At 1.5 T, the equivalent SIR variations for GelDN/P were +/- 1.41% (multiple sessions) and +/-0.41% (single session), and that for GelGP/Th were +/-0.47% (multiple sessions) and +/-0.33% (single session).Sequential changes to the MR sequence parameters resulted in gel SIR variations as follows: 14.07% +/- 2.43% (with/without normalization filters), 7.80% +/- 0.28% (different echo times, TE), and -5.06% +/- 0.59% (selective activation of RF coil elements). The largest variations were noted when the gels were positioned below the scanner isocenter, where SIR measurements were different by 22%.For the HVs, the SIR values were found to be consistently within 0.64% (single session) for the default sequence. Sequential changes to the MR sequence parameters resulted in SIR variations of -24.47% +/- 2.47% (with/without normalization filters), -15.32% +/- 7.71% (different echo times, TE), and -2.90% +/- 0.78% (selective activation of RF coil elements). CONCLUSIONS: This study has demonstrated that SIR percentage changes from baseline of a similar magnitude to brain gadolinium contrast agent signal hyperintensities can be replicated in phantom models and HVs by altering common MR acquisition parameters and hardware. PMID- 30394964 TI - Does Age Interfere With Gadolinium Toxicity and Presence in Brain and Bone Tissues?: A Comparative Gadoterate Versus Gadodiamide Study in Juvenile and Adult Rats. AB - OBJECTIVES: The main objective of the study was to assess the effect of age on target tissue total gadolinium (Gd) retention after repeated administration of gadodiamide (linear) or gadoterate (macrocyclic) Gd-based contrast agent (GBCA) in rats. The secondary objective was to assess the potential developmental and long-term consequences of GBCA administration during neonatal and juvenile periods. MATERIALS AND METHODS: A total of 20 equivalent human clinical doses (cumulated dose, 12 mmol Gd/kg) of either gadoterate or gadodiamide were administered concurrently by the intravenous route to healthy adult and juvenile rats. Saline was administered to juvenile rats forming the control group. In juvenile rats, the doses were administered from postnatal day 12, that is, once the blood-brain barrier is functional as in humans after birth. The tests were conducted on 5 juvenile rats per sex and per group and on 3 adult animals per sex and per group. T1-weighted magnetic resonance imaging of the cerebellum was performed at 4.7 T during both the treatment and treatment-free periods. Behavioral tests were performed in juvenile rats. Rats were euthanatized at 11 to 12 weeks (ie, approximately 3 months) after the last administration. Total Gd concentrations were measured in plasma, skin, bone, and brain by inductively coupled plasma mass spectrometry. Cerebellum samples from the juvenile rats were characterized by histopathological examination (including immunohistochemistry for glial fibrillary acidic protein or GFAP, and CD68). Lipofuscin pigments were also studied by fluorescence microscopy. All tests were performed blindly on randomized animals. RESULTS: Transient skin lesions were observed in juvenile rats (5/5 females and 2/4 males) and not in adult rats having received gadodiamide. Persisting (up to completion of the study) T1 hyperintensity in the deep cerebellar nuclei (DCNs) was observed only in gadodiamide-treated rats. Quantitatively, a slightly higher progressive increase in the DCN/brain stem ratio was observed in adult rats compared with juvenile rats, whereas no difference was noted visually. In all tissues, total Gd concentrations were higher (10- to 30-fold higher) in the gadodiamide-treated groups than in the gadoterate groups. No age-related differences were observed except in bone marrow where total Gd concentrations in gadodiamide-treated juvenile rats were higher than those measured in adults and similar to those measured in cortical bone tissue. No significant treatment-related effects were observed in histopathological findings or in development, behavior, and biochemistry parameters. However, in the elevated plus maze test, a trend toward an anxiogenic effect was observed in the gadodiamide group compared with other groups (nonsignificant). Moreover, in the balance beam test, a high number of trials were excluded in the gadodiamide group because rats (mainly males) did not completely cross the beam, which may also reflect an anxiogenic effect. CONCLUSIONS: No T1 hyperintensity was observed in the DCN after administration of the macrocyclic GBCA gadoterate regardless of age as opposed to administration of the linear GBCA gadodiamide. Repeated administration of gadodiamide in neonatal and juvenile rats resulted in similar total Gd retention in the skin, brain, and bone to that in adult rats with sex having no effect, whereas Gd distribution in bone marrow was influenced by age. Further studies are required to assess the form of the retained Gd and to investigate the potential risks associated with Gd retention in bone marrow in juvenile animals treated with gadodiamide. Regardless of age, total Gd concentration in the brain and bone was 10- to 30-fold higher after administration of gadodiamide compared with gadoterate.This is an open access article distributed under the terms of the Creative Commons Attribution Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30394965 TI - Dental Implants With a Platform-Switched Morse Taper Connection and an Osteo Growth Induction Surface. AB - AIM: The aim of this study was to analyze the clinical outcomes after using an innovative implant system characterized by a modern platform-switched Morse taper connection and an osteo growth induction titanium surface (a particular type of SLA surface). Peri-implant bone loss (PBL) and implant success rate were examined after a 1- to 3-year follow-up. METHODS: The study was conducted as a cross sectional analysis on all patients treated from January 2011 to December 2014 using CLC CONIC implants. Implants were divided into 3 main groups, based on the duration of the follow-up (1 year, 2 years, and 3 years), then subgrouped by diameter, length, and type of prosthetic rehabilitation to compare differences in PBL. X-rays were taken at the time of surgery, at prosthetic loading, at 1 year, and then annually thereafter. Previously-established success criteria were used to assess the implants. Frequency analyses and comparisons between the means (with 95% CI) were conducted for the statistical analysis of the data collected. RESULTS: One hundred twenty patients met inclusion and exclusion criteria, and completed the follow-up, and were thus eligible for the study, with a total of 261 CLC CONIC implants. The mean follow-up was 22.45 months. No implants failed, giving an overall success rate of 100%. The average PBL at 1-year follow-up was 0.047 mm, at 2 years it was 0.128 mm, and at 3 years it was 0.236 mm. CONCLUSIONS: The CLC CONIC implant system had a high success rate after 1 to 3 years of follow-up, in line with previous reports in the scientific literature. Combining platform switching with the Morse taper connection enabled stable bone levels to be achieved in the short to medium term. PMID- 30394966 TI - How to Make the Mesenchymal Stem Cells Therapy More Targeted, More Accurate, and More Efficient? PMID- 30394967 TI - Gridding Microsurgical Anatomy of Far Lateral Approach in the Three-Dimensional Model. AB - OBJECTIVE: The far lateral craniotomy involves osteotomy of various portions of occipital condyle. Intracranial operation exposing clivus encounters complicated neurovascular anatomy. The aim of the present study was to make refinement for the anatomy of far lateral approach by gridding route in the 3-dimensional model. METHODS: Computed tomography and magnetic resonance imaging data were used to construct 3-dimensional model containing osseous and neurovascular structures of skull base. Then, far lateral approach was simulated by triangular prism and divided into gridding surgical route. The relationship of surgical route and osseous and neurovascular structures was observed. Measurement of volume was performed to evaluate surgical exposure. RESULTS: Observation of 3-dimensional model showed bony drilling of far lateral approach started with the occipital condyle and passed through the lateral edge of foramen magnum. The cerebellum and medulla oblongata were exempted from the surgical route exposing clivus. The anatomy variances of operative space, osseous, and neurovascular structures in the gridding route were displayed clearly and compared objectively. CONCLUSION: The gridding operative spaces for the far lateral approach are useful to disclose the detailed discrepancy in the different surgical region. The volumetric measurement provides quantified information to facilitate a better understanding of the anatomy variance. PMID- 30394968 TI - Preliminary Study to Evaluate Marginal Bone Loss in Cases of 2- and 3-Implant Supported Fixed Partial Prostheses of the Posterior Mandible. AB - PURPOSE: The purpose of this study was to evaluate, by radiographic examinations, the marginal bone resorption around implants in cases of 2 and 3 implant supported fixed partial prostheses (FPPs) at the posterior mandible. METHODS: A retrospective study of 41 patients (23 males, 18 females) of an average age of 67 years (range, 53-85), with 2 and 3 implants-supported FPPs in the posterior mandible that were treated during 2006 to 2015. The mean follow-up time was 6.32 years (range, 2-10). Twenty-four patients had FPPs on 2 implants (a total of 48 implants). Seventeen patients had FPPs on 3 implants (a total of 51 implants). Clinical and radiographic follow-up examinations were performed. All radiographs were analyzed for changes in marginal bone height surrounding the implants. RESULTS: The mean marginal bone loss around the most mesial implant was slightly higher in the 2-implant group (0.833 mm) compared with the 3-implant group (0.431 mm). The correlation between the mean marginal bone loss around the most mesial implant and the number of implants was of borderline value (P = 0.055). CONCLUSIONS: Considering the limitations of this preliminary study, the authors found that the mesial implant in the 2-implant group is more susceptible to marginal bone loss. PMID- 30394969 TI - Multisuture Craniosynostosis and Papilledema in Pycnodysostosis: A Paradox? AB - Pycnodysostosis (PYCD) is a rare autosomal-recessive skeletal disorder that typically presents with osteosclerosis of the majority of the postcranial skeleton and osteolysis of the calvarium, manifesting as persistent open cranial fontanelles and widely spaced cranial sutures. Craniosynsostosis in PYCD is a somewhat paradoxical feature, and has only been rarely reported. The authors present a unique case of a 6-year-old girl with PYCD, multisuture craniosynostosis involving the coronal and sagittal sutures, severe obstructive sleep apnoea, and raised intracranial pressure presenting as papilledema. She underwent a frontofacial monobloc distraction advancement which successfully corrected her papilledema and obstructive sleep apnoea.Pycnodysostosis is caused by a loss of function mutation in the CTSK gene that codes for the lysosomal cysteine protease, cathepsin K (CTSK). Loss of CTSK impairs the ability of osteoclasts to degrade bone extracellular matrix. Differences in osteoclast phenotype and extracellular matrix composition between membranous and cartilaginous bone may explain the clinical features of PYCD. Animal model studies suggest that craniosynostosis may arise due to variations in patient genetic background. PMID- 30394970 TI - The External Jugular Vein Used as Recipient Vessel in Head and Neck Free Flap Reconstruction: Outcomes Compared to the Internal Jugular Vein. AB - BACKGROUND: Contradictory data exists on the success rates of employing the external jugular (EJ) vein as a recipient vessel for venous outflow in free flap head and neck reconstruction compared with the internal jugular (IJ) vein. The authors hereby present a retrospective study of prospectively collected data over a 14-year period. METHODS: Five hundred seventy-eight patients underwent 639 free flap head and neck over 14 years. Two hundred seventy-eight free flaps employed the EJ vein as the recipient vessel while 326 free flaps employed the IJ vein. Rates of acute and late complications were compared. RESULTS: There were no differences in rates of complications: flap loss, venous thrombosis, arterial thrombosis, bleeding, hematoma, or infection between the EJ and IJ vein groups. CONCLUSION: The external jugular vein as a recipient vessel for venous outflow in head and neck free flap reconstruction of postoncologic resection defects is a valid option for both primary reconstructions and secondary surgeries. PMID- 30394971 TI - Full-Thickness Skin Grafting for Local Defect Coverage Following Scalp Adjacent Tissue Transfer in the Setting of Cranioplasty. AB - INTRODUCTION: Numerous techniques have been described to overcome scalp deficiency and high-tension closure at time of cranioplasty. However, there is an existing controversy, over when and if a free flap is needed during complex skull reconstruction (ie, cranioplasty). As such the authors present here our experience using full-thickness skin grafts (FTSGs) to cover local defects following scalp adjacent tissue transfer in the setting of cranioplasty. METHODS: By way of an institutional review board-approved database, the authors identified patients treated over a 3-year period spanning January 2015 to December 2017, who underwent scalp reconstruction using the technique presented here. Patient demographics, clinical characteristics, technical details, outcomes, and long term follow up were statistically analyzed for the purpose of this study. RESULTS: Thirty-three patients, who underwent combined cranioplasty and scalp reconstruction using an FTSG for local donor site coverage, were identified. Twenty-five (75%) patients were considered to have "high complexity" scalp defects prior to reconstruction. Of them, 12 patients (36%) were large-sized and 20 (60%) medium-sized; 21 (64%) grafts were inset over vascularized muscle or pericranium while the remaining grafts were placed over bare calvarial bone. In total, the authors found 94% (31/33) success for all FTSGs in this cohort. Two of the skin grafts failed due to unsuccessful take. Owing to the high rate of success in this series, none of the patient's risk factors were found to correlate with graft failure. In addition, the success rate did not differ whether the graft was placed over bone verses over vascularized muscle/pericranium. CONCLUSION: In contrary to previous studies that have reported inconsistent success with full-thickness skin grafting in this setting, the authors present a simple technique with consistent results-as compared to other more complex reconstructive methods-even in the setting of highly complex scalp reconstruction and simultaneous cranioplasty. PMID- 30394972 TI - Reconstructions with Different and New Techniques of Large and Extensive Myelomeningocele Defects. AB - BACKGROUND: Myelomeningocele and/or meningocele is a defect of spine and spinal cord, and it is congenital. Although meningocele is a mild form of spina bifida, myelomeningocele is a more complex and serious form. There is a sac in both forms at the back. Difference is that myelomeningocele contains neural structures or spinal cord elements, and meningocele does not contain these neural or spinal cord elements. METHODS: Between 2012 and 2018, 77 (45 females, 32 males) newborns with myelomeningocele were operated by mean age 35 days. The O-S flap (26 patients) method was used in patients who have circular defect. The Emsen 1 flap (31 patients) was used in patients who have elliptic defect. The Emsen 2 flap (20 patients) was also used in patients who have triangular defect. Mean follow-up was 22 months (9-50 months). RESULTS: A successful tension-free closure was made with these methods. Defects of the newborn were divided the subgroups as circular, elliptic, and triangular. Hydrocephalus was detected in 19 patients. Ventriculoperitoneal shunt was done at the same time with the myelomeningocele surgical procedure. All complications were noted in patients with hydrocephalus such as cerebrospinal fluid leakage (in 8 patients), wound infection (in 3 patients), and partially wound dehiscence (in 4 patients). CONCLUSION: There are many techniques about myelomeningocele closure in literature. The problem is not number of techniques. Literature presents different geometric flap design, muscle flaps, and musculocutaneous flaps on these defects. Large or extensive skin defects need more complex flap methods, and unfortunately, number of these is too limited. Three methods on large or extensive myelomeningocele skin defects are presented in this study. With these flaps, large or extensive skin defects could be easily closed. In all techniques, major advantages are no skin grafting, no abnormal blood loss, no muscle sacrificing, short operation time, and most important one is that 1-step surgery could be sufficient. PMID- 30394973 TI - A Patient With Schimmelpenning Syndrome and Mosaic KRAS Mutation. AB - Schimmelpenning syndrome is a neurocutaneous disorder characterized by craniofacial nevus sebaceus that fall along embryonic cutaneous lines and tend to be associated with neurological, ocular, skeletal, and vascular abnormalities. We report a child with extensive nevus sebaceus of the scalp, face, and thorax and other unusual physical findings who was found to have a mosaic mutation of KRAS c.35G>A p.12D pathognomonic of Schimmelpenning syndrome. PMID- 30394974 TI - Biological Aging Parameters Can Be Improved After Autologous Adipose-Derived Stem Cell Injection. AB - Biological aging (BA) is a comprehensive assessment tool for elderly persons. The authors aimed to develop a rat model that can be used to assess BA by evaluating various blood, biochemical, and hormonal parameters and demonstrate that the intravenous administration of autologous adipose-derived stem cells (ADSCs) improves BA. Twelve elderly (aged 20 months) male Sprague-Dawley rats were used in this study and divided into 2 groups: autologous ADSC administration (n = 6) and saline administration (n = 6). The complete blood count, biochemical and hormonal parameters, and antioxidant potential were evaluated before harvesting the rat inguinal fat tissue and intravenous ADSC administration as well as at 1, 3, and 5 weeks after ADSC administration. Adipose-derived stem cells administration regulated blood content, biochemical parameters, renal function, and antioxidant enzymes in elderly rats. Furthermore, changes in several hormonal levels were identified in the ADSC administration group compared with the saline administration group. An assessment model of BA in elderly rats was successfully developed after the intravenous administration of autologous ADSCs. The authors suggest that intravenously injected ADSC treatment may be a valuable method to improve BA. PMID- 30394975 TI - The Morphology of the Infraorbital Nerve and Foramen in the Presence of an Accessory Infraorbital Foramen. AB - BACKGROUND: The accessory infraorbital foramen (AIOF) is an anatomical variation associated with the infraorbital foramen (IOF) and nerve (ION). Its occurrence and neural contents have clinical implications regarding failure of loco-regional anesthesia and risk of neural damage during surgical interventions involving the maxillary region. Thus, morphologic characterization of the AIOF and neural contents as well as the spatial relationships to the IOF are potentially useful for optimizing surgical procedures. Additionally, predictive features of the AIOF based on its relationship to IOF morphology could enable the surgeon to anticipate its presence and proceed accordingly. The purpose of this study was to determine whether the presence of an AIOF and its neural contents affected the size, shape, and composition of the IOF and ION. The specific hypothesis tested was that the topography and fascicular composition of the ION and IOF differs between individuals possessing an AIOF and those lacking this anatomical variant. METHODS: Gross topographic features of the IOF (42 crania) were compared between specimens possessing (test) or lacking (control) an AIOF. Nerve fascicles of ION (60 cadaveric sides) were examined histologically and compared morphometrically between specimens presenting or lacking an AIOF. An additional sample of 30 crania was subjected to cone-beam computed tomography (CBCT) analysis to determine the course of the canal leading to the AIOF. RESULTS: The AIOF incidence was 47.6% (20 crania) and 32.1% of the sides (27 sides). A single AIOF was observed in 24 sides and double AIOF in three sides. The AIOF occurred bilaterally in 7 specimens (16.7%). The majority of AIOF (86.7%) were located superomedial to IOF. A slightly higher frequency of the AIOF was found in left side compared to the right. Using CBCT, a patient sample showed an AIOF incidence in 21 sides of 16 patients (65.6%). A single AIOF was observed in 19 sides. Only 1 double AIOF was found in the scans, whereas 3 were found in the dry skull group. The AIOF occurred bilaterally in 3 scans (10%). The majority of AIOF (90.4%) were located superomedial to the IOF based on the CBCT scans. The AIOF was consistently seen connected to the infraorbital canal and progressed superiorly and medially from the infraorbital canal to the maxillary surface. The size of the ION without an AIOF was not significantly different than the ION in the presence of an AIOF (1.45 * 10/1.32 * 10 MUm, P < 0.35) based on fascicular area. However, the number of ION fascicles was greater in specimens without an AIOF compared to those showing this feature (15.15/12.71, P < 0.04) CONCLUSION:: Results indicate that the area of the ION is not affected by an AIOF, suggesting that the field of innervation of this area is not modified by its occurrence. However, the ION appears to divide more proximally into its component branches when the AIOF is present. PMID- 30394976 TI - Tranexamic Acid Decreases Blood Transfusion Burden in Open Craniosynostosis Surgery Without Operative Compromise. AB - In the surgical management of craniosynostosis, there is a high red blood cell (RBC) transfusion burden due to the small blood volume of the patients combined with significant blood loss that can occur with open surgery (OS). Tranexamic acid (TXA) is an antifibrinolytic which has been shown to decrease such a burden in particular surgeries. The aim of this study was to compare the operative outcomes of craniosynostosis OS which did and did not utilize TXA. Searches of 7 electronic databases from inception to February 2018 were conducted following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. There were 206 articles screened against selection criteria for inclusion. Relevant data were extracted and analyzed using meta-analysis of proportions. A total of 9 comparative studies were included for meta-analysis. Compared with the control cohort, craniosynostosis OS utilizing TXA demonstrated significantly lower intraoperative RBC transfusion volumes (mean difference, 8.25 mL/kg; P < 0.001), blood loss (mean difference, -10.96 mL/kg; P < 0.001) and postoperative RBC transfusion incidence (odds ratio, OR, 0.12; P = 0.005). Fresh frozen plasma and crystalloid transfusion, operation time, length of stay, and complications were not significantly different with TXA use. Based on the comparative evidence currently available, TXA significantly decreased RBC transfusion burden during craniosynostosis OS without operative compromise. There is significant heterogeneity in reported TXA regimes in the literature. Future studies that are larger, randomized, and account for these factors will further enhance the authors' understanding. PMID- 30394977 TI - Trichoepithelioma Misdiagnosed as Basal Cell Carcinoma. AB - Trichoepithelioma is a benign tumor which can be easily confused with basal cell carcinoma. Since both tumors are histologically similar, it is important to distinguish them correctly as the courses for treatment are very different. Basal cell carcinoma is malignant; therefore, it requires total surgical excision, including a wide healthy margin. In contrast, trichoepithelioma requires only simple excision. A study involving a 69-year-old woman with a simple mass on the nasal tip was described in this study. On examination, a single skin-colored, round protruding mass (approximately 0.5 * 0.5 cm) was observed. Simple excision was performed and basal cell carcinoma was diagnosed at the initial biopsy. However, clinically, we considered it to be a benign tumor; therefore, we sought a histologic reconfirmation. Consequently, trichoepithelioma was diagnosed on histopathologic examination. When a small, round protruding simple mass is histologically diagnosed to be a basal cell carcinoma, it is important to suspect trichoepithelioma and seek histologic reconfirmation. PMID- 30394978 TI - The Influence of Trabectome Surgery on Corneal Endothelial Cells. AB - PURPOSE: To evaluate the influence of Trabectome surgery on corneal endothelial cells by site METHODS:: Retrospective observational study. Trabectome surgeries were performed on 159 eyes of 132 adult Japanese patients. Corneal endothelial cells were measured at the center (C), inferior (I), nasal inferior (NI), nasal superior (NS), superior (S), temporal superior (TS), and temporal inferior (TI) sectors at <1 month preoperatively and 3, 6, 12, 24, and 36 months postoperatively, for changes in corneal endothelial cell density (ECD), coefficient of variation (CV), and incidence of hexagonal cells (6A). RESULTS: Mean preoperative ECD in all groups were 2401+/-451 (SD) cells/mm (C), 2366+/-450 cells/mm (I), 2397+/-479 cells/mm (NI), 2476+/-554 cells/mm (NS), 2493+/-596 cells/mm (S), 2464+/-558 cells/mm (TS), and 2329+/-510 cells/mm (TI). The 12 month postoperative mean ECDs were 2344+/-480 cells/mm (C), 2312+/-469 cells/mm (I), 2325+/-536 cells/mm (NI), 2473+/-517 cells/mm (NS), 2438+/-607cells/m cells/mm (S), 2227+/-578cells/m cells/mm (TS), and 2193+/-523 cells/mm (TI). There was no change in ECD in all sectors before and after surgery. ECD decreased at the TS and TI in combination with cataract surgery (2620+/-430 and 2445+/-384 cells/mm ) preoperatively to 2264+/-501 and 2216+/-477 cells/mm at 12 months postoperatively. CV and 6A did not change at all sites in all surgical procedures before and after surgery. CONCLUSIONS: Trabectome surgery involves minimal effects to corneal endothelial cells, although long-term prospective studies with greater sample sizes are necessary to confirm this conclusion. PMID- 30394979 TI - Smaller-incision Revision of Trabeculectomy With Mitomycin: Long-term Outcomes and Complications. AB - PURPOSE: To assess long-term outcomes and complications of smaller-incision trabeculectomy revision with mitomycin (MMC) in glaucoma patients. METHODS: Review of patients undergoing trabeculectomy revision with MMC for inadequate intraocular pressure (IOP) control. After dissection of subconjunctival fibrosis through a smaller (median 5?mm) incision, MMC was topically applied and episcleral fibrosis was incised. Failure was defined as reoperation for glaucoma, or IOP reduction < 20% over 3 follow up visits. RESULTS: Forty eyes (40 patients; mean age 67+/-13?y) underwent revision; 9 revisions were combined with other surgery. Mean baseline IOP was 20.6+/-6.2?mm Hg on 2.6+/-1.4 glaucoma medications after 2.4+/-1.3 incisional ocular surgeries. At final follow-up (70+/-34?mo), 27 successful eyes (67.5%) had IOP of 9.2+/-2.4?mm Hg on 0.6+/-0.9 medications. Eleven eyes (27.5%) required reoperation for glaucoma, 7 (63%) within 7 months after revision. The Kaplan-Meier estimate of success at years 1, 2, 3, and 5 postoperatively was 77.5%, 72.2%, 69.5%, and 69.5% respectively. Recovery of visual acuity to within 2 lines of baseline was 1.7+/-2.4 weeks (median 1). Complications included sustained hypotony (IOP <=5?mm Hg) in 2 eyes (1 also with corneal decompensation), 1 eye with wound leak, and 2 eyes with bleb leak (1 requiring surgical repair). CONCLUSIONS: Smaller-incision trabeculectomy revision with MMC resulted in substantial, sustained IOP reduction in most eyes with poorly functioning filtering blebs, with few serious complications and rapid recovery of baseline visual acuity in most eyes. PMID- 30394980 TI - Melatonin Levels in Patients with Primary Open Angle Glaucoma with High or Low Intraocular Pressure. AB - PURPOSE: To evaluate circulatory melatonin levels by assessing nocturnal urinary excretion of 6-sulfatoxymelatonin (aMT6s) in patients with primary open angle glaucoma (POAG) and to compare the high-tension group and the low-tension group. METHODS: This study included 80 eyes of 41 POAG patients and 87 eyes of 44 control subjects. POAG group was further classified into high-tension group and low-tension group according to the pretreatment intraocular pressure. The first urine in the morning was collected and aMT6s were measured using a commercial ELISA kit. Urinary aMT6s levels were expressed as ng aMT6s/mg creatinine. Differences in melatonin levels among the control and POAG subgroups were evaluated by generalized estimating equation adjusting age, sex, sleep duration, and inter-eye correlation. RESULTS: Urinary aMT6s/creatinine ratio did not differ between POAG and control group (P=0.097). The difference in the aMT6s/creatinine ratio between the three groups- high-tension group with baseline intraocular pressure (IOP) >=21?mmHg (19.74+/-3.12?ng/mg), low-tension glaucoma group with baseline IOP < 21?mmHg (26.71+/-3.47?ng/mg), and control group (30.35+/ 3.05?ng/mg)-was statistically significant (P=0.046). Post hoc analysis revealed that the difference between the control and high-tension glaucoma groups was significant (P=0.014), while the difference between the control and low-tension glaucoma groups was not (P=0.436). CONCLUSION: This study found low melatonin levels in high-tension glaucoma compared with the control. PMID- 30394981 TI - Variation in Laboratory Test Naming Conventions in EHRs Within and Between Hospitals: A Nationwide Longitudinal Study. AB - BACKGROUND: Electronic health records provide clinically rich data for research and quality improvement work. However, the data are often unstructured text, may be inconsistently recorded and extracted into centralized databases, making them difficult to use for research. OBJECTIVES: We sought to quantify the variation in how key laboratory measures are recorded in the Department of Veterans Affairs (VA) Corporate Data Warehouse (CDW) across hospitals and over time. We included 6 laboratory tests commonly drawn within the first 24 hours of hospital admission (albumin, bilirubin, creatinine, hemoglobin, sodium, white blood cell count) from fiscal years 2005-2015. RESULTS: We assessed laboratory test capture for 5,454,411 acute hospital admissions at 121 sites across the VA. The mapping of standardized laboratory nomenclature (Logical Observation Identifiers Names and Codes, LOINCs) to test results in CDW varied within hospital by laboratory test. The relationship between LOINCs and laboratory test names improved over time; by FY2015, 109 (95.6%) hospitals had >90% of the 6 laboratory tests mapped to an appropriate LOINC. All fields used to classify test results are provided in an Appendix (Supplemental Digital Content 1, http://links.lww.com/MLR/B635). CONCLUSIONS: The use of electronic health record data for research requires assessing data consistency and quality. Using laboratory test results requires the use of both unstructured text fields and the identification of appropriate LOINCs. When using data from multiple facilities, the results should be carefully examined by facility and over time to maximize the capture of data fields. PMID- 30394982 TI - Nocturnal blood pressure measured by home devices: evidence and perspective for clinical application. AB - : Studies using ambulatory blood pressure (BP) monitoring have shown that BP during night-time sleep is a stronger predictor of cardiovascular outcomes than daytime ambulatory or conventional office BP. However, night-time ambulatory BP recordings may interfere with sleep quality because of the device cuff inflation and frequency of measurements. Hence, there is an unmet need for obtaining high quality BP values during sleep. In the last two decades, technological development of home BP devices enabled automated BP measurements during night time. Preliminary data suggest that nocturnal home BP measurements yield similar BP values and show good agreement in detecting nondippers when compared with ambulatory BP monitoring. Thus, nocturnal home BP measurements might be a reliable and practical alternative to ambulatory BP monitoring to evaluate BP during sleep. As the use of home BP devices is widespread, well accepted by users and has relatively low cost, it may prove to be more feasible and widely available for routine clinical assessment of nocturnal BP. At present, however, data on the prognostic relevance of nocturnal BP measured by home devices, the optimal measurement schedule, and other methodological issues are lacking and await further investigation. This article offers a systematic review of the current evidence on nocturnal home BP, highlights the remaining research questions, and provides preliminary recommendations for application of this novel approach in BP management.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc nd/4.0. PMID- 30394983 TI - Emergent Colon Resections: Does Surgeon Specialization Influence Outcomes? AB - BACKGROUND: Relationships between high-volume surgeons and improved postoperative outcomes have been well documented. Colorectal procedures are often performed by general surgeons, particularly in emergent settings, and may form a large component of their practice. The influence of subspecialized training on outcomes after emergent colon surgery, however, is not well described. OBJECTIVE: The purpose of this study was to determine whether subspecialty training in colorectal surgery is associated with differences in postoperative outcomes after emergency colectomy. DESIGN: This was a retrospective cohort study. SETTINGS: Three tertiary care hospitals participating in the National Surgical Quality Improvement Project were included. PATIENTS: Patients undergoing emergent colon resections were identified at each institution and stratified by involvement of either a colorectal surgeon or a general or acute care surgeon. MAIN OUTCOME MEASURES: Propensity score matching was used to isolate the effect of surgeon specialty on the primary outcomes, including postoperative morbidity, mortality, length of stay, and the need for unplanned major reoperation, in comparable cohorts of patients. RESULTS: A total of 889 cases were identified, including 592 by colorectal and 297 by general/acute care surgeons. After propensity score matching, cases performed by colorectal surgeons were associated with significantly lower rates of 30-day mortality (6.7% vs 16.4%; p = 0.001), postoperative morbidity (45.0% vs 56.7%; p = 0.009), and unplann?ed major reoperation (9.7% vs 16.4%; p = 0.04). In addition, length of stay was ~4.4 days longer among patients undergoing surgery by general/acute care surgeons (p < 0.001). LIMITATIONS: This study was limited by its retrospective design, with potential selection bias attributed to referral patterns. CONCLUSIONS: After controlling for underlying disease states and illness severity, emergent colon resections performed by colorectal surgeons were associated with significantly lower rates of postoperative morbidity and mortality when compared with noncolorectal surgeons. These findings may have implications for referral patterns for institutions. See Video Abstract at http://links.lww.com/DCR/A767. PMID- 30394984 TI - A Changing Spectrum of Colorectal Cancer Biology With Age: Implications for the Young Patient. AB - BACKGROUND: The methylator pathway of colorectal carcinogenesis, characterized by CpG island hypermethylation and BRAF mutations, accounts for ~25% of colorectal cancers. Because these cancers tend to be right sided and because DNA methylation in the right colon increases with age, we expect an increasing proportion of right-sided cancer over time. Conversely, we expect young patients (age <50 y) to have less methylated and fewer right-sided cancers OBJECTIVE:: The purpose of this study was to analyze the distribution and genetic traits of colorectal cancer from different age groups. DESIGN: This was a retrospective cohort study. SETTING: The study was conducted at a high-volume tertiary referral center. PATIENTS: Patient samples included those from our colorectal cancer biobank of resected colorectal cancer specimens. MAIN OUTCOME MEASURES: Tumor CpG island hypermethylation, microsatellite instability, and mutations in KRAS and BRAF oncogenes were analyzed in resected specimens and stratified by age and tumor location. Comparisons included age >50 or <50 years and decade of diagnosis (<=50, 51-60, 61-70, 71-80, and >81 y). Patients with IBD or hereditary syndromes were excluded. RESULTS: A total of 497 colorectal cancers were analyzed (266 men and 231 women); 57 patients (11.5%) were <=50 years of age. No young cancers (0/57) were hypermethylated compared with 97 (22%) of 440 cancers of patients aged >50 years (p < 0.001). An increasing percentage of tumors were CpG island phenotype high with each decade of age at diagnosis. No cancers in patients <50 years of age were microsatellite unstable compared with 91 (23.6%) of 346 for those >50 years of age. No young cancers contained a BRAF mutation compared with 46 (10.6%) of 434 in older cancers (p < 0.001). KRAS mutations were less common in young cancers compared with older cancers (13/57 (22.8%) vs 126/410 (30.7%); p < 0.01). Eleven (19.3%) of 57 young cancers were proximal compared with 228 (51.8%) of 440 (p < 0.001) older cancers. LIMITATIONS: This study was limited by its retrospective design. CONCLUSIONS: The lack of CpG island methylator phenotype tumors in young patients is consistent with the dominant left-sided cancer distribution seen in the young and focuses efforts to understand and prevent cancer in this age group on causes of chromosomal instability. See Video Abstract at http://links.lww.com/DCR/A709. PMID- 30394985 TI - Consequences of Increasing Complexity in Anorectal Surgery Performed at an Academic Center. AB - BACKGROUND: Anorectal surgery encompasses a wide range of procedures with varying complexity. The Accreditation Council for Graduate Medical Education Review Committee for Colon and Rectal Surgery recommends minimum case numbers (60) for 1 year specialty trainees in 6 categories of anorectal surgery, with definitions for procedural complexity. OBJECTIVE: The purpose of this study was to assess the scope of anorectal procedures and propose a stratification of procedures based on a consensus of levels of difficulty, as well as to identify a predictive charge cutoff suggestive of procedural complexity. DESIGN: This was a retrospective review. SETTINGS: The study was conducted at a tertiary academic center. PATIENTS: Patients undergoing anorectal procedures between January 2011 and December 2014 identified by Current Procedural Terminology coding were entered into 6 categories. Codes were stratified as routine or complex based on an assessment of perioperative care and technical expertise required. Patients with an abdominal portion to any procedure were excluded. MAIN OUTCOMES MEASURES: The study measured distribution of complexity in anorectal surgical procedures and procedural charge associated with differentiating routine from complex procedures. RESULTS: Seven colorectal surgeons performed 2483 anorectal procedures (mean = 620 per year). Mean age was 48 +/- 16 years. Forty six (64%) of 71 procedures were classified as routine and 25 (36%) of 71 as complex. Most disease processes had subsets with routine or complex procedures, whereas all of the procedures performed for fecal incontinence or advanced anorectal techniques were considered complex. Fistula procedures and transanal excisions were most heterogeneous, with a high procedural complexity rate (37% and 50%). After a procedural complexity rating, intraclass correlation by 6 surgeons was 0.70, demonstrating good correlation. Receiver operating curve assessments of consensus categorization according to billing codes revealed $553 as the optimal cutoff between routine and complex procedures. LIMITATIONS: This was a single institution retrospective review. CONCLUSIONS: Colorectal residents may benefit from anorectal case stratification, because it serves as a dialogue for those interested in complex anorectal surgery during training. Surgeon categorization of procedures correlates well with a charge-based model of complexity. See Video Abstract at http://links.lww.com/DCR/A806. PMID- 30394986 TI - A Decision Analysis for Rectal-Sparing Familial Adenomatous Polyposis: Total Colectomy With Ileorectal Anastomosis Versus Proctocolectomy With IPAA. AB - BACKGROUND: There are different approaches for the surgical management of rectal sparing familial adenomatous polyposis with variable impacts on both quality of life and survival. OBJECTIVE: The aim of this study was to quantify the trade offs between total proctocolectomy with IPAA versus total colectomy with ileorectal anastomosis using decision analysis. DESIGN: We created a disease simulation Markov model to simulate the clinical events after IPAA and ileorectal anastomosis for rectal-sparing familial adenomatous polyposis in a cohort of individuals at the age 30 years. We used available literature to obtain different transition probabilities and health-states utilities. The output parameters were quality-adjusted life-years and life-years. Deterministic and probabilistic sensitivity analyses were performed. SETTINGS: A decision analysis using a Markov model was conducted at a single center. PATIENTS: Patients with rectal-sparing familial adenomatous polyposis at age 30 years were included. Rectal-sparing familial adenomatous polyposis is defined as the presence of 0 to 20 polyps that can be removed endoscopically. MAIN OUTCOME MEASURES: Quality-adjusted life-years were measured. RESULTS: Our model showed that the mean quality-adjusted life years for IPAA was 25.12 and for ileorectal anastomosis was 27.12 in base-case analysis. Mean life-years for IPAA were 28.81 and 28.28 for ileorectal anastomosis. A 1-way sensitivity analysis was performed for all of the parameters in the model. None of the deterministic sensitivity analyses changed the model results across the range of plausible values. Probabilistic analysis identified that, in 86.9% of scenarios, ileorectal anastomosis had improved quality-adjusted life-years compared with IPAA. LIMITATIONS: The study was limited by characteristics inherent to modeling studies. CONCLUSIONS: Ileorectal anastomosis was found to be preferable for patients with rectal-sparing familial adenomatous polyposis when quality of life is taken into consideration. This model was robust based on both deterministic and probabilistic sensitivity analyses. These data should be taken into consideration when counseling patients regarding a surgical approach in rectal-sparing familial adenomatous polyposis. See Video Abstract at http://links.lww.com/DCR/A715. PMID- 30394987 TI - Low Anterior Resection Syndrome and Quality of Life After Sphincter-Sparing Rectal Cancer Surgery: A Long-term Longitudinal Follow-up. AB - BACKGROUND: Despite low anterior resection syndrome being a well-known consequence of sphincter-preserving rectal cancer surgery, the long-term effect on bowel function and quality of life is not fully understood. OBJECTIVE: This study aimed to elucidate whether symptoms of low anterior resection syndrome change over time and if the correlation to quality of life is equivalent when measured at 2 time points. DESIGN: This prospective cohort study included measurements at 2 time points (5 years between; range, 7.1-16.1 years from surgery to second follow-up). SETTINGS: This multicenter study included patients from Sweden and Denmark. PATIENTS: Patients were included if they were >=18 years of age and underwent curative rectal cancer surgery with either total or partial mesorectal excision. MAIN OUTCOME MEASURES: Outcomes were measured with the low anterior resection syndrome questionnaire including a question assessing the impact of bowel function on quality of life and with the validated quality-of life questionnaire EORTC QLQ-C30. RESULTS: In total, 282 patients were included and there were no statistically significant differences in the distribution among the 3 groups (no, minor, and major low anterior resection syndrome) when comparing time points follow-up 1 with follow-up 2 (p = 0.455). At follow-up 2, 138 patients (49%) still experienced major impairment. No both statistically and clinically significant differences were seen in the mean score of EORTC QLQ-C30 when comparing the same low anterior resection syndrome group at follow-up 1 and follow-up 2, and the impact on quality of life was comparable. Global health status/quality of life was impaired in the major low anterior resection syndrome group at both follow-up 1 (p < 0.001) and follow-up 2 (p < 0.001). LIMITATIONS: The study design prevents an evaluation of causality. CONCLUSIONS: Difficulties with low anterior resection syndrome and the impact on patients' quality of life persist over time. See Video Abstract at http://links.lww.com/DCR/A762. PMID- 30394988 TI - Local Excision Versus Radical Resection for 1- to 2-cm Neuroendocrine Tumors of the Rectum: A National Cancer Database Analysis. AB - BACKGROUND: The optimal surgical management for 1- to 2-cm, nonmetastatic rectal neuroendocrine tumors remains unknown. OBJECTIVE: We sought to determine overall survival and operative outcomes in patients who underwent local excision versus radical resection of rectal neuroendocrine tumors. DESIGN: The National Cancer Database (2004-2013) was queried to identify patients with nonmetastatic rectal neuroendocrine tumors who underwent local excision or radical resection. SETTING: The study included national data. PATIENTS: There were 274 patients in the local excision group and 47 patients in the radical resection group. MAIN OUTCOME MEASURES: The primary outcome was overall survival. Secondary outcomes included 30-day mortality, hospital length of stay, and procedural outcomes. RESULTS: There were no differences in demographics between the 2 groups. Patients who underwent radical resection had slightly larger tumors with higher stage and grade. Patients undergoing local excision had higher rates of positive margins (8.23% vs 0%; p = 0.04). There were no deaths within 30 days in either group, but patients who had radical resection had longer median hospital length of stay (0 vs 3 d; p < 0.01). After adjusting with a Cox proportional hazards model, no difference was seen in survival between the 2 patient groups (HR = 2.39 (95% CI, 0.85-6.70); p = 0.10). LIMITATIONS: There are several limitations, which include that this work is a retrospective review; the data set does not include variables such as depth of tumor invasion, which may influence surgical treatment or local recurrence rates; and patients were not randomly assigned to treatment groups. CONCLUSIONS: There is no survival benefit to radical resection of 1- to 2-cm, nonmetastatic rectal neuroendocrine tumors. This suggests that local excision may be a feasible and less morbid option for intermediate-sized rectal neuroendocrine tumors. See Video Abstract at http://links.lww.com/DCR/A744. PMID- 30394989 TI - Seeing From the Eyes of the Beholder: A Pilot Program for Learning Through Reflection in Graduate Nursing Education. AB - A key element in the comprehensive physical exam is the patient interview in which the nurse practitioner (NP) elicits information from the patient to help guide in the discovery of a health issue. Technologies that allow the NP student to view patient interviews from the patient's perspective may enhance interviewing techniques and promote therapeutic interview behaviors. We report the results of a pilot program for NP students enrolled in an advanced health assessment course. Student volunteers conducted interviews with patient actors. Actors wore Google Glass(r), an optical head-mounted device with video-recording capabilities. PMID- 30394990 TI - Biometry in cataract surgery: a review of the current literature. AB - PURPOSE OF REVIEW: To review the literature in 2017 and 2018 pertaining to biometry for cataract surgery and report pertinent findings. RECENT FINDINGS: New devices using swept-source ocular coherence tomography can measure axial length in dense cataracts more frequently than common biometers. Computer-assisted registration may be superior to intraoperative aberrometry for toric intraocular lens (IOL) placement. Soft contact lenses may not require removal as long before biometry as previously thought. The Barrett Universal II IOL formula has been found to perform well at all axial lengths. SUMMARY: New swept-source ocular coherence tomography biometers are more frequently successful at measuring axial length in dense cataracts which promises to improve refractive outcomes. Accuracy in toric IOL placement is likely to increase with improved devices. It may not be necessary to have patients remove soft contact lens any more than 2 days prior to biometry. The Barrett Universal II IOL formula may be used confidently for most eyes. Advancements acknowledged, purchasing new equipment will not be necessary for all surgeons. PMID- 30394991 TI - Advances in capsulorhexis. AB - PURPOSE OF REVIEW: Continuous curvilinear manual capsulorhexis is currently the standard of cataract surgery. In the past several years, new technologies have been developed to improve the consistency and safety of capsulorhexis creation. This article reviews the most recent technologies in capsulotomy formation and their advantages and disadvantages. RECENT FINDINGS: Guidance devices, femtosecond laser capsulotomy and precision pulse capsulotomy improve the centration, circularity and precision of anterior capsulorhexis and capsulotomy. These developments show particular promise for complex cataract surgeries, though clinical data on the refractive outcomes and complication rates of these technologies are currently limited and warrant additional investigation. SUMMARY: New technological advances in capsulorhexis help surgeons achieve a more ideal capsulotomy geometry. Whether this translates into more predictable refractive outcomes and safer surgeries remains an area of future study. PMID- 30394992 TI - Anterior Wall Success at 1 Year After Vaginal Uterosacral Ligament Suspension and Sacral Colpopexy. AB - OBJECTIVES: The primary objective was to evaluate 1-year anterior wall anatomic success rates for vaginal uterosacral ligament suspension (USLS) and minimally invasive sacral colpopexy (SCP) using delayed-absorbable suture. Secondary objectives included assessment of apical success, mesh or suture exposure, and postoperative quality of life (QoL) measures 12 months after surgery. METHODS: This was a retrospective cohort study including women who underwent a hysterectomy with concomitant USLS or SCP with delayed-absorbable suture from January 2011 to December 2015 with 1-year follow-up. Successful anterior vaginal wall support was defined as Ba of less than 0. Successful apical support was defined as no apical descent (point C) greater than one half of the total vaginal length. In addition, 1-year QoL questionnaires were measured postoperatively. RESULTS: A total of 282 women were identified. Sixty-two women (31 vaginal USLS and 31 SCP) met inclusion criteria. Demographics were similar between groups except for a higher body mass index in the USLS group (27.5 +/- 5.6 kg/m vs 24.1 +/- 3.3 kg/m, P < 0.05). Preoperative POP-Q was mostly stage II and III. At 1 year, anatomic success rates for the anterior compartment were 66.7% versus 90.3% for USLS and SCP groups, respectively (P = 0.02). There was no significant difference in apical success (P = 1.00) or QoL scores between groups at 1 year. CONCLUSIONS: Anatomic success rates at 1 year using delayed-absorbable suture were better for SCP when using the anterior wall as a measure of success, but there were no significant differences in apical success rates, mesh or suture exposure, and QoL measures between groups. PMID- 30394993 TI - Toxic Leukoencephalopathy Presenting as Lethal Catatonia. AB - INTRODUCTION: Catatonia is a syndrome that can present in different forms and can occur in multiple psychiatric and somatic conditions. This case report describes lethal catatonia caused by delayed toxic leukoencephalopathy after excessive use of cocaine and methadone. The characteristic radiographic imaging and biphasic course are discussed. CASE REPORT: A 54-year-old woman was presented unconsciously at the emergency department after intoxication with methadone and cocaine. After initial recovery, her condition deteriorated unexpectedly, resulting in lethal catatonia. Magnetic resonance imaging (MRI) showed hyperintense white matter abnormalities and diffusion restriction, evident for leukoencephalopathy. DISCUSSION: Catatonia can develop in multiple psychiatric and somatic diseases, including toxic leukoencephalopathy. A biphasic course and specific MRI findings are characteristics for delayed toxic leukoencephalopathy, due to intoxication with drugs. PMID- 30394994 TI - Pregnancy Intention, Risk Perception, and Contraceptive Use in Pregnant Women Who Use Drugs. AB - OBJECTIVES: The aim of the study was to evaluate pregnancy intention, risk perception, and contraceptive utilization among women reporting substance use during pregnancy. METHODS: Data were obtained from the 2009 to 2011 Tennessee Pregnancy Risk Assessment Monitoring System (PRAMS), an annual cross-sectional survey which assesses behaviors before, during and after pregnancy. Substance use during pregnancy and contraceptive use at the time of conception and after delivery were captured by self-report in the postpartum period. Pregnancy intention was categorized as intended (pregnancy desired then or earlier) or unintended (pregnancy desired later or not at all). Weighted descriptive and multivariable analyses were performed. RESULTS: A total of 3042 women completed the PRAMS survey, with 168 (5.4%) reporting substance use during pregnancy. Compared with women who did not report drug use, women who used drugs were more likely to have an unintended pregnancy (65.6% vs 48.4%, P = 0.003), were more ambivalent towards pregnancy planning or prevention (69.7% vs 46.2%, P < 0.001) and were less likely to report contraceptive use before pregnancy (31.3% vs 46.8%, P = 0.022) or in the postpartum period (79.6% vs 88.1%, P = 0.019). Finally, women reporting substance use in pregnancy had 2 times higher odds of reporting that they did not think they could get pregnant at the time of conception after adjusting for age, race, income, education, insurance, and smoking status (adjusted OR 2.18, 95% confidence interval 1.07-4.49, P = 0.033). CONCLUSIONS: Women who report substance use in pregnancy have unique reproductive health needs and would benefit from additional education and counseling concerning their pregnancy intention, contraceptive use, and ability to conceive. PMID- 30394995 TI - Factors Associated With Marijuana Use Among Treatment-seeking Adult Cigarette Smokers in the Criminal Justice Population. AB - OBJECTIVES: Due to the elevated rates of cigarette use and marijuana use within the criminal justice system, it is critical to develop a stronger understanding of tobacco and marijuana co-use among this population to inform future interventions. METHODS: This study is a secondary analysis of baseline data from a smoking cessation randomized clinical trial of adults (n = 500) in a community correction program. Participants were classified as using cigarettes only or both cigarettes and marijuana through either self-report or positive urine drug screening. Demographics and measures regarding legal, drug use, smoking, mental health, and interpersonal histories were assessed. Logistic regression analyses were conducted to assess factors associated with co-use. RESULTS: Among adults who smoked cigarettes, 25% reported current marijuana use. Individuals who used both cigarettes and marijuana were more likely than those who only used cigarettes to be African American (80%), male (73.6%), and younger (M = 32.4 [SD = 11.0]). Increasing difficulties with last quit attempt was associated with a reduction in the likelihood of co-use (odds ratio [OR] 0.75, 95% confidence interval [CI] 0.60-0.94, P < 0.05), and benzodiazepine (OR 9.09, 95% CI 1.25 65.94, P < 0.05) and opioid (OR 8.17, 95% CI 2.03-32.93, P < 0.01) use was significantly associated with an increased likelihood of co-use. CONCLUSIONS: This study identified several factors that are associated with an increased risk of cigarette and marijuana co-use among a community correction population. These findings will be valuable for informing targeted prevention and treatment interventions. PMID- 30394996 TI - Can Mobile Devices Be Used as an Active Learning Strategy? Student Perceptions of Mobile Device Use in a Nursing Course. AB - BACKGROUND: It can be challenging to engage prelicensure nursing students in theoretical, nonclinical courses. PURPOSE: The purpose of this study was to describe students' experiences with various teaching strategies and describe student perceptions of engagement and learning using a mobile device. METHODS: The study had a mixed-methods design, which included an online survey and oral interviews to elicit student perceptions of engagement and learning using a mobile device. RESULTS: Students, on average, reported high levels of perceived learning and moderate levels of perceived engagement. Analysis of the qualitative transcripts revealed 2 major themes clustered around learner practices and instructor/course practices. CONCLUSIONS: Overall, students reported that using the mobile devices was a positive experience. Students benefited from thoughtful, intentional mobile device use that engaged them with course ideas, limited off task distractions, and improved collaborative experiences with peers and the instructor. PMID- 30394997 TI - The Meaning of Grades: Stories of Undergraduate, Master's, and Doctoral Nursing Students. AB - BACKGROUND: Although the literature is replete with information about grades, there is a lack of empirical evidence about the meaning of grades to nursing students. PURPOSE: This study sought to understand the meaning of grades for nursing students at all educational levels. METHOD: Using Heideggerian hermeneutic phenomenology, 46 nursing students from 14 schools were asked to tell about a time that stood out to them when they were graded. They then reflected on their story and described what this experience meant to them. RESULTS: Data analysis revealed several themes. The main theme was "needing an A." It was discussed by students at every level of nursing education. CONCLUSIONS: Students not only needed to get an A, but also they needed to get an A in every course they took, causing stress and disappointment when they were unable to achieve these grades. It seemed that what they were learning was not as important as the grade they received. PMID- 30394998 TI - Care Bundles, QSEN, and Student Learning. PMID- 30394999 TI - Use of Script Concordance Activity With the Think-Aloud Approach to Foster Clinical Reasoning in Nursing Students. AB - BACKGROUND: Script concordance testing and the think-aloud (TA) approach uses clinical scenarios to evaluate clinical reasoning (CR). PROBLEM: Teaching strategies to both facilitate and evaluate CR are lacking. Adaptation of script concordance testing and the TA approach may be a useful teaching/learning strategy for CR. APPROACH: Script concordance activity with the TA approach (SCA TA method) was created and implemented in a nursing course to facilitate and evaluate CR. EVALUATION: Survey data provided valuable information of students' perception about the SCA-TA method as a teaching strategy. CONCLUSIONS: The SCA TA method holds promise to foster CR. Ongoing research to predict progression of CR is needed. PMID- 30395000 TI - Multicenter Test of an Emergency Department Trigger Tool for Detecting Adverse Events. AB - OBJECTIVES: Traditional approaches to safety and quality screening in the emergency department (ED) are porous and low yield for identifying adverse events (AEs). A better approach may be in the use of trigger tool methodology. We recently developed a novel ED trigger tool using a multidisciplinary, multicenter approach. We conducted a multicenter test of this tool and assess its performance. METHODS: In design and participants, we studied the ED trigger tool for a 13-month period at four EDs. All patients 18 years and older with Emergency Severity Index acuity levels of 1 to 3 seen by a provider were eligible. Reviewers completed standardized training modules. Each site reviewed 50 randomly selected visits per month. A first-level reviewer screened for presence of predefined triggers (findings that increase the probability of an AE). If no trigger is present, the review is deemed complete. When present, a trigger prompts an in-depth review for an AE. Any event identified is assigned a level of harm using the Medication Event Reporting and Prevention (MERP) Index, ranging from a near miss (A) to patient death (I). Events are noted as present on arrival or in the ED, an act of commission or omission, and are assigned one of four event categories. A second-level physician performs a confirmatory review of all AEs and independently reviews 10% of cases to estimate the false-negative rate. All AEs or potential AEs were reviewed in monthly group calls for consensus on findings. The primary outcome is the proportion of visits in which an AE is identified, overall and by site. Secondary outcomes include categories of events, distribution of harm ratings, and association of AEs with sociodemographic and clinical factors and triggers. We present sociodemographic data and details about AEs and results of logistic regression for associations of AEs with of triggers, sociodemographics, and clinical variables. RESULTS: We captured 2594 visits that are representative, within site, of their patient population. Overall, the sample is 64% white, 54% female, and with a mean age of 51. Variability is observed between sites for age, race, and insurance, but not sex. A total of 240 events were identified in 228 visits (8.8%) of which 53.3% were present on arrival, 19.7% were acts of omission, and 44.6% were medication-related, with some variability across sites. A MERP F score (contributing to need for admission, higher level of care, or prolonged hospitalization) was the most common severity level (35.4% of events). Overall, 185 (77.1%) of 240 events involved patient harm (MERP level >= E), affecting 175 visits (6.7%). Triggers were present in 951 visits (36.6%). Presence of any trigger was strongly associated with an AE (adjusted odds ratio = 4.6, 95% confidence interval = 3.2-6.6). Ten triggers were individually associated with AEs (adjusted odds ratio = 2.1-7.7). Variability was observed across sites in individual trigger associations, event rates, and categories, but not in severity ratings of events. The overall false-negative rate was 6.1%. CONCLUSIONS: The trigger tool approach was successful in identifying meaningful events. The ED trigger tool seems to be a promising approach for identifying all-cause harm in the ED. PMID- 30395001 TI - Pediatric trigger thumb caused by a flexor tendon sheath ganglion. AB - Pediatric trigger thumb is a common reason for toddlers to present to a pediatric orthopaedic surgeon. There is controversy over the precise etiology and optimal treatment method. Current accepted diagnostic and treatment algorithms in children have not varied based on etiology. This report describes the clinical presentation and care of a 3-year-old child with pediatric trigger thumb and surgical findings of a large flexor tendon sheath ganglion at the level of the annular pulley with no apparent nodule within the FPL. The potential implications for consideration of etiology in current diagnostic and treatment guidelines are discussed. PMID- 30395002 TI - Postanesthesia alteration of lower limb contractures in children with spastic cerebral palsy. AB - The aim of this study was to clarify the effects of general anesthesia (GA) on joint range of motion (ROM) in children with spastic cerebral palsy (SCP). Eighty four SCP cases (mean age 8.4 years) admitted for first corrective surgery were retrospectively reviewed. Lower limb ROM were measured 1 day before operation and immediately after GA. Contracture of hip, knee, and ankle joints decreased significantly after GA, with +11.1 degrees (39.5%) for the hip abduction angle, 3.7 degrees (18.0%) for the Thomas test, -15.0 degrees (19.1%) for the popliteal angle, +6.6 degrees (39.8%) and 7.0 degrees (109%) for ankle dorsiflexion with knee flexion and extension, respectively (all P<0.001). These changes were correlated positively to pre-GA contracture and body weight, negatively to age, but independent of preoperative functional level, geographic classification of SCP, or modified Ashworth scale. On the basis of these findings, routine post-GA reassessments of joint ROM before corrective surgeries were recommended for pediatric SCP cases. PMID- 30395003 TI - Gross Motor Function Classification System Specific Growth Charts-Utility as a Risk Stratification Tool for Surgical Site Infection Following Spine Surgery. AB - BACKGROUND: There is currently minimal evidence that preoperative malnutrition increases surgical site infection (SSI) risk in children with cerebral palsy (CP) undergoing spinal deformity surgery. Growth charts specifically for patients with CP have been created to aid in the clinical interpretation of body mass index (BMI) as a marker of nutritional status, but to our knowledge these charts have never been used to risk stratify patients before orthopaedic surgery. We hypothesize that patients with CP who have BMI-for-age below the 10th percentile (BMI<=10) on CP-specific growth charts are at increased risk of surgical site infection following spinal deformity surgery compared with patients with BMI-for age above the 10th percentile (BMI>10). METHODS: Single-center, retrospective review comparing the rate of SSI in patients with CP stratified by BMI-for-age percentiles on CP-specific growth charts who underwent spinal deformity surgery. Odds ratios with 95% confidence intervals and Pearson chi tests were used to analyze the association of the measured nutritional indicators with SSI. RESULTS: In total, 65 patients, who underwent 74 procedures, had complete follow-up data and were included in this analysis. Ten patients (15.4%) were GMFCS I-III and 55 (84.6%) were GMFCS IV-V; 39 (60%) were orally fed and 26 (40%) were tube-fed. The rate of SSI in this patient population was 13.5% with 10 SSIs reported within 90 days of surgery. There was a significant association between patients with a BMI below the 10th percentile on GMFCS-stratified growth charts and the development of SSI (OR, 13.6; 95% CI, 2.4-75.4; P=0.005). All SSIs occurred in patients that were GMFCS IV-V. There was no association between height, weight, feeding method, or pelvic instrumentation and development of SSI. CONCLUSIONS: CP-specific growth charts are useful tools for identifying patients at increased risk for SSI following spinal instrumentation procedures, whereas standard CDC growth charts are much less sensitive. There is a strong association between preoperative BMI percentile on GMFCS-stratified growth charts and SSI following spinal deformity surgery. LEVEL OF EVIDENCE: Level III-Retrospective Study. PMID- 30395004 TI - Using "radical candor". PMID- 30395005 TI - Expression alterations of apoptosis repressor with caspase recruitment domain in Abeta25-35-induced hippocampal neurotoxicity. AB - Many proapoptotic and antiapoptotic proteins have been involved in the pathology of Alzheimer's disease. As the first identified antiapoptotic protein, apoptosis repressor with caspase recruitment domain (ARC) is highly expressed in terminally differentiated cells, and its functions and expressions in striated muscles and cancer cells have been widely studied. However, the expression alterations of ARC in amyloid beta-induced early hippocampal neurotoxicity are less known. In this report, we not only confirm previous reports that ARC is expressed in the hippocampal neurons but also demonstrate for the first time that ARC is also expressed in the hippocampal astrocytes. Furthermore, we extend the findings to show that, contrary to the time-dependently decreased ARC levels in the hippocampal neurons, ARC in astrocytes is strikingly increased in Abeta25-35 induced early neurotoxicity. Our data suggest that ARC has distinct roles based on cell type and stimuli. Our results provide valuable information for further exploring the complicated functions and related mechanisms of ARC in amyloid related diseases. PMID- 30395006 TI - Investigating the mechanisms of acupuncture on neural excitability in healthy adults. AB - Acupuncture is gaining interest as a potential treatment modality for various neurological conditions. Yet, the underlying mechanisms and efficacy on brain function are not well understood. Therefore, this study investigated the previously proposed hypothesis that acupuncture suppresses motor cortex excitability using transcranial magnetic stimulation (TMS) in healthy adults. The study was randomised, sham-controlled, and double-blinded. Single and paired pulse TMS was delivered before, during, immediately after, and 30 min after removal of the needle. Acupuncture to the right Hegu acupoint (LI-4) of the hand was delivered by an experienced acupuncturist using standardised manipulations. A disposable (0.22*30 mm, Hwato) needle was used for verum stimulation (penetrating) and a Park retractable needle for sham (nonpenetrating). The peak to-peak amplitude of TMS-induced motor-evoked potentials was recorded from two intrinsic hand muscles. Needling sensations were quantified using the Massachusett's acupuncture sensation scale. Participant needling sensations were not different between verum or sham acupuncture (P>0.54). Corticomotor excitability, intracortical inhibition, and intracortical facilitation were not modulated by verum or sham acupuncture during, immediately after, or 30 min after, recorded from a local or distant hand muscle to the needling site (all P>0.075). Contrary to previous studies, manual acupuncture did not affect motor cortex excitability in healthy adults. Because of the increasing popularity of acupuncture therapy, further research using patient populations should be considered. PMID- 30395007 TI - Alterations in reelin and reelin receptors in Down syndrome. AB - Reelin is an extracellular matrix glycoprotein that modulates synaptic function and plasticity, with a crucial role in neuronal migration. Changes in the expression of this protein have been reported in neurodegenerative diseases, such as Alzheimer's disease (AD). This molecule is produced by Cajal-Retzius neurons during development and by inhibitory neurons in the adult nervous system. Individuals with Down syndrome (DS) present an early development of AD; therefore, we analyzed the alterations in this molecule and its receptors in the murine model for DS Ts65Dn as well as in human with DS. We performed immunofluorescence analysis for reelin and its receptors very-low-density lipoprotein receptor and apolipoprotein R receptor 2 in the temporal cortex of mice and humans and have quantified the density of reelin-expressing neurons and the intensity of expression of both receptors. We have observed an increment in the density of reelin immunoreactive neurons in both the temporal cortex of adult Ts65Dn mice and humans with DS. Moreover, these reelin immunoreactive neurons displayed a disorganized distribution when compared with wild-type mice. Regarding reelin receptors, very-low-density lipoprotein receptor expression remained unaltered in both Ts65Dn and humans with DS, whereas apolipoprotein R receptor 2 decreased in both individuals with DS and Ts65Dn mice. These alterations are similar to those observed in individuals with AD. PMID- 30395008 TI - Effect of Occupational Exposure to Cyanuric Chloride on Respiratory Morbidity: Cross-sectional Analyses of Respiratory Symptoms and Longitudinal Analyses of Lung Function Parameters. AB - OBJECTIVE: The study aimed to investigate the relationship between occupational exposure to cyanuric chloride and respiratory morbidity. METHODS: The cohort comprises former and active workers at three European production sites. Individual cumulative exposure, exposure duration, and long-term average concentration were estimated. In the longitudinal analyses, generalized equation estimates (GEEs) models were used to estimate the risks. To determine a threshold value for cumulative exposure, hockey-stick models were fitted. RESULTS: A sensitization to cyanuric chloride, without an effect on lung function, has been observed. For the total cohort, both the single models and the multimodel analyses provided hints of lung function loss resulting from long-term exposure to cyanuric chloride. With respect to the estimated average loss from a representative model, a cumulative exposure of 0.3 mg/m-years (0.2 to 0.4 mg/m years) yielded the best model fit. CONCLUSION: A shift reference value (time weighted average, 8 hours) of 0.06 mg/m could be derived. For future research, a larger database of exposure measurements and continuing health monitoring will be valuable. PMID- 30395009 TI - The Contributions Made by Job Satisfaction and Psychosocial Stress to the Development and Persistence of Depressive Symptoms: A 1-year Prospective Study. AB - OBJECTIVE: The purpose of this study was to determine the factors that contributed to the development and persistence of depression over the course of 1 year in work environment. METHODS: The subjects were 992 Japanese civil servants aged between 19 and 65 years. Baseline data and linked with data collected at 1 year follow up. RESULTS: After adjusting for baseline depression levels, job satisfaction and work-related psychosocial stress (job control and job demand) were significantly related to depression at 1-year follow up. Moreover, those who reported job dissatisfaction were at higher risk of developing depression (ORs: 1.94) and persistent depression associated with low job control (ORs: 2.64) and high job demand (ORs: 2.20). CONCLUSIONS: Job satisfaction, and psychosocial stress at baseline predicted development of and recovery from depression at 1 year follow up respectively. PMID- 30395010 TI - Occupational Physical Activity Opposes Obesity: A Cross-Sectional Modern Replication of the Morris 1953 London Busmen Study. AB - OBJECTIVE: Examine the importance of occupational light-intensity physical activity (PA) and short bouts of moderate-vigorous PA (LSBPA), to opposing obesity, including an approximate replication of the London busmen study comparing waist circumference of workers with high versus low levels of occupational activity. METHODS: Working adults wore an accelerometer, completed anthropometric measurements, and provided work schedules. Participants' (n = 435) activity was classified as either occupational or non-occupational minutes, and by intensity. RESULTS: Body fat percentage was inversely associated with occupational-LSBPA in participants who did not meet PA guidelines, but not in those who met guidelines. In the London busmen replication, more active workers had smaller waist circumferences than sedentary workers, controlling for non occupational activity. CONCLUSIONS: Work-related LSBPA may be an important and under-recognized source of PA that opposes adiposity for people who do not meet PA guidelines. PMID- 30395012 TI - PERIOPERATIVE GLYCEMIC CONTROL AND POSTOPERATIVE COMPLICATIONS IN PATIENTS UNDERGOING EMERGENCY GENERAL SURGERY: WHAT IS THE ROLE OF HbA1c? PMID- 30395011 TI - Safety and Immunogenicity of a Full-Dose Split-Virion Inactivated Quadrivalent Influenza Vaccine in Healthy Children 6 to 35 Months of Age: A Randomized Controlled Clinical Trial. AB - BACKGROUND: For children aged < 3 years, a half dose of inactivated influenza vaccine (7.5 ug hemagglutinin/strain) has been used for more than 30 years, but several studies indicate that a full dose (15 ug hemagglutinin/strain) can be used in this population without increasing the rate of fever or other reactions. Here we compare the safety and immunogenicity of full and half doses of quadrivalent split-virion inactivated influenza vaccine (IIV4) in children aged 6 to 35 months. METHODS: In this phase IV, randomized, observer-blinded, multi center study, healthy children aged 6 to 35 months were randomized 1:1 to be vaccinated with a half or full dose of IIV4 (NCT02915302). The primary objective was to demonstrate that the rate of any fever (>= 38.0 degrees C) up to 7 days after a full dose of IIV4 was non-inferior to the rate of fever after a half dose. RESULTS: The study included 1950 children. Non-inferiority in the rate of fever was demonstrated for the full dose vs. the half dose of IIV4 (difference in rate = 0.84% [95% confidence interval, -2.13%-3.80%]). Solicited reactions and unsolicited adverse events were similar between the dose groups. No vaccine related serious adverse events were reported. Non-inferiority of both hemagglutination inhibition geometric mean titers and seroconversion rates was demonstrated for all four vaccine strains for the full dose vs. the half dose. CONCLUSIONS: In children aged 6 to 35 months, a full dose of IIV4 was immunogenic and had a safety profile comparable to that of a half dose, with no new safety concerns observed.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30395013 TI - Sarcopenia as a tool for preoperative decision making. PMID- 30395014 TI - Delta hepatitis in resolved hepatitis B. PMID- 30395015 TI - Crohn's disease of the penis and scrotum: a prospective study. PMID- 30395016 TI - Pharmacological therapy alone or in combination with endoscopic therapy for acute variceal bleeding in hepatocellular carcinoma. PMID- 30395018 TI - Smoking Status Among Patients With Newly Diagnosed Lung Cancer in Taiwan. AB - BACKGROUND: Continued smoking after receiving a diagnosis of cancer seriously affects disease prognosis and survival. The prevalence and risk factors of continued smoking among patients with newly diagnosed lung cancer are unknown in Taiwan. PURPOSE: The aims of this study were to assess the smoking status of patients with newly diagnosed lung cancer and to identify the characteristics that are associated with different smoking statuses. METHODS: Baseline data of a longitudinal study on smoking behaviors after lung cancer diagnosis were analyzed in this study. Patients were consecutively recruited from three medical centers in northern Taiwan. A structured questionnaire and medical chart reviews were used to collect data. Multinomial logistic regression analysis was used to examine the factors associated with continuing to smoke after being diagnosed with lung cancer. RESULTS: Among the 406 patients with newly diagnosed lung cancer who were recruited, 47.0% were never-smokers and 53.0% were ever-smokers. Among the second group, 38% were former smokers, 18% were recent quitters, and 44% were current smokers. Compared with former smokers, current smokers were more likely to be younger (OR = 1.05), to not exercise regularly (OR = 2.74), to currently live with smokers (OR = 2.48), and to have lower self-efficacy for refusing to smoke (OR = 0.95). Compared with recent quitters, current smokers were more likely to have lower self-efficacy for refusing to smoke. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: A significant proportion of ever-smoker lung cancer patients in Taiwan will continue to smoke after receiving their diagnosis. Variables known to modify the risk factors associated with continued smoking such as regular exercise and better refusal self-efficacy should be considered and incorporated into future smoking cessation programs for patients with lung cancer. PMID- 30395020 TI - Erratum. PMID- 30395019 TI - Embracing Diversity in Nursing Research Methods. PMID- 30395021 TI - Significant Effect of Acupressure in Elevating Blood Stem Cell Factor During Chemotherapy in Patients With Gynecologic Cancer. AB - BACKGROUND: Chemotherapy is used mainly to treat and control the progression of gynecological cancer. Bone marrow suppression, one of the adverse side effects of chemotherapy, may decrease immune function, increasing the risk of serious, fatal infections. PURPOSE: The aims of this study were to evaluate the effectiveness of noninvasive acupressure in preventing and diminishing chemotherapy-induced myelosuppression in patients with gynecologic cancer and to determine whether this effect is associated with the regulation of the expressions of granulocyte macrophage colony-stimulating factor and stem cell factor (SCF). METHODS: In total, 28 women with gynecological cancer were randomly assigned either to the experimental group (n = 10) or to the control group (n = 18). The experimental group received acupressure of 5-minute duration to the Hegu (LI4), Quchi (LI11), Xuehai (SP10), Sanyinjiao (SP6), Taixi (K3), Zusanli (ST36), Taichong (LR3), and Baihui (GV20) points, respectively, three times per day for 6 weeks. The control group did not receive the acupressure intervention. The blood count, including white blood cells, platelets, and hemoglobin, and serum levels for SCF and granulocyte-macrophage colony-stimulating factor were assessed before (pretest) and 6 weeks after (posttest) the participants' first course of chemotherapy. RESULTS: At posttest, blood hemoglobin had significantly decreased from (mean +/- SD) 11.6 +/- 2.2 to 10.8 +/-1.6 mg/dl (p = .03) in the control group. However, no significant pretest-posttest difference in hemoglobin concentration (11.4 +/- 1.0 vs. 10.9 +/- 1.1 mg/dl) was detected in the experimental group. Levels of SCF increased significantly between pretest and posttest in both the control group (from 1196.10 +/- 293.17 to 1325.05 +/- 253.77 ng/ml; p = .01) and the acupressure group (from 1046.78 +/- 469.52 to 1387.06 +/- 310.00 ng/ml; p = .007). In addition, a borderline difference (p = .05) in mean pretest-posttest SCF increase was found between the acupressure group (340.28 +/- 255.46 ng/ml) and the control group (128.94 +/- 250.64 ng/ml). Finally, a significant time dependent interactive effect was found between acupressure and the increased blood level of SCF at posttest (beta = 211.34, p = .02). CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The findings support that acupressure on specific acupoints increases blood SCF levels significantly, which may help protect chemotherapy patients from experiencing reduced hemoglobin levels and may relieve chemotherapy induced myelosuppression in patients with gynecologic cancer. This noninvasive approach is suggested for practical implementation in patients undergoing a course of chemotherapy. PMID- 30395022 TI - Knowledge of the Warning Signs of Foot Ulcer Deterioration Among Patients With Diabetes. AB - BACKGROUND: Seeking treatment in a timely manner may prevent lower limb amputation subsequent to diabetic foot ulcers. Knowledge regarding the warning signs is one importantfactor that is related to the timely treatment seeking of patients with diabetic foot ulcers. However, there is no previousresearch on which aspects of such knowledge that patients with diabetes are lacking. PURPOSE: The aims of this study were to test the psychometric properties of a questionnaire that was designed to assess the knowledge of the warning signs of diabetic foot ulcer deterioration and to determine the knowledge of these warning signs among patients with a history of diabetic foot ulcers. METHODS: A cross sectional study design was used. Patients with a history of diabetic foot ulcers were recruited using convenience sampling (N = 385). Data were analyzed using Spearman's rank correlation and the Mann-Whitney U test. RESULTS: The questionnaire showed good known-group validity, satisfied internal consistency (Kuder-Richardson Formula 20 = .82), and exhibited acceptable 2-week test-retest reliability (Spearman's rho coefficient = .75). More than 30% of the participants were unaware of the warning signs of peripheral vascular insufficiency and severe infection. Of the participants, 75.8% felt that the time to seek medical treatment of diabetic foot ulcers was when they experienced wound deterioration. Those who held this opinion had significantly less knowledge regarding the warning signs of diabetic foot ulcer deterioration than did those who had not. Other factors that were significantly associated with less knowledge included being older, having less education, not having an existing foot ulcer, having no foot ulcer treatment history, and never having received education regarding foot ulcers. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The questionnaire showed adequate validity and reliability and thus may be used by healthcare practitioners and researchers to assess the knowledge of at-risk patients regarding the warning signs of diabetic foot ulcer deterioration. Patient education regarding the importance of timely treatment seeking and warning signs should be promoted. PMID- 30395023 TI - The Latin American and Spanish Survey on Nutrition in Pediatric Intensive Care (ELAN-CIP2). AB - OBJECTIVE: To characterize the practices of nutritional support in Latin American and Spanish PICUs. DESIGN: Survey with a questionnaire sent to Latin American Society of Pediatric Intensive Care members. SETTING: PICUs of participant hospitals. PATIENTS: Critically ill children between 1 month and 18 years old. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Forty-seven surveys from 17 countries were analyzed. Sixty-seven percent of PICUs were from university affiliated hospitals, with a median of 380 admissions/yr. Sixty-eight percent and 48.9% had a nutritional support team and nutritional support protocol, respectively. Seventy-five percent completed nutritional evaluations, with 34.2% at admission. PICUs with high-volume admissions were likely to have a nutritional support team (p < 0.005), and university-affiliated hospitals showed a trend of having a nutritional support team (p = 0.056). Measured, estimated, and ideal weights were used in 75%, 14.6%, and 10.4%, respectively. Energy requirements were calculated using Holliday & Segar and Schofield equations in 90% of the PICUs; 43% used correction factors. Only three PICUs had indirect calorimetry. At day 3 of initiation of nutritional support, 57.3% of PICUs provided at least 50% of the calculated energy requirement, and 91.5% at day 5. Protein needs were estimated according to American Society for Parenteral and Enteral Nutrition and European Society for Clinical Nutrition and Metabolism/European Society for Paediatric Gastroenterology Hepatology and Nutrition guidelines in 55.3% and 40.4%, respectively. Enteral nutrition was the preferred feeding method, initiated in 97.7% at 48 hours. The feeding route was gastric (82.9%), by bolus (42.5%) or continuous (57.4%). Monitoring methods included gastric residual measurement in 55.3%. Enteral nutrition was discontinued in 82.8% when gastric residual was 50% of the volume. Prokinetics were used in 68%. More than half of PICUs used parenteral nutrition, with 95.8% of them within 72 hours. Parenteral nutrition was administered by central vein in 93.6%. Undernourished children received parenteral nutrition sooner, whether or not enteral nutrition intolerance was present. When enteral nutrition was not tolerated beyond 72 hours, parenteral nutrition was started in 57.4%. Parenteral nutrition was initiated when enteral nutrition delivered less than 50% in 97%. CONCLUSIONS: Nutritional practices are heterogeneous in Latin American PICUs, but the majority use nutritional support strategies consistent with international guidelines. PMID- 30395024 TI - A Pilot Study of the Association of Amino-Terminal Pro-B-Type Natriuretic Peptide and Severity of Illness in Pediatric Septic Shock. AB - OBJECTIVES: Biomarkers that can measure illness severity and predict the risk of delayed recovery may be useful in guiding pediatric septic shock. Amino-terminal pro-B-type natriuretic peptide has not been assessed in pediatric septic patients at the time of presentation to the emergency department prior to any interventions. The primary aim was to assess if emergency department amino terminal pro-B-type natriuretic peptide is associated with worse outcomes and severity of illness. DESIGN: Prospective observational pilot study. SETTINGS: Tertiary free-standing children's hospital. PATIENTS: Children 0-17 years old with a diagnosis of septic shock were enrolled. Patients with preexisting cardiac and renal dysfunction were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Amino-terminal pro-B-type natriuretic peptide analysis was performed on samples obtained in the emergency department prior to any intervention. The association between biomarkers and clinical outcomes and illness severity using Pediatric RISk of Mortality 3 were assessed. Eighty-two patients with septic shock underwent analysis. The median (interquartile range) amino-terminal pro-B type natriuretic peptide levels was 394 pg/mL (102-1,392 pg/mL). Each decile change increase in amino-terminal pro-B-type natriuretic peptide was associated with a change in ICU length of stay by 8.7%, (95% CI, 2.4-15.5), hospital length of stay by 5.7% (95% CI, 0.4-11.2), organ dysfunction by 5.1% (95% CI, 1.8-8.5), a higher inotropic score at 12, 24, and 36 hours, and longer time requiring vasoactive agents. There was a significant correlation between baseline amino terminal pro-B-type natriuretic peptide and the Pediatric RISk of Mortality 3 score (Spearman rho = 0.247; p = 0.029). CONCLUSIONS: This pilot study shows an association between emergency department amino-terminal pro-B-type natriuretic peptide on presentation and worse septic shock outcomes and amino-terminal pro-B type natriuretic peptide levels correlates with an ICU severity score. PMID- 30395025 TI - A National Survey on Interhospital Transport of Children in Cardiac Arrest. AB - OBJECTIVES: To describe the U.S. experience with interhospital transport of children in cardiac arrest undergoing cardiopulmonary resuscitation. DESIGN: Self administered electronic survey. SETTING: Pediatric transport teams listed with the American Academy of Pediatrics Section on Transport Medicine. SUBJECTS: Leaders of U.S. pediatric transport teams. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sixty of the 88 teams surveyed (68%) responded. Nineteen teams (32%) from 13 states transport children undergoing cardiopulmonary resuscitation between hospitals. The most common reasons for transfer of children in cardiac arrest are higher level-of-care (70%), extracorporeal life support (60%), and advanced trauma resuscitation (35%). Eligibility is typically decided on a case by-case basis (85%) and sometimes involves a short interhospital distance (35%), or prompt institution of high-quality cardiopulmonary resuscitation (20%). Of the 19 teams that transport with ongoing cardiopulmonary resuscitation, 42% report no special staff safety features, 42% have guidelines or protocols, 37% train staff on resuscitation during transport, 11% brace with another provider, and 5% use mechanical cardiopulmonary resuscitation devices for patients less than 18 years. In the past 5 years, 18 teams report having done such cardiopulmonary resuscitation transports: 22% did greater than five transports, 44% did two to five transports, 6% did one transport, and the remaining 28% did not recall the number of transports. Seventy-eight percent recall having transported by ambulance, 44% by helicopter, and 22% by fixed-wing. Although patient outcomes were varied, eight teams (44%) reported survivors to ICU and/or hospital discharge. CONCLUSIONS: A minority of U.S. teams perform interhospital transport of children in cardiac arrest undergoing cardiopulmonary resuscitation. Eligibility criteria, transport logistics, and patient outcomes are heterogeneous. Importantly, there is a paucity of established safety protocols for the staff performing cardiopulmonary resuscitation in transport. PMID- 30395026 TI - Efficacy and Safety of Pediatric Critical Care Physician Telemedicine Involvement in Rapid Response Team and Code Response in a Satellite Facility. AB - OBJECTIVES: Satellite inpatient facilities of larger children's hospitals often do not have on-site intensivist support. In-house rapid response teams and code teams may be difficult to operationalize in such facilities. We developed a system using telemedicine to provide pediatric intensivist involvement in rapid response team and code teams at the satellite facility of our children's hospital. Herein, we compare this model with our in-person model at our main campus. DESIGN: Cross-sectional. SETTING: A tertiary pediatric center and its satellite facility. PATIENTS: Patients admitted to the satellite facility. INTERVENTIONS: Implementation of a rapid response team and code team model at a satellite facility using telemedicine to provide intensivist support. MEASUREMENTS AND MAIN RESULTS: We evaluated the success of the telemedicine model through three a priori outcomes: 1) reliability: involvement of intensivist on telemedicine rapid response teams and codes, 2) efficiency: time from rapid response team and code call until intensivist response, and 3) outcomes: disposition of telemedicine rapid response team or code calls. We compared each metric from our telemedicine model with our established main campus model. MAIN RESULTS: Critical care was involved in satellite campus rapid response team activations reliably (94.6% of the time). The process was efficient (median response time 7 min; mean 8.44 min) and effective (54.5 % patients transferred to PICU, similar to the 45-55% monthly rate at main campus). For code activations, the critical care telemedicine response rate was 100% (6/6), with a fast response time (median 1.5 min). We found no additional risk to patients, with no patients transferred from the satellite campus requiring a rapid escalation of care defined as initiation of vasoactive support, greater than 60 mL/kg in fluid resuscitation, or endotracheal intubation. CONCLUSIONS: Telemedicine can provide reliable, timely, and effective critical care involvement in rapid response team and Code Teams at satellite facilities. PMID- 30395027 TI - Cerebrovascular Physiology During Pediatric Extracorporeal Membrane Oxygenation: A Multicenter Study Using Transcranial Doppler Ultrasonography. AB - OBJECTIVES: To explore changes to expected, age-related transcranial Doppler ultrasound variables during pediatric extracorporeal membrane oxygenation. DESIGN: Prospective, observational, multicenter study. SETTING: Tertiary care PICUs. PATIENTS: Children 1 day to 18 years old requiring veno arterial extracorporeal membrane oxygenation. METHODS: Participants underwent daily transcranial Doppler ultrasound measurement of bilateral middle cerebral artery flow velocities. Acute neurologic injury was diagnosed if seizures, cerebral hemorrhage, or diffuse cerebral ischemia was detected. MEASUREMENTS AND MAIN RESULTS: Fifty-two children were enrolled and analyzed. In the 44 children without acute neurologic injury, there was a significant reduction in systolic flow velocity and mean flow velocity compared with predicted values over time (F [8, 434] = 60.44; p <= 0.0001, and F [8, 434] = 17.61; p <= 0.0001). Middle cerebral artery systolic flow velocity was lower than predicted on extracorporeal membrane oxygenation days 1-5, and mean flow velocity was lower than predicted on extracorporeal membrane oxygenation days 1-3. In the six infants less than 90 days old suffering diffuse cerebral ischemia, middle cerebral artery systolic flow velocity, mean flow velocity, and diastolic flow velocity from extracorporeal membrane oxygenation days 1-9 were not significantly different when compared with children of similar age in the cohort that did not suffer acute neurologic injury (systolic flow velocity F [8, 52] = 0.6659; p = 0.07 and diastolic flow velocity F [8, 52] = 1.4; p = 0.21 and mean flow velocity F [8, 52] = 1.93; p = 0.07). Pulsatility index was higher in these infants over time than children of similar age in the cohort on extracorporeal membrane oxygenation that did not suffer acute neurologic injury (F [8, 52] = 3.1; p = 0.006). No patient in the study experienced cerebral hemorrhage. CONCLUSIONS: Flow velocities in the middle cerebral arteries of children requiring extracorporeal membrane oxygenation are significantly lower than published normative values for critically ill, mechanically ventilated, sedated children. Significant differences in measured systolic flow velocity, diastolic flow velocity, and mean flow velocity were not identified in children suffering ischemic injury compared with those who did not. However, increased pulsatility index may be a marker for ischemic injury in young infants on extracorporeal membrane oxygenation. PMID- 30395029 TI - Now Is the Time. PMID- 30395028 TI - Hemodynamic Impact of Oxygen Desaturation During Tracheal Intubation Among Critically Ill Children With Cyanotic and Noncyanotic Heart Disease. AB - OBJECTIVES: To determine a level of oxygen desaturation from baseline that is associated with increased risk of tracheal intubation associated events in children with cyanotic and noncyanotic heart disease. DESIGN: Retrospective analysis of prospectively collected data from the National Emergency Airway Registry for Children, an international multicenter quality improvement collaborative for airway management in critically ill children. SETTING: Thirty eight PICUs from July 2012 to December 2016. PATIENTS: Children with cyanotic and noncyanotic heart disease who underwent tracheal intubation in a pediatric or cardiac ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Our exposure of interest was oxygen desaturation measured by a fall in pulse oximetry from baseline after preoxygenation. Primary outcome was the occurrence of hemodynamic tracheal intubation associated events defined as cardiac arrest, hypotension or dysrhythmia. One-thousand nine-hundred ten children (cyanotic, 999; noncyanotic, 911) were included. Patients with cyanotic heart disease who underwent tracheal intubations were younger (p < 0.001) with higher Pediatric Index of Mortality 2 scores (p < 0.001), more likely to have a cardiac surgical diagnosis (p < 0.001), and less likely to have hemodynamic instability (p = 0.009) or neurologic failure as an indication (p = 0.008). Oxygen desaturation was observed more often in children with cyanotic versus noncyanotic heart disease (desaturation of 15% to < 30%: 23% vs 16%, desaturation >= 30%: 23% vs 17%; p < 0.001), with no significant difference in occurrence of hemodynamic tracheal intubation associated events (7.5% vs 6.9%; p = 0.618). After adjusting for confounders, oxygen desaturation by 30% or more is associated with increased odds for adverse hemodynamic events (odds ratio, 4.03; 95% CI, 2.12-7.67) for children with cyanotic heart disease and (odds ratio, 3.80; 95% CI, 1.96-7.37) for children with noncyanotic heart disease. CONCLUSIONS: Oxygen desaturation was more commonly observed during tracheal intubation in children with cyanotic versus noncyanotic heart disease. However, hemodynamic tracheal intubation associated event rates were similar. In both groups, oxygen desaturation greater than or equal to 30% was significantly associated with increased occurrence of hemodynamic tracheal intubation associated events. PMID- 30395030 TI - Assessing Hyperbaric Oxygen for Carbon Monoxide Poisoning in Trauma Patients: A Call for Representation in Future Studies. AB - Although carbon monoxide (CO) poisoning presents infrequently, it is a consequential and serious component of burn-related injuries, especially those injured via structure fire. A multitude of retrospective reviews and prospective trials have attempted to establish evidence demonstrating the ideal modality for oxygen administration in CO-poisoned patients; however, a consensus recommendation has not been reached. Given that half of fire-related patients succumb to CO poisoning, this is an imperative area of research. PMID- 30395031 TI - Complications and Mortality Among Correctly Triaged and Undertriaged Severely Injured Older Adults With Traumatic Brain Injuries. AB - Determining differences in clinical outcomes of older adults treated at trauma centers (TCs) and nontrauma centers (NTCs) is imperative considering their persistent undertriage and the projected costs of fixing the problem. This study compared the incidence and predictors of complications and mortality among brain injured older adults treated at TCs and NTCs. This secondary analysis of New York inpatient data included patients aged 55+ years, primary brain injury diagnosis, and acute care hospital admission. Interfacility transfers and nontraumatic brain injuries were excluded. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes identified complications and mortality. Injury severity was determined by mapping ICD-9-CM diagnoses to Abbreviated Injury Scale 2005 Revision 2008 dictionary scores. A subgroup analysis of 1,594 patients with New Injury Severity Scores greater than 15 was performed to examine complications and mortality. This study included 7,138 patients who met inclusion criteria. Predictors of subgroup complications included chronic renal failure, odds ratio (OR) = 2.251 (confidence interval [CI] = 1.470-3.447), p < .001; major operating room procedure, OR = 2.349 (CI = 1.679 3.285), p < .001; number of diagnoses, OR = 1.201 (CI = 1.158-1.245), p < .001; and number of procedures, OR = 1.119 (CI = 1.077-1.162), p L .001. Mortality predictors included age, OR = 1.031 (CI = 1.017-1.045), p < .001; preexisting coagulopathy, OR = 1.753 (C = 1.130-2.719), p = .012; number of procedures, OR = 1.122 (CI = 1.081-1.166), p < .001; acute renal failure, OR = 3.114 (CI = 1.672 5.797), p < .001; systemic inflammatory response syndrome, OR = 4.058 (CI = 1.463 11.258), p = .007; adult respiratory distress syndrome, OR = 3.179 (CI = 1.673 6.041), p < .001; and subarachnoid bleed, OR = 2.667 (CI = 1.415-5.029), p = .002. Nearly 23% of the severely/critically injured patients experienced 1 or more complications. Incidence of complications was low and comparable for TCs and NTCs. The proportion of deaths was slightly higher at TCs but not significant. The most prevalent complications carry a high mortality risk. PMID- 30395032 TI - Complications and Mortality Among Correctly Triaged and Undertriaged Severely Injured Older Adults With Traumatic Brain Injuries. PMID- 30395034 TI - Impacting Delirium in the Trauma ICU Utilizing the ICU Liberation Collaborative Benchmark Report. PMID- 30395033 TI - Impacting Delirium in the Trauma ICU Utilizing the ICU Liberation Collaborative Benchmark Report. AB - Delirium is a frequent complication of intensive care unit (ICU) admissions, manifesting as acute confusion with inattention and disordered thinking. Patients in the ICU who develop acute delirium are more likely to experience long-term disability and mortality. The Society of Critical Care Medicine published guidelines for the management of pain, agitation, and delirium (PAD) in the ICU in 2013. Based on these PAD guidelines, the ABCDEF bundle was created. Research is lacking on how adherence to the ABCDEF bundle elements impacts specific populations such as trauma patients. This represents a significant gap for patients whose multisystem injuries and comorbidities add a higher level of complexity to their care and outcomes. The medical ICU at a large community hospital participated in a 2-year quality improvement project as part of the Society of Critical Care Medicine's ICU Liberation Collaborative. However the organization's trauma ICU (TICU) was excluded from the study. The purpose of this study was to conduct a baseline assessment of trauma patient records to determine which bundle elements were already being applied in the TICU, and if the resources required for implementing the full ABCDEF bundle would be beneficial to the TICU patient outcomes. Benchmark data from the organization's participation in the ICU Liberation Collaborative quality improvement project served as the primary source of evidence. Analysis revealed strengths and opportunities for improvement. Incidence of delirium remained unchanged and far below national averages, indicating the need for further investigation into practices to verify this finding. An opportunity was identified to expand implementation of certain elements of the ABCDEF bundle in the trauma ICU. There is an opportunity for nurses to take the lead in improving patient outcomes. With improved education, evidence-based assessment tools, and best practice guidelines, nurses can help decrease the incidence of delirium by as much as 30%. PMID- 30395035 TI - Factors Affecting Urinary Retention in Critically Ill Trauma Patients. AB - The objective of this retrospective study was to gain a better understanding of patient and care factors that may contribute to urinary retention in critically ill trauma patients. Fifty trauma patients over a 1-year period with an International Classification of Diseases, Tenth Revision (ICD-10) code for urinary retention were identified and analyzed. Most patients had an indwelling urinary catheter placed on admission, and it was reinserted in 39 patients. Male gender, orthopedic trauma, and anesthesia were possible contributing factors for urinary retention in our sample population. The use of paralytics and more than one operative intervention had a significant relationship with prescribing bladder medications. It is imperative to have protocols based on best evidence to guide management of urinary retention in this critically ill trauma patient population. PMID- 30395036 TI - Analgesics Administered for Pain During Hospitalization Following Lower Extremity Fracture: A Review of the Literature. AB - Effective treatment of acute pain during hospitalization following lower extremity fracture is critical to improve short-term patient outcomes including wound healing, stress response, hospital length of stay, and cost as well as minimizing long-term negative patient outcomes such as delayed return to work, disability, and chronic pain. As many patients report moderate to severe pain during hospitalization, identifying the analgesics that most effectively reduces pain is a priority to improve patient outcomes. The purpose of this review was to examine published studies describing patient response to analgesics administered orally (PO) or intravenously (IV) in the immediate hospitalization following lower extremity fracture. PubMed was queried for articles published through May 2017 that included information on type of study, population, fracture site, pain measurement tool, analgesic, and result. Of 514 articles found, eight met the inclusion criteria. Analgesics administered PO or IV were fentanyl, hydromorphone, morphine, remifentanil, diclofenac, ibuprofen, ketorolac, and etoricoxib. Five of the studies focused on comparisons between one or more analgesics and three studies compared an IV analgesic to a regional anesthetic agent. Two studies compared different nonsteroidal anti-inflammatory drugs (NSAIDs). Bupivacaine, lignocaine, and levobupivacaine administered as regional nerve blocks were superior to controlling pain compared with IV fentanyl and IV hydromorphone. IV morphine provided faster and better pain relief compared with IV ibuprofen. Based on the limited data available, regional nerve blocks provided superior pain relief compared with opioids, and opioids provided superior pain relief compared with NSAIDs. Different NSAIDs provided similar pain relief. PMID- 30395037 TI - Targeting Catheter-Associated Urinary Tract Infections in a Trauma Population: A 5-S Bundle Preventive Approach. AB - Complications from catheter-associated urinary tract infections (CAUTIs) can cause morbidity and mortality. Our institution's Trauma Quality and Improvement Program analysis identified CAUTIs as an outlier complication in our trauma population. This study aimed to determine whether implemented measures would reduce CAUTI rates in trauma population. A 5-S CAUTI bundle was implemented. Its effects were measured on a prospectively collected dataset of adult trauma patients using our Trauma Registry during the 4-year study period. Implemented measures included (1) staff education, (2) bladder catheter stabilization, (3) patient and caregiver education, (4) keeping the collection bag below the bladder and above the floor, and (5) daily evaluations for discontinuation. Chi-squared and t-test analyses were used with significance defined as p < .05. Twelve thousand nine hundred and sixty-two trauma patients were admitted to trauma service during the 4-year study period. Of these, 94 developed CAUTIs, with an average age of 67 years and 56% were females. The average injury severity score was 16 in patients with CAUTIs compared with 9 in non-CAUTI patients (p < .0002). In the index year, CAUTIs occurred in 41 out of 3,054 (1.34%), the following year there were 34 out of 3,455 (0.98%), in 2016 there were 11 out of 3,246 (0.33%), and 8 out of 3,207 (0.25%) in 2017 (p < .001). Results demonstrated an 80% reduction in CAUTI rate. Execution of the 5-S CAUTI bundle resulted in a significant 80% reduction in CAUTI rate in our trauma population. PMID- 30395038 TI - Collaborative Team Reflective Practice in Trauma Service to Improve Health Care. AB - The importance of reflection and reflective practice is repeatedly reported in trauma literature, with the process of reflective practice being noted as invaluable for clinicians working within trauma settings. Although the literature on medical primary response trauma teams has reported clinicians' management of clinical roles and additional stressors, the practical applications and benefits of reflective practice insofar have not been identified in relation to complex trauma within multidisciplinary mental health services. This study aimed to identify the issues influencing the capacity for collaborative team reflective practice in a multidisciplinary child trauma mental health service within a UK National Health Service trust. Semistructured interviews were used to investigate the issues influencing the capacity for collaborative team reflective practice. The data were fully transcribed verbatim and analyzed using thematic analysis. The results suggest that clinicians working in a multidisciplinary child trauma service experience a positive benefit from collaborative team reflective practice, but that barriers exist, which influence the capacity to reflect. These include the management of reflective practice within the service, and department and service demands including the nature of the work/cases. Recommendations for the service and for future research are suggested to improve the capacity for collaborative team reflective practice. PMID- 30395039 TI - A Narrative Inquiry Into the Experience of Being a Victim of Gun Violence. AB - The purpose of this study was to gain a greater understanding of gun violence from the victim's personal story. The design for the study was narrative inquiry. Sixteen victims of gun violence were interviewed and asked to tell their story. The interview format comprised open-ended interview questions that encouraged participants to tell their stories. The method was narrative inquiry; the victims were encouraged to tell their story. The interview was recorded and transcribed. The transcripts of the interviews were the data for the study. Multiple readings allowed themes to emerge and provided a means of classifying the content. The data were organized by a categorical-content perspective as described by . Four themes emerged that captured the study participants' experience: prevailing nature of everyday violence; feeling abandoned by the institutions of society; living in a context of reactive violence fueled by poverty; lack of employable skills and education; and evolving psychological effect following gun violence. The study provided insight into the personal experience of gun violence. Victims of gun violence experience challenges related to poverty, deficient educational preparation, and community neglect. The presence of gun violence in their neighborhoods has had an everlasting impact on their well-being. Gun violence is a major public health crisis. Thousands of people are killed or injured daily by guns. It is crucial that appropriate interventions be created. Partnerships between neighborhood leaders, health care professionals, and politicians need to be developed and fostered. PMID- 30395040 TI - Mission Zero. PMID- 30395041 TI - Thirty Years of National Institute on Disability, Independent Living, and Rehabilitation Research Traumatic Brain Injury Model Systems Center Research-An Update. AB - The Traumatic Brain Injury Model Systems Center (TBIMSC) program was established by the National Institute on Disability, Independent Living, and Rehabilitation Research in 1987, with the goal of conducting research to improve the care and outcomes for individuals with moderate-to-severe traumatic brain injury (TBI). This article provides an update on TBIMSC research program activities since 2010 when a similar article was published. It includes (1) discussion of TBIMSC program management and infrastructure; (2) detail on the management, data quality, access, use, and knowledge translation of the TBIMSC National Database, with more than 16 000 participants with follow-up out to 25 years postinjury to date; (3) an overview of the TBIMSC site-specific studies and collaborative module research; (4) highlights of several collaborative initiatives between the TBIMSCs and other federal, advocacy, and research stakeholders; (5) an overview of the vast knowledge translation occurring through the TBIMSC program; and (6) discussion of issues that impact on the data collection methods for and contents of the TBIMSC National Database. On the occasion of the 30th anniversary of the TBIMSC program, this article highlights many of the accomplishments of this well established, multicenter TBI research consortium. PMID- 30395042 TI - Assessment of Covert Consciousness in the Intensive Care Unit: Clinical and Ethical Considerations. AB - OBJECTIVE: To propose a practical ethical framework for how task-based functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) may be used in the intensive care unit (ICU) to identify covert consciousness in patients with acute severe traumatic brain injury (TBI). METHODS: We present 2 clinical scenarios in which investigational task-based fMRI and EEG were performed in critically ill patients with acute severe TBI who appeared unconscious on the bedside behavioral assessment. From these cases, we consider the clinical and ethical challenges that emerge and suggest how to reconcile them. We also provide recommendations regarding communication with families about ICU patients with covert consciousness. RESULTS: Covert consciousness was detected acutely in a patient who died in the ICU due to withdrawal of life-sustaining therapy, whereas covert consciousness was not detected in a patient who subsequently recovered consciousness, communication, and functional independence. These cases raise ethical challenges about how assessment of covert consciousness in the ICU might inform treatment decisions, prognostication, and perceptions about the benefits and burdens of ongoing care. CONCLUSIONS: Given that covert consciousness can be detected acutely in the ICU, we recommend that clinicians reconsider evaluative norms for ICU patients. As our clinical appreciation of covert consciousness evolves and its ethical import unfolds, we urge prognostic humility and transparency when clinicians communicate with families in the ICU about goals of care. PMID- 30395043 TI - Trends in Pediatric Emergency Department Utilization for Mild Traumatic Brain Injury Before and After Legislation. AB - OBJECTIVE: To examine the effect of state youth traumatic brain injury (TBI) legislation on pediatric emergency department (ED) utilization for sports and recreation-related mild TBIs (mTBIs). PARTICIPANTS: ED visits by children ages 5 to 18 years between 2006 and 2014 in the Pediatric Health Information System database (N = 452 900). DESIGN: Retrospective analysis. MAIN MEASURES: Rates of ED visits, and injury comparison groups (mTBI, moderate to severe TBI, minor head injury, and long bone fracture). RESULTS: Of the 452 900 ED visits, 123 192 (27.2%) were for mTBI, along with visits for moderate to severe TBIs (n = 5190), minor head injuries (n = 54 566), and long bone fractures (n = 269 952). ED visits for mTBIs were more common among males (67.5%), children ages 10-14 years (42.1%), and the privately insured (50.6%). The proportion of mTBI ED visits increased significantly, particularly from 5 years prelegislation to immediately postlegislation (57.8 to 94.8 mTBI visits per 10 000 ED visits). A similar trend was observed for minor head injuries; however, no significant changes were observed for moderate to severe TBIs and long bone fractures. CONCLUSION: Pediatric ED utilization trends for the injury comparison groups differed from each other, and from pre- and post-TBI legislation. Further research assessing effects of TBI legislation on healthcare utilization is warranted. PMID- 30395044 TI - Sutureless Intrascleral Intraocular Lens Fixation Using a Microtube-Assisted Technique. PMID- 30395045 TI - Effects of Carbon Dioxide Insufflation and Trendelenburg Position on Brain Oxygenation During Laparoscopy in Children. AB - PURPOSE: Laparoscopic appendectomy has become more popular compared with the open appendectomy in children, but there are limited data on the effects of pneumoperitoneum and Trendelenburg position on cerebral oxygenation. This study was designed to evaluate the changes in cerebral saturation using near-infrared spectroscope during laparoscopic surgery in children. METHODS: The children underwent laparoscopic (LAP Group, n=22) or open appendectomy (OPEN Group, n=22). Right and left cerebral oxygenation (RScO2-LScO2), heart rate (HR), mean arterial pressure (MAP), end-tidal CO2pressure (PETCO2), and peripheral oxygen saturations (SpO2) were recorded between anesthesia induction (T0, baseline), after induction (T1), after intubation (T2), 5 minutes after intubation (T3), 5 minutes after pneumoperitoneum-15th minute at OPEN (T4), 5 minutes after Trendelenburg-20th minute at OPEN (T5), 30 minutes after pneumoperitoneum-45th minute at OPEN (T6), 5 minutes after supine position-skin suturing at OPEN (T7), 5 minutes postextubation (T8). RESULTS: Groups were similar with respect to their demographic data. In LAP group, a significant increase in HR was recorded at T5. No significant difference was observed in the MAP, PETCO2, SpO2, RScO2, and LScO2 values between the groups. There was a significant increase in the perioperative T1 to T8 values compared with the T0 values in LScO2 of the LAP group. CONCLUSIONS: Our results suggest that pneumoperitoneum and Trendelenburg position does not alter the hemodynamic values and can be safely performed in children without altering regional brain oxygenation levels. PMID- 30395046 TI - Median Arcuate Ligament Syndrome Related to Bodybuilding. AB - BACKGROUND: Median arcuate ligament syndrome (MALS), also known as celiac artery compression syndrome, is characterized by postprandial abdominal pain and weight loss thought to be secondary to compression of the celiac artery ganglia by the median arcuate ligament (MAL). METHODS: A young female powerlifter presented with a 3-month history of postprandial epigastric pain and involuntary weight loss following the start of a vigorous weightlifting program. The diagnosis of MALS was established after excluding other possibilities and by detailed evaluation including magnetic resonance imaging and celiac plexus block. She was treated by laparoscopic MAL release. RESULTS: The patient experienced immediate and complete cessation of her pain. She has continued to be asymptomatic at 6 months after surgery. CONCLUSIONS: Heavy weightlifting may potentially lead to MALS. The laparoscopic approach to MAL release can be utilized to treat this condition with favorable results. PMID- 30395047 TI - Laparoscopic Endoscopic Cooperative Surgery for Gastrointestinal Stromal Tumors. AB - With the development of laparoscopy and digestive endoscopy, multiple laparoscopic and endoscopic cooperative surgeries (LECSs) for gastrointestinal stromal tumors have recently been developed. Classic LECS has been confirmed as a feasible and safe treatment procedure for gastrointestinal stromal tumors with regard to both short-term surgical and long-term oncological outcomes; however, classic LECS has the potential risk of gastric contents or tumor cells spilling into the abdominal cavity because the gastric wall has to be opened during the procedure. Various modified LECS techniques have aimed at further minimizing invasiveness, such as the full-thickness resection method using the nonexposure technique (combination of laparoscopic and endoscopic approaches to neoplasia with a nonexposure technique), nonexposed endoscopic wall-inversion surgery, and closed LECS. This review describes and summarizes the current LECS for gastrointestinal tumor. PMID- 30395048 TI - Can SUVmax values of Ga-68-PSMA PET/CT scan predict the clinically significant prostate cancer? AB - PURPOSE: The intensity of prostate-specific membrane antigen (PSMA) expression increases as the tumor grade increases and the uptake of Ga-68-PSMA is higher in high-grade tumors. The aim of the present study was to evaluate the correlation of preoperative tracer uptake of primary tumor to Gleason Score in patients who underwent prostatectomy. PATIENTS AND METHODS: We retrospectively evaluated 141 patients who had Ga-68-PSMA positron emission tomography/computed tomography (PET/CT) imaging and who underwent prostatectomy. All patients had a diagnosis of prostate cancer on the basis of 10-24 cores transrectal ultrasound-guided biopsy (TRUS-Bx). Histological assessment was performed according to the New Contemporary Prostate Cancer Grading System. All patients had a prostate-specific antigen (PSA) level measurement within maximum of 28 days before Ga-68-PSMA PET/CT. Region of interests were drawn manually around the prostate gland, avoiding the bladder activity, to calculate the maximum standardized uptake values (SUVmax) values. RESULTS: The median PSA values for all patients were 10.0 ng/ml. PSA values for low-risk patients were significantly lower than those of high-risk patients (P<0.001). There were 41.1% upgrades and 7.8% downgrades following prostatectomy in terms of Grade Groups. According to the final pathology reports, 21% (n=16) of patients moved from a low-risk level (grade groups 1+2) to a high-risk level (grade groups 3+4+5). The median SUVmax value was 8.8, ranging from 2.1 to 62.4. There was a strong correlation between SUVmax values and grade groups (Pearson rho=0.66) (P<0.001). The mean SUVmax values of high-risk patients were significantly higher than those of low-risk patients (18.9+/-12.1 vs. 7.16+/-6.2, respectively) (P<0.001). Receiver operation characteristic curve analysis of SUVmax at the cut-off value of 9.1 showed a high sensitivity (78%) and specificity (81%) for detection of high risk disease. CONCLUSION: SUVmax values correlate significantly with the grade groups of the primary tumor. The intraprostatic accumulation sites may predict clinically significant cancer and potentially serve as a target for biopsy sampling in conjunction with mpMRI in selected patients. PMID- 30395049 TI - Advanced Age Redistributes Positive but Not Negative Leg Joint Work during Walking. AB - INTRODUCTION: Advanced age brings a distal-to-proximal redistribution of positive joint work during walking that is relevant to walking performance and economy. It is unclear whether negative joint work is similarly redistributed in old age. Negative work can affect positive work through elastic energy return in gait. We determined the effects of age, walking speed, and grade on positive and negative joint work in young and older adults. METHODS: Bilateral ground reaction force and marker data were collected from healthy young (age 22.5 years, n=18) and older (age 76.0 years, n=22) adults walking on a split-belt instrumented treadmill at 1.1, 1.4, and 1.7 m/s at each of three grades (0, 10, and -10%). Subjects also performed maximal voluntary eccentric, isometric, and concentric contractions for the knee extensors (120, 90, 0 degrees /s) and plantarflexors (90, 30, 0 degrees /s). RESULTS: Compared to young adults, older adults exhibited a distal-to-proximal redistribution of positive leg joint work during level (p<0.001) and uphill (p<0.001) walking, with larger differences at faster walking speeds. However, the distribution of negative joint work was unaffected by age during level (p=0.150) and downhill (p=0.350) walking. Finally, the age-related loss of maximal voluntary knee extensor (p<0.001) and plantarflexor (p=0.001) strength was smaller during an eccentric contraction vs. concentric contraction for the knee extensors (p<0.001) but not for the plantarflexors (p=0.320). CONCLUSION: The distal-to-proximal redistribution of positive joint work during level and uphill walking is absent for negative joint work during level and downhill walking. Exercise prescription should focus on improving ankle muscle function while preserving knee muscle function in older adults trying to maintain their independence.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30395050 TI - Protein to Maximize Whole-Body Anabolism in Resistance-trained Females after Exercise. AB - INTRODUCTION: Current athlete-specific protein recommendations are based almost exclusively on research in males. PURPOSE: Using the minimally-invasive indicator amino acid oxidation (IAAO) technique, we determined the daily protein intake that maximizes whole body protein synthesis and net protein balance after exercise in strength trained females. METHODS: Eight RT females (23 +/- 3.5 y, 67.0 +/- 7.7 kg, 163.3 +/- 3.7 cm, 24.4 +/- 6.9% body fat; mean +/- SD) completed a 2-d controlled diet during the luteal phase prior to performing an acute bout of whole body resistance exercise. During recovery, participants consumed eight hourly meals providing a randomized test protein intake (0.2-2.9 g?kg?d) as crystalline amino acids modelled after egg protein, with constant phenylalanine (30.5 mg?kg?d) and excess tyrosine (40.0 mg?kg?d) intakes. Steady state whole body phenylalanine rate of appearance (Ra), oxidation (Ox; the reciprocal of protein synthesis, PS) and net protein balance (NB; PS - Ra) were determined from oral [C] phenylalanine ingestion. Total protein oxidation was estimated from the urinary urea to creatinine ratio (U/Cr). RESULTS: A mixed model bi-phase linear regression revealed a breakpoint (i.e., estimated average requirement; EAR) in Ox (r = 0.64) of 1.49 +/- 0.44 g?kg?d (mean +/- 95% CI) and NB (r = 0.65) of 1.53 +/ 0.32 g?kg?d, indicating a saturation in whole body anabolism. U/Cr increased linearly with protein intake (r = 0.56, P < 0.01). CONCLUSIONS: Findings from this investigation indicate that the safe protein intake (upper 95% CI) to maximize anabolism and minimize protein oxidation for strength trained females during the early ~8-h post-exercise recovery period is at the upper end of ACSM recommendations for athletes (i.e., 1.2-2.0 g?kg?d). PMID- 30395051 TI - Exercise Mode Specificity for Preserving Spine and Hip BMD in Prostate Cancer Patients. AB - PURPOSE: Androgen deprivation therapy (ADT) in men with prostate cancer (PCa) is associated with an array of adverse effects including reduced bone mineral density (BMD) predisposing patients to increased fracture risk. Our purpose was to examine effects of targeted exercise modes on BMD in men with PCa undergoing ADT. METHODS: Between 2009 and 2012, 154 PCa patients aged 43-90 years on ADT were randomised to exercise targeting the musculoskeletal system (impact loading+resistance training; ImpRes; n=57) supervised for 12 months, cardiovascular and muscular systems (aerobic+resistance training; AerRes; n=50) supervised for 6 months followed by a 6-month home-based program, or delayed aerobic exercise (DelAer, n=47) received exercise information for 6 months followed by 6 months of supervised aerobic exercise (stationary cycling). Endpoints were lumbar spine, hip and whole-body BMD measured by DXA with secondary endpoints of lean and fat mass, appendicular skeletal muscle mass (ASM) and neuromuscular strength. Analysis of covariance was used to compare the exercise groups to DelAer at 6 and 12 months. RESULTS: There was a between-group difference in BMD for ImpRes and DelAer at the spine (6 months, p=0.039; 12 months, p=0.035) and femoral neck (6 months, p=0.050), with decline attenuated in ImpRes (~ -1.0% vs. ~ -2.0%). Compared to DelAer, ImpRes increased ASM at 6 months (0.3 kg, p=0.045) and improved muscle strength at 6 and 12 months (p<=0.012) by 9-34%. A limitation was inclusion of well-functioning patients. CONCLUSION: Combined impact loading and resistance exercise attenuates bone loss at the spine and enhances overall musculoskeletal function in PCa patients undergoing ADT. PMID- 30395052 TI - Caffeine Augments the Prothrombotic but Not the Fibrinolytic Response to Exercise. AB - : Caffeine, a popular ergogenic supplement, induces neural and vascular changes that may influence coagulation and/or fibrinolysis at rest and during exercise. PURPOSE: The purpose of this study was to assess the effect of a single dose of caffeine on measures of coagulation and fibrinolysis before and after a single bout of high intensity exercise. METHODS: 48 men (age 23 +/- 3 years, BMI 24 +/- 3 kg/m) completed two trials, with 6 mg/kg of caffeine (CAFF) or placebo (PLAC), in random order, followed by a maximal cycle ergometer test. Plasma concentrations of fibrinogen, factor VIII antigen, active tissue plasminogen activator (tPA:c), tissue plasminogen activator antigen (tPA:g), and active plasminogen activator inhibitor-1 (PAI-1:c) were assessed at baseline and immediately after exercise. RESULTS: Exercise led to significant changes in tPA:c (Delta 8.5 +/- 4.36 IU/ml for CAFF, 6.6 +/- 3.7 for PLAC), tPA:g (Delta 2.4 +/- 3.2 ng/ml for CAFF, 1.9 +/- 3.1 for PLAC), fibrinogen (Delta 30.6 +/- 61.4 mg/dL for CAFF, 28.1 +/- 66.4 for PLAC), and PAI-1:c (Delta -3.4 +/- 7.9 IU/ml for CAFF, -4.0 +/- 12.0 for PLAC) (all P < 0.05), but no effect of condition or time x condition interactions were observed. Main effects of time, condition, and a significant time x condition interaction were observed for factor VIII, which increased from 1.0 +/- 0.4 to 3.3 +/- 1.3 IU/ml with CAFF and 1.0 +/- 0.4 to 2.4 +/- 0.9 IU/ml with PLAC. CONCLUSIONS: Coagulation potential during exercise is augmented after caffeine intake, without a similar increase in fibrinolysis. These results suggest caffeine intake may increase risk of a thrombotic event during exercise. PMID- 30395053 TI - Energy Flow Analysis to Investigate Youth Pitching Velocity and Efficiency. AB - PURPOSE: The purposes of this study were (1) to investigate the transfer of energy through the kinetic chain by youth baseball pitchers during the pitching motion, and (2) to provide insight into how the total magnitude of energy flow and its linear and rotational components relate to both velocity and joint torque per unit increment of pitch velocity (joint load efficiency). METHODS: Twenty four youth baseball pitchers participated in this study. Data collection occurred in an indoor research lab equipped with a 14-camera infrared motion capture system and an instrumented pitcher's mound with embedded force plates. Energy flow was calculated by integrating power transfer into and out of each segment. The magnitudes of key instances of energy flow were compared to pitch velocity and velocity-normalized joint torques using simple linear regressions. RESULTS: All of the energy flow variables calculated had a significant correlation to pitch velocity. Energy flow into the arm from the trunk had the strongest correlation to velocity of any variable investigated (r = 0.900, p = 0.000). The total magnitude of energy flow into the trunk had a significant correlation to increased horizontal shoulder adduction efficiency and shoulder internal rotation efficiency. The magnitude of energy flow into the trunk by only joint forces had a significant correlation to increased horizontal shoulder adduction efficiency, shoulder internal rotation efficiency, and elbow varus efficiency. CONCLUSION: Energy flow analysis is an effective tool providing quantitative assessment of the kinetic chain to gain a deeper understanding of how energy moves through an athlete, and how specific pitching mechanics impact this movement. The results of this study support the importance of generating energy flow throughout the body to produce high velocities and energy flow through the trunk to increase pitch efficiency. PMID- 30395054 TI - 25th Year Celebration: Top Procedures in Sports Medicine and Arthroscopy. PMID- 30395055 TI - Knee Dislocation and Multiple Ligament Injuries of the Knee. AB - The purpose of this paper is to present an overview of the progress in treatment of knee dislocations and posterior cruciate ligament (PCL)-based multiple ligament knee injuries over the past 25 years. The perspectives of where we were 25 years ago, where we are today, and where we will be in the future will be explored. PMID- 30395056 TI - Treatment of ACL Tears in the Skeletally Immature Patient. AB - The understanding and treatment of anterior cruciate ligament tears in skeletally immature patients continues to evolve. While conservative management was a mainstay of treatment, poor outcomes have led to several surgical techniques aimed at stabilizing the knee, optimizing outcome, and minimizing the chance of growth disturbance. Current techniques have, in large part, accomplished these goals but challenges remain. Looking to the future, different graft options, primary repair techniques, and rigorous prospective studies will help improve outcomes for this challenging patient population. PMID- 30395057 TI - The Evolution of Patellofemoral Instability Surgery During the Past 25 Years. AB - Surgical treatment of patellofemoral instability has evolved during the past 25 years as we developed a better appreciation of anatomy and a more sophisticated understanding of pathophysiology. Currently, most patellofemoral surgeons use soft tissue procedures like medial patellofemoral ligament reconstruction to treat medial soft tissue insufficiency and tibial tuberosity or femoral osteotomy to correct substantial bony malalignment. Advances in imaging technology and computational analysis have allowed for more precise preoperative planning and outcome modeling so that the optimum operation using >=1 of these procedures can be designed to meet the unique needs of an individual patient. PMID- 30395058 TI - Meniscus Repair and Replacement. AB - The importance of preserving the function of the meniscus is seen with renewed interest. There has been an evolution of arthroscopic meniscus repair from inside out, outside-in, meniscal fixators, to all-inside suturing techniques. Tear patterns once ignored or thought to be irreparable, such as root tears and horizontal cleavage tears, have recently been undergoing repair with promising results. Newer techniques have also recently allowed surgeons to address postmeniscectomy knee pain. Replacing lost tissue with scaffolds or replacing the meniscus with an allograft helps restore function and reduce degenerative changes. PMID- 30395059 TI - Anterior Cruciate Ligament Reconstruction. AB - The past 3+ decades have been a period of intense interest in the anterior cruciate ligament. Graft choices, techniques, and fixation devices have all evolved. Our understanding of the anatomy has improved. Our follow-up and criteria for success have also expanded. Over the next several years advanced repair techniques, extra-articular augmentation, and addressing elevated tibial slope will all have to have their indications defined. PMID- 30395060 TI - Preservation of Knee Articular Cartilage. AB - Hyaline articular cartilage is critical for the normal functioning of the knee joint. Untreated focal cartilage defects have the potential to rapidly progress to diffuse osteoarthritis. Over the last several decades, a variety of interventions aiming at preserving articular cartilage and preventing osteoarthritis have been investigated. Reparative cartilage procedures, such as microfracture, penetrate the subchondral bone plate in effort to fill focal cartilage defects with marrow elements and stimulate fibrocartilaginous repair. In contrast, restorative cartilage procedures aim to replace the defective articular surface with autologous or allogeneic hyaline cartilage. This review focuses on the preservation of articular cartilage, and discusses the current reparative and restorative surgical techniques available for treating focal cartilage defects. PMID- 30395061 TI - Shoulder Instability: Anterior, Posterior, Multidirectional, Arthroscopic Versus Open, Bone Block Procedures. AB - This article presents a retrospective comprehensive review of the history of anterior, posterior, and multidirectional shoulder instability and also reviews key concepts such as open versus arthroscopic repair and glenoid and humeral head bone loss and associated treatments. The future of shoulder instability will continue to evolve as research and clinical experience will determine the direction of the future. PMID- 30395062 TI - Rotator Cuff Repair: Single Row Repair Versus Double Row Repair and Superior Capsular Reconstruction. AB - The surgical management of rotator cuff (RC) tears has progressed considerably in recent decades. Arthroscopic procedures now represent the mainstay of contemporary treatment approaches. The success of repair is predicated upon the achievement of a secure, durable repair that promotes tendon-to-bone healing. Both single and double row (DR) suture anchor configurations have been described to achieve stable fixation. Although consensus is lacking with regard to the clinical superiority of one configuration over another, trends in the literature suggest that DR repairs may optimize the likelihood of tendon healing and restoration of shoulder strength. In cases of truly irreparable RC tears, superior capsular reconstruction is a promising alternative to open tendon transfer and arthroplasty procedures. The purposes of this concise review are to: (1) explain our preference for a DR repair configuration in almost all circumstances; and (2) advocate superior capsular reconstruction as a viable treatment tactic for truly irreparable RC tears in the absence of significant glenohumeral arthritis. PMID- 30395063 TI - Surgical Management of Proximal Long Head Biceps Tendon Disorders. AB - Disorders of the long head of the biceps tendon can make a significant contribution to shoulder pain and dysfunction. Historically, open biceps tenotomy or a proximal tenodesis of the tendon through a deltopectoral approach was used to manage biceps tendonitis and instability. Recent developments have added additional options. Arthroscopic techniques offer minimally invasive methods to secure the biceps in the suprapectoral region at the appropriate length. An open subpectoral tenodesis provides for simple exposure that secures the tendon just proximal to the musculotendinous junction and eliminates potentially diseased tendon and synovium from the biceps groove. Common fixation methods include the use of interference screws, suture anchors, and button devices. Future developments will likely add modified tenotomy techniques that will minimize the Popeye deformity in low-demand individuals. Simpler, but secure methods of fixation for higher demand patients will minimize the operative time required. PMID- 30395064 TI - Elbow Surgery in Athletes. AB - Injuries and disorders of the elbow in athletes are common especially among throwing athletes. Common injuries encountered in the throwing athlete include ulnar collateral ligament injuries, ulnar neuritis, capitellar osteochondritis dissecans, valgus extension overload with posterior olecranon impingement, olecranon stress fracture, and loose bodies. A thorough knowledge of both the functional anatomy as well as throwing biomechanics are required to properly diagnosis and treat these problems. Nonoperative and surgical techniques have continued to advance over the last 25 years allowing for improved prognosis and return to play for athletes affected with elbow pathology. PMID- 30395065 TI - Hip Arthroscopy - State of the Art in 2018. AB - The field of hip arthroscopy has undergone considerable change in the past 25 years and continues to evolve at a rapid pace. Lessons from the early complications and challenges of hip arthroscopy have led to improved safety and refinement of instrumentation and techniques. The pathophysiology of hip injuries is better understood, and advances in surgical technique have helped expand indications, particularly as a shift from pathology resection to anatomic repair and reconstructive procedures has occurred. As the field has progressed, longitudinal outcome studies are now available to help judge efficacy. The purpose of this review is to highlight the past 30 years of hip arthroscopy, the current practice trends, and future directions of the field. PMID- 30395066 TI - Ankle Arthroscopic Surgery. AB - Ankle arthroscopy is a diagnostic and therapeutic surgical procedure which was first attempted on cadavers by Dr Burman in 1931 and first successfully described in patients by Dr Takagi in 1939. Two general approaches to ankle arthroscopy currently exist: (1) anterior ankle arthroscopy and (2) posterior ankle arthroscopy. The indications for ankle arthroscopy have expanded as increased experience has been obtained treating various pathologic entities and as the surgical results have been reported in the literature. There has been significant progress in ankle arthroscopic surgery over the past decades, notably allowing surgical procedures to be performed with fewer complications and with quicker return to work and play. We anticipate that expanding indications for arthroscopic ankle surgical procedures combined with further development of biomedical devices to enhance these procedures will result in improved patient outcomes in the future. PMID- 30395067 TI - The Surgical Applications of Biologics in Sports Medicine. AB - Over the past 25 years an increased appreciation of the positive impact of biologic interventions has driven significant advances in the surgical treatment of shoulder and knee conditions. These biologic adjuncts to treatment promote improved outcomes and have set the stage and increased research and development in this arena. PMID- 30395068 TI - Surgery in Tendinopathies. AB - Tendinopathies are challenging. The term "tendinopathy" refers to clinical condition characterized by pain, swelling, and functional limitations of tendons and nearby structures. Tendinopathies give rise to significant morbidity, and, at present, only limited scientifically proven management modalities exist. Achilles and patellar tendons are among the most vulnerable tendons, and among the most frequent lower extremity overuse injuries. Achilles and patellar tendinopathies can be managed conservatively and surgically. Several surgical procedures have been described for both conditions, and, if performed well, they lead to a relatively higher rate of success with low complication. PMID- 30395071 TI - Pediatric Injuries Treated at a Level 1 Trauma Center After an F5 Tornado. AB - BACKGROUND: On May 22, 2011, an F5 tornado ripped through the city of Joplin, Mo, resulting in over 150 fatalities and over 750 injuries. Pediatric trauma centers in the region needed to be prepared to receive patients. Little data exist on the types of patients who are received at pediatric trauma centers after disasters such as tornados. OBJECTIVE: The purpose of this study is to describe the patients received at the nearest level 1 pediatric trauma center after the tornado. METHODS: Cases were identified through the trauma registry. Data regarding patient demographics, past medical history, characteristics of injury, treatment received, and outcomes were obtained retrospectively from medical records. RESULTS: A total of 10 patients were received at the pediatric trauma center. Traumatic brain injury was the most common diagnosis followed by orthopedic and maxillofacial injuries. Seven patients required surgical procedures in the operating room, but only 1 patient required surgery within the first 24 hours of arrival. Eight patients were intubated and were in the pediatric intensive care unit. The average length of stay in the hospital was 19.4 days with a range of 14 hours to 94 days. CONCLUSIONS: Immediately after a significant tornado in the referral region, pediatric trauma centers need to prepare to receive patients. Head injuries will likely be common, and pediatric trauma centers will likely receive multiple intubated patients. Knowledge of injuries received and resources needed can better prepare these trauma centers for future devastating tornadoes. PMID- 30395072 TI - An Update on Pediatric Stroke Protocol. AB - Pediatric stroke is relatively rare, with approximately 1000 childhood strokes in the United States per year. However, the occurrence of stroke in children leads to significant morbidity and mortality, warranting the development proven screening tools, protocols, and treatment options. Because significant delays in seeking medical attention can occur, time to recognition of pediatric stroke in the emergency department is uniquely challenging and critical. Once recognized, a trained multidisciplinary team with a multifaceted approach is needed to provide the best possible outcome for the patient. Key elements of the pediatric stroke protocol should include recognition tools, stroke alert mechanism, stroke order sets, timely imaging, laboratory evaluation, and treatment options. Substantial advancements have been made in the field of pediatric stroke protocols mainly due to formation of international consortiums and clinical trial. Despite significant progress, treatment options remain controversial. PMID- 30395074 TI - Point-of-Care Ultrasound Facilitates Bedside Diagnosis of Appendicitis With an Appendicolith in a Pediatric Patient. AB - A previously healthy 5-year-old boy presented to the emergency department with a history of tactile fevers, cough, congestion, decreased appetite, and abdominal pain. He had diffuse abdominal pain on examination and pain with ambulation. Emergency point-of-care ultrasound was used to diagnose appendicitis with an appendicolith. The diagnosis was confirmed by a radiology-performed ultrasound, and he was taken to the operating room for an appendectomy. PMID- 30395075 TI - Mycophenolate mofetil alongside high-dose corticosteroids: optimizing the management of combination immune checkpoint inhibitor-induced colitis. AB - Immune checkpoint inhibitor (IO) induced colitis is primarily managed with corticosteroids. Most patients have a rapid resolution of symptoms and do not require additional immunosuppressants. Many patients, however, require prolonged corticosteroid courses to maintain control of toxicity. Mycophenolate mofetil (MMF) is the prodrug of mycophenolic acid; which in turn directly inhibits activated T and B lymphocytes. MMF, in addition to corticosteroids, may enable reduction of corticosteroids without precipitating resurgence of colitis. Metastatic melanoma patients between 1 January 2017 and 31 December 2017 with combination IO-induced colitis were managed with a novel treatment algorithm: upfront oral enteric-coated MMF alongside high-dose corticosteroids. Outcome measures included incidence of colitis flare, time to grade 1 and grade 0 colitis, time to patient-reported normal bowel habit and overall cumulative corticosteroid exposure. Thirteen patients developed high-grade combination IO induced colitis; 11 were managed with the combination of high-dose corticosteroid and MMF. Median patient age was 59 (range: 28-73) years. Four (36%) developed flare of colitis; flares occurred at a median of 11 (interquartile range: 4.5 16.75) days. All colitis flares responded fully to infliximab (5 mg/kg). The remaining seven patients did not develop colitis flare during corticosteroid wean. All patients were successfully weaned from corticosteroids and none had a resurgence of colitis at 8 weeks following discontinuation of MMF. Concomitant enteric-coated MMF alongside high-dose corticosteroids may hasten the improvement of high-grade colitis to normal bowel habit and reduce the incidence of colitis flare. PMID- 30395076 TI - Primary malignant melanotic melanoma and hypomelanotic melanoma of the female urethra: case series and a review of the literature in China. AB - The incidence of primary malignant melanoma (MM) of female urethra is extremely low, leading to paucity of recommendations on management. The objectives of our study were to gain more insight into the clinical features, diagnosis, treatment, and prognosis of this rare type of tumor. We carried out a retrospective analysis of all four cases who underwent an operation in our hospital since 1980. Moreover, other 32 cases of MM that have been reported in Chinese papers were also included for further review. The age of the patients ranged from 38 to 81 years. A mass in the urethral meatus and hematuria are common presentations. The final diagnosis depends on histopathological examination. After surgery alone or combined with chemotherapy/radiotherapy/immunotherapy, all cases were followed for 1-151 months, whereas only one lived for more than 4 years after receiving the diagnosis. A timely and accurate diagnosis of MM is critical, especially for hypomelanotic and amelanotic cases. Immunohistochemical staining and electron microscopy are necessary for a precise diagnosis in some cases. Extensive resection, early chemotherapy, and immunotherapy may help to improve survival. PMID- 30395077 TI - Emergent Themes for Instructional Design: Alpha and Beta Testing During a Faculty Development Course. AB - INTRODUCTION: Instructional design is an established discipline for designing educational activities for learners and is applied during the development of simulation-based healthcare educational activities. Although the iterative process is already being used with alpha/beta testing during development of the simulation, the process has not been described in detail. We sought to describe this process of design changes made during a novice faculty development course for simulation-based healthcare education where participants routinely design scenarios and conduct alpha/beta testing. METHODS: Using a mixed methods study, participant written narratives and checklist/rating scales were collected on changes made during both alpha and beta testing. Narratives were analyzed using the qualitative grounded theory approach to identify emergent themes. Checklist/rating scales were analyzed for changes made to previously identified areas and how critical these changes were to the success of the scenario. RESULTS: Several themes of frequent changes made during the alpha/beta testing process emerged from the participant narratives that included REALISM, PROTOCOLS, INTRODUCTIONS and ROLES. The quantitative analysis of potential areas for change correlated with the emergent themes. CONCLUSIONS: Novice scenario designers make similar changes in thematic areas during the instructional design process. Faculty development courses for novice simulation healthcare educators should anticipate attention to these areas during discussions and consider specific didactics to avoid common design pitfalls of novice educators. PMID- 30395078 TI - Augmented Reality Future Step Visualization for Robust Surgical Telementoring. AB - INTRODUCTION: Surgical telementoring connects expert mentors with trainees performing urgent care in austere environments. However, such environments impose unreliable network quality, with significant latency and low bandwidth. We have developed an augmented reality telementoring system that includes future step visualization of the medical procedure. Pregenerated video instructions of the procedure are dynamically overlaid onto the trainee's view of the operating field when the network connection with a mentor is unreliable. METHODS: Our future step visualization uses a tablet suspended above the patient's body, through which the trainee views the operating field. Before trainee use, an expert records a future library of step-by-step video footage of the operation. Videos are displayed to the trainee as semitransparent graphical overlays. We conducted a study where participants completed a cricothyroidotomy under telementored guidance. Participants used one of two telementoring conditions: conventional telestrator or our system with future step visualization. During the operation, the connection between trainee and mentor was bandwidth throttled. Recorded metrics were idle time ratio, recall error, and task performance. RESULTS: Participants in the future step visualization condition had 48% smaller idle time ratio (14.5% vs. 27.9%, P < 0.001), 26% less recall error (119 vs. 161, P = 0.042), and 10% higher task performance scores (rater 1 = 90.83 vs. 81.88, P = 0.008; rater 2 = 88.54 vs. 79.17, P = 0.042) than participants in the telestrator condition. CONCLUSIONS: Future step visualization in surgical telementoring is an important fallback mechanism when trainee/mentor network connection is poor, and it is a key step towards semiautonomous and then completely mentor-free medical assistance systems. PMID- 30395079 TI - Preparing the Next Generation of Code Blue Leaders Through Simulation: What's Missing? AB - INTRODUCTION: Despite the increasing reliance on simulation to train residents as code blue leaders, the perceived role and effectiveness of code blue simulations from the learners' perspective have not been explored. A code blue Simulation Program (CBSP), developed based on evidence-based simulation principles, was implemented at our institution. We explored the role of simulation in code blue training and the differences between real and simulated code blues from the learner perspective. METHODS: Using a thematic analysis approach and a purposeful sampling strategy, residents who participated in the CBSP were invited to participate in one of the three focus groups. Data were collected through small group discussions guided by semistructured interviews. The interviews were audio recorded and transcribed. Interview transcripts were coded to assess underlying themes. RESULTS: Thematic analysis revealed that participants believed that the CBSP enhanced preparedness by capturing aspects of real codes (eg, inclusion of precode scenarios with awake patients, lack of readily available information) and facilitating automatization of code blue processes. Despite efforts to develop a high-fidelity simulation, participants noted that they experienced more anxiety, observed more chaos in the environment, and encountered different communication challenges in real codes. CONCLUSIONS: The CBSP enhanced resident preparedness to serve as code blue leaders. Learners highlighted that they valued the CBSP; however, differences remain between simulated and real codes that could be addressed to enhance the fidelity of future simulations. PMID- 30395080 TI - Volar Vascularized Strut Graft for Avascular Scaphoid Nonunion Using the 1,2 Intercompartmental Supraretinacular Artery. AB - In this retrospective study, we report the preliminary results of a novel technique for volar vascularized strut grafting to treat avascular scaphoid nonunion by using the 1,2 intercompartmental supraretinacular artery through a single incision. Forty-three of 45 patients with avascular scaphoid nonunion healed at a mean of 13 weeks (range, 3 to 10 mo). Complications consisted of 1 pin tract infection that resolved with oral antibiotics and 4 cases of transient dysesthesia of the radial sensory nerve. In 4 patients with equivocal radiographs, computed tomography scans confirmed bony union. The 2 patients who remained unhealed subsequently underwent proximal row carpectomy. Two other patients had persistent pain with the progression of radiocarpal arthritis. Our technique provides good results for the treatment of avascular scaphoid fracture nonunion. Notable advantages include performance through a single incision, use of an already established vascularized bone graft, volar graft placement, and no requirement for microvascular free graft reconstruction. It also provides the surgeon with the ability to adjust the procedure intraoperatively in the event of unexpected avascularity, without requiring substantially longer operative time or additional equipment. PMID- 30395081 TI - Brachioradialis Flap for Soft Tissue Coverage of Posterior Elbow Wounds: Case Report and Surgical Technique. AB - The posterior aspect of the elbow is an area prone to chronic wound complications due to its prominence and the tensile forces resulting from elbow range of motion. In situations in which local wound care fails, various options for soft tissue coverage are available, including the anconeus, lateral arm, radial forearm, extensor carpi radialis longus, and flexor carpi ulnaris flaps. Each option offers unique considerations depending on the complexity and extent of the soft tissue defect. In situations in which coverage of a large defect is required, or when primary soft tissue coverage options fail, an alternative option is the brachioradialis rotational muscle flap. We present a review of the literature, case report, and surgical technique using the brachioradialis muscle for coverage of a large posterior elbow wound after failure of an anconeus flap. PMID- 30395082 TI - Cirrhotic Patients Admitted to the ICU with Septic Shock: Factors Predicting Short and Long-Term Outcome. AB - Cirrhotic patients with septic shock have a poor prognosis in ICU compared to general population of critically ill patients. Little is known about long-term outcome in these patients. We performed a retrospective analysis of a prospective cohort of cirrhotic patients with septic shock. The aim of this study was to describe both short and long-term outcomes and to evaluate factors predicting mortality. Data from 149 patients were analyzed (mean age: 60 +/- 11 years, sex ratio: 2.4). Mortality rate in the ICU was 54% and at 1 year it was 73%. Among factors associated with adverse outcome, independent factors predicting ICU mortality were early need for renal replacement therapy (odds ratios, OR 13.95, 95% confidence interval, CI 3.30; 59.03) and arterial lactate >5 mmol.L (OR 7.27, 95% CI 2.92; 18.10), and early use of mechanical ventilation (OR 3.05, 95% CI 1.08; 8.58). For 1-year mortality, independent prognostic factors were the need for renal replacement therapy during ICU stay (OR 9.60, 95% CI 2.90; 31.82), prothrombin time <=40% (OR 3.47, 95% CI 1.43; 8.43), and Charlson score (OR 1.36 per point, 95% CI 1.11; 1.67). The results emphasize the poor prognosis of cirrhotic patients with septic shock admitted to the ICU. The need for organ supports appears to be a better predictor of short-term outcome than the underlying hepatic disease. Renal replacement therapy is associated with both short and long-term outcomes. PMID- 30395083 TI - Discrepancies between Patient and Surgeon Expectations of Surgery for Sciatica: A Challenge for Informed Decision Making? AB - STUDY DESIGN: Qualitative study. OBJECTIVE: The objective of this study was to compare the perceptions of patients and surgeons regarding the risks and benefits of lumbar decompressive surgery for sciatica following a consultation meeting. SUMMARY OF BACKGROUND DATA: Evidence regarding pain improvement in patients following lumbar decompressive surgery for sciatica is inconsistent. Given this inconsistency, patients choosing to undergo lumbar decompressive surgery must accept the risks associated with the surgery despite uncertainty regarding benefits. This raises questions as to the nature of informed decision-making for patients choosing to undergo surgery for sciatica. METHODS: We undertook a qualitative descriptive study with 12 adult lumbar decompressive surgery candidates and 6 of their spine surgeons and analyzed data using inductive content analysis. RESULTS: Our analysis revealed that most patients were satisfied with the consultation despite limited understanding of lumbar decompressive surgery. We found discrepancies between patients' preoperative expectations and understanding of information provided by surgeons and what surgeons believed they had conveyed. Surgeons and patients disagreed on how much information is needed about post-surgical activity modifications and long-term outcomes in order to make a decision about whether or not to undergo surgery, with patients desiring more information. As a result, for most patients, the decision-making process extended beyond the information provided by surgeons and incorporated information from family members, friends, family doctors and the internet. CONCLUSION: Our results highlight misunderstandings between patients and surgeons, particularly in regard to prognosis and activity modifications. Since this information is important for patients choosing whether to undergo a surgical intervention, our study provides guidance to improve informed decisions about sciatica and, potentially, other elective surgeries. LEVEL OF EVIDENCE: 4. PMID- 30395084 TI - Effect of Prosthesis width and Depth on Heterotopic Ossification after Cervical Disc Arthroplasty. AB - STUDY DESIGN: Retrospective analysis. OBJECTIVE: To investigate the effect of width and depth of the inserted cervical disc prosthesis on heterotopic ossification (HO) after cervical disc arthroplasty (CDA), and to explore the relationship between clinical outcome and HO. SUMMARY OF BACKGROUND DATA: The mechanism of HO formation still remains unknown. Footprint mismatch of cervical disc prosthesis was common in cervical arthroplasty. Compared with endplate, some inserted prostheses were smaller in width and length. METHODS: Retrospectively analysis the patients underwent CDA with Prestige-LP Disc in our institute. Patients were divided into HO group or non-HO group according to the McAfee classification. The ratio of the width (Rw) and depth (Rd) of prosthesis to endplate were calculated. Radiographic and clinical assessments included: C2-7 angle, segmental angle (SA), range of motion (ROM) of the index level, Visual analogue scale (VAS), neck disability index (NDI), and Japanese orthopaedic association (JOA) scores. RESULTS: The mean follow-up time was 47.7 months. At the last follow-up, the overall incidence of HO was 34.3% (35/102). There were 35 patients in the HO-group, and 67 patients in the non-HO group. The overall Rw and Rd was 0.887 +/- 0.057 and 0.927 +/- 0.048, respectively. Both the Rw and Rd of HO-group were smaller than those of non-HO group (0.869 vs. 0.897, P = 0.033; 0.888 vs. 0.948, P < 0.001).There were no significant differences in VAS, NDI or JOA scores, C2-7 angle, or SA between the two groups. But the HO group had less ROM of the index level than the non-HO group (5.3 degrees vs 9.0 degrees ). CONCLUSIONS: Some of prosthesis had insufficient coverage to the endplate in width and depth. Insufficient coverage of endplate in width and depth may induce the formation of HO. HO could reduce the ROM of the index level, but did not influence the clinical outcome. LEVEL OF EVIDENCE: 3. PMID- 30395085 TI - Surgical and Health-related Quality-of-Life Outcomes of Growing Rod "Graduates" With Severe versus Moderate Early-onset Scoliosis. AB - STUDY DESIGN: A retrospective review of a prospective, multicenter database. OBJECTIVE: The aim of this study was to compare surgical and quality-of-life outcomes at the end of growing rod treatment in patients with severe versus moderate early-onset scoliosis (EOS). SUMMARY OF BACKGROUND DATA: Knowledge of the outcomes of severe EOS after growth-friendly treatment is limited because this condition is uncommon. METHODS: We identified 40 children with severe EOS (major curve >=90 degrees ) treated with growing rods before age 10 with minimum 2-year follow-up after last lengthening or final fusion. From the same registry, we matched 40 patients with moderate EOS (major curve < 90 degrees ). Twenty seven patients in the severe group and 12 in the moderate group underwent final fusion (P < 0.001). RESULTS: Mean preoperative curves were 102 degrees (range, 90 degrees -139 degrees ) in the severe group and 63 degrees (range, 33 degrees 88 degrees ) in the moderate group (P < 0.001). At final follow-up, mean curves were 56 degrees (range, 10 degrees -91 degrees ) and 36 degrees (range, 12 degrees -89 degrees ), respectively (P < 0.001). Fourteen (35%) children in the severe group and 32 (80%) in the moderate group had scoliosis of < 45 degrees at final follow-up [risk ratio (RR), 0.44; 95% confidence interval (95% CI), 0.20 0.57]. At final follow-up, 30 (75%) children in the severe group and 35 (88%) in the moderate group had achieved T1-T12 length of >=18 cm (RR, 0.86; 95% CI, 0.70 1.09). Thirty-five children in the severe group and 26 in the moderate group had at least one complication (RR, 1.35; 95% CI, 1.05-1.73). Mean 24-Item Early-Onset Scoliosis Questionnaire scores were similar between groups at final follow-up. CONCLUSION: Delaying surgery until the major curve has progressed beyond 90 degrees is associated with larger residual deformity and more complications than treating at a lesser curve magnitude. Quality-of-life outcomes were similar between those with severe and moderate EOS. LEVEL OF EVIDENCE: 3. PMID- 30395086 TI - Epidemiology of Spinal Fractures in a level one Trauma Center in the Netherlands; a 10 Years Review. AB - STUDY DESIGN: Retrospective epidemiological study OBJECTIVE.: To describe the epidemiology of spinal fractures over a ten years period in a Level 1 Trauma center in the Netherlands. SUMMARY OF BACKGROUND DATA: Spinal fractures may have large socioeconomic consequences. The prevalence and outcomes likely change over the years due to improved traffic safety, increasing population age and improved medical treatment. This is the first study to address the epidemiology of spinal fractures over a large time period in the Netherlands. METHODS: All patients with a cervical, thoracic or lumbar spine fracture admitted to a level 1 trauma center from 2007 to 2016 were prospective registered and retrospectively analyzed. In addition to patient-, accident- and associated injury characteristics, radiological and surgery data were obtained from the hospital's Electronic Patient File system. RESULTS: Between 2007 and 2016, 1479 patients with a total of 3029 spinal fractures were admitted. 40,8% were female and 59,2% were male, with a mean age of 52,0 years. 4,9% of fractures occurred at a juvenile age (0 18) and 63,6% at the age of 19-64 years. Most fractures occurred in the thoracic spine, followed by the lumbar- and cervical spine. The most common cause of injury was a fall from height, followed by traffic accidents. Spinal cord injury occurred in 8,5% and associated injuries were reported in 73% of the patients. Sixteen percent of the admitted patients were treated operatively. Over time, there was a larger increase in amount of spine fractures in elderly (>65 years) compared to younger people. CONCLUSION: The total amount of spine fractures per year increased over time. Additionally, there was a larger increase in amount of spine fractures in patients over 65 years of age compared to younger patients. Despite this increase, a considerable amount of spine fractures still occur in the age-group 19-64 years. Most fractures were located in the thoracic spine. This study might stimulate development of policy on precautionary actions to prevent spine fractures. LEVEL OF EVIDENCE: level 4. PMID- 30395087 TI - Longer Preoperative Duration of Symptoms Negatively Affects Health-Related Quality of Life After Surgery for Cervical Radiculopathy. AB - STUDY DESIGN: Retrospective Cohort OBJECTIVE.: Determine the effect of duration of symptoms (DOS) on health-related quality of life (HRQOL) outcomes for patients with cervical radiculopathy. SUMMARY OF BACKGROUND DATA: The effect of DOS has not been extensively evaluated for cervical radiculopathy. METHODS: A retrospective analysis of patients who underwent an anterior cervical decompression and fusion for radiculopathy was performed. Patients were grouped based on DOS of less than 6 months, 6 months to 2 years, and more than 2 years and HRQOL outcomes were evaluated. RESULTS: A total of 216 patients were included with a mean follow-up of 16.0 months. There were 86, 61, and 69 patients with symptoms for less than 6 months, 6 months to 2 years, and more than 2 years, respectively. No difference in the absolute postoperative score of the patient reported outcomes was identified between the cohorts. However, in the multivariate analysis, radiculopathy for more than 2 years predicted lower postoperative SF-12 PCS (p = 0.037) and SF-12 MCS (p = 0.029), and higher postoperative NDI (p = 0.003), neck pain (p = 0.001), and arm pain (p = 0.004) than radiculopathy for less than 6 months. Furthermore, the recovery ratios for patients with symptoms for less than 6 months demonstrated a greater improvement in NDI, neck pain, and arm pain than for 6 months to 2 years (p = 0.041; 0.005; 0.044) and more than 2 years (p = 0.016; 0.014; 0.002), respectively. CONCLUSIONS: Patients benefit from spine surgery for cervical radiculopathy at all time points, and the absolute postoperative score for the patient reported outcomes did not vary based on the DOS; however, the regression analysis clearly identified symptoms for more than two years as a predictor of worse outcomes, and the recovery ratio was statistically significantly improved in patients who underwent surgery within six months of the onset of symptoms. LEVEL OF EVIDENCE: 3. PMID- 30395088 TI - Bone Graft Substitutes in Single or Double Level Anterior Cervical Discectomy and Fusion: A Systematic Review. AB - STUDY DESIGN: Systematic Review OBJECTIVE.: To undertake a systematic review of published literature to evaluate efficacy of bone graft substitutes on radiographic and clinical outcomes in single or double level anterior cervical discectomy and fusion (ACDF) for degenerative disease. SUMMARY OF BACKGROUND DATA: Anterior cervical discectomy and fusion (ACDF) is one of the most common spinal surgeries completed in the United States. Today bone graft substitutes including ceramic-based synthetic bone grafts, allografts, bone morphogenetic proteins, mesenchymal stem cells, and bone marrow aspirate are widely used to enhance fusions; even though the efficacy of these substitutes is poorly defined. Critical evaluation of these products is necessary to optimize radiographic and clinical outcomes for ACDF in degenerative disease. METHODS: A systematic literature review of 22 published articles was conducted. All articles reported results on patients who underwent a single or double level ACDF performed using a bone graft substitute and reported results on radiographic fusion rates at least 6 months after surgery. RESULTS: All studies using bone morphogenetic protein (BMP) showed 100% fusion rate despite length of the study or whether additional bone graft substitutes were used. Use of only ceramic-based synthetics had the lowest fusion rate, 80.5%. Use of only mesenchymal stem cells resulted in an average fusion rate of 87.7%. When used alone, allograft resulted in an average fusion rate of 87.3%. This was significantly influenced by one outlier, Kim, et al., which when removed, increased the fusion rate to 93.5%. Clinical outcomes were improved postoperatively irrespective of the graft used, though dysphagia was significantly greater in studies using BMP (p < 0.001). CONCLUSIONS: Allograft alone has the lowest cost with similar fusion rates and clinical outcomes compared to other bone graft substitutes. Physicians should consider this when choosing to use bone graft substitutes for routine ACDFs. LEVEL OF EVIDENCE: 4. PMID- 30395089 TI - An Insight Into the Health-Related Quality of Life of Adolescent Idiopathic Scoliosis Patients Undergoing Bracing, Observation, and Previously Braced. AB - STUDY DESIGN: Prospective cross-sectional study. OBJECTIVE: To determine the health-related quality of life (HRQoL) of adolescent idiopathic scoliosis (AIS) patients undergoing bracing, previously braced and observation only. SUMMARY OF BACKGROUND DATA: HRQoL is an important treatment outcome measure for AIS. A poor HRQoL may also negatively influence the success of bracing by reducing the likelihood of good brace compliance. Yet, the HRQoL thresholds for patients undergoing observation only, brace treatment or previous brace treatment is not well understood. METHODS: Chinese AIS patients with refined Scoliosis Research Society 22-item (SRS-22r) Questionnaire and EuroQol 5-Dimension 5-Level (EQ-5D 5L) Questionnaire scores were consecutively recruited for this cross-sectional study. Patients were grouped based on their treatment modality (observation only, bracing, previously braced, and postoperatively). Coronal and sagittal Cobb angles, degree of apical vertebral rotation, and curve type were studied. Spearman correlation test, independent t test, and one-way analysis of variance (ANOVA) with Tukey Post-hoc test were performed for statistical analysis. RESULTS: A total of 652 AIS patients with mean age of 14.8 +/- 1.9 years and mean Cobb angle of 18.6 degrees +/- 10.0 degrees was studied. The respective mean SRS-22r total scores for bracing, observation, and previously braced groups were 4.20, 4.54, and 4.42, and mean EQ-5D-5L scores were 0.87, 0.95, and 0.92. The total and domain scores were correlated with coronal Cobb angles (P < 0.001) while only EQ-5D-5L correlated with sagittal Cobb angles (P < 0.001). Curves more than 40 degrees had worse HRQoL (P < 0.001). Currently braced patients had significantly worse HRQoL than those under observation, as indicated by lower EQ 5D-5L (0.08) and SRS-22r (0.35) scores (P < 0.001 to P < 0.05). Previously braced patients had better HRQoL than currently braced patients, with 0.05 higher EQ-5D 5L score (P < 0.001), and 0.23 higher SRS-22r score (P < 0.001). However, currently braced patients were more satisfied with treatment (1.94 difference; P < 0.001) than previously braced. There were no gross differences between patients previously braced and undergoing observation only. CONCLUSION: The negative impact of bracing on HRQoL is only transient as previously braced patients have superior HRQoL. It appears as though the EQ-5D-5L scores are more sensitive to changes in the sagittal profile as compared with SRS-22r. Our study highlights the differences in HRQoL between patients only observed, undergoing bracing or previous brace treatment and the importance of monitoring HRQoL throughout follow up. Further longitudinal studies may help determine the timing and threshold of HRQoL changes during the entire duration of bracing as well as after brace weaning. LEVEL OF EVIDENCE: 2. PMID- 30395090 TI - Predictors of Extended Length of Hospital Stay in Adolescent Idiopathic Scoliosis Patients Undergoing Posterior Segmental Instrumented Fusion: An Analysis of 407 Surgeries Performed at a Large Academic Center. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The aims of this study were to (1) compare patient and procedure-specific characteristics among those who had short versus long hospital stays and (2) identify independent risk factors that may correlate with extended length of hospital stay (LOS) in patients with adolescent idiopathic scoliosis (AIS) who underwent posterior segmental instrumented fusion (PSIF). SUMMARY OF BACKGROUND DATA: Reducing the LOS and identifying risk factors associated with extended admission have become increasingly relevant to healthcare policy makers. There is currently limited research identifying risk factors that correlate with extended stay in patients undergoing PSIF for AIS. METHODS: A single-institution, longitudinally maintained database was queried to identify 407 patients who met specific inclusion and exclusion criteria. Based on the distribution and median LOS in the cohort (4 days), patients were divided into those who had long versus short LOS. In both groups, patient demographics, comorbidities, preoperative scoliosis curve measurements, surgery-related characteristics, and complications were analyzed. A univariate and multivariate regression analysis was then conducted to identify independent risk factors associated with extended LOS. RESULTS: Patients who had extended LOS tended to be women (84.6% vs. 75%, P = 0.01), had more levels fused (9 +/- 2 vs. 7 +/- 2 levels, P < 0.001), had more major postoperative complications (0.8% vs. 7.4%, P = 0.002), had more blood loss during surgery (723 +/- 548 vs. 488 +/- 341 cm, P < 0.001), and received less epidural analgesia for pain control (69% vs. 89%, P < 0.001). Except for higher thoracic kyphosis, long LOS patients did not have worse preoperative radiographic curve parameters. Multivariate logistic analysis identified female sex, having >=9 +/- 2 levels of fusion, operative blood loss, major postoperative complications, lack of epidural analgesia, and higher thoracic kyphosis as independent risk factors correlating for extended LOS. CONCLUSION: Independent risk factors identified by this study may be used to recognize patients with AIS at risk of prolonged hospital stay. LEVEL OF EVIDENCE: 3. PMID- 30395091 TI - The Importance of the Pedicle Diameters at the Proximal Thoracic Vertebrae for the Correction of Proximal Thoracic Curve in Asian Patients with Idiopathic Scoliosis. AB - STUDY DESIGN: A retrospective comparative radiographic study OBJECTIVE.: The purpose of this study was to evaluate differences in the pedicle diameters of proximal thoracic vertebrae in relation to the severity of the proximal thoracic curve in Asian patients with idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: A small pedicle diameter at the proximal thoracic vertebra has been reported in normal population but the changes of pedicle diameter in patients with a proximal thoracic curve have not been properly evaluated. METHODS: 182 patients with adolescent idiopathic scoliosis involving a greater than 10-degree proximal thoracic curve were analyzed. Sixty-nine and 113 patients had a structural and non-structural proximal thoracic curve, respectively. The pedicle width was evaluated from T1 to T4 using a reconstructed CT scan. The pedicle widths were compared between the convex and concave side, and between the structural and non structural proximal thoracic curve groups. RESULTS: The pedicle widths at T3 (0.76 +/- 0.92 mm) and T4 (0.50 +/- 0.69 mm) on the concave side for the structural proximal thoracic curves were extremely narrow compared to those for the non-structural proximal thoracic curves (T3,1.17 +/- 0.84 mm; T4,0.82 +/- 0.72 mm) (P = 0.002, 0.003, respectively). However, the T2 pedicle width was comparable on the concave side in both groups (2.44 +/- 0.94 mm for the non structural and 2.32 +/- 0.97 mm for the structural proximal thoracic curve, P = 0.430). CONCLUSION: A pedicle screw insertion at the T3 or T4 vertebra on the concave side is not always possible in cases of a structural proximal thoracic curve, however, the pedicle width of the T2 vertebra is very wide and safe for the standard pedicle screw insertion. These results should be considered when the surgeon decides the upper instrumented vertebra or the correction method for the structural proximal thoracic curve. LEVEL OF EVIDENCE: 3. PMID- 30395092 TI - The Changing position of the Center of Mass of the Thorax During Growth in Relation to Pre-Existent Vertebral Rotation. AB - STUDY DESIGN: Cross-sectional. OBJECTIVE: To analyze the thoracic center of mass (COM) position of children at different ages and evaluate its relation with the previously reported pre-existent rotational pattern of the normal spine. SUMMARY OF BACKGROUND DATA: The normal, non-scoliotic thoracic spine is known to have a rotational pattern that changes direction during growth; a transition from left sided towards right-sided rotation with increasing age. This matches the changing curve convexity seen when idiopathic scoliosis develops at different ages. Furthermore, the direction of pre-existent rotation was shown to be related to organ orientation; in situs inversus the rotation is opposite to situs solitus. METHODS: Computed tomography (CT) scans of the thorax of infantile (0-4 years, n = 40), juvenile (4-10 years, n = 53) and adolescent (10-18 years, n = 62) children without spinal pathology were included from an existing database. The location of the COM inside the thorax was calculated based on Hounsfield-units, representing tissue mass. The COM offset was defined as the shortest distance to the midsagittal plane. RESULTS: At the infantile age the COM was 2.5 +/- 2.1 mm on the right side, at juvenile age not significantly deviated and at adolescent age 3.1 +/- 2.3 mm on the left side of the midsagittal plane. The mean COM offset correlated linearly with age (r = 0.77, p < 0.001). CONCLUSIONS: The COM shifts from slightly on the right side of the thorax at the infantile age, to neutral at juvenile age, to the left at adolescent age. This corresponds to the earlier demonstrated change in direction of pre-existent rotation in the normal spine with age, as well as with the well-known changing direction, from left to right, of thoracic curve convexity in scoliosis at different ages. LEVEL OF EVIDENCE: N/A. PMID- 30395093 TI - Minimum Clinically Important Difference and Patient Acceptable Symptom State of Japanese Orthopaedic Association Score in Degenerative Cervical Myelopathy Patients. AB - STUDY DESIGN: A retrospective analysis. OBJECTIVE: To elucidate the psychometric properties of the original Japanese Orthopaedic Association (JOA) score, including the minimum detectable change (MDC), minimum clinically important difference (MCID) and patient accepted symptom state (PASS). SUMMARY OF BACKGROUND DATA: Despite the worldwide popularity of modified JOA score, the original JOA score is still commonly used in East Asian countries, including Japan. However, unlike mJOA score, the psychometric properties of JOA score remain poorly understood. METHODS: We retrospectively reviewed a consecutive series of laminoplasty for degenerative cervical myelopathy patients in a single academic institution. Pre- and post-operative JOA scores were collected, and the recovery rate was calculated. Anchor-based methods were used to determine the cut off values by a receiver operating characteristic (ROC) curve analysis. The patients were also asked to answer an anchor question analyzing their post operative health transition used for the MDC and another question assessing the patient satisfaction used for the MCID and PASS. RESULTS: A total of 101 patients were included in the analysis. The mean pre-operative JOA score was 10.3 (standard deviation [SD]: 2.4), and the mean post-operative JOA score was 13.4 (SD: 2.5). The mean recovery rate was 44%. A total of 68% of the patients admitted that their health condition was at least "somewhat better" than their pre-operative condition, and 66% were at least "somewhat satisfied" with the treatment results. Based on ROC curve analyses, the MDC and MCID for JOA score in degenerative cervical myelopathy patients were calculated to be 2.5. The PASS was estimated to be 14.5, and the MCID for JOA recovery rate was 52.8%. CONCLUSIONS: The MDC, MCID, and PASS for JOA score for degenerative cervical myelopathy patients were reported by anchor-based ROC curve analyses. LEVEL OF EVIDENCE: 4. PMID- 30395094 TI - A Morphometric Study on Subaxial Cervical Pedicles of Thai People. AB - STUDY DESIGN: This study investigated the subaxial cervical pedicles from C3 to C7 to provide information for accurately transpedicular screw fixation in this region. OBJECTIVE: This study was evaluated the morphology of the subaxial cervical pedicle to determine the size and trajectory of screw fixation. SUMMARY OF BACKGROUND DATA: Cervical vertebrae are an important structure to protect the neurovascular structure. The cervical spine surgery using screw fixation is an effective method to treat the cervical spine instability. There have been many research morphological data of subaxial cervical vertebrae. However, no studies have reports on dried cervical vertebrae of Thai's people. METHODS: The measurement was conducted in 130 dried cervical vertebrae (C3-C7), including 61 males and 69 females. The measurement parameters were pedicle width (PW), pedicle length (PL), pedicle height (PH), pedicle axis length (PAL), pedicle transverse angle (PTA), and pedicle sagittal angle (PSA), which determined using ImageJ software. RESULTS: The results of morphological data of C3 to C7 was found that the mean of PW, PL, PH, PAL, PTA, and PSA that obtained from male were significantly higher than female excepted for PL (C7) and PTA (C3, C5). Except for the C6 PW, C3 PL, C4 to C5 to C7 PTA, and C4 PSA, there were no significant differences of these parameters between male and female. CONCLUSION: The appropriate pedicle screw size is 4.0 mm for C3 and C4, and 4.5 mm for C5 to C7. The results of this study are the useful information for cervical spine fixation while prevent the vascular and neurological injuries from the large screw causing pedicle breakage. LEVEL OF EVIDENCE: 3. PMID- 30395096 TI - You Are Not Alone. PMID- 30395095 TI - Treatment for frailty does not improve complication rates in corrective surgery for adult spinal deformity. AB - STUDY DESIGN: A retrospective multicenter database review of 240 consecutive patients at least 21 years of age (mean 58 +/- 17, range 22-79) who underwent surgery for ASD and were followed at least 2 years. OBJECTIVE: To investigate how treatment for frailty affects complications in surgery for ASD. SUMMARY OF BACKGROUND: Several recent studies have focused on associations between frailty and surgical complications. However, it is not clear whether treating frailty affects complication rates in surgery for adult spinal deformity (ASD). METHODS: Patients were categorized as robust (R group), prefrail, or frail based on the modified frailty index (mFI); prefrail and frail patients were divided by good control of frailty (G group), defined as treatment following the appropriate guidelines for each mFI factor, or poorly controlled frailty (PC group). We compared clinical outcomes and perioperative and 2-year complications between the three groups. RESULTS: Of the 240 patients, 142 (59%) were robust, 81 (34%) were prefrail, and 17 (7%) were frail. Among the frail and prefrail patients, 71 (72%) were classified as G and 27 (28%) as PC. The perioperative complication rate was similar in the G and PC groups (32% vs. 37%) but was significantly lower in the R group (15%, p < .01). The age- and gender-adjusted odds ratio for 2-year complications was not different in the P group when the G group was referenced (odds ratio 1.3 [0.5-3.2], p = .63). In the G and PC groups, which had similar 2 year outcomes, the SRS22 function and total scores were significantly lower than in the R group (function: R 3.9 +/- 0.7, G 3.5 +/- 0.7, P 3.3 +/- 0.6; total: R 3.9 +/- 0.6, 3.7 +/- 0.7, 3.4 +/- 0.6; p < .01). CONCLUSION: Regardless of its treatment status, frailty increases the risk of complications and inferior clinical outcomes in ASD surgery. Surgeons should routinely evaluate frailty and inform patients of frailty-related risks when considering surgery for ASD. LEVEL OF EVIDENCE: 4. PMID- 30395097 TI - Adaptation and Resilience in Families of Children With Spina Bifida in South Korea. AB - PURPOSE: The purpose of this study, which was guided by the Family Resilience Model, was twofold: (1) to assess the risk and protective factors related to adaptation and resilience in families of children with spina bifida (SB) in South Korea and (2) to examine predictors of family adaptation and resilience. DESIGN: This is a descriptive study using survey methodology. METHODS: Data were collected from 203 parents of children with SB between June 2013 and February 2014 at the SB clinic in South Korea and analyzed using stepwise linear regression. FINDINGS: The best predictors of family adaptation and resilience in children with SB included one risk factor (parental depression) and four protective factors (parental health, family cohesion, family communication skills, and supportive friends/relatives). These five factors explained 39.7% of the total variance in family functioning (an indicator of family adaptation and resilience; F = 26.43, p < .001). CONCLUSION AND CLINICAL RELEVANCE: Findings suggest that nursing interventions designed to strengthen protective factors and reduce risk factors are likely to promote adaptation and resilience in families of children with SB. PMID- 30395101 TI - Article Summaries for November-December 2018 Psychosomatic Medicine, Volume 80, Issue 9. PMID- 30395102 TI - The Neuroscience of Pain: Biobehavioral, Developmental, and Psychosocial Mechanisms Relevant to Intervention Targets. AB - Chronic pain is a major problem in clinical medicine and public health, affecting approximately one in five adults, and is associated with significant societal and familial burden. Early-life adversities, psychological, and biobehavioral factors are associated with an elevated risk of the subsequent development of chronic pain. In this special issue of Psychosomatic Medicine, articles address the neuroscientific, psychological, and biobehavioral processes involved in acute and chronic pain. We focus on the following themes that emerged in this special issue: (a) risk factors and early adversity as related to chronic pain; (b) the role of expectations in shaping pain perception; and (c) mechanisms of interventions targeting pain modulation. This article concludes by outlining important new targets for research, including the neurobiology of pain, important methodological challenges, and targets for personalized pain interventions. PMID- 30395104 TI - Author and Subject Index. PMID- 30395105 TI - Hepatitis A outbreak among men who have sex with men, Yokohama, Japan, January to May 2018. AB - Between January and May in 2018, 17 male cases of hepatitis A were reported in Yokohama, Japan. Of these, 14 identified as men who have sex with men (MSM). The viral sequence in this outbreak was same as that of the recent European and Taiwanese outbreaks strain. PMID- 30395106 TI - Associations of Perioperative Renal Oximetry Via Near-Infrared Spectroscopy, Urinary Biomarkers, and Postoperative Acute Kidney Injury in Infants After Congenital Heart Surgery: Should Creatinine Continue to Be the Gold Standard? AB - OBJECTIVES: Examine the relationship between perioperative renal regional tissue oximetry, urinary biomarkers, and acute kidney injury in infants after congenital cardiac surgery with cardiopulmonary bypass. DESIGN: Prospective, observational. SETTING: Cardiac operating room and cardiac ICU. PATIENTS: Neonates and infants without history of kidney injury or anatomic renal abnormality. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Renal regional tissue oximetry was measured intraoperatively and for 48 hours postoperatively. Urinary levels of neutrophil gelatinase-associated lipocalin and tissue inhibitor of metalloproteinases 2 together with insulin-like growth factor-binding protein 7 were measured preoperatively, 2, 12, and 24 hours postoperatively. Patients were categorized as no acute kidney injury, stage 1, or Stage 2-3 acute kidney injury using the Kidney Disease: Improving Global Outcomes criteria with 43 of 70 (61%) meeting criteria for any stage acute kidney injury. Stage 2-3 acute kidney injury patients had higher tissue inhibitor of metalloproteinases 2, insulin-like growth factor-binding protein 7 at 2 hours (0.3 vs 0.14 for stage 1 acute kidney injury and 0.05 for no acute kidney injury; p = 0.052) and 24 hours postoperatively (1.71 vs 0.27 for stage 1 acute kidney injury and 0.19 for no acute kidney injury, p = 0.027) and higher neutrophil gelatinase-associated lipocalin levels at 24 hours postoperatively (10.3 vs 3.4 for stage 1 acute kidney injury and 6.2 for no acute kidney injury, p = 0.019). Stage 2-3 acute kidney injury patients had lower mean cardiac ICU renal regional tissue oximetry (66% vs 79% for stage 1 acute kidney injury and 84% for no acute kidney injury, p = 0.038). Regression analyses showed that tissue inhibitor of metalloproteinases 2, insulin-like growth factor-binding protein 7 at 2 hours postoperatively and nadir intraoperative renal regional tissue oximetry to be independent predictors of postoperative kidney damage as measured by urinary neutrophil gelatinase associated lipocalin. CONCLUSIONS: We observed modest differences in perioperative renal regional tissue oximetry and urinary biomarker levels compared between acute kidney injury groups classified by creatinine-dependent Kidney Disease: Improving Global Outcomes criteria, but there were significant correlations between renal regional tissue oximetry, tissue inhibitor of metalloproteinases 2, insulin-like growth factor-binding protein 7, and postoperative neutrophil gelatinase-associated lipocalin levels. Kidney injury after infant cardiac surgery may be undetectable by functional assessment (creatinine) alone, and continuous monitoring of renal regional tissue oximetry may be more sensitive to important subclinical acute kidney injury. PMID- 30395107 TI - Patterns of Use of Heated Humidified High-Flow Nasal Cannula Therapy in PICUs in the United Kingdom and Republic of Ireland. AB - OBJECTIVES: To 1) describe patterns of use of high-flow nasal cannula therapy, 2) examine differences between patients started on high-flow nasal cannula and those started on noninvasive ventilation, and 3) explore whether patients who failed high-flow nasal cannula therapy were different from those who did not. DESIGN: Retrospective analysis of data collected prospectively by the Paediatric Intensive Care Audit Network. SETTING: All PICUs in the United Kingdom and Republic of Ireland (n = 34). PATIENTS: Admissions to study PICUs (2015-2016) receiving any form of respiratory support at any time during PICU stay. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eligible admissions were classified into nine groups based on the combination of the first-line and second line respiratory support modes. Uni- and multivariate analyses were performed to test the association between PICU and patient characteristics and two outcomes: 1) use of high-flow nasal cannula versus noninvasive ventilation as first-line mode and 2) high-flow nasal cannula failure, requiring escalation to noninvasive ventilation and/or invasive ventilation. We analyzed data from 26,423 admissions; high-flow nasal cannula was used in 5,951 (22.5%) at some point during the PICU stay. High-flow nasal cannula was used for first-line support in 2,080 (7.9%) and postextubation support in 978 admissions (4.5% of patients extubated after first line invasive ventilation). High-flow nasal cannula failure occurred in 559 of 2,080 admissions (26.9%) when used for first-line support. Uni- and multivariate analyses showed that PICU characteristics as well as patient age, primary diagnostic group, and admission type had a significant influence on the choice of first-line mode (high-flow nasal cannula or noninvasive ventilation). Younger age, unplanned admission, and higher admission severity of illness were independent predictors of high-flow nasal cannula failure. CONCLUSIONS: The use of high-flow nasal cannula is common in PICUs in the United Kingdom and Republic of Ireland. Variation in the choice of first-line respiratory support mode (high flow nasal cannula or noninvasive ventilation) between PICUs reflects the need for clinical trial evidence to guide future practice. PMID- 30395108 TI - Derivation and Validation of an Objective Effort of Breathing Score in Critically Ill Children. AB - OBJECTIVES: To derive and validate a score that correlates with an objective measurement of a child's effort of breathing. DESIGN: Secondary analysis of a previously conducted observational study. SETTING: The pediatric and cardiothoracic ICUs of a quaternary-care children's hospital. PATIENTS: Patients more than 37 weeks gestational age to age 18 years who were undergoing extubation. INTERVENTIONS: Effort of breathing was measured in patients following extubation using esophageal manometry to calculate pressure rate product. Simultaneously, members of a multidisciplinary team (nurse, physician, and respiratory therapist) assessed respiratory function using a previously validated tool. Elements of the tool that were significantly associated with pressure rate product in univariate analysis were identified and included in a multivariate model. An Effort of Breathing score was derived from the results of the model using data from half of the subjects (derivation cohort) and then validated using data from the remaining subjects (validation cohort) by calculating the area under the receiver operator characteristic curve for pressure rate product greater than 90th percentile and for the need for reintubation. MEASUREMENTS AND MAIN RESULTS: Among 409 subjects, the median age was 5 months, and nearly half were cardiac surgery patients (49.1%). Retractions, stridor, and pulsus paradoxus were included in the Simple Score. Area under the receiver operator characteristic curve for pressure rate product greater than 90th percentile was 0.8359 (95% CI, 0.7996-0.8722) in the derivation cohort and 0.7930 (0.7524 0.8337) in the validation cohort. Area under the receiver operator characteristic curve for reintubation was 0.7280 (0.6807-0.7752) when all scores were analyzed individually and was 0.7548 (0.6644-0.8452) if scores from three clinicians from different disciplines were summated. Results were similar regardless of provider discipline or training. CONCLUSIONS: A scoring system was derived and validated, performed acceptably to predict increased effort of breathing or need for advanced respiratory support and may function best when used by a team. PMID- 30395109 TI - Outcome Prediction Following Complex Congenital Heart Disease Operations-The Intensivist Perspective. PMID- 30395110 TI - Getting a Head Start: Expediting Neurosurgical Intervention in Children Transported With Intracranial Hemorrhage With Telemedicine. PMID- 30395111 TI - Outcome Measures for Pediatric Traumatic Brain Injury: Comparing Established and Novel Tests. PMID- 30395112 TI - Nutrition Is More Than the Sum of Its Parts. PMID- 30395113 TI - Extracorporeal Membrane Oxygenation and Hemolysis-Still a Challenge. PMID- 30395114 TI - Hertz So Good: Bedside Ultrasound Implementation by Pediatric Critical Care Training Programs. PMID- 30395115 TI - Identifying Factors Associated With Critical Asthma: What (and When) is the Point? PMID- 30395116 TI - PICU in Mozambique-The Real Challenge of Pediatric Intensive Care When Resources Are Less Than What You Might Want (or Need). PMID- 30395117 TI - Optimum Chest Compression Point for Cardiopulmonary Resuscitation in Children Revisited Using a 3D Coordinate System Imposed on CT: A Retrospective, Cross Sectional Study. AB - OBJECTIVES: The optimum chest compression site (P_optimum) in children is debated: European Resuscitation Council recommends one finger breadth above the xiphisternal joint, whereas American Heart Association proposes the lower sternal half. Using a coordinate system imposed on CT, we aimed to determine the pediatric P_optimum to maximize stroke volume, the key point for successful cardiopulmonary resuscitation, while minimizing hepatic injury. DESIGN: Retrospective, cross-sectional study. SETTING: University hospital. PATIENTS: Children 1-15 years old who underwent chest CT. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We defined zero point (0, 0) as the center of the xiphisternal joint designating leftward and upward directions of the patients as positive on each axis. P_optimum (x_max. left ventricle, y_max. left ventricle) was defined as the center of the maximum diameter of the left ventricle, whereas P_aorta (x_aorta, y_aorta) as that of the aortic annulus. To compress the left ventricle exclusively, y_max. left ventricle should range above the y coordinate of hepatic dome (y_liver_dome) and below y_aorta. Data were presented as median (interquartile range) and compared among age groups 1.0-5.0, 5.1-10.0, and 10.1 15.0 years using Kruskal-Wallis test. For universal application regardless of age, y coordinates were converted into relative ones with unit of sternal top: 1 unit of sternal top was the y coordinate of the sternal top. A total of 163 patients were enrolled, median age 8.8 year (4.2-14.3 yr). Among age groups, no significant difference was observed in y_max. left ventricle, relative y_max. left ventricle, y_aorta, and y_liver_dome: 1.0 cm (0.1-1.9 cm), 0.10 unit of sternal top (0.01-0.18 unit of sternal top), 0.39 unit of sternal top (0.30-0.47 unit of sternal top), and -0.14 unit of sternal top (-0.25 to -0.03 unit of sternal top), respectively. The probability to compress the left ventricle exclusively was greater than or equal to 96% when placing hand at 0.05-0.20 unit of sternal top. Subgroup analysis demonstrated the following regression equation: x_max. left ventricle (mm) = 0.173 * (height in cm) + 13 (n = 106; p < 0.001; R = 0.278). CONCLUSIONS: Theoretically, pediatric P_optimum is located 1 cm (or 0.1 unit of sternal top) above the xiphisternal joint. PMID- 30395118 TI - BULL'S EYE MACULOPATHY POSSIBLY DUE TO IRON OVERLOAD IN A CHILD WITH THALASSEMIA MAJOR: A CASE OF POSSIBLE "FERRITIN RETINOPATHY". AB - PURPOSE: To report a case of bull's eye maculopathy probably caused by iron overload in a child with thalassemia major. METHODS: Case report. RESULTS: A 6 year-old girl with thalassemia major who was on chronic multiple blood transfusions since 2 years of age presented with blurred vision in both eyes for 2 months. Blood reports showed very high serum ferritin levels in the range 400 to 2,250 ng/mL (checked every 3 months) since 4 years of age. She was on oral iron chelator deferasirox for 2 years, which was stopped a month ago. Fundus examination of both eyes showed a characteristic bull's eye macula with a purplish hue in the outer ring probably due to iron deposition. The center of the bull's eye had a beaten bronze appearance. CONCLUSION: Careful history-taking is important in children with bull's eye maculopathy because all such retinopathies need not be hereditary fundus dystrophies. Further progression can be arrested by identifying and removing the cause vision loss.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. Thek work cannot be changed in any way or used commercially without permission from the journal. PMID- 30395119 TI - RANIBIZUMAB 0.5 MG TREATMENT IN ADOLESCENTS WITH CHOROIDAL NEOVASCULARIZATION: SUBGROUP ANALYSIS DATA FROM THE MINERVA STUDY. AB - PURPOSE: To evaluate the efficacy and safety of ranibizumab 0.5 mg in adolescent patients with any choroidal neovascularization etiology enrolled in the 12-month MINERVA study. METHODS: In the open-label, non-randomized study arm, ranibizumab 0.5 mg was administered to five adolescents (aged 13-17 years). The findings were assessed descriptively as individual case reports at Month 12. Best-corrected visual acuity changes, central subfield thickness, treatment exposure, and safety were described over 12 months. RESULTS: Baseline choroidal neovascularization etiologies of the study eye included choroidal neovascularization secondary to Best disease (n = 2), idiopathic chorioretinopathy (n = 2), and optic disk drusen (n = 1). At Months 2, 6, and 12, the observed mean best-corrected visual acuity changes in the study eye from baseline were +9.2, +16.6, and +16.6 letters, respectively, and the observed mean central subfield thickness change from baseline was -31.4, -87.6, and -116.4 MUm, respectively. Adolescent patients received a mean of three (range, 2-5) ranibizumab injections in the study eye. No adverse events or serious adverse events related to ranibizumab were reported. CONCLUSION: Ranibizumab 0.5 mg treatment was beneficial in improving visual acuity and stabilizing or reducing central subfield thickness in five adolescents with differing choroidal neovascularization etiologies requiring infrequent injection. No new safety findings were observed over 12 months.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. PMID- 30395120 TI - Biliary Bicarbonate, pH and Glucose Are Suitable Biomarkers of Biliary Viability During Ex Situ Normothermic Machine Perfusion of Human Donor Livers. AB - BACKGROUND: Ex situ normothermic machine perfusion (NMP) can be used to assess viability of suboptimal donor livers prior to implantation. Our aim was to assess the diagnostic accuracy of bile biochemistry for the assessment of bile duct injury (BDI). METHODS: In a preclinical study, 23 human donor livers underwent 6 hours of end-ischemic NMP to determine biomarkers of BDI. Livers were divided into groups with low or high BDI, based on a clinically relevant histological grading system. During NMP, bile was analyzed biochemically and potential biomarkers were correlated with the degree of BDI. Receiver operating characteristics curves were generated to determine optimal cut-off values. For clinical validation, identified biomarkers were subsequently included as viability criteria in a clinical trial (n=6) to identify transplantable liver grafts with low BDI. RESULTS: Biliary bicarbonate and pH were significantly higher and biliary glucose was significantly lower in livers with low BDI, compared to high BDI. The following cut-off values were associated with low BDI: biliary bicarbonate >18 mmol/L (P=0.002), biliary pH >7.48 (P=0.019), biliary glucose <16 mmol/L (P=0.013), and bile/perfusate glucose ratio <0.67 (P=0.013). In the clinical trial, 4 out of 6 livers met these criteria and were transplanted, and none developed clinical evidence of post-transplant cholangiopathy. CONCLUSIONS: Biliary bicarbonate, pH, and glucose during ex situ NMP of liver grafts are accurate biomarkers of BDI and can be easily determined point-of-care, making them suitable for the pre-transplant assessment of bile duct viability. This may improve graft selection and decrease the risk of post transplant cholangiopathy.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30395121 TI - Context for Practice: Wound Care in Pediatrics, Quality of Life in American Military Veterans With Temporary Ostomies, Intermittent Catheterization in Germany and Brazil. PMID- 30395122 TI - Authors' Response to a Letter to the Editor Re: The Effect of Foot Exercises on Wound Healing in Type 2 Diabetic Patients With a Foot Ulcer: A Randomized Control Study. J Wound Ostomy Continence Nursing. 2018;45(2):123-130. PMID- 30395123 TI - Reducing Pressure Injuries in a Pediatric Cardiac Care Unit: A Quality Improvement Project. AB - The purpose of this quality improvement project was to develop an evidence-based protocol designed for pressure injury prevention for neonates and children in a pediatric cardiac care unit located in the Midwestern United States. The ultimate goal of the project was dissemination across all pediatric critical care and acute care inpatient arenas, but the focus of this initial iteration was neonates and children requiring cardiac surgery, extracorporeal support in the form of extracorporeal membranous oxygenation and ventricular assist devices in the cardiac care unit, or cardiac transplantation. A protocol based upon the National Pressure Ulcer Advisory Panel guidelines was developed and implemented in the pediatric cardiac care unit. Pediatric patients were monitored for pressure injury development for 6 months following protocol implementation. During the 40 month preintervention period, 60 hospital-acquired pressure injuries (HAPIs) were observed, 13 of which higher than stage 3. In the 6-month postintervention period, we observed zero HAPI greater than stage 2. We found that development and use of a standardized pressure injury prevention protocol reduced the incidence, prevalence, and severity of HAPIs among patients in our pediatric cardiac care unit. PMID- 30395124 TI - Reducing Pressure Injuries in a Pediatric Cardiac Care Unit: A Quality Improvement Project. PMID- 30395125 TI - Point-of-Care Ultrasound Use in Neonatal Peripheral Intravenous Extravasation Injuries: A Case Series. AB - PURPOSE: The primary aim of this study was to examine and describe peripheral intravenous extravasation (PIVE) injuries using point-of-care ultrasound (POC US). A secondary aim was to define skin tissue changes before and after hyaluronidase application using POC-US. DESIGN: Case series design. SUBJECTS AND SETTING: We report on 10 neonates with stage 3 or 4 PIVE who were studied clinically and with POC-US. All infants were studied during the December 2015 to September 2016 period in a large academic neonatal intensive care unit. METHODS: Initially, neonates with PIVE were staged using 3 criteria: physical findings, nature of the infusate, and the size of the injury. Next, we described different ultrasound appearances of the tissue injury in PIVE based on the type of the infusate (clear fluid, blood, or both). We then located the largest PIVE pocket and measured the skin elevation over it. Skin elevation ratio was measured at 3 time points: before hyaluronidase injection followed by 3 to 6 hours and 24 hours after hyaluronidase therapy. Each ultrasound examination of the skin injury was staged (severe, moderate, mild, or minimal) based on the skin elevation ratio obtained. In addition, we described changes in the skin using ultrasound before and after hyaluronidase treatment. RESULTS: Three types of ultrasound images based on the type of the extravasated fluid were described in detail. Based on the initial ultrasound measurements of the skin elevation ratio, 6 infants were staged with severe PIVE and 4 were staged as moderate PIVE. Finally, POC-US was used to describe the tissue changes before and after hyaluronidase injection. CONCLUSIONS: Point-of-care ultrasound may offer more structured and objective staging of PIVE injuries due to direct visualization of the skin tissue. This method needs to be further studied and introduced as a practical tool to complement physical examination of PIVE injuries. PMID- 30395127 TI - Patients With Temporary Ostomies: Veterans Administration Hospitals Multi institutional Retrospective Study. PMID- 30395126 TI - Patients With Temporary Ostomies: Veterans Administration Hospitals Multi institutional Retrospective Study. AB - PURPOSE: The purpose of this study was to describe clinical outcomes of patients with temporary ostomies in 3 Veterans Health Administration hospitals. DESIGN: Retrospective descriptive study, secondary analysis. SAMPLE AND SETTING: Veterans with temporary ostomies from 3 Veterans Health Administration hospitals who were enrolled in a previous study. The sample comprised 36 participants all were male. Their mean age was 67.05 +/- 9.8 years (mean +/- standard deviation). Twenty patients (55.6%) had ileostomies and 16 patients (44.4%) had colostomies. METHODS: This was a secondary analysis of data collected using medical record data. Variables examined included etiology for creation and type of ostomy, health-related quality of life, time to reversal, reasons for nonreversal, postoperative complications after reversal, and mortality in the follow-up period. RESULTS: Colorectal cancer and diverticular disease were the main reasons for temporary stoma formation. The reversal rate was 50%; the median time to reversal was 9 months in our sample; temporary ileostomies were reversed more often than temporary colostomies (P = .18). Comorbid conditions were identified as the main reason for nonreversal. Mortality was not significantly different between the reversal and nonreversal groups. No significant differences were reported with health-related quality-of-life parameters between reversal and nonreversal groups. CONCLUSIONS: This study identified that the proportion of temporary ostomies was limited to 50%. Complications during the index operation, medical comorbidities, and progression of cancer are the main reasons for nonreversal of temporary stomas. Study findings should be included in the counseling of patients who are likely to get intestinal stomas with temporary intention, and during consideration for later reversal of a stoma. PMID- 30395128 TI - Rectal Trumpet-Associated Hemorrhage in the Intensive Care Unit: A Quality Improvement Initiative. AB - The rectal trumpet (RT) is a nasopharyngeal airway device that is inserted into the rectum for management of fecal incontinence. No published data exist on adverse events caused by the use of an RT. The purpose of this quality improvement project was to determine the rate of RT-associated hemorrhage among patients treated with an RT in our transplant intensive care unit (TICU). This quality improvement initiative and retrospective medical record review included all patients (N = 3933) cared for in a single specialty intensive care unit at a tertiary academic medical center between January 1, 2014, and May 31, 2016. We estimate that approximately 400 patients were treated with an RT. We found 3 possible and 9 probable cases of RT-associated hemorrhage, resulting in an estimated incident rate of 3% among RT-treated patients. All of these patients underwent invasive procedures for hemostasis. They received a mean of 4.9 units of packed red blood cell transfusions, and 9 experienced hypotension. Eight out of the 9 probable RT-associated hemorrhage patients experienced hemorrhage only after greater than 7 days of treatment with an RT. Following this initiative, RT use was banned in our TICU. The use of RTs can cause hemorrhage with clinically significant consequences. PMID- 30395129 TI - Incontinence-Associated Dermatitis (IAD): Prevalence and Associated Factors in 4 Hospitals in Southeast Norway. AB - PURPOSE: The aim of this study was to investigate the prevalence and severity of incontinence-associated dermatitis (IAD) and associated factors in acute care settings in Southeast Norway. DESIGN: Descriptive, multisite epidemiologic survey. SUBJECTS AND SETTING: The study setting was 29 wards across 4 hospitals, in a hospital trust in the southeast of Norway. Data were collected from 340 patients (age >=18 years). More than half (56.2%) were 70 years or older (median age category 70-79 years) and 53.3% were male. METHODS: Data collection was conducted in parallel with a pressure injury prevalence study undertaken in 2016. A modified Pressure Injury Prevalence Minimum Data Set, including documentation of fecal or urinary incontinence, use of indwelling fecal collection system or urinary catheter, and presence of IAD, was completed. RNs participating in the study were trained by the researchers on skin assessment and data extraction from the electronic medical record. Descriptive statistics were used for prevalence figures; the Kruskal-Wallis and chi tests were used to determine associated factors. RESULTS: Analysis revealed that 16.5% (56 out of 340) of the sample were incontinent. The prevalence of IAD in the total population was 7.6% (26 out of 340). The prevalence of IAD was 29% (16 out of 56) among patients with urinary or fecal incontinence. Of those identified with IAD, 5.2% (18 out of 340) had category 1 (red intact skin) and 2.4% (8 of 340) had category 2 (red skin with breakdown). Bivariate analysis revealed that fecal incontinence (P < .001), immobility (P < .01), and 70 years or older (P < .03) were associated with IAD. CONCLUSIONS: The overall prevalence (patients with and without incontinence) of IAD was lower than reported in prior studies; frequent use of indwelling urinary catheters and a relatively low prevalence of incontinence may explain this finding. Similar to prior studies, almost 1 in 3 patients who were incontinent suffered from IAD, showing a need for evidence-based guidelines to prevent IAD in hospitalized patients. Findings suggest that particular attention should be given to prevent IAD among patients with fecal incontinence patients, 70 years and older, and those with immobility. PMID- 30395130 TI - Management of Penile Calciphylaxis: A Case Study. AB - BACKGROUND: Calciphylaxis, also called calcific uremic arteriolopathy, is a highly morbid syndrome characterized by calcium deposition and occlusion of small arterial vessels of the dermis and subdermal adipose tissue, leading to necrosis and gangrene. Penile involvement is rare and its management presents considerable challenges. CASE: We review the case of a 47-year-old man with end-stage renal disease managed with hemodialysis, diabetes mellitus, and urinary incontinence who presented with a painful necrotic lesion on his glans penis, and the second and third toes of his right foot. Following diagnosis of calciphylaxis of the toes and penis, he was conservatively managed with topical wound care, sodium thiosulfate adjustment of hemodialysis, and phosphate binder medications. Over the course of 2 months, his wound worsened in the setting of continued urinary incontinence, and before planned diversion with a suprapubic catheter, he progressed to gangrene and sepsis. After a goals-of-care discussion with the patient and family, he elected to forego debridement and was discharged on home based palliative care. CONCLUSIONS: Penile calciphylaxis is a rare, life threatening disease that portends a poor prognosis. Conservative principles for management include normalization of calcium phosphate levels and local wound care. Penectomy may not impact survival. Ultimately, each case is individualized, and we encourage establishing goals of care in collaborative discussion with an interdisciplinary care team, patient, and family. PMID- 30395131 TI - Best Practice Recommendations for Prevention and Management of Skin Tears in Aged Skin: An Overview. PMID- 30395132 TI - Percutaneous Tubes and Drains. PMID- 30395133 TI - WOCN(r)-Accredited Professional Education Programs. PMID- 30395134 TI - Genome-wide screening for functional long noncoding RNAs in human cells by Cas9 targeting of splice sites. AB - The functions of many long noncoding RNAs (lncRNAs) in the human genome remain unknown owing to the lack of scalable loss-of-function screening tools. We previously used pairs of CRISPR-Cas9 (refs. 1, 2, 3) single guide RNAs (sgRNAs) for small-scale functional screening of lncRNAs. Here we demonstrate genome-wide screening of lncRNA function using sgRNAs to target splice sites and achieve exon skipping or intron retention. Splice-site targeting outperformed a conventional CRISPR library in a negative selection screen targeting 79 ribosomal genes. Using a genome-scale library of splicing-targeting sgRNAs, we performed a screen covering 10,996 lncRNAs and identified 230 that are essential for cellular growth of chronic myeloid leukemia K562 cells. Screening GM12878 lymphoblastoid cells and HeLa cells with the same library identified cell-type-specific differences in lncRNA essentiality. Extensive validation confirmed the robustness of our approach. PMID- 30395137 TI - Iron-sensing is governed by mitochondrial, not by cytosolic iron-sulfur cluster biogenesis in Aspergillus fumigatus. AB - Microorganisms have to adapt their metabolism to the requirements of their ecological niche to avoid iron shortage as well as iron toxicity. Therefore, mechanisms have been evolved to tightly regulate iron uptake, consumption, and detoxification, which depend on sensing the cellular iron status. In the facultative anaerobic yeast Saccharomyces cerevisiae, iron-sensing depends on mitochondrial (ISC) but not cytosolic iron-sulfur cluster assembly (CIA), while in mammals further processing of an ISC product via CIA is required for sensing of the cellular iron state. To address the question of how the obligatory aerobic mold Aspergillus fumigatus senses the cellular iron state, mutant strains allowing the downregulation of ISC and CIA were generated. These studies revealed that: (i) Nfs1 (Afu3g14240) and Nbp35 (Afu2g15960), which are involved in ISC and CIA, respectively, are essential for growth; (ii) a decrease in ISC (Nfs1 depletion) but not CIA (Nbp35 depletion) results in a transcriptional iron starvation response, (iii) a decrease in, ISC as well as CIA, increases the chelatable iron pool, accompanied by increased iron toxicity and increased susceptibility to oxidative stress and phleomycin. In agreement with ISC being essential for iron-sensing, a decrease in mitochondrial iron import by deletion of the mitochondrial iron importer MrsA resulted in an iron starvation response. Taken together, these data underline that iron-sensing in A. fumigatus depends on ISC but not CIA. Moreover, depletion of the glutathione pool via generating a mutant lacking gamma-glutamylcysteine synthase, GshA (Afu3g13900), caused an iron starvation response, underlining a crucial role of glutathione in iron-sensing in A. fumigatus. PMID- 30395136 TI - Fast screening of porous materials for noble gas adsorption and separation: a classical density functional approach. AB - The design and screening of porous materials for noble gas adsorption and separation are an important issue in the production and utilization of gases. The conventional method to do this is via molecular simulation. In this work, we introduced a classical density functional theory (CDFT) to replace molecular simulation because CDFT is more efficient. A molecular dynamics (MD)/CDFT combined method was proposed to consider the flexibility of the adsorbent. The theory was first examined by comparing it to reported experiments and simulations. Then, the theory was applied to determine the most favorable adsorbents for noble gas adsorption/separation from 4764 real adsorbents and 1200 hypothetical adsorbents. A series of favorable adsorbents was identified, and some of them seemed promising. The macroscopic adsorption isotherms and microscopic density profiles of the most favorable adsorbents were examined, and the adsorption mechanisms were revealed. The specific separation of Kr/Xe was examined, and two of the adsorbents showed higher adsorption efficiency than shown in previously reported data. PMID- 30395139 TI - From the Editor's Desk. PMID- 30395140 TI - Clinical characteristics and outcome of lone atrial fibrillation at a tertiary referral centre: the Groote Schuur Hospital experience. AB - INTRODUCTION: Atrial fibrillation (AF) is a relatively common arrhythmia. When AF represents an electrophysiological phenomenon in structurally normal hearts, it is termed lone AF. This study was a retrospective, case-based analysis of patients attending the Cardiac Clinic at Groote Schuur Hospital (GSH) and describes the clinical characteristics and outcomes of patients classified as having lone atrial fibrillation. To the best of our knowledge there are no such studies reported from Africa. METHODS: This was a retrospective, descriptive study in which 289 medical records of patients with AF at the GSH Cardiac Clinic were reviewed from 1992 to 2006. The clinical data were interrogated to exclude identifiable causes of AF. Information on clinical characteristics and outcomes were entered into a data-entry form. Baseline descriptive statistics were expressed as means and range for continuous variables, and counts with percentages for categorical variables. RESULTS: Fifteen per cent (n = 42) of patients were identified as having lone AF, with a mean follow-up time of 5.8 years. Males comprised 57% (n = 24) and females 43% (n = 18). Fifty per cent (n = 21) of the patients had paroxysmal AF, 29% (n = 12) had persistent AF, and 12% (n = 5) progressed from paroxysmal to permanent AF. Subsets of lone AF included concomitant atrial flutter (17%) (n = 7) and sick sinus syndrome (21%) (n = 9). Complications were stroke (10%) (n = 4), tachycardia-related cardiomyopathy (17%) (n = 7) and bleeding complications on warfarin (11%) (n = 3). CONCLUSIONS: Lone AF is not an uncommon arrhythmia, with a preponderance in thin, middle-aged males. The symptoms of lone AF can be debilitating. It has associated morbidity, including tachycardia-related cardiomyopathy and thromboembolism. Rate control and appropriate anticoagulation are the cornerstones of patient management. PMID- 30395138 TI - Template-promoted self-replication in dynamic combinatorial libraries made from a simple building block. AB - We report dynamic combinatorial libraries made from a simple building block that is on the verge of enabling self-assembly driven self-replication. Adding a template provides a sufficient additional push yielding self-replication. Self assembly and self-replication can emerge with building blocks that are considerably smaller than those reported thus far. PMID- 30395143 TI - The use of an electronic health record system reduces errors in the National Hip Fracture Database. AB - Aim: to compare the validity of data submitted from a UK level 1 trauma centre to the National Hip Fracture Database (NHFD) before and after the introduction of an electronic health record system (EHRS). Patients and methods: a total of 3224 records were reviewed from July 2009 to July 2017. 2,133 were submitted between July 2009 and October 2014 and 1,091 between October 2014 and July 2017, representing data submitted before and after the introduction of the EHRS, respectively. Data submitted to the NHFD were scrutinised against locally held data. Results: use of an EHRS was associated with significant reductions in NHFD errors. The operation coding error rate fell significantly from 23.2% (494/2133) to 7.6% (83/1091); P < 0.001. Prior to EHRS introduction, of the 109 deaths recorded in the NHFD, 64 (59%) were incorrect. In the EHRS dataset, all the 112 recorded deaths were correct (P < 0.001). There was no significant difference in the error rate for fracture coding. In the EHRS dataset, after controlling for sample month, entries utilising an operation note template with mandatory fields relevant to NHFD data were more likely to be error free than those not using the template (OR 2.69; 95% CI 1.92-3.78). Conclusion: this study highlights a potential benefit of EHR systems, which offer automated data collection for auditing purposes. However, errors in data submitted to the NHFD remain, particularly in cases where an NHFD-specific operation note template is not used. Clinician engagement with new technologies is vital to avoid human error and ensure database integrity. PMID- 30395141 TI - Comparison of quantitative and qualitative coronary angiography: computer versus the eye. AB - OBJECTIVE: Since visual estimation of the extent of vessel stenosis may vary between operators, we aimed in this study to investigate both inter-observer variability and consistency between the estimation of an operator and quantitative coronary analysis (QCA) measurements. METHODS: A total of 147 elective percutaneous coronary intervention patients with 155 lesions between them were consecutively enrolled in the study. These patients were evaluated for visual estimation of lesion severity by three operators. The lesions were also evaluated with QCA by an operator who was blinded to the visual assessments. Reference diameter, minimal lumen diameter, percentage diameter of stenosis, percentage area of stenosis and diameter of lesion length from the proximal lesion-free segment to the distal lesion-free segment were calculated using a computerised QCA software program. RESULTS: There was a moderate degree of concordance in the categories 70-89% (kappa: 0.406) and 90-99% (kappa: 0.5813), whereas in the categories < 50% and 50-69% there was a low degree of concordance between the visual operators (kappa: 0.323 and kappa: 0.261, respectively). There was a low to moderate grade of concordance between visual estimation and percentage area of stenosis by QCA (kappa: 0.30) but there was no concordance between visual estimation and percentage diameter of stenosis by QCA (kappa: 0.061). Also, there was a statistically significant difference between QCA parameters of percentage diameter of stenosis and percentage area of stenosis (58.4 +/- 14.5 vs 80.6 +/- 11.2 %, p < 0.001). CONCLUSIONS: Visual estimation may overestimate a coronary lesion and may lead to unnecessary coronary intervention. There was low concordance in the categories < 50% and 50-69% between the visual operators. Percentage area of stenosis by QCA had a low to moderate grade of concordance with visual estimation. Percentage area of stenosis by QCA more closely reflected the visual estimation of lesion severity than percentage diameter of stenosis. PMID- 30395144 TI - Pilot Randomized Trial of an Electronic Symptom Monitoring Intervention for Hospitalized Patients with Cancer. AB - Background: Hospitalized patients with cancer experience a high symptom burden, which is associated with poor health outcomes and increased healthcare utilization. However, studies investigating symptom monitoring interventions in this population are lacking. We conducted a pilot randomized trial to assess the feasibility and preliminary efficacy of a symptom monitoring intervention to improve symptom management in hospitalized patients with advanced cancer. Patients and Methods: We randomly assigned patients with advanced cancer who were admitted to the inpatient oncology service to a symptom monitoring intervention or usual care. Patients in both arms self-reported their symptoms daily (Edmonton Symptom Assessment System and Patient Health Questionnaire-4). Patients assigned to the intervention had their symptom reports presented graphically with alerts for moderate/severe symptoms during daily team rounds. The primary endpoint of the study was feasibility. We defined the intervention as feasible if > 75% of participants hospitalized >2 days completed >2 symptom reports. We observed daily rounds to determine if clinicians discussed and developed a plan to address patients' symptoms. We used regression models to assess intervention effects on patients' symptoms throughout their hospitalization, readmission risk, and hospital length of stay (LOS). Results: Among 150 enrolled patients (81.1% enrollment), 94.2% completed >2 symptom reports. Clinicians discussed 60.4% of the symptom reports and developed a plan to address the symptoms highlighted by the symptom reports 20.8% of the time. Compared with usual care, intervention patients had a greater proportion of days with lower psychological distress (B=0.12, P=0.008), but no significant difference in the proportion of days with improved ESAS-physical symptoms (B=0.07, P=0.138). Intervention patients had lower readmission risk (hazard ratio=0.68, P=0.224), although this difference was not significant. We found no significant intervention effects on hospital LOS (B=0.16, P=0.862). Conclusions: This symptom monitoring intervention is feasible and demonstrates encouraging preliminary efficacy for improving patients' symptoms and readmission risk. ClinicalTrials.gov identifier NCT02891993. PMID- 30395145 TI - Effects of Fruit and Vegetable Feeding Messages on Mothers and Fathers: Interactions Between Emotional State and Health Message Framing. AB - Background : There is a pressing need to craft optimal public health messages promoting healthy feeding behaviors among parents. How these messages influence such feeding decisions are affected by multiple interactive factors including emotional states, message framing, and gender, but these factors have not been studied in the domain of parents' feeding of their children. Purpose: To evaluate the role of message framing, emotional state, and parent gender on feeding choices that parents make for their children. Methods: In 2016-2017, 190 parents (126 mothers) of 4- to 7-year-old children were randomly assigned to an anger or fear emotion induction and read either a gain- or loss-framed message about the importance of children's fruit and vegetable (FV) consumption prior to choosing foods for their child from a virtual reality buffet. Results: Mothers in an angry state who received a gain-framed message chose relatively more FV for their child in the virtual buffet, F(3, 180) = 4.77, p = .027. However, fathers in this group did not feed more FV, but rather reported greater intention to improve future FV feeding, F(3, 180) = 4.91, p = .028. Conclusions: Providing gain-framed messages to parents, particularly mothers, in an anger state may be most effective for motivating healthy dietary choices for children. Clinical Trial information: clinicaltrials.gov NCT02622035. PMID- 30395146 TI - Soil fertility and flood regime are correlated with phylogenetic structure of Amazonian palm communities. AB - Background and Aims: Identifying the processes that generate and maintain biodiversity requires understanding of how evolutionary processes interact with abiotic conditions to structure communities. Edaphic gradients are strongly associated with floristic patterns but, compared with climatic gradients, have received relatively little attention. We asked (1) How does the phylogenetic composition of palm communities vary along edaphic gradients within major habitat types? and (2) To what extent are phylogenetic patterns determined by (a) habitat specialists, (b) small versus large palms, and (c) hyperdiverse genera? Methods: We paired data on palm community composition from 501 transects of 0.25 ha located in two main habitat types (non-inundated uplands and seasonally inundated floodplains) in western Amazonian rain forests with information on soil chemistry, climate, phylogeny and metrics of plant size. We focused on exchangeable base concentration (cmol+ kg-1) as a metric of soil fertility and a floristic index of inundation intensity. We used a null model approach to quantify the standard effect size of mean phylogenetic distance for each transect (a metric of phylogenetic community composition) and related this value to edaphic variables using generalized linear mixed models, including a term for spatial autocorrelation. Key Results: Overall, we recorded 112 008 individuals belonging to 110 species. Palm communities in non-inundated upland transects (but not floodplain transects) were more phylogenetically clustered in areas of low soil fertility, measured as exchangeable base concentration. In contrast, floodplain transects with more severe flood regimes (as inferred from floristic structure) tended to be phylogenetically clustered. Nearly half of the species recorded (44 %) were upland specialists while 18 % were floodplain specialists. In both habitat types, phylogenetic clustering was largely due to the co occurrence of small-sized habitat specialists belonging to two hyperdiverse genera (Bactris and Geonoma). Conclusions: Edaphic conditions are associated with the phylogenetic community structure of palms across western Amazonia, and different factors (specifically, soil fertility and inundation intensity) appear to underlie diversity patterns in non-inundated upland versus floodplain habitats. By linking edaphic gradients with palm community phylogenetic structure, our study reinforces the need to integrate edaphic conditions in eco evolutionary studies in order to better understand the processes that generate and maintain tropical forest diversity. Our results suggest a role for edaphic niche conservatism in the evolution and distribution of Amazonian palms, a finding with potential relevance for other clades. PMID- 30395142 TI - Development of the certificate course in the management of hypertension in Africa (CCMH-Africa): proceedings of the first continental faculty meeting, Nairobi, Kenya, 25-26 February 2018. AB - BACKGROUND: In response to the call by the World Health Organisation to reduce premature deaths from non-communicable diseases by 25% by the year 2025 (25*25), the Pan-African Society of Cardiology (PASCAR), in partnership with several organisations, including the World Heart Federation, have developed an urgent 10 point action plan to improve detection, treatment and control of hypertension in Africa. Priority six of this action plan is to promote a task-shifting/task sharing approach in the management of hypertension. AIM: This capacity-building initiative aims to enhance the knowledge, skills and core competences of primary healthcare physicians in the management of hypertension and related complications. METHODS: In a collaborative approach with the International Society of Hypertension, the British and Irish Hypertension Society, the Public Health Foundation of India and the Centre for Chronic Disease Control, the PASCAR hypertension taskforce held a continental faculty meeting in Kenya on 25 and 26 February 2018 to review and discuss a process of effective contextualisation and implementation of the Indian hypertension management course on the African continent. RESULTS: A tailored African course in terms of evidence-based learning, up-to-date curriculum and on-the-job training was developed with a robust monitoring and evaluation strategy. The course will be offered on a modular basis with a judicious mix of case studies, group discussions and contact sessions, with great flexibility to accommodate participants' queries. CONCLUSIONS: Hypertension affects millions of people in Africa and if left untreated is a major cause of heart disease, kidney disease and stroke. CCMH Africa will train in the next 10 years, 25 000 certified general physicians and 50 000 nurses, capable of adequately managing uncomplicated hypertension, thereby freeing the few available specialists to focus on severe or complicated cases. PMID- 30395147 TI - Therapeutic Alliance Between Dietitians and Patients With Head and Neck Cancer: The Effect of Training in a Health Behavior Change Intervention. AB - Background: The relationship between a clinician and their client-the "therapeutic alliance" is a robust predictor of outcome in healthcare settings; yet, few interventions to improve alliance have been tested. Motivational interviewing is a client-centered approach that embodies many principles and strategies consistent with a strong therapeutic alliance. Purpose: To examine whether alliance is enhanced by training dietitians to deliver a motivational interviewing informed health behavior change intervention ("Eating as Treatment"; EAT) as part of routine consultations with patients with head and neck cancer. The predictive ability of motivational interviewing techniques was also assessed. Methods: A secondary analysis of the EAT stepped-wedge cluster-randomized controlled trial was conducted. Patients with head and neck cancer undergoing radiotherapy (n = 307) were treated by radiotherapy dietitians (n = 29) during the control (Treatment as Usual) or intervention (EAT) phase. Alliance was rated during the first and final weeks of radiotherapy, and again 4 and 12 weeks post radiotherapy. Dietetic sessions were audiotaped. Week one sessions were objectively rated for dietitians' use of motivational interviewing techniques. Results: Generalized linear-mixed effects regressions found no effect of EAT on dietitian-rated alliance (p = .237). After excluding outliers, patient-rated alliance was 0.29 points lower after EAT training (p = .016). Post hoc analyses revealed lower patient ratings on perceived support and dietitian confidence. Hierarchical multiple regressions found that no specific motivational interviewing techniques predicted patient-rated alliance. Dietitian acknowledgment of patient challenges was related to dietitian-rated alliance (beta =.15, p =.035). Conclusions: Patient and dietitian ratings of alliance were high after EAT training, but not significantly improved. Further research is needed to better understand the differential impact of intervention training and delivery on patient and clinician ratings of therapeutic alliance. Clinical Trial information: Trial registration number ACTRN12613000320752. PMID- 30395148 TI - Laboratory Monitoring of Platelet P2Y12 Receptor Inhibitors and Reversal of Antiplatelet Agents: An ACLPS Critical Review. AB - Objectives: To review the use of laboratory tests for antiplatelet agents to determine escalation of antiplatelet therapy and for emergent reversal of P2Y12 inhibitors. Methods: A case scenario and review of cardiovascular and neurointerventional literature are described. Results: In cardiovascular disease patients, large randomized trials failed to demonstrate superiority of tailored antiplatelet regimens using the VerifyNow P2Y12 assay, where earlier studies had shown promise. Platelet transfusions restored platelet function measured by vasodilator-stimulated phosphoprotein, light transmission aggregometry, or thromboelastography but not VerifyNow P2Y12, with the most restoration for clopidogrel and the least for ticagrelor. Conclusions: Current evidence does not support changing antiplatelet therapy based on the results of platelet function monitoring tests. For emergent reversal of P2Y12 inhibitors, test method can affect platelet dosing recommendations, as different methods may give different results. PMID- 30395150 TI - Myotomy-Capsulotomy With Intramuscular Fat Grafting: A Novel Technique for Secondary Treatment of Prepectoral Upper Pole Defects in Breast Reconstruction. PMID- 30395149 TI - Effect of chronic corticosterone-induced depression on circadian rhythms and age related phenotypes in mice. AB - Disrupted circadian rhythms are a recognized effect of depression, and our previous article demonstrated an association between depression and premature aging, but the underlying mechanisms are not well understood. In the present study, we used a mouse model of chronic corticosterone (CORT)-treated depression to elucidate a mechanism by which depression may be associated with the circadian clock and mediate age-related phenotypes. Mice received a daily injection of 20 mg/kg CORT for 21 consecutive days, and the depression-like behaviors of mice were identified by the sucrose intake test, tail suspension test and open field test. Our findings indicated that CORT injection may be correlated with the circadian clock by impairing circadian rhythms or shifting the phase values of clock genes. We also showed that CORT-treated mice exhibited a significant gradual reduction in body weight gain with increased oxidative stress, including reduced activity of antioxidant-related enzymes, reduced glutathione:glutathione disulfide ratio and cytochrome (Cyt)-C level, and elevated reactive oxygen species content. Moreover, chronic CORT injection affected inflammatory responses, the production of mitochondrial ATP and telomere shortening, which may be associated with the Sirtuin 3 (SIRT3) signaling pathway. Additionally, chronic CORT injection disrupted the circadian rhythms of some indexes of aging phenotypes and altered the phase values of these indexes. Our findings suggest that psychologically stressful conditions such as depression are linked to changes in circadian rhythms and age-related phenotypes. PMID- 30395151 TI - New Perspectives on Emotional Processing in People with Symptomatic Huntington's Disease: Impaired Emotion Regulation and Recognition of Emotional Body Language. AB - Objective: Emotion regulation and emotional body language (EBL) recognition represent two fundamental components of emotional processing that have recently seen a considerable surge in research interest, in part due to the role they play in optimizing mental health. This appears to be particularly true for clinical conditions that can profoundly affect emotional functioning. Among these is Huntington's disease (HD), a neurodegenerative disorder that is associated with several psychological difficulties and cognitive impairments, including well established deficits in facial emotion recognition. However, although the theoretical case for impairments is strong, the current evidence in HD on other components such as emotion regulation and EBL recognition is sparse. Method: In this study, it was hypothesized that emotion regulation and recognition of EBL are impaired in people with symptomatic HD, and that these impairments significantly and positively correlate with each other. A between-subjects design was adopted to compare 13 people with symptomatic HD with 12 non-affected controls matched for age and education. Results: The results showed that emotion regulation and EBL recognition were significantly impaired in individuals with HD. Moreover, a significant positive correlation was observed between facial and EBL recognition impairments, whereas EBL performance was negatively related to the disease stage. However, emotion regulation and recognition performances were not significantly correlated. Conclusions: This investigation represents the first evidence of a deficit of emotion regulation and EBL recognition in individuals with HD. The clinical implications of these findings are explored, and indications for future research are proposed. PMID- 30395152 TI - Carboplatin in the neoadjuvant treatment of triple-negative breast cancer - ready for prime time? PMID- 30395153 TI - Artemisinin derivatives inhibit epithelial ovarian cancer cells via autophagy mediated cell cycle arrest. AB - Epithelial ovarian cancer (EOC) is the most fatal gynecologic malignancy due to its late diagnosis and lack of curative therapy. The antimalaria compound artemisinin and its derivatives, such as artesunate (ART) and dihydroartemisinin (DHA), have proven to be potent anticancer drugs and act through various anticancer mechanisms. To identify novel targets of artemisinin derivatives in EOC cells, we investigated the effects of ART and DHA on SKOV3 and primary EOC cell growth via CCK-8 assay. Both ART and DHA inhibited EOC cell growth. A cell cycle distribution analysis showed that ART and DHA caused G2/M cell cycle arrest. Moreover, ART and DHA induced autophagy in EOC cells, whereas autophagy inhibitors reversed the cell growth inhibition and cell cycle arrest induced by ART and DHA. Western blot analysis showed that ART and DHA also suppressed the cell cycle-related NF-kappaB-signaling pathway in EOC cells. These data suggest that artemisinin derivatives induce autophagy, block the cell cycle, and inhibit cell growth in EOC cells. Our research provides new targets for artemisinin derivatives for EOC treatment. PMID- 30395154 TI - Membrane cholesterol and substrate stiffness coordinate to induce the remodeling of the cytoskeleton and the alteration in the biomechanics of vascular smooth muscle cells. AB - Aims: Cholesterol not only deposits in foam cells at the atherosclerotic plaque, but also plays an important role as a regulator of cell migration in atherogenesis. In addition, the progression of atherosclerosis leads to arterial wall stiffening, and thus altering the micromechanical environment of vascular smooth muscle cells (VSMCs) in vivo. Our studies aim to test the hypothesis that membrane cholesterol and substrate stiffness coordinate to regulate VSMCs biomechanics, and thus potentially regulate VSMCs migration and atherosclerotic plaque formation. Methods and results: Methyl-beta-cyclodextrin (MbetaCD) was used to manipulate membrane cholesterol content in VSMCs isolated from the descending thoracic aorta of male Sprague Dawley rats and cultured on type I collagen (COL1)-coated polyacrylamide (PA) gel substrates with varying stiffness. Atomic force microscopy (AFM) was used to determine VSMCs stiffness and integrin fibronectin (FN) adhesion. The alignment of submembranous actin filaments was visualized with AFM and confocal microscopy. The constriction force of rat aorta was measured ex vivo using a multi-wire myograph system. Our results demonstrated that cholesterol-depletion and substrate-softening induced a significant decrease in VSMCs stiffness and adhesion to FN, as well as cytoskeletal disorganization. In addition, the contractile force of rat aorta was reduced upon cholesterol depletion. Cholesterol-enrichment resulted in an increase in stiffness, adhesion to FN, cytoskeletal organization of VSMCs compared to the cholesterol-depleted cells and enhanced contractile force of rat aortas compared to the cholesterol depleted vessel rings. Conclusions: Cell membrane cholesterol and substrate stiffness synergistically affect VSMCs elastic modulus (E-modulus) by regulating the organization of the actin cytoskeleton. Except for the 3.5 kPa gel substrate, cholesterol-depletion decreased VSMCs-FN adhesion force, adhesion loading rate, cytoskeletal orientation, and E-modulus compared to the control VSMCs. Conversely, cholesterol-enrichment significantly increased cytoskeleton orientation, stiffness, and VSMCs-FN cell adhesion force compared to both control and cholesterol-depleted VSMCs on a soft substrate. PMID- 30395155 TI - Development of Tumor Mutation Burden as an Immunotherapy Biomarker: Utility for the Oncology Clinic. AB - Background: Treatment with immune checkpoint blockade (ICB) with agents such as anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD L1), and/or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) can result in impressive response rates and durable disease remission but only in a subset of patients with cancer. Expression of PD-L1 has demonstrated utility in selecting patients for response to ICB and has proven to be an important biomarker for patient selection. Tumor mutation burden (TMB) is emerging as a potential biomarker. However, refinement of interpretation and contextualization is required. Materials and methods: In this review, we outline the evolution of TMB as a biomarker in oncology, delineate how TMB can be applied in the clinic, discuss current limitations as a diagnostic test, and highlight mechanistic insights unveiled by the study of TMB. We review available data to date studying TMB as a biomarker for response to ICB by tumor type, focusing on studies proposing a threshold for TMB as a predictive biomarker for ICB activity. Results: High TMB consistently selects for benefit with ICB therapy. In lung, bladder and head and neck cancers, the current predictive TMB thresholds proposed approximates 200 non-synonymous somatic mutations by whole exome sequencing (WES). PD-L1 expression influences response to ICB in high TMB tumors with single agent PD-(L)1 antibodies; however, response may not be dependent on PD-L1 expression in the setting of anti-CTLA4 or anti-PD-1/CTLA-4 combination therapy. Disease-specific TMB thresholds for effective prediction of response in various other malignancies are not well established. Conclusions: TMB, in concert with PD L1 expression, has been demonstrated to be a useful biomarker for ICB selection across some cancer types; however, further prospective validation studies are required. TMB determination by selected targeted panels has been correlated with WES. Calibration and harmonization will be required for optimal utility and alignment across all platforms currently used internationally. Key challenges will need to be addressed prior to broader use in different tumor types. PMID- 30395156 TI - Letter to the Editor. PMID- 30395157 TI - Set of approaches based on 3D structure and Position Specific Scoring Matrix for predicting DNA-binding proteins. AB - Motivation: Because DNA-binding proteins (DNA-BPs) play a vital role in all aspects of genetic activity, the development of reliable and efficient systems for automatic DNA-BP classification is becoming a crucial proteomic technology. Key to this technology is the discovery of powerful protein representations and feature extraction methods. The goal of this paper is to develop experimentally a system for automatic DNA-BP classification by comparing and combining different descriptors taken from different types of protein representations. Results: The descriptors we evaluate include those starting from the Position Specific Scoring Matrix (PSSM) of proteins, those derived from the Amino-Acid Sequence (AAS), various matrix representations of proteins, and features taken from the 3 dimensional tertiary structure of proteins. We also introduce some new variants of protein descriptors. Each descriptor is used to train a separate support vector machine (SVM), and results are combined by sum rule. Our final system obtains state-or-the-art results on three benchmark DNA-BP datasets. Supplementary information: The MATLAB code for replicating the experiments presented in this paper is available at https://github.com/LorisNanni. PMID- 30395158 TI - Neighborhood Poverty Increases Risk for Cigarette Smoking From Age 30 to 39. AB - Background: Lower socioeconomic status (SES) has been associated with higher rates of smoking. Few longitudinal studies have examined indicators of SES at both the neighborhood- and individual-level over time in conjunction with proximal risk factors of cigarette smoking. Purpose: To examine associations of time-varying measures of SES, demographic factors, and proximal risk factors for smoking net of average trajectories of smoking behavior from ages 30 to 39 in a community sample. Methods: Data from the Seattle Social Development Project (N = 752), a theory-driven longitudinal study originating in Seattle, WA, were used to estimate trajectories of smoking from age 30 to 39. Time-varying measures of neighborhood poverty, coworker smoking, partner smoking, depression, anxiety, education, income, marital status, and parenthood were associated with smoking over time using latent growth curve modeling. Results: Results indicated that living in higher poverty neighborhoods was uniquely associated with a greater likelihood of smoking net of average trajectories of smoking from age 30 to 39, gender and race/ethnicity, time-varying measures of SES and demographics, and time-varying measures of proximal risk factors for smoking. Conclusions: Living in higher poverty neighborhoods presents a unique risk for smoking among adults aged 30 to 39 above and beyond multiple aspects of SES and other potential mechanisms relating SES to smoking. PMID- 30395159 TI - Quantitative Lymph Node Burden as a "Very-High Risk" Factor Identifying Head and Neck Cancer Patients Benefiting from Post-operative Chemoradiation. AB - Background: Adjuvant chemoradiation (CRT) is standard for head and neck squamous cell carcinoma (HNSCC) patients with positive margins or extranodal extension (ENE) following surgery. However, emerging evidence suggests the number of positive lymph nodes (LNs) is the dominant determinant of survival in non oropharyngeal HNSCC, and thus may better identify those benefiting from treatment intensification. Patients and methods: Patients from the National Cancer Database diagnosed with non-oropharyngeal HNSCC (oral cavity, larynx, hypopharynx) between 2004-2014 and undergoing surgical resection, neck dissection, and postoperative radiotherapy (RT) were included. Multivariable regression with first-order interaction terms was used to model the interaction between post-operative CRT and continuous number of positive LNs with respect to overall survival. Results: 7144 patients met inclusion criteria. In multivariable analysis, increasing number of positive LNs was associated with both increasing mortality (p<0.001) and increasing benefit from post-operative CRT versus RT alone (interaction p<0.001). While there was no benefit from post-operative CRT in patients with 0-2 LN + (HR 0.96, 95% CI 0.86-1.07, p=0.47), increased benefit was seen in those with 3-5 LN + (HR 0.84, 95% CI 0.70-1.00, p=0.05) and those with 6 or more LN + (HR 0.65, 95% CI 0.51-0.82, p<0.001) in multivariable models. By contrast, margin status and ENE did not reliably identify patients benefitting from post-operative CRT based on statistical tests of interaction. Even in patients with either ENE or positive margins, only those with >=6 LN+ had improved survival from post operative CRT. Conclusion(s): Increasing metastatic nodal burden was associated with increased benefit from CRT compared to RT alone, surpassing conventional high-risk factors in identifying patients benefiting from CRT. Stratification by metastatic LN number may characterize a very-high risk patient cohort best suited for treatment intensification. PMID- 30395160 TI - DrugThatGene: integrative analysis to streamline the identification of druggable genes, pathways, and protein complexes from CRISPR screens. AB - Motivation: The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) nuclease system has allowed for high-throughput, large scale pooled screens for functional genomic studies. To aid in the translation of functional genomics to therapeutics, we developed Drug That Gene (DTG) as a web-based application that streamlines analysis of potential therapeutic targets identified from functional genetic screens. Results: Starting from a gene list as input, DTG offers automated identification of small molecules along with supporting information from human genetic and other relevant databases. Furthermore, DTG aids in the identification of common biological pathways and protein complexes in conjunction with associated small molecule inhibitors. Taken together, DTG aims to expedite the identification of small molecules from the abundance of functional genetic data generated from CRISPR screens. Availability: DTG is an open-source and free software available as a website at http://drugthatgene.pinellolab.org. Source code is available at: https://github.com/pinellolab/DrugThatGene, which can be downloaded in order to run DTG locally. PMID- 30395161 TI - Homocysteine impairs porcine oocyte quality via deregulation of one carbon metabolism and hypermethylation of mitochondrial DNA. AB - Homocysteine (Hcy) is an intermediate in the one-carbon metabolism that donates methyl groups for methylation processes involved in epigenetic gene regulation. Although poor oocyte quality in polycystic ovarian syndrome (PCOS) patients is associated with elevated Hcy concentration in serum and follicular fluid, whether Hcy directly affects oocyte quality and its mechanisms are poorly understood. Here we show that Hcy treatment impaired oocyte quality and developmental competence, indicated by significantly reduced survival rate, polar body extrusion rate and cleavage rate. Hcy treatment resulted in mitochondrial dysfunction, with increased production of mitochondrial ROS, reduced mtDNA copy number and the expression of 7 out of 13 mtDNA-encoded genes and 2 ribosome RNA genes, 12S rRNA and 16S rRNA. Upon Hcy treatment, the expression of one-carbon metabolic enzymes and DNMT1 was enhanced. Interestingly, DNA methyltransferase inhibitor 5'AZA rescued Hcy-induced mitochondrial dysfunction and impaired oocyte quality and developmental competence. Concurrently, expression of one-carbon metabolic enzymes and methylation status of mtDNA coding sequences were also normalized, at least partially, by 5'AZA treatment. Our findings not only extend the understanding about how Hcy induces poor oocyte quality, but also contribute to a novel angle of identifying targets for enhancing the quality of oocyte from PCOS patients. PMID- 30395162 TI - Non-inferiority for Short-HER or short-chemotherapy? PMID- 30395163 TI - Direct role of the C-C motif chemokine receptor 2/monocyte chemoattractant protein 1 system in the feline cumulus oocyte complex. AB - Studies were designed to a) evaluate the mRNA expression of the C-C motif chemokine receptor 2 (CCR2) and its chemokine ligands, as well as genes related to periovulatory events, within the cumulus oocyte complex (COC) and follicle wall after a luteinizing hormone (LH) stimulus in cultured feline antral follicles; b) assess the immunolocalization of CCR2 and its main ligand (monocyte chemoattractant protein 1, MCP1) within the feline COC; and c) examine the direct effects of exogenous recombinant MCP1 on mRNA expression of the CCR2 receptor and MCP1 as well as key periovulatory genes in the COC, using a feline COC culture system. Both culture systems were developed by our laboratory and exhibit physiological response to gonadotropin stimuli. In summary, this study demonstrated mRNA expression of CCR2 receptor and its assessed ligands (MCP1, MCP2, MCP3 and MCP4) within the feline COC and follicle antral wall, and a significant increase in CCR2 mRNA by LH within the COC. Also, CCR2 and MCP1 immunoreactivity was observed in the oocyte and cumulus cells of the feline COC. Remarkably, this is the first report, in any species, describing a direct effect of the recombinant MCP1 in the CCR2/MCP1 system within the COC, by increasing the mRNA levels of key genes involved in the ovulatory cascade, as well as its own receptor CCR2. Together, these data suggest that CCR2 receptor signaling in the COC may regulate events critical for promoting cumulus oocyte expansion and/or oocyte maturation. PMID- 30395164 TI - Resting-State Activity in High-Order Visual Areas as a Window into Natural Human Brain Activations. AB - A major limitation of conventional human brain research has been its basis in highly artificial laboratory experiments. Due to technical constraints, little is known about the nature of cortical activations during ecological real life. We have previously proposed the "spontaneous trait reactivation (STR)" hypothesis arguing that resting-state patterns, which emerge spontaneously in the absence of external stimulus, reflect the statistics of habitual cortical activations during real life. Therefore, these patterns can serve as a window into daily life cortical activity. A straightforward prediction of this hypothesis is that spontaneous patterns should preferentially correlate to patterns generated by naturalistic stimuli compared with artificial ones. Here we targeted high-level category-selective visual areas and tested this prediction by comparing BOLD functional connectivity patterns formed during rest to patterns formed in response to naturalistic stimuli, as well as to more artificial category selective, dynamic stimuli. Our results revealed a significant correlation between the resting-state patterns and functional connectivity patterns generated by naturalistic stimuli. Furthermore, the correlations to naturalistic stimuli were significantly higher than those found between resting-state patterns and those generated by artificial control stimuli. These findings provide evidence of a stringent link between spontaneous patterns and the activation patterns during natural vision. PMID- 30395165 TI - Partially non-homogeneous dynamic Bayesian networks based on Bayesian regression models with partitioned design matrices. AB - Motivation: Non-homogeneous dynamic Bayesian networks (NH-DBNs) are a popular modelling tool for learning cellular networks from time series data. In systems biology, time series are often measured under different experimental conditions, and not rarely only some network interaction parameters depend on the condition while the other parameters stay constant across conditions. For this situation, we propose a new partially NH-DBN, based on Bayesian hierarchical regression models with partitioned design matrices. With regard to our main application to semi-quantitative (immunoblot) timecourse data from mammalian target of rapamycin complex 1 (mTORC1) signalling, we also propose a Gaussian process based method to solve the problem of non-equidistant time series measurements. Results: On synthetic network data and on yeast gene expression data the new model leads to improved network reconstruction accuracies. We then use the new model to reconstruct the topologies of the circadian clock network in A. thaliana and the mTORC1 signalling pathway. The inferred network topologies show features that are consistent with the biological literature. Availability: All data sets have been made available with earlier publications. Our Matlab code is available upon request. Supplementary Information: A supplementary paper is available at Bioinformatics online. PMID- 30395166 TI - ukbREST: efficient and streamlined data access for reproducible research in large biobanks. AB - Summary: Large biobanks, such as UK Biobank with half a million participants, are changing the scale and availability of genotypic and phenotypic data for researchers to ask fundamental questions about the biology of health and disease. The breadth of the UK Biobank data is enabling discoveries at an unprecedented pace. However, this size and complexity pose new challenges to investigators who need to keep the accruing data up to date, comply with potential consent changes, and efficiently and reproducibly extract subsets of the data to answer specific scientific questions. Here we propose a tool called ukbREST designed for the UK Biobank study (easily extensible to other biobanks), which allows authorized users to efficiently retrieve phenotypic and genetic data. It exposes a REST API that makes data highly accessible inside a private and secure network, allowing the data specification in a human readable text format easily shareable with other researchers. These characteristics make ukbREST an important tool to make biobank's valuable data more readily accessible to the research community and facilitate reproducibility of the analysis, a key aspect of science. Availability: It is implemented in Python using the Flask-RESTful framework for the API, and it is under the MIT license. It works with PostgreSQL and a Docker image is available for easy deployment. The source code and documentation is available in Github: https://github.com/hakyimlab/ukbrest. PMID- 30395167 TI - Interleukin-12p35 knockout promotes macrophage differentiation, aggravates vascular dysfunction and elevates blood pressure in angiotensin II-infused mice. AB - Aims: Numerous studies have demonstrated that inflammation is involved in the progression of hypertension. Inflammatory cytokines interleukin (IL)-12 and IL-35 belong to the IL-12 cytokine family and share the same IL-12p35 subunit. Accumulating evidence has demonstrated that IL-12p35 knockout (IL-12p35 KO) leads to cardiovascular disease by regulating the inflammatory response. This study aimed to investigate whether IL-12p35 KO elevates blood pressure in a hypertension mouse model. Methods and Results: Mice with angiotensin (Ang) II infusion showed marked aortic IL-12p35 expression; thus, aortic macrophages may be the main source of IL-12p35. Wild-type and IL-12p35 KO mice were infused with Ang II or saline. IL-12p35 KO promoted M1 macrophage differentiation, amplified the inflammatory response, aggravated vascular dysfunction and elevated blood pressure in Ang II-treated mice. Then, some Ang II-infused mice were given PBS, mouse recombinant IL-12 (rIL-12) or rIL-35, and the results showed that rIL-12 but not rIL-35 treatment had an antihypertensive effect on Ang II-infused mice. In addition, detection of human plasma IL-12 levels in hypertensive patients and control subjects showed that IL-12 was significantly increased in hypertensive patients compared to control subjects. In hypertensive patients, IL-12 levels were positively correlated with blood pressure. Conclusions: IL-12p35 KO amplifies the inflammatory response and promotes blood pressure elevation in Ang II-treated mice. In addition, IL-12, but not IL-35, plays a protective role in the Ang II-induced hypertension model. Thus, IL-12 may be a novel therapeutic agent for the prevention and treatment of clinical hypertension. PMID- 30395168 TI - gwasurvivr : an R package for genome wide survival analysis. AB - Summary: To address the limited software options for performing survival analyses with millions of SNPs, we developed gwasurvivr, an R/Bioconductor package with a simple interface for conducting genome wide survival analyses using VCF (outputted from Michigan or Sanger imputation servers), IMPUTE2 or PLINK files. To decrease the number of iterations needed for convergence when optimizing the parameter estimates in the Cox model we modified the R package survival; covariates in the model are first fit without the SNP, and those parameter estimates are used as initial points. We benchmarked gwasurvivr with other software capable of conducting genome wide survival analysis (genipe, SurvivalGWAS_SV, and GWASTools). gwasurvivr is significantly faster and shows better scalability as sample size, number of SNPs and number of covariates increases. Availability and implementation: gwasurvivr, including source code, documentation, and vignette are available at: http://bioconductor.org/packages/gwasurvivr. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30395169 TI - Age and Ageing to introduce a new category of paper: healthcare improvement science. AB - Age and Ageing is now inviting papers on healthcare improvement for older people. In this article we outline the nature and scope of healthcare improvement and reference improvement models and the tools and methods of improvement science. We emphasise the issues of sustainability, including scale and spread; evaluation - including associated ethical consideration and the involvement of patients and the public in healthcare improvement and associated research. Throughout we refer to resources the authors have found useful in their own work, and provide a bibliography of sources and web-links which will provide essential guidance and support for potential contributors to this new category of submission to Age and Ageing. PMID- 30395170 TI - Application of Dopant-Assisted Atmospheric Pressure Photoionisation HPLC-MS Method for the Sensitive Determination of Polycyclic Aromatic Hydrocarbons in Dark Chocolate. AB - Multiple food research studies have shown that the polycyclic aromatic hydrocarbon (PAHs) are frequently found in processed cocoa products and chocolate. In a present study a method based on dopant-assisted atmospheric pressure photoionisation (DA-APPI) combined with a liquid chromatography/high resolution mass spectrometer (HPLC-HRMS) for high-sensitivity analysis of four EU marker PAHs in dark chocolate samples was developed and fully validated according to the performance criteria set in EU guidelines. PAHs detection was achieved by HRMS in positive electrospray ionization mode with toluene used as a dopant to enhance the ionization efficiency of non-polar PAHs. The on-column instrument detection limits ranged from 0.8 to 1.2 pg for all four marker compounds. The method detection limits ranged from 0.016 to 0.024 MUg kg-1 expressed on fat basis. The elaborated method was successfully applied to the analysis of four EU marker PAHs in dark chocolate samples. The presence of benzo[a]anthracene, benzo[b]fluoranthene and chrysene revealed at detectable levels in 100% of the samples, while benzo[a]pyrene was revealed in 77% of the samples, with its content ranging from 0.08 to 2.90 MUg kg-1 fat. PMID- 30395171 TI - Supervised Non-negative Matrix Factorization Methods for MALDI Imaging Applications. AB - Motivation: Non-negative matrix factorization (NMF) is a common tool for obtaining low-rank approximations of non-negative data matrices and has been widely used in machine learning, e.g., for supporting feature extraction in high dimensional classification tasks. In its classical form NMF is an unsupervised method, i.e. the class labels of the training data are not used when computing the NMF. However, incorporating the classification labels into the NMF algorithms allows to specifically guide them towards the extraction of data patterns relevant for discriminating the respective classes. This approach is particularly suited for the analysis of mass spectrometry imaging (MSI) data in clinical applications, such as tumor typing and classification, which are amongst the most challenging tasks in pathology. Thus, we investigate algorithms for extracting tumor specific spectral patterns from MSI data by NMF methods. Results: In this paper, we incorporate a priori class labels into the NMF cost functional by adding appropriate supervised penalty terms. Numerical experiments on a MALDI imaging dataset confirm that the novel supervised NMF methods lead to significantly better classification accuracy and stability as compared to other standard approaches. Availability: https://gitlab.informatik.uni bremen.de/digipath/Supervised_NMF_Methods_for_MALDI.git. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30395172 TI - Cell-type specific CD73 expression is an independent prognostic factor in bladder cancer. AB - CD73 is an adenosine-producing cell surface enzyme, which exerts strong anti inflammatory and migration modulating effects in many cell types. We evaluated the potential of CD73 as a biomarker in predicting the outcome of bladder carcinoma. CD73 expression in tumor and stromal cells was analyzed using immunohistochemistry in 270 bladder cancer patients (166 non-muscle invasive bladder cancer (NMIBC) and 104 muscle invasive bladder cancer (MIBC) tumors). The correlations of CD73 with clinical and pathological characteristics were evaluated with Pearson's and Fischer's tests. The Kaplan-Meier method and Cox proportional hazards regression models were used to analyze the association between CD73 expression and outcome. CD73 expression showed substantial variation in basal and suprabasal layers of the cancerous epithelium, stromal fibroblasts, endothelial cells and lymphocytes in different tumor specimens. In log-rank analyses CD73 expression in cancer cells associated with better survival both in NMIBC and MIBC, whereas CD73 positivity in stromal fibroblasts associated with impaired survival in NMIBC. In multivariable models CD73 negative epithelial cells in both bladder cancer types and CD73 negative endothelial cells in MIBC were independent factors predicting poor outcome. We conclude that in contrast to many other cancer types, high CD73 expression in bladder cancer predicts favorable prognosis. PMID- 30395173 TI - FAVITES: simultaneous simulation of transmission networks, phylogenetic trees, and sequences. AB - Motivation: The ability to simulate epidemics as a function of model parameters allows insights that are unobtainable from real datasets. Further, reconstructing transmission networks for fast-evolving viruses like HIV may have the potential to greatly enhance epidemic intervention, but transmission network reconstruction methods have been inadequately studied, largely because it is difficult to obtain "truth" sets on which to test them and properly measure their performance. Results: We introduce FAVITES, a robust framework for simulating realistic datasets for epidemics that are caused by fast-evolving pathogens like HIV. FAVITES creates a generative model to produce contact networks, transmission networks, phylogenetic trees, and sequence datasets, and to add error to the data. FAVITES is designed to be extensible by dividing the generative model into modules, each of which is expressed as a fixed API that can be implemented using various models. We use FAVITES to simulate HIV datasets and study the realism of the simulated datasets. We then use the simulated data to study the impact of the increased treatment efforts on epidemiological outcomes. We also study two transmission network reconstruction methods and their effectiveness in detecting fast-growing clusters. Availability and implementation: FAVITES is available at https://github.com/niemasd/FAVITES, and a Docker image can be found on DockerHub (https://hub.docker.com/r/niemasd/favites). PMID- 30395174 TI - Propagation of Information Along the Cortical Hierarchy as a Function of Attention While Reading and Listening to Stories. AB - How does attention route information from sensory to high-order areas as a function of task, within the relatively fixed topology of the brain? In this study, participants were simultaneously presented with 2 unrelated stories-one spoken and one written-and asked to attend one while ignoring the other. We used fMRI and a novel intersubject correlation analysis to track the spread of information along the processing hierarchy as a function of task. Processing the unattended spoken (written) information was confined to auditory (visual) cortices. In contrast, attending to the spoken (written) story enhanced the stimulus-selective responses in sensory regions and allowed it to spread into higher-order areas. Surprisingly, we found that the story-specific spoken (written) responses for the attended story also reached secondary visual (auditory) regions of the unattended sensory modality. These results demonstrate how attention enhances the processing of attended input and allows it to propagate across brain areas. PMID- 30395175 TI - 27-Hydroxycholesterol Induces Aberrant Morphology and Synaptic Dysfunction in Hippocampal Neurons. AB - Hypercholesterolemia is a risk factor for neurodegenerative diseases, but how high blood cholesterol levels are linked to neurodegeneration is still unknown. Here, we show that an excess of the blood-brain barrier permeable cholesterol metabolite 27-hydroxycholesterol (27-OH) impairs neuronal morphology and reduces hippocampal spine density and the levels of the postsynaptic protein PSD95. Dendritic spines are the main postsynaptic elements of excitatory synapses and are crucial structures for memory and cognition. Furthermore, PSD95 has an essential function for synaptic maintenance and plasticity. PSD95 synthesis is controlled by the REST-miR124a-PTBP1 axis. Here, we report that high levels of 27 OH induce REST-miR124a-PTBP1 axis dysregulation in a possible RxRgamma-dependent manner, suggesting that 27-OH reduces PSD95 levels through this mechanism. Our results reveal a possible molecular link between hypercholesterolemia and neurodegeneration. We discuss the possibility that reduction of 27-OH levels could be a useful strategy for preventing memory and cognitive decline in neurodegenerative disorders. PMID- 30395176 TI - FSH Actions and Pregnancy: Looking Beyond Ovarian FSH Receptors. AB - By mediating estrogen synthesis and follicular growth in response to FSH, the ovarian FSH receptor (FSHR) is essential for female fertility. Indeed, ovarian stimulation via administration of FSH to women with infertility is part of the primary therapeutic intervention used in assisted reproductive technology. In physiological and therapeutic contexts, current dogma dictates that once ovulation has occurred, FSH/FSHR signaling is no longer required for successful pregnancy outcomes. However, a continued role for FSH during pregnancy is suggested by recent studies demonstrating extraovarian FSHR in the female reproductive tract. Furthermore, functional roles for FSHR in placenta and in uterine myometrium have now been demonstrated. In placenta, vascular endothelial FSHR of fetal vessels within the chorionic villi (human) or labyrinth (mouse) mediate angiogenesis, and it has further been shown that deletion of placental Fshr in mice has deleterious effects on pregnancy. In uterine myometrium, changes in the densities of FSHR in muscle fiber and stroma in the nonpregnant state, early pregnancy, and term pregnancy differentially regulate contractile activity, suggesting that signaling through myometrial FSHR may contribute to the quieting of contractile activity required for successful implantation and that the temporal upregulation of the FSHR at term pregnancy may be required for the appropriate timing of parturition. In addition, extraovarian expression of mRNAs encoding the glycoprotein hormone alpha subunit and the FSH beta subunit has been demonstrated, suggesting that these novel aspects of extraovarian FSH/FSHR signaling during pregnancy may be mediated by locally synthesized FSH. PMID- 30395177 TI - Breast Cancers With Magee Equation Score of Less Than 18, or 18-25 and Mitosis Score of 1, Do Not Require Oncotype DX Testing: A Value Study. AB - Objectives: To investigate use of Magee equations (MEs) to determine which breast cancer cases can be excluded from Oncotype DX testing. Methods: A prospective value study was carried out using data from pathology reports. Results: If all three MEs scores were less than 18 or 31 or higher, the cases were labeled do not send for testing. If any or all scores were 18 to 25, cases were labeled do not send if mitosis score was 1. Of the total 205 cases, 146 (71%) were labeled do not send; of these, the correct call was made in 143 (98%) cases. Two of the three discordant cases had associated nontumor factors, likely resulting in higher scores. Conclusions: Cases with ME scores less than 18, or 18 to 25 and mitosis score 1, do not require Oncotype DX testing, an estimated saving of US$280,000 per 100 clinical requests. PMID- 30395178 TI - Heavy-tailed prior distributions for sequence count data: removing the noise and preserving large differences. AB - Motivation: In RNA-seq differential expression analysis, investigators aim to detect those genes with changes in expression level across conditions, despite technical and biological variability in the observations. A common task is to accurately estimate the effect size, often in terms of a logarithmic fold change (LFC). Results: When the read counts are low or highly variable, the maximum likelihood estimates for the LFCs has high variance, leading to large estimates not representative of true differences, and poor ranking of genes by effect size. One approach is to introduce filtering thresholds and pseudocounts to exclude or moderate estimated LFCs. Filtering may result in a loss of genes from the analysis with true differences in expression, while pseudocounts provide a limited solution that must be adapted per dataset. Here, we propose the use of a heavy-tailed Cauchy prior distribution for effect sizes, which avoids the use of filter thresholds or pseudocounts. The proposed method, Approximate Posterior Estimation for GLM, apeglm, has lower bias than previously proposed shrinkage estimators, while still reducing variance for those genes with little information for statistical inference. Availability: The apeglm package is available as an R/Bioconductor package at https://bioconductor.org/packages/apeglm, and the methods can be called from within the DESeq2 software. Supplementary Information: Supplementary data are available at Bioinformatics online. PMID- 30395179 TI - A Systematic and Critical Review of Bacteriophage Therapy against Multi-Drug Resistant ESKAPE Organisms in Humans. AB - Bacteriophages (phages) may constitute a natural, safe, and effective strategy to prevent and control multi-drug resistant organisms (MDROs), ESKAPE pathogens in particular. Few clinical studies have assessed the safety and efficacy of phages in patients infected with MDROs. This systematic review summarizes and critically evaluates published studies of phages in clinical practice and presents the appropriate phage selection criteria and recommendations for clinicians and scientists for a successful therapy. Articles were identified through a search of PubMed, Ovid, EMBASE, and Cochrane Library databases. Among 1,102 articles and abstracts, 30 studies were selected and evaluated using selective inclusion criteria, phage criteria, and study characteristics. Most studies showed efficacy (87%) and safety (67%) of the tested phages but few studies examined phage resistance (35%). Clinical studies and regulatory changes are needed to determine the safety and efficacy of phages and to advance their use in patients with MDRO infections. PMID- 30395180 TI - Simplifying the WHO protocol: Three steps versus six steps for performance of hand hygiene - a cluster-randomized trial. AB - Background: In an experimental setting, a simplified 3-step hand hygiene technique for applying alcohol-based hand rub was non-inferior in terms of reduction of bacterial counts as compared to the conventional WHO-6-step technique. We therefore compared compliance and microbiological efficacy between both hand hygiene techniques in routine clinical practice. Methods: We performed a cluster-randomized trial from 10/2015-11/2015 at the University Hospital Basel, Switzerland - a tertiary academic care center (ISRCTN45923734). Twelve wards were randomly assigned to either the 3-step technique or the conventional 6-step technique for use of hand rub. The primary endpoints were compliance with the assigned technique and reduction of bacterial counts on hands of healthcare workers. Results: Overall, 2923 hand hygiene indications were observed and compliance was 70.7% (2066/2923). Compliance with technique and indications was 51.7% (595/1151) and 75.9% (1151/1516) on wards assigned to the 3-step technique, as compared to 12.7% (116/915) and 65.0% (915/1407) on wards assigned to the 6 step technique (p<0.001). The reduction factor (RF) of bacterial colony counts did not differ between both techniques (median RF 0.97 log10 CFU, IQR 0.39-1.59 for the 3-step technique vs. median RF 1.04 log10 CFU, IQR 0.49-1.52 for the 6 step technique, p=0.629). Conclusions: The simpler hand hygiene technique consisting of three steps resulted in higher compliance with both hand hygiene indications and technique as compared to the six steps in a clinical setting. As the results of the microbiological analyses exclude inferiority, the conventional six steps could be safely replaced by a simpler hand hygiene technique. PMID- 30395182 TI - Effect of Temperature and Humidity on the Seasonal Phenology of Drosophila suzukii (Diptera: Drosophilidae) in Wisconsin. AB - Drosophila suzukii (Matsumura) is an invasive pest of soft-skinned fruits that has caused significant economic damage worldwide. In this study, we focused on the seasonal abundance of D. suzukii during the early years of establishment in Wisconsin. We explored the seasonal patterns of summer and winter morphs, their reproductive output, and the effect temperature and humidity may have on their seasonal phenology. The seasonal abundance of D. suzukii during 2 yr (2014-2015) revealed that flies were detected in Wisconsin from early July to late December, with winter morphs being trapped from August through December. The adult populations trapped spanned 1 mo longer in 2015 than in 2014. The peak proportional abundance of D. suzukii in 2015 was recorded in August which was about 2 mo earlier than that in 2014. The combined factor [maximum temperature and maximum humidity] explained the most amount of variation in D. suzukii abundance consistently across the 2 yr in Wisconsin. We did not find significant differences in the fat content, number of mature eggs, proportion of females with immature eggs, or proportion of mated females between summer morph females at the beginning, summer and winter morph females during the middle, or winter morph females at the end of the collecting season in 2015. Our results build on the body of work providing a better understanding of the D. suzukii-overwintering abilities and strengthen the importance of early crop risk assessment and targeted control strategies. PMID- 30395181 TI - Wait, There's a Baby in this Bath Water! Update on Quantitative and Qualitative Cut-Offs for Rey 15-ITEM Recall and Recognition. AB - Objective: Evaluate the effectiveness of Rey 15-item plus recognition data in a large neuropsychological sample. Method: Rey 15-item plus recognition scores were compared in credible (n = 138) and noncredible (n = 353) neuropsychology referrals. Results: Noncredible patients scored significantly worse than credible patients on all Rey 15-item plus recognition scores. When cut-offs were selected to maintain at least 89.9% specificity, cut-offs could be made more stringent, with the highest sensitivity found for recognition correct (cut-off <=11; 62.6% sensitivity) and the combination score (recall + recognition - false positives; cut-off <=22; 60.6% sensitivity), followed by recall correct (cut-off <=11; 49.3% sensitivity), and recognition false positive errors (>=3; 17.9% sensitivity). A cut-off of >=4 applied to a summed qualitative error score for the recall trial resulted in 19.4% sensitivity. Approximately 10% of credible subjects failed either recall correct or recognition correct, whereas two-thirds of noncredible patients (67.7%) showed this pattern. Thirteen percent of credible patients failed either recall correct, recognition correct, or the recall qualitative error score, whereas nearly 70% of noncredible patients failed at least one of the three. Some individual qualitative recognition errors had low false positive rates (<2%) indicating that their presence was virtually pathognomonic for noncredible performance. Older age (>50) and IQ < 80 were associated with increased false positive rates in credible patients. Conclusions: Data on a larger sample than that available in the 2002 validation study show that Rey 15 item plus recognition cut-offs can be made more stringent, and thereby detect up to 70% of noncredible test takers, but the test should be used cautiously in older individuals and in individuals with lowered IQ. PMID- 30395183 TI - The development of a Core Outcome Set for medicines management interventions for people with dementia in primary care. AB - Background: people with dementia (PWD), and their carers, face challenges with medicines management activities. As interventions to support medicines management for PWD are developed, consideration must be given to the outcomes chosen to measure their effectiveness. A Core Outcome Set (COS) is a minimum set of outcomes to be measured in all trials in a particular clinical area, which seeks to reduce heterogeneity of outcome reporting across trials. Objective: to develop a COS for trials assessing the effectiveness of medicines management interventions for PWD in primary care. Methods: a comprehensive list of outcomes was compiled through a systematic review and semi-structured interviews with PWD (n = 18), their carers (n = 15), community pharmacists (n = 15) and general practitioners (n = 15). These outcomes were rated by a Delphi panel (n = 52) on a nine-point Likert scale from 1 (limited importance) to 9 (critical) during three sequential rounds of questionnaire distribution. The Delphi panel comprised participants with expertise in dementia and medicines management, including academics and healthcare professionals. An outcome was eligible for inclusion in the COS if >=70% of participants rated it critical and <15% of participants rated it of limited importance. Results: twenty-nine outcomes identified from the systematic review and stakeholder interviews were presented to the Delphi panel. Consensus was reached on 21 outcomes, of which the 7 most highly rated were recommended for inclusion in the COS. Conclusion: this study used robust methodology to develop a COS for medicines management interventions for PWD. Future work should identify the most appropriate tools to measure these outcomes. PMID- 30395184 TI - Post-Bariatric Buttock Contouring With Gluteal Implants During Circumferential Body Lift: Step-By-Step Video Description and 1-Year Results. PMID- 30395185 TI - The GABA Developmental Shift Is Abolished by Maternal Immune Activation Already at Birth. AB - Epidemiological and experimental studies suggest that maternal immune activation (MIA) leads to developmental brain disorders, but whether the pathogenic mechanism impacts neurons already at birth is not known. We now report that MIA abolishes in mice the oxytocin-mediated delivery gamma-aminobutyric acid (GABA) shift from depolarizing to hyperpolarizing in CA3 pyramidal neurons, and this is restored by the NKCC1 chloride importer antagonist bumetanide. Furthermore, MIA hippocampal pyramidal neurons at birth have a more exuberant apical arbor organization and increased apical dendritic length than age-matched controls. The frequency of spontaneous glutamatergic postsynaptic currents is also increased in MIA offspring, as well as the pairwise correlation of the synchronized firing of active cells in CA3. These alterations produced by MIA persist, since at P14-15 GABA action remains depolarizing, produces excitatory action, and network activity remains elevated with a higher frequency of spontaneous glutamatergic postsynaptic currents. Therefore, the pathogenic actions of MIA lead to important morphophysiological and network alterations in the hippocampus already at birth. PMID- 30395187 TI - An interview with Professor Virendra B. Mahesh. PMID- 30395186 TI - Fusoid cells in the grass family Poaceae (Poales): a developmental study reveals homologies and suggests new insights into their functional role in young leaves. AB - Background and Aims: In mature grass leaf blades as seen in cross-section, oblong cell-like structures have been interpreted most recently as intercellular gas spaces delimited by successive collapsed fusoid cells. These cells have been reported in at least seven of 12 subfamilies of Poaceae and are considered a synapomorphy for the family; however, no developmental work has been performed to verify their meristematic origin or to assess possible homologies within the graminid clade (= Flagellariaceae + [(Joinvilleaceae + Ecdeiocoleaceae) + Poaceae]) or among subfamilies of Poaceae. A developmental study was therefore carried out, including 20 species in three families (Flagellariaceae, Joinvilleaceae and Poaceae), representing the earlier-diverging and derived branches within the graminid clade and Poaceae. Methods: Light microscopy was combined with scanning electron microscopy, cryoscanning electron microscopy and transmission electron microscopy to study the development of leaves taken from the shoot apex of young plants. Mature leaf blades also were taken from living or dried plants and the mid-portion was studied. Key Results: Developmental results show that, in mature leaf blades as seen in cross-section, one apparent fusoid cell is typically a cavity resulting from the collapse of the initial fusoid cell and its internal divisions, which are herein interpreted as derivative cells with formation of cell plates only. Each cavity is delimited by successive collapsed fusoid cells arranged perpendicularly to the veins. Fusoid cells in all studied Poaceae members originate from the ground meristem, as do the colourless cells in Joinvillea ascendens (Joinvilleaceae). These two types of mesophyll cell have a strongly similar ontogeny, distinguished mainly by the collapse of the fusoid cells in Poaceae, which is not observed in the colourless cells in J. ascendens. Conclusions: Within the Poaceae, the meristematic origin of fusoid cells is the same in the early-diverging lineages, BOP clade and Panicoideae, and thus they are homologous within the family. The same topography and meristematic origin suggest that fusoid cells in Poaceae and colourless cells in Joinvilleaceae are homologous. The results also suggest that the role played by the fusoid cells in young grass leaves is related to synthesis and storage of starch granules at early stages of development. PMID- 30395188 TI - Selective Role of the Putamen in Serial Reversal Learning in the Marmoset. AB - Fronto-striatal circuitry involving the orbitofrontal cortex has been identified as mediating successful reversal of stimulus-outcome contingencies. The region of the striatum that most contributes to reversal learning remains unclear, with studies in primates implicating both caudate nucleus and putamen. We trained four marmosets on a touchscreen-based serial reversal task and implanted each with cannulae targeting both putamen and caudate bilaterally. This allowed reversible inactivation of the two areas within the same monkeys, but across separate sessions, to directly investigate their respective contributions to reversal performance. Behavioral sensitivity to the GABAA agonist muscimol varied across subjects and between brain regions, so each marmoset received a range of doses. Intermediate doses of intra-putamen muscimol selectively impaired reversal performance, leaving the baseline discrimination phase unchanged. There was no effect of low doses and high doses were generally disruptive. By contrast, low doses of intra-caudate muscimol improved reversal performance, while high doses impaired both reversal and baseline discrimination performance. These data provide evidence for a specific role of the putamen in serial reversal learning, which may reflect the more habitual nature of repeated reversals using the same stimulus pair. PMID- 30395189 TI - BiXGBoost: a scalable, flexible boosting based method for reconstructing gene regulatory networks. AB - Motivation: Reconstructing gene regulatory networks (GRNs) based on gene expression profiles is still an enormous challenge in systems biology. Random forest based methods have been proved a kind of efficient methods to evaluate the importance of gene regulations. Nevertheless, the accuracy of traditional methods can be further improved. With time-series gene expression data, exploiting inherent time information and high order time lag are promising strategies to improve the power and accuracy of GRNs inference. Results: In this study, we propose a scalable, flexible approach called BiXGBoost to reconstruct GRNs. BiXGBoost is a bidirectional based method by considering both candidate regulatory genes and target genes for a specific gene. Moreover, BiXGBoost utilizes time information efficiently and integrates XGBoost to evaluate the feature importance. Randomization and regularization are also applied in BiXGBoost to address the over-fitting problem. The results on DREAM4 and Escherichia coli datasets show the good performance of BiXGBoost on different scale of networks. Availability: Our Python implementation of BiXGBoost is available at https://github.com/zrq0123/BiXGBoost. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30395190 TI - Longhorn Beetle (Coleoptera: Cerambycidae) Assemblage and the Structural Heterogeneity of Habitat at the Brazilian Atlantic Forest. AB - The longhorn beetles play important roles in the forest ecosystem processes and their diversity is affected by many environmental disturbances worldwide. This study aimed at understanding how the structural heterogeneity of the habitat can affect the longhorn beetle assemblage in three areas of an Atlantic Forest, which suffered differential impacts in the past and are now in different successional stages. The area in the most advanced successional stage had mainly lower density of trees, but with greater availability of dead wood, especially larger diameter classes. They are important forest components that contribute to the structural diversity of the habitat providing resources for a variety of dependent species. This area has also shown the greatest richness and abundance of longhorn beetles. Our results suggest that these beetles are closely associated with the structural heterogeneity of forests and can be valuable indicators for assessing biodiversity and quality of forest habitat. It also shows that old-growth forest remnants can be the key to the maintenance of the diversity of the longhorn beetles and, consequently, of the ecosystem services they provide. PMID- 30395191 TI - Antibody interface prediction with 3D Zernike descriptors and SVM. AB - Motivation: Antibodies are a class of proteins capable of specifically recognizing and binding to a virtually infinite number of antigens. This binding malleability makes them the most valuable category of biopharmaceuticals for both diagnostic and therapeutic applications. The correct identification of the antigen-binding residues in the antibody is crucial for all antibody design and engineering techniques and could also help to understand the complex antigen binding mechanisms. However, the antibody-binding interface prediction field appears to be still rather underdeveloped. Results: We present a novel method for antibody interface prediction from their experimentally-solved structures based on 3D Zernike Descriptors. Roto-translationally invariant descriptors are computed from circular patches of the antibody surface enriched with a chosen subset of physicochemical properties from the AAindex1 amino acid index set, and are used as samples for a binary classification problem. An SVM classifier is used to distinguish interface surface patches from non-interface ones. The proposed method was shown to outperform other antigen-binding interface prediction software. Availability: Linux binaries and Python scripts are available at https://github.com/sebastiandaberdaku/AntibodyInterfacePrediction. The datasets generated and/or analysed during the current study are available at https://doi.org/10.6084/m9.figshare.5442229. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30395192 TI - Homology and Specificity of Natural Sound-Encoding in Human and Monkey Auditory Cortex. AB - Understanding homologies and differences in auditory cortical processing in human and nonhuman primates is an essential step in elucidating the neurobiology of speech and language. Using fMRI responses to natural sounds, we investigated the representation of multiple acoustic features in auditory cortex of awake macaques and humans. Comparative analyses revealed homologous large-scale topographies not only for frequency but also for temporal and spectral modulations. In both species, posterior regions preferably encoded relatively fast temporal and coarse spectral information, whereas anterior regions encoded slow temporal and fine spectral modulations. Conversely, we observed a striking interspecies difference in cortical sensitivity to temporal modulations: While decoding from macaque auditory cortex was most accurate at fast rates (> 30 Hz), humans had highest sensitivity to ~3 Hz, a relevant rate for speech analysis. These findings suggest that characteristic tuning of human auditory cortex to slow temporal modulations is unique and may have emerged as a critical step in the evolution of speech and language. PMID- 30395193 TI - Treatment Attitudes for Belgian Women With Persistent Trichomonas vaginalis Infection in the VlaResT Study. AB - Background: Because of its increasing prevalence worldwide, its sexual transmissibility and its facilitation of human immunodeficiency virus transmission, Trichomonas vaginalis (TV) infection constitutes an important public health concern. The aim of the study: While searching for possible resistant TV cases, adequacy of management of TV-infected women was assessed. Methods: Cervical cytology between July 2007 and July 2014 was tested with TV polymerase chain reaction, and 304 women expressed repeatedly positive results, 718 in total. For each of these positive results, a questionnaire about treatment decisions was sent to the 182 Belgian physicians treating these women. Results: From the 346 returned questionnaires by their physician it was evident that 58.1% of women with repeatedly positive TV had received no treatment. TV was overlooked in 31.5%, and in 17.6% the test result was seen but ignored. Upon seeing the positive result, 23.9% of physicians decided that this finding was not important enough to institute treatment, and/or requested confirmatory tests. Adequate treatment was prescribed in 38.4%. Retreatment after failed therapy was given in only 29.3% of the cases. And 60% of the partners of women with persistent TV infection were not traced, nor treated. Conclusion: Most of the repeatedly positive TV infection may not be due to antibiotics resistance. The low awareness, poor attention, failure of contact tracing, and low rates of proper treatment provided by treating physicians question the adequacy of the current management of TV infection and requires renewed education campaigns and increased surveillance. PMID- 30395194 TI - Ubiquitin D is up-regulated by synergy of Notch signalling and TNF-alpha in the inflamed intestinal epithelia of IBD patients. AB - Background and Aims: The intestinal epithelium of inflammatory bowel disease (IBD) patients is exposed to various pro-inflammatory cytokines, most notably TNF alpha. We have previously shown that the Notch signalling pathway is also up regulated in such an epithelium, contributing to intestinal epithelial cell (IEC) proliferation and regeneration. We aimed to reproduce such environment in vitro and explore the gene regulation involved. Methods: Human IEC cell lines or patient-derived organoids were used to analyse Notch- and TNF-alpha-dependent gene expression. Immunohistochemistry was performed to analyse expression of ubiquitin D (UBD) in various patient-derived intestinal tissues. Results: In human IEC cell lines, we found that Notch signalling and TNF-alpha-induced NFB signalling are reciprocally regulated to promote expression of a specific gene subset. Global gene expression analysis identified UBD to be one of the most highly up-regulated genes due to synergy of Notch and TNF-alpha. The synergistic expression of UBD was regulated at the transcriptional level, whereas the UBD protein had an extremely short half-life due to post-translational, proteasomal degradation. In uninflamed intestinal tissues from IBD patients, UBD expression was limited to IECs residing at the crypt bottom. In contrast, UBD-expressing IECs were seen throughout the crypt in inflamed tissues, indicating substantial induction by the local inflammatory environment. Analysis using patient-derived organoids consistently confirmed conserved Notch- and TNF-alpha-dependent expression of UBD. Notably, post-infliximab (IFX) down-regulation of UBD reflected favourable outcome in IBD patients. Conclusion: We propose that UBD is a novel inflammatory-phase protein expressed in IECs, with a highly rapid responsiveness to anti-TNF-alpha treatment. PMID- 30395195 TI - Discovering network phenotype between genetic risk factors and disease status via diagnosis-aligned multi-modality regression method in Alzheimer's Disease. AB - Motivation: Neuroimaging genetics is an emerging field to identify the associations between genetic variants (e.g., single nucleotide polymorphisms (SNPs)) and quantitative traits (QTs) such as brain imaging phenotypes. However, most of the current studies only focus on the associations between brain structure imaging and genetic variants, while neglecting the connectivity information between brain regions. In addition, the brain itself is a complex network, and the higher-order interaction may contain useful information for the mechanistic understanding of diseases (i.e., Alzheimer's disease (AD)). Results: A general framework is proposed to exploit network voxel information and network connectivity information as intermediate traits that bridge genetic risk factors and disease status. Specifically, we first use the sparse representation (SR) model to build hyper-network to express the connectivity features of the brain. The network voxel node features and network connectivity edge features are extracted from the structural magnetic resonance imaging (sMRI) and resting-state functional magnetic resonance imaging (fMRI), respectively. Secondly, a diagnosis aligned multi-modality regression method is adopted to fully explore the relationships among modalities of different subjects, which can help further mine the relation between the risk genetics and brain network features. In experiments, all methods are tested on the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The experimental results not only verify the effectiveness of our proposed framework but also discover some brain regions and connectivity features that are highly related to diseases. Availability: The Matlab code is available at http://ibrain.nuaa.edu.cn/2018/list.htm. PMID- 30395196 TI - Non-adherence to antidepressants among older patients with depression: a longitudinal cohort study in primary care. AB - Background: Depression is common among older adults and is typically treated with antidepressants. Objective: To determine the non-adherence rates to antidepressants among older adults in primary care, based on non-initiation, suboptimal implementation or non-persistence. Methods: We selected all patients aged >=60 years and diagnosed with depression in 2012, from the Netherlands Institute for Health Services Research (NIVEL) Primary Care Database. Non initiation was defined as no dispensing within 14 days of the first prescription; suboptimal implementation, as fewer than 80% of the days covered by dispensed dosages; and non-persistence, as discontinuation within 294 days after first dispense. First, we determined the antidepressant non-initiation, suboptimal implementation and non-persistence rates. Second, we examined whether comorbidity and chronic drug use were associated with non-adherence by mixed-effects logistic regression (non-initiation or suboptimal implementation as dependent variables) and a clustered Cox regression (time to non-persistence). Results: Non initiation, suboptimal implementation and non-persistence rates were 13.5%, 15.2% and 37.1%, respectively. As the number of chronically used drugs increased, the odds of suboptimal implementation (odds ratio, 0.89; 95% confidence interval, 0.83-0.95) and of non-persistence (hazard ratio, 0.87; 95% confidence interval, 0.82-0.92) reduced. Conclusions: Non-adherence to antidepressants is high among older patients with depression in primary care settings. Adherence is better when patients are accustomed to taking larger numbers of prescribed drugs, but this only provides partial explanation of the variance. GPs should be aware of the high rates of non-adherence. Emphasizing the importance of adhering to the optimal length of antidepressant therapy might be prudent first steps to improving adherence. PMID- 30395197 TI - Judgement over an arbitrary line. PMID- 30395198 TI - Fetal Hypoxia Impacts Methylome and Transcriptome in Developmental Programming of Heart Disease. AB - Aims: Antenatal hypoxia negatively impacts fetal heart development, and increases the risk of heart disease later in life. The molecular mechanisms remain largely elusive. Here, we conducted a genome-wide analysis to study the impact of antenatal hypoxia on DNA methylome and transcriptome profiling in fetal and adult offspring hearts. Methods and Results: Pregnant rats were treated with normoxia or hypoxia (10.5% O2) from day 15 to 21 of gestation. Hearts were isolated from near-term fetuses and 5-month-old male and female offsprings, and DNA methylome and RNA-seq were performed. Methylome data shows a sharp dip in CpG methylation centered at the transcription start site (TSS). CpG islands (CGIs) and CpG island shores (CGSs) within 10kb upstream of the TSS are hypomethylated, compared to CGIs and CGSs within gene bodies. Combining transcriptome, data indicate an inverse relation between gene expression and CpG methylation around the TSS. Of interest, antenatal hypoxia induces opposite changes in methylation patterns in fetal and adult hearts, with hypermethylation in the fetus and hypomethylation in the adult. Also, there is significant sex dimorphism of changes in gene expression patterns in the adult offspring heart. Notably, pathway analysis indicates that enrichment of inflammation-related pathways are significantly greater in the adult male heart than those in the female heart. Conclusion: Our study provides an initial framework and new insights into fetal hypoxia-mediated epigenetic programming of pro-inflammatory phenotype in the heart development, linking antenatal stress and developmental programming of heart vulnerability to disease later in life. PMID- 30395199 TI - Stability-Indicating RP-UPLC Method for Simultaneous Determination of Azilsartan Medoxomil and Chlorthalidone in Tablets in the Presence of Its Degradation Products. AB - Azilsartan Medoxomil (AZL) angiotensin II receptor blocker and chlorthalidone (CLT) were determined by ultraperformance liquid chromatography (UPLC) method in their combined dosage form, they were both subjected to forced degradation studies under extensive stress conditions. The method is a stability indicating by resolving the investigated drugs from their degradation products. Moreover, the degradation products for both drugs obtained from forced degradation were subjected to LC-MS for structure elucidation. The UPLC technique depends on the measurement of spectra for AZL and CLT at 254 nm. Linearity, accuracy and intermediate precision were acceptable over the concentration range of 67.2-268.8 and 40-160 MUg/mL for AZL and CLT, respectively. The method was applied for the determination of the studied drugs in their dosage forms. The UPLC method is inexpensive, simple and considered as green chemistry method for the routine analysis and quality control of both drugs in their combined dosage form. PMID- 30395200 TI - The Impact of Informal Caregiving for Older Adults on the Health of Various Types of Caregivers: A Systematic Review. AB - Objective: Informal care, the provision of unpaid care to dependent friends or family members, is often associated with physical and mental health effects. As some individuals are more likely to provide caregiving tasks than others, estimating the causal impact of caregiving is difficult. This systematic literature review provides an overview of all studies aimed at estimating the causal effect of informal caregiving on the health of various subgroups of caregivers. Methodology: A structured literature search, following PRISMA guidelines, was conducted in 4 databases. Three independent researchers assessed studies for eligibility based on predefined criteria. Results from the studies included in the review were summarized in a predefined extraction form and synthesized narratively. Results: The systematic search yielded a total of 1,331 articles of which 15 are included for synthesis. The studies under review show that there is evidence of a negative impact of caregiving on the mental and physical health of the informal caregiver. The presence and intensity of these health effects strongly differ per subgroup of caregivers. Especially female, and married caregivers, and those providing intensive care appear to incur negative health effects from caregiving. Conclusion: The findings emphasize the need for targeted interventions aimed at reducing the negative impact of caregiving among different subgroups. As the strength and presence of the caregiving effect differ between subgroups of caregivers, policymakers should specifically target those caregivers that experience the largest health effect of informal caregiving. PMID- 30395201 TI - Appendectomy for Therapy-Refractory Ulcerative Colitis Results in Pathological Improvement of Colonic Inflammation. PMID- 30395202 TI - High-Complexity Regions in Mammalian Genomes are Enriched for Developmental Genes. AB - Motivation: Unique sequence regions are associated with genetic function in vertebrate genomes. However, measuring uniqueness, or absence of long repeats, along a genome is conceptually and computationally difficult. Here we use a previously published variant of the Lempel-Ziv complexity, the match complexity, Cm, and augment it by deriving its null distribution for random sequences. We then apply Cm to the human and mouse genomes to investigate the relationship between sequence complexity and function. Results: We implemented Cm in the program macle and show through simulation that the newly derived null distribution of Cm is accurate. This allows us to delineate high-complexity regions in the human and mouse genomes. Using our program macle2go, we find that these regions are two-fold enriched for genes. Moreover, the genes contained in these regions are more than 10-fold enriched for developmental functions. Availability: Source code for macle and macle2go is available from www.github.com/evolbioinf/macle and www.github.com/evolbioinf/macle2go, respectively; Cm browser tracks from guanine.evolbio.mgp.de/complexity. PMID- 30395203 TI - Heparin-induced thrombocytopaenia diagnostic testing after adult cardiac surgery: a single-centre experience and development. AB - OBJECTIVES: To assess the incidence and outcome of heparin-induced thrombocytopaenia (HIT) in patients after cardiac surgery on cardiopulmonary bypass (CPB) and to review the time course of platelet counts and the use of different immunological diagnostic tests. METHODS: All patients >=18 years of age who underwent CPB from 2006 to 2015 and who were postoperatively admitted to our cardiac intensive care unit (ICU) were included in this retrospective study. Screening for heparin/platelet factor-4 antibodies was performed using an antibody test, which was later replaced with a screening test specific for IgG antibodies without IgA/IgM cross-reactivity. The enzyme immunoassay (EIA) for the detection of antibodies of all immunoglobulin classes against heparin/PF4 complexes was replaced with an IgG-specific EIA. HIT was confirmed by a heparin induced platelet aggregation test until 2014. RESULTS: Among 4978 patients admitted between 2006 and 2015, 539 (11%) patients were evaluated for HIT. Patients were excluded because of age <18 years (n = 9), non-cardiac surgery without CPB (n = 10) or incomplete data (n = 3). Of the remaining 517 patients, 43 (8.3%) patients were HIT-positive. HIT incidence was 0.86%. The proportion of HIT-positive patients was similar in men and women (8.4% and 8.2%, respectively). Men and women with suspected HIT also had similar in-hospital mortality (odds ratio ~ 1; P = 0.926). CONCLUSIONS: The incidence of HIT was lower in our study than previously reported. Novel immunological tests have improved to specifically detect IgG antibodies. Furthermore, they are able to detect anti-protamine antibodies, which may be present in patients with high clinical probability of testing negative for HIT. Incidence and clinical relevance of heparin/protamine antibodies will be subjects of future investigation. PMID- 30395204 TI - Critical role of CD6highCD4+ T cells in driving Th1/Th17 cell immune responses and mucosal inflammation in IBD. AB - Background and Aims: CD6 is a crucial regulator of T cell activation and implicated in the pathogenesis of multiple autoimmune diseases. ALCAM is the first identified endogenous ligand of CD6. We sought to investigate potential roles of CD6 in regulating intestinal mucosal inflammation of inflammatory bowel disease [IBD]. Methods: We analysed expression of CD6 and ALCAM in inflamed mucosa of IBD patients using qRT-PCR and immunohistochemistry. Phenotypic properties of CD6low/- and CD6highCD4+ T cells were determined by flow cytometry, qRT-PCR, and ELISA. ALCAM-Fc fusion protein was used to evaluate the role of CD6 ALCAM engagement in regulating IBD CD4+ T cell activation and proliferation. Results: Expression of CD6 and its ligand ALCAM was markedly increased in inflamed mucosa of IBD patients compared with normal controls, and significantly correlated with disease activity indexes of IBD patients. Interestingly, CD6highCD4+ T cells of IBD patients exhibited significantly higher pathogenicity compared with CD6low/-CD4+ T cells, characterized by enhanced T cell activation and preferential Th1 and Th17 cell phenotypes, but markedly decreased proportion of nTreg [CD25highFoxp3+, CD25highCD127low] cells. Importantly, inclusion of ALCAM Fc fusion protein significantly facilitated IBD CD6highCD4+ T cells to proliferate and differentiate into Th1/Th17 cells compared with hIgG1 Fc-treated controls. Conclusions: These data indicate that overexpression of CD6 and ALCAM in inflamed mucosa of IBD patients accelerates intestinal mucosal immune responses via promoting CD4+ T cell proliferation and differentiation into Th1/Th17 cells. Thus, CD6 may serve as a novel therapeutic target for treatment of IBD. PMID- 30395205 TI - Primary care providers' views on a future lung cancer screening program. AB - Background: The National Lung Screening Trial demonstrated that screening with low-dose computed tomography significantly reduces mortality from lung cancer in high-risk individuals. Objective: To describe the role preferences and information needs of primary care providers (PCPs) in a future organized lung cancer screening program. Methods: We purposively sampled PCPs from diverse health regions of Ontario and from different practice models including family health teams and community health centres. We also recruited family physicians with a leadership role in cancer screening. We used focus groups and a nominal group process to identify informational priorities. Two analysts systematically applied a coding scheme to interview transcripts. Results: Four groups were held with 34 providers and administrative staff [28 (82%) female, 21 (62%) physicians, 7 (20%) other health professionals and 6 (18%) administrative staff]. PCPs and staff were generally positive about a potential lung cancer screening program but had variable views on their involvement. Informational needs included evidence of potential benefits and harms of screening. Most providers preferred that a new program be modelled on positive features of an existing breast cancer screening program. Lung cancer screening was viewed as a new opportunity to counsel patients about smoking cessation. Conclusions: The development of a future lung cancer screening program should consider the wide variability in the roles that PCPs preferred. An explicit link to existing smoking cessation programs was seen as essential. As providers had significant information needs, learning materials and opportunities should be developed with them. PMID- 30395206 TI - Development of a Reliable Method for Assessing Coca Alkaloids in Oral Fluid by HPLC-MS-MS. AB - A reliable method based on high-performance liquid chromatography-tandem mass spectrometry has been developed for the assessment of coca alkaloids/metabolites [cocaine (COC), benzoylecgonine (BE), cocaethylene (CE), ecgonine methyl ester (EME), anhydroecgonine methyl ester (AEME), tropococaine (TRO), transcinnamoylcocaine (trCIN), cuscohygrine (CUS) and hygrine (HYG)] in oral fluid samples from cocaine abusers and from coca leaves consumers (coca leaves chewers and coca tea drinkers). Oral fluid samples were collected by the passive drool technique (spitting), and after centrifugation the supernatant was treated for protein removal by adding acidified acetonitrile. The developed method was fully validated according to the international criteria and good results have been obtained (intraday and inter-day precisions were lower than +/-20%, intraday and inter day accuracy was within the 75-116% range, and LODs/LOQs was lower and close to cut-off values for COC and BE). The proposed method has been successfully applied to oral fluid samples from cocaine abusers, and also from coca leave chewers and coca tea drinkers. CUS and HYG were only found in oral fluid from people who chewed coca leaves and drank coca tea and were not detected in cocaine abusers. Both CUS and HYG could be good markers in oral fluid for distinguishing people who consume coca leaves legally (coca leave chewers and coca tea drinkers) from those who consume illegal cocaine. PMID- 30395207 TI - Separation and Characterization of Unknown Impurities and Isomers in Cefminox Sodium and Study of the Forming Mechanisms of Impurities by Liquid Chromatography Coupled with Ion Trap/Time-Of-Flight Mass Spectrometry. AB - Thirteen unknown impurities and isomers in cefminox sodium were separated and characterized by liquid chromatography coupled with high-resolution ion trap/time of-flight mass spectrometry (LC-IT-TOF-MS) with the positive mode of electrospray ionization (ESI) method. New HPLC-gradient elution method was developed for the detection of impurities in cefminox sodium. And the ESI ion trap multiple-stage tandem mass spectrometry had been applied successfully to the direct investigation of impurities and isomers in cefminox sodium. The fragmentation patterns and structural assignment of these impurities were studied. Full scan liquid chromatography-mass spectrometry (LC-MS) was first performed to obtain the m/z value of the protonated molecules and formulas of all detected peaks, LC-MSn (n = 1-6) were then carried out on the compounds of interest. Structures of 13 degradation products in cefminox sodium were deduced based on the high-resolution MSn (n = 1-6) data, assisted by the UV spectra and stress testing. And the forming mechanisms of degradation products in cefminox were also studied. The method of LC-IT-TOF-MSn (n = 1-6) was worthy of widespread use and application for the further improvement of official monographs in pharmacopoeias with the advantages of stability and repeatability. PMID- 30395208 TI - Increasing early surgery within 2 days for hip fracture: a time trend in 15 EU countries (2000-13). AB - Objective: To analyse the trajectories of hip-fracture surgery rates within 2 days of admission to the hospital and the ratios of procedures initiated within the same day (Day 0) and the following day (Days 0-1) to procedures performed on the 2nd day. To study the association between socioeconomic, health input variables and early surgery. Design: A pooled, cross-sectional, time-series analysis was used to evaluate secondary data from 15 European countries, during 2000-13. Results: The rate of patients aged >=65 years that were operated on within 2 days of hip-fracture has changed over time with an EU average annual increase of 0.42% (95% CI = 0.25, 0.59; P < 0.001) and with a significant linear trend. Multiple slopes from all the countries compete with this result. In contrast, the ratios of procedures initiated within the same day (Day 0) and the following day (Days 0-1) compared to procedures performed on the 2nd day are constant. No association was found between the rate of patients treated within 2 days of admission and demographic structure, health expenditure, health resources. However, the rate of patients treated within 2 days of admission is significantly associated with surgical volumes. Conclusions: As the early surgery rate is growing, policy makers should be encouraged to undertake further policies to support the quality of care, and the providers should be driven to improve their organizational effectiveness by taking actions aimed at acting on specific organizational and logistical causes that represent a barrier to early surgery. PMID- 30395209 TI - A parasite's perspective on data sharing. AB - Data generation is expensive in terms of both time and money. Sharing data enables the rapid replication, validation, and application of discoveries, increasing the pace and accuracy of research. As research parasites, or users of other people's data, we recognize that a strong science ecosystem requires that those who share best be recognized. We find that widely accessible benchmark datasets have provided outsized benefits, and we hope that the benefits of sharing will also begin to accrue to individual investigators who share well. Funders can enhance progress by adjusting incentives to better support data sharers, which will make their programmatic investments more effective. We note some funders who are making such efforts. PMID- 30395210 TI - Testosterone to estradiol ratio and plaque inflammation- mechanistic insights and biomarker potential? PMID- 30395211 TI - Aequatus: an open-source homology browser. AB - Background: Phylogenetic information inferred from the study of homologous genes helps us to understand the evolution of genes and gene families, including the identification of ancestral gene duplication events as well as regions under positive or purifying selection within lineages. Gene family and orthogroup characterization enables the identification of syntenic blocks, which can then be visualized with various tools. Unfortunately, currently available tools display only an overview of syntenic regions as a whole, limited to the gene level, and none provide further details about structural changes within genes, such as the conservation of ancestral exon boundaries amongst multiple genomes. Findings: We present Aequatus, an open-source web-based tool that provides an in-depth view of gene structure across gene families, with various options to render and filter visualizations. It relies on precalculated alignment and gene feature information typically held in, but not limited to, the Ensembl Compara and Core databases. We also offer Aequatus.js, a reusable JavaScript module that fulfills the visualization aspects of Aequatus, available within the Galaxy web platform as a visualization plug-in, which can be used to visualize gene trees generated by the GeneSeqToFamily workflow. PMID- 30395212 TI - HPTLC method for Simultaneous Determination of Norfloxacin and Tinidazole in presence of Tinidazole Impurity. AB - Sensitive, selective and accurate high-performance thin layer chromatographic HPTLC method for quantitative determination of Norfloxacin (NF), Tinidazole (TZ) and 2-Methyl-5-nitroimidazole (MNZ) as potential impurity of Tinidazole is developed and validated in the presented work. Calibration curves were linear over the concentration ranges of 0.4-2.4, 0.4-1.6, 0.2-1.2 MUg/band for NF, TZ and MNZ, respectively. The method depends on separation and quantitation of NF, TZ and MNZ on aluminium plates pre-coated with silica gel HPTLC 60F254 as stationary-phase using chloroform: methanol: formic acid (7.5:1: 0.3, by volume) as developing system followed by densitometric measurement of bands at 298 nm. The developed method was validated and proved to meet the requirements delineated by ICH guidelines with respect to linearity, accuracy, precision, specificity and robustness. The validated method was successfully applied for determination of studied drugs in bulk powders and in their pharmaceutical formulation indicating the ability of proposed method to be used for routine quality control analysis of these drugs. PMID- 30395213 TI - Development and Validation of LC-MS-MS Assay for the Determination of the Emerging Alkylating Agent Laromustine and Its Active Metabolite in Human Plasma. AB - The objective of this study was to validate a method for the determination of laromustine (VNP40101M) and short-lived its active metabolite (VNP4090CE) that has a half-life in human blood of <90 s in human plasma by liquid chromatography (LC) with tandem mass spectrometric (MS/MS) detection. We overcome the stability dilemma by acidified the human plasma with citric acid. Laromustine "breaks" down on the source of mass spectrometry to give m/z 249 which is the same m/z for VNP4090CE. Because VNP4090CE and laromustine elute at approximate retention time of 1.93 and 2.94 min, respectively, we were able to quantify both of them in one method. VNP40101M, VNP4090CE and the internal standards were extracted from human plasma by liquid-liquid extraction into ethyl ether. The ethyl ether layer was evaporated, reconstituted and analyzed using LC with MS/MS detection. Validation parameters such as selectivity, limit of quantitation, linearity, precision, accuracy, recovery, autosampler viability, freeze-thaw cycles and compounds stability are evaluated for this method. Results were calculated using peak area ratios, and calibration curves were generated using a weighted (1/x2) linear least-squares regression. Calibration curves for VNP40101M and VNP4090CE in human plasma ranged from 1.00 to 1,000 ng/mL. In this study, both intra- and inter assay results demonstrated a relative standard deviation for calibration standards (inter-assay) and quality control samples (intra- and inter-assay) to be <=15.0%. In this method, there is ~1.79% isotopic interference of VNP40101M to VNP40101M-IS, and ~3.76% isotopic interference of VNP4090CE to VNP4090CE-IS. It was concluded that there was no significant carryover. PMID- 30395214 TI - Reviving Phage Therapy for the Treatment of Cholera. AB - Cholera remains a major risk in developing countries, particularly after natural or man-made disasters. Vibrio cholerae El Tor is the most important cause of these outbreaks, and is becoming increasingly resistant to antibiotics, so alternative therapies are urgently needed. In this study, a single bacteriophage, Phi_1, was used to control cholera prophylactically and therapeutically in an infant rabbit model. In both cases, phage-treated animals showed no clinical signs of disease, compared with 69% of untreated control animals. Bacterial counts in the intestines of phage-treated animals were reduced by up to 4 log10 colony-forming units/g. There was evidence of phage multiplication only in animals that received a V. cholerae challenge. No phage-resistant bacterial mutants were isolated from the animals, despite extensive searching. This is the first evidence that a single phage could be effective in the treatment of cholera, without detectable levels of resistance. Clinical trials in human patients should be considered. PMID- 30395216 TI - Re: Cardiac surgical operative training: a disincentivized necessity. PMID- 30395215 TI - Activated platelets promote an osteogenic programme and the progression of calcific aortic valve stenosis. AB - Aims: Calcific aortic valve stenosis (CAVS) is characterized by a fibrocalcific process. Studies have shown an association between CAVS and the activation of platelets. It is believed that shear stress associated with CAVS promotes the activation of platelets. However, whether platelets actively participate to the mineralization of the aortic valve (AV) and the progression of CAVS is presently unknown. To identify the role of platelets into the pathobiology of CAVS. Methods and results: Explanted control non-mineralized and mineralized AVs were examined by scanning electron microscope (SEM) for the presence of activated platelets. In depth functional assays were carried out with isolated human valve interstitial cells (VICs) and platelets as well as in LDLR-/- apoB100/100 IGFII (IGFII) mice. Scanning electron microscope and immunogold markings for glycoprotein IIb/IIIa (GPIIb/IIIa) revealed the presence of platelet aggregates with fibrin in endothelium-denuded areas of CAVS. In isolated VICs, collagen-activated platelets induced an osteogenic programme. Platelet-derived adenosine diphosphate induced the release of autotaxin (ATX) by VICs. The binding of ATX to GPIIb/IIIa of platelets generated lysophosphatidic acid (LysoPA) with pro-osteogenic properties. In IGFII mice with CAVS, platelet aggregates were found at the surface of AVs. Administration of activated platelets to IGFII mice accelerated the development of CAVS by 2.1-fold, whereas a treatment with Ki16425, an antagonist of LysoPA receptors, prevented platelet-induced mineralization of the AV and the progression of CAVS. Conclusions: These findings suggest a novel role for platelets in the progression of CAVS. PMID- 30395218 TI - Transfer learning improves resting-state functional connectivity pattern analysis using convolutional neural networks. AB - Background: Deep learning is gaining importance in the prediction of cognitive states and brain pathology based on neuroimaging data. Including multiple hidden layers in artificial neural networks enables unprecedented predictive power; however, the proper training of deep neural networks requires thousands of exemplars. Collecting this amount of data is not feasible in typical neuroimaging experiments. A handy solution to this problem, which has largely fallen outside the scope of deep learning applications in neuroimaging, is to repurpose deep networks that have already been trained on large datasets by fine-tuning them to target datasets/tasks with fewer exemplars. Here, we investigated how this method, called transfer learning, can aid age category classification and regression based on brain functional connectivity patterns derived from resting state functional magnetic resonance imaging. We trained a connectome convolutional neural network on a larger public dataset and then examined how the knowledge learned can be used effectively to perform these tasks on smaller target datasets collected with a different type of scanner and/or imaging protocol and pre-processing pipeline. Results: Age classification on the target datasets benefitted from transfer learning. Significant improvement (~9%-13% increase in accuracy) was observed when the convolutional layers' weights were initialized based on the values learned on the public dataset and then fine-tuned to the target datasets. Transfer learning also appeared promising in improving the otherwise poor prediction of chronological age. Conclusions: Transfer learning is a plausible solution to adapt convolutional neural networks to neuroimaging data with few exemplars and different data acquisition and pre processing protocols. PMID- 30395217 TI - A systematic review of the indirect costs of schizophrenia in Europe. AB - Background: Schizophrenia is a chronic disease associated with significant and long-lasting effects on health, and it is also a social and financial burden, not only for patients but also for families, other caregivers, and the wider society. It is essential to conduct the assessment of indirect costs, to understand all the effects of the disease on society. Our aim is to gain a better understanding of the indirect costs of schizophrenia in Europe. Methods: We conducted a comprehensive systematic literature review covering EMBASE, Medline, and PsycINFO as well as reviewing Health Technology Assessment databases from different countries. We used a qualitative research synthesis for presenting information, as most of the studies were methodologically diverse, a quantitative analysis would have been impractical. Results: Indirect cost adjusted to inflation ranged vastly between studies included in the review from 119 Euros to 62, 034 Euros annually. The average proportion of indirect costs of total costs was 44%. Studies highlighted important cost drivers as age, gender, and disease severity, explaining the variation in costs between treatment and patient groups. Conclusions: Regardless of the methodological heterogeneity of the reviewed studies, there was an agreement about the significance of indirect costs of schizophrenia on the society. Considering the relatively high prevalence of schizophrenia in Europe, a need for more cost of illness studies especially from Central Eastern and Southern Europe is suggested. PMID- 30395219 TI - Is triple antithrombotic therapy, or rather its duration and composition, the true culprit for the excess of bleeding events observed in patients with atrial fibrillation undergoing coronary intervention? PMID- 30395220 TI - Inadequate perioperative prophylaxis and postsurgical complications after graft implantation are important risk factors for subsequent vascular graft infections prospective results from the VASGRA Cohort Study. AB - Introduction: Reconstructive vascular surgery has become increasingly common. Vascular graft infections (VGI) are serious complications leading to increased morbidity and mortality. Previously described risk factors for VGI include groin incision, wound infections, and comorbidities. We aimed to identify modifiable predictors for VGI as targets for infection prevention strategies. Methods: Participants of the prospective Vascular Graft Infection Cohort (VASGRA) with surgery between 2013 and 2017 were included. Observation time was calculated from surgery until confirmed VGI or last follow-up. Variables were assessed by infection status using non-parametric tests. Uni- and multivariable Cox proportional hazard regression models, adjusted for demographic factors, were applied to assess risk factors for a VGI. Results: A total of 438, predominantly male (83.1%) patients with a median age of 71 years (IQR 63-76) contributed to 554 person-years (PY) of follow-up. Thereof, 39 (8.9%) developed a vascular graft infection, amounting to an incidence rate of 7.0/100 PY. We found incisional surgical site infections (aHR 10.09 [2.88-35.34]), hemorrhage (aHR 4.92 [1.28 18.94]), renal insufficiency (aHR 4.85 [1.20-19.61]), inadequate perioperative prophylaxis in patients with an established antibiotic treatment compared to additional application of perioperative prophylaxis (aHR 2.87 [95%CI 1.17-7.05]), and procedure time per 1-hour increase (aHR 1.22 [95% CI 1.08-1.39]) to be risk factors for VGI. Conclusions: We identified procedure time, inadequate perioperative prophylaxis, especially among patients with an established antibiotic treatment, and several postsurgical infectious and non-infectious complications as modifiable predictive factors for VGI and therefore key to improved surveillance programs and prevention strategies. PMID- 30395221 TI - A Case of IBD Immunosuppression Related Salmonella Aortitis Requiring Emergency Vascular Grafting. PMID- 30395222 TI - Magnitude and determinants of antibiotic dispensing without prescription in Spain: a simulated patient study. AB - Objectives: Excessive and inappropriate use of antibiotics increases antimicrobial resistance. The aim of this study was to determine the magnitude and determinants of antibiotic dispensing without prescription in Spain by the simulated patient technique. Methods: A cross-sectional study was conducted with all the pharmacies in a region of north-west Spain (n = 977), between December 2016 and January 2017. Four actors visited the pharmacies simulating a respiratory infection. Four incremental levels of pressure were used to obtain an antibiotic. The education and sex of the person who was dispensing and the area where the pharmacy was located were recorded. The effect of these independent variables on the dispensing of an antibiotic without prescription (1 = yes, 0 = no) was modelled by logistic regression. Results: An antibiotic was obtained in 18.83% (95% CI = 16.5%-21.41%) of the visits. The area influenced the dispensing of antibiotics without a medical prescription, with a greater likelihood of dispensing in rural (OR = 1.79; 95% CI = 1.20-2.68) or semi-rural (OR = 1.66; 95% CI = 1.13-2.44) areas than in urban areas. No association was found with the sex or the training of the person who dispensed the antibiotic. In the pharmacies in urban areas, a lower level of pressure was needed to obtain the antibiotic. Conclusions: This study shows that one-fifth of the pharmacies still dispense antibiotics without prescription, especially under patient pressure. A rural setting has been identified as a risk factor for dispensing without prescription, so it must be taken into account for future interventions. PMID- 30395223 TI - Influence of crossbreeding on meat goat doe fitness when comparing Boer F1 with base breeds in the southeastern United States. AB - Understanding fitness level among various breeds is essential for sustainable meat goat production. Research on the relative fitness of Boer F1 does and straightbred base breed has been limited. Meat goat does of various genotypes (Boer, Kiko, Spanish, Boer * Kiko reciprocal F1 crosses, and Boer * Spanish reciprocal F1 crosses) were studied to evaluate breed effects on doe fitness traits and the expression of heterosis over 7 production years. The herd was semi intensively managed under humid subtropical pasture. Doe age affected (P < 0.05) various traits. Boer * Kiko does were heavier (P < 0.05) than Boer does at fall breeding, but Boer * Spanish does did not differ (P > 0.05) from Boer does for breeding weight. The body weights of Boer * Spanish and Boer * Kiko crosses did not differ (P > 0.05) from the weights of their respective Kiko and Spanish base cohorts at breeding, kidding or weaning. Boer does had lower (P < 0.05) kidding rate (KR) and weaning rate (WR) than the other breeds and crosses. Boer * Kiko and Kiko were similar for KR and WR. Boer * Spanish and Spanish were also similar for KR and WR. However, the combined group of Boer F1 does had lower (P < 0.01) KR and WR than the combined purebred biotype group of Kiko and Spanish does. Boer does weaned smaller (P < 0.05) litter sizes per doe exposed compared to Kiko, Spanish, Boer * Kiko and Boer * Spanish does with the latter four doe breedtypes not differing from each other. The combined Boer F1 doe group weaned smaller (P < 0.05) litter sizes per doe exposed than the combined purebred group of Kiko and Spanish does. Boer * Kiko dams had higher (P < 0.05) fecal egg counts at parturition than Kiko dams. Significant heterosis was observed for reproductive traits within each of the two-breed diallels. Boer F1 does exhibited reproductive output similar to or lower than Kiko and Spanish straightbred does and higher than Boer straightbred does. PMID- 30395224 TI - Melanoma skin cancer incidence rates in the world from the Cancer Incidence in Five Continents XI. PMID- 30395225 TI - A nation-wide transition in patient safety culture: a multilevel analysis on two cross-sectional surveys. AB - Quality Problem or Issue: Patient safety is an important topic within healthcare systems. A favourable safety culture might promote safety. We examined whether a nation-wide patient safety programme (PSP) improved patient safety culture. Initial Assessment: We initially measured patient safety culture among 3779 healthcare providers in 45 hospitals in the Netherlands, using the Hospital Survey on Patient Safety Culture. Choice of Solution: A PSP based on two pillars: the implementation of a safety management system and the focus on 10 themes in which harm to patients appeared highly preventable. Elements of the safety management system were safety management, safety culture, risk assessments and continuous safety improvements. Implementation: Implementation was nation-wide. Evaluation: After implementation of the programme, we assessed patient safety culture among 6605 healthcare providers in 24 Dutch hospitals and compared the scores with the initial measurement. We hypothesized that after the programme (1) scores on safety culture dimensions improved, (2) safety culture became more homogeneous within and between hospitals and (3) relative influence of hospitals on safety culture increased. A three-level mixed model for continuous responses was fit for 11 safety culture dimensions. We calculated average individual means, between-department variances, between-hospital variances and total variances per dimension. Lessons Learned: In general, a more favourable safety culture was seen after the PSP. However, hospitals and departments did not become more homogeneous, except for 'frequency of event reporting'. The variety in responses amongst departments and hospitals increased for several dimensions, implying that not all of them improved. PMID- 30395226 TI - Long-term single center outcomes after proctocolectomy with ileoanal anastomosis for paediatric ulcerative colitis. AB - Background and Aims: Childhood-onset ulcerative colitis (UC) requires total colectomy in one quarter of patients at some point of their disease. The study objective was to evaluate long-term outcomes after proctocolectomy with ileoanal anastomosis (IAA) for UC. Methods: Medical records of all children undergoing proctocolectomy with IAA for UC during 1985-2016 in Helsinki University Hospital were retrospectively assessed. Data on disease history, diagnostic and operative details, occurrence of surgical complications, functional outcome, postoperative diagnosis of Crohn's disease (CD) and pouch failure were collected. Risk factors for IAA failure were analysed with Cox regression. Results: Of 87 patients, 85 (98%) had UC and 2 (2%) IBD-U preoperatively. Altogether 66% underwent two-stage and 34% three-stage procedures. During 7.8 (4.1-14.5) years' follow-up, nine (10%) patients were diagnosed with postoperative CD. Postoperative leakages (n=8, 9%) and strictures (n=10, 11%) were equally common while fistulas (78% vs. 9%, p<0.001) and abscesses (56% vs 14%, p=0.009) more frequent among patients with later CD diagnosis. At last follow-up, eight (9%) patients had been converted to a permanent ileostomy while others reported daytime stooling frequency of 5 (4-7) and 0.5 (0-1) at night. CD diagnosis (hazard ratio, HR=23.3, p=0.005), postoperative abscesses (HR=16.3, p=0.013) and fistulas (HR=20.9, p=0.007) as well as 3-stage surgery (p=0.018) increased risk for ileostomy. Conclusions: For paediatric UC, long-term surgical and functional outcomes after proctocolectomy with IAA are reassuring. Need for 3-stage surgery, postoperative fistulas and abscesses, but not leakages or strictures, associate with postoperative CD diagnosis and the risk for ileostomy. PMID- 30395227 TI - Protein Kinase C Binding Protein 1(PRKCBP1) Inhibits Hypoxia Inducible Factor 1 (HIF-1) in the Heart. AB - Aims: Hypoxia-inducible factor 1 alpha (HIF-1alpha) is a key transcription factor responsible for the induction of genes that facilitate adaptation to hypoxia. To study HIF-1 signaling in the heart, we developed a mouse model in which an oxygen stable form of HIF-1alpha can be inducibly expressed in cardiac myocytes, under the regulation of tetracycline. Methods & Results: Remarkably, expression of the transgene in mice generated two distinct phenotypes. One was the expected expression of HIF-regulated transcripts and associated changes in cardiac angiogenesis and contractility. The other was an "unresponsive phenotype" with much less expression of typical HIF-response genes and substantial expression of a zinc-finger protein, Protein Kinase C Binding Protein 1 (PRKCBP1). We have demonstrated that this second phenotype is due to an insertion of a fragment of DNA upstream of the PRKCBP1 gene that contains two additional canonical HIF binding sites and leads to substantial HIF binding, assessed by ChIP, and transcriptional activation. This insertion is found only in the FVB strain of mice that contributed the alphaMHC-tet binding protein transgene to these biallelic mice. In HEK293 cells transfected with oxygen-stable HIF-1alpha and PRKCBP1 we demonstrated inhibition of HIF-1 activity by a luciferase reporter assay. Using mouse primary cells and cell lines we show that transfection with oxygen-stable HIF-1alpha and PRKCBP1 reduced expression of direct HIF-1 gene targets and that knockdown of PRKCBP1 removes that negative inhibition. Consistent with previous reports suggesting that PRKCBP1 modulates the chromatin landscape, we found that HL-1 cells transfected with oxygen-stable HIF-1alpha and PRKCBP1 have reduced global 5-methyl cytosine compared to HIF-1 alone. Conclusions: We show genetic, transcriptional, biochemical, and physiological evidence that PRKCBP1 inhibits HIF activity. Identification of a new oxygen dependent and previously unsuspected regulator of HIF may provide a target for new therapeutic approaches to ischemic heart disease. PMID- 30395228 TI - The promise, problems and pitfalls of mass drug administration for malaria elimination: a qualitative study with scientists and policymakers. AB - Background: The emergence of artemisinin resistance in the Greater Mekong Subregion (GMS) has prompted urgent containment measures. One possible approach is mass drug administration (MDA). This article explores attitudes towards and perceptions of MDA for malaria elimination among policymakers and leading malariologists. Methods: Thirty-two semistructured interviews (SSI) were conducted with policymakers (n=17) and principal investigators (n=15) selected based on their involvement in malaria prevention, control and elimination in the GMS. Interviews were audio recorded and transcribed for qualitative content (thematic) analysis using NVivo (QSR International, Doncaster, Victoria, Australia). Results: Researchers and policymakers described reluctance and consequently delays to pilot MDA for malaria elimination. Most policymakers and some researchers reported concerns around the evidence base, citing a lack of data on its effectiveness and appropriate target populations. There were also worries about promoting resistance. Other issues included a previous lack of support from the World Health Organization, past MDAs, the remoteness of target populations and challenges explaining the rationale for MDA. Conclusions: The complex rationale for MDA for malaria elimination, mistaking pilot studies for implementation, past experiences with MDA, difficulties in selecting appropriate sites and the WHO's lack of clear backing undermined the support for MDA for malaria elimination. PMID- 30395229 TI - The Cat's Meow: Using Novel Serological Approaches to Identify Cat-to-Human Influenza A(H7N2) Transmission. PMID- 30395230 TI - STAT3- and GSK3beta-mediated Mcl-1 regulation modulates TPF resistance in oral squamous cell carcinoma. AB - Cisplatin alone or in combination with 5FU (5-fluorouracil) and docetaxel (TPF) are common regimen chemotherapeutics for treatment of advanced oral squamous cell carcinoma (OSCC). Despite the initial positive response, several patients experience relapse due to chemoresistance. The potential role of Bcl-2 antiapoptotic members in acquired chemoresistance is yet to be explored. To address this, we designed two different relevant OSCC chemoresistant models: (i) acquired chemoresistant cells, where OSCC lines were treated with conventional chemotherapy for a prolonged period to develop chemoresistance, and (ii) chemoresistant patient-derived cells, where primary cells were established from tumor of neoadjuvant-treated OSCC patients who do not respond to TPF. Among all Bcl-2 antiapoptotic members, Mcl-1 expression (but not Bcl-2 or Bcl-xL) was found to be upregulated in both chemoresistant OSCC lines and chemoresistant tumors when compared with their respective sensitive counterparts. Irrespective of all three chemotherapy drugs, Mcl-1 expression was elevated in OSCC cells that are resistant to either cisplatin or 5FU or docetaxel. In chemoresistant OSCC, Mcl-1 mRNA was upregulated by signal transducer and activator of transcription 3 (STAT3) activation, and the protein was stabilized by AKT-mediated glycogen synthase kinase 3 beta (GSK3beta) inactivation. Genetic (siRNA) or pharmacological (Triptolide, a transcriptional repressor of Mcl-1) inhibition of Mcl-1 induces drug-mediated cell death in chemoresistant OSCC. In patient-derived xenograft model of advanced stage and chemoresistant OSCC tumor, Triptolide restores cisplatin-mediated cell death and facilitates significant reduction of tumor burdens. Overall, our data suggest Mcl-1 dependency of chemoresistant OSCC. A combination regimen of Mcl-1 inhibitor with conventional chemotherapy deserves further clinical investigation in advanced OSCC. PMID- 30395231 TI - Baseline Susceptibility of Spodoptera frugiperda (Lepidoptera: Noctuidae) to SfMNPV and Evaluation of Cross-Resistance to Major Insecticides and Bt Proteins. AB - The resistance evolution of Spodoptera frugiperda (J.E. Smith) to insecticides and Bt proteins along with the intensive crop production systems adopted in Brazil make it challenging to implement integrated pest management. The adoption of alternative methods to manage pests is fundamental to the implementation of favorable integrated pest management and insect resistance management. Spodoptera frugiperdamultiple nucleopolyhedrovirus (SfMNPV) is a valuable tool for S. frugiperda control. The characterization of the baseline susceptibility of S. frugiperda populations and cross-resistance involving SfMNPV and major insecticides and Bt proteins have not yet been conducted. The objective of this study was to characterize the baseline susceptibility of S. frugiperda populations from five Brazilian States to SfMNPV (Cartugen, AgBiTech, Fort Worth, TX). Possible cross-resistance to insecticides and Bt proteins among resistant S. frugiperda strains was also assessed. There were no differences in the susceptibility of the studied populations to SfMNPV. The estimated diagnostic concentration may be utilized in future monitoring studies to SfMNPV. The SfMNPV presented no cross-resistance to the chemical insecticides and to the Bt proteins tested. Our results provide evidence of the biological activity and high potential of SfMNPV as a distinct insecticidal mode of action for use in rotation with other tools. This biological insecticide is known to have a favorable toxicological and ecotoxicological profile and will be a valuable tool in insect resistance management and integrated pest management programs for control of S. frugiperda. PMID- 30395232 TI - A Qualitative Evidence Synthesis Review of Longitudinal Qualitative Research in Gerontology. AB - Background and Objectives: Gerontologists have long been interested in longitudinal qualitative research (LQR), yet ambiguity remains about best practices. The purpose of this review was to conduct a qualitative evidence synthesis to identify strengths and limitations in existing gerontological LQR. Research Design and Methods: We searched for studies published in English before September 2017, using longitudinal qualitative methods and focusing on gerontology. We searched the following databases: PubMed and ProQuest. This was followed up by a snowball search to identify additional LQR articles that were not gerontologically focused but provided conceptual or methodological information to enhance gerontological LQR. Article titles and abstracts were reviewed, and selected articles were independently evaluated by all authors and summarized in a descriptive matrix based on design, analysis, and strengths and limitations. Results: Our literature search resulted in 225 articles, which was then narrowed to 71 articles from 47 different journals based on our inclusion/exclusion criteria. LQR in gerontology varies considerably by study design and analysis approach. LQR design considerations involve number of time points and duration; rapport and retention; and consistent or different sampling, data collection, and measures. LQR analysis considerations involve synchronic and diachronic approaches, consistent or evolving coding, and individual- or group level analysis. Gerontological LQR articles vary in the extent to which they address special aging considerations. Discussion and Implications: This review indicates that there are areas where gerontological LQR can be strengthened going forward. We provide researchers with strategies to improve LQR rigor in our field and beyond. PMID- 30395233 TI - Safety of Repeated Imported Fire Ant Ultra-Rush Protocols. AB - Treatment of imported fire ant (IFA) hypersensitivity includes avoidance and venom immunotherapy (VIT) that reduces the risk of reactions to less than 5%. Previous studies have shown that rush immunotherapy (RIT) is safe and efficacious. It is unknown if multiple RIT procedures on individuals with breaks in VIT are safe and effective. This is a retrospective chart review of three patients who have undergone six IFA VIT rush protocols at our institution. Patients were all female with a median age of 27 years. All are active duty service members without medical problems who reside in an IFA endemic area. Reviewed protocols consisted of 10 injections of IFA whole body extract given in 1 day. Local reactions were the only side effect noted. All patients completed the protocols without further incident. Following each protocol, median VIT adherence was 9 months (range 2-72 months). Reasons for stopping VIT were deployment and pregnancy. Non-adherence is common and leads to breaks in VIT. The risk of VIT resumption in patients with previous RIT or VIT is unknown. This case series illustrates the safety and efficacy of repeated IFA VIT rush procedures in patients who for personal and service related reasons had breaks in VIT. PMID- 30395234 TI - Genome assembly and gene expression in the American black bear provides new insights into the renal response to hibernation. AB - The prevalence of chronic kidney disease (CKD) is rising worldwide and 10-15% of the global population currently suffers from CKD and its complications. Given the increasing prevalence of CKD there is an urgent need to find novel treatment options. The American black bear (Ursus americanus) copes with months of lowered kidney function and metabolism during hibernation without the devastating effects on metabolism and other consequences observed in humans. In a biomimetic approach to better understand kidney adaptations and physiology in hibernating black bears, we established a high-quality genome assembly. Subsequent RNA-Seq analysis of kidneys comparing gene expression profiles in black bears entering (late fall) and emerging (early spring) from hibernation identified 169 protein-coding genes that were differentially expressed. Of these, 101 genes were downregulated and 68 genes were upregulated after hibernation. Fold changes ranged from 1.8-fold downregulation (RTN4RL2) to 2.4-fold upregulation (CISH). Most notable was the upregulation of cytokine suppression genes (SOCS2, CISH, and SERPINC1) and the lack of increased expression of cytokines and genes involved in inflammation. The identification of these differences in gene expression in the black bear kidney may provide new insights in the prevention and treatment of CKD. PMID- 30395235 TI - A Tripartite Function of Mindfulness in Adjustment to Aging: Acceptance, Integration, and Transcendence. AB - Mindfulness has been gradually incorporated into clinical intervention and personal growth. Considerable research demonstrates that mindfulness is associated with positive health and well-being outcomes. Researchers have begun to inquire into the mechanisms of mindfulness. Building on empirical and theoretical insights and Buddhist philosophy, this article argues that mindfulness can serve a tripartite function of acceptance, integration, and transcendence in adjustment to aging. More specifically, mindfulness would help older adults (a) to accept phenomenal impermanence, emotional experience, and what they are, (b) to integrate life and death and integrate the ego, and (c) to transcend the ego and develop into the self. This article concludes by highlighting the acceptance-integration-transcendence framework as a heuristic framework for practice and suggesting directions for future research on mindfulness and aging. PMID- 30395236 TI - Sharks, Relationships, and Journals Must Move Forward. PMID- 30395237 TI - Subchronic Pathobiological Response Following Chronic Repetitive Mild Traumatic Brain Injury in an Aged Preclinical Model of Amyloid Pathogenesis. AB - Repetitive mild traumatic brain injury (r-mTBI) is a risk factor for Alzheimer disease (AD). The precise nature of how r-mTBI leads to, or precipitates, AD pathogenesis remains unclear. In this study, we explore subchronic effects of chronic r-mTBI (12-impacts) administered over 1-month in aged-PS1/APP mice and littermate controls. We investigate specific mechanisms that may elucidate the molecular link between AD and r-mTBI, focusing primarily on amyloid and tau pathology, amyloid processing, glial activation states, and associated clearance mechanisms. Herein, we demonstrate r-mTBI in aged PS1/APP mice does not augment, glial activation, amyloid burden, or tau pathology (with exception of pS202 positive Tau) 1 month after exposure to the last-injury. However, we observed a decrease in brain soluble Abeta42 levels without any appreciable change in peripheral soluble Abeta42 levels. This was accompanied by an increase in brain insoluble to soluble Abeta42 ratio in injured PS1/APP mice compared with sham injury. A parallel reduction in phagocytic receptor, triggering receptor expressed on myeloid cells 2, was also observed. This study demonstrates very subtle subchronic effects of r-mTBI on a preexisting amyloid pathology background, which may be on a continuum toward a slow and worsening neurodegenerative outcome compared with sham injury, and therefore, have many implications, especially in the elderly population exposed to TBI. PMID- 30395238 TI - Changes in coordination of growth and the cell cycle in green algae through CDK activity at different temperatures. AB - Progression of the cell cycle in green algae dividing by multiple fission is, under otherwise unlimited conditions, affected by growth rate set by a combination of light intensity and temperature. We compared cell cycle characteristics of Desmodesmus quadricauda at 20 degrees C or 30 degrees C and shifts between them. The duration of the cell cycle in cells grown under continuous illumination was more than doubled at 20 degrees C compared to 30 degrees C, suggesting it was set directly by growth rate. Similarly, DNA, RNA and bulk protein content per cell at 20 degrees C were about double that of cells grown at the higher temperature. For shift experiments, cells grown at either temperature were transferred to darkness to prevent further growth, and cultivated at the same or the other temperature. Upon transfer to the lower temperature, fewer nuclei and daughter cells were produced and not all cells were able to finish the cell cycle by division, remaining multinuclear. Correspondingly, cells put into the dark at the higher temperature divided faster into more daughter cells than control cells. These differences correlated with shifts in the preceding CDK activity, suggesting that cell cycle progression was not related to growth rate or cell biomass but correlates with CDK activity. PMID- 30395239 TI - Pharmacokinetics of First-Line Drugs Among Children With Tuberculosis in Rural Tanzania. AB - Background: Dosing recommendations for treating childhood tuberculosis (TB) were revised by the World Health Organization, yet so far, pharmacokinetic studies that have evaluated these changes are relatively limited. We evaluated plasma drug concentrations of rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) among children undergoing TB treatment in Tanzania when these dosing recommendations were being implemented. Methods: At the end of intensive phase TB therapy, blood was obtained 2 hours after witnessed medication administration to estimate the peak drug concentration (C2h), measured using high performance liquid chromatography or liquid chromatography-tandem mass spectrometry methods. Differences in median drug concentrations were compared on the basis of the weight-based dosing strategy using the Mann-Whitney U test. Risk factors for low drug concentrations were analyzed using multivariate regression analysis. Results: We enrolled 51 human immunodeficiency virus-negative children (median age, 5.3 years [range, 0.75-14 years]). The median C2hs were below the target range for each TB drug studied. Compared with children who received the "old" dosages, those who received the "revised" WHO dosages had a higher median C2h for RIF (P = .049) and PZA (P = .015) but not for INH (P = .624) or EMB (P = .143); however, these revised dosages did not result in the target range for RIF, INH, and EMB being achieved. A low starting dose was associated with a low C2h for RIF (P = .005) and PZA (P = .005). Malnutrition was associated with a low C2h for RIF (P = .001) and INH (P = .001). Conclusions: Among this cohort of human immunodeficiency virus-negative Tanzanian children, use of the revised dosing strategy for treating childhood TB did not result in the target drug concentration for RIF, INH, or EMB being reached. PMID- 30395240 TI - Ca2+ Channels in Anterior Pituitary Somatotrophs: A Therapeutic Perspective. AB - Ca2+ influx through voltage-gated Ca2+ channels (VGCCs) plays a key role in GH secretion. In this review, we summarize the current state of knowledge regarding the physiology and molecular machinery of VGCCs in pituitary somatotrophs. We next discuss the possible involvement of Ca2+ channelopathies in pituitary disease and the potential use of Ca2+ channel blockers to treat pituitary disease. Various types of VGCCs exist in pituitary cells. However, because L-type Ca2+ channels (LTCCs) contribute the major component to Ca2+ influx in somatotrophs, lactotrophs, and corticotrophs, we focused on these channels. An increasing number of studies in recent years have linked genetic missense mutations in LTCCs to diseases of the human cardiovascular, nervous, and endocrine systems. These disease-associated genetic mutations occur at homologous functional positions (activation gates) in LTCCs. Thus, it is plausible that similar homologous missense mutations in pituitary LTCCs can cause abnormal hormone secretion and underlying pituitary disorders. The existence of LTCCs in pituitary cells opens questions about their sensitivity to dihydropyridines, a group of selective LTCC blockers. The dihydropyridine sensitivity of pituitary cells, as with any other excitable cell, depends primarily on two parameters: the pattern of their electrical activity and the dihydropyridine sensitivity of their LTCC isoforms. These two parameters are discussed in detail in relation to somatotrophs. These discussions are also relevant to lactotrophs and corticotrophs. High dihydropyridine sensitivity may facilitate their use as drugs to treat pituitary oversecretion disorders such as acromegaly, hyperprolactinemia, and Cushing disease. PMID- 30395241 TI - Effects of Actinobacillus pleuropneumoniae on barrier function and inflammatory response of pig tracheal epithelial cells. AB - Actinobacillus pleuropneumoniae is a respiratory pathogen that causes porcine pleuropneumonia, a fatal respiratory disease responsible for high economic losses in the swine industry worldwide. With the objective to better understand the interactions between A. pleuropneumoniae and the porcine respiratory epithelium, we investigated the capacity of this pathogen to damage the epithelial barrier and induce an inflammatory response. We showed that A. pleuropneumoniae, even at a multiplicity of infection of 10, is able to break the tracheal epithelial barrier integrity as determined by monitoring the transepithelial electrical resistance and FITC-dextran transport. Immunofluorescence staining analysis suggested that A. pleuropneumoniae is affecting two important tight junction proteins (occludin, zonula occludens-1). As a consequence of the breakdown of the epithelial barrier integrity, A. pleuropneumoniae can translocate across a cell monolayer. We also showed that tracheal epithelial cells secrete pro-inflammatory cytokines (IL-8, IL-6, TNF-alpha) in response to a stimulation with this pathogen. In summary, A. pleuropneumoniae is able to induce damage to the porcine respiratory epithelial barrier. Challenging the epithelial cells with A. pleuropneumoniae was also associated with the secretion of pro-inflammatory cytokines. This better knowledge of the interactions between A. pleuropneumoniae and the epithelial cells may help to design novel strategies to prevent epithelium invasion by this bacterium along with other swine respiratory pathogens. PMID- 30395242 TI - BRENDA in 2019: a European ELIXIR core data resource. AB - The BRENDA enzyme database (www.brenda-enzymes.org), recently appointed ELIXIR Core Data Resource, is the main enzyme and enzyme-ligand information system. The core database provides a comprehensive overview on enzymes. A collection of 4.3 million data for ~84 000 enzymes manually evaluated and extracted from ~140 000 primary literature references is combined with information obtained by text and data mining, data integration and prediction algorithms. Supplements comprise disease-related data, protein sequences, 3D structures, predicted enzyme locations and genome annotations. Major developments are a revised ligand summary page and the structure search now including a similarity and isomer search. BKMS react, an integrated database containing known enzyme-catalyzed reactions, is supplemented with further reactions and improved access to pathway connections. In addition to existing enzyme word maps with graphical information of enzyme specific terms, plant word maps have been developed. They show a graphical overview of terms, e.g. enzyme or plant pathogen information, connected to specific plants. An organism summary page showing all relevant information, e.g. taxonomy and synonyms linked to enzyme data, was implemented. Based on a decision by the IUBMB enzyme task force the enzyme class EC 7 has been established for 'translocases', enzymes that catalyze a transport of ions or metabolites across cellular membranes. PMID- 30395243 TI - Genome-wide transcriptional response to altered levels of the Rpb7 subunit of RNA polymerase II identifies its role in DNA damage response in Schizosaccharomyces pombe. AB - Transcription of protein-coding genes is a highly regulated process. In eukaryotes, it involves cross-talk between the RNA polymerase II enzyme and different proteins of the transcriptional machinery. Twelve different subunits, Rpb1 to Rpb12, constitute RNA polymerase II. The sequence of the Rpb7 subunit is highly conserved across organisms. However, our knowledge and understanding of the role of Rpb7 in Schizosaccharomyces pombe is still limited. Therefore, in the present study we have studied the transcriptional response of S. pombe cells expressing reduced levels of rpb7+. Our global transcriptional analysis revealed that expression of genes belonging to different DNA repair pathways was downregulated by reduced rpb7+ expression. It was observed that survival of S. pombe cells expressing low rpb7+ levels was compromised under genotoxic stress conditions. Rpb7 also exhibited genetic interaction with genes of various DNA repair pathways. Furthermore, the growth sensitivity of S. pombe cells with low rpb7+ levels under DNA-damaging conditions was completely rescued by human Rpb7, indicating a functional conservation between these proteins. In summary, results from our whole-genome level gene expression analysis, as well as phenotypic and genetic experiments suggest a role for Rpb7 in DNA damage response in S. pombe. PMID- 30395244 TI - Probing human sperm metabolism using 13C-magnetic resonance spectroscopy. AB - STUDY QUESTION: Can 13C-Magnetic Resonance Spectroscopy (MRS) of selected metabolites provide useful information about human sperm metabolism and how glycolysis or oxidative phosphorylation are used by different sperm populations? SUMMARY ANSWER: Sperm populations, prepared by density gradient centrifugation (DGC) and incubated with either 13Cu-glucose, 13Cu-fructose or 13C1-pyruvate, showed consistent evidence of metabolism generating principally lactate and more intermittently bicarbonate, and significantly more lactate was produced from 13Cu glucose by vital or motile sperm recovered from the 40/80% interface compared to those from the pellet, which could not be accounted for by differences in the non sperm cells present. WHAT IS KNOWN ALREADY: Previous studies have focused on CO2 or other specific metabolite production by human sperm and there remains considerable debate about whether glycolysis and/or oxidative phosphorylation is the more important pathway for ATP production in sperm. STUDY DESIGN SIZE, DURATION: Sperm populations were prepared by DGC and subjected to 13C-MRS to answer the following questions. (i) Is it possible to detect human sperm metabolism of 13C substrates implicated in energy generation? (ii) What are the kinetics of such reactions? (iii) Do different sperm populations (e.g. '80%' pellet sperm and '40%' interface sperm) utilise substrates in the same way? Semen samples from 97 men were used in these experiments; 52 were used in parallel for aims (i) and (ii) and 45 were used for aim (iii). PARTICIPANTS/MATERIALS, SETTING, METHODS: Sperm populations were prepared from ejaculates of healthy men using a Percoll/Phosphate Buffered Saline (PBS) DGC and then incubated with a range of 13C-labelled substrates (13Cu-glucose, 13Cu-fructose, 13C1-pyruvate, 13C1-butyrate, 13C3-lactate, 13C2,4-D-3-hydroxybutyrate, 13C5-L-glutamate, 13C1,2 glycine or 13Cu-galactose) along with penicillin/streptomycin antibiotic at 37 degrees C for 4 hours, 24 hours or over 48 hours for an estimated rate constant. Sperm concentration, vitality and motility were measured and, for a subset of experiments, non-sperm cell concentration was determined. A 9.4T magnetic resonance spectrometer was used to acquire 1D 13C, inverse gated 1H decoupled, MRS spectra. Spectrum processing was carried out using spectrometer software and Matlab scripts to determine peak integrals for each spectrum. MAIN RESULTS AND THE ROLE OF CHANCE: 13Cu-glucose, 13Cu-fructose and 13C1-pyruvate were consistently converted into lactate and, to a lesser extent, bicarbonate. There was a significant correlation between sperm concentration and lactate peak size for 13Cu-glucose and 13Cu-fructose, which was not observed for 13C1-pyruvate. The lactate peak did not correlate with the non-sperm cell concentration up to 6.9 * 106/ml. The concentration of 13Cu-glucose, 13Cu-fructose or 13C1-pyruvate (1.8, 3.6, 7.2 or 14.4 mM) had no influence on the size of the observed lactate peak over a 4 hour incubation. The rate of conversion of 13C1-pyruvate to lactate was approximately three times faster than for 13Cu-glucose or 13Cu-fructose which were not significantly different from each other. After incubating for 4 hours, the utilisation of 13Cu-glucose, 13Cu-fructose or 13C1-pyruvate by sperm from the '40%' interface of the DGC was no different from those from the pellet when normalised to total sperm concentration. However, after normalising by either the vital or motile sperm concentration, there was a significant increase in conversion of 13Cu-glucose to lactate by '40%' interface sperm compared to pellet sperm (Vital = 3.3 +/- 0.30 * 106 vs 2.0 +/- 0.21 * 106; p = 0.0049; Motile = 7.0 +/- 0.75 * 106 vs 4.8 +/- 0.13 * 106; p = 0.0032. Mann-Whitney test p < 0.0055 taken as statistically significant). No significant differences were observed for 13Cu-fructose or 13C1-pyruvate. LARGE SCALE DATA: Not applicable. LIMITATIONS REASONS FOR CAUTION: Only 13C labelled metabolites that accumulate to a sufficiently high concentration can be observed by 13C MRS. For this reason, intermediary molecules in the metabolic chain are difficult to observe without trapping the molecule at a particular step using inhibitors. Non-sperm cell concentration was typical of the general population and no link was found between these cells and the magnitude of the 13C-lactate peak. However, it is possible that higher concentrations than the maximum observed (6.9 * 106/ml) may contribute to exogenous substrate metabolism in other experiments. WIDER IMPLICATIONS OF THE FINDINGS: 13C-MRS can provide information on the underlying metabolism of multiple pathways in live sperm. Dysfunction in sperm metabolism, as a result of either impaired enzymes of lack of metabolisable substrate, could be detected in sperm by a non-destructive assay, potentially offering new treatment options to improve overall sperm quality and outcomes for reproduction. STUDY FUNDING AND COMPETING INTEREST(S): This work was supported by the Medical Research Council Grant MR/M010473/1. The authors declare no conflicts of interest. PMID- 30395245 TI - Quality Control of Bee-Collected Pollen Using Bumblebee Microcolonies and Molecular Approaches Reveals No Correlation Between Pollen Quality and Pathogen Presence. AB - Bee-collected pollen is an essential protein source for honey bee and bumblebee colonies. Its quality directly affects bee health. We estimated the quality of pollen samples using bumblebee microcolonies and high-throughput sequencing for the presence of microorganisms. The tested samples of bee-collected pollen were of different quality, as estimated from their effect on the development of bumblebee microcolonies. Based on the pollen quality, we selected a subset of high-quality and low-quality pollen samples to further analyze them for the presence of microorganisms and pathogens. High-throughput sequencing revealed that the most common microorganisms in the bee-collected pollen were Acinetobacter spp. and bacteria of the genera Lactobacillus and Lactococcus. No pathogenic bacteria infectious for honey bees (e.g., those causing American and European foulbrood) or bumblebees have been identified in the analyzed pollen samples. Among potentially harmful microorganisms, there were bacteria from the Enterobacteriaceae family. The fungal pathogens Nosema apis and Nosema ceranae were detected in four samples; Ascosphaera sp. was found in six samples. Several viruses were found in the pollen samples, such as chronic bee paralysis virus, Israeli acute paralysis virus, deformed wing virus, sacbrood virus, and Kashmir bee virus. No correlation between the presence of these microorganisms or viruses and the impact of low-quality pollen samples on the bumblebee development was found. It is possible that factors affecting pollen quality are the absence of certain biologically active compounds or the presence of pesticides. PMID- 30395246 TI - Antixenosis Potential in Pulses Against the Pea Aphid (Hemiptera: Aphididae). AB - The aim of the study was to explore the acceptability of 14 species, varieties, and cultivars of grain legumes (Fabales: Fabaceae) to the pea aphid, by investigating the aphid probing behavior using the electrical penetration graph (EPG) technique. Phaseolus coccineus L. 'Felicia', Pisum sativum L. 'Medal', P. sativum arvense (L.) Poir. 'Fidelia' and 'Hubal', and Vicia faba L. 'Dragon' are highly susceptible, with no antixenosis potential against Acyrthosiphon pisum (Harris) (Hemiptera: Aphididae): aphid probing and feeding activities were not impeded. Lathyrus sativus L. 'Derek', Lupinus luteus L.'Perkoz', Vicia faba minor Beck. 'Sonet' are moderately susceptible to A. pisum infestation, with minor antixenosis potential and with antixenosis factors in non-phloem tissues. Aphids on these plants had difficulty to attain the phloem phase and phloem sap ingestion phase. During phloem phase, ingestion lasted for long periods of time. Lens culinaris Medik. 'Green' and Phaseolus vulgaris L. 'Boruta' are moderately susceptible to A. pisum infestation, with minor antixenosis potential and with antixenosis factors in the phloem. Behavior of aphids during pre-phloem phase was similar to that on highly susceptible plants but individual phloem phases and sap ingestion phases were short and contained a high proportion of watery salivation. Glycine max (L.) Merr. 'Aldana', L. angustifolius L. 'Boruta', P. coccineus 'Rothbluende', and P. vulgaris 'Mamut' are highly resistant to A. pisum infestation, with high antixenosis potential and with strong antixenosis factors in non-phloem tissues: aphid probing time was shortened, non-probing intervals between probes were long, and the success rate in reaching phloem phase was very low or none. PMID- 30395247 TI - Prevalence and correlates of beta and gamma human papillomavirus detection in oral samples from mid-adult women. AB - Background: Little is known about the epidemiology of beta and gamma human papillomaviruses (HPVs) in oral cavities of healthy women. Methods: We performed multiplex PCR (46 beta-HPVs and 51 gamma-HPVs) on stored oral rinse samples from healthy mid-adult women, including 407 tested for beta-HPVs and 310 for gamma HPVs. We used log-binomial regression to identify determinants of beta-HPV and gamma-HPV in separate models. Using paired fingernail data from a subset of 184 women, we also evaluated whether fingernail beta-HPV detection was associated with concurrent detection of the same type in the oral cavity. Results: Oral HPV prevalence was 20.6% for beta-HPV, and 10.7% for gamma-HPV. In multivariate analysis, oral beta-HPV detection was associated with increasing age (adjusted prevalence ratio [aPR] per 5-year difference=1.37, 95%CI:1.01-1.86) and greater lifetime number of oral sex partners (aPR for reporting >=6 versus 0-5 partners=2.06, 95%CI:1.01-4.20). In a separate model, concurrent detection of the same beta-HPV type in fingernails was strongly associated with oral beta-HPV detection (aPR=31.44, 95%CI:19.81-49.49). No significant determinants of gamma HPV detection were identified. Conclusions: Our results suggest a sexual transmission route for beta-HPVs, and support the hypothesis that fingers may serve as a source of transmission or autoinoculation of beta-HPVs to the oral cavity. PMID- 30395248 TI - Effect of vocabulary mapping for conditions on phenotype cohorts. AB - Objective: To study the effect on patient cohorts of mapping condition (diagnosis) codes from source billing vocabularies to a clinical vocabulary. Materials and Methods: Nine International Classification of Diseases, Ninth Revision, Clinical Modification (ICD9-CM) concept sets were extracted from eMERGE network phenotypes, translated to Systematized Nomenclature of Medicine - Clinical Terms concept sets, and applied to patient data that were mapped from source ICD9-CM and ICD10-CM codes to Systematized Nomenclature of Medicine - Clinical Terms codes using Observational Health Data Sciences and Informatics (OHDSI) Observational Medical Outcomes Partnership (OMOP) vocabulary mappings. The original ICD9-CM concept set and a concept set extended to ICD10-CM were used to create patient cohorts that served as gold standards. Results: Four phenotype concept sets were able to be translated to Systematized Nomenclature of Medicine Clinical Terms without ambiguities and were able to perform perfectly with respect to the gold standards. The other 5 lost performance when 2 or more ICD9 CM or ICD10-CM codes mapped to the same Systematized Nomenclature of Medicine - Clinical Terms code. The patient cohorts had a total error (false positive and false negative) of up to 0.15% compared to querying ICD9-CM source data and up to 0.26% compared to querying ICD9-CM and ICD10-CM data. Knowledge engineering was required to produce that performance; simple automated methods to generate concept sets had errors up to 10% (one outlier at 250%). Discussion: The translation of data from source vocabularies to Systematized Nomenclature of Medicine - Clinical Terms (SNOMED CT) resulted in very small error rates that were an order of magnitude smaller than other error sources. Conclusion: It appears possible to map diagnoses from disparate vocabularies to a single clinical vocabulary and carry out research using a single set of definitions, thus improving efficiency and transportability of research. PMID- 30395250 TI - On the Utilization of Abbreviations for Phlebotomine Sand Flies (Diptera: Psychodidae: Phlebotominae). PMID- 30395249 TI - Detection of Avian Influenza A(H7N2) Virus Infection Among Animal Shelter Workers Using a Novel Serological Approach-New York City, 2016-2017. AB - Background: In 2016, an influenza A(H7N2) virus outbreak occurred in cats in New York City's municipal animal shelters. One human infection was initially detected. Methods: We conducted a serological survey using a novel approach to rule out cross-reactive antibodies to other seasonal influenza viruses to determine whether additional A(H7N2) human infections had occurred and to assess exposure risk. Results: Of 121 shelter workers, one had serological evidence of A(H7N2) infection, corresponding to a seroprevalence of 0.8% (95% confidence interval, .02%-4.5%). Five persons exhibited low positive titers to A(H7N2) virus, indicating possible infection; however, we could not exclude cross reactive antibody responses to seasonal influenza viruses. The remaining 115 persons were seronegative. The seropositive person reported multiple direct cat exposures without using personal protective equipment and mild illness with subjective fever, runny nose, and sore throat. Conclusions: We identified a second case of A(H7N2) infection from this outbreak, providing further evidence of cat-to-human transmission of A(H7N2) virus. PMID- 30395251 TI - Risk of erythrocytosis during concomitant testosterone and SGLT2-inhibitor treatment: a warning from two clinical cases. AB - Context: erythrocytosis is one of the most common side effects occurring during testosterone replacement therapy (TRT) in male hypogonadism. It is well known that all testosterone formulations may cause Hemoglobin (Hb) and Hematocrit (Hct) increase, especially with short acting injectable formulations. Sodium glucose cotransporter-2 inhibitors (SGLT2i) are a new class of glucose-lowering agents that reduce hyperglycaemia in patients with Type 2 diabetes mellitus (T2DM) by inhibition of renal glucose reabsorption leading to increased urinary glucose excretion. The co-occurrence of T2DM and hypogonadism is known to be increasingly frequent. However, to date, no adverse events with the concomitant use of TRT and SGLT2i are reported. Case description: We report two cases of erythrocytosis during testosterone treatment and SGLT2i in patients with hypogonadism and T2DM. Conclusion: Considering that hypogonadism and T2DM are frequently associated, clinicians should carefully monitor the risk of occurrence of erythrocytosis when prescribing TRT and SGLT2i together. PMID- 30395252 TI - Spectrum of Illness in Migrants to Canada: Sentinel Surveillance through CanTravNet. PMID- 30395253 TI - Autophagy is essential for optimal Fe translocation to seeds in Arabidopsis. AB - Micronutrient deficiencies affect a large part of the world population. They are mostly due to the consumption of grains with insufficient content of Fe or Zn. Both de novo uptake by roots and recycling from leaves may provide seeds with nutrients. Autophagy, which is a conserved mechanism for nutrient recycling in eukaryotes, was shown to be involved in nitrogen remobilization to seeds. Here, we have investigated the role of this mechanism in micronutrient translocation to seeds. We found that several Arabidopsis thaliana plants impaired in autophagy display defects in nutrient remobilization to seeds. In atg5-1 mutant, which is completely defective in autophagy, the efficiency of Fe translocation from vegetative organs to seeds was severely decreased even when Fe was provided during seed formation. Combining atg5-1 with sid2 mutation that counteracts premature senescence associated to autophagy deficiency and using 57Fe pulse labeling, we could propose a two-step mechanism in which iron taken up de novo during seed formation is first accumulated in vegetative organs and subsequently remobilized to seeds. Finally, we showed that translocations of zinc and manganese to seeds are also dependent on autophagy. Fine tuning autophagy during seed formation opens therefore new possibilities to improve micronutrient remobilization to seeds. PMID- 30395254 TI - Tipping the scales: the migration-selection balance leans toward selection in snake venoms. AB - The migration-selection interaction is the strongest determinant of whether a beneficial allele increases in frequency within a population. Results of empirical studies examining the role of gene adaptive context, however, have largely been equivocal, with examples of opposing outcomes being repeatedly documented (e.g., local adaptation with high levels of gene flow versus gene swamping). We compared neutral genomic and venom expression divergence for three sympatric pit vipers with differing ecologies to determine if and how migration selection disequilibria result in local adaptation. We specifically tested whether neutral differentiation predicted phenotypic differentiation within an isolation-by-distance framework. The decoupling of neutral and phenotypic differentiation would indicate selection led to adaptive divergence irrespective of migration, whereas a significant relationship between neutral and venom expression differentiation would provide evidence in favor of the constraining force of gene flow. Neutral differentiation and geographic distance predicted phenotypic differentiation only in the generalist species, indicating that selection was the predominant mechanism in the migration-selection balance underlying adaptive venom evolution in both specialists. Dispersal is thought to be a stronger influence on genetic differentiation than specialization, but our results suggest the opposite. Greater specialization may lead to greater diversification rates, and extreme spatial and temporal variation in selective pressures can favor generalist phenotypes evolving under strong stabilizing selection. Our results are consistent with these expectations, suggesting that the equivocal findings of studies examining the role of gene flow in an adaptive context may be explained by ecological specialization theory. PMID- 30395255 TI - VFDB 2019: a comparative pathogenomic platform with an interactive web interface. AB - The virulence factor database (VFDB, http://www.mgc.ac.cn/VFs/) is devoted to providing the scientific community with a comprehensive warehouse and online platform for deciphering bacterial pathogenesis. The various combinations, organizations and expressions of virulence factors (VFs) are responsible for the diverse clinical symptoms of pathogen infections. Currently, whole-genome sequencing is widely used to decode potential novel or variant pathogens both in emergent outbreaks and in routine clinical practice. However, the efficient characterization of pathogenomic compositions remains a challenge for microbiologists or physicians with limited bioinformatics skills. Therefore, we introduced to VFDB an integrated and automatic pipeline, VFanalyzer, to systematically identify known/potential VFs in complete/draft bacterial genomes. VFanalyzer first constructs orthologous groups within the query genome and preanalyzed reference genomes from VFDB to avoid potential false positives due to paralogs. Then, it conducts iterative and exhaustive sequence similarity searches among the hierarchical prebuilt datasets of VFDB to accurately identify potential untypical/strain-specific VFs. Finally, via a context-based data refinement process for VFs encoded by gene clusters, VFanalyzer can achieve relatively high specificity and sensitivity without manual curation. In addition, a thoroughly optimized interactive web interface is introduced to present VFanalyzer reports in comparative pathogenomic style for easy online analysis. PMID- 30395256 TI - The Use of Actigraphy Differentiates Sleep Disturbances in Active and Inactive Crohn's Disease. AB - Background: Sleep disturbances (SDs) are commonly reported in patients with Crohn's disease (CD). Several survey instruments assessing subjective measures of insufficient sleep have identified SDs in subjects with CD. However, there are limited data on objective measures of SDs in these patients as they relate to disease activity. In this prospective cross-sectional study, we compared objective estimates of sleep obtained using multiday wrist actigraphy in individuals with CD with varying disease activity. Methods: Eighty patients with a diagnosis of CD were recruited to take part in the study. Participants were stratified by disease activity into remission, mild disease, and moderate to severe disease groups using the Harvey-Bradshaw Index and C-reactive protein levels. Participants were excluded on the basis of significant comorbidity (Charlson Comorbidity Index >=3), a known history of a sleep disorder, or the concomitant use of systemic corticosteroids. Participants completed surveys, including the PROMIS-SD Short Form 8a, the Epworth Sleepiness Scale, and the Women's Health Initiative Insomnia Rating scale, and were provided with an accelerometer that estimated sleep-wake patterns over 7 days. Comparisons of actigraphic sleep parameters were performed between disease activity groups. Multivariate logistic regression analyses were performed using covariates determined a priori to have an association with sleep disturbance in CD through a review of the literature. Results: Of the 80 participants enrolled in the study, 72 completed 5 days of actigraphy data: 28 subjects in remission, 22 subjects with mild disease activity, and 22 subjects with moderate to severe disease activity. Self-reported sleep characteristics assessed by questionnaires were similar between groups. By actigraphy, individuals with moderate to severe CD spent a significantly longer time awake after falling asleep compared with subjects with remissive disease or compared with subjects with mild disease (65.8 minutes vs 44.3 minutes and 49.1 minutes, respectively; each P < 0.05). Individuals with moderate to severe CD had significantly lower sleep efficiency compared with those with remissive CD (86.6% vs 89.9%; P = 0.03). In the multivariate analyses, moderate to severe CD disease activity was significantly associated with an increased amount of fragmented sleep (odds ratio [OR], 3.70; 95% confidence interval [CI], 1.23-11.32; P = 0.02; WASO >= 60 minutes). Moreover, the use of controlled substances was associated with poor sleep efficiency (OR, 3.86; 95% CI, 1.01-14.7; P = 0.04; SE <= 85.5%). Conclusions: This is the first study to objectively quantify disturbed sleep using wrist actigraphy in adults with CD with varying disease activity. Wrist actigraphy may serve as a useful modality for discerning SD in subjects with active vs remissive disease that is not evident with questionnaires alone. Although we determined that disease severity is a significant factor that leads to SDs in CD, larger studies using these objective measures may help determine the contribution of other factors. PMID- 30395257 TI - A member of the TERMINAL FLOWER1/CENTRORADIALIS gene family controls sprout growth in potato tubers. AB - Potato tuber bud dormancy break followed by premature sprouting is a major commercial problem which results in quality losses and decreased tuber marketability. An approach to controlling premature tuber sprouting is to develop potato cultivars with a longer dormancy period and/or reduced rate of sprout growth. Our recent studies using a potato diploid population have identified several QTLs that are associated with tuber sprout growth. In the current study we aim to characterise a candidate gene associated with one of the largest effect QTL for rapid tuber sprout growth on potato chromosome 3. Underlying this QTL is a gene encoding a TERMINAL FLOWER 1/ CENTRORADIALIS homologue (PGSC0003DMG400014322). Here we use a transgenic approach to manipulate the expression level of the CEN family member in a potato tetraploid genotype (cv. Desiree). We demonstrate a clear effect of StCEN expression manipulation, with decreased expression levels associated with an increased rate of sprout growth, and over-expressing lines showing a lower rate of sprout growth than controls. Associated with different levels of StCEN expression were different levels of ABA and cytokinins implying a role in controlling the levels of plant growth regulators in the apical meristem. PMID- 30395258 TI - Risk factors for sporadic cryptosporidiosis in the Netherlands: Analysis of a three-year population based case-control study coupled with genotyping, 2013 2016. AB - Background: In 2012, cryptosporidiosis cases increased in the Netherlands, but no single source was identified. In April 2013, we began a three year population based case-control study, coupled with genotyping, to identify risk factors for sporadic cryptosporidiosis. Methods: Cryptosporidium cases were laboratory confirmed (microscopy or PCR), followed by C. hominis and C. parvum species determination testing. We analysed data by study year, combined and by species. We performed single variable analysis and variables with a P-value <=0.10 were included in a multivariable logistic regression model adjusting for age, sex and season. Results: The study included 609 cases and 1,548 frequency-matched controls. C. parvum was the predominant species in the first two study years, shifting to C. hominis in the third year. Household person-to-person transmission and eating barbequed food were strongly associated with being a case. Eating tomatoes was negatively associated. By study year, person-to-person transmission was an independent risk factor. Analysis by species identified different risk factors for C. parvum and C. hominis cases. Conclusion: This was the first case control study examining risk factors for sporadic cryptosporidiosis in the Netherlands. Providing information about Cryptosporidium exposure during outdoor activities and improvements in hygiene within households could prevent future sporadic infections. PMID- 30395259 TI - Reply to: Dual vs. triple antithrombotic therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention. PMID- 30395260 TI - Measles: a re-emerging problem in migrants and travelers. PMID- 30395261 TI - Enhanced expression of TACE contributes to elevated levels of sVCAM-1 in endometriosis. AB - STUDY QUESTION: Are increased sVCAM-1 and sICAM-1 levels associated with tumor necrosis factor-alpha-converting enzyme (TACE) activity in endometriosis? SUMMARY ANSWER: Here we provide the first functional evidence that induced TACE activity in human endometriotic epithelial cells is at least in part responsible for the enhanced release of sVCAM-1 from these cells. WHAT IS KNOWN ALREADY: We and others have shown that serum-soluble (s)VCAM-1 levels are significantly higher in women with endometriosis, compared to disease-free controls. Experimental evidence exists suggesting a role of sICAM-1 and sVCAM-1 in the pathogenesis of endometriosis. TACE was identified as the protease responsible for phorbol 12 myristate 13-acetate (PMA)-induced VCAM-1 release in murine endothelial cells. Additionally, it has recently been shown that TACE is upregulated in the endometrial luminal epithelium of the mid-secretory phase in infertile women. STUDY DESIGN, SIZE, DURATION: This study was conducted at the Tertiary Endometriosis Referral Center of the Medical University of Vienna. Samples from a total number of 97 women were collected between July 2013 and September 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: After complete surgical exploration of the abdominopelvic cavity, 49 women with histologically proven endometriosis and 48 endometriosis-free control women were enrolled. Each participating woman contributed only one sample of eutopic endometrium and normal peritoneum, and some of the women with endometriosis contributed samples of diverse types of endometriotic lesions (in total 52 ectopic samples). Among the 49 women with endometriosis, 36 matched samples of endometriotic lesions and corresponding eutopic endometrium were collected. In order to detect sVCAM-1 and TACE protein by ELISA, peritoneal fluid (PF) samples were collected from 44 cases and 32 controls during surgery. Expression of TACE mRNA was analyzed by qRT-PCR in 111 endometrium tissue samples (28 eutopic control samples, 33 eutopic samples from women with endometriosis, 50 ectopic samples from lesions) and 37 healthy peritoneum samples. Immunohistochemistry was performed in 123 tissue samples (39 eutopic control samples, 42 eutopic samples from women with endometriosis, 42 ectopic samples from lesions) and the relation between tissue TACE protein levels and sVCAM-1 secretion was examined. PMA-induced sVCAM-1 release, and TACE- and VCAM-1-transcripts or proteins were measured in an immortalized endometriotic epithelial cell line (11Z) pre-incubated either with TACE inhibitors or following TACE siRNA knockdown. MAIN RESULTS AND THE ROLE OF CHANCE: Here, we demonstrate that TACE protein is overexpressed in epithelium of tissue samples of both eutopic endometrium and ectopic lesions of women with endometriosis compared to disease-free controls (P < 0.001 both) and that the overexpression of the protein in the lesions is due to activation of TACE gene transcription (P < 0.001). Moreover, epithelial TACE protein was significantly higher in ectopic samples than in corresponding eutopic tissue of women with the disease (P < 0.001). High endometrial tissue TACE protein expression correlated with higher serum sVCAM-1 levels (P < 0.05) but not with sICAM-1 levels. Inhibition of TACE either by TACE inhibitors or by TACE siRNA knockdown resulted in decreased PMA-induced shedding of sVCAM-1 in vitro (P < 0.005 or P < 0.01, respectively), but the TACE inhibitors did not affect transcription of TACE or VCAM-1. Additionally, we observed an upregulation of TACE in proliferative endometrial epithelium of infertile (P < 0.005), compared to fertile women. TACE was increased in infertile women with endometriosis (P = 0.051) but not in infertile women without endometriosis. LIMITATIONS, REASONS FOR CAUTION: Albeit well characterized, our control population included women with other gynecologic diseases, which may have impacted the levels of sVCAM-1 and tissue TACE expression levels, e.g. benign ovarian cysts or uterine fibroids. Thus, the results of our analysis have to be interpreted carefully and in the context of the current experimental settings. WIDER IMPLICATIONS OF THE FINDINGS: The dysregulation of TACE substrate shedding represents a promising yet relatively unexplored area of endometriosis progression and could serve as a basis for the development of new treatments of the disease. STUDY FUNDING AND COMPETING INTEREST(S): This work was supported by the Ingrid Flick Foundation. The authors have no competing interests to declare. PMID- 30395262 TI - No pain, no gain. PMID- 30395263 TI - Instructor and Trainee Judgments of Cohesion in Mixed-Gender Military Teams. AB - Introduction: In integrating women into combat roles, one key question has been whether women will reduce the cohesion of small teams, which is their ability to stick together and perform well under pressure. Among other things, team cohesion protects the mental health of military personnel during initial training as well in operational zones. To provide new converging evidence on the cohesion of all male versus mixed-gender recruit teams at the end of training, cohesion ratings were obtained from both recruits and their instructors. Materials and Methods: The recruits consisted of 83 females, 398 males, and 8 non-specified individuals across 46 small teams. The teams' gender mix varied from 0% female (all males) up to 64% female. The recruit questionnaire comprised 18 items that covered the bonding of the recruits with each other (horizontal), with their instructor leaders (vertical), and with the wider Army (organizational). In addition, two to three instructors rated each team on their horizontal and vertical bonding. This study had Defence ethics approval (DPR-LREP 069-15). Results: (1). The ratings of recruits and instructors were significantly correlated for both horizontal bonding (r = 0.44) and vertical bonding (r = 0.49). These correlations were similar to correlations obtained previously from U.S. Army infantry platoons. (2). The recruits in the present study gave their teams significantly higher ratings for horizontal bonding (M = 4.18, SD =0.33) than did their instructors (M = 3.95, SD =0.31), F(1,45) = 22.12, p < 0.001). Neither the ratings of recruits nor their instructors were significantly correlated with the percentage of females per team, rs = 0.063, 0.249, ps > 0.05. (3). For vertical bonding, the recruits' ratings (M = 4.48, SD =0.37) were high and similar to those of instructors (M = 4.56, SD =0.44), F(1,45) = 1.65, p > 0.20). The vertical bonding scores were also not significantly correlated with the percentage of females per team, rs = -0.168, -0.139, ps > 0.25. Conclusions: Our findings agree with a previously published analysis of recruit performance over a 5-year period (2011 2015). Composite instructor ratings of recruit performance, including their teamwork, were similar for males and females regardless of the gender composition of platoons, which ranged from all male to 45% female. The next step in this research is to determine the pattern and dynamics of bonding between team members and their leaders as soldiers progress through their advanced training and ultimately operational deployment. Such research should reveal whether any differences in cohesion appear in relation to team gender composition. The present results have useful implications for health professionals. When discussing feelings of stress, depression, and/or with male or female military clients, health professionals may find it worthwhile to explore their clients' sense of bonding with their team members, their leaders, and their wider organization as one possible contributor to the individual's concern. By the same token, advice aimed at promoting the three dimensions of cohesion may help capitalize on their protective effects. PMID- 30395264 TI - Effects of serum estradiol and progesterone on estrogen-regulated gene expression in breast cancers of premenopausal patients. AB - Background: Expression of estrogen receptor alpha in breast cancer is essential for estrogen-dependent growth and partially determines the breast cancer subtype. In premenopausal women, expression of estrogen-regulated genes in estrogen receptor-positive breast cancer tissues are reportedly influenced by the menstrual cycle. Methods: We investigated correlations between serum estradiol (E2; tested on the day of surgery) and expression of estrogen-regulated genes and proliferation genes in strongly estrogen receptor alpha-positive breast cancer tissues from 91 premenopausal women by quantitative reverse transcription polymerase chain reaction. We also investigated correlations between serum progesterone levels on the day of surgery and mRNA expression of progesterone regulated genes and proliferation genes. Results: The serum E2 level affected expression of estrogen-regulated genes, including progesterone receptor (P = 0.016, Rs = 0.07) but showed no correlation with expression of genes associated with proliferation. We also observed strong positive correlations between mRNA expression of ESR1 and that of estrogen-regulated genes (P < 0.0001, Rs = 0.329 0.756) and proliferation genes (P < 0.0001, Rs = 0.753-0.843). The serum progesterone level affected expression of RANKL mRNA. However, we observed no correlations between serum progesterone and expression of Wnt-4 or proliferation genes. Conclusions: The serum E2 level on the day of surgery influences estrogen regulated gene expression moderately in patients found to be strongly positive for estrogen receptor alpha by immunohistochemistry. Changes in serum E2 levels might influence the results of molecular profiling tests in premenopausal women with breast cancer. PMID- 30395265 TI - The cytogenetic constitution of human blastocysts: insights from comprehensive chromosome screening strategies. AB - BACKGROUND: Embryos that are able to form blastocysts have succeeded in activating their genome and differentiating into two cell types-an external layer of trophectoderm cells, which will go on to form extra-embryonic tissues such as the placenta, and the inner cell mass, which will give rise to the embryo proper. Culturing embryos to the blastocyst stage has become an increasingly popular IVF practice over the past decade. Additionally, it has been proposed that the identification and transfer of euploid blastocysts could significantly improve IVF outcomes. Toward this end, comprehensive molecular cytogenetic methods have been developed. The application of such methods in both clinical and research contexts has yielded cytogenetic data from large numbers of blastocysts. Questions have been raised concerning the implantation potential of blastocysts diagnosed 'euploid' or 'aneuploid', and there has been particular debate over the detection and viability of embryos categorized as 'mosaic'-composed of a mixture of normal and aneuploid cells. OBJECTIVE AND RATIONALE: This review aims to summarize data from studies using comprehensive molecular cytogenetic methods to examine blastocyst-stage embryos, describing current knowledge related to rates of euploidy, uniform aneuploidy and mosaicism. Issues associated with the developmental capacity of blastocysts of different cytogenetic constitutions will also be addressed. Guidelines on the clinical management of blastocysts with varying chromosome complements will be considered. SEARCH METHODS: Rates of euploidy, uniform aneuploidy (in which all cells have the same abnormal karyotype) and mosaicism were determined via a thorough literature search (PubMed). The keywords used in the search were as follows: preimplantation embryo development, blastocyst stage, embryonic aneuploidy, meiotic chromosome malsegregation, post-zygotic chromosome malsegregation, comprehensive chromosome screening, array comparative genomic hybridization, single-nucleotide polymorphism array, next-generation sequencing, embryo mosaicism and implantation of mosaic embryos. Relevant articles written in English and published up to March 2018 were reviewed. OUTCOMES: Different types of aneuploidy, including some complex forms, are capable of persisting to the blastocyst stage. As expected, euploidy rates decreased with advancing female age, whereas uniform aneuploidy increased. Analysis of multiple cells from individual blastocysts revealed that most of those classified 'abnormal' contained no euploid cells (due to meiotic errors arising in the gametes and therefore present in every cell), some having additional mosaic (post-fertilization, mitotic) errors. Blastocysts with a mix of normal and aneuploid cells were observed less frequently than other classes of embryo. The transfer of embryos with diploid-aneuploid mosaic biopsy specimens is reportedly associated with higher miscarriage and lower implantation rates, compared to embryos in which only euploid cells are detected. WIDER IMPLICATIONS: Detailed investigations into the chromosome constitution of human blastocysts suggest that a significant proportion is euploid in every cell, although the exact fraction is strongly influenced by female age. These findings do not support the notion that mosaic chromosome abnormalities are a natural part of embryo development. Mosaic aneuploidies, arising post-zygotically, were detected by various different comprehensive molecular cytogenetic methods, suggesting that the majority of these represent genuine findings. However, it remains possible that certain comprehensive molecular cytogenetic methods may carry a risk of mosaicism being incorrectly assigned, in a minority of samples, as a result of technical artifact. This may be a consequence of degraded DNA in the trophectoderm biopsy or other technical issues. According to published studies, blastocysts considered to have uniform aneuploidy and, to a lesser extent, those with mosaic abnormalities were associated with poorer clinical outcomes in comparison with euploid embryos. PMID- 30395266 TI - Is IUI with ovarian stimulation effective in couples with unexplained subfertility? AB - STUDY QUESTION: Does starting IUI with ovarian stimulation (IUI-OS) within 1.5 years after completion of the fertility workup increase ongoing pregnancy rates compared to expectant management in couples with unexplained subfertility? SUMMARY ANSWER: IUI-OS is associated with higher chances of ongoing pregnancy compared to expectant management in unexplained subfertile couples, specifically those with poor prognoses of natural conception, i.e. <15% over 6 months or <25% over 1 year. WHAT IS KNOWN ALREADY: IUI-OS is often the first-line treatment for couples with unexplained subfertility. Two randomized controlled trials compared IUI-OS to expectant management using different thresholds for the prognosis of natural conception as inclusion criteria and found conflicting results. A cohort of couples with unexplained subfertility exposed to expectant management and IUI OS offers an opportunity to determine the chances of conception after both strategies and to evaluate whether the effect of IUI-OS depends on a couple's prognosis of natural conception. STUDY DESIGN, SIZE, DURATION: A prospective cohort study on couples with unexplained or mild male subfertility who could start IUI-OS at any point after completion of the fertility workup, recruited in seven Dutch centres between January 2002 and February 2004. Decisions regarding treatment were subject to local protocols, the judgement of the clinician and the wishes of the couple. Couples with bilateral tubal occlusion, anovulation or a total motile sperm count <1 * 106 were excluded. Follow up was censored at the start of IVF, after the last IUI cycle or at last contact and truncated at a maximum of 1.5 years after the fertility workup. PARTICIPANTS/MATERIALS, SETTING, METHODS: The endpoint was time to conception leading to an ongoing pregnancy. We used the sequential Cox approach comparing in each month ongoing pregnancy rates over the next 6 months of couples who started IUI-OS to couples who did not. We calculated the prognosis of natural conception for individual couples, updated this over consecutive failed cycles and evaluated whether prognosis modified the effect of starting IUI-OS. We corrected for known predictors of conception using inverse probability weighting. MAIN RESULTS AND THE ROLE OF CHANCE: Data from 1896 couples were available. There were 800 couples whom had at least one IUI-OS cycle within 1.5 years post fertility workup of whom 142 couples conceived (rate: 0.50 per couple per year, median follow up 4 months). The median period between fertility workup completion and starting IUI-OS was 6.5 months. Out of 1096 untreated couples, 386 conceived naturally (rate: 0.31 per couple per year, median follow up 7 months). Starting IUI-OS was associated with a higher chance of ongoing pregnancy by a pooled, overall hazard ratio of 1.96 (95% CI: 1.47 2.62) compared to expectant management. The effect of treatment was modified by a couple's prognosis of achieving natural conception (P = 0.01), with poorer prognoses or additional failed natural cycles being associated with a stronger effect of treatment. The predicted 6-month ongoing pregnancy rate for a couple with a prognosis of 25% at completion of the fertility workup over the next six cycles (~40% over 1 year) was 25% (95% CI: 21-28%) for expectant management and 24% (95% CI: 9-36%) when starting IUI-OS directly. For a couple with a prognosis of 15% (25% over 1 year), these predicted rates were 17% (95% CI: 15-19%) for expectant management and 24% (95% CI: 15-32%) for starting IUI-OS. LIMITATIONS, REASONS FOR CAUTION: The effect estimates are based on a prospective cohort followed up for 1.5 years after completion of the fertility workup. Although we balanced the known predictors of conception between treated and untreated couples using inverse probability weighting, observational data may be subject to residual confounding. The results need to be confirmed in external datasets. WIDER IMPLICATIONS OF THE FINDINGS: These results explain the discrepancies between previous trials that compared IUI-OS to expectant management, but further studies are required to establish the threshold at which IUI-OS is (cost )effective. STUDY FUNDING/COMPETING INTEREST(S): This study was facilitated by (Grant 945/12/002) from ZonMW, The Netherlands Organization for Health Research and Development, The Hague, The Netherlands. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck and Guerbet. S.B. reports acting as Editor-in-Chief of HROpen. The other authors have no conflicts of interest. PMID- 30395267 TI - RNAcentral: a hub of information for non-coding RNA sequences. AB - RNAcentral is a comprehensive database of non-coding RNA (ncRNA) sequences, collating information on ncRNA sequences of all types from a broad range of organisms. We have recently added a new genome mapping pipeline that identifies genomic locations for ncRNA sequences in 296 species. We have also added several new types of functional annotations, such as tRNA secondary structures, Gene Ontology annotations, and miRNA-target interactions. A new quality control mechanism based on Rfam family assignments identifies potential contamination, incomplete sequences, and more. The RNAcentral database has become a vital component of many workflows in the RNA community, serving as both the primary source of sequence data for academic and commercial groups, as well as a source of stable accessions for the annotation of genomic and functional features. These examples are facilitated by an improved RNAcentral web interface, which features an updated genome browser, a new sequence feature viewer, and improved text search functionality. RNAcentral is freely available at https://rnacentral.org. PMID- 30395268 TI - Genome-wide meta-analysis and replication studies in multiple ethnicities identify novel adolescent idiopathic scoliosis susceptibility loci. AB - Adolescent idiopathic scoliosis (AIS) is the most common musculoskeletal disorder of childhood development. The genetic architecture of AIS is complex, and the great majority of risk factors are undiscovered. To identify new AIS susceptibility loci, we conducted the first genome-wide meta-analysis of AIS genome-wide association studies, including 7956 cases and 88 459 controls from 3 ancestral groups. Three novel loci that surpassed genome-wide significance were uncovered in intragenic regions of the CDH13 (P-value_rs4513093 = 1.7E-15), ABO (P-value_ rs687621 = 7.3E-10) and SOX6 (P-value_rs1455114 = 2.98E-08) genes. Restricting the analysis to females improved the associations at multiple loci, most notably with variants within CDH13 despite the reduction in sample size. Genome-wide gene-functional enrichment analysis identified significant perturbation of pathways involving cartilage and connective tissue development. Expression of both SOX6 and CDH13 was detected in cartilage chondrocytes and chromatin immunoprecipitation sequencing experiments in that tissue revealed multiple HeK27ac-positive peaks overlapping associated loci. Our results further define the genetic architecture of AIS and highlight the importance of vertebral cartilage development in its pathogenesis. PMID- 30395269 TI - Acetylation of ACAP4 regulates CCL18-elicited breast cancer cell migration and invasion. AB - Tumor metastasis represents the main causes of cancer-related death. Our recent study showed that chemokine CCL18 secreted from tumor-associated macrophages regulates breast tumor metastasis, but the underlying mechanisms remain less clear. Here, we show that ARF6 GTPase-activating protein ACAP4 regulates CCL18 elicited breast cancer cell migration via the acetyltransferase PCAF-mediated acetylation. CCL18 stimulation elicited breast cancer cell migration and invasion via PCAF-dependent acetylation. ACAP4 physically interacts with PCAF and is a cognate substrate of PCAF during CCL18 stimulation. The acetylation site of ACAP4 by PCAF was mapped to Lys311 by mass spectrometric analyses. Importantly, dynamic acetylation of ACAP4 is essential for CCL18-induced breast cancer cell migration and invasion, as overexpression of the persistent acetylation-mimicking or non acetylatable ACAP4 mutant blocked CCL18-elicited cell migration and invasion. Mechanistically, the acetylation of ACAP4 at Lys311 reduced the lipid-binding activity of ACAP4 to ensure a robust and dynamic cycling of ARF6-ACAP4 complex with plasma membrane in response to CCL18 stimulation. Thus, these results present a previously undefined mechanism by which CCL18-elicited acetylation of the PH domain controls dynamic interaction between ACAP4 and plasma membrane during breast cancer cell migration and invasion. PMID- 30395270 TI - The European Nucleotide Archive in 2018. AB - The European Nucleotide Archive (ENA; https://www.ebi.ac.uk/ena), provided from EMBL-EBI, has for more than three decades been responsible for archiving the world's public sequencing data and presenting this important resource to the scientific community to support and accelerate the global research effort. Here, we outline ENA services and content in 2018 and provide an overview of a selection of focus areas of development work: extending data coordination services around ENA, sequence submissions through template expansion, early pre submission validation tools and our move towards a new browser and retrieval infrastructure. PMID- 30395271 TI - Cdk1 gates cell cycle-dependent tRNA synthesis by regulating RNA polymerase III activity. PMID- 30395272 TI - Tobacco Use Classification by Inexpensive Urinary Cotinine Immunoassay Test Strips. AB - Urinary cotinine is one of the most commonly measured biomarkers reflecting recent exposure to nicotine. In some cases a simple qualitative dichotomization of smokers and non-smokers is all that is required. NicAlert(r) test strips have been evaluated for this purpose, but other recently introduced, inexpensive single-line test strips have not. In this study we evaluated two such strips with nominal cutoffs of 200 and 10 ng/mL. A total of 800 urine samples with known cotinine concentrations determined by an LC-MS-MS method were examined, including 400 urine samples ranging from 0.23 to more than 24,000 ng/mL by the 200 ng/mL strip, and 400 samples with concentrations <200 ng/mL by the 10 ng/mL cutoff strip. Both test strips performed well in these evaluations. Classification relative to LC-MS-MS by the 200 ng/mL strips had a sensitivity of 99.5% and specificity of 92%, with 95.8% accuracy. The 10 ng/mL strips had a sensitivity of 98.7% and specificity of 90.1%, with 93.3% accuracy. The positive predictive value for the 200 ng/mL strips was 92.6% and the negative predictive value was 99.5%. For the 10 ng/mL strips, the corresponding values were 85.4 and 99.2%, respectively. The prevalence of positive samples was 50% in the 200 ng/mL group, and 37% in the 10 ng/mL set. Each strip was read by two readers with an overall agreement of >98%. Our results suggest that these simple and inexpensive lateral flow immunoassay test strips can provide useful qualitative estimates of nicotine exposures for appropriate applications within the inherent limitations of sensitivity and precision of the immunoassay test strip format. PMID- 30395273 TI - The Modular Adaptive Electrotherapy Delivery System (MAEDS): An Electroceutical Approach for Effective Treatment of Wound Infection and Promotion of Healing. AB - Background: Infected wounds are painful and cannot heal, with antibiotics showing reduced efficacy. Appropriate wound electrotherapy may limit incident planktonic and polymicrobial colonization, inhibit biofilm formation and accelerate healing. Methods: The Modular Adaptive Electrotherapy Delivery System (MAEDS) is a lightweight, flexible, battery-powered disposable bandage which delivers controlled reliable electrotherapy to the wound for up to 7 days. Large full thickness excisional wounds (6 cm diameter) were created in a porcine model and freshly cultured 0.5 McFarland green fluorescent protein-labeled Pseudomonas aeruginosa evenly applied to the wound bed. Control wounds received standard wound care, Tegaderm HP Transparent Dressing (3 M Health Care, St. Paul, MN, USA) applied in a sterile fashion. Treatment wounds received MAEDS electrotherapy for up to 28 days or until healed. Onboard Bluetooth facilitated remote real-time monitoring of MAEDS function. Dressing changes occurred on postoperative day (POD) 1, 3, 5, 7, 10, 14, 21, and 28. Punch biopsies were taken at the wound margin and center. Bacterial samples were processed to determine infection status. Results: Acute infected wounds treated with MAEDS electrotherapy were 92% smaller than baseline by POD21. Healing rate was significantly faster (p < 0.01) and infection significantly decreased (p < 0.0001) at POD10, relative to control wounds. Conclusion: The MAEDS electrotherapy can significantly inhibit infection and enhance healing rate in acute infected wounds. PMID- 30395274 TI - Commentary: Steroid Use Associated With Increased Odds of 30-Day Mortality in Surgical Patients With Metastatic Spinal Tumors in the setting of Disseminated Disease. PMID- 30395275 TI - Responding to the challenges of international collaborations between the east and the west - report of the first JCOG-EORTC symposium and a perspective from young JCOG and EORTC investigators. AB - International/intercontinental collaboration is necessary to set up new innovative clinical trials for cancer treatment. However, the infrastructure, especially Asia-Europe academic partnerships, to enable such collaboration has not been fully structured and differences and similarities between the research groups have not been well studied. In 2015, collaboration started between the biggest cancer research organizations in Asia and EU, Japan Clinical Oncology Group (JCOG) and European Organisation for Research and Treatment of Cancer (EORTC). Following the first pilot collaboration study, the first scientific symposium took place in December 2017 in Tokyo. Before the symposium, a working visit for EORTC investigators from the Early Career Investigator initiative (ECI), willing to develop projects within the JCOG-EORTC partnership, was held. In addition to the digest of the working visit and symposium, we aimed to describe the differences and similarities between the two groups and to identify key factors for collaboration from the perspective of the young investigators of the networks. These findings are described in this article. PMID- 30395276 TI - The First 30 Months Experience in the Non-Doctrinal Operation Inherent Resolve Medical Theater. AB - Introduction: U.S. military forces were redeployed in 2014 in support of Operation Inherent Resolve (OIR), operating in an austere theater without the benefit of an established medical system. We seek to describe the prehospital and hospital-based care delivered in this medically immature, non-doctrinal theater. Materials and Methods: We queried the Department of Defense Trauma Registry (DODTR) for all encounters associated with OIR from August 2014 through June 2017. We sought all available prehospital and hospital-based data. Results: There were a total of 826 adults that met inclusion; 816 were from Iraq and the remaining 10 were from Syria. The median age was 21 years and the most frequent mechanism of injury was explosives (47.7%). Median composite injury severity scores were low (9, IQR 2.75-14) and the most frequent seriously injured body region was the extremities (23.0%). Most subjects (94.9%) survived to hospital discharge. Open fractures were the most frequent major injury (26.0%). In the prehospital setting, opioids were the most frequently administered medication (9.3%) and warming blanket application (48.7%) and intravenous line placement (24.8%) were the most frequent interventions. In the emergency department, Focused Assessment with Sonography in Trauma exams (64.3%) was the most frequently performed study and endotracheal intubations were the most frequent (29.9%) procedure. In the operating room, the most frequently performed procedure was exploratory laparotomy (12.3%). Conclusions: Host nation military males injured by explosion comprised the majority of casualties. Open fracture was the most common major injury. Hence, future research should focus upon the unique challenges of delivering care to members of partner forces with particular focus upon interventions to optimize outcomes among patients sustaining open fractures. PMID- 30395277 TI - PlantPAN3.0: a new and updated resource for reconstructing transcriptional regulatory networks from ChIP-seq experiments in plants. AB - The Plant Promoter Analysis Navigator (PlantPAN; http://PlantPAN.itps.ncku.edu.tw/) is an effective resource for predicting regulatory elements and reconstructing transcriptional regulatory networks for plant genes. In this release (PlantPAN 3.0), 17 230 TFs were collected from 78 plant species. To explore regulatory landscapes, genomic locations of TFBSs have been captured from 662 public ChIP-seq samples using standard data processing. A total of 1 233 999 regulatory linkages were identified from 99 regulatory factors (TFs, histones and other DNA-binding proteins) and their target genes across seven species. Additionally, this new version added 2449 matrices extracted from ChIP-seq peaks for cis-regulatory element prediction. In addition to integrated ChIP-seq data, four major improvements were provided for more comprehensive information of TF binding events, including (i) 1107 experimentally verified TF matrices from the literature, (ii) gene regulation network comparison between two species, (iii) 3D structures of TFs and TF-DNA complexes and (iv) condition specific co-expression networks of TFs and their target genes extended to four species. The PlantPAN 3.0 can not only be efficiently used to investigate critical cis- and trans-regulatory elements in plant promoters, but also to reconstruct high-confidence relationships among TF-targets under specific conditions. PMID- 30395279 TI - Advanced Glycation End Products profiling uncovers abiotic stress specific target proteins in Arabidopsis. AB - Non-enzymatic post-translational modifications of proteins can occur when the nucleophilic amino acid side chains of lysine and arginine encounter a reactive metabolite to form advanced glycation end products (AGEs). Glycation arises predominantly from the degradation of reducing sugars, and glycation has been observed during metabolic stress from glucose metabolism in animals and plants alike. The implications of glycating proteins on plant proteins and biology has received little attention, and here we describe a robust assessment of global glycation profiles. We identified 112 glycated proteins that were common under a range of growth conditions and abiotic stress treatments, but also showed rosette age, diurnal and drought stress specific targets. 18 drought stress specific glycation targets included several thioredoxin and thioredoxin-like proteins. In vitro glycation of two carbohydrate metabolism enzymes either led to a reduction, or a complete inhibition of activity demonstrating the impact of glycation on protein function. Taken together our results suggest that stress specific glycation patterns of a small number of regulatory proteins, may have a much broader impact on downstream target proteins that are, for example, associated with primary metabolism. PMID- 30395278 TI - Demographics, Risk Factors, and Incidence of Melanoma in Patients in the New England VA Healthcare system. AB - Introduction: A recent study found that the incidence of melanoma and melanoma related mortality was decreasing in residents of the New England region. However, it is unknown whether this trend is conserved in Veterans of New England who constitute more than 14% of the national Veteran population. Given this, our goal was to analyze the incidence of melanoma in patients of Veteran Integrated Service Network-1 (VISN-1) (geographically consisting of VA health care facilities in Connecticut, Maine, Massachusetts, New Hampshire, Rhode Island, and Vermont) and to calculate an incidence rate ratio (IRR) of melanoma in VISN-1 compared to the general population. Additional goals were to ascertain the risk/susceptibility of this patient population with a view to improve quality of care and outcomes. Materials and Methods: Data for 523 cases of melanoma [2000 2011] were obtained from the regional branch of the Veterans Affairs Central Cancer Registry (VACCR) within the geographic area comprising VISN-1. A detailed retrospective chart review was conducted on these cases to gather demographic, risk factor, and clinical practice data. Demographic and incidence data from VISN 1 were compared to the general population via data from Surveillance, Epidemiology and End Results Program (SEER) from the same time period. Person years (PY) were calculated for both populations to measure IRRs which was further standardized for age and gender. Results: VISN-1 patients were predominantly older (94.26% >50 years), Caucasian (99.43%) males (96.75%). Compared to the general population, VISN-1 patients experienced more invasive lesions defined as stage T1 or greater (4.33% vs. 57.12%, p < 0.001), but reduced melanoma associated mortality (40.96% vs. 19.05%, p < 0.001) although all-cause mortality was approximately doubled (52.20% vs. 26.14%, p < 0.001). Metastatic disease rates were similar in both [approximately 4% in both]. IRR of melanoma in VISN-1 patients was 0.36 (95% CI: 0.20-0.67; p = 0.0063) which persisted in all age groups/genders. 60.92% of VISN-1 patients had recreational sun-exposure history and 72.41% of tobacco use. 95.02% of melanomas were located in continuously/intermittently sun-exposed areas, 93.28% were surgically-treated with a median treatment delay of 31 days [range 18-48]. Median lost to follow-up was 0 day [range 0-681 days]. Conclusions: Compared to the general population, melanoma incidence was lower in the VISN-1 cohort, possibly due to decreased UV index in the New England region, protective effects of past tobacco use, improved access to care through the VA and regional public health educational efforts. Yet melanomas were more often invasive in the VISN-1 cohort due to advanced age and male sex both of which are associated with more advanced disease at diagnosis. A strength of this study is the calculation of IRR using PY as this method enhances accuracy of incidence calculations. The data were limited by the fact that the population was from one geographic region and consisted mainly of elderly Caucasian males. Descriptive variable data such as sun-protective habits and risk factors from military service are limited by potential recall bias given the retrospective study design. Further study is necessary to replicate these results and to compare our data to Veteran populations from different geographic regions within the USA. PMID- 30395280 TI - RegulonDB v 10.5: tackling challenges to unify classic and high throughput knowledge of gene regulation in E. coli K-12. AB - RegulonDB, first published 20 years ago, is a comprehensive electronic resource about regulation of transcription initiation of Escherichia coli K-12 with decades of knowledge from classic molecular biology experiments, and recently also from high-throughput genomic methodologies. We curated the literature to keep RegulonDB up to date, and initiated curation of ChIP and gSELEX experiments. We estimate that current knowledge describes between 10% and 30% of the expected total number of transcription factor- gene regulatory interactions in E. coli. RegulonDB provides datasets for interactions for which there is no evidence that they affect expression, as well as expression datasets. We developed a proof of concept pipeline to merge binding and expression evidence to identify regulatory interactions. These datasets can be visualized in the RegulonDB JBrowse. We developed the Microbial Conditions Ontology with a controlled vocabulary for the minimal properties to reproduce an experiment, which contributes to integrate data from high throughput and classic literature. At a higher level of integration, we report Genetic Sensory-Response Units for 200 transcription factors, including their regulation at the metabolic level, and include summaries for 70 of them. Finally, we summarize our research with Natural language processing strategies to enhance our biocuration work. PMID- 30395281 TI - The Importance of Understanding the Medical Education System in Partner Nations. PMID- 30395282 TI - Enzyme cycling contributes to efficient induction of genome mutagenesis by the cytidine deaminase APOBEC3B. PMID- 30395283 TI - OrthoDB v10: sampling the diversity of animal, plant, fungal, protist, bacterial and viral genomes for evolutionary and functional annotations of orthologs. AB - OrthoDB (https://www.orthodb.org) provides evolutionary and functional annotations of orthologs. This update features a major scaling up of the resource coverage, sampling the genomic diversity of 1271 eukaryotes, 6013 prokaryotes and 6488 viruses. These include putative orthologs among 448 metazoan, 117 plant, 549 fungal, 148 protist, 5609 bacterial, and 404 archaeal genomes, picking up the best sequenced and annotated representatives for each species or operational taxonomic unit. OrthoDB relies on a concept of hierarchy of levels-of-orthology to enable more finely resolved gene orthologies for more closely related species. Since orthologs are the most likely candidates to retain functions of their ancestor gene, OrthoDB is aimed at narrowing down hypotheses about gene functions and enabling comparative evolutionary studies. Optional registered-user sessions allow on-line BUSCO assessments of gene set completeness and mapping of the uploaded data to OrthoDB to enable further interactive exploration of related annotations and generation of comparative charts. The accelerating expansion of genomics data continues to add valuable information, and OrthoDB strives to provide orthologs from the broadest coverage of species, as well as to extensively collate available functional annotations and to compute evolutionary annotations. The data can be browsed online, downloaded or assessed via REST API or SPARQL RDF compatible with both UniProt and Ensembl. PMID- 30395285 TI - In Reply: External Ventricular Drain and Hemorrhage in Aneurysmal Subarachnoid Hemorrhage Patients on Dual Antiplatelet Therapy: A Retrospective Cohort Study. PMID- 30395284 TI - Haemopedia RNA-seq: a database of gene expression during haematopoiesis in mice and humans. AB - During haematopoiesis, haematopoietic stem cells differentiate into restricted potential progenitors before maturing into the many lineages required for oxygen transport, wound healing and immune response. We have updated Haemopedia, a database of gene-expression profiles from a broad spectrum of haematopoietic cells, to include RNA-seq gene-expression data from both mice and humans. The Haemopedia RNA-seq data set covers a wide range of lineages and progenitors, with 57 mouse blood cell types (flow sorted populations from healthy mice) and 12 human blood cell types. This data set has been made accessible for exploration and analysis, to researchers and clinicians with limited bioinformatics experience, on our online portal Haemosphere: https://www.haemosphere.org. Haemosphere also includes nine other publicly available high-quality data sets relevant to haematopoiesis. We have added the ability to compare gene expression across data sets and species by curating data sets with shared lineage designations or to view expression gene vs gene, with all plots available for download by the user. PMID- 30395286 TI - Proposal for determining absolute biological effectiveness of boron neutron capture therapy-the effect of 10B(n,alpha)7Li dose can be predicted from the nucleocytoplasmic ratio or the cell size. AB - The relationship between the radiation dose delivered to a tumor and its effect is not completely predictable. Uncertainty in the estimation of the boron concentration in a tumor, variation in the radiation sensitivity of the tumor cells, and the complexity of the interactions between the four types of radiation comprising the boron neutron capture therapy (BNCT) dose contribute to this uncertainty. We reanalyzed the data of our previous papers to investigate the variation in radiosensitivity of tumor cells to the 10B(n,alpha)7Li dose: the dose generated by the reaction of thermal neutrons and 10B, hereafter the 'boron neutron dose'. The radiosensitivities of five tumors (EL4, SAS/neo, SAS/mp53, SCCVII and B16-BL6 melanoma) were examined. For the combination of p-boron-L phenylalanine (BPA: C9H12BNO4) with neutron irradiation, D0, the cell survival curve for the boron-neutron dose was the smallest for the SAS/neo, followed by the EL4, SAS/mp53, SCCVII and B16-BL6 melanoma, in that order. For the combination of mercaptoundecahydrododecaborate (BSH: Na2B12H11SH) with neutron irradiation, D0 was the smallest for the EL4, followed by the SAS/neo, B16 BL6melanoma, SAS/mp53 and SCCVII, in that order. The relationships between these D0 values and the nucleocytoplasmic ratios (Xncs) or cell size indices (Xcs) obtained by histopathological microslide image were as follows: (D0 = 0.1341Xnc 1.586, R2 = 0.9721) for all tumor types with BPA-BNCT, and D0 = 0.0122Xcs-0.1319 (R2 = 0.9795) for four tumor types (all except the B16-BL6 melanoma) with BSH BNCT. Based on these results, we proposed a new biologically equivalent effectiveness factor: the absolute biological effectiveness (ABE) factor. The ABE factor is Gy/D0. Thus, the ABE dose is the physical dose multiplied by the ABE factor, and refers to the dose needed to decrease the cell survival rate to e-ABE dose/Gy. PMID- 30395288 TI - RHOA activity in expanding blastocysts is essential to regulate HIPPO-YAP signaling and to maintain the trophectoderm-specific gene expression program in a ROCK/actin filament-independent manner. AB - STUDY QUESTION: What molecular signals are required to maintain the functional trophectoderm (TE) during blastocyst expansion of the late stage of preimplantation development? SUMMARY ANSWER: The activity of ras homology family member A (RHOA) GTPases is necessary to retain the expanded blastocyst cavity and also to sustain the gene expression program specific to TE. WHAT IS KNOWN ALREADY: At the early stages of preimplantation development, the precursor of the TE lineage is generated through the molecular signals that integrate RHOA, RHO associated coiled-coil containing protein kinase (ROCK), the apicobasal cell polarity, and the HIPPO-Yes-associated protein (YAP) signaling pathway. By contrast, molecular mechanisms regulating the maintenance of the TE characteristics at the later stage, which is crucial for blastocyst hatching and implantation, are scarcely understood. STUDY DESIGN SIZE, DURATION: Expanding mouse blastocysts, obtained from crosses of the F1 (C57BL6 * DBA/2) strain, were exposed to chemical agents that interfere with RHOA, ROCK, or the actin cytoskeleton for up to 8 hours, and effects on the blastocyst cavity, HIPPO-YAP signaling, and cell lineage-specific gene expression profiles were examined. PARTICIPANTS/MATERIALS, SETTING, METHODS: Mouse embryos at the embryonic stage E3.5 (expanding blastocysts) and E4.5 (fully expanded blastocysts) were treated with RHOA inhibitor (C3 exoenzyme), ROCK inhibitor (Y27632), or actin filament disruptors (cytochalasin B and latrunculin A). The integrity of the blastocyst cavity was evaluated based on the gross morphology. Effects on HIPPO-YAP signaling were assessed based on the presence of nuclearized YAP protein by immunofluorescence staining and the expression of YAP/ TEA domain family member (TEAD) target genes by quantitative RT-PCR (qRT-PCR). The impact of these disruptors on cell lineages was evaluated based on expression of the TE-specific and inner cell mass-specific marker genes by qRT-PCR. The integrity of the apicobasal cell polarity was assessed by localization of protein kinase C zeta (PRKCZ; apical) and scribbled planar cell polarity (SCRIB; basal) proteins by immunofluorescence staining. For comparisons, cultured cell lines, NIH/3T3 (mouse fibroblast) and P19C5 (mouse embryonal carcinoma), were also treated with RHOA inhibitor, ROCK inhibitor, and actin filament disruptors for up to 8 hours, and effects on HIPPO-YAP signaling were assessed based on expression of YAP/TEAD target genes by qRT-PCR. Each experiment was repeated using three independent batches of embryos (n = 40-80 per batch) or cell collections. Statistical analyses of data were performed, using one-way ANOVA and two-sample t-test. MAIN RESULTS AND THE ROLE OF CHANCE: Inhibition of RHOA deflated the cavity, diminished nuclear YAP (P < 0.01), and down-regulated the YAP/TEAD target and TE specific marker genes in both E3.5 and E4.5 blastocysts (P < 0.05), indicating that the maintenance of the key TE characteristics is dependent on RHOA activity. However, inhibition of ROCK or disruption of actin filament only deflated the blastocyst cavity, but did not alter HIPPO-YAP signaling or lineage-specific gene expressions, suggesting that the action of RHOA to sustain the TE-specific gene expression program is not mediated by ROCK or the actomyosin cytoskeleton. By contrast, ROCK inhibitor and actin filament disruptors diminished YAP/TEAD target gene expressions in cultured cells to a greater extent than RHOA inhibitor, implicating that the regulation of HIPPO-YAP signaling in expanding blastocysts is distinctly different from that in the cell lines. Furthermore, the apicobasal cell polarity proteins in the expanding blastocyst were mislocalized by ROCK inhibition but not by RHOA inhibition, indicating that cell polarity is not linked to regulation of HIPPO-YAP signaling. Taken together, our study suggests that RHOA activity is essential to maintain the TE lineage in the expanding blastocyst and it regulates HIPPO-YAP signaling and the lineage-specific gene expression program through mechanisms that are independent of ROCK or actomyosin cytoskeleton. LARGE-SCALE DATA: Not applicable. LIMITATIONS REASONS FOR CAUTION: This study was conducted using one species, the mouse. Direct translation of the experiments and findings to human fertility preservation and ART requires further investigations. WIDER IMPLICATIONS OF THE FINDINGS: +The elucidation of the mechanisms of TE formation is highly pertinent to fertility preservation in women. Our findings may raise awareness among providers of ART that the TE is sensitive to disturbance even in the late stage of blastocyst expansion and that rational approaches should be devised to avoid conditions that may impair the TE and its function. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by grants from the Ingeborg v.F. McKee Fund of the Hawaii Community Foundation (16ADVC-78882 to V.B.A.), and the National Institutes of Health, USA (P20 GM103457 and R03 HD088839 to V.B.A.). The authors have no conflict of interest to declare. PMID- 30395290 TI - Neutrophilic Ribonucleic Acid Expression as a Clinical Tool in Detecting Cerebral Aneurysms. PMID- 30395289 TI - The PRIDE database and related tools and resources in 2019: improving support for quantification data. AB - The PRoteomics IDEntifications (PRIDE) database (https://www.ebi.ac.uk/pride/) is the world's largest data repository of mass spectrometry-based proteomics data, and is one of the founding members of the global ProteomeXchange (PX) consortium. In this manuscript, we summarize the developments in PRIDE resources and related tools since the previous update manuscript was published in Nucleic Acids Research in 2016. In the last 3 years, public data sharing through PRIDE (as part of PX) has definitely become the norm in the field. In parallel, data re-use of public proteomics data has increased enormously, with multiple applications. We first describe the new architecture of PRIDE Archive, the archival component of PRIDE. PRIDE Archive and the related data submission framework have been further developed to support the increase in submitted data volumes and additional data types. A new scalable and fault tolerant storage backend, Application Programming Interface and web interface have been implemented, as a part of an ongoing process. Additionally, we emphasize the improved support for quantitative proteomics data through the mzTab format. At last, we outline key statistics on the current data contents and volume of downloads, and how PRIDE data are starting to be disseminated to added-value resources including Ensembl, UniProt and Expression Atlas. PMID- 30395291 TI - Life cycle assessment of alternative swine management practices. AB - Life cycle assessment of various alternative management strategies in the swine industry was performed to evaluate their impact on greenhouse gas (GHG) emissions, cumulative energy use, and cumulative water use. The management strategies included use of immunocastration (IC), production without ractopamine (NoRAC), production without antimicrobials used for either growth promotion (NoAGP) and disease prevention (NoPREV), production of entire males (boars) (EM), and use of gestation pens (PENS). A common baseline scenario representing standard management practices in the swine industry was created against which all alternative management practices were compared pairwise. The study scope was from cradle-to-farm gate with a functional unit of one-kilogram live weight at the farm gate. The baseline and each alternative management scenario was simulated in Pig Production Environmental Footprint Calculator (PPEC) model by varying key variables to populate life cycle inventory inputs for SimaPro V7.3 (Pre' Consultant, the Netherlands), an LCA modeling program. Increase in GHG emissions, energy use, and water use were observed for NoAGP (1.56, 1.75, and 1.03% respectively), NoPREV (17.32, 18.40, and 15.58% respectively), and NoRAC (6.52, 4.87, and 7.52% respectively) scenarios. For EM scenario GHG emissions and energy use increased by 2.09, and 3.75% respectively but water use decreased by 2.29%. Lower GHG emissions, energy use, and water use were observed for PENS (0.97, 1.50, and 0.97% respectively) and IC (2.39, 2.57, and 2.96% respectively) scenarios. Based on Monte Carlo Simulation these changes in impact could be reached with at least 75% confidence for lower water consumption for EM, decreased GHG emissions and water consumption for IC, increased energy consumption for NoAGP, and increased GHG emissions, energy and water consumption for NoRAC scenarios. The impact of management practices on sustainability metrics resulted from differences in pig performance parameters, manure production, feed consumption, etc. between various management practices and the baseline scenario. Due to uncertainties in input parameters, the results should be interpreted as general trends which specifically highlight trade-offs that may result from shifts in production practices. The study identified some of the hot spots in pig production and can be useful in determining best management practices to make swine production more environmentally sustainable. PMID- 30395287 TI - UniProt: a worldwide hub of protein knowledge. AB - The UniProt Knowledgebase is a collection of sequences and annotations for over 120 million proteins across all branches of life. Detailed annotations extracted from the literature by expert curators have been collected for over half a million of these proteins. These annotations are supplemented by annotations provided by rule based automated systems, and those imported from other resources. In this article we describe significant updates that we have made over the last 2 years to the resource. We have greatly expanded the number of Reference Proteomes that we provide and in particular we have focussed on improving the number of viral Reference Proteomes. The UniProt website has been augmented with new data visualizations for the subcellular localization of proteins as well as their structure and interactions. UniProt resources are available under a CC-BY (4.0) license via the web at https://www.uniprot.org/. PMID- 30395292 TI - Characterization of a Lipase From the Silkworm Intestinal Bacterium Bacillus pumilus With Antiviral Activity Against Bombyx mori (Lepidoptera: Bombycidae) Nucleopolyhedrovirus In Vitro. AB - To investigate whether Bombyx mori Linnaeus (Lepidoptera: Bombycidae) intestinal microorganism play a role in the host defence system against viral pathogens, a lipase gene from the silkworm intestinal bacterium Bacillus pumilus SW41 was characterized, and antiviral activity of its protein against B. mori nucleopolyhedrovirus (BmNPV) was tested. The lipase gene has an open-reading frame of 648 bp, which encodes a 215-amino-acid enzyme with a 34-amino-acid signal peptide. The recombinant lipase (without signal peptide) was expressed and purified by using an Escherichia coli BL21 (DE3) expression system. The total enzyme activity of this recombinant lipase reached 277.40 U/mg at the optimum temperature of 25 degrees C and optimum pH value of 8.0. The antiviral test showed that a relative high concentration of the recombinant lipase reduced BmNPV infectivity in vitro, which resulted in decreased viral DNA abundance and viral occlusion bodies. Besides, the preincubation method also suggested that the lipase probably directly acting on the budded virions. The results suggest that the lipase from intestinal bacterium B. pumilus SW41 is a potential antiviral factor for silkworm against BmNPV. PMID- 30395294 TI - The antiSMASH database version 2: a comprehensive resource on secondary metabolite biosynthetic gene clusters. AB - Natural products originating from microorganisms are frequently used in antimicrobial and anticancer drugs, pesticides, herbicides or fungicides. In the last years, the increasing availability of microbial genome data has made it possible to access the wealth of biosynthetic clusters responsible for the production of these compounds by genome mining. antiSMASH is one of the most popular tools in this field. The antiSMASH database provides pre-computed antiSMASH results for many publicly available microbial genomes and allows for advanced cross-genome searches. The current version 2 of the antiSMASH database contains annotations for 6200 full bacterial genomes and 18,576 bacterial draft genomes and is available at https://antismash-db.secondarymetabolites.org/. PMID- 30395293 TI - Database resources of the National Center for Biotechnology Information. AB - The National Center for Biotechnology Information (NCBI) provides a large suite of online resources for biological information and data, including the GenBank(r) nucleic acid sequence database and the PubMed database of citations and abstracts published in life science journals. The Entrez system provides search and retrieval operations for most of these data from 38 distinct databases. The E utilities serve as the programming interface for the Entrez system. Augmenting many of the web applications are custom implementations of the BLAST program optimized to search specialized data sets. New resources released in the past year include PubMed Labs and a new sequence database search. Resources that were updated in the past year include PubMed, PMC, Bookshelf, genome data viewer, Assembly, prokaryotic genomes, Genome, BioProject, dbSNP, dbVar, BLAST databases, igBLAST, iCn3D and PubChem. All of these resources can be accessed through the NCBI home page at www.ncbi.nlm.nih.gov. PMID- 30395295 TI - Seven years post-Fukushima: long-term measurement of exposure doses in Tomioka Town. PMID- 30395296 TI - CT thorax miliary pattern-our differential. PMID- 30395297 TI - Sodium valproate correcting hypernatremia of diabetes insipidus-a fortunate incident. PMID- 30395298 TI - Community health assets, frailty and recovery after an acute illness. PMID- 30395299 TI - The virtuous epidemiologist. AB - This article addresses the scholarly gap in the ethics of epidemiology by exploring what virtue ethics, one of the oldest ethical traditions in moral philosophy, has to say about 'the virtuous epidemiologist'. It expounds comparatively the content and merits of a virtue ethics approach against more popular contemporary schools of thought such as consequentialism and deontology. Without necessarily dismissing the value of principles and standards, it presents a vision that a virtuous epidemiologist should cultivate wisdom in making prudential judgments in conditions of uncertainty; fortitude in dealing with powerful politicians and administrators which does not sacrifice truth; temperance and self-restraint in keeping one's ideological views from compromising one's scientific credibility; and justice in giving due weight to individual rights and the public interest when doing research and giving advice on public health interventions. PMID- 30395300 TI - The associations of long-time mobile phone use with sleep disturbances and mental distress in technical college students: a prospective cohort study. AB - Study Objectives: To determine the longitudinal associations of long-time mobile phone use (LTMPU) with sleep disturbances and mental distress in a prospective cohort of technical college students. Methods: A total of 4,333 (response rate: 91.5%) and 3,396 (response rate: 78.4%) participants were recruited at baseline and eight-month follow-up, respectively. Data were collected by a set of questionnaires including socio-demographics, lifestyle practice, duration of mobile phone use per day, sleep patterns on weekdays and weekends, as well as Insomnia Severity Index, Epworth Sleepiness Scale, reduced Morningness Eveningness Questionnaire, Beck Depression Inventory, and Zung Self-Rating Anxiety Scale. LTMPU was defined as using mobile phone >= 4 hours/day. Results: At baseline, 23.5% (n = 1,020) of the participants reported using mobile phone >= 4 hours/day. LTMPU at baseline was positively associated with the new incidences (range, adjusted odds ratio 1.31-1.53) of a series of the sleep disturbances and mental distress at follow-up. The discontinuation of LTMPU was associated with an amelioration of the risks of most of these problems. Cross-lagged analyses revealed bidirectional associations of the duration of mobile phone use with poor sleep and mental health outcomes. Conclusions: LTMPU predicts the new incidences of most sleep disturbances and mental distress, while discontinuation of LTMPU is associated with amelioration of these problems. Moreover, there are bidirectional associations between the duration of mobile phone use and various sleep and mental outcomes. These findings highlight the critical role of prevention and early recognition of excessive mobile phone use and their accompanied mental and sleep problems. PMID- 30395301 TI - The relationship between disability and suicide: prospective evidence from the Ten to Men cohort. AB - Background: People with disabilities often face a range of social and economic adversities. Evidence suggests that these disadvantages result in poorer mental health. Some research also indicates that people with disabilities are more likely experience thoughts about suicide than people without disability, although most of this research is based on small cross-sectional samples. Methods: We explored the relationship between self-reported disability (measured at baseline) and likelihood of reporting thoughts of suicide (measured at follow up) using a large longitudinal cohort of Australian males. A logistic regression model was conducted with thoughts of suicide within the past 12 months (yes or no) as the outcome and disability as the exposure. The models adjusted for relevant confounders, including mental health using the SF-12 MCS, and excluded males who reported thoughts of suicide at baseline. Results: After adjustment, there was a 1.48 (95% CI: 0.98-2.23, P = 0.063) increase in the odds of thoughts of suicide among men who also reported a disability. The size of association was similar to that of being unemployed. Conclusions: Males reporting disability may also suffer from thoughts of suicide. We speculate that discrimination may be one explanation for the observed association. More research on this topic is needed. PMID- 30395302 TI - Dom34 mediates targeting of exogenous RNA in the antiviral OAS/RNase L pathway. AB - The 2'-5'-oligoadenylate synthetase (OAS)/RNase L pathway is an innate immune system that protects hosts against pathogenic viruses and bacteria through cleavage of exogenous single-stranded RNA; however, this system's selective targeting mechanism remains unclear. Here, we identified an mRNA quality control factor Dom34 as a novel restriction factor for a positive-sense single-stranded RNA virus. Downregulation of Dom34 and RNase L increases viral replication, as well as half-life of the viral RNA. Dom34 directly binds RNase L to form a surveillance complex to recognize and eliminate the exogenous RNA in a manner dependent on translation. Interestingly, the feature detected by the surveillance complex is not the specific sequence of the viral RNA but the 'exogenous nature' of the RNA. We propose the following model for the selective targeting of exogenous RNA; OAS3 activated by the exogenous RNA releases 2'-5'-oligoadenylates (2-5A), which in turn converts latent RNase L to an active dimer. This accelerates formation of the Dom34-RNase L surveillance complex, and its selective localization to the ribosome on the exogenous RNA, thereby promoting degradation of the RNA. Our findings reveal that the selective targeting of exogenous RNA in antiviral defense occurs via a mechanism similar to that in the degradation of aberrant transcripts in RNA quality control. PMID- 30395303 TI - Defining the Minimal Clinically Important Difference for Patients With Vestibular Schwannoma: Are all Quality-of-Life Scores Significant? AB - BACKGROUND: The diagnosis of vestibular schwannomas (VS) is associated with reduced patient quality of life (QOL). Minimal clinically important difference (MCID) was introduced as the lowest improvement in a patient-reported outcome (PRO) score discerned as significant by the patient. We formerly presented an MCID for the Penn Acoustic Neuroma QOL (PANQOL) battery based on cross-sectional data from 2 tertiary referral centers. OBJECTIVE: To validate the PANQOL MCID values using prospective data. METHODS: A prospective registry capturing QOL was queried, comprising patients treated at the authors' institution and Acoustic Neuroma Association members. Anchor- and distribution-based techniques were utilized to determine the MCID for domain and total scores. We only included anchors with Spearman's correlation coefficient larger than 0.3 in the MCID threshold calculations. Most domains had multiple anchors with which to estimate the MCID. RESULTS: A total of 1254 patients (mean age: 57.4 yr, 65% females) were analyzed. Anchor-based methods produced a span of MCID values (median, 25th-75th percentile) for each PANQOL domain and the total score: hearing (13.1, 13-16 points), balance (14, 14-19 points), pain (21, 20-28 points), face (25, 16-36 points), energy (16, 15-18 points), anxiety (16 [1 estimate]), general (13 [1 estimate]), and total (12.5, 10-15 points). CONCLUSION: Current findings corroborate our formerly shared experience using multi-institutional, cross sectional information. These MCID thresholds can serve as a pertinent outcome when deciphering the clinical magnitude of VS QOL endpoints in cross-sectional and longitudinal studies. PMID- 30395304 TI - Extent of Resection and Residual Tumor Thresholds for Postoperative Total Seizure Freedom in Epileptic Adult Patients Harboring a Supratentorial Diffuse Low-Grade Glioma. AB - BACKGROUND: Epileptic seizures impair quality of life in diffuse low-grade glioma (DLGG) patients. Tumor resection significantly impacts postoperative seizure control, but the precise extent of resection (EOR) required for optimal seizure control is not clear yet. OBJECTIVE: To identify the EOR and residual tumor volume that correlated to postoperative seizure control, defined as a total seizure freedom (Class 1A in reference to Engel classification system) with and without antiepileptic drugs in patients undergoing surgical resection of supratentorial DLGG. METHODS: A retrospective review was conducted of all patients who underwent first-line surgical resection of supratentorial DLGG who presented with preoperative seizures without adjuvant oncological treatment. EOR and residual tumor volume were quantified from pre- and post-operative magnetic resonance imagings. Receiver operating characteristic curves were plotted to determine the EOR and residual tumor volume that corresponded to optimal postoperative seizure control. RESULTS: Of the 346 included patients, 65.5% had controlled seizures postoperatively, with higher age at resection (adjusted OR per unit, 1.03 [95% confidence interval:1.01-1.06], P = .043) and higher percentage of resection (adjusted OR per unit, 1.02 [95% confidence interval:1.00 1.03], P < .001) found as independent predictors of postoperative seizure control. Optimal EOR was >=91% and optimal residual tumor volume was <=19 cc to improve postoperative seizure control. CONCLUSION: Postoperative seizure control is more likely when EOR is >=91% and/or when residual tumor volume is <=19 cc in supratentorial DLGG gliomas who present with seizures. Resected peritumoral cortex should, however, be taken into account in future studies. PMID- 30395305 TI - Negative Life Events (NLEs) Contributing to Psychological Distress, Pain, and Disability in a U.S. Military Sample. AB - Introduction: The objective was to explore how negative life events (NLEs, e.g., litigation related to pain and disability, failing most recent physical fitness test, and financial difficulties) are related to pain coping and psychological adjustment to pain in active duty military personnel. Materials and Methods: Data were gathered as part of the Evaluation of Suicidality, Cognitions, and Pain Experience study, a DoD-funded cross-sectional assessment of chronic pain and emotional coping among a cohort of military members. The investigators examined data from 147 respondents with complete survey and pain assessment data. Results: The sample was active duty, male (62.6%), in a relationship or married (83.0%), and had children (68.7%). The majority of the sample endorsed zero NLEs (72.0%); 23.8% endorsed one NLE, 4.2% endorsed two NLEs, and no one endorsed all three NLEs. A significantly higher proportion of participants endorsing one or more NLEs reported suicidal ideation compared to those who reported no NLEs (chi2(2) = 8.61, p = 0.014). A higher number of endorsed NLEs coincided with higher symptom severity related to psychosocial distress (depression, thwarted belongingness, perceived burdensomeness, PTSD, and suicide cognitions) and poor pain coping (rumination, helplessness, and less acceptance of chronic pain). Conclusions: Findings revealed that NLEs may impart a significant burden on military pain sufferers. Greater numbers of endorsed NLEs are associated with increased psychosocial distress and poor pain coping. Future longitudinal studies examining long-term psychosocial distress/poor pain coping as related to NLEs would help to elaborate the long-term consequences of NLEs on pain coping and psychosocial distress. PMID- 30395306 TI - Emotion regulation therapy for cancer caregivers-an open trial of a mechanism targeted approach to addressing caregiver distress. AB - Informal caregivers (ICs) are integral to care provided to patients facing life threatening or incurable illnesses. This responsibility causes considerable burden, as approximately one half of ICs report clinically significant symptoms of depression and/or anxiety that persist when left untreated. Psychosocial interventions containing efficacious treatment principles (e.g., cognitive behavior therapy [CBT]) show disappointing results in reducing anxiety and depression in ICs. This may reflect failure of these interventions to specifically target crucial mechanisms underlying the central feature of distress caused by the patient's illness-notably, perseverative negative thinking (PNT). Emotion Regulation Therapy (ERT) is an efficacious CBT developed to explicitly target mechanisms underlying PNT and the emotional concomitants that arise in response to stressful situations. This open trial was conducted to evaluate the acceptability and initial efficacy of ERT adapted to the experience of cancer ICs (ERT-C). Thirty-one ICs provided informed consent and completed eight weekly individual sessions of ERT-C. Participants completed self-report measures of depression and anxiety symptoms, PNT, emotion regulation deficits, and caregiver burden before and after treatment. ERT-C was well tolerated as indicated by 22 treatment completers and feedback provided in exit interviews. ICs demonstrated reduced depression and anxiety symptoms, PNT, and emotion regulation deficits with moderate to large effect sizes (Hedge's g range: 0.36-0.92). Notably, caregiver burden was not reduced but ICs expressed more ability to confront caregiving-related challenges. Findings offer promising but preliminary support for ERT-C as a conceptual model and treatment modality for distressed cancer ICs. PMID- 30395307 TI - BloodSpot: a database of healthy and malignant haematopoiesis updated with purified and single cell mRNA sequencing profiles. AB - BloodSpot is a gene-centric database of mRNA expression of haematopoietic cells. The web-based interface to the database includes three concomitant levels of visualization for a gene query; foremost is the expression across hematopoietic cell types, second is analysis of survival of Acute Myeloid Leukaemia patients based on gene expression, and lastly, the expression visualized in an interactive developmental tree. With the introduction of single cell data we have now also included an unbiased dimensionality reduction method to show gene expression over the continuum of haematopoiesis. The webserver includes a few select analysis functionalities, like Student's t-test, identification of correlating genes and lookup of whole genetic signatures, with the aim of making generation and testing of hypotheses quick and intuitive. The visualizations have been updated to accommodate new datatypes and the database has been largely expanded with RNA sequencing datasets, both purified in bulk and at single cell resolution, increasing the number of single samples more than 10 fold, while keeping simplicity in presentation. The database should be of interest for any researcher within leukaemia, haematopoiesis, cellular development, or stem cells. The database is freely available at www.bloodspot.eu. PMID- 30395308 TI - Pif1 is essential for efficient replisome progression through lagging strand G quadruplex DNA secondary structures. AB - Pif1 DNA helicase is a potent unwinder of G-quadruplex (G4) structures in vitro and functions to maintain genome stability at G4 sequences in Saccharomyces cerevisiae. Here, we developed and utilized a live-cell imaging approach to quantitatively measure the progression rates of single replication forks through different G4 containing sequences in individual yeast cells. We show that in the absence of Pif1, replication rates through specific lagging strand G4 sequences in vivo is significantly decreased. In contrast, we found that in the absence of Pif1, replication rates through the same G4s on the leading strand are not decreased relative to the respective WT strains, showing that Pif1 is essential only for efficient replication through lagging strand G4s. Additionally, we show that a canonical PIP sequence in Pif1 interacts with PCNA and that replication through G4 structures is significantly slower in the absence of this interaction in vitro and in vivo. Thus, Pif1-PCNA interaction is essential for optimal replisome progression through G4 sequences, highlighting the importance of coupling between Pif1 activity and replisome progression during yeast genome replication. PMID- 30395309 TI - In Reply: Symptomatic Adjacent Level Disease Requiring Surgery: Analysis of 10 Year Results From a Prospective, Randomized, Clinical Trial Comparing Cervical Disc Arthroplasty to Anterior Cervical Fusion. PMID- 30395310 TI - Vesiclepedia 2019: a compendium of RNA, proteins, lipids and metabolites in extracellular vesicles. AB - Extracellular vesicles (EVs) are membranous vesicles that are released by both prokaryotic and eukaryotic cells into the extracellular microenvironment. EVs can be categorised as exosomes, ectosomes or shedding microvesicles and apoptotic bodies based on the mode of biogenesis. EVs contain biologically active cargo of nucleic acids, proteins, lipids and metabolites that can be altered based on the precise state of the cell. Vesiclepedia (http://www.microvesicles.org) is a web based compendium of RNA, proteins, lipids and metabolites that are identified in EVs from both published and unpublished studies. Currently, Vesiclepedia contains data obtained from 1254 EV studies, 38 146 RNA entries, 349 988 protein entries and 639 lipid/metabolite entries. Vesiclepedia is publicly available and allows users to query and download EV cargo based on different search criteria. The mode of EV isolation and characterization, the biophysical and molecular properties and EV-METRIC are listed in the database aiding biomedical scientists in assessing the quality of the EV preparation and the corresponding data obtained. In addition, FunRich-based Vesiclepedia plugin is incorporated aiding users in data analysis. PMID- 30395311 TI - Derivation and validation of a prognostic model to predict mortality in patients with advanced chronic kidney disease. AB - Background: Guiding patients with advanced chronic kidney disease (CKD) through advance care planning about future treatment obliges an assessment of prognosis. A patient-specific integrated model to predict mortality could inform shared decision-making for patients with CKD. Methods: Patients with Stages 4 and 5 CKD from Massachusetts (749) and West Virginia (437) were prospectively evaluated for clinical parameters, functional status [Karnofsky Performance Score (KPS)] and their provider's response to the Surprise Question (SQ). A predictive model for 12-month mortality was derived with the Massachusetts cohort and then validated externally on the West Virginia cohort. Logistic regression was used to create the model, and the c-statistic and Hosmer-Lemeshow statistic were used to assess model discrimination and calibration, respectively. Results: In the derivation cohort, the SQ, KPS and age were most predictive of 12-month mortality with odds ratios (ORs) [95% confidence interval (CI)] of 3.29 (1.87-5.78) for a 'No' response to the SQ, 2.09 (95% CI 1.19-3.66) for fair KPS and 1.41 (95% CI 1.15 1.74) per 10-year increase in age. The c-statistic for the 12-month mortality model for the derivation cohort was 0.80 (95% CI 0.75-0.84) and for the validation cohort was 0.74 (95% CI 0.66-0.83). Conclusions: Our integrated prognostic model for 12-month mortality in patients with advanced CKD had good discrimination and calibration. This model provides prognostic information to aid nephrologists in identifying and counseling advanced CKD patients with poor prognosis who are facing the decision to initiate dialysis or pursue medical management without dialysis. PMID- 30395312 TI - Commentary: Ernest Codman and the Impact of Quality Improvement in Neurosurgery: A Century Since the Idea of the "End Result". PMID- 30395313 TI - Structure, subunit organization and behavior of the asymmetric Type IIT restriction endonuclease BbvCI. AB - BbvCI, a Type IIT restriction endonuclease, recognizes and cleaves the seven base pair sequence 5'-CCTCAGC-3', generating 3-base, 5'-overhangs. BbvCI is composed of two protein subunits, each containing one catalytic site. Either site can be inactivated by mutation resulting in enzyme variants that nick DNA in a strand specific manner. Here we demonstrate that the holoenzyme is labile, with the R1 subunit dissociating at low pH. Crystallization of the R2 subunit under such conditions revealed an elongated dimer with the two catalytic sites located on opposite sides. Subsequent crystallization at physiological pH revealed a tetramer comprising two copies of each subunit, with a pair of deep clefts each containing two catalytic sites appropriately positioned and oriented for DNA cleavage. This domain organization was further validated with single-chain protein constructs in which the two enzyme subunits were tethered via peptide linkers of variable length. We were unable to crystallize a DNA-bound complex; however, structural similarity to previously crystallized restriction endonucleases facilitated creation of an energy-minimized model bound to DNA, and identification of candidate residues responsible for target recognition. Mutation of residues predicted to recognize the central C:G base pair resulted in an altered enzyme that recognizes and cleaves CCTNAGC (N = any base). PMID- 30395314 TI - Effects of transcranial direct current stimulation on episodic memory in amnestic mild cognitive impairment: A pilot study. AB - Objectives: Episodic memory is impaired in amnestic mild cognitive impairment (aMCI), which is posited as a potential prodromal form of Alzheimer's disease. Reactivated existing memories become sensitive to modification during reconsolidation. There is evidence that the lateral prefrontal cortex (PFC) plays causal role in episodic memory reconsolidation. Transcranial direct current stimulation (tDCS) applied to the PFC after a contextual reminder enhanced episodic memory performance up to one month, conceivably through reconsolidation, in older adults with subjective memory complaints, a condition that may represent a "pre-MCI" stage. The aim of this pilot study was to test the effect of PFC-tDCS (anode over left lateral PFC, cathode over right supraorbital area) after a contextual reminder on episodic memory in older adults with aMCI. Method: Older adults with aMCI learned a list of words. 24 hours later, tDCS (active or sham) was applied after a contextual reminder. Memory retrieval (free recall and recognition) was tested 48 hours and one month after the learning session. Results: Active tDCS enhanced recognition memory relative to sham stimulation. Discussion: Modulating reconsolidation with PFC-tDCS might be a novel intervention to enhance episodic memories in aMCI. PMID- 30395316 TI - Short sleep duration is associated with inadequate hydration: Cross-cultural evidence from US and Chinese adults. AB - Study Objectives: Short and long sleep duration are linked to reduced kidney function, but little research has examined how sleep is associated with hydration status. Our aim was to assess the relationship between sleep duration and urinary hydration biomarkers among adults in a cross-cultural context. Methods: Three samples of adults aged 20y were analyzed: 2007-2008 National Health and Nutrition Examination Survey (NHANES; n=4,680), 2009-2012 NHANES (n=9,559), and 2012 cross sectional wave of the Chinese Kailuan Study (n=11,903), excluding pregnant women and adults with failing kidneys. We estimated multiple linear regression models between self-reported usual night-time sleep duration (<6, 6, 7, 8 (reference), 9 hrs/day) and urine specific gravity (Usg) and urine osmolality (Uosm) as continuous variables and logistic regression models dichotomized as inadequate hydration (>1.020 g/ml; >831 mOsm/kg). In primary analyses, we estimated models excluding diabetes and diuretic medications for healthier sub-populations (NHANES n=11,353; Kailuan n=8,766). Results: In the healthier NHANES subset, 6 hours was associated with significantly higher Usg and odds of inadequate hydration (adjusted OR: 1.59, 95% CI: 1.25, 2.03) compared to 8 hours. Regression results were mixed using Uosm, but in the same direction as Usg. Among Chinese adults, short sleep duration (<6 and 6 hours) was associated with Usg and higher likelihood of inadequate hydration (6 hours adjusted OR: 1.42, 95% CI: 1.26, 1.60). No consistent association was found with sleeping >=9 hours. Conclusions: Short sleep duration was associated with higher odds of inadequate hydration in US and Chinese adults relative to sleeping 8 hours. PMID- 30395317 TI - An autoregulatory loop controlling orphan nuclear receptor DAX-1 gene expression by orphan nuclear receptor ERRgamma. PMID- 30395315 TI - Cultural influences on the processing of social comparison feedback signals-an ERP study. AB - This study investigated cultural differences regarding social connectedness in association with social vs non-social comparison feedback. We performed electroencephalography in 54 Chinese and 49 Western adults while they performed a time estimation task in which response-accuracy feedback was either delivered pertaining to participants' own performance (non-social reference frame) or to the performance of a reference group (social reference frame). Trait interdependence and independence were assessed using a cultural orientations questionnaire. Applying a principal component approach, we observed divergent effects for the two cultural groups during feedback processing. In particular, Feedback-Related Negativity results indicated that non-social (vs social) reference feedback was more salient/motivating for Chinese participants, while Westerners showed the opposite pattern. The results suggest that Chinese individuals perceive a non-social context as more salient than a social comparison context, possibly due to their extensive experience of social comparisons in daily life. The reverse pattern was found in Western participants, for whom a social comparison context is less common and presumably more salient. The cultural differences in neural responses to social vs non-social feedback might be caused by culturally diverse cognitive traits, as well as by exposure to culturally defined behaviour on a systemic level-such as the education system. PMID- 30395318 TI - Fundoscopy & Malignant Hypertension. PMID- 30395319 TI - Response to Makino: 'Hereditary spherocytosis presenting with branch retinal artery occlusion'. PMID- 30395320 TI - Letter: Symptomatic Adjacent Level Disease Requiring Surgery: Analysis of 10-Year Results From a Prospective, Randomized, Clinical Trial Comparing Cervical Disc Arthroplasty to Anterior Cervical Fusion. PMID- 30395321 TI - Sex-dependent effects of 2,2',3,5',6-pentachlorobiphenyl (PCB 95) on dendritic arborization of primary mouse neurons. AB - Early life exposures to environmental contaminants are implicated in the pathogenesis of many neurodevelopmental disorders (NDDs). These disorders often display sex biases, but whether environmental neurotoxicants act in a sex dependent manner to modify neurodevelopment is largely unknown. Since altered dendritic morphology is associated with many NDDs, we tested the hypothesis that male and female primary mouse neurons are differentially susceptible to the dendrite promoting activity of 2,2',3,5',6-pentachlorobiphenyl (PCB 95). Hippocampal and cortical neuron-glia co-cultures were exposed to vehicle (0.1% DMSO) or PCB 95 (100 fM - 1 MUM) from day in vitro 7-9. As determined by Sholl analysis, PCB 95 enhanced dendritic growth in female but not male hippocampal and cortical neurons. In contrast, both male and female neurons responded to bicuculline with increased dendritic complexity. Detailed morphometric analyses confirmed that PCB 95 effects on the number and length of primary and non-primary dendrites varied depending on sex, brain region and PCB concentration, and that female neurons responded more consistently with increased dendritic growth and at lower concentrations of PCB 95 than their male counterparts. Exposure to PCB 95 did not alter cell viability or the ratio of neurons to glia in cultures of either sex. These results demonstrate that cultured female mouse hippocampal and cortical neurons are more sensitive than male neurons to the dendrite promoting activity of PCB 95, and suggest that mechanisms underlying PCB 95-induced dendritic growth are sex-dependent. These data highlight the importance of sex in neuronal responses to environmental neurotoxicants. PMID- 30395322 TI - On the regulatory evolution of new genes throughout their life history. AB - Every gene has a birthplace and an age, i.e., a cis-regulatory environment and an evolution lifespan since its origination, yet how the two shape the evolution trajectories of genes remains unclear. Here we address this basic question by comparing phylogenetically dated new genes in the context of both their ages and origination mechanisms. In both Drosophila and vertebrates, we confirm a clear 'out of the testis' transition from the specifically expressed young genes to the broadly expressed old housekeeping genes, observed only in testis but not in other tissues. Many new genes have gained important functions during embryogenesis, manifested as either specific activation at maternal-zygotic transition, or different spatiotemporal expressions from their parental genes. These expression patterns are largely driven by an age-dependent evolution of cis regulatory environment. We discover that retrogenes are more frequently born in a pre-existing repressive regulatory domain, and are more diverged in their enhancer repertoire than the DNA-based gene duplications. During evolution, new gene duplications gradually gain active histone modifications and undergo more enhancer turnovers when becoming older, but exhibit complex trends of gaining or losing repressive histone modifications in Drosophila or vertebrates respectively. Interestingly, vertebrate new genes exhibit an 'into the testis' epigenetic transition that older genes become more likely to be co-occupied by both active and repressive ('bivalent') histone modifications specifically in testis. Our results uncover the regulatory mechanisms underpinning the stepwise acquisition of novel and complex functions by new genes, and illuminate the general evolution trajectory of genes throughout their life history. PMID- 30395323 TI - Plasmid ATLAS: plasmid visual analytics and identification in high-throughput sequencing data. AB - Plasmid ATLAS (pATLAS, http://www.patlas.site) provides an easy-to-use web accessible database with visual analytics tools to explore the relationships of plasmids available in NCBI's RefSeq database. pATLAS has two main goals: (i) to provide an easy way to search for plasmids deposited in NCBI RefSeq and their associated metadata; (ii) to visualize the relationships of plasmids in a graph, allowing the exploration of plasmid evolution. pATLAS allows searching by plasmid name, bacterial host taxa, antibiotic resistance and virulence genes, plasmid families, and by sequence length and similarity. pATLAS is also able to represent in the plasmid network, plasmid sets identified by external pipelines using mapping, mash screen or assembly from high-throughput sequencing data. By representing the identified hits within the network of relationships between plasmids, allowing the possibility of removing redundant results, and by taking advantage of the browsing capabilities of pATLAS, users can more easily interpret the pipelines' results. All these analyses can be saved to a JSON file for sharing and future re-evaluation. Furthermore, by offering a REST-API, the pATLAS database and network display are easily accessible by other interfaces or pipelines. PMID- 30395324 TI - Letter: Deep Brain Stimulation of the Pedunculopontine Nucleus Area in Parkinson Disease: Magnetic Resonance Imaging-Based Anatomoclinical Correlations and Optimal Target. PMID- 30395325 TI - Depression, Loneliness, and Suicide Risk among Latino College Students: A Test of a Psychosocial Interaction Model. AB - This study tested a psychosocial model of suicide risk in a sample of 156 Latino college students. Specifically, depression and loneliness were hypothesized to be important predictors of suicide risk (namely, hopelessness and suicidal behaviors) in Latino students. Results of conducting regression analyses indicated that, independent of age and gender, depression and loneliness were significant predictors of both indices of suicide risk examined in the present study. It is noteworthy that within the psychosocial predictor set of depression and loneliness, depression was consistently found to be nearly twice as strong a predictor than was loneliness. Moreover, we found evidence for a significant depression-loneliness interaction effect in predicting suicide risk. That is, the highest level of suicide risk was found among dysphoric Latino students who were also socially isolated. Our findings indicate that depression and loneliness are important factors to consider in understanding suicide risk among Latino college students. PMID- 30395326 TI - Loose ends: almost one in five human genes still have unresolved coding status. PMID- 30395327 TI - Dynamic protein-RNA interactions in mediating splicing catalysis. AB - The spliceosome is assembled via sequential interactions of pre-mRNA with five small nuclear RNAs and many proteins. Recent determination of cryo-EM structures for several spliceosomal complexes has provided deep insights into interactions between spliceosomal components and structural changes of the spliceosome between steps, but information on how the proteins interact with pre-mRNA to mediate the reaction is scarce. By systematic analysis of proteins interacting with the splice sites (SSs), we have identified many previously unknown interactions of spliceosomal components with the pre-mRNA. Prp8 directly binds over the 5'SS and the branch site (BS) for the first catalytic step, and the 5'SS and 3'SS for the second step. Switching the Prp8 interaction from the BS to the 3'SS requires Slu7, which interacts dynamically with pre-mRNA first, and then interacts stably with the 3'-exon after Prp16-mediated spliceosome remodeling. Our results suggest that Prp8 plays a key role in positioning the 5'SS and 3'SS, facilitated by Slu7 through interactions with Prp8 and substrate RNA to advance exon ligation. We also provide evidence that Prp16 first docks on the intron 3' tail, then translocates in the 3' to 5' direction on remodeling the spliceosome. PMID- 30395328 TI - Are TADs supercoiled? AB - Topologically associating domains (TADs) are megabase-sized building blocks of interphase chromosomes in higher eukaryotes. TADs are chromosomal regions with increased frequency of internal interactions. On average a pair of loci separated by a given genomic distance contact each other 2-3 times more frequently when they are in the same TAD as compared to a pair of loci located in two neighbouring TADs. TADs are also functional blocks of chromosomes as enhancers and their cognate promoters are normally located in the same TAD, even if their genomic distance from each other can be as large as a megabase. The internal structure of TADs, causing their increased frequency of internal interactions, is not established yet. We survey here experimental studies investigating presence of supercoiling in interphase chromosomes. We also review numerical simulation studies testing whether transcription-induced supercoiling of chromatin fibres can explain how TADs are formed and how they can assure very efficient interactions between enhancers and their cognate promoters located in the same TAD. PMID- 30395329 TI - Impact of a Residency-Integrated Wellness Program on Resident Mental Health, Sleepiness, and Quality of Life. PMID- 30395330 TI - Jaundice in a Service member Returning From Taiwan; Diagnostic Challenges in a Case of Acute Hepatitis E. AB - When the evaluation of newly elevated liver enzymes is unrevealing, a common diagnosis of exclusion is drug-induced liver injury. A 39-year-old active duty service member who presented with jaundice after returning from a mission in Thailand was found to have an acute hepatitis and developing acute liver failure. He was ultimately diagnosed with acute hepatitis E, but his diagnosis was initially confounded by multiple exposures to supplements known to cause drug induced liver injury. This case illustrates the importance of broadened serologic testing in patients with acute liver injury returning from countries endemic with hepatitis E and also highlights the challenges in diagnosis of acute hepatitis E with currently available testing. PMID- 30395331 TI - The Gene Ontology Resource: 20 years and still GOing strong. AB - The Gene Ontology resource (GO; http://geneontology.org) provides structured, computable knowledge regarding the functions of genes and gene products. Founded in 1998, GO has become widely adopted in the life sciences, and its contents are under continual improvement, both in quantity and in quality. Here, we report the major developments of the GO resource during the past two years. Each monthly release of the GO resource is now packaged and given a unique identifier (DOI), enabling GO-based analyses on a specific release to be reproduced in the future. The molecular function ontology has been refactored to better represent the overall activities of gene products, with a focus on transcription regulator activities. Quality assurance efforts have been ramped up to address potentially out-of-date or inaccurate annotations. New evidence codes for high-throughput experiments now enable users to filter out annotations obtained from these sources. GO-CAM, a new framework for representing gene function that is more expressive than standard GO annotations, has been released, and users can now explore the growing repository of these models. We also provide the 'GO ribbon' widget for visualizing GO annotations to a gene; the widget can be easily embedded in any web page. PMID- 30395332 TI - Phylogenomic Signatures of Ancient Introgression in a Rogue Lineage of Darters (Teleostei: Percidae). AB - Evolutionary history is typically portrayed as a branching phylogenetic tree, yet not all evolution proceeds in a purely bifurcating manner. Introgressive hybridization is one process that results in reticulate evolution. Most known examples of genome-wide introgression occur among closely related species with relatively recent common ancestry; however, we present evidence for ancient hybridization and genome-wide introgression between major stem lineages of darters, a species-rich clade of North American freshwater fishes. Previous attempts to resolve the relationships of darters have been confounded by the uncertain phylogenetic resolution of the lineage Allohistium. In this study we investigate the phylogenomics of darters, specifically the relationships of Allohistium, through analyses of ~30,000 RADseq loci sampled from 112 species. Our phylogenetic inferences are based on traditional approaches in combination with strategies that accommodate reticulate evolution. These analyses result in a novel phylogenetic hypothesis for darters that includes ancient introgression involving Allohistium and other two major darter lineages, minimally occurring 20 million years ago. Darters offer a compelling case for the necessity of incorporating phylogenetic networks in reconstructing the evolutionary history of diversification in species-rich lineages. We anticipate that the growing wealth of genomic data for clades of non-model organisms will reveal more examples of ancient hybridization, eventually requiring a re-evaluation of how evolutionary history is visualized and utilized in macroevolutonary investigations. PMID- 30395333 TI - The Importance of Keeping Your Brain's Pipes Clean: The role of Meningeal Lymphatics in Ageing and Alzheimer's Disease. PMID- 30395335 TI - Evidence for increased surveillance of executive functioning in adolescent and young adult survivors of childhood cancer. AB - Comprehensive long-term follow-up (LTFU) for survivors of childhood cancer is critical for reducing morbidity and mortality. Current standards recommend screening all survivors for psychological and academic problems and certain survivors for neurocognitive problems based upon treatment exposures. This study aimed to determine if differences exist in executive functioning (EF) based on treatment exposures and characterize relationships between EF, treatment exposure, and internalizing problems. Participants included adolescent and young adult (AYA) survivors (N = 70) of non-central nervous system cancer, aged 14-21 presenting for LTFU. Patient-reported data were obtained on survivors' EF, internalizing symptoms, academic performance, and educational supports. Children's Oncology Group's LTFU Guidelines classified survivors as at risk or not at risk for neurocognitive deficits based on treatment exposures. Group differences, relationships, and moderation by risk group were examined. No differences were found in EF, internalizing symptoms, academic performance, or educational supports between survivors who were at risk versus those not at risk for neurocognitive deficits. Problems with EF predicted internalizing symptoms, an effect that was moderated by risk group (R2= .64 for AYA self-report; R2 = .38 for parent-proxy report). Survivors with poorer EF experienced higher levels of internalizing symptoms. These data indicate that current screening practices may not identify survivors who are not at risk for neurocognitive deficits, yet struggle with EF. Survivor care providers should consider universal screening for EF problems in AYAs, regardless of treatment exposure history. Clinical assessment of internalizing problems in survivors with EF problems is also recommended. PMID- 30395334 TI - Contextual valence modulates the effect of choice on incentive processing. AB - Previous research has demonstrated that reward-related neural activity is enhanced for choice relative to no-choice opportunities in the gain context. The current event-related potential study examined whether this modulatory effect of choice can be observed in both the gain and the loss contexts across anticipatory and consummatory phases of incentive processing. Thirty-two participants performed a simple choice task during which choices were made either by themselves (a choice condition) or by a computer (a no-choice condition) during a gain context (gain vs nongain) and a loss context (nonloss vs loss). Behaviorally, participants reported a higher level of perceived control in the choice than the no-choice condition as well as in the gain than loss context. During the anticipatory phase, the choice relative to the no-choice condition elicited an increased cue-P3 in the loss context and an enhanced stimulus preceding negativity in the gain context. During the consummatory phase, the choice condition elicited a larger reward positivity (DeltaRewP) than the no choice condition in the gain relative to the loss context but a comparable feedback P3 across contexts. These findings demonstrate that the crucial role of voluntary choice in reward processing is contingent upon contextual valence. PMID- 30395336 TI - Hot Topic: Title IV-E MSW Education and "Intent to Stay" in Public Child Welfare. AB - The 2018 proposed Family First Prevention Services Act suggests a change in the funding formula of Title IV-E of the Social Security Act-from entitlement to block grants. This study aimed to support the continuation of entitlement support based on the evidence that Title IV-E educational programs are effective in improving retention after the workers have obtained an MSW degree. Using a multigroup, multiple regression approach, this study analyzed secondary data collected from an e-survey sent to public child welfare (PCW) workers in a southern state. Data from 1,025 workers compare "intent to stay" (ITS) factors between PCW workers who received and those who did not receive the Title IV-E MSW educational stipend. The main analysis was conducted using Mplus version 7.4, with R version 3.3.2 used for data screening. Findings indicate that Title IV-E supported education moderates the strength of the following ITS factors: respect from coworkers, team cohesion, self-assessed skills in working with special needs clients, and holding an MSW degree. MSW holders expressed lower ITS levels unless they had received Title IV-E stipends. These results provide evidence that Title IV-E education could help retain MSW graduates in PCW. PMID- 30395338 TI - Delta-24-RGD Adenoviral Therapy Directs Oncolytic and Immune-Mediated Anti-Tumor Effects in Recurrent Malignant Glioma Patients. PMID- 30395337 TI - Effects of acute deltamethrin exposure in adult and developing Sprague-Dawley rats on acoustic startle response in relation to deltamethrin brain and plasma concentrations. AB - Deltamethrin is a commonly used pesticide that helps control crop destruction, disease, and nuisance insects. In rodents deltamethrin can produce choreoathetosis, salivation, and decreased acoustic startle responses (ASR). Herein, adult Sprague-Dawley rats were assessed for ASR 2 h after deltamethrin delivered in 5 mL/kg corn oil, however no decrease was observed. Therefore, a test-retest protocol was used to reduce variability, and the effects on ASR on postnatal day 15 (P15) and adult rats were assessed 2, 4, 6, and 8 h after deltamethrin administration (0, 1, 2, or 4 mg/kg for P15 rats and 0, 2, 8, or 25 mg/kg for adults). In a separate set of rats identically treated, deltamethrin levels were determined in blood and brain. Deltamethrin (8 or 25 mg/kg) in adult rats decreased ASR up to 4 h, whereas in P15 rats decreases were observed between 2-8 h. The adult 25 mg/kg group showed consistent signs of salivation and tremor, whereas in P15 rats salivation was observed in the 2 and 4 mg/kg groups and tremor was observed at all doses over the 8 h period. Mortality was observed in all P15 dose groups but not in adults. Dose-dependent increases of deltamethrin in blood and brain regardless of age were observed. At approximately equivalent whole brain concentrations, effects were more pronounced in P15 rats than in adult rats. Comparable brain levels of deltamethrin do not explain differences in ASR and tremor between the P15 and adult rats. These data indicate age-dependent differences in sensitivity to deltamethrin. PMID- 30395339 TI - Flexibility and structure of flanking DNA impact transcription factor affinity for its core motif. AB - Spatial and temporal expression of genes is essential for maintaining phenotype integrity. Transcription factors (TFs) modulate expression patterns by binding to specific DNA sequences in the genome. Along with the core binding motif, the flanking sequence context can play a role in DNA-TF recognition. Here, we employ high-throughput in vitro and in silico analyses to understand the influence of sequences flanking the cognate sites in binding of three most prevalent eukaryotic TF families (zinc finger, homeodomain and bZIP). In vitro binding preferences of each TF toward the entire DNA sequence space were correlated with a wide range of DNA structural parameters, including DNA flexibility. Results demonstrate that conformational plasticity of flanking regions modulates binding affinity of certain TF families. DNA duplex stability and minor groove width also play an important role in DNA-TF recognition but differ in how exactly they influence the binding in each specific case. Our analyses further reveal that the structural features of preferred flanking sequences are not universal, as similar DNA-binding folds can employ distinct DNA recognition modes. PMID- 30395340 TI - Developing a smartphone-based ecological momentary assessment protocol to collect biopsychosocial data with community-dwelling late-middle-aged and older adults. AB - Although ecological momentary assessment (EMA) has been used in youth and adult populations, very few of the studies provided evidence of the feasibility and utility of smartphone-based EMA protocols to collect biopsychosocial data from aging populations. This study aimed to describe the design and implementation of a smartphone-based EMA protocol, and to evaluate the feasibility and utility of this EMA protocol among community-dwelling late-middle-aged and older Chinese. A sample of 78 community-dwelling Chinese aged between 50 and 70 years was trained to participate in a 1-week EMA data collection, during which each participant carried an Android smartphone loaded with a researcher-developed EMA application and a smartphone-based electrocardiogram (ECG) monitor to provide psychosocial (e.g., daily activities, social interaction, affect) data and ECG recordings six times daily. Adherence was demonstrated with a total response rate of 91.5% of all scheduled assessments (n = 3,822) and a moderately high level of perceived feasibility. Female participants reported higher compliance to the study and rated the overall experience as more pleasant and interesting than male participants. Our study provided the first evidence of the feasibility and utility of smartphone-based EMA protocols among late-middle-aged and older Chinese. Key areas for improvement in future design and implementation of mobile based EMA include the incorporation of usable technology, adequate and training, and timely assistance. PMID- 30395341 TI - Letter: Lumboperitoneal Shunts for the Treatment of Idiopathic Normal Pressure Hydrocephalus: A Comparison of Small-Lumen Abdominal Catheters to Gravitational Add-On Valves in a Single Center. PMID- 30395342 TI - A dual-functional priming-capping loop of rhabdoviral RNA polymerases directs terminal de novo initiation and capping intermediate formation. AB - The L proteins of rhabdoviruses, such as vesicular stomatitis virus (VSV) and rabies virus (RABV), possess an unconventional mRNA capping enzyme (GDP polyribonucleotidyltransferase, PRNTase) domain with a loop structure protruding into an active site cavity of the RNA-dependent RNA polymerase (RdRp) domain. Here, using complementary VSV and RABV systems, we show that the loop governs RNA synthesis and capping during the dynamic stop-start transcription cycle. A conserved tryptophan residue in the loop was identified as critical for terminal de novo initiation from the genomic promoter to synthesize the leader RNA and virus replication in host cells, but not for internal de novo initiation or elongation from the gene-start sequence for mRNA synthesis or pre-mRNA capping. The co-factor P protein was found to be essential for both terminal and internal initiation. A conserved TxPsi motif adjacent the tryptophan residue in the loop was required for pre-mRNA capping in the step of the covalent enzyme-pRNA intermediate formation, but not for either terminal or internal transcription initiation. These results provide insights into the regulation of stop-start transcription by the interplay between the RdRp active site and the dual functional priming-capping loop of the PRNTase domain in non-segmented negative strand RNA viruses. PMID- 30395343 TI - Variability in Wall Thickness and Related Structures of Major Dural Sinuses in Posterior Cranial Fossa: A Microscopic Anatomical Study and Clinical Implications. AB - BACKGROUND: Regional variability in dural sinus (DS) wall thickness in posterior cranial fossa (PCF) have not been studied in detail yet. OBJECTIVE: To clarify the possible regional variability in DS wall thickness and determine the occurrence and localization of the chordae Willisii (CW) in PCF. METHODS: Fifty nine human cadaveric DSs of PCF were investigated. A measurement of the DS walls/dura mater/CW thickness of parafin-embedded/hematoxylin-eosin stained axial sections was performed by using Cell Sens Science Imaging Software (Olympus Corporation, Tokyo, Japan). RESULTS: The osseus wall (OW) was the thickest one in the confluens sinuum (CS) and the thinnest one in the jugular bulb (JB) and sigmoid sinus (P < .05). The biggest differences between individual walls were observed in the JB where the superior wall was almost twice as thick as the OW. At the transverse-sigmoid junction, the thickness of the walls was comparable. In the CS and transverse sinuses, the OW was even thicker than the surrounding dura mater. The occurrence and thickness of the CW increased from the JB towards CS and prevailed on the right side. An overall number of the CW in PCF was comparable to that observed in the superior sagittal sinus. CONCLUSION: The present study displayed for the first time the regional variability in the DS walls thickness and occurrence of the CW in PCF. Application of these findings may afford greater freedom in exposure of the DSs or neoplasms adhering to the DSs. PMID- 30395344 TI - Querying about the Use of Specific E-cigarette Devices May Enhance Accurate Measurement of E-cigarette Prevalence Rates among High School Students. AB - Introduction: Prevalence estimates of e-cigarette use may underestimate actual use in youth. Confusion resulting from the fact that a multitude of devices (e.g., vape-pens, JUULs) fall under the umbrella term "e-cigarettes," the use of different names to refer to e-cigarettes (e.g., vapes, electronic vaping devices), and the use of different terminology to refer to e-cigarette use (e.g., "vaping," "JUULing") may lead some young e-cigarette users to incorrectly indicate non-use. Therefore, we compared rates of endorsing lifetime e-cigarette use when adolescents were asked about lifetime e-cigarette use in two different ways. Methods: In May-June 2018, 1960 students from 2 Connecticut high schools completed a computerized, school-based survey. Participants first reported on lifetime "e-cigarette" use and, subsequently, on lifetime use of five different e cigarette devices: Disposables, Cig-a-Likes, or E-hookahs; Vape pens or Egos; JUULs; pod systems other than JUULs like PHIX or Suorin; and Advanced Personal Vaporizers/Mods. Results: 35.8% of students endorsed lifetime "e-cigarette" use, while 51.3% endorsed lifetime use of 1 e-cigarette device. The kappa statistic indicated only 66.6% agreement between the methods of assessing e-cigarette use. Overall, 31.5% of adolescents who endorsed lifetime device use did not endorse lifetime "e-cigarette" use, although rates of discordant responding varied across subgroups of interest (e.g., sex, race). Conclusions: #0160;Assessing adolescents' use of specific e-cigarette devices likely yields more accurate results than assessing the use of "e-cigarettes." If these findings are replicated in a nationally representative sample, regulatory efforts requiring all e-cigarette devices to be clearly labeled as "e-cigarettes" may help to reduce confusion. Implications: Different prevalence estimates of lifetime e cigarette use were obtained depending on the way that prevalence was assessed. Specifically, fewer adolescents (35.8%) endorsed lifetime e-cigarette use when they were asked "Have you ever tried an e-cigarette, even one or two puffs?" than when they were queried about lifetime use of five different e-cigarette devices (51.3%). Among those who endorsed lifetime use of 1 specific e-cigarette device, 31.5% did not endorse lifetime "e-cigarette" use. These findings suggest that when assessing adolescents' lifetime e-cigarette use, using of terms referring to specific devices likely produces more accurate prevalence estimates than using the term "e-cigarettes." PMID- 30395345 TI - Later high school start times associated with longer actigraphic sleep duration in adolescents. AB - Study Objectives: High school start times (SSTs) directly impact adolescents' sleep timing and duration. This study investigated the associations between SSTs and actigraphically-measured 24-hour sleep duration, sleep onset, sleep offset and sleep quality. Methods: This study included 383 adolescents (Mage=15.5, SDage=0.6 years) participating in the age 15 wave of the Fragile Families & Child Wellbeing Study, a national birth cohort study sampling from 20 large U.S. cities. Multilevel models used daily observations (N=1,116 school days, Mdays =2.9, SDdays=1.4 per adolescent) of sleep and SSTs from concordant daily diary and actigraphy. Results: A diverse range of SSTs were included in our analyses (MSST=8:08, SDSST=39 minutes, RangeSST=6:00-11:05), and are presented in the following categories for ease of interpretation: before 7:30, 7:30-7:59, 8:00 8:29, and 8:30 or later. Adolescents starting school at 8:30 or later exhibited significantly longer actigraphically-assessed 24-hour sleep duration (by 21-34 minutes, p<.05) and later sleep offset (by 32-64 minutes, p<.001) when compared with the adolescents grouped by earlier SSTs. SSTs were also analyzed continuously for comparison with existing literature, and results indicated that every one-hour delay in SST was significantly associated with 21 minutes longer 24-hour sleep duration (p<.001), 16 minutes later sleep onset (p<.01), and 39 minutes later sleep offset (p<.001). All models controlled for covariates including socioeconomic status. Conclusion: These findings support pediatric and public health expert recommendations for SSTs after 8:30 a.m. In our diverse national urban sample, adolescents with SSTs at 8:30 or later, compared with adolescents with earlier SSTs, had significantly longer actigraphy-measured sleep. PMID- 30395346 TI - Use of a Screening Questionnaire to Identify Patients at Risk of Hyperglycemia Prior to Steroid Injection Therapy. AB - Objective: Patients with chronic pain considered for steroid injections are not consistently screened for undiagnosed or poorly controlled diabetes mellitus (DM) prior to steroid administration despite the known impact of corticosteroids on glucose control. A quality improvement project was undertaken to identify the prevalence of at-risk patients prior to steroid exposure through the development and implementation of a screening questionnaire. Subject: Three hundred and five adult patients with chronic pain who were being considered for an outpatient steroid injection were interviewed. Methods: Each patient was asked to complete an American Diabetes Association-validated diabetes mellitus screening questionnaire (ADAQ). In addition, patients responded to a set of nine questions that addressed common signs and symptoms of hyperglycemia. Results: The total prevalence of known DM in the study population was found to be 20% (60 patients), based on a documented history of diabetes mellitus. The ADAQ identified an additional 135 patients (45%) at high risk for undiagnosed DM. The full study questionnaire identified 143 patients (47.3%) who had no known history of diabetes mellitus as being at risk for hyperglycemia. In patients with known diabetes, five of nine symptom-based screening questions occurred with significantly frequency (P < 0.05): excessive thirst, excessive hunger, blurred vision, poor wound healing, and repeated infections. Conclusions: More than 60% of the patients screened had high risk of having inadequately treated DM. Thus, routine screening for DM should be considered in patients prior to treatment involving corticosteroids. The study questionnaire is a potentially cost effective initial screening tool to determine which patients should undergo laboratory testing. PMID- 30395347 TI - Everything at Once, or Nothing at All. PMID- 30395348 TI - Mother-in-Law Reports of Closeness to Daughter-in-Law: The Determinant Triangle with the Son and Husband. AB - For a mother-in-law (MIL) and daughter-in-law (DIL), the benefits of maintaining a close relationship weave through other central family relationships. Those relationship triangles start with one's son, who is the other's husband, and echo through the raising of any grandchildren from the marriage. The current study examined the factors that related to MIL reports of having a close relationship with her DIL. Using survey data gathered from 267 MILs authors report on a regression model that included six factors that predicted closeness. Within the MIL relationship, the MIL reporting that the DIL was helpful and had similar interests to her predicted a close relationship. When the MIL reported being close to her son and the son being happy with the relationship she had with the DIL, this predicted a closer relationship between the MIL and DIL. The MIL feeling left out within the relationship triangle with the son and DIL was associated with less closeness. Closeness was increased when the MIL reported more time spent per month with the DIL. The article concludes with a discussion of research and practice implications. PMID- 30395349 TI - Effect of preoperative biliary drainage on cholestasis-associated inflammatory and fibrotic gene signatures in perihilar cholangiocarcinoma. AB - Preoperative biliary drainage (PBD) is used routinely in the evaluation of patients with potentially resectable perihilar cholangiocarcinoma to relieve cholestasis and improve the liver's resilience to surgery. Little preclinical or translatational data are, however, currently available to guide the use of PBD in this patient group. The effect of PBD on hepatic gene expression profiles was therefore studied by microarray analysis. Drainage affects inflammatory and fibrotic gene signatures. PMID- 30395350 TI - Drinking Risk Level Reductions Associated with Improvements in Physical Health and Quality of Life Among Individuals with Alcohol Use Disorder. AB - BACKGROUND: Abstinence and no heavy drinking days are currently the only Food and Drug Administration-approved end points in clinical trials for alcohol use disorder (AUD). Many individuals who fail to meet these criteria may substantially reduce their drinking during treatment, and most individuals with AUD prefer drinking reduction goals. One- and two-level reductions in World Health Organization (WHO) drinking risk levels have been proposed as alternative end points that reflect reduced drinking and are associated with reductions in drinking consequences, improvements in mental health, and reduced risk of developing alcohol dependence. The current study examined the association between WHO drinking risk level reductions and improvements in physical health and quality of life in a sample of individuals with alcohol dependence. METHODS: Secondary data analysis of individuals with alcohol dependence (n = 1,142) enrolled in the longitudinal, prospective COMBINE study, a multi site randomized placebo-controlled clinical trial, examining the association between reductions in WHO drinking risk levels and change in blood pressure, liver enzyme levels, and self-reported quality of life following treatment for alcohol dependence. RESULTS: One- and two-level reductions in WHO drinking risk level during treatment were associated with significant reductions in systolic blood pressure (p < 0.001), improvements in liver enzyme levels (all p < 0.01), and significantly better quality of life (p < 0.001). CONCLUSIONS: One- and two-level reductions in WHO drinking risk levels predicted significant improvements in markers of physical health and quality of life, suggesting that the WHO drinking risk level reduction could be a meaningful surrogate marker of improvements in how a person "feels and functions" following treatment for alcohol dependence. The WHO drinking risk levels could be useful in medical practice for identifying drinking reduction targets that correspond with clinically significant improvements in health and quality of life. PMID- 30395351 TI - Neutrophil progenitor populations of rhesus macaques. AB - Captive-bred rhesus macaques of Indian origin represent one of the most important large animal models for infectious disease, solid organ transplantation, and stem cell research. There is a dearth of information defining hematopoietic development, including neutrophil leukocyte differentiation in this species using multicolor flow cytometry. In the current study, we sought to identify cell surface markers that delineate neutrophil progenitor populations with characteristic immunophenotypes. We defined four different postmitotic populations based on their CD11b and CD87 expression pattern, and further refined their immunophenotypes using CD32, CD64, lactoferrin, and myeloperoxidase as antigenic markers. The four subsets contained myelocyte, metamyelocyte, band, and segmented neutrophil populations. We compared our flow cytometry-based classification with the classical nuclear morphology-based classification. We found overlap of immunological phenotype between populations of different nuclear morphology and identified phenotypically different subsets within populations of similar nuclear morphology. We assessed the responsiveness of these populations to stimulatory signals, such as LPS, fMLP, or PMA, and demonstrated significant differences between human and rhesus macaque neutrophil progenitors. In this study, we provided evidence for species-specific features of granulopoiesis that ultimately manifested in the divergent immunophenotypes of the fully differentiated segmented neutrophils of humans and rhesus macaques. Additionally, we found functional markers that can be used to accurately quantify neutrophil progenitors by flow cytometry. Although these markers do not coincide with the classical nuclear-morphology-based grading, they enable us to perform functional studies monitoring immunophenotypic markers. PMID- 30395352 TI - Stevens-Johnson syndrome and toxic epidermal necrolysis with antiepileptic drugs: An analysis of the US Food and Drug Administration Adverse Event Reporting System. AB - OBJECTIVE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and potentially fatal adverse skin reactions that are most commonly triggered by certain medications. One class of medications that has been highly associated with SJS/TEN reactions is antiepileptic drugs (AEDs). We sought to quantify the risk of SJS/TEN associated with AEDs as a class, as well as individual AEDs, in the United States. METHODS: An analysis was performed of the US Food and Drug Administration Adverse Event Reporting System (FAERS) from July 2014 through December 2017. Rates of SJS/TEN were calculated for each AED compared with all other non-AEDs. Reporting odds ratios (RORs), proportional reporting ratios (PRRs), and 95% confidence intervals (CIs) were calculated using OpenEpi. RESULTS: With 198 reports, AEDs had more reports of SJS/TEN than any other medication class. AEDs as a class had an ROR of 8.7 (95% CI 7.5-10.2) and a PRR of 8.7 (95% CI 7.5-10.2) compared with all other non-AEDs. The AEDs with the highest risk estimates were zonisamide (ROR 70.2, 95% CI 33.1-148.7; PRR 68.7, 95% CI 32.9-143.5), rufinamide (ROR 60.0, 95% CI 8.3-433.5; PRR 58.9, 95% CI 8.4 411.5), clorazepate (ROR 56.0, 95% CI 7.8-404.1; PRR 55.1, 95% CI 7.8-385.0), lamotrigine (ROR 53.0, 95% CI 43.2-64.9; PRR 52.2, 95% CI 42.7-63.7), phenytoin (ROR 26.3, 95% CI 15.5-44.7; PRR 26.1, 95% CI 15.4-44.2), and carbamazepine (ROR 24.5, 95% CI 16.0-37.5; PRR 24.3, 95% CI 16.0-37.1). SIGNIFICANCE: Although AEDs as a class were associated with 9 times the risk of SJS/TEN compared with non AEDs, there were 6 AEDs with risk estimates greater than 20. Increased awareness of this risk among both prescribers and patients, particularly variations in risk among different AEDs, along with education on early recognition of SJS/TEN signs/symptoms, may help mitigate the number and severity of these adverse events. PMID- 30395353 TI - Surgical and developmental outcomes of corpus callosotomy for West syndrome in patients without MRI lesions. AB - OBJECTIVE: This retrospective study was designed to assess the impact of corpus callosotomy (CC) in patients with intractable West syndrome (WS) without lesions on magnetic resonance imaging (MRI). METHODS: This study involved 56 patients with WS who underwent CC between January 2000 and December 2014. Seizure outcomes and changes in psychomotor development were analyzed. RESULTS: Mean age at the onset of epilepsy and at the time of CC was 5.1 and 22.6 months, respectively. Mean duration of epilepsy before CC was 17.6 months. Video-electroencephalography (EEG) monitoring showed bilateral ictal and interictal abnormalities before CC. Mean follow-up duration was 36.6 months. At final follow-up, seizure outcomes after CC were seizure-free in 18 patients (32.1%), excellent (E: >80% reduction in seizure frequency) in 15 (26.8%), good (G: >50% reduction) in 10 (17.9%), and poor (P: <50% reduction) in 13 (23.2%). Epileptic spasms (ES) were eliminated in 24 patients (42.9%). However, tonic seizure (TS) outcomes were poor (P < 0.05). Of preoperative predictive factors related to seizure outcome, developmental delay before epilepsy onset correlated with poor outcome (P < 0.05). One year post-CC, 6 patients (10.7%) had no epileptic abnormality on EEG, 19 (33.9%) had lateralized epileptic abnormalities, and 31 (55.4%) had bilateral asynchronous epileptic abnormalities. All patients without epileptic discharge achieved seizure freedom. Fifteen of 19 (78.9%) patients in the lateralized group and 12 of 31 (38.7%) in the bilateral asynchronous group had worthwhile outcomes (F + E). The patterns of EEG changes after CC correlated with seizure outcome (P < 0.01). Progressive declines in developmental quotient were prevented in patients with worthwhile outcomes. SIGNIFICANCE: CC represents an important therapeutic option for patients with WS without resectable MRI lesions. Transcallosal seizure bilateralization is critical for bilateral ES generation. Early identification of potential CC candidates and surgical intervention are important for better seizure control and cognitive capacity preservation before severe developmental delay development. PMID- 30395354 TI - Cognitive outcomes following epilepsy in infancy: A longitudinal community-based study. AB - OBJECTIVE: Onset of epilepsy before 2 years of age is associated with poor cognitive outcome; however, the natural course of the range of epilepsies that occur at this age is unknown. The aim of this prospective community-based study was to investigate the neuropsychological development of infants with newly diagnosed epilepsy longitudinally and to identify the clinical factors that predict long-term impairment. METHODS: Sixty-six infants <24 months of age were enrolled in the baseline phase of this study; 40 were seen again at 1-year follow up and 40 at 3-year follow-up. Children underwent a neurological and neuropsychological assessment at each time point. RESULTS: More than 55% of children demonstrated impaired cognitive functioning at each assessment, with a similar percentage showing impaired memory and attention at 3-year follow-up. Cognitive scores obtained at each time point were correlated. More than 20 seizures/seizure clusters prior to assessment and an abnormal neurologic examination predicted poor cognitive functioning at baseline, whereas continuing seizures and baseline cognitive score predicted 3-year intelligence quotient (IQ)/cognitive score. SIGNIFICANCE: These findings demonstrate the following: (1) infants who are performing poorly at baseline continue to display impaired development at follow-up, (2) these children are delayed across a range of neuropsychological functions, and (3) a high number of seizures close to initial diagnosis and continuing seizures at follow-up independently predict cognitive impairment. These findings help to identify those infants with new-onset epilepsy who are most at risk for poor developmental outcome and suggest that multimodal interventions should be instituted early in the course of the disorder to improve outcomes. PMID- 30395355 TI - Outcome of early dental implant placement versus other dental implant placement protocols: A systematic review and meta-analysis. AB - BACKGROUND: The aim of this systematic review and meta-analysis was to compare the clinical efficacy of the early dental implant placement protocol with immediate and delayed dental implant placement protocols. METHODS: An electronic and manual search of literature was made to identify clinical studies comparing early implant placement with immediate or delayed placement. Data from the included studies were pooled and quantitative analyses were performed for the implant outcomes reported as the number of failed implants (primary outcome variable) and for changes in peri-implant marginal bone level, peri-implant probing depth, and peri-implant soft tissue level (secondary outcome variables). RESULTS: Twelve studies met the inclusion criteria. Significant difference in risk of implant failure was found neither between the early and immediate placement protocols (risk difference = -0.018; 95% confidence interval [CI] = 0.06, 0.025; P = 0.416) nor between early and delayed placement protocols (risk difference = -0.008; 95% CI = -0.044, 0.028; P = 0.670). Pooled data of changes in peri-implant marginal bone level demonstrated significantly less marginal bone loss for implants placed using the early placement protocol compared with those placed in fresh extraction sockets (P = 0.001; weighted mean difference = -0.14 mm; 95% CI = -0.22, -0.05). No significant differences were found between the protocols for the other variables. CONCLUSIONS: The available evidence supports the clinical efficacy of the early implant placement protocol. Present findings indicate that the early implant placement protocol results in implant outcomes similar to immediate and delayed placement protocols and a superior stability of peri-implant hard tissue compared with immediate implant placement. PMID- 30395356 TI - CAN ATTACHMENT INFORM DECISION-MAKING IN CHILD PROTECTION AND FORENSIC SETTINGS? AB - The historic publication of the "consensus statement" on not using the "D/disorganized" category in the infant Strange Situation (M. Ainsworth, M. Blehar, E. Waters, & S. Wall, 1978) for case-specific child protection work (P. Granqvist et al., 2017) opens the door for a broader discussion of different branches of attachment theory and different attachment classificatory systems applied to infants, young children, and their parents. We agree with the consensus authors that Strange Situation classifications alone, regardless of coding method, are insufficient for decision-making. The authors, however, have acknowledged that the Dynamic-Maturational Model of Attachment and Adaptation (DMM; Crittenden, 2016) offers a different perspective on classifying Strange Situations. The DMM is a branch of attachment theory that expands the Ainsworth A and C classifications across the life span to reflect the complex attachment strategies that some individuals use in dangerous contexts. We contrast the DMM to the D classification, both for the Strange Situation for infants and its adaptation for young children and also for the Adult Attachment Interview (AAI; C. George, N. Kaplan, & M. Main, 1984-1996) for their parents. We initiate a scientific dialogue by addressing three points: (a) "Attachment" does not imply or require a model that includes a D/disorganization category nor is the D/disorganized category the only clinical expansion of Mary Ainsworth's (1978) original work; (b) the DMM method for classifying Strange Situations may be better attuned to parental inadequacy and child protection than is the D/disorganized category; and (c) with attention to guidelines, DMM classifications from the Strange Situation with both infants and preschool-aged children can be used in a case-specific manner in both treatment and forensic settings. The same is true for other DMM assessments of attachment, including the AAI. We close by suggesting steps that could further understanding and application of Ainsworth's great accomplishment: individual differences in attachment relationships. PMID- 30395357 TI - Field-testing polyethylene passive samplers for the detection of neutral polyfluorinated alkyl substances in air and water. AB - Fluorotelomer alcohols (FTOHs), perfluorooctane-sulfonamidoethanols (FOSEs), perfluorooctane-sulfonamides (FOSAs), and other poly- and perfluorinated alkyl substances (PFASs) are common and ubiquitous byproducts of industrial telomerization processes. They can degrade into various perfluorinated carboxylic acids, which are persistent organic contaminants of concern. We assessed the use of polyethylene (PE) passive samplers as a sampling tool for neutral PFAS precursors during field-deployments in air and water. A wide range of neutral PFASs was detected in polyethylene sheets exposed in wastewater treatment effluents in August 2017. Equilibration times for most neutral PFASs were on the order of 1 to 2 wk. Based on known sampling rates, the partitioning constants between polyethylene and water, KPEw , were derived. Log KPEw values were mostly in the range of 3 to 4.5, with the greatest values for 8:2 FTOH, 10:2 FTOH, and n ethyl-FOSE. To test the utility of polyethylene for gas-phase compounds, parallel active and passive sampling was performed in ambient air in Providence (RI, USA) in April 2016. Most PFASs equilibrated within 2 to 7 d. The greatest concentrations in polyethylene samplers were detected for MeFOSE and EtFOSE. Polyethylene/air partitioning constants, log KPEa , were approximately 7 to 8 for the FTOHs, and approached 9 for n-methyl-FOSA and n-methyl-FOSE. Polyethylene sheets showed promise as a passive sampling approach for neutral PFASs in air and water. Environ Toxicol Chem 2018;37:3002-3010. (c) 2018 SETAC. PMID- 30395358 TI - How chorismatases regulate distinct reaction channels in a single conserved active pocket? Revealed by mechanistic analysis with QM/MM (ONIOM) investigations. AB - FkbO and Hyg5 subfamilies of chorismatases share the same active site architectures, but perform distinct reaction mechanisms which FkbO employs a hydrolysis reaction while Hyg5 proceeds via an intramolecular mechanism. Despite extensive research efforts, the detailed mechanism of product selectivity in chorismatases need to be further unmasked. In this study, the effects of A/G residue group (A244FkbO/G240Hyg5) and V/Q residue group (V209FkbO/Q201Hyg5) on catalytic mechanisms are investigated by employing molecular dynamics simulation and hybrid quantum mechanical/molecular mechanical (QM/MM) calculations of the two wild-type models (FkbO/CHO and Hyg5/CHO) and four mutants models (A244G FkbO/CHO and G240A-Hyg5/CHO; V209Q-FkbO/CHO and Q201V-Hyg5/CHO). Our results showed that the A/G residue group mentioned by the previously works would cause the changes in the binding states of substrate and the orientation of the catalytic glutamate, but only these changes affect the product selectivity in chorismatases limitedly. Interestingly, the distal V/Q residue group which determines the internal water self-regulating ability at the active site has significant impact on the selectivity of catalytic mechanisms. The V/Q residue group was suggested that may be as an important factor to control the catalytic activities in chorismatases. The results are consistent with biochemical and structural experiments, providing novel insight into the mechanism of product selectivity in chorismatases. PMID- 30395359 TI - Results of an early access treatment protocol of daratumumab in United States patients with relapsed or refractory multiple myeloma. AB - BACKGROUND: Daratumumab is a human CD38-directed monoclonal antibody indicated for the treatment of relapsed and refractory multiple myeloma (MM). METHODS: A multicenter, open-label treatment protocol provided early access to daratumumab for patients who had progressive MM after they received >=3 prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent or if they were refractory to both a proteasome inhibitor and an immunomodulatory agent. Patients received daratumumab 16 mg/kg weekly for 8 weeks, every other week for 16 weeks, and monthly until they developed disease progression, unacceptable toxicity, or 60 days after the drug gained US approval. Treatment emergent grade >=3 adverse events (AEs), serious AEs, and AEs of special interest were collected. RESULTS: Three hundred forty-eight patients were enrolled at 39 US sites between June and December 2015. Patients received study therapy for a median of 1.9 months (range, 0.03-6.0 months). Fifty-two percent of patients transitioned to commercially-available daratumumab and 37% discontinued because of progressive disease. Grade >=3 AEs occurred in 50% of patients, including thrombocytopenia (15%) and anemia (14%). Serious AEs occurred in 35% of patients (12% were drug-related), including infections (11%). Infusion reactions occurred in 56%, 2%, and 2% of patients during the first, second, and all subsequent infusions, respectively; respiratory symptoms (cough, dyspnea, throat irritation, nasal congestion) were common. The infusion reaction rate for the first infusion was 38% in 50 patients at 2 sites who received montelukast as premedication for their first infusion and 59% in patients who did not receive montelukast. CONCLUSIONS: The current findings are consistent with previously reported trials and confirm the safety profile of daratumumab in heavily pretreated US patients who have relapsed or refractory MM. Cancer 2018;124:000-000. PMID- 30395360 TI - Microvascular inflammation in renal allograft biopsies assessed by endothelial and leukocyte co-immunostain: a retrospective study on reproducibility and clinical/prognostic correlates. AB - The most prominent histologic lesion in antibody-mediated rejection is microvascular inflammation (MVI), however its recognition and scoring can be challenging and poorly reproducible between pathologists. We developed a dual immunohistochemical (IHC)-stain (anti-CD34/anti-CD45 for endothelium/leukocytes) as ancillary tool to improve on the semi-quantitative Banff scores and allow quantification of MVI. We examined the relationship between CD34-CD45 IHC-based quantitative MVI score (the inflamed peritubular capillary ratio, iptcr) and renal-graft failure or DSA strength at the time of biopsy. Quantitative iptcr score was significantly associated with renal graft failure (hazard ratio 1.81, per 1 SD-unit [0.13 points] of iptcr-increase; P=0.026) and predicted the presence and strength of DSA (ordinal odds ratio: 2.42; P=0.005) (75 biopsies/60 kidney transplant recipients; 30 HLA- and/or ABO-incompatible). Next, we assessed inter-pathologist agreement for ptc score and ptc extent (focal/diffuse) using CD34-CD45 IHC as compared to conventional stain. Compared to conventional stain, CD34-CD45 IHC significantly increased inter-pathologist agreement on ptc score severity and extent (kappa-coefficient from 0.52 to 0.80 and 0.46 to 0.68 respectively, p<0.001). Our findings show that CD34-CD45 IHC improves reproducibility of MVI scoring and facilitates MVI quantification and introduction of a dual anti-CD34/CD45 has the potential to improve recognition of MVI ahead of DSA results. This article is protected by copyright. All rights reserved. PMID- 30395361 TI - Sex differences in national rates of repair of emergency abdominal aortic aneurysm. AB - BACKGROUND: The aim of this study was to assess the sex differences in both the rate and type of repair for emergency abdominal aortic aneurysm (AAA) in England. METHODS: Hospital Episode Statistics (HES) data sets from April 2002 to February 2015 were obtained. Clinical and administrative codes were used to identify patients who underwent primary emergency definitive repair of ruptured or intact AAA, and patients with a diagnosis of AAA who died in hospital without repair. These three groups included all patients with a primary AAA who presented as an emergency. Sex differences between repair rates and type of surgery (endovascular aneurysm repair (EVAR) versus open repair) over time were examined. RESULTS: In total, 15 717 patients (83.3 per cent men) received emergency surgical intervention for ruptured AAA and 10 276 (81.2 per cent men) for intact AAA; 12 767 (62.0 per cent men) died in hospital without attempted repair. The unadjusted odds ratio for no repair in women versus men was 2.88 (95 per cent c.i. 2.75 to 3.02). Women undergoing repair of ruptured AAA were older and had a higher in hospital mortality rate (50.0 versus 41.0 per cent for open repair; 30.9 versus 23.5 per cent for EVAR). After adjustment for age, deprivation and co morbidities, the odds ratio for no repair in women versus men was 1.34 (1.28 to 1.40). The in-hospital mortality rate after emergency repair of an intact AAA was also higher among women. CONCLUSION: Women who present as an emergency with an AAA are less likely to undergo repair than men. Although some of this can be explained by differences in age and co-morbidities, the differences persist after case-mix adjustment. PMID- 30395362 TI - Survival after neoadjuvant chemoradiotherapy and oesophagectomy versus definitive chemoradiotherapy for patients with oesophageal squamous cell carcinoma. AB - BACKGROUND: Whether there is a difference in survival after neoadjuvant chemoradiotherapy plus surgery (CRT-S) compared with definitive chemoradiotherapy (dCRT) in patients with locally advanced oesophageal squamous cell carcinoma (SCC) remains controversial. METHODS: Patients with SCC who underwent curative treatment from 2008 to 2014 were identified from the Taiwan Cancer Registry. Propensity score matching was undertaken to balance pretreatment clinical variables. Overall survival was compared between patients undergoing CRT-S or dCRT. Univariable and multivariable analyses were performed to identify prognostic factors for overall survival. RESULTS: A total of 5832 patients with clinical stage II and III oesophageal SCC receiving CRT-S (1754) or dCRT (4078) were included. After propensity score matching, each group included 1661 patients. The 3-year overall survival rate for patients treated with CRT-S was 41.1 per cent compared with 17.9 per cent for those who had dCRT (P < 0.001). In multivariable analysis, treatment modality was an independent prognostic factor in the overall cohort before propensity score matching: hazard ratio 0.45 (95 per cent c.i. 0.40 to 0.51) for CRT-S versus dCRT (P < 0.001). In separate analyses of patients with clinical stage II and those with stage III disease, CRT-S was associated with significantly better overall survival than dCRT. CONCLUSION: Neoadjuvant chemoradiotherapy and oesophagectomy is associated with better overall survival than dCRT in patients with stage II and III oesophageal SCC. PMID- 30395363 TI - FAM92A Underlies Nonsyndromic Postaxial Polydactyly in Humans and an Abnormal Limb and Digit Skeletal Phenotype in Mice. AB - Polydactyly is a common congenital anomaly of the hand and foot. Postaxial polydactyly (PAP) is characterized by one or more posterior or postaxial digits. In a Pakistani family with autosomal recessive nonsyndromic postaxial polydactyly type A (PAPA), we performed genomewide genotyping, linkage analysis, and exome and Sanger sequencing. Exome sequencing revealed a homozygous nonsense variant (c.478C>T, p.[Arg160*]) in the FAM92A gene within the mapped region on 8q21.13 q24.12 that segregated with the PAPA phenotype. We found that FAM92A is expressed in the developing mouse limb and E11.5 limb bud including the progress zone and the apical ectodermal ridge, where it strongly localizes at the cilia level, suggesting an important role in limb patterning. The identified variant leads to a loss of the FAM92A/Chibby1 complex that is crucial for ciliogenesis and impairs the recruitment and the colocalization of FAM92A with Chibby1 at the base of the cilia. In addition, we show that Fam92a-/- homozygous mice also exhibit an abnormal digit morphology, including metatarsal osteomas and polysyndactyly, in addition to distinct abnormalities on the deltoid tuberosity of their humeri. In conclusion, we present a new nonsyndromic PAPA ciliopathy due to a loss-of function variant in FAM92A. (c) 2018 American Society for Bone and Mineral Research. PMID- 30395364 TI - Light-controlled chemoenzymatic immobilization of proteins towards engineering of bioactive papers. AB - Efficient and reliable methods for the generation of bioactive papers are of growing interest in view of point-of-care testing devices that do not require extensive analytical equipment. Herein, we report on immobilization of functional proteins onto paper fibers using a modular chemoenzymatic approach. The synthetic strategy relies on the combination of highly efficient spatially controllable photo-triggered cycloaddition followed by site-specific sortase A-catalyzed transamidation. This site-directed and regiospecific method allowed unidirectional and covalent immobilization of several proteins possessing different functional properties with ramifications for application in paper-based diagnostics. PMID- 30395365 TI - Morphology Driven by Molecular Structure of Thiazole-Based Polymers for Use in Field-Effect Transistors and Solar Cells. AB - The effects of the molecular structure of thiazole-based polymers on the active layer morphologies and performances of electronic and photovoltaic devices were studied. Thus, thiazole-based conjugated polymers with a novel thiazole-vinylene thiazole (TzVTz) structure were designed and synthesized. The TzVTz structure was introduced to extend the pi conjugation and coplanarity of the polymer chains. By combining alkylthienyl-substituted benzo[1,2-b:4,5-b']dithiophene (BDT) or dithieno[2,3-d:2',3'-d']benzo[1,2-b:4,5-b']dithiophene (DTBDT) electron-donating units and a TzVTz electron-accepting unit, enhanced intermolecular interactions and charge transport were obtained in the novel polymers BDT-TzVTz and DTBDT TzVTz. With a view to using the polymers in transistor and photovoltaic applications, the molecular self-assembly in and their nanoscale morphologies of the active layers were controlled by thermal annealing to enhance the molecular packing and by introducing a diphenyl ether solvent additive to improve the miscibility between polymer donors and [6,6]phenyl-C71-butyric acid methyl ester (PC71 BM) acceptors, respectively. The morphological characterization of the photoactive layers showed that a higher degree of pi-electron delocalization and more favorable molecular packing in DTBDT-TzVTz compared with in BDT-TzVTz leads to distinctly higher performances in transistor and photovoltaic devices. The superior performance of a photovoltaic device incorporating DTBDT-TzVTz was achieved through the superior miscibility of DTBDT-TzVTz with PC71 BM and the improved crystallinity of DTBDT-TzVTz in the nanofibrillar structure. PMID- 30395366 TI - Release of CXCL12 From Apoptotic Skeletal Cells Contributes to Bone Growth Defects Following Dexamethasone Therapy in Rats. AB - Dexamethasone (Dex) is known to cause significant bone growth impairment in childhood. Although previous studies have suggested roles of osteocyte apoptosis in the enhanced osteoclastic recruitment and local bone loss, whether it is so in the growing bone following Dex treatment requires to be established. The current study addressed the potential roles of chemokine CXCL12 in chondroclast/osteoclast recruitment and bone defects following Dex treatment. Significant apoptosis was observed in cultured mature ATDC5 chondrocytes and IDG SW3 osteocytes after 48 hours of 10-6 M Dex treatment, and CXCL12 was identified to exhibit the most prominent induction in Dex-treated cells. Conditioned medium from the treated chondrocytes/osteocytes enhanced migration of RAW264.7 osteoclast precursor cells, which was significantly inhibited by the presence of the anti-CXCL12 neutralizing antibody. To investigate the roles of the induced CXCL12 in bone defects caused by Dex treatment, young rats were orally gavaged daily with saline or Dex at 1 mg/kg/day for 2 weeks, and received an intraperitoneal injection of anti-CXCL12 antibody or control IgG (1 mg/kg, three times per week). Aside from oxidative stress induction systemically, Dex treatment caused reductions in growth plate thickness, primary spongiosa height, and metaphysis trabecular bone volume, which are associated with induced chondrocyte/osteocyte apoptosis and enhanced chondroclast/osteoclast recruitment and osteoclastogenic differentiation potential. CXCL12 was induced in apoptotic growth plate chondrocytes and metaphyseal bone osteocytes. Anti-CXCL12 antibody supplementation considerably attenuated Dex-induced chondroclast/osteoclast recruitment and loss of growth plate cartilage and trabecular bone. CXCL12 neutralization did not affect bone marrow osteogenic potential, adiposity, and microvasculature. Thus, CXCL12 was identified as a potential molecular linker between Dex-induced skeletal cell apoptosis and chondroclastic/osteoclastic recruitment, as well as growth plate cartilage/bone loss, revealing a therapeutic potential of CXCL12 functional blockade in preventing bone growth defects during/after Dex treatment. (c) 2018 American Society for Bone and Mineral Research. PMID- 30395368 TI - Odanacatib Restores Trabecular Bone of Skeletally Mature Female Rabbits With Osteopenia but Induces Brittleness of Cortical Bone: A Comparative Study of the Investigational Drug With PTH, Estrogen, and Alendronate. PMID- 30395369 TI - The Calcium-Sensing Receptor and 25-Hydroxyvitamin D-1alpha-Hydroxylase Interact to Modulate Skeletal Growth and Bone Turnover. PMID- 30395370 TI - Issue Information-Declaration of Helsinki. PMID- 30395371 TI - Discoidin Receptor 2 Controls Bone Formation and Marrow Adipogenesis. PMID- 30395372 TI - All-Polymer Solar Cells: Recent Progress, Challenges, and Prospects. AB - For over two decades bulk-heterojunction polymer solar cell (BHJ-PSC) research was dominated by donor:acceptor BHJ blends based on polymer donors and fullerene molecular acceptors. This situation has changed recently, with non-fullerene PSCs developing very rapidly. The power conversion efficiencies of non-fullerene PSCs have now reached >= 15%, which is far above the most efficient fullerene-based PSCs. Among the various non-fullerene PSCs, all-polymer solar cells (APSCs) based on polymer donor-polymer acceptor BHJs have attracted growing attention, due to the following attractions: (1) large and tunable light absorption of the polymer donor/polymer acceptor pair; (2) robustness of the BHJ film morphology; (3) compatibility with large scale/large area manufacturing; (4) long-term stability of the cell to external environmental and mechanical stresses. This minireview highlights the opportunities offered by APSCs, selected polymer families suitable for these devices with optimization to enhance the performance further, and discusses the challenges facing APSC development for commercial applications. PMID- 30395373 TI - Concise Review: Exploring immunomodulatory features of Mesenchymal Stromal Cells in humanized mouse models. AB - With their immunosuppressive features, human Mesenchymal Stromal Cells (MSCs), sometimes also termed mesenchymal stem cells, hold great potential as a cell based therapy for various immune-mediated diseases. Indeed, MSCs have already been approved as a treatment for Graft versus Host Disease (GvHD). However, contradictory data from clinical trials and lack of conclusive proof of efficacy, hinder the progress toward wider clinical use of MSCs and highlight the need for more relevant disease models. Humanized mice are increasingly used as models to study immune-mediated disease, as they simulate human immunobiology more closely than conventional murine models. With further advances in their resemblance to human immunobiology, it is very likely that humanized mice will be used more commonly as models to investigate MSCs with regard to their therapeutic safety and their immunomodulatory effect and its underlying mechanisms. Recent studies that explore the immunosuppressive features of MSCs in humanized mouse models will be discussed in this review. SIGNIFICANCE STATEMENT: The immunosuppressive features of MSCs have been widely demonstrated. However, a more widespread clinical use of MSCs is hampered by contradictory data from clinical trials and an incomplete understanding of the underlying mechanism by which MSCs exert this immunosuppression, resulting in inconclusive proof of efficacy. The present review discusses humanized mice as a tool to develop a better understanding of the mode of action of MSCs in mitigating the immune response in an in-vivo environment that closely resembles human immunobiology. The goal is that a greater understanding may enable and encourage more studies using humanized mice to investigate the immunomodulatory features of MSCs. (c) AlphaMed Press 2018. PMID- 30395374 TI - Ultra-Tuning of the Aperture Size in Stiffened ZIF-8_Cm Frameworks with Mixed Linker Strategy for Enhanced CO2 /CH4 Separation. AB - ZIF-8 membrane has the potential for CO2 /CH4 separation based on size exclusion. But if traditionally prepared by solvothermal methods, it shows only negligible selectivity due to the linker mobility. Here, ~500 nm-thin hybrid ZIF-7x -8 membranes with suppressed linker mobility and narrowed window aperture are prepared by a fast current-driven synthesis (FCDS) within 20 min. The in situ electric field during FCDS allows the formation of stiffened ZIF-8_Cm as parent skeleton and the mixed-linker strategy is applied to narrow the aperture size simultaneously. The ZIF-722 -8 membrane shows significantly sharpened molecular sieving for CO2 /CH4 with a separation factor above 25, which soared tenfold compared with other unmodified ZIF-8 membranes. Additionally, the membrane shows exceptional separation performance for H2 /CH4 and CO2 /N2 , with separation factors of 71 and 20, respectively. After 180 h temperature swing operation, it still maintains the excellent separation performance. PMID- 30395375 TI - Diagnostic accuracy of the International Classification of Diseases, Tenth Revision, codes of heart failure in an administrative database. AB - PURPOSE: Heart failure (HF) is a common, serious, and still poorly known illness, which might benefit from studies in claims databases. However, to provide reliable estimates, HF patients must be adequately identified. This validation study aimed to estimate the diagnostic accuracy of the International Classification of Diseases, Tenth Revision (ICD-10) codes I50.x, heart failure, in the French hospital discharge diagnoses database. METHODS: This study was performed in two university hospitals, comparing recorded discharge diagnoses and electronic health records (EHRs). Patients with discharge ICD-10 codes 150.x were randomly selected. Their EHRs were reviewed to classify HF diagnosis as definite, potential, or miscoded based on the European Society of Cardiology diagnostic criteria, from which the codes' positive predictive value (PPV) was computed. To estimate sensitivity, patients with an EHR HF diagnosis were identified, and the presence of the I50.x codes was sought for in the hospital discharge database. RESULTS: Two hundred possible cases of HF were selected from the hospital discharge database, and 229 patients with an HF diagnosis were identified from the EHR. The PPV of I50.x codes was 60.5% (95% CI, 53.7%-67.3%) for definite HF and 88.0% (95% CI, 83.5%-92.5%) for definite/potential HF. The sensitivity of I50.x codes was 64.2% (95% CI, 58.0%-70.4%). PPV results were similar in both hospitals; sensitivity depended on the source of EHR: Departments of cardiology had a higher sensitivity than had nonspecialized wards. CONCLUSIONS: Diagnosis codes I50.x in discharge summary databases accurately identify patients with HF but fail to capture some of them. PMID- 30395377 TI - Catalyst-Controlled Dual Reactivity of Sulfonimidamides: Synthesis of Propargylamines and N-propargyl sulfonimidamides. AB - Sulfonimidamides (SIAs) are acting both as surrogate amines and nucleophiles depending on the reaction conditions to access propargylamines and N-propargyl SIAs respectively. The amine part of SIAs has been cleaved in an InCl3-catalyzed three-component A3 coupling reaction with aldehyde and acetylene to yield propargylamine. Moreover, N-propargyl SIAs were obtained via the direct-imination of propargyl alcohols in the presence of BF3.OEt2. PMID- 30395376 TI - Chemically Fueled Dissipative Self-Assembly that Exploits Cooperative Catalysis. AB - In living systems, dissipative processes are driven by the endergonic hydrolysis of chemical fuels such as nucleoside triphosphates. Now, through a simple model system, a transient self-assembled state is realized by utilizing the catalytic effect of histidine on the formation and breaking of ester bonds. First, histidine facilitates the ester bond formation, which then rapidly co-assembles to form a self-supporting gel. An out-of-equilibrium state is realized owing to the cooperative catalysis by the proximal histidines in the assembled state, driving the second pathway and resulting in disassembly to sol. Cooperative effects that use the dual role of imidazoles as nucleophile and as proton donor is utilized to achieve transient assemblies. This simple system mimics the structural journey seen in microtubule formation where the substrate GTP facilitates the non-covalent assembly and triggers a cooperative catalytic process, leading to substrate hydrolysis and subsequent disassembly. PMID- 30395378 TI - Refinement of Highly Flexible Protein Structures using Simulation-Guided Spectroscopy. AB - Highly flexible proteins present a special challenge for structure determination because they are multi-structured yet not disordered, so their conformational ensembles are essential for understanding function. Because spectroscopic measurements of multiple conformational populations often provide sparse data, experiment selection is a limiting factor in conformational refinement. A molecular simulations- and information-theory based approach to select which experiments best refine conformational ensembles has been developed. This approach was tested on three flexible proteins. For proteins where a clear mechanistic hypothesis exists, experiments that test this hypothesis were systematically identified. When available data did not yield such mechanistic hypotheses, experiments that significantly outperform structure-guided approaches in conformational refinement were identified. This approach offers a particular advantage when refining challenging, underdetermined protein conformational ensembles. PMID- 30395379 TI - Identification of Small Molecule Modulators of Diguanylate Cyclase by FRET-based High-Throughput-Screening. AB - The bacterial second messenger cyclic diguanosine monophos-phate (c-di-GMP) is a key regulator of cellular motility, the cell cycle, and biofilm formation with its resultant antibiotic tolerance, which may make chronic infections difficult to treat. Therefore, diguanylate cyclases, which regulate the spatiotemporal production of c-di-GMP, may be attractive drug targets to control biofilm formation that is part of chronic infections. In this paper, we present a FRET based biochemical high-throughput screening approach coupled with detailed structure-activity studies to identify synthetic small molecule modulators of the diguanylate cyclase, DgcA, from Caulobacter crescentus. We identified a set of 7 small molecules that in the low MUM range regulate DgcA enzymatic activity. Subsequent structure activity studies on selected scaffolds revealed a remarkable diversity of modulatory behaviors, including slight chemical substitutions that revert the effects from allosteric enzyme inhibition to activation. The compounds identified represent novel chemotypes and are potentially developable into chemical genetic tools for the dissection of c-di-GMP signaling networks and alteration of c-di-GMP associated phenotypes. In sum, our studies underline the importance for detailed mechanism of action studies for inhibitors of c-di-GMP signaling and demonstrate the complex interplay between synthetic small molecules and the regulatory mechanisms that control the activity of diguanylate cyclases. PMID- 30395380 TI - Application of in situ-Product Crystallization and Related Techniques in Biocatalytic Processes. AB - This review highlights specifically the application of crystallization as a very powerful in situ-product removal (ISPR) technique in biocatalytic process design. Special emphasis is placed on its use as a so-called in situ-product crystallization (ISPC) to overcome unfavorable thermodynamically reaction equilibria, inhibitions and undesired reactions. The combination of these unit operations requires per definition an interdisciplinary perspective to find a holistic solution in the underlying bioprocess intensification approach. Representative examples of successful integrated process options are selected, presented and assessed regarding their overall productivity and applicability. In addition, parallels to the use of adsorption as a very similar technique are drawn and similarities discussed. PMID- 30395381 TI - AMERICAN COLLEGE OF VETERINARY RADIOLOGYEUROPEAN COLLEGE OF VETERINARY DIAGNOSTIC IMAGING: Calendar of Important Dates. PMID- 30395382 TI - Consensus recommendations on standardized magnetic resonance imaging protocols for multicenter canine brain tumor clinical trials. PMID- 30395383 TI - Nonarticular osseous cyst-like lesions of the intermedioradial carpal bone may be incidental magnetic resonance imaging findings in dogs. AB - As magnetic resonance imaging (MRI) becomes more readily available and more frequently utilized in the assessment of canine carpal lameness, both normal variations and early pathologic conditions must be recognized to optimize patient care and provide accurate diagnosis. On cross sectional studies of the canine carpus, cyst-like lesions have been detected at the dorsolateral aspect of the intermedioradial carpal bone. The cross-sectional imaging and histologic properties of these lesions have not been described. The purpose of this observational study is to evaluate the MRI and histologic features of these cyst like lesions in a cohort of clinically sound dogs. It was hypothesized that the lesions would show features similar to intraosseous ganglion cysts of the human wrist. Twenty-five cadaveric canine carpi were obtained and a total of 13 lesions were detected on MRI. Based on MRI, six carpi with lesions of varying size and one normal carpus were submitted for histological evaluation. Five of the abnormal carpi had nonarticular cyst-like lesions; one specimen with a positive magnetic resonance image for a cyst-like lesion had no cyst-like lesion on histology. Conspicuity of a medium-size lesion as evaluated on radiographs was poor. Given the presence of these nonarticular cyst-like lesions in a population of clinically sound patients, their clinical importance is uncertain. The development of these lesions may relate to altered mechanics or genetic predispositions, requiring additional study. PMID- 30395384 TI - Intramolecular Consecutive Dehydro-Diels-Alder Reaction for the Catalytic and Enantioselective Construction of Axial Chirality. AB - Consecutive thermal and metal-catalyzed dehydro-Diels-Alder (DDA) reactions of sulfur-tethered tetraynes, possessing a 1,3-diyne moiety, proceeded efficiently, and axial chirality was achieved for the resulting dibenzothiophenyl moieties. Chiral-rhodium catalysis realized a highly enantioselective synthesis, and transformations into bis(benzocarbazole) derivatives were also achieved. PMID- 30395385 TI - Divergent Late-Stage (Hetero)Aryl C-H Amination by the Pyridinium Radical Cation. AB - (Hetero)arylamines constitute some of the most prevalent functional molecules, especially as pharmaceuticals. But currently, structurally complex aromatics cannot be converted to arylamines, so instead, each product isomer must be assembled through a multistep synthesis from simpler building blocks. Here we describe a late-stage aryl C-H amination reaction for the synthesis of complex primary arylamines that other reactions cannot access directly. We show and rationalize through a mechanistic analysis how to obtain the wide substrate scope and the constitutional diversity of the reaction, which gives access to molecules that would not have been readily available otherwise. PMID- 30395386 TI - Self-Orienting Hydrogel Micro-Buckets as Novel Cell Carriers. AB - Hydrogel microparticles are important in materials engineering, but their applications remain limited owing to the difficulties associated with their manipulation. Herein, we report the self-orientation of crescent-shaped hydrogel microparticles and elucidate its mechanism. Additionally, the microparticles were used, for the first time, as micro-buckets to carry living cells. In aqueous solution, the microparticles spontaneously rotated to a preferred orientation with the cavity facing up. We developed a geometric model that explains the self orienting behavior of crescent-shaped particles by minimizing the potential energy of this specific morphology. Finally, we selectively modified the particles' cavities with RGD peptide and exploited their preferred orientation to load them with living cells. Cells could adhere, proliferate, and be transported and released in vitro. These micro-buckets hold a great potential for applications in smart materials, cell therapy, and biological engineering. PMID- 30395387 TI - Diastolic velocity half time is associated with aortic coarctation gradient at catheterization independent of echocardiographic and clinical blood pressure gradients. AB - OBJECTIVE: The most accurate noninvasive parameter to predict whether a patient with aortic coarctation will meet interventional criteria at catheterization remains elusive. We aim to determine the best independent echocardiographic predictors of a coarctation peak-to-peak pressure gradient >=20 mm Hg at catheterization, the accepted threshold for intervention. DESIGN: Retrospective query of our catheterization database from 1/2007 to 7/2016 for the diagnostic code of aortic coarctation was performed. Multiple echocardiographic measurements and blood pressure gradients prior to cardiac catheterization were collected. Univariate correlation of variables with the continuous catheterization peak were calculated using Spearman's rho. Univariate association with peak-to-peak gradient at catheterization >=20 mm Hg was tested using Mann-Whitney U test and the Pearson chi-square test or Fisher's exact test. Multivariable logistic regression assessed the independent association of the clinically relevant metrics with gradient at catheterization >=20 mm Hg. RESULTS: Sixty-eight patients met study criteria (median age 9.25 years), of whom 84% underwent intervention at catheterization. Echocardiographic peak and mean coarctation velocity, indexed systolic and diastolic velocity half times (SVHTi, DVHTi), and blood pressure gradient all had moderate correlation (Spearman's rho = 0.529 0.617, P < .001) with the continuous catheterization gradient and were significantly associated with the binary outcome of catheterization peak >=20 mm Hg (P < .001). Logistic regression found echocardiographic mean systolic gradient (OR 1.213 [95% CI 1.041-1.414]) and DVHTi (OR 1.039 [95% CI 1.004-1.074]) independently associate with catheterization peak >=20 mm Hg after controlling for blood pressure gradient (OR 1.066 [0.987-1.150]). CONCLUSIONS: Most echocardiographic estimates show moderate correlation with arch gradient at catheterization. Noninvasive four extremity blood pressure gradient is significantly associated with peak-to-peak gradient >=20 mm Hg. DVHTi may provide a unique independently associated echocardiographic estimate of coarctation severity. Further study of these variables with larger cohorts may allow for development of predictive models to direct catheterization. PMID- 30395388 TI - Digital image analysis supports a nuclear-to-cytoplasmic ratio cutoff value below 0.7 for positive for high-grade urothelial carcinoma and suspicious for high grade urothelial carcinoma in urine cytology specimens. AB - BACKGROUND: Urinary cytology is sensitive and specific for diagnosing and screening high-grade urothelial carcinomas (HGUC). The Paris System (TPS) for urinary cytology was introduced in 2016 to standardize reporting. According to TPS diagnostic categories of HGUC and suspicious for HGUC (SHGUC), the average nuclear-to-cytoplasm (N:C) ratio of atypical cells should be >=0.7. The objective of the current study was to measure the N:C ratio of urine cytology specimens with HGUC and SHGUC diagnoses and biopsy-proven HGUC follow-up. METHODS: A cohort of 64 cases (HGUC, 49 cases; SHGUC, 15 cases) from 57 patients was constructed. Urine cytology slides were scanned into whole-slide digital images. The nuclear and cytoplasmic areas were enumerated by digital image analysis (DIA), and the N:C ratios were measured. RESULTS: In total, 640 cells were analyzed by DIA (HGUC, 490 cells; SHGUC, 150 cells). For HGUC and SHGUC, the average N:C ratios were 0.57 and 0.53, respectively. The maximum average N:C ratio was 0.73 for HGUC and 0.68 for SHGUC. HGUC had higher average N:C ratio (P < .001), higher average nuclear area (P < .001), higher average maximum N:C ratio (P = .005), and higher average maximum nuclear area (P = .006) compared with SHGUC. CONCLUSIONS: The N:C ratios for the HGUC (0.57) and SHGUC (0.53) categories are lower than those previously suggested in TPS. The authors advocate reducing the N:C ratio below the current threshold of 0.7. PMID- 30395389 TI - Ausschreibung G. K. Steigleder-Preis fur Dermatohistologie der Arbeitgemeinschaft Dermatologische Histologie (ADH) 2019. PMID- 30395390 TI - Braucht es eine stationare Dermatologie? PMID- 30395391 TI - Ein weiblicher Saugling mit papulovesikularen Lasionen. PMID- 30395392 TI - Seit Jahren bestehende verrukose Tumoren beider Unterschenkel. PMID- 30395394 TI - Kongresskalender 2018. PMID- 30395393 TI - Pengtala-Lappen zur Rekonstruktion von Defekten an der Nasenspitze. PMID- 30395395 TI - Bullous autoimmune dermatoses. AB - Pathophysiologically, bullous autoimmune dermatoses are caused by autoantibodies directed against adhesion molecules or structural proteins of the skin and mucous membranes, clinically resulting in blister formation. Depending on the respective target proteins of the autoimmune response and their location in the skin, a distinction is made between intraepidermal (pemphigus disorders), junctional (pemphigoid disorders), and subepidermal (epidermolysis bullosa acquisita, dermatitis herpetiformis) autoimmune blistering diseases. The most common bullous autoimmune dermatosis, bullous pemphigoid is characterized by marked clinical variability and intense pruritus. Predominantly affecting elderly individuals, there has been a significant increase in its incidence in recent years. While mucosal lesions occur in less than 30 % of bullous pemphigoid patients, the second most common bullous autoimmune dermatosis, pemphigus vulgaris, typically presents with oral erosions as the predominant and - frequently - initial symptom. Its onset is usually in the 4th to 6th decade of life. Scarring is typically found in subepidermal blistering disorders such as epidermolysis bullosa acquisita or mucous membrane pemphigoid. Diagnosis is based on clinical and histological findings as well as direct and indirect immunofluorescence and detection of circulating autoantibodies. Although a number of controlled clinical trials have been conducted in recent years, treatment of bullous autoimmune disorders is still primarily based on clinical experience. Therapeutic options include topical and systemic corticosteroids as well as adjuvant immunosuppressants. Recalcitrant cases may require treatment with immunoadsorption, intravenous immunoglobulins, or the monoclonal anti-CD20 antibody rituximab. PMID- 30395396 TI - Sind flexurale Komedonen im Kindesalter Hamartome? Eine monozentrische Studie. PMID- 30395397 TI - Hochregulation der SLURP1-Immunfarbung in Lasionen von Psoriasis-vulgaris Patienten entspricht dem Schweregrad der Erkrankung. AB - HINTERGRUND UND ZIELE: Die genaue Pathogenese der Psoriasis ist immer noch ungeklart. Da SLURP1 wichtig ist fur die normale Differenzierung von Keratinozyten, konnte es bei Psoriasis eine Rolle spielen. In dieser Studie untersuchten wir die immunhistochemische Farbung von SLURP1 bei Patienten mit Psoriasis vulgaris und deren moglichen Zusammenhang mit der Pathogenese der Erkrankung. PATIENTEN UND METHODEN: Es wurden Hautproben von 20 Patienten mit Psoriasis vulgaris, von 20 Patienten mit psoriasiformer Dermatitis sowie 20 normale Hautproben untersucht. Der Schweregrad der Psoriasis wurde anhand einer Kombination von PASI- und DLQI-Scores gemessen. Bei allen Psoriasis-Patienten wurden Biopsate aus lasionalen und aus nichtlasionalen Hautpartien entnommen. Bei psoriasiformer Dermatitis und Kontrollen wurde jeweils nur ein Hautbiopsat entnommen. Alle Schnitte wurden, entsprechend des Hersteller-Protokolls, einer SLURP1-Immunfarbung unterzogen. ERGEBNISSE: Hinsichtlich der SLURP1-Immunfarbung wurden zwischen lasionalen und nichtlasionalen Biopsaten von Psoriasis-Patienten sowie zwischen lasionalen Biopsaten von Psoriasis-Patienten und Patienten mit psoriasiformer Dermatitis signifikante Unterschiede festgestellt. Die Unterschiede zwischen nichtlasionalen Biopsaten von Psoriasis-Patienten und normalen Hautproben waren jedoch nicht signifikant. Daruber hinaus war der Grad der SLURP1-Immunanfarbung proportional zum Schweregrad der Psoriasis. SCHLUSSFOLGERUNGEN: Bei Psoriasis vulgaris ist die SLURP1-Immunfarbung in lasionaler Haut signifikant erhoht, nicht jedoch bei psoriasiformer Dermatitis. Dies spricht fur eine Rolle von SLURP1 bei der Pathogenese der Psoriasis. SLURP1 lasst sich moglicherweise als biologischer Marker fur den Schweregrad der Psoriasis einsetzen, wobei diese Hypothese noch weiterer Untersuchungen bedarf. PMID- 30395398 TI - Solitarer Tumor am Unterarm. PMID- 30395399 TI - Recommendations for photopatch testing by the Photopatch Test Working Group of the German Contact Dermatitis Research Group (DKG). PMID- 30395400 TI - Therapeutisches Management bei Vitiligo. AB - Vitiligo ist eine erworbene Hauterkrankung, an der weltweit 0,5 % der Bevolkerung erkranken und die eine grobetae Herausforderung in der dermatologischen Versorgung darstellt. Die Erkrankung geht fur Betroffene oftmals aufgrund der fleckigen Depigmentierung mit einer kosmetischen Entstellung und grobetaem Leidensdruck einher. Pathophysiologisch werden als Hauptursachen fur den Verlust funktionierender Melanozyten eine genetische Pradisposition, autoimmune Mechanismen und oxidativer Stress angesehen. Vorgestellt werden die Therapieempfehlungen der europaischen Leitlinie in Erganzung mit Empfehlungen aus aktuellen Ubersichtsarbeiten zu Vitiligo. Bisherige therapeutische Optionen greifen auf drei Wegen: (1.) Regulation der Autoimmunantwort mit topischen und systemischen immunmodulierenden Pharmaka (Kortikosteroide und Calcineurininhibitoren), (2.) Reduktion des melanozytaren, oxidativen Stress mittels topischer und systemischer Antioxidantien sowie (3.) Aktivierung der Melanozytenregeneration durch Phototherapie (v. a. UVB) und Transplantation von pigmentierten Zellen. Daruber hinaus sollten dem Patienten Techniken zur Camouflage angeboten werden. Nach erfolgreicher Repigmentierung ist eine Rezidivprophylaxe mit Calcineurininhibitoren sinnvoll. Kombinationstherapien oben genannter Therapieansatze werden generell als erfolgreicher angesehen als Monotherapien. Auch ist ein moglichst fruher Therapiebeginn prognostisch gunstig. Mit Hilfe der genannten Therapieansatze kann es gelingen das Fortschreiten der Erkrankung aufzuhalten, depigmentierte Herde zu stabilisieren und eine Repigmentierung zu erreichen. Nur in Ausnahmefallen kommt eine dauerhafte Depigmentierung in Frage. Weiterreichende Erkenntnisse zur Pathogenese der Erkrankung lassen auf neue Therapieansatze hoffen. PMID- 30395401 TI - Aktuelle Therapiestudien beim Merkelzellkarzinom. PMID- 30395402 TI - Komorbiditat von lokalisierter Sklerodermie und primar biliarer Cholangitis. PMID- 30395403 TI - Empfehlungen der Arbeitsgruppe "Photopatchtest" der Deutschen Kontaktallergie Gruppe (DKG) zur Durchfuhrung des Photopatchtests. PMID- 30395404 TI - Bullose Autoimmundermatosen. PMID- 30395405 TI - Perforierender Nasenwanddefekt: Verschluss mittels Kombinationslappenplastik. PMID- 30395407 TI - Lesional upregulation of SLURP1 immunostaining parallels disease severity in psoriasis vulgaris patients. AB - BACKGROUND AND OBJECTIVES: The exact pathogenesis of psoriasis is still unclear. SLURP1 is vital for the normal differentiation of keratinocytes, and could therefore be involved in psoriasis. In this study we investigated the immunohistochemical staining reaction of SLURP1 in psoriasis vulgaris patients and its possible relation to disease pathogenesis. PATIENTS AND METHODS: 20 patients with psoriasis vulgaris, 20 patients with psoriasiform dermatitis and 20 normal skin samples were studied. Psoriasis severity was measured with a combination of PASI and DLQI scores. Lesional and non-lesional sites were biopsied for each psoriasis patient. A single biopsy sample was taken for cases with psoriasiform dermatitis and for controls. All sections were immunostained for SLURP1 according to the manufacturer's protocol. RESULTS: Significant differences were noted in SLURP1 immunostaining between lesional and non-lesional biopsies of psoriasis patients and between lesional biopsies of psoriasis patients and lesional sites of psoriasiform dermatitis. However, the differences between non-lesional biopsies of psoriasis patients and normal controls were not significant. Furthermore, the grading of SLURP1 immunostaining paralleled the degree of psoriasis severity. CONCLUSIONS: SLURP1 immunostaining is significantly increased in lesional skin of psoriasis vulgaris and not in psoriasiform dermatitis, which demonstrates the role of SLURP1 in the pathogenesis of psoriasis. SLURP1 could be used as a biological marker for psoriasis severity, and this hypothesis warrants further investigation. PMID- 30395408 TI - Comorbidity of localized scleroderma and primary biliary cholangitis. AB - BACKGROUND AND OBJECTIVES: Morphea is frequently associated with other autoimmune disorders. Little is known about the association of morphea and primary biliary cholangitis (PBC). The objective of this case series was to study the possible association of morphea with PBC and to identify risk factors. PATIENTS AND METHODS: Patients with morphea were screened for anti-mitochondrial antibodies (AMA) by indirect immunofluorescence and/or immunoblot. Human leucocyte antigen (HLA) genotyping and deep sequencing for the HLA DRB1 subgroup were confirmed in AMA-positive patients. RESULTS: 6 of 91 patients (6.6 %) showed positivity for AMA, and 4 (4.39 %) had PBC. The mean age of AMA-positive patients was 69.0 years. Of 6 AMA-positive patients, common predisposing alleles (HLA DRB1*15: 01 and HLA DRB1*08) were detectable in two patients. One patient had predisposing alleles for both diseases (HLA DRB1*03: 01 and HLA DRB1*14). One patient had a PBC-conferring allele. Female gender, menopause and tendency for remission of morphea were common in all patients. CONCLUSION: The coexistence of morphea, AMA positivity and PBC is a rare but possible association. Common predisposing HLA alleles might interact in such a simultaneous manifestation. We suggest AMA screening for female patients with generalized morphea before the initiation of methotrexate. PMID- 30395409 TI - Komplette Remission eines Patienten mit metastasierten Uveamelanom nach initialem Progress unter Immuntherapie mit Pembrolizumab. PMID- 30395410 TI - Zum 90. Geburtstag von Prof. Dr. med. Norbert Hofmann. PMID- 30395411 TI - Wissensstand zur Anaphylaxie und Umgang mit Adrenalinautoinjektoren in Apotheken. AB - HINTERGRUND: Adrenalin intramuskular mit Hilfe eines Autoinjektors ist das Mittel der Wahl zur Selbstbehandlung schwerer allergischer Reaktionen. Zahlen aus dem Anaphylaxie-Register zeigen, dass Adrenalinautoinjektoren selten von Patienten eingesetzt werden. Apotheker sind eine wichtige Schnittstelle zwischen verordnendem Arzt und Patienten. PATIENTEN UND METHODIK: Ziel der vorliegenden Arbeit war es, den Wissensstand bei Apothekern zur Anaphylaxie und deren Behandlung mittels definierter Wissensfragen strukturiert zu erheben. Hierzu wurden Daten von einer standardisierten Fragebogenerhebung von 213 Apotheken analysiert. ERGEBNISSE: Die Daten zeigen, dass Apotheker die Anaphylaxie als eine Erkrankung mit reduzierter Lebensqualitat einschatzen. Die Benennung der haufigsten Ausloser einer Anaphylaxie durch die Apotheker entspricht den Daten aus dem Anaphylaxie-Register (Insektengift, Nahrungsmittel und Medikamente). Die Auswertung zum Wissensstand der Apotheker zeigt, dass Fallbeschreibungen einer Anaphylaxie richtig zugeordnet werden konnen. Es bestehen jedoch Wissensdefizite bei Fragen zur Behandlung einer Anaphylaxie mit Adrenalin und zu den Leitlinien. SCHLUSSFOLGERUNGEN: Die vorliegende Untersuchung zeigt, dass der Wissensstand von Apothekern zur Anaphylaxie verbessert werden kann. Da Apotheker eine wesentliche Schnittstelle bei der Versorgung von Patienten mit allergischen Erkrankungen darstellen, sollte Ziel weiterfuhrender Mabetanahmen sein, diese Schnittstelle durch Aufklarungs- und Schulungsmodule zu verstarken, um somit die Patientenversorgung zu verbessern. PMID- 30395412 TI - Segmentaler Morbus Darier mit ungewohnlich spatem Beginn. PMID- 30395413 TI - Ein dermatoskopisches Portrat von zeitlichen morphologischen Anderungen der vulvaren Melanose. PMID- 30395414 TI - Hyperkeratose der Brustwarze und des Warzenhofs: eine histopathologische Falle! PMID- 30395415 TI - Bifid T waves on the ECG and genetic variation in calcium channel voltage dependent beta 2 subunit gene (CACNB2) in acute Kawasaki disease. AB - BACKGROUND: We previously described the association of genetic variants in calcium channel genes and susceptibility to Kawasaki disease (KD), an acute, self limited vasculitis, and the most common cause of acquired cardiac disease in children. Abnormal repolarization of cardiomyocytes and changes in T wave morphology have been reported in KD but have not been studied systematically. METHODS: We analyzed acute and convalescent ECG T wave morphology in two independent cohorts of KD subjects and studied the association between bifid T waves and genetic variants in previously reported genes with SNVs associated with cardiac repolarization. RESULTS: Bifid T waves in limb leads were identified in 24% and 27% of two independent cohorts of acute KD subjects. Calcium channel voltage-dependent beta 2 subunit gene (CACNB2) (rs1409207) showed association with bifid T waves in both cohorts (nominal P = .04 and P = .0003, respectively). This CACNB2 polymorphism also showed association with KD susceptibility in a previously published KD genome wide association study data (nominal P = .009). CONCLUSION: This genotype/phenotype association study uncovered a variant in CACNB2 that may be associated with both KD susceptibility and bifid T waves, a novel signature of altered myocardial repolarization. The present study combined with published reports suggests that genetic variants in calcium channels and intracellular calcium signaling play a prominent role in shaping susceptibility to KD. PMID- 30395416 TI - Sustained Protein Release from a Core-Shell Drug Carrier System Comprised of Mesoporous Nanoparticles and an Injectable Hydrogel. AB - The manufacture of a biocompatible carrier for controlled delivery of bioactive compounds is described. This carrier is composed of a mesoporous silica nanoparticle as core that is homogenously distributed in an injectable hydrogel. For the synthesis of nanoparticles, a one step sol-gel method is developed to produce pores with the range of 100 nm. BMP2 and Fluorescein-conjugated bovine serum albumin is used as proteinaceous agents for measuring release, and is loaded into mesoporous silica nanoparticles at the optimum conditions of 48 h incubation period using 1:10 ratio of protein to nanoparticles. The release of proteins from either mesoporous nanoparticles or hydrogel individually involves a burst release stage, however the release from the core/shell carrier designed in this study follows a zero order kinetic. In summary, this biomaterial may be favorable for delivery of bioactive compounds such as BMP2 for a range of applications including bone tissue regeneration. PMID- 30395417 TI - Neutron Scattering Investigations of Hydride Species in Heterogeneous Catalysis. AB - In heterogeneous catalysis, hydrides on the surface or in the bulk play a critical role as either active components or reaction intermediates in many hydrogen-involving reactions, but characterization of the nature and structure of these hydride species remains challenging. Neutron scattering, which is extremely sensitive to light elements, such as hydrogen, has shown great potential in meeting this challenge. In this Minireview, recent advances in neutron studies of hydride species, mainly over the two most typical classes of catalysts-metals and oxides-are surveyed. Findings on catalysts outside these categories are raised if they are considered to be relevant for contextualization in the present Minireview. The adsorption, dissociation, spillover, and reactivity of hydrogen, especially hydride species over supported metal and oxide catalysts, have been successfully investigated, mostly by means of neutron vibrational spectroscopy. Insights from these neutron studies, which are otherwise not possible with other techniques, shed light on the interaction mechanism of hydrogen with solid surfaces and reaction mechanisms in which hydrogen is involved. Future research challenges on neutron scattering studies of hydrides, as well as catalysis in general, are also highlighted, and more operando-type neutron studies need be conducted to advance the field. PMID- 30395418 TI - Techniques for Intracranial Stereotaxic Injections of Adeno-Associated Viral Vectors in Adult Mice. AB - Stereotaxic intracranial injection of viral vectors is a valuable technique to directly deliver genetic material to a specific population of cells in the central nervous system of a mouse model. This enables scientists to test candidate gene therapies or disease modulators that can then provide insight into the pathological mechanisms of disease. In this article, we present a standardized method of conducting intracranial stereotaxic injection of adeno associated virus into a specific brain region in a mouse model. Support protocols are provided for virus dialysis and testing new stereotaxic coordinates with dye. (c) 2018 by John Wiley & Sons, Inc. PMID- 30395419 TI - Image features in correlation with biopsy in diabetic mastopathy associated with diabetes type 2 AB - Background: Diabetic mastopathy is an uncommon complication of diabetes mellitus (DM) of long-term evolution which can be confused with breast cancer. Therefore, it is important to know this entity. Clinical case: The aim of the present study is to show the characteristics of mastography and breast ultrasound (US) in a 64 year-old Mexican woman with DM of 27 years of evolution treated with insulin. This patient presented increased volume in both breasts secondary to diabetic mastopathy. We describe the utility of the US-guided core-needle biopsy as well. Conclusion: Diabetic mastopathy is a rare morphological change, which requires clinical correlation and sets out the differential diagnosis in physical examination and imaging studies of breast cancer. Breast US is the most useful diagnostic tool to evaluate a palpable nodule in a patient with suspected diabetic mastopathy and the biopsy is the gold standard test which allows the diagnosis. PMID- 30395421 TI - Code of Ethics and Conduct of the Brazilian Association of Embryologists - PRONUCLEO. AB - For more than three decades, Brazilian Clinical Embryologists have been working without specific regulations and following the standards adopted by other healthcare professionals. This document aims to guide behavior and decision making, while providing directions to embryologist with the purpose of aiding professionals involved with assisted reproduction procedures and their patients. The Code of Ethics and Conduct is an important breakthrough and the first step toward regulating Clinical Embryology as a profession. PMID- 30395429 TI - Hyaluronic Acid-Based Multilayer Films Regulate Hypoxic Multicellular Aggregation of Pancreatic Cancer Cells with Distinct Cancer Stem-Cell-like Properties. AB - In vitro spherical cancer models have been widely used in cancer stem cell (CSC) research, and the ability of CSCs to form multicellular colonies is recognized as a morphological marker. However, although several spherical/colony models share a common three-dimensional (3D) conformation, each model displays its own intrinsic properties. Thus, the CSC phenotypes with distinct multicellular aggregate morphologies must be defined and clarified. Here, a novel 3D model was designed to regulate the type of pancreatic CSC colonies that form using niche mimetic hyaluronic acid (HA)-based multilayer nanofilms and hypoxia. The multicellular aggregate morphology, CSC phenotypes, CSC-related marker expression, cell cycle, invasion, and drug resistance were determined. On the basis of the results of a cell morphology analysis, colonies formed on multilayer nanofilms in response to both normoxia and hypoxia, but round and island-type colonies, were investigated. Immunostaining results revealed a significantly higher expression of stem cell markers, such as OCT4, CXCR4, and CD44v6, in colonies that formed on multilayer nanofilms. These colonies also expressed higher levels of E-cadherin, hypoxia inducible factor-1alpha, and vimentin, particularly the round-type colonies that formed on HA-based multilayer nanofilms, [poly(allylamine) (PAH)/HA]3, indicating that these colonies exhibit hybrid and metastable epithelial/mesenchymal phenotypes. Moreover, the cell cycle and invasion tests revealed that most of the cells in colonies growing on multilayer nanofilms showed a quiescent, slow cycling phenotype but displayed higher invasion after induction. Furthermore, a hypoxic environment strongly influences the drug resistance. This study describes a useful tool to investigate the diverse phenotypes of pancreatic CSC colonies and to study their regulatory factors that may benefit CSC research. PMID- 30395135 TI - Search for heavy particles decaying into top-quark pairs using lepton-plus-jets events in proton-proton collisions at s=13 TeV with the ATLAS detector. AB - A search for new heavy particles that decay into top-quark pairs is performed using data collected from proton-proton collisions at a centre-of-mass energy of 13 TeV by the ATLAS detector at the Large Hadron Collider. The integrated luminosity of the data sample is 36.1 fb -1 . Events consistent with top-quark pair production are selected by requiring a single isolated charged lepton, missing transverse momentum and jet activity compatible with a hadronic top-quark decay. Jets identified as likely to contain b-hadrons are required to reduce the background from other Standard Model processes. The invariant mass spectrum of the candidate top-quark pairs is examined for local excesses above the background expectation. No significant deviations from the Standard Model predictions are found. Exclusion limits are set on the production cross-section times branching ratio for hypothetical Z' bosons, Kaluza-Kein gluons and Kaluza-Klein gravitons that decay into top-quark pairs. PMID- 30395430 TI - Anodized Aluminum with Nanoholes Impregnated with Quaternary Ammonium Compounds Can Kill Pathogenic Bacteria within Seconds of Contact. AB - Bacterial contamination of surfaces results in the spread of pathogens in public spaces such as hospitals and public transport. The development of antibacterial surfaces that rapidly kill bacteria is therefore highly desirable. Here, we investigate the antibacterial efficacy of a novel anodized aluminum surface featuring nanoholes impregnated with quaternary ammonium compounds, referred to as A3S. The antimicrobial activity of A3S was assessed using both Gram-positive and Gram-negative bacteria in a novel assay which simulates pathogen transfer from a contaminated "finger" to a clean finger in a real-world scenario. Enumeration of colony-forming units shows that the number of viable bacteria on the second "finger" contacting A3S is significantly reduced compared to a control surface. Furthermore, bacterial contact with the A3S material results in compromised cell membranes in less than 1 min, and a kill zone assay shows that an exposure time as short as 5 s is sufficient to kill pathogenic bacteria. The rapid antimicrobial action of A3S was particularly evident against Gram-positive bacteria, that account for more than 70% of nosocomial infections. Taken together, these findings demonstrate that A3S is a promising candidate for the fabrication of antibacterial surfaces that can be used in a wide range of clinical and commercial applications to stop the spread of harmful bacteria. PMID- 30395431 TI - Wearable Polyethylene/Polyamide Composite Fabric for Passive Human Body Cooling. AB - Personal cooling technologies (PCTs) locally control the temperature of an individual instead of a whole building and are thus energy saving. However, most PCTs still consume energy and are heavy in weight, restricting their application among human beings. To achieve personal thermal comfort and no energy consumption on hot summer days, we designed a bilayer structure fabric with high thermal comfort by increasing the dissipation of human thermal radiation and reducing solar energy absorption simultaneously. The fabric consisted of two layers, including a polyethylene film with nanopores (100-1000 nm in pore size) and a film made of nylon 6 nanofibers (ca. 100 nm in diameter) with beads (ca. 230 nm in diameter), which could increase the visible light reflectance but not affect the infrared wave radiation. Therefore, the designed fabric showed a high heat dissipation power, which was 14.13, 17.93, and 17.93 W/m2 higher than that of the selected traditional textiles of cotton, linen, and odile, respectively, suggesting good cooling capability. Its cooling performance was better than those reported by the previous research works even at a higher ambient temperature. Meanwhile, the moisture penetrability and hygroscopic property results indicated that the wearing comfort of the designed fabric reached the levels of the selected traditional textiles. PMID- 30395432 TI - Mixing Poly(ethylene glycol) and Poly(2-alkyl-2-oxazoline)s Enhances Hydration and Viscoelasticity of Polymer Brushes and Determines Their Nanotribological and Antifouling Properties. AB - Poly(2-alkyl-2-oxazoline)s (PAOXAs) have progressively emerged as suitable alternatives for replacing poly(ethylene glycol) (PEG) in a variety of biomaterial-related applications, especially in the designing of polymer brush based biointerfaces because of their stealth properties and chemical robustness. When equimolar mixtures of PEG and PAOXAs are assembled on surfaces to yield mixed polymer brushes, the interfacial physicochemical properties of the obtained films are significantly altered, in some cases, surpassing the biopassive and lubricious characteristics displayed by single-component PAOXA and PEG counterparts. With a combination of variable angle spectroscopic ellipsometry, quartz crystal microbalance with dissipation, and atomic force microscopy-based methods, we demonstrate that mixing of PEG brushes with equimolar amounts of PAOXA grafts determines an increment in film's hydration and viscoelasticity. In the case of mixtures of PEG and poly(2-methyl-2-oxazoline) or poly(2-ethyl-2 oxazoline), brushes displaying full inertness toward serum proteins and improved lubricity with respect to the corresponding single-component layers can be generated, while providing a multifunctional surface that substantially enlarges the applicability of the designed coatings. PMID- 30395437 TI - Bioorthogonal Profiling of a Cancer Cell Proteome Identifies a Large Set of 3 Bromopyruvate Targets beyond Glycolysis. AB - 3-Bromopyruvate (3BP) is a potential anticancer agent viewed as a glycolytic inhibitor that preferentially kills cancer cells through inhibition of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), resulting in severe energy depletion. We previously identified four cysteine residues in GAPDH that are alkylated by 3BP, resulting in its inactivation. However, we also showed that addition of excess pyruvate, the final product of glycolysis, was unable to rescue cells from 3BP treatment. This result indicates that GAPDH may not be the only relevant target and is consistent with the chemical reactivity of 3BP that should result in the modification of cysteine residues in many different proteins. To directly test this hypothesis, we first synthesized a probe of 3BP activity bearing an alkyne functionality, termed AO3BP, and then demonstrated that this probe could modify a variety of proteins in living cells. Subsequent competition of AO3BP labeling with pretreatment by 3BP identified 62 statistically significant proteins of various functions as targets of 3BP, confirming that 3BP labeling is indeed widespread. We conclude that 3BP's cytotoxic impact on cancer cells does not only result from selective inhibition of glycolysis but rather from a more widespread effect on cellular proteins that could be driven by the pharmacokinetics of the 3BP. These pleiotropic consequences should be considered when thinking about the potential toxicity of this highly reactive compound. PMID- 30395434 TI - High-Power Aqueous Zinc-Ion Batteries for Customized Electronic Devices. AB - Wireless electronic devices require small, rechargeable batteries that can be rapidly designed and fabricated in customized form factors for shape conformable integration. Here, we demonstrate an integrated design and manufacturing method for aqueous zinc-ion batteries composed of polyaniline (PANI)-coated carbon fiber (PANI/CF) cathodes, laser micromachined zinc (Zn) anodes, and porous separators that are packaged within three-dimensional printed geometries, including rectangular, cylindrical, H-, and ring-shapes. The PANI/CF cathode possesses high surface area and conductivity giving rise to high rate (~600 C) performance. Due to outstanding stability of Zn-PANI batteries against oxygen and moisture, they exhibit long cycling stability in an aqueous electrolyte solution. As exemplar, we demonstrated rechargeable battery packs with tunable voltage and capacity using stacked electrodes that are integrated with electronic components in customized wearable devices. PMID- 30395438 TI - Formation of Si Hollow Structures as Promising Anode Materials through Reduction of Silica in AlCl3-NaCl Molten Salt. AB - Hollow nanostructures are attractive for energy storage and conversion, drug delivery, and catalysis applications. Although these hollow nanostructures of compounds can be generated through the processes involving the well-established Kirkendall effect or ion exchange method, a similar process for the synthesis of the pure-substance one ( e. g., Si) remains elusive. Inspired by the above two methods, we introduce a continuous ultrathin carbon layer on the silica nano/microstructures (Stober spheres, diatom frustules, sphere in sphere) as the stable reaction interface. With the layer as the diffusion mediator of the reactants, silica structures are successfully reduced into their porous silicon hollow counterparts with metal Al powder in AlCl3-NaCl molten salt. The structures are composed of silicon nanocrystallites with sizes of 15-25 nm. The formation mechanism can be explained as an etching-reduction/nucleation-growth process. When used as the anode material, the silicon hollow structure from diatom frustules delivers specific capacities of 2179, 1988, 1798, 1505, 1240, and 974 mA h g-1 at 0.5, 1, 2, 4, 6, and 8 A g-1, respectively. After being prelithiated, it retains 80% of the initial capacity after 1100 cycles at 8 A g 1. This work provides a general way to synthesize versatile silicon hollow structures for high-performance lithium ion batteries due to the existence of ample silica reactants and can be extended to the synthesis of hollow structures of other materials. PMID- 30395436 TI - Tailoring Bond Topologies in Open-Shell Graphene Nanostructures. AB - Polycyclic aromatic hydrocarbons exhibit a rich spectrum of physicochemical properties depending on the size and, more critically, on the edge and bond topologies. Among them, open-shell systems-molecules hosting unpaired electron densities-represent an important class of materials for organic electronic, spintronic, and optoelectronic devices, but remain challenging to synthesize in solution. We report the on-surface synthesis and scanning tunneling microscopy- and spectroscopy-based study of two ultralow-gap open-shell molecules, namely peri-tetracene, a benzenoid graphene fragment with zigzag edge topology, and dibenzo[ a, m]dicyclohepta[ bcde, nopq]rubicene, a nonbenzenoid nonalternant structural isomer of peri-tetracene with two embedded azulene units. Our results provide an understanding of the ramifications of altered bond topologies at the single-molecule scale, with the prospect of designing functionalities in carbon based nanostructures via engineering of bond topology. PMID- 30395435 TI - Affinity Purification of Methyllysine Proteome by Site-Specific Covalent Conjugation. AB - A basic but critical step in targeted proteomics by mass spectrometry is the separation of the targeted proteins from the complex mixture of the whole proteome by affinity purification. The bait protein is usually immobilized on the surface of a solid support to enable affinity-based purification of the targeted proteome. Here, we developed a site-specific covalent immobilization of the bait protein through affinity-guided covalent coupling (AGCC) of a single cysteine residue of an SH2 domain (utilized as an affinity tag for the protein target) with an engineered ligand peptide. Site-specific covalent immobilization of a methyllysine-binding protein HP1beta chromodomain on the agarose resin was used to purify the methyllysine proteome from the whole-protein mixture. This new bait immobilization led to a notably low background in the affinity purification step, markedly outperforming the conventional (His)6 tag-nickel nitrilotriacetic acid (Ni-NTA) immobilization method. Subsequent analysis of the purified proteome identified 275 lysine methylated sites and 184 methylated proteins from 332 HP1beta CD-binding proteins, including 30 novel methylated proteins. This work demonstrates that a robust site-specific covalent protein immobilization method is well-suited for proteomic analysis of low-abundance proteins. This method also enables the identification of new methylated proteins and methylation sites in the methyllysine proteome. PMID- 30395433 TI - Efficient UV Filter Solubilizers Prevent Recrystallization Favoring Accurate and Safe Sun Protection. AB - Sun protection is a global concern, and maximizing sunscreen stability and efficacy depends partially on the prevention of UV filters recrystallization. We aimed to study the efficacy of hydrophobic solubilizers in preventing the recrystallization of solid hydrophobic UV filters in predissolutions, sunscreen formulations, and during simulated human use. Recrystallization of UV filters induced by ultrasonication, temperature variation, or simulated human application was analyzed by different methods. Maximum solubility of UV filters in solubilizers was determined. Surprisingly, the best solubilizer was not necessarily the best solvent to prevent recrystallization, suggesting there are different forces controlling these phenomena. Hydrophobic solubilizers tend to perform better than ethanol in predissolutions, but the presence of other components in final products may change their performance. Results suggest that some UV filters tend to form liquid clusters, which may behave as crystals and affect the desired even distribution of UV filters on the skin. UV filters were also found to respond differently to Hansen Solubility Parameters. Scanning electron microscopy supports the fact that recrystallization upon sunscreen application is an issue to be tested during development. A timesaving method to predict recrystallization of UV filters in clear systems was developed and is presented as a tool to enhance the efficacy of sunscreens. PMID- 30395439 TI - Ultralow Power Dual-Gated Subthreshold Oxide Neuristors: An Enabler for Higher Order Neuronal Temporal Correlations. AB - Inspired by neural computing, the pursuit of ultralow power neuromorphic architectures with highly distributed memory and parallel processing capability has recently gained more traction. However, emulation of biological signal processing via artificial neuromorphic architectures does not exploit the immense interplay between local activities and global neuromodulations observed in biological neural networks and hence are unable to mimic complex biologically plausible adaptive functions like heterosynaptic plasticity and homeostasis. Here, we demonstrate emulation of complex neuronal behaviors like heterosynaptic plasticity, homeostasis, association, correlation, and coincidence in a single neuristor via a dual-gated architecture. This multiple gating approach allows one gate to capture the effect of local activity correlations and the second gate to represent global neuromodulations, allowing additional modulations which augment their plasticity, enabling higher order temporal correlations at a unitary level. Moreover, the dual-gate operation extends the available dynamic range of synaptic conductance while maintaining symmetry in the weight-update operation, expanding the number of accessible memory states. Finally, operating neuristors in the subthreshold regime enable synaptic weight changes with high gain while maintaining ultralow power consumption of the order of femto-Joules. PMID- 30395441 TI - Equipping Inner Central Components of Influenza A Virus with Quantum Dots. AB - Influenza A virus (IAV), a risk to public health, is enveloped and contains viral ribonucleoprotein (vRNP) complexes, where vRNP complexes are central to every aspect of the IAV life cycle. Labeling both the vRNP complexes and viral envelope with quantum dots (QDs) is conducive to achieving global long-term tracking of a single IAV infecting host cell, which has potential to provide valuable information for revealing mechanisms of IAV infection. However, even though some strategies for labeling of the viral envelope with QDs have been developed, there are few strategies for coupling of QDs to the vRNP complexes inside IAV so far. Herein, we devised a convenient electroporation-based strategy, coupled with antibody binding, to transfer green QDs-labeled nucleoprotein antibodies (GQDs NPAb) into H1N1 and achieved the labeling of vRNP complexes with QDs [H1N1(GQDs)]. Under the optimal condition of 20 nM GQDs-NPAb and a single pulse with 20 ms duration and 750 V/cm pulse intensity, the actual efficiency of labeling is ca. 34% and H1N1(GQDs) can retain 93% infectivity. Then, dual labeling of H1N1 was realized by labeling the envelope of H1N1(GQDs) with red QDs (RQDs) via a mild and efficient hydrazine-aldehyde-based strategy. At the optimal RQDs concentration of 5 nM, the actual efficiency of dual labeling can reach to 11% and the dual-labeled H1N1 can retain 93% infectivity. Because of the similar components and structure of different IAV subtypes, this dual-labeling strategy is applicable to other subtypes of IAV, e.g., H9N2. PMID- 30395440 TI - Apolipoprotein E Peptide-Directed Chimeric Polymersomes Mediate an Ultrahigh Efficiency Targeted Protein Therapy for Glioblastoma. AB - The inability to cross the blood-brain barrier (BBB) prevents nearly all chemotherapeutics and biotherapeutics from the effective treatment of brain tumors, rendering few improvements in patient survival rates to date. Here, we report that apolipoprotein E peptide [ApoE, (LRKLRKRLL)2C] specifically binds to low-density lipoprotein receptor members (LDLRs) and mediates superb BBB crossing and highly efficient glioblastoma (GBM)-targeted protein therapy in vivo. The in vitro BBB model studies reveal that ApoE induces 2.2-fold better penetration of the immortalized mouse brain endothelial cell line (bEnd.3) monolayer for chimeric polymersomes (CP) compared to Angiopep-2, the best-known BBB-crossing peptide used in clinical trials for GBM therapy. ApoE-installed CP (ApoE-CP) carrying saporin (SAP) displays a highly specific and potent antitumor effect toward U-87 MG cells with a low half-maximum inhibitory concentration of 14.2 nM SAP. Notably, ApoE-CP shows efficient BBB crossing as well as accumulation and penetration in orthotopic U-87 MG glioblastoma. The systemic administration of SAP-loaded ApoE-CP causes complete growth inhibition of orthotopic U-87 MG GBM without eliciting any observable adverse effects, affording markedly improved survival benefits. ApoE peptide provides an ultrahigh-efficiency targeting strategy for GBM therapy. PMID- 30395442 TI - Mask-Free Laser Lithography for Rapid and Low-Cost Microfluidic Device Fabrication. AB - Microfluidics has become recognized as a powerful platform technology associated with a constantly increasing array of applications across the life sciences. This surge of interest over recent years has led to an increased demand for microfluidic chips, resulting in more time being spent in the cleanroom fabricating devices using soft lithography-a slow and expensive process that requires extensive materials, training and significant engineering resources. This bottleneck limits platform complexity as a byproduct of lengthy delays between device iterations and affects the time spent developing the final application. To address this problem, we report a new, rapid, and economical approach to microfluidic device fabrication using dry resist films to laminate laser cut sheets of acrylic. We term our method laser lithography and show that our technique can be used to engineer 200 MUm width channels for assembling droplet generators capable of generating monodisperse water droplets in oil and micromixers designed to sustain chemical reactions. Our devices offer high transparency, negligible device to device variation, and low X-ray background scattering, demonstrating their suitability for real-time X-ray-based characterization applications. Our approach also requires minimal materials and apparatus, is cleanroom free, and at a cost of around $1.00 per chip could significantly democratize device fabrication, thereby increasing the interdisciplinary accessibility of microfluidics. PMID- 30395443 TI - Assessing Interactions between Helical Aromatic Oligoamide Foldamers and Protein Surfaces: A Tethering Approach. AB - Helically folded aromatic foldamers may constitute suitable candidates for the ab initio design of ligands for protein surfaces. As preliminary steps toward the exploration of this hypothesis, a tethering approach was developed to detect interactions between a protein and a foldamer by confining the former at the surface of the latter. Cysteine mutants of two therapeutically relevant enzymes, CypA and IL4, were produced. Two series of ten foldamers were synthesized bearing different proteinogenic side chains and either a long or a short linker functionalized with an activated disulfide. Disulfide exchange between the mutated cysteines and the activated disulfides yielded 20 foldamer-IL4 and 20 foldamer-CypA adducts. Effectiveness of the reaction was demonstrated by LC-MS, by MS analysis after proteolytic digestion, and by 2D NMR. Circular dichroism then revealed diastereoselective interactions between the proteins and the foldamers confined at their surface which resulted in a preferred handedness of the foldamer helix. Helix sense bias occurred sometimes with both the short and the long linkers and sometimes with only one of them. In a few cases, helix handedness preference is found to be close to quantitative. These cases constitute valid candidates for structural elucidation of the interactions involved. PMID- 30395444 TI - Surface Modification of Macrophages with Nucleic Acid Aptamers for Enhancing the Immune Response against Tumor Cells. AB - Antigen-presenting cells play a dominant role in cancer immunotherapy. Tumor cells, however, can still resort to several mechanisms of immune evasion that ultimately lead to the development of tumor tissues. In the current study, we performed surface modification of live macrophages with nucleic acid aptamers with the aim to enhance their affinity for tumor cells. Intercellular adhesion of tumor cells to surface-modified macrophages and the functions of the macrophages when in contact with tumor cells were investigated. To immobilize thiol terminated nucleic acid aptamers that showed high affinity for the membrane protein of the tumor cells, methacryloyl groups were delivered into the sialic acids of the macrophages via metabolic glycoengineering (MGE). The proposed surface modification was cytocompatible and did not induce any undesirable activation of macrophages. According to the cell proliferation assay, the density of aptamers immobilized on a macrophage was found to decrease over time. However, the presence of aptamers on the cell surface was observed for more than 24 h after the immobilization. The number of adherent tumor cells on aptamer immobilized macrophages was significantly larger than that of non-immobilized macrophages. Although the number of adherent tumor cells on aptamer-immobilized macrophages was not influenced by the pretreatment of doxorubicin to induce apoptosis in tumor cells, the apoptosis-induced tumor cells were highly phagocytosed by the aptamer-immobilized macrophages. The secretion amount of proinflammatory cytokines (TNF-alpha and IL-12) from the macrophages was coincident with the phagocytic index, which increased with the phagocytic uptake of tumor cells by the macrophages. In addition, the expression level of the major histocompatibility complex (MHC) class I and II molecules, required for antigen presentation, increased in nucleic acid aptamer-immobilized macrophages. Overall, the surface modification of macrophages with nucleic acid aptamers improved the tumor cell recognition of macrophages, indicating that the combination of cell surface engineering and anticancer drug treatment could constitute a promising strategy for tumor cell elimination. PMID- 30395445 TI - Nonphotosynthetic Biological CO2 Reduction. AB - Alarming changes in environmental conditions have prompted significant research into producing renewable commodities from sources other than fossil fuels. One such alternative is CO2, a determinate greenhouse gas with historically high atmospheric levels. If sequestered, CO2 could be used as a highly renewable feedstock for industrially relevant products and fuels. The vast majority of atmospheric CO2 fixation is accomplished by photosynthetic organisms, which have unfortunately proven difficult to utilize as chassis for industrial production. Nonphotosynthetic CO2 fixing microorganisms and pathways have recently attracted scientific and commercial interest. This Perspective will review promising alternate CO2 fixation strategies and their potential to supply microbially produced fuels and commodity chemicals, such as higher alcohols. Acetogenic fermentation and microbial electrosynthesis are the primary focuses of this review. PMID- 30395446 TI - Versatile Rh- and Ir-Based Catalysts for CO2 Hydrogenation, Formic Acid Dehydrogenation, and Transfer Hydrogenation of Quinolines. AB - Considering the interest in processes related to hydrogen storage such as CO2 hydrogenation and formic acid (FA) decomposition, we have synthesized a set of Ir, Rh, or Ru complexes to be tested as versatile precatalysts in these reactions. In relation with the formation of H2 from FA, the possible applicability of these complexes in the transfer hydrogenation (TH) of challenging substrates as quinoline derivatives using FA/formate as hydrogen donor has also been addressed. Bearing in mind the importance of secondary coordination sphere interactions, N,N' ligands containing NH2 groups, coordinated or not to the metal center, were used. The general formula of the new complexes are [( p-cymene)RuCl(N,N')]X, X = Cl-, BF4- and [Cp*MCl(N,N')]Cl, M = Rh, Ir, where the N,N' ligands are 8-aminoquinoline (HL1), 6-pyridyl-2,4-diamine-1,3,5 triazine (L2) and 5-amino-1,10-phenanthroline (L3). Some complexes are not active or catalyze only one process. However, the complexes [Cp*MCl(HL1)]Cl with M = Rh, Ir are versatile catalysts that are active in hydrogenation of quinolines, FA decomposition, and also in CO2 hydrogenation with the iridium derivative being more active and robust. The CO2 hydrogenation takes place in mild conditions using only 5 bar of pressure of each gas (CO2 and H2). The behavior of some precatalysts in D2O and after the addition of 9 equiv of HCO2Na (pseudocatalytic conditions) has been studied in detail and mechanisms for the FA decomposition and the hydrogenation of CO2 have been proposed. For the Ru, Ir, or Rh complexes with ligand HL1, the amido species with the deprotonated ligand are observed. In the case of ruthenium, the formate complex is also detected. For the iridium derivative, both the amido intermediate and the hydrido species have been observed. This hydrido complex undergoes a process of umpolung D+<-> Ir-D. All in all, the results of this work reflect the active role of -NH2 in the transfer of H+. PMID- 30395447 TI - siRNA Delivery Using Dithiocarbamate-Anchored Oligonucleotides on Gold Nanorods. AB - We present a robust method for loading small interfering RNA (siRNA) duplexes onto the surfaces of gold nanorods (GNRs) at high density, using near-infrared laser irradiation to trigger their intracellular release with subsequent knockdown activity. Citrate-stabilized GNRs were first coated with oleylsulfobetaine, a zwitterionic amphiphile with low cytotoxicity, which produced stable dispersions at high ionic strength. Amine-modified siRNA duplexes were converted into dithiocarbamate (DTC) ligands and adsorbed onto GNR surfaces in a single incubation step at 0.5 M NaCl, simplifying the charge screening process. The DTC anchors were effective at minimizing premature siRNA desorption and release, a common but often overlooked problem in the use of gold nanoparticles as oligonucleotide carriers. The activity of GNR-siRNA complexes was evaluated systematically against an eGFP-producing ovarian cancer cell line (SKOV-3) using folate receptor-mediated uptake. Efficient knockdown was achieved by using a femtosecond-pulsed laser source to release DTC-anchored siRNA, with essentially no contributions from spontaneous (dark) RNA desorption. GNRs coated with thiol-anchored siRNA duplexes were less effective and also permitted low levels of knockdown activity without photothermal activation. Optimized siRNA delivery conditions were applied toward the targeted knockdown of transglutaminase 2, whose expression is associated with the progression of recurrent ovarian cancer, with a reduction in activity of >80% achieved after a single pulsed laser treatment. PMID- 30395448 TI - RNA Display Methods for the Discovery of Bioactive Macrocycles. AB - The past two decades have witnessed the emergence of macrocycles, including macrocyclic peptides, as a promising yet underexploited class of de novo drug candidates. Both rational/computational design and in vitro display systems have contributed tremendously to the development of cyclic peptide binders of either traditional targets such as cell-surface receptors and enzymes or challenging targets such as protein-protein interaction surfaces. mRNA display, a key platform technology for the discovery of cyclic peptide ligands, has become one of the leading strategies that can generate natural-product-like macrocyclic peptide binders with antibody-like affinities. On the basis of the original cell free transcription/translation system, mRNA display is highly evolvable to realize its full potential by applying genetic reprogramming and chemical/enzymatic modifications. In addition, mRNA display also allows the follow-up hit-to-lead development using high-throughput focused affinity maturation. Finally, mRNA-displayed peptides can be readily engineered to create chemical conjugates based on known small molecules or biologics. This review covers the birth and growth of mRNA display and discusses the above features of mRNA display with success stories and future perspectives and is up to date as of August 2018. PMID- 30395449 TI - Water-in-Water Pickering Emulsion Stabilized by Polydopamine Particles and Cross Linking. AB - All aqueous multiphase systems have attracted significant attention recently, in particular water-in-water Pickering emulsions. In here, polydopamine nanoparticles (PDP) are investigated as stabilizers for dextran and poly(ethylene glycol) (PEG)-based aqueous emulsions. Remarkably, stable emulsions are obtained from the all-biocompatible materials that can be broken either via dilution or surfactant addition. Further cross-linking of PDP via poly(acrylic acid) and carbodiimide strengthens the stability of emulsion droplets in a colloidosome like structure. After cross-linking, demulsification via dilution or surfactant addition was largely hindered. The PDP-mediated formation of all aqueous emulsions is expected to be generalized to different types of water-in-water emulsions with other polymers and offers new opportunities in surface modification as well as microencapsulation. PMID- 30395450 TI - Preparation of Amphiphilic Poly(ethylene glycol)- b-poly(gamma-butyrolactone) Diblock Copolymer via Ring Opening Polymerization Catalyzed by a Cyclic Trimeric Phosphazene Base or Alkali Alkoxide. AB - Biobased poly(gamma-butyrolactone) (PgammaBL) as a fully biodegradable and bioabsorbable biomaterial has shown superior properties compared to those of other aliphatic polyesters. It is of great importance to prepare amphiphilic block copolymer containing PgammaBL block to make ordered nano-objects for biomedical applications such as drug delivery systems. However, such an amphiphilic copolymer containing PgammaBL segment was never successfully prepared mostly due to the synthetic challenges of ring-opening polymerization (ROP) of nonstrained gamma-butyrolactone (gammaBL) monomer. Here, we reported the first preparation of amphiphilic poly(ethylene glycol)- b-poly(gamma-butyrolactone) (PEG- b-PgammaBL) diblock copolymer by using PEG as a macroinitiator. We applied two types of bases to initiate the ROP of gammaBL. An organic cyclic trimeric phosphazene base (CTPB) was first applied to activate the terminal hydroxyl group of PEG as macroinitiator for ROP of gammaBL. On the other hand, sodium hydride was used to activate the hydroxyl group of PEG to form sodium alkoxide as an initiating system for ROP of gammaBL. Both catalytic/initiating system showed moderate control on ROP of gammaBL and successfully produced PEG- b-PgammaBL diblock copolymers with varied molecular weights and relatively narrow molecular weight distributions. The effects of catalytic systems, activation temperatures, and monomer concentrations on gammaBL conversion and molecular weight of PEG- b PgammaBL were carefully explored. The thermal properties and phase behaviors of obtained PEG- b-PgammaBL were also investigated. PMID- 30395451 TI - 2,6-Dihydroxybenzaldehyde Analogues of the Iron Chelator Salicylaldehyde Isonicotinoyl Hydrazone: Increased Hydrolytic Stability and Cytoprotective Activity against Oxidative Stress. AB - Salicylaldehyde isonicotinoyl hydrazone (SIH) is a small molecule and lipophilic chelating agent that firmly binds ferric ions from the cellular labile iron pool and is able to protect various tissues against oxidative damage. Previously, SIH possessed the best ratio of cytoprotective efficiency to toxicity among various iron chelators, including the desferrioxamine, deferiprone, and deferasirox used in clinical practice. Here, we prepared a series of 2,6-dihydroxybenzaldehyde aroylhydrazones as SIH analogues with an additional hydroxyl group that can be involved in the chelation of metal ions. Compound JK-31 (2,6 dihydroxybenzaldehyde 4-chlorobenzohydrazone) showed the best cytoprotective efficiency among the studied compounds including SIH. This compound significantly protected H9c2 cardiomyoblast cells against oxidative stress induced by various pro-oxidants, such as hydrogen peroxide, tert-butyl hydroperoxide, paraquat, epinephrine, N-acetyl- p-benzoquinone imine (a toxic metabolite of paracetamol), and 6-hydroxydopamine. The exceptional cytoprotective activity of JK-31 was confirmed using epifluorescence microscopy, where JK-31-treated H9c2 cells maintained a higher mitochondrial inner membrane potential in the presence of a lethal dose of hydrogen peroxide than was observed with cells treated with SIH. Hence, this study demonstrates the deleterious role of free iron ions in oxidative injury and the potential of 2,6-dihydroxybenzaldehyde aroylhydrazones in the prevention of various types of cardiac injuries, highlighting the need for further investigations into these compounds. PMID- 30395453 TI - Reversible Self-Assembly Nanovesicle of UCST Response Prepared with Multi-l arginyl-poly-l-aspartate Conjugated with Polyethylene Glycol. AB - Multi-L-arginyl-poly-L-aspartate (MAPA), also known as cyanophycin, containing a backbone of polyaspartate with arginine and lysine as side chains, was prepared with recombinant Escherichia coli. The insoluble part (iMAPA) was conjugated with polyethylene glycol (PEG) at two different levels, high (iMAPA(PEG)h) and low (iMAPA(PEG)l). Both levels of conjugation exhibited UCST (upper critical solution temperature)-type responses in the pH range of 3-10 at a concentration of 2 mg/mL. The cloud-point temperature of each conjugate also showed a positive correlation with concentration in PBS, falling between 20 to 58 degrees C at a concentration from 0.1 to 3 mg/mL. Hysteresis was observed to follow approximate paths under the same condition during repeated heating and cooling. Notably, the reversible formation of core-shell vesicles appeared at room temperature in PBS with a size of around 25 to 60 nm, as measured by DLS and observed under TEM. The reversibility was further employed to encapsulate doxorubicin (Dox) at different weight ratios of Dox to iMAPA(PEG)h. An encapsulation efficiency could reach as high as 70% with an equivalent loading capacity of 1.5 mg Dox/mg iMAPA(PEG)h. The Dox-loaded vesicles stayed stable at 4 degrees C for up to 4 weeks, with a minimal leakage below 2% and a slightly dilated morphology. Temperature-triggered release of Dox from the vesicles could be achieved by a step change of 5 degrees C successively from 37 to 62 degrees C in an effort to induce an initial 10% release at 37 degrees C gradually to complete release at 62 degrees C. PMID- 30395454 TI - A Unique Pair: Ag40 and Ag46 Nanoclusters with the Same Surface but Different Cores for Structure-Property Correlation. AB - Understanding the optical properties of nanoclusters is one of the central tasks in fundamental research. In this work, two new Ag nanoclusters that have distinctly different cores but a common protecting shell are achieved, including [Ag40(2,4-DMBT)24(PPh3)8] and [Ag46(2,5-DMBT)24(PPh3)8]2+. Significantly, the Ag40 nanocluster comprises a simple cubic core of Ag8, which is observed experimentally in the field of metal materials for the first time. Using the Ag40 and Ag46 nanoclusters as a unique pair, we have investigated the effect of core structure on the optical absorption properties of these nanoclusters. The compact core-shell in Ag46 makes the frontier orbitals highly degenerate, whereas the loose core-shell of Ag40 leads to much less degeneracy in the frontier orbits. Overall, this work reveals that the core packing mode plays a significant role in determining the optical properties of metal nanoclusters. The new materials with controlled crystalline phases also hold promise in other applications. PMID- 30395455 TI - Effect of Variations in the Fatty Acid Residue of Lactose Monoesters on Their Emulsifying Properties and Biological Activities. AB - Lactose fatty acid esters are high-value-added derivatives of lactose and represent a class of biodegradable, non-ionic, low-molecular-weight surfactants (emulsifiers) that have considerable potential in the food, cosmetic, and pharmaceutical industries. Certain lactose esters have also garnered attention for their biological activities. In this work, we detail syntheses of a homologous series of 6'- O-acyllactose esters of varying alkyl chain length (from 6 to 18 carbons) and report on their activities as surfactants as well as their antimicrobial and cytotoxic properties. The structure-property profiles established in this work revealed that while the medium-chain esters displayed excellent emulsifying properties and moderate antimicrobial activities, their longer chain congeners exhibited the highest cytotoxicities. As such, we have established that certain 6'- O-acyllactose esters are superior to their sucrose derived and commercially exploited counterparts. These results will serve as a useful guide for the development of lactose esters as, inter alia, emulsifiers in the food industry. PMID- 30395456 TI - Polycyclic Arene Synthesis by Annulative pi-Extension. AB - Annulative pi-extension (APEX) has emerged as a powerful and efficient synthetic method for the construction of polycyclic aromatic hydrocarbons, nanographenes, and pi-extended fused heteroarenes. In contrast to classical multistep syntheses requiring substrate prefunctionalization, APEX reactions minimize the number of preparative steps by direct C-H activation of small aromatic templates. In this Perspective, we review recently reported APEX reactions to shed light on the utility, scope, and promise of this approach for next-generation syntheses of polycyclic arenes. PMID- 30395457 TI - AIR-Chem: Authentic Intelligent Robotics for Chemistry. AB - The new era with prosperous artificial intelligence (AI) and robotics technology is reshaping the materials discovery process in a more radical fashion. Here we present authentic intelligent robotics for chemistry (AIR-Chem), integrated with technological innovations in the AI and robotics fields, functionalized with modules including gradient descent-based optimization frameworks, multiple external field modulations, a real-time computer vision (CV) system, and automated guided vehicle (AGV) parts. AIR-Chem is portable and remotely controllable by cloud computing. AIR-Chem can learn the parametric procedures for given targets and carry on laboratory operations in standalone mode, with high reproducibility, precision, and availability for knowledge regeneration. Moreover, an improved nucleation theory of size focusing on inorganic perovskite quantum dots (IPQDs) is theoretically proposed and experimentally testified to by AIR-Chem. This work aims to boost the process of an unmanned chemistry laboratory from the synthesis of chemical materials to the analysis of physical chemical properties, and it provides a vivid demonstration for future chemistry reshaped by AI and robotics technology. PMID- 30395458 TI - Coordination Network That Reversibly Switches between Two Nonporous Polymorphs and a High Surface Area Porous Phase. AB - We report a 2-fold interpenetrated primitive cubic (pcu) network X-pcu-5-Zn, [Zn2(DMTDC)2(dpe)] (H2DMTDC = 3,4-dimethylthieno[2,3- b]thiophene-2,5 dicarboxylic acid, dpe = 1,2-di(4-pyridyl)ethylene), that exhibits reversible switching between an as-synthesized "open" phase, X-pcu-5-Zn-alpha, and two nonporous or "closed" polymorphs, X-pcu-5-Zn-beta and X-pcu-5-Zn-gamma. There are two unusual features of X-pcu-5-Zn. The first relates to its sorption properties, which reveal that the alpha form exhibits high CO2 uptake (ca. 255 cm3/g at 195 K) via reversible closed-to-open switching (type F-IV isotherm) of the type desirable for gas and vapor storage; there are only three other reports of porous materials that combine these two features. Second, we could only isolate the beta form by activation of the CO2 loaded alpha form and it persists through multiple CO2 adsorption/desorption cycles. We are unaware of a new polymorph having been isolated in such a manner. That the observed phase changes of X-pcu-5-Zn-alpha occur in single-crystal-to-single-crystal fashion enabled structural characterization of the three forms; gamma is a coordination isomer of alpha and beta, both of which are based upon "paddlewheel" clusters. PMID- 30395459 TI - Supramolecular Solid-State Microlaser Constructed from Pillar[5]arene-Based Host Guest Complex Microcrystals. AB - Herein we report a novel host-guest complex single crystal material based on a pillar[5]arene (P5) and a laser dye trans-4-[ p-(dimethylamino)styryl]-1 methylpyridinium iodide (DASP). Single crystal structure characterization shows that two P5 molecules act as a supramolecular nanocapsule for one isolated DASP molecule. This spatial confinement effectively restricts aggregation-caused quenching (ACQ) effects and other nonradiative channels (e.g., twisted intramolecular charge transfer), leading to high luminescent efficiency of the isolated DASP. Together with its regular shape and smooth surface, each 2P5?DASP microcrystal forms a Fabry-Perot (F-P) microcavity and produces a stable laser output with a high Q factor and a low threshold. PMID- 30395460 TI - Nuclear Factor Erythroid 2-Related Factor 2 Activating Triterpenoid Saponins from Camellia japonica Roots. AB - Oxidative stress due to the presence of excess reactive oxygen species may cause cancers, aging, and many other conditions. Nuclear factor erythroid 2-related factor 2 (Nrf2) may control abnormal oxidative stress as a transcription factor by inducing antioxidant-related genes via antioxidant response elements (AREs) in the gene promoters. The 11 triterpenoid saponins (1-11) isolated from Camellia japonica roots were tested for ARE-luciferase activity and Nrf2 accumulation in human keratinocytes (HaCaT cells). The ARE-luciferase activity was significantly increased by compounds 1-11 (25 MUM) as a result of nuclear Nrf2 accumulation in the cells. Thus, these compounds may contribute to the induction of Nrf2 activity against oxidative damage in cells. PMID- 30395461 TI - Gramillin A and B: Cyclic Lipopeptides Identified as the Nonribosomal Biosynthetic Products of Fusarium graminearum. AB - The virulence and broad host range of Fusarium graminearum is associated with its ability to secrete an arsenal of phytotoxic secondary metabolites, including the regulated mycotoxins belonging to the deoxynivalenol family. The TRI genes responsible for the biosynthesis of deoxynivalenol and related compounds are usually expressed during fungal infection. However, the F. graminearum genome harbors an array of unexplored biosynthetic gene clusters that are also co induced with the TRI genes, including the nonribosomal peptide synthetase 8 ( NRPS8) gene cluster. Here, we identify two bicyclic lipopeptides, gramillin A (1) and B (2), as the biosynthetic end products of NRPS8. Structural elucidation by high-resolution LC-MS and NMR, including 1H-15N-13C HNCO and HNCA on isotopically enriched compounds, revealed that the gramillins possess a fused bicyclic structure with ring closure of the main peptide macrocycle occurring via an anhydride bond. Through targeted gene disruption, we characterized the GRA1 biosynthetic gene and its transcription factor GRA2 in the NRPS8 gene cluster. Further, we show that the gramillins are produced in planta on maize silks, promoting fungal virulence on maize but have no discernible effect on wheat head infection. Leaf infiltration of the gramillins induces cell death in maize, but not in wheat. Our results show that F. graminearum deploys the gramillins as a virulence agent in maize, but not in wheat, thus displaying host-specific adaptation. PMID- 30395462 TI - Identification of Matrix Metalloproteinase-1-Suppressive Peptides in Feather Keratin Hydrolysate. AB - Inhibition of matrix metalloproteinases (MMPs), which degrade collagen and elastin in the dermis of normal skin, is a key strategy for anti-skin aging. In this study, we identified five low-molecular-weight (LMW, <1 kDa) MMP-1 suppressive peptides in feather keratin hydrolysate (FKH) obtained by anaerobic digestion with an extremophilic bacterium. FKH was first subjected to ultrafiltration, followed by size-exclusion chromatography and liquid chromatography/electrospray ionization tandem mass spectrometry analysis. Chemically synthesized peptides identical to the sequences identified suppressed MMP expression in human dermal fibroblasts (HDFs). To investigate the impact of the MMP-1-suppressive peptides on the signaling pathway, we performed antibody array phosphorylation profiling of HDFs. The results suggested that the peptide GGFDL regulates ultraviolet-B-induced MMP-1 expression by inhibiting mitogen activated protein kinases and nuclear factor kappaB signaling pathways as well as histone modification. Thus, LMW feather keratin peptides could serve as novel bioactive compounds to protect the skin against intrinsic and extrinsic factors. PMID- 30395463 TI - Molecular Mechanism of Depolarization-Dependent Inactivation in W366F Mutant of Kv1.2. AB - Voltage-gated potassium channels play crucial roles in regulating membrane potential. They are activated by membrane depolarization, allowing the selective permeation of K+ ions across the plasma membrane, and enter a nonconducting state after lasting depolarization, a process known as inactivation. Inactivation in voltage-activated potassium channels occurs through two distinct mechanisms, N type and C-type inactivation. C-type inactivation is caused by conformational changes in the extracellular mouth of the channel, whereas N-type inactivation is elicited by changes in the cytoplasmic mouth of the protein. The W434F-mutated Shaker channel is known as a nonconducting mutant and is in a C-type inactivation state at a depolarizing membrane potential. To clarify the structural properties of C-type inactivated protein, we performed molecular dynamics simulations of the wild-type and W366F (corresponding to W434F in Shaker) mutant of the Kv1.2-2.1 chimera channel. The W366F mutant was in a nearly nonconducting state with a depolarizing voltage and recovered from inactivation with a reverse voltage. Our simulations and three-dimensional reference interaction site model analysis suggested that structural changes in the selectivity filter upon membrane depolarization trap K+ ions around the inner mouth of the selectivity filter and prevent ion permeation. This pore restriction is involved in the molecular mechanism of C-type inactivation. PMID- 30395464 TI - Rapid, Selective Extraction of Trace Amounts of Gold from Complex Water Mixtures with a Metal-Organic Framework (MOF)/Polymer Composite. AB - With the ever-increasing production of electronics, there is an ensuing need for gold extraction from sources other than virgin mines. Currently, there are no technologies reported to date that can effectively and selectively concentrate ultratrace amounts of gold from liquid sources. Here, we provide a blueprint for the design of several highly porous composites made up of a metal-organic framework (MOF) template and redox active, polymeric building blocks. One such composite, Fe-BTC/PpPDA, is shown to rapidly extract trace amounts of gold from several complex water mixtures that include wastewater, fresh water, ocean water, and solutions used to leach gold from electronic waste and sewage sludge ash. The material has an exceptional removal capacity, 934 mg gold/g of composite, and extracts gold from these complex mixtures at record-breaking rates, in as little as 2 min. Further, due to the high cyclability, we demonstrate that the composite can effectively concentrate gold and yield purities of 23.9 K. PMID- 30395465 TI - Accurate Single-Sequence Prediction of Protein Intrinsic Disorder by an Ensemble of Deep Recurrent and Convolutional Architectures. AB - Recognizing the widespread existence of intrinsically disordered regions in proteins spurred the development of computational techniques for their detection. All existing techniques can be classified into methods relying on single-sequence information and those relying on evolutionary sequence profiles generated from multiple-sequence alignments. The methods based on sequence profiles are, in general, more accurate because the presence or absence of conserved amino acid residues in a protein sequence provides important information on the structural and functional roles of the residues. However, the wide applicability of profile based techniques is limited by time-consuming calculation of sequence profiles. Here we demonstrate that the performance gap between profile-based techniques and single-sequence methods can be reduced by using an ensemble of deep recurrent and convolutional neural networks that allow whole-sequence learning. In particular, the single-sequence method (called SPOT-Disorder-Single) is more accurate than SPOT-Disorder (a profile-based method) for proteins with few homologous sequences and comparable for proteins in predicting long-disordered regions. The method performance is robust across four independent test sets with different amounts of short- and long-disordered regions. SPOT-Disorder-Single is available as a Web server and as a standalone program at http://sparks-lab.org/jack/server/SPOT Disorder-Single . PMID- 30395466 TI - Read between the Molecules: Computational Insights into Organic Semiconductors. AB - The performance and key electronic properties of "molecular" organic semiconductors are dictated by the interplay between the chemistry of the molecular core and the intermolecular factors of which manipulation has inspired both experimentalists and theorists. This Perspective presents major computational challenges and modern methodological strategies to advance the field. The discussion ranges from insights and design principles at the quantum chemical level, realistic modeling based on multiscale protocols, morphological prediction and characterization as well as energy-property maps involving data driven analysis. A personal overview of the past achievements and future direction is also provided. PMID- 30395467 TI - Synthesis of a Polycyclic Halichondrin C1-C14 Fragment via Intermolecular Oxy Michael/ Trans-Ketalization. AB - Syntheses of a crystalline polycyclic halichondrin C1-C14 building block starting from a d-gulono-1,4-lactone-derived intermediate in the current Halaven manufacturing process are described. Key features of the syntheses include an acid-catalyzed tandem intermolecular oxy-Michael/intramolecular trans ketalization reaction and stereoselective Kishi reductions. PMID- 30395468 TI - Correlating Intermolecular Cross-Relaxation Rates with Distances and Coordination Numbers in Ionic Liquids. AB - The HOESY NMR experiment is commonly used to probe ion associations in ionic liquids and their mixtures. The parameter measured in this experiment is the heteronuclear cross-relaxation rate sigma, which has dimensions of s-1. For intramolecular NOEs this scales as r-6 where r is the internuclear distance, but in the intermolecular case (as typically probed in studies of ionic liquids), theory predicts a more complex behaviour including a distance dependence that is affected by the relative frequencies of the nuclei involved. Specifically, for nuclei with similar resonance frequencies such as 1H and 19F, it has been predicted that intermolecular NOEs will be sensitive to longer range distances than for nuclei with very different frequencies such as 1H and 7Li. In this contribution, we test this theory using a combination of quantitative HOESY analysis and molecular dynamics simulations carried out on two different ionic liquid electrolyte systems. In agreement with theoretical predictions, we find excellent correlations between the experimentally measured 1H-7Li NOEs and carbon lithium distances below 4 A, while longer distances (> 6 A) must be considered in order to obtain good correlations between 1H-19F NOEs and carbon-fluorine coordination numbers. This demonstrates the utility of HOESY NMR in understanding structure and interactions in ionic liquids while also illustrating that care must be taken in interpreting the measured cross-relaxation rates. PMID- 30395469 TI - Alchemical Normal Modes Unify Chemical Space. AB - In silico design of new molecules and materials with desirable quantum properties by high-throughput screening is a major challenge due to the high dimensionality of chemical space. To facilitate its navigation, we present a unification of coordinate and composition space in terms of alchemical normal modes (ANMs) which result from second order perturbation theory. ANMs assume a predominantly smooth nature of chemical space and form a basis in which new compounds can be expanded and identified. We showcase the use of ANMs for the energetics of the iso electronic series of diatomics with 14 electrons, BN doped benzene derivatives (C$_{6-2x}$(BN)$_{x}$H$_6$ with $x = 0, 1, 2, 3$), predictions for over 1.8 million BN doped coronene derivatives, and genetic energy optimizations in the entire BN doped coronene space. Using Ge lattice scans as reference, the applicability ANMs across the periodic table is demonstrated for III-V and IV-IV semiconductors Si, Sn, SiGe, SnGe, SiSn, as well as AlP, AlAs, AlSb, GaP, GaAs, GaSb, InP, InAs, and InSb. Analysis of our results indicates simple qualitative structure property rules for estimating energetic rankings among isomers. Useful quantitative estimates can also be obtained when few atoms are changed to neighboring or lower lying elements in the periodic table. The quality of the predictions often increases with the symmetry of system chosen as reference due to cancellation of odd order terms. Rooted in perturbation theory the ANM approach promises to generally enable unbiased compound exploration campaigns at reduced computational cost. PMID- 30395470 TI - One-Step Generation of Reactive Superhydrophobic Surfaces via SiHCl3-Based Silicone Nanofilaments. AB - Superhydrophobic surfaces gain ever-growing attention because of their applicability in many (consumer) products/materials as they often display, among others, antifouling, anti-icing, and/or self-cleaning properties. A simple way to achieve superhydrophobicity is through the growth of silicone nanofilaments. These nanofilaments, however, are very often nonreactive and thus difficult to utilize in subsequent chemistries. In response, we have developed a single-step procedure to grow (SiHCl3-based) silicone nanofilaments with selective reactivity that are intrinsically superhydrophobic. The silicone nanofilaments could be further functionalized via Pt-catalyzed hydrosilylation of exposed Si-H moieties. These surfaces are easily obtained using mild conditions and are stable under hydrolytic conditions (neutral water, 24 h at 80 degrees C) while remaining highly transparent, which makes them well suited for optical and photochemical experiments. PMID- 30395471 TI - Light-Induced Aggregation and Disaggregation of Stimuli-Responsive Latex Particles Depending on Spiropyran Concentration: Kinetics of Photochromism and Investigation of Reversible Photopatterning. AB - Light-controlling the physical and chemical properties of smart polymers by using photochromic compounds has been an interesting research subject. Incorporation of spiropyran (SP) on the surface of particles can induce photoswitchable aggregation/disaggregation to stimuli-responsive colloids. Herein, we developed a novel class of stimuli-responsive latex particles bearing SP with different contents (0, 0.5, 1, 3, and 5 wt %) by semicontinuous emulsifier-free emulsion copolymerization, which is able to change the particle size by light-induced aggregation/disaggregation in response to ultraviolet (UV) irradiation and visible light. The scanning electron microscopy images revealed the spherical morphology of the latex particles, with the size in the range of 400-900 nm. Light-induced aggregation and disaggregation of stimuli-responsive latex particles were investigated by dynamic light scattering and also confirmed by variation of transmittance during UV illumination time using ultraviolet-visible spectroscopy. The range of the light-induced shift in the particle size is about 200-600 nm (depending on the concentration of SP), where the reduction of transmittance upon UV irradiation (and conversely upon visible light) confirms the ability of latex particles for displaying reversible photoswitchable aggregation/disaggregation and also light-controlling the particle size. The kinetics of SP to merocyanine (MC) and MC to SP isomerizations were experimentally investigated and fitted by exponential equations. The photochromic latexes displayed remarkable photoswitchability and photofatigue resistant properties under alternating UV and visible light irradiation cycles. Additionally, these stimuli-responsive latexes displayed potential applications such as anticounterfeiting inks in erasable and rewritable writings on cellulosic papers for increasing safety in security documents. PMID- 30395472 TI - Cellular Uptake and Intracellular Trafficking of Poly( N-(2-Hydroxypropyl) Methacrylamide). AB - Cellular uptake and intracellular trafficking of polymer conjugates or polymer nanoparticles is typically monitored using fluorescence-based techniques such as confocal microscopy. While these methods have provided a wealth of insight into the internalization and trafficking of polymers and polymer nanoparticles, they require fluorescent labeling of the polymer or polymer nanoparticle. Because in biological media fluorescent dyes may degrade, be cleaved from the polymer or particle, or even change uptake and trafficking pathways, there is an interest in fluorescent label-free methods to study the interactions between cells and polymer nanomedicines. This article presents a first proof-of-concept that demonstrates the feasibility of NanoSIMS to monitor the intracellular localization of polymer conjugates. For the experiments reported here, poly( N-(2 hydroxypropyl) methacrylamide)) (PHPMA) was selected as a prototypical polymer drug conjugate. This PHPMA polymer contained a 19F-label at the alpha-terminus, which was introduced in order to allow NanoSIMS analysis. Prior to the NanoSIMS experiments, the uptake and intracellular trafficking of the polymer was established using confocal microscopy and flow cytometry. These experiments not only provided detailed insight into the kinetics of these processes but were also important to select time points for the NanoSIMS analysis. For the NanoSIMS experiments, HeLa cells were investigated that had been exposed to the PHPMA polymer for a period of 4 or 15 h, which was known to lead to predominant lysosomal accumulation of the polymer. NanoSIMS analysis of resin-embedded and microtomed samples of the cells revealed a punctuated fluorine signal, which was found to colocalize with the sulfur signal that was attributed to the lysosomal compartments. The localization of the polymer in the endolysosomal compartments was confirmed by TEM analysis on the same cell samples. The results of this study illustrate the potential of NanoSIMS to study the uptake and intracellular trafficking of polymer nanomedicines. PMID- 30395473 TI - Developability Assessment of Engineered Monoclonal Antibody Variants with a Complex Self-Association Behavior Using Complementary Analytical and in Silico Tools. AB - Monoclonal antibodies (mAbs) are complex molecular structures. They are often prone to development challenges particularly at high concentrations due to undesired solution properties such as reversible self-association, high viscosity, and liquid-liquid phase separation. In addition to formulation optimization, applying protein engineering can provide an alternative mitigation strategy. Protein engineering during the discovery phase can provide great benefits to optimize molecular properties, resulting in improved developability profiles. Here, we present a case study utilizing complementary analytical and predictive in silico methods. We have systematically identified and reengineered problematic residues responsible for the self-association of a model mAb, driven by a complex combination of hydrophobic and electrostatic interactions. Noteworthy findings include a more dominant contribution of hydrophobic interactions to self-association and potential feasibility of mutations in the CDR regions to mitigate self-association. The engineered mutation panel enabled us to assess potential correlations among commonly utilized developability screening assays, including affinity capture self-interaction nanospectroscopy (AC-SINS), dynamic light scattering (DLS), and apparent solubility by PEG precipitation. In addition, we evaluated the correlations between experimental measurements and computational predictions. CamSol, an in silico computational tool that accounts for complex molecular interactions and neighboring hotspots, was found to be an effective screening tool. Our work led to reengineered mAb variants, better suited for high-concentration liquid formulation development. The engineered mAbs exhibited enhanced in vitro and simulated in vivo solubility and reduced self-association propensity, while maintaining binding affinity and thermal stability. PMID- 30395474 TI - Structure Design of Low-Temperature Regenerative Hyperbranched Polyamine Adsorbent for CO2 Capture. AB - A novel low-temperature regenerative hydroxy-functionalized hyperbranched polyamine adsorbent (0.16OH-HBPA) for CO2 capture was readily prepared using glutaraldehyde to cross-link amino-terminated hyperbranched polymers (HBP) and functionalized with glycidol, followed by the reduction of the imino groups of 0.16OH-HBPA to alkyl aminos using NaBH4. Here, the HBP has been prepared through the one-pot reaction between pentaethylenehexamine and methyl acrylate. The as prepared 0.16OH-HBPA adsorbent showed a high adsorption capacity (4.05 mmol/g) for CO2 (concentration, 10%) in the presence of water at 25 degrees C, and the alkyl amino utilization efficiency reached 73%. More importantly, the CO2 adsorbed 0.16OH-HBPA showed excellent regenerative performance at low temperatures (85 degrees C, under pure CO2 gas) due to the introduced hydroxyl that can cooperatively adsorb CO2 via the amino groups to form stable carbamic acid. This process suppressed the formation of open-chain urea and cyclic urea and could overcome the disadvantages of high regeneration temperatures (>=90 degrees C, under pure inert gas) of CO2-adsorbed traditional solid amine adsorbents. PMID- 30395475 TI - Effect of Dilution on the Nonequilibrium Polyelectrolyte/Surfactant Association. AB - Polyelectrolyte (PE)/surfactant (S) mixtures play a distinguished role in the efficacy of shampoos and toiletries primarily due to the deposition of PE/S precipitates on the hair surface upon dilution of the formulations. The classical interpretation of this phenomenon is a simple composition change during which the system enters the two-phase region. Recent studies, however, indicated that the phase properties of PE/S mixtures could be strongly affected by the applied solution preparation protocols. In the present work, we aimed at studying the impact of dilution on the nonequilibrium aggregate formation in the sodium poly(styrenesulfonate) (NaPSS)/dodecyltrimethylammonium bromide (DTAB)/NaCl system. Mixtures prepared with hundredfold dilution of concentrated NaPSS/DTAB/NaCl solutions in water were compared with those ones made by rapid mixing of dilute NaPSS/NaCl and DTAB/NaCl solutions. The study revealed that the phase-separation concentration range as well as the composition, morphology, and visual appearance of the precipitates were remarkably different in the two cases. These observations clearly demonstrate that the dilution/deposition process is also related to the nonequilibrium phase properties of PE/S systems, which can be used to modulate the efficiency of various commercial applications. PMID- 30395476 TI - Removal of the E-Olefin Barrier of Humulene Leading to Unnatural Terpenoid-like Skeletons. AB - An unnatural terpenoid scaffold containing a bicyclo[5.4.0]undecane moiety, as well as a salvialane skeleton based on an intramolecular C-C bond formation strategy were synthesized. Such a strategy was made possible by the removal of strained E-olefin conformations of the humulene skeleton. Some compounds were identified to show PPARalpha antagonist activity. PMID- 30395477 TI - Receptor-Ligand Interaction Measured by Inductively Coupled Plasma Mass Spectrometry and Selenium Labeling. AB - In the search for an alternative strategy to the radioactivity measurement conventionally performed to probe receptor-ligand interactions in pharmacological assays, we demonstrated that selenium labeling of the studied ligand combined with elemental mass spectrometry was as efficient and robust as the reference method but devoid of its environmental and health hazards. The proof-of-concept was illustrated on two GPCR receptors, vasopressin (V1A) and cholecystokinin B (CCK-B), involving peptides as endogenous ligands. We proposed several methodologies to produce selenium-labeled ligands according to peptide sequences along with binding affinity constraints. A selection of selenopeptides that kept high affinities toward the targeted receptor were engaged in saturation and competitive binding experiments with subsequent sensitive RP-LC-ICP-MS measurements. Experimental values of affinity constant ( Ki) were perfectly correlated to literature data, illustrating the general great potency of replacing radioactive iodine by selenium for ligand labeling to further undergo unaffected pharmacology experiments efficiently monitored by elemental mass spectrometry. PMID- 30395478 TI - High-Temperature Refractory Metasurfaces for Solar Thermophotovoltaic Energy Harvesting. AB - Solar energy promises a viable solution to meet the ever-increasing power demand by providing a clean, renewable energy alternative to fossil fuels. For solar thermophotovoltaics (STPV), high-temperature absorbers and emitters with strong spectral selectivity are imperative to efficiently couple solar radiation into photovoltaic cells. Here, we demonstrate refractory metasurfaces for STPV with tailored absorptance and emittance characterized by in situ high-temperature measurements, featuring thermal stability up to at least 1200 degrees C. Our tungsten-based metasurface absorbers have close-to-unity absorption from visible to near-infrared and strongly suppressed emission at longer wavelengths, while our metasurface emitters provide wavelength-selective emission spectrally matched to the band-edge of InGaAsSb photovoltaic cells. The projected overall STPV efficiency is as high as 18% when a fully integrated absorber/emitter metasurface structure is employed, which is comparable to the efficiencies of the best currently available commercial single-junction PV cells and can be further improved to potentially exceed those in mainstream photovoltaic technologies. Our work opens a path forward for high-performance STPV systems based on refractory metasurface structures. PMID- 30395479 TI - To Be or Not to Be Protonated: Cyclo-N5- in Crystal and Solvent. AB - Pentazole (HN5) and its anion (cyclo-N5-) have been elusive for nearly a century due to the unstable N5 ring. Recently, Zhang et al. reported the first synthesis and characterization of the pentazolate anion cyclo-N5- in (N5)6(H3O)3(NH4)4Cl salt at ambient conditions (Science, 2017, 355, 374). However, if the cyclo-N5- in (N5)6(H3O)3(NH4)4Cl salt is protonated or not has been debated (Science, 2018, 359, eaao3672; Science, 2018, 359, aas8953). Herein, we employed ab initio molecular dynamics (AIMD) simulations, which can well present the dynamic behavior at realistic experimental conditions, to examine the potential protonated state of cyclo-N5- in both crystal and dimethyl sulfoxide (DMSO) solvent. Our simulations revealed that the highly symmetrical force in the crystal isn't enough to prevent the partial protonation of cyclo-N5- under the temperature effect, consequently both deprotonated and protonated cyclo-N5- exist in the crystal; in comparison, the DMSO solvent effect can remarkably reduce the difference of proton affinities among cyclo-N5-, H2O, and NH3, and the temperature effect can finally break these hydrogen bonds and lead to the deprotonated cyclo-N5- in DMSO solvent. Our AIMD simulations reconcile the recent controversy. PMID- 30395480 TI - Identification of Borrelia bissettii in Ixodes scapularis ticks from New Brunswick, Canada. AB - Lyme disease is a tick-borne disease that is emerging in Canada. The disease is caused by spirochetes of the Lyme borreliosis group, which is expanding as new species are discovered. In Canada, Lyme disease risk has so far been assessed primarily by detection of Borrelia burgdorferi sensu stricto. From Ixodes scapularis ticks collected between 2014-2016 in New Brunswick, Canada, 7 were shown to be infected with B. bissettii by nested PCR and sequencing of 5 B. bissettii genes. As different Borrelia species are associated with different clinical manifestations and are not detected with the same diagnostic tests, the identification of a previously undocumented or underreported pathogenic Borrelia species has important implications for public and veterinary medicine. PMID- 30395481 TI - Ginseng for the Treatment of Diabetes and Diabetes-related Cardiovascular Complications. A Discussion of the Evidence. AB - Diabetes mellitus is a chronic metabolic disorder associated with elevated blood glucose levels due either to insufficient insulin production (Type 1 diabetes) or to insulin resistance (Type 2 diabetes). The incidence of diabetes around the world continues to rise dramatically with more than 400 million cases reported today. Among the most serious consequences of chronic diabetes include cardiovascular complications which can result in both cardiac and vascular deleterious effects. Although numerous treatment options are available for treating diabetes, both pharmacological and non- pharmacological, there is substantial emerging interest in the use of traditional medicines for the treatment of this condition and its complications. Among these is ginseng, a medicinal herb which belongs to the genus Panax and which has been used for thousands of years as a medicinal agent especially in Asian cultures. There is emerging evidence from both animal and clinical studies that ginseng, ginseng constituents including ginsenosides and ginseng-containing formulations can produce beneficial effects in terms of normalization of blood glucose levels and attenuation of cardiovascular complications through a multiplicity of mechanisms. Although more research is required, ginseng may offer a useful therapy for the treatment of diabetes as well as its complications. PMID- 30395482 TI - A real-time PCR regimen for testing of environmental samples for Salmonella enterica subsp. enterica serovars of concern to the poultry industry with special focus on Salmonella Enteritidis. AB - A real-time PCR (qPCR) regimen, using up to six genetic targets, was developed for the rapid detection of Salmonella and in particular for the identification of S. Enteritidis. The test regimen was first evaluated using a reference culture collection of Salmonella to confirm the appropriateness of the selected targets including up to three genetic markers for discrimination of S. Enteritidis from other Salmonella serovars commonly found in poultry facilities. The qPCR procedure was then compared with culture methods for Salmonella detection using a collection of enrichment broths previously generated from 239 environmental samples collected from a large number of hatchery facilities across Canada over several years. The qPCR facilitated specific detection of S. Enteritidis and on a sample basis it showed excellent agreement with culture. Moreover in many cases qPCR detected Salmonella earlier in the culture process than the culture method. Application of this method will significantly shorten testing times and allow more timely identification of infected poultry premises and thereby improving present programmes aimed at controlling S. Enteritidis at the environmental source. PMID- 30395483 TI - 3D Modeling: A Future of Cardiovascular Medicine. AB - Cardiovascular disease (CVD) resulting from atypical cardiac structures continues to be a leading health concern despite advancements in diagnostic imaging and surgical techniques. However, the ability to visualize spatial relationships using current technologies remains a challenge. Therefore, 3D modeling has gained significant interest to understand complex and atypical cardiovascular disorders. Moreover, 3D modeling can be personalized and patient-specific. 3D models have been demonstrated to aid surgical planning and simulation, enhance communication among surgeons and patients, optimize medical device design, and can be used as a potential teaching tool in medical schools. In this review, we discuss the key components needed to generate cardiac 3D models. We highlight prevalent structural conditions that have utilized 3D modeling in pre-operative planning. Furthermore, we discuss the current limitations of routine use of 3D models in the clinic as well as future directions for utilization of this technology in the cardiovascular field. PMID- 30395484 TI - Direct Inhibitory Effect of the Phosphodiesterase-4 Inhibitor, Roflumilast, on Neutrophil Migration in COPD. AB - Neutrophilic inflammation is characteristic of COPD, yet there are no effective anti-inflammatory therapies. The phosphodiesterase (PDE)4 inhibitor, roflumilast is approved for use in COPD and suppresses sputum neutrophilia. The mechanism underlying this observation is unclear and therefore this study addressed whether roflumilast directly affected neutrophil migration. Blood-derived neutrophils were isolated from non-smokers, smokers and COPD patients and chemotaxis measured using Boyden chambers. Intracellular calcium ion concentration ([Ca2+]i) was measured by fluorimetry and shape change and CD11b expression by flow cytometry. Neutrophils from COPD patients showed enhanced chemotactic responses towards both CXCL1 and LTB4 compared with control cells. Chemotaxis was inhibited by both the active metabolite, roflumilast-N-oxide, and rolipram in a concentration-dependent manner with no difference in responsiveness between subjects. Roflumilast-N-oxide and rolipram were less efficacious against CXCL1 and LTB4-mediated [Ca2+]i suggesting that inhibition was not via this pathway. Both PDE4 inhibitors attenuated chemoattractant-mediated shape change and CD11b up-regulation suggesting common mechanisms. The stable cAMP analogue, 8-Br-cAMP, inhibited chemotaxis, as did the direct Epac1 activator 8-pCPT-2'-O-Me-cAMP but not the direct PKA activator, 6-Bnz-cAMP. These data suggest that roflumilast inhibits neutrophil chemotaxis directly via a cAMP-mediated mechanism requiring activation of Epac1, and that Epac1 activators could reduce COPD neutrophilic inflammation. PMID- 30395485 TI - Anti-adhesion of probiotic Enterococcus faecium WEFA23 against 5 pathogens and the beneficial effect of its S-layer proteins against Listeria monocytogenes. AB - Enterococcus faecium WEFA23 is a potential probiotic strain isolated from Chinese infant feces. In this study, the antagonistic activity of E. faecium WEFA23 on the adhesion to pathogens was investigated. E. faecium WEFA23 was able to compete, exclude and displace the adhesion of Escherichia coli O157:H7, Salmonella Typhimurium ATCC13311, Listeria monocytogenes CMCC54007, Staphylococcus aureus CMCC26003 and Shigella sonnei ATCC25931 on Caco-2 cells. Among them, L. monocytogenes achieved the strongest inhibition rate in both competition and displacement assays. Those anti-adhesion capacities were related to the bacterial physicochemical properties (hydrophobicity, auto-aggregation and co-aggregation) of bacterial surface. For L. monocytogenes, the anti-adhesion capacity was affected by the heat-treatment, cell density and growth phase of E. faecium WEFA23, 108 cfu/mL of viable cells at the stationary phase exhibited the strongest anti-adhesion activity. In addition, removal of S-layer proteins of E. faecium WEFA23 by treatment with 5 M LiCl significantly decreased its adhesion capacity, and those S-layer proteins were able to compete, displace and exclude L. monocytogenes at different levels. Both cells and S-layer proteins of E. faecium WEFA23 significantly reduced the apoptosis of Caco-2 cells induced by L. monocytogenes, which was mediated by caspase 3 activation. This study might be helpful to understand the anti-adhesion mechanism of probiotics against pathogens. PMID- 30395486 TI - The Combination of Atomoxetine and Oxybutynin Greatly Reduces Obstructive Sleep Apnea Severity: A Randomized, Placebo-Controlled, Double-Blind Crossover Trial. AB - RATIONALE: There is currently no effective pharmacological treatment for obstructive sleep apnea (OSA). Recent investigations indicate that drugs with noradrenergic and antimuscarinic effects improve genioglossus muscle activity and upper airway patency during sleep. OBJECTIVES: We aimed to determine the effects of the combination of a norepinephrine reuptake inhibitor (atomoxetine) and an antimuscarinic (oxybutynin) on OSA severity (apnea-hypopnea index, AHI; primary outcome) and genioglossus responsiveness (secondary outcome) in people with OSA. METHODS: 20 people completed a randomized, placebo-controlled, double-blind, crossover trial comparing one night of atomoxetine 80mg plus oxybutynin 5mg (ato oxy) to placebo administered prior to sleep. The AHI and genioglossus muscle responsiveness to negative esophageal pressure swings were measured via in laboratory polysomnography. In a subgroup of 9 patients the AHI was also measured when the drugs were administered separately. MEASUREMENTS AND MAIN RESULTS: The participants' median [interquartile range] age was 53 [46-58] years and body mass index was 34.8 [30.0-40.2] kg/m2. Ato-oxy lowered AHI by 63% [34-86%], from 28.5 [10.9-51.6] events/h to 7.5 [2.4-18.6] events/h (p<0.001). Of the 15/20 patients with OSA on placebo (AHI>10 events/hr), AHI was lowered by 74% [62-88%] (p<0.001) and all 15 patients exhibited a >=50% reduction. Genioglossus responsiveness increased ~3-fold, from 2.2 [1.1-4.7]%/cmH2O on placebo to 6.3 [3.0 to 18.3]%/cmH2O on ato-oxy (p<0.001). Neither atomoxetine nor oxybutynin reduced the AHI when administered separately. CONCLUSION: A combination of noradrenergic and antimuscarinic agents administered orally before bedtime on one night greatly reduced OSA severity. These findings open new possibilities for the pharmacologic treatment of OSA. Clinical trial registration available at www.clinicaltrials.gov, ID NCT02908529. PMID- 30395487 TI - Transcriptomic characterization elucidates a signaling network that controls antler growth. AB - Deer antlers are amazing appendages with the fastest growth rate among mammalian organs. Antler growth is driven by the growth center through a modified endochondral ossification process. Thus, identification of signaling pathways functioning in antler growth center would help us to uncover the underlying molecular mechanism of rapid antler growth. Furthermore, exploring and dissecting the molecular mechanism that regulates antler growth is extremely important and helpful for identifying methods to enhance long bone growth and treat cartilage- and bone-related diseases. In this study, we build a comprehensive intercellular signaling network in antler growth centers from both the slow growth stage and rapid growth stage using a state-of-art RNA-Seq approach. This network includes differentially expressed genes that regulate the activation of multiple signaling pathways, including the regulation of actin cytoskeleton, calcium signaling and adherens junction. These signaling pathways coordinately control multiple biological processes, including chondrocyte proliferation and differentiation, matrix homeostasis, mechanobiology and aging processes, during antler growth in a comprehensive and efficient manner. Therefore, our study provides novel insights into the molecular mechanisms regulating antler growth and provides valuable and powerful insight for medical research on therapeutic strategies targeting skeletal disorders and related cartilage and bone diseases. PMID- 30395488 TI - Assessment and Management of Patients With Metastatic Spinal Cord Compression: A Multidisciplinary Review. AB - PURPOSE: Metastatic spinal cord compression (MSCC) can be a catastrophic manifestation of advanced cancer that causes immobilizing pain and significant neurologic impairment. Oncologists can protect their patients by having a high index of suspicion for MSCC when patients present with new or worsening back pain before motor, sensory, bowel, or bladder deficits develop. We provide an updated, evidence-based narrative review of the presentation, diagnosis, and treatment of MSCC. METHODS: This narrative review was conducted by searching MEDLINE and Cochrane Database of Systematic Reviews for relevant literature on the presentation, diagnosis, and treatment of patients with MSCC. The article addresses the key elements of MSCC management germane to the medical oncologist, with special attention given to pain and symptom management, decision making with regard to surgery and radiation therapy, the importance of rehabilitative care, and the value of a multidisciplinary approach. RESULTS: Magnetic resonance imaging of the entire spine is recommended for the diagnosis of MSCC. Treatment includes glucocorticoid therapy, pain management, radiation therapy with or without surgery, and specialized rehabilitation. When formulating a treatment plan, clinicians should consider the patient's care goals and psychosocial needs. CONCLUSION: Prompt diagnosis and treatment of MSCC can reduce pain and prevent irreversible functional loss. Regular collaboration among multidisciplinary providers may streamline care and enhance achievement of treatment goals. PMID- 30395489 TI - Endovascular Aneurysm Sealing of a Collapsed and Thrombosed Aortic Stent-Graft With Renovisceral Chimney Stent-Grafts. AB - PURPOSE: To report the use of the Nellix endovascular aneurysm sealing (EVAS) system in the management of proximal stent-graft collapse associated with thrombosis following endovascular aneurysm repair (EVAR). CASE REPORT: A 76-year old man was admitted for proximal collapse of an aortic extension following bifurcated AFX stent-graft implantation associated with chimney grafts in both renal arteries and the superior mesenteric artery 1 month prior. Imaging identified thrombosis of the aortic stent-graft and the iliac limbs. A Nellix EVAS was placed into the AFX stent-graft to recanalize the aneurysm lumen and address the aortic thrombosis. There was no endoleak, and the renovisceral chimney stent-grafts remained patent over a follow-up of 25 months. CONCLUSION: While further studies are required to generalize its use, EVAS appears to be feasible in the management of aortic stent-graft collapse. PMID- 30395490 TI - Modulating Survivin as a Radioresistant Factor, Caspase-3, and Apoptosis by Omega 3 Docosahexaenoic Acid Sensitizes Mutant-p53 Colorectal Cancer Cells to gamma Irradiation. AB - Mutant-p53 colorectal cancer (CRC) cells are often resistant to radiotherapy. Loss of suppressor activity of wt-p53 on survivin is responsible for the enhanced expression of survivin as a radioresistant factor in tumor cells. Yet, no survivin-modulating drug has been approved for clinical application in CRC. Thus, the search for safe compounds that modulate survivin expression and induce apoptosis irrespective of p53 status may potentiate the efficacy of radiotherapy in mutant-p53 CRC cells. Omega-3 docosahexaenoic acid (DHA) induces apoptosis in malignant cells without cytotoxicity in normal cells. However, little is known whether in vitro concentrations of DHA equal to the human plasma levels are able to modulate expression of survivin and sensitize mutant-p53 CRC cells to gamma irradiation. Radioresistant mutant-p53 HT-29 cells were pretreated with 50- and 100-MUM DHA for 48-h before 2-, 4-, 6-, 8-, and 10-Gy of gamma-irradiation. Thereafter, proliferation rates were measured after 6 d. HT-29 cells were also pretreated with 50- and 100-MUM DHA for 4-h before 2- and 10-Gy of gamma irradiation after which, cell number, survivin expression, caspase-3 activation, apoptosis, and ED50 (gamma-irradiation dose causing 50% growth inhibition) were evaluated. Pretreatment of HT-29 cells with 50- and 100-MUM DHA for 48-h followed by 2- to 10-Gy of gamma-irradiation induced a dose-dependent additive decrease in cell proliferation rate and ED50 values were decreased by 88%, 44%, 41%, and 27% for 500-, 1500-, 2500-, and 5000 cells per well pretreated with 100-MUM DHA respectively. Pretreatment of 5 * 105 HT-29 cells per well with 100-MUM DHA for 4 h followed by 2- or 10-Gy of irradiation resulted in 53% and 86% decreases in cell numbers, 2- and 5.1-fold activation in caspase-3 followed by 66% and 60% decreases in survivin mRNA levels respectively. DHA in combination with radiation increased total apoptotic rate 48-h post-treatment. DHA decreases survivin expression and induces caspase-3 activation irrespective of p53 status. Significant decreases in ED50 values at concentrations of DHA equal to human plasma levels, suggesting that DHA could be used as an attractive radiosensitizer agent in CRC patients with mutant-p53. PMID- 30395491 TI - An Electronic Health Record-Based Real-Time Analytics Program For Patient Safety Surveillance And Improvement. AB - Twenty years after publication of the report To Err Is Human, studies demonstrate persisting high levels of patient harm. Most patient safety measurement remains highly retrospective, relying on voluntary reporting and post discharge administrative coding. Progress has been limited by the lack of advances in measurement accuracy, detection sensitivity, and timely actionability. The broad adoption of electronic health records (EHRs) offers a significant opportunity to leverage digital information to improve safety measurement and management using real-time data. We developed a novel method to extract safety indicators from EHRs to identify harm and its precursors by implementing a patient safety active management system (PSAM) in hospitals within a national Patient Safety Organization (PSO). The PSAM generated validated adverse event outcomes and leveraged EHR data to develop a real-time safety predictive model. This study describes the PSAM's pilot at two large community hospitals in 2014-17. We found that the PSAM could detect harm in real time, at higher rates than current levels are detected, and that such harm could be predicted. In addition to outlining future opportunities and challenges with this EHR-enabled PSAM approach, we discuss implications and next steps for policy and practice. PMID- 30395492 TI - Enhancing Safety Culture Through Improved Incident Reporting: A Case Study In Translational Research. AB - The Imperial College Healthcare National Health Service Trust, a large health care provider in London, together with an academic research unit, used a learning health systems cycle of interventions. The goals were to improve patient safety incident reporting and learning and shape a more just organizational safety culture. Following a phase of feedback gathering from front-line staff, seven evidence-based interventions were implemented and evaluated from October 2016 to August 2018. Indicators of safety culture, incident reporting rates, and reported rates of harm to patients and "never events" (events that should not happen in medical practice) were continuously monitored. In this article we report on this initiative, including its early results. We observed improvement on some measures of safety culture and incident reporting rates. Staff members' perceptions of six of the seven interventions were positive. The intervention exercise demonstrated the importance of health care policies in supporting local ownership of safety culture and encouraging the application of rigorous research standards. PMID- 30395493 TI - Can Communication-And-Resolution Programs Achieve Their Potential? Five Key Questions. AB - Communication-and-resolution programs (CRPs) are intended to promote accountability, transparency, and learning after adverse events. In this article we address five key challenges to the programs' future success: implementation fidelity, the evidence base for CRPs and their link to patient safety, fair compensation of harmed patients, alignment of CRP design with participants' needs, and public policy on CRPs. While the field has arrived at an understanding of the core communication-and-resolution practices, limited adherence fuels skepticism that programs are meeting the needs of patients and families who have been injured by care or improving patient safety. Adherence to communication-and resolution practices could be enhanced by adopting measures of CRP quality and implementing programs in a comprehensive, principled, and systematic manner. Of particular importance is offering fair compensation to patients in CRPs and supporting their right to attorney representation. There is evidence that the use of CRPs reduces liability costs, but research on other outcomes is limited. Additional research is especially needed on the links between CRPs and quality and on the programs' alignment with patients' and families' needs. By honoring principles of transparency, quality improvement, and patient and family empowerment, organizations can use their CRPs to help revitalize the medical profession. PMID- 30395494 TI - Interpersonal And Organizational Dynamics Are Key Drivers Of Failure To Rescue. AB - Failure to rescue-mortality following a major surgical complication-is a key driver of variation in postoperative mortality. However, little is known about the impact of interpersonal and organizational dynamics, or microsystem factors, on failure to rescue. In a qualitative study of providers from hospitals with high and low rescue rates, we identified five key factors that providers believe influence the successful rescue of surgical patients: teamwork, action taking, psychological safety, recognition of complications, and communication. Near uniform agreement existed on two targets for improvement: delayed recognition of developing complications and poor interprofessional communication and inability to express clinical concerns. To improve perioperative outcomes, hospitals and payers should shift their attention to improving early detection and effective communication of major complications. PMID- 30395495 TI - A Prescription For Enhancing Electronic Prescribing Safety. AB - While electronic prescribing has been shown to reduce medication errors and improve prescribing safety, it is vulnerable to error-prone processes. We review six intersecting areas in which changes to electronic prescribing systems, particularly in the outpatient setting, could transform medication ordering quality and safety. We recommend incorporating medication indications into electronic prescribing, establishing a single shared online medication list, implementing the transmission of electronic cancellation orders to pharmacies (CancelRx) to ensure that drugs are safely and reliably discontinued, implementing standardized structured and codified prescription instructions, reengineering clinical decision support, and redesigning electronic prescribing to facilitate the ordering of nondrug alternatives. PMID- 30395496 TI - Accurate Measurement In California's Safety-Net Health Systems Has Gaps And Barriers. AB - Patient safety in ambulatory care has not been routinely measured. California implemented a pay-for-performance program in safety-net hospitals that incentivized measurement and improvement in key areas of ambulatory safety: referral completion, medication safety, and test follow-up. We present two years of program data (collected during July 2015-June 2017) and show both suboptimal performance in aspects of ambulatory safety and questionable reliability in data reporting. Performance was better in areas that required limited coordination or patient engagement-for example, annual medication monitoring versus follow-up after high-risk mammograms. Health care systems that lack seamlessly integrated electronic health records and patient registries encountered barriers to reporting reliable ambulatory safety data, particularly for measures that integrated multiple data elements. These data challenges precluded accurate performance measurement in many areas. Policy makers and safety advocates need to support the development of information systems and measures that facilitate the accurate ascertainment of the health systems, patients, and clinical tasks at greatest risk for ambulatory safety failures. PMID- 30395497 TI - Reversing The Rise In Maternal Mortality. AB - A mother's death in the 1950s tears a family apart; sixty years later, maternal mortality is on the rise again. PMID- 30395498 TI - A Medical School For The Community. AB - Funded in part by taxpayer dollars, Dell Medical School has a mandate to improve community health. It's also identifying novel ways to reward value. PMID- 30395499 TI - Patient Safety. AB - The Institute of Medicine's landmark report To Err Is Human drew attention to the large number of avoidable medical errors in the US health care system. Much of the response to the report was focused on hospitals, but safety concerns can arise in many settings. This month's DataGraphic highlights patient safety ranging from adverse events in the hospital to the safety performance of nursing homes and complaints made by patients in inpatient psychiatric settings. It also examines safety concerns regarding electronic health records and reports the results of an experiment using a surgical safety checklist in South Carolina. PMID- 30395500 TI - The Architecture Of Safety: An Emerging Priority For Improving Patient Safety. AB - There is a lack of awareness regarding the pervasive influence of the built environment on caregiving activities, and how its design could reduce risks for patients and providers. This article presents a narrative review summarizing key findings that link health care facility design to key targeted safety outcomes: health care-associated infections, falls, and medication errors. It describes how facility design should be considered in conjunction with quality improvement legislation; projects under way in health systems; and the work of guideline setting organizations, funding agencies, industry, and educational institutions. The article also charts a path forward that consolidates existing challenges and suggests what can be done about them to create safe and high-quality health care environments. PMID- 30395501 TI - Effects Of A Communication-And-Resolution Program On Hospitals' Malpractice Claims And Costs. AB - To promote communication with patients after medical injuries and improve patient safety, numerous hospitals have implemented communication-and-resolution programs (CRPs). Through these programs, hospitals communicate transparently with patients after adverse events; investigate what happened and offer an explanation; and, when warranted, apologize, take responsibility, and proactively offer compensation. Despite growing consensus that CRPs are the right thing to do, concerns over liability risks remain. We evaluated the liability effects of CRP implementation at four Massachusetts hospitals by examining before-and-after trends in claims volume, cost, and time to resolution and comparing them to trends among nonimplementing peer institutions. CRP implementation was associated with improved trends in the rate of new claims and legal defense costs at some hospitals, but it did not significantly alter trends in other outcomes. None of the hospitals experienced worsening liability trends after CRP implementation, which suggests that transparency, apology, and proactive compensation can be pursued without adverse financial consequences. PMID- 30395502 TI - Patient Safety. PMID- 30395503 TI - Challenges And Opportunities For Improving Patient Safety Through Human Factors And Systems Engineering. AB - Despite progress on patient safety since the publication of the Institute of Medicine's 1999 report, To Err Is Human, significant problems remain. Human factors and systems engineering (HF/SE) has been increasingly recognized and advocated for its value in understanding, improving, and redesigning processes for safer care, especially for complex interacting sociotechnical systems. However, broad awareness of HF/SE and its adoption into safety improvement work have been frustratingly slow. We provide an overview of HF/SE, its demonstrated value to a wide range of patient safety problems (in particular, medication safety), and challenges to its broader implementation across health care. We make a variety of recommendations to maximize the spread of HF/SE, including formal and informal education programs, greater adoption of HF/SE by health care organizations, expanded funding to foster more clinician-engineer partnerships, and coordinated national efforts to design and operationalize a system for spreading HF/SE into health care nationally. PMID- 30395504 TI - Consolidation Trends In California. PMID- 30395505 TI - Does Nursing Home Compare Reflect Patient Safety In Nursing Homes? AB - The past several decades have seen significant policy efforts to improve the quality of care in nursing homes, but the patient safety movement has largely ignored this setting. In this study we compared nursing homes' performance on several composite quality measures from Nursing Home Compare, the most prominent recent example of a national policy aimed at improving the quality of nursing home care, to their performance on measures of patient safety in nursing homes such as pressure sores, infections, falls, and medication errors. Although Nursing Home Compare captures some aspects of patient safety, we found the relationship to be weak and somewhat inconsistent, leaving consumers who care about patient safety with little guidance. We recommend that Nursing Home Compare be refined to provide a clearer picture of patient safety and quality of life, allowing consumers to weight these domains according to their preferences and priorities. PMID- 30395506 TI - Consolidation Trends: The Authors Reply. PMID- 30395507 TI - Scaling Safety: The South Carolina Surgical Safety Checklist Experience. AB - Proven patient safety solutions such as the World Health Organization's Surgical Safety Checklist are challenging to implement at scale. A voluntary initiative was launched in South Carolina hospitals in 2010 to encourage use of the checklist in all operating rooms. Hospitals that reported completing implementation of the checklist in their operating rooms by 2017 had significantly higher levels of CEO and physician participation and engaged more in higher-touch activities such as in-person meetings and teamwork skills trainings than comparison hospitals did. Based on our experience and the participation data collected, we suggest three considerations for hospital, hospital association, state, and national policy makers: Successful programs must be designed to engage all stakeholders (CEOs, physicians, nurses, surgical technologists, and others); offering a variety of program activities-both lower touch and higher-touch-over the duration of the program allows more hospital and individual participation; and change takes time and resources. PMID- 30395508 TI - Two Decades Since To Err Is Human: An Assessment Of Progress And Emerging Priorities In Patient Safety. AB - The Institute of Medicine's To Err Is Human, published in 1999, represented a watershed moment for the US health care system. The report dramatically raised the profile of patient safety and stimulated dedicated research funding to this essential aspect of patient care. Highly effective interventions have since been developed and adopted for hospital-acquired infections and medication safety, although the impact of these interventions varies because of their inconsistent implementation and practice. Progress in addressing other hospital-acquired adverse events has been variable. In the past two decades additional areas of safety risk have been identified and targeted for intervention, such as outpatient care, diagnostic errors, and the use of health information technology. In sum, the frequency of preventable harm remains high, and new scientific and policy approaches to address both prior and emerging risk areas are imperative. With the increasing availability of electronic data, investments must now be made in developing and testing methods to routinely and continuously measure the frequency and types of patient harm and even predict risk of harm for specific patients. This progress could lead us from a Bronze Age of rudimentary tool development to a Golden Era of vast improvement in patient safety. PMID- 30395509 TI - Patient Engagement In Health Care Safety: An Overview Of Mixed-Quality Evidence. AB - Patients and caregivers play a central role in health care safety in the hospital, ambulatory care setting, and community. Despite this, interventions to promote patient engagement in safety are still underexplored. We conducted an overview of review articles on patient engagement interventions in safety to examine the current state of the evidence. Of the 2,795 references we evaluated, 52 articles met our full-text inclusion criteria for synthesis in 2018. We identified robust evidence supporting patients' self-management of anticoagulation medications and mixed-quality evidence supporting patient engagement in medication and chronic disease self-management, adverse event reporting, and medical record accuracy. Promising modes of patient engagement in safety, such as anticoagulation management and patient portal access, are not widely implemented. We discuss major implementation priorities and propose directions for future research and policy to enhance patient partnership within safety efforts. PMID- 30395510 TI - Payment Innovations To Improve Diagnostic Accuracy And Reduce Diagnostic Error. AB - Diagnostic accuracy is essential for treatment decisions but is largely unaccounted for by payers, including in fee-for-service Medicare and proposed Alternative Payment Models (APMs). We discuss three payment-related approaches to reducing diagnostic error. First, coding changes in the Medicare Physician Fee Schedule could facilitate the more effective use of teamwork and information technology in the diagnostic process and better support the cognitive work and time commitment that physicians make in the quest for diagnostic accuracy, especially in difficult or uncertain cases. Second, new APMs could be developed to focus on improving diagnostic accuracy in challenging cases and make available support resources for diagnosis, including condition-specific centers of diagnostic expertise or general diagnostic centers of excellence that provide second (or even third) opinions. Performing quality improvement activities that promote safer diagnosis should be a part of the accountability of APM recipients. Third, the accuracy of diagnoses that trigger APM payments and establish payment amounts should be confirmed by APM recipients. Implementation of these multipronged approaches can make current payment models more accountable for addressing diagnostic error and position diagnostic performance as a critical component of quality-based payment. PMID- 30395511 TI - Foundation Funding For Patient Safety. PMID- 30395512 TI - Patient Safety In Inpatient Psychiatry: A Remaining Frontier For Health Policy. AB - Behavioral health care has been slow to take up robust efforts to improve patient safety. This lag is especially apparent in inpatient psychiatry, where there is risk for physical and psychological harm. Recent investigative journalism has provoked public concern about instances of alleged abuse, negligence, understaffing, sexual assault, inappropriate medication use, patient self-harm, poor sanitation, and inappropriate restraint and seclusion. However, empirical evidence describing the scope of unsafe experiences is limited. While evidence based inpatient psychiatry requires care to be trauma-informed, market failures and a lack of payment alignment with patient-centered care leave patients vulnerable to harm. Existing regulatory mechanisms attempt to provide accountability; however, these mechanisms are imperfect. Furthermore, research is sparse. Few health services researchers study inpatient psychiatry, the issue has not been a priority among research funders, and data on inpatient psychiatry is excluded from national surveys of quality. Several policy levers could begin to address these deficiencies. These include aligning incentives with patient centered care, building trauma-informed care into accreditation and monitoring, conducting trend analyses of critical incidents, and improving research capacity. PMID- 30395514 TI - Success In Hospital-Acquired Pressure Ulcer Prevention: A Tale In Two Data Sets. AB - Chart-based surveillance reviews indicate that the incidence of hospital-acquired pressure ulcers (HAPUs) declined 23 percent during 2010-14, equating to an estimated savings of $1 billion during that period. Yet it remains unclear whether the administrative data used to implement three Medicare value-based purchasing programs that target HAPUs indicate similar improvements, and how success varied by HAPU severity. These programs measure and penalize only for more severe ulcers (stage 3 or 4 or unstageable), which are much more costly than less severe cases (stage 1 or 2). We assessed HAPU incidence, severity, and trends using administrative data for 2009-14 from three states. The HAPU incidence we found was approximately one-twentieth of that found in chart-based surveillance review data. HAPU incidence in administrative data declined, but 96 percent of the change was due to a decline in the incidence of less severe HAPUs. Transitioning from administrative data to chart-based surveillance review to measure HAPUs (mirroring changes that have already been made in reporting hospital-acquired infections) and accounting for HAPU severity could improve the validity of HAPU measures for assessing the clinical and financial impact of value-based purchasing interventions. PMID- 30395513 TI - Learning From Patients' Experiences Related To Diagnostic Errors Is Essential For Progress In Patient Safety. AB - Diagnostic error research has largely focused on individual clinicians' decision making and system design, while overlooking information from patients. We analyzed a unique new data source of patient- and family-reported error narratives to explore factors that contribute to diagnostic errors. From reports of adverse medical events submitted in the period January 2010-February 2016, we identified 184 unique patient narratives of diagnostic error. Problems related to patient-physician interactions emerged as major contributors. Our analysis identified 224 instances of behavioral and interpersonal factors that reflected unprofessional clinician behavior, including ignoring patients' knowledge, disrespecting patients, failing to communicate, and manipulation or deception. Patients' perspectives can lead to a more comprehensive understanding of why diagnostic errors occur and help develop strategies for mitigation. Health systems should develop and implement formal programs to collect patients' experiences with the diagnostic process and use these data to promote an organizational culture that strives to reduce harm from diagnostic error. PMID- 30395516 TI - In Patient Safety Efforts, Pharmacists Gain New Prominence. AB - As health care becomes more complex, health systems have sought to enlist those who can engage patients outside the hospital walls. PMID- 30395515 TI - Nurses' And Patients' Appraisals Show Patient Safety In Hospitals Remains A Concern. AB - The Institute of Medicine concluded in To Err Is Human in 1999 that transformation of nurse work environments was needed to reduce patient harm. We studied 535 hospitals in four large states at two points in time between 2005 and 2016 to determine the extent to which their work environments improved, and whether positive changes were associated with greater progress in patient safety. Survey data from thousands of nurses and patients showed that patient safety remains a serious concern. Only 21 percent of study hospitals showed sizable improvements (of more than 10 percent) in work environment scores, while 7 percent had worse scores. For hospitals in which clinical care environments improved, patients and nurses reported improvements in patient safety indicators. These included increases in percentages of patients rating their hospital favorably (a change of 11 percent) and stating that they would definitely recommend the hospital (8 percent) and in percentages of nurses reporting excellent quality of care (15 percent) and giving the hospital a favorable grade on patient safety (15 percent). Where work environments deteriorated, fewer nurses (-19 percent) gave a favorable grade on patient safety. Failure to improve hospital work environments may be hampering progress on patient safety. PMID- 30395518 TI - A physician's response to observational studies of opioid prescribing. PMID- 30395519 TI - How acute pain leads to chronic opioid use. PMID- 30395517 TI - Identifying Electronic Health Record Usability And Safety Challenges In Pediatric Settings. AB - Pediatric populations are uniquely vulnerable to the usability and safety challenges of electronic health records (EHRs), particularly those related to medication, yet little is known about the specific issues contributing to hazards. To understand specific usability issues and medication errors in the care of children, we analyzed 9,000 patient safety reports, made in the period 2012-17, from three different health care institutions that were likely related to EHR use. Of the 9,000 reports, 3,243 (36 percent) had a usability issue that contributed to the medication event, and 609 (18.8 percent) of the 3,243 might have resulted in patient harm. The general pattern of usability challenges and medication errors were the same across the three sites. The most common usability challenges were associated with system feedback and the visual display. The most common medication error was improper dosing. PMID- 30395520 TI - PSA screening: Back to the future. PMID- 30395521 TI - Which patients with pulmonary embolism need echocardiography? PMID- 30395522 TI - Perioperative cardiovascular medicine: 5 questions for 2018. AB - A MEDLINE search was performed from January 2017 to February 2018, and articles were selected for this update based on their significant influence on the practice of perioperative cardiovascular medicine. PMID- 30395523 TI - Influenza update 2018-2019: 100 years after the great pandemic. AB - Four influenza pandemics, starting with the historic 1918 pandemic, have killed thousands of people around the world. Vaccination, still the most important means of preventing influenza, is currently recommended yearly for all people age 6 months and older, with a goal of vaccinating 80% of all Americans and 90% of at risk populations. Neuraminidase inhibitors are underused, and a new drug with a different mechanism of action, baloxavir marboxil, is expected to be approved soon in the United States. PMID- 30395524 TI - Men's health 2018: BPH, prostate cancer, erectile dysfunction, supplements. AB - This review describes the latest research and guidelines for 4 topics in men's health commonly addressed by primary care physicians: the diagnosis and treatment of benign prostatic hyperplasia (BPH), prostate cancer, and erectile dysfunction and the evidence concerning the use of dietary supplements in men. PMID- 30395525 TI - Bisphosphonate-related atypical femoral fracture: Managing a rare but serious complication. AB - Atypical femoral fracture is a rare but serious complication of long-term bisphosphonate therapy. Although the benefit of preventing osteoporotic fractures greatly outweighs the risk of atypical fracture in bisphosphonate users, concern about atypical fracture risk has led to a decrease in bisphosphonate use. What are the risks, and how do we treat atypical femoral fracture? PMID- 30395526 TI - Pulmonary infarction due to pulmonary embolism. PMID- 30395527 TI - Renal vein thrombosis and pulmonary embolism. PMID- 30395528 TI - Back pain as a sign of inferior vena cava filter complications. PMID- 30395529 TI - Correction: Genitourinary syndrome of menopause. AB - In the article by A.C. Moreno, S.K. Sikka, and H.L. Thacker, Genitourinary syndrome of menopause in breast cancer survivors: Treatments are available, Cleve Clin J Med 2018; 85(10):760-766, doi:10.3949/ccjm.85a.17108, Table 2 incorrectly stated that prasterone is contraindicated in women with known or suspected breast cancer. This correction has been made online as follows. "Warning: Estrogen is a metabolite of prasterone; use of exogenous extrogen is contraindicated in women with known or suspected breast cancer; prasterone has not been studied in women with a history of breast cancer." PMID- 30395530 TI - 13th Turkish Congress of Hepato-Pancreato-Biliary Surgery. PMID- 30395531 TI - 9th Surgical Research Congress. PMID- 30395532 TI - Risk Assessment of Recreational Noise-Induced Hearing Loss from Exposure through a Personal Audio System-iPod Touch. AB - BACKGROUND: Recreational noise-induced hearing loss (RNIHL) is a major health issue and presents a huge economic burden on society. Exposure to loud music is not considered hazardous in our society because music is thought to be a source of relaxation and entertainment. However, there is evidence that regardless of the sound source, frequent exposure to loud music, including through personal audio systems (PAS), can lead to hearing loss, tinnitus, difficulty processing speech, and increased susceptibility to age-related hearing loss. PURPOSE: Several studies have documented temporary threshold shifts (TTS) (a risk indicator of future permanent impairment) in subjects that listen to loud music through their PAS. However, there is not enough information regarding volume settings that may be considered to be safe. As a primary step toward quantifying the risk of RNIHL through PAS, we assessed changes in auditory test measures before and after exposure to music through the popular iPod Touch device set at various volume levels. RESEARCH DESIGN: This project design incorporated aspects of both between- and within-subjects and used repeated measures to analyze individual groups. STUDY SAMPLE: A total of 40 adults, aged 18-31 years with normal hearing were recruited and randomly distributed to four groups. Each group consisted of five males and five females. DATA COLLECTION AND ANALYSIS: Subjects underwent two rounds of testing (pre- and postmusic exposure), with a 30-min interval, where they listened to a playlist consisting of popular songs through an iPod at 100%, 75%, 50%, or 0% volume (no music). Based on our analysis on the Knowles Electronic Manikin for Acoustic Research, with a standardized 711 coupler, it was determined that listening to the playlist for 30 min through standard earbuds resulted in an average level of 97.0 dBC at 100% volume, 83.3 dBC at 75% volume, and 65.6 dBC at 50% volume. Pure-tone thresholds from 500-8000 Hz, extended high-frequency pure tones between 9-12.5 kHz, and distortion product otoacoustic emissions (DPOAE) were obtained before and after the 30-min music exposure. Analysis of variance (ANOVA) was performed with two between-subjects factors (volume and gender) and one within-subjects factor (frequency). Change (shift) in auditory test measures was used as the outcome for the ANOVA. RESULTS: Results indicated significant worsening of pure-tone thresholds following music exposure only in the group that was exposed to 100% volume at the following frequencies: 2, 3, 4, 6 and 8 kHz. DPOAEs showed significant decrease at 2000 and 2822 Hz, also only for the 100% volume condition. No significant changes were found between pre- and postmusic exposure measures in groups exposed to 75%, 50%, or 0% volume conditions. Follow-up evaluations conducted a week later indicated that pure-tone thresholds had returned to the premusic exposure levels. CONCLUSIONS: These results provide quantifiable information regarding safe volume control settings on the iPod Touch with standard earbuds. Listening to music using the iPod Touch at 100% volume setting for as little as 30 min leads to TTS and worsening of otoacoustic emissions, a risk for permanent auditory damage. PMID- 30395533 TI - Sound Quality Effects of an Adaptive Nonlinear Frequency Compression Processor with Normal-Hearing and Hearing-Impaired Listeners. AB - BACKGROUND: Frequency lowering (FL) technology offers a means of improving audibility of high-frequency sounds. For some listeners, the benefit of such technology can be accompanied by a perceived degradation in sound quality, depending on the strength of the FL setting. PURPOSE: The studies presented in this article investigate the effect of a new type of FL signal processing for hearing aids, adaptive nonlinear frequency compression (ANFC), on subjective speech quality. RESEARCH DESIGN: Listener ratings of sound quality were collected for speech stimuli processed with systematically varied fitting parameters. STUDY SAMPLE: Study 1 included 40 normal-hearing (NH) adult and child listeners. Study 2 included 11 hearing-impaired (HI) adult and child listeners. HI listeners were fitted with laboratory-worn hearing aids for use during listening tasks. INTERVENTION: Speech quality ratings were assessed across test conditions consisting of various strengths of static nonlinear frequency compression (NFC) and ANFC speech. Test conditions included those that were fine-tuned on an individual basis per hearing aid fitting and conditions that were modified to intentionally alter the sound quality of the signal. DATA COLLECTION AND ANALYSIS: Listeners rated speech quality using the MUlti Stimulus test with Hidden Reference and Anchor (MUSHRA) test paradigm. Ratings were analyzed for reliability and to compare results across conditions. RESULTS: Results show that interrater reliability is high for both studies, indicating that NH and HI listeners from both adult and child age groups can reliably complete the MUSHRA task. Results comparing sound quality ratings across experimental conditions suggest that both the NH and HI listener groups rate the stimuli intended to have poor sound quality (e.g., anchors and the strongest available parameter settings) as having below-average sound quality ratings. A different trend in the results is reported when considering the other experimental conditions across the listener groups in the studies. Speech quality ratings measured with NH listeners improve as the strength of ANFC decreases, with a range of bad to good ratings reported, on average. Speech quality ratings measured with HI listeners are similar and above-average for many of the experimental stimuli, including those with fine-tuned NFC and ANFC parameters. CONCLUSIONS: Overall, HI listeners provide similar sound quality ratings when comparing static and adaptive forms of frequency compression, especially when considering the individualized parameter settings. These findings suggest that a range in settings may result in above average sound quality for adults and children with hearing impairment. Furthermore, the fitter should fine-tune FL parameters for each individual listener, regardless of type of FL technology. PMID- 30395534 TI - EDUCATIONAL SERIES IN CONGENITAL HEART DISEASE: The sequential segmental approach to assessment. AB - Sequential segmental analysis allows clear description of the cardiac structure in a logical fashion without assumptions and confusing nomenclature. Each segment is analysed, and then the connections described followed by any associated anomalies. For the echocardiographer there are several key features of the cardiac structures to help differentiate and accurately describe them. PMID- 30395535 TI - Vitamin D stimulates multiple microRNAs to inhibit CRH and other pro-labor genes in human placenta. AB - Maternal vitamin D-deficiency is linked to adverse pregnancy outcomes including spontaneous preterm birth (SPB). Placental corticotropin-releasing hormone (CRH) has been proposed to be part of a clock that governs the length of gestation in humans, with elevated maternal serum levels predicting early delivery. In this study we test the hypothesis that vitamin D could contribute to the prevention of preterm labor by inhibiting CRH and other pro-labor mediators. The biological activity of vitamin D occurs via two pathways: non-genomic and genomic responses, both of which involve binding of 1,25-dihydroxyvitamin D (1,25(OH)2D), the active metabolite of vitamin D binding to the vitamin D receptor (VDR). By using chromatin immunoprecipitation followed by sequencing (ChIP-seq), we found that 1,25(OH)2D stimulates association of VDR with a number of miRNA genes including MIR181B2 and MIR26B, and their mature products miR-181b-5p and miR-26b-5p are predicted to target CRH and cyclooxygenase-2 (COX-2) mRNA at 3'-untranslated region (UTR), respectively. We performed RT-qPCR analysis to validate that expression of mature miR-181b-5p and miR-26b-5p in term human syncytiotrophoblast increased in response to treatment with 1,25(OH)2D. miR-181b-5p or miR-26b-5p mediated inhibition of CRH or COX-2 was further assessed by the use of miRNA mimics/inhibitors and a luciferase reporter assay. Taken together, this study has identified novel mechanisms vitamin D down regulates pro-labor genes and could lower the risk of preterm delivery. PMID- 30395536 TI - Modeling organ-specific vasculature with organ-on-a-chip devices. AB - Organ-on-a-chip devices, also known as microphysiological systems, have gained significant attention in recent years. Recent advances in tissue engineering and microfabrication have enabled these devices to provide more precise control over cellular microenvironments to mimic the tissue-level or organ-level function of the human body. These more complex tissue models can provide either an improvement in the functional expression and maturation of cells or an avenue to probe biological events and function that would otherwise be difficult to visualize and mechanistically study. This high-value information, when complimented with the existing gold-standards of cell-based assays and animal models, could potentially lead to more informed decision-making in drug development. A prevalent biological component in many organ-on-a-chip devices is an engineered vascular interface that is present in almost all organs of the human body. The vasculature and the vascular interface are particularly susceptible to biomechanical forces, they function as the conduits for inter cellular and inter-organ interactions, and regulate drug transport. In this review, we examine the various approaches taken to model the human vasculature with an emphasis on the engineering of organ-specific vasculatures, and discuss various challenges and opportunities ahead as the field advances. PMID- 30395537 TI - Osteopontin controls immunosuppression in the tumor microenvironment. AB - Cancer cells evade the immune system through a variety of different mechanisms, including the inhibition of antitumor effector T cells via checkpoint ligand receptor interaction. Moreover, studies have shown that blocking these checkpoint pathways can reinvigorate the antitumor immunity, thereby prompting the development of numerous checkpoint immunotherapies, several of which are now being approved to treat multiple types of cancer. However, only a fraction of patients achieves promising long-term outcomes in response to checkpoint inhibition, suggesting the existence of additional unknown tumor-induced immunosuppressive pathways. In this issue of the JCI, Klement and colleagues describe an additional pathway of T cell inhibition in cancer. Specifically, the authors demonstrate that downregulation of IRF8, a molecular determinant of apoptotic resistance, in tumor cells aborts repression of osteopontin, which in turn binds to its physiological receptor CD44 on activated T cells and suppresses their activation. These results suggest that osteopontin may act as another immune checkpoint and may serve as a target to expand the number of patients who respond to immune checkpoint inhibitor therapy. PMID- 30395538 TI - Androgen receptor functions as transcriptional repressor of cancer-associated fibroblast activation. AB - The aging-associated increase of cancer risk is linked with stromal fibroblast senescence and concomitant cancer-associated fibroblast (CAF) activation. Surprisingly little is known about the role of androgen receptor (AR) signaling in this context. We have found downmodulated AR expression in dermal fibroblasts underlying premalignant skin cancer lesions (actinic keratoses and dysplastic nevi) as well as in CAFs from the 3 major skin cancer types, squamous cell carcinomas (SCCs), basal cell carcinomas, and melanomas. Functionally, decreased AR expression in primary human dermal fibroblasts (HDFs) from multiple individuals induced early steps of CAF activation, and in an orthotopic skin cancer model, AR loss in HDFs enhanced tumorigenicity of SCC and melanoma cells. Forming a complex, AR converged with CSL/RBP-Jkappa in transcriptional repression of key CAF effector genes. AR and CSL were positive determinants of each other's expression, with BET inhibitors, which counteract the effects of decreased CSL, restoring AR expression and activity in CAFs. Increased AR expression in these cells overcame the consequences of CSL loss and was by itself sufficient to block the growth and tumor-enhancing effects of CAFs on neighboring cancer cells. As such, the findings establish AR as a target for stroma-focused cancer chemoprevention and treatment. PMID- 30395539 TI - PLK1: a promising and previously unexplored target in double-hit lymphoma. AB - Inhibitors that target specific kinases or oncoproteins have become popular additions to or replacements for cytotoxic chemotherapies to treat many different types of cancer. However, many tumors lack a discernable target kinase and an amplified oncoprotein and/or rely on several cooperating mechanisms for progression. Thus, combinations of targeted therapies are essential for treating many cancers to avoid the rapid emergence of resistance. In this issue of the JCI, Ren et al. use an elegant kinase activity-profiling method and identify activity of the oncogene polo-like kinase-1 (PLK1) as an important driver of double-hit lymphoma (DHL), an aggressive subgroup of B cell lymphoma characterized by chromosomal translocations involving c-MYC and BCL2 or BCL6. Moreover, PLK1 activity was associated with MYC expression and poor prognosis in DHL patients. PLK1 inhibition with volasertib, alone and in combination with the BCL-2 inhibitor venetoclax, was efficacious in multiple DHL models, including mice harboring DHL patient-derived xenografts. Together, these data support PLK1 as a promising prognostic marker and therapeutic target for DHL. PMID- 30395540 TI - An osteopontin/CD44 immune checkpoint controls CD8+ T cell activation and tumor immune evasion. AB - Despite breakthroughs in immune checkpoint inhibitor (ICI) immunotherapy, not all human cancers respond to ICI immunotherapy and a large fraction of patients with the responsive types of cancers do not respond to current ICI immunotherapy. This clinical conundrum suggests that additional immune checkpoints exist. We report here that interferon regulatory factor 8 (IRF8) deficiency led to impairment of cytotoxic T lymphocyte (CTL) activation and allograft tumor tolerance. However, analysis of chimera mice with competitive reconstitution of WT and IRF8-KO bone marrow cells as well as mice with IRF8 deficiency only in T cells indicated that IRF8 plays no intrinsic role in CTL activation. Instead, IRF8 functioned as a repressor of osteopontin (OPN), the physiological ligand for CD44 on T cells, in CD11b+Ly6CloLy6G+ myeloid cells and OPN acted as a potent T cell suppressor. IRF8 bound to the Spp1 promoter to repress OPN expression in colon epithelial cells, and colon carcinoma exhibited decreased IRF8 and increased OPN expression. The elevated expression of OPN in human colon carcinoma was correlated with decreased patient survival. Our data indicate that myeloid and tumor cell-expressed OPN acts as an immune checkpoint to suppress T cell activation and confer host tumor immune tolerance. PMID- 30395541 TI - Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies. AB - We report the molecular, cellular, and clinical features of 5 patients from 3 kindreds with biallelic mutations in the autosomal LIG1 gene encoding DNA ligase 1. The patients exhibited hypogammaglobulinemia, lymphopenia, increased proportions of circulating gammadeltaT cells, and erythrocyte macrocytosis. Clinical severity ranged from a mild antibody deficiency to a combined immunodeficiency requiring hematopoietic stem cell transplantation. Using engineered LIG1-deficient cell lines, we demonstrated chemical and radiation defects associated with the mutant alleles, which variably impaired the DNA repair pathway. We further showed that these LIG1 mutant alleles are amorphic or hypomorphic, and exhibited variably decreased enzymatic activities, which lead to premature release of unligated adenylated DNA. The variability of the LIG1 genotypes in the patients was consistent with that of their immunological and clinical phenotypes. These data suggest that different forms of autosomal recessive, partial DNA ligase 1 deficiency underlie an immunodeficiency of variable severity. PMID- 30395542 TI - A disease mutation reveals a role for NaV1.9 in acute itch. AB - Itch (pruritis) and pain represent two distinct sensory modalities; yet both have evolved to alert us to potentially harmful external stimuli. Compared with pain, our understanding of itch is still nascent. Here, we report a new clinical case of debilitating itch and altered pain perception resulting from the heterozygous de novo p.L811P gain-of-function mutation in NaV1.9, a voltage-gated sodium (NaV) channel subtype that relays sensory information from the periphery to the spine. To investigate the role of NaV1.9 in itch, we developed a mouse line in which the channel is N-terminally tagged with a fluorescent protein, thereby enabling the reliable identification and biophysical characterization of NaV1.9-expressing neurons. We also assessed NaV1.9 involvement in itch by using a newly created NaV1.9-/- and NaV1.9L799P/WT mouse model. We found that NaV1.9 is expressed in a subset of nonmyelinated, nonpeptidergic small-diameter dorsal root ganglia (DRGs). In WT DRGs, but not those of NaV1.9-/- mice, pruritogens altered action potential parameters and NaV channel gating properties. Additionally, NaV1.9-/- mice exhibited a strong reduction in acute scratching behavior in response to pruritogens, whereas NaV1.9L799P/WT mice displayed increased spontaneous scratching. Altogether, our data suggest an important contribution of NaV1.9 to itch signaling. PMID- 30395543 TI - Comparison Between Full-Body vs. Split-Body Resistance Exercise on the Brain Derived Neurotrophic Factor and Immunometabolic Response. AB - Lira, FS, Conrado de Freitas, M, Gerosa-Neto, J, Cholewa, JM, and Rossi, FE. Comparison between full-body vs. split-body resistance exercise on the brain derived neurotrophic factor immunometabolic response. J Strength Cond Res XX(X): 000-000, 2018-Intense aerobic exercise seems to increase serum concentrations of brain-derived neurotrophic factor (BDNF) in conjunction with increasing lactate; however, less is known about the BDNF response to differing resistance exercise protocols. We hypothesized that full-body (FB) resistance exercise will elicit a greater increase in serum BDNF and lactate compared with split-body resistance exercise. Twelve recreationally resistance-trained men (age = 25.3 +/- 5.9 years) performed 3 randomized trials of 18 sets of exercise: upper-body (UB), lower-body (LB), and FB conditions. Serum BDNF levels were assessed at rest, immediately Post-exercise, Post-1 hour, and Post-2 hours during recovery. Lactate concentration was evaluated at rest, after 9 sets, Post-exercise, Post-5, Post 10, and Post-30 minutes during recovery. In addition, interleukin (IL-6 and IL 10) and the IL-6/IL-10 ratio were calculated. Lactate concentration and total volume were greater in the FB condition compared with LB and UB (p < 0.05). For BDNF, effect sizes were largest in the LB (1.4), followed by the FB (0.75), and moderate to UB (0.33), although no significant differences were observed between conditions. There was a statistically significant relationship between lactate and BDNF only for LB condition (rho = 0.72; p = 0.013). There were a greater IL 10 Post-1 hour for FB condition compared with UB and LB (p < 0.001), and lower IL 6/IL-10 ratio in FB compared with UB (p < 0.001). Lower body induced a great BDNF response, and FB resistance exercise elicited a greater increase of serum cytokines than UB in trained men. We speculate that the volume of work performed by larger muscles has a larger influence on BDNF than overall volume. PMID- 30395544 TI - The Person Underneath the Illness. PMID- 30395545 TI - Attraction Versus Action in Pedophilic Desire: The Role of Personality Traits and Childhood Experience. AB - OBJECTIVE: Comparison of pedophilic individuals who do and do not refrain from sexually engaging with children may offer critically important information regarding the differential contributors to pedophilic attraction versus behavior. This study compared 5 traits that are potentially contributory to pedophilic attraction or behavior in both minor-attracted persons (MAPs) who refrain from sexually engaging with minors (nonacting MAPs) and those who have acted on pedophilic attractions and subsequently entered the criminal justice system (forensic MAPs). METHODS: Subjects included 195 nonacting MAPs, 50 forensic MAPs, and 60 healthy controls. Data on nonacting MAPs were drawn from an online survey, and data on the other 2 groups were based on prior in-person evaluations. Measures included the Millon Clinical Multiaxial Inventory-II (MCMI-II), Barratt Impulsiveness Scale (BIS-11), the MAP Questionnaire, and the Sexual History Questionnaire (SHQ). RESULTS: Both MAP groups scored higher than healthy controls on the domains of socially inhibited personality traits, propensity toward cognitive distortions, and subjects' own childhood sexual abuse (CSA). Forensic MAPs scored higher than nonacting MAPs on the CSA domain, but the 2 MAP groups differed little on the other 2 domains. Forensic MAPs also scored higher than the other 2 groups on the antisocial domain, whereas nonacting MAPs did not differ from controls on this measure. Nonacting MAPs scored higher than controls on impulsivity. CONCLUSIONS: Antisocial personality traits may be a primary driver of pedophilic behavior that is unrelated to pedophilic attraction. Socially inhibited personality traits and propensity toward cognitive distortions are associated with pedophilic attraction, although the direction of causation is not clear. CSA seems to increase the risk of both attraction and behavior. PMID- 30395546 TI - Impact of Borderline Personality Pathology on Treatment Outcomes in Adolescents in Residential Treatment: The Role of Emotion Regulation. AB - Despite growing research on the impact of borderline personality pathology (BPP) on treatment outcomes for emotional disorders among adults, no studies have examined this question in adolescents. Moreover, no studies have examined mediators of the relation between BPP and changes in mood and anxiety symptoms during treatment. This study examined the impact of BPP on treatment outcomes in 141 adolescents in psychiatric residential treatment, as well as the mediating role of change in emotion regulation (ie, adaptive responses to emotions) in the relation between baseline BPP and improvements in psychiatric symptoms during treatment. Participants completed questionnaires assessing emotion regulation and depression, anxiety, and posttraumatic stress disorder symptoms at baseline and posttreatment. Although BPP was not directly associated with the magnitude of change in psychiatric symptoms from baseline to posttreatment, it was positively associated with greater improvement in emotion regulation during treatment. Furthermore, results revealed significant indirect effects of BPP on improvements in all psychiatric symptoms through improvement in emotion regulation. PMID- 30395547 TI - Persistent Depressive Symptoms in a Population With High Levels of Occupational Stress: Trajectories Offer Insights Into Both Chronicity and Resilience. AB - Religious participation and spirituality are linked to good mental health. However, clergy may experience more depression than is observed in the general population, which may be due in part to high job strain. The objectives of this study were to identify distinct longitudinal trajectories of depressive symptoms in clergy and to identify variables associated with each course. The sample was 1172 clergy who were followed for up to 66 months. Depressive symptoms were measured using the Patient Health Questionnaire (PHQ-8), which was administered approximately every 6 months. Latent class trajectory analysis was conducted for group identification, and a 3-class trajectory model fit the data best. Class 1 (38% of the sample) had minimal or no depressive symptoms over time, class 2 (47%) had chronic mild symptoms, and class 3 (15%) had persistent moderate/severe symptoms. Occupational distress was significantly associated with trajectory class. The odds of being in either the chronic mild or the persistent moderate/severe depressive symptom class were significantly higher for those who were female, for those with fair/poor self-rated health, for those with more perceived financial or occupational stress, for those with lower levels of perceived emotional support, and/or for those with lower levels of spiritual well being. The class exhibiting resilience to depressive symptoms had higher levels of perceived support and spiritual well-being as well as lower levels of perceived financial and occupational stress. A substantial percentage of clergy, and possibly people in similar helping occupations, may experience significant levels of depressive symptoms that do not remit over time. These individuals may benefit from treatments that address work-related coping. PMID- 30395548 TI - Decreasing Treatment Duration of Electroconvulsive Therapy (ECT) Using Daily Right Unilateral Ultrabrief Instead of Bitemporal ECT. AB - OBJECTIVE: Electroconvulsive therapy (ECT) is an effective treatment for depression, but the standard 2 to 3 times weekly treatment course results in a total treatment duration of >2 weeks. We explored the viability of decreasing treatment duration by using daily right unilateral ultrabrief (RULUB) ECT instead of standard bitemporal (BT) ECT. METHODS: This study involved a retrospective review of records of inpatients 18 to 64 years of age who were treated between 2012 and 2017 at a large tertiary ECT center. Lead placement/technique, treatment duration (days from first to last ECT), number of ECT treatments, and scores on the Patient Health Questionnaire-9 (PHQ-9), and the Hamilton Depression Rating Scale (HamD-24) were collected. Statistical analysis was performed using 1-way analysis of variance and t tests. RESULTS: Of 214 patients, 112 started daily RULUB ECT (86 were completers and 26 were eventually switched to BT), and 83 started and completed BT ECT. Daily RULUB completers finished their course of ECT 6.5 days faster than those who received BT ECT (11.7 vs. 18.2 d, P<0.0001), while the number of ECT treatments did not significantly differ between the 2 groups (daily RULUB 8.6 treatments vs. BT 8.3 treatments, P=0.4402). There were no significant differences in the final PHQ-9 or HamD-24 depression scores between the 2 groups. One case of significant cognitive impairment was observed in the daily RULUB group. CONCLUSIONS: Daily RULUB ECT compared with BT ECT allowed depression to be treated faster and with similar efficacy. Randomized controlled trials, which include the use of formal cognitive and physical side effect measures, are needed to further explore the viability of daily RULUB ECT. PMID- 30395549 TI - Knowledge of the Pharmacology of Antidepressants and Antipsychotics Yields Results Comparable With Pharmacogenetic Testing. AB - Several companies offer pharmacogenetic testing for psychiatry on the basis of the claim that the outcome of drug selection is better when guided by such testing than when such testing is not used. This column examines the results of the GeneSight Psychotropic Test which groups various antidepressants and antipsychotics into 3 bins: green ("use as directed"), yellow ("use with caution"), and red ("use with increased caution and more frequent monitoring"). The authors examined how frequently the same drugs appeared in these different bins in 19 patients. They found that of the 22 antidepressants evaluated, 2 were virtually always (>90%) in the green bin: desvenlafaxine and levomilnacipran; and 8 were almost never (<=10.5%) in the green bin: citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, paroxetine, and sertraline. Of the 16 antipsychotics evaluated, they found that 4 were virtually always (>90%) in the green bin: asenapine, lurasidone, paliperidone, and ziprasidone; and 2 were almost never (<=10.5%) in the green bin: chlorpromazine and thioridazine. What was common among those drugs almost always in the green bin versus those almost never in the green bin were newer versus older marketed drugs and those not dependent versus dependent on oxidative metabolism for their clearance. The authors concluded that the results of this pharmacogenetic testing could be predicted on the basis of knowledge of the pharmacology of the drugs, particularly whether their clearance was dependent on oxidative drug metabolism. PMID- 30395550 TI - Psychotherapy With Suicidal Patients Part 1: Expert Consensus Recommendations. AB - This column reviews and discusses recommendations made by individual experts and by expert panels for treating suicidal patients in psychotherapy. Therapies for suicidal patients that were considered for the extraction of shared elements include cognitive behavioral, psychodynamic, and integrated psychotherapies. There is a large amount of convergence among expert consensus recommendations for treating suicidal patients. PMID- 30395551 TI - Heroin Addiction in Serbian Patients With Tourette Syndrome. AB - INTRODUCTION: Tourette syndrome (TS) is a neurodevelopmental disorder with a high prevalence of psychiatric comorbidity. The most common comorbid disorder in patients with TS is attention-deficit/hyperactivity disorder (ADHD). To date, there have been few reports concerning the association of TS with addiction. METHODS: We report on 4 patients with TS, ADHD, and heroin addiction. RESULTS: All 4 patients were male and initially presented with TS when they were between 5 and 12 years of age, although 2 of the patients were not diagnosed with TS until they were adults. The patients currently range in age from 21 to 52 years, all having experienced the onset of heroin addiction in adolescence. A reduction in tics during periods of heroin abuse was noted in all patients. DISCUSSION: The lifetime prevalence of psychiatric comorbidity in patients with TS is 85.7%, with 57.7% of patients having >=2 psychiatric conditions in addition to TS. All of the 4 patients in our case series demonstrated a pattern of severe tics, ADHD, impulsive behavior, and heroin addiction. Our observation that these 4 patients with TS showed reduced tics during periods of heroin dependence could be related to the previously described effects of opiates on dopaminergic transmission. CONCLUSIONS: The observed reduction of tics during heroin dependence warrants further clinical research. PMID- 30395552 TI - Association Between Delusions of Infestation and Prescribed Narcotic and Stimulant Use. AB - OBJECTIVE: Patients diagnosed with delusions of infestation (DOI) at a psychodermatology clinic appeared to have a higher incidence of being prescribed narcotic or stimulant medications compared with the general dermatologic clinic population with chronic pruritic conditions. A retrospective study was conducted examining the correlation between patients with DOI and prescribed psychoactive medications. METHODS: Ninety-two patients with a diagnosis of DOI, seen at our University Psychodermatology Clinic, served as the study population. The comparison group (N=354) included dermatology patients seen at a dermatology clinic by the same dermatologist for itching, including adults seen for chronic pruritic conditions and contact dermatitis. For both groups, the reported use of any psychoactive prescription medications was noted. RESULTS: Patients with DOI were significantly more likely than other dermatology patients to receive prescriptions for narcotics [adjusted odds ratio (OR)=2.19; confidence interval (CI)=1.21-3.99) and stimulants (OR=5.44; CI=2.37-12.52). Patients with DOI were also more likely to be female (OR=2.49; CI=1.47-4.22) than patients who did not have such delusions. DISCUSSION: Few data are available concerning the etiology and management of DOI. Findings from this study indicated an association between the diagnosis of DOI and the prescribing of narcotics and stimulants, even when sex and age were taken into account. This information may be used to assist with the diagnosis of patients presenting with DOI and possible treatment options. It will be important to determine if these medications are a cause of the condition, or are merely correlated with other medical conditions. PMID- 30395553 TI - Commentary: Role of the Endogenous Opiate System in Psychiatric Disorders Other Than Addiction. AB - Two case reports explore opiate use in relation to 2 different psychiatric disorders. In the first case report, the authors reported the finding that opiate abuse appeared to mitigate premorbid Tourette syndrome in a small series of patients with opiate addiction and that this benefit was maintained with medically supervised opiate agonist therapy. In the second case report, the authors noted a significant correlation between prescription opiate use and delusions of infestation in a large psychodermatology clinic (as well as a separate, stronger correlation with stimulant use). These reports highlight the importance of the opiate system in a range of psychiatric disorders, suggesting that there is much more to learn about the role of the endogenous opiate system in brain functioning, and its potential as a target for therapeutic intervention in psychiatric disorders other than addiction. PMID- 30395554 TI - Second Opinions in Psychiatry: A Review. AB - BACKGROUND: Although second opinions are rather restricted to the surgical disciplines, they have become more and more important to the health system in the last 20 years. The demand has been triggered by rising health costs and the economization of the field. The Internet has also made a considerable contribution to the demand for patient-initiated second opinions. Given these developments, it is surprising that second opinions have not become more important in the field of psychiatry. This article highlights the special situation of second opinions in psychiatry, discusses possible barriers to the adoption of second opinions in psychiatry, and the potential for greater use of second opinions in this field. OBJECTIVE: In psychiatry, second opinions have been neglected by the typical drivers of innovations in health care, including insurers and other commercial drivers as well as psychiatrists and patients themselves. This review identifies current barriers to widespread adoption of second opinions in psychiatric practice, discusses the benefits of second opinions that have been demonstrated in other disciplines, and outlines the potential gains to be realized through use of second opinions in psychiatry. METHODS: Literature in the area was reviewed through a search of the main medical databases. This literature review was supported by in-depth interviews with health care personnel and insurers. CONCLUSIONS: Second opinions are rarely obtained in psychiatry and there is little literature on this subject. The stigmatization of psychiatric disorders and patients and the uniqueness of the patient-doctor relationship in psychiatry, especially in psychotherapeutic care, may pose considerable obstacles to the use of second opinions in this field. In addition, more stakeholders, such as social workers, government agencies and regulators, health care and disability insurers, and social security agencies, are involved in the mental health compared with the somatic health sector, which may make it more difficult to achieve a coordinated approach in psychiatric care. However, we have found no convincingly good reason why second opinions have not been at least discussed in psychiatry. Psychiatry could benefit from ongoing discussions concerning the outcomes of second opinions in other medical disciplines. PMID- 30395555 TI - An Evaluation of the Influence of Body Mass Index on Severity Scoring. AB - OBJECTIVES: Although one third or more of critically ill patients in the United States are obese, obesity is not incorporated as a contributing factor in any of the commonly used severity of illness scores. We hypothesize that selected severity of illness scores would perform differently if body mass index categorization was incorporated and that the performance of these score models would improve after consideration of body mass index as an additional model feature. DESIGN: Retrospective cohort analysis from a multicenter ICU database which contains deidentified data for more than 200,000 ICU admissions from 208 distinct ICUs across the United States between 2014 and 2015. SETTING: First ICU admission of patients with documented height and weight. PATIENTS: One-hundred eight-thousand four-hundred two patients from 189 different ICUs across United States were included in the analyses, of whom 4,661 (4%) were classified as underweight, 32,134 (30%) as normal weight, 32,278 (30%) as overweight, 30,259 (28%) as obese, and 9,070 (8%) as morbidly obese. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: To assess the effect of adding body mass index as a risk adjustment element to the Acute Physiology and Chronic Health Evaluation IV and Oxford Acute Severity of Illness scoring systems, we examined the impact of this addition on both discrimination and calibration. We performed three assessments based upon 1) the original scoring systems, 2) a recalibrated version of the systems, and 3) a recalibrated version incorporating body mass index as a covariate. We also performed a subgroup analysis in groups defined using World Health Organization guidelines for obesity. Incorporating body mass index into the models provided a minor improvement in both discrimination and calibration. In a subgroup analysis, model discrimination was higher in groups with higher body mass index, but calibration worsened. CONCLUSIONS: The performance of ICU prognostic models utilizing body mass index category as a scoring element was inconsistent across body mass index categories. Overall, adding body mass index as a risk adjustment variable led only to a minor improvement in scoring system performance. PMID- 30395556 TI - Family Experiences and Perspectives on Infection Prevention in Pediatric Long Term Care. AB - PURPOSE: Residents of pediatric long-term care facilities (pLTCF) are particularly vulnerable to healthcare-associated infections. The aims of this qualitative study were to (a) explore perspectives on infection prevention among families visiting children in pLTCF and (b) identify facilitators of and barriers to optimal hand hygiene. DESIGN AND METHODS: Semistructured, in-depth interviews with 10 family members visiting two New York City metropolitan area facilities were analyzed to identify themes. FINDINGS: "Everyone follows the rules" and "infections are inevitable" were primary themes. Participants reported "common sense" as a facilitator and "distraction" as a major barrier to prevention practices. CONCLUSION: Current education for visitors may be inadequate to improve infection prevention behaviors. CLINICAL RELEVANCE: Nurse-led education strategies for infection prevention should be tested and modified for families visiting pLTCF. PMID- 30395557 TI - Development of a Postburn Pruritus Relief Protocol. AB - BACKGROUND: Postburn pruritus is a syndrome of stressful symptoms that is pervasive and occurs in over 90% of burn patients and continues for years after the burn has healed. Postburn pruritus is experienced by burn survivors that may require medical management and effective interventions. PURPOSE: This article shows how to effectively relieve postburn pruritus by developing a postburn pruritus relief protocol. DESIGN: A descriptive literature review was conducted, and relevant empirical articles written during the years 2000-2014 were appraised to create a postburn pruritus relief protocol. Twenty-six of 79 articles were selected using preestablished inclusion criteria: any age group experiencing burn related pruritus after second- or third-degree burns. Databases were Cochrane Central Register of Controlled Trials, CINAHL, EBSCO, PubMed, the National Guideline Clearinghouse, Google Scholar, and the American Burn Association website. CONCLUSIONS: This protocol included both nonpharmacological and pharmacological interventions that have been delineated for use and was developed to apply based on the healing stage: prehealing, healing, and posthealing. PMID- 30395558 TI - The Initiation of Rehabilitation Therapies and Observed Outcomes in Pediatric Traumatic Brain Injury. AB - PURPOSE: Pediatric traumatic brain injury (TBI) is associated with immense physical, emotional, social, and economic burden. This study examined timing and frequency of rehabilitation services provided by the inpatient interdisciplinary team in children admitted for a TBI. Understanding the timing and frequency of rehabilitation services could guide TBI recovery. DESIGN AND METHODS: This is a 3 year prospective observational study of previously healthy children (n = 35) admitted for a TBI to an urban Level 1 trauma hospital. Children with mild, moderate, and severe TBI were included. Initiation and frequency of the interdisciplinary rehabilitation team's care and neurocognitive-functional outcomes were analyzed. Outcome measures included the Glasgow Outcome Scale Extended Pediatrics and the Speech Pathology Neurocognitive-Functional Evaluation at hospital discharge and first follow-up visit. RESULTS: The initiation and the frequency of rehabilitation services were found in all severities of TBI. Timing and frequency of services also aligned with varied severities. Children with moderate TBI showed the most improvement in Glasgow Outcome Scale-Extended Pediatrics and the Speech Pathology Neurocognitive-Functional Evaluation on their first follow-up visit, whereas children with mild and severe TBI demonstrated little change in outcome at their first follow-up visit and had varied services based on their hospital course. CONCLUSION: Services by interdisciplinary rehabilitation teams were provided across all brain injury severity groups, despite the lack of comprehensive rehabilitation guidelines. Varied neurocognitive and functional outcome changes measured found children with moderate TBI had the greatest change in outcomes. Further research is warranted to assess the timing and frequency of services and their relationship to neurocognitive-functional outcomes. PMID- 30395559 TI - The Family Burdens and Hopelessness of Turkish Parents of Adolescents With Intellectual Disabilities. AB - PURPOSE: This study was conducted to determine the hopelessness and family burden levels of parents who have children with intellectual disabilities. DESIGN: This was a descriptive correlational study. METHODS: The study was conducted at a specialized education and rehabilitation center in Fethiye, Turkey, using the Sociodemographic Data Form, the Beck Hopelessness Scale, and the Burden Assessment Scale for Families of Children With Intellectual Disabilities, and the study sample included a total of 95 parents of children with intellectual disabilities. FINDINGS: A positive relationship was found between the total scores for hopelessness and the family burden including economic burden, perception of inadequacy, social burden, physical burden, emotional burden, and the required time (p < .05). The study found that the higher the level of family burden on parents, the more hopeless families felt. CONCLUSION: This study's findings may help rehabilitation nurses to understand the hopelessness of parents and help them find appropriate resources to cope with their burden. CLINICAL RELEVANCE: Nurses should be specialized in the field of rehabilitation and, as rehabilitation nurses, be included in providing integrated care, family education, and counseling services for disabled people in Turkey. PMID- 30395560 TI - An Interprofessional Communication Training Program to Improve Nurses' Ability to Communicate With Stroke Patients With Communication Disorders. AB - PURPOSE: The aim of the study was to evaluate change in nurses' knowledge, attitudes, and behaviors after an Interprofessional (IP) Communication Training Program designed to improve nurses' ability to communicate with stroke rehabilitation inpatients with communication disorders. DESIGN/METHODS: A quasi experimental longitudinal study was conducted to evaluate an IP Communication Training Program consisting of a full-day and booster workshop and speech language pathologist support for nurses. The Communication Impairment Questionnaire and the Providers Interactional Comfort Survey were collected prior to and 3 months and 1 year postintervention. Focus groups assessing program acceptability were conducted. RESULTS: Forty-six nurses participated. The Communication Impairment Questionnaire significantly improved postintervention (p = .001), but not at 1 year follow-up (3.76, p = .123). The Providers Interactional Comfort Survey significantly improved postintervention (p = .001) and remained significant 1 year later (8.84, p = .03). Focus groups indicated high acceptability and reported that the education increased their confidence and reduced their frustration. CONCLUSION: Nurses' attitudes toward and knowledge about communication strategies improved, which enhances their ability to care for stroke patients with communication disorders. CLINICAL RELEVANCE: Interdisciplinary workshops and speech language pathologist support appear beneficial to nurses working with patients with communication disorders. PMID- 30395561 TI - Consenting on Principles of Rehabilitation Nursing Care: A Delphi Study. AB - PURPOSE: Patient-centeredness, evidence-based interventions, and interdisciplinary teamwork have been described as key in neurological rehabilitation nursing. In order to develop future action plans, a group of Swiss rehabilitation nurses sought agreement on concrete principles that led the efforts to develop a common understanding of rehabilitation nursing care in Switzerland. DESIGN: A three-round Delphi study was conducted. METHODS: Literature-based statements were formulated and sent out twice to 54 rehabilitation nursing stakeholders. In the third round, the participants ranked the three most important statements out of 13. FINDINGS: Highest priority reached the statements: Rehabilitation nursing care (1) considers the uniqueness of the patients and their family, (2) offers support that promises the greatest potential for patients and their family, and (3) uses evidence-based knowledge. CONCLUSION: Statements on patient- and family-centeredness were ranked highest. Patients and families' preferences have to be considered as much as evidence based knowledge and interventions to support patients and family. CLINICAL RELEVANCE: The study supported the discussion on action plans and enlivened new services and nursing interventions in a Swiss nursing community. PMID- 30395562 TI - Cardiovascular Risk and Neurocognitive Assessment in Young Adults and Their Relationship to Body Adiposity. AB - BACKGROUND We assessed body composition, adiposity, cardiovascular risk, and cognitive functions in healthy young adult females and investigated the possible correlation between neurocognitive decline, adiposity, and cardiovascular risk markers. MATERIAL AND METHODS This cross-sectional study was conducted on 83 healthy, young adult, Saudi women (age 19-23 years). Subjects were classified into group (A) with 19 non-obese subjects and negative family history (FH) of cardiovascular diseases (CVD), group (B) with 38 non-obese subjects with a positive FH of CVD, and group (C) with 18 obese subjects with positive FH of CVD. Body composition was analyzed by bioelectrical impedance analysis. Cognitive functions were evaluated using the Cambridge Neuropsychological Automated Battery (CANTAB). The blood samples were tested for lipoprotein(a) [Lp(a)] and high sensitivity C-reactive Protein (hs-CRP). RESULTS There was significantly prolonged Attention-Switching Task (AST) latency in obese subjects with negative family history of CVD (p=0.014) and those with positive family history of CVD (p=0.026) compared to controls, but the difference in AST Percent Correct Trials, Intra-Extra Dimensional Set Shift (IED) Total Errors, and Simple Reaction Time (SRT) was not significant. Simple response time had a weak but significant inverse correlation with BMI (r=-0.227, p<0.05). BMI was correlated positively with Lp(a) and hs-CRP, while BF% was correlated with hs-CRP only. No correlation was observed between the CANTAB tests, Lp(a), and hs-CRP. CONCLUSIONS Cardiovascular risk increases with higher adiposity and the presence of a positive family history of cardiovascular disease. Neurocognitive function may decline with higher adiposity; however, no relationship was observed between neurocognitive functions and cardiovascular risk markers. PMID- 30395563 TI - Bilateral lateral rectus recession versus unilateral recession/resection for basic intermittent exotropia. AB - INTRODUCTION: Intermittent exotropia requires surgical resolution under some clinical circumstances. The main techniques are bilateral lateral rectus recession and unilateral recess/resection. Although bilateral recession is the most widely used, it is not clear whether it leads to better results. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified five systematic reviews including seven studies overall, of which three were randomized trials. We concluded unilateral recess/resection might achieve greater surgical success and probably decrease the rate of undercorrection/recurrence when compared to bilateral lateral rectus recession. PMID- 30395564 TI - A comparison of Zika and dengue outbreaks using national surveillance data in the Dominican Republic. AB - BACKGROUND: Aedes-borne arboviruses continue to precipitate epidemics worldwide. In Dominican Republic, the appearance of Zika virus cases that closely followed a large dengue epidemic provided an opportunity to study the different transmission drivers behind these two flaviviruses. Retrospective datasets were used to collect information on the populations at risk and descriptive statistics were used to describe the outbreaks on a national scale. METHODOLOGY/ PRINCIPAL FINDINGS: Expectedly, box plots showed that 75% of dengue was reported in those aged <20 years while Zika infections were more widely dispersed among the population. Dengue attack rates were marginally higher among males at 25.9 per 10,000 population vs. 21.5 per 10,000 population for females. Zika infections appeared to be highly clustered among females (73.8% (95% CI 72.6%, 75.0%; p<0.05)); age-adjusted Zika attack rates among females were 7.64 per 10,000 population compared with 2.72 per 10,000 population among males. R0 calculations stratified by sex also showed a significantly higher metric among females: 1.84 (1.82, 1.87; p<0.05) when compared to males at 1.72 (1.69, 1.75; p<0.05). However, GBS attack rates stratified by sex revealed slightly higher risk in males vs. females, at 0.62 and 0.57 per 10,000 population respectively. CONCLUSIONS/ SIGNIFICANCE: Evidence suggests little impact of existing dengue immunity on reported attack rates of Zika at the population level. Confounding of R0 and incident risk calculations by sex-specific over-reporting can alter the reliability of epidemiological metrics, which could be addressed using associated proxy syndromes or conditions to explore seemingly sex-skewed incidence. The findings indicate that community awareness campaigns, through influencing short term health seeking behaviour, remain the most plausible mechanism behind increased reporting among women of reproductive age, although biological susceptibility cannot yet be ruled out. Media campaigns and screening are therefore recommended for women of reproductive age during Zika outbreaks. Future research should focus on clinical Zika outcomes among dengue seropositive individuals. PMID- 30395565 TI - Provision of guideline-based care for drug-resistant tuberculosis in South Africa: Level of concordance between prescribing practices and guidelines. AB - TITLE: Provision of guideline-based care for drug-resistant tuberculosis in South Africa: Level of concordance between prescribing practices and guidelines. OBJECTIVE: We examined the influence of individual and site characteristics on the concordance between prescribed treatment regimens and recommended standardized regimen according to national guidelines for patients with drug resistant tuberculosis (DR-TB) in South Africa. METHODS: Participants were 337 youth and adults treated for DR-TB between November 2014 and August 2016 at ten DR-TB treatment sites in Eastern Cape and KwaZulu Natal provinces, South Africa. Logistic regression was used to determine individual and system characteristics related to concordance at treatment initiation between the prescribed treatment regimens in terms of medication composition, dosage, and frequency and guideline based standardized regimen that included four oral and one injectable medications. RESULTS: The sample was 19% (n = 64) youth (15-24 years), 53% (n = 179) male, 73% (n = 243) HIV coinfected, and 51% (n = 169) with prior history of TB treatment. Guideline medications were correctly prescribed for 88% (n = 295) of patients, but only 33% (n = 103) received the correct medications and doses. Complete guideline adherence to medications, doses, and frequency was achieved for 30% (n = 95) of patients. Younger age, HIV coinfection, and rural treatment setting were associated with the prescription of correct medications. CONCLUSION: Most individuals are prescribed the correct DR-TB medications, yet few individuals receive correct medications, dosages, and frequencies. Further study is needed to examine the root causes for treatment guideline deviations and opportunities for improvement. PMID- 30395566 TI - Evaluation of gastroprotective and ulcer healing activities of yellow mombin juice from Spondias mombin L. AB - Spondias mombin L. (yellow mombin) is a tree with a nutritional fruit that is commonly consumed in the North and Northeast of Brazil, as the juice of its pulp is rich in antioxidant compounds. This study aimed to investigate the gastroprotective and ulcer healing activities of yellow mombin juice (YMJ) in Wistar rats, and to elucidate the possible involved mechanisms. Phytochemical characterization of the lyophilized fruit juice was performed by high-performance liquid chromatography (HPLC). The gastroprotective activity of YMJ was investigated in ethanol (25, 50, and 100% YMJ) and indomethacin (100% YMJ) models of acute gastric ulcer in rats. Then, the effect of YMJ on mucus production and gastric secretions, and the involvement of non-protein sulfhydryl groups and prostaglandins in the gastroprotective process were examined. Moreover, the ulcer healing effect of YMJ was investigated in a model of acetic acid-induced chronic ulcer through histological and immunohistochemical analyses. HPLC results identified the presence of epicatechin (7.1 +/- 1.6 MUg/mL) and quercetin (17.3 +/- 2.5 MUg/mL) in YMJ. Ethanol-induced gastric lesions were inhibited by YMJ (25, 50, and 100%) by 42.42, 45.09, and 98.21% respectively, and indomethacin induced lesions were inhibited by YMJ (100%) by 58.96%, compared to control group. Moreover, YMJ reduced gastric content and total acidy by 57.35 and 71.97%, respectively, compared to the control group. Treatment with YMJ also promoted healing of chronic ulcer, regeneration of the gastric mucosa, and restoration of mucus levels in glandular cells, as confirmed by histological analysis. It also increased cellular proliferation, as demonstrated by high reactivity to Ki-67 and bromodeoxyuridine. In conclusion, YMJ was found to possess gastroprotective and ulcer healing activities that are correlated to its antisecretory action. These results support the commercial exploration of YMJ as a functional food. PMID- 30395567 TI - A highly multiplexed broad pathogen detection assay for infectious disease diagnostics. AB - Rapid pathogen identification during an acute febrile illness is a critical first step for providing appropriate clinical care and patient isolation. Primary screening using sensitive and specific assays, such as real-time PCR and ELISAs, can rapidly test for known circulating infectious diseases. If the initial testing is negative, potentially due to a lack of developed diagnostic assays or an incomplete understanding of the pathogens circulating within a geographic region, additional testing would be required including highly multiplexed assays and metagenomic next generation sequencing. To bridge the gap between rapid point of care diagnostics and sequencing, we developed a highly multiplexed assay designed to detect 164 different viruses, bacteria, and parasites using the NanoString nCounter platform. Included in this assay were high consequence pathogens such as Ebola virus, highly endemic organisms including several Plasmodium species, and a large number of less prevalent pathogens to ensure a broad coverage of potential human pathogens. Evaluation of this panel resulted in positive detection of 113 (encompassing 98 different human pathogen types) of the 126 organisms available to us including the medically important Ebola virus, Lassa virus, dengue virus serotypes 1-4, Chikungunya virus, yellow fever virus, and Plasmodium falciparum. Overall, this assay could improve infectious disease diagnostics and biosurveillance efforts as a quick, highly multiplexed, and easy to use pathogen screening tool. PMID- 30395568 TI - Virtual mortality and near-death experience after a prolonged exposure in a shared virtual reality may lead to positive life-attitude changes. AB - Mortality is an obvious if uncomfortable part of the human condition, yet it is impossible to study its impact on anyone who experiences it. Reports of phenomena associated with death such as out-of-the-body (OBE) and near death experiences (NDE) can only be studied post-hoc, since it is impossible to design a scientific study where an experimental group experiences death (and returns) and a control group does not. Yet NDEs seem to have a profound influence on the subsequent lives of people and are therefore worthy of study. Terror Management Theory, which argues that death anxiety contributes to in-group solidarity and hostility to out-groups, relies on studies that manipulate opinions and cannot be based on experiential evidence. Here we introduce a potential methodology that uses immersive virtual reality (VR) for the study of mortality and NDEs. Participants are embodied in alternate bodies in a beautiful island along with two companions. They explore the island and carry out tasks together. The mechanism of embodiment produces strong illusions of ownership over their life-sized virtual bodies. Over time each participant witnesses the death of the two companions and then her own death-which includes the reported features of an NDE (OBE, life review, the tunnel leading to white light) followed by a period of observation of the continuing activities in the virtual world on an external screen. Fifteen female participants experienced 6 sessions in the island, each starting as a child and gradually maturing, and eventually ageing and dying. Sixteen control subjects formed a waiting group. We introduce this as a methodology for the study of these issues, and present promising results, suggesting that those who experienced the island report life attitude changes, becoming more concerned with others and more interested in global rather than material issues compared to the control group. The results are based on a small sample size, and should be considered as indicative of the possibilities of this new methodology as a way forward for future studies in this field. PMID- 30395569 TI - Laboratory assays on the effects of a novel acaricide, SYP-9625 on Tetranychus cinnabarinus (Boisduval) and its natural enemy, Neoseiulus californicus (McGregor). AB - OBJECTIVE: Tetranychus cinnabarinus (Boisduval) is an agricultural mite pest threatens crops throughout the world, causing serious economic loses. Exploring the effects of acaricides on predatory mites is crucial for the combination of biological and chemical control of T. cinnabarinus. Neoseiulus californicus (McGregor) is one of the principal natural enemies of T. cinnabarinus, which can be applied in protected agriculture. In this study, the effects of sublethal concentrations of a new acaricide, SYP-9625 on two mite species, and the effects of the application concentration on predatory mite, N. californicus were assessed. The aim of the present study was to evaluate the effect of SYP-9625 on life parameters and predation capacity of N. californicus based on the concentration-response bioassay of T. cinnabarinus to explor the application of the new acaricide with natural enemy N. californicus. METHOD: All of the experiments were conducted under laboratory conditions [25 +/- 1 degrees C, 16: 8 h (L: D) and 75 +/- 5% RH]. The sublethal concentrations LC10 (0.375MUg/mL) and the LC30 (0.841MUg/mL) against T. cinnabarinus and the application concentration (100MUg/mL) against N. californicus were used to evaluate the effects of SYP-9625 on population parameters of N. californicus based on an age-stage, two-sex life table and its predation capacity by functional response. RESULT: cinnabarinus females treated with LC30 exhibited significantly reduced net reproductive rates (R0 = 11.02) in their offspring compared with females treated with LC10 (R0 = 14.96) and untreated females (R0 = 32.74). However, the intrinsic rate of increase (rm) and the finite rate of increase (lambda) of N. californicus indicated that the application concentration of SYP-9625 had no significant negative effect on N. californicus eggs (rm = 0.277, lambda = 1.319) compared to the control (rm = 0.292, lambda = 1.338). Additionally, most population parameters of N. californicus showed a dose-dependent manner with the increase of the concentration of SYP-9625 against T. cinnabarinus. SYP-9625 also stimulated the control efficiency of N. californicus against immobile stages including eggs and larvae. CONCLUSION: This study demonstrated that sublethal concentrations of SYP-9625 can inhibit the population growth of T. cinnabarinus. In addition, the sublethal concentrations and the application concentration showed no effect on the population growth of N. californicus. These two advantages described above showed great commercial potential of this new acaricide based on population parameters of the two mite species and predation capacity of the predatory mite under laboratory conditions. PMID- 30395570 TI - Beneficial effects of ascorbic acid to treat lung fibrosis induced by paraquat. AB - Paraquat (PQ) is one of the most widely employed herbicides that is used worldwide and it causes severe toxic effects in humans and animals. A PQ exposition can lead to pulmonary fibrosis (PF) and the mechanisms seem to be linked to oxidative stress, although other pathways have been suggested. Antioxidants can be useful as a therapy, although interventions with this kind of system are still controversial. Hence, this study has investigated the role of ascorbic acid (vitamin C) post-treatment on PQ-induced PF in male C57/BL6 mice. Pulmonary fibrosis was induced by a single PQ injection (10mg/kg; i.p.). The control group received a PQ vehicle. Seven days after the PQ or vehicle injections, the mice received vitamin C (150 mg/kg, ip, once a day) or the vehicle, over the following 7 days. Twenty-four hours after the last dose of vitamin C or the vehicle, the mice were euthanized and their bronchoalveolar lavage fluid (BALF) and their lungs were collected. The data obtained showed that vitamin C reduced the cellular recruitment, the secretion of IL-17 -a cytokine involved in neutrophils migration, TGF-beta-a pro-fibrotic mediator and the collagen deposition. Moreover, vitamin C elevated the superoxide dismutase (SOD) and catalase levels, both antioxidant enzymes, but it did not alter the tracheal contractile response that was evoked by methacholine. Therefore, the researchers have highlighted the mechanisms of vitamin C as being non-invasive and have suggested it as a promising tool to treat lung fibrosis when it is induced by a PQ intoxication. PMID- 30395571 TI - A new bioabsorbable polymer film to prevent peritoneal adhesions validated in a post-surgical animal model. AB - BACKGROUND: Peritoneal adhesions are a serious surgical postoperative complication. The aim of this study is to investigate, in a rat model, the anti adhesive effects of a bioabsorbable film of polymer combining polyethylene glycol and polylactic acid. MATERIALS AND METHODS: Sixty-three animals were randomized into five groups according to the anti-adhesion treatment: Hyalobarrier(r), Seprafilm(r), Polymer A (PA), Polymer B (PB), and control. The rats were euthanized on days 5 and 12 to evaluate the extent, severity and degree of adhesions and histopathological changes. Three animals were euthanized at day 2 in PA, PB and control groups to observe the in vivo elimination. RESULTS: Macroscopic adhesion formation was significantly lower in the PA group than in the control group at day 5 (median adhesion score 0+/-0 vs 9.6 +/-0.5 p = 0.002) and at day 12 (0+/-0 vs 7.3+/-4 p = 0.02). Furthermore, median adhesion score at day 5 was significantly lower in the PA group than in the Seprafilm group (0+/-0 vs 4.2+/- 3.9 p = 0.03). Residence time of PA seems longer than PB. CONCLUSION: The PA bioabsorbable film seems efficient in preventing the formation of peritoneal adhesions. PMID- 30395573 TI - Does early linear growth failure influence later school performance? A cohort study in Karonga district, northern Malawi. AB - INTRODUCTION: Stunting or linear growth retardation in childhood is associated with delayed cognitive development due to related causes (malnutrition, illness, poor stimulation), which leads to poor school outcomes at later ages, although evidence of the association between the timing and persistence of stunting and school outcomes within the sub-Saharan African context is limited. METHODS: Anthropometric data around birth (0-4 months), early (11-16 months) and late childhood (ages 4-8 years) along with school outcomes up until the age of 11 were analysed for a cohort of 1,044 respondents, born between 2002-2004 in Karonga district, northern Malawi. The schooling outcomes were age at school enrolment, grade repetition in Standard 1 and age-for-grade by age 11. Height-for-Age Z scores (HAZ) and growth trajectories were examined as predictors, based on stunting (<-2SD HAZ) and on trajectories between early and late childhood (never stunted, improvers, decliners or persistently stunted). Multinomial and logistic regression were used to estimate the association between stunting/trajectories and schooling, adjusted for socioeconomic confounders. RESULTS: The effects of stunting on schooling were evident in early childhood but were more pronounced in late childhood. Children who were stunted in early childhood (9.3%) were less likely to be underage at enrolment, more likely to repeat Standard 1 and were 2-3 times more likely to be overage for their grade by the age of 11, compared to their non-stunted peers. Those persistently stunted between early and late childhood (7.3%) faced the worst consequences on schooling, being three times as likely to enrol late and 3-5 times more likely to be overage for their grade by the age of 11, compared to those never stunted. Compared to improvers, those persistently stunted were three times as likely to be overage by two or more years by the age of 11, with no effect on enrolment or repetition. CONCLUSION: Our findings confirm the importance of early childhood stunting on schooling outcomes and suggest some mitigation by improvements in growth by the age of starting school. The nutritional and learning needs of those persistently stunted may need to be prioritised in future interventions. PMID- 30395574 TI - Acute liver dysfunction after cardiac arrest. AB - Few data are available regarding hypoxic hepatitis (HH) and acute liver failure (ALF) in patients resuscitated from cardiac arrest (CA). The aim of this study was to describe the occurrence of these complications and their association with outcome. All adult patients admitted to the Department of Intensive Care following CA were considered for inclusion in this retrospective study. Exclusion criteria were early death (<24 hours) or missing biological data. We retrieved data concerning CA characteristics and markers of liver function. ALF was defined as a bilirubin >1.2 mg/dL and an international normalized ratio >=1.5. HH was defined as an aminotransferase level >1000 IU/L. Neurological outcome was assessed at 3 months and an unfavourable neurological outcome was defined as a Cerebral Performance Categories (CPC) score of 3-5. A total of 374 patients (age 62 [52-74] years; 242 male) were included. ALF developed in 208 patients (56%) and HH in 27 (7%); 24 patients developed both conditions. Patients with HH had higher mortality (89% vs. 51% vs. 45%, respectively) and greater rates of unfavourable neurological outcome (93% vs. 60% vs. 59%, respectively) compared to those with ALF without HH (n = 184) and those without ALF or HH (n = 163; p = 0.03). Unwitnessed arrest, non-shockable initial rhythm, lack of bystander cardiopulmonary resuscitation, high adrenaline doses and the development of acute kidney injury were independent predictors of unfavourable neurological outcome; HH (OR: 16.276 [95% CIs: 2.625-81.345; p = 0.003), but not ALF, was also a significant risk-factor for unfavourable outcome. Although ALF occurs frequently after CA, HH is a rare complication. Only HH is significantly associated with poor neurological outcome in this setting. PMID- 30395572 TI - Diagnostic accuracy cohort study and clinical value of the Histoplasma urine antigen (ALPHA Histoplasma EIA) for disseminated histoplasmosis among HIV infected patients: A multicenter study. AB - BACKGROUND: The Histoplasma urine antigen (HUAg) is the preferred method to diagnose progressive disseminated histoplasmosis (PDH) in HIV patients. In 2007, IMMY ALPHA Histoplasma EIA was approved for clinical for on-site use, and therefore useful for regions outside the United States. However, ALPHA-HUAg is considered inferior to the MVista-HUAg which is only available on referral. We aim to evaluate the diagnostic accuracy of ALPHA-HUAg. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a multicenter, prospective, diagnostic test study in two secondary and eight tertiary-care facilities in Mexico. We included HIV patient with PDH suspicion and evaluated ALPHA-HUAg diagnostic accuracy using as reference standard the Histoplasma capsulatum growth on blood, bone marrow, and tissue cultures or compatible histopathologic exam (PDH-proven). We evaluated the results of 288 patients, 29.5% (85/288; 95% confidence interval [CI], 24.3-35.1) had PDH. The sensitivity of ALPHA-HUAg was 67.1% (95% CI, 56-76.8%) and the specificity was 97.5% (95% CI, 94.3%-99.1%). The positive likelihood ratio was 27.2 (95% CI; 11.6-74.4). In 10.5% of the PDH-proven patients, a co-existing opportunistic infection was diagnosed, mostly disseminated Mycobacterium avium complex infection. CONCLUSIONS/SIGNIFICANCE: We observed a high specificity but low sensitivity of IMMY-HUAg. The test may be useful to start early antifungals, but a culture-based approach is necessary since co-infections are frequent and a negative IMMY-HUAg result does not rule out PDH. PMID- 30395575 TI - Medial septal cholinergic mediation of hippocampal theta rhythm induced by vagal nerve stimulation. AB - BACKGROUND: Electrical vagal nerve stimulation (VNS) has been used for years to treat patients with drug-resistant epilepsy. This technique also remains under investigation as a specific treatment of patients with Alzheimer's disease. Recently we discovered that VNS induced hippocampal formation (HPC) type II theta rhythm, which is involved in memory consolidation. In the present study, we have extended our previous observation and addressed the neuronal substrate and pharmacological profile of HPC type II theta rhythm induced by VNS in anesthetized rats. METHODS: Male Wistar rats were implanted with a VNS cuff electrode around the left vagus nerve, a tungsten microelectrode for recording the HPC field activity, and a medial septal (MS) cannula for the injection of a local anesthetic, procaine, and muscarinic agents. A direct, brief effect of VNS on the HPC field potential was evaluated before and after medial-septal drug injection. RESULTS: Medial septal injection of local anesthetic, procaine, reversibly abolished VNS-induced HPC theta rhythm. With the use of cholinergic muscarinic agonist and antagonists, we demonstrated that medial septal M1 receptors are involved in the mediation of the VNS effect on HPC theta field potential. CONCLUSION: The MS cholinergic M1 receptor mechanism integrates not only central inputs from the brainstem synchronizing pathway, which underlies the production of HPC type II theta rhythm, but also the input from the vagal afferents in the brain stem. PMID- 30395576 TI - Data-driven, voxel-based analysis of brain PET images: Application of PCA and LASSO methods to visualize and quantify patterns of neurodegeneration. AB - Spatial patterns of radiotracer binding in positron emission tomography (PET) images may convey information related to the disease topology. However, this information is not captured by the standard PET image analysis that quantifies the mean radiotracer uptake within a region of interest (ROI). On the other hand, spatial analyses that use more advanced radiomic features may be difficult to interpret. Here we propose an alternative data-driven, voxel-based approach to spatial pattern analysis in brain PET, which can be easily interpreted. We apply principal component analysis (PCA) to identify voxel covariance patterns, and optimally combine several patterns using the least absolute shrinkage and selection operator (LASSO). The resulting models predict clinical disease metrics from raw voxel values, allowing for inclusion of clinical covariates. The analysis is performed on high-resolution PET images from healthy controls and subjects affected by Parkinson's disease (PD), acquired with a pre-synaptic and a post-synaptic dopaminergic PET tracer. We demonstrate that PCA identifies robust and tracer-specific binding patterns in sub-cortical brain structures; the patterns evolve as a function of disease progression. Principal component LASSO (PC-LASSO) models of clinical disease metrics achieve higher predictive accuracy compared to the mean tracer binding ratio (BR) alone: the cross-validated test mean squared error of adjusted disease duration (motor impairment score) was 16.3 +/- 0.17 years2 (9.7 +/- 0.15) with mean BR, versus 14.4 +/- 0.18 years2 (8.9 +/- 0.16) with PC-LASSO. We interpret the best-performing PC-LASSO models in the spatial sense and discuss them with reference to the PD pathology and somatotopic organization of the striatum. PC-LASSO is thus shown to be a useful method to analyze clinically-relevant tracer binding patterns, and to construct interpretable, imaging-based predictive models of clinical metrics. PMID- 30395577 TI - The application of post-translational modification oriented serum proteomics to assess experimental diabetes with complications. AB - Proteome analysis of serum from type 2 diabetics with complications may lead to the discovery of diagnostic or prognostic biomarkers. To circumvent the principal barrier of serum proteomics, our investigation aimed to evaluate whether a study of post-translational modification enriched serum proteins could be valuable for the discovery of biomarkers or metabolic pathways related to type 2 diabetes pathogenesis. Type 2 diabetes was induced from high-fat diet fed Sprague Dawley rats with streptozotocin injection. Once diabetic status was confirmed, serum samples from either fasted healthy or diabetic rats were pooled and profiled by two-dimensional difference gel electrophoresis or comparative 2D electrophoresis after protein enrichments using immobilized metal ion, concanavalin A, and lentil affinity chromatography, respectively. Differential expressed proteins were identified and the associated networks were established by an Ingenuity Pathway Analysis. As a result, induced rats became severe diabetic and accompanied by hyperlipidemia, fatty liver, and glomerular hypertrophy. There were 3 total, 14 phosphorylated and 23 glycosylated protein targets differentially expressed. Proteins could be linked to HNF4A, HNF1A, and NFkappaB transcriptional factors and antigen presentation, humoral immune response, and inflammatory response pathways. Predicted organ toxicity in kidney, heart, and liver matched with our histopathological results. In conclusion, post-translational modification based serum protein enrichment could be a valuable approach to enhance the resolution of serum proteomics without depleting potentially valuable abundant proteins. Our results also indicated the potential association of the hepatic secretome and hepatocyte nuclear factors in the pathogenesis of type 2 diabetes and its complications. PMID- 30395579 TI - TRCMGene: A two-step referential compression method for the efficient storage of genetic data. AB - BACKGROUND: The massive quantities of genetic data generated by high-throughput sequencing pose challenges to data storage, transmission and analyses. These problems are effectively solved through data compression, in which the size of data storage is reduced and the speed of data transmission is improved. Several options are available for compressing and storing genetic data. However, most of these options either do not provide sufficient compression rates or require a considerable length of time for decompression and loading. RESULTS: Here, we propose TRCMGene, a lossless genetic data compression method that uses a referential compression scheme. The novel concept of two-step compression method, which builds an index structure using K-means and k-nearest neighbours, is introduced to TRCMGene. Evaluation with several real datasets revealed that the compression factor of TRCMGene ranges from 9 to 21. TRCMGene presents a good balance between compression factor and reading time. On average, the reading time of compressed data is 60% of that of uncompressed data. Thus, TRCMGene not only saves disc space but also saves file access time and speeds up data loading. These effects collectively improve genetic data storage and transmission in the current hardware environment and render system upgrades unnecessary. TRCMGene, user manual and demos could be accessed freely from https://github.com/tangyou79/TRCM. The data mentioned in this manuscript could be downloaded from: https://github.com/tangyou79/TRCM/wiki. PMID- 30395578 TI - Discovery of a Streptococcus pneumoniae serotype 33F capsular polysaccharide locus that lacks wcjE and contains a wcyO pseudogene. AB - As part of large on-going vaccine impact studies in Fiji and Mongolia, we identified 25/2750 (0.9%) of nasopharyngeal swabs by microarray that were positive for Streptococcus pneumoniae contained pneumococci with a divergent 33F capsular polysaccharide locus (designated '33F-1'). We investigated the 33F-1 capsular polysaccharide locus to better understand the genetic variation and its potential impact on serotyping results. Whole genome sequencing was conducted on ten 33F-1 pneumococcal isolates. Initially, sequence reads were used for molecular serotyping by PneumoCaT. Phenotypic typing of 33F-1 isolates was then performed using the Quellung reaction and latex agglutination. Genome assemblies were used in phylogenetic analyses of each gene in the capsular locus to investigate genetic divergence. All ten pneumococcal isolates with the 33F-1 cps locus typed as 33F by Quellung and latex agglutination. Unlike the reference 33F capsule locus sequence, DNA microarray and PneumoCaT analyses found that 33F-1 pneumococci lack the wcjE gene, and instead contain wcyO with a frameshift mutation. Phylogenetic analyses found the wzg, wzh, wzd, wze, wchA, wciG and glf genes in the 33F-1 cps locus had higher DNA sequence similarity to homologues from other serotypes than to the 33F reference sequence. We have discovered a novel genetic variant of serotype 33F, which lacks wcjE and contains a wcyO pseudogene. This finding adds to the understanding of molecular epidemiology of pneumococcal serotype diversity, which is poorly understood in low and middle income countries. PMID- 30395581 TI - Causes of post-installation penetration of jack-up spudcan foundations in clays. AB - This paper examines possible causes of additional spudcan settlement after preloading using both centrifuge model tests and small strain finite element analysis, in which spudcan settlement due to cavity collapse, consolidation settlement and settlement due to cyclic loading are incorporated. Back-analyses of seven jack-up rigs in the Gulf of Mexico show that even complete cavity collapse could only explain part of the measured additional settlements in the majority of the cases. Small strain finite element analyses also show that spudcan consolidation settlement is likely to account for even less of the additional settlement than cavity collapse in the sites considered. On the other hand, centrifuge model tests show that large amplitude cyclic rocking has a very significant effect on spudcan settlement, even if half of the preload has been removed. However, this effect cannot be explained by the exceedance of the yield envelope since the loading combination had not exceeded the yield envelope. One possible explanation is the stiffness and strength degradation of the soil under cyclic loading. In view of this, a conservative approach is recommended in instances where large amplitude cyclic rocking, such as that arising from storm loading, is expected shortly after preloading. The presence of lattice legs is found to reduce the spudcan settlement during large amplitude cyclic rocking. PMID- 30395580 TI - A comparative structural analysis of the surface properties of asco-laccases. AB - Laccases of different biological origins have been widely investigated and these studies have elucidated fundamentals of the generic catalytic mechanism. However, other features such as surface properties and residues located away from the catalytic centres may also have impact on enzyme function. Here we present the crystal structure of laccase from Myceliophthora thermophila (MtL) to a resolution of 1.62 A together with a thorough structural comparison with other members of the CAZy family AA1_3 that comprises fungal laccases from ascomycetes. The recombinant protein produced in A. oryzae has a molecular mass of 75 kDa, a pI of 4.2 and carries 13.5 kDa N-linked glycans. In the crystal, MtL forms a dimer with the phenolic substrate binding pocket blocked, suggesting that the active form of the enzyme is monomeric. Overall, the MtL structure conforms with the canonical fold of fungal laccases as well as the features specific for the asco-laccases. However, the structural comparisons also reveal significant variations within this taxonomic subgroup. Notable differences in the T1-Cu active site topology and polar motifs imply molecular evolution to serve different functional roles. Very few surface residues are conserved and it is noticeable that they encompass residues that interact with the N-glycans and/or are located at domain interfaces. The N-glycosylation sites are surprisingly conserved among asco-laccases and in most cases the glycan displays extensive interactions with the protein. In particular, the glycans at Asn88 and Asn210 appear to have evolved as an integral part of the asco-laccase structure. An uneven distribution of the carbohydrates around the enzyme give unique properties to a distinct part of the surface of the asco-laccases which may have implication for laccase function-in particular towards large substrates. PMID- 30395582 TI - Nasal immunization with recombinant chimeric pneumococcal protein and cell wall from immunobiotic bacteria improve resistance of infant mice to Streptococcus pneumoniae infection. AB - Respiratory tract infections and invasive disease caused by Streptococcus pneumoniae in high-risk groups are a major global health problem. Available human vaccines have reduced immunogenicity and low immunological memory in these populations, as well as high cost as a public health strategy in poor communities. In addition, no single pneumococcal protein antigen has been able to elicit protection comparable to that achieved using protein-polysaccharide conjugate vaccines. In this context, chimeric pneumococcal proteins raise as potential good vaccine candidates because of their simplicity of production and reduced cost. The aim of this work was to study whether the nasal immunization of infant mice with the recombinant chimeric pneumococcal protein (PSFP) was able to improve resistance to S. pneumoniae, and whether the immunomodulatory strain Lactobacillus rhamnosus CRL1505 or its cell wall (CW1505) could be used as effective mucosal adjuvants. Our results showed that the nasal immunization with PSPF improved pneumococcal-specific IgA and IgG levels in broncho-alveolar lavage (BAL), reduced lung bacterial counts, and avoided dissemination of pneumococci into the blood. Of interest, immunization with PSPF elicited cross-protective immunity against different pneumococcal serotypes. It was also observed that the nasal immunization of infant mice with PSPF+CW1505 significantly increased the production of pneumococcal-specific IgA and IgG in BAL, as well as IgM and IgG in serum when compared with PSPF alone. PSPF+CW1505 immunization also improved the reduction of pneumococcal lung colonization and its dissemination in to the bloodstream when compared to PSPF alone. Our results suggest that immunization with PSPF together with the cell wall of the immunomodulatory strain L. rhamnosus CRL1505 as a mucosal adjuvant could be an interesting alternative to improve protection against pneumococcal infection in children. PMID- 30395583 TI - Loss of BAP1 expression is associated with genetic mutation and can predict outcomes in gallbladder cancer. AB - BACKGROUND: BRCA-1 associated protein (BAP1) is a de-ubiquitinating enzyme that regulates gene expression. Recently, the BAP1 mutation and its involvement in cancer survival have been reported in a range of tumor types, including uveal melanoma, mesothelioma, renal cancers, and biliary tract cancers. However, the frequency of BAP1 mutation and down-regulation varies among tumor types, and little is known about the function of BAP1 silencing in cancer cells. Gallbladder carcinoma (GBC) is a type of biliary tract cancer with a poor prognosis. Few mutational studies have investigated the role of BAP1 in GBC, and no functional study in vitro-, or clinical studies about cancer survival have been done. METHODS: GBC cells were studied by following the small interfering RNA mediated silencing of BAP1 with regard to proliferation, migration, invasion, and drug sensitivity. We carried out genomic, epigenomic and immunohistochemical analyses to detect somatic BAP1 alterations in 47 GBC patients undergoing surgical resection. RESULTS: BAP1 depletion resulted in increased migration and invasion, but not proliferation, and also resulted in decreased sensitivity to bortezomib, a proteasome inhibitor. Suppressed expression of BAP1 occurred in 22 GBC cases (46.8%) and showed a strong trend toward a worse median survival time of 13.3 months (95% CI, 17.6-62.6) (p = 0.0034). Sanger sequencing revealed a loss-of function mutation of BAP1 in 11 out of these 22 GBC cases (50%) with low BAP1 expression, whereas 2 out of 25 GBC cases (8%) were detected in cases with high BAP1 expression. Partial changes in methylation were observed in 6 out of 47 cases, but methylation did not show a strong relationship to BAP1 expression or to the prognosis. CONCLUSION: Our findings showed that genetic mutations are involved in BAP1 down-regulation, leading to promotion of the invasive character of cancer cells and poor prognosis in GBC. PMID- 30395584 TI - Antenatal placental assessment in the prediction of adverse pregnancy outcome after reduced fetal movement. AB - OBJECTIVE: To assess the value of in utero placental assessment in predicting adverse pregnancy outcome after reported reduced fetal movements (RFM). METHOD: A non-interventional prospective cohort study of women (N = 300) with subjective RFM at >=28 weeks' gestation in singleton non-anomalous pregnancies at a UK tertiary maternity hospital. Clinical, sonographic (fetal weight, placental size and maternal, fetal and placental arterial Doppler) and biochemical (maternal serum hCG, hPL, progesterone, PlGF and sFlt-1) assessment was conducted. Multiple logistic regression identified combinations of measurements (models) most predictive of adverse pregnancy outcome (perinatal mortality, birth weight <10th centile, five minute Apgar score <7, umbilical arterial pH <7.1 or base excess < 10, neonatal intensive care admission). Models were compared by test performance characteristics (ROC curve, sensitivity, specificity, positive/negative predictive value, positive/negative likelihood ratios) against baseline care (estimated fetal weight centile, amniotic fluid index and gestation at presentation). RESULTS: 61 (20.6%) pregnancies ended in adverse outcome. Models incorporating PlGF/sFlt-1 ratio and umbilical artery free loop Doppler impedance demonstrated modest improvement in ROC area for adverse outcome (baseline care 0.69 vs. proposed models 0.73-0.76, p<0.05). However, there was little improvement in other test characteristics (baseline vs. best proposed model: sensitivity 21.7% [95% confidence interval 13.1-33.6] vs. 35.8%% [24.4-49.3], specificity 96.6% [93.4-98.3] vs. 94.7% [90.7-97.0], PPV 61.9% [40.9-79.3] vs. 63.3% [45.5-78.1], NPV 82.8% [77.9-86.8] vs. 85.2% [80.0-89.2], positive LR 6.3 [2.8-14.6] vs. 6.7 [3.4-3.3], negative LR 0.81 [0.71-0.93] vs. 0.68 [0.55-0.83]) and wide confidence intervals. Negative post-test probability remained high (16.7% vs. 14.0%). CONCLUSION: Antenatal placental assessment may improve identification of RFM pregnancies at highest risk of adverse pregnancy outcome but further work is required to understand and refine currently available outcome definitions and diagnostic techniques to improve clinical utility. PMID- 30395585 TI - Comparative transcriptomics identifies genes differentially expressed in the intestine of a new fast-growing strain of common carp with higher unsaturated fatty acid content in muscle. AB - We have created a new, fast-growing strain of common carp with higher unsaturated fatty acid content in muscle. To better understand the impacts of gene regulation in intestinal tissue on growth and unsaturated fatty acid content, we conducted a comparative RNA-Seq transcriptome analysis between intestine samples of Selected and Control groups (and corroborated selected results by PCR). After eight weeks of cage culture, weight gain of the Selected group was 20.84% higher. In muscles of the control group, monounsaturated fatty acids (FAs) were more abundant, whereas polyunsaturated FAs were more abundant in muscles of the Selected group. In total, we found 106 differentially expressed genes (DEGs) between the two groups. Only the endocytosis pathway was significantly enriched in DEGs, with two upregulated genes: il2rb and ehd1. The latter is involved in the growth hormone/insulin-like growth factor (Gh/Igf) axis, which plays a key role in the regulation of growth in animals. tll2, which is known to be associated with intestinal regeneration, was extremely highly upregulated in both transcriptomic (infinite) and qPCR (610.70) analyses. Two of the upregulated genes are associated with the fatty acid metabolism, several genes are likely to be indicators of heightened transcription levels, several are associated with metabolic and developmental roles, several with neuronal functions (including two with vision), several with the immune system, and two downregulated genes with the development of vasculature. The higher growth rate of the Selected group is likely to be at least partially attributed to increased endocytosis efficiency and genetically-driven behavioural differences (higher aggression levels). There are some indications that this new strain might have slightly impaired immune responses, and a higher propensity for inherited diseases leading to sight impairment, as well for neurodegenerative diseases in general, but these indications still need to be confirmed. PMID- 30395586 TI - Deregulation of the imprinted DLK1-DIO3 locus ncRNAs is associated with replicative senescence of human adipose-derived stem cells. AB - BACKGROUND: Human adult adipose-derived stem cells (hADSCs) have become the most promising cell source for regenerative medicine. However the prolonged ex vivo expansion periods required to obtain the necessary therapeutic dose promotes progressive senescence, with the concomitant reduction of their therapeutic potential. AIM AND SCOPE: A better understanding of the determinants of hADSC senescence is needed to improve biosafety while preserving therapeutic efficiency. Here, we investigated the association between deregulation of the imprinted DLK1-DIO3 region and replicative senescence in hADSC cultures. METHODS: We compared hADSC cultures at short (PS) and prolonged (PL) passages, both in standard and low [O2] (21 and 3%, respectively), in relation to replicative senescence. hADSCs were evaluated for expression alterations in the DLK1-DIO3 region on chromosome 14q32, and particularly in its main miRNA cluster. RESULTS: Comparison of hADSCs cultured at PL or PS surprisingly showed a quite significant fraction (69%) of upregulated miRNAs in PL cultures mapping to the imprinted 14q32 locus, the largest miRNA cluster described in the genome. In agreement, expression of the lncRNA MEG3 (Maternally Expressed 3; Meg3/Gtl2), cultured at 21 and 3% [O2], was also significantly higher in PL than in PS passages. During hADSC replicative senescence the AcK16H4 activating mark was found to be significantly associated with the deregulation of the entire DLK1-DIO3 locus, with a secondary regulatory role for the methylation of DMR regions. CONCLUSION: A direct relationship between DLK1-DIO3 deregulation and replicative senescence of hADSCs is reported, involving upregulation of a very significant fraction of its largest miRNA cluster (14q32.31), paralleled by the progressive overexpression of the lncRNA MEG3, which plays a central role in the regulation of Dlk1/Dio3 activation status in mice. PMID- 30395587 TI - Risk of ischemic stroke after discharge from inpatient surgery: Does the type of surgery matter? AB - OBJECTIVE: Stroke is a well-known and devastating complication during the perioperative period. However, detailed stroke risk profiles within 90 days in patients discharged without stroke after inpatient surgery are not fully understood. Using the case-crossover design, we aimed to evaluate the risk of ischemic stroke in these patients. METHODS: We included adult patients with the first hospitalization for ischemic stroke between 2011 and 2012 from 23 million enrollees in the National Health Insurance Research Database. Admission date of the hospitalization was defined as the case day and exactly 365 days before the admission date as the control day. The exposure was the last hospitalization for surgery within 1-30, 31-60, or 61-90 days (case period) before the case day or similar time intervals (control period) before the control day. Surgical types were grouped based on the International Classification of Diseases procedure codes. We performed conditional logistic regression adjusting for time-varying variables to determine the relationship between surgery and subsequent stroke, and case-time-control analyses to examine whether the results were confounded by the time-trend in surgery. RESULTS: A total of 56596 adult patients (41% female, mean age 69 years) comprised the study population. After adjustment was made for confounding variables, an association between stroke and prior inpatient surgery within 30 days was observed (adjusted odds ratio 1.44; 95% confidence interval 1.29-1.61). Cardiothoracic, vascular, digestive surgery, and musculoskeletal surgery within 30 days independently predicted ischemic stroke in the case crossover analysis. In the case-time-control analysis, inpatient surgery remained an independent risk factor for ischemic stroke, whereas only cardiothoracic, vascular, and digestive surgery independently predicted ischemic stroke. CONCLUSIONS: Surgery as a whole independently increased the risk of ischemic stroke within 30 days. Among various types of surgery, cardiothoracic, vascular, and digestive surgery significantly increased the risk of ischemic stroke. PMID- 30395588 TI - Validity of DXA body volume equations in a four-compartment model for adults with varying body mass index and waist circumference classifications. AB - The purpose of this investigation was to determine the validity of 4-compartment (4C) model body fat percent (BF%) estimates when using dual energy x-ray absorptiometry (DXA) derived body volume (BV) equations (4C-DXA1 and 4C-DXA2) in adults with varying body mass index (BMI) and waist circumference (WC) classifications. Each model was compared to a criterion 4C model with air displacement plethysmography (ADP) generated BV (4C-ADP). Participants were categorized as normal weight (n = 40; NW = BMI<25.0kg/m2); overweight (n = 40; OWBMI = BMI>=25.0 kg/m2); and overweight with at-risk WC (n = 35; OWBMI+WC = BMI>=25.0 kg/m2 and WC>=88.0cm for women and 102.0cm for men). 4C-DXA1 produced lower BF% than that derived using the 4C-ADP in NW (CE = -3.0%; p<0.001) while 4C DXA2 was significantly higher (CE = 4.8%; p<0.001). The SEE and 95% limits of agreement (LOA) were lower for 4C-DXA2 (1.24% and +/-2.5%, respectively) than 4C DXA1 (2.59% and +/-5.0%, respectively) and proportional bias was present for both (p<0.05). 4C-DXA1 BF% was not significant in OWBMI (CE = -0.5%; p = 0.112) whereas 4C-DXA2 was higher (CE = 4.5%; p<0.001). The SEE and 95% LOA were lower for 4C-DXA2 (1.20% and +/-2.9%, respectively) than 4C-DXA1 (1.92% and +/-3.9%, respectively) in OWBMI. Proportional bias was present for 4C-DXA1 (p = 0.007), but not 4C-DXA2 (p = 0.832). 4C-DXA1 and 4C-DXA2 produced significantly higher BF% in OWBMI+WC (CE = 2.2 and 2.3%, respectively; both p<0.001). The SEE and 95% LOA remained lower for 4C-DXA2 (1.15% and +/-2.5%, respectively) than 4C-DXA1 (1.84% and +/-3.8%, respectively). There was proportional bias for 4C-DXA2 (p = 0.020), but not 4C-DXA1 (p = 0.183) in OWBMI+WC. Only one prediction model (i.e., 4C-DXA1 in OWBMI+WC) revealed valid estimates of BF%. Practitioners are encouraged to use criteria for both BMI and WC when utilizing DXA-derived BV in 4C-models for normal and overweight populations. PMID- 30395589 TI - The long term effect of metabolic profile and microbiota status in early gastric cancer patients after subtotal gastrectomy. AB - Long term effects of subtotal gastrectomy on gut microbiota modifications with subsequent metabolic profiles are limited. We aimed to investigate and compare long-term effects of metabolic profiles and microbiota status in early gastric cancer patients post curative subtotal gastrectomy to the controls. In this cross sectional study, we analyzed type II diabetes mellitus and metabolic syndrome occurrence in two groups: 111 patients after curative subtotal gastrectomy with Billroth II (BII) anastomosis and Roux-en-Y gastrojejuno (RYGJ) anastomosis and 344 age-sex matched controls. Fecal samples from those with BII, RYGJ, and controls were analyzed by next-generation sequencing method. Metabolic syndrome and type II diabetes mellitus occurrences were significantly lower in patients after subtotal gastrectomy with RYGJ than in controls over the long term (> 8 years) follow-up (P < 0.05). The richness and diversity of gut microbiota significantly increased after subtotal gastrectomy with RYGJ (P < 0.05). Compared with the control group, the principal component analysis revealed significant differences in bacterial genera abundance after subtotal gastrectomy with BII and RYGJ (P < 0.001). Genera of Oscillospira, Prevotella, Coprococcus, Veillonella, Clostridium, Desulfovibrio, Anaerosinus, Slackia, Oxalobacter, Victivallis, Butyrivibrio, Sporobacter, and Campylobacter shared more abundant roles both in the RYGJ group and BII groups. Early gastric cancer patients after subtotal gastrectomy with RYGJ had a lower occurrence of metabolic syndrome and type II diabetes mellitus than the controls during long term follow-up. In parallel with the metabolic improvements, gut microbial richness and diversity also significantly increased after subtotal gastrectomy with RYGJ. PMID- 30395590 TI - Nanoparticulate matter exposure results in neuroinflammatory changes in the corpus callosum. AB - Epidemiological studies have established an association between air pollution particulate matter exposure (PM2.5) and neurocognitive decline. Experimental data suggest that microglia play an essential role in air pollution PM-induced neuroinflammation and oxidative stress. This study examined the effect of nano sized particulate matter (nPM) on complement C5 deposition and microglial activation in the corpus callosum of mice (C57BL/6J males). nPM was collected in an urban Los Angeles region impacted by traffic emissions. Mice were exposed to 10 weeks of re-aerosolized nPM or filtered air for a cumulative 150 hours. nPM exposed mice exhibited reactive microglia and 2-fold increased local deposition of complement C5/ C5alpha proteins and complement component C5a receptor 1 (CD88) in the corpus callosum. However, serum C5 levels did not differ between nPM and filtered air cohorts. These findings demonstrate white matter C5 deposition and microglial activation secondary to nPM exposure. The C5 upregulation appears to be localized to the brain. PMID- 30395591 TI - Tibiofemoral joint contact forces increase with load magnitude and walking speed but remain almost unchanged with different types of carried load. AB - Musculoskeletal injuries (MSI) in the military reduce soldier capability and impose substantial costs. Characterizing biomechanical surrogates of MSI during commonly performed military tasks (e.g., load carriage) is necessary for evaluating the effectiveness of possible interventions to reduce MSI risk. This study determined the effects of body-borne load distribution, load magnitude, and walking speed on tibiofemoral contact forces. Twenty-one Australian Army Reserve soldiers completed a treadmill walking protocol in an unloaded condition and wearing four armor types (standard-issue and three prototypes) with two load configurations (15 and 30 kg) for a total of 8 armor x load ensembles. In each ensemble, participants completed a 5-minute warm-up, and then walked for 10 minutes at both moderate (1.53 m?s-1) and fast (1.81 m?s-1) speeds. During treadmill walking, three-dimensional kinematics, ground reaction forces, and muscle activity from nine lower-limb muscles were collected in the final minute of each speed. These data were used as inputs into a neuromusculoskeletal model, which estimated medial, lateral and total tibiofemoral contact forces. Repeated measures analyses of variance revealed no differences for any variables between armor types, but peak medial compartment contact forces increased when progressing from moderate to fast walking and with increased load (p<0.001). Acute exposure to load carriage increased estimated tibiofemoral contact forces 10.1 and 19.9% with 15 and 30kg of carried load, respectively, compared to unloaded walking. These results suggest that soldiers carrying loads in excess of 15 kg for prolonged periods could be at greater risk of knee MSI than those with less exposure. PMID- 30395592 TI - Accuracy of commercial electronic nicotine delivery systems (ENDS) temperature control technology. AB - OBJECTIVES: For electronic nicotine delivery systems (ENDS), also commonly called e-cigarettes, coil temperature is a factor in the potential production of toxic chemical constituents. However, data are lacking regarding the temperatures that are achieved in the latest generation of these devices. Fourth-generation ENDS are capable of producing heating coil temperatures well above e-liquid boiling points, and allow the user to monitor and set the heating coil temperature during a puff. In this study, we evaluate the accuracy and consistency of the temperature measurement and control settings for different brands of fourth generation ENDS. METHODS: A study was performed using three commercially available, fourth-generation ENDS. The atomizer coil temperatures were obtained from the device (using the EScribe software) reading and from thermocouples attached to the coils during simulated puffing conditions. In addition, aerosol temperatures were measured inside the atomizer and at the mouthpiece. RESULTS: Measured temperatures varied widely across samples taken from the same brand. For example, thermocouple measurements for one unit were 40 Celsius ( degrees C) below the 300 degrees C set point, while another unit of the same brand exceeded the set point by more than 100 degrees C. We observed a significant variation in temperature (approximately 100 degrees C) along the length of the coil in some cases. CONCLUSIONS: The possibility of wide temperature variation across ENDS samples, as well as variations between maximum coil temperatures and internal temperature readings, may have implications for studies that seek to determine correlations between coil temperature and toxin generation. PMID- 30395593 TI - Rhodopsin gene evolution in early teleost fishes. AB - Rhodopsin mediates an essential step in image capture and is tightly associated with visual adaptations of aquatic organisms, especially species that live in dim light environments (e.g., the deep sea). The rh1 gene encoding rhodopsin was formerly considered a single-copy gene in genomes of vertebrates, but increasing exceptional cases have been found in teleost fish species. The main objective of this study was to determine to what extent the visual adaptation of teleosts might have been shaped by the duplication and loss of rh1 genes. For that purpose, homologous rh1/rh1-like sequences in genomes of ray-finned fishes from a wide taxonomic range were explored using a PCR-based method, data mining of public genetic/genomic databases, and subsequent phylogenomic analyses of the retrieved sequences. We show that a second copy of the fish-specific intron-less rh1 is present in the genomes of most anguillids (Elopomorpha), Hiodon alosoides (Osteoglossomorpha), and several clupeocephalan lineages. The phylogenetic analysis and comparisons of alternative scenarios for putative events of gene duplication and loss suggested that fish rh1 was likely duplicated twice during the early evolutionary history of teleosts, with one event coinciding with the hypothesized fish-specific genome duplication and the other in the common ancestor of the Clupeocephala. After these gene duplication events, duplicated genes were maintained in several teleost lineages, whereas some were secondarily lost in specific lineages. Alternative evolutionary schemes of rh1 and comparison with previous studies of gene evolution are also reviewed. PMID- 30395594 TI - Cross-sectional study of the association between day-to-day home blood pressure variability and visceral fat area measured using the dual impedance method. AB - BACKGROUND: The blood pressure (BP) variability (BPV) is a predictor of cardiovascular disease, independently of the BP itself. In addition, visceral fat accumulation can trigger atherosclerotic disease through various mechanisms. METHODS AND RESULTS: We examined the association between fat accumulation and day to-day BPV in 61 adult hypertensive patients. Visceral fat area (VFA) was measured using the dual bioelectrical impedance analysis method. Participants were divided into three groups based on VFA. The standard deviation (SD) in home systolic BP (SBP) for 7 consecutive days was significantly lower in the high VFA tertile (low VFA, 8.40+/-4.15 mmHg; intermediate VFA, 8.47+/-2.80 mmHg; and high VFA, 5.84+/-2.37 mmHg, p of One-way ANOVA = 0.017, p for trend = 0.0126). A similar association was observed between the coefficient of variance (CV) of home SBP and the VFA tertile. Multiple-regression analysis adjusted for age, sex, antihypertensive drug, diabetes, habitual drinking, and SBP level also showed a significant association between the VFA tertile and the SD or CV of home SBP. The adjusted coefficient of regression for the SD of home SBP was -3.28 (95%CI: -5.60 to -0.97, p = 0.008) and the CV of home SBP was -2.51 (95%CI: -4.31 to -0.71, p = 0.008) for the highest VFA tertile as compared to the lowest VFA tertile. CONCLUSIONS: These results show for the first time negative correlation between VFA and day-to-day BPV. The degree of obesity should be taken into account when evaluating the value of BPV. PMID- 30395595 TI - Modulation of early maize seedling performance via priming under sub-optimal temperatures. AB - Seeds planted in early spring frequently experience low temperature stress in the soil during germination and early plant growth. Seed pretreatments such as priming have been shown to ameliorate the negative effects of cold soil in some crops. However, the potential beneficial effects of priming have not been widely investigated for Zea mays (maize). To investigate seed priming effects, 24 diverse maize inbred lines were primed using a synthetic solid matrix, Micro-Cel E, and then exposed to 10 degrees C soil conditions. Six DSLR cameras captured time lapsed images of emerging seedlings. Manual scoring was used to determine treatment effects on three seedling emergence metrics. Chilling substantially reduced total emergence for two of 24 genotypes evaluated. For these genotypes, priming provided protection allowing nearly full emergence. Priming significantly reduced mean emergence time and increased the emergence uniformity of chilling sensitive genotypes. The results suggest that the cold sensitive genotypes may benefit from priming pretreatment. Kernel density, weight, oil, protein, and starch traits, as determined by single-kernel near infrared spectroscopy, were not correlated with seedling emergence traits supporting a conclusion that early seedling performance cannot be determined from these maize kernel characteristics. PMID- 30395596 TI - Effectiveness and postoperative wound infection of preperitoneal pelvic packing in patients with hemodynamic instability caused by pelvic fracture. AB - INTRODUCTION: Despite the use of a multidisciplinary treatment approach, the mortality rate of hemodynamic instability due to severe pelvic fracture remains 40-60%. Several recent studies have shown that preperitoneal pelvic packing (PPP) was useful for achieving hemostasis in these patients in the acute phase. However, few studies have examined postoperative complications. The purpose of the present study was to evaluate clinical outcomes and wound infections of PPP in these patients. MATERIALS AND METHODS: We retrospectively reviewed the medical charts of 62 patients with hemorrhagic shock due to pelvic fracture between March 2011 and May 2017. Excluding four patients (two with other major hemorrhage sites and two who experienced cardiac arrest in the emergency room), the patients were divided into PPP (n = 30) and non-PPP (n = 28) groups according to PPP application. Clinical outcomes including early-stage mortality, transfusion amount, and surgical site infection (SSI) were compared between the two groups. RESULTS: The overall mortality rate was 48.3% and the mean Injury Severity Score (ISS) was 39 +/- 9. The 30 patients in the PPP group had a significantly lower hemorrhage-induced mortality rate than the 28 patients in the non-PPP group (16.7% vs 50%, p = 0.019), although both groups had similar patient characteristics (age, ISS, and initial serum lactate level). Independent factors associated with hemorrhage-induced mortality were PPP and the requirement of packed red blood cells for 4 h. In the PPP group, SSI occurred in 5 of 25 (20%) patients. CONCLUSIONS: PPP may be considered as a hemostatic modality for hemodynamic instability due to pelvic fracture because it reduces the hemorrhage induced mortality rate. However, wound infections after the procedure should be considered. PMID- 30395597 TI - A comparison of stability metrics based on inverted pendulum models for assessment of ramp walking. AB - Maintaining balance on ramps is important for mobility. However, balance is commonly assessed using inverted pendulum-based metrics (e.g., margin of stability), which may not be appropriate for assessment of human walking on non level surfaces. To investigate this, we analyzed stability on ramps using four different inverted pendulum models: extrapolated center of mass (XCOM), foot placement estimate (FPE), foot placement estimate neglecting angular momentum (FPENoH), and capture point (CAP). We analyzed experimental data from 10 able bodied individuals walking on a ramp at 0 degrees , +/-5 degrees , and +/-10 degrees . Contrary to our hypothesis that the magnitude of differences between metrics would be greatest at +/-10 degrees , we observed the greatest magnitude of differences between metrics at 0 degrees . In general, the stability metrics were bounded by FPE and CAP at each slope, consistent with prior studies of level walking. Our results also suggest that clinical providers and researchers should be aware that assessments that neglect angular momentum (e.g., margin of stability, XCOM) may underestimate stability in the sagittal-plane in comparison to analyses which incorporate angular momentum (e.g., FPE). Except for FPENoH-CAP (r = 0.82), differences between metrics were only moderately correlated (|r|<=0.65) with violations of leg length assumptions in the underlying inverted pendulum models. The differences in FPENoH relative to FPE and CAP were strongly correlated with body center of mass vertical velocity (max |r| = 0.92), suggesting that model representations of center of mass motion influence stability metrics. However, there was not a clear overall relationship between model inputs and differences in stability metrics. Future sensitivity analyses may provide additional insight into model characteristics that influence stability metrics. PMID- 30395598 TI - Association between PR interval prolongation and electro-anatomical substrate in patients with atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical routine. Left atrial (LA) electro-anatomical remodelling in AF patients indicates disease progression and is associated with poor therapeutic success. PR interval prolongation is associated with an increased risk for AF, however, the association between LA remodelling measured as low voltage areas (LVA) during catheter ablation and PR interval is unknown. The aim of this study was to investigate the association between PR interval prolongation and LVA in AF patients. METHODS: We studied 103 patients (62+/-12 years, 59% males, 34% persistent AF) undergoing first AF catheter ablation and presenting with sinus rhythm. PR interval prolongation was defined as PR >200ms and analysed in resting ECG before intervention. LVA were determined using high-density maps and defined as <0.5 mV. RESULTS: There were 24 patients (23%) with PR interval prolongation and 18 patients (17%) with LVA. There were significant correlations between PR prolongation with LVA, CHA2DS2-VASc score and eGFR (r2 = 0.230, 0.216, and 0.307, all p<0.05). PR interval prolongation (OR 3.450, p = 0.024), persistent AF (OR 5.391, p = 0.002), and LA size (OR 1.117, p = 0.018) were significant predictors for LVA, while age (OR 1.072, p = 0.005), LVA (OR 3.450 p = 0.024) and eGFR (OR 0.962, p = 0.004) were associated with PR interval prolongation. CONCLUSIONS: Beside persistent AF and LA size, PR interval prolongation might be useful for the prediction of electro-anatomical substrate in AF patients. Larger studies are needed to confirm these results. PMID- 30395599 TI - The influence of musculoskeletal pain disorders on muscle synergies-A systematic review. AB - BACKGROUND: Musculoskeletal (MSK) pain disorders represent a group of highly prevalent and often disabling conditions. Investigating the structure of motor variability in response to pain may reveal novel motor impairment mechanisms that may lead to enhanced management of motor dysfunction associated with MSK pain disorders. This review aims to systematically synthesize the evidence on the influence of MSK pain disorders on muscle synergies. METHODS: Nine electronic databases were searched using Medical Subject Headings and keywords describing pain, electromyography and synergies. Relevant characteristics of included studies were extracted and assessed for generalizability and risk of bias. Due to the significant heterogeneity, a qualitative synthesis of the results was performed. RESULTS: The search resulted in a total of 1312 hits, of which seven articles were deemed eligible. There was unclear consistency that pain reduced the number of muscle synergies. There were low consistencies of evidence that the synergy vector (W weights) and activation coefficient (C weights) differed in painful compared to asymptomatic conditions. There was a high consistency that muscle synergies were dissimilar between painful and asymptomatic conditions. CONCLUSIONS: MSK pain alters the structure of variability in muscle control, although its specific nature remains unclear. Greater consistency in muscle synergy analysis may be achieved with appropriate selection of muscles assessed and ensuring consistent achievement of motor task outcomes. Synergy analysis is a promising method to reveal novel understandings of altered motor control, which may facilitate the assessment and treatment of MSK pain disorders. PMID- 30395600 TI - Prediction and classification in equation-free collective motion dynamics. AB - Modeling the complex collective behavior is a challenging issue in several material and life sciences. The collective motion has been usually modeled by simple interaction rules and explained by global statistics. However, it remains difficult to bridge the gap between the dynamic properties of the complex interaction and the emerging group-level functions. Here we introduce decomposition methods to directly extract and classify the latent global dynamics of nonlinear dynamical systems in an equation-free manner, even including complex interaction in few data dimensions. We first verified that the basic decomposition method can extract and discriminate the dynamics of a well-known rule-based fish-schooling (or bird-flocking) model. The method extracted different temporal frequency modes with spatial interaction coherence among three distinct emergent motions, whereas these wave properties in multiple spatiotemporal scales showed similar dispersion relations. Second, we extended the basic method to map high-dimensional feature space for application to actual small-dimensional systems complexly changing the interaction rules. Using group sports human data, we classified the dynamics and predicted the group objective achievement. Our methods have a potential for classifying collective motions in various domains which obey in non-trivial dominance law known as active matters. PMID- 30395601 TI - Synthetic protein alignments by CCMgen quantify noise in residue-residue contact prediction. AB - Compensatory mutations between protein residues in physical contact can manifest themselves as statistical couplings between the corresponding columns in a multiple sequence alignment (MSA) of the protein family. Conversely, large coupling coefficients predict residue contacts. Methods for de-novo protein structure prediction based on this approach are becoming increasingly reliable. Their main limitation is the strong systematic and statistical noise in the estimation of coupling coefficients, which has so far limited their application to very large protein families. While most research has focused on improving predictions by adding external information, little progress has been made to improve the statistical procedure at the core, because our lack of understanding of the sources of noise poses a major obstacle. First, we show theoretically that the expectation value of the coupling score assuming no coupling is proportional to the product of the square roots of the column entropies, and we propose a simple entropy bias correction (EntC) that subtracts out this expectation value. Second, we show that the average product correction (APC) includes the correction of the entropy bias, partly explaining its success. Third, we have developed CCMgen, the first method for simulating protein evolution and generating realistic synthetic MSAs with pairwise statistical residue couplings. Fourth, to learn exact statistical models that reliably reproduce observed alignment statistics, we developed CCMpredPy, an implementation of the persistent contrastive divergence (PCD) method for exact inference. Fifth, we demonstrate how CCMgen and CCMpredPy can facilitate the development of contact prediction methods by analysing the systematic noise contributions from phylogeny and entropy. Using the entropy bias correction, we can disentangle both sources of noise and find that entropy contributes roughly twice as much noise as phylogeny. PMID- 30395602 TI - A variably imprinted epiallele impacts seed development. AB - The contribution of epigenetic variation to phenotypic variation is unclear. Imprinted genes, because of their strong association with epigenetic modifications, represent an opportunity for the discovery of such phenomena. In mammals and flowering plants, a subset of genes are expressed from only one parental allele in a process called gene imprinting. Imprinting is associated with differential DNA methylation and chromatin modifications between parental alleles. In flowering plants imprinting occurs in a seed tissue - endosperm. Proper endosperm development is essential for the production of viable seeds. We previously showed that in Arabidopsis thaliana intraspecific imprinting variation is correlated with naturally occurring DNA methylation polymorphisms. Here, we investigated the mechanisms and function of allele-specific imprinting of the class IV homeodomain leucine zipper (HD-ZIP) transcription factor HDG3. In imprinted strains, HDG3 is expressed primarily from the methylated paternally inherited allele. We manipulated the methylation state of endogenous HDG3 in a non-imprinted strain and demonstrated that methylation of a proximal transposable element is sufficient to promote HDG3 expression and imprinting. Gain of HDG3 imprinting was associated with earlier endosperm cellularization and changes in seed weight. These results indicate that epigenetic variation alone is sufficient to explain imprinting variation and demonstrate that epialleles can underlie variation in seed development phenotypes. PMID- 30395603 TI - The economic value of identifying and treating Chagas disease patients earlier and the impact on Trypanosoma cruzi transmission. AB - BACKGROUND: The World Health Organization's 2020 Goals for Chagas disease include access to antiparasitic treatment and care of all infected/ill patients. Policy makers need to know the economic value of identifying and treating patients earlier. However, the economic value of earlier treatment to cure and prevent the Chagas' spread remains unknown. METHODS: We expanded our existing Chagas disease transmission model to include identification and treatment of Chagas disease patients. We linked this to a clinical and economic model that translated chronic Chagas disease cases into health and economic outcomes. We evaluated the impact and economic outcomes (costs, cost-effectiveness, cost-benefit) of identifying and treating different percentages of patients in the acute and indeterminate disease states in a 2,000-person village in Yucatan, Mexico. RESULTS: In the absence of early treatment, 50 acute and 22 new chronic cases occurred over 50 years. Identifying and treating patients in the acute stage averted 0.5-5.4 acute cases, 0.6-5.5 chronic cases, and 0.6-10.8 disability-adjusted life years (DALYs), saving $694-$7,419 and $6,976-$79,950 from the third-party payer and societal perspectives, respectively. Treating in the indeterminate stage averted 2.2-4.9 acute cases, 6.1-12.8 chronic cases, and 11.7-31.1 DALYs, saving $7,666 $21,938 from the third-party payer perspective and $90,530-$243,068 from the societal perspective. Treating patients in both stages averted <=9 acute cases and <=15 chronic cases. Identifying and treating patients early was always economically dominant compared to no treatment. Identifying and treating patients earlier resulted in a cumulative cost-benefit of $7,273-$224,981 at the current cost of identification and treatment. CONCLUSIONS: Even when identifying and treating as little as 5% of cases annually, treating Chagas cases in the acute and indeterminate stages reduces transmission and provides economic and health benefits. This supports the need for improved diagnostics and access to safe and effective treatment. PMID- 30395605 TI - Knowledge and perception of pastoral community members about brucellosis as a cause of abortion in animals and its zoonotic importance in Amibara district, Afar Region, Ethiopia. AB - Sero-epidemiological studies of brucellosis in the Afar Region showed that the disease is prevalent in livestock. However, there is little information regarding the pastoral community members' awareness about brucellosis as a cause of abortion in animals and its zoonotic importance. In this study, we assessed knowledge and perception of pastoral community members about brucellosis as a cause of abortion in animals and its zoonotic importance in Amibara district, Afar Region, Ethiopia. Between October and December 2016, a total of 475 study participants (age range 18-80 years, mean age 35.9 years) were interviewed about abortion in their animals, its causes, and diseases that can be transmitted to humans through consumption of raw milk. Almost all (97.7%) of the study participants reported that abortion in animals, especially in goats, is a major problem in the area, and they mentioned that disease (44.6%), drought (58.4%) and fly bites (29.5%) as the main causes of abortion. The study participantsalso thought that malaria (42.9%) and bovine tuberculosis (19.3%) can be transmitted to humans through consuming raw milk. Five respondents (4.2%) mentioned brucellosis (locally known as "hahayita") as a disease that can be transmitted through frequent consumption of raw milk. The majority (91.9%) mentioned malaria as a cause of febrile illness in humans and 16 (4.4%) participants mentioned brucellosis as a cause of febrile illness. Some participants also mentioned brucellosis as a cause of joint swelling (hygroma) in cattle. In conclusion, the pastoral community members in the present study area lack clear understanding about brucellosis as one of the diseases that cause abortion in their animals and its zoonotic importance. There is a need to create awareness about the zoonotic and animal health importance of brucellosis through various means such as community health extension/veterinary workers and community leaders. PMID- 30395604 TI - Chromatin remodelers couple inchworm motion with twist-defect formation to slide nucleosomal DNA. AB - ATP-dependent chromatin remodelers are molecular machines that control genome organization by repositioning, ejecting, or editing nucleosomes, activities that confer them essential regulatory roles on gene expression and DNA replication. Here, we investigate the molecular mechanism of active nucleosome sliding by means of molecular dynamics simulations of the Snf2 remodeler translocase in complex with a nucleosome. During its inchworm motion driven by ATP consumption, the translocase overwrites the original nucleosome energy landscape via steric and electrostatic interactions to induce sliding of nucleosomal DNA unidirectionally. The sliding is initiated at the remodeler binding location via the generation of a pair of twist defects, which then spontaneously propagate to complete sliding throughout the entire nucleosome. We also reveal how remodeler mutations and DNA sequence control active nucleosome repositioning, explaining several past experimental observations. These results offer a detailed mechanistic picture of remodeling important for the complete understanding of these key biological processes. PMID- 30395606 TI - Pyronaridine exerts potent cytotoxicity on human breast and hematological cancer cells through induction of apoptosis. AB - The potent antimalarial drug pyronaridine (PND) was tested for its potential as an anticancer drug. After exposing cancerous (17) and non-cancerous (2) cells to PND for 72 hr, PND was found to exhibit consistent and potent cytotoxic activity at low micromolar (MUM) concentrations that ranged from 1.6 MUM to 9.4 MUM. Moreover, PND exerted a significant selective cytotoxicity index (SCI) on five out of seven breast cancer cell lines tested, with favorable values of 2.5 to 4.4, as compared with the non-cancerous breast MCF-10A cell line. By using the same comparison, PND exhibited a significant SCI on three out of four leukemia/lymphoma cell lines with promising values of 3.3 to 3.5. One breast cancer and one leukemia cell line were tested further in order to determine the likely mode of action of PND. PND was found to consistently elicit phosphatidylserine externalization, mitochondrial depolarization, and DNA fragmentation, in both the triple negative MDA-MB-231 breast cancer and HL-60 leukemia cell lines. In addition, PND treatment altered cell cycle progression in both cancer cells. Subsequent DNA mobility-shift assays, UV-Visible spectroscopic titrations, and circular dichroism (CD) experiments revealed that PND intercalates with DNA. The findings presented in this study indicates that PND induces apoptosis and interfered with cell cycle progression of cancer cell lines and these results indicate that this drug has the potential as a repurposed drug for cancer therapy. PMID- 30395607 TI - A method for measuring human body composition using digital images. AB - BACKGROUND/OBJECTIVES: Body mass index (BMI) is a proxy for obesity that is commonly used in spite of its limitation in estimating body fatness. Trained observers with repeated exposure to different body types can estimate body fat (BF) of individuals compared to criterion methods with reasonable accuracy. The purpose of this study was to develop and validate a computer algorithm to provide a valid estimate %BF using digital photographs. SUBJECTS/METHODS: Our sample included 97 children and 226 adults (age in years: 11.3+/-3.3; 38.1+/-11.6, respectively). Measured height and weight were used (BMI in kg/m2: 20.4+/-4.4; 28.7+/-6.6 for children and adults, respectively). Dual x-ray absorptiometry (DXA) was the criterion method. Body volume (BVPHOTO) and body shape (BSPHOTO) were derived from two digital images. Final support vector regression (SVR) models were trained using age, sex, race, BMI for % BFNOPHOTO, plus BVPHOTO and BSPHOTO for %BFPHOTO. Separate validation models were used to evaluate the learning algorithm in children and adults. The differences in correlations between %BFDXA, %BFNOPHOTO and %BFPHOTO were tested using the Fisher's Z-score transformation. RESULTS: Mean BFDXA and BFPHOTO were 27.0%+/-9.2 vs. 26.7%+/- 7.4 in children and 32.9+/- 10.4% vs. 32.8%+/-9.3 in adults. SVR models produced %BFPHOTO values strongly correlated with %BFDXA. Our final model produced correlations of rDP = 0.80 and rDP = 0.87 in children and adults, respectively for %BFPHOTO vs. %BFDXA. The correlation between %BFNOPHOTO and %BFDXA was moderate, yet statistically significant in both children rDB = 0.70; p <0.0001 and adults rDB = 0.86; p<0.0001. However, the correlations for rDP were statistically higher than rDB (%BFDXA vs. %BFNOPHOTO) in both children and adults (children: Z = 5.95, p<0.001; adults: Z = 3.27, p<0.0001). CONCLUSIONS: Our photographic method produced valid estimates of BF in both children and adults. Further research is needed to create norms for subgroups by sex, race/ethnicity, and mobility status. PMID- 30395608 TI - Treatment adequacy for social anxiety disorder in primary care patients. AB - OBJECTIVES: There is a gap between clinical practice guidelines for social anxiety disorder and clinical practice that needs to be addressed to ensure the delivery of evidence-based treatments. The objectives of this study were: 1) to describe mental health service utilization in a cohort of primary care patients with social anxiety disorder; 2) to examine treatment adequacy for pharmacotherapy and psychotherapy according to indicators based on clinical practice guidelines; and 3) to explore correlates of treatment adequacy. METHOD: The "Dialogue" project (Quebec, Canada) is a large study conducted in 67 primary care clinics. After a mental health screening in primary care (n = 14 833), participants with anxiety or depressive symptoms took part in a telephone/web structured interview on mental health symptoms and service utilization (n = 1956). This study included 289 participants meeting DSM-IV criteria for social anxiety disorder. RESULTS: Overall, 86.2% of participants reported consulting for mental health reasons over the past 12 months. Only 23.6% of our sample reported the detection of social anxiety disorder by a healthcare professional in the past 12 months. Approximately 2 in 5 respondents with social anxiety disorder reported receiving pharmacotherapy or psychotherapy meeting our treatment adequacy indicators. Antidepressant medication was the most common treatment. Logistic regression models showed that the detection of major depression (OR = 4.651; 95% CI: 2.559-8.453) or other anxiety disorder(s) (OR = 2.957; 95% CI: 1.555-5.625) were associated with receiving any adequate treatment, but the detection of social anxiety disorder itself was not (OR = 1.420; 95% CI: 0.696-2.899). CONCLUSION: Low rates of detection and treatment adequacy based on our indicators demonstrate that efforts must be made to ensure the quality of care for individuals with social anxiety disorder in primary care. PMID- 30395609 TI - Mycobacterium tuberculosis host cell interaction: Role of latency associated protein Acr-1 in differential modulation of macrophages. AB - Mycobacterium tuberculosis (M.tb) contrives intracellular abode as a strategy to combat antibody onslaught. Additionally, to thrive against hostile ambiance inside host macrophages, the pathogen inhibits phago-lysosomal fusion. Finally, to further defy host cell offensives, M.tb opts for dormant phase, where it turns off or slows down most of its metabolic process as an added stratagem. While M.tb restrains most of its metabolic activities during dormancy, surprisingly latency associated alpha-crystallin protein (Acr-1) is expressed most prominently during this phase. Interestingly, several previous studies described the potential of Acr-1 to induce the robust immuno-prophylactic response in the immunized host. It is intriguing to comprehend the apparent discrepancy that the microbe M.tb overexpresses a protein that has the potential to prime host immune system against the pathogen itself. Keeping this apparent ambiguity into consideration, it is imperative to unravel intricacies involved in the exploitation of Acr-1 by M.tb during its interaction with host immune cells. The present study suggests that Acr-1 exhibits diverse role in the maturation of macrophages (MPhis) and related immunological responses. The early encounter of bone marrow derived immune cells (pre-exposure during differentiation to MPhis) with Acr-1 (AcrMPhipre), results in hampering of their function. The pre-exposure of naive MPhis with Acr-1 induces the expression of TIM-3 and IL-10. In contrast, exposure of fully differentiated MPhis to Acr-1 results in their down-modulation and induces the phosphorylation of STAT-1 and STAT-4 in host MPhis. Furthermore, Acr 1 mediated activation of MPhis results in the induction of Th1 and Th17 phenotype by activated T lymphocyte. PMID- 30395610 TI - De novo assembly of wheat root transcriptomes and transcriptional signature of longitudinal differentiation. AB - Hidden underground, root systems constitute an important part of the plant for its development, nourishment and sensing the soil environment around it, but we know very little about its genetic regulation in crop plants like wheat. In the present study, we de novo assembled the root transcriptomes in reference cultivar Chinese Spring from RNA-seq reads generated by the 454-GS-FLX and HiSeq platforms. The FLX reads were assembled into 24,986 transcripts with completeness of 54.84%, and the HiSeq reads were assembled into 91,543 high-confidence protein coding transcripts, 2,404 low-confidence protein-coding transcripts, and 13,181 non-coding transcripts with the completeness of >90%. Combining the FLX and HiSeq assemblies, we assembled a root transcriptome of 92,335 ORF-containing transcripts. Approximately 7% of the coding transcripts and ~2% non-coding transcripts are not present in the current wheat genome assembly. Functional annotation of both assemblies showed similar gene ontology patterns and that ~7% coding and >5% non-coding transcripts are root-specific. Transcription quantification identified 1,728 differentially expressed transcripts between root tips and maturation zone, and functional annotation of these transcripts captured a transcriptional signature of longitudinal development of wheat root. With the transcriptomic resources developed, this study provided the first view of wheat root transcriptome under different developmental zones and laid a foundation for molecular studies of wheat root development and growth using a reverse genetic approach. PMID- 30395612 TI - Approaches to variant discovery for conifer transcriptome sequencing. AB - There is a wide diversity of bioinformatic tools available for the assembly of next generation sequence and subsequence variant calling to identify genetic markers at scale. Integration of genomics tools such as genomic selection, association studies, pedigree analysis and analysis of genetic diversity, into operational breeding is a goal for New Zealand's most widely planted exotic tree species, Pinus radiata. In the absence of full reference genomes for large megagenomes such as in conifers, RNA sequencing in a range of genotypes and tissue types, offers a rich source of genetic markers for downstream application. We compared nine different assembler and variant calling software combinations in a single transcriptomic library and found that Single Nucleotide Polymorphism (SNPs) discovery could vary by as much as an order of magnitude (8,061 SNPs up to 86,815 SNPs). The assembler with the best realignment of the packages trialled, Trinity, in combination with several variant callers was then applied to a much larger multi-genotype, multi-tissue transcriptome and identified 683,135 in silico SNPs across a predicted 449,951 exons when mapped to the Pinus taeda ver 1.01e reference. PMID- 30395611 TI - Iron is a centrally bound cofactor of specifier proteins involved in glucosinolate breakdown. AB - Glucosinolates, a group of sulfur-rich thioglucosides found in plants of the order Brassicales, have attracted a lot of interest as chemical defenses of plants and health promoting substances in human diet. They are accumulated separately from their hydrolyzing enzymes, myrosinases, within the intact plant, but undergo myrosinase-catalyzed hydrolysis upon tissue disruption. This results in various biologically active products, e.g. isothiocyanates, simple nitriles, epithionitriles, and organic thiocyanates. While formation of isothiocyanates proceeds by a spontaneous rearrangement of the glucosinolate aglucone, aglucone conversion to the other products involves specifier proteins under physiological conditions. Specifier proteins appear to act with high specificity, but their exact roles and the structural bases of their specificity are presently unknown. Previous research identified the motif EXXXDXXXH as potential iron binding site required for activity, but crystal structures of recombinant specifier proteins lacked the iron cofactor. Here, we provide experimental evidence for the presence of iron (most likely Fe2+) in purified recombinant thiocyanate-forming protein from Thlaspi arvense (TaTFP) using a Ferene S-based photometric assay as well as Inductively Coupled Plasma-Mass Spectrometry. Iron binding and activity depend on E266, D270, and H274 suggesting a direct interaction of Fe2+ with these residues. Furthermore, we demonstrate presence of iron in epithiospecifier protein and nitrile-specifier protein 3 from Arabidopsis thaliana (AtESP and AtNSP3). We also present a homology model of AtNSP3. In agreement with this model, iron binding and activity of AtNSP3 depend on E386, D390, and H394. The homology model further suggests that the active site of AtNSP3 imposes fewer restrictions to the glucosinolate aglucone conformation than that of TaTFP and AtESP due to its larger size. This may explain why AtNSP3 does not support epithionitrile or thiocyanate formation, which likely requires exact positioning of the aglucone thiolate relative to the side chain. PMID- 30395613 TI - Psychosocial factors as predictors of dropout in ultra-trailers. AB - OBJECTIVE: Although research on the physiological and psychological factors of endurance performance has been extensive, the factors related to dropping out of ultra-trail races have not been well documented. The aim of this study was to examine psychosocial factors as predictors of dropout in ultra-trail runners. METHODS: Two hundred and twenty-one volunteer athletes completed a survey that included measures of: (a) motivational variables (self-determined motivation, basic needs satisfaction, achievement goals), (b) theory of planned behavior constructs (attitudes, subjective norms, self-efficacy and intention to finish the race), and (c) coping strategies in sport. RESULTS: The results showed that finishers had higher scores for self-efficacy and intention to finish the race than withdrawers, whereas withdrawers had higher scores for avoidance coping. Multiple logistic regression showed that the number of started and finished ultra trail races (OR, 0.44; 95% CI 0.22-0.88; p<0.02), self-efficacy (OR, 2.03; 95% CI 1.06-3.89; p<0.04), intention to finish the race (OR, 0.34; 95% CI 0.16-0.71; p<0.004), mastery-approach goals (OR, 0.56; 95% CI 0.31-1.00; p<0.05), and coping strategies of seeking social support (OR, 0.43; 95% CI 0.26-0.71; p<0.001) were associated with a lower risk of race dropout, whereas avoidance coping strategies (OR, 2.26; 95% CI 1.46-3.52; p<0.001) were associated with an increased dropout rate. CONCLUSION: Interventions promoting self-efficacy constructs and specific coping strategies might contribute to preventing dropout in ultra-trailers. PMID- 30395614 TI - Supraglottic airway devices as a strategy for unassisted tracheal intubation: A network meta-analysis. AB - We aimed to compare the effectiveness of supraglottic airway devices as a strategy for unassisted tracheal intubation. Accordingly, we searched the OVID MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, KoreaMed, and Google Scholar databases to identify all relevant randomized controlled trials (RCTs) on supraglottic airway devices as a strategy for tracheal intubation published until May 2017. The primary outcome was the overall success rate of intubation by the intention to treat (ITT) strategy. The secondary outcomes of the study were the overall success rate of tracheal intubation by the per protocol (PP) strategy and the success rate of tracheal intubation at first attempt by ITT and PP. We conducted a network meta-analysis with a mixed treatment comparison method to combine direct and indirect comparisons among supraglottic airway devices. Of 1396 identified references, 16 RCTs (2014 patients) evaluated unassisted intubation with supraglottic airway devices. Patients were grouped according to the type of device used: LMA-CTrach, LMA Fastrach, Air-Q, i-gel, CobraPLA, Ambu-Aura, or single-use LMA devices. Based on the surface under the cumulative ranking curve, the three best supraglottic airway devices for use as a strategy for unassisted tracheal intubation were LMA CTrach (which included video-assisted tracheal tube guidance), single-use LMA Fastrach, and LMA-Fastrach. LMA-Fastrach showed a higher success rate of intubation than did i-gel, CobraPLA, Air-Q, and Ambu-Aura. However, this study was limited by the small number of eligible RCTs. Therefore, well-designed RCTs performed on large patient populations are required to increase the confidence of the results. PMID- 30395615 TI - Prevalence of Plasmodium parasitaemia in blood donors and a survey of the knowledge, attitude and practices of transfusion malaria among health workers in a hospital in Kumasi, Ghana. AB - Malaria is one of the transfusion transmissible infections in malaria endemic countries such as Ghana. Healthy blood donors may harbour Plasmodium parasites without showing signs of malaria. Blood from such donors constitutes a risk to transfusion recipients and the recipients of this blood may go on to develop transfusion transmitted malaria (TTM). In many malaria endemic countries, blood donors are not screened for Plasmodium parasites. We investigated the prevalence of Plasmodium in blood donors in a hospital in Ghana as well as evaluate health workers knowledge, attitude and practices towards TTM. The study was carried out at the Kwadaso Seventh Day Adventist Hospital in Kumasi, Ghana from September 2016 to May 2017. Blood samples from 100 blood donors and 100 non-donors were examined for Plasmodium using microscopy and a rapid diagnostic test (RDT). In addition the blood groups of participants were determined. To obtain information concerning knowledge, attitude and practices of transfusion transmitted malaria, questionnaires were administered to 100 health workers including doctors, nurses and laboratory technicians. The prevalence rate of Plasmodium parasitaemia in blood donors by RDT and microscopy was 8% and 3% respectively, compared to non donors who had a prevalence of 5% and 2% by RDT and microscopy respectively. Out of 100 health workers surveyed, 26% (26/100) had never heard of transfusion transmitted malaria. In an emergency situation, 41% health workers were willing to transfuse malaria positive blood but only 2%, 4% and 8% were willing to transfuse blood that was positive for HIV, Hepatitis B and Syphilis respectively. Regular training workshops may help improve the knowledge of health workers as a quarter of workers had not heard about transfusion transmitted malaria and 6.8% did not know that malaria was transmissible by transfusion. PMID- 30395616 TI - Development of a new 7BS.7HL winter wheat-winter barley Robertsonian translocation line conferring increased salt tolerance and (1,3;1,4)-beta-D glucan content. AB - Interspecific hybridization between bread wheat (Triticum aestivum, 2n = 42) and related species allows the transfer of agronomic and quality traits, whereby subsequent generations comprise an improved genetic background and can be directly applied in wheat breeding programmes. While wild relatives are frequently used as sources of agronomically favourable traits, cultivated species can also improve wheat quality and stress resistance. A salt-tolerant 'Asakaze'/'Manas' 7H disomic addition line (2n = 44) with elevated beta-glucan content, but with low fertility and an unstable genetic background was developed in an earlier wheat-barley prebreeding programme. The aim of the present study was to take this hybridization programme further and transfer the favourable barley traits into a more stable genetic background. Taking advantage of the breakage-fusion mechanism of univalent chromosomes, the 'Rannaya' winter wheat 7B monosomic line was used as female partner to the 7H addition line male, leading to the development of a compensating wheat/barley Robertsonian translocation line (7BS.7HL centric fusion, 2n = 42) exhibiting higher salt tolerance and elevated grain beta-glucan content. Throughout the crossing programme, comprising the F1 F4 generations, genomic in situ hybridization, fluorescence in situ hybridization and chromosome-specific molecular markers were used to trace and identify the wheat and barley chromatin. Investigations on salt tolerance during germination and on the (1,3;1,4)-beta-D-glucan (mixed-linkage glucan [MLG]) content of the seeds confirmed the salt tolerance and elevated grain MLG content of the translocation line, which can be directly applied in current wheat breeding programmes. PMID- 30395617 TI - Urban-rural differences in immunisation status and associated demographic factors among children 12-59 months in a southwestern state, Nigeria. AB - Vaccine preventable diseases (VPDs) are a leading course of child under-five mortality in sub-Saharan Africa. A target of 95% immunization coverage is necessary for the sustained control of VPDs. This study aims to determine the immunization status and its associated demo-graphic factors among children 12-59 months old in Akinyele Local Government area (LGA), Oyo State, Nigeria. A community-based cross-sectional study was carried out in one urban and one rural ward of Akinyele LGA. Fourhundred and forty-four (449) Under-five children were selected by multistage sampling technique. Data were collected from caregivers using interviewer administered questionnaires. Odds ratios at 95% CIand Chi square at 5% significant level were computed to identify the factors associated with non or partial immunisation. Multiple logistics regression at 5% significance level was done to determine the socio-demographic determinants of immunisation status. Overall, 449 children aged 12-59 months were surveyed of which 213(47.4%) were males and 236(52.6%) were from urban area. Overall, 365(81.3%) was fully immunized, 75(16.7%) was partially immunized and 9(2.0%) had never been immunized. Predictors of a child being partially or un-immunised were being in the fourth wealth quintile (AOR 7.9; 95%CI: 2.7-18.0), poorest wealth quintile (AOR 14.5; 95%CI 4.2-20.5), having a mother with no education (AOR 6.4; 95%CI: 2.9-14.1) and a mother that practiced Islam (AOR: 2.2; 95%CI: 1.3-3.7). Immunisation coverage was somewhat high but still suboptimal among the study population. Strategies that improve female literacy and those that target religious institutions may be effective in improving immunisation uptake. PMID- 30395618 TI - Coupling spatial analysis and economic valuation of ecosystem services to inform the management of an UNESCO World Biosphere Reserve. PMID- 30395620 TI - A framework to investigate the impact of topography and product characteristics on electronic cigarette emissions. AB - SIGNIFICANCE: Protocols for testing and reporting emissions of Harmful and Potentially Harmful Constituents (HPHCs) from electronic cigarettes (e-cigs) are lacking. The premise of this study is that multi-path relationships may be developed to describe interactions between product characteristics, use behavior and emissions to develop appropriate protocols for tobacco product regulatory compliance testing. METHODS: This study proposes a framework consisting of three component terms: HPHC mass concentration, HPHC mass ratio and total particulate mass (TPM) concentration. The framework informs experiments to investigate dependence of aerosol emissions from five electronic cigarettes spanning several design generations and three e-liquids for six repeated trials at each of ten flow conditions. RESULTS: Results are reported for TPM concentration as a function of flow conditions spanning the range of natural environment topography observed in prior studies. An empirical correlation describing TPM concentration as a function of flow conditions and coil power setting (6, 7.5 and 10 watts) for the Innokin iTaste MVP 2.0 vaporizer with Innokin iClear 30 dual coil tank is presented. Additional results document the impact of flow conditions and wick and coil design on TPM concentration through comparison of the Innokin iClear 30 (upper coil, capillary action wick) and the Innokin iClear X.I (lower coil, gravity fed wick) operated at 7.5 watts. The impact of e-liquid on TPM concentration is illustrated by comparing emissions from an NJOY Vape Pen filled with AVAIL Arctic Blast, Tobacco Row, and Mardi Gras e-liquids. TPM concentration is shown to depend upon flow conditions across a range of e-cigarette product designs including cig-a-like, pen-style, box-mod and emergent disposable cartridge style devices. CONCLUSIONS: A framework provides a foundation for reporting emissions across a variety of e-cigs, e-liquids and research laboratories. The study demonstrates TPM concentration is a function of topography behavior (i.e. puff flow rate and puff duration) for varying device operating power and product characteristics. PMID- 30395619 TI - Transforming Growth Factor-beta1 in predicting early lung fibroproliferation in patients with acute respiratory distress syndrome. AB - BACKGROUND: Fibroproliferative repair phase of the acute respiratory distress syndrome (ARDS) is followed by a restitutio ad integrum of lung parenchyma or by an irreversible lung fibrosis and patients' death. Transforming Growth Factor beta1 (TGF-beta1) is involved in collagen production and lung repair. We investigated whether alveolar TGF-beta1 was associated with the presence of fibroproliferation and the outcome of ARDS patients. METHODS: Sixty-two patients were included the first day of moderate-to-severe ARDS. Bronchoalveolar lavage fluid (BALF) was collected at day 3 (and day 7 when the patients were still receiving invasive mechanical ventilation) from the onset of ARDS. Survival was evaluated at day 60. TGF-beta1 was measured by immunoassay. The patients were classified as having lung fibroproliferation when the alveolar N-terminal peptide for type III procollagen (NT-PCP-III) measured on day 3 was > 9 MUg/L as recently reported. The main objective of this study was to compare the alveolar levels of total TGF-beta1 according to the presence or not a lung fibroproliferation at day 3. RESULTS: Forty-three patients (30.6%) presented a fibroproliferation at day 3. BALF levels of total TGF-beta1 were not statistically different at day 3 (and at day 7) according to the presence or not lung fibroproliferation. Mortality at day 60 was higher in the group of patients with fibroproliferation as compared with patients with no fibroproliferation (68.4% vs. 18.6% respectively; p < 0.001). Total TGF-beta1 measured on BALF at day 3 was not associated with the outcome. Multiple logistic regression showed that the presence of lung fibroproliferation was associated with death. In contrast, TGF-beta1 was not independently associated with death. CONCLUSIONS: Pulmonary levels of TGF-beta1 during the first week of ARDS were not associated nor with the presence of fibroproliferation neither with death. TGF-beta1 should not be used as a biomarker to direct anti-fibrotic therapies. PMID- 30395622 TI - Summering on the bank: Seasonal distribution and abundance of monkfish on Georges Bank. AB - The American monkfish is an important commercial species that is widely distributed across a range of depths and temperatures from North Carolina to southern Nova Scotia, including on Georges Bank. We examined changes in the seasonal distribution and relative abundance of monkfish in the scallop access areas in Closed Area I and Closed Area II on Georges Bank using catch data from a three-year seasonal scallop dredge survey. Over the course of the survey, more than 6,000 monkfish were caught and measured, and clear seasonal changes in monkfish abundance were documented. Monkfish catch peaked in the summer and early fall when they were caught across the entire survey area, while they were caught only in deeper waters at the edges of the bank in the winter. Monkfish relative abundance was modeled using a generalized linear mixed model with a Tweedie distribution, and the final model, with month, depth, and bottom temperature as fixed effects, effectively explained the seasonal shifts in the location and relative abundance of monkfish observed during this study. The results suggest that monkfish movements are driven by seasonal changes in bottom temperature. Management measures for monkfish are determined primarily based on data collected during the Northeast Fisheries Science Center bottom trawl surveys, yet this survey catches few monkfish, adding uncertainty to stock assessments. Our research indicates that increasing the use of dredge surveys to collect data on monkfish would be a positive step toward improving monkfish assessments. If monkfish movements are impacted by changes in thermal habitat, their distributions may shift in response to climate change, increasing the need for improved monkfish assessment strategies to effectively manage the species in the future. PMID- 30395621 TI - Mutant myocilin impacts sarcomere ultrastructure in mouse gastrocnemius muscle. AB - Myocilin (MYOC) is the gene with mutations most common in glaucoma. In the eye, MYOC is in trabecular meshwork, ciliary body, and retina. Other tissues with high MYOC transcript levels are skeletal muscle and heart. To date, the function of wild-type MYOC remains unknown and how mutant MYOC causes high intraocular pressure and glaucoma is ambiguous. By investigating mutant MYOC in a non-ocular tissue we hoped to obtain novel insight into mutant MYOC pathology. For this study, we utilized a transgenic mouse expressing human mutant MYOC Y437H protein and we examined its skeletal (gastrocnemius) muscle phenotype. Electron micrographs showed that sarcomeres in the skeletal muscle of mutant CMV-MYOC Y437H mice had multiple M-bands. Western blots of soluble muscle lysates from transgenics indicated a decrease in two M-band proteins, myomesin 1 (MYOM1) and muscle creatine kinase (CKM). Immunoprecipitation identified CKM as a MYOC binding partner. Our results suggest that binding of mutant MYOC to CKM is changing sarcomere ultrastructure and this may adversely impact muscle function. We speculate that a person carrying the mutant MYOC mutation will likely have a glaucoma phenotype and may also have undiagnosed muscle ailments or vice versa, both of which will have to be monitored and treated. PMID- 30395624 TI - Improved linear classifier model with Nystrom. AB - Most data sets consist of interlaced-distributed samples from multiple classes and since these samples always cannot be classified correctly by a linear hyperplane, so we name them nonlinearly separable data sets and corresponding classifiers are named nonlinear classifiers. Traditional nonlinear classifiers adopt kernel functions to generate kernel matrices and then get optimal classifier parameters with the solution of these matrices. But computing and storing kernel matrices brings high computational and space complexities. Since INMKMHKS adopts Nystrom approximation technique and NysCK changes nonlinearly separable data to linearly ones so as to reduce the complexities, we combines ideas of them to develop an improved NysCK (INysCK). Moreover, we extend INysCK into multi-view applications and propose multi-view INysCK (MINysCK). Related experiments validate the effectiveness of them in terms of accuracy, convergence, Rademacher complexity, etc. PMID- 30395623 TI - Proposed method of histological separation between connective tissue disease associated interstitial pneumonia and idiopathic interstitial pneumonias. AB - OBJECTIVES: Idiopathic interstitial pneumonia (IIP) and connective tissue disease -associated interstitial pneumonia (CTD-IP) are the two most common types of interstitial pneumonia. IIP and CTD-IP share common histological features, yet their clinical management is different. Separation of the two conditions based solely on histology can be challenging, and there are no established criteria. MATERIALS AND METHODS: We selected 105 consecutive cases of IIP (79 usual interstitial pneumonia and 26 non-specific interstitial pneumonia) and 49 cases of CTD-IP for derivation and 32 cases of IIP and 10 cases of CTD-IP for validation. Fourteen histological parameters were evaluated independently by two pathologists for derivation group and graded into 0 to 3. The association between the score for each marker and a diagnosis of CTD was investigated using Fisher's exact test and stepwise logistic regression analysis. A formula for calculating the probability of IIP and CTD-IP was constructed by the markers identified in the regression test with coefficients for each finding. The formula was confirmed using validation case group. RESULTS: Stepwise logistic regression analysis showed that plasmacytosis, lymphoid follicle with germinal center, and airspace fibrin were suggestive of CTD-IP and that fibroblastic foci, smooth muscle hyperplasia, cellular IP, dense perivascular collagen, and fat metaplasia were suggestive of IIP. The formula used to calculate the probabilities based on estimated values for each finding was created, and user-friendly web based app was composed at www.ctdip.com. On the validation study, 30 out of 32 IIP and eight out of 10 CTD-IPs were distinguished correctly by the app (Specificity: 93%, Sensitivity: 80%). CONCLUSIONS: We identified histological markers and derived a practical formula and user-friendly app to distinguish CTD-IPs from IIP. PMID- 30395625 TI - What conditions enable decentralization to improve the health system? Qualitative analysis of perspectives on decision space after 25 years of devolution in the Philippines. AB - BACKGROUND: Decentralization is promoted as a strategy to improve health system performance by bringing decision-making closer to service delivery. Some studies have investigated if decentralization actually improves the health system. However, few have explored the conditions that enable it to be effective. To determine these conditions, we have analyzed the perspectives of decision-makers in the Philippines where devolution, one form of decentralization, was introduced 25 years ago. METHODS: Drawing from the "decision space" approach, we interviewed 27 decision-makers with an average of 23.6 years of working across different levels of the Philippine government health sector and representing various local settings. Qualitative analysis followed the "Framework Method." Conditions that either enable or hinder the effectiveness of decentralization were identified by exploring decision-making in five health sector functions. RESULTS: These conditions include: for planning, having a multi-stakeholder approach and monitoring implementation; for financing and budget allocation, capacities to raise revenues at local levels and pooling of funds at central level; for resource management, having a central level capable of augmenting resource needs at local levels and a good working relationship between the local health officer and the elected local official; for program implementation and service delivery, promoting innovation at local levels while maintaining fidelity to national objectives; and for monitoring and data management, a central level capable of ensuring that data collection from local levels is performed in a timely and accurate manner. CONCLUSIONS: The Philippine experience suggests that decentralization is a long and complex journey and not an automatic solution for enhancing service delivery. The role of the central decision-maker (e.g. Ministry of Health) remains important to assist local levels unable to perform their functions well. It is policy-relevant to analyze the conditions that make decentralization work and the optimal combination of decentralized and centralized functions that enhance the health system. PMID- 30395626 TI - Choice modelling with Gaussian processes in the social sciences: A case study of neighbourhood choice in Stockholm. AB - We present a non-parametric extension of the conditional logit model, using Gaussian process priors. The conditional logit model is used in quantitative social science for inferring interaction effects between personal features and choice characteristics from observations of individual multinomial decisions, such as where to live, which car to buy or which school to choose. The classic, parametric model presupposes a latent utility function that is a linear combination of choice characteristics and their interactions with personal features. This imposes strong and unrealistic constraints on the form of individuals' preferences. Extensions using non-linear basis functions derived from the original features can ameliorate this problem but at the cost of high model complexity and increased reliance on the user in model specification. In this paper we develop a non-parametric conditional logit model based on Gaussian process logit models. We demonstrate its application on housing choice data from over 50,000 moving households from the Stockholm area over a two year period to reveal complex homophilic patterns in income, ethnicity and parental status. PMID- 30395627 TI - Circulating miRNA measurements are reflective of cholesterol-based changes in rainbow trout (Oncorhynchus mykiss). AB - MicroRNAs (miRNAs) are a class of small non-coding RNAs which are known to posttranscriptionally regulate the expression of most genes in both animals and plants. Meanwhile, studies have shown that numbers of miRNAs are present in body fluids including the plasma. Despite the mode of action of these circulating miRNAs still remains unknown, they have been found to be promising biomarkers for disease diagnosis, prognosis and response to treatment. In order to evaluate the potential of miRNAs as non-invasive biomarkers in aquaculture, a time-course experiment was implemented to investigate the postprandial regulation of miRNAs levels in liver and plasma as well as the hepatic expression of genes involved in cholesterol metabolism. We showed that miR-1, miR-33a, miR-122, miR-128 and miR 223 were expressed in the liver of rainbow trout and present at detectable level in the plasma. We also demonstrated that hepatic expression of miR-1, miR-122 and miR-128 were regulated by feed intake and reached their highest levels 12 hours after the meal. Interestingly, we observed that circulating levels of miR-128 and miR-223 are subjected to postprandial regulations similar to that observed in their hepatic counterparts. Statistical correlations were observed between liver and plasma for miR-128 and miR-223 and between hepatic and circulating miR-122, miR-128 and miR-223 and expression of genes related to cholesterol synthesis and efflux or glucose phosphorylation. These results demonstrated that circulating miR-122, miR-128 and miR-223 are potential biomarkers of cholesterol metabolism in rainbow trout. PMID- 30395628 TI - Burkholderia pseudomallei distribution in Australasia is linked to paleogeographic and anthropogenic history. AB - Burkholderia pseudomallei is the environmental bacillus that causes melioidosis; a disease clinically significant in Australia and Southeast Asia but emerging in tropical and sub-tropical regions around the globe. Previous studies have placed the ancestral population of the organism in Australia with a single lineage disseminated to Southeast Asia. We have previously characterized B. pseudomallei isolates from New Guinea and the Torres Strait archipelago; remote regions that share paleogeographic ties with Australia. These studies identified regional biogeographical boundaries. In this study, we utilize whole-genome sequencing to reconstruct ancient evolutionary relationships and ascertain correlations between paleogeography and present-day distribution of this bacterium in Australasia. Our results indicate that B. pseudomallei from New Guinea fall into a single clade within the Australian population. Furthermore, clades from New Guinea are region specific; an observation possibly linked to limited recent anthropogenic influence in comparison to mainland Australia and Southeast Asia. Isolates from the Torres Strait archipelago were distinct yet scattered among those from mainland Australia. These results provide evidence that the New Guinean and Torres Strait lineages may be remnants of an ancient portion of the Australian population. Rising sea levels isolated New Guinea and the Torres Strait Islands from each other and the Australian mainland, and may have allowed long-term isolated evolution of these lineages, providing support for a theory of microbial biogeography congruent with that of macro flora and fauna. Moreover, these findings indicate that contemporary microbial biogeography theories should consider recent and ongoing impacts of globalisation and human activity. PMID- 30395630 TI - Seeding strategies for new product launch: The role of negative word-of-mouth. AB - When launching a new product, firms often give away free samples to seed the market. This paper aims to identify the optimal seeding targets, such as early adopters, social hubs, or randomly chosen consumers while considering the presence of negative word-of-mouth (WOM). Using agent-based modeling, it was found that seeding early adopters can generate the highest profit and the largest market penetration, followed by the social hubs and random consumers. Moreover, the results show that seeding early adopters can be more beneficial for a low quality product, wherein adopters are more likely to spread negative WOM. These findings challenge a widely accepted notion in the related research that social hubs are often the most promising targets for seeding programs. PMID- 30395629 TI - Characterization of a B16-F10 melanoma model locally implanted into the ear pinnae of C57BL/6 mice. AB - The common experimental use of B16-F10 melanoma cells focuses on exploring their metastatic potential following intravenous injection into mice. In this study, B16-F10 cells are used to develop a primary tumor model by implanting them directly into the ears of C57BL/6J mice. The model represents a reproducible and easily traceable tool for local tumor growth and for making additional in vivo observations, due to the localization of the tumors. This model is relatively simple and involves (i) surgical opening of the ear skin, (ii) removal of a square-piece of cartilage followed by (iii) the implantation of tumor cells with fibrin gel. The remodeling of the fibrin gel within the cartilage chamber, accompanying tumor proliferation, results in the formation of blood vessels, lymphatics and tissue matrix that can be readily distinguished from the pre existing skin structures. Moreover, this method avoids the injection-enforced artificial spread of cells into the pre-existing lymphatic vessels. The tumors have a highly reproducible exponential growth pattern with a tumor doubling time of around 1.8 days, reaching an average volume of 85mm3 16 days after implantation. The melanomas are densely cellular with proliferative indices of between 60 and 80%. The induced angiogenesis and lymphangiogenesis resulted in the development of well-vascularized tumors. Different populations of immunologically active cells were also present in the tumor; the population of macrophages decreases with time while the population of T cells remained quasi constant. The B16-F10 tumors in the ear frequently metastasized to the cervical lymph nodes, reaching an incidence of 75% by day 16. This newly introduced B16 F10 melanoma model in the ear is a powerful tool that provides a new opportunity to study the local tumor growth and metastasis, the associated angiogenesis, lymphangiogenesis and tumor immune responses. It could potentially be used to test different treatment strategies. PMID- 30395631 TI - An integrated analysis of mRNA and sRNA transcriptional profiles in tomato root: Insights on tomato wilt disease. AB - Tomato wilt disease caused by Fusarium oxysporum f. sp. lycopersici (FOL) is a worldwide destructive disease of tomato. As exploring gene expression and function approaches constitute an initial point for investigating pathogen-host interaction, we performed RNA-seq and sRNA-seq analysis to investigate the transcriptome of tomato root under FOL infection. Differentially expressed (DE) protein-coding gene and miRNA gene profiles upon inoculation with FOL were presented at twenty-four hours post-inoculation in four treatments. A total of more than 182.6 million and 132.2 million high quality clean reads were obtained by RNA-seq and sRNA-seq, respectively. A large overlap was found in DE mRNAs between susceptible cultivar Moneymaker and resistant cultivar Motelle. Gene Ontology terms were mainly classified into catalytic activity, metabolic process and binding. Combining with qRT-PCR and Northern blot, we validated the transcriptional profile of five genes and five miRNAs conferred to FOL infection. Our work allowed comprehensive understanding of different transcriptional reaction of genes/miRNAs between the susceptible and resistant cultivars tomato to the FOL challenge, which could offer us with a future direction to generate models of mediated resistance responses. PMID- 30395632 TI - Towards non-invasive characterisation of coronary stent re-endothelialisation - An in-vitro, electrical impedance study. AB - The permanent implantation of a stent has become the most common method for ameliorating coronary artery narrowing arising from atherosclerosis. Following the procedure, optimal arterial wall healing is characterised by the complete regrowth of an Endothelial Cell monolayer over the exposed stent surface and surrounding tissue, thereby reducing the risk of thrombosis. However, excessive proliferation of Smooth Muscle Cells, within the artery wall can lead to unwanted renarrowing of the vessel lumen. Current imaging techniques are unable to adequately identify re-endothelialisation, and it has previously been reported that the stent itself could be used as an electrode in combination with electrical impedance spectroscopic techniques to monitor the post-stenting recovery phase. The utility of such a device will be determined by its ability to characterise between vascular cell types. Here we present in-vitro impedance spectroscopy measurements of pulmonary artery porcine Endothelial Cells, Human Umbilical Vein Endothelial Cells and coronary artery porcine Smooth Muscle Cells grown to confluence over platinum black electrodes in clinically relevant populations. These measurements were obtained, using a bespoke impedance spectroscopy system that autonomously performed impedance sweeps in the 1kHz to 100kHz frequency range. Analysis of the reactance component of impedance revealed distinct frequency dependent profiles for each cell type with post confluence reactance declines in Endothelial Cell populations that have not been previously reported. Such profiles provide a means of non-invasively characterising between the cell types and give an indication that impedance spectroscopic techniques may enable the non-invasive characterisation of the arterial response to stent placement. PMID- 30395634 TI - Polymorphisms in enterovirus 71 receptors associated with susceptibility and clinical severity. AB - OBJECTIVE: To evaluate the association of enterovirus 71 (EV71) susceptibility and clinical severity with polymorphisms in EV71 receptors, including human scavenger receptor class B member 2 (SCARB2), P-selectin glycoprotein ligand-1 (PSGL-1), and annexin II (ANXA2). METHODS: We enrolled laboratory-confirmed EV71 cases and healthy age- and gender-matched controls in Taiwan from 2000 to 2012. We detected genetic polymorphisms in SCARB2, PSGL-1, and ANXA2 and correlated the results with EV71 susceptibility and severity. RESULTS: We collected 599 EV71 cases and 98 controls. Among EV71 patients, the male to female ratio was 1.61, and the mean age was 2.99+/-2.47 years. For clinical severity, 117 (19.6%) had severe central nervous system involvement with or without cardiopulmonary failure. For outcomes, 46 (7.7%) had sequelae, and 14 (2.3%) died. SCARB2 polymorphisms (rs6824953 and rs11097262) were associated with susceptibility to EV71 infection (OR 1.60, 95% CI 1.07-2.39; and OR 1.64, 95% CI 1.09-2.47, respectively). PSGL-1 polymorphisms (rs7137098 and rs8179137) were significantly associated with severe EV71 infection (OR 1.46, 95% CI 1.1-1.96; and OR 1.47, 95% CI 1.07-2.03, respectively). CONCLUSIONS: SCARB2 polymorphisms (rs6824953 and rs11097262) might be associated with EV71 susceptibility. PSGL-1 polymorphisms (rs7137098 and rs8179137) were associated with severe EV71 infection. PMID- 30395633 TI - Past vicariance promoting deep genetic divergence in an endemic frog species of the Espinhaco Range in Brazil: The historical biogeography of Bokermannohyla saxicola (Hylidae). AB - The highland endemic frog Bokermannohyla saxicola occurs within the Espinhaco Range, the most extensive and continuous orogenic belt of the Brazilian territory, located in southeastern Brazil. We used mitochondrial DNA markers to test for spatial structure, to investigate the likely influence of past vicariant events, to evaluate demographic dynamics along the species range, and to understand the role of habitat discontinuities in promoting connectivity and diversity along the range. We found four major monophyletic lineages, each one associated with distinct mountain tops. The divergence time found between the four main clades clearly pre-dated the Pleistocene, except for the most recent separation. We observed no signs of population expansion for most of the sampling sites along the range, and a higher genetic diversity in the most continuous and central highland plateau, compared to smaller marginal regions. The Espinhaco Range harbors four deeply divergent lineages of B. saxicola within areas restricted by barriers for millions of years. These relatively isolated populations were kept apart by discontinuities represented by lowland habitats between mountain tops. Most of the lineage divergences occurred earlier than the Pleistocene, thus they cannot be solely explained by climatic oscillations of this epoch. However, within-lineage divergence times were all dated from the Pleistocene, suggesting an important effect in population dynamics. We also suggest that some marginal populations like those from Serra Negra and Serra de Itacambira can be the result of recent colonization events. Finally, in the southern Espinhaco region, the most continuous central highland area shows greater genetic diversity than the marginal discontinuous areas, where we have also observed a significant correlation between genetic and geographic distances. Bokermannohyla saxicola is a good model to study the biogeography of the Espinhaco Range because its high genetic structure reflects ancient as well as recent geological/climatic events, with important implications for conservation. PMID- 30395635 TI - Economic and epidemiologic impact of guidelines for early ART initiation irrespective of CD4 count in Spain. AB - INTRODUCTION: Emerging data suggest that early antiretroviral therapy (ART) could reduce serious AIDS and non-AIDS events and deaths but could also increase costs. In January 2016, the Spanish guidelines were updated to recommend ART at any CD4 count. However, the epidemiologic and economic impacts of early ART initiation in Spain remain unclear. METHODS: The Johns Hopkins HIV Economic-Epidemiologic Mathematical Model (JHEEM) was utilized to estimate costs, transmissions, and outcomes in Spain over 20 years. We compared implementation of guidelines for early ART initiation to a counterfactual scenario deferring ART until CD4-counts fall below 350 cells/mm3. We additionally studied the impact of early ART initiation in combination with improvements to HIV screening, care linkage and engagement. RESULTS: Early ART initiation (irrespective of CD4-count) is expected to avert 20,100 [95% Uncertainty Range (UR) 11,100-83,000] new HIV cases over the next two decades compared to delayed ART (28% reduction), at an incremental health system cost of ?1.05 billion [?0.66 - ?1.63] billion, and an incremental cost-effectiveness ratio (ICER) of ?29,700 [?13,700 - ?41,200] per QALY gained. Projected ICERs declined further over longer time horizon; e.g., an ICER of ?12,691 over 30 years. Furthermore, the impact of early ART initiation was potentiated by improved HIV screening among high-risk individuals, averting an estimated 41,600 [23,200-172,200] HIV infections (a 58% decline) compared to delayed ART. CONCLUSIONS: Recommendations for ART initiation irrespective of CD4 counts are cost-effective and could avert > 30% of new cases in Spain. Improving HIV diagnosis can amplify this impact. PMID- 30395636 TI - Basal autophagy is required for promoting dendritic terminal branching in Drosophila sensory neurons. AB - Dendrites function as the primary sites for synaptic input and integration with impairments in dendritic arborization being associated with dysfunctional neuronal circuitry. Post-mitotic neurons require high levels of basal autophagy to clear cytotoxic materials and autophagic dysfunction under native or cellular stress conditions has been linked to neuronal cell death as well as axo-dendritic degeneration. However, relatively little is known regarding the developmental role of basal autophagy in directing aspects of dendritic arborization or the mechanisms by which the autophagic machinery may be transcriptionally regulated to promote dendritic diversification. We demonstrate that autophagy-related (Atg) genes are positively regulated by the homeodomain transcription factor Cut, and that basal autophagy functions as a downstream effector pathway for Cut-mediated dendritic terminal branching in Drosophila multidendritic (md) sensory neurons. Further, loss of function analyses implicate Atg genes in promoting cell type specific dendritic arborization and terminal branching, while gain of function studies suggest that excessive autophagy leads to dramatic reductions in dendritic complexity. We demonstrate that the Atg1 initiator kinase interacts with the dual leucine zipper kinase (DLK) pathway by negatively regulating the E3 ubiquitin ligase Highwire and positively regulating the MAPKKK Wallenda. Finally, autophagic induction partially rescues dendritic atrophy defects observed in a model of polyglutamine toxicity. Collectively, these studies implicate transcriptional control of basal autophagy in directing dendritic terminal branching and demonstrate the importance of homeostatic control of autophagic levels for dendritic arbor complexity under native or cellular stress conditions. PMID- 30395638 TI - The imprint of microfibres in southern European deep seas. AB - Pollution of the marine environment by large and microscopic plastic fragments and their potential impacts on organisms has stimulated considerable research interest and has received widespread publicity. However, relatively little attention has been paid to the fate and effects of microplastic particles that are fibrous in shape, also referred as microfibres, which are mostly shed from synthetic textiles during production or washing. Here we assess composition and abundance of microfibres in seafloor sediments in southern European seas, filling gaps in the limited understanding of the long-range transport and magnitude of this type of microplastic pollution. We report abundances of 10-70 microfibres in 50 ml of sediment, including both natural and regenerated cellulose, and synthetic plastic (polyester, acrylic, polyamide, polyethylene, and polypropylene) fibres. Following a shelf-slope-deep basin continuum approach, based on the relative abundance of fibres it would appear that coastal seas retain around 33% of the sea floor microfibres, but greater quantities of the fibres are exported to the open sea, where they accumulate in sediments. Submarine canyons act as preferential conduits for downslope transport of microfibres, with 29% of the seafloor microfibres compared to 18% found on the open slope. Around 20% of the microfibres found had accumulated in the deep open sea beyond 2000m of water depth. The remoteness of the deep sea does not prevent the accumulation of microfibres, being available to become integrated into deep sea organisms. PMID- 30395637 TI - HIV-1 envelope glycan modifications that permit neutralization by germline reverted VRC01-class broadly neutralizing antibodies. AB - Broadly neutralizing antibody (bnAb) induction is a high priority for effective HIV-1 vaccination. VRC01-class bnAbs that target the CD4 binding site (CD4bs) of trimeric HIV-1 envelope (Env) glycoprotein spikes are particularly attractive to elicit because of their extraordinary breadth and potency of neutralization in vitro and their ability to protect against infection in animal models. Glycans bordering the CD4bs impede the binding of germline-reverted forms of VRC01-class bnAbs and therefore constitute a barrier to early events in initiating the correct antibody lineages. Deleting a subset of these glycans permits Env antigen binding but not virus neutralization, suggesting that additional barriers impede germline-reverted VRC01-class antibody binding to functional Env trimers. We investigated the requirements for functional Env trimer engagement of VRC01-class naive B cell receptors by using virus neutralization and germline-reverted antibodies as surrogates for the interaction. Targeted deletion of a subset of N glycans bordering the CD4bs, combined with Man5 enrichment of remaining N-linked glycans that are otherwise processed into larger complex-type glycans, rendered HIV-1 426c Env-pseudotyped virus (subtype C, transmitted/founder) highly susceptible to neutralization by near germline forms of VRC01-class bnAbs. Neither glycan modification alone rendered the virus susceptible to neutralization. The potency of neutralization in some cases rivaled the potency of mature VRC01 against wildtype viruses. Neutralization by the germline-reverted antibodies was abrogated by the known VRC01 resistance mutation, D279K. These findings improve our understanding of the restrictions imposed by glycans in eliciting VRC01-class bnAbs and enable a neutralization-based strategy to monitor vaccine-elicited early precursors of this class of bnAbs. PMID- 30395639 TI - Osteoporosis and dry eye syndrome: A previously unappreciated association that may alert active prevention of fall. AB - OBJECTIVE: Osteoporosis is a multifactorial disease associated with inflammation and hormone imbalance. It is noteworthy that dry eye syndrome shares a similar pathophysiology with osteoporosis. Both diseases are more prevalent among the elderly and females. Dry eye syndrome can result in impaired vision, which increases the risk of fall and fracture when osteoporosis exists. In this study, we investigated whether osteoporosis is associated with an increased risk of developing dry eye syndrome. METHODS: Claims data from the National Health Insurance Research Database (NHIRD) of Taiwan were used to conduct a retrospective population-based cohort study covering the period from January 1, 2000, to December 31, 2011. Multiple logistic regression was used to determine whether osteoporosis is an independent factor in the risk of developing dry eye syndrome, with risk estimates presented in the form of odds ratios (ORs). RESULTS: The exclusion of patients with specific autoimmune diseases and those younger than 50 years old resulted in 42,365 patients in the osteoporosis group and 147,460 patients in the comparison group during the study period. The number of patients newly diagnosed with dry eye syndrome was 6,478 (15.29%) in the osteoporosis group and 15,396 (10.44%) in the comparison group. The crude OR of patients with osteoporosis developing dry eye syndrome was 1.55 and the 95% confidence interval (95% CI) was 1.50-1.60. After adjusting for patients' age, sex, and underlying comorbidities, the adjusted OR was 1.26 and the 95% CI was 1.22-1.30. Subgroup analysis revealed this association in each age group and among females but not among males. CONCLUSIONS: Our results demonstrate that osteoporosis is a risk factor for the subsequent development of dry eye syndrome. Clinicians should be aware of the early symptoms of dry eye syndrome in osteoporotic patients in order to prevent further complications. PMID- 30395641 TI - Correction: Development and Psychometric Validation of the EDE-QS, a 12 Item Short Form of the Eating Disorder Examination Questionnaire (EDE-Q). AB - [This corrects the article DOI: 10.1371/journal.pone.0152744.]. PMID- 30395640 TI - Public knowledge and perception about antimicrobials and antimicrobial resistance in Japan: A national questionnaire survey in 2017. AB - BACKGROUND: Antimicrobial resistance (AMR) is a threat to global health. To increase public awareness about AMR and encourage the prudent use of antimicrobials is one of the goals of the National Action Plan in Japan. METHODS: A nationwide online cross-sectional survey was conducted to evaluate the existing knowledge and perception of AMR in Japan, based on the Antimicrobial Resistance Eurobarometer Survey. Participants included Japanese adults aged 20-69 years, who were not medical professionals. RESULTS: Among a total of 3,390 participants, about half had taken antibiotics over the past 12 months, and majority of them obtained the antimicrobials from healthcare institutions for the common cold. While 11.7% of the participants kept leftover antibiotics, 23.6% of them have adjusted doses by themselves. About 10% of the participants have requested antibiotics from their doctors, and nearly 30% of them preferred doctors who prescribed antibiotics when had a cold. The common informational sources were TV news and newspapers, and more than 40% of the participants reported receiving some information over the past year. However, approximately 80% of the participants did not know that antibiotics do not kill viruses and that antibiotics are ineffective against cold and flu. CONCLUSION: Not many Japanese have adequate information about antimicrobials and AMR, and many have taken antimicrobials inappropriately. Greater educational interventions are, therefore, necessary to increase public awareness and develop effective countermeasures against AMR in Japan. PMID- 30395642 TI - Semi-supervised machine learning approaches for predicting the chronology of archaeological sites: A case study of temples from medieval Angkor, Cambodia. AB - Archaeologists often need to date and group artifact types to discern typologies, chronologies, and classifications. For over a century, statisticians have been using classification and clustering techniques to infer patterns in data that can be defined by algorithms. In the case of archaeology, linear regression algorithms are often used to chronologically date features and sites, and pattern recognition is used to develop typologies and classifications. However, archaeological data is often expensive to collect, and analyses are often limited by poor sample sizes and datasets. Here we show that recent advances in computation allow archaeologists to use machine learning based on much of the same statistical theory to address more complex problems using increased computing power and larger and incomplete datasets. This paper approaches the problem of predicting the chronology of archaeological sites through a case study of medieval temples in Angkor, Cambodia. For this study, we have a large dataset of temples with known architectural elements and artifacts; however, less than ten percent of the sample of temples have known dates, and much of the attribute data is incomplete. Our results suggest that the algorithms can predict dates for temples from 821-1150 CE with a 49-66-year average absolute error. We find that this method surpasses traditional supervised and unsupervised statistical approaches for under-specified portions of the dataset and is a promising new method for anthropological inquiry. PMID- 30395643 TI - Poly(ADP-ribose) polymerase 1 is necessary for coactivating hypoxia-inducible factor-1-dependent gene expression by Epstein-Barr virus latent membrane protein 1. AB - Latent membrane protein 1 (LMP1) is the major transforming protein of Epstein Barr virus (EBV) and is critical for EBV-induced B-cell transformation in vitro. Poly(ADP-ribose) polymerase 1 (PARP1) regulates accessibility of chromatin, alters functions of transcriptional activators and repressors, and has been directly implicated in transcriptional activation. Previously we showed that LMP1 activates PARP1 and increases Poly(ADP-ribos)ylation (PARylation) through PARP1. Therefore, to identify targets of LMP1 that are regulated through PARP1, LMP1 was ectopically expressed in an EBV-negative Burkitt's lymphoma cell line. These LMP1 expressing cells were then treated with the PARP inhibitor olaparib and prepared for RNA sequencing. The LMP1/PARP targets identified through this RNA-seq experiment are largely involved in metabolism and signaling. Interestingly, Ingenuity Pathway Analysis of RNA-seq data suggests that hypoxia-inducible factor 1-alpha (HIF-1alpha) is an LMP1 target mediated through PARP1. PARP1 is acting as a coactivator of HIF-1alpha-dependent gene expression in B cells, and this co activation is enhanced by LMP1-mediated activation of PARP1. HIF-1alpha forms a PARylated complex with PARP1 and both HIF-1alpha and PARP1 are present at promoter regions of HIF-1alpha downstream targets, leading to accumulation of positive histone marks at these regions. Complex formation, PARylation and binding of PARP1 and HIF-1alpha at promoter regions of HIF-1alpha downstream targets can all be attenuated by PARP1 inhibition, subsequently leading to a buildup of repressive histone marks and loss of positive histone marks. In addition, LMP1 switches cells to a glycolytic 'Warburg' metabolism, preferentially using aerobic glycolysis over mitochondrial respiration. Finally, LMP1+ cells are more sensitive to PARP1 inhibition and, therefore, targeting PARP1 activity may be an effective treatment for LMP1+ EBV-associated malignancies. PMID- 30395645 TI - Climate change decreases suitable areas for rapeseed cultivation in Europe but provides new opportunities for white mustard as an alternative oilseed for biofuel production. AB - Oilseed crops, including several mustards, are cultivated as biofuel sources worldwide. However, common mustard crops (e.g., the rapeseed Brassica napus) grow naturally in mesic temperate regions, which are expected to be impaired by global warming and increased aridity. In particular, increased aridity is predicted to reduce the oil concentration and seed yield of rapeseed crops. There is therefore an urgent need to identify alternative bioenergy crops that are preadapted to future climatic conditions. An alternative to conventional Brassica species for biodiesel production is the white mustard Sinapis alba, which is native to the circum-Mediterranean region and has a high seed lipid content. S. alba grows spontaneously in olive groves and other widespread Mediterranean crops; accordingly, it could be easily cultivated by companion planting to improve ecosystem function by decreasing soil loss, controlling microbial disease, and assisting in the maintenance of biodiversity. In this study, using species distribution modeling, we predicted climatically suitable areas for the cultivation of S. alba in Western Europe across the Mediterranean Basin under present climatic conditions and several climate change scenarios. We show that current climatically suitable areas for S. alba cultivation do not overlap with those for B. napus. Unlike B. napus, S. alba could be cultivated throughout most of the circum-Mediterranean region. According to our models, increases in aridity and annual mean temperatures will expand the climatically suitable areas for S. alba in the Mediterranean Basin. However, suitable areas for the cultivation of B. napus will decrease significantly in Western Europe. Our results indicate that S. alba is a strong, environmentally safe candidate for biofuel production throughout the Mediterranean Basin and other Western European countries, especially under climate change scenarios that are expected to impair current oilseed crops. PMID- 30395646 TI - Correction: Learning-induced ribosomal RNA is required for memory consolidation in mice-Evidence of differentially expressed rRNA variants in learning and memory. AB - [This corrects the article DOI: 10.1371/journal.pone.0203374.]. PMID- 30395644 TI - Contributing factors to iron deficiency anemia in women in Jordan: A single center cross-sectional study. AB - OBJECTIVES: This study aimed to understand the impact of iron deficiency anemia in female users of a hematology service in a developing country. DESIGN: Retrospective cross-sectional study of adult and adolescent women with iron deficiency anemia who presented to a hospital department of hematology. SETTING: A tertiary university hospital inpatient and outpatient hematology service. PARTICIPANTS: All female patients who were >=13 years of age with confirmed iron deficiency anemia and received hospital hematology services. RESULTS: A total of 208 patients were enrolled and analyzed in the registry. The mean age of the patients was 41.4 years (range, 14-82). A total of 195 patients had anemia that was moderate or severe according to the World Health Organization anemia classification with 13 patients having mild anemia. A total of 108 patients had comorbidities, which were primarily endocrine and cardiovascular. Iron deficiency anemia was associated with very heavy (n = 56, 30%) or heavy menses (n = 84, 45%) in 140 patients and was associated with poor (<200 g/week of red meat) (n = 101, 54%) or very poor (vegan, strict vegetarian) nutrition (n = 34, 18%) in 135 patients. A total of 101 patients had a previous pregnancy history with a mean of six previous pregnancies (range, 1-11 pregnancy episodes per patient). Blood film was performed on all patients; only four had a picture consistent with thalassemia minor. CONCLUSION: Iron deficiency anemia is caused by multiple factors. Heavy menses and low consumption of red meat were found to be associated with the severity of anemia. Our findings may be useful for healthcare planners and policy makers in increasing efforts to reduce the prevalence and severity of iron deficiency anemia among women in Jordan. PMID- 30395647 TI - HEXIM1-Tat chimera inhibits HIV-1 replication. AB - Transcription of HIV provirus is a key step of the viral cycle, and depends on the recruitment of the cellular positive transcription elongation factor b (P TEFb) to the HIV promoter. The viral transactivator Tat can displace P-TEFb from the 7SK small nuclear ribonucleoprotein, where it is bound and inactivated by HEXIM1, and bring it to TAR, which allows the stalled RNA polymerase II to transition to successful transcription elongation. In this study, we designed a chimeric inhibitor of HIV transcription by combining functional domains from HEXIM1 and Tat. The chimera (HT1) potently inhibited gene expression from the HIV promoter, by competing with Tat for TAR and P-TEFb binding, while keeping the latter inactive. HT1 inhibited spreading infection as well as viral reactivation in lymphocyte T cell line models of HIV latency, with little effect on cellular transcription and metabolism. This proof-of-concept study validates an innovative approach to interfering with HIV transcription via peptide mimicry and competition for RNA-protein interactions. HT1 represents a new candidate for HIV therapy, or HIV cure via the proposed block and lock strategy. PMID- 30395650 TI - Correction: Efficacy of pyrazinoic acid dry powder aerosols in resolving necrotic and non-necrotic granulomas in a guinea pig model of tuberculosis. AB - [This corrects the article DOI: 10.1371/journal.pone.0204495.]. PMID- 30395648 TI - Mucosal immunoglobulins protect the olfactory organ of teleost fish against parasitic infection. AB - The olfactory organ of vertebrates receives chemical cues present in the air or water and, at the same time, they are exposed to invading pathogens. Nasal associated lymphoid tissue (NALT), which serves as a mucosal inductive site for humoral immune responses against antigen stimulation in mammals, is present also in teleosts. IgT in teleosts is responsible for similar functions to those carried out by IgA in mammals. Moreover, teleost NALT is known to contain B-cells and teleost nasal mucus contains immunoglobulins (Igs). Yet, whether nasal B cells and Igs respond to infection remains unknown. We hypothesized that water borne parasites can invade the nasal cavity of fish and elicit local specific immune responses. To address this hypothesis, we developed a model of bath infection with the Ichthyophthirius multifiliis (Ich) parasite in rainbow trout, Oncorhynchus mykiss, an ancient bony fish, and investigated the nasal adaptive immune response against this parasite. Critically, we found that Ich parasites in water could reach the nasal cavity and successfully invade the nasal mucosa. Moreover, strong parasite-specific IgT responses were detected in the nasal mucus, and the accumulation of IgT+ B-cells was noted in the nasal epidermis after Ich infection. Strikingly, local IgT+ B-cell proliferation and parasite specific IgT generation were found in the trout olfactory organ, providing new evidence that nasal-specific immune responses were induced locally by a parasitic challenge. Overall, our findings suggest that nasal mucosal adaptive immune responses are similar to those reported in other fish mucosal sites and that an antibody system with a dedicated mucosal Ig performs evolutionary conserved functions across vertebrate mucosal surfaces. PMID- 30395649 TI - Prevalence, transitions and factors predicting transition between frailty states among rural community-dwelling older adults in Malaysia. AB - OBJECTIVES: This study aims to describe the prevalence and transitions of frailty among rural-community dwelling older adults in Malaysia and to analyse factors associated with different states of frailty transition. Frailty was conceptualized using modified Fried phenotype from the Cardiovascular Health Study. DESIGN: This is a prospective longitudinal study with 12-months follow up among older adults in Malaysia. SETTING: Kuala Pilah, a district in Negeri Sembilan, which is one of the fourteen states in Malaysia. PARTICIPANTS: 2,324 community-dwelling older Malaysians aged 60 years and older. RESULTS: The overall prevalence of frailty in this study was 9.4% (95% CI 7.8-11.2). The prevalence increased at least three-fold with every 10 years of age. This increase was seen higher in women compared to men. Being frail was significantly associated with older age, women, and respondents with a higher number of chronic diseases, poor cognitive function and low socioeconomic status (p<0.05). During the 12-months follow-up, our study showed that the transition towards greater frailty states were more likely (22.9%) than transition toward lesser frailty states (19.9%) while majority (57.2%) remained unchanged. Multivariate logistic regression analysis showed that presence of low physical activity increased the likelihood of worsening transition towards greater frailty states by three times (OR 2.9, 95% CI 2.2-3.7) and lowered the likelihood of transition towards lesser frailty states (OR 0.3, 95% CI 0.2-0.4). CONCLUSION: Frailty is reported among one in every eleven older adults in this study. The prevalence increased across age groups and was higher among women than men. Frailty possesses a dynamic status due to its potential reversibility. This reversibility makes it a cornerstone to delay frailty progression. Our study noted that physical activity conferred the greatest benefit as a modifiable factor in frailty prevention. PMID- 30395651 TI - Impact of the serum albumin level on acute kidney injury after cerebral artery aneurysm clipping. AB - BACKGROUND: Although hypoalbuminemia is a known risk factor for acute kidney injury (AKI) following surgery, little is known about its effects following aneurysm clipping surgery. We aimed to investigate the predictors of AKI and overall mortality and assessed the relationship between preoperative albumin and postoperative outcomes after aneurysm clipping surgery. METHODS: This study included 2,339 patients who underwent aneurysm clipping surgery. According to the criteria updated by the Kidney Disease: Improving Global Outcomes (KDIGO), patients were classified into AKI and no AKI group. Independent AKI predictors were analyzed by multivariate methods, and the influence of AKI on the outcome variables was assessed with by propensity score matching analysis. Survival in relation to AKI was analyzed using the Kaplan-Meier method. RESULTS: The total proportion of patients who developed AKI was 1.9%. The cutoff value of preoperative albumin for predicting AKI was 3.9 g/dL. Multivariate analyses showed that preoperative albumin<= 3.9 g/dL, aneurysmal subarachnoid hemorrhage, male sex, phenylephrine use, and hemoglobin were associated with postoperative AKI development. In multivariate analysis, mortality was increased in AKI patients (p< 0.01). After propensity score matching, preoperative albumin<= 3.9 g/dL was significantly related to AKI and overall mortality. CONCLUSION: Preoperative albumin<= 3.9 g/dL is associated with postoperative AKI and mortality. PMID- 30395652 TI - Bacillus subtilis MraY in detergent-free system of nanodiscs wrapped by styrene maleic acid copolymers. AB - As an integral membrane protein, purification and characterization of phospho-N- acetylmuramyl- pentapeptide translocase MraY have proven difficult. Low yield and concerns of retaining stability and activity after detergent solubilization have hampered the structure-function analysis. The recently developed detergent-free styrene-maleic acid (SMA) co-polymer system offers an alternative approach that may overcome these disadvantages. In this study, we used the detergent free system to purify MraY from Bacillus subtilis. This allowed efficient extraction of MraY that was heterologously produced in Escherichia coli membranes into SMA wrapped nanodiscs. The purified MraY embedded in these nanodiscs (SMA-MraY) was comparable to the micellar MraY extracted with a conventional detergent (DDM) with regard to the yield and the purity of the recombinant protein but required significantly less time. The predominantly alpha-helical secondary structure of the protein in SMA-wrapped nanodiscs was also more stable against heat denaturation compared to the micellar protein. Thus, this detergent-free system is amenable to extract MraY efficiently and effectively while maintaining the biophysical properties of the protein. However, the apparent activity of the SMA MraY was reduced compared to that of the detergent-solubilized protein. The present data indicates that this is caused by a lower accessibility of the enzyme in SMA-wrapped nanodiscs towards its polyisoprenoid substrate. PMID- 30395653 TI - Local enrichment of fatty acid-binding protein 4 in the pericardial cavity of cardiovascular disease patients. AB - BACKGROUND: The pericardial fluid may be representative of the interstitium of the heart. The aim of this study was to discriminate in cardiovascular disease patients between adipocytokines that are produced locally by the heart and those supplied by the circulation. METHODS: Enzyme-linked immunosorbent assays (ELISA) were used to determine levels of N-terminal pro-brain natriuretic peptide (NT pBNP), fatty acid-binding protein 4 (FABP4), leptin, lipocalin-2, neutrophil elastase, proteinase-3, high sensitivity C-reactive protein (hsCRP) and adiponectin in venous plasma and pericardial fluid harvested during elective cardio-thoracic surgery (n = 132-152). RESULTS: In pericardial fluid compared to plasma, the levels were significantly smaller (p < 0.001) for leptin, lipocalin 2, neutrophil elastase, proteinase-3, hsCRP and adiponectin. For these biomarkers, the ratio of pericardial fluid-to-plasma level ([PF]/[P], median (interquartile range)) was 0.65 (0.47-1.01), 0.78 (0.56-1.09), 0.23 (0.11-0.60), 0.17 (0.09-0.36), 0.14 (0.08-0.35), and 0.25 (0.15-0.34), respectively. In contrast, pericardial fluid was significantly enriched (p < 0.001) in NT-pBNP ([PF]/[P]: 1.9 (1.06-2.73)) and even more so for FABP4 ([PF]/[P]: 3.90 (1.47 9.77)). Moreover, in pericardial fluid, the adipocytokines interrelated all significantly positive and correlated negative to hsCRP, whereas for NT-pBNP only a significantly positive correlation with adiponectin was found. These interrelations were distinct from those in the plasma, as were the correlations of the pericardial biomarkers with patient characteristics compared to plasma. CONCLUSIONS: In cardiovascular disease patients, the pericardial cavity is a distinct adipocytokine microenvironment in which especially FABP4 is mainly derived from the heart. PMID- 30395656 TI - ASYMMETRIC HETERO DIELS-ALDER REACTIONS OF DANISHEFSKY'S DIENE AND GLYOXYLATE ESTERS CATALYZED BY CHIRAL BISOXAZOLINE DERIVED CATALYSTS. AB - Asymmetric hetero Diels-Alder reactions of Danishefsky's diene and glyoxylate esters catalyzed by bis(oxazoline)-metal complex afforded the corresponding aldol adduct which upon treatment with trifluoroacetic acid furnished the hetero Diels Alder product in 72% enantiomeric excess and 70% isolated yield. PMID- 30395655 TI - HPV infection and bacterial microbiota in breast milk and infant oral mucosa. AB - OBJECTIVE: We investigated the association between bacterial microbiota in breast milk and the infant mouth. The influence of human papilloma virus (HPV) infection on infant oral microbiota was also assessed. MATERIAL AND METHODS: Altogether 35 breast milk and 35 infant oral samples with known HPV status were selected from the Finnish Family HPV Study cohort. In total, there were 31 mother-infant pairs. The microbiota composition was characterized by 16S rRNA gene sequencing (V3-V4 region). RESULTS: HPV DNA was present in 8.6% (3/35) of the breast milk and 40% (14/35) of the infant oral samples. Eight shared genera between breast milk and infant oral were found; these included Streptococcus, Staphylococcus, Unclassified Gemellaceae, Rothia, Veillonella, Haemophilus, Propionibacterium and Corynebacterium. HPV status was not associated with either microbiota richness or diversity in the infant mouth. However, the infant oral microbiota clustered in different groups according to HPV status. We detected higher abundance of Veillonella dispar (p = 0.048) at species level in HPV negative infant oral samples. We did not detect differences in the breast milk microbiota composition related to HPV infection due to only three HPV positive milk samples. CONCLUSIONS: HPV infection is associated with distinct oral bacterial microbiota composition in infants. The direction of causality underlying the phenomenon remains unclear. PMID- 30395654 TI - Association of hyperuricemia with disease severity in chronic hepatitis C patients. AB - BACKGROUND/AIMS: Hepatitis C virus (HCV) infection is associated with extrahepatic manifestations such as metabolic abnormalities. The association between chronic hepatitis C (CHC) and uric acid levels has rarely been investigated. We aimed to evaluate the levels of serum uric acid in CHC patients. METHODS: Three hundred and seventy-three histologically confirmed CHC patients who were scheduled to receive antiviral therapy were consecutively enrolled, and 746 age- and sex-matched uninfected controls were included for comparison. Hyperuricemia was defined as a uric acid level > 7 mg/dL in men and > 6.0 mg/dL in women. RESULTS: Hyperuricemia was identified in 15.8% of the CHC patients. The uric acid levels did not differ between the CHC patients and the controls (5.54 +/- 1.20 mg/dL vs. 5.45 +/- 1.45 mg/dL, P = 0.3). Among the 373 CHC patients, the factors associated with hyperuricemia included body mass index (BMI) (OR/CI: 1.13/1.04-1.21, P = 0.003) and estimated glomerular filtration rate (eGFR) (OR/CI: 0.98/0.97-1.00, P = 0.02). Logistic regression analysis revealed that the factors associated with hyperuricemia in male patients included BMI (OR/CI: 1.12/1.05-1.30, P = 0.006) and advanced fibrosis (F3-4) (OR/CI: 0.27/0.09-0.83, P = 0.02), whereas the factors associated with hyperuricemia in female patients included eGFR (OR/CI: 0.97/0.95-0.99, P = 0.02) and diabetes (OR/CI: 3.03/1.11 8.25, P = 0.03). There was a significant decreasing trend of serum uric acid levels with the progression of fibrotic stages among male patients (6.21 +/- 1.03 mg/dL 5.82 +/- 1.16 mg/dL and 5.44 +/- 1.28 mg/dL in stages F0-2, F3, and F4, respectively, trend P = 0.01). CONCLUSIONS: Hyperuricemia was inversely associated with liver disease severity in CHC male patients. PMID- 30395657 TI - Leaving the tropics: The successful colonization of cold temperate regions by Dolicheremaeus dorni (Acari, Oribatida). AB - Species diversity is generally higher in the tropics compared to the temperate zones. The phenomenon that one species of an almost exclusively tropical living genus was able to adapt successfully to the cold northern regions is rather rare. However, the oribatid mite Dolicheremaeus dorni represents such a species and is in the focus of this study. While 180 Dolicheremaeus species are confined to the tropics and subtropics, only five species are known to occur in temperate climates and D. dorni represents the only species with a wider distribution in this climatic region. This species is distributed in Central and Southern Europe and was now recorded for the first time in Austria. A morphological and molecular genetic investigation of specimens from Austria, Poland and Croatia confirmed this distribution pattern and revealed specific geographic clades and haplotypes for each population and hence indicate low gene flow between populations. A further molecular genetic analysis of the 18S rRNA gene sequence of D. dorni confirmed its phylogenetic position within Carabodoidea. Based on record information, this species is associated with trees or tree habitats and seems to be rather a generalist than a specialist for a specific substrate (e.g., tree species) or food source. PMID- 30395659 TI - Practical Concepts With the Argus II Retinal Prosthesis. PMID- 30395658 TI - Massive release of volatile organic compounds due to leaf midrib wounding in Populus tremula. AB - We investigated the rapid initial response to wounding damage generated by straight cuts to the leaf lamina and midrib transversal cuts in mature aspen (Populus tremula) leaves that can occur upon herbivore feeding. Wound-induced volatile emission time-courses of 24 compounds were continuously monitored by a proton-transfer-reaction time-of-flight mass spectrometer (PTR-TOF-MS). After the mechanical wounding, an emission cascade was rapidly elicited, resulting in emissions of key stress volatiles methanol, acetaldehyde and volatiles of the lipoxygenase pathway, collectively constituting ca. 99% of the total emission. For the same wounding magnitude, midrib cuts lead to six-fold greater emissions of volatiles per mm2 of surface cut than lamina cuts during the first emission burst (shorter than seven minutes), and exhibited a particularly high methanol emission compared to the emissions of other volatiles. This evidence suggests that feeding by herbivores capable of consuming the leaf midrib can result in disproportionally greater volatile release than feeding by smaller herbivores incapable of biting through the major veins. PMID- 30395660 TI - Characteristics of Polypoidal Choroidal Vasculopathy in OCT Angiography in Latin American Patients. AB - BACKGROUND AND OBJECTIVES: To describe the imaging characteristics of polypoidal choroidal vasculopathy (PCV) in optical coherence tomography angiography (OCTA) and demonstrate its use as diagnostic method for this pathology in a Latin American population. PATIENTS AND METHODS: A case series. RESULTS: Fourteen eyes were evaluated. At baseline, the most frequent morphology was the "oval" type (76.9%), obtaining a reduction of 53.8% after treatment. The intrinsic finding of the polyps was hyporeflective content prior to treatment (80.8%), which reduced after treatment (7.7%) (P = .016). CONCLUSIONS: OCTA is a useful imaging tool for detecting findings that can guide the diagnosis of PCV without contrast medium. Likewise, it provides signs that can suggest the behavior of the lesion prior to and after treatment, enriching the understanding of the pathology and therefore aiming to an efficient therapy. To the best of the authors' knowledge, this is the first study in a Latin American population. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:748-756.]. PMID- 30395661 TI - Outcome of Sutured Scleral-Fixated Intraocular Lens in Blunt and Penetrating Trauma in Children. AB - BACKGROUND AND OBJECTIVE: To determine the anatomical and functional outcomes of sutured scleral-fixated intraocular lens (SSFIOL) implantation in children with blunt and penetrating injuries to the eye. PATIENTS AND METHODS: This is a retrospective, interventional case series study. Case records of children who underwent SSFIOL implantation in a tertiary eye care facility for traumatic aphakia, cataract, or subluxation were screened. Relevant data on demographics, visual acuity (VA) outcomes, and complications and their management were collected. Results for blunt and penetrating trauma were compared. RESULTS: There was stability or improvement of vision in 88.9% of eyes during the follow-up period. Young age at time of trauma (P = .031) and SSFIOL implantation (P = .002), history of retinal detachment (RD) before SSFIOL implantation (P = .019), poor preoperative best-corrected VA (BCVA) (P = .004), and development of RD in the follow-up period (P = .046) were independent risk factors for low final BCVA on univariate regression analysis. RD rate was 6.53% and was comparable in open and closed globe injuries. Intraocular lens (IOL) dislocation rate was 3.9%, and probability of survival was higher for open globe (0.78) as compared to closed globe (0.64) injuries (P = .042). CONCLUSIONS: SSFIOL implantation results in good VA improvement in both open and closed globe injuries. RD remains an important vision-threatening complication. IOL dislocation is more likely to occur in closed globe injuries. A prospective study evaluating the outcomes would better elucidate the role of these IOLs. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:757-764.]. PMID- 30395662 TI - Correlates of Good Vision in Eyes With Subfoveal Scars From Neovascular Age Related Macular Degeneration. AB - BACKGROUND AND OBJECTIVE: To compare subfoveal disciform scars with good and poor vision in patients with neovascular age-related macular degeneration (nAMD). PATIENTS AND METHODS: A retrospective case-control study. Twenty-two eyes of 21 consecutively treated patients with nAMD with subfoveal disciform scar and best corrected visual acuity (BCVA) of 20/63 or better at the final visit were included. Twenty-one eyes of 21 matched patients with disciform scar and final BCVA less than 20/63 served as controls. RESULTS: Subretinal pigment epithelium scar location was more common in the good vision group than in the poor vision group (P < .001). The mean percent disruption of the ellipsoid and the external limiting membrane layers was significantly greater in poor vision eyes than in good vision eyes from scar formation and throughout follow-up (all P < .01). CONCLUSION: Preserved photoreceptor layer correlated with good vision in patients with nAMD and subfoveal disciform scar. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:765-774.]. PMID- 30395663 TI - Prognostic Tomographic Classification of Myopic Choroidal Neovascularization. AB - BACKGROUND AND OBJECTIVES: To investigate the prognostic value of the development of a hyperreflective envelopment of the neovascular tissue in myopic choroidal neovascularization (mCNV) after the first intravitreal ranibizumab injection and to establish a tomographic classification of mCNV depending on this healing process. PATIENTS AND METHODS: Twenty-five eyes of 25 patients with mCNV were retrospectively studied. Patients were classified into type A (presence of a hyperreflective coating of the neovascular tissue 1 month after first intravitreal ranibizumab) and type B (absence of or partial coating). Visual acuity (VA) and number of injections were recorded. Differences between both types were assessed at 6 and 12 months of follow-up. RESULTS: Fifteen patients (60%) were classified as type A and 10 as type B (40%). Type A showed better VA than type B. VA improvement was only significant for type A. No differences in the number of injections were observed; however, a trend to a larger amount in type B was observed. CONCLUSIONS: The proposed classification may have prognostic value, with type A mCNV showing better visual outcomes. Further studies are needed to confirm these findings. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:775-779.]. PMID- 30395664 TI - Multifocal Electroretinography in Diabetic Retinopathy With and Without Macular Edema. AB - BACKGROUND AND OBJECTIVES: To characterize the electroretinographic response of the macula by multifocal electroretinography (mfERG) in nonproliferative diabetic retinopathy (NPDR) with and without diabetic macular edema (DME) and correlate it with best-corrected visual acuity (BCVA) and foveal thickness on spectral-domain optical coherence tomography (SD-OCT). PATIENTS AND METHODS: Prospective, observational case series. Forty eyes of 22 patients with treatment-naive NPDR underwent recording of BCVA, fundus fluorescein angiography (FFA), and SD-OCT. Groups A and B were classified as 20 eyes each having NPDR with DME (central foveal thickness [CFT] >= 275 MUm) and without DME (CFT < 275 MUm), respectively. First-order kernel mfERG responses recorded according to ISCEV guidelines were grouped into five concentric rings centered on the fovea for analysis. RESULTS: Mean P1 and N1 amplitudes (nv/deg2) were significantly decreased compared to normal values in each of the five rings in both groups (P < .01); however, the values between the two groups were comparable. BCVA was significantly and positively correlated with P1 (r = 0.454, P = .003) and N1 amplitude (r = 0.468, P = .002) and significantly and negatively correlated with P1 (r= -0.534, P < .01) and N1 implicit times (r= -0.570, P < .01) in all patients. P1 (r= -0.531, P < .01) and N1 amplitude (r= -0.367, P = .02) in the central ring of mfERG had a significant negative correlation with macular thickness in the corresponding foveal ring of SD-OCT in all patients. CONCLUSIONS: mfERG reflects retinal dysfunction irrespective of the occurrence of DME in patients with NPDR. Correlation with BCVA reinforces that mfERG should be used to objectively assess the macular function in these patients. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:780-786.]. PMID- 30395665 TI - Vital Dyes in Vitreomacular Surgery. AB - Vital dyes contain complex molecules with chromophores that stain living tissues and have greatly enhanced identification and removal of transparent vitreoretinal tissues during surgery. Several "chromovitrectomy" dyes are frequently used by vitreoretinal specialists, including indocyanine green, trypan blue, brilliant blue G, and triamcinolone acetonide; other dyes are also under investigation. Trypan Blue was approved by the U.S. Food and Drug Administration (FDA) for epiretinal membrane removal, and preservative-free triamcinolone acetonide was approved by the FDA for intraocular use. However, currently available chromovitrectomy dyes have their limitations, and of particular concern for some of them is the possibility for acute and chronic toxicity to the neurosensory retina and retinal pigmented epithelium. The potentially irreversible acute toxicity and other limitations, such as lack of long-term safety profiles, highlight the need for further advancements. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:788-798.]. PMID- 30395666 TI - A Novel Approach to In-Office Air-Fluid Exchange Utilizing a 27-Gauge Valved Trocar Cannula. AB - BACKGROUND AND OBJECTIVE: To describe a new approach for in-office air-fluid exchange. PATIENTS AND METHODS: This manuscript describes a procedural technique. A retrospective chart review of three patients on whom the procedure was performed is presented. RESULTS: The authors have performed this novel procedure on three eyes of three patients. All patients were followed for at least 3 months after the procedure. No short-term complications occurred, and no secondary procedures were required to achieve a near-complete air-fluid exchange. CONCLUSION: This novel technique is a reliable and reproducible procedure that allows for in-office air-fluid exchange with good results in this small cohort of patients. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:799-801.]. PMID- 30395667 TI - OCT Angiography of Bilateral, Indolent, Nonprogressive, Multifocal Choroidal Lesions. AB - Indolent, nonprogressive, multifocal, choroidal lesions represent a newly described, benign, nosological entity that is diagnosed after exclusion of funduscopically similar uveitic and neoplastic processes. Although believed to be a unilateral condition, the authors describe the case of a 63-year-old man presenting with bilateral lesions during a 2-year follow-up conducted by means of optical coherence tomography angiography (OCTA). Surprisingly, OCTA revealed that the vascular rarefaction, albeit primarily affecting the choriocapillaris, also involved the overlying retinal plexuses. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:802-805.]. PMID- 30395668 TI - Novel OCT Application and Optimized YAG Laser Enable Visualization and Treatment of Mid- to Posterior Vitreous Floaters. AB - Vitrectomy is an effective treatment for visually disabling vitreous opacities (floaters) but carries significant surgical risk. Nd:YAG laser vitreolysis using newer technology has been shown safe and effective in treating symptomatic Weiss ring vitreous floaters. These Weiss rings, as well as amorphous opacities in the mid- to posterior vitreous, can be impossible to visualize or treat using conventional YAG lasers. In the cases presented here, undetected symptomatic amorphous type posterior vitreous floaters were confirmed with assistance of a novel optical coherence tomography application and successfully treated using a YAG laser optimized for vitreolysis. These cases suggest that with proper technology and technique, laser vitreolysis may be safer and more effective than previously recognized. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:806-811.]. PMID- 30395669 TI - Diagnosis of Bilateral Retinocytoma in an Adolescent Patient Using Multimodal Imaging and Genetic Testing. AB - A 12-year-old male presented for evaluation of asymptomatic bilateral retinal tumors. Both eyes contained whitish-gray retinal tumors with intralesional calcifications. Enhanced depth optical coherence tomography and high-resolution (20 MHz) ultrasonography narrowed the differentiation diagnosis to astrocytic hamartoma versus retinocytoma. Genetic testing of a saliva sample was negative for tuberous sclerosis complex but positive for a novel mutation in the retinoblastoma gene (RB1). Taken together, these findings were consistent with a diagnosis of bilateral retinocytoma in a patient with germline RB1 mutation. This case demonstrates the importance of combining clinical imaging and genetic testing in the evaluation of bilateral intraocular tumors. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:812-814.]. PMID- 30395670 TI - Optic Nerve Compression From MIRAgel Implant Migration in a Monocular Patient. AB - The MIRAgel implantation was popularized in the 1980s as an alternative to silicone for scleral buckle retinal detachment repair. However, long-term follow up has revealed that the implants can expand, creating globe compression and potentially visually devastating intraocular invasion. The authors document a 33 year-old monocular male patient presenting 20 years after MIRAgel implantation with extensive expansion, posterior migration, globe compression, and possible optic nerve compression. Debulking of the MIRAgel stabilized the vision and restored affected extraocular movements. The authors highlight that posterior MIRAgel migration can cause optic nerve compression, and implant debulking may require a multi-disciplinary approach. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:815-818.]. PMID- 30395671 TI - Morphological Difference of Choroidal Vasculature Between Polypoidal Choroidal Vasculopathy and Neovascular AMD on OCT: From the Perspective of Pachychoroid. AB - BACKGROUND AND OBJECTIVE: To investigate the morphological difference of choroidal vasculature between polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (nAMD) on optical coherence tomography (OCT). PATIENTS AND METHODS: One hundred eighty-nine patients with macula-involved PCV (n = 107) or nAMD (n = 82) were retrospectively reviewed. The subfoveal choroidal thickness (SFCT) and thickness of the Haller's layer were determined on enhanced depth imaging optical coherence tomography (EDI-OCT). The mean diameters of subfoveal large choroidal vessels were also calculated. RESULTS: Both the SFCT (257.31 MUm +/- 100.50 MUm vs. 209.95 MUm +/- 97.51 MUm) (P < .01) and the thickness of the Haller's layer (213.68 MUm +/- 82.65 MUm vs. 159.67 MUm +/- 79.86 MUm) (P < .01) were greater in PCV patients than nAMD patients. The ratio of thickness of the Haller's layer to the SFCT was higher in the PCV group (0.83 +/- 0.07) than the nAMD group (0.7 5+/- 0.11) (P < .01). The mean diameter of subfoveal large choroidal vessels was greater in PCV patients (163.55 MUm +/- 62.23 MUm vs. 112.81 +/- 58.87 MUm) (P < .01). CONCLUSION: Choroidal thickening and dilation of large choroidal vessels were commonly seen in PCV patients, supporting that PCV belongs to the pachychoroid spectrum disorders and might be a different entity from nAMD. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e114-e121.]. PMID- 30395672 TI - Quantitative Assessment of the Choriocapillaris in Patients With Retinitis Pigmentosa and in Healthy Individuals Using OCT Angiography. AB - BACKGROUND AND OBJECTIVE: To characterize the choriocapillaris (CC) vasculature in patients with retinitis pigmentosa (RP) and healthy controls using optical coherence tomography angiography (OCTA). PATIENTS AND METHODS: The CC of patients with RP and controls was analyzed using OCTA. Areas of no-flow, termed flow voids (FVs), were denoted in both. Comparisons between groups were done using Wilcox tests and generalized estimating equations. RESULTS: Fifty-four patients were included. There was a significant difference in spherical equivalent (P < .001). The number of FV was 55.5 +/- 20.1 in the RP eyes versus 30.7 +/- 16.3 in the controls (P < .001). The average FV area was 0.33 +/- 0.12 mm2 in the RP eyes and 0.18 +/- 0.10 mm2 in the controls (P < .001). CONCLUSIONS: There are significantly more FV in patients with RP than in healthy subjects, suggesting it is vital to understanding pathophysiology of RP. Further studies should be done to determine if the compromised CC is a result or cause of RP. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e122-e128.]. PMID- 30395673 TI - Comparison of Two Modified Sutureless Techniques of Scleral Fixation of Intraocular Lens. AB - BACKGROUND AND OBJECTIVE: To compare the visual outcome and complications of two different sutureless scleral-fixated intraocular lens (IOL) implantation techniques, that is, intrascleral IOL fixation technique and modified Yamane's technique of scleral fixation of IOL. PATIENTS AND METHODS: Patients who underwent scleral fixation of IOL (SFIOL) from June 2015 to February 2017 with more than 6 months of follow-up were examined retrospectively. Improvement in visual acuity (VA), intraocular pressure (IOP) measurements, endothelial cell count, central macular thickness (CMT), and intraoperative/postoperative complications were compared at 6 months follow-up. RESULTS: Seventy eyes were analyzed. The mean follow-up was 10.5 months +/- 1.5 months. The final visual outcomes in both groups, modified intrascleral IOL fixation technique (Group A, n = 30) and modified Yamane's technique (Group B, n = 40), were comparable. The indications for surgery were aphakia (n = 15), subluxated/dislocated cataract (n = 31), and dislocated/subluxated IOL (n = 24). The majority of the eyes (92%) improved to VA 0.3 logMAR units or better. The uncorrected distance visual acuity (UDVA), endothelial cell density, and CMT at the 6-month follow-up were comparable in both groups. Postoperatively, transient IOP rise occurred in 18 eyes, retinal detachment in one eye, vitreous hemorrhage in one eye, cystoid macular edema in two eyes, and mild IOL decentration in two eyes. CONCLUSION: Both techniques have favorable visual outcomes; however, modified 27-gauge needle assisted Yamane's technique is technically superior because of its transconjunctival approach and less surgical time, and its needle-assisted approach for haptic externalization prevents haptic damage during externalization. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e129-e134.]. PMID- 30395674 TI - Comparative Study of 27-Gauge Versus 25-Gauge Vitrectomy With Air Tamponade in the Treatment of Myopic Foveoschisis. AB - BACKGROUND AND OBJECTIVE: To compare the surgical outcome of 27-gauge pars plana vitrectomy (PPV) with 25-gauge PPV and evaluate the efficacy of air tamponade for the treatment of myopic foveoschisis (MF). PATIENTS AND METHODS: Sixty eyes of 60 consecutive patients were recruited to undergo vitrectomy, internal limiting membrane (ILM) peeling, and air tamponade for treatment of MF. These eyes were divided into two groups: the 27-gauge group (n = 29) and the 25-gauge group (n = 31). RESULTS: There were no significant differences in the mean operating time (P = .32), the mean time for vitrectomy (P = .20), and the suturing rate(P = .46) between the 27-gauge group and the 25-gauge group. At the final follow-up, anatomical resolution rate did not differ between the two groups (P = .65). CONCLUSION: The 27-gauge vitrectomy system is as efficient and feasible as the 25 gauge system for the treatment of MF. Air tamponade can provide good postoperative anatomic resolution of MF. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e135-e142.]. PMID- 30395675 TI - Surgical Repair of Traumatic Macular Holes With Extreme Macular Pathology Using an Internal Limiting Membrane Flap Technique. AB - This report describes the use of inverted internal limiting membrane (ILM) flap technique as a treatment option for traumatic macular holes (MHs) with severe macular pathology. An interventional case series of two patients who experienced blunt trauma is reported. One patient developed two adjacent MHs and the second patient a MH with focal tissue avulsion in the fovea. Each patient underwent pars plana vitrectomy with ILM flap creation and intraocular gas tamponade. The ILM flap technique was successfully used for closure of MHs in one patient with a traumatic double MH and another patient with MH with foveal tissue avulsion. Visual acuity and symptoms improved in both patients. The ILM flap technique is a useful option for patients even with advanced pathologic findings subsequent to traumatic MH formation. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e143 e146.]. PMID- 30395676 TI - Bilateral Acquired Progressive Retinal Nerve Fiber Layer Myelination. AB - The authors present the multimodal imaging findings of an unusual case of bilateral acquired progressive myelination of the optic disc during a 10-year follow-up period in a hyperopic adolescent patient in the absence of an underlying ocular or systemic abnormality. Myelination of the left optic disc was noted at age 7 and of the right optic disc at age 13, but no other ocular or systemic abnormalities were identified. Cross-sectional optical coherence tomography (OCT) and en face OCT angiography confirmed the presence of myelination of the retinal nerve fiber layer and excluded other etiologic possibilities including an astrocytic hamartoma. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e147-e150.]. PMID- 30395677 TI - Bilateral Immediate Sequential Vitrectomy and Lensectomy for Bilateral Lens Dislocation in Severe Neonatal Marfan Syndrome. AB - A newborn with severe neonatal Marfan syndrome (NMS), characterized by aortic root dilation, mitral and tricuspid valve regurgitation, diaphragmatic eventration with respiratory distress, intestinal malrotation, and various skeletal abnormalities, developed bilateral pupillary block from luxated crystalline lenses. He underwent bilateral immediate sequential vitrectomy and lensectomy to prevent further episodes of pupillary block. Bilateral surgery was performed due to the extremely high anesthesia risk. NMS is a rare and severe form of the connective tissue disease that can present with numerous systemic and ocular findings. Measures to decrease anesthesia risk are recommended, including the consideration of bilateral surgery. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e151-e153.]. PMID- 30395678 TI - Terson Syndrome in a Healthy Term Infant: Delivery-Associated Retinopathy and Intracranial Hemorrhage. AB - A term healthy infant was noted to have cephalohematoma following normal spontaneous vaginal delivery (NSVD). At 9 days of age, the attending team performed wide-angle remote digital fundus imaging and the left eye was noted to have scattered multi-laminar hemorrhages. Magnetic resonance imaging was performed which revealed occipital infarct and subarachnoid hemorrhage. A diagnosis of neonatal Terson syndrome was made. The child remained asymptomatic and the fundus hemorrhages resolved without sequelae. This case represents the first documented instance of Terson syndrome following NSVD and may represent a possible etiology of the common newborn retinal hemorrhage. Alternative terminology - delivery-associated retinopathy and intracranial hemorrhages - is proposed to describe these findings. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e154-e156.]. PMID- 30395679 TI - Swept-Source Optical Coherence Tomography Angiography of an Amalric Choroidal Infarction in a Rare Presentation of Giant Cell Arteritis With Bilateral Corneal Edema. AB - A 73-year-old woman with 2 weeks of progressive painless vision loss was found to have bilateral corneal edema, jaw claudication, and temporal headache. Multimodal imaging revealed an Amalric choroidal infarct in the left eye visualized by widefield indocyanine green angiography and swept-source optical coherence tomography angiography (SS-OCTA). Prompt intravenous corticosteroid treatment resulted in 20/20 vision, and giant cell arteritis (GCA) was confirmed by a temporal artery biopsy. The case underscores the use of widefield SS-OCTA as a non-invasive test to aid in the diagnosis of GCA, as well as bilateral cornea edema as a rare presentation of GCA. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e157-e160.]. PMID- 30395680 TI - Beta-Thalassemia Minor Manifesting as Proliferative Retinopathy. AB - Beta-thalassemia (beta-thalassemia) minor is characterized by a mutation in one of the two beta-globin genes (HBB) that produce the beta-globin chains in the hemoglobin molecule. Although other hemoglobinopathies have been frequently associated with retinal disease, there are limited reports of retinal pathology with beta-thalassemia minor. We report two patients with beta-thalassemia minor presenting with decreased vision, vitreous hemorrhage, and proliferative retinopathy. This case report highlights that patients with beta-thalassemia minor may require routine ocular examinations for peripheral retinal pathology, and beta-thalassemia minor should be considered in the differential diagnosis for proliferative retinopathy. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e161 e164.]. PMID- 30395681 TI - Acute Macular Neuroretinopathy Following the Administration of an Influenza Vaccination. AB - This manuscript reports a rare association of the development of acute macular neuroretinopathy (AMN) after administration of an influenza vaccination. A 42 year-old white female presented with a 2-week history of black spots and a paracentral scotoma in the right eye after receiving a seasonal influenza vaccination. Findings on multimodal imaging were classic for AMN, and these findings improved but did not fully resolve 4 weeks after initial presentation with observation alone. Although a febrile illness or the use of oral contraceptives is most commonly associated with the development of AMN, it is important for clinicians to also consider influenza vaccination as a possible etiology. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e165-e168.]. PMID- 30395682 TI - Pars Plana Cysts. AB - A 62-year-old male underwent pars plana vitrectomy for diabetic tractional retinal detachment. Multiple pars plana cysts varying from 2 to 0.5 disc diameter size were noted intraoperatively. These images highlight the utility of intraoperative widefield systems in combination with scleral depression for visualization of periphery of retina. The images also illustrate the details of cysts clearly along with their anatomical relation with ora serrata. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e169-e170.]. PMID- 30395683 TI - Enhanced Depth Imaging Optical Coherence Tomography of Posterior Globe Rupture. AB - Occult globe rupture is a rare but potentially devastating result of eye trauma. The authors present a case of a woman who sustained blunt trauma to the right eye resulting in a peripapillary circumferential posterior globe rupture. Clinically, the eye maintained good vision and normal intraocular pressure with a clear media, though subretinal fluid and retinal hemorrhage were present overlying the scleral defect. Enhanced depth imaging spectral-domain optical coherence tomography (EDI SD-OCT) revealed a sharp step-off of the sclera, choroid, and Bruch's membrane/retinal pigment epithelium, with overlying intact and contiguous inner retina, corresponding to a posterior globe rupture. Following conservative management, the subretinal fluid resolved and visual acuity improved to 20/20 over a month period, whereas the posterior globe step-off remained stable. This case demonstrates the potential for occult open globe injuries with preserved visual function in cases of blunt ocular trauma, and the first to document EDI SD OCT findings of a posterior globe rupture. Multimodal imaging may help in the evaluation and diagnosis of suspected posterior segment globe rupture. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e171-e172.]. PMID- 30395684 TI - En Face Optical Coherence Tomography Angiography of Primary Vitreoretinal Lymphoma. AB - The authors report a case of a female patient affected by primary vitreoretinal lymphoma (PVRL) showing retinal involvement. In particular, multiple subretinal hyperreflective infiltrates were found on optical coherence tomography (OCT). These alterations appeared hyperautofluorescent on fundus autofluorescence images. Interestingly, they also appeared hyperreflective on OCT angiography images. This case report underlined the high utility of OCT-based methodologies in accurately detecting and describing PVRL features. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e173-e174.]. PMID- 30395685 TI - Quantitative Assessment of the Health Risk for Livestock When Animal Viruses Are Applied in Human Oncolytic Therapy: A Case Study for Seneca Valley Virus. AB - Some viruses cause tumor regression and can be used to treat cancer patients; these viruses are called oncolytic viruses. To assess whether oncolytic viruses from animal origin excreted by patients pose a health risk for livestock, a quantitative risk assessment (QRA) was performed to estimate the risk for the Dutch pig industry after environmental release of Seneca Valley virus (SVV). The QRA assumed SVV excretion in stool by one cancer patient on Day 1 in the Netherlands, discharge of SVV with treated wastewater into the river Meuse, downstream intake of river water for drinking water production, and consumption of this drinking water by pigs. Dose-response curves for SVV infection and clinical disease in pigs were constructed from experimental data. In the worst scenario (four log10 virus reduction by drinking water treatment and a farm with 10,000 pigs), the infection risk is less than 1% with 95% certainty. The risk of clinical disease is almost seven orders of magnitude lower. Risks may increase proportionally with the numbers of treated patients and days of virus excretion. These data indicate that application of wild-type oncolytic animal viruses may infect susceptible livestock. A QRA regarding the use of oncolytic animal virus is, therefore, highly recommended. For this, data on excretion by patients, and dose-response parameters for infection and clinical disease in livestock, should be studied. PMID- 30395686 TI - An N-ethyl-N-nitrosourea (ENU)-induced Tyr265Stop mutation of the DNA polymerase accessory subunit gamma 2 (Polg2) is associated with renal calcification in mice. AB - Renal calcification (RCALC) resulting in nephrolithiasis and nephrocalcinosis, which affects ~10% of adults by 70 years of age, involves environmental and genetic etiologies. Thus, nephrolithiasis and nephrocalcinosis occurs as an inherited disorder in ~65% of patients, and may be associated with endocrine and metabolic disorders including: primary hyperparathyroidism, hypercalciuria, renal tubular acidosis, cystinuria, and hyperoxaluria. Investigations of families with nephrolithiasis and nephrocalcinosis have identified some causative genes, but further progress is limited as large families are unavailable for genetic studies. We therefore embarked on establishing mouse models for hereditary nephrolithiasis and nephrocalcinosis by performing abdominal X-rays to identify renal opacities in N-ethyl-N-nitrosourea (ENU)-mutagenized mice. This identified a mouse with RCALC inherited as an autosomal dominant trait, designated RCALC type 2 (RCALC2). Genome-wide mapping located the Rcalc2 locus to a ~16Mbp region on chromosome 11D-E2 and whole-exome sequence analysis identified a heterozygous mutation in the DNA polymerase gamma-2, accessory subunit (Polg2) resulting in a nonsense mutation, Tyr265Stop (Y265X), which co-segregated with RCALC2. Kidneys of mutant mice (Polg2+/Y265X ) had lower POLG2 mRNA and protein expression, compared to wild-type littermates (Polg2+/+ ). The Polg2+/Y265X and Polg2+/+ mice had similar plasma concentrations of sodium, potassium, calcium, phosphate, chloride, urea, creatinine, glucose and alkaline phosphatase activity; and similar urinary fractional excretion of calcium, phosphate, oxalate and protein. Polg2 encodes the minor subunit of the mitochondrial DNA (mtDNA) polymerase and the mtDNA content in Polg2+/Y265X kidneys was reduced compared to Polg2+/+ mice, and cDNA expression profiling revealed differential expression of 26 genes involved in several biological processes including mitochondrial DNA function, apoptosis and ubiquitination, the complement pathway, and inflammatory pathways. In addition, plasma of Polg2+/Y265X mice, compared to Polg2+/+ littermates had higher levels of reactive oxygen species. Thus, our studies have identified a mutant mouse model for inherited renal calcification associated with a Polg2 nonsense mutation. This article is protected by copyright. All rights reserved. PMID- 30395687 TI - Adding Lateral Spine Imaging for Vertebral Fractures to Densitometric Screening: Improving Ascertainment of Patients at High Risk of Incident Osteoporotic Fractures. AB - The current diagnosis of osteoporosis is limited to a T-score <=-2.5. However, asymptomatic vertebral fractures (VF) are known to predict a high risk of subsequent fractures and pharmaceutical intervention is known to reduce future fracture risk in these individuals. In a prospective, population-based cohort of ambulant older women, we sought to evaluate the role of VF detection by screening densitometric lateral spine imaging (LSI) for VF at time of bone density testing to the effect on the magnitude of fracture risk. A total of 1084 women (mean age 75 years +/- SD 3 years) had baseline LSI that identified 100 (9%) women with VFs and 89 (8%) with femoral neck (FN) T-score osteoporosis <=-2.5. Follow-up identified incident clinical spine fracture in 73 (7%), 305 (28%) with any fracture-related hospitalization, and 121 (11%) with a hip fracture-related hospitalization. Compared with those without baseline VF, in those with baseline VF, relative risk (RR) for incident clinical spine, hip, and any fracture were 3.46 (95% confidence interval [CI] 2.14-5.60, p < 0.001); 1.72 (95% CI 1.09-2.71, p = 0.02), and 1.4 (95% CI 1.07-1.84, p = 0.02), respectively. In 675 (62%) of women with femoral neck osteopenia (T-score <-1 to >-2.5), 61 (9%) also had a VF. Compared with those without baseline VF, RR for any incident fragility fractures and fractures at spine and hip in those with baseline VF were 1.6 (95% CI 1.2 2.1, p < 0.01), 3.9 (95% CI 2.2-6.9, p < 0.01), and 1.6 (95% CI 0.9-2.8, p = 0.10), respectively. On basis of the prognosis, older women with LSI VF with osteopenia should be diagnosed with osteoporosis and should be considered for pharmaceutical intervention. (c) 2018 American Society for Bone and Mineral Research. PMID- 30395688 TI - Cross-cultural, population-based study on adolescent body image and eating distress in Japan and Finland. AB - This cross-sectional population-based survey compares the prevalence of self reported body image and eating distress symptoms among adolescents in Japan and Finland, and associations between emotional/behavioral problems, body image and eating distress from a cross-cultural perspective. The study included 1,840 Japanese and 1,135 Finnish 8th grade students. The self-reported questionnaire included the Body Image and Eating Distress Scale and Strengths and Difficulties Questionnaire (SDQ). The female adolescents from both Finland and Japan reported much greater dissatisfaction with, and concern about, their bodies than the males and Japanese females expressed even higher distress than Finnish females. High levels of body image and eating distress were associated with psychiatric problems measured with the SDQ. There was a significant three-way interaction effect of body image and eating distress, gender and country with SDQ peer problems and prosocial behavior. PMID- 30395689 TI - A Review of Risk Matrices Used in Acute Hospitals in England. AB - In healthcare, patient safety has received substantial attention and, in turn, a number of approaches to managing safety have been adopted from other high-risk industries. One of these has been risk assessment, predominantly through the use of risk matrices. However, while other industries have criticized the design and use of these risk matrices, the applicability of such criticism has not been investigated formally in healthcare. This study examines risk matrices as used in acute hospitals in England and the guidance provided for their use. It investigates the applicability of criticisms of risk matrices from outside healthcare through a document analysis of the risk assessment policies, procedures, and strategies used in English hospitals. The findings reveal that there is a large variety of risk matrices used, where the design of some might increase the chance of risk misprioritization. Additionally, findings show that hospitals may provide insufficient guidance on how to use risk matrices as well as what to do in response to the existing criticisms of risk matrices. Consequently, this is likely to lead to variation in the quality of risk assessment and in the subsequent deployment of resources to manage the assessed risk. Finally, the article outlines ways in which hospitals could use risk matrices more effectively. PMID- 30395690 TI - Identification of genes with universally up- or down-regulated expressions in colorectal cancer. AB - BACKGROUND AND AIM: Differentially expressed (DE) genes detected at the population-level through case-control comparison provide no information on the dysregulation frequencies of DE genes in a cancer. In this work, we aimed to identify the genes with universally up- or down-regulated expressions in colorectal cancer. METHODS: We firstly clarified that DE genes in an individual cancer tissue should be the disease-relevant genes which are dysregulated in the cancer tissue in comparison with its own previously normal state. Then, we identified DE genes at the individual level for 2233 colorectal cancer (CRC) samples collected from multiple data sources using the RankComp algorithm. RESULTS: We found 26 genes which were up- or down-regulated in almost all the 2233 CRC samples and validated the results using 124 CRC tissues with paired adjacent normal tissues. Especially, we found two genes (AJUBA and EGFL6), up regulated universally in CRC tissues, were extremely lowly expressed in normal colorectal tissues, which were considered to be oncogenes in CRC oncogenesis and development. Oppositely, we found one gene (LPAR1), down-regulated universally in CRC tissues, were silenced in CRC tissues but highly expressed in normal colorectal tissues, which were considered to be tumor suppressor genes in CRC. Functional evidences revealed these three genes may induce CRC through deregulating pathways for ribosome biogenesis, cell proliferation and cell cycle. CONCLUSIONS: In conclusion, the individual-level DE genes analysis can help us find genes dysregulated universally in CRC tissues, which may be important diagnostic biomarkers and therapy targets. PMID- 30395691 TI - Bariatric Surgery, Physical Activity, and Fracture Risk. PMID- 30395692 TI - Cardiovascular Autonomic Neuropathy as a new complication of post-surgical chronic hypoparathyroidism. AB - Post-surgical hypoparathyroidism (hypoPT) increases fatigue and seems to affect the risk of mortality. Cardiovascular autonomic neuropathy (CAN) is an impairment of the cardiovascular autonomic system, a cause of increased mortality and associated with increased fatigability. The aim of this study is to evaluate CAN in hypoPT and its relationship with hypocalcemia, PTH levels and hyperphosphatemia. This is a cross-sectional study comparing 51 post-surgical hypoparathyroid patients treated with calcium and calcitriol and 43 control subjects without any PTH/calcium/phosphate disorders who underwent thyroidectomy. CAN was assessed by heart rate (HR) response to deep breathing, HR response to the lying-to-standing test, HR response to the Valsalva maneuver and blood pressure response to standing. Participants were considered to have "early CAN" if they had one abnormal result in the HR tests and "definite CAN" with two or more abnormal results. The prevalence of CAN was 23% in the control group and 78% in the hypoPT group (OR: 11.48, 95% CI: 4.48-32.17). Patients with hypoPT and serum calcium (sCa) >= 8.5 mg/dl had a prevalence of early CAN of 72.4% and the prevalence was 86.4% in those with sCa < 8.5 mg/dl. Definite CAN was found in 2.3% of the control group, 24.1% of the hypoPT group without hypocalcemia, and 59.1% of the hypoPT group with hypocalcemia. In the hypoPT group, the OR for definite CAN in the patients with hypocalcemia compared to the patients with normocalcemia was 4.54 (95% CI: 1.36-15.11). The association between low sCa and definite CAN was confirmed after adjustment for confounders with OR 13.62 (95% CI: 2.12-149.84). No association was found between definite CAN and PTH levels or high phosphate levels. HypoPT is associated with CAN and hypocalcemia seems to affect its severity. Larger and prospective studies are needed to confirm our findings. This article is protected by copyright. All rights reserved. PMID- 30395693 TI - Exploring the relation between posttraumatic stress disorder and interpersonal outcomes: The role of social acknowledgment and trauma type. AB - OBJECTIVES: Research demonstrates consistent relations between posttrauma symptoms and interpersonal dysfunction. The current study examined the extent to which perceptions of community rejection account for the relation between posttraumatic stress disorder (PTSD) and interpersonal outcomes in students exposed to assaultive and nonassaultive trauma. METHOD: Participants (N = 137; 66.4% female; M = 20 years) completed a trauma history interview, questionnaires assessing symptom severity, social disapproval, and interpersonal outcomes. RESULTS: Assault survivors (n = 83) reported greater symptoms (d = 0.57), disapproval (d = 0.80), and social impairment (d = 0.51) relative to the nonassault group (n = 54). However, regression analyses indicated stronger associations between PTSD and community disapproval in survivors of nonassaultive (beta = 0.69; p < 0.001) versus assaultive (beta = 0.34; p < 0.001) events. Indirect effects of PTSD on perceived support and interpersonal functioning through social disapproval were also larger for nonassaultive versus assaultive groups (p < 0.05). CONCLUSION: Despite greater dysfunction among assault survivors, perceptions of disapproval may be a more salient factor for interpersonal dynamics following nonassaultive trauma. PMID- 30395694 TI - Communication interventions for autism spectrum disorder in minimally verbal children. AB - BACKGROUND: Autism spectrum disorder (ASD) has an estimated prevalence of around 1.7% of the population. People with ASD often also have language difficulties, and about 25% to 30% of children with ASD either fail to develop functional language or are minimally verbal. The ability to communicate effectively is an essential life skill, and difficulties with communication can have a range of adverse outcomes, including poorer academic achievement, behavioural difficulties and reduced quality of life. Historically, most studies have investigated communication interventions for ASD in verbal children. We cannot assume the same interventions will work for minimally verbal children with ASD. OBJECTIVES: To assess the effects of communication interventions for ASD in minimally verbal children. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase as well as 12 other databases and three trials registers in November 2017. We also checked the reference lists of all included studies and relevant reviews, contacting experts in the field as well as authors of identified studies about other potentially relevant ongoing and unpublished studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) of communication-focused interventions for children (under 12 years of age) diagnosed with ASD and who are minimally verbal (fewer than 30 functional words or unable to use speech alone to communicate), compared with no treatment, wait-list control or treatment as usual. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. MAIN RESULTS: This review includes two RCTs (154 children aged 32 months to 11 years) of communication interventions for ASD in minimally verbal children compared with a control group (treatment as usual). One RCT used a verbally based intervention (focused playtime intervention; FPI) administered by parents in the home, whereas the other used an alternative and augmentative communication (AAC) intervention (Picture Exchange Communication System; PECS) administered by teachers in a school setting.The FPI study took place in the USA and included 70 participants (64 boys) aged 32 to 82 months who were minimally verbal and had received a diagnosis of ASD. This intervention focused on developing coordinated toy play between child and parent. Participants received 12 in-home parent training sessions for 90 minutes per session for 12 weeks, and they were also invited to attend parent advocacy coaching sessions. This study was funded by the National Institute of Child Health and Human Development, the MIND Institute Research Program and a Professional Staff Congress-City University of New York grant. The PECS study included 84 minimally verbal participants (73 boys) aged 4 to 11 years who had a formal diagnosis of ASD and who were not using PECS beyond phase 1 at baseline. All children attended autism-specific classes or units, and most classes had a child to adult ratio of 2:1. Teachers and parents received PECS training (two-day workshop). PECS consultants also conducted six half-day consultations with each class once per month over five months. This study took place in the UK and was funded by the Three Guineas Trust.Both included studies had high or unclear risk of bias in at least four of the seven 'Risk of bias' categories, with a lack of blinding for participants and personnel being the most problematic area. Using the GRADE approach, we rated the overall quality of the evidence as very low due to risk of bias, imprecision (small sample sizes and wide confidence intervals) and because there was only one trial identified per type of intervention (i.e. verbally based or AAC).Both studies focused primarily on communication outcomes (verbal and non-verbal). One of the studies also collected information on social communication. The FPI study found no significant improvement in spoken communication, measured using the expressive language domain of the Mullen Scale of Early Learning expressive language, at postintervention. However, this study found that children with lower expressive language at baseline (less than 11.3 months age-equivalent) improved more than children with better expressive language and that the intervention produced expressive language gains in some children. The PECS study found that children enrolled in the AAC intervention were significantly more likely to use verbal initiations and PECS symbols immediately postintervention; however, gains were not maintained 10 months later. There was no evidence that AAC improved frequency of speech, verbal expressive vocabulary or children's social communication or pragmatic language immediately postintervention. Overall, neither of the interventions (PECS or FPI) resulted in maintained improvements in spoken or non verbal communication in most children.Neither study collected information on adverse events, other communication skills, quality of life or behavioural outcomes. AUTHORS' CONCLUSIONS: There is limited evidence that verbally based and ACC interventions improve spoken and non-verbal communication in minimally verbal children with ASD. A substantial number of studies have investigated communication interventions for minimally verbal children with ASD, yet only two studies met inclusion criteria for this review, and we considered the overall quality of the evidence to be very low. In the study that used an AAC intervention, there were significant gains in frequency of PECS use and verbal and non-verbal initiations, but not in expressive vocabulary or social communication immediately postintervention. In the study that investigated a verbally based intervention, there were no significant gains in expressive language postintervention, but children with lower expressive language at the beginning of the study improved more than those with better expressive language at baseline. Neither study investigated adverse events, other communication skills, quality of life or behavioural outcomes. Future RCTs that compare two interventions and include a control group will allow us to better understand treatment effects in the context of spontaneous maturation and will allow further comparison of different interventions as well as the investigation of moderating factors. PMID- 30395695 TI - A simple quantitative chiral analysis of amino acid esters by fluorine-19 nuclear magnetic resonance using the modified James-Bull method. AB - A simple chiral analysis of amino acid esters by fluorine-19 nuclear magnetic resonance (19 F NMR) through the modified James-Bull method is described. Thus, amino acid ester acid salt was treated with 5-fluoro-2-formylphenylboronic acid and (S)-BINOL in the presence of triethylamine (TEA) and MS4A for 10 minutes. The reaction mixture was analysed by 19 F NMR directly to afford good quantifications. PMID- 30395697 TI - Perspective. PMID- 30395696 TI - Musculoskeletal Radiology Teaching at a UK Medical School: Do We Need to Improve? AB - The United Kingdom is currently facing crisis due to a shortage of radiology consultants despite ever-increasing demand for medical imaging. The specifics of how best to teach radiology has generated increasing interest. This study aims to determine whether musculoskeletal (MSK) radiology teaching at the University of Nottingham (UoN) Medical School is perceived to be satisfactory by medical students, Foundation-Year doctors, and senior medical professionals in preparing students for the demands working as Foundation-Year doctors. Questionnaires were distributed to all medical students and Foundation-Year doctors that graduated from UoN (n = 307). Semi-structured interviews were conducted with consultants and teaching staff (n = 13). Forty-nine percent of preclinical medical students, 43% of clinical students and 27% of Foundation-Year doctors thought MSK radiology teaching was not sufficient in preparing them for the radiology challenges Foundation-Year doctors' face. This difference was statistically significant (P < 0.001). The consensus from senior medical professionals was that MSK Radiology teaching is currently adequate and producing competent students. Interestingly, only 5% of students were considering a career in radiology compared to 34% of Foundation-Year doctors. Overall, there seems to be concern among students regarding MSK radiology teaching and students have a lack of confidence with MSK radiology. Foundation-Year doctors and senior medical professionals do not share this view. This may be due to medical students' lack of clarity on what is required of them. Formal documentation of set learning objectives for MSK radiology throughout the curriculum may address this. PMID- 30395698 TI - A Noble-Metal-Free Heterogeneous Photosensitizer-Relay Catalyst Triad that Catalyzes Water Oxidation under Visible Light. AB - An entirely earth-abundant chromophore-relay water oxidation catalyst triad system, which is robust and efficient at neutral pH, is presented. The synthesis involves the coordination of a porphyrin derivative to a bridging Fe(CN)5 group, which is then reacted with Co ions to prepare a covalently linked chromophore Prussian blue analogue assembly. Light-driven water oxidation studies in the presence of an electron scavenger indicate that the triad is active and it maintains a steady activity for at least three hours. Transient absorption experiments and computational studies reveal that the Fe(CN)5 group is more than a linker as it takes part in electron-transfer and co-operates with porphyrin in the charge separation process. PMID- 30395699 TI - Catalyst-Substrate Effects on Biocompatible SABRE Hyperpolarization. AB - The hyperpolarization technique, Signal Amplification by Reversible Exchange (SABRE), has the potential to improve clinical diagnosis by making molecular magnetic resonance imaging in vivo a reality. Essential to this goal is the ability to produce a biocompatible bolus for administration. We seek here to determine how the identity of the catalyst and substrate affects the cytotoxicity by in vitro study, in addition to reporting how the use of biocompatible solvent mixtures influence the polarization transfer efficiency. By illustrating this across five catalysts and 8 substrates, we are able to identify routes to produce a bolus with minimal cytotoxic effects. PMID- 30395700 TI - A further insight into the metabolic profile of the nuclear receptor Rev-erb agonist, SR9009. AB - The reactions involved in the metabolic pathways of SR9009 were characterized by liquid chromatography-mass spectrometry (LC-MS) to identify the most appropriate marker(s) of use. The effects of gender, genetic polymorphism, and drug-drug interaction on the metabolic profile of SR9009 were also evaluated. In vitro approaches were based on the use of human liver microsomes and cytochrome P450 isoforms. Sample preparation included an enzymatic hydrolysis (performed only for the phase II investigation) followed by liquid-liquid extraction. The chromatographic separation was carried out using a reverse-phase column; detection was performed by either a triple-quadrupole or a time-of-flight system in positive electrospray ionization and different acquisition modes. In the presence of human liver microsomes, SR9009 was biotransformed to 13 metabolites by CYP3A4, CYP3A5, CYP2C19, and CYP2D6 isoenzymes. The reactions included hydroxylation, de-alkylation, oxidation, and combinations thereof, the de alkylated metabolites being the most abundant. Once formed the mentioned metabolites underwent glucuronidation. Concerning the effects of gender, genetic polymorphism, and drug-drug interaction on the metabolic profile of SR9009, our observation have shown the following: (a) No significant alterations were measured between female and male, (b) significant differences were registered using either the CYP2D6 or CYP2C19 allelic variants, and finally (c) significant alterations were registered in the presence of ketoconazole, miconazole, fluoxetine, nefazodone and paroxetine; moderate variation were instead registered with fluconazole, itraconazole, gestodene, and levonorgestrel. This observation put in evidence the importance to take into account both genetic polymorphism and drug-drug interaction to select the most appropriate marker(s) of use in doping analysis. PMID- 30395701 TI - Templating and Catalyzing [2+2] Photocycloaddition in Solution Using a Dynamic G Quadruplex. AB - We describe a templating/covalent capture strategy that enables photochemical formation of 8 cyclobutanes in one noncovalent assembly. This process was characterized by experiment and quantum mechanical/molecular mechanics (ONIOM) calculations. Thus, KI and 16 units of 5'-cinnamate guanosine form a G-quadruplex where C=C pi bonds in neighboring G4 -quartets are separated by 3.3 A, enabling [2+2] photocycloaddition in solution. This reaction is high-yielding (>90 %), regio- and diastereoselective. Since all components are in dynamic equilibrium this photocycloaddition is catalytic in K+ . PMID- 30395702 TI - Assignment of Absolute-Handedness Chirality of Single-Walled Carbon Nanotubes using Organic Molecule Supramolecular Structures. AB - The supramolecular structures of organic molecules on planar nanocarbon surfaces such as highly oriented pyrolytic graphite (HOPG) have been extensively studied and the factors that control them are generally well-established. In contrast, the properties of supramolecular structures on curved nanocarbon surfaces like carbon nanotubes remain challenging to predict and/or to understand. This paper reports an investigation into the first study of the supramolecular structures of 5,15-bisdodecylporphyrin (C12P) on chiral, concentrated single-walled carbon nanotubes (with right-handed helix P- and left-handed helix M-) surfaces using scanning tunneling microscopy (STM). Furthermore, the study is the first of its kind to experimentally assign the absolute handedness chirality of SWNT, as well as to understand their effect on the supramolecular structures of organic molecules on their surfaces. Interestingly, these SWNT enantiomers resulted in opposite chiral supramolecular structures based on the handedness chirality. With molecular modelling, we predicted the absolute handedness chirality of SWNT, before demonstrating this experimentally. PMID- 30395703 TI - Lipophilic Permeability Efficiency (LPE) reconciles the opposing roles of lipophilicity in membrane permeability and aqueous solubility. AB - As drug discovery moves increasingly toward previously "undruggable" targets such as protein-protein interactions, lead compounds are becoming larger and more lipophilic. Although increasing lipophilicity can improve membrane permeability, it can also incur serious liabilities, including poor water solubility, increased toxicity, and faster metabolic clearance. Here we introduce a new efficiency metric, especially relevant to "beyond-Rule of 5" molecules, that captures, in a simple, unitless value, these opposing effects of lipophilicity on molecular properties. Lipophilic permeability efficiency (LPE) is defined as logD7.4dec/w - mlipo*cLogP + bscaffold, where logD7.4dec/w is the experimental decadiene-water distribution coefficient (pH 7.4), cLogP is the calculated octanol-water partition coefficient, and mlipo and bscaffold are scaling factors to standardize LPE values across different cLogP metrics and scaffolds. Using a variety of peptidic and non-peptidic macrocycle drugs, we show that LPE provides a functional assessment of the efficiency with which a compound achieves passive membrane permeability at a given lipophilicity. PMID- 30395704 TI - Bioactive Carbon Based Hybrid 3D Scaffolds for Osteoblast Growth. AB - Bone, nerve and heart tissue engineering place high demands on the conductivity of three-dimensional (3D) scaffolds. Fibrous carbon based scaffolds are excellent material candidates to fulfill these requirements. Here we show that highly porous (up to 94%) hybrid 3D framework structures with hierarchical architecture, consisting of microfiber composites of self-entangled carbon nanotubes (CNTs) and bioactive nanoparticles are highly suitable for growing cells. The hybrid 3D structures are fabricated by infiltrating a combination of CNTs and bioactive materials into a porous (~ 94%) zinc oxide (ZnO) sacrificial template, followed by removal of the ZnO backbone via a H2 thermal reduction process. Simultaneously the bioactive nanoparticles are sintered. In this way, conductive and mechanically stable 3D composites of free-standing CNT-based microfibers and bioactive nanoparticles are formed. The adopted strategy demonstrates great potential for implementing low-dimensional bioactive materials, such as hydroxyapatite (HA) and bioactive glass nanoparticles (BGN), into 3D carbon-based microfibrous networks. It is demonstrated that the incorporation of HA nanoparticles and BGN promotes the biomineralization ability and the protein adsorption capacity of the scaffolds significantly, as well as fibroblast and osteoblast adhesion. These results demonstrate that the developed carbon-based bioactive scaffolds are promising materials for bone tissue engineering and related applications. PMID- 30395705 TI - In Silico Comparative Study of Human and Porcine Amylin. AB - Islet transplantation is a promising treatment for type 2 diabetes, but its success is impaired by progressive graft loss, likely due to cytotoxic aggregation of the hormone human islet amyloid polypeptide (IAPP) secreted by the endocrine pancreas. Alternatively, the effectiveness of porcine xenotransplantations might be explained by the fibrillization-resistance of the porcine mutant. To better elucidate such molecular mechanisms, we performed comparative replica-exchange molecular dynamics simulations of both human (hIAPP) and porcine (pIAPP) isoforms. The accurate force field Charmm22* with explicit aqueous solvation TIP4P/Ew ensured a minimal structural bias around physiological temperatures. Along which, the peptides are shown to present no structural-phase transition of folding from a microcanonical thermodynamics perspective. Both IAPP isoforms predominantly exhibit random-coil structures, but in a minor percentage we observed a direct alpha-helix -> beta-sheet thermal conversion during the folding process of hIAPP, which is absent in pIAPP. The amyloidogenic segment 20 29 in pIAPP, which hosts 5 out of the 10 overall mutations found in this peptide, is strongly depleted of beta-sheet structures in constrast to hIAPP. Hydrogen bond analysis revealed a predominant frequency of 3-helix contacts in this residue range for pIAPP. These features of pIAPP anticorrelate with the presence of a well-known beta-sheet rich monomeric state that in hIAPP acts as an intermediate inducing oligomerization. PMID- 30395706 TI - Ligand-Specific Dissolution of Iron Oxides in Frozen Solutions. AB - The freezing-enhanced dissolution of iron oxides by various ligands has been recently proposed as a new mechanism that may influence the supply of bioavailable iron in frozen environments. The ligand-induced dissolution of iron oxides is sensitively affected by the kind and concentration of ligands, pH, and kind of iron oxides. While most ligands are thought to be freeze-concentrated in the ice grain boundary region along with iron oxides to enhance the iron dissolution, this study found that some ligands, such as ascorbic acid, suppress the iron dissolution in frozen solution relative to that in aqueous solution. Such ligands are proposed to be preferentially incorporated in the ice lattice bulk and not freeze-concentrated in the liquid-like grain boundary. The experimental analysis estimated that the ionized forms of ligands (e.g., iodide ions) are hardly present in the ice bulk region (<3%) and enhance the iron dissolution in frozen solution (relative to that in aqueous solution), whereas some neutral ligands (e.g., undissociated ascorbic acid) are significantly trapped in the ice bulk (>50%) and suppress the iron dissolution compared to the aqueous counterpart. The present results reveal that the ligand-induced dissolution of iron oxide in frozen solution is not always enhanced relative to aqueous solution but depends upon the kind of ligand and experimental conditions. PMID- 30395707 TI - Biological Weighting Functions for Evaluating the Role of Sunlight-Induced Inactivation of Coliphages at Selected Beaches and Nearby Tributaries. AB - Coliphages can indicate contamination of recreational waters and previous studies show that sunlight is important in altering densities of coliphages, other indicator microorganisms, and pathogens in aquatic environments. Here, we report on laboratory studies of light-induced inactivation of two coliphage groups-male specific (F+) and somatic coliphage-under various conditions in phosphate buffered water (PBW). Strains isolated from wastewater treatment facilities and laboratory strains (MS2 and phiX174 coliphages) were evaluated. Inactivation rates were determined in a series of irradiations using simulated solar radiation passed through light filters that blocked different parts of the ultraviolet spectral region. Inactivation rates and spectral irradiance from these experiments were then analyzed to develop biological weighting functions (BWFs) for the light-induced inactivation. BWFs were used to model the inactivation of coliphages over a range of conditions in aquatic environments that included two beach sites in Lake Michigan and one in Lake Erie. For example, modeled effects of sunlight attenuation, using UV absorption data from the three Great Lakes beach sites, inferred that direct photoinactivation rate constants, averaged over a one-meter water column in swimmable areas, were reduced 2- to 5-fold, compared to near-surface rate constants. PMID- 30395708 TI - Hyperconjugative Aromaticity and Antiaromaticity Control the Reactivities and pi Facial Stereoselectivities of 5-Substituted Cyclopentadiene Diels-Alder Cycloadditions. AB - The reactivities and pi-facial stereoselectivities of Diels-Alder reactions of 5 substituted cyclopentadienes were studied using density functional theory. Burnell and co-workers previously showed that the pi-facial selectivities result from the energies required to distort the reactants into the transition state geometries. We have discovered the origins of these distortions. C5-X sigma donors predistort the cyclopentadiene into an envelope conformation that maximizes the stabilizing hyperconjugative interaction between the C5-X sigma bond and the diene pi-system. This envelope conformation geometrically resembles the anti transition state. To minimize the destabilizing effect of negative hyperconjugation, C5-X sigma-acceptors predistort in the opposite direction toward an envelope geometry that resembles the syn transition state. We now show how hyperconjugative effects of the C5-X substituent influence the stereoselectivities and have developed a unified model rationalizing the stereoselectivities and reactivities of 5-substituted cyclopentadiene Diels-Alder reactions. PMID- 30395709 TI - Helix-Coil Transition Courses Through Multiple Pathways and Intermediates: Fast Kinetic Measurements and Dimensionality Reduction. AB - Nanosecond laser temperature jumps with tryptophan fluorescence detection and molecular dynamics simulation with kinetic dimensionality reduction were used to study the helix-coil transition in a 21-residue alpha-helical heteropeptide. Analysis of the temperature- dependent relaxation dynamics of this heteropeptide identified a distinct faster component of 20-35 ns, besides a slower component of 300-400 ns at temperatures between 296 and 280 K. To understand the mechanism of progression from a non-structured coil state to a structured helical state, we carried out a 12 MUs molecular dynamics simulation of this peptide system. Clustering and optimal dimensionality reduction were applied to the molecular dynamics trajectory to generate low-dimensional coarse-grained models of the underlying kinetic network in terms of 2-5 metastable states. In accord with the generally accepted understanding of the multiple conformations and high entropy of the unfolded ensemble of states, the "coil" metastable set contains the largest number of structures. Interestingly, the helix metastable state was also found to be structurally heterogeneous, consisting of the completely helical form and several partly folded conformers that interconvert at a time scale faster that global folding. The intermediate states contain the fewest structures, have lowest populations, and have the shortest lifetimes. As the number of considered metastable states increases, more intermediates and more folding paths appear in the coarse-grained models. One of these intermediates corresponds to the transition state for folding, which involves an "off-center" helical region over residues 11-16. The kinetic network model is consistent with a statistical picture of folding following a simple reaction coordinate counting the helical population of individual residues. On the basis of simulations, we propose that the fast relaxation time should be assigned to cooperative folding/unfolding of segments of 1-4 neighboring residues. PMID- 30395710 TI - Dynamics and Coherent Control of Exciton-Exciton Annihilation in Aqueous J Aggregate. AB - In aqueous solution of 1,1'-diethyl-2,2'-carbocyanine J-aggregate, the exciton self-trapped (EST) state is usually expected to be negligible. However, in this work, by measuring transient absorption spectroscopy under a variety of excitation fluences, the EST state was found to be formed via coherent exciton exciton annihilation (EEA), when the excitation fluence was high enough. With the existence of a shoulder-stimulated emission band at 615 nm and a broad EST state absorption band at long wavelength, diffusion-limited and coherent EEAs can be distinguished. Adaptive coherent control was employed to check if EEA dynamics can be influenced by a shaped excitation pulse. We found that both the diffusion limited and coherent EEAs can be suppressed. Ground-state vibronic coupling and non-Condon-type exciton-phonon coupling were discussed to explain the observations. PMID- 30395711 TI - Synthetic Control of Tertiary Helical Structures in Short Peptides. AB - Helical secondary and tertiary motifs are commonly observed as binding epitopes in natural and engineered protein scaffolds. While several strategies have been described to constrain alpha-helices or reproduce their binding attributes in synthetic mimics, general strategies to mimic tertiary helical motifs remain in their infancy. We recently described a synthetic strategy to develop helical dimers ( J. Am. Chem. Soc. 2015, 137, 11618-11621). We found that replacement of an interhelical salt bridge with a covalent bond can stabilize antiparallel motifs in short sequences. Here we show that the approach can be generalized to obtain antiparallel and parallel dimers as well as trimer motifs. Helical stabilization requires judiciously designed cross-linkers as well as optimal interhelical hydrophobic packing. We anticipate that these mimics would afford new classes of modulators of biological function. PMID- 30395712 TI - Utilizing Native Directing Groups: Synthesis of a Selective IKur Inhibitor, BMS 919373, via a Regioselective C-H Arylation. AB - BMS-919373 is a highly functionalized quinazoline under investigation as a selective, potent IKur current blocker. By utilizing the aminomethylpyridine side chain at C-4, a selective C-H functionalization at C-5 was invented, enabling the efficient synthesis of this molecule. The strategy of leveraging this inherent directing group allowed the synthesis of this complex heterocycle in only six steps from commodity chemicals. The scope of the C-H activation was further investigated, and the generality of the transformation across a series of bicyclic aromatic heterocycles was explored. PMID- 30395713 TI - Structural Basis of Sirtuin 6 Inhibition by the Hydroxamate Trichostatin A: Implications for Protein Deacylase Drug Development. AB - Protein lysine deacylases comprise three zinc-dependent families and the NAD+ dependent sirtuins Sirt1-7, which contribute to aging-related diseases. Few Sirt6 specific inhibitors are available. Trichostatin A, which belongs to the potent, zinc-chelating hydroxamate inhibitors of zinc-dependent deacylases, was recently found to potently and isoform-specifically inhibit Sirt6. We solved a crystal structure of a Sirt6/ADP-ribose/trichostatin A complex, which reveals nicotinamide pocket and acyl channel as binding site and provides interaction details supporting the development of improved deacylase inhibitors. PMID- 30395714 TI - Microencapsulated Paraffin Phase-Change Material with Calcium Carbonate Shell for Thermal Energy Storage and Solar-Thermal Conversion. AB - A series of microencapsulated phase-change materials (MEPCMs) based on paraffin core and calcium carbonate (CaCO3) shell were synthesized, and the effect of emulsifier type and pH value on morphology, structure, and properties of paraffin@CaCO3 MEPCMs were investigated. The results showed that CaCO3 shell was formed in vaterite and calcite crystalline phase when emulsifier was sodium dodecyl benzene sulfonate and styrene-maleic anhydride (SMA), respectively. When sodium dodecyl sulfate was used as an emulsifier, both vaterite and calcite CaCO3 were formed. The forming mechanism of emulsifier type on CaCO3 crystalline phase was studied. Furthermore, phase-change enthalpy and leakage rate of MEPCMs were related with the type of emulsifier and the pH value of the emulsion. With optimum condition of SMA as emulsifier and pH value of 7, paraffin@CaCO3 MEPCMs had an encapsulation ratio at 56.6% and leakage rate at 2.88%, illustrating its considerable heat storage capability and leakage-prevention property. The 50 heating-cooling cycles test indicated that the MEPCMs owned excellent thermal reliability. The thermal conductivity of MEPCMs was significantly improved due to the existence of CaCO3 shell. In addition to excellent thermal storage ability, the paraffin@CaCO3 MEPCMs also owned good mechanical property and light-to-heat energy conversion efficiency. The characteristics of MEPCMs indicated its potential application in solar energy resource. PMID- 30395715 TI - Current status and evolving treatment for primary liver cancers. PMID- 30395716 TI - Hepatocellular carcinoma surgical therapy: perspectives on the current limits to resection. AB - Hepatocellular carcinoma (HCC) patients often present with late stage disease, which removes surgical resection from the therapeutic treatment options. Only patients with very early disease are recommended for a potentially curative surgical resection. These guidelines have been broadly challenged due to the lack of evidence supporting the use of local therapies over surgery for resectable disease. This review highlights the role of surgical resection for HCC by disease stage, and reports data that supports treatment outside of the accepted Barcelona Clinic Liver Cancer (BCLC) treatment algorithm. As such, the role for surgery in advanced disease is also reviewed. We also highlight the limitations of surgical resection for HCC. With the available data, it is crucial that an update of the current clinical guidelines be introduced, as the current guidelines prohibit the benefit of surgical resection to patients who may be able to achieve a survival benefit. PMID- 30395717 TI - Systemic therapy for hepatocellular carcinoma: beyond sorafenib. AB - Hepatocellular carcinoma (HCC) remains the second leading cause of cancer mortality worldwide and the fifth leading cause of cancer-related deaths in the United States. In 2007, sorafenib became the first Food and Drug Administration (FDA) approved first line systemic treatment for HCC, however, it confers only modest benefit in median overall survival (mOS) and comes with significant side effects. This review article will explore systemic treatments for incurable HCC beyond sorafenib. It will pay particular emphasis to various kinase inhibitors, immunotherapies, and new data on combination therapies. PMID- 30395718 TI - Management of fibrolamellar hepatocellular carcinoma. AB - Fibrolamellar hepatocellular carcinoma (FLHCC) is a primary liver tumor. It is a pathologically distinct variety of hepatocellular carcinoma (HCC). The term 'fibrolamellar' is derived from the presence of thick fibrous collagen bands surrounding the tumor cells. It is a relatively rare tumor of unknown biology. It has a distinctive predilection for adolescents and young adults with no underlying liver disease or cirrhosis. FLHCC patients have higher incidence of lymph node involvement than conventional HCC patients probably owing to larger median tumor size at presentation. Most cases present at an advanced stage at the time of initial diagnosis, however, curative intent treatment options can still be offered to up to 70% of patients. Surgery (resection/liver transplantation) is the current mainstay of treatment and remains the only potentially curative option. As recurrences are common, alternative therapies are under investigation. FLHCCs have traditionally been considered less chemo-responsive than their conventional HCC counterparts, but in advanced cases multimodality treatments can be effective. Compared to stage-matched non-cirrhotic patients with HCC, patients with FLHCC do not have a favourable prognosis and do not respond differently to treatment. The survival advantage observed in FLHCC over conventional HCC is most likely due to younger age at presentation and absence of cirrhosis. PMID- 30395719 TI - Nurses who work rotating shifts consume more energy, macronutrients and calcium when they work the night shift versus day shift. AB - BACKGROUND: Shift work has been associated with increased body mass index (BMI), metabolic disruption and increased chronic disease risk. Typically, these reports compare individuals who work the day shift to those who work the night shift. Because shift assignment is not random, differences may reflect other, unmeasured characteristics that account for outcome differences. OBJECTIVE: To compare dietary intake on days on which the participant worked the night shift to days on which she worked the day shift in a population of female nurses who work rotating shifts at a hospital. METHODS: This cross-sectional study recruited 132 female registered nurses who work rotating shifts in surgical or internal medicine departments. Dietary intake was ascertained using food diaries and analyzed on Tzameret Nutrition Analysis Software (Israel Ministry of Health). Demographic and anthropometric variables were also recorded. RESULTS: Compared to dietary intake on a day the nurse worked the day shift, intake of the following nutrients increased significantly on the day she worked the night shift: energy; protein; carbohydrates; total fat; saturated fat; and calcium. DISCUSSION: A significant increase in calorie, macronutrient and calcium intake on days the night shift was worked compared to days the day shift was worked among female nurses who work rotating shifts was demonstrated. These findings could be extended to other professionals who work rotating shifts, including physicians and allied healthcare personnel. It appears that the difference detected may be influenced by the food supplied by the hospital as well as by increased food intake in general. PMID- 30395720 TI - Letting It All Out: Neutrophils in Early CF Airway Inflammation. PMID- 30395721 TI - A psychometric investigation of the sleep, circadian rhythms, and mood (SCRAM) questionnaire. AB - The sleep, circadian rhythms, and mood (SCRAM) questionnaire (Byrne, Bullock et al., 2017) was designed to concurrently measure individual differences in three clinically important functions: diurnal preference, sleep quality, and mood. The 15-item questionnaire consists of three 5-item scales named Morningness, Good Sleep, and Depressed Mood. The overarching aim of the current project was to investigate the validity and reliability of the questionnaire. Here, we report on associations investigated in three data sets. Study 1 (N = 70, 80% females) was used to examine the test-retest reliability of the questionnaire, finding strong test-retest reliability of the three scales over a 2-week period (r's ranging from 0.73 to 0.86). Study 2 (N = 183, 80% females) enabled us to examine the construct validity of the SCRAM scales against well-validated self-report measures of diurnal preference, sleep quality, and depression. Strong correlations were found between each SCRAM scale and their respective measure in bivariate analyses, and associations were robust after the inclusion of the remaining two SCRAM scales as predictors in regression analyses. Data from Study 3 (N = 42, 100% males) were used to measure the extent to which SCRAM scores correlated with objective measures of sleep-wake behavior using actigraphy. Morningness was found to be related to earlier sleep onset and offset times, and Good Sleep was related to higher sleep efficiency but to no other measures of sleep quality; Depressed Mood was not related to actigraphy measures. The findings provide provisional support for construct validity and reliability of the SCRAM questionnaire as a measure of diurnal preference, sleep quality, and depressed mood. Future research into the psychometrics of SCRAM should test the questionnaire's discriminant and predictive validity in clinical samples. PMID- 30395722 TI - A comparison of drug substance predicted chemical stability with ICH compliant stability studies. AB - OBJECTIVE: The aim of this study is to demonstrate the applicability of predictive stability studies to the degradation of drug substances. SIGNIFICANCE: The use of predicted stability studies during pharmaceutical development and in regulatory submissions is increasing, particularly in early phase to support an initial retest period/shelf life claim in the absence of standard stability data. These studies offer an alternative to standard stability testing and can facilitate clinical trials to be started earlier and medicines to reach patients faster. They involve a short-term stressed stability study, typically designed to degrade a drug substance or product to the specification level of the shelf life limiting attribute. The results are used to predict degradation under long-term storage conditions and enable stability understanding to be gained over a short time frame, using limited amounts of material. METHODS: In this work, Accelerated Stability Assessment Program (ASAP) studies were performed for 10 different drug substances and the predictions obtained for chemical degradation were compared to ICH compliant stability data. RESULTS: Across the studies good agreement was achieved, with the initial retest period predictions from the ASAP studies being conservative by design. When minimal degradation was observed during an ASAP study, it was demonstrated that at least a 12-month initial retest period could be supported. CONCLUSION: This comparison of ASAP predictions and ICH compliant stability data has demonstrated the ability of well-designed ASAP studies to predict the long-term chemical stability of drug substances. PMID- 30395723 TI - Pulmonary Vascular Disease in Premature Infants: Early Predictive Models of Late Respiratory Morbidity. PMID- 30395724 TI - Trends in COPD Hospitalization and In-Hospital Deaths in the United States by Sex: 2005-2014. PMID- 30395725 TI - A Mixed-Effects Location Scale Model for Dyadic Interactions. AB - We present a mixed-effects location scale model (MELSM) for examining the daily dynamics of affect in dyads. The MELSM includes person and time-varying variables to predict the location, or individual means, and the scale, or within-person variances. It also incorporates a submodel to account for between-person variances. The dyadic specification can accommodate individual and partner effects in both the location and the scale components, and allows random effects for all location and scale parameters. All covariances among the random effects, within and across the location and the scale are also estimated. These covariances offer new insights into the interplay of individual mean structures, intra-individual variability, and the influence of partner effects on such factors. To illustrate the model, we use data from 274 couples who provided daily ratings on their positive and negative emotions toward their relationship - up to 90 consecutive days. The model is fit using Hamiltonian Monte Carlo methods, and includes subsets of predictors in order to demonstrate the flexibility of this approach. We conclude with a discussion on the usefulness and the limitations of the MELSM for dyadic research. PMID- 30395726 TI - Generational Patterns of Asthma Incidence among Immigrants to Canada over Two Decades: A Population-based Cohort Study. AB - RATIONALE: Canada, an industrialized country with high endemic asthma rates is characterized by a large immigrant population. OBJECTIVES: Comparing asthma rates among recent immigrants relative to long term residents of Canada may provide insight into the relative contribution of environmental exposure to asthma risk. METHODS: This was a population-based retrospective cohort study performed using provincial health administrative data for all residents of Ontario, Canada. Residents with and without a diagnosis of asthma from fiscal years 1996 - 2012 were included. Individuals were categorized as being immigrants (landed in Canada after 1985) or long-term residents of Ontario by linkage with Immigration, Refugees and Citizenship Canada's Permanent Resident Database. We calculated the age- and sex- standardized incidence of asthma among residents of Ontario, and compared the incidence of asthma among immigrants and long-term residents using incidence rate ratios. RESULTS: Analysis of approximately 11.7 million records showed that 2.2 immigrants arrived to Canada during the study period, with >50% from East and South Asia and the Pacific. We found that asthma incidence was lower among immigrants compared to long-term residents (Incidence Rate Ratio (IRR) 0.30 95% CI: 0.30, 0.30, p<0.001). However, Ontario-born children of immigrants from most world regions had significantly higher asthma incidence compared to children of long-term residents (IRR 1.44, 95% CI: 1.43, 1.45, p<0.001). The overall incidence of asthma in Ontario decreased between 1996 and 2012 (ptrend<0.001). Immigrants contributed to only a small proportion of the asthma incidence in Ontario, and changes within this group did not significantly affect trends in the overall Ontario population asthma incidence. CONCLUSIONS: The higher asthma incidence seen among children of immigrants but not in their parents suggests that being born in Canada was critical for determining asthma risk. These findings support the importance of in-utero and/or early life exposures on asthma development. PMID- 30395728 TI - Oral delivery of the anti-tumor necrosis factor alpha domain antibody, V565, results in high intestinal and fecal concentrations with minimal systemic exposure in cynomolgus monkeys. AB - OBJECTIVE: V565 is a novel oral anti-tumor necrosis factor (TNF)-alpha domain antibody being developed for topical treatment of inflammatory bowel disease (IBD) patients. Protein engineering rendered the molecule resistant to intestinal proteases. Here we investigate the formulation of V565 required to provide gastro protection and enable optimal delivery to the lower intestinal tract in monkeys. METHODS: Enteric-coated V565 mini-tablets were prepared and dissolution characteristics tested in vitro. Oral dosing of monkeys with enteric-coated mini tablets containing V565 and methylene blue dye enabled in vivo localization of mini-tablet dissolution. V565 distribution in luminal contents and feces was measured by enzyme-linked immunosorbent assay (ELISA). To mimic transit across the damaged intestinal epithelium seen in IBD patients an intravenous (i.v.) bolus of V565 was given to monkeys and pharmacokinetic parameters of V565 measured in serum and urine by ELISA. RESULTS: Enteric-coated mini-tablets resisted dissolution in 0.1 M HCl, before dissolving in a sustained release fashion at neutral pH. In orally dosed monkeys methylene blue intestinal staining indicated the jejunum and ileum as sites for mini-tablet dissolution. Measurements of V565 in monkey feces confirmed V565 survival through the intestinal tract. Systemic exposure after oral dosing was very low consistent with limited V565 mucosal penetration in healthy monkeys. The rapid clearance of V565 after i.v. dosing was consistent with renal excretion as the primary route for elimination of any V565 reaching the circulation. CONCLUSIONS: These results suggest that mini-tablets with a 24% Eudragit enteric coating are suitable for targeted release of orally delivered V565 in the intestine for topical treatment of IBD. PMID- 30395729 TI - Pharmacologic Exhaustion of Suppressor Cells with Tasquinimod Enhances Bacterial Clearance during TB. PMID- 30395730 TI - Preliminary study of the reliability and validity of the Johns Hopkins Adapted Cognitive Exam (Chinese version) in neurological intensive care unit patients. AB - OBJECTIVE: To evaluate the reliability and validity of the Chinese version of the Johns Hopkins Adapted Cognitive Exam (ACE) in neurological intensive care unit patients. DESIGN: The English version of the ACE was translated and adapted into Chinese. The cognitive function of 40 critically ill NICU patients was assessed using the Chinese version of the ACE and the Mini-mental state examination (MMSE) battery. Scores on the ACE and MMSE were analyzed, and the scale's content validity, construct validity, concurrent validity, internal consistency, inter rater reliability, and test-retest reliability metrics were determined. RESULT: The coefficients for the Pearson correlations between individual item scores and total score ranged from 0.617 to 0.938, and content validity was good. ACE scores were significantly correlated with MMSE scores(r = 0.822, p<0.05). Five factors were extracted during the principal component analysis, the cumulative contribution of which was 85.90%. Overall, the factor loading of each item was 0.5, and the scale had good construct validity. The Chinese version of the ACE demonstrated good internal consistency (Cronbach'alpha = 0.756), inter-rater reliability (ICC>0.95), and test-retest reliability (ICC = 0.652-0.979). CONCLUSIONS: The results of this study suggest that the Chinese version of the ACE was a reliable and valid screening tool for cognitive impairment in NICU patients. List of abbreviations: ACE: (Johns Hopkins Adapted Cognitive Exam); NICU : (neurological intensive care unit); MMSE: (Mini-Mental State Examination); SPSS: (the Statistical package for the Social Sciences); ICC: (Intra-class Correlation Coefficients); SCCM: (Society of Critical Care Medicine); PICS: (post intensive care syndrome); ARDS:(acute respiratory distress syndrome); MoCA; (Montreal Cognitive Assessment); EFA: (exploratory factor analysis). PMID- 30395731 TI - Self-Reported Executive Dysfunction, Fatigue, and Psychological and Emotional Symptoms in Physically Well-Functioning Long-Term Survivors of Pediatric Brain Tumor. AB - Long-term executive function (EF), psychological and emotional difficulties, and fatigue among adult survivors of pediatric brain tumors (PBTs) are sparsely studied. One hundred and fourteen adult PBT survivors, 89 PBT survivor informants, and a healthy control group completed questionnaires assessing these domains. Significant differences between PBT survivors and controls were found on all self-reported measures, most strongly on measures reflecting EF. Patients reported significantly more difficulties with metacognitive aspects of EF compared to behavioral aspects. PBT survivors reported more psychological symptoms and executive dysfunction than their informants. These findings should be taken into consideration in long-term neuropsychological and psychosocial follow-ups. PMID- 30395732 TI - Mood rhythmicity is associated with depressive symptoms and caffeinated drinks consumption in South American young adults. AB - Among the factors that contribute to the onset and maintenance of depressive disorders, rhythmicity of symptoms and consumption of caffeine have recently gained attention. The current study aimed to examine the differential rhythmicity of relevant variables in a sample of young participants, considering the presence of depressive symptomatology and the frequency of caffeinated drinks consumption. A significant 24-hour differential rhythmicity of mood, cognitive and physiological variables was found indicating an evening peak pattern in the participants with depressive symptoms. Interestingly, caffeinated drinks consumption was differentially associated with self-perceived peaks, according to the presence of depressive symptomatology. Our findings are among the first reports about the potential association of the 24-hours rhythmicity of relevant mood-related variables, depressive symptoms, and caffeine intake. These results support the view that the identification of risk factors for depression, and the application of novel measurements and analysis methods in the development of new preventive strategies should be a public health priority. PMID- 30395733 TI - Social jetlag and menstrual symptoms among female university students. AB - Menstrual symptoms may have a significant impact on women's lives. Many women experience menses-related health problems, such as menstrual pain, heavy menstrual bleeding, and premenstrual syndrome, during their reproductively fertile years. Circadian misalignment in shift workers has been reported to contribute to menstrual cycle irregularity and/or painful menstruation. However, the relationship between social jetlag (SJL) and menstrual symptoms/menstrual cycle has not been elucidated. In this study, we aimed to elucidate this relationship among female university students. One-hundred and fifty female university students (mean [SD]: 18.8 [0.71]-years old) completed self-reported questionnaires consisting of menstrual symptoms and menstrual cycle, sleep quality and sleep habits, quality of life, and demographic variables. The average menstrual cycle was 32.0 [5.4] days. The percentage of students who showed menstrual cycle irregularity, having less than 25 days or more than 39 days of menstrual cycle during the previous four menstrual cycles, was 60.6%. SJL, the difference between mid-sleep time on free days and mid-sleep time on school days, was categorized into small (absolute SJL < 1 h) or large (>=1 h). Overall, 78.0% of participants had SJL >= 1 h. Among the menstrual symptoms, pain, behavioral change, and water retention subscale scores were significantly higher in the SJL >= 1 h group than in the SJL < 1 h group. However, no significant differences were found in concentration, autonomic reaction, or negative affect subscale scores between the two groups. The menstrual cycle was 31.2 [5.5] days in the SJL < 1 h group and 32.2 [5.4] days in the SJL >= 1 h group, without significant difference. Logistic regression analysis showed that more than 1 h of SJL was a significant associated factor with severe menstrual symptom, independently of sleep duration and late chronotype. This study indicated that SJL was a significant factor associated with severe menstrual symptoms, suggesting the possibilities of association between circadian system and reproductive function among humans. PMID- 30395735 TI - Intra-aortic Balloon Occlusion for Acetabular Fractures: Concept and Proof. PMID- 30395734 TI - Favorable response to asthma-dosed subcutaneous mepolizumab in eosinophilic pneumonia. AB - INTRODUCTION: Mepolizumab targets eosinophils in the treatment of asthma. The dose used for asthma is considerably lower than that used for treating eosinophilic granulomatosis with polyangiitis, a recently approved indication. While intravenous mepolizumab use has reported utility in non-asthma eosinophilic disorders, the efficacy of the subcutaneous asthma dosing of the drug for eosinophilic pneumonia is not known. CASE STUDY: A middle-aged female was diagnosed with eosinophilic pneumonia. The patient's clinical/radiologic/laboratory findings, response to treatment, and respiratory function studies are described. RESULTS: A woman, born in 1962, had repeated pneumonia hospitalizations from 2007 through 2010. In October 2010, a lung biopsy showed findings consistent with chronic eosinophilic pneumonia and chronic asthma. The patient also had chronic sinusitis. Long term systemic corticosteroids were prescribed but the patient became oxygen dependent by 2014. Omalizumab was administered for 1 year starting in 2015 without improvement in symptoms. In 2016, mepolizumab 100 mg subcutaneously every 4 weeks was initiated. Symptomatic improvement with decreased oxygen and systemic corticosteroid requirements were noted. A chest CT performed in February 2018 showed marked improvement compared to a study in 2016. Interval spirometric improvements were noted. Peripheral blood eosinophils/mm3 prior to mepolizumab were 237, and while on mepolizumab were 10. CONCLUSION: Parenchymal eosinophilic lung disease may respond to asthma-dosed mepolizumab. Mepolizumab treatment in asthma where concomitant interstitial disease is suspected, may offer an advantage over omalizumab in the ability to reduce eosinophils not only in airways, but also in lung parenchyma. PMID- 30395736 TI - Circulating S100A8/A9 Levels Reflect Intraocular Inflammation in Uveitis Patients. AB - PURPOSE: To investigate whether there is an association between circulating S100A8/A9 levels and uveitis activity. METHODS: A total of 549 plasma samples were collected from uveitis patients and non-uveitic controls. RESULTS: S100A8/A9 plasma levels were elevated in uveitis patients compared to non-uveitic controls (P < 0.001). S100A8/A9 plasma levels in patients with active acute anterior uveitis (AAU) were significantly elevated and remarkably decreased in parallel with the severity of intraocular inflammation after corticosteroid treatment (P < 0.001). S100A8/A9 plasma levels were also higher in AAU patients with ankylosing spondylitis (AS) than in patients without AS (P = 0.02). S100A8/A9 plasma levels were significantly increased in uveitis patients with elevated C-reactive protein (CRP, P = 0.004) or erythrocyte sedimentation rates (ESR, P = 0.049) levels compared to uveitis patients with normal CRP or ESR values. CONCLUSION: Circulating S100A8/A9 might be a useful biomarker for the measurement of intraocular inflammation. PMID- 30395737 TI - The Effects of Different Treatments on Postoperative Pancreatic Fistula (POPF). PMID- 30395738 TI - Antituberculous Treatment Itself Might Prevent Visual Impairment in Presumed Tuberculosis-Related Uveitis. AB - PURPOSE: To study the risk factors for visual loss in presumed tuberculosis related uveitis (TRU). METHODS: Retrospective observational cohort study of patients with TRU, either treated or not for tuberculosis, from January 2005 to January 2017. Clinical and demographic variables were recorded. Main outcome measure was a loss of visual acuity (VA) of >=2 Snellen lines. A Generalized Estimation Equation was used to control between-eyes bias. A backward stepwise logistic regression multivariate analysis was conducted to elucidate independent risk factors. RESULTS: One hundred and thirty-eight eyes from 82 patients were included. There were 45 males, median age at onset of uveitis was 40 years (Interquartile range, IQR 24). The median follow-up was 36 months (IQR 49.75) and 51 patients completed antituberculous treatment (ATT) for a mean of 9.37 months. In the multivariate model, ATT was the only independent protective factor for loss of VA (OR 0.13, 95% CI 0.04-0.37, p < 0.001). CONCLUSION: ATT itself may prevent visual loss in TRU. PMID- 30395739 TI - How does one decide the best pharmacotherapeutic strategy for bacterial peritonitis? PMID- 30395740 TI - Evidence-Based and Patient-Centered Medicine with Shared Decision Improves Colonoscopy Efficacy in Poor Bowel Preparation Patients. PMID- 30395741 TI - Intra-Aortic Balloon Occlusion Decreases Blood Loss During Open Reduction and Internal Fixation for Delayed Acetabular Fractures: A Retrospective Study of 43 Patients. AB - AIM: It is difficult to treat delayed acetabular fractures due to massive blood loss during operation. Temporary balloon occlusion of the abdominal aorta was introduced into sacral tumor surgery to reduce intraoperative hemorrhage. The aim of this study was to investigate the effect of this method on reduction of intraoperative blood loss and analyze the complications of this technique in the treatment of delayed acetabular fracture. METHODS: We retrospectively reviewed 43 patients with delayed acetabular fracture who were surgically treated through combined approaches. Nineteen patients underwent temporary balloon occlusion of the abdominal aorta; 10 patients had type B fracture and 9 patients had type C fracture according to the Muller AO classification. The remaining 24 patients were classified into a control group; 14 patients had type B fracture and 10 patients had type C fracture. Surgical time, intraoperative blood loss, blood transfusion, satisfactory reduction rate, and functional recovery were recorded and compared between two groups. Merle d'Aubigne and Postel scoring was applied to evaluate the patients. RESULTS: The patients treated with intra-aortic balloon occlusion had a shorter surgical time (p = 0.008), less intraoperative blood loss (p = 0.005), and less transfused blood units (p = 0.001). No complications caused by balloon occlusion. No significant difference were observed in the outcomes and the complications related to acetabular fractures between two groups. CONCLUSIONS: Temporary balloon occlusion of the abdominal aorta is a reliable technique to control bleeding for the surgery of delayed acetabular fracture. PMID- 30395742 TI - Interprofessional education and practice guide: interprofessional team writing to promote dissemination of interprofessional education scholarship and products. AB - Collaborations to develop, implement, evaluate, replicate, and write about interprofessional education (IPE) activities within and across institutions are wonderful opportunities to experience teamwork, team communication, ethics and values, and the roles and responsibilities of interprofessional team writing. Just as effective communication in interprofessional team-based care is essential for providing safe, high-quality health care, similar communication strategies are necessary to produce high-quality scholarship of IPE curricula and activities. Relationship and communication issues that affect health care teams' abilities to work together effectively (e.g., hierarchy, exclusion, assumptions, non-responsiveness, biases, stereotypes and poor hand-offs of information) can also occur in interprofessional team writing. Between 1970 and 2010, interprofessional practice research publications increased by 2293%. Although there has been tremendous growth in the IPE literature, especially of articles that require collaborative writing, there have not been any papers addressing the challenges of interprofessional team writing. As more teams collaborate to develop IPE, there is a need to establish principles and strategies for effective interprofessional team writing. In this education and practice guide, a cross institutional team of faculty, staff, and graduate students who have collaborated on externally funded IPE grants, conferences, products, and workshops will share lessons learned for successfully collaborating in interprofessional team writing. PMID- 30395743 TI - Mesenchymal stem cells overexpressing Ang1 attenuates phosgene-induced acute lung injury in rats. AB - Phosgene-induced acute lung injury (P-ALI) is characterized by inflammation and effective treatments are lacking. Angiopoietin-1 (Ang1) has the beneficial effects on P-ALI. Mesenchymal stem cells (MSCs) have the potential for re epithelization and recovery in lung injury. Thus, we hypothesized that Ang1 expressing MSCs would have beneficial effects on P-ALI. Here, an Ang1 expressing lentiviral vector was constructed and infected into rat bone marrow MSCs. Histological analyses revealed significant pathological improvements especially after treatment with MSCs in the rats exposed to phosgene. Ang1 facilitated the homing of MSCs to injured lung tissue and significantly increased expression of both epithelial cell marker Aquaporin-5 (AQP5) and surfactant protein-C (SPC) in the lung tissues. Moreover, MSCs-Ang1 reduced level of pro-inflammatory cytokines TGF-beta1 and IL-1beta and increased the expression of the anti-inflammatory cytokine IL-10 in the serum and bronchoalveolar lavage fluid (BALF) of P-ALI rats. In conclusion, our results suggest that Ang1 may improve the therapeutic potential of MSCs for P-ALI treatment. PMID- 30395744 TI - The characterization of asthma with blood eosinophilia in adults in Latin America. AB - OBJECTIVE: To identify and characterize asthma with blood eosinophilia in adults. METHODS: This cross-sectional study consisted of 164 asthma patients, aged 18 years or older. Multivariate analyses by logistic regression were performed to identify clinical characteristics and biomarkers associated with asthma with blood eosinophilia (defined as asthma and a peripheral blood eosinophil count >=400 cells/mm3). To evaluate the diagnostic accuracy of these biomarkers, the sensitivity, specificity and predictive values were calculated. Additionally, the area under the receiver operating characteristic (ROC) curve (AUC) was estimated for each biomarker. RESULTS: Overall, 37.8% (95%CI: 30.7-45.4%) of asthma patients had blood eosinophilia. The following factors were associated with this characteristic: patient age <50 years (OR 3.25; 95% CI: 1.33-7.94), a serum level of IgE >=300 UI/mL (OR 2.32; 95%CI: 1.14-4.75), and an Asthma Control Test (ACT) score <20 points (OR 3.10; 95%CI: 1.35-4.75); asthma with blood eosinophilia was also associated with a baseline FEV1/FVC <70% (OR 2.68; 95%CI: 1.28-5.59). On the other hand, age <50 years and ACT score <20 showed the highest sensitivity (above 80% each). Serum IgE level >=300 UI/mL had the highest specificity (almost 68%). Finally, those with an ACT score <20 had the highest AUC (68%). CONCLUSIONS: In our study population, one-third of asthmatic adults had asthma with blood eosinophilia. Furthermore, the prevalence was greater in those <=50 years of age; these patients experienced more severe, more poorly controlled asthma and had higher total serum IgE levels. PMID- 30395745 TI - Infographics or video; which one is more effective in asthmatic patients' health? a randomized clinical trial. AB - OBJECTIVE: Asthma disease is a complex medical condition for which the control of symptoms depends on sufficient patient knowledge, self-care, and adherence to medication protocols. Researchers conducted this study to evaluate the impact of infographics and video on asthma patients' adherence to medication. METHODS: A randomized clinical trial in which 80 asthmatics were enrolled and allocated to two study groups (infographic and video groups). Researchers used questionnaires to gather demographic data. A nurse assessed Morisky adherence to medication. Researchers performed data analysis using repeated measurements and Least Significant Difference (LSD) in SPSS software version 23. RESULTS: There was no significant difference between the two study tracks (P > 0.05) in the demographic data and adherence to medication in the pretest. The differences between the two intervention groups throughout the one-month follow-up were statistically significant (P < 0.05). There were significant differences between the two intervention groups in pretest and post-test, and pretest and follow-up (P < 0.05). However, there were no significant differences between the two intervention groups in post-test and follow-up (P > 0.05). CONCLUSIONS: According to the study findings, both the infographic and video formats may have led to an increase in adherence to medication protocols among asthma patients; but it seems that the infographic format is preferred for long- term use because it does not require usage of a facility. However, education format of asthmatic people is dependent on conditions and patient preferences. PMID- 30395746 TI - Pleural Pressure Differences Before Removal Are Greater in Patients Who Develop Residual Pneumothorax Post Chest Drain Removal. AB - AIM OF STUDY: We aimed to investigate whether the difference in pleural pressures (DeltaP) is wider among patients who develop a residual pneumothorax after chest tube removal following lung resection surgery. MATERIALS AND METHODS: Ninety eight patients who underwent lung resection were included in the study over a period of 12 months. The DeltaP prior to chest tube removal in patients who developed a residual pneumothorax after chest tube removal was compared with that of patients who did not develop this complication. The receiver operating characteristic (ROC) curve analysis was performed to identify cutoff values of DeltaP for the prediction of residual pneumothorax. Logistic regression analysis was used to formulate a prediction model for the occurrence of residual pneumothorax based on DeltaP. RESULTS: Thirteen patients who developed a residual pneumothorax were compared with 85 patients without this complication. The DeltaP in the residual pneumothorax group was significantly higher (10.8 versus 4.2 cm H2O, p < 0.01). The DeltaP in patients who required intervention was also significantly higher (14.8 versus 4.2 cm H2O, p < 0.01). A DeltaP cutoff value of 8 cm H2O was predictive of the occurrence of residual pneumothorax (sensitivity 85.6%, specificity 84.6%) and a value of 12 cm H2O was predictive of intervention (sensitivity 84%, specificity 85%). Increasing DeltaP was an independent predictor of the occurrence of residual pneumothorax (p = 0.008) on the multivariate logistic regression model. CONCLUSION: Patients with wide DeltaP before chest drain removal may be complicated with residual pneumothorax. PMID- 30395747 TI - Short duration clinically-based interprofessional shadowing and patient review activities may have a role in preparing health professional students to practice collaboratively: a systematic literature review. AB - Interprofessional education is important to help prepare and develop a health professional workforce that practices collaboratively. The aim of this systematic review was to examine the benefits of participation in short duration clinically based interprofessional activities for health care professional students. Eight electronic databases (MEDLINE, CINAHL, PUBMED, EMBASE, PsychINFO, PEDRO, ERIC, OT Seeker) were searched from inception to June 2017. Full-text English-language studies reporting outcomes of short duration clinically-based interprofessional activities involving health professional students from at least two disciplines were included. Studies were excluded if they evaluated longer duration, iterative or simulation-based interprofessional activities. Data were analysed descriptively and using content analysis based on the Core Competencies for Interprofessional Collaborative Practice framework. Of 521 identified articles, 13 were identified for inclusion and assessed for quality independently by two reviewers. The included studies assessed two types of interprofessional activities (shadowing and patient reviews) completed by a range of different student cohorts including those from medicine, pharmacy, nursing, dietetics, physiotherapy, occupational therapy, social work, podiatry, speech pathology, and medical imaging. Students perceived shadowing a health professional from another discipline, for between 2 and 10 hours during the early stages of their training, improved their understanding across all domains of the Core Competencies for Interprofessional Collaborative Practice framework. Students who completed patient review activities with at least one other student or staff member from another discipline, for 2.5 to 4 hours during the later stages of their training, described developing clinical skills in addition to improving their understanding of the roles and responsibilities and teamwork domains of the Core Competencies for Interprofessional Collaborative Practice framework. A low quality body ofevidence suggests short duration clinically-based interprofessional activities may help prepare health professional students to work collaboratively. PMID- 30395748 TI - Cross-sectional survey study to examine underuse of twice daily inhaled maintenance therapy among patients with asthma. AB - OBJECTIVE: Anecdotal evidence suggests that some patients with asthma intentionally use their twice-daily (BID) inhaled controller therapy once daily (QD), thus not achieving optimal dosing levels. This study identified the prevalence of and factors associated with intentional QD use of BID-indicated controllers among adult patients with asthma. METHODS: This was a cross-sectional survey study of adults using inhaled controllers intended for BID dosing for treatment of asthma and/or COPD. Survey responses were linked to administrative claims data for the prior 12 months (baseline). Results of patients indicating both an asthma diagnosis and current intentional QD or BID use of controllers are presented. RESULTS: Of 1401 patients with asthma, 30.9% reported intentional QD use of their controller and 69.1% reported BID use. Intentional QD use was mostly a function of patients' lack of perceived need for BID treatment (44.1%) or physician orders to take their controller QD (34.0%). Patients reporting intentional QD use tended to be healthier (higher health status scores, and lower Charlson comorbidity scores, ambulatory and ER visits, and healthcare costs) with better asthma control (lower asthma-related ER and ambulatory visits and rescue medication use, and higher Asthma Control Test scores) compared with patients reporting BID use. CONCLUSIONS: Perceptions regarding health and the necessity of controller use to control or treat asthma were the main drivers of medication taking behavior. Patients with less severe asthma were more likely to report once daily use of their inhaled controller, but still maintained asthma control. PMID- 30395749 TI - Parent experiences with a nurse-supervised community health worker asthma home visiting program. AB - OBJECTIVE: This study seeks to identify helpful components of a nurse-supervised Community Health Worker (CHW) asthma home-visiting program, obtain feedback from parents and families about their experiences, and receive suggestions for new services that the program could provide. METHODS: Likert scale ratings and semi structured qualitative interviews were conducted with parents who were selected from a representative sample and previously participated in the program. Five point Likert scale ratings from 1 (not helpful) to 5 (very helpful) were obtained for 11 program components. Interviews were analyzed using a grounded theory participatory approach. Data were analyzed and themes were identified by two different coders using Dedoose software. RESULTS: A total of 22 participants were enrolled and 20 participants completed Likert scale ratings and qualitative interviews. Likert scale ratings (mean standard deviation [SD]) show that program strengths include asthma education (4.75 [0.55]), supplies (4.65 [0.99]), help with housing conditions (3.94 [1.56], pest management (3.79 [1.69]) and greater access to community resources (3.70 [1.30]). The ratings suggest that families need more help with other social determinants of health, such as school, lack of enough money or food, and mental health and behavioral concerns (3.05 [1.78]). Interviews echoed these ratings and revealed several themes about family and parental stress, children's activity limitations, desire for outreach after the 12-month intervention, a need for help with other social determinants and more emotional support. CONCLUSIONS: This study shows that the program was well received and reveals the importance of addressing social determinants of health and behavioral health concerns. PMID- 30395751 TI - Compound pesticide controlled release system based on the mixture of poly(butylene succinate) and PLA. AB - Controlled release system has been widely developed and utilised in agriculture to optimise efficacy and minimise environmental pollution. Here, the azoxystrobin and difenoconazole compound pesticide microsphere was constructed by the solvent evaporation method. Blending poly (butylene succinate) (PBS) and poly (lactic acid) (PLA) as shells, in order to increase its entrapment efficiency and match the goal of complex synergism. The resulting microsphere processes high entrapment efficiency with a mean diameter of 7.2 MUm. Acute toxicity suggested microsphere on zebrafish was moderate toxicity. Comparative studies revealed that the microsphere had a longer period of sustained release than difenoconazole azoxystrobin (5:8) 32.5% w/v suspension concentrate (SC). In addition, the concentration ratio of active ingredients closed to the optimum compound stoichiometry, which can achieve the objective of improving the efficacy of the pesticides. These results demonstrated that such a compound pesticide microsphere delivery system may be a considerable potential for further exploration. PMID- 30395750 TI - Association Study of ARMC9 Gene Variants with Vogt-Koyanagi-Harada Disease in Japanese Patients. AB - PURPOSE: To investigate whether variants in the ARMC9 gene encoding KU-MEL-1 are associated with Vogt-Koyanagi-Harada (VKH) disease in a Japanese population. METHODS: We recruited 380 Japanese patients with VKH disease and 744 Japanese healthy controls to genotype seven single-nucleotide polymorphisms (SNPs) in ARMC9. We also performed imputation analysis of the ARMC9 region and 195 imputed SNPs were included in the statistical analysis. RESULTS: We observed an increased frequency of the A allele of rs28690417 in patients compared with controls (P = 0.0097, odds ratio (OR) = 1.46). The A allele had a dominant effect on VKH disease risk (P = 0.011, OR = 1.51). However, these significant differences disappeared after Bonferroni correction (corrected P > 0.05). The remaining 201 SNPs did not show any significant association with disease risk. CONCLUSIONS: Our study suggests that ARMC9 variants do not play a critical role in the development of VKH disease. PMID- 30395752 TI - Serum 1,25(OH)2 Vitamin D and 25(OH) Vitamin D Ratio for the Diagnosis of Sarcoidosis-Related Uveitis. AB - PURPOSE: The diagnostic workup of uveitis is challenging, with 30 to 50% of cases remaining of undetermined etiology despite multiple investigations. Sarcoid granuloma-related increase of 1,25(OH)2D levels could be helpful for the diagnosis of ocular sarcoidosis. METHODS: Monocentric retrospective cohort study of patients for whom serum 25(OH)D and 1,25(OH)2D levels were measured during the etiologic workup of unexplained uveitis in a tertiary referral center. The diagnoses of uveitis' underlying diseases were established according to international diagnostic criteria. RESULTS: Fifty-nine patients were included. The diagnosis of defined, presumed or probable sarcoidosis was made in 37% of patients while 41% of cases remained of undetermined origin. The median serum levels of 25(OH)D in patients with ocular sarcoidosis and in those with uveitis due to another cause were 34.50 [21.2-40.8] and 43.20 [32.2-58.3] nmol/L (P=0.02), respectively. In the same subgroups of patients, the median serum levels of 1,25(OH)2D were 132.4 [107.4-163.9] and 108.0 [84.30-130.5] pmol/l (P=0.02), and the median 1,25(OH)2D/25(OH)D ratio was 4.17 [3.11-5.09] and 2.56 [1.54-3.37] (P=0.0007) respectively. A 1,25(OH)2D/25(OH)D ratio >3.5 was associated with the diagnosis of sarcoidosis with a 68 % sensitivity and a 78% specificity and, in univariate analysis, was associated with an abnormal chest CT scan (OR=5.7, P=0.003), granulomas on bronchial biopsy (OR=14.7, P=0.007) and bronchoalveolar lavage fluid lymphocytosis (OR=12.4, P=0.0006). CONCLUSION: The measurement of serum 25(OH)D and 1,25(OH)2D levels is a useful tool in the etiological workup of patients with unexplained uveitis, since a high 1,25(OH)2D/25(OH)D ratio is suggestive of ocular sarcoidosis. PMID- 30395753 TI - Spectrum of Newly Diagnosed Cytomegalovirus Retinitis in a Developing Country in the HAART Era. AB - PURPOSE: To characterize the presenting features of cytomegalovirus (CMV) retinitis in HIV-positive patients in a developing country in the HAART era. METHODS: Retrospective chart review of all patients with CMV retinitis seen at a tertiary-care referral center between January 2006 to June 2017. Demographic and clinical data were collected to study the presenting features and risk factors for blindness. RESULTS: Fifty-five patients with treatment-naive CMV retinitis were enrolled; 75% were males. CD4 counts were below 50 cells/uL in 51.1%. Bilateral presentation was seen in 61.5%. Half (50.6%) of the eyes were blind at first examination. Zone 1 involvement was present in 46% of the eyes. Retinal area involvement > 25% was the only factor associated significantly with higher incidence of blindness (p = 0.016). CONCLUSIONS: There was extensive and bilateral presentation of CMV retinitis due to delayed presentation. Screening for CMV retinitis, irrespective of CD4 counts, may help in developing nations. PMID- 30395754 TI - Laser treatment for facial acne scars: A review. AB - BACKGROUND AND OBJECTIVES: Acne scarring is a widely prevalent condition that can have a negative impact on a patient's quality of life and is often worsened by aging. A number of options are available for the treatment of acne scarring, including retinoids, microdermabrasion, dermal fillers, and surgical techniques such as subcision. The aim of this review is to evaluate the different laser modalities that have been used in peer-reviewed clinical studies for treatment of atrophic acne scars, and summarize current clinical approaches. MATERIALS AND METHODS: A Medline search spanning from 1990 to 2016 was performed on acne scarring. Search terms included "atrophic acne scars," "ablative'', "nonablative," "fractional," "nonfractional," "neodymium," "alexandrite," "pulsed dye" lasers, and results are summarized. RESULTS: Various types of lasers have been evaluated for the treatment of atrophic acne scars. While they are efficacious overall, they differ in terms of side effects and clinical outcomes, depending on patients skin and acne scar type. A new emerging trend is to combine lasers with other energy-based devices and/or topicals. CONCLUSION: Evaluation of the literature examining acne scar treatment with lasers, revealed that clinical outcomes are dependent on various patient factors, including atrophic acne scar subtype, patient skin type, treatment modality, and side-effect profile. PMID- 30395755 TI - Examining perceptions from in situ simulation-based training on interprofessional collaboration during crisis event management in post-anesthesia care. AB - Due to the potentially life-threatening conditions and risk of severe complications, post-anesthesia care units (PACU) require prompt team interventions. Miscommunication among professionals during crisis event management may directly affect patient safety. Therefore, developing strategies to enhance interprofessional collaboration (IPC) among critical care teams should be prioritized. In situ simulation (ISS) can be valuable in improving patient safety because it allows the practice of care team dynamics within a real clinical environment. However, its impact on IPC has yet to be demonstrated. The aim of this study was to evaluate the effect of in situ simulation-based training on interprofessional collaboration and satisfaction toward co-workers during crisis event management in post-anesthesia care. A quasi-experimental study, pretest and post-test design with a paired control group was performed. A convenience sample (N = 69) was recruited from the healthcare professionals of the regular PACU team. The intervention group (N = 33) underwent a 6-hour ISS based interprofessional training session. Three scenarios of deteriorating cases encountered in critical care settings were used, each followed by a debriefing period. The measured outcomes were evaluated by the Collaborative Work Questionnaire and the Satisfaction Towards Coworkers Questionnaire. Questionnaires were answered by the two groups before the intervention (T1), immediately after (T2) and six to eight weeks later (T3). We found that the change from baseline (T1) was different between the groups for global IPC (F = 3.88; p = 0.025) and for communication (F = 4.09; p = 0.021). Regarding global IPC, we observed a significant group effect from T1 to T2 (F = 5.65; p = 0.021) and from T1 to T3 (F = 5.34; p = 0.024). Furthermore, we observed a significant time effect for the experimental group (F = 4.06; p = 0.027). Regarding communication, we observed a significant group effect from T1 to T2 (F = 7.5; p = 0.001). In conclusion, ISS-based training had a slight impact on self-assessed IPC and communication during crisis event management in the PACU. The use of ISS should be promoted among critical care teams to enhance IPC and contribute to patient safety. PMID- 30395756 TI - Vitamin D supplementation during pregnancy and the risk of wheezing in offspring: a systematic review and dose-response meta-analysis. AB - BACKGROUND: In the past few years, growing evidence supports a preventive role of vitamin D supplementation during pregnancy for wheezing or asthma in offspring. However, the optimal dose of vitamin D intake is unclear. We conducted a meta analysis to examine the linear and nonlinear dose-response pattern of vitamin D intake during pregnancy and asthma or wheezing in offspring. QUESTIONS/PURPOSES: The purpose of this study was to answer the following question: Which dose of vitamin D is more effective in preventing wheezing in offspring? METHOD: We identified relevant studies by searching PubMed, EMBASE and CENTRAL up to December 2017 and by hand-searching reference lists. Meta-analysis and subgroup analysis were performed. Fixed or random effects model linear trends analyses were conducted based on the heterogeneity test. Then, if the data did not show linear trends, we considered a nonlinear trend analysis instead. RESULTS: A total of 6068 participants were included in the study. Our analysis showed an inverse relationship between the intake of vitamin D during pregnancy and the occurrence of wheezing in offspring (pooled OR = 0.68, 95% CI = 0.55-0.83, I2 = 24%, Z statistic = 3.64, p < 0.01). We found a nonlinear U-shaped association between vitamin D supplementation during pregnancy and asthma or wheezing in offspring, with the lowest risk at approximately 800 IU/d. Publication bias was shown in a funnel plot without Egger's test. CONCLUSIONS: Vitamin D intake during pregnancy is inversely related to wheezing or asthma in offspring. Furthermore, the trend analysis indicates that offspring may benefit from approximately 800 IU/d vitamin D intake during pregnancy. PMID- 30395757 TI - Can Tramadol be Used for Maintenance Treatment of Opioid Dependence? AB - BACKGROUND: Certain limitations of the existing opioid substitution therapies necessitate exploration of other options for maintenance of patients with opioid dependence. This study aimed to present the experience of use of tramadol for long-term treatment of patients with opioid dependence. METHODS: This was a cross sectional interview-based observational study conducted in Uttar Pradesh state in India. Patients with opioid dependence who received oral tramadol treatment for a period of more than 6 months were recruited. Outcome was assessed in terms of self-reported abstinence on tramadol. RESULTS: A total of 102 participants were recruited in the study, with a mean age of 41.3 years. All the participants were males. Abstinence to extraneous opioids was reported by 58.8% of the sample, and the median dose of tramadol at which abstinence was achieved was 350 mg/d. Those who reported to be taking natural opioids (raw opium or poppy husk) at the time of seeking treatment had higher rates of achieving abstinence. CONCLUSIONS: Tramadol may be a possible option for the maintenance treatment among some opioid dependent individuals. Further studies are required to establish its efficacy vis a-vis other medications used in opioid substitution treatment. PMID- 30395758 TI - Increased virulence in Pseudomonas aeruginosa at pathological glucose levels. PMID- 30395759 TI - Perceived Discrimination and Substance Use among Adolescents: Examining the Moderating Effect of Distress Tolerance and Negative Urgency. AB - BACKGROUND: Perceived discrimination has been found to increase substance use vulnerability among adolescent populations. However, less is known about individual level factors which may moderate this risk. OBJECTIVES: The aim of the current study is to examine whether two emotion-based personality traits (i.e., distress tolerance and negative urgency) moderates the effect of perceived discrimination on substance use. We hypothesized that high distress tolerance would decrease risk, while high negative urgency would increase risk for substance use as a consequence of discrimination. METHODS: 108 youth ages 12-18 (68.6% male; 56.2% African-American) provided data on perceived discrimination, distress tolerance, negative urgency, and substance use (i.e., alcohol and marijuana use). RESULTS: Contrary to our hypothesis, no moderating effect was observed for negative urgency. Distress tolerance was found to moderate the relationship, but in the opposite direction than expected. CONCLUSIONS: It is speculated that this counterintuitive finding may be due to the racial/ethnic composition of the sample, suggesting that distress tolerance may operate differently among minority youth. Further research examining these relationships among minority youth is warranted. PMID- 30395760 TI - The Direct and Indirect Influences of Parenting: The Facets of Time-Perspective and Impaired Control Along the Alcohol-related Problems Pathway. AB - BACKGROUND: Social Learning Theory suggests how one conceptualizes time will be passed from parent to child (Bandura & Walters, 1963). Through the lens of Behavioral Economics Theory (Vuchinich & Simpson, 1998), impaired control may be characterized as consuming alcohol as a form of immediate gratification as a choice over more distal rewards. Because impaired control reflects a self regulation failure specific to the drinking situation, it may be directly related to time-perspectives. OBJECTIVES: This investigation explored whether or not the indirect influences of perceived parenting styles on alcohol use and related problems is mediated by both facets of time-perspective (e.g. hedonism, present fatalism, future, past-positive, past-negative) and impaired control over drinking. METHODS: We examined a structural equation model with 391 (207 women; 184 men) college student drinkers. We used an asymmetric bias-corrected bootstrap technique to conduct mediational analyses (MacKinnon, 2008). RESULTS: Higher levels of past-positive time-perspective were indirectly linked to both less alcohol use and fewer alcohol-related problems through less impaired control. In contrast, higher levels of present-fatalism were indirectly linked to more alcohol use through more impaired control. Higher levels of father permissiveness and mother authoritarianism were indirectly linked to both more impaired control and alcohol use through more present-fatalism. In addition, higher levels of father authoritarianism were indirectly linked to more alcohol use through more hedonism. CONCLUSIONS/IMPLICATIONS: Our results support the notion that drinking beyond one's self-prescribed limits is associated with time-perspectives related to negative aspects of the parent-offspring socialization process, such as fatalism. PMID- 30395761 TI - The use of in vitro transcriptional data to identify thresholds of effects in a human lens epithelial cell-line exposed to ionizing radiation. AB - PURPOSE: The International Commission on Radiological Protection (ICRP) recently recommended reducing the occupational equivalent dose limit for the lens of the eye. Based primarily on a review of epidemiological data, the absorbed dose threshold is now considered to be 0.5 Gy independent of dose-rate and severity of opacification, reduced from the previous threshold of 2 Gy. However, direct mechanistic evidence to support an understanding of the underlying molecular mechanisms of damage is still lacking. To this end, we explored the effects of a broad dose-range of ionizing radiation exposure on gene expression changes in a human lens epithelial (HLE) cell-line in order to better understand the shape of the dose-response relationship and identify transcriptional thresholds of effects. METHODS: HLE cells were exposed to doses of 0, 0.01, 0.05, 0.25, 0.5, 2, and 5 Gy of X-ray radiation at two dose rates (1.62 cGy/min and 38.2 cGy/min). Cell culture lysates were collected 20 h post-exposure and analyzed using whole genome RNA-sequencing. Pathways and dose-thresholds of biological effects were identified using benchmark dose (BMD) modeling. RESULTS: Transcriptional responses were minimal at doses less than 2 Gy. At higher doses, there were a significant number of differentially expressed genes (DEGs) (p<=.05, fold change>=|1.5|) at both dose rates, with 1308 DEGs for the low dose rate (LDR) and 840 DEGs for the high dose rate (HDR) exposure. Dose-response modeling showed that a number of genes exhibited non-linear bi-phasic responses, which was verified by digital droplet PCR. BMD analysis showed the majority of the pathways responded at BMD median values in the dose range of 1.5-2.5 Gy, with the lowest BMD median value being 0.6 Gy for the HDR exposure. The minimum pathway BMD median value for LDR exposure, however, was 2.5 Gy. Although the LDR and HDR exposures shared pathways involved in extracellular matrix reorganization and collagen production with BMD median value of 2.9 Gy, HDR exposures were more effective in activating pathways associated with DNA damage response, apoptosis, and cell cycling relative to LDR exposure. CONCLUSIONS: Overall, the results suggest that radiation induces complex non-linear transcriptional dose-response relationships that are dose-rate dependent. Pathways shared between the two dose rates may be important contributors to radiation-induced cataractogenesis. BMD analysis suggests that the majority of pathways are activated above 0.6 Gy, which supports current ICRP identified dose thresholds for deterministic effects to the lens of the eye of 0.5 Gy. PMID- 30395762 TI - Knowledge, attitudes, behaviours, and beliefs of healthcare provider students regarding mandatory influenza vaccination. AB - Influenza infection poses the same risk to healthcare students as practicing clinicians. While there is substantial dialog about the benefits, risks, and ethics of mandatory influenza immunization policies in Canada, there has been little engagement of healthcare students. To explore the knowledge, attitudes, beliefs, and behaviours of healthcare students, we administered a web-based survey to students at Dalhousie University. Influenza vaccination status varied by program type, with 86.3% of medical students (n = 124) and 52.4% of nursing students (n = 96) self-reporting receipt of the influenza vaccine both in the previous and current seasons; pharmacy students' coverage fell between the two. Pharmacy students had higher mean knowledge scores (10.0 out of 13 questions) than medical (9.26) and nursing (8.88) students. Between 56.1 and 64.5% of students across disciplines were in support of a mandatory masking or vaccination policy, and between 72.6 and 82.3% of students would comply if such a policy were in place. A sense of duty to be immunized, desire to be taught more about influenza and influenza vaccine, belief that the hospital has a right to know vaccination status, support for declination policy, and willingness to accept consequences of noncompliance were all predictors of student support of mandatory policies. Medical and pharmacy students tended to hold more pro-influenza vaccination attitudes, had higher knowledge scores, and better vaccine coverage than nursing students. Based on the overall vaccination behavior, knowledge, beliefs, and attitudes of students surveyed in this study, mandatory influenza immunization policies are generally supported by the next generation of practitioners. PMID- 30395763 TI - The first World Health Organization International Standard for infliximab products: A step towards maintaining harmonized biological activity. AB - Due to the increase in the number of infliximab products, the need for global harmonization of the bioactivity of this monoclonal antibody was recognized by the World Health Organization (WHO). In response, the National Institute for Biological Standards and Control (NIBSC) developed the first international standard (IS) for infliximab, which targets tumour necrosis factor (TNF). Each ampoule is assigned values of 500 IU of TNF neutralizing activity and 500 IU of binding activity. Two preparations of infliximab were formulated and lyophilized at NIBSC prior to evaluation in a collaborative study for their suitability to serve as an IS for the in vitro biological activity of infliximab. The study involved participants using in vitro cell-based bioassays (TNF neutralization, antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity) and binding assays. The results of this study showed that the candidate preparation, coded 16/170, is suitable as an IS for infliximab bioactivity. This infliximab IS from NIBSC, is intended to support in vitro bioassay calibration and validation by defining international units of bioactivity. The proposed unitages, however, are not intended to revise product labelling or dosing requirements, as any decisions regarding this relies solely with the regulatory authorities. Furthermore, the infliximab IS is not intended for determining the specific activity of products, nor to serve any regulatory role in defining biosimilarity. We briefly discuss the future use of WHO international standards in supporting the global harmonisation of biosimilar infliximab products. PMID- 30395764 TI - Integrated analysis of lncRNA-mRNA co-expression networks in the alpha-particle induced carcinogenesis of human branchial epithelial cells. AB - PURPOSE: To identify the mRNA and long noncoding RNA (lncRNA) expression profiles and explore the lncRNA-mRNA co-expression networks associated with the carcinogenesis induced by alpha-particles. MATERIALS AND METHODS: Immortalized human bronchial epithelial cell line, BEP2D, and its two malignant transformed cell lines, BERP35T-1 and BERP35T-4, were investigated. The lncRNA and mRNA expression profiles of BEP2D, BERP35T-1 and BERP35T-4 were generated. lncRNAs and mRNAs co-expression analysis was performed. RESULTS: The microarray identified 668 lncRNAs in BERP35T-1 cells and 555 in BERP35T-4 cells that were differentially expressed compared to BEP2D cells. The GO terms and KEGG pathway annotation data indicated that mitotic cell cycle, DNA repair, apoptotic processes, and RNA splicing functional pathways were significantly associated with the alpha-particle induced cell carcinogenesis. Co-expression network analysis revealed 8902 interactions between 495 differentially expressed mRNAs and 430 corresponding lncRNAs in BERP35T-1 cells compared with BEP2D cells. The genes, situated at the important nodes of the co-expression network, include B3GNT5, RAD23, YWHAZ (14-3-3zeta), FBXW11, TGFBR2, LRP6, PSMD11, MYL12A, etc. Conclusions: This pilot study is the first to explore epigenetic mechanisms of alpha-particle induced carcinogenesis of human bronchial epithelial cells. It provides basic information for further investigation into the detail mechanisms underlying radiation-induced lung cancer. PMID- 30395765 TI - Myriad of Health Care Financing Reforms in Zambia: Have the Poor Benefited? AB - Zambia has implemented a number of financing and organizational reforms since the 1990s aimed at increasing efficiency, enhancing equity, and improving health outcomes. This study reviews the distributional impact of these health reforms on enhancing equity at the regional level and for different socioeconomic groups. Data from three nationally representative household surveys were collected, and a benefit incidence analysis was conducted to determine the distributional impact over the period 2010-2015. The results show that distribution of subsidies and utilization of outpatient services at public health facilities in Zambia has consistently been in favor of urban provinces. Further, distribution of health subsidies across the ten provinces in Zambia does not correspond to reported illnesses in each province. The study also shows that utilization of outpatient services at public (hospitals and health centers) and private health facilities is generally in favor of the rich, and utilization of both inpatient and outpatient services at public and private health facilities benefits the rich more than the poor. And although the results show a pro-poor redistribution of benefits across income groups in 2015 compared to 2010 whereby the poorest two income groups received more than a 20% share of benefits in each quintile, the benefits were still lower than their health needs. This is contrary to the richest two income groups whose share of benefits was higher than their health needs in both 2010 and 2015. The study concludes that Zambia has not yet fully attained its long-term health reform vision of "equity of access to quality health care" despite years of successive health reforms. The study calls for the Zambian government to complement strategies on financial risk protection with deliberate supply- and demand-side actions in order to enhance equity. Improvements in long- and short-term planning and regular monitoring and evaluation are critical. PMID- 30395766 TI - More than just Alcohol: Marijuana and Illicit Drug Use at Parties Attended by 15 20 Year Olds. AB - BACKGROUND: Parties are a common setting for marijuana and illicit drug use among adolescents. OBJECTIVES: This study examined the context of parties with alcohol, marijuana and illicit drug use attended by adolescents and young adults. METHODS: In 2016, an address-based sample of 1,764 15-20-year-olds in 24 U.S. communities participated in an online survey. Parties were categorized as alcohol-only (Alc only), marijuana + alcohol (Mj + Alc), and illicit + marijuana + alcohol (ID + Mj + Alc) based on survey participants' observations and self-reported drug use at the last party attended. Multivariable logistic regression was used to identify correlates of substance use at parties. RESULTS: 1,089 participants (61.7%) reported ever attending a party where alcohol was consumed. Of those, 60.1% reported that the last party they attended had Alc-only, 24.9% had Mj + Alc, and 10.0% had ID + Mj + Alc. Older participants were more likely to attend a party with Mj + Alc or ID + Mj + Alc. Participants whose mother had a college degree (compared to less than a college degree) were less likely to attend a party with ID + Mj + Alc. Parties with Mj + Alc and ID + Mj + Alc were larger and the majority of attendees were under 21. Parties with ID + Mj + Alc were more likely to be majority female compared to mixed gender. Parties with Mj + Alc were more likely to occur at someone else's home and be in states where medical and recreational marijuana use was legal. CONCLUSION: One-third of parties attended by 15-20-year-olds had marijuana and/or illicit drug use in addition to alcohol consumption. The identified risk factors of parties with marijuana and illicit drug use can be used to develop targeted prevention strategies. PMID- 30395767 TI - LncRNA SNHG5 affects cell proliferation, metastasis and migration of colorectal cancer through regulating miR-132-3p/CREB5. AB - We aimed at the effects of long non-coding RNA (lncRNA) SNHG5 on proliferation, metastasis and migration of colorectal cancer (CRC) cells. We also investigated regulatory relationships among miR-132-3p, SNHG5 and CREB5 and their roles in CRC. 25 pairs of samples containing CRC tissues and matched para-tumor tissues were obtained to examine SNHG5, miR-132-3p and CREB5 expression by qRT-PCR or Western blot. The targeted relationship between miR-132-3p and SNHG5 or CREB5 was confirmed by dual luciferase report assay as well as RNA pull down assay. The expression of SNHG5, miR-132-3p and CREB5 in CRC cells were regulated by cell transfection. CRC cellular proliferation was assayed by CCK-8 and meanwhile flow cytometry was adopted to observe apoptosis. Metastasis and migration of CRC cells were determined respectively by means of Transwell assay and scratch test. The effects of SNHG5 on CRC were researched in vivo, too. SNHG5 or CREB5 was up regulated in CRC tissues and cells, whereas miR-132-3p was down-regulated. Overexpression of SNHG5 and CREB5 resulted in the enhancement of proliferation, metastasis, migration and the inhibition of apoptosis in CRC cells, while miR-132 3p led to the opposite result. LncRNA SNHG5 promoted proliferation, migration and metastasis of CRC cells but inhibited apoptosis by modulating miR-132-3p/CERB5. PMID- 30395768 TI - Pancreatic Cancer Gene Therapy Delivered by Nanoparticles. AB - Pancreatic cancer is one of the most lethal forms of cancer and has proven to be difficult to treat through conventional methods, including surgery and chemotherapy. Gene therapy serves as a potential novel treatment to interfere with genes that make this cancer so aggressive, but free nucleic acids have low cell uptake due to their negative charge and are unstable in circulation. Nanoparticles can serve as an effective carrier for a wide variety of gene therapies for pancreatic cancer as they can improve the circulation time, decrease the recognition by the immune system, and be functionalized to target specific surface proteins. In this review, we focus on therapeutic strategies using nanoparticles as carriers of small interfering RNA (siRNA), microRNA (miRNA), and gene augmentation (DNA) therapies in the context of pancreatic cancer. Lastly, we discuss the future outlook of nanoparticle-based therapies, including challenges in the clinical setting. PMID- 30395769 TI - Multiple Marginality and the Variation in Delinquency and Substance use Among Adolescent Gang Members. AB - BACKGROUND: Gang membership is a significant contributor to delinquency and violent victimization among adolescents. Yet, there is considerable variability in the extent to which gang members engage in delinquency and substance use, and previous research suggests factors beyond the individual level are important to consider. OBJECTIVES: Using the multiple marginality framework, this study examines the factors related to the family, school, and neighborhood contexts that may contribute to delinquency and substance use among current gang members. METHODS: Between 2013 and 2015, we conducted quantitative surveys with 449 self identified gang members between the ages of 14 and 19 years old in Milwaukee, Wisconsin. Surveys included measures to assess delinquency, substance use, parental involvement, educational attainment, drug distribution, and police involvement. We ran simple and multiple regressions to assess the relationship between family, school, and neighborhood factors and delinquency and substance use. RESULTS: Regression analyses revealed several significant predictors of delinquency and substance use among adolescent gang members including parental substance use and incarceration, school safety, police contact, and neighborhood disorder. CONCLUSIONS: Family and school factors are likely important protective factors against delinquency and substance use among gang members. Interventions at the family and community level may be particularly important in reducing poor health and social outcomes for adolescent gang members. PMID- 30395771 TI - Logistical and structural challenges are the major obstacles for family medicine physicians' ability to administer adult vaccines. AB - PURPOSE: This study was conducted to characterize the vaccination practices and challenges of family medicine physicians in Los Angeles County, California. METHODS: The Los Angeles Academy of Family Physicians (LA AFP) sent out electronic surveys to all of their active members (N = 1121) between December 2017 and January 2018, and asked them to answer questions about themselves, their practice, their patient population, and their immunization practices and challenges. We then analyzed the results through basic statistical calculations and Pearson's chi-squared tests. RESULTS: Seventy-four people (6.6%) responded to the survey, and 75% of responders stated that they administer all Advisory Committee on Immunization Practices (ACIP) recommended vaccines. The lowest vaccine administration rates were for the high-dose influenza vaccine, which 66.2% (n = 49) of respondents reported to administer, followed by the meningococcal B vaccine (68.9%; n = 51). The respondents who belonged to practices with more than 11 providers, were part of a large hospital or healthcare system, had electronic medical records (EMRs), and used the California Immunization Registry (CAIR) were more likely to report to vaccinate. The number one responding physician-reported challenge to vaccination was limited time and resources to address patient resistance followed by vaccine cost and lack of infrastructure to store vaccines. CONCLUSIONS: In this pilot study, structural and logistical challenges appeared to make the biggest impact on adult vaccination for the responding family medicine physicians. Solutions addressing these challenges will help improve the adult immunization rates. PMID- 30395770 TI - Anatomical Characterization of an Optic Disc Notch Using SD-OCT in Glaucoma. AB - PURPOSE: To characterize anatomical dimensions of a disc notch using novel methods using spectral domain optical coherence tomography (SD-OCT). PARTICIPANTS: All age- and severity-matched glaucoma patients with disc notch (defined as complete loss of neural rim with no residual rim between disc and cup) seen from 2014 to 2015 who underwent enhanced depth imaging with SD-OCT (Cirrus HD-OCT version 6.5, Carl Zeiss, USA) were included for this retrospective observational study. METHODS: Using known dimensions of the 200 * 200 optic disc cube (6 * 6 mm), the notch width was calculated from the margins of the notch on either side using ImageJ software. The height was calculated from the lowest margin of the cup to the lowest point of the defect on the optic disc. These were compared with the quadrant retinal nerve fiber layer (qRNFT) and sectoral retinal nerve fiber layer (sRNFLT) thickness in notch and the sector 2 clock hours adjacent to the notch region (SaRNFLT). RESULTS: The height and width of the notch in 31 eyes of 27 patients were 2.6 +/- 0.48 mm and 2.23 +/- 0.31 mm. The RNFL thickness in the same sector as that of the notch was 41 +/- 21.06 um while the adjacent two sectors measured 62 +/- 26.5 and 64 +/- 26.5 um on either sides of the sector of the notch. The difference between the sRNFLT and saRNFLT ranged from -9 to 67 and -13 to 50 um, respectively. This difference was significantly associated with height of the notch (R2 = 20.8, p = 0.01). CONCLUSION: Automated analysis of a notch and RNFL thickness in that sector can help in precise glaucoma monitoring in the region of interest. PMID- 30395772 TI - Role of IL-17RA in the proliferative priming of hepatocytes in liver regeneration. AB - A tight link has been established between inflammation and cancer. Liver regeneration is a widely used model to study the correlation between inflammation and proliferation. IL-6 is essentially involved in liver regeneration and in cancer. Recently, IL-17A has been shown to regulate not only inflammation, but also cell proliferation. Here, we analyze the role played by IL-17A signaling in liver regeneration by comparing cell proliferation in Wild Type and IL-17RA-/- mice. Partial hepatectomy experiments performed in IL-17RA-/- mice showed a delay in expression of early-genes to prime the residual hepatocyte to proliferate, with subsequent delay in G1/S-phase transition. We demonstrated that IL-17RA regulates, by recruitment of non-parenchymal cell, the expression of IL-6, which in turn triggers the proliferation of residual hepatocytes. Our data indicate an important role played by IL-17RA in liver proliferation via IL-6. PMID- 30395774 TI - Cost-impact study of rotavirus vaccination programme in Scotland. AB - AIM: In July 2013, the Scottish Government introduced a rotavirus vaccination programme into the childhood immunisation schedule. The aim of this research was to estimate the cost-impact of this programme. METHODS: Data for rotavirus related resource use were identified including laboratory reports, hospitalisations, attendances at accident and emergency departments (A&E), general practice consultations (GP), calls to the National Health Service telephone helpline (NHS24) and prescriptions for common rehydration treatments. We used an interrupted time series analysis approach to assess the impact on resource utilisation in all categories. Appropriate costs were added to the models and predicted pre-and post-vaccination mean annual costs were estimated. The cost of the vaccination programme was estimated using costs from the literature. RESULTS: The vaccination programme was associated with a reduction in utilisation in all measured healthcare resource categories. These reductions were all statistically significant (at the 95% level) with p-values less than 0.001. Reductions ranged from 18% in calls to NHS24 to 73% in positive laboratory reports. The vaccination programme was associated with a reduction in annual healthcare resource costs of 38% (L595,000 per 100,000 infants < 5 years old) in our measured categories (including L495,000 from a reduction in hospital stays). The annual overall cost-impact of the rotavirus vaccination programme (the cost of delivering the programme minus the reduction in resource costs) was estimated at approximately L435,000 per 100,000 infants < 5 years old. CONCLUSION: The rotavirus vaccination programme was associated with a reduction in all measured categories of rotavirus-related resource use by infants < 5 years old. PMID- 30395773 TI - MicroRNAs are involved in the hypothalamic leptin sensitivity. AB - The central nervous system monitors modifications in metabolic parameters or hormone levels (leptin) and elicits adaptive responses such as food intake and glucose homeostasis regulation. Particularly, within the hypothalamus, pro opiomelanocortin (POMC) neurons are crucial regulators of energy balance. Consistent with a pivotal role of the melanocortin system in the control of energy homeostasis, disruption of the Pomc gene causes hyperphagia and obesity. Pomc gene expression is tightly controlled by different mechanisms. Interestingly, recent studies pointed to a key role for micro ribonucleic acid (miRNAs) in the regulation of gene expression. However, the role of miRNAs in the leptin sensitivity in hypothalamic melanocortin system has never been assessed. We developed a transgenic mouse model (PDKO) with a partial deletion of the miRNA processing enzyme DICER specifically in POMC neurons. PDKO mice exhibited a normal body weight but a decrease of food intake. Interestingly, PDKO mice had decreased metabolic rate by reduction of VO2 consumption and CO2 production which could explain that PDKO mice have normal weight while eating less. Interestingly, we observed an increase of leptin sensitivity in the POMC neurons of PDKO mice which could explain the decrease of food intake in this model. We also observed an increase in the expression of genes involved in the function of brown adipose tissue that is in polysynaptic contact with the POMC neurons. In summary, these results support the hypothesis that Dicer-derived miRNAs may be involved in the effect of leptin on POMC neurons activity. PMID- 30395775 TI - Developmental pathways of adolescent cannabis use: Risk factors, outcomes and sex specific differences. AB - BACKGROUND: Characterizing patterns of adolescent cannabis use (CU), as well as risk factors and outcomes uniquely associated with these pathways is essential for informing treatment and prevention efforts. Yet, few studies have examined these issues among youth at-risk of engaging in problematic cannabis use. Further, research accounting for use of other substances or sex differences in patterns of CU remains exceedingly sparse. METHODS: Trajectory-based modeling was used to identify underlying CU pathways among a predominantly Hispanic (90%) sample of at-risk youth (n = 401; 46% female) across adolescence (ages~14-18), controlling for baseline substance use and participant demographics. Adolescent psychopathology (i.e., conduct disorder, attention deficit hyperactivity disorder, anxiety, and depression) was examined as a predictor and outcome of CU. RESULTS: Three trajectories of adolescent CU were identified, with most youth (74%) engaging in relatively "low" levels of use, followed by ~12% exhibiting an early-initiating "chronic" course, and 14% "escalating" in use. Although boys and girls both experienced increased levels of CU across adolescence, boys were more likely to exhibit escalating and chronic patterns of use. Findings revealed unique associations between adolescent CU pathways and facets of psychopathology; most notably, the relatively robust and bidirectional association between CU trajectories and conduct problem symptoms. CONCLUSIONS: Specific facets of psychopathology may confer unique associations with CU across development, including the initiation and exacerbation of CU during adolescence. PMID- 30395776 TI - Inulin-type fructans improve active ulcerative colitis associated with microbiota changes and increased short-chain fatty acids levels. AB - The intestinal microbiota is involved in ulcerative colitis (UC) pathogenesis. Prebiotics are hypothesized to improve health through alterations to gut microbiota composition and/or activity. Our aim was therefore to determine if inulin-type fructans induce clinical benefits in UC, and identify if benefits are linked to compositional and/or functional shifts of the luminal (fecal) and mucosal (biopsy) bacterial communities. Patients (n = 25) with mild/moderately active UC received 7.5 g (n = 12) or 15 g (n = 13) daily oral oligofructose enriched inulin (Orafti(r)Synergy1) for 9 weeks. Total Mayo score, endoscopic activity and fecal calprotectin were assessed. Fecal and mucosal bacterial communities were characterized by 16S rRNA tag sequencing, and short chain fatty acids (SCFA) production were measured in fecal samples. Fructans significantly reduced colitis in the high-dose group, with 77% of patients showing a clinical response versus 33% in the low-dose group (P = 0.04). Fructans increased colonic butyrate production in the 15 g/d dose, and fecal butyrate levels were negatively correlated with Mayo score (r = -0.50; P = 0.036). The high fructan dose led to an increased Bifidobacteriaceae and Lachnospiraceae abundance but these shifts were not correlated with improved disease scores. In summary, this pilot study revealed that 15 g/d dose inulin type fructans in UC produced functional but not compositional shifts of the gut microbiota, suggesting that prebiotic-induced alterations of gut microbiota metabolism are more important than compositional changes for the benefits in UC. The findings warrant future well-powered controlled studies for the use of beta-fructans as adjunct therapy in patients with active UC. PMID- 30395777 TI - A Treatment for Refractory High Ileostomy Output. AB - We present a case where the glucagon-like peptide 2 (GLP-2) analog teduglutide was used successfully to decrease high ostomy output due to short bowel syndrome in a patient not entirely dependent on parenteral nutrition. Short bowel syndrome is known to decrease quality of life and is associated with high health care costs. Although use has been limited by cost, teduglutide appears to be a treatment option for palliative care practice if patients suffer from short bowel syndrome. PMID- 30395778 TI - Mindfulness and health behaviors in college students: The moderating role of sleep. AB - OBJECTIVE: To examine the moderating effects of subjective sleep quality (SSQ) and sleep duration on the relationships between mindfulness and health behaviors (i.e. nutrition and exercise) among undergraduate students. The unique influence of the five facets (i.e. factors) of mindfulness (i.e. observing, describing, acting with awareness, nonreactivity to inner experience and nonjudging of inner experience) on students' health behaviors was also explored. PARTICIPANTS: Three hundred fifty seven undergraduate students enrolled in U.S. colleges. METHODS: Students completed an online survey. Hierarchical multiple regression analyses were conducted to determine whether SSQ moderated the relationship between mindfulness and nutrition behavior. RESULTS: SSQ moderated the relationship between mindfulness and nutrition behavior. The observe facet of mindfulness was the most predictive of nutrition behavior, whereas the observe and describe facets were the most predictive of exercise behavior. CONCLUSIONS: Interventions that target mindfulness and sleep quality may help promote healthy eating and increased exercise engagement in college students. PMID- 30395779 TI - Unique genomic profiles obtained from cerebrospinal fluid cell-free DNA of non small cell lung cancer patients with leptomeningeal metastases. AB - BACKGROUND: Leptomeningeal metastases (LM), associated with poor prognosis, are frequent complications of advanced non-small cell lung cancer (NSCLC) patients, especially in patients with epidermal growth factor receptor (EGFR) mutations. Due to limited access to leptomeningeal lesions, the mutational landscape of LM has not been comprehensively investigated in large cohorts and the underlining biology of LM remains elusive. Some studies have explored the potential of cerebrospinal fluid (CSF) in reflecting the molecular profile of LM but with limited number of patients enrolled. METHODS: In this study, we performed capture based targeted sequencing using a panel consisting of 168 lung cancer-related genes on matched CSF and plasma samples from 72 advanced NSCLC patients with confirmed LM to interrogate the potential of CSF as a source of liquid biopsy. RESULTS: We revealed a rate of detection of 81.5% and 62.5% for CSF and plasma, respectively (p = 0.008). The maximum allelic fraction (MaxAF) was also significantly higher in CSF (43.6% vs. 4.6%) (p < 0.001). CSF, harboring a unique genomic profile by having a significant number of CSF-specific mutations, primarily copy number variations, is superior to plasma in reflecting the mutational profile of LM. Further pathway enrichment analysis revealed that most of CSF-specific mutations participated in pathways relevant to the tumorigenesis and the development of metastases. Moreover, our data also revealed that TP53 loss of heterozygosity (LOH) predominantly existed in CSF (p < 0.001). CONCLUSIONS: Collectively, we demonstrated that CSF provides a more comprehensive profile of LM than plasma in a large cohort, thus can be used as an alternative source of liquid biopsy for LM patients. PMID- 30395780 TI - The importance of equal treatment: Medical students'opinions on affirmative action, equal treatment and discrimination. AB - We assessed medical students' opinion of affirmative action programs (AAPs), perception of gender equality and discrimination. 276 medical students (56.2% female) participated. Women considered AAPs to be more important than did men. Most women (62.6%) and men (71.9%) received equal treatment, but significantly more women (22.6%) than men (11.6%) experienced discrimination. It is necessary to convey the importance of gender equality and equal treatment, including discrimination and mistreatment. Thus, we have to raise awareness for gender equality and equal treatment not only in staff, in students or in health care but also among each other. PMID- 30395781 TI - Study of aluminium in groundwater using chemometric methods. AB - The field dataset including physico-chemical characteristics of Khibiny alkaline massif groundwater aquifer was analysed for the first time by applying chemometric methods to explore the relationships between investigated parameters in both time and frequency domains. Elevated Al concentration in water of this aquifer is described as a serious health concern when used for the household water supply. The time series of 12 physico-chemical parameters were examined by using Pearson correlation, multiple linear regression and spectral analysis based on fast Fourier transform (FFT) algorithm. Computed pairwise correlation coefficients matrix revealed that pH values, NO3-, SO42-, Cl- and TDS correlate with Al concentrations at a statistically significant level (alpha-level = 0.05). The multiple regression model including Cl-, NO3- and pH explains up to 54% of Al concentrations temporal variation in groundwater. Fourier coefficients, power spectral density (PSD) and cumulative spectral power (CSP) were calculated for Al, pH, NO3- and Cl- time series to identify and analyse the strength of their variations as a function of frequency. Calculations revealed the spectrums of these variables include three main frequency bands corresponding approximately to 5-7, 13-17 and 20-34 month periods. The fluctuations within these bands contribute mostly to the total temporal variation of Al, Cl-, NO3- concentrations and pH values. PMID- 30395782 TI - THE ECONOMIC BENEFITS OF FULFILLING THE WORLD HEALTH ORGANISATION'S LIMITS OF PARTICULATES. A CASE STUDY IN ALGECIRAS BAY (SPAIN). AB - Implications PM2.5 has a greater concentration in industrial localities and is linked to the industrial activity. When the particulate matter pollution is reduced to the levels recommended by the WHO in an industrialised area such as Algeciras (Spain), 182 deaths which would be avoided. The result shows that the economic benefit that would come out with the cost of illness valuation is 5,329,110? and from the value of statistical life is 414,787,113?. PMID- 30395783 TI - Preparative enrichment of human tissue cells capable to change a site of growth in vitro or in vivo - Recent developments. AB - Human cells are heterogeneous in regard to their biochemical features and functions. Detailed knowledge about each single cell type is important to understand the whole organism. In order to get a deeper insight in the concert of life, it has to be considered that cell populations such as thyroid cells, epithelial breast cells, endothelial cells, or chondrocytes are heterogeneous in regard to function, RNA expression patterns and protein content. This is true for normal cells and even more relevant for cancer cells. A number of sophisticated methods were developed to enrich cohorts of cells generally belonging to a defined type but outstanding by distinct characteristics, which can be detected by microscopic, proteomic or genomic methods. There is a great interest to investigate human cells, which are able to change their site of growth within the human body leaving an original site, migrating through vessels and reentering another site. In this review experiments are summarized showing that the application of microgravity-exposure of human cells and cell electrophoresis enable a characterization of cells, which leave a site of growth to enter another one. Biochemical features of separated subpopulations are described and their usefulness for deeper investigation is highlighted. PMID- 30395784 TI - Health Effects of Coconut Oil-A Narrative Review of Current Evidence. AB - Coconut oil is a mainstream edible oil that is extracted from the kernel of mature coconuts harvested from the coconut palm. The two main types of coconut oil-copra oil and virgin coconut oil-have similar fatty acid profiles; however the latter contains higher amounts of some nutrients (e.g., vitamin E) and dietary bioactive compounds (e.g., polyphenols). There is increasing popularity for coconut oil products due to perceived health effects of certain medium-chain fatty acids; however, lauric acid (C12:0), the primary fatty acid found in coconut oil, has been suggested to behave as both a medium- and long-chain fatty acid from a metabolic standpoint. Furthermore, research on pure medium-chain fatty acids cannot be directly applied to coconut oil products since it encompasses a large profile of various fatty acids. This narrative review seeks to summarize the current peer-reviewed literature and mechanisms surrounding the health effects of coconut oil products. Limited but consistent evidence supports the topical use for prevention and treatment of atopic dermatitis, as well as in "oil pulling" for prevention of dental caries. Coconut oil products may also be useful in preventing hair damage due to protein loss during grooming processes and ultraviolet (UV) exposure; however, more studies are needed to confirm this effect. Limited evidence does not support use for prevention or treatment of Alzheimer's disease, bone loss, or glycemic control. Evidence on weight loss and cardiovascular disease warrants larger clinical intervention studies. Refined, bleached, and deodorized copra oil seems to have less of an impact on total and low-density lipoprotein (LDL) cholesterol as compared to butter fat, but not cis unsaturated vegetable oils. In many instances, human clinical and observational studies are needed to confirm many claims on coconut oil products, which are largely based on animal and/or in vitro studies or studies of purified medium chain fatty acids. PMID- 30395785 TI - Content, Exposure, and Effects of Public Discourses about Marijuana: A Systematic Review. AB - This review presents a comprehensive picture of research studies about marijuana related content in news, social media, and advertisements. Studies that examined the extent of people's exposure to the messages and its effects were also included. A total of 27 peer-reviewed journal articles and one thesis were located, of which 16 analyzed the content, four contained information about people's exposure to the messages, and ten examined the effects. Over time, news coverage shifted from negative to slightly positive toward marijuana use. Social media and advertisements were overwhelmingly favorable toward marijuana use and legalization by claiming social, romantic, and health benefits of marijuana use while completely downplaying risks. A majority of social media accounts were also run by advocacy groups and industry interests, rather than individuals who were simply sharing opinions or experiences. Furthermore, absence of health authorities among the highly popular social media accounts about marijuana was notable. The news, social media, and advertising messages about marijuana were widely used by the members of public, which in turn generated some demonstrable effects on the audience's marijuana-related perceptions and behaviors. The public and policymakers need to become aware of this information environment for potential marijuana users and take more proactive measures to protect vulnerable populations. PMID- 30395786 TI - Individualized Challenge Point Practice as a Method to Aid Motor Sequence Learning. AB - We conducted two studies to investigate if and how: (1) the rate of skill acquisition was related to motor performance at retention of a serial RT task (Study 1); and (2) whether rate of skill acquisition and baseline performance could be used to design schedules of practice related to contextual interference (CI) to enhance motor learning (Study 2). In Study 1, a slower rate of skill acquisition of repeating sequences in practice was related to faster response times at retention. Based on performance in Study 1, three levels of individualized CI were created for Study 2. Compared to low and moderate levels of CI, the higher CI practice condition led to faster response times in retention. We conclude that an individualized 'challenge point', which generates high CI enhances motor learning by optimizing challenge. PMID- 30395787 TI - Association between somatosensory, visual and vestibular contributions to postural control, reactive balance capacity and healthy ageing in older women. AB - We investigated the biological systems involved in maintaining equilibrium during unstable and perturbed conditions in 39 healthy older women and estimated the annual difference in performance across the older age spectrum using regression. The largest annual difference in equilibrium occurred when the somatosensory system received inaccurate feedback and visual input was removed. With age, weight distribution became asymmetric at the onset of backwards perturbations, possibly in preparation for executing a stepping strategy. When one sensory system was challenged, postural responses were stable suggesting other systems compensated. When multiple sensory systems were challenged, significant differences in postural control emerged with age. PMID- 30395788 TI - The mycorrhiza-induced maize ZmPt9 gene affects root development and phosphate availability in nonmycorrhizal plant. AB - The arbuscular mycorrhizal (AM)-induced ZmPt9 gene is an orthologous to some AM inducible phosphate (Pi) transporter genes involved in Pi-starvation responses. Promoter GFP assay confirmed its transcript was localized surrounding arbuscule in arbuscule-containing cells. But this gene was not an AM fungi-specific gene. Its function in nonmycorrhizal seedlings was verified through phenotypic analysis of ZmPt9-overexpression Arabidopsis. Overexpression of ZmPt9 in Arabidopsis exhibited increased primary root length and lateral root formation. Furthermore, ZmPt9-overexpression Arabidopsis plants contained more phosphorus (P) than that of wild type. The affection of ZmPt9 in nonmycorrhizal Arabidopsis leads to the hypothesis that symbiosis-inducible genes are also involved in root development and Pi accumulation in AM-independent manner. PMID- 30395789 TI - Training Motor Sequences: Effects of Speed and Accuracy Instructions. AB - Participants practiced a fixed 3- and a fixed 6-key press sequence for 144 times each. In the speed group, they were instructed to execute their sequences fast without bothering much about errors while the accurate group was instructed to be careful and prevent errors. In the test phase, participants executed series of 3 and 6 responses (a) when all element-specific stimuli were displayed in the familiar order, (b) in response to just the familiar first stimulus, and (c) by responding to random stimuli. The speed instruction yielded stronger sequencing skill while the accuracy instruction developed stronger reaction skill. PMID- 30395790 TI - The Effect of Added Peanut Butter on the Glycemic Response to a High-Glycemic Index Meal: A Pilot Study. AB - OBJECTIVE: The purpose of this pilot study was to determine whether supplementation of a high-glycemic index breakfast meal with peanut butter attenuates the glycemic response. METHODS: Sixteen healthy adults, aged 24.1 +/- 3.5 years, reported in the morning to a nutrition assessment laboratory for two days of data collection, having fasted 8 to 12 hours. On day 1 (control), fasting blood glucose (BG) was measured using glucometers, then participants consumed two slices of white bread and 250 mL apple juice (60 g carbohydrate) within 15 minutes. BG was measured again at 15, 30, 60, 90, and 120 minutes after the first bite of the meal. On day 2, the protocol was repeated, except 32 g (2 tbsp) of peanut butter was added to the meal (treatment). RESULTS: The spike in BG was significantly lower on the treatment versus control day (35.8 +/- 16.4 vs. 51.0 +/- 20.8 mg/dL, respectively; p < 0.01), and BG was significantly lower on the treatment day at 15, 30, and 60 minutes post-meal consumption (p < 0.05). CONCLUSIONS: This study indicates that supplementation with 32 g (2 tbsp) peanut butter attenuates the magnitude of BG spike and overall glycemic response to high glycemic index meal and may be a practical, beneficial strategy to prevent undesirable elevations in BG. PMID- 30395791 TI - A Pilot Randomized Trial of an Intervention to Enhance the Health-Promoting Effects of Older Adults' Activity Portfolios: The Engaged4Life Program. AB - The purpose of this study was to evaluate the feasibility and outcomes of the Engaged4Life program, an intervention to encourage inactive community-dwelling older adults to embed physical activity, cognitive activity, and social interaction into their everyday lives in contexts that are personally meaningful and natural for them. Fifteen participants were randomized to the intervention group (technology-assisted self-monitoring of daily activity via pedometers and daily tablet-based surveys; psychoeducation + goal-setting via a 3-hour workshop; and peer mentoring via phone 2*/week for 2.5 weeks) and 15 to the control (technology-assisted self-monitoring only). Recruitment was shown to be feasible and efficient, but not able to reach the target for men. Retention rate was 83% and participants manifested high adherence and engagement with the intervention. Though this pilot trial was not powered to demonstrate significant differences between groups, daily steps increased by 431 (11% increase) from baseline to Week 4 for the intervention (p < .05), but decreased by 458 for the control, for a net difference of 889 steps (p < .05). Findings were sustained at Week 8 (p < .01). In a future trial, difficulties in recruiting men, barriers due to the technology intensive design, and the optimization of secondary outcome measures should be addressed. PMID- 30395792 TI - The role of microtubules in the regulation of epithelial junctions. AB - The cytoskeleton is crucially important for the assembly of cell-cell junctions and the homeostatic regulation of their functions. Junctional proteins act, in turn, as anchors for cytoskeletal filaments, and as regulators of cytoskeletal dynamics and signalling proteins. The cross-talk between junctions and the cytoskeleton is critical for the morphogenesis and physiology of epithelial and other tissues, but is not completely understood. Microtubules are implicated in the delivery of junctional proteins to cell-cell contact sites, in the differentiation and spatial organization of the cytoplasm, and in the stabilization of the barrier and adhesive functions of junctions. Here we focus on the relationships between microtubules and junctions of vertebrate epithelial cells. We highlight recent discoveries on the molecular underpinnings of microtubule-junction interactions, and report new data about the interaction of cingulin and paracingulin with microtubules. We also propose a possible new role of junctions as "molecular sinks" for microtubule-associated signalling proteins. PMID- 30395793 TI - Uptake of HPV vaccine in traditional-age undergraduate students: Knowledge, behaviors, and barriers. AB - OBJECTIVE: This study investigated potential factors associated with HPV vaccine uptake in a diverse population of traditional-age undergraduate students. PARTICIPANTS: One hundred and twenty-nine undergraduate students aged 18-24 attending a small southeastern university completed surveys in January to March of 2013. METHODS: Questionnaires included demographic information, basic HPV knowledge, HPV vaccine uptake, and factors influencing uptake decision. Survey results were analyzed with chi-square and t-test analyses. RESULTS: Vaccine uptake was significantly higher in students who reported that health care provider, public health information, parents, and access to vaccine were important factors in their decision to get vaccinated. Female students had a significantly higher vaccine uptake in comparison to males and the HPV knowledge scores differed significantly by race but not gender. CONCLUSIONS: It is especially important to consider how public health campaigns and communication with parents and health care providers help promote HPV vaccine uptake in this high-risk group. PMID- 30395794 TI - From One to Two: Can Visual Feedback Improve the Light Touch Effects on Postural Sway? AB - The postural control is improved by implicit somatosensory information from lightly touching a rigid bar or explicit visual information about the postural sway. Whether these two additional sources provided at the same time further reduce the postural sway is still unknown. Participants stood on a force plate as quiet as possible lightly touching the bar while received or not visual feedback of the center of pressure position on a monitor screen. Postural sway reduced similarly with the light touch regardless of the additional visual feedback. The findings suggested that providing explicit visual feedback of the center of pressure does not increase the light touch effects on the postural sway. The importance of the implicit somatosensory information on postural control is discussed. PMID- 30395795 TI - Post traumatic stress symptoms in parents of children with cancer: A mediation model. AB - OBJECTIVE: Caregivers of pediatric cancer patients are at risk for posttraumatic stress symptoms (PTSS). Previous literature has identified caregiver illness uncertainty as a predictor of PTSS, yet little is known about the mechanism by which illness uncertainty may affect PTSS. Rumination, or perseverations about the cause and consequences of an event, has been related to posttraumtic stress disorder in other populations. However, limited research of this relationship exists for pediatric cancer caregivers. Further, no studies have evaluated rumination in relation to illness uncertainty. The current study examined rumination in relation to illness uncertainty and PTSS in caregivers with children actively receiving treatment for cancer. It was hypothesized that rumination would be related to illness uncertainty and would mediate the relationship between illness uncertainty and PTSS. METHODS: Caregivers (N = 59) completed the Parent Perception of Uncertainty Scale, Ruminative Responses Scale, and the Impact of Event Scale-Revised. RESULTS: illness uncertainty was identified as a significant predictor of rumination (B = 0.148, p = .015), and rumination was a significant predictor of PTSS (B = 1.83, p < .001). Biased corrected bootstrap regression analysis revealed that rumination mediated the relationship between illness uncertainty and PTSS (R2 = 0.53, p < .001). CONCLUSIONS: Rumination was identified as a mediator between the relationship of illness uncertainty and PTSS. These findings underscore the importance of rumination in caregivers of children with cancer, as a potential construct for identifying caregivers at risk of PTSS, and as a possible mechanism for targeted intervention. PMID- 30395796 TI - Complications of percutaneous nephrostomy in a district general hospital. AB - OBJECTIVE: Percutaneous nephrostomy (PCN) is one of the commonest procedures performed. There are currently no European recommendations on the accepted rate of complications. The aim of the present study is to report the complication rate of PCN with the specific emphasis on sepsis and septic shock, the causative organisms, sensitivities to antibiotics, and associated risk factors. MATERIAL AND METHODS: Retrospectively collected data on patients undergoing acute or elective PCN at the Department of Radiology, Countess of Chester Hospital (COCH), in the UK between January 2014 and December 2016 were analyzed after the study was approved by Local Audit Department at COCH. RESULTS: A total of 66 patients underwent 90 acute or elective PCNs. Three patients developed major post-PCN complication (two patients developed septic shock and the third suffered a hemorrhagic episode requiring blood transfusion). Nephrostomy tube complications (blockage, leaking, fracturing and kinking of the catheter) occurred in 4 patients. Complications were more common when the PCN was performed out of working hours (71.4% [10/14], and 17.3% [9/52] for PCNs performed within, and out of working hours, respectively: p<0.001). The age of the patients did not seem to correlate with the development of complications (p<0.001). Of all 25 patients, in whom septicemia was diagnosed prior to PCN tube insertion, 12 developed septic shock and 13 had signs of sepsis for longer than 24 h. Fifteen patients had positive urine cultures. The most common organism isolated was Escherichia coli. Blood culture isolates included: Escherichia coli, Eggerthella lenta, Enterococcus, Proteus mirabilis, Pseudomonas aeruginosa and Streptococcus pneumonia. CONCLUSION: Our complication rates were within United States proposed target ranges. Our data may help to serve as a baseline for outcome targets in the European centres. PMID- 30395797 TI - A case of bilateral perinatal testicular torsion that presented with unilateral torsion; necessity of contralateral testis exploration. AB - Perinatal testicular torsion is a rare emergency in a neonate that prompts immediate attention. Bilateral testicular torsion is extremely rare. We report a case of bilateral torsion that presented with unilateral scrotal swelling but significant atrophy and dark discoloration of the contralateral testis that was secondary to asynchronous prenatal torsion. There is no consensus about exploration of the contralateral testis when exploring a case with unilateral testicular torsion. Nevertheless, findings in this case report indicate that bilateral exploration is mandatory in each case of perinatal testicular torsion to evaluate the condition of contralateral testis and fix it to prevent development of future torsion that may result in anorchia. PMID- 30395798 TI - Fosfomycin as a promising alternative to treat urinary tract infection due to multidrug resistant uropathogens. PMID- 30395800 TI - Monetary costs and hospital burden associated with the management of invasive fungal infections in Mexico: a multicenter study. AB - BACKGROUND: Invasive fungal infections (IFIs) affect >1.5 million people per year. Nevertheless, IFIs are usually neglected and underdiagnosed. IFIs should be considered as a public-health problem and major actions should be taken to tackle them and their associated costs. Aim To report the incidence of IFIs in four Mexican hospitals, to describe the economic cost associated with IFIs therapy and the impact of adverse events such as acute kidney injury (AKI), liver damage (LD), and ICU stay. METHODS: This was a retrospective, transversal study carried out in four Mexican hospitals. All IFIs occurring during 2016 were included. Incidence rates and estimation of antifungal therapy's expenditure for one year were calculated. Adjustments for costs of AKI were done. An analysis of factors associated with death, AKI, and LD was performed. RESULTS: Two-hundred thirty eight cases were included. Among all cases, AKI was diagnosed in 16%, LD in 25%, 35% required ICU stay, with a 23% overall mortality rate. AKI and LD showed higher mortality rates (39% vs 9% and 44% vs 18%, respectively, p<0.0001). The overall incidence of IFIs was 4.8 cases (95% CI=0.72-8.92) per 1000 discharges and 0.7 cases (95% CI=0.03-1.16) per 1000 patients-days. Invasive candidiasis showed the highest incidence rate (1.93 per 1000 discharges, 95% CI=-1.01 to 2.84), followed by endemic IFIs (1.53 per 1000 discharges 95% CI=-3.36 to 6.4) and IA (1.25 per 1000 discharges, 95% CI=-0.90 to 3.45). AKI increased the cost of antifungal therapy 4.3-fold. The total expenditure in antifungal therapy for all IFIs, adjusting for AKI, was $233,435,536 USD (95% CI $6,224,993 to $773,810,330). CONCLUSIONS: IFIs are as frequent as HIV asymptomatic infection and tuberculosis. Costs estimations allow to assess cost-avoidance strategies to increase targeted driven therapy and decrease adverse events and their costs. PMID- 30395801 TI - In vitro effects of Artemisia sieberi on Echinococcus granulosus protoscolices. AB - Hydatidosis is a parasitic zoonotic disease. Surgery is one of its treatment modalities during which protoscolices are likely to be released into the peritoneal cavity and cause recurrence of the disease. Given the above problem and the complications associated with conventional anti-parasitic agents, it is imperative to find an effective and natural protoscolicidal agent. The present study was conducted to evaluate effects of Artemisia sieberi on Echinococcus granulosus protoscolices. Protoscolices were collected from slaughtered livestock in Kerman abattoir and the effect of three concentrations of aqueous extract of A. sieberi (25 mg ml-1, 50 mg ml-1 and 75 mg ml-1) was assessed over three different exposure periods. Results showed that scolicidal effect of this extract at exposure periods of 2, 5 and 10 min was 76 +/- 1.4, 76.8 +/- 1.41 and 85.7 +/- 3.29 percent at concentration of 25 mg ml-1 and 76.8 +/- 1.4, 78 +/- 3.18 and 86.4 +/- 24.9 percent at concentration of 50 mg ml-1 and finally 80 +/- 2.73, 90 +/- 0.79 and 92.6 +/- 1.27 percent at concentration of 75 mg ml-1, respectively. It can be concluded that the aqueous extract of A. sieberi has a protoscolicidal activity and can be considered a natural agent against hydatid cyst protoscolices. PMID- 30395802 TI - Is a discard tube necessary, when drawing blood for P-Ionized calcium analysis? AB - BACKGROUND: Deviation in blood collection procedures is a central source of preanalytical variation affecting overall analytical and diagnostic precision. The procedure of venous blood collection for ionized calcium is hypothesized to affect analytical results. Here, we evaluate the effect of blood collection with and without a discard tube, and storage duration on results of P-Ionized Calcium (pH adjusted = 7.4). METHODS: We collected 100 paired venous blood tubes from randomly selected outpatients using a winged blood collection. No discard tube was drawn before the first tube. The samples were divided in five subsamples, stored at 4 degrees -6 degrees C at 24 (n = 20), 48 (n = 20), 72 (n = 20), 96 (n = 20) and 120 h (n = 20) after venipuncture, and analyzed for P-Ionized Calcium (pH adjusted = 7.4) on Konelab 60i (Thermo Scientific, Finland). Differences between first and second tubes were evaluated for all samples (n = 100) and for subsamples divided by storage duration, using Bland-Altman plot and Wilcoxon's rank-sum test. RESULTS: P-Ionized Calcium (pH adjusted = 7.4) results ranged from 1.13 to 1.37 mmol/L. We observed no statistical significant differences between the first and the second tube when comparing all samples. Dividing samples by storage duration, a statistically significant difference was found (p = .0068) after 120 h, but the difference of individual samples was not clinically relevant. CONCLUSIONS: Our study has shown no significant difference between P Ionized Calcium (pH adjusted = 7.4) values for the first and second tubes. Hence, the use of a discard tube is not required. A statistically significant difference was found on samples stored 120 h but was not considered clinically relevant. PMID- 30395803 TI - Transient exposure of methylparaben to zebrafish (Danio rerio) embryos altered cortisol level, acetylcholinesterase activity and induced anxiety-like behaviour. AB - Parabens are widely used as antimicrobial preservatives. Recent studies have reported the endocrine disrupting effects of these chemicals, especially methylparaben. Previously, we have reported the alteration in Vtg gene expression upon exposure to environmentally relevant doses of methylparaben in zebrafish (Danio rerio) embryos. However, studies reporting neurobehavioural outcomes on exposure to methylparaben are limited. Therefore, this study was aimed at investigating the methylparaben-induced effects on developmental and neurobehavioural endpoints. Zebrafish embryos were exposed to sub-lethal concentrations of methylparaben: 0.1 ppb, 1 ppb, 10 ppb and 100 ppb. Alterations in developmental landmarks such as heart rate and hatching percentage were observed in embryos exposed to 10 ppb and 100 ppb of methylparaben. Results obtained from the novel tank diving test established that anxiety-like behaviour is induced in larvae exposed to 0.1 ppb and 1 ppb of methylparaben. A significant inhibition in the acetylcholinesterase (AChE) activity was also recorded in methylparaben-exposed groups. An increase in cortisol levels was observed in the exposed groups, which further supports the observations made in the novel tank diving test, establishing methylparaben as an anxiogenic agent even at sub-lethal concentrations. The underlying molecular mechanism needs further elucidation to investigate whether the behavioural effects are proximally or distally induced by early developmental exposure to methylparaben. PMID- 30395804 TI - Identification, characterization, expression profiles of OlHavcr2 in medaka (Oryzias latipes). AB - Hepatitis A virus cellular receptor2 (Havcr2) also named T-cell immunoglobulin and mucin domain containing-3 (Tim-3) was initially described as a T helper 1 specific cell surface protein, a member of Tim family implicated in the regulating process of adaptive and innate immune responses. Here, medaka (Oryzias latipes) Havcr2 (OlHavcr2) was isolated and characterized. Unlike other Havcr2 proteins, OlHavcr2 possesses two Ig-like domains but lacks cytoplasmic and transmembrane domains. RT-PCR results revealed that OlHavcr2 mRNA was expressed strongly in the liver, moderately in the intestine, heart and ovary, and weakly in the muscle, gill, brain, eye, spleen, and testis. OlHavcr2 expression begun from gastrula stage and was maintained until hatching. The signal of OlHavcr2 was mainly identified in the blood system in the yolk sac by in situ hybridization. These results indicated that OlHavcr2 is expressed ubiquitously in adult tissues, and is a zygotic gene expressed from gastrula onwards in embryogenesis. OlHavcr2 may play a significant role in the blood system of medaka. In the immune organs, OlHavcr2 expression was affected by the immune stimulants, lipopolysaccharide and poly I:C, suggesting that OlHavcr2 was involved in innate immunity and adaptive immunity in medaka. PMID- 30395805 TI - Of mice and plants: Comparative developmental systems biology. AB - Multicellular animals and plants represent independent evolutionary experiments with complex multicellular bodyplans. Differences in their life history, a mobile versus sessile lifestyle, and predominant embryonic versus postembryonic development, have led to the evolution of highly different body plans. However, also many intriguing parallels exist. Extension of the vertebrate body axis and its segmentation into somites bears striking resemblance to plant root growth and the concomittant prepatterning of lateral root competent sites. Likewise, plant shoot phyllotaxis displays similarities with vertebrate limb and digit patterning. Additionally, both plants and animals use complex signalling systems combining systemic and local signals to fine tune and coordinate organ growth across their body. Identification of these striking examples of convergent evolution provides support for the existence of general design principles: the idea that for particular patterning demands, evolution is likely to arrive at highly similar developmental patterning mechanisms. Furthermore, focussing on these parallels may aid in identifying core mechanistic principles, often obscured by the highly complex nature of multiscale patterning processes. PMID- 30395806 TI - An online mindfulness-based program is effective in improving affect, over commitment, optimism and mucosal immunity. AB - Previous studies have demonstrated mindfulness-based programs are effective in reducing workplace stress; however, few have investigated the effectiveness of online mindfulness-based programs. Physiological measures are also underutilised when examining the efficacy of these programs. Therefore, we assessed the efficacy of an online mindfulness-based program on both short-term and more enduring aspects of psychological and physiological measures of stress and ill health. Participants (N = 22) completed an 8-week online mindfulness-based program. Immediately before and after a mindfulness session, participants completed questionnaires to assess the short-term effects on mood and state anxiety and provided saliva samples to assess salivary alpha amylase (sAA) concentrations. Additionally, pre and post the 8-week intervention, participants completed questionnaires assessing workplace stress, over-commitment, work engagement, dispositional mindfulness and personal resources. Saliva samples were collected to measure the cortisol awakening response, sAA awakening response and secretory immunoglobulin A (sIgA). Our findings demonstrate that online mindfulness-based programs induce short-term improvements in fatigue and anxiety in employees. Additionally, we also report a decrease in over-commitment and increases in optimism and mucosal immunity (sIgA) following the program. PMID- 30395808 TI - Aromatic interactions in beta-hairpin scaffold stability: A historical perspective. AB - Non-covalent interactions between naturally occurring aromatic residues have been widely exploited as scaffold stabilizing agents in de novo designed peptides and in Nature - inspired structures. Our understanding of the factors driving aromatic interactions and their observed interaction geometries have advanced remarkably with improvements in conventional structural studies, availability of novel molecular methods and in silico studies, which have together provided atomistic information on aromatic interactions and interaction strengths. This review attempts to recapitulate the early advances in our understanding of aromatic interactions as stabilizing agents of peptide beta-hairpins. PMID- 30395807 TI - Mathematical modeling of the cGAS pathway reveals robustness of DNA sensing to TREX1 feedback. AB - Cyclic GMP-AMP synthase (cGAS) has recently been identified as the primary protein that detects cytosolic double stranded DNA to invoke a type I interferon response. The cGAS pathway is vital in the recognition of DNA encoded viruses as well as self-DNA leaked from the nucleus of damaged cells. Currently, the dynamics regulating the cGAS pathway are poorly understood; limiting our knowledge of how DNA-induced immune responses are regulated. Using systems biology approaches, we formulated a mathematical model to describe the dynamics of this pathway and examine the resulting system-level emergent properties. Unknown model parameters were fit to data compiled from literature using a Parallel Tempering Markov Chain Monte Carlo (PT-MCMC) approach, resulting in an ensemble of parameterized models. A local sensitivity analysis demonstrated that parameter sensitivity trends across model ensembles were independent of the select parameterization. An in-silico knock-down of TREX1 found that the interferon response is highly robust, showing that complete inhibition is necessary to induce chemical conditions consistent with chronic inflammation. Lastly, we demonstrate that the model recapitulates interferon expression data resulting from small molecule inhibition of cGAS. Overall, the importance of this model is exhibited in its capacity to identify sensitive components of the cGAS pathway, generate testable hypotheses, and confirm experimental observations. PMID- 30395809 TI - Improving action video games abilities increases the phonological decoding speed and phonological short-term memory in children with developmental dyslexia. AB - Learning to read is extremely difficult for about 10% of the children because they are affected by a heritable neurobiological disorder called developmental dyslexia (DD). The causal role of cognitive deficits typically associated to DD can be investigated through intervention studies. It has been demonstrated that visual-attention and reading speed could be simultaneously improved by using action video game (AVG) training both in shallow and deep alphabetic orthographies. Here, in a clinical study we showed that after this general-domain behavioral intervention both the phonological decoding speed and phonological short-term memory were increased only in DD children in which their video game score was improved. These findings confirm that an AVG training enhances the efficiency of both visual and auditory processing. The plasticity of the multi sensory attentional network could explain the reading and reading-related improvements induced by the AVG training in children with DD. PMID- 30395810 TI - Etiology and Management of the Hypertensive Phase in Glaucoma Drainage Device Surgery. AB - Insertion of glaucoma drainage devices has become a mainstay in the surgical management of multiple forms of glaucoma, and the indications for this procedure continue to expand. A unique clinical challenge in the postoperative care of these devices is the hypertensive phase, a period of postoperative intraocular pressure elevation in the first three months after surgery. We discuss the influence of a variety of factors on the development of the hypertensive phase after glaucoma drainage implantation, including type of device, device material, and device surface area. Furthermore, several intraoperative and postoperative interventions are investigated as attempts to mitigate this phenomenon. Included among these are the use of antimetabolites, collagen matrix, and a variety of approaches to postoperative inflammation and intraocular pressure control. We provide an overview of our current knowledge of the etiology and management of the hypertensive phase. PMID- 30395811 TI - Assessment of chemokine and cytokine signatures in patients with dengue infection: A hospital-based study in Kolkata, India. AB - Dengue fever is an acute viral infection transmitted by arthropods but may evolve to severe clinical manifestations. Descriptions of the role of circulating immune modulators such as cytokines or chemokines in dengue immunopathogenesis have largely relied on data from South-east Asia and America, while India is poorly represented. This study characterizes dengue cases from West Bengal, eastern India, with respect to clinical profile and pro-inflammatory and inflammatory cytokines. We evaluated the profile of both inflammatory and anti-inflammatory cytokines (IFNgamma, IL6, IL10, IL12 and TGFbeta) and chemokines (IL8, CXCL9, CXCL10 and RANTES) in 100 hospitalized NS1/IgM confirmed Dengue patients during the epidemic in West Bengal during 2017. Additionally, all necessary blood investigations of the study subjects were performed. The patients mostly hailed from Kolkata, followed by Nadia, 24 Parganas (North and South), Murshidabad and Midnapore. The most common presentations apart from fever and bodyache were gastrointestinal symptoms. An elevated levels of cytokines IL6 and IL10 chemokine IL8 and CXCL10 along with decreased RANTES were found in the patients with Severe Dengue as compared to mild forms of dengue (p < 0.0001) during 3-6 days of infections. A significant association was obtained between most of cytokine and increased SGPT, haematocrit, albumin and decreased platelet count, whereas a negative correlation with the level of RANTES to haematocrit (r=-0.220 with p = 0.029) was found in severe dengue cases with altered liver function parameters. This is the first study demonstrating cytokine and chemokine association with dengue severity from the eastern part of India. Taken together, this study demonstrated that the altered expression levels of IL6, IL10, IL8, CXCL10 and RANTES had significant associations with dengue severity parameters. PMID- 30395813 TI - A velvety cutaneous plaque. PMID- 30395812 TI - RPC4046, a Monoclonal Antibody Against IL13, Reduces Histologic and Endoscopic Activity in Patients With Eosinophilic Esophagitis. PMID- 30395814 TI - Development and validation of a mouse-based primary screening method for testing relative allergenicity of proteins from different wheat genotypes. AB - BACKGROUND: Wheat allergy is a major food allergy that has reached significant levels of global public health concern. Potential variation in allergenicity among different wheat genotypes is not well studied at present largely due to the unavailability of validated methods. Here, we developed and validated a novel mouse-based primary screening method for this purpose. METHODS: Groups of Balb/c mice weaned on-to a plant protein-free diet were sensitized with salt-soluble protein (SSP) extracted from AABB genotype of wheat (durum, Carpio variety). After confirming clinical sensitization for anaphylaxis, mice were boosted 7 times over a 6-month period. Using a pooled-plasma mini bank, a wheat-specific IgE-inhibition (II)-ELISA was optimized. Then the relative allergenicity of SSPs from tetraploid (AABB), hexaploid (AABBDD) and diploid (DD) wheat genotypes were determined. The IC50/IC75 values were estimated using IgE inhibition curves. RESULTS: The optimized II-ELISA with an inhibition time of 2.5 h had a co efficient of variation of <2%. Primary screening for relative allergenicity demonstrated that IgE binding to AABB-SSP was significantly abolished by the other two wheat genotypes. Compared to AABB, the relative allergenicity of SSPs of AABBDD and DD were significantly lower (p < .01). Furthermore, IgE inhibition curves showed significant differences in IC50 and IC75 values among the three wheat genotypes. CONCLUSION: We report a novel mouse-based primary screening method of testing relative allergenicity of wheat proteins from three different wheat genotypes for the first time. This method is expected to have broad applications in wheat allergy research. PMID- 30395815 TI - Validation of an ADCC assay using human primary natural killer cells to evaluate biotherapeutic products bearing an Fc region. AB - The development of biotherapeutics requires continuous improvement in analytical methodologies for the assessment of their quality attributes. A subset of biotherapeutics is designed to interact with specific antigens that are exposed on the membranes of target cells or circulating in a soluble form, and effector functions are achieved via recognition of their Fc region by effector cells that induce mechanisms such as antibody-dependent cell-mediated cytotoxicity (ADCC). Thus, ADCC induction is a critical quality attribute (CQA) that must be evaluated to ensure biotherapeutic efficacy. Induction of ADCC can be evaluated by employing effector cells from different sources, such as peripheral blood mononuclear cells (PBMC) and genetically modified cell lines (e.g., transfected NKs or Jurkat cells), and different approaches can be used for detection and results interpretation depending on the type of effector cells used. In this regard, validation of the assays is relevant to ensure the reliability of the results according to the intended purpose. Herein, we show the standardization and validation of ADCC assays to test the potency of three biotherapeutic proteins using primary NK cells obtained from fresh blood as effector cells and detecting cell death by flow cytometry. The advantage of using primary NKs instead of modified cells is that the response is closer to that occurring in vivo since cytotoxicity is evaluated in a direct manner. Our results indicate that in all cases, the assays exhibited a characteristic sigmoidal dose/response curve complying with accurate, precise and specific parameters. Thereby, the validated ADCC assay is an appropriate alternative to evaluate the biological activities of these type of biotherapeutics. PMID- 30395816 TI - CLEC4C gene expression can be used to quantify circulating plasmacytoid dendritic cells. AB - Plasmacytoid dendritic cells (pDC) are an important type I interferon producer that play an important role in the first line of host defence during viral infection. Abnormalities in pDC numbers and function have been associated with several health conditions. Quantifying pDC is important for understanding pDC related immune responses in viral infections and other diseases, however the current methods for quantifying pDC using flow cytometry have limited utility in large cohort studies involving multiple centres with limited access to flow cytometry. We reasoned that examining gene expression of the pDC marker C-type lectin domain family 4 member C (CLEC4C, also known as CD303 and BDCA2) in combination with pDC exclusive leukocyte immunoglobulin like receptor A4 (LILRA4, also known as CD85g and ILT7) might provide a more practical method that could be applied to multi-centre studies. Our results show a moderate correlation between pDC numbers measured by surface staining and CLEC4C gene expression in whole blood (rho = 0.39, P = .037, as well as a high correlation between CLEC4C gene expression in whole blood and peripheral blood mononuclear cells (rho = 0.79, P < .001). LILRA4 gene expression did not provide additional useful information. Our results indicate that measuring CLEC4C gene expression can provide an alternative method for quantifying pDC numbers in human samples. PMID- 30395817 TI - Secreted and intracellular cytokines are complementary measures for human monocytes treated with Toll-like receptor agonists. AB - Cytokine production by human peripheral blood mononuclear cells including monocytes, is frequently assessed by measuring secreted cytokines using enzyme linked immunosorbent assay (ELISA), whereby the total concentration of one cytokine of interest is obtained without information regarding the cell type responsible for making the cytokine. Cytokines can be retained inside the cell using protein transport inhibitors. Subsequent analysis by flow cytometry not only identifies the cell type producing the cytokine but can semi-quantitate the amount of cytokine produced by measuring the geometric mean fluorescence intensity (gMFI) and is amenable to analyzing more than one protein associated with the same cell (multiplexing). We hypothesized that a more comprehensive and biologically meaningful cytokine profile could be acquired by measuring both secreted and the retained intracellular cytokines in parallel cultures of magnetic-sorted CD14+ monocytes. Peripheral monocytes were isolated from 18 healthy donors and treated with standardized molecules that stimulate cytokine production; Toll-like receptor (TLR)4 agonist (lipopolysaccharide, LPS) or TLR7/8 agonist (R848). Pro-inflammatory cytokines (interleukin (IL)-6, IL-8 and tumour necrosis factor (TNF)) secreted into the culture medium were measured by ELISA. Parallel cultures were treated with LPS and R848 in the presence of brefeldin A (protein transport inhibitor) and the accumulated intracellular cytokines measured by flow cytometry. Each cytokine (IL-6/IL-8/TNF) gave a unique general pattern when secreted versus intracellular cytokine measurements (frequency and gMFI) were plotted to determine correlation. For monocytes treated with the TLR4 agonist, secreted IL-8 correlated with the frequency of IL-8 positive cells (R = 0.559, p = .016) and not with the amount (gMFI) of IL-8 per cell. In contrast, monocytes treated with the TLR7/8 agonist showed no correlation of secreted IL-8 with the frequency of IL-8 positive cells, but with this treatment secreted IL-6 was correlated with an increase in the frequency of IL-6 positive cells (R = 0.501, p = .034). TNF secretion from monocytes treated with either the TLR4 or TLR7/8 agonist did not correlate with the frequency or gMFI of TNF positive cells. However, there were significant correlations between the TLR4 and TLR7/8 induced TNF response (secreted and gMFI). We conclude that there are fundamental differences in secreted and intracellular IL-6/IL-8/TNF production after monocytes are treated with TLR agonists. Furthermore, secreted and intracellular cytokine analyses are complementary measures that should be used in parallel to explore inflammatory response and cytokine biology. PMID- 30395818 TI - Isolation of tumor endothelial cells from murine cancer. AB - Tumor endothelial cells (TECs), which constitute the lining of the tumor blood vessels, have various characteristics as tumor constituent cells. In this study, we describe a novel method for the isolation of highly pure, fresh TECs, which form a small population within the tumor. Tumors were first dissected from tumor bearing mice and digested to a single cell suspension with Collagenase Type II; the single cells were then separated by density gradient centrifugation. TECs were enriched by CD31-positive selection using magnetic activated cell sorting and subsequently purified by fluorescence activated cell sorting. The high purity of the obtained cells was verified by flow cytometry. Upon cell culture, the isolated cells showed a polygonal shape and a cobblestone appearance, which are features of the endothelial cells. Furthermore, a functional assay revealed that the TECs suppressed the proliferation of CD8+ T cells in vitro. We believe that the isolation method described in this study will enable the further elucidation of the characteristics of TECs. PMID- 30395819 TI - Both the Observer's Expertise and the Subject's Facial Symmetry Can Affect Anatomical Position of the Head. AB - PURPOSE: It is easier to judge facial deformity when the patient's head is in anatomic position. The purposes of this study were to determine 1) whether a group of expert observers would agree more than a group of nonexperts on what is the correct anatomic position of the head, 2) whether there would be more variation in the alignment of an asymmetrical face compared with a symmetrical one, and 3) whether the alignments of experts would be more repeatable than those of nonexperts. MATERIALS AND METHODS: Thirty-one orthodontists (experts) and 31 dental students (nonexperts) were recruited for this mixed-model study. They were shown randomly oriented 3-dimensional head photographs of an adult with a symmetrical face and an adolescent with an asymmetrical face. In viewing software, the observers oriented the images into anatomic position. They repeated the orientations 4 weeks later. Data were analyzed using a generalized linear model and Bland-Altman plots. The primary predictor variables were experience and symmetry status. The outcome variable was the anatomic position of the head. The other variables of interest included time and orientation direction. RESULTS: There was a statistically significant difference between measurements completed by experts and nonexperts (F1,60 = 14.83; P < .01). The interaction between expertise and symmetrical status showed a statistically significant difference between symmetrical and asymmetrical faces in the expert and nonexpert groups (F1,60 = 9.93; P = .003). The interaction between expertise and time showed a statistically significant difference in measurement over time in the expert and nonexpert groups (F1,60 = 4.66; P = .03). CONCLUSIONS: The study shows that experts can set a head into anatomic position better than nonexperts. In addition, facial asymmetry has a profound effect on the ability of an observer to align a head in the correct anatomic position. Moreover, observer-guided alignment is not reproducible. PMID- 30395820 TI - Positive Association Between Neutrophil-Lymphocyte Ratio and Presence of Panoramically Imaged Carotid Atheromas Among Men. AB - PURPOSE: Heightened levels of systemic inflammation documented by increased neutrophil-to-lymphocyte ratios (NLRs) characterize a robust atherosclerosis processes evidenced by carotid and coronary artery plaques at ultrasound and angiography with associated strokes and myocardial infarctions (MIs). Therefore, this study investigated whether calcified carotid artery plaques (CCAPs) on panoramic images (PIs), known to herald future stroke and MI, are associated with increased NLRs. MATERIALS AND METHODS: Using a cross-sectional study design, electronic medical records and PIs of non-Hispanic white men at least 55 years old who were treated by the dental service (January 1, 2017 to December 31, 2017) were retrieved. Two groups of patients (n = 50 per group) with plaque (CCAP+) and without plaque (CCAP-) were constituted. The predictor variable was CCAP+ and the outcome variable was the NLR. A t test analyzed the differences in mean NLRs between groups. Other variables of interest, that is, atherogenic risk factors (hypertension, hyperlipidemia, and diabetes mellitus), were included in a logistic regression analysis to assess their influence on the association of CCAP with the NLR. Significance was set at .05 for all tests. RESULTS: The study group of 50 men with CCAP+ (mean age, 71.7 +/- 7.47 yr) evidenced a mean NLR of 3.07 +/ 1.43. The control group of 50 men with CCAP- (mean age, 69.8 +/- 9.29 yr) evidenced a mean NLR of 2.13 +/- 0.68. A t test analysis comparison showed a significant (P = .00007) difference (95% confidence interval, 0.49-1.39). Logistic regression failed to show any relevant relation of the NLR with the covariate and other variables of interest. CONCLUSION: There is a strong association between CCAP+ in older non-Hispanic white men and extent of systemic inflammation as evidenced by increased NLRs. These plaques are "risk factors or indicators" for future stroke and MI. Therefore, maxillofacial surgeons providing care for patients with CCAP+ should consider referring them for a comprehensive cerebrovascular and cardiovascular workup. PMID- 30395821 TI - Patient-Controlled Analgesia and Length of Hospital Stay in Orthognathic Surgery: A Randomized Controlled Trial. AB - PURPOSE: The objective of this prospective, randomized controlled pilot study of patients undergoing orthognathic surgery was to compare the hospital length of stay (LOS) in patients using intravenous patient-controlled analgesia (PCA) versus patients receiving scheduled and as-needed oral analgesia. PATIENTS AND METHODS: A total of 40 patients (19 male and 21 female patients) aged 16 to 56 years (mean, 20.73 years; standard deviation, 6.87 years) were recruited prospectively and randomized to PCA and non-PCA groups of equal size. Recording of the patient-reported pain score using a visual analog scale was commenced at 8:00 am on day 1 after surgery until discharge. The pain score from routine nursing observations during the postoperative period was recorded until the patient was discharged from the hospital. RESULTS: Randomization resulted in approximately equal proportions of male patients (45% vs 50%) and median ages (18.5 years vs 20 years) for the PCA group versus the non-PCA group; however, the PCA group was noted to have a higher proportion of double-jaw surgery (65% vs 40%). The median LOS was 2 days for both the PCA and non-PCA groups (P = .06). No statistically significant difference in pain scores was found between the 2 groups either at rest (P = .27) or on movement (P = .13). CONCLUSIONS: No evidence was found to indicate the superiority of either the PCA or non-PCA regimen with respect to LOS and pain scores; however, this is not evidence of equivalence of the 2 pain management approaches. PMID- 30395822 TI - Evaluation of Parotid Gland Function Before and After Endoscopy-Assisted Stone Removal. AB - PURPOSE: To quantify gland function before and after endoscopy-assisted lithectomy for patients with parotid stones and to analyze correlations among different evaluation modalities. MATERIALS AND METHODS: This study investigated 58 patients (27 men and 31 women) with a stone larger than 5 mm or multiple parotid stones who underwent successful endoscopy-assisted surgery at the authors' center from August 2007 through September 2017. Meticulous postoperative manipulations were administered routinely for 3 to 6 months to promote functional recovery of the affected gland. Gland function was evaluated preoperatively and 6 to 36 months (mean, 12 months) postoperatively by sialography, scintigraphy, and sialometry. Statistical analyses were conducted to quantify gland function recovery and to distinguish correlations among the 3 objective tests. RESULTS: Preoperative sialograms exhibited ductal ectasia at the stone site with ductal stenosis anterior to the stone (n = 53) or duct interruption at the stone site (n = 5). Postoperative sialograms of 45 patients without stones were categorized as approximately normal (type I; n = 17); showing ectasia or stenosis of the main duct without persistent contrast on the functional film (type II; n = 16); showing ectasia or stenosis of the main duct with mild contrast retention (type III; n = 6); or showing poor ductal shape with evident contrast retention (type IV; n = 6). Scintigraphy of 23 preoperative and 12 postoperative patients and sialometry of 24 preoperative and 12 postoperative patients indicated severe preoperative impairment and postoperative improvement of gland function. Postoperatively, although no relevant differences in saliva flow rate were found between the 2 sides, scintigraphy showed lower function of the affected gland compared with the control side. Statistical data showed positive correlations among the 3 methods. Sialography intuitively reflected the ductal shape, whereas sialometry and scintigraphy were more sensitive for evaluating gland function. CONCLUSION: For patients with parotid stones, minimally invasive endoscopic surgery and meticulous postoperative manipulations help preserve the glands and facilitate recovery of gland function. The 3 evaluating modalities have certain positive correlations. PMID- 30395823 TI - Efficacy of Photodynamic Therapy in Minimizing Bisphosphonate-Related Osteonecrosis of the Jaws After Dental Extraction: A Preliminary Animal Study. AB - PURPOSE: Except for a few case reports, there is no study on the efficacy of photodynamic therapy (PDT) in decreasing or preventing bisphosphonate-related osteonecrosis of the jaws (BRONJ). This preliminary animal study assessed the effectiveness of this clinical treatment. MATERIALS AND METHODS: Zoledronic acid was administered to 20 rats for 5 weeks. Two weeks later, a first molar was extracted from each rat. The rats were randomized to control and PDT groups. PDT was performed in the experimental group after surgery and at weeks 1, 2, 3, 4, 5, 6, and 7 after surgery. In the 8th week, BRONJ signs were evaluated by an observer blinded to randomization. Rats were euthanized and underwent histopathologic and histomorphometric evaluations. Clinical signs were compared using the Fisher test. Histomorphometric parameters were compared using the Mann Whitney U test (alpha = 0.05). RESULTS: Two rats were lost from each group. Bone exposure decreased from 7 rats in the control group to 1 rat in the PDT group (P = .010). The stage of BRONJ decreased significantly from 7 rats in stage 1 to only 1 rat in stage 1 (P = .010). PDT decreased inflammation considerably for gingival eosinophils and lymphocytes and bone neutrophils, eosinophils, and lymphocytes. A larger percentage of live bone and smaller percentages of necrotic bone, empty lacunae, and neovascularization were observed in the PDT group. PDT also maintained bone remodeling, indicated by a large number of osteoclasts (P <= .001 for all comparisons by Mann-Whitney U test). CONCLUSIONS: Within the limitation of this preliminary animal study, PDT was found to be considerably effective clinically and histopathologically in decreasing or preventing BRONJ in rats. Future human studies are needed to verify these results. PMID- 30395824 TI - High Density of Intratumor CD45RO+ Memory Tumor-Infiltrating Lymphocytes Predicts Favorable Prognosis in Patients With Oral Squamous Cell Carcinoma. AB - PURPOSE: Although tumor-infiltrating lymphocytes (TILs) have been increasingly appreciated as novel biomarkers for prognostic prediction in cancer, little attention has been paid to the CD45RO+ memory TIL and its associations with clinical outcomes in oral squamous cell carcinoma (OSCC). The purpose of this study was to determine the associations between CD45RO+ TILs and clinicopathologic parameters and prognosis in OSCC. MATERIALS AND METHODS: Tissue sections of primary OSCC from 2 independent tertiary referral cancer centers (Nanjing and Wuxi, China) were retrospectively collected and subjected to immunohistochemical staining for CD45RO. Densities of CD45RO+ TILs in the tumor center (CT) and invasive margin were calculated. Optimal cutoff values of CD45RO+ TILs for patient stratification were generated by X-tile software. Kaplan-Meier and Cox regression analyses were performed to assess associations between CD45RO+ TILs and overall survival and recurrence-free survival. Prognostic prediction of CD45RO+ TILs was estimated by receiver operating characteristic (ROC) curve. RESULTS: One hundred sixty-nine eligible patients with OSCC were included. No relevant associations between CD45RO+ TILs and clinicopathologic parameters were identified. Kaplan-Meier analyses indicated that a high density of CD45RO TILs in the CT was significantly associated with favorable overall and recurrence-free survival (P = .0018 and .0007 by log-rank test). Cox proportional regression analyses showed that presence of CD45RO TILs in the CT was an independent prognostic factor for overall survival of OSCC. ROC curves showed that presence of CD45RO TILs in the CT was comparable to clinical stage in predicting patient survival, whereas their combination was superior to either parameter alone. CONCLUSIONS: The present findings indicate that intratumor density of CD45RO TILs is a viable and independent prognostic predictor for OSCC. PMID- 30395825 TI - What Is the Safety Zone for Palatal Soft Tissue Graft Harvesting Based on the Locations of the Greater Palatine Artery and Foramen? A Systematic Review. AB - PURPOSE: Palatal soft tissue graft harvesting is a common procedure in periodontal and implant dentistry. However, most of the complications after this procedure are associated with the underestimation of anatomic structures, such as the greater palatine artery (GPA). Therefore, the aim of this study was to provide guidelines for a safety zone for palatal harvesting. MATERIALS AND METHODS: A systematic search was conducted to identify cadaveric and computed tomography (CT) or cone beam CT studies assessing the location of the greater palatine foramen (GPF) and the path of the GPA in relation to the maxillary teeth. The effect of age, gender, and cadaveric and CT or cone beam CT studies on the location of the GPF and on the course of the GPA also was assessed. RESULTS: This systematic review included 26 studies, investigating 5,768 hemipalates. The most common location of the GPF was in the midpalatal aspect of the third molar (57.08%). As it traverses the palate anteriorly, the distance from the GPA to the maxillary teeth gradually decreases, except in the second premolar region, where it has the tendency to increase (13.8 +/- 2.1 mm). The least distance from the GPA to the teeth was found in the canine area (9.9 +/- 2.9 mm), whereas the greatest distance was in the second molar region (13.9 +/- 1 mm). A safety zone for palatal harvesting was proposed based on the anatomic findings. CONCLUSIONS: This study provides guidelines for identifying the position of the GPF and defines a safety zone for harvesting a free gingival graft or connective tissue graft, minimizing the risk of GPA injury. PMID- 30395826 TI - CCR4 Expression Is Associated With Poor Prognosis in Patients With Early Stage (pN0) Oral Tongue Cancer. AB - PURPOSE: Chemokine receptors are involved in tumor metastasis and can predict poor prognosis; however, the expression and clinicopathologic relevance of chemokine receptors in early-stage cancer remain largely unknown. This study measured the association between chemokine (C-C motif) receptor-4 (CCR4) expression and prognosis in patients with histologically node-negative (pN0) oral tongue cancer. MATERIALS AND METHODS: A retrospective analysis of CCR4 expression data from a consecutive case series of patients with pN0 oral cancer tongue was conducted. The expression of CCR4 by immunohistochemistry was investigated and the association between CCR4 expression and clinicopathologic variables and overall and disease-free survivals was evaluated using Kaplan-Meier analysis and a Cox regression model. RESULTS: CCR4 expression was examined in 128 human tongue cancerous samples (109 tongue squamous cell carcinomas [TSCCs] and 19 other types) and 10 normal tongue samples and was found to be highly expressed in tumor tissues compared with normal tissues. CCR4 expression was observed in 64.2% of patients with TSCC and showed a significant association with tumor stage (P = .037). Patients with CCR4-positive expression exhibited poorer overall and disease-free survivals compared with those with CCR4-negative expression (P < .001 and P = .001), and CCR4-positive expression was an independent factor of unfavorable overall and disease-free survivals (P = .002 and P = .007). CONCLUSIONS: This study identified CCR4 as a potential prognostic biomarker for recurrence and survival of patients with pN0 oral tongue cancer. Thus, CCR4 might be a possible therapeutic target for patients with early-stage cancer. PMID- 30395827 TI - Comparison of the effect of bioadhesive polymers on stability and drug release kinetics of biocompatible hydrogels for topical application of ibuprofen. AB - The study is focused on formulation of biocompatible hydrogels with a poorly soluble drug ibuprofen (5%) and comprehensive evaluation and comparison of effect of different bioadhesive polymers on their: suitability for application on skin; physical stability during the accelerated and natural aging tests (by performing centrifugation test, light microscopy, differential scanning calorimetry (DSC), rheological and pH measurements); in vitro drug release kinetics. Hydrogels, formulated with xanthan gum 1% (XIB), sodium carboxymethylcellulose 5% (CMCIB), poloxamer 407 16% (PIB), and carbomer 1% (KIB), were soft pseudoplastic semisolids with thixotropy and biocompatible pH. The type of the polymer significantly affected apparent viscosity of the hydrogels and miscibility rate with artificial sweat, their physical stability and shape, size, and aggregation of the drug crystals and degree of crystallization. The drug release in all investigated hydrogels was diffusion-controlled in accordance with the Higuchi model, and sustained for 12 h, with the drug release rate and the amount of drug released depended on the polymer. The described formulation approach enabled discrimination of the hydrogels with unsatisfactory application properties (CMCIB) and physical stability (KIB), and selection of the hydrogel with promising characteristics in terms of all investigated aspects (XIB) which could be considered for further evaluation. PMID- 30395828 TI - Application of a Dynamic Fluid and pH Model to Simulate Intraluminal and Systemic Concentrations of a Weak Base in GastroPlusTM. AB - The application of preclinical in vitro and in silico models can help formulation scientists to predict the in vivo performance of a drug in an early stage of oral drug product development. An important aspect is that these models should include equations that represent mechanisms that are biorelevant and are sensitive to changes in parameter values. Human gastrointestinal physiology involves many processes that change as a function of time. In this work, a dynamic fluid and pH model was applied in GastroPlusTM to simulate intraluminal and systemic concentrations of the weak base posaconazole in a biorelevant manner. Simulated results were compared with observed data, extracted from a previously reported human in vivo gastrointestinal aspiration study. Three different formulations were explored (i.e., 1 solution [20 mg dose strength] and 2 suspensions [both 40 mg dose strength]). Simulated results were compared and in line with the observed results for different intraluminal (e.g., precipitated fraction) and systemic parameters (e.g., plasma Cmax). The optimization of the advanced compartmental and absorption transit model related to fluid dynamics and dynamic pH in this work creates perspectives to validate this model with other reference data derived from aspiration/magnetic resonance imaging studies. PMID- 30395829 TI - Dual-targeting nanoparticles: co-delivery of curcumin and 5-fluorouracil for synergistic treatment of hepatocarcinoma. AB - Chemotherapy has been the standard for cancer therapy, but the non-specific cytotoxicity of chemotherapeutic agents and drug resistance of tumor cells has limited its efficacy. However, multidrug combination therapy and targeting therapy have resulted in enhanced anti-cancer effects and have become increasingly important strategies in clinical applications. In this study, a biotin-/lactobionic acid modified poly(ethylene glycol)-poly(lactic-co-glycolic acid)-poly(ethylene glycol) (BLPP) copolymer was synthesized, and curcumin (CUR) and 5-fluorouracil (5-FU) loaded nanoparticles (BLPPNPs/C+F) were prepared to enhance the treatment of hepatocellular carcinoma (HCC). Blank BLPPNPs were shown to have great biocompatibility via both in vitro and in vivo studies. Good targeting of tumor cells of BLPPNPs was confirmed by flow cytometry, fluorescence microscopy, and biodistribution. The synergistic anticancer effects of BLPPNPs/C+F were demonstrated by cytotoxicity and animal studies, while western blotting was used to further verify the synergistic effect of CUR and 5-FU. The dual-targeting and drug-loaded co-delivery nanosystem demonstrated higher cellular uptake and stronger cytotoxicity for tumor cells. Therefore, these dual targeting NPs are a promising co-delivery carrier that could be made available for cellular targeting of anticancer drugs to achieve better intracellular delivery and synergistic anticancer efficacy. PMID- 30395830 TI - Enrichment of Relevant Oxidative Degradation Products in Pharmaceuticals with Targeted Chemoselective Oxidation. AB - The ability to produce and isolate relatively pure amounts of relevant degradation products is key to several aspects of drug product development: (a) aid in the unambiguous structural identification of such degradation products, fulfilling regulatory requirements to develop safe formulations (ICH Q3B and M7); (b) pursue as appropriate safety evaluations with such material, such as chronic toxicology or Ames testing; (c) for a specified degradation product in a late stage regulatory filing, utilize pure and well-characterized material as the analytical standard. Producing such materials is often a resource- and time intensive activity, relying either on the isolation of slowly formed degradation products from stressed drug product, or by re-purposing the drug substance synthetic route. This problem is exacerbated if the material of interest is an oxidative degradation product, since typical oxidative stressing (H2O2 and radical initiators) tends to produce a myriad of irrelevant species beyond a certain stress threshold, greatly complicating attempts for isolating the relevant degradation product. In this paper, we present reagents and methods that may allow the rapid and selective enrichment of API with the desired oxidative degradation product, which can then be isolated and used for purposes described above. PMID- 30395831 TI - Location of Solvated Probe Molecules within Non-Ionic Surfactant Micelles using Molecular Dynamics. AB - An iconic textbook that pharmaceutical scientists encounter in under-graduate courses is "Martin's Physical Pharmacy and Pharmaceutical Sciences". Within the chapter on Colloids, a figure indicates the location of solubilisation of molecules within spherical, non-ionic surfactant micelles. The surfactant consists of polyethylene glycol (PEG) hydrophilic headgroups and alkane chains for the hydrophobic tail. The figure shows benzene and toluene within the alkane core, salicylic acid (2-hydroxybenzoic acid) at the interface between the core and PEG chains, and then para-hydroxybenzoic acid (4-hydroxybenzoic acid, 4HBA) located between the PEG chains. Molecular dynamics simulations of octaethylene glycol monododecyl ether micelles were performed with a series of probe molecules, including those within the Martin's figure, to determine their solubilisation location. Relative placement of molecules within the micelle was correct, however some specifics were different. In particular, benzene and toluene are excluded from the core, and 4HBA prefers to maintain contact with the core. A series of molecules containing six carbon atoms were also studied to determine the effects of cyclisation (moves out of core), polar functionalisation (anchored to interface) and aromatisation (excluded from central core). Molecular dynamics was found to be a useful tool for gaining insight into interactions important in solubilisation of molecules. PMID- 30395832 TI - Role of Modeling and Simulation in the Development of Novel and Biosimilar Therapeutic Proteins. AB - Modeling and simulation (M&S) is an important enabler of knowledge integration in novel biological product development programs. Given the volume of data generated from clinical trials and the complexity of pharmacokinetic (PK) and pharmacodynamic (PD) properties for reference products, extending the use of M&S to biosimilar development is logical. Assessing PK and PD similarity is normally a critical part of demonstrating biosimilarity to a reference product. Thoughtful considerations are necessary in study design to minimize the PK and PD variability, thereby increasing the sensitivity for detecting potential differences between products. In addition, the sensitivity of PD biomarkers depends partly on their relevance to the mechanism(s) of action and the dynamic range of PD response(s), including the impact of certain structural differences on PD in the relevant population. As such, opportunities exist for leveraging the available M&S knowledgebase to maximize the efficiency in the design and interpretation of PK and PD similarity studies. This article describes M&S applications which have contributed to and can continue to enhance biosimilar development programs. PMID- 30395833 TI - Integration of Precipitation Kinetics From an In Vitro, Multicompartment Transfer System and Mechanistic Oral Absorption Modeling for Pharmacokinetic Prediction of Weakly Basic Drugs. AB - Solubility, dissolution, and precipitation in the gastrointestinal tract can be critical for the oral bioavailability of weakly basic drugs. To understand the dissolution and precipitation during the transfer out of the stomach into the intestine, a multicompartment transfer system was developed by modifying a conventional dissolution system. This transfer system included gastric, intestinal, sink and supersaturation, and reservoir compartments. Simulated gastric fluid and fasted state simulated intestinal fluid were used in the gastric and intestinal compartment, respectively, to mimic fasted condition. The new transfer system was evaluated based on 2 model weak bases, dipyridamole and ketoconazole. Traditional 2-stage dissolution using 250 mL of simulated gastric fluid media, followed by 250 mL of fasted state simulated intestinal fluid, was used as a reference methodology to compare dissolution and precipitation results. An in silico model was built using R software suite to simulate the in vitro time dependent dissolution and precipitation process when formulations were tested using the transfer system. The precipitation rate estimated from the in vitro data was then used as the input for absorption and pharmacokinetic predictions using GastroPlus. The resultant simulated plasma concentration profiles were generally in good agreement with the observed clinical data, supporting the translatability of the transfer system in vitro precipitation kinetics to in vivo. PMID- 30395834 TI - Effects of Surfactants on Itraconazole-HPMCAS Solid Dispersion Prepared by Hot Melt Extrusion. I: Miscibility and Drug Release. AB - Hydroxypropyl methylcellulose acetate succinate (HPMCAS) has been widely investigated as a carrier for amorphous solid dispersion (ASD) of poorly water soluble drugs. However, its use has mostly been limited to ASDs prepared by spray drying using organic solvents, and the solvent-free method, hot melt extrusion (HME), has only limited use since it requires high processing temperature where the polymer and drug may degrade. In this investigation, surfactants were used as plasticizers to reduce the processing temperature. Their effects on drug release were also determined. To determine suitability of using surfactants, the miscibility of HPMCAS with three surfactants (poloxamer 188, poloxamer 407 and TPGS) and a model drug, itraconazole (ITZ), was studied by film casting. HPMCAS was miscible with ITZ (>30%) and each surfactant (>20%), and in ternary HPMCAS ITZ-surfactant (60:20:20) system. ASDs prepared by HME of HPMCAS-ITZ-surfactant mixtures (70:20:10 and 65:20:15) at 160C were physically stable after exposure to 40C/75% RH for 1 month. The presence of 15% w/w surfactant provided up to 50% drug release at pH 1 as compared to only 8% from ASDs with HPMCAS alone. Upon changing pH of dissolution medium from 1 to 6.8 in a step-dissolution process, complete drug release (90-100%) and extremely high apparent supersaturation (~75,000 times) of ITZ was observed when the solutions were filtered through 0.45 MUm filters. The apparently supersaturated solutions consisted of colloidal particles of ~300 nm size. The present study demonstrates that stable ASDs with improved processability and drug release may be prepared by HME. PMID- 30395835 TI - Steric repulsion forces contributed by PEGylation of interleukin-1 receptor antagonist (rhIL-1ra) reduce gelation and aggregation at the silicone oil-water interface. AB - Silicone oil, used as a lubricating coating in pharmaceutical containers, has been implicated as a cause of therapeutic protein aggregation. After adsorbing to silicone oil-water interfaces, proteins may form interfacial gels, which can be transported into solution as insoluble aggregates if the interfaces are perturbed. Mechanical interfacial perturbation of both monomeric recombinant human interleukin-1 receptor antagonist (rhIL-1ra) and PEGylated rhIL-1ra (PEG rhIL-1ra) in siliconized syringes resulted in losses of soluble monomeric protein. However, the loss of rhIL-1ra was twice that for PEG rhIL-1ra, even though in solution, PEG rhIL-1ra had a lower DeltaGunf and exhibited a more perturbed tertiary structure at the interface. Net protein-protein interactions in solution for rhIL-1ra were attractive, but increased steric repulsion due to PEGylation led to net repulsive interactions for PEG rhIL-1ra. Attractive interactions for rhIL-1ra were associated with increases in intermolecular beta sheet content at the interface, whereas no intermolecular beta-sheet structures were observed for adsorbed PEG rhIL-1ra. rhIL-1ra formed interfacial gels that were five times stronger than those formed by PEG rhIL-1ra. Thus, the steric repulsion contributed by the PEGylation resulted in decreased interfacial gelation and in the reduction of aggregation, in spite of the destabilizing effects of PEGylation on the protein's conformational stability. PMID- 30395836 TI - Effects Of Molecular Interactions On Miscibility And Mobility Of Ibuprofen In Amorphous Solid Dispersions With Various Polymers. AB - Hydrogen bonds (HBs) in amorphous solid dispersions (ASDs) may influence physical stability through effects on both drug miscibility and mobility. ASDs containing the HB-donor ibuprofen (IBP) alone or with one of four model polymers (PVP, PVP/VA, PVA or polystyrene (PST)) were monitored by molecular dynamics (MD) simulation. HB distributions and contributions of electrostatic, van der Waals, and internal interactions to miscibility and mobility were analyzed versus drug concentration. The probability of IBP-IBP HBs decreases markedly (0.6->0.0) with dilution (100->10% drug) in PVP due to IBP-PVP HBs while dilution in the nonpolar PST has a more modest effect on IBP-IBP HB probability (0.6->0.3). Concentration dependent Flory-Huggins interaction parameters (X) were determined to assess drug polymer miscibility. XIBP-PVP values were -0.9 to -1.8 with a plateau near 50% w/w PVP while XIBP-PST fluctuated near zero (-0.1 to 0.3), suggesting that IBP is more soluble in PVP than in PST. XIBP-polymer values in polymers varying in pyrrolidone/acetate composition were in the order PVP (most favorable) > PVP/VA > PVA (least favorable). Decreased local mobility of IBP measured by the atomic fluctuation (AF) correlates with more IBP-PVP HBs with increasing PVP content. The opposite trend in IBP-PST may arise from IBP-IBP HB disruption on dilution. PMID- 30395837 TI - Hepatic cytochrome P450 metabolism suppressed by mast cells in type 1 allergic mice. AB - Mast cells and Kupffer cells secrete interleukin (IL)-1beta, interferon (IFN) gamma, and tumor necrosis factor (TNF)-alpha, which stimulate excess nitric oxide (NO) producing-inducible NO synthase (iNOS). Unlike Kupffer cells, immunoglobulin E-sensitized mast cells elicit sustained NO production. We investigated the participation of mast cell-released NO and cytokine-derived iNOS activation in type 1 allergy-suppressed hepatic cytochrome P450 (CYP) metabolism. Aminoguanidine, a selective iNOS inhibitor, completely suppressed serum nitrate plus nitrite (NOx) concentrations after primary and secondary sensitization of ICR mice and markedly attenuated allergy-suppressed hepatic CYP1A2, CYP2C, CYP2E1, and CYP3A activities. In the liver, primary and secondary sensitization enhanced iNOS-stimulating IFN-gamma (5-15-fold) and TNF-alpha (3-5-fold) mRNA levels more than IL-1beta (2-fold) and F4/80-positive Kupffer cell (2-fold) mRNA levels. When mast cell-deficient (-/-) mice were sensitized, hepatic CYP activities were not suppressed. Serum NOx levels in the sensitized -/- mice were similar with those in saline-treated ICR and -/- mice. In the liver of -/- mice, secondary sensitization markedly enhanced mRNA expression of iNOS (20-fold), IFN gamma (15-fold), and TNF-alpha (3-fold). However, hepatic total NOS activities in -/- mice were not significantly different between saline treatment and sensitization. Similarly, primary and secondary ICR mice did not significantly enhance total NOS activities in the liver and hepatocytes. The total NOS activities observed did not relate to the high levels of iNOS, IFN-gamma, and TNF alpha mRNA in the liver. Hepatic c-kit-positive mast cells in sensitized ICR mice were maintained at control levels. Therefore, our data suggest that mast cell released NO participates in type 1 allergy-suppressed CYP1A2, CYP2C, CYP2E1, and CYP3A metabolism. PMID- 30395838 TI - Oxidative Stress Induces Release of 2'-AMP from Microglia. AB - BACKGROUND: Microglia metabolize exogenous 2'-AMP and 3'-AMP (non-canonical nucleotides) to adenosine and exogenous 2'-AMP and 3'-AMP (via conversion to adenosine) inhibit the production of inflammatory cytokines by microglia. This suggests that if microglia release endogenous 2'-AMP and/or 3'-AMP in response to injurious stimuli, this would complete an autocrine/paracrine mechanism that attenuates the over-activation of microglia during brain injury. Here we investigated in microglia (and for comparison astrocytes and neurons) the effects of injurious stimuli on extracellular and intracellular levels of 2',3'-cAMP (2' AMP and 3'-AMP precursor), 2'-AMP, and 3'-AMP. METHODS: Experiments were conducted in primary cultures of rat microglia, astrocytes, and neurons. Cells were exposed to oxygen/glucose deprivation, iodoacetate plus 2,4-dinitrophenol (metabolic inhibitors), glutamate, or H2O2 for one hour, and extracellular and intracellular 2',3'-cAMP, 2'-AMP, and 3'-AMP were measured by UPLC-MS/MS. KEY RESULTS: In microglia, H2O2 increased extracellular levels of 2'-AMP, but not 3' AMP, by ~16-fold (from 0.17+/-0.11 to 2.78+/-0.27 ng/106 cells; n=13; mean +/- SEM; P<0.000005). H2O2 also induced oxidative changes in cellular proteins as detected by an increased number of carbonyl groups in protein side chains. In contrast, oxygen/glucose deprivation, metabolic inhibitors, or glutamate had no effect on either extracellular 2'-AMP or 3'-AMP levels. In astrocytes and neurons, none of the injurious stimuli increased extracellular 2'-AMP or 3'-AMP. CONCLUSIONS: Oxidative stress (but not oxygen/glucose deprivation, energy deprivation, or excitotoxicity) induces microglia (but not astrocytes or neurons) to release 2'-AMP, but not 3'-AMP. The 2',3'-cAMP/2'-AMP/adenosine pathway mechanism may serve to prevent over-activation of microglia in response to oxidative stress. PMID- 30395839 TI - Robot-assisted laparoscopic reoperative repair for failed pyeloplasty in children: an updated series. AB - PURPOSE: Among children with recurrent obstruction after pyeloplasty, reoperative pyeloplasty is commonly utilized. We previously reported on reoperative robot assisted laparoscopic repair for failed pyeloplasty in 16 children and concluded that short term and intermediate outcomes were comparable to open reoperative repair. This updated series reports on longer-term outcomes from an extended series. METHODS: We retrospectively reviewed outcomes of consecutive children with prior failed primary pyeloplasty who underwent robot-assisted laparoscopic reoperative repair at a single institution from 1/2008 to 6/2018. RESULTS: Overall, 36 children aged 0.6-15.2 years (median 3.7) underwent robot-assisted laparoscopic reoperative repair (31 pyeloplasties, 5 ureterocalicostomies) at a median 24.3 months [3.9-136.7] after primary repair. Median reoperative time was 285.0 minutes [207-556] and median length of stay was 1 day [1-8]. Crossing vessels were present in 8/30 children (26.7%) with prior open repair and in 0/6 children with prior minimally invasive repair. Perioperative complications occurred in 6/36 children (16.7%), with 4 Clavien grade 1-2 and 2 Clavien grade 3 5 complications. Median follow-up was 35.3 months [1.4-108.3], with 18 children (50.0%) followed for >3 years. Postoperative ultrasound in 34 children demonstrated improvement in 31 (91.2%), stability in 2 (5.9%), and worsening in 1 (2.9%). All 11 children undergoing both pre- and post-operative diuretic renography demonstrated stable or improved differential renal function. All children were symptom free at last follow-up. CONCLUSIONS: To our knowledge, this is the largest series of robot-assisted laparoscopic reoperative repair for failed pyeloplasty in children. Our results indicate the feasibility, efficacy, safety, and durability of this procedure. PMID- 30395841 TI - From PADUA to RENAL score and vice versa: Development and validation of a mathematical converter. AB - Tumor complexity remains the primary modality by which urologists determine surgical approach and treatment strategy. R.E.N.A.L. and PADUA scores are the most popularly used nephrometry systems. Notwithstanding the common items contributing to the scores, some differences exist between PADUA and R.E.N.A.L. systems, translating into a different final score when assessing the tumor complexity of a renal mass. This represents an issue during quantitative syntheses of literature data and in the setting of retrospective multicentric analyses. We aimed to develop a PADUA-to-R.E.N.A.L. score mathematical converter and vice versa, from a dataset of 488 renal masses who had data about PADUA score, R.E.N.A.L. score and clinical tumor size. PADUA score was modeled as proportional, through a scalar coefficient, to the R.E.N.A.L. score, to obtain the calculated PADUA score (cPADUA=1.14225 * R.E.N.A.L.). Vice versa, the calculated RENAL score (cR.E.N.A.L. = 0.8607 *PADUA) was obtained (adjusted R2 = 0.9831, p = 0.000003). Descriptive statistics of mathematically calculated distributions matched with the real values. A 5-fold cross-validation scheme was used to validate the model. PMID- 30395840 TI - Clinical results of transarterial embolization to control postoperative vascular complications after partial nephrectomy. AB - PURPOSE: To evaluate the safety and clinical efficacy of transarterial embolization for vascular complications after partial nephrectomy. MATERIALS AND METHODS: This retrospective study included 1187 patients who underwent partial nephrectomy between January 2006 and December 2017. In total, 36 patients were referred to the interventional radiology department for vascular complications after partial nephrectomy. Data on demographics, clinical manifestations, angiographic findings, embolization procedure, perioperative details, and the technical and clinical success rates were analyzed. Further, renal functions at diagnosis, after embolization, and at the last follow-up were recorded. RESULTS: A diagnosis of hemorrhage was made at a median of 5 (range, 0-89) days after surgery. The incidence of the requirement of embolization owing to hemorrhage after laparoscopic surgery (5.9%, 17/289) was higher than that after open surgery (1.8%, 8/440; p = 0.003) and robot-assisted surgery (2.4%, 11/458; p = 0.014). The technical and clinical success rates were 100% (36/36) and 94.4% (34/36), with 2 patients requiring additional embolization using n-butyl-2-cyanoacrylate glue. The estimated glomerular filtration rates at diagnosis, post-embolization, and the last follow-up were 81.0 +/- 21.6, 83.7 +/- 21.0, and 84.9 +/- 15.8mL/min/1.73 m2, respectively (p = 0.345). No major complication was observed during follow-up. CONCLUSIONS: Transarterial embolization is safe and effective in the management of vascular complications after partial nephrectomy. Moreover, renal functions were well-preserved with superselective TAE. PMID- 30395842 TI - Effect of Vitamin D Therapy on Sexual Function in Women with Sexual Dysfunction and Vitamin D Deficiency: a Randomized, Double-blind, Placebo-controlled Clinical Trial. AB - PURPOSE: To investigate the effect of vitamin D therapy on sexual function in women with low vitamin D levels and sexual dysfunction. MATERIALS AND METHODS: This randomized, double-blind, placebo-controlled trial was conducted on women aged 18-45 years with sexual dysfunction (Female Sexual Functioning Index score of <26.55) and a serum 25[OH]D level of <30 ng/mL. Participants received an intramuscular injection of 300,000 IU cholecalciferol or a placebo at baseline and then after four weeks. Sexual function was evaluated using the Female Sexual Function Index at baseline, and then after four and eight weeks. The serum level of 25[OH]D and depression symptoms (Beck Depression Inventory) were evaluated at baseline and then after eight weeks. RESULTS: Thirty-eight women in each group completed the study. The serum levels of 25[OH]D increased only in the cholecalciferol group by 14.4 +/- 3.2 ng/mL (P<0.001). The Female Sexual Function Index score was higher in the intervention group at the 4th (19.6 vs. 16.3, P=0.002) and 8th (25.0 vs. 17.1, P <0.001) weeks of the study. The Beck Depression Inventory score was significantly decreased only in the cholecalciferol group by -21.0 +/- 12.3 (P<0.001). The effect of treatment on sexual function was independent from its effect on symptoms of depression. CONCLUSION: Vitamin D therapy in women with sexual dysfunction and vitamin D deficiency can improve their sexual function. This effect does not seem to be mediated by the improvement of depression symptoms. PMID- 30395843 TI - Crotoxin from Crotalus durissus terrificus venom: In vitro cytotoxic activity of a heterodimeric phospholipase A2 on human cancer-derived cell lines. AB - Crotoxin (CTX), a heterodimeric phospholipase present in venom of snakes of the genus Crotalus, has demonstrated a broad spectrum of pharmacological properties, such as antimicrobial, hemostatic, and antitumoral. However, the precise mechanism of its cytotoxicity and antitumoral properties remains to be determined. Therefore, in the present study, we isolated crotoxin (F1 CTX) through two steps DEAE-Sepharose and Heparin-Sepharose FF chromatography. The C terminal sequence of the A- and B-chain protein fragment was determined by LC MS/MS mass spectrometry, which showed 100% identity to crotoxin structure. In order to investigate its cytotoxic effects, we demonstrated that the F1 CTX fraction at 0-30 MUg/mL concentrations for 72 h presented a heterogeneous response profile on nine human cancer-derived cell lines from four tumor types (pancreatic, esophagus, cervical cancer, and glioma). The glioma (GAMG and HCB151) and pancreatic (PSN-1 and PANC-1) cancer cells showed a higher sensitivity with IC50 of <0.5, 4.1, 0.7 and < 0.5 MUg/mL, respectively. Conversely, F1 CTX does not reduce the viability of normal cells. On the other hand, cervical (SiHa) and esophagus (KYSE270) cancer cell lines presented higher resistance, with IC50 higher than 30.2 and 8.7 MUg/mL, respectively. Moreover, F1 CTX did not affect cell cycle distribution under the conditions evaluated and seems to be more cytotoxic than cytostatic. The pro-apoptotic effect of F1 CTX treatment was demonstrated in glioma (HCB151) cell line. In addition, crotoxin revealed a potential to initiate cell responses such as DNA damage in glioma (HCB151) and pancreatic cancer by H2AX activity induction. Conversely, F1 CTX does not reduce the viability of normal cells. Importantly, the comparison of F1 CTX effect with standard chemotherapeutic agents demonstrated a greater cytotoxic potential in the majority of tumor types (glioma, pancreatic, and cervical cancer). On the other hand, F1 CTX was less cytotoxic in esophageal cell lines compared to the gemcitabine agent used in clinical practice. Therefore, this work showed that F1 CTX has a cytotoxic activity and pro-apoptotic potential, contributing to the knowledge about the F1 crotoxin properties as well as its possible use in cancer research, particularly in glioma and pancreatic cancer cell lines. PMID- 30395844 TI - Granzyme K Expressed by Classically Activated Macrophages Contributes to Inflammation and Impaired Remodeling. AB - Granzyme K (GzmK), traditionally described as a pro-apoptotic, granule-secreted serine protease, has been proposed to promote inflammation. Found at low levels in the plasma of healthy individuals, GzmK is markedly elevated in response to sepsis and infection. In the present study we investigated the role of GzmK in inflammation and remodeling in response to thermal injury. In human burn tissue, GzmK was elevated compared to normal skin, with expression predominantly found in macrophages. GzmK was expressed and secreted by cultured human classically activated macrophages. To assess the role of GzmK in response to skin wounding, wild-type or GzmK-/- mice were subjected to a grade 2 thermal injury. GzmK-/- mice exhibited improved wound closure, matrix organization and tensile strength compared to wild-type mice. Reduced pro-inflammatory IL-6, ICAM-1, VCAM-1 and MCP 1 expression was observed at 3 days post-injury. Additionally, GzmK induced IL-6 expression in keratinocytes and skin fibroblasts that was dependent on protease activated receptor-1 (PAR-1) activation. Re-epithelialization showed the greatest degree of improvement of all healing parameters, suggesting keratinocytes are sensitive to GzmK-mediated proteolysis. In support, keratinocytes, but not skin fibroblasts, exposed to GzmK demonstrated impaired wound healing in vitro. In summary, GzmK influences wound healing by augmenting inflammation while impeding epithelialization. PMID- 30395845 TI - Recurrent fusion gene ADCK4-NUMBL in cutaneous squamous cell carcinoma mediates cell proliferation. PMID- 30395846 TI - Culprit drugs induce specific IL-36 overexpression in Acute Generalized Exanthematous Pustulosis. AB - Acute generalized exanthematous pustulosis (AGEP) is a severe adverse cutaneous drug reaction. Although an involvement of drug-specific T cells has been reported, the physiopathology of AGEP and mechanism of neutrophilic skin inflammation remains incompletely understood. Recently, mutations in IL-36RN, the gene encoding the IL-36 receptor antagonist, have been reported to be more frequent in AGEP patients and pustular psoriasis. Here, we show that IL-36 cytokines, in particular IL-36gamma, is highly expressed in lesional skin of AGEP patients, keratinocytes and macrophages being a major source of IL-36gamma. Such an IL-36gamma overexpression could not be observed in patients with drug-induced maculo-papular rash (MPR). In vitro, the causative drug specifically induced IL 36gamma release either directly by peripheral blood monocytes from AGEP patients, or indirectly by keratinocytes in presence of autologous peripheral blood mononuclear cells. Such culprit drug induction of IL-36gamma secretion in vitro was specific for AGEP and involved the sensing of drug/albumin complex as danger signal by Toll-like receptor 4. Our results suggest that IL-36gamma secretion by monocytes/macrophages and keratinocytes in response to culprit drug exposure likely plays a key role in the pathogenesis of AGEP. PMID- 30395847 TI - Potentiation of psoriasis-like inflammation by PCSK9. AB - Psoriasis is a systemic inflammatory disease, associated with metabolic disorders, including high level of low-density lipoprotein(LDL). Proprotein convertase subtilisin/kexin 9 (PCSK9), promoting the degradation of LDL receptors, and therefore the increased concentration of circulating LDL, is also involved in inflammation. This study aims to examine the role of PCSK9 in psoriasis and to investigate the potential of topically applying siRNA targeting Pcsk9 as a psoriasis treatment. We investigated the expression of PCSK9 in lesions of psoriasis patients, the imiquimod (IMQ) induced psoriatic reactions in Pcsk9 knockout and Pcsk9 siRNA treated mice, and also used cultured human keratinocytes to investigate the role of PCSK9 on regulating cell proliferation and apoptosis. We found that PCSK9 is overexpressed in psoriatic lesions, suppressing Pcsk9 can decrease the inflammatory reaction induced by IMQ treatment and inhibit hyper-proliferation of keratinocytes. We also found that suppressing PCSK9 can significantly alter the cell cycle and induce apoptosis of human keratinocytes. Taken together, our findings indicate that PCSK9 plays an important role in psoriasis, and may be a therapeutic target. PMID- 30395848 TI - Non-Histaminergic Itch Mediators Elevated in the Skin of a Porcine Model of Scabies and of Human Scabies Patients. PMID- 30395849 TI - Crocetin inhibits PDGF-BB-induced proliferation and migration of retinal pigment epithelial cells. AB - In proliferative vitreoretinopathy (PVR), the proliferation and migration of retinal pigment epithelial (RPE) cells are important to pathogenesis. Platelet derived growth factor (PDGF) is an important factor in the underlying mechanism. Several studies have shown that PDGF induced the proliferation and migration effects on RPE cells in PVR. Crocetin-anantioxidant carotenoid that is abundant in saffron-has been shown to suppress the migration and proliferation of many cell types, but studies of the effects on RPE cell migration and proliferation are incomplete. Therefore, we investigated the inhibitory effect of crocetin on the proliferation and migration of ARPE-19 cells induced by PDGF-BB, an isoform of PDGF. The proliferation of cells was assessed by Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays. The apoptosis of cells was assessed by flow cytometric analysis. The migration of RPE cells was detected by a Transwell migration assay and an in vitro scratch assay. The levels of main regulatory proteins for apoptosis and the PDGF-BB-induced signaling pathway were determined by western blot analysis. The proliferation and migration of ARPE-19 cells treated with crocetin (100-400 MUM) and PDGF-BB (20 ng/ml) were significantly inhibited in a concentration- and time-dependent manner. Crocetin exhibited potent inducing effects on the apoptosis of PDGF-BB-induced ARPE-19 cells via the modulation of Bcl-2 family regulators in a concentration-dependent manner. The inhibitory effects of crocetin on PDGF-BB-induced platelet-derived growth factor receptor beta (PDGFRbeta) and the underlying pathways of PI3K/Akt and ERK, p38, JNK activation were identified. The results showed that crocetin is an effective inhibitor of PDGF-BB-induced proliferation and migration of ARPE-19 cell through the downregulation of regulatory signaling pathways. PMID- 30395850 TI - Methylhexaneamine causes tachycardia and pressor responses indirectly by releasing noradrenaline in the rat. AB - We have investigated the mode of cardiovascular action of the stimulant methylhexaneamine (MHA) in terms of direct or indirect adrenergic actions in anaesthetised rats. Male and female rats were anaesthetised with pentobarbitone and pressor (changes in diastolic blood pressure) and cardioaccelerator responses to MHA were examined in vehicle treated or chemically sympathectomised rats. MHA produced pressor and cardioaccelerator responses over the same dose range in vehicle treated animals, with significant cardioaccelerator and pressor responses occurring at MHA (0.1 mg/kg). However, tachycardia was more marked than pressor responses. In sympathectomised rats, cardiac and pressor actions of MHA were greatly attenuated. MHA was also studied in isolated tissues. In rat vas deferens, MHA produced small tonic contractions, but these were virtually abolished by sympathectomy In rat aorta, MHA produced almost no contractions. These results are also consistent with largely indirect actions. There were no differences between male and female rats. It is concluded that MHA acts predominantly indirectly in both male and female rats causing noradrenaline release to produce cardiovascular actions and that as a result pressor and cardiac responses occur at similar doses. This propensity for MHA to cause tachycardia and rises in blood pressure at similar doses range may have implications for adverse cardiovascular actions. PMID- 30395851 TI - New tricks for an old dog: A repurposing approach of apomorphine. AB - Apomorphine is a 150-year old nonspecific dopaminergic agonist, currently indicated for treating motor fluctuations in Parkinson's disease. At the era of drug repurposing, its pleiotropic biological functions suggest other possible uses. To further explore new therapeutic and diagnostic applications, the available literature up to July 2018 was reviewed using the PubMed and Google Scholar databases. As many of the retrieved articles consisted of case reports and preclinical studies, we adopted a descriptive approach, tackling each area of research in turn, to give a broad overview of the potential of apomorphine. Apomorphine may play a role in neurological diseases like restless legs syndrome, Huntington's chorea, amyotrophic lateral sclerosis, Alzheimer's disease and disorders of consciousness, but also in sexual disorders, neuroleptic malignant( like) syndrome and cancer. Further work is needed in both basic and clinical research; current developments in novel delivery strategies and apomorphine derivatives are expected to open the way. PMID- 30395852 TI - Diagnostic and Therapeutic Implications of Pulmonary Lymphoma Associated with Nodular Amyloidosis. AB - Pulmonary localization of B-cell lymphoma associated with deposits of amyloid material is a rare finding among the thoracic diseases spectrum. We report a rare case of nodular pulmonary amyloidosis in a 50-year-old patient. He underwent to a left upper lobectomy due to a Mucosa Associated Lymphoid Tissue (MALT) lymphoma which originated from the bronchial lymphoid tissue. PMID- 30395853 TI - Early extubation without increased adverse events in high risk cardiac surgical patients. AB - BACKGROUND: Previous reports of early extubation after cardiac surgery vary in the definition of "early" and may limit findings to patients with less preoperative risk. We sought to determine if an 8-tier multidisciplinary early extubation protocol with the goal of extubating within six hours after surgery would be successful without increasing adverse events in patients with increased preoperative risk. METHODS: Postoperative adult cardiac surgery patients in a tertiary care intensive care unit (ICU)(n=459) were analyzed six months pre- and six months post-implementation of the protocol. Society of Thoracic Surgery (STS) risk scores were utilized as surrogate markers of risk. Patients with STS scores (n=333) were stratified into four equal groups from lowest to highest score. A composite of acute renal failure, reintubation, stroke and mortality was the primary outcome. Secondary outcomes included ICU and hospital lengths of stay, reoperation and sternal wound infection. RESULTS: In all patients, ventilation times were significantly decreased from a median of 7.4 hours to 5.7 hours following protocol implementation. When stratified by STS scores, higher risk patients (Groups 3 and 4) had the largest reduction in ventilation times from median 9.2 hours to 5.7 hours (p<0.0001) without a significant increase in adverse events. The highest risk patients (STS score > 40% (n=14)) all had extubation times < 6 hours post-protocol and no significant increase found in adverse events (p=0.138). CONCLUSIONS: A prudent and diligent multi-faceted early extubation protocol may be successful in high risk cardiac surgical patients without an increase in adverse outcomes. A larger study is needed in the future to confirm the finding. PMID- 30395854 TI - Degenerative Mitral Regurgitation After Non-Mitral Cardiac Surgery: MitraClip Versus Surgical Reconstruction. AB - BACKGROUND: Surgical mitral valve repair is the conventional treatment for severe degenerative mitral regurgitation (MR). MitraClip therapy has emerged as a viable option in high-risk surgical patients. We sought to compare conventional surgery to MitraClip in patients with severe degenerative mitral valve prolapse (MVP) and previous cardiac interventions. METHODS: From Jan-2012 to May-2016, 131 patients with previous cardiac surgery and subsequent intervention for degenerative MVP were included in this analysis: 75 (57.3%) underwent surgical repair, and 56 (42.7%) underwent MitraClip placement. Follow-up was available in all early survivors at median (IQR) of 11 (0, 32) months for surgery and 11 (3-21) months for MitraClip patients. RESULTS: MitraClip patients were older (75.7+/-8.6 vs. 68.6+/-13.1, p<0.001), and had higher STS risk scores (5.8+/-2.4 vs. 2.7+/-2.3, p<0.001). Median length-of-stay was 7 (5, 11) days for surgery and 2 (2, 4) days for MitraClip patients (p<0.001), but 30-day mortality was comparable between the 2 groups (2.7% vs. 3.6%, p=0.77). Recurrent MR (moderate/severe) was significantly higher for MitraClip patients, both at discharge (43.1% vs. 5.4%, p<0.001) and 1-year follow-up (66.7% vs. 33.3%, p=0.02). At 1-year post intervention, freedom from mitral re-intervention was significantly higher for surgical patients (100.0% vs. 87.5%, p=0.006). CONCLUSIONS: In patients with previous cardiac interventions and severe degenerative MVP, a repeat conventional surgery is safe and durable. Percutaneous MitraClip repair is effective but associated with higher risk of residual MR, and should only be considered in selected patients. Careful patient selection using a heart team approach is recommended. PMID- 30395855 TI - Direct true lumen cannulation for acute type A aortic dissection (Reply). PMID- 30395856 TI - Long-term Patency of Individual Segments of Different Internal Thoracic Artery Graft Configurations. AB - BACKGROUND: Internal thoracic artery (ITA) grafts are the most durable conduits available for coronary artery bypass grafting (CABG). However, little is known about long-term angiographic outcomes of ITA grafts used in different configurations and whether sequential or Y-grafting compromises patency of the inflow ITA graft. METHODS: From 1/1972 to 8/2016, 60,500 patients underwent primary isolated CABG, of whom 326 received ITA grafts placed in sequential or Y configuration and were studied angiographically (median 4.8 years to first follow up angiogram). Each sequential or Y-segment was studied individually using a mixed-effects longitudinal model with patient as the random effect. RESULTS: At 15 years, patency of the proximal ITA segment (n=331) was 99%; of a sequential segment (n=222) 97%; and of the segment beyond anastomosis of a Y-graft (n=109) 99%. In the Y-graft (n=109), 5-, 10-, and 15-year patency was 92%, 91%, and 90%, respectively. After adjusting for proximal stenosis and graft location, Y-grafts were associated with greater occlusion than the inflow segment of ITA grafts (odds ratio [OR] 51, 95% confidence interval [CI] 6.1-422; P=.003) and of sequential grafts (OR 12, CI 1.14-120; P=.04). CONCLUSIONS: Long-term patency of ITA grafts in either sequential or Y-configuration is similar qualitatively, but not quantitatively, to the known patency of single ITA to left anterior descending grafts. Sequential or Y-grafting does not compromise patency of the inflow portion of an ITA graft. Y-graft patency is lower than sequential graft patency, but is still better than known patency of saphenous vein grafts. PMID- 30395857 TI - Impact of heparin or non-heparin coated circuits on platelet function in pediatric cardiac surgery. AB - BACKGROUND: Extracorporeal circuit coating has been shown to improve coagulation derangements during pediatric cardiopulmonary bypass (CPB). The aim of this study was to compare platelet function and hemostasis activation in pediatric cardiac surgery conducted with non-heparin coating (Balance(r)) versus heparin-based coating (Carmeda(r)) circuits. METHODS: A prospective, randomized, double-center trial was conducted in children older than one month undergoing congenital heart disease (CHD) treatment. Blood samples were collected at baseline (T0), 15 minutes after the start of CPB (T1), and 15 minutes (T2) and 1 hour after the conclusion of CPB (T3). The primary endpoint of the study was to detect potential differences in Beta-thromboglobulin levels between the two groups at T2. Other coagulation and platelet function parameters were analyzed as secondary endpoints. RESULTS: Beta-thromboglobulin increased significantly at T2 in both groups. However, there was no significant difference between the groups across all time points. There was no difference in the secondary endpoints between the groups. CONCLUSIONS: The two circuits showed similar biological effects on platelet function and coagulation. This observation may be useful in optimizing the conduct of CPB and in rationalizing its cost for the treatment of CHD. PMID- 30395858 TI - Nuanced approach to surgical tricuspid valve endocarditis (Reply). PMID- 30395859 TI - Should we go further with Mitraclip without simultaneously developing percutaneous annuloplasty? PMID- 30395860 TI - Early Prognosis of Reduction Ascending Aortoplasty (Reply). PMID- 30395861 TI - The probability of imcomplete or hypoplastic circle of Willis. PMID- 30395862 TI - Pretreatment with Diazoxide Attenuates Spinal Cord Ischemia-Reperfusion Injury Through STAT3 pathway. AB - BACKGROUND: Delayed paraplegia remains a feared complication of thoracoabdominal aortic intervention. Pharmacological preconditioning with diazoxide (DZ, KATP channel opener) results in neuroprotection against ischemic insult. However, the effects of DZ in spinal cord ischemia-reperfusion injury have not been fully elucidated. We hypothesized that DZ attenuates spinal cord ischemia-reperfusion injury through the signaling transducer and activator of transcription (STAT) 3 Pathway. METHODS: Adult male C57/BL6 mice received DZ (20 mg/kg) by oral gavage. Spinal cords were harvested after 0, 12, 24, 36, 48, and 60 hours after administration of DZ. The expression of pSTAT3 was assessed by western blot analysis. Five groups were studied: DZ (DZ pretreatment, n=8), ischemic control (phosphate-buffered saline (PBS) pretreatment, n=11), DZ+STAT3 inhibitor (LY5R) (DZ pretreatment + LY5, n=8), LY5 (PBS pretreatment + LY5 n=8), and sham (without crossclamping, n=5). Spinal cord ischemia was induced by 4 minutes of thoracic aortic cross-clamp. Functional scoring (Basso Mouse Score) was done at 12-hour intervals until 48 hours, and spinal cords were harvested for the evaluation of both BCL-2 expression and histological changes. RESULTS: The expression of pSTAT3 was significantly upregulated 36 hours after administration of DZ. The motor function in the DZ group was significantly preserved compared to all other groups. The expression of BCL-2 in the DZ group was significantly higher than in the ischemic control, DZ+LY5, and LY5 groups 48 hours after reperfusion. CONCLUSIONS: DZ preserves motor function in spinal cord ischemia-reperfusion injury via the STAT3 pathway. DZ may be beneficial clinically, for use in spinal protection in aortic intervention. PMID- 30395863 TI - A Standardized Musculocutaneous Flap for the Coverage of Deep Sternal Wounds after Cardiac Surgery (Commentary). PMID- 30395864 TI - Extracellular vesicles and energy metabolism. AB - Glycolytic enzymes are among the most frequently identified proteins in proteomics of exosomes/extracellular vesicles. This review brings up the possibility that exosomes/extracellular vesicles during their life-time in bodily fluids power important energy-consuming functions by glycolytic conversion of glucose or fructose into ATP. It was seen that prostasomes (exosomes of the prostate) could produce ATP by glycolysis and that the produced ATP quickly was consumed by adjacent prostasomal ATPases. The glycolytic ATP production appeared to be coupled to self-sustaining energy requirements. It will also be discussed how a failure in this machinery (lowered activity of ATPases) with a resultant polluting leakage of extracellular ATP could affect cancer development. PMID- 30395865 TI - Next generation sequencing in family with MNGIE syndrome associated to optic atrophy: Novel homozygous POLG mutation in the C-terminal sub-domain leading to mtDNA depletion. AB - INTRODUCTION: Mitochondrial diseases are a group of disorders caused mainly by the impairment of the mitochondrial oxidative phosphorylation process, due to mutations either in the mitochondrial or nuclear genome. Among them, the mitochondrial neuro-gastrointestinal encephalo-myopathy (MNGIE) syndrome affects adolescents or young adults, and is mostly caused by TYMP mutations encoding a cytosolic thymidine phosphorylase (TP). PATIENTS AND METHODS: The present study reports the molecular investigation by next-generation re-sequencing of 281 nuclear genes, encoding mitochondrial proteins, of consanguineous family including two individuals with MNGIE syndrome associated to optic atrophy. Bioinformatic analysis was also performed in addition to mtDNA deletion screening and mtDNA copy number quantification in blood of the two patients which were carried out by solf clipping program and qPCR respectively. RESULTS: Next generation re-sequencing revealed a novel homozygous c.2391G > T POLG mutation (p.M797I) co-occurring with the hypomorphic c.1311A > G OPA1 variant (p.I437M). Analysis of the mitochondrial genome in the two patients disclosed mtDNA depletion in blood, but no deletion. Bio-informatics investigations supported the pathogenicity of the novel POLG mutation that is located in the C-terminal subdomain and might change POLG 3D structure, stability and function. CONCLUSION: The novel homozygous p.M797I POLG mutation is responsible for MNGIE combined to optic atrophy and mtDNA depletion in the two patients. PMID- 30395866 TI - Relationship between formalin reagent and success rate of targeted sequencing analysis using formalin fixed paraffin embedded tissues. AB - BACKGROUND: Tumor genetic alterations are determined to aid in selecting therapy and predicting prognosis. In routine clinical practice, targeted sequencing analysis is performed using formalin-fixed paraffin embedded (FFPE) tissues. However, successful genetic analysis remains challenging because FFPE DNA is fragmented during the sample preparation process. METHODS: Real-time PCR was performed to assess DNA quality and quantities. Targeted sequencing was performed using FFPE tissues fixed with different types of formalin. RESULTS: DNA was less fragmented from samples fixed in low formalin concentration (10% vs. 20%) and neutral buffered conditions (neutral buffered vs. non-neutral). DNA fragmentation increased over the fixation time. In a preliminary test study, we compared fixation using 10% neutral buffered formalin (n = 180) and 20% formalin (n = 26). The success rate of targeted analysis was higher using 10% neutral formalin (98.3%; 177/180) compared with 20% formalin (34.6%; 9/26). In a validation study with additional formalin-fixed paraffin embedded tissues fixed with 10% neutral buffered formalin (n = 860), we reproduced these results and achieved a high success rate for targeted sequencing analysis (98.4%; 846/860). CONCLUSION: Our data show that 10% neutral buffered formalin is recommended for fixation of formalin-fixed paraffin embedded samples to achieve high success rate of targeted sequencing analysis. PMID- 30395867 TI - Performance of glycated albumin for type 2 diabetes and prediabetes diagnosis in a South African population. AB - OBJECTIVE: To assess the utility of glycated albumin (GA%) as a diagnostic marker of type 2 diabetes and prediabetes in an African population. METHODS: GA% levels were determined in a sample of 1294 mixed ancestry adults (74.2% women) residing in Cape Town using an enzymatic method. The participants' glycemic status was based on oral glucose tolerance test (OGTT). RESULTS: The mean age was 47.8 years with a mean body mass index (BMI) of 28.7 kg/m2. Obesity was more pronounced in the screen-detected diabetes and prediabetes groups with mean BMI's of 32.5 kg/m2 and 31.5 kg/m2 respectively. The optimal thresholds of GA% to diagnose screen detected diabetes and prediabetes, were 14.90% and 12.75% respectively. For screen-detected diabetes, the C-statistic was higher for HbA1c than GA% (p = .034) with values of 0.899 (95% CI 0.855-0.943) and 0.873 (0.782-0.892) respectively. The agreement between GA% and HbA1c at their optimal thresholds for diagnosing screen-detected diabetes, was kappa = 0.33 (95% CI 0.26-0.40) and was higher than the agreement for prediabetes, kappa = 0.16 (0.11-0.21). The performance of GA% to identify screen-detected diabetes at the optimal threshold of 14.90%, was 64.8% (95% CI 54.1%-74.6%) for sensitivity and 93.5% (92.0%-94.9%) for specificity. GA% was significantly less sensitive, but more specific than HbA1c (at the optimal threshold of 6.15%) for screen-detected diabetes diagnosis (both p <= .002 from McNemar tests for sensitivity and specificity comparisons). CONCLUSIONS: GA% performed less well than HbA1c to identify participants with OGTT-diagnosed type 2 diabetes or prediabetes (HbA1c cut-off of 6.15% and 5.95% respectively) in this population. PMID- 30395868 TI - Can urinary titin be used for predicting Duchenne muscular dystrophy? PMID- 30395869 TI - LC-MS/MS method for simultaneous quantification of heparan sulfate and dermatan sulfate in urine by butanolysis derivatization. AB - Mucopolysaccharidoses are a group of lysosomal storage disorders (LSDs) characterized by the accumulation of glycosaminoglycans (GAGs). Recently, LC MS/MS has been widely applied in GAGs analysis combined with different sample preparations for cleaving GAGs to disaccharide units. The aim of the present is paper is to present a new method for the simultaneous quantification of urinary dermatan sulfate (DS) and heparan sulfate (HS) by LC-MS/MS, after butanolysis reaction. Chromatographic separation was achieved with a gradient of acetonitrile and water in 0.1% formic acid on a Kinetex Biphenyl analytical column in 21 min. Calibration curves ranging from 0.78 to 50 MUg/mL for HS and from 1.56 to 100 MUg/mL for DS were prepared and the coefficient of determination (r2) was higher than 0.99 for both analytes. Intra-day and inter-day imprecisions and the bias for both compounds were <10.0%. Up to now, most analytical procedures for quantifying GAGs have not had a high level of reproducibility among laboratories, despite the availability of various techniques. The adoption of a new protocol incorporating the methods outlined in this paper could significantly improve the quality and reproducibility of MS results. A procedure using simple steps for preparing samples and reagents that are easily available on the market could promote the standardization of analytical procedures and increase the use of these measurements in clinical practice. PMID- 30395870 TI - Ro60 Inhibits Colonic Inflammation and Fibrosis in a Mouse Model of Dextran Sulfate Sodium-Induced Colitis. AB - Inflammatory bowel disease (IBD) is caused by chronic inflammation of the gastrointestinal tract. The pathogenesis of IBD remains unclear. The inflammation is associated with activation of T helper (Th) lymphocytes and chronic production of inflammatory cytokines. Ro60 suppresses the expression of tumor necrosis factor alpha, interleukin (IL)-6, and interferon alpha by inhibiting Alu transcription; control of Ro60 mRNA expression may thus be therapeutically useful. However, few studies have evaluated the anti-inflammatory activity of Ro60. The Ro60 level is decreased in IBD patients; we thus hypothesized that Ro60 was involved in the development of this autoimmune disease. We subjected mice with dextran sodium sulfate (DSS)-induced colitis to gene therapy using a vector that overexpressed Ro60 threefold. We scored IBD progression by repeatedly weighing the mice. Ro60 ameliorated colitis severity and reduced the levels of tumor necrosis factor alpha, IL-6, IL-17, IL-8, and vascular endothelial growth factor. Ro60 overexpression decreased the levels of alpha-smooth muscle actin (a marker of activated myofibroblasts) and type I collagen. The anti-inflammatory and anti-fibrotic activities of Ro60 ameliorated the severity of DSS-induced colitis in mice by repressing inflammation, fibrosis, angiogenesis, and the production of reactive oxygen species. PMID- 30395871 TI - Involvement of oxidative stress in di-2-ethylhexyl phthalate (DEHP)-induced apoptosis of mouse NE-4C neural stem cells. AB - Di-2-ethylhexyl phthalate (DEHP) has been widely used as a plasticizer in industry and can cause neurotoxicity; however, the underlying mechanism remains unclear. In the study, we found that DEHP significantly inhibited viability of mouse NE-4C neural stem cells and caused lactate dehydrogenase (LDH) release from the cells. DEHP dramatically increased the levels of apoptosis-related proteins such as cleaved Caspase-8, cleaved Caspase-3 and Bax, as well as decreased Bcl-2 protein level. DEHP could also significantly increase the total numbers of AnnexinV-positive/PI-negative and AnnexinV-positive/PI-positive staining cells. Hoechst 33342 staining showed that marked DNA condensation and apoptotic bodies could be found in the ZnO NPs-treated cells. These results indicated that DEHP could induce apoptosis of NE-4C cells. Meanwhile, DEHP could significantly increase malondialdehyde (MDA) level, and decrease the content of glutathione (GSH) and activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), respectively, implying that DEHP could induce oxidative stress of NE-4C cells. Furthermore, N-Acetyl-l-cysteine (NAC), an inhibitor of oxidative stress, could rescue the inhibition of cell viability and induction of apoptosis by DEHP. Taken together, our results showed that oxidative stress was involved in DEHP induced apoptosis of mouse NE-4C cells. PMID- 30395872 TI - Novel amodiaquine derivatives potently inhibit Ebola virus infection. AB - Ebola virus disease is a severe disease caused by highly pathogenic Ebolaviruses. Although it shows a high mortality rate in humans, currently there is no licensed therapeutic. During the recent epidemic in West Africa, it was demonstrated that administration of antimalarial medication containing amodiaquine significantly lowered mortality rate of patients infected with the virus. Here, in order to improve its antiviral activity, a series of amodiaquine derivatives were synthesized and tested for Ebola virus infection. We found that multiple compounds were more potent than amodiaquine. The structure-activity relationship analysis revealed that the two independent parts, which are the alkyl chains extending from the aminomethyl group and a halogen bonded to the quinoline ring, were keys for enhancing antiviral potency without increasing toxicity. When these modifications were combined, the antiviral efficacy could be further improved with the selectivity indexes being over 10-times higher than amodiaquine. Mechanistic evaluation demonstrated that the potent derivatives blocked host cell entry of Ebola virus, like the parental amodiaquine. Taken together, our work identified novel potent amodiaquine derivatives, which will aid in further development of effective antiviral therapeutics. PMID- 30395873 TI - Caloric restriction and cellular senescence. AB - Cellular senescence is a state of irreversible growth arrest characterized by hypertrophy and secretion of various bioactive molecules, a phenomenon defined the Senescence-Associated Secretory Phenotype (SASP). Senescent cells are implicated in a number of biological functions, from embryogenesis to aging. Significantly, excessive accumulation of senescent cells is associated to a decline of regenerative capacity and chronic inflammation. In accordance, the removal of senescent cells is sufficient to delay several pathologies and promote healthspan. Calorie restriction (CR) without malnutrition is currently the most effective non-genetic intervention to delay aging phenotypes. Recently, we have shown that CR can prevent accumulation of senescent cells in both mice and humans. Here, we summarize the current knowledge on the molecular and cellular events associated with CR, and define how these events can interfere with the induction of cellular senescence. We discuss the potential side effects of preventing senescence, and the possible alternative dietary interventions with potential senolytic properties. PMID- 30395874 TI - Neuroendocrinology of reward in anorexia nervosa and bulimia nervosa: Beyond leptin and ghrelin. AB - The pathophysiology of anorexia nervosa (AN) and bulimia nervosa (BN) are still poorly understood, but psychobiological models have proposed a key role for disturbances in the neuroendocrines that signal hunger and satiety and maintain energy homeostasis. Mounting evidence suggests that many neuroendocrines involved in the regulation of homeostasis and body weight also play integral roles in food reward valuation and learning via their interactions with the mesolimbic dopamine system. Neuroimaging data have associated altered brain reward responses in this system with the dietary restriction and binge eating and purging characteristic of AN and BN. Thus, neuroendocrine dysfunction may contribute to or perpetuate eating disorder symptoms via effects on reward circuitry. This narrative review focuses on reward-related neuroendocrines that are altered in eating disorder populations, including peptide YY, insulin, stress and gonadal hormones, and orexins. We provide an overview of the animal and human literature implicating these neuroendocrines in dopaminergic reward processes and discuss their potential relevance to eating disorder symptomatology and treatment. PMID- 30395875 TI - A threshold gap size for in situ secondary caries lesion development. AB - OBJECTIVES: This study investigated the influence of very small gaps in secondary caries (SC) development and additionally linked the threshold gap size with the caries activity level from volunteers. METHODS: For 21 days, 15 volunteers wore a modified occlusal splint loaded with dentin-composite samples restored with different interfaces: bonded (B = samples restored with complete adhesive procedure), no-bonded (NB = restored with composite resin without adhesive procedure), and 30, 60 and 90 MUm (no adhesive procedure and with intentional gap). The splint was dipped in a 20% sucrose solution (10 min) 8 x per day. Samples were imaged with transversal wavelength independent microradiography (T WIM) and lesion depth and mineral loss were calculated. Average wall lesion depth from each volunteer was determined and according to the values the volunteers were grouped as high, mid and low caries activity levels. RESULTS: No wall lesion formation was observed in B and NB groups. In general, intentional gaps led to SC lesion depth progression independent of caries activity level of volunteers. No substantial wall lesions were found for two volunteers. A trend for deeper lesion in larger gaps was observed for the high activity group. CONCLUSION: Very small gaps around or wider than 30 MUm develop SC independent of the caries activity level of the patient and SC wall lesion progression seemed to be related to individual factors even in this standardized in situ model. SIGNIFICANCE: Independently of caries activity level of the patient, the threshold gap size for secondary caries wall lesion seems to be 30 MUm at most. PMID- 30395877 TI - Understanding and exploiting prediction errors minimization within the brain in pharmacological treatments. AB - The human brain can be conceptualized as an inference machine that actively predicts and explains its sensations and perceptions: it makes predictions through a probabilistic model. Such a model is continuously and implicitly updated by the computation and minimization of weighted prediction errors, as shown by numerous studies and experimental results. Nevertheless, such an algorithmic functioning of the brain has not been exploited in the neuropharmacological practice. In this manuscript, we show by theoretical analysis and model fitting of previously published data in two different contexts, how it is possible to increase the effectiveness of neuropharmacological and immunosuppressive drugs, through the modulation of the weighted prediction errors. Moreover, on the basis of the proposed model, we derive an optimized drug administration schedule able to increase the drug effectiveness of one order of magnitude, in psoriasis treatment. We make important testable predictions, evidencing the impact and the potential benefit of prediction errors modulation within the brain, in the pharmacotherapeutic practice. Finally, our results lead to a novel formal theory of implicit learning, and shed lights on the actual roles of classical conditioning and UCS revaluation in behavioral and pharmacological conditioning experiments. The potential practical implications of our results are many: the reduction of drugs side effects; the maximization of the therapeutic outcome; a more effective treatment for chronic pain, certain neuropsychiatric diseases, autoimmune diseases and allergic diseases. PMID- 30395876 TI - Peptidylarginine deiminase and deiminated proteins are detected throughout early halibut ontogeny - Complement components C3 and C4 are post-translationally deiminated in halibut (Hippoglossus hippoglossus L.). AB - Post-translational protein deimination is mediated by peptidylarginine deiminases (PADs), which are calcium dependent enzymes conserved throughout phylogeny with physiological and pathophysiological roles. Protein deimination occurs via the conversion of protein arginine into citrulline, leading to structural and functional changes in target proteins. In a continuous series of early halibut development from 37 to 1050 degrees d, PAD, total deiminated proteins and deiminated histone H3 showed variation in temporal and spatial detection in various organs including yolksac, muscle, skin, liver, brain, eye, spinal cord, chondrocytes, heart, intestines, kidney and pancreas throughout early ontogeny. For the first time in any species, deimination of complement components C3 and C4 is shown in halibut serum, indicating a novel mechanism of complement regulation in immune responses and homeostasis. Proteomic analysis of deiminated target proteins in halibut serum further identified complement components C5, C7, C8 C9 and C1 inhibitor, as well as various other immunogenic, metabolic, cytoskeletal and nuclear proteins. Post-translational deimination may facilitate protein moonlighting, an evolutionary conserved phenomenon, allowing one polypeptide chain to carry out various functions to meet functional requirements for diverse roles in immune defences and tissue remodelling. PMID- 30395878 TI - Effects of the application of Vitamin E and silicone dressings vs Conventional dressings on incisional surgical site infection in elective laparoscopic colorectal surgery: A prospective randomized clinical trial. AB - INTRODUCTION: The aim of this study was to evaluate the effect on incisional surgical site infection (SSI) of conventional wound dressing vs vitamin E silicone dressing in patients undergoing elective colorectal laparoscopic surgery. PATIENTS AND METHODS: A prospective, randomized study was performed. Patients were randomly assigned into 2 groups: those patients undergoing a vitamin E-silicone containing dressing (E-Sil) and those using a conventional dressing (CD). Incisional SSI, postoperative pain and acute-phase reactants were investigated. RESULTS: 120 patients were included, 60 in each group. Incisional SSI rate was 3.4% in E-Sil and 17.2% in CD (p=0.013). In the cultures of the infected wounds in E-Sil grew only Bacteroides fragilis, while in the infected wounds of CD grew polymicrobial cultures. Mean postoperative pain 48 hours after surgery was 27.1+10.7mm in E-Sil and 41.6+16.9mm in CD (p<0.001). White blood cell count and C reactive levels were lower in the E-Sil, even excluding the patients presenting postoperative complications. CONCLUSION: The use of Silicone vitamin E dressings, covering the Pfannestiel wound after elective laparoscopic colorectal surgery, leads to a reduction in the incisional SSI rate, lower postoperative pain and decrease in C reactive protein and white blood cell count. PMID- 30395879 TI - Nitrergic neurotransmission in the paraventricular nucleus of the hypothalamus modulates autonomic, neuroendocrine and behavioral responses to acute restraint stress in rats. AB - We investigated the involvement of nitrergic neurotransmission within the paraventricular nucleus of the hypothalamus (PVN) in modulation of local neuronal activation, autonomic and neuroendocrine responses and behavioral consequences of acute restraint stress in rats. Bilateral microinjections of the selective neuronal nitric oxide (NO) synthase (nNOS) inhibitor Nw-Propyl-L-arginine (NPLA) or the NO scavenger carboxy-PTIO into the PVN reduced arterial pressure and heart rate increases, as well as the fall in cutaneous tail temperature induced by restraint stress. PVN injection of either NPLA or carboxy-PTIO also inhibited restraint-induced increases in anxiety-related behaviors in the elevated plus maze 24 h later. Local microinjection of NPLA or carboxy-PTIO into the PVN reduced the number of c-fos-immunoreactive neurons in the dorsal parvocellular, ventromedial, medial parvocellular and lateral magnocelllular portions of the PVN in animals subjected to restraint stress. However, neither NPLA nor carboxy-PTIO into the PVN affected restraint-induced increases in plasma corticosterone concentration. The present results indicate that PVN nitrergic neurotransmission acting via nNOS activation has a facilitatory influence on autonomic responses to acute restraint and the delayed emotional consequences of restraint stress. Our results also provide evidence of a prominent role of local nitrergic neurotransmission in PVN neuronal activation during stress. PMID- 30395880 TI - Efficient glutathione production in metabolically engineered Escherichia coli strains using constitutive promoters. AB - Glutathione (GSH) is an important bioactive tripeptide and widely used in food, medicine and other industries. Recently, the bifunctional glutathione synthetase, GshF, has been applied for efficient GSH production under inducible promoter. In this study, the constitutive expression of GshF from Streptococcus sanguinis (GshFss) was investigated under four different constitutive promoters. Based on previous study, five genes in Escherichia coli JM109 were deleted to eliminate the degradation of precursors and GSH. The effects of gene knockout on the constitutive expression of GshFss and GSH production were evaluated by whole cell catalysis. Finally, the engineered strain JM03Pdel1 produced 24 mM glutathione with addition of 30 mM precursors in 5-L bioreactor fed-batch fermentation. The yield of GSH based on cysteine in JM03Pdel1was reached 80% without any inducer, which was improved by 17.3% than that in the control strain. PMID- 30395881 TI - The protein interaction networks of mucolipins and two-pore channels. AB - BACKGROUND: The endolysosomal, non-selective cation channels, two-pore channels (TPCs) and mucolipins (TRPMLs), regulate intracellular membrane dynamics and autophagy. While partially compensatory for each other, isoform-specific intracellular distribution, cell-type expression patterns, and regulatory mechanisms suggest different channel isoforms confer distinct properties to the cell. SCOPE OF REVIEW: Briefly, established TPC/TRPML functions and interaction partners ('interactomes') are discussed. Novel TRPML3 interactors are shown, and a meta-analysis of experimentally obtained channel interactomes conducted. Accordingly, interactomes are compared and contrasted, and subsequently described in detail for TPC1, TPC2, TRPML1, and TRPML3. MAJOR CONCLUSIONS: TPC interactomes are well-defined, encompassing intracellular membrane organisation proteins. TRPML interactomes are varied, encompassing cardiac contractility- and chaperone mediated autophagy proteins, alongside regulators of intercellular signalling. GENERAL SIGNIFICANCE: Comprising recently proposed targets to treat cancers, infections, metabolic disease and neurodegeneration, the advancement of TPC/TRPML understanding is of considerable importance. This review proposes novel directions elucidating TPC/TRPML relevance in health and disease. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech. PMID- 30395882 TI - Phosphorylation of ELAVL1 (Ser219/Ser316) mediated by PKC is required for erythropoiesis. AB - Elavl1 (also known as HuR), an RNA binding protein highly conserved between zebrafish and human, regulates gene expression by stabilizing target mRNA. Our previous studies have uncovered that the predominant isoform elavl1a is required for zebrafish embryonic erythropoiesis. However, the exact mechanism of how elav11 spatiotemporally stabilizes target mRNAs to regulate specific erythropoiesis is not yet understood. Here we show that phosphorylation of elavl1a at Ser219 and Ser316 by PKC is necessarily required for cytosolic shuttling from the nucleus to stabilize gata1 mRNA and thus promotes erythropoiesis. Knockdown of elavl1a resulted in the hindrance of erythropoiesis and Hemin-induced erythroid differentiation of human myeloid leukemia K562 cells. Interestingly, inhibition of PKC reproduced the phenotype seen during zebrafish embryogenesis and erythroid differentiation of myeloid leukemia. Mechanistically, Hemin induced elavl1a export from nuclear to cytoplasmic space in K562 cells in a manner dependent on phosphorylation on Ser219 and Ser316, as overexpression of elavl1a with mutations on Ser219 and Ser316 resulted in erythropoiesis failure. Additionally, co-administration of low doses of elavl1a morpholino (MO) and three PKC inhibitors showed a combined effect in zebrafish embryonic erythropoiesis dysplasia. In conclusion, our study reveals that PKC-mediated phosphorylation of elavl1a at Ser219 and Ser316 sites controls its nucleo-cytoplasmic translocation in zebrafish, thereby regulating embryonic erythropoiesis. PMID- 30395883 TI - Celastrol ameliorates inflammatory pain and modulates HMGB1/NF-kappaB signaling pathway in dorsal root ganglion. AB - Evidences reported that high mobility group box 1 (HMGB1) played a pivotal role in the modulation of chronic inflammatory pain. Celastrol, a bioactive component extracted from Tripterygium wilfordii Hook, possesses anti-inflammatory activity, but the underlying mechanism remains to be fully clarified. We aim to investigate whether HMGB1 in dorsal root ganglion (DRG) participates in the effect of celastrol on inflammatory pain. Complete Freund's adjuvant (CFA)-induced inflammatory pain rat model was used. Paw withdrawal latency (PWL) was detected to evaluate the effects of celastrol on CFA-evoked inflammatory pain. After application of celastrol (1mg/kg, i.p.) on day 1, 3, 7 and 14 post-CFA injection, the expression levels of HMGB1, NF-kappaB, some proinflammatory markers, GFAP and CD11b in DRG were determined by qRT-PCR and western blot analysis. These results showed that celastrol significantly suppressed HMGB1, NF-kappaB and IL-1beta mRNA and protein expression in DRG and alleviated CFA-evoked thermal hyperalgesia. Furthermore, celastrol obviously inhibited COX-2 protein expression and down regulated IL-6, IL-17, TNF-alpha, MCP-1, GFAP and CD11b mRNA levels in DRG of CFA rats. Collectively, the present study firstly provide evidences of the anti inflammatory effect of celastrol via suppressing CFA-induced the activation of HMGB1/NF-kappaB signaling pathway in DRG, which maybe a potential therapeutic target for celastrol alleviating inflammatory pain. PMID- 30395884 TI - Alteration of O-GlcNAcylation affects assembly and axonal transport of neurofilament via phosphorylation. AB - Neurofilaments (NFs), the most abundant cytoskeletal components in the mature neuron, are hyperphosphorylated and accumulated in the neuronal cell body of AD brain, and the abnormalities of NFs appear to contribute to neurodegeneration. Although previous studies have showed that O-GlcNAcylation and phosphorylation of NFs regulate each other reciprocally, the NFs O-GlcNAcylation and its effects on assembly and axonal transport are poorly explored. Here, we focus on the role of dysregulation of O-GlcNAcylation on structure and function of neurofilaments by corresponding phosphorylation. In the study, we found that decreased O GlcNAcylation by intracerebroventricular administration of Alloxan, 6-diazo-5 oxonorleucine (Don) and okadaic acid (OA) in the rats resulted in increased phosphorylation with assembly of lower and shorter NFs. In contrast, in the sample of NAG-thiazoline (NAG-Ae) causing increased O-GlcNAcylation, NFs showed elongated filaments fibers and higher proportion of assembly. Furthermore, alloxan treatment induced abnormal accumulation of NFs bodies and delayed time of Fluorescence Recovery After Photobleaching (FRAP) in SK-N-SH cells, but the NAG Ae treatment speeded up the axonal transport. Our experiments suggest that increased O-GlcNAcylation plays a key role in protecting the structure and function of NFs including filament assembly and axonal transport via decreased phosphorylation. These results expanded the function of O-GlcNAcylation in AD pathogenesis. PMID- 30395885 TI - Adiponectin confers neuroprotection against cerebral ischemia-reperfusion injury through activating the cAMP/PKA-CREB-BDNF signaling. AB - Ischemic stroke is a severe cerebrovascular disease. Although great progress has been made, the consequent ischemia-reperfusion (I/R) injury is inevitable and affects the therapeutic effect. Adiponectin (APN) is a fat-derived plasma protein that has beneficial actions on cardiovascular disorders. The present study aims to investigate the effect of APN on I/R injury and the potential underlying mechanisms. In step 1, APN were administered for three times (once every 8 h) 24 h before middle cerebral artery occlusion (MCAO). The results indicated that APN treatment reduced infarct volume, neurological deficits and brain water content after I/R injury. Meanwhile, APN was proved to increase the expression of cAMP, PKA, CREB, and BDNF. In step 2, mice were randomly assigned into the Vehicle + I/R, APN + I/R, PKA activator + I/R, PKA inhibitor + APN + I/R groups. PKA activator, PKA inhibitor, as well as APN were administered for three times before MCAO. The results indicated that PKA inhibitor downregulated the expressions of cAMP, PKA, CREB, and BDNF which subsequently weakened the protective effects of APN on cerebral I/R injury. In conclusion, our findings further suggest that APN exerts protective effect against cerebral I/R injury might through the cAMP/PKA CREB-BDNF signaling pathway. APN is a novel candidate in the treatment of I/R diseases in the future. PMID- 30395886 TI - Role of simvastatin and insulin in memory protection in a rat model of diabetes mellitus and dementia. AB - OBJECTIVES: The memory protective role of simvastatin and/or insulin, in a rat model of diabetes mellitus (DM) and dementia was examined. METHODS: DM was induced by an intraperitoneal injection of streptozotocin. Diabetic rats were divided into untreated; insulin treated; simvastatin treated with 10 and 20 mg/kg/day; and combined insulin plus simvastatin treatment in the previous doses. Treatment started after blood glucose elevation and persisted for 6 weeks. Morris water maze and Y maze tests were held to detect behavioral changes. Serum glucose, cholesterol and insulin levels, the hippocampi insulin, amyloid beta (Abeta) 1-42 and oxidative stress markers were measured. RESULTS: Insulin increased the time spent in the target quadrant in the Morris water maze test and the percentage of alternations in the Y maze test, despite the mild improvements in brain parameters demonstrated by amyloid beta 1-42, malondialdehyde and reduced glutathione levels; while simvastatin in both doses improved brain parameters with no positive impact on behavioral tests. Insulin combined with simvastatin 20 mg/kg/day was effective in enhancing the behavioral tests and the measured brain parameters. CONCLUSIONS: Treatment with insulin and simvastatin could provide a promising memory protective effect in diabetics. PMID- 30395887 TI - Reverse transcription-recombinase polymerase amplification combined with lateral flow strip for detection of rice black-streaked dwarf virus in plants. AB - Rice black-streaked dwarf virus (RBSDV) infects rice plants, a major crop, and is transmitted via the small brown planthopper (SBPH: Laodelphax striatellus Fallen), causing significant economic loss in China. To rapidly diagnose RBSDV, a reverse transcription-recombinase polymerase amplification (RT-RPA) method was developed using P10 virus-specific primers and probes. Detection of terminally labeled amplification products was achieved with the lateral flow strip method. Our results demonstrate that RT-RPA and RT-PCR assays offer similar sensitivity and specificity in RBSDV detection using cDNA as template. The optimum RT-RPA reaction temperature and time was 37 degrees C and 20 min, respectively. By screening twenty-one field suspected rice plants, the RT-RPA assay was confirmed to be simple, rapid and reliable. Thus, the RBSDV RT-RPA assay developed here will be a successful tool for quick diagnosis of RBSDV-infected rice plants. PMID- 30395888 TI - Reply to: The role of extracorporeal life support in patients with hypothermic cardiac arrest. PMID- 30395889 TI - School-based Interventions - Where Do We Go From Here? PMID- 30395890 TI - IgE to galactose-alpha-1,3-galactose and the alpha-Gal syndrome: Insights from basophil activation testing. PMID- 30395891 TI - Primary Extrarenal Type 2 Papillary Renal Cell Carcinoma: A Case Report. AB - Type 2 papillary renal cell carcinoma (PRCC) is a malignant tumor originated from renal tubular epithelial cells. Here we present a rare case of extrarenal type 2 PRCC which is located at the right lateral side of the retroperitoneal inferior vena cava. No suspicious lesions were detected in the bilateral kidneys. The diagnosis was confirmed by histopathological examination after complete excision of the tumor. No recurrence was observed in 5 months of follow-up after surgery. PMID- 30395892 TI - Spacial models of malfunctioned protein complexes help to elucidate signal transduction critical for insulin release. AB - Mutations in gene KCNJ11 encoding the Kir6.2 subunit of the ATP-sensitive potassium channel (KATP), a representative of a quite complex biosystem, may affect insulin release from pancreatic beta-cells. Both gain and loss of channel activity are observed, which lead to varied clinical phenotypes ranging from neonatal diabetes to congenital hyperinsulinism. In order to understand the mechanisms of the channel function better we mapped, based on the literature review, known medically relevant Kir6.2/SUR1 mutations into recently (2017) determined CryoEM 3D structures of this complex. We used a clustering algorithm to find hots spots in the 3D structure, thus we may hypothesize about their nano mechanical role in the channel gating and the insulin level control. We also adapted a simple model of the channel gating to cover all currently known factors that can influence the KATP biosystem functions. PMID- 30395893 TI - Different cytotoxic and apoptotic responses of MCF-7 and HT1080 cells to MnO2 nanoparticles are based on similar mode of action. AB - Manganese (IV) oxide nanoparticles (MnO2 NPs) are increasingly used in numerous applications. Multiple applications of MnO2 NPs, however, increase the human exposure and thus potential risk related to their toxicity. There is little information regarding the toxicity mechanisms of MnO2 NPs in human cells. In this study, we explored the toxic potential of MnO2 NPs in human breast cancer epithelial (MCF-7) and human fibrosarcoma epithelial (HT1080) cells in order to examine whether epithelial cells of different origins showed similar responses. Results demonstrated that MnO2 NPs induced cell viability reduction and membrane damage in both MCF-7 and HT1080 cells in a dose-dependent manner. MnO2 NPs were also found to induce pro-oxidants generation and antioxidants depletion in both cells. We further observed that MnO2 NPs induce apoptosis in both MCF-7 and HT1080 cells evident by altered regulation of apoptotic genes (p53, bax & bcl-2), cell cycle arrest and low mitochondrial membrane potential. Interestingly, we noticed that HT1080 cells were more susceptible to MnO2 NPs exposure than those of MCF-7 cells. This could be due to higher level of MnO2 NPs uptake into HT1080 cells as compared to MCF-7 cells. However, the mechanism of toxicity induced by MnO2 NPs in both MCF-7 and HT1080 cells was highly similar. This study warrants further research to delineate the underlying mechanisms of MnO2 NPs toxicity at in vivo level. PMID- 30395894 TI - Antagonistic effect of epigallocatechin-3-gallate on neurotoxicity induced by formaldehyde. AB - The toxicity of formaldehyde (FA) has always been of great concern, particularly since its use is unavoidable. On the other hand, epigallocatechin-3-gallate (EGCG), an active substance in tea polyphenols, has been shown to demonstrate physiological protective functions by in both epidemiological and zoological studies, particularly in the nervous system. The study described here, aims to explore whether EGCG can alleviate the neurotoxic effects induced by formaldehyde. After 14 days of exposure to 3 mg/m3 formaldehyde, mice exhibited significant cognitive impairment. In the FA group, a significant increase in iNOS level compared with the control group was observed. The reduced GSH level was significantly decreased. The levels of IL-1beta, TNF-alpha and Caspase-3 were obviously raised, while H&E and Nissl staining illustrated significant neuronal damage. After administering EGCG as a protective agent, all the above observed changes were reversed, and the protective effect of EGCG became gradually evident in the 20-500 mg/kg range. Immunohistochemistry results showed that EGCG could activate the Nrf2 signaling pathway, thus alleviating the oxidative damage caused by formaldehyde. PMID- 30395895 TI - The detection of canine circovirus in Guangxi, China. AB - Since the first description of canine circovirus (CanineCV)-associated infection, there have been several reports on the distribution of the disease in worldwide. To investigate the prevalence and genetic diversity of CanineCV in China, we conducted PCR screening of 1226 dog serum samples collected from different regions in mainland China between 2014 and 2016. CanineCV DNA was found in 81/926 serum samples from Guangxi Province. Furthermore, 25 full-length genomes of CanineCV from positive samples were sequenced and compared with CanineCV sequences in the GenBank database. Pairwise analysis showed that the determined genome sequences shared 84.9%-100% identity among themselves and 81.4%-90.5% with the other 28 sequences. Phylogenetic analysis revealed that the 52 viral genome sequences could be divided into two genotypes (CanineCV-1 and CanineCV-2). Analysis of the amino acid sequences of the capsid protein revealed the existence of 9 major regions of variation. The present work contributes to the understanding of CanineCV molecular epidemiology. PMID- 30395896 TI - Comparative analysis and characterization of Enterobacteria phage SSL-2009a and 'HK578likevirus' bacteriophages. AB - Enterobacteria phage SSL-2009a is a virulent bacteriophage with strong and abroad lytic ability against lots of engineering E. coli strains. In this study, we re sequenced its whole genome and made a detail analysis on its genomic and proteomic characteristics according to the updated genomic sequence. The genome of SSL-2009a is a circular double-stranded DNA of 44,899 base pairs in length, with a 54.67% G + C content. A total of 67 open reading frames were predicted as protein coding sequences, 24 of which encode products highly homologous to known phage proteins. There are 10 promoters and 22 terminators identified in the genome of SSL-2009a, but no tRNA is found. SSL-2009a belongs to the 'HK578likevirus' genus of Siphoviridae. Comparative analyses indicated that other twelve phages share high homology with SSL-2009a at nucleotide and amino acid levels and also should be clustered into the same genus. In-depth analysis was performed to reveal the genomic, proteomic, and morphological features of these 'HK578likevirus' phages, which may promote our understanding of Enterobacteria phage SSL-2009a and the 'HK578likevirus' genus, even the biodiversity and evolution of bacteriophages. PMID- 30395897 TI - Design, formulation and evaluation of novel dissolving microarray patches containing a long-acting rilpivirine nanosuspension. AB - One means of combating the spread of human immunodeficiency virus (HIV) is through the delivery of long-acting, antiretroviral (ARV) drugs for prevention and treatment. The development of a discreet, self-administered and self disabling delivery vehicle to deliver such ARV drugs could obviate compliance issues with daily oral regimens. Alternatives in development, such as long-acting intramuscular (IM) injections, require regular access to health care facilities and disposal facilities for sharps. Consequently, this proof of concept study was developed to evaluate the use of dissolving microarray patches (MAPs) containing a long-acting (LA) nanosuspension of the candidate ARV drug, rilpivirine (RPV). MAPs were mechanically strong and penetrated skin in vitro, delivering RPV intradermally. In in vivo studies, the mean plasma concentration of RPV in rats (431 ng/ml at the Day 7 time point) was approximately ten-fold greater than the trough concentration observed after a single-dose in previous clinical studies. These results are the first to indicate, by the determination of relative exposures between IM and MAP administration, that larger multi-array dissolving MAPs could potentially be used to effectively deliver human doses of RPV LA. Importantly, RPV was also detected in the lymph nodes, indicating the potential to deliver this ARV agent into one of the primary sites of HIV replication over extended durations. These MAPs could potentially improve patient acceptability and adherence to HIV prevention and treatment regimens and combat instances of needle-stick injury and the transmission of blood-borne diseases, which would have far-reaching benefits, particularly to those in the developing world. PMID- 30395898 TI - Pigeons simultaneously attend to static and dynamic features of complex displays. AB - The simultaneous processing and attention to temporally dynamic and static features remains an open and important question in theories of avian visual cognition. Here, four pigeons (Columba livia) learned to discriminate complex displays involving concurrently available static and dynamic features. These displays consisted of 20 elements built from combinations of two, binary-valued, static visual dimensions: red vs. green element color, large vs. small element size; and two binary-valued dynamic dimensions; fast vs slow element motion, right vs up motion direction. One combination of these four features was reinforced on a VI schedule. The remaining 15 combinations of element color, size, speed and direction were never reinforced. During acquisition, all four dimensions were simultaneously discriminated. Varying the number of elements revealed that a single element was sufficient to support discrimination of all four dimensions. The pigeons agreed on the relative discriminability of stimuli within and across the different dimensions, with the difference in motion direction being the hardest for all birds. Redundant facilitation suggested rapid, perhaps parallel, processing of both dynamic and static features. No attentional trade-offs between dynamic or static dimensions were observed. These results agree with theories of avian vision employing the notion of multiple independent channels for different types of information. PMID- 30395899 TI - Biodegradation of di-n-butyl phthalate by psychrotolerant Sphingobium yanoikuyae strain P4 and protein structural analysis of carboxylesterase involved in the pathway. AB - A priority pollutant Phthalate Esters (PAEs) are widely used as plasticizers and are responsible mainly for carcinogenicity and endocrine disruption in human. For the bioremediation of PAEs, a psychrotolerant Sphingobium yanoikuyae strain P4, capable of utilizing many phthalates di-methyl phthalate (DMP), di-ethyl phthalate (DEP), di-n-butyl phthalate (DBP), di-isobutyl phthalate (DIBP), butyl benzyl phthalate (BBP), and few Polycyclic Aromatic Hydrocarbons as the sole source of carbon and energy was isolated from Palampur, Kangra, Himachal Pradesh, India. 100% utilization of DBP (1 g L-1) by the strain was observed within 24 h of incubation at 28 degrees C. Interestingly the strain also degraded DBP completely at 20 degrees C and 15 degrees C within 36 h and 60 h, respectively. Esterase involved in DBP degradation was found to be inducible in nature and intracellular. Comparative sequence analysis of carboxylesterase enzyme sequences revealed conserved motifs: G-X-S-X-G and -HGG- which were the characteristic peptide motifs reported in different esterases. Structural analysis showed that the enzyme belongs to serine hydrolase superfamily, which has an alpha/beta hydrolase fold. Interaction and binding of DBP to a catalytic Ser184 residue in the esterase enzyme were also analysed. In conclusion, carboxylesterase possess the required active site which may be involved in the catabolism of DBP. PMID- 30395900 TI - Sappanone A prevents hypoxia-induced injury in PC-12 cells by down-regulation of miR-15a. AB - OBJECTIVE: We aimed to explore the effect of Sappanone A on neurologic damage induced by hypoxia. METHODS: PC-12 cells were pre-treated with Sappanone A and were simulated by hypoxia. miRNA transfection was performed to overexpress or suppress the expression of miR-15a in PC-12 cells. Cell viability, apoptosis, migration, and expression levels of miR-15a were tested to evaluate the in vitro impact of Sappanone A on hypoxia-injured PC-12 cells. RESULTS: Hypoxia exposure induced a significant damage in PC-12 cells, as evidenced by the repressed cell growth, the induced apoptosis and the impaired migrating capacity. Sappanone A pretreatment protected PC-12 cells against hypoxia-mediated cell damage. More interestingly, Sappanone A treatment down-regulated miR-15a, and the neuroprotective effects of Sappanone A were attenuated by miR-15a overexpression while were accelerated by miR-15a suppression. Finally, Sappanone A significantly activated Wnt/beta-catenin and PI3K/AKT signaling pathways. And the activation of these two signaling induced by Sappanone A were repressed by miR-15a overexpression and were enhanced by miR-15a suppression. CONCLUSION: Sappanone A exerted protective activity in PC-12 cells which were stimulated by hypoxia. One of the possible mechanisms of the neuroprotective effect is that: Sappanone A down-regulated the expression of miR-15a, and thus activated Wnt/beta-catenin and PI3K/AKT signaling pathways. PMID- 30395902 TI - Single versus multifraction stereotactic radiosurgery for large brain metastases: An international meta-analysis of 24 trials. AB - PURPOSE: Multifraction stereotactic radiosurgery (MF-SRS) purportedly reduces radionecrosis risk over single fraction SRS (SF-SRS) in the treatment of large brain metastases. The purpose of the current work is to compare local control (LC) and radionecrosis rates of SF-SRS and MF-SRS in the definitive (SF-SRSD and MF-SRSD) and postoperative (SF-SRSP and MF-SRSP) settings. METHODS/MATERIALS: PICOS/PRISMA/MOOSE guidelines were used to select articles where patients: diagnosed with "large" brain metastases (Group A: 4-14 cm3, or about 2-3 cm; Group B: >14 cm3, or > 3 cm); 1-year LC and/or rates of radionecrosis were reported; radiosurgery was administered definitively or postoperatively. Random effects meta-analyses using fractionation scheme and size as covariates were conducted. Meta-regression and Wald-type tests were used to determine the effect of increasing tumor size and fractionation on the summary estimate, where the null hypothesis was rejected for p<0.05. RESULTS: Twenty-four studies were included, published between 2008-2017 with 1,887 brain metastases. Local control random effects estimate at 1-year for Group A/SF-SRSD was 77.6% and for Group A/MF-SRSD was 92.9% (p=0.18). Local control random effects estimate at 1-year for Group B/SF-SRSD was 77.1% and for Group B/MF-SRSD was 79.2% (p=0.76). Local control random effects estimate at 1-year for Group B/SF-SRSP was 62.4% and for Group B/MF-SRSP was 85.7% (p=0.13). Radionecrosis incidence random effects estimate for Group A/SF-SRSD was 23.1% and for Group A/MF-SRSD was 7.3% (p=0.003). Radionecrosis incidence random effects estimate for Group B/SF-SRSD was 11.7% and for Group B/MF-SRSD was 6.5% (p=0.29). Radionecrosis incidence random effects estimate for Group B/SF-SRSP was 7.3% and for Group B/MF-SRSP was 7.5% (p=0.85). Meta-regression assessing 1-year LC and radionecrosis as a continuous function of increasing tumor volume was not statistically significant. CONCLUSION: Treatment for large brain metastases with MF-SRS regimens may offer a relative reduction of radionecrosis while maintaining or improving relative rates of 1-year LC when compared to SF-SRS. These findings are hypothesis-generating and require validation by ongoing and planned prospective randomized control trials. PMID- 30395901 TI - Response of intestinal metabolome to polysaccharides from mycelia of Ganoderma lucidum. AB - Polysaccharides from the mycelia of Ganoderma lucidum (GLP) can improve intestinal barrier function, regulate intestinal immunity and modulate intestinal microbiota. In the present study, GLP was given via oral administration to rats (100 mg/kg body weight, 21 days) to investigate the metabolomic profiling of caecal contents induced by GLP. Gas chromatography-time of light/mass spectrometry (GC-TOF/MS) was performed to identify the metabolites, followed by biomarker and pathway analysis. The multivariate analysis indicated clear separated clusters between two groups. The significantly different metabolites were characterized, which mainly involved in vitamin B6 metabolism, pyrimidine metabolism, fructose and mannose metabolism, and alanine, aspartate and glutamate metabolism. Indolelactate and 2,2-dimethylsuccinic acid were selected as key biomarkers responded to GLP administration. Furthermore, significantly different metabolites identified were associated with the improvement of intestinal immunological function and regulation of intestinal microbiota. Our results provided a potential metabolomic mechanism of health-beneficial properties of polysaccharides from the mycelia of G. lucidum, which might be used as functional agents to regulate the intestinal functions. PMID- 30395903 TI - Quality of Life for Patients with Favorable Risk HPV-Associated Oropharyngeal Cancer After De-Intensified Chemoradiotherapy. AB - BACKGROUND: Human Papillomavirus (HPV)-associated oropharynx cancers have a favorable prognosis, but current treatment approaches carry significant long-term morbidity. Strategies to de-intensify treatment in this population are under investigation, but the impact of these approaches on quality of life is not well understood. We present patient-reported outcomes from two prospective studies examining de-intensified chemoradiotherapy METHODS: This study included patients enrolled on two prospective phase II trials of de-intensified chemoradiotherapy in HPV-associated oropharynx cancer patients who had at least one year of follow up. Treatment included concurrent radiotherapy (60 Gy) and chemotherapy (weekly cisplatin 30mg/m2). Patients reported quality of life and symptoms using EORTC QLQ-C30, EORTC H&N-35, and Eating Assessment Tool (EAT-10) instruments prior to treatment and at regular intervals thereafter. Changes in quality of life and individual symptoms were examined over time, and multivariate analysis was used to identify clinical factors associated with recovery to baseline symptom levels. RESULTS: Of the 154 patients enrolled, 126 patients had at least one year of follow-up and were included in this study (median follow-up 25 months). Global quality of life, functional indices, and most individual symptoms returned to baseline 3-6 months after treatment. Swallowing (EAT-10 score) returned to baseline function by two years, but, dry mouth, sticky saliva, and taste/senses did not return to baseline. However, from one to two years, there was continued improvement in dry mouth (55 vs 48), sticky saliva (35 vs 27), and senses (24 vs 20). On multivariate analysis, unilateral radiotherapy was associated with returning to baseline level of swallowing and sticky saliva. CONCLUSIONS: The use of de-intensified chemoradiotherapy in HPV-associated oropharynx cancer led to favorable patient-reported outcomes, with early recovery of quality of life and continued improvement of xerostomia and dysphagia beyond 1-year post-treatment. PMID- 30395904 TI - Daily Lisinopril vs Placebo for Prevention of Chemoradiation-Induced Pulmonary Distress in Patients With Lung Cancer (Alliance MC1221): A Pilot Double-Blind Randomized Trial. AB - PURPOSE: Chemoradiation (CRT) is an integral treatment modality for patients with locally advanced lung cancer. It has been hypothesized that current use of an angiotensin-converting enzyme inhibitor during CRT may be protective for treatment-related lung damage and pneumonitis. METHODS AND MATERIALS: We conducted a pilot, double-blind, placebo-controlled randomized trial. Study eligible patients receiving curative thoracic RT were randomly assigned to 20 mg of lisinopril or placebo once daily during and up to 3 months after RT. All patients received concurrent chemotherapy. The primary end point was adverse event profiling. Multiple patient-reported outcome (PRO) surveys, including Lung Cancer Symptom Scale, Function Assessment of Cancer Therapy-Lung, and the EORTC for Lung Cancer Questionnaire (EORTC-QLQ-LC13), were applied with a symptom experience questionnaire. Exploratory comparative statistics were used to detect differences between arms with chi2 and Kruskal-Wallis testing. RESULTS: Five institutions enrolled 23 patients. However, accrual was less than expected. Eleven and 12 patients were in the placebo and lisinopril arms (mean age, 63.5 years; male, 62%). Baseline characteristics were balanced. Eighteen patients (86%) were former or current smokers. The primary end point was met; neither arm had grade 3 or higher hypotension, acute kidney injury, allergic reaction (medication-induced cough), or anaphylaxis (medication-related angioedema). Few PRO measures suggested that compared with the placebo arm, patients receiving lisinopril had less cough, less shortness of breath, fewer symptoms from lung cancer, less dyspnea with both walking and climbing stairs, and better overall quality of life (for all, P<.05). CONCLUSIONS: Although underpowered because of low accrual, our results suggest that there was a clinical signal for safety-and possibly beneficial by limited PRO measures-in concurrently administering lisinopril during thoracic CRT to mitigate or prevent RT-induced pulmonary distress. Our results showed that a definitive, larger-scale, randomized phase 3 trial is needed in the future. PMID- 30395905 TI - Validity of a Recently-Proposed Prognostic Grading Index, Brain Metastasis Velocity, for Brain Metastasis Patients Undergoing Multiple Radiosurgical Procedures. AB - PURPOSE: This study, based on our brain metastasis (BM) patients undergoing multiple stereotactic radiosurgery (SRS) procedures, aimed to validate whether the recently-proposed prognostic grading system, brain metastasis velocity (BMV, scoring the cumulative number of new BMs that developed after the first SRS divided by time [years] since the initial SRS), is generally applicable. Patients are categorized into three classes by their BMV scores, i.e., <=3, 4-13 and >=14. METHODS AND MATERIALS: This was an institutional review board-approved, retrospective cohort study using our prospectively accumulated database including 833 patients (patients with whole brain radiotherapy were excluded) who underwent a second SRS procedure for newly-detected lesions using a gamma knife for BMs during the 19-year-period between July, 1998 and June, 2017. Furthermore, among these 833 patients, 250 underwent a third and 88 a fourth SRS procedure. RESULTS: The median survival times (MSTs, months) after the second SRS were 12.9 (95% CI; 10.2-17.1), 7.5 (6.5-9.0) and 5.1 (4.0-5.6) in the BMV <=3, 4-13 and >=14 groups (p=0.0001). The corresponding MSTs after the third SRS were 13.2 (95% CI; 9.1 21.6), 8.0 (6.2-11.2) and 5.7 (4.8-7.8). (p=0.0001). Respective MSTs after the fourth SRS were 13.2 (95% CI; 9.1-21.6), 8.0 (6.2-11.2) and 5.7 (4.8-7.8) (p<0.0001). The mean BMV score of small cell lung cancer patients, 24.8, was significantly higher than that of non-small cell lung cancer patients, 17.7 (p=0.032). CONCLUSIONS: Our present results support the validity of BMV for predicting survival not only after the second but also the third and fourth SRS. PMID- 30395906 TI - Introducing proton track-end objectives in intensity modulated proton therapy optimization to reduce linear energy transfer and relative biological effectiveness in critical structures. AB - PURPOSE: We propose the use of proton track-end objectives in intensity modulated proton therapy (IMPT) optimization to reduce the linear energy transfer (LET) and the relative biological effectiveness (RBE) in critical structures. METHODS: IMPT plans were generated for three intracranial patient cases (1.8 Gy (RBE) in 30 fractions) and three head-and neck cases (2 Gy (RBE) in 35 fractions) assuming a constant RBE=1.1. Two plans were generated for each patient: (1) Physical dose objectives only (DOSEopt), (2) same dose objectives as DOSEopt, and with additional proton track-end objectives (TEopt). The track-end objectives penalized protons stopping in the risk volume of choice. Dose evaluations were made using RBE=1.1 and the LET-dependent Wedenberg RBE model, together with estimates of normal tissue complication probabilities (NTCPs). Besides this, the distributions of proton track-ends and dose-average LET (LETd) were analyzed. RESULTS: The TEopt plans reduced the mean LETd in the critical structures studied with 37% on average, and increased the mean LETd in the primary CTV with 23% on average. This was achieved through a redistribution of the proton track-ends, while keeping the physical dose distribution virtually unchanged compared to the DOSEopt plans. This resulted in substantial RBE-weighted dose (DRBE) reductions, allowing the TEopt plans to meet all clinical goals for both RBE models, and reduce the NTCPs with 0-19 percentage points compared to the DOSEopt plans, assuming the Wedenberg RBE model. The DOSEopt plans met all clinical goals assuming RBE=1.1, but failed 10 of 19 normal tissue goals assuming the Wedenberg RBE model. CONCLUSIONS: Proton track-end objectives allow for LETd reductions in critical structures without compromising the physical target dose. Such approach permit lowering of DRBE and NTCP in critical structures independently of the variable RBE model used, and could be introduced in clinical practice without changing current protocols based on the constant RBE=1.1. PMID- 30395907 TI - Combinatorial screening using orthotopic patient derived xenograft-expanded early phase cultures of osteosarcoma identify novel therapeutic drug combinations. AB - Lead discovery in osteosarcoma has been hampered by the lack of new agents, limited representative clinical samples and paucity of accurate preclinical models. We developed orthotopic patient-derived xenografts (PDXs) that recapitulated the molecular, cellular and histologic features of primary tumors, and screened PDX-expanded short-term cultures and commercial cell lines of osteosarcoma against focused drug libraries. Osteosarcoma cells were most sensitive to HDAC, proteasome, and combination PI3K/MEK and PI3K/mTOR inhibitors, and least sensitive to PARP, RAF, ERK and MEK inhibitors. Correspondingly, PI3K signaling pathway genes were up-regulated in metastatic tumors compared to primary tumors. In combinatorial screens, as a class, HDAC inhibitors showed additive effects when combined with standard-of-care agents gemcitabine and doxorubicin. This lead discovery strategy afforded a means to perform high throughput drug screens of tumor cells that accurately recapitulated those from original human tumors, and identified classes of novel and repurposed drugs with activity against osteosarcoma. PMID- 30395908 TI - CircPAN3 mediates drug resistance in acute myeloid leukemia through the miR-153 5p/miR-183-5p-XIAP axis. AB - The contribution and role of circular RNAs (circRNAs) in mediating chemoresistance in acute myeloid leukemia (AML) are still poorly understood and need further investigation. In this study, we established a doxorubicin (ADM) resistant THP-1 AML cell line (THP-1/ADM). A high-throughput microarray was used to identify circRNA expression profiles of THP-1/ADM cells and naive THP-1 cells. The identified potential functional circRNA molecule was further validated in THP 1/ADM cells and bone marrow (BM) specimens from 42 AML patients. The interactions with target microRNAs (miRNAs) and downstream messenger RNAs (mRNAs) were also explored. As a result, 49 circRNAs that are significantly differentially expressed between THP-1/ADM and THP-1 cells were identified. Of these circRNAs, downregulation of circPAN3 by small interfering RNA significantly restored ADM sensitivity of THP-1/ADM cells. Furthermore, BM samples from patients with refractory and recurrent AML showed increased expression of circPAN3. A detailed circRNA/miRNA/mRNA interaction network was predicated for this circRNA. Subsequent mechanistic experiments showed that downregulation of circPAN3 could decrease the expression of X-linked inhibitor of apoptosis protein (XIAP), but this effect was counteracted by miR-153-3p or miR-183-5p specific inhibitors. Luciferase experiments further demonstrated that these molecules are involved in the circPAN3 regulatory network. Our results revealed that circPAN3 may be a key mediator for chemoresistance of AML cells, which may depend on the circPAN3-miR 153-5p/miR-183-5p-XIAP axis. Our findings provide evidence that circPAN3 can be a valuable indicator for predicting clinical efficacy of chemotherapy in AML patients and also can serve as a potential target for reversing drug resistance in AML. PMID- 30395910 TI - A standardized microdilution susceptibility test to determine the resistance capacity of human pathogenic bacteria towards hydrogen peroxide. AB - The susceptibility protocol established in this study takes into account that complex media are capable to buffer H2O2 which otherwise may adulterate test results. Furthermore, we demonstrate that clinical isolates of Staphylococcus aureus showed a higher resistance against H2O2 than Streptococcus pyogenes after 30 mins of incubation but not after 24 h. PMID- 30395909 TI - Membrane-potential compensation reveals mitochondrial volume expansion during HSC commitment. AB - Proper control of mitochondrial function is a key factor in the maintenance of hematopoietic stem cells (HSCs). Mitochondrial content is commonly measured by staining with fluorescent cationic dyes. However, dye staining can be affected, not only by xenobiotic efflux pumps, but also by dye intake, which is dependent on the negative charge of mitochondria. Therefore, mitochondrial membrane potential (DeltaPsimt) must be considered in these measurements because a high DeltaPsimt due to respiratory chain activity can enhance dye intake, leading to the overestimation of mitochondrial volume. Here, we show that HSCs exhibit the highest DeltaPsimt of the hematopoietic lineages and, as a result, DeltaPsimt independent methods most accurately assess the relatively low mitochondrial volumes and DNA amounts of HSC mitochondria. Multipotent progenitor stage or active HSCs display expanded mitochondrial volumes, which decline again with further maturation. Further characterization of the controlled remodeling of the mitochondrial landscape at each hematopoietic stage will contribute to a deeper understanding of the mitochondrial role in HSC homeostasis. PMID- 30395911 TI - Does NGS typing highlight our understanding of HLA population diversity?: Some good reasons to say yes and a few to say be careful. AB - This paper discusses the advantages provided by next generation sequencing (NGS) compared to traditional typings or limited sequencing strategies for the characterization of HLA population diversity based on four documented examples. We also comment the limitations of this approach by highlighting pitfalls in interpreting NGS data. PMID- 30395913 TI - "Tar Smarts" May Have a New Meaning for Atopic Dermatitis and Psoriasis. PMID- 30395912 TI - HCV genotype 1-6 NS3 residue 80 substitutions impact protease inhibitor activity and promote viral escape. AB - BACKGROUND AND AIMS: Protease inhibitors (PIs) are of central importance for treatment of patients with chronic hepatitis C virus (HCV) infection. HCV NS3 protease (NS3P) position 80 displays polymorphisms associated with resistance to the PI simeprevir for HCV genotype 1a. We investigated effects of position-80 substitutions on fitness and PI-resistance for HCV genotypes 1-6, and analysed evolutionary mechanisms underlying viral escape mediated by pre-existing Q80K. METHODS: Fitness of cell culture infectious recombinants with NS3P of HCV genotypes 1-6 and engineered position-80-substitutions was studied by comparison of viral spread kinetics in Huh7.5 cells. EC50 and fold-resistance for PIs simeprevir, asunaprevir, paritaprevir, grazoprevir, glecaprevir and voxilaprevir were determined in short-term treatment assays. Viral escape was studied by long term treatment of genotype 1a recombinants with simeprevir, grazoprevir, glecaprevir and voxilaprevir and of genotype 3a recombinants with glecaprevir and voxilaprevir, next generation sequencing (NGS), NS3P substitution linkage and haplotype analysis. RESULTS: Among tested PIs, only glecaprevir and voxilaprevir showed pan-genotypic activity against the original genotype 1-6 culture viruses. Variants with position-80-substitutions were all viable, but fitness depended on the specific substitution and the HCV isolate. Q80K conferred resistance to simeprevir across genotypes but had only minor effects on the activity of the remaining PIs. For genotype 1a, pre-existing Q80K mediated accelerated escape from simeprevir, grazoprevir and to a lesser extend glecaprevir, but not voxilaprevir. For genotype 3a, Q80K mediated accelerated escape from glecaprevir and voxilaprevir. Escape was mediated by rapid and genotype-, PI- and PI concentration-dependent co-selection of clinically relevant resistance associated substitutions. CONCLUSIONS: Position-80-substitutions had relatively low fitness cost and the potential to promote HCV escape from clinically relevant PIs in vitro, despite minor impact in classical short-term resistance assays. LAY SUMMARY: Among all clinically relevant hepatitis C virus (HCV) protease inhibitors, voxilaprevir and glecaprevir showed the highest and most uniform activity against cell culture infectious HCV with genotype 1-6 proteases. Naturally occurring amino acid changes at protease position 80 had low fitness cost and influenced sensitivity to simeprevir, but not that to other PIs in short term treatment assays. Nevertheless, the pre-existing change Q80K had the potential to promote viral escape from protease inhibitors during long-term treatment by rapid co-selection of additional resistance changes, detected by next generation sequencing. PMID- 30395914 TI - A Retrospective Study: Application Site Pain with the Use of Crisaborole, a Topical PDE4 Inhibitor. PMID- 30395915 TI - Melanoma subsequent to natalizumab exposure: A report from the RADAR (Research on Adverse Drug events And Reports) program. PMID- 30395916 TI - Trends in Incidence of Cutaneous Malignant Melanoma in Canada: 1992-2010 versus 2011-2015. PMID- 30395917 TI - Idiopathic Stevens-Johnson syndrome and toxic epidermal necrolysis: prevalence and patients characteristics. PMID- 30395918 TI - Surgical pearl: Retrograde punch biopsy technique for removal of enlarged earlobe piercings. PMID- 30395919 TI - Insect Repellents: An Updated Review for the Clinician. AB - Malaria, Zika virus, West Nile virus, Dengue fever, and Lyme disease are common causes of morbidity and mortality around the world. While arthropod bites may cause local inflammation and discomfort, a greater concern is the potential to develop deadly systemic infection. The use of insect repellents (IR) to prevent systemic infections constitutes a fundamental public health effort. Cost effectiveness, availability, and high-efficacy against arthropod vectors are key characteristics of an ideal IR. Currently, numerous IRs are available on the market, with DEET (N,N-diethyl-3-methylbenzamide) being the most widely used. DEET has an excellent safety profile and remarkable protection against mosquitoes and various other arthropods. Other EPA-registered IR ingredients (permethrin, picaridin, IR3535, oil of lemon eucalyptus, oil of citronella, catnip oil, and 2 undecanone) are alternative IRs of great interest due to some having efficacies comparable to that of DEET. These alternative IRs possess low toxicity and favorable customer experiences in utilization (e.g., cosmetically pleasant, naturally occurring). This review summarizes currently available EPA-registered IRs: the origins, mechanisms of action, side effect profiles, and available formulations will be discussed. This review will enable the clinician to select the best IR option to meet patients' needs and provide the greatest protection from arthropod bites and sequelae. PMID- 30395920 TI - A nomogram to identify high-risk melanoma patients with a negative sentinel node biopsy. AB - BACKGROUND: Melanoma patients with negative nodes following sentinel node biopsy are a heterogeneous group. Current guidelines fail to adequately stratify surveillance and treatment for this group. Also, there is scarce data on adjuvant treatments for these patients. OBJECTIVES: To create a nomogram based on clinical and pathological characteristics of primary melanoma to evaluate the risk of recurrence in patients with negative SNB. METHODS: Retrospective cohort of patients who underwent SNB from 2000 to 2015 in a single institution. RESULTS: Our cohort comprised 1,213 patients. Among these patients, 967 (79.7%) had a negative SNB and mean follow up was 59.67 months. There were 133 recurrences (13.8%) - 45 (33.8%) presented with nodal recurrence, and 35 (26.3%) recurred where SNB was performed. Breslow thickness, ulceration, and microsatellitosis were found to be predictive of risk of recurrence at one, two, five, and ten years. LIMITATIONS: single center analysis. CONCLUSIONS: we created a predictive nomogram for melanoma patients after a negative SNB. It is easy to use and identifies high-risk patients who should have more strict surveillance and consideration of adjuvant treatment. PMID- 30395921 TI - Tattooing: A national survey in the general population of France. PMID- 30395922 TI - Nutritional interventions and cognitive-related outcomes in patients with late life cognitive disorders: A systematic review. AB - There have been a large number of observational studies on the impact of nutrition on neuroprotection, however, there was a lack of evidence from randomized clinical trials (RCTs). In the present systematic review, from the 32 included RCTs published in the last four years (2014-2017) in patients aged 60 years and older with different late-life cognitive disorders, nutritional intervention through medical food/nutraceutical supplementation and multidomain approach improved magnetic resonance imaging findings and other cognitive-related biomarkers, but without clear effect on cognition in mild Alzheimer's disease (AD) and mild cognitive impairment (MCI). Antioxidant-rich foods (nuts, grapes, cherries) and fatty acid supplementation, mainly n-3 polyunsaturated fatty acids (PUFA), improved specific cognitive domains and cognitive-related outcomes in MCI, mild-to-moderate dementia, and AD. Antioxidant vitamin and trace element supplementations improved only cognitive-related outcomes and biomarkers, high dose B vitamin supplementation in AD and MCI patients improved cognitive outcomes in the subjects with a high baseline plasma n-3 PUFA, while folic acid supplementation had positive impact on specific cognitive domains in those with high homocysteine. PMID- 30395923 TI - Regular cannabis use is associated with altered activation of central executive and default mode networks even after prolonged abstinence in adolescent users: Results from a complementary meta-analysis. AB - Whether the effects of cannabis use on brain function persist or recover following abstinence remains unclear. Therefore, using meta-analytic techniques, we examined whether functional alterations measured using fMRI persist in cannabis users abstinent for over 25 days (or 600 h) as evidence suggests that the effects on cognitive performance no longer persist beyond this period. Systematic literature search identified 20 studies, of which, 12 examined current cannabis users (CCU) (361 CCU versus 394 non-cannabis using controls (NU)) and 3 examined abstinent cannabis users (ACU) in 5 separate comparisons (98 ACU versus 106 NU). Studies in ACU were carried out in adolescents and suggest significantly greater activation in components of the central executive and default mode networks in adolescent ACU compared to NU. While this evidence is to be interpreted with caution because studies were carried out in overlapping samples, they indicate a pressing need for independent confirmation whether certain neurofunctional alterations in adolescent cannabis users may persist even after cannabis and its metabolites are likely to have left their bodies. PMID- 30395924 TI - Review of interventions for the management of anxiety symptoms in children with ASD. AB - BACKGROUND: Anxiety is a common accompanying symptom in people with Autism Spectrum Disorder (ASD). OBJECTIVES: To investigate interventions available for the management of anxietyin children with ASD internationally. METHODS: Review was made of relevant studies found through PubMed, the National Institute of Health (NIH) publications and resources in the libraries of the University of Macedoniaand the Greek NationalResearch Foundation. RESULTS: Of the 372 studies retrieved dealing withinterventionsfor children with ASD who have anxiety disorders published from the 1980s to 2017, 137 were included in this review.Interventions includepharmacological intervention, cognitive behavioral therapy(CBT),socialrecreational (SR)programs,other psychosocial therapies, teaching social skillsand combinations of educational, psychological and medical treatment. CONCLUSIONS: Various methods for coping with anxiety in children with ASD have been applied, including pharmacotherapy, psychosocial andCBT interventions, parent education and school-based programs. A combination of approachesshould be selected, based onassessment of each child's particular characteristics. PMID- 30395925 TI - Sequential monitoring of TIM-3 mRNA expression in blood and urine samples of renal transplant recipients. AB - BACKGROUND: T cell immunoglobulin and mucin domain 3 (TIM-3), as a co-inhibitory receptor expressed on Th1, Th17, CD8T, FoxP3 + Treg and innate immune cells, plays an important role in suppression of T cell-mediated immune responses, tolerance induction and T cell exhaustion. In this study, we evaluated sequential alterations of TIM-3 mRNA expression level in blood and urine samples of renal transplant recipients to predict approaching clinical episodes. METHODS: A total of 52 adult renal transplant recipients (31 male and 21 female) were enrolled in this study. All the patients received kidney transplant from living unrelated donors. TIM-3 mRNA expression in peripheral blood mononuclear cells (PBMCs) and urinary cells were quantified using Real Time TaqMan polymerase chain reaction (PCR) at 4 different time points (pre-transplantation, 2, 90 and 180 days post transplantation). RESULT: TIM-3 mRNA expression level on days 2, 90 and 180 after transplantation was significantly higher in blood and urine samples of patients with graft dysfunction (GD) compared with patients with well-functioning graft (WFG). Our results also showed a high correlation between blood and urinary level of TIM-3 mRNA expression. The data from Receiver Operating Characteristic (ROC) Curve Analysis showed that blood and urinary TIM-3 mRNA expression level at month 3 and 6 could discriminate graft dysfunction (GD) from well-functioning graft (WFG) with high specificity and sensitivity. CONCLUSION: Our data suggested that serial monitoring of TIM-3 mRNA level in the blood and urine samples of renal transplant recipients could be a useful non-invasive biomarker for prediction and diagnosis of allograft dysfunction. PMID- 30395926 TI - Synthesis of zanthoxylamide protoalkaloids and their in silico ADME-Tox screening and in vivo toxicity assessment in zebrafish embryos. AB - Inspired by the simple and attractive structure of zanthoxylamide protoalkaloids: armatamide, rubecenamide, lemairamin, rubemamine and zanthosine; isolated from plants of the genus Zanthoxylum. We report the synthesis of a series of 29 substituted N-phenylethyl cinnamamides through the direct amidation of a variety of cinnamic acids with a broad range of phenylethylamines promoted by tris-(2,2,2 trifluoroethyl) borate (B(OCH2CF3)3) in excellent yields and under mild reaction conditions. Then, the toxicological profile of the prepared compounds was studied through in silico computational methods, analyzing eight toxicity risks (hepatotoxicity, mutagenic, carcinogenicity, tumorigenic, immunotoxicity, cytotoxicity, irritant and reproductive effects) and two toxicity targets (AOFA and PGH1), while the acute toxicity toward zebrafish embryos (96 hpf-LC50, 50% lethal concentration) was also determined in the present study. From the results of the toxicity tests, we concluded that zanthoxylamide protoalkaloids can be classified as slightly toxic compounds, with a LC50 values around 217 MUM that gave an understanding of their toxicity on living organisms and their possible environmental impact. PMID- 30395927 TI - The phosphotransferase system gene ptsH plays an important role in MnSOD production, biofilm formation, swarming motility, and root colonization in Bacillus cereus 905. AB - The rhizosphere bacterium Bacillus cereus 905 is capable of promoting plant growth through effective colonization on plant roots. The sodA2-encoding manganese-containing superoxide dismutase (MnSOD2) is important for survival of B. cereus 905 in the wheat rhizosphere. However, the genes involved in regulating sodA2 expression and the mechanisms of rhizosphere colonization of B. cereus 905 are not well elucidated. In this study, we found that the deletion of the ptsH gene, which encodes the histidine-phosphorylatable protein (HPr), a component of the phosphotransferase system (PTS), causes a decrease of about 60% in the MnSOD2 expression. Evidences indicate that the ptsH dramatically influences resistance to oxidative stress, glucose uptake, as well as biofilm formation and swarming motility of B. cereus 905. Root colonization assay demonstrated that DeltaptsH is defective in colonizing wheat roots, while complementation of the sodA2 gene could partially restore the ability in utilization of arabinose, a non-PTS sugar, and root colonization caused by the loss of the ptsH gene. In toto, based on the current findings, we propose that PtsH contributes to root colonization of B. cereus 905 through multiple indistinct mechanisms, involving PTS and uptake of PTS-sugars, up-regulation of MnSOD2 production, and promotion of biofilm formation and swarming motility. PMID- 30395928 TI - Microtransplantation of human brain receptors into oocytes to tackle key questions in drug discovery. AB - It is important in drug discovery to demonstrate that activity of novel drugs found by screening on recombinant receptors translates to activity on native human receptors in brain areas affected by disease. In this review, we summarise the development and use of the microtransplantation technique. Native receptors are reconstituted from human brain tissues into oocytes from the frog Xenopus laevis where they can be functionally assessed. Oocytes microtransplanted with hippocampal tissue from an epileptic patient were used to demonstrate that new antiepileptic agents act on receptors in diseased tissue. Furthermore, frozen post-mortem human tissues were used to show that drugs are active on receptors in brain areas associated with a disease; but not in areas associated with side effects. PMID- 30395929 TI - Genetic predisposition for inflammation exacerbates effects of striatal iron content on cognitive switching ability in healthy aging. AB - Non-heme iron homeostasis interacts with inflammation bidirectionally, and both contribute to age-related decline in brain structure and function via oxidative stress. Thus, individuals with genetic predisposition for inflammation may be at greater risk for brain iron accumulation during aging and more vulnerable to cognitive decline. We examine this hypothesis in a lifespan sample of healthy adults (N = 183, age 20-94 years) who underwent R2*-weighted magnetic resonance imaging to estimate regional iron content and genotyping of interleukin-1beta (IL 1beta), a pro-inflammatory cytokine for which the T allelle of the single nucleotide polymorphism increases risk for chronic neuroinflammation. Older age was associated with greater striatal iron content that in turn accounted for poorer cognitive switching performance. Heterozygote IL-1beta T-carriers demonstrated poorer switching performance in relation to striatal iron content as compared to IL-1beta C/C counterparts, despite the two groups being of similar age. With increasing genetic inflammation risk, homozygote IL-1beta T/T carriers had lesser age-related variance in striatal iron content as compared to the other groups but showed a similar association of greater striatal iron content predicting poorer cognitive switching. Non-heme iron and inflammation, although necessary for normal neuronal function, both promote oxidative stress that when accumulated in excess, drives a complex mechanism of neural and cognitive decline in aging. PMID- 30395930 TI - Stability of representational geometry across a wide range of fMRI activity levels. AB - Fine-grained activity patterns, as measured with functional magnetic resonance imaging (fMRI), are thought to reflect underlying neural representations. Multivariate analysis techniques, such as representational similarity analysis (RSA), can be used to test models of brain representation by quantifying the representational geometry (the collection of pair-wise dissimilarities between activity patterns). One important caveat, however, is that non-linearities in the coupling between neural activity and the fMRI signal may lead to significant distortions in the representational geometry estimated from fMRI activity patterns. Here we tested the stability of representational dissimilarity measures in primary sensory-motor (S1 and M1) and early visual regions (V1/V2) across a large range of activation levels. Participants were visually cued with different letters to perform single finger presses with one of the 5 fingers at a rate of 0.3-2.6 Hz. For each stimulation frequency, we quantified the difference between the 5 activity patterns in M1, S1, and V1/V2. We found that the representational geometry remained relatively stable, even though the average activity increased over a large dynamic range. These results indicate that the representational geometry of fMRI activity patterns can be reliably assessed, largely independent of the average activity in the region. This has important methodological implications for RSA and other multivariate analysis approaches that use the representational geometry to make inferences about brain representations. PMID- 30395931 TI - Structural dissection of sterol glycosyltransferase UGT51 from Saccharomyces cerevisiae for substrate specificity. AB - Sterol glycosyltransferases catalyze the formation of a variety of glycosylated sterol derivatives and are involved in producing a plethora of bioactive natural products. To understand the molecular mechanism of sterol glycosyltransferases, we determined crystal structures of a sterol glycosyltransferase UGT51 from Saccharomyces cerevisiae. The structures of the UGT51 and its complex with uridine diphosphate glucose (UDPG) were solved at resolutions of 2.77 A and 1.9 A, respectively. The structural analysis revealed that a long hydrophobic cavity, 9.2 A in width and 17.6 A in length located at the N-terminal domain of UGT51, is suitable for the accommodation of sterol acceptor substrates. Furthermore, a short, conserved sequence of S847-M851 was identified at the bottom of the hydrophobic cavity, which might be the steroid binding site and play an important role for the UGT51 catalytic specificity towards sterols. Molecular docking simulations indicated that changed unique interaction network in mutant M7_1 (S801A/L802A/V804A/K812A/E816K/S849A/N892D), with an 1800-fold activity improvement toward an unnatural substrate protopanaxadiol (PPD), might influence its substrate preference. This study reported the first sterol glycosyltransferase structure, providing a molecular blueprint for generating tailored sterol glycosyltransferases as potential catalytic elements in synthetic biology. PMID- 30395932 TI - Changes in the incidence and bacterial aetiology of paediatric parapneumonic pleural effusions/empyema in Germany, 2010-2017: a nationwide surveillance study. AB - OBJECTIVES: Parapneumonic pleural effusions/empyema (PPE/PE) are severe complications of community-acquired pneumonia. We investigated the bacterial aetiology and incidence of paediatric PPE/PE in Germany after the introduction of universal pneumococcal conjugate vaccine (PCV) immunization for infants. METHODS: Children <18 years of age hospitalized with pneumonia-associated PPE/PE necessitating pleural drainage or persisting >7 days were reported to the German Surveillance Unit for Rare Diseases in Childhood between October 2010 and June 2017. All bacteria detected in blood or pleural fluid (by culture/PCR) were included, with serotyping for Streptococcus pneumoniae. RESULTS: The median age of all 1447 PPE/PE patients was 5 years (interquartile range 3-10). In 488 of the 1447 children with PPE/PE (34%), 541 bacteria (>40 species) were detected. Aerobic gram-positive cocci accounted for 469 of 541 bacteria detected (87%); these were most frequently Streptococcus pneumoniae (41%), Streptococcus pyogenes (19%) and Staphylococcus aureus (6%). Serotype 3 accounted for 45% of 78 serotyped S. pneumoniae strains. Annual PPE/PE incidence varied between 14 (95%CI 12-16) and 18 (95%CI 16-21) PPE/PE per million children. Incidence of S. pneumoniae PPE/PE decreased from 3.5 (95%CI 2.5-4.6) per million children in 2010/11 to 1.5 (95%CI 0.9-2.4) in 2013/14 (p 0.002), followed by a re-increase to 2.2 (95%CI 1.5-3.2) by 2016/17 (p 0.205). CONCLUSIONS: In the era of widespread PCV immunization, cases of paediatric PPE/PE were still caused mainly by S. pneumoniae and, increasingly, by S. pyogenes. The re-increase in the incidence of PPE/PE overall and in S. pneumoniae-associated PPE/PE indicates ongoing changes in the bacterial aetiology and requires further surveillance. PMID- 30395933 TI - Amish nemaline myopathy and dilated cardiomyopathy caused by a homozygous contiguous gene deletion of TNNT1 and TNNI3 in a Mennonite child. AB - Amish nemaline myopathy (ANM) is a severe congenital form of NM, known to be fatal in early childhood due to pulmonary insufficiency. Homozygous mutation in TNNT1 was originally ascertained in an Older Amish community in 2000. To date, only five reports with six pathogenic variants in TNNT1 have been described in both Amish and non-Amish families. Here, we describe a 16-month old female from a small Mennonite community from Mexico, presenting with congenital hypotonia and dilated cardiomyopathy, with a novel homozygous deletion of 19q13.42 of about 11 kb in size, encompassing TNNT1 and TNNI3. Cardiomyopathy has not been observed in association with ANM in previous reports. Conversely, homozygous mutation in TNNI3 have been described with dilated cardiomyopathy. Our report underscores the consideration of contiguous gene deletion in children with ANM who present with congenital hypotonia and cardiomyopathy. The report also expands the known spectrum of non-Amish related ANM mutations to include homozygous multi-exonic TNNT1 deletion. PMID- 30395934 TI - Burnout in Pediatric Residents: Comparing Brief Screening Questions to the Maslach Burnout Inventory. AB - BACKGROUND: Measuring burnout symptoms is important, but the Maslach Burnout Inventory (MBI) has 22 items. This project compared three single items with the MBI and other factors related to burnout. METHODS: Data were analyzed from the 2016 and 2017 Pediatric Resident Burnout-Resilience Study Consortium surveys which included standard measures of perceived stress, mindfulness, self compassion, and resilience, the MBI, and the 1- and 2-item screening questions. RESULTS: In 2016 and 2017, data were collected from 1785/2723 (65%) and 2148/3273 (66%) eligible pediatric residents respectively. Burnout rates on the MBI were 56% in 2016 and 54% in 2017. The Physicians' Work Life Study (PWLS) item generated estimates of burnout prevalence of 43%-49%, and compared with the MBI for 2016 and 2017, had sensitivities of 69 -72%, specificities of 79%-82%, positive likelihood ratios (LR+) of 3.4-3.8 and negative likelihood ratios (LR-) of 0.35-0.38. The combination of an Emotional Exhaustion (EE) item and a depersonalization (DP) item generated burnout estimates of 53% in both years, and compared with the full MBI, had sensitivities of 85%-87%, specificities of 84% 85%, LR+ of 5.7-6.4 and LR- of 0.18 in both years; both items were significantly correlated with their parent subscales. The single items were significantly correlated with stress, mindfulness, resilience, and self-compassion. DISCUSSION: The 1- and 2-item screens generated prevalence estimates similar to the MBI and were correlated with variables associated with burnout. The 1- and 2-item screens may be useful for pediatric residency training programs tracking burnout symptoms and response to interventions. PMID- 30395935 TI - Laparoscopic Resection of An Extragastrointestinal Stromal Tumor in Presacral Area. AB - STUDY OBJECTIVE: To show a surgical video in which retroperitoneal extragastrointestinal stromal tumor was resected with laparoscopic approach in presacral area. DESIGN: Case report (Canadian Task Force classification III). The local Ethics Committee waived the requirement for approval. SETTING: A very small proportion of extragastrointestinal stromal tumors (EGIST) is located in the retroperitoneal region. There is insufficient data on clinical, pathologic features and long term follow-up of these tumors [1]. There are a few cases reported in the presacral region in the literature. The gold standart treatment for EGISTs is complete surgical excision of the mass. If it is possible, 'en bloc' excision with its surrounding tissue is very important [2]. PATIENT: A 53 year-old woman. The patient provided informed consent to use images and videos of the procedure. INTERVENTIONS: This is a step-by-step illustration for resection of a retroperitoneal EGIST in presacral area. The patient was a 53-year-old G3P3 white woman. She presented with abdominal pain for 5 months. Magnetic resonance imaging showed a solid mass localized at the presacral area in 4 cm in diameter. Laboratory test results for tumor biomarkers were CA-125: 40 U/ml (normal values < 35 U/ml), CA-19-9: 29 U/ml (normal values < 37 U/ml), CEA: 2.1 ng/ml (normal values < 3 ng/ml), CA 15.3: 18 U/ml (normal values < 35 U/ml). Because of malignancy suspicion, gastroscopy,colonoscopy were performed and revealed no abnormality. Pap smear and endometrial biopsy results were negative. After the patient preparation, laparoscopy was performed. After placement of 11 mm umbilical port and three 5-mm abdominal ports, the pelvis and abdomen were explored and revealed a 4 cm retroperitoneal mass in presacral area. The peritoneum overlying the presacral mass was incised and the retroperitoneum explored. Given the proximity to the mass, left ureterolysis was performed. The mass was located on left internal iliac vein and dissected carefully. The retroperitoneal attachments were resected, and the presacral mass was removed without any complications. In order not to widen the abdominal incisions, a posterior colpotomy was performed in the cul-de-sac at equal distances from the uterosacral ligaments. Endobag (Covidien) was introduced through the 5-mm port site at the posterior colpotomy. The specimen was removed in endobag through posterior colpotomy. MEASUREMENTS AND MAIN RESULTS: The procedure was performed without any complications. The patient had an uneventful postoperative course and was discharged home on postoperative day 2. Pathology revealed a 4 cm retroperitoneal EGIST with negative margins. Immunohistochemistry measurements revealed Hematoxylin eosin, CD 117, S100 positivity and CD34, CD68, Desmin, DOG1 negativity. Cell type was mixed (spindle and epithelioid type). Mitotic rate was 1-2/50 hpf. The patient has been disease free since the completion of surgery. CONCLUSION: Laparoscopic complete resection of the retroperitoneal EGIST in presacral area is successfully performed in this patient. The patient presented by us is an example showing that minimally invasive procedures can be used in the treatment of this type of tumor in presacral area. The key point in this operation is to control the relationship of vascular structures and ureter with tumor in every step to avoid any injury. PMID- 30395936 TI - Probing the function of glycinergic neurons in the mouse respiratory network using optogenetics. AB - Glycine is a primary inhibitory transmitter in the ventral medullary respiratory network, but the functional role of glycinergic neurons for breathing remains a matter of debate. We applied optogenetics to selectively modulate glycinergic neuron activity within regions of the rostral ventral respiratory column (VRC). Responses of the phrenic nerve activity to the light-driven stimulation were studied in the working heart-brainstem preparation from adult glycine transporter 2 Cre mice (GlyT2-Cre), which received a unilateral injection of a Cre-dependent AAV virus into Botzinger and preBotzinger Complex. Sustained light stimulation from the ventral medullary surface resulted in a substantial depression of the phrenic nerve (PN) frequency, which in most cases was compensated by an increase in PN amplitude. Periodic, burst stimulation with variable intervals could alter and reset respiratory rhythm. We conclude that unilateral activation of the rostral VRC glycinergic neurons can significantly affect respiratory pattern by lengthening the expiratory interval and modulating phase transition. PMID- 30395937 TI - Antarctic and sub-Antarctic Nacella limpets reveal novel evolutionary characteristics of mitochondrial genomes in Patellogastropoda. AB - Mitochondrial genomes (mitogenomes) provide valuable phylogenetic information and genome-level characters that are useful in resolving evolutionary relationships within major lineages of gastropods. However, for more than one decade, these relationships and the phylogenetic position of Patellogastropoda have been inferred based on the genomic architecture as well as the nucleotide and protein sequences of a single representative, the limpet Lottia digitalis. This mitogenome exhibits extensive rearrangements and several repetitive units that may not represent universal features for Patellogastropoda. Here, we sequenced the complete mitogenomes of three Nacella limpets, providing new insights into the dynamics of gene order and phylogenetic relationships of Patellogastropoda. Comparative analyses revealed novel gene rearrangements in Gastropoda, characterised by two main translocations that affect the KARNI and the MYCWQ clusters in Nacella limpets. Our phylogenetic reconstructions using combined sequence datasets of 13 mitochondrial protein-coding genes and two rRNAs, recovered Patellogastropoda, and Gastropoda in general, as non-monophyletic. These findings could be related to the long-branch attraction tendency of these groups, and/or taxon sampling bias. In our novel mitogenome-based phylogenetic hypothesis, L. digitalis is placed in a sister position to Bivalvia and Heterobranchia, whereas Nacella limpets are placed sister to a clade containing Caenogastropoda + Neritimorpha and Vetigastropoda + Neomphalina. PMID- 30395938 TI - Involvement of classical neurotransmitter systems in memory reconsolidation: Focus on destabilization. AB - When consolidated long-term memories are reactivated they can destabilize, rendering the memory labile and vulnerable to modification. This period of lability is followed by reconsolidation, a process that restabilizes the memory trace. Reactivation-induced memory destabilization is the gateway process to reconsolidation, but research in this area has focused primarily on the mechanisms underlying post-reactivation restabilization. As a result, our understanding of processes subserving destabilization have lagged behind those responsible for reconsolidation. Here we review the literature investigating the neural basis of reactivation-induced memory destabilization. We begin by reviewing memory destabilization broadly and the boundary conditions that influence the likelihood of reactivated memories to destabilize. We then discuss the fact that boundary conditions can be overcome in the presence of novelty, providing evidence for the theory that reconsolidation is a mechanism for memory updating. From here, we delve into a detailed review of the role of classical neurotransmitter systems, including dopamine, serotonin, noradrenaline, glutamate, GABA and acetylcholine, in reconsolidation, with a focus on their involvement in destabilization. Many of these neurotransmitters appear capable of promoting memory destabilization, and research investigating the cellular pathways through which they influence destabilization is a growing area. However, gaps remain in our understanding of how these neurotransmitters work in conjunction with one another to support destabilization across different types of memory and in different brain regions. Advances in the coming years within this research field should greatly contribute to our understanding of the neural mechanisms that influence the dynamic process of long-term memory storage and modification, information crucial to the development of potential treatments for disorders characterized by strong, maladaptive memories. PMID- 30395939 TI - Pediatric travelers presenting to an Australian emergency department (2014-2015): A retrospective, cross-sectional analysis. AB - BACKGROUND: Epidemiological data on pediatric travelers are lacking, especially from Oceania. We aimed to evaluate travelers presenting to a pediatric emergency department in Sydney during a time of heightened travel surveillance. METHOD: Cases between December 2014 and February 2015 were ascertained by screening medical records for key terms and visa status, as well as laboratory data for malaria testing. Cases were restricted to communicable diseases and evidence of travel within 21 days. RESULTS: 104 children were identified. 82 children were Australian-resident travelers returning from abroad, 11 were visitors to Australia, 8 were recent migrants/refugees and 3 were medical transfers. Travel and behavioral patterns were characterized by exposures to low-income countries in the Asia-Pacific, visiting families and relatives, prolonged exposure periods and limited uptake of prophylaxis. Intrinsic vulnerabilities included extremes of age (median: 3.3 years) and pre-existing co-morbidities (6.7%). Common syndromes were respiratory (38.5%), systemic febrile illness (19.2%), acute diarrhea (17.3%) and dermatological conditions (9.6%). A minority were diagnosed with tropical infections: four typhoid or paratyphoid fever, two dengue and one tropical ulcer. CONCLUSIONS: Young travelers are a heterogeneous group who present with a broad spectrum of diseases, from the benign to the life threatening. Our data may be used to inform diagnostic approaches, empiric therapies and contribute towards public health strategies. PMID- 30395940 TI - Cystic Echinococcosis in immigrants and Italians accessing a single referral center in Lombardy, Italy. PMID- 30395941 TI - Ruptured central nervous system dermoid cyst of the suprasellar region manifesting as unusual epileptic seizure: a case report. AB - Central nervous system dermoid cysts are very rare lesions derived from ectopic epithelial cells. They are slow-growing benign tumors, but may cause significant morbidity through compression of neurological and vascular vascular structures and, rarely, rupture into the subarachnoid space. We present a rare case of a spontaneously ruptured intracranial dermoid cyst in a 32-year-old man presenting as new onset epileptic seizures due to chemical meningitis caused by dissemination of fat or lipid droplets. PMID- 30395942 TI - Co-activation of WT1 and AP-1 proteins on WT1 gene promoter to induce WT1 gene expression in K562 cells. AB - Earlier studies have revealed one function of the inhibitory mechanism of curcumin. Activating PKCalpha induces WT1 gene expression via signalling through downstream JNK and c-JUN. In the present study, the effect of c-JUN/AP-1 binding and transcriptional regulation of the WT1 gene promoter was investigated in K562 leukaemic cells. The non-cytotoxic dose (IC20 values) of curcumin (WT1 and AP-1 inhibitors) was employed to examine its effect on WT1 gene-mediated WT1 and AP-1 protein expression. Non-cytotoxic doses of both tanshinone IIA (AP-1 DNA-binding inhibitor) and SP600125 (JNK inhibitor) were used to test the role of c-JUN/AP-1 in WT1 gene expression. Curcumin, tanshinone IIA, and SP600125 inhibited WT1 protein expression in a dose-dependent manner (5-15 MUM) at 24 h as shown by immunoblotting. A ChIP assay showed that curcumin and tanshinone IIA inhibited AP 1 and WT1 binding to the proximal WT1 promoter (-301 bp), and a luciferase reporter assay showed that the WT1 luciferase gene reporter activity was decreased after curcumin, tanshinone IIA, and SP600126 treatments. Furthermore, depletion of c-JUN abrogated WT1 gene expression. In summary, AP-1 contributes to the WT1 autoregulation of WT1 gene expression in leukaemic K562 cells. PMID- 30395943 TI - Role of SMURF1 ubiquitin ligase in BMP receptor trafficking and signaling. AB - Heterozygous germline mutations in the bone morphogenetic protein type II receptor gene (BMPRII) are associated with hereditary pulmonary arterial hypertension (HPAH). Missense mutations, both in the extracellular ligand-binding and cytoplasmic kinase domains, mostly involve substitution of conserved Cys residues. Singular substitution at any of those Cys residues causes cytoplasmic, perinuclear localization of BMPR with reduced cell surface expression and BMP signaling. The present study examined the effect of Cys residue substitution on BMPR endocytic trafficking and lysosome degradation. We demonstrate that endocytosis/lysosomal degradation of BMPR occurs by two distinct pathways: SMURF1 and Ser/Thr kinase-associated. SMURF1 ubiquitin ligase induces lysosomal degradation of BMPR, while ligase-inactive SMURF1 maintains BMPR protein level and cell surface expression. Substitution of BMPR Cys residues increases lysosomal degradation which is blocked by ligase-inactive SMURF1, elevating protein levels of Cys-substituted BMPRs. Expression of Cys-substituted BMPR suppresses basal BMP signaling activity which is also up-regulated by ligase inactive SMURF1. Cys-residue substitution thus appears to cause BMPR endocytosis to lysosomes in a SMURF1 ubiquitin ligase-associated pathway. In contrast, kinase activated BMPR undergoes endocytic/lysosomal degradation by a pathway which is independent of SMURF1 and characterized with unique properties. Therefore, our results may describe a novel mechanism that SMURF1 ubiquitin ligase regulates constitutive endocytosis of BMPR which may be mediated by its conserved Cys residues. PMID- 30395944 TI - Mechanistic insights into m6A RNA enzymes. AB - The field of RNA modifications, so-called epitranscriptomics, has flourished over the past years owing to improvements of detection methods and the identification of important regulatory players. N6-methyladenosine (m6A) is the most abundant internal modification in messenger (mRNA) and long non-coding (lncRNA), and controls most steps of RNA metabolism. Its physiological roles range from gametogenesis, stem cell differentiation to immunity, neuronal development and functions, while its alterations are associated with cancer development and progression. In this review we focus on the proteins that catalyze formation of m6A (also called writers) on RNA. Interestingly, distinct proteins deposit m6A on different classes of RNA, indicating that specific RNA features dictate recognition mechanisms. Associated factors and post-translational modifications can also alter m6A enzyme activity. A better understanding of the underlying regulation involved in m6A deposition is the first step towards developing tools for cancer therapy and for treatment of other m6A-associated diseases. PMID- 30395945 TI - Development of a Malawi Intensive care Mortality risk Evaluation (MIME) model, a prospective cohort study. AB - INTRODUCTION: Intensive care medicine can contribute to population health in low income countries by reducing premature mortality related to surgery, trauma, obstetrical and other medical emergencies. Quality improvement is guided by risk stratification models, which are developed primarily within high-income settings. Models validated for use in low-income countries are needed. METHODS: This prospective cohort study consisted of 261 patients admitted to the intensive care unit (ICU) of Kamuzu Central Hospital in Malawi, from September 2016 to March 2018. The primary outcome was in-hospital mortality. We performed univariable analyses on putative predictors and included those with a significance of 0.15 in the Malawi Intensive care Mortality risk Evaluation model (MIME). Model discrimination was evaluated using the area under the curve. RESULTS: Males made up 37.9% of the study sample and the mean age was 34.4 years. A majority (73.9%) were admitted to the ICU after a recent surgical procedure, and 59% came directly from the operating theater. In-hospital mortality was 60.5%. The MIME based on age, sex, admitting service, systolic pressure, altered mental status, and fever during the ICU course had a fairly good discrimination, with an AUC of 0.70 (95% CI 0.63-0.76). CONCLUSIONS: The MIME has modest ability to predict in-hospital mortality in a Malawian ICU. Multicenter research is needed to validate the MIME and assess its clinical utility. PMID- 30395946 TI - Salvia miltiorrhiza protects against diabetic nephropathy through metabolome regulation and wnt/beta-catenin and TGF-beta signaling inhibition. AB - Diabetic nephropathy (DN) is a complication of diabetes that is caused by uncontrolled high blood sugar. It has been reported that Salvia miltiorrhiza (SM) possesses the ability to prevent kidney damage, although the mechanisms remain unclear. The study was to investigate whether and how SM improved DN injury via regulation of metabolome and the molecular mechanisms. In this study, SD rats were fed a high glucose / high fat diet accompanied by 0.5% glucose water. Three weeks later, the rats were given one intraperitoneal injection of 30 mg/kg STZ each day for three days for DN model. The biochemical indicators and metabolomics of plasma, urine and renal tissue were analyzed. Then the western blotting analysis of renal tissue and glomerular mesangial cells were investigated. The results showed that Salvia miltiorrhiza extracts improved the renal injury and regulation of abnormal glycolipid metabolism. The metabolites in serum, urine and renal tissues have been changed significantly. The involved metabolic pathways mainly include phospholipid, arachidonic acid, and pyrimidine metabolisms. Meanwhile, SM inhibited the relative expression levels of wnt4, beta-catenin and TGF-beta in renal tissue and high-glucose induced glomerular mesangial cells. PMID- 30395947 TI - Molecular pharmacology of inflammation: Medicinal plants as anti-inflammatory agents. AB - Except for an essential step for the pathology of multiple diseases including atherosclerosis and rheumatoid arthritis, inflammation is an imperative therapeutic target for developing novel approaches for pharmacological interventions. Thus, molecular understanding of inflammation not only revealed the mechanisms of drug action and their biological targets but also has spawned innovative maneuvers to influence multifaceted biological systems, providing new prospects for drug designing and suggesting important new implications for existing clinical medicine. Meanwhile, modulation of inflammation with the use of medicinal plants proposed an alternate to conventional therapeutic strategies for numerous ailments, particularly when suppression of inflammation is expected. In modern literature, several species of medicinal plants have been shown substantial antiinflammatory and immunomodulatory actions including inhibitory effects on suppression of cellular and humoral immunity, lymphocyte activation, and propagation of apoptosis. Herein, we reviewed the molecular pharmacology of inflammation, chemical components and biological activities of medicinal plants such as, curcumin from Curcuma longa, and epigallocatechin-3-gallate from Camellia sinensis as well as their mechanism of action during inflammation at molecular level. An extensive review of the literature and electronic databases was conducted, encompassing PubMed, GoogleScholar, ScienceDirect, medlineplus, www.clinicaltrial.gov, www.fda.gov, www.ema.europa.eu, www.drugbank.ca, TrialBulletin.com, www.theplantlist.org, and www.pharmacodia.com for assembling the information. Additionally, data was attained from books, ethnopharmacological literature, and relevant publications for essential elements of molecular mechanisms, signal transduction networks, transcription factors, complement system, reactive species, and clinical trials are selected for substantial understanding of biochemistry, pathophysiology as well as clinical importance of medicinal plants during inflammatory diseases. PMID- 30395948 TI - Cognition and behavior in sheep repetitively inoculated with aluminum adjuvant containing vaccines or aluminum adjuvant only. AB - Aluminum (Al)-containing vaccines are common in sheep management and they have been associated with the Autoimmune/inflammatory Syndrome Induced by Adjuvants (ASIA syndrome). The aim of this study was to investigate cognitive and behavioral changes in sheep subjected to a protocol of repetitive inoculation with Al-containing products. Twenty-one lambs were assigned to three groups (n = 7 each): A (Control), B (Adjuvant-only), C (Vaccine). Group C was inoculated with commercial Al-containing vaccines; Group B received the equivalent dose of Al only (Alhydrogel(r)) and Group A received PBS. Sixteen inoculations were administered within a 349-day period. Ethologic changes were studied in late summer (7 inoculations) and mid-winter (16 inoculations). Animals in groups B and C exhibited behavioral changes: affiliative interactions were significantly reduced and aggressive interactions and stereotypies increased significantly. They also exhibited a significant increase in excitatory behavior and compulsive eating. In general, changes were more pronounced in the Vaccine group than they were in the Adjuvant-only group. Some changes were already significant in summer, after seven inoculations only. This study is the first to describe behavioral changes in sheep after having received repetitive injections of Al-containing products, explaining some of the clinical signs observed in ovine ASIA syndrome. PMID- 30395949 TI - 3D Organ Models - Revolution in Pharmacological Research? AB - 3D organ models have gained increasing attention as novel preclinical test systems and alternatives to animal testing. Over the years, many excellent in vitro tissue models have been developed. In parallel, microfluidic organ-on-a chip tissue cultures have gained increasing interest for their ability to house several organ models on a single device and interlink these within a human-like environment. In contrast to these advancements, the development of human disease models is still in its infancy. Although major advances have recently been made, efforts still need to be intensified. Human disease models have proven valuable for their ability to closely mimic disease patterns in vitro, permitting the study of pathophysiological features and new treatment options. Although animal studies remain the gold standard for preclinical testing, they have major drawbacks such as high cost and ongoing controversy over their predictive value for several human conditions. Moreover, there is growing political and social pressure to develop alternatives to animal models, clearly promoting the search for valid, cost-efficient and easy-to-handle systems lacking interspecies-related differences. In this review, we discuss the current state of the art regarding 3D organ as well as the opportunities, limitations and future implications of their use. PMID- 30395951 TI - A comparison of sighted and visually impaired children's text comprehension. AB - AIM: Do children with visual impairments outperform their sighted cohorts in reading and auditory comprehension tasks? METHODS: We address this question by applying panel regression techniques on a comprehensive sample of 16 children with visual impairments from a Greek special school for students with visual impairments. RESULTS: By comparing the reader comprehender profile for both children types, we find that the children with visual impairments perform better than their sighted counterparts. The better performance is supported both unconditionally and conditionally on idiosyncratic characteristics, such as age, text complexity, modality, sex and reading ability. CONCLUSION: Decomposing the reader comprehender profile into a literal, global and local type of questions we find that the results are mainly driven by the superior performance of the children with VI in the literal questions. PMID- 30395950 TI - Etrolizumab versus infliximab in the treatment of induction phase of ulcerative colitis: A systematic review and indirect comparison. AB - OBJECTIVES: There is still a need to develop new effective medications for the treatment of ulcerative colitis, particularly for patients who are intolerant or resistant to first line therapies. This article compared the efficacy and safety of etrolizumab and infliximab in moderate to severe ulcerative colitis. METHODS: This meta-analysis was performed according to the PRISMA statement protocol. A systematic literature search of three major bibliographic databases (Scopus, PubMed, and Cochran) was performed until June 30, 2018. This review included studies that evaluated the efficacy of etrolizumab or infliximab in ulcerative colitis and were placebo controlled randomized trials. Pooled data from each treatment were indirectly compared using Bucher's method. RESULTS: Seven trials were sufficiently homogeneous to be used for indirect comparison of the induction phase of the treatment. There were no significant differences in clinical remission and serious adverse events between etrolizumab and infliximab. Moreover, adverse events of etrolizumab were significantly less than those of infliximab. However, further trials are required to compare other parameters of efficacy such as the clinical response and mucosal healing of etrolizumab with infliximab in anti-TNF alpha naive patients. PMID- 30395952 TI - Cell-free transcription-translation: engineering biology from the nanometer to the millimeter scale. AB - Cell-free transcription-translation (TXTL) has become a highly versatile technology to construct, characterize and interrogate genetically programmed biomolecular systems implemented outside living organisms. By recapitulating gene expression in vitro, TXTL offers unparalleled flexibility to take apart, engineer and analyze quantitatively the effects of chemical, physical and genetic contexts on the function of biochemical systems, from simple regulatory elements to millimeter-scale pattern formation. Here, we review the capabilities of the current cell-free platforms for executing DNA programs in vitro. We describe the recent advances in programming using cell-free expression, a multidisciplinary playground that has enabled a myriad of novel applications in synthetic biology, biotechnology, and biological physics. Finally, we discuss the challenges and perspectives in the research area of TXTL-based constructive biology. PMID- 30395953 TI - Biopharmaceutical profile of a clotrimazole nanoemulsion: Evaluation on skin and mucosae as anticandidal agent. AB - Clotrimazole (CLT) was formulated in a nanoemulsion (NE) for the topical treatment of candidiasis consisting of 10% labrafac(r) lipophile, 60% labrasol(r):capryol(r) 90 mixture (ratio 4:1) and 30% propylene glycol. Physicochemical properties, stability, rheology, in vitro drug release, ex vivo drug permeation through human skin and porcine buccal, sublingual and vaginal mucosae, antifungal efficacy, as well as in vivo skin tolerance were evaluated. 1% CLT-NE (CLT-NE1) and 2% CLT-NE (CLT-NE2) exhibited 153 +/- 17.25 and 186 +/- 15.38 nm droplet sizes, low polydispersity indexes, negative zeta potentials and biocompatible pH values. The CLT-NEs exhibited typical Newtonian profiles with viscosities of 42.14 +/- 0.037 mPa.s and 41.35 +/- 0.041 mPa.s, respectively and higher extensibility properties than commercial counterparts retaining their physicochemical properties for 180 days. NEs provided a sustained release of drug according to the first order model. Similar skin permeation properties were observed between CLT-NE1 and commercial reference. However, significant higher CLT amounts retained in mucosae were provided by CLT-NE2 when compared with references. Antifungal efficacies were also higher than commercial references, and the in vivo tolerance study confirmed the suitability for topical application, making CLT-NEs a great tool for clinical investigation of topical candidiasis treatments. PMID- 30395954 TI - Optimization of balloon coating process for paclitaxel coated balloons via micro pipetting method. AB - Drug coated balloons (DCBs) have proven to be a suitable alternative for the treatment of cardiovascular diseases. They allow for uniform delivery of an antiproliferative drug to the stenotic site without permanent implantation of the device in the patient's body. There are, however, regulatory concerns regarding the lack of data associated with variable drug delivery to the target site, which can be related to the coating process. This study describes the process for an in house micro-pipetting coating method that incorporates a laboratory-developed coating equation for determining optimal coating parameters. The coating solutions included a common drug of choice, paclitaxel, along with a hydrophilic excipient, such as iopromide. It was found that using a revolution rate of 240 rev/min, a flow rate of 25 uL/min and a translational speed of 0.033 cm/s resulted in visually uniform coatings. High performance liquid chromatography (HPLC) allowed for the determination of paclitaxel content on the balloon surface. Scanning electron microscopy (SEM) enabled analysis of coating thickness and texture at distal, middle, and proximal positions on the balloon; average thicknesses were determined to be 16.4 +/- 5.8, 14.8 +/- 1.4, and 18.1 +/- 3.9 um, respectively. These optimized coating conditions have been confirmed by in vitro drug release kinetics studies. Overall this study generated a simple and reproducible micro-pipetting coating method for the sustained release of drugs from the drug coated balloons. PMID- 30395955 TI - Effect of friction between powder and tooling on the die-wall pressure evolution during tableting: Experimental and numerical results for flat and concave punches. AB - Tablet final properties are mainly determined during the compaction process by the evolution of the stresses applied to the powder. Any process or product parameter that may influence this stress evolution may have a direct impact on the tablet final properties. In this article, we studied the influence of the friction between the tooling and the powder on the evolution of the die-wall pressure during compaction using flat and concave punches. Experimental studies were performed on microcrystalline cellulose as well as numerical studies using finite element method (FEM) simulation. Both methodologies indicate that increasing the friction between the powder and the tooling promotes an increase in the die-wall pressure during tableting. This is in contradiction with results that can be found in the literature. Moreover, the results of this study showed that for flat punches, the stress evolution is mainly driven by the die/powder friction. On the contrary, for concave punches, changing the punches/powder friction have also a consequence in the evolution of the die-wall pressure. This could have practical consequences in sticking situations where, due film formation on the punches, the friction between the punches and the powder may change during tableting. PMID- 30395956 TI - Effect of solvent selection on drug loading and amorphisation in mesoporous silica particles. AB - Increasing the dissolution rate of poorly water-soluble active pharmaceutical ingredients (APIs) is a key strategy used for improving their oral bioavailability. One of the formulation approaches is API loading to mesoporous carrier particles, which can increase the dissolution rate through the combination of improved powder wettability and dispersion, higher surface area, and API conversion from crystalline to the amorphous state. From the formulation process point of view, the maximum achievable drug loading is a crucial parameter, which depends on the loading method. Drug loading by sorption from a solution is a technologically attractive approach, since it involves familiar unit operations (mixing, filtration, drying). However, the success of the equilibrium sorption approach depends on the choice of the solvent. In this work we present an experimental study of loading efficiency to mesoporous silica particles, based on a set of 10 APIs combined with 6 different solvents at a range of concentrations. We show that due to the competitive nature of the adsorption process, the solvent with the highest API solubility is not necessarily the best candidate for maximising the API loading. Based on the investigated drug-solvent combinations, we show that the dielectric constant of the solvent is a good predictor of loading efficiency and can be used as a general guideline for solvent selection. On the other hand, we did not find any systematic correlation between commonly measured API properties such as logP and their loading efficiency. PMID- 30395957 TI - Variability in the alpha and beta anomer content of commercially available lactose. AB - Lactose, a disaccharide is a ubiquitous excipient in many pharmaceutical formulations which exists in two anomeric forms; either as alpha- or beta lactose. The anomers have different properties which can affect their application. Nevertheless, batches of lactose products are widely produced by many manufacturers, and is available in many grades. However, the anomeric content of these batches has not been accurately characterized and reported previously. Therefore, the aim of this study was to analyse a set of 19 commercially available samples of lactose using a novel H1-NMR technique to establish a library showing the anomeric content of a large range of lactose products. The lactose samples were also analysed by DSC. The anomeric content of the alpha-lactose monohydrate samples were found to vary by more than 10%, which might influence bioavailability from final formulations. The data showed that there is a need to determine and monitor the anomeric content of lactose and this should be a priority to both the manufacturers and the formulators of medicines. PMID- 30395958 TI - Enhanced topical delivery of non-complexed molecular iodine for Methicillin resistant Staphylococcus aureus decolonization. AB - Staphylococcus aureus, a leading cause of serious human infections in both healthcare and community settings, is increasingly difficult to control due to expanding resistance to multiple antibiotic classes. Methicillin-resistant S. aureus (MRSA) strains have disseminated on a global scale and are associated with adverse patient outcomes, increased hospital stays, and significant economic costs to the healthcare system. A proximal step in S. aureus infection is colonization of the nasal mucosa, and effective strategies to decolonize high risk patients to reduce the risk of invasive infection and nosocomial spread represent an important clinical priority. With rising resistance to mupirocin, the most common antibiotic utilized for nasal MRSA decontamination, we are examining the use of pure molecular iodine (I2)-based formulations for this indication. Recently, an iodophor formulation of povidone-iodine (PVP-I) has shown significant promise for nasal MRSA decontamination by swabbing the anterior nares of patients in hospital settings, but the I2 concentration in this treatment is less than 0.01% of total iodine species present and like all providone-iodine formulations causes skin staining. Here we determine that a novel non-staining formulation of I2 combined with the safe organic emollient glycerin delivers high local concentrations of the active antimicrobial entity (I2) with minimal evaporative loss, exhibits activity at ~1 part per million against MRSA and other important Gram-positive and -negative human pathogens. This formulation for I2 topical delivery produced similar reductions in mean bacterial burden and was associated with fewer treatment failures (<2-logfold reduction) than PVP-I in a murine model of MRSA nasal decontamination. Formulations of I2 in glycerin emollient merit further exploration as topical disinfectants for human medical indications. PMID- 30395959 TI - Formulation of aripiprazole-loaded pH-modulated solid dispersions via hot-melt extrusion technology: In vitro and in vivo studies. AB - The objective of this study was to formulate aripiprazole (ARI)-loaded pH modulated solid dispersions (SD) to enhance solubility, dissolution, and bioavailability via hot-melt extrusion (HME) technology. Kollidon(r) 12 PF (PVP) and succinic acid (SA) were selected after solubility screenings of various polymers and acidifiers. Several formulations, varying in screw speed and drug/polymer/acidifier ratios, were extruded using an 11 mm twin-screw extruder and were investigated for the effect of these variables. Scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) were used to perform solid-state characterizations of the pure drug and extrudates. The aqueous solubility and dissolution were evaluated for the pure drug and milled extrudates. Among the prepared formulations, N6 was chosen for in vivo absorption studies. Solid-state characterization demonstrated the transformation of the crystalline ARI to an amorphous state in the formulations. Each formulation showed increased solubility and dissolution compared to the drug powder. The oral bioavailability (Cmax and AUC0-12) of N6 was significantly improved when compared to the pure ARI. This novel study not only discusses the incorporation of acidifiers in SDs but also the preparation of SDs using HME technology as effective techniques to improve drug release and bioavailability. PMID- 30395961 TI - Prolonged pain reducing effect of Sodium Hyaluronate-CarboxyMethyl Cellulose solution in the Selective Nerve Root Block(SNRB) of lumbar radiculopathy: A Prospective, Double-Blind, Randomized Controlled Clinical Trial. AB - BACKGROUND: The pattern of linear graph schematized by visual analogue scale (VAS) score displaying pain worsening between 2 days and 2 weeks after selective nerve root block is called rebound pain. PURPOSE: The purpose of this study was to determine if sodium hyaluronate and carboxymethyl cellulose solution(HA-CMC sol) injection could reduce the occurrence of rebound pain at 3 days to 2 weeks after selective nerve root block in patients with radiculopathy compared to injection with corticosteroids and local anesthetics alone. STUDY DESIGN/SETTING: Double blinded randomized controlled clinical trial. PATIENT SAMPLE: A total of 44 patients (23 of 24 patients in the Guardix group and 21 of 24 patients in the control group) who finished the follow-up session were subjects of this study. OUTCOME MEASUREMENT: Patients were asked to write down their average VAS pain scores daily for 12 weeks. Functional outcomes were assessed by Oswestry Disability Index (ODI), Roland Morris Disability Questionnaire (RMDQ), and SF-36. METHOD: A cocktail of corticosteroids, 1% lidocaine, 0.5% Bupivacaine, and 1 ml of normal saline was used for the control group while a cocktail of corticosteroids, 1% lidocaine, 0.5% Bupivacaine, and 1 ml of HA-CMC solution was used for the G group. Study participants were randomized into one of two treatment regimens. They were followed up for three months. RESULTS: VAS score at 2 weeks after the procedure was 4.19 +/- 1.32 in the control group, which was significantly (p < 0.05) higher than that (2.43 +/- 1.24) in the G group. VAS score at 6 weeks after the procedure was 4.00 +/- 1.23 in the control group and 3.22 +/- 1.45 in the G group, showing no significant (p = 0.077) difference between the two groups. There were no significant differences in functional outcomes at 6 or 12 weeks after the procedure. CONCLUSIONS: Compared to conventional cocktail used for SNRB, addition of HA-CMC sol showed effective control of rebound pain at 3 days to 2 weeks after the procedure. PMID- 30395960 TI - The impact of health literacy on health status and resource utilization in lumbar degenerative disease. AB - BACKGROUND CONTEXT: Health literacy, defined as "the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions," has been demonstrated to affect access to care and appropriate healthcare utilization. PURPOSE: To determine the impact of health literacy in the evaluation and management of patients with chronic low back pain. STUDY DESIGN: Cross sectional. PATIENT SAMPLE: Patients seen at a multisurgeon spine specialty clinic. OUTCOME MEASURES: Oswestry Disability Index, EQ-5D, and Numeric Rating Scales (0-10) for back and leg pain. METHODS: The Newest Vital Sign (NVS) and Health Literacy Survey, Oswestry Disability Index, EQ-5D and pain scales were administered to patients undergoing evaluation and treatment for lumbar degenerative disease in the outpatient setting. Patients were surveyed regarding their use of medication, therapy, and pain management modalities. RESULTS: Of 201 patients approached for participation, 186 completed the health literacy surveys. Thirty (17%) were assessed as having limited literacy, 52 (28%) as possibly having limited literacy and 104 (56%) having adequate literacy based on their NVS scores. The cohort with low NVS scores also had low Health Literacy Survey Scores. Patients with limited literacy had worse back and leg pain scores compared with patients with possibly limited literacy and adequate literacy. Patients with adequate health literacy were more likely to use medications (80% vs. 53%, p = .017) and were more likely to see a specialist (34% vs. 17%) compared with those with limited literacy. Patients with limited health literacy were not more likely to see a chiropractor (7% vs. 7%), but reported more visits (19 vs. 8). CONCLUSIONS: Patients with lower health literacy reported worse back and leg pain scores, indicating either more severe disease or a fundamental difference in their responses to standard health-related quality of life measures. This study also suggests that patients with limited health literacy may underutilize some resources and overutilize other resources. Further study is needed to clarify these patterns, and to examine their impact on health status and clinical outcomes. PMID- 30395962 TI - In vivo self-assembly of small diameter pulmonary visceral pleura artery graft. AB - BACKGROUND: There is a significant clinical need for small vascular grafts <1 mm in diameter. MATERIALS AND METHODS: The structure and composition of swine pulmonary visceral pleura (PVP) were investigated. Two processes, glutaraldehyde (GA) crosslink and decellularization (dc) plus GA crosslink, were used to inhibit the immune response. The thrombosis-resistance of the GA-crosslinked PVP (GA-PVP) was determined with in vitro and in vivo studies. Small vessel grafts with 0.7 diameter mm were constructed using the GA-PVP and surgically interposed in the femoral artery of rats for up to 24 weeks. Blood flow in the GA-PVP grafts were measured and ex vivo vascular reactivity of the prostheses were evaluated along with immuno-histological analysis. RESULTS: The GA-PVP mesothelium contains abundant glycocalyx-like substance and a smooth surface. The mechanical properties of the GA-PVP were similar to the femoral artery of rat in the range of physiological pressures. The in vitro and in vivo studies confirmed poor platelet adhesion on the GA-PVP mesothelial surface in comparison with dc processed PVP (dc-PVP). Patency of the GA-PVP prostheses in femoral arteries of rats was 86% in the 24 weeks postoperative period while patency of dc-PVP in femoral arteries of rats was 33% at 1 week postoperative period. Blood flow in the GA-PVP prostheses were not statistically different than the contralateral femoral artery. Biomarkers of neo-endothelial cells, neo-media smooth muscle cells, and extracellular matrices were observed in the GA-PVP prostheses. The significant agonists-induced vasoconstriction and endothelium-dependent vasodilation were apparent at 12 weeks and further amplified in the 24 weeks postoperative, which suggests self-assembly of functional neo-endothelium and neo media. CONCLUSIONS: The high patency and functionality of the small grafts suggest that the GA-PVP is a promising prosthetic biomaterial for vascular reconstructions. STATEMENT OF SIGNIFICANCE: Small artery graft (diameter <1 mm) in the peripheral circulation that functionally arterializes has not been possible primarily due to thrombosis. Our findings indicate that lung visceral pleura may address thrombogenicity as the major pitfall in small diameter grafts. Here, grafts of 0.7 mm diameter were constructed from swine pulmonary visceral pleura (PVP) and implanted into femoral artery position of rats up to 24 weeks. The total patency of grafts in femoral arteries of rats was 86% in the 24-week period. The neo-endothelial and -medial layers were assembled in the grafts as evidenced by robust biomarkers of endothelial cells, smooth muscle cells, and extracellular matrices observed in the grafts. Agonists-induced vasoconstriction and endothelium-dependent vasodilation were apparent at 12 weeks and were amplified at 24 weeks. The high patency of the small grafts suggests that the PVP is a promising prosthetic biomaterial for vascular reconstructions. PMID- 30395963 TI - A stabilized retro-inverso peptide ligand of transferrin receptor for enhanced liposome-based hepatocellular carcinoma-targeted drug delivery. AB - The application of tumor targeting ligands to the treatment of cancer holds promise for improving efficacy and reducing toxicity. LT7 (L(HAIYPRH)) peptide, a phage display-selected peptide, exhibited high binding affinity to transferrin receptor (TfR) overexpressed on tumor cells. However, its in vivo tumor targeting efficiency was impaired due to enzymatic degradation in blood circulation. To improve the stability and targeting ability, a retro-inverso analogue of LT7 peptide, named DT7 peptide (D(HRPYIAH)), was designed for targeted therapy of hepatocellular carcinoma. The result of computer simulation predicted that DT7 bound to TfR protein more efficiently than LT7, and this prediction was confirmed experimentally by surface plasmon resonance (SPR). Ex vivo stability experiment demonstrated that DT7 possessed stronger ability against proteolysis than LT7 in fresh mouse serum. We further prepared DT7-, LT7-, and transferrin (Tf)-modified liposomes (DT7-LIP, LT7-LIP, and Tf-LIP, respectively). DT7-LIP showed a significantly stronger in vitro targeting ability than LT7-LIP and Tf-LIP under normal condition and simulated biological condition. In addition, the in vitro antitumor effect of DTX-loaded DT7-LIP was markedly enhanced in comparison to DTX loaded LT7-LIP and DTX-loaded Tf-LIP. In vivo imaging indicated that DT7-LIP had better tumor accumulation than LT7-LIP and Tf-LIP. For in vivo antitumor studies, the tumor growth rate of mice treated with DTX-loaded DT7-LIP was significantly inhibited compared to that in mice treated with DTX-loaded LT7-LIP and DTX-loaded Tf-LIP. Overall, this study verified the potential of the stable DT7 peptide in improving the efficacy of docetaxel in the treatment of hepatocellular carcinoma. STATEMENT OF SIGNIFICANCE: A phage display library-selected LT7 (L(HAIYPRH)) peptide exhibited high affinity to transferrin receptor (TfR). However, its bioactivity was impaired in vivo as L-peptides are susceptible to degradation by proteolytic enzymes. Here, we designed a retro-inverso peptide DT7(D(HRPYIAH)) and demonstrated its increased serum stability and higher binding affinity to TfR. A stabilized targeted drug delivery system was further constructed by modified DT7 peptide on the surface of liposomes. The data indicated that DT7 peptide-modified liposomes exhibited higher targeting ability in vitro and in vivo. More importantly, DT7-modified liposomes demonstrated positive preclinical significance in enhancing the therapeutic effects against hepatocellular carcinoma. PMID- 30395964 TI - Tetralogy of Fallot in the Current Era. AB - Only few studies have reported long-term outcome of the transatrial transpulmonary approach in the current era of management of tetralogy of Fallot (ToF). We investigated 15-year outcome of correction via a transatrial transpulmonary approach in a large cohort of successive patients operated in the 21st century. All infant ToF patients undergoing transatrial-transpulmonary ToF correction between 2000 and 2015 were included (N = 177, 106 male, median follow up 7.1 (interquartile range 3.0-10.9) years. Data regarding postoperative complications, reinterventions, development of atrial and ventricular arrhythmia, cardiac function, and survival were evaluated. Prior shunting was performed in 10 patients (6%). The transatrial-transpulmonary approach resulted in valve-sparing surgery in 57 patients (32%). Postoperative surgical complications included junctional ectopic tachycardia (N = 12, 7%), pericardial (N = 10, 6%) or pleural effusion (N = 7, 3%), chylothorax (N = 7, 4%), bleeding requiring reoperation (N = 4, 3%), and superficial wound infection (N = 1). Fifty-one patients underwent 68 reinterventions, mainly due to pulmonary restenosis (PS) (N = 57). ToF correction at age <2 months and double outlet or double-chambered right ventricle variants of the ToF spectrum were independent predictors for reintervention. Patients undergoing valve-sparing ToF correction had a significant longer PR-free survival than those with a transannular patch (8.5 [95% confidence interval 6.8 10.3] years vs 1.1 [95% confidence interval 0.8-1.5] years; P < 0.001). Overall mortality was 2.8%; mortality rates were higher in premature/dysmature newborns (0.7% vs 9.5%; P < 0.001). Although the 15-year outcome of the transatrial transpulmonary approach in terms of postoperative complications and mortality rates is excellent, the high incidence of moderate and severe PR is worrisome. Valve-sparing surgery was associated with a substantially lower incidence of PR, yet was surgically not possible in the majority of patients. PMID- 30395966 TI - Bispecific T-cell engagers: Towards understanding variables influencing the in vitro potency and tumor selectivity and their modulation to enhance their efficacy and safety. AB - Bispecific molecules redirecting the cytotoxicity of T-cells are a growing class of therapeutics with numerous molecules being tested in clinical trials. However, it has been a long way since the proof of concept studies in the mid 1980's. In the process we have learnt about the impact of different variables related to the bispecific molecule and the target antigen on the potency of this type of drugs. This work reviews the insights gained and how that knowledge has been used to design more potent bispecific T-cell engagers. The more recent advancement of antibodies with this modality into safety studies in non-human primates and as well as in clinical studies has revealed potential toxicity liabilities for the mode of action. Modifications in existing antibody formats and new experimental molecules designed to mitigate these problems are discussed. PMID- 30395965 TI - Effect of Perioperative Neuromuscular Electrical Stimulation in Patients Undergoing Cardiovascular Surgery: A Pilot Randomized Controlled Trial. AB - A randomized, controlled trial was conducted to examine the effects of perioperative neuromuscular electrical stimulation on muscle proteolysis and physical function using blinded assessment of physical function. Consecutive patients undergoing cardiovascular surgery were screened for eligibility as study subjects. Participants were randomly assigned to receive either neuromuscular electrical stimulation or the usual postoperative mobilization program. The intervention group received neuromuscular electrical stimulation on bilateral legs 8 times before and after surgery. The primary outcomes were the mean 3 methylhistidine concentration corrected for urinary creatinine content from baseline to postoperative day 6, and knee extensor isometric muscle strength on postoperative day 7. Secondary outcomes were usual walking speed and grip strength. Physical therapists blinded to patient allocation performed measurements of physical function. Of 498 consecutive patients screened for eligibility, 119 participants (intervention group, n = 60; control group, n = 59) were enrolled. In the overall subjects, there were no differences in any outcomes between the intervention and control groups. The results demonstrated no significant effects of neuromuscular electrical stimulation on muscle proteolysis and physical function after cardiovascular surgery, suggesting the need to explore indications for neuromuscular electrical stimulation and to clarify the effects in terms of the dose-response relationship. PMID- 30395967 TI - Surpassing limits of static RNA modification analysis with dynamic NAIL-MS. AB - Ribonucleic acids (RNA) are extensively modified. These modifications are quantified by mass spectrometry (LC-MS/MS) to determine the abundance of a modification under certain conditions or in various genetic backgrounds. With LC MS/MS the steady state of modifications is determined, and thus we only have a static view of the dynamics of RNA modifications. With nucleic acid isotope labeling coupled mass spectrometry (NAIL-MS) we overcome this limitation and get access to the dynamics of RNA modifications. We describe labeling techniques for E. coli, S. cerevisiae and human cell culture and the current instrumental limitations. We present the power of NAIL-MS but we also outline validation experiments, which are necessary for correct data interpretation. As an example, we apply NAIL-MS to study the demethylation of adenine and cytidine, which are methylated by the damaging agent methyl-methanesulfonate in E. coli. With NAIL-MS we exclude the concurrent processes for removal of RNA methylation, namely RNA degradation, turnover and dilution. We use our tool to study the speed and efficiency of 1-methyladenosine and 3-methylcytidine demethylation. We further outline current limitations of NAIL-MS but also potential future uses for e.g. relative quantification of tRNA isoacceptor abundances. PMID- 30395968 TI - Unraveling 3'-end RNA uridylation at nucleotide resolution. AB - Post-transcriptional modification of RNA, the so-called 'Epitranscriptome', can regulate RNA structure, stability, localization, and function. Numerous modifications have been identified in virtually all classes of RNAs, including messenger RNAs (mRNAs), transfer RNAs (tRNAs), ribosomal RNAs (rRNAs), microRNAs (miRNAs), and other noncoding RNAs (ncRNAs). These modifications may occur internally (by base or sugar modifications) and include RNA methylation at different nucleotide positions, or by the addition of various nucleotides at the 3'-end of certain transcripts by a family of terminal nucleotidylyl transferases. Developing methods to specifically and accurately detect and map these modifications is essential for understanding the molecular function(s) of individual RNA modifications and also for identifying and characterizing the proteins that may read, write, or erase them. Here, we focus on the characterization of RNA species targeted by 3' terminal uridylyl transferases (TUTases) (TUT4/7, also known as Zcchc11/6) and a 3'-5' exoribonuclease, Dis3l2, in the recently identified Dis3l2-mediated decay (DMD) pathway - a dedicated quality control pathway for a subset of ncRNAs. We describe the detailed methods used to precisely identify 3'-end modifications at nucleotide level resolution with a particular focus on the U1 and U2 small nuclear RNA (snRNA) components of the Spliceosome. These tools can be applied to investigate any RNA of interest and should facilitate studies aimed at elucidating the functional relevance of 3' end modifications. PMID- 30395969 TI - Pandemic Escherichia coli ST648 isolate harbouring fosA3 and blaCTX-M-8 on an IncI1/ST113 plasmid: A new successful combination for the spread of fosfomycin resistance? AB - OBJECTIVES: The emergence of Enterobacteriaceae isolates resistant to the last resort antibiotic fosfomycin outside of Asia is a public-health issue. Here we report the draft genome of an Escherichia coli isolate presenting both an extended-spectrum beta-lactamase (ESBL) and the fosA3 gene in a healthy cow in Brazil. METHODS: Whole genomic DNA from E. coli E12 was extracted and 2*150-bp paired-end reads were generated using Illumina sequencing technology. De novo genome assembly was performed using SPAdes v.3.11 and the draft genome was annotated by the NCBI Prokaryotic Genome Annotation Pipeline. Further analyses were performed using the Center for Genomic Epidemiology databases. RESULTS: The 5045934-bp genome displayed several resistance genes, including the fosA3 and blaCTX-M-8 genes. Southern blot experiments showed that they were co-located on an IncI1/ST113 plasmid. CONCLUSION: Presence of the fosA3 gene on the same common plasmid as blaCTX-M-8 will have to be monitored. This draft genome provides data that will help in tracing the dissemination of this gene and the evolution of its plasmidic support. PMID- 30395970 TI - Temporal and spatial changes of peroxiredoxin 2 levels in aortic media at very early stages of atherosclerotic lesion formation in apoE-knockout mice. AB - The events that trigger early onset of atherosclerotic lesion formation are poorly understood. Initially, microscopic atherosclerotic lesions appear in the aortic root in 10-week-old apoE-knockout mice that are fed normal chow. Using proteome and immunohistochemical analyses, we investigated proteins in aortic media whose expression changes in athero-prone regions at the beginning of lesion formation. Protein profiles of the root/arch and thoracic/abdominal regions of aortas in 10-week-old apoE-knockout mice were analyzed using 2D-gel electrophoresis. Proteins in 81 spots with different abundance were identified. Among them, we focused on proteins related to oxidative stress and smooth muscle cells (SMCs). The level of peroxiredoxin 2 (Prx2), a major cellular antioxidant enzyme that reduces hydrogen peroxide, was lower in aortic root/arch compared with thoracic/abdominal aorta. Immunohistochemical staining demonstrated that Prx2 expression in SMCs in the aortic root was high at 4 weeks and decreased at 10 weeks in apoE-knockout mice, while Prx2 expression in the aorta was unchanged in wild-type mice. The level of Prx2 expression correlated positively with the SMC differentiation markers, alpha-smooth muscle actin and transgelin, suggesting that a decline in Prx2 expression accompanies SMC dedifferentiation. Accumulated acrolein-modified proteins and the infiltration of macrophages in aortic media were observed in areas with low Prx2 expression. These results showed that Prx2 expression declines in athero-prone aortic root before lesion formation, and this reduction in Prx2 expression correlates with lipid peroxidation, SMC dedifferentiation, and macrophage recruitment. PMID- 30395971 TI - Intensified mitophagy in skeletal muscle with aging is downregulated by PGC 1alpha overexpression in vivo. AB - Mitochondrial dysfunction plays an important role in the etiology of age-related muscle atrophy known as sarcopenia. PGC-1alpha is positioned at the center of crosstalk in regulating mitochondrial quality control, but its role in mitophagy in aged skeletal muscle is currently unclear. The present study investigated the effects of aging and PGC-1alpha overexpression via in vivo DNA transfection on key mitophagy protein markers, as well as mitochondrial dynamics related proteins, metabolic function and antioxidant capacity in mouse muscle. C57BL/6J mice at the age of 2 mo (young, Y; N = 14) and 24 mo (old, O; N = 14) were transfected in vivo with either PGC-1alpha DNA (OE, N = 7) or GFP (N = 7) into the tibialis anterior (TA) muscle followed by electroporation. PINK1 and Parkin protein contents were 3.6 and 1.4-fold higher (P < 0.01), whereas mitochondrial ubiquitination (Ub) increased 1.5-fold (P < 0.05), in O vs. Y mice. PGC-1 OE suppressed PINK and Parkin protein levels by 50-60% (P < 0.01), and decreased Ub by 20% (P < 0.05) in old mice. Aging significantly increased the protein content of LC3II (30%, P < 0.05), p62 (42%, P < 0.05), RheB (5.5-fold, P < 0.01), Beclin 1 (3-fold, P < 0.01) and Mfn2 (~4-fold, P < 0.01) in the TA muscle. However, these age-related increases in mitophagy markers were attenuated by PGC-1alpha OE. Furthermore, aging dramatically increased Fis-1 protein content by 14-fold (P < 0.01), along with a severe reduction of citrate synthase activity (64%, P < 0.01) and cytochrome c oxidase subunit IV (COXIV) protein content (85%, P < 0.01). PGC-1alpha OE mitigated the age effects on Fis-1 and Drp-1 (P < 0.05). Moreover, PGC-1alpha OE enhanced mitochondrial oxidative function and antioxidant enzyme activities, and decreased lipid peroxidation and inner membrane damage found in old mice (P < 0.01). In summary, our data demonstrate that mitophagy protein expression in skeletal muscle was enhanced at old age driven possibly by increased mitochondrial dysfunction, damage, and fission. PGC-1alpha OE was effective in ameliorating mitochondrial deficits but did not restore muscle fiber atrophy. PMID- 30395972 TI - Quantitative proteomics reveals mitochondrial respiratory chain as a dominant target for carbon ion radiation: Delayed reactive oxygen species generation caused DNA damage. AB - Heavy ion radiotherapy has shown great promise for cancer therapy. Understanding the cellular response mechanism to heavy ion radiation is required to explore measures of overcoming devastating side effects. Here, we performed a quantitative proteomic analysis to investigate the mechanism of carbon ion irradiation on human AHH-1 lymphoblastoid cells. We identified 4602 proteins and quantified 4569 proteins showing high coverage in the mitochondria. Data are available via ProteomeXchange with identifier PXD008351. After stringent filtering, 290 proteins were found to be significantly up-regulated and 16 proteins were down-regulated. Functional analysis revealed that these up regulated proteins were enriched in the process of DNA damage repair, mitochondrial ribosome, and particularly mitochondrial respiratory chain, accounting for approximately 50% of the accumulated proteins. Bioinformatics and functional analysis demonstrated that these up-regulated mitochondrial respiratory chain proteins enhanced ATP production and simultaneously reactive oxygen species release. More importantly, increased reactive oxygen species led to secondary organelle injury and lagged DNA double-strand breaks. Consistently, the expression of antioxidant enzymes was up-regulated for free radical scavenging. The mechanism of lagged secondary injury originated from disturbances in the mitochondrial respiratory chain. Our results provided a novel target for cell self-repair against heavy ion radiation-induced cellular damage. PMID- 30395973 TI - Validation of a food frequency questionnaire assessing dietary polyphenol exposure using the method of triads. AB - When conducting research on polyphenols and their effects on health, it is of primary importance to use standardised and validated dietary assessment tools. This paper aims at assessing the validity of a food frequency questionnaire (FFQ) for quantifying dietary polyphenol exposure among healthy adults using the method of triads. Fifty-three healthy adults, aged 20-60, were included in the study. Total dietary polyphenol intake (TDP) estimated by the FFQ was compared with TDP measured by a 3-day food record (FR) and with urinary excretion levels of total polyphenols (TUP). Pearson correlations were calculated between methods. Validity coefficients (VC) were estimated between the three measurements and the 'unknown' true intake. There was a strong correlation between both dietary methods (r = 0.70, p < 0.0001). A moderate but significant association was observed between FFQ-derived TDP and TUP (r = 0.32, p = 0.020). The method of triads yielded a VC for the FFQ of 0.63 (95%CI: 0.41-0.84), indicating a strong relationship between FFQ-derived TDP and the true polyphenol intake. This study shows that the FFQ is an adequate tool not only for measuring dietary polyphenol exposure in nutrition epidemiological studies but also for guiding clinicians in dietary advice and counselling. PMID- 30395974 TI - Less Than Whole Uterus Irradiation for Locally Advanced Cervical Cancer Maintains Locoregional Control and Decreases Radiation Dose to Bowel. AB - OBJECTIVE: This study aimed to evaluate whether our institutional standard of less-than-whole-uterus irradiation affects locoregional control in patients with locally advanced cervical cancer. METHODS AND MATERIALS: We retrospectively reviewed 53 patients with stage IB to IVB cervical carcinoma who were treated with image guided intensity modulated radiation therapy and brachytherapy. The entire uterus was not included in the clinical target volume, as per our institutional standard. Dosimetric parameters were obtained, including positron emission tomography gross tumor volume (GTV), uterus volume excluding GTV, proportion of uterus included in the planning target volume (PTV; percentage), volume of overlap between uterus and prescription dose (cm3), minimum and mean dose to the uterus, and bowel V40 and D200cc. Local, regional, and distant failure and death were recorded. RESULTS: The median proportion of the uterus included in the PTV was 66%. With a median follow-up of 44 months, no patient experienced isolated local recurrence, and 2-year locoregional failure was 10.9%. Positron emission tomography GTV correlated significantly with increased chance of any failure (P = .049; 95% confidence interval, 1.000-1.018). Compared with patients who had >=90% of the uterus included in the PTV (n = 12), patients who had <90% (n = 41) of the uterus included in the PTV had significantly lower bowel V40 (P = .049) and D200cc (P = .006). CONCLUSIONS: Less-than-whole-uterus irradiation for locally advanced cervical cancer does not compromise locoregional control and reduces bowel V40 and D200cc. Further investigation is required to evaluate whether this reduction in bowel dose translates to a clinically significant reduction in bowel toxicity and whether modifications should be made to the recommended definitive cervix intensity modulated radiation therapy volumes. PMID- 30395975 TI - Anti-inflammatory action of an alkaloid, fraction and extract from Alchornea glandulosa in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Alchornea glandulosa (Euphorbiaceae) has traditionally been used in medicine for treating immune-mediated inflammatory diseases. AIM OF STUDY: This work aimed to evaluate the anti-inflammatory effects of a methanolic extract of leaves from A. glandulosa (MEAG), as well as the ethyl acetate fraction (EAFAG) and isolated compound guanidine alkaloid N-1, N-2, N-3 triisopentenylguanidine (AG-1), in experimental in vivo models of inflammation in mice. We also investigated this extract's phenols, flavonoids and flavonol compounds. MATERIALS AND METHODS: MEAG (extracted by maceration with methanol), EAFAG (fraction resulting from the partition of the methanolic extract with ethyl acetate) and AG-1 (alkaloid isolated by chromatographic methods) were analysed. MEAG and EAFAG were analysed by HPLC/DAD. The effects of MEAG (30, 100 and 300 mg/kg), EAFAG (30, 100 and 300 mg/kg) and AG-1 (5 and 30 mg/kg) were studied in the following experimental mouse models: paw oedema and myeloperoxidase (MPO) activity, croton-oil-induced ear oedema, leukocyte migration in a pleurisy model induced by carrageenan and zymosan induction of joint inflammation. RESULTS: MEAG and EAFAG were analysed by LC/DAD, and phenolic acids (gallic acid and caffeic acid) and flavonoids (myricetin-3-O-alpha-rhamnopyranoside and quercetin) were detected. MEAG, EAFAG and AG-1 were used in the carrageenan-induced paw oedema model and showed maximum inhibitions of 60.10% (MEAG, 2 h, 300 mg/kg) and 66.21% (EAFAG, 2 h, 300 mg/kg). AG-1 at 5 mg/kg showed significant inhibition, ranging from 60.92% to 63.13%, at all evaluated times, and the 30 mg/kg dose showed inhibition of 42.12% (1 h) and 40.36% (2 h). MEAG (37%, 46.1% and 68.11%) and EAFAG (31%, 42.21% and 48.93%), at doses of 30, 100 and 300 mg/kg, respectively, significantly reduced the increase in MPO activity, and AG-1 (5 and 30 mg/kg) showed inhibition of 64.62% and 65.12%, respectively. In the pleurisy model, MEAG (300 mg/kg), EAFAG (300 mg/kg) and AG-1 (30 mg/kg) significantly reduced the migration of total leukocytes with maximal inhibition of 80.90%, 83.17% and 89.39%, respectively. In the croton oil model, pretreatment with MEAG (0.1, 0.3 and 1 mg/ear) increased the diameter of the right ear (30.32%, 48.87% and 53.09%, respectively). Finally, MEAG (100 and 300 mg/kg; 33.11% and 56.03%) and EAFAG (100 and 300 mg/kg; 36.89% and 50.53%) reduced zymosan-induced oedema formation. CONCLUSIONS: To the best of our knowledge, these results are the first to demonstrate that A. glandulosa exhibits oral and topical anti-inflammatory activity. This study detected alkaloid and phenol/polyphenolic compounds in A. glandulosa, which may help to explain the ethnobotanical use of this plant in traditional medicine in Brazil to treat immune-mediated inflammatory diseases. PMID- 30395976 TI - Sparassis crispa exerts anti-inflammatory activity via suppression of TLR mediated NF-kappaB and MAPK signaling pathways in LPS-induced RAW264.7 macrophage cells. AB - ETHNOPHARMACOLOGY RELEVANCE: Sparassis crispa, also known as cauliflower mushroom, has been used historically in traditional Asian medicine. It possesses various biological activities, such as immunopotentiation, anti-diabetes, anti cancer, and anti-inflammatory effects. Recently, we isolated the non-aqueous fraction from methanol extract of S. crispa (SCF4) by using water-organic solvent mixtures and high-performance liquid chromatography (HPLC). In the present study, we identified the anti-inflammatory activity and action mechanism of SCF4 in lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophage cells. MATERIALS AND METHODS: The chloroform layer isolated from S. crispa methanol extract was separated into seven fractions using preparative HPLC. The fractions were then applied to NO assay to identify the fraction with the best anti-inflammatory activity. The inflammation inhibitory effect and underlying mechanism of SCF4 in LPS-stimulated RAW264.7 cells were assessed using WST-1 assay, enzyme-linked immunosorbent assay (ELISA), ROS assay, and Western blot analysis. RESULTS: SCF4 significantly suppressed LPS-induced production of pro-inflammatory mediators, such as nitric oxide (NO) and prostaglandin E2 (PGE2), and pro-inflammatory cytokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)- 6, and IL-1beta, without cytotoxicity. In addition, SCF4 downregulated not only the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX 2), but also the activation of nuclear factor-kappa B (NF-kappaB) and mitogen activated protein kinases (MAPKs) stimulated by LPS. SCF4 also blocked the nuclear translocation of NF-kappaB via reduction of inhibitor of kappaB alpha (IkappaBalpha) degradation. Furthermore, SCF4 inhibited the phosphorylation of transforming growth factor beta-activated kinase 1 (TAK1), an important upstream factor of NF-kappaB and MAPK signaling mediated through toll-like receptor (TLR). CONCLUSIONS: These findings demonstrate for the first time the correlation between the anti-inflammatory activity of SCF4 and TLR-mediated NF-kappaB and MAPK signaling pathways in LPS-stimulated RAW264.7 macrophage cells, suggesting that the non-aqueous extract of S. crispa could be applied as a promising natural product for the prevention and treatment of inflammatory diseases. PMID- 30395977 TI - Aspidosperma species: A review of their chemistry and biological activities. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Species of Aspidosperma are known popularly as "peroba, guatambu, carapanauba, pau-pereiro" and "quina". The genus can be found in the Americas, mainly between Mexico and Argentina. Many species of Aspidosperma are used by the population in treating cardiovascular diseases, malaria, fever, diabetes and rheumatism. The phytochemical aspects of the species of the genus Aspidosperma have been studied extensively. The monoterpene indole alkaloids are the main secondary metabolites in Aspidosperma species, and about 250 of them have been isolated showing a considerable structural diversity. Several of them have showed some important pharmacological activities. Aspidosperma subincanum Mart. and Aspidosperma tomentosum Mart. (Apocynaceae) are Brazilian species widely used by the population to treat diabetes mellitus, hypercholesterolemia. The pharmacological activities of both species have been investigated and the biological properties described can be related to their isolated indole alkaloids. However, more pharmacological studies are needed in order to justify the use of these species in folk medicine. In this review, we present reports mainly focused on chemical and biological studies and their relationship with the ethnopharmacological use of both Aspidosperma species. AIM OF THE STUDY: The aim of this review is to present their ethnopharmacological use as correlated to their biological activities as described for the extracts and isolated compounds from Aspidosperma subincanum Mart. and Aspidosperma tomentosum Mart. In addition, some aspects related to the biosynthetic pathways are discussed, also NMR assignments and some synthesis information about indole alkaloids from both Aspidosperma species are included. MATERIAL AND METHODS: The bibliographic search was made in theses and dissertations using some databases such as NDLTD (Networked Digital Library of Theses and Dissertations), OATD (Open Access Theses and Dissertations) and Google Scholar. More data were gathered from books, Brazilian journals and articles available on electronic databases such as, Google Scholar, PubChem, Scifinder, Web of Science, SciELO, PubMed and Science Direct. Additionally, the Google Patents and Espacenet Patent Search (EPO) were also consulted. The keywords Aspidosperma, A. subincanum, A. tomentosum, indole alkaloids were used in the research. The languages were restricted to Portuguese, English and Spanish and references were selected according to their relevance. RESULTS: A. subincanum Mart. and A. tomentosum Mart. (Apocynaceae) are Brazilian species widely used by the population to treat a few diseases. Extracts and isolated compounds of both species have shown antitumor and antimalarial activities. The antitumor activity of isolated compounds has been extensively studied. However, the antiplasmodial activity needs to be investigated further as well as the anti-inflammatory, anti-hyperlipidemic and anorexigenic activities. From A. subincanum twenty-one indole alkaloids were isolated and some of them have been extensively studied. From the leaves and bark of A. tomentosum four alkaloids and one flavonoid were isolated. Furthermore, CG-MS analysis of seeds, branches, leaves and arils identified nine indole alkaloids. Stemmadenine has been proposed as a precursor of indole alkaloids obtained from some species of Aspidosperma. Many of the biosynthetic steps have been characterized at the enzymatic level and appropriate genes have been identified, however, other steps have yet to be investigated and they are still controversial. Some isolated alkaloids from A. subincanum and A. tomentosum were identified only by mass spectrometry. In many cases, their NMR data was either not available or was incomplete. The described meta-analysis of the available NMR data revealed that the chemical shifts belonging to the indole ring might be used to characterize this class of alkaloids within complex matrices such as plant extracts. The biological activities and the structural complexity of these compounds have stimulated the interest of many groups into their synthesis. In this review, some information about the synthesis of indole alkaloids and their derivatives was presented. CONCLUSIONS: A. subincanum and A. tomentosum are used by the population of Brazil to treat many diseases. A few biological activities described for the extracts and isolated compounds of both species are in agreement with the ethnopharmacological use for others species of Aspidosperma, such as, antimalarial, the treatment of diabetes and other illnesses. These species are sources of leading compounds which can be used for developing new drugs. In addition, other biological activities reported and suggested by ethnopharmacological data have yet to be investigated and could be an interesting area in the search for new bioactive compounds. PMID- 30395978 TI - Rapid detection of Banna virus by reverse transcription-loop-mediated isothermal amplification (RT-LAMP). AB - OBJECTIVES: Banna virus (BAV) is classified in the genus Seadornavirus within the Reoviridae family and considered to be an emerging pathogen. We aimed to develop a rapid and simple molecular detection approach for all BAV subgroups in isothermal conditions. METHOD: A set of six specific primers was designed to target the segment 12 of BAV, and the reverse transcription-loop mediated isothermal amplification (RT-LAMP) assay was developed and compared with conventional RT-PCR method. RESULTS: The amplification of the RT-LAMP assay can be obtained within 40min at 65 degrees C. The results from specificity showed that only target BAVs RNA including genotypes A, B and C were amplified and the assay demonstrated a sensitivity of 3.6*10-2PFU/mL, which was higher than conventional RT-PCR measurement. A good reliability for the assay was presented in the further evaluation for BAVs RNA from serial diluted BAV-spiked serum and 47 pools of field mosquito samples. CONCLUSIONS: Our findings present a rapid, sensitive and specific RT-LAMP assay that can be applied for BAV detection in clinical or field samples in the future. PMID- 30395979 TI - Relationship between chest radiographic characteristics, sputum bacterial load, and treatment outcomes in patients with extensively drug-resistant tuberculosis. AB - BACKGROUND: Data about the relationship between chest radiographs and sputum bacillary load, with treatment outcomes, in patients with extensively drug resistant tuberculosis (XDR-TB) from HIV/TB endemic settings are limited. METHODS: Available chest radiographs from 97 South African XDR-TB patients, at the time of diagnosis, were evaluated by two independent readers using a validated scoring system. Chest radiograph findings were correlated with baseline sputum bacillary load (smear-grade and culture time-to-positive in MGIT), and prospectively ascertained clinical outcomes (culture conversion and all-cause mortality). RESULTS: Radiographic bilateral lung disease was present in 75/97 (77%). In the multivariate analysis only a higher total radiographic score (95% CI) was associated with higher likelihood of death [1.16 (1.05-1.28) p=0.003], and failure to culture convert [0.85 (0.74-0.97) p=0.02]. However, when restricting analyses to HIV-infected patients, disease extent, cavitation, and total radiographic scores were not associated with mortality or culture conversion. Finally, cavitary, disease extent, and total radiographic scores all positively correlated with bacterial load (culture time-to-positive). CONCLUSIONS: In endemic settings, XDR-TB radiological disease extent scores are associated with adverse clinical outcomes, including mortality, in HIV uninfected persons. These data may have implications for clinical and programmatic decision making and for evaluation of new regimens in clinical trials. PMID- 30395980 TI - HIV pre-exposure prophylaxis in South East Asia: A focused review on present situation. AB - Pre-exposure prophylaxis (PrEP) with the use of antiretrovirals has been approved for HIV prevention in many western countries and internationally. PrEP is however not yet widely available in South East Asia. Awareness of PrEP among MSM in the region is very variable in different countries. While willingness of PrEP uptake is closely related to the extent of awareness, it is largely affected by factors at the individual level, e.g. financial consideration, risk perception, understanding of PrEP and convenience. Removal of social stigmata and secure data confidentiality can improve willingness of uptake. The diverse religious beliefs in South East Asia could have potential influence on PrEP uptake but there was very limited data in the region. There is no strong evidence suggesting substantial risk compensation among MSM who are on PrEP. As in other parts of the world, education on condom use to prevent other sexually transmitted diseases (STD) should be properly addressed rather than blaming PrEP as a sole cause of rise in STD among MSM. PMID- 30395981 TI - The Female Athlete Triad: A Comparison of Knowledge and Risk in Adolescent and Young Adult Figure Skaters, Dancers and Runners. AB - STUDY OBJECTIVE: The Female Athlete Triad is often found in sports that value leanness and aesthetics and can lead to adverse health effects. We aimed to compare knowledge and risk of the Triad among adolescent figure skaters, dancers, and runners. DESIGN, SETTING, PARTICIPANTS, MAIN OUTCOME MEASURES: We advertised our survey on social media platforms: sports-specific forums; Facebook; and Instagram. We received 928 responses. We included female figure skaters, dancers, and runners aged <=25 years (N=712). We asked participants to name the Triad components and dichotomized knowledge scores as high or low. We developed a 6 question Triad risk scale and defined "at risk" if participants endorsed >=3 questions. RESULTS: Of 712 participants: 60% were figure skaters; 28% dancers; 12% runners; 78% were adolescents (<=17 years); 22% young adults (18-25 years); 12% had heard of the Triad. A higher proportion of runners than figure skaters and dancers had high knowledge of the Triad (16% v. 6% v. 5%, p<0.01). Overall 60% of athletes were "at risk" of the Triad, 25% skipped a period for >=3 months, 34% had a history of stress fractures or shin splints. Young adults vs. adolescents and dancers vs. figure skaters and runners had nearly twice the odds of Triad risk. CONCLUSION: Most athletes were at risk of the Triad but few knew about it. Dancers were at higher risk compared with figure skaters and runners. Efforts should be made to raise awareness of the Triad among athletes, parents, and coaches, with special attention paid to the dance community. PMID- 30395982 TI - Factors influencing adolescent and young adults' first pelvic examination experiences: A qualitative study. AB - STUDY OBJECTIVE: To understand the factors that influence individuals' experiences during their first pelvic examination. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOMES: We conducted semi-structured interviews with adolescents and young adults, aged 18-24, who had received at least one pelvic examination. Interviews explored contextual factors of the first pelvic examination, including visit acuity and clinical setting and individuals' experiences with the pelvic examination itself and elicited recommendations on how to improve the examination experience. Interviews were transcribed and computer-assisted content analysis was performed; salient themes are presented. RESULTS: Thirty participants completed interviews. Nineteen participants described their first pelvic examination experience as positive; 11 described this examination as a negative or neutral experience. Factors influencing the experience include the examination indication and acuity, examination location and physical space, provider features, relational and interpersonal features, and procedural aspects. Recommendations included (1) establish rapport and educate before the examination, (2) establish practices to orient patients, (3) make no assumptions about identity, and (4) elicit continuous feedback. CONCLUSION: Individuals' first pelvic examination experiences are influenced by a variety of factors. While some factors are directly modifiable by providers, other factors which may not be modifiable are important to elicit to optimize the examination experience. These findings call for best-practice guidelines and educational interventions to prepare providers to perform the first pelvic examination. PMID- 30395983 TI - Risky Health Behaviors of Teenage Mothers and Infant Outcomes in the Japan Environment and Children's Study: A Nationwide Cohort Study. AB - STUDY OBJECTIVE: Few studies have investigated the risky health behaviors and psychosocial characteristics of teenage mothers in countries with a low teenage birth rate, like Japan. We examined the differences in maternal prenatal risky health behaviors and psychosocial characteristics, and birth weight of infants between teenage and adult mothers. METHODS: We identified 1,159 teenage (age <20 years) and 73,547 adult mothers (20-34 years) who participated a nationwide birth cohort study between 2011 and 2014. Behavioral and psychosocial characteristics were ascertained using questionnaires during pregnancy. Birth weight of infants was verified through medical records. Univariate and multivariable logistic regression were used to assess the association of teenage motherhood and birth weight of infants with parity, marital status, household income, maternal education, job status, preconception body mass index, gestational weight gain, psychological distress, and smoking status. RESULTS: Teenage mothers were significantly more likely to smoke and have psychological distress and less likely to use alcohol than adult mothers (9.9% vs. 4.6%, p<0.001; 8.9% vs. 3.4%, p<0.001; 1.3% vs. 2.5%, p<0.001, respectively). No association was found between teenage motherhood and low birth weight in infants (Odds ratio 0.99, 95% confidence interval 0.73 to 1.32). Further, no association was found after adjusting for covariates. CONCLUSION: A substantially greater number of Japanese teenage mothers smoked and experienced severe psychological distress than adult mothers. Our findings will be useful for future research and for developing effective policies and programs for teenage mothers and their children. PMID- 30395984 TI - A Nationwide Study Comparing Knowledge and Beliefs about HPV among Female Students before and after HPV Vaccination. AB - STUDY OBJECTIVE: To assess the knowledge and beliefs regarding HPV and the HPV vaccine among girls before and after vaccination in the Malaysian HPV Immunisation Programme. DESIGN: A nationwide longitudinal survey. SETTING: Thirty two randomly selected schools from 13 states and 3 federal territories in Malaysia from February to March 2013, and October to November 2013. PARTICIPANTS: Form One female students (13-year-old). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Mean knowledge score of HPV infection. RESULTS: A total of 2,644 students responded to the pre-vaccination survey, of whom 2,005 (70%) completed the post-vaccination survey. The mean knowledge score was 2.72 (SD +/- 2.20) out of a maximum score of 10 in the pre-vaccination survey, which increased significantly to 3.33 (SD +/- 1.73) after the 3 doses of HPV vaccine (p = 0.001). Many answered incorrectly that, 'Only females can get HPV infection' (91.5% pre vaccination versus 96.1% post-vaccination), and only a few were aware that, 'Vaccinating boys helps to protect girls against HPV infection' (11.7% for pre vaccination versus 10.2% for post-vaccination). The mean knowledge score was significantly higher post-vaccination among higher-income families and those with parents of a higher occupational status. Regarding beliefs about the HPV vaccine, 89.4% in the pre-vaccination survey held the view that they would not get a HPV infection, and the percentage remained similar in the post-vaccination survey. Perceived severity of HPV infection also remained low in both pre- and post intervention groups. Only 21.5% reported receiving health information about HPV along with the provision of the HPV vaccine; those who received health information showed higher levels of knowledge. CONCLUSION: Findings revealed a general lack of knowledge and erroneous beliefs about HPV and the HPV vaccine even after receiving vaccination. This suggests that imparting accurate knowledge about HPV along with vaccine administration is essential. Specifically, girls from lower socioeconomic groups should be a target of educational intervention. PMID- 30395985 TI - The PER extended-spectrum beta-lactamases originate from Pararheinheimera sp. AB - To investigate the origin of the PER extended-spectrum beta-lactamase, publicly available sequence databases were searched for PER-like genes. Three genomes from Pararheinheimera, a genus associated with water and soil environments, were found to carry PER-like genes, but lacked the ISCR1/ISPa12/ISPa13 insertion sequences (IS) commonly associated with PER in clinical isolates. Sequence analysis revealed 78-96% nucleotide identity and conserved synteny between the clinical mobile genetic elements (MGEs) encoding PER-1 and the PER locus in the Pararheinheimera genomes. Notably, PER genes were only identified in 3 of 21 Pararheinheimera and Rheinheimera genomes, whereas the genetic environment of PER genes as found in clinical MGEs was conserved in all Pararheinheimera and Rheinheimera genomes. These findings indicate that PER genes were likely acquired by a branch of the Pararheinheimera genus long before the antibiotic era. Later, PER genes were mobilized, likely through involvement of IS, from one or several Pararheinheimera species, allowing their dissemination into human pathogens. PMID- 30395986 TI - In vitro activity of cefiderocol, a siderophore cephalosporin, against a recent collection of clinically relevant carbapenem-nonsusceptible Gram-negative bacilli, including serine carbapenemase- and metallo-beta-lactamase-producing isolates (SIDERO-WT-2014 Study). AB - Cefiderocol is a siderophore cephalosporin in development for treatment of infections caused by Gram-negative bacilli including carbapenem-resistant and multidrug-resistant isolates. The beta-lactamase carriage and in vitro activity of cefiderocol were determined against 1,272 meropenem-nonsusceptible isolates of Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii collected as part of the SIDERO-WT-2014 surveillance study. MIC values for cefiderocol were <=4 ug/mL against 97.7% of tested isolates, including 100% of IMP-positive (range, 1-2 ug/mL), OXA-58-positive (MIC90, 1 ug/mL), KPC-positive (MIC90, 2 ug/mL), VIM-positive (MIC90, 2 ug/mL), and OXA-48-like-positive (MIC90, 4 ug/mL) isolates; 99.3% of carbapenemase-negative isolates (MIC90, 1 ug/mL); 97.2% of OXA 23-positive isolates (MIC90, 1 ug/mL); 95.2% of OXA-24-positive isolates (MIC90, 1 ug/mL); 91.7% of GES-positive isolates (MIC90, 4 ug/mL); and 64.3% of NDM positive isolates (MIC90, 8 ug/mL). A total of 29 isolates (2.3%; 15 OXA-23 producers, 6 OXA-24-producers, 5 NDM-producers, and 3 carbapenemase-negative isolates) exhibited cefiderocol MIC values of >=8 ug/mL, confirming that there was no clear correlation between carriage of the beta-lactamases included in the molecular testing algorithm and elevated cefiderocol MICs. Similarly, no correlation was observed between cefiderocol MICs and truncation or loss of porin proteins in meropenem-nonsusceptible isolates of E. coli and K. pneumoniae. Cefiderocol MICs were also <=4 ug/mL against 99.3% of 136 colistin-resistant Enterobacteriaceae collected as part of the SIDERO-WT-2014 study, including isolates carrying mcr-1 (MIC90, 2 ug/mL). Cefiderocol demonstrated potent in vitro activity against a collection of carbapenemase-producing and carbapenemase negative meropenem-nonsusceptible Gram-negative bacilli for which few treatment options are currently available, including the majority of metallo-beta-lactamase producing isolates identified. PMID- 30395987 TI - Development and validation of a multiplex PCR assay for the detection of the five families of plasmid-encoded colistin resistance. AB - Plasmid-mediated colistin resistance is increasingly described worldwide in Enterobacteriaceae from animal and from human isolates. Diffusion of these resistance traits among carbapenem-resistant enterobacterial isolates is particularly worrisome, since colistin has become the last resort antibiotic for treating human infections with these organisms. Therefore, being able to monitor the presence of these transferable colistin resistance genes (mcr-1 to mcr-5 variants) is crucial. Here, we have developed a multiplex polymerase chain reaction (PCR) protocol for detection of all currently known transferable colistin resistance genes in Enterobacteriaceae. We designed five primer pairs to amplify mcr-1, -2, -3, -4, -5 gene products, in a multiplex PCR. This assay was validated retrospectively on colonies of 50 Escherichia coli, 44 Klebsiella pneumoniae and 12 Salmonella enterica well characterized isolates of animal and human origin, and prospectively on 450 carbapenem-resistant enterobacterial isolates received by the French National Reference Centre. In addition, we also screened 82 Aeromonas spp. and 10 Shewanella spp. species known to be the progenitors of mcr-3 and mcr-4 alleles, respectively. Mcr-multiplex PCR assay displayed 100% specificity, sensitivity, negative and positive predictive value. The assay was able to detect all variants of the different mcr-alleles, and was able to detect chromosomally-encoded mcr-4-like variants present in two Shewanella bicestrii JAB-1 and S. woodyi S539. We developed and validated a rapid and robust multiplex PCR assay able to detect all known mcr gene families described in Enterobacteriaceae. This kind of test is critical for the epidemiological surveillance of plasmid-encoded resistance, especially in carbapenem-resistant bacteria. PMID- 30395989 TI - Managing Invasive Aspergillosis in haematological patients in the era of resistance PCR and increasing triazole resistance: a modelling study of different strategies. AB - OBJECTIVES: Triazole resistance in Aspergillus spp. is emerging and complicates prophylaxis and treatment of Invasive Aspergillosis (IA) worldwide. New Polymerase Chain Reaction (PCR) tests on broncho-alveolar lavage (BAL) fluid allow for detection of triazole-resistance on a genetic level, which opened up new possibilities for targeted therapy. In the absence of clinical trials, a modelling study delivers estimates of the added value of resistance detection with PCR and which empiric therapy would be optimal when local resistance rates are known. DESIGN: We performed a decision-analytic modelling study based on epidemiological data of IA, extended with estimated dynamics of resistance rates and treatment effectiveness. We compared six clinical strategies that differ in use of PCR diagnostics (used versus not used) and in empiric therapeutic choice in case of unknown triazole-susceptibility: Voriconazole (VOR), Liposomal Amphotericin B (LAmB) or both. Outcome measures were proportion of correct treatment, survival and serious adverse events. RESULTS: Implementing Aspergillus PCR tests was projected to result in residual treatment-susceptibility mismatches of <5% for a triazole resistance rate up to 20% (using VOR). Empiric LAmB outperformed VOR at resistance rates higher than 5-20%, depending on PCR use and estimated survival benefits of VOR over LAmB (figure 1). Combination therapy of VOR and LAmB performed best at all resistance rates but the advantage over the other strategies should be weighed against the expected increased number of drug related serious adverse events (figure 2). The advantage of combination therapy over LAmB monotherapy became smaller at higher triazole-resistance rates. CONCLUSIONS: Introduction of current Aspergillus PCR tests on BAL-fluid is an effective way to increase the proportion of patients that receive targeted therapy for IA. The results indicate that close monitoring of background resistance rates and of adverse drug events are important to attain the potential benefits of LAmB. The choice of strategy ultimately depends on the probability of triazole-resistance, the availability of PCR and individual patient characteristics. PMID- 30395988 TI - Multidrug (MDR) and extensively drug resistant (XDR) Gram negative prosthetic joint infections (PJI): Role of surgery and impact of colistin administration. AB - OBJECTIVE: We analyze factors influencing the treatment outcome of patients with Gram negative (GNB) multi-drug (MDR) and extensively-drug (XDR) resistant prosthetic joint infection (PJI). METHODS: Data were collected from 2000-2015 by 18 centers, endorsed by ESGIAI (European Study Group for Implant Associated Infections). Treatment success was analyzed by the type of surgery for PJI, the type of resistance (MDR/XDR) and antimicrobials (colistin vs non-colistin) through logistic regression and survival analysis. RESULTS: One hundred thirty one patients (mean age 73 years, male 36%, comorbidities 58.8%) with MDR(n=108) or XDR(n=23) GNB PJI were assessed. Most frequent pathogens were E.coli (33.5%) followed by P.aeruginosa (25.1%), K.pneumoniae (21.3%) and E.cloacae (17.5%). P.aeruginosa predominated in XDR cases (n=15).Resistance referred to carbapenems(n=12),fluoroquinolones(n=63) and ESBL(n=94). Treatment outcome was worse in XDR than in MDR cases (p=0.018). Success rates did not differ in colistin vs non-colistin antimicrobials in XDR cases (p=0.657), but in MDR ones colistin was less successful (p=0.018). DAIR (Debridment, Antibiotics and Implant Retention) (n=67) was associated with higher rates of failure vs Non-DAIR (any other procedure with implant removal,n=64) [(OR=3.57,95%CI 1.68-7.58,(p<0.001)]. The superiority of Non-DAIR was confirmed by Kaplan-Meir analysis (HR:0.36,(95%CI 0.20-0.67) and remained unchangeable from the time of infection (early/late), the type of resistance (MDR/XDR) and the antimicrobial treatment (colistin vs non colistin) (Breslow-Day, p=0.737). CONCLUSION: DAIR is associated with higher rates of failure even in early MDR/XDR GNB PJI compared to implant removal. Colistin should be preserved only for XDR cases as its use is detrimental in MDR ones. PMID- 30395990 TI - Anxiety and non-eosinophilic asthma among adults in the United States. PMID- 30395991 TI - Practice patterns among allergists on the early introduction of peanut. PMID- 30395992 TI - A Systematic Review of Patient and Family-Level Inhaled Corticosteroid Adherence Interventions in Adult African-Americans. AB - BACKGROUND: Inhaled corticosteroid (ICS) adherence rates are suboptimal among adult African-Americans. Comprehensive studies characterizing the effectiveness and the methodological approaches to the development of interventions to improve ICS adherence in adult African-Americans have not been performed. OBJECTIVE: Conduct a systematic review of patient/family-level interventions to improve ICS adherence in adult African-Americans. METHODS: Searched MEDLINE, EMBASE, Web of Science, and CINAHL from inception to August 2017 for English-language United States studies enrolling at least 30% African-Americans comparing patient/family level ICS adherence interventions with any comparator. Two investigators independently selected, extracted data from, and rated risk-of-bias. We collected information on intervention characteristics, outcomes, and assessed whether studies were informed by behavior theory and/or stakeholder engagement. RESULTS: Among 1,661 abstracts identified, we reviewed 230 full-texts and identified 4 randomized controlled trials (RCT) and 1 quasi-experimental (pre-post design) study meeting criteria. Study participants (N range 17-333) varied in mean age (22-47 years), proportion African-Americans studied (71%-93%), and gender (69% 82% female). RCTs evaluated problem solving classes, self-efficacy training, technology-based motivational interviewing program and the use of patient advocates. The RCT testing self-efficacy training was the only intervention informed by both behavior theory and stakeholder engagement. All 4 RCTs compared interventions with active control and rated as medium risk-of-bias. No RCTs found a statistically significant improvement in adherence. CONCLUSION: Few studies assessing asthma adherence interventions focused on adult African-American populations. No RCTs demonstrated improved ICS adherence in participants. Future studies are needed that are informed by behavior change theory and stakeholder engagement. PMID- 30395993 TI - Influence of CD4-1+, CD4-2+ and CD8+ T lymphocytes subpopulations on the immune response of B lymphocytes in flounder (Paralichthys olivaceus) immunized with thymus-dependent or thymus-independent antigen. AB - In order to elucidate the influence of T lymphocytes subpopulations on B lymphocytes immune response, in this paper, CD4-1+, CD4-2+, CD8+ T lymphocytes and B lymphocytes responses to thymus-independent (TI) or thymus-dependent (TD) antigen plus immunosuppressant were investigated in flounder (Paralichthys olivaceus). The results showed that in LPS-immunized group, the percentages of CD4-1+, CD4-2+, CD8beta+ T (PCD4-1+ T, PCD4-2+ T and PCD8beta+ T) lymphocytes in peripheral blood leucocytes (PBLs) had no significant variations, the percentages of IgM+ B (PIgM+ B) lymphocytes and LPS-specific antibodies (LA) significantly increased and peaked at 3rd or 4th week post-injection; CsA had no inhibition on both T/B lymphocytes and LA; RaPa only suppressed the PIgM+ B lymphocytes and LA, and the inhibition maximum (Imax) were about 35% and 20%, respectively. In KLH immunized group, the PCD4-1+, PCD4-2+ and PCD8beta+ T lymphocytes significantly increased and peaked at 3rd or 5th day, successively the PIgM+ B lymphocytes and KLH-specific antibodies (KA) significantly increased to the peak at 5th week; the PCD4-1+, PCD4-2+ T and PIgM+ B lymphocytes and LA were inhibited significantly by both CsA and RaPa, and the Imax on them were 13%-33%, 11%-25%, 19%-34%, 22%-26%, respectively, while the PCD8beta+ T lymphocytes showed no significant suppression. The results indicated that the suppression of PIgM+ B lymphocytes in KLH + CsA group was not directly derived from CsA, but due to the suppression of T lymphocytes, especially CD4+ T lymphocytes subpopulations. The results showed for the first time that, similar to higher vertebrates, T lymphocytes didn't respond to TI antigen, moreover, T lymphocyte subpopulations had a regulation on the immune response of B lymphocyte for TD antigen in flounder. PMID- 30395994 TI - Production and Function of Different Regions from Mytichitin-1 of Mytilus coruscus. AB - Chitinase is an important enzyme for many physiological processes. Mytichitin-1 is a chitinase-like protein in Mytilus coruscus, and its C-terminal 55-AA fragment (mytichitin-CB) is a novel antimicrobial peptide, suggesting a new immune process in which chitinase is involved; mytichtin-1 may have various forms in the different biological processes of M. coruscus. Thus, the study of mytichitin-1 will be helpful for understanding the mechanism of mussel immune biology and the functional diversity of chitinase. In this study, mytichitin-1 was recombinantly expressed with different lengths, full-length mytichtin-1 (rMchi-F) and the N-terminal region (rMchi-N) in Escherichia coli BL21 with codon optimization. The results of SDS-PAGE, Western blotting, and mass spectrometry confirmed that the two forms of mytichitin-1 had been successfully recombinant expressed with a yield of 40 mg purified enzyme per L culture. In addition, the 55-AA fragment of mytichitin-CB was chemically synthesized (sMchi-CB). After purification and oxidation, the functions of the three protein products were analysed, including chitin degradation, chitin binding, and antimicrobial activities. Both rMchi-F and rMchi-N displayed enzymatic activity with the optimum pH of 4.0 and optimum temperature of 40 degrees C, and rMchi-N showed a stronger activity than rMchi-F. Enzymatic activities of rMchi-F and rMchi-N were stimulated by the metal ions Fe2+, Ba2+, and Na+ and partially inhibited by Cu2+, Ni2+ and Zn2+. rMchi-F, rMchi-N, and sMchi-CB had the ability to combine with colloid chitin. The antimicrobial activities of these proteins were tested against bacteria and fungi, and the results indicated the strongest activity for sMchi-CB and the weakest activity for rMchi-N. Using a prepared anti-rMchi-F polyclonal antibody, immunohistochemistry and immunoprecipitation were performed and the results revealed the location of mytichitin-1 in mantle, digestive gland and blood cells. In addition, two forms of mytichitin-1, mytichitin-CB (6 kD) and full-length mytichitin-1 (48 kD), were detected, and a 35 kD protein was identified as the third form of mytichitin-1, existing in various tissues of M. coruscus. These findings suggest that mytichitin-1 may play different roles, with at least three forms, in different M. coruscus tissues. PMID- 30395995 TI - Characterization and functional analysis of a novel gC1qR in the swimming crab Portunus trituberculatus. AB - The receptor for the globular head of complement component C1q, gC1qR, is a multifunctional and multiligand binding protein with a crucial role in host defense. In the present study, a full-length cDNA sequence of a gC1qR homolog (PtgC1qR) in Portunus trituberculatus was identified. PtgC1qR was a 268-amino acid polypeptide with a conserved MAM33 domain and a mitochondrial targeting sequence in the first 56 amino acids. The transcripts of PtgC1qR were detected in all examined tissues with the highest level detected in the hepatopancreas. Compared with other early embryonic stages, PtgC1qR was highly expressed in the fertilized eggs and embryos at the cleavage stage, which suggest PtgC1qR may be a maternal gene. The transcripts of PtgC1qR in hemocytes exhibited time-dependent response expression pattern after challenged with bacteria (Vibrio alginolyticus, Micrococcus luteus) and fungi (Pichia pastoris). Moreover, the recombinant PtgC1qR (rPtgC1qR) exhibited strong antibacterial activity and microbial-binding activity, suggesting its crucial role in immune defense and recognition. Further phenoloxidase (PO) assay showed that rPtgC1qR could suppress the crab PO activity in vitro in a dose-dependent manner, and it could result in nearly 100% inhibition of PO activity under the concentration of 11.65 MUM. Knockdown of PtgC1qR could significantly enhance the expression of serine protease related genes (PtSP1-3 and PtSPH), proPO-associated genes (PtproPO and PtPPAF) and C3 like genes (Ptalpha2M1 and PtTEP). However, the phagocytosis related genes (PtMyosin, PtRab5 and PtArp) and Ptalpha2M2 were significantly down-regulated in the PtgC1qR silenced crabs. These findings together demonstrate that PtgC1qR might function in crab immune response via its antibacterial activity, immune recognition or regulating the proPO system, complement pathway and phagocytosis. PMID- 30395996 TI - Chlorine dioxide inhibits the replication of porcine reproductive and respiratory syndrome virus by blocking viral attachment. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) causes a great economic loss to the swine industry globally. Current prevention and treatment measures are not effective to control the outbreak and spread of porcine reproductive and respiratory syndrome (PRRS). In other words, new antiviral strategies are urgently needed. Chlorine dioxide (ClO2) is regarded as a broad spectrum disinfectant with strong inhibitory effects on microbes and parasites. The purpose of this study was to evaluate the inhibitory effects and underlying molecular mechanisms of ClO2 against PRRSV infection in vitro. Here, we identified ClO2 (the purity is 99%) could inhibit the infection and replication of PRRSV in both Marc-145 cells and porcine alveolar macrophages (PAMs). ClO2 could block PRRSV binding to cells rather than internalization and release, suggesting that ClO2 blocks the first stage of the virus life cycle. We also demonstrated that the inhibition exerted by ClO2 was attributed to the degradation of PRRSV genome and proteins. Moreover, we confirmed that ClO2 could decrease the expression of inflammatory cytokines induced by PRRSV. In summary, ClO2 is an efficient agent and potently suppressed PRRSV infection in vitro. PMID- 30395997 TI - Intraspecific phylogeny of Anopheles (Kerteszia) neivai Howard, Dyar & Knab 1913, based on mitochondrial and nuclear ribosomal genes. AB - Three mitochondrial regions and a fragment of a large nuclear ribosomal subunit was used to study the evolutionary patterns of An. neivai, a mosquito inhabiting mangroves and tropical forest in the lowland and coastal areas of the Yucatan Peninsula through the Pacific Ecuadorian coast. This species exhibits epidemiological importance regarding Malaria transmission in natural ecosystems, particularly in rural areas of the Pacific Colombian coast. The results based on phylogenetic networks and Bayesian inference showed no robust evidence supporting the existence of previously suggested cryptic species. Diversification patterns in geographically widespread species such as this one, are complex and therefore could impact malaria control strategies. Further studies focused on behavior, morphology, and phylogenomics will improve the understanding of the evolutionary patterns within An. neivai and its role as a disease vector. PMID- 30395998 TI - Using high-throughput sequencing for investigating intra-host hepatitis C evolution over long retrospective periods. AB - Collections of biological samples held by hospitals represent invaluable resources for conducting retrospective evolutionary studies of chronic infections. Using high-throughput sequencing, those collections permit analysis of within-host genetic diversity over long follow-up periods, and allow a better understanding of resistance to treatment regimes during disease evolution. Here, we studied the evolution of hepatitis C virus (HCV) populations in two patients with an absence of response to dual therapies. We implemented amplicon sequencing to survey genomic variation at the Core and NS5B regions of HCV over a period of 13 years from blood samples obtained at multiple time points. We observed mixed infection by multiple HCV genotypes in both patients. Genetic heterogeneity and sample composition analysis provided information about the changes in viral population over the course of clinical treatment, with NS5B experiencing an increase in diversity after treatment initiation. Secondary infections were estimated to predate treatment year, and our results pointed towards diversifying selection occurring post-treatment, acting on standing genomic variation and maintaining high genetic heterogeneity during infection. For these two patients infected with multiple HCV genotypes, the maintenance of viral diversity was explained with the hypothesis of soft selective sweep started at the same time as antiviral treatment was initiated. PMID- 30395999 TI - Mutation in cyl operon alters hemolytic phenotypes of Streptococcus agalactiae. AB - Streptococcus agalactiae infects numerous fish species, causing considerable economic losses during fish cultivation. This study compared the phenotypic differences among S. agalactiae hemolytic variant isolates and investigated the genetic composition of their hemolysin genes. Hemolysin is encoded by the cyl operon and mainly regulated by covS/R, which also regulates encapsulation. In total, 45 S. agalactiae clinical isolates were collected from cultured fishes in Taiwan. Three different hemolytic phenotypes-alpha, beta, and gamma-were identified. Of the 45 isolates, 39 were beta hemolytic, 3 were alpha hemolytic, and 3 were gamma hemolytic. The gamma-hemolytic isolates demonstrated significantly thicker encapsulation and slower growth rates than did the alpha- and beta-hemolytic isolates. However, no isolate had mutations in the regulatory gene covS/R. A 1252-bp insertion sequence (IS) in the cyl operon of alpha hemolytic isolates, located at cylF region, was found. This IS interrupted cylF through insertion at 23 bp downstream of starting codon, causing incomplete mRNA transcription. The beta-hemolytic isolates showed no mutation in the cyl operon. By contrast, the gamma-hemolytic isolates had lost the entire cyl operon; it had been replaced by a 14-kb genomic island containing genes for DNA recombinase and septum formation proteins. In summary, the differences in hemolysin genes between alpha- and beta-hemolytic isolates were due to the IS in the cylF region, whereas in the gamma-hemolytic isolates, the entire cyl operon was deleted and replaced. These findings explain different hemolysin expressions of the clinical S. agalactiae isolates taken from fish ponds in Taiwan. IMPORTANCE: Streptococcus agalactiae infects both warm- and cold-blooded animals and causes major aquatic cultivation loss. Pathogenic isolates from the outbreak of fish ponds were examined their cyl operon gene. alpha-Hemolytic isolate with mutant cyl operon was observed for the first time in aquaculture animals and was compared to intact or entire cyl operon deletion of beta- and gamma-hemolytic isolates. Hemolysis expression levels of Streptococcus agalactiae are explained. PMID- 30396000 TI - Molecular dynamics simulation analysis of conessine against multi drug resistant Serratia marcescens. AB - Ornithine decarboxylase (ODC) is an immediate precursor of polyamine biosynthesis in Serratia marcescens and a potential target for inhibition of its growth. We predicted the 3D structural conformation of ODC enzyme and validated it using MDS in our previous study. In this current study, the potential inhibitors of ODC were obtained by virtual screening of potential inhibitors from ZINC database and studied in depth for their different binding pose. Among the ten virtually screened inhibitors, Conessine exhibited the best binding with ODC and its inhibition property was studied further by MDS studies. The natural compound conessine is isolated from plant Holarrhena antidysenterica and it is studied against ODC of Serratia marcenses for its inhibitory potentials. This revealed unforeseen twisted position in root mean square fluctuation (RMSF) and ODC modelled conformation that influenced ligand binding. Both predicted model and ligand bound model were compared and found to be stable with Root Mean Square Deviation (RMSD) of approximately 7 nm and 0.25 nm to that of crystallographic structure over simulation time of 55 ns and 70 ns respectively. This work paves the way for future development of new drugs against nosocomial diseases caused by Serratia marcescens. PMID- 30396001 TI - 'It definitely made a difference': A grounded theory study of yoga for pregnancy and women's self-efficacy for labour. AB - OBJECTIVE: To explore women's experience of attending yoga for pregnancy classes in order to generate a theory about which aspects, if any, are effective in enhancing self-efficacy for labour and birth. DESIGN: A longitudinal grounded theory study. METHODS: Semi-structured interviews were undertaken with women before they started yoga for pregnancy classes, after they had attended at least six classes, and finally, postnatally. Interview transcripts were analysed using constructive grounded theory and a self-efficacy framework. SETTING: Three yoga for pregnancy teachers' classes in England. PARTICIPANTS: Twenty two women attending yoga for pregnancy classes. FINDINGS: Analysis of interviews with women at three time points led to a propositional theory that yoga for pregnancy enhances women's self-efficacy for labour by building their confidence and competence through a combination of techniques. These include repeated practice of a variety of pain management strategies, use of affirming language and the telling of positive labour stories, underpinned by yoga practice to lower somatic response to stress. PMID- 30396002 TI - Cognition, emotion, and behaviour in women undergoing pregnancy termination for foetal anomaly: A grounded theory analysis. AB - OBJECTIVE: To understand the cognition, emotions, and behaviour of women who had recently undergone termination due to a foetal anomaly. In this study, we developed and tested a theoretical model to describe how women went through the process after termination. STUDY DESIGN: A grounded theory study. SETTING: Three general hospitals and one special hospital in Changsha, Hunan, China. PARTICIPANTS: 41 women who had recently undergone a pregnancy termination. METHODS: In-depth interviews were conducted from May to September 2017. A combination of convenience sampling and theoretical sampling was used, and conceptual depth criteria were used to measure the progress of the theoretical sampling. FINDINGS: This study developed a cognitive-behavioural experience framework of women undergoing pregnancy termination due to a foetal anomaly. The model included 4 phases: 1. Denial Phase, 2. Confirmation Phase, 3. Decision making Phase and 4. Recovery Phase. Different cognitive appraisal, emotional, and behavioural reactions were included in each phase, and the different reactions influenced one another. KEY CONCLUSIONS & IMPLICATIONS FOR PRACTICE: We built and tested a theoretical framework by interviewing women who had gone through a pregnancy termination. The framework describes their experiences more clearly from three dimensions, including cognitive appraisal, emotional reaction, and behavioural response in the different phases. This framework provides a basic understanding of the women's emotional process and, therefore, provides baseline data for developing an effective intervention to help women cope with termination stresses. PMID- 30396003 TI - Providing quality care for women with vasa praevia: Challenges and barriers faced by Australian midwives. AB - OBJECTIVE: To explore the barriers to providing quality maternity care for women with vasa praevia as identified by Australian midwives. DESIGN: A qualitative descriptive study using semi-structured in-depth telephone interviews. SETTING: Australian maternity system. METHODS: Midwives were recruited from across Australia. Interviews were audio-recorded, transcribed verbatim, and analysed using thematic analysis. PARTICIPANTS: Twenty midwives from five Australian states practising in 15 different public or private hospitals who had cared for at least one woman with vasa praevia during 2010-2016 were interviewed. More than half of the participants held senior positions. Twelve were involved in a neonatal death or 'near-miss' due to vasa praevia. FINDINGS: Two categories and five themes were identified in relation to barriers to the provision of quality care. Practitioner-level barriers included two themes: identifying lack of midwifery education and lack of knowledge. System-level barriers included lack of a local policy to guide practice, limited information for women, and paucity of research about vasa praevia. CONCLUSION: Midwives experienced a number of barriers in caring for women with vasa praevia. Offering more comprehensive pre registration and continuing professional education to midwives, developing local protocols, and providing clear written information for women may improve the provision of quality care. IMPLICATIONS FOR PRACTICE: Midwives have a critical role in caring for and supporting women with vasa praevia. Improving midwives' knowledge with contemporary evidence and clinical guidelines could enable them to deliver safer maternity care and improve a women's journey through this potentially catastrophic condition. PMID- 30396004 TI - Accuracy and Precision in Acupuncture Point Location: A Critical Systematic Review. PMID- 30396005 TI - Effects of commercial aldehydes from green leaf volatiles (green odour) on rumen microbial population and fermentation profile in an artificial rumen (Rusitec). AB - The effects of plant metabolites on rumen metabolism vary greatly depending on their antimicrobial spectrum and applied doses. In this study, the minimum inhibitory concentrations (MICs) of commercial aldehydes, trans-2-hexenal (T2H), cis-3-hexenal (C3H), trans-2-nonenal (T2N), and trans-2-decenal (T2D) from green leaf volatiles, were tested on rumen bacteria. These compounds were found more effective on Gram-positive rumen bacteria than the Gram-negatives, and C3H was the most effective compound. Then, for 14 days, the in vitro effects of C3H compared with monensin (5 mg/day) on the rumen microbial population and ruminal fermentation at 187.5, 375 and 750 mg/day doses were tested based on the MIC value (500 MUg/mL) by using the rumen simulation technique (Rusitec). Supplementation with C3H at 375 mg/day increased the cell numbers of Butyrivibrio fibrisolvens significantly. The addition of C3H at 375 and 750 mg/day doses also increased Streptecoccus bovis cell counts. The use of monensin did not affect the cell numbers of these bacteria. On the other hand, C3H did not change the counts of total bacteria, methanogens, or hyper-ammonia-producing (HAP) bacteria like monensin. The numbers of Ruminococcus albus and Ruminococcus flavefaciens were also stable in the presence of C3H but decreased significantly with the addition of monensin (P < 0.05). Fibrobacter succinogenes, Megasphaera elsdenii, and Selenomonas ruminantium cell counts were not affected by either application. In addition, C3H increased the acetate and methane production along with the acetate to-propionate ratio at all tested concentrations, unlike monensin. Supplementation with C3H decreased propionate production significantly, except at the 187.5 mg/day dose. Butyrate production increased (P < 0.05) only in the presence of 187.5 and 375 mg/day doses of C3H. Production of total volatile fatty acids (VFA) and dry matter digestibility (DMD) did not change in treatment groups. Also, the total protozoa numbers and ammonia-N concentrations significantly decreased (P < 0.05) in C3H-treated samples, similar to monensin. Although C3H did not have favorable effects on energy efficiency, it suppressed rumen protozoa and mitigated rumen ammonia without adversely effecting ruminal fermentation in all applied doses. Based on the result, C3H has the potential to improve protein utilization in the rumen. PMID- 30396007 TI - Seizures in tuberculous meningitis. AB - OBJECTIVE: We report the frequency of seizure, its possible mechanisms and effect of seizure on the outcome of tuberculous meningitis (TBM). METHODS: Seventy-nine patients with TBM admitted during 2014-2017 were evaluated. The seizures were categorized as per International League Against Epilepsy as well as into early (within 1 month of meningitis) and late (>1 month) seizure. The possible association of seizures was recorded and the outcome was assessed using modified Rankin Scale (mRS <= 2 as good, and mRS > 2 as poor). RESULTS: The median age was 27 (18-76) years and 43 (54.4%) of whom were females. Tuberculous meningitis was definite in 31 (39.2%) and highly probable in the remaining. Seizures occurred in 27 (34.2%): early onset in 8 (29.6%) and late in 19 (70.4%) patients. The seizures were focal in 11(13.9%), focal to bilateral in 9 (11.4%), generalised tonic clonic in 7 (8.9%) and status epilepticus in 6 (7.6%) patients. Early seizures were associated with meningeal irritation and late seizures with tuberculoma, infarction and hyponatremia (P = 0.01). Seizure did not affect the mortality but were associated with worse six months outcome (P = 0.03). CONCLUSION: Seizures occurred in 34% patients with TBM and were associated with poor outcome at six months. PMID- 30396006 TI - Alterations in gut microbiota composition and metabolic parameters after dietary intervention with barley beta glucans in patients with high risk for metabolic syndrome development. AB - Metabolic syndrome is a complex disease that is exponentially increasing in the western world, and diet is one of the possible ways to improve the metabolic status of patients. Barley beta glucans are dietary fibres that show promise for improvement cholesterol levels and postprandial glucose response, but they have been rarely investigated in human trials with concurrent focus on gut microbiota. A double-blind, placebo-controlled, randomised clinical trial was conducted with 43 volunteers with high risk for metabolic syndrome development or with diagnosed metabolic syndrome. During a four-week intervention study, participants consumed experimental bread containing 6 g of barley beta glucans or equal bread but without beta glucans. After dietary intervention, total plasma cholesterol decreased in the test group (-0.26 +/- 0.54, p = 0.019), but not in the control group. Short chain fatty acids (SCFA) composition in faeces significantly changed with increase of propionic acid in test group (43.2%, p = 0.045) and with decrease of acetic acid in control group (41.8%, p = 0.011). The microbiome analysis based on Illumina paired end sequencing of 16S rRNA genes showed a decrease in microbial diversity and richness in the test group. The pre intervention gut microbiota composition showed higher abundance of health associated Bifidobacterium spp. and Akkermansia municiphila within cholesterol responsive group, showing that diet-induced metabolic response is possibly dependent on individual gut microbiota composition. PMID- 30396008 TI - Expanding beyond the current core STR loci: An exploration of 73 STR markers with increased diversity for enhanced DNA mixture deconvolution. AB - Current approaches to mixture deconvolution of complex biological samples at times do not have the capability to resolve component contributors in DNA evidence. Additional short tandem repeat (STR) loci were sought that may improve the forensic genetic analysis of mixtures. This study presents exploratory data of a multiplex comprised of 73 highly polymorphic STRs (referred herein as the 73Plex) that were selected because of their high diversity due to sequence variation. These STRs (or a subset of them) may be considered as candidates that may augment current core markers capabilities for DNA mixture deconvolution. Population genetics analyses were performed for each locus using DNA samples from 451 individuals comprising three U.S. populations. Sequence-based heterozygosities ranged from 72% to 98%, where only two loci (D10A97 and D6A7) fell below 80%. Mixture deconvolution capabilities for two-person mixtures were assessed based on complete allele resolution per locus (i.e., four alleles observed) of pairwise mixtures using in silico methods. A subset of 20 highly informative loci (referred herein as the 20Plex) from the 73Plex was compared to the 20 CODIS core loci on all population samples with full DNA profiles for both panels (i.e., no locus dropout; n = 443). Based on proportion of loci displaying four alleles, the 20Plex outperformed the CODIS core loci with increases of 82.6% and 89.3% using length-based and sequence-based alleles, respectively. A combination of 17 STR from the 20Plex and 3 CODIS loci gave the highest capacity for resolving allelic components per locus. These data illustrate the increased value of utilizing sequenced-based alleles of additional STR loci. Furthermore, there are a number of candidate STR loci that could notably augment the current core STR loci and enhance mixture interpretation capabilities. PMID- 30396009 TI - Forensic human identification with targeted microbiome markers using nearest neighbor classification. AB - From the perspective of forensics genetics, the human microbiome is a rich, relatively untapped resource for human identity testing. Since it varies within and among people, and perhaps temporally, the potential forensic applications of the use of the microbiome can exceed that of human identification. However, the same inherent variability in microbial distributions may pose a substantial barrier to forming predictions on an individual as the source of the microbial sample unless stable signatures of the microbiome are identified and targeted. One of the more commonly adopted strategies for microbial human identification relies on quantifying which taxa are present and their respective abundance levels. It remains an open question if such microbial signatures are more individualizing than estimates of the degree of genetic relatedness between microbial samples. This study attempts to address this question by contrasting two prediction strategies. The first approach uses phylogenetic distance to predict the host individual; thus it operates under the premise that microbes within individuals are more closely related than microbes between/among individuals. The second approach uses population genetic measures of diversity at clade-specific markers, serving as a fine-grained assessment of microbial composition and quantification. Both assessments were performed using targeted sequencing of 286 markers from 22 microbial taxa sampled in 51 individuals across three body sites measured in triplicate. Nearest neighbor and reverse nearest neighbor classifiers were constructed based on the pooled data and yielded 71% and 78% accuracy, respectively, when diversity was considered, and performed significantly worse when a phylogenetic distance was used (54% and 63% accuracy, respectively). However, empirical estimates of classification accuracy were 100% when conditioned on a maximum nearest neighbor distance when diversity was used, while identification based on a phylogenetic distance failed to reach saturation. These findings suggest that microbial strain composition is more individualizing than that of a phylogeny, perhaps indicating that microbial composition may be more individualizing than recent common ancestry. One inference that may be drawn from these findings is that host-environment interactions may maintain the targeted microbial profile and that this maintenance may not necessarily be repopulated by intra-individual microbial strains. PMID- 30396010 TI - Interaction of environmental contaminants with zebrafish (Danio rerio) multidrug and toxin extrusion protein 7 (Mate7/Slc47a7). AB - Zebrafish Mate7 belongs to solute carrier protein superfamily and specifically to subfamily of multidrug and toxin extruders. It is co-orthologous to mammalian Mates, and is ubiquitously expressed in zebrafish tissues with the highest expression in kidney. It has been shown to interact with both endogenous (steroid hormones) and xenobiotic compounds (pharmaceuticals), implying a role in efflux of toxic compounds. The objective of our study was to analyse interaction of environmental contaminants with zebrafish Mate7 using a newly developed high throughput screening (HTS) Mate7 assay. A full-length zebrafish mate7 sequence was obtained from zebrafish cDNA originating from male kidney, and a stable expression of Mate7 in genetically engineered HEK293 Flp-In cells was achieved. Stable Mate7 transfectants were then used for development and optimization of a new HTS cellular uptake protocol, with DAPI and ASP + as model fluorescent substrates. The developed assay was used for identifying zebrafish Mate 7 interactors and discerning the type of interaction. A series of 89 diverse environmental contaminants, including industrial chemicals, pesticides, and pharmaceuticals, was tested and highly effective Mate7 interactors were identified in all of the aforementioned groups. Some of the inhibitors identified could be of environmental concern because they may potentially impair Mate7 efflux function, lowering the fish defence capacity against environmental contaminants, or interfering with transport of yet unidentified physiological substrates. In addition, we found significant differences between zebrafish Mate7 and mammalian Mates' substrate preferences, a finding that should be taken into consideration when using zebrafish as a model organism in toxicokinetic studies. PMID- 30396012 TI - The Toll-Like Receptor 2 agonist PEG-Pam2Cys as an immunochemoprophylactic and immunochemotherapeutic against the liver and transmission stages of malaria parasites. AB - Both vaccine and therapeutic approaches to malaria are based on conventional paradigms; whole organism or single antigen epitope-based vaccines administered with or without an adjuvant, and chemotherapeutics (anti-malaria drugs) that are toxic to the parasite. Two major problems that limit the effectiveness of these approaches are i) high levels of antigenic variation within parasite populations rendering vaccination efficacy against all variants difficult, and ii) the capacity of the parasite to quickly evolve resistance to drugs. We describe a new approach to both protection from and treatment of malaria parasites that involves the direct stimulation of the host innate immune response through the administration of a Toll-Like Receptor-2 (TLR2) agonist. The activity of PEG Pam2Cys against the hepatocytic stages, erythrocytic stages and gametocytes of the rodent malaria parasite Plasmodium yoelii was investigated in laboratory mice. We show that administration of PEG-Pam2Cys, a soluble form of the TLR2 agonist S-[2,3-bis(palmitoyloxy)propyl] cysteine (Pam2Cys), significantly and dramatically reduces the numbers of malaria parasites that grow in the livers of mice following subsequent challenge with sporozoites. We also show that treatment can also clear parasites from the liver when administered subsequent to the establishment of infection. Finally, PEG-Pam2Cys can reduce the numbers of mosquitoes that are infected, and the intensity of their infection, following blood feeding on gametocytaemic mice. These results suggest that this compound could represent a novel liver stage anti-malarial that can be used both for the clearance of parasites following exposure and for the prevention of the establishment of infection. PMID- 30396011 TI - Repurposing of an old drug: In vitro and in vivo efficacies of buparvaquone against Echinococcus multilocularis. AB - The metacestode stage of the fox tapeworm Echinococcus multilocularis causes the lethal disease alveolar echinococcosis. Current chemotherapeutic treatment options are based on benzimidazoles (albendazole and mebendazole), which are insufficient and hence alternative drugs are needed. In this study, we screened the 400 compounds of the Medicines for Malaria Venture (MMV) Pathogen Box against E. multilocularis metacestodes. For the screen, we employed the phosphoglucose isomerase (PGI) assay which assesses drug-induced damage on metacestodes, and identified ten new compounds with activity against the parasite. The anti theilerial drug MMV689480 (buparvaquone) and MMV671636 (ELQ-400) were the most promising compounds, with an IC50 of 2.87 MUM and 0.02 MUM respectively against in vitro cultured E. multilocularis metacestodes. Both drugs suggested a therapeutic window based on their cytotoxicity against mammalian cells. Transmission electron microscopy revealed that treatment with buparvaquone impaired parasite mitochondria early on and additional tests showed that buparvaquone had a reduced activity under anaerobic conditions. Furthermore, we established a system to assess mitochondrial respiration in isolated E. multilocularis cells in real time using the Seahorse XFp Analyzer and demonstrated inhibition of the cytochrome bc1 complex by buparvaquone. Mice with secondary alveolar echinococcosis were treated with buparvaquone (100 mg/kg per dose, three doses per week, four weeks of treatment), but the drug failed to reduce the parasite burden in vivo. Future studies will reveal whether improved formulations of buparvaquone could increase its effectivity. PMID- 30396013 TI - Chloroquine analogs as antimalarial candidates with potent in vitro and in vivo activity. AB - In spite of recent efforts to eradicate malaria in the world, this parasitic disease is still considered a major public health problem, with a total of 216 million cases of malaria and 445,000 deaths in 2016. Artemisinin-based combination therapies remain effective in most parts of the world, but recent cases of resistance in Southeast Asia have urged for novel approaches to treat malaria caused by Plasmodium falciparum. In this work, we present chloroquine analogs that exhibited high activity against sensitive and chloroquine-resistant P. falciparum blood parasites and were also active against P. berghei infected mice. Among the compounds tested, DAQ, a chloroquine analog with a more linear side chain, was shown to be the most active in vitro and in vivo, with low cytotoxicity, and therefore may serve as the basis for the development of more effective chloroquine analogs to aid malaria eradication. PMID- 30396015 TI - Modulation of bacterial virulence and fitness by host glutathione. AB - Glutathione is a low molecular weight thiol that is important for maintaining intracellular redox homeostasis. Some bacteria are able to import exogenous glutathione as a nutritional source and to counter oxidative stress. In cytosolic pathogens Burkholderia pseudomallei and Listeria monocytogenes, host glutathione regulates bacterial virulence. In B. pseudomallei, glutathione activates the membrane-bound histidine kinase sensor VirA that leads to activation of the Type VI Secretion System. In L. monocytogenes, host glutathione leads to the binding of bacterial glutathione to the master virulence regulator PrfA as an allosteric activator. Glutathione can also modulate virulence factors to control their activity by S-glutathionylation. Thus, host glutathione acts as a spacio-temporal cue for some pathogens to switch on their virulence programs at the right time and place. PMID- 30396014 TI - Safety profile of subcutaneous trastuzumab for the treatment of patients with HER2-positive early or locally advanced breast cancer: primary analysis of the SCHEARLY study. AB - BACKGROUND: Subcutaneous trastuzumab (H SC) is a valuable alternative to the intravenous formulation. This study assessed H SC safety and tolerability in human epidermal growth factor receptor 2 (HER2)+ early/locally advanced breast cancer (EBC/LABC). METHODS: SCHEARLY is a prospective, two-cohort, non randomised, multicentre Italian trial included in the umbrella study UmbHER1, planning a 1-year treatment with H SC 600 mg in HER2+ EBC/LABC. Patients were sequentially assigned to cohort A (N = 121) and B (N = 119) to receive H SC via a handheld syringe and a single-use injection device, respectively. Adjuvant or neoadjuvant treatment included anthracycline-containing regimens followed by H SC plus taxanes and then alone for 18 cycles totally. RESULTS: Two hundred forty patients were enrolled (adjuvant therapy: 81.7%; neoadjuvant therapy: 18.3%), and 201 completed the treatment (early discontinuation was mainly due to intercurrent adverse events [AEs], 7.5%). Overall, the two cohorts displayed similar safety profiles. From H SC start, the rate of treatment-related AEs in the safety population (N = 228) was 3.9% for grade >=3 AEs; 0.9% for serious AEs (one pleuropericarditis and one anaphylactic shock, both resolved) and 14.5% for cardiac AEs, the most common being the decreased left ventricular ejection fraction (7.9%; mean reduction from the screening to the follow-up visit was 2.9%). No cases of congestive heart failure occurred. The rate of systemic administration-related reactions and local injection site reactions was 68.0% and 21.9%, respectively, mostly of grade 1-2. CONCLUSIONS: H SC 600 mg confirmed to be a safe and tolerable option as adjuvant/neoadjuvant therapy in patients with HER2+ EBC and LABC. CLINICALTRIALS. GOV IDENTIFIER: NCT01940497. PMID- 30396016 TI - A bisulfite treatment and PCR-free global DNA methylation detection method using electrochemical enzymatic signal engagement. AB - In this paper we report on a bisulfite treatment and PCR amplification-free method for sensitive and selective quantifying of global DNA methylation. Our method utilizes a three-step strategy that involves (i) initial isolation and denaturation of global DNA using the standard isolation protocol and direct adsorption onto a bare gold electrode via gold-DNA affinity interaction, (ii) selective interrogation of methylation sites in adsorbed DNA via methylation specific 5mC antibody, and (iii) subsequent signal enhancement using an electrochemical-enzymatic redox cycling reaction. In the redox cycling reaction, glucose oxidase (GOx) is used as an enzyme label, glucose as a substrate and ruthenium complex as a redox mediator. We initially investigated the enzymatic properties of GOx by varying glucose and ruthenium concentration to delineate the redox cyclic mechanism of our assay. Because of the fast electron transfer by ruthenium (Ru) complex and intrinsic signal amplification from GOx label, this method could detect as low as 5% methylation level in 50 ng of total DNA input. Moreover, the use of methylation-specific 5mC antibody conjugated GOx makes this assay relatively highly selective for DNA methylation analysis. The data obtained from the electrochemical response for different levels of methylation showed excellent interassay reproducibility of RSD (relative standard deviation) < 5% for n = 3. We believe that this inexpensive, rapid, and sensitive assay will find high relevance as an alternative method for DNA methylation analysis both in research and clinical platforms. PMID- 30396017 TI - Label-free electrochemical immunosensor for insulin detection by high-efficiency synergy strategy of Pd NPs@3D MoSx towards H2O2. AB - Here, a novel H2O2-based electrochemical immunosensor utilizing Pd nanoparticles functionalized three-dimensional wrinkly amorphous MoSx composites (Pd NPs@3D MoSx) as the platform was developed for the determination of insulin. In this work, Pd NPs@3D MoSx prepared in the presence of CTAB possessed an excellent catalytic activity for the reduction of H2O2. Furthermore, Pd NPs@3D MoSx with favorable biological compatibility can conjugate a great many antibodies to capture insulin. Attributed to the excellent property, electrochemical signals could be greatly amplified, contributing to improving detection sensitivity. Especially, SEM, TEM, and XPS information further confirmed nanomaterial's surface morphology and amorphous structure. Under the optimal conditions, the proposed immunosensor exhibited a sensitively linear relation with logarithmic insulin concentrations from 0.01 to 100 ng/mL with a low detection limit of 3.0 pg/mL (S/N = 3). Characterized by good reproducibility, specificity, and stability, the fabricated immunosensor may blaze a path for insulin detection in a real sample. PMID- 30396018 TI - Paper-based potentiometric sensing of free bilirubin in blood serum. AB - Bilirubin is predominantly formed in the liver as a result of breakdown of hemoglobin. Knowing the concentration of bilirubin in serum is important in evaluating the health of the liver, and for the diagnosis of hyperbilirubinemia (a condition that afflicts approximately 60% of full-term and 80% of pre-term newborns). This paper describes the design and fabrication of a potentiometric sensor for the determination of free bilirubin in serum. The sensor has a polymeric ion-selective membrane, and selectively measures free ionic bilirubin ("unbound" bilirubin - i.e., bilirubin not complexed to albumin or other complexing agents), in the presence of other anions - chloride, phosphate, pyruvate, deoxycholate, and lactate - also present in serum. The linear response range of the sensor (1.0 mM to 0.10 MUM bilirubin, measured in a sodium phosphate buffer with pH 8.6) covers the clinically-relevant concentration of bilirubin in serum (5-500 MUM). Free bilirubin could be detected in human blood serum with this potentiometric sensor. The components of the potentiometric bilirubin sensor were embedded in a paper-based device to provide a sensor that is disposable and easy to use, and thus is suitable for applications at the point-of-care. The paper-based potentiometric bilirubin sensor exhibited a response range of 5.0 0.10 mM (sufficient to cover the clinically-relevant concentration of bilirubin in serum). Only 15 MUL of sample is required for measurement of the concentration of free bilirubin, and the analysis can be performed in less than two minutes. PMID- 30396019 TI - The sensitive detection of ODAM by using sandwich-type biosensors with a cognate pair of aptamers for the early diagnosis of periodontal disease. AB - This research aims to develop biosensors which could diagnose periodontal diseases in early phases and predict the illness stage of patients, in order to give them adequate treatment timely. Human odontogenic ameloblast-associated protein (ODAM) is considered to be a potential biomarker for periodontal diseases, based on high correlation between the level of ODAM in gingival crevicular fluid (GCF) and the degree of periodontitis. Many aptamers, including a cognate pair of aptamers which can bind to the different sites of ODAM, were successfully screened in a very stringent condition employing saliva as a counter target through the graphene oxide-based systemic evolution of ligands by exponential enrichment (GO-SELEX). For the characterization of the aptamer candidates, GO-based fluorescence resonance energy transfer (GO-FRET) and surface plasmon resonance (SPR) assays were conducted. The sandwich-type binding of a cognate pair of aptamers to ODAM was additionally confirmed by employing circular dichroism (CD) and magnetic beads-based fluorescence imaging methods. The resulting cognate pair of aptamers, OD64 and OD35, were found to have their dissociation constant (Kd), 47.71 nM and 51.36 nM, respectively. The minimum detectable concentrations of a sandwich-type SPR biosensor were found to be 0.24 nM and 1.63 nM, respectively, for both buffered and saliva samples. Finally, using this cognate pair of aptamers, a sandwich-type lateral flow strip biosensor was successfully realized. This research shows the potential for implementation of a cognate pair of aptamers on point-of-care biosensors which enables simple, rapid, and non-invasive saliva-based diagnosis of periodontal-related diseases that can overcome current diagnostic methods and improve health care system. PMID- 30396020 TI - Two-photon semiconducting polymer nanoparticles as a new platform for imaging of intracellular pH variation. AB - Intracellular pH (pHi) plays a crucial role in cell physiological and pathological processes. We herein report an efficient pH-sensitive sensor based on two-photon excitable semiconducting polymer nanoparticles (PFV/PSMA-DA NPs) for pHi sensing. PFV/PSMA NPs were functionalized with redox-active dopamine (DA) and the obtained PFV/PSMA-DA NPs showed sensitive and reversible pH response over the pH range of 5.0-9.0. Owning to the high biocompatibility and pH-responsive DA, PFV/PSMA-DA NPs show low cytotoxicity and the quantification and imaging of intracellular pH changes of HeLa cells were successfully realized. Moreover, the detection of intracellular pH fluctuation induced by redox species such as NAC (N acetylcysteine) and H2O2 was also achieved by both one- and two-photon excitation of the PFV/PSMA-DA NPs probe. This work clearly shows that nanoprobe based on two photon PFV/PSMA-DA NPs could serve as a promising platform for quantitatively monitoring the intracellular pH fluctuations. PMID- 30396021 TI - Calorimetric sandwich-type immunosensor for quantification of TNF-alpha. AB - We report a lab-on-a-chip immunosesnor for quantification of the inflammatory cytokine TNF-alpha with picomolar sensitivity. The feasibility of the technology was demonstrated via accurate measurement of the concentration of TNF-alpha in astrocytes cell culture media. The immunoassay was performed in a microfluidic device with an integrated antimony/bismuth thermopile sensor and had a limit of detection of 14 pg mL-1. The device was fabricated using rapid prototyping xurography technique and consisted of two inlets and single outlet. Anti-TNF alpha monoclonal antibody was used to capture the analyte while the detection was performed using glucose oxidase-conjugated secondary antibody. Glucose (55 mM) was injected through a sample loop into the fluid flowing within the microfluidic device. A nanovolt meter connected to the thermoelectric sensor recorded the voltage change caused by the enzymatic reaction. Computer simulations using COMSOL Multiphysics were performed to analyze the effect of fluid velocity on the concentration of glucose within the reaction zone. A standard calibration curve was created using serial dilutions of synthetic TNF-alpha (0-2000 pg mL-1) by plotting the area under the curve of the signal versus the concentration of the analyte. The efficacy of the device was evaluated by quantifying TNF-alpha in the cell culture medium of lipopolysaccharide stimulated and non-stimulated astrocytes. The results demonstrated high accuracy of the calorimetric immunoassay when compared with gold standard commercial ELISA microplate reader. The immunosensor offers excellent reproducibility, accuracy, and versatility in the choice of the detection enzyme. PMID- 30396022 TI - Label free thrombin detection in presence of high concentration of albumin using an aptamer-functionalized nanoporous membrane. AB - Nanoporous alumina membranes have become a ubiquitous biosensing platform for a variety of applications and aptamers are being increasingly utilized as recognition elements in protein sensing devices. Combining the advantages of the two, we report label-free sensitive detection of human alpha-thrombin by an aptamer-functionalized nanoporous alumina membrane using a four-electrode electrochemical cell. The sensor response to alpha-thrombin was determined in the presence of a high concentration (500 MUM) of human serum albumin (HSA) as an interfering protein in the background. The sensor sensitivity was also characterized against gamma-thrombin, which is a modified alpha-thrombin lacking the aptamer binding epitope. The detection limit, within an appreciable signal/noise ratio, was 10 pM of alpha-thrombin in presence of 500 MUM HSA. The proposed scheme involves the use of minimum reagents/sample preparation steps, has appreciable response in presence of high concentrations of interfering molecules and is readily amenable to miniaturization by association with existing chip based electrical systems for application in point-of-care diagnostic devices. PMID- 30396023 TI - Cationic cyanine chromophore-assembled upconversion nanoparticles for sensing and imaging H2S in living cells and zebrafish. AB - Elevated hydrogen sulfide (H2S) level is closely associated with various diseases. So the sensing of H2S is noteworthy for divulging its role in diagnosing these diseases. Herein, we proposed poly(acrylic acid)-modified upconversion nanoparticles assembled with cationic near-infrared cyanine chromophores (Cy7-Cl) as the nanoprobe (Cy7-UCNPs) for monitoring H2S based on thiolation reactions. The presence of H2S resulted into about five-fold enhancement in the luminescence intensity of Cy7-UCNPs and the nanoprobe showed a good linearity (R2 =0.9952) over the range of 1.0 - 90 MUM. Furthermore, Cy7 UCNPs were successfully employed in sensing and imaging of exogenous and endogenous H2S in live cells and zebrafish. The system shows great potential in the field of nanobiomedicine because of the many excellent properties including high sensitivity, good selectivity, and low cytotoxicity. PMID- 30396024 TI - Front-block technical note: dental and bone borne distractors. AB - Orthognathic surgical technique of segmental osteogenesis distraction of the anterior mandible alveolar process (front-block) was introduced by Triaca and al. in 2001 [1] including lower incisors. The technical note describes distraction process used both, dental-borne distractor and bone-borne distractor. A genioplasty plate was used as a bone-borne distractor. The main point here is that distraction depends on two distraction vectors, a dental one and an alveolar one. It provides good stability and controlled segmental osteogenesis translation and allows sufficient alveolar segmental transport without loading the teeth too heavily. PMID- 30396025 TI - Contribution of a better maxillofacial phenotype in Silver-Russell syndrome to define a better orthodontics and surgical management. AB - INTRODUCTION: Maxillofacial phenotype for SRS is incompletely described in literature. The aim of this study was to describe a maxillofacial phenotype for SRS, to determine a better treatment. MATERIALS AND METHODS: A retrospective study was conducted including 37 patients with SRS. 24-control patients had been included and appareled. The subjective clinical examination included analyzes of SRS defined criteria. Frontal and lateral photographs had been reviewed, according to Farkas analysis; dental photographs had been examined for the deep bite and the crowding severity. Radiologic cephalometric analysis had been reviewed. RESULTS: Maxillofacial examination showed protruding forehead (55%), anteverted ears (55%) and low-set ears (16%), small triangular face (48%); retrognatia (29%) and micrognathia (13%). SSR patients presented a lower forehead transverse growth, forehead height, and higher sagittal and transverse mandibular growth than control patients. Deep-bite was present in 21 patients of patient, and crowding in 17 patients. Cephalometric analysis showed 18 patients with the skeletal class II. We did not note a correlation between sleep apnea and retrognatia, neither between genetic anomalies and craniofacial phenotype. CONCLUSION: In this study, we showed new SRS characteristics: small forehead, small mandible, skeletal class II and a dental phenotype, leading to a specific maxillofacial and orthopedic management. PMID- 30396026 TI - The use of intraoral local anaesthetic to aid reduction of acute temporomandibular joint dislocation. AB - Acute temporomandibular joint (TMJ) dislocation is distressing for patients and treatment can often be a challenge for clinicians. This report describes the use of intra oral local anaesthetic (LA) to aid reduction of the joint, reducing the need for conscious sedation, muscle relaxants or general anaesthetic. PMID- 30396027 TI - The effects of piezosurgery and submucosal dexamethasone injection on post operative complications after third molar surgery. AB - BACKGROUND: A retrospective clinical study was performed to compare the post operative effects of the conventional surgery, piezo surgery technique and submucosal dexamethasone injection in lower third molars extractions. METHODS: Data from 62 patients, subjected to surgical extraction of lower third molars, were pooled and divided into three groups such as: Conventional Group (22 patients), Piezo Group (20 patients) and Dex Group (conventional surgery + 4 mg/1 mL dexamethasone) (20 patients). Pain, swelling, trismus, analgesic consumption and operation time were comparatively evaluated. RESULTS: Pain values were found lower in Dex Group in comparison to Conventional Group at 7th day (P = 0.007). Edema found to be higher in Conventional Group than Dex Group at 2nd day (P = 0.025). Minimally trismus values were found in Dex Group and the difference between the Dex and Conventional Group found to be statistically significant both in 2nd (P = 0.048) and 7th days (P = 0.010). The analgesic consumption in the Conventional Group was found to be higher than Piezo Group at 2nd day (P = 0.002). CONCLUSION: The better post-operative values were obtained in the Dex Group. Although longer operative time is considered to be a disadvantage for the piezo technique, piezotome may be preferred for surgical procedures due to its positive results in comparison to the conventional technique. PMID- 30396028 TI - Two auricular epithesis surgical cases retained by a custom titanium implant: result at four years. AB - INTRODUCTION: This article aims at describing the four-year outcome of a surgical procedure implanting a patient specific epithesis system in two patients. TECHNICAL NOTE: After virtual 3D reconstruction of the anatomy and mirroring of the healthy ear, the position of the three Locator(r) attachments were optimized in the software to embed them as accurately as possible in the planned episthesis antihelix. The personalized plate bearing the three Locator(r) implants was then manufactured. Ten osteosynthesis screws were placed around the abutments to ensure bone anchorage. Post-operative antibiotic therapy was prescribed for the duration of ten days. The episthesis was placed two months post-operatively. The follow-up for each patient was 65 and 57 months respectively with no complications to report. CONCLUSION: 3D planning assists the surgeon and eliminates several constraints related to the placement of bone implants. It assists the surgical procedure and improves both the aesthetics and functional result of the surgery. PMID- 30396029 TI - Vascular permeability in the brain is a late pathogenic event during Rift Valley fever virus encephalitis in rats. AB - Rift Valley fever virus (RVFV) is a zoonotic disease of livestock that causes several clinical outcomes in people including febrile disease, hemorrhagic fever, and/or encephalitis. After aerosol infection with RVFV, Lewis rats develop lethal encephalitic disease, and we use this as a model for studying disease mechanisms of RVFV infection in the brain. Permeability of the brain vasculature in relation to virus invasion and replication is not known. Here, we found that vascular permeability in the brain occurred late in the course of infection and corresponded temporally to expression of matrix metalloproteinase-9 (MMP-9). Virus replication was ongoing within the central nervous system for several days prior to detectable vascular leakage. Based on this study, vascular permeability was not required for entry of RVFV into the brain of rats. Prevention of vascular leakage late in infection may be an important component for prevention of lethal neurological disease in the rat model. PMID- 30396030 TI - Use of multiple data sources to identify specific drugs and other factors associated with drug and alcohol screening of fatally injured motor vehicle drivers. AB - OBJECTIVE: Drugged driving crashes have significantly increased over the past two decades. The objectives of this study were to identify and characterize the drugs present in motor vehicle driver fatalities using multiple surveillance data sources; assess concordance of the data sources in identifying drug presence; and identify demographic and crash factors associated with drug and alcohol screening in fatally injured motor vehicle drivers. METHODS: Fatality Analysis Reporting System (FARS), Collision Report Analysis for Safer Highways (CRASH), and mortality data sets were linked; drug screening and positive drug screens were identified. Chi-square and conditional logistic regression were performed. RESULTS: The use of FARS data identified the majority of positive drug screens in the linked data set. Supplementation of FARS data with death certificate and CRASH data increased identification of specific drugs and drug classes detected among fatally injured motor vehicle drivers, although there was a low concordance among the data sources. Alcohol and depressants such as alprazolam had the highest frequencies among fatally injured drivers. Speeding, lack of occupant restraints, young age, commercial truck drivers, and speeding were all factors associated with increased odds of the fatally injured driver being drug or alcohol screened. CONCLUSIONS: These findings indicate that FARS drug information data may be strengthened through increased autopsy and consultation with medical examiners to better understand and interpret decedent toxicology testing results, and that states with low driver drug testing rates should consider mandatory driver drug testing in fatal crashes. PMID- 30396031 TI - Dietary patterns and abdominal obesity in middle-aged and elderly Japanese adults: Waseda Alumni's Sports, Exercise, Daily Activity, Sedentariness and Health Study (WASEDA'S Health Study). AB - OBJECTIVE: The aim of this study was to investigate the associations between dietary patterns and abdominal obesity among middle-aged and elderly Japanese people, using both waist circumference (WC) and visceral fat (VF) as indices. METHODS: A cross-sectional study was conducted with 829 adults (534 men and 295 women), 40 to 79 y of age, who participated in the Waseda Alumni's Sports, Exercise, Daily Activity, Sedentariness and Health Study (WASEDA'S Health Study). Dietary patterns were derived from principal component analysis. VF was measured using magnetic resonance imaging. To examine the associations of each dietary pattern with WC and VF, we calculated multivariate-adjusted means and 95% confidence intervals (CIs) of WC and VF for the tertile of each dietary pattern score. RESULTS: Two main dietary patterns were identified: "healthy Japanese" and "seafood and alcohol." The healthy Japanese dietary pattern score was inversely associated with WC and VF in men only. WC measurements were 84.9 cm (95% CI, 83.7 86.1), 83.9 cm (95% CI, 82.7-85.1), and 82.4 cm (95% CI, 81.2-83.6); Ptrend = 0.006, and VF measurements were 94.0 cm2 (95% CI, 85.6-102.4), 89.4 cm2 (95% CI, 81.1-97.7), and 80.4 cm2 (95% CI, 72.5-88.4); Ptrend = 0.027 for the lowest through the highest tertile of healthy Japanese dietary pattern scores in men. The seafood and alcohol dietary pattern was not associated with WC and VF. CONCLUSION: The healthy Japanese dietary pattern was negatively associated with WC and VF in middle-aged and elderly Japanese men. PMID- 30396032 TI - Leukocyte telomere shortening in Huntington's disease. AB - Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded CAG repeat. Though symptom onset commonly occurs at midlife and inversely correlates with the CAG repeat expansion, age at clinical onset and progression rate are variable. In the present study we investigated the relationship between leukocyte telomere length (LTL) and HD development. LTL was measured by real-time PCR in manifest HD patients (HD, n = 62), pre-manifest HD patients (pre-HD, n = 38), and age-matched controls (n = 76). Significant LTL differences were observed between the three groups (p < .0001), with LTL values in the order: HD < pre-HD < controls. The relationship between LTL and age was different in the three groups. An inverse relationship between mean LTL and CAG repeat number was found in the pre-HD (p = .03). The overall data seem to indicate that after age 30 years, LT begins to shorten markedly in pre-HD patients according to CAG number and increasing age, up to the values observed in HD. This very suggestive picture allowed us to hypothesize that in pre-manifest HD, LTL could be a measure of time to clinical HD onset. The possible use of LTL as a reliable biomarker to track HD development and progression was evaluated and discussed. PMID- 30396033 TI - Medicinal chemistry of vicinal diaryl scaffold: A mini review. AB - The privileged structures have been widely used as a valuable template in new drug discovery. 1,2-Diaryl or vicinal diaryl is a simple scaffold found in many drugs and naturally occurring compounds. From synthetic point of view, the vicinal diaryl derivatives are easily accessible due to their facile and expedient syntheses. These scaffolds have shown numerous interesting pharmacological activities against various diseases with lot of clinical potentials. This review aims to highlight the evidence of vicinal diaryl motif as a privileged scaffold in COX-2 inhibitors and CA-4 analogs. PMID- 30396034 TI - Influence of automation on mind wandering frequency in sustained attention. AB - There is accumulating evidence which shows that mind wandering may be increased within automated environments. This is particularly concerning when considering the negative effect of mind wandering on short-term performance. Seventeen participants performed an obstacle avoidance task under two conditions, manual and automated, each lasting 40 min. Subjects perceived the manual condition as more demanding than the automated one. We noted a significant increase of mind wandering frequency after only approximately 20 min under the automated condition. While learning and workload alone cannot explain these results, more automation-related phenomena, such as complacency or loss of agency, could play a role. Pupil diameter decreased during mind wandering compared to focus periods, revealing a decoupling from the task. The decrease remained stable in amplitude across different times and conditions. Research on mind wandering could be used to characterize an operator's state of mind regarding issues related to system interactions. PMID- 30396036 TI - Is it safe to treat cerebral venous thrombosis with oral rivaroxaban without heparin? A preliminary study from 20 patients. AB - OBJECTIVES: Newer oral anticoagulants like rivaroxaban are increasingly becoming the mainstay of treatment in systemic thrombosis. However cerebral venous thrombosis (CVT) is conventionally treated with heparin followed by oral vitamin K antagonists. Currently very little information is available about the use of rivaroxaban in CVT. Rivaroxaban has been used only after the initial treatment with heparin in the available studies. PATIENTS & METHODS: All patients with CVT between January 2017 and June 2017 were initiated directly on oral rivaroxaban. Critically ill patients including those requiring surgical intervention were excluded. The modified Rankin scale was used to assess clinical severity and a scale of 0-1 was defined as excellent outcome. Recanalization was assessed at 3 months follow-up with MR angiography. Complications of the drug including bleeding episodes during treatment and at follow-up were noted. RESULTS: Twenty patients were initiated on rivaroxaban and followed up for a mean duration of 6 months. Eighty percent (16/20) were males and the mean age was 34.1 years. Associated cerebral hemorrhagic infarcts were seen in 11(55%).Outcome was excellent in 19(95%). Complete recanalization was noted in 12(60%) and partial recanalization in 8(40%). No complications emerged out of the drug use. CONCLUSIONS: In clinically stable CVT rivaroxaban is safe and effective and may be used without previous heparin therapy. This can shorten the duration of hospitalization thereby decreasing the costs of treatment. PMID- 30396035 TI - Curcumin alleviates DSS-induced colitis via inhibiting NLRP3 inflammsome activation and IL-1beta production. AB - BACKGROUND: NLRP3 inflammasome mediates IL-1beta maturation, therefore plays a vital role in the development of IBD. Curcumin is known for possessing strong anti-inflammatory property. OBJECTIVE: The present study was to investigate the protective effects of curcumin on dextran sulfate sodium (DSS)-induced colitis through inhibiting NLRP3 inflammasome activation and IL-1beta production. METHODS: LPS-primed macrophages were treated with curcumin prior to DSS triggering NLRP3 inflammasome activation, IL-1beta secretion and ASC oligomerization were observed. The mechanisms of curcumin in the inhibition of DSS-induced inflammasome activation were explored. Curcumin or caspase-1/NLRP3 inhibitor was administrated respectively in DSS-induced colitis mouse model. The changes of body weight, disease activity index, colon length were measured. Additionally, mature IL-1beta and other inflammatory cytokines, MPO activity and histopathological damage were analyzed for the evaluation of colitis severity. RESULTS: NLRP3 inflammasome activation was dramatically inhibited by curcumin in DSS-stimulated macrophages, as evidenced by decreased IL-1beta secretion, less caspase-1 activation and ASC specks. Mechanistically, curcumin prevented DSS induced K+ efflux, intracellular ROS formation and cathepsin B release, three major cellular events mediating NLRP3 inflammasome activation. In DSS-induced colitis, curcumin administration significantly ameliorated colitis symptoms by reducing weight loss, DAI and colon length shortening. Meanwhile, curcumin significantly decreased the expression of multiple inflammatory cytokines (including mature IL-1beta, IL-6, MCP-1), MPO activity, caspase-1 activity as well as histopathological damage. Furthermore, blockage of NLRP3 inflammasome activation in vivo with specific NLRP3 inhibitor abrogated the further inhibitory effect of curcumin on DSS-induced colitis. CONCLUSION: Curcumin could strongly suppress DSS-induced NLRP3 inflammsome activation and alleviate DSS-induced colitis in mice, thus it may be a promising candidate drug in clinical application for IBD therapy. PMID- 30396037 TI - Assessment of anxiety and stress markers in children submitted to educational strategies and ART-restoration: A randomized clinical trial. AB - OBJECTIVE: Although atraumatic restorative treatment (ART) is considered to be a good option for anxious patients, there is a lack of information whether ART associated to oral health educational strategy (OHES) would positively influence the level of anxiety and stress in children. This study aimed to evaluate the impact of OHES on anxiety and stress markers of schoolchildren submitted to ART. DESIGN: A sample of 78 six- to eight-year-old schoolchildren, with carious lesions in dentin, were randomly divided into groups: OHES + ART-group (n = 39) and ART-group (n = 39). OHES consisted of an educational interactive strategy performed once a week for four weeks. ART was performed using a standardized procedure with hand instruments and glass-ionomer cement. Anxiety and stress markers were assessed subjectively by the modified Venham Picture Test (m-VPT), modified Venham Anxiety Scale (m-VAS), while objective measures consisted of heart rate (HR) and salivary cortisol and alpha-amylase levels evaluated before, during and after treatment. RESULTS: The two groups did not differ in the perceived anxiety and in anxious behavior, and the variation along the treatment was not significant in both groups (p > 0.05). Both groups also showed higher HR "Before ART-restoration" than the other time-points as an anticipatory anxiety. ART group showed higher HR than OHES + ART group during the "Explanation of procedure" (p = 0.041) and "Deep excavation" (p = 0.018), and only ART group showed higher amylase levels "Before ART" compared to "After ART" (p = 0.004). CONCLUSIONS: It was concluded that OHES associated with ART showed a positive effect in modulating heart rate and alpha-amylase levels, that is, those markers of stress objectively measured during ART-restoration. PMID- 30396038 TI - Compensatory interactions between developing maxillary anterior teeth in a sample of twins. AB - OBJECTIVES: The objective of this study was to revisit the topic of compensatory interactions between maxillary anterior teeth during development advanced by Sofaer et al. (1971). We addressed the hypotheses listed by Sofaer and colleagues using data derived from our Australian twin sample to investigate whether final tooth size in permanent maxillary central incisors and canines showed evidence of developmental compensation for adjacent missing or microdont lateral incisors. Such compensation is one factor interacting in the complex system of dental development. MATERIALS AND METHODS: A 2D image analysis system was used to measure crown height from the labial view, labiopalatal crown width from the incisal view, and mesiodistal crown width from both the labial (MDl) and incisal (MDi) views of the permanent maxillary central incisors and canines on the dental study model of twins enrolled in a longitudinal study of dental development. RESULTS: Developmental variations of maxillary lateral incisors influence the morphogenesis of the adjacent teeth. For example, individuals with one missing lateral incisor and one lateral incisor of average dimensions, had significantly larger central incisors than the control group for the MDl and MDi dimensions (p < 0.05). Of the 7 monozygotic twin pairs, 6 were discordant in maxillary anterior hypodontia and microdontia, and 13 out of 14 dizygotic twin pairs were discordant. CONCLUSIONS: This study provides further evidence of developmental interactions in the maxillary anterior region, partially supporting Sofaer and colleagues' hypotheses. These interactions are part of a complex adaptive system involving genetic, epigenetic and environmental factors. PMID- 30396039 TI - Effect of non-surgical periodontal therapy on salivary metabolic fingerprint of generalized chronic periodontitis using nuclear magnetic resonance spectroscopy. AB - OBJECTIVE: Metabolomic analysis of saliva proved its accuracy in discriminating patients with generalized chronic periodontitis (GCP) from healthy subjects by identifying specific molecular signatures of the disease. There is lack of investigations concerning the effect of periodontal treatment on individual metabolic fingerprints. Therefore, the aim of this study was to determine whether non-surgical periodontal therapy could change salivary metabolomic profile in GCP to one more similar to periodontal health. DESIGN: Unstimulated whole saliva of 32 controls and 19 GCP patients were obtained prior to and 3 months after conventional staged non-surgical periodontal therapy. Metabolic profiling was performed using Nuclear Magnetic Resonance (NMR) spectroscopy, followed by univariate and multivariate paired approaches to assess the changes introduced by the therapy. RESULTS: In GCP group, periodontal treatment led to an improvement in all clinical parameters (p < 0.001). The accuracy of the multivariate model in discriminating the metabolomic profile of each GCP patient at two time points was 92.5%. Despite the almost perfect separation of the spectra in the metabolic space, the univariate analysis failed to identify significant variations in single metabolite content. The post-treatment metabolic profile of GCP patients could not be assimilated to that of healthy controls who exhibited different levels of lactate, pyruvate, valine, proline, tyrosine, and formate. CONCLUSIONS: Based on these data, NMR-spectroscopic analysis revealed that, despite significant changes in the overall metabolomic fingerprint after non-surgical therapy, GCP patients maintained a distinctive metabolic profile compared to healthy individuals. PMID- 30396040 TI - A 3D tumor microenvironment regulates cell proliferation, peritoneal growth and expression patterns. AB - Peritoneal invasion through the mesothelial cell layer is a hallmark of ovarian cancer metastasis. Using tissue engineering technologies, we recreated an ovarian tumor microenvironment replicating this aspect of disease progression. Ovarian cancer cell-laden hydrogels were combined with mesothelial cell-layered melt electrospun written scaffolds and characterized with proliferation and transcriptomic analyses and used as intraperitoneal xenografts. Here we show increased cancer cell proliferation in these 3D co-cultures, which we validated using patient-derived cells and linked to peritoneal tumor growth in vivo. Transcriptome-wide expression analysis identified IGFBP7, PTGS2, VEGFC and FGF2 as bidirectional factors deregulated in 3D co-cultures compared to 3D mono cultures, which we confirmed by immunohistochemistry of xenograft and patient derived tumor tissues and correlated with overall and progression-free survival. These factors were further increased upon expression of kallikrein-related proteases. This clinically predictive model allows us to mimic the complexity and processes of the metastatic disease that may lead to therapies that protect from peritoneal invasion or delay the development of metastasis. PMID- 30396041 TI - Quantitative cardiology and computer modeling analysis of heart failure in systole and in diastole. AB - Clinical cardiology diagnosis relies on the assessment of a set of specified parameters. Computer modeling is a powerful tool that can provide a realistic interpretation of the variations of these parameters through computational quantification. Here we present an overview of different aspects of diagnosis that are based on evaluation of either systolic or diastolic cardiac abnormalities. Emphasis is on the quantitative hemodynamic assessment and modeling. For myocardial ischemia and stunning, multi-scale modeling from single fiber to the global ventricular level is demonstrated. The classic force-velocity length relations are found to be applicable even for modern quantitative cardiac assessment. The reduced systolic shortening and delayed diastolic relaxation associated with stunning and ischemia can be reproduced even at the single muscle fiber level. In addition, ejection fraction (EF) which has been viewed as an important index in assessing the state of the heart, is found to be inadequate for the diagnosis and assessment of heart failure (HF) in differentiation of HF patients with reduced EF (HFrEF) or with preserved EF (HFpEF). Parameters that relate to structural changes whether at fiber or the global levels are found to be most appropriate to quantify the cardiac function, hence for its quantitative diagnosis. Parameters that govern heart-arterial system interaction when the LV is single-loaded with pressure-overloaded LV hypertrophy or double-loaded as in LVH with aortic valve stenosis are also quantified. It is shown that a computational modeling approach can be invaluable in delineating parameters that are critical for quantitative cardiology diagnosis. PMID- 30396042 TI - Seizures and recurrence of Takotsubo syndrome: One clinical presentation and trigger, but two different anatomical variants in the same patient. A case to meditate on. PMID- 30396043 TI - A novel micro-grooved collagen substrate for inducing vascular smooth muscle differentiation through cell tissue arrangement and nucleus remodeling. AB - Vascular smooth muscle cells (SMCs) actively remodel arterial walls through biomechanical signals and dedifferentiate from the contractile to the synthetic state under pathological conditions. It is important to determine the differentiation mechanism of SMCs to understand their pathophysiology in disease. Previously, we found that the F-actin cytoskeleton in dedifferentiated SMCs on dishes was firmly connected to the nucleus, and that internal mechanical signals in SMCs are transmitted directly to the nucleus, indicating that nuclear cytoskeletal interactions could be associated with SMC differentiation. However, mechanical environments in vivo are quite different from those of cultured cells: SMCs in vivo show an elongated shape and form a tissue that aligns with the circumferential direction of the walls. Thus, in the present study, we established a simple technique to fabricate a novel micro-grooved native collagen substrate that mimics the elongated cell shapes and alignment observed in vivo. The substrates had "wavy wrinkle" grooves with a width of ~5 um and a Young's modulus of ~500 kPa, which were quite similar to those of the elastic lamina in vascular tissues. Using confocal microscopy image-based analysis, and nano indentation imaging with atomic force microscopy, we found that SMCs on the micro grooved collagen formed significant cell tissue arrangement, and changed their nuclear morphology to a "slim ellipsoid" in response to the force-reduction caused by F-actin remodeling, which consequently improved SMC differentiation. These findings indicated that this type of intracellular force-reduction around the nucleus has a crucial effect on SMC differentiation. Our micro-grooved collagen substrate is a powerful tool to investigate the mechanism of vascular SMC mechanotransduction. PMID- 30396044 TI - Do endodontic retreatment techniques influence the fracture strength of endodontically treated teeth? A systematic review and meta-analysis. AB - One of the major concerns about endodontically retreated teeth (ERT) is undoubtedly its loss of remnant structure, which could lead to consequently greater fracture risk. Therefore, the objective of this systematic review is to assess the influence of endodontic retreatment on the fracture strength of the dental tooth remnant. In vitro studies assessing the influence of mechanical retreatment on the mechanical properties (static or under fatigue) of restored teeth were searched in PubMed and SCOPUS databases. Three independent reviewers screened titles/abstracts of articles and the full-text of potentially eligible studies. The risk of bias was independently assessed by one researcher and verified by another two. Comparison between the mean load to fracture of teeth after endodontic treatment and after endodontic retreatment were estimated using pairwise random effects meta-analysis to calculate pooled mean differences. Three studies were included for the systematic review and 2 for the meta-analysis. The pooled effect indicated a statistical difference (Mean difference: -121.03 95%CI: -183.02, -59.05) between conditions favoring the endodontically treated teeth. However, the low number of studies combined with their heterogeneity made it difficult to prove such phenomenon. ERT might present lower fracture strength than endodontically treated teeth. However, more coherent laboratory tests may provide better evidence and quantitative parameters on how much reliability can be attributed to an endodontic retreatment, in addition to which technique can provide more predictable results in this conservative approach. PMID- 30396045 TI - Simulation of 3D nanomanipulation for rough spherical elastic and viscoelastic particles in a liquid medium; experimentally determination of cell's roughness parameters and Hamaker constant's correction. AB - Due to the softness and vulnerability of biological cells, in manipulation operations, it is not possible to insert excessive force to move these cells. Also, cells in their living environment face with many dynamic factors; therefore, in order to prevent their destruction and death, consideration the environmental conditions, the theoretical studies that underlie the laboratory research should be closer to the actual results. So, in this article by simultaneous consideration of cell's viscoelasticity and asperities on its surface, as well as the correction of the viscoelastic constant in the liquid medium, the effects of the number of asperities on the contact area between cell and substrate on the manipulation process are investigated and by considering different mediums effects, cell's roughness and developed Hamaker for viscoelastic state, more accurate results of simulations are obtained. On the other hand, atomic force microscopy is also a powerful and multifunctional imaging device that provides observation and manipulation of biological samples, including single-cells, in a liquid medium. Consequently, in this study, using this device, the topography of the benign breast cancer cell is carried out in a liquid medium in contact mode. To correct the viscoelastic Hamaker constant, results are obtained using the Gwyddion software for extracting the roughness radius and the particle's height distribution function. In addition, simulation of the 3D manipulation for elastic and viscoelastic spherical bioactive particles in both air and liquid mediums is done applying particle's roughness with elastic and viscoelastic Hamaker constants. Results indicate that in the liquid medium due to changes in the adhesion force as well as the presence of drag force and surface tension, the critical force is reduced compared to air medium, and the effect of particle's roughness on the critical force and time is related to the number of asperities on the contact surface. Also, results are in good agreement with results of applying the particle's folding coefficient in the manipulation. In the second phase of the manipulation, the change trend in the manipulation force varies in different operating conditions. PMID- 30396046 TI - Catalytic conversions of atmospheric sulfur dioxide and formation of acid rain over mineral dusts: Molecular oxygen as the oxygen source. AB - Sulfur dioxide (SO2) ranks as a major air pollutant and is likely to generate acid rain. When molecular oxygen is the oxygen source, the regular surfaces of gibbsite (one of the most abundant mineral dusts) show no reactivity for SO2 conversions to H2SO4, while the partially dehydrated (100) surface with coordination-unsaturated Al sites becomes catalytically effective. Because of the easy availability of molecular oxygen, results manifest that acid rain can form under all atmospheric conditions and may account for the high conversion ratio of atmospheric SO2. The (100) and (001) surfaces show divergent catalytic effects, and hydrolysis is always the rate-limiting step. Path A (hydrolysis and then oxidation) is preferred for (100) surface, whereas a third path with obviously lower activation barriers is presented for (001) surface, which is non-existent for (100) surface. Atomic oxygen originating from the dissociation of molecular oxygen is catalytically active for (100) surface, while the active site of (001) surface fails to be recovered, suggesting that SO2 conversions over gibbsite surfaces are facet-controlled. This work also offers an environmentally friendly route for production of H2SO4 (one of the essential compounds in chemical industry), directly using molecular oxygen as the oxygen source. PMID- 30396047 TI - Effect of coating method on the structure and properties of a novel PbO2 anode for electrochemical oxidation of Amaranth dye. AB - This study deals with the electrochemical degradation of Amaranth in aqueous solution by means of stainless steel (SS) electrodes coated with a SiOx interlayer deposited by Plasma Enhanced Chemical Vapour Deposition and a modified PbO2 top layer deposited by continuous galvanostatic electrodeposition. The morphological characterization of the PbO2 top-layer performed by Field Emission Scanning Electron Microscope put in evidence that the SiOx, interlayer allows obtaining a more integrated PbO2/SS electrode with a very homogeneous PbO2 film. The composition of the lead oxide layer was investigated by X-ray Diffractometry, showing that the beta-PbO2/alpha-PbO2 ratio in the top layer deposited on the SiOx film was four times higher respect to the one deposited directly on the stainless steel surface. In addition, the electrochemical behaviour of SS/SiOx/PbO2 interfaces was studied by electrochemical impedance spectroscopy (EIS). The EIS results showed that the presence of SiOx favors electron transfer within the oxide layer which improves electro-oxidation capability. Moreover, bulk electrolysis showed that over 100% colour removal and 84% COD removal, using SS/SiOx/PbO2 at acidic pH were reached after 300 min. High Performance Liquid Chromatography analysis was used for the quantitative determinations of initial Amaranth dye molecule removal and to evaluate its specific degradation rate. In order to evaluate the phototoxicity of treated solution with different by products, different tests of germination were performed and proved that the electrochemical treatment with modified PbO2 could be as an efficient technology for reducing hazardous wastewater toxicity and able to produce water available for reuse. PMID- 30396048 TI - Letter to the editor: Inadequate evidence to support improved patient outcomes with combinatorial pharmacogenomics. PMID- 30396049 TI - Testosterone therapy and venous thromboembolism: A systematic review and meta analysis. AB - BACKGROUND: Testosterone prescribing for men has dramatically increased, and there have been concerns about inappropriate use and adverse events. While regulatory bodies have warned about increased risk of venous thromboembolism (VTE), published clinical data supporting an increased risk for VTE are limited. OBJECTIVE: To conduct a systematic review of studies examining the association between testosterone therapy in men and VTE. METHODS: Comprehensive searches of multiple databases were performed from inception through October 3rd, 2018. Randomized control trials (RCTs) and observational studies examining the association between exogenous testosterone (any route) and VTE. Study selection and data extraction were performed by two independent investigators. Random effect model meta-analyses were used to estimate pooled odds ratios (OR) and 95% confidence intervals (CIs). Heterogeneity among studies was evaluated using the I2 statistic. Risk of bias was assessed using the Cochrane and Newcastle-Ottawa tools. RESULTS: Six RCTs (n = 2236) and 5 observational studies (n = 1,249,640) were included. Five RCTs were performed in men with documented hypogonadism. The observational studies included: 2 case-control studies, 2 retrospective cohorts, and 1 retrospective cohort with a nested case-control study. There was no evidence of a statistically significant association between VTE and testosterone (OR 1.41, 95%CI 0.96-2.07). Heterogeneity was high (I-squared = 84.4%). The association remained nonsignificant when the analysis was stratified by study design: RCTs (2.05, 95% CI 0.78-5.39); cohort (1.06, 95% CI 0.85-1.33); and case control (1.34, 95% CI 0.78-2.28). The overall risk of bias was moderate. CONCLUSIONS: The current evidence is of low certainty but does not support an association between testosterone use and VTE in men. PMID- 30396050 TI - Quantitative bioanalytical assay for the tropomyosin receptor kinase inhibitor larotrectinib in mouse plasma and tissue homogenates using liquid chromatography tandem mass spectrometry. AB - Larotrectinib is a promising tyrosine kinase inhibitor for solid tumors harboring tropomyosin receptor kinase gene fusions. A bioanalytical assay was developed for this drug in small volume samples using a 96-well format to efficiently support multiple mouse studies. The assay was completely validated for mouse plasma and partially for homogenates of eight different tissues: brain, heart, kidneys, liver, lungs, small intestine, spleen, and testes. Proteins in 10-MUl samples were precipitated using acetonitrile containing momelotinib as internal standard. Chromatographic separation of analyte and internal standard from endogenous interferences was performed on an ethylene bridged octadecyl silica column using 0.1% (v/v) formic acid (in water) and methanol for gradient elution. Electrospray ionization and selected reaction monitoring on a triple quadrupole mass spectrometer were used for detection. In the range 1-2000 ng/ml the drug could be quantified in all 9 matrices with precisions (within-day and between-day) in the range 2.7-11.1% and accuracies in the range 87.4-101.4%. Compounds were sufficiently stable under all investigated conditions except for kidney homogenate. A pilot pharmacokinetic and tissue distribution study in mice demonstrated the applicability of the new presented assay for larotrectinib. PMID- 30396051 TI - Rapid identification of urokinase plasminogen activator inhibitors from Traditional Chinese Medicines based on ultrafiltration, LC-MS and in silico docking. AB - The urokinase plasminogen activator (uPA) is regarded as the crucial trigger for plasmin generation, which is involved in several diseases especially for neoplasm metastasis. In this study, an efficient approach integrating ultrafiltration, LC/MS, bioassay and in silico docking, was proposed for rapidly detecting uPA ligands from Traditional Chinese Medicines (TCMs). Forty-two TCMs were initially assessed, and as illustrative case studies, Galla Chinensis and Sanguisorbae Radix, which appeared significant inhibitory activities on uPA, were chosen to develpe and verify the strategy. A total of seven uPA ligands were successfully detected and identified. Two of them, pentagalloylglucose and 28-O-beta-d glucopyranosyl pomolic acid, were demonstrated to be potential inhibitors, with IC50 at 1.639 MUM and 37.82 MUM repectively. Furthermore, a combinatorial compound library screening combined with in silico docking assay, was revealed that ursolic acid (IC50 = 2.623 MUM) was also speculated to be a potent parent structure for inhibition of uPA. This approach offers a multidimensional perspective to discover uPA-binding leading compounds from TCMs or other complex mixtures, which would provide an efficient route for drug discovery. PMID- 30396052 TI - Non-invasive quantification of malondialdehyde biomarker in human exhaled breath condensate using self-assembled organic-inorganic nanohybrid: A new platform for early diagnosis of lung disease. AB - A novel electrochemical sensor was developed towards recognition of malondialdehyde (MDA) with modifying the glassy carbon electrode (GCE) by self assembled riboflavin-taurine (RFPT) as organic substrate and silver nanoparticle (Ag NPs) as inorganic nano-catalyst. Therefore, a novel biocompatible and anti bacterial substrate were prepared for the construction of electrode. In proposed sensor, the RF-PT polymer film led to the emergence of electroactive and suitable substrate for the immobilization of Ag NPs. The use of the proposed nano-hybrid significantly amplified the electrochemical signals the redox behavior was investigated using various electrochemical methods including cyclic voltammetry (CV), differential pulse voltammetry (DPV), square wave voltammetry (SWV), and linear sweep voltammetry (LSV). It is the adaptation of the established RF-PT-Ag NPs organic-inorganic hybrid for a selective, robust, and generalizable sensing system that is the emphasis of this work. The results show that the proposed platform has a good sensitivity in the detecting of MDA with a low limit of quantification (LLOQ) of 0.59 +/- 0.05 MUM. In addition, the modified electrode reveals promising efficiency against MDA oxidation and its side-products destructive effects. For the first time, the engineered sensor was used to non invasive determination MDA in exhaled breath condensate (EBC) samples without the need to extra sample preparation steps. The results show RF-PT-AgNPs as a novel biocompatible interface can provide appropriate, reliable, in-expensive, fast, and user-friendly diagnostic tools in the detection of MDA in human real samples. PMID- 30396053 TI - Simultaneous LC-MS/MS analysis of simvastatin, atorvastatin, rosuvastatin and their active metabolites for plasma samples of obese patients underwent gastric bypass surgery. AB - Statins, HMG-CoA reductase inhibitors, are considered the first line treatment of hyperlipidemia to reduce the risk of atherosclerotic cardiovascular diseases. The prevalence of hyperlipidemia and the risk of atherosclerotic cardiovascular diseases are higher in obese patients. Published methods for the quantification of statins and their active metabolites did not test for matrix effect of or validate the method in hyperlipidemic plasma. A sensitive, specific, accurate, and reliable LC-MS/MS method for the simultaneous quantification of simvastatin (SMV), active metabolite of simvastatin acid (SMV-A), atorvastatin (ATV), active metabolites of 2-hydroxy atorvastatin (2-OH-ATV), 4-hydroxy atorvastatin (4-OH ATV), and rosuvastatin (RSV) was developed and validated in plasma with low (52 103 mg/dl, <300 mg/dl) and high (352-403 mg/dl, >300 mg/dl) levels of triglyceride. The column used in this method was ACQUITY UPLC BEH C18 column (2.1 * 100 mm I.D., 1.7 MUm). A gradient elution of mobile phase A (10 mM ammonium formate and 0.04% formic acid in water) and mobile phase B (acetonitrile) was used with a flow rate of 0.4 ml/min and run time of 5 min. The transitions of m/z 436.3 -> 285.2 for SMV, m/z 437.2 -> 303.2 for SMV-A, m/z 559.2 -> 440.3 for ATV, m/z 575.4 -> 440.3 for 2-OH-ATV and 4-OH-ATV, m/z 482.3 -> 258.1 for RSV, and m/z 412.3 -> 224.2 for fluvastatin (internal standard, IS) were determined by Selected Reaction Monitoring (SRM) method to detect transitions ions in the positive ion mode. The assay has a linear range of 0.25 (LLOQ) -100 ng/ml for all six analytes. Accuracy (87-114%), precision (3-13%), matrix effect (92-110%), and extraction recovery (88-100%) of the assay were within the 15% acceptable limit of FDA Guidelines in variations for plasma with both low and high triglyceride levels. The method was used successfully for the quantification of SMV, ATV, RSV, and their active metabolites in human plasma samples collected for an ongoing clinical pharmacokinetic and pharmacodynamic study on patients prior to and post gastric bypass surgery (GBS). PMID- 30396054 TI - Development and validation of a sensitive LC-MS/MS method for the estimation of scopolamine in human serum. AB - Scopolamine is an anticholinergic alkaloid that is widely used in the form of a transdermal system to manage nausea associated with motion sickness. Currently available methods to quantify scopolamine require large sample volumes and involve cumbersome sample preparation. In this work, a simple method for the rapid separation and sensitive quantification of scopolamine in human serum was developed. Scopolamine was extracted from 0.5 mL of human serum using solid-phase extraction. The extracted samples were injected onto Zorbax XDB-C18 column (4.6 * 50 mm, 1.8 MUm, and 600 bar) on an Agilent 1200 series HPLC. The chromatographic separation involved gradient elution with water and acetonitrile containing 0.1% v/v formic acid as a mobile phase. The samples were quantified in positive ion mode using a TSQ Quantum triple quadrupole mass spectrometer. The assay was validated and found to be linear over a concentration range of 5-5000 pg/mL. The total assay precision and accuracy was 6.3% and 96%, respectively. The lower limit of quantification (LLOQ) of the assay was 5 pg/mL. The assay was used in a human pharmacokinetic study to measure the concentration of scopolamine in serum after an administering scopolamine as transdermal delivery system or as an intravenous bolus dose. PMID- 30396055 TI - Follicle blood flow and FSH concentration associated with variations in characteristics of follicle selection in heifers. AB - Selection of the dominant follicle during a follicular wave is manifested by diameter deviation. At deviation (day 0), growth rate continues for the future dominant follicle (F1) and begins to decrease for the largest subordinate follicle (F2). The percentage of color-Doppler blood-flow signals in the wall of F1 and F2 and the temporality between FSH concentration and F1 and F2 diameter were determined daily in waves 1 and 2 in 24 Holstein heifers. Diameter and blood flow were compared among classes of deviation: (1) conventional (F2 >= 7.0 mm on day 0), (2) F2-undersized (F2 < 7.0 mm on day 0), and (3) F1,F2-switched (F2 larger than F1 on days -1 or 0). A class-by-day interaction for diameter of F2 (P < 0.004) and for blood-flow percentage of F2 (P < 0.02) represented greatest values on days -1 or 0 in the switched class and greater values in the conventional than undersized class. Changes were similar between diameter and blood flow in F1 and F2 before deviation. Blood flow in F2 decreased sooner than diameter after deviation indicating that a decrease in vascular perfusion preceded a decrease in diameter. Relationships between F1 and FSH in conventional deviation were similar between waves 1 and 2 for (1) growth rate of F1 on days -1 to 0, (2) interval from emergence of F1 at 4 mm to deviation, and (3) decrease in FSH on days -2 to 0. Relationships between F2 diameter and FSH were dissimilar between classes and between waves 1 and 2 indicating other hormones or factors are also involved in the complex control of F2. For example, the growth rate of F2 was greater (P < 0.05) for conventional than undersized class during wave 1 but similar between classes during wave 2. The FSH surge 2 was similar in profile and prominence between classes but the interval from the FSH peak of surge 2 to deviation was shorter (P < 0.05) in the undersized class (1.5 +/- 0.3 d) than in the conventional class (2.3 +/- 0.3 d). This was a novel finding and accounted for some of the dissimilarities in growth rate of follicles between classes in wave 2. Results did not support the hypothesis that the extent of blood flow in the wall of future dominant and largest subordinate follicles before deviation is an earlier indicator of follicle destiny than diameter. Results supported the hypothesis that follicle dynamics and FSH concentrations before deviation are temporally associated within conventional and undersized deviation classes but the temporality differs between classes. PMID- 30396056 TI - Comparing factor structures of depressed patients with and without suicidal ideation, a measurement invariance analysis. AB - BACKGROUND: Suicidality could be associated with specific combinations of biological, social and psychological factors. Therefore, depressive episodes with suicidal ideation could be different from depressive episodes without suicidal ideation in terms of latent variable structures. METHODS: In this study we compared latent variable structures between suicidal and non-suicidal depressed patients using confirmatory factor analysis (CFA), following a measurement invariance test procedure. Patients (N = 919) suffering from major depressive disorder were selected from the Netherlands Study of Depression and Anxiety (NESDA) and split into a group that showed no symptoms of suicidal ideation (non SI; N = 691) and a suicidal ideation (SI) group that had one or more symptoms of suicidal ideation (N = 228). Depression and anxiety symptoms were measured using the short form of the Mood and Anxiety Symptoms Questionnaire (MASQ-D30). RESULTS: CFA implied a difference in latent variable structures between the non SI sample (CFI 0.957; RMSEA 0.041) and the SI sample (CFI 0.900; RMSEA 0.056). Subsequent multiple-group CFA showed violations of measurement invariance. The General distress and Anhedonic depression subscales were best indicated by hopelessness and lack of optimism in the SI sample and by dissatisfaction and not feeling lively in the non-SI sample. Overall, the SI sample had higher scores and lower inter-item correlations on the Anhedonic depression items. LIMITATIONS: We have included very mild cases of suicidal ideation in our SI sample. CONCLUSIONS: On a latent variable level, depression with suicidal ideation differs from depression without suicidal ideation. Results encourage further research into the symptom structure of depression among suicidal patients. PMID- 30396057 TI - Conceptual framework for social connectedness in mental disorders: Systematic review and narrative synthesis. AB - BACKGROUND: Adults with mental disorders are at a high risk of loneliness. Loneliness has been implicated in a wide variety of physical and mental health problems. Social connectedness interventions are one means to tackle loneliness but have shown mixed effectiveness. This study aims to: (1) identify existing measures of social connectedness and (2) develop a conceptual framework of social connectedness to inform future measurement and the development of new interventions. METHODS: A systematic review of studies from six bibliographic databases was conducted. Studies were included if a quantitative measure of social connectedness was used amongst samples of adults with a mental disorder. Two analyses were conducted: a best evidence synthesis of measurement properties for identified measures and a narrative synthesis of items from these measures. RESULTS: Twenty-eight papers were included, employing 21 different measures. Measurement properties were of poor or unknown quality. Data synthesis identified a five-dimension conceptual framework of social connectedness: Closeness, Identity and common bond, Valued relationships, Involvement and Cared for and accepted (giving the acronym CIVIC). LIMITATIONS: The majority of studies were conducted in high-income countries. It was not possible to validate the conceptual framework using the identified psychometric data. CONCLUSIONS: The new five-dimension framework of social connectedness in mental disorders provides the theoretical foundation for developing new measures and interventions for social connectedness. PMID- 30396058 TI - Self-rated walking disability and dynamic ankle joint stiffness in children and adolescents with Juvenile Idiopathic Arthritis receiving intraarticular corticosteroid joint injections of the foot. AB - BACKGROUND: Children and adolescents with Juvenile Idiopathic Arthritis (JIA) exhibit deviations in ankle dynamic joint stiffness (DJS, or moment-angle relationship) compared to healthy peers, but the relationship between ankle DJS and self-reported walking impairments has not been studied. This secondary analysis aimed to investigate the relationship between ankle DJS and self reported walking disability in juveniles with JIA, and to determine whether intraarticular corticosteroid foot injections (IACI) were associated with long term changes in ankle DJS. RESEARCH QUESTIONS: Is ankle DJS altered in children with JIA reporting walking difficulties compared to children with JIA reporting no walking difficulties? Are IACIs associated with persistent alterations in ankle DJS? METHODS: Gait dynamics (DJS), foot pain, and foot-related disability were assessed in 33 children with JIA before intraarticular corticoid foot injection (IACI), and three months after IACI. Using self-reported walking capacity scores, children were classified as either having no walking difficulties (ND) or having walking difficulties (WD). Inferential statistics were used to compare demographics, pain, impairment scores, and ankle DJS between the groups. RESULTS: Before treatment, in the WD group, ankle DJS was significantly decreased both in the early rising phase (ERP = 0.03+0.02 vs. 0.05+0.02 Nm(kg*deg)- 1) and late rising phase (LRP = 0.11+0.06 vs. 0.24+0.22 Nm(kg*deg)-1) compared to the ND group. At three months, the ERP was still significantly decreased in the WD group (ERP = 0.03+0.01 vs. 0.05+0.03 Nm(kg*deg) 1). SIGNIFICANCE: Among children and adolescents with JIA who reported walking difficulties prior to IACIs, alterations in DJS in early stance phase (decreased ERP) remained three months after IACI suggesting persistent gait adaptations, possibly related to pain. Pre-treatment gait analysis may aid in identifying children who will not have long term benefit from IACIs in terms of improved gait, and therefore, may be informed and have the choice to be spared the risk of side effects associated with this treatment. PMID- 30396059 TI - Repeatability of electromyography recordings and muscle synergies during gait among children with cerebral palsy. AB - BACKGROUND: Clinical gait analysis is commonly used in the evaluation and treatment of children with cerebral palsy (CP). While the repeatability of kinematic and kinetic measures of gait has previously been evaluated, the repeatability of electromyography (EMG) recordings or measures calculated from EMG data, such as muscle synergies, remains unclear for this population. RESEARCH QUESTION: Are EMG recordings and muscle synergies from clinical gait analysis repeatable between visits for children with CP? METHODS: We recruited 20 children with bilateral CP who had been referred for clinical gait analysis. The children completed two visits less than six weeks apart with EMG data collected bilaterally from five muscles (rectus femoris, medial hamstrings, vastus lateralis, anterior tibialis, and medial gastrocnemius). Variance ratio and cosine similarity were used to evaluate repeatability of EMG waveforms between visits. Nonnegative matrix factorization was used to calculate synergies from EMG data at each visit to compare synergy weights and activations. RESULTS & SIGNIFICANCE: The inter-visit variance ratios of EMG data for children with CP were similar to previously reported results for typically-developing children and unimpaired adults (range: 0.39 for vastus lateralis to 0.66 for rectus femoris). The average cosine similarity of the EMG waveforms between visits was greater than 0.9 for all muscles, while synergy weights and activations also had high similarity - greater than 0.8 and 0.9 between visits, respectively. These results demonstrate that EMG repeatability between visits during clinical gait analysis for children with CP is similar to unimpaired individuals. These results provide a baseline for evaluating whether observed changes in EMG recordings between visits reflect real changes in muscle activity or are within the range of inter visit variability. PMID- 30396060 TI - Imidazole-pyrazole hybrids: Synthesis, characterization and in-vitro bioevaluation against alpha-glucosidase enzyme with molecular docking studies. AB - Herein, substituted imidazole-pyrazole hybrids (2a-2n) were prepared via a multi component reaction employing pyrazole-4-carbaldehydes (1a-1d), ammonium acetate, benzil and arylamines as reactants. All the new compounds were characterized through their spectral and elemental analyses. Further these compounds were tested against alpha-glucosidase enzyme. The compounds 2k, 2l and 2n possessed good inhibition potencies, however, compounds 2f (IC50 value: 25.19 +/- 0.004 MUM) and 2m (IC50 value: 33.62 +/- 0.03 MUM) were the most effective compounds of the series. Furthermore, molecular docking helped to understand the binding interactions of 2f and 2m with the understudy yeast's alpha-glucosidase enzyme. PMID- 30396061 TI - Bioactive scalemic caged xanthones from the leaves of Garcinia bracteata. AB - Four pairs of previously undescribed caged xanthones (1-4) and twelve known caged xanthones (5-16) were isolated from the leaf extract of Garcinia bracteata. Their structures were unambiguously elucidated on the basis of spectroscopic methods. The planar structure and relative configuration of 1 was confirmed by X-ray crystallographic analysis. The enantiomers of compounds 1, 2, 4 were further resolved by semi-preparative chiral HPLC, and the absolute configurations of enantiomers of compounds 1 and 4 were determined by measurement and calculation of electronic circular dichroism (ECD) spectra and specific rotations. The inhibitory activities of the isolated compounds against human HeLa, A549, PC-3, HT-29, and WPMY-1 cell lines were assayed, and garcibractatin A (4) showed the most potent inhibitory activities in vitro with IC50 values from 1.11 to 2.93 MUM. A preliminary structure-activity relationship has been discussed, and some helpful conclusions have been drawn. PMID- 30396062 TI - NMR fragment-based screening for development of the CD44-binding small molecules. AB - The cell-surface protein CD44, a primary receptor for hyaluronic acid (HA), is one of the most promising targets for cancer therapies. It is prominently involved in the process of tumor growth and metastasis. The possibility of modulating the CD44-HA interaction with a pharmacological inhibitor is therefore of great importance, yet until now there are only few small molecules reported to bind to CD44. Here, we describe the results of the NMR fragment-based screening conducted against CD44 by which we found eight new hit compounds that bind to the receptor with the affinity in milimolar range. The NMR-based characterization revealed that there are two possible binding modes for these compounds, and for some of them the binding is no longer possible in the presence of hyaluronic acid. This could provide an interesting starting point for the development of new high-affinity ligands targeting the CD44-HA axis. PMID- 30396063 TI - Design, synthesis and biological evaluation of fused naphthofuro[3,2-c] quinoline 6,7,12-triones and pyrano[3,2-c]quinoline-6,7,8,13-tetraones derivatives as ERK inhibitors with efficacy in BRAF-mutant melanoma. AB - Approximately 60% of human cancers exhibit enhanced activity of ERK1 and ERK2, reflecting their multiple roles in tumor initiation and progression. Acquired drug resistance, especially mechanisms associated with the reactivation of the MAPK (RAF/MEK/ERK) pathway represent a major challenge to current treatments of melanoma and several other cancers. Recently, targeting ERK has evolved as a potentially attractive strategy to overcome this resistance. Herein, we report the design and synthesis of novel series of fused naphthofuro[3,2-c]quinoline 6,7,12-triones 3a-f and pyrano[3,2-c]quinoline-6,7,8,13-tetraones 5a,b and 6, as potential ERK inhibitors. New inhibitors were synthesized and identified by different spectroscopic techniques and X-ray crystallography. They were evaluated for their ability to inhibit ERK1/2 in an in vitro radioactive kinase assay. 3b and 6 inhibited ERK1 with IC50s of 0.5 and 0.19 uM, and inhibited ERK2 with IC50s of 0.6 and 0.16 uM respectively. Kinetic mechanism studies revealed that the inhibitors are ATP-competitive inhibitors where 6 inhibited ERK2 with a Ki of 0.09 uM. Six of the new inhibitors were tested for their in vitro anticancer activity against the NCI-60 panel of tumor cell lines. Compound 3b and 6 were the most potent against most of the human tumor cell lines tested. Moreover, 3b and 6 inhibited the proliferation of the BRAF mutant A375 melanoma cells with IC50s of 3.7 and 0.13 uM, respectively. In addition, they suppressed anchorage-dependent colony formation. Treatment of the A375 cell line with 3b and 6 inhibited the phosphorylation of ERK substrates p-90RSK and ELK-1 and induced apoptosis in a dose dependent manner. Finally, a molecular docking study showed the potential binding mode of 3b and 6 within the ATP catalytic binding site of ERK2. PMID- 30396064 TI - Human lung epithelial cells cultured in the presence of radon-emitting rock experience gene expression changes similar to those associated with tobacco smoke exposure. AB - Radon is the second leading cause of lung cancer, after tobacco smoke. While tobacco smoke-induced carcinogenesis has been studied extensively, far less is known about radon-induced carcinogenesis, particularly in relation to the influence of radon on gene expression. The objectives of the work described herein were to (a) determine if and how exposure to low dose radon-emitting rock influences cells, at the gene expression level, and (b) compare any gene expression changes resulting from the exposure to radon-emitting rock with those induced by exposure to tobacco smoke. Any potential radiation-induced gene expression changes were also compared to those induced by exposure to cannabis smoke, a non-carcinogen at low doses, used here as a smoke exposure comparator. Human lung epithelial cells were exposed to radon-emitting rock, tobacco smoke or cannabis smoke, over months, and RNA-sequencing was carried out. We found that the rock-exposed cells experienced significant gene expression changes, particularly of the gene AKR1C3, and that these changes, over time, increasingly reflected those associated with exposure to tobacco, but not cannabis, smoke. We postulate that the early gene expression changes common to both the radiation and tobacco smoke exposures constitute a related - potentially pre-carcinogenic - response. Our findings suggest that the length of time a dividing population of cells is exposed to a constant low concentration of radon (with a potential cumulative absorbed dose) could be an important risk parameter for neoplastic transformation/carcinogenesis. PMID- 30396065 TI - Occurrence, chemical composition, biological activities and analytical methods on Copaifera genus-A review. AB - Copaifera is a genus of large trees found in Brazil, mainly in Amazon forest, but also in Atlantic forest and cerrado biomes. It has also been found in other countries in South America. In Africa, it is found mainly in Congo, Cameroon, Guinea and Angola. Its oleoresin has been used in folk medicine in the treatment of numerous healthy disorders, such as urinary, respiratory, skin and inflammatory diseases, for which there are several studies corroborating its ethnopharmacological uses. It is also extensively employed in the pharmaceutical and cosmetic industries in the development of ointments, pills, soaps, perfumes, among others. Copaifera oleoresin contains mainly diterpenes, such as: kaurenoic acid, kaurenol, copalic acid, agathic acid, hardwiickic acid, polyalthic acid, and sesquiterpenes, comprising beta-caryophyllene, caryophyllene oxide, alpha copaene, alpha-humulene, gamma-muurolene and beta-bisabolol, among other compounds. On the other hand, Copaifera leaves contain mainly phenolic compounds, such as flavonoids and methylated galloylquinic acid derivatives. Therefore, considering the economic importance of Copaifera oleoresin, its ethnopharmacological uses, the need to develop new pharmaceuticals for the treatment of many diseases, as well as the pharmacological potential of the compounds found in Copaifera spp., it was undertaken a review covering mostly the last two decades on the distribution, chemistry, pharmacology, quality control and safety of Copaifera species. PMID- 30396066 TI - The nephroprotective properties of taurine in colistin-treated mice is mediated through the regulation of mitochondrial function and mitigation of oxidative stress. AB - Colistin (COL) belongs to the polymixin class of antibiotics used as the last line antibiotic against drug-resistant infections. However, nephrotoxicity is the major deleterious and dose-limiting side effect associated with COL therapy. Oxidative stress and mitochondrial impairment are suspected mechanisms involved in COL-induced nephrotoxicity. Taurine is one of the most abundant amino acids in the human body with antioxidant and mitochondria protecting properties. The current study was designed to evaluate the potential nephroprotective properties of taurine against COL-associated nephrotoxicity. Mice were treated with COL (15 mg/kg/day, i.v, for 7 consecutive days) alone or in combination with taurine (500 and 1000 mg/kg, i.p). Plasma biomarkers of nephrotoxicity in addition of kidney tissue markers of oxidative stress were evaluated. Additionally, kidney mitochondria were isolated, and several mitochondrial indices were assessed. The COL-associated renal injury was evident by a significant increase in plasma markers of renal injury including creatinine (Cr), and blood urine nitrogen (BUN). COL treatment also caused a significant increase in kidney reactive oxygen species (ROS) and lipid peroxidation (LPO). Renal GSH reservoirs and antioxidant capacity were also decreased in COL-treated animals. Mitochondrial parameters including mitochondrial dehydrogenase activity, membrane potential, GSH, and ATP were significantly decreased while mitochondrial LPO, permeabilization, and GSSG content were increased in the kidney of COL-treated mice. It was found that taurine (500 and 1000 mg/kg, i.p) treatment alleviated COL-induced oxidative stress and mitochondrial dysfunction in the kidney tissue. The data obtained from the current study suggest mitochondrial dysfunction and oxidative stress as fundamental mechanisms of renal injury induced by COL. On the other hand, taurine supplementation protected kidney through decreasing oxidative stress and regulating mitochondrial function. PMID- 30396067 TI - Farrerol attenuates beta-amyloid-induced oxidative stress and inflammation through Nrf2/Keap1 pathway in a microglia cell line. AB - Farrerol, an important bioactive constituent of rhododendron, exhibits broad activities such as anti-oxidative and anti-inflammatory effects. Recent studies showed that farrerol possesses neuroprotective activity, however, the mechanism has not been reported. The aim of the present study was to investigate the protective effect of farrerol on beta-amyloid (Abeta)-induced mouse microglial BV 2 cells and the underlying mechanism. BV-2 cells were pretreated with farrerol for 1 h and then subjected to Abeta. MTT assay was performed to measure the mitochondrial metabolic activity in BV-2 cells. The production of reactive oxygen species (ROS) and malondialdehyde (MDA) and superoxide dismutase (SOD) activity were detected to reflect oxidative stress status. The secretion and mRNA levels of interleukin (IL)-1beta (IL-1beta), IL-6 and tumor necrosis factor-alpha (TNF alpha) were measured by ELISA and qRT-PCR. The expressions of NF-E2-related factor (Nrf2), heme oxygenase-1 (HO-1), NAD (P) H: quinone oxidoreductase 1 (NQO1), and Kelch-like ECH-associated protein 1 (Keap1) were measured by western blot. Our results showed that farrerol improved mitochondrial metabolic activity in Abeta-induced BV-2 cells. Abeta induced the production of ROS and MDA, and inhibited the SOD activity and the expression of SOD1 and SOD2 mRNA, while the effects were attenuated by farrerol. Farrerol also inhibited the induction effect of Abeta on IL-6, IL-1beta, and TNF-alpha. In addition, farrerol enhanced the activation of Nrf2/Keap1 pathway in Abeta-induced BV-2 cells. Knockdown of Nrf2 by small interfere RNA (siRNA) targeting Nrf2 (si-Nrf2) abolished the protective effect of farrerol on Abeta-induced BV-2 cells. In conclusion, farrerol attenuated Abeta-induced oxidative stress and inflammation in BV-2 cells through enhancing the activation of Nrf2/Keap1 pathway. The findings indicated that farrerol could be considered as a therapeutic approach for the treatment of Alzheimer's disease (AD). PMID- 30396068 TI - Evaluation of the anti-asthmatic and antitussive potentials of methanol leaf extract of Napoleona vogelii in rodents. AB - Napoleona vogelii is used in ethnomedicine for the treatment of asthma and cough. This study evaluated antiasthmatic and antitussive properties of its methanol leaf extract (NVE) in rodents. Phytochemical screening was conducted using established methods. Acute oral toxicity test was done in mice and guinea pigs. Ovalbumin (OA)-sensitized guinea pigs were orally pretreated with 100, 200 or 400 mg/kg/day of NVE or 0.5 mg/kg/day of salbutamol for 14 days before exposure to 0.2% histamine aerosol. Latency to preconvulsive dyspnea (PCD), tracheal fluid volume (TFV), flow rate (FR), and tracheal morphometry (TM) were evaluated. Tracheal rings from sensitized guinea pigs were tested in organ baths for antispasmodic and spasmolytic effects. Citric acid and ammonium hydroxide cough models were used to evaluate antitussive effects in guinea pigs and mice respectively. Tannins, alkaloids, flavonoids, and phenolic substances were found in NVE. LD50 values in mice and guinea pigs were greater than 5000 mg/kg. NVE caused a significant (P < 0.05) increase in the latency to PCD and a decrease in TFV in the group treated with 200 mg/kg. TM indicated a reduction in airway narrowing in NVE-treated groups. The presence of NVE significantly attenuated responses of tracheal rings to carbachol. Its addition to carbachol precontracted rings resulted in significant relaxation. Emax for calcium concentration-response was significantly (P < 0.01) decreased in the presence of NVE. Cough bouts dose dependently decreased significantly (P < 0.05) in guinea pigs and mice. We conclude that NVE seems safe and possesses anti-asthmatic effect that involves inhibition of calcium influx. It also has antitussive properties that may be peripherally mediated. PMID- 30396069 TI - MiR-221-3p is down-regulated in preeclampsia and affects trophoblast growth, invasion and migration partly via targeting thrombospondin 2. AB - Preeclampsia (PE) is a common obstetrical disorder characterized by hypertension and proteinuria. The aberrant expression of miR-221-3p in placental tissues has been implicated in the pathogenesis of PE. This study examined the role of miR 221-3p in trophoblast growth, invasion and migration, and explored the underlying mechanisms. Our results showed that miR-221-3p was down-regulated in placental tissues from PE patients compared to heathy controls as measured by quantitative real-time PCR assay. CCK-8 assay, Transwell invasion assay and wound healing assay showed that miR-221-3p overexpression promoted trophoblast (HTR-8/SVneo cells) growth, invasion and migration, and knockdown of miR-221-3p exerted the opposite effects. Flow cytometry experiments further demonstrated that miR-221-3p overexpression inhibited apoptosis, increased cell population at S phase, and decreased cell population at G0/G1 phase of HTR-8/SVneo cells; while miR-221-3p knockdown exerted the opposite effects. Bioinformatics prediction and luciferase reporter assay showed that miR-221-3p targeted the 3' untranslated region of thrombospondin 2 (THBS2), and qRT-PCR and western blot assays revealed that miR 221-3p negatively regulated the expression of THBS2 in HTR-8/SVneo cells. Furthermore, overexpression of THBS2 attenuated the in vitro effects of miR-221 3p overexpression on cell growth, invasion and migration of HTR-8/SVneo cells. The clinical sample analysis showed that the mRNA expression levels of THBS2 was significantly increased in placental tissues from PE patients and was negatively correlated with expression levels of miR-221-3p. In summary, our results demonstrated that miR-221-3p was down-regulated in PE, and the in vitro functional assays revealed that miR-221-3p promoted trophoblast growth, invasion and migration partly via targeting THBS2. PMID- 30396070 TI - Exendin-4 promotes actin cytoskeleton rearrangement and protects cells from Nogo A-Delta20 mediated spreading inhibition and growth cone collapse by down regulating RhoA expression and activation via the PI3K pathway. AB - Exendin-4 is a protein of the GLP-1 family currently used to treat diabetes. Recently, a greater number of biological properties have been associated with the GLP-1 family. Our data shows that exendin-4 treatment significantly increases the cytoskeleton rearrangement, which leads to an increasingly differentiated phenotype and reduced cell migration. We also found that exendin-4 could prevent SH-SY5Y and PC12 cells from Nogo-A-Delta20 mediated spreading inhibition and neurite collapse. Western blot analysis indicated that exendin-4 treatment both reduced the expression and activation of RhoA via the PI3K signaling pathway. These data suggest that exendin-4 may protect nerve regeneration by preventing the inhibition of Nogo-A via down-regulating RhoA expression and activation. PMID- 30396071 TI - Fluctuations of epigenetic regulations in human gastric Adenocarcinoma: How does it affect? AB - Gastric cancer (GC) or human gastric adenocarcinoma is one of the most commonplace type of serious cancers and also the most common cause of cancer related mortality in the world. Relatively, many studies have acknowledged that GC is a multi-factorial pathological situation that environmental factors, particularly dietary ones and H.pylori infection are considered to have a strong key role in the etiology of GC. Inappropriate dietary habits are the first cause as they affect main molecular functions related with the onset of the GC tumorigenesis and carcinogenesis. Correspondingly, cancer investigation has impressively zoomed on the different genetic markers and also molecular mechanisms pathways responsible for the progression of the GC. Various molecular signaling pathways such as WNT, NOTCH, SHH, MYC have different functions and analyzing their role in the GC is of great importance particularly for the treatment modalities. Proportionately, fluctuations of epigenetic alterations including DNA methylation, histone modification, histone acetylation and also histone phosphorylation's are involved in all cancers specially the GC. Conspicuously, novel developments in cancer epigenetic have indicated immense reprogramming of every structure of the epigenetic mechanism in cancer, comprising microRNAs, nucleosome positioning, DNA methylation, noncoding RNAs, and histone modifications. In this account, aberrant DNA methylation mechanism in the promoter regions of certain genes, which leads to silencing of some particular genes such as tumor suppressor and other cancer-related genes in carcinogenesis, is the most important epigenetic hallmark in human GC especially as a target for detection and diagnosis in cancer treatment. Here, we review the importance of epigenetic fluctuations alongside with their molecular signaling mechanism in the GC. PMID- 30396072 TI - In vitro anti-Trypanosoma cruzi activity of ternary copper(II) complexes and in vivo evaluation of the most promising complex. AB - In order to improve the previously observed antichagasic activity of Cu(II) complexes containing 2-chlorobenzhydrazide (2-CH), we report herein the synthesis and anti-Trypanosoma cruzi activity of novel copper complexes containing 2 methoxybenzhydrazide (2-MH), 4-methoxybenzhydrazide (4-MH) and three alpha diimine ligands, namely, 1,10-phenanthroline (phen), 2,2-bipyridine (bipy) and 4 4'-dimethoxy-2-2'-bipyridine (dmb). Two of these complexes showed higher in vitro anti-Trypanosoma cruzi activity when compared to benznidazole, the main drug used in Chagas disease treatment. One of them, the copper complex with 4-MH and dmb, [Cu(4-MH)(dmb)(ClO4)2], exhibited a higher selectivity index than that recommended for preclinical studies. Considering this observation, complex [Cu(4 MH)(dmb)(ClO4)2] was selected for preliminary in vivo assays, which verified that this compound was able to reduce parasitemia by 64% at the peak of infection. Further investigations were performed on all compounds. The Cu(II) complexes bind to ct-DNA with Kb values in the range of 103-104 M-1, with [Cu(4-MH)(dmb)(ClO4)2] showing the highest Kb value (1.45 * 104 M-1). Molecular docking simulations predicted that [Cu(4-MH)(dmb)(ClO4)2] binds in the minor groove of the double helix of ct-DNA and forms one hydrogen bond. PMID- 30396073 TI - Adrenomedullin and glucagon-like peptide-1 have additive effects on food intake in mice. AB - Adrenomedullin (ADM) is a vasoactive peptide expressed in several peripheral organs and known primarily for its beneficial vasoactive effects. However, ADM is also known to inhibit insulin secretion, and central administration of ADM has been shown to elicit anorexigenic effects. Here, we investigated if peripheral co administration of ADM and glucagon-like peptide 1 (GLP-1) could subdue the hypoglycaemic effects of ADM while enhancing its anorectic properties. The effects of mono- and combination therapy of ADM and GLP-1 on appetite regulation and glucose homeostasis were assessed acutely in male NMRI mice for 12 h, while effects on glucose homeostasis were assessed by oral glucose tolerance tests (OGTT). While the monotherapy with GLP-1 and ADM resulted in modest anorexigenic effects, co-administration of the two peptides led to a marked additive reduction in food intake. Moreover, while OGTT-evoked blood glucose-excursions were significantly increased by ADM monotherapy, co-administration of ADM with a lower dose of GLP-1 normalized glucose excursions. In conclusion, we demonstrate additive anorectic effects of ADM and GLP-1, and that GLP-1 co-administration prevents ADM-induced impairment of glucose tolerance, suggesting that ADM could be potential anti-obesity target when combined with GLP-1 agonist therapy. PMID- 30396074 TI - Association between catatonia and levels of hair and serum trace elements and minerals in autism spectrum disorder. AB - The objective of the study was to investigate the association between catatonia in autism spectrum disorder (ASD) and the levels of hair and serum trace elements and minerals in children with ASD. The levels of hair and serum trace elements and minerals of boys suffering from ASD with (n = 30) and without (n = 30) catatonia, as well as 30 age- and sex-matched neurotypical controls were assessed using ICP-MS. Hair calcium (Ca) and selenium (Se) levels were lower in ASD patients as compared to the controls. Hair mercury (Hg) levels in ASD patients were more than 3-fold and 2-fold higher as compared to the controls and children with catatonia in ASD. Hair iodine (I) and manganese (Mn) were the lowest and the highest in ASD + Catatonia, respectively. Serum aluminium (Al) and cadmium (Cd) levels in healthy controls were significantly higher in comparison to the patients of both groups. Serum chromium (Cr), copper (Cu) levels were significantly increased in patients with ASD and catatonia, whereas vanadium (V) levels were elevated in patients both with and without catatonia. Multiple regression analysis demonstrated that hair Hg and serum Al and Cd levels were negatively associated with catatonia in ASD in crude and adjusted models. Although the etiology of catatonia in ASD is unclear, the obtained data demonstrate that catatonic symptoms in ASD may be at least partially mediated by altered trace element levels. Further studies are required to elucidate the role of trace elements in the potential signaling mechanisms of catatonia. PMID- 30396075 TI - The neurovascular protective effect of alogliptin in murine MCAO model and brain endothelial cells. AB - Endothelial damage and blood brain barrier disruption contribute to ischemic stroke and brain injury. Gliptins are a novel class of treatment agents for diabetes, and recent studies have linked the use of gliptins to neuroprotection. Alogliptin is a type of orally available gliptin that was approved for clinical use by the FDA in 2013. In this study, we investigated the neurovascular protective effects of alogliptin both in vivo and in vitro. In a murine middle cerebral artery occlusion (MCAO) stroke model, administration of alogliptin ameliorated cerebral infarction and disruption of brain vascular permeability, and restored expression of the endothelial tight junction proteins occludin and zona occludens 1 (ZO-1). In brain vascular endothelial cells exposed to oxygen and glucose deprivation/reperfusion (OGD/R), alogliptin prevented OGD/R-induced high permeability of the endothelial monolayer. Alogliptin treatment recovered the reduction in occludin and ZO-1 induced by OGD/R. Moreover, alogliptin treatment prevented OGD/R-induced induction of metalloproteinase (MMP)-2 and MMP 9, and restored expression of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. Collectively, our data indicate that alogliptin can improve neurovascular integrity and exerts neuroprotective effects. PMID- 30396076 TI - Involvement of AMPK activation in the inhibition of hepatic gluconeogenesis by Ficus carica leaf extract in diabetic mice and HepG2 cells. AB - The aim of this study was to explore the possible mechanisms of Ficus carica leaf (FCL) extract in suppressing hepatic gluconeogenesis in diabetic mice. Diabetic mice (streptozotocin-induced) received 1 g/kg of FCL extract twice a day for 6 weeks. Fasting blood glucose levels were measured and a 2-h oral glucose tolerance test was conducted. AMP-activated protein kinase (AMPK), phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), and peroxisome proliferator activated receptor-gamma coactivator-1alpha (PGC-1alpha) expression was examined. HepG2 hepatocytes were treated with FCL extract and an AMPK inhibitor (compound C) or agonist (AICAR), and PEPCK, G6pase, PGC-1alpha, AMPK, forkhead transcription factor O1 (FOXO1), and hepatic nuclear factor 4alpha (HNF4alpha) expression was determined. The results showed that FCL extract inhibited the expression of PEPCK and G6Pase in the liver of diabetic mice and HepG2 hepatocytes. FCL extract activated AMPK and decreased PGC-1alpha, HNF4alpha, and FOXO1 expression. The AMPK inhibitor attenuated those effects through inhibiting gluconeogenesis, while the AMPK agonist partially enhanced gluconeogenesis. In conclusion, FCL extract inhibits hepatic gluconeogenesis via activation of AMPK and down-regulation of gluconeogenic enzymes. PMID- 30396077 TI - Regulatory mechanisms of miR-145 expression and the importance of its function in cancer metastasis. AB - MicroRNAs are post-transcriptional mediators of gene expression and regulation, which play influential roles in tumorigenesis and cancer metastasis. The expression of tumor suppressor miR-145 is reduced in various cancer cell lines, containing both solid tumors and blood malignancies. However, the responsible mechanisms of its down-regulation are a complicated network. miR-145 is potentially able to inhbit tumor cell metastasis by targeting of multiple oncogenes, including MUC1, FSCN1, Vimentin, Cadherin, Fibronectin, Metadherin, GOLM1, ARF6, SMAD3, MMP11, Snail1, ZEB1/2, HIF-1alpha and Rock-1. This distinctive role of miR-145 in the regulation of metastasis-related gene expression may introduce miR-145 as an ideal candidate for controlling of cancer metastasis by miRNA replacement therapy. The present review aims to discuss the current understanding of the different aspects of molecular mechanisms of miR-145 regulation as well as its role in r metastasis regulation. PMID- 30396078 TI - MiR-31-5p promotes the cell growth, migration and invasion of colorectal cancer cells by targeting NUMB. AB - The aim of this study was to investigate the role and specific molecular mechanism of miR-31-5 in colorectal cancer. The relative expression of miR-31-5p and NUMB in colorectal cancer tissues was analyzed by qRT-PCR. To knock down the expression of miR-31-5p, the transfection of miR-31-5p inhibitor was performed. The transfection with miR-31-5p mimic was used for miR-31-5p overexpression and pcDNA3.0-NUMB plasmid was used for NUMB overexpression. CCK-8 assay was used to analyze the cell proliferation. Flow cytometry was used to evaluate the cell apoptosis and cell cycle. Matrigel invasion assay was performed to assess the invasion potency and migration assay was performed to assess the migration potency. Hoechst 33258 staining assay was performed to analyze the cell apoptosis of HT29 cells after the indicated transfection. Luciferase activity assays were performed to confirmed the potential binding site for miR-31-5p in 3'-UTR region of NUMB. MiR-31-5p is highly expressed in colorectal cancer and is critical for the cell proliferation, cell cycle, migration, invasion and apoptosis. NUMB is target of miR-31-5p and NUMB overexpression inhibited the cell proliferation, migration, invasion and induced cell cycle arrest and apoptosis in HT29 colorectal cancer cells. In conclusion, miR-31-5p promoted the cell growth, migration and invasion by targeting NUMB in colorectal cancer cells. PMID- 30396079 TI - Effects of ADAM2 silencing on isoflurane-induced cognitive dysfunction via the P13K/Akt signaling pathway in immature rats. AB - Volatile anesthetics, including isoflurane, have been reported to have negative effects on cognitive dysfunction characterized by cognitive deficits following anesthesia. The aim of the current study was to investigate the effects involved with disintegrin and metallopeptidase domain 2 (ADAM2) silencing on isoflurane induced cognitive dysfunction via the P13 K/Akt signaling pathway in immature rats. One week old healthy Sprague-Dawley (SD) rats were recruited and administered isoflurane anesthesia. The rats were then subjected to shADAM2 or wortmannin (PI3K/Akt signaling pathway inhibitor) to identify the effects of ADAM2 and the PI3K/Akt signaling pathway on the cognitive function of rats. Morris water maze and passive-avoidance tests were performed to examine the cognitive function of the rats. TUNEL staining was conducted to detect neuronal apoptosis in the hippocampal CA1 region. The obtained experimental results demonstrated that isoflurane anesthesia led to increased escape latency, reaction time, number of errors and TUNEL-positive neurons, along with a decreased latency time. In response to treatment with shADAM2, escape latency, reaction time, number of errors and TUNEL-positive cells were all noted to have decreased, in addition to elevated latency time, while contrasting trends were observed in regard to treatment with wortmannin. Taken together, the key findings of the present study revealed that shADAM2 activated the PI3K/Akt signaling pathway, resulting in elevated expressions of PI3K and Akt. Our study ultimately identified that ADAM2 silencing alleviates isoflurane-induced cognitive dysfunction by activating the P13 K/Akt signaling pathway in immature rats. PMID- 30396080 TI - Upregulation of circular RNA circ_0001721 predicts unfavorable prognosis in osteosarcoma and facilitates cell progression via sponging miR-569 and miR-599. AB - Osteosarcoma (OS) is the most frequent bone malignancy in human. Growing evidence suggests that circular RNAs (circRNAs) play a significant role in regulating tumorigenesis and progression. Previously, circ_0001721 was identified upregulated in OS tissues screened by circRNA microarrays. In the current study, circ_0001721 expression in OS tissue samples and cells were measured by qRT-PCR. Its clinical value was also explored. For the part of functional assays, CCK-8, clone-forming, flow cytometric, Transwell, xenograft assays were performed. Dual luciferase reporter assays were used to examine the mechanism of circ_0001721. We found that circ_0001721 was enhanced in OS tissue samples and cell lines and the overexpression of circ_0001721 is closely related to clinical severity. In addition, circ_0001721 may be used as a prognostic indicator for OS patients. What's more, loss-of-function and gain-of-function assays demonstrated circ_0001721 facilitates cell progression in OS. Circ_0001721 could sponge miR 569 and miR-599. The oncogenic properties of circ_0001721 is partly attributed to its repression on miR-569 and miR-599. Collectively, the present data reveal the participation of circ_0001721 in tumorigenesis of OS cells, and may indicate a novel therapeutic target. PMID- 30396081 TI - Docosahexaenoic acid-flurbiprofen combination ameliorates metaflammation in rats fed on high-carbohydrate high-fat diet. AB - OBJECTIVE: Potential benefits of combining docosahexaenoic acid (DHA), an omega-3 fatty acid with flurbiprofen (Flu), a non-steroidal anti-inflammatory drug in ameliorating obesity remain to be elucidated. This study aimed to investigate the possible protective effects of DHA and Flu, either alone or in combination, against obesity-induced metaflammation and to clarify the underlying molecular mechanisms. METHODS: Seventy-five male Wistar rats were divided into five groups: normal diet (ND) group, high-carbohydrate high-fat diet (HCHFD) control group, DHA group (HCHFD + 200 mg/kg DHA), Flu group (HCHFD + 10 mg/kg Flu), and DHA + Flu group (HCHFD + DHA + Flu). Treatments were administered orally daily for 8 consecutive weeks, parallel with the start of diets. RESULTS: Plasma levels of glucose, insulin, and TGs were significantly reduced in DHA, Flu, and DHA + Flu treated groups, while HDL-C concentrations were significantly elevated in the same groups, compared to HCHFD control group. Only Flu and DHA + Flu groups showed a significant decrease in plasma levels of leptin, TC, and LDL-C, relative to HCHFD control group. Concentrations of phosphorylated adenosine monophosphate activated protein kinase (pAMPK) and resolvin D1 (RvD1) in epididymal adipose tissue (EAT) were significantly increased in the three treated groups, compared with HCHFD control group. Expression of AMPK-alpha1 subunit in EAT was significantly increased, whereas expression of nuclear factor kappa B (NF-kappaB) was significantly decreased in EAT of the three treated groups, relative to HCHFD control group. CONCLUSIONS: Docosahexaenoic acid-flurbiprofen combination showed an ameliorative effect on obesity-associated metaflammation and its consequences in rats. PMID- 30396082 TI - DPP-4 inhibitor impedes lipopolysaccharide-induced osteoclast formation and bone resorption in vivo. AB - OBJECTIVES: Dipeptidyl peptidase 4 (DPP-4) inhibition is a new therapeutic strategy for type 2 diabetic patients. DPP-4 has been reported to enhance inflammation. However, the effect of DPP-4 inhibition on inflammation remains unknown. Lipopolysaccharide (LPS) is a strong inducer of inflammation and osteoclast formation. In this study, we investigated in vivo effects of DPP-4 inhibition on LPS-induced osteoclast formation and bone resorption, as well as in vitro effects of DPP-4 inhibition on RANKL-induced osteoclastogenesis and TNF alpha-induced osteoclastogenesis. METHODS: LPS with or without a DPP-4 inhibitor was subcutaneously injected into mouse calvaria for 5 days. Histological sections of calvaria were stained for tartrate-resistant acid phosphatase, and osteoclast numbers were determined. The ratio of calvaria bone resorption was evaluated via microfocal computed tomography reconstruction images. RESULTS: Osteoclast number and bone resorption were significantly lower in mice that underwent LPS and DPP-4 inhibitor co-administration than in those that underwent LPS administration alone. Moreover, RANKL, TNF-alpha, and M-CSF expression was reduced in the LPS and DPP-4 inhibitor co-administration group. In vitro, there were no direct effects of DPP-4 inhibitor or DPP-4 on RANKL- and TNF-alpha-induced osteoclastogenesis, or on LPS-induced RANKL expression in stromal cells. Nevertheless, macrophages from LPS and DPP-4 inhibitor co-administered mice exhibited lower TNF-alpha expression than macrophages from LPS-only mice. Notably, TNF-alpha expression was not reduced in LPS and DPP-4 inhibitor co treated macrophages in vitro, compared with macrophages treated with LPS alone. PMID- 30396083 TI - Ginsenoside Rb3 protects cardiomyocytes against hypoxia/reoxygenation injury via activating the antioxidation signaling pathway of PERK/Nrf2/HMOX1. AB - OBJECTIVES: This study aimed to investigate the pharmacological function and underlying regulation mechanisms of Ginsenoside-Rb3 (G-Rb3) in cardioprotection. METHODS: Cultured H9C2 cells were pre-treated with gradient concentrations of G Rb3, and subsequently challenged with hypoxia/reoxygenation (H/R) treatment. The generation of intracellular reactive oxygen species (ROS) and cellular antioxidatant capacity were quantified. Cell apoptosis was measured by flow cytometry. Myocardial ischemia reperfusion injury (MIRI) rat models constructed by coronary artery ligation surgery were orally administrated with G-Rb3 for 5 consecutive days, and then infarction area, apoptosis ratio and total antioxidant capacity (T-AOC) of myocardial tissues were measured. PERK phosphorylation inhibitor GSK2656157 and Nrf2 translocation inhibitor ML385 were co-treated with G-Rb3 to further verify the signaling pathway mediated by G-Rb3. RESULTS: H/R treatment induced prominent ROS deposition and elevated cell apoptosis ratio in H9C2 cells. G-Rb3 pretreatment suppressed intracellular ROS accumulation and enhanced T-AOC, partially rescuing cardiomyocytes from oxidative stress and apoptosis induced by H/R. In vivo, the cardiac infarction area of MIRI model rats was reduced by G-Rb3 treatment via improved total antioxidant levels. In the further functional and mechanistic studies, G-Rb3 was found to induce PERK phosphorylation and nuclear translocation of transcriptional factor Nrf2, promoting the expression of antioxidative genes such as HMOX1. Inhibitors GSK2656157 and ML385 reversed the effects of G-Rb3. CONCLUSION: Our studies revealed a novel mechanism of G-Rb3 to attenuates oxidative stress via activating the antioxidation signaling pathway of PERK/Nrf2/HMOX1 in vivo and in vitro, which may help us to enrich the theoretical knewledge of Ginsenoside-Rb3 in cardiopretection. PMID- 30396084 TI - Characterization of polysaccharide from Helicteres angustifolia L. and its immunomodulatory activities on macrophages RAW264.7. AB - Helicteres angustifolia L. (H. angustifolia) has been widely used as a remedy against various types of illness relating to immune response, such as inflammations and fever. In order to characterize the structure and identify the immunomodulatory activity of polysaccharide from H. angustifolia, a polysaccharide fraction (SPF3-1) was purified from H. angustifolia by using DEAE Sepharose Fast Flow and Sephacry S-400 chromatography, successively. Physicochemical analysis demonstrated that SPF3-1 is an acidic heteropolysaccharide with a molecular weight of about 13.36 kDa; in vitro immunomodulatory assay reflects that SPF3-1 could significantly (p < 0.05) enhance the proliferation of macrophages, stimulate the macrophages phagocytic capacity, as well as induce NO and immunomodulatory cytokines generation. All the results suggest that SPF3-1 from H. angustifolia possesses potent immunomodulatory activity and could be further developed as new products for medicines or functional foods. PMID- 30396085 TI - Mitochondrial dysfunction as a mechanism involved in the pathogenesis of cirrhosis-associated cholemic nephropathy. AB - Cholemic nephropathy (CN) is a clinical complication associated with cholestasis and chronic liver diseases. CN could lead to renal failure and the need for kidney transplantation if not appropriately managed. On the other hand, although the clinical features of CN are well described, there is no clear idea on the precise cellular and molecular mechanisms of CN. The current study was designed to evaluate kidney mitochondrial function in cholestasis-associated CN. Rats underwent bile duct ligation (BDL) surgery, and kidney mitochondria were isolated at scheduled time intervals (14, 28, and 42 days after BDL operation). Several mitochondrial indices including mitochondrial permeabilization and swelling, glutathione and ATP content, mitochondrial depolarization, and lipid peroxidation were evaluated. Renal tissue markers of oxidative stress along with tissue histopathological changes and serum biochemistry were also analyzed. Severe kidney tissue histopathological alterations including interstitial inflammation, necrosis, and Bowman capsule dilation were detected in the BDL animals. Moreover, drastic elevation in renal fibrosis and collagen deposition was detected in BDL rats. Oxidative stress markers were also significantly enhanced in the kidney tissue of BDL animals. On the other hand, it was found that mitochondrial indices of functionality were significantly deteriorated in BDL rats. These data introduce mitochondrial dysfunction and energy metabolism disturbances as a fundamental mechanism involved in the pathogenesis of bile acids-associated renal injury during cholestasis. PMID- 30396086 TI - Polyphenol-rich Boswellia serrata gum prevents cognitive impairment and insulin resistance of diabetic rats through inhibition of GSK3beta activity, oxidative stress and pro-inflammatory cytokines. AB - Type 2 diabetes (T2D) is associated with accelerated cognitive decline. To date, there is no T2D-specific treatment to prevent or ameliorate cognitive dysfunction. Boswellia serrate (BS) gum has been shown to possess multiple pharmacological actions including anti-inflammatory, anticancer and ant- apoptotic actions. The present study was aimed to investigate the effect of BS on cognitive impairment associated with T2D induced in rats by high fat/high fructose (HF/HFr) diet with a single injection of streptozotocin (STZ) and to explore the mechanism of action. The effect of 3 doses of BS extract and the reference drug on the behavioral, biochemical, histopathological and glutamate gene expression abnormalities in T2D rates was evaluated. HF/HFr diet/ STZ induces learning and memory deficits, which were reversed by BS extract. It showed a significant decrease in Abeta deposits and p-tau positive cells. BS extract also reduced significantly the hippocampal elevated levels of caspase-3, cholinesterase (ChE), GSK-3beta, TNF-alpha, IL-1beta, IL-6, and MDA. Moreover, BS extract enhanced significantly the suppressed hippocampal level of GSH, SOD and glutamate receptor expression (GluR, NR1, NR2 A, and NR2B). In addition, BS extract alleviated insulin resistance and hyperlipidemia of T2D rats. Our findings suggest that BS extract reversed learning and memory impairment in HF/ HFr diet / STZ induced diabetic rats. This effect may be attributed to the inhibition of insulin resistance, pro-inflammatory cytokines, oxidative stress and hyperlipidemia. PMID- 30396087 TI - Mechanistic approach of the inhibitory effect of chrysin on inflammatory and apoptotic events implicated in radiation-induced premature ovarian failure: Emphasis on TGF-beta/MAPKs signaling pathway. AB - Radiotherapy is one of the most relevant treatment modalities for various types of malignancies. However, it causes premature ovarian failure (POF) and subsequent infertility in women of reproductive age; hence urging the development of effective radioprotective agents. Chrysin, a natural flavone, possesses several pharmacological activities owing to its antioxidant, anti-inflammatory and anti-apoptotic properties. Therefore, the aim of this study was to investigate the efficacy of chrysin in limiting gamma-radiation-mediated POF and to elucidate the underlying molecular mechanisms. Immature female Sprague-Dawley rats were subjected to a single dose of gamma-radiation (3.2 Gy) and/or treated with chrysin (50 mg/kg) once daily for two weeks before and three days post irradiation. Chrysin prevented the radiation-induced ovarian dysfunction by restoring estradiol levels, preserving the normal ovarian histoarchitecture and combating the follicular loss. Eelectron microscopic analysis showed that the disruption of ultrastructure components due to radiation exposure was hampered by chrysin administration. Mechanistically, chrsyin was able to reduce the levels of the inflammatory markers NF-kappaB, TNF-alpha, iNOS and COX-2 in radiation induced ovarian damage. Chrysin also exhibited potent anti-apoptotic effects against radiation-induced cell death by downregulating the expression of cytochrome c and caspase 3. Radiation obviously induced upregulation of TGF-beta protein with subsequent phospholyration and hence activation of downstream mitogen-activated protein kinases (MAPKs); p38 and JNK. Notably, administration of chrysin successfully counteracted these effects. These findings revealed that chrysin may be beneficial in ameliorating radiation-induced POF, predominantly via downregulating TGF-beta/MAPK signaling pathways leading subsequently to hindering inflammatory and apoptotic signal transduction pathways implicated in POF. PMID- 30396088 TI - Stem cells as therapy for heart disease: iPSCs, ESCs, CSCs, and skeletal myoblasts. AB - Heart Diseases are serious and global public health concern. In spite of remarkable therapeutic developments, the prediction of patients with Heart Failure (HF) is weak, and present therapeutic attitudes do not report the fundamental problem of the cardiac tissue loss. Innovative therapies are required to reduce mortality and limit or abolish the necessity for cardiac transplantation. Stem cell-based therapies applied to the treatment of heart disease is according to the understanding that natural self-renewing procedures are inherent to the myocardium, nonetheless may not be adequate to recover the infarcted heart muscle. Following the first account of cell therapy in heart diseases, examination has kept up to rapidity; besides, several animals and human clinical trials have been conducted to preserve the capacity of numerous stem cell population in advance cardiac function and decrease infarct size. The purpose of this study was to censoriously evaluate the works performed regarding the usage of four major subgroups of stem cells, including induced Pluripotent Stem Cells (iPSC), Embryonic Stem Cells (ESCs), Cardiac Stem Cells (CDC), and Skeletal Myoblasts, in heart diseases, at the preclinical and clinical studies. Moreover, it is aimed to argue the existing disagreements, unsolved problems, and prospect directions. PMID- 30396089 TI - Spirulina ameliorates aspirin-induced gastric ulcer in albino mice by alleviating oxidative stress and inflammation. AB - Aspirin is a commonly prescribed non steroidal anti-inflammatory drug, but its prolonged use injures the gastric mucosa. The present study was carried out to evaluate the ameliorative effect of spirulina against aspirin-induced gastric ulcer in albino mice. Gastric ulcer was induced by oral administration of aspirin (500 mg/kg bw). Spirulina (250 and 500 mg/kg bw) was given orally for 3 days after the induction of gastric ulcer. Spirulina ameliorated aspirin-induced gastric ulcer by improving the gross morphology, histology and mucous layer of gastric tissue, augmenting the endogenous enzymatic and non-enzymatic antioxidants (reduced glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase) and the cytoprotective marker (COX-1), and by alleviating tissue levels of the lipid peroxidation marker (malondialdehyde) and inflammatory mediators (TNF-alpha, COX-2 and NO). In conclusion, spirulina has a therapeutic potential in aspirin-induced gastric injury by alleviating oxidative stress and inflammation. PMID- 30396090 TI - A proteomic analysis of the anti-dengue virus activity of andrographolide. AB - Andrographolide is a major bioactive constituent of Andrographis paniculata that has been shown in vitro to have antiviral activity against a number of viruses, including the mosquito transmitted dengue virus (DENV). However, how andrographolide exerts an anti-DENV effect remains unclear. This study therefore sought to further understand the mechanism of action of andrographolide in inhibiting DENV infection of liver cells using a proteomic based approach. Both 1 dimension (D) and 2D proteome systems were used. Initial data was generated through andrographolide treatment of HepG2 cells without DENV infection (1D analysis), while subsequent data was generated through a combination of andrographolide treatment and DENV infection (2D analysis). A total of 17 (1D) and 18 (2D) proteins were identified as differentially regulated. The analyses identified proteins involved in chaperone activities, as well as energy production. In particular evidence suggested an important role for GRP78 and the unfolded protein response in mediating the anti-DENV activity of andrographolide, which might, in part, explain the broad antiviral activity of andrographolide. PMID- 30396091 TI - The impact of Keap1/Nrf2, P38MAPK/NF-kappaB and Bax/Bcl2/caspase-3 signaling pathways in the protective effects of berberine against methotrexate-induced nephrotoxicity. AB - Berberine (BBR) is a natural compound of plant origin belonging to isoquinoline type of alkaloid. Methotrexate (MTX) is an anti-metabolite used widely for a variety of tumors and autoimmune conditions. Clinical uses of MTX were severely limited by its concomitant renal intoxication. The current study was designed to investigate the efficacy of BBR against MTX-induced nephrotoxicity and for exploring the underlying molecular mechanisms through examining the Keap1/Nrf2, NF-kappaB/P38MAPK and Bax/Bcl2/caspase-3 pathways. Adults male rats were assigned to 4 groups: control, BBR, MTX and MTX + BBR. As compared to MTX-treated group, BBR effectively reduced the serum levels of creatinine, urea, uric acid and kidney/body weight ratio with a remarkable increase in serum level of albumin and the final body weight. Moreover, down-regulation of Keap1, P38MAPK and NF-kappaB genes along with marked up-regulation of Nrf2 gene were observed. In addition, BBR negatively regulated both Bax and caspase-3 proteins expression along with increased expression of the Bcl2 protein. Also, BBR restored GSH content and SOD activity while it decreased both TBARS and NO2- contents. Biochemical findings confirmed and markedly supported by alleviation of histopathological changes in kidney tissues. Furthermore, MTX cytotoxic activity was markedly enhanced by BBR in vitro using some human cancer cell lines. In conclusion, the current findings indicated that co-administration of BBR with MTX may be a reasonable therapeutic strategy for attenuation of MTX -induced renal damage. PMID- 30396092 TI - Targeting gap junction in epilepsy: Perspectives and challenges. AB - Gap junctions (GJs) are multiple cellular intercellular connections that allow ions to pass directly into the cytoplasm of neighboring cells. Electrical coupling mediated by GJs plays a role in the generation of highly synchronous electrical activity. Accumulative investigations show that GJs in the brain are involved in the generation, synchronization and maintenance of seizure events. At the same time, GJ blockers exert potent curative potential on epilepsy in vivo or in vitro. This review aims to shed light on the role of GJs in epileptogenesis. Targeting GJs is likely to be served as a novel therapeutic approach on epileptic patients. PMID- 30396093 TI - The SUMO-specific protease family regulates cancer cell radiosensitivity. AB - Abnormalities in the small ubiquitin-related modifier (SUMO) pathway and the SUMO specific proteases (SENPs) pathway are frequently observed in cancer. SUMOylation and deSUMOylation are dynamic processes in cells. SUMOylation of cancer associated proteins may serve as a biomarker for cancer diagnosis and a target for cancer therapy. In recent years, an increasing number of studies have focused on the role of SENPs in the radiosensitivity of cancer cells. SENPs regulate cancer cell radiosensitivity by mediating DNA damage repair, apoptosis, the cell cycle, and tumor angiogenesis. Here, we review the current understanding of the role of SENPs in tumor radiosensitivity. PMID- 30396094 TI - Carvedilol (CAR) combined with carnosic acid (CAA) attenuates doxorubicin-induced cardiotoxicity by suppressing excessive oxidative stress, inflammation, apoptosis and autophagy. AB - Doxorubicin (DOX) is a wide spectrum antitumor drug. However, its clinical application is limited due to the cardiotoxicity. Carvedilol (CAR) is a beta blocker used to treat high blood pressure and heart failure. Accordingly, supplementation with natural antioxidants or plant extracts exerts protective effects against various injury in vivo. Carnosic acid (CAA), the principal constituent of rosemary, has various biological activities, including antioxidant, antitumor, and anti-inflammatory. Here, heart injury mouse model was established using DOX (20 mg/kg) in vivo. And cardiac muscle cell line of H9C2 was subjected to 0.5 MUM of DOX for 24 h in vitro. Then, the protective effects of CAA and CAR alone, or the two in combination on DOX-induced cardiotoxicity in vivo and in vitro were explored. The results indicated that both CAA and CAR, when used alone, were moderately effective in attenuating DOX-induced cardiotoxicity. The combination of two drugs functioned synergistically to ameliorate cardiac injury caused by DOX, as evidenced by the significantly reduced collagen accumulation and improved dysfunction of heart. CAA and CAR exhibited stronger anti-oxidative role in DOX-treated mice partly by augmenting the expression and activities of the anti-oxidative enzymes. In addition, inflammatory response was significantly suppressed by the two in combination, proved by the decreased pro-inflammatory cytokines (COX2, TNF-alpha, IL-6, IL 1beta and IL-18), which was associated with the inactivation of nuclear factor kappaB (NF-kappaB). Furthermore, DOX-stirred apoptosis and autophagy were dramatically attenuated by the co-treatments of CAA and CAR through down regulating cleaved Caspase-3 and LC3B signaling pathways. The effects of CAA and CAR combination against cardiotoxicity were observed in H9C2 cells with DOX stimulation. Our findings above suggested that the use of CAR and CAA in combination could be expected to have synergistic efficacy and significant potential against cardiotoxicity induced by DOX. PMID- 30396095 TI - Protective effects of Astragaloside IV on endoplasmic reticulum stress-induced renal tubular epithelial cells apoptosis in type 2 diabetic nephropathy rats. AB - Diabetic nephropathy (DN) has become the leading cause of end-stage renal disease (ESRD) worldwide. Renal tubular injury plays an important role in the development and progression of DN. And apoptosis of renal tubular epithelial cells (RTEC) contribute to the loss of renal function, increased levels of serum creatinine (SCr), blood urea nitrogen (BUN), urine total protein to urine creatinine and microalbuminuria and reduction of creatinine clear rate (CCr). Moreover, recent findings suggested that endoplasmic reticulum (ER) stress may lead to apoptosis of renal cells. Astragalosides IV (AS-IV) has a variety of pharmacological effects such as anti-apoptosis. Thus, in this study we investigated the effects and mechanisms of AS-IV on apoptosis of RTEC in high-fat diets (HFD) and low-dose streptozotocin (STZ)-induced type 2 DN rats. The results showed that AS-IV (40, 80 mg/kg) could alleviate RTEC apoptosis in DN rats. Furthermore, body weight, the majority of biochemical and renal function parameters and histopathological changes in the diabetic kidney were also improved by AS-IV. And AS-IV could reduce the expression of apoptosis-related proteins cleaved caspase-3, Bax/Bcl-2 ratio. ER stress-related proteins GRP78, p-PERK, ATF4 and CHOP were also inhibited by AS-IV in kidney of DN rats. Taken together, our study suggests that the protective effects of AS-IV may be related to inhibit ER stress-induced apoptosis through down-regulating the expression of p-PERK, ATF4 and CHOP. And our study provides a new theoretical basis for the clinical treatment of patients with kidney diseases. PMID- 30396096 TI - Trichosanthes kirilowii lectin ameliorates streptozocin-induced kidney injury via modulation of the balance between M1/M2 phenotype macrophage. AB - BACKGROUND: Macrophage polarization has been reported to induce podocyte injury, which is a typical characteristic of diabetic nephropathy (DN). Trichosanthes kirilowii is an herb showing renal protective effect as well as immune-regulating effect. Therefore, it was hypothesized that the renal protective effect of Trichosanthes kirilowii was associated with its modulation on macrophage polarization. In the current study, we tested the hypothesis by subjecting DN rats to treatment of Trichosanthes kirilowii lectin (TKL), an active component of Trichosanthes kirilowii. METHOD: DN was induced using streptozocin (STZ) method, and after 3 days, treatments were performed with different doses of TKL for eight weeks. The effect of TKL on the renal function, structure, and inflammation was assessed. To explain the pathway mediating the effect of TKL on renal tissues, the expressions of markers involved in macrophage polarization, podocyte proliferation, and Notch signaling were determined. Moreover, the DN rats were further administrated with Notch signaling inhibitor, Dibenzazepine (DIB), to verify the key role of Notch signaling in the renal protective effect of TKL. RESULTS: STZ induced damages in renal function and structure, which was attenuated by TKL of different doses. Moreover, STZ also increased the production of TNF-alpha and iNOS while suppressed the production of IL-10 and arginase-1 (Arg-1). The induced inflammation by STZ was inhibited by TKL. The polarization of macrophage into M1 type during the development of DN was blocked by TKL, contributing to the increased proliferation potential of podocytes. Regarding Notch signaling, TKL administration inhibited the activation of the pathway by suppressing the expression of Notch1, NICD1, and Hes1. The administration of DIB had similar effect to that of TKL administration on renal function and structure. CONCLUSIONS: The study for the first time showed that TKL attenuated deterioration in renal structure and function by increasing M2 macrophage proportion via inhibition of Notch signaling. PMID- 30396097 TI - Trends and drug-related correlates in residential mobility among young adults in the United States, 2003-2016. AB - INTRODUCTION: Young adulthood, typically conceptualized as stretching from the late teens to the mid-twenties, is a period of elevated risk for residential mobility (i.e., moving or changing residences frequently) and drug involvement. However, our understanding of the trends and drug-related correlates of residential mobility among young adults remains limited. METHODS: We analyzed national trend data from the National Survey on Drug Use and Health (2003-2016) on residential mobility and drug involvement among young adults (N = 230,790) in the United States. For tests of trend, we conducted logistic regression analyses with survey year specified as a continuous independent variable and residential mobility as the dependent variable (no/yes), controlling for sociodemographic factors. RESULTS: The prevalence of residential mobility was stable among females, but decreased significantly-a 20% reduction in the relative proportion of respondents-among males during the study period (AOR = 0.98, 95% CI = 0.97 0.99). Male and female young adults reporting residential mobility were significantly more likely to report involvement in all drug-related outcomes examined, but effects were larger among females for drug selling and drug-related arrests. DISCUSSION: Study findings show that a substantial minority of young adults experience residential mobility and that, while rates are declining among young men, the experience of mobility is connected with risk for drug involvement, particularly among females. Mobility may be an important target for drug prevention/intervention efforts, but further research is needed to provide insight into how mobility and drug involvement are connected in the lives of young adults. PMID- 30396098 TI - Testing a brief motivational-interviewing educational commitment module for at risk college drinkers: A randomized trial. AB - BACKGROUND: The goal of the present study was to test the drink and harm reduction effects of a novel educational commitment (EC) module as a complement to a standard brief MI protocol (i.e., the Brief Alcohol Screening and Intervention for College Students; BASICS, Dimeff, Baer, Kivlahan, & Marlatt, 1999). METHODS: Using a randomized trial design, 180 university students were assigned to one of three conditions: Information, BASICS, or BASICS+EC. Participants completed an alcohol consumption interview and measures of alcohol related problems, partying decision-making, subjective student role investment, and self-control-related traits at baseline and at two- and nine-month follow ups. RESULTS: Linear models showed significant condition effects for two-month and nine-month drink quantity, but not for alcohol problems/consequences. Secondary outcome analyses showed significant condition effects for two-month high-risk high-reward partying decision-making and nine-month conscientiousness. Somewhat larger-sized decreases in consumption were observed at two months for the BASICS+EC condition compared to the BASICS condition, although these differences were not present at nine months. CONCLUSIONS: The differential efficacy between the BASICS and BASICS+EC conditions compared to the Information condition reinforces the utility of in-person feedback modalities as more intensive indicated prevention strategies for at-risk college drinkers. The limited differential efficacy for BASICS+EC compared to BASICS suggests a brief MI module for the academic/vocational aspects of the student role is not associated with greater long-term drink and harm reduction. Future research should examine more intensive educational commitment modalities, the utility of on-going academic goal and action feedback, and mechanisms of differential efficacy across intervention groups. PMID- 30396099 TI - Delayed onset of foot drop after the insertion of a mid-thigh adductor canal catheter. PMID- 30396100 TI - Comparison of the effects of modified pectoral nerve block and erector spinae plane block on postoperative opioid consumption and pain scores of patients after radical mastectomy surgery: A prospective, randomized, controlled trial. AB - STUDY OBJECTIVE: Breast cancer is the most common malignancy of women all over the world. In this study, we compared the effects of ultrasound-guided modified pectoral nerve (PECS) block and erector spinae plane (ESP) block on postoperative opioid consumption, pain scores, and intraoperative fentanyl need of patients undergoing unilateral modified radical mastectomy surgery. DESIGN: Single blinded, prospective, randomized, efficacy study. SETTING: Tertiary university hospital, postoperative recovery room and surgical ward. PATIENTS: Forty patients (ASA I-II) were allocated to two groups. After exclusion, 38 patients were included in the final analysis (18 patients in the PECS groups and 20 in the ESP group). INTERVENTIONS: Modified pectoral nerve block was performed in the PECS group and erector spinae plane block was performed in the ESP group. MEASUREMENTS: Postoperative tramadol consumption and pain scores were compared between the groups. Also, intraoperative fentanyl need was measured. MAIN RESULTS: Postoperative tramadol consumption was 132.78 +/- 22.44 mg in PECS group and 196 +/- 27.03 mg in ESP group (p = 0.001). NRS scores at the 15th and 30th min were similar between the groups. However, median NRS scores were significantly lower in PECS group at the postoperative 60th min, 120th min, 12th hour and 24th hour (p = 0.024, p = 0.018, p = 0.021 and p = 0.011 respectively). Intraoperative fentanyl need was 75 mg in PECS group and 87.5 mg in ESP group. The difference was not statistically significant (p = 0.263). CONCLUSION: Modified PECS block reduced postoperative tramadol consumption and pain scores more effectively than ESP block after radical mastectomy surgery. PMID- 30396101 TI - Effect of mixing intensity on hydrolysis and acidification of sewage sludge in two-stage anaerobic digestion: Characteristics of dissolved organic matter and the key microorganisms. AB - Mixing should be optimized in anaerobic digestion (AD) systems to achieve excellent biomaterials production in the sewage sludge (SS) management in wastewater treatment plant. AD depends on the coordinated activity of hydrolysis, acidification and methanogenesis. However, the effect of mixing intensity on characteristics of hydrolysis and acidification in AD of SS is still poorly understood. This study focused on the mixing intensity (30, 60, 90 and 120 rpm) effect on the characteristics of dissolved organic matter (DOM) and the key microorganisms in the hydrolysis and acidification of SS. Results showed that enhanced hydrolysis and acidification efficiency was obtained at mixing of 90 and 120 rpm (p < 0.05), while the maximum acetic acid (388 +/- 21 mg/L) was produced at 90 rpm. Mixing at 90 rpm enhanced the release of protein and polysaccharide as well as humic acid. Further analyses of DOM molecular features revealed that 90 rpm led to the highest molecular diversity and easily biodegradable molecules (lipid and proteins/amino sugars), which contributed to the maximum hydrolysis and acidification efficiency. Firmicutes and Actinobacteria significantly increased with mixing intensity (p<0.05), and Chloroflexi and Fusobacteria were enriched at mixing of 90 rpm, which favored the hydrolysis of SS. The enrichment of Clostridium XI and Clostridium sensu stricto contributed to the acidification of DOM at 90 and 120 rpm. The results of this study can advance our knowledge about mixing intensity effects on the AD systems of SS. This research also showed how increasing mixing intensity to a relatively high speed can enhance the hydrolysis and acidification efficiency of SS. PMID- 30396102 TI - Reactivation and pilot-scale application of long-term storage denitrification biofilm based on flow cytometry. AB - The work provides a method on the basis of flow cytometry to evaluate the performance of denitrification biofilm during the preservation, reactivation and pilot-scale operation process. The viable cell ratio of denitrification biofilm significantly reduced and further led to the decrease of denitrification capacity after long-term preservation for 5 months. Protein component in tightly bound extracellular polymeric substances (TB-EPS) could serve to enhance microbial adhesion and promote denitrification biofilm formation. With the significant correlation of viable cell ratio and microbial characteristics, 4 degrees C was more appropriate for preserving denitrification biofilm and conducive to maintain the relatively high denitrification capacity. A maximum denitrification rate of 5.80 gNO3--N/m2.d was obtained in pilot-scale anoxic-oxic (AO) process and Dechloromonas became greater prevalence in denitrification suspended carriers. Furthermore, the enrichment of Pseudomonas, Parcubacteria, Acidovorax, Aquabacterium and Unclassified_Flavobacteriaceae enhanced biofilm formation and nutrient conservation. The significantly positive correlation between viable cell ratio and the ratio of nitrate reduction to COD consumption was discovered, and the indices of Chao, ACE, Shannon and Simpson of denitrification biofilm were positively correlated with viable cell ratio, meaning that flow cytometry analysis was reasonable and suitable to evaluate the performances of denitrification biofilm. PMID- 30396103 TI - A pilot-scale, bi-layer bioretention system with biochar and zero-valent iron for enhanced nitrate removal from stormwater. AB - Nitrogen (N) removal in conventional bioretention systems is highly variable owing to the low nitrate (NO3-) elimination efficiency. We hypothesized that amending bioretention cells with biochar and zero-valent iron (ZVI) could improve the NO3- removal performance. A well-instrumented, bi-layer pilot-scale bioretention cell was developed to test the hypothesis by investigating its hydrologic performance and NO3- removal efficacy as affected by biochar and ZVI amendments. The cell containing 18% (v/v) wood biochar in the vadose zone and 10% (v/v) ZVI in the saturation zone was monitored for 18 months of field infiltration tests using synthetic stormwater amended with bromide (tracer) and NO3-. Compared to the Control cell without amendments, the Biochar/ZVI cell increased water retention by 11-27% and mean residence time by 0.7-3.8 h. The vadose zone of the Biochar/ZVI cell removed 30.6-95.7% (0.6-12.7 g) of NO3-N from the influent, as compared with -6.1-89.6% (-0.1-2.9 g) by that of the Control cell. While the performance varied with synthetic storm events and seasons, in all cases the Biochar/ZVI cell resulted in greater NO3- removal than the Control cell. This improvement was presumably due to biochar's ability to improve water retention, facilitate anoxic conditions, increase residence time, and provide electrons for microbial denitrification. The saturation zone with ZVI amendment further promoted NO3- removal: removal was 1.8 times greater relative to the control in the first infiltration test, but was minimal in following tests. The reduction in performance of the ZVI amendment in subsequent tests might be due to diminished NO3-N input to the saturation zone after treatment by the biochar amended vadose zone. The redox potential and dissolved oxygen content at the vadose/saturation zone interface also indicated more favorable denitrification conditions in the Biochar/ZVI cell. Biochar amendment demonstrated significant promise for increasing nitrate removal in bioretention systems. PMID- 30396104 TI - Natural products hybrids: 3,5,4'-Trimethoxystilbene-5,6,7-trimethoxyflavone chimeric analogs as potential cytotoxic agents against diverse human cancer cells. AB - Cancer still represents a major global health problem. All currently available anticancer agents have disadvantages like resistance or side effects. Therefore, introduction of novel anticancer agents is needed. Intrigued by the high success rate for natural products-based drug discovery, we designed and synthesized antiproliferative chemical entities as hybrids of two natural products; 3,5,4' trimethoxystilbene and 5,6,7-trimethoxyflavone. To probe the spectrum of the synthesized compounds, in vitro evaluation was conducted against nine panels representing major cancer diseases. The results revealed the hybrid analogs 4f, 4h, 4k and 4q as promising broad-spectrum anticancer lead compounds eliciting high growth inhibition of several cell lines representing multiple cancers diseases. Evaluation of the promising lead compounds against normal human cell lines suggested a selective cytotoxic effect on cancer cells. Mechanistic investigation of the cytotoxic activity of compound 4f in human cervical cancer HeLa cells showed that it triggers cell death through induction of apoptosis. As a whole, this study presents the natural products hybrid analogs 4f, 4h, 4k and 4q as potential lead compounds for further development of novel anticancer therapeutics. PMID- 30396105 TI - Novel tyrosyl-DNA phosphodiesterase 1 inhibitors enhance the therapeutic impact of topotesan on in vivo tumor models. AB - The druggability of the tyrosyl-DNA phosphodiesterase 1 (Tdp1) enzyme was investigated in conjunction with topoisomerase 1 inhibition. A novel class of thiazole, aminothiazole and hydrazonothiazole usnic acid derivatives was synthesized and evaluated as Tdp1 inhibitors and their ability to sensitize tumors to topotecan, a topoisomerase inhibitor in clinical use. Of all the compounds tested, four hydrazinothiazole derivatives, 20c, 20d, 20h and 20i, inhibited the enzyme in the nanomolar range. The activity of the compounds was verified by affinity experiments as well as supported by molecular modelling. The most effective Tdp1 inhibitor, 20d, was ton-toxic and increased the effect of topotecan both in vitro and in vivo in the Lewis lung carcinoma model. Furthermore, 20d showed significant increase in the antitumor and antimetastatic effect of topotecan in mice. The results presented here justify compound 20d to be considered as a drug lead for antitumor therapy. PMID- 30396106 TI - Synthesis and antiproliferative activities of doxorubicin thiol conjugates and doxorubicin-SS-cyclic peptide. AB - Myocardial toxicity and drug resistance caused by drug efflux are major limitations of doxorubicin (Dox)-based chemotherapy. Dox structure modification could be used to develop conjugates with an improved biological profile, such as antiproliferative activity and higher cellular retention. Thus, Dox thiol conjugates, Dox thiol (Dox-SH), thiol-reactive Dox-SS-pyridine (SS = disulfide), and a Dox-SS-cell-penetrating cyclic peptide, Dox-SS-[C(WR)4K], were synthesized. Dox was reacted with Traut's reagent to generate Dox-SH. The thiol group was activated by the reaction with dithiodipyridine to afford the corresponding Dox SS-Pyridine (Dox-SS-Pyr). A cyclic cell-penetrating peptide containing a cysteine residue [C(WR)4K] was prepared using Fmoc solid-phase strategy. Dox-SS-Py was reacted with the free sulfhydryl of cysteine in [C(WR)4K] to generate Dox-SS [C(WR)4K] as a Dox-cyclic peptide conjugate. Cytotoxicity of the compounds was examined in human embryonic kidney (HEK-293), human ovarian cancer (SKOV-3), human fibrosarcoma (HT-1080), and human leukemia (CCRF-CEM) cells. Dox-SH and Dox SS-pyridine were found to have significantly higher or comparable cytotoxicity when compared to Dox in HEK-293, HT-1080, and CCRF-CEM cells after 24 h and 72 incubation, presumably because of higher activity and retention of the compounds in these cells. Furthermore, Dox-SS-[C(WR)4K] showed significantly higher cytotoxic activity in HEK-293, HT-1080, and SKOV-3 cells when compared with Dox after 72 h incubation. Dox-SS-Pyr exhibited higher cellular uptake than Dox-SS [C(WR)4K] in HT-1080 and HEK-293 cells as shown by flow cytometry. Fluorescence microscopy exhibited that Dox-SS-Pyr, Dox-SH, and Dox-SS-[C(WR)4K] localized in the nucleus as shown in four cell lines, HT-1080, SKOV-3, MDA-MB-468, and MCF-7. Of note, Dox-SS-[C(WR)4K] was significantly less toxic in mouse myoblast cells compared to Dox at the same concentration. Further mechanistic study demonstrated that the level of intracellular reactive oxygen species (ROS) in myoblast cells exposed to Dox-SS-[C(WR)4K] was reduced in comparison of Dox when co-treated with FeCl2. These data indicate that Dox-SH, Dox-SS-Pyr, and Dox-SS-[C(WR)4K] have the potential to be further examined as Dox alternatives and anticancer agents. PMID- 30396107 TI - Intrahepatic cholestasis of pregnancy: Review of six national and regional guidelines. AB - Intrahepatic cholestasis of pregnancy (ICP) is a poorly understood disease of the late second or third trimester of pregnancy, typically associated with rapid resolution following delivery. It is characterized by pruritis, elevated serum bile acids, and abnormal liver function tests and has been linked to stillbirth, meconium passage, respiratory distress syndrome and fetal asphyxial events. The incidence is highly variable, dependent both on the ethnic makeup of the population as well as the diagnostic criteria being used. Management is challenging for clinicians, as laboratory abnormalities often lag behind clinical symptoms making diagnosis difficult. The American Congress of Gastroenterology, Government of Western Australia Department of Health, the Royal College of Obstetricians and Gynaecologists, Society for Maternal Fetal Medicine, European Association for the Study of the Liver, and South Australia Maternal and Neonatal Community of Practice have all released guidelines to address the risks, diagnosis and management of ICP. We performed a descriptive review of these guidelines along with a literature search to address conflicting recommendations and highlight new evidence. The variations in the guidelines reflect the heterogeneity of the literature and the challenges of diagnosing and managing ICP. PMID- 30396108 TI - Significant increase in serum hCG levels following methotrexate therapy is associated with lower treatment success rates in ectopic pregnancy patients. AB - OBJECTIVE: To determine the association between early increase in the serum hCG levels (days 0-4) and treatment success rates following methotrexate therapy in ectopic pregnancy patients. STUDY DESIGN: A level II-2 case-control study of involving 140 patients treated with methotrexate for ectopic pregnancy at the gynecology department in a tertiary care hospital. RESULTS: A logistic regression model for the "failure of treatment" was fitted with serum hCG levels change between day 0 and day 4, patient age, pregnancy age at day-0, and day-0 beta-hCG level as predictors. The logistic regression analysis indicated that having more than 50% increase in the beta-hCG levels between days 0 and 4 significantly (P = 0.011) increases the risk of MTX treatment failure. CONCLUSION: The results of this study indicate that >50% increase in beta-hCG levels between days 0 and 4 significantly increases the risk of methotrexate treatment failure. This novel information could assist patients and physicians in making decisions regarding ectopic pregnancy treatment. PMID- 30396109 TI - Vaginal birth after prior myomectomy. AB - OBJECTIVE: The aim of this retrospective cohort study was to evaluate the obstetrical and perinatal outcomes of vaginal birth in case of pregnancies achieved after prior myomectomy. We also analyzed how operative characteristics at the time of surgery might influence the choice of obstetricians about mode of delivery. STUDY DESIGN: We analyzed retrospectively all women who underwent laparoscopic (LPS) or laparotomic (LPT) myomectomy between January 2002 and December 2014, in a network of three Institutions belonging to the University of Milano Bicocca, Italy. Women were contacted by phone interview and only cases with available follow-up data and who had a subsequent pregnancy were included. Operative characteristics and subsequent obstetrical outcomes were recorded and analyzed. RESULTS: 469 women who underwent myomectomy were contacted by phone interview, and 152 pregnancies were achieved after surgery, 96 after LPS and 56 after LPT. A total of 110 pregnancies ended in deliveries at >=24 weeks. Seventy three (66.4%) women had trial of labor after myomectomy (TOLAM), while 24 (21.8%) had a planned cesarean delivery (CD). Sixty-six (90.4%) of the TOLAM cases successfully accomplished vaginal delivery. No cases of uterine rupture (UR) were reported, and all deliveries ended in live births. The incidence of Neonatal Intensive Care Unit admission was 14.5% (16/110), with no cases of perinatal death. Comparing the surgical details at the time of myomectomy, the incidence of uterine cavity entered was significantly higher in planned CD group compared to TOLAM cases (p < 0.001). No other significant difference between the two groups was reported. CONCLUSIONS: A successful vaginal delivery was accomplished by 90.4% of women who had TOLAM, without any case of UR or severe maternal and perinatal complications. TOLAM may be considered and offered as feasible and relatively safe option. Obstetricians' attitude toward mode of delivery after prior myomectomy seems to be influenced by the reported entry into the uterine cavity at the time of surgery. PMID- 30396110 TI - Rumination in anorexia nervosa: Cognitive-affective and neuroendocrinological aspects. AB - Rumination about body weight/figure as well as food is common in patients with Anorexia Nervosa (AN) and may be a maintenance factor of the disorder. While rumination can generally be considered as a cognitive-affective process, food related rumination may be driven primarily by a physiological response to undernutrition. In the current longitudinal study, we integrate ecological momentary assessment of rumination and affect and, as a biological marker of undernutrition, plasma leptin levels collected from 33 AN patients. At the very acute stage and again after short-term weight-restoration patients answered short questionnaires six times per day over two weeks. Analyses via hierarchical linear modelling confirmed that rumination is closely linked to affect in AN before and after weight-restoration. Rumination about food decreased during weight restoration and was correlated with leptin levels. In contrast, rumination about body weight/figure was not linked to leptin, persisted after weight gain, and showed stronger connections with affect. This suggests that rumination about body weight/figure seems to be a cognitive-affective aspect of the disorder, but food related rumination may need to be considered from a physiological perspective. It is possible that food-related ruminative thoughts reflect a physiological symptom induced by undernutrition, similar to well-described leptin-associated changes in physical activity. PMID- 30396111 TI - The validity of human avoidance paradigms. AB - Excessive avoidance towards innocuous cues is a central diagnostic criterion across anxiety-related disorders. Relevant laboratory paradigms typically include instrumental learning procedures, where the presentation of an aversive cue (e.g., a shock) can be prevented by executing an experimenter-defined response (e.g., a button press) during the presentation of a warning cue (e.g., a square). Despite the popularity of these paradigms, there is no evaluation of how well the experimental findings of conditioned avoidance extend to maladaptive avoidance, or whether findings from animal studies could be informative for human studies. Here, we present a validation of the conditioned avoidance paradigm. We show that although this procedure meets the majority of the tested validity criteria (i.e. face, construct, predictive, and diagnostic validity), it also faces a number of challenges, including the non-consideration of individual differences in learning or the use of procedures that cannot be easily translated to clinical settings. For meeting these challenges, we suggest extensions of the paradigm including the test of individual differences by using ambiguous stimuli as well as the use of virtual reality procedures. Our main conclusion is that despite the significant knowledge provided in conditioned avoidance paradigms, their expansion will allow reaching more theoretical and clinical insights. PMID- 30396112 TI - Enhancement of Monascus pigment productivity via a simultaneous fermentation process and separation system using immobilized-cell fermentation. AB - A mutant Monascus purpureus strain, M183, which produced monascus pigments (MPs) at 8460 U/g via solid-state batch-fermentation, was generated using the atmospheric and room temperature plasma (ARTP) mutation system. The optimal glucose concentration (80 g/L) in traditional fermentation media that yielded the highest MPs productivity was determined. Response surface methodology (RSM) was applied to maximize MPs production using liquid-state batch-fermentation. Under optimal conditions (0.58 g/L MgSO4.7H2O, 0.02 g/L ZnSO4.7H2O, 0.02 g/L FeSO4.7H2O and 4.85 g/L NH4NO3), 207.67 U/mL of MPs were produced with 98.12% validity based on the predicted value. Extracellular MPs production increased significantly to 35.52 U/mL, compared to 14.19 U/mL of the original strain, M. purpureus LQ-6. M. purpureus spores immobilized in sodium alginate were studied. A simultaneous fermentation and separation system was established for MPs using the novel absorption resin LX300C to enhance production efficiency of extracellular MPs. PMID- 30396113 TI - The significance of proline on lignocellulose-derived inhibitors tolerance in Clostridium acetobutylicum ATCC 824. AB - When lignocellulosic biomass was used for acetone-butanol-ethanol (ABE) fermentation, several lignocellulose-derived inhibitors, which are toxic to Clostridium acetobutylicum, were generated during acid hydrolysis process and seriously hindered the industrialization of lignocellulosic butanol. In this study, an engineered strain 824(proABC) with significantly improved tolerance to multiple lignocellulose-derived inhibitors (formic acid and phenolic compounds) was constructed by strengthening the proline biosynthesis. The engineered strain exhibited more effective synthesis ability of proline and scavenging ability of reactive oxygen species (ROS). Consequently, the butanol produced by 824(proABC) was 1-, 2.4- or 3.4-fold higher than that of the wild type strain when using the undetoxified hydrolysate of soybean straw, rice straw or corn straw as the substrate, respectively. Therefore, enhancing the proline biosynthesis can be used as an effective strategy to improve the tolerance of C. acetobutylicum to multiple lignocellulose-derived inhibitors, and 824(proABC) has great potential to produce butanol from undetoxified lignocellulosic hydrolysates. PMID- 30396114 TI - Synthesis and DNA binding profile of monomeric, dimeric, and trimeric derivatives of crystal violet. AB - Monomeric, dimeric, and trimeric derivatives of the triphenylmethane dye crystal violet (1a-1f) have been synthesized for the purpose of evaluating their affinity and sequence selectivity for duplex DNA. Competitive ethidum displacement assays indicate that 1a-1f have apparent association constants for CT DNA in the range of 1.80-16.2 * 107 M-1 and binding site sizes of 10-14 bp. Viscosity experiments performed on ligand 1f confirmed that these dyes associate with duplex DNA by a non-intercalative mode of binding. Circular dichroism and competition binding studies of the tightest binding ligand 1e with known major and minor groove binding molecules suggest that these dye derivatives likely occupy the major groove of DNA. Data from the binding of 1e to polynucleotides indicate close to an order of magnitude preference for associating with AT rich homopolymers over GC rich homopolymers, suggesting a shape-selective match of the sterically bulky ligand with DNA containing a wider major groove. PMID- 30396115 TI - Novel tacrine-coumarin hybrids linked to 1,2,3-triazole as anti-Alzheimer's compounds: In vitro and in vivo biological evaluation and docking study. AB - A new series of tacrine-coumarin hybrids linked to 1,2,3-triazole were designed, synthesized, and tested as potent dual binding site cholinesterase inhibitors (ChEIs) for the treatment of Alzheimer's disease (AD). Among them, compound 8e was the most potent anti-AChE derivative (IC50 = 27 nM) and compound 8m displayed the best anti-BChE activity (IC50 = 6 nM) much more active than tacrine and donepezil as the reference drugs. Compound 8e was also evaluated for its BACE1 inhibitory activity and neuroprotectivity against PC12 cells exposed to Abeta25 35 which indicated low activity. Finally, in vivo studies by Morris water maze task showed that compound 8e significantly reversed scopolamine-induced memory deficit in rats. PMID- 30396116 TI - Rhamnocitrin isolated from Prunus padus var. seoulensis: A potent and selective reversible inhibitor of human monoamine oxidase A. AB - Three flavanones and two flavones were isolated from the leaves of Prunus padus var. seoulensis by the activity-guided screening for new monoamine oxidase (MAO) inhibitors. Among the compounds isolated, rhamnocitrin (5) was found to potently and selectively inhibit human MAO-A (hMAO-A, IC50 = 0.051 uM) and effectively inhibit hMAO-B (IC50 = 2.97 uM). The IC50 value of 5 for hMAO-A was the lowest amongst all natural flavonoids reported to date, and the potency was 20.2 times higher than that of toloxatone (1.03 uM), a marketed drug. In addition, 5 reversibly and competitively inhibited hMAO-A and hMAO-B with Ki values of 0.030 and 0.91 uM, respectively. Genkwanin (4) was also observed to strongly inhibit hMAO-A and hMAO-B (IC50 = 0.14 and 0.35 uM, respectively), and competitively inhibit hMAO-A and hMAO-B (Ki = 0.097 and 0.12 uM, respectively). Molecular docking simulation reveals that the binding affinity of 5 with hMAO-A (-18.49 kcal/mol) is higher than that observed with hMAO-B (0.19 kcal/mol). Compound 5 interacts with hMAO-A at four possible residues (Asn181, Gln215, Thr336, and Tyr444), while hMAO-B forms a single hydrogen bond at Glu84. These findings suggest that compound 5 as well as 4 can be considered as novel potent and reversible hMAO-A and/or hMAO-B inhibitors or useful lead compounds for future development of hMAO inhibitors in neurological disorder therapies. PMID- 30396117 TI - Chemical fabrication of graphene oxide nanosheets attenuates biofilm formation of human clinical pathogens. AB - Graphene oxide (GO) has been recently attracted considerable interest for its potential applications in physical, chemical and biological properties. In the present study, the GO nanosheets were prepared by a chemical exfoliation technique using a modified Hummers method. Initially, the prepared GO nanosheets were confirmed by UV-vis spectroscopy and further characterized by FE-SEM, Edax, HR-TEM and SAED that demonstrated the formation of GO nanosheets with few layers flat sheet structure with hexagonal lattice crystalline nature. The FTIR spectra revealed the presence of various oxygen containing functional groups has been produced from graphite plane by exfoliation technique. The prepared GO nanosheets showed excellent antibiotic resistant activity against planktonic bacteria and more effective to damage the established biofilms and inhibits the biofilm formation of human clinical pathogens like E. coli and P. aeruginosa. Further, the GO nanosheets were found to be non-toxic to normal mammalian cells and there are no apparent morphological changes were observed in control and treated cells. In conclusion, GO nanosheets were effectively preventing the formation of biofilms and kills the represent bacteria that suggested the GO nanosheets could be used for the prevention and treatment of biofilm-related infections. PMID- 30396118 TI - APD1, the unique member of Arabidopsis AP2 family influences systemic acquired resistance and ethylene-jasmonic acid signaling. AB - Arabidopsis AP2 FAMILY PROTEIN INVOLVED IN DISEASE DEFENSE (APD1) is a member of AP2/EREBP super-family that positively regulates SA biosynthesis and defense against virulent bacterial pathogens. Here we report additional roles of APD1 in plant defense and development. We show that APD1 function is required for light mediated defense against bacterial pathogens and systemic acquired resistance (SAR). We demonstrate that APD1 function is not required for generating SAR mobile signal at the site of primary inoculation but is required at the distal end for SAR manifestation. In addition, the APD1 function is required for PTI induced callose deposition, defense against necrotrophic pathogen Botrytis cinerea and Alternaria alternata, which are ethylene (ET) or ethylene-Jasmonate (JA) dependent responses. Development of seedling under dark and ET is partly dependent on APD1. The mutant apd1 plants are non-responsive towards exogenous ACC application regarding apical hook formation and hypocotyl shortening, however, possess WT-like ET-mediated root growth inhibition. JA-mediated root growth inhibition is also impaired in apd1 seedlings. Altogether our results suggest that APD1 impacts multiple aspects of plant growth and development. PMID- 30396119 TI - Parental warmth and flourishing in mid-life. AB - OBJECTIVE: This study examined the longitudinal association between parental warmth and offspring flourishing in mid-life. We also considered associations between parental warmth and a number of mental health problems and adverse health behavioral outcomes. METHOD: Longitudinal data from the Midlife in the United States Study (N = 3,929, mean baseline age = 47.4 years) were analyzed using generalized estimating equations. Parental warmth in childhood was recalled at phase I (1995-1996), while flourishing and other outcomes were self-reported at phase II (2004-2006). Following an approach developed by Keyes, flourishing was operationalized as a combined measure incorporating assessments of three aspects of well-being, including emotional, psychological, and social well-being. RESULTS: The results suggest that parental warmth was positively associated with the continuous score of flourishing (B = 0.21, 95% CI = 0.18, 0.25). The association was not specific to any particular component (emotional, psychological, or social well-being) or subdomain of flourishing. Parental warmth was also inversely associated with several adverse health behavior outcomes such as drug use and smoking. CONCLUSIONS: Parental warmth in childhood may help promote offspring functioning across multiple domains of well-being in mid-life. The findings help to strengthen the call for a public health focus on the importance of parenting for outcomes beyond childhood and well into adulthood, and suggest the value of targeting parenting practices for prevention and intervention strategies to improve population health and well-being. PMID- 30396120 TI - Extracellular vesicles, new actors in the search for biomarkers of dementias. AB - Increased life expectancy impacts directly on the number of older people worldwide with the associated increase in neurodegenerative diseases. Besides their social implications, the different forms of dementia, including Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies or frontotemporal dementia, show clinical and pathological overlaps; this hinders their specific and differential diagnosis. To date, biomarkers for each of these types of dementia have been investigated in the cerebrospinal fluid or blood. More recently, the field of biomarker search found a new opportunity to improve diagnosis in extracellular vesicles (EVs). EVs are released by cells including those of the central nervous system and these can be isolated from cerebrospinal fluid and blood. This review summarizes the current knowledge related to the search for dementia biomarkers in the field of EVs including studies of specific EV content, mainly proteins such as alpha-synuclein or tau and RNA species. PMID- 30396121 TI - Carbon-enhanced centrifugally-spun SnSb/carbon microfiber composite as advanced anode material for sodium-ion battery. AB - Antimony tin (SnSb) based materials have become increasingly attractive as a potential anode material for sodium-ion batteries (SIBs) owing to their prominent merit of high capacity. However, cyclic stability and rate capability of SnSb anodes are currently hindered by their large volume change during repeated cycling, which results in severe capacity fading. Herein, we introduce carbon coated centrifugally-spun SnSb@carbon microfiber (CMF) composites as high performance anodes for SIBs that can maintain their structural stability during repeated charge-discharge cycles. The centrifugal spinning method was performed to fabricate SnSb@CMFs due to its high speed, low cost, and large-scale fabrication features. More importantly, extra carbon coating by chemical vapor deposition (CVD) has been demonstrated as an effective method to improve the capacity retention and Coulombic efficiency of the SnSb@CMF anode. Electrochemical test results indicated that the as-prepared SnSb@CMF@C anode could deliver a large reversible capacity of 798 mA h?g-1 at the 20th cycle as well as a high capacity retention of 86.8% and excellent Coulombic efficiency of 98.1% at the 100th cycle. It is, therefore, demonstrated that SnSb@CMF@C composite is a promising anode material candidate for future high-performance SIBs. PMID- 30396122 TI - Facile molten salt synthesis of atomically thin boron nitride nanosheets and their co-catalytic effect on the performance of carbon nitride photocatalyst. AB - Two-dimensional atomically thin boron nitride (BN) nanosheets possess many distinctive properties but their applications are still being hindered by the technical difficulties in their synthesis methods, due to the strong lip-lip interactions between their basal planes. In this paper, we reported a facile and scalable bottom-up approach to synthsizing atomically thin BN nanosheets in a molten salt medium. As-prepared BN nanosheets can be used as an effective co catalyst to improve the catalytic performance of carbon nitride photocatalyst, owing to the interfacial effect induced by their addition. In the case of photodegradation of rhodamine B, for example, the photodegradation rate of carbon nitride could be approximately doubled when 5 wt% as-prepared BN nanosheets were added. PMID- 30396123 TI - Porous hollow composites assembled by NixCo1-xSe2 nanosheets rooted on carbon polyhedra for superior lithium storage capability. AB - Transition metal chalcogenides (TMCs) have attracted considerable interest owing to their satisfied theoretical capacity, good safety and environmentally benign nature in lithium-ion batteries (LIBs). However, the poor conductivity as well as the severe volume changes during the discharge-charge process cause capacity fading rapidly, which severely impede the practical applications of TMCs. To address this challenge, a hollow hybrid architecture assembled by NixCo1-xSe2 nanosheets and strongly coupled porous carbon have been rational designed. Within this structure, the integration of nanosheets rooted on the surface of porous carbon not only provide three-dimensional conductive network but also offer plentiful pathways and active sites for electrolyte penetration and Li storage, and buffer a large volume expansion/contraction caused by lithium intercalation/deintercalation. As evidenced by electrochemical measurements, the NixCo1-xSe2/C composites used as anodes in LIBs exhibit a superior reversible high capacity of 1667 mA h g-1 at current density of 2.0 A g-1 over 600 cycles and an outstanding rate capability (1580 and 1093 mA h g-1 at 3.2 and 6.4 A g-1, respectively). PMID- 30396124 TI - First case of laparoscopic partial splenectomy in a child with hamartoma: Case report and review of the literature. AB - INTRODUCTION: To date, laparoscopic surgery has played a key role in the treatment of not only splenic hematologic pathologies but also solid ones. Hamartoma is a rare disease; only twenty percent of them are of pediatric relevance; it is a benign tumor, but radiological features never allow proper differentiation from malignant neoplasms. In children, hamartoma may be associated with other morbid conditions, such as sickle cell disease or other hematological alterations. PRESENTATION OF THE CASE: We report a case of hamartoma in a 7-year-old child treated with partial laparoscopic splenectomy. After a multidisciplinary evaluation, the indication of laparoscopic splenectomy was decided; upon evaluating the age of the patient and the affected spleen portion, a partial splenectomy was proposed. The histological examination during surgery was performed to exclude any form of malignancy. The intraoperative frozen section of the specimen was negative for malignancies, and a partial splenectomy was performed. DISCUSSION: Surgery remains the first choice in the definitive treatment of solid lesions of the spleen; minimally invasive technique, namely, laparoscopy, has set itself as the technique of choice for surgical treatment. In this case, the possibility of obtaining an intraoperative pathological diagnosis by frozen section of the specimen, confirming the benign nature of the lesion, allowed the surgeon to decide in favor of a laparoscopic partial splenectomy. CONCLUSION: Partial laparoscopic splenectomy can be considered a safe, effective and reproducible alternative in patients suffering from benign solid diseases, safeguarding the hematological functions of the organ itself in pediatric age. PMID- 30396125 TI - Metastatic melanoma: An unusual cause of gastrointestinal bleeding and intussusception-A case report. AB - INTRODUCTION: Malignant melanoma is responsible for 1-3% of all malignancies being the gastrointestinal tract one of the most common metastatic locations. PRESENTATION OF CASE: We present the case of a 71-year old male with previous history of cutaneous melanoma. Seven years later, while being studied due to suspected small bowel bleeding, he developed small bowel obstruction after being submitted to double balloon enteroscopy. Further investigation revealed small bowel intussusception. He was taken up for emergency laparotomy that confirmed ileal intussusception secondary to an intraluminal mass. We performed segmental enterectomy with primary anastomosis. Histology confirmed intestinal melanoma metastasis. DISCUSSION: Malignant melanoma frequently spreads to the gastrointestinal tract. The presentation is mainly asymptomatic and the diagnosis is often made only after complications develop. Small bowel intussusception and gastrointestinal bleeding are unusual presentations of metastatic melanoma, with few cases reported. Surgical resection not only provides symptom control but also positively affects prognosis. CONCLUSION: Although usually asymptomatic, melanoma metastasis should always be considered in a patient with intestinal symptoms or chronic anemia and personal history of melanoma. Surgical resection is the treatment of choice, leading to an increase in overall survival. PMID- 30396126 TI - Impacted ureteric stone causing iliofemoral vein thrombosis: The first reported case. AB - INTRODUCTION: Extrinsic compression with resulting obstruction of the iliac veins is recognized as a crucial cause of deep vein thrombosis (DVT). We report a case of impacted ureteric stone causing DVT. CASE REPORT: A 65-year-old man presented with left lower limb swelling that diagnosed and treated as extensive DVT. Further evaluation revealed incidental left severe hydroureteronephrosis and impacted ureteric stone compressing iliac vessels. Immediate percutaneous nephrostomy done followed by left ureterolithotripsy 6 weeks later. DISCUSSION: several iliofemoral venous thromboses have been reported due to extrinsic compression by various pathologies, but to best of our knowledge, this is the 1st report of the impacted ureteric stone causing life-threatening proximal DVT. CONCLUSION: Isolated unilateral iliofemoral DVT may raise the suspicion of pelvic pathology including ureteric stone. PMID- 30396127 TI - Unusual complication of seroma after ventral hernia mesh repair: Digestive perforation by tacks. A case report. AB - Intraperitoneal meshes are actually widely used in ventral hernia repair. They can reduce operative time, parietal prejudice and postoperative pain. One of the most well-known complications of intraperitoneal mesh is seroma, but it usually subsides without any therapeutic problems. These meshes can be fixed by tackers, suture or glue. Few complications related to the fixation technique are known. We report the case of a patient who underwent a laparoscopic mesh repair for incisional hernia. He developed an infected bulky seroma for which he had to undergo medical treatment and percutanous drainage in order to avoid the mesh removal. The evolution seemed to be favorable until the occurrence of an unusual and unexpected complication: a digestive fistula of the small bowel in the seroma cavity via a tack adhering to the intestines. The possibility of digestive lesions by a tack is reported by some cases reports. It seems most often to be related to a technical problem. In our case, this adhesion seems to be secondary to the pressure exerted by the seroma. The complicated seroma can be conservatively treated to save the mesh. However the delay before deciding to remove the mesh when using tackers for its fixation may be shortened. PMID- 30396128 TI - A tourniquet-less technique using saline epinephrine irrigation system in an arthroscopic ACL reconstruction in patient with history of popliteal artery ligation. AB - INTRODUCTION: Pneumatic tourniquets use in surgery to create a bloodless surgical field. The majority of orthopaedic surgeon use a tourniquet inflated above systemic blood pressure during arthroscopic anterior cruciate ligament (ACL) reconstruction. A tourniquet use is not free of complications. The disadvantage of tourniquet application include an increased risk of vascular injuries. An arthroscopic ACL reconstruction in patient with history of popliteal artery ligation is challenging. The popliteal artery is the major contributor to the blood supply of the knee joint. This arthroscopic ACL reconstruction does not use tourniquets to preserve the collateral circulation that provides blood supply to the leg and prevent the vascular injuries in patient with history of popliteal artery ligation. PRESENTATION OF CASE: A-23-year-old female brought to the General Hospital with ACL rupture caused by car accident. The patient had a history of knee dislocation with an open wound and rupture of popliteal artery. The patient underwent open reduction surgery of her right knee joint by orthopaedic surgeon and popliteal artery repair by vascular surgeon. The reduction of the knee joint went good, but the popliteal artery repair was failed and the patient underwent popliteal artery ligation 1 week later. The patient received non-operative treatment for her ACL rupture. After 2 years, she did not get a good improvement to her knee and the patient still felt a giving way sensation and unstability of her knee. Then the patient transferred to the General Hospital for ACL reconstruction, but the surgery required a special consideration in the technique of ACL reconstruction because of the history of popliteal artery ligation. DISCUSSION: Positioning of the patient for ACL reconstruction The patient supine on an operating table. The leg to undergo surgery has no tourniquet placed because the patient had no popliteal artery and this operation needs to preserve and prevent the vascular ischemia of the collateral artery. Operating room set up with the patient prepped and draped for the diagnostic arthroscopy. It shows a normal cartilage, rupture of the ACL and PCL, rupture of body of the lateral meniscus in the white zone and rupture of body of the medial meniscus in the white zone. To make the bloodless arthroscopic field, cold saline and epinephrine pumped into the knee. Partial meniscectomy of the lateral and medial meniscus was performed. Single bundled ACL reconstruction was performed using hamstring autograft of the contralatelal site with the diameter was 8 mm and fixated by XO button and bioscrew (ConMed). After six months follow up, the patient did not feel giving way, catched, or locking. The patient had a good vascularity of the right lower extremity. There is improvement in Modified Cincinnati Rating System. The pre operative score was 49. The post operative score was 90. Tegner Lysholm Knee Scoring system before surgery was 35 and post operative score was 91. IKDC Scoring before surgery was 21,8 and the score had a good improvement. The IKDC Scoring after surgery was 73,6. CONCLUSION: ACL reconstruction in patient with popliteal artery ligation is challenging. A tourniquet-less technique using a cold saline and epinephrine solution can be successfully done for pressure controlled into the knee to preserve the collateral arteries flow to the distal limb while still permitting acceptable visual in operative field with good outcome after the surgery. PMID- 30396129 TI - Hearing me hearing you: Reciprocal effects between child and parent language in autism and typical development. AB - Language development in typically developing children (TD) has traditionally been investigated in relation to environmental factors, while language in children with autism spectrum disorder (ASD) has primarily been related to child-based factors. We employ a longitudinal corpus of 32 preschoolers with ASD and 35 linguistically matched TD peers recorded over 6 visits (ranging between 2 and 5 years of age) to investigate the relative importance of child-based and environmental factors in language development for both populations. We also investigate the reciprocal interaction between children's response to parents' input, and parents' response to children's production. We report six major findings. (1) Children's production of word types, tokens, and MLU increased across visits, and were predicted by their Expressive Language (EL) (positively) and diagnosis (negatively) from Visit 1. (2) Parents' production also increased across visits, and was predicted by their child's nonverbal cognition (positively) and diagnosis (negatively) from Visit 1. (3) At all visits and across groups, children and parents matched each other in lexical and syntactic production; (4) Parents who produced longer MLUs during a given visit had children who produced more word types and tokens, and had longer MLUs, at the subsequent visit. (5) When both child EL at Visit 1 and parent MLU were included in the model, both contributed significantly to future child language; however, EL accounted for a greater proportion of the variance. (6) Finally, children's speech significantly predicted parent speech at the next visit. Taken together, these results draw more attention to the importance of child-based factors in the early language development of TD children, and to the importance of parental language factors in the early language development of children with ASD. PMID- 30396131 TI - Photodynamic therapy: Toward a systemic computational model. AB - We have designed a systemic model to understand the effect of Photodynamic Therapy (PDT) on long time scales. The model takes into account cell necrosis due to oxygen reactive species, cell apoptosis through the caspase pathway and the competition between healthy and tumor cells. We attempted to describe the system using state of the art computational techniques (necrosis and apoptosis) and simple models that allow a deeper understanding of the long time scale processes involved (healing and tumor growth). We analyzed the influence of the surface and tumor depth on the effectiveness of different treatment plans and we proposed, for the set of parameters used in this work, an optimum timing between sessions of PDT. PMID- 30396130 TI - Impacts of high temperature on adverse birth outcomes in Seoul, Korea: Disparities by individual- and community-level characteristics. AB - BACKGROUND: Few studies have examined temperature's effect on adverse birth outcomes and relevant effect modifiers. OBJECTIVES: We investigated associations between heat and adverse birth outcomes and how individual and community characteristics affect these associations for Seoul, Korea, 2004-2012. METHODS: We applied logistic regression to estimate associations between heat index during pregnancy, 4 weeks before delivery, and 1 week before delivery and risk of preterm birth and term low birth weight. We investigated effect modification by individual (infant's sex, mother's age, and mother's educational level) and community characteristics (socioeconomic status (SES) and percentage of green areas near residence at the gu level, which is similar to borough in Western countries). We also evaluated associations by combinations of individual- and community-level SES. RESULTS: Heat exposure during whole pregnancy was significantly associated with risk of preterm birth. An interquartile (IQR) increase (5.5 degrees C) in heat index during whole pregnancy was associated with an odds ratio (OR) of 1.033 (95% CI 1.005, 1.061) with NO2 adjustment, and 1.028 (95% CI 0.998, 1.059) with PM10 adjustment, for preterm birth. We also found significant associations with heat exposure during 4 weeks before delivery and 1 week before delivery on preterm birth. We did not observe significant associations with term low birth weight. Higher risk of heat on preterm birth was associated with some individual characteristics such as infants with younger or older mothers and lower community-level SES. For combinations of individual- and community-level SES, the highest and most significant estimated effect was found for infants with low educated mothers living in low SES communities, with suggestions of effects of both individual-and community-level SES. CONCLUSIONS: Our findings have implications for evaluating impacts of high temperatures on birth outcomes, estimating health impacts of climate change, and identifying which subpopulations and factors are most relevant for disparities in this association. PMID- 30396132 TI - Regulation of ROS through proficient modulations of antioxidative defense system maintains the structural and functional integrity of photosynthetic apparatus and confers drought tolerance in the facultative halophyte Salvadora persica L. AB - The facultative halophyte Salvadora persica L. grow in arid, semiarid and saline areas. In present study, drought induced alterations in growth, ion homeostasis, photosynthesis, chlorophyll fluorescence, ROS regulation and antioxidative defense components were analyzed in S. persica with an aim to elucidate the drought tolerance mechanisms. In response to drought, significant reductions in growth, photosynthesis, and photosynthetic pigments were observed in S. persica. However, leaf relative water content (RWC %) did not change significantly. In S. persica seedlings, the growth, photosynthetic pigment contents and photosynthesis were resumed to control level within 7 d, when the drought treated plants were re irrigated. However, quantum yield of PSII (PhiPSII), rate of electron transport (ETR), maximum efficiency of PSII (Fv/Fm), and photochemical quenching (qP) remained unaffected under water deficit stress. The results suggest that both non stomatal as well as stomatal limitations can account for photosynthetic reduction. The ionomics studies revealed no significant alterations in levels of Na+, K+, Ca2+, B, Cu2+, Fe2+, Mo, and Zn2+ in leaf tissue during drought. However, there was increase in levels of Na+, K+, Ca2+ and Mg2+ in root tissue in response to drought. The activity of different enzymatic antioxidants like SOD, APX, and GR remained unaffected during drought, whereas POX activity increased and CAT activity declined under drought stress in comparison to control. This result proposes that vital ROS scavenging enzymes like SOD, APX and GR are at threshold levels to maintain the appropriate concentration of ROS. In S. persica, the ratio of AsA/DHA and GSH/GSSG (which are the indicators of redox potential of cell) remained steady or increased under drought which indicates that cellular redox level is maintained in this halophyte. Although ROS levels (H2O2 and O2*-) increased significantly under drought stress, electrolyte leakage and lipid peroxidation level remained unchanged in response to water deficit condition which indicates that minimal increase in ROS level under drought stress act in signaling for activation of ROS scavenging enzymes. Our results propose that decline in growth and photosynthesis is a vital energy conservation strategy of S. persica under drought condition. The rapid recovery of growth, photosynthesis and water relations in S. persica following drought seems to be a critical mechanism permitting this plant to withstand and survive under drought environment. In addition, our results implicate that efficient regulations of antioxidative enzymes in leaf tissue contribute in regulating the ROS level and cellular redox status, thereby protecting the plant from drought induced oxidative damage in S. persica. Consequently ion homeostasis, plant water status, and integrity of photosynthetic apparatus is maintained in S. persica subjected to drought. The results of present study propose that S. persica is a drought tolerant halophyte and it can be a potential candidate for restoration of degraded saline lands of coastal ecosystem. PMID- 30396133 TI - Manganese enhances the immobilization of trace cadmium from irrigation water in biological soil crust. AB - The effect of biological soil crust (BSC) in paddy field on the immobilization and removal of heavy metal from irrigation water is an important issue. BSC was cultured in solutions with different concentrations of manganese (Mn) salt and cadmium (Cd) sulfate for 15 days. We analyzed the Mn, Cd and Fe contents in the BSC and investigated the effects of Mn salt on the Cd distribution in different binding-forms in BSC as well. The results show that Mn salt was effective at enabling BSC to immobilize the Cd, and its removal efficiency from irrigation water improved with an increase in the Mn concentration used. The removal of 50.00 MUg/L of Cd from irrigation water by BSC reached as high as 95.70% in present of 20.00 mg/L Mn. The highest obtained biological concentrated factor of BSC for Cd is ~2.7 * 104. The mainly Cd species (75%) in BSC is the non-EDTA extracted minerals. Based on the SEM-EDS and XPS analyses, it was reasonably inferred that the Mn ion was oxidized by Mn oxidizing bacteria (MOB), to yield the porous spongy-like birnessite with d-spacing of 2.31 A, while Cd was scavenged and immobilized in the crystal lattice. The MOB was identified as Bacillus. This study provides a potentially novel method to decontaminate irrigation water polluted with Cd by using BSC in presence of Mn. PMID- 30396134 TI - Water soluble and insoluble components of PM2.5 and their functional cardiotoxicities on neonatal rat cardiomyocytes in vitro. AB - A growing number of epidemiological surveys show that PM2.5 is an important promoter for the cardiovascular dysfunction induced by atmospheric pollution. PM2.5 is a complex mixture of solid and liquid airborne particles and its components determine the health risk of PM2.5to a great extent. However, the individual cardiotoxicities of different PM2.5 fractions are still unclear, especially in the cellular level. Here we used the neonatal rat cardiomyocytes (NRCMs) to evaluate the cardiac toxicity of PM2.5 exposure. The cytotoxicities of Total-PM2.5, water soluble components of PM2.5 (WS-PM2.5) and water insoluble components of PM2.5 (WIS-PM2.5), which include the cell viability, cell membrane damage, reactive oxygen species (ROS) generation, were examined with NRCMs in vitro. The results indicated that Total-PM2.5 or WIS-PM2.5 exposure significantly decreased the cell viability, induced the cell membrane damage and increased the ROS level in NRCMs at concentrations above 50 ug/mL. However, WS-PM2.5 exposure could induce the cytotoxicity on NRCMs until the concentration of WS-PM2.5 was raised to a higher concentration (75 ug/mL). Furthermore, the DNA damage was detected in NRCMs after 48 h of exposure with Total-PM2.5, WS-PM2.5 or WIS-PM2.5 (75 ug/mL) and the adverse effects on mitochondrial function and action potentials of NRCMs were detected only both in the Total-PM2.5 and WIS-PM2.5 treatment group. In summary, our project not only estimates the risk of PM2.5 on cardiac cells but also reveal that Total-PM2.5 and WIS-PM2.5 exposure were predominantly associated with the functional cardiotoxicities in NRCMs. PMID- 30396135 TI - Size- and shape-dependent toxicity of silver nanomaterials in green alga Chlorococcum infusionum. AB - Silver nanomaterials (AgNMs) of different shapes and sizes are potentially toxic to aquatic organisms. However, studies on the toxicity of AgNMs and on their shape-dependent effects on algae are scarce. The present study evaluated the effects of three AgNMs (silver nanospheres, AgNPs; silver nanowires, AgNWs; silver nanoplates, AgPLs) with different shapes coated with polyvinylpyrrolidone on the growth and photosynthetic performance of an alga, Chlorococcum infusionum. We used growth measurements and determined the photosynthetic parameters based on chlorophyll fluorescence transients in the algal cells exposed to different concentrations of the three AgNMs. The effective concentrations at 50% (EC50) of AgNPs, AgNWs, and AgPLs were calculated to be 0.1, 0.045, and 0.021 mg/L, respectively. The results showed that the toxicity of AgNMs in C. infusionum was in the order, AgPLs (40 nm diameter) > AgNWs (21,000 nm length * 42 nm diameter) > AgNPs (57 nm diameter), based on the decrease in growth and three photosynthetic activities. We propose that the toxic potential of AgNMs is primarily dependent on their diameter and secondarily on their shape. Overall, this study provides, for the first time, a comparison of the growth and photosynthetic activities of C. infusionum exposed to AgNMs of three different shapes. PMID- 30396136 TI - Association of short-term exposure to ambient air pollutants with exhaled nitric oxide in hospitalized patients with respiratory-system diseases. AB - BACKGROUND: Previous studies have suggested that exposure to ambient air pollutants may adversely affect human health. However, few studies have examined the health effects of exposure to ambient air pollutants in hospitalized patients. OBJECTIVES: To evaluate the association between short-term exposure to ambient air pollutants and exhaled nitric oxide fraction (FeNO) in a large cohort of hospitalized patients. METHODS: FeNO was detected for 2986 hospitalized patients (ages 18-88 years). Daily average concentrations of SO2, NO2, O3, CO, PM2.5 and PM10 in 2014 and 2015 were obtained from nine fixed-site monitoring stations. Multiple linear regression models were chosen to assess the associations of exposure to ambient air pollutants with FeNO while adjusting for confounding variables. Lagged variable models were selected to determine the association between FeNO and ambient air pollutants concentrations with lags of up to 7 days prior to FeNO testing. RESULTS: Interquartile-range (IQR) increases in the daily average SO2 (8.00 MUg/m3) and PM2.5 (37.0 MUg/m3) were strongly associated with increases in FeNO, with increases of 3.41% [95% confidence interval (CI), 0.94-5.93%] and 2.72% (95%CI, -0.09% to 5.61%), respectively. However, FeNO levels were not statistically associated with PM10, NO2, O3 or CO. In the two-pollutant models, the maximum correlation was for ambient SO2. We also found that FeNO was associated with IQR increases in daily average ambient concentrations of SO2 up to 3 and 4 days after the exposure events. CONCLUSIONS: Short-term exposure to SO2 and PM2.5 were positively correlated with FeNO levels in hospitalized patients in Shanghai. PMID- 30396137 TI - Highly efficient degradation of 2,4-dichlorophenol over CeO2/g-C3N4 composites under visible-light irradiation: Detailed reaction pathway and mechanism. AB - Herein, we report for the first time the highly efficient degradation of 2,4 dichlorophenol (2,4-DCP) over CeO2/g-C3N4 composites (xCeO/CN) prepared via wet chemical solution method. It is shown that the resultant nanocomposites with a proper mass ratio percentage (15%) of CeO coupled exhibit greatly enhanced visible-light activity for 2,4-dichlorophenol (2,4-DCP) degradation compared to the bare g-C3N4. From photoluminescence (PL) and Fluorescence (FL) results, it is suggested that enhanced photo-degradation is attributed to the significantly improved charge separation and transfer as a result of the proper band alignments between g-C3N4 and CeO components. Further, from radical trapping experiments, it is confirmed that hydroxyl radicals (OH) are the predominant oxidants involved in the degradation of 2,4-DCP over CeO/CN composites. Furthermore, a possible reaction pathway and detailed photocatalytic mechanism for 2,4-DCP degradation is proposed mainly based on the detected liquid chromatography tandem mass spectrometry (LC-MS) intermediate products, that readily transform into CO2 and H2O. This work would help researchers to deeply understand the reaction mechanism of 2,4-DCP and would provide feasible routes to fabricate g-C3N4-based highly efficient photocatalysts for environmental remediation. PMID- 30396138 TI - Selective adsorption behavior/mechanism of antibiotic contaminants on novel boron nitride bundles. AB - The novel hexagonal boron nitride (BN) bundles, assembled by a plenty of BN fibers with high adsorption capacity and outstanding recyclability, were prepared easily as an efficient adsorbent for antibiotics. It is an excellent substitute for carbonaceous adsorbent to overcome the shortcoming in low adsorption capacity and poor recyclability. Its high surface area can reach up to 871.456 m2 g-1. The adsorption capacity and removal percentage to sulfadiazine (SDZ, 0.328 mmol g-1, 82.192%), oxytetracycline (OTC, 0.202 mmol g-1, 92.890%) and erythromycin (EM, 0.126 mmol g-1, 90.140%) are superior compared with activated carbon and graphene nanoplatelets. It is interesting that BN bundles have a better adsorption to small molecules since huge molecules are easily restricted to enter the micropores, which was defined as micropore-filling effect. Moreover, the adsorption isotherms are well fitted by the Langmuir and Tempkin model, while pseudo-second-order model can better describe the adsorption kinetics. The adsorption mechanisms were deduced to be mainly pi-pi electron-donor-accepter interaction while electrostatic force and hydrophobic interaction played a significant role. The excellent reusability can be seen from the high removal efficiency after five recycles suggesting the BN bundles was a promising adsorbent for the efficient removal of antibiotics pollutants. PMID- 30396139 TI - Biochar-mediated sorption of antibiotics in pig manure. AB - Using manure contaminated with antibiotics as fertilizer is a primary source of soil pollution with antibiotics and concomitantly with antibiotic resistance genes (ARG). Bioavailable antibiotics trigger further ARG amplification during manure storage. Consequently it is aimed to facilitate the immobilization of antibiotics in manure. To this end, five biochars derived from pine cone (BCP), rice husk, sewage sludge, digestate and Miscanthus were tested as additional sorbents in liquid pig manure for sulfamethazine, ciprofloxacin, oxytetracycline and florfenicol. Non-linear sorption was best-fit using the Freundlich isotherm (R2 > 0.82) and the pseudo-second-order model best described sorption kinetics (R2 > 0.94). Antibiotics' sorption onto manure increased in the order sulfamethazine < florfenicol < ciprofloxacin < oxytetracycline. Admixtures of BCP to manure changed the order to sulfamethazine < oxytetracycline < florfenicol = ciprofloxacin. Generally, with the addition of biochar, sorption coefficients of florfenicol increased most (by factors>2.7) followed by sulfamethazine and ciprofloxacin. Yet, oxytetracycline was mostly mobilized probably due to competitive adsorption. Effects depended on the proportion of biochar added and the type of biochar, whereby plant-derived biochar exhibited better immobilization of antibiotics. Depending on the type and portion of biochar, admixtures to manure can be used to lower the mobility and hence bioavailability of fenicols, fluoroquinolones and sulfonamides. PMID- 30396140 TI - Effects of NOx, SO2 and RH on the SOA formation from cyclohexene photooxidation. AB - We performed a laboratory investigation of the secondary organic aerosol (SOA) formation from cyclohexene photooxidation with different initial NOx and SO2 concentrations at low and high relative humidity (RH). Both SOA yield and number concentration first increase drastically and then, decreased when the [VOC]0/[NOx]0 ratio changed from 30 to 10 and from 10 to 3. Though the presence of SO2 could increase the SOA number concentration, the SOA yield could only increase under [VOC]0/[NOx]0 = 10 and high RH, and [VOC]0/[NOx]0 = 3 and low RH experimental conditions, while decreasing under [VOC]0/[NOx]0 = 10 and low RH conditions. In the presence of SO2, the high RH and high NOx conditions were keys to efficient sulfate formation and could promote the SOA formation. The chemical composition of SOA was characterized using hybrid quadrupole-orbitrap mass spectrometer equipped with electrospray ionization (ESI-Q-Orbitrap-HRMS), and few organosulfates were identified. A visible enhancement of organosulfates and the formation of high molecular weight organic compounds were observed at high RH conditions, and this seemed to be the reason for the SOA yield increase at high RH. PMID- 30396141 TI - Lambda-cyhalothrin affects swimming activity and physiological responses of Daphnia magna. AB - lambda-cyhalotrin is a pyrethroid pesticide used for protection of crops against various insect pests. Knowledge on behavioural and physiological responses of non target organisms such as cladocerans is very limited. Daphnia is a sensitive organism commonly used in determination of ecotoxicological risk for various substances introduced to aquatic environment, however the main experimental endpoints used such as mortality or immobilisation may not be sufficient to evaluate subtle alterations in zooplankton. The aim of the present study was to evaluate swimming behaviour and physiological parameters of Daphnia magna exposed to lambda-cyhalothrin (Karate Zeon 050 CS) at concentrations of 0.05, 0.5, 5 and 50 MUg L-1 for 2, 24 and 48 h. The results showed that lambda-cyhalothrin affected D. magna swimming behaviour inducing a concentration-dependent inhibition of swimming track density, speed and turning ability. Depression of physiological parameters such as heart rate and thoracic limb activity was also noted. The results suggest that in natural conditions swimming behaviour and physiological endpoints of D. magna may be disturbed by environmental concentrations of lambda-cyhalothrin leading to ecological consequences. PMID- 30396142 TI - Enhanced stability of bio-oil and diesel fuel emulsion using Span 80 and Tween 60 emulsifiers. AB - Bio-oil (biomass pyrolysis oil) has some undesirable properties (e.g., low heating value, high corrosiveness, and high viscosity) that restrain its direct use as a transportation fuel. The emulsification of bio-oil and diesel is an effective and convenient method to use bio-oil in the present transportation fuel infrastructure. The addition of an emulsifying agent (emulsifier or surfactant) to two immiscible liquids of diesel and bio-oil is an important step in emulsification. The hydrophilic-lipophilic balance (HLB) value, according to the chemical structure and characteristics of the emulsifier, is a key parameter for selecting a surfactant. In this study, an ether treatment of raw bio-oil was carried out to separate the ether-soluble fraction of bio-oil from its heavy (dark brown and highly viscous) fraction, and the ether-extracted bio-oil (EEO) was processed further for emulsification into diesel fuel. The effects of the HLB value of the emulsifier and the contents of EEO, diesel, and emulsifier on the stability of the EEO/diesel emulsion were investigated. To optimize the HLB value of the emulsifier, different HLB values (4.3-8.8), which were prepared by mixing different amounts of Span 80 and Tween 60 as surfactants, were used for the EEO and diesel emulsification. A HLB value of 7.3 with diesel, EEO, and emulsifier contents of 90, 5, 5 wt%, and 86, 7.4, 6.6 wt% resulted in EEO/diesel emulsions (without phase separation) stable for 40 and 35 days, respectively. Measurement of the high heating value (HHV) of the emulsified fuels gave a 44.32 and 43.68 MJ/kg values for the EEO to emulsifier mass ratios of 5:5 and 7.4:6.6, respectively. The stability of emulsified EEO and diesel was verified by TGA and FT-IR methods. PMID- 30396143 TI - Co-evolutionary simulation study of multiple stakeholders in the take-out waste recycling industry chain. AB - Take-out waste causes severe environmental pollution and wastes resources; thus, recycling of take-out waste is an urgent problem that must be addressed. From the co-evolutionary viewpoint, we used evolutionary game theory to build a tripartite game model involving government, consumers and enterprises, and then made simulation analysis using Vensim(r) software, exploring the evolutionary equilibrium and the main driving factors. The simulation results showed that (1) no matter what government's, consumers' or enterprises' initial strategy is, through imitation and evolution, the three will eventually arrive at the state in which government chooses regulation, the consumer chooses a green approach, and an enterprise chooses to participate in the recycling industry chain. (2) The consumer (government) plays a role of promoter (guide) in the evolutionary process in the take-out waste recycling industry chain. (3) The higher the regulatory costs or penalties for enterprises not participating in the recycling industry chain, and the larger the subsidy to consumers for choosing a green approach and to enterprises for participating in the recycling chain, the sooner the government will stabilize a no-regulation strategy. (4) The higher the cost of enterprise participation in the recycling chain, the later the government will arrive at the stabilization strategy. (5) The higher the penalty to an enterprise, the earlier the enterprise will evolve to the stabilization strategy; the higher the subsidy to consumers (enterprises), the earlier consumers (enterprises) will evolve into the stabilization strategy, and the higher the cost of enterprise participation, the later the enterprise will evolve into a stable strategy. This study is expected to provide a reference for governments to formulate effective waste management policies. PMID- 30396144 TI - Incidence and mortality trends in oral and oropharyngeal cancers in China, 2005 2013. AB - BACKGROUND: Oral and oropharyngeal cancers are among the most common cancers globally. This study aimed to assess the incidence and mortality trends of oral and oropharyngeal cancers in China between 2005 and 2013. METHODS: Estimates of national trends of oral and oropharyngeal cancers were based on the data from Chinese Cancer Registry Annual Reports. The crude incidence rates of oral and oropharyngeal cancers between 2015 and 2035 were evaluated. The age-standardized rate was based on the world standard population. RESULTS: It was estimated that 285,857 new cases and 132,698 deaths were related to oral and oropharyngeal cancers in China between 2005 and 2013, with mouth and tongue cancers being the most frequently diagnosed and the leading causes of death among all oral and oropharyngeal cancers. The incidence rates of oral and oropharyngeal cancer fluctuated from 1.69 to 1.89 per 100,000 person-years, and the mortality rate showed an increasing trend, ranging from 0.77 and 0.84 per 100,000 person-years. Males were more susceptible than females to oral and oropharyngeal cancers. The incidence and mortality rates of oral and oropharyngeal cancers were significantly higher in urban regions. The crude incidence rates of oral cancers are projected to increase from 2.26 to 3.21 per 100,000 person-years over the next 20 years in China. CONCLUSION: The incidence of oral and oropharyngeal cancers fluctuated, whereas the mortality rate showed an upward trend from 2005 to 2013. A heavier burden from oral and oropharyngeal cancers is predicted in the next two decades in China. PMID- 30396146 TI - Sex differences in physical activity engagement after ACL reconstruction. AB - OBJECTIVES: To investigate the effects of sex as an effect modifier of objectively measured moderate-to-vigorous physical activity (MVPA) in individuals following ACLR and healthy controls. DESIGN: Cross-sectional research study. SETTING: University community. PARTICIPANTS: 59 participants (42.4% male) with a history of ACLR and 55 healthy control participants (40.0% male). MAIN OUTCOME MEASURES: Participants were outfitted with an ActiGraph wGT3X-BT accelerometer for a period of 7 days to assess MVPA. Weekly time engaged in MVPA (in bouts>= 10 min), % of total time engaged in MVPA, and odds of meeting national physical activity guidelines (MVPA>= 150 min/wk) were compared between males and females with a history of ACLR and healthy controls. RESULTS: There were significant sex X group interactions for weekly MVPA (p = 0.02) and % total time in MVPA (p = 0.01). The odds of a female ACLR participant meeting national physical activity guidelines were significantly worse (X2 = 4.18, OR = 2.54, CI95 = 1.03-6.27) when compared to participants without ACLR. CONCLUSIONS: Female participants with ACLR were found to be less active than healthy control participants and their odds of meeting national MVPA guidelines were also 2.54 times worse than healthy participants. PMID- 30396145 TI - Shorter Phosphorodiamidate Morpholino Splice-Switching Oligonucleotides May Increase Exon-Skipping Efficacy in DMD. AB - Duchenne muscular dystrophy is a fatal muscle disease, caused by mutations in DMD, leading to loss of dystrophin expression. Phosphorodiamidate morpholino splice-switching oligonucleotides (PMO-SSOs) have been used to elicit the restoration of a partially functional truncated dystrophin by excluding disruptive exons from the DMD messenger. The 30-mer PMO eteplirsen (EXONDYS51) developed for exon 51 skipping is the first dystrophin-restoring, conditionally FDA-approved drug in history. Clinical trials had shown a dose-dependent variable and patchy dystrophin restoration. The main obstacle for efficient dystrophin restoration is the inadequate uptake of PMOs into skeletal muscle fibers at low doses. The excessive cost of longer PMOs has limited the utilization of higher dosing. We designed shorter 25-mer PMOs directed to the same eteplirsen-targeted region of exon 51 and compared their efficacies in vitro and in vivo in the mdx52 murine model. Our results showed that skipped-dystrophin induction was comparable between the 30-mer PMO sequence of eteplirsen and one of the shorter PMOs, while the other 25-mer PMOs showed lower exon-skipping efficacies. Shorter PMOs would make higher doses economically feasible, and high dosing would result in better drug uptake into muscle, induce higher levels of dystrophin restoration in DMD muscle, and, ultimately, increase the clinical efficacy. PMID- 30396147 TI - Minimally invasive versus open calcaneal osteotomies - Comparing the intraoperative parameters. PMID- 30396148 TI - DNA on feminine sanitary products. AB - The use of feminine hygiene products is commonplace and chaperones many women for most of their reproductive years. Unless specifically labelled, products are usually not sterile. Any DNA present on their surface could potentially be transferred onto the wearer and subsequently be detected in samples taken from intimate areas during a medical examination. This study investigated whether unused feminine sanitary products normally carry detectable amounts of DNA. Altogether, 52 items of tampons, pads, liners, and wipes were tape lifted and subjected to total and male-specific DNA quantification and STR amplification. Nineteen of these returned quantification values greater than zero. However, only four (one tampon and three liners) displayed one or two Y-STRs, whereas one pad exhibited one autosomal allele and an amelogenin X allele. All peak heights were below 515 RFU. Two liners may have collected partner DNA post purchase since they were not individually wrapped. Thus, feminine sanitary products are normally not a source of DNA. PMID- 30396149 TI - Analysis of elemental and isotopic variation in glass frictionators from 0.22 rimfire primers. AB - The majority of 0.22 calibre rimfire ammunition available in Australia, and overseas, tends to use glass powder rather than antimony sulfide frictionator in the primer. This glass can be the nucleus of a GSR particle, with other primer components condensing around and onto the glass structure. As the composition of glass frictionator remains largely unaltered during ammunition discharge [1] there is the possibility that frictionator composition could be used in GSR examinations to either correlate or discriminate between samples, thereby providing valuable information to an investigation. In this study, the composition of glass frictionator from a wide variety of ammunition was analysed by time-of-flight - secondary ion mass spectrometry (ToF-SIMS), sensitive high resolution ion microprobe (SHRIMP) and scanning electron microscopy - energy dispersive X-ray spectrometry (SEM-EDS). Refractive index (RI) was measured using glass refractive index measurement (GRIM). Across the population of ammunition studied, it was found that the elemental and isotopic composition of frictionator varied. ToF-SIMS was able to discriminate 94.1% of brands in a pairwise comparison and SEM-EDS achieved a pairwise discrimination power of 79.4%. If SHRIMP was combined with the other two techniques, 95.6% of brands could be discriminated. Refractive index measurements supported the elemental data showing that there appeared, in most cases, to be only one population of glass within a cartridge. The results suggest that there is scope for frictionator analysis to contribute valuable, new capability to forensic GSR examinations. PMID- 30396150 TI - Ezh1 Targets Bivalent Genes to Maintain Self-Renewing Stem Cells in Ezh2 Insufficient Myelodysplastic Syndrome. AB - Polycomb repressive complex (PRC) 2 represses transcription through histone H3K27 trimethylation (H3K27me3). We previously reported that the hematopoietic-cell specific deletion of Ezh2, encoding a PRC2 enzyme, induced myelodysplastic syndrome (MDS) in mice, whereas the concurrent Ezh1 deletion depleted hematopoietic stem and progenitor cells (HSPCs). We herein demonstrated that mice with only one Ezh1 allele (Ezh1+/-Ezh2Delta/Delta) maintained HSPCs. A chromatin immunopreciptation sequence analysis revealed that residual PRC2 preferentially targeted genes with high levels of H3K27me3 and H2AK119 monoubiquitination (H2AK119ub1) in HSPCs (designated as Ezh1 core target genes), which were mostly developmental regulators, and maintained H3K27me3 levels in Ezh1+/ Ezh2Delta/Delta HSPCs. Even upon the complete depletion of Ezh1 and Ezh2, H2AK119ub1 levels were largely retained, and only a minimal number of Ezh1 core targets were de-repressed. These results indicate that genes marked with high levels of H3K27me3 and H2AK119ub1 are the core targets of polycomb complexes in HSPCs as well as MDS stem cells. PMID- 30396151 TI - The Mevalonate Pathway Is Indispensable for Adipocyte Survival. AB - The mevalonate pathway is essential for the synthesis of isoprenoids and cholesterol. Adipose tissue is known as a major site for cholesterol storage; however, the role of the local mevalonate pathway and its synthesized isoprenoids remains unclear. In this study, adipose-specific mevalonate pathway-disrupted (aKO) mice were generated through knockout of 3-hydroxy-3-methylglutaryl-CoA (HMG CoA) reductase (HMGCR). aKO mice showed serious lipodystrophy accompanied with glucose and lipid metabolic disorders and hepatomegaly. These metabolic variations in aKO mice were dramatically reversed after fat transplantation. In addition, HMGCR-disrupted adipocytes exhibited loss of lipid accumulation and an increase of cell death, which were ameliorated by the supplementation of mevalonate and geranylgeranyl pyrophosphate but not farnesyl pyrophosphate and squalene. Finally, we found that apoptosis may be involved in adipocyte death induced by HMGCR down-regulation. Our findings indicate that the mevalonate pathway is essential for adipocytes and further suggest that this pathway is an important regulator of adipocyte turnover. PMID- 30396154 TI - Disulfide bridge formation to increase thermostability of DFPase enzyme: A computational study. AB - Organophosphate compounds bioremediation by use of organophosphorus degradation enzymes such as DFPase is a developing interest in industry and medicine. The most important problem with the bio-catalytic enzymes is their instability on high temperatures. This work carried out to find suitable locations for introducing disulfide bridges in DFPase enzyme. We employed some computational approaches to design the disulfide bridges and evaluate their roles in the enzyme structural thermostability. According to the in silico results, mutant 6 (V24C, C76) increased the enzyme thermostability relative to wild-type. PMID- 30396153 TI - Binding of Drug-Activated CAR/Nr1i3 Alters Metabolic Regulation in the Liver. AB - The constitutive androstane receptor (CAR/Nr1i3) regulates detoxification of drugs and other xenobiotics by the liver. Binding of these compounds, activating ligands, causes CAR to translocate to the nucleus and stimulate genes of detoxification. However, CAR activation also changes metabolism and induces rapid liver growth. To explain this gene regulation, we characterized the genome-wide early binding of CAR; its binding partner, RXRalpha; and the acetylation that they induced on H4K5. CAR-linked genes showed either stimulation or inhibition and regulated lipid, carbohydrate, and energy metabolism, as well as detoxification. Stimulation of expression increased, but inhibition did not decrease, H4K5Ac. Transcriptional inhibition occurred when CAR bound with HNF4alpha, PPARalpha, or FXR on the same enhancers. Functional competition among these bound nuclear receptors normally coordinates transcriptional resources as metabolism shifts. However, binding of drug-activated CAR to the same enhancers adds a new competitor that constitutively alters the normal balance of metabolic gene regulation. PMID- 30396152 TI - Unexpected Evolution of Lesion-Recognition Modules in Eukaryotic NER and Kinetoplast DNA Dynamics Proteins from Bacterial Mobile Elements. AB - The provenance of several components of major uniquely eukaryotic molecular machines are increasingly being traced back to prokaryotic biological conflict systems. Here, we demonstrate that the N-terminal single-stranded DNA-binding domain from the anti-restriction protein ArdC, deployed by bacterial mobile elements against their host, was independently acquired twice by eukaryotes, giving rise to the DNA-binding domains of XPC/Rad4 and the Tc-38-like proteins in the stem kinetoplastid. In both instances, the ArdC-N domain tandemly duplicated forming an extensive DNA-binding interface. In XPC/Rad4, the ArdC-N domains (BHDs) also fused to the inactive transglutaminase domain of a peptide-N glycanase ultimately derived from an archaeal conflict system. Alongside, we delineate several parallel acquisitions from conjugative elements/bacteriophages that gave rise to key components of the kinetoplast DNA (kDNA) replication apparatus. These findings resolve two outstanding questions in eukaryote biology: (1) the origin of the unique DNA lesion-recognition component of NER and (2) origin of the unusual, plasmid-like features of kDNA. PMID- 30396155 TI - Identification of novel inhibitor against endonuclease subunit of Influenza pH1N1 polymerase: A combined molecular docking, molecular dynamics, MMPBSA, QMMM and ADME studies to combat influenza A viruses. AB - The influenza H1N1 virus is the causative agent of the flu pandemic in the world. Due to the shortage of effective means of control, it is remained the serious threats to public and avian health. To battle the surge of viral outbreaks, new treatments are crucially needed. The viral RNA polymerase, which is responsible for transcription and replication of the RNA genome, is comprised of subunits PA, PB1 and PB2. PA has endonuclease activity and is a well known target for inhibitor and drug design. In the current study, we employed molecular docking, molecular dynamics (MD), MMPBSA, QMMM and ADME studies to find and propose an inhibitor among 11,873 structures against PA. Our molecular docking, MD, MMPBSA and QMMM studies showed that ZINC15340668 has ideal characteristics as a potent PA inhibitor, and can be used in experimental phase and further development. Also, ADME prediction demonstrated that all physico-chemical parameters are within the acceptable range defined for human use. Molecular mechanism based study revealed that upon inhibitor binding; the flexibility of PA backbone is increased. This observation demonstrates the plasticity of PA active site, and it should be noticed in drug design against PA Influenza A viruses. In the final phase of the study, the efficiency of our proposed hit was tested computationally against mutant drug resistant I38T_PA. Our results exhibited that the hit inhibits the I38T_PA in different manner with high potency. PMID- 30396156 TI - Inner-product NMR spectroscopy: A variant of covariance NMR spectroscopy. AB - We propose a variant of covariance NMR spectroscopy, namely, inner-product NMR spectroscopy, originally suggested in Takeda (2015). The mathematical operation of inner-product NMR is the same as that of covariance NMR, except that subtraction of the average value of the variable is intentionally omitted, so that the correspondence of the spectrum with that of conventional two-dimensional Fourier-transformation is established without having to request the average to become vanishingly small. We demonstrate inner-product NMR for 13C DARR correlation experiments in a polycrystalline sample of 13C-labeled l-alanine. In covariance, we show that the mixing-time dependence of the peaks is influenced considerably by the choice of the carrier frequency and thereby the center of the spectrum, whereas the inner-product approach is free from such an undesirable effect, while keeping the merit of the covariance NMR. PMID- 30396157 TI - Peptide bond conformation in peptides and proteins probed by dipolar coupling chemical shift tensor correlation solid-state NMR. AB - Multidimensional magic-angle spinning solid-state NMR experiments are described that permit cis and trans peptide bonds in uniformly 13C,15N-labeled peptides and proteins to be unambiguously distinguished in residue-specific manner by determining the relative orientations of the amide 13C' CSA and 1H-15N dipolar coupling tensors. The experiments are demonstrated for model peptides glycylglycine and 2,5-diketopiperazine containing trans and cis peptide bonds, respectively. Subsequently, the measurements are extended to two representative proteins that contain exclusively trans peptide bonds, microcrystalline B3 immunoglobulin domain of protein G and Y145Stop human prion protein amyloid fibrils, to illustrate their applicability to a wide range of protein systems. PMID- 30396158 TI - Processing birth experiences: A content analysis of women's preferences. AB - BACKGROUND: Negative birth experiences may have adverse effects on the wellbeing of women and babies. Knowledge about useful interventions to assist women in processing and resolving negative birth experiences is limited. OBJECTIVE: To explore women's experience and preferences of reviewing their birth experience at a special midwifery clinic. DESIGN: The study is a qualitative content analysis of women's written text responses to semi-structured questions, included in a retrospective study. SETTING: A special counselling clinic, 'Ljadu mer eyra', at Landspitali University Hospital in Reykjavik, provides women with an opportunity to review their birth experience and discuss their fears about an upcoming birth with a midwife. SAMPLE, RECRUITMENT AND DATA COLLECTION: A questionnaire was sent to all women attending the clinic from 2006-2011 (n = 301). Of the 131 women completing and returning the questionnaire, 125 provided written responses to the open-ended questions. The questionnaire consisted of demographic and reproductive characteristics of women, questions about why they attended the clinic, whether their expectations were fulfilled, helpful components of the interview and open ended questions about women's views of the process. DATA ANALYSIS: Data on participant characteristics, the reason for attending the clinic, whether the interview fulfilled their expectations and helpful components were analysed using quantitative descriptive data, while written responses to semi-structured questions were analysed using content analysis. FINDINGS: The main reasons for attending the clinic were a previous negative birth experience, anxiety about the upcoming birth, and/or loss of control during a prior birth. Two themes and three subthemes were identified. The overarching theme was 'on my terms' with the subthemes of 'being recognised', 'listening is paramount' and 'mapping the unknown'. The final theme was 'moving on'. KEY CONCLUSIONS: Women want to be recognised and invited to review their birth experience in a tailored conversation on their terms. By fulfilling their expectations of reviewing the birth experience, they regained control and strength to move on. IMPLICATIONS FOR PRACTICE: Findings support the importance of recognising women's need to review their birth experiences and offer an intervention to reflect on their perceptions. A discussion of the birth experience should be a routine part of maternity services. PMID- 30396159 TI - The psychometric properties of the Icelandic version of the Edinburgh Postnatal Depression Scale (EPDS) when used prenatal. AB - OBJECTIVE: To evaluate the psychometric properties of the Icelandic version of the Edinburgh Postnatal Depression Scale (EPDS) when used prenatal, explore the dimensionality of the scale and describe its effectiveness in identifying depression. DESIGN: A sample of Icelandic women filled in the EPDS at week 16 gestation, week 24 and week 36. If screened positive in week 16 they were asked to attend a psychiatric diagnostic interview 2-4 weeks later. Every 10th woman screened negative was also asked to attend an interview. SETTING: Antenatal clinics at primary health care centres in Iceland. PARTICIPANTS: In total, 2512 women receiving prenatal care participated in the study. At week 16 gestation, 2397 women filled in the Edinburgh Postnatal Depression Scale, 2025 at week 25, and 1756 at week 36. 474 women attended diagnostic interview two to four weeks after screening. MEASUREMENTS AND FINDINGS: Internal reliability, convergent validity and test-retest correlation of the Icelandic version of the Edinburgh Postnatal Depression Scale appeared acceptable. An exploratory factor analysis supported a one-factor structure of the Edinburgh Postnatal Depression Scale that was confirmed by confirmatory factor analysis showing best fit for one general factor with two group factors. A cut-off score of 11 or higher had specificity of 0.89, sensitivity of 0.80 and positive predictive value of 0.44. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The Icelandic version of the Edinburgh Postnatal Depression Scale is a valid and reliable one-dimensional instrument suitable to screen for depression prenatally. We recommend using score 11 or higher as a cut off. If women score 11, they should be re-assessed two weeks later, but if they score 12 or higher, they should be referred directly for a further assessment. A time gap of two to four weeks does weaken the scale's ability to discriminate between those suffering from Major Depression and those who screen negative. PMID- 30396160 TI - Perceived job demands and resources of newly qualified midwives working in primary care settings in The Netherlands. AB - OBJECTIVE: The objective of this study is to identify perceived job demands and job resources of newly qualified midwives (NQMs), working in primary midwifery care during their first years in practice. DESIGN/SETTING: A qualitative study, with semi-structured group interviews was conducted. Midwives working less than three years in primary midwifery care in the Netherlands were invited to join a focus group interview. MEASUREMENTS AND FINDINGS: Five focus group interviews were with 31 participants. Interviews were transcribed and analyzed. Data were analyzed thematically by using the different characteristics of the Job Demands Resources model. Working as a locum midwife is demanding for Dutch NQMs, due to a large number of working hours in different practices and a lack of job security. Decision-making and adapting to local guidelines and collaborations demand a high cognitive load. These aspects of the work context negatively impact NQMs' work and private life. Working with clients and working autonomously motivates the newly graduates. Support from colleagues and peers are important job resources, although colleagues are also experienced as a job demand, due to their role as employer. Strictness in boundaries, flexibility and sense of perspective are NQMs' personal resources. On the other hand, NQMs perceived perfectionism and the urge to prove oneself as personal demands. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Dutch NQMs' first years in primary midwifery care are perceived as highly demanding. In primary care, NQMs usually work as locum midwives, self employed and in different practices. Working in different practices requires not only working with different client populations and autonomous decision-making, but also requires adaptation to different local working arrangements. Building adequate support systems might help NQMs finding a balance between work and private life by having experienced midwives available as mentors. Furthermore, training and coaching of NQMs help them to become aware of their personal resources and demands and to help them strengthen their personal resources. Improving NQMs' working position through secure employments require changes in the organization of maternity care in the Netherlands. PMID- 30396161 TI - Urban Chinese midwives' knowledge, attitudes and practices toward umbilical cord blood donation. AB - OBJECTIVE: This study aimed to assess the knowledge, attitudes and factors associated with promotion of umbilical cord blood (CB) donation by Chinese midwives to expectant mothers. DESIGN: An anonymous cross-sectional survey using self-administered questionnaires. SETTING: Hong Kong, China. PARTICIPANTS: One hundred-and-forty-seven registered Chinese midwives were recruited by convenience sampling from government obstetric clinics and public and private hospitals. MEASUREMENTS AND FINDINGS: In addition to collecting demographic background information, the study examined the midwives' cord blood-related knowledge and perceptions as well as past-year practices and future intention of giving cord blood advice. Hong Kong midwives generally showed high levels of knowledge about the medical uses of cord blood but they were not as familiar with the administrative, legal and financial aspects of donation and storage. Only about 10% had received formal cord blood training and the majority felt that it should be integrated into midwifery program curricula. Although the midwives showed strong positive attitudes towards cord blood donation, only 10.9% consistently gave information and 7.5% consistently advised cord blood donation to expectant mothers in the preceding year while slightly higher percentages planned to do so in the future. In the multivariable models, higher educational attainment and hospital employment were the most consistent predictors of past-year practices of giving cord blood information and future intention to provide advice. Higher score in cord blood-related attitudes was significantly associated with giving past-year cord-blood advice, future intention to provide advice and future intention to recommend donation in the multivariable models. Key barriers to advising expectant mothers were the lack of a formal work protocol, lack of time in the clinic routine and fear of criticism by peers. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Increasing education, improving perceptions and changing workplace protocols will likely increase cord blood advising by Hong Kong midwives to their patients. PMID- 30396162 TI - PGC-1alpha Participates in the Protective Effect of Chronic Intermittent Hypobaric Hypoxia on Cardiomyocytes. AB - BACKGROUND/AIMS: Myocardial ischemia/reperfusion (I/R) or hypoxia/reoxygenation (H/R) injury is always characterized by Ca2+ overload, energy metabolism disorder and necrocytosis of cardiomyocytes. We showed previously that chronic intermittent hypobaric hypoxia (CIHH) improves cardiac function during I/R through improving cardiac glucose metabolism. However, the underlying cellular and molecular mechanisms of CIHH treatment improving energy metabolism in cardiomyocytes are still unclear. In this study, we determined whether and how CIHH protects cardiomyocytes from Ca2+ overload and necrocytosis through energy regulating pathway. METHODS: Adult male Sprague-Dawley rats were randomly divided into two groups: control (CON) and CIHH group. CIHH rats received a hypobaric hypoxia simulating 5,000-m altitude for 28 days, 6 hours each day, in hypobaric chamber. Rat ventricular myocytes were obtained by enzymatic dissociation. The intracellular calcium concentration ([Ca2+]i) and cTnI protein expression were used to evaluate the degree of cardiomyocytes injury during and after H/R. The mRNA and protein expressions involved in cardiac energy metabolism were determined using quantitative PCR and Western blot techniques. PGC-1alpha siRNA adenovirus transfection was used to knock down PGC-1alpha gene expression of cardiomyocytes to determine the effect of PGC-1alpha in the energy regulating pathway. RESULTS: H/R increased [Ca2+]i and cTnI protein expression in cardiomyocytes. CIHH treatment decreased [Ca2+]i (p< 0.01) and cTnI protein expression (p< 0.01) in cardiomyocytes after H/R. Both mRNA and protein expression of PGC-1alpha increased after CIHH treatment, which was reversed by PGC-1alpha siRNA adenovirus transfection. Furthermore, CIHH treatment increased the expression of HIF-1alpha, AMPK and p-AMPK in cardiomyocytes, and pretreatment with AMPK inhibitor dorsomorphin abolished the enhancement of PGC-1alpha protein expression in cardiomyocytes by CIHH (p< 0.01). In addition, PGC-1alpha knock down also abolished the increased protein level of GLUT4 (p< 0.01) and decreased the protein level of CPT-1b (p< 0.05) in cardiomyocytes by CIHH treatment. CONCLUSION: CIHH treatment could reduce the calcium overload and H/R injury in cardiomyocytes by up-regulating the expression of PGC-1alpha and regulating the energy metabolism of glucose and lipid. The HIF-1alpha-AMPK signaling pathway might be involved in the process. PMID- 30396163 TI - Circular RNA Expression Profiling Identifies Prostate Cancer- Specific circRNAs in Prostate Cancer. AB - BACKGROUND/AIMS: Prostate cancer (PCa) is one of the main cancers that damage males' health severely with high morbidity and mortality, but there is still no ideal molecular marker for the diagnosis and prognosis of prostate cancer. METHODS: To determine whether the differentially expressed circRNAs in prostate cancer can serve as novel biomarkers for prostate cancer diagnosis, we screened differentially expressed circRNAs using SBC-ceRNA array in 4 pairs of prostate tumor and paracancerous tissues. A circRNA-miRNA-mRNA regulatory network for the differential circRNAs and their host genes was constructed by Cytoscape3.5.1 software. Quantitative real-time polymerase chain reaction analysis (qRT-PCR) was performed to confirm the microarray data. RESULTS: We found 1021 differentially expressed circRNAs in PCa tumor using SBC-ceRNA array and confirmed the expression of circ_0057558, circ_0062019 and SLC19A1 in PCa cell lines and tumor tissues through qRT-PCR analysis. We demonstrated that combination of PSA level and two differentially expressed circRNAs showed significantly increased AUC, sensitivity and specificity (0.938, 84.5% and 90.9%, respectively) than PSA alone (AUC of serum PSA was 0.854). Moreover, circ_0057558 was correlated positively with total cholesterol. The functional network of circRNA-miRNA-mRNA analysis showed that circ_0057558 and circ_0034467 regulated miR-6884, and circ_0062019 and circ_0060325 regulated miR-5008. CONCLUSION: Our results demonstrated that differentially expressed circRNAs (circ_0062019 and circ_0057558) and host gene SLC19A1 of circ_0062019 could be used as potential novel biomarkers for prostate cancer. PMID- 30396164 TI - Serum Procalcitonin Correlates with Renal Function in Hepatitis B Virus-Related Acute-on-Chronic Liver Failure. AB - BACKGROUND/AIMS: To investigate the relationship between elevated serum procalcitonin (PCT) and renal function in hepatitis B virus-related acute-on chronic liver failure (HBV-ACLF). METHODS: HBV-ACLF patients (n = 201) presenting to the State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, from January 2013 to November 2016 were categorized into three groups according to serum PCT levels: (i) normal group (n = 74) had PCT of <= 0.5 ng/mL; (ii) elevated group (n = 85) had PCT in the range 0.5-1.0 ng/mL; and (iii) highly elevated group (n = 42) had PCT of > 1.0 ng/mL. Thirty-five cases received standard care after admission. Serum PCT levels and renal function were determined during a two-week follow-up. RESULTS: Significant increases in serum creatinine (Cr) were recorded in male and female patients in the elevated group and highly elevated group compared with the normal group (P < 0.05). In addition, serum Cr levels in male and female patients were significantly higher in the highly elevated group than in the elevated group (P < 0.05). The glomerular filtration rate (GFR) was significantly lower in the highly elevated group (P < 0.05) and this group had the highest risk of altered Cr (45.9% in males; 80% in females) and abnormal GFR (37.5%). Serum PCT levels correlated significantly with all renal function parameters including homocysteine (Hcy), GFR, Cr, blood urea nitrogen, uric acid, and cystatin C at baseline and during treatment. Univariate and multivariate analyses indicated that serum PCT was a strong predictor of renal dysfunction. CONCLUSION: Serum PCT is closely related to renal dysfunction in HBV-ACLF. PMID- 30396166 TI - Expression Signature and Role of miR-30d-5p in Non-Small Cell Lung Cancer: a Comprehensive Study Based on in Silico Analysis of Public Databases and in Vitro Experiments. AB - BACKGROUND/AIMS: The purpose of this study was to probe the clinico-pathological significance and the underlying mechanism of miR-30d-5p expression in non-small cell lung cancer (NSCLC). METHODS: We initially examined the level of miR-30d-5p expression in NSCLC and non-cancer tissues using RT-qPCR. Then, a series of validation analyses including a meta-analysis of data from microarray chips in Gene Expression Omnibus (GEO), data mining of the cancer genome atlas (TCGA) and an integrated meta-analysis incorporating GEO microarray chips, TCGA data, in house RT-qPCR and literature studies were performed to examine the clinico pathological value of miR-30d-5p expression in NSCLC. In vitro experiments were further conducted to investigate the impact of miR-30d-5p on NSCLC cell growth. The molecular mechanism by which miR-30d-5p regulates the pathogenesis of NSCLC was probed through a bioinformatics analysis of its target genes. Moreover, dual luciferase reporter assay was conducted to verify the targeting regulatory relationship between miR-30d-5p and CCNE2. RESULTS: Based on results from RT qPCR, GEO meta-analysis, TCGA data mining and the integrated meta-analysis incorporating GEO microarray chips, TCGA data, in-house RT-qPCR and literature studies, miR-30d-5p expression was decreased in NSCLC tissues, and patients with NSCLC who presented with lower miR-30d-5p expression tended to display an advanced clinical progression. Significant pathways including the Mucin type O glycan biosynthesis pathway, cell cycle pathway and cysteine and methionine metabolism pathway (all P< 0.05) revealed potential roles of the target genes of miR-30d-5p in the oncogenesis of NSCLC. Results from in vitro experiments indicated that miR-30d-5p could attenuate proliferation and viability of NSCLC cells. Among the 12 identified hub genes, nine genes including E2F3, CCNE2, SKP2, CDK6, TFDP1, LDHA, GOT2, DNMT3B and ST6GALNAC1 were validated by Pearson's correlation test and the human protein atlas (HPA) database as targets of miR-30d 5p with higher probability. Specifically, dual luciferase reporter assay confirmed that CCNE2 was directly targeted by miR-30d-5p. CONCLUSION: In summary, miR-30d-5p expression is decreased in NSCLC, and it might play the role as tumor suppressor in NSCLC by regulating target genes. PMID- 30396165 TI - GOLM1 Stimulation of Glutamine Metabolism Promotes Osteoporosis via Inhibiting Osteogenic Differentiation of BMSCs. AB - BACKGROUND/AIMS: Bone marrow mesenchymal stem cells (BMSCs) play an essential role in osteoporosis. However, the molecular mechanisms and the involvement of glutamine metabolism in osteogenic BMSCs differentiation and osteoporosis remain largely unclear. In this study, we investigated the role of Golgi membrane protein 1 (GOLM1) and glutamine metabolism in BMSCs differentiation and osteoporosis. METHODS: Osteogenic differentiation-inducing media (Odi) was used to induce the osteogenic differentiation of BMSCs. The mRNA expression of GOLM1, ALP, Runx2, Osx, BSP and OCN was determined by qRT-PCR assay. Western blot assay was used to analyze GOLM1, p-mTOR, mTOR, p-S6 and S6 abundance in GOLM1 silencing and over-expressed BMSCs. Glutamine uptake, intracellular glutamine, glutamate and alpha-KG level was detected using indicated Kits. GOLM1 antibody, glutamine metabolism inhibitors EGCG and BPTES were used to treat ovariectomy (OVX)-induced osteoporosis. Bone mineral density and bone volume relative to tissue volume (%) were analyzed by micro-CT. Serum was collected from osteoporosis patients and healthy participants and subjected to GOLM1 determination using ELISA Kit. RESULTS: GOLM1 expression and glutamine metabolism were suppressed by Odi. GOLM1 blockage or inhibition of glutamine metabolism promoted the osteogenic differentiation of BMSCs induced by Odi. GOLM1 activated glutamine metabolism depending on the mTOR signaling pathway. In vivo, GOLM1 antibody or combination of glutamine inhibitor EGCG and BPTES rescued the osteoporosis in an OVX-operated mouse model. Serum GOLM1 level was increased in the patients of osteoporosis compared with healthy people. CONCLUSION: GOLM1 stimulates glutamine metabolism to suppress the osteogenic differentiation of BMSCs and to promote osteoporosis. Therefore, GOLM1 activation of glutamine metabolism is a potential target for osteoporosis. PMID- 30396167 TI - Plasma Galectin-9 Concentrations in Normal and Diseased Condition. AB - BACKGROUND/AIMS: Galectin-9 is a soluble immune modulator with versatile functions, including a role as an immune checkpoint molecule. Therefore, the amount of galectin-9 in the blood may reflect an individual's immunological balance. Many studies have conducted galectin-9 measurements; however, the reported galectin-9 concentration in the blood varies greatly, even within healthy controls. This study investigates the variation between the reported and actual concentrations of galectin-9. METHODS: A GalPharma ELISA and an R&D Systems ELISA kit were directly compared using the same set of plasma and a series of recombinant galectins, including degraded galectin-9. Furthermore, galectin-9 in plasma was concentrated using anti-galectin-9 antibody-conjugated beads, and subjected to western blotting to estimate the quantity and integrity of galectin-9 and assess the consistency of ELISA measurements. RESULTS: The R&D Systems' ELISA indicated a 50-fold higher median concentration of plasma galectin 9 than that indicated by the GalPharma ELISA. This variation is due to aberrantly enhanced reactivity of the R&D Systems' ELISA to degraded galectin-9 present in small quantities in the plasma. The GalPharma ELISA could detect only intact galectin-9 and its results correlated well with the plasma galectin-9 level obtained by western blotting. CONCLUSION: ELISA kits from R&D Systems reacts aberrantly higher against degraded galectin-9 than the intact galectin-9. Therefore, the existence of a small amount of degraded galectin-9 in a test sample hinders the quantification. As galectin-9 is a fragile protein, this is a serious concern when using this kit. Based on quantifications from the GalPharma ELISA, the median (25th-75th percentiles) galectin-9 concentration in healthy subjects in the current study cohort was calculated as 110 pg/mL (67 -154 pg/mL). PMID- 30396168 TI - Secreted Frizzled Related Protein 2 Modulates Epithelial-Mesenchymal Transition and Stemness via Wnt/beta-Catenin Signaling in Choriocarcinoma. AB - BACKGROUND/AIMS: Choriocarcinoma (CC) is a highly aggressive gestational trophoblastic neoplasia; however, the underlying molecular mechanisms of its invasiveness and metastasis remain poorly understood. Human secreted frizzled related protein 2 (SFRP2) could function as a tumor promoter or suppressor in different tumors, yet the role it plays in CC's invasion and metastasis is thoroughly unclear. The current study was aimed to explore the function and underlying mechanism of SFRP2 in CC. METHODS: The expression of SFRP2 in CC tissues was examined via immunohistochemistry. The methylation level and expression of SFRP2 in CC cell lines, JEG-3 and JAR were examined via bisulfite sequencing PCR (BSP), western blotting and quantitative RT-PCR. The biological role of increasing expressed SFRP2 through its promoter demethylation with 5-Aza 2'-deoxycytidine (5-Aza) was examined by a series of in vitro functional studies. Furthermore, lentivirus transfection technology was adopted to investigate the biological roles of SFRP2 knockdown in JEG-3 and JAR cells in vitro and in vivo. Moreover, its downstream signaling pathway was investigated. RESULTS: SFRP2 was downregulated in CC tissues, and its expression was inversely related to its promoter hypermethylation frequency in JEG-3 and JAR cells. Increased SFRP2 through its promoter demethylation inhibited cell migration, invasion and colony formation in JEG-3 and JAR cells, whereas decreased SFRP2 reversed the epithelial mesenchymal transition (EMT) process and stemness in JEG-3 and JAR cells both in vitro and vivo. Mechanistically, SFRP2 regulated the EMT and stemness of CC cell lines via canonical Wnt/beta-catenin signaling, validated by the usage of a Wnt activator and inhibitor. CONCLUSION: The current study indicates that downregulated SFRP2 has potent tumor-promotive effects in CC through the modulation of cancer stemness and the EMT phenotype via activation of Wnt/beta catenin signaling in vitro and in vivo. PMID- 30396170 TI - Crestal Bone Loss Around Submerged and Non-Submerged Dental Implants in Individuals with Type-2 Diabetes Mellitus: A 7-Year Prospective Clinical Study. AB - OBJECTIVE: In establishing an evidence-based rationale for the optimal use of implant therapy in patients with type 2 diabetes mellitus (T2DM), it is essential to first understand the impact of glycemic control on early healing and the success of dental implants. The objective of this study was to evaluate crestal bone loss (CBL) and stability around submerged and non-submerged dental implants in Saudi patients with well- and poorly-controlled type 2 diabetes mellitus (T2DM). SUBJECT AND METHODS: Thirty-five patients with well-controlled T2DM (24 males and 11 females) and 32 poorly-controlled T2DM patients (19 males and 13 females) were included. CBL was measured on digital radiographs; resonance frequency analysis (RFA) measurements were made for each implant at the time of fixture placement and at 3 months in both the groups. A p value less than 0.05 was considered statistically significant. RESULTS: A total of 124 dental implants were placed. Mean RFA values between baseline and 3 months in poorly-controlled T2DM patients was statistically significant (p = 0.048). CBL at first year (p = 0.047), second year (p = 0.041), third year (p = 0.046) and seventh year (p = 0.035) was significantly worse in poorly-controlled T2DM. CBL around non submerged dental implants showed statistically significant differences at all time-intervals (p < 0.05). CONCLUSION: Poorly-controlled T2DM patients present worse peri-implant bone outcomes as compared to patients with well-controlled T2DM. We suggest that the predictability of successful dental implant therapy outcomes depends on the maintenance of optimal HbA1c levels. PMID- 30396171 TI - Robot-Assisted Reconstruction in Head and Neck Surgical Oncology: The Evolving Role of the Reconstructive Microsurgeon. AB - Transoral robotic surgery (TORS) is gaining more widespread use among head and neck surgical procedures. As experience grows with this technique, so do the indications of when and in which patients it can be used. Already established in the treatment of small oral cavity tumours, it is expanding into larger multi site resections and resections, such as through-and-through-into-the-neck defects, that will require reconstruction. With robot-assisted surgery advancing, so robot-assisted reconstruction (RAR) is evolving. In this paper, we discuss the evolving role of reconstruction in post-TORS defects as well as the role of RAR in today's practice. PMID- 30396169 TI - Targeting Thioredoxin System with an Organosulfur Compound, Diallyl Trisulfide (DATS), Attenuates Progression and Metastasis of Triple-Negative Breast Cancer (TNBC). AB - BACKGROUND/AIMS: Metastasis is the leading cause resulting in high mortality in triple negative breast cancer (TNBC) patients. Cancer cells are skilled at utilizing thioredoxin (Trx) system as an efficient antioxidant system to counteract oxidative damage, facilitating the occurrence of metastasis. Here, we identified an organosulfur compound named DATS isolated from garlic, that inhibits the expression of Trx-1 and the enzyme activity of Trx reductase in breast cancer cells. METHODS: Tissue microarray of breast cancer patients and immunohistochemical method were used to analyze the role of Trx-1 in breast cancer metastasis. Spotaneous metastasis model and experimental metastasis model combined with HE staining, immunohistochemistry were used to verify in vivo anti metastatic effect of DATS as well as its regulation on thioredoxin. Western blot, immunofluorescence, redox state assessment and detection of enzyme activity were employed to determine the effect of DATS on thioredoxin system. Trx-1 siRNA interference was used to investigate the conclusive evidence that Trx-1 was the target of DATS. RESULTS: In agreement with reduced Trx-1 nuclear translocation from cytoplasm by DATS, the production of reduced form of Trx-1 was dramatically decreased. Furthermore, in vivo, DATS administration was observed to significantly suppress spontaneous and experimental metastasis in nude mice. Delivery of DATS also resulted in decreased expression of Trx-1 as the direct target, as well as expression of NF-kappaB and MMP2/9 in primary tumor and lung tissue. Notably, the effects of DATS on the expression of downstream metastasis associated genes were mediated by Trx-1, as demonstrated by the combination use of DATS and Trx-1 siRNA. CONCLUSION: Collectively, this present study indicates that targeting Trx system with DATS may provide a promising strategy for treating metastasis of TNBC. PMID- 30396172 TI - Host Peptidic Hormones Affecting Bacterial Biofilm Formation and Virulence. AB - Bacterial biofilms constitute a critical problem in hospitals, especially in resuscitation units or for immunocompromised patients, since bacteria embedded in their own matrix are not only protected against antibiotics but also develop resistant variant strains. In the last decade, an original approach to prevent biofilm formation has consisted of studying the antibacterial potential of host communication molecules. Thus, some of these compounds have been identified for their ability to modify the biofilm formation of both Gram-negative and Gram positive bacteria. In addition to their effect on biofilm production, a detailed study of the mechanism of action of these human hormones on bacterial physiology has allowed the identification of new bacterial pathways involved in biofilm formation. In this review, we focus on the impact of neuropeptidic hormones on bacteria, address some future therapeutic issues, and provide a new view of inter kingdom communication. PMID- 30396173 TI - Transoral Robotic Surgery Total Laryngectomy. AB - OBJECTIVE: The aim of our study is to demonstrate our technique for performing transoral robotic surgical total laryngectomy (TORS-TL) with the use of the da Vinci robotic system. MATERIALS AND METHODS: We provide a comprehensive description of the TORS-TL operative techniques. Two fresh-frozen human cadavers were selected after ethics approval to describe the appropriate step-by-step surgical resection. We adopted a 5-step procedure that was later applied to 2 of our patients. The first patient presented initially with a squamous cell carcinoma (SCC) in the laryngeal glottis area. A lack of clinical response to initial treatment by chemoradiotherapy led to the decision of performing salvage TL surgery. The second patient had a previous history of head and neck SCC (HNSCC); he had no recurrence of his primary tumor but suffered significantly from postoperative breathing and swallowing difficulties due to severe laryngeal incompetence. RESULTS: TORS-TL was successfully performed in all cases. The operative time for the cadavers was approximately 65 and 55 min, respectively. It was significantly longer for the patients, 210 and 235 min, respectively, despite the fact that exactly the same steps were followed throughout all procedures. There were no intra- or postoperative complications or surgical morbidity related to the use of the da Vinci system. CONCLUSION: TORS-SL for SCC was performed in a safe, reliable, and smooth manner and was shown to be successful in treating our patients. We thus believe that our step-by-step surgical technique for TORS-SL is efficient and reproducible. PMID- 30396174 TI - Overexpression of beta-Catenin Decreases the Radiosensitivity of Human Nasopharyngeal Carcinoma CNE-2 Cells. AB - BACKGROUND/AIMS: Nasopharyngeal carcinoma (NPC) is rare worldwide but remains highly prevalent in endemic regions, notably in southern China. Radiotherapy remains the treatment of choice for NPC, but radioresistance has been identified as a major cause of therapeutic failure. The Wnt/beta-catenin signaling has been found to be involved in NPC radioresistance; however, the effect of beta-catenin overexpression on radioresistance remains unknown in NPC until now. This study aimed to examine the impact of beta-catenin overexpression on the radiosensitivity of human NPC CNE-2 cells. METHODS: Immunohistochemistry was performed to detect the beta-catenin expression in normal nasopharyngeal specimens and NPC specimens. The human NPC CNE-2 cell line overexpressing beta catenin was modeled by transfection with the pcDNA3.1/Hygro(+)/beta-catenin recombinant vector (transfection group), while cells transfected with the pcDNA3.1/Hygro(+) vector served as negative controls and non-transfected cells served as blank controls. The expression of key molecules of the Wnt/beta-catenin signaling pathway was determined using Western blotting and qPCR assays, and the changes of radiation sensitivity were measured with a colony-formation assay. Cell viability was measured by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide) assay. In addition, the cell cycle and apoptosis was detected using flow cytometry and the TCF/LEF transcriptional activity was measured with a Dual Luciferase Reporter Assay System. RESULTS: Immunohistochemical staining showed high beta-catenin expression in radioresistant NPC specimens, and low expression in radiosensitive NPC specimens and normal nasopharyngeal specimens. Western blotting and qPCR assays detected higher beta-catenin expression in the transfection group than in the negative and blank controls (P < 0.01). Down-regulation of GSK-3beta expression (P < 0.05) and up-regulation of Cyclin D1 expression (P < 0.01) was detected in beta-catenin overexpressing NPC cells exposed to X-ray radiation relative to negative and blank controls. Colony-formation assay revealed higher D0, Dq and SF in the transfection group than in the negative and blank control groups post-radiation, and the SER in the transfection group was 0.75-fold and 0.68-fold greater than that in the blank and negative control groups, respectively. MTT assay revealed that the viability of CNE-2 cells was significantly higher in the transfection group (96% +/- 8.72%) than in the negative control group (74.67 +/- 7.05%) and the blank control group (75.33% +/- 7.02%) 24 h post-exposure to 6 Gy X-ray radiation (P < 0.05). X-ray radiation led to a lower proportion of CNE-2 cells at the G2/M phase and a lower apoptotic rate in the transfection group than in the negative and blank control groups (P < 0.05). In addition, the TCF/LEF transcriptional activity was higher in the transfection group than in the negative and blank control groups (P < 0.01), and 6 Gy X-ray radiation elevated the TCF/LEF transcriptional activity relative to 0 Gy radiation in the transfection group (P < 0.01). CONCLUSION: beta-catenin overexpression may decrease the radiation sensitivity in NPC CNE-2 cells through activating the downstream transcriptional factors of beta-catenin, and reducing G2/M arrest and cell apoptosis. PMID- 30396175 TI - A Six-LncRNA Expression Signature Associated with Prognosis of Colorectal Cancer Patients. AB - BACKGROUND/AIMS: Colorectal cancer (CRC) is one of the most common malignant tumor with high migration and invasion capacity. Long non-coding RNAs (lncRNAs) have been identified to influence multiple cancers progression through competitively binding microRNAs (miRNAs). In this study, we proposed to develop a lncRNA-based signature for CRC survival outcomes. METHODS: LncRNA expression profiles of CRC patients were extracted from the Gene Expression Omnibus (GEO) data sets GSE38832 (training set) and GSE29621 (testing set) . Associations between lncRNA expression and CRC disease free survival (DFS) were evaluated through univariate Cox regression analysis, and prognosis signature constructed by combination of weighted lncRNA expression values were obtained through multivariate Cox regression analysis. Robustness of the prognosis signature was evaluated through receiver operating characteristics analysis in the testing set. RESULTS: A weighted prognosis signature of six lncRNAs, including LINC01583, LINC00276, LUNAR1, DKFZp434J0226, SFTA1P and OGFOD3, was yielded from multivariate Cox regression analysis. Samples with significantly different DFS dislayed distinct signatures, indicating considerable predictory accuracy of this expression signature. CONCLUSION: Robustness of the prognosis signature was evaluated in the testing set through Kaplan-Meier and receiver operating characteristics (ROC) analysis. Furthermore, functional enrichment analysis of lncRNAs suggested significant enrichment of cancer related pathways. Our results revealed the promise of lncRNAs as prognostic biomarkers. PMID- 30396176 TI - Omalizumab in Chronic Urticaria: An Italian Survey. AB - Omalizumab is approved for use in chronic spontaneous urticaria (CSU); however, it is not approved for chronic inducible urticaria (CIndU). The aim of the present study was to assess the effectiveness of omalizumab in treating CSU and CIndU in Italy. This is a multicentre prospective observational real-life study involving patients with severe urticaria capable of undergoing omalizumab therapy. We enrolled 127 patients (59.1% females), ranging in age from 15 to 83 years, 69.3% had CSU alone, 26.8% had CSU and CIndU, and 3.9% had only CIndU (30.8% delayed pressure, 35.9% dermographic, 15.3% cholinergic, 12.8% cold, 5.1% aquagenic). After the first cycle of omalizumab (300 mg every 4 weeks for 24 weeks), 16 CSU patients and 10 patients (20.5%) with CIndU with or without CSU did not require a second cycle of omalizumab (300 mg every 4 weeks for 20 weeks). The patient with aquagenic urticaria achieved remission after the first cycle. None showed a lack of response to the second cycle of omalizumab. Omalizumab is a promising drug for both spontaneous and inducible chronic urticaria. Current evidence indicates that omalizumab may be approved also for CIndU. PMID- 30396178 TI - Level of Anxiety and Depression in Cardiac Syndrome X. AB - OBJECTIVE: Cardiac syndrome X (CSX) is defined as angina-like symptoms, abnormalities on stress testing and normal epicardial coronary arteries on coronary angiography. The aim of this study was to determine the Hospital Anxiety and Depression scores of patients with CSX and to compare with healthy controls. Materials/Subjects and Methods: Patients undergoing coronary angiography between January 2015 and December 2016 because of clinical indications, including abnormal noninvasive test results were examined. Two hundred and ten subjects (110 patients with CSX, 100 controls) were enrolled. Demographic characteristics including age, education level, marriage status, history of stressful life events were recorded. The Turkish version of the Hospital Anxiety and Depression Scale (HADS) was evaluated in the study population. RESULTS: The anxiety, depression and total scores in the patients with CSX were significantly higher than control group (p < 0.001, p < 0.003, p < 0.001, respectively). Among women, anxiety, depression, total scores and stressful life events were significantly higher in CSX group (p = 0.006, p = 0.015, p = 0.001, p < 0.001, respectively). Patients with lower educational status had higher anxiety scores (p = 0.03) Stressful life events and HAD-A>10 were the only independent predictors of CSX in logistic regression analysis with comparable odds ratios 2.256 (95% CI 1.057-4.817, p = 0.03) and 2,399 (95% CI 1.248-4.613, p = 0.009), respectively. CONCLUSION: The results of our research suggest that patients with CSX have a high prevalence of stress and psychiatric disturbances. Interventions targeted toward improving the quality of life and to give psychological support may have the potential benefits especially for women and individuals with lower education. PMID- 30396177 TI - Early Growth Response 1-Dependent Downregulation of Matrix Metalloproteinase 9 and Mouse Double Minute 2 Attenuates Head and Neck Squamous Cell Carcinoma Metastasis. AB - BACKGROUND/AIMS: The functional relevance of early growth response-1 (EGR1) on cancer invasion remains controversial. The effect of EGR1 on the expression of MMP9, which is important for HNSCC invasion, is still disputed. There is no previous data showing the effect of EGR1 on mouse double minute 2 (MDM2), an enhancer of matrix metalloproteinase 9 (MMP9) expression. Our aim is to clarify the negative correlation between EGR1 expression and head and neck squamous cell carcinoma (HNSCC) metastasis. METHODS: EGR1 mRNA and protein expressions were compared in normal and HNSCC tissues using The Cancer Genome Atlas (TCGA) dataset analysis or immunohistochemistry (IHC), respectively. In vitro cell invasion was evaluated Matrigel invasion assay. EGR1-dependent inhibition of MDM2 transcription was assessed by promoter-luciferase assay and chromatin immunoprecipitation (ChIP). RESULTS: TCGA data showed that EGR1 mRNA levels are significantly higher in normal oral tissues as compared with HNSCC tumor tissues (adjusted P = 1.64x10-16). In addition, nonmetastatic HNSCC tissues showed significantly higher EGR1 mRNA levels as compared with metastatic tissues (adjusted P = 0.023). IHC analysis showed that primary tumor tissues expressed significantly higher levels of nuclear EGR1 compared with paired metastatic lymph node tissues (P < 0.05). EGR1 overexpression downregulated MMP9 and MDM2 protein expression. Consistent with these observations, TCGA data analysis found significantly fewer metastatic patients among a subgroup of population presenting higher EGR1 expressions with lower MMP9 and/or MDM2. CONCLUSION: Our data suggests that EGR1 prevents HNSCC metastasis through downregulation of MMP9 and MDM2. EGR1 might be a potential candidate to attenuate HNSCC metastasis. PMID- 30396180 TI - ORCA Announcements. PMID- 30396179 TI - Transvalvular Volume Flow Rate: A Useful Tool for Assessment of Aortic Valve Stenosis in Preserved Ejection Fraction Patients. PMID- 30396181 TI - Does Tourniquet Time or Pressure Contribute to Intracranial Pressure Increase Following Tourniquet Application? AB - OBJECTIVE: The aim of this study was to determine whether an early increase in intracranial pressure (ICP) following the deflation of a tourniquet is related to the tourniquet time (TT) or tourniquet pressure (TP) and to identify a safe cutoff value for TT or TP. MATERIALS AND METHODS: Patients who underwent elective orthopedic lower extremity surgery under general anesthesia were randomized into two groups: Group A, inflation with a pneumatic TP of systolic blood pressure + 100 mmHg (n = 30) and Group B, inflation using the arterial occlusion pressure formula (n = 30). The initial and maximum TPs, TT, and sonographic measurements of optic nerve sheath diameter (ONSD) and end tidal CO2 values were taken at specific time points (15 minutes before the induction of anesthesia, just before, and 5, 10, and 15 minutes after the tourniquet was deflated). RESULTS: The initial and maximum TPs were found to be significantly higher in Group A compared to Group B. The fifth minute after the tourniquet deflation period showed a significant positive correlation between the TT and ONSD (r = 0.57, p = 0.0001). When ONSD >= 5mm was taken as a standard criterion, the safe cutoff value for the optimal tourniquet time was found to be < 67.5 minutes (sensitivity 87%, specificity 59.5%). CONCLUSION: The ICP increase in the early period after tourniquet deflation was well correlated with TT but not with TP. The TT of >= 67.5 minutes was found to be the cutoff value, which is considered the start point of the increase in ICP after tourniquet deflation. PMID- 30396182 TI - Transaortic Flow in Aortic Stenosis: Stroke Volume Index versus Flow Rate. PMID- 30396183 TI - Subretinal Fluid Optical Density and Spectral-Domain Optical Coherence Tomography Characteristics for the Diagnosis of Circumscribed Choroidal Hemangioma. AB - PURPOSE: To investigate spectral domain-optical coherence tomography (SD-OCT) features of untreated circumscribed choroidal hemangioma (CCH), and the optical density (OD) of the associated subretinal fluid (SRF). PROCEDURES: This international retrospective multicenter study conducted at 5 tertiary retina referral centers included 34 patients with symptomatic CCH imaged on SD-OCT. CCH surface, size, and overlying retinal changes and OD ratio (ODR) were evaluated. RESULTS: The mean ODR of the SRF was 0.808 +/- 0.287. Tumor base measured on ultrasound correlated significantly with the ODR (p = 0.012). ODR values in cases of CCH were similar to those of choroidal metastasis, but significantly lower than those of choroidal melanoma (p = 0.006). Thirty-two out of 34 cases (94%) presented with a regular smooth choroidal surface. OCT demonstrated SRF overlying the CCH in 29 eyes (85%). The presence of SRF correlated significantly with a larger basal tumor diameter (p = 0.035). OCT displayed sub- and intraretinal hyperreflective foci, correlating with both larger maximal retinal thickness overlying the tumor (p = 0.031) and the amount of SRF (p = 0.016) in 29 eyes (85%). CONCLUSION: CCH displays typical findings on SD-OCT. ODR is a new important tool in the differential diagnosis of choroidal tumors and should be considered for enhancing the accuracy of diagnosing CCH. This benefit is especially relevant for cases in which the presentation of CCH is atypical. PMID- 30396184 TI - RUNX1 Mutations Can Lead to Aberrant Expression of CD79a and PAX5 in Acute Myelogenous Leukemias: A Potential Diagnostic Pitfall. AB - BACKGROUND: RUNX1 is a crucial transcription factor for hematological stem cells and well-known for its association with acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML). Besides the translocation t(8; 21) that leads to the RUNX1-RUNX1T1 fusion, somatic mutations of RUNX1 have been discovered. METHODS: Four bone marrow trephine biopsies of patients with CD79a-positive and/or PAX5-positive acute leukemias were investigated by immunohistochemistry (IHC), karyotyping, and next-generation sequencing-based genetic analysis. Data were then compared to a historical collective of AML (n = 42) and 42 cases of AML newly diagnosed at our institution between June 2017 and May 2018. RESULTS: We report on 4 cases of acute leukemia with an equivocal immunophenotype showing expression of CD79a and/or PAX5, which led to a preliminary histopathologic classification as probable ALL/unclassifiable acute leukemia. All cases were positive for CD34 and TdT but negative for several myeloid markers on IHC. Mutational analysis revealed point mutations and indels of RUNX1 and further mutations typical for AML such as TET2, DNMT3A, and SRSF2, and 2 cases had tetrasomy 13 characteristic of RUNX1 mutant AML. CONCLUSION: Aberrant CD79a and/or PAX5 expression can be found in AML cases with RUNX1 mutations even without the translocation t(8; 21). Our series shows the expression of CD79a and PAX5 to be a potential pitfall in the classification of RUNX1 mutant acute leukemia. PMID- 30396186 TI - BRAF V600 Mutational Status in Melanoma Correlates with Cytologic Features in Fine-Needle Aspirate Specimens. AB - Melanomas are known as the great mimicker and must be considered in the differential diagnosis of any fine-needle aspirations (FNA). Despite recent advancements in understanding of the mutational landscape of melanomas, there still exists a divide between the genetic and morphologic correlates. A consecutive cohort of 39 FNA of clinically verified metastatic melanomas with concurrent BRAF V600 assessment were selected [positive (n = 18) and wild-type (n = 21)]. The melanoma cytology specimens were evaluated blinded to the BRAF mutation status in a dichotomized fashion for the presence of 8 selected morphologic classifiers. When comparing the BRAF-mutated vs. BRAF-wild type cohorts, the percentage of cases were, respectively: macronucleoli (56 and 52%), intranuclear inclusions (50 and 33%), pigment (44 and 24%), binucleation/multinucleation (78 and 57%), nuclear pleomorphism (72 and 67%), cytoplasmic vacuolization (22 and 29%), spindle cell morphology (61 and 29%), and necrosis (11 and 10%). The average age of the BRAF-mutated cohort was 52.2 years, compared to the BRAF wild-type cohort at 65.2 years. The prevalence of sex ratio and the location of the primary melanoma were matched between cohorts. Spindle cell morphology was more correlated with BRAF V600-mutated melanomas. Clinicians utilized the BRAF status to alter clinical decisions with use of BRAF inhibitors. PMID- 30396185 TI - Differential Expression of MicroRNA-19b Promotes Proliferation of Cancer Stem Cells by Regulating the TSC1/mTOR Signaling Pathway in Multiple Myeloma. AB - BACKGROUND/AIMS: MiR-19b has been reported to be involved in several malignancies, but its role in multiple myeloma (MM) is still unknown. The objective of this study was to explore the biological mechanism of miR-19b in the progression of MM. METHODS: First, we performed real-time polymerase chain reaction (PCR) and Western blot to study the expression of miR-19b, tuberous sclerosis 1 (TSC1), and caspase-3 in different groups. MTT assay was performed to explore the effect of miR-19b on survival and apoptosis of cancer stem cells (CSCs). Computation analysis and luciferase assay were utilized to confirm the interaction between miR-19b and TSC1. RESULTS: A total of 38 participants comprising 20 subjects with MM and 18 healthy subjects as normal controls were enrolled in our study. Real-time PCR showed dramatic upregulation of miR-19b, but TSC1 was evidently suppressed in the MM group. MiR-19b overexpression substantially promoted clonogenicity and cell viability, and further inhibited apoptosis of CSCs in vitro. Furthermore, miR-19b overexpression downregulated the expression of caspase-3, which induced apoptosis. Using in silico analysis, we identified that TSC1 might be a direct downstream target of miR-19b, and this was further confirmed by luciferase assay showing that miR-19b apparently reduced the luciferase activity of wild-type TSC1 3'-UTR, but not that of mutant TSC1 3'-UTR. There was also evident decrease in TSC1 mRNA and protein in CSCs following introduction of miR-19b. Interestingly, reintroduction of TSC1 abolished the miR 19b-induced proliferation promotion and apoptosis inhibition in CSCs. CONCLUSION: These findings collectively suggest that miR-19b promotes cell survival and suppresses apoptosis of MM CSCs via targeting TSC1 directly, indicating that miR 19b may serve as a potential and novel therapeutic target of MM based on miRNA expression. PMID- 30396188 TI - Improving Empathy in Nursing Students: A Comparative Longitudinal Study of Two Curricula. AB - PURPOSE: This study aimed to examine changes of empathy levels of nursing student in two different curricula structures, one called "traditional" and the other called "integrated" curricula. The study was a longitudinal design to follow a cohort of nursing students to examine the magnitude of changes in empathy in their education years. METHODS: The study was conducted in a public school of nursing giving a baccalaureate degree, which had a fundamental change in their curricula. In all, 81 students from the traditional curricula and 66 students from the integrated curricula completed the study, and data from a total of 147 students were analyzed between 2003 and 2008. The Empathic Communication Skills Scale and the Empathic Tendency Scale were given to the students in the beginning of their freshman year and at the end of the fourth year just before graduation. RESULTS: Although both of the curricula were seemed effective at improving empathic skills of students, especially the scores of students who completed the integrated curricula were higher than the scores of the other group attending the traditional curricula (p<.05). However, the empathic tendency scores of students in both curricula decreased at the end of fourth year. CONCLUSION: Although undergraduate nursing curricula either traditional or integrated improved empathic skills, it seemed that integrated curricula were more effective than traditional curricula in increasing empathic skills. The more hours and more experiential methods contributed to improved empathy. The decrease in empathic tendency requires further attention of educators and nurse managers. PMID- 30396187 TI - Analysis of HCV Isolates Among the Li Ethnic in Hainan Island of South China Reveals Their HCV-6 Unique Evolution and a New Subtype. AB - BACKGROUND/AIMS: Hainan Island has been inhabited by the "Li" aboriginal minority for centuries where the HCV genotype distribution patterns maybe remarkably different from other parts of China. We aimed to provide a better understanding of the infection with HCV genotype 6 among "Li" aboriginals on Hainan Island. METHODS: Firstly, using RT-PCR and DNA sequencing to determined 517 partial HCV Core-E1(115 from Li Ethnic, 402 from Han Ethnic) and 8 full-length genomes from Li ethnic in Hainan Island successfully, and then using the phylogenetic tree to determine the HCV genotype distribution and analyze the evolution of them. RESULTS: Phylogenetic tree analysis showed that the distribution pattern of HCV genotypes among the Han and Li ethnic population exhibits significant diferences: 6a was the most prevalent subtype in Han ethnic of Hainan Island followed by 1b, 3b, 2a, 3a, and 1a. All genomes from Li ethnic were classified into genotype 6, while 84 out of 115 (73%) could not be classified. Nine sequences (HN1350 et al.) from Li ethnic might be assigned to a new subtype 6xh as their p-distances ranged from 5.9~9.7%. Furthermore, we sequenced and characterized full-length genomes for eight HCV-6 isolates which were all from Li ethnic in Hainan Island. Among these isolates, the HN1350 was classified as a new subtype: 6xh. CONCLUSION: Overall, we firstly defined a new subtype of genotype 6xh through partial and new full length genome. And we found a unique distribution pattern of HCV 6 in the Li tribe, which might provide a better way to understand the genetic diversity of HCV-6 and to investigate the phylogeny of HCV strains from Li tribe. PMID- 30396189 TI - [Comparison of Effects of Oral Health Program and Walking Exercise Program on Health Outcomes for Pregnant Women]. AB - PURPOSE: To compare the effects of the Interaction Model of Client Health Behavior (IMCHB)-based oral health program (OHP) and walking exercise program (WEP) on oral health behaviors, periodontal disease, physical activity, and psychological indicators (depression, stress, and quality of life) in pregnant women. METHODS: A nonequivalent control group pretest-posttest design was adopted to compare the effects of a 12-week OHP and WEP on pregnant women (n=65). Pregnant women were randomly assigned to the oral health group (OHG; n=23), walking exercise group (WEG; n=21), or control group (CG; n=21). Data were analyzed by the chi2-test, Fisher's exact test, Scheffe test, and repeated measures ANOVA, using the Statistical Package for the Social Sciences for Windows (version 21.0). RESULTS: The OHG and WEG showed significant improvements in oral health behaviors, periodontal disease, and psychological indicators as compared to the CG. The WEG showed significant improvement in physical activity as compared to the OHG and CG. CONCLUSION: These findings indicate that the IMCHB based OHP and WEP were effective in improving periodontal disease, physical activity, and psychological indicators. However, further studies are needed to identify the positive effects of the OHP and WEP on birth outcomes. PMID- 30396190 TI - [Testing a Middle-Range Theory of Self-Care of Chronic Illness: A Validation for Korean Adult Patients with Severe Hypertension]. AB - PURPOSE: The aims of this study are to provide a theoretical framework for improving the self-care of adults with severe hypertension and to examine the practical suitability of a middle-range theory of self-care for chronic illness by validating the structural model. METHODS: Data were collected at a university hospital in D metropolitan city from July 1 to August 14, 2015. A total of 224 Korean adult patients with severe hypertension were recruited. Data were analyzed using SPSS 22.0 and AMOS 22.0. RESULTS: The results show that the fit index of the hypothetical model meets the recommended level; 7 out of 8 hypothetical model paths were statistically significant. Motivation, self-efficacy, support from others, and accessibility to care showed statistical significance and explained 67.3% of the self-care process. The self-care process explained 45.3%, 63.6%, and 26.5% of quality of life, health, and illness stability, respectively. CONCLUSION: This model can be used as a theoretical framework for improving self care among adult Korean patients with severe hypertension. Moreover, the practical suitability and validity of the middle-range theory of self-care for chronic illness is secured. PMID- 30396191 TI - [Prediction Modeling on Family Life Satisfaction of Old Adults Living at Home]. AB - PURPOSE: This study was conducted to construct and test a structural model on family life satisfaction of aged individuals living at home. The conceptual model was based on Bandura's self-efficacy and social cognitive theories (1977; 1986) and Bowen's (1976) family systems theory. METHODS: From January 25 to March 5, 2016, 227 older adults living at home completed a structured questionnaire. Data were analyzed to calculate the direct and indirect effects of factors affecting family life satisfaction. SPSS WIN 20.0 and AMOS 20.0 were used. RESULTS: The hypothetical model was a good fit for the data. The model fit indices were chi2=78.05, chi2/df=1.35, RMSR=.02, GFI=.98, AGFI=.96, NFI=.94, CFI=.98, and RMSEA=. 05. Family life satisfaction was positively affected by perceived collective family efficacy, status of physical health, family communication, and family support. Depression resulted in a significant negative effect. Family differentiation had a significant indirect effect on family life satisfaction. The model explained 76% of variance in family life satisfaction. CONCLUSION: Perceived collective family efficacy, status of physical health, depression, family differentiation, family communication, and family support were significant factors explaining family life satisfaction among older adults staying at home. Further research should be conducted to seek intervention strategies to improve family life satisfaction among older adults living at home by focusing on the respective contributing factors. PMID- 30396192 TI - Psychosocial Adjustment in Korean Colorectal Cancer Survivors. AB - PURPOSE: The increasing survival rate of colorectal cancer demands various nursing interventions and continuous care for patients to adapt to their psychosocial daily lives. The purpose of this study was to identify factors associated with psychosocial adjustment in colorectal cancer survivors. METHODS: A cross-sectional descriptive study with face-to-face interviews was conducted of 156 colorectal cancer survivors after surgery visiting an outpatient cancer clinic at a tertiary hospital in S city, Korea. Posttraumatic growth, health promoting behavior, length of treatment, difficulty in activities of daily living, and having a stoma were entered into the linear regression model. RESULTS: The strongest factor influencing the level of psychosocial adjustment was health-promoting behavior (beta=.33, p<.001), followed by difficulty in activities of daily living (beta=-.24, p=.001), posttraumatic growth (beta=.20, p=.004), and having a stoma (beta=-.19, p=.004). CONCLUSION: Nursing interventions for psychosocial adjustment in colorectal cancer survivors need to include the contents for posttraumatic growth, as well as health-promoting behavior, and activities of daily living. PMID- 30396193 TI - [Development and Analysis of System Dynamics Model for Predicting on the Effect of Patient Transfer Counseling with Nurses]. AB - PURPOSE: This study aimed to construct a management model for patient transfer in a multilevel healthcare system and to predict the effect of counseling with nurses on the patient transfer process. METHODS: Data were collected from the electronic medical records of 20,400 patients using the referral system in a tertiary hospital in Seoul from May 2015 to April 2017. The data were analyzed using system dynamics methodology. RESULTS: The rates of patients who were referred to a tertiary hospital, continued treatment, and were terminated treatment at a tertiary hospital were affected by the management fee and nursing staffing in a referral center that provided patient transfer counseling. Nursing staffing in a referral center had direct influence on the range of increase or decrease in the rates, whereas the management fee had direct influence on time. They were nonlinear relations that converged the value within a certain period. CONCLUSION: The management fee and nursing staffing in a referral center affect patient transfer counseling, and can improve the patient transfer process. Our findings suggest that nurses play an important role in ensuring smooth transitions between clinics and hospitals. PMID- 30396194 TI - [Impact of Parents' Problem Drinking on Suicidal Ideation of Their University Student Children: The Multiple Mediating Effects of Childhood Trauma, Experiential Avoidance and Depression]. AB - PURPOSE: The purpose of this study was to construct and test a hypothetical model about impact of parents' problem drinking on suicidal ideation of their children who are university students and the multiple mediating effects of childhood trauma, experiential avoidance, and depression based on stress-vulnerability model. METHODS: A purposive sample of 400 university students was recruited from three universities in provincial areas and the data were collected between October and November 2016. The collected data were then analyzed using SPSS 20.0 and AMOS 20.0 programs. For data analysis, descriptive statistics, factor analysis, and structural equation modeling were performed. Multiple mediating effects analysis using phantom variable and bootstrapping were implemented to verify the mediating effect of the research model. RESULTS: We found no significant direct effect on depression and suicidal ideation of parents' problem drinking, but multiple mediating effects of childhood trauma and experiential avoidance between parents' problem drinking and depression (B=.38, p=.001). The path from parents' problem drinking to suicidal ideation was significantly mediated by childhood trauma and depression (B=.02, p=.016) and by childhood trauma, experiential avoidance, and depression (B=.05, p=.011), but experiential avoidance did not have a significant direct effect on suicidal ideation (B=.02, p=.616). CONCLUSION: Based on the results of this study, it can be suggested that in order to decrease depression and prevent suicide of university students, considering of parents' problem drinking and childhood trauma, intervention methods that decreased chronic use of experiential avoidance and strengthen acceptance should be developed and made available to them. PMID- 30396195 TI - [Family Surrogates' Decision Regret and Psychological Stress about End-of-Life Cancer Treatments: Path Analysis]. AB - PURPOSE: This study aimed to understand the mechanisms of decision regret and stress of family surrogates' end-of-life decision making using an exploratory path model. In particular, the research identified the direct effects of perceptions of uncertainty and effective decisions on decision regret and stress, and examined the indirect effects of being informed, having clear values, and being supported for decision regret and the stress of end-of-life decision making through the mediating variables of perceptions of uncertainty and effective decisions. METHODS: Data were collected from 102 family surrogates who had participated in end-of-life decision making for patients with terminal cancer in a tertiary hospital. RESULTS: Perception of effective decisions was a significant direct predictor of decision regret, and uncertainty was a significant predictor of stress among the participants. Being informed, having clear values, and being supported had a significant indirect influence on decision regret through the perception of effective decisions among family surrogates. However, only having clear values had a significant indirect influence on stress through the perception of uncertainty. The model explained 63.0% of decision regret and 20.0% of stress among the participants and showed a good fit with the data, chi2=12.40 (df=8, p=.134), TLI=.97, and RMSEA=.07. CONCLUSION: Nurses can support family surrogates in end-oflife decision-making processes to decrease their decision regret by providing information about end-of-life care choices, clarifying personal values, and supporting the decision-making process, and to relieve their stress by facilitating the clarification of personal values. PMID- 30396196 TI - [A Structural Model on the Nursing Competencies of Nursing Simulation Learners]. AB - PURPOSE: The purpose of this study was to test a model of nursing competencies of nursing simulation learners. The conceptual model was based on the theory of Jeffries's simulaton theory. METHODS: Data collection was conducted in October 2017 for 310 students from two nursing universities in Kyungbuk area for 20 days. Data analysis methods were covariance structure analysis using SPSS 21.0 and AMOS 22.0 statistical programs. RESULTS: The hypothetical model was a good fit for the data. The model fit indices were comparative fit index=.97, normed fit index=.94, Tucker-Lewis Index=.97, root mean square error of approximation=.44, and standardized root mean square residual=.04. Teacher factors were directly related to simulation design characteristics, and it was confirmed that the curriculum, classroom operation and teaching method of the instructors were important factors. Learner factors were found to have a direct effect on nursing competence, self-confidence, and clinical performance that belong to nursing capacity. In particular, the results of this study indicate that the simulation design characteristics have a partial mediating effect on learner factors and clinical performance, and a complete mediating effect on learner factors and clinical judgment ability. CONCLUSION: In order to improve the learner's clinical performance and clinical judgment ability, it is necessary to conduct practical training through nursing simulation besides preparing the learner and the educator. PMID- 30396197 TI - [Shifting of Centricity: Qualitative Meta Synthetic Approach on Caring Experience of Family Members of Patients with Dementia]. AB - PURPOSE: This study aimed to synthesize the caring experiences of Korean family members of patients with dementia through a qualitative meta-synthesis method. METHODS: By searching through nine Korean and English databases, we compared 37 qualitative studies on caring experiences of family members of patients with dementia. The selected studies were synthesized through meta-synthesis, proposed by Sandelowski and Barroso (2007). RESULTS: The meta-synthesis elicited four themes: tough life due to care for patients, changes in relationships, adaptation to caregiver's roles, and new perspectives of life through personal growth. Caregivers were shocked when a sudden diagnosis of dementia was made prior to any preparation on their part. They were tied to their patients all the time and their mind and body got exhausted. Their relationship with patients began to change and they looked at them differently. They experienced conflicts with the other non-caring family members and were alienated from them. They were also socially isolated. However, by building their own care strategies and utilizing social resources, they gradually adapted to their caregiver roles. Finally, they experienced personal growth and acquired a new perspective toward life by accepting their roles and finding meaning in their lives. Shifting the caregiver's centricity from themselves to the patient was the process of becoming human beings who actively constructed their realities while giving meaning to their painful lives and interacting with the environment. CONCLUSION: The results of the study can be useful for nurses in understanding the experiences of caregivers of the patients with dementia and in providing them with practical interventions. PMID- 30396198 TI - [Structural Equation Model for Sleep Quality of Female Shift Work Nurses]. AB - PURPOSE: This study aimed to develop and test a structural model for sleep quality in female shift work nurses. The hypothetical model was constructed on the basis of Spielman's 3P model of insomnia and previous research related to the sleep quality of shift nurses. METHODS: This cross-sectional study used structural equation modeling and recruited 285 female shift work nurses from four general and university hospitals with over 300 beds located in C and J cities in Gyeongsangnamdo. Data were collected from September 27 to October 20, 2016, and then analyzed using descriptive statistics, Pearson's correlation, and structural equation modeling. The study used SPSS/Win 18.0 and AMOS 18.0 in processing the data. RESULTS: The final model showed good fit to the empirical data: chi2/df=2.19, SRMR=.07, RMSEA=.07, AGFI=.85, TLI=.91, GFI=.93, GFI=.89, NFI=.87. The factors that influenced sleep quality were sleep hygiene (beta=.32), perceived shift work status (beta=-.16), stress response (beta=.16), shift work experience (beta=.15), perceived health status (beta=-.14), and circadian rhythm (beta=-.13) explaining 36.0% of the variance. CONCLUSION: The model of sleep quality of the shift work nurses constructed in this study is recommended as a model to understand and predict the sleep quality of shift work nurses. The results suggest that strategies for improving the sleep quality of shift work nurses should focus on sleep hygiene, perceived health status, stress response, circadian rhythm, perceived shift work status, and shift work experience. PMID- 30396201 TI - Efficacy of Liposomal Bupivacaine Compared with Multimodal Periarticular Injections for Postoperative Pain Control following Total Knee Arthroplasty. AB - Single-dose long-acting periarticular anesthetics have been shown to be an effective method of postoperative analgesia in total knee arthroplasty (TKA). This study retrospectively compares the efficacy of multimodal periarticular injection consisting of a combination of ropivacaine, duramorph, epinephrine, and toradol (HC) with liposomal bupivacaine (LB) periarticular injection in TKA. This study was a retrospective matched comparative chart review of two cohorts of patients who underwent TKA within a single health care system and cared for by one provider. We compared 22 patients who were treated with LB intraoperatively (LBG) with 41 matched controls who were treated with HC periarticular injection (HCG). These cases were retrospectively reviewed at 0 to 6, 6 to 12, 12 to 24, 24 to 48, and 48 to 72 hours. We reviewed pain scores and opioid use per the preceding time period, total opioid use, length of stay (LOS), and wound complications between the two groups. The two groups showed no statistical difference in total opioids used. In both the 6- to 12-hour and 12- to 24-hour intervals, the LBG required significantly more opioids than the HCG, with p values of 0.0039 and 0.0061, respectively. Pain scores were not significantly different for any time period. We found no difference in LOS. The LBG tended to have lower doses of antiemetics than the HCG. No significant difference was found in postoperative pain scores and total opioid use between LB and multimodal periarticular intraoperative injections in TKA. Our data demonstrated decreased opioid consumption in the HC group compared with the LB group in both the 6- to 12-hour and 12- to 24-hour time intervals postoperatively. At our institution, LB costs US$314.99, whereas HC costs US$95. PMID- 30396200 TI - Nuestras Historias- Designing a novel digital story intervention through participatory methods to improve maternal and child health in the Peruvian Amazon. AB - BACKGROUND: In rural areas of the Loreto region within the Peruvian Amazon, maternal mortality rate is above the national average and the majority of women deliver at home without care from a trained health care provider. METHODS: To develop community-tailored videos that could be used for future interventions, we conducted Photovoice and digital storytelling workshops with community health workers (CHW) and mothers from 13 rural communities in the Parinari district. Through Photovoice we recognized local barriers to healthy pregnancies. Participants (n = 28) were trained in basic photography skills and ethics. They captured photos representing perceived pregnancy-related road-blocks and supports, and these photos identified central themes. Participants recorded personal stories and "storyboarded" to develop digital stories around these themes, and a Digital Story Curriculum called Nuestras Historias (Our Stories), was created. An acceptability survey of the digital stories was then conducted including 47 men (M) and 60 women (F). RESULTS: According to the PhotoVoice workshops, pregnancy-related problems included: lack of partner support, domestic violence, early pregnancies, difficulty attending prenatal appointments, and complications during pregnancy and delivery. Over 30 stories on these themes were recorded. Seven were selected based on clarity, thematic relevance, and narrative quality and were edited by a professional filmmaker. The acceptability survey showed that local participants found the digital stories novel (M = 89.4%, F = 83.3%), relatable (M = 89.4%, F = 93.2%), educational (M = 91.5%, F = 93.3%) and shareable (M = 100%, F = 100%). Over 90% of respondents rated the digital stories as "Excellent" or "Good", found the videos "Useful" and considered them "Relevant" to their communities. CONCLUSIONS: The digital stories address community-specific problems through narrative persuasion using local voices and photography. This combination had a high acceptability among the target population and can serve as a model for developing educational strategies in a community-tailored manner. This package of seven videos will be further evaluated through a cluster randomized trial. PMID- 30396199 TI - The Value of Older Donors' Klotho Level in Predicting Recipients' Short-Term Renal Function. AB - BACKGROUND The present organ shortage has led to increased use of kidneys from expanded-criteria donors, but the prognosis is disappointing due to poor graft quality. As a promising kidney protector, the Klotho gene's role in predicting short-term prognosis has not been assessed. MATERIAL AND METHODS We retrospectively analyzed data from 41 recipients and 25 donors. Multiple clinical variables were compared between different subgroups of donors or their corresponding recipients. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the distinguishing ability. Dynamic changes in serum Klotho, FGF-23, and urinary NGAL were assessed. RESULTS Serum Klotho level was significantly lower in donors age >=50 years (p=0.017), and there was a moderate negative correlation between serum Klotho expression and age (r=-0.464, p=0.019). Moreover, detection of Klotho mRNA and immunohistochemical analysis in kidneys revealed the same trend as in serum. Furthermore, for older donors (age >=50 years), serum Klotho level had a strong negative correlation with recipient eGFR 1 month post-transplant (r=-0.686, p=0.007), which was proved to be a good predictor for estimating graft function by ROC analysis. Additionally, during the post-transplant follow-up, serum Klotho levels increased slightly after a temporary decline, while serum FGF-23 and urinary NGAL decreased significantly and then stayed low thereafter. CONCLUSIONS Klotho level, which decreases with age, may be a potential predictor of short-term renal function, especially for grafts from older donors. PMID- 30396202 TI - Cementless versus Cemented Fixation in Total Knee Arthroplasty: Usage, Costs, and Complications during the Inpatient Period. AB - Cemented fixation has been the gold standard in total knee arthroplasty (TKA). However, with younger and more active patients requiring TKA, cementless (press fit) fixation has sparked renewed interest. Therefore, we investigated differences in (1) patient demographics, (2) inpatient costs, (3) short-term complications, and (4) discharge disposition between patients who underwent TKA with cemented and cementless fixation. The National Inpatient Sample database was queried for TKA patients with cement or cementless fixation between October 1 and December 31, 2015. Primary outcomes of interest included complications, length of stay (LOS), discharge disposition, and inpatient costs. Student's t-test and chi square analysis were used to assess continuous and categorical data, respectively. Multivariable analysis evaluated the effects of fixation type on the continuous and categorical dependent variables. Patients who received cementless fixation were more often younger (63.5 vs. 65.9 years), male (47.4 vs. 40.3%), Black (10.7 vs. 7.7%), from the Northeast census region (29.1 vs. 17.1%), and under private insurance (49.2 vs. 40.3%; p < 0.001 for all). Cementless fixation involved higher inpatient hospital costs (US$17,357 vs. US$16,888) and charges (US$67,366 vs. US$64,190; p < 0.001 for both), lower mean LOS (2.63 vs. 2.71 days; p < 0.001), and higher odds of being discharged to home (odds ratio = 1.99; p = 0.002). This study revisited the outcomes of TKA with cementless fixation and demonstrated higher inpatient charges and costs, shorter mean LOS, and higher odds of being discharged home. Future studies should investigate patient outcomes and complications past the inpatient period, evaluate long-term survivorship and failure rates, and implement a prospective study design. PMID- 30396203 TI - Improvement of the Gap Adjustment in Total Knee Arthroplasty Using the Posterior Condylar Pre-cut Technique. AB - To provide adequate gaps for knee extension and flexion during total knee arthroplasty, a femoral component placement decreases the extension gap because the posterior capsule tension increases against the protrusion of the posterior part of the femoral component. We thought that the influence of this component on the extension gap depends on the amount of posterior femoral bone resection and the thickness of the posterior femoral components. We hypothesized that less bone resection and a thinner posterior part of the femoral component might avoid these problems. To verify our hypothesis, a 4-mm posterior condylar pre-cut technique and temporary femoral components that were 8 and 4 mm thick in the distal and posterior parts, respectively, were made using the FINE Total Knee System (Teijin Nakashima Medical Co., Okayama, Japan). After bone resection, the pre-cut trial component was set to the femur, and the bone and component setting gaps were estimated. Seventy-one patients (98 knees) were investigated. The average bone gaps were 17.2/15.0 mm (extension/flexion, after pre-cut), 18.3/16.3 mm (after soft tissue release), and 8.7/12.2 mm (after pre-cut trial setting). After pre cut trial setting, the extension gap decreased significantly; the amount was 1.6 mm (0-4 mm) on average (p < 0.0001), whereas a change of 3 mm or more occurred in 15 knees (15.3%), which could be problematic. The degree of these changes after component setting could be reduced by using the posterior femoral condylar pre cut technique. However, the problem of component setting on the extension gap was not completely resolved. To precisely project the intraoperative gap to the ultimate postoperative gap, a posterior small protrusion device such as a pre-cut trial with the pre-cut technique would be necessary. PMID- 30396204 TI - The Treatment of Adult Osteochondritis Dissecans with Autologous Cartilage Implantation: A Systematic Review. AB - We sought to evaluate the effectiveness of autologous chondrocyte implantation (ACI) for the treatment of adult osteochondritis dissecans (OCD) lesions according to patient-reported outcomes, complication rates, and failure rates. A search of MEDLINE, Scopus, and Cochrane Library was performed to identify clinical studies (levels I-IV) reporting outcomes after ACI treatment for OCD in adult knees. Our inclusion criteria included the following: (1) published between January 2000 and April 2017, (2) stable and unstable OCD lesions of the knee, (3) use of ACI in at least one group, (4) subjects >=18 years old or skeletally mature, (5) inclusion of at least one patient-reported clinical outcome measure, and (6) written in English. A total of nine studies (179 patients), mean age of 27.6 years (range: 18-49 years), were included. There were 227 OCD lesions with an average size of 4.1 cm2 (range: 1.2-9.4 cm2). The average follow-up was 61.3 months (range: 6.5-120 months). In general, there was significant improvement in symptoms, but better results occurred among active male patients with smaller lesions as well as younger patients. Statistically significant improvement in patient-reported outcomes was reported in all studies. There were 23 complications reported (15.6%), including 12 failures (8.2%). Significant improvement in clinical outcome measures demonstrates clinical efficacy of autologous cartilage therapies for the treatment of OCD in adult patients. Better outcomes are often observed with males, active patients, smaller lesion sizes, and younger age at the time of surgery. PMID- 30396205 TI - Histological Findings in Infected and Noninfected Second Stage Revision Knee Arthroplasties. AB - Tissues from a periprosthetic joint infection (PJI) of the knee contain a heavy neutrophil polymorph (NP) infiltrate (> 5 NPs per high-powered field [HPF] by Musculoskeletal Infection Society [MSIS] criteria). PJI of the knee can be treated by a two-stage procedure and our aim was to determine whether the MSIS histological criteria for PJI diagnosis are valid in a second-stage revision knee arthroplasty. Periprosthetic tissues from 45 second-stage revision knee cases were analyzed histologically by hematoxylin-eosin and chloroacetate esterase (CAE) staining for the identification of NPs. The number of NPs was determined semiquantitatively and results correlated with the microbiological and clinical findings. In 9 of the 45 cases, an organism was cultured in two or more samples, meeting MSIS microbiological criteria for a definite diagnosis of PJI; histologically, seven of these cases contained > 5 per NPs per HPF on average, with the remaining two cases containing 1 NP and 2 NPs per HPF. In noninfected second-stage revisions, NPs were not seen in 30 cases with 6 cases showing less than 1 NP per HPF on average. The sensitivity, specificity, accuracy, and positive and negative predictive values of MSIS histological criteria (> 5 NPs per HPF) to diagnose PJI were 78%, 100%, 96%, 100%, and 95%, respectively. MSIS histological criteria for the diagnosis of PJI are valid for most but not all infected second-stage revision knee arthroplasties. Correlation of histology with clinical, microbiology and other laboratory findings is required to establish a diagnosis of PJI in second-stage revision knee arthroplasties. PMID- 30396206 TI - Cooled Radio Frequency Ablation for the Treatment of Osteoarthritis-Related Knee Pain: Evidence, Indications, and Outcomes. AB - Knee osteoarthritis (OA) is a common condition associated with pain and physical impairment in a large segment of the population. The traditional treatment algorithm progresses from conservative modalities to nonsurgical options to surgical intervention. Surgical intervention often provides reliable pain relief but not all patients are surgical candidates and there are some patients who prefer not to have surgery. Cooled radio frequency ablation (C-RFA) is a treatment with the potential to provide pain relief for patients who no longer benefit from noninvasive modalities and who desire an alternative to surgery. The objective of this review article is to provide the rationale, available evidence, indications, and outcomes associated with C-RFA for the treatment of chronic knee OA. A total of eight reports that use C-RFA in the treatment of chronic knee pain were identified and analyzed. There were two prospective trials, one retrospective cohort study, and five case reports or case series. C-RFA is an emerging procedure with encouraging early results; however, additional long-term prospective clinical trials are necessary to further characterize how C-RFA can best be used to treat chronic knee pain. PMID- 30396208 TI - Giant Prolactinoma in Men: Clinical Features and Therapeutic Outcomes. AB - The aim of the study was to evaluate the clinical features and long-term therapeutic outcome of giant prolactinoma (gPRLoma) in men and to compare them with those of a group of male patients with non-gPRL macroprolactinomas (non gPRLomas). A retrospective and multicenter study of gPRLomas in men diagnosed in a 20-year period was performed. Clinical data and treatment outcome were registered. The diagnosis of gPRLoma was established when the maximal tumor diameter was >=40 mm or the tumor had >=20 mm of suprasellar extension associated to hyperprolactinemia (PRL>1000 ng/ml). Non-gPRLoma was considered when tumor diameter was >= 10 mm and<40 mm associated to hyperprolactinemia (PRL>=200 ng/ml). Twenty-three patients with gPRLoma (age 38.3+/-13.5 years) followed for at least 3 months (follow-up 87.1+/-60.5 months, range 3-211 months) were evaluated. A group of 42 patients with non-gPRLoma (age 42+/-16.6 years; NS; follow-up 89+/-65.9 months, range 3-222 months; NS) served as a control group. More than half (56.5%) of the gPRLoma patients were younger than 40 years at diagnosis. Visual disturbances were significantly more common in gPRLoma than in non-gPRLoma patients (65.2 vs. 25.6%; p=0.004). Prevalence of hypopituitarism was similar in both groups of patients (73.9% vs. 80.9%; gPRLoma vs non-gPRLoma; NS). Serum PRL concentrations were significantly higher in gPRLoma than in non-gPRLoma patients [median (IR), 3978 ng/ml (1179-9012) vs. 907 ng/ml (428-3119); p<0.001]. Maximum tumor diameter in gPRLomas was 4.8+/-0.8 cm and 2.4+/-0.7 cm in non gPRLoma (p<0.001). All patients were treated with dopamine agonists (DA). Twelve (52.2%) gPRLoma patients and 32 (73.8%) non-gPRLoma patients were treated with DA as monotherapy (p=0.045). Surgery was used in 12 (52.2%) gPRLoma patients and in 12 (28.6%) non-gPRLoma patients (p=0.054). Lastly, radiotherapy was used in 5 (21.7%) gPRLoma patients and in 6 (14.2%) non-gPRLoma patients (NS). At last visit, PRL was similar in both groups of patients [16 ng/ml (4-30) vs. 11 ng/ml (4-25); gPRLomas vs. non-gPRLomas; ns] and tumor size decreased significantly (p<0.001) in both groups of patients. Clinical cure (maintained normoprolactinemia without therapy for>1 year and no radiological evidence of pituitary tumor) was achieved in 2 (8.7%) gPRLoma patients and in 2 (4.8%) non gPRLoma patients (NS). gPRLomas in men are usually diagnosed at a mean age of 40 years, an age similar to that of non-gPRLomas. The only clinical difference with non-gPRLomas is their greater prevalence of visual disturbances. The therapeutic approaches and tumor outcomes were similar to those obtained in patients with non gPRLomas. Complete cure in gPRLoma is rare, but similar to that achieved in non gPRLomas, reached in less than 10% of patients. PMID- 30396207 TI - The Effects of Melatonin Supplementation on Glycemic Control: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - This systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to clarify the effect of melatonin supplementation on glycemic control. Databases including PubMed, MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials were searched until July 30th, 2018. Two reviewers independently assessed study eligibility, extracted data, and evaluated the risk of bias for included trials. Heterogeneity among included studies was assessed using Cochran's Q test and I-square (I2) statistic. Data were pooled using random-effect models and standardized mean difference (MD) was considered as the overall effect size. Twelve trials out of 292 selected reports were identified eligible to be included in current meta-analysis. The pooled findings indicated that melatonin supplementation significantly reduced fasting glucose (SMD=-6.34; 95% CI, -12.28, -0.40; p=0.04; I2: 65.0) and increased the quantitative insulin sensitivity check index (QUICKI) (SMD=0.01; 95% CI, 0.00, 0.02; p=0.01; I2: 0.0). However, melatonin administration did not significantly influence insulin levels (SMD=-1.03; 95% CI, -3.82, 1.77; p=0.47; I2: 0.53), homeostasis model assessment of insulin resistance (HOMA-IR) (SMD=-0.34; 95% CI, 1.25, 0.58; p=0.37; I2: 0.37) or HbA1c levels (SMD=-0.22; 95% CI, -0.47, 0.03; p=0.08; I2: 0.0). In summary, the current meta-analysis showed a promising effect of melatonin supplementation on glycemic control through reducing fasting glucose and increasing QUICKI, yet additional prospective studies are recommended, using higher supplementation doses and longer intervention period, to confirm the impact of melatonin on insulin levels, HOMA-IR and HbA1c. PMID- 30396209 TI - Normocalcemic Primary Hyperparathyroidism: A Comparison with the Hypercalcemic Form in a Tertiary Referral Population. AB - Normocalcemic primary hyperparathyroidism (NPHPT) is a formally recognized variant of primary hyperparathyroidism (PHPT), characterized by normal total and ionized serum calcium concentrations and elevated parathyroid hormone (PTH) levels, in the absence of secondary causes for hyperparathyroidism. NPHPT has been studied previously, but data are limited and confounded. We aimed to compare the clinical and biochemical data of normocalcemic and hypercalcemic subjects in a hospital-based population.We retrospectively analysed the medical records of 131 subjects diagnosed with PHPT at the university hospital Brussels (UZ Brussel) between January 1st 2007 and December 31st 2016, including 25 normocalcemic and 106 hypercalcemic subjects.The mean values of age, BMI, sex, serum 25-OH vitamin D levels and urinary phosphate excretion were comparable between both groups. Subjects diagnosed with NPHPT had significantly lower plasma PTH levels, lower urinary calcium excretion and lower serum creatinine levels compared to the hypercalcemic subjects with PHPT. Corresponding eGFR values were higher in the normocalcemic group. Normocalcemic subjects (NPHPT) presented with a high prevalence of nephrolithiasis (36%), fragility fractures (12%) and osteoporosis (25%). Clinical manifestations and BMD measurements revealed no statistically significant differences between both groups.Our data show a relative prevalence of 19% NPHPT in PHPT. NPHPT may present the earliest form of PHPT with an extension in time, but is not an indolent disease state. Normocalcemic subjects should be managed as hypercalcemic subjects with PHPT. Further research regarding the pathophysiology and natural course of NPHPT is required. PMID- 30396210 TI - Association Between Plasma Concentration of Klotho Protein, Osteocalcin, Leptin, Adiponectin, and Bone Mineral Density in Patients with Chronic Kidney Disease. AB - Patients with early-stage chronic kidney disease (CKD) are susceptible to changes in metabolic processes. Partial loss of kidney function leads to homoeostatic disturbances in bone and fatty tissue. The aim of this study was to investigate the association between plasma concentrations of Klotho protein, FGF23, leptin, adiponectin, osteocalcin, and bone mineral density (BMD) in patients with CKD in the pre-dialysis period. The study involved 52 patients with CKD and 23 patients with no kidney disease. In both groups, BMD, body mass index and serum or plasma concentrations of lipids, glucose, creatinine, calcium, phosphorus, parathormone, leptin, adiponectin, osteocalcin, Klotho, and FGF23 were measured. The group with CKD had statistically significant higher concentrations of leptin (p<0.001), parathormone (p<0.001), and osteocalcin (p<0.001) in comparison with the control group. Patients with CKD also had statistically significant lower BMD in the femoral neck in comparison with the control group. Osteocalcin correlated negatively with BMD. The results of our study suggest that elevated osteocalcin is the most sensitive marker of decreased bone mass in patients with CKD. Osteocalcin correlated negatively with BMD and GFR. The loss of bone mass in CKD patients was greatest in the femoral neck. PMID- 30396211 TI - Levothyroxine Therapy Achieves Physiological FT3/FT4 Ratios at Higher than Normal TSH Levels: A Novel Justification for T3 Supplementation? AB - In euthyroidism, as thyroid Stimulating hormone (TSH) levels increase, the free triiodothyronine (FT3) to free thyroxine (FT4) ratio increases. The aim of this study was to assess if beyond the euthyroid range of TSH levels FT3/FT4 ratio continues to increase and if levothyroxine treatment reduces this ratio, possibly through TSH suppression. This cross sectional retrospective study included a total of 77 832 patients [age 22.76+/-15.17 years (4 days to 112 years)] evaluated and treated in community clinics between January 2009 and September 2013. Blood samples drawn in community clinics for which TSH, FT4, FT3, age, and gender were available were included. Tests with TSH below 0.5 IU/l were excluded as were samples taken during pregnancy. The FT3/FT4 ratio continued to increase significantly even with TSH above 50 mIU/l (p for trend<0.001) with an increase of more than 50% over the entire TSH range. With increasing age and female gender, the phenomenon was less prominent (p<0.001). Levothyroxine treated patients had significantly lower FT3/FT4 ratios in comparison to untreated patients up to TSH levels of 5.0 mIU/l. In conclusion, increasing TSH increases FT3/FT4 ratio even with severe hypothyroidism, less so with aging. With levothyroxine therapy, a ratio similar to untreated patients is achieved at TSH of above 5.0 mIU/l. Since T3 suppresses TSH better than T4, administration of T3 would likely normalize the FT3/FT4 ratio at a lower, ostensibly more physiological, TSH level. This could be seen as a rationale for add-on T3 therapy. PMID- 30396212 TI - Impact of Brain Fatty Acid Signaling on Peripheral Insulin Action in Mice. AB - AIMS AND METHODS: Glucose homeostasis and energy balance are under control by peripheral and brain processes. Especially insulin signaling in the brain seems to impact whole body glucose homeostasis and interacts with fatty acid signaling. In humans circulating saturated fatty acids are negatively associated with brain insulin action while animal studies suggest both positive and negative interactions of fatty acids and insulin brain action. This apparent discrepancy might reflect a difference between acute and chronic fatty acid signaling. To address this question we investigated the acute effect of an intracerebroventricular palmitic acid administration on peripheral glucose homeostasis. We developed and implemented a method for simultaneous monitoring of brain activity and peripheral insulin action in freely moving mice by combining radiotelemetry electrocorticography (ECoG) and euglycemic-hyperinsulinemic clamps. This method allowed gaining insight in the early kinetics of brain fatty acid signaling and its contemporaneous effect on liver function in vivo, which, to our knowledge, has not been assessed so far in mice. RESULTS: Insulin-induced brain activity in the theta and beta band was decreased by acute intracerebroventricular application of palmitic acid. Peripherally it amplified insulin action as demonstrated by a significant inhibition of endogenous glucose production and increased glucose infusion rate. Moreover, our results further revealed that the brain effect of peripheral insulin is modulated by palmitic acid load in the brain. CONCLUSION: These findings suggest that insulin action is amplified in the periphery and attenuated in the brain by acute palmitic acid application. Thus, our results indicate that acute palmitic acid signaling in the brain may be different from chronic effects. PMID- 30396214 TI - Sports Medicine International Open -recently published. PMID- 30396213 TI - Associations of Bone Mineral Density and Bone Metabolism Indices with Urine Albumin to Creatinine Ratio in Chinese Patients with Type 2 Diabetes. AB - OBJECTIVE: To identify correlations of bone mineral density (BMD) and bone metabolism indices with the urine albumin to creatinine ratio (ACR) as an indicator of nephropathy in Chinese patients with type 2 diabetes (T2D). METHODS: In this retrospective analysis, 297 patients with T2D were divided into 3 groups according to the urine ACR. Patients' data were analyzed to identify associations of general conditions, blood glucose level, lipid levels, and uric acid level with BMD and bone metabolism indices. RESULTS: BMD at every location tested (femoral neck, trochanter, inside hip, Ward's triangle, total hip, and lumbar vertebrae) was negatively correlated with the urine ACR (all p<0.05). Osteocalcin, beta-C-terminal telopeptide (beta-CTX), and procollagen type 1 N- peptide (P1NP) were positively correlated with urine ACR (all p<0.05). Finally, 25-hydroxyvitamin D [25(OH)D] was negatively correlated with urine ACR (p<0.05). Multiple regression analysis with adjustment for age, body mass index, disease duration, and other clinical measurements revealed no significant correlation between urine ACR and BMD measurements or beta-CTX (p>0.05). However, significant correlations remained between urine ACR and osteocalcin, P1NP, and 25(OH)D (p<0.05). The same results were obtained for postmenopausal women specifically, with the exception of a significant correlation between the ACR and beta-CTX (p<0.05). CONCLUSION: In the early stage of diabetic nephropathy, BMD changes and bone transformation acceleration may occur, and the acceleration of bone transformation may occur before the change in BMD. Therefore, it is important to monitor bone metabolism indices in the early stage of diabetic nephropathy in T2D patients. PMID- 30396215 TI - Increased Cell-Free Fetal DNA Fraction in the First Trimester: A Sign of Abnormally Invasive Placenta? PMID- 30396216 TI - Ultrasonic Adaptive Sound Speed Estimation for the Diagnosis and Quantification of Hepatic Steatosis: A Pilot Study. AB - PURPOSE: To evaluate the ability of a new ultrasound (US) method based on sound speed estimation (SSE) with respect to the detection, quantification, and grading of hepatic steatosis using magnetic resonance (MR) proton density fat fraction (PDFF) as the reference standard and to calculate one US fat index based on the patient's SSE. MATERIALS AND METHODS: This study received local IRB approval. Written informed consent was obtained from patients. We consecutively included N = 50 patients as the training cohort and a further N = 50 as the validation cohort who underwent both SSE and abdominal MR. Hepatic steatosis was classified according to MR-PDFF cutoffs as: S0 <= 6.5 %, S1 6.5 to 16.5 %, S2 16.5 to 22 %, S3 >= 22 %. Receiver operating curve analysis was performed to evaluate the diagnostic performance of SSE in the diagnosis of steatosis (S1-S3). Based on the optimal data fit derived from our study, we proposed a correspondence between the MR-PDFF and a US fat index. Coefficient of determination R2 was used to evaluate fit quality and was considered robust when R2 > 0.6. RESULTS: The training and validation cohorts presented mean SSE values of 1.570 +/- 0.026 and 1.568 +/- 0.023 mm/us for S0 and 1.521 +/- 0.031 and 1.514 +/- 0.019 mm/us for S1-S3 (p < 0.01) patients, respectively. An SSE threshold of <= 1.537 mm/us had a sensitivity of 80 % and a specificity of 85.7 % in the diagnosis of steatosis (S1 S3) in the training cohort. Robust correspondence between MR-PDFF and the US fat index was found both for the training (R2 = 0.73) and the validation cohort (R2 = 0.76). CONCLUSION: SSE can be used to detect, quantify and grade liver steatosis and to calculate a US fat index. PMID- 30396217 TI - Fetal Doppler Parameters at Term in Pregnancies Affected by Gestational Diabetes: Role in the Prediction of Perinatal Outcomes. AB - OBJECTIVE: The timing of delivery for women affected by gestational diabetes (GDM) is still controversial. Good clinical practice often suggests offering induction of labor at term in order to reduce the complications associated with this condition, while recent evidence supports expectant management. Fetal Doppler parameters represent a validated tool for testing fetal well-being at term and can select pregnancies that need increased surveillance. The aim of the present study was to evaluate the role of fetal Doppler parameters at term for the prediction of pregnancy outcomes in patients affected by GDM. METHODS: Prospective cohort study in a single center. Evaluation of umbilical artery (UA) PI, middle cerebral artery (MCA) PI, cerebroplacental ratio (CPR) and umbilical to-cerebral ratio (UCR) at > 37 weeks of gestation in singleton, morphologically normal pregnancies affected by GDM, was performed in order to estimate the association between ultrasound measurements at term and perinatal outcome. Regression linear analysis was used to estimate the association between fetal Doppler parameters and neonatal pH, neonatal Apgar score, neonatal weight and a composite adverse outcome. The receiver operating characteristic (ROC) curve was used to estimate the possible predictive value of the above association. RESULTS: Our results on 130 women showed MCA PI to be the best predictor of perinatal outcomes in terms of low Apgar score at the 1st minute (p = 0.00), pH (p = 0.02) and composite adverse outcome (p = 0.05). UCR showed a significant correlation with neonatal pH (p = 0.02). No significant correlations for UA PI and CPR MoMs have been demonstrated in our population. However, the small sample size is a limitation of the study. CONCLUSION: Evaluation of MCA Doppler and eventually UCR at term can be a useful tool to discriminate pregnancies affected by GDM that can benefit from IOL before 41 weeks in order to reduce complications related to this condition. PMID- 30396218 TI - Can Sonographic Fetal Biometry Predict Adverse Perinatal Outcome? AB - OBJECTIVE: To evaluate the association of sonographic fetal biometry (sonographic head circumference (soHC), sonographic abdominal circumference (soAC), estimated fetal weight (EFW)) with mode of delivery and adverse perinatal outcome. METHODS: Singleton pregnancies with a gestational age >= 37 weeks and an ultrasound examination with complete biometric parameters within 7 days before delivery were retrospectively included. The association between soHC, soAC, EFW and fetal (5-min Apgar < 7, pH < 7.1, neonatal intensive care unit (NICU) admission, shoulder dystocia (ShD)) and maternal (obstetric intervention (OI): caesarean or vaginal operative delivery, obstetric anal sphincter injury syndrome (OASIS), postpartum hemorrhage (pph)) adverse outcomes were analyzed using univariate and multivariate logistic regression analyses. RESULTS: 12 396 women were included and 3479 (28.07 %) needed an OI. Multivariate analyses demonstrated significant contributions for the prediction of OI by soHC and soAC, whereas EFW did not reach significance. The highest OR was shown for soHC (1087, p < 0.001). ShD occurred in 73 (0.59 %) of the deliveries. Multivariate analyses showed that significant contributions for the prediction of ShD were provided only by soAC (OR 1460, p = 0.007). For the other maternal and neonatal adverse outcome parameters, no significant association with the biometric measurements could be demonstrated in the multivariate analyses. The overall detection rates for the prediction of adverse perinatal outcome by the different biometric parameters and EFW were poor. CONCLUSION: Obstetric management decisions should not be based solely on measurements of biometric parameters or EFW. PMID- 30396219 TI - BRAF V600E and Retinoic Acid in Radioiodine-Refractory Papillary Thyroid Cancer. AB - Radioiodine refractoriness in differentiated thyroid cancer remains an unsolved therapeutic problem. Response to retinoids might depend on specific genetic markers. In this retrospective analysis, associations between BRAF V600E and clinical outcomes after redifferentiation with retinoic acid (RA) and radioiodine therapy (RIT) were investigated. Thirteen patients with radioiodine-refractory (RAI-R) papillary thyroid cancer (PTC) were treated with 13-cis-RA followed by iodine-131 treatment at the Department of Endocrinology, Heidelberg University Hospital, Heidelberg, Germany. DNA sequencing was performed in formalin-fixed paraffin-embedded tissue. Clinical outcome parameters were tumor size, thyroglobulin, and radioiodine uptake in correlation to mutational status. Differences of each parameter were compared before and after RA/RIT. Initial response showed no difference in patients with BRAF V600E compared to patients with wild type. However, after a median follow-up of 2 and a half years, 2 out of 3 patients with BRAF V600E showed response compared to 5 out of 9 with wild type under consideration of all 3 parameters. In this small cohort, more RAI-R PTC patients with BRAF V600E receiving redifferentiation therapy showed response. Verification in a larger study population analyzing mutational status in patients with RAI-R PTC might be helpful to identify patients where redifferentiation therapy might lead to an improved outcome. PMID- 30396220 TI - Central Tolerance Mechanisms to TSHR in Graves' Disease: Contributions to Understand the Genetic Association. AB - In the last 3 years, the association of thyrotropin receptor gene (TSHR) variations to Graves' disease (GD) has been confirmed. It is now well established that a 30 Kb region of intron 1 of the TSHR gene is linked to GD predisposition. Elucidating the mechanism(s) by which these polymorphisms confer susceptibility is difficult but would constitute an important advance in endocrine autoimmunity in general. Two hypotheses, both postulating TSHR gene regulatory mechanisms, are discussed. One postulates differential level of expression in the thymus, involving central tolerance. The other postulates a shift in TSHR differential splicing leading to the production of soluble proteins that will have easy access to antigen presenting cells, so it is focused in peripheral tolerance. A combination of the 2 hypothesis is feasible, especially under the light of recent evidence that have identified epigenetic factors acting on TSHR intron 1. PMID- 30396221 TI - Adherence to Consensus Guidelines for the Management of Labor Arrest Disorders in a Single Academic Tertiary Care Medical Center. AB - OBJECTIVE: To evaluate the degree of adherence to the new the American College of Obstetricians and Gynecologists/Society for Maternal-Fetal Medicine guidelines in labor arrest management. STUDY DESIGN: A retrospective study of term, live, singleton deliveries with intrapartum primary cesarean delivery solely for failed induction of labor or labor arrest. Adherence was defined according to the Safe Prevention of the Primary Cesarean Delivery 2014 criteria. We evaluated adherence and compared maternal and perinatal outcomes, delivery time frame, and billing provider. Multivariable Poisson regression models with robust error variance were used to calculate adjusted relative risk (aRR) and 95% confidence interval (CI). RESULTS: Two-hundred six deliveries met the inclusion criteria; 73% were deemed not adherent to the guidelines. The majority of cases were under the care of nonacademic private practice OB/GYN physicians. The adherence rate was higher in the active phase of labor (45%) than in second stage (17%) and latent phase (14%). There were no differences in perinatal outcomes between the two groups. The adherence to guidelines was higher among academic OB/GYN physicians (aRR, 2.24, 95% CI, 1.49-3.36) and during the weekday-night shift (aRR, 1.81, 95% CI, 1.10-2.98). CONCLUSION: Despite recent guidelines aimed to reduce the primary cesarean delivery rate, most cesarean deliveries performed for labor arrest disorders were not adherent to the guidelines. PMID- 30396222 TI - The Association between Solo versus Group Obstetrical Practice Model and Delivery Outcomes. AB - OBJECTIVE: To determine if women under the care of obstetricians in solo practice have different delivery outcomes from women in a group practice. STUDY DESIGN: This is a retrospective cohort of live, term, singleton, vertex (LTSV) deliveries at one hospital from 2011 to 2015. We compared outcomes between women whose obstetrician was in solo practice with women in a group practice model. RESULTS: There were 18,214 LTSV deliveries by private obstetricians. Solo obstetricians were more likely to deliver at night (41.0 vs. 37.5%, p = 0.002) and less likely to induce labor (22.6 vs. 30.6%, p < 0.001). Solo obstetricians had a significantly higher rate of cesarean delivery (35.7 vs. 27.2%, adjusted odds ratio, aOR: 1.53, 95% confidence interval, CI [1.32, 1.78]), but also had a significantly lower rate of shoulder dystocia (0.4 vs. 1.4, aOR: 0.42, 95% CI [0.19, 0.89]), third or fourth degree lacerations (1.6 vs. 2.4%, aOR: 0.56, 95% CI [0.35, 0.914]), and neonatal intensive care unit admission rates (3.2 vs. 6.2%, aOR: 0.57, 95% CI [0.42, 0.77]). CONCLUSION: In a large, tertiary care hospital, solo obstetricians have similar neonatal outcomes as group obstetricians. Their higher cesarean delivery rate is balanced by fewer shoulder dystocias and third/fourth degree lacerations, indicating a more conservative approach to labor management. Patient outcomes should not be a reason to discourage a solo practice model. PMID- 30396223 TI - Normal Range for Maternal Lactic Acid during Pregnancy and Labor: A Systematic Review and Meta-Analysis of Observational Studies. AB - OBJECTIVE: This article systematically reviews the literature to establish the normal range of lactic acid in healthy pregnant women. STUDY DESIGN: Ovid MEDLINE, Embase.com, and Clinicaltrials.gov were searched to identify studies that reported maternal lactic acid in healthy pregnant women. Pooled aggregate means and two standard deviations for each time period were computed using the inverse variance weighting technique. Analyses were performed separately for 1st, 2nd, and 3rd trimesters, scheduled cesarean delivery, early labor, active labor, 2nd stage of labor, and delivery. RESULTS: Overall, 22 studies met the inclusion criteria. There were 1,193 patients, and 2,008 observations identified. All time periods had maternal venous lactic acid aggregate means and two-standard deviation ranges less than 4 mmol/L. Outside of labor, all ranges were less than 2 mmol/L. All labor periods had a range higher than 2 mmol/L. While the pooled ranges were less than 4 mmol/L, many individual studies reported ranges > 4 mmol/L during labor. CONCLUSION: This meta-analysis suggests that venous lactic acid levels can be used as a screening tool in pregnant women just as the test would be used in nonpregnant women, except that elevations may be seen during labor, especially later in labor when there is maximal skeletal muscle contraction. PMID- 30396224 TI - Pregnancy Outcomes of Exacerbated Chronic Hypertension Compared with Superimposed Preeclampsia. AB - OBJECTIVE: Compare outcomes in women with chronic hypertension who remain normotensive, experience exacerbation, or meet laboratory criteria for superimposed preeclampsia. STUDY DESIGN: This is a retrospective cohort study of singleton pregnancies with chronic hypertension from 2000 to 2014. Delivery admission records were used to categorize women into three groups: stable chronic hypertension, exacerbated hypertension, and superimposed preeclampsia. The primary outcomes were a neonatal composite of death, respiratory support, umbilical arterial pH < 7, 5-minute Apgar <=3, and seizures, in addition to maternal severe hypertension requiring intravenous (IV) antihypertensives. RESULTS: In total, 270 women (31.3%) had stable hypertension, 429 (49.8%) had exacerbated hypertension, and 163 (18.9%) had superimposed preeclampsia. Neonatal composite (10.7 vs. 11.2 vs. 21.5%; p < 0.01) and preterm birth <35 weeks (8.8 vs. 18.3 vs. 35.7%; p < 0.01) were highest in the superimposed preeclampsia group. Severe hypertension requiring the use of IV antihypertensives increased across groups (0 vs. 15.6 vs. 23.3% p < 0.01). With the exception of severe hypertension requiring IV antihypertensive use, outcomes in women with exacerbations were unchanged compared with those with stable hypertension. CONCLUSION: Superimposed preeclampsia is associated with an increased risk of adverse neonatal outcomes compared with stable chronic hypertension, whereas exacerbation of chronic hypertension is not. PMID- 30396225 TI - Maternal Height and Risk of Preeclampsia among Race/Ethnic Groups. AB - OBJECTIVE: Shorter maternal height has been associated with preeclampsia risk in several populations. It has been less evident whether an independent contribution to the risk exists from maternal height consistently across different races/ethnicities. We investigated associations between maternal height and risk of preeclampsia for different races/ethnicities. STUDY DESIGN: California singleton live births from 2007 to 2011 were analyzed. Logistic regression was used to estimate adjusted odds ratios for the association between height and preeclampsia after stratification by race/ethnicity. To determine the contribution of height that is as independent of body composition as possible, we performed one analysis adjusted for body mass index (BMI) and the other for weight. Additional analyses were performed stratified by parity, and the presence of preexisting/gestational diabetes and autoimmune conditions. RESULTS: Among 2,138,012 deliveries, 3.1% preeclampsia/eclampsia cases were observed. The analysis, adjusted for prepregnancy weight, revealed an inverse relation between maternal height and risk of mild and severe preeclampsia/eclampsia. When the analysis was adjusted for BMI, an inverse relation between maternal height was observed for severe preeclampsia/eclampsia. These associations were observed for each race/ethnicity. CONCLUSION: Using a large and diverse cohort, we demonstrated that shorter height, irrespective of prepregnancy weight or BMI, is associated with an increased risk of severe preeclampsia/eclampsia across different races/ethnicities. PMID- 30396226 TI - The Impact of Aspirin on Ultrasound Markers of Uteroplacental Flow in Low-Risk Pregnancy: Secondary Analysis of a Multicenter RCT. AB - OBJECTIVE: This article evaluates the effect of low-dose aspirin on uterine artery (UtA) Doppler, placental volume, and vascularization flow indices in low risk pregnancy. STUDY DESIGN: In this secondary analysis of the TEST randomized controlled trial, low-risk nulliparous women were originally randomized at 11 weeks to: (1) routine aspirin 75 mg; (2) no aspirin; and (3) aspirin based upon the preeclampsia Fetal Medicine Foundation screening test. UtA Doppler, three dimensional (3D) placental volume, and vascularization flow indices were assessed prior to and 6 weeks postaspirin commencement. RESULTS: A total of 546 women were included (aspirin n = 192, no aspirin n = 354). Between first and second trimesters, aspirin use was not associated with a change in UtA Doppler, placental volume, or vascular flow indices. There was no significant difference in the change in UtA Doppler pulsatility index (PI) Z-scores or notching (PI Z score -0.2 vs. -0.2, p = 0.17), nor was there a significant change in placental volume Z-score and vascular flow indices (volume Z-score change: 0.74 vs. 0.62, p = 0.34). CONCLUSION: Low-dose aspirin commenced at 11 weeks in low-risk women does not appear to improve uterine and placental perfusion or placental volume. Any perceived effect on uteroplacental vasculature is not reflected in changes in placental volume nor uteroplacental flow as assessed by two-dimensional and 3D ultrasound. PMID- 30396227 TI - Does the RAM Cannula Provide Continuous Positive Airway Pressure as Effectively as the Hudson Prongs in Preterm Neonates? AB - OBJECTIVE: To compare the level of continuous positive airway pressure (CPAP) delivered by the RAM cannula system (Neotech, Valencia, CA) with that delivered by a traditional CPAP nasal delivery interface (Hudson prongs; Hudson-RCI, Temecula, CA) in preterm infants with respiratory distress. METHODS: This was a crossover intervention study in a convenience sample of preterm infants with respiratory distress requiring treatment with CPAP. We measured the mean intraoral (pharyngeal) pressure, which approximates the applied CPAP level, using both the RAM cannula and Hudson prongs. The primary outcome was a comparison of the differences between the set CPAP levels and the measured intraoral pressures of both delivery systems. RESULTS: We analyzed data from 12 preterm infants with mean (standard deviation) birth weight of 1,225 (405) g and gestational age of 28.4 (2.1) weeks at a median postnatal age of 10 days. The mean difference (95% confidence interval) between the set CPAP level and measured intraoral pressure was -2.45 cm H2O (-3.36, -1.55) with the RAM cannula and +0.40 cm H2O (-0.30, 1.12) with Hudson prongs, p = 0.0002. CONCLUSION: For given set CPAP pressure level in preterm infants, the RAM cannula system consistently delivers lower pharyngeal pressure (effective CPAP) levels than Hudson prongs. PMID- 30396228 TI - Racial and Ethnic Disparities in Maternal Outcomes and the Disadvantage of Peripartum Black Women: A Multistate Analysis, 2007-2014. AB - OBJECTIVE: Racial and ethnic disparities in obstetric care and delivery outcomes have shown that black women experience high rates of pregnancy-related mortality and morbidity, along with high rates of cesarean delivery, compared with other racial and ethnic groups. We aimed to quantify these disparities and test the effects of race/ethnicity in stratified statistical models by insurance payer and socioeconomic status, adjusting for comorbidities specific to an obstetric population. STUDY DESIGN: We analyzed maternal outcomes in a sample of 6,872,588 delivery records from California, Florida, Kentucky, Maryland, and New York from 2007 to 2014 from the State Inpatient Databases, Healthcare Cost and Utilization Project. We compared present-on-admission characteristics of parturients by race/ethnicity, and estimated logistic regression and generalized linear models to assess outcomes of in-hospital mortality, cesarean delivery, and length of stay. RESULTS: Compared with white women, black women were more likely to die in hospital (odds ratio [OR]: 1.90, 95% confidence interval [CI]: 1.47-2.45) and have a longer average length of stay (incidence rate ratio: 1.10, 95% CI: 1.09 1.10). Black women also were more likely to have a cesarean delivery (OR: 1.12, 95% CI 1.12-1.13) than white women. These results largely held in stratified analyses. CONCLUSION: In most insurance payers and socioeconomic strata, race/ethnicity alone is a factor that predicts parturient outcomes. PMID- 30396229 TI - Pregnancy Outcomes after Early Amniotomy among Class III Obese Gravidas Undergoing Induction of Labor. AB - OBJECTIVE: We sought to evaluate differences in pregnancy outcomes following early amniotomy in women with class III obesity (body mass index >=40 kg/m2) undergoing induction of labor. STUDY DESIGN: This is a retrospective cohort study of women with class III obesity undergoing term induction of labor from January 2007 to February 2013. Early amniotomy was defined as artificial membrane rupture at less than 4 cm cervical dilation. The primary outcome was cesarean delivery. Secondary outcomes included length of labor, a maternal morbidity composite, and a neonatal morbidity composite. A subgroup analysis examined the effect of parity. Multivariable logistic regression was used to adjust for covariates. RESULTS: Of 285 women meeting inclusion criteria, 107 (37.5%) underwent early amniotomy and 178 (62.5%) underwent late amniotomy. Early amniotomy was associated with cesarean delivery after multivariable adjustments (adjusted odds ratio [aOR], 2.05; 95% confidence interval [CI], 1.21-3.47). There were no significant differences in length of labor or maternal and neonatal morbidity between groups. When stratified by parity, early amniotomy was associated with increased cesarean delivery (aOR, 3.10; 95% CI, 1.47-6.58) only in nulliparous women. CONCLUSION: Early amniotomy among class III obese women, especially nulliparous women, undergoing labor induction may be associated with an increased risk of cesarean delivery. PMID- 30396230 TI - Psychological impact of psoriasis on Vlamidir Nabokov. AB - Vladimir Nabokov, one of the greatest writers of the twentieth century, is best known for having published in 1954 in France his novel Lolita. Many publications report his psoriasis, but none was interested in its psychological repercussions. He and his wife Vera Slonim remained inseparable from 1923 to 1977, when the writer died. In 2017, the Russian letters to Vera from 1923 to 19771 were translated into English by Olga Voronina and Brian Boyd (figure 1). We searched for all the passages in which Vladimir Nabokov refers to his psoriasis. Vladimir Nabokov reported his psoriasis for the first time on 7 July 1936, which heals after a solar exposure (p.127). This article is protected by copyright. All rights reserved. PMID- 30396231 TI - The relationships between coping, occupational stress, and emotional intelligence in newly hired oncology nurses. AB - OBJECTIVES: Associations between the varying levels of emotional intelligence in newly hired oncology nurses and their responses to stress and coping were examined. The secondary aim was to analyze whether emotional intelligence could moderate their choice of problem-focused or emotion-focused coping strategies. METHODS: Newly hired nurses (n = 114) were recruited from a national cancer institute. Data were collected through surveys using the Ways of Coping Questionnaire, the Nursing Stress Scale, and the Emotional Quotient Inventory between the eighth and twelfth weeks post-hire date. Descriptive and bivariate statistical analyses were conducted on all variables. Regression models determined whether emotional intelligence moderated the choice of coping strategies. RESULTS: Emotional intelligence had a mean value of M = 105.24, SD = 13.02, and occupational stress scores were M = 65.57, SD = 15.68. Significant negative correlations were found for occupational stress and problem-focused coping (r = -.189, P = .022), emotional intelligence and emotion-focused coping (r = -.340, P = .000), and emotional intelligence and occupational stress (r = .428, P < 0.001). Positive correlations were noted between occupational stress and emotion-focused coping (r = .189, P = .022) and emotional intelligence and problem-focused coping (r = .340, P = .000). Emotional intelligence did not predict the choice of coping strategies. CONCLUSIONS: Although emotional intelligence did not moderate coping strategies in newly hired nurses, using problem focused coping to address occupational stress during the initial employment period may be a protective factor for coping with stress in the oncology workplace. PMID- 30396232 TI - Bmi-1 high-expressing cells enrich cardiac stem/progenitor cells and respond to heart injury. AB - Bmi-1 gene is well recognized as an oncogene, but has been recently demonstrated to play a role in the self-renewal of tissue-specific stem cells. By using Bmi 1GFP /+ mice, we investigated the role of Bmi-1 in cardiac stem/progenitor cells and myocardial repair. RT-PCR and flow cytometry analysis indicated that the expression of Bmi-1 was significantly higher in cardiac side population than the main population from CD45- Ter119- CD31- heart cells. More Sca-1+ cardiac stem/progenitor cells were found in Bmi-1 GFPhi subpopulation, and these Bmi-1 GFPhi heart cells showed the potential of differentiation into SMM+ smooth muscle like cells and TnT+ cardiomyocyte-like cells in vitro. The silencing of Bmi-1 significantly inhibited the proliferation and differentiation of heart cells. Otherwise, myocardial infarction induced a significantly increase (2.7-folds) of Bmi-1 GFPhi population, mainly within the infarction and border zones. These preliminary data suggest that Bmi-1hi heart cells are enriched in cardiac stem/progenitor cells and may play a role in myocardial repair. PMID- 30396234 TI - Mineralized Polysaccharide Transplantation Modules Supporting Human MSC Conversion into Osteogenic Cells and Osteoid Tissue in a Non-Union Defect. AB - Regenerative orthopedics needs significant devices to transplant human stem cells into damaged tissue and encourage automatic growth into replacements suitable for the human skeleton. Soft biomaterials have similarities in mechanical, structural and architectural properties to natural extracellular matrix (ECM), but often lack essential ECM molecules and signals. Here we engineer mineralized polysaccharide beads to transform MSCs into osteogenic cells and osteoid tissue for transplantation. Bone morphogenic proteins (BMP-2) and indispensable ECM proteins both directed differentiation inside alginate beads. Laminin and collagen IV basement membrane matrix proteins fixed and organized MSCs onto the alginate matrix, and BMP-2 drove differentiation, osteoid tissue self-assembly, and small-scale mineralization. Augmentation of alginate is necessary, and we showed that a few rationally selected small proteins from the basement membrane (BM) compartment of the ECM were sufficient to upregulate cell expression of Runx 2 and osteocalcin for osteoid formation, resulting in Alizarin red-positive mineral nodules. More significantly, nested BMP-2 and BM beads added to a non union skull defect, self-generated osteoid expressing osteopontin (OPN) and osteocalcin (OCN) in a chain along the defect, at only four weeks, establishing a framework for complete regeneration expected in 6 and 12 weeks. Alginate beads are beneficial surgical devices for transplanting therapeutic cells in programmed (by the ECM components and alginate-chitosan properties) reaction environments ideal for promoting bone tissue. PMID- 30396233 TI - Makorin 1 Regulates Developmental Timing in Drosophila. AB - Drosophila ortholog of mammalian makorin genes, in the regulation of developmental timing. Loss of MKRN1 in mkrn1exS prolonged the 3rd instar stage and delayed the onset of pupariation, resulting in bigger size pupae. MKRN1 was expressed in the prothoracic gland, where the steroid hormone ecdysone is produced. Furthermore, mkrn1exS larvae exhibited reduced mRNA levels of phantom, which encodes ecdysone-synthesizing enzyme and E74, which is a downstream target of ecdysone. Collectively, these results indicate that MKRN1 fine-tunes developmental timing and sexual maturation by affecting ecdysone synthesis in Drosophila. Moreover, our study supports the notion that malfunction of makorin gene family member, mkrn3 dysregulates the timing of puberty in mammals. PMID- 30396235 TI - Proteasome Inhibitor-Induced IkappaB/NF-kappaB Activation is Mediated by Nrf2 Dependent Light Chain 3B Induction in Lung Cancer Cells. AB - IkappaB, a cytoplasmic inhibitor of nuclear factor-kappaB (NF-kappaB), is reportedly degraded via the proteasome. However, we recently found that long-term incubation with proteasome inhibitors (PIs) such as PS-341 or MG132 induces IkappaBalpha degradation via an alternative pathway, lysosome, which results in NF-kappaB activation and confers resistance to PI-induced lung cancer cell death. To enhance the anti-cancer efficacy of PIs, elucidation of the regulatory mechanism of PI-induced IkappaBalpha degradation is necessary. Here, we demonstrated that PI upregulates nuclear factor (erythroid-derived 2)-like 2 (Nrf2) via both de novo protein synthesis and Kelch-like ECH-associated protein 1 (KEAP1) degradation, which is responsible for IkappaBalpha degradation via macroautophagy activation. PIs increased the protein level of light chain 3B (LC3B, macroautophagy marker), but not lysosome-associated membrane protein 2a (Lamp2a, the receptor for chaperone-mediated autophagy) in NCI-H157 and A549 lung cancer cells. Pretreatment with macroautophagy inhibitor or knock-down of LC3B blocked PIinduced IkappaBalpha degradation. PIs up-regulated Nrf2 by increasing its transcription and mediating degradation of KEAP1 (cytoplasmic inhibitor of Nrf2). Overexpression of dominantnegative Nrf2, which lacks an N-terminal transactivating domain, or knock-down of Nrf2 suppressed PI-induced LC3B protein expression and subsequent IkappaBalpha degradation. Thus, blocking of the Nrf2 pathway enhanced PI-induced cell death. These findings suggest that Nrf2-driven induction of LC3B plays an essential role in PI-induced activation of the IkappaB/NF-kappaB pathway, which attenuates the anti-tumor efficacy of PIs. PMID- 30396236 TI - Transcriptome Profiling and Characterization of Drought-Tolerant Potato Plant (Solanum tuberosum L.). AB - Potato (Solanum tuberosum L.) is the third most important food crop, and breeding drought-tolerant varieties is vital research goal. However, detailed molecular mechanisms in response to drought stress in potatoes are not well known. In this study, we developed EMS-mutagenized potatoes that showed significant tolerance to drought stress compared to the wild-type (WT) 'Desiree' cultivar. In addition, changes to transcripts as a result of drought stress in WT and drought-tolerant (DR) plants were investigated by de novo assembly using the Illumina platform. One-week-old WT and DR plants were treated with -1.8 Mpa polyethylene glycol 8000, and total RNA was prepared from plants harvested at 0, 6, 12, 24, and 48 h for subsequent RNA sequencing. In total, 61,100 transcripts and 5,118 differentially expressed genes (DEGs) displaying up- or down-regulation were identified in pairwise comparisons of WT and DR plants following drought conditions. Transcriptome profiling showed the number of DEGs with up-regulation and down-regulation at 909, 977, 1181, 1225 and 826 between WT and DR plants at 0, 6, 12, 24, and 48 h, respectively. Results of KEGG enrichment showed that the drought tolerance mechanism of the DR plant can mainly be explained by two aspects, the 'photosynthetic-antenna protein' and 'protein processing of the endoplasmic reticulum'. We also divided eight expression patterns in four pairwise comparisons of DR plants (DR0 vs DR6, DR12, DR24, DR48) under PEG treatment. Our comprehensive transcriptome data will further enhance our understanding of the mechanisms regulating drought tolerance in tetraploid potato cultivars. PMID- 30396237 TI - Inhibition of MicroRNA-221 and 222 Enhances Hematopoietic Differentiation from Human Pluripotent Stem Cells via c-KIT Upregulation. AB - The stem cell factor (SCF)/c-KIT axis plays an important role in the hematopoietic differentiation of human pluripotent stem cells (hPSCs), but its regulatory mechanisms involving microRNAs (miRs) are not fully elucidated. Here, we demonstrated that supplementation with SCF increases the hematopoietic differentiation of hPSCs via the interaction with its receptor tyrosine kinase c KIT, which is modulated by miR-221 and miR-222. c-KIT is comparably expressed in undifferentiated human embryonic and induced pluripotent stem cells. The inhibition of SCF signaling via treatment with a c-KIT antagonist (imatinib) during hPSC-derived hematopoiesis resulted in reductions in the yield and multi lineage potential of hematopoietic progenitors. We found that the transcript levels of miR-221 and miR-222 targeting c-KIT were significantly lower in the pluripotent state than they were in terminally differentiated somatic cells. Furthermore, suppression of miR-221 and miR-222 in undifferentiated hPSC cultures induced more hematopoiesis by increasing c-KIT expression. Collectively, our data implied that the modulation of c-KIT by miRs may provide further potential strategies to expedite the generation of functional blood cells for therapeutic approaches and the study of the cellular machinery related to hematologic malignant diseases such as leukemia. PMID- 30396238 TI - Laminar Flow Inhibits ER Stress-Induced Endothelial Apoptosis through PI3K/Akt Dependent Signaling Pathway. AB - Atherosclerosis preferentially involves in prone area of low and disturbed blood flow while steady and high levels of laminar blood flow are relatively protected from atherosclerosis. Disturbed flow induces endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). ER stress is caused under stress that disturbs the processing and folding of proteins resulting in the accumulation of misfolded proteins in the ER and activation of the UPR. Prolonged or severe UPR leads to activate apoptotic signaling. Recent studies have indicated that disturbed flow significantly up-regulated p-ATF6alpha, p-IRE1alpha, and its target spliced XBP-1. However, the role of laminar flow in ER stress-mediated endothelial apoptosis has not been reported yet. The present study thus investigated the role of laminar flow in ER stress-dependent endothelial cell death. The results demonstrated that laminar flow protects ER stress-induced cleavage forms of PARP-1 and caspase-3. Also, laminar flow inhibits ER stress induced p-eIF2alpha, ATF4, CHOP, spliced XBP-1, ATF6 and JNK pathway; these effects are abrogated by pharmacological inhibition of PI3K with wortmannin. Finally, nitric oxide affects thapsigargin-induced cell death in response to laminar flow but not UPR. Taken together, these findings indicate that laminar flow inhibits UPR and ER stress-induced endothelial cell death via PI3K/Akt pathway. PMID- 30396239 TI - Dynamic Transcriptome, DNA Methylome, and DNA Hydroxymethylome Networks During T Cell Lineage Commitment. AB - The stepwise development of T cells from a multipotent precursor is guided by diverse mechanisms, including interactions among lineage-specific transcription factors (TFs) and epigenetic changes, such as DNA methylation and hydroxymethylation, which play crucial roles in mammalian development and lineage commitment. To elucidate the transcriptional networks and epigenetic mechanisms underlying T-cell lineage commitment, we investigated genome-wide changes in gene expression, DNA methylation and hydroxymethylation among populations representing five successive stages of T-cell development (DN3, DN4, DP, CD4+, and CD8+) by performing RNA-seq, MBD-seq and hMeDIP-seq, respectively. The most significant changes in the transcriptomes and epigenomes occurred during the DN4 to DP transition. During the DP stage, many genes involved in chromatin modification were up-regulated and exhibited dramatic changes in DNA hydroxymethylation. We also observed 436 alternative splicing events, and approximately 57% (252) of these events occurred during the DP stage. Many stage-specific, differentially methylated regions were observed near the stage-specific, differentially expressed genes. The dynamic changes in DNA methylation and hydroxymethylation were associated with the recruitment of stage-specific TFs. We elucidated interactive networks comprising TFs, chromatin modifiers, and DNA methylation and hope that this study provides a framework for the understanding of the molecular networks underlying T-cell lineage commitment. PMID- 30396240 TI - Spinal Deformity Surgery : It Becomes an Essential Part of Neurosurgery. AB - Among the spinal disorders, the treatment approach for spinal deformities has been discussed least among department of neurosurgery. But nowadays, more and more neurosurgeons are interested in spinal deformities as well as complex spinal disorders and are doing not a few surgeries for these kinds of disease. Nevertheless, it is mandatory to understand the course of spinal deformity, principles of treatment, and surgical outcomes and complications. Understanding of the biology, biomechanics and metallurgy of the spine and instrumentation are also required for successful spinal deformity surgery. We need senior mentors and good surgical and neurophysiologic monitoring team. Knowledge of spinal deformity may be augmented with spine fellowships and surgical experience. Step by step training such as basic knowledge, orthopedic as well as neurosurgical disciplines and surgical skills would be mandatory. Neurosurgeons can have several advantages for spinal deformity surgeries. By high-level technical ability of the spinal cord handling to preserve neurological function and familiarity with microscopic surgery, better synergistic effect could be expected. A fundamental understanding of pediatric spinal deformity and growing spine should be needed for spinal deformity surgery. PMID- 30396241 TI - Activin A/BMP2 Chimera (AB204) Exhibits Better Spinal Bone Fusion Properties than rhBMP2. AB - OBJECTIVE: To compare the spinal bone fusion properties of activin A/BMP2 chimera (AB204) with recombinant human bone morphogenetic protein (rhBMP2) using a rat posterolateral spinal fusion model. METHODS: The study was designed to compare the effects and property at different dosages of AB204 and rhBMP2 on spinal bone fusion. Sixty-one male Sprague-Dawley rats underwent posterolateral lumbar spinal fusion using one of nine treatments during the study, that is, sham; osteon only; 3.0 MUg, 6.0 MUg, or 10.0 MUg of rhBMP2 with osteon; and 1.0 MUg, 3.0 MUg, 6.0 MUg, or 10.0 MUg of AB204 with osteon. The effects and property on spinal bone fusion was calculated at 4 and 8 weeks after treatment using the scores of physical palpation, simple radiograph, micro-computed tomography, and immunohistochemistry. RESULTS: Bone fusion scores were significantly higher for 10.0 MUg AB204 and 10.0 MUg rhBMP2 than for osteon only or 1.0 MUg AB204. AB204 exhibited more prolonged osteoblastic activity than rhBMP2. Bone fusion properties of AB204 were similar with the properties of rhBMP2 at doses of 6.0 and 10.0 MUg, but, the properties of AB204 at doses of 3.0 MUg exhibited better than the properties of rhBMP2 at doses of 3.0 MUg. CONCLUSION: AB204 chimeras could to be more potent for treating spinal bone fusion than rhBMP2 substitutes with increased osteoblastic activity for over a longer period. PMID- 30396242 TI - Bone-Preserving Decompression Procedures Have a Minor Effect on the Flexibility of the Lumbar Spine. AB - OBJECTIVE: To mitigate the risk of iatrogenic instability, new posterior decompression techniques able to preserve musculoskeletal structures have been introduced but never extensively investigated from a biomechanical point of view. This study was aimed to investigate the impact on spinal flexibility caused by a unilateral laminotomy for bilateral decompression, in comparison to the intact condition and a laminectomy with preservation of a bony bridge at the vertebral arch. Secondary aims were to investigate the biomechanical effects of two-level decompression and the quantification of the restoration of stability after posterior fixation. METHODS: A universal spine tester was used to measure the flexibility of six L2-L5 human spine specimens in intact conditions and after decompression and fixation surgeries. An incremental damage protocol was applied : 1) unilateral laminotomy for bilateral decompression at L3-L4; 2) on three specimens, the unilateral laminotomy was extended to L4-L5; 3) laminectomy with preservation of a bony bridge at the vertebral arch (at L3-L4 in the first three specimens and at L4-L5 in the rest); and 4) pedicle screw fixation at the involved levels. RESULTS: Unilateral laminotomy for bilateral decompression had a minor influence on the lumbar flexibility. In flexion-extension, the median range of motion increased by 8%. The bone-preserving laminectomy did not cause major changes in spinal flexibility. Two-level decompression approximately induced a twofold destabilization compared to the single-level treatment, with greater effect on the lower level. Posterior fixation reduced the flexibility to values lower than in the intact conditions in all cases. CONCLUSION: In vitro testing of human lumbar specimens revealed that unilateral laminotomy for bilateral decompression and bone-preserving laminectomy induced a minor destabilization at the operated level. In absence of other pathological factors (e.g., clinical instability, spondylolisthesis), both techniques appear to be safe from a biomechanical point of view. PMID- 30396243 TI - Wall Shear Stress and Flow Patterns in Unruptured and Ruptured Anterior Communicating Artery Aneurysms Using Computational Fluid Dynamics. AB - OBJECTIVE: The goal of this study was to compare several parameters, including wall shear stress (WSS) and flow pattern, between unruptured and ruptured anterior communicating artery (ACoA) aneurysms using patient-specific aneurysm geometry. METHODS: In total, 18 unruptured and 24 ruptured aneurysms were analyzed using computational fluid dynamics (CFD) models. Minimal, average, and maximal wall shear stress were calculated based on CFD simulations. Aneurysm height, ostium diameter, aspect ratio, and area of aneurysm were measured. Aneurysms were classified according to flow complexity (simple or complex) and inflow jet (concentrated or diffused). Statistical analyses were performed to ascertain differences between the aneurysm groups. RESULTS: Average wall shear stress of the ruptured group was greater than that of the unruptured group (9.42% for aneurysm and 10.38% for ostium). The average area of ruptured aneurysms was 31.22% larger than unruptured aneurysms. Simple flow was observed in 14 of 18 (78%) unruptured aneurysms, while all ruptured aneurysms had complex flow (p<0.001). Ruptured aneurysms were more likely to have a concentrated inflow jet (63%), while unruptured aneurysms predominantly had a diffused inflow jet (83%, p=0.004). CONCLUSION: Ruptured aneurysms tended to have a larger geometric size and greater WSS compared to unruptured aneurysms, but the difference was not statistically significant. Flow complexity and inflow jet were significantly different between unruptured and ruptured ACoA aneurysms. PMID- 30396244 TI - Contribution of Lateral Interbody Fusion in Staged Correction of Adult Degenerative Scoliosis. AB - OBJECTIVE: Lateral interbody fusion (LIF) is attractive as a less invasive technique to address anterior spinal pathology in the treatment of adult spinal deformity. Its own uses and benefits in treatment of adult degenerative scoliosis are undefined. To investigate the radiographic and clinical outcomes of LIF, and staged LIF and posterior spinal fusion (PSF) for the treatment of adult degenerative scoliosis patients, we analyzed radiographic and clinical outcomes of adult degenerative scoliosis patients who underwent LIF and posterior spinal fusion. METHODS: Forty consecutive adult degenerative scoliosis patients who underwent LIF followed by staged PSF at a single institution were retrospectively reviewed. Long-standing 36" anterior-posterior and lateral radiographs were taken preoperatively, at inter-stage, 3 months, 1 year, and 2 years after surgery were reviewed. Outcomes were assessed through the visual analogue scale (VAS), 36-Item Short Form Health Survey (SF-36), and Oswestry Disability Index (ODI). RESULTS: Forty patients with a mean age of 66.3 (range, 49-79) met inclusion criteria. A mean of 3.8 levels (range, 2-5) were fused using LIF, while a mean of 9.0 levels (range, 3-16) were fused during the posterior approach. The mean time between stages was 1.4 days (range, 1-6). The mean follow-up was 19.6 months. Lumbar lordosis was significantly restored from 36.4o preoperatively up to 48.9o (71.4% of total correction) after LIF and 53.9o after PSF. Lumbar coronal Cobb was prominently improved from 38.6o preoperatively to 24.1o (55.8% of total correction) after LIF, 12.6o after PSF respectively. The mean pelvic incidence lumbar lordosis mismatch was markedly improved from 22.2o preoperatively to 8.1o (86.5% of total correction) after LIF, 5.9o after PSF. Correction of coronal imbalance and sagittal vertebral axis did not reach significance. The rate of perioperative complication was 37.5%. Five patients underwent revision surgery due to wound infection. No major perioperative medical complications occurred. At last followup, there were significant improvements in VAS, SF-36 Physical Component Summary and ODI scores. CONCLUSION: LIF provides significant corrections in the coronal and sagittal plane in the patients with adult degenerative scoliosis. However, LIF combined with staged PSF provides more excellent radiographic and clinical outcomes, with reduced perioperative risk in the treatment of adult degenerative scoliosis. PMID- 30396245 TI - Total Deformity Angular Ratio as a Risk Factor for Complications after Posterior Vertebral Column Resection Surgery. AB - OBJECTIVE: The aim of the present study was to identify whether the deformity angular ratio (DAR) influences the occurrence of complications after posterior vertebral column resection (PVCR) and to establish the DAR cut-off value. METHODS: Thirty-six consecutive patients undergoing PVCR from December 2010 to October 2016 were reviewed. The relationships between the total, sagittal, and coronal DAR and complications were assessed using receiver operator characteristics curves. The patients were divided into two groups according to a reference value based on the cut-off value of DAR. Demographic, surgical, radiological, and clinical outcomes were compared between the groups. RESULTS: There were no significant differences in the patient demographic and surgical data between the groups. The cut-off values for the total DAR (T-DAR) and the sagittal DAR (S-DAR) were 20.2 and 16.4, respectively (p=0.018 and 0.010). Both values were significantly associated with complications (p=0.016 and 0.005). In the higher T-DAR group, total complications (12 vs. 21, p=0.042) and late-onset complications (3 vs. 9, p=0.036) were significantly correlated with the T-DAR. The number of patients experiencing complications (9 vs. 11, p=0.029) and the total number of complications (13 vs. 20, p=0.015) were significantly correlated with the S-DAR. Worsening intraoperative neurophysiologic monitoring was more frequent in the higher T-DAR group (2 vs. 4) than in the higher S-DAR group (3 vs. 3). There was no difference in neurological deterioration between the groups after surgery. CONCLUSION: Both the T-DAR and the S-DAR are risk factors for complications after PVCR. Those who had a T-DAR >20.2 or S-DAR >16.4 experienced a higher rate of complications after PVCR. PMID- 30396246 TI - Conus Medullaris Levels on Ultrasonography in Term Newborns : Normal Levels and Dermatological Findings. AB - OBJECTIVE: Ultrasonography (US) is the most non-invasive, safe, and, especially in the period of infancy, best method for visualizing and examining the spinal cord. Furthermore, US is the primary work-up for development of the spinal canal, and for follow-up on issues relating to subcutaneous tissues, bone development, and the spinal cord. Conus medullaris terminates at the second lumbar vertebra, according to a consensus in the literature. METHODS: Healthy children under the age of 6 months who were admitted to the radiology clinic for routine USG follow ups between the dates of March 2012 to December 2014 were included in this study. RESULTS: Our study includes data from 1125 lumbosacral ultrasounds. The terminal point of the conus level of the attended infants, superior, middle part, inferior of the vertebrae L1, L2, and L3. Furthermore, the termination of the discal distance ratio did not differ significantly between genders. CONCLUSION: Therefore, according to our results, gender is not an influencing factor in the termination of the spinal cord. Based on the study we performed, as well as the previous literature, in infants without a recognized spinal pathology, the spinal cord is detected below the vertebra L3. PMID- 30396247 TI - Cranioplasty Using Autologous Bone versus Porous Polyethylene versus Custom-Made Titanium Mesh : A Retrospective Review of 108 Patients. AB - OBJECTIVE: The purpose of this study was to compare the cosmetic outcome and complications after cranioplasty (CP) due to three different implant materials, and analyze the mean implant survival and cumulative survival rate based on these results. METHODS: We reviewed 108 patients retrospectively who underwent CP between January 2014 and November 2016. Autologous bone (AB; 45 patients) and synthetic materials with porous polyethylene (PP; 32 patients) and custom-made 3 dimensional printed titanium mesh (CT; 31 patients) were used as implants. RESULTS: Regardless of implanted materials, more than 89.8% of the CP patients were satisfied with the cosmetic outcome. No statistically significant difference was observed among the three groups. The overall postoperative complication rates of each group were 31.1% in the AB group, 15.6% in the PP group and 3.2% in the CT group. The CT group showed lower complication rates compared with AB and PP groups (chi2-test : AB vs. PP, p=0.34; AB vs. CT, p=0.00; PP vs. CT, p=0.03). The AB and PP groups demonstrated a higher post-CP infection rate (11.1% and 6.3%) than the CT group (3.2%). However, no significant difference in the incidence of post-CP infection was observed among the three groups. The PP and CT groups demonstrated a higher mean implant survival time and cumulative survival rate than the AB group at the last follow-up (p<0.05). CONCLUSION: In comparison with AB and PP, cranioplasty with CT shows benefits in terms of lower post-CP complication, less intraoperative bleeding loss, shorter operation time and in hospital stay. The PP and CT groups showed higher implant survival time and cumulative survival rate compared with the AB group. PMID- 30396248 TI - Cyberknife Dosimetric Planning Using a Dose-Limiting Shell Method for Brain Metastases. AB - OBJECTIVE: We investigated the effect of optimization in dose-limiting shell method on the dosimetric quality of CyberKnife (CK) plans in treating brain metastases (BMs). METHODS: We selected 19 BMs previously treated using CK between 2014 and 2015. The original CK plans (CKoriginal) had been produced using 1 to 3 dose-limiting shells : one at the prescription isodose level (PIDL) for dose conformity and the others at lowisodose levels (10-30% of prescription dose) for dose spillage. In each case, a modified CK plan (CKmodified) was generated using 5 dose-limiting shells : one at the PIDL, another at intermediate isodose level (50% of prescription dose) for steeper dose fall-off, and the others at low isodose levels, with an optimized shell-dilation size based on our experience. A Gamma Knife (GK) plan was also produced using the original contour set. Thus, three data sets of dosimetric parameters were generated and compared. RESULTS: There were no differences in the conformity indices among the CKoriginal, CKmodified, and GK plans (mean 1.22, 1.18, and 1.24, respectively; p=0.079) and tumor coverage (mean 99.5%, 99.5%, and 99.4%, respectively; p=0.177), whereas the CKmodified plans produced significantly smaller normal tissue volumes receiving 50% of prescription dose than those produced by the CKoriginal plans (p<0.001), with no statistical differences in those volumes compared with GK plans (p=0.345). CONCLUSION: These results indicate that significantly steeper dose fall-off is able to be achieved in the CK system by optimizing the shell function while maintaining high conformity of dose to tumor. PMID- 30396249 TI - Surfer's Myelopathy : Case Series and Literature Review. AB - Three male patients diagnosed with surfer's myelopathy (19-30 years) were admitted to our hospital. All three patients were novice surfers showing a typical clinical course of rapid progression of paraplegia following the onset of back pain. Typical history and magnetic resonance imaging features indicated the diagnosis of surfer's myelopathy. Two patients received high-dose steroid therapy and the other was treated with induced hypertension. One patient treated with induced hypertension showed almost full recovery; however, two patients who received high-dose steroid therapy remained completely paraplegic and required catheterization for bladder and bowel dysfunction despite months of rehabilitation. Our case series demonstrates the potentially devastating neurological outcome of surfer's myelopathy; however, early recovery in the initial 24-72 hours of presentation can occur in some patients, which is in accordance with previous reports. Ischemic insult to the spinal cord is thought to play a crucial role in the pathophysiology of surfer's myelopathy. Treatment recommendations include hydration, induced hypertension, early spinal angiography with intra-arterial intervention, intravenous tissue plasminogen activator, and high-dose steroid therapy; however, there is no standardized treatment option available. Early recovery appears to be important for long-term neurological outcome. Induced hypertension for initial treatment can be helpful for improving spinal cord perfusion; therefore, it is important for early and long-term neurological recovery. Education and awareness are essential for preventing surfer's myelopathy and avoiding further deterioration of neurological function. PMID- 30396250 TI - Transphenoidal Surgery : The Optimal Approach to Chordoid Gliomas of the Third Ventricle? PMID- 30396252 TI - The importance of treating mild hyperglycemia in pregnant women with diabetes. PMID- 30396251 TI - Clinical implications of anti-thyroglobulin antibody measurement before surgery in thyroid cancer. AB - Thyroglobulin antibody (TgAb) is a class G immunoglobulin and a conventional marker for thyroid autoimmunity. From a clinical perspective, TgAb is less useful than thyroid peroxidase antibodies for predicting thyroid dysfunction. However, TgAb is found more frequently in differentiated thyroid cancer (DTC) and can interfere with thyroglobulin (Tg) measurements, which are used to monitor the recurrence or persistence of DTC. Recent studies suggested a small but consistent role for preoperative TgAb in predicting DTC in thyroid nodules, and in reflecting adverse tumor characteristics or prognosis, including lymph node metastasis, but this is still controversial. Postoperative TgAb can serve as a biomarker for remnant thyroid tissue, so follow-up measures of TgAb are useful for predicting cancer recurrence in DTC patients. Since high serum TgAb levels may also affect the fine needle aspiration washout Tg levels from suspicious lymph nodes of DTC patients, it is important to use caution when interpreting the washout Tg levels in patients who are positive for TgAb. PMID- 30396253 TI - Piggybacked by PEGylation? PMID- 30396255 TI - Comment on "Medication nonadherence in Korean patients with rheumatoid arthritis: the importance of belief about medication and illness perception". PMID- 30396254 TI - Current treatment status and medical costs for hemodialysis vascular access based on analysis of the Korean Health Insurance Database. AB - BACKGROUND/AIMS: The Republic of Korea is a country where the hemodialysis population is growing rapidly. It is believed that the numbers of treatments related to vascular access-related complications are also increasing. This study investigated the current status of treatment and medical expenses for vascular access in Korean patients on hemodialysis. METHODS: This was a descriptive observational study. We inspected the insurance claims of patients with chronic kidney disease who underwent hemodialysis between January 2008 and December 2016. We calculated descriptive statistics of the frequencies and medical expenses of procedures for vascular access. RESULTS: The national medical expenses for access related treatment were 7.12 billion KRW (equivalent to 6.36 million USD) in 2008, and these expenses increased to 42.12 billion KRW (equivalent to 37.67 million USD) in 2016. The population of hemodialysis patients, the annual frequency of access-related procedures, and the total medical cost for access-related procedures increased by 1.6-, 2.6-, and 5.9-fold, respectively, over the past 9 years. The frequency and costs of access care increased as the number of patients on hemodialysis increased. The increase in vascular access-related costs has largely been driven by increased numbers of percutaneous angioplasty. CONCLUSION: The increasing proportion of medical costs for percutaneous angioplasty represents a challenge in the management of end-stage renal disease in Korea. It is essential to identify the clinical and physiological aspects as well as anatomical abnormalities before planning angioplasty. A timely surgical correction could be a viable option to control the rapid growth of access-related medical expenses. PMID- 30396256 TI - Response to comment on "Medication nonadherence in Korean patients with rheumatoid arthritis: the importance of belief about medication and illness perception". PMID- 30396257 TI - Understanding of Neurological Diseases. PMID- 30396258 TI - Up to Date on Astrocytes. PMID- 30396259 TI - New Roles for Old Glue: Astrocyte Function in Synaptic Plasticity and Neurological Disorders. AB - Previously believed to solely play a supportive role in the central nervous system, astrocytes are now considered active players in normal brain function. Evidence in recent decades extends their contributions beyond the classically held brain glue role; it's now known that astrocytes act as a unique excitable component with functions extending into local network modulation, synaptic plasticity, and memory formation, and postinjury repair. In this review article, we highlight our growing understanding of astrocyte function and physiology, the increasing role of gliotransmitters in neuron-glia communication, and the role of astrocytes in modulating synaptic plasticity and cognitive function. Owing to the duality of both beneficial and deleterious roles attributed to astrocytes, we also discuss the implications of this new knowledge as it applies to neurological disorders including Alzheimer disease, epilepsy, and schizophrenia. PMID- 30396262 TI - Therapeutic Potential of Human Turbinate-Derived Mesenchymal Stem Cells in Experimental Acute Ischemic Stroke. AB - PURPOSE: Mesenchymal stem cells (MSCs) have demonstrated great promises for the treatment of ischemic stroke. Previously, we identified a new source of MSCs located in the inferior turbinate. We investigated therapeutic potentials of human turbinate- derived mesenchymal stem cells (hTMSCs) in ischemic stroke. METHODS: Ischemic stroke was induced by the intraluminal occlusion of middle cerebral artery (MCAo) for 50 minutes in rats. At one day after MCAo, hTMSCs, adipose tissue-derived MSCs (AdMSCs), or phosphate buffered saline (PBS) were transplanted into the striatum. Functional recovery was assessed by repeating behavioral tests including modified neurologic severity score and corner test. At 14 days after MCAo, brains were stained with hematoxylin and eosin (H&E) for measuring infarct volume. The survival of grafted MSCs was evaluated by immunohistochemistry to human nuclei (hNU). Immunohistochemistry with anti doublecortin (anti-DCX) was performed to assess hippocampal neurogenesis. RESULTS: Transplantation of hTMSCs following MCAo showed improvements of neurologic function, which was comparable with that of AdMSCs. H&E staining showed no difference in infarct volume among 3 groups. Regarding the survival of grafted MSCs, the number of hNU-expressing cells was not different between hTMSCs and AdMSCs-treated groups. Finally, hTMSCs increased the number of subgranular DCX-positive cells compared to PBS-treated controls, without affecting hilar ectopic migration of newborn neurons. CONCLUSION: hTMSCs could improve functional recovery following ischemic stroke, of which efficacy was similar to AdMSCs. Although hTMSCs showed comparable infarct size and survival of grafted MSCs, transplantation of hTMSCs could upregulate subgranular neurogenesis with no impact on ectopically migrating newborn neurons. PMID- 30396260 TI - Presynaptic Dysfunction by Familial Factors in Parkinson Disease. AB - Parkinson disease (PD) is the second most prevalent neurodegenerative disorder after Alzheimer disease. The loss of specific brain area, the substantia nigra pars compacta is known as a major etiology, however it is not fully understood how this neurodegeneration is initiated and what precisely causes this disease. As one aspect of pathophysiology for PD, synaptic dysfunction (synaptopathy) is thought to be an earlier appearance for neurodegeneration. In addition, some of the familial factors cumulatively exhibit that these factors such as alpha synuclein, leucine-rich repeat kinase 2, parkin, PTEN-induced kinase 1, and DJ-1 are involved in the regulation of synaptic function and missense mutants of familial factors found in PD-patient show dysregulation of synaptic functions. In this review, we have discussed the physiological function of these genetic factors in presynaptic terminal and how dysregulation of presynaptic function by genetic factors might be related to the pathogenesis of Parkinson disease. PMID- 30396261 TI - BubR1 Insufficiency Impairs Affective Behavior and Memory Function in Mice. AB - PURPOSE: Although aging causes functional declines in cognition, the molecular mechanism underlying these declines remains largely unknown. Recently, the spindle checkpoint kinase budding uninhibited by benzimidazole-related 1 (BubR1) has emerged as a key determinant for age-related pathology in various tissues including brain. However, the neurobehavioral impact of BubR1 has not been explored. In this study, we investigated the role of BubR1 in behavioral function. METHODS: To investigate the neurobiological functions of BubR1 in vivo, we utilized transgenic mice harboring BubR1 hypomorphic alleles (BubR1H/H mice), which produce low amounts of BubR1 protein, as well as mice that have specific knockdown of BubR1 in the adult dentate gyrus. To assess anxiety-like behavior, the above groups were subjected to the elevated plus maze and the light-dark test, in addition to utilizing the tail-suspension and forced-swim test to determine depression-like behavior. We used novel object recognition to test for memory-related function. RESULTS: We found that BubR1H/H mice display several behavioral deficits when compared to wild-type littermates, including increased anxiety in the elevated-plus maze test, depression-like behavior in the tail suspension test, as well as impaired memory function in the novel object recognition test. Similar to BubR1H/H mice, knockdown of BubR1 within the adult dentate gyrus led to increased anxiety-like behavior as well as depression-like behavior, and impaired memory function. CONCLUSION: Our study demonstrates a requirement of BubR1 in maintaining proper affective and memory-related behavioral function. These results suggest that a decline in BubR1 levels with advanced age may be a crucial contributor to age-related hippocampal dysfunction. PMID- 30396263 TI - Dexmedetomidine Ameliorates Sleep Deprivation-Induced Depressive Behaviors in Mice. AB - PURPOSE: Sleep deprivation induces depressive symptoms. Dexmedetomidine is a alpha2-adrenoreceptor agonist and this drug possesses sedative, anxiolytic, analgesic, and anesthetic-sparing effect. In this study, the action of dexmedetomidine on sleep deprivation-induced depressive behaviors was investigated using mice. METHODS: For the inducing of sleep deprivation, the mice were placed inside a water cage containing 15 platforms and filled with water up to 1 cm below the platform surface for 7 days. One day after sleep deprivation, dexmedetomidine at the respective dosage (0.5, 1, and 2 MUg/kg) was intraperitoneally treated into the mice, one time per a day during 6 days. Then, forced swimming test and tail suspension test were conducted. Immunohistochemistry for tyrosine hydroxylase (TH), 5-hydroxytryptamine (5-HT; serotonin), tryptophan hydroxylase (TPH) and western blot for D1 dopamine receptor were also performed. RESULTS: Sleep deprivation increased the immobility latency in the forced swimming test and tail suspension test. The expressions of TPH, 5-HT, and D1 dopamine receptor were decreased, whereas, TH expression was increased by sleep deprivation. Dexmedetomidine decreased the immobility latency and increased the expressions of TPH, 5-HT, and D1 dopamine receptor, whereas, HT expression was decreased by dexmedetomidine treatment. CONCLUSION: In our results, dexmedetomidine alleviated sleep deprivation-induced depressive behaviors by increasing 5-HT synthesis and by decreasing dopamine production with up-regulation of D1 dopamine receptor. PMID- 30396264 TI - Treadmill Exercise Improves Motor Function by Suppressing Purkinje Cell Loss in Parkinson Disease Rats. AB - PURPOSE: Rotenone is the most widely used neurotoxin for the making Parkinson disease (PD) animal model. The neurodegenerative disorder PD shows symptoms, such as slowness of movements, tremor at resting, rigidity, disturbance of gait, and instability of posture. We investigated whether treadmill running improves motor ability using rotenone-caused PD rats. The effect of treadmill running on PD was also assessed in relation with apoptosis of cerebellar Purkinje cells. METHODS: Treadmill running was applied to the rats in the exercise groups for 30 minutes once a day for 4 weeks, starting 4 weeks after birth. We used rota-rod test for the determination of motor coordination and balance. In this experiment, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, immunohistochemistry for calbindin, glial fibrillary acidic protein (GFAP), Iba 1, and western blot analysis for Bax and Bcl-2 were performed. RESULTS: Treadmill running enhanced motor balance and coordination by preventing the loss of Purkinje cells in the cerebellar vermis. Treadmill running suppressed PD-induced expression of GFAP-positive reactive astrocytes and Iba-1-positive microglia, showing that treadmill running suppressed reactive astrogliosis and microglia activation. Treadmill running suppressed TUNEL-positive cell number and Bax expression and enhanced Bcl-2 expression, demonstrating that treadmill running inhibited the progress of apoptosis in the cerebellum of rotenone-induced PD rats. CONCLUSION: Treadmill running improved motor ability of the rotenone induced PD rats by inhibiting apoptosis in the cerebellum. Apoptosis suppressing effect of treadmill running on rotenone-induced PD was achieved via suppression of reactive astrocyte and inhibition of microglial activation. PMID- 30396265 TI - PI3K-Akt-Wnt Pathway Is Implicated in Exercise-Induced Improvement of Short-term Memory in Cerebral Palsy Rats. AB - PURPOSE: Maternal lipopolysaccharide (LPS) injection induces neurodevelopmental disorders, such as cerebral palsy. Exercise activates phosphatidylinositol 3 kinase (PI3K)-protein kinase B (Akt) signaling pathway that enhances neurogenesis. Wnt ligands are also implicated in the hippocampal neurogenesis and synaptic plasticity. Glycogen synthase kinase-3beta (GSK-3beta) is a downstream molecule of Akt, and GSK-3beta is known to modulate hippocampal neurogenesis negatively. METHODS: Cerebral palsy was made by maternal LPS-injection. On the 5 weeks after birth, treadmill running was applied to the rat pups of the exercise groups, for 30 minutes, 5 times a week during 6 weeks. RESULTS: Treadmill running alleviated short-term memory impairments of the cerebral palsy rat pups. Hippocampal cell proliferation was increased and hippocampal apoptosis was suppressed by treadmill running in the cerebral palsy rat pups. Hippocampal phosphorylated-PI3K/PI3K ratio, phosphorylated-Akt/Akt ratio, and Wnt expression were enhanced by treadmill running in the cerebral palsy rat pups. In contrast, hippocampal phosphorylated-GSK-3beta/GSK-3beta ratio and beta-catenin expression were suppressed by treadmill running in the cerebral palsy rat pups. CONCLUSION: The results of this study showed that short-term memory improvement due to treadmill running in cerebral palsy occurs via activation of the PI3K-Akt-Wnt pathway. PMID- 30396266 TI - Peak-Tracking Algorithm for Use in Automated Interpretive Method-Development Tools in Liquid Chromatography. AB - A peak-tracking algorithm for chromatograms recorded using liquid chromatography and mass spectrometry was developed. Peaks are tracked across chromatograms using the spectrometric information, the statistical moments of the chromatographic peaks, and the relative retention. The algorithm can be applied to pair chromatographic peaks in two very different chromatograms, obtained for different samples using different methods. A fast version of the algorithm was specifically tailored to process chromatograms obtained during method development or optimization, where a few similar mobile-phase-composition gradients (same eluent components, but different ranges and programming rates) are applied to the same sample for the purpose of obtaining model parameters to describe the retention of sample components. Due to the relative similarity between chromatograms, time saving preselection protocols can be used to locate a candidate peak in another chromatogram. The algorithm was applied to two different samples featuring isomers. The automatically tracked peaks and the resulting retention parameters generally yielded prediction errors of less than 1%. PMID- 30396267 TI - Extracellular Electron Transfer by Shewanella oneidensis Controls Palladium Nanoparticle Phenotype. AB - The relative scarcity of well-defined genetic and metabolic linkages to material properties impedes biological production of inorganic materials. The physiology of electroactive bacteria is intimately tied to inorganic transformations, which makes genetically tractable and well-studied electrogens, such as Shewanella oneidensis, attractive hosts for material synthesis. Notably, this species is capable of reducing a variety of transition-metal ions into functional nanoparticles, but exact mechanisms of nanoparticle biosynthesis remain ill defined. We report two key factors of extracellular electron transfer by S. oneidensis, the outer membrane cytochrome, MtrC, and soluble redox shuttles (flavins), that affect Pd nanoparticle formation. Changes in the expression and availability of these electron transfer components drastically modulated particle synthesis rate and phenotype, including their structure and cellular localization. These relationships may serve as the basis for biologically tailoring Pd nanoparticle catalysts and could potentially be used to direct the biogenesis of other metal nanomaterials. PMID- 30396268 TI - Genetic and Pharmacological Targeting of Heat Shock Protein 70 in the Mouse Amygdala-Kindling Model. AB - Inflammatory responses involving Toll-like receptor signaling represent a key factor contributing to epileptogenesis. Thus, it is of particular interest to explore the relevance of toll-like receptor ligands and modulators, such as heat shock protein 70 (HSP70). Motivated by recent findings demonstrating an upregulation of HSP70 in a model of epileptogenesis, we analyzed the consequences of genetic and pharmacological targeting of HSP70 expression in a mouse kindling paradigm. Lack of inducible HSP70 resulted in increased prekindling seizure thresholds. However, at threshold stimulation the deficiency-promoted seizure spread, as indicated by an increased seizure severity. Subsequent kindling stimulations elicited more severe seizures in knockout mice, whereas endogenous termination of seizure activity remained unaffected with duration of behavioral and electrographic seizure activity comparable to that of wild-type mice. Interestingly, HSP70 deficiency resulted in enhanced microglia activation in the CA1 region. Next, we assessed a pharmacological targeting approach aiming to promote HSP70 expression. Celastrol treatment had no impact on kindling progression but reduced postkindling seizure thresholds and enhanced microglia activation in CA1 and CA3. In conclusion, the findings from HSP70-knockout mice support a protective role of HSP70 with an effect on microglia activation and spread of seizure activity. Unexpectedly, celastrol administration resulted in detrimental consequences. These findings should be considered as a warning about the general safety of celastrol as a drug candidate. The impact of pathophysiological mechanisms on the quality of celastrol effects requires comprehensive future studies exploring influencing factors. Moreover, alternate strategies to increase HSP70 expression should be further developed and validated. PMID- 30396269 TI - Graphene Nucleation Preference at CuO Defects Rather Than Cu2O on Cu(111): A Combination of DFT Calculation and Experiment. AB - It is well-known that reducing the nucleation density is an effective way to enhance the growth quality of graphene. In this work, we explore the mechanism of graphene nucleation and growth around CuO defects on a Cu(111) substrate by using density functional theory combined with the nudged elastic band method. The defect formation mechanism at the initial nucleation stage is also studied. Our calculation results of the C adsorption energy and the reaction barrier of C-C dimer formation illustrate that the initial nucleation of graphene could be promoted by artificially introducing CuO defects on a Cu(111) surface and the nucleation on the clean Cu(111) substrate could thus be suppressed. These conclusions have been verified by graphene growth experiments using a chemical vapor deposition method. Further studies showed that graphene grown around CuO "seed crystals" could maintain its structural integrity without significantly producing defective carbon rings. This work provides a fundamental understanding and theoretical guidance for the controllable preparation of large-dimension and high-quality graphene by artificially introducing CuO seeds. PMID- 30396270 TI - BCC-Phased PdCu Alloy as a Highly Active Electrocatalyst for Hydrogen Oxidation in Alkaline Electrolytes. AB - Anion-exchange membrane fuel cells hold promise to greatly reduce cost by employing nonprecious metal cathode catalysts. More efficient anode catalysts are needed, however, to improve the sluggish hydrogen oxidation reaction in alkaline electrolytes. We report that BCC-phased PdCu alloy nanoparticles, synthesized via a wet-chemistry method with a critical thermal treatment, exhibit up to 20-fold HOR improvement in both mass and specific activities, compared with the FCC phased PdCu counterparts. HOR activity of the BCC-phased PdCu is 4 times or 2 times that of Pd/C or Pt/C, respectively, in the same alkaline electrolyte. In situ HE-XRD measurements reveal that the transformation of PdCu crystalline structure favors, at low annealing temperature (<300 degrees C), the formation of FCC structure. At higher annealing temperatures (300-500 degrees C), a BCC structure dominates the PdCu NPs. Density functional theory (DFT) computations unravel a similar H binding strength and a much stronger OH binding of the PdCu BCC surface (cf. FCC surface), both of which are simultaneously close to those of Pt surfaces. The synergistic optimization of both H and OH binding strengths is responsible for the enhancement of HOR activity on BCC-phased PdCu, which could serve as an efficient anode catalyst for anion-exchange membrane fuel cells. This work might open a new route to develop efficient HOR catalysts from the perspective of crystalline structure transformation. PMID- 30396271 TI - Size-Dependent Memory Effect of the LiFePO4 Electrode in Li-Ion Batteries. AB - In Li-ion batteries, the phase transition usually determines the electrochemical kinetics of some two-phase electrode materials, and it can be adopted to excellently interpret the memory effect of Li-ion batteries, therefore the size dependence of phase transition was expected to affect the memory effect significantly. In this work, we investigated the memory effect and phase transition of olivine LiFePO4 in Li-ion batteries. Through electrochemical measurements, we found that the memory effect of LiFePO4 was dependent on the particle size, especially after a long-time relaxation. By using the in situ X ray diffraction, we found that the phase transition of nano-LiFePO4 was ahead of the charging and discharging processes, while it took place concurrently or later for micro-LiFePO4, which might be attributed to the high-specific two-phase boundary of nano-LiFePO4. Furthermore, the phase-transition diagram was adopted to interpret the size-dependent memory effect schematically. Notably, it is the first time to report the phase transition ahead of (dis)charging for nano LiFePO4, which is significant to understand the phase transition of two-phase electrode materials, as well as the relevant phenomena, such as the memory effect. PMID- 30396272 TI - Synthesis and in Vivo Evaluation of a Novel PET Radiotracer for Imaging of Synaptic Vesicle Glycoprotein 2A (SV2A) in Nonhuman Primates. AB - Structural disruption and alterations of synapses are associated with many brain disorders including Alzheimer's disease, epilepsy, depression, and schizophrenia. We have previously developed the PET radiotracer 11C-UCB-J for imaging and quantification of synaptic vesicle glycoprotein 2A (SV2A) and synaptic density in nonhuman primates and humans. Here we report the synthesis of a novel radiotracer 18F-SDM-8 and its in vivo evaluation in rhesus monkeys. The in vitro binding assay of SDM-8 showed high SV2A binding affinity ( Ki = 0.58 nM). 18F-SDM-8 was prepared in high molar activity (241.7 MBq/nmol) and radiochemical purity (>98%). In the brain, 18F-SDM-8 displayed very high uptake with peak standardized uptake value (SVU) greater than 8 and fast and reversible kinetics. A displacement study with levetiracetam and blocking studies with UCB-J and levetiracetam demonstrated its binding reversibility and specificity toward SV2A. Regional binding potential values were calculated and ranged from 0.8 in the brainstem to 4.5 in the cingulate cortex. By comparing to 11C-UCB-J, 18F-SDM-8 displayed the same attractive imaging properties: very high brain uptake, appropriate tissue kinetics, and high levels of specific binding. Given the longer half-life of F-18 and the feasibility for central production and multisite distribution, 18F-SDM-8 holds promise as an excellent radiotracer for SV2A and as a biomarker for synaptic density measurement in neurodegenerative diseases and psychiatric disorders. PMID- 30396273 TI - Boundary Lubrication Mechanisms for High-Performance Friction Modifiers. AB - We recently reported a new molecular heterocyclic friction modifier (FM) that exhibits excellent friction and wear reduction in the boundary lubrication regime. This paper explores the mechanisms by which friction reduction occurs with heterocyclic alkyl-cyclen FM molecules. We find that these chelating molecules adsorb onto (oxidized) steel surfaces far more tenaciously than conventional FMs such as simple alkylamines. Molecular dynamics simulations argue that the surface coverage of our heterocyclic FM molecules remains close to 100% even at 200 degrees C. This thermal stability allows the FMs to firmly anchor to the surface, allowing the hydrocarbon chains of the molecules to interact and trap base oil lubricant molecules. This results in thicker boundary film thickness compared with conventional FMs, as shown by optical interferometry measurements. PMID- 30396274 TI - Mutational Analysis of the Role of the Glucansucrase Gtf180-DeltaN Active Site Residues in Product and Linkage Specificity with Lactose as Acceptor Substrate. AB - Glucansucrase Gtf180-DeltaN from Lactobacillus reuteri uses lactose as acceptor substrate to synthesize five glucosylated lactose molecules (F1-F5) with a degree of polymerization (DP) of 3-4 (GL34) and with (alpha1->2)/(alpha1->3)/(alpha1->4) glycosidic linkages. Q1140/W1065/N1029 mutations significantly changed the GL34 product ratios. Q1140 mutations clearly decreased F3 3'-glc-lac with an (alpha1 >3) linkage and increased F4 4',2-glc-lac with (alpha1->4)/(alpha1->2) linkages. Formation of F2 2-glc-lac with an (alpha1->2) linkage and F4 was negatively affected in most W1065 and N1029 mutants, respectively. Mutant N1029G synthesized four new products with additional (alpha1->3)-linked glucosyl moieties (2xDP4 and 2xDP5). Sucrose/lactose strongly reduced Gtf180-DeltaN hydrolytic activity and increased transferase activity of Gtf180-DeltaN and mutant N1029G, in comparison to activity with sucrose alone. N1029/W1065/Q1140 thus are key determinants of Gtf180-DeltaN linkage and product specificity in the acceptor reaction with lactose. Mutagenesis of key residues in Gtf180-DeltaN may allow synthesis of tailor-made mixtures of novel lactose-derived oligosaccharides with potential applications as prebiotic compounds in food/feed and in pharmacy/medicine. PMID- 30396275 TI - Epicatechin Adducting with 5-Hydroxymethylfurfural as an Inhibitory Mechanism against Acrylamide Formation in Maillard Reactions. AB - This study aimed to investigate the inhibitory mechanism of epicatechin (EC) on the formation of acrylamide in Maillard reactions. The glucose + asparagine model is a typical chemical system used to investigate acrylamide formation. 5 Hydroxymethylfurfural (HMF) is an important carbonyl intermediate in Maillard reactions and can also react with asparagine to form acrylamide. Time courses showed that EC inhibited more HMF than acrylamide in the glucose + asparagine model heated at 180 degrees C. The reduction of EC on acrylamide formation in the HMF + asparagine model was about 70%, while that in the glucose + asparagine model was about 50%. Moreover, HMF decreased significantly faster when it was heated in the presence of EC. Liquid chromatography-mass spectrometry analysis revealed the formation of adducts between EC and HMF, and the dimeric adducts were verified in fried potato chips. These results suggested that the condensation of EC and HMF was one of the key steps leading to the inhibition of acrylamide. UV-visible spectra analysis showed that some polymerization products had absorption in the visible region and contributed to the development of browning, which was underestimated in the past. PMID- 30396276 TI - A versatile approach to determine instantaneous co-activation: Development, implementation and comparison to existing measures. AB - An adaptable method of computing muscle co-activity is presented. Instantaneous muscle activities from multiple muscles are reduced into commonality and activity level dimensions. Both dimensions are weighted independently and combined into a co-activation measure, Phi. Myoelectric data from relaxed and braced simulated rear vehicle impacts were used to compare Phi to two existing co-activity measures in muscle pair and multi-muscle cases, Phi showed greater sensitivity in the muscle pair case and could better discriminate the relaxed and braced conditions in the multi-muscle case than previous measures. The flexibility of Phi allowed tailoring to reflect the current purpose. PMID- 30396277 TI - Hospital Nurses in Comparison to Community Nurses: Motivation, Empathy, and the Mediating Role of Burnout. AB - BACKGROUND: Hospital nurses' experience of their profession differs from that of community clinic nurses due to different working conditions and settings. PURPOSE: To compare hospital nurses and community clinic nurses as to the mediating role of burnout on motivation and empathy. METHODS: In this cross sectional study, 457 nurses completed four questionnaires: Demographic, Motivation Questionnaire, the Maslach Burnout Inventory, and the Toronto Empathy Questionnaire. RESULTS: Emotional exhaustion and depersonalization among hospital nurses were significantly higher than among community nurses. No significant differences were found in personal accomplishment, empathy, and motivation between the groups. Empathy and motivation were more strongly correlated among hospital nurses than among community nurses. Burnout was found to be a significant mediator between empathy and motivation in both groups but in each group by different burnout subscales. CONCLUSIONS: To reduce burnout, leaders in the nursing field must enhance conditions in the hospital nurses' work environment to lower levels of emotional exhaustion and depersonalization; community nurses should be guided to improve their attitudes toward their on-the job performance to promote their personal accomplishment. Understanding the differences could direct policy makers' desire toward enacting policies that accommodate these differences and focus on the needs of both groups of professionals. PMID- 30396278 TI - Service and support needs following pediatric brain injury: perspectives of children with mild traumatic brain injury and their parents. AB - OBJECTIVE: To provide a qualitative examination of the service and support needs of children who have had a mild traumatic brain injury (mTBI), and their parents, in order to improve clinical services. METHODS: Semi-structured interviews were conducted with 9 children (8-12 years; M = 10.6 years, SD = 0.8) and their parents (n = 9) 29-55 days (M = 34 days; SD = 9.3) after presenting to an Australian Paediatric Emergency Department (PED) for mTBI. Children's post concussive symptoms (PCS) were additionally measured using the Post-Concussive Symptom Inventory (PCSI). Audio recordings were transcribed, and a thematic analysis was conducted. RESULTS: Post-injury needs were reflected in four main themes: Communication; Family Burden; Continuity of Care; and Social and Community Support. These themes reflected children's and parents' needs for information, emotional/social/community support, and follow-up care. Both the children's and parents' needs, and the extent to which they were met, appeared to be related to the severity and duration of the child's PCS. CONCLUSIONS: Dedicated pediatric mTBI follow-up services that build on family's resources and meet their individual needs for information, emotional support, and referral may assist in optimizing post-injury outcomes. PMID- 30396279 TI - Efficacy of carbidopa-levodopa extended-release capsules (IPX066) in the treatment of Parkinson Disease. AB - INTRODUCTION: Levodopa is the most efficacious and best-tolerated drug for treating Parkinson's disease (PD). To improve the treatment of PD, recent research initiatives have aimed to optimize the pharmacokinetic plasma behavior of L-dopa. Areas covered: This non-systematic, narrative drug evaluation brings the therapeutic value of IPX066 up for discussion. IPX066 is an orally applied levodopa/carbidopa containing formulation with modified drug release. It is rapidly absorbed, similar to conventional immediate-release levodopa preparations. The IPX066 capsule continuously releases levodopa during its passage through the gastrointestinal tract. Expert opinion: IPX066 provides more constant therapeutic levodopa plasma concentrations over longer periods. Furthermore, the IPX066 study program showed superior efficacy of IPX066 than conventional oral levodopa/carbidopa preparations for the treatment of motor complications, particularly with OFF intervals. IPX066 also reduced the frequency of oral levodopa intake. IPX066 may also improve the patient's compliance due to its simplified drug regimen. The marketing of IPX066 outside the US is complex since in countries like Germany, health-care payers only consider innovation in terms of mode of action whereas innovation of pharmacokinetic and pharmacodynamic properties is disregarded. PMID- 30396280 TI - Numerical studies of the influence of various geometrical features of a multispiked connecting scaffold prototype on mechanical stresses in peri-implant bone. AB - The multispiked connecting scaffold (MSC-scaffold) prototype is an essential innovation in the fixation of components of resurfacing arthroplasty (RA) endoprostheses, providing their entirely non-cemented and bone-tissue-preserving fixation in peri-articular bone. An FE study is proposed to evaluate the influence of geometrical features of the MSC-scaffold on the transfer of mechanical load in peri-implant bone. For this study, an FE model of Ti-Alloy MSC scaffold prototype embedded in a bilinear elastic, transversely isotropic bone material was built. For the compressive load on the MSC-scaffold, maps of Huber Mises-Hencky (HMH) stress in peri-implant bone were determined. The influence of the distance between the bases of neighbouring spikes, the apex angle of spikes, and the height of the spherical cup of spikes of the MSC-scaffold were analysed. It was found that the changes in the distance between the bases of neighbouring spikes from 0.2 to 0.5 mm cause the HMH stress to increase in bone material by 32%. The changes of the apex angle of spikes from 2 degrees to 4 degrees decrease the HMH stress in bone material by 39%. The changes of height of the spherical cup of spikes from 0 to 0.12 mm increase the HMH stress in bone material by 24%. In conclusion, the spikes' apex angle and the distance between the bases of spikes of the MSC-scaffold are the key geometrical features determining the appropriate MSC-scaffold prototype design. The built FE model was found to be useful in bioengineering design of the novel fixation system for RA endoprostheses by means of the MSC-scaffold. PMID- 30396281 TI - Infant Temperament in the FMR1 Premutation and Fragile X Syndrome. AB - Although temperament has been studied for decades as a predictor of psychopathology in the general population, examining temperament in neurogenetic groups has unique potential to inform the genetic and biological factors that may confer risk for psychopathology in later development. The present study examined early temperament in two heritable neurogenetic conditions associated with atypical CGG repeat expansions on the FMR1 gene: the FMR1 premutation (FXpm; 55 200 repeats) and fragile X syndrome (FXS; > 200 repeats). We focus specifically on the FXpm, as the condition is highly prevalent (1:209-291 female individuals, 1:430-855 male individuals) and has been preliminarily associated with increased risk for pediatric psychopathology, including attention problems, autism, and anxiety. In contrast, FXS is a low-incidence disorder (1:7,143 males, 1:11,111 females) often associated with intellectual disability and severe co-occurring psychosocial conditions, particularly in male individuals. Given information on infant clinical phenotypes in the FXpm and FXS is sparse, we aimed to characterize parent-reported infant temperament in infants with the FXpm (n = 22) relative to FXS (n = 24) and controls (n = 24) assessed on 1 to 3 occasions each. Temperament in infants with the FXpm largely fell between TD and FXS groups, with trends toward suppressed negative affect in younger participants, similar to lower negative affect previously reported in FXS. The FXS group consistently demonstrated lower negative affect and surgency than TD controls. These data suggest that FMR1 gene mutations are associated with atypical temperament that emerges as early as infancy, particularly among infants with FXS, warranting further study of whether temperament may index emergent clinical risks in these populations. PMID- 30396282 TI - The nanotechnology among US: are metal and metal oxides nanoparticles a nano or mega risk for soil microbial communities? AB - Metal nanoparticles and metal oxides nanoparticles (MNPs/MONPs) have been widely included in a great diversity of products and industrial applications and they are already a part of our everyday life. According to estimation studies, their production is expected to increase exponentially in the next few years. Consequently, soil has been suggested as the main sink of MNPs/MONPs once they are deliberately or accidentally released into the environment. The potential negative perturbations that may result on soil microbial communities and ecological processes are resulting in concerns. Several nano-toxicological studies of MNPs/MONPs, reported so far, have focused on aquatic organisms, animals, and soil invertebrates. However, during recent years, the studies have been oriented to understand the effects of MNPs/MONPs on microbial communities and their interaction with soil components. The studies have suggested that MNPs/MONPs are one of the most toxic type to soil biota, amongst different types of nanomaterials. This may threaten soil health and fertility, since microbial communities are known to support important biological processes and ecosystem services such as the nutrient cycling, whereby their protection against the environmental pollution is imperative. Therefore, in this review we summarize the actual knowledge available from the last five years (2013-2018) and gaps about the potential negative, positive or neutral effects produced on soil by different classes of MNPs/MONPs. A particular emphasis has been placed on the associated soil microorganisms and biological processes. Finally, perspectives about future research are discussed. PMID- 30396283 TI - Nucleolin Overexpression Confers Increased Sensitivity to the Anti-Nucleolin Aptamer, AS1411. AB - AS1411 is an antiproliferative DNA aptamer, which binds the ubiquitous protein, nucleolin. In this study, we show that constitutive overexpression of nucleolin confers increased sensitivity to the growth inhibitory effects of AS1411. HeLa cells overexpressing nucleolin have an increased growth rate and invasiveness relative to control cells. Nucleolin overexpressing cells demonstrate increased growth inhibition in response to the AS1411 treatment, which correlates with increased apoptosis and cell cycle arrest, when compared to non-transfected cells. AS1411 induces nucleolin expression at the RNA and protein level in HeLa cells, suggesting a feedback loop with important implications for the clinical use of AS1411. PMID- 30396284 TI - Uncertainty analysis of material properties and morphology parameters in numerical models regarding the motion of lumbar vertebral segments. AB - The kinematics of a spinal motion segment is determined by the material properties of the soft-tissue and the morphology. The material properties can vary within subjects and between vertebral levels, leading to a wide possible range of motion of a spinal segment independently on its morphology. The goal of this numerical study was to identify the most influential material parameters concerning the kinematics of a spinal motion segment and their plausible ranges. Then, a method was tested to deduce the material properties automatically, based on a given ROM and morphology. A fully parametric finite element model of the morphology and material properties of a lumbar spinal motion segment was developed. The impact of uncertainty of twelve spinal material parameters, as well as the size of the gap between the articular surfaces of the facet joints was examined. The simulation results were compared to our own in vitro data. The flexibility of a lumbar segment was especially influenced by the properties of the anterior annulus region, the facet gap size and the interspinous ligament. The high degree of uncertainty in the material properties and facet gap size published in the literature can lead to a wide scatter in the motion of a spinal segment, with a range of 6 degrees -17 degrees in the intact condition in flexion/extension, from 5 degrees -22 degrees in lateral bending and from 3 degrees -14 degrees in axial rotation. Statistical analysis of the variability might help to estimate the sensitivity and total uncertainty propagated through biomechanical simulations, affecting the reliability of the predictions. PMID- 30396285 TI - Tumor suppression by the EGR1, DMP1, ARF, p53, and PTEN Network. AB - Recent studies have indicated that EGR1 is a direct regulator of tumor suppressors including TGFbeta1, PTEN, and p53. The Myb-like transcription factor Dmp1 is a physiological regulator of the Arf-p53 pathway through transactivation of the Arf promoter and physical interaction of p53. The Dmp1 promoter has binding sites for Egr proteins, and Egr1 is a target for Dmp1. Crosstalks between p53 and PTEN have been reported. The Egr1-Dmp1-Arf-p53-Pten pathway displays multiple modes of interaction with each other, suggesting the existence of a functional network of tumor suppressors that maintain normal cell growth and prevent the emergence of incipient cancer cells. PMID- 30396286 TI - Combination of the double-microcatheter technique and triaxial system in coil packing for visceral and renal artery aneurysms. AB - BACKGROUND: In coil packing for visceral artery aneurysms (VAAs), difficulties are sometimes associated with preserving the patency of the parent artery, particularly for wide-neck aneurysms. However, the double-microcatheter technique effectively prevents coil migration, while the triple-coaxial (triaxial) system is useful for reducing microcatheter kick-back. PURPOSE: To assess the feasibility of combining these two techniques in coil packing for VAAs. MATERIAL AND METHODS: Coil packing using the double-microcatheter technique and triaxial system was attempted for seven VAAs in six patients between August 2015 and January 2018. The technical success rate, packing density of aneurysms, complications related to the procedure, and occlusion status were evaluated. Technical success was defined as the completion of coil packing by immediate post embolic angiography. The occlusion status was evaluated using time-resolved magnetic resonance angiography. RESULTS: There were three renal, three splenic, and one anterior superior pancreaticoduodenal aneurysms. The median size of VAAs was 13 mm (range = 8-21 mm), with five being classified as wide-neck aneurysms. The completion of coil packing was confirmed for all VAAs and the technical success rate was 100%. The median packing density was 28% (range = 22-40%). There were no complications related to the procedure. The median follow-up period was 14 months (range = 8-24 months). In six VAAs that were followed up, there were three complete occlusions, three neck remnants, and no body filling; re-treatment was not required in any patient. CONCLUSION: The combination of the double microcatheter technique and triaxial system is a feasible method of coil packing for VAAs. PMID- 30396288 TI - Erratum. PMID- 30396287 TI - Ultrasensitive Doppler as a tool for the diagnosis of testicular ischemia during the Valsalva maneuver: a new way to explore varicoceles? AB - BACKGROUND: Varicocele is among the most common causes of male infertility because of various mechanism, including hypoxia. PURPOSE: To evaluate testicular vascularization (TV) with ultrasensitive Doppler before and during the Valsalva maneuver (VM) and correlate TV changes to varicocele's spermatic venous reflux graduated by color Doppler. MATERIAL AND METHODS: From January to February 2016, 69 men (135 testis) referred for scrotal ultrasound were prospectively enrolled. An institutional review board approved the study. As gold standard, the spermatic venous reflux in the supratesticular region was assessed with color Doppler ultrasound and graded from 0 to III. A new ultra-sensitive Doppler (USD) sequence was performed on testicular parenchyma in an axial view. The TV changes before and during the VM were qualitatively graded from 0 to 2 using a visual scale by consensus. The vessels surface was quantified using customized MATLAB(r) software, and compared to the testicular delineated surface, resulting in a vessels surface ratio (VSR). The absolute and relative VSR difference before and during the VM was calculated. The qualitative scale and the quantitative VSR changes were compared with the spermatic venous reflux grade using an analysis of variance. RESULTS: A strong correlation has been found between the spermatic venous reflux grade and TV decrease during the VM using USD, for qualitative graduation as well as for quantitative measurement ( P < 0.0001). CONCLUSION: TV assessed by USD decreased significantly during the VM in patients with varicocele; this decrease was significantly associated with spermatic venous reflux grade. PMID- 30396290 TI - Engineering of grain seed genes for prevention of heart disease and Alzheimer's disease. PMID- 30396291 TI - Are there patients missing from community heart failure registers? An audit of clinical practice. AB - BACKGROUND: General practitioners in the UK are financially incentivised, via the Quality Outcomes Framework, to maintain a record of all patients at their practice with heart failure and manage them appropriately. The prevalence of heart failure recorded in primary care registers (0.7-1.0%) is less than reported in epidemiological studies (3-5%). Using an audit of clinical practice, we set out to investigate if there are patients 'missing' from primary care heart failure registers and what the underlying mechanisms might be. DESIGN: The design of this study was as an audit of clinical practice at a UK general practice ( n = 9390). METHODS: Audit software (ENHANCE-HF) was used to identify patients who may have heart failure via a series of hierarchical searches of electronic records. Heart failure was then confirmed or excluded based on the electronic records by a heart failure specialist nurse and patients added to the register. Outcome data for patients without heart failure was collected after two years. RESULTS: Heart failure prevalence was 0.63% at baseline and 1.12% after the audit. Inaccurate coding accounted for the majority of missing patients. Amongst patients without heart failure who were taking a loop diuretic, the rate of incident heart failure was 13% and the rate of death or hospitalization with heart failure was 25% respectively during two-year follow-up. CONCLUSION: There are many patients missing from community heart failure registers which may detriment patient outcome and practice income. Patients without heart failure who take loop diuretics are at high risk of heart failure-related events. PMID- 30396292 TI - Ultra-endurance exercise in a heart transplant athlete: Influence on myocardial function and biomarkers. PMID- 30396293 TI - Association between physical activity, occupational sitting time and mortality in a general population: An 18-year prospective survey in Tanushimaru, Japan. AB - AIMS: It is well known that a decline in physical activity is associated with an increase of all-cause death including cardiovascular events and cancer. Few studies have examined the association between occupational sitting time and mortality. Therefore, we investigated this issue in a general population. METHODS: Physical activity and occupational sitting time were measured using the Baecke physical activity questionnaire in 1999. The questionnaire generated indices in three physical activity categories: work, sport and leisure-time. A total physical activity index was calculated by adding these three indices. The Baecke physical activity questionnaire was able to evaluate occupational sitting time. Hazard ratios and 95% confidence intervals (CIs) were calculated using Cox's proportional hazard regression models. RESULTS: We enrolled a total of 1680 participants, who were followed up for 15.9 +/- 3.8 years. The final follow-up rate was 93%. During the follow-up period, 397 subjects died. A significant inverse association ( p < 0.0001) was found between physical activity and mortality after adjustment for age and sex. Compared with lower levels of physical activity, the adjusted hazard ratio for mortality at higher levels of physical activity was 0.85 (95% CI: 0.78-0.92). Longer occupational sitting time was also significantly associated with higher mortality ( p < 0.01). The adjusted hazard ratio for mortality at longer occupational sitting time was 1.16 (95% CI: 1.05-1.27). These findings were observed in males, but not in females. CONCLUSIONS: Our data demonstrated that higher levels of physical activity are associated with a reduced risk of cancer and cardiovascular death. Further, longer occupational sitting time is associated with increased mortality. PMID- 30396294 TI - Postoperative myocardial injury: Trying to square the circle. PMID- 30396295 TI - Regular physical activity prior to myocardial infarction may not protect against the mortality risk induced by sedentary behaviour in myocardial infarction survivors. PMID- 30396296 TI - Oxygen uptake efficiency slope in children: Its role in exercise testing. PMID- 30396297 TI - Rehabilitation after cardiac surgery. PMID- 30396299 TI - MTA1 promotes the invasion and migration of pancreatic cancer cells potentially through the HIF-alpha/VEGF pathway. AB - The metastasis-associated gene 1 (MTA1) has previously been recognized as an oncogene, and abnormal MTA1 expression has been related to progression of numerous cancer types to the metastasis stage. However, the function of MTA1 in the regulation of pancreatic cancer progression and metastasis remains unclear. Western blot analysis was adopted to determine the expression of MTA1 in pancreatic cancer tissues and corresponding near normal tissues. Steady clone with MTA1-overexpression and MTA1-inhibitionweregenerated via lentivirus technology in BxPc-3 cells. Transwell assay was carried out for detecting the invasion of pancreatic cancer cells. The migration activity was assessed using the wound scratch assay. The effect of MTA1 in pancreatic cancer was evaluated in the mice xenografts. Western blot analysis was employed to determine the expression of hypoxia inducible factor-alpha (HIF-alpha) and vascular endothelial growth factor (VEGF) in vitro and in vivo. We observed that MTA1 overexpression enhanced migration and invasion ability of pancreatic cancer cells in vitro and increased HIF-alpha and VEGF protein levels in vitro and in vivo. MTA1 inhibition had the opposite effects. MTA1 protein level was positively related to HIF-alpha and VEGF protein levels. These results indicated that MTA1 potentially promoted pancreatic cancer metastasis via HIF-alpha/VEGF pathway. This research supplies a new molecular mechanism for MTA1 in the pancreatic cancer progression and metastasis. MTA1 may be an effective therapy target in pancreatic cancer. PMID- 30396301 TI - What is the best pharmacotherapeutic strategy for HER-2 positive breast cancer? PMID- 30396302 TI - Reducing the occurrence rate of catheter dysfunction in peritoneal dialysis: a single-center experience about CQI. AB - To reduce the occurrence rate of peritoneal dialysis (PD) catheter dysfunction caused by catheter displacement or plugging, this study screened all patients with peritoneal dialysis catheterization from 2002 to 2015 from the Third Xiangya Hospital of Central South University. There were 256 patients before continuous quality improvement (CQI) (from 2002 to 2007) and 813 patients after CQI (from 2008 to 2015). The occurrence rate of catheter dysfunction was 5.9% in the preCQI group: seven cases were associated with peritonitis, six cases were involved in omentum wrapping, one case was blocked by oviduct, and one case was blocked by blood clot. Through PDCA (plan-do-check-act) four-step of CQI, the following measures were adopted: (1) Preoperative: treat complications, enema and urine catheterization (2) Intraoperative: strengthen analgesia, Lower the insert position of catheter to 7.5 ~ 8.5 cm above the pubic symphysis, extending the straight distance of catheter in rectus abdominis and decrease the times of peritoneal dialysis catheter implantation. (3) Postoperative: strengthen the training of nurses, patients and their families. (4) strengthen anticoagulation therapy during peritonitis treatment. (5) use laparoscopic technology for refractory patients, and so on. The occurrence of catheter dysfunction was 1.5% in the postCQI group (p < 0.05): two cases were associated with peritonitis, ten cases were involved in omentum wrapping. The measures we adopted in CQI reduce the occurrence rate of catheter displacement or plugging in peritoneal dialysis. PMID- 30396300 TI - Wider intraoperative glycemic fluctuation increases risk of acute kidney injury after pediatric cardiac surgery. AB - OBJECTIVE: The association between poor intraoperative glycemic control and postoperative acute kidney injury (AKI) in adult cardiac surgery has been observed, but data in the pediatrics remain unknown. We performed a hypothesis that intraoperative hyperglycemia and/or wider glycemic fluctuation were associated with the incidence of postoperative AKI in pediatric cardiac surgery. METHODS: A retrospective study was performed in pediatrics who underwent cardiac surgery from 2013 to 2016. Perioperative glycemic data up to 48 hours after surgery were collected and analyzed. Patients with AKI were matched 1:1 with patients without AKI by a propensity score. Variables of demographic data, preoperative renal function and glycemic level, perioperative cardiac condition were matched. RESULTS: The incidence of AKI was 11.5% (118/1026), with 53.4% (63/118), 30.5% (36/118), and 16.1% (19/118) categorized as AKIN stages I, II, and III, respectively. Children who experienced AKI were younger and cyanotic, underwent more complex surgeries, had higher peak intraoperative glucose levels, wider intraoperative glycemic fluctuation, greater inotropic scores and more transfusions, and poor outcomes (all p < .05). After matching, the AKI group had significantly wider intraoperative glycemic fluctuation (p < .05). Logistic regression showed intraoperative glycemic fluctuation was one of the risk factors for AKI (p = .033) and degree of AKI severity stage increased when the glycemic fluctuation increased (p < .01). CONCLUSIONS: Wider intraoperative glycemic fluctuation, but not hyperglycemia, was associated with an increased incidence of postoperative AKI after pediatric cardiac surgery. PMID- 30396303 TI - Updates in the management and treatment of HCV genotype 3, what are the remaining challenges? AB - INTRODUCTION: Chronic hepatitis C (CHC) genotype-3 (G-3) infection is the next most prevalent genotype with 54.3 million patients globally. It is associated with an increasing risk of fibrosis, liver-related events, hepatocellular carcinoma, and overall mortality. G-3 infection may have a negative impact on histological and clinical outcomes in CHC patients. In addition, its characteristic features of steatosis and metabolic abnormalities may add more difficulty in the disease management. Area covered: Fortunately, the landscape of management has been drastically changed in the past decade with the blooming of all oral direct antiviral agents (DAAs). The extremely high efficacy, high safety, short treatment duration, low adverse effects, and easy dosing of DAAs provide an excellent exploration of medical therapeutics in human history. The review consisted of the updated management of CHC G-3, and also touched upon what are the remaining challenges currently. Some challenges and unmet needs were also raised in a clinical setting, including treatment barriers, clinical outcomes, and metabolic abnormalities. Expert commentary: There is a pressing need for management of G-3 infection because of its large patient burden and poor clinical outcomes than other genotypes. Further investigation is warranted in terms of its treatment barriers and clinical outcomes. PMID- 30396305 TI - On the plasticizing properties of divalproex sodium: physicochemical and spectroscopic characterization studies. AB - The objective of the research was to demonstrate the plasticization properties of divalproex sodium, due to its component-valproic acid, on ethyl cellulose, which could prove beneficial for film fabrications or hot melt extrusion based formulations. Films containing 10-50% w/w (DVS/EC) as dry weight were prepared using solvent evaporation method and characterized using texture analyzer, hybrid rheometer, differential scanning calorimetry, thermogravimetry, X-ray diffractometry, polarized microscopy, FTIR, and Raman spectroscopy. It was found that there was a decrease in average peak load, melt viscosity, and glass transition temperature (Tg) while increase in elongation, with increase in concentration of DVS in the films. These results demonstrate the plasticization tendency of DVS on EC, which was attributed to the presence of valproic acid (fatty acid) in DVS. XRD studies showed amorphous nature of the films; however, polarized microscopy revealed the presence of scattered undissolved sodium valproate crystals. The presence of a single Tg established complete miscibility between valproic acid and EC. Films showed reasonable physical stability (similar Tg) at 45 degrees C/75% RH for 2 weeks (open condition), attributable to the similar solubility parameters of DVS and EC. FTIR and Raman spectroscopy results proved the presence of hydrogen bonding between DVS and EC. PMID- 30396304 TI - Impact of acute kidney injury in donors on renal graft survival: a systematic review and Meta-Analysis. AB - The acute kidney injury (AKI) of deceased donors was an important strategy to address donor shortage. This meta-analysis was conducted to explore the clinical effect of kidney transplantation from donors with AKI. PubMed, Embase, and Cochrane Library were searched through July 2017. Fourteen cohort studies, involving a total of 15,345 donors, were included. Studies were pooled, and the hazard ratio (HR), relative risk (RR), weighted mean difference (WMD), and their corresponding 95% confidence interval (CI) were calculated. The present meta analysis showed no significant difference in allograft survival between the AKI and non-AKI groups (HR = 1.16, 95% CI = 0.99-1.37, Pheterogeneity = 0.238, I2 = 21.6%) from 12 months to 120 months after kidney transplantation. However, the time of hospital stay was significantly longer (WMD = 2.49, 95% CI = 1.06-3.92, Pheterogeneity = 0.458, I2 = 0%) and the incidence of delayed graft function (DGF) was significantly higher (RR = 1.76, 95% CI = 1.52-2.04, Pheterogeneity < 0.001, I2 = 71.2%) in the AKI group than in the non-AKI group. We concluded that even though hospital stay time was longer and the incidence of DGF was significantly higher in the AKI group, there is no significant difference in allograft survival between the two groups. PMID- 30396306 TI - Vegetarian diet may ameliorate uremic pruritus in hemodialysis patients. AB - OBJECTIVES: Systemic inflammation has been reported to be associated with uremic pruritus (UP). Although a vegetarian diet can reduce systemic inflammation in hemodialysis patients, the effect of vegetarian diet on UP is not clear. The purpose of the study was to know the possible effects of vegetarian diet on UP. METHODS: A cross-sectional study was done to compare the severity of UP and blood levels of systemic inflammatory markers between vegetarian and non-vegetarian hemodialysis patients. Six non-vegetarian patients with uremic pruritus changed their non-vegetarian diet to vegetarian diet for 2 months. Visual Analogue Scale (VAS) and pruritus score (PS) were used to measure the UP severity. The serum high-sensitivity C-reactive protein (hs-CRP), and interleukin-2 (IL-2) were used as markers of inflammation. RESULTS: Both the median VAS scores (p = .043) and the median PS scores (p < .001) were lower in the Vegetarian than in the non vegetarian group. The median values of hs-CRP in Vegetarian were lower than that for the non-vegetarian (p = .020). The median value of IL-2 was also lower in Vegetarian than that of the non-vegetarian (p = .016). There were 6 non vegetarian patients shift to vegetarian for 2 months. The pruritus score improved and IL-2 level decreased after change to vegetarian diet. CONCLUSION: We concluded that vegetarian diet might be associated with the amelioration of the uremic pruritus severity in hemodialysis patients. PMID- 30396307 TI - T-cell lymphoblastic lymphoma involving the ocular adnexa: report of two cases and review of the current literature. AB - The majority of ocular adnexal lymphomas are B-cell in origin. We report two cases of T-cell lymphoblastic lymphoma (T-LBL) involving the ocular adnexa. One patient presented with a painless pink conjunctival lesion and inferior orbital fullness. The second patient presented with a painless orbital mass. The diagnoses were confirmed by histopathology and immunohistochemistry. Both patients had extensive multifocal lesions during staging. Prompt intensified chemotherapy regimens were initiated. T-LBL is an aggressive disease with poor prognosis. This report emphasizes the importance of timely diagnosis by the ophthalmologist with co-management and treatment with an oncologist. PMID- 30396308 TI - Protective potential of Angelica sinensis polysaccharide extract against ethylene glycol-induced calcium oxalate urolithiasis. AB - PURPOSE: To evaluate a Angelica sinensis polysaccharide aqueous extract as a preventive agent in experimentally induced urolithiasis using in- vitro and vivo models. MATERIAL AND METHODS: Angelica sinensis polysaccharide was investigated in vitro to determine its antilithiatic effects on the formation and morphology of calcium oxalate (CaOx) crystals and was analyzed in vivo to determine its ability to prevent CaOx urolithiasis in rats subjected to ethylene glycol-induced urolithiasis. Potassium citrate administration was used in the positive control group. The urolithiasis-related biochemical parameters were evaluated in the rats urine, serum and kidney homogenates. Kidney sections were subjected to histopathological and immunohistochemical analyses, and urolithiasis-related phospho-c-Jun NH2-terminal protein kinase and kidney injury molecule-1proteins were evaluated by Western blot analyses. RESULTS: Angelica sinensis polysaccharide exhibited concentration-dependent inhibition of CaOx crystal formation. The in vitro assay revealed significant inhibition of crystal formation (6.99 +/- 1.07) in the group treated with 4.0 mg/mL Angelica sinensis polysaccharide extract compared with the control group (58.38 +/- 5.63; p < .05). In vivo, after treatment with ethylene glycol for 28 days, urinary oxidative stress, oxalate, creatinine, urea and urolithiasis-related protein were significantly increased (p < .05), except for serum oxidative stress (p > .05). The rats administered the extract of Angelica sinensis polysaccharide showed significantly decreased pathological change and CaOx deposition (p < .05) compared with the urolithiatic rats. Significantly reduced levels of urinary oxidative stress, oxalate, creatinine, urea and urolithiasis-related protein were observed in the Angelica sinensis polysaccharide treatment groups (p < .05) compared with the nephrolithic rats. CONCLUSION: The results presented here suggest that Angelica sinensis polysaccharide has the potential to inhibit CaOx crystallization in vitro and may present anti-urolithiatic effects in vivo. PMID- 30396309 TI - Significance of M2 macrophage in tubulointerstitial disease secondary to primary Sjogren's disease. AB - OBJECTIVE: M2 Macrophages could improve tubulointerstitial disease in animal models. HIF-1alphapromotes macrophage polarization and is involved in tubular injury. The study aims to observe the clinicopathologic significance of M2 macrophage and HIF-1alpha in tubulointerstitial injury secondary to primary Sjogren's disease. METHODS: Renal tissue samples from patients with tubulointerstitial disease secondary to primary Sjogren's disease (SS, n = 10), chronic tubulointerstitial nephritis secondary to drug (CIN, n = 8) were included in this study. The expression of CD163, CD68 and HIF-1alpha were examined by immunohistochemistry or immunofluorescence. RESULTS: (1) Renal involvement was the first manifestation in seven of ten (7/10) patients with pSS, including proteinuria, renal dysfunction, renal tubular acidosis and multiple renal stone; and two patient had intractable hypokalemia. (2) There were numerous CD163- positive cells and CD68- positive cells infiltration in tubulointerstitial injury of pSS, especially in patients with hypokalemia. CD163 positive cells and HIF 1alphawere mainly expressed in acute tubulointerstitial injury of pSS, which positively correlated to N-acetyl-beta-D-glucosaminidase and beta2-microglobulin. (3) Compared with CIN, patients with pSS had higher serum globulin level, erythrocyte sedimentation rate (ESR) and lower urinary osmotic pressure. (4) During follow-up of one year, six patients with pSS and acute tubular injury acquired improved renal function on therapy of steroid and total glucosides of peony. The remaining four patients with pSS had stable renal function. CONCLUSION: M2 macrophages are involved in acute tubular injury in patients with primary Sjogren's disease. Early intervention can improve renal function of tubulointerstitial injury secondary to primary Sjogren's disease. PMID- 30396310 TI - Zerumbone binding to estrogen receptors: an in-silico investigation. AB - Breast cancer is the most frequent malignancy among females worldwide. Estrogen receptor (ER) mediate important pathophysiological signaling pathways induced by estrogens, and is regarded as a promising target for the treatment of breast cancer. Zerumbone (2,6,9,9-tetramethylcycloundeca-2,6,10-trien-1-one; ZER), a chemical constituent present in the Zingiber zerumbet is known to exhibit anti breast cancer activity by modulating several proteins to induce apoptosis. Medicinal chemists usually exploit lead compounds of natural origin to develop molecules with improved pharmacological properties. Current study is intended to utilize molecular modeling techniques to investigate the interaction of ZER with estrogen receptors. AutoDock was used to predict the binding modes of ZER and target receptors. Stability of the ZER-ER complex was verified by molecular dynamics simulation using Desmond software. Docked ZER was further optimized by density functional theory (DFT) using Gaussian09 program. Analysis of docked conformations in terms of binding energy disclosed estrogen receptor-beta (ERbeta) as more promising than estrogen receptor-alpha (ERalpha). Evaluation of MD trajectories of ZER bound to both ERalpha and ERbeta showed appreciable stability with minimum Calpha-atom root mean square deviation shifts. DFT based global reactivity descriptors such as electron affinity, hardness, chemical potential, electronegativity and electrophilicity index, calculated from the energies of highest occupied and lowest unoccupied molecular orbitals underscored the electronic features governing viability of the ZER for interaction with the target receptors. In conclusion, these findings can be exploited to design and develop novel anticancer agents based on the lead compound, ZER. PMID- 30396311 TI - Optical coherence tomography: Translation from 3D-printed vascular models of the anterior cerebral circulation to the first human images of implanted surface modified flow diverters. AB - BACKGROUND: The new generation of flow diverters includes a surface modification with a synthetic biocompatible polymer, which makes the device more biocompatible and less thrombogenic. Optical coherence tomography (OCT) can be used to visualize perforators, stent wall apposition, and intra-stent thrombus. Unfortunately real world application of this technology has been limited because of the limited navigability of these devices in the intracranial vessels. In this report, we share our experience of using 3D-printed neurovascular anatomy models to simulate and test the navigability of a commercially available OCT system and to show the application of this device in a patient treated with the new generation of surface modified flow diverters. MATERIAL AND METHODS: Navigability of OCT catheters was tested in vitro using four different 3D-printed silicone replicas of the intracranial anterior circulation, after the implantation of surface modified devices. Intermediate catheters were used in different tortuous anatomies and positions. After this assessment, we describe the OCT image analysis of a Pipeline Shield for treating an unruptured posterior communicating artery (PCOM) aneurysm. RESULTS: Use of intermediate catheters in the 3D-printed replicas was associated with better navigation of the OCT catheters in favorable anatomies but did not help as much in unfavorable anatomies. OCT image analysis of a PCOM aneurysm treated with Pipeline Embolization Device Shield demonstrated areas of unsatisfactory apposition with no thrombus formation. CONCLUSIONS: OCT improves the understanding of the flow diversion technology. The development of less thrombogenic devices, like the Pipeline Flex with Shield Technology, reinforces the need for intraluminal imaging for neurovascular application. PMID- 30396312 TI - The role of trust in health information from medical authorities in accepting the HPV vaccine among African American parents. AB - This research examines how and why trust in health information from medical authorities (i.e., doctors or health care professionals and government health agencies) predicts acceptance of the HPV vaccine for one's child among African American parents. A survey of African American parents recruited from community venues revealed that low trust in health information from government health agencies was associated with less favorable attitudes and intentions toward vaccinating their child against HPV. Trust in health information from a doctor or health care professional did not predict vaccine acceptance. Mediation analyses indicated that the relationship between trust in health information from government health agencies and vaccine acceptance was partially mediated by perceived vaccine efficacy. Implications of the findings on communicating to the African American community about the HPV vaccine are discussed. PMID- 30396313 TI - Incidence of idiopathic intracranial hypertension in Fife. AB - BACKGROUND AND AIMS: Idiopathic intracranial hypertension is a clinical syndrome of intracranial hypertension with normal cerebrospinal fluid in the absence of a mass lesion or hydrocephalus on brain imaging. Headache is the most common symptom of idiopathic intracranial hypertension, and about 10-15% of patients suffer from irreversible visual impairment. Previous estimates of the annual incidence of idiopathic intracranial hypertension vary worldwide from 0.03 to 2.2 per 100,000. The major risk factor implicated in idiopathic intracranial hypertension is body mass. Scotland has one of the worst records for obesity in the developed world, and the prevalence of obesity in Fife is higher than the Scottish average. Our aim was to record the incidence of idiopathic intracranial hypertension in NHS Fife over a one-year period. METHODS AND RESULTS: Prospective study including every patient who was seen in the ophthalmology department in NHS Fife with a new diagnosis of idiopathic intracranial hypertension over a one-year period. Thirteen patients were seen with a new diagnosis of idiopathic intracranial hypertension from August 2013 to July 2014 giving an incidence of 3.56 per 100,000. Headache was the most common presenting symptom. Three patients were asymptomatic but were noted to have swollen optic discs during a routine sight test. One patient complained of visual symptoms. All patients were overweight. The mean BMI was 36 (range: 28-49). CONCLUSION: The incidence of idiopathic intracranial hypertension in NHS Fife was significantly higher than previous estimates in the literature. This is probably due to a high level of obesity in Fife. Scotland is in the midst of an obesity epidemic and if this continues we may see increasing levels of idiopathic intracranial hypertension nationally with associated increasing incidence of visual impairment in young adults. PMID- 30396314 TI - Optic atrophy after cabazitaxel treatment in a patient with castration-resistant prostate cancer: a case report. AB - Taxanes are a group of cytotoxic anti-cancer agents used in the treatment of solid tumours. The neurotoxic adverse effects of docetaxel and paclitaxel, including optic neuropathy, are well known. Cabazitaxel is a new generation taxane showing lesser drug resistance when compared with previous ones. Optic atrophy due to the use of cabazitaxel has not been previously reported. Herein, we report a patient with prostate cancer who developed optic atrophy after cabazitaxel treatment. PMID- 30396315 TI - Functional magnetic resonance imaging of head and neck cancer: Performance and potential. AB - Functional magnetic resonance imaging (MRI) of tumors of the head and neck usually encompasses diffusion-weighted imaging (DWI) and intravenous (IV) contrast T1 dynamic perfusion imaging (DCE-MRI or PWI). Both techniques can characterize different tissues by probing into their microstructure, providing a novel approach in oncological imaging. In this pictorial review, we will cover the important technical aspects of DWI and PWI, the pathophysiological background and the current applications and potential of these functional MRI techniques in the imaging of head and neck cancer. PMID- 30396316 TI - In silico insights into the identification of potential novel angiogenic inhibitors against human VEGFR-2: a new SAR-based hierarchical clustering approach. AB - In this study, binding efficiency of new pyrrolopyrimidine structural analogs against human vascular endothelial growth factor receptor-2 (VEGFR-2) were elucidated using integrated in silico methods. Optimized high-resolution model of VEGFR-2 was generated and adopted for structure-based virtual screening approaches. Pyrrolopyrimidine inhibitor (CP15) associated compounds were screened from PubChem database and subjected to virtual screening and comparative docking methods against the receptor ligand-binding domain. Accordingly, high efficient compounds were clustered with similarity indices through PubChem structure cluster module using single-linkage algorithm. Moreover, pharmacokinetics including drug metabolism activities of high-binding leads under investigation was portrayed using ADMET and similarity ensemble analysis. Optimal energy orientations of the selected protein model have been shown to be reliable, and highly recommended for screening and docking studies. Docking and clustering strategies were shown that nineteen candidates as most effective binders for VEGFR-2 than CP15, and are grouped as three classes. Lys868, Glu885, Cys919, His1026, Arg1027, Asp1046, and Gly1048 residues were predicted as novel hotspot residues, and participate in H-bonds, pi-cation, pi-stacking, halogen bonds, and salt-bridges formation with ligands. These additional bonds are contributing extent stability that holds the receptor structure at flexible state, this make difficult to any further conformational changes for evoking angiogenic signals. The ADMET and similarity ensemble analysis results were strongly indicated that thirteen candidates as best ligands for angiogenesis targets. Altogether, these findings indicate potential angiogenic templates and their binding levels with VEGFR-2; sorted viewpoints could be useful as a promising way to describe potential angiogenesis inhibitors with related molecular targets. PMID- 30396317 TI - Immunogenicity and safety of an egg-based inactivated quadrivalent influenza vaccine (GC3110A) versus two inactivated trivalent influenza vaccines with alternate B strains: A phase III randomized clinical trial in adults. AB - Two antigenically distinct influenza B lineage viruses (Yamagata/Victoria) have been co-circulating globally since the mid-1980s. The quadrivalent influenza vaccine (QIV) may provide better protection against unpredictable B strains. We conducted a randomized, double-blind, phase III trial to evaluate the immunogenicity and safety of an egg-based inactivated, split-virion QIV (GC3110A). Subjects aged >= 19 years were randomized 2:1:1 to be vaccinated with QIV- GC3110A, trivalent influenza vaccine (TIV) containing the Yamagata lineage strain (TIV-Yamagata), or TIV containing the Victoria lineage strain (TIV Victoria). Hemagglutination inhibition assays were performed 21 days post vaccination. Solicited/unsolicited adverse events (AEs) were assessed within 21 days after vaccination, while serious AEs were reported up to six months after vaccination. A total of 1,299 were randomized to receive QIV-GC3110A (648 subjects), TIV-Yamagata (325 subjects), or TIV-Victoria (326 subjects). Compared to the TIVs, the QIV-GC3110A met the non-inferiority criteria for all four subtype/lineage strains with respect to the geometric mean titer (GMT) ratio and the difference of seroconversion rate. The safety profiles of QIV-GC3110A were consistent with those of TIV. In conclusion, QIV-GC3110A is safe, immunogenic, and comparable to strain-matched TIV. PMID- 30396318 TI - Acceptability and efficacy of partner notification for curable sexually transmitted infections in sub-Saharan Africa: A systematic review. AB - Comprehensive case management of sexually transmitted infections (STIs) includes partner notification. We reviewed the recent literature evaluating the acceptability and efficacy of partner notification strategies (i.e. direct patient referral, provider referral, or expedited partner treatment) for curable STIs in sub-Saharan Africa. We conducted a systematic search following PRISMA guidelines: published January 2008 to June 2017 in the English language, study in sub-Saharan Africa, and discussion of any curable STI with an outcome on partner notification. We searched six electronic databases, conference abstracts, online clinical trial registries, and article bibliographies. The results showed that out of the 74 identified articles, 55 did not meet inclusion criteria. Of the 11 studies evaluating direct patient referral, the proportion of index cases ( n = 4163) who successfully notified sex partner(s) was 53% (range 23-95%). Among those who notified ( n = 1727), 25% (range 0-77%) had partner(s) that sought evaluation (95% CI 0.51-0.54; 95% CI 0.23-0.27). Both provider referral and expedited partner treatment had higher proportions of partner(s) who sought treatment ( n = 208, 69% and n = 44, 84%, respectively). Direct patient referral is the most commonly used and evaluated partner notification strategy for STIs in sub-Saharan Africa with mixed success. We recommend future research to investigate other strategies such as expedited partner treatment. PMID- 30396319 TI - Burden of genital warts in Peru: an observational study. AB - Genital warts (GW) are mucosal or skin lesions caused by sexual transmission of human papillomavirus (HPV). This study estimates the frequency of GW cases in physicians' clinics and physicians' usual practices of GW referral and diagnosis in Peru. Participants in this study were a convenience sample of 100 physicians in five specialties: primary care (17), gynecology (37), urology (10), dermatology (31), and infectious diseases (5). Physicians completed a survey and daily log of all patients aged 18-60 years seen over ten days in their offices located in Peru. The survey recorded GW referral patterns and the daily log recorded patient demographic information and GW diagnosis. Among 12,058 patients, the annual GW prevalence (95% confidence interval [CI]) was 2.28% (2.02-2.56) and cumulative incidence (95% CI) was 1.60% (1.38-1.84). Physicians reported that most GW patients were direct consult (73.5% of male and 67.9% of females) and physicians treated most GW patients themselves (73.4% of males and 76.7% of females). As reported, the most common reasons for referring were 'serious cases requiring more specialized treatment' (73.2% of male and 72.2% of female) and 'lack of resources to treat' (26.8% of male and 27.8% of female). We conclude that GW cases are commonly seen by physicians in Peru. PMID- 30396320 TI - Promotion of cell-invasive activity through the induction of LPA receptor-1 in pancreatic cancer cells. AB - Lysophosphatidic acid (LPA) is a simple biological lipid and mediates several biological functions with LPA receptors (LPA1 to LPA6). In the present study, to assess whether LPA receptors promote cell-invasive activity of pancreatic cancer cells, highly invasion PANC-R9 cells were established from PANC-1 cells, using Matrigel-coated Cell Culture Insert. The cell-invasive activity of PANC-R9 cells was shown to be approximately 15 times higher than that of PANC-1 cells. LPAR1 expression level was markedly elevated in PANC-R9 cells in comparison with PANC-1 cells, while LPAR3 expression level was reduced. The cell-invasive activity of PANC-R9 cells was enhanced by LPA, but LPA had no impact on PANC-1 cell invasion. Before initiation of the cell invasion assay, PANC-R9 cells were pretreated with dioctanoylglycerol pyrophosphate (DGPP), an antagonist of LPA1/LPA3. The invasive activity of PANC-R9 cells was markedly suppressed by DGPP. Autotaxin (ATX) is a key enzyme that catalyzes the conversion of lysophosphatidylcholine (LPC) to LPA. ATX expression level was elevated in PANC-R9 cells compared with PANC-1 cells. In the presence of LPC, the cell motile activity of PANC-R9 cells was markedly stimulated. In contrast, LPC did not affect the cell motile activity of PANC-1 cells. PANC-R9 cell motility was inhibited by an ATX inhibitor, PF-8380. These results suggest that LPA signaling via LPA1 is a potent molecular target for the regulation of tumor progression in PANC-1 cells. PMID- 30396321 TI - Short- and Long-term Opioid Use in Patients with Oral and Oropharynx Cancer. AB - OBJECTIVE: Opioid use and abuse is a national health care crisis, yet opioids remain the cornerstone of pain management in cancer. We sought to determine the risk of acute and chronic opioid use with head and neck squamous cell cancer (HNSCC) treatment. STUDY DESIGN: Retrospective population-based study. SETTING: Surveillance, Epidemiology and End Results (SEER)-Medicare database from 2008 to 2011. SUBJECTS AND METHODS: In total, 976 nondistant metastatic oral cavity and oropharynx patients undergoing cancer-directed treatment enrolled in Medicare were included. Opiate use was the primary end point. Univariate and multivariable logistic analyses were completed to determine risk factors. RESULTS: Of the patients, 811 (83.1%) received an opioid prescription during the treatment period, and 150 patients (15.4%) had continued opioid prescriptions at 3 months and 68 (7.0%) at 6 months. Opioid use during treatment was associated with prescriptions prior to treatment (odds ratio [OR], 3.28; 95% confidence interval [CI], 2.11-5.12) and was least likely to be associated with radiation treatment alone (OR, 0.35; 95% CI, 0.18-0.68). Risk factors for continued opioid use at both 3 and 6 months included tobacco use (OR, 2.23; 95% CI, 1.05-4.71 and OR, 3.84; 95% CI, 1.44-10.24) and opioids prescribed prior to treatment (OR, 3.84; 95% CI, 2.45-5.91 and OR, 3.56; 95% CI, 1.95-6.50). Oxycodone prescribed as the first opioid was the least likely to lead to ongoing use at 3 and 6 months (OR, 0.33; 95% CI, 0.17-0.62 and OR, 0.26; 95% CI, 0.10-0.67). CONCLUSION: Patients with oral/oropharyngeal cancer are at a very high risk for receiving opioids as part of symptom management during treatment, and a significant portion continues use at 3 and 6 months after treatment completion. PMID- 30396322 TI - Accuracy of Self-reported Diagnosis of Chronic Rhinosinusitis. AB - Large cohort studies of chronic rhinosinusitis (CRS) prevalence often include patients who have been inappropriately diagnosed with the disease. In this investigation, new patients presenting to a tertiary rhinology practice completed a screening questionnaire that included questions about self-reported CRS status, demographic information, and symptomatology. Treating rhinologists evaluated patients according to clinical practice guideline criteria for CRS; 91 patients were ultimately diagnosed with CRS. The sensitivity of self-report for CRS was 84%; the specificity was 82%; and the estimated negative predictive value ranged from 97% to 99%. Prior sinus surgery or oral steroid use correlated with CRS self report, and a concurrent self-report of nasal polyps or nasal steroid use improved the positive predictive value of CRS self-report. Self-report of CRS status may represent an effective and relatively inexpensive screening mechanism for CRS in large cohort studies, particularly when combined with other associated diagnostic features that improve performance parameters of self-report. PMID- 30396323 TI - Predicting Alcohol Misuse Among Australian 19-Year-Olds from Adolescent Drinking Trajectories. AB - BACKGROUND: Alcohol use in adolescence predicts future alcohol misuse. However, the extent to which different patterns of adolescent use present risk remains unclear. OBJECTIVES: This study investigated how adolescent trajectories of alcohol consumption during the school years predict alcohol misuse at age 19 years. METHODS: Data were drawn from 707 students from Victoria, Australia, longitudinally followed for 7 years. Five alcohol use trajectories were identified based on the frequency of alcohol use from Grade 6 (age 12 years) to Grade 11 (age 17 years). At age 19 years, participants completed measures indicating Heavy Episodic Drinking (HED), dependency - Alcohol Use Disorders Identification Test (AUDIT) and social harms. RESULTS: At 19 years of age, 64% of participants reported HED, 42% high AUDIT scores (8+), and 23% social harms. Participants belonging to a steep escalator trajectory during adolescence had twice the odds at 19 years of age of high AUDIT scores and social harms, and three times greater odds of HED than participants whose alcohol use slowly increased. Stable moderate consumption was also associated with an increased risk of HED compared to slowly increasing use. Abstinence predicted a reduced likelihood of all forms of misuse at 19 years of age compared to slowly increased alcohol use. CONCLUSIONS: Trajectories of drinking frequency during adolescence predict alcohol misuse at age 19 years. Although rapid increasing use presents the greatest risk, even slowly increasing drinking predicts increased risk compared to abstinence. The findings indicate that alcohol policies should recommend nonuse and reduced frequency of use during adolescence. PMID- 30396324 TI - Emerging Technologies for the Diagnosis of Otitis Media. AB - OBJECTIVE: To review new experimental techniques for the diagnosis of otitis media (OM). DATA SOURCES: Literature search in English in the following databases: MEDLINE (via PubMed), Ovid Medline, Google Scholar, and Clinical Evidence (BMJ Publishing) between January 1, 2005, and April 30, 2018. Subsequently, articles were reviewed and included only if relevant. REVIEW METHODS: MeSH terms: ["diagnosis"] AND [all forms of OM] AND ["human"] AND ["ear"] and ["tympanic membrane"]. The retrieved innovative diagnostic techniques rely on and take advantage of the physical properties of the tympanomastoid cavity components: tympanic membrane (TM) thickness, its translucency and compliance; middle ear fluid characteristics; biofilm presence; increased tissue metabolic activity in OM states; and fluid presence in the mastoid cavity. These parameters are taken into account to establish OM diagnosis objectively. We review spectral gradient acoustic reflectometry, digital otoscopy, TM image analysis, multicolor reflectance imaging, anticonfocal middle ear assessment, optical coherence tomography, quantitative pneumatic otoscopy, transmastoid ultrasound, wideband measurements, TM thickness mapping, shortwave infrared imaging, and wideband acoustic transfer functions. CONCLUSIONS: New experimental techniques are gradually introduced to overcome the limitations of standard otoscopy. The aforementioned techniques are still under investigation and are pending widespread clinical use. The implementation of these techniques in the market is dependent on their success in clinical trials, as well as on their future cost. IMPLICATION FOR PRACTICE: New techniques for the diagnosis of OM can objectively evaluate the morphology of the TM, determine the presence of middle ear fluid and evaluate its content, and thus potentially replace standard otoscopy. PMID- 30396325 TI - Microstructure, mechanical properties, and preliminary biocompatibility evaluation of binary Ti-Zr alloys for dental application. AB - The microstructure, mechanical properties, and in vitro biocompatibility of vacuum-sintered Ti-xZr binary alloys (x = 5, 15, 25, 35, 45 wt%) were investigated. The results indicated that alpha and alpha' phase existed in Ti-xZr alloys. The hardness of the Ti-Zr alloys increased as the contents increased and ranged from 473 HV (Ti-5Zr) to 525 HV (Ti-45Zr). Increasing Zr content could lead to an increase in compressive and bending strength. Additionally, the Ti-45Zr alloy exhibited the maximum bending strength of 867.1 MPa and the maximum compressive strength of 1599.8 MPa which were much larger than that of CP-Ti. Moreover, all Ti-Zr alloys showed a lower elastic modulus (ranging from 53.5 to 59.3 GPa) compared with CP-Ti (103 GPa). The in vitro cytotoxicity tests were carried out for biocompatibility evaluation. The alloys presented no cytotoxic effects and the surface of the alloys exhibited great growth conditions for MG-63 cells. The Ti-45Zr alloy exhibited better mechanical properties and biocompatibility. In conclusion, Ti-45Zr alloy is of great potential for dental applications. PMID- 30396326 TI - Effect of water glass coating of tricalcium phosphate granules on in vivo bone formation. AB - BACKGROUND: Recently, some authors introduced a water glass (WG, sodium-silicate glass; Na2O.SiO2.nH2O) coating over tricalcium phosphate (TCP) bioceramic to modulate its resorption rate and enhance the bone cell behaviors. In this study, four different types of granular samples were prepared to evaluate the ability of new bone formation in vivo using micro-computed tomography and histology. METHODS: Four types sample groups: group A (pure HA as a negative resorption control); group B (pure TCP as a positive resorption control); group C (WG-coated TCP as an early resorption model); and group D (same as group C but heat-treated at 500 degrees C as a delayed resorption model). Cylindrical tube-type carriers with holes were fabricated with HA by extrusion and sintering. Each carrier was filled densely with each granular sample. Four types of tubes were implanted into the medial femoral condyle and medial tibial condyle of New Zealand White rabbits. RESULTS: The HA group (A) showed the lowest amount of new bone formation. All the TCP sample groups (B, C, and D) showed more new bone formation. On the other hand, among the TCP groups, group C (early resorption model) showed slightly more bone formation. The amount of residual bioceramics was most abundant in the HA group (A). All the TCP sample groups showed less residual bioceramics than group A. Among the TCP groups, group C showed slightly more residual bioceramics. Group B showed the lowest amount of residual bioceramics. CONCLUSIONS: The WG-coated TCP sample (group C) is the best bone substitute candidate because of its proper biodegradation rate and the Si ions release because the WG-coated layer reduces the material resorption and enhances the new bone formation. That is, the WG-coated TCP is believed to be the best material for the application of an artificial bone substitute material. PMID- 30396327 TI - Distribution of mercury in the combustion products from coal-fired power plants in Guizhou, southwest China. AB - Method 30B and the Ontario Hydro Method (OHM) were used to sample the mercury in the flue gas discharged from the seven power plants in Guizhou Province, southwest China. In order to investigate the mercury migration and transformation during coal combustion and pollution control process, the contents of mercury in coal samples, bottom ash, fly ash, and gypsum were measured. The mercury in the flue gas released into the atmosphere mainly existed in the form of Hg degrees . The precipitator shows a superior ability to remove Hgp (particulate mercury) from flue gas. The removal efficiency of Hg2+ by wet flue gas desulfurization (WFGD) was significantly higher than that for the other two forms of mercury. The synergistic removal efficiency of mercury by the air pollution control devices (APCDs) installed in the studied power plants is 66.69-97.56%. The Hg mass balance for the tested seven coal-fired power plants varied from 72.87% to 109.67% during the sampling time. After flue gas flowing through APCDs, most of the mercury in coal was enriched in fly ash and gypsum, with only a small portion released into the atmosphere with the flue gas. The maximum discharge source of Hg for power plants was fly ash and gypsum instead of Hg emitted with flue gas through the chimney into the atmosphere. With the continuous upgrading of APCDs, more and more mercury will be enriched in fly ash and gypsum. Extra attention should be paid to the re-release of mercury from the reutilization of by-products from APCDs. Implications: Method 30B and the Ontario Hydro Method (OHM) were used to test the mercury concentration in the flue gas discharged from seven power plants in Guizhou Province, China. The concentrations of mercury in coal samples, bottom ash, fly ash, and gypsum were also measured. By comparison of the mercury content of different products, we found that the maximum discharge source of Hg for power plants was fly ash and gypsum, instead of Hg emitted with flue gas through the chimney into the atmosphere. With the continuous upgrading of APCDs, more and more mercury will be enriched in fly ash and gypsum. Extra attention should be paid to the re-release of mercury from the reutilization of by-products from APCDs. PMID- 30396328 TI - Conservative management of type 1A endoleaks at completion angiogram in endovascular repair of infra-renal abdominal aortic aneurysms with current generation stent grafts. AB - PURPOSE: Proximal type 1A endoleaks on completion intra-operative angiography are not infrequently seen following endovascular abdominal aneurysm repair (EVAR). The natural course of these leaks is not well established. We sought to determine the rate of spontaneous resolution and a conservative treatment approach to these endoleaks. METHODS: All cases involving endovascular repairs of infra-renal abdominal aortic aneurysms resulting in proximal type 1A endoleak on final intra operative completion angiography were retrospectively reviewed from 1 April 2010 and 30 March 2015. Demographic, pre and post-procedural imaging, and clinical outcomes were reviewed. Summarizing descriptive statistics are reported. RESULTS: Of the 337 patients who underwent an EVAR, 24 patients (7.1%) had a proximal type 1A endoleak on final intra-operative angiography. Twenty-two of 24 patients (92%) with proximal type 1A endoleaks had spontaneous resolution on follow-up imaging without any intervention, while two (8%) patients had a persistent endoleak. One of these patients required intervention. The median follow-up for patients with resolved endoleaks was 2.5 years vs. 4 and 6 years, respectively, for patients that did not resolve spontaneously. CONCLUSION: A conservative approach may be used in the management of patients with proximal type 1A endoleaks on completion angiography once maximum proximal seal was achieved intra-operatively as the vast majority of these leaks spontaneously seal. PMID- 30396329 TI - Population Health Solutions for Assessing Cognitive Impairment in Geriatric Patients. AB - In December 2017, the National Academy of Neuropsychology convened an interorganizational Summit on Population Health Solutions for Assessing Cognitive Impairment in Geriatric Patients in Denver, Colorado. The Summit brought together representatives of a broad range of stakeholders invested in the care of older adults to focus on the topic of cognitive health and aging. Summit participants specifically examined questions of who should be screened for cognitive impairment and how they should be screened in medical settings. This is important in the context of an acute illness given that the presence of cognitive impairment can have significant implications for care and for the management of concomitant diseases as well as pose a major risk factor for dementia. Participants arrived at general principles to guide future screening approaches in medical populations and identified knowledge gaps to direct future research. Key learning points of the summit included: recognizing the importance of educating patients and healthcare providers about the value of assessing current and baseline cognition; emphasizing that any screening tool must be appropriately normalized and validated in the population in which it is used to obtain accurate information, including considerations of language, cultural factors, and education; and recognizing the great potential, with appropriate caveats, of electronic health records to augment cognitive screening and tracking of changes in cognitive health over time. PMID- 30396330 TI - Common ancestry of heterodimerizing TALE homeobox transcription factors across Metazoa and Archaeplastida. AB - BACKGROUND: Complex multicellularity requires elaborate developmental mechanisms, often based on the versatility of heterodimeric transcription factor (TF) interactions. Homeobox TFs in the TALE superclass are deeply embedded in the gene regulatory networks that orchestrate embryogenesis. Knotted-like homeobox (KNOX) TFs, homologous to animal MEIS, have been found to drive the haploid-to-diploid transition in both unicellular green algae and land plants via heterodimerization with other TALE superclass TFs, demonstrating remarkable functional conservation of a developmental TF across lineages that diverged one billion years ago. Here, we sought to delineate whether TALE-TALE heterodimerization is ancestral to eukaryotes. RESULTS: We analyzed TALE endowment in the algal radiations of Archaeplastida, ancestral to land plants. Homeodomain phylogeny and bioinformatics analysis partitioned TALEs into two broad groups, KNOX and non KNOX. Each group shares previously defined heterodimerization domains, plant KNOX homology in the KNOX group and animal PBC-homology in the non-KNOX group, indicating their deep ancestry. Protein-protein interaction experiments showed that the TALEs in the two groups all participated in heterodimerization. CONCLUSIONS: Our study indicates that the TF dyads consisting of KNOX/MEIS and PBC-containing TALEs must have evolved early in eukaryotic evolution. Based on our results, we hypothesize that in early eukaryotes, the TALE heterodimeric configuration provided transcription-on switches via dimerization-dependent subcellular localization, ensuring execution of the haploid-to-diploid transition only when the gamete fusion is correctly executed between appropriate partner gametes. The TALE switch then diversified in the several lineages that engage in a complex multicellular organization. PMID- 30396331 TI - Study protocol: Care of Late-Stage Parkinsonism (CLaSP): a longitudinal cohort study. AB - BACKGROUND: Parkinson's disease (PD) is a chronic progressive disorder leading to increasing disability. While the symptoms and needs of patients in the early stages of their disease are well characterized, little information is available on patients in the late stage of the disease. METHODS/DESIGN: The Care of Late Stage Parkinsonism (CLaSP) study is a longitudinal, multicenter, prospective cohort study to assess the needs and provision of care for patients with late stage Parkinsonism and their carers in six European countries (UK, France, Germany, Netherlands, Portugal, Sweden). In addition, it will compare the effectiveness of different health and social care systems. Patients with Parkinsonism with Hoehn and Yahr stage >=IV in the "On"-state or Schwab and England stage 50% or less are evaluated at baseline and three follow-up time points. Standardised questionnaires and tests are applied for detailed clinical, neuropsychological, behavioural and health-economic assessments. A qualitative study explores the health care needs and experiences of patients and carers, and an interventional sub-study evaluates the impact of specialist recommendations on their outcomes. DISCUSSION: Through the combined assessment of a range of quantitative measures and qualitative assessments of patients with late stage parkinsonism, this study will provide for the first time comprehensive and in depth information on the clinical presentation, needs and health care provision in this population in Europe, and lay the foundation for improved outcomes in these patients. TRIAL REGISTRATION: The protocol was registered at ClinicalTrials.gov as NCT02333175 on 07/01/2015. PMID- 30396332 TI - Growth patterns from birth to 24 months in Chinese children: a birth cohorts study across China. AB - BACKGROUND: Assessment of child growth is important in detecting under- and over growth. We aimed to examine the growth patterns of healthy Chinese infants from birth to 24 months. METHODS: This study was based on six recent birth cohorts across China, which provided data (from 2015) on 4251 children (2174 boys, 2077 girls) who were born at term to mothers without gestational or preexisting diabetes, chronic hypertension, preeclampsia, or eclampsia. Analyses were performed using 28,298 longitudinal anthropometric measures in 4251 children and the LMS method to generate smoothed Z-score growth curves, which were compared to the WHO growth standards (which are based on data from 2003) and current Chinese growth references (which are based on data from 2005). RESULTS: Most (80.3%) of mother had college education or more, and maternal smoking was rare (0.4%). Compared to the WHO longitudinal growth standards for children aged 0 to 2 years, the growth references from this longitudinal study (length-, weight-, head circumference-, BMI-for-age, and weight-for-length) were significantly higher, for boys and girls; Specifically, the median length-, weight-, head circumference , BMI-for-age, and weight-for-length was on average 0.9 (range 0.2-1.3) cm, 0.51 (range 0.09-0.74) kg, 0.17 (range - 0.24 to 0.37) cm, 0.70 (range 0.01 to 0.92) kg/m2, and 0.43 (range 0.01 to 1.07) kg higher in Chinese boys, and 1.3 (range 0.5-1.9) cm, 0.73 (range 0.10-0.91) kg, 0.45 (range 0.15-0.62) cm, 0.7 (range 0.0 to 1.0) kg/m2, and 0.42 (range 0.00 to 0.64) kg greater in Chinese girls, respectively. Compared to the current China cross-sectional growth references (based on data from a decade ago), growth references from this study were also higher, but the difference was less than that between growth references of this study and WHO growth standards. CONCLUSIONS: This recent multicenter prospective birth cohort study examined early growth patterns in China. The new growth curves represent the growth patterns of healthy Chinese infants evaluated longitudinally from 0 to 24 months of age, and provide references for monitoring growth in early life in modern China that are more recent than WHO longitudinal growth standards from other countries and previous cross-sectional growth references for China. PMID- 30396333 TI - Exosomal miR-99a-5p is elevated in sera of ovarian cancer patients and promotes cancer cell invasion by increasing fibronectin and vitronectin expression in neighboring peritoneal mesothelial cells. AB - BACKGROUND: microRNAs (miRNAs) stably exist in circulating blood and are encapsulated in extracellular vesicles such as exosomes. The aims of this study were to identify which exosomal miRNAs are highly produced from epithelial ovarian cancer (EOC) cells, to analyze whether serum miRNA can be used to discriminate patients with EOC from healthy volunteers, and to investigate the functional role of exosomal miRNAs in ovarian cancer progression. METHODS: Exosomes were collected from the culture media of serous ovarian cancer cell lines, namely TYK-nu and HeyA8 cells. An exosomal miRNA microarray revealed that several miRNAs including miR-99a-5p were specifically elevated in EOC-derived exosomes. Expression levels of serum miR-99a-5p in 62 patients with EOC, 26 patients with benign ovarian tumors, and 20 healthy volunteers were determined by miRNA quantitative reverse transcription-polymerase chain reaction. To investigate the role of exosomal miR-99a-5p in peritoneal dissemination, neighboring human peritoneal mesothelial cells (HPMCs) were treated with EOC derived exosomes and then expression levels of miR-99a-5p were examined. Furthermore, mimics of miR-99a-5p were transfected into HPMCs and the effect of miR-99a-5p on cancer invasion was analyzed using a 3D culture model. Proteomic analysis with the tandem mass tag method was performed on HPMCs transfected with miR-99a-5p and then potential target genes of miR-99a-5p were examined. RESULTS: The serum miR-99a-5p levels were significantly increased in patients with EOC, compared with those in benign tumor patients and healthy volunteers (1.7-fold and 2.8-fold, respectively). A receiver operating characteristic curve analysis showed with a cut-off of 1.41 showed sensitivity and specificity of 0.85 and 0.75, respectively, for detecting EOC (area under the curve = 0.88). Serum miR 99a-5p expression levels were significantly decreased after EOC surgeries (1.8 to 1.3, p = 0.002), indicating that miR-99a-5p reflects tumor burden. Treatment with EOC-derived exosomes significantly increased miR-99a-5p expression in HPMCs. HPMCs transfected with miR-99a-5p promoted ovarian cancer invasion and exhibited increased expression levels of fibronectin and vitronectin. CONCLUSIONS: Serum miR-99a-5p is significantly elevated in ovarian cancer patients. Exosomal miR-99a 5p from EOC cells promotes cell invasion by affecting HPMCs through fibronectin and vitronectin upregulation and may serve as a target for inhibiting ovarian cancer progression. PMID- 30396334 TI - Growth during the first year in infants affected by neonatal abstinence syndrome. AB - BACKGROUND: Infants with neonatal abstinence syndrome (NAS) initially experience neurologic excitability, poor feeding, and/or hyperphagia in the setting of increased metabolic demand. Because the longitudinal effects of these early symptoms and behaviors on weight trends are unknown, we sought to contrast weight gain patterns through age 1 year for infants diagnosed with NAS with matched controls. METHODS: Retrospective cohort of 70 singletons with a gestational age of >=37 weeks and an ICD-9 or ICD-10 diagnosis of NAS made <=7 days after birth with institutional follow-up matched to patients without NAS. Infants were matched on gestational age (+/-2 weeks), birth weight (+/-20 g), sex (exact), and insurance type (exact). Quantile regression methods were used to estimate 10th, 25th, 50th, 75th and 90th percentiles of weight over time. RESULTS: The mean gestational age for an infant with NAS was 38.8 weeks (standard deviation [SD], 1.3). The mean birth weight was 3.141 kg (SD, 0.510). NAS patients had a median of 24 weights recorded between birth and 400 days (inter-quartile range [IQR], 16 32 weights). Patients without NAS had a median of 12 weights recorded (IQR, 10 16). Growth curves were similar over the first 400 days of life. Patients with NAS had non-significantly higher and lower estimated weights for the 90th and 10th percentiles, respectively. CONCLUSION: Infants with a diagnosis of NAS grew similarly to controls during their first year. Given the frequently-encountered NAS symptoms of hyperphagia and irritability, future studies may evaluate whether early differences in caregiver feeding exist and whether they have longer-term impacts on growth. PMID- 30396335 TI - Is traumatic brain injury a risk factor for neurodegeneration? A meta-analysis of population-based studies. AB - BACKGROUND: To determine the association of prior traumatic brain injury (TBI) with subsequent diagnosis of neurodegeneration disease. METHODS: All studies from 1980 to 2016 reporting TBI as a risk factor for diagnoses of interest were identified by searching PubMed, Embase, study references, and review articles. The data and study design were assessed by 2 investigators independently. A meta analysis was performed by RevMan 5.3. RESULTS: There were 18 studies comprising 3,263,207 patients. Meta-analysis revealed a significant association of prior TBI with subsequent dementia. The pooled odds ratio (OR) for TBI on development of dementia, FTD and TDP-43 associated disease were 1.93 (95% CI 1.47-2.55, p < 0.001), 4.44 (95% CI 3.86-5.10, p < 0.001), and 2.97 (95% CI 1.35-6.53, p < 0.001). However, analyses of individual diagnoses found no evidence that the risk of Alzheimer's disease, and Parkinson's disease in individuals with previous TBI compared to those without TBI. CONCLUSIONS: History of TBI is not associated with the development of subsequent neurodegeneration disease. Care must be taken in extrapolating from these results because no suitable criteria define post TBI neurodegenerative processes. Therefore, further research in this area is needed to confirm these questions and uncover the link between TBI and neurodegeneration disease. PMID- 30396336 TI - Intracranial pressure responsiveness to positive end-expiratory pressure in different respiratory mechanics: a preliminary experimental study in pigs. AB - BACKGROUND: Respiratory mechanics affects the effect of positive end-expiratory pressure (PEEP) on intracranial pressure (ICP). Respiratory mechanics of the lung and the chest wall was not differentiated in previous studies. In the present study, we investigated the influence of the following possible determinants of ICP responsiveness to PEEP: chest wall elastance (ECW), lung elastance (EL), and baseline ICP. METHODS: Eight healthy Bama miniature pigs were studied. The increase of EL was induced by instillation of hydrochloride, and the increase of ECW was induced by strapping the animals' chest wall and abdomen. A balloon tipped catheter was placed intracranially for inducing intracranial hypertension. Six experimental conditions were investigated in sequence: 1) Normal; 2) Stiff Chest Wall; 3) Lung Injury; 4) Lung Injury + Stiff Chest Wall; 5) Lung Injury + Stiff Chest Wall + Intracranial Hypertension and 6) Lung Injury + Intracranial Hypertension. PEEP was gradually increased in a 5 cm H2O interval from 5 to 25 cm H2O in each condition. Blood pressure, central venous pressure, ICP, airway pressure and esophageal pressure were measured. RESULTS: Hydrochloride instillation significantly increased EL in conditions with lung injury. ECW significantly increased in the conditions with chest wall and abdomen strapping (all p < 0.05). ICP significantly increased with increments of PEEP in all non intracranial hypertension conditions (p < 0.001). The greatest cumulative increase in ICP was observed in the Stiff Chest Wall condition (6 [5.3, 6.8] mm Hg), while the lowest cumulative increase in ICP was observed in the Lung Injury condition (2 [1.3, 3.8] mm Hg). ICP significantly decreased when PEEP was increased in the intracranial hypertension conditions (p < 0.001). There was no significant difference in cumulative ICP change between the two intracranial hypertension conditions (p = 0.924). CONCLUSIONS: Different respiratory mechanics models can be established via hydrochloride induced lung injury and chest wall and abdominal strapping. The effect of PEEP on ICP is determined by respiratory mechanics in pigs with normal ICP. However, the responsiveness of ICP to PEEP is independent of respiratory mechanics when there is intracranial hypertension. PMID- 30396338 TI - 15 years of BMC Biology. PMID- 30396337 TI - Data assimilation and multisource decision-making in systems biology based on unobtrusive Internet-of-Things devices. AB - Biological and medical diagnoses depend on high-quality measurements. A wearable device based on Internet of Things (IoT) must be unobtrusive to the human body to encourage users to accept continuous monitoring. However, unobtrusive IoT devices are usually of low quality and unreliable because of the limitation of technology progress that has slowed down at high peak. Therefore, advanced inference techniques must be developed to address the limitations of IoT devices. This review proposes that IoT technology in biological and medical applications should be based on a new data assimilation process that fuses multiple data scales from several sources to provide diagnoses. Moreover, the required technologies are ready to support the desired disease diagnosis levels, such as hypothesis test, multiple evidence fusion, machine learning, data assimilation, and systems biology. Furthermore, cross-disciplinary integration has emerged with advancements in IoT. For example, the multiscale modeling of systems biology from proteins and cells to organs integrates current developments in biology, medicine, mathematics, engineering, artificial intelligence, and semiconductor technologies. Based on the monitoring objectives of IoT devices, researchers have gradually developed ambulant, wearable, noninvasive, unobtrusive, low-cost, and pervasive monitoring devices with data assimilation methods that can overcome the limitations of devices in terms of quality measurement. In the future, the novel features of data assimilation in systems biology and ubiquitous sensory development can describe patients' physical conditions based on few but long-term measurements. PMID- 30396339 TI - Robust IoT-based nursing-care support system with smart bio-objects. AB - BACKGROUND: The significant advancement in the mobile sensing technologies has brought great interests on application development for the Internet-of-Things (IoT). With the advantages of contactlessness data retrieval and efficient data processing of intelligent IoT-based objects, versatile innovative types of on demand medical relevant services have promptly been developed and deployed. Critical characteristics involved within the data processing and operation must thoroughly be considered. To achieve the efficiency of data retrieval and the robustness of communications among IoT-based objects, sturdy security primitives are required to preserve data confidentiality and entity authentication. METHODS: A robust nursing-care support system is developed for efficient and secure communication among mobile bio-sensors, active intelligent objects, the IoT gateway and the backend nursing-care server in which further data analysis can be performed to provide high-quality and on-demand nursing-care service. RESULTS: We realize the system implementation with an IoT-based testbed, i.e. the Raspberry PI II platform, to present the practicability of the proposed IoT-oriented nursing-care support system in which a user-friendly computation cost, i.e. 6.33 ms, is required for a normal session of our proposed system. Based on the protocol analysis we conducted, the security robustness of the proposed nursing care support system is guaranteed. CONCLUSIONS: According to the protocol analysis and performance evaluation, the practicability of the proposed method is demonstrated. In brief, we can claim that our proposed system is very suitable for IoT-based environments and will be a highly competitive candidate for the next generation of nursing-care service systems. PMID- 30396340 TI - Comparison of named entity recognition methodologies in biomedical documents. AB - BACKGROUND: Biomedical named entity recognition (Bio-NER) is a fundamental task in handling biomedical text terms, such as RNA, protein, cell type, cell line, and DNA. Bio-NER is one of the most elementary and core tasks in biomedical knowledge discovery from texts. The system described here is developed by using the BioNLP/NLPBA 2004 shared task. Experiments are conducted on a training and evaluation set provided by the task organizers. RESULTS: Our results show that, compared with a baseline having a 70.09% F1 score, the RNN Jordan- and Elman-type algorithms have F1 scores of approximately 60.53% and 58.80%, respectively. When we use CRF as a machine learning algorithm, CCA, GloVe, and Word2Vec have F1 scores of 72.73%, 72.74%, and 72.82%, respectively. CONCLUSIONS: By using the word embedding constructed through the unsupervised learning, the time and cost required to construct the learning data can be saved. PMID- 30396341 TI - Best serum biomarker combination for ovarian cancer classification. AB - BACKGROUND: Screening test using CA-125 is the most common test for detecting ovarian cancer. However, the level of CA-125 is diverse by variable condition other than ovarian cancer. It has led to misdiagnosis of ovarian cancer. METHODS: In this paper, we explore the 16 serum biomarker for finding alternative biomarker combination to reduce misdiagnosis. For experiment, we use the serum samples that contain 101 cancer and 92 healthy samples. We perform two major tasks: Marker selection and Classification. For optimal marker selection, we use genetic algorithm, random forest, T-test and logistic regression. For classification, we compare linear discriminative analysis, K-nearest neighbor and logistic regression. RESULTS: The final results show that the logistic regression gives high performance for both tasks, and HE4-ELISA, PDGF-AA, Prolactin, TTR is the best biomarker combination for detecting ovarian cancer. CONCLUSIONS: We find the combination which contains TTR and Prolactin gives high performance for cancer detection. Early detection of ovarian cancer can reduce high mortality rates. Finding a combination of multiple biomarkers for diagnostic tests with high sensitivity and specificity is very important. PMID- 30396343 TI - Randomized controlled trial testing weight loss and abdominal obesity outcomes of moxibustion. AB - BACKGROUND: The purpose of this study was to investigate the efficacy of moxibustion therapy on weight loss, waist circumference and waist-to-hip ratio in young adult females. An experimental design, 51 Asian females were enrolled. Inclusion criteria included females with ages between 21 and 25 years-old and waist circumference >= 80 cm, and the exclusion criteria included intolerance to moxibustion therapy and current illness. Two groups were formed, and the subjects in the experimental group received moxibustion sessions lasting 20 min and an educational video program for 30 min; however, participants in the control group received only the educational program every other week for 8 weeks. Dependent variable measurements (e.g., body weight, waist circumference and waist-to-hip ratio) were collected at baseline and follow-up for 8 weeks. RESULTS: Average body weight of the treatment group decreased significantly from - 1.478 kg (p < 0.0001), while the average body weight in the control group did not decrease significantly - 0.038 kg (p = 0.7197). Also, individuals in the moxibustion experimental group showed significant reductions (p < 0.0001) in both waist circumference and waist-to-hip ratio. CONCLUSION: Positive effects on anthropometry can be achieved by moxibustion intervention in conjunction with a weight loss education program. Especially waist circumference and waist-to-hip ratio had more clinically significant and more pronounced for health reasons Future studies can focus on the functional assessment of biomarkers associated with the immune system and relevant mechanisms of action. PMID- 30396342 TI - Retrieving hidden atrial repolarization waves from standard surface ECGs. AB - BACKGROUND: This study estimates atrial repolarization activities (Ta waves), which are typically hidden most of the time from body surface electrocardiography when diagnosing cardiovascular diseases. The morphology of Ta waves has been proven to be an important marker for the early sign of inferior injury, such as acute atrial infarction, or arrhythmia, such as atrial fibrillation. However, Ta waves are usually unseen except during conduction system malfunction, such as long QT interval or atrioventricular block. Therefore, justifying heart diseases based on atrial repolarization becomes impossible in sinus rhythm. METHODS: We obtain TMPs in the atrial part of the myocardium which reflects the correct excitation sequence starting from the atrium to the end of the apex. RESULTS: The resulting TMP shows the hidden atrial part of ECG waves. CONCLUSIONS: This extraction makes many diseases, such as acute atrial infarction or arrhythmia, become easily diagnosed. PMID- 30396344 TI - A novel intensity-based multi-level classification approach for coronary plaque characterization in intravascular ultrasound images. AB - BACKGROUND: Intravascular ultrasound (IVUS) is a commonly used diagnostic imaging method for coronary artery disease. Virtual histology (VH) characterizes the plaque components into fibrous tissue (FT), fibro-fatty tissue (FFT), necrotic core (NC), or dense calcium (DC). However, VH can obtain only a single-frame image in one cardiac cycle, and specific software is needed to obtain the radio frequency data. This study proposed a novel intensity-based multi-level classification model for plaque characterization. METHODS: The plaque-containing regions between the intima and the media-adventitia were segmented manually for all IVUS frames. A total of 54 features including first order statistics, grey level co-occurrence matrix, Law's energy measures, extended grey level run length matrix, intensity, and local binary pattern were estimated from the plaque containing regions. After feature extraction, optimal features were selected using principle component analysis (PCA), and these were utilized as the input for the classification models. Plaque components were classified into FT, FFT, NC, or DC using an intensity-based multi-level classification model consisting of three different nets. Net 1 differentiated low-intensity components into FT/FFT and NC/DC groups. Then, net 2 subsequently divided FT/FFT into FT or FFT, whereas the remainder and high-intensity components were classified into NC or DC via net 3. To improve classification accuracy, each net utilized three different input features obtained by PCA. Classification performance was evaluated in terms of sensitivity, specificity, accuracy, and receiver operating characteristic curve. RESULTS: Quantitative results indicated that the proposed method showed significantly high classification accuracy for all tissue types. The classifiers had classification accuracies of 85.1%, 71.9%, and 77.2%, respectively, and the areas under the curve were 0.845, 0.704, and 0.783. In particular, the proposed method achieved relatively high sensitivity (82.0%) and specificity (87.1%) for differentiating between the FT/FFT and NC/DC groups. CONCLUSIONS: These results confirmed the clinical applicability of the proposed approach for IVUS-based tissue characterization. PMID- 30396345 TI - A method of inferring the relationship between Biomedical entities through correlation analysis on text. AB - BACKGROUND: One of the most important processes in a machine learning-based natural language processing is to represent words. The one-hot representation that has been commonly used has a large size of vector and assumes that the features that make up the vector are independent of each other. On the other hand, it is known that word embedding has a great effect in estimating the similarity between words because it expresses the meaning of the word well. In this study, we try to clarify the correlation between various terms in the biomedical texts based on the excellent ability of estimating similarity between words shown by word embedding. Therefore, we used word embedding to find new biomarkers and microorganisms related to a specific diseases. METHODS: In this study, we try to analyze the correlation between diseases-markers and diseases microorganisms. First, we need to construct a corpus that seems to be related to them. To do this, we extract the titles and abstracts from the biomedical texts on the PubMed site. Second, we express diseases, markers, and microorganisms' terms in word embedding using Canonical Correlation Analysis (CCA). CCA is a statistical based methodology that has a very good performance on vector dimension reduction. Finally, we tried to estimate the relationship between diseases-markers pairs and diseases-microorganisms pairs by measuring their similarity. RESULTS: In the experiment, we tried to confirm the correlation derived through word embedding using Google Scholar search results. Of the top 20 highly correlated disease-marker pairs, about 85% of the pairs have actually undergone a lot of research as a result of Google Scholars search. Conversely, for 85% of the 20 pairs with the lowest correlation, we could not actually find any other study to determine the relationship between the disease and the marker. This trend was similar for disease-microbe pairs. CONCLUSIONS: The correlation between diseases and markers and diseases and microorganisms calculated through word embedding reflects actual research trends. If the word-embedding correlation is high, but there are not many published actual studies, additional research can be proposed for the pair. PMID- 30396346 TI - The climatic factors affecting dengue fever outbreaks in southern Taiwan: an application of symbolic data analysis. AB - BACKGROUND: Dengue fever is a leading cause of severe illness and hospitalization in Taiwan. This study sought to elucidate the linkage between dengue fever incidence and climate factors. RESULTS: The result indicated that temperature, accumulated rainfall, and sunshine play an important role in the transmission cycles of dengue fever. A predictive model equation plots dengue fever incidence versus temperature, rainfall, and sunshine, and it suggests that temperature, rainfall, and sunshine are significantly correlated with dengue fever incidence. CONCLUSIONS: The data suggests that climate factors are important determinants of dengue fever in southern Taiwan. Dengue fever viruses and the mosquito vectors are sensitive to their environment. Temperature, rainfall and sunshine have well defined roles in the transmission cycle. This finding suggests that control of mosquito by climatic factor during high temperature seasons may be an important strategy for containing the burden of dengue fever. PMID- 30396347 TI - Sleeping posture recognition using fuzzy c-means algorithm. AB - BACKGROUND: Pressure sensors have been used for sleeping posture detection, which meet privacy requirements. Most of the existing techniques for sleeping posture recognition used force-sensitive resistor (FSR) sensors. However, lower limbs cannot be recognized accurately unless thousands of sensors are deployed on the bedsheet. METHOD: We designed a sleeping posture recognition scheme in which FSR sensors were deployed on the upper part of the bedsheet to record the pressure distribution of the upper body. In addition, an infrared array sensor was deployed to collect data for the lower body. Posture recognition was performed using a fuzzy c-means clustering algorithm. Six types of sleeping body posture were recognized from the combination of the upper and lower body postures. RESULTS: The experimental results showed that the proposed method achieved an accuracy of above 88%. Moreover, the proposed scheme is cost-efficient and easy to deploy. CONCLUSIONS: The proposed sleeping posture recognition system can be used for pressure ulcer prevention and sleep quality assessment. Compared to wearable sensors and cameras, FSR sensors and infrared array sensors are unobstructed and meet privacy requirements. Moreover, the proposed method provides a cost-effective solution for the recognition of sleeping posture. PMID- 30396348 TI - Comfort level discussion for prosthetic sockets with different fabricating processing conditions. AB - BACKGROUND: In the past, manufacture of prosthetic socket by using traditional handmade method not only consumed research time but also required a special assembly approach. Recently, reverse engineering and rapid prototype technology have grown up explosively, and thus, provide a choice to fabricate prosthetic socket. METHODS: Application 3D computer aided design and manufacturing (computer aided design/computer-aided engineering) tools approach the surface shape stump data is digitized and can be easily modified and reused. Collocation investigates gait parameters of prosthetic socket, and interface stress between stump and socket with different processing conditions. Meanwhile, questionnaire was utilized to survey satisfaction rating scale, comfort level, of subjects using this kind of artificial device. RESULTS: The main outcome of current research including gait parameters, stress interface and satisfaction rating scale those would be an informative reference for further studies in design and manufacture as well as clinical applications of prosthetic sockets. CONCLUSIONS: This study found that, regardless of the method used for socket fabrication, most stress was concentrated in tibia end pressure-relief area. This caused discomfort in the area of tibia end to the participant wearing prosthesis. This discomfort was most evident in case when the prosthetic socket was fabricated using RE and RP. PMID- 30396349 TI - Gestational diabetes and ultrasound-assessed fetal growth in South Asian and White European women: findings from a prospective pregnancy cohort. AB - BACKGROUND: Maternal gestational diabetes (GDM) is an established risk factor for large size at birth, but its influence on intrauterine fetal growth in different ethnic populations is less well understood. Here, we examine the joint associations of GDM and ethnicity with longitudinal fetal growth in South Asian and White European origin women. METHODS: This study included 10,705 singletons (4747 White European and 5958 South Asian) from a prospective cohort of women attending an antenatal clinic in Bradford, in the North of England. All women completed a 75-g oral glucose tolerance test at 26-28 weeks' gestation. Ultrasound measurements of fetal head circumference (HC), femur length (FL) abdominal circumference (AC), and estimated fetal weight (EFW), and corresponding anthropometric measurements at birth were used to derive fetal growth trajectories. Associations of GDM and ethnicity with these trajectories were assessed using multilevel fractional polynomial models. RESULTS: Eight hundred thirty-two pregnancies (7.8%) were affected by GDM: 10.4% of South Asians and 4.4% of White Europeans. GDM was associated with a smaller fetal size in early pregnancy [differences (95% CI) in mean HC at 12 weeks and mean AC and EFW at 16 weeks comparing fetuses exposed to GDM to fetuses unexposed (reference) = - 1.8 mm (- 2.6; - 1.0), - 1.7 mm (- 2.5; - 0.9), and - 6 g (- 10; - 2)] and a greater fetal size from 24 weeks' gestation through to term [differences (95% CI) in mean HC, AC, and EFW comparing fetuses exposed to GDM to those unexposed = 0.9 mm (0.3; 1.4), 0.9 mm (0.2; 1.7), and 7 g (0; 13) at 24 weeks]. Associations of GDM with fetal growth were of similar magnitude in both ethnic groups. Growth trajectories, however, differed by ethnicity with South Asians being smaller than White Europeans irrespective of GDM status. Consequently, South Asian fetuses exposed to GDM were smaller across gestation than fetuses of White Europeans without GDM. CONCLUSIONS: In both ethnic groups, GDM is associated with early fetal size deviations prior to GDM diagnosis, highlighting the need for novel strategies to diagnose pregnancy hyperglycemia earlier than current methods. Our findings also suggest that ethnic-specific fetal growth criteria are important in identifying hyperglycemia-associated pathological effects. PMID- 30396350 TI - An empirical investigation of the impact of smoking on body weight using an endogenous treatment effects model approach: the role of food consumption patterns. AB - BACKGROUND: This study explored the influence of cigarette smoking and food consumption patterns on BMI after adjusting for various socio-demographic characteristics. Since weight-based stereotypes may have an impact on smoking behaviour and both obesity and smoking have been associated with detrimental health effects, an interdependency between them is quite possible. METHODS: Cross sectional data were collected via a formal standardized questionnaire administered in personal interviews and two additional self-completion questionnaires from a random sample of 3471 German adults. The empirical framework considered potential endogeneity between smoking and body weight by employing an endogenous treatment effects model with an ordered outcome. The estimations derived from the endogenous treatment effects approach were also compared to the univariate ordered probit model results. RESULTS: Our findings showed that ignoring potential endogeneity may affect both the statistical significance of the smoking estimate and the direction of the influence of smoking on BMI. Smoking was positively associated with BMI in both male (beta = 1.236, p < 0.01) and female (beta = 0.634, p < 0.10) participants. Smokers presented a 23.1% higher risk of obesity and a 24.3% lower likelihood of being within a healthy weight range. Male smokers also appeared to have a considerably augmented probability of being obese compared to their female counterparts (23.6% vs 15.1%). The relationship between smoking and BMI may be attributed to dietary practices, since smoking was correlated with poor dietary habits characterized by the frequent intake of more energy-dense foods (meat products and white-toasted bread) and less frequent consumption of healthy food items, such as whole-grain bread, vegetables and fruits. Concerning the impact of eating habits on body weight, frequent consumption of meat products and confectionery was found to have a direct association with BMI in both genders. Furthermore, white-toasted bread consumption was negatively linked with body weight in males (beta = - 0.337, p < 0.01). CONCLUSIONS: Our findings raised questions about the general belief that smoking is an effective weight control tool. Health interventions should be oriented toward a simultaneous decrease in smoking and obesity, since both behaviours seem to be interdependent. Nutrition programmes should also be designed according to the characteristics of different target groups in order to promote a healthy lifestyle. PMID- 30396351 TI - Permanent magnet actuation for magnetic bead-based DNA extraction. AB - BACKGROUND: Recently, automatic molecular diagnostic devices to extract DNA have been extensively developed using magnetic beads. While various methods can be applied to the control of the beads, the efficiency of the control when incorporated in automatic devices has not been studied. This paper proposes a compact magnet actuation method for the control of magnetic beads for DNA extraction, and compares the efficiency to the already available magnetic bead based DNA extraction device. A permanent magnet was preferred for its compactness, while an electro-magnet provides easy operation. After investigating various methods to actuate the magnet with perspective to the size, circuit complexity, and power requirement, we determined the solenoid actuation method to be most efficient. To further reduce the dimension of the overall actuation device, direct actuation of the permanent magnet to control the hold/release of the beads was employed in this paper. The proposed method was compared with the conventional solenoid actuator with a metal plunger. An experimental fluidics device was set up with a fluidic channel and a syringe pump. The bead holding performance against the fluid speed was tested while a fixed amount of beads was loaded into the center of the channel. The group velocity of the beads was analyzed via image processing to determine whether the magnet was sufficient to hold the beads. The required power and space was analyzed and compared qualitatively and quantitatively. RESULT: The proposed direct actuation method was capable of holding the beads at faster fluidic speed than the conventional solenoid actuator. The required power was comparable contemplating the high initial power of the solenoid actuator, and required much smaller space since no plunger was needed. CONCLUSIONS: The direct actuation of the permanent magnet using a solenoid coil showed enhanced performance in holding the beads via permanent magnet, with less complexity of the actuation circuit and space. The proposed method therefore can efficiently improve the overall performance of the bead-based DNA extraction. PMID- 30396352 TI - Performance evaluation of optimal real-time polymerase chain reaction achieved with reduced voltage. AB - BACKGROUND: Polymerase chain reaction (PCR) is used in nucleic acid tests of infectious diseases in point-of-care testing. Previous studies have demonstrated real-time PCR that uses a micro-PCR chip made of packing tape, double-sided tape, and a plastic cover with polycarbonate or polypropylene on a black matte printed circuit board substrate. Despite the success of DNA amplification and fluorescence detection using an early version of the micro-PCR chip, reaching the target temperature was fairly slow and, as a result, the total running time was getting longer. To reduce this runtime, the micro-PCR chip was modified by reducing the heater pattern size of the PCB substrate to one-quarter of the original size or less, while maintaining the ability of the heating pattern to cover the reservoir area of the microfluidic channel. In subsequent experiments, DNA amplification failed several times. During the analysis of the cause of this failure, it was found that the reagent was boiling with the heating range from 25 to 95 degrees C. METHODS: As a method of DNA amplification verification, images were captured by digital single-lens reflex camera to detect FAM fluorescence using diagonal illumination from a blue LED light source. The images were automatically captured at 72 degrees C (the extension step in nucleic acid amplification) and the brightness of the captured images was analyzed to con-firm the success of DNA amplification. RESULTS: Compared to the previous chip with a larger heating pattern size, the current chip appears to generate excess energy as the size of the heating pattern was reduced. To reduce this excess energy, the initial voltage was lowered to 2 V and 2.5 V, which is equivalent to a one-fifth and one-quarter voltage-power reduction in pulse width modulation control, respectively. In both voltage reduction cases, the DNA amplification was successful. CONCLUSIONS: DNA amplification tests may fail due to the excess energy generated by reducing the heater pattern size of the PCB substrate. However, the tests succeeded when the voltage was reduced to 2 V or 2.5 V. The 2.5 V power test was more efficient for reducing the overall running time. PMID- 30396353 TI - Meta-analysis of ART outcomes in women with different preconception TSH levels. AB - BACKGROUND: To assess whether elevated thyroid-stimulating hormone (TSH) levels before conception can predict poor outcomes of assisted reproductive technology (ART). METHODS: Prior to July 2018, we searched the PubMed, EMBASE, COCHRANE, Google Scholar, and CNKI databases for studies. Retrospective or prospective reports that compared ART results in patients with subclinical hypothyroidism (SCH) with normal thyroid function were selected. Two reviewers separately reviewed each potential article for qualification, analyzed the quality of the studies according to the Newcastle-Ottawa scale, and extracted the data. The PRISMA guidelines were adopted. RESULTS: We selected a total of 18 publications that included 14,846 participants for this meta-analysis. When the TSH cut-off value for SCH was set at 2.5 mIU/L, no significant differences were observed in ART-related outcomes between SCH patients and normal women. The evaluated outcomes included the live birth rate (LBR) (OR: 0.93; 95% CI (0.77,1.12), P = 0.43), clinical pregnancy rate (CPR) (OR:1.02; 95% CI (0.90,1.17); P = 0.74), pregnancy rate (PR) (OR: 1.00; 95% CI (0.89,1.12); P = 0.99), and miscarriage rate (MR) (OR:1.24; 95% CI (0.85, 1.80); P = 0.26). Furthermore, when a higher TSH level was used as the cut-off value to diagnose SCH (i.e., 3.5-5 mIU/L), a significant difference was found in the MR (OR: 1.91; 95% CI (1.09, 3.35); P = 0.02) between the two groups of ART-treated women. However, when a broader cut off value was used to define SCH, no significant differences were observed in the LBR (OR: 0.72; 95% CI (0.47,1.11); P = 0.14), CPR (OR: 0.82; 95% CI (0.66,1.00); P = 0.052), or PR (OR: 1.07; 95% CI (0.72,1.60); P = 0.74) between the two groups of ART-treated women. CONCLUSION: No difference was observed in ART outcomes when a TSH cut-off value of 2.5 mIU/L was used. However, when a broader TSH cut-off value was used, preconception SCH resulted in a higher miscarriage rate than in normal women. PMID- 30396354 TI - Evaluation-independent system for DNA section amplification. AB - BACKGROUND: In general, the image analysis of nucleic acid for detecting DNA is dependent on the gel documentation system. These experiments may deal with harmful staining agents and are time consuming. To address these issues, real time polymerase chain reaction (PCR) devices have been developed. The advantages of real-time PCR are its capabilities for real-time diagnosis, improved sensitivity, and digitization of measurement results. However, real-time PCR equipment is still too bulky and expensive for use in small hospitals and laboratories. METHODS: This paper describes an evaluation-independent real-time PCR system that differs from conventional systems in that it uses a side illumination optical detection system and a temperature adjustment coefficient for DNA detection. The overall configuration of the evaluation-independent system includes the PCR chip and system hardware and software. The use of the side illumination method for detection enables the system size to be reduced compared to systems using a typical illumination method. Furthermore, the results of a PCR test are strongly affected by the reaction temperature. Thus, extremely precise control of the temperature of the reaction is needed to obtain accurate results and good reliability. We derived a temperature compensation coefficient that allows us to compensate for the differences between the measured temperature of the negative temperature coefficient (NTC) thermistor sensor and the real temperature of the thermocouple. RESULTS: Applying the temperature compensation coefficient parameter using the NTC thermistor and using the side-illumination method resulted in an increase in the initial sensor value. The occurrence of the DNA section amplification decreased to 22 cycles from 24 cycles. CONCLUSIONS: The proposed system showed comparable performance to that of an existing real-time PCR, even with the use of simpler and smaller optical devices. PMID- 30396355 TI - A study of polymerase chain reaction device control via cloud using Firebase Cloud Messaging protocol. AB - BACKGROUND: In this paper, we propose a system for data monitoring and control of polymerase chain reaction (PCR) externally. PCR is a technique for amplifying a desired DNA molecule by repeatedly synthesizing a specific part of DNA sequence. Currently, commercially available systems are standalone systems or operate PCR devices through a computer in the vicinity of devices for control purposes. These systems are limited in the number of devices that the host system can monitor at the same time, and there are limitations in controlling devices or accessing experimental data externally. Therefore, we propose a system to control the PCR device via the cloud for the convenience of the user and to overcome the limitation of the place. METHODS: The cloud system used in this study is Google's Firebase. At this time, we use Firebase Cloud Messaging (FCM) protocol to send and receive data. In this paper, we have experimented on the possibility of data transmission and reception using FCM between device, cloud and user. Since the PCR chips used in the research are generally operated at about 10 degrees /s, and the temperature can be controlled within 0.5 degrees , the processing period of the control process should be made much smaller than 1/20 s (50 ms). RESULTS: As a result of experiments, the time of the data round-trip using FCM was measured at 150 ms on the average. Therefore, the data exchange time using FCM is three times slower than the reference time of 50 ms. CONCLUSIONS: Since the data round trip time using FCM is measured to be three times slower than the reference time of 50 ms, it is impossible for the user to control the device such as the PCR device used in this study through the cloud. However, it is possible for the user to monitor the status of the PCR device from the outside in real time. PMID- 30396356 TI - Validation of a rapid semi-automated method to assess left atrial longitudinal phasic strains on cine cardiovascular magnetic resonance imaging. AB - BACKGROUND: Abnormal left atrial (LA) function is a marker of cardiac dysfunction and adverse cardiovascular outcome, but is difficult to assess, and hence not, routinely quantified. We aimed to determine the feasibility and effectiveness of a fast method to measure long-axis LA strain and strain rate (SR) with standard cardiovascular magnetic resonance (CMR) compared to conventional feature tracking (FT) derived longitudinal strain. METHODS: We studied 50 normal controls, 30 patients with hypertrophic cardiomyopathy, and 100 heart failure (HF) patients, including 40 with reduced ejection fraction (HFrEF), 30 mid-range ejection fraction (HFmrEF) and 30 preserved ejection fraction (HFpEF). LA longitudinal strain and SR parameters were derived by tracking the distance between the left atrioventricular junction and a user-defined point at the mid posterior LA wall on standard cine CMR two- and four-chamber views. LA performance was analyzed at three distinct cardiac phases: reservoir function (reservoir strain epsilons and strain rate SRs), conduit function (conduit strain epsilone and strain rate SRe) and booster pump function (booster strain epsilona and strain rate SRa). RESULTS: There was good agreement between LA longitudinal strain and SR assessed using the fast and conventional FT-CMR approaches (r = 0.89 to 0.99, p < 0.001). The fast strain and SRs showed a better intra- and inter-observer reproducibility and a 55% reduction in evaluation time (85 +/- 10 vs. 190 +/- 12 s, p < 0.001) compared to FT-CMR. Fast LA measurements in normal controls were 35.3 +/- 5.2% for epsilons, 18.1 +/- 4.3% for epsilone, 17.2 +/- 3.5% for epsilona, and 1.8 +/- 0.4, - 2.0 +/- 0.5, - 2.3 +/- 0.6 s- 1 for the respective phasic SRs. Significantly reduced LA strains and SRs were observed in all patient groups compared to normal controls. Patients with HFpEF and HFmrEF had significantly smaller epsilons, SRs, epsilone and SRe than hypertrophic cardiomyopathy, and HFmrEF had significantly impaired LA reservoir and booster function compared to HFpEF. The fast LA strains and SRs were similar to FT-CMR for discriminating patients from controls (area under the curve (AUC) = 0.79 to 0.96 vs. 0.76 to 0.93, p = NS). CONCLUSIONS: Novel quantitative LA strain and SR derived from conventional cine CMR images are fast assessable parameters for LA phasic function analysis. PMID- 30396357 TI - Automated pipette failure monitoring using image processing for point-of-care testing devices. AB - BACKGROUND: The accuracy and precision of liquid handling can be altered by several causes including wearing or failure of parts, and human error. The last cause is crucial since point-of-care testing (POCT) devices can be used by non experienced users or patients themselves. Therefore it is important to improve the method of informing the users of POCT device malfunctions due to damage of parts or human error. METHODS: In this paper, image-based failure monitoring of the automated pipetting was introduced for POCT devices. An inexpensive, high performance camera for smartphones was employed in our previous work to resolve various malfunctions such as incorrect insertion of the tip, false positioning of the tip and pump, and improper operation of the pump. The image acquired from the camera was analyzed to detect the malfunctions. In this paper, the reagent volume in the tip was estimated from the image processing to verify the pump operation. First, the color component corresponding to the reagent intrinsic color was extracted to identify the reagent area in the tip before applying the binary image processing. The extracted reagent area was projected horizontally and the support length of the projection image was calculated. As the support length was related to the reagent volume, it was referred to the volume length. The relationship between the measured volume length and the previously measured solution mass was investigated. If we can predict the mass of the solution by the volume length, we will be able to detect the pump malfunction. RESULTS: The cube of the volume length obtained by the proposed image processing method showed a very linear relationship with the reagent mass in the tip injected by the pumping operation (R2 = 0.996), indicating that the volume length could be utilized to estimate the reagent volume to monitor the accuracy and precision of the pumping operation. CONCLUSIONS: An inexpensive smartphone camera was enough to detect various malfunctions of a POCT device with pumping operation. The proposed image processing could monitor the level of inaccuracy of pumping volume in limited range. The simple image processing such as a fixed threshold and projections was employed for the cost optimization and system robustness. However it delivered the promising results because the imaging condition was highly controllable in the devices. PMID- 30396360 TI - The unsolved problem of otitis media in indigenous populations: a systematic review of upper respiratory and middle ear microbiology in indigenous children with otitis media. AB - BACKGROUND: Otitis media (OM) imposes a great burden of disease in indigenous populations around the world, despite a variety of treatment and prevention programs. Improved understanding of the pathogenesis of OM in indigenous populations is required to advance treatment and reduce prevalence. We conducted a systematic review of the literature exploring the upper airway and middle ear microbiota in relation to OM in indigenous children. METHODS: Papers targeting microbiota in relation to OM in children < 18 years indigenous to Australia, New Zealand, North America, and Greenland were sought. MEDLINE, CINAHL, EMBASE, Cochrane Library, and Informit databases were searched using key words. Two independent reviewers screened titles, abstracts, and then full-text papers against inclusion criteria according to PRISMA guidelines. RESULTS: Twenty-five papers considering indigenous Australian, Alaskan, and Greenlandic children were included. There were high rates of nasopharyngeal colonization with the three main otopathogens (Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis) in indigenous children with OM. Middle ear samples had lower rates of otopathogen detection, although detection rates increased when molecular methods were used. Pseudomonas aeruginosa and Staphylococcus aureus were commonly detected in middle ear discharge of children with chronic suppurative OM. There was a significant heterogeneity between studies, particularly in microbiological methods, which were largely limited to culture based detection of the main otopathogens. CONCLUSIONS: There are high rates of otopathogen colonization in indigenous children with OM. Chronic suppurative OM appears to be associated with a different microbial profile. Beyond the main otopathogens, the data are limited. Further research is required to explore the entire upper respiratory tract/middle ear microbiota in relation to OM, with the inclusion of healthy indigenous peers as controls. PMID- 30396361 TI - The European challenges of funding orphan medicinal products. AB - BACKGROUND: Funding of orphan medicinal products (OMPs) is an increasing challenge in the European Union (EU). OBJECTIVES: To identify the different methods for public funding of OMPs in order to map the availability for rare disease patients, as well as to compare the public expenditures on OMPs in 8 EU member states. METHODS: Information on the reimbursement status of 83 OMPs was collected in 8 countries by distinguishing standard and special reimbursements. In two consecutive years, the total public expenditures on OMPs were calculated by using annual EUR exchange rates. Annual total public expenditures were calculated per capita, and as a proportion of GDP, total public pharmaceutical and healthcare budgets. Differences between countries were compared by calculating the deviations from the average spending of countries. RESULTS: In 2015 29.4-92.8% of the 83 OMPs were available with any kind of public reimbursement in participant countries including special reimbursement on an individual basis. In Austria, Belgium and France more OMPs were accessible for patients with public reimbursement than in Bulgaria, Czech Republic, Hungary and Poland. Standard reimbursement through retail pharmacies and/or hospitals was applied from 0 to 41% of OMPs. The average annual total public expenditure ranged between 1.4-23.5 ?/capita in 2013 and 2014. Higher income countries spent more OMPs in absolute terms. Participant countries spent 0.018-0.066% of their GDPs on funding OMPs. Average expenditures on OMPs were ranged between 2.25-6.51% of the public pharmaceutical budget, and 0.44-0.96% of public healthcare expenditures. CONCLUSIONS: Standard and special reimbursement techniques play different roles in participant countries. The number of accessible OMPs indicated an equity gap between Eastern and Western Europe. The spending on OMPs as a proportion of GDP, public pharmaceutical and healthcare expenditure was not higher in lower income countries, which indicates substantial differences in patient access to OMPs in favour of higher-income countries. Equity in access for patients with rare diseases is an important policy objective in each member state of the EU; however, equity in access should be harmonized at the European level. PMID- 30396358 TI - Gestational weight gain charts for different body mass index groups for women in Europe, North America, and Oceania. AB - BACKGROUND: Gestational weight gain differs according to pre-pregnancy body mass index and is related to the risks of adverse maternal and child health outcomes. Gestational weight gain charts for women in different pre-pregnancy body mass index groups enable identification of women and offspring at risk for adverse health outcomes. We aimed to construct gestational weight gain reference charts for underweight, normal weight, overweight, and grades 1, 2 and 3 obese women and to compare these charts with those obtained in women with uncomplicated term pregnancies. METHODS: We used individual participant data from 218,216 pregnant women participating in 33 cohorts from Europe, North America, and Oceania. Of these women, 9065 (4.2%), 148,697 (68.1%), 42,678 (19.6%), 13,084 (6.0%), 3597 (1.6%), and 1095 (0.5%) were underweight, normal weight, overweight, and grades 1, 2, and 3 obese women, respectively. A total of 138, 517 women from 26 cohorts had pregnancies with no hypertensive or diabetic disorders and with term deliveries of appropriate for gestational age at birth infants. Gestational weight gain charts for underweight, normal weight, overweight, and grade 1, 2, and 3 obese women were derived by the Box-Cox t method using the generalized additive model for location, scale, and shape. RESULTS: We observed that gestational weight gain strongly differed per maternal pre-pregnancy body mass index group. The median (interquartile range) gestational weight gain at 40 weeks was 14.2 kg (11.4-17.4) for underweight women, 14.5 kg (11.5-17.7) for normal weight women, 13.9 kg (10.1-17.9) for overweight women, and 11.2 kg (7.0-15.7), 8.7 kg (4.3-13.4) and 6.3 kg (1.9-11.1) for grades 1, 2, and 3 obese women, respectively. The rate of weight gain was lower in the first half than in the second half of pregnancy. No differences in the patterns of weight gain were observed between cohorts or countries. Similar weight gain patterns were observed in mothers without pregnancy complications. CONCLUSIONS: Gestational weight gain patterns are strongly related to pre-pregnancy body mass index. The derived charts can be used to assess gestational weight gain in etiological research and as a monitoring tool for weight gain during pregnancy in clinical practice. PMID- 30396362 TI - Unexpected dislocation following accurate total hip arthroplasty caused by excessive hip joint laxity during myasthenic crisis: a case report. AB - BACKGROUND: Dislocation following total hip arthroplasty is mainly caused by malposition. However, the coexistence of neuromuscular disorders is also considered a risk for dislocation due to excessive hip joint laxity. To minimize risk of dislocation, preoperative planning using combined anteversion has been widely used. The recommended combined anteversion angle (the total of cup and stem anteversion angles) is 50 +/- 10 degrees . CASE PRESENTATION: A 33-year-old Japanese woman underwent elective total hip arthroplasty due to osteonecrosis of the femoral head associated with corticosteroid pulse therapy for myasthenia gravis. Intraoperatively, no tendency of dislocation was found when simulating an evoking position under general anesthesia. In postoperative X-ray and computed tomography scans, cup inclination, cup anteversion, and stem anteversion angles were 37 degrees , 13 degrees , and 35 degrees respectively. The resulting combined anteversion was 48 degrees , which was set as the target along with accurate placement. Her postoperative course was normal and she was discharged without adverse events. Three months postoperatively, due to worsening of myasthenic weakness in her lower extremities while resting, she tended to raise her left limb up using both hands for sitting up. An anterior dislocation occurred when her legs were in a figure-of-four position. She was brought to an emergency department, and reduction of dislocation was performed. It was inferred that myasthenic crisis in the affected limb enabled excessive passive motion due to joint hyperlaxity. At the end of 2016, elective total hip arthroplasty on the contralateral side was performed. Cup anteversion, stem anteversion, and the combined anteversion angles were 27 degrees , 24 degrees , and 51 degrees respectively. We instructed her to exercise care during passive leg movement, which may worsen her myasthenic condition. She returned to a normal life and was able to walk long distances without a cane. No recurrence of dislocation was seen at final follow-up. CONCLUSIONS: Even if accurate component orientation is attained in total hip arthroplasty, patients with neuromuscular disorders such as myasthenia gravis have a potential risk of muscle weakness in the affected limb. Therefore, physicians' instructions and patients' careful attention are required to prevent dislocation due to excessive hip joint laxity under conditions of motor weakness. PMID- 30396363 TI - Clinical effects of constant rate infusions of medetomidine-propofol combined with sevoflurane anesthesia in Thoroughbred racehorses undergoing arthroscopic surgery. AB - BACKGROUND: The aim of the present study was to evaluate clinical efficacy of constant rate infusions (CRIs) of medetomidine-propofol combined with sevoflurane anesthesia in Thoroughbred racehorses undergoing arthroscopic surgery. Thirty horses were sedated intravenously (IV) with medetomidine (6.0 MUg/kg) and midazolam (0.02 mg/kg) and induced IV with ketamine (1.0 mg/kg) and propofol (1.0 mg/kg). These horses were randomly allocated to three groups and maintained with sevoflurane and CRI of either medetomidine (3.0 MUg/kg/h) (Group M; n = 10); or medetomidine (3.0 MUg/kg/h) and propofol (3.0 mg/kg/h) (Group MP3; n = 10); or medetomidine (3.0 MUg/kg/h) and propofol (6.0 mg/kg/h) (Group MP6; n = 10). End tidal sevoflurane concentration (ETSEVO), cardiovascular parameters, plasma propofol concentration, and recovery time and quality were compared among groups. Data were analyzed by using ANOVA with Tukey's multiple comparison test, considering P < 0.05 significant. RESULTS: ETSEVO (%) was 2.4 +/- 0.1 in Group M, 1.7 +/- 0.2 in Group MP3, and 1.4 +/- 0.2 in Group MP6; ETSEVO declined significantly in a propofol-dose-dependent manner. The rates of dobutamine infusion (MUg/kg/min) required to keep the mean arterial blood pressure over 70 mmHg were significantly lower in Group MP3 (0.20 +/- 0.10) and Group MP6 (0.15 +/ 0.06) than in Group M (0.37 +/- 0.18). Recovery time and quality did not differ among groups. All horses in Group MP3 required only one attempt to stand, and recovery quality was excellent. Plasma propofol concentrations were stable throughout maintenance of anesthesia in Group MP3, whereas those in Group MP6 increased significantly with increasing duration of maintenance. CONCLUSIONS: CRIs of medetomidine-propofol reduced the sevoflurane requirement for surgical anesthesia as the propofol dose increased, compared with a CRI of medetomidine alone. Additionally, the two propofol protocols provided good maintenance of cardiovascular function. CRIs of medetomidine (3.0 MUg/kg/h) and propofol (3.0 mg/kg/h) resulted in excellent-quality recovery. This protocol could therefore be an especially useful additive to sevoflurane anesthesia in Thoroughbred racehorses undergoing arthroscopic surgery. PMID- 30396359 TI - TLR4 inhibitor TAK-242 attenuates the adverse neural effects of diet-induced obesity. AB - BACKGROUND: Obesity exerts negative effects on brain health, including decreased neurogenesis, impaired learning and memory, and increased risk for Alzheimer's disease and related dementias. Because obesity promotes glial activation, chronic neuroinflammation, and neural injury, microglia are implicated in the deleterious effects of obesity. One pathway that is particularly important in mediating the effects of obesity in peripheral tissues is toll-like receptor 4 (TLR4) signaling. The potential contribution of TLR4 pathways in mediating adverse neural outcomes of obesity has not been well addressed. To investigate this possibility, we examined how pharmacological inhibition of TLR4 affects the peripheral and neural outcomes of diet-induced obesity. METHODS: Male C57BL6/J mice were maintained on either a control or high-fat diet for 12 weeks in the presence or absence of the specific TLR4 signaling inhibitor TAK-242. Outcomes examined included metabolic indices, a range of behavioral assessments, microglial activation, systemic and neuroinflammation, and neural health endpoints. RESULTS: Peripherally, TAK-242 treatment was associated with partial inhibition of inflammation in the adipose tissue but exerted no significant effects on body weight, adiposity, and a range of metabolic measures. In the brain, obese mice treated with TAK-242 exhibited a significant reduction in microglial activation, improved levels of neurogenesis, and inhibition of Alzheimer-related amyloidogenic pathways. High-fat diet and TAK-242 were associated with only very modest effects on a range of behavioral measures. CONCLUSIONS: These results demonstrate a significant protective effect of TLR4 inhibition on neural consequences of obesity, findings that further define the role of microglia in obesity-mediated outcomes and identify a strategy for improving brain health in obese individuals. PMID- 30396364 TI - New guidance to improve sample size calculations for trials: eliciting the target difference. AB - BACKGROUND: Sample size calculations are central to the design of health research trials. To ensure that the trial provides good evidence to answer the trial's research question, the target effect size (difference in means or proportions, odds ratio, relative risk or hazard ratio between trial arms) must be specified under the conventional approach to determining the sample size. However, until now, there has not been comprehensive guidance on how to specify this effect. MAIN TEXT: This is a commentary on a collection of papers from two important projects, DELTA (Difference ELicitation in TriAls) and DELTA2 that aim to provide evidence-based guidance on systematically determining the target effect size, or difference and the resultant sample sizes for trials. In addition to surveying methods that researchers are using in practice, the research team met with various experts (statisticians, methodologists, clinicians and funders); reviewed guidelines from funding agencies; and reviewed recent methodological literature. The DELTA2 guidance stresses specifying important and realistic differences, and undertaking sensitivity analyses in calculating sample sizes. It gives recommendations on how to find appropriate differences, conduct the sample size calculation(s) and how to report these in grant applications, protocols and manuscripts. It is hoped that this will contribute not only to better powered studies, but better reporting and reproducibility and thinking about what a trial should be designed to achieve. CONCLUSIONS: The DELTA researchers have developed a set of comprehensive guidance documents that are welcome and will almost certainly improve the way that trials are designed and reported. PMID- 30396365 TI - CD33/CD3-bispecific T-cell engaging (BiTE(r)) antibody construct targets monocytic AML myeloid-derived suppressor cells. AB - Acute myeloid leukemia (AML) is the most common acute leukemia amongst adults with a 5-year overall survival lower than 30%. Emerging evidence suggest that immune alterations favor leukemogenesis and/or AML relapse thereby negatively impacting disease outcome. Over the last years myeloid derived suppressor cells (MDSCs) have been gaining momentum in the field of cancer research. MDSCs are a heterogeneous cell population morphologically resembling either monocytes or granulocytes and sharing some key features including myeloid origin, aberrant (immature) phenotype, and immunosuppressive activity. Increasing evidence suggests that accumulating MDSCs are involved in hampering anti-tumor immune responses and immune-based therapies. Here, we demonstrate increased frequencies of CD14+ monocytic MDSCs in newly diagnosed AML that co-express CD33 but lack HLA DR (HLA-DRlo). AML-blasts induce HLA-DRlo cells from healthy donor-derived monocytes in vitro that suppress T-cells and express indoleamine-2,3-dioxygenase (IDO). We investigated whether a CD33/CD3-bispecific BiTE(r) antibody construct (AMG 330) with pre-clinical activity against AML-blasts by redirection of T-cells can eradicate CD33+ MDSCs. In fact, T-cells eliminate IDO+CD33+ MDSCs in the presence of AMG 330. Depletion of total CD14+ cells (including MDSCs) in peripheral blood mononuclear cells from AML patients did not enhance AMG 330 triggered T-cell activation and expansion, but boosted AML-blast lysis. This finding was corroborated in experiments showing that adding MDSCs into co cultures of T- and AML-cells reduced AML-blast killing, while IDO inhibition promotes AMG 330-mediated clearance of AML-blasts. Taken together, our results suggest that AMG 330 may achieve anti-leukemic efficacy not only through T-cell mediated cytotoxicity against AML-blasts but also against CD33+ MDSCs, suggesting that it is worth exploring the predictive role of MDSCs for responsiveness towards an AMG 330-based therapy. PMID- 30396366 TI - Novel BRAF alteration in desmoplastic infantile ganglioglioma with response to targeted therapy. PMID- 30396367 TI - Transcriptomic and epigenetic profiling of 'diffuse midline gliomas, H3 K27M mutant' discriminate two subgroups based on the type of histone H3 mutated and not supratentorial or infratentorial location. AB - Diffuse midline glioma (DMG), H3 K27M-mutant, is a new entity in the updated WHO classification grouping together diffuse intrinsic pontine gliomas and infiltrating glial neoplasms of the midline harboring the same canonical mutation at the Lysine 27 of the histones H3 tail.Two hundred and fifteen patients younger than 18 years old with centrally-reviewed pediatric high-grade gliomas (pHGG) were included in this study. Comprehensive transcriptomic (n = 140) and methylation (n = 80) profiling was performed depending on the material available, in order to assess the biological uniqueness of this new entity compared to other midline and hemispheric pHGG.Tumor classification based on gene expression (GE) data highlighted the similarity of K27M DMG independently of their location along the midline. T-distributed Stochastic Neighbor Embedding (tSNE) analysis of methylation profiling confirms the discrimination of DMG from other well defined supratentorial tumor subgroups. Patients with diffuse intrinsic pontine gliomas (DIPG) and thalamic DMG exhibited a similarly poor prognosis (11.1 and 10.8 months median overall survival, respectively). Interestingly, H3.1-K27M and H3.3 K27M primary tumor samples could be distinguished based both on their GE and DNA methylation profiles, suggesting that they might arise from a different precursor or from a different epigenetic reorganization.These differences in DNA methylation profiles were conserved in glioma stem-like cell culture models of DIPG which mimicked their corresponding primary tumor. ChIP-seq profiling of H3K27me3 in these models indicate that H3.3-K27M mutated DIPG stem cells exhibit higher levels of H3K27 trimethylation which are correlated with fewer genes expressed by RNAseq. When considering the global distribution of the H3K27me3 mark, we observed that intergenic regions were more trimethylated in the H3.3 K27M mutated cells compared to the H3.1-K27M mutated ones.H3 K27M-mutant DMG represent a homogenous group of neoplasms compared to other pediatric gliomas that could be further separated based on the type of histone H3 variant mutated and their respective epigenetic landscapes. As these characteristics drive different phenotypes, these findings may have important implication for the design of future trials in these specific types of neoplasms. PMID- 30396368 TI - Association between helminth infections and diabetes mellitus in adults from the Lao People's Democratic Republic: a cross-sectional study. AB - BACKGROUND: As a result of epidemiological transition, the health systems of low- and middle-income countries are increasingly faced with a dual disease burden of infectious diseases and emerging non-communicable diseases. Little is known about the mutual influence of these two disease groups. The aim of this study was to investigate the co-occurrence of helminth infections and diabetes mellitus in adults in Lao People's Democratic Republic (Lao PDR). METHODS: We conducted a cross-sectional study among 1600 randomly selected adults aged 35 and older from four different socio-economical and ecological provinces. Information on socio demographics, risk factors and health conditions was obtained from personal interviews. Clinical assessments including anthropometry (height, weight, waist and hip circumference) and blood pressure measurements were also conducted. Diabetes was classified based on self-reported diagnoses and a point-of-care glycated haemoglobin (HbA1c) test from finger prick blood samples. Stool samples for helminth diagnosis were examined with formalin-ether concentration technique for intestinal parasitic infections. The independent associations of helminth infections with diabetic status and HbA1c were assessed using multiple regression analyses. RESULTS: The prevalence of pre-diabetes and diabetes was 37.3% and 22.8%, respectively. Fifty-six percent of diabetic cases were undiagnosed and 85% of diagnosed diabetic cases had poor glycemic control. Participants from rural areas and from southern parts of the country had higher infection rates, with Opisthorchis viverrini, being the most common helminth infection (30.5%). We found a positive association between Taenia spp. infections and HbA1c (beta = 0.117; 95% CI: 0.042-0.200) and diabetes mellitus risk (OR = 2.98; 95% CI: 1.10 8.05). No other helminth species was associated with glycated hemoglobin. CONCLUSIONS: Hyperglycaemia and diabetic rates in Lao PDR are alarmingly high, but consistent with other high rates in the region. Given the high rates of under diagnosis and poorly-controlled glycaemia in diabetes mellitus patients, routine diabetes screening and treatment is essential for the local healthcare system. Large longitudinal cohorts integrating biomarkers are warranted in the search of causal diabetes mellitus risk factors in the region. Common intestinal helminth infections, including O. viverrini, are unlikely to explain the high diabetes mellitus rates observed. PMID- 30396370 TI - Correction to: Is the exposure to bisphosphonates or osteoporosis the predictor of spinal radiographic progression in ankylosing spondylitis? AB - Following publication of the original article [1], the authors reported a typesetting error. PMID- 30396369 TI - An exploration of Prevotella-rich microbiomes in HIV and men who have sex with men. AB - BACKGROUND: Gut microbiome characteristics associated with HIV infection are of intense research interest but a deep understanding has been challenged by confounding factors across studied populations. Notably, a Prevotella-rich microbiome described in HIV-infected populations is now understood to be common in men who have sex with men (MSM) regardless of HIV status, but driving factors and potential health implications are unknown. RESULTS: Here, we further define the MSM-associated gut microbiome and describe compositional differences between the fecal microbiomes of Prevotella-rich MSM and non-MSM that may underlie observed pro-inflammatory properties. Furthermore, we show relatively subtle gut microbiome changes in HIV infection in MSM and women that include an increase in potential pathogens that is ameliorated with antiretroviral therapy (ART). Lastly, using a longitudinal cohort, we describe microbiome changes that happen after ART initiation. CONCLUSIONS: This study provides an in-depth characterization of microbiome differences that occur in a US population infected with HIV and demonstrates the degree to which these differences may be driven by lifestyle factors, ART, and HIV infection itself. Understanding microbiome compositions that occur with sexual behaviors that are high risk for acquiring HIV and untreated and ART-treated HIV infection will guide the investigation of immune and metabolic functional implications to ultimately target the microbiome therapeutically. PMID- 30396373 TI - Cognition in psychiatry: population health, clinical, and research implications. PMID- 30396374 TI - Foodborne illness outbreak due to Staphylococcus aureus among hospital staff following Hurricane Harvey. PMID- 30396372 TI - Digestible indispensable amino acid scores of nine cooked cereal grains. AB - True ileal digestibility (TID) values of amino acid (AA) obtained using growing rats are often used for the characterisation of protein quality in different foods and acquisition of digestible indispensable amino acid scores (DIAAS) in adult humans. Here, we conducted an experiment to determine the TID values of AA obtained from nine cooked cereal grains (brown rice, polished rice, buckwheat, oats, proso millet, foxtail millet, tartary buckwheat, adlay and whole wheat) fed to growing Sprague-Dawley male rats. All rats were fed a standard basal diet for 7 d and then received each diet for 7 d. Ileal contents were collected from the terminal 20 cm of ileum. Among the TID values obtained, whole wheat had the highest values (P<0.05), and polished rice, proso millet and tartary buckwheat had relatively low values. The TID indispensable AA concentrations in whole wheat were greater than those of brown rice or polished rice (P<0.05), and polished rice was the lowest total TID concentrations among the other cereal grains. The DIAAS was 68 for buckwheat, 47 for tartary buckwheat, 43 for oats, 42 for brown rice, 37 for polished rice, 20 for whole wheat, 13 for adlay, 10 for foxtail millet and 7 for proso millet. In this study, the TID values of the nine cooked cereal grains commonly consumed in China were used for the creation of a DIAAS database and thus gained public health outcomes. PMID- 30396371 TI - Current progress and future opportunities in applications of bioinformatics for biodefense and pathogen detection: report from the Winter Mid-Atlantic Microbiome Meet-up, College Park, MD, January 10, 2018. AB - The Mid-Atlantic Microbiome Meet-up (M3) organization brings together academic, government, and industry groups to share ideas and develop best practices for microbiome research. In January of 2018, M3 held its fourth meeting, which focused on recent advances in biodefense, specifically those relating to infectious disease, and the use of metagenomic methods for pathogen detection. Presentations highlighted the utility of next-generation sequencing technologies for identifying and tracking microbial community members across space and time. However, they also stressed the current limitations of genomic approaches for biodefense, including insufficient sensitivity to detect low-abundance pathogens and the inability to quantify viable organisms. Participants discussed ways in which the community can improve software usability and shared new computational tools for metagenomic processing, assembly, annotation, and visualization. Looking to the future, they identified the need for better bioinformatics toolkits for longitudinal analyses, improved sample processing approaches for characterizing viruses and fungi, and more consistent maintenance of database resources. Finally, they addressed the necessity of improving data standards to incentivize data sharing. Here, we summarize the presentations and discussions from the meeting, identifying the areas where microbiome analyses have improved our ability to detect and manage biological threats and infectious disease, as well as gaps of knowledge in the field that require future funding and focus. PMID- 30396375 TI - Nutrition risk among an ethnically diverse sample of community-dwelling older adults. AB - OBJECTIVE: To assess the prevalence of nutritional risk among an ethnically diverse group of urban community-dwelling older adults and to explore if risk varied by race/ethnicity. DESIGN: Demographic characteristics, Katz's activities of daily living and health-care resource utilization were ascertained cross sectionally via telephone surveys with trained interviewers. Nutrition risk and nutrition symptomology were assessed via the abridged Patient Generated Subjective Global Assessment (abPG-SGA); scores of >=6 points delineated 'high' nutrition risk. Descriptive statistics and logistic regression analyses were conducted. SETTING: Urban.ParticipantsWhite, Black or Hispanic community-dwelling adults, >=55 years of age, fluent in English or Spanish, residing in the city limits of Chicago, IL, USA. RESULTS: A total of 1001 participants (37 % white, 37 % Black, 26 % Hispanic) were surveyed. On average, participants were 66.9 years old, predominantly female and overweight/obese. Twenty-six per cent (n 263) of participants were classified as 'high' nutrition risk with 24, 14 and 31 % endorsing decreased oral intake, weight loss and compromised functioning, respectively. Black respondents constituted the greatest proportion of those with high risk scores, yet Hispanic participants displayed the most concerning nutrition risk profiles. Younger age, female sex, Black or Hispanic race/ethnicity, emergency room visits, eating alone and taking three or more different prescribed or over-the-counter drugs daily were significantly associated with high risk scores (P<0.05). CONCLUSIONS: One in four older adults living in an urban community prone to health disparities was classified as 'high' nutrition risk. Targeted interventions to promote healthy ageing are needed, especially for overweight/obese and minority community members. PMID- 30396377 TI - Comparison of Dexmedetomidine-Ketamine- Midazolam and Isoflurane for Anesthesia of Black-tailed Prairie Dogs (Cynomys ludovicianus). AB - Few studies evaluate anesthesia in black-tailed prairie dogs (Cynomys ludovicianus). Isoflurane inhalant anesthesia is usedin this species most commonly, but injectable protocols are poorly described. Here we compared the physiologic effects, including anesthetic depth, vital signs, and hematologic changes, of anesthetic protocols using isoflurane or a combination ofdexmedetomidine, ketamine, and midazolam in black-tailed prairie dogs. In a randomized, complete crossover study design, intact male black-tailed prairie dogs (n = 9; age, 6 mo) were anesthetized by using a combination of dexmedetomidine (0.25mg/kg IM), ketamine (40 mg/kg IM), and midazolam (1.5 mg/kg IM). For reversal, atipamezole (0.15 mg/kg) and flumazenil(0.05 mg/kg) were administered 45 min after induction. For comparison, isoflurane was administered at 5% in 100% oxygen at 5 L/min in an anesthetic induction chamber, followed by maintenance isoflurane 2% in 2 L/min oxygen through a tightfitting facemask for 45 min. Induction and recovery time, respiratory rate, heart rate, body temperature, SpO2, indirect blood pressure, and reflexes were monitored every 5 min during the anesthetic period. Blood samples for venous blood gases, PCV, and refractometric total protein were obtained from the cranial vena cava at 5 min and 45 min. Both protocols appeared to achieve safe and effective anesthesia. Except for blood pressure, all vital signs differed between the 2 treatments. Isoflurane anesthesia resulted in a slightly longer induction and lower respiratory rate and body temperature but increased likelihood of absent reflexes. DKM anesthesia resulted in a faster induction and less hypothermia but also prolonged recovery and lower heart rate and SpO2 readings. These findings suggest that isoflurane provides a more stable and consistent anesthetic plane, whereas dexmedetomidine-ketamine-midazolam anesthesia may be an effective alternative for short procedures that require fast induction and limited analgesia. PMID- 30396376 TI - Promoting cross-jurisdictional primary health care research: developing a set of common indicators across 12 community-based primary health care teams in Canada. AB - AimTo describe the process by which the 12 community-based primary health care (CBPHC) research teams worked together and fostered cross-jurisdictional collaboration, including collection of common indicators with the goal of using the same measures and data sources. BACKGROUND: A pan-Canadian mechanism for common measurement of the impact of primary care innovations across Canada is lacking. The Canadian Institutes for Health Research and its partners funded 12 teams to conduct research and collaborate on development of a set of commonly collected indicators. METHODS: A working group representing the 12 teams was established. They undertook an iterative process to consider existing primary care indicators identified from the literature and by stakeholders. Indicators were agreed upon with the intention of addressing three objectives across the 12 teams: (1) describing the impact of improving access to CBPHC; (2) examining the impact of alternative models of chronic disease prevention and management in CBPHC; and (3) describing the structures and context that influence the implementation, delivery, cost, and potential for scale-up of CBPHC innovations.FindingsNineteen common indicators within the core dimensions of primary care were identified: access, comprehensiveness, coordination, effectiveness, and equity. We also agreed to collect data on health care costs and utilization within each team. Data sources include surveys, health administrative data, interviews, focus groups, and case studies. Collaboration across these teams sets the foundation for a unique opportunity for new knowledge generation, over and above any knowledge developed by any one team. Keys to success are each team's willingness to engage and commitment to working across teams, funding to support this collaboration, and distributed leadership across the working group. Reaching consensus on collection of common indicators is challenging but achievable. PMID- 30396378 TI - CYP2C19 polymorphism in relation to the pharmacotherapy optimization of commonly used drugs. AB - Purpose: The CYP2C19 isoenzyme plays an important role in the efficacy and safe use of many drugs. The aim of this review is to demonstrate how CYP2C19 mutations influence everyday patient treatment, leading to adverse drug reactions or therapy failure in many common diseases. Methods: A PubMed literature search was performed on clinical publications evaluating the impact of CYP2C19 on pharmacotherapy outcome. Main fields of medicine with strong outcome dependency on the CYP2C19 genotype were selected. We also focused on clinical recommendations for the use of drugs referring to CYP2C19 polymorphism. Results: The fields of medicine where clinical outcome particularly depends on CYP2C19 polymorphism are gastroenterology, cardiology, psychiatry, mycology and oncology. CYP2C19 is involved in proton pump inhibitors metabolism, thus it can influence reflux therapy, ulcer prevention and Helicobacter pylori eradication treatment. The CYP2C19 enzyme plays also a vital role in the two bioactivation steps of clopidogrel leading to lower (CYP2C19*17 carriers) or higher (CYP2C19*2 carriers) risk of major adverse cardiovascular events. It affects the antidepressant treatment and methadone replacement therapy as well as voriconazole prophylaxis. The presence of a *2 allele is associated with longer relapse-free time or better survival, and the *17 allele with more favorable outcomes in breast cancer patients treated with tamoxifen. Conclusions: Knowledge of the CYP2C19 polymorphism could positively affect individual treatment and lead to better patient outcomes in many cases. The introduction of pharmacogenetic testing into medical practice would be a good way to minimize negative outcomes of therapy, and to reduce unnecessary medical costs. PMID- 30396379 TI - A simple and sensitive HPLC-fluorescence method for the determination of moxifloxacin in human plasma and its application in a pharmacokinetic study. AB - A simple sample preparation technique coupled with the specific and sensitive fluorescence detection for the determination of moxifloxacin in human plasma was developed and fully validated. Levofloxacin was chosen as an internal standard. Chromatographic separation was achieved using a Shiseido C18 MGII (250*4.6mm i.d.; 5 MUm) column under an isocratic mobile phase comprising of 50 mM potassium dihydrogen phosphate (pH 2.4) - acetonitrile (77:23, v/v) at a flow rate of 1.5 mL/min. Fluorescence detection was optimized for the determination of moxifloxacin in human plasma at an excitation wavelength of 296 nm and an emission wavelength of 504 nm. The total chromatographic run time was 8 min with the retention times of moxifloxacin and internal standard at 6.5 and 3.0 min, respectively. Calibration curves were established over the dynamic range of 20 3000 ng/mL. The analytical method was validated as per US-FDA and EMA guidelines for specificity, sensitivity, linearity, accuracy, precision, recovery, hemolytic effect, lipemic effect, dilution integrity and stability. The validated analytical method was successfully applied in a pharmacokinetic study of a single dose oral administration of a moxifloxacin 400 mg tablet in Thai healthy volunteers. PMID- 30396380 TI - An UPLC-MS/MS method for the determination of EAI045 in plasma and tissues and its application to pharmacokinetic and distribution studies in rats. AB - EAI045 represents a fourth generation allosteric EGFR TKI compound which targets T790M and C797S EGFR mutants. The study reported herein describes a method to explore the distribution of EAI045 in rat tissues as well as to quantify it in plasma. The method used here is an ultra-performance liquid chromatography-tandem mass spectrometry with high sensitivity and selectivity. An ACQUITY UPLC BEN HILIC column with dimensions of 2.1 * 100 mm, 1.7 MUm was used to separate the analytes and IS. As mobile phase acetonitrile as well as 0.1 % of formic acid/water was used combined with an elution gradient and 0.40 mL/min flow rate. This eluent was also used for electrospray ionization in positive ion mode. A mode on multiple reactions monitoring (MRM) was also employed in the quantification. This quantification included the use of targeted segment ions with m/z 384.1->100.8 for EAI045, and m/z 285.1->193.3 for IS, respectively. It was found that the linearity of this method was appropriate and the concentration range could be kept within a range of 2-2000 ng/mL for EAI045 in rat plasma and tissues. The level of EAI045 was found to be highest in the liver, followed by kidneys, lungs and heart. Furthermore, the results provided evidence that EAI045 could be absorbed quickly and distributed widely in different tissue types. PMID- 30396381 TI - Drug likeness, targets, molecular docking and ADMET studies for some indolizine derivatives. AB - The aim of this work was to investigate the biomolecular targets for a library of indolizines, study their molecular properties, drug likeness, target prediction, performing docking studies and exploring their ADMET profile in search for a lead compound. All compounds appeared to comply with Lipinski's rule without any violation, additionally their solubility is viewed good except for compounds 4a-c which are anticipated to be reasonably soluble, their Milog P score was 4.18-4.9, proposing that these compounds are the most lipophilic with least water solubility, however this may be helpful as the cannabinoid receptor-1 is the most probable target for these three compounds. The inclusive target for the selected library was tau protein. Structure based studies demonstrated great fitting of indolizines with tau protein, along these lines they are expected to have pharmacological action in vivo. This urged us to think about the ADMET properties of this library. These investigations suggested the ability of the selected compounds to pass the blood brain barrier (BBB) (aside from them compounds 2c and 3c) and affect tau proteins, which will be valuable for the treatment of Alzheimer's disease, particularly compound 5 which does not require any SAR modifications to attain the BBB. PMID- 30396382 TI - Levetiracetam inhibits endocytosis and augments short-term depression. AB - Levetiracetam (LEV) is an anti-epileptic drug with demonstrated efficacy against generalized seizures. Recent studies have found that LEV affects the release of neurotransmitters by binding to synaptic vesicle protein 2A (SV2A). However, the details of LEV regulation of synaptic transmission remain poorly understood. Here, we used the whole-cell patch-clamp technique to further characterize the effects of LEV on synaptic transmission at a large mammalian central synapse, the calyx of Held. Our results showed that two common forms of vesicle endocytosis, including slow and rapid endocytosis, were dramatically inhibited when slices were incubated in 100 MUM LEV for 1 h, however, the action potential (AP), calcium influx and exocytosis were not affected. Furthermore, by measuring the level of steady-state depression induced by 100 Hz stimulus trains, we found that the steady state level of depression was significantly stronger after LEV treatment, indicating that LEV enhanced short-term depression (STD). Thus, these findings suggested that the mechanisms of the antiepileptic of LEV seem to be mediated, at least partly, by regulating endocytosis and STD. PMID- 30396383 TI - Effects of dexmedetomidine, propofol and etomidate on the intraoperative wake-up in the cerebral functional area under the guidance of entropy index. AB - Objective: The study observed the efficacy and safety of dexmedetomidine, propofol and etomidate on brain functional areas in patients undergoing wake-up brain surgery under the guidance of entropy index. Methods: Sixty patients undergoing wake-up brain surgery on brain functional areas were enrolled, and randomly divided into three groups: dexmedetomidine group (group D), propofol group (group P) and etomidate group (group E), 20 in each. The vital signs, entropy indices of each time point, wake-up time, wake-up quality and adverse reaction in the wake-up period were observed and compared. Results: There were no differences in the duration of wake-up, duration of anesthesia, duration of surgery and postoperative wake-up time between the three groups (P> 0.05). The wake-up quality in group D was significantly better than group P and group E (P <0.05), group P was better than group E (P <0.05). The incidence of adverse events in group D was lower than that in groups P and E (P <0.05). The incidence of adverse events in group P was lower than that in group E (P <0.05). Conclusion: Under the guidance of entropy index, anesthesia induced by dexmedetomidine, propofol and etomidate combined with remifentanil can safely and effectively be used to the wake-up brain functional areas surgery, but the wake up quality with use of dexmedetomidine is highest, and the incidence of adverse events is the lowest during wake-up period. PMID- 30396384 TI - Pterostilbene's protective effects against photodamage caused by UVA/UVB irradiation. AB - Aim: The aim of this study was to further elucidate the mechanism of pterostilbene against UVA/UVB irradiation and the Nuclear factor E2-related factor 2 (Nrf2) signal pathway. Methods: A photo-damage model with UVA/UVB irradiation in HaCat cells was established and used in this study. The dose of pterostilbene was selected through MTS assay. Cell proliferation and apoptosis in Nrf2 and knockdown Nrf2 cells was detected by MTS assay. Expression of CAT, HO-1, and SOD in Nrf2 and knockdown Nrf2 cells was explored by qPCR. Western blot was used to analysis of Nrf2 nuclear translocation changes in Nrf2 and knockdown Nrf2 cells. Protein carbonyl content and MDA content was tested. Results: Our photo damage model was successfully established and 20J/cm2 UVA and 57mJ/cm2 UVB irradiation was the suitable dose for HaCaT cell damage study. UVA/UVB irradiation would affect Nrf2 protein location, especial for 9.75 MUM pterostilbene dose. In addition, cell proliferation could be significantly inhibited by UVA/UVB treatments (P<0.05), whereas, 9.75 MUM pterostilbene treatment can alleviate the photo-damage. UVA/UVB irradiation would lead to decreased expressions of CAT, HO-1, and SOD. Carbonyl content and MDA was significantly changed by UVA/UVB treatments (P<0.05). The adverse events could be reversed by adding 9.75 MUM pterostilbene. Western blot analysis showed that Nrf2 cytoplasm content in UVA/UVB treated cells was reduced and Nrf2 nuclear content was increased, which are different with the normal HaCaT cells without knockdown Nrf2 treatment (P<0.05). The results of cell proliferation, apoptosis, and cell antioxidant capacity in knockdown Nrf2 treated HaCaT cells were also significantly different with the normal HaCaT cells without knockdown Nrf2 treatment (P<0.05). Conclusion: We hypothesize that pterostilbene could play an anti-oxidation role via the Nrf2 signal pathway. PMID- 30396385 TI - Analgesic effects of the novel alpha2delta ligand mirogabalin in a rat model of spinal cord injury. AB - Mirogabalin, which is a novel ligand for the alpha2delta subunit of voltage-gated calcium channels, is under development for the treatment of pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. Mirogabalin possesses unique binding characteristics to alpha2delta subunits and potent and long lasting analgesic effects in peripheral neuropathic pain models. In the present study, we investigated the analgesic effects of mirogabalin in a rat model of spinal cord injury as an experimental animal model for central neuropathic pain. The spinal cord injury model was established by acute compression of the spinal cord at the T6/7 level with a microvascular clip in male rats. Twenty-eight days after spinal cord injury, the animals received the test compound orally, and the paw withdrawal threshold to mechanical stimulation was determined using the von Frey test at 0 (before administration), 2, 4, 6, 8, and 24 h after administration. The area under the curve of the paw withdrawal threshold (paw withdrawal threshold AUC) was also calculated. In rats subjected to spinal cord injury, mechanical allodynia was demonstrated by a decreased paw withdrawal threshold. A single oral administration of mirogabalin (2.5, 5, or 10 mg/kg) significantly increased the paw withdrawal threshold. The effects of mirogabalin were still significant 6 or 8 h after administration. The paw withdrawal threshold AUC was significantly higher in the treated animals than in the control group. In conclusion, mirogabalin showed potent and long-lasting analgesic effects in a rat model of spinal cord injury and may therefore provide effective pain relief for patients with central neuropathic pain. PMID- 30396386 TI - High expression of TAZ/YAP promotes the progression of malignant melanoma and affects the postoperative survival of patients. AB - Background: YAP/TAZ have been reported to be highly expressed in malignant tumors. This research was aimed to study the expression of TAZ/YAP protein in malignant melanoma and to investigate its relationship to the clinicopathology and prognosis of patients with malignant melanoma. Methods: A total of 156 pairs of malignant melanoma tumor tissues and melanocytic nevi tissues were collected. The expression of TAZ and YAP proteins were detected by immunohistochemistry and western blotting. Relationship between TAZ/YAP and clinical data of malignant melanoma were analyzed. Results: The number of positive cells of TAZ and YAP in malignant melanoma tumor tissues was significantly higher than that in melanocytic nevi tissues, and the expression of both proteins was positively correlated with malignant melanoma (r = 0.687, P <0.01); TAZ and YAP protein expression in malignant melanoma tissue was significantly correlated with tumor thickness, invasive depth grade, lymph node metastasis and TNM stages (P <0.05), and increased with TNM staging. The expression of TAZ and YAP in patients with lymph node metastasis was significantly higher than that in non-metastatic patients (P <0.05). High expression of TAZ/YAP significantly reduced the postoperative survival rate in patients with malignant melanoma. Conclusion: TAZ/YAP is highly expressed in malignant melanoma tumor tissues. The high expression of TAZ/YAP promotes the progression of malignant melanoma and affects the postoperative survival of patients. PMID- 30396387 TI - Protective effects and possible molecular mechanism of Hovenia dulcis Thunb. extract on acetaminophen-induced hepatotoxicity. AB - Hovenia dulcis Thunb. is a traditional hepatoprotective Chinese medicine, and in research, much effort has been focused on the protection against alcoholic liver injury. In this study, the protective effects of a fruit ethanol extract of Hovenia dulcis (FE) against APAP-induced acute hepatotoxicity in mice and the possibly involved molecular mechanisms were investigated. Hepatoprotective activity of FE is clearly indicated by histopathological and biochemical examination. Treatment with FE resulted in inhibition of CYP2E1 activity involved in the transformation of APAP in vivo. Expressions of the altered bile acid metabolism and transport-related genes and relative proteins of apoptosis were normalized by preconditioning with FE before APAP treatment. These results suggested FE to alleviate APAP-induced liver injury in a dose-dependent manner by inhibition of cytochrome P450 activity, hepatocyte apoptosis and regulation of bile acid homeostasis imbalance. PMID- 30396388 TI - Risk factors increasing blood pressure in Japanese colorectal cancer patients treated with bevacizumab. AB - Bevacizumab has been reported to increase blood pressure. However, the factors, including patient characteristics and laboratory data contributing to this side effect remain unclear. Therefore, we investigated the relationships between increased blood pressure and bevacizumab administration, patient characteristics, and laboratory data. Between April 2007 and January 2018, factor analysis was retrospectively conducted by monitoring increases in blood pressure, the status of bevacizumab administration, patient characteristics, and laboratory data before the first administration in Japanese patients with colorectal cancer who satisfied the criteria for this study. Sixty-seven patients were included, 34 of whom (50.7%) had an increase in blood pressure after bevacizumab administration. On univariate analysis, liver metastasis, antihypertensive drug use, systolic blood pressure at rest before the first bevacizumab administration, body mass index, creatinine, and blood platelet count were significantly different between the two groups. Multivariate analysis was conducted using increased blood pressure as an objective variable and the factors extracted by the univariate analysis as explanatory variables. The results suggested that liver metastasis, antihypertensive drugs, systolic blood pressure at rest before the first bevacizumab administration, and creatinine were associated with the increase in blood pressure. Furthermore, a log-rank test performed based on Kaplan-Meier curves demonstrated that liver metastasis in patients not taking antihypertensive drugs and antihypertensive drug use in patients without liver metastasis were significantly associated with increased blood pressure. Additionally, liver metastasis in patients with antihypertensive drug use was significantly associated with increased blood pressure. Our findings suggest that liver metastasis and antihypertensive drug use, which was previously reported, are risk factors for increased blood pressure. PMID- 30396389 TI - Cleopatra: from turpentine and juniper to ionone and irone. AB - Cleopatra VII (69-30 BC), the last Ptolemaic ruler of Egypt, is probably best known for her love affairs with Julius Caesar (100-44 BC) and Marcus Antonius (83 30 BC). Rightly or wrongly she became the epitome of shrewd seduction, leading brave Roman commanders on a path to debauchery and destruction. Among the seductive strategies attributed to her is the ingestion of small amounts of turpentine [the resin of the terebinth tree (Pistacia terebinthus)] or of derived oil (Oleum terebinthinae) with the purpose of conferring to her urine a more pleasant scent reminding of violets. Turpentine components are metabolized among other compounds to ionones and irones, which - renally excreted - are responsible for the flowery scent. Having obviously worked with great generals, the strategy is said to have been embraced for everyday use by many affluent Roman women. Complicating the issue somewhat is the fact that juniper berries (Fructus juniperi) and derived oil (Oleum juniperi) containing many of the same terpenoids as turpentine have a similar effect on urine. The purpose of this contribution is to briefly review the pharmacology of turpentine and juniper derived compounds assumed to be responsible for altering the scent of urine and to examine the origin and veracity of the mentioned habit. While the effect of ingested turpentine on the scent of urine is well documented our attempts at identifying Greek or Latin authors mentioning its intentional use for this explicit purpose (by Cleopatra or anybody else) failed. PMID- 30396390 TI - Structural characterization and biological evaluation of Staphylosan (dimannooleate), a new glycolipid surfactant produced by a marine Staphylococcus saprophyticus SBPS-15. AB - Marine microbes have gained significant attention as potential biofactories for broad spectrum bioactive compounds. In the recent years, bioactive biosurfactants have warranted renewed interest from both environmental and clinical sectors as anti-biofilm agents due to their excellent properties of dispersing microbial biofilms. The present study explores a new glycolipid biosurfactant produced by a marine Staphylococcus saprophyticus exhibiting interesting biological activities. This glycolipid biosurfactant was purified and identified as Mannose-Mannose Oleic acid (named as Staphylosan) based on the results of NMR, GC, GC-MS, MALDI TOF-MS and tandem MS analysis. The surface tension and critical micelle concentration of purified Staphylosan was 30.9 mN m-1 and 24 mg L-1. Further, it showed promising biofilm inhibition and dislodging activities against a panel of profuse biofilm forming bacteria at both single and multi-species level which were isolated from boat hull biofilm environment such as Bacillus subtilis BHKH 7, Acinetobacter beijerinckii BHKH-11, Pseudomonas aeruginosa BHKH-19, Serratia liquefaciens BHKH-23, Marinobacter lipolyticus BHKH-31 and Micrococcus luteus BHKH-39. Moreover, it exhibited anionic charge and revealed non-toxicity towards brine shrimps, suggesting its environmental safety. This is a first report on Staphylosan, a multifunctional glycolipid surfactant from a marine Staphylococcus saprophyticus SBPS-15, exhibiting promising anti-biofilm activities and non-toxic in nature and thus finds possible potential use in many environmental applications especially under marine conditions. PMID- 30396391 TI - The role of enzyme adsorption in the enzymatic degradation of an aliphatic polyester. AB - The enzyme catalyzed degradation of poly(3-hydroxybutyrate) (PHB) is a two-step process consisting of the adsorption of the enzyme on the surface of a PHB substrate and the cleavage of ester bonds. A deactivated enzyme was prepared by point mutagenesis to separate the two steps from each other. Measurements carried out with active and inactive enzymes on PHB particles proved that mutagenesis was successful and the modified enzyme did not catalyze degradation. Based on the Michaelis-Menten approach a kinetic model was proposed which could describe the processes quantitatively, the agreement between prediction and the measured data was excellent. The separation of the two processes allowed the determination of the adsorption kinetics of the enzyme; the rate constants of the adsorption and desorption process were determined for the first time. Comparison of these constants to reaction rates showed that adsorption is not instantaneous and can be the rate-determining step. The area occupied by an enzyme molecule was also determined (13.1 nm2) and it was found to be smaller than the value published in the literature (17 +/- 8 nm2). The separation of the two steps makes possible the prediction and control of the degradation process. PMID- 30396392 TI - Evaluation of angiotensin converting enzyme inhibitors by SPR biosensor and theoretical studies. AB - Surface plasmon resonance (SPR) biosensor has been utilized for monitoring analyte-ligand interactions in modern drug discovery processes. SPR biosensors measure the change in refractive indexes over the course of analyte molecules' binding to a specific immobilized ligand on sensor chip. This effort highlights a comprehensive SPR study besides enzymatic assay for discovery of new Angiotensin Converting Enzyme (ACE) inhibitors via screening of medicinal plants. At first, five medicinal plants were selected as potential sources for developing new ACE inhibitors through hydrolyzing hippuryl-L-histidyl-L-leucine (HHL) assay. The interaction of selected extracts with immobilized ACE on the sensor chip (500D) confirmed that the Onopordum acanthium L. had the greatest ACE inhibition activity among the set of compounds and its active compound (onopordia) was isolated. SPR biosensor used to evaluate binding affinity of onopordia and ACE. Equilibrium constant (KD), and changes in Gibb's free energy of the binding (DeltaGbinding) values for the interaction of onopordia with ACE were found to be 10.24 MUM and -28.48 kJ/mol, respectively. Computational analysis supported the binding of onopordia to the ACE active site. Kinetic and thermodynamic parameters of binding revealed that onopordia is an acceptable ACE inhibitor and could treat hypertension. SPR biosensor can be used to improve the drug discovery process for many important classes of drug targets due to its great sensitivity. PMID- 30396393 TI - Screening of novel feruloyl esterases from Talaromyces wortmannii for the development of efficient and sustainable syntheses of feruloyl derivatives. AB - The feruloyl esterases Fae125, Fae7262 and Fae68 from Talaromyces wortmannii were screened in 10 different solvent: buffer systems in terms of residual hydrolytic activity and of the ability for the transesterification of vinyl ferulate with prenol or l-arabinose. Among the tested enzymes, the acetyl xylan-related Fae125 belonging to the phylogenetic subfamily 5 showed highest yield and selectivity for both products in alkane: buffer systems (n-hexane or n-octane). Response surface methodology, based on a 5-level and 6-factor central composite design, revealed that the substrate molar ratio and the water content were the most significant variables for the bioconversion yield and selectivity. The effect of agitation, the possibility of DMSO addition and the increase of donor concentration were investigated. After optimization, competitive transesterification yields were obtained for prenyl ferulate (87.5-92.6%) and l arabinose ferulate (56.2-61.7%) at reduced reaction times (<=24 h) resulting in good productivities (>1 g/L/h, >300 kg product/kg FAE). The enzyme could be recycled for six consecutive cycles retaining 66.6% of the synthetic activity and 100% of the selectivity. PMID- 30396394 TI - Synergetic effect of Ni2+ and 5-acrylamidobenzoboroxole functional groups anchoring on magnetic nanoparticles for enhanced immobilization of horseradish peroxidase. AB - In this work, a novel Ni2+&AABOB bifunctional core-shell magnetic composite nanoparticles (MNPs), Fe3O4@p(AABOB-co-AIM-Ni2+), were synthesized for the immobilization of horseradish peroxidase (HRP). Two kinds of interaction are simultaneously incorporated to improve the stability and reusability of immobilized HRP: one is the coordination between Ni2+ and amide group in HRP, and the other is the interaction of the wulff-type boronic acid group with cis-diol containing HRP which belongs to a type of glycoproteins. Accordingly, the proposed approach achieved high enrichment capacity (174.75 mg/g, protein/beads), and the activity of immobilized HRP still achieved 80% after reuse for 5 cycles. The degradation efficiency of phenol in the presence of immobilized HRP reached 93% within 10 min, which was significantly higher than that of free HRP only about 50% within 20 min. In addition, the immobilized HRP can be easily separated from the reaction solution by an external magnetic field. PMID- 30396395 TI - Xylanase from Aspergillus tamarii shows different kinetic parameters and substrate specificity in the presence of ferulic acid. AB - A 22 kDa xylanase (AtXyl1) from Aspergillus tamarii was purified by two chromatographic steps and presented preference for oat spelt (OSX), birchwood (BrX) and beechwood (BeX) xylans respectively, as substrates. AtXyl1 displays the highest activity at pH 5.5 and 55 degrees C and showed tolerance over a range of different phenolic compounds. The activity of AtXyl1 was not inhibited when the enzyme was incubated with ferulic acid (FA) using OSX or BrX as substrate. On the other hand, the incubation of AtXyl1 with BeX and FA resulted in an increase in enzyme activity. The molecular docking of a GH11 xylanase from Aspergillus niger with FA showed the preference for binding within the catalytic site. The position of FA was based on the presence or absence of a complexed substrate. When the enzyme from A. niger was docked in the absence of xylan in its crystal structure, FA interacted with Tyr164 and a water molecule. For the enzyme socked with xylo oligosaccharides, FA interacted with Ser94, Tyr89 and the xylo-oligosaccharide present in the catalytic site. Thermodynamic parameters from the reaction of AtXyl1 with different xylans and FA indicate that FA can cause a conformational change in the enzyme, and this can influence the substrate fitting and makes the enzyme tolerant or active toward the substrate. Our findings suggest that enzyme activation or tolerance to phenolic compounds can be correlated to subtle changes in enzyme conformation due to the presence of the phenolic compound. PMID- 30396396 TI - Functional characterization and comparative analysis of two heterologous endoglucanases from diverging subfamilies of glycosyl hydrolase family 45. AB - Lignocellulosic materials are abundant, renewable and are emerging as valuable substrates for many industrial applications such as the production of second generation biofuels, green chemicals and pharmaceuticals. However, the recalcitrance and the complexity of cell wall polysaccharides require multiple enzymes for their complete conversion to oligo- and monosaccharides. The endoglucanases from GH45 family are a small and relatively poorly studied group of enzymes with potential industrial application. The present study reports cloning, heterologous expression and functional characterization of two GH45 endoglucanases from mesophilic fungi Gloeophyllum trabeum (GtGH45) and thermophilic fungi Myceliophthora thermophila (MtGH45), which belong to subfamilies GH45C and GH45A, respectively. Both enzymes have optimal pH 5.0 and melting temperatures (Tm) of 66.0 degrees C and 80.9 degrees C, respectively, as estimated from circular dichroism experiments. The recombinant proteins also exhibited different mode of action when incubated with oligosaccharides ranging from cellotriose to cellohexaose, generating mainly cellobiose and cellotriose (MtGH45) or glucose and cellobiose (GtGH45). The MtGH45 did not show activity against oligosaccharides smaller than cellopentaose while the enzyme GtGH45 was able to depolymerize cellotriose, however with lower efficiency when compared to larger oligosaccharides. Furthermore, both GHs45 were stable up to 70 degrees C for 24 h and useful to enhance initial glucan hydrolysis rates during saccharification of sugarcane pith by a mixture of cellulolytic enzymes. Recombinant GHs45 from diverging subfamilies stand out for differences in substrate specificity appearing as new tools for preparation of enzyme cocktails used in cellulose hydrolysis. PMID- 30396397 TI - A facile method to oriented immobilization of His-tagged BirA on Co3+-NTA agarose beads. AB - A facile and economical method was established for the oriented immobilization of biotin ligase (BirA) on Co3+-NTA sepharose through H2O2 oxidation of Co2+ and His tag. His-tag of the BirA were designed at both N-terminal (His-BirA) and C terminal (BirA-His), respectively. Immobilization of the His-BirA was performed, realized to 92.85% using by 10 mM H2O2 without compromising catalytic activity. Because amounts of ions on matrix were far more than that of the immobilized BirA, EDTA should be used to remove residual ions before catalyzing, while it should be limited to lower than 30 mM, and imidazole ranging from 50 to 250 mM could be added in the catalytic system. When 10 mM EDTA and 50 mM imidazole were used, over 90% of substrates were obtained from the matrix. Moreover, the His BirA showed higher immobilization rate than the BirA-His, while both of them appeared high catalytic abilities at pH ranging from 6.5 to 9.0, indicating versatile options in the biotinylation of proteins with different pH stabilities. Under the best catalytic conditions, the both immobilized His-BirA and BirA-His exhibited the same activity as the free. When the enzyme was incubated at different pH (pH 3.0, 4.0, 5.0, 10.0 and 11.0) and temperature (40 degrees C, 50 degrees C and 60 degrees C), the immobilized His-BirA showed less pH-sensitive, overall preferable thermo-stability than the free, making it a more desirable option for storage and transportation. More importantly, the reusability of the immobilized His-BirA implied a promising value in industrialization. PMID- 30396398 TI - Early biofouling detection using fluorescence-based extracellular enzyme activity. AB - Membrane-based filtration technologies have seen rapid inclusion in a variety of industrial processes, especially production of drinking water by desalination. Biological fouling of membranes is a challenge that leads to increased costs from efficiency reductions, membrane damage and ultimately, membrane replacement over time. Such costs can be mitigated by monitoring and optimizing cleaning processes for better prognosis. Monitoring bacterial accumulation in situ can therefore advance understanding of cleaning efficiency. A fluorescence-based sensor for early biofouling detection capable of measuring extracellular enzyme activity was developed and tested in a lab-scale seawater reverse osmosis (SWRO) biofouling model for use in monitoring bacterial accumulation proximal to the surface of a membrane. We tracked bacterial biomass accumulation rapidly and non-invasively using exogenously applied fluorogen-substrates and corroborated with optical coherence tomography imaging of the membrane surface in real-time. The selected fluorogen and fluorogen-substrate were characterized and down selected by high throughput screening in vitro for compatibility in seawater and profiled over relevant Red Sea desalination parameters (pH and temperature). This approach demonstrates the practicality of prototyping an early-detection biofouling sensor in membrane based processes, such as seawater desalination, using extracellular enzyme activity as a measure of bacterial abundance. PMID- 30396399 TI - Enzymatic synthesis of sitagliptin intermediate using a novel omega-transaminase. AB - Enantiopure beta-amino acids are essential precursors of various pharmaceuticals, agrochemicals and other industrially important chemicals. In this study, we selected sixteen potential omega-Transaminases (omega-TAs) by BLAST and phylogenetic tree analysis. These omega-TAs were cloned, purified and tested for their reactivity for the synthesis of model beta-amino acid (R)-3-amino-4-(2,4,5 triflurophenyl) butanoic acid [3-ATfBA], a key precursor for sitagliptin. In an enzymatic cascade, lipase converted beta-ketoester substrate to beta-keto acid, which was subsequently aminated by the selected omega-TA to its corresponding beta-amino acid. A potent enzyme from Ilumatobacter coccineus (omega-TAIC) was identified for the production of 3-ATfBA. The pH dependency of the product inhibition suggested that lowering the reaction pH to 7.0 can circumvent the inhibition of omega-TAIC by 3-ATfBA and about 92.3% conversion of 100 mM beta keto ester substrate could be achieved. The applicability of this enzymatic system was further evaluated at the scale of 140 mM, wherein 3-ATfBA was generated with excellent conversion (81.9%) and enantioselectivity (99% ee). Furthermore, omega-TAIC was successfully used for the synthesis of various beta amino acids from their corresponding beta-keto ester substrates. PMID- 30396400 TI - Functional analysis of active amino acid residues of the mercaptosuccinate dioxygenase of Variovorax paradoxus B4. AB - Thiol dioxygenases are non-heme mononuclear-iron proteins and belong to the cupin superfamily. In 2014, mercaptosuccinate dioxygenase (Msdo) of Variovorax paradoxus B4 was identified as another bacterial cysteine dioxygenase (Cdo) homolog catalyzing the conversion of mercaptosuccinate (MS) into succinate and sulfite. To gain further insights into potentially important amino acid residues for enzyme activity, seven enzyme variants were generated and analyzed. (i) Three variants comprised the substitution of one conserved histidine residue each by leucine, either supposed to be mandatory for coordination of the Fe(II) cofactor (H93 and H95) or to be important for substrate positioning within the active site (H163). The corresponding enzyme variants were completely inactive confirming their essential roles for enzyme activity. (ii) Mutation C100S resulted as well in an inactive enzyme demonstrating its importance for either stability or activity of the protein. (iii) For eukaryotic Cdo, a hydrogen bond network for substrate positioning was postulated, and the corresponding amino acids are basically present in Msdo. Albeit the MsdoQ64A mutation exhibited an increased Km of 0.29 mM when compared to the wildtype with 0.06 mM, it did not significantly affect the specific activity. (iv) The variant MsdoR66A showed only very low activity even when high amounts of enzyme were applied indicating that this residue might be important for catalysis. (v) No strong effect had the mutation Y165F for which a specific enzyme activity of 10.22 MUmol min-1 mg-1 protein and a Km value of 0.06 mM with high similarity to those of the wildtype enzyme were obtained. This residue corresponds to Y157 of human Cdo, which is part of the catalytic triad and is supposed to be involved in substrate positioning. Apparently, another residue could fulfill this role in Msdo, since the loss of Y165 did not have a strong effect. PMID- 30396402 TI - Bilirubin oxidase-based silica macrocellular robust catalyst for on line dyes degradation. AB - We present a new heterogeneous biocatalyst based on the grafting of Bilirubin Oxidase from Bacillus pumilus into macrocellular Si(HIPE) materials dedicated to water treatment. Due to the host intrinsic high porosity and monolithic character, on-line catalytic process is reached. We thus used this biocatalyst toward uni-axial flux decolorizations of Congo Red and Remazol Brilliant Blue (RBBR) at two different pH (4 and 8.2), both in presence or absence of redox mediator. In absence of redox mediators, 40% decolorization efficiency was reached within 24 h at pH 4 for Congo Red and 80% for RBBR at pH 8.2 in 24 h. In presence of 10MUM ABTS, it respectively attained 100% efficiency after 2h and 12h. We have also demonstrated that non-toxic species were generated upon dyes decolorization. These results show that unlike laccases, this new biocatalyst exhibits excellent decolorization properties over a wide range of pH. Beyond, this enzymatic-based heterogeneous catalyst can be reused during two months being simply stored at room temperature while maintaining its decolorization efficiency. This study shows that this biocatalyst is a promising and robust candidate toward wastewater treatments, both in acidic and alkaline conditions where in the latter efficient decolorization strategies were still missing. PMID- 30396401 TI - Glucansucrase catalyzed synthesis and functional characterization of nordihydroguaiaretic acid glucosides. AB - Nordihydroguaiaretic acid (NDGA) is the major lignan of the creosote bush Larrea tridentata known for its antioxidative and pharmacological properties. Here we present the identification of glucansucrases for NDGA glucosylation and the physicochemical and biological characterization of the glucosides. Extracellular glucansucrase of L. pseudomesenteroides DSM 20193 was selected from 19 glucansucrase positive Leuconostoc and Weissella strains. Kinetic analysis of the PEG-fractionated enzyme revealed a KM of 6.6 mM and a kcat of 2.6 s-1 for NDGA. Full-factorial design methodology was used to optimize conversion resulting in 95.5% total NDGA glucosides. In total 7 glucosides were detected by LC-MS ranging from mono- to triglucoside. The 4-O-alpha-D-monoglucoside and the symmetrical 4,4'-O-alpha-D-diglucoside were the major products in all biotransformations. Water solubility and half-life stability at 45 degrees C increased significantly in the order diglucoside > monoglucoside > aglycon. Analysis of cellular antioxidative capacity exhibited a time-dependent activity increase pointing towards glucoside hydrolysis. Accordingly, NDGA-glucosides impaired metastasis of triple negative breast cancer cells to the same degree as the aglycon with 35% reduction of cell migration by the mono- and 34% reduction by the diglucoside after 20 h. PMID- 30396403 TI - A novel low pH fermentation process for the production of acetate and propylene glycol from carbohydrate wastes. AB - A novel low pH fermentation process was studied for the conversion of lactose using Lactobacillus plantarum and Lactobacillus buchneri under anoxic conditions in single co-culture, and two-stage sequential fermentations. This is aimed at producing acetate and propylene glycol (PG) as environmentally benign substitutes for currently used road and aircraft deicing chemicals. The results indicate that in the case of two-stage fermentation with immobilized L. buchneri in the second stage, lactose degradation rate increased markedly producing acetate and PG concentrations of 12.1 and 10.7 g L-1 at pH 3.8. In the case of coculture fermentation, the acetate and PG concentrations were 8.2 and 6.8 g L-1, respectively. Fermentation of lactose and whey powder was conducted at pH 4.25 using a high cell density culture of L. buchneri. The acetate and PG yields were similar for both substrates at ~0.3 g/g and ~0.33 g/g respectively. With a starting lactose concentration of 60 g/L, acetate and PG concentrations of 18 g/L and 21 g/L respectively were obtained. The low pH conversion of wastes to value added products under anoxic conditions provides substantial operating benefits over neutral pH fermentations that require strict anaerobic conditions for effective operation. Moreover, the low product pH at around 4.0 will provide substantial savings in downstream processing costs due to the much higher extraction efficiency of weak- and moderate- base resins for acetic acid compared to acetate ion. PMID- 30396404 TI - High-efficiency enzymatic production of alpha-isoquercitrin glucosides by amylosucrase from Deinococcus geothermalis. AB - Isoquercitrin (IQ, quercetin-3-O-beta-d-glucopyranoside) has diverse biological functions, such as anti-oxidant and anti-cancer activity, but its use is limited by poor solubility and bioavailability. Enzymatically modified IQ (EMIQ) is a mixture of transglycosylated IQs that have better solubility and bioavailability than do quercetin and IQ. Two different enzymes, cyclodextrin glucanotransferase (CGTase) and amylosucrase (ASase), have the transglycosylation activity to produce EMIQ. Both enzymes produce a variety of EMIQs including IQ, IQ-glucoside (IQ-G1), IQ-diglucoside (IQ-G2), and IQ-triglucoside (IQ-G3). ASase had a higher bioconversion yield from IQ to EMIQ (97.6%) than did CGTase (76.8%). In addition, the yield of IQ-G3, which was the most bioavailable form, was higher with ASase (46%) than with CGTases (8%). Taken together, these results suggest that ASase can be used to synthesize EMIQ in a simple and specific process. PMID- 30396405 TI - A single point mutation in hmgA leads to melanin accumulation in Bacillus thuringiensis BMB181. AB - Bacillus thuringiensis BMB181 (Bt BMB181), with high melanin production, is an ideal candidate for industrial scale production of light-stable insecticides. However, its melanogenic pathways remain unclear. In the present study, we demonstrated that Bt BMB181 failed to produce melanin after treatment with mesotrione, an inhibitor of 4-hydroxyphenylpyruvate dioxygenase in the homogentisic acid pathway of melanin synthesis. Heterologous expression experiments suggested that homogentisate-1,2-dioxygenase (HmgA) in Bt BMB171 functions normally, yet HmgA in Bt BMB181 had lost its activity, at least partly. Using the CRISPR-Cas9 system, the hmgA gene in Bt BMB171 was knocked out and the mutant strain gained the ability to produce melanin. Furthermore, the complemented strain reverted to the wild-type phenotype. In addition, overexpression of its own hmgA gene in Bt BMB181 also resulted in failure to produce the pigment. BLAST results indicated that the amino acid alteration (G272E) in HmgA of Bt BMB181 was caused by a single point mutation (815G-> A). The enzyme activity of purified HmgA171 was more than 10-fold higher than that of HmgA181. Finally, we determined that the mutation in hmgA was responsible for melanin accumulation in Bt BMB181. Our results provided new insights into the synthesis and regulation of melanin production in B.thuringiensis and will promote its future industrial application. PMID- 30396406 TI - Bioprocess optimization for the overproduction of catalytic domain of ubiquitin like protease 1 (Ulp1) from S. cerevisiae in E. coli fed-batch culture. AB - The exploitation of SUMO (small ubiquitin-related modifier) fusion technology at a large scale for the production of therapeutic proteins with an authentic N terminus is majorly limited due to the higher cost of ScUlp1 protease. Therefore, the cost-effective production of Saccharomyces cerevisiae Ulp1 protease catalytic domain (402-621 aa) was targeted via its cloning under strong T7 promoter with and without histidine tag. The optimization of cultivation conditions at shake flask resulted in ScUlp1 expression of 195 mg/L in TB medium with a specific product yield of 98 mg/g DCW. The leaky expression of the ScUlp1 protease was controlled using the chemically defined minimal medium. The Ni-NTA affinity purification of ScUlp1 was done near homogeneity using different additives (0.1% Triton X-100, 0.01 mM DTT, 0.02 mM EDTA and 1% glycerol) where a product purity of ~95% with a recovery yield of 80% was obtained. The specific activity of purified ScUlp1 was found to be 3.986 * 105 U/mg. The ScUlp1 protease successfully cleaved the SUMO tag even at 1:10,000 enzyme to substrate ratio with high efficacy and also showed a comparable catalytic efficiency as of commercial control. Moreover, the in vivo cleavage of SUMO tag via co-expression strategy also resulted in more than 80% cleavage of SUMO fusion protein. The optimization of high cell density cultivation strategies and maintenance of higher plasmid stability at bioreactor level resulted in the ScUlp1 production of 3.25 g/L with a specific product yield of 45.41 mg/g DCW when cells were induced at an OD600 of 132 (63.66 g/L DCW). PMID- 30396407 TI - Airway Anomalies. AB - This article reviews congenital anomalies involving the larynx and trachea, including congenital subglottic stenosis, laryngeal webs, laryngeal cleft, and tracheal stenosis. Presenting signs and symptoms, prevailing surgical repair techniques, and postoperative care are discussed. PMID- 30396408 TI - Fetal Evaluation and Airway Management. AB - Congenital causes of airway obstruction once noted at birth are now diagnosed prenatally. The adoption of ex utero intrapartum treatment has allowed for planned airway stabilization on placental support, dramatically decreasing the incidence of hypoxic injury or peripartum demise related to neonatal airway obstruction. Airway access is gained either through laryngoscopy, bronchoscopy, or a surgical airway. In complete airway obstruction, primary resection of the obstructing lesion may be performed before completion of delivery. This article reviews the current and emerging methods of fetal evaluation, indications for ex utero intrapartum treatment, and provides a detailed description of the procedure and necessary personnel. PMID- 30396409 TI - Hearing Loss and Failed Newborn Hearing Screen. AB - Hearing loss is the most common congenital defect. With early diagnosis and intervention, we are able to improve speech and language outcomes in this population. In this article, we discuss the implications of the newborn hearing screen, as well as diagnostic interventions, management, and intervention, and the increasing role of congenital cytomegalovirus screening. PMID- 30396410 TI - Aspiration and Dysphagia in the Neonatal Patient. AB - Dysphagia and aspiration are commonly encountered problems in the neonatal population. It is often multifactorial in nature and management should be tailored to the individual patient. Multiple causes should be considered, including anatomic abnormalities, neurologic/developmental delay, cardiopulmonary disease/infection, and gastroesophageal reflux disease, in addition to those cases where a definitive reason may not be identified. Management should be multidisciplinary in nature and surgical intervention may be indicated in certain populations of patients. Here, we discuss the presentation, workup, and management of the neonatal patient with dysphagia and aspiration. PMID- 30396411 TI - Cleft Lip and Palate. AB - Orofacial clefts are common congenital malformations with genetic and environmental risk factors. In the perinatal period, feeding and nutrition can be a challenge and the need for specialized feeders is common. Lip taping and nasoalveolar molding are early interventions that can be used to preoperatively modify cleft defects to enhance surgical outcomes. Multiple techniques are available for repair of orofacial clefts and choice of technique depends on cleft extent and surgeon preference. After definitive repair, children remain at increased risk for middle ear disease, velopharyngeal dysfunction, and malocclusion and require ongoing follow-up with a multidisciplinary team. PMID- 30396412 TI - Microtia and Related Facial Anomalies. AB - Infants may be born with external ear deformities or malformations that can present a diagnostic clue to an affiliated syndrome while also presenting the possibility of surgical intervention. Microtia is a malformation of the ear that is associated with other craniofacial or systemic anomalies in 50% of cases. Surgical correction of microtia and associated facial anomalies is complex and must be integrated thoughtfully into the overall care plan for children with complex medical needs. Familiarity with types of ear and facial anomalies and their association with more global concerns can allow perinatal practitioners to better serve their patients. PMID- 30396413 TI - Identification and Management of Cranial Anomalies in Perinatology. AB - Neonatal skull and head shape anomalies are rare. The most common cranial malformations encountered include craniosynostosis, deformational plagiocephaly, cutis aplasia, and encephalocele. Improved prenatal imaging can diagnose morphologic changes as early as the second trimester. Prenatal identification also provides perinatologists and neonatologists with valuable information that helps to optimize care during and after delivery. Cranial anomalies require a multidisciplinary team approach and occasionally a lifetime of care. Today, care begins with the perinatologist as many cranial anomalies can be identified in utero with recent advances in prenatal testing. PMID- 30396414 TI - Peripartum Management of Neonatal Pierre Robin Sequence. AB - Pierre Robin sequence (PRS) is a congenital condition characterized by the presence of micrognathia, glossoptosis, and cleft palate. PRS has varying effects on airway patency and feeding ability and thus has a broad range of management options. The purpose of this article is to describe the nature of the background of the condition and address the previous and current trends in diagnosis and management of PRS. PMID- 30396415 TI - Vascular Anomalies. AB - Classified by their most prominent vessel type, congenital vascular tumors and malformations are frequently evident neonatally. Although many are identified in the first month of life, management is often delayed due to their slow expansion. Urgent interventions may be necessary in fast-growing, obstructive, destructive, or bleeding anomalies. Treatment is based on the impact on vital structures, impending aesthetic outcome, or functional risks. Frequent and fast-growing hemangiomas and lymphatic malformations are the most commonly treated neonatally. This article reviews lesions that might require early intervention, including hemangiomas, lymphatic and venous malformations, and the rare kaposiform hemangioendothelioma. PMID- 30396416 TI - Choanal Atresia and Other Neonatal Nasal Anomalies. AB - Congenital nasal deformities can cause nasal obstruction with early respiratory distress. Choanal atresia is characterized by no communication between the nasal cavity and nasopharynx. Pyriform aperture stenosis involves more anterior nasal obstruction with limited intranasal space. Nasal masses such as encephaloceles, gliomas, and dermoids are thought to be related through a skull base defect in utero. Imaging with computed tomography and MRI are helpful in distinguishing lesions and identifying intracranial communication. Nasolacrimal duct cysts can get infected and cause obstruction. Nasal septal deviation can be corrected at bedside if detected early. Evaluation and treatment are discussed with all these entities. PMID- 30396417 TI - Congenital Neck Masses. AB - Congenital neck masses can be a developmental anomaly of cystic, solid, or vascular origin. They can also constitute neoplasms, including malignancies, although this is rare in the pediatric population. The history and examination can help quickly narrow the differential diagnosis. Imaging also plays an essential role in defining the characteristics and likely cause of neck masses. The most common neck masses in young children are thyroglossal duct cysts, branchial cleft anomalies, and dermoid cysts. Also important to consider in the differential diagnosis are solid tumors, such as teratomas, or vascular lesions, such as hemangiomas. PMID- 30396418 TI - Subglottic Stenosis. AB - The subglottis is a narrow region of the pediatric airway that is exquisitely susceptible to the development of airway stenosis. The incidence of acquired subglottic stenosis in the setting of prolonged intubation has significantly decreased because of improved endotracheal tube management protocols. Advances in otolaryngology interventions, such as balloon dilation and endoscopic cricoid split techniques, may allow the avoidance of tracheostomy in patients with mild to moderate subglottic stenosis. However, patients with severe subglottic stenosis are often tracheostomy dependent. Open surgical techniques to treat severe disease, such as laryngotracheal reconstruction and cricotracheal resection, offer high rates of tracheostomy decannulation. PMID- 30396419 TI - Neonatal Tracheostomy. AB - Neonatal and infant tracheostomies have been valuable in the care and survival of children over the past century. With the implementation of neonatal and pediatric intensive care units, more infants are surviving conditions that were considered fatal. Neonatal tracheostomy plays a vital role in many of these conditions, with significant implications and association with overall mortality, morbidity, and developmental outcomes. Although the technique has not changed much, there have been significant evolutions in indications, survival, complications, and technological advances. Improved outcomes research to decrease the high associated morbidities is needed. PMID- 30396420 TI - Neonatal Stridor: Diagnosis and Management. AB - Stridor, a common presenting sign of respiratory distress in a newborn, has many systemic causes. It may arise from the larynx or the tracheobronchial airway. This article presents the most common pathologic conditions in this anatomic region, with highlights on management. PMID- 30396421 TI - Head and Neck Pathology and Pathophysiology in Neonates and Children from the Otolaryngologist Perspective. PMID- 30396422 TI - Three-Dimensional Printing and Beyond: What Lies Ahead for Pediatric Otolaryngology. PMID- 30396423 TI - Changes in salivary analytes in canine parvovirus: A high-resolution quantitative proteomic study. AB - The present study evaluated the changes in salivary proteome in parvoviral enteritis (PVE) in dogs through a high-throughput quantitative proteomic analysis. Saliva samples from healthy dogs and dogs with severe parvovirosis that survived or perished due to the disease were analysed and compared by Tandem Mass Tags (TMT) analysis. Proteomic analysis quantified 1516 peptides, and 287 (corresponding to 190 proteins) showed significantly different abundances between studied groups. Ten proteins were observed to change significantly between dogs that survived or perished due to PVE. Bioinformatics' analysis revealed that saliva reflects the involvement of different pathways in PVE such as catalytic activity and binding, and indicates antimicrobial humoral response as a pathway with a major role in the development of the disease. These results indicate that saliva proteins reflect physiopathological changes that occur in PVE and could be a potential source of biomarkers for this disease. PMID- 30396424 TI - High diversity of hemotropic mycoplasmas in Iberian wild carnivores. AB - Two-hundred and thirty-one wild carnivores belonging to 10 species of in Spain were analyzed for the presence of DNA of hemotropic mycoplasmas (hemoplasmas) by means of a universal real-time PCR targeting a 16S rRNA gene fragment. Positive reactions were found for wolf (Canis lupus: 6/37), fox (Vulpes vulpes: 1/41), Eurasian badger (Meles meles: 49/85), pine marten (Martes martes: 11/23), stone marten (Martes foina: 6/9), least weasel (Mustela nivalis: 4/4), European wildcat (Felis s. silvestris: 1/2) and common genet (Genetta genetta: 7/27). Sixty-four readable sequences were obtained, resulting in 14 nucleotide sequence types (ntST). The highest diversity was detected in badger (6 ntST) and pine marten (5 ntST). The sequencing of a fragment of the RNase P gene showed that all positive reactions in wolves corresponded to Mycoplasma haemocanis. Three ntST showed an identity between 98-100% with Candidatus M. haemominutum, C. M. turicensis and C. M. haematoparvum, respectively. Four ntST were closely related to C. M. haemomeles and/or diverse genotypes reported from raccoons (Procyon lotor) in the USA. One ntST from a badger showed only 88% similarity to the closest published sequence and was phylogenetically unrelated to any other hemoplasma sequence reported. Three ntST were 99-100% similar to two different sequences reported in Spanish bats. This study confirms the widespread nature and the high genetic diversity of hemoplasma infection in carnivores. Wild carnivores might be natural hosts of some hemoplasmas infecting dogs and cats. PMID- 30396425 TI - Use of camel single-domain antibodies for the diagnosis and treatment of zoonotic diseases. AB - Camelids produce both conventional heterotetrameric antibodies and homodimeric heavy-chain only antibodies. The antigen-binding region of such homodimeric heavy chain only antibodies consists of one single domain, called VHH. VHHs provide many advantages over conventional full-sized antibodies and currently used antibody-based fragments (Fab, scFv), including high specificity, stability and solubility, and small size, allowing them to recognize unusual antigenic sites and deeply penetrate tissues. Since their discovery, VHHs have been used extensively in diagnostics and therapy. In recent decades, the number of outbreaks of diseases transmissible from animals to humans has been on the rise. In this review, we evaluate the status of VHHs as diagnostic and therapeutic biomolecular agents for the detection and treatment of zoonotic diseases, such as bacterial, parasitic, and viral zoonosis. VHHs show great adaptability to inhibit or neutralize pathogenic agents for the creation of multifunctional VHH-based diagnostic and therapeutic molecules against zoonotic diseases. PMID- 30396426 TI - In vivo therapeutic efficacy of the Allium sativum ME in experimentally Echinococcus granulosus infected mice. AB - Plant-based anthelmintics suggest an alternative treatment for cystic echinococcosis. The present study was conducted to evaluate the efficacy of methanolic extract (ME) of A. sativum (garlic) on the treatment of hydatid cysts in the murine model. After gas chromatography and mass spectrometry of prepared ME, sixty laboratory BALB/c mice were infected intraperitoneally by injection of 1500 viable protoscoleces. Five months after infection, the infected mice were allocated into six treatment groups, 1- Albendazole (100 mg/kg); 2- Allium sativum ME (10 mL/L); 3- A. sativum ME (20 mL/L); 4- A. sativum ME (40 mL/L); 5- A. sativum ME (80 mL/L) and 6- untreated control group. After 30 days of daily treatment, the total number of cysts, size and weight of the largest cyst were significantly lower in three treated groups including A. sativum ME 80 mL/L, A. sativum ME 40 mL /L and albendazole in comparison to those of the control group (p < 0.05). The activity of alanine amino transferase (ALT) enzyme, as well as bilirubin concentration were significantly lower in the mice treated with A. sativum ME 80, 40, 20 and 10 mL/L when compared to the control group. In addition, bilirubin concentration revealed significant decrease in A. sativum ME 10, 20 and 80 mL/L groups, when compared to the albendazole group. In conclusions, administration of A. sativum ME used at 40 and 80 mL/L concentrations might be beneficial in the treatment of CE due to anti-parasitic effects similar to albendazole but less hepatotoxic effects. PMID- 30396427 TI - Response of goats to intramuscular vaccination with heat-killed Mycobacterium bovis and natural challenge. AB - Caprine TB causes chronic disease with severe economic and health consequences. We assessed the effect of intramuscularly administered heat-inactivated Mycobacterium bovis (M. bovis) on 20 kid goats (10 vaccinated, 10 controls), naturally exposed to M. caprae through close contact with infected goats. At necropsy, visible TB-compatible lesions were recorded in all animals with the exception of 1 control and 2 vaccinated goats. The median of the total lesion score was 9 (IQR 3-13.5) and 5 (IQR 3-6.75) in control and vaccinated goats, respectively (median lesion reduction 44.4%, p = 0.224). The lung lesions of the vaccinated goats were restricted to the caudal lobes, while 6 controls had additional lung lobes affected (p = 0.01). The median lung lesion score reduction in vaccinated goats was 100%; however, this reduction was not significant (p = 0.124), possibly due to the low sample size. Regarding the abdomen, only one vaccinated goat presented visible lesions compared to three goats in the control group. The results provide further evidence of the potential of heat-inactivated M. bovis for controlling TB in different host species, including ruminants. PMID- 30396428 TI - Molecular Detection of New SHV beta-lactamase Variants in Clinical Escherichia coli and Klebsiella pneumoniae Isolates from Egypt. AB - The emergence of multidrug-resistant (MDR) pathogens was reported worldwide. Herein, SHV extended-spectrum beta-lactamase (SHV-ESBL) variants detection was investigated in MDR E. coli and K. pneumoniae isolates recovered from human subjects (n = 144), one day-old chicks (n = 36) and broiler clinical samples (n = 90). All examined samples were positive for E. coli (n = 246/270; 91.11%) and Klebsiella pneumoniae (n = 24/270; 8.89%). Antimicrobial susceptibility testing was performed on E. coli and K. pneumoniae. SHV-ESBL producing isolates were defined followed by SHV-ESBL amino acids sequence and proteins structure-function analyses. Phylogenetic analysis of 11 MDR isolates resistant to at least 6 beta lactams was designed to determine their genetic relationship with those previously identified in Egypt. SHV-ESBL variants were detected in 28% and 16% of E. coli and K. pneumoniae isolates, respectively. Among the 11 SHV-ESBL producing isolates, one isolate displayed 100% blaSHV-12 similarity with three point mutations, while the other 10 isolates displayed amino acid substitutions at previously non-reported sites. Amino acid sequence analyses of these 10 isolates displayed 96-100% identity to blaSHV-10 (2 isolates with 3-6 point mutations), blaSHV-18 (one isolate with 4 point mutations), blaSHV-58 (4 isolates with 4-5 point mutations), and blaSHV-91 (3 isolates with 3-7 point mutations). These mutations altered SHV-enzyme pocket dimensions and its binding sites chargeability. The blaSHV phylogeny analysis revealed occurrence of variants in closely related lineages with blaSHV-5 and blaSHV-12 with possibility of blaSHV gene transfer between human and birds. The occurrence of these variants in Egypt could help in epidemiological studies and could explain the emergent resistance to beta-lactams. PMID- 30396429 TI - Toxoplasma gondii infection in raptors from Italy: Seroepidemiology and risk factors analysis. AB - Toxoplasma gondii is a zoonotic parasite infecting a wide range of intermediate hosts, including birds. Nevertheless, scant information on the spread of infection in wild bird populations is available to date. With the aim of updating information on T. gondii infection in birds of prey and possible risk factors associated with the infection, a serosurvey was planned on both wild and captive raptors. An overall of 93 raptors from Northern Italy were tested for the presence of anti-T. gondii antibodies with a commercial modified agglutination test (MAT). A T. gondii prevalence of 10.7% was recorded; the highest seroprevalence was observed within the Family Strigidae (12.5%). Only wild animals tested positive; any statistical difference among species, taxonomic family, age, origin, use, migratory behavior and diet composition was not highlighted. Toxoplasmosis in birds of prey, sentinel species for the environmental spread of T. gondii, should always be considered within sanitary programs devoted to avian species protection. PMID- 30396431 TI - Environmental racism: time to tackle social injustice. PMID- 30396430 TI - Apparent prevalence and risk factors associated with occurrence of Coxiella burnetii infection in goats and humans in Chhattisgarh and Odisha, India. AB - Coxiella burnetii is one of the most contagious pathogen associated with Q fever in humans, while, ruminants act as important source of infection for humans. In the present cross sectional study, a total of 464 samples were collected from 218 goats comprising of 218 sera, 218 blood and 28 milk from various parts of Chhattisgarh and Odisha region, India. Besides, environmental (33; soil- 4, faecal- 10, feed-6, drainage water- 6, drinking water- 7) and rodent (38) samples were also collected from the premises of the animals. Human sera samples (93) were collected from same sampling area comprised of workers at an organized dairy farm (43), and farmers (50). The samples were subjected to PCR targeting the trans and com1 genes and detection of antibodies using commercial ELISA kits. An overall 14.22% (95% CI: 10.2-19.47%) of the goat samples were positive using either PCR or ELISA. While, by using PCR and ELISA, 11.93% (26/218) and 9.63% (21/218) of the samples were positive for C. burnetii. A higher seropositivity (46.24%; 95% CI: 36.46-56.32%) was observed for antibodies against C. burnetii in samples collected from humans. None of the human, environmental and rodent samples were positive for C. burnetii using PCR. This seems to be the first cross sectional study to focus the hidden threat of coxiellosis among goat population and associated risk factors in India. PMID- 30396432 TI - Coffee consumers in university settings and planetary health. PMID- 30396433 TI - Sunscreens, cancer, and protecting our planet. PMID- 30396434 TI - Why "Culture" matters for planetary health. PMID- 30396436 TI - Antimicrobial resistance at a community level. PMID- 30396435 TI - Space technologies for monitoring health and environmental impact of hydraulic fracturing. PMID- 30396437 TI - Wind: a neglected factor in the spread of infectious diseases. PMID- 30396438 TI - Wind: a neglected factor in the spread of infectious diseases - Authors' reply. PMID- 30396439 TI - Correction to Lancet Planet Health 2018; 2: e414. PMID- 30396440 TI - Identification of risk factors associated with carriage of resistant Escherichia coli in three culturally diverse ethnic groups in Tanzania: a biological and socioeconomic analysis. AB - BACKGOUND: Improved antimicrobial stewardship, sanitation, and hygiene are WHO inspired priorities for restriction of the spread of antimicrobial resistance. Prioritisation among these objectives is essential, particularly in low-income and middle-income countries, but the factors contributing most to antimicrobial resistance are typically unknown and could vary substantially between and within countries. We aimed to identify the biological and socioeconomic risk factors associated with carriage of resistant Escherichia coli in three culturally diverse ethnic groups in northern Tanzania. METHODS: We developed a survey containing more than 200 items and administered it in randomly selected households in 13 Chagga, Arusha, or Maasai villages chosen on the basis of ethnic composition and distance to urban centres. Human stool samples were collected from a subset of households, as were liquid milk samples and swabs of milk containers. Samples were processed and plated onto MacConkey agar plates, then presumptive E coli isolates were identified on the basis of colony morphology. Susceptibility of isolates was then tested against a panel of nine antimicrobials (ampicillin, ceftazidime, chloramphenicol, ciprofloxacin, kanamycin, streptomycin, sulfamethoxazole, tetracycline, and trimethoprim) via a breakpoint assay. Susceptibility findings were matched with data across a wide range of household characteristics, including education, hygiene practices, wealth, livestock husbandry, and antibiotic use. FINDINGS: Between March 23, 2012, and July 30, 2015, we interviewed 391 households (118 Arusha, 100 Chagga, and 173 Maasai). Human stool samples were collected at 226 (58%) households across the 13 villages. 181 milk samples and 191 milk-container swabs were collected from 117 households across seven villages. 11 470 putative E coli samples were isolated from stool samples. Antimicrobial use in people and livestock was not associated with prevalence of resistance at the household level. Instead, the factors with the greatest predictive value involved exposure to bacteria, and were intimately connected with fundamental cultural differences across study groups. These factors included how different subsistence types (pastoralists vs farmers) access water sources and consumption of unboiled milk, reflecting increased exposure to resistant bacteria in milk. INTERPRETATION: When cultural and ecological conditions favour bacterial transmission, there is a high likelihood that people will harbour antimicrobial-resistant bacteria irrespective of antimicrobial use practices. Public health interventions to limit antimicrobial resistance need to be tailored to local practices that affect bacterial transmission. FUNDING: US National Science Foundation; Biotechnology and Biological Sciences Research Council, UK Medical Research Council; and the Allen School. PMID- 30396441 TI - How house design affects malaria mosquito density, temperature, and relative humidity: an experimental study in rural Gambia. AB - INTRODUCTION: Unprecedented improvements in housing are occurring across much of rural sub-Saharan Africa, but the consequences of these changes on malaria transmission remain poorly explored. We examined how different typologies of rural housing affect mosquito house entry and indoor climate. METHODS: Five typologies of mud-block houses were constructed in rural Gambia: four were traditional designs with poorly fitted doors and one was a novel design with gable windows to improve ventilation. In each house, one male volunteer slept under a bednet and mosquitoes were collected indoors with a light trap. Typologies were rotated between houses weekly. Indoor conditions were monitored with data loggers and the perceived comfort of sleepers recorded with questionnaires. We used pyschrometric modelling to quantify the comfort of the indoor climate using the logger data. Primary measurements were mean number of Anopheles gambiae and mean temperature for each house typology. FINDINGS: In thatched-roofed houses, closing the eaves reduced A gambiae house entry by 94% (95% CI 89-97) but increased the temperature compared with thatched-roofed houses with open eaves. In houses with closed eaves, those with metal roofs had more A gambiae, were hotter (1.5 degrees C hotter [95% CI 1.3-1.7]) between 2100h and 2300 h, and had 25% higher concentrations of carbon dioxide (211.1 ppm higher [117.8-304.6]) than those with thatched roofs. In metal-roofed houses with closed eaves, mosquito house entry was reduced by 96% (91-98) by well fitted screened doors. Improved ventilation of metal-roofed houses made them as cool as thatched houses with open eaves. Metal-roofed houses with closed eaves were considered more uncomfortable than thatched ones with closed eaves. In metal-roofed houses, ventilated houses were more comfortable than unventilated houses before midnight, when people retired to bed. INTERPRETATION: Closing the eaves reduced vector entry in thatched houses but increased entry in metal-roofed houses. Metal-roofed houses with closed eaves were, however, protected against malaria vectors by well fitted screened doors and were made comfortable by increasing ventilation. House designs that exclude mosquitoes and are comfortable to live in should be a priority in sub-Saharan Africa. FUNDING: Sir Halley Stewart Trust, Global Clinical Trials, and Global Challenges Research Fund. PMID- 30396442 TI - The Evolution of Oral Appliance Therapy for Snoring and Sleep Apnea: Where Did We Come From, Where Are We, and Where Are We Going? AB - Oral appliance therapy (OAT) for the treatment of snoring and obstructive sleep apnea is accepted as the most effective noninvasive therapy second only to continuous positive airway pressure. This article explains the innovations of the previous 200 years and how they laid the groundwork for OAT today. The expansion of this treatment over the past 40 years has been explosive and evidence based. The future will be linked to changes in the medical field, continued research on appliance design, and development of personalized medicine that will appropriately identify therapy options. PMID- 30396443 TI - Clinical Evaluation for Oral Appliance Therapy. AB - This article outlines the steps dentists must take before treating obstructive sleep apnea patients with oral appliance therapy. It describes a proper clinical examination, the appropriate appliance for specific cases, patient discussion points, and the necessary history and consent forms. PMID- 30396444 TI - Avoiding and Managing Oral Appliance Therapy Side Effects. AB - There is a serious need to consider all potential side effects thoughtfully before commencing individual treatment with oral appliance therapy. Although many of these side effects are self-limiting, easily corrected, or innocuous, others are difficult or impossible to correct and can affect the patient in serious ways. As this field evolves, new information is discovered, and new products are introduced at a rather rapid pace, continuing education and prudent practice are critical to ethical care in the practice of dental sleep medicine. PMID- 30396445 TI - Oral Appliance Therapy and Temporomandibular Disorders. AB - This article focuses on clinical examination to assist in maintaining stable function between jaw posture, muscle function, and temporomandibular joint stability. It describes a simple and understandable approach for assessment and management of common temporomandibular symptoms arising as side effects from use of mandibular advancement device therapy for obstructive sleep apnea. Follow-up visits are necessary to assess efficacy of sleep oral devices. An interdisciplinary approach is necessary for better treatment outcome. Qualified dentists offering this therapy should be educated and gain knowledge about diagnosis, prevention, and management of common side effects, and adhere to current standards of dental sleep medicine practice. PMID- 30396446 TI - Obstructive Sleep Apnea's Connections with Clinical Dentistry. AB - Adding airway services to a dental practice disrupts scheduling, examinations, treatment planning, billing, and team roles. Problems connected with the airway can be addressed with more precise therapy and better prognosis while building confidence between the patient and the dental team. Each team member must understand the connections between airway problems and patient health and be able to talk about it with confidence. If the entire team supports the inclusion of airway therapy into the service mix, patients will feel well cared for and rewards to the office will be plentiful. PMID- 30396447 TI - Pediatric Considerations for Dental Sleep Medicine. AB - Pediatric obstructive sleep apnea (OSA) is a serious medical condition with numerous health consequences. Dentists are well suited to recognize and provide medical referrals for pediatric patients at risk for OSA. Timely dental sleep medicine interventions may improve signs and symptoms of OSA in growing children. Orthodontic and dentofacial orthopedic treatment may decrease obstructive respiratory events in some pediatric patients. Palatal expansion may be part of a comprehensive orthodontic treatment plan to correct a malocclusion and treat OSA. Orthognathic surgery, mandibular advancement devices, and oropharyngeal exercises may have a role in the management of OSA in pediatric and adolescent patients. PMID- 30396448 TI - Skeletal Surgery for Obstructive Sleep Apnea. AB - Multilevel surgery has been established as the mainstay of treatment for the surgical management of obstructive sleep apnea (OSA). Combined with uvulopalatopharyngoplasty, tongue-base surgeries, including the genioglossus advancement (GA), sliding genioplasty, and hyoid myotomy and suspension, have been developed to target hypopharyngeal obstruction. Total airway surgery consisting of maxillomandibular advancement (MMA) with/without GA has shown significant success. Skeletal procedures for OSA with or without a palatal procedure is a proven technique for relieving airway obstruction during sleep. A case study demonstrating the utility of virtual surgical planning for MMA surgery is presented. PMID- 30396449 TI - Controversies in Obstructive Sleep Apnea Surgery. AB - Obstructive sleep apnea (OSA) is a common chronic disease characterized by repetitive pharyngeal collapse during sleep. OSA is associated with cardiovascular disease and increased mortality, among other issues. Continuous positive airway pressure (CPAP) is considered first line therapy for OSA, but is not always tolerated. Both non-surgical and surgical alternative management strategies are available for the CPAP intolerant patient. This article explores controversies surrounding airway evaluation, definition of successful treatment, and surgical management of the CPAP intolerant patient with moderate to severe OSA. Controversies specific to maxillomandibular advancement (MMA) are also discussed. PMID- 30396450 TI - Transcranial Magnetic Stimulation: Potential Use in Obstructive Sleep Apnea and Sleep Bruxism. AB - The aim of this article is to introduce transcranial magnetic stimulation (TMS) to dental practitioners and to explain its use in obstructive sleep apnea (OSA) and sleep bruxism (SB). In these 2 sleep disorders, TMS has proven to be a useful tool to explore pathophysiological pathways and disease mechanisms, and in a more limited way, to recruit upper airway muscles in OSA and reduce muscle activity and pain intensity in SB. Although promising, research using TMS in these conditions is still very limited and future investigations should be conducted before its clinical application can be considered. PMID- 30396451 TI - Beyond Blowing: Oral Appliance Therapy, Surgery, and Transcranial Magnetic Stimulation. PMID- 30396452 TI - Protein Phosphatases as Critical Regulators for Cellular Homeostasis. PMID- 30396453 TI - The UK's anomalous 10-year limit on oocyte storage: time to change the law. AB - There has been a growing recognition in the UK that the statutory storage limit for frozen eggs, which currently stands at 10 years, requires a review. The UK regulator, the Human Fertilization and Embryology Authority (HFEA), has recognized the problem and the Equality and Human Rights Commission is also sympathetic with the demand to change the current legislation. There is also strong desire on the part of assisted reproductive technology (ART) professionals and patients to change the current guidelines. For many women, the available alternatives of transporting their eggs to an overseas destination or having them fertilized with donor sperm and then stored as embryos is objectionable. PMID- 30396454 TI - GnRH antagonist for endometrial priming in an oocyte donation programme: a prospective, randomized controlled trial. AB - RESEARCH QUESTION: Can gonadotrophin releasing hormone (GnRH) antagonist be used in egg donation recipients with ovulatory cycles for the purpose of achieving synchronization between the donor's and recipient's cycle? DESIGN: Prospective randomized controlled trial to compare 7-day dosage of GnRH antagonist for endometrial priming in an oocyte donation programme with a single dose of long acting GnRH agonist. A total of 563 women were randomized in a private single centre, and 473 women underwent embryo transfer. Ongoing pregnancy rate was the primary end point. Analysis was adjusted for embryonic stage at the time of embryo transfer; data collected included days on the waiting list; number of fresh-vitrified oocytes collected; and oocyte donor's age at the time of retrieval. RESULTS: No statistically significant differences were found between groups in per intention-to-treat analysis: adjusted OR 1.42 (CI 0.97 to 2.09); per treatment received: adjusted OR 1.43 (CI 0.97 to 2.09); per embryo transfer: adjusted OR for ongoing pregnancy rate 1.47 (CI 1.01 to 2.13), P = 0.047. CONCLUSIONS: For women with ovulatory cycles undergoing oocyte donation, the outcomes are similar between GnRH antagonist and down-regulated hormone replacement protocols. PMID- 30396455 TI - Reproductive outcomes after oocyte banking for fertility preservation. AB - RESEARCH QUESTION: What are the reproductive outcomes of women who bank oocytes for fertility preservation? DESIGN: A prospective follow-up study of a cohort of 327 women who banked their oocytes for fertility preservation was carried out between July 2009 and August 2015. The indications for oocyte banking and outcomes of ovarian stimulation were collected from medical files. Follow-up data were obtained from an additional questionnaire. RESULTS: In total, 243 out of 327 women (74%) responded and 228 women (70%) consented to participate and returned the questionnaire. The median time to follow-up of these women was 31 months. A total of 101 women (44%) were trying, or had tried, to become pregnant after oocyte banking, of which 66 became pregnant (65%). Five women reported an unintended pregnancy. Of these, 71 women became pregnant, 76% conceived naturally, 7% through intracytoplasmic sperm injection with their vitrified warmed oocytes and 17% by other medically assisted reproduction treatments. Six women attempted to achieve a pregnancy using their banked oocytes. Of the six pregnancies achieved in five women, two resulted in a live birth. A total of thirty-eight women reported a live birth at the time of follow-up. CONCLUSION: Oocyte banking can be considered a form of risk management or preventive medicine because it is not certain that the women will experience sterility in the future. PMID- 30396456 TI - The dilemma of social oocyte freezing: usage rate is too low to make it cost effective. AB - Delayed childbearing in affluent countries and the financial crisis of the Y generation have contributed to the dramatic decline in birth rate. Social oocyte freezing (SOF) has fuelled the imagination of patients and doctors to offer it as a solution to single, presumably fertile, women to preserve their fertility potential by egg banking at an early age. Some are calling on governments to support large-scale 'fertility preservation', but is it cost-effective? Social oocyte freezing is effectively expensive insurance, where future utilization is unknown. Theoretical studies have suggested that SOF is only cost-effective with a usage rate of 50% or over, and when getting married is not set as a condition. Maximal possible utilization of frozen eggs, however, is much lower. Recent studies have found usage rates of 3.1-9.3%, which sets the cost of each extra live birth between $600,000 and 1,000,000. As IVF is being privatized and business-driven, it is hard for experts to decipher scientific- from business oriented claims. The cost-effectiveness of SOF for individuals or society unclear. These facts place the burden of responsibility on the treating physician, who should inform patients about the true likelihood of using their eggs, the age at which to freeze and possible alternatives. PMID- 30396457 TI - In-depth quantitative proteome analysis of seminal plasma from men with oligoasthenozoospermia and normozoospermia. AB - RESEARCH QUESTION: Can seminal plasma markers for oligoasthenozoospermia be identified by comparison of the human seminal plasma proteome in men with oligoasthenozoospermia and normozoospermia? DESIGN: An in-depth quantitative proteome analysis was conducted using a high-throughput method named isobaric tag for relative and absolute quantification. A total of 734 seminal plasma proteins were quantified by mass spectrometry. RESULTS: Compared with the seminal plasma from men with normozoospermia, 22 upregulated proteins and 20 downregulated proteins were identified in the oligoasthenozoospermic seminal plasma. These differential seminal plasma proteins were involved in various physiological processes, including metabolism, transport, antioxidation and immune response. The confidence of some proteome data was further verified by western blot of (prostate-specific antigen [KLK3], lactotransferrin [LTF], alpha-1-antitrypsin [SERPINA1] and glyceraldehyde-3-phosphate dehydrogenase [GAPDH]). Additionally, 38% of the seminal plasma proteins identified in this study have not been reported in previously published studies on seminal plasma proteome, and 53% of our seminal plasma proteins were shared with published studies on human plasma proteome. CONCLUSIONS: Our seminal plasma proteome research provides new complementary high-confidence data, and also enhances understanding of the pathogenic mechanisms in oligoasthenozoospermia. PMID- 30396458 TI - Virtual reality: A possible approach to myopia prevention and control? AB - In East Asian countries including China, myopia has become a public hygiene issue that threatens the health of vast populations. In response to the huge market demand, a variety of products purportedly capable of treating myopia have been launched onto the market. Some manufacturers claim that juvenile myopia can be effectively controlled, or even cured, using their VR devices and software. Can VR devices be used for the prevention and control of juvenile myopia under existing technical conditions? In order to answer this question, the authors of this article analyzed the pathogenesis of myopia and the technical features of VR. PMID- 30396459 TI - Novel 4-in-1 strategy to combat colon cancer, drug resistance and cancer relapse utilizing functionalized bioinspiring lignin nanoparticle. AB - Colon cancer is one of the fatal forms of cancer all round the world with a equal frequency of occurrence in both male and female population. Mutational changes and defects in APC (Adenomatous Polyposis Coli) and DNA mismatch repair genes accompanied by genetic chaos in oncogenic pathways leads to colon cancer. Intensive study on pathogenesis of colon cancer has been made to decipher the mechanisms underlying the development and progress of the disease so as to develop effective treatment. However, a complete therapeutic regimen is still not available for combating this deadly disease. Hurdles faced by chemotherapy include drug resistance due to P-glycoprotein transporters, untoward effects on normal cells, high cost, bio-burden of the therapy, and the most dreadful drawback is cancer relapse. The concept of cancer relapse is related to development of oxidative stress that causes cell apoptosis. If the level of oxidative stress is inadequate to cause apoptosis then it leads to cell dormancy which may revive post chemotherapy. This hypothesis aims to put forward a combinatorial approach that includes utilizing a cost effective, biocompatible and environmentally benign nanoparticulate carrier made up of lignin, loaded with anti-cancer agent and P-gp modulator, and functionalized with ligand for CD44 receptors that are over expressed on cancer cells. Antioxidant effect of lignin will overcome dormancy of cancer cells making it possible for cell cycle specific drugs to kill them and prevent relapse and active targeting will prevent untoward effects on normal cells. Thus a robust and wholesome formulation can be developed to combat colon cancer. PMID- 30396460 TI - A two-piece dental implant comprising a replaceable thin titanium sleeve may be a new approach to re-osseointegration following peri-implant disease. AB - Bacteria initiated peri-implantitis can lead to bone destruction around a dental implant, modifying its surface and preventing re-osseointegration. Consequently, all available methods for treating periimplantitis have disappointing long-term results. Implant failure will lead to loss of the prosthetic reconstruction as well. A fresh new implant surface enables re-osseointegration. Our hypothesis is that a fresh new surface replacing a contaminated implant surface may be a new treatment approach for peri-implantitis and may allow re-osseointegration. A new two-piece dental implant, having a replaceable thin titanium sleeve may be designed. The replacement of a contaminated sleeve by a fresh new sleeve will solve the peri-implant disease by removing the contaminated surface, enabling re osseointegration and ensuring long-term stability of the implant without endangering the prosthetic reconstruction. This minimally-invasive therapy is expected to be conducted in a simple manner, by every practicing dentist, during supportive periodontal treatment, thereby facilitating the treatment of peri implantitis. PMID- 30396461 TI - Stochastic resonance as a proposed neurobiological model for Eye Movement Desensitization and Reprocessing (EMDR) therapy. AB - EMDR therapy is recommended in several guidelines in the International field of psychological trauma. The dual attention stimuli/alternating bilateral stimulation (DAS/ABS) element of EMDR therapy has no proposed mechanism of action agreed upon, which explains the rapid shifts in cognitions and dysfunctional traumatic memory networks that are central to its observable efficacy. This paper discusses an innate, biological mechanism found in biological systems, including the human nervous system that may explain the efficacy of DAS/ABS. This mechanism is stochastic resonance (SR). SR is observed to make unintelligible, subthreshold signals intelligible and facilitates signal transmission. It provides a potential mechanism for discrimination and the selective focusing of attention, which are important factors in effective psychotherapy for the psychologically traumatised individual. The body/mind complex aims to achieve the functional encoding of memories in the neocortex and a key structural crossroads in this process is the thalamus. Activity in the thalamus is decreased in Post-Traumatic Stress Disorder (PTSD) compared to non-PTSD patients and a form of 'gating' is known to occur at the thalamic level. This 'gating' is adaptive and it is postulated to protect the higher neocortical systems in times of trauma. Although the model is initially somewhat counterintuitive, Stochastic Resonance; a form of random 'noise', can be considered 'helpful randomness' and when present in the thalamus SR can help filter and control sensitivity to incoming signals; helping to discriminate what is communicated. Naturally occurring SR is normally present as a result of descending cortico-thalamic activity, but appears attenuated as a result of exposure to trauma. The view of 'noise' in the current era of cell phones and High Definition is generally negative with science going to significant lengths to clean up signals: i.e. removing noise from them. We do not want white noise in our music or during our cell phone calls. However, some researchers invite us to consider that not all noise is bad and the downward cortico-thalamic 'noise' is an example of this category of 'helpful noise'. This paper will discuss the potential role of SR, as the mechanism by which DAS/ABS generates a random (stochastic) signal, facilitating a return to functional memory processing, where there is a lack of naturally occurring noise from the descending cortico-thalamic connections because of exposure to trauma. Modelling the mechanism as SR will facilitate further study into EMDR therapy and this will hopefully encourage perspicacity, where there has previously been derision. PMID- 30396462 TI - The pharyngeal recess/Eustachian tube complex forms an acoustic passageway. AB - We propose that the complex formed by the Pharyngeal Recess and Eustachian Tube, acts as an acoustic passageway for sounds originating inside the body: sounds made by one's voice, breathing, mastication, one's heartbeats. The antagonistic effect of two sets of muscles, one innervated by the trigeminal nerve, the other by the vagal nerve and cervical plexus, enables the body to modulate transmission of sound via this passageway and hence modulate the awareness of body sounds. Impairment of this system can be due to local factors, such as adhesions over the pharyngeal recess or inflammation inside the pharyngeal recess and/or Eustachian tube; or to tensions of the muscles involved, related to other causes. Dysfunction of the system can lead to symptoms related to increased or decreased awareness of body sounds, such as autophony, hearing of pulsating sounds and clicks in the ear; sensory symptoms related to increased activation of the nerves such as fullness feeling in the ear, facial pain, burning mouth syndrome, globus pharyngeus, pharyngeal pain; and symptoms related to inappropriate muscular contraction such as masticatory and cervical muscle tensions, bruxism, and tension type headache. The functioning of this acoustic passageway is related to the concept of the Trigeminocervical complex. The concept of Vagocervical complex is proposed. PMID- 30396463 TI - Four questions regarding the association of infection with sporadic amyotrophic lateral sclerosis. PMID- 30396464 TI - Secretome from bone marrow mesenchymal stem cells: A promising, cell-free therapy for allergic rhinitis. AB - Allergic rhinitis (AR), characterized by the symptoms of sneezing, rhinorrhea, itchiness and nasal blockage, is a type I allergic disease of nasal mucosa, which is mainly mediated by IgE after exposure to allergens. At present, general drug therapy is limited to alleviating allergic symptoms but fails to regulate the allergic reaction; the recurrence of symptoms and the side effects of the drugs make many patients with AR resist treatments and bring serious impacts on the quality of life. Bone marrow mesenchymal stem cells (BMSCs) are a population of adult stem cells with multipotential differentiation capability, low immunogenicity, and immunoregulatory effects. The unique immunoregulatory properties of BMSCs make them hold great promise in the treatment of chronic inflammation and immune disorders through a paracrine mechanism of anti inflammatory and anti-allergic effects. The stem cell secretome is defined as the set of molecules secreted to the extracellular space. The secretome such as conditioned media (CM) obtained from BMSCs contains various bioactive molecules and vesicular elements, which may act as therapeutic mediators to support their immunoregulatory effects. Therefore, we hypothesize that the BMSCs secretome may represent a promising treatment for AR by anti-allergic effects via the paracrine mechanism. PMID- 30396465 TI - A prophylactic low-dose aspirin earlier than 12 weeks until delivery should be considered to prevent preeclampsia. AB - Clinical trials and meta-analyses have demonstrated that low-dose aspirin can reduce the risk of preeclampsia and fetal growth restriction in high-risk pregnant women. Current obstetric guidelines recommend that the administration of low-dose aspirin to prevent preeclampsia be initiated after 12 weeks' gestation. This starting time was chosen to minimize possible risks of maternal bleeding and fetal anomalies. However, evidence from reproductive medicine, where low-dose aspirin is commonly recommended to use before and in early pregnancy, as well as existing literature, does not support these concerns. On the other hand, defective placentation resulting in a subsequent ischemic placenta is considered as the starting point of preeclampsia. Low-dose aspirin initiated in early pregnancy can balance the levels of thromboxane A2 and prostacyclin and maintain adequate uteroplacental blood flow and, therefore, improve placentation. Thus, an initiation of low-dose aspirin earlier than 12 weeks can be considered. Meanwhile, evidence shows that low-dose aspirin can improve maternal vascular endothelial function without increasing the risks of adverse maternal and perinatal outcomes. Therefore, it appears safe to use low-dose aspirin as a prophylactic until delivery. PMID- 30396466 TI - Differential proteomics analysis of bile between gangrenous cholecystitis and chronic cholecystitis. AB - To establish human biliary protein expression profiles of gangrenous cholecystitis, chronic cholecystitis, and to discover differently expressed proteins for gangrenous cholecystitis by comparative proteomics, we gathered human gallbladder bile samples from gangrenous cholecystitis and chronic cholecystitis patients, respectively After removing the bile salts and lipid peptide fragments were identified by the iTRAQ-coupled LC-MS/MS technology,then identified in SwissProt with Mascot software. A total of 2251 proteins from chronic cholecystitis patients and 2180 proteins from gangrenous cholecystitis patients were identified. A total of 575 differential proteins were found between gangrenous cholecystitis and chronic cholecystitis, 159 proteins were over expressed and 416 proteins were under-expressed in gangrenous cholecystitis. By bio-informatics analysis, in gangrenous cholecystitis, cell death, necrosis,immune response of neutrophils, apoptosis and degranulation of cells were activated; while cell survival, fatty acid metabolism, transport of molecular and proliferation of cells were inhibited, which might reflect the de compensatory phase. Pathway analysis showed acute phase proteins were changed, indicating the role of the inflammatory response in the pathogenesis of gangrenous cholecystitis. Six acute phase proteins were found up regulated,implying a close linkage to gangrenous gallbladder. Our study could be applicable in the biomarker discovery of gangrenous cholecystitis. PMID- 30396467 TI - A road to bring Brij52 back to attention: Shear stress sensitive Brij52 niosomal carriers for targeted drug delivery to obstructed blood vessels. AB - Thrombosis is a shared perpetrating event in the pathophysiology of several cardiovascular disorders such as ischemic stroke, venous thromboembolism, atherosclerosis, and myocardial infarction. Despite holding a wide range of ammunition in our arsenal to ameliorate such conditions, we are still facing with many stumbling blocks in the satisfactory pharmacotherapy of cardiovascular diseases among which the risk of hemorrhage and life threatening drug interactions can be highlighted. Our hypothesis focuses on mimicking the nature of platelet activation, to design a novel targeted delivery system based on the alterations of a physical parameter, the hemodynamic shear stress, to aim at the offending thrombi in an attempt to offer a noninvasive, rapid, and monitoring free method that not only can prolong the circulation time of the cargo, but also deliver it locally and reduce both the undesirable adverse effects and drug interactions. Brij52 is our chosen candidate due to its unique non-spherical morphology after forming a niosomal vesicle. We surmised that thanks to its non spherical shape, diverse shear rates may generate different shear stresses to its equators and axes which might result in the breakdown or at least distortion of niosomal structure under elevated shear stress. The vesicles have to be synthesized in the size of platelets or in the nano-sized scale. In order to prolong the time vesicles are circulating in the blood, PEGylation may help and to make such carriers highly selective to be only activated during pathophysiological clot formation, attachment of domain A1 von Willebrand factor can be of benefit to lead this proposed delivery system to the site of thrombus formation where shear rate exceeds those of 1000 s-1. There is now an emerging fast growing universal research on shear activated carriers, and the present theory is an endeavor to reach a successful treatment strategy to combat cardiovascular diseases based on the hypothesis that a non-spherical nano-carrier such as Brij 52 niosomal vesicle can be of paramount benefit to deliver current antithrombotic agents in a targeted and controlled manner in the presence of elevated shear stress of the obstructed blood vessels. With more radical advanced drug delivery systems being developed and new strategies being pursued, there will be more options in our arsenal to represent a promising avenue for achieving preventive, well-tolerated, and intelligent drug carriers to circumvent the drawbacks of antithrombotic pharmacotherapy. PMID- 30396469 TI - B-type natriuretic peptides in pregnant women with normal heart or cardiac disorders. AB - Pregnancy is characterized by complex physiological changes of the cardiovascular system. B-type natriuretic peptides, represented by the bioactive molecule (BNP) and its inactive amino terminal fragment (NT-proBNP) are important biomarkers used in the management of the heart failure. Besides cardiac causes, BNP can grow in other noncardiac conditions such as pregnancy. The levels of natriuretic peptides during pregnancy have been the subject of multiple studies, whether it is a normal pregnancy, or there are pre-existing or developed cardiac conditions during pregnancy. It depends on the stage of pregnancy and comorbidities: obesity, preeclampsia, pre-existing cardiomyopathies or peripartum cardiomyopathy. High levels of NT-proBNP in pregnancy are associated with increased risk of cardiovascular events and involve careful supervision of pregnancy, including imaging procedures. PMID- 30396468 TI - The CD44 variant induces K562 cell acquired with resistance to adriamycin via NF kappaB/Snail/Bcl-2 pathway. AB - Chemotherapy resistance of cancer mainly has innate resistance and acquired drug resistance, which is mainly caused by the gene mutation induced by chemotherapy drugs. Alternative splicing of CD44 has been shown to be associated with the occurrence and development of tumors especially the multidrug resistance, but the underlying mechanism of CD44 in drug resistance remains unclear. Previous studies have found CD44 variants could significantly improve tumor resistance, therefore, we hypothesized the CD44v16, a CD44 variant found in our lab, might confer drug resistance in K562 cell. Through lentiviral expression system, the CD44v16 gene was introduced into the sensitive K562 cell, and the result indicated it could remarkably improve the drug resistance index. Real-time PCR and western blot experiments showed the expressions of protein p65, Bcl-2, Snail, and IKKbeta in CD44v16-positive cell group were higher than the CD44v16-negative group. Therefore, we suggest the CD44v16 could induce the K562 cell acquired with resistance to adriamycin via NF-kappaB/Snail/Bcl-2 pathway, which paved the way for further study the function of CD44v16 in drug resistance. PMID- 30396470 TI - Decision making process for amputation in case of therapy resistant complex regional pain syndrome type-I in a Dutch specialist centre. AB - Deciding for an amputation in case of complex regional pain syndrome type I (CRPS I) is controversial. Evidence for favorable or adverse effects of an amputation is weak. We therefore follow a careful and well-structured decision making process. After referral of the patient with the request to amputate the affected limb, it is checked if the diagnosis CRPS-I is correct, duration of complaints is more than 1 year, all treatments described in the Dutch guidelines have been tried and if consequences of an amputation have been well considered by the patient. Thereafter the patient is assessed by a multidisciplinary team (psychologist, physical therapist, anesthesiologist-pain specialist, physiatrist and vascular surgeon). During a multidisciplinary meeting professionals summarize their assessment. Pros and cons of an amputation are discussed, taking into account level of amputation and expectations about post amputation functioning of patient and team. Based on assessments and discussion a consensus based decision is formulated and the patient is informed. If it is decided that an amputation is to be performed, the amputation will follow shortly. If it is decided not to amputate, the decision is extensively explained to the patient. Incidence of patients suffering from therapy resistant CRPS-I referred for amputation is low and because referred patients are strongly in favor of an amputation, a randomized controlled trial will be difficult to perform. Hence level of evidence in favor or against an amputation will remain low. We therefore report our decision making process to facilitate discussion about this difficult and delicate matter. PMID- 30396471 TI - Maternal stress and early-onset colorectal cancer. AB - Early-onset colorectal cancer (EOCRC) is defined as colorectal cancer (CRC) diagnosed before the age of 50. Alarmingly, there has been a significant increase in EOCRC diagnoses' worldwide over the past several decades. Emerging data suggest EOCRCs have distinguishing clinical, pathological, biological and molecular features; and thus, are a fundamentally different subtype of CRCs. Unfortunately, there is no simple explanation for the causes of EOCRC. Scientifically rigorous studies are needed to determine what may be driving the challenging epidemiology of EOCRC. We contend here that a reasonable hypothesis is that prenatal risk factors such as maternal stress and associated sleeping disorders influence offspring epigenetic make-up, and shape immune system and gut health contributing to an increased risk for EOCRC. PMID- 30396472 TI - Blood is thicker than water: Flaws in a National Toxicology Program study. AB - Municipal fluoridation was a mid-twentieth century innovation based on the medical hypothesis that consuming low doses of fluoride when young provided protection against cavities with only a small risk of mild dental fluorosis, a cosmetic effect. In the 21st century, more than half of American teens are afflicted by dental fluorosis with approximately one in five having moderate to severe dental fluorosis in at least two teeth. Scientific literature since the 1990s has found that even low doses of fluoride adversely affect cognitive behavioral development and that deficits are correlated with the severity of dental fluorosis in afflicted individuals. Evidence of neurotoxic impact from low dose systemic exposure to fluoride prompted an investigation by a branch of the governmental agency that has promoted fluoridation policy since its 1940's inception. This review identifies ten significant flaws in the design of an animal experiment conducted by the U.S. National Toxicology Program as part of that investigation into the neurotoxic impact of systemic prenatal and postnatal fluoride exposure. The authors hypothesize that organizational bias can and does compromise the integrity of fluoride research. PMID- 30396473 TI - Inverse relationship between human erythrocyte fructose-6-phosphate and short chain fatty acid levels. AB - In muscle cells, fructose is initially metabolised to fructose-6-phosphate. In the liver, fructose is metabolised to fructose-1-phosphate and thence to glyceraldehydes, which in turn can either enter glycogenolysis via pyruvate or gluconeogenesis via fructose-1,6-bisphosphate and fructose-6-phosphate. High levels of fructose-1-phosphate inhibit both glycogenolysis and gluconeogenesis. We hypothesised that, if systemically absorbed short-chain fatty acids constitute a major metabolic fate of unabsorbed dietary fructose, then levels of erythrocyte fructose-6-phosphate would be inversely correlated with plasma levels of short chain fatty acids. The aim of this study was to test this hypothesis in respect of the three main short-chain fatty acids acetate, propionate and butyrate. Venous blood samples from 39 patients (16 male, 23 female, mean (standard error) age 42.4 (3.3) years) were analysed. Erythrocyte fructose-6-phosphate was measured using quantitative Fourier transform infrared spectrometry following gel electrophoresis, while plasma acetate, propionate and butyrate levels were measured using gas-liquid chromatography. The erythrocyte fructose-6-phosphate level was inversely correlated with the plasma acetate (r = -0.30, p = 0.06), propionate (r = -0.31, p = 0.05) and butyrate (r = -0.40, p = 0.01). These results support our hypothesis. The conversion of unabsorbed dietary fructose into short-chain fatty acids may represent a protective mechanism against the adverse effects of hypoglycaemia. PMID- 30396474 TI - Minimisation of dissipated energy in the airways during mechanical ventilation by using constant inspiratory and expiratory flows - Flow-controlled ventilation (FCV). AB - It has been suggested that energy dissipation in the airways during mechanical ventilation is associated with an increased probability of ventilator induced lung injury (VILI). We hypothesise that energy dissipation in the airways may be minimised by ventilating with constant flow during both the inspiration and expiration phases of the respiratory cycle. We present a simple analysis and numerical calculations that support our hypothesis and show that for ventilation with minimum dissipated energy not only should the flows during inspiration and expiration be controlled to be constant and continuous, but the ventilation should also be undertaken with an I:E ratio that is close to 1:1. PMID- 30396475 TI - Is melatonin effective for pruritus caused by liver disease? AB - There is still no definitive treatment to relieve pruritus associated with liver disease, because the precise mechanism of itching has not yet been determined. Different mechanisms have been proposed. One recent explanation is thought to be the rise in serum levels of lysophosphatidic acid which is a metabolite of lysophosphatidyl choline conversion by autotaxin enzyme in liver disease is. Over expression of autotaxin which occurs in atopic dermatitis has been shown to be involved in itching pathology. Importantly, gene amplification of autotaxin also occurs in cholestasis. Melatonin has pleiotropic properties such as suppressive effects on serum level of autotaxin which relieves itching of atopic dermatitis. Due to some similarities in mechanism of itching, it is hypothesized that melatonin may improve itching of liver diseases. PMID- 30396476 TI - Autoimmune thyroiditis and central serous chorioretinopathy may have a relation. AB - Autoimmune thyroiditis (AT) is an important cause of hypothyroidism, and central serous chorioretinopathy (CSCR) is an independent disease of the choroid and retina that leads to accumulation of fluid beneath the retina. While AT has been associated with multiple antibodies, CSCR is still regarded as idiopathic despite extensive research. We hypothesize a causative association between these 2 conditions on the basis of our experience of a case where both CSCR and AT presented simultaneously and depicted a parallel course. CSCR was documented with retinal imaging while AT was documented with serum antibody titers. Further, we discuss the possible mechanisms that may be involved in this intriguing association. PMID- 30396477 TI - Cartilage degradation in osteoarthritis: A process of osteochondral remodeling resembles the endochondral ossification in growth plate? AB - Osteoarthritis (OA) is one of the most common degenerative disease which causes pain and disability of joint and brings heavy socioeconomic burden in the world. However, the pathogenesis of OA has not been fully understood. Articular cartilage degradation or loss was often regarded as the characteristic of osteoarthritis. But we believe that there may had a illusion that OA was simply considered to be a process of wear and tear because evidences have supported all joint tissues remodeling including cartilage, subchondral bone, synovium, ligament, fat pad, and etc, were engaged in OA, in particular the cartilage and subchondral bone. Many factors such as mechanics, inflammation and immunological abnormality could drive the joint tissues metabolic and disturb the steady state of cartilage and bone, which further devoted to a serial pathological manifestations, consisting of hypertrophy and apoptosis of articular chondrocytes, degradation of cartilage matrix, angiogenesis and calcification of hyaline cartilage, replication of tidemark, formation of osteophytes, degeneration of ligaments and, in the knee, the menisci, hypertrophy of the joint capsule and remodeling of subchondral bone along with increased permeability of the osteochondral interface. The thickening of calcified cartilage, the thinning of superficial hyaline cartilage and the remodeling of subchondral bone indicated that the cartilage degradation could be a procedure of enchondral ossification similar to the growth plate, of driven by a host of cytokines within the affected joint. Articular cartilage loses stable state from normal resting to a high turnover in the stimulation of abnormal mechanical stresses and cytokines would subsequently contributed to slowly sustained remodeling and calcification, which might be the key features of the initiation and development of OA. In this article, the development and structural comparison of articular cartilage and growth plate as well as the major pathologic features of OA will be discussed to explain that cartilage degeneration in OA might be a process of enchondral ossification similar to growth plate. This would provide a new perspective for understanding OA's pathogenesis and the treatment in the future. PMID- 30396478 TI - Towards the targeted management of hereditary gingival fibromatosis. AB - Although hereditary gingival fibromatosis is a rare condition, it leaves unrestroable psychological, esthetical as well as functional problems to the affected patients. The purpose of the current research is to find a non-surgical pharmacological mechanism that could provide a control of the active phase of such disease helping individual to continue their lives. PMID- 30396479 TI - Oral manifestations in stem cell transplantation for acute myeloid leukemia. AB - Acute myeloid leukemia is a highly aggressive malignancy with a high morbidity rate, for which an accurate and rapid diagnostic is essential. Acute myeloid leukemia manifestations frequently include oral abnormalities. Still, there is a limited number of studies reporting the incidence of oral manifestations in acute leukemia, the prevalence of periodontal status and periodontal parameters in these patients. Our aim was to emphasize the importance of early recognition by the dental practitioners of oral cavity manifestations as signs of acute myeloid leukemia, so that prompt referral to the hematologists is being done, and appropriate treatment is offered. PMID- 30396480 TI - The 11p15.5 chromosomal region: When did the instability occur? AB - The disturbances of the 11p15.5 chromosomal region are associated with Beckwith Wiedemann syndrome, Russell-Silver syndrome, Wilms tumor, IMAGe syndrome, and idiopathic hemihyperplasia. The aim of this research was to examine the hypothesis that 11p15.5 initially became unstable in the European population about 200 years ago. The medical literature from 1557 onwards, especially treatises on teratology, body asymmetry, and books of normal and pathologic anatomy, was searched for any mentioning of lateral body asymmetry, macroglossia and other possible visually detectable symptoms associated with the above mentioned syndromes. The results indicate that lateral body asymmetry was not described before the first half of the 19th century, it was mentioned in the 1820s, and the first description of a true case was published in 1850. All first cases of hemihyperplasia were reported in continental Europe. Historical data suggest that the 11p15.5 chromosomal region became unstable in the first half of the 19th century. Our preliminary hypothesis is that de novo mutation occurred in continental Europe. Additional genetic research is needed to investigate the development of 11p15.5 instability during this period. PMID- 30396481 TI - Flavonoids as adjuvant in psoralen based photochemotherapy in the management of vitiligo/leucoderma. AB - Vitiligo is a disorder characterized by the decrease in melanin pigment of skin. This depigmenting disorder has prevalence among worldwide, irrespective of age and sex. There is an existence of different treatment modalities for the management of vitiligo. But irrespective of treatment methods, the main drawback in the management of vitiligo is the occurrence of side effects during the implication of treatment. Among the treatment modalities, photochemotherapy seems to be the better choice of treatment for vitiligo. Photochemotherapy involves the usage of UV rays for photoactivation of the drug to cause photosensitization of skin which in turn leads to repigmentation. The main aim of the study is to develop novel combination strategy of lipid based nanoemulsion gel for the treatment of leucoderma using trimethylpsoralen and flavonoid. We assume that if this hypothesis of combination therapy proves successful it can be used as an additional novel treatment strategy in the management of vitiligo. PMID- 30396482 TI - Hypoxic stress: A risk factor for post-concussive hypopituitarism? AB - Hypopituitarism diagnosed months or years following concussive injury can cause a variety of endocrine disturbances including insufficient secretion of human growth, luteinizing, follicle stimulating, thyroid stimulating, adrenocorticotrophic, and antidiuretic hormones. Recent evidence suggests that autoimmune reactions against pituitary and/or hypothalamic tissue constitute an etiologic factor for this hypopituitarism. One important trigger for autoimmunity is hypoxic stress. This trigger may be especially important in the post concussive brain, which is particularly vulnerable to hypoxic stress. The vulnerable vasculature of the hypothalamic infundibulum can be a source of local exacerbation of any systemic hypoxia. Taking the above into account, it seems reasonable to hypothesize that hypoxic stress is a risk factor for post concussive hypopituitarism. Following a discussion of literature relevant to this hypothesis, we suggest retrospective and prospective research methods for testing the hypothesis. Retrospective methods for hypothesis testing include comparing post-concussion victims with and without evidence of hypopituitarism in terms of their history of respiratory problems such as smoking, exposure to indoor and outdoor air pollution, chronic obstructive pulmonary disease, asthma, obstructive sleep apnea, and opioid use or abuse. Significantly greater incidence of respiratory history among the hypopituitarism patients would support the hypothesis. Prospective methods include performing detailed respiratory history and examination immediately post-injury, then performing periodic endocrine panels to detect hypopituitarism during long-term follow up. The hypothesis will be supported if development of hypopituitarism among patients with positive respiratory history or examination findings post-injury is more frequent than hypopituitarism among concussion victims with negative respiratory history and exam findings. If the hypothesis is supported, effective prevention of post concussive hypopituitarism should include efforts to support optimal respiratory function. Such efforts may be relevant to treatment as well. These efforts would include respiratory therapy, smoking cessation, treatment of obstructive sleep apnea, prudent stepping down of opioid use, incentive spirometry, aerobic exercise, and other conventional measures as indicated. Non-Western measures such as yoga should be considered as well. In addition, chiropractic care as an intervention that may ameliorate hypoxia at the systemic and local levels is discussed. PMID- 30396483 TI - Ciprofloxacin and acute aortic valve damage. PMID- 30396484 TI - Are naive T cells and class-switched memory (IgD- CD27+) B cells not essential for establishment and maintenance of pregnancy? Insights from a case of common variable immunodeficiency with pregnancy. AB - The disruption of adaptive immune response has adverse effects on the establishment and maintenance of pregnancy. The adaptive immune system is regulated by several types of immune cells. However, there is limited information about cell hierarchy in the adaptive immune response to the establishment and maintenance of pregnancy in women. The assessment of the outcome of pregnancy in primary immunodeficiency diseases could help in understanding the cell hierarchy in the adaptive immune system during pregnancy. Common variable immunodeficiency (CVID) is a heterogeneous adaptive immune system disorder characterized by primary hypogammaglobulinemia. A few studies have previously reported the assessment of the T and B cell subpopulations in CVID patients. However, an assessment of the subpopulations of T and B cells and the outcome of pregnancy in women with CVID has not been reported till date. Most CVID patients show a general decrease in the expression of CD27 in B cells. The assessment of pregnancy and the subpopulations of T and B cells in CVID women with severe reduction in the naive T and switched B cells could help understand whether these cells are essential for the establishment and maintenance of pregnancy in women. PMID- 30396485 TI - Distraction-suppression effect on osteosarcoma. AB - Osteosarcoma is the most common primary malignant bone tumor. It occurs mainly in children and adolescents. In patients with open growth plate, epiphyseal distraction is used to separate the uninvolved epiphysis from adjacent tumor. This helps preserve the growth potential and restore joint and limb function to a great extent. Interestingly, epiphyseal distraction also appears to inhibit the proliferation of osteosarcoma tumor cells and to increase sensitivity to chemotherapy. Tumor interstitial pressure (TIP) is often elevated in the microenvironment of most solid tumors, including osteosarcoma. Elevated TIP can promote the proliferation, invasion, and migration ability of osteosarcoma cells and also decrease the uptake and distribution of chemotherapeutic agents. Studies have confirmed that the sustained volumetric strain produced in distracted tissue decreases TIP; it stretches extracellular matrix, decreases interstitial density, and increases vessel diameter. We hypothesize that lowering of TIP during the period of epiphyseal distraction inhibits the proliferation and invasion of osteosarcoma cell and, at the same time, increases blood perfusion in the tumor and thus enhances uptake and distribution of chemotherapy agents. If the hypothesis is proved to be true, distraction of tumor segment could be a novel supplementary treatment for osteosarcoma by manipulation of TIP. PMID- 30396486 TI - The swinging effect intervention: CBT based guided imagery and breathing technique integrated with mindfulness therapy for cancer patients. PMID- 30396487 TI - In diabetic ketoacidosis brain injury including cerebral oedema and infarction is caused by interleukin-1. AB - BACKGROUND: Brain injury in diabetic ketoacidosis (DKA) is common but under recognized and affects up to 54% of patients with this complication. It's manifestations include cerebral oedema (CE) and cerebral infarction (CI). The etiology of CE in DKA has up to the present time been uncertain. Practical management had been guided by the assumption that rapid osmotic shifts due to rapid correction of hypovolemia and reduction of plasma glucose could cause a shift of water into the cells. The osmotic effect of glucose can cause inflammation by activation of inflammasomes. Recently it has been recognized that the body is in a pro-inflammatory state during DKA involving interleukin-1 production by inflammasomes. Interleukin-1 has been involved in the pathogenesis of cerebral oedema and CI. HYPOTHESIS: In diabetic ketoacidosis brain injury including cerebral oedema and infarction is caused by interleukin-1. CONFIRMATION OF HYPOTHESIS AND IMPLICATIONS: Inflammasome activity could be quantified in peripheral blood mononuclear cells and in patients with and without clinical and/or subclinical CE and/or stroke or features of cerebral ischemia on MRI. Surrogates of brain injury in peripheral blood like neuron specific enolase could be measured and correlated with inflammasome activity. Interleukin-1 receptor antagonists and inflammasome inhibitors including telmisartan could be assessed in their effect on MRI changes consistent with CE or CI in patients with DKA in randomised placebo-controlled trials. PMID- 30396488 TI - Enoxaparin: A cause of postoperative fever? AB - Enoxaparin (clexane) is a low-molecular-weight heparin commonly prescribed for the chemoprophylaxis of venous thromboembolism in postoperative hip or knee replacement or abdominal surgery patients. We herein report a case of persistent postoperative fever in a patient, likely due to enoxaparin use. Prompt resolution of the patient's fever was observed after discontinuation of subcutaneous enoxaparin for chemical thromboprophylaxis. Reliable incidence data are lacking. A comprehensive search of PubMed, MEDLINE and EMBASE databases, as well as grey literature, found only two prior single case reports on enoxaparin-related fever. The mechanism responsible for the febrile reaction is likely an idiosyncratic response. Enoxaparin is typically derived from bovine or porcine intestines and lungs, hence its potential to cause hypersensitivity reactions is perhaps unsurprising. Clinicians should be alert to this possibility. PMID- 30396489 TI - Cortical riders of zonular cataracts as "reverse cuneiform" cataracts: A hypothesis. AB - Zonular cataracts are childhood cataracts involving one or more zone(s) of lens. They often show 'riders' which are wedge-shaped opacifications of inner cortex of the lens seen to radiate towards the lens equator, though little is known about the exact mechanism behind their development. Cortical riders may be described as 'reverse cuneiform' cataracts on the basis of their evolution pattern being exact opposite to that of senile cuneiform cortical cataracts. PMID- 30396490 TI - In lupus nephritis, how do extracellular DNAs trigger type I interferon secretion: Under the assistance of HMGB1-cGAS? AB - Systemic lupus erythematosus (SLE) is an autoimmune disease with multiple organs involved. Kidney damage is common among SLE patients. In lupus nephritis, extracellular DNA accumulation from necrosis cells and activated cells is perceived as initial step of inflammation. The up-regulated type I IFN is one pivotal cytokine causing downstream inflammation enlargement. Currently, intracellular DNA sensor cGAS signaling has been found to be related to lupus nephritis and the aberrant up-regulation of type I IFN. However, how extracellular accumulated DNA activates intracellular cGAS is still unknown. It was reported that nuclear protein HMGB1 takes part in multiple autoimmune diseases and inflammation induction. When HMGB1 is secreted to extracellular environment under certain conditions, it combines with DNA and triggers IFN-I secretion. It has been reported that HMGB1 level in renal tissue and cGAS level in peripheral blood mononuclear cells were both significantly up-regulated in SLE patients. Hence, we present a hypothesis that in lupus nephritis, the released HMGB1 helps extracellular accumulated DNA endocytosis and cGAS signaling pathway activation, followed by IFN-I secretion. We infer this is one pivotal pro inflammation pathway in lupus nephritis progression. PMID- 30396491 TI - Succinylation as a novel mode of energy metabolism regulation during atrial fibrillation. AB - Atrial fibrillation (AF) is the most common arrhythmia, resulting in significant morbidity and mortality. AF is associated with a higher demand of energy and impaired energy synthesis in cardiomyocytes. The succinate group is far bulkier cause it to have a larger impact on the structure and function of the proteins. So far, the study of the maximum fluence of the healthy heart sample proteome has mapped the cardiac proteomics map and builded a model of the heart proteome at the subcellular level. Compared with the normal sample, the most significantly downregulated proteins in the AF group were enriched for "mitochondrion". Succinylation of proteins appears to be prevalent in mechanisms involving cellular metabolism within the mitochondria. Experiment has show that heart has a much higher concentration of succinyl-CoA than any other organ. This supports the knowledge that the heart would need to prioritize energy production through the tricarboxylic acid cycle. So, we put forward this hypothesis: Succinylation is a new potential regulation model of cardiac energy metabolism during atrial fibrillation. PMID- 30396492 TI - How to safeguard an appropriate "all trans retinoic acid" concentration to keep cell division on track: Exploring therapeutic hotspots from metabolomics. AB - In this letter to editor, I hypothesize a potential affinity of retinol saturase (RetSat) enzyme towards a conjugated trienoic fatty acid; alpha-eleostearic acid (alpha-ESA) and subsequent hindrance of the action on its usual substrate; all trans retinol. Hence, RetSat is speculated to be involved in a rapid unusual conversion of alpha-ESA to conjugated linoleic acid (CLA), giving a less priority to its usual substrate all trans retinol, which would subsequently be converted into "all trans retinoic acid" (atRA). Otherwise, all trans retinol is converted by RetSat into all-trans-13,14-dihydroretinol and eventually forms all-trans 13,14-dihydroretinoic acid, but not the atRA. The atRA controls differentiation, proliferation and apoptosis of cells and it's deficiencies end up as neoplasms. Thus, here it is emphasized that safeguarding atRA would help controlling cell division and growth in a favourable manner. Hence, inhibition of RetSat could be a hot target to control unwarranted cell growths within the body. This hypothesis could be easily tested in a RetSat ablated (RetSat -/-) animal model or using antagonists on RetSat activity or alpha-ESA. PMID- 30396493 TI - The relationship between ehrlichiosis and the development of hematologic malignancies. AB - Viral and bacterial infections cause chronic inflammation and produce bacterial metabolites that may lead to carcinogenesis. Ehrlichiosis is an intracellular infection that primarily infects white blood cells. Given that infections can lead to cancer, and that Ehrlichia has tropism for white blood cells, it can be deduced that Ehrlichia may cause hematologic malignancies, such as acute leukemia. A prospective study was performed that tested the blood of ten patients with acute leukemia for prior exposure to Ehrlichia. The RT-PCR that was performed did not detect Ehrlichia DNA in any of the ten samples. Therefore, based on this small study, one cannot conclude that Ehrlichia can lead to hematologic malignancies. PMID- 30396494 TI - Molecular hydrogen may enhance the production of testosterone hormone in male infertility through hormone signal modulation and redox balance. AB - Since the discovery of molecular hydrogen (H2) as a selective scavenger of free radicals like reactive oxygen species (ROS) and reactive nitrogen species (RNS), numerous studies have proved the potential application of H2 in therapeutic and preventative medicine. Moreover, H2 can regulate the intracellular signal as a signal modulator. However, it is still unclear in cell signaling involved in testosterone hormone production. Male fertility depends on the intra-testicular testosterone concentration, which is produced by the Leydig cell in the seminiferous tubules in testes. Although moderate amounts of ROS are needed for normal sperm function, the higher amounts might decrease testosterone production. High ROS decreases testosterone hormone production by dysregulation of hormonal signal from the hypothalamus to the Leydig cell as a result of redox imbalance. Lower level of testosterone fails to support the Leydig cell for the progression of spermatogenesis. Superoxide anion (O2-), hydroxyl radical (OH) and peroxynitrite (ONOO-) could also attack the DNA, lipid and protein, disrupting sperm structure and function and aggravating the milieu of male fertility and spermatogenesis. H2 regulates intracellular MAPK downstream cAMP signal and Ca2+ signal as a signal modulator to antagonize ROS signaling. Thus H2 can play a role in modulating signals involved in testosterone hormone production to improve male fertility caused by redox imbalance. We therefore hypothesize that molecular hydrogen may enhance testosterone production via cellular redox balance. By this hypothesis, we anticipate that molecular hydrogen may be an effective remedy in male infertility. PMID- 30396495 TI - Inborn coagulation factors are more important cardiovascular risk factors than high LDL-cholesterol in familial hypercholesterolemia. AB - High low-density-lipoprotein cholesterol (LDL-C) is routinely described as the main cause of cardiovascular disease (CVD) in familial hypercholesterolemia (FH). However, numerous observations are in conflict with Bradford Hill's criteria for causality: a) degree of atherosclerosis is not associated with LDL-C; b) on average the life span of people with FH is about the same as for other people; c) LDL-C of people with FH without CVD is almost as high as in FH patients of the same age with CVD; and d) questionable benefit or none at all have been achieved in the controlled, randomized cholesterol-lowering trials that have included FH individuals only. Obviously, those individuals with FH who suffer from CVD may have inherited other and more important risk factors of CVD than high LDL-C. In accordance, several studies of FH individuals have shown that various coagulation factors may cause CVD. Equally, some non-FH members of an FH kindred with early CVD, have been found to suffer from early CVD as well. Cholesterol-lowering has only been successful in an animal experiment by using probucol, which has anticoagulant effects as well. We conclude that systematic studies of all kinds of risk factors among FH individuals are urgently required, because today millions of people with FH are treated with statins, the benefit of which in FH is unproven, and which have many serious side effects. We predict that treatment of FH individuals with elevated coagulation factors with anticoagulative drugs is more effective than statin treatment alone. PMID- 30396496 TI - Living dangerously: Burkholderia pseudomallei modulates phagocyte cell death to survive. AB - Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is a major cause of sepsis and mortality in endemic regions of Southeast Asia and Northern Australia. As a facultative intracellular pathogen, B. pseudomallei produces virulence factors to evade innate host response and survive within host cells. Neutrophils and macrophages are phagocytes that play critical roles in host defense against pathogens by their ability to detect and eliminate microbes. Host defense processes against B. pseudomallei including phagocytosis, oxidative burst, autophagy, apoptosis, and proinflammatory cytokine release are all initiated by these two phagocytes in the fight against this bacterium. In vitro studies with mouse macrophage cell lines revealed multiple evasion strategies used by B. pseudomallei to counteract these innate processes. B. pseudomallei invades and replicates in neutrophils but little is known regarding its evasion mechanisms. The bidirectional interaction of neutrophils and macrophages in controlling B. pseudomallei infection has also been overlooked. Here the hypothesis that B. pseudomallei hijacks neutrophils and uses them to transport and infect new phagocytes is proposed as an evasion strategy to survive and persist in host phagocytes. This two-pronged approach by B. pseudomallei to replicate in two different types of phagocytes and to modulate their cell death modes is effective in promoting persistence and survival of the bacterium. PMID- 30396497 TI - Alternative way to find sacral hiatus for blind caudal block - Based on 3D pelvis CT anthropometry: A retrospective study. AB - The aim of this study is to develop an alternative way to locate the sacral hiatus for blind caudal block from the anthropometrical data measured on 3D pelvic CT. The intersection of the line connecting two sacral cornua and the midline is considered the ideal point (IP) for caudal block. The mean length from the coccyx tip to the IP was measured using 3D pelvic CT images in 30 men and 30 women and was 6.5 cm and 6.0 cm, respectively. For the conventional method group, we used the conventional equilateral triangle method to find the sacral hiatus, which was named conventional method group needling point (CNP). For the experimental method group, the point 6.5 cm or 6.0 cm (mean length from the coccyx tip to the IP) away from the coccyx tip was called the experimental method group needling point (ENP). Drawing the three points of the IP, CNP, and ENP on the same patient's 3D pelvic CT, we compared the distance from the IP to the CNP with the distance from the IP to the ENP. We propose that the experimental method is comparable to the conventional method in locating the sacral hiatus, which is crucial for a successful caudal block procedure. Anthropometric measurements and virtual comparative test between two methods were done on the 3D pelvis CT. In men, the distance from the CNP to the IP was 0.8 +/- 0.5 cm in the conventional method group, while the distance from the ENP to the IP was 0.5 +/- 0.4 cm in the experimental method group (p < 0.05). In women, the same distances were 1.5 +/- 0.8 cm and 0.7 +/- 0.3 cm, respectively (p < 0.05). In conclusion, finding a point of 6.5 cm from the coccyx tip in men and 6.0 cm in women could be an alternative way to find the sacral hiatus for blind caudal block. PMID- 30396498 TI - Racial difference in preterm birth and low birthweight: Towards a new hypothesis involving the interaction of 25-hydroxyvitamin D with maternal fat mass. AB - Preterm birth (PB) and low birthweight (LBW) remain a leading cause of infant mortality worldwide. Persistent racial disparities in prevalence rates have been reported, with the highest values observed in Subsaharan Africa and South Asia. In United States, non-Hispanic Black women are more likely to have a premature or low-birth-weight baby. Beyond the speculative debate on factors explaining such racial disparity, the key-question remains about the path from race to birth outcomes. Several hypotheses emerged from the published literature to explain the racial difference in likelihood for PB and LBW. However, the 'Hispanic paradox' remains unexplained. We relied here on published data to hypothesize that the racial disparity in PB/LBW is a consequence to the joint influence of 25 hydroxyvitamin D and fat mass. Beyond its role as a source of 1,25 dihydroxyvitamin D, the 25-hydroxyvitamin D is directly implicated in the fetal growth and the normal completion of pregnancy. Because of its lipophilic property, a large part of 25-hydroxyvitamin D is swiftly trapped into fat mass and the circulating fraction impact the body development during fetal period. We postulate that the positive effect of vitamin D to prevent PB/LBW is less beneficial for women with high fat mass, independent of race. The core problem may be related to bioavailable 25-hydroxyvitamin D, not directly to race. PMID- 30396499 TI - The myth of autoimmunity. AB - Within the more than one hundred disease entities for which autoimmunity causation have been alleged, two subgroups can be identified. The first group is characterized by ability of disruption of the effector arm of the immune response to temporarily reverse the signs and symptoms of disease. The second group is characterized by the presence of antibodies directed against the target organ's cellular or subcellular components. As long as therapeutic palliation of the signs and symptoms of disease can be achieved, attributing causation to autoimmunity has tended to arrest therapeutics focus on attaining cure. Data relevant to a prime disease entity within each of the two allegedly autoimmune disease, Crohn's disease and Type 1 diabetes mellitus, refute the claim of autoimmunity. In particular, the events that combine to produce Crohn's disease have identified a mechanism by which a dysfunctional immune-mediated response against a specific set of antigens/agent can produces disease. Identification of this mechanism opens to rethinking the pathogenesis of other classic autoimmune diseases within that 5 subgroup. PMID- 30396500 TI - Moving the systemic evolutionary approach to cancer forward: Therapeutic implications. AB - We have previously presented a new Systemic Evolutionary Theory of Cancer (SETOC) based on the failure of proper endosymbiosis in eukaryotic cells. Here, we propose that the progressive uncoupling of two endosymbiotic subsystems (information and energy) inside the cell, as a consequence of long-term injuries, gives rise to alterations (i) in tissue interactions and (ii) in cell organization. In the first case, we argue that the impairment of both the coherent state and the synergy between intercellular communications underpins the onset of tissue dysplasia, that usually evolves towards cancer development. In the second case, we suggest that the rupture of endosymbiosis drives a sort of cell regression towards a protist-like entity represented by the concept of "de emergence" postulated in our systemic evolutionary approach to carcinogenesis. This conceptual association of the cancer cell with a protist-like organism could support the development of novel cancer therapeutic approaches. To this end, we propose a paradigm shift in cancer pharmacology since: i) our knowledge of cancer pathophysiology as a complex system is insufficient, despite a vast knowledge of molecular mechanisms underlying cancer; ii) current cancer pharmacology deals only with microvariables (e.g. gene or protein targets), which do not account for the integrated pathophysiology of cancer, rather than with macrovariables (e.g. pH, membrane potential, electromagnetic fields, cell communications and so on) and mesovariables (between micro and macro), such as the interaction between various cellular components including cellular organelles. This paradigm shift should allow cancer pharmacology to move forward from molecular treatments (focusing on single targets) to modular treatments that consider cancer-related processes (i.e. inflammation, coagulation, etc.) or even to a sort of ecosystemic treatment addressing the whole functioning of the "cancer ecosystem". Examples of ecosystems treatment may be natural plant derivatives that act synergistically or pulsed electromagnetic fields which can act on particular biological processes in cancer cells. In addition, we need different working theoretical models on which to base new anticancer pharmacological approaches. Finally, we examine what value our systemic evolutionary approach could add to cancer treatments, in particular in liver cancer as a paradigm for developing potential applications. PMID- 30396502 TI - Cognitive disorders in allergic rhinitis may be induced by decline of respiration entrained rhythm in the brain. PMID- 30396501 TI - Corrigendum to "Phenylalanine hydroxylase: A biomarker of disease susceptibility in Parkinson's disease and amyotrophic lateral sclerosis" [Med. Hypotheses 118 (2018) 29-33]. PMID- 30396503 TI - Eosinophilic inflammation in spontaneous coronary artery dissection: A potential therapeutic target? AB - Spontaneous coronary artery dissection (SCAD), defined as non-traumatic, non iatrogenic dissociation of coronary vessel wall resulting from intimal disruption or intramural hemorrhage, represents an important cause of sudden death and myocardial infarction among young or middle-aged women without conventional risk factors for atherosclerosis. On histopathological examination, SCAD is featured by prominent eosinophilic infiltration of the adventitia or periadventitial layer of coronary artery. It has been estimated that approximately 15-30% of SCAD patients experience recurrent episodes of dissection despite medical therapy. Preliminary evidence suggests that injury to the vascular endothelium and myocytes in the arterial wall may be explained by cytotoxic products released from eosinophils in response to inflammatory mediators. In addition, neovascularization of vasa vasorum and dilatation of intimal capillaries may be stimulated by localized eosinophils. Newly formed fragile vasa vasorum may disrupt due to high intraluminal pressure from the interconnected capillary network, leading to the expansion of intramural hemorrhage. It is hypothesized that anti-inflammatory therapy targeting eosinophilic coronary periarteritis would be effective in preventing the recurrence of SCAD by promoting the healing of dissection. The article delineates the biological plausibility, empirical data, and future perspective regarding eosinophilic inflammation as a potential therapeutic target for SCAD. PMID- 30396504 TI - Impaired glucose metabolism - A potential risk factor for idiopathic nodular glomerulosclerosis: A single center study. AB - Nodular glomerulosclerosis is a characteristic histological finding of diabetic nephropathy (DN) with thickened glomerular basement membrane and hyalinized arterioles. Idiopathic nodular glomerulosclerosis (ING), a distinct clinicopathologic entity, is the term used to denote classic DN confirmed by light microscopy, immuno-fluorescence, and electron microscopy but in the absence of diabetes mellitus (DM). ING has been linked to heavy tobacco smoking, chronic hypertension, and obesity. We report the result of a retrospective study identifying seventeen subjects from Thomas Jefferson University (1999-2014) with biopsy-proven nodular glomerulosclerosis but no pre-existing history of DM. The main indications for percutaneous kidney biopsy (PKB) were either reduced renal function or the presence of proteinuria. The subjects' mean (+/-SD) age was 60.2 (14.4) years, their highest documented random glucose level was 104.4 (23.5) mg/dL, serum creatinine measured 2.35 (1.03) mg/dL, and body mass index calculated 29.4 (6.2) kg/m2. None of the patients fulfilled criteria for diabetes at the time of PKB. However, review of medical records revealed history of intermittently elevated blood glucose or borderline-high HgbA1c levels. The role of impaired glucose metabolism or insulin resistance, as a possible etiology for ING is potentially underestimated and needs additional studies. PMID- 30396505 TI - The S-curve discontinuity theory predicts the path towards a "well" society and increased longevity. AB - The logistic function or logistic growth curve is an "S" shape (sigmoid curve) that has been applied to numerous fields, including geology, physics, biology, mathematics, chemistry, economics, sociology, oncology, and statistics. The S curve initiates with exponential growth, followed by slowing of growth as saturation occurs, and completion of growth at maturity. The S-curve follows the law of natural growth with a limiting factor, whether it be a competition for resources, investigation and demand for new products, or an economic bubble. The concept of the S-curve has been utilized in medicine to describe the advancements in the 20th century based on the diagnosis and treatment of disease (the "illness" curve [first S-curve]) and predict the future focused on disease prevention and health promotion (the "wellness" curve [second S-curve]). Herein, we propose a third S-curve that we are labeling the "longevity" curve. PMID- 30396506 TI - [Evaluation of management disparity in patients with chronic lymphocytic leukemia in France]. AB - Environmental factors have an impact on the effectiveness of treatments for chronic lymphocytic leukemia: vulnerability, organization of the supply of care and proximity of the patient to health professionals. The disparity of care was assessed; vulnerability by the European index of deprivation, the provision of care by values of localized potential accessibility to general practitioners, nurses and pharmacists and hospital supply by the density of hematologists and time access to the center. The data, extracted from the public databases for each grouped island for statistical information, were cross-referenced to apply a principal component analysis and group them into 4 clusters. Cluster 1 has an average EDI, easy access to city professionals, remote access to the referral center, and a good density of hematologists. Cluster 2 has low EDI, satisfactory access to professionals, satisfactory proximity to the referral center and average density of hematologists. Cluster 3 has good EDI, access to professionals is difficult, access to the reference center is long, and the density of hematologists remains average. Cluster 4 has a good EDI, with access to professionals easier than in Cluster 3 but still difficult. The access time to the reference center is better than that of cluster 3 but remains elongated, the density of hematologists remaining average. Mapping is a tool for hospitals and institutions to evaluate care and compare it to other territories. PMID- 30396508 TI - Solid-liquid-liquid wettability and its prediction with surface free energy models. AB - Understanding wettability in solid-liquid-liquid (SLL or immersed) systems is important for numerous applications. However, predicting SLL wetting behavior on smooth surfaces has received little attention. The objective of this work was to explore alternatives to predict SLL wettability. To this end, we first present a review of solid surface free energy (sigmaS) data obtained from solid-liquid-air (SLA) contact angle (thetaLa) data and a summary of available SLL contact angle data for selected materials. Next, the existing surface free energy models for SLA systems are discussed in terms of their applicability to predict wettability of SLL systems. Finally, the SLL wettability of toluene drops on glass, mica, stainless steel and PTFE immersed in equilibrated Toluene-water-isopropyl alcohol (IPA) solutions was determined via contact angle (thetaO) measurements through the oil phase using the inverted sessile drop method over a wide range of interfacial tensions (gammao-aq). The results were plotted as gammao-aq.costhetaO vs. gammao-aq, showing a smooth wetting transition from water-wetting to oil wetting with decreasing gammao-aq for glass and stainless steel. Mica remained water-wetting, while PTFE oil-wetting. The Geometric (GM) and Harmonic (HM) mean approaches, and the Equation-of-State (EQS), originally developed for SLA systems, were extended to SLL systems. The extended GM and HM approaches could fit the SLL behavior after fitting the dispersive and polar contributions of the solid surface free energy (sigmaSd, sigmaSp), which required additional SLA thetaLa measurements using PTFE as the reference surface. However, attempts at predicting thetaO for systems with high gammao-aq resulted in significant deviations, a problem linked to the high sigmaSd values required to fit the wettability of low gammao-aq systems (toluene-water-IPA). The extended EQS (e EQS) method produced reasonable predictions of gammao-aq.costhetaO for all the available experimental and literature data. The e-EQS method required fitting one of the interfacial energy terms (gammaS-L). For low surface energy materials, such as PTFE, the gammaS-o value should be fitted. For high surface energy materials, the gammaS-aq should be fitted instead. The fitted values of gammaS-o for PTFE and gammaS-aq for glass were consistent with the values obtained from Young's equation applied to SLA data. PMID- 30396509 TI - Mendelian Randomization in Case Only Studies: A Promising Approach to be Applied With Caution. PMID- 30396507 TI - Reverse engineering the ultrasound contrast agent. AB - In this review, a brief history and current state-of-the-art is given to stimulate the rational design of new microbubbles through the reverse engineering of current ultrasound contrast agents (UCAs). It is shown that an effective microbubble should be biocompatible, echogenic and stable. Physical mechanisms and engineering calculations have been provided to illustrate these properties and how they can be achieved. The reverse-engineering design paradigm is applied to study current FDA-approved and commercially available UCAs. Given the sophistication of microbubble designs reported in the literature, rapid development and adoption of ultrasound device hardware and techniques, and the growing number of revolutionary biomedical applications moving toward the clinic, the field of Microbubble Engineering is fertile for breakthroughs in next generation UCA technology. It is up to current and future microbubble engineers and clinicians to push forward with regulatory approval and clinical adoption of advanced UCA technologies in the years to come. PMID- 30396510 TI - Dermatologic Manifestations in kidney transplant recipients. PMID- 30396511 TI - A Unified Walking Model for Dimeric Motor Proteins. AB - Dimeric motor proteins, kinesin-1, cytoplasmic dynein-1, and myosin-V, move stepwise along microtubules and actin filaments with a regular step size. The motors take backward as well as forward steps. The step ratio r and dwell time tau, which are the ratio of the number of backward steps to the number of forward steps and the time between consecutive steps, respectively, were observed to change with the load. To understand the movement of motor proteins, we constructed a unified and simple mathematical model to explain the load dependencies of r and of tau measured for the above three types of motors quantitatively. Our model consists of three states, and the forward and backward steps are represented by the cycles of transitions visiting different pairs of states among the three, implying that a backward step is not the reversal of a forward step. Each of r and tau is given by a simple expression containing two exponential functions. The experimental data for r and tau for dynein available in the literature are not sufficient for a quantitative analysis, which is in contrast to those for kinesin and myosin-V. We reanalyze the data to obtain r and tau of native dynein to make up the insufficient data to fit them to the model. Our model successfully describes the behavior of r and tau for all of the motors in a wide range of loads from large assisting loads to superstall loads. PMID- 30396512 TI - Depression. AB - Major depression is a common illness that severely limits psychosocial functioning and diminishes quality of life. In 2008, WHO ranked major depression as the third cause of burden of disease worldwide and projected that the disease will rank first by 2030.1 In practice, its detection, diagnosis, and management often pose challenges for clinicians because of its various presentations, unpredictable course and prognosis, and variable response to treatment. PMID- 30396513 TI - Framing an agenda for children thriving in the SDG era: a WHO-UNICEF-Lancet Commission on Child Health and Wellbeing. PMID- 30396514 TI - A Japanese Bioventure Company's Application of Stem Cell Technology in Regenerative Medicine. AB - Regenerative medicine mediated by the transplantation of somatic stem cells and functional cells derived from induced pluripotent stem cells has great potential in the treatment of currently incurable diseases and thus has attracted significant public attention. To put this into practice, several functional cell lines were developed and laws regarding regenerative medicine were put in force in Japan. In this report, we introduce recent efforts of a bioventure company with special attention to the case of Healios K.K. PMID- 30396515 TI - Assumptions in Clinical Trial Designs and Therapies. PMID- 30396516 TI - Colchicine in Stable Coronary Artery Disease. AB - PURPOSE: Disease management of stable coronary artery disease consists of controlling hemostasis and lipid regulation. No treatment strategies preventing plaque erosion or rupture are yet available. Cholesterol crystal-induced inflammation leading to plaque destabilization is believed to be an important factor contributing to plaque instability and might well be amenable to treatment with anti-inflammatory drugs. Colchicine has anti-inflammatory properties with the potential to address both the direct and indirect inflammatory mechanisms in the plaque. METHODS: A literature search was performed in MEDLINE (PubMed), EMBASE, and the Cochrane Central Register of Controlled Trials, as well as in the clinical trial registries, to identify finished and ongoing clinical studies on colchicine in stable coronary artery disease. FINDINGS: Preclinical findings of colchicine in stable coronary artery disease have shown protective effects on surrogate outcomes, such as myocardial infarction size and postangioplasty restenosis. Retrospective cohort studies in patients with gout report a lower incidence of combined cardiovascular outcomes in those treated with colchicine. Thus far, one prospective, randomized clinical trial has provided evidence on a possible protective effect of colchicine in stable coronary artery disease. Meta analysis of trials of colchicine in multiple cardiovascular diseases revealed a decrease in myocardial infarction with varying levels of evidence. Currently, 5 major clinical trials involving >10,000 patients are recruiting patients, all focusing on major cardiovascular outcomes. IMPLICATIONS: The body and quality of evidence regarding the efficacy of colchicine for secondary prevention of stable and acute phases of coronary artery disease will be greatly expanded in the upcoming years, providing less biased and more accurate effect estimates. If colchicine's anti-inflammatory characteristics translate to improved event-free cardiovascular survival, this relatively safe, low-cost, and well-known drug may become the third pillar (next to lipid regulation and platelet inhibition) in the medical management of stable coronary artery disease. PMID- 30396517 TI - Kurt Benirschke: In Memoriam. PMID- 30396519 TI - Epidemiology and Pathophysiology of Gastroparesis. AB - Gastroparesis is a complex syndrome with symptoms that include nausea, vomiting, and postprandial abdominal pain, and is frequently accompanied by significant delays in gastric emptying. The pathophysiology of diabetic gastroparesis is fairly well understood; however, idiopathic gastroparesis, which accounts for one third of all cases, may stem from infections, or autoimmune or neurologic disorders, among other causes. To date, few population-based studies have estimated the true prevalence and incidence of gastroparesis. Nonetheless, its prevalence appears to be rising, as does its incidence among minority populations, documented via hospitalizations, which can impose significant economic burdens on patients. PMID- 30396520 TI - Stent Placement for the Treatment of Gastroparesis. AB - Gastroparesis is a syndrome of delayed gastric emptying. First-line treatment includes prokinetic medications. Those refractory to medical treatment are occasionally considered for endoscopic or surgical treatment options, with unpredictable response. The pylorus plays a key role in gastric emptying, with pylorospasm as the underlying mechanism of gastroparesis in some patients. Procedures aiming at disruption of the pylorus have improved gastroparesis symptoms in this subset of patients. These include transpyloric stenting, used for inpatients with refractory symptoms to allow hospital discharge or as a triage to assess symptoms response in patients considered for more definite therapies such as pyloromyotomy. PMID- 30396518 TI - Placenta Imaging Workshop 2018 report: Multiscale and multimodal approaches. AB - The Centre for Medical Image Computing (CMIC) at University College London (UCL) hosted a two-day workshop on placenta imaging on April 12th and 13th 2018. The workshop consisted of 10 invited talks, 3 contributed talks, a poster session, a public interaction session and a panel discussion about the future direction of placental imaging. With approximately 50 placental researchers in attendance, the workshop was a platform for engineers, clinicians and medical experts in the field to network and exchange ideas. Attendees had the chance to explore over 20 posters with subjects ranging from the movement of blood within the placenta to the efficient segmentation of fetal MRI using deep learning tools. UCL public engagement specialists also presented a poster, encouraging attendees to learn more about how to engage patients and the public with their research, creating spaces for mutual learning and dialogue. PMID- 30396521 TI - Technical Aspects of Peroral Endoscopic Pyloromyotomy. AB - Gastric peroral endoscopic pyloromyotomy (G-POEM or POP) is a feasible and effective procedure for the treatment of refractory gastroparesis. G-POEM is a technically demanding endoscopic procedure. As of yet, there is no consensus on the technique. A variety of techniques have been reported in published studies. The essential technical steps of the procedure are (1) establishment of submucosal tunnel in gastric antrum, (2) identification of the pyloric muscular ring, (3) selective circular myotomy, and (4) a 2.5-cm to 3.0-cm length of myotomy. There are still some technical questions unanswered, and more studies are needed to establish standardized techniques and possible improvement of outcomes. PMID- 30396522 TI - Gastric Emptying Scintigraphy Before Gastric per Oral Endoscopic Myotomy: Imaging May Inform Treatment. AB - Gastric emptying scintigraphy (GES) helps to diagnose gastroparesis and is typically only used for whole stomach retention patterns. However, it may provide significantly more information when looking specifically at proximal and distal retention patterns. This article reviews global GES changes following gastric per oral endoscopic myotomy; how global, proximal, and distal GES measurements correlate to gastroparesis symptoms; and how proximal and distal GES may serve as proxies for the various mechanisms involved in gastroparesis. The authors' data on how GES may be used to select which patients will have success from G-POEM is also reviewed. PMID- 30396523 TI - Outcomes and Future Directions of Per-Oral Endoscopic Pyloromyotomy: A View from France. AB - Gastroparesis is a challenging functional gastroenterological disorder, the complex pathophysiology of which hampers development of therapeutic modalities. Per-oral pyloromyotomy (POP) is a promising endoscopic therapy with a short-term clinical success rate of greater than 80%. Interest in POP is increasing, particularly in France, a country in which there is considerable expertise in submucosal endoscopy and functional disorders. Long-term follow-up and pyloric function evaluation are needed to assess the efficacy of POP in gastroparetic patients. PMID- 30396524 TI - Diabetic Gastroparesis and Nondiabetic Gastroparesis. AB - Gastroparesis can be divided into diabetic and nondiabetic, and the 3 main causes of gastroparesis are diabetic, postsurgical, and idiopathic. Delayed gastric emptying is the main manifestation of motility disorders for gastroparesis. Symptoms of gastroparesis are nonspecific and severity can vary. Nausea and vomiting are more common in diabetic gastroparesis whereas abdominal pain and early satiety are more frequent in idiopathic gastroparesis. Medication is still the mainstay of treatment of gastroparesis; however, the development of gastric electric stimulation and gastric peroral endoscopic pyloromyotomy brings more options for the treatment of diabetic and nondiabetic gastroparesis. PMID- 30396525 TI - Outcomes of Per Oral Endoscopic Pyloromyotomy in the United States. AB - Per oral endoscopic pyloromyotomy (POP) has emerged as an endoscopic intervention for refractory gastroparesis. Early experience in the United States showed exciting clinical response rate, reduced gastroparesis symptoms, improved quality of life, and decreased gastric-emptying time during midterm follow-up up to 18 months. One recent study also showed that the number of patient emergency room visits and hospitalizations decreased significantly after POP. The procedure is technically feasible and safe. As more data become available, it is important to identify patients who would benefit most from this novel procedure. PMID- 30396526 TI - Clinical Manifestation and Natural History of Gastroparesis. AB - Although gastroparesis was described more than 60 years ago, the natural history and the long-term outcome are still being clarified. The patients with more severe gastroparesis often seek health care treatment in university medical centers specializing in gastrointestinal motility disorders and hence reports in the literature tend to be based on this population and may not be representative of the entire spectrum. The clinical manifestations of gastroparesis are heterogeneous but a significant proportion of patients end up with substantially poorer quality of life. In this article, the focus is on the clinical presentation and natural history of gastroparesis. PMID- 30396527 TI - Evaluation of Patients with Suspected Gastroparesis. AB - There is substantial overlap between the symptoms of gastroparesis and a variety of alternative disorders. These conditions include rumination syndrome, drug induced gastric emptying delay, cannabinoid hyperemesis syndrome, and eating disorders, which can be identified based on the history alone. The remaining patients require a diagnostic approach of physical examination, laboratory tests, evaluation with esophagogastroduodenoscopy or contrast radiography, and a test to measure gastric emptying. Symptomatic patients who have normal nutritional status and gastric emptying that is either normal or mildly delayed should be diagnosed with functional dyspepsia, whereas patients with moderate or severe gastric emptying delay are diagnosed with gastroparesis. PMID- 30396528 TI - Symptomatic Management of Gastroparesis. AB - Gastroparesis is a chronic and debilitating neuromuscular disorder of the upper gastrointestinal tract. Symptoms of gastroparesis include nausea, vomiting, epigastric pain, early satiety, and weight loss. Treating gastroparesis can be difficult. Dietary changes may improve symptoms in patients with mild disease. A variety of medications can be used to treat symptoms of nausea and vomiting, although most have not been subjected to randomized controlled trials and only one is approved by the Food and Drug Administration (metoclopramide). Pain management is essential, as nearly 90% of patients report symptoms of epigastric pain. This article reviews treatment options for symptoms of gastroparesis. PMID- 30396529 TI - Gastric Electrical Stimulator for Treatment of Gastroparesis. AB - Patients with gastroparesis sometimes suffer from intractable nausea and vomiting, abdominal pain, and bloating, as well as a host of other symptoms that can often be difficult to control. Initially, patients are treated conservatively; some do well with conservative management but unfortunately some do not. Over the years, studies have shown the benefits of gastric electrical stimulation, which often results in symptomatic improvement and improvement in gastric emptying times. This article discusses the history of gastric electrical stimulation and its use in clinical practice to help those suffering from gastroparesis that is refractory to conservative medical management. PMID- 30396530 TI - Surgical Management for Gastroparesis. AB - Gastroparesis is a debilitating chronic condition of indeterminate cause. Although conservative management is the mainstay of treatment, a significant percentage of patients will need interventions. Interventions range from supportive measures, such as feeding tubes, to more radical surgeries, including endoscopic pyloromyotomy (per oral pyloromyotomy), laparoscopic pyloroplasty, laparoscopic gastric stimulator placement, and even subtotal or total gastrectomy. The authors present some current treatment algorithms focused on the treatment side of the spectrum along with outcomes data to support the various approaches. PMID- 30396532 TI - Gastroparesis: New Approaches in Management. PMID- 30396533 TI - Gastroparesis: Current Opinions and New Endoscopic Therapies. PMID- 30396531 TI - Botulinum Toxin Injection for Treatment of Gastroparesis. AB - Refractory gastroparesis is among the most difficult therapeutic challenges in gastroenterology. Pyloric dysfunction has been described in a subset of patients with gastroparesis, prompting experimentation with botulinum toxin injections into the pylorus, which is relatively safe and has been successfully used in other gastrointestinal disorders. However, causality between pyloric dysfunction and symptoms of gastroparesis has never been demonstrated. Although several open label studies showed initial promise, 2 randomized clinical trials failed to elicit a difference in clinical outcomes in botulinum toxin versus placebo. Based on current evidence, further use of botulinum toxin for gastroparesis is discouraged outside of a research trial. PMID- 30396535 TI - Against seminal principles: ethics, hubris, and lessons to learn from illicit inseminations. PMID- 30396534 TI - E-cigarettes, alcohol use, and mental health: Use and perceptions of e-cigarettes among college students, by alcohol use and mental health status. AB - INTRODUCTION: Electronic cigarettes (e-cigarettes) are popular among college students, who display risky alcohol use patterns. However, little is known about patterns of co-use of e-cigarettes and alcohol. Further, relationships between e cigarette use and mental illness among college students are unclear. METHODS: College student participants (N = 631) at a northeastern U.S. university were invited via email to participate in a survey about e-cigarettes and alcohol use. Mental health was self-reported diagnosis of psychiatric (depression, bipolar disorder, schizophrenia, PTSD, anxiety disorder, personality disorder), and substance (alcohol and other drug) use disorders. Current use of e-cigarette, combustible cigarette, and other tobacco products were assessed via self-reported past 30-day use frequency. Alcohol consumption was assessed via number of self reported standard alcoholic beverages consumed during a typical drinking episode. Participants also reported regarding co-use of alcohol, e-cigarettes and/or combustible cigarettes. Participants were categorized as non-drinkers, moderate drinkers or binge drinkers, and associations between e-cigarette use, drinking patterns and mental health diagnoses were examined. RESULTS: E-cigarette use was associated with drinking alcohol chi2 = 18.62, p < .001, and binge drinking (vs. moderate drinking) chi2 = 12.20, p < .001. Students who had tried e-cigarettes reported drinking more alcohol per episode (chi2 = 15.94, p < .001). E-cigarette use was more prevalent among those with psychiatric and substance use disorders chi2 = 11.65, p < .001. CONCLUSIONS: Drinking college students (especially binge drinkers) and those with mental illness may have heightened risks for e-cigarette use. More research is needed to elucidate relationships between risky alcohol and/or nicotine use and mental illness, and to guide appropriate prevention and intervention efforts for vulnerable college students. PMID- 30396536 TI - Effects of medical comorbidity on male infertility and comorbidity treatment on spermatogenesis. AB - OBJECTIVE: To investigate the prevalence and effects of medical comorbidities on spermatogenesis and to determine whether the treatment of medical comorbidities effectively improves spermatogenesis. DESIGN: Single-center case-control study. SETTING: University hospital. PATIENT(S): A total of 3,328 infertile men and 452 men with normal results on semen examination, with mean age of 35 years. INTERVENTION(S): Hormonal and spermatogenic parameters were compared between the men with and without medical comorbidities. For the men diagnosed with medical comorbidities during the infertility evaluation, semen parameters were compared between those who did and did not undergo treatment of the comorbidities. MAIN OUTCOME MEASURE(S): Rate of comorbidity, relationship between infertility and comorbidity, comorbidity treatment on total motile sperm count. RESULT(S): The prevalence of comorbidities was significantly higher in the infertile men (21.7%) than in the fertile men (9.1%), particularly for hypertension (17.8%), hyperlipidemia (5.9%), hyperuricemia (5.2%), and skin disease (3.0%). Among the infertile men, the reproductive functions were aberrant in the men with comorbidity compared with those without comorbidity. After treatment for comorbidities, a significant increase was observed in the total motile sperm count compared with both the baseline values and with the poorly controlled men. A multivariate analysis showed that varicocele and comorbidity treatments were independent predictors of an improved total motile sperm count, with odds ratios of 2.895 and 2.057, respectively. CONCLUSION(S): Medical comorbidities are associated with impaired sperm production. Male infertility evaluation offers not only specific therapy to improve semen parameters but also therapy for nonspecific medical comorbidities, which may benefit general health status and spermatogenesis restoration. PMID- 30396537 TI - Misconduct in third-party assisted reproduction: an Ethics Committee opinion. AB - Professionals who discover misconduct or other undisclosed information that would be material to the participation of another party (such as a donor, gestational carrier, intended parent, or lawyer) in an assisted reproductive technology arrangement should encourage disclosure to that party. In some instances, it is ethically permissible for the physician either to disclose material information to the affected party or to decline to provide care. In all cases involving the legal status or rights of the parties, referral to legal professionals is advised. This document replaces the document of the same name, last published in 2014 (Fertil Steril 2014;101:38-42). PMID- 30396538 TI - Consideration of the gestational carrier: an Ethics Committee opinion. AB - Intended parents engage with gestational carriers in an attempt to achieve their personal reproductive goals. All gestational carriers have a right to be fully informed of the risks as well as the contractual and legal aspects of the gestational-carrier process. Gestational carriers have autonomy in making their own decisions regarding medical care and should be free from undue influences by the stakeholders involved. They should have free access to and receive psychological evaluation and counseling before, during, and after participating. Gestational carriers require independent legal counsel regarding the execution of contracts. This document replaces the document of the same name, last published in 2013 (Fertil Steril 2013;99:1838-1841). PMID- 30396540 TI - Medical treatment of comorbidities among infertile men: a step toward improving semen quality and general health status of infertile men? PMID- 30396539 TI - Planned oocyte cryopreservation for women seeking to preserve future reproductive potential: an Ethics Committee opinion. AB - Planned oocyte cryopreservation ("planned OC") is an emerging but ethically permissible procedure that may help women avoid future infertility. Because planned OC is new and evolving, it is essential that women who are considering using it be informed about the uncertainties regarding its efficacy and long-term effects. PMID- 30396541 TI - Is in vitro organotypic culture the key to spermatogenesis of human immature testicular tissue? PMID- 30396542 TI - Relevance of International Committee for Monitoring Assisted Reproductive Technology (ICMART) Registry report 2011. PMID- 30396543 TI - Universal assisted reproductive technology coverage: a worthy cause that promotes safety. PMID- 30396544 TI - Simplifying luteal phase support in stimulated assisted reproduction cycles. PMID- 30396545 TI - Conflicting messages on diet and fertility: food for thought. PMID- 30396546 TI - Elusive adenomyosis: a plea for an international classification system to allow artificial intelligence approaches to reset our clinical management. PMID- 30396547 TI - In vitro culture of ovarian preantral follicles: a promising alternative for preserving fertility in cancer patients. PMID- 30396548 TI - Facts often fail to overcome preconceived notions. AB - "Study the past if you would define the future." - Confucius. PMID- 30396549 TI - Influence of temperature, serum, and gonadotropin supplementation in short- and long-term organotypic culture of human immature testicular tissue. AB - OBJECTIVE: To study how temperature, serum, and gonadotropin supplementation affect the organotypic culture of human immature testicular tissue (ITT) in vitro. DESIGN: Experimental basic science study. SETTING: Reproductive biology laboratory. PATIENT(S): ITT from 4 boys with cancer that had testicular tissue cryopreserved as part of their fertility preservation treatment. INTERVENTION(S): In vitro organotypic culture of ITT, exposed to different temperatures (37 degrees C vs. 34 degrees C), serum (fetal bovine serum [FBS] vs. Knockout Serum Replacement [KOS]), and gonadotropin supplementation (with and without FSH and LH). MAIN OUTCOME MEASURE(S): Characterization of the tissue was performed at days 0, 14, and 70 with the use of reverse-transcription quantitative polymerase chain reaction, terminal deoxynucleotide transferase-mediated dUTP nick-end labeling, histologic analysis by means of hematoxylin-eosin staining, and immunohistochemical staining. Hormonal secretion was determined at days 3, 14, 28, and 70 by means of immunofluorescent assay. RESULT(S): The 37 degrees C conditions showed an accelerated loss of tubular morphology and higher intratubular apoptosis. KOS supplementation triggered the up-regulation of STAR, SOX9, DAZL, DDX4, PLZF, and UTF1, the percentage of SOX9+/androgen receptor (AR) positive mature Sertoli cells at day 14, and testosterone secretion. Gonadotropin supplementation increased the numbers of both undifferentiated UTF1+ spermatogonia and premeiotic VASA+/SYCP3+ spermatogonia at day 14, and the number of SOX9+ Sertoli cells at day 70. The low SOX9+/AR+ colocalization, the disorganized pattern of ZO-1, and the progressive decrease of antimullerian hormone secretion indicated inefficient Sertoli cell maturation in vitro. CONCLUSION(S): The 34 degrees C condition in KOS showed the best results for the survival of both spermatogonia and Sertoli cells. FSH/LH supplementation also improved long-term survival of Sertoli cells and the maturation of spermatogonia up to meiotic initiation in short-term culture. PMID- 30396550 TI - Supplementation of cryopreservation medium with TAT-Peroxiredoxin 2 fusion protein improves human sperm quality and function. AB - OBJECTIVE: To investigate the potential effects of TAT-PRDX2 protein supplementation to the cryopreservation medium on post-thaw sperm quality and function. DESIGN: In vitro prospective study. SETTING: Medical university hospital. PATIENT(S): Fifty normozoospermic, 50 asthenozoospermic, and 50 oligoasthenozoospermic men undergoing semen analysis for couple infertility. INTERVENTION(S): Each semen sample was divided into three aliquots: fresh, cryopreserved control (without additive), and cryopreserved with TAT-PRDX2 protein. MAIN OUTCOME MEASURE(S): Sperm motility, viability, mitochondrial potential, and DNA damage as well as reactive oxygen species (ROS) levels and lipid peroxidation were analyzed. Acrosome reaction and zona-free hamster oocyte penetration tests were performed to assess the fertilization ability of cryopreserved spermatozoa. RESULT(S): In normozoospermic and asthenozoospermic groups, the addition of 150 MUg/mL TAT-PRDX2 significantly reduced intracellular ROS and malondialdehyde levels and enhanced post-thaw sperm motility and viability when compared with the cryopreserved control of the respective groups but did not produce any significant protective effect in the oligoasthenozoospermic group. Mitochondrial potential was significantly increased, whereas DNA fragmentation was significantly decreased, after TAT-PRDX2 supplementation only in the asthenozoospermic group when compared with the cryopreserved control. Although the penetration rate and the penetration index were not markedly improved, TAT-PRDX2 supplementation obviously reduced spontaneous acrosome reaction and increased calcium ionophore-induced acrosome reaction in the normozoospermic and asthenozoospermic groups. CONCLUSION(S): TAT PRDX2 protein effectively exerted cryoprotective effects on spermatozoa by reducing intracellular ROS level and thereby improved post-thaw sperm quality and function, especially for asthenozoospermic samples. TAT-PRDX2 protein is a promising additive for developing a new and highly efficient semen cryoprotectant. PMID- 30396551 TI - International Committee for Monitoring Assisted Reproductive Technology: world report on assisted reproductive technology, 2011. AB - OBJECTIVE: To report the utilization, effectiveness, and safety of practices in assisted reproductive technology (ART) globally in 2011 and assess global trends over time. DESIGN: Retrospective, cross-sectional survey on the utilization, effectiveness, and safety of ART procedures performed globally during 2011. SETTING: Sixty-five countries and 2,560 ART clinics. PATIENT(S): Women and men undergoing ART procedures. INTERVENTION(S): All ART. MAIN OUTCOME MEASURE(S): The ART cycles and outcomes on country-by-country, regional, and global levels. Aggregate country data were processed and analyzed based on methods developed by the International Committee for Monitoring Assisted Reproductive Technology (ICMART). RESULT(S): A total of 1,115,272 ART cycles were reported for the treatment year 2011. Imputing data for nonreporting clinics, 1,643,912 cycles resulted in >394,662 babies, excluding People's Republic of China. The best estimate of global utilization including People's Republic of China is approximately 2.0 million cycles and 0.5 million babies. From 2010 to 2011, the number of reported aspiration and frozen ET cycles increased 13.1% and 13.8%, respectively. The proportion of women aged >=40 years undergoing nondonor ART increased from 23.2% in 2010 to 24.0% in 2011. As a percentage of nondonor aspiration cycles, intracytoplasmic sperm injection (ICSI) decreased slightly from 67.4% in 2010 to 66.5% in 2011. The IVF/ICSI combined delivery rates per fresh aspiration and frozen ET cycles were 19.8% and 21.4%, respectively. In fresh nondonor cycles, single ET increased from 30.0% in 2010 to 31.4% in 2011, whereas the average number of transferred embryos decreased from 1.95 in 2010 to 1.91 in 2011-again with wide country variation. The rates of twin deliveries after fresh nondonor transfers decreased from 20.4% in 2010 to 19.6% in 2011; the triplet rate decreased from 1.1%-0.9%. In frozen ET cycles performed in 2011, single ET was 51.6%, with an average of 1.59 embryos transferred and twin and triplet rates were 11.1% and 0.4%, respectively. The cumulative delivery rate per aspiration increased from 27.1% in 2010 to 28.0% in 2011. Fresh IVF/ICSI carried a perinatal mortality rate per 1,000 births of 21.0 in 2010 and 16.3 in 2011. This compared with a perinatal mortality rate after frozen ET of 14.6 per 1,000 births in 2010 and 8.6 in 2011. The data presented depend on the quality and completeness of data submitted by individual countries. This report covers approximately two-thirds of'world ART activity. CONCLUSION(S): Global ART utilization, effectiveness, and safety increased between 2010 and 2011. PMID- 30396552 TI - National survey of the Society for Assisted Reproductive Technology membership regarding insurance coverage for assisted reproductive technologies. AB - OBJECTIVE: To assess the attitudes of Society for Assisted Reproductive Technology (SART) members regarding expanding insurance coverage for patients seeking assisted reproductive technologies (ART) and identify some of the factors that may influence such attitudes. DESIGN: An anonymous online 14-question survey of SART membership; 1,556 surveys were sent through the SART Research Portal from June to December 2017. Questions were incremental in scope, beginning with expanding insurance coverage for ART for vulnerable populations (e.g., fertility preservation for cancer, couples with same recessive gene, fertility preservation for transgender individuals) to extending coverage to include patients who were uninsured for ART. Additional questions assessed attitudes about assuming some fiscal responsibility if mandated insurance were contingent on elective single embryo transfer (eSET) and lower charges in anticipation of increased number of cases. SETTING: Not applicable. PATIENT(S): Not applicable. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Specific response to 14 survey questions. RESULT(S): The overall response rate was 43.4% (675/1,556). A large majority (>95%) favored insurance for fertility preservation for cancer patients and for avoidance of genetic disorders; 62.3% were supportive of infertility insurance coverage for transgender patients; 78% supported expanding insurance for the broadest segment of the general uninsured population; 76.7% supported expanding insurance contingent on eSET; and 51.3% would consider expanding insurance contingent on lowering charge per cycle in general, but only 23% responded as to what lower charge would be acceptable. Three of four factors were shown by multivariable logistic regression to be predictive of attitudes willing to expand insurance: practice setting (academic > hybrid > private), practicing in a mandated state, and higher annual volume of cases (>500 cycles); these had significant increased adjusted odds ratios ranging from 1.7 to 2.9. A fourth factor, the professional role one had in the practice, was not found to be of significant predictive value. CONCLUSION(S): The great majority of respondents were supportive of expanding insurance for specific segments of vulnerable populations with special needs and for the population who are presently uninsured. Furthermore, the majority of respondents would consider expanding insurance coverage contingent on age-appropriate eSET but have concerns about reduced reimbursement. Those most likely to be willing to expand insurance are those who practice in an academic setting or a mandated state and/or have a high annual volume of cases. PMID- 30396553 TI - The role of immunotherapy in in vitro fertilization and recurrent pregnancy loss: a systematic review and meta-analysis. AB - OBJECTIVE: To study the current evidence on the role of immunotherapy in IVF and in the management of recurrent pregnancy loss (RPL). DESIGN: Systematic review and meta-analysis. SETTING: A literature search was performed using MEDLINE, PUBMED, CINAHL, and EMBASE until May 2017. Only randomized controlled trials were included, and a meta-analysis was carried out where appropriate. PATIENT(S): Women undergoing IVF treatment with or without a history of recurrent implantation failure and women with idiopathic RPL. INTERVENTION(S): Assessment of the efficacy of commonly used immunomodulators such as IV use of [1] immunoglobulin, [2] lymphocyte immunotherapy and [3] intralipid; intrauterine infusion of [4] granulocyte colony-stimulating factor and [5] peripheral blood mononuclear cells; subcutaneous administration of [6] TNF-alpha inhibitors, [7] leukaemia inhibitory factor; and oral administration of [8] glucocorticoids. MAIN OUTCOME MEASURE(S): The primary outcomes were live birth rate and miscarriage rate; secondary outcome was clinical pregnancy rate. RESULT(S): Of the 7,226 publications identified, 53 were selected during the initial screening; 30 satisfied the selection criteria and were included in this review. CONCLUSION(S): The available medical literature shows controversial results about the role of immunotherapy when used for improving reproductive outcomes. This study did not show a role for immunotherapy in improving the live birth rate in women undergoing IVF treatment or in the prevention of idiopathic RPL. Currently, immunotherapy should be used in the context of research and should not be used in routine clinical practice to improve reproductive outcomes. PMID- 30396554 TI - Patient experience in a randomized trial of a weekly progesterone vaginal ring versus a daily progesterone gel for luteal support after in vitro fertilization. AB - OBJECTIVE: To assess patient experience and convenience of using progesterone vaginal ring (VR) versus vaginal gel for women requiring luteal phase support during in vitro fertilization (IVF). DESIGN: Post hoc analysis of a prospective, randomized, single-blind, multicenter, phase 3 clinical trial. SETTING: Twenty two U.S. IVF centers. PATIENT(S): Women undergoing IVF (N = 1,297). INTERVENTION(S): Randomization to weekly VR or daily gel the day after egg retrieval for up to 10 weeks, with fresh embryo transfer IVF per site-specific procedures. MAIN OUTCOME MEASURE(S): Patient satisfaction questionnaire completed at final study visit. RESULT(S): In the women who were taking >=1 dose of either VR (n = 647) or gel (n = 650), >97% reported that learning to use the formulation, remembering to take it at the correct time, and using it as prescribed was "easy" or "somewhat easy." More VR than gel users reported noninterference with daily activity (93.3% vs. 74.7%, P<.001), sexual comfort (80.3% vs. 67.8%, P<.001), and sexual desire (73.8% vs. 61.8%, P<.001), as well as not being bothered during sexual intercourse (66.9% vs. 39.2%, P<.001). More gel than VR users reported no difficulty with application (97.4% vs. 80.9%, P<.001). Among women who had previously used progesterone during IVF, more VR users than gel users preferred their currently assigned treatment to their previous treatment (91.4% vs. 83.0%, P=.03). CONCLUSION(S): Weekly progesterone VR and daily progesterone gel were easy to use, with limited impact on quality of life. Overall, the VR appeared to interfere less with daily life, social activities, and sexual activity although the gel was less difficult or stressful to apply. CLINICAL TRIAL REGISTRATION NUMBER: NCT00615251. PMID- 30396555 TI - Singleton fetal growth kinetics depend on the mode of conception. AB - OBJECTIVE: To study the impact of in vitro fertilization, with or without intracytoplasmic sperm injection (IVF/ICSI), frozen-embryo transfer (FET), and intrauterine insemination (IUI) on fetal growth kinetics throughout pregnancy and to compare the different modes of conception. DESIGN: Retrospective cohort study. SETTING: University. PATIENT(S): A total of 560 singleton pregnancies were included (96 IVF, 210 ICSI, 121 FET, and 133 IUI). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): We compared crown-rump length (CRL) at the first trimester (T1: 11-13 weeks of gestation [WG] + 6 days), estimated fetal weight (EFW) at the second (T2: 21-23 WG + 6 days) and third (T3: 31-33 WG + 6 days) trimesters, and birth weight (BW) z-scores with those in the reference curves (Papageorghiou for T1, and Ego M2 for T2, T3, and birth). Multivariate analyses were performed. RESULT(S): For T1, the CRL was longer than the reference curve whatever the assisted reproductive technique (ART). For T2, EFW was significantly greater for all groups compared with the reference curve, and for T3 only FET singletons had a greater EFW. ICSI, IVF, and IUI singletons had a significantly lower BW compared with reference curves. For all ART fetuses, growth kinetics differed from T2. Only FET fetuses maintained their significantly above-reference growth values. The proportion of fetuses for which at least one period of growth loss was observed from T2 to birth was higher after IVF, ICSI, and IUI than after FET. CONCLUSION(S): For the first time, we have highlighted that fetal growth kinetics differed from T2 depending on the ART protocols used. They could have an impact on trophoblastic invasiveness and might lead to long-term health effects. PMID- 30396556 TI - Experimental pain tolerance is decreased and independent of clinical pain intensity in patients with endometriosis. AB - OBJECTIVE: To investigate alterations in tactile, pain thresholds and pain tolerance thresholds in patients with endometriosis using a multimodality approach. DESIGN: Cross-sectional study. SETTING: Multidisciplinary referral center. PATIENT(S): Women with proven endometriosis (N = 35) and healthy controls (N = 38). INTERVENTION(S): Pain processing was tested using quantitative sensory testing (QST) to investigate sensation, pain, and pain tolerance thresholds for thermal, electrical, and pressure stimuli. MAIN OUTCOME MEASURE(S): Differences in QST measures in patients with endometriosis and in healthy controls on the endometriosis site and control sites, and the association between QST outcomes and patient characteristics. RESULT(S): We observed a significantly decreased pain tolerance in patients with endometriosis, independent of clinical pain intensity or revised American Society for Reproductive Medicine stage, compared with healthy controls. CONCLUSION(S): Increasing knowledge concerning mechanisms underlying the pain of women with endometriosis creates opportunities to develop new treatment options. More attention should be paid not only to treat endometriosis in a surgical or pharmacologic way, but also to desensitize by pain education or cognitive therapy. PMID- 30396557 TI - Control of endometriosis-associated pain with etonogestrel-releasing contraceptive implant and 52-mg levonorgestrel-releasing intrauterine system: randomized clinical trial. AB - OBJECTIVE: To assess the efficacy of an etonogestrel (ENG)-releasing contraceptive implant or the 52-mg levonorgestrel-releasing intrauterine system (LNG-IUS) in the control of endometriosis-associated pelvic pain. DESIGN: Noninferiority randomized clinical trial in which women with endometriosis were assigned to use an ENG implant (experimental treatment) or an LNG-IUS (active comparator). Monthly follow-up visits were conducted up to 6 months. SETTING: University teaching hospital. PATIENT(S): One hundred three women, with endometriosis-associated chronic pelvic pain, dysmenorrhea, or both for more than 6 months. In cases of deep endometriosis, vaginal ultrasonography and magnetic resonance imaging were used as additional diagnostic tools. INTERVENTION(S): The ENG implant or the LNG-IUS were inserted within the first 5 days of the menstrual cycle. MAIN OUTCOME MEASURE(S): Daily scores of noncyclic pelvic pain and dysmenorrhea were evaluated using a daily visual analogue scale. Health-related quality of life was evaluated using the Endometriosis Health Profile-30 questionnaire at baseline and up to 6 months. Bleeding patterns were assessed daily from a menstrual calendar. RESULT(S): Both contraceptives improved significantly the mean visual analogue scale endometriosis-associated pelvic pain and dysmenorrhea, without significant differences between treatment group profiles. Health-related quality of life improved significantly in all domains of the core and modular segments of the Endometriosis Health Profile-30 questionnaire, with no difference between both treatment groups. The most common bleeding patterns at 180 days of follow-up were amenorrhea and infrequent bleeding and infrequent bleeding and spotting among ENG implant and LNG-IUS users, respectively. CONCLUSION(S): In this noninferiority study both contraceptives improved significantly pelvic pain, dysmenorrhea, and health related quality of life in endometriosis. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov under number NCT02480647. PMID- 30396558 TI - Organophosphate flame-retardant metabolite concentrations and pregnancy loss among women conceiving with assisted reproductive technology. AB - OBJECTIVE: To evaluate whether urinary concentrations of organophosphate flame retardant (PFR) metabolites are associated with pregnancy loss among women conceiving with assisted reproductive technology (ART). DESIGN: Prospective preconception cohort of subfertile women. SETTING: Academic hospital fertility center in Boston, Massachusetts. PATIENT(S): A total of 155 women conceiving 179 pregnancies with ART. INTERVENTION(S): None. Mean exposure to each of five PFR metabolites was estimated by averaging the specific-gravity adjusted natural log concentrations from two urine samples collected during the ART cycle of conception. MAIN OUTCOME MEASURE(S): Adjusted risk ratios (RRs) and 95% confidence intervals (CIs) for biochemical and total pregnancy loss (all losses <20 weeks' gestation) by quartiles of PFR metabolite concentrations were estimated using a repeated measures log-binomial model, accounting for multiple pregnancies per woman. RESULT(S): Of the 179 pregnancies, 31% ended in pregnancy loss (12% in biochemical loss). Among the three metabolites with high detection frequency [bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), and isopropylphenyl phenyl phosphate (ip-PPP)], an increased risk of biochemical loss was observed for women with DPHP concentrations in the fourth vs. first quartile (RR 1.64; 95% CI 0.61-4.39). Also found was an elevated risk of biochemical pregnancy loss among women in the highest quartile of the molar sum of urinary PFR metabolites compared with the lowest (RR 1.89; 95% CI 0.64 5.58). Urinary concentrations of ip-PPP and BDCIPP were not associated with either outcome. CONCLUSION(S): Among subfertile women, urinary DPHP metabolite concentrations measured during the ART cycle of conception may be associated with early pregnancy loss. Although this study is uniquely designed to investigate early markers of pregnancy success and maintenance, the small sample size likely contributed to imprecision. Given their increasing use as replacement chemicals for traditional flame retardants, exposure to PFRs may increase, and more studies will be needed to investigate their potential to impact pregnancy and reproduction. PMID- 30396559 TI - Dietary factors and serum antimullerian hormone concentrations in late premenopausal women. AB - OBJECTIVE: To study the associations between dietary factors and circulating antimullerian hormone (AMH) concentrations among late premenopausal women. DESIGN: AMH concentrations were measured in serum samples collected at enrollment from 296 women (aged 35-45 years) in the Sister Study cohort. Usual dietary intakes in the past 12 months were assessed using a validated food frequency questionnaire. Dietary exposures of interest included macronutrients, dietary fat subtypes, fiber, and glycemic index. Multivariable linear regression was used to evaluate associations between dietary variables and serum AMH concentrations. We also used nutrient density models to examine isocaloric replacement of macronutrients. SETTING: Not applicable. PATIENTS: Women aged 35-45 years. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Serum AMH concentrations in nanograms per milliliter (ng/mL). RESULTS: AMH concentrations were positively associated with percentage of energy from carbohydrates (beta per 5% calories = 0.141 [95% CI 0.023, 0.259]; P trend = .019), and inversely associated with percentage of energy from fat (beta per 5% calories = -0.152 [95% CI -0.299, 0.004]; P trend = .044). In analyses of dietary fat subtypes, AMH decreased with increasing monounsaturated fatty acids (P trend = .082) and polyunsaturated fatty acids (P trend = .043), particularly omega-6 fatty acids (P trend = .044), whereas no strong trend was observed for saturated fatty acids. Protein and alcohol intake were not strongly associated with AMH. CONCLUSIONS: Our cross sectional analyses in a sample of late premenopausal women suggest that dietary fat intake may be inversely associated with circulating AMH concentrations. Further research in prospective studies is warranted to evaluate dietary factors as potential modifiers of ovarian reserve. PMID- 30396560 TI - A sonographic classification of adenomyosis: interobserver reproducibility in the evaluation of type and degree of the myometrial involvement. AB - OBJECTIVE: To study the interobserver reproducibility of our new ultrasonographic mapping system to define the type and extension of uterine adenomyosis. DESIGN: Interobserver study involving two observers with different medical backgrounds and gynecological ultrasound experience. SETTING: University hospital. PATIENTS: Seventy consecutive women who underwent transvaginal ultrasound for suspected endometriosis, pelvic pain, heavy menstrual bleeding, and infertility. INTERVENTION: Two operators (observers A and B), who were blinded, independently reviewed the ultrasound videos offline, assessing the type of adenomyosis and the severity of the disease. Diagnosis of adenomyosis was made when typical ultrasonographic features of the disease were observed at the examination. Adenomyosis was defined as diffuse, focal, and adenomyoma according to the ultrasonographic characteristics. The severity of adenomyosis was described using a new schematic scoring system that describes the extension of the disease considering all possible ultrasound adenomyosis features. MAIN OUTCOME MEASURES: Reproducibility of the new mapping system for adenomyosis and rate agreement between two operators. RESULTS: Multiple rate agreements to classify the different features and the score of adenomyosis (diffuse, focal adenomyoma, and focal or diffuse alteration of junctional zone) ranged from substantial to almost perfect (Cohen kappa = 0.658 - 1) except for adenomyoma score 4 (one or more adenomyomas with the largest diameter >40 mm) in which interobserver agreement was moderate (kappa = 0.479). CONCLUSION: Our new scoring system for uterine adenomyosis is reproducible and could be useful in clinical practice. The standardization of the transvaginal approach and of the sonographer training represent a crucial point for a correct diagnosis of myometrial disease. PMID- 30396562 TI - Changes in serum antimullerian hormone levels in patients 6 and 12 months after endometrioma stripping surgery. AB - OBJECTIVE: To investigate the impact of laparoscopic endometrioma cystectomy on the ovarian reserve and to identify the most important factors that predict the ovarian reserve in patients with endometriomas. DESIGN: Prospective study. SETTINGS: Endoscopy unit of a general hospital. PATIENT(S): Fifty-four patients with unilateral (n = 37) and bilateral endometriomas (n = 17). INTERVENTIONS(S): The serum antimullerian hormone (AMH) concentration was assessed before surgery and at 6 and 12 months after surgery. MAIN OUTCOME MEASURE(S): The primary outcome was the damage to the ovarian reserve, as assessed by the serum AMH concentration. Secondary end points were the persistence or recovery of ovarian damage after 1 year. RESULT(S): AMH concentrations decreased after the laparoscopic excision of cystic ovarian endometriomas. Before surgery and at 6 and 12 months after surgery, the concentrations were, respectively 3.07, 1.29, and 1.46 ng/mL. In the unilateral group, the median AMH levels were 3.31, 1.43, and 1.72 ng/mL, and in the bilateral group the levels were 2.55, 0.98, and 0.89 ng/mL. The serum AMH concentrations thus decreased by 53.27 +/- 38.2% and 49.43 +/- 38.3% at 6 and 12 months after cystectomy, respectively. CONCLUSION(S): In patients with endometriomas, the decrease in ovarian reserve occurs immediately after the excision of the endometrioma. Significant predictors of AMH values at 6 and 12 months after surgery include the baseline AMH level, patient age, and bilateral endometriomas. PMID- 30396561 TI - Stage-specific modulation of antimullerian hormone promotes primate follicular development and oocyte maturation in the matrix-free three-dimensional culture. AB - OBJECTIVE: To study whether follicular growth and oocyte maturation can be improved by antimullerian hormone (AMH) modulation at specific stages of follicular development. DESIGN: Primary and secondary follicles were cultured in a matrix-free system and were assigned to the control group and the group with AMH supplementation during the preantral stage and neutralizing AMH antibody addition during the antral stage. SETTING: National primate research center. ANIMAL(S): Adult, female rhesus macaques (Macaca mulatta). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Follicle survival, growth, steroid and paracrine factor production, and oocyte competence were evaluated. Follicles were assessed for expression of genes that are critical for gonadotropin signaling, cumulus cell glycolysis, and oocyte quality. RESULT(S): Primary follicles formed "organoids" and developed to the antral stage in group culture. AMH exposure during the preantral stage increased organoid diameters. Oocytes from the AMH-treated organoids had greater diameters and matured to the metaphase II (MII) stage. Secondary follicles developed to the antral stage during individual culture. The AMH exposure during the preantral stage and AMH antibody treatment during the antral stage increased follicle diameters, vascular endothelial growth factor and follistatin production, differentiation factor 9 expression, and oocyte diameters. The MII oocytes from the AMH-modulated group developed to the morula stage after IVF, with one to the blastocyst stage. CONCLUSION(S): AMH supplementation at the preantral stage and depletion at the antral stage enhanced primate follicular development and oocyte competence in vitro. The improved embryonic development supports in vitro follicle maturation as a potential approach for fertility preservation. PMID- 30396563 TI - Autotransplantation of fragmented ovarian cortical tissue: a laparoscopic demonstration. AB - OBJECTIVE: To describe and demonstrate a simple and secure procedure for laparoscopic autotransplantation of fragmented ovarian cortical tissue in women with diminished ovarian reserve as part of in vitro activation (IVA) of ovarian follicles. DESIGN: Step-by-step video explanation of the surgical procedure with still pictures and surgical video clips to demonstrate the detailed technique. SETTING: Fertility clinic and obstetrics and gynecology department at a university hospital. PATIENT(S): Women with idiopathic diminished ovarian reserve and indication for in vitro fertilization (IVF), aged 25 to 39 years with an antral follicle count bilaterally of <=5, antimullerian hormone level of <=5 pmol/L, and two ovaries. INTERVENTION(S): The laparoscopic autotransplantation consists of six steps: [1] obtaining ovarian cortical biopsy samples, [2] preparing the peritoneal pocket, [3] fragmenting the ovarian cortical tissue into pieces of approximately 1 mm3, [4] installing the tissue fragments into a catheter, [5] transplanting the tissue fragments into the peritoneal pocket, and [6] closing the peritoneal pocket with a surgical clip. After the procedure, the patients are evaluated with blood samples and ultrasound scans followed by controlled ovarian stimulation. Ethics committee approval was obtained. MAIN OUTCOME MEASURE(S): Feasibility of a six-step laparoscopic autotransplantation procedure using fragmented ovarian cortical tissue. RESULT(S): A simple, fast laparoscopic procedure for taking biopsy samples and autotransplanting cortical tissue fragments in an all-in-one procedure ensures the rapid handling and correct placement of the small tissue fragments. The procedure is performed in an outpatient setting with an operation time of 1 hour. We have performed this procedure on 20 patients with no complications. CONCLUSION(S): In vitro activation is a new, developing option for women in fertility treatment who have diminished ovarian reserve. Fragmentation of murine ovarian tissue has shown to suppress the Hippo pathway, thereby initiating proliferation and growth. This surgical procedure resembles that used when transplanting pieces of frozen-thawed ovarian tissue for fertility restoration, but the fragmented ovarian tissue is only 1 mm3, which makes it difficult to transplant. Until now no surgical procedures for transplanting small IVA fragments of cortical tissue has been published. With this video we report in detail a simple way of autotransplanting small fragments of IVA cortical tissue using what is already accessible in the operating theater. Among the many advantages of this procedure are its short duration (1 hour) and outpatient setting, which enable fast recovery and minimal postoperative pain. The procedure also allows fast handling and minimal manipulation of the tissue (limited to the fragmentation). The effect of autotransplantation of fragmented tissue in women with diminished ovarian reserve is currently being studied in ongoing trials. If the technique is combined with chemical IVA, a better outcome may be seen. PMID- 30396564 TI - Oocyte donation: lessons from the past, directions for the future. AB - Oocyte donation has its origins in the clandestine use of donated sperm more than 140 years ago. Since first described in 1983, oocyte donation has resulted in more than 50,000 births in the United States alone and today now accounts for more than 10% of all IVF cycles performed yearly in the United States. The use of donated oocytes has changed the human reproductive landscape, challenging the traditional norms of conception and parenthood. Oocyte donation has also provided a unique scientific model that separates the egg from the uterus, allowing the independent study of each in normal physiologic and pathological conditions and providing insights into the fundamental aspects of reproduction, cell biology, and genetics. This Views and Reviews takes us through the historical development of oocyte donation, its scientific insights, and its application to daily practice and management, as well as insights into what the future may hold for this field. PMID- 30396565 TI - Revisiting the early days of oocyte and embryo donation: relevance to contemporary clinical practice. AB - Oocyte and embryo donation have evolved significantly since they were first introduced to treat human infertility nearly four decades ago. Social, ethical, and regulatory challenges to oocyte and embryo donation have generated controversy and invited public scrutiny. However, oocyte and embryo donation continued to provide physicians the opportunity to treat the "untreatable." Undoubtedly, clinical practices related to oocyte and embryo donation have greatly changed over the years. Yet, they have endured as viable choices of treatment for many patients and their physicians, remained popular owing to their versatility, and, perhaps most importantly, provided consistently high pregnancy success rates. PMID- 30396566 TI - Oocyte donation: insights gleaned and future challenges. AB - With the first successful report of an IVF pregnancy achieved via donor oocytes in 1984, the applications of assisted reproductive technology (ART) were further expanded to include women unable to conceive with their own oocytes. Today, oocyte donation makes up an increasingly large percentage of all ART cycles worldwide. Oocyte donation presents several unique challenges to clinicians as two separate interests, those of the donor and those of the recipient, must be represented. These challenges include successful preparation of the endometrium in donor oocyte recipients, the synchronization of donor/recipient cycles, and the optimization of ovarian stimulation while maximizing donor safety. Facing these challenges has not only allowed for the creation of successful donor egg programs but has also provided insights into many aspects of ART. Much of what we know about the window of implantation, frozen ET procedures, triggering of oocyte maturation, and fertility preservation has been learned through experience and investigations with donor egg cycles. Not only has oocyte donation, through its optimization and wide use, provided new treatment opportunities for patients, it has also become a critical scientific tool to study many aspects of menstrual cycle dynamics and implantation. Concomitantly, with its increased efficiency, it has also raised several clinical and ethical challenges. PMID- 30396567 TI - Innovations in assisted reproductive technologies: impact on contemporary donor egg practice and future advances. AB - Innovations in assisted reproductive technologies (ART) have driven progress in the donor egg field since the birth of the first baby derived from a donor egg in 1983. Over time, donor oocytes have become an increasingly used option for patients unable to conceive with autologous oocytes. In donor egg, the unique separation of the oocyte source and recipient uterus has created a model that has propelled advances in ART. Progressive ART innovations that have optimized the oocyte donor and resulting embryo include the following: evaluation of ovarian reserve, controlled ovarian hyperstimulation regimens that reduce the risk of ovarian hyperstimulation syndrome, blastocyst culture, oocyte cryopreservation, and preimplantation genetic testing. For donor egg recipients, methods to optimize the endometrium to maximize implantation include endometrial receptivity testing, immunologic donor-recipient matching, and increased understanding of the uterine microbiome. PMID- 30396568 TI - Nuclear import of transcriptional corepressor BCOR occurs through interaction with karyopherin alpha expressed in human periodontal ligament. AB - Mutations in the gene encoding BCL-6 corepressor (BCOR) are responsible for oculofaciocardiodental (OFCD) syndrome, which is a rare X-linked dominant disorder characterized by radiculomegaly of permanent teeth as the most typical symptom. To function as a transcriptional corepressor, BCOR needs to enter the nucleus; however, the molecular pathway for its nuclear translocation during dental root formation remains unclear. The purpose of this study was to determine the mechanism underlying BCOR transport into the nucleus. Our results showed that human periodontal ligament (PDL) cells expressed karyopherin alpha (KPNA)2, KPNA4, and KPNA6 belonging to a family of nuclear import proteins, which interacted with BCOR in the immunoprecipitation assay. Site-directed mutagenesis targeting the two nuclear localization signals (NLSs) within BCOR reduced its nuclear translocation; however, co-expression of KPNA2, KPNA4, or KPNA6 with BCOR carrying a previously described mutation which eliminated one of the two NLSs significantly increased nuclear accumulation of the mutant BCOR, indicating participation of KPNA in BCOR nuclear translocation. Comparative expression profiling of PDL cells isolated from normal and OFCD patients revealed significant downregulation of SMAD4, GLI1, and nuclear factor 1-C (NFIC) mRNA expression, suggesting that BCOR mutations cause hyperactive root formation in OFCD syndrome by inhibiting SMAD4-Hedgehog-NFIC signaling implicated in dental root development. Our study contributes to understanding of the mechanisms providing nuclear import of BCOR during root formation. PMID- 30396569 TI - Cdh1 degradation is mediated by APC/C-Cdh1 and SCF-Cdc4 in budding yeast. AB - Cdh1, a substrate-recognition subunit of anaphase-promoting complex/cyclosome (APC/C), is a tumor suppressor, and it is downregulated in various tumor cells in humans. APC/C-Cdh1 is activated from late M phase to G1 phase by antagonizing Cdk1-mediated inhibitory phosphorylation. However, how Cdh1 protein levels are properly regulated is ill-defined. Here we show that Cdh1 is degraded via APC/C Cdh1 and Skp1-Cullin1-F-box (SCF)-Cdc4 in the budding yeast Saccharomyces cerevisiae. Cdh1 degradation was promoted by forced localization of Cdh1 into the nucleus, where APC/C and SCF are present. Cdk1 promoted APC/C-Cdh1-mediated Cdh1 degradation, whereas polo kinase Cdc5 elicited SCF-Cdc4-mediated degradation. Thus, Cdh1 degradation is controlled via multiple pathways. PMID- 30396570 TI - Imatinib mesylate elicits extracellular signal-related kinase (ERK) activation and enhances the survival of gamma-irradiated epithelial cells. AB - Imatinib mesylate, commercially known as Gleevec/Glivec, is the first targeted anticancer drug that inhibits activity of the tyrosine kinases, c-ABL, c-KIT, and PDGFR. A number of studies have shown that treatment with imatinib mesylate elicits extracellular signal-related kinase (ERK) activation, which, in turn, has been shown to confer radioresistance. Here, we investigated whether treatment with imatinib mesylate protects skin-derived epithelial cells, including normal keratinocytes, immortalized HaCaT and A431 cancer cell lines, from the effects of gamma-radiation. ERK activation was detected 30 min after imatinib mesylate treatment in all three cell lines. In cells exposed to gamma-irradiation in the presence of imatinib mesylate, this activation of ERK was associated with a reduction in radiation-induced apoptosis and enhanced cell survival. Similar effects of imatinib mesylate treatment were observed following gamma-irradiation of a three-dimensional human skin culture system that reproduces a fully differentiated epithelium. Collectively, our findings provide the evidence of a protective effect of imatinib mesylate against the effects of gamma-irradiation on epithelial-derived cells, regardless of their malignancy status. PMID- 30396571 TI - Overview of Lead Management. AB - Lead management describes a comprehensive approach to cardiac implantable electronic device lead utilization, encompassing lead and device selection, vascular access, implant techniques, handling lead failures and recalls, managing infectious and other complications, and performing device and lead extraction. Device and lead selection should be based on the latest guidelines and the available data to choose the optimal device system for each patient. Lead extraction is a highly specialized procedure and should be carried out by a team of personnel extensively trained in the procedure at centers with cardiac surgical support. PMID- 30396572 TI - Vein Management for Cardiac Device Implantation. AB - Transvenous approaches for pacemaker and defibrillator lead insertion offer numerous advantages over epicardial techniques. Although the cephalic, axillary, and subclavian veins are most commonly used in clinical practice, they each offer their own set of advantages and disadvantages that leave their usage dependent on patient anatomy and physician preference. Alternative methods using the upper and lower venous circulation have been described when these veins are not available or practical for lead insertion. Until current technology is superseded by leadless pacing systems, the search for the optimal lead insertion technique continues. PMID- 30396573 TI - Monitoring for and Diagnosis of Lead Dysfunction. AB - The predominant structural mechanisms of transvenous lead dysfunction (LD) are conductor fracture and insulation breach. LD typically presents as an abnormality of electrical performance; the earliest sign usually is either oversensing or out of-range pacing or shock impedance. Accurate diagnosis of LD requires discriminating patterns of oversensing and impedance trends that are characteristic of LD from similar patterns that occur in other conditions. Implantable cardioverter-defibrillators have advanced features to detect and mitigate the consequences of LD; these features operate both independently and in conjunction with remote monitoring networks. PMID- 30396574 TI - Infection Management. AB - Cardiovascular implantable electronic devices (CIEDs) and the indications for their use have significantly risen over the past decades to include patients who are older with more medical comorbidities. Predictably, the rates of CIED infection have increased substantially. CIED infection is associated with high morbidity, mortality, and financial costs. This article discusses the appropriate management of CIED infections, which is imperative to limit the problems associated with infection. PMID- 30396575 TI - Nomenclature, Definitions, and Metrics of Cardiovascular Implantable Electronic Device Lead Management. AB - Quality has a foundation that consists of the nomenclature, definitions, and metrics of success, failure, and complications. There is now a firm foundation for reporting outcomes and for making clinical decisions with patients and their families. This has developed from an international consensus, ratified by the four continental heart rhythm societies and by the overlapping cardiovascular, surgical, anesthesiology, and infectious disease societies. Reporting of outcomes, using these metrics and definitions, is now mandated to promote transparency and facilitate clinical decision making with patients. The best path to accomplishing this goal is to participate in a center-specific or multicenter registry. PMID- 30396576 TI - Anesthesia Considerations for Lead Extraction. AB - The role of the anesthesiologist in lead extraction procedures is multifaceted and highlights the collaborative, multidisciplinary teamwork needed to ensure patient safety and procedural success in these complex cases. Thorough preoperative evaluation and identification of high-risk characteristics enable the anesthesiologist to tailor a comprehensive intraoperative and postoperative care plan for each case. Institutional practices may vary but anesthetic management typically includes general anesthesia with an endotracheal tube, invasive measurement of arterial blood pressure, vascular access for rapid volume expansion, echocardiographic monitoring, preparation for blood transfusion, and initiation of cardiopulmonary bypass in the event of an emergency. PMID- 30396577 TI - Lead Extraction Imaging. AB - Lead extraction procedures have a low but real risk of major complications, such as superior vena cava tear and cardiac tamponade. Complications during lead removal are commonly related to lead binding sites, lead malposition, and lead perforation. Lead extraction imaging may indicate lead vascular binding sites, lead position, and perforation. Several imaging modalities are available, including chest radiograph, cardiac computed tomography, and echocardiography. The information provided by various imaging modalities will help assess the challenges of each lead extraction procedure and allows for better preprocedure planning. PMID- 30396578 TI - A Practical Approach to Lead Removal: Transvenous Tools and Techniques. AB - Removal of cardiovascular implantable electronic devices (CIED) is an important and growing field when managing patients presenting with device infections, need for upgrades, and lead failure. The complex skillset of transvenous lead removal is in high demand along with increasing numbers of implanted CIEDs. A systematic and comprehensive approach to this field, including knowledge of all available tools and vascular access techniques is essential for successful outcomes. This article serves as a practical resource presenting tools and techniques of transvenous lead extraction to help refine and master one's skill. PMID- 30396579 TI - Cardiac and Vascular Injuries Sustained During Transvenous Lead Extraction. AB - The rise in indications for cardiac implantable electronic devices has necessitated the development of tools for removal of the electrodes that connect the heart to these externally located pacemakers and defibrillators. After implant of a cardiac electrode, variable but progressive fibrous adhesion occurs. Removal of these adhesions can cause devastating complications with high risk of mortality if not treated surgically in a highly expeditious and appropriate manner. This article describes the incidence, risk factors, and diagnosis of these injuries followed by discussion of recent evidence for use of superior vena cava balloon occlusion, and conventional surgical repair of these injuries. PMID- 30396580 TI - Surgical and Hybrid Lead Extraction. AB - Surgical and hybrid lead extraction has developed considerably over the past several decades. Although transvenous lead extraction is the standard approach to remove infected or malfunctioning cardiac implantable electronic device leads, surgical approaches may be necessary in complex cases not amenable to transvenous lead extraction or in cases that involve concomitant pathologies, such as tricuspid valve regurgitation. We describe our experience with 4 minimally invasive surgical approaches to lead extraction as well as our experience with hybrid open heart surgery and transvenous lead extraction as an option for patients who present with concomitant conditions. PMID- 30396581 TI - Reimplantation After Lead Removal. AB - The number of implanted cardiovascular implantable electronic devices (CIEDs) has increased significantly in the last 30 years, which has led to an upsurge in CIED complications, such as infection and lead malfunction requiring CIED extraction. The decision-making process of CIED reimplantation requires meticulous planning that includes careful consideration of several aspects: the reason for extraction, the indication for CIED reimplantation, patients' wishes, timing of reimplantation, the need for a bridging device, and the type and location of device to be reimplanted. In this article, the authors review this decision making process and the necessary steps to achieve optimal patient outcomes. PMID- 30396582 TI - Venoplasty and Stenting. AB - With expanding indications for cardiac resynchronization therapy and increased survival of patients with cardiovascular disease, the need for lead addition or revision in the presence of an existing implantable electronic device is likely to increase. Partial or complete venous occlusion is frequently encountered and can be a significant barrier to successful procedural outcomes. Percutaneous options, including subclavian venoplasty, can reduce the need for significantly more invasive and morbid procedures and can readily be learned by the implanting physician. Additional invasive techniques, such as coronary sinus venoplasty and stenting, can be useful in cases of difficult left ventricular lead placement. PMID- 30396583 TI - Palliation and Nonextraction Approaches. AB - Although definitive therapy for infected cardiac implantable electronic device systems requires removal of all hardware in the infected areas with extraction of intravascular components as well, there are situations where extraction is not available or appropriate. Palliative procedures and chronic suppressive antibiotics may be used in these cases. There are also options that may in some cases result in long-term freedom from infection. PMID- 30396584 TI - Lead Management. PMID- 30396585 TI - Lead Management for Electrophysiologists. PMID- 30396586 TI - Identification and control of dynamical systems using different architectures of recurrent fuzzy system. AB - Fuzzy logic based systems are very widely used for modeling and control of complex non-linear, plants. Fuzzy systems require the knowledge about the structure of the dynamic plant in order to achieve fruitful results. Recurrent Fuzzy systems (RFS) are a variation of fuzzy systems and have the ability to model and control dynamic plants without using the information about the structure of the plant. This paper presents identification and control of non linear dynamical systems using two different architectures of recurrent fuzzy system (RFS). It highlights the importance of RFS over the conventional type-1 fuzzy based system. The objective of system identification as well as control has been achieved using both the architectures of RFS and the simulation results clearly show their efficiency. This paper also highlights yet another advantage of RFS over the conventional type-1 fuzzy systems which comes into light when dealing with higher order systems. The paper explains how the computational complexity can be greatly reduced by using RFS for higher order dynamical systems. A comparative analysis between the conventional type-1 fuzzy system and the two recurrent fuzzy systems has also been performed. PMID- 30396587 TI - Fault detection and diagnosis based on particle filters combined with interactive multiple-model estimation in dynamic process systems. AB - A new approach to fault detection and diagnosis (FDD) is developed for nonlinear stochastic dynamic process systems in this paper. It is called PFs-IMM, which combines particle filters (PFs) and the interactive multiple model (IMM) estimation. In this method, a multiple-model estimation scheme is first formulated to describe the complex process system poorly represented by a single model. The IMM algorithm can deal with abrupt changes in the behavior of operating processes. The residuals of the multiple models are examined for the likelihood of each model. A decision rule is employed to adaptively determine which model is the most appropriate one at each time step. Then based on IMM, a set of PFs run in parallel is used to estimate the states and the reconciled measurements even when the operating mode changes. Each of the PFs utilizes a particular mode to derive the estimation of the state variables as well as the reconciliation of the measured variables based on the probabilistic weighting scheme. From the multiple filters, the interaction among PFs allows the fusing of dynamic estimates. To achieve higher sensitivity to faults and more robustness to disturbances and noises, a new fault index function is developed for FDD. The proposed PFs-IMM approach provides an integrated framework. It can estimate the current operational or faulty mode of the system and derive the overall state estimation and the measurement reconciliation as well. The simulation solutions to the problems are obtained to demonstrate the effectiveness of the proposed method in highly nonlinear dynamic processes. PMID- 30396588 TI - [Defending the authors of Gaceta Sanitaria]. PMID- 30396589 TI - Grantsmanship: What? Who? How? PMID- 30396590 TI - Cerebral fat embolism after autologous fat injection for reconstructive eye surgery. PMID- 30396591 TI - Getting evidence into practice - Managing hares and tortoises. PMID- 30396592 TI - Added value of combining methotrexate with a biological agent compared to biological monotherapy in rheumatoid arthritis patients: A systematic review and meta-analysis of randomised trials. AB - OBJECTIVES: To assess the efficacy and safety of methotrexate (MTX) in combination with an approved biological agent compared to biological monotherapy, in the management of patients with rheumatoid arthritis (RA). METHODS: MEDLINE, EMBASE, CENTRAL and other sources were searched for randomised trials evaluating a biological agent plus MTX versus the same biological agent in monotherapy. Co primary outcomes were ACR50 and the number of patients who discontinued due to adverse events (AEs). Random-effects models were applied for meta-analyses with risk ratio and 95% confidence intervals and the GRADE approach was used to assess confidence in the estimates. RESULTS: The analysis comprised 16 trials (4965 patients), including all biological agents approved for RA except anakinra and certolizumab. The overall likelihood of responding to therapy (i.e. ACR50) after 6 months was 32% better when MTX was given concomitantly with biological agents (1.32 [1.20-1.45]; P < 0.001) corresponding to 11 more out of 100 patients (7-16 more); Moderate Quality Evidence. Discontinuing due to AEs from concomitant use of MTX was potentially 20% increased (1.21 [0.97-1.50]; P = 0.09) compared to biological monotherapy corresponding to 1 more out of 100 patients (0-3 more); Moderate Quality Evidence. CONCLUSIONS: Randomised trials provide Moderate Quality Evidence for a favourable benefit-harm balance supporting concomitant use of MTX rather than monotherapy when prescribing a biological agent in patients with RA although in absolute terms only 7-16 more out of 100 patients will achieve an ACR50 response after 6 months of this combination therapy. PMID- 30396594 TI - Sex differences in forebrain estrogen receptor regulation of hypoglycemic patterns of counter-regulatory hormone secretion and ventromedial hypothalamic nucleus glucoregulatory neurotransmitter and astrocyte glycogen metabolic enzyme expression. AB - The female ventromedial hypothalamic nucleus (VMN) is a focal substrate for estradiol (E) regulation of energy balance, feeding, and body weight, but how E shapes VMN gluco-regulatory signaling in each sex is unclear. This study investigated the hypothesis that estrogen receptor-alpha (ERalpha) and/or -beta (ERbeta) control VMN signals that inhibit [gamma-aminobutyric acid] or stimulate [nitric oxide, steroidogenic factor-1 (SF-1)] counter-regulation in a sex dependent manner. VMN nitrergic neurons monitor astrocyte fuel provision; here, we examined how these ER regulate astrocyte glycogen metabolic enzyme, monocarboxylate transporter, and adrenoreceptor protein responses to insulin induced hypoglycemia (IIH) in each sex. Testes-intact male and E-replaced ovariectomized female rats were pretreated by intracerebroventricular ERalpha antagonist (MPP) or ERbeta antagonist (PHTPP) administration before IIH. Data implicate both ER in hypoglycemic inhibition of neuronal nitric oxide synthase protein in each sex and up-regulation of glutamate decarboxylase65/67 and SF-1 expression in females. ERalpha and -beta enhance astrocyte AMPK and glycogen synthase expression and inhibit glycogen phosphorylase in hypoglycemic females, while ERbeta suppresses the same proteins in males. Differential VMN astrocyte protein responses to IIH may partially reflect ERalpha and -beta augmentation of ERbeta and down-regulation of alpha1, alpha2, and beta1 adrenoreceptor proteins in females, versus ERbeta repression of GPER and alpha2 adrenoreceptor profiles in males. MPP or PHTPP pretreatment blunted counter-regulatory hormone secretion in hypoglycemic males only, suggesting that in males one or more VMN neurotransmitters exhibiting sensitivity to forebrain ER may passively regulate this endocrine outflow, whereas female forebrain ERalpha and -beta are apparently uninvolved in these contra-regulatory responses. PMID- 30396593 TI - Etanercept concentration and immunogenicity do not influence the response to Etanercept in patients with juvenile idiopathic arthritis. AB - OBJECTIVE: To investigate the relationship of clinical response of Juvenile Idiopathic Arthritis (JIA) to etanercept (ETN) with ETN levels, and the presence of anti-drug antibodies to ETN (ADAb). METHODS: Prospective study of JIA patients under 18 years old. Clinical and pharmacological data were collected at two visits. JIA clinical inactivity and activity were assessed according to the Wallace criteria and to the Juvenile Arthritis Disease Activity Score (JADAS). ETN and ADAb serum levels assessments were determined using ELISA-based assays. RESULTS: 126 patients were enrolled. The median duration of ETN treatment at inclusion was 569 days (range 53-2340). ADAb were undetectable (<10 ng/ml) in 171/218 (78%) samples and were > 25 ng/mL in 2/218 samples. No significant relationship between ETN concentration and the clinical inactivity status and JIA activity was found using either univariate logistic regression or multiple logistic regression analysis, adjusted on one individual descriptors, time since diagnosis, time of sampling, use of corticosteroids or methotrexate and classification of JIA. No correlation was found between the remission status and the detection of ADAb. CONCLUSION: This study did not demonstrate any correlation between JIA activity and circulating ETN levels in a large population of patients with JIA previously treated with ETN for at least 1.5 months. As described for adults, our study confirms that ETN is marginally immunogenic in pediatric patients. These results do not support the clinical usefulness of a monitoring of ADAb or ETN concentrations for the management of this group of JIA patients if they fail to achieve clinical inactive disease. PMID- 30396595 TI - Dexmedetomidine reduces oxidative stress and provides neuroprotection in a model of traumatic brain injury via the PGC-1alpha signaling pathway. AB - The protective effects of dexmedetomidine (DEX) mediated by reductions of oxidative stress, mitochondrial damage and disintegration have been demonstrated in many injury models. However, whether DEX has a beneficial effect on traumatic brain injury (TBI) remains unknown. In this study, the neuroprotective effect of DEX and its potential mechanism were assessed in a model of TBI. DEX treatment relieved encephala edema and neuron cell apoptosis and increased behavioral function. These protective effects were accompanied by upregulation of peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1alpha) expression. These findings imply that DEX protects neurons following TBI, possibly by activating the PGC-1alpha pathway. The data will help clarify the mechanisms responsible for the anti-apoptosis effect of DEX with possible involvement of the PGC-1alpha pathway. PMID- 30396596 TI - Effects of RVD-hemopressin (alpha) on feeding and body weight after standard or cafeteria diet in rats. AB - Palatability and variety of foods are major reasons for hedonic eating, and hence for obesity. Hemopressin, a hemoglobin alpha chain-derived peptide, plays antagonist/inverse agonist role on cannabinoid (CB)1 receptors, while RVD hemopressin(alpha)[RVD-hp(alpha)], a N-terminally extended form of hemopressin, has been reported as an allosteric modulator of CB1 and CB2 receptors. We investigated the effects of 14 daily intraperitoneal injections of RVD-hp(alpha), in Sprague-Dawley rats fed a highly palatable cafeteria-style (CAF) diet (30% fat, 56% carbohydrate, 14% protein; 4.20 kcal/g) compared to standard laboratory chow (STD) food (3.5% fat, 63% carbohydrate, 14% protein, 19.5% other components without caloric value; 3.20 kcal). Food intake, body weight and locomotor activity were recorded throughout the study. Finally, rats were sacrificed and agouti-related peptide (AgRP), neuropeptide Y (NPY), pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) and fatty acid amide hydrolase (FAAH) gene expression in the hypothalamus was measured by real-time reverse transcription polymerase chain reaction. We found that CAF diet increased food intake as compared to STD diet. In both STD and CAF diet fed rats, RVD hp(alpha) treatment inhibited food intake, increased locomotor activity but did not modify body weight. In vehicle injected animals, CAF as compared to STD diet increased AgRP gene expression. RVD-hp(alpha) treatment decreased POMC mRNA levels in both diet groups and lowered the elevated AgRP levels induced by CAF diet. RVD-hp(alpha) treatment plays an anorexigenic role paralleled by increased locomotor activity both in STD and CAF diet fed rats. The inhibition of feeding could be partially mediated by lowering of hypothalamic POMC and AgRP gene expression levels. PMID- 30396597 TI - Ultrasound Imaging of Hepatocellular Adenoma Using the New Histology Classification. AB - Hepatocellular adenoma is a rare benign liver tumor. Predisposing factors include hepatic storage diseases and some genetic conditions. A new histology-based classification has been proposed but to date, the corresponding ultrasound imaging features have not been reported. Here we review the new classification scheme and discuss the corresponding features on contrast-enhanced ultrasound imaging. PMID- 30396598 TI - Impact of Food Intake on Liver Stiffness Determined by 2-D Shear Wave Elastography: Prospective Interventional Study in 100 Healthy Patients. AB - The aim was to evaluate the influence of food intake on liver stiffness measurement (LSM), performed with 2-D shear wave elastography (Logiq E9, GE Medical Systems, Wauwatosa, WI, USA). One hundred healthy volunteers were prospectively enrolled. Mean age was 25.8 (19-55) y, and mean body mass index was 22.43 (17.3-30.8) kg/m2. Patients fasted for at least 3 h and subsequently ingested a liquid meal of 800 kcal. Liver stiffness and portal vein velocity were measured before and after food intake. Food intake resulted in significantly higher LSM values compared with baseline LSM (5.74 +/- 0.94 kPa vs. 4.80 +/- 0.94 kPa, p < 0.001). On multiple linear regression analysis, body mass index was significantly positively correlated with the LSM increase after food intake (p = 0.01). No correlation between the increase in LSM and the increase in post prandial portal vein velocity was observed (r = 0.09). In summary, food intake has a significant influence on LSM. There is an 11% risk of misclassifying non fasting, healthy patients as having significant fibrosis. PMID- 30396599 TI - Modulating the Inflammatory Reflex in Rats Using Low-Intensity Focused Ultrasound Stimulation of the Vagus Nerve. AB - Tumor necrosis factor alpha (TNF-alpha) is linked to several chronic inflammatory diseases. Electrical vagus nerve stimulation reduces serum TNF-alpha levels but may cause chronic nerve damage and requires surgery. Alternatively, we proposed focused ultrasound stimulation of the vagus nerve (uVNS), which can be applied non-invasively. In this study, we induced an inflammatory response in rats using lipopolysaccharides (LPS) and collected blood to analyze the effects of uVNS on cytokine concentrations. We applied one or three 5-min pulsed focused ultrasound stimulation treatments to the vagus nerve (250 kHz, ISPPA = 3 W/cm2). Animals receiving a single ultrasound application had an average reduction in TNF-alpha levels of 19%, similar to the 16% reduction observed in electrically stimulated animals. With multiple applications, uVNS therapy statistically reduced serum TNF alpha levels by 73% compared with control animals without any observed damage to the nerve. These findings suggest that uVNS is a suitable way to attenuate TNF alpha levels. PMID- 30396600 TI - Non-invasive Quantitative Assessment of Muscle Force Based on Ultrasonic Shear Wave Elastography. AB - The objective of this study was to investigate the feasibility of using shear wave elastography (SWE) to indirectly measure passive muscle force and to examine the effects of muscle mass and scan angle. We measured the Young's moduli of 24 specimens from six muscles of four swine at different passive muscle loads under different scan angles (0 degrees , 30 degrees , 60 degrees and 90 degrees ) using SWE. Highly linear relationships between Young's modulus E and passive muscle force F were found for all 24 muscle specimens at 0o scan angle with coefficients of determination R2 ranging from 0.984 to 0.999. The results indicate that the muscle mass has no significant effect on the muscle E-F relationship, whereas E-F linearity decreases disproportionately with increased scan angle. These findings suggest that SWE, when carefully applied, can provide a highly reliable tool to measure muscle Young's modulus, and could be used to assess the muscle force quantitatively. PMID- 30396601 TI - Pediatric urology fall congress 2017. PMID- 30396602 TI - Featuring: The association between continuous antibiotic prophylaxis and UTI from birth until initial postnatal imaging evaluation among newborns with antenatal hydronephrosis. PMID- 30396603 TI - Robot-assisted laparoscopic excision of prostatic utricle in a 3-year old. AB - Prostatic utricles have traditionally been excised via the open approach or laparoscopically. Recently, the robot-assisted laparoscopic approach has been described in a 19-year-old male. the case of a 3-year-old male with a disorder of sex development (mosaic 45X/46 XY), with multiple associated anomalies, who presented with recurrent UTI is presented. Renal/bladder ultrasound revealed normal bilateral kidneys, and a 4.3 * 2.8 * 3.3 cm cystic mass in the midline posterior to the bladder. Voiding cystourethrogram demonstrated a large cystic mass behind the bladder, concerning for large prostatic utricle. The patient was brought to the operating room and placed in lithotomy. The urethra was examined cystoscopically. The os of the utricle was identified, an open-ended catheter was advanced, the cystoscope was removed, and a Foley was placed. The camera port was introduced supraumbilically, and robotic ports were introduced inferolaterally. Irrigation of the catheter and distension of the utricle allowed manipulation of the utricle to facilitate identification of a plane of dissection. The neck of the utricle was identified and incised. The catheter was removed, transection was completed, and the stump was oversewn. CONCLUSION: Combined cystoscopic and robotic approach to prostatic utricle excision is feasible, safe, and effective in this patient population. PMID- 30396604 TI - Combined surgery and embolization to treat ruptured cerebral aneurysms with cerebral hematoma and intracranial hypertension: a retrospective analysis and review of the literature. AB - OBJECTIVE: To determine whether the urgent embolization of a cerebral aneurysms and posterior surgery on cerebral hematomas is safe and efficacious in patients with hematomas and signs of intracranial hypertension due to the rupture of cerebral aneurysms. METHODS: We included 23 consecutive patients in poor clinical condition due to an intracranial hematoma caused by a ruptured cerebral aneurysm who were treated with both embolization and surgery within 4hours of the onset of symptoms. All patients had clinical signs of intracranial hypertension and / or altered levels of consciousness, including coma due to rostrocaudal deterioration. We evaluated the efficacy of the combined technique by determining the degree of closure of the aneurysms and the patients' prognosis one month after the procedures; we evaluated safety by analyzing the complications of the treatments. RESULTS: All but two of the patients (21/23; 91.3%) had an aneurysm of the middle cerebral artery. All patients scored 4 on the Fisher scale and were classified as Hunt and Hess IV or V. The mean time from the identification of the aneurysm on computed tomography to embolization was 115minutes. A balloon remodeling technique was used in 18 (78%) patients; embolization achieved adequate closure in 19 (82.6%) patients. During surgery, a ventricular drain was placed in 9 (39.1%) patients. One month after treatment, 13 (56.5%) patients were functionally independent and 3 (13%) had died. No episodes of rebleeding were observed. CONCLUSION: In our experience, combined treatment including embolization of the aneurysm and surgical decompression with evacuation of the hematoma is a safe and effective alternative to surgical treatment alone. PMID- 30396605 TI - Short-term effects of connective tissue manipulation in women with primary dysmenorrhea: A randomized controlled trial. AB - AIM: To evaluate the short-term effectiveness of connective tissue manipulation (CTM) for relieving menstrual pain and symptoms in primary dysmenorrhea (PD). METHODS: Forty-four women with PD were randomly assigned to treatment (n = 21) or control group (n = 23). While the control group was given only advising, the treatment group additionally received CTM. The primary outcome was the menstrual pain intensity by Visual Analogue Scale. Secondary outcomes included the number of pain medications, menstrual pain catastrophizing by Pain Catastrophizing Scale (PCS), menstrual symptoms by Menstrual Symptom Questionnaire (MSQ) and menstrual attitude by Menstrual Attitude Questionnaire (MAQ). RESULTS: Compared with the control group, CTM group showed statistically significant improvement in pain, medication use, PCS, MSQ (p = 0.001) and in the perception of menstruation as a natural event (p = 0.029). However, no significant differences were detected between groups for some aspects of MAQ (p > 0.05). CONCLUSIONS: CTM seems to be an effective approach in the short-term in PD. PMID- 30396606 TI - Associations between complementary medicine utilisation and the use of contraceptive methods: Results of a national cross-sectional survey. AB - BACKGROUND AND PURPOSE: This study examines the relationship between the use of complementary medicine (CM) interventions or consultations with CM practitioners and women's choice of contraceptive method. MATERIALS AND METHODS: A secondary analysis of a cross-sectional survey of Australian Women aged 34-39 years from the Australian Longitudinal Study on Women's Health (ALSWH) was conducted. Associations between use of CM and contraception were analysed using Chi-squared tests and multivariate logistic regression. RESULTS: Based on the responses from the included women (n = 7299), women who consulted a naturopath/herbalist were less likely to use implant contraceptives (OR 0.56; 95% confidence interval (CI) 0.33; 0.95). Those consulting a chiropractor (OR 1.54; 95%CI 1.05; 2.25) or an osteopath (OR 2.16; 95% CI 1.32; 3.54) were more likely to use natural contraception. CONCLUSION: There may be a link between women's choice of contraceptive method and their use of CM, in particular, with CM practitioner consultations. PMID- 30396607 TI - The effectiveness and safety of Kava Kava for treating anxiety symptoms: A systematic review and analysis of randomized clinical trials. AB - BACKGROUND: To determine if Kava Kava is an effective treatment for combating symptoms of anxiety despite warnings of hepatotoxicity from the Centers for Disease Control and Prevention (CDC). METHODS: Databases PubMed, CINAHL, and PsycINFO were utilized to obtain clinical trials on Kava Kava and its effects on anxiety. A total of 11 articles met inclusion/exclusion criteria: 2 for Kava Kava vs. another anti-anxiety medication, 2 detailing additional adverse events, and 7 for Kava Kava vs. placebo. Mantel-Haenszel fixed-effects model was used to analyze the data, with responder rates being pooled to compute weighted risk ratios. RESULTS: Kava Kava was shown to be more effective than placebo in 3 of the 7 trials. A final risk ratio of 1.50 (95% CI: 1.12, 2.01) from responder rates was calculated in favor of the intervention from 5 clinical trials (n = 330). Adverse events were shown to be the same as placebo (P = 0.574), and laboratory values analyzing hepatotoxicity were no different when compared to baseline except in two studies. CONCLUSIONS: Kava Kava appears to be a short-term treatment for anxiety, but not a replacement for prolonged anti-anxiety use. Although not witnessed in this review, liver toxicity is especially possible if taken longer than 8 weeks. PMID- 30396608 TI - Fish oil supplement use in New Zealand: A cross-sectional survey. AB - OBJECTIVE: The aims of the survey were to determine: (i) the percentage of fish oil supplement users in a sample population; (ii) why people take fish oil supplements; (iii) where fish oil supplements are stored as well as the average daily dosage; (iv) what dietary and lifestyle behaviours are associated with fish oil supplement use. DESIGN: An online cross-sectional survey. SETTING: New Zealand. RESPONDENTS: A total of 334 New Zealand residents over the age of 18. RESULTS: Fish oil supplements were taken by 21.9% of respondents. Reasons for taking fish oil supplements were - 72.6% for 'general well-being', 54.8% to 'improve brain function', 31.5% for 'pain/inflammation', 12.3% to 'lower cholesterol levels' and 11% for 'a dietary insufficiency'. Approximately 26% of fish oil users reported taking a dose of fish oil supplements that would meet the recommended daily intake of 400-600 mg combined docosahexaenoic acid and eicosapentaenoic acid, and only 6.8% of fish oil users reported storing their fish oil supplements in the refrigerator. After controlling for other characteristics including age, gender, ethnicity and body mass index, fish oil supplementation use was most likely among respondents who already eat oily fish and least likely in respondents who regularly eat nuts and seeds. CONCLUSIONS: Fish oil supplements are a commonly used supplement in New Zealand, yet questions remain about the role of these supplements in improving health outcomes. Safety issues related to manufacturing and storage conditions indicate that there is an urgency in answering these questions. PMID- 30396609 TI - Mindfulness-based intervention among People living with HIV/AIDS: A Systematic Review. PMID- 30396610 TI - Adjunctive herbal medicine treatment for patients with acute ischemic stroke: A systematic review and meta-analysis. AB - BACKGROUND AND PURPOSE: In the East-Asian countries, the combined treatment of Western medicine and herbal medicine has been widely administered. The purpose of this study was to evaluate the efficacy and safety of herbal medicine in the treatment of acute ischemic stroke. METHODS: We searched the PubMed, Cochrane Central Register of Controlled Trials, EMBASE, and CNKI up to January 2017. Randomized Controlled Trials evaluating the effect of adjunctive herbal medicine on acute ischemic stroke were included. RESULTS: A total of 80 studies (8057 patients) were collected. The overall methodological quality was low. In the herbal group, meta-analysis indicated a statistically significant improvement in the neurologic deficits and activity of daily living compared with the non-herbal group. Furthermore, herbal treatments were relatively safe. CONCLUSION: The treatment can induce neurological improvements without side effects. However, concrete conclusions cannot be made due to the methodological problems of the included studies. PMID- 30396611 TI - Correspondence regarding Anshasi and Ahmad's "an assessment of methodological quality of systematic reviews of acupuncture and related therapies for cancer related pain" in complement ther clin pract 2018 August. PMID- 30396612 TI - A case study: Effects of foot reflexotherapy on ADHD symptoms and enuresis nocturia in a child with ADHD and enuresis nocturia. AB - BACKGROUND AND PURPOSE: Symptoms of Attention-Deficit Hyperactivity Disorder (ADHD) can occur in association with enuresis nocturia. Alternative therapies may be effective in addressing the maladies of children with ADHD comorbidities. The purpose of this study was to investigate the effects of foot reflexotherapy in a child with ADHD and enuresis nocturia. MATERIALS AND METHODS: The patient was an 8-year-old child with ADHD and enuresis nocturia. Pre- and post-tests for ADHD were completed using Vanderbilt ADHD Diagnostic Teacher Rating Scale. The subject was treated with foot reflexotherapy for 20-min per session twice per week for a period of 8 weeks. RESULTS: The child showed improvement in ADHD symptoms and his enuresis nocturia disappeared completely after foot reflexotherapy. CONCLUSION: Foot reflexotherapy was effective in improving inattention, hyperactivity in the child with ADHD. The results of this novel study suggest that foot reflexotherapy can be effective in treating ADHD child with enuresis nocturia. PMID- 30396613 TI - Association between having a hot spring water supply in the home and prevention of long-term care. AB - BACKGROUND AND OBJECTIVE: According to basic studies, hot spring use has positive effects on the mind and body. However, the association between habitual hot spring use and prevention of long-term care is unknown. Using long-term care insurance data for the residents of Atami City, Japan, who can choose to install hot spring water supply in their homes, this study aimed to determine the association between the installation of a hot spring water supply in the home and prevention of long-term care. METHODS: 1. STUDY DESIGN: case-control study 2. SUBJECTS: 2719 residents (754 men, 1965 women) of Atami City, Shizuoka Prefecture, Japan, who received long-term care insurance and were certified as "Needing Support" or "Needing Long-Term Care" as of March 2017. 3. Survey methods: Information on long-term care insurance certification was linked to subjects' care level dating back to their initial certification. Also, the installation (or lack thereof) of hot spring water supply in each subject's home was linked to information on Atami household water use as of March 2017. 4. Analysis methods: The age distribution of the subjects was determined. Initial care status and care status as of March 2017 were then compared for the 2194 subjects who received long-term care certification at least twice. These subjects were classified into two groups: those whose care level had not changed or had improved (no change/improvement group) and those whose care level had worsened (worsening group). Subjects were then compared by sex and initial care level in terms of hot spring installation and percentages of no change/improvement or worsening of care level; odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the chi-square test. Lastly, the same analysis was performed for all subjects grouped together, and ORs and 95% CIs were calculated using the Mantel-Haenszel test. RESULTS: Hot springs were installed in the homes of 2359 subjects overall (86.8%). The no change/improvement group and the worsening group comprised 1192 and 1002 subjects, respectively. Overall, improvement or no change in care level was observed in 1050 subjects (55.2%) in the hot spring group and 142 subjects in the no hot spring group (48.5%). Sex adjusted OR (95% CI) was 1.311 (1.025-1.677, p = 0.036), which represented a significant association. Having a hot spring water supply in the home may be associated with preventing worsening of care level. CONCLUSION: Having a hot spring water supply in the home may be associated with preventing worsening of care level. PMID- 30396614 TI - Development of a community-based golf and exercise program for people with Parkinson's disease. AB - Individuals with Parkinson's disease (PD) typically display symptoms of rigidity, bradykinesia, and postural instability that can limit participation in recreational activities. The purpose of this clinical report is to describe the development, implementation, and outcomes of a novel and innovative community based golf and exercise program for individuals with PD. In response to community interest, the program was developed through a unique partnership that blended the expertise of physical therapists and golf professionals. The 6-week program consisted of golf instruction and task-specific exercises. Improvements were noted in seven of eight participants for golf performance (driving distance and club head speed) and quality of life (PD Questionnaire-39) outcome measures. This report describes the design and implementation of a golf and exercise program for people with PD based on community need, evidence, and clinical expertise. Considerations and recommendations for future programs are discussed, such as program length, staffing, volunteers, funding, location, and resources. PMID- 30396615 TI - Utilization of traditional and complementary medicine in Indonesia: Results of a national survey in 2014-15. AB - BACKGROUND AND PURPOSE: Scant information exists about traditional, complementary and alternative medicine (TCAM) use in Indonesia, which prompted investigating its prevalence and correlates in Indonesia. MATERIALS AND METHODS: Participants were 31,415 individuals 15 years and older that participated in the cross sectional Indonesia Family Life Survey in 2014-15. RESULTS: In all, 24.4% had used a traditional practitioner and/or traditional medicine in the past four weeks, and 32.9% had used complementary medicine in the past four weeks. In adjusted logistic regression analysis, being of older age, being a Muslim, residing in an urban area or on Java, being unhealthy, having a chronic condition, having depression symptoms, experiencing sleep disturbance, and having high social support were associated with both current traditional practitioner and/or medicine use and complementary medicine use. CONCLUSION: The study shows a high prevalence of TCAM use in Indonesia and several sociodemographic and health related factors of its use were identified. PMID- 30396616 TI - Understanding preferences for a mindfulness-based stress management program among caregivers of hematopoietic cell transplant patients. AB - Informal caregivers of allogeneic hematopoietic cell transplant patients experience significant levels of stress throughout the caregiving process. One strategy that has been shown to aid in stress management in other populations is mindfulness. The goal of this study was to understand caregivers' experiences with mindfulness and evaluate their receptiveness to a mindfulness-based stress management program. Data were collected via in-depth phone interviews from 18 caregivers (55% female). Results indicated that about half the sample was familiar with mindfulness and/or had practiced meditation. The majority indicated that they believed a mindfulness program would have been useful for them and that they would have been willing to participate. Most indicated that a program delivered once-weekly for 60 min, during both inpatient and outpatient phases, would be preferable through a combination of in-person and mobile-based delivery. These data provide critical information for the development of future mindfulness based interventions for this caregiving population. PMID- 30396617 TI - Effects of a massage-like essential oil application procedure using Copaiba and Deep Blue oils in individuals with hand arthritis. AB - BACKGROUND AND PURPOSE: Existing research suggests that both massage and essential oils may have analgesic and anti-inflammatory benefits. We investigate the benefits of the AromaTouch Hand Technique(r) (ATHT), a procedure that combines a moderate pressure touch with the application of essential oils to the hand, in individuals with hand arthritis. METHODS AND MATERIALS: Thirty-six participants with rheumatoid arthritis, osteoarthritis, and/or chronic inflammation received ATHTs with either a 50/50 preparation of Deep Blue(r) and Copaiba oil or a coconut oil placebo twice daily for 5 consecutive days. Changes in maximum flexion in finger and thumb joints, items from the Arthritis Hand Function Test, and hand pain scores were evaluated. RESULTS: Participants treated with the essential oil preparation required significantly less time to complete dexterity tasks and showed about 50% decrease in pain scores, increased finger strength, and significantly increased angle of maximum flexion compared to subjects treated with coconut oil. CONCLUSION: The ATHT with Copaiba and Deep Blue may have ameliorative effects on hand arthritis. PMID- 30396618 TI - The influence of asthma severity on patients' music preferences:Hints for music therapists. PMID- 30396619 TI - The effect of guided imagery on anxiety, depression and vital signs in patients on hemodialysis. AB - BACKGROUND AND PURPOSE: Patients on hemodialysis experience anxiety and depression. This study aimed to investigate the effect of guided imagery on anxiety, depression, and vital signs in patients on hemodialysis. MATERIALS AND METHODS: This randomized controlled clinical trial was conducted on 80 patients undergoing hemodialysis. The subjects were randomly assigned into two groups: a guided intervention group and a control group. Anxiety and depression were measured using the Hospital Anxiety and Depression Scale. RESULTS: After the intervention, the level of anxiety and depression were significantly lower in the intervention group compared with the control group (p = 0.030, p = 0.001, respectively). A statistically significant reduction in the respiratory rate and heart rate was reported in the intervention group (p < 0.05). CONCLUSION: Nurses are suggested to use guided imagery along with other interventions for the management of anxiety and depression. It can alleviate adverse psychological responses among patients on hemodialysis. PMID- 30396620 TI - The effect of Tai Chi on quality of life in male older people: A randomized controlled clinical trial. AB - BACKGROUND AND AIM: Physical activity can improve the mental and physical functioning of older people. This study investigated the impact of Tai Chi exercise on the quality of life of older men. METHODS: This randomized controlled clinical trial was conducted on 132 older men in an urban area of Iran. The subjects were randomly assigned into two groups: a Tai Chi intervention group and a control group (n = 66 per group). Quality of life was evaluated using the Leiden-Padua quality of life questionnaire before and after the intervention. Data analysis was performed using analytical statistics via the SPSS software. RESULTS: After eight weeks of Tai Chi exercise, the mean scores of quality of life in different areas demonstrated a statistically significant difference between the two groups (p < 0 0.05). CONCLUSION: This study illustrated that the 8-week Tai Chi intervention had a positive effect on quality of life in older men. PMID- 30396621 TI - Methodological and reporting quality evaluation of systematic reviews on acupuncture in women with polycystic ovarian syndrome: A systematic review. AB - PURPOSE: To evaluate the methodological and reporting quality of systematic reviews (SRs) on acupuncture treatment for women with polycystic ovarian syndrome (PCOS). METHODS: A comprehensive search on multiple databases was performed. Methodological and reporting quality of reviews were assessed by revised assessment of multiple systematic reviews (AMSTAR 2) and preferred reporting items for SRs and meta-analyses (PRISMA), respectively. RESULTS: Ten SRs were included. Among the SRs using AMSTAR 2, two achieved a good overall rating (percentage of items with "yes" > 50%) and severe limitation existed in eleven items (percentage of items with "yes" < 50%). Among the SRs using PRISMA, six reviews achieved a good overall rating (percentage of items with "yes" > 50%), while twelve items were poorly reported (percentage of items with "yes" < 50%). CONCLUSION: There were many deficiencies in the methodological and reporting quality of SRs assessing acupuncture in women with PCOS. PMID- 30396622 TI - Effects of yogic intervention on pulmonary functions and health status in patients of COPD and the possible mechanisms. PMID- 30396623 TI - Naturopathy in Australia: Where are we now? Where are we heading? AB - Naturopathy is the general practice of natural therapies. It emphasizes prevention, treatment, and promotion of optimal health through therapeutic modalities which encourage the self-healing process of the body. Formalized in the 19th century by the hydrotherapy and nature cure movement in Austria and Germany, naturopathy was introduced to Australia at the turn of the 20th century. It became popular since the 1970s due to social and cultural change characterized by the post-modern philosophy, as well as government policies highlighting individual responsibility and freedom of choice. Naturopathy is one of the most popular forms of complementary medicine in Australia today with naturopaths received 4.9 million consultations annually. Naturopathic consultations are sought for a variety of conditions and, in some areas, as a form of primary care, especially by middle-aged women who have a higher education level and a higher annual income. The number of Australian naturopaths was estimated to be over 4000 in 2017 and expects to grow to over 4600 by 2022, although this number is likely to be an underestimation. Australian naturopaths, as a predominantly female profession, work mainly in private clinical practice with nutritional medicine, herbal medicine, homeopathy, as well as massage therapies being the most common modalities used. There are also signs of greater integration with community pharmacies and integrative medicine clinics in major cities. The Bachelor's degree programs in Naturopathy has just become the only accredited entry-level qualification since late 2015. Currently, there are only 5 private colleges offering naturopathic education, a far cry from the 40 over in mid-2000. The profession continues to be self-regulated. There is no barrier of entry to practice and unqualified practitioners of naturopathy can potentially do harm to the public. The registration of naturopaths remains unresolved due to fragmented representation under many professional associations, disunity among the profession, and objections by certain health care lobbyists. There is a dearth of research demonstrating efficacy of the whole practice of naturopathy in Australia, which has directed the government's decision to withdraw it from private health insurance coverage from 2019. Moving forward, the whole system research of naturopathy in Australia will be in focus with the recent establishment of a practice-based research network and an international research consortium. With increasing scrutiny from evidence-based medicine, the present and future challenge to Australian naturopaths is centered on the integration of both scientific and traditional evidence to form the foundation of a person centered, evidence-informed practice. PMID- 30396624 TI - The effects of mental practice based on motor imagery for mobility recovery after subacute stroke: Protocol for a randomized controlled trial. AB - BACKGROUND AND PURPOSE: Mental practice of motor imagery has shown beneficial effects in stroke recovery. However, there are few clinical trials investigating it on the subacute phase. This study will investigate the effects of mental practice in the mobility of patients with subacute stroke. MATERIALS AND METHODS: Randomized controlled trial including persons with subacute stroke (<3 months). All participants will receive physical exercises and will be randomly allocated into an experimental group (Mental Practice) or into a control group (cognitive training) for 4 weeks(12 sessions). RESULTS: Primary outcomes will be assessed at baseline and after intervention and will be related to mobility, using Timed Up and Go test and 5 m walking speed test. Whereas secondary outcomes will be muscular strength, biomechanical strategies, mental health and quality of life. CONCLUSION: The beneficial effects that may be found in this trial can be greatly relevant in clinical practice, justifying this scientific question. PMID- 30396625 TI - Medical cannabis: A needs analysis for people with epilepsy. AB - BACKGROUND AND PURPOSE: Medical cannabis may be effective treatment for refractory epilepsy. It is timely to seek users' and potential users' opinions in regard to its place in the management of epilepsy. MATERIALS AND METHODS: An online survey was administered to members of an epilepsy support organisation in Western Australia. Experience with cannabis for management of epilepsy was explored, along with desire to trial a particular pharmaceutical formulation(s). RESULTS: People with epilepsy (33/71) and carers (38/71) participated. Fifty-four participants indicated no experience with medical cannabis, although 35, mainly with inadequate response to prescription medicines, were willing to ask for a prescription. Concerns included difficulty accessing cannabis and high cost of this treatment. Tablets/capsules was the most acceptable dosage form for development. CONCLUSION: These findings suggest wide interest in trialling medical cannabis in individual cases of refractory epilepsy, despite the developing body of literature and some concerns about cost and procurement. PMID- 30396626 TI - A meta-analysis of Animal Assisted Interventions targeting pain, anxiety and distress in medical settings. AB - OBJECTIVES: Research suggests Animal Assisted Interventions (AAI) reduce negative outcomes in medical settings, but quantitative examinations of their effects on medical outcomes such as pain, anxiety, and distress are lacking. DESIGN: A comprehensive literature search and meta-analysis were conducted in which 22 studies (13 child, 9 adult) met inclusion criteria. Both intervention versus control and intervention pre-post effect sizes were computed using a random effects model. RESULTS: The overall intervention versus control effect size was large and significant (d = 1.65, 95% CI = 0.46-2.832). Similarly, the pre-post effect size was large and significant (d = 2.19, 95% CI = 0.74-3.64). CONCLUSIONS: The results of this meta-analysis indicate that AAI can yield large effects across a number of medically relevant outcomes. There is, however, substantial methodological variation across studies and more randomized clinical trials with stronger methodological controls are needed to establish the effectiveness of AAI compared to other interventions. PMID- 30396627 TI - The effect of Cinnamon on primary dysmenorrhea: A randomized, double-blind clinical trial. AB - BACKGROUND: Primary dysmenorrhea is a cyclic cramp in pelvic which interferes with daily activity. This study determined the effect of Cinnamon on relieving dysmenorrhea. METHODS: This is a randomized, double-blind clinical trial. The intervention group received Cinnamon (capsules contained 1000 mg cinnamon) and the control group received placebo (capsules contained 1000 mg starch) during the first 72 h of menstruation for two cycles continuously. The Visual Analogue Scale was used to determine the severity of pain. The subjects were followed up for two cycles. Descriptive statistics, Independent T test, analysis of variance (ANOVA) with repeated measures were used for continuous quantitative variables. Mann Whitney and Chi-square tests were used for nominal and ordinal qualitative variables. RESULTS: The results showed the mean intensity of dysmenorrhea significantly decreased over time in both groups (time: P < 0.001) and this reduction was significantly different over time between two groups (time*group: P = 0.02). There is significantly more reduction in the intervention group. Also the pain reduction in the intervention group was significantly lower than the placebo group after the first treatment (P = 0.001) and the second treatment (P = 0.002) compared to before treatment. CONCLUSIONS: Cinnamon can reduce the intensity of primary dysmenorrhea. This aromatic spice for relive of primary dysmenorrhea is recommended. PMID- 30396628 TI - Does auriculotherapy have therapeutic effectiveness? An overview of systematic reviews. AB - BACKGROUND AND PURPOSE: Auriculotherapy is a therapeutic technique used for a wide variety of conditions. Nevertheless, similarly to any health related intervention, the clinical use of this therapy requires scientific evidence of effectiveness in order to support its rational use. The main goal of this article is to critically analyze published literature on auriculotherapy and to provide an overview of the effectiveness of this technique in the management of health disorders. METHODS: The inventory of published reviews on this subject was carried out in November 2017, by assessing the following computerized databases: PubMed, MEDLINE, PsycINFO, EBMR, Cochrane Database of Systematic Reviews, CINAHL Plus NRC and Science Direct. Were only considered the systematic reviews based on meta-analysis with high methodological quality described according to AMSTAR (Assessment of Multiple Systematic Reviews). The eligible articles were systematically reviewed to find out in which health conditions auriculotherapy can be used with effectiveness. RESULTS: A total of 14 reviews were eligible according to the inclusion and exclusion criterions. Those reviews were focused on the management of insomnia, smoking cessation and pain, within the clinical scope of Neurology, Orthopaedics and Rheumatology. CONCLUSIONS: Auriculotherapy has shown to have positive effects while associated to conventional treatments of insomnia, chronic and acute pain. Further well designed studies are required to evaluate the effectiveness of this technique in the treatment of other health conditions. PMID- 30396629 TI - The effect of wheelchair Tai Chi on balance control and quality of life among survivors of spinal cord injuries: A randomized controlled trial. AB - BACKGROUND: Wheelchair-related falls are common in survivors with spinal cord injury (SCI). We aimed to assess the effects of wheelchair Tai Chi (WCTC) practice on balance control and quality of life (QOL) among SCI survivors. MATERIALS AND METHODS: Forty SCI survivors were equally divided into WCTC and control groups. The control participants only received the normal rehabilitation intervention, while the WCTC intervention involved 30-min sessions, 2 sessions/day, and 5 days/week for 6 weeks. Static sitting balance, trunk muscle strength, handgrip strength, and QOL were evaluated and statistically analyzed. RESULTS: Compared with the control group, static sitting balance, left handgrip strength, and the psychological domain of QOL improved significantly in the WCTC group (time by group interaction, p < 0.05). CONCLUSION: Six weeks' WCTC training improved static sitting balance and QOL in survivors with SCI. It may be a feasible, safe, and effective exercise for SCI survivors. PMID- 30396630 TI - Complementary and alternative medicine (CAM) disclosure to health care providers: A qualitative insight from Malaysian thalassemia patients. AB - BACKGROUND AND PURPOSE: This study investigated the disclosure of complementary and alternative medicine (CAM) use to health care providers by Malaysian thalassemia patients. METHODS: The semi-structured interviews were audio taped, transcribed verbatim, and translated into English. RESULTS: Thematic analysis identified four themes: 1) reason for CAM disclosure, 2) attempt to disclose CAM, 3) withdrawal from CAM disclosure, and 4) non-disclosure of CAM use. The reason for patients' disclosure of CAM use to healthcare providers is because they wanted to find information about CAM and were afraid of the interaction between the conventional medicine and CAM. Patients also disclosed the use of CAM because they were not satisfied with the conventional medicine that had caused them harm. CONCLUSION: Effective communication between patients and health care providers is important, especially for patients who are undergoing conventional thalassemia treatment, for fear that there is an interaction between conventional treatment and CAM use. PMID- 30396631 TI - The effect of hypnobirthing training given in the antenatal period on birth pain and fear. PMID- 30396632 TI - A systematic review of acupuncture and Chinese herbal medicine for postpartum depression. AB - BACKGROUND AND PURPOSE: Chinese medicine is increasingly used by women with postpartum depression (PPD). We systematically analyzed randomized controlled trials of acupuncture and Chinese herbal medicine (CHM) for PPD. METHODS: Studies were retrieved from English and Chinese databases. The Cochrane risk of bias tool was used to assess methodological quality. RESULTS: Fifteen CHM, and three acupuncture studies were included. Low quality evidence suggested that CHM alone or combined with antidepressants as add-on therapy may reduce symptoms of depression compared to placebo or antidepressants on the Edinburgh Postnatal Depression Scale (EPDS). There was no statistically significant difference between acupuncture and antidepressants. Adverse events were rare. CONCLUSIONS: CHM reduced PPD symptoms greater than placebo or antidepressants. Acupuncture was neither superior nor inferior to antidepressants. More rigorously designed studies are required to confirm the effect of CHM and acupuncture for PPD. PMID- 30396633 TI - Accessibility and feasibility of using technology to support mindfulness practice, reduce stress and promote long term mental health. AB - BACKGROUND AND PURPOSE: We evaluated the feasibility of using an activity monitor to support mindfulness practice, reduce self-reported stress and physiological indicators of stress. MATERIALS AND METHODS: Adult women (N = 19) who previously participated in a mindfulness intervention wore an activity monitor for eight weeks. The activity monitor notified them when they were stressed (based on standard deviation pulse pressure). Heart rate and pulse pressure were continuously collected via the activity monitor. Mindfulness, stress, depression and trauma symptoms were collected via self-report surveys. RESULTS: There were no significant changes in self-reported stress, depression, post-traumatic stress and mindfulness from baseline to eight-weeks. Pulse pressure and standard deviation of pulse pressure increased over time. Those who were high on the non judge mindfulness subscale had a lower standard deviation pulse pressure and spent less time stressed. CONCLUSION: Those who are more mindful are less likely to have physiological signs of stress. PMID- 30396634 TI - Re: Paternal Lifestyle Factors in Relation to Semen Quality and In Vitro Reproductive Outcomes. PMID- 30396635 TI - A Multicentre Evaluation of the Role of the Prostate Health Index (PHI) in Regions with Differing Prevalence of Prostate Cancer: Adjustment of PHI Reference Ranges is Needed for European and Asian Settings. AB - Asians have a lower incidence of prostate cancer (PC). We compared the performance of the Prostate Health Index (PHI) for 2488 men in different ethnic groups (1688 Asian and 800 European men from 9 sites) with PSA 2-20ng/ml and PHI test and transrectal ultrasound-guided biopsy results available. Of these, 1652 men had PSA 2-10ng/ml and a normal digital rectal examination and underwent initial biopsy. The proportions of PC (Gleason >=6) and higher-grade PC (HGPC, Gleason >=7) across different PHI ranges were compared. The performance of PSA and PHI was compared using the area under the receiver operating characteristic curve (AUC) and decision curve analyses (DCA). Among Asian men, HGPC would be diagnosed in 1.0%, 1.9%, 13%, and 30% of men using PHI thresholds of <25, 25-35, 35-55, and >55, respectively. At 90% sensitivity for HGPC (PHI >30), 56% of biopsies and 33% of Gleason 6 PC diagnoses could have been avoided. Among European men, HGPC would be diagnosed in 4.1%, 4.3%, 30%, and 34% of men using PHI thresholds of <25, 25-35, 35-55, and >55, respectively. At 90% sensitivity for HGPC (PHI >40), 40% of biopsies and 31% of Gleason 6 PC diagnoses could have been avoided. AUC and DCA confirmed the benefit of PHI over PSA. The benefit of PHI was also seen at repeat biopsy (n=397) and for PSA 10-20ng/ml (n=439). PHI is effective in cancer risk stratification for both European and Asian men. However, population-specific PHI reference ranges should be used. PATIENT SUMMARY: The Prostate Health Index (PHI) blood test helps to identify individuals at higher risk of prostate cancer among Asian and European men, and could significantly reduce unnecessary biopsies and overdiagnosis of prostate cancer. Different PHI reference ranges should be used for different ethnic groups. PMID- 30396636 TI - Variability in Partial Nephrectomy Outcomes: Does Your Surgeon Matter? AB - BACKGROUND: Understanding physician-level discrepancies is increasingly a target of US healthcare reform for the delivery of quality-focused patient care. OBJECTIVE: To estimate the relative contributions of patient and surgeon characteristics to the variability in key outcomes after partial nephrectomy (PN). DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of 1461 patients undergoing PN performed by 19 surgeons between 2011 and 2016 at a tertiary care referral center. INTERVENTION: PN for a renal mass. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS: Hierarchical linear and logistic regression models were built to determine the percentage variability contributed by fixed patient and surgeon factors on peri- and postoperative outcomes. Residual between- and within surgeon variability was calculated while adjusting for fixed factors. RESULTS AND LIMITATIONS: On null hierarchical models, there was significant between-surgeon variability in operative time, estimated blood loss (EBL), ischemia time, excisional volume loss, length of stay, positive margins, Clavien complications, and 30-d readmission rate (all p<0.001), but not chronic kidney disease upstaging (p=0.47) or percentage preservation of glomerular filtration rate (p=0.49). Patient factors explained 82% of the variability in excisional volume loss and 0 32% of the variability in the remainder of outcomes. Quantifiable surgeon factors explained modest amounts (10-40%) of variability in intraoperative outcomes, and noteworthy amounts of variability (90-100%) in margin rates and patient morbidity outcomes. Immeasurable surgeon factors explained the residual variability in operative time (27%), EBL (6%), and ischemia time (31%). CONCLUSIONS: There is significant between-surgeon variability in outcomes after PN, even after adjusting for patient characteristics. While renal functional outcomes are consistent across surgeons, measured and unmeasured surgeon factors account for 18-100% of variability of the remaining peri- and postoperative variables. With the increasing utilization of value-based medicine, this has important implications for the goal of optimizing patient care. PATIENT SUMMARY: We reviewed our institutional database on partial nephrectomy performed for renal cancer. We found significant variability between surgeons for key outcomes after the intervention, even after adjusting for patient characteristics. PMID- 30396637 TI - Introducing the new "Movement Disorders Rounds". PMID- 30396640 TI - Can different regions of interest influence the diagnosis of benign and malignant breast lesions using quantitative parameters of contrast-enhanced sonography? AB - OBJECTIVES: To evaluate the diagnostic utility of quantitative parameters which generated in different regions of interests (ROIs) of benign and malignant breast lesions using contrast-enhanced sonography(CEUS). MATERIALS AND METHODS: 130 patients were evaluated with contrast harmonic imaging after the injection of a bolus dose of 4.8 ml SonoVue (Bracco Sp A, Milan, Italy). Quantitative analyses using the TIC were performed in two types of ROI (manually tracing the whole lesions and using 3-mm rectangular sampling frames to depict local lesions).Wash in slope (WIS), rise time (RT), time to peak (TTP),peak intensity (PI),strengthening intensity (SI),wash out slope(WOS) and mean transit time(MTT) were investigated in each ROI, SI includes the strengthening intensity of the lesion itself(SIs) and its strengthening intensity relative to the reference area(SIr). RESULTS: Pathologic analysis showed 52 benign and 78 malignant lesions. There were significant differences in the quantitative parameters obtained by the two ROI types (P < 0.05). There were significant differences between benign and malignant lesions in the WIS-e(P < 0.05), TTP-e(P < 0.05), and SIr-e (P < 0.05) for the manual ROI. Significant differences were found between benign and malignant lesions in the WIS-l(P < 0.05), TTP-l(P < 0.05), PI-l(P < 0.05), SIs-l(P < 0.05), and SIr-l (P < 0.05) for the 3-mm ROI. The regression equation obtained by ROI-e was P = 1/[1 + e-(2.65-0.184TTP-e)]. The regression equation obtained by ROI-l was P = 1/[1 + e-(2.472+0.024SIr-l-0.279TTP-l)]. There was statistically significant difference in the diagnostic efficacy between the two ROI types (P < 0.05). CONCLUSIONS: CEUS quantitative analysis has a certain value in the diagnosis of benign and malignant breast lesions. The ROI type which depicts local lesions can better reflect the hemodynamic characteristics of the lesions. PMID- 30396641 TI - Diurnal stability and long-term repeatability of neurometabolites using single voxel 1H magnetic resonance spectroscopy. AB - PURPOSE: This study was designed to evaluate the diurnal stability and long-term repeatability and reliability of one-dimensional (1D) hydrogen magnetic resonance spectroscopy (1H-MRS) in vitro and in vivo at 3 T. MATERIAL AND METHOD: A standard brain phantom was used for in vitro study. In vivo diurnal evaluation involved ten healthy subjects, while repeatability study involved six subjects. MRS was acquired from posterior cingulate gyrus (PCG), and processed with LCModel. Diurnal effects were assessed with repeated measures ANOVAs, repeatability was evaluated using coefficient of variation (CV), while reliability was assessed with standard error measurement (SEM) and intra-class correlation coefficient (ICC). RESULTS: Diurnal metabolic changes in vitro were non-significant. The intra/inter-in vitro CVs for the major metabolites; N acetylaspartate (NAA), creatine (Cr), myo-inositol (mI), glutamate + glutamine (Glx) and total choline (tCho) were 1-3%/2-6%, respectively. Statistically significant in vivo diurnal effects were only seen for glycerophosphocholine (GPC, +10%, F = 10.6, p = 0.001) and Glx (+6%, F = 5.1, p = 0.018). The intra/inter-subject CVs for the major metabolites ranged from 2-5%/ 5-9%, respectively. The major metabolites displayed ICC ranging from 0.5-0.7 and low SEM (0.001-0.078) reflecting high reliability in detecting neurometabolites. The inter-week interval for in vivo measurements had minimal effect on metabolite ratios (F = 1.4, p = 0.09). CONCLUSION: In vitro MRS showed no diurnal effects and minimal variation in metabolite levels. Most PCG metabolites are not altered diurnally. The low in vivo variability of metabolite concentration supports the use of localised MRS on clinical 3 T scanners for reliable neurometabolic profiling of the brain. PMID- 30396638 TI - Antimicrobial resistance: A round table discussion on the "One Health" concept from the Gulf Cooperation Council Countries. Part One: A focus on Leadership. AB - The threat of Antimicrobial Resistance (AMR) has attracted the highest level of attention after the United Nation (UN) General Assembly's High Level meeting on AMR in 2016. During that meeting a temporary committee, the inter agency coordination group (IACG) [1] was formulated, under the chairmanship of the Director General of the World Health Organization (DG-WHO) and the UN Deputy Secretary General. The IACG group was tasked to link, guide and advise on political steps needed to address and mitigate the emergence of AMR globally [2]. Efforts to combat AMR, however, have previously been developed prior to this initiative by several decades. Yet, the emergence of resistance continues to be on the rise. The Gulf Cooperation Council Center for Infection Control (GCC-IC) was been established in 2005 and has made major efforts to address all aspects related to human infection control in the member countries. Many of which have been reached. In 2015, the board was able to draft through its multidisciplinary meeting the first roadmap for the counties on this issue [3]. Two years later a follow-up meeting took place in Riyadh on April 2017. Regional and international experts joined in to share and contribute to the understanding of AMR and to advise on further steps needed for this initiative. We dedicated 3 papers on this meeting. The first paper is to provide an update on progress form the GCC countries and further steps that need to be taken, (in press). The second paper is part one out of two round table discussions. The first round table discussion paper, which is the current paper, addresses AMR and the "One Health" concept with a focus on leadership. The second round table discussion paper addresses AMR and the "One Health" concept with a focus on human health [4]. PMID- 30396642 TI - Evidence of axonal damage in cerebellar peduncles without T2-lesions in multiple sclerosis. AB - BACKGROUND AND AIM: Cerebellar peduncles (CP) can be probed by diffusion tensor imaging (DTI) to evaluate the integrity of cerebellar afferent and efferent networks. Damage to the CP in multiple sclerosis (MS) could lead to serious cognitive and mobility impairment. The aim of this study was to investigate the extent and the clinical impact of CP damage in MS. METHODS: Sixty-eight MS patients were included in this study along with 27 healthy controls (HC) and underwent an MRI on a 1.5T including T1, T2, FLAIR and DTI. Using DTI, the microstructural integrity within the CP regions (superior (SCP), inferior (ICP) and middle (MCP)) was probed while controlling for focal T2-lesions presence or absence. A general linear model was performed to test for associations between clinical scores and DTI metrics for each CP. RESULTS: Significantly decreased fractional anisotropy (FA) and increased radial diffusivity (RD) were found in the CP of all MS patients compared to those of HC, but to a lesser extent in non lesioned CP than those with lesions. Axial diffusivity (AD) was significantly and similarly increased in both non-lesioned and lesioned CP, but only in the SCP and ICP. Expanded disability status scale (EDSS) significantly correlated with MCP's FA (p < 0.05) and RD (p < 0.05), while MS functional composite (MSFC) significantly correlated with SCP's FA (p < 0.01) and RD (p < 0.01). CONCLUSION: The diffusion changes (FA and RD) measured in lesioned CP are probably directly related to the presence of inflammatory and/or demyelinating lesions. In contrast, the microstructural alterations reflected by AD increase in non lesioned CP may result either from remote effects of cerebral white matter injury (diaschisis) or primary axonal degeneration, that are associated with cognitive, sensory and motor impairments of MS patients. PMID- 30396643 TI - Is there a correlation between 3T multiparametric MRI and molecular subtypes of breast cancer? AB - OBJECTIVES: To test whether 3 T multiparametric magnetic resonance imaging (mMRI) provides information related to molecular subtypes of breast cancer. METHODS: Women with mammographic or US findings of breast lesions (BI-RADS 4-5) underwent 3 T mMRI (DCE, DWI and MR spectroscopy). The histological type of breast cancer was assessed. Estrogen-receptor (ER), progesterone-receptor (PgR), Ki-67 status and HER-2 expression, assessed by immunohistochemistry (IHC), defined four molecular subtypes: Luminal-A, Luminal-B, HER2-enriched and triple-negative. Non parametric tests (Kruskal-Wallis, k-sample equality of medians, and Mann Whitney), logistic regression or ANOVA, and a multivariate analysis were performed to investigate correlations between the four molecular subtypes and mMRI (lesion volume, margins or distribution, enhancement pattern, ADC, type of kinetic curve, and total choline (tCho) signal-to-noise-ratio (SNR)). A ROC analysis was finally performed to test the diagnostic power of a multivariate logistic regression model. RESULTS: 433 patients (453 lesions) were considered. Volume was smaller in Luminal-B and larger in triple-negative tumours compared to the other subtypes combined. Margins were significantly correlated to Luminal-A and Luminal-B. The type of curve was significantly correlated to Luminal-A. ADC values were higher in Luminal-A. tCho SNR was higher in triple-negative tumours. The ROC analysis showed that the area under the curve (AUC) significantly improved when multiple MRI features were used compared to individual parameters. CONCLUSIONS: A significant correlation was found between some MRI features and molecular subtypes of breast tumours. A multiparametric approach improved the diagnostic power of MRI. However, further research is needed in order to predict the molecular subtype on the sole basis of mMRI. PMID- 30396639 TI - Antimicrobial resistance: A round table discussion on the "One Health" concept from the Gulf Cooperation Council Countries. Part Two: A focus on Human Health. AB - The Gulf Cooperation Council Center for Infection Control (GCC-IC) has moved forward over the past several years on the antimicrobial resistance (AMR) agenda. Many of the GCC countries have now developed a national plan to combat AMR and have engaged the leadership of the involved sectors in the discussion on how to mitigate this threat. During the first meeting for the GCC-IC center on AMR, which took place early 2015, the roadmap for combating AMR was developed [1] and since then much more has been done. We present here the discussion that took place during the second GCC-IC center meeting on AMR where not only have the countries presented their progress, but we conducted 2 round table discussions inviting international and regional experts in the field to share their thoughts, progress and knowledge on this topic [2]. Within is the 2nd round table discussion at the 2017 GCC AMR meeting which took place in Riyadh, Saudi Arabia, April 2017. Where the 1st round table discussion during this meeting addressed the role of leadership in managing AMR [2]. PMID- 30396644 TI - Magnetic resonance imaging for evaluation of foetal multicystic dysplastic kidney. AB - We sought to evaluate the diagnostic value of foetal magnetic resonance imaging (MRI) for multicystic dysplastic kidney (MCDK) disease. We retrospectively identified 55 foetuses with MCDK diagnosed (51 unilateral; 4 bilateral) by foetal MRI. We analysed the anatomical findings by prenatal MRI and compared them with the prenatal ultrasound (US) and postnatal findings. Additional diagnostic information added by MRI was recorded. The gestational age of the 55 foetuses ranged from 22 to 35 weeks (mean, 26.5 +/- 3.6 weeks). The age of the pregnant women ranged from 23 to 40 years (mean, 31 +/- 4.2 years). All 55 cases were performed at 1.5 T magnetic resonance unit. MRI sequences, including steady-state free precession (SSFP), single-shot fast spin echo (SSFSE), T1-weighted imaging (T1WI), and diffusion weighted imaging (DWI) sequences. Follow-up was obtained for 53 cases (2 cases of autopsy, 51 cases of postnatal imaging or surgery confirmed). Among the 51 unilateral cases, 16 cases were associated with other urinary tract anomalies, 3 cases with extra-renal anomalies, and the remaining 32 cases without associated anomalies. 2 of 16 cases with contralateral renal agenesis were with oligohydramnios and pulmonary hypoplasia. 2 of 4 bilateral MCDK presented with oligohydramnios and pulmonary hypoplasia. 52 of 53 cases were correctly diagnosed by MRI compared with the final diagnoses; 40 of 53 (75.5%) cases were correctly diagnosed by prenatal ultrasound. Both prenatal ultrasound and MRI failed to correctly diagnose one case bilateral MCDK, and MRI correctly changed the ultrasound diagnosis in 12 cases. Foetal MRI can add additional diagnostic information to prenatal US in the assessment of MCDK, even change the prenatal counselling and decisions. PMID- 30396645 TI - The use of magnetic resonance elastography in differentiating autoimmune pancreatitis from pancreatic ductal adenocarcinoma: A preliminary study. AB - PURPOSE: To assess the value of magnetic resonance elastography (MRE) in patients with autoimmune pancreatitis (AIP) and in the differentiation of AIP from pancreatic ductal adenocarcinoma (PDAC). METHOD AND MATERIALS: This prospective study included 14 AIP patients, 26 PDAC patients, and 14 healthy volunteers. All participants underwent pancreatic MRE (40-Hz; 3 T scanner) at enrollment, and 7 AIP patients underwent a second MRE after initiation of steroid therapy. Pancreatic stiffness values were obtained by MRE and a new logistic regression model (the calculated Rad score) was used to combine pancreatic stiffness and the distribution and shape of high-stiffness areas for differentiation of AIP and PDAC. The area under the curve (AUC) was calculated for all parameters using receiver operating characteristic (ROC) analysis. RESULTS: Pancreatic stiffness was significantly higher (2.67 kPa [interquartile range, 2.24-3.56 kPa]) in AIP than in healthy pancreas (1.24 kPa [1.18-1.24 kPa]) and significantly lower in AIP than in PDAC (3.78 kPa [3.22-5.11 kPa]; both P < 0.05). Diffuse (n = 4 vs 1; P = 0.043) and multiple (n = 3 vs 0; P = 0.037) lesions were more common in AIP, while solitary (n = 25 vs 7; P = 0.001) and nodular lesions (n = 18 vs 2; P = 0.002) were more frequent in PDAC. Rad scores outperformed individual imaging parameters in distinguishing AIP from PDAC (AUC, 0.948 vs 0.607 to 0.782; all P < 0.05), with 84.6% specificity and 92.9% sensitivity. Pancreatic stiffness in AIP decreased significantly, from 2.66 kPa [2.29 to 3.05 kPa] to 1.55 kPa [1.43 to 1.67 kPa] (P = 0.016), during treatment. CONCLUSIONS: MRE shows promise as a quantitative imaging method for differentiating AIP from PDAC and for monitoring the treatment response in AIP. PMID- 30396646 TI - Doppler ultrasonography devices, including elastography, allow for accurate diagnosis of severe liver fibrosis. AB - OBJECTIVES: Advanced chronic liver disease is frequent yet largely underdiagnosed. Doppler-US is a common examination and we recently identified three simple Doppler-US signs associated with severe liver fibrosis. Recent Doppler-US devices include elastography modules, allowing for liver stiffness measurement (LSM). Our aim was to assess whether the use of elastography following positive simple Doppler-US signs improves the detection of severe liver fibrosis in a single Doppler-US examination. METHODS: 514 patients with chronic liver disease who consecutively underwent percutaneous liver biopsy were included in the study. All patients had a Doppler-US examination and LSM with Virtual Touch Quantification (VTQ) on the same day as a liver biopsy. A subset of 326 patients also had LSM with 2D shear wave elastography (SSI). Severe fibrosis was defined as Metavir F >= 3 on liver biopsy. RESULTS: Multivariate analysis confirmed our three simple Doppler-US signs (liver surface irregularity, splenomegaly >=110 mm, and demodulation of hepatic veins) as independently associated with severe fibrosis. The presence of at least one of these three signs showed 85.6% sensitivity and 36.1% specificity for the diagnosis of severe liver fibrosis. Using VTQ (>=1.59 m/s) where there was a positive Doppler-US sign increased the specificity to 80.8%, at the cost of a decrease in sensitivity (73.7%). Similar results were obtained with SSI (>=9.5 kPa), with 73.3% specificity and 81.5% sensitivity. CONCLUSION: Elastography improves the accuracy of Doppler-US in the detection of severe fibrosis. This two-step procedure will help radiologists to accurately identify patients who need to be referred to specialist hepatologists during routine Doppler-US examinations. PMID- 30396647 TI - Multi-observer comparison study between unenhanced quiescent-interval single-shot magnetic resonance angiography and invasive carbon dioxide angiography in patients with peripheral arterial disease and chronic renal insufficiency. AB - OBJECTIVES: Non-contrast-enhanced quiescent-interval single-shot magnetic resonance angiography (QISS-MRA) and invasive carbon dioxide (CO2) angiography are suggested as nephroprotective methods for accurate staging of peripheral arterial disease (PAD) in patients with chronic renal insufficiency (CRI). The aim of our study was to compare the image quality of both examinations. METHODS: 16 consecutive PAD patients with highly impaired renal function (estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2) who underwent 3 T MRA with QISS and catheter angiography with CO2 within 90 days were retrospectively included. Subjective image quality was determined using a five-point Likert scale (1, non-diagnostic; 5, excellent) and presence of significant (>=50%) stenoses of pelvic and lower extremity arteries (21-segment-model) was evaluated per-region and per-segment, respectively, in random order by four independent readers with different levels of experience. CO2 angiography of an experienced interventional radiologist was considered the standard reference method. RESULTS: 167 segments were available for direct comparison with a prevalence of >=50% stenoses of 28.1%. QISS-MRA yield was: sensitivity 91.5%, specificity 94.2%, positive predictive value 86.0% and negative predictive value 96.6%, with an intraclass correlation coeffcient (ICC) of 0.88. Median values of qualitative imaging parameters for QISS-MRA were as follows: arterial signal intensity: 4 (pelvis), 5 (thigh), 5 (calf); venous overlay: 4, 5, 5; susceptibility artifacts: 5, 5, 5; motion artifacts: 4, 5, 5; ECG-related artifacts: 5, 5, 5. ICC-values for image quality were 0.74, 0.73, 0.93, 0.69 and 0.79, respectively. Arterial opacification at CO2 angiography was rated 3, 4, 3, with an ICC of 0.63. CONCLUSIONS: Image quality of non-invasive unenhanced MR angiography with QISS was preferred over invasive CO2 angiography, whilst taking into account that it offers high diagnostic performance for the detection and ruling out of PAD. PMID- 30396648 TI - Machine learning based on multi-parametric magnetic resonance imaging to differentiate glioblastoma multiforme from primary cerebral nervous system lymphoma. AB - PURPOSE: To evaluate the performance of a machine learning method based on texture features in multi-parametric magnetic resonance imaging (MRI) to differentiate a glioblastoma multiforme (GBM) from a primary cerebral nervous system lymphoma (PCNSL). MATERIALS AND METHODS: We included 70 patients who underwent contrast enhanced brain MRI at 3 T with brain tumors diagnosed as GBM (n = 45) and PCNSL (n = 25) in this retrospective study. Twelve histograms and texture parameters were assessed on T2-weighted images (T2WIs), apparent diffusion coefficient maps, relative cerebral blood volume (rCBV) map, and contrast-enhanced T1-weighted images (CE-T1WIs). A prediction model was developed using a machine learning method (univariate logistic regression and multivariate eXtreme gradient boosting-XGBoost) and the area under the receiver operating characteristic curve of this model was calculated via 10-fold cross validation. In addition, the performance of the machine learning method was compared with the judgments of two board certified radiologists. RESULTS: With the univariate logistic regression model, the standard deviation of rCBV offered the highest AUC (0.86), followed by mean value of rCBV (0.83), skewness of CE-T1WI (0.78), mean value of CET1 (0.78), and max value of rCBV (0.77). The AUC of the XGBoost was significantly higher than the two radiologists (0.98 vs. 0.84; p < 0.01 and 0.98 vs. 0.79; p < 0.01, respectively). CONCLUSION: The performance of machine learning based on histogram and texture features in multi-parametric MRI was superior to that of conventional cut-off method and the board certified radiologists to differentiate a GBM from a PCNSL. PMID- 30396649 TI - Magnetic resonance imaging of muscle injury in elite American football players: Predictors for return to play and performance. AB - Muscle injury accounts for about one-third of total sports-related injuries. The lower limb muscles have one of the highest predisposition for injury in high level professional athletic sports, such as the National Football League. The commonest group of muscles injured among football players include the hamstrings, followed by the quadriceps. Muscle injuries lead to significant time, off the field and affect return to play. Sports physicians and teams have been keen on assessing such injuries and also relying on multiple tools to safely return the player back to the field. MRI plays a key role in evaluation, follow-up, and assessment for return to play (RTP). In this review, we will discuss details of muscle anatomy, incidence of muscle injuries, injury mechanisms, and use of MRI in assessment, grading, follow-up and in predicting the natural course of muscle injuries in the high-end athletic players. While the use of MRI is clear in diagnosis, and for follow up of muscle injuries, there is some limitation in its ability to predict RTP, based on current MRI classification systems. Footballers who have clinical injuries without MRI evidence of significant muscle injury (grade 0 and 1) have a shorter period of RTP. Injuries classified as high grade (3 and 4) on MRI do not correlate well with time to RTP. Further trials are required to improve the capability of MRI in its prediction of RTP. PMID- 30396650 TI - Gastric cancer with synchronous and metachronous hepatic metastasis predicted by enhancement pattern on multiphasic contrast-enhanced CT. AB - OBJECTIVE: The purpose of this study was to examine the relationship between the CT features of the primary-site gastric cancer and the concurrent existence or postoperative recurrence of hepatic metastasis. MATERIALS AND METHODS: From January 2013 to July 2016, 125 patients with advanced gastric cancer who were evaluated by gastroscopy and contrast-enhanced CT at our institution were included. Eleven patients had hepatic metastasis at the time of diagnosis (synchronous hepatic metastasis). Five patients had hepatic recurrence after surgery (metachronous hepatic metastasis, median follow-up period of 313 days), and another 56 patients had no hepatic recurrence during follow-up period (negative hepatic metastasis, median follow-up period of 1102 days). Two radiologists independently reviewed the CT images and they determined the peak enhancement phase, and then measured the CT attenuation value of the gastric lesion for each phase. We compared the parameters of synchronous, metachronous and negative hepatic-metastasis. We calculated diagnostic performance of CT for diagnosing synchronous and metachronous hepatic metastasis. RESULTS: The peak enhancement was significantly diff ;erent between the three groups for both readers (reader 1, p = 0.0001; reader 2, p = 0.0002). Most of the synchronous and metachronous hepatic metastasis had peak enhancement in the arterial or portal phase. The CT attenuation values of synchronous and metachronous hepatic metastasis were significantly higher than those of negative hepatic metastasis in the delayed phase according to both readers (reader 1, p = 0.0003; reader 2, p = 0.0002). In predicting synchronous hepatic metastasis using peak enhancement, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 72.7%, 89.3%, 57.1%, 94.3%, and 86.6% for reader 1, and 54.5%, 94.6%, 66.7%, 91.4%, and 88.1% for reader 2. In predicting metachronous hepatic metastasis, the sensitivity, specificity, PPV, NPV, and accuracy were 60.0%, 89.3%, 33.0%, 94.3%, and 86.9% for reader 1, and 40.0%, 94.6%, 40.0%, 94.6%, and 90.2% for reader 2. CONCLUSION: Our study showed that gastric cancer with synchronous and metachronous hepatic metastasis tends to show early enhancement with a washout pattern on contrast-enhanced CT. This feature would be helpful in image surveillance for synchronous or metachronous hepatic metastasis of gastric cancer. PMID- 30396651 TI - The effectiveness of ultrasonography and ultrasonographic elastography in the diagnosis of carpal tunnel syndrome and evaluation of treatment response after steroid injection. AB - PURPOSE: To evaluate if there is a place for ultrasonography (US) and ultrasonographic elastography (UE) in the diagnosis and follow up of carpal tunnel syndrome treatment. MATERIALS AND METHODS: The study was performed on 25 patients (study group) and 17 healthy volunteers (control group). Measured US and UE criteria were median nerve area (MNA), proximal median nerve area (pMNA), difference between MNA and pMNA (dMNA) and strain values of carpal tunnel content (CTC) and median nerve (MN). Patients in the study group were also evaluated using the Boston questionnaire, Visual Analogue Scale (VAS) and nerve conduction studies. Thirty-three wrists in 23 patients received steroid injections on the same day. Patients were re-evaluated 6 weeks after steroid injection. To establish a cut off value for MNA, ROC Curve analysis was used. RESULTS: Mean MNA and dMNA values in the control group were significantly lower than in the study group (7.33 +/- 1.31 vs. 15.44 +/- 5.10; p=<0.05 and 1.58 +/- 0.75 vs. 8.91 +/- 4.93; p = 0.00 respectively). Median nerve and CTC strain indices were significantly higher in the control group (p = 0.00 and p = 0.036). Decrease in MNA and dMNA values after treatment was meaningful (p = 0.00). While there was no significant change in MN elasticity, mean CTC strain index of the study group (4.680 +/- 1.664) decreased significantly after treatment (3.621 +/- 1.054 p = 0.002). This decrease in the CTC index was more pronounced in patients who benefited from treatment (p = 0.001). CONCLUSION: US and UE can be useful in the diagnosis of CTS and its response to treatment, if used together with clinical and electroneurophysiological tests. PMID- 30396652 TI - Dual-layer detector CT of the head: Initial experience in visualization of intracranial hemorrhage and hypodense brain lesions using virtual monoenergetic images. AB - PURPOSE: Retrospective comparison of diagnostic quality of virtual monoenergetic images (VMI) and conventional images (CI) reconstructed from dual-layer detector CT (DLCT) regarding intraparenchymal hemorrhage (IPH) and hypodense parenchymal lesions (HPL) of the brain. METHODS: 58 patients underwent unenhanced DLCT of the head. CI and VMI ranging from 40 to 120 keV were reconstructed. Objective image quality was assessed using ROI-based measurements within IPH, HPL, grey matter, white matter and cerebrospinal fluid, from which contrast to noise ratio (CNR) was calculated. Two radiologists assessed IPH, HPL, artifacts and image noise on a 5-point Likert-scale. Statistical significance was determined using Wilcoxon rank sum test. RESULTS: In comparison to conventional images, CNR of HPL to white matter was significantly increased in VMI at 120 keV (p <= 0.01), whereas at 40 keV, CNR to grey matter was enhanced (p <= 0.0001). Contrary, CNR of IPH to white matter was increased at 40 keV (p <= 0.01), while CNR to grey matter was improved at 120 keV (p <= 0.01). Subjective readings confirmed best delineation of IPH within grey matter at 120 keV. Both readers detected four additional hyperdense lesions within white and one within grey matter at 40 keV. CONCLUSIONS: VMI obtained with DLCT can improve depiction of hypodense parenchymal lesions and intraparenchymal hemorrhage. The initial data show a great dependency on the type of pathology and on its location: hypodense lesions in white matter and hyperdense lesions in grey matter are better visualized in higher keV reconstructions, while hyperdense lesion in white matter and hypodense lesions in grey matter are better visualized at low keV values. PMID- 30396653 TI - Impact of body mass index on CT attenuation of adrenal adenoma. AB - OBJECTIVE: To investigate whether lipid metabolism-related factors regulate unenhanced CT attenuation in adrenal adenoma (AA). MATERIALS AND METHODS: Thirty six patients with surgically proven AAs were enrolled in this study. The patients' underlying diseases were the following: primary aldosteronism (n = 24), Cushing's syndrome (n = 8), subclinical Cushing's syndrome (n = 3) and non functioning AA (n = 1). Unenhanced CT attenuation of AAs and liver was measured. Pathologically, clear cell ratio (CCR) constituting each AA was qualitatively assessed. Clinical data including tumor diameter, body mass index (BMI), hemoglobin A1c, triglyceride, total cholesterol, blood cortisol and plasma aldosterone levels were also obtained. Simple and multiple linear regression analyses were performed to evaluate the radiological and clinicopathological factors associated with CT attenuation of AAs for all patients and separately for 25 patients with primary aldosteronism or non-functioning AA. RESULTS: For all patients, there was a significant correlation between CT attenuation and each of CCR, BMI and blood cortisol levels (p < 0.05). For patients with primary aldosteronism or non-functioning AA, there was also a significant correlation between CT attenuation and CCR or BMI (p < 0.05). CONCLUSION: In addition to pathological factors, lipid-metabolism-related factors including BMI and blood cortisol levels can affect unenhanced CT attenuation of AA. PMID- 30396654 TI - Placental MRI shows preservation of brain volume in growth-restricted fetuses who suffer substantial reduction of putative functional placenta tissue (PFPT). AB - OBJECTIVE: Recently, a potentially useful diagnostic approach based on MR diffusion-tensor-imaging (DTI) was reported for the estimation of putative functional placenta tissue (PFPT), thus providing direct information about placental function. Yet, the relation between reduced PFPT and the phenomenon of brain-sparing remains unclear. This study aimed to investigate the relation between brain-sparing and reduced PFPT volume, as found in fetuses with intrauterine growth restriction (IUGR). METHODS: A total of 40 consecutive patients with a US-based diagnosis of placental IUGR were examined using fetal MRI. A control group of 78 patients who received fetal MRI, due to non-placental pathologies, was established. A somatic energy index was calculated as IE=1 (Vbrain/Vpfpt) from brain and PFPT volumes measured with DTI in both groups. IE, Vpfpt, and Vbrain were analyzed with respect to the gestational week. RESULTS: Vbrain corrected for gestational weeks was no different between both groups, while Vpfpt was significantly reduced in IUGR patients. IE was significantly different between both groups and indicated a higher Vbrain at a comparable Vpfpt. CONCLUSIONS: Fetuses with IUGR show preserved energetic resources necessary for brain growth. Because IE drops in IUGR more rapidly as pregnancy progresses, depending on Vpfpt, IE could prove useful for estimating fetal well being. PMID- 30396655 TI - Combination of renal apparent diffusion coefficient and renal parenchymal volume for better assessment of split renal function in chronic kidney disease. AB - OBJECTIVE: To investigate the value of the combination of the split renal apparent diffusion coefficient (ADC) and renal parenchyma volume (RPV) by diffusion-weighted imaging (DWI) for assessment of split renal function in patients with chronic kidney disease (CKD). METHODS: Forty-eight eligible participants (36 CKD patients and 12 healthy individuals) were included in the study. All of them underwent DWI (b = 0 and 800 s/mm2) examination with a 1.5 T MRI scanner to determine the split renal ADC and RPV. Glomerular filtration rate (GFR) was measured by 99Tcm-DTPA scintigraphy using Gates' method and used as the reference standard. All statistical tests were performed using SPSS 20.0 and MedCalc 10.0 statistical software packages. RESULTS: Split renal ADC, RPV, and their product were significantly correlated with GFR (gamma = 0.493, p < 0.0001; gamma = 0.337, p = 0.018; gamma = 0.708, p < 0.0001, respectively). The product of split renal ADC and RPV had a significantly higher correlation with GFR (gamma = 0.708) than split renal ADC (p = 0.0002) and RPV (p = 0.016). ROC curve analysis showed that the product of split renal ADC and RPV was a significantly better indicator of reduced split renal function (AUC = 0.893) compared to split renal ADC (p = 0.0455) and RPV (p = 0.0326). CONCLUSION: The combination of split renal ADC and RPV obtained by DWI can significantly improve the assessment of split renal function in CKD patients. PMID- 30396656 TI - Dedicated breast PET value to evaluate BI-RADS 4 breast lesions. AB - PURPOSE: To evaluate the diagnostic value of dedicated breast PET (dbPET) parallel imaging in mammographically or sonographically detected BI-RADS 4 (Breast Imaging Reporting And Data Systems) lesions. MATERIALS AND METHODS: After institutional review board and patient approvals, 50 consecutive women with 60 BI RADS 4 breast lesions were prospectively included in the study. All patients underwent Magnetic Resonance Imaging (MRI) and dbPET before biopsy and fusion of both MRI and dbPET images was performed to better locate corresponding lesions. Final findings were compared with histological results. Sensitivity and specificity for dbPET were determined along with their respective 95%-confidence intervals. RESULTS: Histopathology examination revealed 18 malignant lesions (7 in situ and 11 invasive carcinomas) and 42 benign entities. The dedicated breast PET reported no evidence of malignancy in 41 patients, 9 of them with histological diagnosis of neoplasm. Besides, dbPET showed increased metabolically activity in 10 benign lesions and in 9 breast cancers. Two invasive carcinomas were located less than 1 cm from the pectoral muscle, which can explain that they were missed by dbPET because they were outside the field of view (FOV). There were other 6 false negative results, which corresponded to a 0.1 cm invasive lobular carcinoma and 5 in situ carcinomas. Sensitivity and specificity of dbPET were 50% and 76%, respectively. CONCLUSIONS: Our analysis does not allow the recommendation of dbPET for diagnosis of malignancy in BI-RADS 4 mammographic or US abnormalities, mainly due to its high false-negative rate for the detection of in situ carcinomas (85.7%). However, considering the lesions greater than 0.1 cm and included in the FOV, dbPET depicted all invasive carcinomas. PMID- 30396657 TI - Using CT texture analysis to differentiate between nasopharyngeal carcinoma and age-matched adenoid controls. AB - OBJECTIVES: To investigate the use of texture analysis to quantitatively distinguish nasopharyngeal carcinoma (NPC) from normal adenoid on CT. METHODS: In this IRB-approved, retrospective study, nasopharyngeal tissues in 13 patients with NPC and 13 control patients were manually contoured, segmented, and imported to an in-house developed texture analysis program, which extracted 41 texture features. Basic descriptive statistics were performed to evaluate for differences in texture parameters between NPC and controls. RESULTS: Statistically significant differences between NPC and controls were seen in 32 of 41 texture features. These significant differences were present in 11 of 12 histogram features, 4 of 5 gray-level co-occurrence matrix features, 7 of 11 gray-level run length features, 4 of 4 gray-level gradient matrix features, and 6 of 9 Laws features. CONCLUSION: Significant differences in many texture features were seen between NPC and normal adenoids. CT texture analysis may aid in differentiating NPC from normal adenoid tissue. PMID- 30396658 TI - Paediatric bowel ultrasound in inflammatory bowel disease. AB - Ultrasound has long been favoured as first line when imaging children, primarily due to it being a non-invasive, relatively low cost, easily accessible modality. The many advantages of ultrasound evaluation in paediatric inflammatory bowel disease (IBD) vastly outweighs its limitations in both initial assessment and long term follow up. High frequency ultrasound provides excellent spatial resolution, and Doppler evaluation and compression sonography aids in providing real-time dynamic assessment in IBD where other modalities cannot. This paper outlines our ultrasound technique to maximise image quality and diagnostic accuracy, describes the imaging findings in paediatric IBD, and explores the advantages and limitations that ultrasound offers. We aim to illustrate to the reader that ultrasound is an invaluable imaging tool and should be the first line modality when imaging IBD in the paediatric patient. PMID- 30396659 TI - Tumour characteristics of bilateral screen-detected cancers and bilateral interval cancers in women participating at biennial screening mammography. AB - BACKGROUND: Unilateral interval breast cancers show less favourable prognostic features than unilateral screen-detected cancers, but data on tumour characteristics of bilateral interval cancers in a systematically screened population are sparse. Therefore, we compared tumour characteristics of bilateral interval cancers with those of bilateral screen-detected cancers. METHODS: We included all 468,720 screening mammograms of women who underwent biennial screening mammography in the South of the Netherlands between January 2005 and January 2015. We collected breast imaging reports, biopsy results and surgical reports of all recalled women and of all women who presented with interval breast cancer. In women with synchronous bilateral breast cancer, the tumour with the highest tumour stage was defined as the index cancer. For comparison of data between both groups Fisher exact test and Chi-square test were used. RESULTS: Synchronous bilateral cancer was diagnosed in 2.2% of screen-detected cancers (64/2947) and in 3.2% of interval cancers (24/753) (P = 0.1). Index tumours of bilateral screen-detected cancers and interval cancers showed similar characteristics, except for a larger proportion of T-stage 2 or worse (T2+) cancers among interval cancers (16/24 (66.7%) versus 23/58 (39.7%) (P = 0.03). Index cancers, compared to contralateral cancers, were less frequently stage T1 in both bilateral screen-detected cancers and bilateral interval cancers (35/64 (60.3%) versus 40/64 (88.9%) (P = 0.001) and 8/24 (33.3%) versus 18/24 (85.7%) (P < 0.001), respectively). In bilateral screen-detected cancers, contralateral cancers were more often stage 1a-c (P < 0.001) compared to index cancers. In bilateral index cancers, index cancers were more often of the lobular subtype (P < 0.001). CONCLUSION: Index cancers of bilateral screen-detected cancers and bilateral interval cancers show significant differences in tumour size, whereas nodal status, receptor status and final surgical treatment are comparable. In bilateral screen-detected cancer, index cancers had a significantly higher tumour stage. In bilateral screen-detected cancer, index cancers were more often the ductal invasive subtype compared to contralateral cancers. PMID- 30396660 TI - Investigating the correlation of arterial spin labeling and dynamic contrast enhanced perfusion in primary tumor of nasopharyngeal carcinoma. AB - PURPOSE: This prospective study aimed to investigate the correlation between two perfusion methods: arterial spin labeling (ASL) and dynamic contrast enhanced (DCE) technique in patients with nasopharyngeal carcinoma (NPC) and to optimize ASL protocol. MATERIALS AND METHODS: Forty-five newly diagnosed NPC patients underwent MR examinations with both 3D pseudo-continuous ASL (pCASL) and DCE-MRI sequences. Tumor blood flow (TBF) derived in pCASL with three post-labeling delay (PLD) times (i.e. 1.0 s, 1.5 s, and 2.0 s) and DCE derived parameters including MaxSlop, contrast enhancement ratio (CER), Initial area under the gadolinium curve (IAUGC), Ktrans, Kep and Ve were measured by two independent observers, and their correlation coefficients were investigated using Spearman test. RESULTS: Inter-observer reproducibility (ICC = 0.931-0.998) was observed to be excellent. Positive correlations between mean, maximum and minimum value of TBFs with different PLDs and DCE-MRI parameters (except Ve) were respectively observed (r = 0.308-0.688, P = 0.000-0.040). CONCLUSION: pCASL may be an alternative method for DCE-MRI in assessing the perfusion level in NPC in the future. PMID- 30396661 TI - Primary and metastatic malignancies of the lung: Retrospective analysis of the CT guided high-dose rate brachytherapy (CT-HDRBT) ablation in tumours <4 cm and >=4 cm. AB - BACKGROUND: Minimal invasive local therapies are alternative treatment options in patients with primary and metastatic lung malignancies being not eligible for resection. However, thermal ablations are often limited by large tumour volumes. PURPOSE: To evaluate the efficacy and safety of CT-HDRBT in pulmonary tumours >=4 cm compared to smaller tumours. MATERIAL AND METHODS: In this retrospective study, 74 consecutive patients (mean age: 63 +/- 12; m: 39, w: 35) with a total of 175 tumours treated in 132 interventions were enrolled between October 2003 and September 2016. Primary and assisted local tumour control (LTC), progression free survival (PFS) and overall survival (OS) after first CT-HDBRT were identified for two subgroups with tumours <4 cm (A) as well as >=4 cm (B) using the Kaplan-Meier-Method. Radiation parameters and side effects were recorded. Log Rank-Test and Mann-Whitney-U-Test were performed for statistical analyses with p values <0.05 considered as significant. RESULTS: There was no statistical difference in coverage with prescribed radiation dose (A:19.78 +/- 8.62 mm (range 5-39 mm), 99.56 +/- 0.99%; B:61.70 +/- 21.09 mm (41-100 mm), 94.81 +/- 7.19%, p = 0.263). LTC rates after 0.5-,1-,2-,3- and 5-years were higher in A compared to B (A:85%/74%/63%/60%/46%, B:71%/37%/32%/32%/32%) with longer primary (A:11months, B:5months, p = 0.003) and assisted LTC (A:9months B:20months, p = 0.339). Longer OS was observed in A (A:18.5months, B:14.5months, p = 0.011) with longer OS rates (A:96%/87%/60%/48%/19%, B:92%/73%/20%/20%/0%). Complication assessment revealed no bleedings, 16.6% pneumothoraxes and 48.5% of mild radiation fibrosis without clinical symptoms. CONCLUSION: In conclusion, higher LTC and OS were observed in patients with primary lung malignancies <4 cm. Nevertheless, CT-HDRBT is a safe and feasible alternative even in larger tumours >=4 cm. PMID- 30396662 TI - Optimal threshold for the diagnosis of anemia severity on unenhanced thoracic CT: A preliminary study. AB - OBJECTIVE: To investigate and evaluate the value as accuracy of diagnosis different degrees of anemia through the unenhanced thoracic computed tomography (CT) scan. MATERIALS AND METHODS: The CT attenuation of right ventricle (RV) cavity, left ventricular (LV) cavity, interventricular septum and difference between the interventricular septum and left ventricle cavity (IVS-LV) were retrospectively analyzed and measured in 317 patients with different degrees of anemia and the normal patients. The hemoglobin (Hb) level was estimated within 24 h. Statistical analysis was made to obtain the best diagnostic threshold of anemia levels by CT scan, measurement repeatability was assessed using the intra class correlation coefficient (ICC) values. RESULTS: An obvious parallel correlation of hemoglobin concentration and CT attenuation of IVS-LV existed (the determination coefficient was 0.818; P < .001). Based on receiver operating characteristic (ROC) curves, the conclusion was that when the threshold of CT attenuation of IVS-LV at (5.5-9.5) HU in male and (4.5-8.5) HU in female, the specificity for diagnosing mild anemia was low, while the sensitivity was very high (87.1%, 100%, respectively), if the CT value was among (9.5-13.5) HU in male or (8.5-13.5) HU in female, the sensitivity and specificity for diagnosing moderate anemia were fine (92.9% and 74.8% in male; 93.9% and 60.0% in female), and once the CT value was more than 13.5 HU the sensitivity and specificity for diagnosing severe anemia in all gender were greatly good (94.7% and 83.6% in male; 82.4% and 84.6% in female). The intra-and inter-observer reliability and reproducibility were good (ICC were all more than 0.99). CONCLUSION: The CT attenuation of IVS-LV could predict the severity of anemia with good sensitivity and specificity, which could add value to clinical practice and more importantly facilitating patient care as hematologic laboratory investigations are lacking. PMID- 30396663 TI - Impact of computed tomography (CT)-derived fractional flow reserve on reader confidence for interpretation of coronary CT angiography. AB - PURPOSE: To assess the impact of computed tomography-derived fractional flow reserve (FFRCT) on reader confidence and reader time for interpretation of coronary computed tomography angiography (CCTA). MATERIAL AND METHODS: This IRB approved, HIPAA-compliant, consent waivered, quality-improvement study included 50 patients (23 women, age 67 +/- 12years, body mass index 28.7 +/- 5.3 kg/m2). CCTA was acquired on 2nd and 3rd generation dual-source MDCT with use of beta blockers and nitroglycerin, and FFRCT was calculated (HeartFlow,Redwood City,CA). Two readers with experience level COCATS2 (Core- Cardiology-Training-Symposium) and two with COCATS3 assessed severity of epicardial coronary artery disease (CAD) using CCTA alone and CCTA with FFRCT. Reader confidence for CAD and hemodynamically significant stenosis (HS) was rated on a 4-point Likert-scale (1=high, 2=good, 3=limited, 4=none) for the four major epicardial coronary artery (CA) vessels. Time to interpret was recorded. RESULTS: The severity of CAD in the cohort population was CAD-RADS1 (Coronary-Artery-Disease Reporting-and-Data System) n = 15, CAD-RADS2 n = 8, CAD-RADS3 n = 11, and CAD-RADS4A n = 16. Sixty three CA in 30 patients had minimal FFRCT values <=0.8. Reader confidence when using FFRCT increased for CAD and HS (p = 0.0001) with a reduction of "non confident" patient reads (rank 3&4) by 27% and 75%, respectively. The change in confidence was not associated with CAD-RADS (p = 0.1) but correlated with reader experience (p < 0.001). The median time-to-read a CCTA study decreased by 5 min when FFRCT was available (p < 0.001). CONCLUSION: Interpretation of CCTA in conjunction with FFRCT improved reader for assessment of severity of CAD and HS with reduction of "non-confident" reads and decreased the median time-to interpretation of a CCTA. PMID- 30396664 TI - Apparent diffusion coefficient reproducibility in brain tumors measured on 1.5 and 3 T clinical scanners: A pilot study. AB - BACKGROUND: Gradient and coil systems, pulse sequence design, and imaging parameters, as well as different scanners, can influence apparent diffusion coefficient (ADC) values. The aim of this study was to evaluate the effect of two different field strengths on the reproducibility of mean absolute ADC measurements in various primary and secondary brain tumors. METHODS: Fifty patients with histologically proven brain tumors were prospectively examined on two MR scanners from the same vendor, with different field strengths-1.5T and 3T on the same day. Absolute ADC values were compared using the Wilcoxon matched pairs signed-rank test. Inter-scanner agreement between two different fields in the same tumor was examined using correlation coefficients, and the discrepancy between the highest and the lowest mean absolute ADC values between scanners was tested using a one-way analysis of variance. Statistical significance was set at p < 0.05. RESULTS: There was no statistically significant difference between mean absolute ADC values obtained on 1.5T and 3T scanners for all patients and all brain tumor types. The intratumoral difference in ADC values, averaged from two scanners in the same tumor type, ranged from 1.58 to 4.5% for 1.5T, and from 1.18 to 4.37% for 3T.Inter-scanner agreement was high, and the kappa coefficient ranged from 0.88 to 0.99, with no significant difference between obtained values on different field strengths. CONCLUSION: Based on the results obtained in our study, there is no significant difference between mean absolute ADC values measured in various primary and secondary brain tumors at different field strengths (1.5 and 3.0T MR systems), in the same patient, and in the same tumor, measured on the same day. PMID- 30396665 TI - Correlation between quantitative liver and spleen volumes and disease severity in primary sclerosing cholangitis as determined by Mayo risk score. AB - OBJECTIVES: To correlate total and lobar liver and spleen volume with disease severity in primary sclerosing cholangitis (PSC) as determined by Mayo risk score. METHODS: This HIPAA-compliant single center retrospective study included 147 PSC patients with available imaging studies (MRCP/CT) and laboratory data between January 2003 and January 2018. Total and lobar (right, left and caudate) liver volume and spleen volume were measured. ANOVA test was performed to assess the differences in volumes between low, intermediate and high-risk groups (Mayo risk score <0, >0 and <2, >2, respectively). Correlations between volumes and Mayo risk score were calculated. ROC analysis was performed to assess the accuracy of the variable with the strongest correlation to PSC severity to predict Mayo risk score. P value <0.05 was considered statistically significant. RESULTS: The mean age of this cohort was 45 +/- 17 years; 58% were men. Absolute volumes of left lobe, caudate and spleen and volume ratios of left lobe and caudate to total liver volume of the high-risk group were significantly higher compared to those of low and intermediate risk groups (p < 0.05). Left lobe to total liver volume ratio had the highest correlation to Mayo risk score (Pearson correlation coefficient 0.61, p < 0.05) and on ROC analysis it had 84.4% accuracy in detecting high-risk PSC. CONCLUSIONS: In this single institution large cohort study, the left lobe to total liver volume ratio was the best quantifiable volumetric biomarker to correlate with severity of PSC as identified by Mayo risk score. PMID- 30396666 TI - Comparison of mammography, digital breast tomosynthesis, automated breast ultrasound, magnetic resonance imaging in evaluation of residual tumor after neoadjuvant chemotherapy. AB - BACKGROUND: To compare the accuracy of mammography (MG), digital breast tomosynthesis (DBT), automated breast ultrasound (ABUS) and magnetic resonance imaging (MRI) for the assessment of residual tumor extent in breast cancer after neoadjuvant chemotherapy (NAC). METHODS: Fifty-one stage II-III breast cancer undergoing NAC were enrolled from March 2015 to December 2016. The longest diameter of residual tumor measured with MG, DBT, ABUS and MRI was compared with the pathologic tumor size. Statistical analysis was performed using intraclass correlation coefficients (ICC) and marginal homogeneity test. Receiver operating characteristics (ROC) analysis was used to evaluate the diagnostic performance for predicting pathologic complete response (pCR). RESULTS: MRI size correlated well with pathology (ICC = 0.83), significantly better than MG, DBT and ABUS size (ICC = 0.56, ICC = 0.63 and ICC = 0.55, respectively). The discrepancy between MRI and pathology was statistical different from that of MG and ABUS (p = 0.0231 and 0.0039, respectively), but not different from that of DBT (p = 0.5727). For predicting pCR, MRI and DBT had a better performance compared to MG and US (area under the ROC curve: 0.92, 0.84, 0.72, 0.75, respectively; p = 0.3749 for DBT, p = 0.0972 for MG and p = 0.0596 for ABUS, when MRI being reference). CONCLUSIONS: MRI and DBT allow more accurate assessment of tumor size compared to pathology compared with MG and ABUS. MRI and DBT outperform MG and ABUS in the prediction of pathologic complete response. PMID- 30396667 TI - Histogram-based comparison between dynamic and static lung perfused blood volume images using dual energy CT. AB - OBJECTIVE: The purpose of this study was to compare the results of a histogram based analysis of static and dynamic lung perfused blood volume (LPBV) images. METHODS: Sixty-five patients (mean age: 61.3 years, 36 male) underwent dynamic and static LPBV for evaluation of pulmonary vascular diseases (n = 11), lung carcinoma (n = 27) or pulmonary thromboembolism (PTE: n = 27). Seven sets of dynamic sequential scans were performed at the pulmonary trunk using dual-energy technique before the static LPBV scan. The image of lung parenchyma that showed the greatest mean attenuation in dynamic series was defined as the peak dynamic LPBV image. The differences and correlations in the mean attenuation, image noise, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), histogram skewness and histogram kurtosis were evaluated according to the type of disease in static and dynamic LPBV images. RESULTS: Static LPBV images showed significantly larger mean attenuation (Rt:24.2, Lt: 24.2), SNR (Rt:2.31, Lt:2.30), and CNR (Rt:2.40, Lt:2.39), and smaller kurtosis values (Rt:1.06, Lt:0.61) values in comparison to dynamic LPBV images (p < 0.001); however, with the exception of kurtosis of the left lung (r = 0.17), these values were well corrected with that of the dynamic LPBV images in these values (r = 0.4-0.77, p <= 0.001) without kurtosis of left lung (r = 0.17) in all patients. The histogram kurtosis of static LPBV image showed a good correlation with that of dynamic LPBV (r = 0.41-0.77, p < 0.05), especially in patients with PTE. CONCLUSION: In patients with PTE, the static LPBV image valueswere well correlated with the peak dynamic LPBV images which demonstrated pulmonary artery-dominant flow. PMID- 30396668 TI - Quantitative assessment of pulmonary vascular alterations in chronic obstructive lung disease: Associations with pulmonary function test and survival in the KOLD cohort. AB - PURPOSE: Despite the high prevalence of pulmonary vascular alterations and their substantial impact on chronic obstructive pulmonary disease (COPD), tools for the direct in vivo assessment of pulmonary vascular alterations remain limited. Thus, the purpose of this study was to automatically extract pulmonary vessels from volumetric chest CT and evaluate the associations between the derived quantitative pulmonary vessel features and clinical parameters, including survival, in COPD patients. METHODS: This study included 344 adult COPD patients. Pulmonary vessels were automatically extracted from volumetric chest CT data. Quantitative pulmonary vessel features were obtained from various lung surface areas (LSAs), which are theoretical surface areas drawn at different depths from the pleural borders. The total number of vessels (Ntotal) and number of vessels with vessel area (VA) less than 5 mm2 (N<5mm) were counted as both robust values and as values per 10 cm2 of LSA (Ntotal/LSA; N<5mm/LSA). The average VA (VAmean) and percentage of measured VA in the corresponding LSA (%VA) were measured. Associations between quantitative pulmonary vessel features and clinical parameters, including survival and the pulmonary function test (PFT), were evaluated. RESULTS: The pulmonary vessels were automatically extracted with 100% technical success. Cox regression analysis showed Ntotal/LSA, N<5mm/LSA, VAmean, and %VA to be significant predictors of survival (hazard ratio (HR), 0.80, 0.75, 0.70, 0.49, respectively). Patients classified into high-risk groups by %VA18mm (cut-off = 3.258), chosen because it demonstrated the strongest statistical influence on survival in a univariate Cox analysis, were associated with worse overall survival before (HR, 4.83; p < 0.001) and after adjustment for patient age and BMI (HR, 2.18; p = 0.014). Of the quantitative pulmonary vessel features, Ntotal/LSA, N<5mm/LSA, and %VA were correlated with FEV1, FEV1/FVC, and DLCO in all LSAs. The strongest correlation with PFTs was noted at LSA9mm for both Ntotal (FEV1, r = 0.33; FEV1/FVC, r = 0.51) and N<5mm (FEV1, r = 0.35; FEV1/FVC, r = 0.52). For %VA, the association was most evident at LSA18mm (FEV1, r = 0.27; FEV1/FVC, r = 0.47). Significant moderate to strong correlations were consistently observed between the extent of emphysema and quantitative pulmonary vessel features (r = 0.44-0.66; all p < 0.001). CONCLUSIONS: The automated extraction of pulmonary vessels and their quantitative assessment are technically feasible. Various quantitative pulmonary vessel features demonstrated significant relationships with survival and PFT in COPD patients. Of the various quantitative features, the percentage of total VA measured at 18 mm depth from the pleural surface (%VA18mm) and the number of small vessels counted per 10 cm2 of LSA at 9 mm depth from the pleural surface (N<5mm/LSA9mm) had the strongest predictability for the clinical parameters. PMID- 30396669 TI - Pars interarticularis injury in elite athletes - The role of imaging in diagnosis and management. AB - Injuries of the lumbar neural arch, in particular the pars interarticularis, are widely considered to be due to abnormal bone stress secondary to repetitive loading/shearing, and are a common pathology and a main cause of lower back pain in elite athletes across a range of sports. Medical imaging plays a pivotal role in the diagnosis, monitoring and prognostication of neural arch injury. Early detection is highly desirable in the young elite athlete, as early injuries have been shown to require shorter recovery time and have a higher potential of full healing, whilst accurate grading of injury allows appropriate rehabilitation planning. Various imaging modalities are used in the diagnosis and management of pars stress injury, each with their strengths and weaknesses. There is currently a lack of general consensus over the most appropriate imaging pathway for neural arch injury in this specific group of patients. In this review article, we present an overview of neural arch injury, the various imaging modalities used and their imaging appearances with a brief pictorial review, and a proposed imaging algorithm with special considerations in the young elite athletes. PMID- 30396670 TI - Quantitative MRI in post-operative paediatric cerebellar mutism syndrome. AB - Post-operative paediatric cerebellar mutism syndrome (pCMS) occurs in around 25% of children undergoing surgery for cerebellar and fourth ventricular tumours. Reversible mutism is the hallmark of a syndrome which comprises severe motor, cognitive and linguistic deficits. Recent evidence from advanced neuroimaging studies has led to the current theoretical understanding of the condition as a form of diaschisis contingent on damage to efferent cerebellar circuitry. Tractography data derived from diffusion MRI studies have shown disruption of the dentato-rubro-thalamo-cortical tract in patients with pCMS, and perfusion studies have indicated widespread supratentorial regions which may give rise to the florid signs and symptoms of pCMS. Given the difficulties in predicting pCMS from standard structural MRI, this review discusses findings from quantitative MRI modalities which have contributed to our understanding of this debilitating syndrome, and considers the goals and challenges which lie ahead in the field. PMID- 30396671 TI - MRI characteristics of adductor longus lesions in professional football players and prognostic factors for return to play. AB - PURPOSE: To correctly define through Magnetic Resonance Imaging (MRI), diagnosis, staging and prognosis of the adductor longus (AL) acute lesions and to identify a correlation between Return to Play (RTP) and sport-related injury predisposing conditions and complications. MATERIALS AND METHODS: Twenty professional football players with acute groin pain and clinical suspicion of AL injury subsequent to sport's activity were evaluated. MRI examinations were performed by one and reviewed by other two radiologists with more than 10 years of experience. Lesions were stratified according to both Munich consensus statement and British Athletics Muscle Injury Classification (BAMIC). Patients were monitored until clinical recovery occurred. RESULTS: According to the Munich consensus statement, 75% of lesions were defined as type 3 and 25%as type 4; while according to the BAMIC, 45% were considered as Grade 1, 20% as Grade 2, 10% as Grade 3, and 25% as Grade 4. RTP was 1-2 weeks for minor lesions (45%), 4-6 weeks for moderate lesions (30%), and more than 6 weeks for complete lesions (25%). Both BAMIC and Munich consensus significantly correlated with RTP (R = 0.958 and 0.974, respectively). The extent of gap was the only independent prognosticator of RTP always present in all three different models of multivariate analysis (p < 0.006, p < 0.002, and p < 0.001, respectively). CONCLUSIONS: MRI represents the gold standard imaging technique for the evaluation of AL due to its ability not only to recognize but also to classify acute lesions and define patient's prognosis. MRI is also useful to detect potential predisposing conditions and complications, which may correlate with RTP. PMID- 30396672 TI - Quantitative evaluation of T2* relaxation times for the differentiation of acute benign and malignant vertebral body fractures. AB - OBJECTIVES: The aim of this prospective study was to evaluate the diagnostic performance of T2*-weighted magnetic resonance imaging (MRI) to differentiate between acute benign and neoplastic vertebral compression fractures (VCFs). MATERIALS AND METHODS: Thirty-seven consecutive patients with a total of 52 VCFs were prospectively enrolled in this IRB approved study. All VCFs were categorized as either benign or malignant according to direct bone biopsy and histopathologic confirmation. In addition to routine clinical spine MRI including at least sagittal T1-weighted, T2-weighted and T2 spectral attenuated inversion recovery (SPAIR)-weighted sequences, all patients underwent an additional sagittal six echo modified Dixon gradient-echo sequence of the spine at 3.0-T. Intravertebral T2* and T2*ratio (fracture T2*/normal vertebrae T2*) for acute benign and malignant VCFs were calculated using region-of-interest analysis and compared between both groups. Additional receiver operating characteristic analyses were performed. Five healthy subjects were scanned three times to determine the short term reproducibility of vertebral T2* measurements. RESULTS: There were 27 acute benign and 25 malignant VCFs. Both T2* and T2*ratio of malignant VCFs were significantly higher compared to acute benign VCFs (T2*, 30 +/- 11 vs. 19 +/- 11 ms [p = 0.001]; T2*ratio, 2.9 +/- 1.6 vs. 1.2 +/- 0.7 [p < 0.001]). The areas under the curve were 0.77 for T2* and 0.88 for T2*ratio, yielding an accuracy of 73% and 89% for distinguishing acute benign from malignant VCFs. The root mean square absolute precision error was 0.44 ms as a measure for the T2* short-term reproducibility. CONCLUSION: Quantitative assessment of vertebral bone marrow T2* relaxation times provides good diagnostic accuracy for the differentiation of acute benign and malignant VCFs. PMID- 30396673 TI - Diagnostic performance of CT densities in selected gray- and white-matter regions for the clinical diagnosis of brain death: A retrospective study in a tertiary level general hospital. AB - INTRODUCTION: We aimed to determine the diagnostic performance of Hounsfield Units (HUs) in selected brain region using computed tomography for the clinical diagnosis of brain death (BD). METHODS: A retrospective, case-control study design. A total of 66 subjects (22 cases, 44 controls) underwent brain tomography between January 2011 and December 2016. Inclusion criteria for cases considered patients with a CT performed within the 24 first hours of a clinical diagnosis of brain death. Exclusion criteria applied to patients with no CT scan performed before BD diagnosis. Brain-healthy-control subjects were identified from the hospital's CT scan database. We selected 12 regions for each cerebral hemisphere (4 basal ganglia; 2 regions gray matter (GM) regions; 4 white matter (WM) regions; 2 brain stem regions); two GM and WM regions in each cerebellar hemisphere, and 4 GM/WM ratios. Measurements included analysis of variance, receiver operating characteristic (ROC) curve, and of pooled effect sizes. RESULTS: 72 measures per subject were recorded. Without contrast material, the best performance was the GM/WM ratio at the basal ganglia level (AUROC = 0.893, 95% C.I. = 0.83, 0.96; p-value <.001). After contrast enhancement, the greatest AUROC value corresponded to the thalamus (AUROC = .959, 95% C.I. = .93, .99; p value < .001). CONCLUSIONS: There is not an absolute threshold of GM-WM differentiation below which all patients are diagnosed with BD, but a group of HUs in selected brain regions, some of them with very high sensitivity and specificity to be used as early predictors of BD. PMID- 30396674 TI - Dual-energy computed tomography colonography using dual-layer spectral detector computed tomography: Utility of virtual monochromatic imaging for electronic cleansing. AB - OBJECTIVE: To assess the utility of virtual monochromatic imaging (VMI) using a dual-layer spectral detector CT for electronic cleansing in fecal-tagging CT colonography (CTC). METHODS: This study included 35 patients who underwent fecal tagging CTC with a dual-layer detector spectral CT scanner. Conventional images at 120 kVp and VMI at 40, 50, and 60 keV were reconstructed. Quantitative image quality parameters, i.e., tagging density and image noise, were compared and the visual image quality was scored on a four-point scale. We recorded the number of the colon segments with appropriate tagging density (>=300 HU) for each patient and used these data to compare the reconstructions. In addition, electronic cleansing performance was semi-quantitatively assessed using a four-point scale. RESULTS: The mean tagging density on VMI was significantly higher than that on conventional 120 kVp images. The number of colon segments with appropriate tagging density on VMI were significantly higher than that on conventional 120 kVp images. There was no significant difference among the reconstructed images with respect to image noise. Scores for subjective image quality and electronic cleansing performance on VMI were significantly higher than those on conventional 120 kVp images. CONCLUSION: With dual-layer spectral detector CT, VMI can yield significantly better fecal-tagged CTC image quality and improve electronic cleansing performance. PMID- 30396675 TI - Comparison of breast cancer detection and depiction between planar and rotating synthetic mammography generated from breast tomosynthesis. AB - PURPOSE: To compare breast cancer detection and depiction between planar synthetic mammography (SM) and rotating synthetic mammography (RM) generated from digital breast tomosynthesis (DBT). MATERIALS AND METHODS: In a fully-crossed multi-reader multi-case (MRMC) study, three radiologists retrospectively reviewed 190 cases (27 malignant, 31 benign, 132 normal), once with SM alone and once with RM alone, the DBT stack of slices was not reviewed. Lesions were scored using BI RADS(r) and level of suspiciousness (1-10). Sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were computed using MRMC Analysis of Variance using the open-access software iMRMC. Additionally, readers were asked to make a visual grading analysis (VGA) on visibility of calcifications and soft tissue lesions (1-5 scale with 5 = Excellent visualization). The VGA scores were analyzed using the visual grading characteristics (VGC) method. RESULTS: On average, the AUC was similar between SM and RM (0.66 versus 0.67, P = 0.818). The sensitivity was equivalent (0.62 versus 0.60, P = 0.794), while specificity was significantly lower in SM than in RM (0.66 versus 0.72, P = 0.028). Radiologists significantly (P < 0.05) preferred the display of all types of lesions in RM over SM. The average reading time per case was higher for RM than for SM (30 s versus 23 s, P < 0.05). CONCLUSION: Radiologists achieve similar cancer detection with RM as with SM. They prefer the 3D-like rotating representation of soft tissue lesions and calcifications in comparison to the 2D visualization, which might improve their specificity, but at the expense of longer reading time. PMID- 30396676 TI - Construction and validation of a low cost paediatric pelvis phantom. AB - PURPOSE: Imaging phantoms can be cost prohibitive, therefore a need exists to produce low cost alternatives which are fit for purpose. This paper describes the development and validation of a low cost paediatric pelvis phantom based on the anatomy of a 5-year-old child. METHODS: Tissue equivalent materials representing paediatric bone (Plaster of Paris; PoP) and soft tissue (Poly methyl methacrylate; PMMA) were used. PMMA was machined to match the bony anatomy identified from a CT scan of a 5-year-old child and cavities were created for infusing the PoP. Phantom validation comprised physical and visual measures. Physical included CT density comparison between a CT scan of a 5-year old child and the phantom and Signal to Noise Ratio (SNR) comparative analysis of anteroposterior phantom X-ray images against a commercial anthropomorphic phantom. Visual analysis using a psychometric image quality scale (face validity). RESULTS: CT density, the percentage difference between cortical bone, soft tissue and their equivalent tissue substitutes were -4.7 to -4.1% and 23.4%, respectively. For SNR, (mAs response) there was a strong positive correlation between the two phantoms (r > 0.95 for all kVps). For kVp response, there was a strong positive correlation between 1 and 8 mAs (r = 0.85), this then decreased as mAs increased (r = -0.21 at 20 mAs). Psychometric scale results produced a Cronbach's Alpha of almost 0.8. CONCLUSIONS: Physical and visual measures suggest our low-cost phantom has suitable anatomical characteristics for X-ray imaging. Our phantom could have utility in dose and image quality optimisation studies. PMID- 30396677 TI - Dynamic contrast-enhanced MRI perfusion of normal muscle in adult hips: Variation of permeability and semi-quantitative parameters. AB - The purpose of this prospective study was to ascertain the degree of variation of semi-quantitative and permeability parameters on DCE-MRI of normally appearing striated muscles. Dynamic contrast-enhanced MRI of the right hip was performed in 20 women and 24 men. Mean age was 39.1 +/- 12.4 years. Two regions of interest (ROI) were drawn in twelve muscles of anterior, medial and gluteal compartments: a free-form ROI covering the largest muscle section and a smaller elliptical ROI. Semi-quantitative and permeability parameters were calculated using the extended Tofts model. Statistical analysis was performed with a linear mixed model to assess perfusion parameters variation. Intra- and inter-observer agreements were assessed. The intra-observer agreement was considered to be good for free-form ROI (minimum Intra-Class Coefficient (ICC) = 0.72) and moderate for elliptical ROI (minimum ICC = 0.51), while the inter-observer agreement was considered to be bad in both cases (minimum ICC = 0.11). There was a high inter-individual variation in most of the perfusion parameters evaluated. The average coefficients of variation were: Time To Peak = 9%, Area Under the Curve = 44%, Ve = 61%, Kep = 90%, Initial Slope = 99%, and Ktrans = 128%. A considerable variation in resting muscle perfusion parameters was seen. This could lead to errors in the analysis of muscle DCE-MRI studies or oncologic/non oncologic studies using muscle as a referential. Further studies targeted on acquisition protocols and post processing software are necessary to improve the performance of muscle MR perfusion. PMID- 30396678 TI - Radiation dose for pediatric scoliosis patients undergoing whole spine radiography: Effect of the radiographic length in an auto-stitching digital radiography system. AB - OBJECTIVE: This study investigated the influence of spatial overlap and radiographic length (RL) on the effective dose (ED) and organ dose for pediatric patients undergoing whole spine radiography using an auto-stitching digital radiography (DR) system. METHODS: First, the system parameters were tested on a 10-year-old pediatric anthropomorphic phantom with a Shimadzu DR system, and the effects of the spatial overlap and RL on radiation doses were validated. The ED and organ dose were calculated on the basis of a Monte Carlo simulation program. Subsequently, 82 patients with adolescent idiopathic scoliosis were recruited. The spatial overlap and RL for each patient were modified to further investigate the dose reduction feasibility. RESULTS: RL and ED were appropriately correlated on the basis of patients' height. For a patient measuring 158 cm, the Shimadzu DR system was equipped with a 17-inch detector with a cut-off RL of 75 cm. The phantom simulations indicated that ED was reduced to a minimum value of 0.188 +/- 0.001 mSv with a high RL for RL < 75 cm. The minimum value increased to 0.300 +/- 0.002 mSv for an RL of 75 cm and dropped to 0.222 +/- 0.001 mSv for the maximum RL. By employing optimized RLs for patients, EDs were significantly reduced (p < 0.05). Moreover, ED reductions were higher when longer RLs were employed. CONCLUSION: A decrease in the spatial overlap and number of radiographic acquisitions by adjusting RLs when possible could reduce ED and almost all organ doses. This study emphasized the effects of RL on the radiation dose and provided useful guidance for modifying the RL for patients to reduce the whole spine radiography dose using a modern auto-stitching DR system. PMID- 30396679 TI - Uterotonic drug usage in Canada: a snapshot of the practice in obstetric units of university-affiliated hospitals. AB - OBJECTIVE: The objective of this study was to determine the pattern of uterotonic drug usage in obstetric units of university-affiliated hospitals in Canada. METHODS: This was a prospective observational study conducted in the form of an electronic survey. The target group consisted of chiefs or directors of Obstetrics and Anaesthesia at university-affiliated hospitals across Canada. The survey was sent out between November 2016 and January 2017, using the program 'SurveyMonkey'. Data on institutional obstetric practices and usage of uterotonic agents were collected. RESULTS: The survey was sent to 92 obstetricians and anesthesiologists from 46 institutions, of which 33 clinicians from 24 institutions responded. About 65% of clinicians were unaware of the rate of postpartum hemorrhage in their institution. The first-line agent for vaginal deliveries was reported as oxytocin by 94% and carbetocin by 6% of physicians. For women at low-risk for postpartum hemorrhage when undergoing cesarean deliveries (CD), 66% reported oxytocin as the first-line uterotonic, while 34% reported carbetocin. For CDs at high-risk of postpartum hemorrhage, 60% of physicians reported oxytocin and 40% reported using carbetocin initially. The use of second-line uterotonics was also variable. The choice of uterotonic was mainly based on perceived efficacy and Society of Obstetricians and Gynaecologists of Canada guidelines. CONCLUSION: There is a lack of a unified approach to the use of uterotonic drugs for postpartum hemorrhage management in Canada. To improve the management of postpartum hemorrhage due to uterine atony, an evidence-based approach to usage and consensus between obstetricians and anesthesiologists is warranted. PMID- 30396680 TI - Flow optimisations with increased channel thickness in asymmetrical flow field flow fractionation. AB - Retention in flow field-flow fractionation (flow FFF) is generally governed by the combination of crossflow and migration flowrates. Especially for an asymmetrical flow FFF (AF4) channel in which the channel-inlet flow is divided into crossflow and outflow, the separation of low-molecular-weight proteins or macromolecules requires a relatively high crossflow rate along with a very low outflow rate for a reasonable level of resolution, which often leads to a limitation in channel pressure. In this study, the performances of AF4 with increased channel thicknesses have been investigated by adjusting the effective channel flowrates in the asymmetrical channels according to the variation of channel thickness. Four AF4 channels of different channel thicknesses (350, 490, 600, and 740 MUm) were employed to examine the potential usefulness of employing a thick channel in the high-resolution separation of low-molecular-weight proteins (< 100 kDa) and to determine the relationship between higher channel thickness and the recovery of elution. Experiments showed that the ratio of crossflow rate to the effective channel flowrate should be considered in the selection of a run condition at an increased channel thickness. The study also demonstrated that a thick AF4 channel can be useful for the high-resolution separation of low-molecular-weight species such as protein aggregates without using extremely high crossflow rates. PMID- 30396681 TI - Retention time prediction in thermally modulated comprehensive two-dimensional gas chromatography: Correcting second dimension retention time modeling error. AB - Thermodynamic retention modeling to a thermally modulated comprehensive two dimensional gas chromatography (GC * GC) system run under constant flow is performed. Significant errors in modeled second dimension retention time (tr,2) were observed, in line with past work on thermally modulated GC * GC modeling. A comprehensive study of tr,2 modeling error for alkane separations across a wide range of heating ramp rates and carrier gas flow rates was performed. Modeling errors were found to be systematic and a function of analyte elution temperature and mobile phase velocity. A model to account for these systematic errors was generated, and associated coefficients were determined which reduced average tr,2 retention time error in 144 hydrocarbon separations by an order of magnitude resulting in significant improvement in prediction accuracy. The model was used to correct the separation of 139 Grob mix analyte separations, providing an average tr,2 modeling error of 0.030 +/- 0.022 s. The model successfully predicted the separation of n-alkanes on a longer second dimension column configuration. PMID- 30396682 TI - Enhanced coagulation of low-turbidity micro-polluted surface water: Properties and optimization. AB - Micro-polluted surface water with low turbidity and low content of dissolved organic matter (DOM) is usually inefficiently purified. In this work, a combined technique for the enhanced coagulation of this surface water was proposed and investigated using cationic grafted starch (St-G) and polyaluminum chloride (PACl) as co-coagulants, followed by a magnetic ion-exchange resin (MIER). St-G was fed before PACl, and this procedure not only efficiently removes turbidity but also largely reduces the doses of the two coagulants. MIER remarkably removed DOM, and raw water was effectively purified. The entire coagulation process was further optimized through response surface methodology based on a central composite design by using the doses of St-G, PACl, and MIER as input variables. The dose effects of the three chemicals on the coagulation performance for turbidity and DOM removal were examined, and the coagulation mechanisms, including the interactive effect among various chemicals, were discussed in detail. This work provided a new strategy for the efficient treatment of low turbidity micro-polluted surface water by utilizing organic and inorganic co coagulants with magnetic ion-exchange resin in practical applications. PMID- 30396683 TI - Digital Screen Time and Pediatric Sleep: Evidence from a Preregistered Cohort Study. AB - OBJECTIVES: To determine the extent to which time spent with digital devices predicts meaningful variability in pediatric sleep. STUDY DESIGN: Following a preregistered analysis plan, data from a sample of American children (n = 50 212) derived from the 2016 National Survey of Children's Health were analyzed. Models adjusted for child-, caregiver-, household-, and community-level covariates to estimate the potential effects of digital screen use. RESULTS: Each hour devoted to digital screens was associated with 3-8 fewer minutes of nightly sleep and significantly lower levels of sleep consistency. Furthermore, those children who complied with 2010 and 2016 American Academy of Pediatrics guidance on screen time limits reported between 20 and 26 more minutes, respectively, of nightly sleep. However, links between digital screen time and pediatric sleep outcomes were modest, accounting for less than 1.9% of observed variability in sleep outcomes. CONCLUSIONS: Digital screen time, on its own, has little practical effect on pediatric sleep. Contextual factors surrounding screen time exert a more pronounced influence on pediatric sleep compared to screen time itself. These findings provide an empirically robust template for those investigating the digital displacement hypothesis as well as informing policy-making. PMID- 30396685 TI - Have We Outgrown the Existing Models of Growth? AB - Theories of growth have a long history in biology. Two major branches of theory (mechanistic and phenomenological) describe the dynamics of growth and explain variation in the size of organisms. Both theory branches usually assume that reproductive output scales proportionately with body size, in other words that reproductive output is isometric. A meta-analysis of hundreds of marine fishes contradicts this assumption, larger mothers reproduce disproportionately more in 95% of species studied, and patterns in other taxa suggest that reproductive hyperallometry is widespread. We argue here that reproductive hyperallometry represents a profound challenge to mechanistic theories of growth in particular, and that they should be revised accordingly. We suspect that hyperallometric reproduction drives growth trajectories in ways that are largely unanticipated by current theories. PMID- 30396684 TI - Sildenafil Use in Children with Pulmonary Hypertension. AB - OBJECTIVE: To assess the demographics, treatment algorithm, and outcomes in a large cohort of children treated with sildenafil. STUDY DESIGN: A retrospective cohort study of children with pulmonary hypertension (PH) treated with sildenafil at a single institution between 2004 and 2015. Baseline and follow-up data collected by chart review. RESULTS: There were 269 children included in this study: 47 with idiopathic pulmonary arterial hypertension, 53 with congenital heart disease, 135 with bronchopulmonary dysplasia, 24 with congenital diaphragmatic hernia, and 7 with other causes. Sildenafil was initial monotherapy in 84.8% and add-on therapy in 15.2%. Median follow-up time was 3.1 years (2 weeks-12.4 years). On follow-up, 99 (37%) remained on sildenafil or transitioned to tadalafil, 93 (35%) stopped sildenafil for improvement in PH, 54 (20%) died, and 20 (7%) were lost to follow-up. PH was most likely to improve in those with bronchopulmonary dysplasia, allowing for the discontinuation of sildenafil in 45%. Eighteen deaths were related to PH and 36 from other systemic causes. Two patients stopped sildenafil owing to airway spasm with desaturation. Overall survival was significantly lower in World Health Organization group 3 PH (bronchopulmonary dysplasia and congenital diaphragmatic hernia) vs group 1 (idiopathic pulmonary arterial hypertension and congenital heart disease), P = .02. CONCLUSIONS: In this retrospective experience in children with mainly World Health Organization groups 1 and 3 PH, low-dose sildenafil was well-tolerated, safe, and had an acceptable side effect profile. Although patients with group 3 PH have high mortality, survivors have a high likelihood of PH improving. PMID- 30396686 TI - Psychosocial Distress and Health Service Utilization in Patients Undergoing Hemodialysis: A Prospective Study. AB - BACKGROUND: End-stage renal disease is associated with significant morbidity, high-symptom burden, and health care use. Studies have not yet assessed psychosocial distress and health care utilization in this population. OBJECTIVE: This study examines psychosocial distress and its association with hospitalization and emergency room (ER) visits in patients on maintenance hemodialysis (HD). METHODS: The Distress Assessment and Response Tool (DART) was administered to 80 adults on HD in a single treatment center. The DART assessed for anxiety, depression, and social distress. Health care utilization data were extracted prospectively from electronic medical charts. The time between psychosocial distress and hospitalization or ER visits during 12-month follow-up was examined using Cox proportional hazard models. RESULTS: Overall 46% of the sample reported psychosocial distress, with 33% screening above the threshold for depression, 14% for anxiety, and 36% for significant social distress. In multivariable regression adjusting for age, sex, and comorbidity, the presence of psychosocial distress was associated with shorter time to hospitalization (hazard ratio: 2.4 [1.1, 5.0], p = 0.03) during 12-month follow-up. Psychosocial distress was not significantly associated with ER visits in either univariable (hazard ratio: 1.3 [0.7, 2.3], p = 0.5) or multivariable (hazard ratio: 1.4 [0.8, 2.6], p = 0.3) analyses. CONCLUSION: Psychosocial distress is frequent in patients undergoing maintenance HD and is associated with shorter time to hospitalization. Future longitudinal studies should examine if health service use can be reduced through routine distress screening and psychosocial distress intervention. PMID- 30396687 TI - Triggering of CD99 on monocytes by a specific monoclonal antibody regulates T cell activation. AB - CD99, a leukocyte surface glycoprotein, has been implicated in many cellular processes including cell adhesion, cell migration and T cell activation. Our previous study demonstrated the anti-CD99 monoclonal antibody (mAb) clone MT99/3 inhibited T cell activation; however, the mechanism is unclear. In this study, we demonstrated that CD99 expressed on monocytes played a role in the inhibition of T cell activation. Anti-CD99 mAb MT99/3 downregulated the expression of costimulatory molecule CD86, but upregulated IL-6, IL-10 and TNF-alpha production by monocytes. The inhibitory effect of mAb MT99/3 required cell to cell contact between monocytes and lymphocytes. The soluble mediators produced by monocytes alone were insufficient to induce hypo-function of T lymphocytes. In summary, we demonstrated that ligation of CD99 on monocytes by anti-CD99 mAb MT99/3 could mediate T cell hypo-responsiveness. These findings provide the first evidence of the role of CD99 on monocytes that contributes to T cell activation. PMID- 30396688 TI - How do Nursing Staff Perform the Bronchodilation Challenge Test? Multicenter Study Performed in the Community of Madrid. PMID- 30396689 TI - Lessons from a Life: The Manuel Tapia Lecture 2018. PMID- 30396690 TI - Perineural invasion (PNI) in vulvar carcinoma: A review of 421 cases. AB - OBJECTIVES: To evaluate the prevalence and associated prognostic indicators in patients with vulvar carcinoma with and without evidence of perineural invasion (PNI). METHODS: A retrospective review identified 421 patients with invasive vulvar carcinoma evaluated at a single institution between 1993 and 2011. Medical records were reviewed for demographic data, pathologic information and presence or absence of PNI, treatment type, and recurrence/outcome information. Variables were compared between patients with PNI to those without PNI. RESULTS: Of the 421 patients included in the study, 32 (7.6%) had tumors with PNI. There were no significant differences in age, race/ethnicity, smoking history, histologic subtype, or grade between the group of patients with PNI and the group without PNI. The group with PNI was more likely to have lichen sclerosus (25.0% vs. 15.4%, p = 0.024), stage III/IV disease (59.4% vs. 36.0%, p = 0.007), lymph node involvement (50.0% vs. 21.6%, p = 0.002), and lymphovascular space invasion (LVSI) (53.1% vs. 15.9%, p < 0.001). A higher proportion of patients in the PNI group underwent primary or adjuvant radiation therapy (68.8% vs. 45.0%, p = 0.016). The median follow-up was 67.1 months (range < 1.0 to 284.3). Patients with PNI had significantly shorter overall survival (OS), median 25.5 vs. 94.3 months (p < 0.001), and progression-free survival (PFS), median 17.5 vs. 29.0 months (p = 0.004). After adjusting for stage, patients with PNI had a greater risk for death and progression (OS: hazard ratio, 2.71; p < 0.001; PFS: hazard ratio, 1.64; p-value = 0.020). CONCLUSION: PNI should be considered an independent poor prognostic factor for patients with vulvar carcinoma, and should be included as part of the pathologic analysis. PMID- 30396691 TI - Elevated body mass index is a risk factor associated with possible liver cirrhosis across different etiologies of chronic liver disease: More questions than answer? PMID- 30396692 TI - Night eating syndrome in patients with eating disorders: Is night eating syndrome distinct from bulimia nervosa? AB - BACKGROUND/PURPOSE: Night eating syndrome (NES) is a diagnosis newly introduced in the fifth version of the Diagnostic and Statistical Manual of Mental Disorders. This study investigated the characteristics of NES in individuals with eating disorders and the clinical significance of NES in individuals with bulimia nervosa (BN). METHODS: We recruited participants with eating problems at psychiatric outpatient clinics and from Internet referrals and age, sex, and educational level-comparable controls from September 2013 to April 2017. All participants received in-face structured clinical interviews to establish their eating disorder and NES diagnoses and completed questionnaires assessing NES, eating attitudes/behaviors, depression, sleep disturbances, morningness/eveningness preference, and functional impairment. Comparisons of measurements were made across patients with eating disorder subtypes and across patients with NES-only, BN-only, comorbid BN and NES, and controls. RESULTS: NES was identified in 10.3%, 34.9%, and 51.7% of the individuals with anorexia nervosa, BN, and binge-eating disorder, respectively. NES-only group had more frequent binge-eating, higher degrees of eating pathology, depression, sleep disturbances, and functional impairment compared to controls; however, NES-only group shared similar levels of disordered eating, depression, sleep disturbances, and functional impairment with BN-only group. BN-NES group had no difference from BN-only group on most eating pathology, psychopathology, and functional impairment, except for the presence of greater eating and weight concerns. CONCLUSION: NES has its clinical significance; however, it overlaps with BN in several dimensions of psychopathology. Presence of night eating in a BN group may not contribute clinically meaningful psychopathology. PMID- 30396693 TI - Giant bipolar intramedullary nondysraphic spinal cord lipoma: A case report. AB - INTRODUCTION: Intramedullary spinal cord lipomas (IMSCL) are a rare entity, accounting for less than 1% of spinal tumors. Most cases are associated with lumbosacral dysraphism and occur predominantly in the pediatric population. MATERIAL AND METHOD: We report the case of an isolated bipolar lipoma, which was very large in the cervicodorsal region and small in the conus medularis. The patient was a 9-years-old male who had muscle weakness for approximately 6 months. MRI showed a hyperintense lesion on T1, which was less intense on T2, without contrast enhancement at the cervicodorsal location and the conus medularis. At his admission, the patient experienced severe decompensation with flaccid tetraplegia and abdominal respiration. He immediately underwent decompression and partial resection of the cervical lesion. The anatomical pathology evaluation confirmed the diagnosis of a lipoma. DISCUSSION/CONCLUSION: The possibility of quality resection of intramedullary spinal cord lipomas is controversial due to the lack of a cleavage plane with the anterior tracts. Any attempt at total resection would expose the patient to the risk of neurological worsening which is often irreversible. In our case, the surgical indication was self-imposed, the main objective of which was decompression. PMID- 30396694 TI - Natural killer cell infiltration is discriminative for antibody-mediated rejection and predicts outcome after kidney transplantation. AB - Despite partial elucidation of the pathophysiology of antibody-mediated rejection (ABMR) after kidney transplantation, it remains largely unclear which of the involved immune cell types determine disease activity and outcome. We used microarray transcriptomic data from a case-control study (n=95) to identify genes that are differentially expressed in ABMR. Given the co-occurrence of ABMR and T cell-mediated rejection (TCMR), we built a bioinformatics pipeline to distinguish ABMR-specific mRNA markers. Differential expression of 503 unique genes was identified in ABMR, with significant enrichment of natural killer (NK) cell pathways. CIBERSORT (Cell type Identification By Estimating Relative Subsets Of known RNA Transcripts) deconvolution analysis was performed to elucidate the corresponding cell subtypes and showed increased NK cell infiltration in ABMR in comparison to TCMR and normal biopsies. Other leukocyte types (including monocytes/macrophages, CD4 and CD8 T cells, and dendritic cells) were increased in rejection, but could not discriminate ABMR from TCMR. Deconvolution-based estimation of NK cell infiltration was validated using computerized morphometry, and specifically associated with glomerulitis and peritubular capillaritis. In an external data set of kidney transplant biopsies, activated NK cell infiltration best predicted graft failure amongst all immune cell subtypes and even outperformed a histologic diagnosis of acute rejection. These data suggest that NK cells play a central role in the pathophysiology of ABMR and graft failure after kidney transplantation. PMID- 30396695 TI - Reprint of "Animal models of early-stage Parkinson's disease and acute dopamine deficiency to study compensatory neurodegenerative mechanisms". AB - Parkinson's disease is a common neurodegenerative disease characterized by a widely variety of motor and non-motor symptoms. While the motor deficits are only visible following a severe dopamine depletion, neurodegenerative process and some non-motor symptoms are manifested years before the motor deficits. Importantly, chronic degeneration of dopaminergic neurons leads to the development of compensatory mechanisms that play roles in the progression of the disease and the response to anti-parkinsonian therapies. The identification of these mechanisms will be of great importance for improving our understanding of factors with important contributions to the disease course and the underlying adaptive process. To date, most of the data obtained from animal models reflect the late, chronic, dopamine-depleted states, when compensatory mechanisms have already been established. Thus, adequate animal models with which researchers are able to dissect early- and late-phase mechanisms are necessary. Here, we reviewed the literature related to animal models of early-stage PD and pharmacological treatments capable of inducing acute dopamine impairments and/or depletion, such as reserpine, haloperidol and tetrodotoxin. We highlighted the advantages, limitations and the future prospective uses of these models, as well as their applications in the identification of novel agents for treating this neurological disorder. PMID- 30396696 TI - Contemporary stethoscope cleaning practices: What we haven't learned in 150 years. AB - BACKGROUND: Stethoscopes can be microorganism reservoirs. The US Centers for Disease Control and Prevention (CDC) has published medical equipment disinfection guidelines to minimize infection transmission risk, but studies of guideline adherence have been predominately survey based, with little direct observation of disinfection practices. METHODS: We performed an observational, cross-sectional, anonymous study of patient-provider interactions, assessing practitioners' frequency and methods of stethoscope and hand disinfection practices. RESULTS: Stethoscopes were disinfected in 18% of 400 observed interactions, with less than 4% verified as conforming to CDC guidelines. None was disinfected before patient examinations involving open chest or abdominal wounds, as recommended by the CDC. Hands were cleaned before and after encounters 27 times (6.8%) but were not cleaned at all in 231 (58%) encounters, although gloves were worn in 197 (85.3%) of these cases. DISCUSSION: Stethoscope disinfection is grossly overlooked, possibly jeopardizing patient safety, particularly in acute care interactions. Periodic stethoscope disinfection, although inconvenient, helps reduce bacterial contamination and may reduce health care-associated infections. CONCLUSIONS: Stethoscopes were disinfected per CDC guidelines in less than 4% of encounters and were not disinfected at all in 82% of encounters. Although hands were rarely cleaned (6.8%) per CDC guidelines, gloves were usually worn, but no convenient stethoscope equivalent exists. Stethoscope cleanliness must be addressed. PMID- 30396697 TI - Dalbavancin for the management of gram-positive osteomyelitis: Effectiveness and potential utility. AB - Dalbavancin is approved by the US Food and Drug Administration for the treatment of acute bacterial skin and skin structure infections. It has promising pharmacokinetic/pharmacodynamic profiles in treating bone infections and safety data after multiple weekly dosing. The primary objective of this study is to describe the effectiveness and tolerability of dalbavancin in the treatment of osteomyelitis in adults. This study is a multicenter retrospective review, designed to identify patients with osteomyelitis who were treated with dalbavancin. Thirty-six patients with confirmed diagnosis of osteomyelitis who received dalbavancin were identified. Thirty-one patients met inclusion criteria for evaluation of clinical success at the end of the antibiotic course and 3 months after the completion of therapy. Twenty-eight (90%) patients achieved clinical success and there were no adverse events noted. Dalbavancin appears to be safe and effective in the treatment of osteomyelitis. More studies are needed to validate these findings. PMID- 30396698 TI - The antidepressant-like effect of probiotics and their faecal abundance may be modulated by the cohabiting gut microbiota in rats. AB - Numerous studies have been published describing the effect of various probiotics (PRO) on behaviours related to psychiatric disease. We have previously shown a robust antidepressant-like effect of PRO in rats, but over time, the treatment effect seems to vary significantly between different sets of rats from the same commercial vendor. Therefore, we hypothesised that the antidepressant-like response may be modulated by the cohabiting gut microbiota. The aims of the present study were (1) to investigate any differences in the gut microbiota composition between responders (Resp) and non-responders (Non-resp) to PRO with regards to depressive-like behaviour, and (2) to evaluate the effects of PRO on the microbiota composition. Two sets of 20 male Sprague-Dawley rats each were treated with multi-species PRO (nine Bifidobacterium, Lactococcus and Lactobacillus species) for eight weeks and subjected to a behavioural assessment. Faecal samples were collected for 16 s rRNA (VR4) gene amplicon sequencing (Illumina MiSeq). As previously reported, PRO-treated Resp animals showed a marked decrease in depressive-like behaviour, whereas no such response was seen in Non-resp. We observed profound differences in the gut microbiota composition between the two sets of rats, and the relative faecal abundance of the genera that comprised PRO was higher in Resp than in Non-resp although treated with the same dose of PRO. Particularly, the relative abundance of the Lactobacillus genus was not increased in PRO-treated Non-resp animals. In conclusion, the cohabiting microbiota and the faecal abundance of PRO may modulate the antidepressant-like effect of PRO in rats. PMID- 30396699 TI - Reply to: "Type of organ failure and acute insult have important bearings in outcomes of liver transplantation: A pragmatic discourse". PMID- 30396700 TI - Rapid decline of kidney function in diabetic kidney disease is associated with high soluble Klotho levels. AB - BACKGROUND: Klotho is found in two forms: a transmembrane form and a soluble form (s-Klotho). In order to be excreted, s-Klotho, that is too large to be filtered, will probably reach the proximal convoluted tubule by a transcytosis process. The aim of our study was to show the relationship between the levels of s-Klotho and tubular injury in patients with diabetic kidney disease (DKD), using as tubular injury marker the kidney injury molecule-1 (KIM-1). METHODS: Our study included 63 DKD patients (stages 1-5, mean eGFR 65.15+/-32.45ml/min) with a mean age 58.13+/-12 years. In all patients we determined serum levels of: KIM-1 and s Klotho using ELISA, urinary albumin/creatinine ratio (UACR) and reduction in the estimated glomerular filtration rate (eGFR) per year. RESULTS: We found a strong statistically significant correlation of s-Klotho with the rate of reduction of eGFR/year (r=0.714, p=0.0004) and with the tubular injury marker KIM-1 (r=0.758, p=0.005) and strong correlations of UACR with the rate of reduction of eGFR/year (r=0.53, p<0.01), KIM-1 (r=0.49, p<0.05) and s-Klotho (r=0.52, p<0.01). CONCLUSION: Despite previous published data, that shows a decrease of s-Klotho in chronic kidney disease, in our study the rapid annual decline of kidney function but not the level of eGFR was associated with increased s-Klotho. A possible explanation could be a more severe proximal tubule injury that could lead to a reduction of tubular excretion of s-Klotho as suggested by the correlation of s Klotho levels with the serum levels of KIM-1. PMID- 30396701 TI - Voice Disorders are Associated With Stress Among Teachers: A Cross-Sectional Study in Finland. AB - OBJECTIVES: Voice disorders are considered to be more common among teachers than other occupations. However, epidemiological data are scarce and only a few researchers have studied stress as a risk factor in voice disorders in teachers. This paper presents data from a study on Finnish school teachers which investigated the prevalence of voice disorders and evaluated the risk factors for voice disorders, especially stress. STUDY DESIGN: A cross-sectional study was conducted among primary and secondary education teachers across Finland. METHODS: Voice disorders were assessed with a seven-item voice questionnaire and stress at work was measured with a validated single-item question. RESULTS: The prevalence of voice disorders over the 12-month period was 54% in the sample of 1198 primary and secondary education teachers in Finland. Of the teachers, 81% were female, and they suffered more voice disorders than the males. Stress was the most significant explanatory variable with a 3.6-fold risk as regards voice disorders. The association between voice disorders and stress was even stronger than that of asthma, asthma medication, and allergic rhinitis, which are known to cause serious risks for voice disorders in general. CONCLUSIONS: Our results hypothesize that stress may be a multi-dimensional problem associated with various risk factors and result in an even more urgent risk of voice disorders in teachers than estimated. Longitudinal research is needed to investigate the causality between voice disorders and stress among teachers. In addition, it is recommended that in the occupational health care of teachers' consideration should be given to the fact that voice disorders and stress may have a multi dimensional association. PMID- 30396702 TI - Prediction of quadriceps strength recovery after anterior cruciate ligament reconstruction with a hamstring autograft: Decision tree analysis. AB - BACKGROUND: The wide variations in patient demographics and concomitant injuries make the prediction of which patients will regain strength quickly following anterior cruciate ligament (ACL) reconstruction challenging. This study aimed to identify the dominant factor affecting quadriceps strength recovery after ACL reconstruction with a hamstring tendon autograft and to construct a predictive model for quadriceps strength recovery using decision tree analysis. METHODS: Three hundred and eighty-six patients who underwent ACL reconstruction with a hamstring tendon autograft were included in this study. The isokinetic quadriceps strength at 60 degrees /s was measured preoperatively and at 6 months after surgery. The quadriceps strength index (QSI) was calculated by normalising the peak torque of the involved leg with the uninvolved leg and multiplying it by 100. A stepwise multiple linear regression and a decision tree analysis were performed to assess whether or not the following parameters affect quadriceps strength recovery at 6 months: socio-demographic data and maximum isokinetic quadriceps strength. RESULTS: The preoperative QSI, age, and pre-injury Tegner activity scale were independently correlated with quadriceps strength recovery at 6 month after surgery. The decision tree analysis demonstrated that patients were expected to have a QSI >=85% at 6 months after surgery if they met one of the following conditions: (1) age <23 years with a preoperative QSI >=78.8%, (2) age >=29 years with a preoperative QSI >=98.0%, or (3) age <16 years with a preoperative QSI <58.5% and pre-injury Tegner activity scale >=9. By contrast, patients >=29 years with a preoperative QSI <98.0% were likely to achieve a quadriceps strength index <70% at 6 months after surgery. CONCLUSIONS: Based on the results of the decision tree analysis, younger patients could achieve good quadriceps recovery even if they have a lower preoperative QSI, whereas patients >=29 years need a higher preoperative QSI to obtain good muscle recovery. PMID- 30396703 TI - Is femoral trochlear dysplasia related to global joint hypermobility? AB - BACKGROUND: Hypermobility is a known risk factor for patellar instability. In this study, we hypothesized that a significant relationship exists between global joint hypermobility and trochlear dysplasia. METHODS: Follow-up patients from the shoulder department of our institution with global joint hypermobility (Group 1, n = 42) and healthy volunteers (Group 2, n = 42) without known knee complaints were included in our study. All participants underwent knee magnetic resonance imaging (MRI) for the evaluation of possible trochlear dysplasia, and the measurements included lateral trochlear inclination; trochlear facet asymmetry; the depth of the trochlear groove; condylar asymmetry; lateralization of the patella; sulcus angle; and the lateral, medial and central trochlear height. The Dejour classification was also assessed. RESULTS: The age and gender distributions of the groups were similar (p > 0.05). The radiological evaluations revealed that the lateral trochlear inclination (p < 0.001), trochlear facet asymmetry (p < 0.001), depth of the trochlear groove (p < 0.001), lateralization of the patella (p < 0.001), sulcus angle (p < 0.001), and central trochlear height (p < 0.001) were significantly different between the two groups. The condylar asymmetry and lateral and femoral condylar height parameters were similar between the groups (p = 0.297, p = 0.890 and p = 0.521, respectively). According to the Dejour classification, 39 patients had dysplasia in Group 1, whereas dysplasia was detected in only 4 of the participants in Group 2. CONCLUSIONS: Our study revealed that most of the trochlear dysplasia criteria were met in patients with global joint hypermobility. In addition to a clinical patellofemoral examination, the precise radiological evaluation of the joint is beneficial in patellofemoral instability patients with concomitant hypermobility. Patient cohort of this study was consist of patients underwent shoulder surgery. PMID- 30396704 TI - [Biosimilars in France, to understand the stakes in order to use them well]. PMID- 30396705 TI - Per labor Vasa Previa discovery: A simple clinical diagnosis. PMID- 30396706 TI - Stress and executive control: Mechanisms, moderators, and malleability. AB - Stress pervades everyday life and more importantly, affects prefrontal cortices that support executive control functions, processes that are critical to learning and memory as well as a range of life outcomes. The positive or negative effect of stress on cognition depends on an interaction of factors related to the situation and the individual. Research has shown that psychological characteristics related to self-relevance and the availability of resources may lead individuals to perceive a stressor as a threat or challenge, driving performance outcomes. Given that perception is arguably the key to stress reactivity, positive affect and self-belief constructs are discussed in the context of how they may lead to preserved performance in the face of stress. Understanding the underlying mechanisms of stress perception could inform the development of interventions, a socially important endeavor given the impact of stress on health and cognitive functions. PMID- 30396707 TI - Bond strength durability of self-adhesive resin cements to zirconia ceramic: An in vitro study. AB - STATEMENT OF PROBLEM: How contamination, cleaning, and artificial aging affect the bond strength of self-adhesive resin cements to zirconia ceramics is unclear. PURPOSE: The purpose of this in vitro study was to assess the durability and bond strength of different self-adhesive resin cements to zirconia ceramics subjected to contamination, cleaning, and aging. MATERIAL AND METHODS: A total 192 zirconia ceramic squares were airborne-particle abraded with 50 MUm Al2O3 at a pressure of 100 kPa. The specimens were then divided into 4 main experimental groups (n=48) according to the type of self-adhesive resin. Specimens in the subgroups (n=16) were exposed to 3 different treatment methods: alcohol bath cleaning only, contamination with saliva and alcohol bath cleaning, and contamination with saliva and cleaning with Ivoclean followed by alcohol bath cleaning. Bonded specimens were stored in distilled water (37 degrees C), either for 3 days with no thermocycling or for 150 days interrupted by 37500 thermocycles between 5 degrees C and 55 degrees C. After storage, the bond strength was determined using a universal testing machine. Results were analyzed statistically, using nonparametric tests. RESULTS: After saliva contamination, the tensile bond strength for all specimens decreased significantly (P<.001). Furthermore, after saliva contamination and during 150 days of water storage with thermocycling, all specimens debonded spontaneously. However, use of the cleaning medium (Ivoclean) significantly increased the tensile bond strength for almost all specimens (P<.05). CONCLUSIONS: Saliva contamination significantly negatively influenced the bond strength and durability to zirconia ceramic. Ceramic cleaning using Ivoclean significantly improved the bond strength to saliva contaminated zirconia ceramics. PMID- 30396708 TI - Randomized controlled clinical trial of digital and conventional workflows for the fabrication of zirconia-ceramic fixed partial dentures. Part III: Marginal and internal fit. AB - STATEMENT OF PROBLEM: Trials comparing the overall performances of digital and conventional workflows in restorative dentistry are lacking. PURPOSE: The purpose of the third part of this clinical study was to test whether the fit of zirconia 3-unit frameworks for fixed partial dentures fabricated with fully digital workflows differed from that of metal frameworks fabricated with the conventional workflow. MATERIAL AND METHODS: In each of 10 participants, 4 fixed-partial denture frameworks were fabricated for the same abutment teeth according to a randomly generated sequence. Digital workflows were applied for the fabrication of 3 zirconia frameworks with Lava, iTero, and Cerec infiniDent systems. The conventional workflow included a polyether impression, manual waxing, the lost wax technique, and the casting of a metal framework. The discrepancies between the frameworks and the abutment teeth were registered using the replica technique with polyvinyl siloxane. The dimensions of the marginal discrepancy (Discrepancymarginal) and the internal discrepancy in 4 different regions of interest (Discrepancyshoulder, Discrepancyaxial, Discrepancycusp, and Discrepancyocclusal) were assessed using a light microscope. Post hoc t tests with Bonferroni correction were applied to detect differences (alpha=.05). RESULTS: Discrepancyshoulder was 96.1 +/-61.7 MUm for the iTero, 106.9 +/-96.0 MUm for the Lava, 112.2 +/-76.7 MUm for the Cerec infiniDent, and 126.5 +/-91.0 MUm for the conventional workflow. The difference between the iTero and the conventional workflow was statistically significant (P=.029). Discrepancyocclusal was 153.5 +/-66.8 MUm for the iTero, 203.3 +/-127.9 MUm for the Lava, 179.7 +/ 63.1 MUm for the Cerec infiniDent, and 148.8 +/-66.8 MUm for the conventional workflow. Discrepancyocclusal was significantly lower for the conventional workflow than for the Lava and the Cerec infindent workflows (P<.01). The iTero resulted in significantly lower values of Discrepancyocclusal than the Lava and the Cerec infiniDent workflows (P<.01). CONCLUSIONS: In terms of framework fit in the region of the shoulder, digitally fabricated zirconia 3-unit frameworks presented similar or better fit than the conventionally fabricated metal frameworks. In the occlusal regions, the conventionally fabricated metal frameworks achieved a more favorable fit than the CAD-CAM zirconia frameworks. PMID- 30396709 TI - Accuracy of three digital workflows for implant abutment and crown fabrication using a digital measuring technique. AB - STATEMENT OF PROBLEM: The accuracy of a full digital workflow using an Atlantis abutment and a milled zirconia crown; a full digital workflow with a 3Shape split file workflow using a zirconia abutment and crown; and an interrupted digital workflow using an Atlantis abutment and a milled zirconia crown is unclear. PURPOSE: The purpose of this in vitro study was to compare 2 full digital workflows relative to an interrupted workflow for restoring an implant with a custom abutment and crown. The secondary purpose of this study was to validate a digital means of measuring internal fit and marginal discrepancy using engineering software programs. MATERIAL AND METHODS: Three workflows were evaluated. The first group, interrupted digital Atlantis (IDA) workflow, included a customized Atlantis abutment that was designed, received, and then rescanned for the definitive crown design. The second group, full digital Atlantis (FDA) workflow, included a customized Atlantis abutment and its corresponding standard tessellation language (STL) file, the Atlantis Core File, which was immediately imported into design software and used for crown design and milling. The third group, full digital split-file (FDSF) workflow, used 3Shape's full digital workflow for abutment and crown design called the split-file workflow, in which the crown and abutment were designed and milled simultaneously. All restorations were evaluated with standardized measurements using a scanning electron microscope (SEM) for 2D measurements, followed by standardized measurements using Geomagic Control, an engineering software program, which facilitated 3D evaluations of the specimens. RESULTS: The 2 Atlantis workflows, IDA and FDA, had statistically smaller marginal openings (P=.002) than the FDSF when measured using 2D SEM. The FDA had a statistically smaller 2D SEM marginal gap than the other 2 groups, IDA (P=.002) and FDSF (P=.002). The FDA had a statistically smaller 3D Geomagic marginal gap than the other 2 groups, IDA (P=.004) and FDSF (P=.006). The FDSF had a statistically smaller 3D Geomagic internal fit than the other 2 groups, FDA and IDA (both P=.006). CONCLUSIONS: All 3 workflows evaluated in this study showed clinically acceptable results in terms of mean marginal gap below 120 MUm. The SEM evaluation of mean marginal opening revealed that IDA and FDA mean marginal openings were statistically smaller than the FDSF mean marginal opening. SEM and Geomagic measurements revealed that the FDA mean marginal gap was significantly smaller than IDA and FDSF mean marginal gaps. Geomagic evaluation of mean internal fit revealed that the FDSF was significantly smaller than IDA and FDA. The use of Geomagic to measure and evaluate mean marginal gap and mean internal fit as defined in this study proved to be an acceptable form of measurement with statistical validation. PMID- 30396710 TI - Use of a dental surveyor to ensure optimal seating of implant overdenture attachments. AB - Many implant overdenture attachments accommodate divergent abutments. However, there can be instances where the denture base resin surrounding the abutment may impede seating by binding on the axial surface(s) of the abutment. This article describes the use of a dental surveyor to aid clinicians in determining where the resin denture base might be preventing the seating of overdenture attachments. The surveyor can be used for judicious adjustment to allow optimal seating of the attachments. PMID- 30396711 TI - Retrospective analysis of porous tantalum trabecular metal-enhanced titanium dental implants. AB - STATEMENT OF PROBLEM: The design of porous tantalum trabecular metal-enhanced titanium (TM) dental implants promises improved osseointegration, especially when grafting materials such as demineralized bone matrix are used; however, studies are lacking. PURPOSE: The purpose of this retrospective study was to compare TM implants with conventional titanium alloy (Ti) implants with and without demineralized bone matrix in terms of peri-implant bone remodeling in the first year after implant loading. MATERIAL AND METHODS: A chart review was used for all patients receiving Tapered Screw-Vent Ti and TM implants. Implants were placed and restored by a single provider between 2011 and 2015. Peri-implant bone remodeling was compared by using a paired t test (alpha=.05). RESULTS: A total of 82 patients received 205 implants, 44 TM and 161 Ti implants (control). No implants failed in the TM group (survival rate of 100%), and 3 implants in total, 1 immediate, failed in the Ti groups (survival rate of 98.1%). TM implants exhibited a 0.28-mm bone gain on average, whereas the control group demonstrated 0.20 mm of marginal bone loss after the first year of implant loading. Multivariate logistic regression analysis demonstrated that the odds of having bone loss was 64% less (odds ratio: 0.36; 95% confidence interval: 0.14-0.94) in the TM group than in the Ti group after controlling for bone grafting, implant location, immediate placement, bone type, and pretreatment bone level. CONCLUSIONS: TM implants exhibited less peri-implant bone loss than the control Ti implants. PMID- 30396712 TI - Restoration of a single darkened central incisor with a modified ceramic veneer. AB - Restoring a single darkened central incisor can be challenging. Both direct and indirect options may be acceptable to mask discoloration and achieve functional requirements. This report describes placement of a modified feldspathic porcelain veneer to reproduce the appearance of a maxillary central incisor discolored after trauma. PMID- 30396713 TI - Smartphone-based prenatal education for parents with preterm birth risk factors. AB - OBJECTIVE: To develop an educational mobile application (app) for expectant parents diagnosed with risk factors for premature birth. METHODS: Parent and medical advisory panels delineated the vision for the app. The app helps prepare for preterm birth. For pilot testing, obstetricians offered the app between 18-22 weeks gestational age to English speaking parents with risk factors for preterm birth. After 4 weeks of use, each participant completed a questionnaire. The software tracked topics accessed and duration of use. RESULTS: For pilot testing, 31 participants were recruited and 28 completed the questionnaire. After app utilization, participants reported heightened awareness of preterm birth (93%), more discussion of pregnancy or prematurity issues with partner (86%), increased questions at clinic visits (43%), and increased anxiety (21%). Participants reported receiving more prematurity information from the app than from their healthcare providers. The 15 participants for whom tracking data was available accessed the app for an average of 8 h. CONCLUSION: Parents with increased risk for preterm birth may benefit from this mobile app educational program. PRACTICE IMPLICATIONS: If the pregnancy results in preterm birth hospitalization, parents would have built a foundation of knowledge to make informed medical care choices. PMID- 30396714 TI - Ultrasound-assisted mark for internal jugular vein catheterization. PMID- 30396716 TI - The Safari for Adequate Landing Zones in EVAR Continues: Bilateral Use of Cook Zenith Iliac Branch Devices. PMID- 30396715 TI - Operative management of non-iatrogenic pediatric and adolescence peripheral arterial trauma: An experience from a resource challenged setting. AB - OBJECTIVES: To evaluates the management and outcome of non-iatrogenic pediatric and adolescence extremity arterial injuries in a resource-challenged setting. METHODS: A retrospective study of the surgical management for non-iatrogenic extremity arterial trauma in pediatric and adolescence during the period from January 2008 to December 2015. This study was performed in two different countries at tertiary referral university and teaching hospitals having a specialized emergency and trauma centers. A thorough study of each patient record was collected from these centers including, the original demographic data and their clinical presentations. Operative data of each patient was also reported. RESULTS: During the 8-year period of the study, 149 pediatric and adolescent extremity arterial trauma patients were treated. They were 93.3% male, and 6.7% female, respectively. The age ranged from 2 to 18 years with a mean of 10.25 +/- 4.05 years. Lower extremity arterial trauma was recorded in 51%, while 49% were having upper extremity injuries. Primary repair with end-to-end vascular anastomosis was performed in 51.7%, while an interposition reversed saphenous vein graft was performed in 48.3%. The operative procedures were performed by an experienced vascular surgeon and well-trained pediatric surgeons and general surgeons. Pseudoaneurysms was recorded in 9% of cases. Fasciotomy was performed in 15% of cases. CONCLUSION: Treatment of pediatric and adolescent extremity arterial injuries with primary end-to-end vascular anastomoses or with the use of an interposition reversed saphenous vein graft is a reliable, feasible, and more cost-effectiveness technique with good results. Moreover, it should be adopted for all vascular trauma patients, whenever possible. PMID- 30396717 TI - Traumatic Deviation of the Popliteal Artery. PMID- 30396719 TI - Biopiracy of medicinal plants: Finding fair solutions for the use of natural resources. PMID- 30396718 TI - The protective effects of Aquilariae Lignum Resinatum extract on 5-Fuorouracil induced intestinal mucositis in mice. AB - BACKGROUND: Aquilariae Lignum Resinatum as a traditional Chinese medicine is used in prescription for treatment of gastrointestinal diseases. Phytochemical investigations show that there are many anti-ulcer and anti-inflammatory ingredients in A. agallocha methanol extract (AEE). However, scarce data is available about the constituents absorbed into the blood, activity and mechanisms of AEE on intestinal mucositis. HYPOTHESIS/PURPOSE: To analyze the bioactive constituents of AEE absorbed in the blood, and further explore the potential mechanisms of the protection against chemotherapy-induced intestinal mucositis. METHODS: The serum pharmacochemistry using UHPLC-Q-TOF/MS was performed to screen the bioactive compounds of AEE absorbed in serum. The intestinal mucositis was induced by 5-Fuorouracil (5-Fu) and treated with AEE. The severity of intestinal mucositis was evaluated based on body weight, food-intake and diarrhea. Furthermore, the mechanism of AEE was investigated involved in the pathogenesis of mucositis on repairing injury of intestinal mucosa, immune functions, and inflammatory response. RESULTS: Altogether, 11 components were identified or tentatively characterized in dosed plasma. In pharmacodynamics study, intestinal mucositis caused by 5-Fu was effectively attenuated after AEE treatment. AEE treatment improved food-intake and injury of the intestinal mucosa, relieved body weight loss and severe diarrhea through up-regulating expression of proliferating cell nuclear antigen (PCNA) and inhibiting the levels of cyclooxygenase-2 (COX-2) and tumor necrosis factor-alpha (TNF-alpha) in ileum segments. CONCLUSIONS: AEE protected against 5-Fu-induced intestinal mucositis (IM) in mice through mechanisms that involved in promoting the enterocyte proliferative activity, maintaining the integrity of tight junction proteins, inhibiting oxidative stress and ameliorating the inflammatory disturbances. Accordingly, A. agallocha may be a promising therapeutic candidate used for the prevention of IM during cancer chemotherapy. PMID- 30396720 TI - In vitro activity of temocillin against extended-spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae strains isolated from urinary tract infections in France. AB - OBJECTIVES: Temocillin was introduced in 2015 in the French guidelines for the treatment of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae urinary tract infections. Little susceptibility data is available. We investigated the in vitro activity of temocillin against ESBL-producing Enterobacteriaceae isolated from samples of cytobacteriological examinations of urine. MATERIAL AND METHODS: Susceptibility testing was performed on 157 ESBL producing E. coli and 95 ESBL-producing K. pneumoniae strains using the disk diffusion method. MICs of resistant strains were measured with the Etest method. RESULTS: Using current breakpoints, 71.3% of E. coli strains and 77.9% of K. pneumoniae strains were classified as susceptible. However, diameter and MIC breakpoints vary by country, and we reported discordance of clinical categorization between diameters and MIC determination for some strains. The measure of diameters was also sometimes difficult because of contaminating colonies within the inhibition zone. CONCLUSION: We highlighted difficulties related to the determination of temocillin susceptibility, such as culture of resistant colonies in the inhibition zone and discordance of clinical categorizations obtained with the disk diffusion method or the Etest method. Overall, 42% of tested Enterobacteriaceae had a diameter or MIC close to the current breakpoints; thus, it is necessary to determine the MIC for these strains before considering the clinical use of this molecule. PMID- 30396721 TI - Evaluation of Margin Status of a Breast Lumpectomy Specimen: What the Radiologist Should Know. AB - Breast Conserving Therapy (BCS) or lumpectomy has been an established treatment option for women with early-stage invasive breast cancers. Surgical margin status has a significant impact on local recurrence. However, there is much complexity in achieving a negative lumpectomy margin. There are multiple risks and predictors of positive surgical margins that the radiologist needs to be familiar with. When working as a member of a multidisciplinary team, it is important to be cognizant of the pathologist's and surgeon's roles in reducing the number of failed breast conserving surgeries. Despite the common use of imaging to help avoid positive surgical margins, it is important to remember the limitations of standard intraoperative specimen radiographs. A negative resection margin is the goal of BCS ensuring decrease of local recurrence, increased cosmesis, and improved long-term survival. PMID- 30396722 TI - Familial congenital choanal atresia with GATA3 associated hypoparathyroidism deafness-renal dysplasia syndrome unidentified on auditory brainstem response. AB - Hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome is a rare autosomal dominant disorder primarily caused by GATA3 haploinsufficiency and is challenging to diagnose in early childhood. We report a Japanese family with HDR syndrome and congenital choanal atresia. The 6-year-old female proband was diagnosed with epilepsy at the age of three. Under carbamazepine monotherapy, the patient presented hypoparathyroidism accompanied by severe hypocalcemia. Subsequently, renal ultrasound analysis revealed bilateral multicystic dysplastic kidneys. Because she had difficulty hearing, we sequenced GATA3 and determined that she had a c.708_709insC (p.Ser237Glnfs*66) allelic variant in exon 3. As a result, we found a family of this disease. Each family member, including her grandfather, mother, and two siblings, had HDR syndrome of varying clinical penetrance. We found a craniofacial anomaly, congenital choanal atresia, which was inherited as an autosomal dominant trait. Hypocalcemia coupled with vitamin D deficiency, triggered by carbamazepine treatment, ultimately revealed the proband's childhood onset HDR syndrome. Pure-tone audiometry revealed different severities of deafness as well as the progression of sensory hearing loss. However, auditory brainstem response for hearing screening is probably insufficient for ascertaining HDR syndrome in the early stages of life. We presented new clinical clues to diagnose the HDR syndrome. PMID- 30396723 TI - Parent and Adolescent Attitudes Towards Preventive Care and Confidentiality. AB - PURPOSE: Little is known about whether parents and adolescents agree in their attitudes towards preventive care, private time, and confidentiality for adolescent care. METHODS: We surveyed a nationally representative sample of 1,209 13-18 year-old U.S. adolescents and their parents. Parent and adolescents attitudes towards preventive services, private time, and confidentiality were compared. Parent-youth dyad agreement was measured using Cohen's kappa and Spearman coefficients and modeled for association with demographic variables. RESULTS: Parents are more likely than adolescents to think preventive services are important (71% vs. 48%; p < .001). Parent-youth attitudes were weakly to moderately correlated (Cohen's kappa coefficient = .22; p < .001). Parents and adolescents report similar ages for when teens should start having private time (median 16 years for both) and many think this age should be at 18, the legal age of adulthood). Fewer than half believe confidentiality should be provided for 10 services, ranging from routine care to abortion care (parents range: 12.8%-52.3%; adolescents: 24.0%-58.8%). While most adolescents agreed with their parents, teens were more likely to report wanting confidential access than parents. Older age, Hispanic ethnicity, having divorced parents and higher family income were associated with both adolescent/parent and adolescent endorsement of confidentiality. CONCLUSIONS: Adolescents and parents generally agree about the importance of preventive services, private time, confidentiality, and what should and should not be confidential. On average, parents value clinical preventive services more than youth, and youth value confidentiality more than parents. Both believe private time should start at ages older than those recommended in clinical guidelines. PMID- 30396724 TI - Extreme Weight Loss Behaviors in Racially Diverse Urban Adolescents. AB - PURPOSE: Extreme weight loss behaviors (EWLBs) pose a serious health risk to adolescents. Studies suggest a link between EWLBs and other health-compromising behaviors. Extending these findings, this study examines correlates of EWLB in a predominantly minority adolescent population. METHODS: A secondary analysis of EWLB data from adolescents in an inner city pediatric emergency department was conducted. The sample (n = 3,876) included 60% African-American, 20% Hispanic, 16% Caucasian, and 4% Asian-Pacific Islander individuals. Comparative analyses and multivariate logistic regressions were applied. RESULTS: Fifteen percent of the sample endorsed use of EWLBs; endorsement did not differ between minority and Caucasian groups, or among minority subgroups. EWLB correlates included female gender, hopelessness, abuse history, current smoking, and alcohol use. CONCLUSIONS: Endorsement of EWLBs is not different between minority and Caucasian adolescents surveyed in an emergency department. Identified correlates are potential targets for prevention and early intervention. PMID- 30396725 TI - Radiographic predictors of IMRT for treating regional lymph nodes in breast cancer. AB - Regional nodal irradiation (RNI) is an essential part of the treatment of high risk early stage (Stage IIb) and locally advanced (Stage III) breast cancer. Acceptable radiation plans can usually be achieved using 3-dimensional conformal radiation therapy with deep-inspiration breath hold to limit dose to the heart, although in some cases intensity-modulated radiation therapy produces superior results. The goal of this study is to identify radiographic parameters that predict the need for IMRT when delivering RNI. We retrospectively examined breast cancer patients treated with comprehensive RNI including internal mammary lymph nodes, supraclavicular lymph nodes, and undissected axillary lymph nodes at our institution from January 2016 to February 2018. Radiographic parameters including lung volume, internal mammary lymph nodes depth, modified central lung distance (mCLD), tangent length, and target height were recorded. Univariate and multivariate logistic regression was performed using IMRT as a binary endpoint (yes/no). A total of 46 patients were evaluated, of which 9 (20%) required IMRT. Five of the 9 (56%) IMRT patients were postmastectomy with a tissue expander in place. There was an increased likelihood of IMRT per 0.5 cm increase in mCLD (odds ratios [OR]: 3.27; 95% confidence interval [CI]: 1.39 to 9.63; p = 0.01) and per 1 cm increase in target height (OR: 1.77; 95% CI: 1.08 to 3.40; p = 0.04). A threshold value of 3.38 cm was identified for mCLD (OR 10.3; 95% CI: 2.14 to 61.4; p value = 0.005), and 25.2 cm for target height (OR 10.9; 95% CI: 2.19 to 82.7; p value = 0.007). When delivering RNI, larger values of mCLD and target height corresponded to the use of IMRT. Further investigations are warranted to confirm these findings, which may improve the efficiency of the treatment planning process and in turn patient care. PMID- 30396726 TI - Association Between 25-Hydroxyvitamin D and Bone Mineral Density in People With Obstructive Sleep Apnea Syndrome. AB - The aim of this study was to evaluate the association between bone mineral density (BMD) and 25-hydroxyvitamin D [25(OH) D] levels in patients with obstructive sleep apnea syndrome (OSAS). This study was designed as a cross sectional and observational study. Patients who underwent polysomnography evaluation were classified as normal, mild, moderate, severe, or position dependent OSAS, and OSAS + obesity hypoventilation syndrome (OHS). BMD was measured with the dual-energy X-ray absorptiometry method at the femur and lumbar spine. The chemiluminescence microparticle immunoassay was used for the measurement of 25(OH) D levels. A total of 126 patients (73 males, 53 females) with a mean age of 48.55 +/- 11.8 years were included. Body mass index was significantly higher in the OSAS + OHS group than in the other groups (p < 0.01). There was no statistically significant difference between the groups in terms of total BMD, T-scores and Z-scores of the lumbar spine, femural neck, and total femur (p > 0.05 for all). Post hoc analyses showed that OSAS + OHS subgroup had lower level of 25(OH) D compared to the normal subjects (p = 0.006). Yet no significant difference was observed between the other OSAS groups. No significant correlation was observed between the apnea hypopnea index, the Epworth Sleepiness Scale scores, desaturation index, and BMD parameters (all for p > 0.05). While 25(OH) D levels were lower in OSAS + OHS patients, there was no statistically significant relationship between OSAS and BMD values. PMID- 30396727 TI - Ongoing advancements in the understanding of tricuspid valve dynamics and functional geometry. PMID- 30396728 TI - Hold 'em or fold 'em. PMID- 30396729 TI - Clamp-on...clamp-off. PMID- 30396730 TI - Coronary patients on dialysis: Coronary artery bypass grafting or percutaneous coronary intervention? A complex question for a complex scenario. PMID- 30396731 TI - Untreated distal intimal tears may be associated with paraplegia after total arch replacement and frozen elephant trunk treatment of acute Stanford type A aortic dissection. AB - OBJECTIVE: To investigate the possible overlooked causes of early postoperative paraplegia, a severe complication of acute Stanford type A aortic dissection (ATAAD) after total arch replacement and frozen elephant trunk (FET). METHODS: We reviewed the clinical data and perioperative aortic computed tomography angiography records of 110 consecutive patients with ATAAD who underwent total arch replacement and FET (12 cm) between December 2014 and September 2017 and investigated the possible risk factors related to early postoperative paraplegia. RESULTS: Paraplegia occurred in 5 (4.5%) patients. No significant differences were found between patients with and without paraplegia in terms of sex, age, medical history, cardiopulmonary bypass time, antegrade cerebral perfusion time, rectal temperature during antegrade cerebral perfusion, postoperative hypotension, maximum first 24-hour vasoactive-inotropic score, upper-lower pressure gradient, or false lumen thrombosis. Postoperative aortic computed tomography angiography showed a "cutoff" phenomenon in the lower descending aorta in 4 of the 5 patients. Univariate logistical analysis showed that paraplegia was associated with the "cutoff" phenomenon (P < .05). The patients with a distance >=30 mm from the distal end of the stent to the first untreated intimal tear had significantly greater rates of the "cutoff" phenomenon and paraplegia than those with the distance <30 mm (P < .05). CONCLUSIONS: Total arch replacement and FET is safe and feasible for ATAAD involving the descending aorta. Early postoperative paraplegia is associated with the "cutoff" phenomenon in the lower descending aorta. The position of the first untreated intimal tear may be related with the occurrence of the "cutoff" phenomenon and paraplegia. PMID- 30396732 TI - Is a more extensive operation justified for acute type A dissection repair? PMID- 30396733 TI - The ring of fire: Nuances in the surgical management of mitral annular calcification. PMID- 30396734 TI - Influence of aortic stiffness on ventricular function in patients with Fontan circulation. AB - OBJECTIVE: Elastic properties of the thoracic aorta are responsible for buffering systemic afterload, and may be particularly important in patients with Fontan circulation, in whom heart failure is a major source of attrition. The purpose of this study was to characterize regional stiffness in the ascending and descending aorta in patients with hypoplastic left heart syndrome and single left ventricle morphology after Fontan operation by cardiac magnetic resonance imaging, and to assess whether changes in aortic stiffness are associated with the ventricular function. METHODS: Phase-contrast-derived pulse-wave velocity (PWV) and relative area change (RAC) were measured in the ascending and descending aorta of patients with hypoplastic left heart syndrome (n = 9), patients with single left ventricle circulation (n = 18), and normal controls (n = 8) by magnetic resonance imaging. Stiffness metrics were then correlated with the ventricular volumetric and functional indices. RESULTS: Patients with hypoplastic left heart syndrome had elevated ascending aortic PWV along with reduced RAC when compared with controls (both P values < .001). Patients with a single left ventricle presented no change in PWV but had reduced RAC in comparison to controls (P < .01). There were no differences in PWV and RAC between all considered groups in the descending aorta. PWV and RAC measured in the ascending aorta correlated with end-systolic and end diastolic volume indices, ventricular ejection fraction, and ventricular-vascular coupling ratio. CONCLUSIONS: Aortic stiffness is most elevated in patients with hypoplastic left heart syndrome, yet patients with single left ventricle morphology show signs of abnormal stiffness as well in the form of reduced aortic strain. Stiffness indices measured in the ascending aorta were associated with overall ventricular function and measures of aortoventricular coupling in both patient populations. PMID- 30396736 TI - An old off-pump coronary artery bypass surgeon's reflections: A retrospective. PMID- 30396735 TI - Acute aortic dissections with entry tear in the arch: A report from the International Registry of Acute Aortic Dissection. AB - OBJECTIVE: To analyze presentation, management, and outcomes of acute aortic dissections with proximal entry tear in the arch. METHODS: Patients enrolled in the International Registry of Acute Aortic Dissection and entry tear in the arch were classified into 2 groups: arch A (retrograde extension into the ascending aorta with or without antegrade extension) and arch B (only antegrade extension into the descending aorta or further distally). Presentation, management, and in hospital outcomes of the 2 groups were compared. RESULTS: The arch A (n = 228) and arch B (n = 140) groups were similar concerning the presence of any preoperative complication (68.4% vs 60.0%; P = .115), but the types of complication were different. Arch A presented more commonly with shock, neurologic complications, cardiac tamponade, and grade 3 or 4 aortic valve insufficiency and less frequently with refractory hypertension, visceral ischemia, extension of dissection, and aortic rupture. Management for both groups were open surgery (77.6% vs 18.6%; P < .001), endovascular treatment (3.5% vs 25.0%; P < .001), and medical management (16.2% vs 51.4%; P < .001). Overall in hospital mortality was similar (16.7% vs 19.3%; P = .574), but mortality tended to be lower in the arch A group after open surgery (15.3% vs 30.8%; P = .090), and higher after endovascular (25.0% vs 14.3%; P = .597) or medical treatment (24.3% vs 13.9%; P = .191), although the differences were not significant. CONCLUSIONS: Acute aortic dissection patients with primary entry tear in the arch are currently managed by a patient-specific approach. In choosing the management type of these patients, it may be advisable to stratify them based on retrograde or only antegrade extension of the dissection. PMID- 30396737 TI - Three-year efficacy and patency follow-up of decellularized human internal mammary artery as a novel vascular graft in animal models. AB - BACKGROUND: Various investigations have reported that the internal mammary artery (IMA) is an efficient and functional choice of conduit for vascular graft surgeries, especially for coronary artery bypass grafts; however, the quest to find an ideal vascular substitute remains. We hypothesized that acellular IMA could be an appropriate graft for small-diameter vascular bypasses that could be used in various surgeries including coronary artery bypass grafting. METHODS: We decellularized human IMAs and performed histologic evaluations and scanning electron microscopy to confirm the decellularization process and the preservation of the extracellular matrix. Subsequently, we grafted the scaffolds into the superficial femoral arteries of 8 New Zealand rabbits with an end-to-end anastomosis. Computed tomography angiograms were provided at 3, 12, and 36 months postoperatively. Subsequently, the animals were killed, and biopsies were taken for histologic and immunohistochemical assessments. RESULTS: Evaluation of the acellular tissue confirmed the efficacy of the decellularization protocol and the preservation of the extracellular matrix. All 8 animals survived the entire follow-up period. Doppler ultrasonography and computed tomography angiographies verified the conduit's patency. Histologic assessments depicted the recellularization of all 3 layers of the scaffold. Smooth muscle cells were detected in tunica media. Immunohistochemical assessments confirmed these findings. CONCLUSIONS: In conclusion, we demonstrated that acellular human IMA could be used as an efficient small-diameter vascular substitute with high patency. These findings could pave the path for future investigations on the clinical application of acellular IMA as a novel vascular graft for small diameter bypass surgeries. PMID- 30396738 TI - Cold-inducible RNA-binding protein as a novel target to alleviate blood-brain barrier damage induced by cardiopulmonary bypass. AB - BACKGROUND: Hypothermia provides neuroprotection and alleviates cerebral injury after cardiopulmonary bypass (CPB). The mechanism of cold-inducible RNA-binding protein (CIRP), which has been reported to be facilitated by hypothermia and act as a critical regulatory protein in the brain, remains unclear in CPB. Hence, the role of CIRP on hypothermia CPB-induced brain injury was investigated in a rat model. METHODS: Cirp-/- rats were generated using the transcription activator like effector nucleases-based genome editing technique. The animals were randomly allocated to 3 groups (n = 5, each group): sham group, CPB group, and CPB in Cirp /- group (Cirp-/- group). Three biological replicates received RNA sequencing in the CPB and Cirp-/- groups. The relative protein expression of the hippocampus was detected. The integrity of the blood-brain barrier (BBB) was measured using transmission electron microscopy and immunoglobulin G immunostaining. Glial fibrillary acidic protein in serum was detected. The brain was fixed for histopathological assessment. RESULTS: More differentially expressed genes of BBB leakage were clustered functionally by gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Transforming growth factor-beta1, matrix metallopeptidase-9, tumor necrosis factor-alpha, and malondialdehyde in the hippocampus were higher in the Cirp-/- group, whereas the interleukin-4 level was opposite. Furthermore, more serious BBB disruption in the Cirp-/- group was shown using transmission electron microscopy and immunoglobulin G extravasation. Moreover, Cirp-/- showed enhanced tight junction protein degradation and histopathologic injury in the hippocampus (pathological score, surviving hippocampal neurons, and terminal deoxynucleotidyl transferase-mediated 2' deoxyuridine, 5'-triphosphate nick-end labeling-positive neurons). Therefore, CIRP significantly alleviated neurologic injury. CONCLUSIONS: CIRP exerted important neuroprotective effects by alleviating BBB breakdown, which might be associated with transforming growth factor-beta1-matrix metallopeptidase-9 signals in hypothermia CPB. PMID- 30396739 TI - Effect of preoperative inhaled budesonide on pulmonary injury after cardiopulmonary bypass: A randomized pilot study. AB - BACKGROUND: Cardiopulmonary bypass can result in lung injury. This prospective, double-blinded, randomized trial aimed to evaluate the protective effect of inhaled budesonide on lung injury after cardiopulmonary bypass. METHODS: Sixty patients, aged 25 to 65 years, requiring cardiopulmonary bypass were randomized to groups treated with saline or budesonide inhalation preoperatively. The respiratory mechanics were recorded. Bronchoalveolar lavage fluid was collected before cardiopulmonary bypass and after sternal closure. Serum and bronchoalveolar lavage fluid levels of proinflammatory and anti-inflammatory factors were analyzed. The primary end point was the lowest ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen after cardiopulmonary bypass. The durations of ventilation and postoperative recovery time were noted. RESULTS: Budesonide significantly improved respiratory mechanics after cardiopulmonary bypass. Budesonide improved the partial pressure of arterial oxygen to the fraction of inspired oxygen ratio from 8 to 48 hours after the operation. Budesonide shortened the durations of mechanical ventilation and postoperative recovery time. Budesonide decreased the levels of proinflammatory factors while increasing the levels of anti-inflammatory factors in bronchoalveolar lavage fluid and serum (all P < .05). The macrophage and neutrophil counts, and protein and elastase concentrations were decreased by budesonide treatment. CONCLUSIONS: Budesonide treatment shortened the durations of mechanical ventilation, inhibited local and systemic inflammation, and improved respiratory function after cardiopulmonary bypass. PMID- 30396740 TI - Cardiac paraganglioma: The surgical challenge. PMID- 30396741 TI - The Aggressive Cholesterol Therapy to Inhibit Vein Graft Events trial: To continue or not? How to answer the question. PMID- 30396742 TI - The timing of chemotherapy in multimodality treatment of locally advanced lung cancer: One size does not fit all. PMID- 30396743 TI - An examination on composition of spermatozoa obtained from pre-operative and post operative varicocele patients. AB - Varicocele is one of the main and surgically repairable causes of male infertility, which arises from dilatation and torsion of the testicular veins in the plexus pampiniformis. In this study, we examined semen samples from 40 patients diagnosed with varicocele between the ages of 15 and 30 years, according to WHO criteria (pre-operatively, and at 3, 6, and 12 months post-operatively). The mean spermatozoa concentration was found to be 45.25 +/- 34.83 million/ml pre operatively, while the mean post-operative concentration was 48.85 +/- 35.73 million/ml at three months, 51.72 +/- 32.82 million/ml at six months, and 49.63 +/- 28.05 million/ml at 12 months (P > 0.05). The mean rate of A + B motile spermatozoa was 35.5 +/- 14.71% pre-operatively, 42.65 +/- 16.80% at three months, 43 +/- 13.52%at six months and 44 +/- 14.76 percent at 12 months post operatively (P < 0.05). The mean Kruger morphology score was 3.15 +/- 3.0% pre operatively, and 3.20 +/- 2.83% at three months, 2.97 +/- 2.61%at six months and 3.27 +/- 2.50%at 12 months post-operatively (P > 0.05). The nucleus, acrosomal cap, mitochondrial structure and microtubules of the tail of the spermatozoa were examined under electron microscopy. The mean DNA fragmentation index (DFI%) of the spermatozoa was 20.57 +/- 4.60% pre-operatively, and post-operatively at 17.27 +/- 3.65% at three months, 15.5 +/- 3.23% at six months and 15.3 +/- 3.63% at 12 months (P < 0.001). The findings suggest that despite the increased count and motility, as well as the improved DNA fractures observed post-operatively in the spermatozoa of varicocele patients, the morphology rates remain intact. PMID- 30396744 TI - Medicaid Insurance Correlates With Increased Resource Utilization Following Total Hip Arthroplasty. AB - BACKGROUND: With increased restraints and efforts to contain costs in total hip arthroplasty (THA), an emphasis has been placed on risk stratification. The purpose of this study was to determine whether Medicaid patients have increased resource utilization (including 90-day emergency department [ED] visits and readmissions) compared to Medicare or commercial insurance carriers. The study hypothesized that the Medicaid population would represent a high-risk cohort with increased resource utilization. METHODS: The institutional database was retrospectively queried for primary THAs from 2013 to 2017 based on Current Procedural Terminology codes and patients undergoing revision surgery were excluded. Demographic information including age, sex, and body mass index (BMI) and medical comorbidities including American Society of Anesthesiologists (ASA) scores were evaluated. Patients were stratified by insurance type and length of stay (LOS), and 90-day ED visits and 90-day readmissions were assessed in univariable and multivariable analysis. RESULTS: A total of 3674 primary THA patients were included in the analysis (including 116 with Medicaid, 1713 with Medicare, and 1845 with other insurance providers). Medicaid patients had significantly higher ASA scores (P < .001) and BMI (P < .001), with corresponding increase in procedure duration (115 vs 99 vs 105 minutes; P < .001). They had a prolonged LOS (2.5 vs 2.5 vs 1.5 days; P < .001) compared with other insurances, but similar to Medicare patients. Following discharge, in multivariable analysis controlling for age, BMI, and ASA score, Medicare patients were significantly more likely to return to the ED (odds ratio, 3.15; 95% confidence interval, 1.88 5.27; P < .001) and be readmitted (odds ratio, 2.46; 95% confidence interval, 1.26-4.81; P = .009). CONCLUSION: Medicaid patients represent a higher risk cohort with increased resource utilization perioperatively, including longer LOS, and more 90-day ED visits and readmissions. This should be considered in outcome assessments and alternative expectations for the episode of care should be set for this population. PMID- 30396745 TI - PD-1 immunobiology in systemic lupus erythematosus. AB - Programmed death (PD)-1 receptors and their ligands have been identified in the pathogenesis and development of systemic lupus erythematosus (SLE). Two key pathways, toll-like receptor and type I interferon, are significant to SLE pathogenesis and modulate the expression of PD-1 and the ligands (PD-L1, PD-L2) through activation of NF-kappaB and/or STAT1. These cell signals are regulated by tyrosine kinase (Tyro, Axl, Mer) receptors (TAMs) that are aberrantly activated in SLE. STAT1 and NF-kappaB also exhibit crosstalk with the aryl hydrocarbon receptor (AHR). Ligands to AHR are identified in SLE etiology and pathogenesis. These ligands also regulate the activity of the Epstein-Barr virus (EBV), which is an identified factor in SLE and PD-1 immunobiology. AHR is important in the maintenance of immune tolerance and the development of distinct immune subsets, highlighting a potential role of AHR in PD-1 immunobiology. Understanding the functions of AHR ligands as well as AHR crosstalk with STAT1, NF-kappaB, and EBV may provide insight into disease development, the PD-1 axis and immunotherapies that target PD-1 and its ligand, PD-L1. PMID- 30396746 TI - De novo autoimmune hepatitis -is this different in adults compared to children? AB - De novo autoimmune hepatitis (AIH) is an unusual cause of graft dysfunction after liver transplantation. This entity was originally described in 1996 in children transplanted for conditions other than AIH, who developed biochemical and histological features similar to AIH and responded to the therapy of classical AIH with steroids and azathioprine. In the last two decades, there have been reports of occurrence of de novo AIH in pediatric and adult liver transplant recipients, in the latter often being given different nomenclature including 'plasma cell hepatitis'. Typical causes of graft dysfunction in liver transplant recipients include rejection, infection, vascular and biliary complications as well as recurrence of disease that was the indication for liver transplantation like hepatitis C and primary biliary cholangitis. While acute cellular rejection and chronic rejection are well recognized complications post liver transplantation, in the last 5 years, antibody mediated rejection has become increasingly important in liver transplantation. In 2016, in the course of developing guidelines for the diagnosis of antibody mediated rejection, it was suggested that both de novo AIH and 'plasma cell hepatitis' be categorized as 'plasma cell rejection'. This review explores the literature on de novo AIH in pediatrics and adults, sheds light on the substantive differences between these two entities and suggests that they be kept distinct from each other as the two are not the same. This difference in the cause of graft dysfunction in pediatric and adult liver transplant recipients is important as the management of the two conditions is not the same. PMID- 30396747 TI - Deactivating cochlear implant electrodes to improve speech perception: A computational approach. AB - A potential bottleneck to improving speech perception performance in cochlear implant (CI) users is that some of their electrodes may poorly encode speech information. Several studies have examined the effect of deactivating poorly encoding electrodes on speech perception with mixed results. Many of these studies focused on identifying poorly encoding electrodes by some measure (e.g. electrode discrimination, pitch ordering, threshold, CT-guided, masked modulation detection), but provide inconsistent criteria about which electrodes, and how many, should be deactivated, and without considering how speech information becomes distributed across the electrode array. The present simulation study addresses this issue using computational approaches. Previously validated models were used to generate predictions of speech scores as a function of all possible combinations of active electrodes in a 22-electrode array in three groups of hypothetical subjects representative of relatively better, moderate, and poorer performing CI users. Using high-performance computing, over 500 million predictions were generated. Although deactivation of the poorest encoding electrodes sometimes resulted in predicted benefit, this benefit was significantly less relative to predictions resulting from model-optimized deactivations. This trend persisted when using novel stimuli (i.e. other than those used for optimization) and when using different processing strategies. Optimum electrode deactivation patterns produced an average predicted increase in word scores of 10% with some scores increasing by more than 20%. Optimum electrode deactivation patterns typically included 11 to 19 (out of 22) active electrodes, depending on the performance group. Optimal active electrode combinations were those that maximized discrimination of speech cues, maintaining 80%-100% of the physical span of the array. The present study demonstrates the potential for further improving CI users' speech scores with appropriate selection of active electrodes. PMID- 30396748 TI - Skin infection by Corynebacterium diphtheriae and Streptococcus pyogenes: an unusual association. PMID- 30396749 TI - Epidemiological analysis of acute respiratory infections caused by enterovirus D68 clade A, subclade A1 in the adult population. PMID- 30396750 TI - Guided antibiotic therapy for Mycoplasma genitalium infections: Analysis of mutations associated with resistance to macrolides and fluoroquinolones. AB - INTRODUCTION: The objective of this study was to analyse the susceptibility of Mycoplasma genitalium to macrolides and fluoroquinolones using molecular techniques. METHODS: Susceptibility to macrolides was tested (Gipuzkoa, 2014 2017) by a rapid probe-based real-time polymerase chain reaction assay (23S rRNA gene) and to fluoroquinolones by sequencing the parC and gyrA genes. RESULTS: Mutations associated with macrolide resistance were detected in 43/263 (16.3%) cases and potential fluoroquinolone resistance in 21/267 (7.9%). Macrolide resistance was more frequent in patients previously treated with azithromycin (76.5% vs 7.4%, P<.001) as well as in those treated with a single 1g dose (31.3%) vs the extended regimen (7%, P<.001). There were 5/245 (2%) cases with mutations probably associated with resistance to both antibiotics. CONCLUSIONS: The technique used for testing Mycoplasma genitalium susceptibility to azithromycin allowed the rapid implementation of resistance-guided antibiotic therapy. Moxifloxacin could be a good option in cases of macrolide resistance. PMID- 30396751 TI - Consideration of Occult Infection and Sepsis Mimics in the Sick Patient Without an Apparent Infectious Source. AB - BACKGROUND: Evaluation and treatment of the acutely ill patient is typically complicated by multiple comorbidities and incomplete medical histories. This is exemplified by patients with sepsis, whose care is complicated by variable presentations, shifting definitions, and a variety of potential sources. Many practitioners fail to consider and recognize less-common sources of infection in a timely manner. Additionally, multiple noninfectious conditions can present with the fever and tachycardia typical of the septic patient. The errors of anchoring and premature closure may lead to delay in, or failure of, diagnosis of these conditions. OBJECTIVE: This review addresses the evaluation of the acutely ill appearing patient without an apparent source, focusing on occult sources of infection and conditions that mimic sepsis. DISCUSSION: Musculoskeletal, cardiac, neuraxial, and abdominal sources of sepsis should be considered in the acutely ill patient. Indwelling devices should be carefully examined for signs of infection. Consideration for sepsis mimics, such as neuroleptic malignant syndrome, malignant hyperthermia, medication toxicity, and thyroid storm, in patients who fail to respond to standard therapies for sepsis, may lead the physician to potentially reversible life-threatening diagnoses and management. CONCLUSION: In the seemingly septic patient who does not respond to antimicrobials and fluids, the differential should be broadened to include acutely life-threatening conditions that can mimic sepsis. A review of the patient's medical history, medications, and recent exposures can assist in identifying the source of the patient's elevated body temperature and tachycardia. Consideration of potential sources and other mimics of sepsis is needed in the emergency department. PMID- 30396752 TI - Multifaceted characterization of recombinant protein-based vaccines: An immunochemical toolbox for epitope-specific analyses of the hepatitis E vaccine. AB - The integrity of functional epitopes is a critical quality attribute for recombinant protein based vaccines since the presence of these native-like epitopes is the structural basis for vaccines to elicit functional antibodies. To demonstrate the quality and quantity of functional epitopes on vaccine antigens, a toolbox of assessing antigen characteristics is essential. Among the physicochemical, biophysical, immunochemical and in vivo potency analyses, the epitope-specific assays are most critical assessment of the antigen functionality. In this study, we used hepatitis E virus vaccine as an example to illustrated how the monoclonal antibody (mAb) based immunochemical assays were established for in-depth and multifaceted antigen characterization. A large panel of mAbs were developed and characterized using epitope clustering analysis. A subset of these mAbs recognizing non-overlapping epitopes were chosen to be used for assay development. Orthogonal methods, including surface plasma resonance based BIAcore, solution competitive ELISA and sandwich ELISA, were developed for the antigenicity assessment. The sandwich ELISA with a pair of mAbs, recognizing two different epitopes, was used to assess the accelerated antigen stability, showing enhanced stability with adjuvant adsorption. Such a sandwich ELISA with robust performance has the potentials to be used for in vitro potency analysis to replace animal-based potency assay as product release test. In summary, using hepatitis E vaccine as an example, we demonstrated the importance and establishment of a mAb-based immunochemical toolbox for multifaceted antigen characterization. This is particularly important to demonstrate the successful reconstruction of the native-like and functional epitopes on a recombinant antigen post expression and purification. These epitope-specific and multifaceted assays serve as critical tools for process monitoring or lot consistency tests in support of vaccine development and manufacturing. PMID- 30396753 TI - Music and movement: Towards a translational approach. AB - Rhythmic abilities are highly widespread in the general population. Most people can extract the regular beat of music, and align their movements with it. The aim of a translational approach for music and movement is to build on current fundamental research and theories of beat perception and synchronization to devise music-based interventions, which are informed by theory. To illustrate this approach, Parkinson's disease is taken as a model, with a focus on the positive effects of rhythmic auditory cueing on walking. In Parkinson's disease, a relation is found between the success of this music-based intervention and individual differences in rhythmic abilities. Patients with relatively spared rhythmic abilities are the most likely to benefit from cueing. Moreover, rhythmic auditory cueing can be optimized by using mobile technologies (tablets and smartphones), in the form of dedicated apps or serious games. A similar translational approach to the study of music, rhythm, and movement can be extended to remediation of cognitive, speech and language functions in other patient populations, such as children and adults with neurodevelopemental disorders. PMID- 30396754 TI - MicroRNA-17 promotes osteosarcoma cells proliferation and migration and inhibits apoptosis by regulating SASH1 expression. AB - MicroRNAs (miRNAs) are abnormally expressed in numerous diseases, which are intimately associated with cell proliferation, migration and invasion. Recent study indicated that miR-17 may be involved in regulating osteosarcoma (OS) occurrence and development, but its function and mechanism have not been reported. In this study, quantitative real-time PCR (qRT-PCR) was used to measure the expression of miR-17, and Western blotting assay was performed to measure the expressions of SAM and SH3 domain containing 1 (SASH1), phosphoinoinositide-3 kinase (PI3K), protein kinase B (AKT), Caspase3, Bcl-2 gene family (Bcl-2, Bax) and matrix metalloprotein (MMP-2, MMP-9) in MG-63 cells. Luciferase reporter assay was conducted to confirm the target of SASH1 by miR-17. Cell proliferation, migration, invasion and apoptosis assay was performed to investigate the role of miR-17 in OS cells. We found that the expression of miR-17 was significantly up regulated in OS cell lines. MiR-17 inhibitor inhibited the proliferation ability, and induced apoptosis of OS cells. Besides, miR-17 inhibitor prevented the migration and invasion of OS cells. Further, we identified that SASH1 was a target gene of miR-17. In addition, knockdown of miR-17 increased the protein expression of SASH1, and regulate related genes of cell proliferation, invasion and anti-apoptosis in the downstream of OS cells. These findings indicated that miR-17 was over-expressed and promoted cell proliferation, migration and inhibited cell apoptosis by targeting SASH1 in OS cells. PMID- 30396755 TI - Actin related protein 3 (ARP3) promotes apoptosis of intestinal epithelial cells in ulcerative colitis. AB - Apoptosis in intestinal epithelial cells (IECs) promotes the development of ulcerative colitis (UC), a type of inflammatory bowel disease (IBD). Efficient clearance of apoptotic cells is essential for tissue homeostasis in metazoans. Actin related protein 3 (ARP3) promotes endothelial dysfunction. The expression and function of ARP3 in UC remains unclear. In this study, the expression of apoptotic markers as p53, Bax, Cleaved-Caspease9 and Cleaved-Caspease3 were proved to be increased in the intestinal epithelial cells (IECs) of UC patients and in a mouse disuccinimidyl suberate(DSS)-induced colitis model; meanwhile, ARP3 expression was elevated. ARP3 expression levels and the severity of symptoms in patients with UC were positively correlated. By knocking down ARP3 in a TNF alpha-treated NCM-460 cell colitis model, the apoptotic markers described above were all decreased. In conclusion, our data indicates that ARP3 might promote the apoptosis of IECs in UC, revealing a potential molecular target for treating UC. PMID- 30396756 TI - Magnesium isoglycyrrhizinate alleviates liver injury in obese rats with acute necrotizing pancreatitis. AB - OBJECTIVE: For patients with acute necrotizing pancreatitis (ANP), a high body mass index (BMI) increases the likelihood of acute hepatic injury (AHI). In the current study, we explored whether magnesium isoglycyrrhizinate (MgIg) could alleviate ANP-induced liver injury in obese rats. METHODS: Sprague-Dawley (SD) rats were selected for the present study, and the ANP model was established by retrograde injection of 5% sodium taurocholate into the biliary-pancreatic duct. Thirty-six SD rats were randomly assigned to six groups: the normal (N), standard rat chow (SRC) normal (SN), SRC ANP (S-ANP), high-fat diet (HFD) normal (H-N), HFD ANP (H-ANP), and MgIg pretreatment HFD ANP (H-ANPT) groups. The rats in the H ANPT group were treated with MgIg (30 mg/kg) intragastrically for 7 days before the ANP model was established. The rats were sacrificed 12 h after ANP was established, and the blood and pancreatic and liver tissues were collected. Differences in the physiology, pathology and cellular and molecular responses of the rats in each group were examined. RESULT: Analyses of serum amylase lipase, alanine aminotransferase and aspartate aminotransferase indicated that obesity aggravated ANP-induced hepatic injury and that MgIg improved liver function. The superoxide dismutase, malondialdehyde, M1 macrophage, M2 macrophage, neutrophil, NF-kappaB, IL-1beta and caspase-3 levels in liver tissue showed that MgIg attenuated H-ANP-induced hepatic injury by inhibiting oxidative stress and inflammation. CONCLUSION: Obesity aggravated ANP-induced liver injury via oxidative stress and inflammatory reactions. MgIg alleviated oxidative stress and decreased the inflammatory reaction, protecting the liver against the AHI induced by ANP in obese rats. PMID- 30396758 TI - Synthesis of new coumarin tethered isoxazolines as potential anticancer agents. AB - A series of new coumarin tethered isoxazolines (7a-l) were synthesized and evaluated for their cytotoxic potency against human melanoma cancer cell line (UACC 903) as well as fibroblast normal cell line (FF2441). Preliminary results revealed that some of these coumarin tethered isoxazolines 7b, 7c, 7f and 7j exhibited significant antiproliferative effect against human melanoma cancer (UACC 903) with IC50 values of 8.8, 10.5, 9.2 and 4.5 MUM respectively. However, compound 7c was non-toxic to normal human cells at the tested concentration. Further, we have chosen compound 7c to check its efficacy in Ehrlich Ascites Carcinoma animal model in-vivo for its antitumor and antiangiogenic properties. Our lead compound significantly reduced the cell viability, body weight, ascites volume and downregulated the formation of neovasculature such as regression of tumor volume. The present study indicates the scope of developing into potent anticancer drug in near future. PMID- 30396757 TI - Structural biology of intraepithelial neuroendocrine cells in the larynx: Literature review. AB - Current knowledge of laryngeal neuroendocrine cells in man and other vertebrates is reviewed. Particular attention is paid to differences in the distribution of neuroendocrine cells between squamous and respiratory laryngeal mucosa, foetal versus post-natal spatial arrangements, relation to the laryngeal cavity and nerve fibres, and immunoreactivities of these cells. Methodological deficiencies and gaps in knowledge are outlined. Comparisons with neuroendocrine cells in lung and gut are drawn, caution with regard to existing histogenetic models of laryngeal neuroendocrine neoplasia is advised and lines of future research are suggested. PMID- 30396759 TI - In vivo evaluation of [11C]TMI, a COX-2 selective PET tracer, in baboons. AB - Overexpression of Cyclooxygenase-2 (COX-2) enzyme is associated with the pathogenesis of inflammation, cancers, stroke, arthritis, and neurological disorders. Because of the involvement of COX-2 in these diseases, quantification of COX-2 expression using Positron Emission Tomography (PET) may be a biological marker for early diagnosis, monitoring of disease progression, and an indicator of effective treatment. At present there is no target-specific or validated PET tracer available for in vivo quantification of COX-2. The objective of this study is to evaluate [11C]TMI, a selective COX-2 inhibitor (Ki <= 1 nM) in nonhuman primates using PET imaging. PET imaging in baboons showed that [11C]TMI penetrates the blood brain barrier (BBB) and accumulates in brain in a somewhat heterogeneous pattern. Metabolite analyses indicated that [11C]TMI undergoes no significant metabolism of parent tracer in the plasma for baseline scans, however a relative faster metabolism was found for blocking scan. All the tested quantification approaches provide comparable tracer total distribution volume (VT) estimates in the range of 3.2-7 (mL/cm3). We observed about 25% lower VT values in blocking studies with meloxicam, a nonselective COX-2 inhibitor, compared to baseline [11C]TMI binding. Our findings indicate that [11C]TMI may be a suitable PET tracer for the quantification of COX-2 in vivo. Further experiments are needed to confirm the potential of this tracer in COX-2 overexpressing models for brain diseases. PMID- 30396760 TI - Is it possible to safely prevent late preterm and early term births? AB - Late preterm and early term birth is associated with adverse short- and long-term consequences, particularly for neurodevelopment. A clear reduction in these births can be achieved by avoidance of non-medically indicated births prior to 39 weeks gestation, as shown following the introduction of prohibitive policies in the USA. However, clinicians and policy-makers must always consider the potential for unintended adverse consequences of such action, such as a potential for an increase in term stillbirth. Finding the balance between optimising long-term neurological outcomes and avoiding rare but devastating term stillbirths is one of the challenges of modern maternity care. In this article we review the current evidence for whether this balance can be found, where early births can be safely prevented, and what remains to be addressed to optimise this balance safely. PMID- 30396761 TI - Impact of an ambulatory care pharmacist in an occupational health clinic. AB - OBJECTIVES: To describe and evaluate a novel practice setting for a pharmacist within an occupational health clinic. SETTING: Ambulatory care facility. PRACTICE DESCRIPTION: Implementation and evaluation of a new practice site embedding a clinical pharmacist into the workplace to provide ambulatory care services, such as comprehensive medication management, disease state management, and immunizations to a broad diversity of patients. PRACTICE INNOVATION: A clinical pharmacist provides pharmacy services as part of a collaborative occupational health clinic at a large, self-insured company. The pharmacy services are open to employees and family members with any chronic disease states, elevated biometric results, or medication questions, with the goal of improving patient care on a consistent basis. During visits, the pharmacist works to identify and resolve drug-related problems by educating the patient or reaching out to the patient's health care provider and to develop strategies with the patient to achieve desired health care outcomes. The pharmacist assists with patient outreach events and immunizations during the flu clinic. EVALUATION: Identification of drug related problems, resolution status, patient satisfaction via survey results, immunizations provided. RESULTS: In 4.3 years of operation, the pharmacist conducted 604 visits with 172 patients. During these visits, the pharmacist identified 611 drug-related problems, of which 49.4% have been confirmed as resolved. All patients who completed the patient satisfaction survey said that they would recommend the pharmacy services to others. For the past 3 years, the pharmacist and pharmacy students immunized approximately 1000 patients each year during the company flu clinic. CONCLUSION: An occupational health clinic is a unique and convenient location for a pharmacist to provide ambulatory care services to employees and family members, as long as methods to identify patients and appropriate sources of referral exist. The pharmacist was able to help patients resolve approximately 50% of identified drug-related problems, and patients were highly satisfied with services provided. PMID- 30396762 TI - [Childbirth pelvic floor trauma: Anatomy, physiology, pathophysiology and special situations - CNGOF Perineal Prevention and Protection in Obstetrics Guidelines]. AB - OBJECTIVES: To assess whether pelvic size and shape, spinal curvature, perineal body length and genital hiatus size are associated with the incidence of childbirth pelvic floor trauma. Special situations, such as obesity, ethnicity and hyperlaxity, will also be studied. METHODS: A bibliographic research using Pubmed and Cochrane Library databases was conducted until May 2018. Publications in English and French were selected by initial reading of the abstracts. Randomized trials, meta-analyzes, case-control studies and large cohorts were studied in a privileged way. RESULTS: A pubic arch angle<90 degrees (measured clinically) does not appear to increase the risk of OASIS (Level 3), but appears to be a risk factor for postnatal anal incontinence at short-term, but not at long-term (Level 3). Measurement of pelvic dimensions and the subpubic angle is not recommended to predict OASIS or to choose the mode of delivery for the purpose of protecting the perineum (GradeC). Prenatal measurement of both perineal body (Level 3) and genital hiatus (Level 2) does not predict the incidence of 2nd or 3rd degree OASIS. Therefore, the routine prenatal measurement of the length of the perineal body or the genital hiatus is not recommended for any objective related to perineal protection (Grade C). Levator avulsion, resulting in a widening of the genital hiatus, is potentially a source of long term pelvic floor dysfunction. Biomechanical models suggest that performing a mediolateral episiotomy and applying the fingers to the posterior perineum at the time of expulsive phase may reduce pelvic floor trauma. Obese women have a longer perineal body (Level 3), and obesity does not seem to increase the risk of OASIS (Level 2). There is no difference between Asian and non-Asian women perineal body (Level 3). No studies have validated that the liberal practice of episiotomy in Asian women reduced the risk of OASIS. It is therefore not recommended to practice an episiotomy for simple ethnic reasons in Asian women (GradeC). Compared to white women, black women do not appear to have an increased risk of OASIS and even appear to have a decreased risk of perineal tears of all stages (Level 2). Ligament hyperlaxity seems to be associated with an increased risk of OASIS (Level 2). CONCLUSIONS: Prenatal assessment of pelvis bone, spine curvature, perineal body and genital hiatus do not allow to predict the incidence of childbirth pelvic floor trauma. Obesity and ethnicity are not risk factors for OASIS. PMID- 30396763 TI - Innovative Teaching Methods in Radiology-Building on the Experiences of Other Disciplines. PMID- 30396764 TI - Therapeutic Mechanism(s) of the Benefit-Finding Intervention for Dementia Caregivers: A Reply to Canto. PMID- 30396765 TI - Primum Nil Nocere: Prescription of Potentially Inappropriate Psychotropic Medications to Older Adults. PMID- 30396766 TI - Using an Integrated Care Pathway for Late-Life Schizophrenia Improves Monitoring of Adverse Effects of Antipsychotics and Reduces Antipsychotic Polypharmacy. AB - OBJECTIVE: Antipsychotic use in older patients is associated with many adverse effects, including tardive dyskinesia and extrapyramidal symptoms, which, in turn, increase the risk of falling. Antipsychotics are also associated with metabolic syndrome and cognitive impairment in older patients. Integrated care pathways (ICPs) are designed to manage specific conditions using standardized assessments and measurement-based interventions. This study aims to compare the use of recommended tools to monitor for adverse effects associated with antipsychotics in older patients managed within an ICP and those managed under usual care conditions-i.e., treatment as usual (TAU). METHODS: We reviewed and compared the health records of 100 older patients enrolled in an ICP for late life schizophrenia with those of 100 older patients treated with antipsychotics under TAU conditions. RESULTS: Monitoring rates were significantly higher in the ICP group than in the TAU group for all assessments: extrapyramidal symptoms (94% versus 5%), metabolic disturbances (91% versus 25%), fall risk (82% versus 35%), and cognitive impairment (72% versus 28%). Rates of antipsychotic polypharmacy were also six times higher in the TAU group. CONCLUSION: Older patients with schizophrenia treated with antipsychotics within an ICP experience higher rates of monitoring and less psychotropic polypharmacy than older patients treated with antipsychotics under TAU conditions. These findings suggest that an ICP can improve the quality of antipsychotic pharmacotherapy in older patients and thus possibly its effectiveness. This needs to be confirmed by a randomized controlled trial. PMID- 30396767 TI - [This clock that governs us]. PMID- 30396769 TI - Application of a Ni-Ti arched shape-memory connector in unstable lateral malleolus fractures: A retrospective study. AB - PURPOSE: To compare the outcomes of the arched shape-memory connector (ASC) only fixation and the lateral one-third tubular plate fixation in managing unstable Type A or B lateral malleolus fractures according to the Weber (AO) classification, and to evaluate the feasibility and reliability of ASC only fixation in treating these fractures. METHODS: From January 2010 to January 2015, 148 patients with Type A or B (Weber (AO) classification) lateral malleolus fractures treated with the arched shape-memory connector (ASC) only fixation or lateral plate fixation were included. There were 66 patients in the ASC only fixation group and 82 patients in the lateral plate group. Intergroup differences were absent regarding patient and fracture characteristics. The incision length, complete-union time, major complications and complaints, incidence of hardware removal, and final radiographic and functional evaluations were compared. RESULTS: The follow-up time averaged 18.2 months in the ASC fixation group and 17.2 months in the lateral plate group. The ASC only fixation group had significantly decreased wound infection (4.55% versus 14.63%) and skin necrosis (none versus 7.32%). Of patients who underwent ASC only fixation 3.03% reported lateral ankle pain, 7.58% received palpable hardware, and 3.03% reported hardware irritation, while the corresponding observations in the lateral plate group were 19.51%, 54.88%, and 14.63%, respectively, representing a statistical difference. Furthermore, compared with the lateral plate group, the incidence of hardware removal was markedly lower in the ASC fixation group (12.12% versus 30.49%). In terms of reduction accuracy, complete-union time, and AOFAS scores, no appreciable differences were observed. CONCLUSIONS: ASC only fixation is a reliable alternative for managing Type A or B lateral malleolus fractures, leading to fewer soft tissue complications, fewer hardware complaints, and a reduced need for hardware removal, and a reduced need for hardware removal. In addition, ASC can be used for augmented plate fixation in certain comminuted fracture patterns. PMID- 30396768 TI - Imaging Social and Environmental Factors as Modulators of Brain Dysfunction: Time to Focus on Developing Non-Western Societies. AB - Social and environmental factors are known risk factors and modulators of mental health disorders. We here conducted a nonsystematic review of the neuroimaging literature studying the effects of poverty, urbanicity, and community violence, highlighting the opportunities of studying non-Western developing societies such as those in Latin America. Social and environmental factors in these communities are widespread and have a large magnitude, as well as an unequal distribution, providing a good opportunity for their characterization. Studying the effect of poverty in these settings could help to explore the brain effect of economic improvements, disentangle the effect of absolute and relative poverty, and characterize the modulating impact of poverty on the underlying biology of mental health disorders. Exploring urbanicity effects in highly unequal cities could help identify the specific factors that modulate this effect as well as examine a possible dose-response effect by studying megacities. Studying brain changes in those living among violence, which is particularly high in places such as Latin America, could help to characterize the interplay between brain predisposition and exposure to violence. Furthermore, exploring the brain in an adverse environment should shed light on the mechanisms underlying resilience. We finally provide examples of two methodological approaches that could contribute to this field, namely a big cohort study in the developing world and a consortium-based meta-analytic approach, and argue about the potential translational value of this research on the development of effective social policies and successful personalized medicine in disadvantaged societies. PMID- 30396770 TI - Risk factors for reoperation, readmission, and early complications after below knee amputation. AB - BACKGROUND: Many patients undergoing below knee amputations (BKA) return for subsequent unplanned operations, hospital readmission, or postoperative complications. This unplanned medical management negatively impacts both patient outcomes and our healthcare system. This study primarily investigates the risk factors for unplanned reoperation following BKA. METHODS: Below knee amputations from the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database from the years 2012-2014 were identified by CPT code 27880 for amputation through the tibia and fibula. Our query identified 4631 BKA cases, including 30 day complications. Multivariate logistic regression modeling was performed on several patient demographic and disease factors to assess for independent predictors of unplanned reoperation. Secondary outcomes of unplanned and related readmissions (related to the procedure), major complications, minor complications, and mortality were also included in the analysis. RESULTS: Of 4631 BKAs identified, 9.63% (446/4631) underwent unplanned reoperations and 8.75% (405/4631) had unplanned and related readmissions. Major complications were experienced by 12.8% (593/4631) and minor complications by 8.7% (401/4631). Thirty day mortality rate was 5.14% (238/4631). The most common procedures for unplanned operations were thigh amputations (128/446, 28.7%), debridement/secondary closure (114/446, 25.6%), and revision leg amputations (46/446, 10.32%). Factors associated with an increased risk of unplanned reoperation included patients transferred from another facility (Adjusted Odds Ratio [AOR] = 1.28; p = .04), recent smokers (AOR = 1.34; p = .02), bleeding disorder (AOR = 1.30; p = .02), and preoperative ventilator use (AOR = 2.38; p = .01). CONCLUSION: Patients that were ongoing/recent smokers, had diagnosed bleeding disorders, required preoperative ventilator use, or were transferred in from another facility were associated with the highest risks of reoperation following BKA. This patient population experiences high rates of reoperation, readmission, complication, and mortality. PMID- 30396771 TI - Predictive nomogram for postoperative delirium in elderly patients with a hip fracture. AB - To evaluate the risk factors for the development of postoperative delirium and design a predictive nomogram for the prevention of delirium in elderly patients with a hip fracture, we retrospectively studied 825 patients who sustained a femoral neck fracture from January 2005 to December 2015. Independent risk factors for developing delirium within 6 months of surgery were identified using multivariable logistic regression analyses. A predictive nomogram model was built based on the results, and the discrimination and calibration were determined by C index and calibration plot. Of the 825 patients who met inclusion criteria, 118 (14.3%) developed postoperative delirium. According to the results, preoperative cognitive impairment (OR, 4.132, 95% CI, 1.831 to 9.324, P<0.001), multiple medical comorbidities (OR, 1.452, 95% CI, 0.958-2.202, P = 0.079), ASA classification (OR, 1.655, 95% CI, 1.073-2.553, P = 0.023), transfusion exceeding 2 units of red blood cell (OR, 1.599, 95% CI, 1.043-2.451, P = 0.035), and intensive care (OR, 1.817, 95% CI, 1.127-2.930, P = 0.014) were identified to be the independent predictors of the development of postoperative delirium. The risk of postoperative delirium increased with the increasing risk score of predictive nomogram, and the C-index was 0.67 (0.62 - 0.72). The calibration showed that the predicted probabilities of delirium in the predictive nomogram were close to the observed frequency of delirium, and the decision curve analysis confirmed the clinical utility of the nomogram when the threshold probabilities were between 8% and 35% due to the net benefit. PMID- 30396772 TI - An iso-osmolar oral supplement increases natriuresis and does not increase stomal output in patients with an ileostomy: A randomised, double-blinded, active comparator, crossover intervention study. AB - BACKGROUND: Patients with an ileostomy often experience fluid and electrolyte depletion because of gastrointestinal loss. This study aimed to compare how an iso-osmolar and a hyperosmolar oral supplement affect ileostomy output, urine production, and natriuresis as proxy measurements of water-electrolyte balance. METHODS: In a randomised, double-blinded, active comparator, crossover intervention study, we included eight adult ileostomy patients who were independent of parenteral support. We investigated how an iso-osmolar (279 mOsm/kg) and a hyperosmolar (681 mOsm/kg) oral supplement affected ileostomy output mass, urine volume, and natriuresis. In addition to their habitual diet, each participant ingested 800 mL/day of either the iso-osmolar or hyperosmolar supplement in each of two study periods. Each period started with 24-hour baseline measurements, and the supplements were ingested during the following 48 h. All measurements were repeated in the last 24 h. RESULTS: No statistically significant changes in ileostomy output were detected following the intake of either oral supplement (median (range) 67 (-728 to 290) g/day, p = 0.25) despite increased fluid intake. Compared with the hyperosmolar supplement, the iso osmolar supplement induced a statistically significant increase in urine volume (470 (0-780) mL/day, p = 0.02) and natriuresis (36 (0-66) mmol/day, p = 0.02). CONCLUSION: Intake of the two oral supplements did not affect ileostomy output during this short intervention. Natriuresis increased following intake of the iso osmolar supplement compared to that after ingesting the hyperosmolar supplement, indicating that patients with an ileostomy may benefit from increasing their ingestion of iso-osmolar fluids. ClinicalTrials.gov identifier:NCT03348709. PMID- 30396773 TI - No independent associations between preconception paternal dietary patterns and embryonic growth; the Predict Study. AB - BACKGROUND & AIM: Several studies show the importance of periconceptional maternal dietary patterns on human embryonic growth. Healthy paternal nutrition has been associated with better semen quality and fecundability, however, evidence on the impact on pregnancy outcome is limited. Therefore, the aim of this study was to investigate the association between preconception paternal dietary patterns and first trimester embryonic growth using the parameters longitudinal crown-rump length (CRL) and embryonic volume (EV). METHODS: A total of 638 couples were enrolled in the Rotterdam Periconceptional Cohort and received longitudinal three dimensional transvaginal ultrasound scans from 7+0 up to 12+0 weeks of gestation. Virtual reality software was used to perform offline measurements of the embryonic CRL and EV. Food frequency questionnaires (FFQ) were used to estimate habitual food intake in couples. Principal component analysis (PCA) was performed to identify paternal and maternal dietary patterns. Linear mixed models adjusted for potential confounders were applied to analyze associations between paternal and maternal dietary patterns and embryonic growth parameters. RESULTS: The paternal dietary patterns retrieved were identified as "Whole wheat grains and Vegetables", "Sauces and Snacks Refined Grains", "Fish and Legumes" and explained 27.5% of the total variance of the dietary intake. No significant additional effects, independent of maternal dietary patters and other maternal and paternal potential confounders, were shown of these paternal dietary patterns on embryonic growth in spontaneous or IVF/ICSI pregnancies. CONCLUSION: No significant effects of paternal dietary patterns independent of maternal dietary patters and other parental potential confounders on embryonic growth parameters could be established in spontaneous or IVF/ICSI pregnancies. The biological importance of paternal nutrition on semen quality, however, supports the need of periconceptional tailored nutritional counselling of couples trying to conceive. PMID- 30396774 TI - The Krakow Declaration: The last chance for Europe to eradicate iodine deficiency. PMID- 30396775 TI - Corrigendum to "Precision medicine in ALK rearranged NSCLC: A rapidly evolving scenario" [Crit. Rev. Oncol./Hematol. 122 (February) (2018) 150-156]. PMID- 30396776 TI - Pathological roles of the homeostatic chemokine CXCL12. AB - CXCL12 is a CXC chemokine that traditionally has been classified as a homeostatic chemokine. It contributes to physiological processes such as embryogenesis, hematopoiesis and angiogenesis. In contrast to these homeostatic functions, increased expression of CXCL12 in general, or of a specific CXCL12 splicing variant has been demonstrated in various pathologies. In addition to this increased or differential transcription of CXCL12, also upregulation of its receptors CXC chemokine receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) contributes to the onset or progression of diseases. Moreover, posttranslational modification of CXCL12 during disease progression, through interaction with locally produced molecules or enzymes, also affects CXCL12 activity, adding further complexity. As CXCL12, CXCR4 and ACKR3 are broadly expressed, the number of pathologies wherein CXCL12 is involved is growing. In this review, the role of the CXCL12/CXCR4/ACKR3 axis will be discussed for the most prevalent pathologies. Administration of CXCL12-neutralizing antibodies or small-molecule antagonists of CXCR4 or ACKR3 delays disease onset or prevents disease progression in cancer, viral infections, inflammatory bowel diseases, rheumatoid arthritis and osteoarthritis, asthma and acute lung injury, amyotrophic lateral sclerosis and WHIM syndrome. On the other hand, CXCL12 has protective properties in Alzheimer's disease and multiple sclerosis, has a beneficial role in wound healing and has crucial homeostatic properties in general. PMID- 30396777 TI - Corrigendum to "Breast cancer susceptibility protein 1 (BRCA1) rescues neurons from cerebral ischemia/reperfusion injury through NRF2-mediated antioxidant pathway" [Redox Biol. 18 (2018) 158-172]. PMID- 30396778 TI - Sleep, pain, and the problem with treating sleep to relieve pain. PMID- 30396779 TI - The effect of bariatric surgery on the direct oral anticoagulant rivaroxaban: the extension study. AB - BACKGROUND: Thromboembolic disease is a potentially serious complication in bariatric surgery patients. Direct oral anticoagulants (DOAC) have been investigated in orthopedic surgery patients. DOAC data after bariatric surgery are still limited to the early postsurgical period. Whether postsurgical midterm adaptations due to anatomic and physiologic alterations influence drug pharmacology is currently not known. OBJECTIVE: The aim of this study was to investigate the influence of weight loss and type of bariatric surgery on midterm postsurgical pharmacokinetic and pharmacodynamic parameters of rivaroxaban. SETTING: University hospital. METHODS: In this monocentric study, bariatric patients received a single oral dose of rivaroxaban (10 mg) 6 to 8 months after sleeve gastrectomy (SG) or Roux-en-Y-gastric bypass (RYGB). Pharmacokinetic and pharmacodynamic parameters were assessed and compared with prebariatric surgery results. RESULTS: We included 6 RYGB and 6 SG patients. Percent excess weight loss was 71.4% (interquartile range 56.4, 87.9) in the SG group and 76.6% (64.5, 85.7) in the RYGB group. Rivaroxaban mean areas under the curve 6 to 8 months after the bariatric procedure (922.4 ug * h/L, coefficient of variation 43.2) were comparable to those measured preoperatively (952.6 ug * h/L, 16.8). There was no relevant difference between the 2 surgical procedure groups. Rivaroxaban led to a decrease of prothrombin fragments F1+2 over 12 hours after oral intake confirming in vivo efficacy. CONCLUSIONS: Significant weight loss and altered anatomy after RYGB and SG procedures do not appear to affect the pharmacokinetics and pharmacodynamics of prophylactic rivaroxaban. A single dose of Rivaroxaban was well tolerated and considered safe in this trial. PMID- 30396780 TI - [Omalizumab and allergen immunotherapy: A clinical report and review of the literature]. AB - INTRODUCTION: Several authors have proposed combined omalizumab and allergen immunotherapy (AIT) in patients suffering from severe allergic asthma to both increase disease control and decrease the severity through targeting the main allergen responsible for the respiratory symptoms. OBSERVATION: In a female pediatric patient suffering from severe asthma, followed-up at the University Hospital of Montpellier (France), we prescribed an AIT to Alternaria after obtaining symptom control with omalizumab. The patient showed an overall improvement in symptoms after AIT was administered and the disease remained controlled long after cessation of omalizumab. CONCLUSIONS: There are only a few publications evaluating the efficacy of the association of these two biotherapies in the management of severe allergic asthma. In addition there is, as yet, no common protocol for the administration of the two prescriptions. This approach to treatment would benefit from standardization in order to optimize the management of severe allergic asthma. PMID- 30396781 TI - [Two cases of hot tub lung disease: Environmental investigations]. AB - INTRODUCTION: Hot tub lung is a hypersensitivity pneumonitis (HP) due to exposure to inhaled non-tuberculous mycobacteria, the most frequent being Mycobacterium avium complex (MAC). CASE REPORT: A French couple developed typicalHP in the context of a repeated use of hot tubs. The husband had a severe hypoxemic form whereas his wife had a micronodular form with patchy ground glass on the thoracic scan, with less severe functional impairment. MAC was recovered in the hot tub water, but not in broncho-alveolar lavage fluid, and serologies were negative. Samples taken at home showed unusual exposure to Aureobasidium pullulans and Aspergillus flavus, as well as the presence of potentially responsible domestic molds. Blood precipitins for these microorganisms were identified. The evolution was favorable after removal of the hot tub. CONCLUSIONS: These cases represent two of the typical presentations of hot tub lung, with a possible HP to an antigen other than MAC, which may have been enhanced by chronic exposure to multiple microorganisms. PMID- 30396782 TI - The diverse cutoff of PD-L1 positivity and negativity in studies regarding head and neck squamous cell carcinoma. PMID- 30396783 TI - MY APPROACH to cybersecurity for cardiac implantable electronic devices. PMID- 30396784 TI - [Encephalopathy in an elderly patient after an influenza B flu diagnosis: A case report]. PMID- 30396785 TI - [The times they are changing]. PMID- 30396786 TI - [Effectiveness and safety of alpha-erythropoietin in the (orthopaedic) patient over 65 years old]. PMID- 30396787 TI - [Norovirus: One more guest in residential homes for the elderly?] PMID- 30396788 TI - [Chronic eosinophilic pneumonia in octogenarian patient]. PMID- 30396789 TI - Neuromuscular blocking agents for acute respiratory distress syndrome. AB - Acute respiratory distress syndrome (ARDS) is an acute inflammatory process that impairs the ability of the lungs to oxygenate thereby resulting in respiratory failure. Treatment of ARDS is often a multimodal approach using both nonpharmacologic and pharmacologic treatment strategies in addition to trying to reverse the underlying cause of ARDS. Neuromuscular blocking agents (NMBAs) have been prescribed to patients with ARDS as they are thought to decrease inflammation, oxygen consumption, and cardiac output and help facilitate ventilator synchrony. NMBAs have only been evaluated in patients with early, severe ARDS in three multicenter, randomized, controlled trials (n = 432), but have resulted in decreased inflammation and improved oxygenation, ventilator-free days, and mortality. Despite reports of NMBAs being associated with adverse effects like postparalytic quadriparesis, myopathy, and prolonged recovery, these effects have not been seen in patients receiving short courses of NMBAs for ARDS. A large multicenter, prospective, randomized, placebo-controlled trial is ongoing to confirm benefit of NMBAs in early, severe ARDS when adjusting for limitations of the previous studies. The current available literature suggests that 48 h of NMBA therapy in patients with early, severe ARDS improves mortality, without resulting in additional patient harm. PMID- 30396790 TI - Laboratory study of creosote removal from sand at elevated temperatures. AB - In situ thermal treatment (ISTT) technologies have been applied at sites impacted by non-aqueous phase liquids (NAPLs). There is a need to establish expectations for the treatment of semi-volatile NAPLs, including those consisting primarily of polycyclic aromatic hydrocarbons (PAHs), and the potential benefits and limitations of partial NAPL removal. A series of laboratory experiments was conducted to investigate NAPL removal and soil concentrations during the heating of creosote-impacted sand, as well as aqueous concentrations during post-heating dissolution. The results showed co-boiling near the water boiling temperature due to the low volatility of most creosote components, with limited decreases in NAPL saturation (from 30% to 21% of the pore space). Decreases in soil concentration were more substantial than decreases in NAPL saturation (by a factor of 2-180), with greater removal for higher-volatility components at higher treatment temperatures. Results of the dissolution experiments showed mixed results, with decreases in the aqueous concentrations for 12 of 15 components, but increases in aqueous concentrations for phenanthrene, fluoranthene and pyrene after heating to 205 degrees C or 320 degrees C. Overall, the results illustrate the utility of bench-scale treatability tests in helping to establish ISTT goals and expectations. PMID- 30396791 TI - Donor referral from outside the intensive care unit: A multidisciplinary cooperation model using communication apps and redefining refereal criteria. AB - OBJECTIVE: We evaluate the impact of a web-based collaborative system on the referral of possible organ donors from outside of the intensive care unit (ICU). STUDY DESIGN: Cohort prospective study. SETTINGS: University hospital. PATIENTS AND INTERVENTION: In 2015 a virtual collaborative system using a cross-platform instant messaging application replaced the previous 2014 protocol for the referral of patients outside of the ICU with a severe brain injury in whom all treatment options were deemed futile by the attending team to the donor coordination (DC). Once the DC evaluated the medical suitability and likelihood of progression to brain death (BD), the option of intensive care to facilitate organ donation (ICOD) was offered to the patient's relatives. This included admission to the ICU and elective non-therapeutic ventilation (ENTV), where appropriate. RESULTS: A two-fold increase of referrals was noted in 2015 [n=46/74; (62%)] compared to 2014 [n=13/40; (32%)]; p<0.05. Patients were mostly referred from the stroke unit (58.6%) in 2015 and from the emergency department (69.2%) in 2014 (p<0.01). Twenty (2015: 42.5%) and 4 (2014: 30.7%) patients were discarded as donors mostly due to medical unsuitability. Family accepted donation in 16 (2015: 62%) and 6 (2014: 66%) cases, all admitted to the ICU and 10 (2015: 62.5%) and 3 (50%) being subject to ENTV. Ten (2015: 66.6%) and 5 (2014: 83.3%) patients progressed to BD, 60.5+/-20.2 and 44.4+/-12.2h after referral respectively. Nine (2015) and 4 (2014) of these patients became utilized donors, representing 29.0% (2015) and 13.0% (2014) of the BD donors in the hospital during the study period (p<0.05). CONCLUSION: The implementation of a virtual community doubled the number of patients whose families were presented with the option of donation prior to their death. PMID- 30396792 TI - Antisepsis in the handling of vascular access connections. AB - Needleless connectors provide easy access points to the vascular system for the administration of fluids, avoiding the risk of accidental punctures and increasing safety in vascular access manipulation. Non-aseptic manipulation can favor contamination, turning connectors into the penetration route for endoluminal contaminants with the capacity of triggering infectious complications, with serious consequences for the patient. Considering catheter related bacteremia as a serious and avoidable adverse effect, prevention programs should incorporate measures to combat predisposing factors, such as improved staff training, the safe design of devices, improved disinfection procedures, and optimized antiseptic use. Monitoring adherence to safe practices and reporting results are important to promote understanding of the risks and benefits of decontaminating connections and thus to improve patient safety. PMID- 30396793 TI - Antiseptic urinary catheterization and maintenance of the bladder catheter. AB - Catheter-related urinary tract infections are very common both in the community and in the acute hospital care setting, particularly in the critical care environment. In order to minimize this problem, it is essential to adopt a correct approach from insertion to withdrawal of the urinary catheter, and always perform proper antisepsis. There is too much information on antisepsis measures with no consistent results. The present article reviews the existing scientific evidence on the subject and establishes recommendations based on the evidence, in order to optimize outcomes. The entire process is complemented with considerations on how to secure proper management of the indwelling urinary catheter. PMID- 30396794 TI - Oropharyngeal antisepsis in the critical patient and in the patient subjected to mechanical ventilation. AB - Lower respiratory tract infections in the intubated patient constitute a serious health problem due to their associated morbidity and mortality. Microaspiration of the buccopharyngeal secretions is the main physiopathological mechanism underlying the development of pneumonia and tracheobronchitis in intubated patients. All care bundles designed to prevent these infections include the use of antiseptics to reduce buccopharyngeal colonization. Chlorhexidine is the antiseptic most frequently assessed in clinical trials and meta-analyses that conclude that oral hygiene with chlorhexidine reduces the incidence of ventilator associated pneumonia - maximum effectiveness being achieved when the product is administered at a concentration of 2%. However, 2meta-analyses have warned of a possible increase in mortality when chlorhexidine is used as an oral antiseptic. We therefore recommend its use but with extreme caution during application in order to avoid aspiration of the antiseptic. PMID- 30396795 TI - Barriers and enablers for smoking cessation amongst pregnant women: An Umbrella Review. AB - AIM: The aim of this study is to summarise the qualitative findings from systematic reviews to identify what pregnant women perceive as barriers and enablers to smoking cessation during pregnancy. BACKGROUND: Smoking during pregnancy is a predictor of adverse maternal and infant outcomes. Despite known health risks, less than half of pregnant smokers quit during pregnancy. METHODS: An umbrella review using the Johanna Briggs Institute methodology was conducted. A comprehensive literature review was completed in July 2017. All included papers were subject to an eligibility criterion and checked for quality by at least two reviewers. FINDINGS: A total of n=529 papers were identified and screened. Of these, only two met all inclusion and quality criteria and were included for review. More barriers than facilitators were identified from the available literature. CONCLUSION: An enabler or barrier to smoking cessation for pregnant women is not a fixed entity but dependent on the context of an individual's life. What is an enabler for one woman may be considered a barrier for another, and these are dependent on support provided by family and friends. Further research is needed to optimise ways of addressing these barriers. PMID- 30396796 TI - Measurement of Glenoid Bone Loss With 3-Dimensional Magnetic Resonance Imaging: A Matched Computed Tomography Analysis. AB - PURPOSE: To compare the measurement of glenoid bone surface area (GBSA) and glenoid bone loss (GBL) between 3-dimensional computed tomography (3D CT) and an autosegmentation approach for 3D magnetic resonance imaging (MRI) of patients with recurrent shoulder instability. METHODS: Eight subjects (2 women and 6 men; age range, 15-72 years [mean, 44 +/- 19 years]) were consecutively enrolled who had both CT and MRI of the shoulder for clinical shoulder instability. Inclusion criteria were patients with shoulder instability or other shoulder injury who had both a CT scan and MRI performed of the same shoulder. All patients underwent a 3D CT scan and a 3-Tesla 3D MRI with additional volumetric and autosegmented sequences. En face views of the glenoid for both CT and MRI were auto- and manually measured for overall GBSA and GBL using best-fit circle technique; the amount of GBL was compared with loss of GBSA and was expressed as a percentage of bone loss. RESULTS: There were no differences in GBL measured by 3D CT (41 mm2, 6.6%) vs 3D MRI (40 mm2, 6.5%, P = .852). The mean GBSA was not different among the manual- and autocalculated 3D CT (644 mm2 vs 640 mm2, P = .482). In addition, the manual MRI scan glenoid area was similar to the autocalculated 3D MRI (622 mm2 vs 618 mm2, respectively; P = .482). Overall regression analysis demonstrated excellent correlation between CT and MRI for both GBSA and GBL calculations (R2 = 0.84-0.90). CONCLUSIONS: 3D MRI of the glenoid is nearly identical to 3D CT scans for measurement of GBSA and GBL, making 3D MRI a reliable alternative to a CT scan for a preoperative shoulder evaluation of the glenoid pathology. This study shows that a 3D MRI could be a radiation-free and reliable alternative to a preoperative CT shoulder scan. LEVEL OF EVIDENCE: Level III, case-control study. PMID- 30396797 TI - Opioid Overprescription After Knee Arthroscopy and Related Surgery in Adolescents and Young Adults. AB - PURPOSE: The purpose of this study was to compare the number of opioids prescribed with the amount of pain medication required after knee arthroscopy and related surgery in adolescent and young adult patients to determine the effectiveness of current pain-control practices at a single institution. The secondary purpose was to determine what demographic or surgical factors are associated with increased opioid intake. METHODS: Adolescent and young adult patients who underwent knee arthroscopy and related surgery, including ligament reconstruction or tibial tubercle osteotomy, between May and August 2016 were provided pain-control logbooks in which they were asked to maintain a record of daily pain medication intake. The outcome of the study was defined as the total number of opioids consumed per patient. RESULTS: One hundred patients returned completed logbooks, 56% of whom were female patients. The average age was 17.54 years (standard deviation [SD], 3.51 years). Most patients underwent an open procedure concurrent with knee arthroscopy (60%), underwent nerve block placement (51%), and underwent injection of local anesthesia (91%). Use of both intravenous acetaminophen and ketorolac during the perioperative period was also common (41%). Patients were prescribed an average of 50.98 oxycodone pills (SD, 12.50 pills) and reported consuming an average of 16.52 pills (SD, 13.94 pills), approximately 32.4% of those prescribed. Eleven percent never consumed opioids, and only 1 patient requested a refill during the 21-day postoperative period. Multivariate analysis showed that increased weight, longer surgery time, and increased diazepam use were most closely associated with increased opioid consumption. CONCLUSIONS: After knee arthroscopy and related surgery, including ligament reconstruction or tibial tubercle osteotomy, adolescent and young adult patients are commonly overprescribed opioids, consuming on average only approximately one-third of those prescribed. LEVEL OF EVIDENCE: Level IV, case series. PMID- 30396798 TI - Extra-articular Lateral Hinge Fracture Does Not Affect the Outcomes in Medial Open-Wedge High Tibial Osteotomy Using a Locked Plate System. AB - PURPOSE: To compare the radiologic and clinical outcomes in patients with and without lateral hinge fractures (LHFs) during medial open-wedge high tibial osteotomy (MOWHTO) using a locked plate system, as well as to assess whether LHFs could affect the midterm outcomes. METHODS: From May 2008 to November 2015, 164 knees underwent MOWHTO using a locked plate system for the treatment of knee osteoarthritis. LHFs were recognized by radiographs during or after the high tibial osteotomy and were not additionally treated. In all patients, we applied the same rehabilitation protocol that allowed full weight bearing at 6 weeks. Patients were divided into LHF (types I and II) and nonfracture groups. Radiologically, we compared any serial changes in the hip-knee-ankle angle, femorotibial angle, medial proximal tibial angle, and posterior tibial slope angle from the immediate postoperative radiographs to the final radiographs. The union process of the osteotomy site among the groups was also evaluated. Clinically, the postoperative American Knee Society Score and knee range of motion at latest follow-up were compared. Postoperative complications were also evaluated. RESULTS: The average age at operation was 56.0 years (range, 42-67 years), and the average follow-up period was 62.2 months (range, 24-120 months). LHFs were observed in 37 knees (22.6%) and were divided into the type I (16 knees) and type II (21 knees) groups. All groups showed no significant changes in serial evaluations of the postoperative hip-knee-ankle angle, femorotibial angle, medial proximal tibial angle, and posterior tibial slope angle. The improvements in the American Knee Society Score and knee range of motion were not significantly different among the groups. No patients showed correction loss or union problems. CONCLUSIONS: Type I and II LHFs in MOWHTO using a medial locked plate system and relatively conservative rehabilitation protocol with full weight bearing walking commenced at 6 weeks postoperatively showed no radiologic changes or functional deterioration during midterm follow-up. LEVEL OF EVIDENCE: Level IV, case series. PMID- 30396799 TI - The Influence of Pain in Other Major Joints and the Spine on 2-Year Outcomes After Hip Arthroscopy. AB - PURPOSE: To determine whether patients who have pain in other major joints or the spine have poorer postsurgical outcomes than patients without comorbid orthopaedic pain. METHODS: We performed a review of a prospectively maintained institutional surgical registry of patients who underwent hip arthroscopy between January 1, 2012, and July 16, 2015, by a single surgeon, with a minimum of 2 years of postoperative follow-up. A musculoskeletal morbidity (MSM) score was assigned to each patient preoperatively based on the presence of pain in other joints and the spine (grade 1, hip only; grade 2, hip and other major joints without spine; grade 3, hip with spine; and grade 4, hip and other major joints with spine). Preoperatively and at 2 years postoperatively, functional outcomes were measured using the Hip Outcome Score-Activities of Daily Living (HOS-ADL), and the percentages of patients achieving a minimal clinically important difference (MCID) and patient-acceptable symptom state (PASS) were calculated. RESULTS: In total, 821 patients were identified, of whom 700 (85.3%) completed 2 year follow-up. Preoperatively, MSM grade 1 patients had a higher HOS-ADL than grade 2 patients (P = .02), but there was no difference between grade 1 and grade 3 patients (P = .63) or between grade 1 and grade 4 patients (P = .14). Likewise, there was no difference in the preoperative HOS-ADL among grades 2, 3, and 4. Patients with MSM grades 1 and 2 were younger than those with grades 3 and 4. At 2 years postoperatively, MSM grade 1 patients had higher HOS-ADL values than grade 3 (P = .01) and grade 4 (P = .02) but not grade 2 (P = .07) patients. Overall, 84% of patients showed an MCID and 72% of patients achieved a PASS with regard to the HOS-ADL. There were no statistically significant differences among MSM grades in terms of the MCID or PASS. CONCLUSIONS: Overall, 84% of patients improved with hip arthroscopy by MCID criteria for the HOS-ADL. Patients with no pain in other joints (MSM grade 1) had better 2-year postoperative HOS-ADL values after hip arthroscopy than patients with spine pain (grades 3 and 4). However, there were no significant differences in the MCID or PASS among patients with regard to MSM grade. A total of 40.5% of patients who underwent hip arthroscopy had pain in another joint. A limitation, however, is that there is potential for a type II error, in that there may not have been a sufficient number of patients studied to detect a significant difference in outcome among patients with different grades of musculoskeletal comorbidity. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 30396800 TI - Autograft or Allograft? Irradiated or Not? A Contrast Between Autograft and Allograft in Anterior Cruciate Ligament Reconstruction: A Meta-analysis. AB - PURPOSE: To compare the clinical outcomes and adverse events associated with irradiated and nonirradiated allografts in anterior cruciate ligament (ACL) reconstruction. METHODS: PubMed, Web of Science, and EMBASE were searched for randomized controlled trials from January 1990 to March 2018 to compare autograft with allograft in ACL reconstruction. Both objective and subjective outcomes of the function and adverse events were meta-analyzed. Two comparisons were summarized: (1) autograft and nonirradiated allograft and (2) autograft and irradiated allograft. The bias risk was based on the Cochrane Handbook for Systematic Reviews of Interventions. The overall risk ratio or weighted mean difference was calculated using a fixed- or random-effects model. Heterogeneity between studies was evaluated by the Q and the I2 statistics. RESULTS: Eleven trials were included in this review for meta-analysis. A total of 1,172 patients were involved (465 autograft and 461 nonirradiated allograft; 141 autograft and 138 irradiated allograft patients). The average follow-up varied from 2 to >10 years. The mean patient age varied from 22 to 32.8 years. The total failure rate was 2.5%. Our analyses demonstrated better clinical outcomes in autograft than irradiated allograft, which could be observed clearly through the International Knee Documentation Committee score (3.84; 95% confidence interval [CI], 1.93 5.76; P < .0001; I2 = 0%), Lysholm score (2.94; 95% CI, 0.66-5.22; P = .01; I2 = 0%), and Tegner score (0.14; 95% CI, -0.08 to 0.36; P = .22; I2 = 0%) with fewer adverse events 0.20 (95% CI, 0.11-0.39; P < .00001; I2 = 0%). There were no significant differences in autograft and nonirradiated allograft groups (P = .47, P = .27, P = .24, and P = .24, respectively). CONCLUSIONS: Autograft offered greater advantages in functional outcomes and adverse events than irradiated allograft in ACL reconstruction; however, there were no significant differences between autograft and nonirradiated allograft in ACL reconstruction. LEVEL OF EVIDENCE: Level II, meta-analysis of Level I and Level II studies. PMID- 30396801 TI - Femoral Contact Forces in the Anterior Cruciate Ligament Deficient Knee: A Robotic Study. AB - PURPOSE: To measure contact forces (CFs) at standardized locations representative of clinical articular cartilage defects on the medial and lateral femoral condyles during robotic tests with simulated weightbearing knee flexion. METHODS: Eleven human knees had 20-mm-diameter cylinders of native bone/cartilage cored from both femoral condyles at standardized locations, with each cylinder attached to a custom-built load cell that maintained the plug in its precise anatomic position. A robotic test system was used to flex the knee from 0 degrees to 50 degrees under 200-N tibiofemoral compression without and with a 2 Nm internal tibial torque, 5 Nm external tibial torque, and 45 N anterior tibial force (AF). CFs and knee kinematics were recorded before and after cutting the anterior cruciate ligament (ACL). RESULTS: ACL sectioning did not significantly increase medial or lateral CFs for any loading condition, with the exception of AF, in which increases in medial CF ranged from 38 N (at 15 degrees flexion, P < .01) to 77 N (at 50 degrees flexion, P < .002). Compared with the intact condition, ACL sectioning significantly increased anterior tibial translation by 12.33 mm (at 15 degrees flexion, P < .001) and 17.4 mm (at 50 degrees flexion, P < .001), and increased valgus rotation by 2.4 degrees (at 15 degrees flexion, P < .001) and 3.8 degrees (at 50 degrees flexion, P < .001). CONCLUSIONS: Our hypothesis that CF would increase after ACL section was confirmed for the AF test condition only, and only for the medial condyle beyond 10 degrees flexion. With the ACL sectioned, it appeared that the increased CF was owing to the medial condyle riding up over the posterior tibial plateau resulting from the large anterior tibial displacements. CLINICAL RELEVANCE: Aside from our limited finding with AF, we concluded that CFs were generally unaffected by ACL section. PMID- 30396802 TI - Complexity of Lymphoid Tissue Organizers: A Response to Onder and Ludewig. PMID- 30396803 TI - Redefining the Nature of Lymphoid Tissue Organizer Cells: Response to 'Complexity of Lymphoid Tissue Organizers' by Koning and Mebius. PMID- 30396804 TI - Corrections. PMID- 30396805 TI - Evaluation of extent and pattern of neurocognitive functions in mild and moderate traumatic brain injury patients by using Montreal Cognitive Assessment (MoCA) score as a screening tool: An observational study from India. AB - INTRODUCTION: Cognitive impairment is one of the most important culprit influencing the long-term neurological outcome commonlyobserved in TBI survivors. AIMS: To examine the performance of patients with Mild and Moderate traumatic brain injury (TBI) on the Montreal Cognitive Assessment (MoCA) using as a screening tool. RESULTS: Total 228 (127 Mild TBI & 101 Moderate TBI) patients were recruited in this study. Results showed that patients with moderate TBI had lower score on the MoCA as compared to patients with mild TBI (p Value = 0.031). This difference was observed statistically significant among mild and moderate TBI for the cube copy (p = 0.039) and clock (p = 0.017) i.e. visuospatial/executive function, Digit span test (p value = 0.040) i.e. concentration and recall memory (p = 0.04). MoCA Score were higher for patients with higher GCS score at admission. Education status was also correlated with MoCA scores; those patients with higher level of education had significant association with higher MoCA scores (p value = 0.012). This study showed that age and gender were insignificant variables to determine cognitive function. CONCLUSION: Assessment of cognitive impairment should be considered as a mandatory protocol while evaluating post TBI patients, even in cases of mild TBI. Visuospatial/Executive function, memory and attention are the most commonly impaired cognitive functions in patients of TBI, and these are the main domain of cognition which differentiates mild impairment from moderate impairment. This information enables us and provides insight to our experience to predict the burdens of problem and plan to develop post TBI dedicated rehabilitating programme. PMID- 30396806 TI - Management Strategies for Severe and Refractory Acute Respiratory Distress Syndrome: Where Do We Stand in 2018? PMID- 30396807 TI - Infection and Thrombosis in Cardiac Surgery: Is There a Common Ground? PMID- 30396808 TI - Immunotherapy in Gliomas. AB - OBJECTIVES: To describe the immunotherapy approaches currently under investigation for the treatment of gliomas. To discuss the management of immune related adverse effects. DATA SOURCES: Published literature, clinical trials, and oncology association guidance documents. CONCLUSION: There are numerous modalities of immune treatment currently being evaluated in patients with glioma, including peptide vaccines, dendritic cell vaccines, oncolytic viruses, CAR-T cells, and checkpoint inhibitor therapy. Immunotherapy utilizes new mechanisms of treatment that may lead us to the eradication of gliomas. IMPLICATIONS FOR NURSING PRACTICE: Immunotherapy is a rapidly growing field in the treatment of gliomas. Oncology nurses are often involved in the safe administration of these therapies, as well as the identification and management of immune-related toxicities. PMID- 30396809 TI - Influence of the surgical technique on survival in the treatment of carcinomas of the true cardia (Siewert Type II) - Right thoracoabdominal vs. transhiatal abdominal approach. AB - INTRODUCTION: It is still a matter of debate whether subtotal esophagectomy via a right thoracoabdominal approach (RTA) or extended gastrectomy using a transhiatal abdominal approach (TH) is the favorable technique in the treatment of Siewert type II esophago-gastric junction adenocarcinoma (EJA). MATERIALS AND METHODS: Patients undergoing RTA or TH for EJA at our institution between 2000 and 2013 were extracted from a prospective database. Of 270 patients 91 (33.7%) underwent RTA and 179 (66.3%) were treated by TH. Differences in baseline characteristics, 30d mortality and complications were investigated using the chi2-test or exact testing. Survival analysis was performed using the Kaplan-Meier method and log rank testing. Median survival and hazard ratios were calculated and multivariable analysis of predictors was performed using a Cox model. Confounders were balanced using propensity score matching (PSM). RESULTS: No significant difference between the two procedures was detected regarding overall-survival (OS) and disease-free survival (DFS). 30d mortality rates were 1.1% in the RTA group and 4.5% in the TH group (p = 0.134). Morbidity was 34.1% in the RTA and 24.6% in the TH group (p = 0.006). Cox regression analysis identified age, ASA class and UICC stage as independent prognostic factors for OS. After PSM survival curves (OS + PFS) showed no significant difference. CONCLUSION: The present study could not detect a difference between RTA and TH from the oncologic point of view; RTA was not associated with higher 30d mortality. RTA for Siewert Type II EJA is justified whenever the oral tumor margin cannot be safely reached via a transhiatal approach. PMID- 30396810 TI - The epigenetics of inflammaging: The contribution of age-related heterochromatin loss and locus-specific remodelling and the modulation by environmental stimuli. AB - A growing amount of evidences indicates that inflammaging - the chronic, low grade inflammation state characteristic of the elderly - is the result of genetic as well as environmental or stochastic factors. Some of these, such as the accumulation of senescent cells that are persistent during aging or accompany its progression, seem to be sufficient to initiate the aging process and to fuel it. Others, like exposure to environmental compounds or infections, are temporary and resolve within a (relatively) short time. In both cases, however, a cellular memory of the event can be established by means of epigenetic modulation of the genome. In this review we will specifically discuss the relationship between epigenetics and inflammaging. In particular, we will show how age-associated epigenetic modifications concerned with heterochromatin loss and gene-specific remodelling, can promote inflammaging. Furthermore, we will recall how the exposure to specific nutritional, environmental and microbial stimuli can affect the rate of inflammaging through epigenetic mechanisms, touching also on the recent insight given by the concept of trained immunity. PMID- 30396811 TI - Immunocorrelates of CAF family adjuvants. AB - The development of the CAF family adjuvant was initiated around 20 years ago when Statens Serum Institut was preparing its first generation protein based recombinant subunit vaccine against tuberculosis for clinical testing, but realized that there were no clinically relevant adjuvants available that would support the strong CMI response needed. Since then the aim for the adjuvant research at Statens Serum Institut has been to provide adjuvants with distinct immunogenicity profiles correlating with protection for any given infectious disease. Two of the adjuvants CAF01 and CAF09 are currently being evaluated in human clinical trials. The purpose of this review is to give an overview of the immunocorrelates of those CAF adjuvants furthest in development. We further aim at giving an overview of the mechanism of action of the CAF adjuvants. PMID- 30396812 TI - Predictors for Survival and Distribution of 21-Gene Recurrence Score in Patients With Pure Mucinous Breast Cancer: A SEER Population-Based Retrospective Analysis. AB - BACKGROUND: Pure mucinous breast cancer (PMBC) is a rare pathologic type of breast cancer, the prognostic factors of which have not been clearly defined. This study aimed to analyze the prognostic markers and distribution of 21-gene recurrence score (RS) in patients with PMBC. PATIENTS AND METHODS: Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, a retrospective analysis of PMBC cases was conducted. Multivariate analyses were used to evaluate the indicators for prognosis and the correlations between RS and traditional clinicopathologic characteristics. Disease was subdivided into 4 molecular phenotypes using estrogen receptor (ER) status and tumor grade. RESULTS: Of the 8048 patients, most had ER-positive and node-negative tumors. Multivariate analysis revealed that molecular phenotype as well as age, race, tumor size, and lymph node status was an independent prognostic factor for patients with PMBC (P < .05). The 5-year breast cancer-specific survival of patients among different phenotypes was significantly different (97.9% for ER-positive and grade I tumor, 96.9% for ER-positive and grade II-III tumor, 96% for ER-negative and grade I tumor, 90.1% for ER-negative and grade II-III tumors, P < .001). The proportions of patients categorized into low, intermediate, and high RS risk group were 64.9%, 31.9%, and 3.2%, respectively. Grade, progesterone receptor status, and age were identified as independent variables associated with RS. CONCLUSION: PMBC had favorable biological features and relatively good prognosis. Molecular phenotype as well as age, race, tumor size, and lymph node status were independent prognostic markers. Furthermore, age, progesterone receptor status, and grade could independently predict RS. PMID- 30396813 TI - Chiripa technique. Report of a novel technique to protect the spinal cord from incidental durotomies during complex spinal procedures. AB - BACKGROUND CONTEXT: Incidental durotomy is the most frequent intraoperative complication reported in spinal literature. Multiple strategies have been suggested to manage it. METHODS: A brief technical report. DISCUSSION: The use of cottonoids is a recommended measure to avoid incidental durotomies during spinal surgeries; thus, ventral protection might be difficult to achieve. This "Chiripa technique" provides circumferential protection to the neurostructures, so that surgical procedures can be safely carried out. CONCLUSION: Taking into account the low costs and ease of execution, this can be a valuable tip that may widely extended in all cases where a circumferential dural protection is needed. PMID- 30396814 TI - Seroconversion of JCV antibodies is strongly associated to natalizumab therapy. AB - Previous infection with John Cunningham virus (JCV) increases the risk of progressive multifocal leukoencephalopathy in patients with multiple sclerosis (MS) undergoing treatment with natalizumab. Patients who test negative for JCV antibodies must be assessed every six months due to the risk of seroconversion. Data from the United States of America, Portugal, Holland, France, United Kingdom and Sweden have shown a strong correlation between the use of natalizumab and JCV seroconversion. The authors present now data on patients from Brazil, as there are no data from Latin American countries published on this subject yet. A group of 86 patients with MS with negative results for antibodies against JCV were included in this analyses with at least two JCV antibodies testing. Twenty-five patients (29% of the total group) did not use natalizumab at any time, while the remaining 71% used natalizumab for a median period of 800 days (equivalent to 28 monthly infusions). Seroconversion was observed in 19 patients (22.1%). There was no association of seroconversion with gender, age, previous pulses of corticosteroid or specific MS-modifying drugs. The use of natalizumab was strongly associated to seroconversion (p < 0.0001). The present results confirm the influence of natalizumab therapy on JCV antibodies in several countries and continents. PMID- 30396815 TI - Time-of-flight MRA signal intensity predicts the cerebral hemodynamic status after superficial temporal artery to middle cerebral artery anastomosis. AB - Arterial signal intensities on magnetic resonance angiography (MRA) correlate with the relevant hemisphere's hemodynamics in patients with cerebrovascular diseases. We evaluated whether superficial temporal artery (STA) signal intensities (SI) on MRA were useful to evaluate the postoperative cerebral hemodynamics of patients with symptomatic internal carotid artery (ICA) or middle cerebral artery (MCA) steno-occlusive disease who underwent unilateral STA-MCA anastomosis. Twenty-one consecutive patients undergoing unilateral STA-MCA anastomosis for symptomatic ICA or MCA steno-occlusive disease were enrolled. All patients underwent MRA and superficial temporal artery duplex ultrasonography (STDU) at 3 months and 1 year postoperatively. Bilateral region of interests (ROIs) on time-of-flight (TOF)-MRA source images were placed on the STA just before its bifurcation. The STA-SI ratio, which was the ratio of the SI on the operated STA to that of the contralateral STA, was calculated; the correlation between the ratio and STDU parameters was investigated. The STA diameter and flow velocities (systolic, end-diastolic, and mean) significantly correlated with the STA-SI ratio at 1 year postoperatively (p = .0302, p = .0002, p = .0029, p = .002). The end-diastolic flow velocity ratio was significantly correlated with the STA-SI ratio at 1 year postoperatively (p = .0014, r = 0.6518). The STA-SI ratio can be used to predict the extent of postoperative collateral bypass flow, and it may help predict postoperative cerebrovascular reserve. PMID- 30396816 TI - The diagnostic value of clinical examinations when diagnosing carpal tunnel syndrome assisted by nerve conduction studies. AB - BACKGROUND: Our study aims to evaluate the reliability of clinical findings in diagnosing carpal tunnel syndrome (CTS), with the help of nerve conduction studies (NCSs) and the detection of comorbidities likely to be risk factors. METHODS: 512 patients were included in the study who described pain or paresthesia in the median nerve sensory distribution. Sensory and motor NCSs were performed on the median and ulnar nerves of all patients. 49 patients who showed pathological abnormalities of the ulnar nerve were excluded. Demographic information, clinical findings and comorbidities were recorded. According to the results of the NCSs, the patients were divided and analyzed as either positive and negative for the diagnosis of CTS. RESULTS: The highest sensitivity was seen from the Durkan test (95.6%) and the lowest was from thenar atrophy (22.1%). The highest specificity and positive predictive values were seen for thenar atrophy (100%) and the lowest were from the Tinel test (40.9% and 59.1%). The highest negative predictive value was the Durkan test (94%) and thenar atrophy was the lowest (57.4%). There was a significant difference in NCSs groups for clinical findings and comorbidities. CONCLUSIONS: Thenar atrophy and sensory loss were highly specific in CTS but had limited value in early detection. Due to their low specificity, provocative tests do not appear sufficient enough to establish a definite CTS diagnosis. Only Durkan's test could possibly be considered initially as it has more balanced values. Diabetes, obesity, rheumatoid arthritis, hypothyroidism and gout significantly increase the risk of CTS. PMID- 30396817 TI - Comparison between autologous bone grafts and acrylic (PMMA) implants - A retrospective analysis of 286 cranioplasty procedures. AB - Decompressive craniectomy (DC) is an accepted surgical technique for reducing life-threatening levels of intracranial pressure. Remodelling the cranial vault following DC can constitute a reconstructive challenge and is known to carry significant morbidity. The aim of our study was to evaluate acrylic versus autologous cranioplasty with regard to specific complication rates. A retrospective analysis was conducted of 286 consecutive adult patients who underwent cranioplasty following supratentorial decompressive craniectomy at our institution between January 2003 and June 2013. The patients were followed based on medical records, operative reports, imaging and outpatient contacts in the postoperative course. A total of 221/286 patients in our series received an autologous bone flap. 65/286 cranioplasty procedures were carried out using acrylic (PMMA) implants to cover uni- or bilateral defects. Within the follow-up period a total of 100 operative revisions were performed. 33.3% patients in the autologous bone group and 40.6% of patients in the acrylic group developed complications requiring surgical attention. The main reason for revision was infection with a total of 37 revisions necessary to treat disturbed wound healing. Postoperative sub- and epidural hematomas requiring revision were more frequent in the acrylic group. Resorption of the autologous bone flap requiring operative revision was seen in 8/222 (3.6%) cases. Other complications included loosening of the implant or dislocation. From our data it can be concluded that cranioplasty procedures using autologous bone-flaps and acrylic implants carry signifikant morbidity, but that both are justifiable techniques for cranioplasty in adult patients. PMID- 30396818 TI - Characterization of long-term prognosis in acute pancreatitis: An explorative analysis. AB - BACKGROUND/OBJECTIVES: Severity classification systems of acute pancreatitis (AP) assess inpatient morbidity and mortality without predicting outpatient course of AP. To provide appropriate outpatient care, determinants of long-term prognosis must also be identified. The aim of this study was to define clinical groups that carry long-term prognostic significance in AP. METHODS: A retrospective study that included patients admitted with AP was conducted. Determinants of long-term prognosis were extracted: These included Revised Atlanta and Determinant Based Classification (RAC), Charlson Comorbidity Index (CCI), Modified CT Severity Index (MCTSI), etiology, and local complications (LCs). Seven surrogates of morbidity up to 1 year after discharge were also collected and subsequently imputed into a clustering algorithm. The algorithm was set to produce three categories and multinomial regression analysis was performed. RESULTS: 281 patients were included. The incidences of morbidity endpoints were similar among the 3 RAC categories. Three clusters were identified that carried long-term prognostic significance. Each cluster was given a name to reflect prognosis. The limited AP had the best prognosis and included patients without LCs with a low co morbidity burden. The brittle AP had a low co-morbidity burden and high MCTSI (LCs 94%). It ran a very morbid course but had excellent survival. The high-risk AP had the worst prognosis with the highest mortality rate (28%). They had a high co-morbidity burden without local complications. CONCLUSION: Categories that carry long-term prognostic significance in AP have been developed. This study could help formulate appropriate follow-up and ultimately improve AP outcomes. PMID- 30396819 TI - Tumor treating fields in combination with gemcitabine or gemcitabine plus nab paclitaxel in pancreatic cancer: Results of the PANOVA phase 2 study. AB - BACKGROUND: Tumor Treating Fields (TTFields), low intensity alternating electric fields with antimitotic activity, have demonstrated survival benefit in patients with glioblastoma. This phase 2 PANOVA study was conducted to examine the combination of TTFields plus chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Forty patients with newly-diagnosed, locally advanced or metastatic PDAC received continuous TTFields (150 KHz for >=18 h/day) plus gemcitabine (1000 mg/m2), or gemcitabine plus nab-paclitaxel (125 mg/m2). The primary endpoint was safety and secondary endpoints included compliance to TTFields, progression-free survival (PFS), and overall survival (OS). RESULTS: Seventeen patients (85%) in each cohort reported Grade >=3 adverse events (AEs). No increase in serious AEs (SAEs) was observed compared to that anticipated with systemic chemotherapy alone. Twenty-one patients reported TTFields-related skin toxicity, of which 7 were Grade 3; all resolved following temporary reduction of daily TTFields usage. No TTFields-related SAEs were reported. Compliance to TTFields was 68-78% of the recommended average daily use in both cohorts. Median PFS was 8.3 months (95% CI 4.3, 10.3) and median OS was 14.9 months (95% CI 6.2, NA) in the TTFields + gemcitabine cohort. In the TTFields + gemcitabine + nab paclitaxel cohort, the median PFS was 12.7 months (95% CI 5.4, NA); median OS has not been reached. CONCLUSION: The PANOVA trial demonstrated that the combination of TTFields and systemic chemotherapy is safe and tolerable in patients with advanced PDAC. Based on the safety and preliminary efficacy results of this phase 2 study, a randomized phase 3 study (PANOVA-3) is underway. PMID- 30396820 TI - Nationwide study of outpatient oral antimicrobial utilization patterns for children in Japan (2013-2016). AB - BACKGROUND: Antimicrobial resistance (AMR) is a major multinational public health concern. The Japanese government set goals in its AMR action plan to reduce use of oral cephalosporins, macrolides, and quinolones by half between 2013 and 2020. We aimed to evaluate antimicrobial use in children in Japan by observing prescription patterns as an interim assessment of the national AMR action plan. METHODS: Using the national health claims database, we retrospectively analyzed all oral antimicrobials dispensed from outpatient pharmacies in Japan to children under 15 years old from 2013 to 2016 by age, prefecture, type of antimicrobial, and year. Data were presented as days of therapy (DOTs) per 1000 pediatric inhabitants per day (DOTs/PID). The chi2 test for trends was performed to evaluate annual changes in DOTs/PID overall as well as within each stratum. RESULTS: A total of 721,627,553 oral antimicrobial DOTs were identified during 2013-2016. No statistically significant changes were observed in total antimicrobial use in children (2013: 28.54 DOTs/PID; 2016: 28.70 DOTs/PID; Ptrend = 0.25) and amount of cephalosporins, macrolides, and quinolones prescribed. Prescription rates of all antimicrobials were highest among children 1-5 years old, peaking at 1 year old. Targeted antimicrobials for the AMR action plan showed similar distribution by age. CONCLUSION: The amount of antimicrobials prescribed to children in Japan is not decreasing. Overall antimicrobial prescriptions, as well as prescriptions of cephalosporins, macrolides, and quinolones, were most prevalent in children <=5 years old. Rigorous antimicrobial stewardship interventions targeting infants and younger children are necessary. PMID- 30396821 TI - Greater burden of chronic comorbidities and co-medications among people living with HIV versus people without HIV in Japan: A hospital claims database study. AB - OBJECTIVE: This study examined the prevalence of chronic comorbidities and the use of co-medications among people living with HIV (PLWH) on antiretrovirals in Japan, compared with age-matched controls without HIV. METHODS: This was an observational, retrospective, cross-sectional study using a hospital claims database of Japanese hospitals with advanced medical capabilities (i.e., advanced treatment hospitals, general hospitals, acute care hospitals). We extracted data for PLWH aged >=18 years with a prescription record of antiretrovirals between January 2010 and December 2015, and for age-, sex-, and hospital-matched people without HIV. For each group, chronic comorbidities (diabetes, hypertension, lipid disorders, vascular diseases, chronic kidney failure, cancers, psychiatric disorders, osteoporosis, and hepatitis B/C co-infection), and co-medications were examined by age group. RESULTS: We analyzed data for 1445 PLWH and 14,450 people without HIV. The proportion of patients with multiple comorbidities was much greater among PLWH than controls of the same age group. Lipid disorders and diabetes were more prevalent in PLWH than controls (31.6% vs. 10.3% and 26.8% vs. 13.2%, respectively), both of which were more common in PLWH at earlier ages. Cancer was present in 8.1% of PLWH and 8.9% of controls. A greater proportion of PLWH used multiple co-medications other than antiretrovirals at earlier ages than controls. CONCLUSION: PLWH taking antiretrovirals in Japan had a greater burden of comorbidities and co-medications with increasing age than people without HIV. In addition to appropriate management of comorbidities, medication reconciliation according to patients' co-medication profiles is important for successful management of this patient population. PMID- 30396823 TI - Histiocytic Sarcoma Associated With Follicular Lymphoma: Evidence for Dramatic Response With Rituximab and Bendamustine Alone and a Review of the Literature. AB - Histiocytic sarcoma (HS) is a rare aggressive malignancy with a dismal prognosis and no agreed-upon standard treatment. Classically, the diagnosis of HS has been difficult to confirm and has relied on inaccurate, crude techniques. Therapy often involves intensive chemotherapeutic regimens, surgery, and/or radiotherapy, which are poorly tolerated with variable response rates. Patients often die of diffusely metastatic disease. Modern diagnostic techniques are helping to slowly uncover more uniquely customized therapeutic approaches in this enigmatic disease. We present a review of the current literature regarding HS diagnosis, treatment, and outcomes. Additionally, we describe the first reported case of HS transdifferentiated from follicular lymphoma that had a dramatic and durable response to rituximab/bendamustine alone as initial treatment. Unlike traditional chemotherapy regimens, this treatment was well tolerated and had a good toxicity profile. The combination of rituximab and bendamustine warrants further investigation in the treatment of HS, especially those originating from prior follicular lymphoma. Modern immunohistochemical and molecular profiling techniques are beginning to reveal heterogeneity among HS tumors and potentially therapeutic targets. PMID- 30396822 TI - An alpha-Lipoic acid derivative, and anti-ROS agent, prevents the acquisition of multi-drug resistance in clinical isolates of Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is one of the most common causes of nosocomial infections, and its multi-drug resistance has been a serious problem worldwide. The aim of this study was to evaluate whether exposure to piperacillin and reactive oxygen species (ROS) could lead to multi-drug resistance for clinical isolates of P. aeruginosa. The inhibition of this acquired resistance by the anti-ROS agent was also examined. In vitro inducement of multi-drug resistance was performed against 20 clinical isolates. These strains were incubated for 24 h and transferred 5 times after being exposed to 1 mM H2O2 (ROS) in addition to a sub-MIC of piperacillin by the agar dilution method. Each MIC of piperacillin and levofloxacin was determined. As the mechanism of levofloxacin resistance, mutation of QRDR was investigated. The expression level of genes encoding efflux pumps; mexA, mexY, mexC, and D2 porin; oprD were determined by real-time PCR. Multi-resistance to both piperacillin and levofloxacin was induced with 4 of 20 strains (20%). No amino acid change was confirmed in QRDR. These strains showed overexpression of mexA, mexY, mexC, and another one showed decrease of oprD expression. Resistance development in 4 strains was inhibited by the same method including the anti-ROS agent, sodium zinc histidine dithiooctanamide (DHL-His Zn). In conclusion, stimulation by ROS promoted acquisition of multi-drug resistance in 20% of isolates of P. aeruginosa, and DHL-His-Zn completely inhibited this acquisition of resistance. Therefore, this anti-ROS agent may be useful to assist antimicrobial chemotherapy by preventing multi-drug resistance. PMID- 30396824 TI - The role of sleep diagnostics and non-invasive ventilation in children with spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is a degenerative motor neurone disorder causing progressive muscular weakness. Without assisted ventilation or novel therapies, most children with SMA type 1 die before the second year of life due to respiratory failure as the respiratory muscles and bulbar function are severely affected. Active respiratory treatment (mechanically assisted cough, invasive or non-invasive ventilation) has improved survival significantly in recent decades, but often at the cost of becoming ventilator dependent. The advent of a new oligonucleotide based therapy (Nusinersen) has created new optimism for improving motor function. However, the long-term effect on respiratory function is unclear and non-invasive respiratory support will remain an important part of medical management in patients with SMA. This review summarises the existing knowledge about sleep-disordered breathing and respiratory failure in patients with SMA, especially type 1, as well as the evidence of improved outcome and survival in patients treated with non-invasive or invasive ventilation. Practical considerations and ethical concerns are delineated with discussion on how these may be affected by the advent of new therapies such as Nusinersen. PMID- 30396825 TI - Routine opioid outcome monitoring in community pharmacy: Pilot implementation study protocol. AB - BACKGROUND: Increases in opioid use and related harms such as mortality are occurring in many high income countries. Community pharmacists are often in contact with patients at risk of opioid-related harm and represent an ideal point for intervention. Best practice in monitoring opioid-related outcomes involves assessing analgesia, pain functioning, mood, risks and harms associated with opioid use. Community pharmacists are well-placed to undertake these tasks. OBJECTIVES: Our pilot study will test the implementation of a computer facilitated screening and brief intervention (SBI). The SBI will support pharmacist identification of opioid-related problems and provide capacity for brief intervention including verbal reinforcement of tailored information sheets, supply of naloxone and referral back to the opioid prescriber. The SBI utilises software that embeds study procedures into dispensing workflow and assesses opioid outcomes with domains aligned with a widely accepted clinical framework. METHODS: We will recruit and train 75 pharmacists from 25 pharmacies to deliver the Routine Opioid Outcome Monitoring (ROOM) SBI. Pharmacists will complete the SBI with up to 500 patients in total (20 per pharmacy). Data will be collected on pharmacists' knowledge and confidence through pre- and post-intervention online surveys. Data on feasibility, acceptability and implementation outcomes, including naloxone supply, will also be collected. PROJECT IMPACT: Our study will examine changes in pharmacists' knowledge and confidence to deliver the SBI. Through the implementation pilot, we will establish the feasibility and acceptability of a pharmacist SBI that aims to improve monitoring and clinical management of patients who are prescribed opioids. PMID- 30396826 TI - A comparison of warfarin monitoring service models. AB - BACKGROUND: Warfarin-related knowledge and patient satisfaction with warfarin monitoring services are generally high with respect to anticoagulation-related care received. Providing a cost-effective warfarin monitoring service while improving warfarin-related knowledge, patient safety and satisfaction can be challenging. OBJECTIVES: To compare 'post and dose' service offered by the Calderdale Royal Hospital (CRH) and 'face-to-face' service offered by Huddersfield Royal Infirmary (HRI) in terms of costs of service delivery, patient satisfaction, warfarin-related knowledge and safety indicators. METHODS: A cross sectional sample of 160 patients on long-term warfarin therapy from anticoagulation (outpatient) clinics at CRH and HRI using interviewer administered data collection form. International Normalized Ratio (INR), Time in Therapeutic Range (TTR) and Variance Growth Rate (VGR) values of last 12 months and the data on costs of service delivery, knowledge and satisfaction were collected. RESULTS: Patients monitored at HRI had higher mean VGR value (0.35 +/- 0.62 vs. 0.17 +/- 0.17, p = 0.092) and slightly lower mean TTR (68.70 +/- 19.43 vs. 69.63 +/- 17.71, p = 0.756) compared with CRH patients. Patients monitored in 'post and dose' were estimated at a price of L11.06 per patient per visit and each patient in face-to-face service only cost L9.70 per visit. Patients monitored at HRI had marginally higher overall knowledge score (65.22 +/- 23.29 vs. 60.31 +/- 20.93, p = 0.165) and overall satisfaction score (15.59 +/- 3.16 vs. 15.05 +/- 3.10, p = 0.279) compared with CRH patients. A positive and significant correlation was found between patients' knowledge and patient satisfaction (r = +0.327, p = 0.001). CONCLUSION: Although, HRI provided monitoring service at a slightly lower cost than CRH, patients monitored at CRH had better anticoagulation control and favourable indicators. Warfarin-related knowledge needs to be improved to achieve further improvement in quality of warfarin use. PMID- 30396827 TI - "Relaxed" natural kinds and psychiatric classification. AB - This paper starts out highlighting a particular criticism that psychiatry faces and continues by investigating approaches to classification in psychiatry that operate with a "relaxed" (non-essentialist) notion of natural kind. Two accounts are examined, one by Rachel Cooper (2005; 2013) and one based on the work of Richard Boyd (1991; 1999; 2003; 2010). While these accounts do not directly pursue such a goal, the main aim is to probe whether deploying a "relaxed" notion of natural kind would be able to neutralize the criticism. While the conclusion is in the negative, the analysis raises doubts that it is possible to completely neutralize this criticism without assuming an overly simplistic view of the causal structure of the world. PMID- 30396829 TI - Mass-Like Lesion on Brain Magnetic Resonance Imaging. PMID- 30396828 TI - Safety and Efficacy of Pazopanib in First-Line Metastatic Renal-Cell Carcinoma With or Without Renal Failure: CORE-URO-01 Study. AB - BACKGROUND: Pazopanib has been approved for first-line treatment of patients with metastatic renal-cell carcinoma on the basis of clinical trials that enrolled only patients with adequate renal function. Few data are available on the safety and efficacy of pazopanib in patients with renal insufficiency. This study investigated the effect of kidney function on treatment outcomes in such patients. PATIENTS AND METHODS: We retrospectively analyzed data of metastatic renal-cell carcinoma patients treated with pazopanib from January 2010 to June 2016 with respect to renal function. Patients with Modification of Diet in Renal Disease <= 60 mL/min/1.73 m2 (group A) were compared to patients with Modification of Diet in Renal Disease > 60 mL/min/1.73 m2 (group B) in terms of progression-free survival, toxicities, response rates, and overall survival. RESULTS: A total of 229 patients were included: 128 in group A and 101 in group B. Median progression-free survival was 14 months (95% confidence interval [CI], 9.4-18.5) and 17 months (95% CI, 11.4-22.8), and overall survival was 30.5 months (95% CI, 8-53) and 41.4 months (95% CI, 21-62) for group A and group B, respectively, with no significant difference (P = .6). No significant difference between the 2 groups was reported in the incidence of adverse events. Dose reductions were more frequent in group A patients (66% vs. 36%; P = .04). CONCLUSION: Although the dose of pazopanib was reduced more frequently in patients with renal impairment, kidney function at therapy initiation does not adversely affect the safety and efficacy of pazopanib. PMID- 30396830 TI - "Black Toenail" Sign. AB - A 11-year-old boy with genetically confirmed MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome with mutation at mt.3243A>G) presented with extreme fatigue. Upon presentation, he had elevated lactic acid of 5.2 mmol/L. His magnetic resonance imaging scan of the brain showed progression of multifocal gyral necrosis and cerebral atrophy compared to the images done 3 years prior to presentation(Fig). He was discharged soon after his fatigue resolved in response to supportive therapy.This image finding of gyral necrosis is known as "black toenail" sign, representing the MELAS-related gyral necrosis that is commonly seen in chronic MELAS patients. Although the etiology of gyral necrosis has not been clearly elucidated, it is assumed that the necrosis is associated with multifactorial etiologies including hypoxic ischemic injury, decreased substrate delivery, decreased toxin removal, and superimposed neuronal excitation leading to energy depletion. PMID- 30396831 TI - Extrapontine Myelinolysis and Microhemorrhages: Rare Finding in Pediatric Diabetic Ketoacidosis. PMID- 30396832 TI - Progressive Head Enlargement in a Child With Motor Delay. PMID- 30396833 TI - Volumetric Analysis of the Basal Ganglia and Cerebellar Structures in Patients with Phelan-McDermid Syndrome. AB - OBJECTIVE: Phelan-McDermid syndrome is caused by haploinsufficiency of SHANK3 on terminal chromosome 22. Knowledge about altered neuroanatomic circuitry in Phelan McDermid syndrome comes from mouse models showing striatal hypertrophy in the basal ganglia, and from humans with evidence of cerebellar atrophy. To date, no studies have performed volumetric analysis on Phelan-McDermid syndrome patients. METHODS: We performed volumetric analysis on baseline brain MRIs of Phelan McDermid syndrome patients (ages three to 21 years) enrolled in a prospective natural history study (ClinicalTrials.gov NCT02461420). Using MRI segmentations carried out with PSTAPLE algorithm, we measured relative volumes (volume of the structure divided by the volume of the brain parenchyma) of basal ganglia and cerebellar structures. We compared these measurements to those of age- and sex matched healthy controls part of another study. Among the patients, we performed linear regression of each relative volume using Repetitive Behavior Scale-Revised total score and Aberrant Behavior Checklist stereotypy score. Eleven patients with Phelan-McDermid syndrome (six females, five males) and 11 healthy controls were in this analysis. RESULTS: At time of MRI, the mean age of the patients and controls was 9.24 (5.29) years and 9.00 (4.49) years, respectively (P = 0.66). Compared to controls, patients had decreased caudate (P <= 0.013), putamen (P <= 0.026), and left pallidum (P = 0.033) relative volumes. Relative volume of cerebellar vermal lobules I to V (beta coefficient = -17119, P = 0.017) decreased with increasing Repetitive Behavior Scale-Revised total score. CONCLUSIONS: The volumes of the striatum and left pallidum are decreased in individuals with Phelan-McDermid syndrome. Cerebellar vermis volume may predict repetitive behavior severity in Phelan-McDermid syndrome. These findings warrant further investigation in larger samples. PMID- 30396834 TI - Unusual Clinical Course and Imaging of D-Bifunctional Protein Deficiency, a Rare Leukodystrophy. PMID- 30396835 TI - Management of acquired hemophilia A: Review of current evidence. AB - Acquired hemophilia A (AHA) is a rare acquired bleeding disorder caused by autoantibodies against autologous factor VIII (FVIII). It is a disease that most commonly affects the elderly, but it has been described in children and during the post-partum period. It is idiopathic in 50% of cases and is associated with autoimmune disease, malignancy, pregnancy, infection or certain medications in the other 50%. The diagnosis should be suspected in patients with an isolated prolonged aPPT without previous personal or familial bleeding history. Treating the bleeding and eradication of the inhibitor is the mainstay of treatment. The first line of treatment for acute bleeding is the use of bypassing agents. The most commonly used method for eradicating the inhibitor is immunosuppression, namely corticosteroids alone or in combination with cyclophosphamide. This review summarises current knowledge and reviews management options and guidelines. PMID- 30396836 TI - Validation of the French 3-year prognostic score using the Canadian Cystic Fibrosis registry. AB - Studies of large CF populations using registry data are important to identify people at high risk for death. Nkam et al. published a prognostic score developed on French CF registry data to predict death or lung transplantation (LT) over a 3 year period in the adult CF population. The goal of our study was to validate the proposed tool using the Canadian CF registry. Using data between 2011 and 2014, a total of 2043 adult CF patients were included. We found that the French prognostic score was a good predictor of death or LT in the Canadian CF population (OR for each unit increase: 3.12, 95% CI: 2.74-3.55; p value < 0.001). The proposed prognostic score accurately categorizes patients when applied to an external dataset. This score provides an important tool for early identification of patients at high risk for death or LT, in whom specific therapeutic intervention can be proposed. PMID- 30396837 TI - Early Magnetic Resonance Imaging Decreases Hospital Length of Stay in Patients with Ischemic Stroke. AB - BACKGROUND: Imaging modalities are important part of stroke evaluation. Noncontrast head computed tomography (CT) is the initial imaging modality in acute stroke and although important to rule out acute hemorrhage and making a decision on thrombolytic treatment, ischemic changes may not be visible on CT for up to 24 hours. Magnetic resonance imaging (MRI) brain is an invaluable tool to confirm an ischemic stroke and facilitates stroke evaluation. Objective of this study was to investigate the correlation between time to MRI and length of hospital stay. METHODS: A total of 432 patients admitted to Hartford Hospital (Comprehensive Stroke Center) with a focal neurological deficit in the year 2014 and got a CT head and MRI brain were enrolled in the study. Data collection was done via stroke database and retrospective chart review. Patients with any hemorrhage or age <18 years were excluded from the study. Patients were categorized as having had an early (within 12 hours) or a late (more than 12 hours) MRI. We used chi-square and Wilcoxon ranked sum test to compare time from arrival to MRI and length of stay in the hospital. RESULTS: There was a statistically significant difference in hospital length of stay between patients who obtained MRI within 12 hours, as compared with patients who had MRI greater than 12 hours after admission, early MRI group 3 days (1.8, 4.9) versus 4 days (2.6, 7.0), P < .001. CONCLUSIONS: Our study suggests that brain MRI performed within 12 hours of admission facilitates stroke evaluation and decreases hospital length of stay. It provides evidence for cost effectiveness of MRI in ischemic stroke. PMID- 30396838 TI - Residual Shunt after Patent Foramen Ovale Device Closure in Patients With Cryptogenic Stroke: Serial Bubble Contrast Transesophageal Echocardiography Data. AB - BACKGROUND: Percutaneous closure of patent foramen ovale (PFO) is an alternative option to medical treatment for secondary prevention for cryptogenic stroke (CS). Despite technical success of procedure, residual shunt (RS) which is a presumable cause for recurrent stroke is observed in some patients. We evaluated the RS with serial follow-up bubble contrast transesophageal echocardiography (BCTEE) after PFO closure. METHODS: Among consecutive 47 CS patients who underwent PFO closure, a serial follow-up BCTEE at 3 and 9 months after the index procedure was completed in 38 patients (81%, 46 +/- 10 years, 19 men). To evaluate the efficacy of PFO closure, the incidence of any and significant RS (>= moderate) was assessed. RESULTS: All PFO closure procedures were successful. The Amplatzer PFO Occluder (n = 19) or the Gore Septal Occluder (n = 19) were used. Any RS was observed in 13 (34%) and 10 patients (26%) at 3 and 9 months after the procedure. Significant RS was observed in 6 (16%) and 4 (11%) patients at 3- and 9-month follow-up BCTEE. Patients who were treated with the Gore Septal Occluder have a less incidence of any RS in 3 months, and any/significant RS in 3- and 9-month follow-up BCTEE without statistical significance. CONCLUSIONS: RS grade keeps decreasing after PFO closure, but it remains even after 9 months in some patients. Incomplete sealing of PFO should be taken into consideration in management of CS patients even after technically successful PFO closure. PMID- 30396839 TI - Left Ventricular Ejection Fraction and Clinically Defined Heart Failure to Predict 90-Day Functional Outcome After Ischemic Stroke. AB - BACKGROUND: Heart failure (HF) is a risk factor for atrial fibrillation (AF), stroke, and post-stroke disability. However, differing definitions and application of HF-criteria may impact model prediction. We compared the predictive ability of left ventricular ejection fraction (LVEF), a readily available objective echocardiographic index, with clinical HF definitions for functional disability and AF in stroke patients. METHODS: We retrospectively analyzed ischemic stroke patients evaluated between January 2013 and May 2015. Outcomes of interest were: (a) 90-day functional disability (modified Rankin score 3-6) and (b) AF. We compared: (1) LVEF (continuous variable), (2) left ventricular systolic dysfunction (LVSD)-categories (absent to severe), (3) clinical history of HF, and (4) HF/LVSD-categories: (i) HF absent without LVSD, (ii) HF absent with LVSD, (iii) HF with preserved ejection fraction (HFpEF), and (iv) HF with reduced ejection fraction (HFrEF). Multivariable logistic regression was used to determine the predictive ability for 90-day disability and AF, respectively. RESULTS: Six hundred eighty five consecutive patients (44.5% female) fulfilled the study criteria and were included. After adjustment, the LVEF was independently associated with 90-day disability (OR .98, 95% CI .96-.99, P = .011) with similar predictive ability (area under the curve [AUC] = .85) to models including the LVSD-categories (AUC = .85), clinically define HF (AUC = .86), and HF/LVSD-categories (AUC = .86). The LVEF, HF, LVSD-, and HF/LVSD categories were independently associated with AF (P < .01, each) with similar predictive ability (AUC = .74, .74, .73, and .75, respectively). CONCLUSIONS: Compared to commonly defined HF definitions, the objectively determined LVEF possesses comparable predictive ability for 90-day disability and AF in stroke patients. PMID- 30396840 TI - Vernet's Syndrome Associated with Internal Jugular Vein Thrombosis. AB - Our objective is to present a case of Vernet's syndrome (cranial nerve (CN) IX, X, and XI palsy) associated with cerebral venous thrombosis (CVT) in an internal jugular vein. The patient presented with acutely developed dysphagia. The weakness of the left sternocleidomastoid and trapezius muscles was observed. The initial magnetic resonance imaging and computed tomography (CT) with contrast enhancement showed contrast-filling defect in the left internal jugular vein inside the jugular foramen. The magnetic resonance venography with contrast enhancement revealed a partial filling defect in the left sigmoid sinus and total occlusion of the left internal jugular vein. Under the diagnosis of CVT associated with CN IX, X palsy, anticoagulation therapy with low-molecular weighted heparin was initiated. Despite the continued anticoagulation therapy for 3 months, neither the burden of thrombosis in the left sigmoid sinus and internal jugular vein on neck CT nor dysphagia symptoms improved. Clinicians need to be aware of internal jugular venous thrombosis as one of the differential diagnoses in Vernet's syndrome in patients in a hypercoagulable state. Further reporting of similar cases is needed to confirm the association between CVT and Vernet's syndrome. PMID- 30396841 TI - Evidence-based treatment of multicystic dysplastic kidney: a systematic review. AB - OBJECTIVES: There is a lack of a standardised protocol for the investigation and non-operative management of paediatric multicystic dysplastic kidney (MCDK). Institutional protocols for non-operative management remain essentially ad hoc. The primary outcome of this systematic review is to establish the incidence of hypertension associated with an MCDK. The secondary outcome is to determine the malignancy risk associated with an MCDK. The tertiary outcome is to assess the rate of MCDK involution. Subsequent to these, an evidence-based algorithm for follow-up is described. METHODOLOGY: A systematic review of all relevant studies published between 1968 and April 2017 was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies were identified by specific inclusion and exclusion criteria, all of which included data relevant to the primary, secondary and tertiary outcomes. Hypertension was defined as systolic blood pressure greater than the 95th centile for gender, age and height centile. Subset analysis was performed for hypertension associated with an MCDK. RESULTS: The primary outcome measure revealed a 3.2% (27/838) risk of developing hypertension associated with an MCDK. The secondary outcome measure noted a 0.07% malignancy risk (2/2820). The tertiary outcome measure established that 53.3% (1502/2820) had evidence of involution of the dysplastic kidney. A total of 44 cohort studies (2820 patients) were analysed. CONCLUSION: Given the low risk of hypertension and malignancy, which is similar to the general population, the current conservative non-operative pathway is an appropriate management strategy. An algorithm to help support clinicians with ongoing management is proposed. PMID- 30396842 TI - Comparison of alpha-Fetoprotein Criteria and Modified Response Evaluation Criteria in Solid Tumors for the Prediction of Overall Survival of Patients with Hepatocellular Carcinoma after Transarterial Chemoembolization. AB - PURPOSE: To evaluate the value of alpha-fetoprotein (AFP) classification criteria in predicting tumor response and patient survival and to discuss the agreement between AFP criteria and modified Response Evaluation Criteria In Solid Tumors (mRECIST). MATERIALS AND METHODS: Between January 2011 and December 2014, 147 patients with unresectable hepatocellular carcinoma (HCC) with baseline AFP levels >= 400 ng/mL who underwent transarterial chemoembolization as initial treatment were retrospectively enrolled for AFP/imaging correlation analysis. AFP based response was classified as complete response (CR) in cases of AFP level normalization, partial response (PR) in cases of > 50% decrease vs baseline, stable disease (SD) in cases of -50% to +30% change vs baseline, or progressive disease (PD) in cases of > 30% increase vs baseline. Intermethod agreement between the 2 methods was assessed by Cohen kappa coefficient. Response rates according to AFP and mRECIST were compared, and the association between response rate and overall survival (OS) was evaluated. RESULTS: The kappa value for agreement between AFP criteria and mRECIST was 0.549 (ie, moderate), with objective response and disease control rates of 36.1% and 63.3% per AFP criteria and 34.7% and 46.3% per RECIST (P = .807 and P = .003), respectively. Although AFP criteria and mRECIST showed significantly prognostic strata for CR, PR, SD, and PD after chemoembolization (P < .001 for both), some overlap in radiologic PD survival curves was observed. The OS of AFP-based disease control (ie, CR/PR/SD) was significantly longer than that of AFP-based PD among patients with radiologic PD (9.0 vs 6.0 mo; P < .001). CONCLUSIONS: The defined AFP response moderately correlated with mRECIST response and yielded accurate prognostic prediction in patients with HCC and AFP levels >= 400 ng/mL treated with chemoembolization. PMID- 30396843 TI - The Feasibility of Using Volumetric Phase-Contrast MR Imaging (4D Flow) to Assess for Transjugular Intrahepatic Portosystemic Shunt Dysfunction. AB - PURPOSE: To demonstrate the feasibility of detecting patency, stenosis, or occlusion of transjugular intrahepatic portosystemic shunt (TIPS) with four dimensional (4D) flow MR imaging. MATERIALS AND METHODS: Sequential adult patients with TIPS were eligible for enrollment. Volumetric phase-contrast sequence was used to image TIPS. Particle tracing cine images were used for qualitative assessment of stenosis. TIPS was segmented to generate quantitative data sets of peak velocity. Segmentation and quantitative measurement of flow throughout an entire TIPS defined technical success. Doppler US was used for comparison. Venography, when available, and 6-month clinical follow-up were used as reference standards. RESULTS: 4D flow MR imaging was performed in 23 patient encounters and was technically successful in 16/23 (69.6%) encounters. Three cases demonstrated both focal turbulence and abnormal velocities (> 190 cm/s or < 90 cm/s) on 4D flow and had venography-confirmed stenosis (true-positive cases). Seven cases had normal velocities and no turbulence on 4D flow, and all were confirmed negative with clinical follow-up or venography (true-negative cases). Six cases had discordant 4D flow results, with abnormal velocities but no turbulence or focal turbulence but normal velocities. All 6 discordant cases had no evidence of dysfunction during 6-month follow-up. CONCLUSION: 4D flow MR imaging can detect TIPS patency and stenosis, but further investigation is required before it can be used to assess for TIPS dysfunction. PMID- 30396844 TI - Primary Endovascular Elective Repair and Repair of Ruptured Isolated Iliac Artery Aneurysms Is Durable-Results of 72 Consecutive Patients. AB - PURPOSE: To evaluate outcome of endovascular elective repair and repair of ruptured isolated iliac artery aneurysms (IIAAs) as a primary treatment strategy. MATERIALS AND METHODS: All patients with an IIAA undergoing endovascular treatment were included. Aneurysms were classified according to an anatomic classification and treated with coiling of the internal iliac artery, stent graft placement in the common to external iliac artery, or placement of a bifurcated aortoiliac stent graft. Between November 1996 and November 2015, 72 patients with 85 IIAAs underwent endovascular repair. Mean age was 73.9 years +/- 9.2. Common iliac artery was involved in 63 patients (74.1%), internal iliac artery was involved in 21 patients (24.7%), and external iliac artery was involved in 1 patient (1.2%). Mean diameter was 5 cm (range, 2.5-11 cm). Emergency repair was performed in 19 patients owing to rupture (26.4%). RESULTS: Overall primary technical success rate was 95.8% with conversion rate to open surgery of 4.2% (all in the emergency group) and in-hospital mortality rate of 1.4%. During mean follow-up of 4.3 years +/- 3.3 (median 3.8 y; range, 0-14.2 y), 17 endoleaks were observed (6 type I, 10 type II, 1 type IIIa). Overall reintervention rate was 16.7%. Primary patency rate was 98.6%. During the follow-up period, 22 deaths occurred (30.6%), including 2 aneurysm-related deaths (2.8%). CONCLUSIONS: Primary endovascular repair of IIAAs shows excellent results and should be considered as first-line therapy. Surgical backup should be available in emergency cases. PMID- 30396845 TI - Is Long-Term Anticoagulation Required after Stent Placement for Benign Superior Vena Cava Syndrome? AB - PURPOSE: To identify whether symptom relief and stent patency vary with use of long-term anticoagulation after stent placement for benign superior vena cava (SVC) syndrome. MATERIALS AND METHODS: Patients with benign SVC syndrome treated with stent placement between January 1999 and July 2017 were retrospectively identified (n = 58). Average age was 49 years (range, 24-80 y); 34 (58%) were women, and 24 (42%) were men. Average follow-up was 2.4 years (range, 0.1-11.1 y, SD 2.6). Of cases, 37 (64%) were due to a long-term line/pacemaker, and 21 (36%) were due to fibrosing mediastinitis. After stent placement, 36 (62%) patients were placed on long-term anticoagulation, and 22 (38%) were not placed on anticoagulation. Percent stenosis was evaluated on follow-up imaging by dividing smallest diameter of the stent by a normal nonstenotic segment of the stent and multiplying by 100. RESULTS: Technical success was achieved in all cases. There was no significant difference in number of patients who reported a return of symptoms characteristic of benign SVC syndrome between the anticoagulated (16 of 36; 44.4%) and nonanticoagulated (11 of 22; 50%) groups (P = .68). There was no significant difference in the mean percent stenosis between the anticoagulated (40.4% +/- 34.7% [range, 0-100%]) and nonanticoagulated (32.1% +/- 29.2% [range, 1.7%-100%]) groups (P = .36). No significant difference was found in the time (days) between date of procedure and date of return of symptoms (anticoagulated, 735.9 d +/- 1,003.1 [range, 23-3,851 d]; nonanticoagulated, 478 d +/- 826.6 [range, 28-2,922 d]) (P = .49). There was no difference in primary patency between groups (P = .59). Finally, 1 patient (2.8%) in the anticoagulated group required surgical intervention, whereas none in the nonanticoagulated group required surgical intervention. CONCLUSIONS: No significant difference was observed in clinical and treatment outcomes in patients who did and did not receive anticoagulation after stent placement for benign SVC syndrome. Management of benign SVC syndrome after stent placement may not require anticoagulation if confirmed by additional studies. PMID- 30396846 TI - Usefulness of a temporary endovascular left ventricular assist system as a bridge to facilitate treatment of mediastinitis associated with a permanent device. PMID- 30396847 TI - When a Surgical Trainee Is Sued: Supporting Residents Through Interactions With the Medicolegal System. PMID- 30396848 TI - Epstein-Barr Virus (EBV)-derived BARF1 encodes CD4- and CD8-restricted epitopes as targets for T-cell immunotherapy. AB - BACKGROUND AIMS: EBV type II latency tumors, such as Hodgkin lymphoma (HL), Non Hodgkin lymphoma (NHL) and nasopharyngeal carcinoma, express a limited array of EBV antigens including Epstein-Barr nuclear antigen (EBNA)1, latent membrane protein (LMP)1, LMP2, and BamH1-A right frame 1 (BARF1). Adoptive immunotherapy for these malignancies have focused on EBNA1, LMP1 and LMP2 because little is known about the cellular immune response to BARF1. METHODS: To investigate whether BARF1 is a potential T-cell immunotherapy target, we determined the frequency of BARF1-specific T-cell responses in the peripheral blood of EBV seropositive healthy donor and patients with EBV-positive malignancies, mapped epitopes and evaluated the effector function of ex vivo-generated BARF1-specific T-cell lines. RESULTS: BARF1-specific T cells were present in the peripheral blood of 12/16 (75%) EBV-positive healthy donors and 13/20 (65%) patients with EBV-positive malignancies. Ex vivo expanded BARF1-specific T-cell lines contained CD4- and CD8-positive T-cell subpopulations, and we identified 23 BARF1 peptides, which encoded major histocompatibility complex class I- and/or II-restricted epitopes. Epitope mapping identified one human leukocyte antigen (HLA)-A*02 restricted epitope that was recognized by 50% of HLA-A*02, EBV-seropositive donors and one HLA-B*15(62)-restricted epitope. Ex vivo expanded BARF1-specific T cells recognized and killed autologous, EBV-transformed lymphoblastoid cell lines and partially HLA-matched EBV-positive lymphoma cell lines. DISCUSSION: BARF1 should be considered as an immunotherapy target for EBV type II (and III) latency. Targeting BARF1, in addition to EBNA1, LMP1 and LMP2, has the potential to improve the efficacy of current T-cell immunotherapy approaches for these malignancies. PMID- 30396849 TI - Role of 18F-FDG PET/CT in restaging and follow-up of patients with uterine sarcomas. AB - PURPOSE: Uterine sarcomas are rare tumors with poor prognosis due to the high recurrence rates. The current role of 18F-FDG PET/CT in the post-therapy surveillance is not established yet. MATERIALS AND METHODS: Forty-one women with uterine sarcoma underwent 73 18F-FDG PET/CT for restaging in suspected recurrence or during follow-up in asymptomatic patients. Histopathology results and/or clinical/imaging follow-up for at least 12 months were considered the reference standard. The diagnostic accuracy and clinical impact of 18F-FDG PET/CT was calculated. RESULTS: Thirty-three 18F-FDG PET/CT were positive, while the remaining 40 studies were negative. The overall sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of 18F-FDG PET/CT were 88%, 98%, 97%, 91% and 93%, respectively. Considering patients with clinical or radiological suspicion of recurrence (n=47) and those during follow-up (n=26), sensitivity, specificity, PPV, NPV and accuracy of 18F FDG PET/CT were 89%, 100%, 100%, 86% and 94%, and 80%, 95%, 80%, 95% and 92%, respectively. 18F-FDG PET/CT had a positive clinical impact in 9/73 (12%) studies and changed the clinical management in 8/41 (20%) patients. CONCLUSIONS: 18F-FDG PET/CT seems to be an accurate method for detection and localization of local and distant recurrence in patients with uterine sarcoma with good sensitivity and specificity and significant impact on clinical decision making. PMID- 30396850 TI - Bolus 5-fluorouracil (5-FU) In Combination With Oxaliplatin Is Safe and Well Tolerated in Patients Who Experienced Coronary Vasospasm With Infusional 5-FU or Capecitabine. AB - INTRODUCTION: Coronary vasospasm associated with fluoropyrimidine (FP)-based chemotherapy is a potentially serious complication and reported to occur more often with infusional 5-fluorouracil (5-FU) or capecitabine than with bolus 5-FU. Given the additional benefit of oxaliplatin over FP alone in the management of colorectal cancer, retaining oxaliplatin in the treatment regimen is desirable, but the safety of combining bolus 5-FU with oxaliplatin in patients with FP induced vasospasm is not well established. We performed a retrospective review to explore the safety of substituting FLOX (bolus 5-FU, oxaliplatin, leucovorin) for FOLFOX (infusional 5-FU, oxaliplatin, leucovorin) and CAPOX (capecitabine, oxaliplatin) in patients who had FP-induced coronary vasospasm. PATIENTS AND METHODS: The pharmacy database of Mayo Clinic was queried to identify patients who developed coronary vasospasm associated with FOLFOX or CAPOX between January 2011 and January 2018 and were subsequently treated with FLOX. Detailed information was obtained on these patients by retrospective electronic chart review. RESULTS: A total of 10 patients (median age, 56.5 years; range, 36-77 years) were identified, 9 with FOLFOX and 1 with CAPOX. Among the patients treated with FOLFOX, 8 patients had chest pain as the presenting complaint that had started within 48 hours of beginning of the 5-FU infusion. In 9 of 10 patients, coronary vasospasm occurred with the first cycle of therapy. All patients made full recovery after discontinuation of infusional 5-FU or capecitabine. All patients subsequently received FLOX with 7 median bolus 5-FU doses (range, 2-22 doses) and 7 median oxaliplatin doses (range, 2-12 doses) at 7 days to 18 months after the event, with 7 patients treated within 4 weeks of the event. FLOX did not cause any cardiovascular adverse events in any of the 10 patients. CONCLUSION: Bolus 5-FU in combination with oxaliplatin is safe in patients who have experienced coronary vasospasm with infusional 5-FU or capecitabine. PMID- 30396851 TI - Child marriage in the USA: persistent but little understood. PMID- 30396852 TI - National trends in the emergency department management of adult patients with elevated blood pressure from 2005 to 2015. AB - Emergency department (ED)-based screening and referral of patients with elevated blood pressure (BP) are recommended by 2006 and 2013 American College of Emergency Physicians guidelines; however, it is unknown if these recommendations or disparities in care impact clinical practice. The objectives of the study were to assess temporal trends in antihypertensive prescriptions, outpatient follow-up referrals, and diagnosis of hypertension (HTN)/elevated BP and to identify potential disparities by patient characteristics. Using the 2005-2015 National Hospital Ambulatory Medical Care Survey, we examined the frequency and trends over time of antihypertensive prescriptions, outpatient follow-up referrals, and BP diagnoses for US ED visits by adult patients with an elevated triage BP and identified potential disparities in management by patient demography and socioeconomic status. Of the 594 million eligible ED visits by patients from 2005 to 2015, 1.2% (1.0%-1.4%) received antihypertensive prescriptions at discharge, 82.3% (80.0%-83.6%) outpatient follow-up referrals, and 2.1% (1.9%-2.4%) an HTN/elevated BP diagnosis. There were small annual increases over time in the odds of antihypertensive prescriptions at discharge (adjusted odds ratio [aOR] 1.05 [1.00-1.10]), follow-up referrals (aOR 1.04 [1.01-1.07]), and HTN/elevated BP diagnosis (aOR 1.05 [1.02-1.08]). For BPs >=160/100 mm Hg, prescriptions were more common for Blacks (aOR 2.36 [1.93, 2.88]) and uninsured patients (aOR 1.81 [1.38, 2.38]), and diagnoses were more common for Blacks (aOR 1.95 [1.70, 2.24]) and uninsured patients (aOR 1.30 [1.09, 1.55]). These data suggest little change in and the need for improvement in the management of ED patients with elevated BP, despite the American College of Emergency Physicians guidelines, and raise concern about patient care disparities. PMID- 30396853 TI - Actigraphy-based sleep characteristics and aortic stiffness: the Multi-Ethnic Study of Atherosclerosis. AB - The study aimed to examine the association between objective estimates of sleep duration and quality and aortic stiffness while accounting for the potential confounding effect of sleep-disordered breathing. Participants were part of the Multi-Ethnic Study of Atherosclerosis Sleep study. Sleep duration and quality were assessed by 7-day wrist actigraphy, sleep-disordered breathing by home polysomnography, and aortic stiffness by magnetic resonance imaging-based aortic pulse wave velocity (aPWV), ascending and descending aorta distensibility. Aortic stiffness of participants with "normal" sleep duration (6-8 hours) were compared with those of "short" (<6 hours) and "long" sleep duration (>8 hours) adjusting for common cardiovascular risk factors and apnea-hypopnea index. The sample consisted of 908 participants (mean age 68.4 +/- 9.1 years, 55.3% female). There was a significant linear trend of increased aPWV across short (n = 252), normal (n = 552), and long sleep durations (n = 104) (P for trend = .008). Multivariable analysis showed that people with short sleep duration had 0.94 m/s lower aPWV (95% CI: -1.54, -0.35), compared with those with normal sleep duration. In this ethnically diverse community cohort, habitual short sleep duration as estimated by actigraphy was associated with lower aortic stiffness. PMID- 30396854 TI - A systematic review comparing radiation toxicity after various endorectal techniques. AB - PURPOSE: A clinical complete response is seen after neoadjuvant chemoradiation for rectal tumors in 15%-20% of patients. These patients can potentially be spared mutilating total mesorectal excision surgery through a watch-and-wait policy. Recent studies show that dose escalation by a radiation boost increases the clinical complete response rate. The boost dose to the tumor can be administered through external beam radiotherapy or through internal radiotherapy using techniques like contact therapy, low-dose-rate or high-dose-rate brachytherapy (BT). However, limited information is available concerning treatment-related toxicity of these techniques. With this systematic review, we aim to summarize and compare published data concerning acute and late toxicity after contact X-ray therapy (CXT) and BT for rectal cancer. METHODS AND MATERIALS/RESULTS: Thirty-eight studies reporting toxicity after endorectal radiation techniques for rectal cancer were included, resulting in 3682 patients for analysis. Direct comparison of toxicity by the different radiation modes was hampered by various combinations of endorectal techniques, a lack of clear reporting of toxicity scores, dose prescription, technique used, and treated volumes. >= Grade 3 rectal toxicity was reported in 2.9% of patients having received only CXT; 6.3% of patients who received only BT had Grade 3 rectal toxicity, and BT also caused Grade 3 urinary toxicity in 1 patient. CONCLUSION: All techniques reported some >= Grade 3 toxicity. Toxicity after CXT was confined to the rectum, whereas after BT, urogenital toxicity and skin toxicity were seen as well. Unfortunately, few specific conclusions could be drawn regarding the dose-related risk of toxicity for the various techniques due to nonuniform reporting strategies and missing information. To enable future comparisons and improvements, the endorectal radiation field urgently needs consensus guidelines on dose reporting, dose prescription, treatment volume specification, and toxicity reporting. PMID- 30396856 TI - Salidroside improves the hypoxic tumor microenvironment and reverses the drug resistance of platinum drugs via HIF-1alpha signaling pathway. AB - BACKGROUND: Hypoxia commonly occurs in solid tumors. The hypoxia in the center of solid tumors considerably decreases the chemosensitivity of tumor cells and induces epithelial-mesenchymal transition (EMT) as well as drug resistance of antitumor drugs. METHODS: Here, the effects of salidroside (Sal) combined with platinum drugs on human hepatocellular carcinoma were examined in vitro and in vivo. We investigated the antitumor effects of Sal by inhibiting the drug resistance and explained its mechanism in inhibiting tumor growth. FINDINGS: The results showed that Sal co-administration reverses the drug resistance of platinum drugs and suppressed metastasis induced by the hypoxic tumor microenvironment. Sal promoted the degradation of HIF-1alpha. In conclusion, Sal significantly increased the sensitivity to platinum drugs and inhibited hypoxia induced EMT in hepatocellular carcinoma (HCC) through inhibiting HIF-1alpha signaling pathway. INTERPRETATION: Therefore, Sal may be an effective platinum drug sensitizer that can improve the chemotherapeutic efficacy in patients with HCC. PMID- 30396855 TI - Evaluation of point-of-care tests for cutaneous leishmaniasis diagnosis in Kabul, Afghanistan. AB - BACKGROUND: Kabul (Afghanistan) is a major focus of cutaneous leishmaniasis (CL) caused by Leishmania tropica. Microscopy remains the reference test for diagnosis despite its low performance. We evaluated whether LoopampTM Leishmania Detection Kit (Loopamp) and CL DetectTM Rapid Test (CL Detect), detecting Leishmania DNA and antigen, respectively could improve CL diagnosis. METHODS: A diagnostic accuracy study with prospective inclusion was conducted in a leishmaniasis reference clinic in Kabul. Slit skin samples from CL suspects were analysed by microscopy. Samples taken with a dental broach were tested with CL Detect, Loopamp, and PCR. All samples were transferred to the Academic Medical Center (AMC, the Netherlands) for PCR and Loopamp analyses. The diagnostic performance of the tests was evaluated against a reference combining microscopy and PCR. FINDINGS: 274 CL suspects were included in the study. In Kabul, CL Detect had a 65.4% sensitivity [95% Confidence Interval (CI): 59.2-71.2%] and a 100% specificity [95% CI: 80.5-100%], while these were 87.6% [95%CI: 82.9-91.3%] and 70.6% [95% CI: 44.0-89.7%] for Loopamp. At AMC the Loopamp's sensitivity (92.2% [95% CI: 88.2-95.2%]) and specificity (94.1% [95% CI: 71.3-99.8%]) were higher. An algorithm where CL Detect negative suspects would be tested by Loopamp yielded a 93.4% sensitivity [95% CI: 89.6-96.1%] and a 94.1% specificity [95% CI: 71.3 99.8%] when Loopamp's performance at AMC was used. INTERPRETATION: The high specificity of CL Detect and the performance of Loopamp allow their use in a diagnostic algorithm that would minimize the number of CL patients referred for confirmation. FUND: Federal Ministry of Education and Research, Germany. PMID- 30396858 TI - How frequently should asymptomatic patients be dilated? 20-year results. PMID- 30396857 TI - Dual-center, dual-platform microRNA profiling identifies potential plasma biomarkers of adult temporal lobe epilepsy. AB - BACKGROUND: There are no blood-based molecular biomarkers of temporal lobe epilepsy (TLE) to support clinical diagnosis. MicroRNAs are short noncoding RNAs with strong biomarker potential due to their cell-specific expression, mechanistic links to brain excitability, and stable detection in biofluids. Altered levels of circulating microRNAs have been reported in human epilepsy, but most studies collected samples from one clinical site, used a single profiling platform or conducted minimal validation. METHOD: Using a case-control design, we collected plasma samples from video-electroencephalogram-monitored adult TLE patients at epilepsy specialist centers in two countries, performed genome-wide PCR-based and RNA sequencing during the discovery phase and validated findings in a large (>250) cohort of samples that included patients with psychogenic non epileptic seizures (PNES). FINDINGS: After profiling and validation, we identified miR-27a-3p, miR-328-3p and miR-654-3p with biomarker potential. Plasma levels of these microRNAs were also changed in a mouse model of TLE but were not different to healthy controls in PNES patients. We determined copy number of the three microRNAs in plasma and demonstrate their rapid detection using an electrochemical RNA microfluidic disk as a prototype point-of-care device. Analysis of the microRNAs within the exosome-enriched fraction provided high diagnostic accuracy while Argonaute-bound miR-328-3p selectively increased in patient samples after seizures. In situ hybridization localized miR-27a-3p and miR-328-3p within neurons in human brain and bioinformatics predicted targets linked to growth factor signaling and apoptosis. INTERPRETATION: This study demonstrates the biomarker potential of circulating microRNAs for epilepsy diagnosis and mechanistic links to underlying pathomechanisms. PMID- 30396859 TI - Management of post cholecystectomy vascular injuries. AB - INTRODUCTION: Vasculobiliary and vascular injuries following cholecystectomy are the most serious complications requiring complex surgical management resulting in greater patient morbidity and mortality. METHODOLOGY: The study was performed at a tertiary teaching hospital of North India. Records of patients referred for biliary or vascular injury sustained during cholecystectomy were reviewed retrospectively to identify patients with vascular injury between January 2009 and March 2018. Clinical profile, hospital course and outcome of these patients were analysed. RESULTS: Over nine years, 117 patients were referred for cholecystectomy related complications. Total incidence of vascular injury was 5.1% (6/117). Combined vasculobiliary injury (VBI) occurred in 3.4% (4/117) while isolated vascular injury was present in 1.7% patients (2/117). Most (5/6) patients were operated for uncomplicated gall stone disease. Incidences of portal vein (PV) and right hepatic artery (RHA) injuries were equal (3/6). PV injuries were repaired either during cholecystectomy (1/3) or during re-exploration after damage control packing (2/3). RHA injuries presented as pseudoaneurysm and were managed surgically (2/3) or by coil embolization (1/3). All VBI referrals (4/117) were following open cholecystectomy. In VBI patients, vascular injury was diagnosed intra-operatively in two while it was diagnosed several weeks after cholecystectomy in two others. Biliary injury manifested as bile leak post operatively in all four of them. Nature of biliary injury could be characterized in only 50% (2/4) patients. Definitive repair of biliary injury was performed in one patient only. There was one mortality in our series. CONCLUSION: Vascular injury is an uncommon complication of cholecystectomy with catastrophic outcome if not managed timely and properly. Adequate surgeon training, keeping the possibility of aberrant vasculobiliary anatomy in all cases, and proper surgical technique is crucial for prevention of such injuries. However in such an event, proper documentation and referral to tertiary centre will help in decreasing morbidity and further litigation. PMID- 30396860 TI - Baloxavir heralds a new era in influenza virus biology. AB - Baloxavir marboxil is an orally available prodrug of baloxavir acid. Japan was the first country to approve baloxavir marboxil as a treatment for influenza. The antiviral mechanism of action of baloxavir is unique; the drug blocks initiation of viral mRNA synthesis, thus preventing proliferation of the influenza virus. A single oral dose of baloxavir is usually well tolerated; it hastens alleviation of influenza symptoms and shortens the duration of viral shedding. However, novel influenza variants exhibiting over 10-fold reductions in baloxavir susceptibility emerged in baloxavir-treated patients. Although further clinical investigation is required to explore this issue, baloxavir may revolutionize our understanding of influenza virus biology. PMID- 30396861 TI - On becoming an academician. PMID- 30396862 TI - Terror in the dirt: Sensory determinants of host seeking in soil-transmitted mammalian-parasitic nematodes. AB - Infection with gastrointestinal parasitic nematodes is a major cause of chronic morbidity and economic burden around the world, particularly in low-resource settings. Some parasitic nematode species, including the human-parasitic threadworm Strongyloides stercoralis and human-parasitic hookworms in the genera Ancylostoma and Necator, feature a soil-dwelling infective larval stage that seeks out hosts for infection using a variety of host-emitted sensory cues. Here, we review our current understanding of the behavioral responses of soil-dwelling infective larvae to host-emitted sensory cues, and the molecular and cellular mechanisms that mediate these responses. We also discuss the development of methods for transgenesis and CRISPR/Cas9-mediated targeted mutagenesis in Strongyloides stercoralis and the closely related rat parasite Strongyloides ratti. These methods have established S. stercoralis and S. ratti as genetic model systems for gastrointestinal parasitic nematodes and are enabling more detailed investigations into the neural mechanisms that underlie the sensory driven behaviors of this medically and economically important class of parasites. PMID- 30396863 TI - Lost to Follow-Up: Analysis of Never-Viewed Radiology Examinations. PMID- 30396864 TI - Global longitudinal strain assessment by computed tomography in severe aortic stenosis patients - Feasibility using feature tracking analysis. AB - BACKGROUND: Global longitudinal strain (GLS) detects subclinical myocardial changes in patients with aortic stenosis (AS). Although GLS is typically measured by transthoracic echocardiography (TTE), assessment by multiphasic gated computed tomography angiography (CTA) has become recently available. We sought to evaluate the feasibility of CTA-derived GLS assessment and compare its agreement with TTE using the same post-processing software in severe AS patients undergoing transcatheter aortic valve replacement (TAVR) evaluation. METHODS: We evaluated patients with severe AS, sinus rhythm and adequate image quality for GLS analysis by both CTA and TTE pre-TAVR using 2D CT-Cardiac Performance Analysis prototype software (TomTec). The 18-segment model was used for GLS analysis by averaging the three long-axis views in both CTA and TTE studies. Agreement was assessed using linear regression and Bland-Altman analysis. RESULTS: A total of 123 consecutive patients were included (mean age 84 +/- 7 years, 45% female). The mean left ventricular ejection fraction (LVEF) by CTA and TTE were similar 53 +/- 14% for both. On average, CTA-derived GLS was greater than by TTE (-20 +/- 6.5% vs. -16 +/- 4.9%, respectively, p < 0.001). There was a moderate correlation between GLS assessed by CTA vs. TTE (r = 0.62, p < 0.001), although variability between imaging methods existed. The correlation between GLS and LVEF was strong (r = -0.90, p < 0.001 for CTA, r = -0.88, p < 0.001 for TTE) using the same imaging modality. CONCLUSION: CTA-derived GLS assessment is feasible in selected patients with sinus rhythm and adequate image quality. The agreement of GLS between TTE and CTA is moderate but not interchangeable suggesting a potential modality-specific GLS threshold. PMID- 30396865 TI - Polyvascular disease, type 2 diabetes, and long-term vascular risk: a secondary analysis of the IMPROVE-IT trial. AB - BACKGROUND: Polyvascular disease and type 2 diabetes are each associated with increased cardiovascular risk, but whether these risks are additive is unknown. In this exploratory analysis of a randomised trial, we explored the long-term cardiovascular risk associated with polyvascular disease, type 2 diabetes, and their combination in patients with acute coronary syndrome, and assessed the effect of ezetimibe given on top of statin therapy in patients with these concomitant conditions. METHODS: IMPROVE-IT was a multicentre, double-blind, randomised, placebo-controlled trial assessing the effect of ezetimibe added to statin therapy after acute coronary syndrome. Recruitment was from Oct 26, 2005, to July 8, 2010, and the trial was done at 1158 sites in 39 countries. 18 144 patients aged 50 years and older who had been stabilised after an acute coronary syndrome were randomly assigned to 40 mg per day simvastatin plus either 10 mg per day ezetimibe or matched placebo, for a median duration of 6 years. In this post-hoc exploratory analysis, we assessed the prespecified endpoints of the trial, including the primary composite endpoint (cardiovascular death, a major coronary event [non-fatal myocardial infarction, documented unstable angina requiring hospital admission, or coronary revascularisation occurring at least 30 days after randomisation], or stroke [ischaemic or haemorrhagic]) by concomitant polyvascular disease at baseline (peripheral artery disease or previous stroke or transient ischaemic attack) and stratified by concomitant type 2 diabetes. Efficacy analyses were done according to intention to treat and event rates. IMPROVE-IT is registered with ClinicalTrials.gov, number NCT00202878. FINDINGS: 1005 patients (6%) had peripheral artery disease and 1071 (6%) had stroke or transient ischaemic attack at baseline. Of these, 388 (39%) and 409 (38%) also had concomitant type 2 diabetes, respectively. At 7 years, patients with either polyvascular disease or type 2 diabetes had similar rates of the primary endpoint (39.8% and 39.9%, respectively), which were higher than patients without polyvascular disease or diabetes (29.6%). Polyvascular disease with concomitant type 2 diabetes was associated with further heightened risk (60.0% 7-year Kaplan Meier rate, adjusted hazard ratio versus those with polyvascular disease 1.60, 95% CI 1.38-1.85; p<0.0001). Ezetimibe reduced cardiovascular risk consistently across groups with greater numerical absolute risk reductions in the highest-risk subgroups. INTERPRETATION: In patients with coronary artery disease, concomitant polyvascular disease or type 2 diabetes are associated with increased long-term cardiovascular risk. The combination of polyvascular disease and diabetes is additive, resulting in very high risk. The benefit of ezetimibe is consistent in patients with and without polyvascular disease and type 2 diabetes; however, by nature of their higher risk patients with one, or especially both, of these diseases might derive the greatest absolute benefits. FUNDING: Merck. PMID- 30396866 TI - The perils of polyvascular disease in type 2 diabetes. PMID- 30396867 TI - Human long-term deregulated circadian rhythm alters regenerative properties of skin and hair precursor cells. AB - In mammals, desynchronized circadian rhythm leads to various biological symptoms. In skin and hair, human epidermal stem cell function in vitro is regulated by circadian oscillations, and thus contributes to tissue aging when deregulated. In mice, circadian arrhythmia of hair follicle stem cells contributes to age-related hair follicle cycling defects. Despite the well-described impact of circadian oscillations through a feedback loop involving the clock pathway on hair and skin stem cell function in vitro, little is known about the change in characteristics or regenerative properties of hHF (human hair follicle keratinocytes), hEpi (human interfollicular epidermal keratinocytes), and hHFDP (hair follicle dermal papilla stem cells) after long-term alteration of circadian rhythm in vivo. The present study was designed to asses hHF, hEpi, and hHFDP precursors and stem cell properties in response to clock pathway alteration due to long-term deregulated circadian rhythm in vivo. A clinical study protocol was designed to include two groups of women: diurnal workers (control) and shift workers (deregulated). After informed consent, two 3-mm fresh punch biopsies were taken from the occipital region of each donor (10 donors/group). Cell culture characterization, measurement of colony area, culture medium analysis, and RT-qPCR analysis were carried out. Long-term circadian rhythm deregulation affected clock pathway protein expression and correlated with alterations in hHF, hEpi, and hHFDP properties. This study provides, for the first time in humans, evidence that in vivo deregulation of the clock pathway affects regenerative properties of human skin and hair precursor cells. PMID- 30396868 TI - Intravascularly disseminated cutaneous angiosarcoma arising in a non-irradiated lymphatic-venous malformation mimicking intravascular lymphoma. PMID- 30396869 TI - The effect of oral royal jelly administration on skin barrier function: a double blind randomized placebo-controlled trial. PMID- 30396870 TI - What's new this month? PMID- 30396871 TI - And next... Adnexa: Ulerythema ophryogenes and keratosis pilaris. PMID- 30396872 TI - Dermpath and Clinic: A red scaly lesion on the forearm. PMID- 30396873 TI - sQuiz your knowledge: Recurrent ulcerative skin nodules on the extremities. PMID- 30396874 TI - sQuiz your knowledge: How would you reconstruct? PMID- 30396875 TI - Evaluation of Cerebral Blood Flow Alterations and Acute Neuronal Damage due to the Water Pipe Smoking. AB - BACKGROUND: Although water pipe smoking is a great public health problem, data regarding the acute and chronic effects and the degree of toxin exposure are limited. While water pipe-related malignancy, pulmonary, infectious, cardiac effects, infertility and biological effects have been described in a meta analysis, there are no studies in the literature about its neurologic effects. AIMS: To evaluate water pipe-related acute neurological effects and cerebral blood flow through transcranial doppler ultrasonography and serum s100b protein level measurements. STUDY DESIGN: Prospective observational study. METHODS: Vital signs and baseline carboxyhemoglobin (COHb) and S100b levels, cerebral flood changes with Transcranial Doppler Ultrasound were evaluated and recorded before and after water-pipe smoking. CONCLUSION: Cerebral vasodilation develops due to the increase in cerebral blood flow rate and the decrease in pulsatility index, resistivity index values, and the elevation in COHb, S100b level indicates that water pipe smoking leads to neuron damage in the acute period. PMID- 30396876 TI - Urine Levels of Matrix Metalloproteinases and Tissue Inhibitor of Metalloproteinases in Children with Type 1 Diabetes Mellitus. AB - OBJECTIVE: Histopathological changes of the kidney in type 1 diabetes mellitus (T1DM) begin before the microalbuminuria. Therefore, efforts are focused on finding a biomarker for the detection of early diabetic kidney injury. The aim of the study is to determine whether urine levels of indicators of fibrosis alter in diabetic children and if they may predict a progressive renal injury in T1DM. METHODS: Urinary matrix metalloproteinase 2 and 9 (MMP2 and MMP9), tissue inhibitor of metalloproteinase 1 and 2 (TIMP1 and TIMP2), Transforming growth factor betaeta-1 (TGF-beta1) were assessed in 33 patients with T1DM with normal renal functions as well as in 24 healthy children. Microalbuminuria was not present in the patient group except three. The results were adjusted to urine creatinine and the comparison between patients and controls was evaluated. Also, same measurements were repeated after one year and were compared to the first year results. RESULTS: Urine MMP2/Creatinine (Cr), MMP9/Cr, TIMP1/Cr, TIMP2/Cr, TGF-beta1/Cr were not different between the patient and control groups (p>0.05). There was also no significant difference between the results of first and second year according to these biomarkers (p>0.05). All these parameters were not correlated to HbA1c, body mass index (BMI) and duration of T1DM. Interestingly, all parameters were negatively correlated to the age of onset of T1DM (p<0.05) Conclusion: Our findings suggest that urinary biomarkers of fibrosis do not increase in diabetic children without microalbuminuria. As the age of onset of T1DM decreases, the risk of early fibrosis may increase according to our results. PMID- 30396877 TI - The effect of cadaveric hands-on training model on surgical skills and confidence for transobturator tape surgery. AB - OBJECTIVE: To demonstrate the role of cadaveric hands-on training model on surgical skills and confidence level of surgeons during transobturator tape (TOT) surgery. MATERIAL AND METHODS: A pre-test and post-test evaluation to measure the skills during the practice of the steps of TOT operation was performed to a total of 15 postgraduate urologists and gynecologists during the urogynecologic cadaveric dissection course. The course was shaped with regard to theoretical lessons, full pelvic cadaveric dissection and TOT surgery on cadavers. RESULTS: Good handling of TOT needle, identifying the right place for groin incision, adequate size of groin incision, identifying the right place for incision at the anterior vagina, dissection of bladder pillars from the vagina, identifying the right place at the vaginal foramina for TOT needle insertion and good placement of mesh were reviewed. The post-test scores were statistically significant for all parameters and also for self confidence level (p<0.001). CONCLUSION: Cadaveric workshops are important landmarks of surgical education to improve surgical skills, gain experience and confidence. PMID- 30396878 TI - Clinical and Laboratory Characteristics of Hyperprolactinemia in Children and Adolescents: National Survey. AB - OBJECTIVE: We aimed to study the characteristics on admission, diagnosis, treatment, and follow-up of hyperprolactinemic cases in a large multicenter study. METHODS: We reviewed 233 hyperprolactinemic patients under 18 years of age who were followed by different centers. The patients were divided as having microadenomas, macroadenomas, drug-induced hyperprolactinemia, and idiopathic hyperprolactinemia. Complaints of the patients and their treatment (medication and/or surgery) responses were evaluated in detail. RESULTS: The mean age of the patients with hyperprolactinemia was 14.5 years, and 88.4% were female. In terms of etiology, microadenomas were observed in 32.6%, macroadenomas in 27%, idiopathic hyperprolactinemia in 22.7%, and drug-induced hyperprolactinemia in 6.4%. Common complaints in females (n = 206) were sorted into menstrual irregularities, headaches, galactorrhea, primary or secondary amenorrhea, and weight gain, whereas a headache, gynecomastia, short stature, and blurred vision were common in males (n = 27). Median prolactin levels were 93.15 ng/ml, 241.8 ng/ml, 74.5 ng/ml, 93.2 ng/ml, and 69 ng/ml for microadenomas, macroadenomas, idiopathic hyperprolactinemia, drug-induced hyperprolactinemia, and other causes of hyperprolactinemia, respectively. Of 172 patients with hyperprolactinemia, 77.3% was treated with cabergoline and 13.4% with bromocriptine. 20.1% of the patients with pituitary adenomas underwent pituitary surgery. CONCLUSIONS: We present the largest cohort of children and adolescents with hyperprolactinemia in the literature thus far. Hyperprolactinemia is more common in females, and cabergoline is highly effective and practical to use in adolescents due to its biweekly dosing. Surgery indication should be revised in childhood. PMID- 30396879 TI - Cytotoxic Effects of Some Flavonoids and Imatinib on K562 Chronic Myeloid Leukemia Cell Line: Data Analysis Using the Combination Index Method AB - Background: Flavonoids, known as natural compounds have antioxidant, anticarcinogenic, and anti-inflammatory effects. Aim: This study aim to determine the cytotoxic effects of flavonoids and drug resistance related P-gp on K562 human chronic myeloid leukemia cells. We also aim to evaluate of theurapeutic potential for imatinib and flavonoid combinations. Study Design: Cell culture study. Materials and Methods: In this study, K562 cells were treated with apigenin, luteolin, 5-desmethyl sinensetin and imatinib mesylate, an anticancer drug. The effect of flavonoids on K562 cell proliferation was detected using MTT assay. Concentrations of apigenin, luteolin, 5-desmethyl sinensetin ranging from 25 to 200 uM and imatinib 5 to 50 uM for 72 h were studied. Apoptosis/necrosis and P-gp activity was measured using flow cytometry. The combined effects of different concentrations of flavonoids with imatinib were evaluated with combination index value using CompuSyn software. Results: In our study, IC50 values for apigenin, luteolin, and 5-desmethyl sinensetin were found as 140 MUM, 100 MUM, and >200 MUM respectively. Luteolin (100 MUM) was found the most effective when we compared the cytotoxic activity of these flavonoids. These results are statistically significant (p < 0.05). Luteolin and imatinib combinations were the most effective and recommendable for cytotoxic activity in K562 cell line among the flavonoids that we studied. After 72 hours of incubation at IC50 concentrations, all flavonoids had about 50% apoptotic effect on the cells. P-gp activity was increased in all groups. Combination treatment may provide better outcomes and reduce the use of imatinib dosages for cytotoxicity. Conclusion: Although imatinib and some tyrosine kinase inhibitors is widely used in the treatment of chronic myeloid leukemia, more effective new drug research continues. An advantage of using drug combinations is that this would let cells to be given lower doses of anticancer drugs because of each drug can act through different mechanisms. Finally, the combination of these flavonoids and imatinib mesylate was able to enhance the cytotoxic effect but the antagonistic effect should be considered in the combined use for K562 cells. PMID- 30396880 TI - Comparison of Treatment Regimens for the Management of Severe Hypercalcemia due to Vitamin D Intoxication in Children. AB - BACKGROUND/AIMS: No large study has been conducted so far to compare the efficiencies of prednisolone, alendronate, and pamidronate as first-line treatment in children with hypercalcemia due to vitamin D intoxication. We aimed to perform a multicenter, retrospective study assessing clinical characteristics and treatment results. METHODS: A standard questionnaire was uploaded to an online national database system to collect data of children with hypercalcemia (serum calcium level >10.5 mg/dL) due to vitamin D intoxication (serum 25 hydroxyvitamin D level >150 ng/mL) who were treated in pediatric endocrinology clinics. RESULTS: Seventy-four children [median age 1.06 (0.65-1.60) years, 45 males (61%) from 11 centers] were included. High-dose vitamin D intake was obvious in 77% of the cases. At diagnosis, serum calcium, phosphorus, ALP, 25 hydroxyvitamin D, and PTH levels were 15+/-3.2 mg/dl, 5.2+/-1.2 mg/dL, 268+/-132 IU/L, 322 (236-454) ng/mL, and 5.5 (3-10.5) pg/mL, respectively. Calcium levels showed only weak correlation with 25-hydroxyvitamin D levels (rs=0.402, p<0.001). Patients were designated into five groups according to the initial specific treatment regimens (hydration-only, prednisolone, alendronate, pamidronate, and combination). Need for another type of specific drug treatment was higher in children who initially received prednisolone (p<0.001). Recurrence rate of hypercalcemia was significantly lower in children who were treated with pamidronate (p=0.02). CONCLUSION: In mild cases, prednisolone or bisphosphonate treatments are not needed. Prednisolone is less effective in the treatment of children with severe hypercalcaemia secondary to vitamin D intoxication and timely implementation of other treatment regimens would be considered. PMID- 30396881 TI - The G-rich Repeats in FMR1 and C9orf72 Loci Are Hotspots for Local Unpairing of DNA. AB - Pathological mutations involving noncoding microsatellite repeats are typically located near promoters in CpG islands and are coupled with extensive repeat instability when sufficiently long. What causes these regions to be prone to repeat instability is not fully understood. There is a general consensus that instability results from the induction of unusual structures in the DNA by the repeats as a consequence of mispairing between complementary strands. In addition, there is some evidence that repeat instability is mediated by RNA transcription through the formation of three-stranded nucleic structures composed of persistent DNA:RNA hybrids, concomitant with single-strand DNA displacements (R-loops). Using human embryonic stem cells with wild-type and repeat expanded alleles in the FMR1 (CGGs) and C9orf72 (GGGGCCs) genes, we show that these loci constitute preferential sites (hotspots) for DNA unpairing. When R-loops are formed, DNA unpairing is more extensive, and is coupled with the interruptions of double-strand structures by the nontranscribing (G-rich) DNA strand. These interruptions are likely to reflect unusual structures in the DNA that drive repeat instability when the G-rich repeats considerably expand. Further, we demonstrate that when the CGGs in FMR1 are hyper-methylated and transcriptionally inactive, local DNA unpairing is abolished. Our study thus takes one more step toward the identification of dynamic, unconventional DNA structures across the G rich repeats at FMR1 and C9orf72 disease-associated loci. PMID- 30396882 TI - Redox-Mediated Regulatory Mechanisms of Endoplasmic Reticulum Homeostasis. AB - The endoplasmic reticulum (ER) is a dynamic organelle responsible for many cellular functions in eukaryotic cells. Proper redox conditions in the ER are necessary for the functions of many luminal pathways and the maintenance of homeostasis. The redox environment in the ER is oxidative compared with that of the cytosol, and a network of oxidoreductases centering on the protein disulfide isomerase (PDI)-Ero1alpha hub complex is constructed for efficient electron transfer. Although these oxidizing environments are advantageous for oxidative folding for protein maturation, electron transfer is strictly controlled by Ero1alpha structurally and spatially. The ER redox environment shifts to a reductive environment under certain stress conditions. In this review, we focus on the reducing reactions that maintain ER homeostasis and introduce their significance in an oxidative ER environment. PMID- 30396883 TI - Early Events in the Endoplasmic Reticulum Unfolded Protein Response. AB - The physiological consequences of the unfolded protein response (UPR) are mediated by changes in gene expression. Underlying them are rapid processes involving preexisting components. We review recent insights gained into the regulation of the endoplasmic reticulum (ER) Hsp70 chaperone BiP, whose incorporation into inactive oligomers and reversible AMPylation and de-AMPylation present a first line of response to fluctuating levels of unfolded proteins. BiP activity is tied to the regulation of the UPR transducers by a recently discovered cycle of ER-localized, J protein-mediated formation of a repressive IRE1-BiP complex, whose working we contrast to an alternative model for UPR regulation that relies on direct recognition of unfolded proteins. We conclude with a discussion of mechanisms that repress messenger RNA (mRNA) translation to limit the flux of newly synthesized proteins into the ER, a rapid adaptation that does not rely on new macromolecule biosynthesis. PMID- 30396884 TI - Peer power: A women's peer-mentoring program at the workplace: example from the academia. PMID- 30396885 TI - Jones lacrimal bypass tubes in children and adults. AB - BACKGROUND/AIMS: Although a Jones tube is considered the mainstay for epiphora in patients with total blockage of the canalicular system, it has been discouraged in children for reasons of inadequate self-care and maintenance. The purpose of this study is to compare the long-term outcome of Jones tube surgery in paediatric versus adult patients. METHODS: Retrospective, interventional case series of a single academic institution. The medical records of all children (<=16 years old) and adults (>16 years old) who underwent conjunctivorhinostomy with placement of a 130 degrees angled extended Jones tube were reviewed. The outcome measures were patency and anatomical position of the tube, type and frequency of complications and subjective relief of epiphora. RESULTS: The study included 10 children (11 eyes) (range, 5.1-16.0 years old) and 102 adults (127 eyes) (range, 19.7-82.4 years old). The success and complication rate did not differ between the two age groups. Tube dislodgement and obstruction occurred in 4 (36.4%) of the paediatric tubes with an incidence rate of 6.1%/year and in 47 (37.0%) of the adult tubes with an incidence rate of 9.3%/year (p=0.3867). Two adults required routine self-irrigation of the tube. The median follow-up was 6.7 years for the children and 8.7 years for the adults (p=0.3430). CONCLUSION: With a similar outcome profile and minimal self-care, young age is not a prognostic nor limiting factor for surgery with angled Jones tubes. Exchange with tubes of a longer length is not required during growth. PMID- 30396886 TI - CT coronary angiography does not reduce mortality or myocardial infarction in low risk patients with acute chest pain. PMID- 30396887 TI - Intracerebral haemorrhage is hard to stop, and must be attacked before, during and after. PMID- 30396889 TI - Repetitive transcranial magnetic stimulation (rTMS) as a treatment for chronic dizziness following mild traumatic brain injury. AB - A 61-year-old man sustained a mild traumatic brain injury (mTBI) following a pedestrian versus vehicle traffic accident. Post injury, he began to experience symptoms including light-headedness, spatial disorientation, nausea, fatigue and prominent dizziness brought on by postural change, physical activity or eye movements. Symptoms of dizziness persisted for over 5 years, despite numerous extensive and rigorous vestibular and vision therapy regimens. All investigations suggested normal peripheral and central vestibular functioning. The patient underwent 10 sessions of repetitive transcranial magnetic stimulation (rTMS) treatment, with stimulation of the left dorsolateral prefrontal cortex at 70% of resting motor threshold and a frequency of 10 Hz. Dizziness symptom severity and frequency were reduced by greater than 50% at 3 months post treatment, with a clinically significant reduction of dizziness disability from 40 to 21 points on the Dizziness Handicap Inventory. We propose rTMS as a safe, effective and cost effective treatment option for patients who experience persistent post-traumatic dizziness secondary to mTBI. PMID- 30396888 TI - Recurrent complications of PAAG implants during lactation. AB - A 35-year-old lactating woman with pre-existing polyacrylamide gel (PAAG) implants for 10 years presented on numerous occasions following both her pregnancies with bilateral recurrent breast infection, pain and finally massive breast enlargement with a ruptured galactocoele necessitating surgical intervention. As the safety of PAAG for the breastfeeding baby is not known, breastfeeding with PAAG implants is not recommended. PMID- 30396890 TI - Successful endoscopic management of efferent loop syndrome after Billroth II distal gastrectomy. PMID- 30396891 TI - Use of mineral trioxide aggregate for retreatment of a tooth with large periapical lesion, wide-open apices and vertical root fracture. AB - Chronic periapical lesions in necrotic teeth with open apex are difficult to manage. The situation becomes more complex if the tooth has a fracture line. This case report describes the management of a traumatised tooth that had already undergone unsuccessful endodontic treatment with a large periapical lesion and open apex along with a fracture line in the root. An attempt was made to save the tooth by using mineral trioxide aggregate (MTA) cement for orthograde filling, retrograde filling and also for sealing of the fracture line. Moreover, the bone defect was filled with autogenous bone harvested from the external oblique ridge. MTA, a bioactive tricalcium silicate cement, has been used in treating complex endodontic cases as it shows promising potential by inducing the biological mechanisms necessary for repair of involved teeth. A 1-year follow-up showed progressive healing as evident by radiographs and lack of any clinical signs and symptoms. PMID- 30396892 TI - Antibodies to protein but not glycolipid structures are important for host defense against Mycoplasma pneumoniae. AB - Antibody responses to Mycoplasma pneumoniae (Mp) correlate with pulmonary Mp clearance. However, Mp-specific IgG antibodies can cross-react with the myelin glycolipid galactocerebroside (GalC) and cause neurologic disorders. We assessed whether anti-glycolipid antibody formation is part of the physiological immune response to Mp We show that antibodies against Mp-proteins and -glycolipids arise in serum of Mp-infected children and mice. Although antibodies to Mp-glycolipids were mainly IgG, anti-GalC antibodies were only of IgM. B-1a cells, shown to aid in protection against pathogen-derived glycolipids, are lacking in Bruton tyrosine kinase (Btk)-deficient mice. Mp-infected Btk-deficient mice developed Mp specific IgG responses to Mp-proteins but not to Mp-glycolipids, including GalC. The equal recovery from Mp infection in Btk-deficient as wild-type mice suggests that pulmonary Mp clearance is predominantly mediated by IgG reactive with Mp proteins and that Mp-glycolipid-specific IgG or IgM is not essential. These data will guide development of Mp-targeting vaccines avoiding induction of neurotoxic antibodies. PMID- 30396893 TI - Genomic, phenotypic, and virulence analysis of Streptococcus sanguinis oral and infective endocarditis isolates. AB - Streptococcus sanguinis, an abundant and benign inhabitant of the oral cavity, is an important etiologic agent of infective endocarditis (IE), particularly in people with pre-disposing cardiac valvular damage. Although commonly isolated from patients with IE, little is known about the factors that make any particular S. sanguinis isolate more virulent than another or, indeed, whether significant differences in virulence exist among isolates. In this study we compared the genomes of a collection of S. sanguinis strains, comprising both oral isolates and bloodstream isolates from patients diagnosed with IE. Oral and IE isolates could not be distinguished by phylogenetic analyses, nor did we succeed in identifying virulence genes unique to the IE strains. We then investigated the virulence of these strains in a rabbit model of IE using a variation of the Bar seq method wherein we pooled the strains and used Illumina sequencing to count unique barcodes that had been inserted into each isolate at a conserved intergenic region. After we determined that several of the genome sequences were misidentified in GenBank, our virulence results were used to inform our bioinformatic analyses, identifying genes that may explain the heterogeneity in virulence. We further characterized these strains by assaying for phenotypes potentially contributing to virulence. Neither strain competition via bacteriocin production nor biofilm formation showed any apparent relationship with virulence. Increased cell-associated manganese was, however, correlated with blood isolates. These results combined with additional phenotypic assays suggest that S. sanguinis virulence is highly variable and likely results from multiple genetic factors. PMID- 30396894 TI - Probiotic exopolysaccharide protects from systemic Staphylococcus aureus infection, inducing dual-functioning macrophages that restrict bacterial growth and limit inflammation. AB - Staphylococcus aureus causes severe systemic infection with high mortality rates. We previously identified exopolysaccharide (EPS) from a probiotic, Bacillus subtilis, that induces anti-inflammatory macrophages with an M2 phenotype and protects mice from Citrobacter rodentium-induced colitis. We tested if EPS could protect from systemic infection induced by S. aureus and found that EPS-treated mice had enhanced survival as well as reduced weight loss, systemic inflammation, and bacterial burden. While macrophages from EPS-treated mice display an M2 phenotype, they also restrict growth of internalized S. aureus through reactive oxygen species (ROS), reminiscent of pro-inflammatory phagocytes. These EPS induced macrophages also limit T cell activation by S. aureus superantigens, and EPS abrogates systemic induction of IFN-gamma after infection. We conclude that B. subtilis EPS is an immunomodulatory agent that induces "hybrid" macrophages that bolster anti-bacterial immunity and simultaneously limit inflammation, reducing disease burden and promoting host survival. PMID- 30396895 TI - Salmonella Pathogenicity Island One is Expressed in the Chicken Intestine and Promotes Bacterial Proliferation. AB - Salmonella Enteritidis is a common cause of foodborne illness in the United States. This bacterium can be transmitted to humans via contaminated chicken meat and eggs, and virulence in humans requires the Type Three Secretion System-1 (TTSS-1), encoded on Salmonella Pathogenicity Island One (SPI-1). Chickens often carry S. Enteritidis sub-clinically, obscuring the role of SPI-1 in facilitating bacterial colonization. To evaluate the role of SPI-1 in the infection of chicks by Salmonella, we created and utilized strains harboring a stable fluorescent reporter fusion designed to quantify SPI-1 expression within the intestinal tract of animals. Using mutants unable to express the TTSS-1, we demonstrated the important role of this secretion system in facilitating bacterial colonization. We further showed that co-inoculation of a SPI-1 mutant with the wild type strain increased the number of mutant organisms in intestinal tissue and contents, suggesting that the wild type rescues the mutant. Our results support the hypothesis that SPI-1 facilitates S. Enteritidis colonization of the chicken and make SPI-1 an attractive target in preventing Salmonella carriage and colonization in chickens to reduce contamination of poultry meat and eggs by this foodborne pathogen. PMID- 30396896 TI - Bacterial clearance enhanced by alpha2, 3- and alpha2, 6-sialyllactose via receptor-mediated endocytosis and phagocytosis. AB - Sialyllactose (SL) is a representative human milk oligosaccharide (HMO) of human breast milk. The roles of SL in infant brain development and immunity have been reported in previous studies. In this study, we identified the impact of SL on innate immunity. Our results showed that the administration of SL had significant efficacy on bacterial clearance in Pseudomonas aeruginosa K-infected mice. We also examined the role of SL in the human THP-1 macrophage-like cell line. SL effectively promoted receptor-mediated endocytosis and phagocytosis. Furthermore, SL accelerated the recruitment of Rac1 to the cell membrane, leading to the generation of reactive oxygen species for the elimination of phagocytosed bacteria. Our findings provide a new perspective on the role of SL in breast milk and suggest its potential application as a therapeutic agent to treat bacterial and viral infections. PMID- 30396897 TI - Phosphothreonine lyase promotes p65 degradation in a MAPK-MSK1-dependent manner. AB - Bacterial phosphothreonine lyases are identified type III secretion system (T3SS) effectors that irreversibly dephosphorylate host mitogen-activated protein kinase (MAPK) signaling to promote infection. However, the effects of phosphothreonine lyase on nuclear factor-kappaB (NF-kappaB) signaling remain largely unknown. In this study, we detected significant phosphothreonine lyase-dependent p65 degradation during Edwardsiella piscicida infection in macrophages, and this degradative effect was blocked by the protease inhibitor, MG132. Further analysis revealed that the phosphothreonine lyase promotes the dephosphorylation and ubiquitination of p65 via inhibiting the phosphorylation of mitogen- and stress activated protein kinase-1 (MSK1), through inhibiting the phosphorylation of extracellular signal-related kinase 1/2 (ERK1/2), p38alpha and c-Jun N-terminal kinase (JNK). Moreover, we revealed that the catalytic active site of phosphothreonine lyase plays critical role in regulating the MAPKs-MSK1-p65 signaling axis. Collectively, the mechanism described here expands our understanding of the pathogenic effector in not only regulating MAPKs signaling, but also regulating p65. These findings uncover a new mechanism by which pathogenic bacteria overcome host innate immunity to promote pathogenesis. PMID- 30396898 TI - Rickettsia rickettsii whole cell antigens offer protection against Rocky Mountain spotted fever in the canine host. AB - Rocky Mountain Spotted Fever (RMSF) is a potentially fatal tick-borne disease in people and dogs. RMSF is reported in the USA and several countries in north, central and south Americas. The causing agent of this disease, Rickettsia rickettsii, is transmitted by several species of ticks, including Dermacentor andersoni, Rhipicephalus sanguineus, and Amblyomma americanum RMSF clinical signs generally include fever, headache, nausea, vomiting, muscle pain, lack of appetite, and rash. If untreated, it can quickly progress into a life-threatening illness in people and dogs with high fatality rates ranging from 30-80%. While RMSF has been known for over a century, recent epidemiological data suggest that the documented cases and the fatality rates remain high in people, particularly during the last two decades in parts of North America. Currently, there are no vaccines available to prevent RMSF in either dogs or people. In this study, we investigated the efficacy of two experimental vaccines, a subunit vaccine containing two recombinant outer membrane proteins (RCA) and a whole cell inactivated antigen vaccine (WCA), in conferring protection against virulent R. rickettsii infection challenge in a newly established canine model for RMSF. Dogs vaccinated with WCA were protected from RMSF, whereas those receiving RCA developed the disease similar to non-vaccinated R. rickettsii-infected dogs. WCA also reduced the pathogen loads to nearly undetected levels in the blood, lungs, liver, spleen and brain, and induced bacterial antigen-specific immune response. This study provides the first evidence of the protective ability of WCA against RMSF in dogs. PMID- 30396899 TI - Initial Characterization of the Two ClpP Paralogs of Chlamydia trachomatis Suggests Unique Functionality for Each. AB - Chlamydia is an obligate intracellular bacterium that differentiates between two distinct functional and morphological forms during its developmental cycle: elementary bodies (EBs) and reticulate bodies (RBs). EBs are non-dividing, small electron dense forms that infect host cells. RBs are larger, non-infectious replicative forms that develop within a membrane-bound vesicle, termed an inclusion. Given the unique properties of each developmental form of this bacterium, we hypothesized that the Clp protease system plays an integral role in proteomic turnover by degrading specific proteins from one developmental form or the other. Chlamydia has five uncharacterized clp genes: clpX, clpC, two clpP paralogs, and clpB In other bacteria, ClpC and ClpX are ATPases that unfold and feed proteins into the ClpP protease to be degraded, and ClpB is a deaggregase. Here, we focused on characterizing the ClpP paralogs. Transcriptional analyses and immunoblotting determined these genes are expressed mid-cycle. Bioinformatic analyses of these proteins identified key residues important for activity. Over expression of inactive clpP mutants in Chlamydia suggested independent function of each ClpP paralog. To further probe these differences, we determined interactions between the ClpP proteins using bacterial two-hybrid assays and native gel analysis of recombinant proteins. Homotypic interactions of the ClpP proteins, but not heterotypic interactions between the ClpP paralogs, were detected. Interestingly, ClpP2, but not ClpP1, protease activity was detected in vitro This activity was stimulated by antibiotics known to activate ClpP, which also blocked chlamydial growth. Our data suggest the chlamydial ClpP paralogs likely serve distinct and critical roles in this important pathogen.IMPORTANCE Chlamydia trachomatis is the leading cause of preventable infectious blindness and of bacterial sexually transmitted infections worldwide. Chlamydiae are developmentally regulated, obligate intracellular pathogens that alternate between two functional and morphologic forms with distinct repertoires of proteins. We hypothesize that protein degradation is a critical aspect to the developmental cycle. A key system involved in protein turnover in bacteria is the Clp protease system. Here, we characterized the two chlamydial ClpP paralogs by examining their expression in Chlamydia, their ability to oligomerize, and their proteolytic activity. This work will help understand the evolutionarily diverse Clp proteases in the context of intracellular organisms, which may aid in the study of other clinically relevant intracellular bacteria. PMID- 30396900 TI - Regulation of biofilm aging and dispersal in Bacillus subtilis by the alternative sigma factor SigB. AB - Bacterial biofilms are important in natural settings, biotechnology and medicine. However, regulation of biofilm development and its persistence in different niches is complex and only partially understood. One key step during the biofilm life cycle is dispersal, when motile cells abandon the mature biofilm to spread out and colonize new niches. Here, we show that in the model bacterium Bacillus subtilis the general stress transcription factor SigB is essential for halting detrimental overgrowth of mature biofilm and for triggering dispersal when nutrients become limited. Specifically, SigB-deficient biofilms were larger than wild-type biofilms but exhibited accelerated cell death, significantly greater sensitivity to different stresses and reduced dispersal. Interestingly, the signal detected by SigB to limit biofilm growth was transduced through the RsbP dependent metabolic arm of the SigB regulatory cascade, which in turn positively controlled expression of SinR, the master regulator of biofilm formation and cell motility. This novel SigB-SinR regulatory circuit might be important in controlling the fitness of biofilms (either beneficial or harmful) in diverse environments.Importance Biofilms are crucial for bacterial survival, adaptation and dissemination in natural, industrial and medical systems. Sessile cells embedded in the self-produced extracellular matrix of the biofilm benefit from a division of labor and are protected from environmental insults. However, as the biofilm ages, cells become stressed because of overcrowding, starvation and accumulation of waste products. How does the sessile biofilm community sense and respond to stressful conditions? Here, we show that in Bacillus subtilis, the transcription factors SigB and SinR control whether cells remain in or leave a biofilm when metabolic conditions become unfavorable. This novel SigB-SinR regulatory circuit might be important for controlling the fitness of biofilms (either beneficial or harmful) in diverse environments. PMID- 30396901 TI - State of the Journal. AB - The Journal of Bacteriology (JB) is a prestigious periodical that publishes research articles that probe fundamental processes in bacteria, archaea, and their viruses, and the molecular mechanisms by which they interact with each other and with their hosts and their environments..... PMID- 30396902 TI - Combating pancreatic cancer with PI3K pathway inhibitors in the era of personalised medicine. AB - Pancreatic ductal adenocarcinoma (PDAC) is among the most deadly solid tumours. This is due to a generally late-stage diagnosis of a primarily treatment refractory disease. Several large-scale sequencing and mass spectrometry approaches have identified key drivers of this disease and in doing so highlighted the vast heterogeneity of lower frequency mutations that make clinical trials of targeted agents in unselected patients increasingly futile. There is a clear need for improved biomarkers to guide effective targeted therapies, with biomarker-driven clinical trials for personalised medicine becoming increasingly common in several cancers. Interestingly, many of the aberrant signalling pathways in PDAC rely on downstream signal transduction through the mitogen-activated protein kinase and phosphoinositide 3-kinase (PI3K) pathways, which has led to the development of several approaches to target these key regulators, primarily as combination therapies. The following review discusses the trend of PDAC therapy towards molecular subtyping for biomarker driven personalised therapies, highlighting the key pathways under investigation and their relationship to the PI3K pathway. PMID- 30396903 TI - To switch or not to switch: results of a nationwide guideline of mandatory switching from originator to biosimilar etanercept. One-year treatment outcomes in 2061 patients with inflammatory arthritis from the DANBIO registry. AB - OBJECTIVES: Real-world evidence on effectiveness of switching to biosimila r etanercept is scarce. In Denmark, a nationwide guideline of mandatory switch from 50 mg originator (ETA) to biosimilar (SB4) etanercept was issued for patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA) in 2016. Clinical characteristics and treatment outcomes were studied in ETA-treated patients, who switched to SB4 (switchers) or maintained ETA (non-switchers). Retention rates were compared with that of a historic cohort of ETA-treated patients. Switchers who resumed ETA treatment (back-switchers) were characterised. METHODS: Observational cohort study based on the DANBIO registry. Treatment retention was explored by Kaplan-Meier plots and Cox regression (crude, adjusted). RESULTS: 1621 (79%) of 2061 ETA-treated patients switched to SB4. Disease activity was unchanged 3 months' preswitch/postswitch. Non-switchers often received 25 mg ETA (ETA 25 mg pens/syringes and powder solution were still available). One-year adjusted retention rates were: non-switchers: 77% (95% CI: 72% to 82%)/switchers: 83% (79% to 87%)/historic cohort: 90% (88% to 92%). Patients not in remission had lower retention rates than patients in remission, both in switchers (crude HR 1.7 (1.3 to 2.2)) and non-switchers (2.4 (1.7 to 3.6)). During follow-up, 120 patients (7% of switchers) back-switched to ETA. Back-switchers' clinical characteristics were similar to switchers, and reasons for SB4 withdrawal were mainly subjective. CONCLUSION: Seventy-nine per cent of patients switched from ETA to SB4. After 1 year, adjusted treatment retention rates were lower in switchers versus the historic ETA cohort, but higher than in non-switchers. Withdrawal was more common in patients not in remission. The results suggest that switch outcomes in routine care are affected by patient-related factors and non-specific drug effects. PMID- 30396904 TI - Insulin-Like Growth Factor Binding Protein 2 (IGFBP-2) and the Risk of Developing Type 2 Diabetes. AB - Recent studies suggest that insulin-like growth factor binding protein-2 (IGFBP 2) may protect against type 2 diabetes but population-based human studies are scarce. We aimed to investigate the prospective association of circulating IGFBP 2 concentrations and of differential methylation in the IGFBP-2 gene with type 2 diabetes risk.Within the EPIC-Potsdam cohort (n=27,548), circulating IGFBP-2 concentration was assessed in a nested case-cohort (random subcohort, n=2500, all incident type 2 diabetes cases, n=820). A nested 1:1 matched case-control sample (300 incident type 2 diabetes cases, 300 controls) was constructed for DNA methylation profiling. Longitudinal associations were evaluated in Cox models (case-cohort) and conditional logistic models (case-control), adjusting for age, sex, anthropometry, lifestyle and a large set of type 2 diabetes-related biomarkers.Higher circulating IGFBP-2 concentrations (median 92 ng/mL) were cross sectional linked to lower BMI, waist circumference, fatty liver index, triglycerides, fetuin A, ALT and gamma-GT, and longitudinal associated with lower type 2 diabetes risk (HR per SD 0.65, 95%CI 0.53, 0.8). A methylation score based on seven type 2 diabetes-related CpGs in the IGFBP-2 gene was associated with higher type 2 diabetes risk (OR per SD 2.7, 95%CI 2.1, 3.5).Our results are consistent with a type 2 diabetes-protective effect of high circulating IGFBP-2 concentration, and suggest that epigenetic silencing of the IGFBP-2 gene might predispose for type 2 diabetes. PMID- 30396905 TI - Macrophages enhance Vegfa-driven angiogenesis in an embryonic zebrafish tumour xenograft model. AB - Tumour angiogenesis has long been a focus of anti-cancer therapy; however, anti angiogenic cancer treatment strategies have had limited clinical success. Tumour associated myeloid cells are believed to play a role in the resistance of cancer towards anti-angiogenesis therapy, but the mechanisms by which they do this are unclear. An embryonic zebrafish xenograft model has been developed to investigate the mechanisms of tumour angiogenesis and as an assay to screen anti-angiogenic compounds. In this study, we used cell ablation techniques to remove either macrophages or neutrophils and assessed their contribution towards zebrafish xenograft angiogenesis by quantitating levels of graft vascularisation. The ablation of macrophages, but not neutrophils, caused a strong reduction in tumour xenograft vascularisation and time-lapse imaging demonstrated that tumour xenograft macrophages directly associated with the migrating tip of developing tumour blood vessels. Finally, we found that, although macrophages are required for vascularisation in xenografts that either secrete VEGFA or overexpress zebrafish vegfaa, they are not required for the vascularisation of grafts with low levels of VEGFA, suggesting that zebrafish macrophages can enhance Vegfa driven tumour angiogenesis. The importance of macrophages to this angiogenic response suggests that this model could be used to further investigate the interplay between myeloid cells and tumour vascularisation. PMID- 30396906 TI - Use of a novel suction cervical retractor for intrauterine device insertion: a pilot feasibility trial. AB - INTRODUCTION: The Bioceptive suction cervical retractor (SCR) is a novel device that can replace the standard single-tooth tenaculum to place traction on the cervix. A feasibility trial was conducted on the device for intrauterine device (IUD) placement. METHODS: Our three-stage feasibility process began with Stage 1, where the device was tested on in-vitro and ex-vivo samples. In Stage 2, 10 women received their IUD using the device. In Stage 3, a feasibility trial, we randomly assigned 25 consenting women to receive their IUD using either the Bioceptive SCR or the standard single-tooth tenaculum. In Stages 2 and 3, we collected pain scores using an electronically adapted 100-point visual analogue scale (VAS) at eight timepoints during and after the insertion procedure, as well as satisfaction and acceptability measures. The primary outcome was the pain score after attaching the SCR or tenaculum (VAS 3). Wilcoxon rank sum tests compared pain scores between devices. RESULTS: In Stage 2, pain scores with the SCR were lower than historical controls with the single-tooth tenaculum. In Stage 3, the median VAS 3 pain scores were 31 and 57 for the intervention and control groups, respectively. The differences in pain scores were not statistically significant but the trend was to lower pain scores with the intervention. Reported patient satisfaction with the SCR device was 80% in Stage 2% and 90% in Stage 3. CONCLUSIONS: The Bioceptive SCR has potential as an atraumatic alternative to standard cervical retractor devices for gynaecological procedures. These findings can guide point estimates for future clinical studies. TRIAL REGISTRATION: NCT02283463. PMID- 30396907 TI - Muscle strength deficiency and mitochondrial dysfunction in a muscular dystrophy model of Caenorhabditis elegans and its functional response to drugs. AB - Muscle strength is a key clinical parameter used to monitor the progression of human muscular dystrophies, including Duchenne and Becker muscular dystrophies. Although Caenorhabditis elegans is an established genetic model for studying the mechanisms and treatments of muscular dystrophies, analogous strength-based measurements in this disease model are lacking. Here, we describe the first demonstration of the direct measurement of muscular strength in dystrophin deficient C. elegans mutants using a micropillar-based force measurement system called NemaFlex. We show that dys-1(eg33) mutants, but not dys-1(cx18) mutants, are significantly weaker than their wild-type counterparts in early adulthood, cannot thrash in liquid at wild-type rates, display mitochondrial network fragmentation in the body wall muscles, and have an abnormally high baseline mitochondrial respiration. Furthermore, treatment with prednisone, the standard treatment for muscular dystrophy in humans, and melatonin both improve muscular strength, thrashing rate and mitochondrial network integrity in dys-1(eg33), and prednisone treatment also returns baseline respiration to normal levels. Thus, our results demonstrate that the dys-1(eg33) strain is more clinically relevant than dys-1(cx18) for muscular dystrophy studies in C. elegans This finding, in combination with the novel NemaFlex platform, can be used as an efficient workflow for identifying candidate compounds that can improve strength in the C. elegans muscular dystrophy model. Our study also lays the foundation for further probing of the mechanism of muscle function loss in dystrophin-deficient C. elegans, leading to knowledge translatable to human muscular dystrophy.This article has an associated First Person interview with the first author of the paper. PMID- 30396908 TI - Phase 1 Trial of Autologous CAR T Cells Targeting NKG2D Ligands in Patients with AML/MDS and Multiple Myeloma. AB - NKG2D ligands are widely expressed in solid and hematologic malignancies but absent or poorly expressed on healthy tissues. We conducted a phase 1 dose escalation study to evaluate the safety and feasibility of a single infusion of NKG2D-chimeric antigen receptor (CAR) T cells, without lymphodepleting conditioning in subjects with acute myeloid leukemia/myelodysplastic syndrome or relapsed/refractory multiple myeloma. Autologous T cells were transfected with a gamma-retroviral vector encoding a CAR fusing human NKG2D with the CD3zeta signaling domain. Four dose levels (1x10e6-3x10e7 total viable T cells) were evaluated. Twelve subjects were infused (7 AML, 5 MM). NKG2D-CAR products demonstrated a median 75% vector-driven NKG2D expression on CD3+ T cells. No dose limiting toxicities, cytokine release syndrome, or CAR T cell-related neurotoxicity was observed. No significant autoimmune reactions were noted, and none of the >/= Grade 3 adverse events were attributable to NKG2D-CAR T cells. At the single injection of low cell doses employed in this trial, no objective tumor responses were observed. However, hematologic parameters transiently improved in one subject with AML at the highest dose, and cases of disease stability without further therapy or on subsequent treatments were noted. At 24 hours, the cytokine RANTES increased a median of 1.9-fold among all subjects and 5.8-fold among 6 AML patients. Consistent with preclinical studies, NKG2D-CAR T cell-expansion and persistence were limited. Manufactured NKG2D-CAR T cells exhibited functional activity against autologous tumor cells in vitro, but modifications to enhance CAR T-cell expansion and target density may be needed to boost clinical activity. PMID- 30396909 TI - Exosomes Released from Tumor-Associated Macrophages Transfer miRNAs That Induce a Treg/Th17 Cell Imbalance in Epithelial Ovarian Cancer. AB - The immune microenvironment is crucial for epithelial ovarian cancer (EOC) progression and consists of tumor-associated macrophages (TAM) and T lymphocytes, such as regulatory T cells (Treg) and T helper 17 (Th17) cells. In this study, the Treg/Th17 ratio was significantly higher in EOC in situ and in metastatic peritoneal tissues than in benign ovarian tumors and benign peritoneum. The Treg/Th17 ratio was associated with histologic grade and was an independent prognostic factor for overall survival of EOC patients. On the basis of microarray analysis of exosomes derived from TAMs, we identified miRNAs enriched in the exosomes, including miR-29a-3p and miR-21-5p. When the two miRNA mimics were transfected into CD4+ T cells, they directly suppressed STAT3 and regulated Treg/Th17 cells, inducing an imbalance, and they had a synergistic effect on STAT3 inhibition. Taken together, these results indicate that exosomes mediate the interaction between TAMs and T cells, generating an immune-suppressive microenvironment that facilitates EOC progression and metastasis. These findings suggest that targeting these exosomes or their associated miRNAs might pave the way for the development of novel treatments for EOC. PMID- 30396910 TI - Recombinant factor VIII Fc fusion protein drives regulatory macrophage polarization. AB - The main complication of replacement therapy with factor in hemophilia A (HemA) is the formation of inhibitors (neutralizing anti-factor VIII [FVIII] antibodies) in ~30% of severe HemA patients. Because these inhibitors render replacement FVIII treatment essentially ineffective, preventing or eliminating them is of top priority in disease management. The extended half-life recombinant FVIII Fc fusion protein (rFVIIIFc) is an approved therapy for HemA patients. In addition, it has been reported that rFVIIIFc may induce tolerance to FVIII more readily than FVIII alone in HemA patients that have developed inhibitors. Given that the immunoglobulin G1 Fc region has the potential to interact with immune cells expressing Fc receptors (FcRs) and thereby affect the immune response to rFVIII, we investigated how human macrophages, expressing both FcRs and receptors reported to bind FVIII, respond to rFVIIIFc. We show herein that rFVIIIFc, but not rFVIII, uniquely skews macrophages toward an alternatively activated regulatory phenotype. rFVIIIFc initiates signaling events that result in morphological changes, as well as a specific gene expression and metabolic profile that is characteristic of the regulatory type Mox/M2-like macrophages. Further, these changes are dependent on rFVIIIFc-FcR interactions. Our findings elucidate mechanisms of potential immunomodulatory properties of rFVIIIFc. PMID- 30396911 TI - Persistence of endothelial thrombomodulin in a patient with infectious purpura fulminans treated with protein C concentrate. PMID- 30396913 TI - Detailed visual cortical responses generated by retinal sheet transplants in rats with severe retinal degeneration. AB - To combat retinal degeneration, healthy fetal retinal sheets have been successfully transplanted into both rodent models and humans, with synaptic connectivity between transplant and degenerated host retina having been confirmed. In rodent studies transplants have been shown to restore responses to flashes of light in a region of the superior colliculus corresponding to the location of the transplant in the host retina. To determine the quality and detail of visual information provided by the transplant, visual responsivity was studied here at the level of visual cortex where higher visual perception is processed. For our model, we used the transgenic Rho-S334ter line-3 rat (both sexes) which loses photoreceptors at an early age and is effectively blind at post-natal day 30. These rats received fetal retinal sheet transplants in one eye between 24-40 days of age. Three to ten months following surgery, visually responsive neurons were found in regions of primary visual cortex (V1) matching the transplanted region of the retina that were as highly selective as normal rat to stimulus orientation, size, contrast, and spatial and temporal frequencies. Conversely, we found that selective response properties were largely absent in non-transplanted line-3 rats. Our data show that fetal retinal sheet transplants can result in remarkably normal visual function in visual cortex of rats with a degenerated host retina and represents a critical step towards developing an effective remedy for the visually impaired human population.SIGNIFICANCE STATEMENTAge-related macular degeneration and retinitis pigmentosa lead to profound vision loss in millions of people worldwide. Many patients lose both retinal pigment epithelium and photoreceptors. Hence there is a great demand for the development of efficient techniques that allow for long term vision restoration. In this study, we transplanted dissected fetal retinal sheets which can differentiate into photoreceptors and integrate with the host retina of rats with severe retinal degeneration. Remarkably, we show that transplants generated visual responses in cortex similar in quality to normal rats. Furthermore, transplants preserved connectivity within visual cortex and the retinal relay from the lateral geniculate nucleus to visual cortex, supporting their potential application in curing vision loss associated with retinal degeneration. PMID- 30396914 TI - Structure, activity and function of a singing-CPG interneuron controlling cricket. AB - The evolution of species-specific song patterns is a driving force in the speciation of acoustic communicating insects. It must be closely linked to adaptations of the neuronal network controlling the underlying singing motor activity. What are the cellular and network properties that allow generating different songs? In five cricket species, we analyzed the structure and activity of the identified abdominal ascending opener interneuron, a homologous key component of the singing central pattern generator. The structure of the interneuron, based on the position of the cell body, ascending axon, dendritic arborization pattern, and dye-coupling is highly similar across species. The neuron's spike activity shows a tight coupling to the singing motor activity. In all species, current injection into the interneuron drives artificial song patterns, highlighting the key functional role of this neuron. However, the pattern of the membrane depolarization during singing, the fine dendritic and axonal ramifications and the number of dye-coupled neurons, indicate species specific adaptations of the neuronal network, which might be closely linked to the evolution of species-specific singing.Significance Statement: A fundamental question in evolutionary neuroscience is how species-specific behaviors arise in closely-related species. We demonstrate behavioral, neurophysiological and morphological evidence for homology of one key identified interneuron of the singing central pattern generator in five cricket species. Across species differences of this interneuron are also observed, which might be important to the generation of the species-specific song patterns. This work offers a comprehensive and detailed comparative analysis addressing the neuronal basis of species-specific behavior. PMID- 30396915 TI - Suppression of canine ABCB1 in MDCKII cells unmasks human ABCG2-mediated efflux of olaparib. AB - Endogenous cABCB1 is expressed abundantly in MDCKII cells, and its presence often complicates the phenotyping of the transport process. Errors in estimating cER, as the result of the variable expression of cABCB1, were examined for the dual substrates of ABCB1 and ABCG2 in MDCKII cells expressing hABCG2. The mRNA and protein expression of cABCB1 was 60% and 55% lower, respectively, in MDCKII cells expressing hABCG2 compared to the values for the wild type, suggesting that the expression of endogenous cABCB1 became variable after the expression of hABCG2. To minimize the contribution of endogenous efflux, cABCB1 was suppressed kinetically (i.e., using verapamil as a selective inhibitor), or biochemically (i.e., transfecting short-hairpin RNA against cABCB1). Under these conditions of suppression, the cER values for irinotecan and topotecan, dual substrates of ABCB1 and ABCG2, were elevated by over 4-fold and 2-fold, respectively, in comparison to the values without the suppression. The cER of olaparib was similarly increased to 3- and 5-fold in MDCKII cells under the kinetic and biochemical suppression of cABCB1, respectively, suggesting that hABCG2-mediated efflux cannot be ruled out for olaparib. Since the substrate selectivity for ABCB1 and ABCG2 is considerably overlapped, the possibility of an inaccurate estimation of cER needs to be taken into consideration for the dual substrates in the case of the variable expression of cABCB1 in MDCKII cells. PMID- 30396912 TI - Myeloablative vs reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chronic myeloid leukemia. AB - Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment of chronic myeloid leukemia (CML). Optimal conditioning intensity for allo-HCT for CML in the era of tyrosine kinase inhibitors (TKIs) is unknown. Using the Center for International Blood and Marrow Transplant Research database, we sought to determine whether reduced-intensity/nonmyeloablative conditioning (RIC) allo-HCT and myeloablative conditioning (MAC) result in similar outcomes in CML patients. We evaluated 1395 CML allo-HCT recipients between the ages of 18 and 60 years. The disease status at transplant was divided into the following categories: chronic phase 1, chronic phase 2 or greater, and accelerated phase. Patients in blast phase at transplant and alternative donor transplants were excluded. The primary outcome was overall survival (OS) after allo-HCT. MAC (n = 1204) and RIC allo-HCT recipients (n = 191) from 2007 to 2014 were included. Patient, disease, and transplantation characteristics were similar, with a few exceptions. Multivariable analysis showed no significant difference in OS between MAC and RIC groups. In addition, leukemia-free survival and nonrelapse mortality did not differ significantly between the 2 groups. Compared with MAC, the RIC group had a higher risk of early relapse after allo HCT (hazard ratio [HR], 1.85; P = .001). The cumulative incidence of chronic graft-versus-host disease (cGVHD) was lower with RIC than with MAC (HR, 0.77; P = .02). RIC provides similar survival and lower cGVHD compared with MAC and therefore may be a reasonable alternative to MAC for CML patients in the TKI era. PMID- 30396916 TI - Plasma and brain concentrations of doxycycline after single and repeated doses in wild-type and APP23 mice. AB - Repurposing doxycycline for the treatment of amyloidosis has recently been put forward based on the anti-aggregating and anti-inflammatory properties of this drug. Most of the investigations on the therapeutic potential of doxycycline for neurodegenerative amyloidosis, e.g. prion and Alzheimer disease (AD), are carried out in mouse models but, surprisingly, no data are available as regards the concentrations reached in the brain after systemic administration. We filled this gap by analysing the pharmacokinetic profile of doxycycline in plasma and brain after single and repeated intraperitoneal injections of 10 and 100 mg/kg, in wild type mice and the APP23 mouse model of the AD. The main outcomes of our study are: i) peak plasma concentrations ranged 2-10 MUg/mL, superimposable to those in humans; ii) brain-to-plasma ratio was ~0.2, comparable to the CSF/serum ratios in humans; iii) brain Cmax, 4-6 h after a single dose, was ~0.5 MUM (10 mg/kg) and ~5 MUM (100 mg/kg). Notably, these concentrations are lower than those required for the drug's anti-aggregating properties as observed in cell-free studies, suggesting that other features underlie the positive cognitive effects in AD mice; iv) elimination half-life was shorter than in humans (3-6h vs 15-30h), therefore no significant accumulation was observed in mouse brain following repeated treatments; v) there were no differences between doxycycline concentrations in brain areas of age-matched wild-type and APP23 mice. These data are useful for planning preclinical studies with translational validity, and to identify the mechanism(s) of action underlying the central in vivo effects of doxycycline more reliably. PMID- 30396917 TI - Molecular Basis of Drug Resistance and Insights for New Treatment Approaches in mCRPC. AB - Inhibiting androgen receptor (AR) signaling with androgen deprivation therapy (ADT) represents the mainstay of therapy for advanced and metastatic prostate cancer. However, about 20-60% of patients receiving first-line treatment for prostate cancer will relapse, evolving in a more aggressive and lethal form of the disease, the castration-resistant prostate cancer (CRPC), despite the use of ADT. Multiple approved systemic therapies able to prolong survival of patients with metastatic CRPC (mCRPC) exist, but almost invariably, patients treated with these drugs develop primary or acquired resistance. Multiple factors are involved in CRPC treatment resistance and elucidating the mechanisms of action of these factors is a key question and an active area of research. Due to such a complex scenario, treatment personalization is necessary to improve treatment effectiveness and reduce relapse rates in CRPC. In this review, current evidence about the major mechanisms of resistance to the available prostate cancer treatments were examined by introducing insights on new and future therapeutic approaches. PMID- 30396918 TI - Technical Advances in Radiation Therapy for Brain Tumors. AB - Radiation therapy plays a critical role in the management of brain tumors. Recent advances in radiation techniques include the use of intensity-modulated radiotherapy (IMRT), volumetric-modulated arc therapy (VMAT) and stereotactic radiosurgery (SRS). All of these techniques allow the delivery of higher radiation doses to the target volume, at the same time reducing the risk of toxicity to normal tissues as compared with conventional 3D conformal radiotherapy (3D-CRT). Proton therapy may represent a treatment alternative to photon irradiation, due to the more favorable dose distribution to the target volume. This review summarizes current developments in radiation therapy and their clinical impact on the management of patients with brain tumors. PMID- 30396919 TI - Collision Tumors of the Gastrointestinal Tract: A Systematic Review of the Literature. AB - BACKGROUND/AIM: Collision tumors are rare neoplasms which consist of two or more distinct neoplasms that develop adjacent to one another and coexist with no or minimal intermingling between them. Their diagnosis is often incidental and their behavior remains widely unknown. Several theories have been proposed regarding their pathogenesis. The objective of this study was the evaluation of current evidence on collision tumors of the gastrointestinal tract regarding their pathology, biological behavior and treatment approach. MATERIALS AND METHODS: The PubMed and Cochrane bibliographical databases were searched from January 1997 to July 2018 (last search: July 5th, 2018) for studies reporting on collision tumors of the gastrointestinal tract that also included a therapeutic approach. RESULTS: Forty-seven studies reporting on collision tumors of the gastrointestinal tract were identified. They reported collectively on 53 cases (43 males, 10 females) with collision tumors of the esophagus, stomach, small intestine and large intestine. The vast majority (96.2%) of tumors consisted of two distinct histological components and only two cases involved a greater number of histological subtypes. Fifty-one patients underwent a surgical or endoscopic tumor resection, accompanied in 22 cases by adjuvant or neoadjuvant therapy. The remaining two patients underwent palliative operations. In total, three patients experienced immediate postoperative complications. CONCLUSION: Collision tumors of the gastrointestinal tract, despite their rare nature, constitute a quite interesting field of study. This review offers a thorough insight into the clinicopathological characteristics and biological behavior of these rare tumors. PMID- 30396920 TI - Metastasis Suppressor NME1 Directly Activates Transcription of the ALDOC Gene in Melanoma Cells. AB - BACKGROUND/AIM: NME/NM23 nucleoside diphosphate kinase 1 (NME1) is a metastasis suppressor gene, exhibiting reduced expression in metastatic cancers and the ability to suppress metastatic activity of cancer cells. We previously identified NME1-regulated genes with prognostic value in human melanoma. This study was conducted in melanoma cell lines aiming to elucidate the mechanism through which NME regulates one of these genes, aldolase C (ALDOC). MATERIALS AND METHODS: ALDOC mRNA and protein expression was measured using qRT-PCR and immunoblot analyses. Promoter-luciferase constructs and chromatin immunoprecipitation were employed to measure the impact of NME1 on ALDOC transcription. RESULTS: NME1 enhanced ALDOC transcription, evidenced by increased expression of ALDOC pre-mRNA and activity of an ALDOC promoter-luciferase module. NME1 was detected at the ALDOC promoter, and forced NME1 expression resulted in enhanced occupancy of the promoter by NME1, increased presence of epigenetic activation markers (H3K4me3 and H3K27ac), and recruitment of RNA polymerase II. CONCLUSION: This is the first study to indicate that NME1 induces transcription through its direct binding to the promoter region of a target gene. PMID- 30396922 TI - Cystathione beta-Synthase Is Increased in Thyroid Malignancies. AB - BACKGROUND: Cystathione beta-synthase (CBS) catalyzes the conversion of homocysteine and cysteine to hydrogen sulfide (H2S) and cystathione, via the trans-sulfuration pathway. CBS protein expression levels are increased in several different human malignancies, with increased protein expression correlating with parameters such as tumor stage, anaplasia, metastases, and chemotherapy resistance. MATERIALS AND METHODS: This study employed tissue microarrays to examine CBS expression in benign thyroid tissue, thyroid oncocytomas, thyroid follicular adenomas, and in follicular, papillary, anaplastic, and medullary thyroid carcinomas. RESULTS: CBS expression was increased in all thyroid carcinomas types compared to benign thyroid tissue, but not in thyroid follicular adenomas or oncocytomas. A similar pattern was observed for nicotinamide phosphoribosyltransferase (NAMPT) tissue microarray analysis comparing thyroid adenomas and follicular carcinomas. CONCLUSION: For the first time, we showed that an H2S-syntheszing enzyme plays a role in thyroid malignancies. Additionally, our data suggest that CBS and NAMPT immunohistochemistry may be useful in differentiating follicular adenomas from follicular carcinomas. PMID- 30396921 TI - Transcriptomic Analysis of Histone Methyltransferase Setd7 Knockdown and Phenethyl Isothiocyanate in Human Prostate Cancer Cells. AB - BACKGROUND/AIM: Transcriptomic analysis was performed to evaluate the differential gene expression profiles of Setd7 knockdown (KD) and the effects of phenethyl isothiocyanate (PEITC) in human prostate cancer (PCa) LNCaP cells. MATERIALS AND METHODS: RNA isolated from wild-type and Setd7-KD LNCaP cells in the presence or absence of PEITC was subjected to microarray analysis followed by Ingenuity(r) Pathway Analysis (IPA). RESULTS: Setd7 KD impacted a larger set of genes and caused a higher fold change compared to PEITC treatment. Several signaling pathways were altered particularly inflammation-related TNFR signaling and PTEN/PI3K/AKT signaling by Setd7 KD and PEITC. Interestingly, PEITC and Setd7 KD at a small subset of genes that could be potential molecular targets. CONCLUSION: This study offers new insights into the mechanisms of action of the epigenetic modifier Setd7 and the effects of PEITC treatment in PCa cells and enhances our understanding of the potential cancer preventive/treatment effects of isothiocyanate compounds such as PEITC in PCa. PMID- 30396923 TI - 7,8-Dihydroxy-3-arylcoumarin Induces Cell Death Through S-Phase Arrest in MDA-MB 231 Breast Cancer Cells. AB - BACKGROUND/AIM: Coumarins remain one of the most versatile classes of compounds for anticancer drug design and discovery. The present study aimed to evaluate the in vitro cytotoxic activity of 7,8-Dihydroxy-3-arylcoumarin derivatives (7a-i) in A549, MDA-MB-231and PC-3 cancer cell lines. MATERIALS AND METHODS: Cell viability, cell-cycle progression and regulatory protein expression were evaluated using crystal violet dye-binding assay, flow cytometry and western blot analysis. RESULTS: 7,8-Diacetoxy-3-(4-nitrophenyl)coumarin (7h) showed the highest cytotoxic activity with CC50 of 7.51+/-0.07 MUM in MDA-MB-231 cell line. The mechanism of cytotoxic action indicated that 7h caused significant (p<0.05) MDA-MB-231 cells arrest in the S phase as well as moderate cells arrest in the G2/M phase; confirmed by up-regulation of cyclins A/B1, p21 and CDKs 4/6, and down-regulation of cyclin E2 and CDK2 regulatory proteins. CONCLUSION: These results suggest that 7h could serve as a valuable template for the development of novel synthetic compounds for breast cancer treatment. PMID- 30396924 TI - BUBR1 Insufficiency Is Correlated with eNOS Reduction Experimentally In Vitro and In Vivo, and in Gastric Cancer Tissue. AB - BACKGROUND/AIM: Budding uninhibited by benzimidazole-related 1 (BUBR1) and endothelial nitric oxide synthase (eNOS) are related to aging and angiogenesis. This study examined the effect of low BUBR1 expression on eNOS expression in vivo, in vitro, and human gastric cancer tissues. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVECs) were passaged to investigate the effect of aging on BUBR1 and eNOS expression; expression of eNOS and phospho-eNOS protein was assessed in BUBR1 siRNA-transfected HUVECs. Additionally, guanosine 3',5' cyclic monophosphate (cGMP) and eNOS protein levels were measured in BUBR1 insufficient mice (Bubr1L/-). BUBR1 and eNOS expression levels were also evaluated in human gastric cancer tissues. RESULTS: BUBR1 and eNOS, but not p eNOS, levels were reduced significantly in aged and BUBR1 siRNA-transfected HUVECs. Additionally, cGMP production and the eNOS protein level were reduced in Bubr1L/- mice. Human gastric cancer tissues with low BUBR1 expression showed no eNOS expression. CONCLUSION: A decrease in BUBR1 reduced eNOS bioavailability through a pathway other than eNOS phosphorylation. PMID- 30396925 TI - CUB Domain-containing Protein 1 (CDCP1) Is Down-regulated by Active Hexose correlated Compound in Human Pancreatic Cancer Cells. AB - BACKGROUND/AIM: We have previously reported that treatment of pancreatic cancer cells with active hexose-correlated compound (AHCC), an extract of a basidiomycete mushroom, decreases the levels of tumor-associated proteins including heat-shock protein 27 (HSP27), heat shock factor 1 (HSF1) and sex determining region Y-box 2 (SOX2). The transmembrane glycoprotein, CUB domain containing protein 1 (CDCP1) has been reported to be up-regulated in various cancers, and be associated with invasion and metastasis. The aim of this study was to examine the effect of AHCC on the expression of CDCP1 in KLM1-R cells. MATERIALS AND METHODS: Gemcitabine-resistant pancreatic cancer cells (KLM1-R) were treated with AHCC (10 mg/ml) for 48 h. Western blot analysis of cell extracts with anti-CDCP1 or anti-actin antibodies was performed to assess the expression of CDCP1. RESULTS: Expression of CDCP1 was reduced by AHCC treatment of KLM1-R cells, whereas expression of actin was not affected. The ratio of intensities of CDCP1/actin in AHCC-treated KLM1-R cells was significantly suppressed (p<0.05) compared to untreated cells. CONCLUSION: AHCC down-regulated CDCP1 expression and inhibited the malignant progression of pancreatic cancer cells. PMID- 30396926 TI - Modified Nucleosides - Molecular Markers Suitable for Small-volume Cancer? AB - BACKGROUND: Modified nucleosides (mNS) in urine are shown to be encouraging markers in cancer, mostly in patients presenting with high tumor mass such is breast and lung cancer. To our knowledge, mNS have not been investigated in head and neck squamous cell carcinoma (HNSCC). HNSCC is characterized by early metastasis into locoregional lymph nodes and slow infiltrating growth, but even in the advanced stage exhibits only a relatively low cancer volume. Therefore, reliable distinction between HNSCC and healthy controls by urinary mNS might pose substantial analytical problems and even more as patients with HNSCC mostly have an increased exposure to tobacco smoke and excessive alcohol consumption which affect the renal mNS pattern. MATERIALS AND METHODS: Urinary mNS in samples of 93 therapy-naive patients with HNSCC and 242 healthy controls were quantified by reversed-phase high-performance liquid chromatography. Considering that the circadian rhythm causes diuresis-induced variations in concentration, the mNS-to creatinine ratio was chosen to compare patients and controls. For sensitivity and specificity in discriminating between patients and controls, the corresponding curve was plotted. Additionally, logistic regression was carried out and a multilayer perceptron neuronal network (NN) was created. RESULTS: Fifteen mNS were detectable in cases and controls; concentrations of 11 were found to be significantly different. The sensitivity and specificity depend on the total volume of the lesion; HNSCC with volume <20 ml was reliably detected, but those with a volume of 20 ml or greater produced amounts of mNS which led to the most accurate detection of HNSCC based on HNSCC-specific mNS patterns. CONCLUSION: Analysis of urinary mNS allows for detection of small-volume HNSCC, with acceptable specificity and sensitivity if the tumor volume exceeds 20 ml. PMID- 30396927 TI - A Novel Combination Therapy for Human Oxaliplatin-resistant Colorectal Cancer Using Oxaliplatin and Coxsackievirus A11. AB - BACKGROUND: Colorectal cancer (CRC) is a major cause of morbidity and mortality throughout the world. It is the third most common cancer worldwide and the fourth most common cause of cancer-related death. FOLFOX, a combination of leucovorin calcium, fluorouracil, and oxaliplatin, is the first-line chemotherapy for stage III and stage IV CRC. However, patients with FOLFOX-resistant CRC have a poor prognosis. In recent years, virochemotherapy has been proposed as a potential treatment for chemotherapy-resistant cancer. MATERIALS AND METHODS: Through our first screening assay, we found that coxsackievirus A11 (CVA11) displayed potent oncolytic activities. We tested whether coxsackievirus A11 (CVA11) has oncolytic activity in human CRC cells in vitro and in vivo. We also examined whether pretreatment of oxaliplatin-resistant CRC cells with oxaliplatin enhances the oncolytic activity of CVA11. RESULTS: We found that CVA11 was potently oncolytic against the oxaliplatin-sensitive Caco-2 cell line, but had little effect on the oxaliplatin-resistant line WiDr. However, pretreatment of WiDr cells with oxaliplatin enhanced the oncolytic activity of CVA11, and the combination therapy was more cytotoxic than either oxaliplatin treatment or CVA11 infection alone. Furthermore, growth of subcutaneous WiDr tumors in a xenograft model was significantly lower in mice treated with oxaliplatin followed by intratumoral CVA11 injection compared with mice receiving either treatment alone. CONCLUSION: Oxaliplatin pretreatment sensitized oxaliplatin-resistant CRC cells to lysis by CVA11 infection in vitro and in vivo. Taken together, these findings identify a novel potential chemovirotherapeutic modality for the treatment of oxaliplatin resistant human CRC. PMID- 30396928 TI - IL-1beta Induces Fascin Expression and Increases Cancer Invasion. AB - BACKGROUND/AIM: Tumor microenvironment plays an important role in tumor growth and metastasis. Cancer cells can promote their growth and malignancy by altering the surrounding stroma. Fascin is an actin-bundling protein that regulates the dynamics of the cytoskeletal structure and plays a significant role in cancer invasion and metastasis. In this study, we observed stromal factors controlling fascin expression in cancer cells and investigated underlying signal transduction pathways. MATERIALS AND METHODS: Fascin depletion was performed with lentiviral short-hairpin RNA (shRNA) against fascin mRNA and a stable cell line (Fascindep) was established. Fascin expression and invasion activity induced by IL-1beta treatement were observed through Matrigel-Transwell invasion and 3D culture system. Intermediated signaling molecules involved in fascin expression induced by IL-1beta were elucidated using western blotting. RESULTS: Fascin was more highly expressed in human OSCC cells than normal cells. Cancer invasion activity was decreased by fascin depletion using lentiviral shRNA. However, fascin expression was increased by IL-1beta treatement, leading to increased extracellular matrix (ECM) degradation and infiltration into 3-dimensional (3-D) collagen matrix. Specific inhibitors of extracellular signal-regulated kinases 1/2 [ERK1/2, (PD98059)], c-Jun N-terminal kinase [JNK, (SP600125)], nuclear factor kappa light chain enhancer of activted B cells [NF-kappaB, (parthenolide)], and cAMP response element binding protein [CREB, (CREB inhibitor)] suppressed IL-1beta -induced fascin expression. IL-1beta induced phosphorylation of ERK1/2, JNK, NF-kappaB and CREB while IL-1 receptor (IL-1R) antagonist abolished their activation. CONCLUSION: IL-1beta is a critical inducer of fascin expression. ERK1/2, JNK, NF-kappaB, and CREB signaling pathways are involved in IL-1beta-induced fascin expression and these paracrine signaling pathways can induce cancer cell invasion. PMID- 30396929 TI - Colorectal Cancer Cell Line SW480 and SW620 Released Extravascular Vesicles: Focus on Hypoxia-induced Surface Proteome Changes. AB - BACKGROUND/AIM: Extravascular vesicle (EV) proteome closely reflects the proteome of the cell of origin. Therefore, cancer cell-derived EV proteomic analysis could help in identifying cancer biomarkers. This study's goal was to investigate hypoxia-induced proteomic changes in EV released from hypoxic human isogenic non metastatic colorectal cancer cells SW480 and metastatic colorectal cancer cells SW620. MATERIALS AND METHODS: EV were characterized by western blot, transmission electron microscopy, proteomic analysis using liquid chromatography time-of flight-mass spectrometry and quantified by an label-free intensity-based absolute quantitation (iBAQ) approach. RESULTS: A total of 16 proteins in hypoxic EV exceeded normoxic EV protein levels in SW480 EV. Of them, 15 were also found in EV of hypoxic SW620 cells. The expression levels of proteins differed quantitatively: iBAQ (log 10) scores of the levels of five proteins in SW620 EV exceeded those in hypoxic SW480 EV and levels of 11 proteins in SW480 EV exceeded those of SW620 EV. CONCLUSION: Under hypoxia, colorectal cancer cells release EV that qualitatively and quantitatively change the surface proteome. In the future, the specific hypoxia-induced proteins could be developed as new biomarkers for non-invasive assessment of tumour hypoxia. PMID- 30396930 TI - PROX1 Is Associated with Cancer Progression and Prognosis in Gastric Cancer. AB - BACKGROUND: It was recently reported that expression of prospero homeobox protein 1 (PROX1) is correlated with the prognosis of esophageal cancer and colorectal cancer. However, its correlation with gastric cancer is unclear. MATERIALS AND METHODS: Our study analyzed the effect of PROX1 knockdown on the migration, invasion and proliferation of the MKN45 human gastric cancer cell line. The correlation between PROX1 expression levels and clinicopathological factors were also analyzed in tumor samples from 99 patients with gastric cancer. RESULTS: Migration, invasion and proliferation were significantly reduced in MKN45 cells with PROX1 knockdown. PROX1 expression was detected in gastric cancer tissues at various levels. PROX1 expression levels were positively correlated with cancer stage, N factor, lymphatic vascular invasion, and vascular invasion in patients with gastric cancer. Analysis of overall and recurrence-free survival indicated that high PROX1 expression was significantly correlated with poor prognosis. CONCLUSION: PROX1 can be an indicator of poor prognosis and a molecular target for gastric cancer treatment. PMID- 30396931 TI - TAK-733, a Selective MEK Inhibitor, Enhances Voreloxin-induced Apoptosis in Myeloid Leukemia Cells. AB - BACKGROUND/AIM: MEK inhibitors are new promising anticancer drugs. The aim of this study was to investigate the effect of the combination treatment of voreloxin with the MEK inhibitor TAK-733 on HL60 myeloid leukemia cells. MATERIALS AND METHODS: MAPK activity, cell viability, apoptosis, oxidative stress induction and AIF (apoptosis-inducing factor) distribution were assessed in HL60 cells cultured with each drug alone or with both drugs. RESULTS: TAK-733 alone at 5 MUM significantly reduced MAPK activity and did not influence viability and apoptosis in HL60 cells. Voreloxin at concentration of 0.03-0.48 MUM reduced cell viability and increased apoptosis rate. Incubation with both drugs caused further inhibition of cell viability and increased apoptosis associated with generation of reactive oxygen species (ROS) and nuclear translocation of AIF. CONCLUSION: Combination of TAK-733 and voreloxin can exert a synergistic anticancer effect in myeloid leukemia cells. PMID- 30396932 TI - Lymphangiogenesis and Lymph Node Metastasis in Oral Squamous Cell Carcinoma. AB - BACKGROUND/AIM: Tumor lymphangiogenesis plays a key role in lymph node (LN) metastasis in oral squamous cell carcinoma (OSCC). The purpose of this study was to investigate podoplanin and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) and their relationship to nodal metastasis and other clinicopathological variables. PATIENTS AND METHODS: Podoplanin and LYVE-1 expression of the primary tumor and normal tissue were investigated by means of a quantitative real-time PCR assay and immunohistochemistry in samples from 33 cases of OSCC. RESULTS: The mRNA high expression levels of both genes had a statistically significantly higher rate of LN metastasis (p<0.01) and histological grade (p<0.01 for podoplanin, p<0.05 for LYVE-1). High expression of each gene, as shown by immunohistochemistry, had a statistically significant higher rate of LN metastasis (p<0.01 for podoplanin, p<0.05 for LYVE-1). CONCLUSION: Podoplanin and LYVE-1 were strongly associated with LN metastasis. PMID- 30396933 TI - Inhibiting xCT Improves 5-Fluorouracil Resistance of Gastric Cancer Induced by CD44 Variant 9 Expression. AB - BACKGROUND/AIM: Cancer stem cells (CSCs) play a critical role in resistance to chemotherapy. CD44 is a cell surface marker of CSCs. CD44 variant 9 (CD44v9) interacts with a cystine-glutamate antiporter (xCT) and is an unfavorable predictive factor in gastric cancer. We investigated the impact of CD44v9 expression on 5-fluorouracil (5-FU) resistance and the efficacy of the xCT inhibitor, sulfasalazine (SASP), in improving drug resistance. MATERIALS AND METHODS: The human gastric cancer cell line MKN28 was transfected with pRc/CMV plasmids encoding human CD44 or CD44v9, which were used for in vitro and in vivo experiments. RESULTS: CD44v9 expression results in 5-FU resistance by increasing intracellular glutathione and suppressing the drug-induced production of reactive oxygen species (ROS). SASP improved the drug sensitivity of CD44v9-expressing cells. CONCLUSION: Inhibition of xCT improved the clinical efficacy of chemotherapy against gastric cancer. CD44v9 expression can be a novel biomarker to predict resistance against 5-FU in gastric cancer. PMID- 30396934 TI - Casein Kinase 2 Inhibitor, CX-4945, as a Potential Targeted Anticancer Agent in Gastric Cancer. AB - BACKGROUND/AIM: Casein kinase 2 (CK2) is involved in multiple cellular processes. Furthermore, its overexpression in several human cancers has been associated with tumor progression. In this study, we evaluated the efficacy of the CK2 inhibitor, CX-4945, in gastric cancer cell lines and explored the potential predictive biomarkers for CX-4945 sensitivity. MATERIALS AND METHODS: The sensitivity to CX 4945 was screened in 49 gastric cancer cell lines by the MTT assay. The mRNA and protein expression of CK2 subunits (alpha and alpha') were determined using qRT PCR and western blot. Furthermore, the activity of CK2alpha was measured by ELISA. Gene expression and mutations were analyzed via whole-exome and RNA sequencing. RESULTS: The sensitivity to CX-4945 was determined by the inhibition rate (%) at the effective dose (10 MUM) which ranged from -1% to 89% in 49 gastric cancer cell lines. CK2alpha', but not CK2alpha, mRNA expression was correlated with CX-4945 sensitivity. CONCLUSION: In this study, CX-4945 showed modest antitumor efficacy in gastric cancer cell lines. CK2 might represent a potential therapeutic target for gastric cancer. PMID- 30396935 TI - Benzoxazole-based Zn(II) and Cu(II) Complexes Overcome Multidrug-resistance in Cancer. AB - BACKGROUND/AIM: Multidrug resistance (MDR) represents a significant impediment to successful cancer treatment. In this study, novel metal [Zn(II), Cu(II), Mg(II), Ni(II), Pd(II), and Ag(I)] complexes of 2-trifluoroacetonylbenzoxazole previously synthesized and characterized by our group were tested for their MDR-reversing activity in comparison with the free ligands in L5178Y mouse T-lymphoma (MDR) cells transfected with human ATP-binding cassette sub-family B member 1 (ABCB1; P glycoprotein) gene. MATERIALS AND METHODS: Cytotoxic and antiproliferative effects of the complexes were assessed by the thiazolyl blue tetrazolium bromide (MTT) method. Modulation of ABCB1 activity was measured by rhodamine 123 accumulation assay using flow cytometry. The apoptosis-inducing activity of some complexes was also tested on the multidrug resistant L5178Y mouse T-lymphoma cells, using the annexin-V/propidium iodide assay. RESULTS: When compared to the free ligand, a remarkable enhancement in MDR reversal and cytotoxic activity was found for the Zn(II) and Cu(II) complexes. The activity of the complexes proved to be up to 29- and 5-fold higher than that of the ligands and the ABCB1 inhibitor verapamil as positive control, respectively. The complexes possessed a remarkable potential to induce apoptosis of MDR cells. CONCLUSION: Our results suggest that the Zn(II) and Cu(II) complexes display significant MDR-reversing activity in a dose-dependent manner and possess strong cytotoxic activity and a remarkable potential to induce apoptosis in MDR L5178Y mouse T-lymphoma cells. PMID- 30396936 TI - Predicting Cytotoxicity of 2-Phenylindole Derivatives Against Breast Cancer Cells Using Index of Ideality of Correlation. AB - BACKGROUND: Breast cancer is one of the leading types of cancer in women worldwide. Quantitative structure-activity relationship (QSAR) methods play an important role in the search for new anticancer agents. A QSAR model for cytotoxicity against the breast cancer cell line MCF7, based on hybrid optimal descriptors, has been suggested. A modified version of the hybrid descriptor is suggested. MATERIALS AND METHODS: A QSAR model for the anticancer activity of 2 phenylindole derivatives was built using the Index of Ideality of Correlation (IIC), which is a new criterion for predictive potential. The calculation can be carried out with a modified version of the CORAL software. RESULTS: The model for the anticancer activity suggested here is better than the one described in the literature. CONCLUSION: Taking into account the data on molecular rings together with the use of new criterion of predictive potential (IIC), the QSAR improves the prediction for anticancer activity. PMID- 30396937 TI - Pharmacological Inhibition of Casein Kinase 2 Enhances the Effectiveness of PI3K Inhibition in Colon Cancer Cells. AB - BACKGROUND/AIM: Serine/threonine kinase B-Raf proto-oncogene (BRAF) mutant colon cancer has a poor prognosis and there is an absence of targeted treatments for this subtype. Here, we investigated the effects of inhibition of casein kinase 2 (CK2) on the inhibitory effects of BRAF and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibition in BRAF-mutant colon cancer cells. MATERIALS AND METHODS: Colon cancer cell lines with mutations in components of the mitogen activated protein kinase (MAPK) and PI3K signalling pathway were used. Cell viability was determined after exposure to single agent and combinations of erlotinib (EGFR inhibitor), dabrafenib (MEK inhibitor), GDC0941 (PI3K inhibitor) and CX4945 (CK2 inhibitor). Western blots were used to examine MAPK and AKT serine/threonine kinase (AKT) pathway activation. RESULTS: Addition of CX4945 to dabrafenib did not enhance the antiproliferative effects of single-agent dabrafenib. Use of GDC0941 alone was highly effective in controlling growth of both BRAF-mutant and wild-type cells and this effect was enhanced by CK2 inhibition. CONCLUSION: Inhibition of the PI3K/AKT pathway is central to regulating growth of colon cancer cells and this can be enhanced by CK2 inhibition. PMID- 30396938 TI - Chronic Sulforaphane Application Does Not Induce Resistance in Renal Cell Carcinoma Cells. AB - BACKGROUND/AIM: Since the natural compound sulforaphane (SFN) has been shown to stop tumor growth, renal cell carcinoma (RCC) patients often use this drug in addition to their prescribed oncotherapy. The aim of this study was to examine whether resistance to SFN may develop after long-term application. MATERIALS AND METHODS: Several RCC cell lines were incubated with SFN for short periods of time (24-72 h) or long periods of time (8 weeks) and cell growth, proliferation, and cell-cycle proteins were analyzed. RESULTS: Both short- and long-term application of SFN distinctly reduced RCC cell growth and proliferation. However, differences in the distribution of cells in each phase of the cell cycle and in the expression of cell-cycle proteins were apparent. Short-term treatment induced S phase arrest, whereas long-term treatment induced G0/G1-phase arrest. Expression of Cdk1 and Cdk2 increased over short-term incubation, but decreased long-term. Expression of pCdk2, Akt, and Raptor were reduced following long-term SFN exposure, but remained unchanged when SFN was applied for short periods of time. CONCLUSION: Chronic use of SFN did not evoke resistance, but differentially altered signaling pathways, compared to short-term use. PMID- 30396940 TI - Oolong Tea Extract Induces DNA Damage and Cleavage and Inhibits Breast Cancer Cell Growth and Tumorigenesis. AB - BACKGROUND/AIM: Breast cancer is the most prevalent and devastating malignant disease among women worldwide. Green tea has been extensively studied for its anti-cancer effects, however, existing literature on the correlation of other types of tea with breast cancer is very limited. MATERIALS AND METHODS: We used six different breast cancer cell lines (ER+, PR+ or HER2+ and triple-negative), treated under different concentrations of green, oolong, black and dark tea extracts, and determined their biological effects. RESULTS: We determined cell viability, observed the changes of cell morphology, measured DNA damage and cleavage, and analyzed the effect on soft agar colony formation and growth. CONCLUSION: Oolong tea, same as green tea, can induce DNA damage and cleavage, play an inhibitory role in breast cancer cell growth, proliferation and tumorigenesis, and was a great potential as a chemo-preventive agent against breast cancer. PMID- 30396939 TI - Suppression of Taxanes Cytotoxicity by Citrus Flavonoid Hesperetin in PPC-1 Human Prostate Cancer Cells. AB - BACKGROUND/AIM: More than half of prostate cancer patients use, in addition to conventional therapies, some kind of complementary medicine, including flavonoid rich products. However, knowledge about the co-effects of flavonoids with cytotoxic chemotherapies is still rather poor. Therefore, this study was undertaken to assess the cytotoxic activity of flavonoids and their interactions with taxanes in human advanced prostate cancer cells. MATERIALS AND METHODS: Cytotoxicity of different flavonoids and their effects on the efficacy of docetaxel and cabazitaxel were studied in the human metastatic prostate cancer cell line PPC-1, using MTT colorimetric assay. RESULTS: Both taxanes suppressed the viability of PPC-1 cells with IC50 values in the nanomolar range. Tested flavonoids exerted cytotoxic activity only at high micromolar concentrations or revealed no remarkable effect on cell survival. Simultaneous treatment of cells with taxanes and flavonoids baicalein, chrysin, luteolin, fisetin, quercetin, genistein or daidzein did not lead to any change in chemotherapy-induced cytotoxicity. However, simultaneous exposure of cells to hesperetin and taxanes resulted in 9.8- and 13.1-fold reduction in cytotoxicity of docetaxel and cabazitaxel, respectively. CONCLUSION: Flavonoid hesperetin remarkably suppressed the cytotoxic efficacy of taxanes in prostate cancer cells. Therefore, caution is required from prostate cancer patients who take hesperetin-containing oral supplements. PMID- 30396941 TI - Dclk1 Inhibition Cancels 5-FU-induced Cell-cycle Arrest and Decreases Cell Survival in Colorectal Cancer. AB - BACKGROUND/AIM: 5-Fluorouracil (5-FU) is frequently used in colorectal cancer treatment, but with limited success. The aim of the present study was to explore the cytotoxic effects of 5-FU, in combination with inhibition of doublecortin like kinase 1 (Dclk1), a tumor stem cell marker that regulates pro-survival signaling in colorectal cancer cells, in the human colon cancer cell line, COLO 320. MATERIALS AND METHODS: The effects of 5-FU treatment plus Dclk1 inhibition on the phosphorylation of checkpoint kinase 1 (Chk1), cell cycle, DNA damage, apoptosis, and cell survival in COLO-320 cells were evaluated. RESULTS: Combined treatment with 5-FU and a Dclk1 inhibitor, LRRK2-IN-1 (LRRK), decreased 5-FU induced phosphorylation of Chk1 and canceled 5-FU-induced cell-cycle arrest at the S phase. Combined treatment with 5-FU and LRRK failed to induce poly (ADP ribose) polymerase 1 (PARP-1) cleavage, but tended to decrease cell survival compared to individual treatment with 5-FU or LRRK. CONCLUSION: These results indicate that a combination of 5-FU and LRRK may be an effective, novel approach for colorectal cancer therapy. PMID- 30396942 TI - Piperlongumine Induces Apoptosis in Colorectal Cancer HCT 116 Cells Independent of Bax, p21 and p53 Status. AB - BACKGROUND/AIM: Colorectal cancer is a common type of cancer with reported resistance to treatment, in most cases due to loss of function of apoptotic and cell-cycle proteins. Piperlongumine (PPLGM) is a natural alkaloid isolated from Piper species, with promising anti-cancer properties. This study investigated whether PPLGM is able to induce cell death in colorectal carcinoma HCT 116 cells expressing wild-type or deficient in Bax, p21 or p53. MATERIALS AND METHODS: PPLGM was extracted from roots of Piper tuberculatum. Cell viability was determined by reduction of 3-(4,5-dimethilthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and clonogenic assay. Cell death was evaluated by acridine orange/ethidium bromide staining and flow cytometry. Plasmid cleavage activity and circular dichroism DNA interaction were also analyzed. RESULTS: PPLGM induced selective cell death in all cell lines (IC50 range from 10.7 to 13.9 MUM) with an increase in the number of late apoptotic cells and different profiles in cell cycle distribution. Plasmid DNA analysis showed that PPLGM does not interact directly with DNA. CONCLUSION: This paper suggests that PPLGM may be a promising candidate in colorectal cancer therapy. PMID- 30396943 TI - An Experimental Model of Breast Cancer Cells: Informative Protocol for In Vitro Culture. AB - BACKGROUND: Cryopreservation of ovarian tissue for patients with cancer comes with the concern for the existence of cancer cells in the grafts. Data about cancer cell viability after cryopreservation are currently lacking. For the experimental study of cryo-stability of cancer cells, different protocols of in vitro culture of various cell lines are used. The existing protocols are not able to mimic the effectiveness of in vivo/in situ development of cancer cells. This study aimed to test the new protocol for in vitro culture of breast cancer cells. MATERIALS AND METHODS: ZR-75-1 and MDA-MB-231 cells were in vitro-cultured in standard [RPMI 1640 and Dulbecco's modified Eagle's medium (DMEM), respectively] and experimental (AIM V) medium. Cell phenotypes were tested by CCK-8 cell proliferation measurement, wound-healing assay, transmembrane cell migration and invasion assay and immunofluorescent staining. A 10-day in vitro culture without cell passaging was conducted on both cell lines in culture medium to observe the generation of a cell layer as a model of solid tumor tissue. The density of the cell layers was revealed by immunofluorescent staining. RESULTS: AIM V significantly promoted continued proliferation of both cell lines. Cell motility of ZR-75-1 cells was increased considerably more in AIM V than in RPMI-1640. For MDA-MB-231 cells cultured in AIM V and DMEM, no significant differences in mobility and invasion were observed. Both cell lines maintained in AIM V medium generated a cell layer on day 7 and formed a compact structure on day 10 of in vitro culture. CONCLUSION: In vitro culture of ZR-75-1 and MDA-MB-231 cells in AIM V medium is more informative than culture in standard medium. The described protocol provides a means for the formation of compact structures from in vitro cultured cancer cells as a model of solid tumor tissue. PMID- 30396944 TI - Epigallocatechin-3-gallate Enhances Radiation Sensitivity in Colorectal Cancer Cells Through Nrf2 Activation and Autophagy. AB - BACKGROUND/AIM: Epigallocatechin-3-gallate (EGCG) is a major polyphenolic component of green tea. EGCG plays a potential role in radio-sensitizing cancer cells. The combined effect of EGCG and radiation was investigated in a colorectal cancer cell line, focusing on nuclear factor (erythroid-derived 2)-like 2 (Nrf2) autophagy signalling. MATERIALS AND METHODS: HCT-116 cells were treated with 12.5 MUM EGCG for different periods of time, 2 Gy radiation, or both. Cell viability was determined with the WST-8 assay. The number of colonies was determined with the colony formation assay. mRNA expression of LC3 and caspase-9 was analyzed with quantitative real-time polymerase chain reaction. RESULTS: Combination treatment with EGCG and radiation significantly decreased the growth of HCT-116 cells. The number of colonies was reduced to 34.2% compared to the control group. Immunofluorescence microscopy images showed that nuclear translocation of Nrf2 was significantly increased when cells were treated with the combination of EGCG and radiation compared to the control and single-treatment groups. Combined treatment with EGCG and radiation significantly induced LC3 and caspase-9 mRNA expression. CONCLUSION: EGCG increased the sensitivity of colorectal cancer cells to radiation by inhibiting cell proliferation and inducing Nrf2 nuclear translocation and autophagy. PMID- 30396945 TI - Coupling Dichloroacetate Treatment with Curcumin Significantly Enhances Anticancer Potential. AB - BACKGROUND/AIM: Dichloroacetate (DCA) and curcumin have been shown to be potent drug candidates in cancer therapy. Our study aimed to investigate the combined effects of DCA and essential oil-blended curcumin (ECUR) using the hepatoma Huh-7 cell model. MATERIALS AND METHODS: MuseTM Cell Cycle assay, MuseTM Annexin V & Dead Cell assay, MuseTM Oxidative Stress assay, and western blot analysis were applied to explore the underlying mechanisms. RESULTS: DCA combined with ECUR dramatically augmented inhibition of cell survival and enhanced apoptotic induction. The enhanced apoptosis was accompanied by mitochondria-dependent apoptotic signaling activation and corroborated with significant cellular morphological alternations. CONCLUSION: Apoptosis was the major event contributing to the synergistically boosted antiproliferative effect. Coupling DCA treatment with curcumin may rationally be expected to lower the DCA dose needed and relatively reduce accompanying toxicity and oxidative damage while enhancing anticancer potential. This novel 'add-on' approach is, thus, of enormous value to the current DCA therapy. PMID- 30396946 TI - The Antitumor Effects of Metformin on Gastric Cancer In Vitro and on Peritoneal Metastasis. AB - BACKGROUND/AIM: Gastric cancer (GC) with peritoneal metastasis remains difficult to treat. The anti-diabetic drug metformin exerts various antitumor effects via the 5'-adenosine monophosphate-activated protein kinase (AMPK) pathway and nuclear factor-kappa B (NF-KB). Therefore, we evaluated the antitumor effects of metformin for GC in vitro and on peritoneal metastasis. MATERIALS AND METHODS: The human GC cell lines MKN1, MKN45, KATO-III and SNU-1 were used. The antiproliferative effect was evaluated in vitro with 0.5 mM or 25 mM glucose and in vivo using tumor xenograft peritoneal models of metastasis. The protein expression of AMPK, liver kinase B1 (LKB1) and NF-KB in tumors was examined by western blotting. RESULTS: Metformin inhibited cell proliferation in all GC lines and sensitivity was increased under low-glucose conditions in vitro. Metformin also suppressed peritoneal metastasis. In tumors, metformin reduced the numbers of proliferating cells and NF-KB expression, but a similar trend was not noted for AMPK. CONCLUSION: Metformin may be a useful drug for the treatment of GC with peritoneal metastasis. PMID- 30396947 TI - Blocking Interleukin-6 and Interleukin-8 Signaling Inhibits Cell Viability, Colony-forming Activity, and Cell Migration in Human Triple-negative Breast Cancer and Pancreatic Cancer Cells. AB - BACKGROUND/AIM: Interleukin-6 (IL-6) and interleukin-8 (IL-8) play important roles in the progression of triple-negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDAC). This is the first experiment to combine small molecules targeting these two signaling pathways to treat TNBC and PDAC cells. MATERIALS AND METHODS: Cell viability, colony formation and cell migration assays were conducted when TNBC or PDAC cells were treated with bazedoxifene (targeting IL-6) or reparixin/SCH527123 (targeting IL-8) or their combination. RESULTS: The combined treatment had a more potent inhibition of cell viability, colony formation and cell migration than monotherapy in TNBC and PDAC cells. The results also showed that the combination of bazedoxifene with SCH527123 seemed to be more effective than that with reparixin in inhibiting cell viability and colony formation of TNBC. CONCLUSION: Novel drug combinations of bazedoxifene and reparixin, as well as bazedoxifene and SCH527123 may provide more effective treatments for TNBC and PDAC. PMID- 30396948 TI - Phoyunnanin E Induces Apoptosis of Non-small Cell Lung Cancer Cells via p53 Activation and Down-regulation of Survivin. AB - BACKGROUND/AIM: Lung cancer is by far the most common cause of cancer mortality, accounting for nearly 20% of all global cancer deaths. Therefore, potent and effective compounds for treatment of this cancer type are essential. Phoyunnanin E, isolated from Dendrobium venustum (Orchidaceae), has promising pharmacological activities; however, it is unknown if phoyunnanin E affects apoptosis of lung cancer cells. MATERIALS AND METHODS: The apoptosis-inducing activity of phoyunnanin E on H460 lung cancer cells was investigated by Hoechst 33342, and annexin V-fluorescein isothiocyanate/propidium iodide staining. The underlying mechanism was determined via monitoring apoptosis-regulatory proteins by western blot analysis. The apoptotic effect of the compound was confirmed in H23 lung cancer cells. RESULTS: Phoyunnanin E significantly induced apoptotic cell death of H460 lung cancer cells, as indicated by condensed and fragmented nuclei with the activation of caspase-3 and -9 and poly (ADP-ribose) polymerase cleavage. Phoyunnanin E mediated apoptosis via a p53-dependent pathway by increasing the accumulation of cellular p53 protein. As a consequence, anti-apoptotic proteins including induced myeloid leukemia cell differentiation protein (MCL1) and B-cell lymphoma 2 (BCL2) were found to be significantly depleted, while pro-apoptotic BCL-2-associated X protein (BAX) protein was up-regulated. Furthermore, it was found that expression of an inhibitor of apoptosis, survivin, markedly reduced in response to phoyunnanin E treatment. The apoptosis-inducting effect was also found in phoyunnanin E-treated H23 lung cancer cells. CONCLUSION: These results indicate the promising effect of phoyunnanin E in induction of apoptosis, that may be useful for the development of novel anticancer agents. PMID- 30396949 TI - Atypical Protein Kinase C lambda/iota Expression Is Associated with Malignancy of Oral Squamous Cell Carcinoma. AB - BACKGROUND/AIM: Atypical protein kinase C lambda/iota (aPKClambda/iota) is a cell polarity-regulator localized in the tight junction and apical membrane in epithelial cells. Previous studies suggested that aPKClambda/iota overexpression and abnormal localization were involved in tumor progression in several cancers. We investigated the relationship between aPKClambda/iota and oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: The correlation between the aPKClambda/iota expression and the clinicopathological parameters in 76 OSCC cases was examined using immunohistochemical analyses. RESULTS: aPKClambda/iota overexpression was observed in 36.8% of cases. aPKClambda/iota expression was more intense in poorly differentiated OSCC and younger patients (<60 years of age). Although expression of aPKClambda/iota was not significantly associated with clinical parameters, the correlation was found between aPKClambda/iota localization and progression-free survival. CONCLUSION: This is the first study to assess the association of aPKClambda/iota expression in OSCC with clinical results. Expression and localization of aPKClambda/iota may be involved in the degree of malignancy in OSCC. PMID- 30396950 TI - Hypoxia Stimulates the Epithelial-to-Mesenchymal Transition in Lung Cancer Cells Through Accumulation of Nuclear beta-Catenin. AB - BACKGROUND/AIM: Recent studies implied a significant role of hypoxia-inducible factor-1alpha (HIF1alpha) in cell transformation. This study aimed to assess the effects of HIF1alpha on the epithelial-to-mesenchymal transition (EMT) and tumorigenesis of lung adenocarcinoma cells. MATERIALS AND METHODS: Invasion, migration and colony formation assays were used to evaluate cell transformation. Expression of EMT-related markers were analyzed by western blot, reverse transcription polymerase chain reaction or zymography. A luciferase assay was carried out to access the transcriptional activity of beta-catenin. RESULTS: Hypoxia enhanced migration, invasion and transformation of A549 lung adenocarcinoma cells. Hypoxic stimulation promoted the expression of EMT-related markers in lung cancer cells. The expression of HIF1alpha was found to be involved in hypoxia-mediated modulation of expression of snail family transcriptional repressors 1 (SNAI1) and 2 (SLUG). Hypoxia enhanced nuclear accumulation and transcriptional activity of beta-catenin. CONCLUSION: beta Catenin promotes expression of EMT-related genes and eventually contributes to the metastatic process. PMID- 30396951 TI - MicroRNA-107 Targets IKBKG and Sensitizes A549 Cells to Parthenolide. AB - BACKGROUND/AIM: Patients with advanced non-small cell lung cancer (NSCLC) frequently face a dismal prognosis because of lack of curative therapies. We, therefore, conducted a preclinical investigation of the therapeutic efficacy of microRNA-107 (miR-107). MATERIALS AND METHODS: The effects of miR-107 on cell proliferation and target gene expression were studied. Combinatorial effects of miR-107 and parthenolide were evaluated. RESULTS: Cell proliferation was repressed in A549 NSCLC cells transfected with miR-107. Inhibitor of nuclear factor kappa B kinase subunit gamma was directly targeted by miR-107. Overexpression of miR-107 in A549 cells sensitized them to parthenolide along with a marked reduction of cyclin-dependent kinase 2. CONCLUSION: Our findings unveil an important biological function of miR-107 in regulating lung cancer cell proliferation and elevating an antiproliferative effect of parthenolide on lung cancer cells, suggesting that miR-107 could be beneficial benefit treatment for advanced NSCLC. PMID- 30396952 TI - Deregulation of the SRC Family Tyrosine Kinases in Gastric Carcinogenesis in Non human Primates. AB - BACKGROUND/AIM: The evolution of gastric carcinogenesis remains largely unknown, as the regulatory mechanisms involved in the aggressiveness of gastric cancer are still poorly understood. Kinases are downstream modulators and effectors of various cell signaling cascades and play key roles in the development of neoplastic diseases. The objective of this study was to evaluate the expression of genes and proteins of the SRC family, including FYN, YES, BLK, FGR, LYN and SRC, in a model of intestinal gastric carcinogenesis generated by treating Cebus apella, a New World non-human primate, with N-methyl nitrosourea (MNU). MATERIALS AND METHODS: mRNA expression of genes was measured by real-time reverse transcription quantitative PCR (RT-qPCR) and protein expression was measured by western blotting in six Cebus apella treated with N-methyl-nitrosourea (MNU) for about 2.5 years. RESULTS: Elevated mRNA and protein expression mainly of the SRC and LYN kinases was observed. Their expression was gradually increasing as non atrophic gastritis was evolving to gastric cancer. CONCLUSION: SRC family kinases play a key role in tumor progression and metastasis and may be a promising target for the treatment of gastric cancer. PMID- 30396953 TI - The Contribution of Interleukin-12 Genetic Variations to Taiwanese Lung Cancer. AB - BACKGROUND/AIM: Lung cancer is the leading cause of cancer-related death and a better marker for advanced personalized therapeutic approaches, such as immunotherapies, is in urgent need. Interleukin-12 (IL-12) is a cytokine that has been reported to exhibit potent tumoricidal effects, however, the contribution of IL-12 genotypes to lung cancer is still largely unrevealed. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in IL-12A and IL-12B are associated with lung cancer in a Taiwanese population. MATERIALS AND METHODS: Genotypes of 358 lung cancer patients and 716 controls were determined by the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The distributions of genotypic (p=0.0036) and allelic (p=0.0005) frequencies of IL-12A rs568408 demonstrated significant differences between cases and controls. In detail, the AA genotype of IL-12A rs568408 was associated with a significantly elevated risk of lung cancer compared with the GG genotype (odds ratio(OR)=2.41, 95% confidence interval(CI)=1.36-4.29, p=0.0021). No difference was observed regarding IL-12A rs2243115 and IL-12B rs3212227 genotypes between the case and control groups. In addition, the results of interaction analysis showed that the AA genotype of IL-12A rs568408 was associated with elevated lung cancer risk, especially among those with smoking habits (p=0.0043). CONCLUSION: IL-12A rs568404 AA genotype may contribute to the etiology and serve as a genomic determinant of lung cancer in Taiwanese, especially smokers. PMID- 30396955 TI - Expression Pattern of Cdkn2b and Its Regulators in Canine Mammary Tumors. AB - BACKGROUND/AIM: In female dogs, mammary cancer is the most frequent cancer type, accounting for 50% of all tumors affecting these animals. Amongst the commonly altered genes in cancer is the cell-cycle regulator cyclin-dependent kinase inhibitor 2B (Cdkn2b), whose expression is negatively regulated by protein products of BMI1 proto-oncogene (Bmi1), MYC proto-oncogene (Myc) and T-box gene transcription factor 2 (Tbx2) genes. Considering this, the aim of this study was to evaluate the expression pattern of the Cdkn2b gene and these regulators in canine mammary tumors of dogs from Northern Brazil (Belem, Para). MATERIAL AND METHODS: Gene expression in samples from 33 animals was assessed by real-time polymerase chain reaction. To check the influence of methylation on gene expression, bisulfite sequencing polymerase chain reaction was also performed. RESULTS: All studied genes, except Cdkn2b, were found at increased expression levels in tumor tissue when compared with control samples. No correlation between expression and methylation data was observed. CONCLUSION: Our results suggest these markers may have a diagnostic value in the veterinary clinic. PMID- 30396954 TI - GLI1 and CTNNB1 Knockdown Activates NOTCH and mTOR Signalling in NB4 Myeloid Leukaemia Cells. AB - BACKGROUND: Hedgehog (HH), WNT, NOTCH, and mechanistic target of rapamycin (mTOR) signalling pathways are known to regulate the progression of cancer; however, their interaction in leukaemia cells is not fully clarified. MATERIALS AND METHODS: Myeloid and T-lymphoblastic leukaemia cell lines (NB4, THP-1, Jurkat, and DND-41) were transfected with small interfering RNAs targeting the glioma associated oncogene homolog 1 (GLI1) and catenin beta-1 (CTNNB1) genes involved in the regulation of HH and WNT pathways, respectively, and we examined cell proliferation and gene expression. RESULTS: The knockdown of GLI1 and CTNNB1 did not significantly affect proliferation of any cell line; however, it up-regulated the expression of NOTCH1, cleaved NOTCH1 fragment, and phosphorylated mTOR in NB4 cells, but not in the other cell lines. CONCLUSION: Our data suggest that HH and WNT act upstream of NOTCH and mTOR pathways and negatively regulate them in myeloid NB4 cells. Further studies are required to determine the biological significance of this signalling crosstalk in leukaemia. PMID- 30396956 TI - Evodiamine Suppresses Survival, Proliferation, Migration and Epithelial Mesenchymal Transition of Thyroid Carcinoma Cells. AB - BACKGROUND/AIM: The aim of this study was to evaluate the effect of evodiamine alone or in combination with chemotherapeutic agents on thyroid carcinoma cells. MATERIALS AND METHODS: TPC-1 and SW1736 thyroid carcinoma cells were used. Cell viability, cytotoxic activity, apoptosis and migration were examined by applying appropriate methods. Drug combination analysis was performed. RESULTS: Evodiamine treatment of cells decreased cell viability, and Bcl2 and phospho-AKT protein levels. Cytotoxic activity and the percentage of apoptotic cells increased. After co-treatment of wortmannin, cell viability, and phospho-AKT and Bcl2 protein levels decreased, and cytotoxic activity increased. In transforming growth factor beta-treated cells, evodiamine attenuated variations in morphology, growth and migration, and increased p21 and p53 protein levels, and decreased beta-catenin, N-cadherin, vimentin, phospho-AKT, matrix metalloproteinase-2 and matrix metalloproteinase-9 protein levels. When cells were treated with both evodiamine and chemotherapeutic agents, all combination index values were lower than 1.0. CONCLUSION: Evodiamine was cytotoxic towards thyroid carcinoma cells, and repression of AKT reinforced evodiamine-induced cytotoxicity. Furthermore, evodiamine ameliorated proliferation, migration and epithelial-mesenchymal transition, and synergized with chemotherapeutic agents. PMID- 30396957 TI - Combined Hepatic Resection and Radio-frequency Ablation for Patients with Colorectal Cancer Liver Metastasis: A Viable Option for Patients with a Large Number of Tumors. AB - BACKGROUND/AIM: Radiofrequency ablation (RFA) is thought to result in inferior prognosis than hepatic resection among patients with colorectal liver metastasis (CRLM). However, resection plus RFA may be an option for patients with a large number of tumors (>=4 liver lesions) and borderline resectability. MATERIALS AND METHODS: A total of 717 patients with CRLM who underwent hepatic resection +/- RFA at two tertiary institutions between 09/01/2000-12/01/2015 were eligible for inclusion in this study. RESULTS: Among patients with <4 lesions (n=568), OS in the resection + RFA group (n=48) was significantly worse than in the resection alone group (n=520) (5-year OS: 34.4 % versus 58.9%, p=0.007). Conversely, in patients with >=4 lesions, OS in the resection + RFA (n=68) and resection alone(n=81) groups were not significantly different (5-year OS: 31.9% versus 34.1%, p=0.48). In patients with <4 lesions, carcinoembryonic antigen (CEA) >=30 ng/ml, extrahepatic metastasis, preoperative chemotherapy and resection + RFA were independently associated with poor prognosis. Interestingly, in patients with >=4 lesions, positive primary lymph nodes, KRAS mutation, CEA >=30 ng/ml and extrahepatic metastasis were independent predictors of poor prognosis; however, the combination of hepatic resection with RFA was not associated with worse survival (p=0.93). CONCLUSION: Although surgeons should always strive for R0 resection when feasible, combined resection and RFA may be a viable alternative for CRLM patients with a large number of tumors. PMID- 30396958 TI - Overexpression of the Pluripotent Stem Cell Marker Podocalyxin in Prostate Cancer. AB - BACKGROUND/AIM: Podocalyxin, a member of the CD34 family of cell surface sialomucins, is overexpressed in human embryonal carcinoma cell lines, as well as in several cancer types, and is associated with poor prognosis. Podocalyxin variants are associated with an increased risk and aggressiveness of prostate cancer. Herein podocalyxin protein expression in prostate cancer was characterized. MATERIALS AND METHODS: Expression of podocalyxin as well as of TRA 1-60 and TRA-1-81 antigens was assessed immunohistochemically in 84 radical prostatectomy specimens and in adjacent normal tissues. RESULTS: Podocalyxin expression and H-scores were considerably higher in prostate tumors compared to normal tissues. High TRA-1-60 and TRA-1-81 staining was detected, however, in a much smaller percentage of prostate tumors, while their expression and H-scores were low in normal tissues. Similar trends for all three proteins were observed in prostatic intraepithelial neoplasia. CONCLUSION: Overexpression of podocalyxin in prostate cancer renders the protein a putative immunohistochemical marker of prostate cancer that may contribute to stratification of patients for optimal treatment. PMID- 30396959 TI - Improvement of Dysgeusia by Polaprezinc, a Zinc-L-carnosine, in Outpatients Receiving Cancer Chemotherapy. AB - BACKGROUND/AIM: Dysgeusia is one of the adverse events frequently affecting patients undergoing cancer chemotherapy. Dysgeusia-induced anorexia could decrease patient's quality of life. The present study was designed to determine whether the zinc-containing compound polaprezinc improves chemotherapy-induced dysgeusia. PATIENTS AND METHODS: The incidence of grade 2 dysgeusia was assessed in 634 patients receiving cancer chemotherapy in outpatient settings during January 2013 and June 2017. Polaprezinc was administered to patients showing grade 2 dysgeusia and the effect was compared with that in patients subjected to follow-up observation. RESULTS: Grade 2 dysgeusia appeared in 80 patients (12.6%), in whom pancreatic cancer and treatment with fluoropyrimidines were significant risks for dysgeusia. Polaprezinc, when administered to patients with grade 2 dysgeusia, significantly shortened the duration of dysgeusia compared with that in the follow-up observation group. Subgroup analysis indicated that polaprezinc was less effective in patients with pancreatic cancer, those receiving gemcitabine, or those whose age was 65 year-old and over. CONCLUSION: Chemotherapy-induced dysgeusia occurred with high frequency in patients with pancreatic cancer or in those receiving fluoropyrimidines. Polaprezinc was highly effective in improving the symptom of dysgeusia, except for patients with pancreatic cancer, those receiving gemcitabine and the elderly. PMID- 30396960 TI - Underutilization of the CROSS Regimen Among US Radiation Oncologists: A National Survey of Practice Patterns. AB - AIM: To examine patterns of clinical practice in locally advanced esophageal cancer among US radiation oncologists after publication of the CROSS trial. MATERIALS AND METHODS: US radiation oncologists were surveyed on 13 questions pertaining to the management of esophageal cancer. Respondents' demographics and their clinical rationale were analyzed for statistical association with their treatment recommendations. RESULTS: Few respondents (15%) offered the CROSS regimen to patients considered suitable surgical candidates, while a near equivalent number (16%) prescribed between 41.4 and 50.4 Gy contingent upon radiation planning parameters. Among respondents who prescribed 50.4 Gy, 50% and 17% reported concurrent administration of carboplatin/paclitaxel and cisplatin/5 FU, respectively. Higher radiation doses, over 50.4 Gy, were utilized by 15% and 38% of respondents for borderline surgical candidates and candidates unfit for surgery, respectively. The majority of respondents believed that higher complete pathological response and R0 resection would be achieved, as well as higher toxicity conferred using 50.4 Gy instead of 41.4 Gy. A clinical trial comparing 41.4 Gy to 50.4 Gy with concurrent carboplatin/paclitaxel was supported by 76% of respondents. CONCLUSION: Despite results from the CROSS trial, the majority of responding US radiation oncologists do not offer 41.4 Gy with concurrent chemotherapy for surgically-fit patients with locally advanced esophageal cancer, believing that a higher dose will translate to improved response. PMID- 30396961 TI - Radiofrequency Ablation vs. Cryoablation for Localized Hepatocellular Carcinoma: A Propensity-matched Population Study. AB - BACKGROUND/AIM: To compare overall survival (OS) and liver cancer-specific survival (LCSS) of Surveillance, Epidemiology and End Results (SEER) hepatocellular carcinoma (HCC) database patients treated with cryoablation (cryo) or radiofrequency ablation (RFA). MATERIALS AND METHODS: This was a retrospective review of Stage I or II HCC patients from the SEER database treated with cryo and RFA from 2004-2013. Kaplan-Meier and Cox regressions were performed on pooled and propensity-matched cohort. RESULTS: Out of 3,239 patients, RFA showed a significant survival advantage over cryo in liver cancer specific survival (LCSS) (HR=1.634 p=0.0004). A total of 91 propensity-matched pairs had similar OS (HR=1.006 p=0.9768), but no difference in LCSS was observed between the groups [HR=1.412 (95%CI=0.933-2.137) p=0.1023]. Survival Cox models did not reveal treatment type as an independent prognostic factor. CONCLUSION: Propensity matched cohort showed no significant difference in terms of OS and LCSS was found for patients treated with either cryo or RFA for localized HCC. PMID- 30396962 TI - Cancer Patients in the Emergency Department: A "Nightmare" that Might Become a Virtuous Clinical Pathway. AB - BACKGROUND/AIM: Emergency departments (EDs) often face overcrowding issues while simultaneously confronting with the increasing clinical needs of patients, such as cancer patients, with both acute and chronic illnesses. In order to guarantee a prompt and specialized treatment of ED-attending cancer patients and reduce inappropriate inpatient admissions, a dedicated ED cancer pathway (EDCP) consisting of ED-bound Medical Oncology (MO) resident doctor and direct admission for candidate patients exclusively to the MO division was established at the Tor Vergata University Hospital in April 2015. PATIENTS AND METHODS: Consecutive cancer patients attending the ED in two reference three-month periods were enrolled: pre-EDCP period, from 1st October 2014 to 31st December 2014, and post EDCP period, from 1st October 2014 to 31st December 2015. Inpatient admission rate, mortality rate and both ED and inpatient length of stay were compared between the two analyzed periods, pre- and post-EDCP. RESULTS: In the pre- and post-EDCP periods 127 and 123 cancer patients, respectively, were included. Most of the analyzed indicators were improved by EDCP implementation: Inpatient admission rate from 70% to 41% (p<0.0001), ED mortality rate from 10-4% (p=0.04), mean ED length of stay, from 58 to 42 h (p=0.03), mean inpatient length of stay, from 15.5 to 6.5 days (p<0.0001), in the pre- and post-EDCp period, respectively. CONCLUSION: EDCP implementation led to a significant improvement of health care delivery to cancer patients attending the Emergency Department. PMID- 30396963 TI - Long-term Survival of Stage IV Melanoma Patients Treated with BOLD Combination Chemotherapy and Intermediate-dose Subcutaneous Interferon-alpha. AB - BACKGROUND: Immune checkpoint and serine/threonine-protein kinase inhibitors have become a standard of care for advanced cutaneous melanoma, but dacarbazine-based chemotherapies are occasionally used. This study assessed the long-term efficacy of chemoimmunotherapy (bleomycin, vincristine, lomustine and dacarbazine with/without subcutaneous interferon-alpha: BOLD-INF-alpha) as real-world data in patients with metastatic melanoma not eligible for clinical trials. PATIENTS AND METHODS: Medical data of 146 patients with stage IV melanoma who had received BOLD/BOLD-INFalpha regimen during 1991-2010 were analyzed. RESULTS: The median overall survival was 8.9 months (95% confidence intervaI=7.5-10.4 months). The 1 year survival rate was 36%, 2-year 18%, and 5-year 13%. The 5-year survival rates in the M1a, M1b and M1c subgroups were 28%, 10% and 6%, respectively. Overall, 7% (n=11) of the patients were alive at the end of the follow-up. CONCLUSION: Our study showed similar overall survival among patients with stage IV cutaneous melanoma treated with BOLD/BOLD-INFalpha as noted previously with chemotherapy. PMID- 30396965 TI - Whole-brain Radiation Therapy for Breast Cancer Patients with Dural Metastasis Without Concomitant Brain Metastasis and Leptomeningeal Metastasis. AB - AIM: To evaluate outcomes of breast cancer patients with confirmed dural metastasis (DM) alone who received whole-brain radiation therapy (WBRT). PATIENTS AND METHODS: The medical records of thirty-three breast cancer patients who received WBRT to treat intracranial metastasis were retrospectively reviewed. The clinical presentation of DM-only was compared with that of brain metastasis (BM)/leptomeningeal metastasis (LM). RESULTS: Eight patients had DM and 25 patients had BM/LM. Median survival was 12 months in patients with DM and 7 months in those with BM/LM. Multivariate analysis found that only a Karnofsky performance status of >=70 was significantly associated with improved OS. DM did not cause the death of any patient. Symptoms did not worsen in any DM patient. CONCLUSION: WBRT can be considered for patients with DM alone for symptom improvement and preventing DM-related death. PMID- 30396964 TI - Patients with hMLH1 or/and hMSH2-deficient Metastatic Colorectal Cancer Are Associated with Reduced Levels of Vascular Endothelial Growth Factor-1 Expression and Higher Response Rate to Irinotecan-based Regimen. AB - BACKGROUND/AIM: The benefit of IFL (irinotecan, fluorouracil and leucovorin) regimen for metastatic colorectal cancer patients (mCRCs) with high levels of microsatellite instability (MSI-H) or loss of mismatch repair (dMMR) protein expression, is uncertain. This study investigated the association of tumour MMR status and VEGF-1 expression with response to first-line IFL regimen in mCRCs. PATIENTS AND METHODS: This prospective study analyzed patients diagnosed with mCRC between August 1st, 1998, and August 30th, 2003, at the Turku University Hospital, Finland. All patients received postoperative IFL regimen. Tumour expression of the MMR proteins, hMLH1 and hMSH2, and VEGF-1 expression were assessed by immunohistochemistry (IHC). Tumours with dMMR were those demonstrating loss of MMR protein expression, and tumours with high VEGF-1 expression were those showing moderate or strong cytoplasmic staining. The primary endpoint was the association between tumour hMLH1 or/and hMSH2-deficient and VEGF-1 expression; the relation between tumour MMR-status and IFL response rate was the secondary endpoint. RESULTS: Of the 67 mCRCs patients, 29 (43%) were hMLH1 or/and hMSH2-deficient and 15 (22%) were pMMR mCRCs. At diagnosis, patients with hMLH1 or/and hMSH2-deficient tumours expressed lower levels of VEGF-1 compared to pMMR tumour patients (p=0.01). More than half (n=17, 59%) of those with dMMR were chemosensitive to first-line IFL regimen, while just one-fifth (n=3, 20%) of those with pMMR were chemosensitive to the IFL regimen (p=0.045). CONCLUSION: Association between MMR-status and VEGF-1 expression predicts clinical outcome in mCRC patients. PMID- 30396966 TI - Sunitinib Treatment Modification in First-Line Metastatic Renal Cell Carcinoma: Analysis of the STAR-TOR Registry. AB - BACKGROUND/AIM: Sunitinib is the current standard of care for first-line (1L) treatment of metastatic renal cell carcinoma (mRCC). Previous studies suggest that a modified treatment schedule may benefit patients. Our aim was to evaluate efficacy and safety regarding sunitinib treatment modification in 1L treatment of mRCC. MATERIALS AND METHODS: Data were drawn from STAR-TOR, a German real-world registry to evaluate outcomes of patients with mRCC who received 1L sunitinib. Patients were divided into two groups: subsequent treatment modification (SM) or remaining on standard dose/schedule (SS). Time on treatment (TT), progression free survival (PFS), and overall survival (OS) were estimated. RESULTS: Overall, 297 patients were analyzed; 33% underwent treatment modification. Significant baseline differences between groups were observed; SM patients were older and had a more favourable Karnofsky performance status. SM patients achieved better outcomes than SS patients for median TT (15.1 versus 3.9 months; p<0.0001), PFS (15.1 versus 6.0; p<0.0001), and OS (38.1 versus 13.7; p<0.0001). Diarrhoea (34%/17%), fatigue (30%/11%), hand-foot syndrome (28%/10%), and stomatitis (20%/6%) were more frequently reported in SM versus SS; incidence was reduced following schedule/dose modification (except diarrhoea). CONCLUSION: In addition to AE mitigation, sunitinib treatment modification may help improve efficacy outcomes in mRCC by prolonging treatment duration. PMID- 30396967 TI - Hairy Cell Leukemia: Retrospective Analysis of Demographic Data and Outcome of 203 Patients from 12 Medical Centers in Israel. AB - BACKGROUND/AIM: In this retrospective study, we summarized the national Israeli experience with hairy cell leukemia (HCL) in a large cohort of patients with a long follow-up. PATIENTS AND METHODS: Demographic data, and relevant laboratory and clinical parameters were analyzed, emphasizing the outcome after first-line treatment with cladribine. RESULTS: Data on 203 patients was collected from 12 medical centers during 1985-2015. Mean and median follow-up were 7.5 years and 5.18 years (interquartile range=0.1-40 years), and 5- and 10-year survival were 96% and 90.62%, respectively. The median age of diagnosis was 55.5 years for Jews and 49 years for Arabs (p=0.021), and most patients were males (81.77%); 52.2% were Ashkenazi Jews, 36.1% Sephardic Jews and 11.7% were Arab, Druze or other ethnicity. Cladribine was given to 159 patients (80.7%%) and most (62%) received intravenous (i.v.) and 38% received subcutaneous (s.c.) therapy. Overall survival and time to next treatment were not significantly different between the two schedules (i.v., s.c.). In univariate analysis of a variety of factors, only age >65 years had a negative impact on outcome, with shorter overall survival. It is of interest that Arab patients with HCL were diagnosed at an earlier age, but had a similar clinical course and outcome to both Ashkenazi and Sephardic Jews. PMID- 30396968 TI - The Issue of Survival After Colorectal Liver Metastasis Surgery: Parenchyma Sparing vs. Radicality. AB - BACKGROUND/AIM: Nowadays, obtaining optimal surgical margin of the resected metastasis and the parenchyma- sparing surgical technique are a great challenge for hepatic surgeons. The aim of this follow-up study was to investigate the prognostic value of the surgical margin and the parenchyma- sparing liver resection technique. PATIENTS AND METHODS: We performed a retrospective analysis of the data of 319 patients [123 (36.6%) female and 196 (61.4%) male] who had colorectal cancer and underwent surgery to treat colorectal liver metastases in our Department between 2005 and 2014. RESULTS: The most commonly used resection type was the non-anatomic resection (43%). Multivariate analysis indicated that there was no significant difference in survival (p=0.473) between the microscopically-negative (R0) and microscopically-positive (R1) resections, as well as between the resection types (p=0.257). CONCLUSION: Parenchymal-sparing non-anatomic resection and spray diathermy on the resection surface of the liver should be applied not only for hemostasis, but also to destroy the area containing possible tumor cells after an R1 resection and not to have worse survival outcomes. PMID- 30396969 TI - Atypical Femoral Fractures (AFF) from Bone Remodeling Agents in Patients with Cancer. AB - Anti-resorptive drugs like bisphosphonates (BP) and denosumab are widely used for prevention and treatment of skeletal diseases, such as osteoporosis and bone metastases and mainly work through the prevention of osteoclast-mediated bones resorption. BP can lead to atypical femoral fractures (AFF) that is a rare, easily misdiagnosed treatment-related complication with great impact on the quality of life of patients. We present a concise review of the literature on BP related AFF based on the cases of 3 breast cancer patients that reflect the diagnostic pitfall of this rare entity. In conclusion, breast cancer patients very often are exposed to BP use and are at risk of developing AFF. PMID- 30396970 TI - Novel Extracorporeal Hemoperfusion System for Hepatic Arterial Infusion of Cisplatin. AB - BACKGROUND/AIM: Hepatic venous isolation and extracorporeal charcoal hemoperfusion (HVI-CHP) can reduce systemic exposure to hepatic arterial infusion (HAI) chemotherapy. The pre-existing HVI-CHP system has limited effectiveness against high-dose cisplatin; therefore, we designed a new system and evaluated its efficacy in a canine model. MATERIALS AND METHODS: Cisplatin was administered via HAI under HVI-CHP. HVI-CHP was performed using one charcoal column in group I and two charcoal columns in group II; it was not performed in group III. The plasma cisplatin levels in the systemic circulation and at the column inlet and outlet, and the column extraction rate of were analyzed. RESULTS: The column extraction rates of free and total cisplatin in group II were significantly higher than those in group I. The systemic concentration of free cisplatin was significantly lower in group II than in groups I and III after HAI. No significant differences were observed in cisplatin concentrations in the liver tissue among all groups. CONCLUSION: A novel HVI-CHP system for HAI of cisplatin was successfully developed. PMID- 30396971 TI - Salvage Carbon-ion Radiotherapy for Isolated Lymph Node Recurrence Following Curative Resection of Esophageal Cancer. AB - AIM: Evaluation of the therapeutic efficacy of carbon-ion radiation therapy for isolated lymph node recurrence following curative resection of esophageal cancer. MATERIALS AND METHODS: Ten cases with lymph node recurrence after esophageal cancer surgery were treated with carbon-ion radiation therapy. A total of 48.0 Gy [relative biologic effectiveness (RBE)] was delivered over 3 weeks with a daily dose of 4.0 Gy (RBE). RESULTS: The median follow-up duration was 27.1 months (range=3-92.0 months) after carbon-ion radiation therapy. The local control rates at 2, 3 and 5 years were 92.4%. The overall survival rates at 2, 3 and 5 years were 70.0%, 58.3% and 21.9%. The median survival period was 45.3 months after carbon-ion radiation therapy. There were no toxicities of grade 3 or higher. CONCLUSION: Carbon-ion radiation therapy may be a safe and effective treatment option for isolated lymph node recurrence after radical surgery for esophageal cancer. PMID- 30396972 TI - Geo-location of Oncological Diseases in the Extra-urban Areas of Naples and Creation of Territorial Biobanks: An Important Tool to Study Potential Connections Between Environmental Factors and Cancer. AB - Many areas of the Campania region of Italy are more frequently at risk of neoplastic diseases due to environmental factors. However, the results of epidemiological studies, although numerous and detailed, do not explain tumor pathogenesis mechanisms in relation to the contribution of exposure to environmental pollutants. The Oncological Biobank of the G. Pascale Foundation (BBI) centralizes the collection and storage of biomaterials, both healthy and pathological human tissues, from urban and extra-urban areas of Naples, associating them with clinicopathological characteristics (type of tumor, histological type, grading, immunohistochemical and molecular profile, etc.). Geo location of tumor samples is made by an IT platform in which demographic and clinical data are systematically uploaded. For the extra-urban areas of Naples, our experience of tumor sample geolocation highlighted cancer types with high impact of environmental pollutants as being lung, gastric and bladder cancer. In this mini-review, we underline that the possibility of specifically selecting tumor samples in circumscribed territories may allow targeted studies to verify potential connections between environmental factors and cancer. Moreover, the collection of biological fluids (serum, saliva, urine) from healthy individuals from specific areas may be a useful tool for the research of specific genetic polymorphisms linked to individual susceptibility. PMID- 30396973 TI - Impact of Osteopenia in Liver Cirrhosis: Special Reference to Standard Bone Mineral Density with Age. AB - BACKGROUND/AIM: Computed tomography (CT) has recently been applied to measure bone mineral density (BMD). However, the definition of osteopenia, which means depletion of BMD, using CT remains controversial. The aim of this study was to establish formulae to calculate standard BMD. PATIENTS AND METHODS: Fifty healthy donors for liver transplantation underwent CT. BMD was measured as cross sectional average pixel density (Hounsfield units) only in trabecular-bone at Th11 bottom. Validation was performed on another 50 healthy donors to check the accuracy of formulae for standard BMD. RESULTS: Measured BMD was significantly correlated with age in both males and females (p<0.0001). The formulae to calculate standard BMD were 308.82-2.49 * Age in males and 311.84-2.41 * Age in females. Estimated BMD was significantly correlated with measured BMD in males and females (p<0.0001). CONCLUSION: Osteopenia can be defined by the difference between measured data and calculated data using our new formula based on each age. PMID- 30396974 TI - Prognostic Significance of Conversion Surgery Following First- or Second-line Chemotherapy for Unresectable Gastric Cancer. AB - BACKGROUND/AIM: Advances in chemotherapy for gastric cancer have encouraged surgeons to perform conversion surgery following a response to first-line chemotherapy in patients with initially unresectable gastric cancer. In this study we evaluated the efficacy of conversion surgery following first- or second line chemotherapy for unresectable gastric cancer. PATIENTS AND METHODS: We retrospectively analyzed clinicopathological and survival data of 94 patients with unresectable gastric cancer treated with first- (n=94) or second-line (n=43) chemotherapy. RESULTS: Patients who converted to surgery following first- (n=26) or second-line (n=5) chemotherapy had significantly longer survival times than those treated with chemotherapy alone (n=63) (p<0.01). Survival length did not differ significantly between patients converted to surgery following first- and second-line chemotherapy. Among 31 patients who underwent conversion surgery, one initial non-curative factor (odds ratio(OR)=0.49; 95% confidence interval (95%CI)=0.22-0.95; p=0.03) was the only significant independent predictor of longer survival in multivariate Cox regression analysis. CONCLUSION: Patients with unresectable gastric cancer initially exhibiting one noncurative factor may obtain survival benefit from conversion surgery after a response to both first- and second-line chemotherapy. PMID- 30396975 TI - Plasma Catalase in Relation to Pain Following Midline Laparotomy: A Prospective Study of Patients with Benign Diseases and Patients with Cancer. AB - BACKGROUND/AIM: The relationship of plasma concentrations of the oxidative stress biomarker catalase with pain on numeric rating scale at rest (NRSr) and under wound pressure 24 hours postoperatively (NRSp) in midline laparotomy patients with rectus sheath block (RSB) analgesia are unknown. Our original hypothesis was that RSB analgesia might reduce postoperative pain. PATIENTS AND METHODS: Initially, 56 patients were randomized to four groups: control group (n=12), single-dose (n=16), repeated-dose (n=12) and continuous infusion (n=16) RSB analgesia groups. The plasma concentrations of catalase were measured immediately before, immediately after and 24 hours after surgery. The pain at rest and under pressure were scored on an 11-point numeric rating scale 24 hours postoperatively (NRSr and NRSp; 0: no pain; 10: worst pain). RESULTS: The median plasma concentration of catalase increased immediately after surgery (p=0.007), but then decreased 24 hours postoperatively compared with immediately after surgery (p<0.001). The control group and the RSB groups did not differ in individual NRSr and NRSp values following surgery. Scatter plots of the plasma catalase versus superoxide dismutase concentrations were positively correlated in the patients (r=0.314, p<0.001). In addition, scatter plots of the individual NRSr and NRSp values versus plasma values of catalase were inversely correlated in patients (r= 0.221, p=0.03 and r=-0.238, p=0.02, respectively). CONCLUSION: The RSB analgesia does not reduce postoperative pain. Plasma catalase levels and pain following surgery are significantly correlated in patients regardless of disease type. PMID- 30396976 TI - Primary Tumor Size Predicts Distant Metastasis of Mucosal Malignant Melanoma in Head and Neck. AB - BACKGROUND/AIM: To investigate the possible association between primary tumor size and overall survival and/or distant metastasis-free survival of patients with mucosal malignant melanoma of the head and neck. PATIENTS AND METHODS: A total of 25 patients that have had primary tumor resection were enrolled in this study. Primary tumor size was assessed as the maximum size of the primary tumor in pathological and surgical reports. RESULTS: Patients with a primary tumor size of >=43 mm showed a significant association with shorter overall survival (p=0.007) and distant metastasis-free survival (p=0.005) by the log-rank test. Multivariate survival analyses of two Cox's hazards proportional models showed that, in model1, pT4a-4b (p=0.01) and primary tumor size >=43 mm (p=0.03) were significantly associated with shorter overall survival, and primary tumor size >=43 mm (p=0.02) was significantly associated with shorter distant metastasis free survival. In model2, pStage IVA-IVB (p=0.02) and primary tumor size >=43 mm (p=0.03) were significantly associated with shorter overall survival, and primary tumor size >=43 mm (p=0.02) was significantly associated with shorter distant metastasis-free survival. CONCLUSION: Large tumor size (>=43 mm) is a predictor of shorter overall survival and distant metastasis-free survival after primary tumor resection of mucosal malignant melanoma of the head and neck. PMID- 30396977 TI - C-Reactive Protein-based Prognostic Measures Are Superior at Predicting Survival Compared with Peripheral Blood Cell Count-based Ones in Patients After Curative Resection for Pancreatic Cancer. AB - AIM: Prognostic factors of recurrence and survival in various cancer types have been reported and include C-reactive protein (CRP)-based measures as evidenced by the Glasgow prognostic score (GPS), as well as peripheral blood cell-based prognostic values such as the prognostic index (PI), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR). The aim of this study was to identify significant prognostic values and compare them for suitability for use in patients after curative pancreatic resection for pancreatic cancer. MATERIALS AND METHODS: Between 2000 and 2015, 188 patients were enrolled in this retrospective study. The relationship between clinicopathological variables including various prognostic values and disease-free (DFS) and overall (OS) survival was investigated by univariate analysis. The area under the receiver operating characteristics curve (AUC) was evaluated to compare the predictive ability of each of these scoring systems. Multivariate analysis was then performed to identify clinicopathological variables that associated DFS and OS. RESULTS: In univariate analysis, GPS, modified GPS, CRP to albumin ratio and PI were significant risk factors for both DFS and OS. The AUC of CRP-based scores (GPS, modified GPS, and CRP to albumin ratio) were consistently larger in comparison with PI, which consists of both CRP and peripheral blood cell scores, at all time points for both DFS and OS. In multivariate analysis, GPS was the only independent risk factor of tumor recurrence and survival. CONCLUSION: CRP based prognostic scores have an independent value for both tumor recurrence and prognosis in patients after curative resection for pancreatic cancer, and are superior to other peripheral blood cell count-based prognostic scores. PMID- 30396978 TI - Morphologic Response and Tumor Shrinkage as Early Predictive Markers in Unresectable Colorectal Liver Metastases. AB - BACKGROUND/AIM: Anti-EGFR antibodies or bevacizumab comprise first-line treatment for patients with RAS wild-type colorectal liver metastases (CLM). Which marker better predicts efficacy, early tumor shrinkage or morphologic response, still remains unclear. PATIENTS AND METHODS: We retrospectively evaluated 155 patients with KRAS exon 2 wild-type CLM treated with bevacizumab (BEV group) or anti-EGFR antibodies (EGFR group). Three radiologists independently assessed early tumor shrinkage (ETS) and early optimal morphologic response (EOMR) from baseline and first follow-up CT scan. RESULTS: Patients with ETS had longer progression-free survival (PFS) than those without ETS [hazard ratio (HR)=0.69] and ETS tended to be observed in the EGFR group, while patients with EOMR had longer PFS than those without EOMR (HR=0.64) and EOMR tended to be observed in the BEV group. CONCLUSION: Among patients with KRAS exon 2 wild-type CLM, EOMR and ETS may predict better PFS, especially in patients treated with bevacizumab and anti-EGFR antibodies, respectively. PMID- 30396979 TI - Comparison of Primary Tumor Size in Stage I and III Epithelial Ovarian Cancer. AB - BACKGROUND: Two studies have found primary ovarian carcinomas in stage I disease to be larger than those in stage III. Thus, these stages may represent different tumor entities. MATERIALS AND METHODS: The clinical data from 553 patients operated on between 1985 and 2012 for epithelial ovarian cancer were retrospectively analyzed. RESULTS: Primary lesions including invasive, borderline and benign components were significantly larger in stage I compared to stage III disease (p<0.001). However, the maximum diameter of invasive components in those with stage III disease were significantly larger than in those with stage I disease (p=0.001). The size of the invasive component was not associated with the largest size of intraperitoneal metastasis. CONCLUSION: We were only, in part, able to reproduce the data from the two smaller published studies. The prognosis of patients with stage III disease strongly depends on the size of intraperitoneal metastases. PMID- 30396980 TI - Relationship Between Postoperative CRP and Prognosis in Thoracic Esophageal Squamous Cell Carcinoma. AB - BACKGROUND/AIM: Few studies have examined postoperative CRP in esophageal cancer. We investigated the relationship between postoperative CRP values according to the postoperative period and prognosis in esophageal cancer. PATIENTS AND METHODS: We performed a retrospective cohort study including 187 patients who underwent esophagectomy for esophageal squamous cell carcinoma (ESCC) between January 2008 and October 2016. RESULTS: CRP within 1 month of surgery was not related to overall survival (OS) or recurrence-free survival (RFS). In a univariate analysis, postoperative 2 months (2M)-CRP >=0.15 ml/dl was associated with poorer OS (41.4 vs. 71.4%, p=0.0002) and RFS (28.9 vs. 51.3%, p=0.007). In a multivariate analysis, 2M-CRP >=0.15 ml/dl was an independent factor for poorer OS (HR=2.27, 95%CI=1.03-3.34, p=0.005) and RFS (HR=1.65, 95%CI=1.08-2.52, p=0.020). The incidence of postoperative pneumonia was significantly higher in the 2M-CRP >=0.15 ml/dl group (p=0.026). CONCLUSION: 2M-CRP >=0.15 ml/dl is an independent prognostic factor for ESCC. Furthermore, postoperative pneumonia may be associated with patient prognosis after esophagectomy. PMID- 30396981 TI - The Potential Use of a Ketogenic Diet in Pancreatobiliary Cancer Patients After Pancreatectomy. AB - BACKGROUND/AIM: High-carbohydrate diets are generally provided to post pancreatectomy cancer patients. Low energy density of this diet may obstruct proper energy intake and recovery. This study aimed to assess the effects of high fat, high-energy ketogenic diet (KD) in these patients. PATIENTS AND METHODS: After pancreatectomy, 9 patients were provided with general diet (GD) while 10 were served KD. Meal compliance, energy intake rate, meal satisfaction and presence of complications were monitored throughout hospital stay. Data on nutritional status, serum lipids and body composition were collected and compared between groups. RESULTS: Meal compliance, energy intake rate and meal satisfaction score were higher in KD. There were no differences in complications, nutritional status and serum lipids. The decrease in body cell mass (BCM) was greater in GD. CONCLUSION: Post-pancreatectomy cancer patients who consumed KD had a higher energy intake and BCM. These results suggest the potential use of KD as an adjuvant anti-cancer therapy. PMID- 30396982 TI - Aggressive Cancer Behavior of Latent Gleason Pattern 5 in Prostatectomy Specimens. AB - BACKGROUND/AIM: The aim of this study was to demonstrate the clinical significance of latent Gleason pattern (GP) 5 occasionally found in prostatectomy specimens. MATERIALS AND METHODS: Patients (n=605) undergoing radical prostatectomy were classified into three groups according to the presence of GP5 in the biopsy or in the prostatectomy specimens: 'GP5 negative', absence of GP in both specimens 'latent GP5', absence of GP5 in the biopsy specimen, but presense of GP5 in the prostatectomy specimen, and 'GP5 positive', presense of GP in both specimens. The characteristics of these three groups were analyzed. RESULTS: There were 381 men in the GP5-negative group, 155 in the latent GP5 group, and 69 in the GP5-positive group. Low- or intermediate-risk for prostate cancer, latent GP5 and surgical margin positivity were independent predictors of biochemical recurrence (Hazard ratio (HR): 3.1, 5.8, respectively, p=0.001, 0.0002, respectively). CONCLUSION: Latent GP5 is an important prognostic factor that should be evaluated in patients with low- and intermediate-risk for prostate cancer before the initiation of treatment. PMID- 30396983 TI - Feasibility of Combination Therapy with Nab-paclitaxel Plus Gemcitabine in Patients with Recurrent Pancreatic Cancer. AB - BACKGROUND/AIM: Nab-paclitaxel plus gemcitabine (nab-P+Gem) is one of most reliable and effective regimens for borderline or unresectable pancreatic cancer (PC). However, the feasibility and clinical benefits of this regimen have never been evaluated for patients with recurrent PC after pancreatectomy. The aim of this study was to investigate the feasibility of combination therapy with nab paclitaxel plus gemcitabine (nab-P+Gem) for patients with recurrent PC. PATIENTS AND METHODS: Twenty-two patients with recurrent PC received an intravenous infusion of nab-P (125 mg/m2) and Gem (1,000 mg/m2) on days 1, 8, and 15 of a 4 week cycle. The primary end-point of this study was completion of the 4 cycles. The secondary end-points were the safety, efficacy, and disease control rate. RESULTS: The treatment completion rate of the 4 cycles was 90.9%. The objective response rate was 13.6% and the disease control rate was 63.6%. The median progression-free survival was 7.2 months. The most common grade 3 or higher hematological toxicity was neutropenia (72.7%). There was no treatment-related death. Furthermore, the chemotherapeutic effects varied with the time of recurrence. CONCLUSION: Combination nab-P+Gem therapy was well-tolerated and effective in patients with recurrent PC. PMID- 30396984 TI - Negative Impact of Coexisting Interstitial Lung Disease on Clinical Outcomes in Small-cell Lung Cancer Patients. AB - BACKGROUND/AIM: The impact of interstitial lung disease (ILD) on the clinical outcome of patients with small-cell lung cancer (SCLC) is not fully understood. The aim of this study was to investigate the impact of ILD on treatment and survival outcomes of SCLC patients. PATIENTS AND METHODS: A retrospective analysis was performed on the clinical outcomes of SCLC patients, treated with chemotherapy, with or without ILD ([ILD group (n=16) and non-ILD group (n=51)]. RESULTS: Median PFS and OS were significantly shorter in the ILD group than in the non-ILD group (median PFS, 184 vs. 290 days, p=0.008; median OS, 236 vs. 691 days, p<0.001). Multivariate analysis revealed that coexisting ILD was an independent predictive factor of PFS (hazard ratio [HR]=2.06; 95% confidence interval [CI]=1.01-4.18; p=0.046) and OS (HR=3.29; 95%CI=1.53-7.08; p=0.002). CONCLUSION: Coexisting ILD might be a negative predictive factor of PFS and OS of SCLC patients treated with chemotherapy. PMID- 30396985 TI - HSP27, ALDH6A1 and Prohibitin Act as a Trio-biomarker to Predict Survival in Late Metastatic Prostate Cancer. AB - BACKGROUND/AIM: The aim of this study was to evaluate the usefulness of biomarkers related to prostate cancer metastasis and survival of patients. MATERIALS AND METHODS: Proteomics were used for detecting significant differences in protein expression among normal prostate, localized prostate cancer and metastatic cancer using 2-dimensional gel electrophoresis and mass spectrometry. mRNA expression was then examined in order to further confirm significant differences in protein expression. A total of 7 proteins were found to be differentially expressed. Immunochemistry (IHC), was also used to confirm the levels of expression of the 7 proteins in prostate cancer. Survival analysis using the candidate markers was finally performed in 98 metastatic prostate cancer patients according to IHC results. RESULTS: In metastatic lesions, proteomic analysis indicated that heat shock protein (HSP) 27, prohibitin, glutathione S-transferase 1, fibrinogen beta chain, and aldehyde dehydrogenase 6A1 were up-regulated, while alpha1 antitrypsin, and HSP 60 were down-regulated. IHC revealed that HSP 27, ALDH6A1 and prohibitin were highly specific to metastatic tumor cells. HSP27 and prohibitin appeared more strongly in the incipient stage of cancer than metastatic cancer, and ALDH6A1 was significantly reduced in metastatic cancer (p<0.01). Of all proteins, phohibitin had the highest value in predicting survival. However, all three proteins were a stronger marker than each one separately. CONCLUSION: Trio-biomarker composed of HSP27, ALDH6A1 and prohibitin may predict survival of metastatic prostate cancer patients. PMID- 30396986 TI - Case Report of a Patient with Breast Metastasis from Gastric Cancer Treated with Paclitaxel and Ramucirumab Plus Regional Hyperthermia. AB - BACKGROUND: Breast metastases from extra mammary tumors are extremely rare. CASE REPORT: Here we report the case of a 50-year-old female with histologically confirmed gastric cancer metastasis to the breast who was adequately treated with loco-regional hyperthermia plus standard second-line chemotherapy (paclitaxel plus ramucirumab). The best response achieved was a relatively long disease stabilization. CONCLUSION: Chemotherapy plus regional hyperthermia has been shown to have a synergistic antitumor effect and possible favorable immunomodulatory effects. Such an approach merits further investigation especially for the treatment of rare superficial metastatic sites. PMID- 30396988 TI - Risk Factors for Regional and Systemic Metastases in Patients with Sentinel Lymph Node-negative Melanoma. AB - BACKGROUND: Sentinel lymph node status is a strong prognostic factor in melanoma. However, up to 21% of sentinel lymph node-negative patients develop locoregional and distant metastases during follow-up. AIM: To analyze risk factors for locoregional and distant metastasis in patients with sentinel lymph node-negative melanoma. PATIENTS AND METHODS: A total of 545 patients underwent sentinel lymph node biopsy (SNB) between 2005 and 2013 at our hospital. Data for 449 patients with a negative SNB were analyzed regarding risk factors and development of metastases. Follow-up was performed until 2016. RESULTS: A total of 72 SNB negative patients developed metastases, including 25 (34.7%) distant and 47 (63.3%) locoregional metastases. Locoregional metastases occurred earlier compared to distant metastases (with a mean of 24.2 and 23.5 months for regional lymph node and cutaneous metastases, respectively, vs. 31.4 months for distant metastases). Patients with metastases despite negative SNB had a greater tumor thickness (p=0.001), a higher rate of nodular melanoma (p=0.001), ulceration (p<0.001), and were older (p=0.05) compared to SNB-negative patients without subsequent metastases. Out of SNB-negative patients, 16% developed metastases. CONCLUSION: Close clinical follow-up including sonography of the draining lymph node region is mandatory for melanoma patients regardless of SNB status. PMID- 30396990 TI - Book Reviews. PMID- 30396989 TI - Patterns of Recurrence After Salvage Radiotherapy Encompassing Pelvic Lymphatics in Men with High-risk Prostate Cancer. AB - BACKGROUND/AIM: The efficacy of adjuvant or salvage radiation to the regional lymph node area has not been fully investigated in high-risk prostate cancer patients; instead, radiotherapy is limited to the prostate fossa. The present study aimed to assess patterns of recurrence in prostate cancer patients with biochemical failure (BCF) who were treated with whole-pelvic salvage radiotherapy (SRT) following radical prostatectomy. PATIENTS AND METHODS: The clinical data from 196 high-risk prostate cancer patients who received SRT for BCF after radical prostatectomy were reviewed. BCF after SRT was detected in 80 patients, and 59 patients underwent imaging studies. RESULTS: Twenty four recurrences in 16 patients were identified, including 13 bone metastases, 6 vesicourethral anastomosis site recurrences, and 5 lymph node recurrences (one simultaneous with vesicourethral anastomosis). Regarding the treatment field, no in-field nodal recurrence was observed, whereas 4 out-of-field and 1 edge-of-field recurrences were detected. CONCLUSION: Locoregional recurrence was most common at the anastomosis site. Most nodal recurrences were located outside the pelvis, suggesting that elective pelvic nodal irradiation should be recommended in a selected patient population. PMID- 30396991 TI - Genetic Epidemiology. Methods and Protocols. PMID- 30396992 TI - The Heterogeneity of Cancer Metabolism. PMID- 30396987 TI - Subcutaneous Trastuzumab Combined with Pertuzumab and Docetaxel as First-line Treatment of Advanced HER2-positive Breast Cancer. AB - BACKGROUND/AIM: Subcutaneous (s.c.) trastuzumab was introduced in the (neo)adjuvant setting, based on the non-inferiority results and patient preference. In the advanced setting, preliminary safety data have only been reported. We conducted an observational study of s.c. trastuzumab in combination with i.v. pertuzumab and docetaxel in the first-line setting of human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. PATIENTS AND METHODS: In this single-institution study, patients received 600 mg s.c. trastuzumab in combination with 840 mg pertuzumab for the first cycle and 420 mg for the following cycles, and 75-100 mg/m2 docetaxel, followed by maintenance with s.c. trastuzumab and pertuzumab until disease progression or unacceptable toxicity. Endpoints were efficacy and safety. RESULTS: Forty patients were enrolled. The median number of cycles with docetaxel was six, while the median number of maintenance cycles was 21. With a median follow-up of 37 months, median progression-free survival and overall survival were 24 and 35 months. CONCLUSION: Subcutaneous trastuzumab in combination with pertuzumab and docetaxel is well tolerated and effective in HER2-positive advanced breast cancer. PMID- 30396993 TI - Behavioral Neurobiology of PTSD. PMID- 30396994 TI - Ultrafast optogenetic stimulation of the auditory pathway by targeting-optimized Chronos. AB - Optogenetic tools, providing non-invasive control over selected cells, have the potential to revolutionize sensory prostheses for humans. Optogenetic stimulation of spiral ganglion neurons (SGNs) in the ear provides a future alternative to electrical stimulation used in cochlear implants. However, most channelrhodopsins do not support the high temporal fidelity pertinent to auditory coding because they require milliseconds to close after light-off. Here, we biophysically characterized the fast channelrhodopsin Chronos and revealed a deactivation time constant of less than a millisecond at body temperature. In order to enhance neural expression, we improved its trafficking to the plasma membrane (Chronos ES/TS). Following efficient transduction of SGNs using early postnatal injection of the adeno-associated virus AAV-PHPB into the mouse cochlea, fiber-based optical stimulation elicited optical auditory brainstem responses (oABR) with minimal latencies of 1 ms, thresholds of 5 MUJ and 100 MUs per pulse, and sizable amplitudes even at 1,000 Hz of stimulation. Recordings from single SGNs demonstrated good temporal precision of light-evoked spiking. In conclusion, efficient virus-mediated expression of targeting-optimized Chronos-ES/TS achieves ultrafast optogenetic control of neurons. PMID- 30396995 TI - Pentraxin 3 regulates synaptic function by inducing AMPA receptor clustering via ECM remodeling and beta1-integrin. AB - Control of synapse number and function in the developing central nervous system is critical to the formation of neural circuits. Astrocytes play a key role in this process by releasing factors that promote the formation of excitatory synapses. Astrocyte-secreted thrombospondins (TSPs) induce the formation of structural synapses, which however remain post-synaptically silent, suggesting that completion of early synaptogenesis may require a two-step mechanism. Here, we show that the humoral innate immune molecule Pentraxin 3 (PTX3) is expressed in the developing rodent brain. PTX3 plays a key role in promoting functionally active CNS synapses, by increasing the surface levels and synaptic clustering of AMPA glutamate receptors. This process involves tumor necrosis factor-induced protein 6 (TSG6), remodeling of the perineuronal network, and a beta1 integrin/ERK pathway. Furthermore, PTX3 activity is regulated by TSP1, which directly interacts with the N-terminal region of PTX3. These data unveil a fundamental role of PTX3 in promoting the first wave of synaptogenesis, and show that interplay of TSP1 and PTX3 sets the proper balance between synaptic growth and synapse function in the developing brain. PMID- 30396996 TI - Loss of VGLL4 suppresses tumor PD-L1 expression and immune evasion. AB - Targeting immune checkpoints, such as PD-L1 and its receptor PD-1, has opened a new avenue for treating cancers. Understanding the regulatory mechanism of PD-L1 and PD-1 will improve the clinical response rate and efficacy of PD-1/PD-L1 blockade in cancer patients and the development of combinatorial strategies. VGLL4 inhibits YAP-induced cell proliferation and tumorigenesis through competition with YAP for binding to TEADs. However, whether VGLL4 has a role in anti-tumor immunity is largely unknown. Here, we found that disruption of Vgll4 results in potent T cell-mediated tumor regression in murine syngeneic models. VGLL4 deficiency reduces PD-L1 expression in tumor cells. VGLL4 interacts with IRF2BP2 and promotes its protein stability through inhibiting proteasome-mediated protein degradation. Loss of IRF2BP2 results in persistent binding of IRF2, a transcriptional repressor, to PD-L1 promoter. In addition, YAP inhibits IFNgamma inducible PD-L1 expression partially through suppressing the expression of VGLL4 and IRF1 by YAP target gene miR-130a. Our study identifies VGLL4 as an important regulator of PD-L1 expression and highlights a central role of VGLL4 and YAP in the regulation of tumor immunity. PMID- 30396997 TI - An inter-dimer allosteric switch controls NMDA receptor activity. AB - NMDA receptors (NMDARs) are glutamate-gated ion channels that are key mediators of excitatory neurotransmission and synaptic plasticity throughout the central nervous system. They form massive heterotetrameric complexes endowed with unique allosteric capacity provided by eight extracellular clamshell-like domains arranged as two superimposed layers. Despite an increasing number of full-length NMDAR structures, how these domains cooperate in an intact receptor to control its activity remains poorly understood. Here, combining single-molecule and macroscopic electrophysiological recordings, cysteine biochemistry, and in silico analysis, we identify a rolling motion at a yet unexplored interface between the two constitute dimers in the agonist-binding domain (ABD) layer as a key structural determinant in NMDAR activation and allosteric modulation. This rotation acts as a gating switch that tunes channel opening depending on the conformation of the membrane-distal N-terminal domain (NTD) layer. Remarkably, receptors locked in a rolled state display "super-activity" and resistance to NTD mediated allosteric modulators. Our work unveils how NMDAR domains move in a concerted manner to transduce long-range conformational changes between layers and command receptor channel activity. PMID- 30396998 TI - 3D genomic architecture reveals that neocentromeres associate with heterochromatin regions. AB - The centromere is an important genomic locus for chromosomal segregation. Although the centromere is specified by sequence-independent epigenetic mechanisms in most organisms, it is usually composed of highly repetitive sequences, which associate with heterochromatin. We have previously generated various chicken DT40 cell lines containing differently positioned neocentromeres, which do not contain repetitive sequences and do not associate with heterochromatin. In this study, we performed systematic 4C analysis using three cell lines containing differently positioned neocentromeres to identify neocentromere-associated regions at the 3D level. This analysis reveals that these neocentromeres commonly associate with specific heterochromatin-rich regions, which were distantly located from neocentromeres. In addition, we demonstrate that centromeric chromatin adopts a compact structure, and centromere clustering also occurs in vertebrate interphase nuclei. Interestingly, the occurrence of centromere-heterochromatin associations depend on CENP-H, but not CENP-C. Our analyses provide an insight into understanding the 3D architecture of the genome, including the centromeres. PMID- 30396999 TI - DIP-2 suppresses ectopic neurite sprouting and axonal regeneration in mature neurons. AB - Neuronal morphology and circuitry established during early development must often be maintained over the entirety of animal lifespans. Compared with neuronal development, the mechanisms that maintain mature neuronal structures and architecture are little understood. The conserved disco-interacting protein 2 (DIP2) consists of a DMAP1-binding domain and two adenylate-forming domains (AFDs). We show that the Caenorhabditis elegans DIP-2 maintains morphology of mature neurons. dip-2 loss-of-function mutants display a progressive increase in ectopic neurite sprouting and branching during late larval and adult life. In adults, dip-2 also inhibits initial stages of axon regeneration cell autonomously and acts in parallel to DLK-1 MAP kinase and EFA-6 pathways. The function of DIP 2 in maintenance of neuron morphology and in axon regrowth requires its AFD domains and is independent of its DMAP1-binding domain. Our findings reveal a new conserved regulator of neuronal morphology maintenance and axon regrowth after injury. PMID- 30397000 TI - N-Phthalyl-l-Tryptophan (RG108), like Clozapine (CLO), Induces Chromatin Remodeling in Brains of Prenatally Stressed Mice. AB - Schizophrenia (SZ), schizoaffective (SZA), and bipolar (BP) disorder are neurodevelopmental psychopathological conditions related, in part, to genetic load and, in part, to environmentally induced epigenetic dysregulation of chromatin structure and function in neocortical GABAergic, glutamatergic, and monoaminergic neurons. To test the above hypothesis, we targeted our scientific efforts on identifying whether the molecular epigenetic signature of postmortem brains of patients with SZ, SZA, and BP disorder are also present in the brains of adult mice born from dams prenatally restraint stressed (PRS) during gestation. The brains of PRS mice, which are similar to the brains of patients with SZ and BP disorder, show an ~2-fold increased binding of DNMT1 to psychiatric candidate promoters (glutamic acid decarboxylase 67, Reelin, and brain-derived neurotrophic factor), leading to their hypermethylation, reduced expression, as well as the behavioral endophenotypes reminiscent of those observed in the above psychiatric disorders. To establish whether clozapine (CLO) produces its behavioral and molecular action through a causal involvement of DNA methylation/demethylation processes, we compared the epigenetic action of CLO with that of the DNMT1 competitive inhibitor N-phthalyl-l-tryptophan (RG108). The intracerebroventricular injection of RG108 (20 nmol/day per 5 days), similar to the systemic administration of CLO, corrects the altered behavioral and molecular endophenotypes that are typical of PRS mice. These results are consistent with an epigenetic etiology underlying the behavioral endophenotypic profile in PRS mice. Further, it suggests that PRS mice may be useful in the preclinical screening of antipsychotic drugs acting to correct altered epigenetic mechanisms. PMID- 30397001 TI - Cell Cycle and Apoptosis Regulator 1, CCAR1, Regulates Enhancer-Dependent Nuclear Receptor CAR Transactivation. AB - The constitutive active/androstane receptor (CAR) controls genes involved in xenochemical metabolism. Although numerous cofactors have been reported to be involved in CAR-mediated transactivation, unknown and poorly defined proteins recruited by CAR have yet to be characterized. In this study, a novel CAR interacting protein, cell cycle and apoptosis regulator 1 (CCAR1), was identified by coimmunoprecipitation analysis using human hepatocarcinoma HepG2 cells expressing FLAG epitope-tagged CAR. We demonstrated that CCAR1 can act as an enhancer-dependent coactivator of CAR. First, we showed that overexpression of CCAR1 enhanced CAR-induced reporter gene activity with triplicate consensus direct repeat 4 motif (DR4-Luc), xenobiotic-responsive enhancer module (XREM) enhancer of CYP3A4 (XREM-Luc), and phenobarbital-responsive enhancer module of UDP-glucuronosyltransferases 1A1 (UGT1A1) (gtPBREM)-enhancer of UGT1A1 (gtPBREM Luc)-driven reporter plasmids but not PBREM-enhancer of CYP2B6 (PBREM-Luc)-driven reporter activity. Furthermore, we showed that knockdown of CCAR1 suppressed CAR induced UGT1A1 mRNA expression but did not affect CAR-induced CYP2B6 mRNA expression in HepTR/CAR and HepaRG cells. Moreover, CCAR1 could be recruited to the gtPBREM of the UGT1A1 enhancer by CAR but not to the PBREM of the CYP2B6 enhancer. Moreover, we showed that CCAR1 can act as a secondary coactivator by cooperating with the p160 family of steroid receptor coactivators (SRCs). These findings demonstrated CCAR1 to be a novel transcriptional cofactor for CAR and provided insight regarding the mechanism of CAR-mediated gene-selective transactivation. PMID- 30397002 TI - Multiple waxy papules unmasking an underlying multiple myeloma. PMID- 30397003 TI - Mild cognitive impairment in primary care: a clinical review. AB - Dementia is projected to become a global health priority but often not diagnosed in its earlier preclinical stage which is mild cognitive impairment (MCI). MCI is generally referred as a transition state between normal cognition and Alzheimer's disease. Primary care physicians play an important role in its early diagnosis and identification of patients most likely to progress to Alzheimer's disease while offering evidenced-based interventions that may reverse or halt the progression to further cognitive impairment. The aim of this review is to introduce the concept of MCI in primary care through a case-based clinical review. We discuss the case of a patient with MCI and provide an evidence-based framework for assessment, early recognition and management of MCI while addressing associated risk factors, neuropsychiatric symptoms and prognosis. PMID- 30397004 TI - Severe hyperammonaemic encephalopathy resulting from the overlap between hepatic and valproate encephalopathy. PMID- 30397006 TI - Is cupping therapy effective in patients with neck pain? A systematic review and meta-analysis. AB - OBJECTIVES: Neck pain is a significant condition that is second only to depression as a cause of years lived with disability worldwide. Thus, identifying and understanding effective treatment modalities for neck pain is of heightened importance. This systematic review aimed to investigate the effects of cupping on neck pain from the current literature. DESIGN: Systematic review and meta analysis of randomised controlled trials (RCTs). SETTING: Nine databases, including Chinese, Korean and Japanese databases, were searched for data up to January 2018 with no restrictions on publication language. PARTICIPANTS: Patients with neck pain. INTERVENTIONS: Cupping therapy as the sole or add-on intervention compared with no treatment or active controls. PRIMARY AND SECONDARY OUTCOME MEASURES: Pain severity, functional disability and quality of life. RESULTS: Eighteen RCTs were selected. Compared with the no intervention group, the cupping group exhibited significant reduction in pain (mean difference (MD) -2.42(95% CI 3.98 to -0.86)) and improvement in function (MD -4.34(95% CI -6.77 to -1.19)). Compared with the active control, the cupping group reported significant reduction in pain (p=0.0009) and significantly improved quality of life (p=0.001). The group that received control treatment with cupping therapy (add-on group) displayed significant pain reduction compared with the active control group (p=0.001). Of the 18 studies, only 8 reported occurrence of adverse events, which were mostly mild and temporary. CONCLUSIONS: Cupping was found to reduce neck pain in patients compared with no intervention or active control groups, or as an add-on treatment. Depending on the type of control group, cupping was also associated with significant improvement in terms of function and quality of life; however, due to the low quality of evidence of the included studies, definitive conclusions could not be drawn from this review. Future well-designed studies are needed to substantiate the effectiveness of cupping on neck pain. PROSPERO REGISTRATION NUMBER: CRD42016047218. PMID- 30397007 TI - Comparison of efficacy and safety between electroacupuncture at 'four sacral points' and conventional electroacupuncture for the treatment of urinary incontinence after stroke: study protocol for a randomised controlled trial. AB - INTRODUCTION: Electroacupuncture at 'four sacral points', also known as electrical pudendal nerve stimulation therapy, combines the advantages of pudendal nerve neuromodulation and the technique of deep insertion of long acupuncture needles. It has been used to treat stress urinary incontinence, female urgency-frequency syndrome, idiopathic urgency urinary incontinence and neurological bladders in previous studies. Here, we describe the protocol for a randomised controlled trial for evaluation of the efficacy and safety of electroacupuncture at 'four sacral points' for the management of urinary incontinence after stroke. METHODS AND ANALYSIS: This is an open-label randomised controlled trial with blinded assessments and analyses. A total of 140 eligible patients will be randomly allocated to two groups. The treatment group (n=70) will receive electroacupuncture at 'four sacral points' along with routine medical care, while the control group will receive conventional electroacupuncture along with routine medical care. Twenty treatment sessions will occur over a period of 4 weeks. The primary outcome measures will be the self-recorded findings in an incontinent episode diary at baseline and at 4 weeks after baseline. The secondary outcome measures will be the International Consultation on Incontinence Questionnaire Urinary Incontinence-Short Form (ICIQ UI SF) score and the Barthel Activities of Daily Living Index (Barthel ADL Index) score at baseline and at 4 and 28 weeks after baseline. ETHICS AND DISSEMINATION: This protocol has been approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang Chinese Medical University (approval No. 2018-K-059-01). Written informed consent will be obtained from each participant. The results of the study will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ChiCTR-IOR-17012847; Pre-result. PMID- 30397005 TI - Synthesis and degradation of FtsZ quantitatively predict the first cell division in starved bacteria. AB - In natural environments, microbes are typically non-dividing and gauge when nutrients permit division. Current models are phenomenological and specific to nutrient-rich, exponentially growing cells, thus cannot predict the first division under limiting nutrient availability. To assess this regime, we supplied starving Escherichia coli with glucose pulses at increasing frequencies. Real time metabolomics and microfluidic single-cell microscopy revealed unexpected, rapid protein, and nucleic acid synthesis already from minuscule glucose pulses in non-dividing cells. Additionally, the lag time to first division shortened as pulsing frequency increased. We pinpointed division timing and dependence on nutrient frequency to the changing abundance of the division protein FtsZ. A dynamic, mechanistic model quantitatively relates lag time to FtsZ synthesis from nutrient pulses and FtsZ protease-dependent degradation. Lag time changed in model-congruent manners, when we experimentally modulated the synthesis or degradation of FtsZ. Thus, limiting abundance of FtsZ can quantitatively predict timing of the first cell division. PMID- 30397008 TI - Development and prospective external validation of a tool to predict poor recovery at 9 months after acute ankle sprain in UK emergency departments: the SPRAINED prognostic model. AB - OBJECTIVES: To develop and externally validate a prognostic model for poor recovery after ankle sprain. SETTING AND PARTICIPANTS: Model development used secondary data analysis of 584 participants from a UK multicentre randomised clinical trial. External validation used data from 682 participants recruited in 10 UK emergency departments for a prospective observational cohort. OUTCOME AND ANALYSIS: Poor recovery was defined as presence of pain, functional difficulty or lack of confidence in the ankle at 9 months after injury. Twenty-three baseline candidate predictors were included together in a multivariable logistic regression model to identify the best predictors of poor recovery. Relationships between continuous variables and the outcome were modelled using fractional polynomials. Regression parameters were combined over 50 imputed data sets using Rubin's rule. To minimise overfitting, regression coefficients were multiplied by a heuristic shrinkage factor and the intercept re-estimated. Incremental value of candidate predictors assessed at 4 weeks after injury was explored using decision curve analysis and the baseline model updated. The final models included predictors selected based on the Akaike information criterion (p<0.157). Model performance was assessed by calibration and discrimination. RESULTS: Outcome rate was lower in the development (6.7%) than in the external validation data set (19.9%). Mean age (29.9 and 33.6 years), body mass index (BMI; 26.3 and 27.1 kg/m2), pain when resting (37.8 and 38.5 points) or bearing weight on the ankle (75.4 and 71.3 points) were similar in both data sets. Age, BMI, pain when resting, pain bearing weight, ability to bear weight, days from injury until assessment and injury recurrence were the selected predictors. The baseline model had fair discriminatory ability (C-statistic 0.72; 95% CI 0.66 to 0.79) but poor calibration. The updated model presented better discrimination (C-statistic 0.78; 95% CI 0.72 to 0.84), but equivalent calibration. CONCLUSIONS: The models include predictors easy to assess clinically and show benefit when compared with not using any model. TRIAL REGISTRATION NUMBER: ISRCTN12726986; Results. PMID- 30397009 TI - Association between normal tension glaucoma and the risk of Alzheimer's disease: a nationwide population-based cohort study in Taiwan. AB - OBJECTIVES: To investigate a possible association between normal tension glaucoma (NTG) and an increased risk of developing Alzheimer's disease (AD). DESIGN: Retrospective cohort study. SETTING: NTG group and the comparison group were retrieved from the whole population of the Taiwan National Health Insurance Research Database from 1 January 2001 to 31 December 2013. PARTICIPANTS: A total of 15 317 subjects with NTG were enrolled in the NTG group, and 61 268 age matched and gender-matched subjects without glaucoma were enrolled in the comparison group. PRIMARY AND SECONDARY OUTCOME MEASURES: Kaplan-Meier curves were generated to compare the cumulative hazard of AD between the two groups. A multivariable Cox regression analysis was used to estimate the adjusted hazard ratios (HRs) of AD, adjusted for diabetes, hypertension, hyperlipidaemia, coronary artery disease and stroke. Furthermore, risk factors for developing AD among the NTG group were investigated. RESULTS: The mean age of the cohort was 62.1+/-12.5 years. Patients with NTG had significantly higher proportions of diabetes, hypertension, hyperlipidaemia, coronary artery disease and stroke than the comparisons. Patients with NTG had a significantly higher cumulative hazard for AD than the comparisons (p<0.0001). In the multivariable Cox regression after adjustment for confounders, the NTG group had a significantly higher risk of AD (adjusted HR 1.52; 95% CI 1.41 to 1.63). Moreover, in the NTG group, when we compared the effects of different types of glaucoma eye drops, none of the eye drops used were significant risk factors or protective factors for AD. CONCLUSIONS: People with NTG are at a significantly greater risk of developing AD compared with individuals without glaucoma. Among patients with NTG, none of the glaucoma eye drops used significantly changed the risk of subsequent AD. PMID- 30397011 TI - FDA Issues Draft Guidance on MRD Testing. AB - Experts from industry and academia welcomed new draft guidelines from the FDA on how best to use minimal residual disease (MRD) testing as a surrogate endpoint in blood cancer trials. However, they called for more guidance on the technological aspects of MRD testing. PMID- 30397010 TI - Comparing pharmacological venous thromboembolism prophylaxis to intermittent pneumatic compression in acute intracerebral haemorrhage: protocol for a systematic review and network meta-analysis. AB - INTRODUCTION: Patients with an intracerebral haemorrhage are at increased risk of venous thromboembolism. Pharmacotherapy and pneumatic compression devices are capable of preventing venous thromboembolism, however both interventions have limitations. There are no head-to-head comparisons between these two interventions. To address this knowledge gap, we plan to perform a systematic review and network meta-analysis to examine the comparative effectiveness of pharmacological prophylaxis and mechanical compression devices in the context of intracerebral haemorrhage. METHODS AND ANALYSIS: MEDLINE, PUBMED, EMBASE, CENTRAL, ClinicalTrials.gov and the Internet Stroke Trials Registry will be searched with assistance from an experienced information specialist. Eligible studies will include those that have enrolled adults presenting with spontaneous intracerebral haemorrhage and compared one or more of the respective interventions against each other and/or a control. Primary outcomes to be assessed are occurrence of new venous thromboembolism (deep vein thrombosis and/or pulmonary embolism) and haematoma expansion, defined as a significant enlargement of baseline haemorrhage or new haemorrhage occurrence. Both randomised and non-randomised comparative studies will be included. Data on participant characteristics, study design, intervention details and outcomes will be extracted. Study quality will be assessed using the Cochrane Risk of Bias Tool and the Robins-I tool. Bayesian network meta-analyses will be performed to compare interventions based on all available direct and indirect evidence. If the transitivity assumption for network meta-analysis cannot be met, we will perform a qualitative assessment. ETHICS AND DISSEMINATION: Formal ethics is not required as primary data will not be collected. The findings of this study will be disseminated through conference presentations, and peer-reviewed publications. In an area of clinical practice where equipoise exists, the findings of this study may assist in determining which treatment intervention is most effective in venous thromboembolism prevention. PROSPERO REGISTRATION NUMBER: CRD42018090960. PMID- 30397012 TI - The tarantula toxin GxTx detains K+ channel gating charges in their resting conformation. AB - Allosteric ligands modulate protein activity by altering the energy landscape of conformational space in ligand-protein complexes. Here we investigate how ligand binding to a K+ channel's voltage sensor allosterically modulates opening of its K+-conductive pore. The tarantula venom peptide guangxitoxin-1E (GxTx) binds to the voltage sensors of the rat voltage-gated K+ (Kv) channel Kv2.1 and acts as a partial inverse agonist. When bound to GxTx, Kv2.1 activates more slowly, deactivates more rapidly, and requires more positive voltage to reach the same K+ conductance as the unbound channel. Further, activation kinetics are more sigmoidal, indicating that multiple conformational changes coupled to opening are modulated. Single-channel current amplitudes reveal that each channel opens to full conductance when GxTx is bound. Inhibition of Kv2.1 channels by GxTx results from decreased open probability due to increased occurrence of long-lived closed states; the time constant of the final pore opening step itself is not impacted by GxTx. When intracellular potential is less than 0 mV, GxTx traps the gating charges on Kv2.1's voltage sensors in their most intracellular position. Gating charges translocate at positive voltages, however, indicating that GxTx stabilizes the most intracellular conformation of the voltage sensors (their resting conformation). Kinetic modeling suggests a modulatory mechanism: GxTx reduces the probability of voltage sensors activating, giving the pore opening step less frequent opportunities to occur. This mechanism results in K+ conductance activation kinetics that are voltage-dependent, even if pore opening (the rate-limiting step) has no inherent voltage dependence. We conclude that GxTx stabilizes voltage sensors in a resting conformation, and inhibits K+ currents by limiting opportunities for the channel pore to open, but has little, if any, direct effect on the microscopic kinetics of pore opening. The impact of GxTx on channel gating suggests that Kv2.1's pore opening step does not involve movement of its voltage sensors. PMID- 30397013 TI - GPs' and nurses' perceptions of electronic cigarettes in England: a qualitative interview study. AB - BACKGROUND: Reports from royal colleges and organisations such as Public Health England suggest that GPs and nurses should advise patients to switch to electronic cigarettes (e-cigarettes) if they do not want to stop smoking using licensed medication. However, there are no data on what practitioners think, feel, or do about e-cigarettes. AIM: To explore practitioners' perceptions and attitudes towards e-cigarettes, and their experiences of discussing e-cigarettes with patients. DESIGN AND SETTING: A qualitative interview study was carried out with semi-structured interviews conducted with nurses and GPs across England in 2017. METHOD: Participants were interviewed once either via telephone or face to face. Data were analysed using thematic analysis. RESULTS: Interviews were conducted with 23 practitioners (eight nurses and 15 GPs). There were three key themes: ambivalence and uncertainty; pragmatism; and responsibility. Many practitioners had uncertainties about the safety and long-term risks of e cigarettes. Some had ambivalence about their own knowledge and ability to advise on their use, as well as uncertainty about whether to and what to advise patients. Despite this, many sought to provide honesty in consultations by acknowledging these uncertainties about e-cigarettes with patients and taking a pragmatic approach, believing that e-cigarettes were a 'step in the right direction'. Practitioners wanted advice from healthcare regulators such as the National Institute for Health and Care Excellence to reassure them about the safety of e-cigarettes, practical tools to support the consultation, and to control their use by providing behavioural support programmes for reduction or cessation. CONCLUSION: Current dissemination strategies for guidelines are not effective in reaching practitioners, who are offering more cautious advice about e-cigarettes than guidelines suggest is reasonable. PMID- 30397014 TI - Incidence of indications for tonsillectomy and frequency of evidence-based surgery: a 12-year retrospective cohort study of primary care electronic records. AB - BACKGROUND: Neither the incidence of indications for childhood tonsillectomy nor the proportion of tonsillectomies that are evidence-based is known. AIM: To determine the incidence of indications for tonsillectomy in UK children, and the proportion of tonsillectomies meeting evidence-based criteria. DESIGN AND SETTING: A retrospective cohort study of electronic medical records of children aged 0-15 years registered with 739 UK general practices contributing to a research database. METHOD: Children with recorded indications for tonsillectomy were identified from electronic medical records. Evidence-based indications included documented sore throats of sufficient frequency and severity (Paradise criteria); periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome (PFAPA); or tonsillar tumour. Other indications were considered non-evidence-based. The numbers of children subsequently undergoing tonsillectomy was then identified. The numbers with evidence-based and non-evidence-based indications for surgery among children who had undergone tonsillectomy were determined. RESULTS: The authors included 1 630 807 children followed up for 7 200 159 person-years between 2005 and 2016. Incidence of evidence-based indications for tonsillectomy was 4.2 per 1000 person years; 13.6% (2144/15 760) underwent tonsillectomy. Incidence of childhood tonsillectomy was 2.5 per 1000 person years; 11.7% (2144/18 281) had evidence-based indications, almost all with Paradise criteria. The proportion of evidence-based tonsillectomies was unchanged over 12 years. Most childhood tonsillectomies followed non-evidence-based indications: five to six sore throats (12.4%) in 1 year, two to four sore throats (44.6%) in 1 year, sleep disordered breathing (12.3%), or obstructive sleep apnoea (3.9%). CONCLUSION: In the UK, few children with evidence-based indications undergo tonsillectomy and seven in eight of those who do (32 500 of 37 000 annually) are unlikely to benefit. PMID- 30397015 TI - Barriers to a software reminder system for risk assessment of stroke in atrial fibrillation: a process evaluation of a cluster randomised trial in general practice. AB - BACKGROUND: Oral anticoagulants reduce the risk of stroke in patients with atrial fibrillation (AF), but are underused. AURAS-AF (AUtomated Risk Assessment for Stroke in AF) is a software tool designed to identify eligible patients and promote discussions within consultations about initiating anticoagulants. AIM: To investigate the implementation of the software in UK general practice. DESIGN AND SETTING: Process evaluation involving 23 practices randomly allocated to use AURAS-AF during a cluster randomised trial. METHOD: An initial invitation to discuss anticoagulation was followed by screen reminders appearing during consultations until a decision had been made. The reminders required responses, giving reasons for cases where an anticoagulant was not initiated. Qualitative interviews with clinicians and patients explored acceptability and usability. RESULTS: In a sample of 476 patients eligible for the invitation letter, only 159 (33.4%) were considered suitable for invitation by their GPs. Reasons given were frequently based on frailty, and risk of falls or haemorrhage. Of those invited, 35 (22%) started an anticoagulant (7.4% of those originally identified). A total of 1695 main-screen reminders occurred in 940 patients. In 883 instances, the decision was taken not to initiate and a range of reasons offered. Interviews with 15 patients and seven clinicians indicated that the intervention was acceptable, though the issue of disruptive screen reminders was raised. CONCLUSION: Automated risk assessment for stroke in atrial fibrillation and prompting during consultations are feasible and generally acceptable, but did not overcome concerns about frailty and risk of haemorrhage as barriers to anticoagulant uptake. PMID- 30397016 TI - Influence of financial and reputational incentives on primary care performance: a longitudinal study. AB - BACKGROUND: The Quality and Outcomes Framework has generated reputational as well as financial rewards for general practices because the number of quality points a practice receives is publicly reported. These rewards vary across diseases and practices, and over time. AIM: To determine the relative effects on performance of the financial and reputational rewards resulting from a pay-for-performance programme. DESIGN AND SETTING: Observational study of the published performance on 42 indicators of 8929 practices in England between 2004 and 2013. METHOD: The authors calculated the revenue offered (financial reward, measured in L100s) and the points offered (reputational reward) per additional patient treated for each indicator for each practice in each year. Fixed-effects multivariable regression models were used to estimate whether the percentage of eligible patients treated responded to changes in these financial and reputational rewards. RESULTS: Both the offered financial rewards and reputational rewards had small but statistically significant associations with practice performance. The effect of the financial reward on performance decreased from 0.797 percentage points per L100 (95% confidence interval [CI] = 0.614 to 0.979) in 2004, to 0.092 (95% CI = 0.045 to 0.138) in 2013. The effect of the reputational reward increased from 0.121 percentage points per quality point (95% CI = -0.220 to -0.022) in 2004, to 0.209 (95% CI = 0.147 to 0.271) in 2013. CONCLUSION: In the short term, general practices were more sensitive to revenue than reputational rewards. In the long term, general practices appeared to divert their focus towards the reputational reward, once benchmarks of performance became established. PMID- 30397017 TI - Nuclear Transcriptomes of the Seven Neuronal Cell Types That Constitute the Drosophila Mushroom Bodies. AB - The insect mushroom body (MB) is a conserved brain structure that plays key roles in a diverse array of behaviors. The Drosophila melanogaster MB is the primary invertebrate model of neural circuits related to memory formation and storage, and its development, morphology, wiring, and function has been extensively studied. MBs consist of intrinsic Kenyon Cells that are divided into three major neuron classes (gamma, alpha'/beta' and alpha/beta) and 7 cell subtypes (gammad, gammam, alpha'/beta'ap, alpha'/beta'm, alpha/betap, alpha/betas and alpha/betac) based on their birth order, morphology, and connectivity. These subtypes play distinct roles in memory processing, however the underlying transcriptional differences are unknown. Here, we used RNA sequencing (RNA-seq) to profile the nuclear transcriptomes of each MB neuronal cell subtypes. We identified 350 MB class- or subtype-specific genes, including the widely used alpha/beta class marker Fas2 and the alpha'/beta' class marker trio Immunostaining corroborates the RNA-seq measurements at the protein level for several cases. Importantly, our data provide a full accounting of the neurotransmitter receptors, transporters, neurotransmitter biosynthetic enzymes, neuropeptides, and neuropeptide receptors expressed within each of these cell types. This high-quality, cell type-level transcriptome catalog for the Drosophila MB provides a valuable resource for the fly neuroscience community. PMID- 30397018 TI - A de Novo EDA-Variant in a Litter of Shorthaired Standard Dachshunds with X Linked Hypohidrotic Ectodermal Dysplasia. AB - In this study, we present a detailed phenotype description and genetic elucidation of the first case of X-linked hypohidrotic ectodermal dysplasia in the shorthaired standard Dachshund. This condition is characterized by partial congenital hypotrichosis, missing and malformed teeth and a lack of eccrine sweat glands. Clinical signs including dental radiographs and histopathological findings were consistent with ectodermal dysplasia. Pedigree analysis supported an X-recessive mode of inheritance. Whole-genome sequencing of one affected puppy and his dam identified a 1-basepair deletion within the ectodysplasin-A (EDA) gene (CM000039.3:g.54509504delT, c.458delT). Sanger sequencing of further family members confirmed the EDA:c.458delT-variant. Validation in all available family members, 37 unrelated shorthaired standard Dachshunds, 128 further Dachshunds from all other coat and size varieties and samples from 34 dog breeds revealed the EDA:c.458delT-variant to be private for this family. Two heterozygous females showed very mild congenital hypotrichosis but normal dentition. Since the dam is demonstrably the only heterozygous animal in the ancestry of the affected animals, we assume that the EDA:c.458delT-variant arose in the germline of the granddam or in an early embryonic stage of the dam. In conclusion, we detected a very recent de-novo EDA mutation causing X-linked hypohidrotic ectodermal dysplasia in the shorthaired standard Dachshund. PMID- 30397019 TI - iProteinDB: An Integrative Database of Drosophila Post-translational Modifications. AB - Post-translational modification (PTM) serves as a regulatory mechanism for protein function, influencing their stability, interactions, activity and localization, and is critical in many signaling pathways. The best characterized PTM is phosphorylation, whereby a phosphate is added to an acceptor residue, most commonly serine, threonine and tyrosine in metazoans. As proteins are often phosphorylated at multiple sites, identifying those sites that are important for function is a challenging problem. Considering that any given phosphorylation site might be non-functional, prioritizing evolutionarily conserved phosphosites provides a general strategy to identify the putative functional sites. To facilitate the identification of conserved phosphosites, we generated a large scale phosphoproteomics dataset from Drosophila embryos collected from six closely-related species. We built iProteinDB (https://www.flyrnai.org/tools/iproteindb/), a resource integrating these data with other high-throughput PTM datasets, including vertebrates, and manually curated information for Drosophila At iProteinDB, scientists can view the PTM landscape for any Drosophila protein and identify predicted functional phosphosites based on a comparative analysis of data from closely-related Drosophila species. Further, iProteinDB enables comparison of PTM data from Drosophila to that of orthologous proteins from other model organisms, including human, mouse, rat, Xenopus tropicalis, Danio rerio, and Caenorhabditis elegans. PMID- 30397020 TI - The Impact of Next-Generation Sequencing on Cancer Genomics: From Discovery to Clinic. AB - The application of next-generation sequencing (NGS) technology to the study of cancer genomes has been transformational. Not only has this technology revealed the genetic and epigenetic underpinnings of disease onset and progression, but also has redefined our clinical diagnosis and treatment paradigms. This rapid translation from discovery to clinical platform has occurred in the context of new pharmaceutical paradigms, enabling the use of NGS for the diagnosis and definition of therapeutic vulnerabilities of cancer. This review explores this transformation and identifies cutting-edge applications of NGS that will result in its additional utility in cancer care. PMID- 30397021 TI - Identification and microbial production of the raspberry phenol salidroside that is active against Huntington's disease. AB - Edible berries are considered to be among nature's treasure chests as they contain a large number of (poly)phenols with potentially health-promoting properties. However, as berries contain complex (poly)phenol mixtures, it is challenging to associate any interesting pharmacological activity with a single compound. Thus, identification of pharmacologically interesting phenols requires systematic analyses of berry extracts. Here, raspberry (Rubus idaeus, var. Prestige) extracts were systematically analyzed to identify bioactive compounds against pathological processes of neurodegenerative diseases. Berry extracts were tested on different Saccharomyces cerevisiae strains expressing disease proteins associated with Alzheimer's, Parkinson's, or Huntington's disease or amyotrophic lateral sclerosis. After identifying bioactivity against Huntington's disease, the extract was fractionated and the obtained fractions were tested in the yeast model, which revealed that salidroside, a glycosylated phenol, displayed significant bioactivity. Subsequently, a metabolic route to salidroside was reconstructed in S. cerevisiae and Corynebacterium glutamicum. The best performing S. cerevisiae strain was capable of producing 2.1 mM (640 mg L-1) salidroside from glucose in shake flasks, whereas an engineered C. glutamicum strain could efficiently convert the precursor tyrosol to salidroside, accumulating up to 32 mM (9,700 mg L-1) salidroside in bioreactor cultivations (yield: 0.81 mol mol-1). Targeted yeast assays verified that salidroside produced by both organisms has the same positive effects as salidroside of natural origin. PMID- 30397022 TI - Healthy roots and leaves: comparative genome structure of horseradish and watercress. AB - Horseradish and watercress are economically important cruciferous vegetable species with limited genomic resources. We used comparative chromosome painting to identify the extent of chromosomal collinearity between horseradish (Armoracia rusticana) and watercress (Nasturtium officinale), and to reconstruct the origin and evolution of the two tetraploid genomes (2n = 4x = 32). Our results show that horseradish and watercress genomes originated from a common ancestral (n = 8) genome, structurally resembling the Ancestral Crucifer Karyotype (n = 8), which, however, contained two unique translocation chromosomes (AK6/8 and AK8/6). Except for a 2.4-Mb unequal chromosome translocation in watercress, both genomes are structurally identical. The structural similarity of the two parental subgenomes might suggest an autotetraploid origin of horseradish and watercress genomes. The subgenome stasis, apart from the single-chromosome translocation, indicates that homeologous recombination played a limited role in post-polyploid evolution in both tetraploid genomes. The octoploid genome of one-rowed watercress (N. microphyllum, 2n = 8x = 64), structurally mirroring the tetraploid horseradish and watercress genomes, originated via autopolyploidization from the immediate tetraploid predecessor of watercress or hybridization between this and another now-extinct tetraploid Nasturtium species. These comparative cytogenomic maps in horseradish and watercress represent a first stepping stone for future whole genome sequencing efforts and genetic improvement of both crop species. PMID- 30397023 TI - OHP1, OHP2, and HCF244 form a transient functional complex with the photosystem II reaction center. AB - The reaction center (RC) of photosystem II (PSII), which is composed of D1, D2, PsbI, and cytochrome b559 subunits, forms at an early stage of PSII biogenesis. However, it is largely unclear how these components assemble to form a functional unit. In this work, we show that synthesis of the PSII core proteins D1/D2 and formation of the PSII RC is specifically blocked in the absence of ONE-HELIX PROTEIN1 (OHP1) and OHP2 proteins in Arabidopsis thaliana, indicating that OHP1 and OHP2 are essential for the formation of the PSII RC. Mutagenesis of the chlorophyll (Chl) binding residues in OHP proteins impairs their function and/or stability, suggesting that they may function in the binding of Chl in vivo. We further show that OHP1, OHP2, and HIGH CHLOROPHYLL FLUORESCENCE244 (HCF244), together with D1, D2, PsbI, and cytochrome b559 form a complex. We designated this complex the PSII RC-like complex, to distinguish it from the RC subcomplex in the intact PSII complex. Our data imply that OHP1, OHP2, and HCF244 are present in this PSII RC-like complex for a limited time at an early stage of PSII de novo assembly and of PSII repair under high light conditions. In a subsequent stage of PSII biogenesis, OHP1, OHP2, and HCF244 are released from the PSII RC like complex and replaced by the other PSII subunits. Together with previous reports in the cyanobacteria Synechocystis, our results demonstrate that the process of PSII RC assembly is highly conserved among photosynthetic species. PMID- 30397024 TI - Phytoparasitic nematode control of plant hormone pathways. PMID- 30397025 TI - Association of community food environment and obesity among US adults: a geographical information system analysis. AB - BACKGROUND: Emerging studies have investigated the contribution of food environment to obesity in the USA. However, the findings were inconsistent. Methodological explanations for the inconsistent findings included: (1) using individual store/restaurant exposure as food environment indicator, and (2) not accounting for non-stationarity assumption. This study aimed to describe the spatial distribution of obesity and examine the association between community food environment and obesity, and the variation of magnitude and direction of this association across the USA. METHODS: Data from 20 897 adults who participated in the REasons for Geographic and Racial Differences in Stroke study and completed baseline assessment between January 2003 and October 2007 were eligible in analysis. Hot Spot analysis was used to assess the spatial distribution of obesity. The association between community food environment and obesity and the variation of this association across the USA were examined using global ordinary least squares regression and local geographically weighted regression. RESULTS: Higher body mass index (BMI) clusters were more likely to locate in socioeconomically disadvantaged, rural, minority neighbourhoods with a smaller population size, while lower BMI clusters were more likely to appear in more affluent, urban neighbourhoods with a higher percentage of non-Hispanic white residences. There was an overall significant, inverse association between community food environment and obesity (beta=-0.0210; p<0.0001). Moreover, the magnitude and direction of this association varied significantly across the US regions. CONCLUSIONS: The findings underscored the need for geographically tailored public health interventions and policies to address unique local food environment issues to achieve maximum effects on obesity prevention. PMID- 30397026 TI - Fostering Innovation in Symptom Management among Hemodialysis Patients: Paths Forward for Insomnia, Muscle Cramps, and Fatigue. AB - Individuals receiving in-center maintenance hemodialysis bear a high burden of both physical and mood symptoms. More than half of patients on hemodialysis report sleep disturbance, muscle cramps, and fatigue. Patients describe symptoms as having a deleterious effect on their quality of life, suggesting that symptom alleviation may meaningfully improve patient-reported outcomes. Moreover, patients on hemodialysis have identified symptom management as a key area for research and innovation, prioritizing symptom alleviation over other health outcomes such as mortality and biochemical indices. Despite the importance of symptoms to patients, there has been little research explicitly geared toward improving patient symptoms, and therefore minimal innovation in symptom management. In general, the physiologic underpinnings of symptoms are poorly understood, hampering the development of targeted therapies. In fact, there have been few drugs or devices approved by the US Food and Drug Administration for the indication of improving any patient-reported outcomes for patients on hemodialysis. Recognizing this gap in innovation, the Kidney Health Initiative, a public-private partnership between the American Society of Nephrology and US Food and Drug Administration, convened a workgroup to first prioritize symptoms for the development of therapeutic interventions, and then identify near-term actionable research goals for the prioritized physical symptoms of insomnia, muscle cramps, and fatigue. This paper summarizes the pathophysiology of the three prioritized symptoms, identifies key knowledge gaps, acknowledges factors that challenge development of new therapies, and offers the nephrology community actionable research goals for insomnia, muscle cramps, and fatigue. PMID- 30397028 TI - Treatment of Drug-Induced Acute Tubulointerstitial Nephritis: The Search for Better Evidence. PMID- 30397027 TI - Duration of Treatment with Corticosteroids and Recovery of Kidney Function in Acute Interstitial Nephritis. AB - BACKGROUND AND OBJECTIVES: Drug-induced acute interstitial nephritis represents an emerging cause of acute kidney disease, especially among polymedicated elderly patients. Although corticosteroids are frequently used, controversy exists about the timing of initiation, efficacy, safety, and duration of treatment. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a retrospective study of 182 patients with biopsy-proven drug-induced acute interstitial nephritis from 13 Spanish centers. Exposure was defined as the length of corticosteroid treatment. The main outcome was the level of serum creatinine at month 6, with respect to baseline values. RESULTS: The most common offending agents were nonsteroidal anti inflammatory drugs (27%). In 30% of patients, the offending drug could not be identified. The median time to suspected drug withdrawal was 11 days (interquartile range, 5-22). All patients presented with acute kidney disease and were treated with corticosteroids. The mean initial dose of prednisone was 0.8+/ 0.2 mg/kg per day. High-dose corticosteroid treatment was maintained for 2 weeks (interquartile range, 1-4). After 6 months, the mean recovered GFR was 34+/-26 ml/min per 1.73 m2 and ten patients required maintenance dialysis. Use of high dose corticosteroids for 3 weeks or treatment duration >8 weeks were not associated with better recovery of kidney function. In the multivariable analysis, delayed onset of steroid treatment (odds ratio, 1.02; 95% confidence interval, 1.0 to 1.04) and the presence of interstitial fibrosis of >50% on the kidney biopsy specimen (odds ratio, 8.7; 95% confidence interval, 2.7 to 27.4) were both associated with serum creatinine level at month 6 of >75%, with respect to baseline values. CONCLUSIONS: High-dose corticosteroid treatment for 3 weeks or prolonged treatment for >8 weeks were not associated with greater kidney function recovery in drug-induced acute interstitial nephritis. A delay in the initiation of corticosteroids resulted in worse recovery of kidney function. PMID- 30397029 TI - Methodological systematic review of studies on social inequalities in smoking among young adults: A field coming of age? AB - OBJECTIVE: Socioeconomic circumstances are critically important to addressing smoking. In young adulthood (ages 18-25), dynamic transitions in education, employment, family and housing complicate the measurement of socioeconomic circumstances. To better understand approaches to capturing these circumstances, this methodological systematic review examined how socioeconomic characteristics used to identify social inequalities in smoking among young adults are measured. DATA SOURCES: We searched PubMed/MEDLINE, Scopus, EMBASE, ERIC and Sociological Abstracts, and used three prior reviews. We updated the search in March 2018. STUDY SELECTION: Two reviewers independently screened peer-reviewed records from OECD countries published in English, French, German or Spanish after 1995 whose samples covered at least 1 year between the ages of 18 and 25. We included 89 of 1320 records. DATA EXTRACTION: One reviewer extracted study characteristics, indicators used to operationalise socioeconomic circumstances and each indicator's relation to results on smoking (ie, significance and direction). We found 39 indicators of socioeconomic circumstances related to six broad domains. These indicators were used in 425 results. DATA SYNTHESIS: We descriptively analysed the extracted data using evidence tables. Educational attainment was most common. Evidence of inequalities varied by indicator used. For example, there was inconsistent evidence regarding the role of parental characteristics and transition stages and insufficient evidence regarding personal income on smoking. CONCLUSION: Despite its importance, studies have disproportionally examined inequalities among young adults using traditional indicators. The mismatch between young adults' life transitions and measurement strategies may attenuate evidence of inequalities. We suggest strategies to improve future measurement. PMID- 30397030 TI - Tobacco control within and beyond WHO MPOWER: outcomes from Taiwan SimSmoke. AB - INTRODUCTION: Adult smoking prevalence in Taiwan rapidly declined from 26.5% in 2005 to 20.0% in 2015. Nevertheless, future projections on smoking-attributable deaths and current per capita consumption do not paint an equally bright picture. METHODS: We used SimSmoke, a tobacco control simulation model to assess the impact of tax increases and other policies by predicting past and projecting over future decades smoking rates and smoking-attributable mortality. RESULTS: The model accurately depicts the decline in smoking prevalence observed in Taiwan from 2000 to 2015. Nonetheless, under the 'status quo' scenario, smoking attributable mortality is projected to continue growing, peaking at 26 602 annual deaths in 2039 and cumulative deaths >1 million by 2044. By comparing projections with current policies with a counterfactual scenario based on the 2000 policy levels, SimSmoke estimates that tobacco control in Taiwan has been able to reduce smoking prevalence by 30% in 2015 with 450 000 fewer smoking-attributable deaths by 2060. Modified scenarios show that doubling the retail price of cigarettes and fully implementing the remaining MPOWER measures would avert approximately 45 000 lives by 2040 and 130 000 by 2060. CONCLUSIONS: Tobacco will be a leading cause of death in Taiwan for the coming decades, showing yet again the long-term consequences of smoking on public health. The MPOWER package, even if adopted at the highest level with a large tax increase, is unlikely to reduce smoking prevalence to the endgame goal of 5% in the next five decades. PMID- 30397031 TI - TLR-7 Stress Signaling in Differentiating and Mature Eosinophils Is Mediated by the Prolyl Isomerase Pin1. AB - The response of eosinophils (Eos) to respiratory virus has emerged as an important link between pulmonary infection and allergic asthmatic exacerbations. Eos activate innate immune responses through TLR signaling. In this study, using mouse and human Eos and mice lacking the prolyl isomerase Pin1 selectively in Eos, we show that Pin1 is indispensable for eosinophilopoiesis in the bone marrow (BM) and mature cell function in the presence of TLR7 activation. Unbiased in vivo analysis of mouse models of allergic airway inflammation revealed that TLR7 activation in knockout mice resulted in systemic loss of Eos, reduced IFN production, and an inability to clear respiratory viruses. Consistent with this finding, BM mouse Eos progenitors lacking Pin1 showed markedly reduced cell proliferation and survival after TLR7 activation. Mechanistically, unlike wild type cells, Pin1 null mouse Eos were defective in the activation of the endoplasmic reticulum stress-induced unfolded protein response. We observed significant reductions in the expression of unfolded protein response components and target genes, aberrant TLR7 cleavage and trafficking, and reduced granule protein production in knockout Eos. Our data strongly suggest that Pin1 is required for BM Eos generation and function during concurrent allergen challenge and viral infection. PMID- 30397032 TI - Essential Role of Canonical NF-kappaB Activity in the Development of Stromal Cell Subsets in Secondary Lymphoid Organs. AB - Organized tissue structure in the secondary lymphoid organs (SLOs) tightly depends on the development of fibroblastic stromal cells (FSCs) of mesenchymal origin; however, the mechanisms of this relationship are poorly understood. In this study, we specifically inactivated the canonical NF-kappaB pathway in FSCs in vivo by conditionally inducing IkappaBalpha mutant in a Ccl19-IkappaBSR mouse system in which NF-kappaB activity is likely to be suppressed in fetal FSC progenitors. Given that NF-kappaB activation in fetal FSCs is essential for SLO development, the animals were expected to lack SLOs. However, all SLOs were preserved in Ccl19-IkappaBSR mice. Instead, the T cell area was severely disturbed by the lack of CCL21-expressing FSCs, whereas the follicles and associated FSC networks were formed. Fate mapping revealed that IkappaBSR expressing cells constituted only a small fraction of stromal compartment outside the follicles. Taken together, our findings indicate an essential role of the canonical NF-kappaB pathway activity in the development of three FSC subsets common to SLOs and suggest transient or stochastic CCL19 expression in FSC progenitors and a compensatory differentiation program of follicular FSCs. PMID- 30397033 TI - Filtering Next-Generation Sequencing of the Ig Gene Repertoire Data Using Antibody Structural Information. AB - Next-generation sequencing of the Ig gene repertoire (Ig-seq) produces large volumes of information at the nucleotide sequence level. Such data have improved our understanding of immune systems across numerous species and have already been successfully applied in vaccine development and drug discovery. However, the high throughput nature of Ig-seq means that it is afflicted by high error rates. This has led to the development of error-correction approaches. Computational error correction methods use sequence information alone, primarily designating sequences as likely to be correct if they are observed frequently. In this work, we describe an orthogonal method for filtering Ig-seq data, which considers the structural viability of each sequence. A typical natural Ab structure requires the presence of a disulfide bridge within each of its variable chains to maintain the fold. Our Ab Sequence Selector (ABOSS) uses the presence/absence of this bridge as a way of both identifying structurally viable sequences and estimating the sequencing error rate. On simulated Ig-seq datasets, ABOSS is able to identify more than 99% of structurally viable sequences. Applying our method to six independent Ig-seq datasets (one mouse and five human), we show that our error calculations are in line with previous experimental and computational error estimates. We also show how ABOSS is able to identify structurally impossible sequences missed by other error-correction methods. PMID- 30397034 TI - Blocking Matrix Metalloproteinase-9 Abrogates Collagen-Induced Arthritis via Inhibiting Dendritic Cell Migration. AB - Trafficking of dendritic cells (DCs) to lymph nodes (LNs) to present Ags is a crucial step in the pathogenesis of rheumatoid arthritis (RA). Matrix metalloproteinase-9 (MMP-9) is the key molecule for DC migration. Thus, blocking MMP-9 to inhibit DC migration may be a novel strategy to treat RA. In this study, we used anti-MMP-9 Ab to treat collagen-induced arthritis (CIA) in DBA/1J mice and demonstrated that anti-MMP-9 Ab treatment significantly suppressed the development of CIA via the modulation of DC trafficking. In anti-MMP-9 Ab-treated CIA mice, the number of DCs in draining LNs was obviously decreased. In vitro, anti-MMP-9 Ab and MMP-9 inhibitor restrained the migration of mature bone marrow derived DCs in Matrigel in response to CCR7 ligand CCL21. In addition, blocking MMP-9 decreased T and B cell numbers in LNs of CIA mice but had no direct influence on the T cell response to collagen II by CD4+ T cells purified from LNs or spleen. Besides, anti-MMP-9 Ab did not impact on the expression of MHC class II, CD40, CD80, CD86, and chemokine receptors (CCR5 and CCR7) of DCs both in vivo and in vitro. Furthermore, we discovered the number of MMP-9-/- DCs trafficking from footpads to popliteal LNs was dramatically reduced as compared with wild type DCs in both MMP-9-/- mice and wild type mice. Taken together, these results indicated that DC-derived MMP-9 is the crucial factor for DC migration, and blocking MMP-9 to inhibit DC migration may constitute a novel strategy of future therapy for RA and other similar autoimmune diseases. PMID- 30397035 TI - Critical Role of Macrophage FcgammaR Signaling and Reactive Oxygen Species in Alloantibody-Mediated Hepatocyte Rejection. AB - Humoral alloimmunity negatively impacts both short- and long-term cell and solid organ transplant survival. We previously reported that alloantibody-mediated rejection of transplanted hepatocytes is critically dependent on host macrophages. However, the effector mechanism(s) of macrophage-mediated injury to allogeneic liver parenchymal cells is not known. We hypothesized that macrophage mediated destruction of allogeneic hepatocytes occurs by cell-cell interactions requiring FcgammaRs. To examine this, alloantibody-dependent hepatocyte rejection in CD8-depleted wild-type (WT) and Fcgamma-chain knockout (KO; lacking all functional FcgammaR) transplant recipients was evaluated. Alloantibody-mediated hepatocellular allograft rejection was abrogated in recipients lacking FcgammaR compared with WT recipients. We also investigated anti-FcgammaRI mAb, anti FcgammaRIII mAb, and inhibitors of intracellular signaling (to block phagocytosis, cytokines, and reactive oxygen species [ROS]) in an in vitro alloantibody-dependent, macrophage-mediated hepatocytoxicity assay. Results showed that in vitro alloantibody-dependent, macrophage-mediated hepatocytotoxicity was critically dependent on FcgammaRs and ROS. The adoptive transfer of WT macrophages into CD8-depleted FcgammaR-deficient recipients was sufficient to induce alloantibody-mediated rejection, whereas adoptive transfer of macrophages from Fcgamma-chain KO mice or ROS-deficient (p47 KO) macrophages was not. These results provide the first evidence, to our knowledge, that alloantibody-dependent hepatocellular allograft rejection is mediated by host macrophages through FcgammaR signaling and ROS cytotoxic effector mechanisms. These results support the investigation of novel immunotherapeutic strategies targeting macrophages, FcgammaRs, and/or downstream molecules, including ROS, to inhibit humoral immune damage of transplanted hepatocytes and perhaps other cell and solid organ transplants. PMID- 30397036 TI - High FcgammaR Expression on Intratumoral Macrophages Enhances Tumor-Targeting Antibody Therapy. AB - Therapy with tumor-specific Abs is common in the clinic but has limited success against solid malignancies. We aimed at improving the efficacy of this therapy by combining a tumor-specific Ab with immune-activating compounds. In this study, we demonstrate in the aggressive B16F10 mouse melanoma model that concomitant application of the anti-TRP1 Ab (clone TA99) with TLR3-7/8 or -9 ligands, and IL 2 strongly enhanced tumor control in a therapeutic setting. Depletion of NK cells, macrophages, or CD8+ T cells all mitigated the therapeutic response, showing a coordinated immune rejection by innate and adaptive immune cells. FcgammaRs were essential for the therapeutic effect, with a dominant role for FcgammaRI and a minor role for FcgammaRIII and FcgammaRIV. FcgammaR expression on NK cells and granulocytes was dispensable, indicating that other tumoricidal functions of NK cells were involved and implicating that FcgammaRI, -III, and -IV exerted their activity on macrophages. Indeed, F4/80+Ly-6C+ inflammatory macrophages in the tumor microenvironment displayed high levels of these receptors. Whereas administration of the anti-TRP1 Ab alone reduced the frequency of these macrophages, the combination with a TLR agonist retained these cells in the tumor microenvironment. Thus, the addition of innate stimulatory compounds, such as TLR ligands, to tumor-specific Ab therapy could greatly enhance its efficacy in solid cancers via optimal exploitation of FcgammaRs. PMID- 30397038 TI - What's happening in Innovations in Care Delivery. PMID- 30397037 TI - What's happening in Neurology (r). PMID- 30397039 TI - Intrasellar herniation: A newly described variant of downward central herniation. PMID- 30397040 TI - Clinical Reasoning: A 22-year-old man presenting with headache and right leg jerks. PMID- 30397041 TI - Editors' note: Teaching Video NeuroImages: Pulsatile proptosis and wall-eyed bilateral internuclear ophthalmoplegia. PMID- 30397042 TI - Reader response: Teaching Video NeuroImages: Pulsatile proptosis and wall-eyed bilateral internuclear ophthalmoplegia. PMID- 30397043 TI - Author response: Teaching Video NeuroImages: Pulsatile proptosis and wall-eyed bilateral internuclear ophthalmoplegia. PMID- 30397044 TI - Editors' note: Usefulness of ADAMTS13 to predict response to recanalization therapies in acute ischemic stroke. PMID- 30397045 TI - Reader response: Usefulness of ADAMTS13 to predict response to recanalization therapies in acute ischemic stroke. PMID- 30397047 TI - Teaching Video NeuroImages: Pulsatile proptosis and wall-eyed bilateral internuclear ophthalmoplegia. PMID- 30397046 TI - Author response: Usefulness of ADAMTS13 to predict response to recanalization therapies in acute ischemic stroke. PMID- 30397048 TI - Pearls & Oy-sters: Windmill nystagmus in paraneoplastic cerebellar degeneration. PMID- 30397049 TI - Teaching NeuroImages: Morphology of lumbosacral dorsal root ganglia and plexus in hereditary transthyretin amyloidosis. PMID- 30397050 TI - Teaching Video NeuroImages: Ictal vomiting in a child. PMID- 30397051 TI - Rapid Detection of ERG11-Associated Azole Resistance and FKS-Associated Echinocandin Resistance in Candida auris. AB - Candida auris is an emerging multidrug-resistant yeast that can cause serious invasive infections. Accurate and rapid assessment of antifungal resistance is important for effective patient management. A novel and highly accurate diagnostic platform was established for rapid identification of ERG11 mutations conferring azole resistance and FKS1 mutations associated with echinocandin resistance in C. auris Using allele-specific molecular beacons and DNA melting curve analysis following asymmetric PCR, a duplex ERG11 assay and a simplex FKS1 HS1 assay were developed to identify the most prominent resistance-associated mutations (Y132F and K143R in ERG11; S639F in FKS1 HS1) within 2 h. Assays were validated by testing a blinded panel of 94 C. auris clinical isolates. The molecular diagnostic results from the assays were 100% concordant with DNA sequencing results. This platform has the potential to overcome the deficiencies of existing in vitro susceptibility-based assays to identify azole and/or echinocandin resistant C. auris, and thus, it holds promise as a surrogate diagnostic method to direct antifungal therapy more effectively. PMID- 30397052 TI - Microbiological Profile of Sarecycline: A Novel Targeted Spectrum Tetracycline for the Treatment of Acne Vulgaris. AB - Sarecycline is the first narrow spectrum tetracycline-class antibiotic being developed for acne treatment. In addition to exhibiting activity against important skin/soft tissue pathogens, sarecycline exhibits targeted antibacterial activity against clinical isolates of Cutibacterium acnes In the current study, sarecycline was 16 to 32-fold less active than broad spectrum tetracyclines-such as minocycline and doxycycline-against aerobic Gram-negative bacilli associated with normal human intestinal microbiome. Also, reduced activity against Escherichia coli was observed in vivo in a murine septicemia model with PD50 values at >40 mg/kg and 5.72 mg/kg for sarecycline and doxycycline, respectively. Sarecycline was also 4 to 8-fold less active against representative anaerobic bacteria that also comprise normal human intestinal microbiome. Additionally, sarecycline displayed a low propensity for resistance development in C. acnes strains, with spontaneous mutation frequencies of 10-10 at 4 to 8-times the MIC, similar to minocycline and vancomycin. When tested against Gram-positive pathogens with defined tetracycline resistance mechanisms, sarecycline was more active than tetracycline against the tet(K) and tet(M) strains, with MIC ranging from 0.125 to 1.0 ug/mL and 8 ug/mL, respectively, compared with 16 to 64 ug/mL and 64 ug/mL for tetracycline, respectively. However, sarecycline activity in the tet(K) and tet(M) strains were decreased compared to wildtype, which demonstrated MIC ranging from 0.06 to 0.25 ug/mL, though not as pronounced as tetracycline. These findings support sarecycline as a narrow spectrum tetracycline-class antibiotic that is an effective agent for the treatment of acne and further warrants investigation into the potential reduced effects on the gut microbiome. PMID- 30397053 TI - Characterization of the first OXA-10 natural variant with increased carbapenemase activity. AB - While carbapenem resistance in Gram-negatives is mainly due to production of efficient carbapenemases, beta-lactamases with narrower spectrum may also contribute to resistance when combined with additional mechanisms. OXA-10 type class D beta-lactamases, previously shown to be weak carbapenemases, could represent such a case. In this study two novel OXA-10 variants were identified as the sole carbapenem hydrolyzing enzymes in meropenem resistant Enterobacteria isolated from hospital waste water and found by NGS to express additional beta lactam resistance mechanisms. The new variants, OXA-655 and OXA-656, were carried by two related IncQ1 broad-host plasmids. Compared to OXA-10 they both harbor a Thr26Met substitution with OXA-655 also baring leucine instead of valine in position 117 of the SAV catalytic motif. Susceptibility profiling of laboratory strains replicating the natural bla OXA plasmids and of recombinant clones expressing OXA-10 and the novel variants in isogenic background indicated that OXA-655 is a more efficient carbapenemase. The carbapenemase activity of OXA-655 is due to the Val117Leu substitution as shown by steady state kinetic experiments where the k cat of meropenem hydrolysis was increased 4-fold. In contrast, OXA 655 has no activity towards oxyimino beta-lactams while its catalytic efficiency against oxacillin is significantly reduced. Moreover, the Val117Leu variant is more efficient against temocillin and cefoxitin. Molecular dynamics indicated that Val117Leu affects the 117-Leu155 interaction leading to structural shifts in the active site that may alter carbapenem alignment. The evolutionary potential of OXA-10 enzymes towards carbapenem hydrolysis combined with their spread by promiscuous plasmids indicates that they may pose a future clinical threat. PMID- 30397054 TI - Genetic correlation of antibiotic susceptibility and resistance genotyping for Mycobacterium abscessus group. AB - Treatment efficacy of Mycobacterium abscessus infections depends on bacterial genotype. Here the relationship between genotype, as determined using sequence analysis, and antibiotic resistance phenotype was analyzed. The results demonstrate that Mycobacterium abscessus genotype characteristics, including erm(41) sequevar, and mutations of rrl and rrs, are predictive of clarithromycin and amikacin resistance. PMID- 30397055 TI - Daptomycin resistance and tolerance due to loss-of-function in Staphylococcus aureus dsp1 and asp23. AB - Lipopeptide daptomycin is a last line cell membrane-targeting antibiotic to treat multidrug-resistant Staphylococcus aureus Alarmingly, daptomycin-resistant S. aureus isolates have emerged. The mechanisms underlying daptomycin resistance are diverse, share similarities with resistance to cationic antimicrobial peptides and other lipopeptides, but remain to be fully elucidated. We selected mutants with increased resistance to daptomycin from a library of transposon insertions in ST8 S. aureus HG003. Insertions in conferring increased daptomycin resistance were localized to two genes, one coding for a hypothetical lipoprotein (SAOUHSC_00362, Dsp1), and the other for an alkaline shock protein (SAOUHSC_02441, Asp23). Markerless loss of function mutants were then generated for comparison. All transposon mutants and knockout strains exhibited increased daptomycin resistance compared to wild type and complemented strains. Null and transposon insertion mutants also exhibited increased resistance to cationic antimicrobial peptides. Interestingly, Deltadsp1 also showed increased resistance to vancomycin, a cell wall targeting drug with a different mode of action. Null mutations in both dsp1 and asp23 displayed increased tolerance as reflected by reduced killing to both daptomycin and vancomycin, as well as an increased tolerance to surfactant (Triton X-100). Neither mutant exhibited increased resistance to lysostaphin, a cell wall targeting endopeptidase. These findings identified two genes core to the S. aureus species, that make previously uncharacterized contributions to antimicrobial resistance and tolerance in S. aureus. PMID- 30397057 TI - Azole resistance reduces susceptibility to the tetrazole antifungal VT-1161. AB - Tetrazole antifungals designed to target fungal lanosterol 14alpha-demethylase (LDM) appear effective against a range of fungal pathogens. In addition, a crystal structure of the catalytic domain of Candida albicans LDM in complex with the tetrazole VT-1161 has been obtained. We have addressed concern about artefacts that might arise from crystallizing VT-1161 with truncated recombinant CYP51s and measured the impact on VT-1161 susceptibility of genotypes known to confer azole resistance. A yeast system was used to overexpress recombinant full length Saccharomyces cerevisiae LDM with a C-terminal hexahistidine tag (ScLDM6*His) for phenotypic analysis and crystallographic studies with VT-1161 or with the widely-used triazole drug posaconazole (PCZ). We determined the effect of characterized mutations in LDM on VT-1161 activity and identified drug efflux pumps from fungi, including key fungal pathogens, that efflux VT-1161. The relevance of these yeast-based observations on drug efflux was verified using clinical isolates of C. albicans and C. glabrata VT-1161 binding elicits a significant conformational difference between the full-length and truncated enzymes not found when posaconazole is bound. Susceptibility to VT-1161 is reduced by ATP-binding cassette (ABC) and major facilitator superfamily (MFS) drug efflux pumps, the overexpression of LDM and mutations within the drug binding pocket of LDM that affect interaction with the tertiary alcohol of the drug. PMID- 30397056 TI - In Vitro Activity of Sulopenem, an Oral Penem, Against Urinary Isolates of Escherichia coli. AB - The in vitro activity of sulopenem was assessed against a 2014-2016 collection of 539 urinary isolates of Escherichia coli from Canadian patients using CLSI defined broth microdilution methodology. A concentration of sulopenem of 0.03 ug/ml inhibited both 50% (MIC50) and 90% (MIC90) of isolates tested; sulopenem MICs ranged from 0.015 to 0.25 ug/ml. The in vitro activity of sulopenem was unaffected by non-susceptibility to trimethoprim-sulfamethoxazole and/or ciprofloxacin, multidrug-resistant (MDR) phenotypes, extended-spectrum beta lactamases (ESBLs), or AmpC beta-lactamases. PMID- 30397058 TI - Effect of Moxifloxacin plus Pretomanid against Mycobacterium tuberculosis in Log phase, Acid-phase and Non-Replicating-Persister (NRP)-phase in an in vitro Assay. AB - Combination therapy is a successful approach to treat tuberculosis in patients with susceptible strains of Mycobacterium tuberculosis (M. tuberculosis). However, the emergence of resistant strains requires identification of new, effective therapies. Pretomanid (PA824) and moxifloxacin (MXF) are promising options currently under evaluation in clinical trials for the treatment of susceptible and resistant mycobacteria. We applied our recently described screening strategy to characterize the interaction between PA824 and MXF towards killing of M. tuberculosis in Logarithmic growth phase (Log-phase), Acid-phase and Non-Replicating Persister phase (NRP-phase). Respective in vitro data generated for H37Rv and 18b strains, was evaluated in a microdilution plate system containing both drugs in combination. The Universal Response Surface Approach model from Greco was used to characterize the nature of interaction between both drugs; synergistic or additive combinations would prompt additional evaluation in the hollow fiber infection model (HFIM) and in animal studies. The interaction between MXF and PA824 was additive against M. tuberculosis in Acid phase (alpha = 5.56e-8 with 95% CI = -0.278 to 0.278 and alpha = 0.408; 95% CI = 0.105 to 0.711), NRP-phase (alpha = 0.625 with 95% CI =-0.556 to 1.81 and alpha = 2.92 with 95% CI = 0.215 to 5.63), and Log-phase organisms (alpha = 1.57e-6 with 95% CI = -0.930 to 0.930 and alpha = 1.83e-6 with 95% CI= -0.929 and 0.929), prompting further testing of this promising combination for the treatment of tuberculosis in the HFIM and in animal studies. PMID- 30397059 TI - Pharmacodynamics of Minocycline Against Acinetobacter baumannii in a Rat Pneumonia Model. AB - Minocycline is currently approved in the US for the treatment of infections caused by susceptible isolates of Acinetobacter spp The objective of these studies was to determine the minocycline exposures associated with antibacterial effect against A. baumannii in a rat pneumonia model. Rats received minocycline doses as 30 minute intravenous infusions. In the rat pneumonia model, six clinical isolates of A. baumannii, with MICs ranging between 0.03 - 4 mg/L, were studied. In this model, minocycline produced a bacteriostatic effect with a free 24h AUC/MIC of 10 - 16 and produced 1-log of bacterial killing with a free 24h AUC/MIC of 13 - 24. These exposures can be achieved with the current FDA approved dosage regimens of IV minocycline. PMID- 30397060 TI - Rutin attenuates vancomycin-induced nephrotoxicity by ameliorating oxidative stress, apoptosis and inflammation in rats. AB - Nephrotoxicity is the major limiting factor for the clinical use of vancomycin (VCM) for treatment of serious infections caused by multi-resistant Gram-positive bacteria. This study investigated the renal protective activity of rutin in a rat model of VCM-induced kidney injury in male Wistar rats. VCM intraperitoneally at 200 mg/kg twice daily for 7 successive days resulted in significant elevation of blood urea nitrogen and creatinine as well as urinary N-acetyl-beta-D glucosaminidase. Co-administration of VCM with oral rutin at 150 mg/kg significantly reduced these markers of kidney damage. Rutin also significantly attenuated VCM-induced oxidative stress, inflammatory cell infiltration, apoptosis and decreased IL-1beta and TNF-alpha levels (all P<0.05 or 0.01) in kidneys. Renal recovery from VCM injury was achieved by rutin through increases in Nrf2 and HO-1 and a decrease in NF-kB expression. Our results demonstrated a protective effect of rutin on VCM-induced kidney injury through suppression of oxidative stress, apoptosis and down regulation of the inflammatory response. This study highlights a role for oral rutin as an effective intervention to ameliorate nephrotoxicity in patients undergoing VCM therapy. PMID- 30397061 TI - A systematic review of single-dose aminoglycoside therapy for urinary tract infection: Is it time to resurrect an old strategy? AB - Background/Objective: Increasing bacterial resistance and poor patient adherence rates limit the effectiveness of conventional antibiotic therapies for urinary tract infection (UTI). The objective of this study was to investigate whether a single aminoglycoside dose adequately treated UTI.Methods: A systematic search of PubMed/MEDLINE and Google Scholar databases was performed through September 2018 for English-language original research articles assessing the efficacy of one time parenteral aminoglycoside as UTI monotherapy.Results: Of 252 potentially relevant studies, 13 met inclusion criteria, representing 13,804 patients. Patient age ranged from 2 weeks to >70 years; both inpatient and outpatient settings were represented. Cystitis was more common than pyelonephritis and more females were represented than males. Escherichia coli was the most commonly isolated uropathogen. The pooled microbiologic cure rate with single-dose aminoglycoside therapy was 94.5% +/- 4.3%. Cure was sustained (no recurrence) for 73.4% +/- 9.6% of patients at day 30. Lower cure rates were observed among patients with radiographic urinary tract abnormality (Chi-square P<0.01). Across all studies, 63/13804 (0.5%) cases of nephrotoxicity, vestibular toxicity, or injection site reaction were reported; no hearing loss was observed.Conclusions: Single-dose aminoglycoside therapy appears to be an effective treatment option for lower UTI in non-septic patients, with minimal toxicity. Additional studies would be beneficial to confirm efficacy for pyelonephritis. When resistance to first-line UTI agents is endemic, aminoglycosides may serve as beta-lactam and fluoroquinolone-sparing options. PMID- 30397062 TI - Evolution of rifampicin resistance due to substandard drugs in E. coli and M. smegmatis. AB - Poor-quality medicines undermine the treatment of infectious diseases such as tuberculosis, which requires months of treatment with rifampicin and other drugs. Rifampicin resistance is a critical concern for tuberculosis treatment. While sub therapeutic doses of medicine are known to select for antibiotic resistance, the effect of drug degradation products on the evolution of resistance is unknown. Here, we demonstrate that substandard drugs that contain degraded active pharmaceutical ingredients select for gene alterations that confer resistance to standard drugs. We generated drug resistant E. coli and M. smegmatis strains by serially culturing bacteria in the presence of the degradation product of rifampicin, rifampicin quinone. We conducted Sanger sequencing to identify mutations in rifampicin resistant populations. Strains resistant to rifampicin quinone developed cross-resistance to the standard drug rifampicin, with some populations showing no growth inhibition at maximum concentrations of rifampicin. Sequencing of the rifampicin quinone treated strains indicated that they acquired mutations in the DNA-dependent RNA polymerase B subunit. These mutations were localized in the rifampicin resistance determining region (RRDR), consistent with other reports of rifampicin resistant E. coli and Mycobacteria. Rifampicin quinone treated mycobacteria also had cross-resistance to other rifamycin class drugs: rifabutin and rifapentine. Our results strongly suggest that substandard drugs not only hinder individual patient outcomes, but also restrict future treatment options by actively contributing to the development of resistance to standard medicines. PMID- 30397063 TI - Pharmacokinetics/Pharmacodynamics of Vaborbactam, a Novel Beta-lactamase Inhibitor, in Combination with Meropenem. AB - Vaborbactam is a novel beta-lactamase inhibitor with activity against important beta-lactamases, in particular, serine carbapenemases, and is currently approved in combination with meropenem as VabomereTM for the treatment of complicated urinary tract infections, including pyelonephritis. This combination is highly active against Gram-negative pathogens, especially KPC-producing, carbapenem resistant, Enterobacteriaceae The objective of these studies was to evaluate vaborbactam pharmacokinetics (PK) and pharmacodynamics (PD) relationships for efficacy in a neutropenic mouse thigh infection model and as well in an in vitro hollow fiber infection model, in combination with a fixed exposure of meropenem using KPC-containing strains of Enterobacteriaceae For both models, the meropenem dosage regimen was designed to simulate a 2 g dose administered every eight hours (q8h) by three hour infusion. Vaborbactam dosage regimens were designed to produce a wide range of 24 hour AUCs in the thigh infection model. However, for the hollow fiber model, the AUCs were limited to values of 192, 320 or 550 mg*h/L. In both the animal and in vitro models, the PK-PD parameter that best described the antibacterial activity of vaborbactam, when administered in combination with meropenem at exposures equivalent to 2 g dosed q8h by three hour infusion in humans, was the 24 hour free vaborbactam AUC/meropenem-vaborbactam (with vaborbactam at 8 mg/L) MIC ratio. The magnitude of this ratio for bacteriostasis was 9 -12 and the magnitude to observe a 1-log kill was 18 - 38. In addition, a magnitude greater than 24 suppressed the development of resistance in the in vitro hollow fiber model. PMID- 30397064 TI - Emergence of Voriconazole-resistant Aspergillus flavus Isolates in Korean Hospitals: Microsatellite Typing and Resistance Mechanism Analysis. AB - A recent surveillance study in Korea revealed that 14% (7/50) of Aspergilus flavus clinical isolates had a voriconazole minimum inhibitory concentration >= 4 ug/mL. Of seven non-wild-type (non-WT) isolates, six ear isolates from four hospitals shared the same microsatellite genotype. None of non-WT isolates showed cyp51 mutations associated with azole resistance. However, the mean expression levels of efflux pumps (MDR2, atrF, and mfs1) and target (cyp51A) genes exhibited significant differences between non-WT and other isolates. PMID- 30397065 TI - Cidofovir Diphosphate Inhibits Adenovirus 5 DNA Polymerase via Both Non-Obligate Chain Termination and Direct Inhibition, and Polymerase Mutations Confer Cidofovir Resistance on Intact Virus. AB - Human adenovirus (AdV) can cause fatal disease in immune suppressed individuals, but treatment options are limited - in part because the antiviral cytidine analog, cidofovir (CDV), is nephrotoxic. The investigational agent brincidofovir (BCV) is orally bioavailable, non-nephrotoxic, and generates the same active metabolite, cidofovir diphosphate (CDVpp). However, its mechanism of action against AdV is poorly understood. We have therefore examined the effect of CDVpp on DNA synthesis by a purified AdV5 DNA polymerase (pol). CDVpp was incorporated into nascent DNA strands, and promoted a non-obligate form of chain termination (i.e., AdV5 pol can extend, albeit inefficiently, a DNA chain even after the incorporation of a first CDVpp molecule). Moreover, unlike a conventional mismatched base pair, misincorporated CDVpp was not readily excised by the AdV5 pol. At elevated concentrations, CDVpp inhibited AdV5 pol in a manner consistent with both chain termination and direct inhibition of pol activity. Finally, a recombinant AdV5 virus was constructed, containing pol mutations (V303I, T87I) that were selected following extended passage of wild-type AdV5 in the presence of BCV. This virus had a 2.1-fold elevated EC50 for BCV, and 1.9 fold increased EC50 for CDV - thus confirming that viral resistance to BCV and CDV can be attributed to mutations in the viral pol. These findings show that the anti-AdV5 activity of CDV and BCV is mediated through the viral DNA pol, and that their antiviral activity may occur via both (non-obligate) chain termination and (at high concentration) direct inhibition of AdV5 pol activity. PMID- 30397066 TI - Effect of rifampin/isoniazid-containing antituberculosis therapy on efavirenz pharmacokinetics in HIV-infected children aged 3 to 14 years old. AB - We compared efavirenz pharmacokinetic (PK) parameters in children with TB/HIV coinfection on and off first-line antituberculosis therapy to that in HIV infected children. Children aged 3 to 14 years old with HIV infection with and without TB were treated with standard efavirenz-based antiretroviral therapy without any efavirenz dose adjustments. The new World Health Organization recommended antituberculosis drugs dosages were used in the co-infected participants. Steady-state efavirenz concentrations after 4 weeks of antiretroviral therapy were measured using validated LC/MS/MS assays. Pharmacokinetic parameters were calculated using noncompartmental analysis. Between groups, PK parameters were compared by Wilcoxon Rank-sum test and within group by Signed-rank test. Of the 105 participants, 43 (41.0%) had TB coinfection. Children with TB/HIV coinfection compared to those with HIV infection were younger, had lower median weight-for-age-Z-score and received a higher median efavirenz weight-adjusted dose. Geometric mean (GM) efavirenz Cmax, C12h, Cmin and AUC0-24h were similar in children with HIV infection and those with TB/HIV coinfection during anti-TB therapy. Geometric mean efavirenz C12h, Cmin and AUC0-24h were lower in TB/HIV co-infected patients off anti-TB therapy than in the children with HIV infection or TB/HIV coinfection on anti-TB therapy. Efavirenz clearance was lower and AUC0-24h was higher on than off anti-TB therapy. Reduced efavirenz clearance by first-line anti-TB therapy at the population level led to similar PK parameters in HIV-infected children with and without TB coinfection. Our findings do not support modification of efavirenz weight-band dosing guidelines based on TB coinfection status in children. PMID- 30397067 TI - Single-Center Evaluation of the Pharmacokinetics of WCK 5222 (Cefepime-Zidebactam Combination) in Subjects with Renal Impairment. AB - WCK 5222 is a novel beta-lactam-beta-lactam enhancer combination of cefepime (FEP) and zidebactam (ZID). ZID is a novel beta-lactam enhancer with a dual action of binding to Gram-negative PBP2 and beta-lactamase inhibition. WCK 5222 is being developed as a new therapeutic option for the treatment of complicated multidrug-resistant Gram-negative pathogens. We investigated the effect of renal impairment on the pharmacokinetics (PK) and safety of WCK 5222 in forty-eight subjects based on Cockcroft-Gault-estimated creatinine clearance (CLCR). We enrolled mild (n = 6; CLCR 60 to < 90 mL/min), moderate (n = 6; CLCR 30 to < 60 mL/min), severe (n = 6; CLCR < 30 mL/min; not on dialysis), end-stage renal disease (ESRD) on hemodialysis (HD) (n = 6), and matched normal controls (n = 24; CLCR >= 90 mL/min). Healthy control subjects, mild and moderate renal impairment subjects received a single 60-min IV infusion of 3 g WCK 5222 (2 g FEP/1 g ZID); severe renal impairment and HD subjects received a single 60-min IV infusion of WCK 5222, 1.5 g (1 g FEP/0.5 g ZID). Body and renal clearance decreased and plasma half-life (T1/2) and AUC0-infinity (hr*ug/mL) increased in a graded relationship with severity of renal impairment for both FEP and ZID. Our findings suggest that dose adjustments for WCK 5222 will be required according to the degree of renal impairment. Overall, WCK 5222 (FEP-ZID) was found to be safe and well tolerated in subjects with normal and impaired renal function. PMID- 30397068 TI - MSH2 gene point mutations are not antifungal resistance markers in Candida glabrata. AB - The high rates of antifungal resistance in Candida glabrata may be facilitated by the presence of alterations in the MSH2 gene. We aimed to study the sequence of the MSH2 gene in 124 invasive C. glabrata isolates causing incident episodes of candidemia (n=81), subsequent candidemia episodes (n=9), endocarditis (n=2), and in vitro-generated echinocandin-resistant isolates (n=32) and assessed its relationship with genotypes, acquisition of antifungal resistance in vivo and in vitro, and patient prognosis. MSH2 gene was sequenced and isolates were genotyped using six microsatellite markers and MLST based on six housekeeping genes. According to EUCAST, isolates causing candidemia (n = 90) were echinocandin susceptible, and four of them were fluconazole resistant (MIC >= 64 mg/L). One isolate from the heart valve was resistant to micafungin and anidulafungin (MIC= 2 mg/L and 1 mg/L, respectively). MSH2 gene mutations were present in 44.4% of incident isolates, the most common being V239L. Presence of MSH2 mutations was not correlated with in vitro or in vivo antifungal resistance. Microsatellite and MLST respectively revealed 27 genotypes and 17 sequence types. Fluconazole resistant isolates were unrelated. Most MSH2 mutations were found in cluster isolates; conversely, some mutations were found in more than one genotype. No clinical differences - including previous antifungal use - were found between patients infected by wild-type MSH2 gene isolates and isolates with any point mutation. The presence of MSH2 gene mutations in C. glabrata isolates causing candidemia is not correlated with specific genotypes, the promotion of antifungal resistance, or the clinical outcome. PMID- 30397069 TI - Whole genome sequencing for predicting clarithromycin resistance in Mycobacterium abscessus. AB - Mycobacterium abscessus is emerging as an important pathogen in chronic lung diseases with concern regarding patient to patient transmission. The recent introduction of routine whole genome sequencing (WGS) as a replacement for existing reference techniques in England provides an opportunity to characterise the genetic determinants of resistance. We conducted a systematic review to catalogue all known resistance determining mutations. This knowledge was used to construct a predictive algorithm based on mutations in the erm(41) and rrl genes which was tested on a collection of 203 sequentially acquired clinical isolates for which there was paired genotype/phenotype data. A search for novel resistance determining mutations was conducted using an heuristic algorithm.The sensitivity of existing knowledge for predicting resistance in clarithromycin was 95% (95% CI 89 - 98%) and the specificity was 66% (95% CI 54 - 76%). Subspecies alone was a poor predictor of resistance to clarithromycin. Eight potential new resistance conferring SNPs were identified. WGS demonstrates probable resistance determining SNPs in regions the NTM-DR line probe cannot detect. These mutations are potentially clinically important as they all occurred in samples predicted to be inducibly resistant, and for which a macrolide would therefore currently be indicated. We were unable to explain all resistance, raising the possibility of the involvement of other as yet unidentified genes. PMID- 30397070 TI - Effects of Microplate Type and Broth Additives on Microdilution MIC Susceptibility Assays. AB - The determination of antibiotic potency against bacterial strains by assessment of their minimum inhibitory concentration normally uses a standardized broth microdilution assay procedure developed more than 50 years ago. However, certain antibiotics require modified assay conditions in order to observe optimal activity. For example, daptomycin requires media supplemented with Ca2+ and the lipoglycopeptides dalbavancin and oritavancin require Tween-80 to be added to the growth media to prevent depletion of free drug via adsorption to the plastic microplate. In this report we examine systematically the effects of several different plate types on microdilution broth MIC values for a set of antibiotics against Gram-positive and Gram-negative bacteria, both in media alone and in media supplemented with commonly used additives Tween-80, lysed horse blood, and 50% human serum. We observe very significant differences in measured MICs (up to 100-fold) for some lipophilic antibiotics, such as the Gram-positive lipoglycopeptide dalbavancin and the Gram-negative lipopeptide polymyxins, and find that non-specific binding plates can replace the need for surfactant additives. Microtitre plate types and any additives should be specified when reporting broth dilution MIC values as results can vary dramatically for some classes of antibiotics. PMID- 30397071 TI - Inducible cell fusion permits use of competitive fitness profiling in the human pathogenic fungus Aspergillus fumigatus. AB - Antifungal agents directed against novel therapeutic targets are required for treating invasive, chronic and allergic Aspergillus infections. Competitive fitness profiling technologies have been used in a number of bacterial and yeast systems to identify druggable targets however, development of similar systems in filamentous fungi are complicated by the fact that they undergo cell fusion and heterokaryosis. Here we demonstrate that cell fusion in A. fumigatus under standard culture conditions is not predominately constitutive, as with most ascomycetes, but can be induced by a range of extracellular stressors. Using this knowledge, we have developed a barcode-free genetic profiling system that permits high throughput parallel determination of strain fitness in a collection of diploid A. fumigatus mutants. We show heterozygous null mutants in cyp51A and arf2 have reduced fitness in the presence of Itraconazole and Brefeldin A respectively and a heterozygous null of atp17 is resistant to Brefeldin A. PMID- 30397072 TI - IL-8 Activates Breast Cancer-Associated Adipocytes and Promotes Their Angiogenic and Tumorigenic Promoting Effects. AB - Increasing evidence supports the critical role of active stromal adipocytes in breast cancer development and spread. However, the mediators and the mechanisms of action are still elusive. We have shown here that cancer-associated adipocytes (CAAs) isolated from 10 invasive breast carcinomas are pro-inflammatory and exhibit active phenotypes, including higher proliferative, invasive and migratory capacities as compared to their adjacent tumor-counterpart adipocytes (TCAs). Furthermore, all CAAs secreted higher level of IL-8, which is critical in mediating the paracrine pro-carcinogenic effects of these cells. Importantly, ectopic expression of IL-8 in TCA cells activated them and enhanced their pro carcinogenic effects both in vitro, in a STAT3-dependent manner, and in vivo By contrast, inhibition of the IL-8 signaling using specific shRNA, anti-IL-8 antibody, or reparixin suppressed the active features of CAAs, including their non-cell-autonomous tumor-promoting activities both on breast luminal cells and in orthotopic tumor xenografts in mice. IL-8 played also an important role in enhancing the pro-angiogenic effects of breast adipocytes. These results provide clear indication that IL-8 plays key roles in the activation of breast CAAs, and acts as a major mediator for their paracrine pro-tumorigenic effects. Thereby, targeting CAAs through inhibiting the IL-8 pathway could be of great therapeutic values. PMID- 30397073 TI - Hypoxia Restrains Lipid Utilization via Protein Kinase A and ATGL Downregulation through Hypoxia Inducible Factor. AB - Oxygen is a key molecule for efficient energy production in living organisms. Although aerobic organisms have adaptive processes to survive in low-oxygen environments, it is poorly understood how lipolysis, the first step of energy production from stored lipid metabolites, would be modulated during hypoxia. Here, we demonstrate that fasting-induced lipolysis is downregulated by hypoxia through the hypoxia-inducible factor (HIF) signaling pathway. In Caenorhabditis elegans and mammalian adipocytes, hypoxia suppressed protein kinase A (PKA) stimulated lipolysis, which is evolutionarily well conserved. During hypoxia, the levels of PKA activity and adipose triglyceride lipase (ATGL) protein were downregulated, resulting in attenuated fasting-induced lipolysis. In worms, HIF stabilization was sufficient to moderate the suppressive effect of hypoxia on lipolysis through ATGL and PKA inhibition. These data suggest that HIF activation under hypoxia plays key roles in the suppression of lipolysis, which might preserve energy resources in both C. elegans and mammalian adipocytes. PMID- 30397074 TI - Novel Lines of Evidence for the Asymmetric Strand Displacement Model of Mitochondrial DNA Replication. AB - The mitochondrial (mt) genome, which consists of 16,569 base pairs of DNA with a cytosine rich light (L) strand and a heavy (H) strand, exists as a multi-copy closed circular genome within the mitochondrial matrix. The machinery for replication of the mammalian mitochondrial genome is distinct from that for replication of the nuclear genome. Three models have been proposed for mtDNA replication, and one of the key differences among them is whether extensive single-stranded regions exist on the H-strand. Here, three different methods that can detect single-stranded DNA (ssDNA) are utilized to identify the presence, location, and abundance of ssDNA on mtDNA. Importantly, none of these newly described methods involve the complication of prior mtDNA fractionation. The H strand is found to have extensive single-stranded regions with a profile consistent with the strand displacement model of mtDNA replication whereas single strandedness is predominantly absent on the L-strand. These findings are consistent with the in vivo occupancy of mitochondrial single-stranded DNA binding protein reported previously and provide strong new qualitative and quantitative evidence for the asymmetric strand displacement model of mtDNA replication. PMID- 30397075 TI - SNW1 as a novel transcriptional regulator of the NF-kappaB pathway. AB - The nuclear factor-kappa B (NF-kappaB) family of transcription factors plays a central role in coordinating the expression of genes that control inflammation, immune responses, cell-proliferation, and a variety of other biological processes. In an attempt to identify novel regulators of this pathway, we performed whole-genome RNAi screens in physiologically relevant human macrophages in response to Lipopolysaccharides and Tumor Necrosis Factor Alpha. The top hit was SNW1, a splicing factor and transcriptional co-activator. PMID- 30397076 TI - Coordinated regulation of intracellular fascin distribution governs tumor microvesicle release and invasive cell capacity. AB - Tumor cell invasion is one result of the bidirectional interactions occurring between tumor cells and the surrounding milieu. The ability of tumor cells to invade through the extracellular matrix is in part regulated by the formation of a class of protease-loaded extracellular vesicles, called tumor microvesicles (TMVs), which are released directly from the cell surface. Here we show that the actin bundling protein, fascin, redistributes to the cell periphery in a ternary complex with podocalyxin and ezrin, where it promotes TMV release. The peripheral localization of fascin is prompted by the loss of Rab35 signaling which in turn unleashes ARF6 activation. The results, is a mechanism through which Rab35 and ARF6 cooperatively and simultaneously regulate the distribution and localization of fascin; and promote oncogenic signaling which leads to TMV release while inhibiting invadopodia formation. These studies are clinically significant as fascin-loaded TMVs can be detected in bodily fluids and elevated fascin expression coupled with low Rab35 levels correlates with poor overall survival in some cancers. PMID- 30397077 TI - Senescent breast luminal cells promote carcinogenesis through IL-8-dependent activation of stromal fibroblasts. AB - Aging and stress promote senescence, which has intrinsic tumor suppressor functions and extrinsic tumor promoting properties. Therefore, it is of utmost importance to delineate the effects of senescence-inducers on the various types of cells that compose the different organs. We have shown here that primary normal breast luminal (NBL) cells are more sensitive than their corresponding stromal fibroblasts to proliferative as well as oxidative damage-induced senescence. Like fibroblasts, senescent NBL cells secreted elevated amount of various cytokines including IL-6 and Il-8, expressed high level of p16, p21 and p53 while LaminB1 was down-regulated. When senescent, luminal cells activated stromal fibroblasts in an IL-8-dependent manner, through the activation of the STAT3 pathway. These myofibroblasts promoted the epithelial-to-mesenchymal transition and the stemness processes in breast cancer cells in a paracrine manner both in vitro and in breast cancer animal model. These results show the role of senescent breast luminal cells in promoting imflammatory/carcinogenic microenvironment through the activation of fibroblasts in an IL-8-dependent manner. PMID- 30397079 TI - Tar Heel Footprints in Health Care: Jeff Spade. PMID- 30397078 TI - Effects and costs of implementing predictive risk stratification in primary care: a randomised stepped wedge trial. AB - AIM: We evaluated the introduction of a predictive risk stratification model (PRISM) into primary care. Contemporaneously National Health Service (NHS) Wales introduced Quality and Outcomes Framework payments to general practices to focus care on those at highest risk of emergency admission to hospital. The aim of this study was to evaluate the costs and effects of introducing PRISM into primary care. METHODS: Randomised stepped wedge trial with 32 general practices in one Welsh health board. The intervention comprised: PRISM software; practice-based training; clinical support through two 'general practitioner (GP) champions' and technical support. The primary outcome was emergency hospital admissions. RESULTS: Across 230 099 participants, PRISM implementation increased use of health services: emergency hospital admission rates by 1 % when untransformed (while change in log-transformed rate DeltaL=0.011, 95% CI 0.010 to 0.013); emergency department (ED) attendance rates by untransformed 3 % (while DeltaL=0.030, 95% CI 0.028 to 0.032); outpatient visit rates by untransformed 5 % (while DeltaL=0.055, 95% CI 0.051 to 0.058); the proportion of days with recorded GP activity by untransformed 1 % (while DeltaL=0.011, 95% CI 0.007 to 0.014) and time in hospital by untransformed 3 % (while DeltaL=0.029, 95% CI 0.026 to 0.031). Thus NHS costs per participant increased by L76 (95% CI L46 to L106). CONCLUSIONS: Introduction of PRISM resulted in a statistically significant increase in emergency hospital admissions and use of other NHS services without evidence of benefits to patients or the NHS. PMID- 30397080 TI - Motor Vehicle Crash Case Definitions and How They Impact Injury Surveillance. AB - BACKGROUND Motor vehicle crashes are a leading cause of injury in North Carolina. Motor vehicle crash injury surveillance that relies on hospital diagnostic codes alone may underestimate injury. Our objective was to describe how motor vehicle crash injury case definitions can impact results when using hospital data.METHODS We received motor vehicle crash-related emergency department visits from 1 large metropolitan county in North Carolina for the year 2013. Emergency department visits were categorized based on 3 mutually exclusive case definitions: motor vehicle crash injuries identified using external cause-of-injury codes, text searches for motor vehicle crash-related key words in triage notes or chief complaint fields, and motor vehicle crash injuries identified using both text searches and external cause-of-injury codes. Descriptive statistics were used to examine differences in patient characteristics according to case definition.RESULTS Most emergency department visits contained both motor vehicle crash text and motor vehicle crash external cause-of-injury codes (N = 13,422, 76%). Patients identified using external cause-of-injury codes only were more likely to be male, arrive by ambulance, and be admitted to the hospital compared to patients identified by text searches or both text and external cause-of-injury codes. Twenty-eight percent of the patients (N = 5,021) received non-injury related diagnoses in the emergency department. Among these patients, the most frequently used first diagnoses were for vague or chronic pain conditions.LIMITATIONS We relied on secondary data and were unable to perform medical chart reviews; hospital data have limited information surrounding the crash event.CONCLUSION The choice of case definition used for motor vehicle crash surveillance impacts the picture of motor vehicle crash injury severity. It is important for researchers to be aware of the impact case definition has on their results. PMID- 30397082 TI - Say It Ain't So-But Tellin' It Like It Is. PMID- 30397081 TI - Challenges Faced by Latino Caregivers in Transportation of Children with Medical Complexity. AB - BACKGROUND Transportation challenges affect access to health care. Our objective was to describe transportation challenges faced by Latino children with medical complexity and identify strategies that could address these challenges.METHODS This is a qualitative study. Seventy Latino children with medical complexity who were enrolled in a complex care program of a tertiary care children's hospital were followed for a median duration of 18 months. Qualitative data were care coordination notes for each child obtained from care coordinators' encounter logs and reported experiences. Using thematic content analysis and an iterative process, we identified recurrent themes related to transportation challenges.RESULTS Caregivers of Latino children with medical complexity face many challenges transporting their children to medical appointments. These include lack of vehicle, inability to drive, lack of driver's license due to immigration status, and lack of resources to maintain a vehicle. As a result, Latino children with medical complexity often need non-emergency medical transportation, but caregivers find these systems difficult to use, in part because of language difficulties. Thus, they rely on care coordinators to access non-emergency medical transportation. Transportation problems can lead to missed medical appointments for the child and lost work for the caregiver. We identified interrelated factors that contributed to transportation issues for Latino children with medical complexity and potential strategies to address them.LIMITATIONS The extent of transportation challenges cannot be discerned because this is a qualitative study.CONCLUSIONS Transportation is difficult for Latino children with medical complexity, who rely on non-emergency medical transportation to access medical services. Care coordinators play a major role in addressing transportation problems for Latino children with medical complexity and their caregivers. PMID- 30397083 TI - Looking Back But Leaning Forward: New Opportunities and Challenges for North Carolina's Rural Communities. AB - Rural North Carolina is as diverse as it is beautiful. Each community, county, and region presents a unique set of challenges and opportunities in maintaining and improving the health of its people. Forty-five years ago, Jim Bernstein and other leaders in the state understood that in order to provide access to care and equalize the chances rural North Carolinians have to thrive, a focused approach was necessary. And so it began: through the efforts of these leaders, the first Office of Rural Health was born in North Carolina. There is much to celebrate this year and there is much work ahead. Rural North Carolina is celebrated because of the engagement of rural citizens in their communities and their grit and resourcefulness in tough times and good times. This volume of the North Carolina Medical Journal (NCMJ) is dedicated to those leaders, rural providers, and their communities as they strive to make the best of whatever situation they find themselves in. This is also an opportunity for each of us to consider and learn from the past and bring our best thinking to the future. PMID- 30397084 TI - The Sufficiency of Health Care Professional Supply in Rural North Carolina. AB - For most health professions, rural North Carolina has lower relative supply than urban parts of the state. Although there are plenty of innovative models addressing this disparity, a holistic approach is necessary if we want to effect real change. PMID- 30397085 TI - A Rural Hospital Gets A Second Chance. PMID- 30397086 TI - A Legislative View of Our Rural Health Care. PMID- 30397087 TI - Behavioral Health Issues of NC Farmers: What Can't be Fixed with Tape and Twine. AB - Pressures on North Carolina's agricultural community are at an unprecedented level. Known stressors are compounded by lawsuits, tariffs, and beliefs that others have a negative perception of agriculture. Individuals find themselves with an array of negative emotions precipitating stress, anxiety, depression, and increased risk of suicide without needed prevention. PMID- 30397088 TI - What's Economic Development Got to Do With It? The Economic Impact of Healthy Rural Communities. AB - Healthy people are vital to a community's ability to be economically competitive. Sustainable rural economic growth requires a healthy workforce supported by accessible and affordable local health systems. The issues facing rural health access are complex but there are tangible steps that can be taken to address them. PMID- 30397090 TI - Optimal Care for All: The Critical Need for Clinician Retention in Rural North Carolina. AB - Despite its increasing urbanization, North Carolina still has a large rural population that lacks optimal health care. While multiple programs have been successful in recruiting clinicians to rural communities, improving the retention of those clinicians will require the development and implementation of novel strategies along with the evaluation of their effectiveness. PMID- 30397089 TI - Broadband: The Critical Infrastructure for Delivery of Today's Health Care. PMID- 30397091 TI - Collaboration: The Key to Early Childhood Success in Rural North Carolina. AB - Early childhood is a critical time of development. Differences in each child's health, education, and environment create observable developmental outcomes even before their first birthdays. Those who fall behind early often stay behind, and children in rural North Carolina face increased challenges. PMID- 30397092 TI - "What's Love Got to Do with It?" AB - Traditional rural lifestyles are often identified as contributors to poor health and disparities. A diverse group of unique partners in Hertford County, North Carolina, are focusing on key components of strengths through the Farm to School to Healthcare initiative as a way to long-lasting positive, overall health and happiness. PMID- 30397093 TI - Running the Numbers: Health Insurance Coverage in North Carolina: The Rural-Urban Uninsured Gap. PMID- 30397094 TI - Philanthropy Profile: Focus on Philanthropy: Empowering Rural Communities. PMID- 30397095 TI - The Rural Health Action Plan: An Update from the NCIOM. PMID- 30397096 TI - Erratum to "Health and the Environment in North Carolina" 79(5):302-305. PMID- 30397097 TI - 5' and 3' modifications controlling RNA degradation: from safeguards to executioners. AB - RNA degradation is a key process in the regulation of gene expression. In all organisms, RNA degradation participates in controlling coding and non-coding RNA levels in response to developmental and environmental cues. RNA degradation is also crucial for the elimination of defective RNAs. Those defective RNAs are mostly produced by 'mistakes' made by the RNA processing machinery during the maturation of functional transcripts from their precursors. The constant control of RNA quality prevents potential deleterious effects caused by the accumulation of aberrant non-coding transcripts or by the translation of defective messenger RNAs (mRNAs). Prokaryotic and eukaryotic organisms are also under the constant threat of attacks from pathogens, mostly viruses, and one common line of defence involves the ribonucleolytic digestion of the invader's RNA. Finally, mutations in components involved in RNA degradation are associated with numerous diseases in humans, and this together with the multiplicity of its roles illustrates the biological importance of RNA degradation. RNA degradation is mostly viewed as a default pathway: any functional RNA (including a successful pathogenic RNA) must be protected from the scavenging RNA degradation machinery. Yet, this protection must be temporary, and it will be overcome at one point because the ultimate fate of any cellular RNA is to be eliminated. This special issue focuses on modifications deposited at the 5' or the 3' extremities of RNA, and how these modifications control RNA stability or degradation.This article is part of the theme issue '5' and 3' modifications controlling RNA degradation'. PMID- 30397098 TI - Human RNA cap1 methyltransferase CMTr1 cooperates with RNA helicase DHX15 to modify RNAs with highly structured 5' termini. AB - The 5'-cap structure, characteristic for RNA polymerase II-transcribed RNAs, plays important roles in RNA metabolism. In humans, RNA cap formation includes post-transcriptional modification of the first transcribed nucleotide by RNA cap1 methyltransferase (CMTr1). Here, we report that CMTr1 activity is hindered towards RNA substrates with highly structured 5' termini. We found that CMTr1 binds ATP-dependent RNA DHX15 helicase and that this interaction, mediated by the G-patch domain of CMTr1, has an advantageous effect on CMTr1 activity towards highly structured RNA substrates. The effect of DHX15 helicase activity is consistent with the strength of the secondary structure that has to be removed for CMTr1 to access the 5'-terminal residues in a single-stranded conformation. This is, to our knowledge, the first demonstration of the involvement of DHX15 in post-transcriptional RNA modification, and the first example of a molecular process in which DHX15 directly affects the activity of another enzyme. Our findings suggest a new mechanism underlying the regulatory role of DHX15 in the RNA capping process. RNAs with highly structured 5' termini constitute a significant fraction of the human transcriptome. Hence, CMTr1-DHX15 cooperation is likely to be important for the metabolism of RNA polymerase II-transcribed RNAs.This article is part of the theme issue '5' and 3' modifications controlling RNA degradation'. PMID- 30397100 TI - RNA uridylation and decay in plants. AB - RNA uridylation consists of the untemplated addition of uridines at the 3' extremity of an RNA molecule. RNA uridylation is catalysed by terminal uridylyltransferases (TUTases), which form a subgroup of the terminal nucleotidyltransferase family, to which poly(A) polymerases also belong. The key role of RNA uridylation is to regulate RNA degradation in a variety of eukaryotes, including fission yeast, plants and animals. In plants, RNA uridylation has been mostly studied in two model species, the green algae Chlamydomonas reinhardtii and the flowering plant Arabidopsis thaliana Plant TUTases target a variety of RNA substrates, differing in size and function. These RNA substrates include microRNAs (miRNAs), small interfering silencing RNAs (siRNAs), ribosomal RNAs (rRNAs), messenger RNAs (mRNAs) and mRNA fragments generated during post-transcriptional gene silencing. Viral RNAs can also get uridylated during plant infection. We describe here the evolutionary history of plant TUTases and we summarize the diverse molecular functions of uridylation during RNA degradation processes in plants. We also outline key points of future research.This article is part of the theme issue '5' and 3' modifications controlling RNA degradation'. PMID- 30397099 TI - Terminal nucleotidyl transferases (TENTs) in mammalian RNA metabolism. AB - In eukaryotes, almost all RNA species are processed at their 3' ends and most mRNAs are polyadenylated in the nucleus by canonical poly(A) polymerases. In recent years, several terminal nucleotidyl transferases (TENTs) including non canonical poly(A) polymerases (ncPAPs) and terminal uridyl transferases (TUTases) have been discovered. In contrast to canonical polymerases, TENTs' functions are more diverse; some, especially TUTases, induce RNA decay while others, such as cytoplasmic ncPAPs, activate translationally dormant deadenylated mRNAs. The mammalian genome encodes 11 different TENTs. This review summarizes the current knowledge about the functions and mechanisms of action of these enzymes.This article is part of the theme issue '5' and 3' modifications controlling RNA degradation'. PMID- 30397102 TI - RNA polyadenylation and its consequences in prokaryotes. AB - Post-transcriptional addition of poly(A) tails to the 3' end of RNA is one of the fundamental events controlling the functionality and fate of RNA in all kingdoms of life. Although an enzyme with poly(A)-adding activity was discovered in Escherichia coli more than 50 years ago, its existence and role in prokaryotic RNA metabolism were neglected for many years. As a result, it was not until 1992 that E. coli poly(A) polymerase I was purified to homogeneity and its gene was finally identified. Further work revealed that, similar to its role in surveillance of aberrant nuclear RNAs of eukaryotes, the addition of poly(A) tails often destabilizes prokaryotic RNAs and their decay intermediates, thus facilitating RNA turnover. Moreover, numerous studies carried out over the last three decades have shown that polyadenylation greatly contributes to the control of prokaryotic gene expression by affecting the steady-state level of diverse protein-coding and non-coding transcripts including antisense RNAs involved in plasmid copy number control, expression of toxin-antitoxin systems and bacteriophage development. Here, we review the main findings related to the discovery of polyadenylation in prokaryotes, isolation, and characterization and regulation of bacterial poly(A)-adding activities, and discuss the impact of polyadenylation on prokaryotic mRNA metabolism and gene expression.This article is part of the theme issue '5' and 3' modifications controlling RNA degradation'. PMID- 30397101 TI - mRNA decapping: finding the right structures. AB - In eukaryotes, the elimination of the m7GpppN mRNA cap, a process known as decapping, is a critical, largely irreversible and highly regulated step of mRNA decay that withdraws the targeted mRNAs from the pool of translatable templates. The decapping reaction is catalysed by a multi-protein complex formed by the Dcp2 catalytic subunit and its Dcp1 cofactor, a holoenzyme that is poorly active on its own and needs several accessory proteins (Lsm1-7 complex, Pat1, Edc1-2, Edc3 and/or EDC4) to be fully efficient. Here, we discuss the several crystal structures of Dcp2 domains bound to various partners (proteins or small molecules) determined in the last couple of years that have considerably improved our current understanding of how Dcp2, assisted by its various activators, is recruited to its mRNA targets and adopts its active conformation upon substrate recognition. We also describe how, over the years, elegant integrative structural biology approaches combined to biochemistry and genetics led to the identification of the correct structure of the active Dcp1-Dcp2 holoenzyme among the many available conformations trapped by X-ray crystallography.This article is part of the theme issue '5' and 3' modifications controlling RNA degradation'. PMID- 30397103 TI - mRNAs biotinylated within the 5' cap and protected against decapping: new tools to capture RNA-protein complexes. AB - The 5'-terminus of eukaryotic mRNAs comprises a 7-methylguanosine cap linked to the first transcribed nucleotide via a 5'-5' triphosphate bond. This cap structure facilitates numerous interactions with molecules participating in mRNA processing, turnover and RNA translation. Here, we report the synthesis and biochemical properties of a set of biotin-labelled cap analogues modified within the triphosphate bridge and increasing mRNA stability while retaining biological activity. Successful co-transcriptional incorporation of the cap analogues allowed for the quantification of cap-dependent translation efficiency, capping efficiency and the susceptibility to decapping by Dcp2. The utility of such cap biotinylated RNAs as molecular tool was demonstrated by ultraviolet-cross-linking and affinity capture of protein-RNA complexes. In conclusion, RNAs labelled with biotin via the 5' cap structure can be applied to a variety of biological experiments based on biotin-avidin interaction or by means of biotin-specific antibodies, including protein affinity purification, pull-down assays, in vivo visualization, cellular delivery and many others.This article is part of the theme issue '5' and 3' modifications controlling RNA degradation'. PMID- 30397104 TI - Fidelity in RNA-based recognition of transposable elements. AB - Genomes are under constant threat of invasion by transposable elements and other genomic parasites. How can host genomes recognize these elements and target them for degradation? This requires a system that is highly adaptable, and at the same time highly specific. Current data suggest that perturbation of transcription patterns by transposon insertions could be detected by the RNAi surveillance pathway. Multiple transposon insertions might generate sufficient amounts of primal small RNAs to initiate generation of secondary small RNAs and silencing. At the same time primal small RNAs need to be constantly degraded to reduce the level of noise small RNAs below the threshold required for initiation of silencing. Failure in RNA degradation results in loss of fidelity of small RNA pathways and silencing of ectopic targets.This article is part of the theme issue '5' and 3' modifications controlling RNA degradation'. PMID- 30397105 TI - The multitasking polyA tail: nuclear RNA maturation, degradation and export. AB - A polyA (pA) tail is an essential modification added to the 3' ends of a wide range of RNAs at different stages of their metabolism. Here, we describe the main sources of polyadenylation and outline their underlying biochemical interactions within the nuclei of budding yeast Saccharomyces cerevisiae, human cells and, when relevant, the fission yeast Schizosaccharomyces pombe Polyadenylation mediated by the S. cerevisiae Trf4/5 enzymes, and their human homologues PAPD5/7, typically leads to the 3'-end trimming or complete decay of non-coding RNAs. By contrast, the primary function of canonical pA polymerases (PAPs) is to produce stable and nuclear export-competent mRNAs. However, this dichotomy is becoming increasingly blurred, at least in S. pombe and human cells, where polyadenylation mediated by canonical PAPs may also result in transcript decay.This article is part of the theme issue '5' and 3' modifications controlling RNA degradation'. PMID- 30397106 TI - Role of oligouridylation in normal metabolism and regulated degradation of mammalian histone mRNAs. AB - Metazoan replication-dependent histone mRNAs are the only known cellular mRNAs that are not polyadenylated. Histone mRNAs are present in large amounts only in S phase cells, and their levels are coordinately regulated with the rate of DNA replication. In mammals, the stemloop at the 3' end of histone mRNA is bound to stemloop binding protein, a protein required for both synthesis and degradation of histone mRNA, and an exonuclease, 3'hExo (ERI1). Histone mRNAs are rapidly degraded when DNA synthesis is inhibited in S-phase cells and at the end of S phase. Upf1 is also required for rapid degradation of histone mRNA as is the S phase checkpoint. We report that Smg1 is required for histone mRNA degradation when DNA replication is inhibited, suggesting it is the PI-like kinase that activates Upf1 for histone mRNA degradation. We also show that some mutant Upf1 proteins are recruited to histone mRNAs when DNA replication is inhibited and act as dominant negative factors in histone mRNA degradation. We report that the pathway of rapid histone mRNA degradation when DNA replication is inhibited in S phase cells that are activating the S-phase checkpoint is similar to the pathway of rapid degradation of histone mRNA at the end of S-phase.This article is part of the theme issue '5' and 3' modifications controlling RNA degradation'. PMID- 30397108 TI - Broadening horizons: Sample diversity and socioecological theory are essential to the future of psychological science. AB - The present lack of sample diversity and ecological theory in psychological science fundamentally limits generalizability and obstructs scientific progress. A focus on the role of socioecology in shaping the evolution of morphology, physiology, and behavior has not yet been widely applied toward psychology. To date, evolutionary approaches to psychology have focused more on finding universals than explaining variability. However, contrasts between small-scale, kin-based rural subsistence societies and large-scale urban, market-based populations, have not been well appreciated. Nor has the variability within high income countries, or the socioeconomic and cultural transformations affecting even the most remote tribal populations today. Elucidating the causes and effects of such broad changes on psychology and behavior is a fundamental concern of the social sciences; expanding study participants beyond students and other convenience samples is necessary to improve understanding of flexible psychological reaction norms among and within populations. Here I highlight two examples demonstrating how socioecological variability can help explain psychological trait expression: (i) the role of environmental harshness and unpredictability on shaping time preference and related traits, such as impulsivity, vigilance, and self-efficacy; and (ii) the effects of industrialization, market integration, and niche complexity on personality structure. These cases illustrate how appropriate theory can be a powerful tool to help determine choices of diverse study populations and improve the social sciences. PMID- 30397109 TI - Habitat choice meets thermal specialization: Competition with specialists may drive suboptimal habitat preferences in generalists. AB - Limited dispersal is classically considered as a prerequisite for ecological specialization to evolve, such that generalists are expected to show greater dispersal propensity compared with specialists. However, when individuals choose habitats that maximize their performance instead of dispersing randomly, theory predicts dispersal with habitat choice to evolve in specialists, while generalists should disperse more randomly. We tested whether habitat choice is associated with thermal niche specialization using microcosms of the ciliate Tetrahymena thermophila, a species that performs active dispersal. We found that thermal specialists preferred optimal habitats as predicted by theory, a link that should make specialists more likely to track suitable conditions under environmental changes than expected under the random dispersal assumption. Surprisingly, generalists also performed habitat choice but with a preference for suboptimal habitats. Since this result challenges current theory, we developed a metapopulation model to understand under which circumstances such a preference for suboptimal habitats should evolve. We showed that competition between generalists and specialists may favor a preference for niche margins in generalists under environmental variability. Our results demonstrate that the behavioral dimension of dispersal-here, habitat choice-fundamentally alters our predictions of how dispersal evolve with niche specialization, making dispersal behaviors crucial for ecological forecasting facing environmental changes. PMID- 30397110 TI - Bulk electronic transport impacts on electron transfer at conducting polymer electrode-electrolyte interfaces. AB - Electrochemistry is an old but still flourishing field of research due to the importance of the efficiency and kinetics of electrochemical reactions in industrial processes and (bio-)electrochemical devices. The heterogeneous electron transfer from an electrode to a reactant in the solution has been well studied for metal, semiconductor, metal oxide, and carbon electrodes. For those electrode materials, there is little correlation between the electronic transport within the electrode material and the electron transfer occurring at the interface between the electrode and the solution. Here, we investigate the heterogeneous electron transfer between a conducting polymer electrode and a redox couple in an electrolyte. As a benchmark system, we use poly(3,4 ethylenedioxythiophene) (PEDOT) and the Ferro/ferricyanide redox couple in an aqueous electrolyte. We discovered a strong correlation between the electronic transport within the PEDOT electrode and the rate of electron transfer to the organometallic molecules in solution. We attribute this to a percolation-based charge transport within the polymer electrode directly involved in the electron transfer. We show the impact of this finding by optimizing an electrochemical thermogalvanic cell that transforms a heat flux into electrical power. The power generated by the cell increased by four orders of magnitude on changing the morphology and conductivity of the polymer electrode. As all conducting polymers are recognized to have percolation transport, we believe that this is a general phenomenon for this family of conductors. PMID- 30397107 TI - The role of 3' end uridylation in RNA metabolism and cellular physiology. AB - Most eukaryotic RNAs are posttranscriptionally modified. The majority of modifications promote RNA maturation, others may regulate function and stability. The 3' terminal non-templated oligouridylation is a widespread modification affecting many cellular RNAs at some stage of their life cycle. It has diverse roles in RNA metabolism. The most prevalent is the regulation of stability and quality control. On the cellular and organismal level, it plays a critical role in a number of pathways, such as cell cycle regulation, cell death, development or viral infection. Defects in uridylation have been linked to several diseases. This review summarizes the current knowledge about the role of the 3' terminal oligo(U)-tailing in biology of various RNAs in eukaryotes and describes key factors involved in these pathways.This article is part of the theme issue '5' and 3' modifications controlling RNA degradation'. PMID- 30397111 TI - Engineering the protein secretory pathway of Saccharomyces cerevisiae enables improved protein production. AB - Baker's yeast Saccharomyces cerevisiae is one of the most important and widely used cell factories for recombinant protein production. Many strategies have been applied to engineer this yeast for improving its protein production capacity, but productivity is still relatively low, and with increasing market demand, it is important to identify new gene targets, especially targets that have synergistic effects with previously identified targets. Despite improved protein production, previous studies rarely focused on processes associated with intracellular protein retention. Here we identified genetic modifications involved in the secretory and trafficking pathways, the histone deacetylase complex, and carbohydrate metabolic processes as targets for improving protein secretion in yeast. Especially modifications on the endosome-to-Golgi trafficking was found to effectively reduce protein retention besides increasing protein secretion. Through combinatorial genetic manipulations of several of the newly identified gene targets, we enhanced the protein production capacity of yeast by more than fivefold, and the best engineered strains could produce 2.5 g/L of a fungal alpha amylase with less than 10% of the recombinant protein retained within the cells, using fed-batch cultivation. PMID- 30397112 TI - Arginine-rich cell-penetrating peptides induce membrane multilamellarity and subsequently enter via formation of a fusion pore. AB - Arginine-rich cell-penetrating peptides do not enter cells by directly passing through a lipid membrane; they instead passively enter vesicles and live cells by inducing membrane multilamellarity and fusion. The molecular picture of this penetration mode, which differs qualitatively from the previously proposed direct mechanism, is provided by molecular dynamics simulations. The kinetics of vesicle agglomeration and fusion by an iconic cell-penetrating peptide-nonaarginine-are documented via real-time fluorescence techniques, while the induction of multilamellar phases in vesicles and live cells is demonstrated by a combination of electron and fluorescence microscopies. This concert of experiments and simulations reveals that the identified passive cell penetration mechanism bears analogy to vesicle fusion induced by calcium ions, indicating that the two processes may share a common mechanistic origin. PMID- 30397114 TI - Toward a psychology of Homo sapiens: Making psychological science more representative of the human population. AB - Two primary goals of psychological science should be to understand what aspects of human psychology are universal and the way that context and culture produce variability. This requires that we take into account the importance of culture and context in the way that we write our papers and in the types of populations that we sample. However, most research published in our leading journals has relied on sampling WEIRD (Western, educated, industrialized, rich, and democratic) populations. One might expect that our scholarly work and editorial choices would by now reflect the knowledge that Western populations may not be representative of humans generally with respect to any given psychological phenomenon. However, as we show here, almost all research published by one of our leading journals, Psychological Science, relies on Western samples and uses these data in an unreflective way to make inferences about humans in general. To take us forward, we offer a set of concrete proposals for authors, journal editors, and reviewers that may lead to a psychological science that is more representative of the human condition. PMID- 30397113 TI - Population-specific social dynamics in chimpanzees. AB - Understanding intraspecific variation in sociality is essential for characterizing the flexibility and evolution of social systems, yet its study in nonhuman animals is rare. Here, we investigated whether chimpanzees exhibit population-level differences in sociality that cannot be easily explained by differences in genetics or ecology. We compared social proximity and grooming tendencies across four semiwild populations of chimpanzees living in the same ecological environment over three consecutive years, using both linear mixed models and social network analysis. Results indicated temporally stable, population-level differences in dyadic-level sociality. Moreover, group cohesion measures capturing network characteristics beyond dyadic interactions (clustering, modularity, and social differentiation) showed population-level differences consistent with the dyadic indices. Subsequently, we explored whether the observed intraspecific variation in sociality could be attributed to cultural processes by ruling out alternative sources of variation including the influences of ecology, genetics, and differences in population demographics. We conclude that substantial variation in social behavior exists across neighboring populations of chimpanzees and that this variation is in part shaped by cultural processes. PMID- 30397115 TI - Cultural impediments to learning to cooperate: An experimental study of high- and low-caste men in rural India. AB - We report experimental findings on how individuals from different cultures solve a repeated coordination game of common interest. The results overturn earlier findings that fixed pairs are almost assured to coordinate on an efficient and cooperative equilibrium. Subjects in the prior experiments were US university students, whereas the subjects in our study are men drawn from high and low castes in rural India. Most low-caste pairs quickly established an efficient and cooperative convention, but most high-caste pairs did not. The largest difference in behavior occurred when a player suffered a loss because he had tried to cooperate but his partner did not: In this situation, high-caste men were far less likely than low-caste men to continue trying to cooperate in the next period. Our interpretation is that for many high-caste men, the loss resulting from coordination failure triggered retaliation. Our results are robust to controls for education and wealth, and they hold by subcaste as well as by caste status. A survey we conducted supports the ethnographic evidence that more high caste than low-caste men prefer to retaliate against a slight. We find no evidence that caste differences in trust or self-efficacy explain the caste gap in cooperation in our experiment. Our findings are of general interest because many societies throughout the world have cultures that lead individuals to (mis)perceive some actions as insults and to respond aggressively and dysfunctionally. PMID- 30397117 TI - Correction for Belsky et al., Genetic analysis of social-class mobility in five longitudinal studies. PMID- 30397116 TI - An abundance of developmental anomalies and abnormalities in Pleistocene people. AB - Diverse developmental abnormalities and anomalous features are evident in the Pleistocene Homo fossil record, varying from minor but rare dental, vertebral, and carpal variants to exceptional systemic disorders. There are currently 75 documented anomalies or abnormalities from 66 individuals, spanning the Pleistocene but primarily from the Late Pleistocene Middle and Upper Paleolithic with their more complete skeletal remains. The expected probabilities of finding these variants or developmental disorders vary from <5% to <0.0001%, based on either recent human incidences or relevant Pleistocene sample distributions. Given the modest sample sizes available for the skeletal or dental elements in question, especially if the samples are appropriately limited in time and geography, the cumulative multiplicative probability of finding these developmental changes is vanishingly small. These data raise questions regarding social survival abilities, differing mortuary treatments of the biologically unusual, the role of ubiquitous stress among these Pleistocene foragers, and their levels of consanguinity. No single factor sufficiently accounts for the elevated level of these developmental variants or the low probability of finding them in the available paleontological record. PMID- 30397119 TI - Should social scientists be distanced from or engaged with the people they study? AB - This commentary focuses on two important contrasts in the behavioral sciences: (i) default versus nondefault study populations, where default samples have been used disproportionately (for psychology, the default is undergraduates at major research universities), and (ii) the adoption of a distant versus close (engaged) attitude toward study samples. Previous research has shown a strong correlation between these contrasts, where default samples and distant perspectives are the norm. Distancing is sometimes seen as necessary for objectivity, and an engaged orientation is sometimes criticized as biased, advocacy research, especially if the researcher shares a social group membership with the study population (e.g., a black male researcher studying black male students). The lack of diversity in study samples has been paralleled by a lack of diversity in the researchers themselves. The salience of default samples and distancing in prior research creates potential (and presumed) risk factors for engaged research with nondefault samples. However, a distant perspective poses risks as well, and particularly so for research with nondefault populations. We suggest that engaged research can usefully encourage attention to the study context and taking the perspective of study samples, both of which are good research practices. More broadly, we argue that social and educational sciences need skepticism, interestedness, and engagement, not distancing. Fostering an engaged perspective in research may also foster a more diverse population of social scientists. PMID- 30397118 TI - Expression of ABCA4 in the retinal pigment epithelium and its implications for Stargardt macular degeneration. AB - Recessive Stargardt disease (STGD1) is an inherited blinding disorder caused by mutations in the Abca4 gene. ABCA4 is a flippase in photoreceptor outer segments (OS) that translocates retinaldehyde conjugated to phosphatidylethanolamine across OS disc membranes. Loss of ABCA4 in Abca4 -/- mice and STGD1 patients causes buildup of lipofuscin in the retinal pigment epithelium (RPE) and degeneration of photoreceptors, leading to blindness. No effective treatment currently exists for STGD1. Here we show by several approaches that ABCA4 is additionally expressed in RPE cells. (i) By in situ hybridization analysis and by RNA-sequencing analysis, we show the Abca4 mRNA is expressed in human and mouse RPE cells. (ii) By quantitative immunoblotting, we show that the level of ABCA4 protein in homogenates of wild-type mouse RPE is about 1% of the level in neural retina homogenates. (iii) ABCA4 immunofluorescence is present in RPE cells of wild-type and Mertk -/- but not Abca4 -/- mouse retina sections, where it colocalizes with endolysosomal proteins. To elucidate the role of ABCA4 in RPE cells, we generated a line of genetically modified mice that express ABCA4 in RPE cells but not in photoreceptors. Mice from this line on the Abca4 -/- background showed partial rescue of photoreceptor degeneration and decreased lipofuscin accumulation compared with nontransgenic Abca4 -/- mice. We propose that ABCA4 functions to recycle retinaldehyde released during proteolysis of rhodopsin in RPE endolysosomes following daily phagocytosis of distal photoreceptor OS. ABCA4 deficiency in the RPE may play a role in the pathogenesis of STGD1. PMID- 30397121 TI - Universality claim of attachment theory: Children's socioemotional development across cultures. AB - The first part of this paper reviews the basic tenets of attachment theory with respect to differences in cultural socialization strategies. In one strategy infants have the lead, and the social environment is responsive to the infant's wishes and preferences. In another strategy the caregivers-children or adults-are experts who know what is best for a baby without exploring his or her mental states. Accordingly, the definition of attachment is conceived as a negotiable emotional bond or a network of responsibilities. Attachment theory represents the Western middle-class perspective, ignoring the caregiving values and practices in the majority of the world. However, attachment theory claims universality in all its components. Since the claim of universality implies moral judgments about good and bad parenting, ethical questions need to be addressed. These issues are discussed in the second part of the paper. It is first demonstrated that sensitive responsiveness in attachment theory is built on a different concept of the person and self than concepts of good caregiving in many rural subsistence based farming families. Evaluating one system with the standards of another ignores different realities and different value systems. The common practice of large-scale interventions in rural subsistence-based contexts promoting Western style parenting strategies without knowing the local culture positions a false understanding of scientific evidence against cultural knowledge. This practice is unethical. Diversity needs to be recognized as the human condition, and the recognition of diversity is an obligation for better science as well as for improving people's lives. PMID- 30397120 TI - Combinatorial regulation of hepatic cytoplasmic signaling and nuclear transcriptional events by the OGT/REV-ERBalpha complex. AB - The nuclear receptor REV-ERBalpha integrates the circadian clock with hepatic glucose and lipid metabolism by nucleating transcriptional comodulators at genomic regulatory regions. An interactomic approach identified O-GlcNAc transferase (OGT) as a REV-ERBalpha-interacting protein. By shielding cytoplasmic OGT from proteasomal degradation and favoring OGT activity in the nucleus, REV ERBalpha cyclically increased O-GlcNAcylation of multiple cytoplasmic and nuclear proteins as a function of its rhythmically regulated expression, while REV ERBalpha ligands mostly affected cytoplasmic OGT activity. We illustrate this finding by showing that REV-ERBalpha controls OGT-dependent activities of the cytoplasmic protein kinase AKT, an essential relay in insulin signaling, and of ten-of-eleven translocation (TET) enzymes in the nucleus. AKT phosphorylation was inversely correlated to REV-ERBalpha expression. REV-ERBalpha enhanced TET activity and DNA hydroxymethylated cytosine (5hmC) levels in the vicinity of REV ERBalpha genomic binding sites. As an example, we show that the REV-ERBalpha/OGT complex modulates SREBP-1c gene expression throughout the fasting/feeding periods by first repressing AKT phosphorylation and by epigenomically priming the Srebf1 promoter for a further rapid response to insulin. Conclusion: REV-ERBalpha regulates cytoplasmic and nuclear OGT-controlled processes that integrate at the hepatic SREBF1 locus to control basal and insulin-induced expression of the temporally and nutritionally regulated lipogenic SREBP-1c transcript. PMID- 30397122 TI - Face cells in orbitofrontal cortex represent social categories. AB - Perceiving social and emotional information from faces is a critical primate skill. For this purpose, primates evolved dedicated cortical architecture, especially in occipitotemporal areas, utilizing face-selective cells. Less understood face-selective neurons are present in the orbitofrontal cortex (OFC) and are our object of study. We examined 179 face-selective cells in the lateral sulcus of the OFC by characterizing their responses to a rich set of photographs of conspecific faces varying in age, gender, and facial expression. Principal component analysis and unsupervised cluster analysis of stimulus space both revealed that face cells encode face dimensions for social categories and emotions. Categories represented strongly were facial expressions (grin and threat versus lip smack), juvenile, and female monkeys. Cluster analyses of a control population of nearby cells lacking face selectivity did not categorize face stimuli in a meaningful way, suggesting that only face-selective cells directly support face categorization in OFC. Time course analyses of face cell activity from stimulus onset showed that faces were discriminated from nonfaces early, followed by within-face categorization for social and emotion content (i.e., young and facial expression). Face cells revealed no response to acoustic stimuli such as vocalizations and were poorly modulated by vocalizations added to faces. Neuronal responses remained stable when paired with positive or negative reinforcement, implying that face cells encode social information but not learned reward value associated to faces. Overall, our results shed light on a substantial role of the OFC in the characterizations of facial information bearing on social and emotional behavior. PMID- 30397123 TI - Allosteric landscapes of eukaryotic cytoplasmic Hsp70s are shaped by evolutionary tuning of key interfaces. AB - The 70-kDa heat shock proteins (Hsp70s) are molecular chaperones that perform a wide range of critical cellular functions. They assist in the folding of newly synthesized proteins, facilitate assembly of specific protein complexes, shepherd proteins across membranes, and prevent protein misfolding and aggregation. Hsp70s perform these functions by a conserved mechanism that relies on allosteric cycles of nucleotide-modulated binding and release of client proteins. Current models for Hsp70 allostery have come from extensive study of the bacterial Hsp70, DnaK. Extending our understanding to eukaryotic Hsp70s is extremely important not only in providing a likely common mechanistic framework but also because of their central roles in cellular physiology. In this study, we examined the allosteric behaviors of the eukaryotic cytoplasmic Hsp70s, HspA1 and Hsc70, and found significant differences from that of DnaK. We found that HspA1 and Hsc70 favor a state in which the nucleotide-binding domain (NBD) and substrate-binding domain (SBD) are intimately docked significantly more as compared to DnaK. Past work established that the NBD-SBD interface and the helical lid-beta-SBD interface govern the allosteric landscape of DnaK. Here, we identified sites on these interfaces that differ between eukaryotic cytoplasmic Hsp70s and DnaK. Our mutational analysis has revealed key evolutionary variations that account for the population shifts between the docked and undocked conformations. These results underline the tunability of Hsp70 functions by modulation of allosteric interfaces through evolutionary diversification and also suggest sites where the binding of small-molecule modulators could influence Hsp70 function. PMID- 30397124 TI - A multiscale approach to balance trade-offs among dam infrastructure, river restoration, and cost. AB - Aging infrastructure and growing interests in river restoration have led to a substantial rise in dam removals in the United States. However, the decision to remove a dam involves many complex trade-offs. The benefits of dam removal for hazard reduction and ecological restoration are potentially offset by the loss of hydroelectricity production, water supply, and other important services. We use a multiobjective approach to examine a wide array of trade-offs and synergies involved with strategic dam removal at three spatial scales in New England. We find that increasing the scale of decision-making improves the efficiency of trade-offs among ecosystem services, river safety, and economic costs resulting from dam removal, but this may lead to heterogeneous and less equitable local scale outcomes. Our model may help facilitate multilateral funding, policy, and stakeholder agreements by analyzing the trade-offs of coordinated dam decisions, including net benefit alternatives to dam removal, at scales that satisfy these agreements. PMID- 30397126 TI - Unique pelvic fin in a tetrapod-like fossil fish, and the evolution of limb patterning. AB - All living tetrapods have a one-to-two branching pattern in the embryonic proximal limb skeleton, with a single element at the base of the limb (the humerus or femur) that articulates distally with two parallel radials (the ulna and radius or the tibia and fibula). This pattern is also seen in the fossilized remains of stem-tetrapods, including the fishlike members of the group, in which despite the absence of digits, the proximal parts of the fin skeleton clearly resemble those of later tetrapods. However, little is known about the developmental mechanisms that establish and canalize this highly conserved pattern. We describe the well-preserved pelvic fin skeleton of Rhizodus hibberti, a Carboniferous sarcopterygian (lobe-finned) fish, and member of the tetrapod stem group. In this specimen, three parallel radials, each robust with a distinct morphology, articulate with the femur. We review this unexpected morphology in a phylogenetic and developmental context. It implies that the developmental patterning mechanisms seen in living tetrapods, now highly constrained, evolved from mechanisms flexible enough to accommodate variation in the zeugopod (even between pectoral and pelvic fins), while also allowing each element to have a unique morphology. PMID- 30397125 TI - Bronze Age population dynamics and the rise of dairy pastoralism on the eastern Eurasian steppe. AB - Recent paleogenomic studies have shown that migrations of Western steppe herders (WSH) beginning in the Eneolithic (ca. 3300-2700 BCE) profoundly transformed the genes and cultures of Europe and central Asia. Compared with Europe, however, the eastern extent of this WSH expansion is not well defined. Here we present genomic and proteomic data from 22 directly dated Late Bronze Age burials putatively associated with early pastoralism in northern Mongolia (ca. 1380-975 BCE). Genome wide analysis reveals that they are largely descended from a population represented by Early Bronze Age hunter-gatherers in the Baikal region, with only a limited contribution (~7%) of WSH ancestry. At the same time, however, mass spectrometry analysis of dental calculus provides direct protein evidence of bovine, sheep, and goat milk consumption in seven of nine individuals. No individuals showed molecular evidence of lactase persistence, and only one individual exhibited evidence of >10% WSH ancestry, despite the presence of WSH populations in the nearby Altai-Sayan region for more than a millennium. Unlike the spread of Neolithic farming in Europe and the expansion of Bronze Age pastoralism on the Western steppe, our results indicate that ruminant dairy pastoralism was adopted on the Eastern steppe by local hunter-gatherers through a process of cultural transmission and minimal genetic exchange with outside groups. PMID- 30397127 TI - Intrinsic anion diffusivity in lead halide perovskites is facilitated by a soft lattice. AB - Facile ionic transport in lead halide perovskites plays a critical role in device performance. Understanding the microscopic origins of high ionic conductivities has been complicated by indirect measurements and sample microstructural heterogeneities. Here, we report the direct visualization of halide anion interdiffusion in CsPbCl3-CsPbBr3 single crystalline perovskite nanowire heterojunctions using wide-field and confocal photoluminescence measurements. The combination of nanoscale imaging techniques with these single crystalline materials allows us to measure intrinsic anionic lattice diffusivities, free from complications of microscale inhomogeneity. Halide diffusivities were found to be between 10-13 and ~10-12 cm2/second at about 100 degrees C, which are several orders of magnitudes lower than those reported in polycrystalline thin films. Spatially resolved photoluminescence lifetimes and surface potential measurements provide evidence of the central role of halide vacancies in facilitating ionic diffusion. Vacancy formation free energies computed from molecular simulation are small due to the easily deformable perovskite lattice, accounting for the high equilibrium vacancy concentration. Furthermore, molecular simulations suggest that ionic motion is facilitated by low-frequency lattice modes, resulting in low activation barriers for vacancy-mediated transport. This work elucidates the intrinsic solid-state ion diffusion mechanisms in this class of semisoft materials and offers guidelines for engineering materials with long-term stability in functional devices. PMID- 30397128 TI - Optimal molecular crowding accelerates group II intron folding and maximizes catalysis. AB - Unlike in vivo conditions, group II intron ribozymes are known to require high magnesium(II) concentrations ([Mg2+]) and high temperatures (42 degrees C) for folding and catalysis in vitro. A possible explanation for this difference is the highly crowded cellular environment, which can be mimicked in vitro by macromolecular crowding agents. Here, we combined bulk activity assays and single molecule Forster Resonance Energy Transfer (smFRET) to study the influence of polyethylene glycol (PEG) on catalysis and folding of the ribozyme. Our activity studies reveal that PEG reduces the [Mg2+] required, and we found an "optimum" [PEG] that yields maximum activity. smFRET experiments show that the most compact state population, the putative active state, increases with increasing [PEG]. Dynamic transitions between folded states also increase. Therefore, this study shows that optimal molecular crowding concentrations help the ribozyme not only to reach the native fold but also to increase its in vitro activity to approach that in physiological conditions. PMID- 30397129 TI - Crystal structure of human mARC1 reveals its exceptional position among eukaryotic molybdenum enzymes. AB - Biotransformation enzymes ensure a viable homeostasis by regulating reversible cycles of oxidative and reductive reactions. The metabolism of nitrogen containing compounds is of high pharmaceutical and toxicological relevance because N-oxygenated metabolites derived from reactions mediated by cytochrome P450 enzymes or flavin-dependent monooxygenases are in some cases highly toxic or mutagenic. The molybdenum-dependent mitochondrial amidoxime-reducing component (mARC) was found to be an extremely efficient counterpart, which is able to reduce the full range of N-oxygenated compounds and thereby mediates detoxification reactions. However, the 3D structure of this enzyme was unknown. Here we present the high-resolution crystal structure of human mARC. We give detailed insight into the coordination of its molybdenum cofactor (Moco), the catalytic mechanism, and its ability to reduce a wide range of N-oxygenated compounds. The identification of two key residues will allow future discrimination between mARC paralogs and ensure correct annotation. Since our structural findings contradict in silico predictions that are currently made by online databases, we propose domain definitions for members of the superfamily of Moco sulfurase C-terminal (MOSC) domain-containing proteins. Furthermore, we present evidence for an evolutionary role of mARC for the emergence of the xanthine oxidase protein superfamily. We anticipate the hereby presented crystal structure to be a starting point for future descriptions of MOSC proteins, which are currently poorly structurally characterized. PMID- 30397130 TI - Crystal structure of heme A synthase from Bacillus subtilis. AB - Heme A is an essential cofactor for respiratory terminal oxidases and vital for respiration in aerobic organisms. The final step of heme A biosynthesis is formylation of the C-8 methyl group of heme molecule by heme A synthase (HAS). HAS is a heme-containing integral membrane protein, and its structure and reaction mechanisms have remained unknown. Thus, little is known about HAS despite of its importance. Here we report the crystal structure of HAS from Bacillus subtilis at 2.2-A resolution. The N- and C-terminal halves of HAS consist of four-helix bundles and they align in a pseudo twofold symmetry manner. Each bundle contains a pair of histidine residues and forms a heme-binding domain. The C-half domain binds a cofactor-heme molecule, while the N-half domain is vacant. Many water molecules are found in the transmembrane region and around the substrate-binding site, and some of them interact with the main chain of transmembrane helix. Comparison of these two domain structures enables us to construct a substrate-heme binding state structure. This structure implies that a completely conserved glutamate, Glu57 in B. subtilis, is the catalytic residue for the formylation reaction. These results provide valuable suggestions of the substrate-heme binding mechanism. Our results present significant insight into the heme A biosynthesis. PMID- 30397131 TI - Inclusive fitness consequences of dispersal decisions in a cooperatively breeding bird, the long-tailed tit (Aegithalos caudatus). AB - Natal dispersal is a demographic trait with profound evolutionary, ecological, and behavioral consequences. However, our understanding of the adaptive value of dispersal patterns is severely hampered by the difficulty of measuring the relative fitness consequences of alternative dispersal strategies in natural populations. This is especially true in social species, in which natal philopatry allows kin selection to operate, so direct and indirect components of inclusive fitness have to be considered when evaluating selection on dispersal. Here, we use lifetime reproductive success data from a long-term study of a cooperative breeder, the long-tailed tit Aegithalos caudatus, to quantify the direct and indirect components of inclusive fitness. We show that dispersal has a negative effect on the accrual of indirect fitness, and hence inclusive fitness, by males. In contrast, the inclusive, predominantly direct, fitness of females increases with dispersal distance. We conclude that the conflicting fitness consequences of dispersal in this species result in sexually antagonistic selection on this key demographic parameter. PMID- 30397132 TI - Inhibition of HDAC3 reverses Alzheimer's disease-related pathologies in vitro and in the 3xTg-AD mouse model. AB - Alzheimer's disease (AD) is the leading cause of age-related dementia. Neuropathological hallmarks of AD include brain deposition of beta-amyloid (Abeta) plaques and accumulation of both hyperphosphorylated and acetylated tau. RGFP-966, a brain-penetrant and selective HDAC3 inhibitor, or HDAC3 silencing, increases BDNF expression, increases histone H3 and H4 acetylation, decreases tau phosphorylation and tau acetylation at disease-associated sites, reduces beta secretase cleavage of the amyloid precursor protein (APP), and decreases Abeta1 42 accumulation in HEK-293 cells overexpressing APP with the double Swedish mutation (HEK/APPsw). In the triple transgenic AD mouse model (3xTg-AD), repeated administration of 3 and 10 mg/kg of RGFP-966 reverses pathological tau phosphorylation at Thr181, Ser202, and Ser396, increases levels of the Abeta degrading enzyme Neprilysin in plasma, decreases Abeta1-42 protein levels in the brain and periphery, and improves spatial learning and memory. Finally, we show that RGFP-966 decreases Abeta1-42 accumulation and both tau acetylation and phosphorylation at disease residues in neurons derived from induced pluripotent stem cells obtained from APOEepsilon4-carrying AD patients. These data indicate that HDAC3 plays an important regulatory role in the expression and regulation of proteins associated with AD pathophysiology, supporting the notion that HDAC3 may be a disease-modifying therapeutic target. PMID- 30397133 TI - Engineering selectivity into RGK GTPase inhibition of voltage-dependent calcium channels. AB - Genetically encoded inhibitors for voltage-dependent Ca2+ (CaV) channels (GECCIs) are useful research tools and potential therapeutics. Rad/Rem/Rem2/Gem (RGK) proteins are Ras-like G proteins that potently inhibit high voltage-activated (HVA) Ca2+ (CaV1/CaV2 family) channels, but their nonselectivity limits their potential applications. We hypothesized that nonselectivity of RGK inhibition derives from their binding to auxiliary CaVbeta-subunits. To investigate latent CaVbeta-independent components of inhibition, we coexpressed each RGK individually with CaV1 (CaV1.2/CaV1.3) or CaV2 (CaV2.1/CaV2.2) channels reconstituted in HEK293 cells with either wild-type (WT) beta2a or a mutant version (beta2a,TM) that does not bind RGKs. All four RGKs strongly inhibited CaV1/CaV2 channels reconstituted with WT beta2a By contrast, when channels were reconstituted with beta2a,TM, Rem inhibited only CaV1.2, Rad selectively inhibited CaV1.2 and CaV2.2, while Gem and Rem2 were ineffective. We generated mutant RGKs (Rem[R200A/L227A] and Rad[R208A/L235A]) unable to bind WT CaVbeta, as confirmed by fluorescence resonance energy transfer. Rem[R200A/L227A] selectively blocked reconstituted CaV1.2 while Rad[R208A/L235A] inhibited CaV1.2/CaV2.2 but not CaV1.3/CaV2.1. Rem[R200A/L227A] and Rad[R208A/L235A] both suppressed endogenous CaV1.2 channels in ventricular cardiomyocytes and selectively blocked 25 and 62%, respectively, of HVA currents in somatosensory neurons of the dorsal root ganglion, corresponding to their distinctive selectivity for CaV1.2 and CaV1.2/CaV2.2 channels. Thus, we have exploited latent beta-binding-independent Rem and Rad inhibition of specific CaV1/CaV2 channels to develop selective GECCIs with properties unmatched by current small-molecule CaV channel blockers. PMID- 30397134 TI - Expanding the interpretive power of psychological science by attending to culture. AB - A lack of interpretive power (i.e., the ability to understand individuals' experiences and behaviors in relation to their cultural contexts) undermines psychology's understanding of diverse psychological phenomena. Building interpretive power requires attending to cultural influences in research. We describe three characteristics of research that lacks interpretive power: normalizing and overgeneralizing from behaviors and processes of people in Western, educated, industrialized, rich, and democratic (WEIRD) contexts; making non-WEIRD people and processes invisible; and misapplying WEIRD findings in non WEIRD contexts. We also describe research in which leveraging interpretive power prevented these negative consequences. Finally, using the culture-cycle framework, we outline a vision for creating culture change within psychology by implementing culture-conscious practices to guide the formation of research questions, empirical design, and data analysis and interpretation. PMID- 30397135 TI - Differential coding of perception in the world's languages. AB - Is there a universal hierarchy of the senses, such that some senses (e.g., vision) are more accessible to consciousness and linguistic description than others (e.g., smell)? The long-standing presumption in Western thought has been that vision and audition are more objective than the other senses, serving as the basis of knowledge and understanding, whereas touch, taste, and smell are crude and of little value. This predicts that humans ought to be better at communicating about sight and hearing than the other senses, and decades of work based on English and related languages certainly suggests this is true. However, how well does this reflect the diversity of languages and communities worldwide? To test whether there is a universal hierarchy of the senses, stimuli from the five basic senses were used to elicit descriptions in 20 diverse languages, including 3 unrelated sign languages. We found that languages differ fundamentally in which sensory domains they linguistically code systematically, and how they do so. The tendency for better coding in some domains can be explained in part by cultural preoccupations. Although languages seem free to elaborate specific sensory domains, some general tendencies emerge: for example, with some exceptions, smell is poorly coded. The surprise is that, despite the gradual phylogenetic accumulation of the senses, and the imbalances in the neural tissue dedicated to them, no single hierarchy of the senses imposes itself upon language. PMID- 30397137 TI - Sophisticated collaboration is common among Mexican-heritage US children. AB - In light of calls for improving people's skill in collaboration, this paper examines strengths in processes of collaboration of Mexican immigrant children. Sibling pairs (6-10 years old) in California were asked to collaborate in planning the shortest route through a model grocery store. On average, 14 sibling pairs with Mexican Indigenous-heritage backgrounds engaged together collaboratively as an ensemble, making decisions in common and fluidly building on each other's ideas, more often than 16 middle-class European American sibling pairs, who on average more often divided decision making into a solo activity (often ignoring the other or simply bossing the other). Siblings who spent more time collaborating fluidly as an ensemble in the shared planning task were also more likely to collaborate with initiative at home, according to their mothers, which suggests that family socialization practices may contribute to cultural differences in collaboration. PMID- 30397136 TI - Functional connectivity in central executive network protects youth against cardiometabolic risks linked with neighborhood violence. AB - Although violent crime has declined in recent decades, it remains a recurring feature of daily life in some neighborhoods. Mounting evidence indicates that such violence has a long reach, which goes beyond family and friends of the victim and undermines the health of people in the surrounding community. However, like all forms of adversity, community violence elicits a heterogeneous response: Some remain healthy, but others deteriorate. Despite much scientific attention, the neural circuitries that contribute to differential adaptation remain poorly understood. Drawing on knowledge of the brain's intrinsic functional architecture, we predicted that individual differences in resting-state connectivity would explain variability in the strength of the association between neighborhood violence and cardiometabolic health. We enrolled 218 urban youth (age 12-14 years, 66% female; 65% black or Latino) and used geocoding to characterize their exposure to neighborhood murder over the past five years. Multiple aspects of cardiometabolic health were assessed, including obesity, insulin resistance, and metabolic syndrome. Functional MRI was used to quantify the connectivity of major intrinsic networks. Consistent with predictions, resting-state connectivity within the central executive network (CEN) emerged as a moderator of adaptation. Across six distinct outcomes, a higher neighborhood murder rate was associated with greater cardiometabolic risk, but this relationship was apparent only among youth who displayed lower CEN resting-state connectivity. By contrast, there was little evidence of moderation by the anterior salience and default mode networks. These findings advance basic and applied knowledge about adaptation by highlighting intrinsic CEN connectivity as a potential neurobiological contributor to resilience. PMID- 30397139 TI - Pressing questions in the study of psychological and behavioral diversity. PMID- 30397138 TI - Learning from failures of protocol in cross-cultural research. AB - The many tools that social and behavioral scientists use to gather data from their fellow humans have, in most cases, been honed on a rarefied subset of humanity: highly educated participants with unique capacities, experiences, motivations, and social expectations. Through this honing process, researchers have developed protocols that extract information from these participants with great efficiency. However, as researchers reach out to broader populations, it is unclear whether these highly refined protocols are robust to cultural differences in skills, motivations, and expected modes of social interaction. In this paper, we illustrate the kinds of mismatches that can arise when using these highly refined protocols with nontypical populations by describing our experience translating an apparently simple social discounting protocol to work in rural Bangladesh. Multiple rounds of piloting and revision revealed a number of tacit assumptions about how participants should perceive, understand, and respond to key elements of the protocol. These included facility with numbers, letters, abstract number lines, and 2D geometric shapes, and the treatment of decisions as a series of isolated events. Through on-the-ground observation and a collaborative refinement process, we developed a protocol that worked both in Bangladesh and among US college students. More systematic study of the process of adapting common protocols to new contexts will provide valuable information about the range of skills, motivations, and modes of interaction that participants bring to studies as we develop a more diverse and inclusive social and behavioral science. PMID- 30397140 TI - Species interactions limit the occurrence of urban-adapted birds in cities. AB - Urbanization represents an extreme transformation of more natural systems. Populations of most species decline or disappear with urbanization, and yet some species persist and even thrive in cities. What determines which species persist or thrive in urban habitats? Direct competitive interactions among species can influence their distributions and resource use, particularly along gradients of environmental challenge. Given the challenges of urbanization, similar interactions may be important for determining which species persist or thrive in cities; however, their role remains poorly understood. Here, we use a global dataset to test among three alternative hypotheses for how direct competitive interactions and behavioral dominance may influence the breeding occurrence of birds in cities. We find evidence to support the competitive interference hypothesis: behaviorally dominant species were more widespread in urban habitats than closely related subordinate species, but only in taxa that thrive in urban environments (hereafter, urban adapted), and only when dominant and subordinate species overlapped their geographic ranges. This result was evident across diverse phylogenetic groups but varied significantly with a country's level of economic development. Urban-adapted, dominant species were more widespread than closely related subordinate species in cities in developed, but not developing, countries; countries in economic transition showed an intermediate pattern. Our results provide evidence that competitive interactions broadly influence species responses to urbanization, and that these interactions have asymmetric effects on subordinate species that otherwise could be widespread in urban environments. Results further suggest that economic development might accentuate the consequences of competitive interactions, thereby reducing local diversity in cities. PMID- 30397141 TI - Narrow thermal tolerance and low dispersal drive higher speciation in tropical mountains. AB - Species richness is greatest in the tropics, and much of this diversity is concentrated in mountains. Janzen proposed that reduced seasonal temperature variation selects for narrower thermal tolerances and limited dispersal along tropical elevation gradients [Janzen DH (1967) Am Nat 101:233-249]. These locally adapted traits should, in turn, promote reproductive isolation and higher speciation rates in tropical mountains compared with temperate ones. Here, we show that tropical and temperate montane stream insects have diverged in thermal tolerance and dispersal capacity, two key traits that are drivers of isolation in montane populations. Tropical species in each of three insect clades have markedly narrower thermal tolerances and lower dispersal than temperate species, resulting in significantly greater population divergence, higher cryptic diversity, higher tropical speciation rates, and greater accumulation of species over time. Our study also indicates that tropical montane species, with narrower thermal tolerance and reduced dispersal ability, will be especially vulnerable to rapid climate change. PMID- 30397143 TI - Peculiarly pleasant weather for US maize. AB - Continuation of historical trends in crop yield are critical to meeting the demands of a growing and more affluent world population. Climate change may compromise our ability to meet these demands, but estimates vary widely, highlighting the importance of understanding historical interactions between yield and climate trends. The relationship between temperature and yield is nuanced, involving differential yield outcomes to warm ([Formula: see text]C) and hot ([Formula: see text]C) temperatures and differing sensitivity across growth phases. Here, we use a crop model that resolves temperature responses according to magnitude and growth phase to show that US maize has benefited from weather shifts since 1981. Improvements are related to lengthening of the growing season and cooling of the hottest temperatures. Furthermore, current farmer cropping schedules are more beneficial in the climate of the last decade than they would have been in earlier decades, indicating statistically significant adaptation to a changing climate of 13 kg.ha-1. decade-1 All together, the better weather experienced by US maize accounts for 28% of the yield trends since 1981. Sustaining positive trends in yield depends on whether improvements in agricultural climate continue and the degree to which farmers adapt to future climates. PMID- 30397142 TI - Behavior-dependent cis regulation reveals genes and pathways associated with bower building in cichlid fishes. AB - Many behaviors are associated with heritable genetic variation [Kendler and Greenspan (2006) Am J Psychiatry 163:1683-1694]. Genetic mapping has revealed genomic regions or, in a few cases, specific genes explaining part of this variation [Bendesky and Bargmann (2011) Nat Rev Gen 12:809-820]. However, the genetic basis of behavioral evolution remains unclear. Here we investigate the evolution of an innate extended phenotype, bower building, among cichlid fishes of Lake Malawi. Males build bowers of two types, pits or castles, to attract females for mating. We performed comparative genome-wide analyses of 20 bower building species and found that these phenotypes have evolved multiple times with thousands of genetic variants strongly associated with this behavior, suggesting a polygenic architecture. Remarkably, F1 hybrids of a pit-digging and a castle building species perform sequential construction of first a pit and then a castle bower. Analysis of brain gene expression in these hybrids showed that genes near behavior-associated variants display behavior-dependent allele-specific expression with preferential expression of the pit-digging species allele during pit digging and of the castle-building species allele during castle building. These genes are highly enriched for functions related to neurodevelopment and neural plasticity. Our results suggest that natural behaviors are associated with complex genetic architectures that alter behavior via cis-regulatory differences whose effects on gene expression are specific to the behavior itself. PMID- 30397144 TI - Limiting the high impacts of Amazon forest dieback with no-regrets science and policy action. AB - Large uncertainties still dominate the hypothesis of an abrupt large-scale shift of the Amazon forest caused by climate change [Amazonian forest dieback (AFD)] even though observational evidence shows the forest and regional climate changing. Here, we assess whether mitigation or adaptation action should be taken now, later, or not at all in light of such uncertainties. No action/later action would result in major social impacts that may influence migration to large Amazonian cities through a causal chain of climate change and forest degradation leading to lower river-water levels that affect transportation, food security, and health. Net-present value socioeconomic damage over a 30-year period after AFD is estimated between US dollar (USD) $957 billion (*109) and $3,589 billion (compared with Gross Brazilian Amazon Product of USD $150 billion per year), arising primarily from changes in the provision of ecosystem services. Costs of acting now would be one to two orders of magnitude lower than economic damages. However, while AFD mitigation alternatives-e.g., curbing deforestation-are attainable (USD $64 billion), their efficacy in achieving a forest resilience that prevents AFD is uncertain. Concurrently, a proposed set of 20 adaptation measures is also attainable (USD $122 billion) and could bring benefits even if AFD never occurs. An interdisciplinary research agenda to fill lingering knowledge gaps and constrain the risk of AFD should focus on developing sound experimental and modeling evidence regarding its likelihood, integrated with socioeconomic assessments to anticipate its impacts and evaluate the feasibility and efficacy of mitigation/adaptation options. PMID- 30397145 TI - Sustainable hydropower in the 21st century. AB - Hydropower has been the leading source of renewable energy across the world, accounting for up to 71% of this supply as of 2016. This capacity was built up in North America and Europe between 1920 and 1970 when thousands of dams were built. Big dams stopped being built in developed nations, because the best sites for dams were already developed and environmental and social concerns made the costs unacceptable. Nowadays, more dams are being removed in North America and Europe than are being built. The hydropower industry moved to building dams in the developing world and since the 1970s, began to build even larger hydropower dams along the Mekong River Basin, the Amazon River Basin, and the Congo River Basin. The same problems are being repeated: disrupting river ecology, deforestation, losing aquatic and terrestrial biodiversity, releasing substantial greenhouse gases, displacing thousands of people, and altering people's livelihoods plus affecting the food systems, water quality, and agriculture near them. This paper studies the proliferation of large dams in developing countries and the importance of incorporating climate change into considerations of whether to build a dam along with some of the governance and compensation challenges. We also examine the overestimation of benefits and underestimation of costs along with changes that are needed to address the legitimate social and environmental concerns of people living in areas where dams are planned. Finally, we propose innovative solutions that can move hydropower toward sustainable practices together with solar, wind, and other renewable sources. PMID- 30397146 TI - Decomposition responses to climate depend on microbial community composition. AB - Bacteria and fungi drive decomposition, a fundamental process in the carbon cycle, yet the importance of microbial community composition for decomposition remains elusive. Here, we used an 18-month reciprocal transplant experiment along a climate gradient in Southern California to disentangle the effects of the microbial community versus the environment on decomposition. Specifically, we tested whether the decomposition response to climate change depends on the microbial community. We inoculated microbial decomposers from each site onto a common, irradiated leaf litter within "microbial cages" that prevent microbial exchange with the environment. We characterized fungal and bacterial composition and abundance over time and investigated the functional consequences through litter mass loss and chemistry. After 12 months, microbial communities altered both decomposition rate and litter chemistry. Further, the functional measurements depended on an interaction between the community and its climate in a manner not predicted by current theory. Moreover, microbial ecologists have traditionally considered fungi to be the primary agents of decomposition and for bacteria to play a minor role. Our results indicate that not only does climate change and transplantation have differential legacy effects among bacteria and fungi, but also that bacterial communities might be less functionally redundant than fungi with regards to decomposition. Thus, it may be time to reevaluate both the role of microbial community composition in its decomposition response to climate and the relative roles of bacterial and fungal communities in decomposition. PMID- 30397147 TI - Site-selective chemoenzymatic glycoengineering of Fab and Fc glycans of a therapeutic antibody. AB - The N-glycans attached to the Fab and Fc domains play distinct roles in modulating the functions of antibodies. However, posttranslational site-selective modifications of glycans in antibodies and other multiply glycosylated proteins remain a challenging task. Here, we report a chemoenzymatic method that permits independent manipulation of the Fab and Fc N-glycans, using cetuximab as a model therapeutic monoclonal antibody. Taking advantage of the substrate specificity of three endoglycosidases (Endo-S, Endo-S2, and Endo-F3) and their glycosynthase mutants, together with an unexpected substrate site-selectivity of a bacterial alpha1,6-fucosidase from Lactobacillus casei (AlfC), we were able to synthesize an optimal homogeneous glycoform of cetuximab in which the heterogeneous and immunogenic Fab N-glycans were replaced with a single sialylated N-glycan, and the core-fucosylated Fc N-glycans were remodeled with a nonfucosylated and fully galactosylated N-glycan. The glycoengineered cetuximab demonstrated increased affinity for the FcgammaIIIa receptor and significantly enhanced antibody dependent cell-mediated cytotoxicity (ADCC) activity. PMID- 30397149 TI - QnAs with Emilio F. Moran. PMID- 30397148 TI - Arabidopsis thaliana NGATHA1 transcription factor induces ABA biosynthesis by activating NCED3 gene during dehydration stress. AB - The plant hormone abscisic acid (ABA) is accumulated after drought stress and plays critical roles in the responses to drought stress in plants, such as gene regulation, stomatal closure, seed maturation, and dormancy. Although previous reports revealed detailed molecular roles of ABA in stress responses, the factors that contribute to the drought-stress responses-in particular, regulation of ABA accumulation-remain unclear. The enzyme NINE-CIS-EPOXYCAROTENOID DIOXYGENASE 3 (NCED3) is essential for ABA biosynthesis during drought stress, and the NCED3 gene is highly induced by drought stress. In the present study, we isolated NGATHAs (NGAs) as candidate transcriptional regulators of NCED3 through a screen of a plant library harboring the transcription factors fused to a chimeric repressor domain, SRDX. The NGA proteins were directly bound to a cis-element NGA binding element (NBE) in the 5' untranslated region (5' UTR) of the NCED3 promoter and were suggested to be transcriptional activators of NCED3 Among the single-knockout mutants of four NGA family genes, we found that the NGATHA1 (NGA1) knockout mutant was drought-stress-sensitive with a decreased expression level of NCED3 during dehydration stress. These results suggested that NGA1 essentially functions as a transcriptional activator of NCED3 among the NGA family proteins. Moreover, the NGA1 protein was degraded under nonstressed conditions, and dehydration stress enhanced the accumulation of NGA1 proteins, even in ABA-deficient mutant plants, indicating that there should be ABA independent posttranslational regulations. These findings emphasize the regulatory mechanisms of ABA biosynthesis during early drought stress. PMID- 30397152 TI - Escalator to extinction. PMID- 30397151 TI - Self-cleavage of the glmS ribozyme core is controlled by a fragile folding element. AB - Riboswitches modulate gene expression in response to small-molecule ligands. Switching is generally thought to occur via the stabilization of a specific RNA structure conferred by binding the cognate ligand. However, it is unclear whether any such stabilization occurs for riboswitches whose ligands also play functional roles, such as the glmS ribozyme riboswitch, which undergoes self-cleavage using its regulatory ligand, glucosamine 6-phosphate, as a catalytic cofactor. To address this question, it is necessary to determine both the conformational ensemble and its ligand dependence. We used optical tweezers to measure folding dynamics and cleavage rates for the core glmS ribozyme over a range of forces and ligand conditions. We found that the folding of a specific structural element, the P2.2 duplex, controls active-site formation and catalysis. However, the folded state is only weakly stable, regardless of cofactor concentration, supplying a clear exception to the ligand-based stabilization model of riboswitch function. PMID- 30397150 TI - Human-like hyperplastic prostate with low ZIP1 induced solely by Zn deficiency in rats. AB - Prostate cancer is a leading cause of cancer death in men over 50 years of age, and there is a characteristic marked decrease in Zn content in the malignant prostate cells. The cause and consequences of this loss have thus far been unknown. We found that in middle-aged rats a Zn-deficient diet reduces prostatic Zn levels (P = 0.025), increases cellular proliferation, and induces an inflammatory phenotype with COX-2 overexpression. This hyperplastic/inflammatory prostate has a human prostate cancer-like microRNA profile, with up-regulation of the Zn-homeostasis-regulating miR-183-96-182 cluster (fold change = 1.41-2.38; P = 0.029-0.0003) and down-regulation of the Zn importer ZIP1 (target of miR-182), leading to a reduction of prostatic Zn. This inverse relationship between miR-182 and ZIP1 also occurs in human prostate cancer tissue, which is known for Zn loss. The discovery that the Zn-depleted middle-aged rat prostate has a metabolic phenotype resembling that of human prostate cancer, with a 10-fold down regulation of citric acid (P = 0.0003), links citrate reduction directly to prostatic Zn loss, providing the underlying mechanism linking dietary Zn deficiency with miR-183-96-182 overexpression, ZIP1 down-regulation, prostatic Zn loss, and the resultant citrate down-regulation, changes mimicking features of human prostate cancer. Thus, dietary Zn deficiency during rat middle age produces changes that mimic those of human prostate carcinoma and may increase the risk for prostate cancer, supporting the need for assessment of Zn supplementation in its prevention. PMID- 30397153 TI - Awareness of what is learned as a characteristic of hippocampus-dependent memory. AB - We explored the relationship between memory performance and conscious knowledge (or awareness) of what has been learned in memory-impaired patients with hippocampal lesions or larger medial temporal lesions. Participants viewed familiar scenes or familiar scenes where a change had been introduced. Patients identified many fewer of the changes than controls. Across all of the scenes, controls preferentially directed their gaze toward the regions that had been changed whenever they had what we term robust knowledge about the change: They could identify that a change occurred, report what had changed, and indicate where the change occurred. Preferential looking did not occur when they were unaware of the change or had only partial knowledge about it. The patients, overall, did not direct their gaze toward the regions that had been changed, but on the few occasions when they had robust knowledge about the change they (like controls) did exhibit this effect. Patients did not exhibit this effect when they were unaware of the change or had partial knowledge. The findings support the idea that awareness of what has been learned is a key feature of hippocampus dependent memory. PMID- 30397155 TI - Alcohol use, opioid overdose and socioeconomic status in Canada: A threat to life expectancy? PMID- 30397157 TI - Organ donation after medical assistance in dying at home. PMID- 30397154 TI - Autocrine signaling by an Aplysia neurotrophin forms a presynaptic positive feedback loop. AB - Whereas short-term plasticity is often initiated on one side of the synapse, long term plasticity involves coordinated changes on both sides, implying extracellular signaling. We have investigated the possible signaling role of an Aplysia neurotrophin (ApNT) in facilitation induced by serotonin (5HT) at sensory to-motor neuron synapses in culture. ApNT is an ortholog of mammalian BDNF, which has been reported to act as either an anterograde, retrograde, or autocrine signal, so that its pre- and postsynaptic sources and targets remain unclear. We now report that ApNT acts as a presynaptic autocrine signal that forms part of a positive feedback loop with ApTrk and PKA. That loop stimulates spontaneous transmitter release, which recruits postsynaptic mechanisms, and presynaptic protein synthesis during the transition from short- to intermediate-term facilitation and may also initiate gene regulation to trigger the transition to long-term facilitation. These results suggest that a presynaptic ApNT feedback loop plays several key roles during consolidation of learning-related synaptic plasticity. PMID- 30397158 TI - The "dimple swallow" sign for branchial cleft anomalies. PMID- 30397159 TI - Losing doctors with integrity will harm patients and profession. PMID- 30397156 TI - Global Burden of Disease Study trends for Canada from 1990 to 2016. AB - BACKGROUND: The Global Burden of Disease Study represents a large and systematic effort to describe the burden of diseases and injuries over the past 3 decades. We aimed to summarize the Canadian data on burden of diseases and injuries. METHODS: We summarized data from the 2016 iteration of the Global Burden of Disease Study to provide current (2016) and historical estimates for all-cause and cause-specific diseases and injuries using mortality, years of life lost, years lived with disability and disability-adjusted life years in Canada. We also compared changes in life expectancy and health-adjusted life expectancy between Canada and 21 countries with a high sociodemographic index. RESULTS: In 2016, leading causes of all-age disability-adjusted life years were neoplasms, cardiovascular diseases, musculoskeletal diseases, and mental and substance use disorders, which together accounted for about 56% of disability-adjusted life years. Between 2006 and 2016, the rate of all-cause age-standardized years of life lost declined by 12%, while the rate of all-cause age-standardized years lived with disability remained relatively stable (+1%), and the rate of all-cause age-standardized disability-adjusted life year declined by 5%. In 2016, Canada aligned with countries that have a similar high sociodemographic index in terms of life expectancy (82 yr) and health-adjusted life expectancy (71 yr). INTERPRETATION: The patterns of mortality and morbidity in Canada reflect an aging population and improving patterns of population health. If current trends continue, Canada will continue to face challenges of increasing population morbidity and disability alongside decreasing premature mortality. PMID- 30397161 TI - Medical leaders urge system change to reduce physician burnout. PMID- 30397160 TI - The conscience rights of Canadian physicians require protection. PMID- 30397162 TI - Medical school reserves seats for low-income students to increase diversity. PMID- 30397163 TI - Doctors conflicted about patients recording clinical visits. PMID- 30397164 TI - Effective Discipline to Raise Healthy Children. AB - Pediatricians are a source of advice for parents and guardians concerning the management of child behavior, including discipline strategies that are used to teach appropriate behavior and protect their children and others from the adverse effects of challenging behavior. Aversive disciplinary strategies, including all forms of corporal punishment and yelling at or shaming children, are minimally effective in the short-term and not effective in the long-term. With new evidence, researchers link corporal punishment to an increased risk of negative behavioral, cognitive, psychosocial, and emotional outcomes for children. In this Policy Statement, the American Academy of Pediatrics provides guidance for pediatricians and other child health care providers on educating parents about positive and effective parenting strategies of discipline for children at each stage of development as well as references to educational materials. This statement supports the need for adults to avoid physical punishment and verbal abuse of children. PMID- 30397165 TI - E-cigarette Use and Subsequent Smoking Frequency Among Adolescents. AB - : : media-1vid110.1542/5839992666001PEDS-VA_2018-0486Video Abstract BACKGROUND AND OBJECTIVES: Electronic cigarette (e-cigarette) use is associated with cigarette initiation among adolescents. However, it is unclear whether e cigarette use is associated with more frequent cigarette use after initiation. Also, the extent to which cigarette or dual cigarette and e-cigarette users transition to exclusive e-cigarette use or to the nonuse of either product is not yet known. METHODS: Data were pooled from 3 prospective cohort studies in California and Connecticut (baseline: 2013-2014; follow-up: 2014-2016; N = 6258). Polytomous regression models were used to evaluate the association of baseline e cigarette use (never or ever) with cigarette use frequency at follow-up (experimental: initiation but no past-30-day use; infrequent: 1-2 of the past 30 days; frequent: 3-5 or more of the past 30 days). Polytomous regression models were also used to evaluate transitions between baseline ever or past-30-day single or dual product use and past-30-day single or dual product use at follow up. RESULTS: Among baseline never smokers, e-cigarette users had greater odds of subsequent experimental (odds ratio [OR] = 4.58; 95% confidence interval [CI]: 3.56-5.88), infrequent (OR = 4.27; 95% CI: 2.75-6.62) or frequent (OR = 3.51; 95% CI: 1.97-6.24) cigarette use; the 3 OR estimates were not significantly different. Baseline past-30-day exclusive cigarette use was associated with higher odds at follow-up of exclusive cigarette or dual product use than of exclusive e-cigarette use. CONCLUSIONS: Tobacco control policy to reduce adolescent use of both e-cigarettes and cigarettes is needed to prevent progression to more frequent tobacco use patterns and reduce combustible cigarette use (with or without concurrent e-cigarette use) to lessen the adverse public health impact of e-cigarettes. PMID- 30397166 TI - The Effects of Armed Conflict on Children. AB - Children are increasingly exposed to armed conflict and targeted by governmental and nongovernmental combatants. Armed conflict directly and indirectly affects children's physical, mental, and behavioral health. It can affect every organ system, and its impact can persist throughout the life course. In addition, children are disproportionately impacted by morbidity and mortality associated with armed conflict. A children's rights-based approach provides a framework for collaboration by the American Academy of Pediatrics, child health professionals, and national and international partners to respond in the domains of clinical care, systems development, and policy formulation. The American Academy of Pediatrics and child health professionals have critical and synergistic roles to play in the global response to the impact of armed conflict on children. PMID- 30397168 TI - The Effects of Armed Conflict on Children. AB - More than 1 in 10 children worldwide are affected by armed conflict. The effects are both direct and indirect and are associated with immediate and long-term harm. The direct effects of conflict include death, physical and psychological trauma, and displacement. Indirect effects are related to a large number of factors, including inadequate and unsafe living conditions, environmental hazards, caregiver mental health, separation from family, displacement-related health risks, and the destruction of health, public health, education, and economic infrastructure. Children and health workers are targeted by combatants during attacks, and children are recruited or forced to take part in combat in a variety of ways. Armed conflict is both a toxic stress and a significant social determinant of child health. In this Technical Report, we review the available knowledge on the effects of armed conflict on children and support the recommendations in the accompanying Policy Statement on children and armed conflict. PMID- 30397169 TI - Does T Cell Activation Require a Quorum of Lymphocytes? AB - Recent reports suggest a quorum of T cells is required to activate T lymphocytes and that this requirement may help explain why scarce lymphocytes, specific for peripheral self-antigen, are rarely activated by Ag. This proposal runs counter to the commonly held framework that the Ag-dependent, but CD4 T lymphocyte independent, activation of CD8 T lymphocytes, and the activation of CD4 T lymphocytes themselves, can occur when a single CD8 or CD4 T lymphocyte encounters Ag under appropriately dangerous circumstances. We argue that a review of older literature often ignored, as well as of contemporary studies, supports the quorum concept and is difficult to reconcile with the Danger Model. PMID- 30397167 TI - Tobacco Product Harm Perceptions and New Use. AB - : : media-1vid110.1542/5839992833001PEDS-VA_2018-1505Video Abstract BACKGROUND: Researchers in several studies have examined correlations between tobacco harm perceptions and tobacco use in youth, but none have prospectively addressed the association between harm perceptions and subsequent new use across multiple noncigarette products. METHODS: Product-specific absolute and relative harm perceptions for cigarettes, electronic cigarettes (e-cigarettes), cigars, pipes, hookah, and smokeless tobacco were collected at wave 1 (W1) (2013-2014) among youth in the nationally representative US Population Assessment of Tobacco and Health Study (12-17 years of age; n = 10 081). At wave 2 (W2) (2014-2015), product-specific new use was calculated. Adjusted relative risks were used to estimate if harm perceptions at W1 predicted W2 new tobacco use. RESULTS: The proportion of youth who endorsed "a lot of harm" was highest for cigarettes (84.8%) and lowest for e-cigarettes (26.6%); the proportion of youth who thought products were "more harmful" than cigarettes was highest for cigars (30.6%) and lowest for e-cigarettes (5.1%). Among youth who had not used those products at W1, product-specific new use at W2 ranged from 9.1% (e-cigarettes) to 0.6% (pipes). Youth who believed that noncombustible tobacco products posed "no or little harm" at W1 were more likely to have tried those products at W2 (P < .05). Youth who viewed e-cigarettes, hookah, and smokeless tobacco as "less harmful" than cigarettes at W1 were more likely to try those tobacco products at W2 (P < .05). CONCLUSIONS: Low harm perceptions of noncigarette tobacco products predict new use of these products by youth within the next year. Targeting product specific harm perceptions may prevent new tobacco use among youth. PMID- 30397170 TI - The Diverse Family of MR1-Restricted T Cells. AB - Mucosal-associated invariant T (MAIT) cells are characterized by a semi-invariant TCR that recognizes vitamin B metabolite Ags presented by the MHC-related molecule MR1. Their Ag restriction determines a unique developmental lineage, imbuing a tissue-homing, preprimed phenotype with antimicrobial function. A growing body of literature indicates that MR1-restricted T cells are more diverse than the MAIT term implies. Namely, it is increasingly clear that TCR alpha- and TCR beta-chain diversity within the MR1-restricted repertoire provides a potential mechanism of Ag discrimination, and context-dependent functional variation suggests a role for MR1-restricted T cells in diverse physiological settings. In this paper, we summarize MR1-restricted T cell biology, with an emphasis on TCR diversity, Ag discrimination, and functional heterogeneity. PMID- 30397171 TI - Periodic, moderate water flow reversibly increases hair bundle density and size in Nematostella vectensis. AB - Animals employ hair bundles on hair cells to detect flow, vibrations, and gravity. Hair bundles on sea anemone tentacles detect nearby vibrations in the water column produced by prey movements and then regulate discharge of cnidae to capture prey. This study investigates (i): the progressive effects of periodic water flow on hair bundle morphology and density of hair bundles and cnidae in sea anemones, (ii): the reversibility of the flow response and (iii): the ability of the response to be expedited with increased flow duration. Linear density of hair bundles along tentacles and each hair bundle's dimensions was measured in anemones exposed to flow and in the absence of flow. With increasing days of flow, hair bundles in anemones exposed to flow for one hour every week day for twenty days increased in density and grew longer and wider at bases and middles whereas controls did not. Time courses fit to a linear function exhibited significantly larger positive slopes from animals exposed to flow compared to controls. Hair bundles in anemones exposed to flow for three hours each day increased in linear density, length, base-width and middle-width after ten days of flow and returned to control levels after ten days following cessation of flow. An apparent increase in density of cnidae with flow barely missed statistical significance. Therefore, anemone hair bundles are dynamically and reversibly modified by periodic, moderate flow to become more abundant and robust. These findings may have relevance to hair cells in acoustico-lateralis systems of higher animals. PMID- 30397172 TI - Transforming growth factor-beta 1 (TGF-beta1) induces the differentiation of rainbow trout (Oncorhynchus mykiss) cardiac fibroblasts into myofibroblasts. AB - The collagen content of the rainbow trout heart increases in response to cold acclimation, and decreases with warm acclimation. This ability to remodel the myocardial extracellular matrix (ECM) makes these fish useful models to study the cellular pathways involved in collagen regulation in the vertebrate heart. Remodeling of the ECM in the mammalian heart is regulated, in part, by myofibroblasts which arise from pre-existing fibroblasts in response to transforming growth factor-beta 1 (TGF-beta1). We have previously demonstrated that treatment of cultured rainbow trout cardiac fibroblasts with human TGF-beta1 causes an increase in collagen production. Here we show that repetitive treatment of rainbow trout cardiac fibroblasts with a physiologically relevant concentration of human recombinant TGF-beta1 results in a ~29-fold increase in phosphorylated small mothers against decapentaplegic 2 (pSmad2); a 2.9-fold increase in vinculin protein, a 1.2-fold increase in cellular size and a 3-fold increase in filamentous actin (F-actin). These are common markers of the transition of fibroblasts to myofibroblasts. Cells treated with TGF-beta1 also had highly organized cytoskeletal alpha-smooth muscle actin, as well as increased transcript abundances of mmp-9, timp-2, and col1a1 Furthermore, using gelatin zymography, we demonstrate that TGF-beta1 treatment causes a 5.3-fold increase in gelatinase activity. Together, these results demonstrate that trout cardiac fibroblasts have the capacity to differentiate into myofibroblasts and that this cell type can increase extracellular collagen turnover via gelatinase activity. Cardiac myofibroblasts are, therefore, likely involved in the remodeling of the cardiac ECM in the trout heart during thermal acclimation. PMID- 30397173 TI - Deletion of a specific exon in the voltage-gated calcium channel, cacophony, causes disrupted locomotion in Drosophila larvae. AB - Tar DNA binding protein 43 (TDP-43) is an RNA binding protein that regulates transcription, translation, and alternative splicing of mRNA. We have shown previously that null mutations of the Drosophila orthologue, Tar DNA-binding homologue (tbph), causes severe locomotion defects in larvae that are mediated by a reduction in the expression of the type II voltage-gated calcium channel, cacophony (cac). We also showed that TDP-43 regulates the inclusion of alternatively spliced exons of cacophony; tbph mutants showed significantly increased expression of cacophony isoforms lacking exon 7, a particularly notable finding as only one out of the 15 predicted isoforms lacks exon 7. To investigate the function of exon 7, we generated Drosophila mutant lines with a deletion that eliminates exon 7. This deletion phenocopies many defects in tbph mutants: a reduction in cacophony protein expression, locomotion defects in male and female third instar larvae, disrupted larval motor output, and also reduced activity levels in adult male flies. All these defects were rescued by expression of cacophony transcripts containing exon 7. By contrast, expression of a cacophony cDNA lacking exon 7 resulted in reduced cacophony protein levels and failed to rescue larval locomotion. PMID- 30397174 TI - The role of parasitism in the energy management of a free-ranging bird. AB - Parasites often prompt sub-lethal costs to the host by eliciting immune responses. These costs can be hard to quantify but are crucial to our understanding of their host's ecology. Energy is a fundamental currency to quantify these costs, as energetic trade-offs often exist between key fitness related processes. Daily energy expenditure (DEE) comprises of resting metabolic rate (RMR) and energy available for activity which are linked via the energy management strategy of an organism. Parasitism may play a role in the balance between self-maintenance and activity, as immune costs can be expressed in elevated RMR. Therefore, understanding energy use in the presence of parasitism enables mechanistic elucidation of potential parasite costs. Using a gradient of natural parasite load and proxies for RMR and DEE in a wild population of breeding European shags (Phalacrocorax aristotelis), we tested the effect of parasitism on maintenance costs as well as the relationship between proxies for RMR and DEE. We found a positive relationship between parasite load and our RMR proxy in females but not males and no relationship between proxies for RMR and DEE. This provides evidence for increased maintenance costs in individuals with higher parasite loads and suggests the use of an allocation energy management strategy, whereby an increase to RMR creates restrictions on energy allocation to other activities. This is likely to have fitness consequences as energy allocated to immunity is traded-off against reproduction. Our findings demonstrate that understanding energy management strategies alongside fitness drivers is central to understanding the mechanisms by which these drivers influence individual fitness. PMID- 30397175 TI - A Combined Nomogram Model to Preoperatively Predict Histologic Grade in Pancreatic Neuroendocrine Tumors. AB - PURPOSE: To develop and validate a nomogram model combing radiomics features and clinical characteristics to preoperatively differentiate Grade1 and Grade2/3 tumors in patients with pancreatic neuroendocrine tumors (pNETs). EXPERIMENTAL DESIGN: A total of 137 patients who underwent contrast-enhanced CT from two hospitals were included in this study. The patients from the second hospital (n=51) were selected as an independent validation set. The arterial phase in contrast-enhanced CT was selected for radiomics feature extraction. The Mann Whitney U test and LASSO regression were applied for feature selection and radiomics signature construction. A combined nomogram model was developed by incorporating the radiomics signature with clinical factors. The association between the nomogram model and the Ki-67 index and rate of nuclear mitosis were also investigated respectively. The utility of the proposed model was evaluated using the ROC, area under ROC curve(AUC), calibration curve and decision curve analysis(DCA). The Kaplan-Meier(KM) analysis was employed for survival analysis. RESULTS: An eight-feature-combined radiomics signature was constructed as a tumor grade predictor. The nomogram model combining the radiomics signature with clinical stage showed the best performance (training set: AUC=0.907; validation set: AUC=0.891). The calibration curve and DCA demonstrated the clinical usefulness of the proposed nomogram. A significant correlation was observed between the developed nomogram and Ki-67 index and rate of nuclear mitosis, respectively. The KM analysis showed a significant difference between the survival of predicted Grade1 and Grade2/3 groups (p=0.002). CONCLUSIONS: The combined nomogram model developed could be useful in differentiating Grade1 and Grade2/3 tumor in patients with pNETs. PMID- 30397176 TI - A combination CDK4/6 and IGF1R inhibitor strategy for Ewing sarcoma. AB - INTRODUCTION: Novel targeted therapeutics have transformed the care of subsets of patients with cancer. In pediatric malignancies, however, with simple tumor genomes and infrequent targetable mutations, there have been few new FDA-approved targeted drugs. The cyclin-dependent kinase (CDK)4/6 pathway recently emerged as a dependency in Ewing sarcoma, an aggressive pediatric malignancy. Given the heightened efficacy of this class with targeted drug combinations in other cancers, as well as the propensity of resistance to emerge with single agents, we aimed to identify genes mediating resistance to CDK4/6 inhibitors (CDK4/6i) and biologically relevant combinations for use with CDK4/6i in Ewing. EXPERIMENTAL DESIGN: We performed a genome-scale open-reading frame (ORF) screen in two Ewing cell lines sensitive to CDK4/6i to identify genes conferring resistance. Concurrently, we established resistance to CDK4/6i in a Ewing cell line. RESULTS: The ORF screen revealed IGF1R as a gene whose overexpression promoted drug escape. We also found elevated levels of phospho-IGF1R in our resistant Ewing cell line, supporting the relevance of IGF1R signaling to acquired resistance. In a small molecule screen, an IGF1R inhibitor scored as synergistic with CDK4/6i treatment. The combination of CDK4/6i and IGF1Ri were synergistic in vitro and active in mouse models. Mechanistically, this combination more profoundly repressed cell cycle and PI3K/mTOR signaling than either single drug perturbation. CONCLUSIONS: Taken together, these results suggest that IGF1R activation is an escape mechanism to CDK4/6i in Ewing sarcoma and that dual targeting of CDK4/6 and IGF1R provides a candidate synergistic combination for clinical application in this disease. PMID- 30397177 TI - Targeting an Autocrine Regulatory Loop in Cancer Stem-Like Cells Impairs the Progression and Chemotherapy Resistance of Bladder Cancer. AB - PURPOSE: Cancer stem-like cells (CSCs) contribute to bladder cancer (BCa) chemotherapy resistance and progression, but the associated mechanisms have not been elucidated. This study determined whether blocking an autocrine signaling loop in CSCs improves the therapeutic effects of cis-platinum on BCa. EXPERIMENTAL DESIGN: The expression of the epithelial marker OV6 and other markers in human BCa specimens was examined by immunohistochemistry. The CSC properties of magnetic-activated cell sorting (MACS)-isolated OV6+ and OV6- BCa cells were examined. Molecular mechanisms were assessed through RNA-Seq, cytokine antibody arrays, co-immunoprecipitation (co-IP), chromatin immunoprecipitation (ChIP), and other assays. An orthotopic BCa mouse model was established to evaluate the in vivo effects of a YAP inhibitor (verteporfin) and a PDGFR inhibitor (CP-673451) on the cis-platinum resistance of OV6+ CSCs in BCa. RESULTS: Up-regulated OV6 expression positively associated with disease progression and poor prognosis for BCa patients. Compared with OV6- cells, OV6+ BCa cells exhibited strong CSC characteristics, including self-renewal, tumor initiation in NOD/SCID mice and chemotherapy resistance. YAP, which maintains the stemness of OV6+ CSCs, triggered PDGFB transcription by recruiting TEAD1. Autocrine PDGF-BB signaling through its receptor PDGFR stabilized YAP and facilitated YAP nuclear translocation. Furthermore, blocking the YAP/TEAD1/PDGF BB/PDGFR loop with verteporfin or CP-673451 inhibited the cis-platinum resistance of OV6+ BCa CSCs in an orthotopic BCa model. CONCLUSIONS: OV6 could be a helpful indicator of disease progression and prognosis for BCa patients, and targeting the autocrine YAP/TEAD1/PDGF-BB/PDGFR loop might serve as a remedy for cis platinum resistance in patients with advanced BCa. PMID- 30397179 TI - Immunotherapy and Hyperprogression: Unwanted Outcomes, Unclear Mechanism. AB - Hyperprogression (HP) is a recently defined clinical phenomenon in which patients treated with immunotherapy paradoxically exhibit rapid tumor growth. The mechanisms of hyperprogression remain ill-defined, although recent studies in this issue point to a possible role for Fc receptors in this process. Clin Cancer Res; 1-3. (c)2018 AACR. See related article by Lo Russo et al. PMID- 30397178 TI - Long noncoding RNA LBCS inhibits self-renewal and chemoresistance of bladder cancer stem cells through epigenetic silencing of SOX2. AB - PURPOSE: Chemoresistance and tumor relapse are the leading cause of deaths in bladder cancer patients. Bladder cancer stem cells (BCSCs) have been reported contribute to these pathological properties. However, the molecular mechanisms underlying their self-renewal and chemoresistance remain largely unknown. In the current study, a novel lncRNA-LBCS has been identified and explored in BCSCs. EXPERIMENTAL DESIGN: Firstly, we establish BCSCs model and explore the BCSCs associated lncRNAs by transcriptome microarray. The expression and clinical features of lnc-LBCS are analyzed in three independent large-scale cohorts. The functional role and mechanism of lnc-LBCS are further investigated by gain and loss of function assays in vitro and in vivo. RESULTS: Lnc-LBCS is significantly downregulated in BCSCs and cancer tissues, and correlates with tumor grade, chemotherapy response and prognosis. Moreover, lnc-LBCS markedly inhibits self renewal, chemoresistance and tumor initiation of BCSCs both in vitro and in vivo. Mechanistically, lnc-LBCS directly binds to hnRNPK and EZH2, and serves as a scaffold to induce the formation of this complex to repress SOX2 transcription via mediating histone H3 lysine 27 tri-methylation (H3K27me3). SOX2 is essential for self-renewal and chemoresistance of BCSCs, and correlates with the clinical severity and prognosis of bladder cancer patients. CONCLUSIONS: As a novel regulator, lnc-LBCS plays an important tumor suppressor role in BCSCs self renewal and chemoresistance, contributing to weak tumorigenesis and enhanced chemosensitivity. The lnc-LBCS-hnRNPK-EZH2-SOX2 regulatory axis may represent a therapeutic target for clinical intervention in chemoresistant bladder cancer. PMID- 30397181 TI - p62/SQSTM1 - steering the cell through health and disease. AB - SQSTM1 (also known as p62) is a multifunctional stress-inducible scaffold protein involved in diverse cellular processes. Its functions are tightly regulated through an extensive pattern of post-translational modifications, and include the isolation of cargos degraded by autophagy, induction of the antioxidant response by the Keap1-Nrf2 system, as well as the regulation of endosomal trafficking, apoptosis and inflammation. Accordingly, malfunction of SQSTM1 is associated with a wide range of diseases, including bone and muscle disorders, neurodegenerative and metabolic diseases, and multiple forms of cancer. In this Review, we summarize current knowledge regarding regulation, post-translational modifications and functions of SQSTM1, as well as how they are dysregulated in various pathogenic contexts. PMID- 30397180 TI - Cell surface Notch ligand DLL3 is a therapeutic target in isocitrate dehydrogenase mutant glioma. AB - PURPOSE: Isocitrate dehydrogenase (IDH) mutant gliomas are a distinct glioma molecular subtype for which no effective molecularly-directed therapy exists. Low grade gliomas, which are 80-90% IDH mutant, have high RNA levels of the cell surface Notch ligand DLL3. We sought to determine DLL3 expression by immunohistochemistry in glioma molecular subtypes and the potential efficacy of an anti-DLL3 antibody drug conjugate (ADC), rovalpituzumab tesirine (Rova-T), in IDH mutant glioma. EXPERIMENTAL DESIGN: We evaluated DLL3 expression by RNA using TCGA data and by immunohistochemistry in a discovery set of 63 gliomas and 20 non tumor brain tissues and a validation set of 62 known IDH wildtype and mutant gliomas using a monoclonal anti-DLL3 antibody. Genotype was determined using a DNA methylation array classifier or by sequencing. The effect of Rova-T on patient-derived endogenous IDH mutant glioma tumorspheres was determined by cell viability assay. RESULTS: Compared to IDH wildtype glioblastoma, IDH mutant gliomas have significantly higher DLL3 RNA (P<1x10-15) and protein by immunohistochemistry (P=0.0014 and P<4.3x10-6 in the discovery and validation set, respectively). DLL3 immunostaining was intense and homogeneous in IDH mutant gliomas, retained in all recurrent tumors, and detected in only 1 of 20 non-tumor brains. Patient-derived IDH mutant glioma tumorspheres overexpressed DLL3 and were potently sensitive to Rova-T in an antigen-dependent manner. CONCLUSIONS: DLL3 is selectively and homogeneously expressed in IDH mutant gliomas and can be targeted with Rova-T in patient-derived IDH mutant glioma tumorspheres. Our findings are potentially immediately translatable and have implications for therapeutic strategies that exploit cell surface tumor-associated antigens. PMID- 30397182 TI - Recombinant prion protein vaccination of transgenic elk PrP mice and reindeer overcomes self-tolerance and protects mice against chronic wasting disease. AB - Chronic wasting disease (CWD) is a fatal neurodegenerative disease that affects cervids in North America and now Europe. No effective measures are available to control CWD. We hypothesized that active vaccination with homologous and aggregation-prone recombinant prion protein (PrP) could overcome self-tolerance and induce autoantibody production against the cellular isoform of PrP (PrPC), which would be protective against CWD infection from peripheral routes. Five groups of transgenic mice expressing elk PrP (TgElk) were vaccinated with either the adjuvant CpG alone or one of four recombinant PrP immunogens: deer dimer (Ddi), deer monomer (Dmo), mouse dimer (Mdi), and mouse monomer (Mmo). Mice were then challenged intraperitoneally with elk CWD prions. All vaccinated mice developed ELISA-detectable antibody titers against PrP. Importantly, all four vaccinated groups survived longer than the control group, with the Mmo-immunized group exhibiting 60% prolongation of mean survival time compared with the control group (183 vs. 114 days postinoculation). We tested for prion infection in brain and spleen of all clinically sick mice. Notably, the attack rate was 100% as revealed by positive CWD signals in all tested tissues when assessed with Western blotting, real-time quaking-induced conversion, and immunohistochemistry. Our pilot study in reindeers indicated appreciable humoral immune responses to Mdi and Ddi immunogens, and the post-immune sera from the Ddi vaccinated reindeer mitigated CWD propagation in a cell culture model (CWD-RK13). Taken together, our study provides very promising vaccine candidates against CWD, but further studies in cervids are required to investigate vaccine efficacy in the natural CWD hosts. PMID- 30397183 TI - beta-cell mass restoration by alpha7-nicotinic acetylcholine receptor activation. AB - Although it is well established how nutrients, growth factors, and hormones impact functional beta-cell mass (BCM), the influence of the central nervous system in this regard and, especially in the context of islet immune modulation, has been understudied. Here we have investigated the expression and activity of pancreatic islet alpha7 nicotinic acetylcholine receptor (alpha7nAChR) in islet anti-inflammatory and pro-survival signaling. Systemic administration of alpha7nAChR agonists in mice improves glucose tolerance and curtails streptozotocin (STZ)-induced hyperglycemia by retaining BCM, in part, through maintaining Pdx1 and MafA expression and reducing apoptosis. alpha7nAChR activation of mouse islets ex vivo leads to reduced inflammatory drive through a JAK2-STAT3 pathway that couples with CREB/Irs2/Akt survival signaling. Since the vagus nerve conveys anti-inflammatory signals to immune cells of the spleen and other non-neural tissues in the viscera by activating alpha7nAChRs, our study suggests a novel role for beta-cell alpha7nAChRs that function to maintain beta cell survival and mass homeostasis through modulating islet cytokine and PI3 kinase dependent signaling pathways. Exploiting this pathway may have therapeutic potential for treating autoimmune diabetes. PMID- 30397184 TI - The SH3 domain of Fyn kinase interacts with and induces liquid-liquid phase separation of the low complexity domain of hnRNPA2. AB - Liquid-liquid phase separation of proteins and nucleic acids into membraneless organelles (MLOs) spatially organizes cellular components and reactions. The RNA binding protein heterogeneous nuclear ribonucleoprotein A2 (hnRNPA2) carries mRNA targets in MLOs called transport granules in neurons and oligodendrocytes. At sites of local translation, hnRNPA2 is phosphorylated by the tyrosine protein kinase Fyn, releasing the mRNA for translation. Fyn recognizes targets through its SH3 domain (Fyn-SH3). However, hnRNPA2 lacks canonical SH3 binding sequences, raising the question of how Fyn-SH3 binds hnRNPA2 in phase-separated transport granules. Here, we characterize the structural details of the interaction of the hnRNPA2 low complexity domain (LC) with Fyn-SH3 and the effect of Fyn-SH3 on hnRNPA2 phase separation. We combined in vitro microscopy and solution NMR spectroscopy to evaluate assembly of hnRNPA2 and Fyn-SH3 into in vitro phase separated granules and probe the structural details of their interaction. We observed that Fyn-SH3 induces hnRNPA2 LC phase separation and that Fyn-SH3 is incorporated into in vitro hnRNPA2 LC granules. Moreover, we identified hnRNPA2 LC interaction sites on the surface of Fyn-SH3. Our data offer a structural view of how hnRNPA2 LC may interact with Fyn. To our knowledge, our study provides the first example of a single globular domain inducing phase separation of a disordered MLO scaffold protein. PMID- 30397185 TI - VPS34 complexes from a structural perspective. AB - VPS34 phosphorylates phosphatidylinositol to produce PtdIns3P and is the progenitor of the PI3K family. VPS34 has a simpler domain organization than class I PI3Ks, which belies the complexity of its quaternary organization, with the enzyme always functioning within larger assemblies. PtdIns3P recruits specific recognition modules that are common in protein sorting pathways such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and ATG14L, whereas complex II replaces ATG14L with UVRAG. Because VPS34 can form a component of several distinct complexes, it enables independent regulation of various pathways that are controlled by PtdIns3P. Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. Autophagy has a complex association with cancer. In early stages, it inhibits tumorigenesis, but in later stages, it acts as a survival factor for tumors. Recently, various disease associated somatic mutations were found in genes encoding complexes I and II subunits. Lipid kinase activities of the complexes are also influenced by post translational modifications (PTMs). Mapping PTMs and somatic mutations on three dimensional models of the complexes suggests mechanisms for how these affect VPS34 activity. PMID- 30397186 TI - Lysosomal oxidation of LDL alters lysosomal pH, induces senescence and increases secretion of pro-inflammatory cytokines in human macrophages. AB - Objective We have shown that aggregated low density lipoproteins (LDL) is internalised by macrophages and oxidised in lysosomes by redox-active iron. We have now investigated if the lysosomal oxidation of LDL impairs lysosomal function and if a lysosomotropic antioxidant can prevent these alterations. Approach and Results LDL aggregated by sphingomyelinase (SMase-LDL) caused increased lysosomal lipid peroxidation in human monocyte-derived macrophages or THP-1 macrophage-like cells, as shown by a fluorescent probe, Foam-LPO. The pH of the lysosomes was increased considerably by lysosomal LDL oxidation as shown by Lysosensor Yellow/Blue and LysoTracker Red. SMase-LDL induced senescence-like properties in the cells as shown by beta-galactosidase staining and levels of p53 and p21. Inflammation plays a key role in atherosclerosis. SMase-LDL treatment increased the LPS-induced secretion of TNF-alpha, IL-6 and MCP-1. The lysosomotropic antioxidant, cysteamine inhibited all of the above changes. Conclusions Targeting lysosomes with antioxidants, such as cysteamine, to prevent the intralysosomal oxidation of LDL might be a novel therapy for atherosclerosis. PMID- 30397187 TI - Hepatic VLDL secretion: DGAT1 determines particle size but not particle number which is supported by DGAT2 activity in the absence of DGAT1. AB - DGAT1 activity is expressed on both aspects of the endoplasmic reticulum (dual membrane-topology) and plays a distinctive role in determining the triglyceride (TAG) content of VLDL particles secreted by the liver. Mice specific DGAT1 ablation in hepatocytes (DGAT1-LKO mice) had the same number of VLDL particles (apoB concentration) in the plasma, but these particles were approximately halve the size of VLDL particles secreted by control mice, and had a proportionately decreased content of TAG, with normal cholesterol and cholesterol ester contents. Analyses of purified microsomal fractions prepared from 16h-fasted control and DAGT1-LKO mice showed that the TAG/protein ratio in the endoplasmic reticulum (ER) was significantly lower in the latter. Electron micrographs of these livers showed that those from DGAT1-LKO mice did not show the increased lipid content of the smooth ER shown by control livers. The effects of DGAT1- and DGAT2-specific inhibitors on apoB secretion by HepG2 cells showed that DGAT1 is not indispensable for apoB secretion, and demonstrated redundancy in the ability of the two enzymes to support apoB secretion. Therefore, our findings show that DGAT1 is essential for the complete lipidation and maturation of VLDL particles within the lumen of the ER, consistent with its dual topology within the ER membrane. In the mouse, DGAT2 can support apoB secretion (particle number) even when TAG availability for full VLDL lipidation is restricted in the absence of DGAT1. PMID- 30397188 TI - Association of Kidney Donor Risk Index with the Outcome after Kidney Transplantation in the Eurotransplant Senior Program. AB - BACKGROUND We evaluated the Kidney Donor Risk Index (KDRI) scoring system for kidney transplantation in the Eurotransplant Senior Program (ESP) that allocates kidneys from older donors to older recipients (>=65 years). MATERIAL AND METHODS We retrospectively analyzed data of 37 kidney transplant recipients and 36 kidney donors who participated in kidney transplantation program according to the ESP at our center from January 2004 until December 2013. RESULTS Mean recipient and donor age was 67.9+/-2.6 and 70.5+/-4.0 years respectively. The mean KDRI score was 1.7+/-0.27. Uncensored graft survival after 1 year and 5 years was 64.2% and 53.7% respectively. Subgroup analysis showed that in kidney transplantation with KDRI >1.83, graft survival was significantly reduced compared to lower KDRI subgroups. KDRI was significantly correlated with serum creatinine level at discharge (r=0.4). CONCLUSIONS ESP kidneys represent a group of high-risk grafts with high KDRI scores. Higher KDRI scores in ESP kidneys was associated with reduced postoperative short-term and long-term graft outcomes. KDRI might be useful in decision-making for selecting donors for ESP kidney transplantation. PMID- 30397189 TI - Evaluation of a Novel General Pituitary Hormone Score to Evaluate the Function of the Residual Anterior Pituitary (Adenohypophysis) in Patients Following Surgery for Pituitary Adenoma. AB - BACKGROUND The aim was to develop and assess a general pituitary hormone score to evaluate the function of the anterior pituitary (adenohypophysis) in patients following resection of pituitary adenomas. MATERIAL AND METHODS Sixty-six patients with pituitary null cell macroadenoma (1-3 cm diameter) (N=38) and pituitary null cell giant adenoma (>=3 cm diameter) (N=28) had preoperative and postoperative data including magnetic resonance imaging (MRI) and measurement of six pituitary hormones levels, adrenocorticotropic hormone (ACTH), growth hormone (GH), thyroid-stimulating hormone (TSH), prolactin (PRL), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). The postoperative general pituitary hormone score, for 57 patients who underwent subtotal resection (>60%) and nine patients who underwent partial resection (<=60%), was 1-5 for each hormone level (score range, 6-30). RESULTS ACTH, GH, TSH, PRL, FSH, and LH levels in 38 patients with pituitary null cell macroadenoma were not statistically different from the 28 patients with pituitary null cell giant adenoma; the general pituitary hormone score in the former group was significantly increased compared with the latter group (P<0.05). ACTH, GH, TSH, PRL, FSH, and LH levels in the 57 patients with subtotal tumor resection were not significantly different from the nine patients with partial tumor resection; the general pituitary hormone score in the former group was significantly reduced compared with the latter group (P<0.05). CONCLUSIONS A general pituitary hormone score was developed that might be relevant to the evaluation of pituitary function following surgical resection of pituitary null cell macroadenoma and giant adenoma. PMID- 30397190 TI - Delirium History and Preoperative Mild Neurocognitive Disorder: An Opportunity for Multidisciplinary Patient-Centered Care. AB - BACKGROUND Delirium is a well-established clinical phenomenon that remains largely underdiagnosed. In light of its association with diminished postoperative outcomes, recent efforts involve implementing preventive strategies and fostering early detection. This report highlights how multidisciplinary interventions can inform risk for delirium and the challenges that accompany identifying at-risk patients. CASE REPORT A 75-year-old male with a history of postoperative cognitive complications including delirium and mild cognitive impairment. He was attending an outpatient preoperative anesthesia clearance assessment prior to a planned removal for a left frontoethmoidal sinus mucocele. As part of clinical care, an in-house neuropsychologist completed a neurobehavioral exam to assess current cognitive status and guide perioperative cognitive care recommendations. Findings were consistent with mild neurocognitive disorder. CONCLUSIONS Given the patient's history and current status, he was listed as a high delirium risk. The team provided information on delirium and delirium risk factors, encouraged the patient to speak to his surgeon and also a geriatric specialist to assist with decision making. Due to their concern about delirium, the patient and his caregiver opted to postpone the left frontoethmoidal sinus mucocele removal. PMID- 30397191 TI - Effect of the BTK inhibitor ibrutinib on macrophage- and gammadelta T cell mediated response against Mycobacterium tuberculosis. PMID- 30397192 TI - Evidence for Weyl fermions in a canonical heavy-fermion semimetal YbPtBi. AB - The manifestation of Weyl fermions in strongly correlated electron systems is of particular interest. We report evidence for Weyl fermions in the heavy fermion semimetal YbPtBi from electronic structure calculations, angle-resolved photoemission spectroscopy, magnetotransport and calorimetric measurements. At elevated temperatures where 4f-electrons are localized, there are triply degenerate points, yielding Weyl nodes in applied magnetic fields. These are revealed by a contribution from the chiral anomaly in the magnetotransport, which at low temperatures becomes negligible due to the influence of electronic correlations. Instead, Weyl fermions are inferred from the topological Hall effect, which provides evidence for a Berry curvature, and a cubic temperature dependence of the specific heat, as expected from the linear dispersion near the Weyl nodes. The results suggest that YbPtBi is a Weyl heavy fermion semimetal, where the Kondo interaction renormalizes the bands hosting Weyl points. These findings open up an opportunity to explore the interplay between topology and strong electronic correlations. PMID- 30397193 TI - Deferred autologous stem cell transplantation in systemic AL amyloidosis. AB - High-dose melphalan with autologous stem cell transplantation (ASCT) can induce durable haematological and organ responses in systemic AL amyloidosis (AL). Stringent selection criteria have improved safety of ASCT in AL but most patients are transplant-ineligible. We report our experience of deferred ASCT in AL patients who were transplant-ineligible at presentation but had improvements in organ function after induction chemotherapy, enabling them to undergo ASCT. Twenty-two AL patients underwent deferred ASCT from 2011 to 2017. All had serial organ function and clonal response assessment. Organ involvement and responses were defined by amyloidosis consensus criteria. All patients were transplant ineligible at presentation, predominantly due to advanced cardiac involvement. All received bortezomib-based therapy, with 100% haematologic response (86% complete response (CR)/very good partial response (VGPR)), enabling reversal of ASCT exclusion criteria. Patients underwent deferred ASCT for haematologic progression (45%) or consolidation (55%). There was no transplant-related mortality. Haematologic responses post-ASCT: CR 50%, VGPR 27%, PR 18%, non response 5%. In all, 85.7% achieved cardiac responses. Median overall survival (OS) was not reached. Median progression-free survival (PFS) was 54 months. This selected cohort achieved excellent haematologic responses, organ responses, PFS and OS with deferred ASCT. If larger studies confirm these findings, this may widen the applicability of ASCT in AL. PMID- 30397194 TI - Adjuvant role of macrophages in stem cell-induced cardiac repair in rats. AB - Bone marrow-derived mesenchymal stem cells (BMMSCs) are used extensively for cardiac repair and interact with immune cells in the damaged heart. Macrophages are known to be modulated by stem cells, and we hypothesized that priming macrophages with BMMSCs would enhance their therapeutic efficacy. Rat bone marrow derived macrophages (BMDMs) were stimulated by lipopolysaccharide (LPS) with or without coculture with rat BMCs. In the LPS-stimulated BMDMs, induction of the inflammatory marker iNOS was attenuated, and the anti-inflammatory marker Arg1 was markedly upregulated by coculture with BMMSCs. Myocardial infarction (MI) was induced in rats. One group was injected with BMMSCs, and a second group was injected with MIX (a mixture of BMMSCs and BMDMs after coculture). The reduction in cardiac fibrosis was greater in the MIX group than in the BMC group. Cardiac function was improved in the BMMSC group and was substantially improved in the MIX group. Angiogenesis was better in the MIX group, and anti-inflammatory macrophages were more abundant in the MIX group than in the BMMSC group. In the BMMSCs, interferon regulatory factor 5 (IRF5) was exclusively induced by coculture with macrophages. IRF5 knockdown in BMMSCs failed to suppress inflammatory marker induction in the macrophages. In this study, we demonstrated the successful application of BMDMs primed with BMMSCs as an adjuvant to cell therapy for cardiac repair. PMID- 30397196 TI - Predicting the naturalistic course of depression from a wide range of clinical, psychological, and biological data: a machine learning approach. AB - Many variables have been linked to different course trajectories of depression. These findings, however, are based on group comparisons with unknown translational value. This study evaluated the prognostic value of a wide range of clinical, psychological, and biological characteristics for predicting the course of depression and aimed to identify the best set of predictors. Eight hundred four unipolar depressed patients (major depressive disorder or dysthymia) patients were assessed on a set involving 81 demographic, clinical, psychological, and biological measures and were clinically followed-up for 2 years. Subjects were grouped according to (i) the presence of a depression diagnosis at 2-year follow-up (yes n = 397, no n = 407), and (ii) three disease course trajectory groups (rapid remission, n = 356, gradual improvement n = 273, and chronic n = 175) identified by a latent class growth analysis. A penalized logistic regression, followed by tight control over type I error, was used to predict depression course and to evaluate the prognostic value of individual variables. Based on the inventory of depressive symptomatology (IDS), we could predict a rapid remission course of depression with an AUROC of 0.69 and 62% accuracy, and the presence of an MDD diagnosis at follow-up with an AUROC of 0.66 and 66% accuracy. Other clinical, psychological, or biological variables did not significantly improve the prediction. Among the large set of variables considered, only the IDS provided predictive value for course prediction on an individual level, although this analysis represents only one possible methodological approach. However, accuracy of course prediction was moderate at best and further improvement is required for these findings to be clinically useful. PMID- 30397195 TI - Methylenetetrahydrofolate reductase and psychiatric diseases. AB - Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme for the critical process of one-carbon metabolism involving folate and homocysteine metabolisms. It is known that some polymorphism of MTHFR would result in reduction of MTHFR enzyme activity as well as DNA methylation process, later shown to have significant impacts in various psychiatric diseases. However, it is unclear whether the polymorphism of MTHFR could be an independent or an add-on risk factor for specific psychiatric symptoms, such as anxiety, depression, positive, or negative symptoms of schizophrenia, or acts as risk factor for specific psychiatric disorders, such as schizophrenia, major depression, autisms, and bipolar disorders. It is also understudied on whether folate supplements could be an effective treatment for psychiatric patients with defect MTHFR activity. In this review, we not only gathered the most recent discoveries on MTHFR polymorphism and related DNA methylation in various psychiatric disorders, but also highlighted the potential relationships between MTHFR activity and implication of folate-related function in specific mental diseases. PMID- 30397197 TI - Inhibition of mTORC1 by lncRNA H19 via disrupting 4E-BP1/Raptor interaction in pituitary tumours. AB - Aberrant expression of long noncoding RNA H19 has been associated with tumour progression, but the underlying molecular tumourigenesis mechanisms remain largely unknown. Here, we report that H19 expression is frequently downregulated in human primary pituitary adenomas and is negatively correlated with tumour progression. Consistently, upregulation of H19 expression inhibits pituitary tumour cell proliferation in vitro and tumour growth in vivo. Importantly, we uncover a function of H19, which controls cell/tumour growth through inhibiting function of mTORC1 but not mTORC2. Mechanistically, we show that H19 could block mTORC1-mediated 4E-BP1 phosphorylation without affecting S6K1 activation. At the molecular level, H19 interacted with 4E-BP1 at the TOS motif and competitively inhibited 4E-BP1 binding to Raptor. Finally, we demonstrate that H19 is more effective than cabergoline treatment in the suppression of pituitary tumours. Together, our study uncovered the role of H19-mTOR-4E-BP1 axis in pituitary tumour growth regulation that may be a potential therapeutic target for human pituitary tumours. PMID- 30397199 TI - Controlling reaction pathways of selective C-O bond cleavage of glycerol. AB - The selective hydrodeoxygenation (HDO) reaction is desirable to convert glycerol into various value-added products by breaking different numbers of C-O bonds while maintaining C-C bonds. Here we combine experimental and density functional theory (DFT) results to reveal that the Cu modifier can significantly reduce the oxophilicity of the molybdenum carbide (Mo2C) surface and change the product distribution. The Mo2C surface is active for breaking all C-O bonds to produce propylene. As the Cu coverage increases to 0.5 monolayer (ML), the Cu/Mo2C surface shows activity towards breaking two C-O bonds and forming ally-alcohol and propanal. As the Cu coverage further increases, the Cu/Mo2C surface cleaves one C-O bond to form acetol. DFT calculations reveal that the Mo2C surface, Cu-Mo interface, and Cu surface are distinct sites for the production of propylene, ally-alcohol, and acetol, respectively. This study explores the feasibility of tuning the glycerol HDO selectivity by modifying the surface oxophilicity. PMID- 30397202 TI - Effect of hydrophobic cations on the oxygen reduction reaction on single-crystal platinum electrodes. AB - Highly active catalysts for the oxygen reduction reaction are essential for the widespread and economically viable use of polymer electrolyte fuel cells. Here we report the oxygen reduction reaction activities of single-crystal platinum electrodes in acidic solutions containing tetraalkylammonium cations with different alkyl chain lengths. The high hydrophobicity of a tetraalkylammonium cation with a longer alkyl chain enhances the oxygen reduction reaction activity. The activity on Pt(111) in the presence of tetra-n-hexylammonium cation is eight times as high as that without this cation, which is comparable to the activities on Pt3Co(111) and Pt3Ni(111) electrodes. Hydrophobic cations and their hydration shells destabilize the adsorbed hydroxide and adsorbed water. The hydrophobic characteristics of non-specifically adsorbed cations can prevent the adsorption of poisoning species on the platinum electrode and form a highly efficient interface for the oxygen reduction reaction. PMID- 30397201 TI - Recognition of host Clr-b by the inhibitory NKR-P1B receptor provides a basis for missing-self recognition. AB - The interaction between natural killer (NK) cell inhibitory receptors and their cognate ligands constitutes a key mechanism by which healthy tissues are protected from NK cell-mediated lysis. However, self-ligand recognition remains poorly understood within the prototypical NKR-P1 receptor family. Here we report the structure of the inhibitory NKR-P1B receptor bound to its cognate host ligand, Clr-b. NKR-P1B and Clr-b interact via a head-to-head docking mode through an interface that includes a large array of polar interactions. NKR-P1B:Clr-b recognition is extremely sensitive to mutations at the heterodimeric interface, with most mutations severely impacting both Clr-b binding and NKR-P1B receptor function to implicate a low affinity interaction. Within the structure, two NKR P1B:Clr-b complexes are cross-linked by a non-classic NKR-P1B homodimer, and the disruption of homodimer formation abrogates Clr-b recognition. These data provide an insight into a fundamental missing-self recognition system and suggest an avidity-based mechanism underpins NKR-P1B receptor function. PMID- 30397204 TI - Changes in human footprint drive changes in species extinction risk. AB - Predicting how species respond to human pressure is essential to anticipate their decline and identify appropriate conservation strategies. Both human pressure and extinction risk change over time, but their inter-relationship is rarely considered in extinction risk modelling. Here we measure the relationship between the change in terrestrial human footprint (HFP)-representing cumulative human pressure on the environment-and the change in extinction risk of the world's terrestrial mammals. We find the values of HFP across space, and its change over time, are significantly correlated to trends in species extinction risk, with higher predictive importance than environmental or life-history variables. The anthropogenic conversion of areas with low pressure values (HFP < 3 out of 50) is the most significant predictor of change in extinction risk, but there are biogeographical variations. Our framework, calibrated on past extinction risk trends, can be used to predict the impact of increasing human pressure on biodiversity. PMID- 30397203 TI - Copper adparticle enabled selective electrosynthesis of n-propanol. AB - The electrochemical reduction of carbon monoxide is a promising approach for the renewable production of carbon-based fuels and chemicals. Copper shows activity toward multi-carbon products from CO reduction, with reaction selectivity favoring two-carbon products; however, efficient conversion of CO to higher carbon products such as n-propanol, a liquid fuel, has yet to be achieved. We hypothesize that copper adparticles, possessing a high density of under coordinated atoms, could serve as preferential sites for n-propanol formation. Density functional theory calculations suggest that copper adparticles increase CO binding energy and stabilize two-carbon intermediates, facilitating coupling between adsorbed *CO and two-carbon intermediates to form three-carbon products. We form adparticle-covered catalysts in-situ by mediating catalyst growth with strong CO chemisorption. The new catalysts exhibit an n-propanol Faradaic efficiency of 23% from CO reduction at an n-propanol partial current density of 11 mA cm-2. PMID- 30397200 TI - Potassium channel-based optogenetic silencing. AB - Optogenetics enables manipulation of biological processes with light at high spatio-temporal resolution to control the behavior of cells, networks, or even whole animals. In contrast to the performance of excitatory rhodopsins, the effectiveness of inhibitory optogenetic tools is still insufficient. Here we report a two-component optical silencer system comprising photoactivated adenylyl cyclases (PACs) and the small cyclic nucleotide-gated potassium channel SthK. Activation of this 'PAC-K' silencer by brief pulses of low-intensity blue light causes robust and reversible silencing of cardiomyocyte excitation and neuronal firing. In vivo expression of PAC-K in mouse and zebrafish neurons is well tolerated, where blue light inhibits neuronal activity and blocks motor responses. In combination with red-light absorbing channelrhodopsins, the distinct action spectra of PACs allow independent bimodal control of neuronal activity. PAC-K represents a reliable optogenetic silencer with intrinsic amplification for sustained potassium-mediated hyperpolarization, conferring high operational light sensitivity to the cells of interest. PMID- 30397206 TI - Magnetic field compatible circuit quantum electrodynamics with graphene Josephson junctions. AB - Circuit quantum electrodynamics has proven to be a powerful tool to probe mesoscopic effects in hybrid systems and is used in several quantum computing (QC) proposals that require a transmon qubit able to operate in strong magnetic fields. To address this we integrate monolayer graphene Josephson junctions into microwave frequency superconducting circuits to create graphene based transmons. Using dispersive microwave spectroscopy we resolve graphene's characteristic band dispersion and observe coherent electronic interference effects confirming the ballistic nature of our graphene Josephson junctions. We show that the monoatomic thickness of graphene renders the device insensitive to an applied magnetic field, allowing us to perform energy level spectroscopy of the circuit in a parallel magnetic field of 1 T, an order of magnitude higher than previous studies. These results establish graphene based superconducting circuits as a promising platform for QC and the study of mesoscopic quantum effects that appear in strong magnetic fields. PMID- 30397205 TI - Mechanical strain determines the site-specific localization of inflammation and tissue damage in arthritis. AB - Many pro-inflammatory pathways leading to arthritis have global effects on the immune system rather than only acting locally in joints. The reason behind the regional and patchy distribution of arthritis represents a longstanding paradox. Here we show that biomechanical loading acts as a decisive factor in the transition from systemic autoimmunity to joint inflammation. Distribution of inflammation and erosive disease is confined to mechano-sensitive regions with a unique microanatomy. Curiously, this pathway relies on stromal cells but not adaptive immunity. Mechano-stimulation of mesenchymal cells induces CXCL1 and CCL2 for the recruitment of classical monocytes, which can differentiate into bone-resorbing osteoclasts. Genetic ablation of CCL2 or pharmacologic targeting of its receptor CCR2 abates mechanically-induced exacerbation of arthritis, indicating that stress-induced chemokine release by mesenchymal cells and chemo attraction of monocytes determines preferential homing of arthritis to certain hot spots. Thus, mechanical strain controls the site-specific localisation of inflammation and tissue damage in arthritis. PMID- 30397207 TI - Deep Analysis of Mitochondria and Cell Health Using Machine Learning. AB - There is a critical need for better analytical methods to study mitochondria in normal and diseased states. Mitochondrial image analysis is typically done on still images using slow manual methods or automated methods of limited types of features. MitoMo integrated software overcomes these bottlenecks by automating rapid unbiased quantitative analysis of mitochondrial morphology, texture, motion, and morphogenesis and advances machine-learning classification to predict cell health by combining features. Our pixel-based approach for motion analysis evaluates the magnitude and direction of motion of: (1) molecules within mitochondria, (2) individual mitochondria, and (3) distinct morphological classes of mitochondria. MitoMo allows analysis of mitochondrial morphogenesis in time lapse videos to study early progression of cellular stress. Biological applications are presented including: (1) establishing normal phenotypes of mitochondria in different cell types; (2) quantifying stress-induced mitochondrial hyperfusion in cells treated with an environmental toxicant, (3) tracking morphogenesis in mitochondria undergoing swelling, and (4) evaluating early changes in cell health when morphological abnormalities are not apparent. MitoMo unlocks new information on mitochondrial phenotypes and dynamics by enabling deep analysis of mitochondrial features in any cell type and can be applied to a broad spectrum of research problems in cell biology, drug testing, toxicology, and medicine. PMID- 30397208 TI - Proteomic landscape of seminal plasma associated with dairy bull fertility. AB - Male fertility is the ability of sperm to fertilize the egg and sustain embryo development. Several factors determine the fertilizing capacity of mammalian sperm, including those intrinsic to sperm and components of the seminal plasma. The present study analyzed the seminal fluid proteome of Bos taurus and potential associations between proteins and fertility scores. Mass spectrometry coupled with nano HPLC allowed the identification of 1,159 proteins in the dairy bull seminal plasma. There were 50 and 29 seminal proteins more abundant in high (HF) low fertility (LF) bulls, respectively. Based on multivariate analysis, C-type natriuretic peptide, TIMP-2, BSP5 and sulfhydryl oxidase indicated relationship with HF bulls. Clusterin, tissue factor pathway inhibitor 2, galectin-3-binding protein and 5'-nucleotidase were associated with LF bulls. Abundance of NAD(P)(+) arginine ADP-ribosyltransferase, prosaposin and transmembrane protein 2 proteins had the highest positive correlations with fertility ranking. Quantities of vitamin D-binding protein, nucleotide exchange factor SIL1 and galectin-3-binding protein showed the highest negative correlations with fertility ranking. A fertility ranking score was calculated and the relationship with these proteins was significant (Spearman's rho = 0.94). The present findings represent a major and novel contribution to the study of bovine seminal proteins. Indicators of fertility can be used to improve reproductive biotechnologies. PMID- 30397209 TI - Diversity and convergence of mechanisms involved in pyrethroid resistance in the stored grain weevils, Sitophilus spp. AB - Target-site mutations and changes in insect metabolism or behavior are common mechanisms in insecticide-resistant insects. The co-occurrence of such mechanisms in a pest strain is a prominent threat to their management, particularly when alternative compounds are scarce. Pyrethroid resistance among stored grain weevils (i.e., Sitophilus spp.) is an example of a long-standing concern, for which reports of resistance generally focus on a single mechanism in a single species. Here, we investigated pyrethroid resistance in maize and rice weevils (i.e., Sitophilus zeamais and S. oryzae), exploring potential knockdown resistance (kdr) mutations in their sodium channels (primary site for pyrethroid actions) and potential changes in their detoxification and walking processes. Resistance in pyrethroid-resistant rice weevils was associated with the combination of a kdr mutation (L1014F) and increases in walking and detoxification activities, while another kdr mutation (T929I) combined with increases in walking activity were the primary pyrethroid resistance mechanisms in maize weevils. Our results suggest that the selection of pyrethroid-resistant individuals in these weevil species may result from multiple and differential mechanisms because the L1014F mutation was only detected in Latin American rice weevils (e.g., Brazil, Argentina and Uruguay), not in Australian and Turkish rice weevils or Brazilian maize weevils. PMID- 30397210 TI - Impact of DNA extraction method and targeted 16S-rRNA hypervariable region on oral microbiota profiling. AB - Amplification and sequencing of 16S amplicons are widely used for profiling the structure of oral microbiota. However, it remains not clear whether and to what degree DNA extraction and targeted 16S rRNA hypervariable regions influence the analysis. Based on a mock community consisting of five oral bacterial species in equal abundance, we compared the 16S amplicon sequencing results on the Illumina MiSeq platform from six frequently employed DNA extraction procedures and three pairs of widely used 16S rRNA hypervariable primers targeting different 16S rRNA regions. Technical reproducibility of selected 16S regions was also assessed. DNA extraction method exerted considerable influence on the observed bacterial diversity while hypervariable regions had a relatively minor effect. Protocols with beads added to the enzyme-mediated DNA extraction reaction produced more accurate bacterial community structure than those without either beads or enzymes. Hypervariable regions targeting V3-V4 and V4-V5 seemed to produce more reproducible results than V1-V3. Neither sequencing batch nor change of operator affected the reproducibility of bacterial diversity profiles. Therefore, DNA extraction strategy and 16S rDNA hypervariable regions both influenced the results of oral microbiota biodiversity profiling, thus should be carefully considered in study design and data interpretation. PMID- 30397211 TI - Improvement in reading performance through training with simulated thalamic visual prostheses. AB - Simulations of artificial vision are used to provide the researcher an opportunity to explore different aspects of visual prosthesis device design by observing subject performance on various tasks viewed through the simulation. Such studies typically use normal, sighted subjects to measure performance at a given point in time. Relatively few studies examine performance changes longitudinally to quantitatively assess the benefits from a training plan that would be akin to post-implantation rehabilitation. Here, we had six normal, sighted subjects use a standard reading task with daily practice over eight weeks to understand the effects of an intensive training schedule on adaptation to artificial sight. Subjects read 40 MNREAD-style sentences per session, with a new set each session, that were presented at five font sizes (logMAR 1.0-1.4) and through three center-weighted phosphene patterns (2,000, 1,000, 500 phosphenes). We found that subjects improved their reading accuracy across sessions, and that the training lead to an increase of reading speed that was equivalent to a doubling of available phosphenes. Most importantly, the hardest condition, while initially illegible, supported functional reading after training. Consistent with experience-driven neuroplastic changes, gaps in the training schedule lead to transient decreases in reading speed, but, surprisingly, not reading accuracy. Our findings contribute to our larger project of developing a thalamic visual prosthesis and to post-implant rehabilitation strategies. PMID- 30397213 TI - Stent graft coverage of dual-stent strategy in the management of abdominal aortic aneurysms. AB - Treating an abdominal aortic aneurysm (AAA) with a stent graft (SG) and a multilayer stent (MS) is a key technology in isolating flow fields. Clinically, dual stents (an SG in the proximal and an MS in the distal of AAA) are used for treatment of AAA, but only a few studies have examined the relationship between SG coverage and treatment effects. Through numerical simulation of the hemodynamics after SG and MS implantation, the SG coverage and position were simulated at 0% (0 mm), 25% (13.75 mm), 50% (27.5 mm), and 75% (41.25 mm). With increasing SG coverage, the pressure on the aneurysm sac wall and the flow of branch vessels gradually decreased, and the lower wall shear stress (WSS) gradually increased. The changes in pressure, lower WSS, and the mass flow rate of the branch vessels did not change significantly. The coverage of the SG has a nonsignificant effect on hemodynamics in the treatment of AAA; the implantation position need not be very precise. This research can provide theoretic support for clinicians' decision-making. PMID- 30397212 TI - Angiotensin II-induced hypertension in rats is only transiently accompanied by lower renal oxygenation. AB - Activation of the renin-angiotensin system may initiate chronic kidney disease. We hypothesised that renal hypoxia is a consequence of hemodynamic changes induced by angiotensin II and occurs prior to development of severe renal damage. Male Sprague-Dawley rats were infused continuously with angiotensin II (350 ng/kg/min) for 8 days. Mean arterial pressure (n = 5), cortical (n = 6) and medullary (n = 7) oxygenation (pO2) were continuously recorded by telemetry and renal tissue injury was scored. Angiotensin II increased arterial pressure gradually to 150 +/- 18 mmHg. This was associated with transient reduction of oxygen levels in renal cortex (by 18 +/- 2%) and medulla (by 17 +/- 6%) at 10 +/- 2 and 6 +/- 1 hours, respectively after starting infusion. Thereafter oxygen levels normalised to pre-infusion levels and were maintained during the remainder of the infusion period. In rats receiving angiotensin II, adding losartan to drinking water (300 mg/L) only induced transient increase in renal oxygenation, despite normalisation of arterial pressure. In rats, renal hypoxia is only a transient phenomenon during initiation of angiotensin II-induced hypertension. PMID- 30397198 TI - Germline variation at 8q24 and prostate cancer risk in men of European ancestry. AB - Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 * 10-15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62-4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification. PMID- 30397214 TI - Proteomic approach for understanding milder neurotoxicity of Carfilzomib against Bortezomib. AB - The proteasomal system is responsible for the turnover of damaged proteins. Because of its important functions in oncogenesis, inhibiting the proteasomal system is a promising therapeutic approach for cancer treatment. Bortezomib (BTZ) is the first proteasome inhibitor approved by FDA for clinical applications. However neuropathic side effects are dose limiting for BTZ as many other chemotherapeutic agents. Therefore second-generation proteasome inhibitors have been developed including carfilzomib (CFZ). Aim of the present work was investigating the mechanisms of peripheral neuropathy triggered by the proteasome inhibitor BTZ and comparing the pathways affected by BTZ and CFZ, respectively. Neural stem cells, isolated from the cortex of E14 mouse embryos, were treated with BTZ and CFZ and mass spectrometry was used to compare the global protein pool of treated cells. BTZ was shown to cause more severe cytoskeletal damage, which is crucial in neural cell integrity. Excessive protein carbonylation and actin filament destabilization were also detected following BTZ treatment that was lower following CFZ treatment. Our data on cytoskeletal proteins, chaperone system, and protein oxidation may explain the milder neurotoxic effects of CFZ in clinical applications. PMID- 30397215 TI - Timing variability of sensorimotor integration during vocalization in individuals who stutter. AB - Persistent developmental stuttering affects close to 1% of adults and is thought to be a problem of sensorimotor integration. Previous research has demonstrated that individuals who stutter respond differently to changes in their auditory feedback while speaking. Here we explore a number of changes that accompany alterations in the feedback of pitch during vocal production. Participants sustained the vowel /a/ while hearing on-line feedback of their own voice through headphones. In some trials, feedback was briefly shifted up or down by 100 cents to simulate a vocal production error. As previously shown, participants compensated for the auditory pitch change by altering their vocal production in the opposite direction of the shift. The average compensatory response was smaller for adults who stuttered than for adult controls. Detailed analyses revealed that adults who stuttered had fewer trials with a robust corrective response, and that within the trials showing compensation, the timing of their responses was more variable. These results support the idea that dysfunctional sensorimotor integration in stuttering is characterized by timing variability, reflecting reduced coupling of the auditory and speech motor systems. PMID- 30397216 TI - Roads do not increase carrion use by a vertebrate scavenging community. AB - Wildlife-vehicle collisions introduce a considerable amount of carrion into the environment, but scavenger use of this resource has not been extensively investigated. Scavengers may use roads for reliable foraging opportunities, but might also use roads for other purposes and encounter carrion opportunistically. We examined scavenging of carrion along linear features by placing 52 rabbit carcasses in each of three treatments in forested habitat during winter (Dec 2016 Mar 2017) in South Carolina, USA: roads, power line clearings (linear feature with fewer carcasses than roads due to lack of road kill), and forest interior. We used motion-activated cameras to compare arrival times and presence of vertebrate scavengers among treatments. There was no difference in proportion of carcasses scavenged or scavenger arrival time across treatments. No species arrived at roads quicker than other treatments. Turkey vultures (Cathartes aura) and coyotes (Canis latrans) scavenged equally across treatments, whereas gray foxes (Urocyon cinereoargenteus) scavenged along roads and power lines, but not in forests. We suggest that scavenger use of carrion near roads at this location during winter relates to factors other than carrion availability. Because some scavengers readily consumed carrion on roads, this resource has the potential to influence the ecology of these species. PMID- 30397218 TI - Genetic analysis of endangered hog deer (Axis porcinus) reveals two distinct lineages from the Indian subcontinent. AB - The hog deer (Axis porcinus) is threatened by habitat alteration, fragmentation, and poaching, which have led to a drastic decline of its wild population. Two subspecies of A. porcinus have been described from its distribution range. A. p. porcinus is reported to occur from Pakistan along the Himalayan foothills through Nepal, India and Myanmar, and A. p. annamiticus is found in Thailand, Indo-China, Laos, Cambodia, and Vietnam. However, the current distribution range of A. p. annamiticus is still unclear. We used the partial control region (CR) of mitochondrial DNA (mtDNA) and seven microsatellite loci to investigate the intra species structure, differentiation, and demographic history of hog deer populations from three landscapes, the Terai Arc, Northeast, and Indo-Burma (Keibul Lamjao National Park (KLNP), Manipur, India) landscapes. We also carried out divergence time estimation using the complete mitogenome. The level of variation was ~4%, and the time of divergence of the KLNP population and the other Indian populations was about 0.22 Mya, i.e., during the last glaciation periods of the Late Pleistocene/Early Holocene. The KLNP haplotypes of the control region were shared with the Southeast Asian subspecies, A. p. annamiticus. The results of the investigations of the microsatellite loci supported the mtDNA results unambiguously. Two genetically distinct lineages are found in India: one is found from the Terai Arc to Assam (A. p. porcinus) and the other in Manipur (A. p. annamiticus). The genetic diversity in KLNP was low and exhibited a higher degree of genetic differentiation compared with major Indian populations. The Bayesian skyline plots indicated that after a long phase of historic demographic stability, the populations of both the lineages of hog deer suffered pronounced declines during the period from ~800 years BP to 5000 years BP. In summary, our finding provided evidence that the KLNP population is probably a prime, isolated and sustaining stock of A. p. annamiticus and should be managed as evolutionarily significant units (ESUs). PMID- 30397217 TI - Tri-ponderal mass index in survivors of childhood brain tumors: A cross-sectional study. AB - Survivors of childhood brain tumors (SCBT) face a higher risk of cardiometabolic disorders and premature mortality compared to the general population. Excess adiposity is a known risk factor for these comorbidities. However, while SCBT have higher adiposity compared to healthy controls, measuring adiposity in clinical practice involves access to specialized equipment and may impact busy clinical services. Tri-ponderal Mass Index (TMI; kg/m3) may be a superior measure of adiposity when compared to Body Mass Index (BMI; kg/m2). However, its use in determining adiposity in SCBT has not been assessed. This study aims to validate TMI as a clinical measure of adiposity in SCBT. This was a cross-sectional study including 44 SCBT (n = 20 female) and 137 (n = 64 female) non-cancer control children, 5-17 years of age. BMI and TMI were calculated from height and weight measurements. Fat mass percentage was assessed using bioelectrical impedance analysis and waist to hip and waist to height ratios were used to assess central adiposity. Regression analyses were adjusted for age, sex, puberty and treatment. TMI demonstrated strong correlations to measures of total and central adiposity and predicted adiposity in SCBT and non-cancer controls, with stronger trends in the latter group. TMI may serve as a reliable clinical measure of adiposity in both SCBT and healthy children. PMID- 30397219 TI - Angstrom Thick ZnO Passivation Layer to Improve the Photoelectrochemical Water Splitting Performance of a TiO2 Nanowire Photoanode: The Role of Deposition Temperature. AB - In this paper, we demonstrate that angstrom thick single atomic layer deposited (ALD) ZnO passivation can significantly improve the photoelectrochemical (PEC) activity of hydrothermally grown TiO2 NWs. It is found that this ultrathin ZnO coating can passivate the TiO2 surface defect states without hampering the carrier's transfer dynamics. Moreover, a substantial improvement can be acquired by changing the deposition temperature of the ZnO layer (80 degrees C, and 250 degrees C) and named as 80 degrees C TiO2-ZnO, and 250 degrees C TiO2-ZnO. It was found that the deposition of this single layer in lower temperatures can lead to higher PEC activity compared to that deposited in higher ones. As a result of our PEC characterizations, it is proved that photoconversion efficiency of bare TiO2 NWs can be improved by a factor of 1.5 upon coating it with a single ZnO layer at 80 degrees C. Moreover, considering the fact that this layer is a passivating coating rather than a continuous layer, it also keeps the PEC stability of the design while this feature cannot be obtained in a thick shell layer case. This paper proposes a bottom up approach to control the electron transfer dynamics in a heterojunction design and it can be applied to other metal oxide combinations. PMID- 30397220 TI - High-energy spin fluctuation in low-Tc iron-based superconductor LaFePO0.9. AB - Spin fluctuations are widely believed to play an important role in the superconducting mechanisms of unconventional high temperature superconductors. Spin fluctuations have been observed in iron-based superconductors as well. However, in some iron-based superconductors such as LaFePO0.9, they have not been observed by inelastic neutron scattering (INS). LaFePO0.9 is an iron-based superconductor with a low superconducting transition temperature (Tc = 5 K), where line nodes are observed in the superconducting gap function. The line-node symmetry typically originates from sign reversal of the order parameter in spin fluctuation-mediated superconductivity. This contradiction has been a long standing mystery of this superconductor. Herein, spin fluctuations were found at high energies such as 30-50 meV with comparable intensities to an optimally doped LaFeAs(O, F). Based on this finding, the line-node symmetry can be explained naturally as spin-fluctuation-mediated superconductivity. PMID- 30397221 TI - Genetic background and window of exposure contribute to thyroid dysfunction promoted by low-dose exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice. AB - Genetic and environmental factors contribute to thyroid diseases. Although still debated, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is thought to induce thyroid dysfunction in humans and rodents. The data here reported point out the contribution of the exposure window and genetic background in mediating the low dose TCDD effects on thyroid. Indeed, early (from E0.5 to PND30) and low-dose (0,001 MUg/kg/day) TCDD exposure reduced the circulating fT4 and altered the expression of thyroid specific transcripts. The role of genetic components was estimated monitoring the same markers in Pax8+/- and Nkx2-1+/- mice, susceptible to thyroid dysfunction, exposed to 0, 1 MUg/kg/day TCDD from E15.5 to PND60. Haploinsufficiency of either Pax8 or Nkx2-1 genes exacerbated the effects of the exposure impairing the thyroid enriched mRNAs in sex dependent manner. Such effect was mediated by mechanisms involving the Nkx2-1/p53/p65/IKBalpha pathway in vitro and in vivo. Foetal exposure to TCDD impaired both thyroid function and genes expression while thyroid development and differentiation did not appear significantly affected. In mouse, stronger effects were related to earlier exposure or specific genetic background such as either Pax8 or Nkx2-1 haploinsufficiency, both associated to hypothyroidism in humans. Furthermore, our data underline that long exposure time are needed to model in vitro and in vivo results. PMID- 30397223 TI - Generation of Bose-Einstein Condensates' Ground State Through Machine Learning. AB - We show that both single-component and two-component Bose-Einstein condensates' (BECs) ground states can be simulated by a deep convolutional neural network. We trained the neural network via inputting the parameters in the dimensionless Gross-Pitaevskii equation (GPE) and outputting the ground-state wave function. After the training, the neural network generates ground-state wave functions with high precision. We benchmark the neural network for either inputting different coupling strength in the GPE or inputting an arbitrary potential under the infinite double walls trapping potential, and it is found that the ground state wave function generated by the neural network gives the relative chemical potential error magnitude below 10-3. Furthermore, the neural network trained with random potentials shows prediction ability on other types of potentials. Therefore, the BEC ground states, which are continuous wave functions, can be represented by deep convolutional neural networks. PMID- 30397222 TI - Early movement restriction leads to maladaptive plasticity in the sensorimotor cortex and to movement disorders. AB - Motor control and body representations in the central nervous system are built, i.e., patterned, during development by sensorimotor experience and somatosensory feedback/reafference. Yet, early emergence of locomotor disorders remains a matter of debate, especially in the absence of brain damage. For instance, children with developmental coordination disorders (DCD) display deficits in planning, executing and controlling movements, concomitant with deficits in executive functions. Thus, are early sensorimotor atypicalities at the origin of long-lasting abnormal development of brain anatomy and functions? We hypothesize that degraded locomotor outcomes in adulthood originate as a consequence of early atypical sensorimotor experiences that induce developmental disorganization of sensorimotor circuitry. We showed recently that postnatal sensorimotor restriction (SMR), through hind limb immobilization from birth to one month, led to enduring digitigrade locomotion with ankle-knee overextension, degraded musculoskeletal tissues (e.g., gastrocnemius atrophy), and clear signs of spinal hyperreflexia in adult rats, suggestive of spasticity; each individual disorder likely interplaying in self-perpetuating cycles. In the present study, we investigated the impact of postnatal SMR on the anatomical and functional organization of hind limb representations in the sensorimotor cortex and processes representative of maladaptive neuroplasticity. We found that 28 days of daily SMR degraded the topographical organization of somatosensory hind limb maps, reduced both somatosensory and motor map areas devoted to the hind limb representation and altered neuronal response properties in the sensorimotor cortex several weeks after the cessation of SMR. We found no neuroanatomical histopathology in hind limb sensorimotor cortex, yet increased glutamatergic neurotransmission that matched clear signs of spasticity and hyperexcitability in the adult lumbar spinal network. Thus, even in the absence of a brain insult, movement disorders and brain dysfunction can emerge as a consequence of reduced and atypical patterns of motor outputs and somatosensory feedback that induce maladaptive neuroplasticity. Our results may contribute to understanding the inception and mechanisms underlying neurodevelopmental disorders, such as DCD. PMID- 30397224 TI - UV light assisted antibiotics for eradication of in vitro biofilms. AB - The overuse of antibiotics is accelerating the bacterial resistance, and therefore there is a need to reduce the amount of antibiotics used for treatment. Here, we demonstrate in vitro that specific wavelengths in a narrow range around 296 nm are able to eradicate bacteria in the biofilm state (grown for 24 hours) more effectively, than antibiotics and the combination of irradiation and antibiotics is even better, introducing a novel concept light assisted antibiotics. The investigated wavelength range was 249 nm to 338 nm with an approximate step of 5 nm. The novel concept that consists of a UV irradiation treatment followed by a tobramycin treatment can significantly reduce the amount of antibiotics needed for eradicating mature bacterial biofilms. The efficiency of the proposed light assisted antibiotics method was compared to combinatory antibiotic treatment and highly concentrated antibiotic monotherapy. The eradication efficacies, on mature biofilms, achieved by light assisted antibiotic and by the antibiotic monotherapy at approximately 10-fold higher concentration, were equivalent. The present achievement could motivate the development of light assisted antibiotic treatments for treating infections. PMID- 30397225 TI - Dairy calves' personality traits predict social proximity and response to an emotional challenge. AB - The assessment of individual traits requires that tests are reliable (i.e. consistency over time) and externally valid, meaning that they predict future responses in similar contexts (i.e. convergent validity) but do not predict responses to unrelated situations (i.e. discriminant validity). The aim of this study was to determine if dairy calf personality traits (Fearfulness, Sociability and Pessimism), derived from behaviours expressed in standardized tests, predict individuals' responses in related situations. The first experiment tested if the trait 'Sociability' was related to the expression of social behaviour in the home pen, with calves assigned individual proximity scores (based on proximity to other calves) while they were in their home-pen at approximately 113 and 118 d of age. The second experiment aimed at exploring whether traits 'Fearfulness' and 'Pessimism' were related to the calves' emotional response to transportation. All calves were subjected to two 10-min transportation challenges done on two consecutive days. Emotional response was assessed using the maximum eye temperature (measured using infrared thermography) and the number of vocalizations emitted. Social proximity scores (Experiment 1), vocalizations emitted and maximum eye temperature after loading (Experiment 2) were consistent over time. In addition, the results showed good convergent validity with calves scoring higher in Sociability also having higher proximity scores in the home pen, and animals scoring higher in Fearfulness and Pessimism showing a more intense emotional response to transportation. The results also showed good discriminant validity, as neither Fearfulness nor Pessimism were associated with the expression of social behaviours (Experiment 1) and Sociability was not associated with the animal's emotional response to transportation (Experiment 2). We conclude that the methodology used to measure personality traits shows good reliability and external validity. PMID- 30397226 TI - Nanopore sequencing for rapid diagnostics of salmonid RNA viruses. AB - Analysis of pathogen genome variation is essential for informing disease management and control measures in farmed animals. For farmed fish, the standard approach is to use PCR and Sanger sequencing to study partial regions of pathogen genomes, with second and third-generation sequencing tools yet to be widely applied. Here we demonstrate rapid and accurate sequencing of two disease-causing viruses affecting global salmonid aquaculture, salmonid alphavirus (SAV) and infectious salmon anaemia virus (ISAV), using third-generation nanopore sequencing on the MinION platform (Oxford Nanopore Technologies). Our approach complements PCR from infected material with MinION sequencing to recover genomic information that matches near perfectly to Sanger-verified references. We use this method to present the first SAV subtype-6 genome, which branches as the sister to all other SAV lineages in a genome-wide phylogenetic reconstruction. MinION sequencing offers an effective strategy for fast, genome-wide analysis of fish viruses, with major potential applications for diagnostics and robust investigations into the origins and spread of disease outbreaks. PMID- 30397227 TI - Vitamin D5 in Arabidopsis thaliana. AB - Vitamin D3 is a secosterol hormone critical for bone growth and calcium homeostasis, produced in vertebrate skin by photolytic conversion of the cholesterol biosynthetic intermediate provitamin D3. Insufficient levels of vitamin D3 especially in the case of low solar UV-B irradiation is often compensated by an intake of a dietary source of vitamin D3 of animal origin. Small amounts of vitamin D3 were described in a few plant species and considered as a peculiar feature of their phytochemical diversity. In this report we show the presence of vitamin D5 in the model plant Arabidopsis thaliana. This plant secosterol is a UV-B mediated derivative of provitamin D5, the precursor of sitosterol. The present work will allow a further survey of vitamin D distribution in plant species. PMID- 30397228 TI - Epigenome-wide methylation differences in a group of lean and obese women - A HUNT Study. AB - Knowledge of epigenetically regulated biomarkers linked to obesity development is still scarce. Improving molecular understanding of the involved factors and pathways would improve obesity phenotype characterization and reveal potentially relevant targets for obesity intervention. The Illumina Infinium HumanMethylation450 BeadChip was used in a leucocyte epigenome-wide association study (EWAS) to quantify differential DNA methylation in 60 lean compared with 60 obese young women. Replication was done in monozygotic twins discordant for obesity. At adolescence and adulthood, the two weight groups differed significantly in obesity-related traits and metabolic risk factors. Differential hypomethylation was overrepresented in obese compared to lean women. In the adjusted model, the EWAS revealed 10 differentially methylated CpG sites linked to 8 gene loci - COX6A1P2/FGD2, SBNO2, TEX41, RPS6KA2, IGHE/IGHG1/IGHD, DMAP1, SOCS3, and SETBP1- and an enhancer locus at chromosome 2 (2p25.1). The sites linked to TEX41, IGHE/IGHG1/IGHD, DMAP1, and SETBP1 were novel findings, while COX6A1P/FGD2, SBNO2, RPS6KA2, and SOCS3 had been identified previously with concordant direction of effects. RPS6KA2, DMAP1, and SETBP1 were replicated in the BMI-discordant monozygotic twin cohort using the FDR of 5%. PMID- 30397229 TI - Potential of Oryza officinalis to augment the cold tolerance genetic mechanisms of Oryza sativa by network complementation. AB - Oryza officinalis is an accessible alien donor for genetic improvement of rice. Comparison across a representative panel of Oryza species showed that the wild O. officinalis and cultivated O. sativa ssp. japonica have similar cold tolerance potentials. The possibility that either distinct or similar genetic mechanisms are involved in the low temperature responses of each species was addressed by comparing their transcriptional networks. General similarities were supported by shared transcriptomic signatures indicative of equivalent metabolic, hormonal, and defense status. However, O. officinalis has maintained an elaborate cold responsive brassinosteroid-regulated BES1-network that appeared to have been fragmented in O. sativa. BES1-network is potentially important for integrating growth-related responses with physiological adjustments and defenses through the protection of photosynthetic machinery and maintenance of stomatal aperture, oxidative defenses, and osmotic adjustment. Equivalent physiological processes are functional in O. sativa but their genetic mechanisms are under the direct control of ABA-dependent, DREB-dependent and/or oxidative-mediated networks uncoupled to BES1. While O. officinalis and O. sativa represent long periods of speciation and domestication, their comparable cold tolerance potentials involve equivalent physiological processes but distinct genetic networks. BES1-network represents a novel attribute of O. officinalis with potential applications in diversifying or complementing other mechanisms in the cultivated germplasm. PMID- 30397231 TI - EEG sharp waves are a biomarker of striatal neuronal survival after hypoxia ischemia in preterm fetal sheep. AB - The timing of hypoxia-ischemia (HI) in preterm infants is often uncertain and there are few biomarkers to determine whether infants are in a treatable stage of injury. We evaluated whether epileptiform sharp waves recorded from the parietal cortex could provide early prediction of neuronal loss after HI. Preterm fetal sheep (0.7 gestation) underwent acute HI induced by complete umbilical cord occlusion for 25 minutes (n = 6) or sham occlusion (control, n = 6). Neuronal survival was assessed 7 days after HI by immunohistochemistry. Sharp waves were quantified manually and using a wavelet-type-2-fuzzy-logic-system during the first 4 hours of recovery. HI resulted in significant subcortical neuronal loss. Sharp waves counted by the automated classifier in the first 30 minutes after HI were associated with greater neuronal survival in the caudate nucleus (r = 0.80), whereas sharp waves between 2-4 hours after HI were associated with reduced neuronal survival (r = -0.83). Manual and automated counts were closely correlated. This study suggests that automated quantification of sharp waves may be useful for early assessment of HI injury in preterm infants. However, the pattern of evolution of sharp waves after HI was markedly affected by the severity of neuronal loss, and therefore early, continuous monitoring is essential. PMID- 30397232 TI - Aberrant DNA methylation of Tgfb1 in diabetic kidney mesangial cells. AB - Epigenetic modulation may underlie the progression of diabetic nephropathy (DN). Involvement of TGFB1 in mesangial fibrosis of DN led us to hypothesize that Tgfb1 DNA demethylation contributes to progression of DN. In primary mesangial cells from diabetic (db/db) mouse kidneys, demethylation of Tgfb1 DNA and upregulation of Tgfb1 mRNA progressed simultaneously. USF1 binding site in Tgfb1 promoter region were demethylated, and binding of USF1 increased, with decreased binding of DNMT1 in db/db compared with control. Given downregulation of Tgfb1 expression by folic acid, antioxidant Tempol reversed DNA demethylation, with increased and decreased recruitment of DNMT1 and USF1 to the promoter, resulting in decreased Tgfb1 expression in db/db mice. Addition of H2O2 to mesangial cells induced DNA demethylation and upregulated Tgfb1 expression. Finally, Tempol attenuated mesangial fibrosis in db/db mice. We conclude that aberrant DNA methylation of Tgfb1 due to ROS overproduction play a key to mesangial fibrosis during DN progression. PMID- 30397233 TI - Long-term efavirenz pharmacokinetics is comparable between Tanzanian HIV and HIV/Tuberculosis patients with the same CYP2B6*6 genotype. AB - The impact of anti-tuberculosis co-treatment on efavirenz (EFV) exposure is still uncertain as contradictory reports exist, and the relevance of CYP2B6*6 genetic polymorphism on efavirenz clearance while on-and-off anti-tuberculosis co treatment is not well investigated. We investigated the determinants of long-term efavirenz pharmacokinetics by enrolling HIV (n = 20) and HIV/Tuberculosis (n = 36) subjects undergoing efavirenz and efavirenz/rifampicin co-treatment respectively. Pharmacokinetic samplings were done 16 weeks after initiation of efavirenz-based anti-retroviral therapy and eight weeks after completion of rifampicin-based anti-tuberculosis treatment. Population pharmacokinetic modeling was used to characterize variabilities and covariates of efavirenz pharmacokinetic parameters. CYP2B6*6 genetic polymorphism but not rifampicin co treatment was the statistically significant covariate. The estimated typical efavirenz clearance in the HIV only subjects with the CYP2B6*1/*1 genotype was 23.6 L/h/70 kg, while it was 38% and 69% lower in subjects with the CYP2B6*1/*6 and *6/*6 genotypes, respectively. Among subjects with the same CYP2B6 genotypes, efavirenz clearances were comparable between HIV and HIV/Tuberculosis subjects. Typical efavirenz clearances before and after completion of anti-tuberculosis therapy were comparable. In conclusion, after 16 weeks of treatment, efavirenz clearance is comparable between HIV and HIV/Tuberculosis patients with the same CYP2B6 genotype. CYP2B6 genotyping but not anti-tuberculosis co-treatment should guide efavirenz dosing to optimize treatment outcomes. PMID- 30397234 TI - Breed Differences in Pig Liver Esterase (PLE) between Tongcheng (Chinese Local Breed) and Large White Pigs. AB - Human carboxylesterases has been proven to be age and race-related and a sound basis of clinical medication. PLE involve in signal transduction and highly catalyze hydrolysis. Therefore, the expression level of PLE most probably exist age and breed difference and lead to significant differences of pharmacology and physiology. Four age groups of Tongcheng (TC) and Large White (LW) pigs were selected to explore PLE breed and age differences, and it was found that PLE mRNA was most abundant in liver in both breeds. In liver, PLE levels and hydrolytic activities increased with age, and PLE levels (except for 3 month) and the hydrolytic activities were higher in LW than in TC across all age groups. Abundance of PLE isoenzymes was obvious different between breeds and among age groups. The most abundant PLE isoenzyme in LW and TC pigs was PLE-A1 (all age groups) and PLE-B9 (three early age groups) or PLE-G3 (adult groups), respectively. 103 new PLE isoenzymes were found, and 55 high-frequency PLE isoenzymes were accordingly classified into seven categories (A-G). The results of this research provide a necessary basis not only for clinical medication of pigs but also for pig breeding purposes. PMID- 30397230 TI - CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language. AB - Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language. PMID- 30397235 TI - Cultural variation in cognitive flexibility reveals diversity in the development of executive functions. AB - Cognitive flexibility, the adaptation of representations and responses to new task demands, improves dramatically in early childhood. It is unclear, however, whether flexibility is a coherent, unitary cognitive trait, or is an emergent dimension of task-specific performance that varies across populations with divergent experiences. Three- to 5-year-old English-speaking U.S. children and Tswana-speaking South African children completed two distinct language-processing cognitive flexibility tests: the FIM-Animates, a word-learning test, and the 3DCCS, a rule-switching test. U.S. and South African children did not differ in word-learning flexibility but showed similar age-related increases. In contrast, U.S. preschoolers showed an age-related increase in rule-switching flexibility but South African children did not. Verbal recall explained additional variance in both tests but did not modulate the interaction between population sample (i.e., country) and task. We hypothesize that rule-switching flexibility might be more dependent upon particular kinds of cultural experiences, whereas word learning flexibility is less cross-culturally variable. PMID- 30397236 TI - A Randomized Control Trial Of Anti-Inflammatory Regional Hypothermia On Urinary Continence During Robot-Assisted Radical Prostatectomy. AB - The present study seeks to present a single-blind, randomized control trial of a hypothermic anti-inflammatory device, the endorectal cooling balloon (ECB), to assess whether regional hypothermia could improve 90-day and time to pad-free continence following robot-assisted radical prostatectomy (RARP). Five high volume surgeons at three institutions had patients randomized (1:1) to regional hypothermia with ECB versus control. Patients were blinded to device use, as it was inserted and removed intraoperatively. Knowledge of device use was restricted to the operating room personnel only; recovery room and ward nursing staff were not informed of device use and instructed to indicate such if a patient inquired. An independent and blinded data acquisition contractor assessed outcomes via components of the EPIC and IPSS. The primary outcome was categorical pad-free continence at 90-days and the secondary outcome was a Kaplan-Meier time-to pad free continence at 90 days. 100 hypothermia and 99 control patients were included. The primary outcome of 90-day pad-free continence was 50.0% (27.8 70.0%) in the hypothermia group versus 59.2% (33.3-78.6%) in the control (p = 0.194). The secondary outcome of Kaplan Meier analysis for time to 90-day continence was not statistically significant. At one year, there were also no statistically significant differences in continence recovery. Post-hoc analysis revealed a trend towards improvement in continence in one of three sites. Overall, the trial demonstrated no benefit to regional hypothermia either in our primary or secondary outcomes. It is suggested that surgical technique and prevention of surgical trauma may be more advantageous to improving continence recovery. PMID- 30397238 TI - Correction: CpG island hypermethylation-associated silencing of non-coding RNAs transcribed from ultraconserved regions in human cancer. AB - In the original article the authors have noted that the wrong image was used to illustrate the Uc.346 + Lu1-Lu2-Lu3 subpanel of Figure 5a. The correct image is now provided as Figure 1 in this article. This change does not affect the legend of the figure, the results, or conclusions reported in the manuscript. The authors apologize for the error, and regret any inconvenience this may have caused. PMID- 30397239 TI - On the expedient solution of the magneto-hydrodynamic Jeffery-Hamel flow of Casson fluid. AB - The equation of magneto-hydrodynamic Jeffery-Hamel flow of non-Newtonian Casson fluid in a stretching/shrinking convergent/divergent channel is derived and solved using a new modified Adomian decomposition method (ADM). So far in all problems where semi-analytical methods are used the boundary conditions are not satisfied completely. In the present research, a hybrid of the Fourier transform and the Adomian decomposition method (FTADM), is presented in order to incorporate all boundary conditions into our solution of magneto-hydrodynamic Jeffery-Hamel flow of non-Newtonian Casson fluid in a stretching/shrinking convergent/divergent channel flow. The effects of various emerging parameters such as channel angle, stretching/shrinking parameter, Casson fluid parameter, Reynolds number and Hartmann number on velocity profile are considered. The results using the FTADM are compared with the results of ADM and numerical Range Kutta fourth-order method. The comparison reveals that, for the same number of components of the recursive sequences over a wide range of spatial domain, the relative errors associated with the new method, FTADM, are much less than the ADM. The results of the new method show that the method is an accurate and expedient approximate analytic method in solving the third-order nonlinear equation of Jeffery-Hamel flow of non-Newtonian Casson fluid. PMID- 30397237 TI - Viral diversity of Rhipicephalus microplus parasitizing cattle in southern Brazil. AB - Ticks are ectoparasites spread worldwide and are well known as vectors of many viruses of great importance to human and animal health. However, the viral diversity in ticks is still poorly understood, particularly in South America. Here we characterized the viral diversity present in Rhipicephalus microplus parasitizing cattle in the southern region of Brazil using metagenomics. Our study revealed the presence of viruses that had not been previously described in the region, including lihan tick virus (Phenuiviridae family) and wuhan tick virus 2 (Chuviridae family), as well as expands the biogeography of jingmen tick virus (Flaviviridae family) in Brazil. Also, we described three novel tymoviruses (Tymovirales order), named guarapuava tymovirus-like 1 to 3. We described the genomic and phylogenetic characterization of these viruses. Our study sheds light on the viral diversity of Rhipicephalus microplus in South America, and also expands the biogeography of tick viruses that were previously described only in Asia. PMID- 30397240 TI - AutoImpute: Autoencoder based imputation of single-cell RNA-seq data. AB - The emergence of single-cell RNA sequencing (scRNA-seq) technologies has enabled us to measure the expression levels of thousands of genes at single-cell resolution. However, insufficient quantities of starting RNA in the individual cells cause significant dropout events, introducing a large number of zero counts in the expression matrix. To circumvent this, we developed an autoencoder-based sparse gene expression matrix imputation method. AutoImpute, which learns the inherent distribution of the input scRNA-seq data and imputes the missing values accordingly with minimal modification to the biologically silent genes. When tested on real scRNA-seq datasets, AutoImpute performed competitively wrt., the existing single-cell imputation methods, on the grounds of expression recovery from subsampled data, cell-clustering accuracy, variance stabilization and cell type separability. PMID- 30397241 TI - Molecular imaging of telomerase and the enzyme activity-triggered drug release by using a conformation-switchable nanoprobe in cancerous cells. AB - So far, the development of a unique strategy for specific biomolecules activity monitoring and precise drugs release in cancerous cells is still challenging. Here, we designed a conformation-switchable smart nanoprobe to monitor telomerase activity and to enable activity-triggered drug release in cancerous cells. The straightforward nanoprobe contained a gold nanoparticle (AuNP) core and a dense layer of 5-carboxyfluorescein (FAM)-labeled hairpin DNA shell. The 3' region of hairpin DNA sequence could function as the telomerase primer to be elongated in the presence of telomerase, resulting in the conformational switch of hairpin DNA. As a result, the FAM fluorescence was activated and the anticancer drug doxorubicin (Dox) molecules which intercalated into the stem region of the hairpin DNA sequence were released into cancerous cells simultaneously. The smart method could specifically distinguish cancerous cells from normal cells based on telomerase activity. It also showed a good performance for monitoring telomerase activity in the cytoplasm by molecular imaging and precise release of Dox triggered by telomerase activity in cancerous cells. These advantages may offer a great potential of this method for monitoring telomerase activity in cancer progression and estimating therapeutic effect. PMID- 30397242 TI - Urothelium proliferation is a trigger for renal crystal deposits in a murine lithogenesis model. AB - Most mouse kidney stone models induce nephrocalcinosis rather than urolithiasis. The aim of our study was to find an accelerated experimental model in order to study the early events of stone formation, that is, at the time of crystal binding to intrarenal urothelium. C57B6 mice exposed to vitamin D supplements and water containing hydroxyl-L-proline, ammonium chloride and calcium chloride were studied for 42 days. A group receiving urothelial cell mitogen Fibroblast Growth Factor 7 (FGF7) was compared to control group receiving saline. Calcium oxalate monohydrate (COM) crystals were detected in urines by day 2 and within urinary spaces in specialized fornix areas in both groups as soon as day 14 with enhanced deposits in FGF7 group compared to controls at day 21. Urothelial cells proliferation, uroplakin III downregulation and de novo expression of osteopontin receptor CD44 detected in FGF7 group, were delayed in the control group (day 42). Crystal aggregates within specialized fornix areas by day 42 were located in urinary spaces but also within and under a multilayered metaplastic urothelium, simultaneous to macrophages influx. Point of note, administration of a normal diet by day 21 was responsible for a spontaneous crystal clearance. Our data show that under supersaturation conditions, urothelial cell proliferation and calcium oxalate crystal retention occur within specialized fornix areas. Enhanced crystal deposits following FGF7 administration suggest that urothelium proliferation would be a relevant trigger for renal stone formation. PMID- 30397243 TI - Probing heat generation during tensile plastic deformation of a bulk metallic glass at cryogenic temperature. AB - Despite significant research efforts, the deformation and failure mechanisms of metallic glasses remain not well understood. In the absence of periodic structure, these materials typically deform in highly localized, thin shear bands at ambient and low temperatures. This process usually leads to an abrupt fracture, hindering their wider use in structural applications. The dynamics and temperature effects on the formation and operation of those shear bands have been the focus of long-standing debate. Here, we use a new experimental approach based on localized boiling of liquid nitrogen by the heat generated in the shear bands to monitor the tensile plastic deformation of a bulk metallic glass submerged in a cryogenic bath. With the "nitrogen bubbles heat sensor", we could capture the heat dissipation along the primary shear banding plane and follow the dynamics of the shear band operation. The observation of nitrogen boiling on the surface of the deforming metallic glass gives direct evidence of temperature increase in the shear bands, even at cryogenic temperatures. An acceleration in bubble nucleation towards the end of the apparent plastic deformation suggests a change from steady state to runaway shear and premonitions the fracture, allowing us to resolve the sequence of deformation and failure events. PMID- 30397244 TI - Comparison of cell-based assays to quantify treatment effects of anticancer drugs identifies a new application for Bodipy-L-cystine to measure apoptosis. AB - Cell-based assays that measure anticancer drug effects are essential for evaluating chemotherapeutic agents. Many assays targeting various cellular mechanisms are available, leading to inconsistent results when using different techniques. We critically compared six common assays, as well as a new assay using Bodipy.FL.L-cystine (BFC), to identify the most accurate and reproducible in measuring anticancer drug effects. We tested three common chemotherapies (methotrexate, paclitaxel, and etoposide) in two cell lines (Ln229 and MDA MB231). Spectroscopic assays such as Cell Titer Blue, and 2',7' dichlorofluorescin diacetate (DCFDA) yielded a strong drug dose response, especially for paclitaxel and etoposide (R2 = 0.9). MTT and Calcein-AM fluorescent dye-based assays were less consistent in that regard. Among three flow cytometry assays, Propidium Iodide (PI)-based DNA content analysis and a new BFC-based glutathione-redox (GSH) assay produced drug dose dependent results. Compared to PI, BFC showed a better correlation (R2 = 0.7-0.9) in depicting live and apoptotic cells. We found that the combination of Cell Titer Blue spectroscopy and BFC flow cytometry assays were most accurate in assessing anticancer drug effects by clear distinction between live and apoptotic cells, independent of drug mechanism of action. We present a new application of BFC as an agent for measuring cellular apoptosis. PMID- 30397245 TI - Characterizing directed functional pathways in the visual system by multivariate nonlinear coherence of fMRI data. AB - A multivariate measure of directed functional connectivity is used with resting state fMRI data of 40 healthy subjects to identify directed pathways of signal progression in the human visual system. The method utilizes 4-nodes networks of mutual interacted BOLD signals to obtains their temporal hierarchy and functional connectivity. Patterns of signal progression were defined at frequency windows by appealing to a hierarchy based upon phase differences, and their significance was assessed by permutation testing. Assuming consistent phase relationship between neuronal and fMRI signals and unidirectional coupling, we were able to characterize directed pathways in the visual system. The ventral and dorsal systems were found to have different functional organizations. The dorsal system, particularly of the left hemisphere, had numerous feedforward pathways connecting the striate and extrastriate cortices with non-visual regions. The ventral system had fewer pathways primarily of two types: (1) feedback pathways initiated in the fusiform gyrus that were either confined to the striate and the extrastriate cortices or connected to the temporal cortex, (2) feedforward pathways initiated in V2, excluded the striate cortex, and connected to non-visual regions. The multivariate measure demonstrated higher specificity than bivariate (pairwise) measure. The analysis can be applied to other neuroimaging and electrophysiological data. PMID- 30397246 TI - Multiplex real-time PCR assay to detect illegal trade of CITES-listed shark species. AB - The Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) is a multilateral environmental agreement to ensure that the international trade of threatened species is either prohibited (Appendix I listed species) or being conducted legally, sustainably, and transparently (Appendix II listed species). Twelve threatened shark species exploited for their fins, meat, and other products have been listed under CITES Appendix II. Sharks are often traded in high volumes, some of their products are visually indistinguishable, and most importing/exporting nations have limited capacity to detect illicit trade and enforce the regulations. High volume shipments often must be screened after only a short period of detainment (e.g., a maximum of 24 hours), which together with costs and capacity issues have limited the use of DNA approaches to identify illicit trade. Here, we present a reliable, field-based, fast (<4 hours), and cost effective ($0.94 USD per sample) multiplex real-time PCR protocol capable of detecting nine of the twelve sharks listed under CITES in a single reaction. This approach facilitates detection of illicit trade, with positive results providing probable cause to detain shipments for more robust forensic analysis. We also provide evidence of its application in real law enforcement scenarios in Hong Kong. Adoption of this approach can help parties meet their CITES requirements, avoiding potential international trade sanctions in the future. PMID- 30397247 TI - How wind drives the correlation between leaf shape and mechanical properties. AB - From a geometrical point of view, a non-sessile leaf is composed of two parts: a large flat plate called the lamina, and a long beam called the petiole which connects the lamina to the branch/stem. While wind is exerting force (e.g. drag) on the lamina, the petiole undergoes twisting and bending motions. To survive in harsh abiotic conditions, leaves may have evolved to form in different shapes, resulting from a coupling between the lamina geometry and the petiole mechanical properties. In this study, we measure the shape of laminae from 120 simple leaf species (no leaflets). Leaves of the same species are found to be geometrically similar regardless of their size. From tensile/torsional tests, we characterize the bending rigidity (EI) and the twisting rigidity (GJ) of 15 petioles of 4 species in the Spring/Summer: Red Oak (Quercus Rubra), American Sycamore (Platanus occidentalis), Yellow Poplar (Liriodendron tulipifera), and Sugar Maple (Acer saccharum). A twist-to-bend ratio EI/GJ is found to be around 4.3, within the range in previous studies conducted on similar species (EI/GJ = 2.7~8.0 reported in S. Vogel, 1992). In addition, we develop a simple energetic model to find a relation between geometrical shapes and mechanical properties (EI/GJ = 2LL/WC where LL is the laminar length and WC is the laminar width), verified with experimental data. Lastly, we discuss leaf's ability to reduce stress at the stem petiole junction by choosing certain geometry, and also present exploratory results on the effect that seasons have on the Young's and twisting moduli. PMID- 30397248 TI - Machine Learning Reveals Protein Signatures in CSF and Plasma Fluids of Clinical Value for ALS. AB - We use shotgun proteomics to identify biomarkers of diagnostic and prognostic value in individuals diagnosed with amyotrophic lateral sclerosis. Matched cerebrospinal and plasma fluids were subjected to abundant protein depletion and analyzed by nano-flow liquid chromatography high resolution tandem mass spectrometry. Label free quantitation was used to identify differential proteins between individuals with ALS (n = 33) and healthy controls (n = 30) in both fluids. In CSF, 118 (p-value < 0.05) and 27 proteins (q-value < 0.05) were identified as significantly altered between ALS and controls. In plasma, 20 (p value < 0.05) and 0 (q-value < 0.05) proteins were identified as significantly altered between ALS and controls. Proteins involved in complement activation, acute phase response and retinoid signaling pathways were significantly enriched in the CSF from ALS patients. Subsequently various machine learning methods were evaluated for disease classification using a repeated Monte Carlo cross validation approach. A linear discriminant analysis model achieved a median area under the receiver operating characteristic curve of 0.94 with an interquartile range of 0.88-1.0. Three proteins composed a prognostic model (p = 5e-4) that explained 49% of the variation in the ALS-FRS scores. Finally we investigated the specificity of two promising proteins from our discovery data set, chitinase-3 like 1 protein and alpha-1-antichymotrypsin, using targeted proteomics in a separate set of CSF samples derived from individuals diagnosed with ALS (n = 11) and other neurological diseases (n = 15). These results demonstrate the potential of a panel of targeted proteins for objective measurements of clinical value in ALS. PMID- 30397250 TI - Earth tectonics as seen by GOCE - Enhanced satellite gravity gradient imaging. AB - Curvature components derived from satellite gravity gradients provide new global views of Earth's structure. The satellite gravity gradients are based on the GOCE satellite mission and we illustrate by curvature images how the Earth is seen differently compared to seismic imaging. Tectonic domains with similar seismic characteristic can exhibit distinct differences in satellite gravity gradients maps, which points to differences in the lithospheric build-up. This is particularly apparent for the cratonic regions of the Earth. The comparisons demonstrate that the combination of seismological, and satellite gravity gradient imaging has significant potential to enhance our knowledge of Earth's structure. In remote frontiers like the Antarctic continent, where even basic knowledge of lithospheric scale features remains incomplete, the curvature images help unveil the heterogeneity in lithospheric structure, e.g. between the composite East Antarctic Craton and the West Antarctic Rift System. PMID- 30397249 TI - Step Sizes and Rate Constants of Single-headed Cytoplasmic Dynein Measured with Optical Tweezers. AB - A power stroke of dynein is thought to be responsible for the stepping of dimeric dynein. However, the actual size of the displacement driven by a power stroke has not been directly measured. Here, the displacements of single-headed cytoplasmic dynein were measured by optical tweezers. The mean displacement of dynein interacting with microtubule was ~8 nm at 100 uM ATP, and decreased sigmoidally with a decrease in the ATP concentration. The ATP dependence of the mean displacement was explained by a model that some dynein molecules bind to microtubule in pre-stroke conformation and generate 8-nm displacement, while others bind in the post-stroke one and detach without producing a power stroke. Biochemical assays showed that the binding affinity of the post-stroke dynein to a microtubule was ~5 times higher than that of pre-stroke dynein, and the dissociation rate was ~4 times lower. Taking account of these rates, we conclude that the displacement driven by a power stroke is 8.3 nm. A working model of dimeric dynein driven by the 8-nm power stroke was proposed. PMID- 30397253 TI - Consulting the consultants: Avastin in the treatment of wet AMD. PMID- 30397252 TI - Coevolution of Environmental Perception and Cooperative Behavior in Evacuation Crowd. AB - For the evacuation crowd of social agents, environment plays a big effect on the behavior and decision of the agents. When facing the uncertain environment, the behavior and decision of agents depend heavily on the perception of environment. Therefore, the cooperation between agents and their perception of environment may coexist during evacuation. Here we establish a mechanism to analyze the coevolution between the cooperation of agents and the perception of environment. In detail, we use a regular square lattice with periodic boundaries, where two payoff matrices are used to describe two kinds of games between neighbors in the safe and dangerous environments. For individual agent, its perception can be adjusted by interacting with neighboring agents. When the environment is generally considered dangerous, the fraction of cooperative agents keeps at a high level, even if the value of b is very large. When all the agents think that the environment is safe, the fraction of cooperation will decrease as the value of b increases. PMID- 30397254 TI - Are patients with ectopia lentis known to cardiology services? PMID- 30397251 TI - Usefulness of peripapillary nerve fiber layer thickness assessed by optical coherence tomography as a biomarker for Alzheimer's disease. AB - The use of optical coherence tomography (OCT) has been suggested as a potential biomarker for Alzheimer's Disease based on previously reported thinning of the retinal nerve fiber layer (RNFL) in Alzheimer's disease's (AD) and Mild Cognitive Impairment (MCI). However, other studies have not shown such results. 930 individuals (414 cognitively healthy individuals, 192 probable amnestic MCI and 324 probable AD) attending a memory clinic were consecutively included and underwent spectral domain OCT (Maestro, Topcon) examinations to assess differences in peripapillary RNFL thickness, using a design of high ecological validity. Adjustment by age, education, sex and OCT image quality was performed. We found a non-significant decrease in mean RNFL thickness as follows: control group: 100,20 +/- 14,60 um, MCI group: 98,54 +/- 14,43 um and AD group: 96,61 +/- 15,27 um. The multivariate adjusted analysis revealed no significant differences in mean overall (p = 0.352), temporal (p = 0,119), nasal (p = 0,151), superior (p = 0,435) or inferior (p = 0,825) quadrants between AD, MCI and control groups. These results do not support the usefulness of peripapillary RNFL analysis as a marker of cognitive impairment or in discriminating between cognitive groups. The analysis of other OCT measurements in other retinal areas and layers as biomarkers for AD should be tested further. PMID- 30397256 TI - Traumatic brain injury: sex, gender and intersecting vulnerabilities. AB - Over the past decade, traumatic brain injury (TBI) has emerged as a major public health concern, attracting considerable interest from the scientific community, clinical and behavioural services and policymakers, owing to its rising prevalence, wide-ranging risk factors and substantial lifelong familial and societal impact. This increased attention to TBI has resulted in increased funding and advances in legislation. However, many questions surrounding TBI remain unanswered, including questions on sex and gender trends with respect to vulnerability to injury, presentation of injury, response to treatment, and outcomes. Here, we review recent research efforts aimed at advancing knowledge on the constructs of sex and gender and their respective influences in the context of TBI, and discuss methodological challenges in disentangling the differential impacts of these two constructs, particularly in marginalized populations. PMID- 30397255 TI - Receptor-Ligand Interaction Mediates Targeting of Endothelial Colony Forming Cell derived Exosomes to the Kidney after Ischemic Injury. AB - Endothelial colony forming cell (ECFC)-derived exosomes protect mice against ischemic kidney injury, via transfer of microRNA-(miR)-486-5p. Mechanisms mediating exosome recruitment to tissues are unclear. We hypothesized that ECFC exosomes target ischemic kidneys, involving interaction between exosomal CXC chemokine receptor type 4 (CXCR4) and stromal cell-derived factor (SDF)-1alpha. Ischemia-reperfusion was induced in mice by bilateral renal vascular clamp, with intravenous infusion of exosomes at reperfusion. Optical imaging determined exosome biodistribution, and miR-486-5p was measured by real-time PCR. Human umbilical vein endothelial cells (HUVECs) were cultured to study the CXCR4/SDF 1alpha interaction. Targeting of administered exosomes to ischemic kidneys was detected 30 min and 4 hrs after reperfusion. Exosomes increased miR-486-5p levels only in kidneys, within proximal tubules, glomeruli, and endothelial cells. Uptake of fluorescently-labeled exosomes into HUVECs, and exosomal transfer of miR-486-5p were enhanced by hypoxia, effects blocked by neutralizing antibody to SDF-1alpha or by the CXCR4 inhibitor plerixafor. Infusion of ECFC exosomes prevented ischemic kidney injury in vivo, an effect that was not observed when exosomes were pre-incubated with plerixafor. These data indicate that ECFC exosomes selectively target the kidneys after ischemic injury, with rapid cellular transfer of miR486-5p. Targeting of exosomes may involve interaction of CXCR4 with endothelial cell SDF-1alpha. PMID- 30397257 TI - Longitudinal effect of 20-year infancy-onset dietary intervention on food consumption and nutrient intake: the randomized controlled STRIP study. AB - BACKGROUND/OBJECTIVES: Coronary heart disease begins in childhood and warrants prevention strategies such as dietary modification. The objective was to determine the effect of the Special Turku Coronary Risk Factor Intervention Project (STRIP) dietary intervention on food consumption and nutrient intake over 20-year intervention period. SUBJECTS/METHODS: The STRIP is a prospective, randomized trial conducted between 1990 and 2011. Enrolled 6-month-old infants (n = 1062) were randomized to an intervention group (n = 540) receiving dietary counseling biannually from age 7 months to 20 years or control group (n = 522) not receiving any intervention. Food and nutrient intake was assessed annually using 4-day food records. A food-based diet score was calculated. RESULTS: The intervention led to (1) higher consumption of low-fat unsweetened dairy (beta = 177.76, 95% CI 157.36-198.16 g/day), vegetable-oil based fats (beta = 6.00, 5.37 6.63 g/day), fish (beta = 2.45, 1.44-3.45 g/day), fiber-rich grain products (beta = 5.53, 3.17-7.89 g/day), fruits/berries (beta = 9.93, 4.44-15.43 g/day), vegetables (beta = 11.95, 7.74-16.16 g/day); (2) lower consumption of desserts (beta = - 4.10, 95% CI - 6.50 to - 1.70 g/day); (3) lower intake of sucrose (beta = - 1.61, 95% CI - 2.88 to - 0.35 g/day), and higher intake of fiber (beta = 0.83, 0.55-1.11 g/day), folate (beta = 11.14, 95% CI 8.23-14.05 MUg/day), vitamin D (beta = 0.52, 0.39-0.64 MUg/day), C (beta = 8.08, 4.79-11.38 mg/day), E (beta = 0.93, 0.81-1.05 mg/day), iron (beta = 0.31, 0.18-0.44 mg/day), zinc (beta = 0.29, 0.17-0.40 mg/day), magnesium (beta = 12.17, 9.02-15.33 mg/day), sodium (beta = 55.00, 24.40-85.60 mg/day), potassium (beta = 157.11, 107.24-206.98 mg/day). No effect was found on nut/seed, red/processed meat, sugar-sweetened beverage, salty snack consumption, or vitamin A and calcium intake. Intervention effect was more pronounced in boys. CONCLUSIONS: The STRIP intervention improved children's diet quality over 20 years, indicating that beneficial dietary changes can be introduced and sustained in youth. PMID- 30397258 TI - Wicked problems: the challenge of food safety versus food security-working towards the SDG goals? PMID- 30397260 TI - The Vanderbilt staging system for retroperitoneal sarcoma: a validation study of 6857 patients from the National Cancer Database. AB - The Vanderbilt staging system for retroperitoneal sarcoma incorporates information regarding the histologic subtype of sarcoma and outperforms the 7th and 8th editions of the AJCC staging systems by several different statistical criteria. The current study was performed using an independent patient cohort from the National Cancer Database (n = 6857) to validate this proposed staging system. Each staging system was assessed for degree of discrimination by pairwise comparisons of adjacent stage categories. Predictive accuracy of 5-year overall survival was performed by comparison of areas under receiver operating characteristic curves generated from logistic regression. Three different concordance indices (Harrell's c, Somers' D, and Gonen and Heller's K) were calculated using bootstrap methods. Amount of variation in observed outcomes explained by each staging system was assessed using O'Quigley's rho2k and Royston's R2. Bayesian information criteria were also assessed as measures of model fit. The revised AJCC 8th edition T categories were not effective in categorizing risk of death. The Vanderbilt staging system showed the best discrimination between adjacent tumor stages, highest predictive accuracy for 5 year overall survival, a higher degree of concordance with and explained variation of clinical outcomes, and resulted in the best fitting regression model. These results obtained with an independent dataset validate the Vanderbilt staging system for retroperitoneal sarcoma and demonstrate its superiority in risk stratification over current and prior editions of the AJCC staging system. PMID- 30397259 TI - Whole-genome landscape of Medicago truncatula symbiotic genes. AB - Advances in deciphering the functional architecture of eukaryotic genomes have been facilitated by recent breakthroughs in sequencing technologies, enabling a more comprehensive representation of genes and repeat elements in genome sequence assemblies, as well as more sensitive and tissue-specific analyses of gene expression. Here we show that PacBio sequencing has led to a substantially improved genome assembly of Medicago truncatula A17, a legume model species notable for endosymbiosis studies1, and has enabled the identification of genome rearrangements between genotypes at a near-base-pair resolution. Annotation of the new M. truncatula genome sequence has allowed for a thorough analysis of transposable elements and their dynamics, as well as the identification of new players involved in symbiotic nodule development, in particular 1,037 upregulated long non-coding RNAs (lncRNAs). We have also discovered that a substantial proportion (~35% and 38%, respectively) of the genes upregulated in nodules or expressed in the nodule differentiation zone colocalize in genomic clusters (270 and 211, respectively), here termed symbiotic islands. These islands contain numerous expressed lncRNA genes and display differentially both DNA methylation and histone marks. Epigenetic regulations and lncRNAs are therefore attractive candidate elements for the orchestration of symbiotic gene expression in the M. truncatula genome. PMID- 30397261 TI - Quantifying the changes in genetic diversity within sequence-discrete bacterial populations across a spatial and temporal riverine gradient. AB - Recent diversity studies have revealed that microbial communities of natural environments are dominated by species-like, sequence-discrete populations. However, how stable the sequence and gene-content diversity are within these populations and especially in highly dynamic lotic habitats remain unclear. Here we quantified the dynamics of intra-population diversity in samples spanning two years and five sites in the Kalamas River (Northwest Greece). A significant positive correlation was observed between higher intra-population sequence diversity and longer persistence over time, revealing that more diverse populations tended to represent more autochthonous (vs. allochthonous) community members. Assessment of intra-population gene-content changes caused by strain replacement or gene loss over time revealed different profiles with the majority of populations exhibiting gene-content changes close to 10% of the total genes, while one population exhibited ~21% change. The variable genes were enriched in hypothetical proteins and mobile elements, and thus, were probably functionally neutral or attributable to phage predation. A few notable exceptions to this pattern were also noted such as phototrophy-related proteins in summer vs. winter populations. Taken together, these results revealed that some freshwater genomes are remarkably dynamic, even across short time and spatial scales, and have implications for the bacterial species concept and microbial source tracking. PMID- 30397262 TI - Interaction of MTHFR C677T polymorphism with smoking in susceptibility to diabetic nephropathy in Chinese men with type 2 diabetes. AB - We investigated the interaction of MTHFR C677T polymorphism (rs1801133) with smoking in susceptibility to diabetic nephropathy (DN) in Chinese men with type 2 diabetes mellitus (T2DM). We studied 655 Chinese men with T2DM, who were divided into two groups (321 with DN and 334 without DN). The genotype of MTHFR C677T polymorphism was detected by real-time polymerase chain reaction. MTHFR TT genotype carried a higher risk of DN compared with the CC genotype (OR = 2.05; P = 0.002). The T allele showed marked association with DN development in patients who smoked, using additive, recessive, and dominant models (OR = 1.60, 1.83, and 1.88, respectively; P = 0.006, 0.002, and 0.04, respectively), which was not observed in the nonsmoking group. Patients with TT and CT genotypes, who smoked had a higher risk of DN compared with the control group (non-smoking with CC genotype; OR = 3.73 and 2.28, respectively; P < 0.001 and P = 0.004, respectively), whereas the other groups were not observed. In conclusion, the T allele of rs1801133 may be a risk factor for DN in Chinese men with T2DM, and synergy appears to exist between the MTHFR rs1801133 and smoking in susceptibility to DN. PMID- 30397265 TI - Reply to "Clarification on a contradiction". PMID- 30397263 TI - Associations between back pain across adulthood and spine shape in early old age in a British birth cohort. AB - We aimed to examine whether back pain across adulthood was associated with spine shape at age 60-64 years. Data were from 1405 participants in the MRC National Survey of Health and Development, a nationally representative British birth cohort. Back pain was ascertained during nurse interviews at ages 36, 43, 53 and 60-64 years. Cumulative exposure to back pain was then derived by counting the number of ages at which back pain was reported. Statistical shape modelling was used to characterise thoracolumbar spine shape using lateral dual-energy x-ray absorptiometry images which were ascertained at age 60-64 years. Linear regression models were used to test associations of spine shape modes (SM) with: (1) cumulative exposure to back pain; (2) back pain reports during different periods of adulthood. After adjusting for sex, higher cumulative exposure to back pain across adulthood was associated with wedge-shaped L4-5 disc (lower SM4 scores) and smaller disc spaces (higher SM8 scores) in both sexes. In addition, reporting of back pain at ages 53 and/or 60-64 years was associated with smaller L4-5 disc space (lower SM6 scores) in men but not women. These findings suggest that back pain across adulthood may be associated with specific variations in spine shapes in early old age. PMID- 30397266 TI - Clarification on a contradiction. PMID- 30397264 TI - Discovery of Novaculina myanmarensis sp. nov. (Bivalvia: Pharidae: Pharellinae) closes the freshwater razor clams range disjunction in Southeast Asia. AB - The razor clam genus Novaculina represents an example of a marine-derived, secondary freshwater group. It was thought to comprise three species: N. gangetica (Ganges and smaller basins in Bangladesh and northwestern Myanmar), N. siamensis (Bang Pakong and Pasak rivers in Thailand and Mekong River in Vietnam), and N. chinensis (lower Yangtze River, China). Here we describe Novaculina myanmarensis sp. nov., an additional species from the Ayeyarwady and Salween basins representing a divergent lineage that appears to be sister to N. gangetica. This new record closes a Novaculina range disjunction between northwestern Myanmar and Thailand. The populations of this novel species share a shallow molecular divergence from each other indicating potential dispersal events between the two distant freshwater basins during the Late Pleistocene. Our ancestral area modeling suggests that the MRCA of Novaculina crown group was a salt-tolerant freshwater species. The recent Novaculina species most likely originated via allopatric speciation. Our findings highlight that generalist estuarine species could have played the role as a source for bivalve expansions into freshwater and that western Indochina is a separate biogeographic subregion, which is clearly distinct from India. A new synonymy is proposed as follows: Pharellinae Stoliczka, 1870 = Novaculininae Ghosh, 1920 syn. nov. PMID- 30397267 TI - Discussing the future of amphibians in research. PMID- 30397269 TI - A new link for heart failure and diabetes. PMID- 30397270 TI - Types and origins of bacterial membrane vesicles. AB - Most bacteria release membrane vesicles (MVs) that contain specific cargo molecules and have diverse functions, including the transport of virulence factors, DNA transfer, interception of bacteriophages, antibiotics and eukaryotic host defence factors, cell detoxification and bacterial communication. MVs not only are abundant in nature but also show great promise for applications in biomedicine and nanotechnology. MVs were first discovered to originate from controlled blebbing of the outer membrane of Gram-negative bacteria and are therefore often called outer-membrane vesicles (OMVs). However, recent work has shown that Gram-positive bacteria can produce MVs, that different types of MVs besides OMVs exist and that, in addition to membrane blebbing, MVs can also be formed by endolysin-triggered cell lysis. In this Review, we provide an overview of the structures and compositions of the various vesicle types and discuss novel formation routes, which may lead to distinct vesicle types that serve particular functions. PMID- 30397268 TI - Estimating the effect size of surgery to improve walking in children with cerebral palsy from retrospective observational clinical data. AB - Single-event multilevel surgery (SEMLS) is a standard treatment approach aimed at improving gait for patients with cerebral palsy, but the effect of this approach compared to natural progression without surgical intervention is unclear. In this study, we used retrospective patient history, physical exam, and three dimensional gait analysis data from 2,333 limbs to build regression models estimating the effect of SEMLS on gait, while controlling for expected natural progression. Post-hoc classifications using the regression model results identified which limbs would exhibit gait within two standard deviations of typical gait at the follow-up visit with or without a SEMLS with 73% and 77% accuracy, respectively. Using these models, we found that, while surgery was expected to have a positive effect on 93% of limbs compared to natural progression, in only 37% of limbs was this expected effect a clinically meaningful improvement. We identified 26% of the non-surgically treated limbs that may have shown a clinically meaningful improvement in gait had they received surgery. Our models suggest that pre-operative physical therapy focused on improving biomechanical characteristics, such as walking speed and strength, may improve likelihood of positive surgical outcomes. These models are shared with the community to use as an evaluation tool when considering whether or not a patient should undergo a SEMLS. PMID- 30397271 TI - Self-structuring in Zr1-xAlxN films as a function of composition and growth temperature. AB - Nanostructure formation via surface-diffusion-mediated segregation of ZrN and AlN in Zr1-xAlxN films during high mobility growth conditions is investigated for 0 <= * <= 1. The large immiscibility combined with interfacial surface and strain energy balance resulted in a hard nanolabyrinthine lamellar structure with well defined (semi) coherent c-ZrN and w-AlN domains of sub-nm to ~4 nm in 0.2 <= * <= 0.4 films, as controlled by atom mobility. For high AlN contents (x > 0.49) Al rich ZrN domains attain wurtzite structure within fine equiaxed nanocomposite wurtzite lattice. Slow diffusion in wurtzite films points towards crystal structure dependent driving force for decomposition. The findings of unlikelihood of iso-structural decomposition in c-Zr1-xAlxN, and stability of w-Zr1-xAlxN (in large * films) is complemented with first principles calculations. PMID- 30397272 TI - Impact of Stokes Shift on the Performance of Near-Infrared Harvesting Transparent Luminescent Solar Concentrators. AB - Visibly transparent luminescent solar concentrators (TLSC) have the potential to turn existing infrastructures into net-zero-energy buildings. However, the reabsorption loss currently limits the device performance and scalability. This loss is typically defined by the Stokes shift between the absorption and emission spectra of luminophores. In this work, the Stokes shifts (SS) of near-infrared selective-harvesting cyanines are altered by substitution of the central methine carbon with dialkylamines. We demonstrate varying SS with values over 80 nm and ideal infrared-visible absorption cutoffs. The corresponding TLSC with such modification shows a power conversion efficiency (PCE) of 0.4% for a >25 cm2 device area with excellent visible transparency >80% and up to 0.6% PCE over smaller areas. However, experiments and simulations show that it is not the Stokes shift that is critical, but the total degree of overlap that depends on the shape of the absorption tails. We show with a series of SS-modulated cyanine dyes that the SS is not necessarily correlated to improvements in performance or scalability. Accordingly, we define a new parameter, the overlap integral, to sensitively correlate reabsorption losses in any LSC. In deriving this parameter, new approaches to improve the scalability and performance are discussed to fully optimize TLSC designs to enhance commercialization efforts. PMID- 30397273 TI - Increasing muscle co-contraction speeds up internal model acquisition during dynamic motor learning. AB - During reaching movements in the presence of novel dynamics, participants initially co-contract their muscles to reduce kinematic errors and improve task performance. As learning proceeds, muscle co-contraction decreases as an accurate internal model develops. The initial co-contraction could affect the learning of the internal model in several ways. By ensuring the limb remains close to the target state, co-contraction could speed up learning. Conversely, by reducing kinematic errors, a key training signal, it could slow down learning. Alternatively, given that the effects of muscle co-contraction on kinematic errors are predictable and could be discounted when assessing the internal model error, it could have no effect on learning. Using a sequence of force pulses, we pretrained two groups to either co-contract (stiff group) or relax (relaxed group) their arm muscles in the presence of dynamic perturbations. A third group (control group) was not pretrained. All groups performed reaching movements in a velocity-dependent curl field. We measured adaptation using channel trials and found greater adaptation in the stiff group during early learning. We also found a positive correlation between muscle co-contraction, as measured by surface electromyography, and adaptation. These results show that muscle co-contraction accelerates the rate of dynamic motor learning. PMID- 30397275 TI - Author Correction: Cryo-EM structure of the exocyst complex. AB - In the version of this article originally published, the value given for electron dose in Table 1 was incorrect. This value was originally stated as 4.8 but should have been 50. The error has been corrected in the HTML and PDF versions of the article. PMID- 30397276 TI - Ten years of screening for congenital disorders of glycosylation in Argentina: case studies and pitfalls. AB - BACKGROUND: Congenital Disorders of Glycosylation (CDG) are genetic diseases caused by hypoglycosylation of glycoproteins and glycolipids. Most CDG are multisystem disorders with mild to severe involvement. METHODS: We studied 554 patients (2007-2017) with a clinical phenotype compatible with a CDG. Screening was performed by serum transferrin isoelectric focusing. The diagnosis was confirmed by genetic testing (Sanger or exome sequencing). RESULTS: A confirmed abnormal pattern was found in nine patients. Seven patients showed a type 1 pattern: four with PMM2-CDG, two with ALG2-CDG, and one with classical galactosemia. A type 2 pattern was found in two patients: one with a CDG-IIx and one with a transferrin protein variant. Abnormal transferrin pattern were observed in a patient with a myopathy due to a COL6A2 gene variant. CONCLUSIONS: CDG screening in Argentina from 2007 to 2017 revealed 4 PMM2-CDG patients, 2 ALG2 CDG patients with a novel homozygous gene variant and 1 CDG-IIx. PMID- 30397274 TI - Dysregulated gene expression predicts tumor aggressiveness in African-American prostate cancer patients. AB - Molecular mechanisms underlying the health disparity of prostate cancer (PCa) have not been fully determined. In this study, we applied bioinformatic approach to identify and validate dysregulated genes associated with tumor aggressiveness in African American (AA) compared to Caucasian American (CA) men with PCa. We retrieved and analyzed microarray data from 619 PCa patients, 412 AA and 207 CA, and we validated these genes in tumor tissues and cell lines by Real-Time PCR, Western blot, immunocytochemistry (ICC) and immunohistochemistry (IHC) analyses. We identified 362 differentially expressed genes in AA men and involved in regulating signaling pathways associated with tumor aggressiveness. In PCa tissues and cells, NKX3.1, APPL2, TPD52, LTC4S, ALDH1A3 and AMD1 transcripts were significantly upregulated (p < 0.05) compared to normal cells. IHC confirmed the overexpression of TPD52 (p = 0.0098) and LTC4S (p < 0.0005) in AA compared to CA men. ICC and Western blot analyses additionally corroborated this observation in PCa cells. These findings suggest that dysregulation of transcripts in PCa may drive the disparity of PCa outcomes and provide new insights into development of new therapeutic agents against aggressive tumors. More studies are warranted to investigate the clinical significance of these dysregulated genes in promoting the oncogenic pathways in AA men. PMID- 30397277 TI - The time has come to mitigate the risk of lead exposure from blood transfusions. PMID- 30397278 TI - Developmental influence of unconjugated hyperbilirubinemia and neurobehavioral disorders. AB - Bilirubin-induced brain injury in the neonatal period has detrimental effects on neurodevelopment that persist into childhood and adulthood, contributing to childhood developmental disorders. Unconjugated bilirubin is a potent antioxidant that may be useful for protecting against oxidative injuries, but it becomes a potent neurotoxin once it crosses the blood brain barrier. Because bilirubin toxicity involves a myriad of pathological mechanisms, can damage most types of brain cells, and affects brain circuits or loops that influence cognition, learning, behavior, sensory, and language, the clinical effects of bilirubin induced neurotoxicity are likely to be manifold. One possible effect that several experts have identified is bilirubin-induced neurological dysfunction (subtle kernicterus). However, the underlying biological mechanisms or pathways by which subtle kernicterus could lead to developmental disorders has not been elucidated previously. Our aim in this review is to describe a spectrum of developmental disorders that may reflect subtle kernicterus and outline plausible biological mechanisms for this possible association. We review existing evidence that support or refute the association between unconjugated hyperbilirubinemia and developmental disorders, and limitations associated with these studies. PMID- 30397279 TI - Erythropoietin and neonatal treatment: still more questions than answers. PMID- 30397280 TI - Enhanced microbubble contrast agent oscillation following 250 kHz insonation. AB - Microbubble contrast agents are widely used in ultrasound imaging and therapy, typically with transmission center frequencies in the MHz range. Currently, an ultrasound center frequency near 250 kHz is proposed for clinical trials in which ultrasound combined with microbubble contrast agents is applied to open the blood brain barrier, since at this low frequency focusing through the human skull to a predetermined location can be performed with reduced distortion and attenuation compared to higher frequencies. However, the microbubble vibrational response has not yet been carefully evaluated at this low frequency (an order of magnitude below the resonance frequency of these contrast agents). In the past, it was assumed that encapsulated microbubble expansion is maximized near the resonance frequency and monotonically decreases with decreasing frequency. Our results indicated that microbubble expansion was enhanced for 250 kHz transmission as compared with the 1 MHz center frequency. Following 250 kHz insonation, microbubble expansion increased nonlinearly with increasing ultrasonic pressure, and was accurately predicted by either the modified Rayleigh-Plesset equation for a clean bubble or the Marmottant model of a lipid-shelled microbubble. The expansion ratio reached 30-fold with 250 kHz at a peak negative pressure of 400 kPa, as compared to a measured expansion ratio of 1.6 fold for 1 MHz transmission at a similar peak negative pressure. Further, the range of peak negative pressure yielding stable cavitation in vitro was narrow (~100 kPa) for the 250 kHz transmission frequency. Blood brain barrier opening using in vivo transcranial ultrasound in mice followed the same trend as the in vitro experiments, and the pressure range for safe and effective treatment was 75-150 kPa. For pressures above 150 kPa, inertial cavitation and hemorrhage occurred. Therefore, we conclude that (1) at this low frequency, and for the large oscillations, lipid shelled microbubbles can be approximately modeled as clean gas microbubbles and (2) the development of safe and successful protocols for therapeutic delivery to the brain utilizing 250 kHz or a similar center frequency requires consideration of the narrow pressure window between stable and inertial cavitation. PMID- 30397283 TI - Detecting short RNA sequences of pathogens. PMID- 30397284 TI - Steering a single nuclear spin. PMID- 30397282 TI - Application of Wearable Inertial Sensors and A New Test Battery for Distinguishing Retrospective Fallers from Non-fallers among Community-dwelling Older People. AB - Considering the challenge of population ageing and the substantial health problem among the elderly population from falls, the purpose of this study was to verify whether it is possible to distinguish accurately between older fallers and non fallers, based on data from wearable inertial sensors collected during a specially designed test battery. A comprehensive but practical test battery using 5 wearable inertial sensors for multifactorial fall risk assessment was designed. This was followed by an experimental study on 196 community-dwelling Korean older women, categorized as fallers (N1 = 82) and non-fallers (N2 = 114) based on prior history of falls. Six machine learning models (logistic regression, naive bayes, decision tree, random forest, boosted tree and support vector machine) were proposed for faller classification. Results indicated that compared with non fallers, fallers performed significantly worse on the test battery. In addition, the application of sensor data and support vector machine for faller classification achieved an overall accuracy of 89.4% with 92.7% sensitivity and 84.9% specificity. These findings suggest that wearable inertial sensor based systems show promise for elderly fall risk assessment, which could be implemented in clinical practice to identify "at-risk" individuals reliably to promote proactive fall prevention. PMID- 30397281 TI - Brain-machine interface cursor position only weakly affects monkey and human motor cortical activity in the absence of arm movements. AB - Brain-machine interfaces (BMIs) that decode movement intentions should ignore neural modulation sources distinct from the intended command. However, neurophysiology and control theory suggest that motor cortex reflects the motor effector's position, which could be a nuisance variable. We investigated motor cortical correlates of BMI cursor position with or without concurrent arm movement. We show in two monkeys that subtracting away estimated neural correlates of position improves online BMI performance only if the animals were allowed to move their arm. To understand why, we compared the neural variance attributable to cursor position when the same task was performed using arm reaching, versus arms-restrained BMI use. Firing rates correlated with both BMI cursor and hand positions, but hand positional effects were greater. To examine whether BMI position influences decoding in people with paralysis, we analyzed data from two intracortical BMI clinical trial participants and performed an online decoder comparison in one participant. We found only small motor cortical correlates, which did not affect performance. These results suggest that arm movement and proprioception are the major contributors to position-related motor cortical correlates. Cursor position visual feedback is therefore unlikely to affect the performance of BMI-driven prosthetic systems being developed for people with paralysis. PMID- 30397285 TI - Electrically controlled nuclear polarization of individual atoms. AB - Nuclear spins serve as sensitive probes in chemistry1 and materials science2 and are promising candidates for quantum information processing3-6. NMR, the resonant control of nuclear spins, is a powerful tool for probing local magnetic environments in condensed matter systems, which range from magnetic ordering in high-temperature superconductors7,8 and spin liquids9 to quantum magnetism in nanomagnets10,11. Increasing the sensitivity of NMR to the single-atom scale is challenging as it requires a strong polarization of nuclear spins, well in excess of the low polarizations obtained at thermal equilibrium, as well as driving and detecting them individually4,5,12. Strong nuclear spin polarization, known as hyperpolarization, can be achieved through hyperfine coupling with electron spins2. The fundamental mechanism is the conservation of angular momentum: an electron spin flips and a nuclear spin flops. The nuclear hyperpolarization enables applications such as in vivo magnetic resonance imaging using nanoparticles13, and is harnessed for spin-based quantum information processing in quantum dots14 and doped silicon15-17. Here we polarize the nuclear spins of individual copper atoms on a surface using a spin-polarized current in a scanning tunnelling microscope. By employing the electron-nuclear flip-flop hyperfine interaction, the spin angular momentum is transferred from tunnelling electrons to the nucleus of individual Cu atoms. The direction and magnitude of the nuclear polarization is controlled by the direction and amplitude of the current. The nuclear polarization permits the detection of the NMR of individual Cu atoms, which is used to sense the local magnetic environment of the Cu electron spin. PMID- 30397286 TI - Detection and identification of genetic material via single-molecule conductance. AB - The ongoing discoveries of RNA modalities (for example, non-coding, micro and enhancer) have resulted in an increased desire for detecting, sequencing and identifying RNA segments for applications in food safety, water and environmental protection, plant and animal pathology, clinical diagnosis and research, and bio security. Here, we demonstrate that single-molecule conductance techniques can be used to extract biologically relevant information from short RNA oligonucleotides, that these measurements are sensitive to attomolar target concentrations, that they are capable of being multiplexed, and that they can detect targets of interest in the presence of other, possibly interfering, RNA sequences. We also demonstrate that the charge transport properties of RNA:DNA hybrids are sensitive to single-nucleotide polymorphisms, thus enabling differentiation between specific serotypes of Escherichia coli. Using a combination of spectroscopic and computational approaches, we determine that the conductance sensitivity primarily arises from the effects that the mutations have on the conformational structure of the molecules, rather than from the direct chemical substitutions. We believe that this approach can be further developed to make an electrically based sensor for diagnostic purposes. PMID- 30397288 TI - Jacob Israelachvili (1944-2018). PMID- 30397287 TI - The amount of activating EGFR mutations in circulating cell-free DNA is a marker to monitor osimertinib response. AB - BACKGROUND: Circulating cell-free DNA (cfDNA) may help understand the molecular response to pharmacologic treatment and provide information on dynamics of clonal heterogeneity. Therefore, this study evaluated the correlation between treatment outcome and activating EGFR mutations (act-EGFR) and T790M in cfDNA in patients with advanced NSCLC given osimertinib. METHODS: Thirty-four NSCLC patients resistant to first/second-generation EGFR-TKIs, positive for both act-EGFR and T790M in cfDNA at the time of progression were enrolled in this study. Plasma samples were obtained at osimertinib baseline and after 3 months of therapy; cfDNA was analyzed by droplet digital PCR and results were expressed as mutant allele frequency (MAF). RESULTS: At baseline, act-EGFR MAF was significantly higher than T790M (p < 0.0001). act-EGFR MAF and T790M/act-EGFR MAF ratio were significantly correlated with disease response (p = 0.02). Cut-off values of act EGFR MAF and T790M/act-EGFR ratio of 2.6% and 0.22 were found, respectively. The PFS of patients with act-EGFR MAF of > 2.6% and < 2.6%, were 10 months vs. not reached, respectively (p = 0.03), whereas patients with T790M/act-EGFR <= 0.22 had poorer PFS than patients with a value of > 0.22 (6 months vs. not reached, respectively, p = 0.01). CONCLUSION: act-EGFR MAF and T790M/act-EGFR MAF ratio are potential markers of outcome in patients treated with osimertinib. PMID- 30397289 TI - Opportunities and challenges of interlayer exciton control and manipulation. PMID- 30397290 TI - Proteins aggregate not. PMID- 30397291 TI - A furled superconductor. PMID- 30397292 TI - Porous hierarchy. PMID- 30397293 TI - Inhibiting collective cell migration. PMID- 30397294 TI - Inching closer to realistic exposure models. PMID- 30397295 TI - Electron quantum metamaterials in van der Waals heterostructures. AB - In recent decades, scientists have developed the means to engineer synthetic periodic arrays with feature sizes below the wavelength of light. When such features are appropriately structured, electromagnetic radiation can be manipulated in unusual ways, resulting in optical metamaterials whose function is directly controlled through nanoscale structure. Nature, too, has adopted such techniques-for example in the unique colouring of butterfly wings-to manipulate photons as they propagate through nanoscale periodic assemblies. In this Perspective, we highlight the intriguing potential of designer structuring of electronic matter at scales at and below the electron wavelength, which affords a new range of synthetic quantum metamaterials with unconventional responses. Driven by experimental developments in stacking atomically layered heterostructures-such as mechanical pick-up/transfer assembly-atomic-scale registrations and structures can be readily tuned over distances smaller than characteristic electronic length scales (such as the electron wavelength, screening length and electron mean free path). Yet electronic metamaterials promise far richer categories of behaviour than those found in conventional optical metamaterial technologies. This is because, unlike photons, which scarcely interact with each other, electrons in subwavelength-structured metamaterials are charged and strongly interact. As a result, an enormous variety of emergent phenomena can be expected and radically new classes of interacting quantum metamaterials designed. PMID- 30397297 TI - Excitation that lasts. PMID- 30397296 TI - Ultrafast dynamics in van der Waals heterostructures. AB - Van der Waals heterostructures are synthetic quantum materials composed of stacks of atomically thin two-dimensional (2D) layers. Because the electrons in the atomically thin 2D layers are exposed to layer-to-layer coupling, the properties of van der Waals heterostructures are defined not only by the constituent monolayers, but also by the interactions between the layers. Many fascinating electrical, optical and magnetic properties have recently been reported in different types of van der Waals heterostructures. In this Review, we focus on unique excited-state dynamics in transition metal dichalcogenide (TMDC) heterostructures. TMDC monolayers are the most widely studied 2D semiconductors, featuring prominent exciton states and accessibility to the valley degree of freedom. Many TMDC heterostructures are characterized by a staggered band alignment. This band alignment has profound effects on the evolution of the excited states in heterostructures, including ultrafast charge transfer between the layers, the formation of interlayer excitons, and the existence of long-lived spin and valley polarization in resident carriers. Here we review recent experimental and theoretical efforts to elucidate electron dynamics in TMDC heterostructures, extending from timescales of femtoseconds to microseconds, and comment on the relevance of these effects for potential applications in optoelectronic, valleytronic and spintronic devices. PMID- 30397299 TI - Dispersal dilemmas. PMID- 30397298 TI - Bottom-up and top-down control of dispersal across major organismal groups. AB - Ecology and evolution unfold in spatially structured communities, where dispersal links dynamics across scales. Because dispersal is multicausal, identifying general drivers remains challenging. In a coordinated distributed experiment spanning organisms from protozoa to vertebrates, we tested whether two fundamental determinants of local dynamics, top-down and bottom-up control, generally explain active dispersal. We show that both factors consistently increased emigration rates and use metacommunity modelling to highlight consequences on local and regional dynamics. PMID- 30397300 TI - China's tuberculosis epidemic stems from historical expansion of four strains of Mycobacterium tuberculosis. AB - A small number of high-burden countries account for the majority of tuberculosis cases worldwide. Detailed data are lacking from these regions. To explore the evolutionary history of Mycobacterium tuberculosis in China-the country with the third highest tuberculosis burden-we analysed a countrywide collection of 4,578 isolates. Little genetic diversity was detected, with 99.4% of the bacterial population belonging to lineage 2 and three sublineages of lineage 4. The deeply rooted phylogenetic positions and geographic restriction of these four genotypes indicate that their populations expanded in situ following a small number of introductions to China. Coalescent analyses suggest that these bacterial subpopulations emerged in China around 1,000 years ago, and expanded in parallel from the twelfth century onwards, and that the whole population peaked in the late eighteenth century. More recently, sublineage L2.3, which is indigenous to China and exhibited relatively high transmissibility and extensive global dissemination, came to dominate the population dynamics of M. tuberculosis in China. Our results indicate that historical expansion of four M. tuberculosis strains shaped the current tuberculosis epidemic in China, and highlight the long term genetic continuity of the indigenous M. tuberculosis population. PMID- 30397302 TI - Biomimicry can help humans to coexist sustainably with fire. PMID- 30397301 TI - A global test of ecoregions. AB - A foundational paradigm in biological and Earth sciences is that our planet is divided into distinct ecoregions and biomes demarking unique assemblages of species. This notion has profoundly influenced scientific research and environmental policy. Given recent advances in technology and data availability, however, we are now poised to ask whether ecoregions meaningfully delimit biological communities. Using over 200 million observations of plants, animals and fungi we show compelling evidence that ecoregions delineate terrestrial biodiversity patterns. We achieve this by testing two competing hypotheses: the sharp-transition hypothesis, positing that ecoregion borders divide differentiated biotic communities; and the gradual-transition hypothesis, proposing instead that species turnover is continuous and largely independent of ecoregion borders. We find strong support for the sharp-transition hypothesis across all taxa, although adherence to ecoregion boundaries varies across taxa. Although plant and vertebrate species are tightly linked to sharp ecoregion boundaries, arthropods and fungi show weaker affiliations to this set of ecoregion borders. Our results highlight the essential value of ecological data for setting conservation priorities and reinforce the importance of protecting habitats across as many ecoregions as possible. Specifically, we conclude that ecoregion-based conservation planning can guide investments that simultaneously protect species-, community- and ecosystem-level biodiversity, key for securing Earth's life support systems into the future. PMID- 30397304 TI - Wind farms have cascading impacts on ecosystems across trophic levels. AB - Wind farms are a cleaner alternative to fossil fuels for mitigating the effects of climate change, but they also have complex ecological consequences. In the biodiversity hotspot of the Western Ghats in India, we find that wind farms reduce the abundance and activity of predatory birds (for example, Buteo, Butastur and Elanus species), which consequently increases the density of lizards, Sarada superba. The cascading effects of wind turbines on lizards include changes in behaviour, physiology and morphology that reflect a combination of predator release and density-dependent competition. By adding an effective trophic level to the top of food webs, we find that wind farms have emerging impacts that are greatly underestimated. There is thus a strong need for an ecosystem-wide view when aligning green-energy goals with environment protection. PMID- 30397303 TI - A plant biodiversity effect resolved to a single chromosomal region. AB - Despite extensive evidence that biodiversity promotes plant community productivity, progress towards understanding the mechanistic basis of this effect remains slow, impeding the development of predictive ecological theory and agricultural applications. Here, we analysed non-additive interactions between genetically divergent Arabidopsis accessions in experimental plant communities. By combining methods from ecology and quantitative genetics, we identify a major effect locus at which allelic differences between individuals increase the above ground productivity of communities. In experiments with near-isogenic lines, we show that this diversity effect acts independently of other genomic regions and can be resolved to a single region representing less than 0.3% of the genome. Using plant-soil feedback experiments, we also demonstrate that allelic diversity causes genotype-specific soil legacy responses in a consecutive growing period, even after the original community has disappeared. Our work thus suggests that positive diversity effects can be linked to single Mendelian factors, and that a range of complex community properties can have a simple cause. This may pave the way to novel breeding strategies, focusing on phenotypic properties that manifest themselves beyond isolated individuals; that is, at a higher level of biological organization. PMID- 30397305 TI - Focus on a locus. PMID- 30397307 TI - Learning to be More Positive About FIT. AB - Systematic application of the fecal immunochemical test (FIT) as a screen for colorectal cancer has been shown to meaningfully impact colorectal cancer incidence and mortality. However, there is room for improvement. FIT performance is impacted by a host of patient level factors such as sex and medication use. Meta-analysis has defined those factors most likely to result in a false positive or false negative test. Further work determining how best to gather information on important factors and incorporate them into the FIT result will further enhance the accuracy and outcomes accomplished with this valuable screening test. PMID- 30397306 TI - Differential lateral and basal tension drive folding of Drosophila wing discs through two distinct mechanisms. AB - Epithelial folding transforms simple sheets of cells into complex three dimensional tissues and organs during animal development. Epithelial folding has mainly been attributed to mechanical forces generated by an apically localized actomyosin network, however, contributions of forces generated at basal and lateral cell surfaces remain largely unknown. Here we show that a local decrease of basal tension and an increased lateral tension, but not apical constriction, drive the formation of two neighboring folds in developing Drosophila wing imaginal discs. Spatially defined reduction of extracellular matrix density results in local decrease of basal tension in the first fold; fluctuations in F actin lead to increased lateral tension in the second fold. Simulations using a 3D vertex model show that the two distinct mechanisms can drive epithelial folding. Our combination of lateral and basal tension measurements with a mechanical tissue model reveals how simple modulations of surface and edge tension drive complex three-dimensional morphological changes. PMID- 30397309 TI - An efficient nanosieve. PMID- 30397308 TI - Epitaxial growth of ultraflat stanene with topological band inversion. AB - Two-dimensional (2D) topological materials, including quantum spin/anomalous Hall insulators, have attracted intense research efforts owing to their promise for applications ranging from low-power electronics and high-performance thermoelectrics to fault-tolerant quantum computation. One key challenge is to fabricate topological materials with a large energy gap for room-temperature use. Stanene-the tin counterpart of graphene-is a promising material candidate distinguished by its tunable topological states and sizeable bandgap. Recent experiments have successfully fabricated stanene, but none of them have yet observed topological states. Here we demonstrate the growth of high-quality stanene on Cu(111) by low-temperature molecular beam epitaxy. Importantly, we discovered an unusually ultraflat stanene showing an in-plane s-p band inversion together with a spin-orbit-coupling-induced topological gap (~0.3 eV) at the Gamma point, which represents a foremost group-IV ultraflat graphene-like material displaying topological features in experiment. The finding of ultraflat stanene opens opportunities for exploring two-dimensional topological physics and device applications. PMID- 30397310 TI - Whirling spins with a ferroelectric. PMID- 30397311 TI - Solving mazes with single-molecule DNA navigators. AB - Molecular devices with information-processing capabilities hold great promise for developing intelligent nanorobotics. Here we demonstrate a DNA navigator system that can perform single-molecule parallel depth-first search on a ten-vertex rooted tree defined on a two-dimensional DNA origami platform. Pathfinding by the DNA navigators exploits a localized strand exchange cascade, which is initiated at a unique trigger site on the origami with subsequent automatic progression along paths defined by DNA hairpins containing a universal traversal sequence. Each single-molecule navigator autonomously explores one of the possible paths through the tree. A specific solution path connecting a given pair of start and end vertices can then be easily extracted from the set of all paths taken by the navigators collectively. The solution path laid out on origami is illustrated with single-molecule imaging. Our approach points towards the realization of molecular materials with embedded computational functions operating at the single molecule level. PMID- 30397312 TI - Molecular sieving of ethylene from ethane using a rigid metal-organic framework. AB - There are great challenges in developing efficient adsorbents to replace the currently used and energy-intensive cryogenic distillation processes for olefin/paraffin separation, owing to the similar physical properties of the two molecules. Here we report an ultramicroporous metal-organic framework [Ca(C4O4)(H2O)], synthesized from calcium nitrate and squaric acid, that possesses rigid one-dimensional channels. These apertures are of a similar size to ethylene molecules, but owing to the size, shape and rigidity of the pores, act as molecular sieves to prevent the transport of ethane. The efficiency of this molecular sieve for the separation of ethylene/ethane mixtures is validated by breakthrough experiments with high ethylene productivity under ambient conditions. This material can be easily synthesized at the kilogram scale using an environmentally friendly method and is water-stable, which is important for potential industrial implementation. The strategy of using highly rigid metal organic frameworks with well defined and rigid pores could also be extended to other porous materials for chemical separation processes. PMID- 30397313 TI - Ferroelectrically tunable magnetic skyrmions in ultrathin oxide heterostructures. AB - Magnetic skyrmions are topologically protected whirling spin texture. Their nanoscale dimensions, topologically protected stability and solitonic nature, together are promising for future spintronics applications. To translate these compelling features into practical spintronic devices, a key challenge lies in achieving effective control of skyrmion properties, such as size, density and thermodynamic stability. Here, we report the discovery of ferroelectrically tunable skyrmions in ultrathin BaTiO3/SrRuO3 bilayer heterostructures. The ferroelectric proximity effect at the BaTiO3/SrRuO3 heterointerface triggers a sizeable Dzyaloshinskii-Moriya interaction, thus stabilizing robust skyrmions with diameters less than a hundred nanometres. Moreover, by manipulating the ferroelectric polarization of the BaTiO3 layer, we achieve local, switchable and nonvolatile control of both skyrmion density and thermodynamic stability. This ferroelectrically tunable skyrmion system can simultaneously enhance the integratability and addressability of skyrmion-based functional devices. PMID- 30397316 TI - CLN8 safeguards lysosome biogenesis. PMID- 30397314 TI - CLN8 is an endoplasmic reticulum cargo receptor that regulates lysosome biogenesis. AB - Organelle biogenesis requires proper transport of proteins from their site of synthesis to their target subcellular compartment1-3. Lysosomal enzymes are synthesized in the endoplasmic reticulum (ER) and traffic through the Golgi complex before being transferred to the endolysosomal system4-6, but how they are transferred from the ER to the Golgi is unknown. Here, we show that ER-to-Golgi transfer of lysosomal enzymes requires CLN8, an ER-associated membrane protein whose loss of function leads to the lysosomal storage disorder, neuronal ceroid lipofuscinosis 8 (a type of Batten disease)7. ER-to-Golgi trafficking of CLN8 requires interaction with the COPII and COPI machineries via specific export and retrieval signals localized in the cytosolic carboxy terminus of CLN8. CLN8 deficiency leads to depletion of soluble enzymes in the lysosome, thus impairing lysosome biogenesis. Binding to lysosomal enzymes requires the second luminal loop of CLN8 and is abolished by some disease-causing mutations within this region. Our data establish an unanticipated example of an ER receptor serving the biogenesis of an organelle and indicate that impaired transport of lysosomal enzymes underlies Batten disease caused by mutations in CLN8. PMID- 30397315 TI - A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation. AB - Mammalian SWI/SNF chromatin remodelling complexes exist in three distinct, final form assemblies: canonical BAF (cBAF), PBAF and a newly characterized non canonical complex (ncBAF). However, their complex-specific targeting on chromatin, functions and roles in disease remain largely undefined. Here, we comprehensively mapped complex assemblies on chromatin and found that ncBAF complexes uniquely localize to CTCF sites and promoters. We identified ncBAF subunits as synthetic lethal targets specific to synovial sarcoma and malignant rhabdoid tumours, which both exhibit cBAF complex (SMARCB1 subunit) perturbation. Chemical and biological depletion of the ncBAF subunit, BRD9, rapidly attenuates synovial sarcoma and malignant rhabdoid tumour cell proliferation. Importantly, in cBAF-perturbed cancers, ncBAF complexes maintain gene expression at retained CTCF-promoter sites and function in a manner distinct from fusion oncoprotein bound complexes. Together, these findings unmask the unique targeting and functional roles of ncBAF complexes and present new cancer-specific therapeutic targets. PMID- 30397318 TI - Staining a porous catalyst. PMID- 30397317 TI - A genetically encoded photosensitizer protein facilitates the rational design of a miniature photocatalytic CO2-reducing enzyme. AB - Photosensitizers, which harness light energy to upgrade weak reductants to strong reductants, are pivotal components of the natural and artificial photosynthesis machineries. However, it has proved difficult to enhance and expand their functions through genetic engineering. Here we report a genetically encoded, 27 kDa photosensitizer protein (PSP), which facilitates the rational design of miniature photocatalytic CO2-reducing enzymes. Visible light drives PSP efficiently into a long-lived triplet excited state (PSP*), which reacts rapidly with reduced nicotinamide adenine dinucleotide to generate a super-reducing radical (PSP*), which is strong enough to reduce many CO2-reducing catalysts. We determined the three-dimensional structure of PSP* at 1.8 A resolution by X-ray crystallography. Genetic engineering enabled the site-specific attachment of a nickel-terpyridine complex and the modular optimization of the photochemical properties of PSP, the chromophore/catalytic centre distance and the catalytic centre microenvironment, which culminated in a miniature photocatalytic CO2 reducing enzyme that has a CO2/CO conversion quantum efficiency of 2.6%. PMID- 30397319 TI - Visualizing pore architecture and molecular transport boundaries in catalyst bodies with fluorescent nanoprobes. AB - The performances of porous materials are closely related to the accessibility and interconnectivity of their porous domains. Visualizing pore architecture and its role on functionality-for example, mass transport-has been a challenge so far, and traditional bulk and often non-visual pore measurements have to suffice in most cases. Here, we present an integrated, facile fluorescence microscopy approach to visualize the pore accessibility and interconnectivity of industrial grade catalyst bodies, and link it unequivocally with their catalytic performance. Fluorescent nanoprobes of various sizes were imaged and correlated with the molecular transport of fluorescent molecules formed during a separate catalytic reaction. A direct visual relationship between the pore architecture which depends on the pore sizes and interconnectivity of the material selected and molecular transport was established. This approach can be applied to other porous materials, and the insight gained may prove useful in the design of more efficient heterogeneous catalysts. PMID- 30397320 TI - A chemoselective strategy for late-stage functionalization of complex small molecules with polypeptides and proteins. AB - Conjugates between proteins and small molecules enable access to a vast chemical space that is not achievable with either type of molecule alone; however, the paucity of specific reactions capable of functionalizing proteins and natural products presents a formidable challenge for preparing conjugates. Here we report a strategy for conjugating electron-rich (hetero)arenes to polypeptides and proteins. Our bioconjugation technique exploits the electrophilic reactivity of an oxidized selenocysteine residue in polypeptides and proteins, and the electron rich character of certain small molecules to provide bioconjugates in excellent yields under mild conditions. This conjugation chemistry enabled the synthesis of peptide-vancomycin conjugates without the prefunctionalization of vancomycin. These conjugates have an enhanced in vitro potency for resistant Gram-positive and Gram-negative pathogens. Additionally, we show that a 6 kDa affibody protein and a 150 kDa immunoglobulin-G antibody could be modified without diminishing bioactivity. PMID- 30397321 TI - Catalytic activation of unstrained C(aryl)-C(aryl) bonds in 2,2'-biphenols. AB - Transition metal catalysis has emerged as an important means for C-C activation that allows mild and selective transformations. However, the current scope of C-C bonds that can be activated is primarily restricted to either highly strained systems or more polarized C-C bonds. In contrast, the catalytic activation of non polar and unstrained C-C moieties remains an unmet challenge. Here we report a general approach for the catalytic activation of the unstrained C(aryl)-C(aryl) bonds in 2,2'-biphenols. The key is to utilize the phenol moiety as a handle to install phosphinites as a recyclable directing group. Using hydrogen gas as the reductant, monophenols are obtained with a low catalyst loading and high functional group tolerance. This approach is also applied to the synthesis of 2,3,4-trisubstituted phenols. A further mechanistic study suggests that the C-C activation step is mediated by a rhodium(I) monohydride species. Finally, a preliminary study on breaking the inert biphenolic moieties in lignin models is illustrated. PMID- 30397322 TI - Towards a neuroscience of active sampling and curiosity. AB - In natural behaviour, animals actively interrogate their environments using endogenously generated 'question-and-answer' strategies. However, in laboratory settings participants typically engage with externally imposed stimuli and tasks, and the mechanisms of active sampling remain poorly understood. We review a nascent neuroscientific literature that examines active-sampling policies and their relation to attention and curiosity. We distinguish between information sampling, in which organisms reduce uncertainty relevant to a familiar task, and information search, in which they investigate in an open-ended fashion to discover new tasks. We review evidence that both sampling and search depend on individual preferences over cognitive states, including attitudes towards uncertainty, learning progress and types of information. We propose that, although these preferences are non-instrumental and can on occasion interfere with external goals, they are important heuristics that allow organisms to cope with the high complexity of both sampling and search, and generate curiosity driven investigations in large, open environments in which rewards are sparse and ex ante unknown. PMID- 30397323 TI - Nearly significant if only.... PMID- 30397324 TI - Fabrication of highly effective hybrid biofuel cell based on integral colloidal platinum and bilirubin oxidase on gold support. AB - A hybrid biofuel cell (HBFC) is explored as a low-cost alternative to abiotic and enzymatic biofuel cells. Here the HBFC provides an enzymeless approach for the fabrication of the anodic electrode while employing an enzymatic approach for the fabrication of the cathodic electrode to develop energy harvesting platform to power bioelectronic devices. The anode employed 250 MUm braided gold wire modified with colloidal platinum (Au-co-Pt) and bilirubin oxidase (BODx) modified gold coated Buckypaper (BP-Au-BODx) cathode. The functionalization of the gold coated multi-walled carbon nanotube (MWCNT) structures of the BP electrodes is achieved by 3-mercaptopropionic acid surface modification to possess negatively charged carboxylic groups and subsequently followed by EDC/Sulfo-NHS (1-Ethyl-3 (3-dimethylaminopropyl) carbodiimide hydrochloride and N-Hydroxysulfosuccinimide) crosslinking with BODx. The integration of the BODx and gold coated MWCNTs is evaluated for bioelectrocatalytic activity. The Au-co-Pt and BP-Au-BODx exhibited excellent electrocatalytic activity towards glucose oxidation with a linear dynamic range up to 20 mM glucose and molecular oxygen reduction, respectively. The HBFC demonstrated excellent performance with the largest open circuit voltages of 0.735 V and power density of 46.31 MUW/cm2 in 3 mM glucose. In addition, the HBFC operating on 3 mM glucose exhibited excellent uninterrupted operational stability while continuously powering a small electronic device. These results provide great opportunities for implementing this simple but efficient HBFC to harvest the biochemical energy of target fuel(s) in diverse medical and environmental applications. PMID- 30397326 TI - Nanobody immunostaining for correlated light and electron microscopy with preservation of ultrastructure. AB - Morphological and molecular characteristics determine the function of biological tissues. Attempts to combine immunofluorescence and electron microscopy invariably compromise the quality of the ultrastructure of tissue sections. We developed NATIVE, a correlated light and electron microscopy approach that preserves ultrastructure while showing the locations of multiple molecular moieties, even deep within tissues. This technique allowed the large-scale 3D reconstruction of a volume of mouse hippocampal CA3 tissue at nanometer resolution. PMID- 30397327 TI - Publisher Correction: Transparent Danionella translucida as a genetically tractable vertebrate brain model. AB - The version of this paper originally published contained errors in reference citations: in the first paragraph of the Results section, the text "This extent of optical clarity probably results from the absence of skull above the brain22. In our specimens, Nissl-stained coronal sections through the head showed that the skull surrounds the brain only laterally and ventrally" should have read "This extent of optical clarity probably results from the absence of skull above the brain21. In our specimens, Nissl-stained coronal sections through the head22 showed that the skull surrounds the brain only laterally and ventrally." In addition, the unit abbreviation "MUm" was incorrectly divided at a line break in the third paragraph of the Discussion, which might have led to some confusion. These errors have been corrected in the PDF and HTML versions of the article. PMID- 30397328 TI - HIP1R targets PD-L1 to lysosomal degradation to alter T cell-mediated cytotoxicity. AB - Expression of programmed cell death 1 (PD-1) ligand 1 (PD-L1) protects tumor cells from T cell-mediated immune surveillance, and immune checkpoint blockade (ICB) therapies targeting PD-1 and PD-L1 have exhibited significant clinical benefits. However, the relatively low response rate and observed ICB resistance highlight the need to understand the molecular regulation of PD-L1. Here we show that HIP1R targets PD-L1 to lysosomal degradation to alter T cell-mediated cytotoxicity. HIP1R physically interacts with PD-L1 and delivers PD-L1 to the lysosome through a lysosomal targeting signal. Depletion of HIP1R in tumor cells caused PD-L1 accumulation and suppressed T cell-mediated cytotoxicity. A rationally designed peptide (PD-LYSO) incorporating the lysosome-sorting signal and the PD-L1-binding sequence of HIP1R successfully depleted PD-L1 expression in tumor cells. Our results identify the molecular machineries governing the lysosomal degradation of PD-L1 and exemplify the development of a chimeric peptide for targeted degradation of PD-L1 as a crucial anticancer target. PMID- 30397329 TI - Penis evolution across species: divergence and diversity. AB - The penis is an incredibly diverse and rapidly evolving structure, such that even in closely related species that otherwise differ very little in their morphology, penis form can be highly differentiated. Penises are also much more complex than their fundamental function - sperm transfer - would seem to require. The rapid divergent evolution of male structures is typically the signature of traits under sexual selection and the current evidence suggests the penis is no different in this regard. Despite the general agreement that sexual selection is the main driver of penis evolution, many questions about penis evolution remain unresolved. Furthermore, the penis might be an ideal characteristic on which to focus in the drive to link phenotype with genotype. PMID- 30397330 TI - Nonsurgical management of Peyronie's disease. AB - Peyronie's disease is not a rare disorder, and it can be devastating to the affected man. Although the gold-standard treatment of Peyronie's disease is surgery in the stable phase, nonoperative management is preferred by some men and is the only treatment option in the acute phase of the disease, when surgery is contraindicated. No oral or topical therapy has been shown to be efficacious when administered alone, but some evidence supports their use as part of a combination therapy regimen. Intralesional therapies, particularly collagenase clostridium histolyticum (CCH), have shown promise. Mechanical therapies can provide benefit when applied for prolonged periods of time, improving penile curvature, indentation, and even restoring length. Regardless of the modality chosen, patient counselling is paramount, as recovery of the penis to its predisease state is highly unlikely. Thus, although many options exist for nonsurgical management of Peyronie's disease, surgery remains the best option for men who desire the most reliable and rapid pathway to a functionally straight, erect penis. The goal of nonsurgical therapy should be a scientifically feasible, safe approach to prevent the progression of, or reduce, deformity and improve sexual function. PMID- 30397331 TI - Survival data from PALOMA-3 reported. PMID- 30397325 TI - Partial loss of psychiatric risk gene Mir137 in mice causes repetitive behavior and impairs sociability and learning via increased Pde10a. AB - Genetic analyses have linked microRNA-137 (MIR137) to neuropsychiatric disorders, including schizophrenia and autism spectrum disorder. miR-137 plays important roles in neurogenesis and neuronal maturation, but the impact of miR-137 loss-of function in vivo remains unclear. Here we show the complete loss of miR-137 in the mouse germline knockout or nervous system knockout (cKO) leads to postnatal lethality, while heterozygous germline knockout and cKO mice remain viable. Partial loss of miR-137 in heterozygous cKO mice results in dysregulated synaptic plasticity, repetitive behavior, and impaired learning and social behavior. Transcriptomic and proteomic analyses revealed that the miR-137 mRNA target, phosphodiesterase 10a (Pde10a), is elevated in heterozygous knockout mice. Treatment with the Pde10a inhibitor papaverine or knockdown of Pde10a ameliorates the deficits observed in the heterozygous cKO mice. Collectively, our results suggest that MIR137 plays essential roles in postnatal neurodevelopment and that dysregulation of miR-137 potentially contributes to neuropsychiatric disorders in humans. PMID- 30397332 TI - Mapping innate variation. PMID- 30397333 TI - Comparative genomics of the major parasitic worms. AB - Parasitic nematodes (roundworms) and platyhelminths (flatworms) cause debilitating chronic infections of humans and animals, decimate crop production and are a major impediment to socioeconomic development. Here we report a broad comparative study of 81 genomes of parasitic and non-parasitic worms. We have identified gene family births and hundreds of expanded gene families at key nodes in the phylogeny that are relevant to parasitism. Examples include gene families that modulate host immune responses, enable parasite migration though host tissues or allow the parasite to feed. We reveal extensive lineage-specific differences in core metabolism and protein families historically targeted for drug development. From an in silico screen, we have identified and prioritized new potential drug targets and compounds for testing. This comparative genomics resource provides a much-needed boost for the research community to understand and combat parasitic worms. PMID- 30397334 TI - Whole-genome sequencing of 175 Mongolians uncovers population-specific genetic architecture and gene flow throughout North and East Asia. AB - The genetic variation in Northern Asian populations is currently undersampled. To address this, we generated a new genetic variation reference panel by whole genome sequencing of 175 ethnic Mongolians, representing six tribes. The cataloged variation in the panel shows strong population stratification among these tribes, which correlates with the diverse demographic histories in the region. Incorporating our results with the 1000 Genomes Project panel identifies derived alleles shared between Finns and Mongolians/Siberians, suggesting that substantial gene flow between northern Eurasian populations has occurred in the past. Furthermore, we highlight that North, East, and Southeast Asian populations are more aligned with each other than these groups are with South Asian and Oceanian populations. PMID- 30397336 TI - Identification of phagocytosis regulators using magnetic genome-wide CRISPR screens. AB - Phagocytosis is required for a broad range of physiological functions, from pathogen defense to tissue homeostasis, but the mechanisms required for phagocytosis of diverse substrates remain incompletely understood. Here, we developed a rapid magnet-based phenotypic screening strategy, and performed eight genome-wide CRISPR screens in human cells to identify genes regulating phagocytosis of distinct substrates. After validating select hits in focused miniscreens, orthogonal assays and primary human macrophages, we show that (1) the previously uncharacterized gene NHLRC2 is a central player in phagocytosis, regulating RhoA-Rac1 signaling cascades that control actin polymerization and filopodia formation, (2) very-long-chain fatty acids are essential for efficient phagocytosis of certain substrates and (3) the previously uncharacterized Alzheimer's disease-associated gene TM2D3 can preferentially influence uptake of amyloid-beta aggregates. These findings illuminate new regulators and core principles of phagocytosis, and more generally establish an efficient method for unbiased identification of cellular uptake mechanisms across diverse physiological and pathological contexts. PMID- 30397337 TI - A deep learning approach to automate refinement of somatic variant calling from cancer sequencing data. AB - Cancer genomic analysis requires accurate identification of somatic variants in sequencing data. Manual review to refine somatic variant calls is required as a final step after automated processing. However, manual variant refinement is time consuming, costly, poorly standardized, and non-reproducible. Here, we systematized and standardized somatic variant refinement using a machine learning approach. The final model incorporates 41,000 variants from 440 sequencing cases. This model accurately recapitulated manual refinement labels for three independent testing sets (13,579 variants) and accurately predicted somatic variants confirmed by orthogonal validation sequencing data (212,158 variants). The model improves on manual somatic refinement by reducing bias on calls otherwise subject to high inter-reviewer variability. PMID- 30397335 TI - Retinoic acid and BMP4 cooperate with p63 to alter chromatin dynamics during surface epithelial commitment. AB - Human embryonic stem cell (hESC) differentiation promises advances in regenerative medicine1-3, yet conversion of hESCs into transplantable cells or tissues remains poorly understood. Using our keratinocyte differentiation system, we employ a multi-dimensional genomics approach to interrogate the contributions of inductive morphogens retinoic acid and bone morphogenetic protein 4 (BMP4) and the epidermal master regulator p63 (encoded by TP63)4,5 during surface ectoderm commitment. In contrast to other master regulators6-9, p63 effects major transcriptional changes only after morphogens alter chromatin accessibility, establishing an epigenetic landscape for p63 to modify. p63 distally closes chromatin accessibility and promotes accumulation of H3K27me3 (trimethylated histone H3 lysine 27). Cohesin HiChIP10 visualizations of chromosome conformation show that p63 and the morphogens contribute to dynamic long-range chromatin interactions, as illustrated by TFAP2C regulation11. Our study demonstrates the unexpected dependency of p63 on morphogenetic signaling and provides novel insights into how a master regulator can specify diverse transcriptional programs based on the chromatin landscape induced by exposure to specific morphogens. PMID- 30397338 TI - Multiple transmissions of de novo mutations in families. AB - De novo mutations (DNMs) cause a large proportion of severe rare diseases of childhood. DNMs that occur early may result in mosaicism of both somatic and germ cells. Such early mutations can cause recurrence of disease. We scanned 1,007 sibling pairs from 251 families and identified 878 DNMs shared by siblings (ssDNMs) at 448 genomic sites. We estimated DNM recurrence probability based on parental mosaicism, sharing of DNMs among siblings, parent-of-origin, mutation type and genomic position. We detected 57.2% of ssDNMs in the parental blood. The recurrence probability of a DNM decreases by 2.27% per year for paternal DNMs and 1.78% per year for maternal DNMs. Maternal ssDNMs are more likely to be T>C mutations than paternal ssDNMs, and less likely to be C>T mutations. Depending on the properties of the DNM, the recurrence probability ranges from 0.011% to 28.5%. We have launched an online calculator to allow estimation of DNM recurrence probability for research purposes. PMID- 30397339 TI - Author Correction: Public resources aid diabetes gene discovery. AB - In the version of this article originally published, the text was incorrect in the first paragraph of the 'Remaining challenges' section. The first two sentences appeared as "Even though this current study substantially increases the number of loci associated with T2D, only approximately 18% of the genetic component of T2D risk is explained by the total complement of genetic variants uncovered genome wide in Mahajan et al.6. Interestingly, only a small proportion of that heritability was explained by low-frequency or rare variants (~1.1%), thus potentially indicating that many more of these variants still remain to be characterized in even larger sample sizes." However, they should have read "Even though this current study substantially increases the number of loci associated with T2D, only a proportion of the genetic component of T2D risk is explained by the total complement of genetic variants uncovered genome wide in Mahajan et al.6. Interestingly, only a relatively small proportion of that heritability was explained by low-frequency or rare variants, thus potentially indicating that many more of these variants still remain to be characterized in even larger sample sizes." The text has been corrected in the HTML and PDF versions of the paper. PMID- 30397340 TI - A Chlamydia effector combining deubiquitination and acetylation activities induces Golgi fragmentation. AB - Pathogenic bacteria are armed with potent effector proteins that subvert host signalling processes during infection1. The activities of bacterial effectors and their associated roles within the host cell are often poorly understood, particularly for Chlamydia trachomatis2, a World Health Organization designated neglected disease pathogen. We identify and explain remarkable dual Lys63 deubiquitinase (DUB) and Lys-acetyltransferase activities in the Chlamydia effector ChlaDUB1. Crystal structures capturing intermediate stages of each reaction reveal how the same catalytic centre of ChlaDUB1 can facilitate such distinct processes, and enable the generation of mutations that uncouple the two activities. Targeted Chlamydia mutant strains allow us to link the DUB activity of ChlaDUB1 and the related, dedicated DUB ChlaDUB2 to fragmentation of the host Golgi apparatus, a key process in Chlamydia infection for which effectors have remained elusive. Our work illustrates the incredible versatility of bacterial effector proteins, and provides important insights towards understanding Chlamydia pathogenesis. PMID- 30397341 TI - Atomic structures of enterovirus D68 in complex with two monoclonal antibodies define distinct mechanisms of viral neutralization. AB - Enterovirus D68 (EV-D68) undergoes structural transformation between mature, cell entry intermediate (A-particle) and empty forms throughout its life cycle. Structural information for the various forms and antibody-bound capsids will facilitate the development of effective vaccines and therapeutics against EV-D68 infection, which causes childhood respiratory and paralytic diseases worldwide. Here, we report the structures of three EV-D68 capsid states representing the virus at major phases. We further describe two original monoclonal antibodies (15C5 and 11G1) with distinct structurally defined mechanisms for virus neutralization. 15C5 and 11G1 engage the capsid loci at icosahedral three-fold and five-fold axes, respectively. To block viral attachment, 15C5 binds three forms of capsids, and triggers mature virions to transform into A-particles, mimicking engagement by the functional receptor ICAM-5, whereas 11G1 exclusively recognizes the A-particle. Our data provide a structural and molecular explanation for the transition of picornavirus capsid conformations and demonstrate distinct mechanisms for antibody-mediated neutralization. PMID- 30397342 TI - Ecological selection for small microbial genomes along a temperate-to-thermal soil gradient. AB - Small bacterial and archaeal genomes provide insights into the minimal requirements for life1 and are phylogenetically widespread2. However, the precise environmental pressures that constrain genome size in free-living microorganisms are unknown. A study including isolates has shown that thermophiles and other bacteria with high optimum growth temperatures often have small genomes3. It is unclear whether this relationship extends generally to microorganisms in nature4,5 and more specifically to microorganisms that inhabit complex and highly variable environments, such as soils3,6,7. To understand the genomic traits of thermally adapted microorganisms, here we investigated metagenomes from a 45 degrees C gradient of temperate-to-thermal soils that lie over the ongoing Centralia, Pennsylvania (USA) coal-seam fire. We found that hot soils harboured distinct communities with small genomes and small cell sizes relative to those in ambient soils. Hot soils notably lacked genes that encode known two-component regulatory systems, and antimicrobial production and resistance genes. Our results provide field evidence for the inverse relationship between microbial genome size and temperature in a diverse, free-living community over a wide range of temperatures that support microbial life. PMID- 30397343 TI - Type IV CRISPR RNA processing and effector complex formation in Aromatoleum aromaticum. AB - Type IV CRISPR-Cas modules belong to class 1 prokaryotic adaptive immune systems, which are defined by the presence of multisubunit effector complexes. They usually lack the known Cas proteins involved in adaptation and target cleavage, and their function has not been experimentally addressed. To investigate RNA and protein components of this CRISPR-Cas type, we located a complete type IV cas gene locus and an adjacent CRISPR array on a megaplasmid of Aromatoleum aromaticum EbN1, which contains an additional type I-C system on its chromosome. RNA sequencing analyses verified CRISPR RNA (crRNA) production and maturation for both systems. Type IV crRNAs were shown to harbour unusually short 7 nucleotide 5'-repeat tags and stable 3' hairpin structures. A unique Cas6 variant (Csf5) was identified that generates crRNAs that are specifically incorporated into type IV CRISPR-ribonucleoprotein (crRNP) complexes. Structures of RNA-bound Csf5 were obtained. Recombinant production and purification of the type IV Cas proteins, together with electron microscopy, revealed that Csf2 acts as a helical backbone for type IV crRNPs that include Csf5, Csf3 and a large subunit (Csf1). Mass spectrometry analyses identified protein-protein and protein-RNA contact sites. These results highlight evolutionary connections between type IV and type I CRISPR-Cas systems and demonstrate that type IV CRISPR-Cas systems employ crRNA guided effector complexes. PMID- 30397345 TI - Repeated multi-qubit readout and feedback with a mixed-species trapped-ion register. AB - Quantum error correction is essential for realizing the full potential of large scale quantum information processing devices1,2. Fundamental to its experimental realization is the repetitive detection of errors via projective measurements of quantum correlations among qubits, as well as corrections using conditional feedback3. Repetitive application of such tasks requires that they neither induce unwanted crosstalk nor impede further control operations, which is challenging owing to the need to dissipatively couple qubits to the classical world for detection and reinitialization. For trapped ions, state readout involves scattering large numbers of resonant photons, which increases the probability of stray light causing errors on nearby qubits and leads to undesirable recoil heating of the ion motion. Here we demonstrate up to 50 sequential measurements of correlations between two beryllium ion microwave qubits using an ancillary optical qubit in a calcium ion, and implement feedback that allows us to stabilize two-qubit subspaces as well as Bell states, a class of maximally entangled states. Multi-qubit mixed-species gates are used to transfer information within the register from the qubit to the ancilla, enabling readout with negligible crosstalk to the data qubits. Heating of the ion motion during detection is mitigated by recooling all three ions using light that interacts with only the calcium ion, known as sympathetic cooling. A key element of our experimental setup is a powerful classical control system that features flexible in-sequence processing for feedback control. The methods employed here provide essential tools for scaling trapped-ion quantum computing, quantum-state control and entanglement-enhanced quantum metrology4. PMID- 30397344 TI - Interactions between Roseburia intestinalis and diet modulate atherogenesis in a murine model. AB - Humans with metabolic and inflammatory diseases frequently harbour lower levels of butyrate-producing bacteria in their gut. However, it is not known whether variation in the levels of these organisms is causally linked with disease development and whether diet modifies the impact of these bacteria on health. Here we show that a prominent gut-associated butyrate-producing bacterial genus (Roseburia) is inversely correlated with atherosclerotic lesion development in a genetically diverse mouse population. We use germ-free apolipoprotein E-deficient mice colonized with synthetic microbial communities that differ in their capacity to generate butyrate to demonstrate that Roseburia intestinalis interacts with dietary plant polysaccharides to: impact gene expression in the intestine, directing metabolism away from glycolysis and toward fatty acid utilization; lower systemic inflammation; and ameliorate atherosclerosis. Furthermore, intestinal administration of butyrate reduces endotoxaemia and atherosclerosis development. Together, our results illustrate how modifiable diet-by-microbiota interactions impact cardiovascular disease, and suggest that interventions aimed at increasing the representation of butyrate-producing bacteria may provide protection against atherosclerosis. PMID- 30397346 TI - Publisher Correction: Antibody and TLR7 agonist delay viral rebound in SHIV infected monkeys. AB - In Fig. 4b of this Article, the x-axis labels 'PGT121' and 'GS-9620' were inadvertently swapped in both graphs. In Fig. 5a, b, 'TLR7' should have been 'GS 9620'. These figures have been corrected online. PMID- 30397347 TI - Publisher Correction: Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease. AB - Change history: In this Article, Extended Data Fig. 9 was appearing as Fig. 2 in the HTML, and in Fig. 2, the panel labels 'n' and 'o' overlapped the figure; these errors have been corrected online. PMID- 30397348 TI - Tumor immunoevasion via acidosis-dependent induction of regulatory tumor associated macrophages. AB - Many tumors evolve sophisticated strategies to evade the immune system, and these represent major obstacles for efficient antitumor immune responses. Here we explored a molecular mechanism of metabolic communication deployed by highly glycolytic tumors for immunoevasion. In contrast to colon adenocarcinomas, melanomas showed comparatively high glycolytic activity, which resulted in high acidification of the tumor microenvironment. This tumor acidosis induced Gprotein coupled receptor-dependent expression of the transcriptional repressor ICER in tumor-associated macrophages that led to their functional polarization toward a non-inflammatory phenotype and promoted tumor growth. Collectively, our findings identify a molecular mechanism of metabolic communication between non-lymphoid tissue and the immune system that was exploited by high-glycolytic-rate tumors for evasion of the immune system. PMID- 30397351 TI - Tumors sweeten macrophages with acids. PMID- 30397352 TI - Leon Lederman (1922-2018). PMID- 30397350 TI - Human retinoic acid-regulated CD161+ regulatory T cells support wound repair in intestinal mucosa. AB - Repair of tissue damaged during inflammatory processes is key to the return of local homeostasis and restoration of epithelial integrity. Here we describe CD161+ regulatory T (Treg) cells as a distinct, highly suppressive population of Treg cells that mediate wound healing. These Treg cells were enriched in intestinal lamina propria, particularly in Crohn's disease. CD161+ Treg cells had an all-trans retinoic acid (ATRA)-regulated gene signature, and CD161 expression on Treg cells was induced by ATRA, which directly regulated the CD161 gene. CD161 was co-stimulatory, and ligation with the T cell antigen receptor induced cytokines that accelerated the wound healing of intestinal epithelial cells. We identified a transcription-factor network, including BACH2, RORgammat, FOSL2, AP 1 and RUNX1, that controlled expression of the wound-healing program, and found a CD161+ Treg cell signature in Crohn's disease mucosa associated with reduced inflammation. These findings identify CD161+ Treg cells as a population involved in controlling the balance between inflammation and epithelial barrier healing in the gut. PMID- 30397349 TI - Autocrine-paracrine prostaglandin E2 signaling restricts TLR4 internalization and TRIF signaling. AB - The unique cell biology of Toll-like receptor 4 (TLR4) allows it to initiate two signal-transduction cascades: a signal dependent on the adaptors TIRAP (Mal) and MyD88 that begins at the cell surface and regulates proinflammatory cytokines, and a signal dependent on the adaptors TRAM and TRIF that begins in the endosomes and drives the production of type I interferons. Negative feedback circuits to limit TLR4 signals from both locations are necessary to balance the inflammatory response. We describe a negative feedback loop driven by autocrine-paracrine prostaglandin E2 (PGE2) and the PGE2 receptor EP4 that restricted TRIF-dependent signals and the induction of interferon-beta through the regulation of TLR4 trafficking. Inhibition of PGE2 production or antagonism of EP4 increased the rate at which TLR4 translocated to endosomes and amplified TRIF-dependent activation of the transcription factor IRF3 and caspase-8. This PGE2-driven mechanism restricted TLR4-TRIF signaling in vitro after infection of macrophages by the Gram-negative pathogens Escherichia coli or Citrobacter rodentium and protected mice against mortality induced by Salmonella enteritidis serovar Typhimurium. Thus, PGE2 restricted TLR4-TRIF signaling specifically in response to lipopolysaccharide. PMID- 30397353 TI - Radiotherapy induces responses of lung cancer to CTLA-4 blockade. AB - Focal radiation therapy enhances systemic responses to anti-CTLA-4 antibodies in preclinical studies and in some patients with melanoma1-3, but its efficacy in inducing systemic responses (abscopal responses) against tumors unresponsive to CTLA-4 blockade remained uncertain. Radiation therapy promotes the activation of anti-tumor T cells, an effect dependent on type I interferon induction in the irradiated tumor4-6. The latter is essential for achieving abscopal responses in murine cancers6. The mechanisms underlying abscopal responses in patients treated with radiation therapy and CTLA-4 blockade remain unclear. Here we report that radiation therapy and CTLA-4 blockade induced systemic anti-tumor T cells in chemo-refractory metastatic non-small-cell lung cancer (NSCLC), where anti-CTLA-4 antibodies had failed to demonstrate significant efficacy alone or in combination with chemotherapy7,8. Objective responses were observed in 18% of enrolled patients, and 31% had disease control. Increased serum interferon-beta after radiation and early dynamic changes of blood T cell clones were the strongest response predictors, confirming preclinical mechanistic data. Functional analysis in one responding patient showed the rapid in vivo expansion of CD8 T cells recognizing a neoantigen encoded in a gene upregulated by radiation, supporting the hypothesis that one explanation for the abscopal response is radiation induced exposure of immunogenic mutations to the immune system. PMID- 30397355 TI - A patient-level pooled analysis of treatment-shortening regimens for drug susceptible pulmonary tuberculosis. AB - Tuberculosis kills more people than any other infectious disease. Three pivotal trials testing 4-month regimens failed to meet non-inferiority margins; however, approximately four-fifths of participants were cured. Through a pooled analysis of patient-level data with external validation, we identify populations eligible for 4-month treatment, define phenotypes that are hard to treat and evaluate the impact of adherence and dosing strategy on outcomes. In 3,405 participants included in analyses, baseline smear grade of 3+ relative to <2+, HIV seropositivity and adherence of <=90% were significant risk factors for unfavorable outcome. Four-month regimens were non-inferior in participants with minimal disease defined by <2+ sputum smear grade or non-cavitary disease. A hard to-treat phenotype, defined by high smear grades and cavitation, may require durations >6 months to cure all. Regimen duration can be selected in order to improve outcomes, providing a stratified medicine approach as an alternative to the 'one-size-fits-all' treatment currently used worldwide. PMID- 30397354 TI - Cancer cells exploit an orphan RNA to drive metastatic progression. AB - Here we performed a systematic search to identify breast-cancer-specific small noncoding RNAs, which we have collectively termed orphan noncoding RNAs (oncRNAs). We subsequently discovered that one of these oncRNAs, which originates from the 3' end of TERC, acts as a regulator of gene expression and is a robust promoter of breast cancer metastasis. This oncRNA, which we have named T3p, exerts its prometastatic effects by acting as an inhibitor of RISC complex activity and increasing the expression of the prometastatic genes NUPR1 and PANX2. Furthermore, we have shown that oncRNAs are present in cancer-cell-derived extracellular vesicles, raising the possibility that these circulating oncRNAs may also have a role in non-cell autonomous disease pathogenesis. Additionally, these circulating oncRNAs present a novel avenue for cancer fingerprinting using liquid biopsies. PMID- 30397356 TI - Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. AB - The anti-hyperglycemic effect of metformin is believed to be caused by its direct action on signaling processes in hepatocytes, leading to lower hepatic gluconeogenesis. Recently, metformin was reported to alter the gut microbiota community in humans, suggesting that the hyperglycemia-lowering action of the drug could be the result of modulating the population of gut microbiota. However, the critical microbial signaling metabolites and the host targets associated with the metabolic benefits of metformin remained elusive. Here, we performed metagenomic and metabolomic analysis of samples from individuals with newly diagnosed type 2 diabetes (T2D) naively treated with metformin for 3 d, which revealed that Bacteroides fragilis was decreased and the bile acid glycoursodeoxycholic acid (GUDCA) was increased in the gut. These changes were accompanied by inhibition of intestinal farnesoid X receptor (FXR) signaling. We further found that high-fat-diet (HFD)-fed mice colonized with B. fragilis were predisposed to more severe glucose intolerance, and the metabolic benefits of metformin treatment on glucose intolerance were abrogated. GUDCA was further identified as an intestinal FXR antagonist that improved various metabolic endpoints in mice with established obesity. Thus, we conclude that metformin acts in part through a B. fragilis-GUDCA-intestinal FXR axis to improve metabolic dysfunction, including hyperglycemia. PMID- 30397358 TI - Longitudinal personal DNA methylome dynamics in a human with a chronic condition. AB - Epigenomics regulates gene expression and is as important as genomics in precision personal health, as it is heavily influenced by environment and lifestyle. We profiled whole-genome DNA methylation and the corresponding transcriptome of peripheral blood mononuclear cells collected from a human volunteer over a period of 36 months, generating 28 methylome and 57 transcriptome datasets. We found that DNA methylomic changes are associated with infrequent glucose level alteration, whereas the transcriptome underwent dynamic changes during events such as viral infections. Most DNA meta-methylome changes occurred 80-90 days before clinically detectable glucose elevation. Analysis of the deep personal methylome dataset revealed an unprecedented number of allelic differentially methylated regions that remain stable longitudinally and are preferentially associated with allele-specific gene regulation. Our results revealed that changes in different types of 'omics' data associate with different physiological aspects of this individual: DNA methylation with chronic conditions and transcriptome with acute events. PMID- 30397357 TI - Expanded skin virome in DOCK8-deficient patients. AB - Human microbiome studies have revealed the intricate interplay of host immunity and bacterial communities to achieve homeostatic balance. Healthy skin microbial communities are dominated by bacteria with low viral representation1-3, mainly bacteriophage. Specific eukaryotic viruses have been implicated in both common and rare skin diseases, but cataloging skin viral communities has been limited. Alterations in host immunity provide an opportunity to expand our understanding of microbial-host interactions. Primary immunodeficient patients manifest with various viral, bacterial, fungal, and parasitic infections, including skin infections4. Dedicator of cytokinesis 8 (DOCK8) deficiency is a rare primary human immunodeficiency characterized by recurrent cutaneous and systemic infections, as well as atopy and cancer susceptibility5. DOCK8, encoding a guanine nucleotide exchange factor highly expressed in lymphocytes, regulates actin cytoskeleton, which is critical for migration through collagen-dense tissues such as skin6. Analyzing deep metagenomic sequencing data from DOCK8 deficient skin samples demonstrated a notable increase in eukaryotic viral representation and diversity compared with healthy volunteers. De novo assembly approaches identified hundreds of novel human papillomavirus genomes, illuminating microbial dark matter. Expansion of the skin virome in DOCK8 deficient patients underscores the importance of immune surveillance in controlling eukaryotic viral colonization and infection. PMID- 30397359 TI - Individualized sepsis treatment using reinforcement learning. PMID- 30397362 TI - Single agent daratumumab in advanced multiple myeloma possesses significant efficacy even in an unselected "real-world" population. AB - OBJECTIVE: The treatment of relapsed and refractory multiple myeloma (RRMM) remains challenging. The outcomes in highly pretreated populations are unsatisfactory and there is urgent need for novel and safe therapeutic approaches. Recently, daratumumab has been approved for RRMM with promising results even in monotherapy. The aim of this study was to assess the efficacy of single agent daratumumab outside a clinical trial. PATIENTS AND METHODS: 14 patients with RRMM and significant pretreatment (median 4.5 previous lines) entered a specific healthcare program and received treatment with single agent daratumumab. They were followed for therapeutic response based on IMWG criteria, and incidence of adverse events. The data were collected using the Registry of Monoclonal Gammopathies. RESULTS: The overall response rate was 38.5%. 23.1% of patients reached very good partial response, 15.4% reached partial remission, 15.4% had minimal response, 38.5% had stable disease and 7.7% had progressive disease. The median progression free survival was 4.6 months and median overall survival was not achieved. The toxicities were mostly mild, only infectious complications and hematological toxicity reached grade III. CONCLUSION: We conclude that daratumumab has significant activity in highly pretreated RRMM even as a single agent, with an acceptable toxicity profile and survival impact. PMID- 30397361 TI - Relationship between cardiovascular health metrics and physical performance in community-living people: Results from the Longevity check-up (Lookup) 7+ project. AB - Cardiovascular health metrics (CHMs) may predict disability independent of vascular events. Though, the link between CHMs and physical performance is unclear. This relationship was explored using data from the Longevity check-up (Lookup) 7+ project. Lookup 7+ is an ongoing cross-sectional survey conducted in unconventional settings across Italy. People who are at least 18-year-old and provide written informed consent are eligible. CHMs [i.e., smoking status, healthy diet, body mass index (BMI), blood pressure, blood cholesterol, and diabetes status] are assessed through closed questions and objective measurements. Physical performance is measured via the 5-repetition chair-stand test. Analyses included 7446 participants (55.5 +/- 14.9 years; 56% women). Physical performance positively correlated with CHMs scores, such that participants who scored higher (6-7 points) completed the chair-stand test about 2 s faster than those scoring lower (1-2 points). In fully adjusted analysis, better physical performance was more frequently observed in younger, non-smoking, physically active men, with ideal BMI, and no diabetes. Our findings indicate a gradient of better physical function with increasing CHMs scores. Future investigations should establish the longitudinal effect of unhealthy behaviours and cardiovascular risk factors on physical performance and verify whether implementation of large-scale primordial cardiovascular prevention may positively impact physical fitness. PMID- 30397360 TI - Genetic variation determines VEGF-A plasma levels in cancer patients. AB - Angiogenesis is essential in tumor biology and is regulated by vascular endothelial growth factor (VEGF) ligands and receptors. Here we aimed to discover genetic variants associated with levels of circulating angiogenic proteins in cancer patients. Plasma was collected at baseline in 216 pancreatic and 114 colorectal cancer patients. Thirty-one angiogenic proteins were measured by ELISA. 484,523 Single Nucleotide Polymorphisms (SNP) were tested for association with plasma levels for each protein in pancreatic cancer patients. Three top ranked hits were then genotyped in colorectal cancer patients, where associations with the same proteins were measured. The results demonstrated rs2284284 and MCP1 (P-value = 6.7e-08), rs7504372 and VEGF-C (P-value = 9.8e-09), and rs7767396 and VEGF-A (P-value = 5.8e-09) were SNP-protein pairs identified in pancreatic cancer patients. In colorectal cancer patients, only rs7767396 (A > G) and VEGF-A was validated (P-value = 5.18e-05). The AA genotype of rs7767396 exhibited 2.04-2.3 and 2.7-3.4-fold higher VEGF-A levels than those with AG and GG genotypes. The G allele of rs7767396 reduces binding of the NF-AT1 transcription factor. In conclusion, a common genetic variant predicts the plasma levels of VEGF-A in cancer patients through altered binding of NF-AT1. PMID- 30397363 TI - Twittering Pupae of Papilionid and Nymphalid Butterflies (Lepidoptera): Novel Structures and Sounds. AB - Pupae of numerous Papilionidae and Nymphalidae produce twitter sounds when wriggling in response to mechanical stimulation. The structural basis comprises distinct pairs of sound-producing organs (SPOs) located at intersegmental membranes of the abdomen. They differ-as the twitters do-in sampled taxa of Papilioninae, Epicaliini, and Heliconiini. The opposing sculptured cuticular sound plates (SPs) of each SPO appear structurally the same but are actually mirror-images of each other. Results suggest that sounds are not generated by stridulation (friction of a file and a scraper) but when these inversely sculptured and interlocking surfaces separate during pupal wriggling, representing a stick-slip mechanism. Twitter sounds comprise series of short broadband pulses with the main energy in the frequency range 3-13 kHz; they can be heard by humans but extend into ultrasonic frequencies up to 100 kHz. PMID- 30397364 TI - Imminent danger:: Characterizing uncertainty in critically hazardous mining situations. AB - ? Mineworkers are routinely tasked with making critically important decisions about whether or not a hazard presents an imminent danger. Researchers from the U.S. National Institute for Occupational Safety and Health collected formative data to investigate mine safety professional perspectives on workplace examinations, which revealed a potential gap in how mineworkers are assessing risk. During interviews, participants revealed not having a systematic methodology for mineworkers to use to determine if a hazard is considered imminent danger. In this paper, we identify and describe three distinct categories of imminent danger complexity and discuss potential steps that could lead to improved identification of imminent danger situations. Finally, we identify potential practices to incorporate into risk management efforts, including feedback, communication and specialized training, to increase awareness of imminent danger situations. PMID- 30397365 TI - Low level determination of gallium isotopes by ICP-QQQ. AB - Determination of low concentrations of Ga in environmental or biological samples can benefit from interference free measurement of both Ga isotopes. Unfortunately, both isotopes have potential interferences, i.e doubly charged Ba at m/z 69 and MnO at 71. Analysis using collision and reaction gases by ICP-QQQ as an alternative to HR-ICP-MS is investigated here using conventional nebulization and a desolvating nebulizer. Analysis at m/z 71 is not appreciably affected by MnO at 200 ug/l Mn or in either water reference material; excellent detection limits of < 0.1 ng/l were obtained for He, H2, or on-mass O2 and NH3 gas modes. Analysis of Ga at m/z 69 was severely affected by doubly charged Ba across all gas modes except +17 mass-shift (i.e. 69 - 86) NH3 gas mode. Despite Ga being only 1-2% reactive at the 69-86 mass shift, the doubly-charged interference was not mass-shifted and detection limits of < 1 ng/l and precise and accurate quantification of two water reference materials and nine natural water samples were achievable for this analysis mode. PMID- 30397366 TI - More than Taking a Chair: The Perceived Group Social Dynamics of Alcoholics Anonymous Related to Changes in Spiritual Practices. AB - Alcoholics Anonymous (AA) meeting attendance and spiritual practices are established predictors of abstinence. This study utilized longitudinal data from two studies of AA to investigate 1) how perceived within meeting social dynamics in AA meetings affect later AA attendance, and thus exposure to the emphasis of spiritual practices and 2) influence the extent that spiritual gains are mobilized, beyond AA attendance. Findings revealed that greater group cohesion was associated with lower AA attrition, and that expressiveness, or openness, of the group predicted reported practice of spiritual behaviors. Findings reveal distinct group dynamics may foster distinct mechanism of change of AA attendees. PMID- 30397367 TI - Comparative Evaluation of Mucosal Vibrator with Topical Anesthetic Gel to reduce Pain during Administration of Local Anesthesia in Pediatric Patients: An in vivo Study. AB - Introduction: Usually discomfort and pain are associated with dental work, especially for young patients. Pain control can be achieved by using anesthesia. Sight of injection can terrify any patient and if the patient is a child it is really difficult to convince them for injections. Alternatives to injections have been explored. Pediatric dentists are using anesthesia in the form of jelly and patch. Recently, the concept of mucosal vibration has been put forward to enhance the effectiveness of local anesthesia. Aim: The aim of the present study was to compare and evaluate the effectiveness of lignocaine jelly and mucosal vibration in reducing pain during administration of local anesthesia in pediatric dental patients. Materials and methods: Thirty children in the age group 6 to 11 years who required bilateral anesthesia for dental treatment in mandible were selected for this study. Pain was compared using Wilcoxon signed-rank test at the time of injection using Sound, Eye, Motor (SEM) scale as objective criteria and facial pain rating (FPR) scale as subjective criteria after administration of injection by a trained assistant who was blinded to the procedure. Results: Local anesthetic injection along with mucosal vibration resulted in significantly less pain (p = 0.001) in comparison with the injections without the use of mucosal vibration. Conclusion: The result shows that mucosal vibration can be used as an effective means to reduce the intensity of pain during local anesthetic injection in dentistry.How to cite this article: Tandon S, Kalia G, Sharma M, Mathur R, Rathore K, Gandhi M. Comparative Evaluation of Mucosal Vibrator with Topical Anesthetic Gel to reduce Pain during Administration of Local Anesthesia in Pediatric Patients: An in vivo Study. Int J Clin Pediatr Dent 2018;11(4):261-265. PMID- 30397368 TI - Use of "Surface Analyzer" to evaluate the Effect of Two Polishing Systems on Surface Texture of Four Newer Composites. AB - Composites polymerized with a clear matrix on the surface will leave a resin-rich surface layer that is easily abraded in the oral environment, exposing unpolished, rough, inorganic filler material. The purpose of this study was to evaluate the polishing effect of two different polishing systems: One-step (PoGo) system and Sof-Lex (multistep) system on four different resin composites: Synergy D6, Clearfil APX Esthetics, Filtek Z 350 XT, Ceram X Mono. After polishing, the specimens were analyzed for average surface roughness using a two-dimensional surface profilometer. How to cite this article: Garg S, Goel M, Verma S, Mahajan N, Kaul B, Garg V. Use of "Surface Analyzer" to evaluate the Effect of Two Polishing Systems on Surface Texture of Four Newer Composites. Int J Clin Pediatr Dent 2018;11(4):266-270. PMID- 30397369 TI - Validity and Reliability of the Hindi Version of the Modified Child Perceptions Questionnaire 11 to 14. AB - Introduction: The study was conceived to formulate a tool to evaluate child perceptions related to oral health in 11- to 14-year-olds tailor-made for Indian children in Hindi. The original child perceptions questionnaire (CPQ11-14) was translated into Hindi and it was tested for validity and reliability. Materials and methods: The original CPQ11-14 was translated into Hindi and some questions were rephrased to suit the sociocultural situation in India. The domains of self esteem and psychological well-being were added to the questionnaire to broaden the scope of parameters to thoroughly assess the impact on child perceptions toward oral health. The English and Hindi versions of the CPQ11-14 were administered during the first visit to test for validity and the children were recalled after 1 week and administered the Hindi questionnaire again after 1 week to check for reliability. Results: The results showed significant positive correlation between oral symptoms, decayed, missing and filled teeth (DMFT) functional limitation and malocclusion. The mean functional limitation score was found to be higher in subjects with malocclusion in both the English and Hindi questionnaires. The test-retest samples were evaluated using the paired t-test and showed no significant difference between the first and second administration which suggested good reliability. Conclusion: The translated and modified Hindi CPQ11-14 was found to be valid and highly reliable for use in India. The adaptation of the original questionnaire by modifying certain questions to suit the Indian condition was found to be culturally relevant.How to cite this article: Kumar P, Mandanna DCM, Londhe SM, Sharma M. Validity and Reliability of the Hindi Version of the Modified Child Perceptions Questionnaire 11 to 14. Int J Clin Pediatr Dent 2018;11(4):271-276. PMID- 30397370 TI - Comparative Evaluation of the Fracture Resistance of Two Different Fiber reinforced Composite Restorations with Particulate Filler Composite Restorations. AB - : Uncomplicated crown fractures are the most common form of traumatic dental injuries (TDIs) in children affecting their personal and social well-being. Aim: To evaluate the fracture resistance of fractured incisors restored with particulate filler composites, glass fiber-reinforced composites, and Polyethylene fiber-reinforced composite restorations. Materials and methods: Standardized incisal and mesio-incisal fractures with chamfer preparation were prepared on human maxillary central incisors. Test samples were restored using particulate filler composites (Filtek Z 250), glass fiber-reinforced composites (Fiber-Splint) and polyethylene-reinforced composites (Ribbond). Static load was applied to the test samples using Universal testing machine at a cross-head speed of 1 mm/min. Data were tabulated and analyzed using analysis of variance (ANOVA) (p = 0.05). Results: Descriptive statistics of mean [standard deviation (SD)] peak failure load in incisal restorations for particular filler composite, glass fiber-reinforced composites, and polyethylene fiber-reinforced composites were 196.00 (+/- 67.46), 186.28 (+/- 66.44), and 246.71 (+/- 24.52) respectively, whereas for mesio-incisal restorations, mean (SD) peak failure loads were 169.28 (+/- 33.53), 218.57 (+/- 74.41), and 225.71 (+/- 57.52) respectively. Conclusion: Polyethylene-reinforced composites showed an improved load-bearing capacity in incisal and mesio-incisal restorations when compared with particulate filler composites and glass fiber-reinforced composites.How to cite this article: Patnana AK, Rao VVN, Chandrabhatla SK, Rajasekhar VR. Comparative Evaluation of the Fracture Resistance of Two Different Fiber-reinforced Composite Restorations with Particulate Filler Composite Restorations. Int J Clin Pediatr Dent 2018;11(4):277-282. PMID- 30397371 TI - Clinical, Radiological, and Histological Assessment of Magnetic Nanoparticles as Pulpotomy Medicament in Primary Molars. AB - Aim and objectives: Aim of the study was to evaluate the success of magnetic nanoparticles (MNPs) as pulpotomy medicament by clinical, radiologic, and histological assessment in primary molars. Materials and methods: The sample included 30 primary molars from 25 children aged between 3 and 9 years requiring pulpotomy treatment. Pulpotomy was carried out with MNPs. The teeth were evaluated after a period of 3, 6, and 12 months clinically and with the aid of radiographs. After 1 year, 10 teeth were extracted for histological evaluation under field emission scanning electron microscope (FE-SEM; ZEISS, Model No. Supra 55vp). Results: Of the samples, 98% showed clinical success rate with absence of pain, swelling, mobility, and abscess formation. After 3 months, 98% radiological success with absence of periodontal ligament widening, root resorption, and inter radicular radiolucency was noted. Histological examination carried out under FE SEM revealed a zone of odontoblastic proliferation at the interface between MNPs and odontoblastic layer of pulp and viable pulpal cells from the canal orifice till apical foramen. Conclusion: Magnetic nanoparticles can be recommended as an effective pulpotomy medicament with hard tissue barrier formation and preservation of vitality of remaining radicular pulp.How to cite this article: Konyala HR, Mareddy AR, Puppala N, Reddy NV, Mallela MK, Susheela KP. Clinical, Radiological, and Histological Assessment of Magnetic Nanoparticles as Pulpotomy Medicament in Primary Molars. Int J Clin Pediatr Dent 2018;11(4):283-287. PMID- 30397372 TI - Evaluation of Chemokines in the Gingival Crevicular Fluid of Children with Down Syndrome. AB - Aim: The goal of the study was to detect the presence of macrophage inflammatory protein (MIP)-1alpha and MIP-1beta and to estimate their levels in gingival crevicular fluid (GCF) of children with Down syndrome. Materials and methods: MIP 1alpha and MIP-1beta levels were estimated in GCF samples of 20 healthy and 20 Down syndrome individuals. Gingival status was assessed by measuring the gingival index (GI), plaque index (PI), clinical attachment level (CAL), and probing pocket depth (PPD).The GCF samples were obtained from the subjects and MIP-1alpha and MIP-1beta levels were quantified by enzyme-linked immunosorbent assay (ELISA). Results: The mean MIP-1alpha concentrations in healthy and Down syndrome individuals were 209 and 1411 pg/MUL respectively, and MIP-1alpha levels were 342 and 1404 pg/MUL respectively.The levels of MIP-1alpha and MIP-1beta in the GCF of subjects with Down syndrome were significantly higher than in the healthy individual, and statistically significant differences were present among the two groups. Conclusion: The GCF showed dynamic changes according to the severity of periodontal disease, and the levels of MIP-1alpha and MIP-1beta had a strong relationship with clinical parameters. The MIP-1alpha and MIP-1beta can therefore be considered as novel biomarkers in the biological mechanism underlying the patho-genesis of periodontal disease.How to cite this article: Reddy VK, Kommineni NK, Padakandla P, Togaru H, Indupalli JP, Nanga SP. Evaluation of Chemokines in the Gingival Crevicular Fluid of Children with Down Syndrome. Int J Clin Pediatr Dent 2018;11(4):288-293. PMID- 30397373 TI - Evaluation of Surgical Options for Supernumerary Teeth in the Anterior Maxilla. AB - Aim: The purpose of this study was to evaluate the surgical options for supernumerary teeth (SNT) in the premaxillary region of children. Materials and methods: A total of 69 patients with 82 partially or completely formed SNT in the anterior maxillary region were identified over a 3-year period. All selected patients were assessed for the number, location, and family history of SNT, damage to adjacent roots, and associated symptoms. The surgical approaches used for removal were recorded. Postoperative clinical sequelae (loss of vitality, periodontal problems, pain, bleeding, and enanthema) were evaluated. Results: A total of 43, 30, and 9 SNT were extracted with palatal, buccal, and bicortical approaches respectively. Peri-odontal and vitality assessments revealed no problems in adjacent teeth at 6 months after surgery. Postoperative pain was within acceptable levels in all patients and subsided within 3 to 7 days. Mild postoperative bleeding occurred in eight patients. Enanthema subsided within 10 days in all patients. Conclusion: Our results suggest that early diagnosis and appropriate surgical treatment of SNT are important to decrease the risk of clinical complications.How to cite this article: Maddalone M, Rota E, Amosso E, Porcaro G, Mirabelli L. Evaluation of Surgical Options for Supernumerary Teeth in the Anterior Maxilla. Int J Clin Pediatr Dent 2018;11(4):294-298. PMID- 30397374 TI - Comparative Evaluation of Effects of Triphala, Garlic Extracts, and Chlorhexidine Mouthwashes on Salivary Streptococcus mutans Counts and Oral Hygiene Status. AB - Aims and objectives: To determine and compare the effect of triphala, chlorhexidine gluconate, and garlic extract mouthwash on salivary Streptococcus mutans count and the oral hygiene status. Materials and methods: Sixty children aged 9 to 12 years were randomly allocated into the study groups of triphala mouthwash, chlorhexidine mouthwash, garlic extracts mouth-wash, and distilled water mouthwash. Examination included decayed, missing, and filled teeth (dmft)/decayed, missing, filled surface (dmfs) and DMFT/DMFS, plaque index, and S. mutans count on days 1, 15, and 30. Results: The results were statistically analyzed using Friedman test, Wilcoxon signed rank, repeated-measures analysis of variance (ANOVA), paired t-test, one-way ANOVA, post hoc Tukey's honestly significant different (HSD), Kruskal-Wallis test, and Mann-Whitney test; all calculations were done by MEDCALC software 14.0.0 version. Discussion: Streptococcus mutans count had significant reductions using different mouthwashes at 15 days, but the chlorhexidine group showed significant difference from the remaining three groups. Intergroup comparison for plaque index scores of triphala, chlorhexidine, and garlic groups was similar in preventing plaque build up during the 15 days of mouthwash use. Conclusion: All the three mouthwashes containing triphala, chlorhexidine gluconate, and garlic were comparably efficient in reducing the salivary S. mutans count as well as in limiting plaque score; however, chlorhexidine was the most effective in this aspect. In comparison of the two natural ingredients, Triphala is more effective in its antimicrobial effect.How to cite this article: Padiyar B, Marwah N, Gupta S, Padiyar N. Comparative Evaluation of Effects of Triphala, Garlic Extracts, and Chlorhexidine Mouthwashes on Salivary Streptococcus mutans Counts and Oral Hygiene Status. Int J Clin Pediatr Dent 2018;11(4):299-306. PMID- 30397376 TI - Alveolar Bone and Epithelial Attachment Status following Two Different Closed eruption Surgical Techniques for Impacted Maxillary Central Incisors. AB - Aim: Two eruption surgical techniques are commonly described for the treatment of upper impacted central incisors (ICIs): Open and closed. Currently, the closed eruption surgical technique (CEST) is the most commonly used, as it allows for the best esthetic and periodontal results.The aim of this study was to determine the effect of traction discontinuation on maxillary central incisor sulcal depth and alveolar bone ridge levels compared with contralateral incisors, when CEST is used. Materials and methods: Our study involved 28 unilateral impacted maxillary central incisors treated by CEST. Thirteen teeth were subjected to traction interruption for a month at the time of emergence of the crown, while 15 teeth underwent continuous traction. One year after treatment, periapical digital X rays, anterosuperior cone beam computerized tomography (CBCT) scanning, and periodontal probing of the ICIs and contralateral central incisors (CCIs) were performed. Student's t-test was used to study whether a statistically significant difference between continuous and interrupted tractions takes place while using the CCI measurements as reference. Results: There was a statistically significant difference between the two techniques only for the following measurements: Mesial probing (p-value 0.039352), labial bone level (p-value 2.58E-08), and palatal bone level (p-value 2.56E-06). Limitations: A larger sample size and longer term follow-up are needed to draw more robust conclusions. Conclusion: A temporary discontinuation during traction of the tooth appears to positively impact treatment outcome on ICIs. Clinical significance: * The CEST leads to the best periodontal status for ICIs.* The discontinuation of traction at the emergence of the tooth allows the supracrestal fibers to insert into the cement in a proper way.How to cite this article: Sfeir E, Gholmieh M, Skaf Z, Mourad A. Alveolar Bone and Epithelial Attachment Status following Two Different Closed-eruption Surgical Techniques for Impacted Maxillary Central Incisors. Int J Clin Pediatr Dent 2018;11(4):317-322. PMID- 30397375 TI - Orthodontic Treatment Needs of 12-year-old School-going Children of Mysuru District, Karnataka, India: A Cross-sectional Study. AB - Health is the extent of functional or metabolic regulation of a living body. Many researchers have shown that oral health is directly related to the systemic condition of a person. The various researches done has shown that there is an increase in need for orthodontic treatment in most of the countries. Hence judicious planning of providing orthodontic services on a population basis is necessary to appraise the requirement of resources and manoeuvre for providing such a service. How to cite this article: Avinash B, Shivalinga BM, Balasubramanian S, Shekar S, Chandrashekar BR, Avinash BS. Orthodontic Treatment Needs of 12-year-old School-going Children of Mysuru District, Karnataka, India: A Cross-sectional Study. Int J Clin Pediatr Dent 2018;11(4):307-316. PMID- 30397377 TI - Efficacy of Caries Removal by Carie-Care and Erbium-doped Yttrium Aluminum Garnet Laser in Primary Molars: A Scanning Electron Microscope Study. AB - Aim: To compare and evaluate morphological changes and bacterial deposits in primary carious molars after caries excavation with Carie-Care, erbium-doped yttrium aluminum garnet (Er:YAG) laser, and round tungsten carbide bur. Materials and methods: Thirty human carious primary molars extracted for therapeutic reasons were sectioned mesiodistally. These sectioned samples were allocated into three groups (20 samples each): group I: Carie Care, group II: Er:YAG laser, and group III: round tungsten carbide bur. After caries excavation, all samples were processed and examined under conventional light microscope to examine for bacterial deposits. Representative samples from each group were processed and analyzed to examine the morphology of caries-excavated tissue by scanning electron microscope (SEM). Statistical analysis was done using Fisher's exact test, Kruskal-Wallis test, and Mann-Whitney U test. Results: The Er:YAG laser showed best results with no smear layer followed by chemomechanically excavated surfaces with Carie-Care. Amount of bacterial deposits was observed to be more in group I while least in group II (p-value < 0.001). Mann-Whitney U test and Fisher's exact test revealed that there was statistically significant difference among all the three groups. Conclusion: Among the three different methods of caries excavation, Er:YAG laser was found to be more effective compared with Carie-Care and round tungsten carbide bur. Clinical significance: Laser-induced caries excavation by Er:YAG laser and chemomechanical method of caries removal by Carie-Care can be considered as future of noninvasive pediatric and preventive dentistry.How to cite this article: Prabhakar A, Lokeshwari M, Naik SV, Yavagal C. Efficacy of Caries Removal by Carie-Care and Erbium-doped Yttrium Aluminum Garnet Laser in Primary Molars: A Scanning Electron Microscope Study. Int J Clin Pediatr Dent 2018;11(4):323-329. PMID- 30397378 TI - Time and Eruption Sequence of Permanent Teeth in Hyderabad Children: A Descriptive Cross-sectional Study. AB - Context: Eruption of teeth is influenced by various factors. Very few studies were carried out in the past on the eruption time of teeth in the Indian population. Aim: The aim of the study is to determine the time and sequence, gender differences, pattern of symmetry in the eruption of permanent teeth in Hyderabad children. Materials and methods: In this cross-sectional study, 1654 schoolchildren (806 girls and 848 boys) in the age group of 5 to 15 years from Hyderabad were examined for the status of eruption of permanent teeth. Statistical analysis used: Results were subjected to probit's regression analysis. The average age at eruption of permanent teeth, excluding third molars, was given as the mean [+/- standard deviation (SD)] in months for each gender. A table of percentiles of the eruption time was also determined. Results: Unlike most of the earlier studies which showed that girls are ahead of boys in permanent teeth emergence, no such pattern was observed. No significant difference was found in the eruption of permanent teeth in right and left arches. Eruption of all the mandibular teeth, with the exception of right first premolar (44) in both the genders, was earlier than their maxillary counterparts. There was overall delay in the eruption of permanent teeth and significant delay in the eruption of lower canines in both genders. Conclusion: The significant delay in the eruption of permanent mandibular canines is relevant for orthodontic treatment planning.How to cite this article: Chaitanya P, Reddy JS, Suhasini K, Chandrika IH, Praveen D. Time and Eruption Sequence of Permanent Teeth in Hyderabad Children: A Descriptive Cross-sectional Study. Int J Clin Pediatr Dent 2018;11(4):330-337. PMID- 30397379 TI - Knowledge, Attitude, and Practice of Mothers regarding Oral Hygiene of Primary School children in Chennai, Tamil Nadu, India. AB - Introduction: Children depend on their parents and caretakers for maintenance of their oral health. Parents play a major role in both preventive and treatment regime in these children. This study was conducted with the aim of evaluating the influence of parental education on knowledge, attitude, and practice of mothers regarding oral health of primary schoolchildren in Chennai. Materials and methods: A 15-item self-administered questionnaire was used among 465 parents of preschool children in Chennai, of which 432 mothers returned the filled questionnaire. The data collected were subjected to statistical analysis using frequency of responses and chi-square test (p < 0.01). Data were analyzed using statistical package. Results: Of the 432 mothers who participated in the study, 150 (35%) have studied up to school level and 282 (65%) have completed diploma/degree. The knowledge of mothers regarding the knowledge of importance of oral health for general health is appreciable, but the awareness of proper brushing habit, treatment of caries, and importance of dental visits is less in mothers who have school education when compared with graduate mothers. Conclusion: Mothers who are graduates are more aware of the importance of oral health in children, treatment of dental caries, and brushing technique than mothers with school education. Hence, it is essential that government and health care providers impart oral health knowledge to mothers, as they are the role models for their children.How to cite this article: Gurunathan D, Moses J, Arunachalam SK. Knowledge, Attitude, and Practice of Mothers regarding Oral Hygiene of Primary School children in Chennai, Tamil Nadu, India. Int J Clin Pediatr Dent 2018;11(4):338-343. PMID- 30397380 TI - Multidisciplinary Clinical Management of a Localized Aggressive Periodontitis diagnosed in a Child with Glanzmann's Thrombasthenia. AB - Localized aggressive periodontitis (LAP) in child involving primary dentition is a rare disease. The main characteristics of LAP are deep periodontal pockets, bone loss, tooth mobility, and, sometimes, spontaneous tooth loss. The LAP involves only some specific teeth. Glanzmann's thrombasthenia (GT) is a rare autosomal recessive bleeding disorder. The paper's aim is to present the case of a 5-year-old girl with GT presenting LAP, and discuss her clinical management. How to cite this article: Prud'homme T, Roy E, Soueidan A, Fouassier M, Dajean Trutaud S, Badran Z. Multidisciplinary Clinical Management of a Localized Aggressive Periodontitis diagnosed in a Child with Glanzmann's Thrombasthenia. Int J Clin Pediatr Dent 2018;11(4):344-348. PMID- 30397381 TI - Large Follicular Odontogenic Keratocyst affecting Maxillary Sinus mimicking Dentigerous Cyst in an 8-year-old Boy: A Case Report and Review. AB - Cyst with relatively high recurrence and having nature to invade the underlying tissue is "odontogenic keratocyst (OKC)." Radiographically, OKC can appear as different varieties, such as follicular, replacemental, extraneous, envelopmental, and collateral. Each radiographic variety of OKC varies in biological behavior, prognosis, recurrence, and therapeutic approaches. Many studies done till date have not established any relationship between markers of proliferation and aggressiveness in regard to radiographic varieties of OKC. The present article reports a case of follicular OKC in an 8-year-old boy which was concluded as a dentigerous cyst by radiographic features. How to cite this article: Madhireddy MR, Prakash AJ, Mahanthi V, Chalapathi KV. Large Follicular Odontogenic Keratocyst affecting Maxillary Sinus mimicking Dentigerous Cyst in an 8-year-old Boy: A Case Report and Review. Int J Clin Pediatr Dent 2018;11(4):349 351. PMID- 30397382 TI - Papillon-Lefevre Syndrome: A Rare Case Report of Two Brothers and Review of the Literature. AB - Papillon-Lefevre is an autosomal recessive syndrome that starts in early periods of childhood. Characteristic features include palmar plantar hyperkeratosis, aggressive periodontal disease, and a tendency for dry and chopped skin, thin and sparse hair. Patients show signs of premature tooth loss at the age of 2 to 4 years, which is then followed by the loss of permanent dentition during adolescence. The presence of both skin and oral lesions in this syndrome differentiates this unusual genodermatosis from other pathology of palmoplantar keratoderma (PPK). The etiopathogenesis of this syndrome is somewhat obscure; however, immunologic, genetic, and possible bacterial etiologies have been proposed. The dental practitioner is often the first to diagnose the disease, as there is a significant degree of periodontal breakdown that is involved at an early age. This report presents a clinical presentation of two brothers detected with Papillon-Lefevre syndrome (PLS). How to cite this article: Fageeh HN. Papillon-Lefevre Syndrome: A Rare Case Report of Two Brothers and Review of the Literature. Int J Clin Pediatr Dent 2018;11(4):352-355. PMID- 30397384 TI - Priorities and Challenges Accessing Health Care Among Female Migrants. AB - Women's ability to access health care requires access to and control of resources as well as the ability to make personal health decisions. Female migrants may experience additional challenges in accessing health care due to marginalization and vulnerability resulting from both their gender and their migrant status. Rural-to-urban migrant women working in the informal sector, such as Ghana's head porters (kayayei), experience exclusion from the health system, risk of being uninsured, and poor health outcomes. Kayayei's survival needs (eg, food, water) and a need to provide for their families can mean that migrant kayayei avoid health care expenses for illnesses or injuries. To ensure equal access to health care for migrant and non-migrant populations, health insurance is crucial. Yet, improving access to health care and service uptake requires more than health insurance. Incorporating culturally appropriate care into the provision of health services, or even developing specific migrant-friendly health services, could improve health service uptake and health awareness among migrants. Public health systems should also take account of migrants' financial situations and priorities in the design and delivery of health services. PMID- 30397383 TI - Integration of Biomarkers Into a Signature Profile of Persistent Traumatic Brain Injury Involving Autoimmune Processes Following Water Hammer Injury From Repetitive Head Impacts. AB - Objectives: To assemble an algorithm that will describe a "Signature" predictive of an individual's vulnerability to persistent traumatic brain injury (TBI). Subjects and Methods: Studies of athletes and warriors who are subjected to repeated head impacts with rapid acceleration/deceleration forces are used to assist in the diagnosis and management of TBI-affected individuals. Data from multiple areas, including clinical, anatomical, magnetic resonance imaging, cognitive function, and biochemical analyses, are integrated to provide a Signature of persistent TBI. Results: Studies to date indicate that susceptibility to TBI results from an interaction between host genetic and structural vulnerability factors and force and torque of impact on the head and torso. The host factors include molecular markers affecting immune and inflammatory responses to stress/insult as well as anatomical features such as the degree of transcortical fiber projections and vascular malformations. The host response to forceful impact includes the release of intracellular neural proteins and nucleic acids into the cerebrospinal fluid and vascular compartment as well as mobilization of cytokines and macrophages into the central nervous system with subsequent activation of microglia and inflammatory responses including autoimmune processes. Maximum impact to the base of the sulci via a "water hammer effect" is consistent with the localization of microvascular and inflammatory responses in the affected brain region. Conclusions: An assessment of an individuals' predisposition to persistent TBI with delayed cognitive deficits and behavioral changes requires an understanding of host vulnerability (genetic factors and brain structure) and external stressors (force and torque of impact as well as repetitive head injury and time interval between impacts). An algorithm that has utility in predicting vulnerability to TBI will include qualitative and quantitative measures of the host factors weighted against post impact markers of neural injury. Implementation of the resulting "Signature" of vulnerability at early stages of injury will help inform athletes and warriors, along with commanders and management, of the risk/benefit approaches that will markedly diminish health care costs to the nation and suffering to this population. This report attempts to define a strategy to create such an algorithm. PMID- 30397385 TI - Unconventional Practitioners' Causal Beliefs and Treatment Strategies for Chronic Low Back Pain in Rural Nigeria. AB - Chronic low back pain (CLBP) is highly prevalent and CLBP disability reinforces poverty and Nigerian rural-urban inequality. Most rural Nigerian dwellers with CLBP consult unconventional practitioners due to difficulty in accessing conventional health care. This interaction may influence back pain beliefs and behaviours, and health outcomes including disability. In line with the recent Lancet Low Back Pain series call to address widespread misconceptions in the population and among health practitioners about low back pain, this study explored the beliefs and management strategies of unconventional practitioners consulted by people living with CLBP in rural Nigeria. Qualitative semi structured face-to-face individual interviews. Thematic analysis of transcripts was performed using the Framework approach. Nine unconventional practitioners consented to participate in this study. Patent medicine sellers and herbalists had biomedical beliefs about CLBP and encouraged passivity and drug dependence in patients. Pastors adopted spiritual or biopsychosocial-spiritual management models and either encouraged spiritual CLBP causal beliefs and spiritual healing expectations; or patients' resilience and acceptance, respectively. Unconventional practitioners' CLBP beliefs and management strategies aligned with the beliefs and coping strategies of patients who consulted them. Unconventional practitioners' beliefs and management strategies may therefore contribute to the adverse impact of CLBP in rural Nigeria. PMID- 30397386 TI - The Path to New Halogenated Quinolines With Enhanced Activities Against Staphylococcus epidermidis. AB - Antibiotic-resistant bacteria and surface-attached bacterial biofilms play a significant role in human disease. Conventional antibiotics target actively replicating free-floating, planktonic cells. Unfortunately, biofilm communities are endowed with nonreplicating persister cells that are tolerant to antibiotics. Innovative approaches are necessary to identify new molecules able to eradicate resistant and tolerant bacterial cells. Our group has discovered that select halogenated quinolines (HQs) can eradicate drug-resistant, gram-positive bacterial pathogens and their corresponding biofilms. Interestingly, the HQ scaffold is synthetically tunable and we have discovered unique antibacterial profiles through extensive analogue synthesis and microbiologic studies. We recently reported the synthesis of 14 new HQs to investigate the impact of ClogP values on antibacterial and biofilm eradication activities. We conducted diverse synthetic modifications at the 2-position of the HQ scaffold in an attempt to enhance water solubility and found new compounds that display enhanced activities against Staphylococcus epidermidis. In particular, HQ 2 (ClogP = 3.44) demonstrated more potent antibacterial activities against methicillin-resistant S epidermidis (MRSE) 35984 planktonic cells (minimum inhibitory concentration = 0.59 uM) compared with methicillin-resistant Staphylococcus aureus and vancomycin resistant Enterococcus isolates while demonstrating potent MRSE biofilm eradication activities (minimum biofilm eradication concentration = 2.35 uM). We believe that HQ could play a critical role in the development of next-generation antibacterial therapeutics. PMID- 30397388 TI - Variation in late L1 acquisition? PMID- 30397387 TI - Skeletal Muscle Modulates Huntington's Disease Pathogenesis in Mice: Role of Physical Exercise. AB - Huntington's disease (HD) is a monogenic fatal neurodegenerative disorder. However, there is increasing evidence that HD is a pleiotropic systemic disorder. In particular, skeletal muscle metabolism is greatly affected in HD, which in turn can have a major impact on whole-body metabolism and energetic balance. Throughout an unbiased mutagenesis approach in HD mice, we have found that Scn4a, a skeletal muscle-specific sodium channel gene, is a modifier of the disease. Mutations in Scn4a enhance HD disease progression and weight loss by accelerating muscle waste and cachexia, increasing skeletal muscle activity and energy demands. At the molecular level, Scn4a mutations activate AMP-activated protein kinase (AMPK), leading to a fibre switch towards more oxidative types. These adaptations seen in HD; Scn4a double mutant muscles are similar to those observed in healthy individuals after endurance exercise training regimes. This prompted us to assess the effects of an endurance exercise regime in HD mice, independently showing that skeletal muscle adaptations leading to the activation of AMPK are detrimental for HD pathogenesis. Although it is undeniable that physical exercise can lead to many health benefits, our work shows that, at least under certain situations such as in HD, an endurance exercise routine could be a detrimental therapeutic option. PMID- 30397389 TI - Fia Yi, MD, FACS, FASCRS, LtCol. PMID- 30397390 TI - Anal Intraepithelial Neoplasia and Squamous Cell Cancer of the Anus: Past, Present, and Future. PMID- 30397391 TI - Vaccinations for Anal Squamous Cancer: Current and Emerging Therapies. AB - Human papillomavirus (HPV) infection is responsible for 4.3% of the global cancer burden. Since 2006, current HPV vaccines have reduced the prevalence of the virus in adolescent girls, reduced the prevalence of genital warts, and been proven to reduce the progression of anal intraepithelial neoplasia in men. Herein, we review the epidemiology, virology, and immunology behind the prophylactic HPV vaccines and current recommendations for its use. We also review future immune therapies being trialed for use against HPV-related cancers including anal cancer. PMID- 30397392 TI - Anal Intraepithelial Neoplasia from a Pathologists Point of View. AB - Anal squamous cell carcinoma is a relatively rare diagnosis, but its incidence has continued to rise. Anal squamous cell carcinoma and its precursor lesion, anal intraepithelial neoplasia (AIN), are human papillomavirus (HPV)-associated squamous neoplasias. High-risk HPV subtypes cause cellular proliferation in the anal transformation zone mucosa leading to similar dysplastic changes as seen in the cervix. Unified cytologic and histologic classification systems have emerged for all HPV-associated squamous lesions of the lower anogenital tract due to recent advancements in the understanding of these lesions. P16 immunohistochemical stain, a biomarker for HPV, is recommended in the diagnosis of HPV-associated lesions. The unity of terminology will aid in communication between pathologists and clinicians, ultimately leading to improved patient care. PMID- 30397393 TI - Anal Intraepithelial Neoplasia and Squamous Cell Cancer of the Anus. AB - Anal intraepithelial neoplasia (AIN) is the premalignant condition of the anal squamous tissue. It is associated with the human papilloma virus and is considered the transition prior to the invasive anal squamous cell carcinoma. It is typically asymptomatic and can be either an incidental finding after anorectal surgery or identified when high-risk patient populations are screened. Once AIN is diagnosed, the optimal management remains controversial, partly because the natural history of the disease is unclear. Surgical management of the disease has essentially been replaced by more conservative treatment options and can range from expectant management to topical therapy to photodynamic therapy. The aim of this article is to review the varied treatment options and to briefly review prevention strategies. PMID- 30397394 TI - So Now My Patient Has Squamous Cell Cancer: Diagnosis, Staging, and Treatment of Squamous Cell Carcinoma of the Anal Canal and Anal Margin. AB - Squamous cell carcinomas of the anal canal and the anal margin are rare malignancies that are increasing in incidence. Patients with these tumors often experience delayed treatment due to delay in diagnosis or misdiagnosis of the condition. Distinguishing between anal canal and anal margin tumors has implications for staging and treatment. Chemoradiation therapy is the mainstay of treatment for anal canal squamous cell, with abdominoperineal resection reserved for salvage treatment in cases of persistent or recurrent disease. Early anal margin squamous cell carcinoma can be treated with wide local excision, but more advanced tumors require a combination of chemoradiation therapy and surgical excision. PMID- 30397395 TI - Multidisciplinary Approach to the Management and Treatment of Anal Dysplasia. AB - The incidence of anal intraepithelial neoplasia (AIN) has been increasing over the years. AIN acts as a precursor lesion for anal squamous cell cancer. Factors leading to progression of AIN into malignancy are complex and involve grade of the lesion, human papillomavirus and HIV coinfection, as well as patient-related risk factors such as immunocompromised state and men who have sex with men. The multifaced aspects of this disease make its management challenging, as it involves several disciplines including pathology, primary care, infectious disease, and colorectal specialties. Each of these fields brings its own expertize to the management of AIN, and their collaborative, coordinated work culminates into best practice and optimized outcomes in the care of the AIN patient. PMID- 30397397 TI - Handler training improves decontamination of working canines with oil-based exposure in field conditions using disposable kits. AB - Exposure to contaminants in the field is a reality for deployed canines. To date, there is no data evaluating the benefits of training for handlers associated with canine decontamination efforts. The objective of our work was to investigate the impact of handler training on the reduction of oil-based contaminants in working canines. Canine teams (n = 10) were randomly assigned to either TRAINED or UNTRAINED groups. Each team (handler and dog) in the TRAINED group received 30 minutes of interactive training using an illustrated guide on proper utilization of equipment provided. Teams in the UNTRAINED group received the same equipment and illustrated guide but no interactive training. Decontamination efforts were measured using an oil-based pseudo-contaminant (GloGerm(r), Moab, UT) topically applied to four anatomical locations: cranial neck, between the shoulder blades, left medial hindlimb and left hind paw with pre- and post-washing images collected from a fixed distance of 20 inches. Visual assessment of contaminant reduction was scored as follows: 0 = <24% contaminant reduction; 1 = 25-50% contaminant reduction; 2 = 51-75% contaminant reduction; and 3 = >76% contaminant reduction. No score discrepancies >1 were reported between reviewers. Trained handlers were more effective at contamination reduction (P = .0093) as compared to their untrained counterparts. These results indicate that handlers, when properly trained, can achieve reduction of oil-based contaminants with a disposable decontamination kit and a garden hose. PMID- 30397396 TI - Basic Science, Epidemiology, and Screening for Anal Intraepithelial Neoplasia and Its Relationship to Anal Squamous Cell Cancer. AB - Despite the progress made in the reduction of squamous cell carcinoma of the cervix, the incidence of anal squamous cell carcinoma (ASCC) has been increasing since 1992. While it remains an uncommon disease, the prevalence is climbing steadily. Among human immunodeficiency virus (HIV)-infected adults, especially men who have sex with men, ASCC is one of the more common non-AIDS-defining malignancies. The precursor lesion, anal intraepithelial neoplasia (AIN), is prevalent in the HIV-infected population. More than 90% of ASCCs are related to human papilloma virus (HPV), oncogenic types (HPV 16, 18). While the biology of HPV-related intraepithelial neoplasia is consistent in the anogenital area, the natural history of AIN is poorly understood and is not identical to cervical intraepithelial neoplasia (CIN). CIN is also considered an AIDS-defining malignancy, and the methods for screening and prevention of AIN are derived from the CIN literature. This article will discuss the epidemiology of ASCC and its association with HPV and the life cycle of the HPV, and the molecular changes that lead to clearance, productive infection, latency, and persistence. The immunology of HPV infection will discuss natural immunity, humoral and cellular immunity, and how the HPV virus evades and interferes with these mechanisms. We will also discuss high-risk factors for developing AIN in high-risk patient populations with relation to infections (HIV, HPV, and chlamydia infections), prolonged immunocompromised people, and sexual behavior and tobacco abuse. We will also discuss the pre- and post-HAART era and its effect on AINs and ASCC. Finally, we will discuss the importance of anal cytology and high-resolution anoscopy with and without biopsy in this high-risk population. PMID- 30397399 TI - Adjuvant Therapy of Breast Cancer: Can We Do Better? PMID- 30397398 TI - Differential Efficacy of 2 Vibrating Orthodontic Devices to Alter the Cellular Response in Osteoblasts, Fibroblasts, and Osteoclasts. AB - Modalities that increase the rate of tooth movement have received considerable attention, but direct comparisons between devices are rare. Here, we contrasted 2 mechanical vibratory devices designed to directly transfer vibrations into alveolar bone as a means to influence bone remodeling. To this end, 3 cells types intimately involved in modulating tooth movements-osteoblasts, periodontal ligament fibroblasts, and osteoclasts-were subjected to in vitro vibrations at bout durations prescribed by the manufacturers. As quantified by an accelerometer, vibration frequency and peak accelerations were 400% and 70% greater in the VPro5 (Propel Orthodontics) than in the AcceleDent (OrthoAccel Technologies) device. Both devices caused increased cell proliferation and gene expression in osteoblasts and fibroblasts, but the response to VPro5 treatment was greater than for the AcceleDent. In contrast, the ability to increase osteoclast activity was device independent. These data present an important first step in determining how specific cell types important for facilitating tooth movement respond to different vibration profiles. The device that engendered a higher vibration frequency and larger acceleration (VPro5) was superior in stimulating osteoblast and fibroblast cell proliferation/gene expression, although the duration of each treatment bout was 75% shorter than for the AcceleDent. PMID- 30397400 TI - Documentation and Communication of Psychooncological Findings in an Interdisciplinary Breast Cancer Center. AB - Background: Psychooncological interventions are an integral component of the treatment of breast cancer patients in certified breast cancer centers. Effective multidisciplinary care requires excellent communication among the team members, including written communication. The study explores how written communication can be implemented in a multidisciplinary team treating cancer patients. Patients and Methods: A computerized form to enter psychooncological findings into a software designed for the documentation of the diagnostics and therapy of patients with breast cancer was developed. Results: The psychooncological module includes the sections phase of therapy, mood disturbances, difficulties in handling the disease/treatment, psychosocial burdens, psychosocial resources and treatment recommendations as well as notes about a psychological diagnosis (International Classification of Diseases (ICD)-10) where appropriate. 555 psychooncological findings were documented in the newly designed module. 28% of the patients were diagnosed with a mental disorder. 45% received at least one intervention. Conclusions: The psychooncological module facilitates the combination of oncological and psychooncological documentation. It can give structured psychooncological information to the physicians. However, the development of the module has to be continued. PMID- 30397401 TI - An Analysis of the Use of Complementary and Alternative Therapies in Patients with Breast Cancer. AB - Background: The aim of the present study was to investigate the use of complementary and alternative medicine (CAM) and the factors that influence their use in patients with breast cancer. Patients and Methods: This descriptive and cross-sectional study was carried out with 135 breast cancer patients on chemotherapy. Results: 30.4% of patients admitted using one or more CAM methods. The most common method was herbal therapy (97.6%). There were statistically significant differences among CAM users and non-users in terms of time elapsed since initial diagnosis, current stage of the disease, and current type of therapy. As the time since the initial diagnosis increased, so did the percentage of CAM users. Those patients with advanced stage cancer or relapsed disease who were receiving palliative therapy used CAM methods more than those receiving adjuvant therapy. As far as quality of life was concerned, symptoms such as nausea and vomiting, dyspnea, and diarrhea were more common among CAM users. Conclusion: It is important and necessary that health professionals working in oncology clinics are made aware of the common use of CAM methods so that they can provide the necessary communication between patients and other health professionals on these treatment modalities. PMID- 30397402 TI - A Clinicopathological Evaluation of Male Patients with Breast Cancer. AB - Background: Although male breast cancer constitutes only 1% of all breast cancers, its incidence is increasing and it is becoming an important public health issue. The present study aims to present the clinicopathological characteristics of surgically treated male breast cancer patients from multiple centers. Patients and Methods: Twenty-one male patients operated on for breast cancer were retrospectively examined in terms of clinical presentation, pathological characteristics, TNM staging status, and type of surgical treatment. Results: The mean age of the 21 patients was 62.3 years (range 38-94), with the majority being in the range of 50-69 years (61.9%). The most frequent finding was breast mass (85.7%). Most patients underwent modified radical mastectomy (76.1%), and the most prevalent histological type was invasive ductal carcinoma (85.7%). The majority of patients had stage II or III disease, and estrogen receptors were positive in 18 (85.7%) of the patients. Conclusion: Since male breast cancer is a rare condition, it is challenging to conduct prospective randomized trials. Currently, there is a lack of comprehensive data on the diagnosis and management of this condition. Thus, further studies and the implementation of specific guidelines or protocols for this subgroup of patients will aid better management. PMID- 30397403 TI - Reproductive Factors, Steroid Receptor Status, and Tumour Markers of HER2 Positive Breast Cancer in Northern China. AB - Background: Although China has a breast cancer incidence that surpasses all other cancer registries, there have been few reports to evaluate the relationships of reproductive history, steroid receptor status, and tumour markers with HER2 status of breast cancer. Patients and Methods: This project included 274 primary invasive ductal breast cancer patients. Information concerning the reproductive factors and tumour characteristics of the patients had previously been collected. HER2 and steroid receptor status were detected in tumour tissues. Serum CEA, CA15 3, and CA125 levels were analyzed for all patients. Results: Younger age at menarche was observed in patients with HER2-positive than in those with HER2negative status (p = 0.03). Statistically significant differences were found between the HER2-positive group and HER2-negative group for estrogen receptor (ER) and progesterone receptor (PR) status (p < 0.01). Age of onset, other reproductive factors, tumour characteristics, and serum tumour marker level were not significantly different between those patients with HER2-positive and those with HER2-negative status. Conclusion: We confirm that age at menarche may plausibly be differentially correlated with the risk of HER2-positive invasive ductal breast cancer because it is presumed to impact exposure to endogenous sex hormones. HER2 is inversely related to ER and PR in invasive ductal breast cancer patients of Northern China. PMID- 30397404 TI - Arthralgia in 329 Patients Taking Aromatase Inhibitors. AB - Background: Arthralgia is common in post-menopausal women taking aromatase inhibitors. However, the underlying mechanism remains unknown. Patients and Methods: We retrospectively examined the records of outpatients taking aromatase inhibitors to ascertain the frequency and severity of arthralgia. Results: Among 329 patients taking aromatase inhibitors (anastrozole in 239 and exemestane in 90 patients), 27% had arthralgia. There were 51 patients (16%) who switched from one aromatase inhibitor to another or quit aromatase inhibitor treatment. Arthralgia was the second most common reason for treatment changes in these 51 cases. In most cases, symptoms resolved after switching to a selective estrogen receptor modulator (SERM). We examined the relationships of arthralgia with other factors such as age, type of medication, prior treatments, and bone density. The arthralgia rate was significantly lower (p < 0.05) in patients with preceding endocrine therapy. No significant difference was detected between patients with versus patients without chemotherapy. Furthermore, there was no relationship between bone density and arthralgia. Conclusion: Our observations suggest SERM treatment combined with an aromatase inhibitor to be perhaps the most practical clinical solution to the problem of arthralgia. PMID- 30397405 TI - Neuroendocrine Carcinoma of the Breast: Case Report and Literature Review. AB - Background: Neuroendocrine carcinoma of the breast is a rare disease. Case Report: We present a 65-yearold female patient with an enlarged breast mass within 2 months. Solid neuroendocrine carcinoma of the breast was diagnosed by excision biopsy and histopathological analysis. A lumpectomy with the right axillary sentinel lymph node biopsy was performed, and the mass was completely resected. The literature on neuroendocrine carcinoma of the breast is reviewed. Conclusion: Due to the diversity of imaging findings from primary breast neuroendocrine carcinomas, the diagnosis is based on immunohistochemical staining of neuroendocrine markers. Surgery has turned out to be the first-line treatment and subsequently radiation may play a role in palliative treatment. PMID- 30397406 TI - Dislocation of Intravenous Port Systems - Three Case Reports. AB - Background: Many patients with intravenous chemotherapy have an intravenous port system because of high tissue toxicity of most chemotherapeutic agents in the case of paravasation. With more port systems implanted, the rate of complications is increasing. Apart from catheter thrombosis, we primarily know of fracture of the port catheter. Case Report: We describe 3 patients of our chemotherapeutic clinic who experienced complications of the intravenous port system implanted in the vena brachialis. All of them showed fracture and loss of the port catheter, followed in some cases by symptoms such as cardiac problems. Conclusion: We have to discuss the use of intravenous port systems. Besides their comfortable use, intravenous port systems have to be handled with care and it has to be considered in every case if there really is the need for an implantation. PMID- 30397408 TI - Adjuvant Chemotherapy of Breast Cancer. PMID- 30397407 TI - Clinical Relevance of Disseminated Tumor Cells in the Bone Marrow and Circulating Tumor Cells in the Blood of Breast Cancer Patients. AB - Subclinical tumor cell spread, as the putative precursor stage of subsequent solid metastases, can be assessed in breast patients via the detection of disseminated tumor cells (DTC) in bone marrow aspirates or circulating tumor cells (CTC) in the peripheral blood with immunocytochemical and molecular techniques. In the context of a growing number of treatment strategies for cancer patients in the adjuvant setting as well as in the metastatic situation, markers predicting therapy efficacy are urgently needed. The detection of DTC or CTC may become one of the most interesting parameters not just for the prediction of survival or therapy monitoring but also for the characterization and specific targeting of residual tumor cells. Progress in this field now permits clinical studies that should lead to improvements in the treatment of breast cancer patients. PMID- 30397410 TI - Jointly Improving Women's Health Worldwide - Current Focus of the 'International Working Group' of the German Society of Obstetrics and Gynaecology (AG FIDE). PMID- 30397409 TI - Organisierte, qualitatsgesicherte Brustkrebsfruherkennung: Herausforderungen und Erfolge des Wiener Mammographiemodellprojektes "Ich schau auf mich". PMID- 30397411 TI - Meeting Report: Hereditary Breast and Ovarian Cancer (HBOC): Risks and Challenges. September 10-12, 2009 Bari, Italy. PMID- 30397413 TI - Economic burden of hospitalisation for congestive heart failure among adults in the Philippines. AB - Objectives: Hospitalisation for congestive heart failure (CHF) was reported to be 1648 cases for every 100 000 patient claims in 2014 in the Philippines; however, there are no data regarding its economic impact. This study determined CHF hospitalisation cost and its total economic burden. It compared the healthcare related hospitalisation cost from the societal perspective with the payer's perspective, the Philippine Health Insurance Corporation (PhilHealth). Methods: This is a cost analysis study. Data were obtained from representative government/private hospitals and a drugstore in all regions of the country. Healthcare costs included cost of diagnostics/treatment, professional fees and other CHF-related hospital charges, while non-healthcare costs included production losses, transportation and food expenses. Results: The overall mean healthcare-related cost for CHF hospitalisation (class III) in government hospitals in the Philippines in 2014 was PHP19 340-PHP28 220 (US$436-US$636). In private hospitals, it was PHP28 370-PHP41 800 (US$639-US$941). In comparison, PhilHealth's coverage/CHF case rate payment is PHP15 700 (US$354). The mean non healthcare cost was PHP10 700-PHP14 600 (US$241-US$329). Using PhilHealth's case rate payment and the prevalence of CHF hospitalisation in 2014, the total economic burden was PHP691 522 200 (US$15 574 824). Using the study results on healthcare-related cost meant that the total economic burden for CHF hospitalisation would instead be PHP851 850 000-PHP1 841 563 000 (US$19 185 811 US$41 476 644). Conclusions: The calculated healthcare-related hospitalisation cost for CHF in the Philippines in 2014 demonstrates the disparity between the actual cost and PhilHealth's coverage. This implies a need for policymakers to review its coverage to make healthcare delivery affordable. PMID- 30397412 TI - Insights into the evaluation and management of dyspepsia: recent developments and new guidelines. AB - Dyspepsia is a very common gastrointestinal (GI) condition worldwide. We critically examine the recommendations of recently published guidelines for the management of dyspepsia, including those produced jointly by the American College of Gastroenterology and the Canadian Association of Gastroenterology, and those published by the UK National Institute for Health and Care Excellence. Dyspepsia is a symptom complex, characterized by a range of upper GI symptoms including epigastric pain or burning, early satiety, and post-prandial fullness. Although alarm features are used to help prioritize access to upper GI endoscopy, they are of limited utility in predicting endoscopic findings, and the majority of patients with dyspepsia will have no organic pathology identified at upper GI endoscopy. These patients are labelled as having functional dyspepsia (FD). The Rome IV criteria, which are used to define FD, further subclassify patients with FD as having either epigastric pain syndrome or post-prandial distress syndrome, depending on their predominant symptoms. Unfortunately, the Rome criteria perform poorly at identifying FD without the need for upper GI endoscopy. This has led to the investigation of alternative diagnostic approaches, including whether a capsaicin pill or combined serum biomarkers can accurately identify patients with FD. However, there is insufficient evidence to support either of these approaches at the present time. Patients with FD should be tested for H. pylori infection and be prescribed eradication therapy if they test positive. If they continue to have symptoms following this, then a trial of treatment with a proton pump inhibitor (PPI) should be given for up to 8 weeks. In cases where symptoms fail to adequately respond to PPI treatment, a tricyclic antidepressant may be of benefit, and should be continued for 6 to 12 months in patients who respond. Prokinetics demonstrate limited efficacy for treating FD, but could be considered if other strategies have failed. However, there are practical difficulties due to their limited availability in some countries and the risk of serious side effects. Patients with FD who fail to respond to drug treatments should be offered psychological therapy, where available. Overall, with the exception of recommendations relating to H. pylori testing and the prescription of PPIs, which are made on the basis of high-quality evidence, the evidence underpinning other elements of dyspepsia management is largely of low-quality. Consequently, there are still many aspects of the evaluation and management of dyspepsia that require further research. PMID- 30397414 TI - Association between apparent temperature and acute coronary syndrome admission in Rasht, Iran. AB - Objective: Our objective was to assess the relations between apparent temperature and incidence of acute coronary syndrome (ACS) in Rasht, Iran. Methods: We used a time-series analysis to investigate the relationship between apparent temperature and hospital admission from 2005 to 2014. Distributed lag non-linear models were used to estimate the association between ACS hospitalisation and apparent temperature. To examine the high-temperature effect on ACS hospital admission, the relative risk of ACS hospital admission associated with high temperature, the 99th percentile of temperature (34.7 degrees C) compared with the 75th percentile of temperature (26.9 degrees C), was calculated. To assess the cold effect on ACS hospital admission, the relative risk of ACS hospital admission associated with cold temperature, the first percentile of temperature (-0.2 degrees C) compared with the 25th percentile of temperature (8.2 degrees C), was evaluated. Results: The cumulative effect of hot exposure on ACS admissions was statistically significant, with a relative risk of 2.04 (95% CI 1.06 to 4.16). The cumulative effect of cold temperature on ACS admissions was found to be non-significant. The highest risk of ACS admission in women was in 38 degrees C (RR, 2.03, 95% CI 1.04 to 4.18). The effect of hot temperature on ACS admission occurred immediately (lag 0) (RR, 1.09, 95% CI 1.001 to 1.19). Conclusions: The high apparent temperature is correlated with a higher ACS admission especially on the same day. These findings may have implications for developing intervention strategies to reduce and prevent temperature-related morbidity especially in the elderly. PMID- 30397415 TI - Preoperative cigarette smoking and short-term morbidity and mortality after cardiac surgery: a meta-analysis. AB - Currently, the choice of whether or not to electively operate on current smokers is varied among cardiothoracic surgeons. This meta-analysis aims to determine whether preoperative current versus ex-smoking status is related to short-term postoperative morbidity and mortality in cardiac surgical patients. Systematic literature searches of the PubMed, MEDLINE and Cochrane databases were carried out to identify all studies in cardiac surgery that investigated the relationship between smoking status and postoperative outcomes. Extracted data were analysed by random effects models. Primary outcomes included 30-day or in-hospital all cause mortality and pulmonary morbidity. Overall, 13 relevant studies were identified, with 34 230 patients in current or ex-smoking subgroups. There was no difference in mortality (p=0.93). Current smokers had significantly higher risk of overall pulmonary complications (OR 1.44; 95% CI 1.27 to 1.64; p<0.001) and postoperative pneumonia (OR 1.62; 95% CI 1.27 to 2.06; p<0.001) as well as lower risk of postoperative renal complications (OR 0.82; 95% CI 0.70 to 0.96; p=0.01) compared with ex-smokers. There was a trend towards an increased risk of postoperative MI (OR 1.29; 95% CI 0.95 to 1.75; p=0.10). No difference in postoperative neurological complications (p=0.15), postoperative sternal surgical site infections (p=0.20) or postoperative length of intensive care unit stay (p=0.86) was seen. Cardiac surgical patients who are current smokers at the time of operation do not have an increased 30-day mortality risk compared with ex smokers, although they are at significantly increased risk of postoperative pulmonary complications. PMID- 30397417 TI - Potential of ITO thin film for electrical probe memory applications. AB - Electrical probe memory has received considerable attention during the last decade due to its prospective potential for the future mass storage device. However, the electrical probe device with conventional diamond-like carbon capping and bottom layers encounters with large interfacial contact resistance and difficulty to match the experimentally measured properties, while its analog with titanium nitride capping and bottom layers also faces serious heat dissipation through either probe and silicon substrate. Therefore, the feasibility of using indium tin oxide (ITO) media for the capping and bottom layers of the electrical probe device is investigated by tailoring the thickness and electrothermal properties of the ITO capping and bottom layers within experimentally established range and subsequently calculating the resultant temperature at several predefined points based on a previously developed three dimensional model. To meet the required temperature and to fit the experimentally reported values, the thickness, electrical conductivity, and thermal conductivity of the ITO capping and bottom layers are found to be 5 nm, 103 Omega-1 m-1, 0.84 W m-1 K-1, and 200 nm, 1.25 * 106 Omega-1 m-1, 0.84 W m-1 K-1, respectively. The practicality of using this optimized device to achieve ultrahigh density, ultralow energy consumption, ultrafast switching speed, low interfacial contact resistance, and high thermal reliability has also been demonstrated. PMID- 30397418 TI - Biological functions of 12(S)-hydroxyheptadecatrienoic acid as a ligand of leukotriene B4 receptor 2. AB - Although 12(S)-hydroxyheptadecatrienoic acid (12-HHT) is an abundant fatty acid, it is long considered a byproduct of thromboxane A2 production. We identified a leukotriene B4 receptor 2 (BLT2)-specific agonistic activity in lipid extracts from rat small intestine, and mass spectrometric analysis of partially purified lipids containing BLT2 agonistic activity revealed that 12-HHT is an endogenous ligand of BLT2. In a dextran sulfate sodium (DSS)-induced inflammatory colitis model, BLT2-deficient mice exhibited enhanced intestinal inflammation, possibly due to impaired epithelial barrier function. In a skin wound healing model, BLT2 deficient mice exhibited delayed wound healing via dampened keratinocyte migration. BLT2 also accelerates corneal wound healing, and eye drops containing a non-steroidal anti-inflammatory drug (NSAID) inhibit the production of 12-HHT, resulting in delayed corneal wound healing. Furthermore, BLT2 is expressed in pulmonary epithelial type II cells and vascular endothelial cells in the mouse lung, and BLT2-deficient mice are more susceptible to lung damage by pneumolysin. In this review, we summarize the identification and characterization of 12-HHT as a ligand for BLT2 and discuss recent research on the physiological and pathophysiological roles of the 12-HHT-BLT2 axis. Some side effects of NSAIDs such as delayed wound healing may be caused by reduced 12-HHT production rather than diminished production of prostaglandins. PMID- 30397416 TI - Adipose mesenchymal stem cells-derived exosomes attenuate retina degeneration of streptozotocin-induced diabetes in rabbits. AB - This study aimed to evaluate the effect of mesenchymal stem cells (MSCs)-derived exosomes in retina regeneration of experimentally induced diabetes mellitus (DM) in a rabbit model. Exosomes are extracellular vesicles that contain many microRNAs (micRNAs), mRNAs, and proteins from their cells of origin. DM was induced by intravenous (IV) injection of streptozotocin in rabbits. MSCs were isolated from adipose tissue of rabbits. Exosomes were extracted from MSCs by ultracentrifugation. Exosomes were injected by different routes (IV, subconjunctival (SC), and intraocular (IO)). Evaluation of the treatment was carried out by histopathological examination of retinal tissues and assessment of micRNA-222 expression level in retinal tissue by real-time polymerase chain reaction. Histologically, by 12 weeks following SC exosomal treatment, the cellular components of the retina were organized in well-defined layers, while IO exosomal injection showed well-defined retinal layers which were obviously similar to layers of the normal retina. However, the retina appeared after IV exosomal injection as irregular ganglionic layer with increased thickness. MicRNA 222 expression level was significantly reduced in diabetic controls when compared to each of healthy controls and other diabetic groups with IV, SC, and IO routes of injected exosomes (0.06 +/- 0.02 vs. 0.51 +/- 0.07, 0.28 +/- 0.08, 0.48 +/- 0.06, and 0.42 +/- 0.11, respectively). We detected a significant negative correlation between serum glucose and retinal tissue micRNA-222 expression level (r = -0.749, p = 0.001). We can associate the increased expression of micRNA-222 with regenerative changes of retina following administration of MSCs-derived exosomes. The study demonstrates the potency of rabbit adipose tissue-derived MSCs exosomes in retinal repair. So, exosomes are considered as novel therapeutic vectors in MSCs-based therapy through its role in shuttling of many factors including micRNA-222. PMID- 30397419 TI - Stochasticity in materials structure, properties, and processing-A review. AB - We review the concept of stochasticity-i.e., unpredictable or uncontrolled fluctuations in structure, chemistry, or kinetic processes-in materials. We first define six broad classes of stochasticity: equilibrium (thermodynamic) fluctuations; structural/compositional fluctuations; kinetic fluctuations; frustration and degeneracy; imprecision in measurements; and stochasticity in modeling and simulation. In this review, we focus on the first four classes that are inherent to materials phenomena. We next develop a mathematical framework for describing materials stochasticity and then show how it can be broadly applied to these four materials-related stochastic classes. In subsequent sections, we describe structural and compositional fluctuations at small length scales that modify material properties and behavior at larger length scales; systems with engineered fluctuations, concentrating primarily on composite materials; systems in which stochasticity is developed through nucleation and kinetic phenomena; and configurations in which constraints in a given system prevent it from attaining its ground state and cause it to attain several, equally likely (degenerate) states. We next describe how stochasticity in these processes results in variations in physical properties and how these variations are then accentuated by-or amplify-stochasticity in processing and manufacturing procedures. In summary, the origins of materials stochasticity, the degree to which it can be predicted and/or controlled, and the possibility of using stochastic descriptions of materials structure, properties, and processing as a new degree of freedom in materials design are described. PMID- 30397420 TI - Intentions to use emergency contraception: The role of accurate knowledge and information source credibility. AB - Background: Emergency contraception (EC) is a highly effective form of birth control that may lower rates of unintended pregnancy among young women. But efforts to disseminate EC to women are hampered by misinformation and inadequate information. Purpose: The purpose of this study was to determine the sources from which young women learn about EC (including health care providers, friends/interpersonal sources, media sources, or no information sources), and to examine source credibility with the accuracy of EC knowledge and intentions to use EC. Method: Using a computer-based survey, 339 college women (M age = 18.4) reported their EC information sources, knowledge about EC, and behavioral intentions to use EC. Results: In total, 97% of participants had heard of EC from at least one source and 49% indicated they were highly likely to use EC in the future if needed. Results demonstrated that EC knowledge mediated the relationship between EC information source credibility and intentions to use EC. Discussion: This study contributes important insights to a scarce literature on EC information sources and the factors that predict intentions to use EC. Translation to Health Education Practice: Future EC promotion efforts should target health education sources instead of media or interpersonal sources to promote EC knowledge and use among young, sexually at-risk populations. PMID- 30397421 TI - A Virtual Reality Haptic Robotic Simulator for Central Venous Catheterization Training. PMID- 30397422 TI - Children and Adults With Rare Diseases Need Innovative Medical Devices. AB - Rare diseases (RD) affect approximately 30 million Americans, half of whom are children. This study is the first to comprehensively evaluate their medical device needs via a survey of physicians. The study sought to identify and document the presumed unmet diagnostic and therapeutic device needs for RD management; clarify the magnitude of the potential unmet need; and generate meaningful data to inform medical device stakeholders. A cross-sectional nonprobability survey was conducted. The study population was drawn from the membership files of four groups: FDA Medical Devices Advisory Committee, Pediatric Advisory Committee, Pediatric Device Consortia, and National Institutes of Health (NIH) Rare Diseases Clinical Research Network. Only physician respondents with experience or knowledge regarding RD were eligible. Among eligible respondents, 90% confirmed the need for innovative devices to care for people with RD. Over 850 device needs were identified for 436 RD, with 74% of needs related to children. Pediatric physicians (OR = 2.11, 95% CI 1.01-4.39, P = 0.046) and physicians with more RD experience reflected greater dissatisfaction with existing devices (OR = 4.49, 95% CI 2.25-8.96, P < 0.0001). Creation of entirely new devices is the top recommendation for mitigating needs. This study demonstrates a major public health need for innovative medical devices to care for children and adults with RD. FDA and NIH support and seek opportunities to accelerate device development for these vulnerable patients. PMID- 30397423 TI - Hematopoietic stem cell transplantation for Crohn's disease: Gaps, doubts and perspectives. AB - Crohn's disease (CD) is an inflammatory bowel disease that can affect any site of the digestive system. It occurs due to an immunological imbalance and is responsible for intestinal mucosal lesions and complications such as fistulas and stenoses. Treatment aims to stabilize the disease, reducing the symptoms and healing intestinal lesions. Surgical procedures are common in patients. Cell therapy was initially used to treat this disease in patients who also suffered from lymphoma and leukemia and were considered to be good candidates for autologous and allogeneic transplantation. After transplantation, an improvement was also observed in their CD. In 2003, the procedure began to be used to treat the disease itself, and several case series and randomized studies have been published since then; this approach currently comprises a new option in the treatment of CD. However, considerable doubt along with significant gaps in our knowledge continue to exist in relation to cell therapy for CD. Cell therapy is currently restricted to the autologous modality of hematopoietic stem cell transplantation and, experimentally, to mesenchymal stromal cells to directly treat lesions of the anal mucosa. This article presents the supporting claims for transplantation as well as aspects related to the mobilization regime, conditioning and perspectives of cell therapy. PMID- 30397424 TI - Efficacy and safety of autologous stem cell transplantation for decompensated liver cirrhosis: A retrospective cohort study. AB - AIM: To evaluate the long-term efficacy and safety of autologous stem cell transplantation (SCT) for decompensated liver cirrhosis. METHODS: Consecutive patients with decompensated liver cirrhosis were included and assigned into the SCT group and non-transplantation (non-SCT) group according to whether they received SCT treatment. Patients were followed up for ten years. The long-term survival rate and incidence of hepatocellular carcinoma (HCC) were compared between groups. RESULTS: A total of 159 patients were enrolled, including 27 cases in the SCT group and 132 cases in the non-SCT group. The baseline characteristics were significantly different between the two groups. Propensity score matching (PSM) was used to match SCT and non-SCT patients. After PSM, 92 subjects were enrolled in the final analysis, including 23 cases in the SCT group and 69 cases in the non-SCT group. The overall mortality was 73.9% and 55.1%, and the median survival period was 48 and 64 mo, respectively. However, no significant difference was found in the long-term survival rate between the two groups (P > 0.05). In addition, the incidence of HCC was higher in the SCT group than in the non-SCT group (47.8% vs 21.7%, P < 0.05). After adjusting for other covariates, SCT (OR = 3.065, 95%CI: 1.378-6.814) and age (OR = 1.061, 95%CI: 1.021-1.102) were independently correlated with the development of HCC in this decompensated liver cirrhosis cohort. CONCLUSION: Autologous SCT may fail to improve the long-term efficacy and increase the incidence of HCC for decompensated liver cirrhosis. Close monitoring of HCC is strongly recommended in patients undergoing autologous SCT. PMID- 30397425 TI - Current role of palliative interventions in advanced pancreatic cancer. AB - Pancreatic adenocarcinoma is the third leading cause of cancer death in the United States. Unfortunately, at diagnosis, most patients are not candidates for curative resection. Surgical palliation, a procedure performed with the intention of relieving symptoms or improving quality of life, comes to the forefront of management. This article reviews the palliative management of unresectable pancreatic cancer, including obstructive jaundice, duodenal obstruction and pain control with celiac plexus block. Although surgical bypasses for both biliary and duodenal obstructions usually achieve good technical success, they result in considerable perioperative morbidity and mortality, even when performed laparoscopically. The effectiveness of self-expanding metal stents for biliary drainage is excellent with low morbidity. Surgical gastrojejunostomy for duodenal obstruction appears to be best for patients with a life expectancy of greater than 2 mo while endoscopic stenting has been shown to be feasible with good symptom relief in those with a shorter life expectancy. Regardless of the palliative procedure performed, all physicians involved must be adequately trained in end of life management to ensure the best possible care for patients. PMID- 30397427 TI - How do placebos work? PMID- 30397426 TI - Prevalence and correlates of probable post-traumatic stress disorder and common mental disorders in a population with a high prevalence of HIV in Zimbabwe. AB - Background: We investigated the prevalence of and factors associated with post traumatic stress disorder (PTSD) and common mental disorders (CMDs), which include depression and anxiety disorders, in a setting with a prevalence of high human immunodeficiency virus (HIV) within a primary care clinic, using the PTSD Checklist for DSM-5 and the 14-item Shona Symptom Questionnaire, both locally validated screening tools. Methods: A cross-sectional survey was carried out with adult patients (n = 204) from the largest primary care clinic facility in Harare, Zimbabwe, in June 2016. Results: A total of 83 patients (40.7%) met the criteria for probable PTSD, of whom 57 (69.5%) had comorbid CMDs. Among people living with HIV, 42 (55.3%) had PTSD. Probable PTSD was associated with having experienced a negative life event in the past 6 months [adjusted odds ratio (OR) 3.73, 95% confidence interval (CI) 1.49-9.34] or screening positive for one or more CMD (adjusted OR 6.48, 95% CI 3.35-2.54). Conclusion: People living with HIV showed a high prevalence of PTSD and CMD comorbidity. PTSD screening should be considered when the CMD screen is positive and there is a history of negative life events. PMID- 30397428 TI - Assessing the impact of bacteriophages in the treatment of Salmonella in broiler chickens. AB - Salmonellosis is one of the main bacterial infections affecting commercial poultry, causing losses to poultry production, and posing a public health concern. Samples from internal organs (liver, cecum and spleen) of one hundred diseased broiler chickens were collected and subjected to Salmonella isolation, identification and serotyping. S. typhimurium and S. enteritidis were selected from the isolated Salmonella to prepare bacteriophages from sewage water taken at broiler farms. An experimental infection of one day old specific pathogen free (SPF) chicks followed by treatment with the prepared bacteriophages isolated from both Salmonella was performed. Caecal samples from infected chicks were subjected at intervals to bacteriophage isolation and Salmonella quantitation. The effectiveness of bacteriophage treatments on Salmonella colonization in cecum of infected chicks increased after five successive doses. At 3 day post infection (dpi), cecal contents showed a marginal decrease in Salmonella loads with more reduction at 5 dpi. From 7 dpi to the end of the experiment at 15 dpi, all the chicks were cleared for both Salmonella. The findings of this study demonstrate that bacteriophage treatment is efficacious in reducing S. typhimurium and S. enteritidis colonization in broiler chickens within a short period and could be used as an alternative to antibiotics. PMID- 30397429 TI - Do Explicit Estimates of Angular Declination Become Ungrounded in the Presence of a Ground Plane? AB - In a series of seven experiments (total N = 220), it is shown that explicit angular declination judgments are influenced by the presence of a ground plane in the background. This is of theoretical importance because it bears on the interpretation of the relationship between angular declination and perceived distance on a ground plane. Explicit estimates of ground distance are consistent with a simple 1.5 gain in the underlying perceived angular declination function. The experiments show that, in general, functions of estimates of perceived angular declination have a slope of 1.5, but that an additional intercept can often be observed as a result of incorporating changes in ground distance into reports of changes in angular declination. By varying the background context, a variety of functions were observed that are consistent with this contamination hypothesis. PMID- 30397430 TI - Reformulated mineral trioxide aggregate components and the assessments for use as future dental regenerative cements. AB - Mineral trioxide aggregate, which comprises three major inorganic components, namely, tricalcium silicate (C3S), dicalcium silicate (C2S), and tricalcium aluminate (C3A), is promising regenerative cement for dentistry. While mineral trioxide aggregate has been successfully applied in retrograde filling, the exact role of each component in the mineral trioxide aggregate system is largely unexplored. In this study, we individually synthesized the three components, namely, C3S, C2A, and C3A, and then mixed them to achieve various compositions (a total of 14 compositions including those similar to mineral trioxide aggregate). All powders were fabricated to obtain high purity. The setting reaction of all cement compositions was within 40 min, which is shorter than for commercial mineral trioxide aggregate (~150 min). Over time, the pH of the composed cements initially showed an abrupt increase and then plateaued (pH 10-12), which is a typical behavior of mineral trioxide aggregate. The compression and tensile strength of the composed cements increased (2-4 times the initial values) with time for up to 21 days in an aqueous medium, the degree to which largely depended on the composition. The cell viability test with rat mesenchymal stem cells revealed no toxicity for any composition except C3A, which contained aluminum. To confirm the in vivo biological response, cement was retro-filled into an extracted rat tooth and the complex was re-implanted. Four weeks post-operation, histological assessments revealed that C3A caused significant tissue toxicity, while good tissue compatibility was observed with the other compositions. Taken together, these results reveal that of the three major constituents of mineral trioxide aggregate, C3A generated significant toxicity in vitro and in vivo, although it accelerated setting time. This study highlights the need for careful consideration with regard to the composition of mineral trioxide aggregate, and if possible (when other properties are satisfactory), the C3A component should be avoided, which can be achieved by the mixture of individual components. PMID- 30397433 TI - Non-operative management of isolated spontaneous superior mesenteric artery dissection. AB - Isolated spontaneous superior mesenteric artery (SMA) dissection is a rare differential for patients presenting with abdominal pain. Due to limited cases reported, management strategies have been poorly defined. We present the case of a 49-year-old male with history of hypertension and ischemic colitis, presenting with abdominal pain. CT imaging demonstrated a thrombosed dissection of the SMA extending into second and third order braches. He was managed conservatively with therapeutic anticoagulation. His symptoms improved and upon discharge he was transitioned to aspirin and warfarin. Repeat CT imaging continued to show the dissection with resolution of the SMA thrombus. Spontaneous SMA dissection is exceedingly rare with no universally agreed upon standard of care for treatment. Operative intervention should be reserved for failed conservative management or vascular compromise. Understanding the current treatment options helps ensure a favorable patient outcome. PMID- 30397432 TI - Magnetic ion channel activation of TREK1 in human mesenchymal stem cells using nanoparticles promotes osteogenesis in surrounding cells. AB - Magnetic ion channel activation technology uses superparamagnetic nanoparticles conjugated with targeting antibodies to apply mechanical force directly to stretch-activated ion channels on the cell surface, stimulating mechanotransduction and downstream processes. This technique has been reported to promote differentiation towards musculoskeletal cell types and enhance mineralisation. Previous studies have shown how mesenchymal stem cells injected into a pre-mineralised environment such as a foetal chick epiphysis, results in large-scale osteogenesis at the target site. However, the relative contributions of stem cells and surrounding host tissue has not been resolved, that is, are the mesenchymal stem cells solely responsible for the observed mineralisation or do mechanically stimulated mesenchymal stem cells also promote a host-tissue mineralisation response? To address this, we established a novel two-dimensional co-culture assay, which indicated that magnetic ion channel activation stimulation of human mesenchymal stem cells does not significantly promote migration but does enhance collagen deposition and mineralisation in the surrounding cells. We conclude that one of the important functions of injected human mesenchymal stem cells is to release biological factors (e.g., cytokines and microvesicles) which guide the surrounding tissue response, and that remote control of this signalling process using magnetic ion channel activation technology may be a useful way to both drive and regulate tissue regeneration and healing. PMID- 30397431 TI - Auditory disorders and future therapies with delivery systems. AB - Auditory function takes a major part in human life. While sensorineural hearing loss is related with many factors including genetic disorders, age and noise, the clear causes are not well understood. Even more, the currently available treatments with drugs cause side effects, which thus are considered suboptimal. Here, we communicate the delivery systems with biomaterials that can be possible therapeutic options to restore hearing and vestibular functions. We introduce briefly the various pathological factors related with hearing loss and the limitation of current therapies, detail the recent studies on delivery systems including nanoparticles and hydrogels and discuss future clinical availability. PMID- 30397434 TI - Resection of a mature cystic teratoma of the liver harboring a carcinoid tumor. AB - Cystic teratomas are rare pluripotent embryonic tumors which most commonly originate in gonadal organs. Extra-gonadal cystic teratomas are exceedingly uncommon, accounting for only 1% of all cystic teratomas, and have been reported in unusual locations including the kidney, mediastinum and liver. These extra ovarian cystic teratomas have also been known to harbor other neoplasms including carcinoid tumors. In this report, we describe a unique case of a hepatic cystic teratoma occurring as a combined tumor with a carcinoid in a young female. The patient underwent elective laparoscopic resection of her tumor after extensive radiographic and endoscopic work-up for chronic, non-localizable abdominal pain. We believe the carcinoid tumor arose de novofrom committed differentiation of a cell line within the teratoma, and not metastatic spread. PMID- 30397435 TI - Malignant proliferating trichilemmal tumor of the forearm: a case report of an unusual location of a rare cutaneous adnexal tumor. AB - Proliferating trichilemmal tumor (PTT) is a rare cutaneous adnexal neoplasm of the hair follicle that undergoes outer root sheath differentiation in the isthmus. Histological hallmarks include trichilemmal keratinization, lack of granular layer and lobular proliferation of squamous epithelium with glycogenated clear cells. It affects predominantly elderly women, especially over the scalp. In some cases, malignant transformation can occur. However, only a few cases are reported in the literature. We hereby describe the case of a patient diagnosed with malignant PTT (MPTT) in the dorsal forearm, 2 years after undergoing surgical excision of a squamous cell carcinoma in the same topography. Thus, providing a thorough description of the clinical presentation of MPTT will assist surgeons in diagnosing and treating this rare tumor. PMID- 30397436 TI - Decompressive laparotomy for a patient on VA-ECMO for massive pulmonary embolism that suffered traumatic liver laceration after mechanical CPR. AB - Massive pulmonary embolism (PE) is an embolus sufficiently obstructing pulmonary blood flow to cause right ventricular (RV) failure and hemodynamic instability. We have utilized veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for early and aggressive intervention for massive PE patients. We present a case of a 61-year-old female placed on VA-ECMO for a massive PE while presenting in cardiac arrest and receiving mechanical cardiopulmonary resuscitation (CPR) via the LUCAS 2.0 device (Physio-Control Inc., Lund, Sweden). The patient suffered a severe liver laceration secondary to mechanical CPR and required a decompressive laparotomy. This case highlights that mechanical CPR during other interventions can lead to malposition of the device and could result in solid organ injury. PMID- 30397437 TI - Giant solitary fibrous tumor of the pleura. AB - INTRODUCTION: Solitary fibrous tumors of the pleura (SFTP) are rare mesenchymal tumors representing <5% of all tumors of the pleura. Literature reveals only two case series and a few solitary reports. CASE REPORT: A 68-year-old male presented to our hospital after experiencing exertional dyspnea. A chest CT revealed a giant heterogeneous mass. CT-guided transthoracic core needle biopsy demonstrated SFTP. The well-circumscribed, encapsulated resected mass was measured to be 30 cm * 21 cm * 15 cm and weighed 6900 g. DISCUSSION: SFTP are a rare pathology of the pleural cavity, which most of the time develop from submesothelial fibroblasts of the visceral pleura. Due to their non-characteristic clinical picture, SFTP are usually diagnosed in the later stages of the development. A significant issue in the management of giant SFTP is radical resection of the tumor to relieve compression of the lung parenchyma and other mediastinal structures. CONCLUSION: SFTP are rare neoplasms that fortunately are benign 80% of the time. Only a few cases of giant SFTP that cover almost the entire pleural space are described in the literature. This report represents one of the largest resected SFTP reports in the literature. PMID- 30397438 TI - A primary germ cell tumour in the gastrointestinal tract: a caecal lesion of yolk sac morphology in a young patient. AB - A 24-year-old man with a history of Crohns disease, whilst undergoing surveillance colonoscopy was found to have an ulcerated caecal lesion. The histopathology from the mucosal biopsy was suggestive of a yolk sac tumour. After thorough re-examination, the patient had no radiological evidence of malignancy in his testes or retroperitoneum. His alpha-fetoprotein levels returned as 2145, whilst his carcinoembryonic antigen was negligible. The patient was therefore consented for and underwent a laparoscopic right hemi-colectomy with an ileocolic anastomosis, without any complications. The formal histopathology confirmed the results from the biopsy, of a yolk sac non seminous germ cell tumour with positive lymph nodes and lymphovascular invasion. The patient was referred on to medical oncology for neoadjuvant chemotherapy. As the literature in his instance is scarce, the patient's overall prognosis remains unclear. To the best of our knowledge this is the first reported primary germ cell tumour of the gastrointestinal tract. PMID- 30397439 TI - Transforming mentorship in STEM by training scientists to be better leaders. AB - Effective mentoring is a key component of academic and career success that contributes to overall measures of productivity. Mentoring relationships also play an important role in mental health and in recruiting and retaining students from groups underrepresented in STEM fields. Despite these clear and measurable benefits, faculty generally do not receive mentorship training, and feedback mechanisms and assessment to improve mentoring in academia are limited. Ineffective mentoring can negatively impact students, faculty, departments, and institutions via decreased productivity, increased stress, and the loss of valuable research products and talented personnel. Thus, there are clear incentives to invest in and implement formal training to improve mentorship in STEM fields. Here, we outline the unique challenges of mentoring in academia and present results from a survey of STEM scientists that support both the need and desire for more formal mentorship training. Using survey results and the primary literature, we identify common behaviors of effective mentors and outline a set of mentorship best practices. We argue that these best practices, as well as the key qualities of flexibility, communication, and trust, are skills that can be taught to prospective and current faculty. We present a model and resources for mentorship training based on our research, which we successfully implemented at the University of Colorado, Boulder, with graduate students and postdocs. We conclude that such training is an important and cost-effective step toward improving mentorship in STEM fields. PMID- 30397440 TI - Morphological and biological characterization of a light-colored mutant in the multicolored Asian lady beetle, Harmonia axyridis. AB - Insect cuticle color formed with melanin pigments has numerous types of mutants which usually cause pleiotropic effects. Melanism has been widely studied, but mutants with light-colored phenotype as well as the consequent fitness changes have rarely been reported.Here, in the laboratory strain of Harmonia axyridis, we found a novel mutant gr and confirmed that the mutation was inherited in a simple Mendelian autosomal recessive manner. This mutant (HAM) continuously displayed a light-colored pigmentation versus dark blackish in the wild phenotype (HAW). L DOPA and dopamine are melanin precursors, and less L-DOPA was present in the cuticle of larval and adult HAM mutants compared to HAW wild type, but more dopamine was detected in the larval cuticle of HAM (p <= 0.0235). For the orange background of elytra, the composition as well as total concentration of carotenoids was different between HAM and HAW, which resulted in significantly lower saturation value but significantly higher hue value in HAM than in HAW (p < 0.0001).Extensive fitness changes were detected in HAM. (a) HAM larvae had similar predation capacity and preimaginal development time as HAW, but the newly emerged adults were much smaller (p < 0.0001). (b) Both fecundity and egg hatch rate in cross ?(HAM) * ?(HAM) were significantly lower than those in ?(HAW) * ?(HAW) (p <= 0.0087), but were not different with those in ?(HAW) * ?(HAM). PMID- 30397441 TI - Interactions between two parasites of brown trout (Salmo trutta): Consequences of preinfection. AB - Preinfection by one parasitic species may facilitate or by contrast hamper the subsequent penetration and/or establishment of other parasites in a host. The biology of interacting species, timing of preinfection, and dosage of subsequent parasite exposure are likely important variables in this multiparasite dynamic infection process. The increased vulnerability to subsequent infection can be an important and often overlooked factor influencing parasite virulence. We investigated how the preinfection by freshwater pearl mussel Margaritifera margaritifera glochidia could influence the success of subsequent infection by the common trematode Diplostomum pseudospathaceum in brown trout Salmo trutta and vice versa whether preinfection by the trematode made fish more susceptible to glochidia infection. The first experiment was repeated twice with different (low and high) exposure doses to initiate the subsequent trematode infection, while in the second experiment we varied the timing of the preinfection with trematodes. The preinfection with glochidia made fish more vulnerable to subsequent infection with trematodes. Since the trematodes penetrate through the gills, we suggest that increased host vulnerability was most likely the result of increased respiration caused by the freshwater pearl mussel glochidia encysted on gills. In turn, brown trout preinfected with trematodes were more vulnerable to the subsequent glochidial infection, but only if they were preinfected shortly before the subsequent infection (20 hr). Fish preinfected with trematodes earlier (2 weeks before the subsequent infection) did not differ in their vulnerability to glochidia. These effects were observed at moderate intensities of infections similar to those that occur in nature. Our study demonstrates how the timing and sequence of exposure to parasitic species can influence infection success in a host-multiparasite system. It indicates that the negative influence of glochidia on host fitness is likely to be underestimated and that this should be taken into consideration when organizing freshwater pearl mussel restoration procedures. PMID- 30397442 TI - Nitrogen enrichment alters nutrient resorption and exacerbates phosphorus limitation in the desert shrub Artemisia ordosica. AB - Increasing nitrogen (N) deposition and precipitation are major drivers of global changes that are expected to influence plant nutrient resorption in desert ecosystems, where plant growth is often nutrient and water limited. However, knowledge on the effects of increased N and precipitation on them remain poorly understood. This study determined the effects of increased N (ambient, 60 kg N ha 1 year-1) and water supply (ambient, +20%, +40%), and their combination on the leaf nutrient resorption of Artemisia ordosica, a dominant shrub in the Mu Us Desert of northern China. After 2 years of treatments, only N addition significantly decreased the N resorption efficiency of A. ordosica. Both N and water addition had no effect on the phosphorus (P) resorption efficiency of this shrub, and there were no interactive effects of N and water availability on shrub nutrient resorption. The responses of shrub leaf N:P ratio tended to saturate as soil available N:P increased. The aboveground net primary productivity of A. ordosica was positively correlated with leaf P resorption efficiency, rather than N resorption efficiency. Our results suggest that N addition exacerbated the P limitation of the shrub growth and played a more fundamental role than water addition in controlling the nutrient resorption process of the desert shrub A. ordosica. This information contributes to understand the relationship between nutrient conservation strategy and plant growth of desert shrub species under global environmental changes. PMID- 30397443 TI - Host specificity driving genetic structure and diversity in ectoparasite populations: Coevolutionary patterns in Apodemus mice and their lice. AB - A degree of host specificity, manifested by the processes of host-parasite cospeciations and host switches, is assumed to be a major determinant of parasites' evolution. To understand these patterns and formulate appropriate ecological hypotheses, we need better insight into the coevolutionary processes at the intraspecific level, including the maintenance of genetic diversity and population structure of parasites and their hosts. Here, we address these questions by analyzing large-scale molecular data on the louse Polyplax serrata and its hosts, mice of the genus Apodemus, across a broad range of European localities. Using mitochondrial DNA sequences and microsatellite data, we demonstrate the general genetic correspondence of the Apodemus/Polyplax system to the scenario of the postglacial recolonization of Europe, but we also show several striking discrepancies. Among the most interesting are the evolution of different degrees of host specificity in closely related louse lineages in sympatry, or decoupled population structures of the host and parasites in central Europe. We also find strong support for the prediction that parasites with narrower host specificity possess a lower level of genetic diversity and a deeper pattern of interpopulation structure as a result of limited dispersal and smaller effective population size. PMID- 30397444 TI - DAR (diversity-area relationship): Extending classic SAR (species-area relationship) for biodiversity and biogeography analyses. AB - I extend the classic SAR, which has achieved status of ecological law and plays a critical role in global biodiversity and biogeography analyses, to general DAR (diversity-area relationship). The extension was aimed to remedy a serious application limitation of the traditional SAR that only addressed one aspect of biodiversity scaling-species richness scaling over space, but ignoring species abundance information. The extension was further inspired by a recent consensus that Hill numbers offer the most appropriate measures for alpha-diversity and multiplicative beta-diversity. In particular, Hill numbers are essentially a series of Renyi's entropy values weighted differently along the rare-common dominant spectrum of species abundance distribution and are in the units of effective number of species (or species equivalents such as OTUs). I therefore postulate that Hill numbers should follow the same or similar law of the traditional SAR. I test the postulation with the American gut microbiome project (AGP) dataset of 1,473 healthy North American individuals. I further propose three new concepts and develop their statistical estimation formulae based on the new DAR extension, including: (i) DAR profile-z-q relationship (DAR scaling parameter z at different diversity order q), (ii) PDO (pair-wise diversity overlap) profile-g-q relationship (PDO parameter g at order q, and (iii) MAD (maximal accrual diversity: D max) profile-D max-q. While the classic SAR is a special case of our new DAR profile, the PDO and MAD profiles offer novel tools for analyzing biodiversity (including alpha-diversity and beta-diversity) and biogeography over space. PMID- 30397445 TI - Predicted 2100 climate scenarios affects growth and skeletal development of tambaqui (Colossoma macropomum) larvae. AB - Climate changes driven by greenhouse gas emissions have been occurring in an accelerated degree, affecting environmental dynamics and living beings. Among all affected biomes, the Amazon is particularly subjected to adverse impacts, such as temperature rises and water acidification. This study aimed to evaluate the impacts of predicted climate change on initial growth and development of an important Amazonian food fish, the tambaqui. We analyzed growth performance, and monitored the initial osteogenic process and the emergence of skeletal anomalies, when larvae were exposed to three climate change scenarios: mild (B1, increase of 1.8 degrees C, 200 ppm of CO2); moderate (A1B, 2.8 degrees C, 400 ppm of CO2); and drastic (A2, 3.4 degrees C, 850 ppm of CO2), in addition to a control room that simulated the current climatic conditions of a pristine tropical forest. The exposure to climate change scenarios (B1, A1B, and A2) resulted in low survival, especially for the animals exposed to A2, (24.7 +/- 1.0%). Zootechnical performance under the B1 and A1B scenarios was higher when compared to current and A2, except for condition factor, which was higher in current (2.64 +/- 0.09) and A1B (2.41 +/- 0.14) scenarios. However, skeletal analysis revealed higher incidences of abnormalities in larvae exposed to A1B (34.82%) and A2 (39.91%) scenarios when compared to current (15.38%). Furthermore, the bone-staining process revealed that after 16 days posthatch (7.8 +/- 0.01 mm total length), skeletal structures were still cartilaginous, showing no mineralization in all scenarios. We concluded that tambaqui larvae are well-adapted to high temperatures and may survive mild climate change. However, facing more severe climate conditions, its initial development may be compromised, resulting in high mortality rates and increased incidence of skeletal anomalies, giving evidence that global climate change will hamper tambaqui larvae growth and skeletal ontogeny. PMID- 30397446 TI - Invasive alien shredders clear up invasive alien leaf litter. AB - Biological invasions have the potential to alter ecosystem processes profoundly, but invaders are rarely found alone. Interactions between different invasive alien species, and their cumulative impact on ecosystem functioning, have led to hypotheses of invasion meltdown whereby effects become additive leading to further ecosystem stress. Invasive riparian plants (e.g., Rhododendron ponticum) deposit leaf litter in freshwaters, which may be unconsumed by indigenous species, potentially affecting habitat heterogeneity and flow of energy to the food web. However, invasive alien decapod crustaceans are effective consumers of leaf litter, and it was hypothesized that they would also consume inputs of invasive riparian leaf litter. This study shows that invasive alien signal crayfish (Pacifastacus leniusculus) and Chinese mitten crab (Eriocheir sinensis) effectively break down different types of leaf litter, including invasive alien R. ponticum, at higher rates than indigenous white-clawed crayfish. Secondary products were more varied, with more fine particulate organic matter generated for the less palatable alien leaf litter species. Leaf species caused different changes in body mass of decapods but effects were heterogeneous by leaf and decapod: P. leniusculus showed lower mass loss when consuming R. ponticum while E. sinensis lost mass when consuming A. pseudoplatanus. Impacts of riparian invasions on detritus accumulation in freshwaters are thus potentially buffered by invasive alien decapods, illustrating a need for a more detailed consideration of both positive and negative interspecific feedbacks during biological invasions. PMID- 30397447 TI - Allometry and integration do not strongly constrain beak shape evolution in large billed (Corvus macrorhynchos) and carrion crows (Corvus corone). AB - A recent geometric morphometric study on certain landbird lineages revealed that a major part of the variation in beak shape is accounted for by skull size and cranial shape. The study interpreted this result as evidence for the presence of strong evolutionary constraints that severely prevented beak shape from evolving substantially away from predictions of allometry and morphological integration. However, there is another overlooked but similarly plausible explanation for this result: The reason why beak shape does not depart much from predictions might simply be that selection pressures favoring such changes in shape are themselves rare. Here, to evaluate the intensity of evolutionary constraints on avian beak shape more appropriately, we selected large-billed (Corvus macrorhynchos) and carrion crows (Corvus corone) as study objects. These landbird species seem to experience selection pressures favoring a departure from an allometric trajectory. A landmark-based geometric morphometric approach using three dimensional reconstructions of CT scan images revealed that only 45.4% of the total shape variation was explained by allometry and beak-braincase integration. This suggests that when a selection pressure acts in a different direction to allometry and integration, avian beak shape can react to it and evolve flexibly. As traditionally considered, evolutionary constraints on avian beak shape might not be all that strong. PMID- 30397448 TI - Development of a PCR-RFLP assay to identify Drosophila melanogaster among field collected larvae. AB - The fruit fly Drosophila melanogaster is a model organism to study several aspects of metazoan biology. Most of the work has been conducted in adult fruit flies, including laboratory and field-derived specimens, but Drosophila melanogaster larvae recently became a valuable model to better understand animal physiology, development, or host-microbe interactions. While adult flies can be easily assigned to a given Drosophila species based on morphological characteristics, such visual identification is more intricate at the larval stage. This could explain the limited number of studies focusing on larvae, especially field-derived samples. Here, we developed a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay that discriminates D. melanogaster from other ecologically relevant Drosophila species at the larval stage. The method, which targets the cytochrome oxidase I (COI) gene, was validated using laboratory-derived larvae from seven D. melanogaster populations originating from different geographic areas as well as six Drosophila species. We further validated this PCR-RFLP assay in a natural context, by identifying wild larvae collected in two locations in France. Notably, among all PCR-RFLP profiles that matched the D. melanogaster species, 100% were correctly identified, as confirmed by COI sequencing. In summary, our work provides a rapid, simple, and accurate molecular tool to identify D. melanogaster from field-collected larvae. PMID- 30397449 TI - Behavioral differences following ingestion of large meals and consequences for management of a harmful invasive snake: A field experiment. AB - Many snakes are uniquely adapted to ingest large prey at infrequent intervals. Digestion of large prey is metabolically and aerobically costly, and large prey boluses can impair snake locomotion, increasing vulnerability to predation. Cessation of foraging and use of refugia with microclimates facilitating digestion are expected to be strategies employed by free-ranging snakes to cope with the demands of digestion while minimizing risk of predation. However, empirical observations of such submergent behavior from field experiments are limited. The brown treesnake (Serpentes: Colubridae: Boiga irregularis) is a nocturnal, arboreal, colubrid snake that was accidentally introduced to the island of Guam, with ecologically and economically costly consequences. Because tools for brown treesnake damage prevention generally rely on snakes being visible or responding to lures or baits while foraging, cessation of foraging activities after feeding would complicate management. We sought to characterize differences in brown treesnake activity, movement, habitat use, and detectability following feeding of large meals (rodents 33% of the snake's unfed body mass) via radio telemetry, trapping, and visual surveys. Compared to unfed snakes, snakes in the feeding treatment group showed drastic decreases in hourly and nightly activity rates, differences in refuge height and microhabitat type, and a marked decrease in detectability by trapping and visual surveys. Depression of activity lasted approximately 5-7 days, a period that corresponds to previous studies of brown treesnake digestion and cycles of detectability. Our results indicate that management strategies for invasive brown treesnakes need to account for cycles of unavailability and underscore the importance of preventing spread of brown treesnakes to new environments where large prey are abundant and periods of cryptic behavior are likely to be frequent. Characterization of postfeeding behavior changes provides a richer understanding of snake ecology and foraging models for species that consume large prey. PMID- 30397450 TI - Biodiversity explains maximum variation in productivity under experimental warming, nitrogen addition, and grazing in mountain grasslands. AB - Anthropogenic global warming, nitrogen addition, and overgrazing alter plant communities and threaten plant biodiversity, potentially impacting community productivity, especially in sensitive mountain grassland ecosystems. However, it still remains unknown whether the relationship between plant biodiversity and community productivity varies across different anthropogenic influences, and especially how changes in multiple biodiversity facets drive these impacts on productivity. Here, we measured different facets of biodiversity including functional and phylogenetic richness and evenness in mountain grasslands along an environmental gradient of elevation in Yulong Mountain, Yunnan, China. We combined biodiversity metrics in a series of linear mixed-effect models to determine the most parsimonious predictors for productivity, which was estimated by aboveground biomass in community. We examined how biodiversity-productivity relationships were affected by experimental warming, nitrogen addition, and livestock-grazing. Species richness, phylogenetic diversity, and single functional traits (leaf nitrogen content, mg/g) represented the most parsimonious combination in these scenarios, supporting a consensus that single-biodiversity metrics alone cannot fully explain ecosystem function. The biodiversity productivity relationships were positive and strong, but the effects of treatment on biodiversity-productivity relationship were negligible. Our findings indicate that the strong biodiversity-productivity relationships are consistent in various anthropogenic drivers of environmental change. PMID- 30397451 TI - The effects of warming and nitrogen addition on ecosystem respiration in a Tibetan alpine meadow: The significance of winter warming. AB - In recent decades, global warming has become an indisputable fact on the Tibetan Plateau. Alpine ecosystems are very sensitive to global warming, and the impact may depend on the degree of atmospheric nitrogen (N) deposition. The previous studies have paid more attention to year-round warming, but the effect of winter warming has been unstudied. In this study, a manipulative experiment was conducted, consisting of warming and N addition. It was carried out since 2010 in an alpine meadow, and three types of warming treatments were set up: no warming (NW), year-round (YW), and winter warming (WW). Warming significantly increased air and soil temperature, but decreased soil moisture. Under no N addition, YW showed significantly decreased ecosystem respiration (Reco) in 2012, and WW decreased Reco in 2014. Under N addition, neither YW nor WW had significant effects on Reco, indicating that N addition compensated the negative effect of warming on Reco. Annually, YW and WW decreased ecosystem carbon (C) emissions, and the extent of the reduction was even larger under WW. Under no N addition, both YW and WW significantly decreased aboveground biomass. Moreover, especially under no N, YW and WW significantly decreased soil inorganic N. WW also had negative effects on soil microbial biomass C. Structure equation modeling showed that soil moisture was the most important factors controlling Reco, and soil inorganic N content and microbial biomass C could explain 46.6% and 16.8% of the variation of Reco. The findings indicate that soil property changes under warming had substantial effects on ecosystem C efflux. The inhibitory effects of winter warming on ecosystem C efflux were mainly attributed to the decline of soil N and microbial biomass. Thus, the effects of winter warming on ecosystem C emissions in this semiarid alpine meadow are not as serious as expected and largely depend on N deposition. PMID- 30397452 TI - Long-lasting effects of logging on beetles in hollow oaks. AB - There is growing evidence that biodiversity is important for ecosystem functions. Thus, identification of habitat requirements essential for current species richness and abundance to persist is crucial. Hollow oaks (Quercus spp.) are biodiversity hot spots for deadwood-dependent insect species, and the main objective of this paper was to test the effect of habitat history and current habitat distribution at various spatial scales on the associated beetle community. We used a gradient spanning 40 km from the coast to inland areas reflecting historical logging intensity (later and lower intensities inland) through 500 years in Southern Norway, to investigate whether the historical variation in oak density is influencing the structure of beetle communities in hollow oaks today. We trapped beetles in 32 hollow oaks along this gradient in forested and seminatural landscapes over two summers. We found higher species richness and total abundance inland consistent with our expectation based on historic logging intensity. Scale-specific environmental variables also affected the response; beetle abundances were controlled by local conditions, whereas beetle species richness responded to habitat on the landscape scale. This indicates that long time continuity as well as large areas of favorable habitat is necessary to maintain beetle species richness through time in these highly long-lasting structures. PMID- 30397453 TI - Evolutionary history of the endemic water shrew Neomys anomalus: Recurrent phylogeographic patterns in semi-aquatic mammals of the Iberian Peninsula. AB - The Cabrera's water shrew (Neomys anomalus) is a small semi-aquatic mammal whose taxonomic status was recently elevated from subspecies to species; as a consequence of this change, this species is now endemic to the Iberian Peninsula. In this study, we looked at its evolutionary history by combining phylogeography, the spatial distribution of genetic diversity, and species distribution modeling. To perform these analyses, we used noninvasive samples collected across the species distribution range and sequenced partial mitochondrial cytochrome b and D loop genes. Maximum-likelihood and Bayesian phylogenetic trees derived from these sequences indicated that N. anomalus is divided into two main phylogroups that correlate strongly with geography, with two contact zones between the groups that showed limited spatial mixing between them. River basins were responsible for only a small percentage of the structure of the genetic diversity of this species despite its riparian habitat. The nucleotide diversity variation map showed the highest genetic diversity to be in the north of the Iberian Peninsula. Finally, species distribution modeling allowed the inference of an optimal area during the Last Interglacial in the north of the Iberian Peninsula, and multiple glacial refugia during the Last Glacial Maximum. The phylogeographic pattern of N. anomalus is strikingly similar to that of another semi-aquatic Iberian mammal, the Pyrenean desman (Galemys pyrenaicus), revealing how Pleistocene glaciations could have had equivalent effects on species of similar ecology and distribution. This phylogeographic structure is consistent with N. anomalus having been isolated for long periods in multiple glacial refugia within the Iberian Peninsula, in agreement with the "refugia-within-refugia" hypothesis, and further supporting its status as a distinct species. PMID- 30397454 TI - Foraging investment in a long-lived herbivore and vulnerability to coursing and stalking predators. AB - Allocating resources to growth and reproduction requires grazers to invest time in foraging, but foraging promotes dental senescence and constrains expression of proactive antipredator behaviors such as vigilance. We explored the relationship between carnivore prey selection and prey foraging effort using incisors collected from the kills of coursing and stalking carnivores. We predicted that prey investing less effort in foraging would be killed more frequently by coursers, predators that often exploit physical deficiencies. However, such prey could expect delayed dental senescence. We predicted that individuals investing more effort in foraging would be killed more frequently by stalkers, predators that often exploit behavioral vulnerabilities. Further these prey could expect earlier dental senescence. We tested these predictions by comparing variation in age-corrected tooth wear, a proxy of cumulative foraging effort, in adult (3.4 11.9 years) wildebeest killed by coursing and stalking carnivores. Predator type was a strong predictor of age-corrected tooth wear within each gender. We found greater foraging effort and earlier expected dental senescence, equivalent to 2.6 additional years of foraging, in female wildebeest killed by stalkers than in females killed by coursers. However, male wildebeest showed the opposite pattern with the equivalent of 2.4 years of additional tooth wear in males killed by coursers as compared to those killed by stalkers. Sex-specific variation in the effects of foraging effort on vulnerability was unexpected and suggests that behavioral and physical aspects of vulnerability may not be subject to the same selective pressures across genders in multipredator landscapes. PMID- 30397455 TI - Limited introgression supports division of giraffe into four species. AB - All giraffe (Giraffa) were previously assigned to a single species (G. camelopardalis) and nine subspecies. However, multi-locus analyses of all subspecies have shown that there are four genetically distinct clades and suggest four giraffe species. This conclusion might not be fully accepted due to limited data and lack of explicit gene flow analyses. Here, we present an extended study based on 21 independent nuclear loci from 137 individuals. Explicit gene flow analyses identify less than one migrant per generation, including between the closely related northern and reticulated giraffe. Thus, gene flow analyses and population genetics of the extended dataset confirm four genetically distinct giraffe clades and support four independent giraffe species. The new findings support a revision of the IUCN classification of giraffe taxonomy. Three of the four species are threatened with extinction, and mostly occurring in politically unstable regions, and as such, require the highest conservation support possible. PMID- 30397456 TI - How to quantify animal activity from radio-frequency identification (RFID) recordings. AB - Automated animal monitoring via radio-frequency identification (RFID) technology allows efficient and extensive data sampling of individual activity levels and is therefore commonly used for ecological research. However, processing RFID data is still a largely unresolved problem, which potentially leads to inaccurate estimates for behavioral activity. One of the major challenges during data processing is to isolate independent behavioral actions from a set of superfluous, nonindependent detections. As a case study, individual blue tits (Cyanistes caeruleus) were simultaneously monitored during reproduction with both video recordings and RFID technology. We demonstrated how RFID data can be processed based on the time spent in- and outside a nest box. We then validated the number and timing of nest visits obtained from the processed RFID dataset by calibration against video recordings. The video observations revealed a limited overlap between the time spent in- and outside the nest box, with the least overlap at 23 s for both sexes. We then isolated exact arrival times from redundant RFID registrations by erasing all successive registrations within 23 s after the preceding registration. After aligning the processed RFID data with the corresponding video recordings, we observed a high accuracy in three behavioral estimates of parental care (individual nest visit rates, within-pair alternation and synchronization of nest visits). We provide a clear guideline for future studies that aim to implement RFID technology in their research. We argue that our suggested RFID data processing procedure improves the precision of behavioral estimates, despite some inevitable drawbacks inherent to the technology. Our method is useful, not only for other cavity breeding birds, but for a wide range of (in)vertebrate species that are large enough to be fitted with a tag and that regularly pass near or through a fixed antenna. PMID- 30397457 TI - Evaluating the ability of community-protected forests in Cambodia to prevent deforestation and degradation using temporal remote sensing data. AB - Community forests are known to play an important role in preserving forests in Cambodia, a country that has seen rapid deforestation in recent decades. The detailed evaluation of the ability of community-protected forests to retain forest cover and prevent degradation in Cambodia will help to guide future conservation management. In this study, a combination of remotely sensing data was used to compare the temporal variation in forest structure for six different community forests located in the Phnom Kulen National Park (PKNP) in Cambodia and to assess how these dynamics vary between community-protected forests and a wider study area. Medium-resolution Landsat, ALOS PALSAR data, and high-resolution LiDAR data were used to study the spatial distribution of forest degradation patterns and their impacts on above-ground biomass (AGB) changes. Analysis of the remotely sensing data acquired at different spatial resolutions revealed that between 2012 and 2015, the community forests had higher forest cover persistence and lower rates of forest cover loss compared to the entire study area. Furthermore, they faced lower encroachment from cashew plantations compared to the wider landscape. Four of the six community forests showed a recovery in canopy gap fractions and subsequently, an increase in the AGB stock. The levels of degradation decreased in forests that had an increase in AGB values. However, all community forests experienced an increase in understory damage as a result of selective tree removal, and the community forests with the sharpest increase in understory damage experienced AGB losses. This is the first time multitemporal high-resolution LiDAR data have been used to analyze the impact of human-induced forest degradation on forest structure and AGB. The findings of this work indicate that while community-protected forests can improve conservation outcomes to some extent, more interventions are needed to curb the illegal selective logging of valuable timber trees. PMID- 30397458 TI - Dynamic occupancy modeling of temperate marine fish in area-based closures. AB - Species distribution models (SDMs) are commonly used to model the spatial structure of species in the marine environment, however, most fail to account for detectability of the target species. This can result in underestimates of occupancy, where nondetection is conflated with absence. The site occupancy model (SOM) overcomes this failure by treating occupancy as a latent variable of the model and incorporates a detection submodel to account for variability in detection rates. These have rarely been applied in the context of marine fish and never for the multiseason dynamic occupancy model (DOM). In this study, a DOM is developed for a designated species of concern, cusk (Brosme brosme), over a four season period. Making novel use of a high-resolution 3-dimensional hydrodynamic model, detectability of cusk is considered as a function of current speed and algae cover. Algal cover on the seabed is measured from video surveys to divide the study area into two distinct regions: those with canopy forming species of algae and those without (henceforth bottom types). Modeled estimates of the proportion of sites occupied in each season are 0.88, 0.45, 0.74, and 0.83. These are significantly greater than the proportion of occupied sites measured from underwater video observations which are 0.57, 0.28, 0.43, and 0.57. Individual fish are detected more frequently with increasing current speed in areas lacking canopy and less frequently with increasing current speed in areas with canopy. The results indicate that, where possible, SDM studies for all marine species should take account of detectability to avoid underestimating the proportion of sites occupied at a given study area. Sampling closed areas or areas of conservation often requires the use of nonphysical, low impact sampling methods like camera surveys. These methods inherently result in detection probabilities less than one, an issue compounded by time-varying features of the environment that are rarely accounted for marine studies. This work highlights the use of modeled hydrodynamics as a tool to correct some of this imbalance. PMID- 30397459 TI - Assessing scale-wise similarity of curves with a thick pen: As illustrated through comparisons of spectral irradiance. AB - Forest canopies create dynamic light environments in their understorey, where spectral composition changes among patterns of shade and sunflecks, and through the seasons with canopy phenology and sun angle. Plants use spectral composition as a cue to adjust their growth strategy for optimal resource use. Quantifying the ever-changing nature of the understorey light environment is technically challenging with respect to data collection. Thus, to capture the simultaneous variation occurring in multiple regions of the solar spectrum, we recorded spectral irradiance from forest understoreys over the wavelength range 300-800 nm using an array spectroradiometer. It is also methodologically challenging to analyze solar spectra because of their multi-scale nature and multivariate lay out. To compare spectra, we therefore used a novel method termed thick pen transform (TPT), which is simple and visually interpretable. This enabled us to show that sunlight position in the forest understorey (i.e., shade, semi-shade, or sunfleck) was the most important factor in determining shape similarity of spectral irradiance. Likewise, the contributions of stand identity and time of year could be distinguished. Spectra from sunflecks were consistently the most similar, irrespective of differences in global irradiance. On average, the degree of cross-dependence increased with increasing scale, sometimes shifting from negative (dissimilar) to positive (similar) values. We conclude that the interplay of sunlight position, stand identity, and date cannot be ignored when quantifying and comparing spectral composition in forest understoreys. Technological advances mean that array spectroradiometers, which can record spectra contiguously over very short time intervals, are being widely adopted, not only to measure irradiance under pollution, clouds, atmospheric changes, and in biological systems, but also spectral changes at small scales in the photonics industry. We consider that TPT is an applicable method for spectral analysis in any field and can be a useful tool to analyze large datasets in general. PMID- 30397460 TI - Evolution of nuchal glands, unusual defensive organs of Asian natricine snakes (Serpentes: Colubridae), inferred from a molecular phylogeny. AB - A large body of evidence indicates that evolutionary innovations of novel organs have facilitated the subsequent diversification of species. Investigation of the evolutionary history of such organs should provide important clues for understanding the basis for species diversification. An Asian natricine snake, Rhabdophis tigrinus, possesses a series of unusual organs, called nuchal glands, which contain cardiotonic steroid toxins known as bufadienolides. Rhabdophis tigrinus sequesters bufadienolides from its toad prey and stores them in the nuchal glands as a defensive mechanism. Among more than 3,500 species of snakes, only 17 Asian natricine species are known to possess nuchal glands or their homologues. These 17 species belong to three nominal genera, Balanophis, Macropisthodon, and Rhabdophis. In Macropisthodon and Rhabdophis, however, species without nuchal glands also exist. To infer the evolutionary history of the nuchal glands, we investigated the molecular phylogenetic relationships among Asian natricine species with and without nuchal glands, based on variations in partial sequences of Mt-CYB, Cmos, and RAG1 (total 2,767 bp). Results show that all species with nuchal glands belong to a single clade (NGC). Therefore, we infer that the common ancestor of this clade possessed nuchal glands with no independent origins of the glands within the members. Our results also imply that some species have secondarily lost the glands. Given the estimated divergence time of related species, the ancestor of the nuchal gland clade emerged 19.18 mya. Our study shows that nuchal glands are fruitful subjects for exploring the evolution of novel organs. In addition, our analysis indicates that reevaluation of the taxonomic status of the genera Balanophis and Macropisthodon is required. We propose to assign all species belonging to the NGC to the genus Rhabdophis, pending further study. PMID- 30397461 TI - The population and landscape genetics of the European badger (Meles meles) in Ireland. AB - The population genetic structure of free-ranging species is expected to reflect landscape-level effects. Quantifying the role of these factors and their relative contribution often has important implications for wildlife management. The population genetics of the European badger (Meles meles) have received considerable attention, not least because the species acts as a potential wildlife reservoir for bovine tuberculosis (bTB) in Britain and Ireland. Herein, we detail the most comprehensive population and landscape genetic study of the badger in Ireland to date-comprised of 454 Irish badger samples, genotyped at 14 microsatellite loci. Bayesian and multivariate clustering methods demonstrated continuous clinal variation across the island, with potentially distinct differentiation observed in Northern Ireland. Landscape genetic analyses identified geographic distance and elevation as the primary drivers of genetic differentiation, in keeping with badgers exhibiting high levels of philopatry. Other factors hypothesized to affect gene flow, including earth worm habitat suitability, land cover type, and the River Shannon, had little to no detectable effect. By providing a more accurate picture of badger population structure and the factors effecting it, these data can guide current efforts to manage the species in Ireland and to better understand its role in bTB. PMID- 30397462 TI - Giant coral reef fishes display markedly different susceptibility to night spearfishing. AB - The humphead wrasse (Cheilinus undulatus) and bumphead parrotfish (Bolbometopon muricatum) are two of the largest, most iconic fishes of Indo-Pacific coral reefs. Both species form prized components of subsistence and commercial fisheries and are vulnerable to overfishing. C. undulatus is listed as Endangered and B. muricatum as Vulnerable on the IUCN Red List of Threatened Species. We investigated how night spearfishing pressure and habitat associations affected both species in a relatively lightly exploited setting; the Kia fishing grounds, Isabel Province, Solomon Islands. We used fisheries-independent data from underwater visual census surveys and negative binomial models to estimate abundances of adult C. undulatus and B. muricatum as a function of spearfishing pressure and reef strata. Our results showed that, in Kia, night spearfishing pressure from free divers had no measurable effect on C. undulatus abundances, but abundances of B. muricatum were 3.6 times lower in areas of high spearfishing pressure, after accounting for natural variations due to habitat preferences. It is likely the species' different nocturnal aggregation behaviors, combined with the fishers' use of night spearfishing by spot-checking underpin these species' varying susceptibility. Our study highlights that B. muricatum is extremely susceptible to night spearfishing; however, we do not intend to draw conservation attention away from C. undulatus. Our data relate only to the Kia fishing grounds, where human population density is low, the spot-checking strategy is effective for reliably spearing large numbers of fish, particularly B. muricatum, and fisheries have only recently begun to be commercialized; such conditions are increasingly rare. Instead, we recommend that regional managers assess the state of their fisheries and the dynamics affecting the vulnerability of the fishes to fishing pressure based on local-scale, fisheries-independent data, where resources permit. PMID- 30397463 TI - Social density, but not sex ratio, drives ecdysteroid hormone provisioning to eggs by female house crickets (Acheta domesticus). AB - Social environment profoundly influences the fitness of animals, affecting their probability of survival to adulthood, longevity, and reproductive output. The social conditions experienced by parents at the time of reproduction can predict the social environments that offspring will face. Despite clear challenges in predicting future environmental conditions, adaptive maternal effects provide a mechanism of passing environmental information from parent to offspring and are now considered pervasive in natural systems. Maternal effects have been widely studied in vertebrates, especially in the context of social environment, and are often mediated by steroid hormone (SH) deposition to eggs. In insects, although many species dramatically alter phenotype and life-history traits in response to social density, the mechanisms of these alterations, and the role of hormone deposition by insect mothers into their eggs, remains unknown. In the experiments described here, we assess the effects of social environment on maternal hormone deposition to eggs in house crickets (Acheta domesticus). Specifically, we tested the hypotheses that variable deposition of ecdysteroid hormones (ESH) to eggs is affected by both maternal (a) social density and (b) social composition. We found that while maternal hormone deposition to eggs does not respond to social composition (sex ratio), it does reflect social density; females provision their eggs with higher ESH doses under low-density conditions. This finding is consistent with the interpretation that variable ESH provisioning is an adaptive maternal response to social environment and congruent with similar patterns of variable maternal provisioning across the tree of life. Moreover, our results confirm that maternal hormone provisioning may mediate delayed density dependence by introducing a time lag in the response of offspring phenotype to population size. PMID- 30397464 TI - SamplEase: a simple application for collection and organization of biological specimen data in the field. AB - Careful collection and organization of biological specimens and their associated data are at the core of field research (e.g., ecology, genetics). Fieldwork data are often collected by handwriting or unsystematically via an electronic device (e.g., laptop), a process that is time-intensive, disorganized, and may lead to transcription errors, as data are copied to a more permanent repository. SamplEase is an iOS and Android application that is designed to ease the process of collecting biological specimen data in the field (data associated with biological samples, such as location, age, and sex). In addition to biological specimen data, SamplEase allows for the assignment of photographs to each collected sample, which provides visual records of each specimen in its environment. SamplEase outputs biological specimen data in a tabular format, facilitating subsequent analyses and dissemination. Despite the simplicity of SamplEase, no similar data management application is readily available for researchers. PMID- 30397466 TI - Nematode community responses to range-expanding and native plant communities in original and new range soils. AB - Many plant species expand their range to higher latitudes in response to climate change. However, it is poorly understood how biotic interactions in the new range differ from interactions in the original range. Here, in a mesocosm experiment, we analyze nematode community responses in original and new range soils to plant communities with either (a) species native in both the original and new range, (b) range-expanding species related to these natives (related range expanders), or (c) range expanders without native congeneric species in the new range (unrelated range expanders). We hypothesized that nematode community shifts between ranges are strongest for unrelated range expanders and minimal for plant species that are native in both ranges. As a part of these community shifts, we hypothesized that range expanders, but not natives, would accumulate fewer root feeding nematodes in their new range compared to their original range. Analyses of responses of nematodes from both original and new ranges and comparison between range expanders with and without close relatives have not been made before. Our study reveals that none of the plant communities experienced evident nematode community shifts between the original and new range. However, in soils from the new range, root-feeding nematode communities of natives and related range expanders were more similar than in soils from the original range, whereas the nematode community of unrelated range expanders was distinct from the communities of natives and related range expanders in soils from both ranges. The abundances of root-feeding nematodes were comparable between the original and new range for all plant communities. Unexpectedly, unrelated range expanders overall accumulated most root-feeding nematodes, whereas related range expanders accumulated fewest. We conclude that nematode communities associated with native and range-expanding plant species differ between the original and the new range, but that range-expanding plant species do not accumulate fewer root-feeding nematodes in their new than in their original range. PMID- 30397467 TI - Using ring-recovery and within-season recapture data to estimate fecundity and population growth. AB - Tag-recovery data from organisms captured and marked post breeding are commonly used to estimate juvenile and adult survival. If annual fecundity could also be estimated, tagging studies such as European and North American bird-ringing schemes could provide all parameters needed to estimate population growth. I modified existing tag-recovery models to allow estimation of annual fecundity using age composition and recapture probabilities obtained during routine banding operations of northern pintails (Anas acuta) and dark-eyed juncos (Junco hyemalis), and I conducted simulations to assess estimator performance in relation to sample size. For pintails, population growth rate from band-recovery data (lambda = 0.93, SD: 0.06) was similar but less precise than count-based estimates from the Waterfowl Breeding Pair and Habitat Survey (lambda: 0.945, SE: 0.001). Models with temporal variation in vital rates indicated that annual population growth in pintails was driven primarily by variation in fecundity. Juncos had lower survival but greater fecundity, and their estimated population growth rate (lambda: 1.01, SD: 0.19) was consistent with count-based surveys (lambda: 0.986). Simulations indicated that reliable (CV < 0.10) estimates of fecundity could be obtained with >1,000 within-season live encounters. Although precision of survival estimates depended primarily on numbers of adult recoveries, estimates of fecundity and population growth were most sensitive to total number of live encounters. Synthesis and applications: Large-scale ring recovery programs could be used to estimate annual fecundity in many species of birds, but the approach requires better data curation, including accurate assessment of age, better reporting of banding totals, and greater emphasis on obtaining and reporting within-season live encounters. PMID- 30397465 TI - Methylation divergence of invasive Ciona ascidians: Significant population structure and local environmental influence. AB - The geographical expansion of invasive species usually leads to temporary and/or permanent changes at multiple levels (genetics, epigenetics, gene expression, etc.) to acclimatize to abiotic and/or biotic stresses in novel environments. Epigenetic variation such as DNA methylation is often involved in response to diverse local environments, thus representing one crucial mechanism to promote invasion success. However, evidence is scant on the potential role of DNA methylation variation in rapid environmental response and invasion success during biological invasions. In particular, DNA methylation patterns and possible contributions of varied environmental factors to methylation differentiation have been largely unknown in many invaders, especially for invasive species in marine systems where extremely complex interactions exist between species and surrounding environments. Using the methylation-sensitive amplification polymorphism (MSAP) technique, here we investigated population methylation structure at the genome level in two highly invasive model ascidians, Ciona robusta and C. intestinalis, collected from habitats with varied environmental factors such as temperature and salinity. We found high intrapopulation methylation diversity and significant population methylation differentiation in both species. Multiple analyses, such as variation partitioning analysis, showed that both genetic variation and environmental factors contributed to the observed DNA methylation variation. Further analyses found that 24 and 20 subepiloci were associated with temperature and/or salinity in C. robusta and C. intestinalis, respectively. All these results clearly showed significant methylation divergence among populations of both invasive ascidians, and varied local environmental factors, as well as genetic variation, were responsible for the observed DNA methylation patterns. The consistent findings in both species here suggest that DNA methylation, coupled with genetic variation, may facilitate local environmental adaptation during biological invasions, and DNA methylation variation molded by local environments may contribute to invasion success. PMID- 30397468 TI - At the confluence of vicariance and dispersal: Phylogeography of cavernicolous springtails (Collembola: Arrhopalitidae, Tomoceridae) codistributed across a geologically complex karst landscape in Illinois and Missouri. AB - The processes of vicariance and dispersal are central to our understanding of diversification, yet determining the factors that influence these processes remains a significant challenge in evolutionary biology. Caves offer ideal systems for examining the mechanisms underlying isolation, divergence, and speciation. Intrinsic ecological differences among cavernicolous organisms, such as the degree of cave dependence, are thought to be major factors influencing patterns of genetic isolation in caves. Using a comparative phylogeographic approach, we employed mitochondrial and nuclear markers to assess the evolutionary history of two ecologically distinct groups of terrestrial cave dwelling springtails (Collembola) in the genera Pygmarrhopalites (Arrhopalitidae) and Pogonognathellus (Tomoceridae) that are codistributed in caves throughout the Salem Plateau-a once continuous karst region, now bisected by the Mississippi River Valley in Illinois and Missouri. Contrasting phylogeographic patterns recovered for troglobiotic Pygmarrhopalites sp. and eutroglophilic Pogonognathellus sp. suggests that obligate associations with cave habitats can restrict dispersal across major geographic barriers such as rivers and valleys, but may also facilitate subterranean dispersal between neighboring cave systems. Pygmarrhopalites sp. populations spanning the Mississippi River Valley were estimated to have diverged 2.9-4.8 Ma, which we attribute to vicariance resulting from climatic and geological processes involved in Mississippi River Valley formation beginning during the late Pliocene/early Pleistocene. Lastly, we conclude that the detection of many deeply divergent, morphologically cryptic, and microendemic lineages highlights our poor understanding of microarthropod diversity in caves and exposes potential conservation concerns. PMID- 30397469 TI - Vegetation type and grazing intensity jointly shape grazing effects on grassland biodiversity. AB - In the Palaearctic steppe zone, overgrazing was identified as one of the key drivers of declining grassland biodiversity, which underlines the necessity of the functional evaluation of increased grazing pressure on grassland vegetation. We tested the following hypotheses: (a) The effect of grazing intensity on species and functional diversity is strongly dependent on grassland type. (b) The magnitude of diet selectivity of grazers decreases with increasing grazing intensity. (c) Increasing grazing intensity increases evenness and functional evenness of the subjected grasslands. We analyzed vegetation patterns in four types of grasslands (Dry alkali short-grass steppes, Dry loess steppes, Non alkali wet and Alkali wet grasslands) along an intensity gradient of beef cattle grazing at 73 sites in Hungary. Species richness, Shannon diversity, evenness, and four leaf traits were analyzed. We calculated community-weighted means for each single trait, and multi-trait functional richness, functional evenness, and divergence for all leaf traits. All species and functional diversity metrics were significantly affected by the grassland type, except leaf dry matter content. The effect of interaction between grazing intensity and grassland type was also significant for functional richness, functional evenness, community-weighted means of leaf area, and for species richness and evenness. An upward trend of specific leaf area was detected in all grasslands with the highest scores for the overgrazed sites, but the change was also grassland type dependent. The detected trend suggests that with increased intensity the overall selectivity of grazing decreased. We found that evenness was affected but functional evenness was not affected by grazing intensity. Functional evenness scores were more related to the grassland type than to changes in grazing intensity, and displayed a high variability. We stress that one-size-fits-all strategies cannot be recommended and actions should be fine-tuned at least at the level of grassland type. PMID- 30397470 TI - State space and movement specification in open population spatial capture recapture models. AB - With continued global changes, such as climate change, biodiversity loss, and habitat fragmentation, the need for assessment of long-term population dynamics and population monitoring of threatened species is growing. One powerful way to estimate population size and dynamics is through capture-recapture methods. Spatial capture (SCR) models for open populations make efficient use of capture recapture data, while being robust to design changes. Relatively few studies have implemented open SCR models, and to date, very few have explored potential issues in defining these models. We develop a series of simulation studies to examine the effects of the state-space definition and between-primary-period movement models on demographic parameter estimation. We demonstrate the implications on a 10-year camera-trap study of tigers in India. The results of our simulation study show that movement biases survival estimates in open SCR models when little is known about between-primary-period movements of animals. The size of the state space delineation can also bias the estimates of survival in certain cases.We found that both the state-space definition and the between-primary-period movement specification affected survival estimates in the analysis of the tiger dataset (posterior mean estimates of survival ranged from 0.71 to 0.89). In general, we suggest that open SCR models can provide an efficient and flexible framework for long-term monitoring of populations; however, in many cases, realistic modeling of between-primary-period movements is crucial for unbiased estimates of survival and density. PMID- 30397471 TI - Help at hand: Women's experiences of using a mobile health application upon diagnosis of asymptomatic osteoporosis. AB - Objectives: This study aims to test a mobile health application (mHealth app) developed to meet the needs of women newly diagnosed with asymptomatic osteoporosis. We investigate how the women experience using an mHealth app upon diagnosis of osteoporosis and whether the app can help them to be prepared for treatment decision-making and support them in osteoporosis self-management. We also tested the usability of the app, to find out whether any adjustments were necessary prior to implementation. Methods: A test was conducted at a Danish university hospital with 18 women aged 50-65, newly diagnosed with asymptomatic osteoporosis. On presenting for a bone density scan at the hospital, they were provided with the app, which was named 'My Osteoporosis Journey'. Data were collected through semi-structured interviews. Giorgi's descriptive phenomenological method guided the data analysis in four steps. Findings: In total, 17 women succeeded in downloading the app, thereby accessing information on asymptomatic osteoporosis, their bone density scan results and treatment recommendations prior to visiting their general practitioner. Three overall themes were identified. Women experienced that the app (1) gave a feeling of confidence and reassurance, (2) prepared the women on treatment decision-making in the general practitioner visit and (3) provided help at hand in self management of osteoporosis. Conclusion: Our findings show that the mHealth app helps women to feel confident and reassured upon diagnosis of asymptomatic osteoporosis. The women felt that the app promoted an equal dialogue in the osteoporosis consultation since they felt prepared for visiting their general practitioner and were able to articulate their individual needs regarding treatment. After diagnosis, the women felt that the app provided support in self management, right at their fingertips. PMID- 30397473 TI - Reference intervals for hematology test parameters from apparently healthy individuals in southwest Ethiopia. AB - Background: Clinical laboratory reference intervals are an important tool to identify abnormal laboratory test results. The generating of hematological parameters reference intervals for local population is very crucial to improve quality of health care, which otherwise may lead to unnecessary expenditure or denying care for the needy. There are no well-established reference intervals for hematological parameters in southwest Ethiopia. Objective: To generate hematological parameters reference intervals for apparently healthy individuals in southwest Ethiopia. Methods: A community-based cross-sectional study was conducted involving 883 individuals from March to May 2017. Four milliliter of blood sample was collected and transported to Jimma University Medical Center Laboratory for hematological analysis and screening tests. A hematological parameters were measured by Sysmex XS-500i hematology analyzer (Sysmex Corporation Kobe, Japan). The data were analyzed by SPSS version 20 statistical software. The non-parametric independent Kruskal-Wallis test and Wilcoxon rank sum test (Mann-Whitney U test) were used to compare the parameters between age groups and genders. The 97.5 percentile and 2.5 percentile were the upper and lower reference limit for the population. Results: The reference interval of red blood cell, white blood cell, and platelet count in children were 4.99 * 1012/L (4.26-5.99 * 1012/L), 7.04 * 109/L (4.00-11.67 * 109/L), and 324.00 * 109/L (188.00-463.50 * 109/L), respectively. The reference interval of red blood cell, white blood cell, and platelet count in adults was 5.19 * 1012/L (4.08-6.33 * 1012/L), 6.35 * 109/L (3.28-11.22 * 109/L), and 282.00 * 109/L (172.50-415.25 * 109/L), respectively. The reference interval of red blood cell, white blood cell, and platelet count in geriatrics were 5.02 * 1012/L (4.21-5.87 * 1012/L), 6.21 * 109/L (3.33-10.03 * 109/L), and 265.50 * 109/L (165.53-418.80 * 109/L), respectively. Most of the hematological parameters showed significant differences across all age groups. Conclusion: Most of the hematological parameters in this study showed differences from similar studies done in the country. This study provided population-specific hematological reference interval for southwest Ethiopians. Reference intervals should also be established in the other regions of the country. PMID- 30397474 TI - Angiosarcoma complicating lower leg elephantiasis in a male patient: An unusual clinical complication, case report and literature review. AB - Chronic lymphedema is rarely complicated by an angiosarcoma. Angiosarcoma superimposed on chronic lymphedema (Stewart-Treves syndrome) is usually seen post breast cancer surgery accompanied by lymph node resection of the axilla. This is a case report of a 59-year-old male patient with elephantiasis that developed an angiosarcoma of the lower leg. He died a month after the diagnostic biopsy was obtained. This is a rare multifocal tumor in a male with an unusual lower leg location. We reviewed the literature and the need to differentiate this often deadly lesion from a Kaposi's sarcoma. PMID- 30397475 TI - Trichohepatoenteric syndrome: A rare mutation in SKIV2L gene in the first Balkan reported case. AB - Trichohepatoenteric syndrome or syndromic diarrhea is a rare and severe Mendelian autosomal recessive syndrome characterized by intractable diarrhea, facial and hair abnormalities, liver dysfunction, immunodeficiency and failure to thrive. It has been associated with mutations in TTC37 and SKIV2L genes, which encode proteins of the SKI complex that contributes to the cytosolic degradation of the messenger RNA by the cell's exosome. We report a case of a male infant who suffered from typical symptoms and signs of trichohepatoenteric syndrome without immunodeficiency. The patient's genetic testing showed a very rare mutation in SKIV2L gene's 25 exons (p.Glu1038 fs*7 (c.3112_3140del)). Even though our patient was provided with total parenteral nutrition from birth, the child's death in the third year of age highlights the severity of the disease and the poor prognosis of this particular type of genetic predisposition. PMID- 30397476 TI - Management of fractured root canal treated mandibular molar with separated endodontic instrument extending in periapical region. AB - The aim of this article is to present a case which demonstrates that debriding and disinfecting the infected, under-obturated canal of a tooth using standardized orthograde technique along with surgical retrieval of separated periapical instrument, heals the lesion of endodontic origin. Restoring the tooth with a definitive restoration involving core and crown reinstates the fractured tooth as a functional member of dental arch. PMID- 30397477 TI - Gemcitabine-induced skin necrosis. AB - Since its emergence as a chemotherapy agent, gemcitabine has been associated with cutaneous adverse reactions. Rash is reported to be the most common cutaneous adverse effect. Other reported cutaneous reactions in the literature include bullous dermatosis, pseudocellulitis, subacute cutaneous lupus alopecia, and palmar-plantar erythrodysesthesia. Skin necrosis is a very rare adverse effect of this otherwise well-tolerated chemotherapeutic agent. In searching the literature, only one other case has been reported. In our report, we present a 74 year-old male with adenocarcinoma of the pancreas, status-post pancreaticoduodenectomy (Whipple procedure), who developed a rare case of skin necrosis of the lower leg 2 weeks after completing six cycles of monotherapy gemcitabine treatment. PMID- 30397472 TI - The abortion and mental health controversy: A comprehensive literature review of common ground agreements, disagreements, actionable recommendations, and research opportunities. AB - The abortion and mental health controversy is driven by two different perspectives regarding how best to interpret accepted facts. When interpreting the data, abortion and mental health proponents are inclined to emphasize risks associated with abortion, whereas abortion and mental health minimalists emphasize pre-existing risk factors as the primary explanation for the correlations with more negative outcomes. Still, both sides agree that (a) abortion is consistently associated with elevated rates of mental illness compared to women without a history of abortion; (b) the abortion experience directly contributes to mental health problems for at least some women; (c) there are risk factors, such as pre-existing mental illness, that identify women at greatest risk of mental health problems after an abortion; and (d) it is impossible to conduct research in this field in a manner that can definitively identify the extent to which any mental illnesses following abortion can be reliably attributed to abortion in and of itself. The areas of disagreement, which are more nuanced, are addressed at length. Obstacles in the way of research and further consensus include (a) multiple pathways for abortion and mental health risks, (b) concurrent positive and negative reactions, (c) indeterminate time frames and degrees of reactions, (d) poorly defined terms, (e) multiple factors of causation, and (f) inherent preconceptions based on ideology and disproportionate exposure to different types of women. Recommendations for collaboration include (a) mixed research teams, (b) co-design of national longitudinal prospective studies accessible to any researcher, (c) better adherence to data sharing and re-analysis standards, and (d) attention to a broader list of research questions. PMID- 30397478 TI - The effect of capture and handling stress in Lophius americanus in the scallop dredge fishery. AB - Capture and handling stress studies are considered a primary research priority, particularly for species and fisheries where discard rates are high, and/or for overfished stocks and species of concern. Lophius americanus, a commercially valuable finfish in New England, constitutes the second highest bycatch species within the sea scallop dredge fishery. Despite its commercial importance, no data exists on the capture and handling stress of monkfish for any gear type. Given these shortcomings, our goals were to evaluate the stress response of monkfish captured in scallop dredge gear by evaluating physical, behavioural and physiological responses to scallop fishing practices. While 80% of monkfish displayed little to no physical trauma, behavioural and physiological assessment indicated high levels of stress, especially as air exposure and tow duration increased. This finding suggests that the manifestation of stress in monkfish may be a cryptic response necessitating further research in addition to estimates of post-release mortality rates to appropriately advise fisheries management regarding the mortality of monkfish bycatch in the sea scallop fishery. PMID- 30397479 TI - Methicillin-resistant Staphylococcus aureus in health-care workers with cystic fibrosis in Sydney. AB - Cystic Fibrosis (CF), the most common lethal inherited disorder in Australia, is associated with increased respiratory tract colonization/infection. Given that many adults with CF work as health-care workers (HCW), which has been associated with an increased risk of methicillin-resistant Staphylococcus aureus (MRSA) colonization/infection, we examined these risks in 252 adults with CF at our centre between 2001-2015. Demographic and clinical characteristics, including pathogens, were compared for HCW and non-HCW groups. MRSA colonization/infection was found in 20 subjects, comprising 2/19 HCW, and 18/233 non-HCW (p = 0.66). Sixteen of these 20 subjects undertook eradication therapy, with success in 2/2 HCW and 5/14 non-HCW. This study showed that the rate of MRSA colonization/infection did not differ between adults with CF who work in the health-care setting versus other areas. This suggests that choosing a health-care profession does not necessarily result in an increased risk of MRSA colonization/infection for an adult with CF. PMID- 30397480 TI - Male reproductive health statement (XIIIth international symposium on Spermatology, may 9th-12th 2018, Stockholm, Sweden. AB - On the occasion of the XIIIth International Symposium on Spermatology held from 9 to 13 May 2018 in Stockholm (Sweden), participants (guest speakers and audience) collectively felt the need to make a public statement on the general issue of male reproductive health. Our intention is to raise awareness of what we believe is a neglected area of research despite alarming situations around the world. The disclosure strategy desired by the co-authors is to bring it to the attention of the greatest number partly by considering co-publication in the various periodicals dealing with Reproductive Biology and Andrology. BaCA's editorial office accepted this mission and found it natural that our periodical, the official journal of the French Andrology Society (SALF), should carry this message. PMID- 30397481 TI - Epidemiology, clinical characteristics, resistance, and treatment of infections by Candida auris. AB - Candida spp. infections are a major cause of morbidity and mortality in critically ill patients. Candida auris is an emerging multi-drug-resistant fungus that is rapidly spreading worldwide. Since the first reports in 2009, many isolates across five continents have been identified as agents of hospital associated infections. Independent and simultaneous outbreaks of C. auris are becoming a major concern for healthcare and scientific community. Moreover, laboratory misidentification and multi-drug-resistant profiles, rarely observed for other non-albicans Candida species, result in difficult eradication and frequent therapeutic failures of C. auris infections. The aim of this review was to provide an updated and comprehensive report of the global spread of C. auris, focusing on clinical and microbiological characteristics, mechanisms of virulence and antifungal resistance, and efficacy of available control, preventive, and therapeutic strategies. PMID- 30397483 TI - Comparison of patient-reported outcomes during acute exacerbations of chronic obstructive pulmonary disease. AB - Introduction: The aim of this study was to investigate which patient-reported outcome measure was the best during the recovery phase from severe exacerbation of chronic obstructive pulmonary disease (COPD). Methods: The Exacerbations of Chronic Pulmonary Disease Tool (EXACT), the COPD Assessment Test (CAT), the St George's Respiratory Questionnaire (SGRQ), the Dyspnoea-12 (D-12) and the Hyland Scale (global scale) were recorded every week for the first month and at 2 and 3 months in 33 hospitalised subjects with acute exacerbation of COPD (AECOPD). Results: On the day of admission (day 1), the internal consistency of the EXACT total score was high (Cronbach's alpha coefficient=0.89). The EXACT total, CAT, SGRQ total and Hyland Scale scores obtained on day 1 appeared to be normally distributed. Neither floor nor ceiling effects were observed for the EXACT total and SGRQ total scores. The EXACT total score improved from 50.5+/-12.4 to 32.5+/ 14.3, and the CAT score also improved from 24.4+/-8.5 to 13.5+/-8.4 during the first 2 weeks, and the effect sizes (ES) of the EXACT total and CAT score were 1.40 and -1.36, respectively. The SGRQ, Hyland Scale and D-12 were less responsive, with ES of -0.59, 0.96 and -0.90, respectively. Discussion: The EXACT total and CAT scores are shown to be more responsive measures during the recovery phase from severe exacerbation. Considering the conceptual framework, it is recommended that the EXACT total score may be the best measure during the recovery phase from AECOPD. The reasons for the outstanding responsiveness of the CAT are still unknown. PMID- 30397482 TI - Incidence of tuberculosis and the influence of surveillance strategy on tuberculosis case-finding and all-cause mortality: a cluster randomised trial in Indian neonates vaccinated with BCG. AB - Introduction: Accurate tuberculosis (TB) incidence and optimal surveillance strategies are pertinent to TB vaccine trial design. Infants are a targeted population for new TB vaccines, but data from India, with the highest global burden of TB cases, is limited. Methods: In a population-based prospective trial conducted between November 2006 and July 2008, BCG-vaccinated neonates in South India were enrolled and cluster-randomised to active or passive surveillance. We assessed the influence of surveillance strategy on TB incidence, case-finding rates and all-cause mortality. Predefined criteria were used to diagnose TB. All deaths were evaluated using a verbal autopsy. Results: 4382 children contributed to 8164 person-years (py) of follow-up (loss to follow-up 6.9%); 749 children were admitted for TB evaluation (active surveillance: 641; passive surveillance: 108). The TB incidence was 159.2/100 000 py and the overall case-finding rate was 3.19 per 100 py (95% CI 0.82 to 18.1). Whereas, the case-finding rate for definite TB was similar using active or passive case finding, the case-finding rate for probable TB was 1.92/100 py (95% CI 0.83 to 3.78) with active surveillance, significantly higher than 0.3/100 py (95% CI 0.01 to 1.39, p=0.02) with passive surveillance. Compared to passive surveillance, children with active surveillance had decreased risk of dying (OR 0.68, 95%CI 0.47 to 0.98) which was mostly attributable to reduction of death from pneumonia/respiratory infections (OR 0.34, 95%CI 0.14 to 0.80). Conclusion: We provide reliable estimates of TB incidence in South Indian children <2 years of age. Active surveillance increased the case-finding rates for probable TB and was associated with reduced all-cause mortality. PMID- 30397484 TI - Novel pharmacist-led intervention secures the minimally important difference (MID) in Asthma Control Test (ACT) score: better outcomes for patients and the healthcare provider. AB - Introduction: A key priority in asthma management is achieving control. The Asthma Control Test (ACT) is a validated tool showing a numerical indicator which has the potential to provide a target to drive management. A novel pharmacist-led intervention recently evaluated and introduced in the Italian setting with a cluster randomised controlled trial (C-RCT) showed effectiveness and cost effectiveness. This paper evaluates whether the intervention is successful in securing the minimally important difference (MID) in the ACT score and provides better health outcomes and economic savings. Methods: Clinical data were sourced from 816 adult patients with asthma participating in the C-RCT. The success of the intervention was measured looking at the proportion of patients reaching MID in the ACT score. Different levels of asthma control were grouped according to international guidelines and graded using the traffic light rating system. Asthma control levels were linked to economic (National Health Service (NHS) costs) and quality-adjusted life years outcomes using published data. Results: The median ACT score was 19 (partially controlled) at baseline, and 20 and 21 (controlled) at 3-month and 6-month-follow up, respectively (p<0.01). The percentage of patients reaching MID at 3 and 6 months was 15.8% (129) and 19.9% (162), respectively. The overall annual NHS cost savings per 1000 patients attached to the shift towards the MID target were equal to ?346 012 at 3 months and increased to ?425 483 at 6 months. Health utility gains were equal to 35.42 and 45.12 years in full health gained, respectively. Discussion: The pharmacist-led intervention secured the MID in the ACT score and provided better outcomes for both patients and providers. PMID- 30397485 TI - Specialist emergency care and COPD outcomes. AB - Introduction: In exacerbation of chronic obstructive pulmonary disease (ECOPD) requiring hospitalisation greater access to respiratory specialists improves outcome, but is not consistently delivered. The UK National Confidential Enquiry into Patient Outcome and Death 2015 enquiry showed over 25% of patients receiving acute non-invasive ventilation (NIV) for ECOPD died in hospital. On 16 June 2015 the Northumbria Specialist Emergency Care Hospital (NSECH) opened, introducing 24/7 specialty consultant on-call, direct admission from the emergency department to specialty wards and 7-day consultant review. A Respiratory Support Unit opened for patients requiring NIV. Before NSECH the NIV service included mandated training and competency assessment, 24/7 single point of access, initiation of ventilation in the emergency department, a door-to-mask time target, early titration of ventilation pressures and structured weaning. Pneumonia or hypercapnic coma complicating ECOPD have never been considered contraindications to NIV. After NSECH staff-patient ratios increased, the NIV pathway was streamlined and structured daily multidisciplinary review introduced. We compared our outcomes with historical and national data. Methods: Patients hospitalised with ECOPD between 1 January 2013 and 31 December 2016 were identified from coding, with ventilation status and radiological consolidation confirmed from records. Age, gender, admission from nursing home, consolidation, revised Charlson Index, key comorbidities, length of stay, and inpatient and 30-day mortality were captured. Outcomes pre-NSECH and post-NSECH opening were compared and independent predictors of survival identified via logistic regression. Results: There were 6291 cases. 24/7 specialist emergency care was a strong independent predictor of lower mortality. Length of stay reduced by 1 day, but 90-day readmission rose in both ventilated and non-ventilated patients. Conclusion: Provision of 24/7 respiratory specialist emergency care improved ECOPD survival and shortened length of stay for both non-ventilated and ventilated patients. The potential implications in respect to service design and provision nationally are substantial and challenging. PMID- 30397486 TI - Study investigating the generalisability of a COPD trial based in primary care (Salford Lung Study) and the presence of a Hawthorne effect. AB - Introduction: Traditional phase IIIb randomised trials may not reflect routine clinical practice. The Salford Lung Study in chronic obstructive pulmonary disease (SLS COPD) allowed broad inclusion criteria and followed patients in routine practice. We assessed whether SLS COPD approximated the England COPD population and evidence for a Hawthorne effect. Methods: This observational cohort study compared patients with COPD in the usual care arm of SLS COPD (2012 2014) with matched non-trial patients with COPD in England from the Clinical Practice Research Datalink database. Generalisability was explored with baseline demographics, clinical and treatment variables; outcomes included COPD exacerbations in adjusted models and pretrial versus peritrial comparisons. Results: Trial participants were younger (mean, 66.7 vs 71.1 years), more deprived (most deprived quintile, 51.5% vs 21.4%), more current smokers (47.5% vs 32.1%), with more severe Global initiative for chronic Obstructive Lung Disease stages but less comorbidity than non-trial patients. There were no material differences in other characteristics. Acute COPD exacerbation rates were high in the trial population (98.37th percentile). Conclusion: The trial population was similar to the non-trial COPD population. We observed some evidence of a Hawthorne effect, with more exacerbations recorded in trial patients; however, the largest effect was observed through behavioural changes in patients and general practitioner coding practices. PMID- 30397487 TI - Monitoring tuberculosis contact tracing outcomes in Western Sydney, Australia. AB - Treatment of latent tuberculosis infection (LTBI) is an important component of strategies to achieve global tuberculosis (TB) elimination, but implementation is rarely monitored. This is a retrospective review of TB contact tracing outcomes at one of the busiest TB clinics in Australia, measured against the Centre for Disease Control and Prevention performance indicators. In total, 45 of 53 (85%) pulmonary TB cases had 171 close contacts, of whom 139 (81%) were evaluated with a tuberculin skin test (TST); 58 of 139 (42%) were positive at baseline. Among 57 close contacts of 16 sputum smear-positive TB cases, the elicitation, evaluation, initiation of LTBI treatment and completion rates were 93%, 86%, 14% and 100%, and among 114 close contacts of 37 sputum smear-negative pulmonary TB cases 81%, 83%, 16% and 89%, respectively. Of 79 contacts with an initial negative TST, 19 of 47 (40%) demonstrated TST conversion when retested; 5 of 19 (26%) were offered LTBI treatment. Four secondary TB cases were identified. One incident TB case developed a pleural effusion 5 months after TST conversion, despite LTBI treatment. Apart from young children, LTBI treatment was inconsistently initiated in household TB contacts. Safe and pragmatic treatment options, as well as functional monitoring frameworks, are essential to improve LTBI treatment implementation. PMID- 30397488 TI - Acute exacerbation of idiopathic pulmonary fibrosis: a 10-year single-centre retrospective study. AB - Introduction: In 2016, an international working group proposed a revised definition and new diagnostic criteria for the acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). Based on these criteria, AE-IPF was diagnosed regardless of the presence or absence of a known trigger and categorised as triggered (T-AE) or idiopathic (I-AE) AE-IPF. However, the clinical characteristics of the newly defined AE-IPF and clinical differences between T-AE and I-AE are unresolved. Methods: We retrospectively analysed 64 patients with AE IPF (I-AE (42), T-AE (22)) admitted to our hospital over a 10- year period. Results: I-AE and T-AE cases did not show differences in in-hospital and long term outcomes (in-hospital mortality: I-AE 52.4%, T-AE 59.1%, p=0.61; long-term mortality: p=0.68). In the I-AE group, significantly more patients received corticosteroid therapy before an AE (I-AE 35.7%, T-AE 4.5%; p=0.01). Significantly more patients in the T-AE group had lung cancer (I-AE 7.1%, T-AE 59.1%, p<0.001). I-AE occurred more frequently in winter while T-AE did not show seasonality. The white blood cell (WBC) count and haemoglobin (Hb) level were independent predictors of in-hospital deaths in I-AE (WBC: OR 1.87; 95% CI 1.09 to 4.95, p=0.01; Hb: OR 0.26, 95% CI 0.04 to 0.78, p=0.01) but not T-AE. Discussion: With the introduction of new criteria for AE-IPF, a retrospective study over a 10-year period showed a lack of prognostic difference between I-AE and T-AE. The WBC count and Hb level predicted in-hospital outcome in I-AE cases. PMID- 30397490 TI - Factors influencing variation in participation in the National Diabetes Audit and the impact on the Quality and Outcomes Framework indicators of diabetes care management. AB - Objective: Participation in the National Diabetes Audit (NDA) has become a contractual requirement for all general practices in England and is used as part of the assessment framework for sustainability and transformation partnership (STP) footprints. The study aimed to investigate general practice-related factors which may influence participation in the NDA, and the impact that participation in the NDA may have on diabetes management and patient care. Research design: A cross-sectional analysis of routine primary care data from 45 725 646 patients aged 17+ years registered across 7779 general practices in England was performed using logistic regression. The main outcome measures included general practice voluntary participation in the NDA, general practice-related factors (practice size, deprivation, diabetes prevalence, geographic area, practice population age) and diabetes management outcomes (cholesterol, blood pressure, hemoglobin A1c (HbA1c)). Results: Participation in the NDA differed significantly according to practice size (t(7653)=-9.93, p=0.001), level of deprivation (chi2(9)=36.17, p<0.0001), diabetes prevalence (p<0.0001), practice population age (p<0.0001), and geographic area (chi2(26)=676.9, p<0.0001). In addition, the Quality and Outcomes Framework diabetes indicator HbA1c (OR 1.01, CI 1.0 to 1.01, p=0.0001) but not cholesterol (p=0.055) or blood pressure (p=0.76) was independently associated with NDA participation when controlling for practice-related factors. Conclusion: Variation in NDA participation exists. It is suggested that some practices may need additional support when submitting data to the NDA and that NDA participation may have an impact on diabetes outcomes. However, the use of NDA outcomes as a measure of progress with diabetes care by STPs is still unclear and further investigation is needed. PMID- 30397489 TI - Medical nutrition therapy for gestational diabetes mellitus based on Mediterranean Diet principles: a subanalysis of the St Carlos GDM Prevention Study. AB - Objectives: To assess whether Mediterranean Diet (MedDiet)-based medical nutrition therapy facilitates near-normoglycemia in women with gestational diabetes mellitus (GDMw) and observe the effects on adverse pregnancy outcomes. Research design and methods: This is a secondary analysis of the St Carlos GDM Prevention Study, conducted between January and December 2015 in Hospital Clinico San Carlos (Madrid, Spain). One thousand consecutive women with normoglycemia were included before 12 gestational weeks (GWs), with 874 included in the final analysis. Of these, 177 women were diagnosed with gestational diabetes mellitus (GDM) and 697 had normal glucose tolerance. All GDMw received MedDiet-based medical nutrition therapy with a recommended daily extra virgin olive oil intake >=40 mL and a daily handful of nuts. The primary goal was comparison of hemoglobin A1c (HbA1c) levels at 36-38 GWs in GDMw and women with normal glucose tolerance (NGTw). Results: GDMw as compared with NGTw had higher HbA1c levels at 24-28 GWs (5.1%+/-0.3% (32+/-0.9 mmol/mol) vs 4.9%+/-0.3% (30+/-0.9 mmol/mol), p=0.001). At 36-38 GWs values were similar between the groups. Similarly, fasting serum insulin and homeostatic model assessment insulin resitance (HOMA-IR) were higher in GDMw at 24-28 GWs (p=0.001) but became similar at 36-38 GWs. 26.6% of GDMw required insulin for glycemic control. GDMw compared with NGTw had higher rates of insufficient weight gain (39.5% vs 22.0%, p=0.001), small for gestational age (6.8% vs 2.6%, p=0.009), and neonatal intensive care unit admission (5.6% vs 1.7%, p=0.006). The rates of macrosomia, large for gestational age, pregnancy-induced hypertensive disorders, prematurity and cesarean sections were comparable with NGTw. Conclusions: Using a MedDiet-based medical nutrition therapy as part of GDM management is associated with achievement of near normoglycemia, subsequently making most pregnancy outcomes similar to those of NGTw. PMID- 30397491 TI - Self-efficacy and diabetes prevention in overweight South Asians with pre diabetes. AB - Objective: We evaluated the effects of a diabetes prevention itervention on self efficacy (SE) and the associations between SE and diabetes-related outcomes among overweight Asian Indian adults with pre-diabetes in a randomized controlled translational trial (the Diabetes Community Lifestyle Improvement Program, D CLIP). Research design and methods: Data were obtained from 550 adults who were randomized to a diabetes prevention program or standard of care. Dietary and exercise-related SEs were measured at baseline, core intervention completion (4 months), and annually until the end of follow-up (3 years or diabetes diagnosis). Mixed-effects regressions described changes in SE over time by treatment group. Among treatment participants, multivariable-adjusted models described associations of SE at baseline and intervention completion with diabetes incidence and other secondary outcomes (weight, waist circumference (WC), exercise, and energy intake). Results: From baseline to 4 months, dietary (beta=10.3, p=0.04) and exercise (beta=0.49, p=0.04) SE increased significantly in the treatment arm only; however, this increase from baseline was no longer significant at later time points. Among treatment participants, there was no association of dietary or exercise SE with diabetes incidence, but baseline exercise SE was independently associated with improved weight, WC, and exercise at 4 months (p<0.05). Change in exercise SE from baseline to intervention completion also predicted increased exercise at 4, 12, and 24 months (p<0.05). Conclusions: Exposure to D-CLIP resulted in improved SE at treatment completion, but this effect was not sustained over longer follow-up. Several short-term and long-term secondary outcomes, but not diabetes risk, were significantly associated with exercise SE, suggesting this psychosocial trait may facilitate success in achieving certain health goals. Trial registration number: NCT01283308. PMID- 30397492 TI - Newly diagnosed type 2 diabetes in an ethnic minority population: clinical presentation and comparison to other populations. AB - Objective: To characterize the clinical presentation of newly diagnosed type 2 diabetes of ethnic minority adults in Chicago and compare with other populations. Research design and methods: Cross-sectional study examining the data of 2280 patients newly diagnosed with type 2 diabetes treated between 2003 and 2013 in a large Chicago public healthcare system. Results: Mean age of the patients was 49+/-11.3 years, men 54.4%, African-Americans 48.1%, Hispanics 32.5%, unemployed 69.9%, uninsured 82.2%, English-speaking 75.1%, and body mass index was 32.8+/ 7.4 kg/m2. Microvascular complications were present in 50.1% and macrovascular complications in 13.4%. There was a presence of either macrovascular or microvascular complications correlated with older age, hypertension, dyslipidemia, inactivity, speaking English, and being insured (p<0.01). Glycosylated hemoglobin A1c (HbA1c) at presentation did not correlate with diabetes complications. In our cohort, when compared with a diverse population in the UK and insured population in the USA, HbA1c at presentation was 10.0% (86 mmol/mol), 6.6% (49 mmol/mol), and 8.2% (66 mmol/mol); nephropathy was 22.2%, 16.7%, and 5.7%; retinopathy was 10.7%, 7.9%, and 1.4%; and neuropathy was 27.7%, and 6.7% in the UK (p<0.001). There were no significant differences between groups in the prevalence of macrovascular complications. Conclusion: These results show the vulnerability of underserved and underinsured patients for developing diabetes complications possibly related to a delayed diagnosis. PMID- 30397493 TI - Is chronic low back pain a risk factor for diabetes? The Nord-Trondelag Health Study. AB - Objective: The purpose of this study was to examine the risk of diabetes associated with the presence or absence of chronic low back pain, considering both cross-sectional and cohort data. Research design and methods: Analyses were based on the Norwegian HUNT2 and HUNT3 surveys of Nord-Trondelag County. The prevalence of diabetes was compared in groups with and without chronic low back pain among 45 157 participants aged 30-69 years. Associations between low back pain at baseline and risk of diabetes were examined in an 11-year follow-up of 30 380 individuals with no baseline diagnosis of diabetes. The comorbidity between diabetes and low back pain was assessed at the end of follow-up. All analyses were carried out considering generalized linear models incorporating adjustment for other relevant risk factors. Results: Cross-sectional analyses did not reveal any association between low back pain and diabetes. With adjustment for age, body mass index, physical activity and smoking, the cohort study of women showed a significant association between low back pain at baseline and risk of diabetes (RR 1.30; 95% CI 1.09 to 1.54, p=0.003). The association differed between age groups (p=0.015), with a stronger association in relatively young women. In men, no association was found in the whole age range (RR 1.02; 95% CI 0.86 to 1.21, p=0.82). No association was observed between diabetes and chronic low back pain at the end of follow-up. Conclusion: Among younger women, those with chronic low back pain may have an increased risk of diabetes. PMID- 30397494 TI - Exercise modes and their association with hypoglycemia episodes in adults with type 1 diabetes mellitus: a systematic review. AB - Objective: Type 1 diabetes mellitus rates are rising worldwide. The health benefits of physical exercise in this condition are many, but more than 60% do not participate, mainly from fear of hypoglycemia. This systematic review explores the effects of physical exercise modes on blood glucose levels in adults for hypoglycemia prevention. Research design and methods: Predefined inclusion criteria were randomized or non-randomized cross-over trials of healthy non-obese adults with type 1 diabetes mellitus. Exercise interventions used standardized protocols of intensity and timing. Outcomes included hypoglycemia during or after exercise, and acute glycemic control. Medline, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database, SPORTDiscus, CochraneCENTRAL (1990 to 11 January 2018), and Embase (1988 to 9 April 2018) were searched using keywords and Medical Subject Heading (MeSH) terms. Inclusions, data extraction and quality assessment using the Critical Appraisal Skills Programme checklists were done by one researcher and checked by a second. Review Manager (V.5.3) was used for meta-analysis where four or more outcomes were reported. Results: From 5459 citations, we included 15 small cross over studies (3 non-randomized), 13 assessing aerobic (intermittent high intensity exercise (IHE) vs continuous, or continuous vs rest) and 2 assessing resistance exercise versus rest. Study quality was good, and all outcome measures were reported. Thirteen gave hypoglycemia results, of which five had no episodes. Meta-analysis of hypoglycemia during or after IHE compared with continuous exercise showed no significant differences (n=5, OR=0.68 (95% CI 0.16 to 2.86), I2=56%). For blood glucose there was little difference between groups at any time point. Conclusion: IHE may be safer than continuous exercise because of lesser decline in blood glucose, but more research needs to demonstrate if this would be reflected in hypoglycemic episode rates. Trial registration number: CRD42018068358. PMID- 30397495 TI - Analysis of urinary macrophage migration inhibitory factor in systemic lupus erythematosus. AB - Objective: To characterise the clinical relevance of urinary macrophage migration inhibitory factor (uMIF) concentrations in patients with systemic lupus erythematosus (SLE). Methods: MIF, adjusted for urine creatinine, was quantified by ELISA in urine samples from 64 prospectively recruited patients with SLE. Serum MIF and urinary monocyte chemoattractant protein 1 (uMCP-1) were quantified by ELISA in a subset of patients (n = 39). Disease activity was assessed using the SLE Disease Activity Index-2000 (SLEDAI-2K) score. Results: uMIF was detectable in all patients with SLE. uMIF was positively correlated with overall SLEDAI-2K, was significantly higher in patients with SLE with high disease activity (SLEDAI-2K>=10) compared with those with inactive disease (SLEDAI-2K<4), and this association remained significant after adjusting for ethnicity, flare and use of immunosuppressants. uMIF was also significantly higher in SLE patients with flare of disease, although not confirmed in multivariable analysis. No significant differences in uMIF levels were observed according to the presence of renal disease activity, as assessed by renal SLEDAI-2K or biopsy-confirmed lupus nephritis. In contrast, uMCP-1 was significantly higher in SLE patients with active renal disease. uMIF expression was not associated with irreversible organ damage accrual or glucocorticoid use. Conclusions: These data suggest uMIF as a potential overall but not renal-specific SLE biomarker, whereas uMCP-1 is a renal specific SLE biomarker. PMID- 30397496 TI - Elevation of serum anti-glucose-regulated protein 78 antibodies in neuropsychiatric systemic lupus erythematosus. AB - Objective: Recent studies have demonstrated that autoantibodies directed against glucose-regulated protein 78 (GRP78) on endothelial cells promote blood-brain barrier (BBB) damages. The present study examined whether serum anti-GRP78 antibodies might be involved in the pathogenesis of neuropsychiatric SLE (NPSLE). Methods: Serum samples were obtained from 129 patients with SLE (58 patients with diffuse psychiatric/neuropsychological syndromes of NPSLE (diffuse NPSLE), 30 with neurological syndromes (focal NPSLE), 21 with lupus nephritis (LN), 20 without NPSLE or LN (SLE alone)), from 35 patients with non-SLE rheumatic diseases (non-SLE RD) and from 24 healthy controls (HC). Anti-GRP78 levels were measured with an ELISA, using recombinant GRP78 as antigens. Cerebrospinal fluid (CSF) samples were also obtained from 88 patients with NPSLE. The BBB function was evaluated by Q albumin ((CSF albumin/serum albumin)*103). Results: Serum anti GRP78 levels were significantly elevated in SLE compared with non-SLE RD or HC. There were no significant differences in serum anti-GRP78 levels among NPSLE, LN and SLE alone. Of note, serum anti-GRP78 levels were significantly higher in acute confusional state (ACS) than in non-ACS diffuse NPSLE (p=0.0001) or in focal NPSLE (p=0.0002). Finally, serum anti-GRP78 levels were significantly correlated with Q albumin (r=0.294, p=0.0054) in NPSLE. Conclusion: These results indicate that anti-GRP78 antibodies are associated with the development of diffuse NPSLE, especially ACS. Thus, the data suggest that anti-GRP78 antibodies might contribute to the development of ACS through the damages of BBB. PMID- 30397499 TI - Correction: Patient-reported outcome measures for use in clinical trials of SLE: a review. AB - [This corrects the article DOI: 10.1136/lupus-2018-000279.]. PMID- 30397498 TI - Cytoplasmic FOXO1 identifies a novel disease-activity associated B cell phenotype in SLE. AB - Systemic lupus erythematosus (SLE) is a manifestation of hyperactivated lymphocytes and results, in part, from the loss of normal tolerance checkpoints. FOXO1 is a transcription factor involved at critical early and late B cell development checkpoints; however, its role in regulating peripheral B cell tolerance is not fully understood. We have applied our published approach for using imaging flow cytometry to study native FOXO1 localisation in human lymphocytes to peripheral blood samples from healthy individuals versus patients with SLE. We report, here, on dramatic cytoplasmic localisation of FOXO1 in two peripheral B cell SLE subsets: IgD-CD27+ (class-switched memory) B cells and IgD CD27- (atypical memory) B cells. The latter, so-called 'Double Negative' (DN) B cells have previously been shown to be increased in SLE and enriched in autoreactive clones. Cytoplasmic-predominant FOXO1 (CytoFOX) B cells are significantly increased in patients with SLE as compared to healthy controls, and the levels of CytoFoOX DN B cells correlate directly with SLE disease activity. The highest abundance of CytoFox DN B cells was observed in African American females with SLE Disease Activity Index (SLEDAI)>=6. The phenotype of CytoFOX DN B cells in SLE includes uniquely low CD20 expression and high granularity/side scatter. As FOXO1 phosphorylation downstream of B cell receptor-dependent signalling is required for nuclear exclusion, CytoFOX B cells likely represent a high state of B cell activation with excess signalling and/or loss of phosphatase activity. We hypothesise that CytoFOX B cells in lupus represent a novel biomarker for the expansion of pathological, autoreactive B cells which may provide new insights into the pathophysiology of SLE. PMID- 30397497 TI - Alopecias in lupus erythematosus. AB - Several patterns of hair loss can occur in lupus erythematosus (LE). Alopecias which show histological characteristics of LE are LE-specific, and include discoid LE (DLE), diffuse or patchy hair loss in acute LE, subacute cutaneous LE, and rarely tumid LE. Lupus hair in SLE is a poorly characterised entity and may be a form of telogen effluvium. Alopecia areata can coexist with LE and may mimic DLE. Non-lupus alopecias such as telogen effluvium and anagen effluvium have a myriad of causes which include disease flares, drugs and stress in the setting of LE. The latest validated Systemic Lupus International Collaborating Clinics classification criteria for SLE includes non-scarring alopecia as a criterion; therefore, recognising the aetiology of hair loss in the setting of LE is crucial in classifying a patient to have systemic disease. PMID- 30397500 TI - Acetazolamide promotes decreased consumption of carbonated drinks and weight loss. AB - Excessive consumption of carbonated drinks contributes to the dietary surplus of carbohydrates, and is a main driver of the obesity epidemic in the USA. From a public health standpoint, it is therefore crucial to develop strategies that enable individuals to regulate this calorie-rich, but nutrient-poor food intake. However, conservative medical approaches to this end have met with limited success. Using a pharmacological strategy to eliminate the effervescent aspect of carbonated drinks, we report significant weight loss in a patient with long standing obesity. Administration of low-dose acetazolamide, a carbonic anhydrase inhibitor, resulted in altered taste of carbonation, and in turn a marked reduction in the patient's carbonated drink intake and the loss of almost 1 kg of body weight per week. The pharmacological intervention also resulted in appetite suppression, which might synergistically contribute to weight loss. These findings point to the use of low-dose acetazolamide as a novel weight reduction strategy. PMID- 30397501 TI - Accidental hypothermia in Parkinson's disease. AB - We describe two patients with Parkinson's disease who presented with accidental hypothermia and review seven patients to delineate the characteristics of hypothermia. All cases of hypothermia occurred in the winter. As clinical symptoms preceding the onset of hypothermia, deterioration of bradykinesia or limb coldness was evident. Most cases of hypothermia were accompanied by impaired consciousness and deterioration of parkinsonian features. After warming the body, the hypothermia improved in a relatively short period. Levodopa, dopamine agonists or anticholinergic agents were given to five patients, three patients and three patients, respectively. Bradykinesia developed in most patients a short time before the onset of hypothermia. In various neurological diseases, deterioration of the disease can occur on the background of metabolic/electrolyte disturbance. However, the fact that the bradykinesia developed a short time prior to the onset of hypothermia warrants close observation for signs of temperature dysregulation in patients with substantial neurologic deterioration, especially in the winter. PMID- 30397502 TI - Beriberi disease in an 11-year-old girl with total colectomy. AB - Beriberi or vitamin B1 deficiency is a rare disease in the developed world and more common in developing countries due to poverty and malnutrition. It usually presents with neurological manifestations (dry beriberi) or cardiovascular signs (wet beriberi). We report a case of dry beriberi in an 11-year-old girl with total colectomy who presented to our hospital with ataxic gait and muscle weakness. Her symptoms started 1 week after she underwent cholecystectomy for her chronic abdominal pain. Nerve conduction study showed sensory demyelinating neuropathy and she had low levels of serum vitamin B1. Her condition improved significantly after taking vitamin B1 supplementation. To the best of our knowledge, this is the first case report of thiamine deficiency in a child with a total colectomy. PMID- 30397503 TI - A rare combination of giant right retroperitoneal schwannoma and right adrenal oncocytoma as an incidental finding. AB - Adrenal oncocytomas and retroperitoneal schwannomas are two groups of very rare tumors with distinct histologic features. Both tumors are usually incidentally found and are mostly benign. Optimal management is usually with surgical resection. We report a unique case of a 74-year-old woman who was incidentally found to have these two exceptionally rare tumors at the same time. She was successfully managed with surgical resection of the retroperitoneal schwannoma and adrenalectomy for the adrenal oncocytoma and both diagnoses were confirmed with histopathology and immunochemistry. PMID- 30397504 TI - A male Korean who was diagnosed with chronic enteropathy associated with SLCO2A1 (CEAS): case report with literature review. AB - Objective: To further disseminate the nomenclature of chronic enteropathy associated with SLCO2A1 (CEAS), especially for physicians in China and Korea where the genetic feature of SLCO2A1 gene mutations related hypertrophic osteoarthropathy and pachydermia had been extensively studied. SLCO2A1 gene mutations related hypertrophic osteoarthropathy and pachydermia had been extensively studied. Design: A case report with literature review of SLCO2A1 gene mutations-related disorders. Results: A 38-year-old Korean presented to a tertiary hospital with dizziness, abdominal pain and melena. He had a positive faecal occult blood test on initial workup. Oesophagogastroduodenal endoscopy (OGD), colonoscopy and CT scan were unremarkable and showed no obvious cause for his melena. Capsule endoscope and roentgen barium studies were performed, revealing an erythematous mucosa with ulcers in the jejunum and stenosis to the jejunal-ileal junction. Next-generation sequencing was then performed and discovered point mutations of SLCO2A1 gene's seven exon (940+1 G>A) and 13 exon (1807 C>T) allele. This Korean patient with CEAS is the first documented case noted outside of the Japanese population. Conclusion: CEAS is not uniquely found in Japanese individuals. There are lots of similarities between CEAS and primary hypertrophic osteoarthropathy, the two entity may just be the two sides of one same coin. International and multidisciplined efforts are required to further study this complicated disorder. PMID- 30397505 TI - Five-year single-centre experience of carcinoma of the oesophagus from Blantyre, Malawi. AB - Background: Oesophageal squamous cell carcinoma (OSCC) is increasing worldwide and has an exceptionally high prevalence in certain distinct geographical locations such as the African oesophageal SCC corridor. Despite this, there is a paucity of evidence to characterise the disease particularly in the Malawian context. Method: We retrospectively audited our endoscopy database over 5 years, including for patient demographics, endoscopy findings, therapeutic intervention and recommendations for treatment. Results: 1586 patients with oesophageal cancer were identified from a total of 5882 endoscopy records from 2013 to 2017. Our cohort showed a larger proportion of oesophageal cancers found higher in the oesophagus compared with other African studies and a female preponderance in this upper-oesophagus disease subset though a male preponderance overall. 39% of patients with oesophageal cancer underwent bougie dilatation and 11% underwent palliative stent placement, which likely reflects local availability of resources. Conclusion: This study validates the observation that OSCC predominates in sub-Saharan Africa in Malawi over other forms of oesophageal carcinoma, though our cohort appears to have subtly distinct demographics and disease-specific data. This highlights the need to prioritise preventative and therapeutic strategies for OSCC in this and similar settings. PMID- 30397506 TI - Feasibility of collecting and assessing patient-reported outcomes for emergency admissions: laparotomy for gastrointestinal conditions. AB - Introduction: Audit of emergency surgery is usually limited to immediate clinical outcomes relating to outcomes during the acute hospital episode with little attempt to capture patients' views of their longer-term outcomes. Our aim was to determine the response rate to patient-reported outcome measures (PROMs) for patients who underwent an emergency laparotomy for gastrointestinal conditions, identify response bias and explore the feasibility of comparing outcomes with their prior health based on their recalled view collected during their admission. Methods: Patients undergoing emergency laparotomy in 11 hospitals were recruited to complete a retrospective questionnaire containing the EQ-5D-3L and Gastrointestinal Quality of Life Index (GIQLI). Response rate for 3-month mailed follow-up questionnaire and potential response biases were assessed. Patients' outcomes were compared with their baseline using chi2 and paired t-test to assess for differences. Results: Of 255 patients contacted at 3 months, 190 (74.1%) responded. Responders were more likely to be older, female and more affluent. Patients' health improved significantly as regards the GIQLI (93.3 vs 97.9; p=0.048) and the subscale on symptoms (51.9 vs 59.6; p<0.001). No significant change in subscales on emotion or physical aspects or for overall health status (EQ-5D: 0.58 vs 0.64; p=0.06). According to the social subscale, patients had deteriorated (11.0 vs 9.8; p<0.0006). Differences in change scores by patient characteristics were slight, suggesting minimal response bias. Conclusion: This approach offers the opportunity for assessing the impact of treatment, from the patient's perspective and the potential to evaluate emergency laparotomy care using PROMs. PMID- 30397507 TI - Characterization of vitamin D supplementation and clinical outcomes in a large cohort of early Parkinson's disease. AB - Background: Vitamin D (VitD) deficiency is common in Parkinson's disease (PD) and has been raised as a possible PD risk factor. In the past decade, VitD supplementation for potential prevention of age related conditions has become more common. In this study, we sought to characterize VitD supplementation in early PD and determine as an exploratory analysis whether baseline characteristics or disease progression differed according to reported VitD use. Methods: We analyzed data from the National Institutes of Health Exploratory Trials in Parkinson's Disease (NET-PD) Long-term study (LS-1), a longitudinal study of 1741 participants. Subjects were divided into following supplement groups according to subject exposure (6 months prior to baseline and during the study): no VitD supplement, multivitamin (MVI), VitD >=400 IU/day, and VitD + multivitamin (VitD+MVI). Clinical status was followed using the Unified Parkinson's Disease Rating Scale, Symbol Digit Modalities Test, total daily levodopa equivalent dose, and Parkinson's Disease Questionnaire. Results: About 5% of subjects took VitD alone, 7% took VitD+MVI, 34% took MVI alone, while 54% took no supplement. Clinical outcomes at 3 years were similar across all groups. Conclusion: This study shows VitD supplementation >=400 IU/day was not common in early PD and that its use was similar to that seen in the US population. At 3 years, there was no difference in disease progression according to vitamin D supplement use. PMID- 30397508 TI - The feasibility of using the EQ-5D-3L with adults with mild to moderate learning disabilities within a randomized control trial: a qualitative evaluation. AB - Background: In trials incorporating a health economic evaluation component, reliable validated measures for health-related quality of life (HRQOL) are essential. The EQ-5D is the preferred measure for cost-effectiveness analysis in UK trials. This paper presents a qualitative evaluation of the use of the EQ-5D 3L in a feasibility randomised control trial with participants who had a mild- to moderate learning disability and type 2 diabetes. Methods: Researchers administered the EQ-5D-3L to 82 participants at baseline and 77 at follow-up. After each interview, researchers rated the ease of administering the EQ-5D-3L and made free-text entries on the administration experience. For a subset of 16 interviews, researchers audio-recorded more detailed journal entries. Ease of administration data were analysed using descriptive statistics. Free-text responses were subject to a basic content analysis. The EQ-5D-3L-related journal entries were transcribed, coded and analysed thematically. Results: Over half of participants were perceived to experience difficulty answering some or all of the items in the EQ-5D-3L (60% at baseline; 54% at follow-up). Analysis of the free text entries and audio journals identified four themes that question the use of the EQ-5D-3L in this population. The first theme is related to observations of participant intellectual ability and difficulties, for example, in understanding the wording of the measure. Theme 2 is related to the normalisation of adjustments for impairments, which rendered the measure less sensitive in this population. Theme 3 is related to researcher adaptation and non-standard administration. An overarching fourth theme was identified in that people with learning disabilities were viewed as 'unreliable witnesses' by both researchers and supporters. Conclusions: It is recommended that the EQ-5D-3L should not be used in isolation to assess health-related quality of life outcomes in trials research in adults with a learning disability. Further research is required to develop and evaluate a version of the EQ-5D appropriate for this population in trials research. It is unrealistic to expect that adjustments to the wording alone will deliver an appropriate measure: supporter or researcher involvement will almost always be required. This requirement needs to be factored into the development and administration guidelines of any new version of the EQ-5D for adults with a learning disability. Trial registration: Current Controlled Trials ISRCTN41897033 [registered 21 January 2013]. PMID- 30397509 TI - Reflections and experiences of a co-researcher involved in a renal research study. AB - Background: Patient and Public Involvement (PPI) is seen as a prerequisite for health research. However, current Patient and public involvement literature has noted a paucity of recording of patient and public involvement within research studies. There have been calls for more recordings and reflections, specifically on impact. Renal medicine has also had similar criticisms and any reflections on patient and public involvement has usually been from the viewpoint of the researcher. Roles of patient and public involvement can vary greatly from sitting on an Advisory Group to analysing data. Different PPI roles have been described within studies; one being a co-researcher. However, the role of the co-researcher is largely undefined and appears to vary from study to study. Methods: The aims of this paper are to share one first time co-researcher's reflections on the impact of PPI within a mixed methods (non-clinical trial) renal research study. A retrospective, reflective approach was taken using data available to the co researcher as part of the day-to-day research activity. Electronic correspondence and documents such as meeting notes, minutes, interview thematic analysis and comments on documents were re-examined. The co-researcher led on writing this paper. Results: This paper offers a broad definition of the role of the co researcher. The co-researcher reflects on undertaking and leading on the thematic analysis of interview transcripts, something she had not previously done before. The co-researcher identified a number of key themes; the differences in time and responsibility between being a co-researcher and an Advisory Group member; how the role evolved and involvement activities could match the co-researchers strengths (and the need for flexibility); the need for training and support and lastly, the time commitment. It was also noted that it is preferable that a co researcher needs to be involved from the very beginning of the grant application. Conclusions: The reflections, voices and views of those undertaking PPI has been largely under-represented in the literature. The role of co-researcher was seen to be rewarding but demanding, requiring a large time commitment. It is hoped that the learning from sharing this experience will encourage others to undertake this role, and encourage researchers to reflect on the needs of those involved. PMID- 30397510 TI - Hidden diversity and evolution of viruses in market fish. AB - Aquaculture is the fastest growing industry worldwide. Aquatic diseases have had enormous economic and environmental impacts in the recent past and the emergence of new aquatic pathogens, particularly viruses, poses a continuous threat. Nevertheless, little is known about the diversity, abundance and evolution of fish viruses. We used a meta-transcriptomic approach to help determine the virome of seemingly healthy fish sold at a market in Sydney, Australia. Specifically, by identifying and quantifying virus transcripts we aimed to determine (i) the abundance of viruses in market fish, (ii) test a key component of epidemiological theory that large and dense host populations harbour a greater number of viruses compared to their more solitary counterparts and (iii) reveal the relative roles of virus-host co-divergence and cross-species transmission in the evolution of fish viruses. The species studied comprised both shoaling fish-eastern sea garfish (Hyporhamphus australis) and Australasian snapper (Chrysophrys auratus) and more solitary fish-eastern red scorpionfish (Scorpaena jacksoniensis) and largetooth flounder (Pseudorhombus arsius). Our analysis identified twelve potentially novel viruses, eight of which were likely vertebrate-associated across four viral families and that exhibited frequent cross-species transmission. Notably, the most solitary of the fish species studied, the largetooth flounder, harboured the least number of viruses while eastern sea garfish, a densely shoaling fish, had the highest number of viruses. These results support the emerging view that fish harbour a large and largely uncharacterised virome. PMID- 30397511 TI - Unconscious associative learning with conscious cues. AB - Despite extensive research, the very existence of unconscious learning in humans remains much debated. Skepticism arises chiefly from the difficulty in assessing the level of awareness of the complex associations learned in classical implicit learning paradigms. Here, we show that simple associations between colors and motion directions can be learned unconsciously. In each trial, participants had to report the motion direction of a patch of colored dots but unbeknownst to the participants, two out of the three possible colors were always associated with a given direction/response, while one was uninformative. We confirm the lack of awareness by using several tasks, fulfilling the most stringent criteria. In addition, we show the crucial role of trial-by-trial feedback, and that both the stimulus-response (motor) and stimulus-stimulus (perceptual) associations were learned. In conclusion, we demonstrate that simple associations between supraliminal stimulus features can be learned unconsciously, providing a novel framework to study unconscious learning. PMID- 30397514 TI - What explains the lacklustre response to Zika in Brazil? Exploring institutional, economic and health system context. AB - By early-2016, the international community began to pressure Brazil for a stronger policy response to Zika. In contrast to what was seen in the past, however, these international pressures did not elicit such a response. In this article, we explore why this was the case, reviewing the government's policy response and the broader political and economic context shaping this response. The authors used single case study analysis and qualitative sources, such as books, journal articles, and government policy reports to support their empirical claims. We found that despite increased international pressures from the WHO, domestic political factors and economic recession hampered the government's ability to strengthen its health systems response to Zika. Consequently, those states most afflicted by Zika have seen policy initiatives that lack sufficient funding, administrative and human resource capacity. This study revealed that despite a government's deep foreign policy history of positively responding to international pressures through a stronger policy response to health epidemics, a sudden change in government, rising political instability, and economic recession can motivate governments to abandon this foreign policy tradition and undermine its response to new public health threats. PMID- 30397512 TI - Self-specific processing in the meditating brain: a MEG neurophenomenology study. AB - Self-specific processes (SSPs) specify the self as an embodied subject and agent, implementing a functional self/nonself distinction in perception, cognition, and action. Despite recent interest, it is still undetermined whether SSPs are all-or nothing or graded phenomena; whether they can be identified in neuroimaging data; and whether they can be altered through attentional training. These issues are approached through a neurophenomenological exploration of the sense-of-boundaries (SB), the fundamental experience of being an 'I' (self) separated from the 'world' (nonself). The SB experience was explored in collaboration with a uniquely qualified meditation practitioner, who volitionally produced, while being scanned by magnetoencephalogram (MEG), three mental states characterized by a graded SB experience. The results were then partly validated in an independent group of 10 long-term meditators. Implicated neural mechanisms include right lateralized beta oscillations in the temporo-parietal junction, a region known to mediate the experiential unity of self and body; and in the medial parietal cortex, a central node of the self's representational system. The graded nature as well as the trainable flexibility and neural plasticity of SSPs may hold clinical implications for populations with a disturbed SB. PMID- 30397513 TI - Protocol for the development of a CONSORT extension for RCTs using cohorts and routinely collected health data. AB - Background: Randomized controlled trials (RCTs) are often complex and expensive to perform. Less than one third achieve planned recruitment targets, follow-up can be labor-intensive, and many have limited real-world generalizability. Designs for RCTs conducted using cohorts and routinely collected health data, including registries, electronic health records, and administrative databases, have been proposed to address these challenges and are being rapidly adopted. These designs, however, are relatively recent innovations, and published RCT reports often do not describe important aspects of their methodology in a standardized way. Our objective is to extend the Consolidated Standards of Reporting Trials (CONSORT) statement with a consensus-driven reporting guideline for RCTs using cohorts and routinely collected health data. Methods: The development of this CONSORT extension will consist of five phases. Phase 1 (completed) consisted of the project launch, including fundraising, the establishment of a research team, and development of a conceptual framework. In phase 2, a systematic review will be performed to identify publications (1) that describe methods or reporting considerations for RCTs conducted using cohorts and routinely collected health data or (2) that are protocols or report results from such RCTs. An initial "long list" of possible modifications to CONSORT checklist items and possible new items for the reporting guideline will be generated based on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) and The REporting of studies Conducted using Observational Routinely collected health Data (RECORD) statements. Additional possible modifications and new items will be identified based on the results of the systematic review. Phase 3 will consist of a three-round Delphi exercise with methods and content experts to evaluate the "long list" and generate a "short list" of key items. In phase 4, these items will serve as the basis for an in-person consensus meeting to finalize a core set of items to be included in the reporting guideline and checklist. Phase 5 will involve drafting the checklist and elaboration explanation documents, and dissemination and implementation of the guideline. Discussion: Development of this CONSORT extension will contribute to more transparent reporting of RCTs conducted using cohorts and routinely collected health data. PMID- 30397515 TI - Emerging implications of policies on malaria treatment: genetic changes in the Pfmdr-1 gene affecting susceptibility to artemether-lumefantrine and artesunate amodiaquine in Africa. AB - Artemether-lumefantrine (AL) and artesunate-amodiaquine (AS-AQ) are the most commonly used artemisinin-based combination therapies (ACT) for treatment of Plasmodium falciparum in Africa. Both treatments remain efficacious, but single nucleotide polymorphisms (SNPs) in the Plasmodium falciparum multidrug resistance 1 (Pfmdr1) gene may compromise sensitivity. AL and AS-AQ exert opposing selective pressures: parasites with genotype 86Y, Y184 and 1246Y are partially resistant to AS-AQ treatment, while N86, 184 F and D1246 are favoured by AL treatment. Through a systematic review, we identified 397 surveys measuring the prevalence of Pfmdr1 polymorphisms at positions 86 184 or 1246 in 30 countries in Africa. Temporal trends in SNP frequencies after introduction of AL or AS-AQ as first-line treatment were analysed in 32 locations, and selection coefficients estimated. We examined associations between antimalarial policies, consumption, transmission intensity and rate of SNP selection. 1246Y frequency decreased on average more rapidly in locations where national policy recommended AL (median selection coefficient(s) of -0.083), compared with policies of AS-AQ or both AL and AS-AQ (median s=-0.035 and 0.021, p<0.001 respectively). 86Y frequency declined markedly after ACT policy introduction, with a borderline significant trend for a more rapid decline in countries with AL policies (p=0.055). However, these trends could also be explained by a difference in initial SNP frequencies at the time of ACT introduction. There were non-significant trends for faster selection of N86 and D1246 in areas with higher AL consumption and no trend with transmission intensity. Recorded consumption of AS-AQ was low in the locations and times Pfmdr1 data were collected. SNP trends in countries with AL policies suggest a broad increase in sensitivity of parasites to AS-AQ, by 7-10 years after AL introduction. Observed rates of selection have implications for planning strategies to cycle drugs or use multiple first-line therapies to maintain drug efficacy. PMID- 30397516 TI - Trends and drivers of change in the prevalence of anaemia among 1 million women and children in India, 2006 to 2016. AB - Introduction: India carries the largest burden of anaemia globally. Progress to reduce anaemia has been slow despite substantial economic growth and 50 years of programmatic efforts. Identification of the factors that contribute to anaemia reductions is needed to accelerate progress. We examined changes in haemoglobin (Hb) and anaemia among women and children in India from 2006 to 2016 and identified drivers of changes in these outcomes over time. Methods: We used two rounds of National Family Health Survey data collected in 2005-2006 and 2015-2016 (n=245 346 children 6-59 months; 37 165 pregnant women (PW) 15-49 years; 760 460 non-pregnant women (NPW) 15-49 years). We first examined trends in Hb and anaemia, and changes in 30 selected variables (including immediate and underlying determinants, and nutrition and health interventions (NHIs)). We identified drivers of Hb and anaemia using multivariate regression and estimated their contribution to changes in these outcomes over time using regression-based decomposition. Results: Hb and anaemia improved significantly between 2006 and 2016 in children (4.5 g/L and 11 percentage points (pp), respectively) and PW (3.2 g/L and 7.6 pp), but not in NPW. Despite these changes, anaemia is still very high (>50%) and progress varied considerably by state (-33 pp to +16 pp). Most immediate and underlying determinants, and NHIs improved significantly over time. Changes among a set of drivers common to children and PW accounted for the changes in Hb; these included maternal schooling (children, 10%; PW, 24%), coverage of NHIs (children, 18%; PW, 7%), socioeconomic status (children, 7%; PW, 17%), sanitation (children, 3%; PW, 9%), and meat and fish consumption (children, 3%; PW, 1%). The decomposition models moderately explained Hb changes over time (children, 49%; PW, 66%). Conclusions: Multiple common drivers have contributed to the anaemia changes among children and pregnant women in India. Further improvements in these drivers can have population-level effects by simultaneously influencing both maternal and child anaemia. PMID- 30397517 TI - Making the world a simpler place: the modeller's temptation to seek alternative trial results. PMID- 30397518 TI - Strengthening the quality of paediatric primary care: protocol for the process evaluation of a health systems intervention in South Africa. AB - Background: Despite significant reductions in mortality, preventable and treatable conditions remain the leading causes of death in children under five within South Africa. The WHO's Integrated Management of Childhood Illness (IMCI) programme has been widely implemented to address the most common causes of mortality in children under five. Although effective, limitations in IMCI scope and adherence have emerged. The Practical Approach to Care Kit (PACK) Child guide has been developed to expand on IMCI and address these limitations. It is intended as a clinical decision support tool for health workers with additional systems strengthening components, including active implementation and training strategy to address contextual and organisational factors hindering quality of care for children. Implementation is complex, requiring comprehensive pilot and process evaluation. The PACK Child pilot and feasibility study will sample 10 primary care facilities in the Western Cape Province. Staff will be trained to integrate the PACK Child guide into routine practice. The process evaluation will investigate implementation and health systems components to establish how to optimise delivery, strengthen IMCI principles and factors required to support effective and sustained uptake into everyday practice. Methods: Mixed method process evaluation. Qualitative data include interviews with managers, staff, caregivers and policymakers; observations of training, consultations and clinic flow. Quantitative data include training logs and staff questionnaires. Quantitative and qualitative analysis will be integrated to describe study sites and develop explanations for implementation variation. Discussion: The process evaluation will provide the opportunity to document implementation and refine the programme prior to a larger pragmatic trial or scale-up. PMID- 30397519 TI - PACK Child: the development of a practical guide to extend the scope of integrated primary care for children and young adolescents. AB - Pioneering strategies like WHO's Integrated Management of Childhood Illness (IMCI) have resulted in substantial progress in addressing infant and child mortality. However, large inequalities exist in access to and the quality of care provided in different regions of the world. In many low-income and middle-income countries, childhood mortality remains a major concern, and the needs of children present a large burden upon primary care services. The capacity of services and quality of care offered require greater support to address these needs and extend integrated curative and preventive care, specifically, for the well child, the child with a long-term health need and the child older than 5 years, not currently included in IMCI. In response to these needs, we have developed an innovative method, based on experience with a similar approach in adults, that expands the scope and reach of integrated management and training programmes for paediatric primary care. This paper describes the development and key features of the PACK Child clinical decision support tool for the care of children up to 13 years, and lessons learnt during its development. PMID- 30397520 TI - Using a mentorship model to localise the Practical Approach to Care Kit (PACK): from South Africa to Nigeria. AB - Nigeria, in its quest to strengthen its primary healthcare system, is faced with a number of challenges including a shortage of clinicians and skills. Methods are being sought to better equip primary healthcare clinicians for the clinical demands that they face. Using a mentorship model between developers in South Africa and Nigerian clinicians, the Practical Approach to Care Kit (PACK) for adult patients, a health systems strengthening programme, has been localised and piloted in 51 primary healthcare facilities in three Nigerian states. Lessons learnt from this experience include the value of this remote model of localisation for rapid localisation, the importance of early, continuous stakeholder engagement, the need expressed by Nigeria's primary healthcare clinicians for clinical guidance that is user friendly and up-to-date, a preference for the tablet version of the PACK Adult guide over hard copies and the added value of WhatsApp groups to complement the programme of face-to-face continuous learning. Introduction of the PACK programme in Nigeria prompted uptake of evidence-informed recommendations within primary healthcare services. PMID- 30397521 TI - Experimental Models of Spinal Cord Injury in Laboratory Rats. AB - Pathologies associated with spinal cord injury are some of the leading diseases in the world. The search for new therapeutic agents and 3D biodegradable materials for the recovery of spinal cord functions is a topical issue. In this review, we have summarized the literature data on the most common experimental models of spinal cord injury in laboratory rats and analyzed the experience of using 3D biodegradable materials (scaffolds) in experimental studies of spinal trauma. The advantages and disadvantages of the described models are systematically analyzed in this review. PMID- 30397522 TI - B Cell Regulation in Autoimmune Diseases. AB - Antibody-independent B cell effector functions play an important role in the development and suppression of the immune response. An extensive body of data on cytokine regulation of the immune response by B lymphocytes has been accumulated over the past fifteen years. In this review, we focused on the mechanisms of inflammatory response suppression by subpopulations of regulatory B cells in health and autoimmune pathologies. PMID- 30397523 TI - High-Throughput Screening of Biodiversity for Antibiotic Discovery. AB - The increasing number of infections caused by antibiotic-resistant strains of pathogens challenges modern technologies of drug discovery. Combinatorial chemistry approaches are based on chemical libraries. They enable the creation of high-affinity low-molecular-weight ligands of the therapeutically significant molecular targets of human cells, thus opening an avenue toward a directed design of highly effective therapeutic agents. Nevertheless, these approaches face insurmountable difficulties in antibiotic discovery. Natural compounds that have evolved for such important characteristics as broad specificity and efficiency are a good alternative to chemical libraries. However, unrestricted use of natural antibiotics and their analogues leads to avalanche-like spread of resistance among bacteria. The search for new natural antibiotics, in its turn, is extremely complicated nowadays by the problem of antibiotic rediscovery. This calls for the application of alternative high-throughput platforms for antibiotic activity screening, cultivation of "unculturable" microorganisms, exploration of novel antibiotic biosynthetic gene clusters, as well as their activation and heterologous expression. Microfluidic technologies for the screening of antibiotic activity at the level of single cells are, therefore, of great interest, since they enable the use of a single platform to combine the technology of ultrahigh-throughput screening, next-generation sequencing, and genome mining, thus opening up unique opportunities for antibiotic discovery. PMID- 30397524 TI - Possibilities for Using Pluripotent Stem Cells for Restoring Damaged Eye Retinal Pigment Epithelium. AB - The retinal pigment epithelium is a monolayer of pigmented, hexagonal cells connected by tight junctions. These cells compose part of the outer blood-retina barrier, protect the eye from excessive light, have important secretory functions, and support the function of photoreceptors, ensuring the coordination of a variety of regulatory mechanisms. It is the degeneration of the pigment epithelium that is the root cause of many retinal degenerative diseases. The search for reliable cell sources for the transplantation of retinal pigment epithelium is of extreme urgency. Pluripotent stem cells (embryonic stem or induced pluripotent) can be differentiated with high efficiency into the pigment epithelium of the retina, which opens up possibilities for cellular therapy in macular degeneration and can slow down the development of pathology and, perhaps, restore a patient's vision. Pioneering clinical trials on transplantation of retinal pigment epithelial cells differentiated from pluripotent stem cells in the United States and Japan confirmed the need for developing and optimizing such approaches to cell therapy. For effective use, pigment epithelial cells differentiated from pluripotent stem cells should have a set of functional properties characteristic of such cells in vivo. This review summarizes the current state of preclinical and clinical studies in the field of retinal pigment epithelial transplantation therapy. We also discuss different differentiation protocols based on data in the literature and our own data, and the problems holding back the widespread therapeutic application of retinal pigment epithelium differentiated from pluripotent stem cells. PMID- 30397525 TI - Production of Recombinant Proteins in the Milk of Transgenic Animals: Current State and Prospects. AB - The use of transgenic animals as bioreactors for the synthesis of the recombinant proteins secreted into milk is a current trend in the development of biotechnologies. Advances in genetic engineering, in particular the emergence of targeted genome editing technologies, have provided new opportunities and significantly improved efficiency in the generation of animals that produce recombinant proteins in milk, including economically important animals. Here, we present a retrospective review of technologies for generating transgenic animals, with emphasis on the creation of animals that produce recombinant proteins in milk. The current state and prospects for the development of this area of biotechnology are discussed in relation to the emergence of novel genome editing technologies. Experimental and practical techniques are briefly discussed. PMID- 30397526 TI - Three-Dimensional Structure of Cytochrome c Nitrite Reductase As Determined by Cryo-Electron Microscopy. AB - The structure of cytochrome c nitrite reductase from the bacterium Thioalkalivibrio nitratireducens was determined by cryo-electron microscopy (cryo EM) at a 2.56 A resolution. Possible structural heterogeneity of the enzyme was assessed. The backbone and side-chain orientations in the cryo-EM-based model are, in general, similar to those in the high-resolution X-ray diffraction structure of this enzyme. PMID- 30397527 TI - Lynx1 Prevents Long-Term Potentiation Blockade and Reduction of Neuromodulator Expression Caused by Abeta1-42 and JNK Activation. AB - Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels. Many neurodegenerative diseases are accompanied by cognitive impairment associated with the dysfunction of nAChRs. The human membrane-tethered prototoxin Lynx1 modulates nAChR function in the brain areas responsible for learning and memory. In this study, we have demonstrated for the first time that the beta-amyloid peptide Abeta1-42 decreases Lynx1 mRNA expression in rat primary cortical neurons, and that this decrease is associated with the activation of c-Jun N terminal kinase (JNK). In addition, we have demonstrated that the Lynx1 expression decrease, as well as the blockade of the long-term potentiation underlying learning and memory, caused by Abeta1-42, may be prevented by incubation with a water-soluble Lynx1 analogue. Our findings suggest that the water-soluble Lynx1 analogue may be a promising agent for the improvement of cognitive deficits in neurodegenerative diseases. PMID- 30397528 TI - Biochemical and Functional Changes in the Eye As a Manifestation of Systemic Degeneration of the Nervous System in Parkinsonism. AB - Parkinson's disease (PD) is a systemic neurodegenerative condition caused by the death of dopaminergic neurons of the nigrostriatal system of the brain. This disease is diagnosed after most neurons have already been lost, which explains the low efficiency of treatment. Hope for increasing treatment efficiency rests in the development of new strategies for early diagnosis of PD based on a search for peripheral markers that appear as early changes in non-motor functions. Since impairment of the visual function is one of the manifestations of PD, the purpose of our work was to identify biochemical and physiological changes in a mouse's eye and eyelid in models of preclinical (presymptomatic) and clinical (symptomatic) stages of PD. We found that the norepinephrine, dopamine, and serotonin levels in the mouse eye reduced not only in the model of the early clinical stage, but also in the model of preclinical stage, an indication that pathological changes in the monoaminergic systems of the brain had affected the eye even before the motor disorders emerged. Moreover, in both models of PD, mice had increased intraocular pressure, indicating the development of both metabolic and functional impairments, which can be used as diagnostic markers. Unlike in the eye, the serotonin level in the eyelid was increased in mice at both parkinsonism stages and in presymptomatic mice to a much higher extent than in symptomatic ones. Given that serotonin is involved in the regulation of lacrimal glands of the eyelid, an increase in its level in parkinsonian mice should alter the composition of tear fluid, which could serve as a diagnostic marker of early stage of PD. Thus, the changes in the metabolism of monoamines in the eye and eyelid observed in mice at the early stage of parkinsonism are accompanied by changes in the function of these structures and, therefore, can be used as diagnostic markers of the early stage of PD. PMID- 30397529 TI - Whole-Genome Sequencing of Russian Neisseria Gonorrhoeae Isolates Related to ST 1407 Genogroup. AB - The whole-genome sequencing data of three N. gonorrhoeae strains isolated in the Russian Federation in 2015 are presented. According to the NG-MAST protocol, these strains are related to the globally spread ST 1407 genogroup. The analysis of their resistomes showed the absence of ermA/B/C/F genes and the presence of wild-type alleles of rpsE, rrs, rrl, rplD, rplV, macAB, and mefA genes, and these patterns explain the susceptibility of the sequenced strains to aminocyclitols (spectinomycin) and macrolides (azithromycin). Conjugative resistance determinants (blaTEM, tetM) were absent in the genomes, and the penC/ pilQ, parE, and norM alleles were shown to be wild-type, whereas single or multiple nucleotide substitutions were identified in the genes encoding targets for beta lactams (ponA, penA), tetracyclines (rpsJ), and fluoroquinolones (gyrA, parC). The additional mutations were found in porB gene and the promoter of mtrR gene, which nonspecifically reduced the susceptibility to antimicrobials due to the membrane permeability decrease and efflux pump overexpression. The diversity of mutations observed in the analyzed genomes prompted a revision of the phylogenetic relationships between the strains by comparing more than 790 groups of housekeeping genes. A high homology between the N. gonorrhoeae ST 1407 and N. gonorrhoeae ST 12556 genomes was confirmed; the latter had probably diverged from a common ancestor as a result of single mutation events. On the other hand, N. gonorrhoeae ST 12450 was an example of phenotypic convergence which appeared in the emergence of new drug resistance determinants that partially coincide with those of the ST 1407 genogroup. PMID- 30397530 TI - Antibacterial Effect of Thiosulfinates on Multiresistant Strains of Bacteria Isolated from Patients with Cystic Fibrosis. AB - The multiresistance of A. ruhlandii 155B, B. cenocepacia 122, and P. aeruginosa 48B strains isolated from patients with cystic fibrosis was established. The antibacterial effect of allicin, dimethyl thiosulfinate, and dipropyl thiosulfinate on multidrug-resistant strains was shown. Thiosulfinates can have both bacteriostatic and bactericidal effects depending on the microorganism and the concentration. The studied thiosulfinates may be candidates for the development of alternative antibiotic drugs to treat infections caused by multidrug-resistant pathogens. PMID- 30397531 TI - Antidepressant Effect of an Orally Administered Dipeptide Mimetic of the Brain Derived Neurotrophic Factor. AB - Involvement of BDNF in the regulation of neuroplasticity and neurogenesis in the hippocampus, impairment of which underlies the pathophysiology of depression, makes this endogenous protein a promising object for the development of new generation antidepressants with a neurophysiologically based mechanism of action. A low-molecular-weight BDNF mimetic, GSB-106 (a substituted dimeric dipeptide, bis-(N-monosuccinyl- L-seryl-L-lysine) hexamethylenediamide), was designed and synthesized at the Zakusov Institute of Pharmacology. GSB-106 was found to activate BDNF-specific TrkB receptors and their main post-receptor signaling pathways MAPK/ERK and PI3K/AKT. GSB-106 exhibited pronounced antidepressant activity in a rodent test battery at a dose of 0.1 to 1.0 mg/kg administered intraperitoneally. Because oral administration is preferable in the treatment of depression, which is associated with a prolonged duration and outpatient character of pharmacotherapy, we examined the antidepressant properties of GSB 106 administered orally as a pharmaceutical substance (PS) and in tablet dosage form (TDF). In the study, we used the Porsolt forced swim test in rats; a conventional antidepressant, Amitriptyline, was used as a reference drug. The antidepressant activity of GSB-106 was found to retain upon oral administration and to manifest at doses of 0.5-5.0 mg/kg for PS and 0.01-5.0 mg/kg for TDF. The effective dose of TDF was 50-fold lower than that of PS, and the efficacy of tableted GSB-106 exceeded that of Amitriptyline, the "gold standard" in antidepression care. Therefore, GSB-106, both as a substance and as a tablet dosage form, exhibits antidepressant activity when administered orally, which makes it a promising antidepressant agent, the first in the class of BDNF mimetics. PMID- 30397532 TI - A Novel Approach to Anticancer Therapy: Molecular Modules Based on the Barnase:Barstar Pair for Targeted Delivery of HSP70 to Tumor Cells. AB - One important distinction between many tumor cell types and normal cells consists in the translocation of a number of intracellular proteins, in particular the 70 kDa heat shock protein (HSP70), to the surface of the plasma membrane. It has been demonstrated that such surface localization of HSP70 on tumor cells is recognized by cytotoxic effectors of the immune system, which increases their cytolytic activity. The mechanisms behind this interaction are not fully clear; however, the phenomenon of surface localization of HSP70 on cancer cells can be used to develop new approaches to antitumor immunotherapy. At the same time, it is known that the presence of HSP70 on a cell's surface is not a universal feature of cancer cells. Many types of tumor tissues do not express membrane associated HSP70, which limits the clinical potential of these approaches. In this context, targeted delivery of exogenous HSP70 to the surface of cancer cells with the aim of attracting and activating the cytotoxic effectors of the immune system can be considered a promising means of antitumor immunotherapy. Molecular constructs containing recombinant mini-antibodies specific to tumor-associated antigens (in particular, antibodies specific to HER2/neu-antigen and other markers highly expressed on the surface of a wide range of cancer cells) can be used to target the delivery of HSP70 to tumor tissues. In order to assess the feasibility and effectiveness of this approach, recombinant constructs containing a mini-antibody specific to the HER2/ neu-antigen in the first module and HSP70 molecule or a fragment of this protein in the second module were developed in this study. Strong selective interaction between the modules was ensured by a cohesive unit formed by the barnase:barstar pair, a heterodimer characterized by an unusually high constant of association. During testing of the developed constructs in in vitro models the constructs exhibited targeted binding to tumor cells expressing the HER2/neu antigen and the agents had a significant stimulating effect on the cytotoxic activity of NK cells against the respective cancer cells. PMID- 30397533 TI - Expression and Intracellular Localization of Paraoxonase 2 in Different Types of Malignancies. AB - PON2 belongs to the paraoxonase protein family that consists of lactone hydrolyzing enzymes with different substrate specificities. Unlike other members of the family, PON2 exhibits substantial antioxidant activity, is localized predominantly inside the cell, and is ubiquitously expressed in all human tissues. Previously, it was proffered that defense against pathogens, such as Pseudomonas aeruginosa, is the main function of paraoxonases. However, recent findings have highlighted the important role played by PON2 in protection against oxidative stress, inhibition of apoptosis, and progression of various types of malignancies. In the current study, we performed a bioinformatic analysis of RNA and DNA sequencing data extracted from tumor samples taken from more than 10,000 patients with 31 different types of cancer and determined expression levels and mutations in the PON2 gene. Next, we investigated the intracellular localization of PON2 in multiple cancer cell lines and identified the proteins interacting with PON2 using the LC-MS/MS technique. Our data indicate that a high PON2 expression level correlates with a worse prognosis for patients with multiple types of solid tumors and suggest that PON2, when localized on the nuclear envelope and endoplasmic reticulum, may protect cancer cells against unfavorable environmental conditions and chemotherapy. PMID- 30397534 TI - Influence of the Activation of NMDA Receptors on the Resting Membrane Potential of the Postsynaptic Cell at the Neuromuscular Junction. AB - Impaired function or insufficient expression of glutamate N-methyl-D-aspartate (NMDA) receptors underlies a number of brain pathologies; these receptors are, therefore, regarded as a pharmacological target for many neuroactive drugs. It was shown that in the CNS, this type of glutamate receptors participate in the processes of neuronal excitation, synaptic plasticity [1, 2], and excitotoxicity in neurodegenerative diseases and are also involved in the pathogenesis of epilepsy and seizures. However, until recently, the presence and activity of NMDA receptors beyond the CNS had never been considered. This research shows that activation of NMDA receptors at the mammalian neuromuscular junction alters the resting membrane potential of the postsynaptic cell evoked by cation entry through the receptor-associated channel. PMID- 30397535 TI - Challenges in the management of pancreatic exocrine insufficiency. AB - Pancreatic exocrine insufficiency (PEI) occurs when the insufficient secretion or function of pancreatic enzymes leads to maldigestion, most commonly as a result of chronic pancreatitis and pancreatic cancer. The condition is associated with significant morbidity and reductions in quality of life, even in milder forms. The challenges in approaching this condition include the non-specific presentation of mild to moderate PEI, and the lack of a convenient, accurate diagnostic test in this cohort. Classical symptoms appear late in the disease, and the diagnosis should be considered before steatorrhoea develops. Direct pancreatic function tests are the reference standard for diagnosis, but are invasive and not widely available. The faecal elastase-1 (FE-1) stool test is widely available and has been shown to be as effective as the 13C-mixed triglyceride breath test in more advanced disease. We recommend a pragmatic diagnostic approach that combines clinical history, assessment of nutritional status and measurement of FE-1. The critical first step is to consider the diagnosis. Once the diagnosis is confirmed, pancreatic enzyme replacement therapy should be initiated. The variety of enzyme preparations and recommended dosing regimens can present a challenge when selecting an adequate initial dose. Non response should be actively sought and addressed in a systematic manner. This article discusses these challenges, and presents a practical approach to the diagnosis and management of PEI. PMID- 30397536 TI - Intra-Articular Tranexamic Acid Injection During the Hip Hemi-Arthroplasty in Elderly Patients: A Retrospective Study. AB - Introduction: The objective was to evaluate the safety and efficacy of intra articular injection of tranexamic acid (TXA) in patients between 80 and 100 years of age with femoral neck fracture undergoing hip hemi-arthroplasty (HA). Material and Methods: We conducted a retrospective review to assess perioperative blood loss and transfusion rate after intra-articular injection of TXA during HA. This was a single-center, retrospective, single-surgeon, and standard care cohort study covering the period between January and December 2016. One hundred three consecutive patients undergoing HA under spinal or general anesthesia were included. Fifty-four and 49 patients received and did not receive intra-articular injection of TXA during the HA, respectively. After closing the capsule, 50 mL of a TXA solution at a concentration of 1 g/100 mL of saline was injected into joint capsule. We compared the following outcomes: preoperative hemoglobin (HB) level, postoperative day 1 HB level, postoperative day 3 HB level, the net reduction of HB level by postoperative day 3, transfusion rate, and 30- and 90-day postoperative mortality rates. In addition, we use logistic regression to analyze the factors affecting the transfusion rate. Result: Day 3 postoperative HB level and the net reduction in HB level within 3 days following surgery were 93.22 +/- 11.70 g/L and 25.98 +/- 6.29 g/L in TXA group, respectively, while were 87.10 +/- 10.52 g/L and 35.44+/-8.61 g/L in no-TXA group. Transfusion rate was 9% (5/54) in TXA group and 24% (12/49) in no-TXA group, respectively. The differences were statistically significant between the both groups. Logistic regression indicated that the topical administration of TXA would reduce the risk for transfusion, while in male diabetes mellitus would increase the risk. There were no significant differences in the deep venous thrombosis, pulmonary embolism, and mortality rates of 30 and 90 days postoperatively (P > .05). Discussion: Because of lower systemic absorption and a higher concentration in the wound, topical use of TXA is safer for elderly patients who may have renal or liver dysfunction. TXA at therapeutic concentration does not affect platelet count, platelet aggregation, or coagulation parameters, and is of value in elderly patients who take antiplatelet drug for secondary prevention of cardiovascular diseases. Conclusion: For patients between 80 and 100 years of age with femoral neck fracture undergoing HA, intra-articular injection of TXA may reduce the perioperative blood loss and transfusion rate without increasing risk of thrombosis. PMID- 30397537 TI - Egg perivitelline fluid of the invasive snail Pomacea canaliculata affects mice gastrointestinal function and morphology. AB - Background: Species beloging to the genus Pomacea (Ampullariidae), often referred as apple snails, are freshwater, amphibious snails native to South, Central and North America. Some species such as P. canaliculata have become a driver of ecosystem changes in wetlands and an important rice and taro pest after its introduction to Asia and other parts of the world. Females deposit colored egg clutches above the waterline, a reproductive strategy that exposes the eggs to harsh conditions and terrestrial predation. However, eggs have no reported predators in their native range, probably because of the acquisition of unparalleled biochemical defenses provided by a set of proteins (perivitellins) that nourish embryos and protect them from predators and abiotic factors. Notably, ingestion of egg perivitelline fluid (PVF) decreases rat growth rate and alters their gastrointestinal morphology. The aim of the study is to determine the effect of apple snail egg PVF on mice gut digestive activity, morphology and nutrient absorption. Methods: Carbohydrate digestion by intestinal disaccharidases (sucrase-isomaltase and maltase-glucoamylase) was evaluated ex vivo in mice gavaged with 1 or 4 doses of PVF. Changes in gut morphological and absorptive surface were measured. In addition, alteration on nutrient absorption rates, transport pathways and intestinal permeability was evaluated by luminal perfusions of small intestine with radiolabeled L-proline (absorbed by paracellular and transcellular pathways) and L-arabinose (absorbed exclusively by paracellular pathway). Results: Perivitelline fluid affected mice displayed significant morphological changes in the small intestine epithelium inducing the appearance of shorter and wider villi as well as fused villi. This resulted in a diminished absorptive surface, notably in the proximal portion. Likewise, the activity of disaccharidases diminished in the proximal portion of the intestine. Total absorption of L-proline increased in treated mice in a dose-dependent manner. There were no differences neither in the ratio of paracellular-to transcellular absorption of L-proline nor in gut permeability as revealed by the clearance of L-arabinose. Discussion: Oral administration of apple snail PVF to mice adversely alters gut morphophysiology by reducing the intestinal absorptive surface, affecting enzymes of sugar metabolism and increasing the absorption rate of nutrients without affecting the relative contribution of the absorption pathways or gut permeability. These results further support the role of PVF in passive anti-predator defenses in Pomacea snail eggs that target the digestive system. PMID- 30397538 TI - From the cage to the wild: introductions of Psittaciformes to Puerto Rico. AB - Introduced psittacine birds can become highly invasive. In this study, we assessed invasions of Psittaciformes in Puerto Rico. We reviewed the literature, public databases, citizen science records, and performed in situ population surveys across the island to determine the historical and current status and distribution of psittacine species. We used count data from Ebird to determine population trends. For species whose populations were increasing, we modelled their potential distribution using niche modeling techniques. We found 46 Psittaciformes in Puerto Rico, of which 26% are only present as pets, at least 29 species have been reported in the wild, and of those, there is evidence that at least 12 species are breeding. Our results indicate that most introduced species which have been detected as established still persist, although mostly in localized areas and small populations. Clear evidence of invasiveness was found for Brotogeris versicolurus and Myiopsitta monachus, which have greatly expanded their range in recent years. Psittacara erythrogenys and Eupsittacula canicularis also showed population increases, although to a lesser degree. The niche models predicted suitable areas for the four species, and also indicate the potential for range expansion. We discuss the factors leading to invasion success, assess the potential impacts, and we discuss possible management strategies and research prospects. PMID- 30397539 TI - Body size and temperature effects on standard metabolic rate for determining metabolic scope for activity of the polychaete Hediste (Nereis) diversicolor. AB - Considering the ecological importance and potential value of Hediste diversicolor, a better understanding of its metabolic rate and potential growth rates is required. The aims of this study are: (i) to describe key biometric relationships; (ii) to test the effects of temperature and body size on standard metabolic rate (as measure by oxygen consumption) to determine critical parameters, namely Arrhenius temperature (TA ), allometric coefficient (b) and reaction rate; and (iii) to determine the metabolic scope for activity (MSA) of H. diversicolor for further comparison with published specific growth rates. Individuals were collected in a Mediterranean lagoon (France). After 10 days of acclimatization, 7 days at a fixed temperature and 24 h of fasting, resting oxygen consumption rates (VO2 ) were individually measured in the dark at four different temperatures (11, 17, 22 and 27 degrees C) in worms weighing from 4 to 94 mgDW (n = 27 per temperature). Results showed that DW and L3 were the most accurate measurements of weight and length, respectively, among all the metrics tested. Conversion of WW (mg), DW (mg) and L3 (mm) were quantified with the following equations: DW = 0.15 * WW, L3 = 0.025 * TL(mm) + 1.44 and DW = 0.8 * L33.68. Using an equation based on temperature and allometric effects, the allometric coefficient (b) was estimated at 0.8 for DW and at 2.83 for L3. The reaction rate (VO2 ) equaled to 12.33 umol gDW-1 h-1 and 0.05 umol mm L3-1 h-1 at the reference temperature (20 degrees C, 293.15 K). Arrhenius temperature (TA ) was 5,707 and 5,664 K (for DW and L3, respectively). Metabolic scope for activity ranged from 120.1 to 627.6 J gDW-1 d-1. Predicted maximum growth rate increased with temperature, with expected values of 7-10% in the range of 15-20 degrees C. MSA was then used to evaluate specific growth rates (SGR) in several experiments. This paper may be used as a reference and could have interesting applications in the fields of aquaculture, ecology and biogeochemical processes. PMID- 30397540 TI - Effects of agricultural management on phyllosphere fungal diversity in vineyards and the association with adjacent native forests. AB - Agriculture is one of the main drivers of land conversion, and agriculture practices can impact on microbial diversity. Here we characterized the phyllosphere fungal diversity associated with Carmenere grapevines under conventional and organic agricultural management. We also explored the fungal diversity present in the adjacent sclerophyllous forests to explore the potential role of native forest on vineyard phyllosphere. After conducting D2 and ITS2 amplicon sequencing, we found that fungal diversity indices did not change between conventional and organic vineyards, but community structure was sensitive to the agricultural management. On the other hand, we found a high proportion of shared fungal OTUs between vineyards and native forests. In addition, both habitats had similar levels of fungal diversity despite forest samples were derived from multiple plant species. In contrast, the community structure was different in both habitats. Interestingly, the native forest had more unidentified species and unique OTUs than vineyards. Forest dominant species were Aureobasidium pullulans and Endoconidioma populi, whereas Davidiella tassiana, Didymella sp., and Alternaria eichhorniae were more abundant in vineyards. Overall, this study argues that a better understanding of the relationship native forests and agroecosystems is needed for maintaining and enhancing ecosystem services provided by natural ecosystems. Finally, knowledge of microbial communities living in the Chilean Mediterranean biome is needed for appropriate conservation management of these biomes and their classification as biodiversity hotspots. PMID- 30397541 TI - Using the validated Reflective Functioning Questionnaire to investigate mentalizing in individuals presenting with eating disorders with and without self harm. AB - Background: The present study builds on previous research which explored the relationship between mentalizing and eating disorders (ED) in a subgroup of patients with comorbid self-harm (SH). Whereas previous literature had linked this comorbidity to impulse-control difficulties, more recent advances have suggested that a lack of a mentalizing stance might be responsible for a more treatment-resistant and severe symptomatology in this subgroup of clients. Methods: A cross-sectional, quasi-experimental, questionnaire-based, between groups design was employed and a measure of mentalizing was compared in individuals presenting with ED only, individuals presenting with ED and concurrent SH and a control group. Results: Individuals with ED with concurrent SH reported significantly more mentalizing ability impairment than individuals without concurrent SH. In addition, both groups differed significantly from the control group. Opposite scoring patterns were identified in hypo- and hypermentalizing with the comorbid group reporting the lowest scores in hypermentalizing and the highest scores in hypomentalizing. Conclusions: The current findings confirm that individuals with concurrent ED and SH report more severe impairments in mentalizing ability. Such impairments entail difficulties in symbolic capacity and abstract thinking and a concretisation of inner life, exemplified by a rigid, often inflexible focus on the physical world. The clinical implications that a lack of a mentalizing stance can have on individuals' ability to engage with the therapeutic process and to initiate change are reflected upon. PMID- 30397542 TI - Adipose tissues of MPC1+/- mice display altered lipid metabolism-related enzyme expression levels. AB - Mitochondrial pyruvate carrier 1 (MPC1) is a component of the MPC1/MPC2 heterodimer that facilitates the transport of pyruvate into mitochondria. Pyruvate plays a central role in carbohydrate, fatty, and amino acid catabolism. The present study examined epididymal white adipose tissue (eWAT) and intrascapular brown adipose tissue (iBAT) from MPC1+/- mice following 24 weeks of feeding, which indicated low energy accumulation as evidenced by low body and eWAT weight and adipocyte volume. To characterize molecular changes in energy metabolism, we analyzed the transcriptomes of the adipose tissues using RNA Sequencing (RNA-Seq). The results showed that the fatty acid oxidation pathway was activated and several genes involved in this pathway were upregulated. Furthermore, qPCR and western blotting indicated that numerous genes and proteins that participate in lipolysis were also upregulated. Based on these findings, we propose that the energy deficiency caused by reduced MPC1 activity can be alleviated by activating the lipolytic pathway. PMID- 30397543 TI - Uncovering full-length transcript isoforms of sugarcane cultivar Khon Kaen 3 using single-molecule long-read sequencing. AB - Background: Sugarcane is an important global food crop and energy resource. To facilitate the sugarcane improvement program, genome and gene information are important for studying traits at the molecular level. Most currently available transcriptome data for sugarcane were generated using second-generation sequencing platforms, which provide short reads. The de novo assembled transcripts from these data are limited in length, and hence may be incomplete and inaccurate, especially for long RNAs. Methods: We generated a transcriptome dataset of leaf tissue from a commercial Thai sugarcane cultivar Khon Kaen 3 (KK3) using PacBio RS II single-molecule long-read sequencing by the Iso-Seq method. Short-read RNA-Seq data were generated from the same RNA sample using the Ion Proton platform for reducing base calling errors. Results: A total of 119,339 error-corrected transcripts were generated with the N50 length of 3,611 bp, which is on average longer than any previously reported sugarcane transcriptome dataset. 110,253 sequences (92.4%) contain an open reading frame (ORF) of at least 300 bp long with ORF N50 of 1,416 bp. The mean lengths of 5' and 3' untranslated regions in 73,795 sequences with complete ORFs are 1,249 and 1,187 bp, respectively. 4,774 transcripts are putatively novel full-length transcripts which do not match with a previous Iso-Seq study of sugarcane. We annotated the functions of 68,962 putative full-length transcripts with at least 90% coverage when compared with homologous protein coding sequences in other plants. Discussion: The new catalog of transcripts will be useful for genome annotation, identification of splicing variants, SNP identification, and other research pertaining to the sugarcane improvement program. The putatively novel transcripts suggest unique features of KK3, although more data from different tissues and stages of development are needed to establish a reference transcriptome of this cultivar. PMID- 30397545 TI - Association of urban forest landscape characteristics with biomass and soil carbon stocks in Harbin City, Northeastern China. AB - Background: Urban forests help in mitigating carbon emissions; however, their associations with landscape patterns are unclear. Understanding the associations would help us to evaluate urban forest ecological services and favor urban forest management via landscape regulations. We used Harbin, capital city of the northernmost province in China, as an example and hypothesized that the urban forests had different landscape metrics among different forest types, administrative districts, and urban-rural gradients, and these differences were closely associated with forest carbon sequestration in the biomass and soils. Methods: We extracted the urban forest tree coverage area on the basis of 2 GF-1 remote sensing images and object-oriented based classification method. The analysis of forest landscape patterns and estimation of carbon storage were based on tree coverage data and 199 plots. We also examined the relationships between forest landscape metrics and carbon storage on the basis of forest types, administrative districts, ring roads, and history of urban settlements by using statistical methods. Results: The small patches covering an area of less than 0.5 ha accounted for 72.6% of all patches (average patch size, 0.31 ha). The mean patch size (AREA_MN) and largest patch index (LPI) were the highest in the landscape and relaxation forest and Songbei District. The landscape shape index (LSI) and number of patches linearly decreased along rural-urban gradients (p < 0.05). The tree biomass carbon storage varied from less than 10 thousand tons in the urban center (first ring road region and 100-year regions) to more than 100 thousand tons in the rural regions (fourth ring road and newly urbanized regions). In the same urban-rural gradients, soil carbon storage varied from less than five thousand tons in the urban centers to 73-103 thousand tons in the rural regions. The association analysis indicated that the total forest area was the key factor that regulates total carbon storage in trees and soils. However, in the case of carbon density (ton ha-1), AREA_MN was strongly associated with tree biomass carbon, and soil carbon density was negatively related to LSI (p < 0.01) and AREA_MN (p < 0.05), but positively related to LPI (p < 0.05). Discussion: The urban forests were more fragmented in Harbin than in other provincial cities in Northeastern China, as shown by the smaller patch size, more complex patch shape, and larger patch density. The decrease in LSI along the rural-urban gradients may contribute to the forest carbon sequestrations in downtown regions, particularly underground soil carbon accumulation, and the increasing patch size may benefit tree carbon sequestration. Our findings help us to understand how forest landscape metrics are associated with carbon storage function. These findings related to urban forest design may maximize forest carbon sequestration services and facilitate in precisely estimating the forest carbon sink. PMID- 30397544 TI - Comparative functional analysis of proteins containing low-complexity predicted amyloid regions. AB - Background: In both prokaryotic and eukaryotic proteins, repeated occurrence of a single or a group of few amino acids are found. These regions are termed as low complexity regions (LCRs). It has been observed that amino acid bias in LCR is directly linked to their uncontrolled expansion and amyloid formation. But a comparative analysis of the behavior of LCR based on their constituent amino acids and their association with amyloidogenic propensity is not available. Methods: Firstly we grouped all LCRs on the basis of their composition: homo polymers, positively charged amino acids, negatively charged amino acids, polar amino acids and hydrophobic amino acids. We analyzed the compositional pattern of LCRs in each group and their propensity to form amyloids. The functional characteristics of proteins containing different groups of LCRs were explored using DAVID. In addition, we also analyzed the classes, pathways and functions of human proteins that form amyloids in LCRs. Results: Among homopolymeric LCRs, the most common was Gln repeats. LCRs composed of repeats of Met and aromatic amino acids were amongst the least occurring. The results revealed that LCRs composed of negatively charged and polar amino acids were more common in comparison to LCRs formed by positively charged and hydrophobic amino acids. We also noted that generally proteins with LCRs were involved in transcription but those with Gly repeats were associated to translational activities. Our analysis suggests that proteins in which LCR is composed of hydrophobic residues are more prone toward amyloid formation. We also found that the human proteins with amyloid forming LCRs were generally involved in binding and catalytic activity. Discussion: The presented analysis summarizes the most common and least occurring LCRs in proteins. Our results show that though repeats of Gln are the most abundant but Asn repeats make longest stretch of low complexity. The results showed that potential of LCRs to form amyloids varies with their amino acid composition. PMID- 30397546 TI - Microbiome analysis of Pacific white shrimp gut and rearing water from Malaysia and Vietnam: implications for aquaculture research and management. AB - Aquaculture production of the Pacific white shrimp is the largest in the world for crustacean species. Crucial to the sustainable global production of this important seafood species is a fundamental understanding of the shrimp gut microbiota and its relationship to the microbial ecology of shrimp pond. This is especially true, given the recently recognized role of beneficial microbes in promoting shrimp nutrient intake and in conferring resistance against pathogens. Unfortunately, aquaculture-related microbiome studies are scarce in Southeast Asia countries despite the severe impact of early mortality syndrome outbreaks on shrimp production in the region. In this study, we employed the 16S rRNA amplicon (V3-V4 region) sequencing and amplicon sequence variants (ASV) method to investigate the microbial diversity of shrimp guts and pond water samples collected from aquaculture farms located in Malaysia and Vietnam. Substantial differences in the pond microbiota were observed between countries with the presence and absence of several taxa extending to the family level. Microbial diversity of the shrimp gut was found to be generally lower than that of the pond environments with a few ubiquitous genera representing a majority of the shrimp gut microbial diversity such as Vibrio and Photobacterium, indicating host specific selection of microbial species. Given the high sequence conservation of the 16S rRNA gene, we assessed its veracity at distinguishing Vibrio species based on nucleotide alignment against type strain reference sequences and demonstrated the utility of ASV approach in uncovering a wider diversity of Vibrio species compared to the conventional OTU clustering approach. PMID- 30397547 TI - Don't worry, be active: how to facilitate the detection of errors in immersive virtual environments. AB - The current research aims to study the link between the type of vision experienced in a collaborative immersive virtual environment (active vs. multiple passive), the type of error one looks for during a cooperative multi-user exploration of a design project (affordance vs. perceptual violations), and the type of setting in which multi-user perform (field in Experiment 1 vs. laboratory in Experiment 2). The relevance of this link is backed by the lack of conclusive evidence on an active vs. passive vision advantage in cooperative search tasks within software based on immersive virtual reality (IVR). Using a yoking paradigm based on the mixed usage of simultaneous active and multiple passive viewings, we found that the likelihood of error detection in a complex 3D environment was characterized by an active vs. multi-passive viewing advantage depending on: (1) the degree of knowledge dependence of the type of error the passive/active observers were looking for (low for perceptual violations, vs. high for affordance violations), as the advantage tended to manifest itself irrespectively from the setting for affordance, but not for perceptual violations; and (2) the degree of social desirability possibly induced by the setting in which the task was performed, as the advantage occurred irrespectively from the type of error in the laboratory (Experiment 2) but not in the field (Experiment 1) setting. Results are relevant to future development of cooperative software based on IVR used for supporting the design review. A multi-user design review experience in which designers, engineers and end-users all cooperate actively within the IVR wearing their own head mounted display, seems more suitable for the detection of relevant errors than standard systems characterized by a mixed usage of active and passive viewing. PMID- 30397548 TI - Using stiffness to assess injury risk: comparison of methods for quantifying stiffness and their reliability in triathletes. AB - Background: A review of the literature has indicated that lower body stiffness, defined as the extent to which the lower extremity joints resists deformation upon contact with the ground, may be a useful measure for assessing Achilles injury risk in triathletes. The nature of overuse injuries suggests that a variety of different movement patterns could conceivably contribute to the final injury outcome, any number and combination of which might be observed in a single individual. Measurements which incorporate both kinetics and kinematics (such as stiffness) of a movement may be better able to shed light on individuals at risk of injury, with further analysis then providing the exact mechanism of injury for the individual. Stiffness can be measured as vertical, leg or joint stiffness to model how the individual interacts with the environment upon landing. However, several issues with stiffness assessments limit the effectiveness of these measures to monitor athletes' performance and/or injury risk. This may reflect the variety of common biomechanical stiffness calculations (dynamic, time, true leg and joint) that have been used to examine these three stiffness levels (vertical, leg and joint) across a variety of human movements (i.e. running or hopping) as well as potential issues with the reliability of these measures, especially joint stiffness. Therefore, the aims of this study were to provide a comparison of the various methods for measuring stiffness during two forms of human bouncing locomotion (running and hopping) along with the measurement reliability to determine the best methods to assess links with injury risk in triathletes. Methods: Vertical, leg and joint stiffness were estimated in 12 healthy male competitive triathletes on two occasions, 7 days apart, using both running at 5.0 ms-1 and hopping (2.2 Hz) tasks. Results: Inter-day reliability was good for vertical (ICC = 0.85) and leg (ICC = 0.98) stiffness using the time method. Joint stiffness reliability was poor when assessed individually. Reliability was improved when taken as the sum of the hip, knee and ankle (ICC = 0.86). The knee and ankle combination provided the best correlation with leg stiffness during running (Pearson's Correlation = 0.82). Discussion: The dynamic and time methods of calculating leg stiffness had better reliability than the "true" method. The time and dynamic methods had the best correlation with the different combinations of joint stiffness, which suggests that they should be considered for biomechanical screening of triathletes. The knee and ankle combination had the best correlation with leg stiffness and is therefore proposed to provide the most information regarding lower limb mechanics during gait in triathletes. PMID- 30397549 TI - Effectiveness of telephone-based interventions for managing osteoarthritis and spinal pain: a systematic review and meta-analysis. AB - Background: Osteoarthritis and spinal pain are common and burdensome conditions; however, the majority of patients with these conditions do not receive care that is consistent with clinical practice guidelines. Telehealth models of care have the potential to improve care for osteoarthritis and spinal pain patients. The aim of this review was to assess the effectiveness of verbal real-time telehealth interventions, including telephone-based and videoconferencing interventions to reduce pain intensity and disability in patients with osteoarthritis of the knee or hip and spinal pain (back or neck pain). Methods: We searched seven electronic databases from inception to May 2018. Randomised controlled trials (RCTs), cluster-RCTs, and non-randomised controlled trials were included. Two review authors independently extracted data for each included study. Primary outcomes were pain intensity and disability. We conducted primary meta-analyses combining all conditions with similar interventions and comparators. Standardised mean difference (SMD) and 95% confidence intervals (CIs) were calculated using random effects models. We used the Cochrane Risk of Bias tool to assess risk of bias, and GRADE to evaluate the quality of evidence. Results: We included 23 studies with 56 trial arms and 4,994 participants. All studies utilised telephone-based interventions. Only two studies used a telephone only approach and the remainder included educational materials and/or face-to-face components. We found no studies utilising videoconferencing. Meta-analysis showed telephone-based interventions (with educational materials) for osteoarthritis and spinal pain improved pain intensity (n = 5 trials, n = 1,357 participants, SMD -0.27, 95% CI [-0.53, -0.01], Tau2 = 0.06, I 2 = 74%; moderate-quality evidence) and disability (n = 7 trials, n = 1,537 participants, SMD -0.21, 95% CI [-0.40, -0.02], Tau2 = 0.03, I 2 = 56%; moderate-quality evidence) compared to usual care. Meta-analyses found telephone with face-to-face interventions does not improve pain and disability compared to usual care or face-to-face care alone. Discussion: We are moderately confident that telephone-based interventions reduce pain intensity and disability in patients with osteoarthritis and spinal pain compared to usual care, but telephone plus face-to-face interventions are no more effective than usual care or face-to-face interventions alone. PMID- 30397550 TI - HAHap: a read-based haplotyping method using hierarchical assembly. AB - Background: The need for read-based phasing arises with advances in sequencing technologies. The minimum error correction (MEC) approach is the primary trend to resolve haplotypes by reducing conflicts in a single nucleotide polymorphism fragment matrix. However, it is frequently observed that the solution with the optimal MEC might not be the real haplotypes, due to the fact that MEC methods consider all positions together and sometimes the conflicts in noisy regions might mislead the selection of corrections. To tackle this problem, we present a hierarchical assembly-based method designed to progressively resolve local conflicts. Results: This study presents HAHap, a new phasing algorithm based on hierarchical assembly. HAHap leverages high-confident variant pairs to build haplotypes progressively. The phasing results by HAHap on both real and simulated data, compared to other MEC-based methods, revealed better phasing error rates for constructing haplotypes using short reads from whole-genome sequencing. We compared the number of error corrections (ECs) on real data with other methods, and it reveals the ability of HAHap to predict haplotypes with a lower number of ECs. We also used simulated data to investigate the behavior of HAHap under different sequencing conditions, highlighting the applicability of HAHap in certain situations. PMID- 30397552 TI - Habitat fragmentation is linked to cascading effects on soil functioning and CO2 emissions in Mediterranean holm-oak-forests. AB - We studied key mechanisms and drivers of soil functioning by analyzing soil respiration and enzymatic activity in Mediterranean holm oak forest fragments with different influence of the agricultural matrix. For this, structural equation models (SEM) were built including data on soil abiotic (moisture, temperature, organic matter, pH, nutrients), biotic (microbial biomass, bacterial and fungal richness), and tree-structure-related (basal area) as explanatory variables of soil enzymatic activity and respiration. Our results show that increased tree growth induced by forest fragmentation in scenarios of high agricultural matrix influence triggered a cascade of causal-effect relations, affecting soil functioning. On the one hand, soil enzymatic activity was strongly stimulated by the abiotic (changes in pH and microclimate) and biotic (microbial biomass) modifications of the soil environment arising from the increased tree size and subsequent soil organic matter accumulation. Soil CO2 emissions (soil respiration), which integrate releases from all the biological activity occurring in soils (autotrophic and heterotrophic components), were mainly affected by the abiotic (moisture, temperature) modifications of the soil environment caused by trees. These results, therefore, suggest that the increasing fragmentation of forests may profoundly impact the functioning of the plant-soil-microbial system, with important effects over soil CO2 emissions and nutrient cycling at the ecosystem level. Forest fragmentation is thus revealed as a key albeit neglected factor for accurate estimations of soil carbon dynamics under global change scenarios. PMID- 30397551 TI - Ensemble learning for detecting gene-gene interactions in colorectal cancer. AB - Colorectal cancer (CRC) has a high incident rate in both men and women and is affecting millions of people every year. Genome-wide association studies (GWAS) on CRC have successfully revealed common single-nucleotide polymorphisms (SNPs) associated with CRC risk. However, they can only explain a very limited fraction of the disease heritability. One reason may be the common uni-variable analyses in GWAS where genetic variants are examined one at a time. Given the complexity of cancers, the non-additive interaction effects among multiple genetic variants have a potential of explaining the missing heritability. In this study, we employed two powerful ensemble learning algorithms, random forests and gradient boosting machine (GBM), to search for SNPs that contribute to the disease risk through non-additive gene-gene interactions. We were able to find 44 possible susceptibility SNPs that were ranked most significant by both algorithms. Out of those 44 SNPs, 29 are in coding regions. The 29 genes include ARRDC5, DCC, ALK, and ITGA1, which have been found previously associated with CRC, and E2F3 and NID2, which are potentially related to CRC since they have known associations with other types of cancer. We performed pairwise and three-way interaction analysis on the 44 SNPs using information theoretical techniques and found 17 pairwise (p < 0.02) and 16 three-way (p <= 0.001) interactions among them. Moreover, functional enrichment analysis suggested 16 functional terms or biological pathways that may help us better understand the etiology of the disease. PMID- 30397553 TI - Effect of operational parameters, characterization and antibacterial studies of green synthesis of silver nanoparticles using Tithonia diversifolia. AB - Background: There is a growing interest in the green synthesis of silver nanoparticles (AgNPs) using plant extract because the technique is cost effective, eco-friendly and environmentally benign. This is phasing out the use of toxic and hazardous chemical earlier reported. Tithonia diversifolia is a wild sunflower that grows widely in the western part of Nigeria with a proven medicinal benefit. However, several studies carried out have left doubts on the basic operational parameters needed for the green synthesis of AgNPs. The objective of this work was to carry out green synthesis of AgNPs using T. diversifolia extract via an eco-friendly route through optimization of various operational parameters, characterization, and antimicrobial studies. Method: Green synthesis of TD-AgNPs was done via bottom-up approach through wet chemistry technique using environmentally benign T. diversifolia plant extract as both reducing and stabilizing agent. Phytochemical Screening of the TD plant extract was carried out. Experimental optimization of various operational parameters reaction time, concentration, volume ratio, and temperature was investigated. TD AgNPs were characterized by UV-Vis spectroscopy, FTIR Spectroscopy, SEM/energy dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD), and transmission electron microscopy (TEM). Antimicrobial studies against multi drug resistant microorganisms (MDRM) were studied using the agar well diffusion method. Results: This study reveals the importance of various operational parameters in the synthesis of TD-AgNPs. Excellent surface plasmon resonance peaks (SPR) were obtained at optimum experimental factors of 90 min reaction time under room temperature at 0.001M concentration with the volume ratio of 1:9 (TD extract:Ag ion solution). The synthesis was monitored using UV-Vis and maximum wavelength obtained at 430 nm was due to SPR. The morphology and elemental constituents obtained by TEM, SEM, and EDX results revealed a spherical shape of AgNPs with prominent peak of Ag at 3.0 kV in EDX spectrum. The crystallinity nature was confirmed by XRD studies. FTIR analysis proved presence of biomolecules functioning as reducing, stabilizing, and capping agents. These biomolecules were confirmed to be flavonoid, triterpenes, and saponin from phytochemical screening. The antimicrobial studies of TD-AgNPs were tested against MDRM-Escherichia coli, Salmonella typhi, Salmonella enterica, and Bacillus subtilis. Discussion: The variation of reaction time, temperature, concentration, and volume ratio played substantive and fundamental roles in the synthesis of TD-AgNPs. A good dispersion of small spherical size between 10 and 26 nm was confirmed by TEM and SEM. A dual action mechanism of anti-microbial effects was provided by TD-AgNPs which are bactericidal and membrane-disruption. Based on the antimicrobial activity, the synthesized TD-AgNPs could find good application in medicine, pharmaceutical, biotechnology, and food science. PMID- 30397554 TI - Confidence in eating disorder knowledge does not predict actual knowledge in collegiate female athletes. AB - Background: Eating disorders are serious psychological disorders with long term health impacts. Athletic populations, tend to have higher incidences of eating disorders compared to the general population. Yet there is little known about athletes' eating disorder knowledge and how it relates to their confidence in their knowledge. Therefore, the purpose of our study was to evaluate collegiate female athletes' eating disorder (ED) knowledge and confidence in their knowledge. 51 participants were recruited from a National Association of Intercollegiate Athletics (NAIA) university in the mid-west and asked to complete a 30-question exam assessing one's knowledge of five different categories related to eating disorders. Confidence in the correctness of answers was assessed with a 5-point Likert-scale (1 = very unconfident, 5 = very confident). A one-way ANOVA was used to determine differences between scores on different categories and overall scores. A simple regression analysis was used to determine if confidence or age was predictive in knowledge scores. Results: The average score of participants was 69.1%, SD = 10.8% with an average confidence of 3.69/5, SD = 0.33. Athletes scored lowest with regards to Identifying Signs and Symptoms of EDs compared to other sub-scores (p < 0.05). There was no relationship between knowledge and confidence scores. Discussion: There is limited ED knowledge among collegiate female athletes. This may be problematic as many athletes appear confident in the correctness of their answers despite these low scores. Coaches should be aware of this lack of knowledge and work with clinical practitioners, such as dieticians, team physicians and athletic trainers to educate and monitor their athletes on eating disorders, specifically signs and symptoms. PMID- 30397555 TI - The Role of Thrombolytic Therapy for Patients with a Submassive Pulmonary Embolism. AB - A pulmonary embolism (PE) is an acute life-threatening respiratory event that results in upwards of 200,000 deaths per year in the United States. While anticoagulation is currently the standard of treatment for PEs, there is increasing evidence to suggest that in certain cases anticoagulation in combination with thrombolytic therapy may improve patient outcomes and reduce mortality. This article aims to compare the effects of combined intervention with thrombolytic therapy and anticoagulation to the effects of anticoagulation alone in patients with submassive PEs in terms of various outcome measures, including but not limited to: mortality, hemodynamic status, length of hospital stay, and safety. The methodology consisted of the critical appraisal of the primary literature articles pertaining to intervention with thrombolytic agents in cases of a submassive or intermediate risk PE, including a discussion of each study's strengths and limitations. Ultimately, this review found that the use of thrombolytic agents in conjunction with anticoagulants has been associated with decreased hemodynamic decompensation and decreased length of hospital stay, with no change in mortality outcomes, at a cost of increased rate of bleeding and stroke. The use of thrombolytic agents with anticoagulants may be warranted in a specific subset of patients, but clinicians should consider the potential benefits and harms of this intervention. PMID- 30397556 TI - Elucidation of Therapeutic Peptide Binding Partners from Isolated Mitochondria. AB - CT20p is a protein derived from the C-terminus of Bax. It has selective cytotoxicity for cancer cells, such as the sensitive triple-negative MDA-MB-231 breast adenocarcinoma cells, but not normal cells like the resistant MCF-10A epithelial breast cells. To understand the reason for the peptide's selective toxicity, a "pull-down" experiment with biotinylated CT20p (biotin-CT20p) and whole-cell protein lysates from breast cancer and normal cells were performed. These studies revealed that CT20p binds to a cytosolic protein called chaperonin containing TCP-1 (CCT), a molecular chaperone that folds actin and tubulin. However, this method could not detect possible rare interactions made by CT20p with mitochondrial proteins. To determine whether CT20p is associated with mitochondrial proteins as part of the mechanism by which it induces cell death, mitochondrial protein lysates from MDA-MB-231 and MCF-10A cells were isolated and a streptavidin-agarose pulldown procedure using biotin-CT20p was performed. Protein interactions were visualized by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) using silver staining. The results of the experimental procedure showed that biotin-CT20p did not "pull down" any observable mitochondrial proteins from the sensitive MDA-MB-231 cells, indicating that the peptide may not interact with mitochondrial proteins in breast cancer cells. Rather, the interactions observed with biotin-CT20p were with mitochondrial proteins derived from resistant MCF-10A cells, indicating that these interactions were not driving the cancer-selective cell death process. The absence of CT20p associated proteins from the mitochondrial lysates of MDA-MB-231 breast cancer cells supports the hypothesis that CT20p, unlike the parent protein, Bax, exerts its cytotoxic effects via a cytosolic protein. PMID- 30397557 TI - Daptomycin-induced Acute Eosinophilic Pneumonia. AB - Acute eosinophilic pneumonia (AEP) is a rare entity, often resulting in respiratory failure and the attended mortality. Daptomycin-induced AEP results from immune-mediated pulmonary epithelial cell injury. A 65-year-old male on treatment with intravenous daptomycin for three weeks came to the hospital for worsening dyspnea and acute hypoxemic respiratory failure. Computerized tomography (CT) of the chest was done, revealing bilateral pulmonary infiltrates. He underwent bronchoscopy that showed predominant pulmonary eosinophilia. The bacterial, fungal, viral, and mycobacterial cultures were all negative. Daptomycin was discontinued, and the patient was started on steroid therapy. He received a two-week course of steroids with a rapid taper, attaining complete recovery with a near-complete resolution of pulmonary infiltrates. A shorter course of steroid therapy should be sufficient to treat a case, as indicated in our case. Commonly used diagnostic criteria for AEP using more than 25% of pulmonary eosinophilia should be tailored to patient-related factors. PMID- 30397558 TI - Summer Camp Health Initiative: An Overview of Injury and Illness in Two Canadian Summer Camps. AB - INTRODUCTION: Summer camp is an important part of the lives of millions of youth worldwide. Injuries and illnesses at general residential camps have not been quantified in a Canadian setting. The objective of this study was to examine the incidence of injuries and illnesses that present to camp health centres at two Canadian residential summer camps. METHOD: This prospective cross-sectional study examined the incidence of new-onset injuries and illnesses that presented to camp infirmaries and circumstances surrounding their occurrence. Data collection forms were completed by trained infirmary staff during each camper's presentation to the infirmary at two general residential camps in Canada in the summers of 2015 and 2016. RESULTS: There were 1872 infirmary presentations, resulting in a frequency of 52.6 presentations per 1000 camp days (CD). The incidence of illness was 34.8 per 1000 CD and the incidence of injury was 17.9 per 1000 CD. Communicable disease was the most common diagnosis (15.2/1000 CD), most often an upper respiratory tract infection. The most common symptoms upon presentation were sore throat (14.1/1000 CD), headache (9.9/1000 CD), runny nose/congestion (6.2/1000 CD), cough (6.0/1000 CD) and nausea and vomiting (4.8/1000 CD). The most common injuries were cuts/lacerations/bruises (4.9/1000 CD), followed by muscle/tendon injury (4.9/1000 CD). The most frequent cause of injuries was participation in sports (3.9/1000 CD) and sports fields and courts were the most frequent location for injuries to occur (2.7/1000 CD). Females accounted for 52.8% of infirmary presentations. Senior campers (ages 12-16 years) presented most frequently (43.4%), followed by junior campers (ages 6-11 years; 38.1%) and staff (age >=17 years; 18.0%). When age-specific CDs were calculated, junior campers had the highest frequency of infirmary presentations relative to their time spent at camp (79.7/1000 CD). Fifty people (1.4/1000 CD) were sent to a hospital for further assessment. CONCLUSION: Injuries and illnesses presenting for infirmary care in summer camp are generally minor in nature. Canadian data compares similarly to United States (US) studies. Future studies should focus on interventions to reduce these injuries and illnesses, particularly communicable illnesses. PMID- 30397559 TI - Bisphosphonates-induced Atypical Subtrochanteric Fracture Femur: A Case Report. AB - A 71-year-old female came to our institute with a subtrochanteric left femur fracture following a fall from her bed. It was a low-energy trauma, and the X rays were suggestive of an atypical fracture following bisphosphonate therapy for five years. The fracture was fixed with intramedullary nailing following which she was started on partial weight-bearing walking after three weeks. The fracture went on to a nonunion; after one year, the fracture site was opened and bone grafting with bone marrow injection, along with augmented plating, was done. The fracture showed signs of union three months postoperatively. Fractures associated with bisphosphonate therapy may be associated with delayed union or nonunion and should be explained to the patient. PMID- 30397560 TI - Large Unilateral Pleural Effusion with Pacemaker-associated Post-cardiac Injury Syndrome. AB - Post-cardiac injury syndrome (PCIS) as a delayed complication of permanent pacemaker implantation has rarely been reported in the literature. A 67-year-old man who recently underwent a dual chamber permanent pacemaker implantation came to the hospital for increasing dyspnea and chest discomfort. A diagnosis of pericarditis was made, and the patient was discharged on ibuprofen therapy. He presented to our facility a month later with worsening dyspnea and chest discomfort despite recommended therapy. A computerized tomography (CT) scan of the chest revealed a large right-sided pleural effusion, requiring chest tube placement and drainage. A pleural fluid analysis revealed exudative effusion with elevated pH. The pleural fluid analysis was negative for infectious etiology. A perforation of the atrial wall was considered given the proximity of the atrial pacer lead and overlying pericardial effusion. However, no conclusive evidence of cardiac chamber perforation was found on echocardiogram or CT scan. A pacemaker interrogation was normal. A repeat CT scan showed the resolution of pleural effusion, and the chest tube was discontinued. A possible explanation for the absence of predominant pericardial findings may be the previous use of non steroidal anti-inflammatory therapy. PMID- 30397561 TI - Small Cell Carcinoma of the Hypopharynx. AB - Small cell carcinoma is rarely found to originate from the hypopharynx and there exists no treatment guidelines due to the small number of cases. Here, we present a case of a female patient with metastatic small cell carcinoma originating from the posterior hypopharynx with lymph node involvement. Her treatment consisted of chemotherapy with etoposide and cisplatin as well as radiation therapy. Her post treatment computed tomography (CT) scan indicated resolution of the disease at the primary site and follow-up positron emission tomography (PET)-CT scan at three-month post radiation therapy revealed that the patient is clear of the disease. PMID- 30397562 TI - Percutaneous Transluminal Angioplasty with Stent Placement versus Best Medical Therapy Alone in Symptomatic Intracranial Arterial Stenosis: A Best Evidence Review. AB - Intracranial arterial stenosis (ICAS) is a common cause of stroke, and the risk of ischemic stroke from a stenotic intracranial artery remains high despite best medical therapy (BMT). As a result, clinicians have increasingly turned to percutaneous transluminal angioplasty and stenting (PTAS) over the last decade as an alternative therapy in high-risk patients with symptomatic ICAS. In this review, we will critically analyze multiple clinical trials to assess the safety and efficacy of PTAS with BMT versus BMT alone. The Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial reported a higher rate of stroke or death within 30 days in the PTAS plus BMT group (14.7%) than the BMT only group (5.8%, p = 0.002). The rate of any stroke during the follow-up period (mean = 32 months) was higher in the PTAS plus BMT group (22.3%) than the BMT only group (14.1%, p = 0.03). The Vitesse Intracranial Stent Study for Ischemic Stroke Therapy (VISSIT) trial reported a higher rate of stroke or death within 30 days in the PTAS plus BMT cohort (24.1%) than the BMT only cohort (9.4%, p = 0.05). There was also a higher rate of hard transient ischemic attack (TIA) or stroke within one year in the PTAS plus BMT group (36.2%) than the BMT only group (15.1%, p = 0.02). The Vertebral Artery Ischaemia Stenting (VIST) trial reported the rate of any stroke during the follow-up period to be two events in 50 person-years in the PTAS plus BMT cohort versus four events in 45 person-years in the BMT only cohort, with a calculated hazard ratio of 0.47 (p = 0.39). Vertebral Artery Stenting Trial (VAST) reported a higher incidence of stroke, MI, or vascular death in the PTAS with BMT cohort (22%) than the BMT only cohort (0%). Tang et al. reported no significant difference in the incidence of vascular events at one year and three years between the PTAS plus BMT and BMT only cohorts. However, the distribution of vascular events was more concentrated in the first postoperative week in the PTAS plus BMT cohort (75% of all vascular events) versus the BMT only cohort (17%). Feng et al. reported a lower periprocedural complication rate (9.1%) with the Enterprise stent in comparison to the Wingspan and balloon-expandable stents used in the SAMMPRIS and VISSIT trials. We conclude that PTAS should not be employed as first-line treatment in patients with symptomatic ICAS. However, PTAS should be considered in symptomatic ICAS patients that are hemodynamically unstable or have repeatedly failed BMT, especially at sites with lower rates of perioperative complications than those reported here. PMID- 30397563 TI - Adult Medulloblastoma: Occurrence of a Rare Event. AB - Medulloblastoma is the most common type of aggressive pediatric primary brain malignancy. This case describes a 45-year-old Hispanic male with no significant past medical history who presented to the emergency department (ED) complaining of 15 days of 10/10 intractable headaches with one day of lightheadedness, confusion, and loss of balance. An urgent magnetic resonance imaging (MRI) of the brain revealed a 4.1 x 3.3 x 3.2 cm mass at the cerebellum, exerting a mass effect on the brainstem and mild tonsillar herniation. A pre-surgical physical exam revealed only a positive Babinski sign bilaterally with normal proprioception and cerebellar function. The intraoperative report concluded an undifferentiated neoplasm with a histological differential diagnosis of medulloblastoma, ependymoma, or other neuroepithelial neoplasms, suggesting a referral to a tertiary care center for further evaluation of the mass. Postsurgical complications included a severe vasogenic edema, causing obstructive hydrocephalus treated with frontal ventricular drainage, signs of meningitis treated with antibiotics, and hyponatremia. This case describes a rare occurrence of medulloblastoma in an adult patient, which required prompt diagnosis and urgent life-saving treatment. PMID- 30397564 TI - Online Mastermind Groups: A Non-hierarchical Mentorship Model for Professional Development. AB - Mentorship is an important driver of professional development and scholarship in academic medicine. Several mentorship models have been described in the medical education literature, with the majority featuring a hierarchical relationship between senior and junior members of an institution. 'Mastermind Groups', popularized in the business world, offer an alternative model of group mentorship that benefits from the combined intelligence and accumulated experience of the participants involved. We describe an online application of the Mastermind model, used as an opportunity for faculty development by a globally distributed team of health professions educators. The majority of our participants rated their experiences over two online Mastermind group mentoring sessions as 'very valuable', resulting in recommendations of specific developmental resources, professional referrals, and identifiable immediate 'next steps' for their careers. Our experience suggests that online Mastermind groups are an effective, feasible, zero-cost model for group mentorship and professional development in medicine. PMID- 30397565 TI - The Prevalence and Effect of Comorbid Cystic Fibrosis and Attention Deficit Hyperactivity Disorders on Hospitalizations: A Retrospective Analysis. AB - INTRODUCTION: The prevalence of attention-deficit/hyperactivity disorder (ADHD) in pediatric cystic fibrosis (CF) patients is comparable to the general population, but the effects of ADHD on CF treatment and the outcomes have been minimally investigated. METHODS: Two cohorts were retrospectively reviewed, pediatric patients with comorbid CF/ADHD and patients with CF only. Each patient with CF/ADHD was age and sex-matched to a CF-only patient based on their most recent pulmonary office visit. Each patient was reviewed for forced expiratory volume in one-second percent predicted (FEV1%pred), body mass index (BMI) percentile, and hospitalizations for one year prior to the last pulmonary visit. RESULTS: A total of 624 patients with CF were identified, with 52 having co morbid CF/ADHD (8.3%). Of those identified, 46 met inclusion criteria and were analyzed in the CF/ADHD cohort. The mean total hospital admissions between the CF/ADHD cohort and the CF-only cohort were not statistically significant (2.22 vs 1.834, p=.467). The difference between the BMI percentiles was not statistically significant (48.634 vs 38.634, p=.135). The difference between FEV1%pred was statistically significant at 84% for the CF/ADHD group and 74% for the CF-only group (p=.042). CONCLUSION: The difference in total hospital admissions between the CF/ADHD cohort and the CF-only cohort did not reach statistical significance, but the study was underpowered. There was a significant difference between FEV1%pred between the two groups, in favor of the comorbid CF/ADHD population. More research is needed to further evaluate the effects of a comorbid ADHD diagnosis on outcomes in the CF pediatric population. PMID- 30397566 TI - The Impact of Breastfeeding on Health Outcomes for Infants Diagnosed with Neonatal Abstinence Syndrome: A Review. AB - Neonatal abstinence syndrome (NAS) is a neurologic condition resulting from prenatal exposure to opioids. The sudden cessation of opioids in neonates can lead to withdrawal symptoms affecting the neurologic, respiratory, and gastrointestinal systems. Rising opioid use in the United States has led to an increased incidence of infants born with NAS. Despite the growing incidence of NAS, there is a lack of standardized guidelines for intervention and management. Recent studies suggest that non-pharmacological methods should be used as first line interventions for the reduction of NAS symptoms. Of the non-pharmacological methods, growing literature suggests that breastfeeding may have the potential to reduce symptom severity and improve outcomes. We searched the PubMed and Medline databases for experimental/quasi-experimental studies published from 1997-2018 regarding outcomes in breastfed versus formula-fed neonates with prenatal exposure to opioids. Seven retrospective studies fulfilling the inclusion criteria were reviewed. Collectively, the studies show a strong correlation between breastfeeding and a reduced length of hospital stay, a decreased severity of NAS presentation, and a decreased necessity of pharmacological interventions in infants diagnosed with NAS. From these findings, we recommend breastfeeding as an integral component of the early management of NAS. PMID- 30397567 TI - Treatment of anxiety disorders in patients with comorbid bipolar disorder. AB - Anxiety disorders are the most prevalent comorbid diagnoses in patients with bipolar disorder (BD). A comorbid anxiety diagnosis can significantly impact the severity of bipolar symptoms, increase the risk of suicidality, and decrease psychosocial functioning and quality of life. The Canadian Network for Mood and Anxiety Treatments (CANMAT) task force published recommendations for treatment in 2012 suggesting that specific anticonvulsant mood stabilizers and second generation antipsychotics are the medications of choice to treat these comorbidities. Serotonergic antidepressant medications are first-line medications for the treatment of most anxiety disorders; however, this can be problematic for a patient with BD. Antidepressant use in BD has been associated with a risk of manic switch as well as potential destabilization of mood. Mood stabilizer therapy should be established for patients with comorbid BD and an anxiety disorder before other medications are added to address the anxiety disorder. While benzodiazepine medications are recommended as third-line therapy in the CANMAT task force recommendations, their use should be avoided in patients with comorbid BD, posttraumatic stress disorder, and substance use disorders. The use of benzodiazepines should in general be avoided for all patients if possible, based upon current clinical research. Interpersonal, cognitive behavioral, and relaxation therapy are effective for the treatment of anxiety symptoms, especially emotional experiences, in patients who are euthymic. PMID- 30397568 TI - Recognition and treatment of mood dysregulation in adults with intellectual disability. AB - Mood dysregulation is a common feature in the psychopathology of people with intellectual disability (ID) and co-occurring behavioral/psychiatric disorders. It can present with a host of dangerous behaviors, including aggression, self injury, and property damage. There are special techniques that are used to assess these behaviors in people with ID, that can eventually inform an appropriate approach to pharmacologic and nonpharmacologic treatment. Two case studies are presented that illustrate the elements in the assessment and treatment of mood dysregulation in ID. PMID- 30397569 TI - Major depressive disorder in children and adolescents. AB - Major depressive disorder (MDD) is one of the most common psychiatric disorders of childhood and adolescence, but because of symptom variation from the adult criteria, it is often unrecognized and untreated. Symptom severity predicts the initial mode of treatment ranging from psychotherapy to medications to combination treatment. Several studies have assessed the efficacy of treatment in children and adolescents, and others have evaluated the risk of developing adverse effects and/or new or worsening suicidal thoughts and behaviors. Optimal treatment often includes a combination of therapy and antidepressant medication. The most studied combination includes fluoxetine with cognitive behavioral therapy. Once symptom remission is obtained, treatment should be continued for 6 to 12 months before a slow taper is initiated. Although most children and adolescents recover from their first depressive episode, a large number will continue to present with MDD in adulthood. Untreated depression in children and adolescents may increase the risk of substance abuse; poor work, academic, and social functioning; and risk of suicidal behaviors. PMID- 30397570 TI - Pharmacologic management of behavioral and psychological symptoms of major neurocognitive disorder. AB - Behavioral and psychological symptoms of dementia (BPSD) occur in approximately 80% of patients who receive a diagnosis of major neurocognitive disorder. Nonpharmacologic strategies are the first-line treatment for BPSD. However, psychotropic medications are often necessary when nonpharmacologic methods are not effective in treating symptoms that are distressing or are causing behaviors that are dangerous to the patient or the patient's caregivers. The article provides a review of evidence-based recommendations for the use of antipsychotics, cognitive enhancers, and serotonin reuptake inhibitors for the treatment of BPSD. Different pharmacologic approaches are demonstrated through 2 patient cases in which nonpharmacologic management was not effective. The severity of BPSD must be weighed against the risks and benefits of pharmacologic intervention in order to implement an optimal medication regimen. PMID- 30397571 TI - The use of pharmacogenetic testing in patients with schizophrenia or bipolar disorder: A systematic review. AB - Introduction: Pharmacogenetic testing may assist in identifying an individual's risk of developing a mental illness as well as predict an individual's response to treatment. The objective of this study is to report published outcomes of pharmacogenetic testing in patients with schizophrenia or bipolar disorder. Methods: A systematic review using PubMed and EBSCOhost through April 2017 was performed to identify articles that reported pharmacogenetic testing in adult patients with either bipolar disorder or schizophrenia using the keywords pharmacy, pharmacogenomics, pharmacogenetics, psychiatry, bipolar disorder, schizophrenia, mood stabilizer, and antipsychotic. Results: A total of 18 articles were included in the final literature review. A wide variety of genes amongst adult patients with varying ethnicities were found to be correlated with the development of schizophrenia or bipolar disorder as well as response to antipsychotics and mood stabilizers. Discussion: While current studies show a correlation between genetic variations and medication response or disease predisposition for patients with schizophrenia and bipolar disorder, research is unclear on the type of therapeutic recommendations that should occur based on the results of the pharmacogenetic testing. Hopefully interpreting pharmacogenetic results will one day assist with optimizing medication recommendations for individuals with schizophrenia and bipolar disorder. PMID- 30397572 TI - Clozapine-induced myocarditis: Two case reports and review of clinical presentation and recognition. AB - Myocarditis is a potentially fatal cardiac disease marked by inflammation of the heart muscle. With a noted black-box warning, rates of clozapine-induced myocarditis are reportedly as high as 3%. Since the first case of clozapine induced myocarditis was documented in 1994, more than 250 cases have been described in literature with an approximate 33% case-fatality rate. We report 2 cases of patients with primary psychotic disorders treated with clozapine, who developed signs and symptoms of myocarditis. The first was a 35-year-old white male patient with a primary diagnosis of schizoaffective disorder (bipolar type) who was initiated on clozapine after nonresponse to several therapies. On day 26, the patient was admitted to the emergency department for chest pain presenting with eosinophilia and notable elevations in several biomarkers, including troponin and C-reactive protein. The second patient was a 45-year-old black male who was initiated on clozapine for treatment-resistant schizophrenia. On day 13, the patient reported cardiac-related concerns (tachycardia) and flu-like symptoms resulting in hospitalization. Similarly, this patient demonstrated elevated biomarkers (troponin and creatine kinase). Both patients experienced resolution of symptoms after discontinuation of clozapine. Clozapine was not rechallenged for either patient. Review of literature further elucidates the relationship between clozapine and myocarditis, including potential risk factors, pathophysiology, and symptom presentation. Due to the potentially fatal nature of this condition, clinical vigilance and awareness is warranted upon initiation of clozapine through monitoring of symptoms along with cardiac and inflammatory biomarkers as indicated. PMID- 30397573 TI - Nortriptyline-induced oral ulceration: A case report. AB - Drug-induced oral ulcers are lesions of the oral mucosa accompanied by painful symptoms, such as burning mouth, metallic taste, dysgeusia, or ageusia. This report demonstrates the first documented case of drug-induced oral ulcers with the tricyclic antidepressant nortriptyline. In this case, a 49-year-old female initiated treatment for refractory neuropathy with nortriptyline. Within 2 weeks of therapy, painful, oral, bubble-like ulcers developed. Complete symptom resolution occurred approximately 1 month after discontinuation of nortriptyline. Clinicians should be cognizant of nortriptyline's ability to potentially induce oral ulcers; however, the exact mechanism for this adverse event is unknown. PMID- 30397574 TI - Clozapine-induced myocarditis in an adolescent male with DiGeorge Syndrome. AB - DiGeorge Syndrome (22q11.2 deletion syndrome) is a chromosomal disorder associated with both congenital heart malformations and schizophrenia, which is often treatment-resistant and may warrant treatment with clozapine. Clozapine induced myocarditis (CIM) is a rare complication of clozapine therapy, with a reported incidence ranging from 0.015% to 3%. Fulminant CIM has a nonspecific presentation in both adult and pediatric populations and a mortality rate approaching 50%. Few cases of pediatric CIM have been documented in the literature. This report highlights a case of CIM in an adolescent male with DiGeorge Syndrome whose clinical course was characterized by a subtle, nonspecific presentation and resolution with supportive care. PMID- 30397575 TI - Case reports of interprofessional care for clients enrolled in a mental health court. AB - Background: An interprofessional mental health court (MHC) team was created in Milwaukee, Wisconsin, in 2014 to help keep low-level offenders with mental health (MH) disorders out of the correctional system. The focus of MHC is on stabilization of MH disorders and rehabilitation rather than incarceration. A clinical MH pharmacist was added to the team in 2015 to provide expertise on psychotropic medication regimens and to meet with clients for medication education. Case Reports: A 58-year-old black male was admitted to the MHC after he failed to provide sex registry information. His past medical history was significant for major depressive disorder, schizophrenia, substance use disorders, and seizures. At the time of pharmacy review, medications included aspirin, levetiracetam, risperidone, ziprasidone, and paroxetine. The pharmacist identified 3 potential drug therapy problems (duplicate therapy, potential adverse drug reaction, and inadequate dosage) and sent a letter to his psychiatrist. Risperidone and ziprasidone were switched to aripiprazole, and he was referred to a neurologist. He was eventually terminated from the MHC because of multiple violations. A 34-year-old black male was admitted to the MHC for disorderly conduct and destruction of property. His past MH history was significant for schizophrenia and substance use disorders. He was not taking psychiatric medication upon admission to MHC. While the client was institutionalized for competency determination, collaboration between the MHC pharmacist and psychiatrist resulted in the prescribing of a long-acting injectable antipsychotic, which the client was stabilized on. He subsequently graduated from the MHC. Discussion: Clinical MH pharmacists play a key role on MHC teams by providing medication education, identifying drug therapy problems, and communicating with the clients' medical providers. Lack of access to medical records, court schedule conflicts, and collaboration between interprofessional groups that historically have not worked together are challenges to a pharmacist working on an MHC team. PMID- 30397576 TI - Effects of 3-Bromo-4,5-dihydroisoxazole Derivatives on Nrf2 Activation and Heme Oxygenase-1 Expression. AB - Natural and synthetic electrophilic compounds have been shown to activate the antioxidant protective Nrf2 (nuclear factor erythroid 2-related factor 2)/heme oxygenase-1 (HO-1) axis in cells and tissues. Here, we tested the ability of different isoxazoline-based electrophiles to up-regulate Nrf2/HO-1. The potency of activation is dependent on the leaving group at the 3-position of the isoxazoline nucleus, and an additional ring on the molecule limits the Nrf2/HO-1 activating properties. Among the synthetized compounds, we identified 3-bromo-5 phenyl-4,5-dihydroisoxazole 1 as the derivative with best activating properties in THP-1 human monocytic cells. We have confirmed that the target of our compounds is the Cys151 of the BTB domain of Keap1 by using mass spectrometry analyses and X-ray crystallography. Our findings demonstrate that these compounds affect the Nrf2/HO-1 axis and highlight a positive activity that can be of relevance from a therapeutic perspective in inflammation and infection. PMID- 30397578 TI - Microfluidic paper-based analytical devices (uPADs) for fast and ultrasensitive sensing of biomarkers and monitoring of diseases. AB - Through the development of analytical techniques, microscaled devices have displayed attractive advantages, including ultrasensitive detection and analysis, cost-effectiveness, portability, process integrity, multi-process functionality, and in-situ analysis. In the last decade, a new generation of analytical devices has emerged based on the cellulose materials - so-called microfluidic paper-based analytical devices (uPADs) - a field that will change the face of the diagnosis of different diseases and sensing of a wide range of biological/chemical/biochemical phenomena. The main aim of the current editorial is to highlight the importance of the uPADs in the research and development of diagnostic devices and pharmaceuticals. PMID- 30397577 TI - Mobile App Tools for Identifying and Managing Mental Health Disorders in Primary Care. AB - Purpose of Review: Mental health apps are intriguing yet challenging tools for addressing barriers to treatment in primary care. In the current review, we seek to assist primary care professionals with evaluating and integrating mental health apps into practice. We briefly summarize two leading frameworks for evaluating mental health apps and conduct a systematic review of mental health apps across a variety of areas commonly encountered in primary care. Recent Findings: Existing frameworks can guide professionals and patients through the process of identifying apps and evaluating dimensions such as privacy and security, credibility, and user experience. For specific apps, several problem areas appear to have relatively more scientific evaluation in the current app landscape, including PTSD, smoking, and alcohol use. Other areas such as eating disorders not only lack evaluation, but contain a significant subset of apps providing potentially harmful advice. Summary: Overall, individuals seeking mental health apps will likely encounter strengths such as symptom tracking and psychoeducational components, while encountering common weaknesses such as insufficient privacy settings and little integration of empirically-supported techniques. While mental health apps may have more promise than ever, significant barriers to finding functional, usable, effective apps remain for health professionals and patients alike. PMID- 30397580 TI - Characterization and partial purification of an antibacterial agent from halophilic actinomycetes Kocuria sp. strain rsk4. AB - Introduction : The inevitable rise of antibiotic-resistant bacteria is a global health problem. These pathogens erode the utility of available antibiotics. Staphylococcus aureus is one of the major causes of community-acquired infections. The aim of work was to evaluate the marine actinomycetes for production of the antibacterial agent against pathogens. Methods : Halophilic actinomycetes were isolated, characterized and screened for production of antibacterial agent against pathogenic bacteria. The antibacterial compounds were extracted by solvent extraction and separated by TLC based bioautography. Antibacterial compound was further purified by flash chromatography followed by high-performance liquid chromatography (HPLC) techniques. The active fraction was characterized by spectroscopy techniques. The minimum inhibitory concentration of antibiotic was determined against pathogens. Results : A new halophilic actinomycetes strain rsk4 was isolated from marine water. It was designated as Kocuria sp. based on the physiological, biochemical and 16S rDNA sequencebased characters. It was able to produce broad-spectrum antibacterial compound and exhibited significant inhibitory activities against antibiotic-resistant S. aureus. The antibacterial compound was secreted optimally at 5% NaCl and neutral pH in the starch casein medium during stationary phase. The crude ethyl acetate extract was separated by chloroform-methanol, 24:1, v/v having Rf value 0.45. Bioassay of HPLC fractions confirms the presence of antibiotics picks at retention time: 3.24 minutes. The UV-Visible and mass spectra of the compound revealed that the active compound was different from other known antibiotics. The lowest minimum inhibitory concentration was recorded against S. aureus (30 ug/mL). Conclusion : The result suggests that a broad-spectrum antibacterial compound obtained from halophilic actinomycetes is effective against pathogenic bacteria. This compound may be a good alternative treatment against antibiotic resistant pathogen S. aureus. PMID- 30397579 TI - Effect of PEGylation on assembly morphology and cellular uptake of poly ethyleneimine-cholesterol conjugates for delivery of sorafenib tosylate in hepatocellular carcinoma. AB - Introduction: Sorafenib (SFB) is an FDA-approved chemotherapeutic agent with a high partition coefficient (log P = 4.34) for monotherapy of hepatocellular carcinoma (HCC). The oral bioavailability is low and variable, so it was aimed to study the application of the polymeric nanoassembly of cholesterol conjugates of branched polyethyleneimine (PEI) for micellar solubilization of SFB and to investigate the impact of the polymer PEGylation on the physicochemical and cellular characteristics of the lipopolymeric dispersions. Methods: Successful synthesis of cholesterol-PEI lipopolymers, either native or PEGylated, was confirmed by FTIR, 1H-NMR, pyrene assay methods. The nanoassemblies were also characterized in terms of morphology, particle size distribution and zeta potential by TEM and dynamic light scattering (DLS). The SFB loading was optimized using general factorial design. Finally, the effect of particle characteristics on cellular uptake and specific cytotoxicity was investigated by flow cytometry and MTT assay in HepG2 cells. Results: Transmission electron microscopy (TEM) showed that PEGylation of the lipopolymers reduces the size and changes the morphology of the nanoassembly from rod-like to spherical shape. However, PEGylation of the lipopolymer increased critical micelle concentration (CMC) and reduced the drug loading. Moreover, the particle shape changes from large rods to small spheres promoted the cellular uptake and SFB-related cytotoxicity. Conclusion: The combinatory effects of enhanced cellular uptake and reduced general cytotoxicity can present PEGylated PEI-cholesterol conjugates as a potential carrier for delivery of poorly soluble chemotherapeutic agents such as SFB in HCC that certainly requires further investigations in vitro and in vivo. PMID- 30397581 TI - Nafion-coated cadmium pentacyanonitrosylferrate-modified glassy carbon electrode for detection of dopamine in biological samples. AB - Introduction : Dopamine is one of the key neurotransmitters (NTs) in nature, which plays a crucial role in the mammalian central nervous system (CNS). Its selective determination in the biological fluids is an essential need in the field of biomedicine studies. Methods : In this work, an amperometric sensor was developed using Nafion-coated cadmium pentacyanonitrosylferrate (CdPCNF) modified glassy carbon (GC) electrode (Nafion|CdPCNF|GC electrode) as an electrocatalyst to detect dopamine (DA) in human serum samples. To develop this sensor, the surface of bare GC electrode was coated with the film of CdPCNF through an electropolymerization method and then the modified electrode was coated with Nafion to minimize interferences, especially those arising from the presence of anionic compounds. The electrocatalytic behavior of the modified electrodes was studied using the cyclic voltammetry and amperometry, and then the ability of the sensor for the determination of DA in synthetic and biological samples was investigated. Results : The modified electrode was showed a significant electrocatalytic activity for the oxidation of DA at pH 7.4. The limit of detection (LOD) was 0.7 uM and also no interference effects arose from ascorbic acid (AA), uric acid (UA) or the other biological NTs was observed in the DA detection using the modified Nafion|CdPCNF|GC electrode. Conclusion : In comparison with the bare electrode, the Nafion|CdPCNF|GC electrode could determine DA in the biological samples with adequate sensitivity and selectivity. Therefore, we propose that the modified electrode is utilizable as an amperometric DA sensor for the biological sample analysis. PMID- 30397582 TI - Numerical study on the impulsive growth of a gaseous plug inside a cylindrical vein with compliant coating. AB - Introduction : Employing of gaseous plugs inside a vein for preventing of blood flow to the damaged or cancerous tissues has been known as a gas embolism in the medicine. In this research, a numerical investigation has been carried out on the delivery of the liquid drug DDFP, encapsulated in the microlipidcoated spheres (MLCSs), to target the human vein for construction of the gaseous plug inside the veins. Methods : The encapsulated liquid drug DDFP were delivered to the vein by injection of an emulsion. Releasing of the liquid drug DDFP results in an explosive growth of a gaseous plug inside the vein. The targeted vein was served as a rigid cylinder with a compliant coating. The boundary integral equation method has been employed for the numerical simulation of the hydrodynamic behavior of the gaseous plug inside the vein. Results : Numerical results showed that in the case of a rigid cylinder vein with an internal compliant coating, the maximum volume of the gaseous plug was smaller than the case of just a rigid cylinder vein. Furthermore, its elapsed time from the instant of bubble generation to the instant when the bubble reaches its maximum volume was shorter. Numerical results also showed that the compliant coating on the internal wall of the rigid cylindrical vein had a tendency of reducing the impact of the explosive growth of the gaseous plug. Conclusion : This numerical research showed that the compliant coating on the internal wall of the rigid cylindrical vein had the tendency of reducing the impact of the impulsive growth of the gaseous plug. Therefore, in the case of having severed arteriosclerosis, treatment of the cancerous or damaged tissues by use of the gaseous embolism must be done very carefully in order to prevent the hazardous effects of the gaseous plug's impulsive growth. PMID- 30397584 TI - An fMRI investigation of the neural correlates underlying the autonomous sensory meridian response (ASMR). AB - Introduction : The "autonomous sensory meridian response" (ASMR) is a neologism used to describe an internal sensation of deep relaxation and pleasant head tingling which is often stimulated by gentle sounds, light touch, and personal attention. Methods : An fMRI-based methodology was employed to examine the brain activation of subjects prescreened for ASMR-receptivity (n=10) as they watched ASMR videos and identified specific moments of relaxation and tingling. Results : Subjects who experienced ASMR showed significant activation in regions associated with both reward (NAcc) and emotional arousal (dACC and Insula/IFG). Brain activation during ASMR showed similarities to patterns previously observed in musical frisson as well as affiliative behaviors. Conclusion : This is the first study to measure the activation of various brain regions during ASMR and these results may help to reveal the mechanistic underpinnings of this sensation. PMID- 30397583 TI - Comparative in vitro/theoretical studies on the anti-angiogenic activity of date pollen hydro-alcoholic extract: Highlighting the important roles of its hot polyphenols. AB - Introduction: Date palm pollen (DPP) is the male reproductive soft powder from date flowers widely used as the valuable dietary supplement to fortify the size of testis and ovarian to increase the power of sex. This part of date palm significantly exhibited anti-diabetic, anti-inflammation and protective effects against male and female infertility. Though the anticancer activity of date fruits was previously reported, the DPP anti-angiogenic effects were not reported, and as the first study, its inhibitory effects were examined in the current study. Methods: The DPP soft powder was collected to prepare its hydro alcoholic extract to examine its anti-angiogenic activity in an in vitro model. At different concentrations, the cytotoxicity of the prepared extract was examined on human umbilical vein endothelial cells (HUVECs) using lactate dehydrogenase method. Cell proliferation was determined using the MTT assay and cytodex-3D model in collagen gel was used to assay its possible anti-angiogenic activity. The expression of VEGF, MMP-2 and MMP-9 genes was measured using real time polymerase chain reaction (PCR). Finally, molecular docking simulation was used to highlight the possible role of DPP polyphenols to interact with the associated receptors. Results: The prepared hydro-alcoholic extract exhibited significant anti-angiogenic activity in a dose-dependent manner and decreased the endothelial cell proliferation. The calculated IC50 value for the examined extract in angiogenesis model was 260 ug.mL, respectively. Also, the expression of VEGF, MMP-2 and MMP-9 genes were significantly decreased. Docking simulation results unveiled that the isolated DPP polyphenols have the affinity to interact with ctDNA, VEGF and its receptors. Conclusion: The DPP is the new source of non toxic anti-cancer agents to use as a dietary supplement in the pre-treatment of cancer. PMID- 30397586 TI - Retraction Note: Inhibition of hTERT Gene Expression by SilibininLoaded PLGA-PEG Fe3O4 in T47D Breast Cancer Cell Line. AB - [This retracts the article DOI: 10.5681/bi.2013.005.]. PMID- 30397585 TI - Recent advances in improving oral drug bioavailability by cocrystals. AB - Introduction : Oral drug delivery is the most favored route of drug administration. However, poor oral bioavailability is one of the leading reasons for insufficient clinical efficacy. Improving oral absorption of drugs with low water solubility and/or low intestinal membrane permeability is an active field of research. Cocrystallization of drugs with appropriate coformers is a promising approach for enhancing oral bioavailability. Methods : In the present review, we have focused on recent advances that have been made in improving oral absorption through cocrystallization. The covered areas include supersaturation and its importance on oral absorption of cocrystals, permeability of cocrystals through membranes, drug-coformer pharmacokinetic (PK) interactions, conducting in vivo-in vitro correlations for cocrystals. Additionally, a discussion has been made on the integration of nanocrystal technology with supramolecular design. Marketed cocrystal products and PK studies in human subjects are also reported. Results : Considering supersaturation and consequent precipitation properties is necessary when evaluating dissolution and bioavailability of cocrystals. Appropriate excipients should be included to control precipitation kinetics and to capture solubility advantage of cocrystals. Beside to solubility, cocrystals may modify membrane permeability of drugs. Therefore, cocrystals can find applications in improving oral bioavailability of poorly permeable drugs. It has been shown that cocrystals may interrupt cellular integrity of cellular monolayers which can raise toxicity concerns. Some of coformers may interact with intestinal absorption of drugs through changing intestinal blood flow, metabolism and inhibiting efflux pumps. Therefore, caution should be taken into account when conducting bioavailability studies. Nanosized cocrystals have shown a high potential towards improving absorption of poorly soluble drugs. Conclusions : Cocrystals have found their way from the proof-of-principle stage to the clinic. Up to now, at least two cocrystal products have gained approval from regulatory bodies. However, there are remaining challenges on safety, predicting in vivo behavior and revealing real potential of cocrystals in the human. PMID- 30397587 TI - Diverse Ischemic Postconditioning Protocols Affect the Infarction Size in Focal Ischemic Stroke. AB - Objective: Ischemic postconditioning (IPostC), consisted of transient brain ischemia/reperfusion cycles, is considered to have neuroprotective effect. However, there is no best single protocol of IPostC, because varied factors like species tested and characteristics of the tissue may affect the efficacy of IPostC. Thus, we investgated whether different protocols of IPostC affect neuroprotective effects in experimental animal models. Materials and Methods: Through occlusion of middle cerebral artery (MCA) with intraluminal suture, stroke was induced in a transient focal ischemia model in mice. We conducted IPostC via brief and repeated MCA occlusion, 2 minutes after reperfusion, followed by different ischemia and reperfusion protocols. After procedure, functional neurological score and histological examination were evaluated. Results: IPostC with different protocols resulted in diverse effects. Among them, a protocol that consists of 3 cycle of IPostC significantly reduced the infarction size 3 days after stroke. Conclusion: IPostC was confirmed to reduce infarction size. The effects of IPostC are definitely affected by differences in the protocol used, including the number of cycles, the duration of individual ischemia/reperfusion episode and the entire duration of the IPostC stimuli. PMID- 30397588 TI - Implications of Mechanical Endovascular Thrombectomy for Acute Basilar and Posterior Cerebral Artery Occlusion. AB - Objective: Protocols for posterior circulation ischemic stroke have not been established by randomized clinical trials. Mechanical endovascular thrombectomy (MET) devices are evolving, and many of these devices already developed or in development are suitable for posterior circulation MET. Materials and Methods: We investigated the medical records of patients who underwent MET for posterior circulation ischemic stroke from January 2012 to August 2016. Fifteen patients were included. MET was performed in patients with or without injected intravenous tissue plasminogen activator. MET was considered in patients with a National Institute of Health Stroke Scale score of 4 or more, older than 18 years, with definite occlusion of the basilar artery or posterior cerebral artery (PCA), and who arrived at the hospital within 24 hours from onset. Results: The direct catheter aspiration technique was used in five cases, and the stent retrieval technique was used in seven cases. The stent retrieval technique with the direct aspiration technique was used in three cases. Recanalization failed in two cases. Basilar occlusion without PCA involvement is the only effective factor of successful recanalization (p = 0.03). Successful recanalization (p = 0.005) and the presence of a posterior communicating artery (p = 0.005) affected the good outcome at discharge. Conclusion: An early diagnosis and active MET may improve the patient outcome. MET may help recanalization and good flow restoration and the potential for a good outcome. PMID- 30397589 TI - Cavernous Malformations at Optic Apparatus: Three Cases. AB - Cavernous malformations (CMs) are angiographically occult vascular lesions, and their clinical presentations vary widely according to location of the lesion. Here, we reviewed three cases of CM located at the optic apparatus. All three patients experienced visual deterioration and underwent surgical resection. One achieved complete resection of the CM, whereas the others achieved subtotal resection. Visual symptoms of the two patients who achieved subtotal resection improved, but the visual symptom of the patient who achieved complete resection remained unchanged. One patient with subtotal resection presented postoperative improvement of visual symptoms but experienced deterioration in two years after surgical resection due to rebleeding from the remnant lesion, and he required a second operation. We recommend total resection of CM when feasible and regular follow-up after subtotal resection due to the risk of rebleeding. PMID- 30397590 TI - Endovascular Coiling for a Wide-neck Bifurcated Aneurysm with Anterograde Horizontal Stenting via Microcatheter Looping: A Technical Case Report. AB - Technical advances with devices such as catheters, balloons, and stents have widened the indications for endovascular coiling for unfavorable aneurysms. The authors report two cases of coil embolization for a wide-neck bifurcated aneurysm with anterograde horizontal stenting via microcatheter looping. Two women, aged 56 and 38 years, respectively, had an undertall- and overwide-neck aneurysm with bifurcated branches at the basilar bifurcation and middle cerebral bifurcation, respectively. The delivery microcatheter was steamed so that it could be looped deliberately to the opposite vessel. The enterprise stent was first anchored to the vessel of the posterior cerebral artery on one side. The remaining portion was spanned into a looped microcatheter to the opposite branch while pushing the stent. The Neuroform Atlas stent was passed directly through the looped segment of the microcatheter at the M2 branch and spanned horizontally by unsheathing. Under horizontal stenting, complete coil embolization was achieved without immediate or delayed complications in both cases. This novel technique presents a viable option for stent-assisted coiling within an optimal anatomy. PMID- 30397591 TI - Rupture of a Middle Meningeal Artery Pseudoaneurysm in Moyamoya Syndrome Related with Tuberculous Meningitis. AB - We report a rare case of a patient with Moyamoya syndrome who presented with intracerebral hemorrhage resulting from rupture of a middle meningeal artery pseudoaneurysm. This 38-year-old woman was unconscious and hemiplegic when she was admitted to our hospital. The patient had mental retardation as a result of tuberculous meningitis infection at the age of one year. On radiologic examination, she had intracerebral hemorrhage in the right temporo-parietal lobe and an aneurysm in the middle meningeal artery with right internal carotid artery occlusion. The patient underwent surgical treatment for the hemorrhage and aneurysm. The radiologic data, intraoperative findings, and pathology were consistent with a diagnosis of pseudoaneurysm. In the current report, we describe a rare case of a patient with a history of tuberculous meningitis who developed Moyamoya syndrome and pseudoaneurysm, which resulted in a ruptured middle meningeal artery pseudoaneurysm and brain hemorrhage. PMID- 30397592 TI - STA-Distal ACA Bypass Using a Contralateral STA Interposition Graft for Symptomatic ACA Stenosis. AB - Intracranial arterial stenosis usually occurs due to atherosclerosis and is considered the most common cause of stroke worldwide. Although the effectiveness of bypass surgery for ischemic stroke is controversial, the superficial temporal artery to the middle cerebral artery bypass for ischemic stroke is a common procedure. In our report, a 50-year-old man presented with sudden-onset left side weakness and dysarthria. An angiogram showed significant stenosis in the junction of the right cavernous-supraclinoid internal carotid artery and right pericallosal artery. Symptoms altered between improvement and deterioration. Magnetic resonance imaging showed a repeated progression of anterior cerebral artery (ACA) infarction despite maximal medical therapy. We performed a STA-ACA bypass with contralateral STA interposition. Postoperative course was uneventful with no further progression of symptoms. Thus, bypass surgery may be considered in patients with symptomatic stenosis or occlusion of the ACA, especially when patients present progressive symptoms despite maximal medical therapy. PMID- 30397593 TI - Verrucous carcinoma arising from a previous cystic lesion: a case report. AB - Background: Verrucous carcinoma (VC) accounts for 1-10% of cases of squamous cell carcinoma (SCC) in the oral cavity, and 75% of VC occur in the oral cavity. Only 3% of primary intraosseous squamous cell carcinomas (PIOSCC), which means SCC occurring primarily in the bone, are VC. Verrucous carcinoma arising from odontogenic cysts (OC) is very rare, with only seven cases reported to date. Case presentation: This study reported a case of a patient who underwent partial maxillectomy and neck dissection for VC that occurred in the right anterior maxilla. The patient was admitted to the emergency department at our institution 8 years ago and showed cystic lesions in the anterior maxilla on facial computed tomography (CT) images. Treatment through other departments including assessment of laceration in the mental region and only suture was performed. This report highlights a very rare case of VC in the right anterior maxilla arising from a previous cystic lesion. Conclusions: Since PIOSCC can arise from OC, appropriate treatment of intraosseous cysts and regular radiologic evaluation are necesssary. Surgical exicision of the primary lesion without neck dissection can lead to good prognosis for patients with primary intraosseous verrucous carcinoma. PMID- 30397594 TI - Attenuated Mismatch Negativity in Attenuated Psychosis Syndrome Predicts Psychosis: Can Galantamine-Memantine Combination Prevent Psychosis? AB - Although first proposed in 1987, early diagnosis and intervention of psychotic disorders has only recently become a priority in the field. The interest in clinical high risk (CHR) for psychosis skyrocketed after attenuated psychosis syndrome (APS) was added to the DSM-5. There is evidence that in individuals with APS, attenuated mismatch negativity (MMN: functioning of the auditory sensory memory system) is a robust biomarker that can predict transition to psychosis. The underlying pathophysiological mechanism of MMN is via the interaction of N methyl-D-aspartate (NMDA) and alpha-7 nicotinic acetylcholine (alpha-7nACh) receptors. Galantamine is an acetylcholinesterase inhibitor and a positive allosteric modulator of the alpha-7nACh receptors. Memantine is an NMDA receptor antagonist. Memantine has been shown to enhance MMN in people with schizophrenia. Although no studies with galantamine have measured MMN, encenicline, an alpha-7 nicotinic partial agonist, increased MMN in people with schizophrenia. MMN has been suggested as a potential biomarker with the galantamine-memantine combination for the treatment of neuropsychiatric disorders. Hence, the galantamine-memantine combination may enhance MMN, thereby preventing CHR to psychosis. With no treatments available, randomized controlled trials are warranted with the galantamine-memantine combination to delay or prevent conversion to psychosis in individuals with CHR. PMID- 30397595 TI - Altered White Matter Diffusivity of the Cingulum Angular Bundle in Posttraumatic Stress Disorder. AB - Purpose of the Study: Prior studies showed posttraumatic stress disorder (PTSD) related alterations in white matter integrity, but most of these studies have used region-based approaches. We address this limitation by investigating the relationship between PTSD severity and fractional anisotropy (FA) using a tract based approach. Procedures: Structural and diffusion magnetic resonance imaging were acquired from 67 combat-exposed US Veterans and processed using FSL/FreeSurfer TRActs Constrained by UnderLying Anatomy. Partial correlations were conducted between PTSD severity and FA of the cingulum and uncinate fasciculi covarying for age, sex, and head motion. Results: Only FA of the left cingulum angular bundle (CAB) was positively correlated with PTSD symptom severity (r = 0.433, p = 0.001, df = 57) and remained significant after Bonferroni correction. Conclusions: This finding may imply greater organization of the CAB with increasing PTSD severity. The CAB connects directly to the cingulate cortex and the hippocampal subiculum, critical nodes of the default mode network, as well as being implicated in neurodegeneration pathology, decision-making, and executive functions, which may help explain previously shown alterations in this network in PTSD. Message of the Paper: Further study of white matter tract integrity in PTSD is warranted, particularly to investigate whether the CAB connections with both higher-order cognitive functioning and emotion processing regions contribute to the pathophysiology and comorbidity of PTSD. PMID- 30397596 TI - The Sex Chromosome Hypothesis of Schizophrenia: Alive, Dead, or Forgotten? A Commentary and Review. AB - The X chromosome has long been an intriguing site for harboring genes that have importance in brain development and function. It has received the most attention for having specific genes underlying the X-linked inherited intellectual disabilities, but has also been associated with schizophrenia in a number of early studies. An X chromosome hypothesis for a genetic predisposition for schizophrenia initially came from the X chromosome anomaly population data showing an excess of schizophrenia in Klinefelter's (XXY) males and triple X (XXX) females. Crow and colleagues later expanded the X chromosome hypothesis to include the possibility of a locus on the Y chromosome and, specifically, genes on X that escaped inactivation and are X-Y homologous loci. Some new information about possible risk loci on these chromosomes has come from the current large genetic consortia genome-wide association studies, suggesting that perhaps this hypothesis needs to be revisited for some schizophrenias. The following commentary reviews the early and more recent literature supporting or refuting this dormant hypothesis and emphasizes the possible candidate genes still of interest that could be explored in further studies. PMID- 30397598 TI - Perturbations of Neuron-Restrictive Silencing Factor Modulate Corticotropin Releasing Hormone Gene Expression in the Human Cell Line BeWo. AB - Stress exacerbates disease, and understanding its molecular mechanisms is crucial to the development of novel therapeutic interventions to combat stress-related disorders. The driver of the stress response in the hypothalamic-pituitary adrenal axis (HPA) is corticotropin-releasing hormone (CRH), a neuropeptide synthesized in the paraventricular nucleus of the hypothalamus. Evidence supports that CRH expression is epigenetically modified at the molecular level by environmental stimuli, causing changes in the stress response. This effect is mediated by a concert of factors that translate environmental change into alterations in gene expression. An important regulator and epigenetic modulator of CRH expression is neuron-restrictive silencing factor (NRSF). Previously, our lab identified numerous splice variants of NRSF that are specific to humans and predictive of differential regulatory effects of NRSF variants on targeted gene expression. The human cell line BeWo has endogenous CRH and NRSF expression providing an in vitro model system. Here, we show that manipulation of NRSF expression through siRNA technology, overexpression by plasmid vectors, and direct cAMP induction that CRH expression is linked to changes in NRSF expression. Accordingly, this epigenetic regulatory pathway in humans might be a critical mechanism involved in the regulation of the stress response. PMID- 30397597 TI - Epigenetic Age in Male Combat-Exposed War Veterans: Associations with Posttraumatic Stress Disorder Status. AB - DNA methylation patterns change with age and can be used to derive an estimate of "epigenetic age," an indicator of biological age. Several studies have shown associations of posttraumatic stress disorder (PTSD) with worse somatic health and early mortality, raising the possibility of accelerated biological aging. This study examined associations between estimated epigenetic age and various variables in 160 male combat-exposed war veterans with (n = 79) and without PTSD (n = 81). DNA methylation was assessed in leukocyte genomic DNA using the Illumina 450K DNA methylation arrays. Epigenetic age was estimated using Horvath's epigenetic clock algorithm and Deltaage (epigenetic age-chronological age) was calculated. In veterans with PTSD (Deltaage = 3.2), Deltaage was on average lower compared to those without PTSD (Deltaage = 5.0; p = 0.02; Cohen's d = 0.42). This between-group difference was not explained by race/ethnicity, lifestyle factors or childhood trauma. Antidepressant use, however, explained part of the association. In the PTSD positive group, telomerase activity was negatively related to Deltaage (beta = -0.35; p = 0.007). In conclusion, veterans with PTSD had significantly lower epigenetic age profiles than those without PTSD. Further, current antidepressant use and higher telomerase activity were related to relatively less epigenetic aging in veterans with PTSD, speculative of a mechanistic pathway that might attenuate biological aging-related processes in the context of PTSD. PMID- 30397600 TI - Three Severe Cases of Viral Infections with Post-Kidney Transplantation Successfully Confirmed by Polymerase Chain Reaction and Flow Cytometry. AB - Viral infections in patients with post-kidney transplantation are often difficult to diagnose as well as treat. We herein report three cases with severe viral infections after kidney transplantation. All their causative pathogens could be detected promptly by polymerase chain reaction and flow cytometry during the early stages of infection. These examinations would also be of great use to monitor therapeutic responses and disease activity. It is indeed true that no specific treatment is available for most of the viral infections, but we should be aware that some infections, such as Epstein-Barr virus infection, can be treatable with prompt and specific treatment, such as rituximab. PMID- 30397599 TI - Associations between the LEP -2548G/A Promoter and Baseline Weight and between LEPR Gln223Arg and Lys656Asn Variants and Change in BMI z Scores in Arab Children and Adolescents Treated with Risperidone. AB - Data on baseline (antipsychotics-naive) age, weight, and height, and change in these at 3 subsequent follow-up time points up to 313.6 days (95% CI 303.5-323.7) were collected from 181 risperidone-treated children and adolescents (mean age 12.58 years, SD 4.99, range 2.17-17.7) attending a pediatric neurology clinic in Saudi Arabia. Owing to differences in genotypic distributions in the subsamples, results are reported for the white Arab population (n = 144). Age- and gender normed body mass index (BMI)-standardized z scores (BMI z) were calculated (LMSgrowth program). Linear regression was performed for baseline weight and BMI z, while change in BMI z was assessed using random effects ordered logistic regression. The following single nucleotide polymorphisms (SNPs) were analyzed: rs7799039 in the LEP promoter, rs1805094 (previously rs8179183), rs1137100 and rs1137101 in the LEPR, and rs1414334 in HTR2C. We found a nominally significant association between rs7799309 and baseline weight, adjusting for height, age, gender, and diagnosis (A/G, p = 0.035, beta = -3.62 vs. G/G). The rs1137101 (G/G, p = 0.018, odds ratio [OR] = 4.13 vs. A/A) and rs1805094 C allele carriers (p = 0.019, OR = 0.51) showed nominally significant associations with change in BMI z categories. Our data support and replicate previous relevant associations for these variants (including with weight gain when on risperidone), whilst being the first report of such associations in patients of Arab ethnicity. PMID- 30397601 TI - Bile Cast Nephropathy: A Pathologic Finding with Manifold Causes Displayed in an Adult with Alcoholic Steatohepatitis and in a Child with Wilson's Disease. AB - Bile cast nephropathy (BCN) is seen in patients who have acute kidney injury and severe hyperbilirubinemia due to a wide range of hepatobiliary system diseases. Findings seen by renal biopsy include acute tubular injury with necrotic and sloughed epithelial cells, yellow-green pigment within tubular epithelial cells, and pigmented granular casts. Hall's special stain for bile turns these casts green. In recent years, BCN has been described in a small number of case reports and clinical studies primarily in the setting of severe liver dysfunction. We present 2 diverse cases of BCN. The first involves an adult with hepatorenal syndrome secondary to alcoholic steatohepatitis and early cirrhosis. Second, we describe the first reported case of BCN in a child with fulminant hepatic failure due to Wilson's disease. Our cases expand the spectrum of causative diseases, and they provide further evidence that BCN is a distinct pathologic entity which may be found in both adult and pediatric patients with a variety of severe liver diseases. PMID- 30397602 TI - Bioptically Proven "Anticoagulation-Related Nephropathy" Induced by Dual Antiplatelet Therapy. AB - Anticoagulation-related nephropathy (ARN) is a significant and underdiagnosed complication in patients who receive anticoagulation therapy. It is characterized by acute kidney injury in the setting of excessive anticoagulation defined as an international normalized ratio > 3.0 in patients treated with warfarin. A definitive diagnosis is made by renal biopsy showing acute tubular necrosis with obstruction of the tubuli by red blood cell casts. However, the evidence shows that ARN can occur during treatment with novel oral anticoagulants as well. Although it has been suggested that antiplatelet therapy, such as aspirin, might contribute to coagulopathy (and therefore the hypothetical risk of ARN), there are no reports of ARN induced by antiplatelet therapy according to our knowledge. It is also reported that glomerular lesions (i.e., kidney disease) represent a risk factor for ARN. We present a case of an 82-year-old man who developed biopsy proven ARN after the administration of dual antiplatelet therapy with no previous anticoagulation treatment and normal coagulation tests. PMID- 30397603 TI - Primary Hyperoxaluria Type 1 with Thrombophilia in Pregnancy: A Case Report. AB - Background: Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disease caused by a mutation in the AGXT gene, resulting in deficiency of the alanineglyoxylate:aminotransferase enzyme. It is characterized by accumulation of oxalate in the kidneys and other organs. Case Presentation: A Syrian woman with a history of nephrolithiasis and heterozygosity for factor V Leiden and prothrombin gene mutations presented with postpartum renal failure. She required initiation of renal replacement therapy at 14 weeks postpartum. Kidney biopsy showed severe acute and chronic crystalline deposition consistent with oxalate nephropathy. Genetic testing revealed a Gly170Arg mutation in the AGXT gene, confirming the diagnosis of PH1. Conclusions: The diagnosis of PH should be considered in patients with severe, recurrent calcium oxalate nephrolithiasis. Early treatment with pyridoxine reduces urinary oxalate excretion and can delay progression to end-stage renal disease (ESRD). After ESRD, intensive dialysis is needed to prevent systemic oxalate accumulation and deposition. Combined liver and kidney transplantation is curative. In our patient, we anticipate that liver transplantation will cure both the hyperoxaluria and the hypercoagulable state. PMID- 30397605 TI - One more chance of fistula healing in inflammatory bowel disease: Stem cell therapy. AB - Patients with fistulizing inflammatory bowel disease are traditionally difficult to treat. This patient population often experiences delayed or insufficient healing of fistulas using current standard regimens including antibiotics, immunomodulators, anti-tumor necrosis factor-alpha drug, placement of setons, and surgical repair. Several studies over the last ten to fifteen years have been conducted using stem cell therapies with promising results in this patient population. These studies show stem cell therapy in fistulizing disease to be successful in healing between 60%-88% compared to currently 50% with infliximab. Moreover, remission was seen 24 wk to 52 wk in these studies. Further research with a multi-approach treatment using medications, stem cell therapy, and surgical interventions will likely be the future of this innovative treatment approach. PMID- 30397604 TI - Cancer and comorbidity: The role of leptin in breast cancer and associated pathologies. AB - Obesity is an important risk factor for postmenopausal breast cancer and also a poor prognostic factor among cancer patients. Moreover, obesity is associated with a number of health disorders such as insulin resistance/type-2 diabetes mellitus, hypertension, and other cardiovascular diseases. Frequently, these health disorders exhibit as components/complications of the metabolic syndrome. Nevertheless, obesity-related diseases may coexist with postmenopausal breast cancer; and these comorbid conditions could be substantial. Therefore, it may be assumed that different diseases including breast cancer could originate from a common pathological background in excessive adipose tissue. Adipocyte-released hormone-like cytokine (or adipokine) leptin behaves differently in a normal healthy state and obesity. A growing body of evidence suggests an important role of leptin in our major obesity-related health issues such as insulin resistance, hypertension, and neoplasia. In this context, this review describes the relationships of the abovementioned pathologies with leptin. PMID- 30397606 TI - Treat-to-target in Crohn's disease: Will transmural healing become a therapeutic endpoint? AB - Crohn's disease (CD) represents a chronic transmural inflammatory condition of the gastrointestinal tract, which usually leads to structural damage and significant disability. Deep remission - defined by both clinical and endoscopic remission, signifying mucosal healing - represents the current endpoint in the treat-to-target strategy, significantly improving patients' long-term outcomes. Transmural healing (TH) could be a more effective target, but this possibility remains unclear. This narrative review aims to critically review and summarize the available literature relating TH to long-term outcomes, being the first of its kind and to the best of the author's knowledge. A systematic literature search (from inception to March 31 2018) was performed, using multiple databases, and identifying seven full-text manuscripts. In those studies, long-term favorable outcomes (>= 52 wk) included sustained clinical remission, as well as fewer therapeutic changes, CD-related hospitalizations, and surgeries. Despite heterogeneous design and methodological limitations, six of the studies demonstrated that TH or intestinal healing (TH plus mucosal healing) were predictive for the aforementioned favorable outcomes. Therefore, TH may become a reasonable therapeutic target and be included in the concept of deep remission. Further prospective, well-designed, multicenter trials aiming to better define the role of TH in personalized therapy for CD and to determine the long-term influence of TH on bowel damage and disability are warranted. PMID- 30397607 TI - CYP2C19 polymorphism has no influence on rabeprazole-based hybrid therapy for Helicobacter pylori eradication. AB - AIM: To evaluate the impact of cytochrome P450 2C19 (CYP2C19) and interleukin 1beta (IL-1beta) polymorphisms on the efficacy of Helicobacter pylori (H. pylori) eradication by using rabeprazole-based hybrid therapy. METHODS: A total of 88 H. pylori-infected patients were recruited to receive 14-d of hybrid therapy from March 2013 to May 2014. Three patients were excluded from analysis because of incomplete compliance. Either a follow-up endoscopy or 13C-urea test was performed to determine the results of H. pylori eradication therapy. The genotypes of CYP2C19 and IL-1beta were analyzed to investigate the impact on treatment effect. RESULTS: The total eradication rate of H. pylori was 92.94% (79/85). According to the CYP2C19 genotypes, the rates of H. pylori eradication were 89.19% in extensive metabolizers (EM) and 95.83% in non-EM. The H. pylori eradication rates regarding the IL-1beta genotypes were 92.59% in the normal acid secretion group and 93.10% in the low acid secretion group. After multivariable logistic regression analysis, both the genotypes of CYP2C19 and IL-1beta had no significant influences on the eradication rates of H. pylori. CONCLUSION: The CYP2C19 and IL-1beta polymorphisms are not significantly independent factors of H. pylori eradication using rabeprazole-based hybrid therapy. PMID- 30397608 TI - Declining diagnostic accuracy of non-invasive fibrosis tests is associated with elevated alanine aminotransferase in chronic hepatitis B. AB - AIM: To explore the effect of alanine aminotransferase (ALT) on the performance of non-invasive fibrosis tests in chronic hepatitis B (CHB) patients. METHODS: A total of 599 treatment-naive and biopsy-proven CHB patients were included in the study. The cohort was divided into the following three groups: Normal ALT (ALT <= 40), slightly elevated ALT (40 < ALT <= 80) and elevated ALT (ALT > 80). The diagnostic performance of five common non-invasive fibrosis tests for liver fibrosis (stages S2-4), including the aspartate aminotransferase (AST)-to platelet (PLT) ratio index (APRI), fibrosis index based on 4 factors (FIB-4), King's score, Forns index and gamma-glutamyl transpeptidase (GGT)-to-PLT ratio (GPR), were evaluated for each group. RESULTS: Higher ALT levels were associated with higher non-invasive fibrosis test scores. Patients with the same fibrosis stage but higher ALT levels showed higher non-invasive test scores. The areas under the receiver operating characteristics curves (AUROCs) of the non-invasive tests for prediction of >= S2 were higher for patients with ALT <= 40 U/L (range 0.705-0.755) and 40 < ALT <= 80 U/L (range 0.726-0.79) than for patients with ALT > 80 U/L (range 0.604-0.701). The AUROCs for predicting >= S3 and S4 were higher in patients with ALT <= 40 U/L (range 0.736-0.814 for >= S3, 0.79-0.833 for S4) than in patients with 40 < ALT <= 80 U/L (range 0.732-0.754 for >= S3, range 0.626-0.723 for S4) and ALT > 80 U/L (range 0.7-0.784 for >= S3, range 0.662 0.719 for S4). The diagnostic accuracy of the non-invasive tests decreased in a stepwise manner with the increase in ALT. CONCLUSION: ALT has a significant effect on the diagnostic performance of non-invasive fibrosis tests. The ALT level should be considered before performing these non-invasive tests. PMID- 30397609 TI - Gemcitabine-induced haemolytic uremic syndrome, although infrequent, can it be prevented: A case report and review of literature. AB - Gemcitabine is an antineoplastic used to treat several malignancies including pancreatic cancer. Its toxicity profile is well known with myelotoxicity, increased vascular permeability and peripheral oedema as most frequent adverse events. However, several cases of acute renal failure have been reported and haemolytic uremic syndrome (HUS) seems to be the underlying process. The cause of HUS remains unknown but its consequences can be lethal. Therefore, a high grade of suspicion is crucial to diagnose it and promptly treat it. This hopefully will reduce its morbidity. HUS is characterized by progressive renal failure associated with microangiopathic haemolytic anaemia and thrombocytopenia. The primary event is damage to endothelial cells and thrombotic microangiopathy (TMA) is the histopathological lesion. TMA affects mainly renal microvasculature. However, some cases evolve with central nervous or cardiovascular systems involvement. We present here a case of gemcitabine-induced HUS, with renal and cardiovascular system affected at the time of diagnosis which to our knowledge this is the first time of such case to be reported. PMID- 30397610 TI - Colovesical fistula as the initial manifestation of advanced colon cancer: A case report and review of literature. AB - Colovesical fistulas (CVFs) are rare complications of very advanced cancers of the abdominal or pelvic cavity and often cause diagnostic troubles. CVFs are found more often in males, whereas females usually suffer from rectovaginal or vesicovaginal fistulas. This article presents a case of a female patient who was admitted to the hospital because of acute diarrhea, presumably of infectious origin, and with only subtle abnormalities in blood tests and urinalysis. Owing to the ineffectiveness of the performed treatment and progressive intensification of symptoms, diagnostics were extended to include a computed tomography scan, sigmoidoscopy and cystography. The imaging results revealed a large heterogeneous conglomerate of solid and fluid structures in the pelvis, which involved reproductive organs, the bladder and sigmoid colon. The excrement leaking from the digestive tract was urine, and CVF was the first manifestation of colon cancer. Shortly after the final diagnosis, the patient deteriorated and eventually died after an urgent colostomy was performed because of a bowel obstruction. PMID- 30397611 TI - Robotic transoral vestibular parathyroidectomy: Two case reports and review of literature. AB - Advances in preoperative localization studies and demands for scarless surgery have promoted the investigation for remote techniques in parathyroid surgery. Transoral vestibular approach seems to provide the most comfortable and safest access to the neck. In this paper, we report our initial experience with robotic transoral vestibular parathyroidectomy (RTVP) in four patients with primary hyperparathyroidism. The surgery was performed with the Da Vinci system through three trocars introduced from the lower lip vestibule. The procedure was converted to open in two patients due to inappropriate preoperative localization. The mean operative time was 169 min. No postoperative complications were seen. Patients were discharged on postoperative day 1. RTVP is a feasible and safe technique, which allows better surgical exposure and manipulation of the instruments. The advantages of transoral vestibular approach can be enhanced by robotics. Further studies are needed to analyze complications and costs. PMID- 30397612 TI - Atypical lipomatous tumor in the ligamentum teres of liver: A case report and review of the literature. AB - A 61-year-old male was referred to our hospital with a three-month history of persistent epigastralgia and right hypochondralgia. Initial examination revealed a fist-size mass at the epigastric fossa. Ultrasonography showed a hemangioma and a mosaic echoic lesion in the ventromedian with poor blood-flow signal and linear hyperechoic part inside, and a clear border to the surroundings. Dynamic computed tomography revealed a highly enhanced effect from the portal-venous phase continuing to the equilibrium phase. T1-weighted gadolinium-ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced image revealed a high intensity effect at the early phase that continued to the next phase. On the other hand, it contained a low intensity area by a fat suppression of that image. In addition, a T2-weighted image did not show a high intensity effect. Laparotomy was performed on the second day of hospitalization. The tumor had arisen from the ligamentum teres of the liver, and no metastasis or invasion of other organs was noted. It consisted of a lipid component of mature adipocytes and a fibrous component of deep dyeing pleomorphic or multinuclear atypical stromal cells. Immunohistochemical study of the atypical stromal cells demonstrated that they were positive for MDM2 and CDK4. A pathological diagnosis of atypical lipomatous tumor (ALT) was made, and the patient was discharged on the eighth day following the procedure. At the 6-mo follow-up dynamic CT, the patient was free of recurrence or metastasis. We experienced a patient with ALT in the ligamentum teres of the liver. This case suggests the need for a careful and detailed examination when encountering patients presenting with a mass; when neoplastic lesion is confirmed by image inspection, we should thoroughly investigate, including further image investigations and pathologic examination. The latter is the most important. PMID- 30397613 TI - Computed tomography and magnetic resonance imaging findings of metastatic rectal linitis plastica from prostate cancer: A case report and review of literature. AB - Linitis plastica is a rare condition showing circumferentially infiltrating intramural anaplastic carcinoma in a hollow viscus, resulting in a tissue thickening of the involved organ as constricted, inelastic, and rigid. While most secondary rectal linitis plastica (RLP) is caused by metastasis from stomach, breast, gallbladder, or bladder cancer, we report an extremely rare and unique case of secondary RLP due to prostate cancer with computed tomography (CT) and magnetic resonance imaging (MRI) findings, including diffusion weighted imaging (DWI). A 78-year-old man presented with approximately a 2-mo history of constipation and without cancer history. On sigmoidoscopy, there was a luminal narrowing and thickening of rectum with mucosa being grossly normal in its appearance. On contrast-enhanced CT, marked contrast enhancement with wall thickening of rectum was noted. On pelvic MRI, rectal wall thickening showed a target sign on both T2-weighted imaging and DWI. A diffuse infiltrative lesion was suspected in the prostate gland based on low signal intensity on T2-weighted imaging and restricted diffusion. A transanal full-thickness excisional biopsy revealed metastasis from a prostate adenocarcinoma invading the submucosa to the muscularis propria consistent with metastatic RLP. We would like to emphasize the CT and MRI findings of metastatic RLP due to prostate cancer. PMID- 30397614 TI - Live birth after hysteroscopy performed inadvertently during early pregnancy: A case report and review of literature. AB - Generally, hysteroscopy is not appropriate for pregnant women without an indication. What if a patient undergoes hysteroscopy accidentally during the early gestational period? We here report a rare case of a woman who continued pregnancy after a diagnostic hysteroscopy was performed in early pregnancy and delivered a healthy baby. The patient had a history of infertility and oligomenorrhea, probably due to a previous induced abortion. A hysteroscopy was performed after the end of her "menstruation" for assessment of her uterine cavity. Early pregnancy, instead of the expected intrauterine adhesions, was suspected, and the procedure was immediately ceased. Subsequent tests confirmed the diagnosis of pregnancy. She had a full-term delivery by elective caesarean section. The success of this case was attributed to the use of vaginoscopic techniques in hysteroscopy and correct judgment and decision-making during the procedure. This case report provides some useful methods and experience that might be helpful when a similar situation occurs in clinical practice. PMID- 30397615 TI - Mesh migration into the sigmoid colon after inguinal hernia repair presenting as a colonic polyp: A case report and review of literature. AB - Mesh migration and penetration into abdominal viscera rarely occur after laparoscopic inguinal hernia repair. We present the first case of mesh migration into the sigmoid colon identified as a colonic polyp at initial colonoscopic examination. The patient complained of mild abdominal distention in the lower abdomen over the previous year without changes in bowel habits or stool appearance and without weight loss. By complementary endoscopic ultrasonography, a cavity-like structure beneath the suspected polyp was further confirmed. Enhanced abdominal computed tomography merely revealed local bowel wall thickening and inflammation of the colosigmoid junction. The migrating mesh, which was lodged in the sigmoid colon and caused intra-abdominal adhesion in the lower abdominal cavity, was finally identified via exploratory surgery. The components of inflammatory granulation tissue around the mesh material were diagnosed based on histological examination of the surgical specimen after sigmoidectomy. In this patient, nonspecific endoscopic and imaging outcomes during clinical work-up led to the diagnostic dilemma of mesh migration. Therefore, the clinical, radiological and endoscopic challenges specific to this case as well as the underlying reasons for mesh migration are discussed in detail. PMID- 30397616 TI - CNKSR2 mutation causes the X-linked epilepsy-aphasia syndrome: A case report and review of literature. AB - The mutation in CNKSR2 leads to a broad spectrum of phenotypic variability and manifests as an X-linked intellectual disability. However, we reported that the male patient in this study not only had intellectual disability but also epileptic seizures. In addition, there were progressive language impairment, attention deficit hyperactivity disorder and autism. Electroencephalograms showed continuous spike-and-wave during sleep. Genetic testing revealed a de novo mutation of the CNKSR2 gene (c.2185C>T, p.Arg729Ter) in the child that was not detected in the parents. Therefore, the child was diagnosed with X-linked epilepsy aphasia syndrome. Deletion of the CNKSR2 gene has been rarely reported in epilepsy aphasia syndrome, but no de novo mutation has been found in this gene. This report not only adds to the spectrum of epilepsy aphasia syndrome but also helps clinicians in diagnosis and genetic counseling. PMID- 30397617 TI - Valuable prognostic indicators for severe burn sepsis with inhalation lesion: age, platelet count, and procalcitonin. AB - Background: Severe burn sepsis can lead to high mortality. We explored the valuable prognostic indicators for severe burn sepsis with inhalation lesion. Methods: Thirty-eight severe burn patients with sepsis who were admitted to the Third Affiliated Hospital of Soochow University from August 2014 to December 2017 were retrospectively analyzed. Among them, 22 patients were assigned to the death group and 16 patients to the survival group. Their general information, vital signs, and blood index including serum procalcitonin (PCT) and C-reactive protein (CRP) levels at admission, diagnosis of sepsis, and 1-week post-diagnosis of sepsis were compared. Results: Patients in the death group were older and had lower platelet count (PLT) at diagnosis of sepsis and 1-week post-diagnosis as well as higher PCT level at 1-week post-diagnosis than patients in the survival group (all p < 0.05). According to receiver operating characteristic (ROC) curves, the above four indicators could be used to predict the prognosis, and the area under the curve (AUC) of PLT at diagnosis and 1-week post-diagnosis was larger (0.888 and 0.911), and PLT at diagnosis had the highest sensitivity and specificity (0.842 and 0.937). In addition, these patients were divided into two groups by the optimal cutoff age of 38 years. According to multivariate logistic regression analysis and COX regression analysis, only age group and PLT at diagnosis were statistically significant (all p < 0.05). The risk of death in the older group was 28 times higher than that in the younger group, and the risk of death increased by 3% for each unit reduction in PLT at diagnosis. Moreover, age group was an independent factor affecting the patients' survival (beta = - 1.370, p = 0.026). Considering the survival time after sepsis, the mortality risk was lower for patients in the older group than for patients in the younger group (hazard ratio (HR) = 0.254, 95% confidence interval (CI) 0.076-0.851). Conclusion: Age, PLT at diagnosis of sepsis, and 1-week post-diagnosis as well as PCT level at 1-week post-diagnosis are indicators for the evaluation of prognosis of severe burn sepsis with inhalation lesion. Among them, PLT at diagnosis has the greatest prognostic value. In addition, age can predict the patients' mortality and survival time after sepsis. PMID- 30397618 TI - Vertebral Osteomyelitis, Discitis, and Epidural Abscess: A Rare Complication of Cardiobacterium Endocarditis. AB - In this article, we report the case of a 75-year-old man who was presented with new low back pain for 2 weeks. His past history was significant for severe aortic stenosis necessitating bioprosthetic aortic valve placement 4 years ago, hypertension, and coronary artery disease. His physical examination was positive for point tenderness over the lower lumbar spine. He was found to be bacteremic with Cardiobacterium hominis. Magnetic resonance imaging of the spine showed lumbar (L4-L5) epidural abscess and vertebral osteomyelitis, discitis. He underwent a computed tomography-guided needle biopsy of L4-L5. The biopsy culture was also positive for Cardiobacterium hominis. A transesophageal echocardiogram showed small vegetation on the mitral valve with mild regurgitation. He was started on intravenous ceftriaxone 2 g once daily for a planned duration of 6 weeks and was discharged. However, he, unfortunately, expired at an outside facility secondary to an unknown illness 4 weeks into the treatment course. PMID- 30397619 TI - Relationship Between Pitching a Complete Game and Spending Time on the Disabled List for Major League Baseball Pitchers: Letter to the Editor. PMID- 30397620 TI - CFTR Heterozygotes Are at Increased Risk of Respiratory Infections: A Population Based Study. AB - Background: Patients heterozygous for mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene may be more susceptible to respiratory infections than the general population. Methods : We conducted a retrospective case-control study using health insurance claims. We identified patients as either highly likely to be CFTR heterozygotes (CF carriers diagnosed during genetic counseling, parents of children with a diagnosis of CF, and children of mothers diagnosed with CF) or likely CFTR heterozygotes (children of CF carriers diagnosed during genetic counseling and parents of CF carriers diagnosed during genetic counseling). Next, we examined the rates of respiratory infections and antimicrobial prescriptions between both groups of CFTR patients and only the highly likely subcohort, compared with age/sex-matched controls. We examined the presence of any claim using McNemar's test and the number of claims using the sign test. Results: CFTR heterozygotes (the pooled highly likely and likely heterozygotes) were more prone to have at least 1 claim for a respiratory infection (odds ratio [OR], 1.28; P = .020) and to have a greater number of claims for respiratory infections (53.5%; P = .043) than controls. Patients in the highly likely cohort were also more prone to have at least 1 claim for a respiratory infection (OR, 1.30; P = .028) and more claims (54.3%; P = .039) than controls. In addition, the highly likely CFTR heterozygotes were more prone to be prescribed an antibiotic used to treat respiratory infections (OR, 1.34; P = .018) and to have more of these prescriptions (54.3%; P = .035) than controls. Conclusions: Patients heterozygous for CFTR mutations are at higher risk for respiratory infections. Future work to describe clinical outcomes for CFTR heterozygotes is needed. PMID- 30397621 TI - Validation of Apolipoprotein A-1 and Fibronectin Fragments as Markers of Parasitological Cure for Congenital Chagas Disease in Children Treated With Benznidazole. AB - Background: No reliable tests or validated biomarkers exist to ensure parasitological cure following treatment of Chagas disease (CD) patients chronically infected with Trypanosoma cruzi. As seroreversion, the only marker of cure, happens more quickly in children, we investigated the correlation between previously identified biomarkers and seroreversion in children. Methods: Thirty CD children (age 1 month to 10 years) diagnosed as T. cruzi positive (time point S0) were treated with benznidazole (BZ) 5-8 mg/kg/d for 60 days. At least 2 serological tests were used to evaluate treatment efficacy from the end of treatment (S1) until seroreversion (S2). Thirty children (age 1 month to 10 years) and 15 adults were used as healthy controls (HCs). Immunoblot and a proteomic-based assay were used to validate previously identified fragments of apolipoprotein A-1 (ApoA1) and fibronectin (FBN) as CD biomarkers. Results: Correlation between seroreversion and absence of ApoA1 and FBN fragments by immunoblot was observed in 30/30 (100%) and 29/30 (96.6%) CD children, respectively. ApoA1 and FBN fragments were absent at the end of BZ treatment in 20/30 (66.6%) and 16/30 (53.3%) children, respectively. Absence of fragments in serum profiles was confirmed by mass spectrometry. Using intact protein analysis, a 28 109-Da protein identified as full-length ApoA1 by tandem mass spectrometry was detected in HC serum samples. Conclusions: These data confirm that ApoA1 and FBN fragments can discriminate between healthy and T. cruzi-infected samples. Correlation with seroreversion was shown for the first time; results suggest predictive capacity potentially superior to serology, making them potentially useful as surrogate biomarkers. PMID- 30397622 TI - Multiplicity of Infection Is a Poor Predictor of Village-Level Plasmodium vivax and P. falciparum Population Prevalence in the Southwest Pacific. AB - Across 8101 individuals in 46 villages, the proportion of Plasmodium spp. multiple clone infections (0%-53.8%) did not reflect prevalence by quantitative polymerase chain reaction (qPCR; 1.9%-38.4%), except for P. vivax in Solomon Islands (P < .001). Thus this parameter was not informative to identify transmission foci. In contrast, prevalence by microscopy and qPCR correlated well. PMID- 30397623 TI - Fatal Measles Virus Infection After Rituximab-Containing Chemotherapy in a Previously Vaccinated Patient. AB - We report the case of a young patient treated with rituximab-containing chemotherapy who was infected with measles despite previous vaccination. Treatment with vitamin A, ribavirin, and immunoglobulins was started; nevertheless he developed severe pneumonitis and deceased. Broad vaccination coverage is crucial in protecting vulnerable subjects. PMID- 30397624 TI - Variability of Zika Virus Incubation Period in Humans. AB - Zika virus (ZIKV) has recently emerged in numerous tropical countries worldwide. In this study, we estimated ZIKV incubation period distribution using time-to event models adapted to interval-censored data based on declared date of travels from 123 symptomatic travelers returning from areas with active ZIKV transmission. The median time and 95th percentile of ZIKV incubation period was estimated to 6.8 days (95% confidence interval [CI], 5.8-7.7 days) and 15.4 days (95% CI, 12.7-19.7 days), respectively. Determining the incubation period for ZIKV is beneficial to improve protection guidelines. PMID- 30397625 TI - Erratum. AB - [This corrects the article DOI: 10.1093/ofid/ofy035.][This corrects the article DOI: 10.1093/ofid/ofy035.]. PMID- 30397626 TI - Development of a Novel Recombinant Adeno-Associated Virus Production System Using Human Bocavirus 1 Helper Genes. AB - Human bocavirus 1 (HBoV1), an autonomous parvovirus, is a helper virus supporting replication of wild-type adeno-associated virus 2 (AAV2). In this study, we compared the helper functions from HBoV1 with those from adenovirus (Ad) for the production of recombinant AAV (rAAV) vector in HEK293 cells. We demonstrated that triple plasmids transfection of (1) a cloned HBoV1 helper minigenome (pBocaHelper) that expresses HBoV1 genes NP1, NS2, and BocaSR, (2) pAAV transfer plasmid, and (3) pAAVRepCap supports rAAV production in HEK293 cells. Despite a production yield of 1-2 log lower than that using pAdHelper (expressing Ad genes E2A, E4, and VA), rAAV vector produced using pBocaHelper transduced cells as efficiently as that produced using pAdHelper. The low vector production is largely due to the inefficient expression of the AAV Rep52 and capsid proteins, as well as reduced rAAV genome replication. When the AAV capsid proteins and Rep52 were ectopically expressed under strong promoters, the enhanced protein expression significantly improved the rAAV production using pBocaHelper, approaching a level of 50%-70% of that produced using pAdHelper. Through further dissection of the helper functions from pAdHelper in a five-plasmid transfection system, we found that the addition of the Ad E2A gene to the above HBoV1 helper system significantly increased rAAV DNA replication, which increased the rAAV vector production to a level of 3-7 times higher than that using pAdHelper. We finally combined HBoV1 NP1 and NS2 genes with Ad helper genes to create a novel dual helper plasmid (pABHelper) for rAAV vector production in the conventional three-plasmid transfection system. The pABHelper facilitated rAAV production at a yield ~2 times higher than that using the pAdHelper. PMID- 30397627 TI - Getting the Most: Enhancing Efficacy by Promoting Erythropoiesis and Thrombopoiesis after Gene Therapy in Mice with Hurler Syndrome. AB - Novel strategies are needed to solve the conundrum of achieving clinical efficacy with high vector copy numbers (VCNs) in hematopoietic stem cells (HSCs) while attempting to minimize the potential risk of oncogenesis in lentiviral vector (LV)-mediated gene therapy clinical trials. We previously reported the benefits of reprogramming erythroid-megakaryocytic (EMK) cells for high-level lysosomal enzyme production with less risk of activating oncogenes in HSCs. Herein, using a murine model of mucopolysaccharidosis type I (MPS I) with a deficiency of alpha-L iduronidase (IDUA), we sought to determine the transgene minimum effective doses (MEDs) in major organs, and if a transient increase of IDUA-containing red blood cells and platelets by repeated phlebotomy would provide further therapeutic benefits in diseased mice after EMK-restricted LV-mediated gene therapy. The MEDs for complete metabolic correction ranged from 0.1 to 2 VCNs in major visceral organs, which were dramatically reduced to 0.005-0.1 VCN by one cycle of stress induction and were associated with a further reduction of pathological deficits in mice with 0.005 VCN. This work provides a proof of concept that transiently stimulating erythropoiesis and thrombopoiesis can further improve therapeutic benefits in HSC-mediated gene therapy for MPS I, a repeatable and reversible approach to enhance clinical efficacy in the treatment of lysosomal storage diseases. PMID- 30397628 TI - Adeno-Associated Virus Neutralizing Antibodies in Large Animals and Their Impact on Brain Intraparenchymal Gene Transfer. AB - Pre-existing neutralizing antibody (NAb) against adeno-associated virus (AAV) commonly found in primates is a major host barrier that can severely compromise in vivo gene transfer by AAV vectors. To achieve proof-of-concept success in clinical development of recombinant AAV (rAAV)-based in vivo gene therapy, it is crucial to consider the potential interference of NAb and to enroll serologically compatible study subjects. In this study, we report a large AAV NAb dataset comprising multiple large animal species and AAV serotypes and compare two NAb assays based on in vitro or in vivo transduction inhibition, respectively. Together with previously published AAV seroepidemiology studies, these data can serve as a reference for selecting suitable serotypes, study subjects of large animal species, and potentially human patients for rAAV treatment. In addition, we modeled the intrathalamus rAAV9 delivery in the presence of circulating anti AAV9 NAb generated by either pre-immunization or passive transfer of NAb-positive large animal serum to mice. The data showed that circulating NAb may not be the sole determinant to inhibit brain transduction. Other aspects of pre-existing AAV immunity following natural infection or rAAV administration may be further studied to establish a more accurate inclusion criterion for clinical studies employing intraparenchymal rAAV9 injections. PMID- 30397629 TI - Effect of prewhitening in resting-state functional near-infrared spectroscopy data. AB - Near-infrared spectroscopy (NIRS) offers the potential to characterize resting state functional connectivity (RSFC) in populations that are not easily assessed otherwise, such as young infants. In addition to the advantages of NIRS, one should also consider that the RS-NIRS signal requires specific data preprocessing and analysis. In particular, the RS-NIRS signal shows a colored frequency spectrum, which can be observed as temporal autocorrelation, thereby introducing spurious correlations. To address this issue, prewhitening of the RS-NIRS signal has been recently proposed as a necessary step to remove the signal temporal autocorrelation and therefore reduce false-discovery rates. However, the impact of this step on the analysis of experimental RS-NIRS data has not been thoroughly assessed prior to the present study. Here, the results of a standard preprocessing pipeline in a RS-NIRS dataset acquired in infants are compared with the results after incorporating two different prewhitening algorithms. Our results with a standard preprocessing replicated previous studies. Prewhitening altered RSFC patterns and disrupted the antiphase relationship between oxyhemoglobin and deoxyhemoglobin. We conclude that a better understanding of the effect of prewhitening on RS-NIRS data is still needed before directly considering its incorporation to the standard preprocessing pipeline. PMID- 30397631 TI - Dynamic fluence field modulation for miscentered patients in computed tomography. AB - Traditional CT image acquisition uses bowtie filters to reduce dose, x-ray scatter, and detector dynamic range requirements. However, accurate patient centering within the bore of the CT scanner takes time and is often difficult to achieve precisely. Patient miscentering combined with a static bowtie filter can result in significant increases in dose, reconstruction noise, and CT number variations, and consequently raise overall exposure requirements. Approaches to estimate the patient position from scout scans and perform dynamic spatial beam filtration during acquisition are developed and applied in physical experiments on a CT test bench using different beam filtration strategies. While various dynamic beam modulation strategies have been developed, we focus on two approaches: (1) a simple approach using attenuation-based beam modulation using a translating bowtie filter and (2) dynamic beam modulation using multiple aperture devices (MADs)-an emerging beam filtration strategy based on binary filtration of the x-ray beam using variable width slits in a high-density beam blocker. Improved dose utilization and more consistent image performance with respect to an unmodulated baseline (static filter) are demonstrated for miscentered objects and dynamic beam filtration in physical experiments. For a homogeneous object miscentered by 4 cm, the dynamic filter reduced the maximum regional noise and dose penalties (compared with a centered object) from 173% to 16% and 42% to 14%, respectively, for a traditional bowtie, 29% to 8% and 24% to 15%, respectively, for a single MAD, and 275% to 11% and 56% to 18%, respectively, for a dual-MAD filter. The proposed methodology has the potential to relax patient centering requirements within the scanner, reduce setup time, and facilitate additional CT dose reduction. PMID- 30397632 TI - Fully connected neural network for virtual monochromatic imaging in spectral computed tomography. AB - Spectral computed tomography (SCT) has advantages in multienergy material decomposition for material discrimination and quantitative image reconstruction. However, due to the nonideal physical effects of photon counting detectors, including charge sharing, pulse pileup and K -escape, it is difficult to obtain precise system models in practical SCT systems. Serious spectral distortion is unavoidable, which introduces error into the decomposition model and affects material decomposition accuracy. Recently, neural networks demonstrated great potential in image segmentation, object detection, natural language processing, etc. By adjusting the interconnection relationship among internal nodes, it provides a way to mine information from data. Considering the difficulty in modeling SCT system spectra and the superiority of data-driven characteristics of neural networks, we proposed a spectral information extraction method for virtual monochromatic attenuation maps using a simple fully connected neural network without knowing spectral information. In our method, virtual monochromatic linear attenuation coefficients can be obtained directly through our neural network, which could contribute to further material recognition. Our method also provides outstanding performance on denoising and artifacts suppression. It can be furnished for SCT systems with different settings of energy bins or thresholds. Various substances available can be used for training. The trained neural network has a good generalization ability according to our results. The testing mean square errors are about 1*10-05 cm-2 . PMID- 30397633 TI - Reconstruction of a metacarpal head defect due to bite injury: two case reports. AB - We present two rare cases of acute osteomyelitis after bite injury that were reconstructed with a third metacarpal base osteoarticular flap and a vascularised medial femoral trochlea osteocartilaginous flap. The outcomes show that a vascularised osteoarticular flap is a good treatment option for a metacarpal head defect. PMID- 30397630 TI - Multichannel optrodes for photonic stimulation. AB - An emerging method in the field of neural stimulation is the use of photons to activate neurons. The possible advantage of optical stimulation over electrical is attributable to its spatially selective activation of small neuron populations, which is promising in generating superior spatial resolution in neural interfaces. Two principal methods are explored for cochlear prostheses: direct stimulation of nerves with infrared light and optogenetics. This paper discusses basic requirements for developing a light delivery system (LDS) for the cochlea and provides examples for building such devices. The proposed device relies on small optical sources, which are assembled in an array to be inserted into the cochlea. The mechanical properties, the biocompatibility, and the efficacy of optrodes have been tested in animal models. The force required to insert optrodes into a model of the human scala tympani was comparable to insertion forces obtained for contemporary cochlear implant electrodes. Side emitting diodes are powerful enough to evoke auditory responses in guinea pigs. Chronic implantation of the LDS did not elevate auditory brainstem responses over 26 weeks. PMID- 30397634 TI - Rare finding in peripheral nerve surgery: an unicentric Castleman disease presenting as median nerve tumour. AB - A 51 year old man presented with progressive swelling in the upper arm. MRI revealed a solitary mass extending from the median nerve. Intraoperative finding was a tumour extending within the nerve in its proximal fibres. The histological result showed a Castleman disease. PMID- 30397635 TI - Hyperbaric oxygen therapy for digital ulcers due to Raynaud's disease. AB - We present a case of Raynaud's disease with digital ulcers that was successfully treated with hyperbaric oxygen therapy. Hyperbaric oxygen therapy can be considered as a safe and useful adjunct treatment for intractable digital ulcers in patients with Raynaud's disease. PMID- 30397636 TI - Delayed deep dermal necrosis after jellyfish sting in a 4-year-old female infant. AB - We report the case of a 4-year-old female infant who developed ongoing deep dermal necrosis of the bilateral legs after jellyfish contact in Thailand. Stepwise radical debridement and vacuum assisted wound therapy seemed to be an effective strategy to prevent progressive soft tissue loss. PMID- 30397637 TI - A Ricoeur-Inspired Approach to Interpret Participant Observations and Interviews. AB - In-depth knowledge of what it means to patients to receive health care services is crucial to the development of adequate protocols for nursing. Qualitative research allows us to gain important insight into what is experienced by and meaningful to patients. The French philosopher Paul Ricoeur's thoughts have inspired qualitative researchers to conduct various forms of analysis and interpretation that increase our knowledge of ways of being-in-the-world. This article describes and discusses how a specific approach to derive in-depth knowledge of patients' lived experiences can be taken. A combination of participant observations and interviews was used to generate data. Field notes and transcribed interviews were gathered as one collective text and analyzed and interpreted with inspiration from Ricoeur's thoughts on narratives and interpretation. This approach is argued to be a significant way of developing in depth knowledge of patients' lived experiences. Such knowledge is important within nursing science. PMID- 30397639 TI - Micro- and Macrobioprinting: Current Trends in Tissue Modeling and Organ Fabrication. AB - The recapitulation of human anatomy and physiology is critical for organ regeneration. Due to this fundamental requirement, bioprinting holds great promise in tissue engineering and regenerative medicine due to the possibility of fabricating complex scaffolds that host cells and biochemical cues in a physiologically relevant fashion. The ever-growing research in this field has been proceeding along two different, yet complementary, routes: on the one hand, the development of bioprinting to fabricate large tissue surrogates for transplantation purposes in vivo (macrobioprinting), and on the other the spread of bioprinting-based miniaturized systems to model the tissue microenvironment in vitro (microbioprinting). The latest advances in both macro- and microbioprinting are reviewed, emphasizing their impact on specific areas of tissue engineering. Additionally, a critical comparison of macro- versus microbioprinting is presented together with advantages and limitations of each approach. Ultimately, findings obtained both at the macro-and microscale are expected to provide a deeper insight in tissue biology and offer clinically relevant solutions for organ regeneration. PMID- 30397638 TI - Successful Aging in Colombia: The Role of Disease. AB - Objective: This study aimed to determine the prevalence of successful aging (SA) and identify its predictive factors in a cohort of older people in the Colombian Andes Mountain. Method: Data were drawn from a prospective longitudinal study of community-dwelling elderly people in Manizales. SA encompassed indicators in four domains: physical, cognitive, emotional, and social functioning. Results: The prevalence of SA was 24.4%. The independent predictors were good and very good self-rated health, middle-high/high-income level, absence of chronic conditions, married status, high educational level, and very high spirituality. Discussion: The prevalence of SA was low: One of 10 people older than 65 years showed SA when presence of diseases was included in the criteria, compared with one of four when such an item was excluded. The identification of predictive factors allows distinguishing this population in primary care services and promoting strategies that ensure high functionality levels for as long as possible. PMID- 30397640 TI - Cell chirality regulates intercellular junctions and endothelial permeability. AB - Cell chirality is a newly discovered intrinsic property of the cell, reflecting the bias of the cell to polarize in the left-right axis. Despite increasing evidence on its substantial role in the asymmetric development of embryos, little is known about implications of cell chirality in physiology and disease. We demonstrate that cell chirality accounts for the nonmonotonic, dose-response relationship between endothelial permeability and protein kinase C (PKC) activation. The permeability of the endothelial cell layer is tightly controlled in our body, and dysregulation often leads to tissue inflammation and diseases. Our results show that low-level PKC activation is sufficient to reverse cell chirality through phosphatidylinositol 3-kinase/AKT signaling and alters junctional protein organization between cells with opposite chirality, leading to an unexpected substantial change in endothelial permeability. Our findings suggest that cell chirality regulates intercellular junctions in important ways, providing new opportunities for drug delivery across tightly connected semipermeable cellular sheets. PMID- 30397641 TI - Uncovering the psychoactivity of a cannabinoid from liverworts associated with a legal high. AB - Phytochemical studies on the liverwort Radula genus have previously identified the bibenzyl (-)-cis-perrottetinene (cis-PET), which structurally resembles (-) Delta9-trans-tetrahydrocannabinol (Delta9-trans-THC) from Cannabis sativa L. Radula preparations are sold as cannabinoid-like legal high on the internet, even though pharmacological data are lacking. Herein, we describe a versatile total synthesis of (-)-cis-PET and its (-)-trans diastereoisomer and demonstrate that both molecules readily penetrate the brain and induce hypothermia, catalepsy, hypolocomotion, and analgesia in a CB1 receptor-dependent manner in mice. The natural product (-)-cis-PET was profiled on major brain receptors, showing a selective cannabinoid pharmacology. This study also uncovers pharmacological differences between Delta9-THC and PET diastereoisomers. Most notably, (-)-cis PET and (-)-trans-PET significantly reduced basal brain prostaglandin levels associated with Delta9-trans-THC side effects in a CB1 receptor-dependent manner, thus mimicking the action of the endocannabinoid 2-arachidonoyl glycerol. Therefore, the natural product (-)-cis-PET is a psychoactive cannabinoid from bryophytes, illustrating the existence of convergent evolution of bioactive cannabinoids in the plant kingdom. Our findings may have implications for bioprospecting and drug discovery and provide a molecular rationale for the reported effects upon consumption of certain Radula preparations as moderately active legal highs. PMID- 30397642 TI - Transistor in a tube: A route to three-dimensional bioelectronics. AB - Advances in three-dimensional (3D) cell culture materials and techniques, which more accurately mimic in vivo systems to study biological phenomena, have fostered the development of organ and tissue models. While sophisticated 3D tissues can be generated, technology that can accurately assess the functionality of these complex models in a high-throughput and dynamic manner is not well adapted. Here, we present an organic bioelectronic device based on a conducting polymer scaffold integrated into an electrochemical transistor configuration. This platform supports the dual purpose of enabling 3D cell culture growth and real-time monitoring of the adhesion and growth of cells. We have adapted our system to a 3D tubular geometry facilitating free flow of nutrients, given its relevance in a variety of biological tissues (e.g., vascular, gastrointestinal, and kidney) and processes (e.g., blood flow). This biomimetic transistor in a tube does not require photolithography methods for preparation, allowing facile adaptation to the purpose. We demonstrate that epithelial and fibroblast cells grow readily and form tissue-like architectures within the conducting polymer scaffold that constitutes the channel of the transistor. The process of tissue formation inside the conducting polymer channel gradually modulates the transistor characteristics. Correlating the real-time changes in the steady-state characteristics of the transistor with the growth of the cultured tissue, we extract valuable insights regarding the transients of tissue formation. Our biomimetic platform enabling label-free, dynamic, and in situ measurements illustrates the potential for real-time monitoring of 3D cell culture and compatibility for use in long-term organ-on-chip platforms. PMID- 30397643 TI - Pre-Clovis projectile points at the Debra L. Friedkin site, Texas-Implications for the Late Pleistocene peopling of the Americas. AB - Lanceolate projectile points of the Clovis complex and stemmed projectile points of the Western Stemmed Tradition first appeared in North America by ~13 thousand years (ka) ago. The origin, age, and chronological superposition of these stemmed and lanceolate traditions are unclear. At the Debra L. Friedkin site, Texas, below Folsom and Clovis horizons, we find stemmed projectile points dating from ~13.5 to ~15.5 ka ago, with a triangular lanceolate point form appearing ~14 ka ago. The sequential relationship of stemmed projectile points followed by lanceolate forms suggests that lanceolate points are derived from stemmed forms or that they originated from two separate migrations into the Americas. PMID- 30397644 TI - Single-molecule observation of nucleotide induced conformational changes in basal SecA-ATP hydrolysis. AB - SecA is the critical adenosine triphosphatase that drives preprotein transport through the translocon, SecYEG, in Escherichia coli. This process is thought to be regulated by conformational changes of specific domains of SecA, but real time, real-space measurement of these changes is lacking. We use single-molecule atomic force microscopy (AFM) to visualize nucleotide-dependent conformations and conformational dynamics of SecA. Distinct topographical populations were observed in the presence of specific nucleotides. AFM investigations during basal adenosine triphosphate (ATP) hydrolysis revealed rapid, reversible transitions between a compact and an extended state at the ~100-ms time scale. A SecA mutant lacking the precursor-binding domain (PBD) aided interpretation. Further, the biochemical activity of SecA prepared for AFM was confirmed by tracking inorganic phosphate release. We conclude that ATP-driven dynamics are largely due to PBD motion but that other segments of SecA contribute to this motion during the transition state of the ATP hydrolysis cycle. PMID- 30397645 TI - Room temperature long-range coherent exciton polariton condensate flow in lead halide perovskites. AB - Novel technological applications significantly favor alternatives to electrons toward constructing low power-consuming, high-speed all-optical integrated optoelectronic devices. Polariton condensates, exhibiting high-speed coherent propagation and spin-based behavior, attract considerable interest for implementing the basic elements of integrated optoelectronic devices: switching, transport, and logic. However, the implementation of this coherent polariton condensate flow is typically limited to cryogenic temperatures, constrained by small exciton binding energy in most semiconductor microcavities. Here, we demonstrate the capability of long-range nonresonantly excited polariton condensate flow at room temperature in a one-dimensional all-inorganic cesium lead bromide (CsPbBr3) perovskite microwire microcavity. The polariton condensate exhibits high-speed propagation over macroscopic distances of 60 MUm while still preserving the long-range off-diagonal order. Our findings pave the way for using coherent polariton condensate flow for all-optical integrated logic circuits and polaritonic devices operating at room temperature. PMID- 30397646 TI - Evaluating the extent of a large-scale transformation in gateway science courses. AB - We evaluate the impact of an institutional effort to transform undergraduate science courses using an approach based on course assessments. The approach is guided by A Framework for K-12 Science Education and focuses on scientific and engineering practices, crosscutting concepts, and core ideas, together called three-dimensional learning. To evaluate the extent of change, we applied the Three-dimensional Learning Assessment Protocol to 4 years of chemistry, physics, and biology course exams. Changes in exams differed by discipline and even by course, apparently depending on an interplay between departmental culture, course organization, and perceived course ownership, demonstrating the complex nature of transformation in higher education. We conclude that while transformation must be supported at all organizational levels, ultimately, change is controlled by factors at the course and departmental levels. PMID- 30397647 TI - Minimal PAM specificity of a highly similar SpCas9 ortholog. AB - RNA-guided DNA endonucleases of the CRISPR-Cas system are widely used for genome engineering and thus have numerous applications in a wide variety of fields. CRISPR endonucleases, however, require a specific protospacer adjacent motif (PAM) flanking the target site, thus constraining their targetable sequence space. In this study, we demonstrate the natural PAM plasticity of a highly similar, yet previously uncharacterized, Cas9 from Streptococcus canis (ScCas9) through rational manipulation of distinguishing motif insertions. To this end, we report affinity to minimal 5'-NNG-3' PAM sequences and demonstrate the accurate editing capabilities of the ortholog in both bacterial and human cells. Last, we build an automated bioinformatics pipeline, the Search for PAMs by ALignment Of Targets (SPAMALOT), which further explores the microbial PAM diversity of otherwise overlooked Streptococcus Cas9 orthologs. Our results establish that ScCas9 can be used both as an alternative genome editing tool and as a functional platform to discover novel Streptococcus PAM specificities. PMID- 30397648 TI - Moisture availability in the southwest United States over the last three glacial interglacial cycles. AB - The projected long-term drying of the southwest (SW) United States in response to climate warming raises a sobering alarm for this already water-limited region, yet the climatic controls on moisture availability over longer time scales remain a topic of debate. Here, we present a 350,000-year record of past water table fluctuations in Devils Hole 2 cave that are driven by variations in recharge amount to the local groundwater flow system. Because of the unprecedented length and precision of our record, we can observe variations in regional moisture availability over the last three glacial-interglacial cycles at a millennial scale resolution. The timing of past water table rises and falls (>9 m in amplitude) closely coincides with the expansion and reduction of Northern Hemisphere ice volume, which in turn influences the position and intensity of westerly winter storms on orbital time scales. Superimposed on this long-term trend are millennial-scale highstands recorded during the last glaciation that coincide with North Atlantic Heinrich events. Earlier millennial-scale highstands provide the first evidence of multiple short-lived wet periods in the SW United States linked to coeval cooling intervals in the North Atlantic during marine isotope stages 6 and 8. The Devils Hole 2 water table record is currently the longest independently dated paleomoisture record in the SW United States and thus provides a critical testbed to examine the controls on regional moisture availability over larger time scales. PMID- 30397649 TI - Unique ion rectification in hypersaline environment: A high-performance and sustainable power generator system. AB - The development of membrane science plays a fundamental role in harvesting osmotic power, which is considered a future clean and renewable energy source. However, the existing designs of the membrane cannot handle the low conversion efficiency and power density. Theory has predicted that the Janus membrane with ionic diode-type current would be the most efficient material. Therefore, rectified ionic transportation in a hypersaline environment (the salt concentration is at least 0.5 M in sea) is highly desired, but it still remains a challenge. Here, we demonstrate a versatile strategy for creating a scale-up Janus three-dimensional (3D) porous membrane-based osmotic power generator system. Janus membranes with tunable surface charge density and porosity were obtained by compounding two kinds of ionomers. Under electric fields or chemical gradients, the Janus membrane has ionic current rectification properties and anion selectivities in a hypersaline environment. Experiments and theoretical calculation demonstrate that abundant surface charge and narrow pore size distribution benefit this unique ionic transport behavior in high salt solution. Thus, the output power density of this membrane-based generator reaches 2.66 W/m2 (mixing seawater and river water) and up to 5.10 W/m2 at a 500-fold salinity gradient (i.e., flowing salt lake into river water). Furthermore, a generator, built by connecting a series of membranes, could power a calculator for 120 hours without obvious current decline, proving the excellent physical and chemical stabilities. Therefore, we believe that this work advances the fundamental understanding of fluid transport and materials design as a paradigm for a high performance energy conversion generator. PMID- 30397650 TI - Poly(amide-imide) materials for transparent and flexible displays. AB - The key component currently missing for the next generation of transparent and flexible displays is a high-performance polymer material that is flexible, while showing optical and thermal properties of glass. It must be transparent to visible light and show a low coefficient of thermal expansion (CTE). While specialty plastics such as aromatic polyimides are promising, reducing their CTE and improving transparency simultaneously proved challenging, with increasing coloration the main problem to be resolved. We report a new poly(amide-imide) material that is flexible and displays glass-like behavior with a CTE value of 4 parts per million/ degrees C. This novel polymer was successfully used as a substrate to fabricate transparent and flexible indium-gallium-zinc oxide thin film transistors. PMID- 30397651 TI - Structure and dynamics conspire in the evolution of affinity between intrinsically disordered proteins. AB - In every established species, protein-protein interactions have evolved such that they are fit for purpose. However, the molecular details of the evolution of new protein-protein interactions are poorly understood. We have used nuclear magnetic resonance spectroscopy to investigate the changes in structure and dynamics during the evolution of a protein-protein interaction involving the intrinsically disordered CREBBP (CREB-binding protein) interaction domain (CID) and nuclear coactivator binding domain (NCBD) from the transcriptional coregulators NCOA (nuclear receptor coactivator) and CREBBP/p300, respectively. The most ancient low-affinity "Cambrian-like" [540 to 600 million years (Ma) ago] CID/NCBD complex contained less secondary structure and was more dynamic than the complexes from an evolutionarily younger "Ordovician-Silurian" fish ancestor (ca. 440 Ma ago) and extant human. The most ancient Cambrian-like CID/NCBD complex lacked one helix and several interdomain interactions, resulting in a larger solvent accessible surface area. Furthermore, the most ancient complex had a high degree of millisecond-to-microsecond dynamics distributed along the entire sequences of both CID and NCBD. These motions were reduced in the Ordovician-Silurian CID/NCBD complex and further redistributed in the extant human CID/NCBD complex. Isothermal calorimetry experiments show that complex formation is enthalpically favorable and that affinity is modulated by a largely unfavorable entropic contribution to binding. Our data demonstrate how changes in structure and motion conspire to shape affinity during the evolution of a protein-protein complex and provide direct evidence for the role of structural, dynamic, and frustrational plasticity in the evolution of interactions between intrinsically disordered proteins. PMID- 30397653 TI - Design of magnetic spirals in layered perovskites: Extending the stability range far beyond room temperature. AB - In insulating materials with ordered magnetic spiral phases, ferroelectricity can emerge owing to the breaking of inversion symmetry. This property is of both fundamental and practical interest, particularly with a view to exploiting it in low-power electronic devices. Advances toward technological applications have been hindered, however, by the relatively low ordering temperatures T spiral of most magnetic spiral phases, which rarely exceed 100 K. We have recently established that the ordering temperature of a magnetic spiral can be increased up to 310 K by the introduction of chemical disorder. Here, we explore the design space opened up by this novel mechanism by combining it with a targeted lattice control of some magnetic interactions. In Cu-Fe layered perovskites, we obtain T spiral values close to 400 K, comfortably far from room temperature and almost 100 K higher than using chemical disorder alone. Moreover, we reveal a linear relationship between the spiral's wave vector and the onset temperature of the spiral phase. This linear law ends at a paramagnetic-collinear-spiral triple point, which defines the highest spiral ordering temperature that can be achieved in this class of materials. On the basis of these findings, we propose a general set of rules for designing magnetic spirals in layered perovskites using external pressure, chemical substitutions, and/or epitaxial strain, which should guide future efforts to engineer magnetic spiral phases with ordering temperatures suitable for technological applications. PMID- 30397652 TI - Bacterial virulence against an oceanic bloom-forming phytoplankter is mediated by algal DMSP. AB - Emiliania huxleyi is a bloom-forming microalga that affects the global sulfur cycle by producing large amounts of dimethylsulfoniopropionate (DMSP) and its volatile metabolic product dimethyl sulfide. Top-down regulation of E. huxleyi blooms has been attributed to viruses and grazers; however, the possible involvement of algicidal bacteria in bloom demise has remained elusive. We demonstrate that a Roseobacter strain, Sulfitobacter D7, that we isolated from a North Atlantic E. huxleyi bloom, exhibited algicidal effects against E. huxleyi upon coculturing. Both the alga and the bacterium were found to co-occur during a natural E. huxleyi bloom, therefore establishing this host-pathogen system as an attractive, ecologically relevant model for studying algal-bacterial interactions in the oceans. During interaction, Sulfitobacter D7 consumed and metabolized algal DMSP to produce high amounts of methanethiol, an alternative product of DMSP catabolism. We revealed a unique strain-specific response, in which E. huxleyi strains that exuded higher amounts of DMSP were more susceptible to Sulfitobacter D7 infection. Intriguingly, exogenous application of DMSP enhanced bacterial virulence and induced susceptibility in an algal strain typically resistant to the bacterial pathogen. This enhanced virulence was highly specific to DMSP compared to addition of propionate and glycerol which had no effect on bacterial virulence. We propose a novel function for DMSP, in addition to its central role in mutualistic interactions among marine organisms, as a mediator of bacterial virulence that may regulate E. huxleyi blooms. PMID- 30397654 TI - Electrochemically induced phase separation and in situ formation of mesoporous structures in ionic liquid mixtures. AB - Liquid-liquid phase separation is mainly dependent on temperature and composition. Electric fields have also been shown to influence demixing of binary liquid mixtures. However, a puzzling behavior that remains elusive is the electric field-induced phase separation in ion-containing solvents at low voltages, as predicted by Tsori and Leibler. Here, we report the first experimental study of such a phenomenon in ionic liquid-silane mixtures, which not only results in phase separation at the electrode-electrolyte interface (EEI) but also is accompanied by deposition of porous structures of micrometer size on the electrode. This multiscale phenomenon at the EEI was found to be triggered by an electrochemically induced process. Using several analytical methods, we reveal the involved mechanism in which the formation of new Si-N bonds becomes unstable and eventually decomposes into the formation of silane-rich and silane-poor phases. The deposition of porous structures on the electrode surface is therefore a realization of the silane-rich phase. The finding of an electrochemically induced phase separation not only brings a paradigm shift in understanding the EEI in ionic liquids but also provides alternative strategies toward designing porous surfaces. PMID- 30397655 TI - Massive Bleed Following Optical Internal Urethrotomy: An Unforeseen Doom Discussing the Unique Management Technique. AB - Objective: To demonstrate the unique management technique of ultrasound (USG) guided compression repair for bulbourethral artery pseudoaneurysm following optical internal urethrotomy (OIU) for short segment bulbar urethral stricture. Methods: A 40-year-old man underwent day care OIU for short segment bulbar urethral stricture. The procedure was uneventful and the patient was discharged the same day. After catheter removal on day 7, the patient had massive bleed from urethra. Perineal compression stopped the bleeding; however, the patient bled again and needed blood transfusion. CT angiography revealed right bulbourethral artery pseudoaneurysm. Results: USG colour Doppler was performed to find out the exact site of pseudoaneurysm, and focused compression was given for 25 minutes. Later assessment showed no flow in pseudoaneurysm and tract was obliterated. Conclusion: Minor bleed following OIU is quite common and generally subsides spontaneously or with pressure dressing. Massive bleed is uncommon, although reported in the literature, and requires angioembolization of the feeding vessel. Before going for invasive procedure, this simple technique of USG-guided compression can be tried as it is simple, cost-effective, and highly successful in small pseudoaneurysm. PMID- 30397656 TI - Improving comprehensive care for patients with diabetes. AB - Patients with diabetes require access to systematic and ongoing care delivered by a team of healthcare providers. Despite national attention and well-accepted best practices, diabetic care, blood pressure and haemoglobin A1c (A1c) levels for patients with diabetes in our primary care setting were highly variable and below the Healthcare Effectiveness Data and Information Set (HEDIS) 75th percentile benchmark. From January 2015 to January 2016, 22% of patients with diabetes in our primary care setting had both blood pressure and A1c levels controlled and 23% had their annual diabetic care bundle completed, which includes A1c and blood pressure measurements, foot examination and nephropathy attention. Lack of standardised care algorithms, electronic health record documentation and education was identified. Lean Six Sigma methodologies were used to re-engineer the care that patients with diabetes receive. Key improvement initiatives focused on standardisation of accepted care practices through electronic templates, education and re-evaluation of patients to make 90-day, rapid cycle changes. Interventions were piloted in one primary care clinic then expanded to eight additional clinics. At the pilot site, the per cent of patients who completed the diabetic care bundle increased from 33% to 71% and the per cent of patients with diabetes with both A1c and blood pressure controlled increased from 31% to 43% (two-proportion test, p<0.01) postintervention. On rollout to eight additional clinics, the per cent of patients who completed the diabetic care bundle increased from 23% to 67% and the per cent of patients with diabetes with both their A1c and their blood pressure controlled increased from 22% to 41% (two proportion test, p<0.01). After the interventions, nephropathy attention, A1c and blood pressure metrics exceeded HEDIS 75th percentile. Standardisation of accepted care practices for patients with diabetes improved compliance with diabetic care bundle completion and patient outcomes in the primary care setting. PMID- 30397657 TI - Challenges in reducing TIA clinic waiting times from 9 to 3 days in an acute Welsh hospital. AB - A patient impact project which successfully reduced the transient ischaemic attack (TIA) clinic waiting time from 9 to 3 days in an acute Welsh hospital, revealing the challenges faced and how alternative thinking and team work improved care given to our service users. Evaluating current situation, careful planning with multiple brainstorming meetings, 4 N chart and driver diagram with change ideas laid the foundation for this service improvement. Run charts, statistical process control and Pareto charts helped to identify the issues that are hindering the progress, which when rectified, reduced the clinic waiting times. Avoiding clinic cancellations by cross covering TIA clinics with mutual agreement among consultants and redeployment of ward staff to support clinics resulted in a positive impact to the patients. The average waiting time to see a patient in TIA clinic dropped from 9 days to just 3 days as a result of this, reflecting the hard-working and proactive nature of a team following a collaborative leadership journey. The service improvement initiative for 'avoiding clinic cancellations' was implemented in January 2017 and has reduced our waiting times by three times. Repeat analysis by six monthly Plan Do Study Act cycles revealed that this improvement is sustained. PMID- 30397658 TI - Can we improve the prescribing and delivery of oxygen on a respiratory ward in accordance with new British Thoracic Society oxygen guidelines? AB - The British Thoracic Society recommends oxygen delivery to achieve target oxygen saturation range between 94% and 98% for medically unwell adult patients, and 88% to 92% in patients at risk of hypercapnic respiratory failure. Interviews with our medical and nursing staff suggested that oxygen was sometimes being given to patients without a valid order and there was a failure to titrate oxygen to the stated oxygen saturation range. Our aim was to improve appropriate oxygen delivery to 90% of our patients on a 30-bedded respiratory ward within 3 months. We identified several key steps to safe oxygen delivery on our ward. These include the recording of target oxygen saturation range, the prescribing of an oxygen order on drug chart and the correct bedside delivery of oxygen to the patient. To help improve compliance of these key steps, the following plan-do study-act (PDSA) interventions were undertaken: (1) Educational announcements at board rounds. (2) A communication oxygen poster. (3) Highlighting improvement progress to teams via email. (4) Pharmacist review of inpatient drug chart. (5) Display of target oxygen saturation range at patient bedside. At baseline, only 50% of drug charts had a recorded oxygen order and 60% of drug charts had a set target oxygen saturation range. Following PDSA interventions, both measures improved to 93%. Our main outcome measure of appropriate oxygen delivery to the patient improved from a baseline of 20% to 80% on completion. Our quality improvement programme has shown simple interventions can improve oxygen prescribing and appropriate delivery of oxygen to the patient. The most effective PDSA interventions were sharing our measurements via email and displaying target oxygen saturation ranges by the patient bedside. We aim to provide future oxygen educational sessions at induction to our staff and scale our quality improvement programme to other wards including our acute medical unit. PMID- 30397659 TI - Sustainable approach to reducing unnecessary combined biochemistry tests on a paediatric cardiology ward. AB - We describe a quality improvement project (QIP) designed to reduce unnecessary biochemistry samples requested on a paediatric cardiology ward in Great Ormond Street Hospital. Prior to the intervention biochemistry tests were requested on a daily basis by nursing and junior doctor staff at an annual cost of around L27 000 for the ward. The lead author observed that for the majority the true indication for these biochemistry tests was for the purpose of monitoring renal function and plasma electrolytes. However, during a diagnostic analysis trying to understand the behaviours around ordering tests it appeared that a broader profile and more expensive combined test set was being requested that included unnecessary liver and bone profile analyses. A driver diagram identified three areas to target in order to rationalise blood test requests: (1) a critical understanding of the purpose of the test by those requesting the tests; (2) effective communication between professionals; and (3) improved utilisation of the computer system. An education-based QIP was initiated with the aim of reducing requests of these costly, unnecessary combined biochemical tests by half, by supporting and encouraging staff to switch to a simpler renal function assay. The project was designed to be engaging and fun and invited clinical teams to consider the cost of wasted resources in terms of the financial implications for the hospital, and in terms of the wider environmental impact of wasted resources illustrated in terms of estimated carbon dioxide use. This perhaps unusual approach of encouraging an awareness of both financial and environmental cost led to a sustained reduction in the ordering of expensive combined biochemical tests, saving an estimated L11 338 (or 13.5%) on biochemistry tests and around 17.8 tonnes of carbon dioxide across a 32-month follow-up period. PMID- 30397660 TI - Improving communication of patient issues on transfer out of intensive care. AB - The written medical handover document is frequently poor in quality and highly variable which raises concerns about patient safety. Intensive care unit (ICU) patients have complex medical and social issues which increases the risk of errors during ongoing hospital treatment. Our project team of four doctors and two nurses aimed to improve the documentation of patient problems as they leave the ICU. A literature review and process mapping of both medical and nursing transfer documentation helped in understanding the current process. Current problems (CP) were defined as any patient issues which require ongoing thought, management or follow-up. Our progress was tracked using a measure of the number of CPs listed in the free-text field titled 'Current Problems' in 50 medical transfer documents. This was graphed on a control chart showing a process in statistical control. Means and control limits were recalculated whenever a process shift occurred. There was no relationship between the number of CPs listed and length of ICU stay, age of patient, or severity of illness on presentation (Acute Physiologic Assessment and Chronic Health Evaluation II score). An inter-relationship graph identified the key drivers which were amenable to change: (1) the doctors completing the clinical summary at the time of discharge did not have all the information readily available to them and (2) the doctors were uncertain of the types of problem which should be communicated. Improvements were designed and trialled using Plan-Do-Study-Act cycles to address these two key drivers. At baseline, the average number of CPs per patient was 1.8. After implementation of a paper problem list at the patient bedside, with supporting education, the average increased to 2.7. This was further improved by the addition of a checklist of common patient problems. This increased the average to 3.85. These improvements were permanently implemented and ongoing audits have shown sustained improvement using statistical process control methods. PMID- 30397661 TI - Point-of-care C-reactive protein testing to optimise antibiotic use in a primary care urgent care centre setting. PMID- 30397662 TI - Faecal immunochemical testing implementation to increase colorectal cancer screening in primary care. AB - Colorectal cancer (CRC) is the second leading cause of cancer death in USA, and CRC screening remains suboptimal. The aim of this quality improvement was to increase CRC screening in the internal medicine clinic (IMC) patients, between the ages of 50-75 years, from a baseline rate of 50%-70% over 12 months with the introduction of faecal immunochemical test (FIT) testing. We used the Plan-Do Study-Act (PDSA) method and performed a root cause analysis to identify barriers to acceptance of CRC screening. The quality improvement team created a driver diagram to identify and prioritise change ideas. We developed a process flow map to optimise opportunities to improve CRC screening. We performed eight PDSA cycles. The major components of interventions included: (1) leveraging health information technology; (2) optimising team work, (3) education to patient, physicians and IMC staff, (4) use of patient navigator for tracking FIT completion and (5) interactive workshops for the staff and physicians to learn motivational interview techniques. The outcome measure included CRC screening rates with either FIT or colonoscopy. The process measures included FIT order and completion rates. Data were analysed using a statistical process control and run charts. Four hundred and seven patients visiting the IMC were offered FIT, and 252 (62%) completed the test. Twenty-two (8.7%) of patients were FIT positive, 14 of those (63.6%) underwent a subsequent diagnostic colonoscopy. We achieved 75% CRC screening with FIT or colonoscopy within 12 months and exceeded our goal. Successful strategies included engaging the leadership, the front-line staff and a highly effective multidisciplinary team. For average-risk patients, FIT was the preferred method of screening. We were able to sustain a CRC screening rate of 75% during the 6-month postproject period. Sustainable annual FIT is required for successful CRC screening. PMID- 30397663 TI - Pain, agitation and delirium assessment and management in a community medical surgical ICU: results from a prospective observational study and nurse survey. AB - Background: Delirium is a common manifestation in the intensive care unit (ICU) that is associated with increased mortality and morbidity. Guidelines suggested appropriate management of pain, agitation and delirium (PAD) is crucial in improving patient outcomes. However, the practice of PAD assessment and management in community hospitals is unclear and the mechanisms contributing to the potential care gap are unknown. Objectives: This quality improvement initiative aimed to review the practice of PAD assessment and management in a community medical-surgical ICU (MSICU) and to explore the community MSICU nurses' perceived comfort and satisfaction with PAD management in order to understand the mechanisms of the observed care gap and to inform subsequent quality improvement interventions. Methods: We prospectively collected basic demographic data, clinical information and daily data on PAD process measures including PAD assessment and target Richmond Agitation-Sedation Scale (RASS) score ordered by intensivists on all patients admitted to a community MSICU for >24 hours over a 20-week period. All ICU nurses in the same community MSICU were invited to participate in an anonymous survey. Results: We collected data on a total of 1101 patient-days (PD). 653 PD (59%), 861 PD (78%) and 439 PD (39%) had PAD assessment performed, respectively. Target RASS was ordered by the intensivists on 515 PD (47%). Our nurse survey revealed that 88%, 85% and 41% of nurses were comfortable with PAD assessment, respectively. Conclusions: Delirium assessment was not routinely performed. This is partly explained by the discomfort nurses felt towards conducting delirium assessment. Our results suggested that improvement in nurse comfort with delirium assessment and management is needed in the community MSICU setting. PMID- 30397664 TI - A comparison of hospital-acquired pressure injuries in intensive care and non intensive care units: a multifaceted quality improvement initiative. AB - Hospital-acquired pressure injuries (HAPI) are a significant cause of morbidity and mortality, and represent a major health concern worldwide. Patients suffering from HAPI report a poor quality of life on several dimensions of health. Moreover, HAPI is reported to lengthen in-hospital stay in the acute setting, posing significant healthcare resource utilisations and costs. Given the clinical and economic burden of HAPI, recent best practice guidelines provide recommendations to reduce the prevalence of pressure injuries. Humber River Hospital (HRH), a large community hospital in Toronto, Canada, has a daily census of approximately 500 patients. The aim of this project was to reduce the prevalence of HAPI within the intensive care unit (ICU) and non-ICU setting at HRH within a 1-year period. Using the International Pressure Injury/Ulcer Prevalence (IPUP) Survey we established a baseline prevalence of HAPI of 27.6% (n=315) for non-ICU and 30% for ICU (n=33) patients at our institution in 2015. Using the Plan-Do-Study-Act (PDSA) method for quality improvement, we implemented a multifaceted approach aimed at improving equipment, digital documentation and education on risk assessment, prevention and treatment strategies. Over multiple PDSA cycles, our prevalence of HAPI reduced to 16% for non-ICU patients with no changes to the HAPI prevalence in ICU patients in 2016. Sustainability continues with HAPI prevalence currently at 10% in 2017 for non-ICU patients, which outperforms the Canadian prevalence (13.7%) by census size for 2017. However, the prevalence of HAPI in the ICU increased to 45% in 2017 despite multiple quality improvement initiatives, suggesting critically ill patients represent a unique challenge for reducing HAPI for these patients at our institution. PMID- 30397665 TI - STI initiative: Improving testing for sexually transmitted infections in women. AB - Canadian urgent care and walk-in medical clinics provide health care for a population that may be poorly covered by traditional health care structures. Despite evidence suggesting that women with urinary complaints experience a high incidence of sexually transmitted infections (STIs), this population may be under tested in this particular setting. The aim of this quality improvement initiative was to increase STI testing in women presenting with GU complaints. Implementation of an opt-out method of STI testing for women ages 16 and older was introduced at three walk-in clinics. Women presenting with GU complaints were given the opportunity to provide samples for both conventional urine culture and nucleic acid amplification testing (NAAT) for non-viral STIs. Patients received treatment according to standard of care and public health was notified as per local regulations. Testing rate and STI incidence was tracked via clinic electronic medical records (EMRs). Overall results were tracked using run charts and compared to historical data for the year prior to the start of the project. Over a 1 year period prior to this intervention, only 65 STI tests were performed in over 1100 GU complaints (5.5%). Six STIs were identified during this time. During the 36-week project period, testing increased to 45% of the patient population (320/707). The STI detected incidence increased from 0.51% to 1.4% in all women, and from 0.84% to 3.4% in women aged 16-29 years. An opt-out method was an effective intervention for increasing STI testing within the walk-in clinic setting. With optimisation, significant increases in testing rates can be obtained without substantially increasing clinic workload and at no economic cost to the clinic. As expected, detected incidence rates of STIs were higher than the recognised population prevalence. PMID- 30397666 TI - High body mass index in children with sickle cell disease: a retrospective single centre audit. AB - Objective: To assess the prevalence of high body mass index (BMI) in children with sickle cell disease and assess correlation between BMI and disease severity. Design: Retrospective chart review followed by statistical analysis. Setting: A single tertiary paediatric clinic in inner city London. Patients: All patients with sickle cell disease, including homozygous haemoglobin (HbSS) and compound heterozygous Hb (HbSC), age 2-18 years receiving clinical care at the centre, were included in the study. Interventions: Height and weight measurements, steady state laboratory blood tests, hospital admission rates, adjunct therapy such as hydroxycarbamide or blood transfusions and obstructive sleep apnoea (OSA) data were obtained from the hospital electronic patient records. Main outcome measures: To study the prevalence of high BMI and to identify any correlation between BMI and disease severity. Results: 385 patients were included. 64 children (17%) were overweight or obese, of which a significantly higher number of children with HbSC were obese or overweight (23 out of 91, 25%) compared with those with HbSS (36 out of 273, 13%), p<=0.001. No correlation was found between high BMI and presence of OSA, and markers of disease severity such as admission rates, fetal haemoglobin or lactate dehydrogenase levels. Conclusions: High BMI did not correlate with disease severity in this cohort of patients with sickle cell disease. Obesity was more prevalent in females and those with HbSC. Further prospective studies are needed to determine long-term effects of BMI in disease severity and outcome. PMID- 30397667 TI - New anthropometric classification scheme of preoperative nutritional status in children: a retrospective observational cohort study. AB - Objective: WHO uses anthropometric classification scheme of childhood acute and chronic malnutrition based on low body mass index (BMI) ('wasting') and height for age ('stunting'), respectively. The goal of this study was to describe a novel two-axis nutritional classification scheme to (1) characterise nutritional profiles in children undergoing abdominal surgery and (2) characterise relationships between preoperative nutritional status and postoperative morbidity. Design: This was a retrospective observational cohort study. Setting: The setting was 50 hospitals caring for children in North America that participated in the American College of Surgeons National Surgical Quality Improvement Program Paediatric from 2011 to 2013. Participants: Children >28 days who underwent major abdominal operations were identified. Interventions/main predictor: The cohort of children was divided into five nutritional profile groups based on both BMI and height for age Z-scores: (1) underweight/short, (2) underweight/tall, (3) overweight/short, (4) overweight/tall and (5) non-outliers (controls). Main outcome measures: Multiple variable logistic regressions were used to quantify the association between 30-day morbidity and nutritional profile groups while adjusting for procedure case mix, age and American Society of Anaesthesiologists class. Results: A total of 39 520 cases distributed as follows: underweight/short (656, 2.2%); underweight/tall (252, 0.8%); overweight/short (733, 2.4%) and overweight/tall (1534, 5.1%). Regression analyses revealed increased adjusted odds of composite morbidity (35%) and reintervention events (75%) in the underweight/short group, while overweight/short patients had increased adjusted odds of composite morbidity and healthcare-associated infections (43%), and reintervention events (79%) compared with controls. Conclusion: Stratification of preoperative nutritional status using a scheme incorporating both BMI and height for age is feasible. Further research is needed to validate this nutritional risk classification scheme for other surgical procedures in children. PMID- 30397668 TI - Maternal attitude towards delaying puberty in girls with and without a disability: a questionnaire-based study from the United Arab Emirates. AB - Background: Parental anxiety about the impact of puberty/menses, particularly in girls with severe disability leads to seeking therapeutic pubertal suppression. We aim to explore maternal attitudes and reasons for seeking pubertal suppression. Methods: Mothers of girls receiving gonadotropin -releasing hormone analogue therapy in Mafraq hospital, Abu Dhabi were enrolled in the study. A semistructured interview was conducted to ascertain possible reasons for delaying puberty. The study group was divided into girls with a disability with central precocious puberty (CPP) or normal puberty and girls without a disability presenting with CPP. Results: 42 mother-daughter pairs were enrolled and divided into two groups; group A: 15 girls with CPP with no disability; group B: 27 girls with disability (10 had CPP (group B1) and 17 had normal pubertal timing (group B2)). Mothers in group A aimed to delay puberty, while in group B, 13 (48%) mothers desired to halt puberty and 7 (26%) requested permanent surgical intervention. Fear of short stature (15, 100%), inability to cope psychologically (10, 67%) and fear of peer rejection (9, 60%) were the main concerns in group A. In group B, mothers were concerned about menstrual hygiene management (25, 92.5%), fear of child abuse or unwanted pregnancy (15, 55%) and fear of inability to express pain/discomfort with menstruation (8, 30%). Conclusion: Mothers of girls with a disability commonly seek medical help to delay/halt puberty due to concerns about menstrual hygiene. Short final height was the main concern for girls without a disability. Culture and religion play an important role in puberty management in girls with a disability. PMID- 30397670 TI - Spirometry monitoring in asthmatic children in Lombardy Region, Italy. AB - Objectives: To evaluate the diagnostic and therapeutic approaches in a cohort of asthmatic children before and after starting drug therapy. Methods: Data were retrieved from administrative databases of the Lombardy Region. The study population was composed of 78 184 children born in the Lombardy Region in 2002 and followed until their 10th birthday.Children with at least one antiasthmatic drug prescription per year (with the exclusion of nebulised suspension/solution formulations) in 2 consecutive years and at least one antiasthmatic drug prescription after the fifth birthday were identified as potential asthmatics (PA).Each PA was monitored for a period starting from 12 months before and ending 24 months after the first prescription (index prescription, IP). During the monitoring period antiasthmatic drug prescriptions were analysed, as well as spirometry and/or specialist visits. Results: A total of 59 975 children (76.7%) received >=1 prescription of antiasthmatic drugs in their first 10 years of life, and 4475 (5.7%) were identified as PAs. In all, 24% of PAs started with short acting beta2-agonists (SABA), 23% with inhaled corticosteroids (ICS) and 20% with SABA+ICS.A total of 33% of PAs had at least one prescription for specialist visit/spirometry: 11% before and 28% after the IP. The factors associated with a greater likelihood of receiving visit/spirometry prescriptions were local health unit of residence, age and high use of asthma drugs. Conclusions: Despite international guideline recommendations, spirometry monitoring is still underused in asthmatic children, even in subjects who initiated pharmacological treatment and therefore need an airway function evaluation. Moreover, the choice of drug therapy appears not always rational, since one out of four children were commenced on ICS as monotherapy. PMID- 30397669 TI - Serum concentrations of endothelial cell adhesion molecules and their shedding enzymes and early onset sepsis in newborns in Suriname. AB - Background: Early onset sepsis (EOS) is defined as onset of sepsis within 72 hours after birth. Leucocyte-endothelial interactions play a pivotal part in EOS pathophysiology. Endothelial cell adhesion molecules (CAMs) orchestrate these interactions and their soluble isoforms (sCAMs) are released into the vasculature by enzymes called sheddases. Purpose: This study was undertaken to explore further the pathophysiology of EOS and to investigate the potential of sCAM and their sheddases as potential biomarkers for EOS. Methods: Stored serum aliquots were used from 71 Surinamese newborns suspected of EOS and 20 healthy newborns from an earlier study. Serum had been collected within 72 hours after birth and six (8.6%) newborns had a positive blood culture with gram-negative pathogens. Concentrations of sCAMs sP-selectin, sE-selectin, soluble vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and platelet and endothelial cell adhesion molecule-1, sheddases matrix metalloproteinase-9 (MMP-9) and neutrophil elastase (NE) and sheddase antagonist tissue-inhibitor of metalloproteinases-1 (TIMP-1) were measured simultaneously with Luminex and ELISA. Results: MMP-9 and TIMP-1 levels were measured in serum of n=91 newborns and sCAMs and NE levels in serum of n=80 newborns, respectively. We found no differences in median concentrations of sCAMs, MMP-9 and TIMP-1 or NE between blood culture positive EOS, blood culture negative EOS and control groups at start of antibiotic treatment. Conclusions: Our data indicate that serum concentrations of sCAMs and their sheddases have no clinical utility as biomarkers for EOS. Trial registration number: NCT02486783. Results. PMID- 30397671 TI - Assessment of the performance of blood glucose monitoring systems for monitoring dysglycaemia in neonatal patients. AB - Objective: To validate a three-step protocol that assesses the clinical risk associated with using blood glucose monitoring systems (BGMS) in neonates for the management of dysglycaemia. Method: The three-step validation approach included confirmation of the accuracy of the reference method using National Institute of Standards and Technology (NIST) glucose standards, assessment of analytical risk performed on whole blood collected from paediatric patients routinely tested for glucose and a clinical risk assessment performed using heel stick capillary samples collected from 147 new-born babies and neonates admitted to intensive care. BGMS glucose measurements were compared with the NIST aligned laboratory reference method. Results: The accuracy of the laboratory reference method was confirmed with the NIST standards. Specificity studies demonstrated that the accuracy of one of the BGMS was affected, particularly, in the hypoglycaemic range, by known interference factors including haematocrit, ascorbic acid, lactose, galactose, N-acetylcysteine and glutathione. The accuracy of the other BGMS was unaffected. The clinical performance of this BGMS in neonates met the system accuracy criteria of Clinical and Laboratory Standards Institute (CLSI) POCT 12-A3 standard for evaluating hospital BGMS with 95.1% of glucose measurements within+/-0.67 mmol/L for samples <=5.55 mmol/L and 95.6% within+/ 12.5% for samples>5.55 mmol/L. Conclusions: This three-step validation protocol provides a challenging approach for determining the accuracy and reliability of BGMS for managing dysglycaemia in neonates. StatStrip BGMS achieved analytical and clinical performance criteria confirming its suitability for use in neonates. We advocate that this validation approach should be considered for performance evaluations of both BGMS and continuous glucose monitoring systems going forward. PMID- 30397672 TI - Parent, patient and clinician perceptions of outcomes during and following neonatal care: a systematic review of qualitative research. AB - Objective: Multiple outcomes can be measured in infants that receive neonatal care. It is unknown whether outcomes of importance to parents and patients differ from those of health professionals. Our objective was to systematically map neonatal care outcomes discussed in qualitative research by patients, parents and healthcare professionals and test whether the frequency with which outcomes are discussed differs between groups. Design: Systematic review of qualitative literature. The following databases were searched: Medline, CINAHL, EMBASE, PsycINFO and ASSIA from 1997 to 2017. Publications describing qualitative data relating to neonatal care outcomes, reported by former patients, parents or healthcare professionals, were included. Narrative text was analysed and outcomes grouped thematically by organ system. Permutation testing was applied to assess an association between the outcomes identified and stakeholder group. Results: Sixty-two papers containing the views of over 4100 stakeholders were identified; 146 discrete outcomes were discussed; 58 outcomes related to organ systems and 88 to other more global domains. Permutation testing provides evidence that parents, former patients and health professionals reported outcomes with different frequencies (p=0.037). Conclusions: Parents, patients and health professionals focus on different outcomes when discussing their experience of neonatal care. A wide range of neonatal care outcomes are reported in qualitative research; many are global outcomes relating to the overall status of the infant. The views of former patients and parents should be taken into consideration when designing research; the development of a core outcomes set for neonatal research will facilitate this. PMID- 30397674 TI - Do Tuscan people adhere to meningococcal C vaccination during an emergency campaign? AB - Objectives: Tuscany region (Italy) recorded a rise in the number of meningococcal disease cases between January 2015 and February 2016, (52 cases) compared to 2014 (16 cases). The aim of this study was to describe the emergency meningococcal C (MenC) vaccination programme in Tuscany and the population's adherence to the activities performed in the Local Health Unit (LHU) of Florence. Methods: The MenC vaccination programme and the planning of the prevention and communication activities were analysed in the LHU of Florence. As an indicator of population's adherence, the vaccination coverage (VC) during the emergency campaign was investigated and adverse drug reactions (ADR) surveillance was reported. Results: The communication campaign included a dedicated toll-free telephone number, press releases (newspapers, radio, television, websites), and informative letters addressed to mayors, secondary schools, and sports associations. Citizens aged 11 20 years were the primary target of the campaign. Due to the high incidence of cases among older people, the vaccination was extended to subjects over 45 years. The population's adherence to the vaccination campaign was satisfactory: VC reached 47.1% for the primary target. The ADR reporting rate (3.1/10,000) on meningococcal vaccine in our study confirmed the safety of the vaccination. Conclusions: In 2017, only 10 cases of invasive meningococcal diseases (IMD) were reported, suggesting the effectiveness of the immunization campaign. Similar VC during emergency MenC vaccination programmes have been reached in other Italian regions and other EU countries, too. The achievement of greater vaccination coverage is restricted by a sentiment of hesitancy towards vaccines among the general population. PMID- 30397673 TI - Prevention of pertussis: from clinical trials to Real World Evidence. AB - Pertussis, a highly contagious infective disease caused by Bordetella pertussis, was in the past very common among newborns and children, causing significant medical, social and economic issues burden, also due to frequent need of hospitalization and high mortality. Following the introduction of vaccines against pertussis, the burden of the disease dramatically decreased, although nowadays, this disease it is still the most widespread among the vaccine preventable ones. First vaccine formulations were composed with whole cell antigen of Bordetella pertussis and were followed by formulations with acellular antigens (PT, FHA, PRN, FIM), that showed to have similar efficacy and less reactogenicity. In particular, all the acellular vaccines, regardless the number of antigenic component included, demonstrated good immunogenicity in clinical trials and high effectiveness in real world evidence studies. Nevertheless, in the recent years it has been notified an increasing number of cases of pertussis. The most recent evidence demonstrated that for an effective control and prevention of pertussis it is necessary to strengthen vaccination coverage among the whole population, providing primary vaccination to newborns and booster in infancy, adolescence and adulthood every 10 years. Finally, vaccination of women at the third trimester of every pregnancy is the most effective intervention to protect the newborn from pertussis in his first months of life, before developing a protective response after the primary vaccination. PMID- 30397675 TI - HPV vaccine and autoimmune diseases: systematic review and meta-analysis of the literature. AB - Background: In the literature conflicting opinions are detectable on the onset of adverse events as autoimmune disease post HPV vaccine and often case reports describes the onset of one of these events, but don't emerge a clear relationship and we don't have data to support it. Methods: We carried out a systematic review to identify all scientific publications dealing with the correlation between vaccine anti-papillomavirus and new onset of autoimmune diseases. We searched the main scientific databases (PubMed, Sciverse Scopus, Web of knowledge and Cochrane Central Register of Controlled Clinical Trials) for the following search terms: "vaccine"; "anti-papillomavirus"; "autoimmune"; "disease"; "disorder". To evaluate the safety of HPV vaccines, the dichotomous data on the number of subjects experiencing an autoimmune disorder in the study vaccine group and the placebo group were extracted from each study with subsequent determination of the risk ratios and their 95% confidence intervals. We combined data statistically using a random effects model. Results: We conduct a meta-analysis on six studies on bivalent and quadrivalent HPV vaccine. The total number of subjects included in the meta-analysis comprised 243,289 in the vaccine group and 248,820 in control groups. Four of the six trials had a Jadad score of 3 or 4 indicating an adequate trial quality. The most frequent autoimmune disease observed across the six studies were musculoskeletal,CNS conditions and endocrinological conditions . The results of the meta-analysis demonstrated no correlation between autoimmune disorders and HPV vaccines (pooled OR 1.038, 95% CI 0.689-1.562). Conclusions: No correlation was identified for bivalent and quadrivalent HPV vaccines. It's therefore essential to correctly inform the general population in order to try to increase both Italian and international vaccination coverage. PMID- 30397676 TI - Health and safety of pesticide applicators in a high income agricultural setting: a knowledge, attitude, practice, and toxicity study from North-Eastern Italy. AB - Background: We assessed knowledge, attitudes and practices regarding pesticide handling and related health problems among pesticide applicators (PAs) from the Autonomous Province of Trento, Italy. Methods: A cross-sectional questionnaire based study was performed in spring 2016, involving 260 PAs. Logistic regression analyses were used to identify factors associated with a safer use of pesticides. Results: The mean age of participants was 48.8 +/- 13.2 years. 89.2% were males. Use of personal protective equipment (PPE) was diffuse, particularly gloves (92.7%), face mask (91.2%), and post-spraying personal hygiene practices were extensively applied. Overall, 43.5% had experienced pesticide-related symptoms especially in subjects misusing PPE, but also for avoiding hygienic procedures. Knowledge about pesticides was a significant predictor for frequency of symptoms. Conclusions: As a better knowledge of pesticide-related risks was a significant predictor to reduce symptoms, our results stress that improving awareness and promoting safe use of pesticide may improve the health of PAs. PMID- 30397677 TI - Isolation of Mycobacterium tuberculosis from livestock workers and implications for zooanthroponotic transmission in Ibadan, South-western Nigeria. AB - Introduction: Tuberculosis (TB) remains a public health problem in sub-Saharan Africa coupled with dearth of information about the disease among livestock workers at risk of infection. We determined the prevalence of pulmonary TB infection and factors associated with its occurrence among livestock workers in south-western Nigeria. Methods: A cross-sectional study was conducted using active case-finding among livestock workers with sub-clinical pulmonary TB between August 2014 and March 2015. Sputum samples were cultured and subjected to a two-step multiplex-PCR technique based on genus-typing and genomic regions-of difference. Interviewer-administered questionnaire was utilized in assessing worker's TB related knowledge and practices. Data were analysed using STATA 12. Results: Overall, 206 livestock workers (traders = 136; butchers = 70) were screened; 5.1% (7/136) of the traders and 7.1% (5/70) of the butchers had positive mycobacterial cultures. Molecular techniques identified one Mycobacterium tuberculosis with six non-tuberculous mycobacteria (NTM) from the traders and four M. tuberculosis with one NTM from the butchers.Participants within the age range of 50 years and above were at higher risk of being infected with TB (OR = 7.7; 95%CI:1.7-35.6) and majority had poor knowledge and practices regarding TB. Conclusions: We confirmed M. tuberculosis as the cause of pulmonary TB among the livestock workers, with implications for zooanthroponotic transmission of the disease along the human-animal ecosystem interface in Nigeria. PMID- 30397678 TI - Availability and utilization of sanitation facilities in Enderta district, Tigray, Ethiopia. AB - Introduction: Despite concerted efforts by governmental and non-governmental organizations, water and adequate sanitation still remain a challenge worldwide. Therefore, this study assessed the availability and utilization of sanitation facilities in Enderta district of Tigray, Ethiopia. Methods: A cross-sectional study was conducted in May 2016. An interview and observation were conducted in a total of 450 households. An interviewer administered questionnaire and observation checklist were used to collect the data. Multivariable logistic regression was done to identify the predictors of availability and utilization of latrine, hand washing, and drinking water. Results: Out of 450 households, only 68.4% had latrine of which only 21.4% had hand washing facility near the toilet. Likewise, only 9.3% washed their hand after toilet. However, all households had access to improved water source. In this study, proper utilization of latrine, hand washing, and water facilities was observed in 53%, 42.4% and 36.2% of the study households, respectively. The family size and getting sanitation information from health care providers, health extension workers, and health development army had a positive effect on availability and utilization. Conclusions: Though Community-Led total sanitation and hygiene approach has been implemented in the study area, the availability and proper utilization of latrine, and hand washing are still low. Only few households used drinking water properly. The education or information on hygienic practices found to affect the availability and utilization of the sanitation facilities positively. Therefore, strengthening the health extension workers and health development army to provide sustainable education and health information is needed. PMID- 30397679 TI - A study on the microbial quality of sealed products for feminine hygiene. AB - Introduction: Sanitary tampons have been in existence for over 60 years. Their use may present certain health risks, potentially associated with an abnormal change of microbial flora in the vagina (e.g., toxic shock syndrome). Tampon production and marketing are regulated differently in different countries. In Australia, Canada and the USA, tampons are classified as Class-II medical devices and their marketing requires pre-clinical and clinical studies, including microbiological trials. In Europe, tampons are considered consumer products and safety-related data are provided only if the manufacturer deems them to be useful. Sterility of these products is not requested by law; thus they may represent a potential vehicle for microorganisms. Due to the lack of data on microbial characteristics of tampons, an analytical investigation was carried out to characterize and quantify the microbial flora present on sealed tampons of various brands present on the market in Italy. Methods: Traditional cultural methods were used to characterize and quantify bacteria and fungi. Identification of colonies was performed with biochemical techniques. Results: Results showed low microbial concentrations in 93% of the positive samples. A rare presence of opportunistic pathogens was detected and a few samples (6%) were characterized by bacterial species of human origin. Conclusions: In the light of these data, the examined tampons were found to have good hygienic quality. Nevertheless, to minimize the microbial risks linked to the use of these products, strict hygienic rules during their production and manipulation have to be adopted. PMID- 30397680 TI - Lifestyles and discomfort in a sample of young Romanian students. AB - Introduction: The 40.3% of the Romanian youth population is at risk of poverty or social exclusion, and, in addition, the abuse of substances increases. It was interesting to evaluate the attitudes shared by pupils as well as their knowledge of these substances with a view to analyzing causes and types of risky behaviour in young people. Methods: This is an observational study on the harassment influence in the lifestyle of a sample of Craiova high-school students The Fagerstrom Test was applied to evaluate the degree of nicotine dependence, and the data processed to assess the Odds Ratio. Results: The sample was composed by 1,980 students with an average age of 17, of which 1,727 correctly responded to the questionnaire. The 37.4% of students admit to smoke, and the 67% to drink alcohol. The Fagerstrom test showed that the 68.2% of respondents are not highly addicted to smoke while the 31.8% was associated with a middle-to-high addiction level. A worrying weekly consumption of beer has been registered in the students. Regarding psychological distress caused by harassment a high Odds Ratio was recorded between the smokers and the drug users. Conclusions: More than half of students did not know about the health consequences of smoking, and the same result was recorded about the consumption of alcohol. A special attention should be done to the understanding of harassment problem in the young people. In fact, almost all the respondents declared to have suffered abuse and admits to use drug and cigarettes. PMID- 30397681 TI - Fast food consumption and overweight/obesity prevalence in students and its association with general and abdominal obesity. AB - Nowadays, the prevalence of both fast food consumption and overweight/obesity has been increased. This study aimed to estimate the prevalence of fast food consumption and to assess its association with abdominal and general obesity. In an analytical cross-sectional study, 300 students were selected randomly from two largest universities in Qom, center of Iran, studying in medical and basic sciences fields in 2015. Data collection was conducted by a modified version of NELSON's fast food questionnaire and anthropometric measures including Waist-Hip Ratio (WHR) and Body Mass Index (BMI). Chi-square, independent t-test, and multivariate logistic regression were used for statistical analysis. According to our results, 72.4% (67.4% in females vs 80.7% in males) had at least one type of fast food consumption in the recent month including sandwich 44.4%, pizza 39.7%, and fried chicken 13.8%, The obesity prevalence based on BMI and WHR was 21.3% (95% CI: 19.4, 23.2%) and 33.2% (95% CI: 0.7, 35.7), respectively. Fast food consumption was related to abdominal obesity as WHR (OR: 1.46, 95% CI: 1.11, 2.26), but was not related to general obesity as BMI (OR: 0.97, 95% CI: 0.63, 1.52). The prevalence of fast food consumption and obesity/overweight in Iranian student is high. Fast food consumption was associated with abdominal obesity based WHR, but did not related to general obesity based on BMI. PMID- 30397683 TI - Errata. AB - [This corrects the article on p. E128-E131 in vol. 59, PMID: 30083619.]. PMID- 30397682 TI - The never-ending story of the fight against tuberculosis: from Koch's bacillus to global control programs. AB - Tuberculosis (TB) is one of the oldest diseases known to affect humanity, and is still a major public health problem. It is caused by the bacillus Mycobacterium tuberculosis (MT), isolated in 1882 by Robert Koch. Until the 1950s, X rays were used as a cheap method of diagnostic screening together with the tuberculin skin sensitivity test. In the diagnosis and treatment of TB, an important role was also played by surgery. The late Nineteenth century saw the introduction of the tuberculosis sanatorium, which proved to be one of the first useful measures against TB. Subsequently, Albert Calmette and Camille Guerin used a non-virulent MT strain to produce a live attenuated vaccine. In the 1980s and 1990s, the incidence of tuberculosis surged as a major opportunistic infection in people with HIV infection and AIDS; for this reason, a combined strategy based on improving drug treatment, diagnostic instruments and prevention was needed. PMID- 30397684 TI - Mathematically universal and biologically consistent astrocytoma genotype encodes for transformation and predicts survival phenotype. AB - DNA alterations have been observed in astrocytoma for decades. A copy-number genotype predictive of a survival phenotype was only discovered by using the generalized singular value decomposition (GSVD) formulated as a comparative spectral decomposition. Here, we use the GSVD to compare whole-genome sequencing (WGS) profiles of patient-matched astrocytoma and normal DNA. First, the GSVD uncovers a genome-wide pattern of copy-number alterations, which is bounded by patterns recently uncovered by the GSVDs of microarray-profiled patient-matched glioblastoma (GBM) and, separately, lower-grade astrocytoma and normal genomes. Like the microarray patterns, the WGS pattern is correlated with an approximately one-year median survival time. By filling in gaps in the microarray patterns, the WGS pattern reveals that this biologically consistent genotype encodes for transformation via the Notch together with the Ras and Shh pathways. Second, like the GSVDs of the microarray profiles, the GSVD of the WGS profiles separates the tumor-exclusive pattern from normal copy-number variations and experimental inconsistencies. These include the WGS technology-specific effects of guaninecytosine content variations across the genomes that are correlated with experimental batches. Third, by identifying the biologically consistent phenotype among the WGS-profiled tumors, the GBM pattern proves to be a technology independent predictor of survival and response to chemotherapy and radiation, statistically better than the patient's age and tumor's grade, the best other indicators, and MGMT promoter methylation and IDH1 mutation. We conclude that by using the complex structure of the data, comparative spectral decompositions underlie a mathematically universal description of the genotype-phenotype relations in cancer that other methods miss. PMID- 30397686 TI - Identification of Aberrant Muscle Bellies in the Carpal Tunnel using Sonography. AB - Musculoskeletal sonography is being widely used for evaluation of structures within the carpal tunnel. While some anatomical variants, such as bifurcated median nerves and persistent median arteries, have been well documented, limited literature describes the sonographic appearance of aberrant muscle bellies within the carpal tunnel. Multiple examples of the sonographic appearance of flexor digitorum superficialis and lumbrical muscle bellies extending into the carpal tunnel are provided. Techniques for static image acquisition and analysis are discussed, and the use of dynamic imaging to confirm which specific muscle belly is involved is described. Knowledge of the potential presence of muscle bellies in these images and ability to identify these structures is vital to avoid misclassification or misdiagnosis as abnormal pathology. The case examples are situated among current published evidence regarding how such anomalies may be related to the development of pathologies, such as carpal tunnel syndrome. PMID- 30397685 TI - Differences in von Willebrand factor function in type 2A von Willebrand disease and left ventricular assist device-induced acquired von Willebrand syndrome. AB - Background: Patients with von Willebrand disease (VWD) type 2A or acquired von Willebrand syndrome (aVWS) as a consequence of implantation of left ventricular assist devices (LVAD) are both characterized by a loss of von Willebrand factor (VWF) function. Loss of VWF function is however more severe in VWD type 2A than in LVAD patients. Objectives: To compare VWF function in patients with VWD type 2A and LVAD-induced aVWS to highlight the differences in VWF activity and to stress the importance of VWF multimer analysis for correct diagnosis of aVWS in LVAD patients. Patients/Methods: Plasma samples from nine VWD type 2A, nine LVAD patients, and 20 healthy donors (HD) were analyzed for VWF function (VWF:CB/VWF:Ag and VWF:RCo/VWF:Ag) and loss of high molecular weight (HMW) VWF multimers. Results: A severely impaired VWF function was indeed confirmed in all VWD 2A patients. HMW VWF multimers were severely reduced compared to HD (0% [0, 12.29] vs 34.19% [31.68, 38.88] for HD, P < 0.001) and this loss was reflected by VWF:CB/VWF:Ag and VWF:RCo/VWF:Ag ratios <0.7. In contrast, VWF function was less affected in LVAD patients. Although HMW VWF multimers were reduced in all patients (20.31% [15.84, 21.71], vs 34.19% [31.68, 38.88] for HD, P < 0.001), six out of nine LVAD patients had normal VWF:CB/VWF:Ag or VWF:RCo/VWF:Ag ratios (>0.7). Conclusions: VWF:CB/VWF:Ag or VWF:RCo/VWF:Ag analysis allows detection of impaired VWF function in VWD type 2A but not always in LVAD-induced aVWS patients. In contrast, VWF multimeric analysis allows detection of the loss of HMW VWF multimers in both groups of patients. Hence, performing VWF multimer analysis is crucial to detect aVWS in LVAD patients. PMID- 30397687 TI - A hierarchical Food-Energy-Water Nexus (FEW-N) decision-making approach for Land Use Optimization. AB - The land use allocation problem is an important issue for a sustainable development. Land use optimization can have a profound influence on the provisions of interconnected elements that strongly rely on the same land resources, such as food, energy, and water. However, a major challenge in land use optimization arises from the multiple stakeholders and their differing, and often conflicting, objectives. Industries, agricultural producers and developers are mainly concerned with profits and costs, while government agents are concerned with a host of economic, environmental and sustainability factors. In this work, we developed a hierarchical FEW-N approach to tackle the problem of land use optimization and facilitate decision making to decrease the competition for resources and significantly contribute to the sustainable development of the land. We formulate the problem as a Stackelberg duopoly game, a sequential game with two players - a leader and a follower (Stackelberg, 2011). The government agents are treated as the leader (with the objective to minimize the competition between the FEW-N), and the agricultural producers and land developers as the followers (with the objective to maximize their profit). This formulation results into a bi-level mixed-integer programming problem that is solved using a novel bi level optimization algorithm through ARGONAUT. ARGONAUT is a hybrid optimization framework which is tailored to solve high- dimensional constrained grey-box optimization problems via connecting surrogate model identification and deterministic global optimization. Results show that our data-driven approach allows us to provide feasible solutions to complex bi-level problems, which are essentially very difficult to solve deterministically. PMID- 30397688 TI - Coarse-grained residue-based models of disordered protein condensates: utility and limitations of simple charge pattern parameters. AB - Biomolecular condensates undergirded by phase separations of proteins and nucleic acids serve crucial biological functions. To gain physical insights into their genetic basis, we study how liquid-liquid phase separation (LLPS) of intrinsically disordered proteins (IDPs) depends on their sequence charge patterns using a continuum Langevin chain model wherein each amino acid residue is represented by a single bead. Charge patterns are characterized by the "blockiness" measure kappa and the "sequence charge decoration" (SCD) parameter. Consistent with random phase approximation (RPA) theory and lattice simulations, LLPS propensity as characterized by critical temperature Tcr* increases with increasingly negative SCD for a set of sequences showing a positive correlation between kappa and -SCD. Relative to RPA, the simulated sequence-dependent variation in Tcr* is often-though not always-smaller, whereas the simulated critical volume fractions are higher. However, for a set of sequences exhibiting an anti-correlation between kappa and -SCD, the simulated Tcr*'s are quite insensitive to either parameter. Additionally, we find that blocky sequences that allow for strong electrostatic repulsion can lead to coexistence curves with upward concavity as stipulated by RPA, but the LLPS propensity of a strictly alternating charge sequence was likely overestimated by RPA and lattice models because interchain stabilization of this sequence requires spatial alignments that are difficult to achieve in real space. These results help delineate the utility and limitations of the charge pattern parameters and of RPA, pointing to further efforts necessary for rationalizing the newly observed subtleties. PMID- 30397690 TI - Protective effects of enhanced minor ginsenosides in Lactobacillus fermentum KP-3 fermented ginseng in mice fed a high fat diet. AB - Lactobacillus fermentum KP-3 was isolated from Korean pickle and used to ferment ginseng. The changes in the minor ginsenosides in the fermented ginseng were analyzed and the material was evaluated in high fat diet-fed mice. Total ginsenosides increased from 0.746 mg g-1 to 0.939 mg g-1 after fermentation, and the levels of minor ginsenosides (Rg2, Rg3, Rh1, Rh2, F2, and Ro) increased from 0.186 mg g-1 to 0.704 mg g-1. In an animal study, the serum TC and LDL levels in the HFD group were significantly higher than those of the control group. Compared with the HFD group, the probiotic-fermented ginseng significantly decreased the serum TC and LDL levels. In addition, the serum and liver ALT and AST levels were dramatically increased in the HFD group, but these increases were significantly inhibited by treatment with the probiotic-fermented ginseng. Furthermore, fermented ginseng reduced high fat diet-induced liver lipid accumulation. Overall, fermentation with L. fermentum KP-3 enhanced minor ginsenosides in ginseng and this probiotic-fermented ginseng ameliorated hyperlipidemia and liver injury induced by a high fat diet. PMID- 30397691 TI - Atomic layer deposition for membrane interface engineering. AB - In many applications, interfaces govern the performance of membranes. Structure, chemistry, electrostatics, and other properties of interfaces can dominate the selectivity, flux, fouling resistance, and other critical aspects of membrane functionality. Control over membrane interfacial properties, therefore, is a powerful means of tailoring performance. In this Minireview, we discuss the application of atomic layer deposition (ALD) and related techniques in the design of novel membrane interfaces. We discuss recent literature in which ALD is used to (1) modify the surface chemistry and interfacial properties of membranes, (2) tailor the pore sizes and separation characteristics of membranes, and (3) enable novel advanced functional membranes. PMID- 30397689 TI - Functional TCR T cell screening using single-cell droplet microfluidics. AB - Adoptive T cell transfer, in particular TCR T cell therapy, holds great promise for cancer immunotherapy with encouraging clinical results. However, finding the right TCR T cell clone is a tedious, time-consuming, and costly process. Thus, there is a critical need for single cell technologies to conduct fast and multiplexed functional analyses followed by recovery of the clone of interest. Here, we use droplet microfluidics for functional screening and real-time monitoring of single TCR T cell activation upon recognition of target tumor cells. Notably, our platform includes a tracking system for each clone as well as a sorting procedure with 100% specificity validated by downstream single cell reverse-transcription PCR and sequencing of TCR chains. Our TCR screening prototype will facilitate immunotherapeutic screening and development of T cell therapies. PMID- 30397692 TI - Solution-phase synthesized iron telluride nanostructures with controllable thermally triggered p-type to n-type transition. AB - The switchability of electrical properties has recently attracted much attention due to its potential applications in memory, sensors, and resistive switches. Here, a solution-phase synthesis of iron telluride nanostructures with reversible and reproducible switching behavior between p- and n-type conduction is demonstrated by a simple change of temperature without crystal structure changes. The transition temperature of FeTe2 to switch from p-type to n-type is strongly dependent on the original ratio of the precursors and sintering time. Further studies confirm that the switching is derived from the valence change effect and a proof-of-concept thermally triggered p-n diode has been demonstrated. PMID- 30397693 TI - Low wintertime pre-diagnostic vitamin D status is associated with an increased risk of internal malignancies in kidney transplant recipients. AB - Low serum 25-hydroxyvitamin D (25OHD) concentrations have been associated with increased cancer risk, but the relative importance of seasonality, i.e. high summer concentrations versus low winter concentrations, is unclear. We investigated this issue in a high risk group: kidney transplant recipients with known increased risk of cancer and low vitamin D statuses. We examined the relationship between registered concentrations of 25OHD binned by quarter and subsequent risk of internal malignancy or cutaneous squamous cell carcinoma in 1112 kidney transplant recipients. Hazard ratios for internal malignancies were significantly increased with lower pre-diagnostic 25OHD concentrations in the first quarter of the year (January-March); a 1.4 fold increase (95%CI 1.1;1.7) per 10 nmol L-1 decrease in 25OHD. Except for women in April-June (1.3 (1.01;1.7) per 10 nmol L-1 decrease) pre-diagnostic 25OHD concentrations in the other quarters were not statistically significantly associated with internal malignancies. Higher 25OHD concentrations tended to be associated with the development of cutaneous squamous cell carcinomas, independent of the time of the year. Our study indicates that low wintertime 25OHD concentrations are associated with an increased risk of internal malignancies and that transplant recipients may benefit from wintertime vitamin D supplementation. Our findings need further corroboration, but suggest that the lowest concentrations of vitamin D, which occur in winter, are important for the risk of internal malignancies. PMID- 30397694 TI - Three-dimensional supramolecular polymerization based on pillar[n]arenes (n = 5, 6) and halogen bonding interactions. AB - Herein we demonstrate that three dimensional supramolecular polymerization networks were constructed both in solution and in the solid state by the combination of pillar[5,6]arene-based host-guest complexes and 1,4 diiodotetrafluorobenzene involving halogen bonding systems. PMID- 30397695 TI - Guide column array: a versatile approach to aligning and patterning ceramic nanofibers. AB - Ceramic fibers have been manufactured via electrospinning for a variety of applications, including microelectronics, gas sensing, and memory systems. Preferentially ordering ceramic fibers as uniaxially aligned mats, as layered arrays, or as patterned structures has enormous potential to enhance current applications and add utility to electrospun ceramic fibers. Here, we developed a versatile guide column array-based method for manufacturing uniaxially aligned and patterned arrays of ceramic fibers. The guide column array was designed to control the electrospinning jet via electrostatic interactions between the electrified jet and the electrodes, resulting in fibers that preferentially oriented during deposition. A relationship between the ceramic precursor solution conductivity was correlated to the optimal operating voltage for the realization of aligned ceramic nanofibers using the guide column array. PMID- 30397696 TI - Cross-linked Ni(OH)2/CuCo2S4/Ni networks as binder-free electrodes for high performance supercapatteries. AB - The heterogeneous Ni(OH)2/CuCo2S4/Ni electrode is constructed by appropriately adjusting the time-dependent hydrothermal and electrodeposition process. A hybrid device exhibits 39.7 W h kg-1 of specific energy and 365.3 W kg-1 of specific power, with a good cycling stability of 88% capacity retention after 5000 cycles at 6 A g-1. PMID- 30397697 TI - A multiple target chemosensor for the sequential fluorescence detection of Zn2+ and S2- and the colorimetric detection of Fe3+/2+ in aqueous media and living cells. AB - A novel multiple target sensor, (E)-5-((4-(diethylamino)-2 hydroxybenzyldene)amino)-1H-imidazole-4-carboxamide (DHIC), was synthesized for fluorescence detection of Zn2+ and S2- and colorimetric detection of Fe3+/2+ in aqueous media. DHIC can operate as a turn "on-off" sequential fluorescent sensor for Zn2+ and S2-. Detection limits (1.59 MUM and 8.03 MUM) for Zn2+ and S2- are below the WHO standards (76.0 MUM and 14.7 MUM). The DHIC-Zn2+ complex could be reversibly reused with ethylenediaminetetraacetic acid. Importantly, DHIC could image sequentially Zn2+ and S2- in living cells. Moreover, DHIC displayed a discriminatory color change from pale yellow to orange yellow to Fe3+/2+. The detection limit of DHIC for Fe3+/2+ (0.73 MUM and 1.11 MUM) is far below the EPA drinking water standard (5.37 MUM). The sensor DHIC could be applied to analyze Fe3+ in real samples. PMID- 30397698 TI - Electrokinetic flow of an aqueous electrolyte in amorphous silica nanotubes. AB - We study the pressure-driven flow of aqueous NaCl in amorphous silica nanotubes using nonequilibrium molecular dynamics simulations featuring both polarizable and non-polarizable molecular models. Different pressures, electrolyte concentrations and pore sizes are examined. Our results indicate a flow that deviates considerably from the predictions of Poiseuille fluid mechanics. Due to preferential adsorption of the different ionic species by surface SiO- or SiOH groups, we find that a significant electric current is generated, but with opposite polarities using polarizable vs. fixed charge models for water and ions, emphasizing the need for careful parameterization in such complex systems. We also examine the influence of partial deprotonation of the silica surface, and we find that much more current is generated in a dehydrogenated nanopore, even though the overall efficiency remains low. These findings indicate that different methods of nanopore preparation, which can produce a range of surface properties, should be examined more closely in the related experimental methods to generate electrokinetic current. PMID- 30397699 TI - Asynchrony of spectral blue-shifts of quantum dot based digital homogeneous immunoassay. AB - A femtomolar digital homogenous immunoassay is developed based on sensitively distinguishing the immunocomplexes labeled with quantum dot (QD) aggregates from the excessive free monodisperse single QDs. The success in quantifying the carcino-embryonic antigen and alpha-fetoprotein in plasma validated the feasibility of our approach for clinical tests. PMID- 30397701 TI - A fiber-optic nanoplasmonic hydrogen sensor via pattern-transfer of nanofabricated PdAu alloy nanostructures. AB - We demonstrate the transfer of arrays of nanofabricated noble metal and alloy nanostructures obtained by high-temperature annealing on a flat parent support onto optical fibers, to create a hysteresis-free fiber optic nanoplasmonic hydrogen sensor. This work enables the integration of complex nanofabricated structures and their arrangements in tailored arrays with fiber optics to realize optical sensors, which will find application in a wide range of disciplines. PMID- 30397700 TI - Evaluation of 3D gold nanodendrite layers obtained by templated galvanic displacement reactions for SERS sensing and heterogeneous catalysis. AB - Dense layers of overlapping three-dimensional (3D) gold nanodendrites characterized by high specific surfaces as well as by abundance of sharp edges and vertices creating high densities of SERS hotspots are promising substrates for SERS-based sensing and catalysis. We have evaluated to what extent structural features of 3D gold nanodendrite layers can be optimized by the initiation of 3D gold nanodendrite growth at gold particles rationally positioned on silicon wafers. For this purpose, galvanic displacement reactions yielding 3D gold nanodendrites were guided by hexagonal arrays of parent gold particles with a lattice constant of 1.5 MUm obtained by solid-state dewetting of gold on topographically patterned silicon wafers. Initiation of the growth of dendritic features at the edges of the gold particles resulted in the formation of 3D gold nanodendrites while limitation of dendritic growth to the substrate plane was prevented. The regular arrangement of the parent gold particles supported the formation of dense layers of overlapping 3D gold nanodendrites that were sufficiently homogeneous within the resolution limits of Raman microscopy. Consequently, SERS mapping experiments revealed a reasonable degree of uniformity. The proposed preparation algorithm comprises only bottom-up process steps that can be carried out without the use of costly instrumentation. PMID- 30397702 TI - Ultrafast fluorescence dynamics of DNA-based silver clusters. AB - Atomic-level understanding of the nature of the electronically excited states in ligand-stabilized metal nanoclusters (NCs) is a prerequisite for the design of new NCs with desired properties. In this study, we investigate the emission dynamics of a Ag-DNA complex using the fluorescence up-conversion technique. We show that most of the relaxation from the Franck-Condon state to the emissive state takes place in less than 100 fs, in spite of a relatively large Stokes shift of 4500 cm-1. This relaxation is much faster than typical solvent/DNA relaxation rates. A further small relaxation occurs with time constants ranging from a few to hundreds of picoseconds. We also calculate the Stokes shift for model complexes of a small three-atom Ag3+ cluster with cytosine and guanine. The results of our calculations show that a substantial geometry change of the Ag3+ cluster is observed in the S1 state of both complexes, which results in Stokes shifts comparable with the experimental value. We conclude that the Stokes shift in the Ag-DNA complex arises mostly due to the change in the geometry of the Ag cluster in the excited state rather than to the solvent/DNA reorganization. Also, a different structure of the Ag-DNA complex ("dark cluster"), the excited state of which decays in 200 fs, is observed. The nature of this ultrafast deactivation is unclear, which requires further investigations. PMID- 30397703 TI - The potential of magnetic hyperthermia for triggering the differentiation of cancer cells. AB - Magnetic hyperthermia is a potential technique for cancer therapy that exploits heat generated by magnetic nanoparticles to kill cancerous cells. Many studies have shown that magnetic hyperthermia is effective at killing cancer cells both in vitro and in vivo, however little attention has been paid to the cellular functioning of the surviving cells. We report here new evidence demonstrating the onset of thermally triggered differentiation in osteosarcoma cancer cells that survive magnetic hyperthermia treatment. This raises the possibility that in addition to causing cell death, magnetic hyperthermia could induce surviving cancer cells to form more mature cell types and thereby inhibit their capacity to self-renew. Such processes could prove to be as important as cell death when considering magnetic hyperthermia for treating cancer. PMID- 30397704 TI - Symmetry controlled excited state dynamics. AB - Symmetry effects in internal conversion are studied by means of two isomeric cyclic tertiary aliphatic amines in a velocity map imaging (VMI) experiment on the femtosecond timescale. It is demonstrated that there is a delicate structural dependence on when coherence is preserved after the transition between the 3p and 3s Rydberg states. N-Methyl morpholine (NMM) shows unambiguous preserved coherence, consistent with previous work, which is decidedly switched off by the repositioning of oxygen within the ring. From the differences in these dynamics, and an examination of the potential energy surface following the normal modes of vibration, it becomes clear that there is a striking dependence on atom substitution, which manifests itself in the permitted modes of vibration that take the system out of the Franck-Condon region through to the 3s minimum. It is shown that the non Fermi-like behaviour of NMM is due to a conical intersection (CI) between the 3px and 3s states lying directly along the symmetry allowed path of steepest descent out of the Franck-Condon region. NMI, where the symmetry has been changed, is shown to undergo internal conversion in a more Fermi-like manner as the energy spreads through the available modes ergodically. PMID- 30397705 TI - The process of litigation for medical errors in Saudi Arabia and the United Kingdom. AB - Efficient process of litigation of medical errors is a key to ensure fair, speedy, and accessible justice system. The conditions of establishing medical negligence are similar in both legal systems. These conditions include the duty of care, breach of that duty of care, the damages, and establishing causation. A culture of litigation and compensation is growing in the United Kingdom and Kingdom of Saudi Arabia; however the cost of medical claims and awarded compensations are much more in the United Kingdom compared to Kingdom of Saudi Arabia. In Kingdom of Saudi Arabia, there is a need for more transparency in the documentation and publication of litigated medical errors. In addition, there is a need to introduce interventions to shorten the duration of litigation in both legal systems. Financial caps on awarded compensation and caps on expert and legal fees are potential strategies to control the cost of medical errors which seems to work well in the Saudi model. PMID- 30397706 TI - AuraGain and i-Gel laryngeal masks in general anesthesia for laparoscopic cholecystectomy. Performance characteristics and effects on hemodynamics. AB - OBJECTIVES: To evaluate and compare the performances of new types of supraglottic airway devices (SADs) with endotracheal intubation regarding their ease of insertions, perioperative complications, and effects on hemodynamic parameters and peak airway pressures in laparascopic cholecystectomy (LC). Methods: One hundred and fourteen patients with ASA 1-2 physical status scheduled for elective LC were recruited for this prospective randomized controlled trial. The study was completed between January 2016 and January 2017 in Adiyaman University Research and Educational Hospital, Adiyaman, Turkey. The patients were divided into AuraGain(Ambu, Ballerup, Denmark) (n=38), i-Gel(r) (Intersurgical Ltd, UK) (n=35), and endotracheal tube (ETT)(n=32) groups. Ease of insertion, airway pressures, complications, and hemodynamic variables were compared. Results: The trial was completed with 105 patients. Ease of insertion for SADs which was evaluated with insertion procedure duration, attempts, first insertion success rates, and oropharyngeal leak pressures were similar between the groups. Heart rate, systolic and diastolic arterial pressures, and peak airway pressures were significantly lower in the AuraGain and i-Gel(r) groups, compared with the ETT, p less than 0.017. Conclusion: Both AuraGain and i-Gel(r) SADs are comparable with ETT used for airway control in general anesthesia for LC, regarding application ease and perioperative complications. Favorable hemodynamic responses to AuraGain and i-Gel(r) SADs may put them in a better place than ETT. PMID- 30397707 TI - Clinical efficacy of low dose recombinant tissue-type plasminogen activator for the treatment of acute intermediate-risk pulmonary embolism. AB - OBJECTIVES: To investigate the efficacy and safety of initial thrombolysis by recombinant tissue-type plasminogen activator (rt-PA) in compared with anticoagulant therapy in patients with acute intermediate-risk pulmonary embolism (PE). Methods: Sixty-six patients with acute intermediate-risk PE were randomly assigned to receive rt-PA or LMWH between June 2014 and June 2017 in our department. We obtained information regarding the difference in the right ventricle/left ventricle (RV/LV) ratio, pulmonary artery systolic pressure (PASP), clinical symptoms improvement, PE-related mortality, hemodynamic decompensation, recurrent PE, and major and minor bleeding. Results: In the rt PA group, the mean PASP was reduced from 52.0+/-12.2 at baseline to 34.8+/-9.4 (p less than 0.001) and the mean RV/LV ratio was reduced from 1.26+/-0.22 at baseline to 0.96+/-0.18 (p less than 0.001) at 24 hours. In the LMWH group, the mean PASP was 53.4+/-12.8 at baseline and 48.5+/-11.9 at 24 hours (p=0.11), and the mean RV/LV ratio was 1.22+/-0.19 at baseline and 1.17+/-0.21 at 24 hours (p=0.31). In comparison with the LMWH group, there was a significant reduction in PASP and an improvement in the symptom severity in the rt-PA group. At 90 days, there was no difference in mortality, recurrent venous thromboembolism and major bleeding as a safety outcome, but increased minor bleeding and decreased hemodynamic decompensation occurred in the rt-PA group. Conclusions: In patients with acute intermediate-risk PE, low dose thrombolytic therapy is considered safe and effective, it can be recommended as an alternative option in clinical treatment. PMID- 30397708 TI - Venous thromboembolism after total knee and hip arthroplasty. A retrospective study. AB - OBJECTIVES: To evaluate the incidence and risk factors of Venous thromboembolism (VTE) among total knee arthroplasty (TKA) and total hip arthroplasty (THA) patients following surgery. Methods: We conducted a retrospective review of electronic medical records of consecutive patients between January 2010 and January 2015 who underwent TKA or THA at King Abdulaziz Medical City (KAMC), Riyadh, Saudi Arabia. Results: The incidence of symptomatic VTE was 1.9% (17 events, 95% CI: 1.1-2.8) in 756 patients who underwent 889 surgeries. All VTE cases developed before hospital discharge. Twelve (1.4%) patients developed pulmonary embolism, and 5 (0.6%) patients developed deep vein thrombosis. The majority of patients (n=557, 62.7%) underwent surgery for single TKA, and 138 (15.5%) patients underwent bilateral arthroplasty. Based on univariate risk analysis, bilateral arthroplasty was the only potential predictor for VTE after surgery. Conclusion: The rate of symptomatic VTE in a Saudi population following arthroplasty is low and comparable to the international data. However, efforts and more trials are needed to further improve in-hospital thromboprophylaxis measures. PMID- 30397709 TI - Natural cycle versus hormone replacement therapy cycle in frozen-thawed embryo transfer. AB - OBJECTIVES: To compare implantation rates, clinical pregnancy rates and live birth rates associated with natural and hormone replacement therapy (HRT) methods of endometrial preparation in frozen-thawed embryo transfer (FET) cycles. Methods: The results of 108 natural cycles and 224 HRT cycles of FET transfers performed in a private in vitro fertilization (IVF) center between June 2013 and August 2015 were retrospectively compared with respect to implantation rate, clinical pregnancy rate, and live birth rate. Results: A total of 144 embryos were transferred in 108 natural cycles and 357 embryos were transferred in 224 HRT cycles. No statistically significant differences were found in the implantation rate (p=0.796), clinical pregnancy rate per cycle (p=0.900), clinical pregnancy rate per transferred embryo (p=0.283), live birth rate per cycle (p=0.821), or live birth rate per transferred embryo (p=0.481) between the 2 groups. Conclusion: This study showed no difference between the implantation rate, clinical pregnancy rate or live birth rate between the natural cycle group and HRT cycle group. These results may provide clinicians with more freedom to individualize patient treatment, particularly with respect to the selection of the endometrial preparation method, if these results are supported by large randomized controlled studies in the future. PMID- 30397710 TI - Contraceptive use as limiters and spacers among women of reproductive age in southwestern, Saudi Arabia. AB - OBJECTIVES: To examine the prevalence, socioeconomic, and demographic determinants of contraceptive use among women of reproductive age residing in Abha, Kingdom of Saudi Arabia. METHODS: The data of this study was collected through a cross sectional survey conducted on unmet need for family planning in Abha, Kingdom of Saudi Arabia, between March and May 2016. Three hundred and seventy-four married women were recruited from 6 primary health care centers by a consecutive sampling technique. Data was collected via an interviewer administered questionnaire. Chi-square test was carried out to identify the factors associated with contraceptive use. RESULTS: The prevalence of contraceptive use rate was 58.8%. Among users, 60% were spacers and 40% were limiters. Among more than two-thirds of the women, the decision to use a family planning method was a joint decision of the couple; and 25% reported it as their own decision. Oral pills and intrauterine contraceptive device (IUCD)were the most popular methods. The most significant associated factors were age, education of women, gravida, number of living children, gender, and age of the last child. Younger age was related with the spacers and older age with birth limiting. Woman's education level showed a significant positive association with birth spacing. CONCLUSION: This study demonstrated that a sizable percentage of women in Abha, Kingdom of Saudi Arabia, are using contraceptions. This finding indicates the need of comprehensive family planning program in the region. PMID- 30397711 TI - Breastfeeding self efficacy among pregnant women in Saudi Arabia. AB - OBJECTIVES: To examine the association between prenatal breastfeeding self efficacy among Saudi pregnant women and type of feeding at 4 weeks post partum, and also to examine the association of maternal socio-demographic variables with the breastfeeding self-efficacy levels of Saudi pregnant women. Methods: A cross sectional design has been applied in the study by recruiting 101 pregnant women from the General Hospital, Umluj, Kingdom of Saudi Arabia. The prenatal breastfeeding self-efficacy scale was used to measure self-efficacy for breastfeeding during pregnancy. Descriptive statistics, Chi-square, Pearson correlation coefficient were used for statistical purposes. A p-value <=0.05 was considered significant. Results: The average breastfeeding self-efficacy score was 70+/-11.9. No significant relationship was existed between breastfeeding self efficacy and the maternal sociodemographic variables. A significant relationship was found between type of feeding at 4 weeks postpartum and prenatal breastfeeding self-efficacy (r=0.061, p less than 0.05). Women who exclusively breastfeed their babies had high scores on prenatal breastfeeding self-efficacy scale than those who mixed feed or bottle feed their infants. Conclusion: Levels of prenatal breastfeeding self-efficacy among Saudi pregnant women were high and can be predictive of breastfeeding exclusivity at 4 weeks postpartum. The prenatal breastfeeding self-efficacy could be used to measure whether the woman could organize and execute the causes of action needed to perform breastfeeding behavior. PMID- 30397712 TI - Knowledge, attitudes, and practices of emergency department staff towards disaster and emergency preparedness at tertiary health care hospital in central Saudi Arabia. AB - OBJECTIVES: To assess the knowledge, practices, and attitudes regarding disaster and emergency preparedness among Emergency Department (ED) staff. Methods: This cross-sectional study was conducted at Tertiary health care hospital in central Riyadh, Kingdom of Saudi Arabia. A self-administered survey was utilized to collect data from ED physicians and nurses. The questionnaire was divided into 5 sections viz; demographics, knowledge about disaster management and preparedness, attitudes about disaster planning, current role and practices, and familiarity towards emergency. Results: A 189 participants have completed the questionnaire. Two-third of the participants were below 30 years, and more than 85% were female. One hundred and eleven (58.7%) had a clinical experience of more than 5 years, while 78 (41.3%) participants had more than 3 years of clinical service at the Tertiary care hospital in Riyadh, Kingdom of Saudi Arabia. Correct responses of knowledge towards disaster and emergency preparedness score was 6.2+/-2.5. Participants with more than 5-years of experience had a statistically significant (p=0.009) knowledge scale score for disaster and emergency preparedness. Overall, 186 (98.4%) patients believed that training is necessary for all healthcare workers. Approximately 153 (81%) participants reported the conduct of disaster drill at their hospital. The mean score (Mean+/-SD) for the overall familiarity of the study participants with emergency preparedness information questionnaire (EPIQ) scale was 3.2+/-1.3. Conclusion: The level of knowledge was satisfactory among healthcare providers with neutral level of attitude, practice, and familiarity regarding disaster preparedness. Follow-up research is necessary for maximizing ED preparedness. PMID- 30397713 TI - Doctors' knowledge of the doses and risks of radiological investigations performed in the emergency department. AB - OBJECTIVES: To assess emergency doctors' knowledge of radiation exposure doses and risks, and the increasing use of radiological investigations in emergency medicine practice is very concerning because of the associated risks of cancer. METHODS: Doctors from different specialties and with different levels of training working in emergency departments of 8 hospitals in Jeddah, Kingdom of Saudi Arabia, filled out a questionnaire. Participants estimated the radiation doses of different imaging modalities and answered questions regarding possible associated risks. Results: One hundred seventy-one doctors returned completed questionnaires. The overall correct dose estimation rate was 20.8%. Doses were more correctly estimated by consultants versus specialists and residents (p=0.007), and by emergency physicians versus doctors from other specialties (p=0.05). The correct answer rate was insignificantly higher among doctors with formal training on radiation protection (p=0.065). The overall correct answer rate was unsatisfactory for 4 questions assessing physicians' knowledge of risks. Questions about the lifetime risk of cancer due to ionizing radiation were more correctly answered by consultants versus residents and specialists (p=0.05). Specialists were more knowledgeable about the risk of imaging on fetuses (p=0.05). Doctors with formal training answered 3 out of 4 questions more correctly than doctors without formal training, but no difference existed between them regarding imaging modalities, that they selected for pregnant patients (p=0.297). Conclusion: Doctors working in emergency departments had poor knowledge about radiation doses and risks. This issue warrants urgent attention. PMID- 30397714 TI - Knowledge, attitudes, and practice behavior of dental hygienists regarding the impact of systemic diseases on oral health. AB - OBJECTIVES: To assess the knowledge levels of dental hygienists in Saudi Arabia regarding the association between systemic and oral disease in addition to evaluating their attitude about integrating this knowledge into clinical practice. Methods: This was a cross-sectional survey using a questionnaire of 102 items among 192 randomly selected dental hygienists practicing in Riyadh, Saudi Arabia by individual interview. The research tool was pilot tested among 12 dental hygienists (8 females and 4 males) to obtain feedback about clarity and objectivity. Results: The response rate was 83%, and the majority of respondents were female (77.5%). The respondents' knowledge about the risk factors of cardiovascular diseases was better than other conditions. The level of education was considered to be a significant predictor in many items related to risk factors. More than the half, rated the evidence linking periodontal disease and diabetes mellitus as strong; however, the knowledge level of oral-systemic evidence was less than expected. A high percentage of the respondents were confident and comfortable managing patients with systemic conditions. Most agreed that dental hygienists must be prepared efficiently to manage medically compromised patients. Conclusion: Dental hygienists in Riyadh, Saudi Arabia have low level of knowledge about the oral-systemic disease relationship. This study suggests that greater emphasis should be placed on this association in current and continuing education programs. PMID- 30397715 TI - Human immunodeficiency virus related discrimination in general dentistry. AB - OBJECTIVES: To investigate HIV related discrimination among general dentists in Jeddah, Saudi Arabia; and to list factors affecting or causing healthcare providers to discriminate people living with HIV (PLWH). Methods: The current study takes place in Jeddah, western Saudi Arabia. The duration for accepting all responses was between March and November, 2017. In this cross-sectional study, we used a self-administered, structured questionnaire. The sample size was 430 general dentists practicing in Jeddah, Saudi Arabia. Descriptive statistics, mean, and standard deviation were calculated. Bivariate and multivariate analysis was carried out at p less than 0.05 level of significance. The Statistical Package for the Social Sciences (SPSS) version 22 (IBM Corp., Armonk, NY, USA) was used for data analysis. Results: In our study population, the total HIV related discrimination was 67.4%. Approximately 98.1% defer PLWH to the last appointment of the day, while 84.7% refer them to specialists. Furthermore,100% reported wearing double gloves, and 94.7% where wearing protective eye shields if they encounter HIV-patient in the clinic. Male participants were found to be 23% more likely to be discriminative compared to female participants, Moreover, participants who are confident to provide both surgical and non-surgical dental treatment for PLWH were found to be 52% less likely to be discriminative towards PLWH. Also, HIV discrimination is 33% higher in the private practice compared to the governmental practice. Conclusion: Human immunodeficiency virus related discrimination in the study population was affected by dentists' gender, type of practice, and self-protective attitudes. PMID- 30397716 TI - Cesarean sections. Associated factors and frequency at King Abdulaziz Medical City in the Central Region of the Kingdom of Saudi Arabia. AB - OBJECTIVES: To study the associated factors for cesarean section (C-section) in a sample of pregnant women and to estimate its frequency at King Abdulaziz Medical City in Riyadh, Kingdom of Saudi Arabia (KAMC-R). Methods: We studied 364 pregnant women who attended the Gynecology and Obstetrics Clinic at KAMC-R between March and June 2017. Results: Our 3-month study had higher rates of C sections: women with older maternal age; (adjusted risk ratio [aRR]=1.08, p=0.001), lack of education (aRR=1.39, p=0.022), no personal history of vaginal delivery (aRR=1.85, p=0.001), undergoing C-section due to medical indications (aRR=2.28, p=0.001), and willing to repeat a C-section in the absence of medical indications (aRR=1.49, p=0.006). Cesarean section occurred in 27% of the total deliveries in 2016. Conclusion: Cesarean section are very frequent and prevalent in our center, and may be increasing. The frequency of C-sections was significantly higher for women of older maternal age, little education, no personal history of vaginal delivery, undergoing C-sections due to medical indications, and those willing to repeat a C-section in the absence of medical indications. PMID- 30397718 TI - Comment on: Growth characteristics in children with congenital adrenal hyperplasia. AB - [No Abstract Available]. PMID- 30397717 TI - Oncology nurses' knowledge, practice, and confidence toward chemotherapy-induced peripheral neuropathy in Jordan. AB - OBJECTIVES: To assess the knowledge, practice, and confidence of oncology nurses toward chemotherapy-induced peripheral neuropathy (CIPN) among patients with cancer in Jordan. Methods: Descriptive, and cross sectional study was conducted on a convenience sample of 148 Jordanian registered oncology nurses recruited from a Specialized Oncology Center in Jordan. Data collection took place in June, 2015. As a data collection tool, the assessment of oncology nurses' knowledge and practice-revised questionnaire was used. Results: The mean CIPN knowledge score of 8.98/16 (SD=1.9) indicated that there were knowledge deficits regarding CIPN among Jordanian oncology nurses. Only 58.8% of the subjects indicated that CIPN assessment is necessary for their oncology practices, but the majority rated their CIPN assessment skills as inadequate. Neurologic physical assessment usually is not included in practices assessment. In addition, 57.1% believed that CIPN was a significant problem for patients and their families. Conclusion: There is a significant requirement to enhance the neurological assessment skills of oncology nurses and an efficient approach to CIPN assessment is demanded. Creating guidelines to manage and assess CIPN, and further investigations in different health institutions to generalize the results across Jordan are highly needed. PMID- 30397719 TI - Erratum: Evaluation of disaster preparedness for mass casualty incidents in private hospitals in Central Saudi Arabia. AB - [No Abstract Available]. PMID- 30397720 TI - ? PMID- 30397721 TI - [Prostate cancer screening: controversies and suggested solutions]. AB - Prostate cancer is the most common cancer among men in industrialized countries. The annual incidence rate in Germany is about 60,000. Every year, 13,000 men die of this disease. Nevertheless, the 10-year survival rate is relatively favorable compared to other carcinomas.Prostate cancer screening is discussed controversially both nationally and internationally. This is due to the fact that the determination of the prostate-specific antigen (PSA) for tumor detection beginning in the 1980s led to over-diagnosis of clinically insignificant prostate cancer and consequently to over-therapy-usually by radical prostatectomy or radiotherapy.This review article will discuss the largest randomized controlled trials of PSA-based prostate cancer screening to date. It will highlight the advantages and disadvantages of this screening and give an outlook on the development of future strategies for prostate cancer screening.For PSA screening, the European Randomized Study for Screening of Prostate Cancer (ERSPC) study showed a relative reduction in prostate cancer-specific mortality of approximately 21% after a median follow-up period of 13 years. However, in absolute figures, relatively few men will benefit from population-based screening and the rate of over-diagnosed men remains high.The procedure in a Swedish long term study, in which risk-adapted screening intervals were applied on the basis of the assessment of a baseline PSA level at a young age (40-50) showed promising results and may provide a solution to this dilemma. This strategy is the basis for the currently largest study on risk-adapted prostate cancer screening ( www.PROBASE.de ), which evaluates this concept for the first time with a randomized design. PMID- 30397722 TI - [Cervical cancer screening in Germany]. AB - Cytological examination for the early detection of cervical cancer (CCS) has been available in Germany since 1971. Women over the age of 20 are entitled to a Pap smear every year; however, thus far an organized screening program and personal invitations have been missing.The incidence rate of cervical carcinoma declined dramatically in the decades following the introduction of CCS, but the incidence rate has stagnated in recent years. The cause of cervical cancer is a persistent infection with high-risk types of human papillomavirus (HPV). HPV tests have been approved by the American Food and Drug Administration (FDA) for CCS for several years. Furthermore, since 2006, the HPV vaccination has been offered as a form of primary prevention.As part of the German National Cancer Plan, the European Guideline for Cervical Cancer Screening was implemented and adopted into the 2013 Law on Cancer Screening and Registration. The Federal Joint Committee (G-BA) was commissioned with the implementation of an organized cervical cancer screening program.In April 2018, the G-BA published updated key points for the implementation of an organized nationwide screening program in Germany. While annual cytological screening for women between the ages of 20 and 34 will continue, women over the age of 34 years will be given a co-test comprising a Pap smear and an HPV test, every three years. Women between the ages of 20 and 60 will be contacted by their health insurance provider every five years and receive an information leaflet. After a test phase of at least six years, the new program will be evaluated. PMID- 30397723 TI - [The health economics of cancer screening in Germany: Which population-based interventions are cost-effective?] AB - Only a small proportion of German health expenditure is spent on prevention and early detection (screening). The rationale for screening is to identify persons with disease precursors or at the early stage of diseases when they are still asymptomatic, in order to decrease disease-specific morbidity and mortality. In Germany, the economic evidence is one of the evaluation criteria for screening measures, which, among other things, takes into account the additional cost per additional case detected or per case-related event avoided, as well as a cost benefit balance.For this purpose, cost-effectiveness analyses, which report marginal or incremental cost effectiveness ratios, comparing a measure with its appropriate alternatives, may be a useful tool. Their application requires a defensible benchmark (threshold) for cost effectiveness and a supplementary analysis of the necessary infrastructure and the budgetary impact associated with program implementation. Also (albeit not only) because of the usually long time required to observe the clinical outcomes of a screening measure, the economic evaluation of such programs regularly involves the application of decision analytic simulation models. With regard to cancer screening programs, the available models indicate an excellent cost-benefit ratio for the fecal occult blood test and colonoscopy for colorectal cancer screening and, similarly, for the use of mammography for breast cancer screening. On the other hand, the economic evidence in favor of low-dose computed tomography for lung cancer screening does not yet appear sufficiently strong, and the currently available health economic evidence does not support the use of PSA testing for prostate screening. PMID- 30397724 TI - [Online information about early detection of colorectal cancer to support informed decision-making : Evaluation and reception analysis of an information module at the women's health portal and the men's health portal of the Federal Center for Health Education (BZgA)]. AB - Colorectal cancer is one of the most prevalent types of cancer in Germany. The provided governmental program for early detection of colorectal cancer intends to increase the chances of recovery by identifying colorectal cancer at an early, more treatable stage.An information module with quality-assured, balanced, and target-group specific information about colorectal cancer and early detection was designed for the women's health portal and the men's health portal of the Federal Center for Health Education (BZgA) to promote informed decision-making. A multilevel and multimethodological procedure was chosen to examine if the information module achieved this intended goal and to evaluate how users and experts experienced the information module. User experience was evaluated using an eye-tracking, retrospective think aloud (RTA) technique combined with a quantitative questionnaire, and experts' evaluations using a half-standardized questionnaire. Additionally, factors like age, education level, sex, previous experience, and health literacy were analyzed.Altogether, users and experts rated the information module very positive, comprehensible, and informative. Reception of the information module increased the knowledge about colorectal cancer and early detection of colorectal cancer significantly. Therefore, the designed information module provides the crucial basis for an informed decision-making process. PMID- 30397725 TI - [Double plate osteosynthesis of proximal ulna fractures]. PMID- 30397726 TI - Engineering of Yeast Glycoprotein Expression. AB - Yeasts are valuable hosts for recombinant protein production, as these unicellular eukaryotes are easy to handle, grow rapidly to a high cell density on cost-effective defined media, often offer a high space-time yield, and are able to perform posttranslational modifications. However, a key difference between yeasts and mammalian cells involves the type of glycosylation structures, which hampers the use of yeasts for the production of many biopharmaceuticals. Glycosylation is not only important for the folding process of most recombinant proteins; it has a large impact on pharmacokinetics and pharmacodynamics of the therapeutic proteins as well. Yeasts' hypermannosylated glycosyl structures in some cases can evoke immune responses and lead to rapid clearance of the therapeutic protein from the blood. This chapter highlights the efforts made so far regarding the glyco-engineering of N- and O-type glycosylation, removing or reducing yeast-specific glycans. In some cases, this is combined with the introduction of humanized glycosylation pathways. After many years of patient development to overcome remaining challenges, these efforts have now culminated in effective solutions that should allow yeasts to reclaim the primary position in biopharmaceutical manufacturing that they enjoyed in the early days of biotechnology. Graphical Abstract. PMID- 30397727 TI - Arterial Spin Labeling and Central Precocious Puberty. AB - PURPOSE: To evaluate a non-invasive method to assess the progressivity of idiopathic central precocious puberty (CPP) by quantifying perfusion of the pituitary stalk with arterial spin labeling (ASL) and using the gonadotropin releasing hormone (GnRH) test as a reference test to define progressive CPP. METHODS: In a single center retrospective study, 52 consecutive patients, observed between October 2015 and April 2017 and referred with early signs of puberty, were evaluated using the GnRH test and cerebral magnetic resonance imaging (MRI). Patients with peripheral or non-idiopathic puberty were excluded. The distribution of perfusion values between patients with progressive and non progressive CPP was compared using a nonparametric Mann-Whitney U-test. RESULTS: In this study 35 patients were included and 29 had progressive CPP. These patients displayed significantly higher cerebral blood flow (CBF) values than the 6 patients with non-progressive CPP (p = 0.006). The median CBF for patients with non-progressive and progressive CPP was 45.25 ml/min/100 g (interquartile range 36.9-54) vs. 65 ml/min/100 g (interquartile range 55.5-74.5), respectively. To determine if the CPP was progressive, the best CBF threshold was 55.5 ml/min/100 g with a sensitivity of 76%, a specificity of 83% and an accuracy of 77%. There were strong significant correlations between CBF and LH peak (r = 0.67, p < 0.001) and between CBF and LH/FSH peaks ratio [r = 0.71, p < 0.001] during the GnRH test. CONCLUSION: Arterial spin labelling (ASL) offers a novel tool to assess the progressivity of idiopathic CPP. PMID- 30397728 TI - Image Quality of CT Angiography of Supra-Aortic Arteries : Comparison Between Advanced Modelled Iterative Reconstruction (ADMIRE), Sinogram Affirmed Iterative Reconstruction (SAFIRE) and Filtered Back Projection (FBP) in One Patients' Group. AB - PURPOSE: To evaluate the potential benefit in image quality of the iterative reconstruction (IR) technique advanced modelled iterative reconstruction (ADMIRE) in CT angiography (CTA) of supra-aortic arteries compared to sinogram affirmed iterative reconstruction (SAFIRE) and standard filtered back projection (FBP) in one patients' group. METHODS: In this study 29 patients underwent standard CTA of supra-aortic arteries. Images were reconstructed using three different reconstruction algorithms, FBP, and IR techniques ADMIRE and SAFIRE. General image quality was assessed by two radiologists in different arterial segments using a 5-point Likert scale. Mean attenuation and noise were measured at different levels of each vessel and signal-to-noise ratio (SNR) was calculated. Interrater variability was determined. RESULTS: Regarding total image quality IR showed only excellent, very good and good results and was more often graded excellent and very good than FBP reconstruction. Image noise levels and SNR were significantly (p < 0.01) improved in IR at the bilateral subclavian arteries (only in SAFIRE), vertebral V1 and V3 segments, common carotid arteries and proximal and distal internal carotid arteries. No significant differences in image quality were found when comparing SAFIRE and ADMIRE reconstructions except for V1 and V3. In these regions ADMIRE showed significantly better image quality than SAFIRE (p < 0.001 and p < 0.01). Interrater agreement was almost perfect (kappa = 0.88) for different image quality parameters. CONCLUSION: The CTA of supra-aortic arteries using the IR techniques SAFIRE and ADMIRE was superior to FBP when comparing the objective and subjective image quality and ADMIRE has the potential to overcome SAFIRE. PMID- 30397730 TI - Deep Deterministic Learning for Pattern Recognition of Different Cardiac Diseases through the Internet of Medical Things. AB - Electrocardiography (ECG) sensors play a vital role in the Internet of Medical Things, and these sensors help in monitoring the electrical activity of the heart. ECG signal analysis can improve human life in many ways, from diagnosing diseases among cardiac patients to managing the lifestyles of diabetic patients. Abnormalities in heart activities lead to different cardiac diseases and arrhythmia. However, some cardiac diseases, such as myocardial infarction (MI) and atrial fibrillation (Af), require special attention due to their direct impact on human life. The classification of flattened T wave cases of MI in ECG signals and how much of these cases are similar to ST-T changes in MI remain an open issue for researchers. This article presents a novel contribution to classify MI and Af. To this end, we propose a new approach called deep deterministic learning (DDL), which works by combining predefined heart activities with fused datasets. In this research, we used two datasets. The first dataset, Massachusetts Institute of Technology-Beth Israel Hospital, is publicly available, and we exclusively obtained the second dataset from the University of Malaya Medical Center, Kuala Lumpur Malaysia. We first initiated predefined activities on each individual dataset to recognize patterns between the ST-T change and flattened T wave cases and then used the data fusion approach to merge both datasets in a manner that delivers the most accurate pattern recognition results. The proposed DDL approach is a systematic stage-wise methodology that relies on accurate detection of R peaks in ECG signals, time domain features of ECG signals, and fine tune-up of artificial neural networks. The empirical evaluation shows high accuracy (i.e., <=99.97%) in pattern matching ST-T changes and flattened T waves using the proposed DDL approach. The proposed pattern recognition approach is a significant contribution to the diagnosis of special cases of MI. PMID- 30397731 TI - Assessing the performance of sand filter basins in treating urban stormwater runoff. AB - This study has assessed the efficiency of sand filter basins in treating urban stormwater runoff by analyzing available data in the literature, the International Stormwater BMP Database, and data collected in a sand filter basin located in the main campus of the University of Texas at San Antonio (UTSA). Ten storm events were monitored starting in March 2016 until February 2017. Total suspended solids, volatile suspended solids, nitrate, ortho-phosphate, copper, zinc, lead, pH, and conductivity were measured in the inlet and the outlet of the basin. Statistical analysis, including linear regression modeling, scatter plotting, and non-parametric testing, using data from the literature and the International Stormwater BMP Database was performed. The sand filter basin removed, on average, 94% and 86% of TSS and VSS, respectively. Such high removal rates were not observed for other constituents, with exception of lead (79%) that already showed a low mean concentration in the inlet of the basin (41.47 +/- 27.41 MUg/L). Nitrate and ortho-phosphate mean concentrations were not significantly different in the outlet than inlet. The basin effluent concentration of zinc was higher than acceptable stormwater benchmarks defined by EPA. The results indicated that the monitored sand filter basin met its primarily design criteria, which is TSS removal by at least 80% of mass. Better stormwater treatment practices, however, are needed to remove other pollutants more efficiently, in particular, because this area is located on top of the recharge zone of the Edwards Aquifer, a major source of water supply for the region. PMID- 30397729 TI - Management of Advanced Small Bowel Cancer. AB - OPINION STATEMENT: Small bower cancer is a rare disease, despite its incidence is increasing in the last decade. Both benign and malignant tumors can arise from the small intestine. The main histological cancer types are adenocarcinomas, neuroendocrine tumors, sarcomas, gastrointestinal stromal tumors (GISTs), and lymphomas. Due to the rarity of these malignances, all the currently available data are based on small studies or retrospective series, although recent breakthroughs are redirecting our approach to these patients. Immunotherapy for small bowel adenocarcinomas, several multikinase inhibitors in resistant GIST patients, as well as everolimus and 177Lu-DOTATATE in neuroendocrine tumors are only few of the novel therapeutic options that have changed, or may change in the future, the therapeutic landscape of these rare cancers. Larger and more powerful studies on the molecular profile of these tumors may lead to a better design of clinical trials, which eventually would provide our patients with more efficacious treatments to improve both overall survival and quality of life. PMID- 30397732 TI - Changes in bone mineral density in women before critical illness: a matched control nested cohort study. AB - : The contribution of premorbid bone health to accelerated bone loss following critical illness is unknown. This study compared bone density in women before critical illness to women who did not become critically ill. Overall bone density was similar, although femoral neck bone mass increased immediately prior to critical illness. PURPOSE: The relative contribution of acute and chronic factors to accelerated loss of bone mineral density (BMD) following critical illness is unknown. This study compared the BMD trajectory of women before critical illness to the BMD trajectory of women who did not become critically ill. METHODS: This prospective, nested, age- and medication-matched, case-control study compared trajectory of BMD in women in the Geelong Osteoporosis study (GOS) requiring admission to an Australian Intensive Care Unit (ICU) between June 1998 and March 2016, to women not admitted to ICU. The main outcome was age and medication use adjusted change in BMD. RESULTS: A total of 52 women, with a mean age of 77 +/- 9 years were admitted to ICU, predominantly post-surgery (75%), during the study period. A greater age-adjusted annual rate of decline was observed for pre-ICU women compared to no-ICU women for AP spine BMD (-0.010 +/- 0.002 g/cm2 vs -0.005 +/- 0.002 g/cm2, p = 0.01) over the 15-year study period. In participants with multiple BMDs 2 years before critical illness, a significantly greater increase in femoral neck BMD compared to age- and medication-matched controls was observed (difference in BMD, ICU vs no-ICU = 0.037 +/- 0.013 g/cm2, p = 0.006). CONCLUSION: In a cohort of women with predominantly surgical ICU admission, bone health prior to critical illness was comparable to age- and medication-matched controls, with a relative increase in femoral neck bone mass immediately prior to critical illness. These findings suggest critical illness-related bone loss cannot be entirely explained as a continuation of pre-morbid bone trajectory. PMID- 30397733 TI - Effect of temperature on the cyclic fatigue resistance of thermally treated reciprocating instruments. AB - OBJECTIVES: The aim of this study was to evaluate the impact of body temperature on the cyclic fatigue resistance of different NiTi alloys used for the manufacturing of Reciproc Blue R25 (RB 25.08; VDW, Munich, Germany), X1 Blue File 25 (X1 25.06; MK Life Medical and Dental Products, Porto Alegre, Brazil) and WaveOne Gold Primary (WOG 25.07; Dentsply Maillefer, Ballaigues, Switzerland). MATERIALS AND METHODS: Sixty instruments of the RB 25.08, X1 25.06 and WOG 25.07 systems were used (n = 20). Cyclic fatigue tests were performed at room temperature (20 degrees +/- 1 degrees C) and at body temperature (37 degrees +/- 1 degrees C). The instruments were reciprocated until fracture occurred in an artificial stainless steel canal with a 60 degrees angle and a 5-mm radius of curvature. The time to fracture (TTF) was recorded. Also, the number of cycles to fracture (NCF) was calculated. Data were analysed using one-way ANOVA and Tukey's tests for inter-group comparison at both temperatures and for the reduction of cyclic fatigue at body temperature. For intra-group comparison at the different temperatures, the unpaired t test was used. RESULTS: The cyclic fatigue test at 20 degrees C showed that RB 25.08 and X1 25.06 presented significantly higher TTF and NCF than WOG 25.07 (P < 0.05). At 37 degrees C, all groups presented significant reduction of TTF and NCF (P < 0.05). RB 25.08 presented significant higher TTF than WOG 25.07 (P < 0.05). Regarding the NCF, there was no significant difference among the groups (P > 0.05). The WOG 25.07 presented the lowest percentage reduction of cyclic fatigue (P < 0.05). CONCLUSION: The body temperature treatment caused a marked reduction of the cyclic fatigue resistance for all reciprocating instruments tested. The RB 25.08 and X1 25.06 systems presented similar results at both temperatures tested. However, WOG 25.07 presented the lowest percentage reduction in fatigue resistance at body temperature. CLINICAL RELEVANCE: The cyclic fatigue resistance of NiTi reciprocating instruments has been evaluated at room temperature. However, the fatigue resistance significantly decreases upon exposure to body temperature, which could affect the mechanical behaviour of the NiTi instruments during root canal preparation. PMID- 30397734 TI - Impact of a modified motion on the fatigue life of NiTi reciprocating instruments: a Weibull analysis. AB - OBJECTIVES: To evaluate the impact of a modified motion on the fatigue life of four brands of nickel-titanium (NiTi) reciprocating instruments. MATERIALS AND METHODS: Cyclic fatigue (CF) resistance of 160 instruments was evaluated in an artificial stainless-steel canal (90 degrees angle, 5-mm radius of curvature). WaveOne and WaveOne Gold (Denstply Maillefer, Baillagues, Switzerland) and Reciproc and Reciproc Blue (VDW, Munich, Germany) were tested with two different motions: (1) X-Smart Plus (Denstply Maillefer) endodontic motor and (2) a 4:1 contra-angle with an experimental motion (EVO) with different rotation angles and based on a sinusoidal acceleration. Motions with X-Smart Plus and EVO were recorded and analyzed at a reduced speed with VLC Media Player software for a more accurate analysis. Mean half-life, beta, and eta Weibull parameters were determined and compared. RESULTS: Reciproc Blue resulted the most resistant instruments either with EVO or X-Smart. WaveOne Gold lasted significantly longer than WaveOne with EVO (probability of 91%) while no significant differences were found with X-Smart. Considering NCF, Reciproc, WaveOne Gold, and Reciproc Blue lasted significantly longer with EVO (probabilities of 66%, 80%, and 89% respectively). WaveOne Gold showed the highest beta parameter. CONCLUSIONS: The experimental motion was found to have a positive impact on fatigue lifetime of reciprocating instruments. CLINICAL RELEVANCE: Current findings provide insight for future improvements in the clinical use of reciprocating files. Experimental motions may be considered when searching for additional strategies in order to increase the safer use of NiTi files during endodontic procedures. PMID- 30397736 TI - [Results of the LuPSMA trial show high response rates with low toxicity and pain relief]. PMID- 30397735 TI - Post-obturation pain following the use of carrier-based system with AH Plus or iRoot SP sealers: a randomized controlled clinical trial. AB - OBJECTIVES: The aim of this study was to compare the postoperative pain after root canal treatment using a carrier-based obturation system and two different sealers. MATERIALS AND METHODS: In this prospective randomized clinical trial, 160 patients were selected. Patients with vital and devital teeth were randomized into four groups using a randomized block design with block sizes of 10 patients each. The groups were devital/vital teeth treated with iRoot SP sealer and devital/vital teeth treated with AH Plus sealer. Patients were prescribed ibuprofen, a 200-mg analgesic, if needed, and postoperative pain was recorded by visual analogue scale at 6, 12, 24, and 72 h after obturation. Pain score and frequency of tablet intake were recorded and statistically analyzed. RESULTS: Results showed that there was no significant difference between groups in the incidence of postoperative pain; however, iRoot SP sealer was associated with less analgesic intake compared to AH Plus sealer. CONCLUSION: The use of different sealers did not significantly affect pain levels. CLINICAL RELEVANCE: iRoot SP sealer was associated with less analgesic intake compared to AH Plus sealer. PMID- 30397737 TI - Growing from Our Roots: Strategies for Developing Culturally Grounded Health Promotion Interventions in American Indian, Alaska Native, and Native Hawaiian Communities. AB - Given the paucity of empirically based health promotion interventions designed by and for American Indian, Alaska Native, and Native Hawaiian (i.e., Native) communities, researchers and partnering communities have had to rely on the adaptation of evidence-based interventions (EBIs) designed for non-Native populations, a decidedly sub-optimal approach. Native communities have called for development of Indigenous health promotion programs in which their cultural worldviews and protocols are prioritized in the design, development, testing, and implementation. There is limited information regarding how Native communities and scholars have successfully collaborated to design and implement culturally based prevention efforts "from the ground up." Drawing on five diverse community-based Native health intervention studies, we describe strategies for designing and implementing culturally grounded models of health promotion developed in partnership with Native communities. Additionally, we highlight indigenist worldviews and protocols that undergird Native health interventions with an emphasis on the incorporation of (1) original instructions, (2) relational restoration, (3) narrative-[em]bodied transformation, and (4) indigenist community-based participatory research (ICBPR) processes. Finally, we demonstrate how culturally grounded interventions can improve population health when they prioritize local Indigenous knowledge and health-positive messages for individual to multi-level community interventions. PMID- 30397739 TI - [Pain and ageing]. PMID- 30397738 TI - The utility of current criteria for split-night polysomnography for predicting CPAP eligibility. AB - INTRODUCTION: Traditionally, evaluation of obstructive sleep apnea (OSA) has consisted of a diagnostic polysomnogram (PSG), followed by a continuous positive pressure (CPAP) titration. However, to reduce costs, many third-party payers mandate performance of split-night studies (SPL), combining diagnostic and CPAP titration testing. We ascertained the utility of performing SPL for diagnosis and treatment of OSA. METHODS: We reviewed the PSG records of 200 patients suspected of having OSA. Using both American Academy of Sleep Medicine (AASM) and Medicare (CMS) criteria for scoring, we calculated the sensitivity, specificity, positive (PPV), and negative predictive value (NPV) of the AHI in the first 2 h of sleep for predicting an overall AHI > 15. RESULTS: For predicting an overall AHI > 15, the sensitivity, specificity, PPV, and NPV of an AHI (AASM criteria) > 40 in the first 2 h were respectively: 0.304, 1.000, 1.000, and 0.335. For an AHI > 20 in the first 2 h, the corresponding values were 0.770, 0.962, 0.983, and 0.595. Corresponding values using CMS criteria were 0.347, 1.0, 1.0, and 0.6 for AHI > 40, and 0.693, 0.99, 0.986, and 0.76 for AHI > 20, respectively. CONCLUSION: For justification of CPAP (overall AHI > 15), the sensitivity is slightly lower when using an AHI > 40 vs AHI > 20, but the specificity and PPV are much higher. Using AHI > 20 as criteria for SPL as opposed to the guideline criteria of AHI > 40 may be more effective in obtaining CPAP for patients with moderate to severe OSA. PMID- 30397740 TI - ? PMID- 30397741 TI - Chloroplast transport and import. PMID- 30397742 TI - Management and survival trends for adult patients with malignant gliomas in the setting of multiple primary tumors: a population based analysis. AB - INTRODUCTION: The impact of multiple primary tumors, in the setting of malignant glioma (MG), has not been heavily explored. METHODS: We extracted demographics and clinical data from the SEER-18 registry for adult patients with MGs. The cases were separated based on the sequence of MG diagnosis relative to the other primary tumors: Group (A) One primary only or first primary of multiple primaries and Group (B) second primary or subsequent primary tumor. Incidences, frequencies, and glioma-related survivals were analyzed. RESULTS: Group B constituted 12.8% of new MG. The incidences of group B, relative to those of all new MG, range from 0.14 to 0.18. Compared to group A, group B exhibited an older age. Moreover, group B exhibited a higher proportion of females, Caucasians, smaller tumors, non-operative cases, and those receiving radiation (p < 0.05); the proportion with GTR remained comparable. Multiple groupings (oral cavity, digestive system, respiratory system, skin, breast, genital systems, urinary system, lymphoma) exhibited lower glioma-related observed survival (p < 0.05) compared to Group A. An active diagnosis of "leukemia" appears to confer longer glioma-related survival while a history of "breast" or "digestive system" malignancies portends a shorter glioma-related survival. CONCLUSION: For newly diagnosed MG, a high proportion does have history of extra-CNS primary tumors. Generally, these patients appear to have worse glioma-related observed survival compare to those with malignant glioma as the only primary or the first of multiple primary tumors. Knowledge regarding epidemiology, clinical factors, and observed survival can help guide clinical management/consultation for this subset of patients. PMID- 30397743 TI - A rare case of peritoneal deposits with carbon pigmentation after preoperative endoscopic tattooing for sigmoid colon cancer. AB - PURPOSE: We report a case in which pigmented peritoneal deposits were found during laparoscopic surgery following preoperative endoscopic tattooing for sigmoid colon cancer. METHODS: The patient's clinical, endoscopic, and histological data from the Niigata City General Hospital were reviewed, as well as the literature on laparoscopic surgery involving the preoperative endoscopic tattoo, with a focus on the relevance of peritoneal deposits and tattooing ink. RESULTS: A 71-year-old man presented to our hospital complaining of vomiting and abdominal distention. Abdominal computed tomography revealed obstructive sigmoid colon cancer. An emergency endoscopic colon stenting procedure and injection of 0.2 ml India ink to the submucosal layer of the tumor's anal side were performed. Laparoscopic-assisted sigmoid colectomy was done 14 days after stenting. At surgery, seven small peritoneal deposits were seen in the rectovesical pouch and at the site adjacent to the tumor. All peritoneal deposits were stained by the ink. Gross leakage of the ink into extraintestinal sites was seen. The seven peritoneal deposits were resected under laparoscope. Histological findings revealed that the seven peritoneal deposits were composed of adenocarcinoma and carbon pigments. Immunohistochemical staining for cluster of differentiation 163 showed that the carbon pigments in the peritoneal deposits were within macrophages. CONCLUSIONS: The possibility of the tattooing procedure causing peritoneal dissemination cannot be completely denied, but it can be hypothesized that the carbon pigmentation was transferred to peritoneal deposits by macrophages. In the future, we hope that this phenomenon becomes a keystone for diagnoses and treatments for peritoneal dissemination. PMID- 30397744 TI - Survival benefits of additional surgery after non-curative endoscopic resection in patients with early gastric cancer: a meta-analysis. AB - BACKGROUND: The survival benefit of additional surgery after non-curative endoscopic resection of early gastric cancer is a matter of debate. This meta analysis is intended to draw a convincing conclusion on this issue based on data currently available. METHODS: A systematic review of PubMed/Medline database was performed from 2010 to 2018 for studies comparing survival outcomes of additional surgery versus simple follow-up after non-curative endoscopic resection for early gastric cancer. Differences between groups were calculated using either the fixed effects model or random effects model. RESULTS: Ten retrospective studies with 4225 patients met the inclusion criteria. Additional surgery significantly provided better 5 years overall survival [odds ratios (OR) 3.50, 95% confidence interval (95% CI) 2.89-4.24] and disease-specific survival (OR 3.99, 95% CI 2.50 6.36). CONCLUSIONS: Additional surgery offers survival benefits to patients undergoing non-curative endoscopic resection of early gastric cancer. PMID- 30397745 TI - False-negative double-balloon enteroscopy in overt small bowel bleeding: long term follow-up after negative results. AB - BACKGROUND AND AIM: Double-balloon enteroscopy (DBE) performed to investigate overt small bowel bleeding can miss the source of bleeding. We investigated the clinical outcomes of patients with negative DBE results for suspected overt small bowel bleeding, which is defined in the current guidelines as obscure gastrointestinal bleeding. METHODS: We reviewed the prospectively collected medical records of patients who underwent DBE at our hospital between May 1, 2004 and April 30, 2016. During this period, 297 patients underwent DBE for suspected overt small bowel bleeding. The first DBE yielded negative results for 83 patients (27.9%). Written interviews, telephone interviews, and medical records of these patients were reviewed in April 2017. Follow-up data were collected for 63 patients (75.9%). RESULTS: During a mean follow-up period of 83.5 months, re bleeding occurred in 21 of 63 patients (33.3%) after a mean of 23.0 months after the first DBE yielded negative results. The bleeding source was identified in 19 of 21 patients (90.5%). In 15 of these 19 patients (78.9%), the source was the small intestine. Among these 15 patients, 14 (93.3%) had bleeding sites within reach of the first DBE and 3 (20%) experienced their first incidence of re bleeding more than 3 years after the first DBE. The need for transfusion for the first bleeding episode was a predictor of re-bleeding (odds ratio 7.5; 95% confidence interval 1.7-33.0). CONCLUSIONS: False-negative DBE results for overt small bowel bleeding are not rare, and the first re-bleeding episode can occur 3 years later. Repeat DBE when re-bleeding occurs should be considered, even if the first DBE results were negative. PMID- 30397746 TI - [Proceedings of the 13th congress of the German-Japanese Society of Dermatology]. PMID- 30397747 TI - [Skin diseases and fertility/hormone disorders]. AB - Male fertility can be impaired by a multitude of factors. In addition to environmental and life style factors, such as stress, noise, smoking and overweight, diverse diseases can also have a negative effect on the ability to father a child and the hormone balance, particularly the testosterone level. In many diseases the currently available data do not go beyond observations of limited fertility. In this article the focus is on diseases in the treatment field of dermatology. Special attention is paid to chronic inflammatory and autoimmune skin diseases. Data from recent years show that the excessive inflammatory reaction that these diseases have in common, most probably also has an influence on fertility and interacts with the testosterone concentration in serum. In addition, the impact of hereditary skin diseases on male fertility is discussed, which can have a direct influence on the ability to father a child due to disruption of the hypothalamus-pituitary-gonad axis. PMID- 30397749 TI - Duckweed biomarkers for identifying toxic water contaminants? AB - Surface or ground waters can be contaminated with numerous toxic substances. The duckweeds Lemna minor and Lemna gibba are widely used for assaying waterborne toxicity to higher plants in terms of growth inhibition and photosynthetic pigment reduction. These tests cannot, however, in themselves determine the nature of the agents responsible for toxicity. Morphological, developmental, physiological, biochemical, and genetic responses of duckweeds to exposure to toxic water contaminants constitute biomarkers of toxic effect. In principle, the very detection of these biomarkers should enable the contaminants having elicited them (and being responsible for the toxicity) to be identified. However, in practice, this is severely compromised by insufficient specificity of biomarkers for their corresponding toxicants and by the lack of documentation of biomarker/toxin relationships. The present contribution illustrates the difficulties of using known water contaminant-related duckweed biomarkers to identify toxins, and discusses possibilities for achieving this goal. PMID- 30397750 TI - Characterization of differentially expressed genes to Cu stress in Brassica nigra by Arabidopsis genome arrays. AB - Phytoremediation is an efficient and promising cleanup technology to extract or inactivate heavy metals and several organic and inorganic pollutants from soil and water. In this study, different Brassica nigra L. ecotypes, including Diyarbakir, collected from mining areas were exposed to different concentrations of copper and harvested after 72 h of Cu stress for the assessment of phytoremediation capacity. The Diyarbakir ecotype was called as "metallophyte" because of surviving at 500 MUM Cu. To better understand Cu stress mechanism, ArabidopsisATH1 genome array was used to compare the gene expression in root and shoot tissues of B. nigra under 25 MUM Cu. The response to Cu was much stronger in roots (88 genes showing increased or decreased mRNA levels) than in leaf tissues (24 responding genes). These genes were classified into the metal transport and accumulation-related genes, signal transduction and metabolism related genes, and transport facilitation genes. Glutathione pathway-related genes (gamma-ECS, PC, etc.) mRNAs were identified as differentially expressed in root and shoot tissues. QRT-PCR validation experiments showed that gamma-ECS and PC expression was upregulated in the shoot and leaf tissues of the 100 MUM Cu subjected B. nigra-tolerant ecotype. This is the first study showing global expression profiles in response to Cu stress in B. nigra by Arabidopsis genome array. This work presented herein provides a well-illustrated insight into the global gene expression to Cu stress response in plants, and identified genes from microarray data will serve as molecular tools for the phytoremediation applications in the future. PMID- 30397748 TI - Reconstituted Discoidal High-Density Lipoproteins: Bioinspired Nanodiscs with Many Unexpected Applications. AB - PURPOSE OF REVIEW: Summarize the initial discovery of discoidal high-density lipoprotein (HDL) in human plasma and review more recent innovations that span the use of reconstituted nanodisc HDL for membrane protein characterization to its use as a drug carrier and a novel therapeutic agent for cardiovascular disease. RECENT FINDINGS: Using a wide variety of biophysical techniques, the structure and composition of endogenous discoidal HDL have now largely been solved. This has led to the development of new methods for the in vitro reconstitution of nanodisc HDL, which have proven to have a wide variety of biomedical applications. Nanodisc HDL has been used as a platform for mimicking the plasma membrane for the reconstitution and investigation of the structures of several plasma membrane proteins, such as cytochrome P450s and ABC transporters. Nanodisc HDL has also been designed as drug carriers to transport amphipathic, as well as hydrophobic small molecules, and has potential therapeutic applications for several diseases. Finally, nanodisc HDL itself like native discoidal HDL can mediate cholesterol efflux from cells and are currently being tested in late stage clinical trials for cardiovascular disease. The discovery of the characterization of native discoidal HDL has inspired a new field of synthetic nanodisc HDL, which has offered a growing number of unanticipated biomedical applications. PMID- 30397751 TI - China's provincial CO2 emissions and interprovincial transfer caused by investment demand. AB - Based on the China's 1997, 2002, 2007, and 2012 multiregional input-output model, this study calculates China's provincial CO2 emissions from investment demand and interprovincial transfer of CO2 emissions caused by investment demand. The findings of this study are as follows: (1) From 1997 to 2012, the CO2 emissions from China's investment demand have seen rapid growth-the CO2 emissions from investment demand has increased by 4.52 times, and the per capita CO2 emissions caused by investment demand has increased by 4.13 times. Investment demand is an important driver of growth of China's CO2 emissions. The proportion of CO2 emissions from investment demand in CO2 emissions from China's three final demands rose from 37.72% in 1997 to 50.68% in 2012. (2) The CO2 emissions from investment demand are relatively large in provinces which have large-scale industries. Affected by investment-driven economic growth, CO2 emissions from investment demand in central, western, and northeastern provinces have increased more rapidly. (3) Large amounts of CO2 are emitted in the less-developed central and western provinces to meet the investment demand of the developed eastern provinces. As China's economy enters the "new normal," economic growth is shifting from investment-driven to consumption-driven, and the growth of CO2 emissions from investment demand will slow down. PMID- 30397752 TI - A fugacity model assessment of ibuprofen, diclofenac, carbamazepine, and their transformation product concentrations in an aquatic environment. AB - An updated version of FATEMOD, a multimedia fugacity model for environmental fate of organic chemicals, was set up to assess environmental behaviour of three pharmaceuticals in northern Lake Paijanne, Finland. Concentrations of ibuprofen, diclofenac, and carbamazepine were estimated at various depths at two sites: near a wastewater treatment plant and 3.5 km downstream the plant. When compared with environmental sampling data from corresponding depths and sites, the predicted concentrations, ranging from nanograms to hundreds of nanograms per litre, were found to be in good agreement. Weather data were utilised with the model to rationalise the effects of various environmental parameters on the sampling results, and, e.g. the roles of various properties of lake dynamics and photodegradation were identified. The new model also enables simultaneous assessment of transformation products. Environmentally formed transformation product concentrations were estimated to be at highest an order of magnitude lower than those of the parent compounds, and unlikely to reach a detectable level. However, a possibility that conjugates of ibuprofen are present at higher levels than the parent compound was identified. Simulation results suggest that environmental degradation half-lives of the inspected contaminants under stratified lake conditions are in the range of some weeks to months. PMID- 30397753 TI - Evaluating polar pesticide pollution with a combined approach: a survey of agricultural practices and POCIS passive samplers in a Tunisian lagoon watershed. AB - A study of pesticides in the Bizerte lagoon watershed on the Mediterranean coast of Tunisia showed that herbicides and fungicides are the most commonly used compounds. A survey was made of selected farmers. Pesticide contamination was monitored in the water column and sediments at four selected sampling sites (lagoon (A) and in three oueds-Chegui (B), Garaa (C), and Tinja (D)). Polar organic chemical integrative samplers (POCIS) were used to assess pesticide contamination. Thirty-two pesticides were investigated; the total concentration of active ingredients ranged from 35.9 ng L-1 in Tinja oued to 1246 ng L-1 in Chegui oued. In the lagoon, the total concentration of pesticides was 67.7 ng L 1. In the sediments, the highest concentration was measured in Chegui oued in the spring (31 ng g-1 dw). The main compounds found in the analyzed sediments were prosulfocarb and tebuconazole molecules. PMID- 30397754 TI - Environmental risk assessment of psychoactive drugs in the aquatic environment. AB - The consumption of psychoactive pharmaceuticals has increased worldwide, and wastewater treatment plants are not able to eliminate them from the effluent. An extensive review was carried out to assess the environmental risk (ERA model) based on secondary data about potential impacts on non-target organisms of seven psychoactive drugs consumed worldwide (alprazolam, bromazepam, citalopram, clonazepam, diazepam, lorazepam, and oxazepam). Risk quotients (RQs) were calculated according to the European Medicines Agency (EMA) on ERA of Medicinal Products For Human Use based on (i) the predicted and measured environmental concentrations (PEC and MEC, respectively) of the psychoactive drug in surface water, groundwater, and wastewater effluent and (ii) the predicted no-effect concentration (PNEC) derived from ecotoxicological assays or ECOSAR software. Furthermore, this study reviews and discusses non-standardized ecotoxicity assays, such as sublethal and behavioral effects on different organisms. In total, 903 MEC entries of psychoactive drugs and 162 data on ecotoxicological assays were gathered from the literature survey addressing behavioral effects (115), acute/chronic effects (35), and sublethal effects (12). Citalopram and diazepam were the only substances that are likely to pose an environmental risk (RQ > 1) to surface waters. Even though there is considerable amount of data on behavioral effects of psychoactive drugs to aquatic species, results are currently not integrated into the EMA risk assessment framework. The large amount of data on psychoactive drug concentrations and effects on non-target organisms collected, interpreted, and discussed in the present study should be used as a baseline for future improvement of ERA strategies. PMID- 30397755 TI - A multivariate analysis of physiological and antioxidant responses and health hazards of wheat under cadmium and lead stress. AB - Soil contamination with heavy metals is a global issue confronting the environmental pollution and human/animal health. Much work has been done on physiological and antioxidant responses of wheat in hydroponic experiments and health risks from individual heavy metal contamination to human, but limited information is available on their combined application in soil. Therefore, this pot study delineates the uptake of lead and cadmium, as well as physiological responses of wheat and associated health risks under different levels of alone and combined Cd and Pb treatments. Metal uptake increased with their increasing applied levels. The highest Cd (4.24, 1.38, and 0.92 mg kg-1) and Pb (763.33, 39.63, and 16.35 mg kg-1) concentrations in root, shoot, and grain, respectively, were observed at highest applied levels (0.4 mM Cd and 10 mM Pb). Furthermore, all the treatments increased lipid peroxidation and activities of superoxide dismutase, catalase, ascorbate peroxidase, and peroxidase, while decreased total chlorophyll contents and membrane stability index. Under combined application of Cd and Pb, the toxicity and detoxification responses of wheat increased compared to alone treatments. Multivariate analysis further confirmed the toxicity and accumulation pattern of metals under alone and combined treatments. Target hazard quotient values of Cd and Pb were < 1 under alone and combined treatments. The health hazard index values of Pb (97.07 and 87.89%) were higher than those of Cd (2.93 and 12.10%) in combined application for human and buffalo, respectively. This study highlights that the multi-metal contamination (Cd and Pb) is detrimental for wheat growth and human/animal health. PMID- 30397756 TI - Fast and facile analysis of glycosylation and phosphorylation of fibrinogen from human plasma-correlation with liver cancer and liver cirrhosis. AB - Hepatocellular carcinoma (HCC) is one of the deadliest cancers due to its late diagnosis with the main risk factor being liver cirrhosis (LC). Glycan structures from glycoproteins are usually altered in cancer. Blood plasma from 111 healthy and sick donors was analyzed to determine the post-translational modifications (PTM) of intact Aalpha-, Bbeta-, and gamma-subunits of fibrinogen, a glycoprotein predominantly produced in liver cells. Glycosylation and phosphorylation of the protein species were quantified by liquid chromatography coupled to mass spectrometry to correlate PTMs to pathological cases. Quantities of the PTMs were used for statistical classification by principal component analysis (PCA) and multivariate analysis of variance (MANOVA). As relevant clinical finding, patients with liver disease (HCC and/or LC) were distinguished from individuals without relevant chronic liver disease with 91% sensitivity and 100% specificity. Within the group of patients with liver disease, a robust separation between LC and HCC was not possible. In more detail, the phosphorylation of Aalpha-subunit is decreased in HCC patients, whereas the monophosphorylated state is significantly increased in LC patients. In terms of glycosylation, the amount of O-glycans in the Aalpha-subunit is decreased in LC patients, while sialylation and fucosylation of N-type glycans of Bbeta- and gamma-subunits are increased in LC and HCC. Based on PTM of fibrinogen, starting from plasma we can assign the status of an individual as healthy or as liver disease in less than 3 h. PMID- 30397757 TI - Nanowell-mediated multidimensional separations combining nanoLC with SLIM IM-MS for rapid, high-peak-capacity proteomic analyses. AB - Mass spectrometry (MS)-based analysis of complex biological samples is essential for biomedical research and clinical diagnostics. The separation prior to MS plays a key role in the overall analysis, with separations having larger peak capacities often leading to more identified species and improved confidence in those identifications. High-resolution ion mobility (IM) separations enabled by Structures for Lossless Ion Manipulation (SLIM) can provide extremely rapid, high resolution separations and are well suited as a second dimension of separation following nanoscale liquid chromatography (nanoLC). However, existing sample handling approaches for offline coupling of separation modes require microliter fraction volumes and are thus not well suited for analysis of trace biological samples. We have developed a novel nanowell-mediated fractionation system that enables nanoLC-separated samples to be efficiently preconcentrated and directly infused at nanoelectrospray flow rates for downstream analysis. When coupled with SLIM IM-MS, the platform enables rapid and high-peak-capacity multidimensional separations of small biological samples. In this study, peptides eluting from a 100 nL/min nanoLC separation were fractionated into ~ 60 nanowells on a microfluidic glass chip using an in-house-developed robotic system. The dried samples on the chip were individually reconstituted and ionized by nanoelectrospray for SLIM IM-MS analysis. Using model peptides for characterization of the nanowell platform, we found that at least 80% of the peptide components of the fractionated samples were recovered from the nanowells, providing up to ~tenfold preconcentration for SLIM IM-MS analysis. The combined LC-SLIM IM separation peak capacities exceeded 3600 with a measurement throughput that is similar to current one-dimensional (1D) LC-MS proteomic analyses. Graphical abstract A nanowell-mediated multidimensional separation platform that combines nanoLC with SLIM IM-MS enables rapid, high-peak-capacity proteomic analyses. PMID- 30397758 TI - Corona discharge electrospray ionization of formate-containing solutions enables in-source reduction of disulfide bonds. AB - Disulfide bonds are critical linkages for maintaining protein structure and enzyme activity. These linkages, however, can limit peptide sequencing efforts by mass spectrometry (MS) and often require chemical reduction and alkylation. Under such conditions, information regarding cysteine connectivity is lost. Online partial disulfide reduction within the electrospray (ESI) source has recently been established as a means to identify complex cysteine linkage patterns in a liquid chromatography-MS experiment without the need for sample pre-treatment. Corona discharge (CD) is invoked as the causative factor of this in-source reduction (ISR); however, evidence remains largely circumstantial. In this study, we demonstrate that instrumental factors-nebulizing gas, ESI capillary material, organic solvent content, ESI spray needle-to-MS distance-all modulate the degree of reduction observed for the single disulfide in oxytocin, further implicating CD in ISR. Rigorous analysis of solution conditions, however, reveals that corona discharge alone can induce only minor disulfide reduction. We establish that CD ESI of peptide solutions containing formic acid or its conjugate base results in a dramatic increase in disulfide reduction. It is also determined that ISR is exacerbated at low pH for complex peptides containing multiple disulfide bonds and possessing higher-order structure, as well as for a small protein. Overall, our results demonstrate that ESI of formate/formic acid-containing solutions under corona discharge conditions facilitates disulfide ISR, likely by a similar reduction pathway measured in gamma-radiolysis studies nearly three decades ago. PMID- 30397759 TI - Towards metrologically traceable and comparable results in GM quantification. AB - The GM content in a food or feed product produced from or containing genetically modified organisms (GMO) has to be expressed in Europe in the form of a GM mass fraction. However, the most widely used quantification methods, based on PCR, are basically counting PCR-amplifiable DNA fragments in a sample extract. This paper outlines the requirements for obtaining comparable measurement results which are fit for regulatory decision-making. It introduces the concept of a reference measurement system which enables GMO analysis laboratories to relate their results to a universally accessible reference, thus establishing metrological traceability to a unique reference point. The conversion factors required for transforming data from one measurement unit into the other have to carry a minimum uncertainty and are anchored to specified certified reference materials. The establishment of such conversion factors and related calibration approaches to achieve comparable GM quantification results are sketched. Graphical abstract ?. PMID- 30397760 TI - Silver and gold nanoparticles as multi-chromatic lateral flow assay probes for the detection of food allergens. AB - In this study, we report the simultaneous use of gold and silver nanoparticles to set a multicolor multiplex lateral flow immunoassay (xLFIA). Silver nanoparticles (AgNPs), spherical in shape and characterized by a brilliant yellow color, were obtained by a new viable one-step synthetic protocol. AgNPs were stable over time and acceptably robust to conditions used for fabricating LFIA devices. These AgNPs were employed as a colorimetric probe in combination with two different kinds of gold nanoparticles (AuNPs) to set a visual xLFIA for detecting allergens. Surface plasmon resonance peaks of probes (AgNPs, spherical and desert rose-like AuNPs) were centered at 420, 525, and 620 nm, respectively. Therefore, the xLFIA output was easily interpreted through a "yellow magenta cyan (YMC)" color code. The prospect of the YMC xLFIA was demonstrated by simultaneously detecting three major allergens in bakery products. Antibodies directed towards casein, ovalbumin, and hazelnut allergenic proteins were individually adsorbed onto metal nanoparticles to produce three differently colored specific probes. These were inserted in a LFIA comprising three lines, each responsive for one allergen. The trichromatic xLFIA was able to detect allergenic proteins at levels as low as 0.1 mg/l and enabled the easy identification of the allergens in commercial biscuits based on the color of the probes. Graphical Abstract. PMID- 30397761 TI - [Airway management in intensive care and emergency medicine : What is new?] AB - In acute respiratory insufficiency, oxygenation and/or ventilation support by mechanical ventilation is an integral part of intensive care and emergency medicine. Effective airway management is essential to prevent hypoxic complications during the securing of the airway. This includes for example the recognition of difficult airways and adequate pre-oxygenation. While the laryngeal tube can be used in the context of cardiopulmonary resuscitation in emergency medicine, endotracheal intubation is standard in intensive care medicine. In addition to direct laryngoscopy (DL), indirect laryngoscopy using video laryngoscopy (VL) is also available. Compared to DL, advantages in intubation success, anticipated difficult airways, and a reduction of mucosa damage have been shown for VL, whereas the advantage for intubation success could only be demonstrated for experienced physicians who should always be present due to the potential complications of intubation. With regard to mortality and incidence of hypoxia, no difference between DL and VL could be shown. According to current data, the VL should not be used preclinically. A tracheostomy is often performed for long-term ventilation. It is still unclear which patients benefit from an early tracheostomy. Usually the bed-side percutaneous dilatation tracheostomy technique is used, which is often performed under bronchoscopic guidance. PMID- 30397762 TI - [Relationship between body temperature, neuron-specific enolase, and clinical course in patients after out-of-hospital cardiac arrest]. AB - BACKGROUND: According to ILCOR (International Liaison Committee on Resuscitation) recommendations (released in 2003), use of therapeutic hypothermia is recommended for unconscious adult patients who have survived a cardiac arrest regardless of the initial monitored cardiac rhythm. Thereby, the treatment goal is to achieve and maintain a body temperature of 32-34 degrees C for a period of 12-24 h. According to the October 2015 recommendations of the European Resuscitation Council (ERC), targeted temperature management (TTM) remains part of treatment, but, as an option, it is advised that the targeted body temperature be 36 degrees C rather than 32-34 degrees C. PATIENT POPULATION AND METHODS: For a non randomized retrospective observational study, a total of 149 patients were treated with cardiopulmonary resuscitation (CPR) between May 1999 and September 2009. For the first 4 days after CPR, data associated with demography, resuscitation, therapy (temperature course, neuron-specific enolase [NSE]) and clinical-neurological development (Glasgow Outcome Scale [GOS]) were collected. In the study, patients receiving mild hyperthermia were compared with those who did not receive hypothermia. RESULTS: Of the 149 patients included, 90 were treated with mild hypothermia (as decided by the attending physician), while 59 received no hypothermia therapy. Assessment reveals that mild hypothermia positively influences clinical-neurological progression, but not survival. On day three and four, patients with an unfavorable neurological progression exhibited significantly increased serum levels of NSE (day 4: 108.7 +/- 137.3 ng/ml versus 25.5 +/- 15.4 ng/ml). Patients receiving hypothermia showed lower average NSE levels compared with persons not receiving hypothermia. Furthermore, during the first 4 days, their NSE values tended to increase slower (NSE value at day 4: 55.9 +/- 64.9 ng/ml versus 129.9 +/- 174.9 ng/ml). The best cut-off-value for an unfavorable neurological result was 74.2 ng/ml at day four (specificity 100%, sensitivity 48.6%). For the group of patients who received hypothermia, the best cut-off-value was 74.2 ng/ml at day four (specificity 100%, sensitivity 40.9%), and, for the comparison group, best cut-off-value was 25.5 ng/ml at day three (specificity 100%, sensitivity 88.2%). CONCLUSION: After out-of-hospital resuscitation, there is a trend for improved clinical-neurological progression with mild hypothermia but it does not influence the prognostic significance of serum NSE. After assessment of available data, it is not possible to recommend uniform cut-off values for patients who received mild therapeutic hypothermia and for those who did not receive hypothermia treatment. PMID- 30397764 TI - Identification and characterization of GH11 xylanase and GH43 xylosidase from the chytridiomycetous fungus, Rhizophlyctis rosea. AB - The early-lineage, aerobic, zoosporic fungi from the Chytridiomycota constitute less than 1% of the described fungi and can use diverse sources of nutrition from plant or animal products. One of the ancestral sources of fungal nutrition could be products following enzymatic degradation of plant material. However, carbohydrate-active enzymes from these ancient fungi have been less studied. A GH11 xylanase (RrXyn11A) (EC 3.2.1.8) and a GH43 xylosidase (RrXyl43A) (EC 3.2.1.37) were identified from an early-lineage aerobic zoosporic fungus, Rhizophlyctis rosea NBRC 105426. Both genes were heterologously expressed in Pichia pastoris and the recombinant enzymes were purified and characterized. The optimal pH for recombinant RrXyn11A and RrXyl43A was pH 7. RrXyn11A had high stability over a wide range of pH (4-8) and temperature (25-70 degrees C). RrXyn11A also showed high substrate specificity on both azurine-cross-linked (AZCL) arabinoxylan and AZCL xylan. RrXyl43A had beta-xylosidase and minor alpha L-arabinofuranosidase activity. This enzyme showed low product inhibition and retained 51% activity in the presence of 100 mM xylose. A combination of RrXyn11A and RrXyl43A exhibited significantly higher hydrolytic and polymer degradation capability and xylose release on wheat bran and beechwood xylan compared to treatment with commercial enzymes. This study was the first to heterologously express and characterize the GH11 xylanase (RrXyn11A) and GH43 xylosidase (RrXyl43A) from the ancient fungus, R. rosea. Meanwhile, this study also demonstrated that the enzymes from the ancient fungus R. rosea can be easily handled and heterologously expressed in Pichia, which presents a promising path to a new source of enzymes for biomass degradation. PMID- 30397765 TI - Recent developments in non-biodegradable biopolymers: Precursors, production processes, and future perspectives. AB - During the last decades, biopolymers experienced a renaissance. The increasing limitation of fossil resources in combination with a public demand for environmental-friendly and sustainable processes has led to the formation of a market for biobased plastics. Especially non-biodegradable bioplastics are very interesting materials, as they combine the benefits of reduced carbon footprint during production and increased resource efficiency with the persistence to microbial degradation. Consequently, persistent biomass-derived plastic materials are highly promising to substitute conventional fossil-based plastics in applications, which require durability and longevity. Non-biodegradable bioplastics derived from renewable resources represent 57% of all bioplastics with partially biobased polyethylene terephthalate currently leading the market, followed by biobased polyamides and fully biomass-derived polyethylene. An exceptional biopolymer with thermoplastic properties was discovered only two decades ago, when-for the first time-polythioesters were synthesized by microbial fermentation. Though synthesized by bacteria, it turned out that polythioesters are non-biodegradable by microorganisms in contrast to all other biopolymers and thus, represent a novel non-biodegradable bioplastic material. This review gives an overview about the recent development and progress regarding bioplastics with special focus on persistent bioplastics. We describe the generation of the respective monomers from biomass-derived substrates and summarize the current status of production, which range from the laboratory-scale up to large-scale industrial processes. PMID- 30397763 TI - [Amendment to the documentation of decisions to withhold or withdraw life sustaining therapies in consideration of wish to donate organs : Recommendation of the Ethics Section and the Organ Donation and Transplantation Section of the German Interdisciplinary Association of Critical Care and Emergency Medicine (DIVI) in collaboration with the Ethics Section of the German Society of Medical Intensive Care Medicine and Emergency Medicine (DGIIN)]. AB - The Ethics Section of the German Interdisciplinary Association of Critical Care and Emergency Medicine (DIVI) recently published a documentation for decisions to withhold or withdraw life-sustaining therapies. The wish to donate organs was not considered explicitly. Therefore the Ethics Section and the Organ Donation and Transplantation Section of the DIVI together with the Ethics Section of the German Society of Medical Intensive Care Medicine and Emergency Medicine worked out a supplementary footnote for the documentation form to address the individual case of a patient's wish to donate organs. PMID- 30397766 TI - Identification of novel bacteriophage vB_EcoP-EG1 with lytic activity against planktonic and biofilm forms of uropathogenic Escherichia coli. AB - Urinary tract infections are one of the most common infectious diseases worldwide. Uropathogenic Escherichia coli (UPEC) is a major cause of unary tract infection. Due to increasing prevalence of multidrug resistance, alternative methods to eradicate the UPECs are urgently needed. In this respect, phage therapy has been demonstrated to be a good candidate. Here, we described a novel bacteriophage named vB_EcoP-EG1, which can infect several strains of UPEC. Phage morphology and genome sequencing analysis show that vB_EcoP-EG1 belongs to the T7 like Podoviridae. vB_EcoP-EG1 possesses a genome (39,919 bp) containing 51 predicted genes and 149 bp terminal repeats. vB_EcoP-EG1 genome does not encode toxic proteins or proteins related to lysogeny. And no known virulent proteins were found in purified phage particles by mass spectrometry. vB_EcoP-EG1 appeared to be relatively specific and sensitive to clinical UPEC strains, which could infect 10 out of 21 clinical multidrug-resistant UPEC strains. In addition, vB_EcoP-EG1 suspension can eliminate biofilm formed by E. coli MG1655 and multidrug-resistant UPEC strain 390G7. Therefore, we concluded that vB_EcoP-EG1 has desirable characteristics for potential therapy, which may serve as an alternative to antibiotic therapy against urinary tract infections caused by multidrug-resistant UPEC. PMID- 30397767 TI - Probiotics-fermented Massa Medicata Fermentata ameliorates weaning stress in piglets related to improving intestinal homeostasis. AB - Weaning stress has serious negative effects on piglets' health and the swine industry. Probiotics-fermented Chinese herbal medicines are potential feed additives to ameliorate weaning stress. In this study, the effects of probiotics fermented Massa Medicata Fermentata (MMFP) on intestinal homeostasis were evaluated in weaning piglets. Dietary supplementation with MMFP promoted the development of the intestinal structure and elevated the concentrations of lactic acid and short-chain fatty acids (SCFAs) in the intestinal contents and antioxidant capacities in serum. MMFP reduced the levels of inflammatory factors in the intestinal mucosa. Microbial community analysis demonstrated that MMFP led to the selective and progressive enrichment of lactic acid- and SCFA-producing bacteria along the gastrointestinal tract, in particular, OTUs corresponding to Lactobacillus, Streptococcus, Acetitomaculum, Roseburia, and Eubacterium xylanophilum group, while MMFP reduced the relative abundance of pathogenic bacteria. On the contrary, antibiotics had negative effects on intestinal histology and increased the relative abundance of pro-inflammatory bacterium, such as Marvinbryantia, Peptococcus, Turicibacter, and Blautia. Correlation analysis reflected that the bacteria enriched in MMFP group were positively correlated with enhanced intestinal homeostasis, which suggested that dietary supplementation with MMFP enhanced host intestinal homeostasis by modulating the composition of gut microbiota and the levels of beneficial SCFAs, thus ameliorating weaning stress in piglets. PMID- 30397768 TI - Molecular and physiological basis of Saccharomyces cerevisiae tolerance to adverse lignocellulose-based process conditions. AB - Lignocellulose-based biorefineries have been gaining increasing attention to substitute current petroleum-based refineries. Biomass processing requires a pretreatment step to break lignocellulosic biomass recalcitrant structure, which results in the release of a broad range of microbial inhibitors, mainly weak acids, furans, and phenolic compounds. Saccharomyces cerevisiae is the most commonly used organism for ethanol production; however, it can be severely distressed by these lignocellulose-derived inhibitors, in addition to other challenging conditions, such as pentose sugar utilization and the high temperatures required for an efficient simultaneous saccharification and fermentation step. Therefore, a better understanding of the yeast response and adaptation towards the presence of these multiple stresses is of crucial importance to design strategies to improve yeast robustness and bioconversion capacity from lignocellulosic biomass. This review includes an overview of the main inhibitors derived from diverse raw material resultants from different biomass pretreatments, and describes the main mechanisms of yeast response to their presence, as well as to the presence of stresses imposed by xylose utilization and high-temperature conditions, with a special emphasis on the synergistic effect of multiple inhibitors/stressors. Furthermore, successful cases of tolerance improvement of S. cerevisiae are highlighted, in particular those associated with other process-related physiologically relevant conditions. Decoding the overall yeast response mechanisms will pave the way for the integrated development of sustainable yeast cell-based biorefineries. PMID- 30397769 TI - Functional analysis of Mig1 and Rag5 as expressional regulators in thermotolerant yeast Kluyveromyces marxianus. AB - To analyze the glucose repression mechanism in the thermotolerant yeast Kluyveromyces marxianus, disrupted mutants of genes for Mig1 and Rag5 as orthologs of Mig1 and Hxk2, respectively, in Saccharomyces cerevisiae were constructed, and their characteristics were compared with those of the corresponding mutants of S. cerevisiae. MIG1 mutants of both yeasts exhibited more resistance than the corresponding parental strains to 2-deoxyglucose (2 DOG). Histidine was found to be essential for the growth of Kmmig1, but not that of Kmrag5, suggesting that MIG1 is required for histidine biosynthesis in K. marxianus. Moreover, Kmrag5 and Schxk2 were more resistant than the corresponding MIG1 mutant to 2-DOG, and only the latter increased the utilization speed of sucrose in the presence of glucose. Kmrag5 exhibited very low activities for gluco-hexokinase and hexokinase and, unlike Schxk2, showed very slow growth and a low level of ethanol production in a glucose medium. Furthermore, Kmrag5, but not Kmmig1, exhibited high inulinase activity in a glucose medium and exhibited greatly delayed utilization of accumulated fructose in the medium containing both glucose and sucrose. Transcription analysis revealed that the expression levels of INU1 for inulinase and GLK1 for glucokinase in Kmrag5 were higher than those in the parental strain; the expression level of INU1 in Kmmig1 was higher, but the expression levels of RAG1 for a low-affinity glucose transporter in Kmmig1 and Kmrag5 were lower. These findings suggest that except for regulation of histidine biosynthesis, Mig1 and Rag5 of K. marxianus play similar roles in the regulation of gene expression and share some functions with Mig1 and Hxk2, respectively, in S. cerevisiae. PMID- 30397770 TI - Trabecular microstructure is influenced by race and sex in Black and White young adults. AB - : Lower fracture rates in Black men and women compared to their White counterparts are incompletely understood. High-resolution imaging specific to trabecular bone may provide insight. Black participants have enhanced trabecular morphology. These differences may contribute to the lower fracture risk in Black versus White individuals. INTRODUCTION: Lower fracture rates in Black men and women compared to their White counterparts may be explained by favorable bone microstructure in Black individuals. Individual trabecular segmentation (ITS) analysis, which characterizes the alignment and plate- and rod-like nature of trabecular bone using high-resolution peripheral quantitative computed tomography (HR-pQCT), may provide insight into trabecular differences by race/ethnic origin. PURPOSE: We determined differences in trabecular bone microarchitecture, connectivity, and alignment according to race/ethnic origin and sex in young adults. METHODS: We analyzed HR-pQCT scans of 184 adult (24.2 +/- 3.4 years) women (n = 51 Black, n = 50 White) and men (n = 34 Black, n = 49 White). We used ANCOVA to compare bone outcomes, and adjusted for age, height, and weight. RESULTS: Overall, the effect of race on bone outcomes did not differ by sex, and the effect of sex on bone outcomes did not differ by race. After adjusting for covariates, Black participants and men of both races had greater trabecular plate volume fraction, plate thickness, plate number density, plate surface area, and greater axial alignment of trabeculae, leading to higher trabecular bone stiffness compared to White participants and women, respectively (p < 0.05 for all). CONCLUSION: These findings demonstrate that more favorable bone microarchitecture in Black individuals compared to White individuals and in men compared to women is not unique to the cortical bone compartment. Enhanced plate like morphology and greater trabecular axial alignment, established in young adulthood, may contribute to the improved bone strength and lower fracture risk in Black versus White individuals and in men compared to women. PMID- 30397771 TI - Magnetic resonance imaging of sacroiliitis in children: reply to Jalalvandi and Naderi. PMID- 30397773 TI - Use of Amplatzer Vascular Plug to Embolize Errant Chest Tube Tract in Liver. PMID- 30397772 TI - The Role of PD-1 Checkpoint Inhibition in Gynecologic Malignancies. AB - OPINION STATEMENT: Activity of PD-1 and PD-L1 inhibitors has been demonstrated in ovarian, endometrial, and cervical cancer, with a tolerable side effect profile and the highest response rate seen in mismatch repair-deficient endometrial cancers. Other biomarkers are under active investigation. Tumor testing for mismatch repair deficiency or high microsatellite instability for treatment with pembrolizumab should be considered an option for all women with progressive gynecologic malignancy. PMID- 30397774 TI - Aquaporins in the lung. AB - The lung is the interface between air and blood where the exchange of oxygen and carbon dioxide occurs. The surface liquid that is directly exposed to the gaseous compartment covers both conducting airways and respiratory zone and forms the air liquid interface. The barrier that separates this lining fluid of the airways and alveoli from the extracellular compartment is the pulmonary epithelium. The volume of the lining fluid must be kept in a range that guarantees an appropriate gas exchange and other functions, such as mucociliary clearance. It is generally accepted that this is maintained by balancing resorptive and secretory fluid transport across the pulmonary epithelium. Whereas osmosis is considered as the exclusive principle of fluid transport in the airways, filtration may contribute to alveolar fluid accumulation under pathologic conditions. Aquaporins (AQP) facilitate water flux across cell membranes, and as such, they provide a transcellular route for water transport across epithelia. However, their contribution to near-isosmolar fluid conditions in the lung still remains elusive. Herein, we discuss the role of AQPs in the lung with regard to fluid homeostasis across the respiratory epithelium. PMID- 30397775 TI - Structure-activity relationships of bath salt components: substituted cathinones and benzofurans at biogenic amine transporters. AB - RATIONALE: New psychoactive substances (NPSs), including substituted cathinones and other stimulants, are synthesized, sold on the Internet, and ingested without knowledge of their pharmacological activity and/or toxicity. In vitro pharmacology plays a role in therapeutic drug development, drug-protein in silico interaction modeling, and drug scheduling. OBJECTIVES: The goal of this research was to determine mechanisms of action that may indicate NPS abuse liability. METHODS: Affinities to displace the radioligand [125I]RTI-55 and potencies to inhibit [3H]neurotransmitter uptake for 22 cathinones, 6 benzofurans and another stimulant were characterized using human embryonic kidney cells stably expressing recombinant human transporters for dopamine, norepinephrine, or serotonin (hDAT, hNET, or hSERT, respectively). Selected compounds were tested for potencies and efficacies at inducing [3H]neurotransmitter release via the transporters. Computational modeling was conducted to explain plausible molecular interactions established by NPS and transporters. RESULTS: Most alpha-pyrrolidinophenones had high hDAT potencies and selectivities in uptake assays, with hDAT/hSERT uptake selectivity ratios of 83-360. Other substituted cathinones varied in their potencies and selectivities, with N-ethyl-hexedrone and N-ethyl-pentylone having highest hDAT potencies and N-propyl-pentedrone having highest hDAT selectivity. 4 Cl-ethcathinone and 3,4-methylenedioxy-N-propylcathinone had higher hSERT selectivity. Benzofurans generally had low hDAT selectivity, especially 1-(2,3 dihydrobenzofuran-5-yl)-N-methylpropan-2-amine, with 25-fold higher hSERT potency. Consistent with this selectivity, the benzofurans were releasers at hSERT. Modeling indicated key amino acids in the transporters' binding pockets that influence drug affinities. CONCLUSIONS: The alpha-pyrrolidinophenones, with high hDAT selectivity, have high abuse potential. Lower hDAT selectivity among benzofurans suggests similarity to methylenedioxymethamphetamine, entactogens with lower stimulant activity. PMID- 30397776 TI - Canine and feline dirofilariosis in a highly enzootic area: first report of feline dirofilariosis in Greece. AB - Dirofilaria immitis (heartworm) is enzootic in many areas of the world and quite prevalent in southern European countries. Although dogs are the main host of the parasite, cats may also be infected, and the prevalence of feline dirofilariosis is associated with the respective prevalence of canine infection in any given area. The aim of the present study was to investigate the proportion of D. immitis infection among dogs and cats that were not under any kind of prophylactic treatment and were living in a heartworm enzootic area. In total, 180 stray animals (148 dogs and 32 cats) living in a shelter in Northern Greece were examined for heartworm infection by the Knott's test and serology (antigen and in cats also antibody detection), and additionally echocardiography in the infected cats. Thirty-seven (25%, CI 18.7-32.5%) of the dogs and 3 (9.4%, CI 3.2 24.2%) of cats were found to be positive, by at least one of the tests applied. In 2 of the infected cats, the parasites were also detected by echocardiography. One of the positive cats died suddenly 1 year after diagnosis and at necropsy two decomposing D. immitis were found in the right ventricle and pulmonary artery. This is the first report of confirmed feline dirofilariosis in Greece. The detected proportion of infection in cats was 38% of the respective canine infection in the examined shelter. The results of the present study underline the high risk of infection of cats living in enzootic areas and the imperative character of preventive measures in such conditions. PMID- 30397777 TI - Biological evaluation of mimetic peptides as active molecules for a new and simple skin test in an animal model. AB - A skin test is a widely used tool in diagnostic evaluations to investigate cutaneous leishmaniases (CL). The actual antigen (Montenegro skin test [MST] antigen) presents some difficulties that pertain to its manufacturing and validation. To contribute to overcoming this problem, we propose the application of new-generation molecules that are based on skin antigen tests. These antigens were obtained through biotechnology pathways by manufacturing synthetic mimetic peptides. Three peptides, which were selected by phage display, were tested as skin test antigens in an animal model (Cavia porcellus) that was immunized with Leishmania amazonensis or Leishmania braziliensis. The peptide antigens, individually (PA1, PA2, PA3) or in a mix (PAMix), promoted induration reactions at 48 and 72 h after the test was performed. The indurations varied from 0.5 to 0.7 cm. In the animals immunized with L. amazonensis, the PA3 antigen showed better results than the standard MST antigen. In animals immunized with L. braziliensis, two peptide antigens (PA2 and PAMix) promoted induration reactions for a longer period of time than the standard MST antigen. These results validate our hypothesis that peptides could be used as antigens in skin tests and may replace the current antigen for CL diagnosis. PMID- 30397778 TI - Risk for hemorrhage after pancreatoduodenectomy with venous resection. AB - PURPOSE: No consensus exists on the optimal anticoagulation therapy after pancreatoduodenectomy with venous resection (PDVR). The aim of the study was to analyze perioperative outcomes of patients receiving low- vs high-dose anticoagulation therapy and to identify risk factors for postpancreatectomy hemorrhage in patients undergoing PDVR. METHODS: Retrospective study of patients undergoing PDVR at a tertiary referral center between January 2006 and April 2017. Patients were investigated according to the dose of postoperative anticoagulation given (low- or high-dose low-molecular-weight heparin). Uni- and multivariate analysis were performed to assess risk factors for postpancreatectomy hemorrhage. RESULTS: A total of 141 patients underwent PDVR. Low-dose anticoagulation was given to 45 (31.9%) patients. Operative time (428 min vs 398 min, p = 0.025) and the use of interposition grafts (27% vs 11%, P = 0.033) were significantly higher in the high-dose group. There was no difference in the rate of early portal vein thrombosis (4.4% vs 4.2%, p = 0.939) or postpancreatectomy hemorrhage (13.3% vs 16.7%, p = 0.611) between the low- and high-dose groups. On multivariate analysis, serum bilirubin >= 200 MUmol/L and clinically relevant postoperative fistula were the only factors associated with postpancreatectomy hemorrhage (OR 10.28, 95% CI 3.51-30.07, P < 0.001, and OR 6.39, 95% CI 1.59-25.74, P = 0.009). CONCLUSION: Preoperative hyperbilirubinemia and clinically relevant postoperative fistula are risk factors for postpancreatectomy hemorrhage after PDVR. Rates of postpancreatectomy hemorrhage did not differ between patients receiving high- vs low-dose low-molecular-weight heparin. PMID- 30397779 TI - Neoadjuvant and adjuvant chemotherapy in pancreatic cancer. AB - BACKGROUND: Only 15-20% of patients with pancreatic ductal adenocarcinoma (PDAC) have a resectable tumor at the time of diagnosis. Effective multimodal treatment concepts including neoadjuvant chemotherapy are therefore needed. Following upfront resection, adjuvant chemotherapy has become mandatory to prevent early tumor recurrence. PURPOSE: The aim of this article was to summarize existing evidence on neoadjuvant and adjuvant chemotherapy in PDAC with a focus on high level evidence based on randomized controlled phase III clinical trials. RESULTS AND CONCLUSIONS: Neoadjuvant chemotherapy represents an emerging concept for borderline resectable and locally advanced PDAC. To date, randomized trials have failed to provide proof-of-concept outcomes, mostly because of failure to achieve recruitment targets. Nevertheless, this approach needs to be further evaluated scientifically as recent data from a large single-arm cohort study showed that neoadjuvant multimodal therapy could achieve a resection rate in the order of 60% of patients with locally advanced PDAC. For patients with a primarily resectable tumor, however, study results remain unconvincing, and therefore, neoadjuvant therapy should not be used routinely outside of a clinical trial. Adjuvant chemotherapy with gemcitabine and capecitabine in unselected patients can double 5-year overall survival to around 30% compared to mono-chemotherapy with either 5 fluorouracil with folinic acid or gemcitabine. In selected patients, adjuvant modified FOLFIRINOX can produce a 5-year survival rate of around 50%. Further potential gains are to be made in the selection of patients for particular therapies based on the transcriptomic and genetic signature of individual tumors. PMID- 30397780 TI - Pancreatic surgery: we need clear definitions. AB - BACKGROUND: Pancreatic surgery has undergone substantial changes during the last decades. Improved surgical techniques and perioperative care have contributed to improved outcomes and allow safe surgery with mortality rates below 5% in specialized centers today. In parallel, surgical indications and procedures have been continuously extended especially with regard to pancreatic cancer surgery including vascular resections and multivisceral approaches for advanced findings. PURPOSE: With the growing awareness of the need to report outcomes scientifically, it has become obvious that only standardized definitions allow a reasonable description and comparability with regard to indications, procedures, and especially complications. Consequently, a number of efforts have been undertaken to achieve this aim, including basic nomenclatures, preoperative definition of resectability, and specific outcome parameters. CONCLUSION: This review gives an overview on the development of international standardizations in pancreatic surgery and the current status and discusses their scientific importance and the most important current controversies in the context of the present literature as well as the ongoing future approaches in this field. PMID- 30397781 TI - Focus on fluid therapy and nutritional support. PMID- 30397782 TI - Iron deficiency and infection: another pathway to explore in critically ill patients? PMID- 30397783 TI - Focus on the brain and systemic organ systems: when essential interactions become toxic relationships. PMID- 30397784 TI - Correction to: Sulforaphane protects granulosa cells against oxidative stress via activation of NRF2-ARE pathway. AB - There is an error in the original publication of this paper. Figures 1-6 were shown in the wrong version, thus corrected figures provided were in this article. PMID- 30397785 TI - [Report by the Haematopathology Working Group of the German Society of Pathology : Annual meeting 2018]. PMID- 30397786 TI - ["Digital Pathology in Diagnostics-reporting on digital images" guideline of the Professional Association of German Pathologists]. PMID- 30397787 TI - [Genetic predisposition to childhood cancer]. AB - Tackling the topic of genetic predisposition to childhood cancer requires close co-operation between pathologists, pediatric oncologists, and human geneticists. It is not just about the precise diagnosis and the most effective treatment of the cancer, but also to prevent further cancerous diseases for those affected and also their family members. On the basis of examples such as Li-Fraumeni syndrome, constitutional mismatch repair deficiency (CMMRD), medullo- and neuroblastoma, as well as hematological neoplasias, we will discuss the criteria for tumor predisposition genetic syndromes, the relationship between somatic and germline variants, and the immediate clinical consequences. In some cases, the diagnosis of a genetic tumor predisposition syndrome has immediate consequences for the treatment, e. g. to avoid radiotherapy for Li-Fraumeni syndrome, which would otherwise significantly increase the probability of secondary, independent tumors. Predictive diagnostics can be offered to identify the family members who carry the pathogenic variant. Because of their increased tumor risk, they should be integrated into cancer surveillance programs. Evidence-based data show that this significantly improves overall survival. PMID- 30397788 TI - [Injury patterns in interstitial lung diseases]. AB - Interstitial lung diseases (ILD) consist of a complex group of hundreds of non neoplastic pulmonary diseases with divergent clinical presentation, morphology and progression tendency. This great number of clinical entities contrasts with a limited number of injury patterns. By definition, an adequate classification requires a synopsis of the clinical, radiological and morphological findings. The ATS/ERS (American Thoracic Society/ European Respiratory Society) guidelines recommend an open lung biopsy if high-resolution computed tomography does not provide conclusive results. Due to the focal nature and overlapping features of injury patterns, microscopic categorization is not always possible. In order to broaden the diagnostic criteria by using molecular patterns the Lung Research Working Group of the Institute of Pathology of Hannover Medical School, Europe's leading transplant center, is working up fresh explanted human lungs in a standardized manner. These fresh specimens are used for translational research by means of functional, morphological and molecular techniques in order to identify disease-specific regulatory processes and to make them usable diagnostically and therapeutically. PMID- 30397789 TI - Long-term safety and tolerability of valsartan in children aged 6 to 17 years with hypertension. AB - OBJECTIVE: The present study aimed to assess the long-term safety and tolerability of valsartan in hypertensive children aged 6-17 years, with or without chronic kidney disease (CKD). METHODS: This was an 18-month, open-label, multicentre, prospective study conducted in 150 patients with history of hypertension with or without CKD. The primary endpoint was long-term safety and tolerability of valsartan and valsartan-based treatments, assessed in terms of adverse events (AEs), serious AEs, laboratory measurements, estimated glomerular filtration rate (eGFR), urinalysis and electrocardiogram. RESULTS: Of 150 enrolled patients, 117 (78%) completed the study. At week 78, a clinically and statistically significant reduction in mean sitting systolic and diastolic blood pressures was observed in all patients (- 14.9 mmHg and - 10.6 mmHg, respectively). Within the first 3 months of treatment, mean urine albumin creatinine ratio decreased in CKD population, which was sustained. A higher percentage of CKD patients had at least one AE compared to non-CKD patients (85.3% vs. 73.3%, respectively). The majority of AEs were mild (50.7%) or moderate (18.7%) in severity. As expected, in patients with underlying CKD, increases in serum potassium, creatinine and blood urea nitrogen were more commonly reported compared to non-CKD patients. A > 25% decrease in Schwartz eGFR was observed in 28.4% of CKD patients and 13.5% of non-CKD patients. CONCLUSIONS: Valsartan was generally well tolerated, with an AE profile consistent with angiotensin receptor blockers in the overall population and in patients with underlying CKD. Long-term efficacy was maintained and a beneficial effect on proteinuria was observed. PMID- 30397790 TI - Propionibacterium acnes induces discogenic low back pain via stimulating nucleus pulposus cells to secrete pro-algesic factor of IL-8/CINC-1 through TLR2-NF kappaB p65 pathway. AB - Latent infection of Propionibacterium acnes was considered as a new pathogeny for low back pain (LBP); however, there is no credible animal evidence or mechanism hypothesis. This study proved that P. acnes is a causative pathogen of bacteria induced LBP and investigated its underlying mechanism. For this, P. acnes was firstly identified in patients' degenerated intervertebral disc (IVDs) samples. The results of patients' Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ), Japanese Orthopaedic Association (JOA), and Oswestry Disability Index (ODI) scores indicated that P. acnes-positive patients showed more severe LBP and physical disability. Then, a P. acnes-inoculated lumbar IVDs model was established in rats. The results of paw/foot withdrawal threshold and qRT-PCR indicated that P. acnes-inoculated rats had obvious LBP in behavioral evaluation and over-expression of substance P (SP) and calcitonin gene-related peptide (CGRP) in IVDs. Subsequently, enzyme-linked immunosorbent assay (ELISA) results demonstrated that increased expression of IL-8 or CINC-1 (the homolog of IL-8 in rats) in the P. acnes-positive IVDs of human and rats. The CINC-1 injected animal model proved that the cytokines were able to induce LBP. Finally, the co-culture experiments showed that nucleus pulposus cells (NPCs) were able to respond to P. acnes and secreted IL-8/CINC-1 via TLR-2/NF-kappaB p65 pathway. In conclusion, P. acnes had strong association with LBP by stimulating NPCs to secrete pro-algesic factor of IL-8/CINC-1 via TLR2/NF-kappaBp65 pathway. The finding may provide a promising alternative therapy strategy for LBP in clinical. KEY MESSAGES: Patients with P. acnes-positive IVDs tended to have more severe LBP, physical disability, and increased IL-8 expressions. P. acnes can induce LBP via IL-8/CINC-1 in IVDs. P. acnes stimulate the NPCs to secrete pro-algesic factor of IL-8/CINC-1 via TLR2/NF-kappaBp65 pathway. PMID- 30397791 TI - Refractive adaptation and efficacy of occlusion therapy in untreated amblyopic patients aged 12 to 40 years. AB - PURPOSE: Since neurophysiological and clinical trials have shown evidence for plasticity in the adult visual system, the upper age limit for amblyopia treatment is not rigid. The aim of this study was to investigate the efficacy of occlusion therapy and refractive adaptation in untreated amblyopic patients 12 to 40 years of age. METHODS: In a prospective study, all patients had full orthoptic and ophthalmic assessment including cycloplegic retinoscopy. Patients with a newly prescribed optical correction underwent an 18-week refractive adaptation. All patients were treated with occlusion for 3 h a day for 18 weeks. Acuity gain and responder rates (>= 0.2 log units) were calculated. The rate of recurrence (visual acuity 9 months after end of the occlusion therapy; >= 0.2 log units) and the acuity gain after refractive adaptation were determined. Self-reported compliance to occlusion therapy was assessed. RESULTS: Median age of patients (n = 24) was 32.4 years (IQR 19.2). Best corrected visual acuity at start of occlusion therapy was 0.35 logMAR (IQR 0.5) and 0.30 (IQR 0.4) logMAR at the end of occlusion therapy, an acuity gain of 0.05 logMAR (P = 0.004). Six (25%) patients had an acuity gain of at least 0.2 logMAR units. Reading acuity was improved from 0.4 logMAR (IQR 0.4) to 0.3 logMAR (IQR 0.4) (P = 0.004). Visual acuity was stable 9 months after occlusion therapy. The acuity gain after 18 weeks of refractive adaptation was 0.05 logMAR (P = 0.238, n = 8). Acuity gain by correcting refractive errors was 0.25 logMAR (P = 0.006). Twenty-one (92%) of 24 patients achieved full recording in the calendar. Overall compliance was 17% (IQR 38). Only 5 out of 22 (23%) had acceptable compliance (>= 50%) to occlusion therapy. Improvement of visual acuity was significantly better in patients with at least 50% compliance (P = 0.013). Compliance was worse in non-native patients than in native patients (P = 0.022). CONCLUSIONS: In adulthood, compliance to occlusion therapy is even more challenging than in children. Noncompliance is the main reason for treatment failure. Only a few patients with acceptable compliance to occlusion therapy had a small but significant improvement of visual acuity. The results suggest that some adults with amblyopia retain a degree of cortical plasticity. We found that untreated adult amblyopic patients did not wear optical correction on the amblyopic eye. The highest treatment benefit was achieved by correcting refractive errors prior to following period of refractive adaptation. PMID- 30397792 TI - Choriocapillaris flow features and choroidal vasculature in the fellow eyes of patients with acute central serous chorioretinopathy. AB - PURPOSE: The purpose of the study is to investigate the characteristics of choriocapillaris flow based on the underlying choroidal vasculature in fellow eyes with central serous chorioretinopathy (CSC). METHODS: We included 57 patients with CSC and normal controls. Characteristics of choriocapillaris flow were evaluated using swept-source optical coherence tomography (OCT) angiography. We divided the choroidal layer into the vascular and stromal beds according to the choroid vessels on en-face OCT images. We compared the flow void area and mean vascular density of the choriocapillaris according to the underlying choroidal beds in the CSC and control group. RESULTS: The mean vascular density of the choriocapillaris in the CSC group was not different from that of the control group (P = 0.289). The flow void area was more frequently found in the CSC group (59.6%) than in the control group (29.8%, P = 0.002). The presence of the flow void area in the CSC group was associated with greater macular choroidal thickness (P = 0.004). In the CSC group, the mean flow void area and ratio of the choriocapillaris over the vascular bed were larger than those over the stromal bed (all P < 0.001). CONCLUSIONS: The location of the flow void area of the choriocapillaris was associated with the distribution of the underlying choroidal vessels. This suggests that the underlying choroidal vessels may affect choriocapillaris perfusion in pachychoroid eyes. PMID- 30397793 TI - Comparison of clinical outcomes of intravitreal ranibizumab and aflibercept treatment for retinopathy of prematurity. AB - PURPOSE: To compare the results of ranibizumab and aflibercept treatment in infants with treatment-requiring retinopathy of prematurity (ROP) in the posterior zone. METHODS: In this single-center, retrospective study, the records of the infants, who were treated between January 2015 and June 2017 in a tertiary center for screening and treatment of ROP, were reviewed. Infants who were administered ranibizumab or aflibercept as initial treatment and completed at least 1 year of corrected age were included. The patients were evaluated in terms of regression, progression or recurrence of the disease, vascularization of the peripheral retina, and ocular complication profile in early or late period. RESULTS: Fifty-four eyes of 27 infants who received ranibizumab treatment (ranibizumab group) and 72 eyes of 36 infants who received aflibercept treatment (aflibercept group) were enrolled. The rate of recurrence was 48.1% in ranibizumab group and 13.9% in aflibercept group. The mean recurrence times were at 8.2 +/- 0.92 weeks following the injection of ranibizumab and at 14.2 +/- 1.03 weeks following the injection of aflibercept. There were significant statistical differences between the groups in the rate of ROP recurrence, the time of recurrence, and the time of vascularization of peripheral retina (p = 0.001, p < 0.001, p < 0.001, respectively). CONCLUSION: Although both ranibizumab and aflibercept are effective therapies for the treatment of ROP, more frequent and much earlier recurrences can be seen with ranibizumab treatment. Further studies are needed to obtain ideal options for the treatment of ROP. PMID- 30397794 TI - Diversity and Coding Potential of the Microbiota in the Photic and Aphotic Zones of Tropical Man-Made Lake with Intensive Aquaculture Activities: a Case Study on Temengor Lake, Malaysia. AB - Although freshwater biomes cover less than 1% of the Earth's surface, they have disproportionate ecological significances. Attempts to study the taxonomy and function of freshwater microbiota are currently limited to samples collected from temperate lakes. In this study, we investigated samples from the photic and aphotic of an aquaculture site (disturbed) of Temengor Lake, a tropical lake in comparison with the undisturbed site of the lake using 16S rRNA amplicon and shotgun metagenomic approaches. Vertical changes in bacterial community composition and function of the Temengor Lake metagenomes were observed. The photic water layer of Temengor Lake was dominated by typical freshwater assemblages consisting of Proteobacteria, Actinobacteria, Bacteroidetes, Verrucomicrobia, and Cyanobacteria lineages. On the other hand, the aphotic water featured in addition to Proteobacteria, Bacteroidetes, Verrucomicrobia, and two more abundant bacterial phyla that are typically ubiquitous in anoxic habitats (Chloroflexi and Firmicutes). The aphotic zone of Temengor Lake exhibited genetic potential for nitrogen and sulfur metabolisms for which terminal electron acceptors other than oxygen are used in the reactions. The aphotic water of the disturbed site also showed an overrepresentation of genes associated with the metabolism of carbohydrates, likely driven by the enrichment of nutrient resulting from aquaculture activities at the site. The results presented in this study can serve as a basis for understanding the structure and functional capacity of the microbial communities in the photic and aphotic zones/water layers of tropical man-made lakes. PMID- 30397795 TI - Early Changes in Nutritional Conditions Affect Formation of Synthetic Mutualism Between Chlorella sorokiniana and the Bacterium Azospirillum brasilense. AB - The effect of three different nutritional conditions during the initial 12 h of interaction between the microalgae Chlorella sorokiniana UTEX 2714 and the plant growth-promoting bacterium Azospirillum brasilense Cd on formation of synthetic mutualism was assessed by changes in population growth, production of signal molecules tryptophan and indole-3-acetic acid, starch accumulation, and patterns of cell aggregation. When the interaction was supported by a nutrient-rich medium, production of both signal molecules was detected, but not when this interaction began with nitrogen-free (N-free) or carbon-free (C-free) media. Overall, populations of bacteria and microalgae were larger when co-immobilized. However, the highest starch production was measured in C. sorokiniana immobilized alone and growing continuously in a C-free mineral medium. In this interaction, the initial nutritional condition influenced the time at which the highest accumulation of starch occurred in Chlorella, where the N-free medium induced faster starch production and the richer medium delayed its accumulation. Formation of aggregates made of microalgae and bacteria occurred in all nutritional conditions, with maximum at 83 h in mineral medium, and coincided with declining starch content. This study demonstrates that synthetic mutualism between C. sorokiniana and A. brasilense can be modulated by the initial nutritional condition, mainly by the presence or absence of nitrogen and carbon in the medium in which they are interacting. PMID- 30397797 TI - Improving Head Rice Yield and Milling Quality: State-of-the-Art and Future Prospects. AB - Increasing paddy yield in rice does not directly translate to enhancing food security because significant decrease in grain yield can happen during postharvest processing of the rice paddy. In parallel with enhancing paddy yield, improving the milling quality of rice is essential in ensuring food security by mitigating the impact of significant losses during the postharvest processing of rice grains. From an industrial standpoint, maximizing the milling recovery of whole grain polished rice is crucial in fetching higher revenues to rice farmers. Significant advances in rice postharvest processing technology have been achieved which are geared toward reducing the incidence of fissures and chalkiness to increase head rice yield (HRY) in rice. The genetic bases of kernel development and grain dimension are also characterized. In addition to these advancements, an integrated phenotyping suite to simultaneously characterize phenotypes related to milling quality will help in screening for breeding lines with high HRY. Toward this goal, modern imaging tools and computer algorithms are currently being developed for high-throughput characterization of rice milling quality. With the availability of more sophisticated, affordable, automated, and nondestructive phenotyping methods of milling quality, it is envisioned that significant improvement in HRY will be made possible to ensure rice food security in the future. PMID- 30397796 TI - Temporal Development of the Culturable, Endophytic Fungal Community in Healthy Grapevine Branches and Occurrence of GTD-Associated Fungi. AB - Endophytic fungi play an important role in the life of grapevine, either as beneficial microorganisms or as pathogens. Many surveys concerning the fungal grapevine community have been conducted. Nevertheless, exactly how the fungal community arises within the plant and develops from young shoots to mature vines is still unknown. Therefore, it was the aim of this study to investigate the early development of endophytic fungal communities in healthy grapevine branches from 2 months to 8 years old. More than 3800 fungi belonging to 86 operational taxonomic units (OTUs) were isolated from wood samples and assigned to eight age groups. The community composition within the age groups changed and significant differences between young (<= 1 year) and old (> 1 year) branches were found. The former were primarily dominated by ubiquitous, fast-growing fungi like Alternaria spp., Aureobasidium pullulans, Cladosporium spp., or Epicoccum nigrum, while communities of perennial branches additionally harbored many grapevine trunk disease (GTD)-associated fungi such as Diplodia seriata or Eutypa lata. This work gives an insight into the early development of fungal communities in grapevine, the nature and composition of primary settlers and core communities, as well as the emergence of GTD-associated fungi in perennial wood. This information may help grapevine growers to better estimate the risk in relation to the applied training system, producing mainly old branches or young shoots. PMID- 30397798 TI - Improving Rice Grain Quality: State-of-the-Art and Future Prospects. AB - Rice grain quality encompasses complex interrelated traits that cover biochemical composition, cooking, eating, nutritional, and sensory properties. Because rice endosperm is composed mainly of starch, rice grain quality is traditionally defined by characterizing starch structure and composition, which is then subsequently correlated with functional properties of the grain. The current proxy tests routinely used to describe rice grain quality preferences are rather limited to the estimation of apparent amylose content, gelatinization temperature, and gel consistency. Additional tests that characterize starch property, viscoelasticity, grain texture, and aroma are also employed in more advanced laboratories. However, these tests are not routinely applied in breeding programs to distinguish cooking quality classes to reflect evolving consumer preference and market demand. As consumer preferences in Asia and all over the world are diverse due to varied demographics and culture, defining uniform attributes to capture regional grain quality preferences becomes more challenging. Hence, novel and innovative proxy tests are needed to characterize rice grain quality to meet the demand for consumer preferences of commercially released cultivars. In this chapter, the current methods employed in rice grain quality monitoring are succinctly reviewed. Future prospects for improvement are identified, introducing cutting edge technologies that can facilitate high throughput screening of rice diversity panels and breeding lines. Aside from addressing the requirements for quality improvement in the traditional inbred rice breeding programs, we also tackled the need to enhance grain quality in the hybrid rice sector. PMID- 30397799 TI - Morphology of Rice Seed Development and Its Influence on Grain Quality. AB - Various quality attributes of rice seed are affected by the wide array of biochemical products accumulated during the course of reproductive development and the environmental conditions which impact the grain composition. The staging of rice plant reproductive development is needed in experiments to define phase transitions of seed biology. The application of the nomenclature and criteria of the rice growth staging system can facilitate recording the reproductive development by distinct stages. The meaningful progression from one stage to another in time can then be evaluated in a tabular or graphic manner. In order to determine the developmental stages of rice in experiments, it is desirable to select a representative group of plants and to record the development of those plants. We provide procedures for efficiently (1) observing and recording development of rice plants and (2) collecting, storing and seperating seed by developmental stages. It is necessary to divide seeds into differing groups to track development from fertilization until maturity. The earliest seeds to be fertilized on a panicle are superior grains and the latter seeds to develop are inferior grains. In some cases, it is necessary to divide individual seeds into the aforementioned groups and the different stages of development for various analyses. A procedure for dividing seeds into differing stages of development is presented to more appropriately select seeds for further analysis. The developmental record can then be statistically and graphically analyzed to better understand responses to treatments and interactions among treatments, years, and locations. PMID- 30397800 TI - Novel Imaging Techniques to Analyze Panicle Architecture. AB - Panicle architecture is known to directly influence grain yield in rice, and thus is an important trait for rice varietal improvement. However, spike branching consequences trigger variation in number of superior and inferior grains and thus affect grain quality. The genetics behind the length of both primary and secondary branches were studied resulting in the identification of cloned genes. Extending this knowledge to include other physiological parameters of panicle architecture is not yet well studied, and it requires high-throughput imaging techniques that are accurate. In this chapter we put the spotlight on Panicle Trait Phenotyping Tool (P-TRAP), a freely available platform independent software to analyze the panicle architecture of rice, as one of such methods that can be used to generate a comprehensive and reproducible panicle architecture data and identify superior breeding lines. P-TRAP measures 15 panicle structure and nine spikelet traits. These quantitative traits can be used in genome-wide association studies to understand their genetic basis. PMID- 30397801 TI - Measuring Head Rice Recovery in Rice. AB - Head rice recovery (HRR) is a milling quality attribute that is highly influential toward the market price of rice. It is defined as the proportion of paddy rice that retains 75% of its length after milling. For a new rice variety to be accepted and adopted by farmers, the new variety's HRR should satisfy consumer requirements of at least 55% or above. Hence, HRR is a crucial attribute by which new varieties are selected for release. Although the amount of head rice recovered depends on the genetic background of a rice variety, HRR is also highly affected by postharvest processing conditions that the variety goes through. To determine the maximum HRR, therefore, one must ensure that the processing conditions are as optimal as possible. This book chapter outlines how paddy rice is processed into head rice and how HRR is measured. It also proposes an improved laboratory-scale means for postharvest drying to minimize head rice losses. PMID- 30397802 TI - Measurement of Rice Grain Dimensions and Chalkiness, and Rice Grain Elongation Using Image Analysis. AB - Measurements of rice grain dimensions, percent grain chalkiness, and grain elongation used to be tedious and slow due to the manual nature of measurements (e.g., use of calipers to measure grains one at a time) and the subjective nature of scoring based on visual inspection (i.e., chalkiness). Recent developments in imaging technologies have enabled more high-throughput means for measuring physical traits (i.e., grain dimensions and chalkiness) in raw grains and grain elongation by comparing ratio between raw versus cooked rice. The digital images of rice grains are captured through computer scanning and analyzed using software that can calculate area and pixel value statistics of user-defined parameters. The improvements in throughput made possible by the use of imaging technologies will allow faster quality grading of rice varieties. Market quality is usually defined based on the rice grain physical traits (grain size and shape), degree of chalkiness, and the ability of rice to elongate on cooking. In this chapter, the routine methods to measure the physical traits of rice and grain elongation using image analysis are described. PMID- 30397803 TI - Method Development of Near-Infrared Spectroscopy Approaches for Nondestructive and Rapid Estimation of Total Protein in Brown Rice Flour. AB - Rice varietal development and improvement programs are constantly seeking means to shorten the breeding cycle in order to deliver new, consumer-acceptable rice varieties to farmers and to consumers. Advances in molecular biology technologies have enabled breeders to use high-throughput genotyping to screen breeding lines. However, current phenotyping technologies, particularly for rice cooking and eating properties, have yet to match the efficiency of genotyping methodologies. A high-throughput and cost-effective phenotyping suite is essential because without phenotype, the value of genotypic information cannot be maximized. In this book chapter, we explore the application of near-infrared spectroscopy (NIRS), a high-throughput and nondestructive approach in characterizing rice grains, primarily describing method development and validation, instrument calibration, upgrading, and maintenance. We then focus on estimating protein content (PC) in brown rice as a case study because (1) PC is an attribute that contributes to the cooking behavior and the eating properties of cooked rice; and (2) proteins contain chemical bonds that can easily be detected by NIRS. PMID- 30397804 TI - Multi-Dimensional Cooking Quality Classification Using Routine Quality Evaluation Methods. AB - A battery of assays to characterize the cooking and eating attributes of rice have been in routine use for several decades. The classification system to group rice varieties into different quality types are often based on cooking and eating attributes defined based on amylose content, rather than being considered a set of attributes contributing to an overall quality type based on multi-dimensional approach. In this chapter, the methods developed to measure the cooking quality attributes of rice are described. Instead of considering each attribute on its own, the authors employ multidimensional data generated from the estimation of amylose content, gel consistency, gelatinization temperature, Rapid Visco Analyzer parameters to classify rice into distinct cooking quality ideotypes. If used universally, such an approach can improve prediction of cooking quality classifications of rice varieties in the breeding programs. PMID- 30397805 TI - Characterization of Mechanical Texture Attributes of Cooked Milled Rice by Texture Profile Analyses and Unraveling Viscoelasticity Properties Through Rheometry. AB - The mechanical attributes of cooked rice grains reflected by textural characteristics capture consumers preferences. Two of these attributes such as hardness and stickiness are typically indicated in grain quality evaluation programs by the amylose content of rice. However, the association of amylose content with two other textural attributes such as cohesiveness and springiness remains unknown. Hence, texture profile analyses play a role in quantifying these mechanical parameters of texture. Rheometry on the other hand can be utilized to characterize both viscous and elastic properties of rice during cooking in a water-rice proportion closer to what consumers typically use for cooking. In this chapter, methods for texture profiling and rheometry are presented to capture inferences on cooking quality modeling. Data extracted from rice texture and viscoelastic properties that go beyond what amylose content can predict, has been deciphered through mathematical modeling, which can help predict cooking quality of new rice breeding lines to improve textural and cooking quality specifications. PMID- 30397806 TI - Characterizing Starch Molecular Structure of Rice. AB - A better understanding of the nutritional properties of rice starch is important because of the rapid rise of diet-related health complications, particularly obesity, type 2 diabetes, and colorectal cancers. Rice starch that is slowly digested to glucose, and where significant quantities of starch which reach the lower gut ("resistant starch"), can mitigate, and also delay the onset of, these diseases. These digestibility properties depend to some extent on starch molecular structure. The characterization of this structure is therefore significant for understanding and developing healthier slower digestible rice. In this chapter, a series of techniques used for characterizing starch structure are reviewed and the procedure for preparing rice starch samples with minimum degradation for characterizing starch chain length distribution (CLD) and overall molecular structure is given. Some methods for choosing or developing plants showing desirable structural characteristics are briefly summarized. PMID- 30397807 TI - Rice Grain Quality Benchmarking Through Profiling of Volatiles and Metabolites in Grains Using Gas Chromatography Mass Spectrometry. AB - Gas chromatograph coupled with mass spectrometer is widely used to profile volatiles and metabolites from the homogenized rice flour obtained from mature grains. Rice grains consist of central endosperm which stores majorly starch and, in addition, accumulate various storage proteins as storage reserves. The outer nutritious aleurone layer stores lipids, sugar alcohols, volatiles, antioxidants, vitamins, and various micronutrients. Once paddy sample is dehulled, milled, and ground cryogenically, the brown rice flour is subjected to extraction of primary metabolites and volatiles using an appropriate extraction method. In metabolite profiling of the liquid extract obtained from the rice sample, mixture is initially subjected to methoxyamination then silylation before being subjected to untargeted metabolite profiling. Peaks obtained are processed for noise reduction and specific signal selection. Volatile compounds are initially extracted using a solid phase adsorbent prior to analysis. All these compounds, metabolites, and volatiles are detected in the mass selective detector by fragmentation at 70 eV ionization energy and the resultant mass spectrum compared with a built-in library of compounds. Data mined from the gas chromatography mass spectrometry analysis are then subjected to post-processing statistical analysis. PMID- 30397808 TI - Re-sequencing Resources to Improve Starch and Grain Quality in Rice. AB - Next-generation sequencing can identify differences in the rice genome that explain the genetic basis of grain quality variation. Differences in rice grain quality are mainly associated with differences in the major component of the grain, starch. Association of rice quality variation with rice genome variation can be conducted at the gene or whole-genome level. Re-sequencing of specific genes or whole genomes can be used depending on the extent to which candidate genes for the traits of interest are known. Amplicon sequencing of genes involved in starch metabolism can help in targeted discovery of the molecular genetic basis of differences in starch related quality attributes. Whole-genome re sequencing can complement this, when the genetic basis of the trait is expected to be outside the coding region of starch metabolism genes. These approaches have been used successfully to understand the rice genome at specific loci and over the whole genome. PMID- 30397809 TI - Quantifying Grain Digestibility of Starch Fractions in Milled Rice. AB - Rice is one of the staple foods which serves as the major source of carbohydrate in the human diet. A typical milled rice grain is mainly composed of starch of up to 80-90%, with an average of 6-8% proteins and some trace amounts of dietary fiber. Although cooked white rice can elicit variable glycemic response, a portion of rice starch may evade digestion in the human small intestine. The digested portion of rice can be estimated and characterized in vitro based on starch digestion extent and rate (kinetics). The indigestible portion of starch can also be quantified. This chapter will present micro-scale methods to quantify rice starch digestion rate and extent based on the sugar fractions released after treating the samples with digestive enzymes. PMID- 30397810 TI - Determination of Macronutrient and Micronutrient Content in Rice Grains Using Inductively Coupled Plasma-Optical Emission Spectrometry (ICP-OES). AB - The rice grain endosperm is mostly composed of starch , which serves as the major source of calories for more than half of the world's population. Macro and micronutrients make a minor proportion of the rice grain, which particularly gets accumulated in outer aleurone layer, which are in general eliminated upon milling. Because rice is the major staple, it is seen as an efficient mechanism for delivering both macro- and micronutrients, particularly for the poor who do not have ample access to diversified diets. Enriching micronutrient and macronutrient concentrations in milled rice of endosperm and/or in brown rice, is an important dietary intervention to create health benefits of rice consumers. Efforts are underway to increase the nutritional content of rice through bio/fortification approaches. The plant takes up these same elements from the soil, redirect the transport of these elements into the grain. Thus besides biofortification strategies, scientists can also use the knowledge to design proper soil nutrient management to enrich micronutrients in the grains. Therefore, it is important to be able to determine the macro- and the micronutrient composition of the vegetative parts of the rice plant and of the rice grain. In this chapter, nitric-perchloric acid digestion and inductively coupled plasma-optical emission spectrometry (ICP-OES) methods routinely used in IRRI's Grain Quality and Nutrition Services Laboratory (GQNSL) to determine the concentrations of various macro- and micronutrients found in the rice grain and the rice plant, are described. PMID- 30397811 TI - Determination of Cadmium Concentration in Milled and Brown Rice Grains Using Graphite Furnace Atomic Absorption Spectrometry. AB - Heavy metal pollution is a growing public health concern since it poses a food risk to public health via metal transfer. Cadmium is of particular concern because it is a potential carcinogen if exceed tolerable limits in the grain. Hence, it is important to monitor the cadmium content of rice before it reaches the market to ensure public healthy safety, especially in areas known to have high cadmium levels in soil. In this chapter, the method used to determine the concentration of cadmium in milled and brown rice grain samples is described. This method involves sample digestion with concentrated nitric acid and hydrogen peroxide and analysis of cadmium by Graphite Furnace Atomic Absorption Spectrometry (GF-AAS). Because cadmium concentrations are low in rice grains, quantification of cadmium content requires the use of a more sensitive instrument, such as GF-AAS. PMID- 30397812 TI - Analysis of Developing Rice Grain Transcriptome Using the Agilent Microarray Platform. AB - Transcriptome analysis reflects the status quo of transcribed genetic code present in the form of mRNA, which helps to infer biological processes and unravel metabolic status. Despite the increasing adoption of RNA-Seq technique in recent years, transcriptome analysis using the microarray platform remains the gold standard technique, which offers a simpler, more cost-effective, and efficient method for high-throughput gene expression profiling. In this chapter, we described a streamlined transcriptomic analyses pipeline employed to study developing rice grains that can also be applied to other tissue samples and species. We described a novel RNA extraction method that obviates the problem introduced by high-starch content during rice grain development that usually leads to reduction in RNA yield and quality. The detailed procedure of microarray analysis involved in cDNA synthesis, cRNA labeling, microarray hybridization, slide scanning, feature extraction to QC validation has been described. The description of a newly developed Indica- and Japonica-specific microarray slides developed from the genome information of subpopulation to study gene expression of 60,000 genes has been highlighted. The downstream bioinformatics analyses including expression QTL mapping and gene regulatory network analyses were mentioned. PMID- 30397813 TI - Quantification of DNA Methylation as Biomarker for Grain Quality. AB - DNA methylation is an important biomarker for gene activity. It contributes to gene silencing and is involved in regulating various seed developmental processes in plants. Many of these processes are involved in important traits associated with aspects of grain quality. A reliable, fast, and cheap method is the estimation of DNA methylation utilizing methylation sensitive restriction enzymes (MSRE) and quantitative real-time PCR (qPCR) for selected candidate regions. The presented method can be used to confirm an effect of RNAi constructs on their target genes or trans-activity. Analysis of promoter regions can contribute to estimation of gene activity and related traits. PMID- 30397814 TI - CRISPR-Cas9-Mediated Genome Editing of Rice Towards Better Grain Quality. AB - With continued economic development in Asia the demand for high yielding varieties with premium grain quality traits is set to increase. This presents a significant challenge to plant breeders because varieties must be tailored to meet regional preferences. It is already apparent that traditional breeding techniques cannot meet this challenge and so emerging genomics technologies will have to be utilized. Genome editing tools afford the ability to efficiently and precisely manipulate the genome. Among these, the bacterial clustered, regularly interspaced, short palindromic repeat (CRISPR) associated protein 9 (Cas9) or CRISPR-Cas9 has emerged as the easiest, most economic, and efficient technology to undertake genome editing in rice. This technique allows precise site-specific gene modification or integration. In this chapter we present a method for utilizing CRISPR-Cas9 for improving grain quality traits in rice; this should enable molecular breeders to quickly and efficiently produce high yielding rice varieties tailored to meet specific cultural and regional requirements for grain quality. PMID- 30397815 TI - Does including neck CTA in work-up of suspected intracranial hemorrhage add value? AB - PURPOSE: Neck CT angiography (CTA) is frequently performed in conjunction with head CTA in patients presenting with clinical signs and symptoms concerning for acute intracranial hemorrhage, despite relatively low appropriateness (ACR Appropriateness Criteria 2-6). This decision is sometimes justified by suggesting that CTA neck findings are useful in planning subsequent catheter angiography. METHODS: We investigated the value of neck CTA in patients with suspected acute intracranial hemorrhage by reviewing 220 head and neck CTAs performed in our emergency room over a 24-month period for the indication of hemorrhage or headache. Images were reviewed by two neurointerventionalists to address the value of the neck CTA for planning catheter angiography. RESULTS: Findings helpful for performing catheter angiography were observed on neck CTA in 22% (Cohen kappa 0.65), and included anatomical arch variants such as a bovine arch, direct vertebral artery arch origin, and aberrant subclavian artery. However, findings that might substantially prolong angiography for more than 10 min if unknown occurred in 5% (Cohen kappa 0.69). Incidental findings prompting additional imaging or significant clinical action occurred in 20%. Subarachnoid hemorrhage on noncontrast head CT was strongly associated with a need for subsequent angiography. CONCLUSIONS: Although CTA neck can provide helpful information for planning catheter angiography, it rarely uncovers findings that would significantly prolong the procedure if unknown. Neck CTA is therefore only recommended in patients with a confirmed intracranial hemorrhage in a pattern consistent with aneurysm or arteriovenous shunt. PMID- 30397816 TI - Subjective cognitive decline: preclinical manifestation of Alzheimer's disease. AB - Subjective cognitive decline (SCD), characterized by a very early and subtle cognitive decline prior to the appearance of objective cognitive impairment, is considered to be the preclinical manifestation of Alzheimer's disease (AD). Given the lack of significant abnormalities in standardized neuropsychological assessments for individuals with SCD, biochemical and neuroimaging biomarkers may be important indicators of the preclinical stage of AD. The application of various biomarkers derived from the cerebrospinal fluid and neuroimaging thus has the potential to make AD-related pathology detectable in vivo. In this review, we discuss the conceptual evolution of SCD as an entity and further elucidate characteristic cerebrospinal fluid and neuroimaging biomarkers of SCD. PMID- 30397817 TI - Prepulse modulation and recovery of trigemino-cervical reflex in normal subjects. AB - OBJECTIVE: In this study, we analyzed the inhibitory control on the trigemino cervical reflex (TCR), and whether or not prepulse modulation (PPM) has an effect on TCR. Thus, we studied the PPM of TCR. We hypothesized that TCR would presumably be under the modulatory effect after the prepulse stimulus similar to blink reflex (BR). We also studied the recovery of TCR which was previously shown. METHODS: We included 13 healthy individuals. All subjects underwent recordings of TCR, TCR-PPM, and recovery of TCR. For TCR-PPM, a subthreshold stimulus to second finger 50 or 100 ms before the test stimulus was applied. For recovery of TCR, two stimuli at the infraorbital nerve were applied at 300, 500, and 800 ms interstimulus intervals (ISIs). RESULTS: There was an inhibition of bilateral late responses of TCR at the ISIs of both 50 ms and 100 ms. There was no change of latencies. Full recovery of TCR did not develop even at the ISI 800 ms. DISCUSSION: We have provided an evidence for the TCR-PPM in healthy subjects for the first time in this study. The prepulse inhibition is attributed to the functions of the pedunculopontine tegmental nucleus. Our study provides a strong indication that there are connections between pedunculopontine tegmental nucleus and trigemino-cervical circuit, which produces TCR. PMID- 30397818 TI - Theoretical bounds and approximation of the probability mass function of future hospital bed demand. AB - Failing to match the supply of resources to the demand for resources in a hospital can cause non-clinical transfers, diversions, safety risks, and expensive under-utilized resource capacity. Forecasting bed demand helps achieve appropriate safety standards and cost management by proactively adjusting staffing levels and patient flow protocols. This paper defines the theoretical bounds on optimal bed demand prediction accuracy and develops a flexible statistical model to approximate the probability mass function of future bed demand. A case study validates the model using blinded data from a mid-sized Massachusetts community hospital. This approach expands upon similar work by forecasting multiple days in advance instead of a single day, providing a probability mass function of demand instead of a point estimate, using the exact surgery schedule instead of assuming a cyclic schedule, and using patient-level duration-varying length-of-stay distributions instead of assuming patient homogeneity and exponential length of stay distributions. The primary results of this work are an accurate and lengthy forecast, which provides managers better information and more time to optimize short-term staffing adaptations to stochastic bed demand, and a derivation of the minimum mean absolute error of an ideal forecast. PMID- 30397819 TI - The Cost-Effectiveness of Bike Share Expansion to Low-Income Communities in New York City. AB - The "Citi Bike" bike share program in New York City is the largest bike share program in the USA. We ask whether expanding this program to lower-income communities is cost-effective means of encouraging exercise and reducing pollution in New York City. We built a stochastic Markov model to evaluate the cost-effectiveness of the Citi Bike expansion program, an effort to extend bike share to areas with higher costs and risks over a 10-year time horizon. We used one-way sensitivity analyses and Monte Carlo simulation to test the model uncertainty. The incremental cost-effectiveness ratio of the Citi Bike expansion program relative to the current program (status quo) was $7869/quality-adjusted life year gained. The Citi Bike expansion program in New York City offers good value relative to most health interventions. PMID- 30397821 TI - Psychotropics, Antidepressants, and Visceral Analgesics in Functional Gastrointestinal Disorders. AB - PURPOSE OF REVIEW: The functional gastrointestinal disorders, or disorders of gut brain interaction as defined by the Rome IV criteria, are the most common diagnostic entities in gastroenterology. Treatments that address the dysregulation of gut-brain interaction with these disorders are increasingly gaining interest as a better option than for example traditional analgesics, particularly opioids. Antidepressants, antianxiety and antipsychotic medications, and visceral analgesics, now termed neuromodulators, are included in this update addressing the evidence of treatment benefit in disorders of brain-gut interaction. RECENT FINDINGS: By a careful selection based on a multidimensional clinical profile, a decreased symptom burden, particularly regarding abdominal pain, nausea, and vomiting, as well as improved social function and quality of life, can be obtained by use of neuromodulators. There is good evidence for the peripheral neuromodulators from studies in bowel disorders, and the central neuromodulators both from indirect evidence in chronic pain disorders as well as selected disorders of brain-gut interaction. Basic knowledge about the pharmacologic properties and clinical use of neuromodulators in disorders of brain-gut interaction improves the treatment outcome and avoids use of traditional analgesics. PMID- 30397820 TI - A Review of the Emerging Role of Silk for the Treatment of the Eye. AB - Silk is a remarkable biopolymer with a long history of medical use. Silk fabrications have a robust track record for load-bearing applications, including surgical threads and meshes, which are clinically approved for use in humans. The progression of top-down and bottom-up engineering approaches using silk as the basis of a drug delivery or cell-loaded matrix helped to re-ignite interest in this ancient material. This review comprehensively summarises the current applications of silk for tissue engineering and drug delivery, with specific reference to the eye. Additionally, the review also covers emerging trends for the use of silk as a biologically active biopolymer for the treatment of eye disorders. The review concludes with future capabilities of silk to contribute to advanced, electronically-enhanced ocular drug delivery concepts. PMID- 30397822 TI - Bioaccumulation of cadmium, lead, and zinc in agriculture-based insect food chains. AB - Globally, the metal concentration in soil is increasing due to different anthropogenic and geogenic factors. These metals are taken up by plants and further transferred in the food chain through different routes. The present study was designed to assess the transfer and bioaccumulation of the heavy metals, cadmium (Cd), lead (Pb), and zinc (Zn), in food chains from soil to berseem plants (Triofolium alexandrinum), to insect herbivores (the grasshopper Ailopus thalassinus and the aphid Sitobion avenae) and to an insect carnivore (the ladybird beetle Coccinella septempunctata). The soil of studied berseem fields were slightly alkaline, silty loam in texture and moderate in organic matter. In soil, the concentration of Zn and Pb were under permissible level while Cd was above the permissible level. The accumulation of metals in T. alexandrinum were found in the order Zn > Cd > Pb. Grasshoppers showed higher accumulation of Pb than of Cd and Zn. In the soil-berseem-aphid-beetle food chain, metal enrichment was recorded. However, aphids did not show bioaccumulation for Cd. Metals accumulation in beetles showed that translocation of Zn, Cd, and Pb was taking place in the third trophic level. Our study highlights the mobility of metals in insect food chains and showed that insect feeding style greatly influenced the bioaccumulation. However, different metals showed variable bioaccumulation rates depending on their toxicity and retention. PMID- 30397823 TI - Anorexia nervosa in adolescents: evolution of weight history and impact of excess premorbid weight. AB - The purpose of our study is to establish if the proportion of patients diagnosed with anorexia nervosa that have a history of excess weight has increased over a 10-year period and to study how different premorbid weight groups vary in terms of clinical characteristics. We performed a single-center, retrospective cohort study of all new patients presenting with anorexia nervosa, restrictive and binge/purge subtypes, in 2004 and 2014 at the Adolescent Medicine Clinic of Sainte-Justine University Health Centre (n = 172). The prevalence of excess premorbid weight was similar in both cohorts (32% in 2004 versus 29.5% in 2014). The historically overweight subgroup had a lower heart rate at intake (64.77 versus 69.75, p = 0.03). Patients with excess premorbid weight lost an average of 1 kg more per month than their historically thinner counterparts (2.6 kg versus 1.6 kg/month, p = 0.0011). The total decrease in BMI was much greater in patients with a history of excess weight (7 BMI points versus 3.8, p = 0.0001).Conclusion: Since overweight and obese patients present with significant weight suppression values, our study stresses the importance of screening for AN in all patients rather than in only the noticeably underweight. What is Known: * More than one third of patients presenting with AN have a history of overweight or obesity, which is comparable to the general population. * A delay between AN onset and diagnosis has been described in overweight adolescents. What is New: * Historically overweight patients presenting with AN demonstrate increased speed of weight loss, greater drop in BMI, and lower heart rate at presentation. * For patients with a history of excess weight considered as having recovered from AN, the average BMI at discharge was within normal limits. PMID- 30397824 TI - Neuroinvasion of influenza A/H3N2: a fatal case in an immunocompetent adult. AB - Acute necrotizing encephalopathy (ANE) is a severe neurologic complication caused by influenza virus that has been infrequently reported in adult population. The diagnosis is made on epidemiological, clinical, and neuroimaging suspicion, but is rarely confirmed by microbiological findings in samples from the central nervous system (CNS), thus making it difficult to define the mechanism of pathogenesis of influenza-associated encephalitis/encephalopathies (IAE). We report a microbiologically documented case of ANE caused by influenza A/H3N2, in a previously healthy adult patient infected during a flu epidemic in Asturias (Spain). Direct viral invasion of the CNS was demonstrated with the isolation of the virus in a brain biopsy. PMID- 30397825 TI - Vibrio vulnificus meningoencephalitis in a patient with thalassemia and a splenectomy. AB - Vibrio vulnificus usually causes wound infection, gastroenteritis, and septicemia. However, it is a rare conditional pathogen causing meningoencephalitis. We report a case of a young, immunocompromised man presenting with severe sepsis after exposure to sea water and consumption of seafood. The patient subsequently developed meningoencephalitis, and Vibrio vulnificus was isolated from his blood culture. The sequence was confirmed by Next-generation sequencing of a sample of cerebrospinal fluid, as well as from a bacteria culture. After the pathogen was detected, the patient was treated with ceftriaxone, doxycycline, and moxifloxacin for 6 weeks, which controlled his infection. In this case, we acquired his clinical and dynamic MRI presentations, which were never reported. Physicians should consider Vibrio vulnificus infections when they see a similar clinical course, brain CT and MRI findings, susceptibility factors and recent seafood ingestion or exposure to seawater. Due to high mortality, the early diagnosis and treatment of Vibrio vulnificus infections are crucial. Next-generation sequencing was found to be useful for diagnosis. PMID- 30397826 TI - HERV-W env regulates calcium influx via activating TRPC3 channel together with depressing DISC1 in human neuroblastoma cells. AB - The activation and involvement of human endogenous retroviruses W family envelope gene (HERV-W env, also called ERVWE1) have been reported in several neuropsychiatric disorders, including schizophrenia, as well as in multiple sclerosis (MS). Dysregulation of intracellular calcium content is also involved in the pathogenesis of these diseases. Our previous studies showed that HERV-W env overexpression results in activation of small conductance Ca2+-activated K+ channel protein 3 (SK3), a potential risk factor for schizophrenia. In the present study, we aimed to elucidate the relationship between HERV-W env and calcium signaling in schizophrenia. Our results showed that HERV-W env could induce Ca2+ influx in two human neuroblastoma cell lines and upregulate the expression and activation of TRPC3 in cells. The abnormal increase in intracellular Ca2+ concentration was inhibited by addition of the TRPC3 channel blocker pyr3, demonstrating that the Ca2+ influx induced by HERV-W env was TRPC3 dependent. Further experiments showed that HERV-W env overexpression downregulated DISC1, while knockdown of DISC1 promoted activation of TRPC3 without affecting TRPC3 expression. In conclusion, HERV-W env induced Ca2+ influx in human neuroblastoma cells by activating the TRPC3 channel through directly regulating its expression or downregulating DISC1, which could also increase TRPC3 activation without affecting TRPC3 expression. These findings provide new insights into how HERV-W env affects neuronal activity and contributes to the pathogenesis of schizophrenia. PMID- 30397827 TI - Astrocytes as an HIV CNS reservoir: highlights and reflections of an NIMH sponsored symposium. AB - This a summary of a National Institute of Mental Health (NIMH) sponsored symposium that was focused on the role of astrocytes as a reservoir of the human immunodeficiency virus in the brain. The talks were grouped into four themes. The first theme reviewed the evidence for HIV infection of astrocytes and discussed the challenges in the use of traditional methods of immunostaining and in situ hybridization for detection of infected astrocytes. The second theme focused on mechanisms of HIV entry into astrocytes and discussed CD4 independent mechanisms, such as receptor-mediated endocytosis and transmission of HIV by cell-to-cell contact with infected lymphocytes. The third theme focused on epigenetic regulation of HIV latency in astrocytes and other factors, such as cytokines and transcriptional factors regulating HIV replication in astrocytes. The fourth theme focused on therapeutic approaches, such as gene editing to block persistently infected astrocytes. A discussion that followed was focused on major unanswered questions in the field and future directions for research. PMID- 30397828 TI - Multimodal techniques failed to detect cytomegalovirus in human glioblastoma samples. AB - The role of the human cytomegalovirus (HCMV) in gliomagenesis is largely debated. Contradictory data exist regarding the sensitivity and specificity of HCMV detection techniques, including immunohistochemistry (IHC), in situ hybridization (ISH), and RNA and DNA sequencing. The aim of this study is to detect HCMV in glioblastoma (GBM) tumor samples using IHC, ISH, and real-time PCR (qPCR), as well as to correlate the findings with serological status and HCMV DNA load in blood. Forty-seven patients with histopathological diagnosis of GBM and HCMV serological status were retrospectively reviewed. HCMV DNA quantification in whole blood was performed in 31 patients. The detection of HCMV in tumor samples was performed using IHC in 42 cases, ISH in 10 cases, and qPCR in 29 cases. All but two patients were taking high steroid doses at the time of biological testing. HCMV seroprevalence was 68%. Active infection with HCMV DNA detected in blood was diagnosed in 6 out of 21 (28%) seropositive patients. HCMV was not detected in GBM samples using IHC or ISH, while qPCR was positive in one case (also positive for blood HCMV DNA). These data do not support a crucial role of HCMV in GBM tumorigenesis. HCMV might be reactivated in GBM patients, due to steroid treatment. PMID- 30397829 TI - Herpes zoster increased risk of neuralgic amyotrophy: a retrospective, population based matched cohort study. AB - Although neuralgic amyotrophy (NA) has occasionally been reported to be associated with reactivated herpes zoster, their associated risk remains unknown. The aim of this study was to assess the risk of developing NA following preceding herpes zoster. The authors used the National Health Insurance Research Database of Taiwan to select 41,548 patients with newly diagnosed herpes zoster during the period 2000 to 2010 and randomly extracted 166,192 matched control subjects. All participants in the study and control groups were followed for 3 months after the diagnosis to identify those who developed NA. Cox proportional hazards regression analyses were performed to evaluate the subsequent risk of NA. Twenty-one subjects from the group with herpes zoster (0.05%) developed NA over the 3-month period and 46 from the group without herpes zoster (0.03%). The patients with herpes zoster had a higher risk of developing NA (adjusted hazard ratio = 1.408, 95% confidence interval = 1.013-2.319, P = 0.030). In the patients with herpes zoster, female sex, age >= 65, hepatitis E virus (HEV), and having had a recent infectious event including pneumonia and influenza were risk factors for developing NA (adjusted HR 2.746, 1.998, 2.735, 2.016, and 1.718, respectively, all P < 0.05). Patients with herpes zoster attack have a higher risk of developing NA over a 3-month period after diagnosis, especially those who are female, age >= 65, HEV, or have experienced a recent infectious event or pneumonia and influenza. PMID- 30397832 TI - Ethnic and Racial Specificity, or Not, in Bisexuality Research: A Practical Commentary. AB - This commentary focuses on reflecting on how we, as bisexuality researchers, consider the effects of, and contribute toward addressing, systemic racism and ethnic discrimination affecting bisexual individuals in different global contexts. This commentary is intended to provoke critical thinking among bisexuality and other sex researchers on how we may best consider (or not) racism and ethnic oppression when dealing with ethnically, racially, or culturally diverse bisexual samples of individuals. In this commentary, I argue that current social and behavioral science researchers who focus on bisexuality tend to follow one or more of the following three approaches: a "color blind" approach, an inclusive approach or, a racially-ethnically specific approach. I will identify the advantages and considerations for taking one approach versus another. PMID- 30397831 TI - Prognostic Factors in Pediatric Sport-Related Concussion. AB - PURPOSE OF REVIEW: Sport-related concussion (SRC) and mild traumatic brain injury (mTBI) have been thrust into the national spotlight, with youth athletes bearing the burden of this public health problem. The current review aims to provide a practical summary of pediatric SRC, including key terminology, return to play/school, and risk factors for post-concussion syndrome (PCS). RECENT FINDINGS: While the majority of youth athletes recover within 2 to 4 weeks, approximately 10% of athletes experience a protracted recovery with symptoms lasting months, impacting social, scholastic, and sporting activities. In the pediatric population, the strongest predictors of PCS are initial symptom burden and prior concussion, with mixed results behind the factors of gender, headaches, and learning disability. The role of psychiatric, family history, sports, and socioeconomic factors remain in their infancy. PMID- 30397830 TI - Cardiovascular and Metabolic Comorbidities in Rheumatoid Arthritis. AB - PURPOSE OF THE REVIEW: An increased prevalence of cardiovascular risk factors in rheumatoid arthritis (RA) is reported. The absolute cardiovascular risk in RA patients is higher than in the general population, and although the RA prognosis has gradually improved, premature cardiovascular (CV) mortality remains a matter of fact. The purpose of this review is to shed light on CV and metabolic involvement in RA, with the aim of defining its best management. RECENT FINDINGS: Multiple lines of evidence have revealed common mechanisms behind inflammatory and CV diseases and clarified the metabolic and CV pathways involved in RA and the effects of different pharmacological treatments. CV risk assessment should be mandatory in all RA patients, taking into account the impact of both diseases on patient's prognosis. Therefore, a multidisciplinary approach is the best management, and rheumatologists, cardiologists, and general practitioners must work together to significantly improve outcome and quality of life in RA patients. Future research could investigate the potential beneficial effects of a more aggressive pharmacological treatment of CV and metabolic risk factors. PMID- 30397833 TI - The challenges of living with bipolar disorder: a qualitative study of the implications for health care and research. AB - BACKGROUND: In mental health care, clinical practice is often based on the best available research evidence. However, research findings are difficult to apply to clinical practice, resulting in an implementation gap. To bridge the gap between research and clinical practice, patients' perspectives should be used in health care and research. This study aimed to understand the challenges people with bipolar disorder (BD) experience and examine what these challenges imply for health care and research needs. METHODS: Two qualitative studies were used, one to formulate research needs and another to formulate healthcare needs. In both studies focus group discussions were conducted with patients to explore their challenges in living with BD and associated needs, focusing on the themes diagnosis, treatment and recovery. RESULTS: Patients' needs are clustered in 'disorder-specific' and 'generic' needs. Specific needs concern preventing late or incorrect diagnosis, support in search for individualized treatment and supporting clinical, functional, social and personal recovery. Generic needs concern health professionals, communication and the healthcare system. CONCLUSION: Patients with BD address disorder-specific and generic healthcare and research needs. This indicates that disorder-specific treatment guidelines address only in part the needs of patients in everyday clinical practice. PMID- 30397834 TI - New Metrics in High-Resolution and High-Definition Anorectal Manometry. AB - PURPOSE OF REVIEW: To review recently published diagnostic methods that use high resolution (HR-) or high-definition- (HD-) anorectal manometry (ARM) techniques. RECENT FINDINGS: The integrated pressurized volume (IPV) is a new measure based on spatiotemporal plots obtained from HR-ARM. The IPV may be clinically useful for improving the prediction of abnormal balloon expulsion test in patients with constipation and for discriminating patients with anorectal disorders from asymptomatic controls. Combination of IPV parameters was superior to conventional manometric parameters in predicting the responsiveness to biofeedback therapy. Moreover, several novel parameters including the HR-ARM resting integral, HR-ARM squeeze profile, and anorectal asymmetry index may each be useful as predictive factors for identifying patients with fecal incontinence. HR- and HD-ARM are increasingly performed worldwide for evaluation of anorectal function. Here, we describe new metrics whose clinical significance has not been fully established. Further standardization and validation of these metrics could provide clinically important new information and could help improve our understanding of the pathophysiology of anorectal disorders. PMID- 30397836 TI - Mass balance, routes of excretion, and pharmacokinetics of investigational oral [14C]-alisertib (MLN8237), an Aurora A kinase inhibitor in patients with advanced solid tumors. AB - Aims This two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics and safety of the investigational aurora A kinase inhibitor, alisertib, in three patients with advanced malignancies. Methods Part A; patients received a single 35-mg dose of [14C]-alisertib oral solution (~80 MUCi total radioactivity [TRA]). Serial blood, urine, and fecal samples were collected up to 336 h post-dose for alisertib mass balance and pharmacokinetics in plasma and urine by liquid chromatography-tandem mass spectrometry, and mass balance/recovery of [14C]-radioactivity in urine and feces by liquid scintillation counting. Part B; patients received non-radiolabeled alisertib 50 mg as enteric-coated tablets twice-daily for 7 days in 21-day cycles. Results In part A, absorption was fast (median plasma Tmax, 1 h) for alisertib and TRA. Mean plasma t1/2 for alisertib and TRA were 23.4 and 42.0 h, respectively. Mean plasma alisertib/TRA AUC0-inf ratio was 0.45, indicating presence of alisertib metabolites in circulation. Mean TRA blood/plasma AUC0-last ratio was 0.60, indicating preferential distribution of drug-related material in plasma. On average, 87.8% and 2.7% of administered radioactivity was recovered in feces and urine, respectively (total recovery, 90.5% by 14 days post-dose). In part B, patients received a median 3 cycles of alisertib. The most common any-grade adverse events were fatigue and alopecia. Conclusions Findings suggest that alisertib is eliminated mainly via feces, consistent with hepatic metabolism and biliary excretion of drug-related material. Further investigation of alisertib pharmacokinetics in patients with moderate-severe hepatic impairment is warranted to inform dosing recommendations in these patient populations. PMID- 30397837 TI - Implications of the CANVAS Study in Reducing Cardiovascular Outcomes. AB - PURPOSE OF REVIEW: In recent years, Cardiovascular Outcome Event Trials (CVOTs) in type 2 diabetes mellitus (T2DM) have demonstrated that sodium glucose transporter 2 inhibitors (SGLT2i) could reduce major adverse cardiovascular events (MACE) and cardiovascular mortality independent of a glucose lowering mechanism. SGLT2i trials reported significant results that have generated biologically plausible theories with regard to the macrovascular benefit. In this review, we have summarized and discussed the results of the CANVAS program. RECENT FINDINGS: The CANVAS program is unique as it is an analysis of two aggregated cohorts. The two cohorts were similar at baseline but had different durations of exposure to canagliflozin. It showed a 14% reduction in the primary MACE composite. However, the individual components of the MACE composite were not significantly different from placebo. Initial analysis also indicated a reno protective effect. The results of the CANVAS program are similar overall yet different when compared to the EMPA-REG OUTCOMES trial, especially with regard to cardiovascular mortality and adverse event profile. This could possibly be due to the differences in the cardiovascular risk profile of the enrolled population in the two trials. Other possibilities include drug-specific effects and different mechanisms of lowering overall MACE. In addition, a brief comparison of CANVAS to the CVD-REAL indicates that the CANVAS trial results may apply to a larger, more generalized population than those in the CANVAS program. PMID- 30397835 TI - Update on the Diagnosis and Management of Wilson Disease. AB - PURPOSE OF REVIEW: Exciting developments relating to Wilson disease (WD) have taken place with respect to both basic biological and clinical research. This review critically examines some of these findings and considers their implications for current thinking about WD. It is not a comprehensive review of WD as a clinical disorder. RECENT FINDINGS: The structure of the gene product of ATP7B, abnormal in WD, is being worked out in detail, along with a broader description of how the protein ATP7B (Wilson ATPase) functions in cells including enterocytes, not only in relation to copper disposition but also to lipid synthesis. Recent population studies raise the possibility that WD displays incomplete penetrance. Innovative screening techniques may increase ascertainment. New strategies for diagnosing and treating WD are being developed. Several disorders have been identified which might qualify as WD-mimics. WD can be difficult to diagnose and treat. Insights from its pathobiology are providing new options for managing WD. PMID- 30397838 TI - Is knee osteoarthritis related to coffee drinking? A nationwide cross-sectional observational study. AB - AIMS: Coffee is one of the most consumed beverages globally, and coffee consumption is increasing. Osteoarthritis (OA), the most common musculoskeletal disease in the elderly, is also becoming more prevalent. Coffee is associated with various diseases, but there has not yet been a study of the relationship between coffee and knee OA. Therefore, we investigated this relationship in elderly Koreans. METHODS: Data from 2012 to 2013 were collected from the Korea National Health and Nutrition Examination Survey. We included 2302 participants in our study: 897 men and 1405 women. Participants with knee OA were defined as those whose knee joints exhibited radiographic change of Kellgren-Lawrence grade 2 or higher. Daily coffee consumption amounts were categorized as none, < 2 cups, 2-3 cups, 4-6 cups, and >= 7 cups based on self-reporting. RESULTS: A multiple logistic regression model, the odds ratios (ORs) of knee OA in the < 2 cup, 2-3 cup, 4-6 cup, and >= 7 cup groups compared to the no-coffee group in men were 1.13 (95% CI 0.50-2.55), 1.79 (95% CI 0.81-3.97), 2.21 (95% CI 0.91-5.35), and 3.81 (95% CI 1.46-12.45), respectively. There was no significant association between coffee consumption and knee OA prevalence in women. CONCLUSION: Daily more than 7 cups of coffee drinking was associated with a prevalence of knee OA in Korean men, and although the ORs did not increase significantly across consumption levels, the prevalence of knee OA tended to increase with increasing coffee consumption. PMID- 30397839 TI - Letter to editor: New onset/recurrence of inflammatory arthralgia/spondyloarthritis in patients treated with vedolizumab for intestinal bowel disease. PMID- 30397840 TI - How does chronic temperature exposure affect hypoxia tolerance in sheepshead minnows' (Cyprinodon variegatus variegatus) ability to tolerate oxidative stress? AB - Estuarine environments are characterized by cyclical fluctuations in tides, with tidal shifts drastically, frequently, and acutely altering temperature, dissolved oxygen, and salinity. Despite these ecological challenges, the sheepshead minnow, Cyprinodon variegatus, seems to dominate estuarine landscapes. Here, we held sheepshead minnows to four temperature treatment groups for 1 month. We then tested whether temperature exposure had an effect on acute hypoxia tolerance via oxidative stress. We measured superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities, as well as total antioxidant capacity and lipid peroxidation (LPO) damage in white muscle. We found that exposure to increasing temperatures (15, 20, 25, and 30 degrees C) for 1 month led to significantly higher CTmax in sheepshead minnows. We also found that CAT activity significantly increased in the 20 and 25 degrees C temperature treatment groups, whereas it did not change between control and hypoxia trials. SOD activity was significantly higher in control groups of the 15 and 30 degrees C temperature treatment groups compared with hypoxia groups of these same temperature treatments. GPx activity was significantly lower in the 30 degrees C temperature treatment group regardless of control or hypoxia trials. Hydroxyl scavenging capacity varied across temperature treatment and control/hypoxia groups. Peroxyl scavenging capacity and LPO damage showed no significant differences across temperature treatment groups or between control and hypoxia trials. PMID- 30397842 TI - Deep brain stimulation in pediatric dystonia: a systematic review. AB - While deep brain stimulation (DBS) treatment is relatively rare in children, it may have a role in dystonia to reduce motor symptoms and disability. Pediatric DBS studies are sparse and limited by small sample size, and thus, outcomes are poorly understood. Thus, we performed a systematic review of the literature including studies of DBS for pediatric (age < 21) dystonia. Patient demographics, disease causes and characteristics, motor scores, and disability scores were recorded at baseline and at last post-operative follow-up. We identified 19 studies reporting DBS outcomes in 76 children with dystonia. Age at surgery was 13.8 +/- 3.9 (mean +/- SD) years, and 58% of individuals were male. Post operative follow-up duration was 2.8 +/- 2.8 years. Sixty-eight percent of patients had primary dystonia (PD), of whom 56% had a pathological mutation in DYT1 (DYT1+). Across all patients, regardless of dystonia type, 43.8 +/- 36% improvement was seen in Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) motor ( M) scores after DBS, while 43.7 +/- 31% improvement was observed in BFMDRS disability (-D) scores. Patients with PD were more likely to experience >= 50% improvement (56%) in BFMDRS-M scores compared to patients with secondary causes of dystonia (21%, p = 0.004). DYT1+ patients were more likely to achieve >= 50% improvement (65%) in BFMDRS-D than DTY1- individuals (29%, p = 0.02), although there was no difference in BFMDRS-M >= 50% improvement rates between DYT1+ (66%) or DYT1- (43%) children (p = 0.11). While DBS is less common in pediatric patients, individuals with severe dystonia may receive worthwhile benefit with neuromodulation treatment. PMID- 30397841 TI - Nutrition and water temperature regulate the expression of heat-shock proteins in golden pompano larvae (Trachinotus ovata, Limmaeus 1758). AB - Understanding fish larval development is of a great interest for aquaculture production efficiency. Identifying possible indicators of fish larvae stress could improve the production and limit the mortality rate that larval stage is subjected to. Heat-shock proteins (HSPs) and heat-shock factors (HSFs) are well known as indicators of response to many kinds of stressor (e.g., environmental, morphological, or pathological changes). In this study, golden pompano larvae were raised at different temperatures (23 degrees C, 26 degrees C, and 29 degrees C), as well as three different diets (Artemia nauplii unenriched, Artemia nauplii enriched with Nannochloropsis sp., and Artemia nauplii enriched with Algamac 3080), and the expression of HSP60, HSP70, HSF1, HSP2, and GRP94 were monitored. While stress genes were widely expressed in the larval tissues, HSP60 and HSP70 were principally from the gills and heart; HSF1 principally from the muscle, brain, and heart; and GRP94 principally from the head kidney and spleen. Golden pompano larvae were found to be more sensitive to thermal changes at later larval stage, and 29 degrees C was showed to likely be the best condition for golden pompano larval development. Nannochloropsis sp.-enriched Artemia nauplii treatment was found to be the most appropriate feed type with moderate relative expressions of HSP60, HSP70, HSF1, HSF2, and GRP94. PMID- 30397843 TI - Individualized evaluation of lumbar bone mineral density in children with cerebral palsy. AB - : Lumbar spine bone mineral density (LS-BMD) assessed by dual-energy X-ray absorptiometry (DXA) is used in children with cerebral palsy (CP) to evaluate bone health. LS-BMD results in children with CP are influenced significantly by their height, BMI, and mobility level. An adjustment for these parameters might improve the clinical significance of the method. PURPOSE/INTRODUCTION: DXA evaluation is considered useful in children with CP to assess bone health. For this purpose, LS-BMD is often used. The aim of the study was to estimate the effect of height, BMI, and reduced mobility level of children with CP on LS-BMD and to develop a method to adjust individual results of LS-BMD for these factors. METHODS: We conducted a monocentric retrospective analysis of data collected in children and adolescents with CP, who participated in a rehabilitation program and had no history of recurrent fractures. The DXA scan was part of the routine examination for participants older than 4 years of age. The relationship between height and BMI for age Z-scores and age-adjusted LS-BMD Z-scores was analyzed. RESULTS: LS-DXA scans of 500 children and adolescents with CP (Gross Motor Function Classification System levels I-V) were included in the statistical analysis (217 female). The mean age was 9.4 years (+/- 3.7 years). Children with moderate to severe CP had significantly (p < 0.001) lower LS-BMD Z-scores than children with mild CP. We provided nomograms to adjust individual LS-BMD results to their height, BMI, and mobility level. CONCLUSIONS: LS-BMD results in children with CP were influenced significantly by their height, BMI, and mobility level. An adjustment of the LS-BMD results to height, BMI, and mobility level might improve the clinical significance of an individual result. PMID- 30397844 TI - Intraosseous Administration of 23.4% NaCl for Treatment of Intracranial Hypertension. AB - BACKGROUND/OBJECTIVE: Prompt treatment of acute intracranial hypertension is vital to preserving neurological function and frequently includes administration of 23.4% NaCl. However, 23.4% NaCl administration requires central venous catheterization that can delay treatment. Intraosseous catheterization is an alternative route of venous access that may result in more rapid administration of 23.4% NaCl. METHODS: Single-center retrospective analysis of 76 consecutive patients, between January 2015 and January 2018, with clinical signs of intracranial hypertension received 23.4% NaCl through either central venous catheter or intraosseous access. RESULTS: Intraosseous cannulation was successful on the first attempt in 97% of patients. No immediate untoward effects were seen with intraosseous cannulation. Time to treatment with 23.4% NaCl was significantly shorter in patients with intraosseous access compared to central venous catheter (p < 0.0001). CONCLUSIONS: Intraosseous cannulation resulted in more rapid administration of 23.4% NaCl with no immediate serious complications. Further investigations to identify the clinical benefits and safety of hypertonic medication administration via intraosseous cannulation are warranted. PMID- 30397846 TI - Hodgkin lymphoma at Groote Schuur Hospital, South Africa: the effect of HIV and bone marrow infiltration. AB - Human immunodeficiency virus (HIV) is associated with an increased risk of developing Hodgkin lymphoma (HL). South Africa (SA) has the highest HIV prevalence rate in the world. There is currently no outcome-based data for HIV associated HL from SA. A bone marrow database was compiled of all bone marrow biopsies (BMB) reported at National Health Laboratory Service (NHLS) Groote Schuur Hospital (GSH) between January 2005 and December 2012. Patients who had a BMB performed for staging of HL or where HL was diagnosed on the BMB were included for further analysis. Clinical and laboratory data was extracted from medical and laboratory records. Primary outcome measures included histological subtype, bone marrow infiltration (BMI) by HL, CD4 count, HIV-viral load (HIV VL), tuberculosis (TB) data, treatment with chemotherapy and 5-year overall survival (OS). The database included 6569 BMB and 219 patients of these had HL and were included for analysis. The median age at presentation (32 years) was similar in the HIV+ and HIV- populations. While males predominated in the HIV- group, females predominated in the HIV+ group (male:female ratio of 1.5:1 vs 0.7:1, respectively). The majority of patients (71%) were HIV negative (HIV-) and 29% were HIV positive (HIV+). The diagnosis of HL was made on BMB in 17% of cases. BMI was seen in 37% (82/219) overall, and was found in more HIV+ patients (61%; 39/64) than HIV- patients (28%; 43/155; p = 0.03). The histological subtype varied according to HIV status with nodular sclerosis classical Hodgkin lymphoma (NSCHL) being most frequent in the HIV- group and classical Hodgkin lymphoma (CHL)-unclassifiable the most frequent in the HIV+ group. HIV+ patients had a median CD4 count of 149 * 106/L and 39% were anti-retroviral therapy (cART) naive at HL diagnosis. HIV+ patients had received anti-TB therapy more frequently than HIV- patients (72% vs 17%; p = 0.007). More HIV+ patients did not receive chemotherapy than HIV- patients (31% vs 3%; p = 0.001). The 5-year OS was 56%. HIV+ patients with BMI had a 5-year OS of 18%. BMI, HIV status, low CD4 count, histological subtype and TB therapy had a statistical significant impact on 5 year OS (p < 0.01). The 5-year OS was 56%, with both BMI and HIV+ status being associated with poor survival. BMB provided the diagnosis of HL in 17% of cases, confirming its diagnostic utility in our setting. Our cohort showed similar survival outcomes to other countries in Africa, Asia and Central America with comparable socio-economic constraints to SA. PMID- 30397845 TI - Chronic Periaortitis: an Update. AB - PURPOSE OF REVIEW: We aim to review traditional concepts and recent developments on the nosology, pathophysiology, clinical phenotypes and treatment of chronic periaortitis (CP). RECENT FINDINGS: CP is a rare disorder hallmarked by a periaortic fibro-inflammatory tissue. It can present as an isolated disease, but it can also be associated with other autoimmune and fibro-inflammatory lesions (e.g., fibrosing mediastinitis, sclerosing pancreato-cholangitis) that are part of the spectrum of IgG4-related disease. In a subgroup of patients, it also involves the thoracic aorta (so-called "diffuse periaortitis"), which supports the notion of an inflammatory disorder of large arteries. The pathogenesis of CP is multifactorial: recent studies have elucidated the predisposing role of immunogenetic variants and exposures to environmental agents such as smoking and asbestos. CP is a rare immune-mediated disease that affects the abdominal aorta and the iliac arteries and, in some cases, the thoracic aorta. It may overlap with manifestations of IgG4-related disease, and its treatment comprises glucocorticoids, conventional and biological immunosuppressive agents. PMID- 30397847 TI - Epidemiological investigations of contagious caprine pleuropneumonia in selected districts of Borana zone, Southern Oromia, Ethiopia. AB - From November 2016 to April 2017, a cross-sectional study to determine the sero prevalence of contagious caprine pleuropneumonia (CCPP) and to investigate its epidemiology was conducted in selected districts of Borana zone in Ethiopia. In addition, the study aimed at identifying Mccp antigens using species specific primer of PCR. A multistage random sampling was implemented to select districts, pastoral associations (villages), and households. A total of 890 serum samples of small ruminants that had not been vaccinated (goats n = 789 and sheep n = 101) were collected and screened for the presence of antibodies against Mycoplasma capricolum subspecies capripneumoniae using a competitive enzyme-linked immunosorbent assay. Lung tissues and pleural fluid samples were collected from 3 sero-positive and clinically suspected goats for isolation of Mycoplasma capricolum subspecies capripneumoniae. Serology showed that overall 31.2% (246/789) of goats and 12.9% (13/101) of sheep were positive with statistically significant differences between districts (p = 0.001). Multivariable logistic regression analysis revealed that goats from Moyale and Yabello districts had higher odds of being positive than goats from Elwoya district with odd ratios of 2.05 and 1.61, respectively. Age of goats was also significantly associated with sero-positivity (OR = 1.47; CI 95% 1.2-1.8). Mycoplasma capricolum subspecies capripneumoniae was identified in 6 (75%) of the tissue samples using species specific primer of PCR. Besides improving the understanding of the epidemiology of CCPP in the selected districts and demonstrating its wide distribution, the study highly also provides evidence of the possible role of sheep in the maintenance of the disease. PMID- 30397848 TI - Correction to: Internet gaming disorder: deficits in functional and structural connectivity in the ventral tegmental area-Accumbens pathway. AB - The original version of this article contained mistakes, and the authors would like to correct them. The correct details are given below. PMID- 30397850 TI - Cellular and Molecular Aspects of Parkinson Treatment: Future Therapeutic Perspectives. AB - Parkinson's disease is a neurodegenerative disorder accompanied by depletion of dopamine and loss of dopaminergic neurons in the brain that is believed to be responsible for the motor and non-motor symptoms in this disease. The main drug prescribed for Parkinsonian patients is L-dopa, which can be converted to dopamine by passing through the blood-brain barrier. Although L-dopa is able to improve motor function and improve the quality of life in the patients, there is inter-individual variability and some patients do not achieve the therapeutic effect. Variations in treatment response and side effects of current drugs have convinced scientists to think of treating Parkinson's disease at the cellular and molecular level. Molecular and cellular therapy for Parkinson's disease include (i) cell transplantation therapy with human embryonic stem (ES) cells, human induced pluripotent stem (iPS) cells and human fetal mesencephalic tissue, (ii) immunological and inflammatory therapy which is done using antibodies, and (iii) gene therapy with AADC-TH-GCH gene therapy, viral vector-mediated gene delivery, RNA interference-based therapy, CRISPR-Cas9 gene editing system, and alternative methods such as optogenetics and chemogenetics. Although these methods currently have a series of challenges, they seem to be promising techniques for Parkinson's treatment in future. In this study, these prospective therapeutic approaches are reviewed. PMID- 30397851 TI - "Man and his Mission". PMID- 30397849 TI - The Role of Botox in Colorectal Disorders. AB - PURPOSE OF REVIEW: To overview the current medical literature on the efficacy of botulism toxin treatment (BTX-A) for lower gastrointestinal disorders (GIT). RECENT FINDINGS: BTX-A was found to have a short-term efficacy for the treatment of dyssynergic defecation. Surgical treatment was found to be more effective than BTX-A for the healing of chronic anal fissures, and BTX-A can be considered when surgery is undesirable. Data regarding the effects of BTX-A injection for the treatment of chronic anal pain is limited. Beneficial effects were observed only in a minority of patients. BTX-A treatment was found to be effective for the treatment of obstructive symptoms after surgery for Hirsprung's disease as well as for the treatment of internal anal sphincter achalasia. BTX-A treatment has a short-term efficacy and is safe. Further research is still needed in order to establish the exact place of BTX-A treatment of lower GIT disorders. PMID- 30397852 TI - PD-L1 Expression on Lung Cancer Stem Cells in Metastatic Lymph Nodes Aspirates. AB - OBJECTIVES: An immunotherapy was found to be effective in achieving long-term survival in some lung cancer patients. It has emerged to searching for new immune biomarkers for select the best candidates to this therapy. It is suggested that cancer stem cells (CSCs) are responsible for tumor initiation, maintenance and its metastatic potential. However, a role of CSCs in escape of cancer from immunosurveillance is unknown. The aim of the study was assess the phenotype of putative CSCs and to examine the expression of PD-L1 on CSCs in metastatic lymph nodes (LNs) in lung cancer patients. MATERIAL AND METHODS: Flow cytometry was used for CSCs evaluation in peripheral blood and EBUS/TBNA aspirates from N1,N2 lymph nodes in lung cancer patients. RESULTS: Of 30 patients the LNs metastases were confirmed in 18 patients. We noticed presence of PD-L1 on putative lung CSCs CD133 + EpCAM+ cells. A higher percentage of CD133 + EpCAM+PD-L1+ cells was observed in patients with metastatic in LNs- median value = 4.38% than in patients without LNs metastases- median value = 0,015% (p < 0.05). The highest proportion of PD-L1+ CSCs was found in adenocarcinoma patients and in those with oncogene addiction what indicate an particular biology of this type of lung cancer. CONCLUSION: The presence of CSCs with expression of PD-L1 in the metastatic LNs might suggest their immunogenic potential. EBUS/TBNA is commonly used in diagnosis and staging of lung cancer, so the analysis of the cells in metastatic LNs may fit in "immunoscoring" before immunotherapy. PMID- 30397853 TI - Use of a PTFE Micro-Bioreactor to Promote 3D Cell Rearrangement and Maintain High Plasticity in Epigenetically Erased Fibroblasts. AB - Phenotype definition is driven by epigenetic mechanisms as well as directly influenced by the cell microenvironment and by biophysical signals deriving from the extracellular matrix. The possibility to interact with the epigenetic signature of an adult mature cell, reversing its differentiated state and inducing a short transient high plasticity window, was previously demonstrated. In parallel, in vitro studies have shown that 3D culture systems, mimicking cell native tissue, exert significant effects on cell behavior and functions. Here we report the production of "PTFE micro-bioreactors" for long-term culture of epigenetically derived high plasticity cells. The system promotes 3D cell rearrangement, global DNA demethylation and elevated transcription of pluripotency markers, that is dependent on WW domain containing transcription regulator 1 (TAZ) nuclear accumulation and SMAD family member 2 (SMAD2) co shuttling. Our findings demonstrate that the use of 3D culture strategies greatly improves the induction and maintenance of a high plasticity state. PMID- 30397854 TI - Should Gender Reassignment Surgery be Publicly Funded? AB - Transgender people have among the highest rates of suicide attempts of any group in society, driven strongly by the perception that they do not belong in the sex of their physical body. Gender reassignment surgery (GRS) is a procedure that can change the transgender person's physical body to accord with their gender identity. The procedure raises important ethical and distributive justice concerns, given the controversy of whether it is a cosmetic or medical procedure and the economic costs associated with performing the procedure. This paper argues that there is a strong case for funding GRS as a matter of clinical necessity and justice. This paper will be divided in four key sections: First, the state of transgender health will be outlined, including the role of GRS and common objections to it. Second, a number of common objections to GRS will be analysed at the outset and shown to be unconvincing. Third, a constructive argument will be advanced, arguing that publicly funded GRS is clinically necessary, cost-effective, and demanded by principles of justice. Fourth, the paper will briefly discuss moralistic biases and why we demand a higher burden of justification for funding GRS compared with other analogous procedures. PMID- 30397855 TI - Production of 8-nitro-cGMP in osteocytic cells and its upregulation by parathyroid hormone and prostaglandin E2. AB - Osteocytes regulate bone remodeling, especially in response to mechanical loading and unloading of bone, with nitric oxide reported to play an important role in that process. In the present study, we found that 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), a second messenger of nitric oxide in various types of cells, was produced by osteocytes in bone tissue as well as cultured osteocytic Ocy454 cells. The amount of 8-nitro-cGMP in Ocy454 cells increased during incubation with parathyroid hormone or prostaglandin E2, both of which are known to upregulate receptor activator of nuclear factor-kappaB ligand (RANKL) mRNA expression in osteocytes. On the other hand, exogenous 8-nitro-cGMP did not have effects on either the presence or absence of these bioactive substances. Furthermore, neither an inhibitor of nitric oxide synthase nor 8-bromo-cGMP, a cell-permeable analog of cGMP, showed remarkable effects on mRNA expression of sclerostin or RANKL. These results indicate that neither nitric oxide nor its downstream compounds, including 8-nitro-cGMP, alone are sufficient for induction of functional changes in osteocytes. PMID- 30397856 TI - Radio-pathological Correlation of 18F-FDG PET in Characterizing Gallbladder Wall Thickening. AB - AIM: Thick-walled gallbladder is difficult to characterize on conventional imaging. 18F-FDG PET was used to differentiate benign and malignant wall thickness and compared with histopathology. METHODS: Thirty patients with gallbladder (GB) wall thickening (focal > 4 mm and diffuse > 7 mm), underwents uspected on ultrasound, or CT scan, and underwent 18F-FDG PET. Histopathology of the specimen was compared with imaging findings. RESULTS: The mean age was 48.22 +/- 31.33 years with a M:F 1:4 ratio. Twenty patients had diffuse and 10 had focal thickening. On 18F-FDG PET, lesion was benign in 12, malignant in 13, and indeterminate in 5. Histopathology was malignancy in 12; benign in 18-chronic cholecystitis in 11, xanthogranulomatous in 4, IgG4 related in 2, and polyp in 1. The mean GB wall thickness was 7.79 +/- 3.59 mm (10.34 malignant and 6.10 in benign, p = 0.001). At a cutoff of 8.5 mm, the sensitivity and specificity of detecting malignancy was 94% and 67%. The mean SUV uptake was 7.46 (benign 4.51, malignant 14.26, p = 0.0102). At a cutoff of 5.95, the sensitivity and specificity of detecting malignancy was 92% and 79%. For 18F-FDG PET, overall sensitivity was 91%, specificity 79%, PPV 77%, NPV 92%, and diagnostic accuracy was 84%. CONCLUSION: 18F-FDG PET is a reliable method of differentiation between benign and malignant thickening of the gallbladder particularly when wall thickness and SUV value is taken into account. PMID- 30397857 TI - Synchronous Adeno-squamous Carcinoma of Gallbladder and Adenocarcinoma of Common Bile Duct: Twin Trouble. PMID- 30397858 TI - Caregiver Burden and Work Productivity Among Japanese Working Family Caregivers of People with Dementia. AB - BACKGROUND: We examined the association between caregiver burden and work productivity (i.e., absenteeism, presenteeism, and overall work impairment) among working family caregivers of people with dementia and whether job characteristics (i.e., job demands, job control, supervisor and coworker support) moderate this association. METHODS: A cross-sectional correlational study design using a web based questionnaire survey was conducted among 379 Japanese working family caregivers of people with dementia (105 female, age range 20-77) in May 2016, which measured caregiver burden, work productivity, care situation, job characteristics, and demographics. Caregiver burden was designated as an independent variable and each aspect of work productivity as a dependent variable in a hierarchical multiple regression analysis, adjusting for demographics. Interaction terms between caregiver burden and each job characteristic were also included in the model. RESULTS: Caregiver burden was significantly and positively associated with presenteeism (beta = 0.219, p < 0.001) and overall work impairment (beta = 0.181, p < 0.001), while the association of caregiver burden with absenteeism was not significant (beta = - 0.003, p = 0.953). Interaction effects of caregiver burden * coworker support on presenteeism (beta = - 0.189, p = 0.023) and overall work impairment (beta = - 0.172, p = 0.034) were significant. According to simple slope analyses, caregiver burden was greater at lower levels of coworker support compared to higher levels of coworker support for both presenteeism and overall work impairment. CONCLUSIONS: Our study suggests that higher caregiver burden is associated with a decrease in work productivity. Additionally, coworker support appears to buffer the association of caregiver burden with presenteeism and overall work impairment among working family caregivers of people with dementia. PMID- 30397859 TI - A Pilot Study of Texture Analysis of Primary Tumor [18F]FDG Uptake to Predict Recurrence in Surgically Treated Patients with Non-small Cell Lung Cancer. AB - PURPOSE: To examine whether the heterogeneous texture parameters in primary tumor can predict prognosis of patients with non-small cell lung cancer (NSCLC) received surgery after 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET)/X-ray computed tomography (CT). PROCEDURE: This retrospective study included 55 patients with NSCLC who underwent [18F]FDG-PET/CT before surgery from January 2011 and December 2015. SUV-related (SUVmax and SUVmean), volumetric (metabolic tumor volume [SUV >= 2.5], and total lesion glycolysis) and texture parameters (local parameters; entropy, homogeneity, and dissimilarity and regional parameters; intensity variability [IV], size-zone variability [SZV], and zone percentage [ZP]) were obtained. Tumor size, TNM stage, SUV-related, volumetric, and texture parameters were compared between the patients with progression and without progression using Mann-Whitney's U or chi2 test and progression-free survival (PFS) and prognostic significance were assessed by Kaplan-Meier method and Cox regression analysis, respectively. RESULTS: Nineteen patients eventually showed progression, and 36 patients were alive without progression during clinical follow-up (median follow-up PFS; 23 months [range, 1-71]). The patients with progression showed significantly larger tumor size (p < 0.001), higher IV (p = 0.010), and higher SZV (p = 0.007) than those without progression. PFS was significantly shorter in patients with large tumor size (p = 0.008), high T stage (p = 0.009), high stage (p = 0.013), high IV (p = 0.012), and high SZV (p = 0.015) at univariate analysis. At multivariate analysis, stage (hazard ratio [HR] 1.62, p = 0.035) and IV (hazard ratio 6.19, p = 0.048) were only remained independent predictors for PFS. CONCLUSIONS: The regional heterogeneity texture parameters IV and SZV can predict tumor progression, and IV has the potential to predict prognosis of surgically treated NSCLC patients. PMID- 30397860 TI - In Vitro and In Vivo Efficacy of the Monocarboxylate Transporter 1 Inhibitor AR C155858 in the Murine 4T1 Breast Cancer Tumor Model. AB - Monocarboxylate transporter 1 (MCT1), also known as a L-lactate transporter, is a potential therapeutic target in cancer. The objectives of this study were to evaluate efficacy and assess concentration-effect relationships of AR-C155858 (a selective and potent MCT1 inhibitor) in murine 4T1 breast cancer cells and in the 4T1 tumor xenograft model. Western blotting of 4T1 cells demonstrated triple negative breast cancer (TNBC) characteristics and overexpression of MCT1 and CD147 (a MCT1 accessory protein), but absence of MCT4 expression. AR-C155858 inhibited the cellular L-lactate uptake and cellular proliferation at low nanomolar potencies (IC50 values of 25.0 +/- 4.2 and 20.2 +/- 0.2 nM, respectively). In the xenograft 4T1 mouse model of immunocompetent animals, AR C155858 (10 mg/kg i.p. once daily) had no effect on tumor volume and weight. Treatment with AR-C155858 resulted in slightly increased tumor lactate concentrations; however, the changes were not statistically significant. AR C155858 was well tolerated, as demonstrated by the unchanged body weight and blood lactate concentrations. Average blood and tumor AR-C155858 concentrations (110 +/- 22 and 574 +/- 245 nM, respectively), 24 h after the last dose, were well above the IC50 values. These data indicate that AR-C155858 penetrated 4T1 xenograft tumors and was present at high concentrations but was ineffective in decreasing tumor growth. Evaluations of AR-C155858 in other preclinical models of breast cancer are needed to further assess its efficacy. PMID- 30397862 TI - Editorial and Review: 30th ASMS Sanibel Conference on Mass Spectrometry Computational Modelling in Mass Spectrometry and Ion Mobility: Methods for Ion Structure and Reactivity Determination. PMID- 30397861 TI - Is the aquatic thermal environment a suitable place for providing rehabilitative treatment for person with Parkinson's disease? A retrospective study. AB - Many authors showed that aquatic physiotherapy could improve quality of life and reduce postural instability and risk of falling in elderly subjects. The aim of this research was to explore if the thermal aquatic environment is a suitable place for rehabilitative training in person with Parkinson disease (PwP) with results comparable to the standard physiotherapy. A retrospective study was conducted on a database of 14 persons with Parkinson who were admitted to a thermal aquatic rehabilitation to undergo treatments made to improve gait and balance impairments. The rehabilitation training consisted of 45-min sessions conducted twice a week, on non-consecutive days, over 4 weeks of functional re education and kinesitherapy in the thermal pool. Educational and prevention instructions were also given to the patients during each session. Additionally, nutrition (diet), health education, and cognitive behavioral advice were given to our patients by therapists. The clinical characteristics of the sample were age 66 +/- 9, disease duration 7 +/- 5, and Hoehn and Yahr 1.5 +/- 0.5. The statistical analysis showed a statistically significant improvement for the UPDRS p = 0.0005, for The Berg Balance Scale p = 0.0078, for the PDQ8 p = 0.0039, Tinetti p = 0.0068, and for Mini BESTest p = 0.0002. Our data suggest that this intervention could become a useful strategy in the rehabilitation program of PwP. The simplicity of treatment and the lack of side effects endorse the use of thermal aquatic environment for the gait and balance recovery in PwP. PMID- 30397863 TI - Early nuclear stress testing after CABG: The new standard or too soon to tell? PMID- 30397865 TI - Case presentation commentary on "Rosai-Dorfman disease and left ventricular noncompaction cardiomyopathy: A heart failure conundrum." PMID- 30397864 TI - Utility of nuclear stress imaging in predicting long-term outcomes one-year post CABG Surgery. AB - BACKGROUND: Early MPI after CABG is currently considered rarely appropriate in asymptomatic patients. This study aimed to identify prognostic value of nuclear stress-imaging post-CABG. METHODS: This was a single center prospective study looking at long-term outcomes post-CABG. Per protocol participants underwent SPECT-MPI stress testing and coronary angiogram on the same day, 1-year following CABG. Defect size was semi-quantified. The primary outcomes were the composite of death and congestive heart failure. RESULTS: Eighty-four participants underwent nuclear stress-imaging and angiography, with a median follow-up of 11.1 years. Three separate stress findings predicted the primary outcome: inability to reach stage 3 of a Bruce protocol (OR 7.3, CI 2.4-22.1, P < 0.001), LVEF < 45% (OR 4.0, CI 1.1-15.3, P = 0.041) and a moderate-large stress defect size (HR 2.31, CI 1.1 1.5, P = 0.04). These findings appear to be additive and strongest among patients who underwent exercise stress testing (HR 10.6, CI 3.6-30.6, P < 0.001). Graft disease was identified in 39 (46%) patients and compared to those individuals with no graft disease, did not predict long-term adverse outcomes (P = 0.29). CONCLUSION: In clinically stable patients early after revascularization with CABG, SPECT-MPI can identify patients at higher risk of heart failure and death. PMID- 30397866 TI - Patients with incidental findings on MPS CTAC. PMID- 30397867 TI - Gastric wall uptake of Tc-99m sestamibi: Techniques to decrease uptake and minimize its consequences in myocardial perfusion SPECT. PMID- 30397868 TI - Simplified quantification PET myocardial blood flow: The need for technical standardization. PMID- 30397869 TI - Nutrition, risk factors, prevention, and imaging: The 2018 Mario Verani Lecture. AB - Heart disease has been the leading cause of death in the United States since 1918. Cardiac mortality rates have dramatically decreased in this era of advanced medical and interventional therapies. However, this has been aptly described as "mopping up the floor instead of turning off the faucet." With this recognition, prevention in cardiology is poised to become a central focus. Within prevention, dietary intervention is recognized as the single largest opportunity for improved cardiovascular outcomes, including improvement or elimination of cardiac risk factors, prevention of myocardial infarction, stroke and cardiovascular death, and reduction of plaque burden and myocardial ischemia. Cardiac imaging, particularly nuclear perfusion and coronary computed tomographic angiography, plays a critical role in early diagnosis and serial evaluation of myocardial ischemia and coronary artery disease. These techniques have the potential to help refine research protocols and evaluate their success by providing intermediate markers of improved myocardial blood flow and coronary plaque morphology. PMID- 30397870 TI - Obturator hernia and the elderly. AB - An 84-year-old woman with a history of weight loss, anorexia and episodic vomiting was admitted to hospital where she died soon afterwards. Her diagnosis was acute renal injury due to dehydration and malnutrition. At autopsy the body was cachectic with a small intestinal obstruction due to herniation through a defect at the anterolateral aspect of the obturator foramen. A poorly differentiated adenocarcinoma of the gastroesophageal junction was also identified with small peripheral pulmonary thromboemboli. Death was due to small bowel obstruction from a left obturator hernia with scattered peripheral pulmonary thromboemboli complicating cachexia due to gastroesophageal adenocarcinoma. Obturator hernias are called the "little old lady's hernia" and occur mainly in elderly, multiparous and malnourished women. The broader female pelvis and wider obturator canal with laxity of ligaments and loss of preperitoneal adipose tissue padding around the canal predispose to herniation. This rare hernia is often first identified at autopsy. PMID- 30397871 TI - Fatal intussusception in infancy: forensic implications. AB - Intussusception is one of the most common causes of intestinal obstructions in younger children, especially infants. Though rare, fatalities due to intussusception are known to be caused by intestinal obstruction associated with peritonitis, generalized sepsis and shock from intestinal infarction due to disruption in blood supply or electrolyte and fluid imbalance. An eight-month-old female infant, who initially presented with a single episode of vomiting and fever (37.8 degrees C), was examined as an outpatient at the department of pediatrics of a general hospital. Clinical examination revealed no characteristic features of acute abdomen, so the child was sent home. Nine to ten hours later her condition deteriorated: she became hyperpyretic and stuporous. On her way to the University Children's Hospital, the infant died; the death was confirmed upon admission, i.e. some 15 h after the onset of symptoms. The autopsy revealed an 8 cm long intussusception of the distal part of the ileum to the cecum. There was no gross or microscopic evidence of peritonitis at autopsy. The shock caused by intestinal obstruction with consequent intestinal necrosis was considered to be the cause of death. PMID- 30397872 TI - Toxicological findings in suicides - frequency of antidepressant and antipsychotic substances. AB - The role of psychoactive substances in the treatment of mental disorders and the risk of suicide are major public health issues. This cross-sectional study examined the prevalence of antidepressants and antipsychotics detected in toxicological screenings in suicides. Cases from the Institute of Legal Medicine of the Charite-University Medicine Berlin were reviewed over a 4-year-period. All cases (n = 477) with positive toxicology for antidepressants and antipsychotics in blood or organ tissue were included. Frequencies of the detected substances in non-suicide cases (n = 212; male n = 177, 55.2%; female n = 95, 52.5%) and suicide cases (n = 235; male n = 149, 63.4%; female n = 86, 36.6%) were examined. Tricyclic antidepressants (48.1%) were found most frequently in suicides, followed by atypical neuroleptics (37.0%), selective serotonin reuptake inhibitors (28.1%), typical neuroleptics (17.4%), tetracyclic antidepressants (16.2%) and other substances (8.9%). Alcohol was detected in 37.2% of suicides. The leading cause of death was drug poisoning (35.6%) followed by polytrauma (26.8%) and death by hanging (18.5%). A mental disorder (depression, schizophrenia, bipolar disorder, suicidality) was known in 22.9% of suicides. The most common location of death was the person's own house (63.8%) followed by public places (28.1%) and hospitals (8.1%) The five most common substances in the suicide group were doxepin (20%) citalopram (15.3%), mirtazapine (14.9%), quetiapine (13.6%) and amitriptyline (12.3%). Toxicological findings from cross sectional studies provide insight into how often certain types of antidepressants and antipsychotics are associated with suicide. A complementary approach is valuable for assessing the risk of suicide during medical treatment because the various available approaches (analysis of suicidal behavior/ideation, toxicity of drugs) each have strengths and limitations. PMID- 30397873 TI - Changes in metabolic parameters and cardiovascular risk factors after therapeutic control of acromegaly vary with the treatment modality. Data from the Bicetre cohort, and review of the literature. AB - CONTEXT: Untreated acromegaly is associated with increased morbidity and mortality due to malignant, cardiovascular, and cerebrovascular disorders. Effective treatment of acromegaly reduces excess mortality, but its impact on cardiovascular risk factors and metabolic parameters are poorly documented. AIM: We analyzed changes in cardiovascular risk factors and metabolic parameters in patients receiving various treatment modalities. PATIENTS AND METHODS: We retrospectively studied 96 patients with acromegaly, both at diagnosis and after IGF-I normalization following surgery alone (n = 51) or medical therapy with first generation somatostatin analogues (SSA, n = 23), or pegvisomant (n = 22). Duration of follow-up was 77 (42-161) months, 75 (42-112) months, and 62 (31-93) months, in patients treated with surgery alone, SSA, and pegvisomant, respectively. In all the cases except four, patients treated medically had underwent previous unsuccessful surgery. RESULTS: IGF-I normalization was associated with increased body weight, decreased systolic blood pressure (SBP) in hypertensive patients, decreased fasting plasma glucose (FPG) and HOMA-IR and HOMA-B levels, increased HDL cholesterol (HDLc); whereas, LDL cholesterol (LDLc) was not significantly different. Plasma PCSK9 levels were unchanged in patients with available values. Cardiovascular and metabolic changes varied with the treatment modality: surgery, but not pegvisomant, had a beneficial effect on SBP; FPG decreased after surgery but increased after SSA; the decline in HOMA-IR was only significant after surgery; pegvisomant significantly increased LDLc and total cholesterol; whereas SA increased HDLc and had no effect on LDLc levels. CONCLUSION: Treatments used to normalize IGF-I levels in patients with acromegaly could have differential effects on cardiovascular risk factors and metabolic parameters. PMID- 30397874 TI - Author's Reply to "Liver Dysfunction with Both Roux-en-Y and One Anastomosis Gastric Bypass Is Almost Exclusively Seen with Longer Than Standard Limb Lengths" by Kamal K. Mahawar. PMID- 30397875 TI - Reproductive Function Abnormalities and Bariatric Surgery: Is a Matter of Time? PMID- 30397876 TI - Outcomes of Bariatric Surgery in Patients with Cirrhosis. AB - CONTEXT: Information concerning the risk-benefit profile of bariatric surgery in subjects with liver cirrhosis is scarce. Our aim was to describe the long-term outcomes of bariatric surgery in a cohort of patients with liver cirrhosis submitted to bariatric surgery. METHODS: This was a multicenter, retrospective observational study performed by the Obesity Group of the Spanish Society of Endocrinology and Nutrition (GOSEEN), with a review of patients with cirrhosis who had undergone bariatric surgery during the period from April 2004 to March 2017 in ten public reference hospitals in Spain. RESULTS: Data on 41 patients with cirrhosis submitted to obesity surgery were collected (mean age 53.8 +/- 7.9 years, 46.3% women, presurgical BMI 45 +/- 8.3 kg/m2). All but one patient belonged to Child-Pugh class A, and sleeve gastrectomy was conducted in 68.3% of cases. Percentage of total weight loss (%TWL) was 26.33 +/- 8.3% and 21.16 +/- 15.32% at 1 and 5 years after surgery, respectively. This was accompanied by a significant reduction of type 2 diabetes, high blood pressure, and dyslipidemia and by an improvement of liver enzymes over time. Model for End-Stage Liver Disease (MELD) index increased from 7.2 +/- 1.9 to 9.8 +/- 4.6 after 5 years. Seven patients (17%) developed early postsurgical complications. No postsurgical mortality was observed. During follow-up, only five patients developed liver decompensation. CONCLUSIONS: Bariatric surgery in selected patients with liver cirrhosis has metabolic benefits that could have a positive impact on liver prognosis. TRIAL REGISTRATION: Controlledtrials.com Identifier: 10.1186/ISRCTN15009106. PMID- 30397877 TI - Patients with Schizophrenia Do Not Demonstrate Worse Outcome After Sleeve Gastrectomy: a Short-Term Cohort Study. AB - PURPOSE: The aim of this study was to compare surgical and psychiatric outcome and weight loss in schizophrenia patients with mentally healthy patients after sleeve gastrectomy. MATERIALS AND METHODS: A cohort study design was selected, comprising patients with schizophrenia with mentally healthy patients who underwent sleeve gastrectomy and were adherent to a follow-up at least 12 months after surgery. RESULTS: Seven schizophrenia (5 male, 2 female) and 59 (12 male, 47 female) mentally healthy patients were included in this study. A laparoscopic sleeve gastrectomy was performed safely in all 66 patients. The calculated excess weight loss (%EWL) showed no significant differences in both groups and reached 51.68 +/- 15.84% for schizophrenia group and 60.68 +/- 19.95% for mentally healthy group at 24-month follow-up (p = 0.33). The decrease in the HbA1c levels within 2 years after sleeve gastrectomy was similar in both groups (p = 0.79, 0.88, 0.82, 0.73 for surgery time, time of 6-, 12-, and 24-month follow-up respectively). The psychiatric status of the patients of the schizophrenia group was stable in all cases and no exacerbation of psychiatric symptoms was observed during time of follow-up. Furthermore, an overall significant improvement of the self-estimated mood and satisfaction was observed in both groups (Manova: f = 1.26, p < 0.0001). CONCLUSIONS: The results 2 years after sleeve gastrectomy in stable patients with schizophrenia and after an adequate psychological evaluation were encouraging and comparable to the outcome in mentally healthy patients. PMID- 30397878 TI - The Changes of Serum Metabolites in Diabetic GK Rats after Ileal Transposition Surgery. AB - BACKGROUND: Ileal transposition (IT) surgery could improve metabolism. Metabolomics has been applied comprehensively in analyzing the global dynamic alterations of metabolites. In the present study, we aimed to investigate serum metabolite alterations in diabetic Goto-Kakizaki (GK) rats after IT surgery. METHODS: Male GK rats were subjected to IT and Sham-IT surgery. Six weeks later, body weight, food intake, fat mass, and serum biochemical parameters were measured. The serum metabolomic fingerprint was analyzed using ultra-performance liquid chromatography-mass spectrometry (LC-MS)-based, non-targeted metabolomic approach. The differential metabolites were identified using principal component analysis and orthogonal partial least squares discriminant analysis. Metabolic pathway analysis was performed using HMDB and KEGG databases. RESULTS: The body weight, food intake, fat mass, serum levels of glucose and insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) of IT rats were significantly decreased when compared with Sham-IT rats (all P < 0.05). In the metabolomics analysis, ten serum differential metabolites were identified. Compared with Sham-IT rats, serum LysoPC(O-18:0) and PG(20:4/20:0) of IT rats were decreased, while genistein 4'-O-glucuronide, 5,6:8,9-Diepoxyergost-22-ene 3,7beta-diol, PI(16:0/18:2(9Z,12Z)), docosapentaenoic acid, 3-Oxo-4,6 choladienoic acid, 3-Oxocholic acid, and TG were increased. Pathway analysis highlighted the following pathways: ether lipid metabolism, alpha linolenic acid and linolenic acid metabolism, incretin synthesis and secretion, free fatty acid receptors, and biosynthesis of unsaturated fatty acids. CONCLUSIONS: IT surgery could significantly decrease body weight and fat mass and improve glucose metabolism in diabetic GK rats. These beneficial effects might be related to the changes of serum metabolites which involved in lipid metabolism, bile acids, and incretin. PMID- 30397879 TI - A panorama of radial nerve pathologies- an imaging diagnosis: a step ahead. AB - The radial nerve has a long and tortuous course in the upper limb. Injury to the nerve can occur due to a multitude of causes at many potential sites along its course. The most common site of involvement is in the proximal forearm affecting the posterior interosseous branch while the main branch of the radial nerve is injured in fractures of the humeral shaft. Signs and symptoms of radial neuropathy depend upon the site of injury. Injury to the nerve distal to innervation of triceps brachii results in loss of extensor function with sparing of function of the triceps resulting in the characteristic 'wrist drop'. Injury in the mid-arm is associated with loss of sensation in the dorsolateral aspect of the hand, the dorsal aspect of the radial three-and-a-half digits and in the first web space. Involvement of only the posterior interosseous nerve (PIN) results in weakness of the wrist and digit extensors. Diagnosis relies on clinical examination, electrodiagnostic studies and imaging findings. Plain radiographs are used to identify fracture sites, callus or tumours as cause of compression. Technological advances in ultrasonography have allowed direct visualisation of the involved nerve with assessment of the exact site, extent and type of injury. It yields unmatched information about anatomical details of the nerve. MR imaging adds to soft-tissue details and helps in characterising the lesion. This pictorial review aims to illustrate a wide spectrum of causes of radial neuropathy and emphasises the importance of imaging modalities in diagnosis of neuropathies. TEACHING POINTS: * Radial nerve injuries are assessed by clinical examination and diagnosed using electrodiagnostic and imaging studies. * Knowledge of anatomical relations and course of the nerve is necessary to identify the nerve at pre-determined anatomical locations. * Altered echogenicity and signal intensity, discontinuity of the nerve, focal thickening and cause of compression can be assessed by imaging modalities. * MR imaging helps in confirmation of the ultrasound findings, differentiating similar appearing lesions and provides additional soft-tissue details. PMID- 30397881 TI - A New DNA Break Repair Pathway Involving PARP3 and Base Excision Repair Proteins. AB - Poly(ADP-ribosyl)ation, which is catalyzed by PARP family proteins, is one of the main reactions in the cell response to genomic DNA damage. Massive impact of DNA damaging agents (such as oxidative stress and ionizing radiation) causes numerous breaks in DNA. In this case, the development of a fast cell response, which allows the genomic DNA integrity to be retained, may be more important than the repair by more accurate but long-term restoration of the DNA structure. This is the first study to show the possibility of eliminating DNA breaks through their PARP3-dependent mono(ADP-ribosyl)ation followed by ligation and repair of the formed ribo-AP sites by the base excision repair (BER) enzyme complex. Taken together, the results of the studies on ADP-ribosylation of DNA and the data obtained in this study suggest that PARP3 may be a component of the DNA break repair system involving the BER enzyme complex. PMID- 30397880 TI - NLRP1 and NTN1, Deregulated Blood Differentially Methylated Regions in Mild Cognitive Impairment Patients. AB - Epigenetic dysregulation has been known to be involved in neurodegenerative diseases, including amnestic mild cognitive impairment (MCI). The aim of this study was to investigate the genome-wide DNA methylation analysis, in order to identify epigenetic dysregulation in blood from patients with MCI. Here, we investigated whether epigenetic dysregulation in MCI and whether such an aberration could be detected in blood circulation. Genome-wide bisulfite sequencing targeted 84 million bases covering 3.7 million CpG sites was comparatively analyzed in MCI and control groups. And correlation between DNA methylation and transcriptomic changes was sought. Significant differentially methylated regions (DMRs) distinguishing the MCI and control groups were identified and functionally annotated. Most DMRs specific to MCI were enriched between - 2 kb and + 2 kb of the CpG island start sites located within or near gene promoters. Representative hypo- and hypermethylated DMRs in MCI were confirmed to be correlated to mRNA expression changes with the comparative delta Ct method. DNA methylation aberrations involving metal ion homeostasis, axon growth, inflammasome, and others in this study may be less-invasive, easily measurable blood biomarker candidates for MCI. PMID- 30397882 TI - Effect of Methyl Jasmonate on the Expression of Wcs Genes and the Activity of Antioxidant Enzymes at Wheat Cold Adaptation. AB - We studied the effect of phytohormone methyl jasmonate (MJ) on the expression of WCS (wheat cold specific) family genes and the activity of the key antioxidant enzymes in wheat seedling leaves at a low hardening temperature (4 degrees C). Incubation at 4 degrees C induced an increase in the cold tolerance of seedlings, which was accompanied by an increase in the levels of transcripts of WCS120 and WCS19 genes as well as an increase in the activity of superoxide dismutase (SOD) and peroxidase (PO). The pretreatment of seedlings with MJ significantly increased the mRNA content of WCS120 and WCS19 genes and, at the same time, caused an increase in the activity of SOD and PO, thus contributing to further increase in the cold tolerance of the plants (i.e., enhanced the hardening effect induced by low temperature). PMID- 30397883 TI - New Haplotypes of the Mitochondrial Gene CytB in the Nesting Population of the Siberian Black Kite Milvus migrans lineatus Gray, 1831 in the Territory of the Republic of Tyva. AB - We analyzed a fragment of mitochondrial CytB locus obtained from young and adult black kites Milvus migrans lineatus from 19 nests in the Republic of Tyva, Russia. Three previously known (CytB-6, CytB-14, CytB-19) and three new haplotypes identified as CytB-6.1, CytB-6.2, and CytB-19.1 were detected. We described a set of substitutions specific to M. migrans lineatus but not to M. migrans migrans, the European subspecies of black kite. PMID- 30397884 TI - The Application of Recombinant Phototoxins 4D5scFv-miniSOG and DARPin-miniSOG to Study the HER2 Receptor Internalization. AB - It was found that the fluorescent properties of the phototoxic domain of miniSOG allow to assess the ability of toxins to bind to human breast adenocarcinoma cells SK-BR-3 and study the dynamics of their internalization. We established that the main cause of the decrease of the fluorescence intensity of the recombinant proteins 4D5scFv-miniSOG and DARPin-miniSOG during their internalization in the complex with the HER2 receptor is their shielding and absorption of the fluorescence of miniSOG by the cells fluorophores. PMID- 30397885 TI - Estrogen Receptors alpha and beta in Ovarian Cancer: Expression Level and Prognosis. AB - The quantitative immunofluorescence assay of serous ovarian cancer tissue for the expression of estrogen receptors (ERalpha and ERbeta) revealed a higher expression level of ERbeta in comparison with ERalpha in all surgical tumor samples investigated. Significant differences in the expression level of the markers were detected "from tumor to tumor." A high expression level of both ERalpha (>= 25%) and ERbeta (>= 44%) in the tumor predicts a significantly longer progression-free survival time (p < 0.01) in the patients after the first line of platinum and taxane-based adjuvant chemotherapy. PMID- 30397886 TI - Azelaic Acid-Induced Enzymes of Phenolic Defense in Pea Roots. AB - The treatment of pea roots with azelaic acid for 72 h led to a change in the content of 28 proteins: the content of 20 proteins decreased, and the content of 8 proteins (including the phenylpropanoid metabolism enzymes, which are involved in the synthesis of phytoalexins) increased. PMID- 30397887 TI - The Role of GC-Rich Sequences from the Promoter Region of the Drosophila melanogaster yellow Gene in the Enhancer- Dependent Activation of Transcription. AB - It is shown that mutations in two GC-rich sequences (GC-boxes) from the promoter region of the yellow gene during enhancer-dependent transcription activation do not affect the basal level of the yellow gene transcription but destabilize the interaction between the enhancers and the promoter. PMID- 30397888 TI - Polyprenyl Phosphates Induce a High Humoral and Cellular Response to Immunization with Recombinant Proteins of the Replicative Complex of the Hepatitis C Virus. AB - The search for new adjuvants remains the critical task for the creation of hepatitis C vaccines due to the weak immunogenicity of biotechnological products. When immunizing mice with the recombinant proteins NS3 and NS5B of the hepatitis C virus (HCV), the adjuvant activity of three immunomodulators was compared. Phosprenyl(r) on the basis of polyprenyl phosphate (PPP), chemically synthesized analogue of the bacterial cell wall glucosaminyl muramyl dipeptide (GMDP), and IFN-alpha recombinant protein were tested. GMDP increased the activity of IgG1 antibodies 4-6 times but did not stimulate the production of IFN-gamma; IFN-alpha has not shown any adjuvant properties. The introduction of recombinant HCV proteins together with PPP in low doses increased the activity of IgG2a isotype antibodies 4-7 times and increased IFN-gamma secretion 3 times. Thus, it was first shown that PPP polarizes the immune response to Th1-type and is a promising adjuvant for the development of a vaccine against hepatitis C. PMID- 30397889 TI - Selenium Nanoparticles-an Inducer of Tomato Resistance to the Root-Knot Nematode Meloidogyne incognita (Kofoid et White, 1919) Chitwood 1949. AB - We investigated the mechanisms of action of selenium nanoparticles obtained by laser ablation for their use as an abiogenic elicitor of tomato resistance to parasitic nematodes. Selenium nanoparticles induced systemic resistance of tomatoes to the root-knot nematode, stimulated plant growth and development, was involved in the PR-6 gene expression in the roots and leaves of plants subjected to invasion, and increased the activity of proteinase inhibitors (markers of systemic resistance of plants to infection). Exogenous treatment of plants with solutions of selenium nanoparticles reduced the invasion of plants by affecting the morphological and physiological parameters of the parasites in the roots. PMID- 30397890 TI - Effect of Promising Antitumor Phenolic Antioxidant Anphen Sodium on the BCL-2 Family Proteins. AB - The proapoptotic effect of anphen (the effect on the level of the antiapoptotic protein Bcl-2) was investigated by immunoblotting. Incubation of Lewis carcinoma cell suspension with anphen at a concentration of 10-6 M for 0-3 h caused a 80% reduction in the level of the Bcl-2 protein and its homodimer. In vivo, when administered for 4 days to outbred mice, anphen (10-4 M) induced a decrease in the level of the Bcl-2 homodimer in the spleen cells by 20% and an increase in the content of the Bad protein (apoptosis activator) and the Bcl-XL protein. The antitumor effect of anphen may be due to blocking the hydrophobic pocket of the Bcl-2 protein. PMID- 30397891 TI - Synthesis of Proteins Encoded by the Early Genes E2, E6, and E7 of Papillomavirus of Type 16 in the Plant Expression System. AB - An expression system for the synthesis of early antigenic proteins HPV16 E2, HPV16 E6, and HPV16 E7 of high-risk papillomavirus based on transgenic tomato fruits was developed. It is planned to use the early antigenic proteins synthesized to create a therapeutic vaccine against cervical cancer. PMID- 30397892 TI - Features of Interspecific Contacts and Hybridization of Ground Squirrels (Marmotinae, Sciuridae, Rodentia) in Mongolia. AB - Using molecular genetic methods, we investigated the secondary contact zones of two pairs of species of ground squirrels of Mongolia. In common colonies of marmots M. sibirica and M. baibacina, we revealed a high frequency of occurrence of hybrid individuals that were viable and fertile. A hybridization between S. alaschanicus and S. pallidicauda was sporadic in nature. The hypothesis about an extensive hybrid zone in these species of ground squirrels was not confirmed. An occupation of suboptimal biotopes by individuals of different species was the main factor contributing to hybridization in both case. The complex social behavior in marmots affected on the localization and diffusion of the hybridization process. PMID- 30397893 TI - Diversity of the CO1 Gene of Mitochondrial DNA in Representatives of Genus Antimora (Moridae, Gadiformes) in the World Oceans. AB - The frequency of occurrence of the COI gene of mitochondrial DNA in the Pacific flatnose Antimora microlepis and blue antimora Antimora rostrata (Moridae, Gadiformes) was analyzed in samples collected in different areas of the World Ocean. The revealed maximum haplotype diversity of COI in the blue antimora in the North Atlantics may indicate that this species emerged in this region, from which it widely distributed in the World Ocean. The Pacific flatnose Antimora microlepis originated from Antimora rostrata. Antimora might penetrate into the North Pacific by several routes: through the Panama Strait, along the coast of Antarctica, or through the Indian Ocean along the coast of Australia. PMID- 30397895 TI - Death Mechanism of Breast Adenocarcinoma Cells Caused by BRET-Induced Cytotoxicity of miniSOG Depends on the Intracellular Localization of the NanoLuc miniSOG Fusion Protein. AB - Photodynamic therapy (PDT) is widely used in clinical practice to influence neoplasms in the presence of a photosensitizer, oxygen, and light source. The main problem of PDT of deep tumors is the problem of delivering excitation light (without lost of its intensity) inside the body. An alternative to the external light sources can be the internal light sources based on luciferase-substrate bioluminescent systems. In our work, we used the NanoLuc-furimazine system as an internal light source. This system can be successfully used to excite the protein photosensitizer miniSOG and to induce the phototoxicity of this flavoprotein in cancer cells during bioluminescent resonance energy transfer (BRET). It was shown that the mechanism of cell death caused by BRET-induced phototoxicity of mimiSOG in the presence of furimazine depends on the intracellular localization of the NanoLuc-miniSOG fusion protein: BRET-mediated activation of miniSOG in mitochondrial localization causes apoptosis, while the membrane localization of PS causes necrosis of cancer cells. PMID- 30397894 TI - Membrane-Bound Bacteriophytochrome-Like Complex of Phototrophic Purple Non-Sulfur Bacterium Rhodopseudomonas palustris. AB - A pigment-protein complex of yellow color with absorption maxima at 682 and 776 nm, characteristic for bacteriophytochromes, was isolated from the photosynthetic membranes of the purple bacterium Rhodopseudomonas palustris. Zinc-induced fluorescence of the complex indicated the presence of the biliverdin chromophore covalently bound to the protein. The parameters of low-temperature fluorescence (lambda excitation at 680 nm, lambda emission at 695 nm) indicated the ability of the complex to undergo photoconversion. These data, as well as the kinetics of accumulation of the red (Pr)-form on far red light, allowed the complex to be classified as a bacteriophytochrome-like complex with its localization in the photosynthetic membranes of Rps. palustris. PMID- 30397896 TI - An Assessment of Amplicon-Sequencing Based Method for Viral Intrahost Analysis. PMID- 30397897 TI - Effect of endometrial mechanical stimulation in an unselected population undergoing in vitro fertilization: futility analysis of a double-blind randomized controlled trial. AB - PURPOSE: Implantation failure is a major limiting factor of successful in vitro fertilization (IVF). The objective of this study was to determine if endometrial mechanical stimulation (EMS) by endometrial biopsy in the luteal phase of the cycle prior to embryo transfer (ET) improves clinical outcomes in an unselected subfertile population. METHODS: Double-blind, randomized controlled trial of EMS versus sham biopsy and odds of clinical pregnancy after IVF and embryo transfer. Secondary outcomes included spontaneous miscarriage and live birth. RESULTS: One hundred women enrolled and were randomized from 2013 to 2017. Enrollment was terminated after futility analysis showed no difference in clinical pregnancy between EMS versus control, 47.2% vs 61.7% (OR 0.55, 95% CI 0.25-1.23, p = 0.15). There were no significant differences between women who underwent EMS and those who did not in terms of positive pregnancy test 54.7% vs 63.8% (OR 0.69, 95% CI 0.31-1.53, p = 0.36), miscarriage 7.5% vs 2.1% (OR 3.76 95% CI 0.41-34.85, p = 0.22), or live birth 43.4% vs 61.7% (OR 0.48 95% CI 0.21-1.06, p = 0.07). CONCLUSIONS: EMS in the luteal phase of the cycle preceding embryo transfer does not improve clinical outcomes in an unselected subfertile population and may result in a lower live birth rate. We caution the routine use of EMS in an unselected population. PMID- 30397899 TI - QR code based patient data protection in ECG steganography. AB - Connected health enables patient centric interventions resulting in better healthcare and hence better living. In order to accomplish this, bio-signals, medical and diagnosis information are shared and accessed by multiple actors and it is important to protect the privacy of patient data. Steganography is widely used to protect patient data by hiding it in the medical information. Current work investigates ECG steganography using Discrete Wavelet Transform (DWT) and Quick Response (QR) code. Steganography deteriorates the ECG signal and it is important to minimize this deterioration to preserve diagnosability. 1D ECG signal is converted to 2D ECG image and decomposed into sub-bands by subjecting it to DWT. The novelty of the proposed approach lies in converting the patient data into QR code and using it as watermark in ECG steganography. The QR code is embedded in the 2D image using additive quantization scheme. The performance of proposed method is measured using Peak Signal to Noise Ratio, Percentage Residual Difference and Kullback-Leibler distance. These metrics are used as a measure of imperceptibility while the data loss during retrieval is measured by Bit Retrieval Rate. The proposed method is demonstrated on normal ECG signals obtained from MIT-BIH database for different QR code versions. Metrics reveal that imperceptibility decreased for increasing patient data size and increasing scaling factors. Metrics were independent of the sub-band and the proposed method allows reliable patient data protection with full retrieval ability. PMID- 30397898 TI - Histone modification signatures in human sperm distinguish clinical abnormalities. AB - PURPOSE: Alternations to the paternal epigenome, specifically the components of sperm chromatin, can lead to infertility in humans and potentially transmit aberrant information to the embryo. One key component of sperm chromatin is the post-translational modification of histones (PTMs). We previously identified a comprehensive profile of histone PTMs in normozoospermic sperm; however, only specific histone PTMs have been identified in abnormal sperm by antibody-based approaches and comprehensive changes to histone PTM profiles remain unknown. Here, we investigate if sperm with abnormalities of total motility, progressive motility, and morphology have altered histone PTM profiles compared to normozoospermic sperm samples. METHODS: Discarded semen samples from 31 men with normal or abnormal semen parameters were analyzed for relative abundance of PTMs on histone H3 and H4 by "bottom-up" nano-liquid chromatography-tandem mass spectrometry. RESULTS: Asthenoteratozoospermic samples (abnormal motility, forward progression, and morphology, n = 6) displayed overall decreased H4 acetylation (p = 0.001) as well as alterations in H4K20 (p = 0.003) and H3K9 methylation (p < 0.04) when compared to normozoospermic samples (n = 8). Asthenozoospermic samples (abnormal motility and progression, n = 5) also demonstrated decreased H4 acetylation (p = 0.04) and altered H4K20 (p = 0.005) and H3K9 methylation (p < 0.04). Samples with isolated abnormal progression (n = 6) primarily demonstrated decreased acetylation on H4 (p < 0.02), and teratozoospermic samples (n = 6) appeared similar to normozoospermic samples (n = 8). CONCLUSION: Sperm samples with combined and isolated abnormalities of total motility, progressive motility, and morphology display distinct and altered histone PTM signatures compared to normozoospermic sperm. This provides evidence that alterations in histone PTMs may be important for normal sperm function and fertility. PMID- 30397900 TI - Incidence and predictors of venous thromboembolism in medically ill hospitalized elderly cancer patients: a prospective observational study. AB - PURPOSE: The aim of this study was to estimate the incidence and predictors of venous thromboembolism (VTE) in medically ill hospitalized elderly cancer patients in a single Korean tertiary hospital. METHODS: Patients were examined for deep vein thrombosis (DVT) by duplex and color Doppler ultrasonography (DUS) of both legs between days 5 and 14 of their hospital stays. The primary endpoint was the incidence of VTE by day 14, which was determined via a composite of DVT detected by routine DUS and symptomatic VTE. RESULTS: A total of 140 patients with 31 hematologic and 109 nonhematologic malignancies were analyzed. The median age was 73 years, and 45.7% of the patients were female. The median length of hospital stay was 12 days. The modified Padua prediction score (PPS) >= 4 was 92.9%. The incidence of VTE by day 14 was 7.1%, including six proximal and four distal DVT cases. Being female, having a length of hospital stay of >= 13 days, and having a modified Padua prediction score of >= 6 were risk factors of VTE in univariate analysis. The incidence of VTE was 2.3%, 7.3%, and 41.7% in patients with 0-1, 2, and 3 of these risk factors, respectively. CONCLUSION: The incidence of VTE in medically ill hospitalized elderly cancer patients was lower in Korean patients than in Western patients. However, the risk of VTE in those with more than two risk factors (female, long length of hospitalization, and high PPS) increased considerably, and pharmacologic thromboprophylaxis is warranted in these cases. PMID- 30397901 TI - Preferences of Specialist and Generalist Mammalian Herbivores for Mixtures Versus Individual Plant Secondary Metabolites. AB - Herbivores that forage on chemically defended plants consume complex mixtures of plant secondary metabolites (PSMs). However, the mechanisms by which herbivores tolerate mixtures of PSMs are relatively poorly understood. As such, it remains difficult to predict how PSMs, singly or as complex mixtures, influence diet selection by herbivores. Although relative rates of detoxification of PSMs have been used to explain tolerance of PSMs by dietary specialist herbivores, few studies have used the rate of detoxification of individual PSMs to understand dietary preferences of individual herbivores for individual versus mixtures of PSMs. We coupled in vivo experiments using captive feeding trials with in vitro experiments using enzymatic detoxification assays to evaluate the dietary preferences and detoxification capacities of pygmy rabbits (Brachylagus idahoensis), dietary specialists on sagebrush (Artemisia spp.), and mountain cottontails (Sylvilagus nuttallii), dietary generalists. We compared preference for five single PSMs in sagebrush compared to a mixture containing those same five PSMs. We hypothesized that relative preference for individual PSMs would coincide with faster detoxification capacity for those PSMs by specialists and generalists. Pygmy rabbits generally showed little preference among individual PSMs compared to mixed PSMs, whereas mountain cottontails exhibited stronger preferences. Pygmy rabbits had faster detoxification capacities for all PSMs and consumed higher concentrations of individual PSMs versus a mixture than cottontails. However, detoxification capacity for an individual PSM did not generally coincide with preferences or avoidance of individual PSMs by either species. Cottontails avoided, but pygmy rabbits preferred, camphor, the PSM with the slowest detoxification rate by both species. Both species avoided beta-pinene despite it having one of the fastest detoxification rate. Taken together our in vivo and in vitro results add to existing evidence that detoxification capacity is higher in dietary specialist than generalist herbivores. However, results also suggest that alternative mechanisms such as absorption and the pharmacological action of individual or mixtures of PSMs may play a role in determining preference of PSMs within herbivore species. PMID- 30397902 TI - Myopathies Related to Glycogen Metabolism Disorders. AB - Most of the glycogen metabolism disorders that affect skeletal muscle involve enzymes in glycogenolysis (myophosphorylase (PYGM), glycogen debranching enzyme (AGL), phosphorylase b kinase (PHKB)) and glycolysis (phosphofructokinase (PFK), phosphoglycerate mutase (PGAM2), aldolase A (ALDOA), beta-enolase (ENO3)); however, 3 involve glycogen synthesis (glycogenin-1 (GYG1), glycogen synthase (GSE), and branching enzyme (GBE1)). Many present with exercise-induced cramps and rhabdomyolysis with higher-intensity exercise (i.e., PYGM, PFK, PGAM2), yet others present with muscle atrophy and weakness (GYG1, AGL, GBE1). A failure of serum lactate to rise with exercise with an exaggerated ammonia response is a common, but not invariant, finding. The serum creatine kinase (CK) is often elevated in the myopathic forms and in PYGM deficiency, but can be normal and increase only with rhabdomyolysis (PGAM2, PFK, ENO3). Therapy for glycogen storage diseases that result in exercise-induced symptoms includes lifestyle adaptation and carefully titrated exercise. Immediate pre-exercise carbohydrate improves symptoms in the glycogenolytic defects (i.e., PYGM), but can exacerbate symptoms in glycolytic defects (i.e., PFK). Creatine monohydrate in low dose may provide a mild benefit in PYGM mutations. PMID- 30397903 TI - Energy expenditure of patients on ECMO: A prospective pilot study. AB - BACKGROUND: An optimal nutritional approach sustained by convenient monitoring of metabolic status and reliable assessment of energy expenditure (EE) may improve the outcome of critically ill patients on extracorporeal membrane oxygenation (ECMO). We previously demonstrated the feasibility of indirect calorimetry (IC) the standard of care technique to determine caloric targets-in patients undergoing ECMO. This study aims to compare measured with calculated EE during ECMO treatment. We additionally provide median EE values for use in settings where IC is not available. METHODS: IC was performed in seven stable ECMO patients. Gas exchange was analyzed at the ventilator, and ECMO side and values were introduced in a modified Weir formula to calculate resting EE. Results were compared with EE calculated with the Harris-Benedict equation and with the 25 kcal/kg/day ESPEN recommendation. RESULTS: Total median oxygen consumption rate was 196 (Q1-Q3 158-331) mL/min, and total median carbon dioxide production was 150 (Q1-Q3 104-203) mL/min. Clinically relevant differences between calculated and measured EE were observed in all patients. The median EE was 1334 (Q1-Q3 1134 2119) kcal/24 hours or 18 (Q1-Q3 15-27) kcal/kg/day. CONCLUSION: Compared with measured EE, calculation of EE both over- and underestimated caloric needs during ECMO treatment. Despite a median EE of 21 kcal/kg/day, large variability in metabolic rate was found and demands further investigation. PMID- 30397904 TI - Randomized trial of acupuncture with antiemetics for reducing postoperative nausea in children. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) is common after tonsillectomy in children. There is evidence that perioperative acupuncture at the pericardium 6 (P6) point is effective for preventing PONV in adults. Our goal was to determine if intraoperative acupuncture at the P6 point, in addition to usual antiemetics, is more effective than antiemetics alone in preventing PONV in children. METHODS: In a randomized double-blind trial, 161 children age 3 through 9 years undergoing tonsillectomy with or without adenoidectomy were randomized to either bilateral acupuncture at P6 plus antiemetics (n = 86) or antiemetics only (n = 75). All participants received ondansetron 0.15 mg/kg and dexamethasone 0.25 mg/kg, up to 10 mg. The presence of nausea, retching, emesis and administration of additional antiemetics were recorded during phases I and II of PACU recovery. Follow-up calls occurred on postoperative day 1 (POD 1). RESULT: During phase I and II recovery, the incidence of PONV was significantly less with acupuncture than without (7.0% vs 34.7%, RR: 0.2, 95% CI: 0.09-0.46; P < 0.001). The difference in PONV was driven by less nausea in the acupuncture group (5.0% vs 24.0%), with no difference in vomiting between the two groups. In the first 24 hours, PONV occurred in 36.1% with acupuncture and 49.3% without; these values did not differ significantly (P = 0.09). CONCLUSIONS: Children receiving acupuncture plus antiemetic therapy had less risk of developing nausea during phase I and II recovery, but there was no difference in PONV on POD 1. Acupuncture may reduce nausea in the PACU, even when combined with antiemetics. PMID- 30397905 TI - Preoperative neutrophil-to-lymphocyte ratio as a new prognostic predictor after microsurgical subinguinal varicocelectomy. AB - Various studies have been reported to predict the success of varicocelectomy. Neutrophil-lymphocyte ratio (NLR) is a frequently used indicator of systemic inflammation. We aimed to evaluate the effect of inflammation on the success of varicocelectomy using the NLR. The data of 86 patients who underwent varicocelectomy for infertility were evaluated retrospectively. Pre-operative demographic characteristics of patients, laboratory results such as haemogram, and semen analysis and clinical data were recorded. The semen analysis with the highest total motile sperm count was accepted as pre-operative value. Control was performed with semen analysis at post-operative 6th month. As described in previous studies, in our study, more than 50% increase in total motile sperm count in post-operative semen analysis was defined as a significant improvement. However, at least a 100% increase was required for patients with a total motile sperm count <5 million in the definition of recovery. Patients were divided into two groups as those with improvement in the semen parameters (Group 1) and those without (Group 2). NLR was statistically significantly higher in Group 2 compared with Group 1. The area under the curve (AUC) in the ROC curve for NLR was 0.89. According to the Youden index, the best cut-off value of NLR for varicocelectomy success was 1.98 (sensitivity: 94.7%, specificity: 75.9%, p < 0.001). Logistic regression analysis showed that NLR (odds ratio: 3.6, 95% confidence interval: 1.69-8.38, p < 0.001) is independent predictor factors in predicting the success of varicocelectomy. The results of this study show that systemic inflammation adversely affects the likelihood of improvement in sperm parameters by varicocelectomy. Additionally, NLR has been shown to be an independent factor in the prediction of varicocelectomy success. PMID- 30397906 TI - The effect of isocapnic hyperventilation on early recovery after remifentanil/sevoflurane anesthesia in O2 /air: A randomized trial. AB - BACKGROUND: Isocapnic hyperventilation (ICHV) may hasten emergence from general anesthesia but remains inadequately studied. We prospectively determined emergence time after sevoflurane anesthesia of variable duration with and without ICHV. METHODS: In 25 ASA I-II patients, general anesthesia was maintained with one age-adjusted MAC sevoflurane in O2 /air and target-controlled remifentanil delivery. At the start of skin closure, the remifentanil effect-site concentration was reduced to 1.5 ng/mL, any residual neuromuscular block reversed, and once the remifentanil effect-site concentration had decreased to 1.5 ng/mL, remifentanil and sevoflurane administration was stopped, and the fresh gas flow increased above minute ventilation. Patients randomly received either normoventilation (n = 13) or ICHV (doubling minute ventilation while titrating CO2 into the inspiratory limb to maintain isocapnia [n = 12]). Three early recovery end points were determined: time to proper response to verbal command; time to extubation; and time to stating one's name. RESULTS: Demographics were the same in both groups. Recovery end points were reached faster in the ICHV group compared to the normoventilation group: time to proper response to verbal command was 7.6 +/- 2.2 vs 9.9 +/- 2.9 min (P = 0.03); time to extubation was 7.6 +/- 2.6 vs 11.0 +/- 2.4 min (P = 0.002); and time to stating one's name was 8.9 +/- 2.8 vs 12.5 +/- 2.6 min (P = 0.003). Within each group, duration of anesthesia only marginally affected the times to reach these recovery end points. CONCLUSION: Isocapnic hyperventilation only had a small effect on emergence times after anesthesia, suggesting that isocapnic hyperventilation may have limited clinical benefits with modern potent inhaled anesthetics. PMID- 30397907 TI - Sample size estimation for case-crossover studies. AB - Case-crossover study designs are observational studies used to assess postmarket safety of medical products (eg, vaccines or drugs). As a case-crossover study is self-controlled, its advantages include better control for confounding because the design controls for any time-invariant measured and unmeasured confounding and potentially greater feasibility as only data from those experiencing an event (or cases) are required. However, self-matching also introduces correlation between case and control periods within a subject or matched unit. To estimate sample size in a case-crossover study, investigators currently use Dupont's formula (Biometrics 1988; 43:1157-1168), which was originally developed for a matched case-control study. This formula is relevant as it takes into account correlation in exposure between controls and cases, which are expected to be high in self-controlled studies. However, in our study, we show that Dupont's formula and other currently used methods to determine sample size for case-crossover studies may be inadequate. Specifically, these formulas tend to underestimate the true required sample size, determined through simulations, for a range of values in the parameter space. We present mathematical derivations to explain where some currently used methods fail and propose two new sample size estimation methods that provide a more accurate estimate of the true required sample size. PMID- 30397908 TI - Comment on "Pre-hospital emergency anaesthesia in awake hypotensive trauma patients: Beneficial or detrimental?" by Crewdson et al Acta Anaesthesiol Scand 2018; 62: 504-14. PMID- 30397909 TI - Capsular-defective Porphyromonas Gingivalis mutant strains induce less alveolar bone resorption than W50 wild-type strain due to a decreased Th1/Th17 immune response and less osteoclast activity. AB - BACKGROUND: Encapsulation of Porphyromonas gingivalis has been demonstrated as responsible of several host immunological changes, which have been associated with the pathogenesis of periodontitis. Using a murine model of periodontitis and two isogenic non-capsulated mutants of P. gingivalis, this study aimed to analyze whether P. gingivalis encapsulation induces more severe alveolar bone resorption, and whether this bone loss is associated with a Th1 and Th17-pattern of immune response. METHODS: Experimental periodontal infections were generated by oral inoculation with the encapsulated W50 wild-type strain or isogenic non encapsulated GPA and GPC mutants of P. gingivalis. Periodontal infections induced with the encapsulated HG184 or non-encapsulated ATCC 33277 strains of P. gingivalis were used as controls. Alveolar bone resorption was analyzed using micro-computed-tomography and scanning-electron-microscopy. The expression levels of Th1, Th2, Th17, or T regulatory-associated cytokines and RANKL, as well as the periodontal bacterial load, were quantified by qPCR. The detection of Th1 and Th17 lymphocytes was analyzed by flow cytometry. RESULTS: In the periodontal lesions, both capsular-defective knockout mutant strains of P. gingivalis induced less alveolar bone resorption than the encapsulated W50 wild-type strain. This decreased bone loss was associated with a dismissed RANKL expression, decreased Th1 and Th17-type of cytokine expression, reduced Th1 and Th17 lymphocyte detection, and low osteoclast finding. CONCLUSION: These data demonstrate that encapsulation of P. gingivalis plays a key role in the alveolar bone resorption induced during periodontitis, and this bone loss is associated with a Th1 and Th17-pattern of immune response triggered in the periodontal lesions. This article is protected by copyright. All rights reserved. PMID- 30397910 TI - Left atrial appendage electrical isolation for persistent atrial fibrillation. AB - Left atrial appendage (LAA) may be the source for initiation and maintenance of atrial fibrillation (AF). This report shows restoration of sinus rhythm in the atria during radiofrequency wide-area LAA electrical isolation, whereas AF persists in the LAA. PMID- 30397911 TI - Impaired mobility is associated with risk of ICU admission but not outcome after ICU treatment. PMID- 30397912 TI - An liquid chromatography-tandem mass spectrometry method for preclinical pharmacokinetics and tissue distribution of hydrolysable tannins chebulinic acid and chebulagic acid in rats. AB - A simple and sensitive liquid chromatography-tandem mass spectrometry method was developed for the simultaneous determination of chebulinic acid and chebulagic acid in rat plasma and tissues and well used in the pharmacokinetic and tissue distribution studies after intraperitoneal injection administration. Samples were processed with methanol by https://www.baidu.com/link?url=FOVX8Mk3VJfv9yGajBBuEAw47Gd5WbKUHmEQUD6M0anovgIJxA ds6RKegwc2wsIBXrVbKALIBOTruMZjlClvnzjswEIrnkGfklAGORlGHNLm3g3xquR7XZ w_ad8TlZ&wd=&eqid=d3dffa2e0002213a000000035a77e5c1, and chromatographic separation was performed on an Agilent ZORBAX SB-C18 column (50 mm * 2.1 mm, 1.8 MUm) with a mobile phase consisting of methanol and water containing 0.1% formic acid (60:40, v/v). Quantification was performed by selected reaction monitoring with m/z 977.1->806.8 for chebulagic acid, m/z 979.0-> 808.7 for chebulinic acid, and m/z 851.2->704.9 for the internal standard. Good linearity was observed over their respective concentration range. The pharmacokinetic study showed that both compounds reached their Cmax values (605.8+/-35.6 ng/mL for chebulinic acid and 1327.1+/-118.6 ng/mL for chebulagic acid) at the same Tmax of 0.9 h following intraperitoneal injection administration. The two compounds could be detected in blood-abundant tissues. The kidney had the highest concentrations (462.6+/-138.5 ng/g for chebulinic acid, and 1651.7+/-167.7 ng/g for chebulagic acid) at 1 h post-dose, followed by the heart, liver, spleen and lung. PMID- 30397913 TI - Mortality from scale drop disease in farmed Lates calcarifer in Southeast Asia. AB - In Southeast Asia, a new disease called scale drop disease (SDD) caused by a novel Megalocytivirus (SDDV) has emerged in farmed Asian sea bass (Lates calcarifer) in Singapore, Malaysia and Indonesia. We received samples from an Eastern Thai province that also showed gross signs of SDD (loss of scales). Clinical samples of 0.2-1.1 kg L. calcarifer collected between 2016 and 2018 were examined for evidence of SDDV infection. Histopathology was similar to that in the first report of SDDV from Singapore including necrosis, inflammation and nuclear pyknosis and karyorrhexis in the multiple organs. Intracytoplasmic inclusion bodies were also observed in the muscle tissue. In a density-gradient fraction from muscle extracts, TEM revealed enveloped, hexagonal megalocytiviral like particles (~100-180 nm). By PCR using primers derived from the Singaporean SDDV genome sequence, four different genes were amplified and sequenced from the Thai isolate revealing 98.7%-99.9% identity between the two isolates. Since viral inclusions were rarely observed, clinical signs and histopathology could not be used to easily distinguish between SDD caused by bacteria or SDDV. We therefore recommend that PCR screening be used to monitor broodstock, fry and grow-out fish to estimate the current impact of SDDV in Southeast Asia and to prevent its spread. PMID- 30397914 TI - Long-term mortality and cause of death for patients treated in Intensive Care Units due to poisoning. AB - BACKGROUND: Poisoned patients treated in the Intensive Care Unit are common, representing up to 6% of all ICU admissions. The in-hospital mortality is generally low but little is known about the long-term mortality in these patients. The aim of this study was to describe long-term mortality and cause of death in patients treated in the ICU for poisoning. METHOD: A national observational study based on three registers: the National Patient Register, the Swedish Intensive Care Register and the Cause of Death Register. All patients >=19 years admitted to a Swedish Intensive Care Unit between January 1, 2010 and December 31, 2011 with an ICD-10 code for poisoning were included. RESULTS: A total of 6730 patients were included. The one-year mortality was 4.5% (n = 303), with an overweight of men among the deceased (59.1%, P = 0.002). Patients aged 19 39 years had a 48 times increased one-year mortality compared to the age-matched general population and 94% of these patients died from suicide and/or accident, of which 70% were from a new poisoning. The two-year mortality was 7.2%. Women have a slightly higher overall long-term survival over two years (P< 0.001). CONCLUSION: The risk of premature death is markedly increased in younger patients one and two years after an ICU hospitalisation for non-fatal poisoning compared to the general population. A large majority die due to a new poisoning incident despite a previously known recent severe poisoning. EDITORIAL COMMENT: Admission to ICU with poisoning, and particularly self-poisoning, may be associated with long-term mortaliity. In this study of 6730 patients admitted to a Swedish ICU for poisoning, the in-hospital mortality was low for that admission, but there is an increased risk of later mortality in young patients one and two years after hospital discharge. PMID- 30397915 TI - Cross-sectional analysis of risk factors for subclinical periodontitis; active matrix metalloproteinase-8 as a potential indicator in initial periodontitis in adolescents. AB - BACKGROUND: The aim of this study was to investigate how different patient related risk indicators might be associated with the odds of developing subclinical periodontitis in adolescents. METHODS: This cross-sectional study included 252 Finnish individuals aged 15 to 16 years, of whom 141 were boys and 111 girls. A specially trained dentist performed clinical examinations: measurements included periodontal indexes (bleeding on probing, visible plaque index, root calculus, and probing depth, smoking by pack-years, periodontal bacteria (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Prevotella intermedia, Prevotella nigrescens, and Treponema denticola) and the potential salivary periodontal biomarkers (active matrix metalloproteinase-8 [aMMP-8], polymorphonuclear leukocyte elastase [PMN elastase], and total protein, albumin, immunoglobulin A, immunoglobulin G, and immunoglobulin M). Results were analyzed by ordinal logistic regression, one-way analysis of variance, Fisher exact test, and Kruskal-Wallis H test. RESULTS: The main finding of this study was that subclinical periodontitis in adolescents was statistically significantly associated with elevated salivary aMMP-8 but not with PMN elastase. Also, adolescents with subclinical periodontitis had statistically significantly higher levels of bleeding on probing, root calculus, and dental plaque than adolescents without subclinical periodontitis. CONCLUSIONS: We suggest that the main risk factor for subclinical periodontitis in adolescents is the partly calcified, dysbiotic bacterial biofilm, which interacts with the immune defenses of the host; this leads to gingival inflammation and eventually to deepening periodontal pockets. This proinflammatory subclinical periodontitis stage, which represents stage I periodontitis in the new classification, is reflected as elevated salivary aMMP-8 levels in oral fluids. PMID- 30397916 TI - On-fiber display of a functional peptide at sites distant from the cell surface using a long bacterionanofiber of a trimeric autotransporter adhesin. AB - In the cell surface display system, the distance of a surface-displayed molecule from the cell surface should influence its functionality due to the interference by other surface structures. For the purpose of developing this distance-variable surface display system, we utilized a long fibrous adhesin, Acinetobacter trimeric autotransporter adhesin (AtaA) of the strain Tol 5. We constructed His tagged full length and shorter AtaA fibers designed by N-terminal deletion and expressed them in the DeltaataA mutant. Immuno-electron microscopy clearly showed that they formed fibers on the cell surface and the His-tag was displayed on the fiber tip located at fixed distances from the cell surface. N-terminal deletion of AtaA shortened the distance between the His-tag and the cell surface, as designed. Time-course analyses of the cell-to-Ni-Sepharose beads binding revealed that cells producing the longer fibers bound more rapidly to the beads. The His tagged AtaA derivatives were also displayed on Escherichia coli cells, and a similar tendency was shown; the His-tag on the longer fiber was more functional than that on the shorter one. Thus, we developed an on-fiber display system of a functional peptide using a long TAA fiber, which can vary the distance between the displayed molecule and the cell surface. This article is protected by copyright. All rights reserved. PMID- 30397917 TI - Effects of general anesthesia on postoperative sleep cycles in dentally disabled patients. AB - AIMS: Although it has been reported that general anesthesia affect the perioperative sleep cycle, no studies have yet evaluated how general anesthesia affects dentally disabled patients. In this study, we investigated the alteration of perioperative sleep cycles in dentally disabled patients receiving dental treatment under general anesthesia. SUBJECTS AND METHODS: The study included 16 patients receiving dental procedures under general anesthesia. Using a sleep monitoring mat, the patients' sleep cycles were measured at home from 5 days before the scheduled surgery date until 5 days after discharge following general anesthesia. The change in all the variables of sleep cycles were analyzed in comparison to the value in preoperative period. Daily differences in these variables were assessed for statistical analysis. RESULTS: The percentage of deep sleep (Stages 3 and 4) decreased significantly on postoperative day 1, and the percentage of light sleep increased. Furthermore, sleep cycles were significantly extended on postoperative day 1. CONCLUSION: The percentage of deep sleep decreased significantly on postoperative day 1 while the percentage of light sleep increased. Sleep cycles were also significantly extended on postoperative day 1. These results reveal that the sleep cycle is somehow affected on the first day following general anesthesia. PMID- 30397918 TI - Changes in primary care access at community health centers between 2012/2013 and 2016. AB - OBJECTIVE: To compare access at community health centers (CHCs) vs private offices (non-CHCs) under the Affordable Care Act. DATA SOURCE: Ten state primary care audit conducted in 2012/2013 and 2016. STUDY DESIGN: CHCs and non-CHCs were called. We calculated difference in differences comparing CHCs vs non-CHCs by caller insurance type. PRINCIPAL FINDINGS: In both rounds, Medicaid and uninsured callers had higher appointment rates at CHC than non-CHCs. CHC appointment rates significantly increased between 2012/2013 and 2016 for both employer-sponsored and Medicaid callers, with no significant wait time changes. Appointment rates increased (13.5% points, P < 0.001) and wait times decreased (-5.7 days, P = 0.017) at CHCs relative to non-CHCs for employer-sponsored insurance. CONCLUSION: Appointment availability at CHCs improved after ACA implementation, without increased wait times. PMID- 30397919 TI - Exaggerated systemic oxidative-inflammatory-nitrosative stress in chronic mountain sickness is associated with cognitive decline and depression. AB - KEY POINTS: Chronic mountain sickness (CMS) is a maladaptation syndrome encountered at high altitude (HA) characterised by severe hypoxaemia that carries a higher risk of stroke and migraine and is associated with increased morbidity and mortality. We examined if exaggerated oxidative-inflammatory-nitrosative stress (OXINOS) and corresponding decrease in vascular nitric oxide bioavailability in patients with CMS (CMS+) is associated with impaired cerebrovascular function and adverse neurological outcome. Systemic OXINOS was markedly elevated in CMS+ compared to healthy HA (CMS-) and low-altitude controls. OXINOS was associated with blunted cerebral perfusion and vasoreactivity to hypercapnia, impaired cognition and, in CMS+, symptoms of depression. These findings are the first to suggest that a physiological continuum exists for hypoxaemia-induced systemic OXINOS in HA dwellers that when excessive is associated with accelerated cognitive decline and depression, helping identify those in need of more specialist neurological assessment and targeted support. ABSTRACT: Chronic mountain sickness (CMS) is a maladaptation syndrome encountered at high altitude (HA) characterised by severe hypoxaemia that carries a higher risk of stroke and migraine and is associated with increased morbidity and mortality. The present cross-sectional study examined to what extent exaggerated systemic oxidative-inflammatory-nitrosative stress (OXINOS), defined by an increase in free radical formation and corresponding decrease in vascular nitric oxide (NO) bioavailability, is associated with impaired cerebrovascular function, accelerated cognitive decline and depression in CMS. Venous blood was obtained from healthy male lowlanders (80 m, n = 17), and age- and gender-matched HA dwellers born and bred in La Paz, Bolivia (3600 m) with (CMS+, n = 23) and without (CMS-, n = 14) CMS. We sampled blood for oxidative (electron paramagnetic resonance spectroscopy, HPLC), nitrosative (ozone-based chemiluminescence) and inflammatory (fluorescence) biomarkers. We employed transcranial Doppler ultrasound to measure cerebral blood flow (CBF) and reactivity. We utilised psychometric tests and validated questionnaires to assess cognition and depression. Highlanders exhibited elevated systemic OXINOS (P < 0.05 vs. lowlanders) that was especially exaggerated in the more hypoxaemic CMS+ patients (P < 0.05 vs. CMS-). OXINOS was associated with blunted cerebral perfusion and vasoreactivity to hypercapnia, impaired cognition and, in CMS+, symptoms of depression. Collectively, these findings are the first to suggest that a physiological continuum exists for hypoxaemia-induced OXINOS in HA dwellers that when excessive is associated with accelerated cognitive decline and depression, helping identify those in need of specialist neurological assessment and support. PMID- 30397920 TI - Outbreak of viral haemorrhagic septicaemia (VHS) in lumpfish (Cyclopterus lumpus) in Iceland caused by VHS virus genotype IV. AB - A novel viral haemorrhagic septicaemia virus (VHSV) of genotype IV was isolated from wild lumpfish (Cyclopterus lumpus), brought to a land-based farm in Iceland, to serve as broodfish. Two groups of lumpfish juveniles, kept in tanks in the same facility, got infected. The virus isolated was identified as VHSV by ELISA and real-time RT-PCR. Phylogenetic analysis, based on the glycoprotein (G) gene sequences, may indicate a novel subgroup of VHSV genotype IV. In controlled laboratory exposure studies with this new isolate, there was 3% survival in the I.P. injection challenged group while there was 90% survival in the immersion group. VHSV was not re-isolated from fish challenged by immersion. In a cohabitation trial, lumpfish infected I.P. (shedders) were placed in tanks with naive lumpfish as well as naive Atlantic salmon (Salmo salar L.). 10% of the lumpfish shedders and 43%-50% of the cohabiting lumpfish survived after 4 weeks. 80%-92% of the Atlantic salmon survived, but no viral RNA was detected by real time RT-PCR nor VHSV was isolated from Atlantic salmon. This is the first isolation of a notifiable virus in Iceland and the first report of VHSV of genotype IV in European waters. PMID- 30397921 TI - Your love makes me feel more secure: Boosting attachment security decreases materialistic values. AB - Enhanced interpersonal security has been shown to diminish the desire for money and possessions. In the present study, we focus on attachment security to examine the relationship between attachment security and materialism. By employing the experience in close relationships - short scale and material values scale, we observed a positive relationship between attachment insecurity and materialism in Study 1. In Study 2, we primed participants' feeling of attachment security to further explore the impact of attachment security on materialistic values. The results showed that participants in the security-priming group exhibited lower levels of state materialism (Study 2a) and a longer time to respond to materialism-related words (Studies 2b and 2c) than participants in the neutral condition. However, attachment styles did not moderate the attachment security materialism relationship. Our findings reveal that regardless of attachment style, boosting attachment security can effectively decrease materialism. PMID- 30397922 TI - A novel technique for performing transseptal puncture guided by a non fluoroscopic 3D mapping system. AB - BACKGROUND: Transseptal puncture (TSP) is commonly performed under fluoroscopic guidance in left atrial ablation procedures. This exposes patients and healthcare professionals to deleterious ionizing radiation. We describe a novel technique for performing TSP non-fluoroscopically using a three-dimensional (3D) mapping system only. The safety and efficacy of this technique is compared to traditional fluoroscopy guided TSP. METHODS: Retrospective, single-center study of patients undergoing TSP for left atrial ablation. Those undergoing TSP using 3D mapping system alone (nonfluoroscopy group) were compared to those undergoing fluoroscopic guided TSP (Fluoroscopy group). Clinical, procedural data and complications were analyzed from a prospective registry. RESULTS: Twenty patients (32 TSPs) in the nonfluoroscopy (NF) group were compared to 14 patients (25 TSPs) in fluoroscopy (F) group. TSP success rates were similar across the groups (88% vs 96% in the NF and F groups, P = 0.97). In the NF group, there was one cardiac tamponade, two unsuccessful TSPs (previous cardiac surgery-required TOE guided TSP), and one patient required fluoroscopy on a background of CRTD device to avoid lead displacement. The mean fluoroscopy time and dose were significantly lower in the nonfluoroscopy group (0.75 +/- 0.50 vs 5.32 +/- 3.23 min, P < 0.001; 92.5 +/- 60.7 vs 394.3 +/- 182.7 cGy/cm2 , P < 0.001). CONCLUSION: Our study shows that TSPs can be performed safely and effectively using this non fluoroscopic novel technique in a select group of patients. Radiation exposure is reduced significantly without compromising patient safety. Larger studies are required to substantiate these results. Patients with cardiac implantable devices and previous cardiac surgery may pose a challenge to using this technique. PMID- 30397923 TI - Modulation of the leniency bias in the discursive dilemma. AB - We experimentally approach the discursive dilemma to gain insight into people's procedural appropriateness judgments. We relied on a vignette in which three people had formed opinions about two skills (premises) of a candidate to decide whether to hire her/him (conclusion). The dilemma arises when different outcomes (hire vs. not hire) are achieved depending on whether the majority opinion is independently considered for each premise or for the global conclusion of each judge. Participants were asked to choose the procedure they thought to be more appropriate to reach a decision. In Experiment 1, we found a leniency effect (a bias to prefer the aggregation procedure that led to hiring the candidate), which was reduced by introducing the participant as a juror with an exogenously provided negative opinion about the candidate's skills. In Experiment 2, we replicated the opinion effect, even when subjects did not participate as jury members. In Experiment 3, we found that the leniency bias was only reduced when participants' negative opinion was aligned with a majority of negative premises, but not with a majority of negative conclusions. We discuss present findings in terms of the identification of empirical regularities that may affect people's procedural legitimacy judgments. PMID- 30397925 TI - Tribute to Reviewers. PMID- 30397926 TI - Experimental evidence on prevention of infection by the ectoparasitic protozoans Ichthyobodo salmonis and Trichodina truttae in juvenile chum salmon using ultraviolet disinfection of rearing water. AB - In northern Japan, juvenile chum salmon Oncorhynchus keta (Walbaum) are released from hatcheries to enhance the fishery resource. Infections with ectoparasitic protozoans, particularly the flagellate Ichthyobodo salmonis and the ciliate Trichodina truttae, occasionally cause severe mortality among hatchery-reared juveniles. This study examined the susceptibility of the two parasites to wide ranging UV irradiation (experiment 1) and then investigated whether UV disinfection of the rearing water using a commercial device was useful for preventing infections among juveniles in a small-scale rearing system over a 28 day period (experiment 2). In experiment 1, parasite mortality reached 100% with UV irradiation doses of >=9.60 * 105 MUW s/cm2 for I. salmonis and >=8.40 * 105 MUW s/cm2 for T. truttae. In experiment 2, disinfection of the rearing water at a UV irradiation dose of 2.2 * 106 MUW s/cm2 succeeded in complete prevention of both parasites in the juvenile salmon. These results elucidate the minimum dose of UV irradiation for inactivation of I. salmonis and T. truttae, and demonstrate the usefulness of water disinfection using a commercial UV irradiation device to prevent infections by these parasites in hatchery-reared juvenile chum salmon. PMID- 30397927 TI - Lithiophilic 3D Nanoporous Nitrogen-Doped Graphene for Dendrite-Free and Ultrahigh-Rate Lithium-Metal Anodes. AB - The key bottlenecks hindering the practical implementations of lithium-metal anodes in high-energy-density rechargeable batteries are the uncontrolled dendrite growth and infinite volume changes during charging and discharging, which lead to short lifespan and catastrophic safety hazards. In principle, these problems can be mitigated or even solved by loading lithium into a high-surface area, conductive, and lithiophilic porous scaffold. However, a suitable material that can synchronously host a large loading amount of lithium and endure a large current density has not been achieved. Here, a lithiophilic 3D nanoporous nitrogen-doped graphene as the sought-after scaffold material for lithium anodes is reported. The high surface area, large porosity, and high conductivity of the nanoporous graphene concede not only dendrite-free stripping/plating but also abundant open space accommodating volume fluctuations of lithium. This ingenious scaffold endows the lithium composite anode with a long-term cycling stability and ultrahigh rate capability, significantly improving the charge storage performance of high-energy-density rechargeable lithium batteries. PMID- 30397929 TI - Structural features of cross-sectional wing bones in the griffon vulture (Gyps fulvus) as a prediction of flight style. AB - Flight is an energetically costly form of transport imparting biomechanical stress that acts upon the wing bones. Previous studies have suggested that the cross-sectional and microstructural features of wing bones may be adapted to resist biomechanical loads. During flight, however, each wing bone potentially experiences a unique loading regime. To assess possible differences among wing bones, we analyzed the microstructural features of the humerus, radius, ulna, and carpometacarpus (CMC) in eight griffon vultures (Gyps fulvus). Vascular canal orientation was evaluated in the diaphysis of the wing bones. Laminarity index (LI) was significantly different in the humerus versus CMC and ulna versus CMC. Results showed a lower proportion of circular vascular canals, due to resistance to torsional loads, in CMC than in humerus and ulna. The midshaft cross-section revealed an elliptical shape in the CMC compared to the circular shape observed in the other wing bones, with a maximum second moment of inertia (Imax ) orientation which suggests a capacity to withstand bending loads in a dorsoventral direction. The volumetric bone mineral density in the diaphysis was statistically different in CMC compared to the other bones analyzed. Its lower mineral density may reflect an adaptation to a different type and load of stresses in CMC compared to the proximal wing bones. No significant difference was found in the relative cortical area (CA/TA) among the four elements, while the polar moment of area J (Length-standardized) revealed a higher resistance to torsional load in the humerus than in the other bones. Our results would seem to indicate that griffon wing bones are structured as an adaptation, represented by two segments that respond to force in two ways: the proximal segment is specially adapted to resist torsional loads, whereas the distal one is adapted to resist bending loads. PMID- 30397930 TI - Isolation and identification of nucleosides/nucleotides raising testosterone and NO levels of mice serum from Chinese chive (Allium tuberosum) leaves. AB - Our previous study found that Chinese chive could significantly (p < 0.01) raise testosterone and nitric oxide (NO) levels in mice serum. However, the specific functional components of this traditional remedy are still unknown. In order to isolate and identify the active constituents from Chinese chive for enhancing testosterone and NO levels, the Chinese chive leaves were extracted by petroleum ether, ethyl acetate, n-butanol and water respectively. Results indicated that the n-butanol extract had a significant effect on NO and testosterone blood levels. Subsequently, n-butanol extract was further isolated by D101 macroporous adsorption and eluted with 50% ethanol and then isolated by Sephadex LH-20 and preparative high-performance liquid chromatography to obtain nucleosides. The fraction eluted with 70% ethanol was further isolated by RP-18 and pre-HPLC to obtain nucleotides. Four novel compounds were identified, and their effects on testosterone and NO levels of male mice were evaluated. Results showed that nucleotides, especially the adenosine in Chinese chive leaves, increased serum testosterone and NO levels in male mice, which had not been reported before. This finding might bring into perspective the treatment strategy for those doctors who treat hormone deficiencies, and might be suitable for using in functional food. PMID- 30397931 TI - Infection prevention climate and its influence on nursing students' compliance with standard precautions. AB - AIM: This study examined the influence of the training hospital's infection prevention climate on the nursing students' compliance with standard precautions during clinical training. BACKGROUND: The concept of infection prevention climate has emerged in healthcare facilities due to the acknowledged influence of organizational culture on the compliance of healthcare workers on infection prevention and control practices. However, the influence of training hospital's infection prevention climate on nursing students' compliance with standard precautions has never been investigated. DESIGN: A descriptive, cross-sectional design. METHODS: A convenience sample of 254 nursing students in Saudi Arabia was surveyed using the Leading Culture of Quality in Infection Prevention and the Compliance with Standard Precautions Scale from October 2017 - January 2018. RESULTS: The students perceived their training hospital's infection prevention climate as moderately positive. The students' age, year of study and attendance to infection prevention and control training in the last 6 months exerted multivariate effects on the four dimensions and on the overall infection prevention climate. The nursing students' compliance with standard precautions was moderate. Age, gender, year of study, attendance to infection prevention and control training and perceived training hospital's infection prevention climate were identified as factors that significantly influenced the students' compliance with SPs. CONCLUSIONS: This study underscored the importance of maintaining high quality of infection prevention climate of training hospitals as it influences the development of competencies in infection prevention and control of nursing students. This article is protected by copyright. All rights reserved. PMID- 30397928 TI - Near-Infrared Electron Acceptors with Fluorinated Regioisomeric Backbone for Highly Efficient Polymer Solar Cells. AB - Solar photon-to-electron conversion with polymer solar cells (PSCs) has experienced rapid development in the recent few years. Even so, the exploration of molecules and devices in efficiently converting near-infrared (NIR) photons into electrons remains critical, yet challenging. Herein presented is a family of near-infrared nonfullerene acceptors (NIR NFAs, T1-T4) with fluorinated regioisomeric A-Api-D-Api-A backbones for constructing efficient single-junction and tandem PSCs with photon response up to 1000 nm. It is found that the tuning of the regioisomeric bridge (Api) and fluoro (F)-substituents on a molecular skeleton strongly influences the backbone conformation and conjugation, leading to the optimized optoelectronic and stable stacking of resultant NFAs, which eventually impacts the performance of derived PSCs. In PSCs, the proximal NFAs with varied F-atoms (T1-T3) mostly outperform than that of distal NFA (T4). Notably, single-junction PSC with PTB7-Th:T2 blend can reach 10.87% power conversion efficiency (PCE), after implementing a solvent additive to improve blend morphology. Moreover, efficient tandem PSCs are fabricated through integrating such NIR cells with mediate bandgap nonfullerene-based subcells, to achieve a PCE of 14.64%. The results reveal the structural design of organic semiconductor and device with improved photovoltaic performance. PMID- 30397932 TI - Impact of right heart function on outcome in patients with functional mitral regurgitation and chronic heart failure undergoing percutaneous edge-to-edge repair. AB - AIMS: To evaluate the impact of right ventricular dysfunction (RVD) on outcome after transcatheter mitral valve repair (TMVR) in patients with chronic heart failure (CHF) and severe functional mitral regurgitation (FMR). METHODS AND RESULTS: One hundred thirty patients (median age 72.7 +/- 10.7 years; 63.8% male) at high operative risk (LogEuroSCORE 23.8 +/- 13.9%) with FMR and CHF (left ventricular ejection fraction 32 +/- 7%) were enrolled and separated into two groups according to the RVD. RVD was assessed by the tricuspid annular plane systolic excursion (TAPSE) method (A: TAPSE <= 16 mm, n = 58; B: TAPSE > 16 mm, n = 72). The rate of successful reduction of mitral regurgitation (MR <=2+) by TMVR was similar in both groups (94.6% vs 91.2%; P: n.s.) with low in-hospital major adverse event rates. During a median follow-up period of 10.5 +/- 4 months, the Kaplan-Meier analysis revealed a significantly higher all-cause mortality in group A (43.1% vs 23.6%; log-rank P = 0.039) and a significantly higher rate of hospital readmission due to congestive heart failure (56.9% vs 26.4%; log-rank P < 0.001). At long-term follow-up, 25% of patients in group A remained in NYHA functional class IV (none in group B). Preexisting RVD as assessed by TAPSE and Doppler tissue imaging (DTI-S') was an independent predictor of all-cause mortality after TMVR (hazard ratio 2.84; 95% confidence interval 1.15-7.65; P = 0.039; hazard ratio 4.70; 95% confidence interval 1.14-20.21; P = 0.044, respectively). CONCLUSIONS: Patients with CHF and RVD were with regard to functional capacity less often responder and showed an unfavorable long-term outcome. Thus, patients with CHF and RVD seem to benefit less frequently from TMVR. PMID- 30397933 TI - Taxonomic and ecomorphological diversity of temnospondyl amphibians across the Permian-Triassic boundary in the Karoo Basin (South Africa). AB - Temnospondyl amphibians experienced a geologically brief interval of success in the wake of the end-Permian mass extinction. This study examines the relationship between taxonomic and ecological diversity of temnospondyls across the Permian Triassic boundary in the Karoo Basin of South Africa. Ecomorphological diversity, as implied by differences in cranial shape, was incorporated into the study by the use of a landmark-based geometric morphometric analysis. Both taxonomic diversity and cranial disparity are low during the Permian and increase across the Permian-Triassic boundary. Taxonomic diversity is stable through the Triassic, but disparity shows subsequent increases during the Olenekian and Anisian. Temnospondyls are restricted in size immediately following the extinction, but size range fully rebounds by the Olenekian. Cranial shape is heavily influenced by phylogenetic relatedness, and the observed increases in disparity may be partly the result of decreases in the net relatedness of coeval Karoo stereospondylomorph temnospondyls in younger faunas. The increase in community level taxonomic diversity for temnospondyls in the Karoo following the end-Permian mass extinction was likely facilitated by an influx of distantly related and ecologically distinct species. PMID- 30397934 TI - An mHealth Intervention Program to Promote Healthy Behaviors and Prevent Adolescent Obesity (TeenPower): a Study Protocol. AB - AIM: This paper describes the design and rationale of multicenter practice-based research that aims to develop and evaluate an innovative mobile health (mHealth) intervention program directed to promote healthy behaviors and prevent adolescent obesity. DESIGN: This study is designed as a nonrandomized controlled trial with a three-arm structure. METHODS: Twelve to sixteen years old participants will be recruited from schools, with access to the internet and smartphone/tablet devices. The intervention group will be invited to engage in the TeenPower mHealth program and divided into two subgroups: Group A (additionally engaged in a structured school-based intervention program) and Group B (only engaged in the mHealth program). The mHealth app includes educational resources, self monitoring, social support, interactive training modules and motivational tools. The control group will only follow the structured school-based intervention program. The intervention length will be 3 months, including the direct support of an interdisciplinary team (nursing, nutrition, sports, psychology, among others). This research was approved and funded in August 2017. DISCUSSION: The positive evaluation of the intervention program will stimulate the inclusion of technologies in the promotion of salutogenic behaviors and obesity prevention. IMPACT: Adolescent obesity reached epidemic proportions. It is urgent to find effective prevention strategies to induce change at the individual, family and community level. If effective, this protocol can be used by health and exercise professionals in improving community interventions tailored to teenagers. This article is protected by copyright. All rights reserved. PMID- 30397935 TI - An investigation of the molecular and biochemical basis underlying chlorantraniliprole-resistant Drosophila strains and their cross-resistance to other insecticides. AB - Chlorantraniliprole is an anthranilic diamide insecticide that binds to the insect ryanodine receptor (RyR) and induces an uncontrolled release of Ca2+ , resulting in paralysis and ultimately death of the target insects. Recently, it was reported that chlorantraniliprole-resistant diamondback moths, Plutella xylostella Linnaeus, have mutations in their RyR. In this study, we developed two different chlorantraniliprole-resistant Drosophila melanogaster strain. The resistance ratio (RR) of the low-concentration chlorantraniliprole-treated resistant (Low-Res) strain was 2.3, while that of the high-concentration chlorantraniliprole-treated resistant (High-Res) strain was 21.3. The LC 50 of the untreated control (Con) strain was 23.8~25.9 ppm, which was significantly higher than that reported for the susceptible diamondback moth (0.03~0.51 ppm). The high LC 50 of the Con may be because the helix S2 amino acid sequence of D. melanogaster RyR ( DmRyR) is identical to the I4790M mutation of the chlorantraniliprole-resistant diamondback moths, resulting in a lower binding affinity of DmRyR for chlorantraniliprole. Among the tested detoxification enzymes, the activity of esterase was significantly increased in the two Res strains, but glutathione S-transferases and acetylcholinesterase were significantly decreased in the two Res strains. The cross-resistance of the High Res strain to other insecticides with different modes of actions (MoAs) revealed that the RRs of the neuronal acetylcholine receptor allosteric and competitive modulators were significantly increased, while those of the Na 2+ channel modulators were significantly reduced. Our studies showed that RRs against the same insecticide vary with the treatment concentration, and that RRs against other insecticides with different MoAs can be altered. PMID- 30397936 TI - Functional anatomy of the female reproductive system of the American lobster (Homarus americanus). AB - Light microscopy studies of the female American lobster Homarus americanus reproductive system are essentially nonexistent or outdated. Based on samples taken in the spring, summer, and autumn from the southern Gulf of St. Lawrence between 1994 and 2014, and using a combination of histological and scanning electron microscope techniques, we propose an ovarian cycle with 10 stages, identifying for the first time a recovery stage. Also, an atypical resorption stage, characterized by massive reabsorption of mature oocytes, is occasionally observed during summer months. The oviducts are composed of connective tissue (elastic and collagen fibers) with no muscle or secretory activities. Their epithelium shows a cyclic pattern and phagocytosis activities linked to spawning. Although the role of the seminal receptacle is to store and protect semen, free spermatozoa (i.e., without the spermatophoric wall and the acellular gelatinous substance that constitute the semen) were also observed in its posteriolateral grooves immediately prior to spawning, which is consistent with an external fertilization mechanism at the seminal receptacle. Unexpectedly, free spermatozoa were observed externally near two pore-like structures located on the gonopore's operculum, not at the seminal receptacle, after spawning; hence, more work is needed to fully understand the fertilization mechanism for the American lobster. PMID- 30397937 TI - Physical performance and cognitive functioning among individuals with diabetes: Findings from the China Health and Retirement Longitudinal Study Baseline Survey. AB - AIMS: The purpose of this study was to examine individual associations of each physical performance measure with domains of cognitive functioning and to determine best physical performance measures strongly associated with each domain of cognitive functioning among middle-aged and older adults with diabetes. BACKGROUND: Tests of physical performance are strongly correlated with cognitive decline in general elderly population. However, far less is known about individual associations of each individual physical performance measure with domains of cognitive functioning among individuals with diabetes. DESIGN: The study employed a retrospective, cross-sectional design. METHODS: Baseline data from a national baseline survey collected from May 2011 - March 2012 were used. A total of 17,314 individuals aged >=45 years completed the baseline survey. Diabetes was confirmed for 1,905 participants and these individuals were included in the current study. RESULTS: When grip strength, walking speed, repeated chair stands and standing balance test were added in the regression models, walking speed was the only variable that was significantly associated with figure drawing and grip strength was the only variable that was significantly associated with episodic memory, orientation/attention and overall cognitive score. CONCLUSION: Since grip strength was the most important factor associated with several domains of cognitive functioning, strategies that improve grip strength in patients with diabetes are prudent. Early interventions to increase levels of physical activity may be important to improve both grip strength and cognitive functioning in this growing population with diabetes. This article is protected by copyright. All rights reserved. PMID- 30397938 TI - Ultrastructural variation and adaptive evolution of the ovipositor in the endemic Hawaiian Drosophilidae. AB - Ecological diversification of the endemic Hawaiian Drosophilidae has been accompanied by striking divergence in egg morphology, and ovarian structure and function. To determine how these flies successfully oviposit in a variety of breeding substrates, we used Scanning Electron Microscopy to examine the ultrastructure of the ovipositor of a sample of 65 Drosophila species and five Scaptomyza species of this hyperdiverse monophyletic group. The Drosophila species analyzed included representatives of the fungus-breeding haleakalae group, the leaf-breeding antopocerus and modified tarsus groups, the modified mouthparts species group, the nudidrosophila, and the picture wing clade; the latter sample of 41 species from four species groups included stem- and bark breeders, as well as tree sap flux-breeders. Ovipositor length was found to vary more than 12-fold among Hawaiian drosophilids, with the longest ovipositors observed in the bark-breeding species and the shortest among the Scaptomyza and fungus-breeders. More noteworthy is the striking variation in overall shape and proportions of the ovipositor, in the shape of the apical region, and in the pattern of sensory structures or ovisensilla. Ultrastructural observations of the pair of long subapical sensilla on the ventral side identify these, for the first time, as taste bristles. Ovipositor form correlates strongly with the oviposition substrate used by the species, being of a distinctive shape and size in each case. We infer that the observed morphological divergence in the ovipositor is adaptive and the product of natural selection for successful reproduction in alternate microhabitats. The array of ovipositor forms that have evolved among the Hawaiian Drosophila species represent a series of ecomorphs that along with other divergent traits of the female reproductive system, have contributed to the successful adaptive radiation of this remarkable fauna. PMID- 30397939 TI - Periprocedural antibiotic treatment in transvascular aortic valve replacement. AB - BACKGROUND: To date, there are no guidelines recommending a specific prophylactic antibiotic treatment in transcatheter aortic valve replacement (TAVR). The aim of this study is to evaluate clinical data after TAVR with different periprocedural antibiotic regimens. METHODS: In May 2015 the institutional rules for periprocedural antibiotic prophylaxis were changed from 3 days to 1 day. Thus, a total of 450 consecutive TAVR patients between February 2014 and June 2016 were classified into two intention-to-treat groups: patients receiving a 1-day Cefuroxime prophylaxis (N = 225); patients receiving a 3-day Cefuroxime prophylaxis (N = 225). RESULTS: One-day Cefuroxime regimen was not associated with shorter hospitalization (3-day Cefuroxime 9 +/- 4.7 vs 1-day Cefuroxime 8.9 +/- 4.0; P = 0.87). Incidence of diarrhea (26.2% vs 18.2%; P = 0.04) and Clostridium difficile infections (4% vs 0.4%; P = 0.01) were significantly higher in the 3-day group. No endocarditis was registered after 1 year follow-up. There was no difference in 30-day overall mortality rate, major vascular complications, bleeding complications, pacemaker-implantation rate, paravalvular regurgitation, or acute kidney injury between patients groups. CONCLUSION: Three-day Cefuroxime prophylaxis does not seem to be advantageous compared to a shorter 1-day regimen, but even shows a significantly higher incidence of diarrhea and Clostridium difficile infection. PMID- 30397940 TI - Effectiveness of nursing interventions for breathlessness in people with chronic obstructive pulmonary disease: A systematic review and meta-analysis. AB - AIM: To critically review and synthesize the findings of studies that evaluated the effectiveness of nursing interventions for improving breathlessness in adults with chronic obstructive pulmonary disease. BACKGROUND: Systematic reviews of nursing interventions for breathlessness in people with chronic obstructive pulmonary disease have not been specifically addressed. DESIGN: Systematic review with meta-analysis. DATA SOURCES: A systematic search of Medline, CINAHL, PsycINFO and Embase was performed for studies published between January 2000 - June 2017. REVIEW METHODS: Risk of bias, data extraction and meta-analysis were conducted using Cochrane methodology. The quality of evidence was assessed using the GRADE approach. RESULTS: Twenty papers were included. A meta-analysis of interventions performed at home, including two trials, showed a significant effect in favour of experimental groups for the symptom score of the St. George Respiratory Questionnaire compared with controls. A meta-analysis of interventions performed in clinics with home follow-up showed a significant effect in favour of experimental groups for the mastery and fatigue scores of the Chronic Respiratory Questionnaire compared with controls. In this category of intervention, an additional meta-analysis showed a significant effect in favour of experimental groups for the symptom, activity and total scores of the St. George Respiratory Questionnaire compared with controls. The quality of evidence was assessed to be very low to moderate. CONCLUSION: The results are equivocal as to whether nursing interventions performed at home and nursing interventions performed in hospital with follow-up improve breathlessness in people with chronic obstructive pulmonary disease. This article is protected by copyright. All rights reserved. PMID- 30397941 TI - An Integrative Review of the Theory of Unpleasant Symptoms. AB - AIMS: To explore how the Theory of Unpleasant Symptoms has been used in the methodological design and analysis of symptom research. DESIGN: An integrative review, using Whittemore and Knafl's approach. DATA SOURCES: Searches were conducted between January 26 and February 10, 2018. Databases included CINAHL Complete, PubMed, Proquest Nursing and Allied Health Source, Health Source: Nursing/Academic Edition, Academic Search Complete and Google Scholar. REVIEW METHODS: A systematic approach to searching, screening and analyzing the literature was applied. The matrix method, content analysis, constant comparison, counting and clustering were used. RESULTS: Sixty-four records were included. Most studies were quantitative, cross-sectional, instrument-based and conducted in the United States. Various symptoms and patient populations were represented and each of the Theory of Unpleasant Symptoms concepts were explored. CONCLUSION: Though the theory has a role to play in furthering symptom science, attention should be paid to the areas of the model and of symptom research that have received less attention. More complex statistical approaches and big data will help to illuminate symptom experiences. Additional focus on intervention studies and all symptom dimensions will help to advance symptom science research. IMPACT: This review is the first to provide a comprehensive, systematic summary of the uses of the Theory of Unpleasant Symptoms across the research literature to date. This theory is a diverse, holistic middle-range theory capable of being applied to multiple symptoms and populations. Researchers should consider using the theory as a conceptual framework for studies to advance symptom science and explore symptoms holistically. This article is protected by copyright. All rights reserved. PMID- 30397942 TI - Diet to beat the odds of prodromal Parkinson's disease? PMID- 30397943 TI - Self-Care Interventions for Adults with Heart Failure: A Systematic Review and Meta-analysis Protocol. AB - AIM: To synthesize and compare outcomes from controlled trials of interventions to improve heart failure self-care among adults. BACKGROUND: Heart failure self care interventions are recommended for preventing and detecting exacerbations, improving symptom management and preventing hospitalizations. Little is known about the overall effectiveness of heart failure self-care programs and which types of interventions show the greatest improvement in outcomes. DESIGN: Systematic review and meta-analysis, including moderator analyses. METHODS: Multiple databases (including MEDLINE/PubMed, CINAHL, PsycINFO, Scopus, Cochrane Central Register of Controlled Trials) will be searched from inception through 2018 along with grey literature searches to identify trials testing interventions to improve self-care outcomes of adults with heart failure. Data will be extracted from eligible studies on sample, methodological and intervention characteristics as well as data to calculate effect sizes. Data will be analyzed using random-effects models. Moderator variables will be analyzed with meta regression and subgroup analyses. Risk for bias will be assessed using the Cochrane Risk for Bias tool and by examining potential sources of bias as moderator variables. Funding for this project began in July 2017. DISCUSSION: We will analyze self-care behavior outcomes as well as clinical outcomes including hospitalizations, mortality, disease severity and quality of life. This will be the most extensive meta-analysis of heart failure self-care interventions to date. IMPACT: Comparative effectiveness of existing self-care interventions is not yet known. This research will identify the most promising self-care intervention components for designing better interventions and guide targeting of interventions to specific sub-populations. This article is protected by copyright. All rights reserved. PMID- 30397944 TI - Tender nodular lesion on the thigh of a 15-year-old boy. PMID- 30397945 TI - A 4-year-old with photosensitivity, recurrent blistering, and heart murmur. PMID- 30397946 TI - An 8-year-old boy with dermal plaques and scaly papules of the face and ears. PMID- 30397947 TI - Vesiculopapular eruption in an infant with trisomy 21. PMID- 30397948 TI - Comment on "Proportionate growth of congenital nevi: Blow a balloon to explain". PMID- 30397949 TI - Comment on "Dermatoscopic features of lichen nitidus". PMID- 30397950 TI - Hypopigmented papules in a 16-month-old Arabic girl. PMID- 30397951 TI - A 14-year-old girl with keratotic interphalangeal palmar papules. PMID- 30397952 TI - Comment on "Usefulness of ultrasonography in the diagnosis of subcutaneous granuloma annulare". PMID- 30397953 TI - Annular lesions in a newborn. PMID- 30397954 TI - Fine scaly plaques on the vulva of a 2-year-old girl. PMID- 30397955 TI - Comment on "Proportionate growth of congenital nevi: Blow a balloon to explain". PMID- 30397956 TI - Pruritic, scaly, serpiginous plaques in a 10-year-old boy. PMID- 30397957 TI - A case of spotty scrotum. PMID- 30397958 TI - Thick nails and itchy rash. PMID- 30397959 TI - Asymptomatic cutaneous lesions in an infant. PMID- 30397960 TI - Eyelid papules and patchy alopecia in an 8-month-old boy. PMID- 30397961 TI - Patient Perspectives: What is a Spitz nevus? PMID- 30397962 TI - Linear papules and plaques on the posterior shoulders of a teenage male. PMID- 30397963 TI - Effects of an educational program on disaster nursing competency. AB - OBJECTIVE: The purpose of this study was to examine the effects of an educational program on disaster nursing competency among Korean nursing students. DESIGN AND SAMPLE: A quasi-experimental design with a nonequivalent control group was used. We randomly assigned 60 junior nursing students from two nursing colleges in Korea to an experimental group (n = 30) and a control group (n = 30). MEASURES: A disaster educational program for nursing students was developed based on the International Council of Nurses framework of disaster nursing competencies. The program sought to teach nursing activities by stage of disaster (i.e., prevention/mitigation, preparedness, response, and recovery/rehabilitation). Disaster nursing knowledge, disaster triage, and disaster readiness were measured as dependent variables. RESULTS: Compared with the control group, the experimental group showed a significant increase in disaster nursing knowledge (t = 14.37, p < 0.001), disaster triage (t = 7.90, p = 0.002), and disaster readiness (t = 10.82, p < 0.001). CONCLUSION: The disaster educational program developed in this study was effective in increasing disaster nursing competency among nursing students and is therefore a useful intervention strategy for nursing students. PMID- 30397965 TI - Perspective. PMID- 30397966 TI - Self-Healing Polymer Electrolytes Formed via Dual-Networks: A New Strategy for Flexible Lithium Metal Batteries. AB - A novel polymer electrolyte with mechanically robust and self-healing properties was fabricated through a dual-network structure, crosslinked by quadruple hydrogen bonding and chemical bonding. The dynamic ureido-pyrimidinone (UPy) dimers were the first network in the polymer matrix. This group endows the polymer electrolyte with good self-healing capacity and improves the reliability and lifetime of the polymer lithium batteries. The crosslinked polyethylene glycol-bis-carbamate dimethacrylate (PEGBCDMA) is the second network and guarantees dimensional stability and good mechanical properties of the polymer electrolyte. The dual-network self-healing polymer electrolyte (DN-SHPE) exhibits improved ionic conductivity versus the polymer electrolyte fabricated by poly(ethylene glycol) diacrylate (PEGDA). It has high thermal stability (up to 350 degrees C) and excellent interfacial stability with the electrodes. When the DN-SHPE-based cells were fabricated with LiFePO4 and Li metal, the resulting cells show good reversible specific capacity and considerable rate capability. Moreover, the pouch cell could maintain electrochemical function even under deformation or folding conditions. PMID- 30397964 TI - Early depletion of contact system in patients with sepsis: a prospective matched control observational study. AB - Activation of the contact system generates bradykinin from high-molecular-weight kininogen and has been suggested to participate in the pathophysiology of sepsis. To test this, we prospectively measured bradykinin and high-molecular-weight kininogen levels in a cohort of sepsis patients requiring intensive care. From 29 patients meeting criteria for sepsis or septic shock according to Sepsis-3, blood was sampled within 24 h and on the fourth day following admittance to intensive care. Patients planned for neurosurgery served as matched controls. Sequential organ failure assessment score and 90-day mortality was registered. Bradykinin levels (median [interquartile range]) were lower in sepsis patients (79 [62-172] pg/ml) compared to controls (130 [86-255] pg/ml, p < 0.025) and did not correlate with mortality or severity of circulatory derangement. High-molecular-weight kininogen levels were lower in sepsis patients (1.6 [0.8-4.8] densitometry units) compared to controls (4.4 [2.9-7.7] densitometry units, p < 0.001), suggesting previous contact system activation. High-molecular-weight kininogen levels were lower in non-survivors than survivors (p = 0.003) and negatively correlated to severity of circulatory derangement. We conclude that a role for bradykinin in later stages of severe sepsis must be challenged. Low high-molecular-weight kininogen concentrations suggest that the decrease in bradykinin is due to substrate depletion. PMID- 30397967 TI - Sequence and structural analysis of fibronectin-binding protein reveals importance of multiple intrinsic disordered tandem repeats. AB - The location of certain amino acid sequences like repeats along the polypeptide chain is very important in the context of forming the overall shape of the protein molecule which in fact determines its function. In gram-positive bacteria, fibronectin-binding protein (FnBP) is one such repeat containing protein, and it is a cell wall-attached protein responsible for various acute infections in human. Several studies on sequence, structure, and function of fibronectin-binding regions of FnBPs were reported; however, no detailed study was carried out on the full-length protein sequence. In the present study, we have made a thorough sequence and structure analysis on FnBP_A of Staphylococcus aureus and explored the presence of dual ligand-binding ability of fibrinogen (fg)-binding region and its molecular recognition processes. Multiple sequence alignment and protein-protein docking analysis reveal the regions which are likely involved in dual ligand binding. Further analysis of docking of FnBP_A fg binding region and fn N-terminal modules suggests that if the latter binds to the fg-binding region of FnBP_A, it would inhibit the subsequent binding of fg because of steric hindrance. The sequence analysis further suggests that the abundance of disorder promoting residue glutamic acid and dual personality (both order/disorder promoting) residue threonine in tandem repeats of FnBP_A and B proteins possibly would help the molecule to undergo a conformational change while binding with fn by beta-zipper mechanism. The segment-based power spectral analysis was carried out which helps to understand the distribution of hydrophobic residues along the sequence particularly in intrinsic disordered tandem repeats. The results presented here will help to understand the role of internal repeats and intrinsic disorder in the molecular recognition process of a pathogenic cell surface protein. PMID- 30397968 TI - Helical Ullazine-Quinoxaline-Based Polycyclic Aromatic Hydrocarbons. AB - Polycyclic aromatic azomethine ylides (PAMYs) are powerful building blocks in the bottom-up synthesis of internally nitrogen-containing polycyclic aromatic hydrocarbons (N-PAHs) through 1,3-cycloaddition reactions. In this work, we demonstrate the cycloaddition reaction of PAMYs to asymmetric ortho-quinones which -in contrast to the addition to symmetric para-quinones facilitates subsequent condensation reactions and allows the synthesis of three helical N PAHs with ullazine-quinoxaline (UQ-1-3) backbones. While UQ-1 and UQ-2 possess two helical centers, single-crystal X-ray analysis together with the computational modelling of UQ-3 elucidate the formation of only the thermodynamic most stable geometry with four helical centers in a (P,P,M,M) configuration. For the series UQ-1-3, the number of redox steps is directly correlated with the number of ullazine or quinoxaline units incorporated into the targeted molecular backbones. The detailed investigation of the spectroscopic and magnetic properties of the radical cation and anion as well as the dication and dianion species by in situ EPR/UV-Vis-NIR spectroelectrochemistry was provided. The excellent optical and redox properties combined with helical geometries render them possible application as chiral emitter or ambipolar charge transport material in organic electronics. PMID- 30397969 TI - Sleep duration in Mexican American children: Do mothers' and fathers' parenting and family practices play a role? AB - This study examined parenting styles, parenting practices and family practices that may be associated with weeknight sleep duration among 8- to 10-year-old Mexican American (MA) children. This cross-sectional study of MA children used baseline data from a 2-year cohort study of mother-child pairs (n = 308) with additional data on fathers (n = 166). Children's weeknight sleep duration was accelerometer estimated and averaged for 2 weeknights. Parents reported on their parenting styles and practices regarding food and family food-related practices. Multivariable linear regression analysis was used to examine sleep duration with parenting styles and practices, and family practices, and adjusting for child gender and body mass index. Model 1 included mothers' parenting styles and practices; Model 2 included both mothers' and fathers' parenting styles and practices. Children's average sleep duration was 9.5 (SD = 0.8) hr. Mothers who used pressure to encourage their children to eat and those who used food to control behavior had children with longer sleep duration (beta = 0.21, p < 0.01; beta = 0.15, p = 0.03, respectively). Mothers who reported their children ate dinner with the TV on and those who valued eating dinner as a family had children with shorter sleep duration (beta = -0.16, p = 0.01; beta = -0.18, p = 0.01, respectively). Fathers who restricted the amount of food their children ate had children with shorter sleep duration (beta = -0.27, p = 0.01). Mothers' and fathers' feeding practices, the child's eating dinner with the TV on, and valuing family dinners, played a role in children's weeknight sleep duration among Mexican American families. Parental feeding practices and family mealtime contexts may have an effect on children's weeknight sleep duration. PMID- 30397970 TI - Effects of simulated microgravity on the expression profiles of RNA during osteogenic differentiation of human bone marrow mesenchymal stem cells. AB - OBJECTIVES: Exposure to microgravity induces many adaptive and pathological changes in human bone marrow mesenchymal stem cells (hBMSCs). However, the underlying mechanisms of these changes are poorly understood. We revealed the gene expression patterns of hBMSCs under normal ground (NG) and simulated microgravity (SMG), which showed an interpretation for these changes by gene regulation and signal pathways analysis. MATERIALS AND METHODS: In this study, hBMSCs were osteogenically induced for 0, 2, 7 and 14 days under normal ground gravity and simulated microgravity, followed by analysis of the differences in transcriptome expression during osteogenic differentiation by RNA sequencing and some experimental verification for these results. RESULTS: The results indicated that 837, 399 and 894 differentially expressed genes (DEGs) were identified in 2, 7 and 14 days samples, respectively, out of which 13 genes were selected for qRT PCR analysis to confirm the RNA-sequencing results. After analysis, we found that proliferation was inhibited in the early stage of induction. In the middle stage, osteogenic differentiation was inhibited, whereas adipogenic differentiation benefited from SMG. Moreover, SMG resulted in the up-regulation of genes specific for tumorigenesis in the later stage. CONCLUSION: Our data revealed that SMG inhibits the proliferation and inhibits the differentiation towards osteoblasts but promotes adipogenesis. SMG also selects highly tumorigenic cells for survival under prolonged SMG. PMID- 30397971 TI - Total Synthesis of Callyspongiolide, Part 2 The Ynoate Metathesis / cis-Reduction Strategy. AB - The macrocyclic core of the cytotoxic marine natural product callyspongiolide (1) was forged by ring closing alkyne metathesis (RCAM) of an ynoate precursor using a molybdenum alkylidyne complex endowed with triarylsilanolate ligands as the catalyst. This result is remarkable in view of the failed attempts documented in the literature at converting electron deficient alkynes with the aid of more classical catalysts. The subsequent Z-selective semi-reduction of the resulting cycloalkyne by hydrogenation over nickel boride required careful optimization in order to minimize overreduction and competing dehalogenation of the compound's alkenyl iodide terminus as needed for final attachment of the side chain of 1 by Sonogashira coupling. The required cyclization precursor itself was prepared via Kocienski olefination. PMID- 30397972 TI - Are abuse-deterrent opioid formulations all they are crushed up to be? PMID- 30397973 TI - Synthesis and Molecular Editing of Callyspongiolide, Part 1 The Alkyne Metathesis / trans-Reduction Strategy. AB - A path-scouting investigation into the highly cytotoxic marine macrolide callyspongiolide is reported that capitalizes on the selective formation of the C10-C11 alkene site. While the closure of the macrocycle by ring closing alkyne metathesis (RCAM) with the aid of a molybdenum alkylidyne complex was high yielding, the envisaged semi-reduction of the cycloalkyne to the corresponding E alkene proved challenging. The reasons are likely steric in origin, in that the methyl branches on either side of the alkyne seem to prevent effective coordination of the substrate to the ruthenium catalyst, which must carry a bulky Cp* ligand to ensure high trans-selectivity. This notion is supported by the preparation of a callyspongiolide analogue, in which the two methyl groups in question are excised; its formation by RCAM followed by trans hydrostannation/proto-destannation was straightforward. In parallel work the formation of the fully functional building block 54 showed that the presence of an unprotected -OH group allows even hindered substrates to be processed: the protic group adjacent to the triple bond engages with a chloride ligand on the ruthenium catalyst in hydrogen bonding and hence assists in substrate binding. Moreover, the preparation of an alkynylogous callyspongiolide analogue is described. PMID- 30397974 TI - Bidirectional regulation of osteogenic differentiation by the FOXO subfamily of Forkhead transcription factors in mammalian MSCs. AB - Through loss- and gain-of-function experiments in knockout and transgenic mice, Forkhead box O (FOXO) family transcription factors have been demonstrated to play essential roles in many biological processes, including cellular proliferation, apoptosis and differentiation. Osteogenic differentiation from mesenchymal stem cells (MSCs) into osteoblasts is a well-organized process that is carefully guided and characterized by various factors, such as runt-related transcription factor 2 (Runx2), beta-catenin, osteocalcin (OCN), alkaline phosphatase (ALP) and activating transcription factor 4 (ATF4). Accumulating evidence suggests multiple interactions among FOXO members and the differentiation regulatory factors listed above, resulting in an enhancement or inhibition of osteogenesis in different stages of osteogenic differentiation. To systematically and integrally understand the role of FOXOs in osteogenic differentiation and explain the contrary phenomena observed in vitro and in vivo, we herein summarized FOXO-interacting differentiation regulatory genes/factors and following alterations in differentiation. The underlying mechanism was further discussed on the basis of binding types, sites, phases and the consequent downstream transcriptional alterations of interactions among FOXOs and differentiation regulatory factors. Interestingly, a bidirectional effect of FOXOs on balancing osteogenic differentiation was discovered in MSCs. Moreover, FOXO factors are reported to be activated or suppressed by several context-dependent signalling inputs during differentiation, and the underlying molecular basis may offer new drug development targets for treatments of bone formation defect diseases. PMID- 30397975 TI - Recent progress in the emerging role of exosome in hepatocellular carcinoma. AB - Exosomes are small membrane vesicles 50-150 nm in diameter released by a variety of cells, which contain miRNAs, mRNAs and proteins with the potential to regulate signalling pathways in recipient cells. Exosomes deliver nucleic acids and proteins to participate in orchestrating cell-cell communication and microenvironment modulation. In this review, we summarize recent progress in our understanding of the role of exosomes in hepatocellular carcinoma (HCC). This review focuses on recent studies on HCC exosomes, considering biogenesis, cargo and their effects on the development and progression of HCC, including chemoresistance, epithelial-mesenchymal transition, angiogenesis, metastasis and immune response. Finally, we discuss the clinical application of exosomes as a therapeutic agent for HCC. PMID- 30397976 TI - An analysis of issues in the classification and reporting of heroin-related deaths. AB - AIMS: To investigate the extent of variability in the reporting of heroin-related deaths in Victoria, Australia. Additionally, to identify opportunities to improve the accuracy and consistency of heroin-related death reporting by examining variability in the attribution, death certification, classification and coding of heroin-related death cases. METHODS: Heroin-related deaths in Victoria, Australia during a 2-year period (2012-13) were identified using the National Coronial Information System (NCIS) and used as the 'gold standard' measure in this study. Heroin-related death data from the Australian Institute of Health and Welfare (AIHW) and Australian Bureau of Statistics (ABS) were then compared. Differences in the number of deaths reported as well as the classification and coding assigned to the identified heroin-related death cases were investigated by cross referencing these data sets and examining the assigned ICD-10 codes. RESULTS: A total of 243 heroin-related deaths were identified through the NCIS compared with 165 heroin-related deaths reported by the AIHW and assigned the heroin-specific ICD-10 code of T40.1. Forty per cent of all the missed heroin-related death cases resulted from either the attribution of the death to morphine toxicity or with non-specific drug toxicity certification; 30% occurred where the cases had been attributed to heroin but there were irregularities in death certification. Additional missed heroin-related death cases occurred as a result of late initial registration of these deaths to the Registry of Births, Deaths and Marriages, and where these cases were then not assessed by the ABS for classification and coding purposes. CONCLUSIONS: In Victoria, Australia, in 2012 and 2013, the overall number of heroin-related deaths was under-reported by 32% compared with the number of deaths currently identified by the Australian Bureau of Statistics and reported by the Australian Institute of Health and Welfare. PMID- 30397977 TI - Extension for Community Healthcare Outcomes (ECHO) as a tool for continuing medical education on opioid use disorder and comorbidities. PMID- 30397978 TI - Overexpression of ASIC1A in the nucleus accumbens of rats potentiates cocaine seeking behavior. AB - Acid-sensing ion channels (ASICs) are abundantly expressed in the nucleus accumbens core (NAcore), a region of the mesolimbocortical system that has an established role in regulating drug-seeking behavior. Previous work shows that a single dose of cocaine reduced the AMPA-to-NMDA ratio in Asic1a-/- mice, an effect observed after withdrawal in wild-type mice, whereas ASIC1A overexpression in the NAcore of rats decreases cocaine self-administration. However, whether ASIC1A overexpression in the NAcore alters measures of drug-seeking behavior after the self-administration period is unknown. To examine this issue, the ASIC1A subunit was overexpressed in male Sprague-Dawley rats by injecting them with adeno-associated virus, targeted at the NAcore, after completion of 2 weeks of cocaine or food self-administration. After 21 days of homecage abstinence, rats underwent a cue-/context-driven drug/food-seeking test, followed by extinction training and then drug/food-primed, cued, and cued + drug/food-primed reinstatement tests. The results indicate that ASIC1A overexpression in the NAcore enhanced cue-/context-driven cocaine seeking, cocaine-primed reinstatement, and cued + cocaine-primed reinstatement but had no effect on food seeking behavior, indicating a selective effect for ASIC1A in the processes underlying extinction and cocaine-seeking behavior. PMID- 30397979 TI - Total Internal Reflection-Based Extinction Spectroscopy of Single Nanoparticles. AB - Herein we report a reflection-mode total internal reflection microscopy (TIRM) to measure the extinction spectrum of individual dielectric, plasmonic, or light absorbing nanoparticles, and to differentiate absorption and scattering components from the total optical output. These capabilities were enabled via illuminating the sample with evanescent wave of which the lightpath length was comparable with the size of single nanoparticles, leading to a dramatically improved reflectance change (DeltaI/I0 ) up to tens of percent. It was further found that scattering and absorption of light contributed to bright and dark centroids, respectively, in the optical patterns of single nanoparticles, allowing to distinguish scattering and absorption components from the extinction spectrum by the use of an appropriate image processing method. In addition, wide field feature of TIRM enabled the studies on tens of nanoparticles simultaneously with gentle illumination. PMID- 30397980 TI - 24th Chinese Society of Dermatology Annual Meeting Kunming, Yunnan, China. PMID- 30397981 TI - Telomere length, ZNF208 genetic variants and risk of chronic obstructive pulmonary disease in the Hainan Li population. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a disease characterized by airflow limitation. It is not completely reversible and shows progressive development. ZNF208 rs8105767 affects telomere length, although the impact of telomere on COPD is still controversial. In the present study, we aimed to explore the impact of the ZNF208 gene polymorphism on telomere length and also that of telomere length on COPD in the Hainan Li population. METHODS: In total, 270 COPD patients and 288 controls were recruited. Telomere length was measured by a quantitative real-time polymerase chain reaction. Five single nucleotide polymorphisms in ZNF208 were selected and genotyping was performed using MassARRAY software (Agena Bioscience Co. Ltd, San Diego, CA, USA). Differences in telomere length among the subjects with three genotypes of related genes were assessed using analysis of variance. Unconditional logistic regression was used to calculate odds ratios (OR) as the indicator of association between telomere length and COPD risk. RESULTS: Relative telomere length in the COPD group and control group was 0.66 +/- 0.47 and 1.44 +/- 0.89, respectively. We grouped according to a median of 0.8284 for telomere length and observed that the risk of COPD for individuals with a telomere length less than 0.8284 is 2.92 times that for individuals with a telomere length longer than 0.8284 (OR = 2.92, 95% confidence interval = 2.01-4.25, p = 1.91 * 10-8 ). Subjects carrying the G allele of rs2188972 had a longer telomere length. Subjects carrying the carrying the CA genotype of rs8103163 and AC genotype of rs7248488 had a longer telomere length compared to wild-type individuals. CONCLUSIONS: Shorter telomeres increase COPD risk and the ZNF208 polymorphism affects telomere length in COPD patients. PMID- 30397982 TI - Direct In Situ TEM Visualization and Insight into the Facet-Dependent Sintering Behaviors of Gold on TiO2. AB - Preventing sintering of supported nanocatalysts is an important issue in nanocatalysis. A feasible way is to choose a suitable support. However, whether the metal-support interactions promote or prevent the sintering has not been fully identified. Now, completely different sintering behaviors of Au nanoparticles on distinct anatase TiO2 surfaces have been determined by in situ TEM. The full in situ sintering processes of Au nanoparticles were visualized on TiO2 (101) surface, which coupled the Ostwald ripening and particle migration coalescence. In contrast, no sintering of Au on TiO2 anatase (001) surface was observed under the same conditions. This facet-dependent sintering mechanism is fully explained by the density function theory calculations. This work not only offers direct evidence of the important role of supports in the sintering process, but also provides insightful information for the design of sintering resistant nanocatalysts. PMID- 30397983 TI - Association between smoking type and prevalence of atopic dermatitis and asthma in men and women. AB - AIM: This study aimed to examine the association between smoking type and the prevalence of atopic dermatitis and asthma in men and women. BACKGROUND: Cases of allergic diseases have been steadily increasing worldwide. Smoking is associated with serious diseases. Only a few studies have assessed the association between smoking and atopic dermatitis and asthma in adults, and gender difference studies are scarce despite a significant difference in smoking rates. METHODS: We conducted a secondary cross-sectional analysis of 17 886 adults with atopic dermatitis and 17 889 with asthma aged >=19 years, using raw data from the Fifth Korea national Health and Nutrition Examination Survey (2010-2012). RESULTS: The prevalence of atopic dermatitis in men was not associated with active or passive smoking, whereas asthma prevalence in men was associated with indoor passive smoking exposure at home. We found that atopic dermatitis prevalence in women was associated with current smoking status, whereas asthma prevalence in women was associated with the presence of an indoor daily smoker at home and indoor passive smoking exposure at home. CONCLUSION: Asthmatic adults should be informed of the hazards of passive smoking, and women with atopic dermatitis should in particular be dissuaded from smoking. PMID- 30397984 TI - The effect of continuous high versus low dose oral isotretinoin regimens on dermcidin expression in patients with moderate to severe acne vulgaris. AB - The continuous low dose (LD) isotretinoin is frequently used in the treatment regimen for acne vulgaris. However, data about its antimicrobial are lacking. The present study aimed to investigate dermcidin expression and the effects of low and conventional dose isotretinoin on its expression in acne vulgaris patients. Skin dermcidin expression was investigated in 30 patients with moderate-severe acne vulgaris and 15 healthy control subjects using ELISA. 15 patients were given continuous low-dose isotretinoin (20 mg/day) and the other 15 given the conventional high dose (0.5 mg/kg/day). Skin biopsies were taken at the start of the study and 6 months later. Dermcidin was significantly lower in acne vulgaris patients (p < .001). Both isotretinoin regimens significantly raised dermcidin levels compared to pre-treatment values (p < .001). Relapse after 12 months was not statistically different among the two isotretinoin regimens (p = .464). Pretreatment global acne grading system score of 28.6 +/- 6.4 was reduced to 6 +/ 6.1 following isotretinoin treatment (p < .001). Relapse was significantly related to posttreatment dermcidin levels (p = .017). Dermcidin expression is reduced in acne vulgaris. Conventional and LD isotretinoin regimens are associated with increased dermcidin expression. PMID- 30397985 TI - Light-Addressable Ion Sensing for Real-Time Monitoring of Extracellular Potassium. AB - We report here on a light addressable potassium (K+ ) sensor where light illumination of a semiconducting silicon electrode substrate results in a localized activation of the faradaic electrochemistry at the illuminated spot. This allows one, by electrochemical control, to oxidize surface bound ferrocene moieties that in turn trigger K+ transfer from the overlaid K+ -selective film to the solution phase. The resulting voltammetric response is shown to be K+ selective, where peak position is a direct function of K+ activity at the surface of electrode. This concept was used to measure extracellular K+ concentration changes by stimulating living breast cancer cells. The associated decrease of intracellular K+ level was confirmed with a fluorescent K+ indicator. In contrast to light addressable potentiometry, the approach introduced here relies on dynamic electrochemistry and may be performed in tandem with other electrochemical analysis when studying biological events on the electrode. PMID- 30397986 TI - Effects of rumen-protected methionine on milk production in early lactation dairy cattle fed with a diet containing 14.5% crude protein. AB - We evaluated the influence on milk production of feeding early lactation cows a diet that included 14.5% crude protein (CP) and that did not meet methionine (Met) requirements or that met them by supplying rumen-protected Met (RPMet). Thirty-nine multiparous Holstein cows were allocated into two groups. For 15 weeks after calving, each group was fed one of the two total mixed rations, Control (n = 20) or Treatment (n = 19). The Treatment group received added RPMet at 0.034% (8 g/day) of the Control diet on dry matter basis. The adequacies of Met for the Control and Treatment groups were 96% and 106%, respectively, and for other amino acids, >110%. The CP level (14.5%) was 1 percentage point lower than that recommended by the Japanese Feeding Standard (2006). No between-group differences were found in milk yield (40 kg/day), milk composition, plasma profile, rumen fermentation, nitrogen balance, or cow health. Met intake and the amount of rumen-undegradable feed Met were higher in the Treatment group (p < 0.05). Microbial Met and total metabolizable Met did not differ between groups. Supplying RPMet in a 14.5% CP diet during early lactation did not dramatically affect milk production, because the amount of total metabolizable Met was unchanged. PMID- 30397987 TI - Treatment of nail lichen Striatus with Intralesional steroid injection: A case report and literature review. PMID- 30397988 TI - Propagation of Oscillating Chemical Signals through Reaction Networks. AB - Akin to electronic systems that can tune to and process signals of select frequencies, systems/networks of chemical reactions also "propagate" time-varying concentration inputs in a frequency-dependent manner. Whereas signals of low frequencies are transmitted, higher frequency inputs are dampened and converted into steady-concentration outputs. Such behavior is observed in both idealized reaction chains as well as realistic signaling cascades, in the latter case explaining the experimentally observed responses of such cascades to input calcium oscillations. These and other results are supported by numerical simulations within the freely available Kinetix web application we developed to study chemical systems of arbitrary architectures, reaction kinetics, and boundary conditions. PMID- 30397989 TI - Effect of interaction between leucine and acetate on the milk protein synthesis in bovine mammary epithelial cells. AB - The interaction between Leucine (Leu) and acetate affecting milk protein synthesis in the bovine mammary epithelial cells (BMECs), and underlying the molecular mechanisms are not well understood. The objectives of this study were to investigate the effect of Leu, acetate, and their interaction on the expression of genes involved in milk protein synthesis, and JACK2/STAT5, mTOR and AMP-activated protein kinase (AMPK) signaling pathway. The study was a 2 * 6 factorial arrangement with treatments: Leu concentration (0.45 and 1.8 mM) and acetate concentration (0, 4, 6, 8, 10, and 12 mM). The results showed that 1.8 mM Leu or 8-10 mM acetate had positive effect on ATP content, the expression of casein genes, JACK2/STAT5 and phosphorylation of mTOR pathway, but reduced AMPK phosphorylation. Leu at 1.8mM had a positive effect on the up-regulation of acetate on ATP content, the expression of CSN1S1, CSN2, CSN3, and JACK2, the expression and phosphorylation of eukaryotic initiation factor 4E, p70 ribosomal protein S6 kinase-1, and mTOR, but reducing AMPK phosphorylation. The results suggest that acetate, Leu, and their interaction have effect on milk protein synthesis through the JACK2/STAT5, mTOR, and AMPK pathway. Acetate addition up regulated the effect of Leu on milk protein synthesis, and Leu facilitated the up regulation of acetate on milk protein synthesis through these pathways. PMID- 30397990 TI - A Dual-Targeted Organic Photothermal Agent for Enhanced Photothermal Therapy. AB - The development of highly effective anticancer drugs that cause minimal damage to the surrounding normal tissues represents a challenging topic in cancer therapy. Herein, we demonstrate a dual-targeted organic molecule that functions as a photothermal agent via active targeting of tumor tissues and mitochondria for selectively killing cancer cells. The synthesized photothermal agent exhibits high photothermal conversion efficiency, low cytotoxicity and good biological compatibility in photothermal therapy. In vivo experiments show that an excellent tumor inhibitory effect can be achieved with the dual-targeted photothermal agent. PMID- 30397991 TI - Efficient Docking-Migration Strategy for Selective Radical Difluoromethylation of Alkenes. AB - Radical-mediated difunctionalization of alkenes is a powerful tactic for olefin utilization. However, the transformation of unactivated alkenes still remains a formidable challenge. Now a conceptually new docking-migration strategy is presented for the difunctionalization of alkenes with photoredox catalysis. Both activated and unactivated alkenes are suitable substrates. A vast array of functional groups are compatible with the mild reaction conditions. Heteroaryl and difluoromethyl are concomitantly incorporated into alkenes, leading to synthetically valuable products that are readily converted into a variety of fluorine-containing molecules. The protocol provides a kinetic control of stereoselectivity for cycloalkenes to generate the unusual cis-products, and offers an efficient approach for the late-stage functionalization of complex natural products and drug molecules. A portfolio of dual-function reagents are prepared for the elusive radical difunctionalization of alkenes. PMID- 30397992 TI - Carbonylative C-C Bond Activation of Electron-Poor Cyclopropanes: Rhodium Catalyzed (3+1+2) Cycloadditions of Cyclopropylamides. AB - Rh-catalyzed carbonylative C-C bond activation of cyclopropylamides generates configurationally stable rhodacyclopentanones that engage tethered alkenes in (3+1+2) cycloadditions. These studies provide the first examples of multicomponent cycloadditions that proceed through C-C bond activation of "simple" electron poor cyclopropanes. PMID- 30397993 TI - Legal, Regulatory and Ethical Frameworks or Standards for AI and Autonomous Robotic Surgery. AB - BACKGROUND: This paper aims to move the debate forward regarding the potential of AI and autonomous robotic surgery with a particular focus on ethical and legal aspects. METHODS: We conducted a literature search on current and emerging surgical robot technologies, relevant standards and legal systems worldwide. We provide a discussion of unique challenges for robotic surgery faced by proposals made for AI more generally (e.g. Explainable AI) as well as recommendations for developing/improving relevant standards or legal and regulatory frameworks. CONCLUSION: We distinguished three types of robot responsibility by classifying responsibility into: I. Accountability; II. Liability and III. Culpability. The component which produces the least clarity is Culpability, since it is unthinkable in the current state of technology. We envision in the nearer future that, as with autonomous driving, a robot can learn routine tasks which can then be supervised by the surgeon (a doctor-in-the-loop) being in the driving seat. PMID- 30397994 TI - RNA interference of a trehalose-6-phosphate synthase gene reveals its roles in the biosynthesis of chitin and lipids in Heortia vitessoides Moore (Lepidoptera: Crambidae). AB - Trehalose-6-phosphate synthase, an enzyme that hydrolyzes two glucose molecules to yield trehalose, plays a pivotal role in various physiological processes. In this study, we cloned the Trehalose-6-phosphate synthase gene (HvTPS) and investigated its expression patterns in various tissues and developmental stages in Heortia vitessoides Moore (Lepidoptera: Crambidae). HvTPS was highly expressed in the fat body and after pupation or before molting. We knocked down TPS in H. vitessoides by RNA interference and found that 3.0 MUg of dsHvTPS resulted in optimal interference at 24 h and 36 h post-injection and caused a sharp decline in the survival rate during the 5th instar larval-pupal stage and obviously abnormal or lethal phenotypes. Additionally, compared to the controls, TPS activity and trehalose contents were significantly lower and the glucose content was significantly higher 24 h or 36 h after injection with 3.0 MUg of dsHvTPS. Furthermore, the silencing of HvTPS suppressed the expression of six key genes in the chitin biosynthesis pathway and one key gene related to lipid catabolism. The expression levels of two genes associated with lipid biosynthesis were upregulated. These results strongly suggest that HvTPS is essential for the normal growth and development of H. vitessoides and provide a reference for further studies of the utility of key genes involved in chitin and lipid biosynthesis for controlling insect development. This article is protected by copyright. All rights reserved. PMID- 30397996 TI - t-Si64 : A Novel Silicon Allotrope. AB - Utilizing first principle calculations, a novel Si64 silicon allotrope in the I41 /amd space group with tetragonal symmetry (denoted as t-Si64 below) is proposed in this work. In addition, also its structural, anisotropic mechanical, and electronic properties along with its minimum thermal conductivity kappamin were predicted. The mechanical and thermodynamic stability of t-Si64 were evaluated by means of elastic constants and phonon spectra. The electronic band structure indicates that t-Si64 is an indirect band gap semiconductor with a band gap: 0.67 eV (primitive cell) compared to a direct band gap of 0.70 eV with respect to a conventional cell. The minimum thermal conductivity of t-Si64 (0.74 W cm-1 K-1 ) is much smaller than that of diamond silicon (1.13 W cm-1 K-1 ). Therefore, Si Ge alloys in the I41 /amd space group are potential thermoelectric materials. PMID- 30397995 TI - Direct Visualization of Li Dendrite Effect on LiCoO2 Cathode by In Situ TEM. AB - Nonuniform and highly localized Li dendrites are known to cause deleterious and, in many cases, catastrophic effects on the performance of rechargeable Li batteries. However, the mechanisms of cathode failures upon contact with Li metal are far from clear. In this study, using in situ transmission electron microscopy, the interaction of Li metal with well-defined, epitaxial thin films of LiCoO2 , the most widely used cathode material, is directly visualized at an atomic scale. It is shown that a spontaneous and prompt chemical reaction is triggered once Li contact is made, leading to expansion and pulverization of LiCoO2 and ending with the final reaction products of Li2 O and Co metal. A topotactic phase transition is identified close to the reaction front, resulting in the formation of CoO as a metastable intermediate. Dynamic structural and chemical imaging, in combination with ab initio simulations, reveal that a high density of grain and antiphase boundaries is formed at the reaction front, which are critical for enabling the short-range topotactic reactions and long-range Li propagation. The fundamental insights are of general importance in mitigating Li dendrites related issues and guiding the design principle for more robust energy materials. PMID- 30397997 TI - Childhood-onset Takayasu arteritis: A 15-year experience from a tertiary referral center. AB - AIM: To describe clinical manifestations, angiographic findings, treatment, activity and damage of our Takayasu arteritis patients. METHOD: The patients who met European League Against Rheumatism/Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society classification criteria for childhood-onset Takayasu arteritis were reviewed in a retrospective longitudinal manner from 2002 to 2017. Extent of the disease was assessed by Disease Extent Index for Takayasu Arteritis (DEI.Tak), activity by Pediatric Vasculitis Activity Score and Indian Takayasu's Arteritis Activity Score (ITAS 2010) and damage by Pediatric Vasculitis Damage Index and Takayasu Arteritis Damage Score (TADS). RESULTS: Sixteen subjects (75% female) with a median disease duration of 3.1 years were enrolled in this study. While the median age at disease onset was 12.1 years, there was only a 2.5 months diagnostic delay. Treatment regime included corticosteroids (100%), which were combined with azathioprine or methotrexate in 93.8% and 37.5% of the subjects, respectively. Severe and refractory cases were treated with cyclophosphamide (62.5%) and subsequently with tocilizumab (37.5%). Seven patients (43.8%) required either percutaneous endovascular intervention or bypass for severe disease refractory to medications. The correlation of the activity and damage scores with each other was fairly good. Damage was found to be associated only with high disease activity and extensive disease at disease onset, but not with other parameters. CONCLUSION: Despite high usage rates of aggressive immunosuppressive therapy and biologic agents, almost half of the patients underwent interventional procedures. When medications failed, endovascular and surgical interventions were of great importance to avoid end-organ ischemia. The performance of the new activity (DEI.Tak and ITAS2010) and damage indices (TADS) seems satisfactory. PMID- 30397998 TI - High prevalence and correlates of osteoporosis in men aged 50 years and over: A nationwide osteoporosis survey in Taiwan. AB - AIMS: Osteoporosis is one of the consequences of aging, and it remains underdiagnosed and undertreated; this study aimed to present the characteristics and prevalence of osteoporosis in elderly men by conducting a nationwide survey in Taiwan. METHODS: The participants were enrolled between 2008 and 2011, and bone mineral density (BMD) was measured via dual-energy X-ray absorptiometry for the hip (total), lumbar spine (L1-4), and femoral neck (FN). Patients with rheumatoid arthritis, female patients, and those using steroids were excluded. Osteoporosis was defined as a T-score at the FN of <=-2.5. RESULTS: This study included 3734 men of mean age 70.0 +/- 9.3 years, accounting for the prevalence of osteoporosis at 9.7%. Participants with osteoporosis had a significantly older age, lower body weight, shorter height and more previous fractures than those without osteoporosis. The mean BMD at FN was 0.534 +/- 0.056 and 0.791 +/- 0.115 (g/cm2 ) in participants with and without osteoporosis, respectively (P < 0.001). The FN and hip (total) BMD showed a significant negative correlation with age (r = -0.234, P < 0.001) and (r = -0.003, P < 0.001), respectively, but not at L1-4 (r = 0.00, P = 0.540). A history of fracture is the most important risk factor associated with male osteoporosis (odds ratio, 2.50; 95% CI, 1.49-4.21; P = 0.006). CONCLUSIONS: The associated factors for male osteoporosis are aging, lower body weight, and a history of fracture; the BMDs at FN and hip (total), but not L1-4, are inversely correlated with age. We recommend that BMD at the proximal femur be the preferred site to evaluate osteoporosis for elderly male subjects. PMID- 30397999 TI - Decision-making styles, anxiety levels, and critical thinking levels of nurses. PMID- 30398000 TI - 2D Crystals in Three Dimensions: Electronic Decoupling of Single-Layered Platelets in Colloidal Nanoparticles. AB - 2D crystals, single sheets of layered materials, often show distinct properties desired for optoelectronic applications, such as larger and direct band gaps, valley- and spin-orbit effects. Being atomically thin, the low amount of material is a bottleneck in photophysical and photochemical applications. Here, the formation of stacks of 2D crystals intercalated with small surfactant molecules is proposed. It is shown, using first principles calculations, that the very short surfactant methyl amine electronically decouples the layers. The indirect direct band gap transition characteristic for Group 6 transition metal dichalcogenides is demonstrated experimentally by observing the emergence of a strong photoluminescence signal for ethoxide-intercalated WSe2 and MoSe2 multilayered nanoparticles with lateral size of about 10 nm and beyond. The proposed hybrid materials offer the highest possible density of the 2D crystals with electronic properties typical of monolayers. Variation of the surfactant's chemical potential allows fine-tuning of electronic properties and potentially elimination of trap states caused by defects. PMID- 30398001 TI - Elevated expression of miR-21 and miR-155 in peripheral blood mononuclear cells as potential biomarkers for lupus nephritis. AB - AIM: Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE). There is a great interest in using microRNAs (miRNAs) as diagnostic and prognostic biomarkers in autoimmune diseases. MATERIALS AND METHODS: This study evaluated miR-16, miR-21, miR-141, miR-146a, and miR-155 expression levels in peripheral blood mononuclear cells (PBMCs) of 55 female SLE patients with absent, inactive, or active nephritis, and 30 healthy controls (HCs) using quantitative polymerase chain reaction. RESULTS: MiR-21 and miR-155 levels were significantly greater in the active nephritis group than in the absent, inactive or HC groups. Moreover, receiver operating characteristic and logistic regression analyses revealed miR-21 and miR-155 were significant risk factors for LN. CONCLUSION: Overexpression of miR-21 and miR-155 in PBMCs may participate in LN pathophysiology and these miRNAs could be used as biomarkers for the condition. PMID- 30398002 TI - Classification of diagnostic subcategories for obesity and diabetes based on eating patterns. AB - AIM: To investigate whether eating patterns of specific food groups can be used to predict and classify Mexican adults who have been diagnosed as having obesity, diabetes or both, when compared to those without a diagnosis. Additionally, we aim to show the benefit of data mining techniques in nutritional studies. METHODS: Statistical analysis of self-reported eating patterns based on designated food groups is conducted. Predictive models for health status based on dietary patterns are built using a naive Bayes classifier. RESULTS: Clear patterns emerge in the model building where adults are categorised as having obesity, diabetes or both. The model for diabetics showed the greatest degree of predictability, producing sensitivity results 2.4 times higher than the average, using score decile testing. The models for people with obesity and for those with both obesity and diabetes both reported sensitivity doubling the average. Coverage also showed greatest response for the diabetic model, the first decile containing 24% of all diabetics. CONCLUSIONS: Classifier models using dietary habits as inputs succeed in subcategorising Mexican adults based on health status. Diabetics are associated with a very different, and more appropriate dietary pattern (significantly less sugar consumption) for their condition, relative to the non-diagnosed group. Adults with obesity are also associated with a very different, but inappropriate (higher overall consumption), dietary pattern. We hypothesise that obesity, unlike diabetes, is not seen as a sufficiently serious condition, leading to an inadequate response to the diagnosis. Furthermore, data mining techniques can provide new results in nutritional studies. PMID- 30398003 TI - Anti-TIF1gamma antibody and the expression of TIF1gamma in idiopathic inflammatory myopathies. AB - OBJECTIVE: Anti-transcriptional intermediary factor 1 (TIF1) antibody is associated with idiopathic inflammatory myopathies (IIMs). The aim of this study was to investigate the expression of TIF1s in IIMs. METHOD: TIF1alpha, beta or gamma expression in the skin and muscle of patients and controls was studied by immunohistochemistry. Serum myositis-specific autoantibodies were detected by immunoblot. RESULTS: TIF1alpha was expressed in the skin of most dermatomyositis (DM) patients but not in the controls (80% vs 0%, P < 0.001). TIF1beta was expressed in all tissues of patients and controls. TIF1gamma was expressed in the muscle of DM patients compared to controls (42.1% vs 0%, P = 0.039) and associated with tubuloreticular bodies (P = 0.003). Anti-TIF1gamma was related with TIF1gamma expression in the muscle (P = 0.042). CONCLUSION: TIF1alpha expression in the skin and TIF1gamma in the muscle of DM was increased compared to controls. TIF1gamma expression in the muscle of IIMs was related to anti TIF1gamma antibody. PMID- 30398004 TI - An evaluation of depression, anxiety and fatigue in patients with Behcet's disease. AB - OBJECTIVES: Behcet's disease (BD) is a type of systemic vasculitis and inflammatory disease of unknown etiology, which is associated with fatigue and lower quality of life (QoL). The aim of this study was to assess the relationship between Behcet's Disease Current Activity Form (BDCAF) and Behcet's Disease Quality of Life (BDQoL), depression, anxiety and fatigue in Behcet's disease. METHODS: We conducted a cross-sectional study of 155 BD patients and 107 healthy subjects in a single center over a 1 year period. All participants completed the Multidimensional Assessment of Fatigue (MAF) questionnaire, and the Hospital Anxiety and Depression (HADS) scale. Disease activity in the BD patients was assessed using the BDCAF, and the physician's global assessment (PGA). BD patients also completed the BDQoL questionnaire. RESULTS: There was no significant difference in age and gender between the groups. BD patients had significantly higher HADS-anxiety (HADS-A), HADS-depression (HADS-D) and MAF scores than the healthy control group (P < 0.05). BD patients with active disease had significantly higher MAF and HADS-A scores compared to inactive BD patients (P < 0.05). MAF scores showed positive correlations with HADS-A, HADS-D, BDCAF and BDQoL. CONCLUSIONS: Fatigue and anxiety are common in clinically active BD patients compared with healthy control subjects and inactive BD patients. PMID- 30398005 TI - Treatment of deep vein thrombosis in a patient with Behcet syndrome using ultrasound-accelerated catheter-directed thrombolysis. PMID- 30398006 TI - Cross-cultural adaptation and validation of the Korean Version of the Functional Index for Hand Osteoarthritis (FIHOA). AB - AIM: This study aimed to translate the Functional Index for Hand Osteoarthritis (FIHOA) into Korean, and establish its reliability and validity in Korean patients with hand osteoarthritis (OA). METHOD: The FIHOA was translated into Korean (K-FIHOA) following cross-cultural adaptation guidelines. The K-FIHOA was pretested on 40 patients with hand OA. The adapted K-FIHOA was then administered to 100 consecutive hand OA patients together with the modified Health Assessment Questionnaire (mHAQ) and visual analog scale (VAS) for hand pain. The test-retest reliability of each item and total scores were assessed using Spearman's correlation coefficient and intraclass correlation coefficient (ICC). The internal consistency reliability was evaluated as Cronbach's alpha. The external construct validity was assessed using the correlation between K-FIHOA, mHAQ and hand pain VAS. RESULTS: The test-retest reliability for the total score was strong (r = 0.87 and ICC = 0.83). Cronbach's alpha was also high (0.88), which suggests that there is strong internal coherence in the test items. We identified significant correlations between K-FIHOA and mHAQ (r = 0.52, P < 0.01), mHAQ hand function score, (r = 0.57, P < 0.01) and hand pain VAS (r = 0.53, P < 0.01). CONCLUSION: The K-FIHOA is a reliable and valid instrument for evaluating functional disability in Korean hand OA patients. PMID- 30398007 TI - Group therapy in a cohort study of Egyptian patients with rheumatoid arthritis. AB - INTRODUCTION: Rheumatoid arthritis (RA) affects many individuals' issues beyond those which are medically treated. OBJECTIVE: To study the impact of group therapy sessions on disease activity and functional abilities in RA patients. METHODS: One hundred and two patients with RA were divided into two groups; group A included 52 RA patients receiving their regular medical care in addition to group therapy sessions (cases); and group B included 50 RA patients receiving their regular medical care only (controls). Demographic, clinical and serological data were prospectively evaluated. All patients were assessed by using the Disease Activity Score of 28 joints (DAS28) and modified Health Assessment Questionnaire - Disability Index (mHAQ-DI), Hospital Anxiety and Depression scale (HAD) before, during and after group therapy sessions. RESULTS: Group A showed a statistically significant improvement in DAS28 at the 3rd and 6th months (P < 0.01 and P < 0.04) respectively, significant improvement in mHAQ score at the 3rd and 6th months (P < 0.02 and P < 0.00) respectively, and significant improvement in HAD scale for depression and anxiety (P <0.001). In group A there was no significant correlation between DAS28 and both anxiety or depression (P = 0.6, r = 0.5 and P = 0.06, r = 0.06) respectively, but on correlating mHAQ to both anxiety and depression, there was a statistically significant positive correlation at 6 months (P = 0.01, r = 0.3 and P = 0.03, r = 0.3) respectively. CONCLUSION: Group therapy sessions improve disease outcome, functional disability and psychological well-being in RA patients. PMID- 30398008 TI - Complex interventions of abdominal aorta and its branches in children with Takayasu arteritis: Clinical experience from a tertiary care center in north-west India. AB - AIM: To report our experience on complex percutaneous interventions of the abdominal aorta and its branches in six children with Takayasu arteritis (TA). METHODS: A review of records of children with TA, who underwent percutaneous interventions of the abdominal aorta and its major branches. RESULTS: In this analysis, we included six children with TA who underwent intervention of the abdominal aorta and its major branches. The endovascular interventions were performed mostly for treatment-resistant renovascular hypertension and mesentery artery ischemia. Mean age (+/-SD) at time of intervention was 10.6 +/- 2.5 years (four boys and two girls). Percutaneous interventions included stenting of abdominal aorta (n = 2), renal arteries (n = 4), mesenteric arteries (n = 2), repeat stenting for renal artery in-stent restenosis (n = 1), and renal autotransplantation (n = 4). All 13 interventions were successful and enabled us to obtain good control of blood pressure. CONCLUSION: We hereby report six children with TA who were successfully managed with complex percutaneous interventions of the abdominal aorta and its major branches. Balloon dilatation and stent placement constitutes the mainstay of management of TA with stenosis of the large vessels. PMID- 30398009 TI - Anti-HCV for treatment of HCV-positive psoriatic patients: A promising therapy. AB - Psoriasis is a chronic inflammatory disease that has been associated to liver disease, includinghepatitis C virus infection. TNF-alpha is a key cytokine for both hepatitis C progression and psoriasis. HCV high-prevalence countries are likely to show clear association of the two conditions. We reviewed the current literature on the effect of anti-HCV therapy on the course of psoriasis in patient affected with both diseases. PMID- 30398010 TI - Musculoskeletal symptoms and disorders among 350 garment workers in Bangladesh: A cross-sectional pilot study. AB - OBJECTIVE: To study the prevalence of musculoskeletal (MSK) symptoms and disorders among garment workers in Bangladesh, to look for possible relationships between pain location and type of work performed and to estimate the prevalence of rheumatological diagnoses. METHODS: A cross-sectional pilot study among 350 garment workers using the COPCORD (Community Oriented Program for Control of Rheumatic Disorders) methodology. Subjects with musculoskeletal pain were examined by rheumatologists for rheumatological diagnosis. The workers were classified into cutting, sewing, finishing and quality control operators. RESULTS: Most of the workers were aged below 35 years (88%) and females (82.9%) and the majority had only primary education (74.6%). The prevalence of MSK pain within 7 days of the interview was 77.1%, a much higher figure than in the general population. The most affected sites were: shoulder (17.9%), lower back (15.2%), neck (13.8%) and knee (10.8%). Multiple regional pain was the commonest finding in 173 of 350 workers. In this pilot study rheumatoid arthritis was diagnosed in 0.9%, undifferentiated arthritis in 1.1%, nonspecific low back pain in 4.6%, soft tissue rheumatism in 3.7%, osteoarthritis in 0.9% and lumbar spondylosis in 1.1%, figures comparable with those observed in the general population; spondyloarthropathy was seen more often, in 1.42%, possibly explained by the small numbers. CONCLUSIONS: Musculoskeletal pains are common among garment workers of Bangladesh and may cause morbidity, disability, and work loss. Our findings may be important to plan ergonomic measures preventing complaints and may be of interest for international companies ordering garments in Bangladesh. PMID- 30398011 TI - Polyarticular evolution and late-onset psoriasis may be associated with cardiovascular disease in psoriatic arthritis. AB - BACKGROUND AND AIMS: Patients with psoriatic arthritis (PsA) have high prevalence of cardiovascular risk factors (CVRF), and they also show higher rates of cardiovascular disease (CVD). We aimed to corroborate these findings and identify factors associated with these events in our clinical setting. METHODS: This cross sectional study included 340 consecutive patients seen in a tertiary care hospital. The prevalence of CVRF was compared to that of 600 outpatients without inflammatory conditions. To analyze CVD-associated factors, odds ratio (OR) values were calculated by conditional logistic regression analysis. Significant variables in the univariate analysis were then introduced in a multivariate analysis with a backward stepwise approach. RESULTS: Patients with psoriatic arthritis had higher frequencies of hypertension (36% vs 23%, OR 2.4, 95%CI: 1.6 2.7, P < 0.0001), diabetes (13.8% vs 5%, OR 2.8, 95%CI: 1.7-4.3, P < 0.0001), obesity (35% vs 22%, OR 2.1, 95%CI: 1.5-2.8, P < 0.0001) and tobacco use (26% vs 21%, OR 1.4, 95%CI: 1.0-1.8, P < 0.05). More PsA patients had CVD compared to non inflammatory patients (9.4% vs 5.8%, OR 1.68, 95%CI: 1.02-2.76, P < 0.05). Independent CVD-associated factors were: an age of onset of psoriasis >40 years (OR 3.4, 95%CI: 1.1-10.0, P < 0.05), a high number of swollen joints during evolution (OR 2.9, 95%CI: 1.1-8.0, P < 0.05), hypertension (OR 5.3, 95%CI: 1.6 17.6, P < 0.01) and dyslipidemia (OR 2.6, 95%CI: 1.0-7.2, P < 0.05). CONCLUSIONS: Cardiovascular risk should be carefully evaluated in patients with PsA whose disease presents a high inflammatory burden and in those with late-onset psoriasis. PMID- 30398012 TI - Antineutrophilic cytoplasmic antibody-associated vasculitis with and without renal involvement: C3 contributes to prognosis, but renal involvement does not. AB - OBJECTIVES: We investigated the impact of renal involvement at diagnosis on the prognosis of patients with antineutrophilic cytoplasmic antibody (ANCA) associated vasculitis (AAV). METHODS: The relationship between renal involvement at diagnosis, clinical variables at diagnosis, and prognosis (including relapse episodes, initiation of dialysis, and death) was examined in 101 Japanese patients with AAV. RESULTS: Sixty-eight patients had renal involvement at diagnosis. The renal-involvement patients had significantly higher ages at diagnosis, significantly lower hemoglobin levels, and significantly lower platelet levels. They had significantly lower C3 levels, but showed no significant difference in C4 levels. Overall survival rate was significantly worse in patients with than in patients without renal involvement (P = 0.003, log rank test). Multivariable analysis using a logistic regression model demonstrated that C3 contributed to dialysis initiation: odds ratio (per 10 mg/dL of C3): 0.68; range: 0.49-0.90; P = 0.007. A Cox proportional hazard model revealed that the C3 level and age at diagnosis contributed significantly to overall survival: hazard ratio (per 10 mg/dL of C3) 0.81, range 0.69-0.95, P = 0.011; 1.08, 1.02 1.15, P = 0.013, respectively. Renal involvement did not contribute significantly to overall survival. Patients with C3 levels >=100 mg/dL had a better survival rate than patients with C3 levels <100 mg/dL. CONCLUSIONS: Although patients with renal involvement had higher ages, lower C3 levels at diagnosis, and poorer prognoses, multivariable analysis demonstrated that the C3 level and age at diagnosis, but not renal involvement, contributed significantly to overall survival. Our results demonstrate the relationship between C3 hidden behind renal involvement and AAV prognosis. PMID- 30398013 TI - Development of the Asia Pacific Lupus Collaboration cohort. AB - AIM: The aim of this manuscript is to describe the development of the Asia Pacific Lupus Collaboration (APLC) cohort. METHOD: The APLC cohort is an ongoing, prospective longitudinal cohort. Adult patients who meet either the American College of Rheumatology (ACR) Modified Classification Criteria for systemic lupus erythematosus (SLE), or the Systemic Lupus International Collaborating Clinics (SLICC) Classification Criteria, and provide informed consent are recruited into the cohort. Patients are routinely followed up at 3- to 6-monthly intervals. Information on demographics, clinical manifestations, treatment, pathology results, outcomes, and patient-reported quality of life (Short-form 36 version 2) are collected using a standardized case report form. Each site is responsible for obtaining local ethics and governance approval, patient recruitment, data collection, and data transfer into a centralized APLC database. RESULTS: The latest APLC cohort comprises 2160 patients with >12 000 visits from Australia, China, Hong Kong, Indonesia, Japan, Malaysia, Philippines, Singapore, Taiwan and Thailand. The APLC has proposed the Lupus Low Disease Activity State (LLDAS) as a treat-to-target (T2T) endpoint, and reported several retrospective and cross sectional analyses consistent with the validity of LLDAS. Longitudinal validation of LLDAS as a T2T endpoint is currently underway. CONCLUSION: The APLC cohort is one of the largest contemporary SLE patient cohorts in the world. It is the only cohort with substantial representation of Asian patients. This cohort represents a unique resource for future clinical research including evaluation of other endpoints and quality of care. PMID- 30398014 TI - Temporal trends in optimal diabetic care and complications of elderly type 2 diabetes patients in Thailand: A nationwide study. AB - BACKGROUND: This study aimed to assess the nationwide trends in optimal diabetic care and complications of elderly type 2 diabetes mellitus (T2DM) patients over a 6-year period in Thailand. METHODS: T2DM patients aged 65 years or older who received medical care at public hospitals in Thailand from 2010 to 2015 were included. The optimal T2DM care in elderly patients was defined as (1) blood pressure (BP) < 140/90, (2) hemoglobin A1C (HbA1c) < 7%, (3) low-density lipoprotein cholesterol (LDL-C) < 100 mg/dL, (4) use of antiplatelet medications, and (5) use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) in hypertensive patients. T2DM treatment-related complications included hospital admissions due to dysglycemia. RESULTS: A total of 54 295 elderly T2DM patients were enrolled in this study. From 2010 to 2015, there was an increasing trend in the achievement of BP control and use of antiplatelet medications (P for trend < 0.01), whereas there was a decreasing trend in the achievement of HbA1c and LDL-C control among elderly T2DM patients (P for trend < 0.001). There was an increasing trend in the use of ACEI/ARB among elderly T2DM patients with hypertension (P for trend < 0.001). Hospital admissions due to dysglycemia decreased over the study period (P for trend < 0.001). CONCLUSION: There has been a trend change for diabetic care among elderly T2DM patients in Thailand. Further studies are needed to assess the impact on patient outcomes. PMID- 30398015 TI - Rituximab-associated posterior reversible encephalopathy syndrome. PMID- 30398016 TI - Muscle mass measures and incident osteoporosis in a large cohort of postmenopausal women. AB - BACKGROUND: Despite several muscle mass measures being used in the current definitions of sarcopenia, their usefulness is uncertain because of limited data on their association with health outcomes. The aim of the study was to compare the performance of different muscle mass measures for predicting incident osteoporosis in postmenopausal women. METHODS: This study included data from 149 166 participants (aged 60.3 +/- 5.5 years) as part of the UK Biobank cohort. Body composition was assessed using bioelectrical impedance. The muscle mass measures included were total body skeletal muscle mass (SMM) and appendicular SMM (aSMM) divided by height squared (ht2 ), derived residuals, SMM, SMM adjusted for body mass (SMM/bm * 100), and aSMM normalized for body mass index (aSMM/BMI). Diagnoses of the events were confirmed by primary care physicians and coded according to the World Health Organization's International Classification of Diseases 10th Revision (ICD-10: M80-M82). RESULTS: Over a median follow-up of 6.75 (5th to 95th percentile interval, 1.53 to 8.37) years, 394 newly diagnosed cases of osteoporosis occurred, with 40 (10.2%) cases being associated with a pathological fracture. SMM/ht2 , aSMM/ht2 residual, and SMM were lower in postmenopausal women with osteoporosis compared with women without (all P < 0.0001), while SMM/bm * 100 (P = 0.003), but not aSMM/BMI (P = 0.59), was higher in the osteoporosis group. The unadjusted rates of osteoporosis increased with decreasing quintiles for SMM/ht2 , aSMM/ht2 , residuals, and SMM (all P trend <0.0001), while the incidence of osteoporosis increased with increasing SMM/bm * 100 (P trend =0.001), but not for aSMM/BMI (P = 0.45). After minimally adjusting for age and after full adjustment, SMM/ht2 , aSMM/ht2 , and SMM were the only measure that consistently predicted osteoporosis in the total group of postmenopausal women [hazard ratio (HR) 0.65-0.67, all P <= 0.0001], in lean women (HR 0.62-0.68; all P <= 0.001), and women with increased adiposity (HR 0.64 0.68; all P <= 0.01). In fully adjusted models, the changes in the R2 statistic were 13.4%, 11.6%, and 15.3% for the SMM/ht2 (aSMM/ht2 ), residual, and SMM, but only 4.9% and 1.3% for SMM/bm * 100 and aSMM/BMI. CONCLUSIONS: Muscle mass measures adjusted for height only (SMM/ht2 , aSMM/ht2 ) appear to be better muscle-relevant risk factors for incident osteoporosis in postmenopausal women, including when stratified into lean participants and participants with increased adiposity. PMID- 30398017 TI - Surfactant Free Delivery of Docetaxel by Poly[(R)-3-hydroxybutyrate-(R)-3 hydroxyhexanoate]-Based Polymeric Micelles for Effective Melanoma Treatments. AB - Docetaxel (DTX) is a new semisynthetic chemical in the taxoid family and serves a wide spectrum of chemotherapeutics. Current commercial formulation of DTX is based on the addition of the nonionic surfactants (i.e., ethanol and Tween 80), which are reported to cause severe hemolysis, hypersensitivity reactions, or neurotoxic toxicity and greatly hinders patient tolerance or compliance. In this report, a novel low-toxic, biodegradable, and amphiphilic poly[(R)-3 hydroxybutyrate-(R)-3-hydroxyhexanoate] (PHBHx)-based polyurethane (a copolymer made of hydrophobic PHBHx with biocompatible D-3-hydroxybutyric acid as degradation product, thermosensitive polypropylene glycol (PPG), and hydrophilic polyethylene glycol (PEG) segments) with nanosized micelle formation ability to encapsulate DTX, as a surfactant free formulation, is reported. Interestingly, this DTX-loaded poly(PHBHx/PEG/PPG urethane) micelle formulation with >90% drug loading efficiency shows significantly improved DTX solubility in aqueous medium, reduced hemolysis for better blood compatibility, and increased drug uptake in A375 melanoma cells, which provides the possibility of systematic delivery of DTX. As a proof-of-concept, an A375 melanoma xenograft mouse model is established to verify the therapeutic effect of this DTX-loaded poly(PHBHx/PEG/PPG urethane) micelle formulation, indicating the promising application of PHBHx-based polymeric nanosized micelle as a surfactant free formulation of chemotherapeutics which might greatly be beneficial for controllable delivery of pharmaceutics and cancer therapy. PMID- 30398018 TI - P in the right place: Revisiting the evidential value of P-values. AB - P-values are often calculated when testing hypotheses in quantitative settings, and low P-values are typically used as evidential measures to support research findings in published medical research. This article reviews old and new arguments questioning the evidential value of P-values. Critiques of the P-value include that it is confounded, fickle, and overestimates the evidence against the null. P-values may turn out falsely low in studies due to random or systematic errors. Even correctly low P-values do not logically provide support to any hypothesis. Recent studies show low replication rates of significant findings, questioning the dependability of published low P-values. P-values are poor indicators in support of scientific propositions. P-values must be inferred by a thorough understanding of the study's question, design, and conduct. Null hypothesis significance testing will likely remain an important method in quantitative analysis but may be complemented with other statistical techniques that more straightforwardly address the size and precision of an effect or the plausibility that a hypothesis is true. PMID- 30398020 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 46/2018. PMID- 30398019 TI - Mortality in autoimmune rheumatic diseases with anti-Ro/SSA antibody in Korea: Single center-based retrospective study. AB - AIM: The clinical importance of the anti-Ro antibody has not been completely understood. This study investigated identification of the association between mortality and clinical features in patients with autoimmune rheumatic diseases and detectable anti-Ro antibody titers. METHODS: We retrospectively analyzed a total of 336 patients with autoimmune rheumatic diseases and positive anti-Ro antibody titers from January 2012 to January 2015. Clinical manifestations and other autoantibodies detected during the follow-up period were identified. Cumulative survival rates were assessed by Kaplan-Meier analysis. Differences between survival curves for each risk factor were analyzed by log-rank test. The relative risk of mortality was assessed using standardized mortality ratios (SMRs). RESULTS: There was no difference in the mortality rates of patients with autoimmune rheumatic diseases with or without detectable anti-Ro antibody (SMR: 1.373, 95% CI: 0.539-2.791). Six patients (4 with systemic lupus erythematosus [SLE] and two with Sjogren's syndrome [SS]) died during the follow-up period. In the whole study population, the mortality rate of patients with lymphopenia was higher than those without lymphopenia (P = 0.023). In a sub-group of patients with both SLE and SS, Kaplan-Meier analysis showed that lymphopenia and interstitial lung disease were associated with increased mortality (P = 0.024 and P = 0.023, respectively). CONCLUSION: This study demonstrated that presence of the anti-Ro antibody was not associated with increased mortality in patients with autoimmune rheumatic disease. Conversely, we found that lymphopenia was independently associated with mortality in patients with autoimmune rheumatic disease. PMID- 30398021 TI - Corrigendum: Structural Revisions of a Class of Natural Products: Scaffolds of Aglycon Analogues of Fusicoccins and Cotylenins Isolated from Fungi. PMID- 30398022 TI - Corrigendum: Unraveling the Mechanism for the Sharp-Tip Enhanced Electrocatalytic Carbon Dioxide Reduction: The Kinetics Decide. PMID- 30398023 TI - Corrigendum: Palladium-Catalyzed Synthesis of Heteroarene-Fused Cyclooctatetraenes through Dehydrogenative Cyclodimerization. PMID- 30398024 TI - Corrigendum: 7-Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir. PMID- 30398025 TI - Prior fracture and refracture among patients admitted with hip fracture: Data from a regional hip fracture registry in Sri Lanka. AB - AIM: Fragility hip fracture has become a major global health concern. Data related to recurrent fragility fractures are sparse in the South Asian region. METHOD: We assessed the prevalence of prior fragility fracture among patients admitted with new hip fracture to a tertiary care hospital in southern Sri Lanka. Also the incidence of refracture was assessed among hip fracture survivors followed up for 24 months after discharge. RESULTS: Three hundred and nine patients with incident hip fracture were admitted during the study period (June 2014-February 2015) and 11 patients died while in the ward. We detected previous fracture in the contralateral hip in eight patients, while two others had distal radius fracture and one patient clinical vertebral fracture (rate = 3.6%). During the follow up two patients developed fractures in the contralateral hip while either clinical vertebral or distal forearm fractures were not detected (refracture rate = 0.004/person years). CONCLUSION: This analysis based on a regional hip fracture registry shows a low prevalence of prior fracture among patients admitted with incident hip fracture and a low rate of refracture among survivors. More studies are needed to assess whether there are geographical variations in the prevalence of prior fracture or refracture among patients with incident hip fracture. PMID- 30398026 TI - Preparation of Ordered Mesoporous Au using Double Gyroid Mesoporous Silica KIT-6 via a Seed-Mediated Growth Process. AB - Ordered mesoporous Au was prepared using double gyroid (cubic Ia-3d) mesoporous silica KIT-6 as a template. The Au frameworks were formed within the template via a seed-mediated growth process. Au nanoparticles were initially prepared as seeds within the mesopores, and subsequently, they were grown under mild and controlled reducing conditions. The transmission electron micrographs and scanning electron micrographs of mesoporous Au after the removal of the template revealed the formation of mesoporous Au replicas. The small-angle X-ray scattering pattern of mesoporous Au reveals that the obtained mesoporous Au has a cubic I41 32 mesostructure, which is different from that of the original template, implying that Au was deposited within only one mesochannel of the two interconnected ones. The seed-mediated growth process is a key factor in the successful formation of ordered mesoporous Au using a mesoporous silica template. Our preparative method can serve as a guide for further development of synthetic and materials chemistry of mesoporous Au. PMID- 30398027 TI - Conjoint Removal of Hip Screw-Femur Head during Hip Replacement after Previous Dynamic Hip Screw Fixation. AB - The purpose of this study was to demonstrate the reduced chances of iatrogenic femoral neck fracture while removing the Richard's screw using the dynamic hip screw-femur head conjoint removal technique. This retrospective cohort study analyzed 16 hips operated on with total hip arthroplasty from March 2010 to February 2015. All cases were previously treated with dynamic hip screws (DHS) for proximal femur fractures. The age of the patients ranged from 20 to 75 years. We used uncemented sockets in 15 patients and cemented sockets in 1 patient. We used conical fluted straight stems in 9 cases, ML (Mediolateral) tapered stems in 5 patients and CLS (Cementless Spotorno) stems in 2 patients. The head of the femur was removed together with the attached Richard's screw after taking a neck cut during hip replacement after previous dynamic hip screw fixation. At 2-year follow-up, there was a statistically significant improvement in the Harris hip score: from a mean preoperative score of 35 +/- 7.975 to a mean postoperative score of 89.38 +/- 4.870 (P < 0.001). Stem sinking and Type AL (Vancouver classification for periprosthetic fracture) periprosthetic fracture in 1 patient with a tapered stem was noted. Good acetabular inclination was achieved in all cases. At 2-year follow-up, all patients were able to carry out their daily activities. This is a novel technique with the advantage of avoiding iatrogenic femoral neck fracture in an osteoporotic bone. PMID- 30398029 TI - Trans-repression of NFkappaB pathway mediated by PPARgamma improves vascular endothelium insulin resistance. AB - Previous study has shown that thiazolidinediones (TZDs) improved endothelium insulin resistance (IR) induced by high glucose concentration (HG)/hyperglycaemia through a PPARgamma-dependent-NFkappaB trans-repression mechanism. However, it is unclear, whether changes in PPARgamma expression affect the endothelium IR and what the underlying mechanism is. In the present study, we aimed to address this issue. HG-treated human umbilical vascular endothelial cells (HUVEC) were transfected by either PPARgamma-overexpressing (Ad-PPARgamma) or PPARgamma-shRNA containing (Ad-PPARgamma-shRNA) adenoviral vectors. Likewise, the rats fed by high-fat diet (HFD) were infected by intravenous administration of Ad-PPARgamma or Ad-PPARgamma-shRNA. The levels of nitric oxide (NO), endothelin-1 (ET-1) and cytokines (TNFalpha, IL-6, sICAM-1 and sVCAM-1) and the expression levels of PPARgamma, eNOS, AKT, p-AKT, IKKalpha/beta and p-IKKalpha/beta and IkappaBalpha were examined; and the interaction between PPARgamma and NFkappaB-P65 as well as vascular function were evaluated. Our present results showed that overexpression of PPARgamma notably increased the levels of NO, eNOS, p-AKT and IkappaBalpha as well as the interaction of PPARgamma and NFkappaB-P65, and decreased the levels of ET-1, p-IKKalpha/beta, TNFalpha, IL-6, sICAM-1 and sVCAM-1. In contrast, down expression of PPARgamma displayed the opposite effects. The results demonstrate that the overexpression of PPARgamma improves while the down-expression worsens the endothelium IR via a PPARgamma-mediated NFkappaB trans-repression dependent manner. The findings suggest PPARgamma is a potential therapeutic target for diabetic vascular complications. PMID- 30398028 TI - Association study between killer immunoglobulin-like receptor polymorphisms and ankylosing spondylitis disease: An updated meta-analysis. AB - BACKGROUND: Several genetic studies have assessed the association between polymorphisms in killer immunoglobulin-like receptors (KIR) genes and susceptibility of individuals to ankylosing spondylitis (AS), but the findings have been inconclusive and incongruous. Therefore, we conducted this meta analysis of all case-control studies meeting the inclusion criteria for obtaining an exact conclusion of the effect of KIR polymorphisms on the risk of AS. METHODS: A systematic literature search was conducted in electronic databases, including Scopus web of science, ScienceDirect, and PubMed to find all eligible studies exploring the association between KIR polymorphisms and the risk of AS, prior to June 2017. Pooled odds ratios (OR) and their corresponding 95% CIs were used to evaluate the strength of the association between KIR polymorphisms and the risk of AS. RESULTS: A total of 16 case-control studies, encompassed in 12 papers, with 1770 cases and 2907 healthy subjects were included in the meta analysis. This meta-analysis revealed three significant positive associations of 2DS1, 2DS5, and 3DS1 with susceptibility to AS, while two significant negative associations of 2DL2 and 2DS2 with susceptibility to AS were identified. In the subgroup analysis based on human leukocyte antigen (HLA)-B*27 positive patients and healthy subjects, results indicated that there were four significant positive associations between 2DL5, 2DS4, 2DS5, 3DS1 polymorphisms and susceptibility to AS in HLA-B*27-positive patients; a significant negative association of 3DL1 in HLA-B*27-positive patients was found. CONCLUSIONS: While 2DS1, 2DS5, and 3DS1 polymorphisms increased AS risk, 2DL2 and 2DS2 polymorphisms were associated with reduced AS susceptibility. PMID- 30398030 TI - IL-17A haplotype confers susceptibility to systemic lupus erythematosus but not to rheumatoid arthritis in Mexican patients. AB - AIM: Recent studies highlight the importance of the interleukin (IL)-17A cytokine in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). There are also reports of associations between some single nucleotide polymorphisms (SNPs) in IL-17A and RA but not SLE. Notably, these findings have not been replicated in all studied populations. The aim of this study was to investigate whether the IL 17A -737 T/C (rs8193036), -444A/G (rs3819024), -197G/A (rs2275913), and -121G/A (rs8193037) SNPs conferred susceptibility to SLE (or lupus nephritis) or to RA in a Mexican population. METHODS: The study included 1367 Mexican subjects, 501 with RA, 367 with SLE, and 499 healthy controls. IL-17A was genotyped using a TaqMan 5' allelic discrimination assay. RESULTS: Our results showed that the IL-17A -737 T/C, -444A/G, -197G/A, and -121G/A SNPs had similar genotype and allele frequencies in patients with SLE (or lupus nephritis) or RA and in controls. However, an IL-17A haplotype (TAGA) showed an association with SLE susceptibility (odds ratio 2.43, P = 0.004) but not with RA susceptibility. CONCLUSIONS: These results confirm that the IL-17A -737T/C, -444A/G, -197G/A, and -121G/A SNPs are not risk factors for RA, but the IL-17A TAGA haplotype is a risk factor for SLE. This is the first report to document an association between IL-17A and SLE susceptibility in adults. PMID- 30398031 TI - A longitudinal analysis of pain experience and recall in fibromyalgia. AB - AIM: To evaluate pain experiences and memories in fibromyalgia (FM) patients over time. METHOD: Participants included 572 females who were members of a large health maintenance organization who had a diagnosis of FM syndrome (FMS) and met inclusion criteria for the study. Recruitment was for an intervention study that tested the effects of social support and education treatment arms, but there were no treatment effects. Reports of experiential pain (EP), historical peak pain (HPP), and historical valley pain (HVP) for FM were collected. Differences between HPP and EP and EP and HVP (bias) were calculated to determine whether HPP and HVP were distributed evenly around EP over time across participants. Models were performed to assess personal history and psychosocial factors that affect EP, HPP, HVP, and bias. RESULTS: There was systematic tendency for HPP to be significantly larger than EP relative to EP vs HVP. EP and HPP decreased significantly over time, but not HVP. There were significant predictors of EP, HPP, HVP, and bias, including depression, self-efficacy, and sleep quality, among others. CONCLUSION: The experiences and recollections of pain in FM appear to provide a unique means of understanding the maintenance of chronic pain-including factors that affect this process. PMID- 30398032 TI - Use of cannabis and risk of advanced liver fibrosis in patients with chronic hepatitis C virus infection: A systematic review and meta-analysis. AB - OBJECTIVES: Chronic hepatitis C virus (HCV) infection is one of the most common chronic liver diseases. Several risk factors for the progression of liver fibrosis among these patients have been identified. Use of cannabis could be another risk factor, but the results from epidemiological studies remain inconclusive. METHODS: Comprehensive literature review was conducted using MEDLINE and EMBASE databases through December 2017 to identify studies that compared the risk of advanced liver fibrosis among HCV-infected patients who use and who do not use cannabis. Effect estimates from each study were extracted and combined together using the random-effect, generic inverse variance method of DerSimonian and Laird. RESULTS: A total of three cohort studies with 898 participants met the eligibility criteria and were included in the meta-analysis. The risk of advanced liver fibrosis among HCV-infected patients who use cannabis was numerically higher than those who do not use cannabis, although the result did not achieve statistical significance (pooled odds ratio, 1.77; 95% confidence interval, 0.78-4.02). The statistical heterogeneity was high with an I2 of 75%. CONCLUSIONS: This meta-analysis showed that the risk of advanced liver fibrosis among HCV-infected patients who use cannabis was higher than those who do not use cannabis, but the result was not statistically significant. Further studies are required to better characterize the risk. PMID- 30398033 TI - Impact of EUSTAR standardized training on accuracy of modified Rodnan skin score in patients with systemic sclerosis. AB - OBJECTIVES: To investigate the impact of European Scleroderma Trials and Research (EUSTAR) standardized training on the accuracy of modified Rodnan skin score (mRSS) in patients with systemic sclerosis (SSc). METHODS: Eight SSc patients (four diffuse, four limited) and 10 physicians (4 fellows, 6 professors) were included. Gold-standard mRSS was performed by a senior instructor. Training comprised a video presentation and a live demonstration. Each physician performed mRSS with no clinical information in all patients: (a) before training; (b) after video session; and (c) after live demonstration. Primary outcome was the change in scoring accuracy, which was defined as the difference from the gold-standard skin score, as analyzed using a linear mixed model. RESULTS: Mean (standard deviation) difference from the gold-standard score in all measurements by participants before the training was 7.7 (9.5). Completion of training significantly enhanced mRSS accuracy (adjusted beta = -7.61; 95% CI: -11.91 to 3.32). This was largely attributable to the video presentation (adjusted beta = 5.47; -9.16 to -1.78), although the live demonstration was associated with numerical reduction in the difference from the gold-standard score (adjusted beta = -2.15; -5.84 to 1.55). Effect of training was prominent in fellows whereas professors showed an increase in the difference from gold-standard score after training (P value for interaction <0.001). The intraclass correlation coefficient for physician skin scores was acceptable. However, no significant change was observed after training. CONCLUSION: New EUSTAR standardized mRSS training significantly enhanced mRSS accuracy, especially in participant with less previous experience in skin scoring. PMID- 30398034 TI - Efficacy and safety of oral high-trough level tacrolimus in acute/subacute interstitial pneumonia with dermatomyositis. AB - OBJECTIVES: We assessed the efficacy and safety of combination therapy with glucocorticoids and high-trough level tacrolimus (TAC) for the treatment of acute/subacute interstitial pneumonia (A/SIP) in patients with dermatomyositis (DM). METHODS: Eleven DM-A/SIP patients were enrolled. The combination therapy with glucocorticoids and TAC was started as early as possible after DM-A/SIP was diagnosed. We monitored the trough concentration of TAC. In the initial 3 months, we maintained the trough concentration of TAC at relatively high levels within a range of 15-20 ng/mL. Then, we decreased the TAC doses stepwise to keep the trough concentration at 10-15 ng/mL in the next 3 months and 5-10 ng/mL as a maintenance dose. RESULTS: Seven patients had clinically amyopathic DM. Six patients were positive for anti-aminoacyl-tRNA synthetase antibody and two were positive for anti-melanoma differentiation-associated gene 5 antibody. Ten patients survived for the period of the 24-week follow up. One patient died under a tentative diagnosis of viral encephalitis at 4 months after the treatment. In the 10 surviving patients, interstitial pneumonia improved in eight patients and was not worse in two patients. Clinical examinations, including the Krebs von den Lungen-6 levels, % forced vital capacity, and chest computed tomography score, were significantly improved by this combination therapy. Although grade 1 and 2 renal damage occurred in 4 and 2 patients, respectively. CONCLUSIONS: The present findings suggest that early therapeutic intervention by a combination with glucocorticoids and initial high-trough level TAC is effective for DM-A/SIP although consideration of the risks of infection and renal damage is required. PMID- 30398035 TI - Association between Serum Cystatin C and Vascular Complications in Type 2 Diabetes Mellitus without Nephropathy. AB - BACKGROUND: Recent studies have correlated serum cystatin C (CysC) with vascular complications, but few studies have investigated this correlation in diabetes patients without nephropathy. This study aimed to evaluate if higher serum CysC levels increase the risk for vascular complications in type 2 diabetes mellitus patients with normal renal function or mild renal impairment. METHODS: A total of 806 consecutive patients with type 2 diabetes mellitus who were admitted to the diabetes center of Soonchunhyang University Hospital for blood glucose control were retrospectively reviewed. Patients with nephropathy were excluded. Subjects were categorized into quartiles of serum CysC levels (Q1, <=0.65 mg/L; Q2, 0.66 to 0.79 mg/L; Q3, 0.80 to 0.94 mg/L; and Q4, >=0.95 mg/L). RESULTS: The proportion of patients with diabetic retinopathy (DR) (P for trend <0.001), coronary heart disease (CHD) (P for trend <0.001), and stroke (P for trend <0.001) increased across the serum CysC quartiles. After adjustment for confounding factors, the highest serum CysC level remained a significant risk factor for DR (odds ratio [OR], 1.929; 95% confidence interval [CI], 1.007 to 4.144; P=0.040). Compared with Q1, a significant positive association was observed between serum CysC and CHD in Q2 (OR, 7.321; 95% CI, 1.114 to 48.114; P=0.012), Q3 (OR, 6.027; 95% CI, 0.952 to 38.161; P=0.020), and Q4 (OR, 8.122; 95% CI, 1.258 to 52.453; P=0.007). No associations were observed between CysC and stroke after additional adjustment for confounding variables. CONCLUSION: Serum CysC levels are independently associated with DR and CHD, suggesting that CysC may be useful for identifying type 2 diabetes mellitus patients without nephropathy who are at high risk for vascular complications. PMID- 30398036 TI - Serum R-Spondin 1 Is a New Surrogate Marker for Obesity and Insulin Resistance. AB - BACKGROUND: Recent in vivo studies indicated that R-spondin 1 (RSPO1) regulates food intake and increases insulin secretion, but its role in humans remains unknown. This study investigated the association between serum levels of RSPO1 and diverse metabolic parameters in humans. METHODS: The study population consisted of 43 subjects with newly diagnosed diabetes mellitus, and 79 non diabetic participants. Serum levels of RSPO1 were measured using the enzyme linked immunosorbent assay. The relationships between circulating RSPO1 and diverse metabolic parameters were analyzed. RESULTS: Circulating RSPO1 levels increased to a greater extent in the obese group than in the lean group. Moreover, serum levels of RSPO1 were higher in the insulin-resistant group than in the insulin-sensitive group. Serum levels of RSPO1 were significantly correlated with a range of metabolic parameters including body mass index, fasting C-peptide, homeostasis model assessment of insulin resistance index, and lipid profile. Moreover, levels were significantly associated with insulin resistance and obesity in non-diabetic subjects. CONCLUSION: This study demonstrated the association between serum levels of RSPO1 and a range of metabolic parameters in humans. Serum levels of RSPO1 are significantly related to obesity and insulin resistance, although the precise mechanisms remain unknown. PMID- 30398037 TI - Patterns of Nerve Conduction Abnormalities in Patients with Type 2 Diabetes Mellitus According to the Clinical Phenotype Determined by the Current Perception Threshold. AB - BACKGROUND: Clinical manifestations of diabetic peripheral neuropathy (DPN) vary along the course of nerve damage. Nerve conduction studies (NCS) have been suggested as a way to confirm diagnoses of DPN, but the results have limited utility for evaluating clinical phenotypes. The current perception threshold (CPT) is a complementary method for diagnosing DPN and assessing DPN symptoms. We compared NCS variables according to clinical phenotypes determined by CPT measurements. METHODS: We retrospectively enrolled patients with type 2 diabetes mellitus who underwent both NCS and CPT tests using a neurometer. CPT grades were used to determine the clinical phenotypes of DPN: normoesthesia (0 to 1.66), hyperesthesia (1.67 to 6.62), and hypoesthesia/anesthesia (6.63 to 12.0). The Michigan Neuropathy Screening Instrument (MNSI) was used to determine a subjective symptom score. DPN was diagnosed based on both patient symptoms (MNSI score >=3) and abnormal NCS results. RESULTS: A total of 202 patients (117 men and 85 women) were included in the final analysis. The average age was 62.6 years, and 71 patients (35.1%) were diagnosed with DPN. The CPT variables correlated with MNSI scores and NCS variables in patients with diabetes. Linear regression analyses indicated that hypoesthesia was associated with significantly lower summed velocities and sural amplitudes and velocities, and higher summed latencies, than normoesthesia. Sural amplitude was significantly lower in patients with hyperesthesia than in patients with normoesthesia. CONCLUSION: NCS variables differed among patients with diabetes according to clinical phenotypes based on CPT and decreased sural nerve velocities was associated with hyperesthesia. PMID- 30398038 TI - Projection of Diabetes Prevalence in Korean Adults for the Year 2030 Using Risk Factors Identified from National Data. AB - BACKGROUND: A number of studies have reported future prevalence estimates for diabetes mellitus (DM), but these studies have been limited for the Korean population. The present study aimed to construct a forecasting model that includes risk factors for type 2 DM using individual- and national-level data for Korean adults to produce prevalence estimates for the year 2030. METHODS: Time series data from the Korea National Health and Nutrition Examination Survey and national statistics from 2005 to 2013 were used. The study subjects were 13,908 male and 18,697 female adults aged 30 years or older who were free of liver cirrhosis. Stepwise logistic regression analysis was used to select significant factors associated with DM prevalence. RESULTS: The results showed that survey year, age, sex, marital, educational, or occupational status, the presence of obesity or hypertension, smoking status, alcohol consumption, sleep duration, psychological distress or depression, and fertility rate significantly contributed to the 8-year trend in DM prevalence (P<0.05). Based on sex-specific forecasting models that included the above factors, DM prevalence for the year 2030 was predicted to be 29.2% (95% confidence interval [CI], 27.6% to 30.8%) in men and 19.7% (95% CI, 18.2% to 21.2%) in women. CONCLUSION: The present study projected a two-fold increase in the prevalence of DM in 2030 compared with that for the years 2013 and 2014 in Korean adults. Modifiable factors contributing to this increase in DM prevalence, such as obesity, smoking, and psychological factors, may require attention in order to reduce national and individual costs associated with DM. PMID- 30398039 TI - Hospital-Based Korean Diabetes Prevention Study (H-KDPS): A Prospective, Multi Center, Randomized, Open-Label Controlled Study. AB - BACKGROUND: The prevalence of diabetes mellitus (DM) continues to increase, and the disease burden is the highest of any medical condition in Korea. However, large-scale clinical studies have not yet conducted to establish the basis for diabetes prevention in Korea. METHODS: The hospital-based Korean Diabetes Prevention Study (H-KDPS) is a prospective, multi-center, randomized, open-label controlled study conducted at university hospitals for the purpose of gathering data to help in efforts to prevent type 2 DM. Ten university hospitals are participating, and 744 subjects will be recruited. The subjects are randomly assigned to the standard care group, lifestyle modification group, or metformin group, and their clinical course will be observed for 36 months. RESULTS: All intervention methodologies were developed, validated, and approved by Korean Diabetes Association (KDA) multi-disciplinary team members. The standard control group will engage in individual education based on the current KDA guidelines, and the lifestyle modification group will participate in a professionally guided healthcare intervention aiming for >=5% weight loss. The metformin group will begin dosing at 250 mg/day, increasing to a maximum of 1,000 mg/day. The primary endpoint of this study is the cumulative incidence of DM during the 3 years after randomization. CONCLUSION: The H-KDPS study is the first large-scale clinical study to establish evidence-based interventions for the prevention of type 2 DM in Koreans. The evidence gathered by this study will be useful for enhancing the health of Koreans and improving the stability of the Korean healthcare system (Trial registration: CRIS KCT0002260, NCT02981121). PMID- 30398040 TI - A Journey to Understand Glucose Homeostasis: Starting from Rat Glucose Transporter Type 2 Promoter Cloning to Hyperglycemia. AB - My professional journey to understand the glucose homeostasis began in the 1990s, starting from cloning of the promoter region of glucose transporter type 2 (GLUT2) gene that led us to establish research foundation of my group. When I was a graduate student, I simply thought that hyperglycemia, a typical clinical manifestation of type 2 diabetes mellitus (T2DM), could be caused by a defect in the glucose transport system in the body. Thus, if a molecular mechanism controlling glucose transport system could be understood, treatment of T2DM could be possible. In the early 70s, hyperglycemia was thought to develop primarily due to a defect in the muscle and adipose tissue; thus, muscle/adipose tissue type glucose transporter (GLUT4) became a major research interest in the diabetology. However, glucose utilization occurs not only in muscle/adipose tissue but also in liver and brain. Thus, I was interested in the hepatic glucose transport system, where glucose storage and release are the most actively occurring. PMID- 30398041 TI - Discrepancies between Glycosylated Hemoglobin and Fasting Plasma Glucose for Diagnosing Impaired Fasting Glucose and Diabetes Mellitus in Korean Youth and Young Adults. AB - BACKGROUND: Glycosylated hemoglobin (HbA1c) has been recommended as a diagnostic test for prediabetes and diabetes. Here, we evaluated the level of agreement between diagnoses based on fasting plasma glucose (FPG) versus HbA1c levels and determined optimal HbA1c cutoff values for these diseases in youth and young adults. METHODS: The study included 7,332 subjects (n=4,129, aged 10 to 19 years in youth group; and n=3,203 aged 20 to 29 years in young adult group) from the 2011 to 2016 Korea National Health and Nutrition Examination Survey. Prediabetes and diabetes were defined as 100 to 125 mg/dL (impaired fasting glucose [IFG]) and >=126 mg/dL for FPG (diabetes mellitus [DM] by FPG [DMFPG]), and 5.7% to 6.4% and >=6.5% for HbA1c, respectively. RESULTS: In the youth group, 32.5% with IFG had an HbA1c level of 5.7% to 6.4%, and 72.2% with DMFPG had an HbA1c >=6.5%. In the young adult group, 27.5% with IFG had an HbA1c level of 5.7% to 6.4%, and 66.6% with DMFPG had an HbA1c >=6.5%. Kappa coefficients for agreement between the FPG and HbA1c results were 0.12 for the youth group and 0.19 for the young adult group. In receiver operating characteristic curve analysis, the optimal HbA1c cutoff for IFG and DMFPG were 5.6% and 5.9% in youths and 5.5% and 5.8% in young adults, respectively. CONCLUSION: Usefulness of HbA1c for diagnosis of IFG and DMFPG in Koreans aged <30 years remains to be determined due to discrepancies between the results of glucose- and HbA1c-based tests. Additional testing might be warranted at lower HbA1c levels to detect IFG and DMFPG in this age group. PMID- 30398042 TI - A case of bleomycin-induced lung toxicity. AB - A 64-year-old female was admitted for dry cough, dyspnea, fever, loss of appetite, and weight loss. Past medical history revealed scoliosis, cholecystectomy, and Hodgkin lymphoma. ABG values were: pH: 7.42, pCO2: 40.2 mm Hg, pO2: 61.4 mm Hg. Chest CT showed cystic lesions, emphysema, ground glass, and reticular opacities. ABG values worsened under 8L/min nasal oxygen. The patient underwent bilevel positive airway pressure (BiPAP) and methylprednisolone 60 mg/day bid was commenced. The final diagnosis was respiratory insufficiency due to bleomycin toxicity. The patient deceased on the sixth day after transfer to the intensive care unit. Bleomycin is an effective chemotherapeutic agent used for Hodgkin lymphoma treatment. It causes significant lung toxicity in half of the patients. Clinicians should always remember that bleomycin toxicity may lead to fatal complications in patients with comorbid conditions. We present this case to remark the possible consequences of bleomycin toxicity and the precautions taken to preclude bleomycin-induced pulmonary complications are discussed. PMID- 30398043 TI - High-Performance All-Solution-Processed Flexible Photodetector Arrays Based on Ultrashort Channel Amorphous Oxide Semiconductor Transistors. AB - Amorphous oxide semiconductor (AOS) field-effect phototransistors (FEPTs) are promising candidates for emerging photodetectors. Unfortunately, traditional lateral AOS FEPTs suffer from low photosensitivity, slow response time and inadequate mechanical flexibility, which restrict their widespread commercial application. In this work, novel AOS-based vertical field-effect phototransistor (VFEPT) arrays are presented, where the semiconducting layer and source and drain electrodes are deposited by inkjet printing. Benefitted from the unique vertical structure and ultrashort channel length, the exciton dissociation, carrier transfer, and collection efficiency were dramatically enhanced, resulting in excellent photoelectric performance in VFEPT devices, which was better than that of the traditional lateral AOS phototransistors. Moreover, flexible AOS VFEPT arrays were investigated for the first time on polyimide substrates. Due to the unique vertical architecture, the carrier transport was negligibly affected by the strain-induced in-plane cracks of the semiconductor channel layer during the mechanical bending process, which overcame the maximum bending limit of traditional lateral AOS thin-film transistors to ensure a transistor technique that gives notable mechanical robustness against repeated mechanical bending. Hence, this work provided a new pathway in emerging applications for AOS photodetectors with sensitivity, transparency, and flexibility. PMID- 30398044 TI - Robust Nanoporous Supramolecular Network through Charge-Transfer Interaction. AB - A robust nanoporous supramolecular network stabilized by charge-transfer interactions has been successfully constructed based on the bipyridinium and bicarboxylic acid with electron-donating hydroxyl pendant group, which exhibits high durability towards extensive acid/base condition (pH: 2-12), organic solvents and the plucking of metal ions. Furthermore, the separation capacity toward Rhodamine B and other dyes with the same charge and smaller molecular sizes has been realized in it. PMID- 30398045 TI - Organic Upconversion Display with an over 100% Photon-to-photon Upconversion Efficiency and a Simple Pixelless Device Structure. AB - Compared to traditional near-infrared (NIR) imaging devices, NIR-to-visible upconversion displays, which integrated a NIR photodetector with a visible light emitting diode, have merits of simple device structure, low cost, high resolution, and a simple pixelless structure. However, photon-to-photon upconversion efficiencies of these devices are typically much lower than unity. Here we report an all-organic NIR-to-visible upconversion display with a photon to-photon upconversion efficiency higher than 100% by integrating a photomultiplying organic NIR photodetector with a high-efficiency thermally activated delayed fluorescent organic light-emitting diode. To the best of our knowledge, this is the first report showing a photon-to-photon upconversion efficiency over 100% without using a built-in transistor for current amplification. PMID- 30398046 TI - Zwitterionic Covalent Organic Frameworks as Catalysts for Hierarchical Reduction of CO2 with Amine and Hydrosilane. AB - Controllable hierarchical reduction of carbon dioxide (CO2) to selectively afford versatile chemicals with specific carbon oxidation state is important but still remains a huge challenge to be realized. Here, we report new zwitterionic covalent organic frameworks ([BE] X%-TD-COFs), prepared by introducing betaine groups (BE) onto the channel walls of presynthesized frameworks via pore surface engineering methodology, as the heterogeneous organocatalysts for CO2 reduction. The adjustable density of immobilized BE groups as well as good preservation of crystallinity and porosity inherited from their parent COFs endow [BE] X%-TD-COFs with highly ordered catalytic site distribution and one-dimensional mass transport pathway in favor of catalysis. By controlling the reaction temperature and amount of CO2, [BE] X%-TD-COFs present high activity in catalyzing reduction of CO2 with amine and phenylsilane (PhSiH3) to produce formamides, aminals, and methylamines, respectively, with high yield and selectivity. Furthermore, high stability and insolubility bring excellent reusability to [BE]X%-TD-COFs with well-maintained catalytic performance after four cycles of use. Notably, this is a novel example that COFs are developed as heterogeneous catalysts for hierarchical two-, four-, and six-electron reduction of CO2 with amines and PhSiH3 to form C-N bonds as well as afford C+II, C0, and C-II species efficiently and selectively. PMID- 30398047 TI - Epidermis-Inspired Ultrathin 3D Cellular Sensor Array for Self-Powered Biomedical Monitoring. AB - Sensing devices with wearability would open the door to many advanced applications including soft robotics, artificial intelligence, and healthcare monitoring. Here, inspired by the configuration of the human epidermis, we present a flexible three-dimensional (3D) cellular sensor array (CSA) via a one step thermally induced phase separation method. The CSA was framed by the 3D cellular electret with caged piezoelectric nanoparticles, which was ultrathin (80 MUm), lightweight, and highly robust. For biomedical sensing, the 3D-CSA holds a decent pressure sensitivity up to 0.19 V kPa-1 with a response time of less than 16 ms. Owing to its rigid structural symmetry, the 3D-CSA could be identically operated from its both sides. It was demonstrated to successfully measure the human heartbeat, detect the eyeball motion for sleeping monitoring, and tactile imaging. Mimicking the functionalities of the human skin with a self-powered operation feature, the 3D-CSA was expected to represent a substantial advancement in wearable electronics for healthcare. PMID- 30398048 TI - Dynamic Interplay between Transport and Reaction Kinetics of Luminophores on the Operation of AC-Driven Electrochemiluminescence Devices. AB - Electrochemiluminescence (ECL) involves light emission accompanied by a series of electrochemical processes on luminophores, which has been recently exploited in a new light-emitting device platform, referred to as the ECL device (ECLD). Here, we investigate the influence of the transport of the ECL luminophores and their reaction kinetics on the emission properties of alternating current-voltage driven ECLDs. A model based on the diffusion and reaction rate equations is developed to predict the operational frequency ( f)-dependent luminance properties of the ECLD. It is found that more frequent generation of the redox precursors with a shorter time interval enhances their probability of encountering each other, and therefore the luminance of the device increases with increasing f initially. The luminance at a higher f, however, is suppressed eventually due to the decreased rate of the electrode reactions. Using the model, the influence of diffusion and reaction rates on the performance of an ECLD is analyzed separately and systematically. The results provide insight on the operation of this emerging class of a light-emitting device platform. PMID- 30398049 TI - High-Performance Photocoupler Based on Perovskite Light Emitting Diode and Photodetector. AB - Photocoupler is a kind of semiconductor optoelectronic device that integrates light-emitting device (LED) and photodetector. It has found wide application in various fields because of its capability to transmit the electrical signal through the conversion of the electricity-light-electricity. Herein, we report the fabrication of a new photocoupler by simply integrating perovskite quantum dots LED and perovskite photodetector on a glass substrate. The as-fabricated photocoupler showed outstanding characteristics with high current transfer ratio (CTR) of 3.35%, which is highly competitive in comparison with other materials based devices. Furthermore, the perovskite photocoupler had a fast response speed of 8 MUs/8.26 MUs. By further adding an amplification circuit, the CTR could be enhanced by around 50 times to 172.6%. These results indicate that the present perovskite-based photocouplers may find potential application in future integrated circuit and optoelectronic system. PMID- 30398050 TI - Nonhalogenated Solvent-Processed All-Polymer Solar Cells over 7.4% Efficiency from Quinoxaline-Based Polymers. AB - Two conjugated polymers, with different side chains of alkoxy-substituted difluorobenzene and alkyl-substituted difluorobenzene based on quinoxaline (Qx) as the electron acceptor unit and benzodithiophene as the electron donor unit, named HFQx-T and HFAQx-T, were used as electron donor polymers to fabricate all polymer solar cells (all-PSCs) with a naphthalenediimide-bithiophene n-type semiconducting polymer (N2200). Usually, halogenated solvents are harmful to natural environment and human beings, and solvent additives were disadvantageous in the process of roll-to-roll technology. The Qx-based polymers are successfully used to fabricate high-performance all-PSCs, which processed with the nonhalogenated solvent tetrahydrofuran (THF) at room temperature. With THF as the processing solvent, the active layer showed a higher absorption coefficient, better phase separation, exciton dissociation, and charge carrier mobilities than that processed with CHCl3. Moreover, the photovoltaic properties have been dramatically improved with THF. The optimized device of HFAQx-T:N2200 processed with THF delivered an efficient power conversion efficiency (PCE) of 7.45%, which is the highest PCE for all-PSCs from Qx-based polymers processed by a nonhalogenated solvent. PMID- 30398051 TI - Insights into Interfaces, Stability, Electronic Properties, and Catalytic Activities of Atomically Precise Metal Nanoclusters from First Principles. AB - Atomically precise, ligand-protected metal nanoclusters are of great interest for their well-defined structures, intriguing physicochemical properties, and potential applications in catalysis, biology, and nanotechnology. Their structure precision provides many opportunities to correlate their geometries, stability, electronic properties, and catalytic activities by closely integrating theory and experiment. In this Account, we highlight recent theoretical advances from our efforts to understand the metal-ligand interfaces, the energy landscape, the electronic structure and optical absorption, and the catalytic applications of atomically precise metal nanoclusters. We mainly focus on gold nanoclusters. The bonding motifs and energetics at the gold-ligand interfaces are two main interests from a computational perspective. For the gold-thiolate interface, the RS-Au-SR- staple motif is not always preferred; in fact, the bridging motif (-SR ) is preferred at the more open facets such as Au(100) and Au(110). This finding helps understand the diversity of the gold-thiolate motifs for different core geometries and sizes. A great similarity is demonstrated between gold-thiolate and gold-alkynyl interfaces, regarding formation of the staple-type motifs with PhC=C- as an example. In addition, N-heterocyclic carbenes (NHCs) without bulky groups also form the staple-type motif. Alkynyls and bulky NHCs have the strongest binding with the gold surface from comparing 27 ligands of six types, suggesting a potential to synthesize NHC-protected gold clusters. The energy landscape of nanosystems is usually complex, but experimental progress in synthesizing clusters of the same Au-S composition with different R groups and isomers of the same Au n(SR) m formula have made detailed theoretical analyses of energetic contributions possible. Ligand-ligand interactions turn out to play an important role in the cluster stability, while metastable isomers can be obtained via kinetic control. Although the superatom-complex theory is the starting point to understand the electronic structure of atomically precise gold clusters, other factors also greatly affect the orbital levels that manifest themselves in the experimental optical absorption spectra. For example, spin-orbit coupling needs to be included to reproduce the splitting of the HOMO-LUMO transition observed experimentally for Au25(SR)18-, the poster child of the family. In addition, doping can lead to structural changes and charge states that do not follow the superatomic electron count. Atomically precise metal nanoclusters are an ideal system for understanding nanocatalysis due to their well-defined structures. Active sites and catalytic mechanisms are explored for selective hydrogenation and hydrogen evolution on thiolate-protected gold nanoclusters with and without dopants. The behavior of H in nanogold is analyzed in detail, and the most promising site to attract H is found to be coordinately unsaturated Au atoms. Many insights have been gained from first-principles studies of atomically precise, ligand-protected gold nanoclusters. Interesting and important questions remaining to be addressed are pointed out in the end. PMID- 30398052 TI - Exploring the Versatility of Membrane-Free Battery Concept Using Different Combinations of Immiscible Redox Electrolytes. AB - Lately, the field of redox flow batteries is flourishing because of the emergence of new redox chemistries, including organic compounds, new electrolytes, and innovative designs. Recently, we reported an original membrane-free battery concept based on the mutual immiscibility of an aqueous catholyte containing hydroquinone and an ionic liquid anolyte containing para-benzoquinone as redox species. Here, we investigate the versatility of this concept exploring the electrochemical performance of 10 redox electrolytes based on different solvents, such as propylene carbonate, 2-butanone, or neutral-pH media, and containing different redox organic molecules, such as 2,2,6,6-tetramethylpiperidine-1-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidine1-oxyl (OH-TEMPO), or substituted anthraquinones. The most representative electrolytes were paired and used as immiscible anolyte-catholyte in 5 different membrane-free batteries. Those batteries with substituted anthraquinones in the anolyte exhibited up to 50% improved open-circuit voltage (2.1 V), an operating voltage of 1.75 V, and 62% higher power density compared with our previous work. On the other hand, the partition coefficient of redox molecules between the two immiscible phases and the inherent self-discharge occurring at the interphase are revealed as intrinsic features affecting the performance of this type of membrane-free battery. It was successfully demonstrated that the functionalization of redox molecules is an interesting strategy to tune the partition coefficients mitigating the crossover that provokes low battery efficiency. As a result, the cycling life of a battery having OH-TEMPO as active species in the catholyte and containing propylene carbonate-based anolyte was evaluated over 300 cycles, achieving 85% capacity retention. These results demonstrated the huge versatility and countless possibilities of this new membrane-free battery concept. PMID- 30398053 TI - Hydrogen-Bonding-Assisted Ketimine Formation of Benzophenone Derivatives. AB - The favorable effect of 2-hydroxyphenyl groups for ketimine formation with benzophenone was demonstrated by combining computational and experimental studies. Although direct imine formation between benzophenone and primary amines is challenging, 2-hydroxybenzophenone or 2,2'-dihydroxybenzophenone was readily used for ketimine formation with various primary alkyl amines and anilines. Measured activation parameters and calculated energy profiles indicated that the 2-hydroxyphenyl group can lower both activation barriers and equilibrium energies by establishing intramolecular and intermolecular hydrogen-bonding interactions. PMID- 30398054 TI - Stability of Vegetal Diamine Oxidase in Simulated Intestinal Media: Protective Role of Cholic Acids. AB - Food biogenic amines, in particular, histamine, are often responsible for various enteric and vascular dysfunctions. Several years ago, the oral administration of copper-containing diamine oxidase (DAO), also called histaminase, able to oxidatively deaminate biogenic amines, had been suggested as a food supplement to control food allergy and enteric dysfunctions. This report is aimed to generate a global image on the behavior of orally administrated DAO dosage forms in the intestinal tract. The catalytic stability of DAO from Lathyrus sativus seedlings in various simulated intestinal media with different pH and containing different association of cholic acids, pancreatic proteases, bicarbonate, lipids, or alcohol was investigated. Cholic acids and lipids protected the enzyme in the simulated intestinal fluids. However, they were not able to protect against the inhibitory effect of 24-36% (v/v) ethanol. These observations may be relevant for oral administration of enzymes as food supplements or therapeutic bioactive agents. PMID- 30398055 TI - Eliminating Competition: Characterizing and Eliminating Competitive Binding at Separate Sites between DAHP Synthase's Essential Metal Ion and the Inhibitor DAHP Oxime. AB - 3-Deoxy-d- arabinoheptulosonate 7-phosphate (DAHP) oxime is a transition state mimic inhibitor of bacterial DAHP synthase, with K i = 1.5 MUM and a residence time of tR = 83 min. Unexpectedly, DAHP oxime inhibition is competitive with respect to the essential metal ion, Mn2+, even though the inhibitor and metal ion do not occupy the same physical space in the active site. This is problematic because DAHP synthase is activated by multiple divalent metal cations, some of which have significant intracellular concentrations and some of which dissociate slowly. The nature of DAHP oxime's competition with the metal ion was investigated. Inhibition shifted from metal-competitive at physiological pH to metal-noncompetitive at pH > 8.7 in response to deprotonation of the Cys61 side chain. The modes of inhibition of DAHP synthase mutants and inhibitor fragments demonstrated that metal-competitive inhibition arose from interactions between Mn2+, DAHP oxime's O4 hydroxyl group, and the Cys61 and Asp326 side chains. The majority of potent DAHP synthase inhibitors in the literature possess a 4 hydroxyl group. Removing it could avoid metal-competitive inhibition and avoid them being outcompeted by metal ions in vivo. PMID- 30398056 TI - Radical-Based Organic Light-Emitting Diodes with Maximum External Quantum Efficiency of 10.6. AB - A new luminescent radical, tris-2,4,6-trichlorophenylmethyl-1,5-diazarcarbazole (TTM-DACz), was synthesized and characterized. The photoluminescence quantum yield of TTM-DACz in solid 1,3,5-tris(1-phenyl-1H-benzimidazol-2-yl)benzene matrix film (5 wt %) is as high as 57.0%. Organic light-emitting diodes (OLEDs) employing TTM-DACz as the emitter were fabricated. By rational design of the device structure and host-guest doping system, external quantum efficiency (EQE) of up to 10.6% of the optimized device with a red CIE chromaticity of (0.62, 0.36) was obtained, which is among the highest values for red OLEDs using nonphosphorescent materials as the emitters. This work will accelerate the development of luminescent radical materials for high-performance OLEDs. PMID- 30398057 TI - Encapsulating Quantum Dots within HIV-1 Virions through Site-Specific Decoration of the Matrix Protein Enables Single Virus Tracking in Live Primary Macrophages. AB - Labeling and imaging with quantum dots (QDs) provides powerful tools to visualize viral infection in living cells. Encapsulating QDs within virions represents a novel strategy for virus labeling. Here, we developed infectious HIV-1 virions encapsulating QDs through site-specific decoration of the viral matrix protein (MA) and used them to visualize early infection events in human primary macrophages by single-particle imaging. The MA protein was fused to a biotin acceptor peptide (BAP) tag, biotinylated, complexed with streptavidin-conjugated QDs in live cells, and incorporated into virions during virus assembly. The QD encapsulated virions were tracked during infection of macrophages at a single particle level. The dynamic dissociation of MA and Vpr was also tracked in real time, and the results demonstrated that MA has multiple dynamic behaviors and functions during virus entry. More importantly, we tracked the dynamic interplay of QD-encapsulated virions with cellular mitochondria in live primary macrophages. We also found that HIV-1 can induce fission of mitochondria during the early phases of infection. In summary, we have constructed a type of QD encapsulated virus particle and used this technology to further our understanding of the early events of HIV-1 infection. PMID- 30398058 TI - Nickle Catalysis Enables Access to Thiazolidines from Thioureas via Oxidative Double Isocyanide Insertion Reactions. AB - An efficient synthesis of thiazolidine-2,4,5-triimine derivatives was developed via Ni-catalyzed oxidative double isocyanide insertion to thioureas under air conditions, in which thioureas play three roles as a substrate, a ligand, and overcoming isocyanide polymerization. The reaction is featured by employing a low cost and low loading Ni(acac)2 catalyst, without any additives, and high atom economy. This is the first example to directly apply a Ni(II) catalyst in oxidative double isocyanide insertion reactions. PMID- 30398059 TI - Early Antischistosomal Leads Identified from in Vitro and in Vivo Screening of the Medicines for Malaria Venture Pathogen Box. AB - As part of the control and elimination strategy of human schistosomiasis, preventive chemotherapy relies on a single drug, praziquantel. Facing an almost dry drug development pipeline, screening the Pathogen Box from the Medicines for Malaria Venture (MMV), provides a unique opportunity to possibly expand the pool of potent molecules against schistosomiasis. The activity of 400 compounds from this open-access library was first screened in vitro on the larval stage of Schistosoma mansoni. The hits were then tested on adult worms. Eleven leads were identified and tested for albumin-binding and activity on adult S. haematobium. In parallel, a rudimental structure-activity relationship analysis was performed on the 112 available analogues of three leads, yielding another 30 molecules active against both larval and adult stages of S. mansoni. Seven leads, selected on druglikeness, pharmacokinetic properties, and availability, plus auranofin were tested in mice harboring a chronic S. mansoni infection. MMV022029 and MMV022478 revealed the highest worm burden reductions of 67.8 and 70.7%, respectively. This study provided a series of new potent scaffolds and pharmacophores that could be used to design and develop suitable alternative(s) to praziquantel. PMID- 30398060 TI - Antidiabetic Effects of Lactobacillus casei Fermented Yogurt through Reshaping Gut Microbiota Structure in Type 2 Diabetic Rats. AB - The viable bacterial strains in conventional yogurt are intolerant to bile acid, which consequently cannot survive the conditions and their beneficial bioactivities are thus lost. We have previously shown that Lactobacillus casei Q14 ( Lac-Q14), a probiotic, has the potential to alleviate diabetes in rats. Herein, we used Lac-Q14 as the starter culture to ferment yogurt and explore the mechanisms of the bioactivity in diabetic rats. The results showed that Lac-Q14 yogurt improved blood glucose and insulin level, lowered gene expression of critical enzymes involved in liver gluconeogenesis. Pyrosequencing showed an obvious change in the composition of intestinal microbiota in Lac-Q14 yogurt treated rats. The abundance of 21 genera differed significantly between the Lac Q14 yogurt group and diabetes group. Quite a few short-chain fatty acid (SCFA) producing bacteria were selectively enriched, along with increased concentrations of SCFA and downstream Glucagon-like peptide-1 (GLP-1) and Peptide YY (PYY) secretion. PMID- 30398061 TI - Active Components from Sea Buckthorn ( Hippophae rhamnoides L.) Regulate Hepatic Stellate Cell Activation and Liver Fibrogenesis. AB - Sea buckthorn ( Hippophae rhamnoides L.) is a berry bearing multiple nutritional properties. In this study, 46 compounds were isolated from sea buckthorn berries. Preliminary data showed that the components, C13, C15, and C32, exhibited profound inhibitory effect on the activation of hepatic stellate cells (HSCs) induced by transforming growth factor-beta (TGF-beta) and decreased the levels of inflammatory factors. Furthermore, these compounds over-regulated the proteins of DNA damage signaling pathway and alpha-smooth muscle actin (alpha-SMA). Moreover, active components of sea buckthorn berry (ACSB) treatment attenuated fibrosis development in rats after bile duct ligation (BDL), reducing liver injury and inflammation, and reviving liver function in a dose-dependent manner. Moreover, ACSB down-regulated the expression of alpha-SMA, while over-regulating the DNA damage signaling pathway and the related genes. These suggest that ACSB inhibit DNA repair of HSCs, make them in a damaged state, inhibit the expression of TGF beta, and induce apoptosis. PMID- 30398062 TI - On-Demand Dissolvable Self-Healing Hydrogel Based on Carboxymethyl Chitosan and Cellulose Nanocrystal for Deep Partial Thickness Burn Wound Healing. AB - Deep partial thickness burn wounds present big challenges due to the long healing time, large size and irregular shape, pain and reinjury at wound dressing changes, as well as scarring. The clinically effective therapy to alleviate pain at wound dressing changes, and the scar left on the skin after the healing of wound is still unavailable. To combat this, we develop a nanocomposite self healing hydrogel that can be injected into irregular and deep burn wound beds and subsequently rapidly self-heal to reform into an integrated piece of hydrogel that thoroughly fills the wound area and protects the wound site from external environment, finally being painlessly removed by on-demand dissolving using amino acid solution at wound dressing changes, which accelerates deep partial thickness burn wound healing and prevents scarring. The hydrogel is made out of naturally occurring polymers, namely, water-soluble carboxymethyl chitosan (CMC) and rigid rod-like dialdehyde-modified cellulose nanocrystal (DACNC). They are cross-linked by dynamic Schiff-base linkages between amines from CMC and aldehydes from DACNC. The large aspect ratio and specific surface area of DACNC raise massive active junctions within the hydrogel, which can be readily broken and reformed, allowing hydrogel to rapidly self-heal. Moreover, DACNC serves as nanoreinforcing fillers to improve the hydrogel strength, which also restricts the "soft" CMC chains' motion when soaked in aqueous system, endowing high fluid uptake capacity (350%) to hydrogel while maintaining integrity. Cytotoxicity assay and three-dimensional cell culture demonstrate excellent biocompatibility of the hydrogel and capacity as extracellular matrix to support cell growth. This work opens a novel pathway to fabricate on-demand dissolvable self-healing hydrogels to speed deep partial thickness burn wound healing and eliminate pain at wound dressing changes and prevent scar formation. PMID- 30398063 TI - Novel methods for segment-specific blood flow simulation for the liver. AB - One challenge for hepatic flow simulation is to divide the hepatic vasculature into individual Couinaud segments, and to simulate flow at both segmental and organ levels. We propose to integrate a segment simulation algorithm with the flow solver in a Constructive Constraint Optimisation (CCO) algorithm to address this problem. In this way blood flow simulations can be conducted for large segment-specific vasculatures as relevant to surgical procedures. In this short communication we outline the methods and present some preliminary results. PMID- 30398064 TI - Numerical study to evaluate the effect of a surface-based sensor on arterial tonometry. AB - Arterial tonometry is a widely used non-invasive blood pressure measurement method. In contrast to the cuff-based method, it is possible to obtain a continuous pressure profile with respect to systolic and diastolic pressures using this method. However, due to a requirement of arterial tonometry-that a sensor needs to be placed directly above a blood vessel-placement error is inevitable if the measurement device is only capable of measuring local regions. This study assumed that the plate sensor is flexible, thus reducing the placement error. We investigated the pressure distribution along the wrist surface rather than the local region through the contact simulation between the flexible plate sensor and the wrist. As a result, we concluded that there is a unique pressure distribution for any specific wrist, regardless of the length and position of the plate, and that it is possible to measure the blood pressure using the response at the wrist surface to the pressure inside the radial artery. PMID- 30398065 TI - Rosuvastatin pharmacogenetics in African populations. PMID- 30398066 TI - Numerical evaluation of the efficacy of small-caliber colonoscopes in reducing patient pain during a colonoscopy. AB - Patient pain caused by a colonoscope is one of the main complications in completing a colonoscopy. Currently, randomized controlled trial (RCT) is one of the most used methods to evaluate the efficacy of small-caliber (SC) colonoscopes in reducing patient pain during a colonoscopy, compared with a standard colonoscope (SDC). However, many disturbing factors, including endoscopists' skills, characteristics of patients and new technical features of the colonoscope (passive bending and high force transmission shaft), limit the reliability and generalizability of each finding in current RCTs. This paper focuses on modeling the insertion of colonoscopes within colon models using an explicit finite element method (FEM). Such a numerical model could overcome the limitations in RCTs. At the same time, it is expected to evaluate the efficacy of the small caliber colonoscopes in reducing patient pain during a colonoscopy, while considering the effects of patient characteristics, including age, region and gender. The simulation results in this work showed that: compared with the SDC, a SC colonoscope may be more helpful in reducing discomfort for older patients, patients with smaller colon diameters and females. PMID- 30398067 TI - A musculoskeletal model customized for squatting task. AB - Most musculoskeletal models (MSKM) are designed to evaluate gait and running, which have limited range of motion (ROM). The purpose of this study was to examine the effect of wrapping surfaces (WS) at the knee and hip joints in a MSKM, on the muscle moment arms (MA) and activations during squatting. The MSKM was then customized by changing parameters of the original WS and by implementing additional WS. The WS prevent muscles from crossing into the bones, providing realistic muscle MA for large ROM. The modified MSKM is suitable for analysis up to 138 degrees hip and 145 degrees knee flexions. PMID- 30398068 TI - Boundary layer considerations in a multi-layer model for LDL accumulation. AB - Boundary layer effects for Low-Density Lipoprotein (LDL) concentration problems in a multi-layer artery model are analyzed in this work. Both a straight artery and aorta-iliac bifurcation are analyzed. Mass, momentum and species governing equations are based on the porous media theory and solved with the commercial finite-element based code COMSOL Multiphysics. For the straight artery, various inlet velocities, arterial sizes and intramural pressure values are investigated. Results are presented in terms of concentration profiles close to the lumen/endothelium interface and boundary layer thickness. It is shown that the boundary layer is affected by all of the three analyzed parameters. The results in this work will further clarify the concentration polarization effects imposed by the arterial wall. PMID- 30398069 TI - Hemodynamic investigation of a patient-specific abdominal aortic aneurysm with iliac artery tortuosity. AB - This paper describes a systematic investigation on the hemodynamic environment in a patient-specific AAA with tortuous common iliac artery(CIA) and external iliac artery (EIA). 3D reconstructions from CT scans and subsequent computational simulation are carried out. It is found out that the Newtonian and non-Newtonian models have very similar flow field and WSS distribution. More importantly, it is revealed that the torturous CIA maintained its helical flow. It is concluded that the assumption of Newtonian blood is adequate in capturing the intra-aneurysmal hemodynamics. Moreover, it is speculated that the physiological spiral flow protects the twisted CIA from the thrombosis formation. PMID- 30398070 TI - Performance criteria for generating predictive optimal control simulations of bicycle pedaling. AB - The purpose of this study was to identify one or more performance-based criteria that may be used to generate predictive optimal control simulations of submaximal pedaling. Two-legged pedaling simulations were generated based on minimizing muscle activation, muscle stress, metabolic energy, time derivative of muscle force, and minimizing metabolic energy while pedaling smoothly. The simulations based on minimizing muscle activation and muscle stress most closely matched experimental pedaling data, with the activation criterion better matching experimental muscle activation timing. We conclude that predictive simulations of submaximal pedaling may be generated using a cost function based on minimizing muscle activation. PMID- 30398071 TI - Comorbid chronic pain and opioid use disorder: literature review and potential treatment innovations. AB - Chronic pain (CP) and opioid use disorder (OUD) remain challenging complex public health concerns. This is an updated review on the relationship between CP and OUD and the use of stepped care models for assessment and management of this vulnerable population. A literature search was conducted from 2008 to the present in PubMed, Embase, and PsycInfo using the terms pain or chronic pain and opioid related disorders, opiate, methadone, buprenorphine, naltrexone, opioid abuse, opioid misuse, opioid dependen*, heroin addict, heroin abuse, heroin misuse, heroin dependen*, or analgesic opioids, and stepped care, integrated services, multidisciplinary treatment, or reinforcement-based treatment. Evidenced-based data exists on the feasibility, implementation, and efficacy of stepped care models in primary care settings for the management of CP and opioid use. Although these studies did not enroll participants with OUD, they included a sub-set of patients at risk for the development of OUD. There remains a dearth of treatment options for those with comorbid CP and OUD. Future research is needed to explore the aetiology and impact of CP and OUD, and greater emphasis is needed to improve access to comprehensive pain and substance use programmes for high-risk individuals. PMID- 30398072 TI - Integrating metabolomics with genomics. PMID- 30398073 TI - Challenges of inclusion: a qualitative study exploring barriers and pathways to inclusion of persons with mental disabilities in technical and vocational education and training programmes in East Africa. AB - PURPOSE: To explore barriers and pathways to the inclusion of persons with mental and intellectual disabilities in technical and vocational education and training programmes in four East African countries, in order to pave the way to greater inclusion. MATERIALS AND METHODS: An explorative, qualitative study including 10 in-depth interviews and a group discussion was conducted with coordinators of different programmes in four East African countries. Two independent researchers coded the interviews inductively using Atlas.ti. The underlying framework used is the culture, structure, and practice model. RESULTS: Barriers and pathways to inclusion were found in the three interrelated components of the model. They are mutually reinforcing and are thus not independent of one another. Barriers regarding culture include negative attitudes towards persons with mental illnesses, structural barriers relate to exclusion from primary school, rigid curricula and untrained teachers and unclear policies. Culture and structure hence severely hinder a practice of including persons with mental disabilities in technical and vocational education and training programmes. Pathways suggested are aiming for a clearer policy, more flexible curricula, improved teacher training and more inclusive attitudes. CONCLUSIONS: In order to overcome the identified complex barriers, systemic changes are necessary. Suggested pathways for programme coordinators serve as a starting point. Implications for rehabilitation Clear and up-to-date information on mental disability is required to engender societal participation; especially that of stakeholders in technical and vocational education and training programmes. Affirmative action and policy implementations of national and international human rights legislations are required to address the challenges of enrolment in technical and vocational education and training programmes. Disability organisations and government should adopt a more open and strengths-based attitude, tailor-made curricula, specific teacher training as well as clearer policies to ensure better inclusion of persons with mental disabilities in technical and vocational education and training programmes. PMID- 30398074 TI - MRI based 3D finite element modelling to investigate deep tissue injury. AB - Pressure ulcers occur due to sustained mechanical loading. Deep tissue injury is a severe type of pressure ulcer, which is believed to originate in subcutaneous tissues adjacent to bony prominences. In previous experimental-numerical studies the relationship between internal tissue state and damage development was investigated using a 2D analysis. However, recent studies suggest that a local analysis is not sufficient. In the present study we developed a method to create animal-specific 3D finite element models of an indentation test on the tibialis anterior muscle of rats based on MRI data. A detailed description on how the animal specific models are created is given. Furthermore, two indenter geometries are compared and the influence of errors in determining the indenter orientation on the resulting internal strain distribution in a defined volume of tissue was investigated. We conclude that with a spherically-shaped indenter errors in estimating the indenter orientation do not unduly influence the results of the simulation. PMID- 30398075 TI - Cortical astroglia undergo transcriptomic dysregulation in the G93A SOD1 ALS mouse model. AB - Astroglia are the most abundant glia cell in the central nervous system, playing essential roles in maintaining homeostasis. Key functions of astroglia include, but are not limited to, neurotransmitter recycling, ion buffering, immune modulation, neurotrophin secretion, neuronal synaptogenesis and elimination, and blood-brain barrier maintenance. In neurological diseases, it is well appreciated that astroglia play crucial roles in the disease pathogenesis. In amyotrophic lateral sclerosis (ALS), a motor neuron degenerative disease, astroglia in the spinal cord and cortex downregulate essential transporters, among other proteins, that exacerbate disease progression. Spinal cord astroglia undergo dramatic transcriptome dysregulation. However, in the cortex, it has not been well studied what effects glia, especially astroglia, have on upper motor neurons in the pathology of ALS. To begin to shed light on the involvement and dysregulation that astroglia undergo in ALS, we isolated pure grey-matter cortical astroglia and subjected them to microarray analysis. We uncovered a vast number of genes that show dysregulation at end-stage in the ALS mouse model, G93A SOD1. Many of these genes play essential roles in ion homeostasis and the Wnt-signaling pathway. Several of these dysregulated genes are common in ALS spinal cord astroglia, while many of them are unique. This database serves as an approach for understanding the significance of dysfunctional genes and pathways in cortical astroglia in the context of motor neuron disease, as well as determining regional astroglia heterogeneity, and providing insight into ALS pathogenesis. PMID- 30398076 TI - Implication of obesity on motion, posture and internal stress of the foot: an experimental and finite element analysis. AB - Obesity causes increased loading on the foot which can damage the soft tissue and bone ultimately leading to foot problems. Experimental and computational methods were used to analyse the chain of biomechanical changes in the lower limb due to obesity. The experimental study shows some changes in foot posture and gait where obese subjects were more likely to have pronated feet, smaller joint angles in the sagittal and frontal planes, smaller cadence, and smaller stride length. Anatomically correct finite element models generated on obese subjects showed increased and altered internal and plantar stress. Altered foot posture was identified as a key indicator of increased internal stress indicating the importance of foot posture correction. PMID- 30398077 TI - A fully coupled fluid-structure interaction model of the secondary lymphatic valve. AB - The secondary lymphatic valve is a bi-leaflet structure frequent throughout collecting vessels that serves to prevent retrograde flow of lymph. Despite its vital function in lymph flow and apparent importance in disease development, the lymphatic valve and its associated fluid dynamics have been largely understudied. The goal of this work was to construct a physiologically relevant computational model of an idealized rat mesenteric lymphatic valve using fully coupled fluid structure interactions to investigate the relationship between three-dimensional flow patterns and stress/deformation within the valve leaflets. The minimum valve resistance to flow, which has been shown to be an important parameter in effective lymphatic pumping, was computed as 268 g/mm4-s. Hysteretic behavior of the lymphatic valve was confirmed by comparing resistance values for a given transvalvular pressure drop during opening and closing. Furthermore, eddy structures were present within the sinus adjacent to the valve leaflets in what appear to be areas of vortical flow; the eddy structures were characterized by non-zero velocity values (up to ~4 mm/s) in response to an applied unsteady transvalvular pressure. These modeling capabilities present a useful platform for investigating the complex interplay between soft tissue motion and fluid dynamics of lymphatic valves and contribute to the breadth of knowledge regarding the importance of biomechanics in lymphatic system function. PMID- 30398078 TI - Advanced adenomas and early colorectal cancers - SATC center (SATCC). A Danish initiative for the standardization and improvement of treatment of early, significant colorectal neoplasms. PMID- 30398079 TI - The MERlin database as a standardisation tool for UK medical curricula. PMID- 30398080 TI - Double jeopardy: a review of weight gain and weight management strategies for psychotropic medication prescribing during methadone maintenance treatment. AB - Methadone maintenance treatment (MMT) is an important treatment tool for the opioid epidemic. One challenge is that many persons who present for MMT also have co-occurring psychiatric disorders. Individually, both methadone and psychiatric medications carry risk of weight gain. Therefore, concurrent prescribing of methadone and psychiatric medications places dual diagnosis patients at even greater risk. As a parallel obesity epidemic grows, results from clinical trials assessing weight gain and weight management strategies among MMT and psychiatric patients can both inform and guide clinical practice. This study reviews findings from a literature search for recent clinical trials that focused on weight gain and weight management strategies during MMT with concurrent psychotropic medication use. While several studies have documented weight gain during MMT and psychotropic medication treatment, this study failed to identify recent work that explored concurrent prescribing. Most weight management strategies involved the use of additional medications and available data suggests that MMT and concurrent use of psychotropic medications increases the risk for obesity. More robust research is needed on weight gain and potential mitigation strategies when these treatment modalities are jointly utilized. Clarification of underlying biological mechanisms and development of non-pharmacological interventions merit further consideration. PMID- 30398081 TI - Social mission and medical school admissions - A medical student's response. PMID- 30398082 TI - Analysis of outpatient HER2 testing in New York state using the statewide planning and research cooperative system. AB - AIM: HER2 testing is necessary in the context of therapy with trastuzumab, pertuzumab, lapatinib and neratinib. There is a paucity of reports describing the utilization rates of HER2 testing in large outpatient populations. METHODS: The Statewide Planning and Research Cooperative System (SPARCS) was used to examine HER2 testing across the state of New York (USA) during the 2012-2016 period. RESULTS: There was a linear increase in HER2 testing (r = 0.91, p = 0.030). There were increases in HER2 testing observed among minorities, including 0.5-fold and 3.5-fold increases in individuals identified as black and Asian, respectively. Major state population centers showed the highest HER2 testing. CONCLUSION: This study establishes a platform to further evaluate clinical utility, outcomes and equity of access for 'precision oncology' testing. PMID- 30398083 TI - The effect of hyperglycemia on neurovascular coupling and cerebrovascular patterning in zebrafish. AB - Neurovascular coupling (through which local cerebral blood flow changes in response to neural activation are mediated) is impaired in many diseases including diabetes. Current preclinical rodent models of neurovascular coupling rely on invasive surgery and instrumentation, but transgenic zebrafish coupled with advances in imaging techniques allow non-invasive quantification of cerebrovascular anatomy, neural activation, and cerebral vessel haemodynamics. We therefore established a novel non-invasive, non-anaesthetised zebrafish larval model of neurovascular coupling, in which visual stimulus evokes neuronal activation in the optic tectum that is associated with a specific increase in red blood cell speed in tectal blood vessels. We applied this model to the examination of the effect of glucose exposure on cerebrovascular patterning and neurovascular coupling. We found that chronic exposure of zebrafish to glucose impaired tectal blood vessel patterning and neurovascular coupling. The nitric oxide donor sodium nitroprusside rescued all these adverse effects of glucose exposure on cerebrovascular patterning and function. Our results establish the first non-mammalian model of neurovascular coupling, offering the potential to perform more rapid genetic modifications and high-throughput screening than is currently possible using rodents. Furthermore, using this zebrafish model, we reveal a potential strategy to ameliorate the effects of hyperglycemia on cerebrovascular function. PMID- 30398084 TI - Ultrasonic-assisted synthesis and DNA interaction studies of two new Ru complexes; RuO2 nanoparticles preparation. AB - AIM: To study of the interactions of two new ruthenium(II) complexes (C1 and C2) with calf thymus (CT)-DNA; production of RuO2 nanoparticles using the complexes precursor. MATERIALS & METHODS: Complex C1 was characterized by x-ray crystallography. The binding of the complexes with (CT)-DNA was studied using techniques that include electronic absorption spectra, fluorescence and redox behavior. The preparation of RuO2 nanoparticles was carried out by thermal decomposition. RESULTS: The interaction mode of DNA with complexes is the type of electrostatic. It was revealed that sonication of the samples, before thermal decomposition, has been affected the morphologies and sizes of the resulting nanoparticles. CONCLUSION: The complexes are capable of interaction with DNA molecules and they have a good potential to prepare nanostructures. PMID- 30398085 TI - Pharmacogenetic relevance of endothelial nitric oxide synthase polymorphisms and gene interactions. AB - Endothelial nitric oxide synthase (NOS3) is a key enzyme responsible for nitric oxide (NO) generation in the vascular endothelium. Endothelial dysfunction is characterized by reduced NO production, and is a hallmark of cardiovascular diseases. Drugs with cardiovascular action may activate NOS3 and result in NO release and vasodilation. Moreover, genetic variations affect NOS3 expression and activity, and may partially explain the variability in the responses to cardiovascular drugs. We reviewed NO signaling and genetic effects on NO formation, and the effects of NOS3 polymorphisms, haplotypes and gene-gene interactions within NO signaling pathways on the responses to cardiovascular drugs. We discuss the role of rare NOS3 variants and further gene-gene interactions analysis for the development of novel therapies for cardiovascular diseases. PMID- 30398086 TI - Pharmacogenetics to prevent heparin-induced thrombocytopenia: what do we know? AB - Heparin-induced thrombocytopenia (HIT) is a life-threatening, immune-mediated adverse reaction to heparin anticoagulants. The inability to predict HIT represents a considerable liability associated with heparin administration. Genetic studies of HIT are challenging due to the scarcity of true HIT cases, potential for misclassification, and many environmental risk factors. Genetic studies have not consistently identified risk alleles for HIT, the production of platelet factor 4/heparin antibodies or the thromboembolic complications of HIT. Genes implicated in HIT and platelet factor 4/heparin antibody levels include FCGR2A, TDAG8, HLA-DR and others. Compelling evidence also suggests that the FCGR2A H131R polymorphism is associated with HIT-related thrombosis. There is a need for well-powered, multiethnic studies with laboratory confirmation of HIT, detailed patient- and drug-specific data, and inclusion of both serologic and thromboembolic outcomes. Genomic biomarkers identified from such studies offer the possibility of shifting current clinical practice paradigms from early detection and treatment to prevention. PMID- 30398088 TI - Experiences of telephone communication training at the University of Bristol. PMID- 30398087 TI - Risk factors for social withdrawal in amyotrophic lateral sclerosis/motor neurone disease. AB - BACKGROUND: Greater social withdrawal is related to higher levels of psychological distress and poorer adaptation to a diagnosis of amyotrophic lateral sclerosis. OBJECTIVES: To examine whether demographics and functional deficits can be used to assess which patients may be at risk of social withdrawal and whether symptoms including depression and anxiety can provide additional information for identifying individuals at risk. Furthermore, to examine whether patient-perceived stigma has a role in mediating the effects of any of the predictors of social withdrawal. METHODS: A total of 559 participants in the ongoing Trajectories of Outcomes in Neurological Conditions (TONiC) study completed a questionnaire pack collecting data on demographics and a range of patient reported measures. Multiple regression analysis was employed to assess associations of functional ability, demographics, physical symptoms, anxiety, and depression with social withdrawal. The mediating role of stigma was assessed through the development of a bivariate linear regression model for stigma and social withdrawal. RESULTS: Disability in the bulbar and motor domains, anxiety and depression were found to be significant predictors of social withdrawal. Stigma was the strongest single predictor of social withdrawal and was found to partially mediate the effects of functional deficits and mood on social withdrawal. CONCLUSIONS: Social withdrawal is associated with worse motor disability and poorer bulbar function, as well as increased anxiety and depression. Stigma is a powerful predictor for social withdrawal; further work should investigate whether stigma is a potential target for psychological interventions aimed at reducing social withdrawal and improving quality of life. PMID- 30398089 TI - An approach to generate noncontact ACL-injury prone situations on a computer using kinematic data of non-injury situations and Monte Carlo simulation. AB - ACL-injuries are one of the most common knee injuries in noncontact sports. Kinematic data of injury prone situations provide important information to study the underlying ACL-injury mechanisms. However, these data are rare. In this work an approach is presented to generate injury prone situations for noncontact ACL injuries on a computer. The injury prone situations are generated by a musculoskeletal simulation model using kinematic data of a non-injury situation and the method of Monte Carlo simulation. The approach is successfully applied to generate injury prone landings in downhill ski racing. The characteristics of the obtained injury prone landings are consistent with video recordings of injury cases. PMID- 30398090 TI - Comparison of the automatic segmentation of multiple organs at risk in CT images of lung cancer between deep convolutional neural network-based and atlas-based techniques. AB - BACKGROUND: In this study, a deep convolutional neural network (CNN)-based automatic segmentation technique was applied to multiple organs at risk (OARs) depicted in computed tomography (CT) images of lung cancer patients, and the results were compared with those generated through atlas-based automatic segmentation. MATERIALS AND METHODS: An encoder-decoder U-Net neural network was produced. The trained deep CNN performed the automatic segmentation of CT images for 36 cases of lung cancer. The Dice similarity coefficient (DSC), the mean surface distance (MSD) and the 95% Hausdorff distance (95% HD) were calculated, with manual segmentation results used as the standard, and were compared with the results obtained through atlas-based segmentation. RESULTS: For the heart, lungs and liver, both the deep CNN-based and atlas-based techniques performed satisfactorily (average values: 0.87 < DSC < 0.95, 1.8 mm < MSD < 3.8 mm, 7.9 mm < 95% HD <11 mm). For the spinal cord and the oesophagus, the two methods had statistically significant differences. For the atlas-based technique, the average values were 0.54 < DSC < 0.71, 2.6 mm < MSD < 3.1 mm and 9.4 mm < 95% HD <12 mm. For the deep CNN-based technique, the average values were 0.71 < DSC < 0.79, 1.2 mm < MSD <2.2 mm and 4.0 mm < 95% HD < 7.9 mm. CONCLUSION: Our results showed that automatic segmentation based on a deep convolutional neural network enabled us to complete automatic segmentation tasks rapidly. Deep convolutional neural networks can be satisfactorily adapted to segment OARs during radiation treatment planning for lung cancer patients. PMID- 30398091 TI - A student's perspective on emotional intelligence education. PMID- 30398092 TI - Potential Dietary Supplement and Medication Interactions in a Subset of the Older Adult Population Attending Congregate Sites. AB - This study assessed possible dietary supplement-medication interactions of 62 older adults recruited from 8 senior congregate sites in Bexar County, Texas. Dietary supplement and medication use were collected by paper questionnaire and potential supplement-medication interactions were assessed using online databases. The majority of participants reported dietary supplements (77%), non prescription medication (50%), and prescription medication (73%) use. Fifty percent of participants who reported dietary supplement and medication use were at-risk for a potential supplement-medication interaction, ranging from one to eight potential interactions. Calcium and multivitamin-mineral supplements were the most common dietary supplements with potential medication interactions. Surveyed older adults reported dietary supplements should be reported to a physician (97%), but over 20% believe herbal products are pure (38%) and dietary supplements are risk free (34%) and will not cause harm (22%). In conclusion, regular education and screening of dietary supplement and medication use among older adults is recommended. PMID- 30398093 TI - 19. Unionstagung der Schweizerischen Gesellschaften fur Gefasskrankheiten gemeinsam mit der Schweizerischen Gesellschaft fur Ultraschall in der Medizin Sektion Gefasse / 19e Congres de l'Union des Societes Suisses des Maladies Vasculaires en collaboration avec la Societe Suisse d'Ultrasons en Medecine Section Vaisseaux. PMID- 30398094 TI - Nuclear medicine and anatomic pathology in personalized medicine: a challenging alliance. PMID- 30398095 TI - Listening to Bedouin fathers of children with autism spectrum disorder. AB - Although children across the world experience autism spectrum disorder (ASD), most research on ASD has been conducted using Western cultural perspectives and has focused primarily on mothers, leaving significant gaps in the literature. This study aimed to address these gaps by exploring the experiences of fathers raising children with ASD in a Bedouin community. To this end, a sample of 19 fathers of children (aged 6-15 years) with ASD living in recognized and unrecognized Bedouin settlements in the Negev participated in ethnographic, semi structured interviews designed to investigate their experiences with raising a child with ASD in their community. Two major themes emerged: the challenges that Bedouin fathers of children with ASD face, and the influence of socio-demographic and cultural characteristics on their experience. Findings reflect the complex experiences of fathers raising children with ASD in the Bedouin community, stemming from their socio-cultural context and the limited knowledge and support services that are available in the community for these children. This article concludes with recommendations on how to enhance professional sensitivity and provide more culturally tailored services for parents of children with ASD. PMID- 30398096 TI - Attitudes Toward Organ Donation and Transplantation Among Transplant-Related Health Care Workers and the Local Population of Montenegro. AB - OBJECTIVES: The aim of this research was to determine the attitudes of transplant related health care workers and the local population of Montenegro toward organ donation and transplantation. MATERIALS AND METHODS: Our study included 200 transplant-related health care professionals (from the Clinical Center of Montenegro, the only transplant hospital in the country) and 200 volunteers from Podgorica (the capital of Montenegro). Their attitudes were evaluated using an anonymous, self-administered, multiple-choice questionnaire. RESULTS: Most health care workers would donate their organs only on specific occasions (43.6%), whereas the general population was divided between willingness to donate only on specific occasions and the need to consider the decision of donating (34.6% each). Both groups of respondents predominantly claimed that they would donate their organs to any potential recipient, regardless of sensory or physical disability. A positive opinion regarding the promotion of organ donation, as well as the need for legal regulation of the transplant process, was noted in both groups of responders. CONCLUSIONS: There is a need to increase the generosity of the Montenegrin population and its health care workers regarding organ donation at all times and not exclusively on specific occasions. PMID- 30398097 TI - Comparison of Standard and Modified Standard Organ Procurement Techniques for Deceased Donors. AB - OBJECTIVES: This study aimed to compare the impact of deceased-donor organ procurement techniques (standard versus modified standard) on biochemical outcomes after liver transplant. MATERIALS AND METHODS: From February 2006 to December 2013, organs were recovered from 105 consecutive deceased donors by our transplant team. All organ procurement procedures were performed by a pioneer surgeon experienced in organ recovery from deceased donors. Donors were divided into those who had the abdominothoracic approach, which is referred to as the standard technique, and those who had the abdominal approach, which is referred to as the modified standard technique. Both groups were compared in terms of age, sex, weight, height, body mass index, liver graft weight, cross-clamping time, cold ischemia time, and liver function tests in recipients over the first 3 postoperative days. RESULTS: Our study group included 66 male and 39 female donors, with an age range of 1 to 93 years (median of 44 y, means +/- standard deviation of 43.8 +/- 23.7 y). Among the deceased donors, 73 underwent the modified standard technique and 32 underwent the standard technique. There were no statistically significant differences between groups in terms of age, sex, weight, height, body mass index, graft weight, cold ischemia time, and liver function tests in recipients over the first 3 postoperative days. We observed a statistically significant difference between groups in terms of cross-clamping time (P < .001). CONCLUSIONS: Except for the decreased cross-clamping time, the modified standard technique for deceased organ retrieval had no effect on clinical outcomes in recipients after liver transplant. However, this retrospective study requires additional prospective investigations to more fully understand the differences. PMID- 30398098 TI - Acoustic Radiation Force Impulse Elastography Findings of Achilles Tendons in Patients on Chronic Hemodialysis and in Renal Transplant Patients. AB - OBJECTIVES: The Achilles tendon, which is composed of tendinous parts of gastrocnemius and soleus muscles, is the strongest and the largest tendon in the human body. Chronic renal disease can lead to reduced physical activity and exercise capacity. Spontaneous rupture of the Achilles tendon can occur in patients with chronic renal failure, with recurrent microtraumas, hypoxia, and chronic acidosis as predisposing factors. Here, we assessed and compared the elastographic findings in the Achilles tendon using acoustic radiation force impulse elastography in patients on chronic hemodialysis, in renal transplant patients, and in healthy volunteers. MATERIALS AND METHODS: Our study included 25 patients on chronic hemodialysis, 25 renal transplant patients, and 25 healthy individuals (control group). The thickness and shear wave velocity of the Achilles tendons were measured bilaterally by ultrasonography and acoustic radiation force impulse elastography. RESULTS: The mean shear wave velocity was 3.67 m/s in the right and 3.64 m/s in the left Achilles tendon in the hemodialysis group. In the renal transplant group, the mean shear wave velocity was 4.29 and 4.25 m/s for the right and left Achilles tendon, respectively. In the control group, the mean shear wave velocity was 6.68 and 6.59 m/s, respectively for the right and left Achilles tendon. A statistically significant difference in shear wave velocities was shown among the groups (P < .05). CONCLUSIONS: Achilles tendons in patients with chronic renal failure and on hemodialysis were softer than in renal transplant patients and softer than in the control group. Chronic tendinopathy causes softening of the tendon. In the renal transplant group, stiffness of the Achilles tendon was increased versus the hemodialysis group but still softer than the control group, which could be explained as a positive clinical effect of renal transplant. Acoustic radiation force impulse elastography is an objective, easy, and noninvasive method to assess Achilles tendinopathy. PMID- 30398099 TI - De Novo Primary Liver Cancer After Liver Transplantation: A French National Study on 15803 Patients. PMID- 30398100 TI - Use of Computed Tomography Volumetry to Assess Liver Weight in Patients With Cirrhosis During Evaluation Before Living-Donor Liver Transplant. AB - OBJECTIVES: Computed tomography liver volumetry has been widely used to detect total and segmental liver volume in living-donor liver transplantation. However, use of this technique to evaluate the cirrhotic liver remains unclear. In this study, we evaluated the accuracy of freehand computed tomography volumetry to assess total liver volume by comparing weights of total hepatectomy specimens in patients with cirrhosis. For our analyses, we considered the density of a cirrhotic liver to be 1.1 kg/L. MATERIALS AND METHODS: Liver volume was measured using a freehand computed tomography technique in 52 patients with cirrhosis from different causes and who had no solid lesions before transplant. Measurements were made with a 16-slice multidetector computed tomography scanner (Siemens Somatom Sensation 16, Erlangen, Germany). For volumetric measurements, 10-mm thick slices with 10-mm reconstruction intervals were preferred. Total hepatectomy weights of explant livers and computed tomography volumetry data were compared. RESULTS: We excluded 3 cirrhotic patients with Budd-Chiari syndrome due to wide variations in scatterplot results. In the 49 patients included in the final analyses, average estimated liver volume by computed tomography was 721 +/- 398 mL and actual cirrhotic liver weight was 727.8 +/- 415 g. No significant differences were shown between these measurements. A simple regression analysis used to analyze correlations between estimated liver volume by computed tomography and real cirrhotic liver weight showed correlation of 0.957 (P < .001). When computed tomography liver volumetry as the independent variable and cirrhotic liver weight as dependent variable were considered, regression analyses showed R2 = 0.915. CONCLUSIONS: Freehand computed tomography liver volumetry can be confidently used to evaluate liver volume in cirrhotic liver patients similar to use of this technique to estimate actual weights in normal livers. This technique can also be valuable during pretransplant and liver resection evaluations to ensure a more successful outcome. PMID- 30398101 TI - Simultaneous Pancreas-Kidney Transplant After Bricker Loop Urinary Diversion: A Case Report. AB - Simultaneous pancreas-kidney transplant is the ultimate therapy for patients who have uncontrolled and complicated type 1 diabetes mellitus with end-stage renal disease. The combined pancreas transplant provides a euglycemic milieu for the kidney and protects it from recurrence of diabetic complications. Our patient, a 41-year-old woman with end-stage diabetic nephropathy and history of multiple abdominal surgeries (ovarian cyst fenestration, adnexal extirpation, abdominal wall reconstruction), including urinary diversion (Bricker loop, above double J stent), underwent simultaneous pancreas-kidney transplant. After reperfusion, the kidney had immediate function and creatinine levels dropped to normal levels during the early postoperative period (creatinine of 102 MUmol/L, estimated glomerular filtration rate of 52 mL/min/1.73 m2) and remained stable during follow-up. Serum glucose levels dropped to within normal ranges postoperatively and remained so during follow-up. The postoperative course was complicated by hydronephrosis due to transient edema of the anastomosis of the ureter to the Bricker loop, after early incidental removal of the double J catheter. This was successfully treated with a temporary percutaneous nephrostomy. Multiple previous surgeries, including a Bricker deviation, may not be a definitive contraindication for simultaneous pancreas-kidney transplant. In selected cases, special considerations may lead to a successful procedure providing better quality of life and life expectancy, even for patients with multiple comorbidities. PMID- 30398102 TI - Manipulation of the immune system for cancer defeat: a focus on the T cell inhibitory checkpoint molecules. AB - The immune system actively counteracts the tumorigenesis process; a breakout of the immune system function, or its ability to recognize transformed cells, can favor cancer development. Cancer becomes able to escape from immune system control by using multiple mechanisms, which are only in part known at a cellular and molecular level. Among these mechanisms, in the last decade, the role played by the so-called "inhibitory immune checkpoints" is emerging as pivotal in preventing the tumor attack by the immune system. Physiologically, the inhibitory immune checkpoints work to maintain the self-tolerance and attenuate the tissue injury caused by pathogenic infections. Cancer cell exploits such immune inhibitory molecules to contrast the immune intervention and induce tumor tolerance. Molecular agents that target these checkpoints represent the new frontier for cancer treatment. Despite the heterogeneity and multiplicity of molecular alterations among the tumors, the immune checkpoint targeted therapy has been shown to be helpful in selected and even histologically different types of cancer, and are currently being adopted against an increasing variety of tumors. The most frequently used is the moAb-based immunotherapy that targets the Programmed Cell Death 1 protein (PD-1) or the PD-1 Ligand (PD-L1) or the cytotoxic T lymphocyte antigen-4 (CTLA4). However, new therapeutic approaches are currently in development, along with the discovery of new immune checkpoints exploited by the cancer cell. This article aims to review the inhibitory checkpoints, which are known up to now, along with the mechanisms of cancer immunoediting. An outline of the immune checkpoint targeting approaches, also including combined immunotherapies and the existing trials, is also provided. Notwithstanding the great efforts devoted by researchers in the field of biomarkers of response, to date, no validated FDA-approved immunological biomarkers exist for cancer patients. We highlight relevant studies on predictive biomarkers and attempt to discuss the challenges in this field, due to the complex and largely unknown dynamic mechanisms that drive the tumor immune tolerance. PMID- 30398104 TI - Polyphenols: plant sources and food industry applications. AB - BACKGROUND: Numerous epidemiological studies have demonstrated the association between (poly)phenol-rich foods and human health. Growing consumer knowledge of the relationship between diet, good health and disease prevention stimulated manufacturing opportunities. Functional foods and their synergistic health benefits, beyond just being a source of individual nutrients, are highly demanded by consumers. OBJECTIVE: Therefore, the aim of this study was to review available literature focusing on the nutraceutical role of (poly)phenols, and role in functional foods production, with specific focus on (poly)phenols derived from by products. RESULTS: The review of the literature showed that antioxidant extracted from residual sources could prevent lipid peroxidation and protect against oxidative damage by scavenging oxygen radicals, and therefore contribute to the longer stability of foods.be used for increasing the stability of foods by preventing These effects may also translate to humans, improving the effects on health of certain foods. CONCLUSIONS: However, careful monitoring of production is needed in order to maximize the (poly)phenol content of plant foods. PMID- 30398105 TI - Cancer Immunomics in the Age of Information: Role in Diagnostics and Beyond. AB - Cancer genome sequencing is useful for diagnosis and personalized treatment. Analysis of the sequencing data involves integration of computation, statistics and system biology methods. The amalgam of such methods which help study interaction of cancer cells with immune system, harnessing immune system for cancer therapy or its prevention through vaccines has led to the foundation of cancer immunomics. It is, therefore, a combinatorial science which merges diverse techniques from genomics and proteomics for diagnosis and drug design/treatment. There has been a gradual increase in establishment of cancer immune focused start ups, research facilities and pharma giants working on state-of-the-art methods for improving diagnostics, treatment and prevention or minimizing side effects, applying immunomics. However, we are still far away from making precise, quick and reliable diagnostic and treatment predictions. We need decision support systems to facilitate diagnosis, tumor evaluation prediction and assessment of individual profile for making personalized therapy a reality. The future is centered not only on data management but wise decision aided by artificially intelligent algorithms. In this review, we provide an overall picture and focus on immune biomarkers and relevant softwares that aid in diagnostics and analysis of cancer. PMID- 30398106 TI - Cancer Immunoinformatics: A Promising Era in the Development of Peptide Vaccines for Human Papillomavirus induced Cervical cancer. AB - Cancer immunoinformatics have new directions towards in vaccine design from predicted potential epitope candidates, able to stimulate a correct cellular or humoral immune responses have been reported. It employed to accomplish an advanced vaccine design through Reverse vaccinology by replacing the whole organisms. In this review, computational tools play an essential role in evaluating multiple proteomes to identify and select the potential targeted epitopes or combinations of distinct epitopes candidates may afford a rationale design competent towards obtaining suitable cytotoxic T lymphocytes (T cell) or B cell-mediated immune responses. This review explains a complete collection of the most beneficial online and user-friendly immunological tools, servers and databases; with the intention of the peptide vaccine's designing and development. In addition, the mechanism of major histocompatability (MHC) restricted peptide presentation and how these tools are supporting the vaccine development is also presented. Human papillomavirus (HPV) has been taken as model microbial strain for peptide vaccine design and discussed their sensitization against HPV induced cervical cancer significantly. PMID- 30398107 TI - A Network-Based Cancer Drug Discovery: From Integrated Multi-Omics Approaches to Precision Medicine. AB - A complex framework of interacting partners including genetic, proteomic, and metabolic networks that cooperate to mediate specific functional phenotypes drives human biological processes. Recent technological and analytical advances in "omic" sciences allow the identification and elucidation of reprogramming biological functions in response to perturbations in cells and tissues. To understand such a complex system, biological networks are generated to reduce the complexity into relatively simple models, and the integration of these molecular networks from different perspectives is implemented for a holistic interpretation of the entire system. Ultimately, network-based methods will effectively facilitate the development and improvement of precision medicine by directing therapies based on the underlying biology of a given patient's disease. The goal of precision medicine is to identify novel therapeutic strategies that can be optimized for each disease type or each patient based on the underlying genetic, environmental, and lifestyle factors. Pharmaco-omics analyses based on an integration of pharmacology and various "omics" data types can be employed to develop effective treatment strategies using particular drugs and doses that are tailored to each individual. In the current review, we first present the core elements of network-based systems biology in the context of pharmaco-omics followed by integration of multi-omics data using various biological networks. Next, we provide an opening into precise medicine and drug targeting based on network approaches. Lastly, we review the current significant efforts as well as the accomplishments and limitations in precise drug targeting with the utility of network-based guided drug discovery methods for effective treatment of breast cancer. PMID- 30398108 TI - The Landscape of Protein Tyrosine Phosphatase (Shp2) and Cancer. AB - Role of Shp2: The dysregulation of cell signaling cascades associated with the cell differentiation and growth, due to the deletion, insertion or point mutation in specific amino acids which alters the intrinsic conformation of the protein, can ultimately lead to a fatal cancer disease. The protein tyrosine phosphatase has been recognized as a key regulator of extracellular stimuli such as cytokine receptor and receptor tyrosine kinase signaling. In the last era, the PTPN11 gene (encode a Shp2 protein) and its association with acute myeloid, juvenile myelomonocytic, and B-cell acute lymphoblastic leukemia, Noonan syndrome, and myelodysplastic has been recognized, the cause of such deadly disease due to the occurrence of germline mutations in the interface of PTP and SH2 domain. Conclusion: The current study was designed to focus on the allosteric regulation (autoinhibition) of the of Shp2 protein. Subsequently, it will cover the last 10 year recap of Shp2 protein, their role in cancer, and regulation in numerous ways (allosteric regulation). PMID- 30398109 TI - Computational and experimental binding mechanism ofDNA- drug interactions. AB - Nucleic acid are the key unit and predominant genetic material for interpreting the fundamental basis of genetic information in an organism and now it's used for the evolution of a novel group of therapeutics. To identify the potential impact in the biological science, it receives high recognition in therapeutic applications.Due to their selective recognition of molecular targets and pathways, DNA significantly imparts tremendous specificity of action. With its high advantages in the assembly of device, interconnects and computational elements DNA has shown great potential fabrication and construction of nanostructures and devices. The interaction of low molecular weight small molecules with DNA is significant feature in pharmacology. Based on mode of binding mechanisms small molecules are categorized as intercalators and groove binders which has significant role in target-based drug development. The understanding mechanism of drug-DNA interaction plays a crucial part in the development of novel drug molecules with more effective and lesser side effects. This article is attempts to outline those interactions of drug-DNA with both experimental and computational advances, including ultraviolet (UV)-visible spectroscopy, fluorescent spectroscopy, circular dichroism, Nuclear magnetic resonance (NMR), molecular docking & dynamics and quantum mechanical applications. PMID- 30398110 TI - Detecting personalized determinates during drug treatment from omics big data. AB - BACKGROUNDS: The targeted therapy is the foundation of personalized medicine in cancer, which is often understood as the right patient using the right drug. Thinking from the viewpoint of determinates during personalized drug treatment, the genetics, epigenetics and metagenomics would provide individual-specific biological elements to characterize the personalized responses for therapy. METHODS: Such personalized determinates should be not extremely understood as specificity for only one person, while they should have certain replicate observations in a group of individuals but no all, which actually provide more credible and reproducible personalized biological features. And the requirement of detecting personalized determinates is well supported by novel high-throughput sequencing technologies and newly temporal-spatial experimental protocols, which quickly produce the omics big data. RESULTS: In this mini-review, we would like to give a brief introduction firstly on the advanced drug or drug-like therapy with genetics, epigenetics and metagenomics respectively from the viewpoint of personalized determinates; then summarize the computational methods helpful to analyze the corresponding omics data under the consideration of personalized biological context; and particularly focus on the metagenomics to discuss current data, method, and opportunity for personalized medicine. CONCLUSIONS: Totally, detecting personalized determinates during drug treatment from omics big data will bring the precision medicine or personalized medicine from concept to application. More and more inspiring bio-technologies, data resources, and analytic approaches will benefit All of US in the near future. PMID- 30398111 TI - Prospecting and Structural insight into the binding of Novel Plant-Derived Molecules of Leea indica as Inhibitors of BACE-1. AB - Alzheimer disease (AD) can be considered as the most common age related neurodegenerative disorder, undoubtedly; and also a very important cause of death in elderly patients. A number of studies found the correlation of this disease pathology with BACE1 inhibitor and it is also evident that BACE1 inhibitor can function as a very potent treatment strategy in treating AD. In this present study, we aimed to prospect for novel plant-derived BACE1 inhibitors from Leea indica and to realise structural basis of their interaction mechanism using combined molecular docking and molecular dynamics based approaches. An extensive library of Leea indica plant derived molecule was compiled and computationally screened for inhibitory action against BACE1, through virtual screening approaches. Furthermore, induced fit docking and classical molecular dynamics along with steered molecular dynamics simulations were employed to get insight the binding mechanisms. Two triterpenoids, ursolic acid and lupeol were identified through virtual screening; wherein, lupeol showed better binding free energy in MM/GBSA, MM/PBSA and MM/GBVI approaches. Furthermore classical and steered dynamics revealed the favourable hydrophobic interactions between the lupeol and the residues of flap or catalytic dyad of BACE1; however, ursolic acid showed disfavorable interactions with the BACE1. This study therefore unveiled the potent BACE1 inhibitor from a manually curated dataset of Leea indica molecules, which may provide a dimension of designing novel BACE1 inhibitors for AD therapy. PMID- 30398113 TI - Preparation and characterization of a novel room temperature dicationic ionic liquid and its application in the synthesis of xanthenediones under solvent-free conditions. AB - A novel room temperature dicationic ionic liquid, namely 1, 1' sulfinyldiethylammonium bis (hydrogen sulfate), was prepared and characterized by 1H NMR, 13C NMR, and FT-IR as well as Hammett acidity function and used as a powerful and recyclable catalyst for the synthesis of xanthenediones with high to excellent yields as well as short reaction times under solvent-free conditions. PMID- 30398112 TI - Regulation of feeding behavior and energy metabolism by galanin-like peptide (GALP): a novel strategy to conquer fight against obesity. AB - Galanin-like peptide (GALP) is composed of 60 amino acid residues and its sequence is highly homologous across species. GALP is produced in the hypothalamic arcuate nucleus and has diverse physiological effects such as the regulation of feeding, energy metabolism, and reproductive behavior. GALP containing neurons express leptin receptors and these neurons form networks in the hypothalamus that contain various peptides that regulate feeding behavior. Recent studies have revealed that GALP has a central anti-obesity action in addition to its role in food intake regulation. Furthermore, we have found that the respiratory quotient declines shortly after administration of GALP into the lateral ventricle. This suggests that lipid metabolism is accelerated by GALP administration, and identifies a new physiological action for this peptide. In this review article, we summarize our recent research focusing on the mechanism whereby GALP regulates feeding and energy metabolism. We concentrate on the mechanism of regulation of lipid metabolism in peripheral tissues via the autonomic nervous system and outline the effectiveness of the nasal administration of GALP and basic research towards its clinical application. PMID- 30398114 TI - Scorpion toxins targeting voltage-gated sodium channels associated with pain. AB - Pain affects approximately 30% of people and places a large economic and social burden on society. Despite the availability of a range of analgesics, complete alleviation of symptoms are still rarely occurred. Effective and safe drugs for the treatment of pain are still an unmet clinical need. In recent years, the voltage-gated sodium channels (VGSCs) have been recognized as potential targets for analgesic development. VGSCs are major players in generating and propagating action potentials. They represent an appealing target for the development of new and safer drugs in the treatment of pain. The majority of the research has been focused on Nav1.7 in particular, other VGSC subtypes, such as Nav1.1, Nav1.3, Nav1.6, Nav1.8 and Nav1.9 have recently come to the forefront of analgesic research. Peptides from scorpion have been proved to be a valuable tool in neuroscience, playing a significant role in the identification and characterization of VGSC subtypes and many of them resulting in analgesia in pain. This review assesses the potential of scorpion toxin targeting VGSCs for analgesic development. PMID- 30398115 TI - Alleviating the Neglected Tropical Diseases: Recent Developments in Diagnostics and Detection. AB - Background Neglected tropical diseases (NTDs) are communicable diseases caused by a group of bacteria, viruses, protozoa and helminths prevalent in more than 145 countries that affect the world's poverty stricken populations. WHO enlists 18 NTDs amongst people living in endemic areas having inaccessibility to preventive measures. Steps to reduce the global disease burden of the NTDs need attention at multi-factorial levels. Control programmes, mass drug administrations, transmission checks, eradication surveillances and diagnoses are some of them. The foremost in this list is confirmatory diagnosis. A comprehensive summary of the innovative, high-impact, multiplexed, low-cost diagnostic tools developed in the last decade that helped to meet the needs of users can depict a holistic approach to further evaluate potential technologies and reagents currently in research. Major advancements A literature survey based on developing nano biotechnological platforms to meet the diagnostic challenges in NTDs towards development of a useful point-of-care (POC) unit is reported. However, in order to pave the way for complete eradication more sensitive tools are required that are user-friendly and applicable for use in endemic and low-resource settings. There are various novel research progresses/advancements made for qualitative and quantitative measurement of infectious load in some diseases like dengue, Chagas disease and leishmaniasis; though further improvements on the specificity and sensitivity front are still awaited. Strategies to combat the problem of antimicrobial drug resistance in diagnosis of NTDs have also been put forward by various research groups and organizations. Moreover, the state-of-the-art "omics" approaches like metabolomics and metagenomics have also started to contribute constructively towards diagnosis and prevention of the NTDs. Conclusion A concrete solution towards a single specimen based common biomarker detection platform for NTDs is lacking. Identifying robust biomarkers and implementing them on simple diagnostic tools to ease the process of pathogen detection can help us understand the obstacles in current diagnostic measures of the NTDs. PMID- 30398116 TI - The role of Angiotensin-(1-7)/Mas axis and Angiotensin Type 2 Receptors in the Central Nervous System in Cardiovascular Disease and therapeutics: A riddle to be solved. AB - In recent years, the Angiotensin-(1-7)/Mas receptor [Ang-(1-7)/Mas] sub-branch of the Renin-Angiotensin System (RAS) in the brain, as well as Angiotensin Type 2 Receptors (AT2R), have attracted scientific interest, as there is evidence that they constitute an essential pathway in cardiovascular regulation, in health and in disease. By acting centrally, the Ang-(1-7)/Mas axis - that has been termed 'the axis of good'- can exert blood pressure-lowering effects, while also favourably altering baroreflex sensitivity and noradrenergic neurotransmission. Thus, research has focused on the possible neuro- and cardioprotective effects of this pathway in the setting of cardiovascular disease, ultimately aiming to evaluate the potential for development of novel therapeutic strategies based on its modulation. We summarize the available evidence from experimental studies in this context, aiming to assess current limits of scientific knowledge relevant to this newly-described 'player' in haemodynamic regulation, that may become a potential therapeutic target. PMID- 30398117 TI - Design, Synthesis and Pharmacological evalution of 1,3,4-Oxadiazole Derivatives As Collapsin Response Mediator Protein 1 (CRMP 1) Inhibitors. AB - CONTEXT: objective: The series of 2-(4-Phenylamino)-N-(5-((4-nitrophenoxy)methyl) -1,3,4-oxadiazol-2-yl)acetamide (5a-5e) and substituted N-(5-(Phenoxymethyl) 1,3,4-oxadiazol-2-yl)-2-(phenylamino)acetamide (5f-5i) were designed, synthesized and investigated for Collapsin response mediator protein 1 (CRMP 1) inhibitors as small lung cancer. DESIGN: Design of compounds was done by literature review and molecular docking studies in iGEMDOCK 2.0. METHODS AND MATERIAL: Novel 1, 3, 4 Oxadiazole derivatives were synthesized and characterized by melting point, TLC, IR Spectroscopy, Mass spectroscopy and 1H NMR. In vitro biological evaluation was performed on NCI-H2066 cell line for different concentrations 10-1000uM by telomeric repeat amplification protocol assay. The assay of telomerase in cellular extracts was modified from the PCR-based telomeric-repeat amplification protocol (TRAP), using the oligonucleotides TS and CX. RESULTS: Novel substituted 2-(4-Phenylamino)-N-(5-((4-nitrophenoxy)methyl)-1,3,4-oxadiazol-2-yl) acetamide (5a-5e) and substituted N-(5-(Phenoxymethyl)-1,3,4-oxadiazol-2-yl)-2 (phenylamino) acetamide (5f-5i) were synthesized, and characterized using spectral and analytical data. All compounds have shown considerable % inhibition of Cell Growth with respect to Bevacizumab, but compound 5a and 5f were equipotent with respect to activity as compared to standard Bevacizumab. CONCLUSION: Amongst the hybrids, p-nitro substituted derivative (5a) and p-chloro substituted (5f) showed highest activity against human lung cancer cell line NCI H2066 by TRAP assay. PMID- 30398118 TI - Design and synthesis novel sulfonamide-derived triazoles and bioactivity exploration. AB - OBJECTIVE: Due to incidence of resistance, a series of sulfonamide-derived 1,2,4 triazoles were synthesized and evaluated. RESULTS: In vitro antimicrobial evaluation found that 2-chlorobenzyl sulfonamide 1,2,4-triazole 7c exhibited excellent antibacterial activities against MRSA, B. subtilis, B. typhi and E. coli with MIC values of 0.02?0.16 MUmol/mL, which were comparable or even better than Chloromycin. The preliminary mechanism suggested that compound 7c could effectively bind with DNA, and also it could bind with human microsomal heme through hydrogen bonds in molecular docking. Computational chemical studies were performed on compound 7c to understand the structural features that are essential for activity. Additionally, compound 7c could generate small amount of reactive oxygen species (ROS). CONCLUSION: Compound 7c could serve as potential clinical antimicrobial candidate. PMID- 30398119 TI - Design, synthesis and in vitro evaluation of novel anti-HIV 3-pyrazol-3-yl pyridin-2-one analogs. AB - BACKGROUND: Natural products have shown potent anti-HIV activity, but some of these also possess toxicity. The pharmacophoric fragments of these natural products have scope of combination with other pharmacophoric fragment and derivatization to reduce toxicity and increase the potency. Combination of natural product fragments from different classes of anti-HIV compounds may lead to a new class of potent anti-HIV agents. OBJECTIVE: Design, in silico prediction of drug-likeness, ADMET properties and synthesis of pyrazol-pyridones. Evaluation of the anti-HIV1 activity of synthesized pyrazol-pyridones. METHOD: Pyrazol pyridones were designed by combining reported anti-HIV pharmacophoric fragments. Designed molecules were synthesized after in silico prediction of drug-likeness and ADMET properties. Compounds were evaluated for activity against HIV-1VB59 and HIV-1UG070. RESULT: QED value of designed pyrazol-pyridones was greater than the known drug zidovudine. The designed compounds were predicted to be noncarcinogenic and nonmutagenic in nature. Seventeen novel pyrazol-pyridones were synthesized with good yield. Compound 6q and 6l showed activity with IC50 values 6.14 uM and 15.34 uM against HIV-1VB59 and 16.21 uM and 18.21 uM against HIV-1UG070, respectively. CONCLUSION: Compound 6q was found to be most potent among the synthesized compounds with a therapeutic index of 54.31against HIV 1VB59. This is the first report of anti-HIV1 activity of pyrazol-pyridone class of compounds. Although the anti-HIV1 activity of these compounds is moderate, this study opens up a new class for exploration of chemical space for anti-HIV1 activity. PMID- 30398120 TI - Small Molecular Leads Differentially Active against HER2 Positive and Triple Negative Breast Cancer Cell Lines. AB - BACKGROUND: Breast cancer is the most prevalent cancer type in women globally. It is characterized by distinct subtypes depending on different gene expression pattern. Oncogene HER2 is expressed on the surface of cell, and is responsible for cell growth regulation. Increase in HER2 receptor protein due to gene amplification, results in aggressive growth, and high metastasis in cancer cells. METHOD: The current study evaluates and compares the anti-breast cancer effect of commercially available compounds against HER2 overexpressing BT-474, and estrogen and HER2 negative MDA-MB-231 breast cancer cell lines. RESULTS: Preliminary in vitro cell viability assays on these cell lines identified 6 lead molecules active against breast cancer. Convallatoxin, a steroidal lactone glycoside, showed the most potent activity with IC50 values of 0.63 +/- 0.56, and 0.69 +/- 0.08 uM against BT-474 and MDA-MB-231, respectively, whereas compounds 3 a phenol derivative, and compound 5 an indole alkaloid selectively inhibited the growth of BT-474, and MDA-MB-231 breast cancer cells, respectively. CONCLUSION: These results exhibited the potential of small molecules in the treatment of HER2 amplified and triple negative breast cancer in vitro. PMID- 30398121 TI - Synthesis and biological evaluation of polyfluoroalkylated antipyrines and their isomeric O-methylpyrazoles. AB - BACKGROUND: Formally belonging to the non-steroidal anti-inflammatory drug class pyrazolones have long been used in medical practices. OBJECTIVE: Our goal is to synthesize N-methylated 1-aryl-3-polyfluoroalkylpyrazolones as fluorinated analogs of antipyrine, their isomeric O-methylated derivatives resembling celecoxib structure and evaluate biological activities of obtained compounds. METHODS: In vitro (permeability) and in vivo (anti-inflammatory and analgesic activities, acute toxicity, hyperalgesia, antipyretic activity, "open field" test) experiments. To suggest the mechanism of biological activity, molecular docking of the synthesized compounds was carried out into the tyrosine site of COX-1/2. RESULTS: We developed the convenient methods for regioselective methylation of 1-aryl-3-polyfluoroalkylpyrazol-5-ols leading to the synthesis N methylpyrazolones and O-methylpyrazoles as antipyrine and celecoxib analogs respectively. For the first time the biological properties of new derivatives were investigated in vitro and in vivo. CONCLUSION: The trifluoromethyl antipyrine represents a valuable starting point in design of the lead series for discovery new antipyretic analgecics with anti-inflammatory properties. PMID- 30398122 TI - 3, 3'-Dimethylquercetin Inhibits the Proliferation of Human Colon Cancer RKO Cells through Inducing G2/M Cell Cycle Arrest and Apoptosis. AB - BACKGROUND: Our previous study successfully identified that 3,3' Dimethylquercetin (DMQ) acted as a potent anticancer agent against human colon cancer cell lines RKO. Thus, this study was conducted to investigate the underlying mechanism by which DMQ displayed inhibitory activity in RKO cells. METHODS: Flow cytometry was used to evaluate the effect of DMQ on the cell cycle arrest, as well as the mitochondrial membrane potential in RKO cells. DAPI staining and DNA fragmentation ladder assays were performed to assess the apoptosis inducing activity of DMQ. Furthermore, western blot analysis was conducted to examine the expression of related proteins responsible for the cell cycle arrest and apoptosis. RESULTS: Treatment with DMQ caused a significant increase in the fraction of G2/M cells, and induced remarkable apoptosis. Furthermore, western blot analysis showed that DMQ arrested cells at G2/M checkpoint by down-regulation of cyclin B1, cdc2 and cdc25c and up-regulation of p21, and induced cell apoptosis via affecting the ratio of Bax/Bcl-2, causing loss of the mitochondrial membrane potential and enhancing the expression of cleaved caspase-9 (C-caspase-9) and cleaved caspase-3 (C-caspase-3). CONCLUSION: These data showed that DMQ could suppress RKO cell growth by arresting RKO cells at G2/M checkpoint and inducing mitochondria-dependent cell apoptosis. Our findings shed light on the potential use of DMQ as a chemotherapeutic agent for CRC. PMID- 30398123 TI - Phytochemicals in anticancer drug development. AB - Phytochemicals are gradually emerging as a rich source of effective but safer agents against many life threatening diseases. In spite of major technological advances in the conventional therapies, cancer still continues to remain the leading cause of mortality worldwide. Although numerous potent synthetic drugs have been introduced for cancer chemotherapy yet their serious toxicity concerns to normal cells apart from drug resistance have emerged as the major obstacles for their clinical utility over prolonged duration of time. The scientific community has been trying hard to find better and cheaper therapeutics to combat this dreadful disease. For many years, phytochemicals, or active constituents from plants, have been widely subjected to intense search for anti-cancer agents with minimum or no side effects. In the last decade, the usage of phytochemicals in cancer treatment has increased considerably. Current status and potential of phytochemical sand their derivatives in cancer therapy has been briefly reviewed in present manuscript. PMID- 30398124 TI - Efficacy of Celecoxib adjunct treatment on bipolar disorder: systematic review and meta-analysis. AB - BACKGROUND: Bipolar Disorder (BD) is a psychiatric disorder characterized by mood disturbances. The pathophysiology of BD is still poorly precise. In the last years, the study involving the role of inflammation in BD. OBJECTIVE: Performed a systematic review and meta-analysis to evaluated the potential effect of the cyclo-oxygenases (Cox)-2 inhibitor Celecoxib adjunct treatment in BD, through of randomized controlled trials (RCT). METHOD: A search of the electronic databases was proceeded, on MEDLINE, EMBASE, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), Biomed Central, Web of Science, IBECS, LILACS, PsycINFO, Congress Abstracts, and Grey literature (Google Scholar and the British Library) for studies published from January 1990 to February 2018. A search strategy was developed using the terms: "Bipolar disorder" or "Bipolar mania" or "Bipolar depression" or "Bipolar mixed" or "Bipolar euthymic" and "Celecoxib" or "Cyclooxygenase-2 inhibitors" or "Cox-2 inhibitors" as text words and Medical Subject Headings (i.e., MeSH and EMTREE) and searched. The therapeutic effects of adjunctive treatment with Celecoxib were analyzed. The meta-analysis was performed including the results of the Young Mania Rating Scale (YMRS) at the end of RCT. RESULTS: Three primary studies were included in the systematic review, with a total of 121 patients. In the meta-analysis showed a significant effect in the YMRS scores from patients with BD who used Celecoxib adjuvant treatment in comparison placebo. CONCLUSION: The systematic review suggests that adjuvant treatment with Celecoxib improves the response of major treatments in patients with BD when compared with adjuvant placebo treatment. PMID- 30398125 TI - Leukocytoclastic Vasculitis Associated with HHV6-A/ciHHV6-A and HHV6-B Coinfection in an Immunocompetent Woman. LCV with HHV6-A/ciHHV6-A and HHV6-B Coinfection. AB - BACKGROUND AND OBJECTIVE: Leukocytoclastic vasculitis (LCV) is a small vessel vasculitis that can be limited to the skin but may also affect other organs. Often, its cause is unknown. LCV has previously been reported to occur with the reactivation of human herpesvirus 6 (HHV-6). Here, we report a second instance of HHV-6 reactivation in a 43-year-old woman with idiopathic cutaneous LCV. CASE DESCRIPTION: In this case, the patient was immunocompetent, and testing revealed that she had inherited chromosomally integrated human herpesvirus 6 variant A (iciHHV6-A) with a parallel skin infection of HHV-6B. The integrated ciHHV-6A strain was found to be transcriptionally active in the blood, while HHV-6B late antigen was detected in a skin biopsy. The patient's rash was not accompanied by fever nor systemic symptoms and resolved over four weeks without any therapeutic intervention. CONCLUSION: In light of the transcriptional activity documented in our case, further examination of a possible role for HHV-6 in the etiology of LCV is warranted. PMID- 30398127 TI - Management of visual hallucinations in dementia and Parkinson's disease. AB - : ABSTRACTObjectives:Visual hallucinations are a common symptom in dementia and Parkinson's disease and have been associated with greater cognitive and functional decline, but optimal management strategies are unclear. We review the frequency and pathogenesis of visual hallucinations in dementia and Parkinson's disease and examine the evidence base for their management. DESIGN: We undertook a systematic review of the visual hallucinations in dementia, searching studies published between January 1980 and July 2017 using PubMed with the search terms visual hallucinations AND review AND (dementia OR parkinson*). RESULTS: We found 645 articles and screened them for relevance, finally including 89 papers (11 meta-analyses, 34 randomized controlled trials, six other trials and a number of relevant review articles). Only six of the trials reported visual hallucination outcomes separately from other neuropsychiatric symptoms. CONCLUSIONS: Atypical antipsychotics were frequently studied, but with the exception of clozapine in Parkinson's disease dementia, results were equivocal. There was some evidence that acetylcholinesterase inhibitors may help visual hallucinations. Overall, effect sizes for most treatments were small and there were few studies with long term follow up. Treatments need to be carefully weighed up with the risks and reviewed often, and many patients improved without treatment. There is a lack of data regarding visual hallucinations due to the grouping of psychotic symptoms together in commonly used rating scales. The lack of a specific rating scales, or analyzable items within other scales, for visual hallucinations, limited efficacy of current and small evidence base with short follow up are important areas for future studies to address. PMID- 30398126 TI - Effect of Aqueous Extract of Azadirachta indica Leaves on Pharmacokinetics and Pharmacodynamics of Glipizide. AB - The intake of complementary and alternative medicines leads to various drug interactions, which may affect pharmacodynamics or pharmacokinetics. This study was conducted to determine the interaction of glipizide (GZ) with an aqueous extract of Azadirachta indica (AZI) leaves. The pharmacokinetics and pharmacodynamics were evaluated through the oral glucose tolerance test, high Fat diet (HFD) and streptozotocin-induced diabetes in Wistar rats. In vitro CYP3A Activity of AZI at 50ug and 100 ug was assessed using liver microsomes. Two doses of the AZI leaf extract (250 and 500 mg/kg) were administered alone or in combination with GZ (5 mg/kg) and serum glucose, AST, ALT, and ALP levels were estimated. In the glucose tolerance test, AZI and GZ showed a hypoglycemic effect. However, the hypoglycemic effect was lower when AZI was administered in combination with GZ compared with GZ alone. AZI at 100 ug has shown significant potentiation of CYP3A activity. AZI (500 mg/kg) pretreatment significantly decreased AUC and increased Tmax to 8 h. This indicates that the pharmacokinetics of GZ was altered by AZI and also suggesting that absorption of GZ was decreased may be due to P-glycoprotein induction. In conclusion, AZI can decrease the bioavailability of GZ, and hence, it should be cautiously used. PMID- 30398128 TI - Environmental Heat Exposure and Heat-Related Symptoms in United States Coast Guard Deepwater Horizon Disaster Responders. AB - OBJECTIVES: The response to the 2010 Deepwater Horizon oil spill was impacted by heat. We evaluated the association between environmental heat exposure and self reported heat-related symptoms in US Coast Guard Deepwater Horizon disaster responders. METHODS: Utilizing climate data and postdeployment survey responses from 3648 responders, we assigned heat exposure categories based on both wet bulb globe temperature (WBGT) and heat index (HI) measurements (median, mean, maximum). We calculated prevalence ratios (PRs) and 95% confidence intervals (CIs) via adjusted Poisson regression models with robust error variance to estimate associations with reported heat-related symptoms. We also evaluated the association between use of personal protective equipment (PPE) and heat-related symptoms. RESULTS: Those in the highest WBGT median-based heat exposure category had increased prevalence of heat-related symptoms compared to those in the lowest category (PR=2.22 [95% CI: 1.61, 3.06]), and there was a significant exposure response trend (P<.001). Results were similar for exposure categories based on WBGT and HI metrics. Analyses stratified by use of PPE found significantly stronger associations between environmental heat exposure and heat-related symptoms in those who did not use PPE (PR=2.23 [95% CI: 1.10, 4.51]) than in those who did (PR=1.64 [95% CI: 1.14, 2.36]). CONCLUSIONS: US Coast Guard Deepwater Horizon disaster responders who experienced higher levels of environmental heat had higher prevalences of heat-related symptoms. These symptoms may impact health, safety, and mission effectiveness. As global climate change increases the frequency of disasters and weather extremes, actions must be taken to prevent heat-related health impacts among disaster responders. (Disaster Med Public Health Preparedness. 2018; Page 1 of 9). PMID- 30398129 TI - Reconsidering the seizure threshold? A retrospective study about seizure quality among patients with maintenance ECT. AB - OBJECTIVES: Electroconvulsive therapy (ECT) is a safe and validated technique used to treat various psychiatric conditions. It triggers an artificially-induced seizure. This seizure is defined using several parameters such as the amount of energy, duration, frequency, pulse width and intensity. Efficacy and adverse events depend on the amount of energy delivered. Due to technical control, the amount of energy delivered by our unit's ECT device was limited to 614 mC, 60% of the maximum possible output of the device. We wondered if lowering the dose would lead to better seizure quality among maintenance ECT patients. METHODS: We assessed seizure quality based on the EEG, using a validated tool created by MacPherson. Two evaluators independently rated the seizures. Pre- and post control scores were compared using Student's t-test for paired samples. RESULTS: We analysed data from 15 patients. Mean age was 65 years old. Twelve had depressive disorder, two had schizophrenia and one had schizo-affective disorder. Mean duration of seizure before control was 41.1 s [95% confidence interval (95CI)=26.1, 51.1]. The mean MacPherson's score was 20.3 (95CI=16.2, 24.4). After control, the mean MacPherson's score was 28.2 (23.1, 33.3), showing a significant difference with the pre-control dataset (p=0.032; t=-2.4; df=14). Specifically, peak mid-ictal amplitude increased from 6.9 (95CI=5.1, 8.7) to 10.0 (95CI=7.2, 12.8). Other sub-scores remained unchanged. CONCLUSION: Lowering the energy delivered led to an overall increase of seizure quality among our sample. This highlights the necessity and utility of retitration during ECT maintenance, possibly leading to better management of our patients. PMID- 30398130 TI - Ultrastructural Deformities in the Scales of Cyprinus carpio Inhabiting Two Government-Sponsored Fish Farms in North-East India Contaminated by Municipal Wastes and Other Pollutants. AB - Scanning electron microscopy of the scales of Cyprinus carpio, inhabiting two government-sponsored fish farms, with different sources of pollutants, in the North-East state of Meghalaya, India revealed extensive damage to them. Lepidonts, which are teeth-like structures present on the edge of circulii, were discovered to be either partly or completely damaged. The dislodgment of complete rows of lepidonts along with broken lepidonts was also observed. Loss of symmetry and torn areas of circulii are some of the abnormalities also observed as compared to control samples. The alterations observed could be because of the high sensitivity of the scales to environmental stress and their capacity to react to low concentrations of pollutants, which makes them a sensitive bioindicator of water pollution. The study hence not only represents an advance in pollution research, by employing a highly sophisticated analytical approach to reveal the above-mentioned microstructural scale abnormalities, but it can also have scientific impact on the society at large and the fish culturist in particular in understanding the destructive impact of pollution caused by mismanagement of city garbage and agricultural effluents. PMID- 30398131 TI - Joining of TiAl Alloy Using Novel Ag-Cu Sputtered Coated Ti Brazing Filler. AB - The aim of this study is to evaluate the potential use of titanium foil coated with sputtered silver and copper films as a novel brazing filler for joining TiAl alloys. For this purpose, a detailed microstructural characterization of the resulting brazing interfaces was carried out. The development of brazing fillers that allow the joining of TiAl alloys without compromising the service temperature is a fruitful prospect. Brazing experiments were performed in a vacuum at 900, 950, and 980 degrees C, with a dwell time of 30 min. Microstructural characterization reveals that brazing joints can be obtained successfully at 950 and 980 degrees C. The interface consists of a large central region of alpha-Ti with an amount of Al and Ti-Ag compound and thin layers, mainly composed of intermetallic compounds, formed close to the base material. A novel brazing filler consisting of Ti foil coated with sputtered Ag and Cu films inhibits the extensive formation of soft (Ag) zones or coarse brittle Ti-Al (Cu,Ni) particles. Hence, the need for post-brazing heat treatments for the joining of TiAl alloys was avoided. PMID- 30398132 TI - Perceived burden among caregivers of patients with frontotemporal degeneration in the United States. AB - : ABSTRACTBackground:Frontotemporal degeneration (FTD) dementia often begins before age 60 and predominantly presents as four subtypes with prominent features of language, behavior, cognition, and motor symptoms. The early onset and unique symptoms place a distinct burden on caregivers of individuals with FTD versus other dementia types, such as Alzheimer's disease. This is the first known study to examine the domains of the FTD caregiver burden and the caregiver and patient characteristics associated with these domains. METHODS: In 2017, 674 FTD caregivers in the United States (US) completed a web-based survey of caregiver and patient demographics, disease severity/symptoms, caregiver burden, and financial costs of caregiving. The major factors of caregiver burden (Zarit Burden Inventory) were determined using a principal axis factor analysis with varimax rotation. Multiple linear regression analyses examined caregiver and patient characteristics associated with overall burden and three major factors of burden: role strain, personal strain, and performance strain. RESULTS: Increased neuropsychiatric symptoms was associated with overall caregiver burden and greater role, personal, and performance strain. Younger caregivers experienced greater overall burden and performance strain, female caregivers experienced increased role strain, and male caregivers experienced greater performance strain. Financial costs of caregiving and experiencing a caregiving crisis in the past year were associated with higher overall burden and role strain. CONCLUSIONS: This study suggests that the severity and sources of burden differ for caregivers of FTD patients versus patients with other dementia types. Differing predictors for each burden domain suggest targeted interventions to address the unique FTD caregiving challenges. PMID- 30398133 TI - Infant and young child feeding practices, sociodemographic factors and their association with nutritional status of children aged <3 years in India: findings of the National Nutrition Monitoring Bureau survey, 2011-2012. AB - OBJECTIVE: To study infant and young child feeding (IYCF) practices and their association with nutritional status among young children. DESIGN: A community based, cross-sectional study was carried out in ten states of India, using a multistage random sampling method. Anthropometric measurements such as length/height and weight were conducted and nutritional assessment was done using the WHO child growth standards. SETTING: National Nutrition Monitoring Bureau survey, 2011-2012.ParticipantsChildren aged <3 years and their mothers. RESULTS: Only 36 % of infants received breast-feeding within an hour of birth and 50 % were exclusively breast-fed up to 6 months. Prevalence of underweight, stunting and wasting was 38, 41 and 22 %, respectively. The chance of undernutrition among <3-year-old children was significantly higher among those from scheduled caste/scheduled tribe communities, the lowest-income group, with illiterate mothers and lack of sanitary latrine. Among infants, the chance of undernutrition was significantly higher among low-birth-weight babies, and among children whose mother had not consumed iron-folic acid tablets during pregnancy. Immunization practices and minimum dietary diversity were observed to be associated with undernutrition among 12-23-month-old children. CONCLUSIONS: Undernutrition is still an important public health problem in India and observed to be associated with low socio-economic status, illiteracy of mother, low birth weight and dietary diversity. Improving socio-economic and literacy status of mothers can help in improving maternal nutrition during pregnancy and thus low birth weight. Also, improving knowledge of mothers about IYCF practices will help in improving children's nutritional status. PMID- 30398134 TI - Association of age with risk of major depression among patients with chronic kidney disease over midlife: a nationwide cohort study in Taiwan. AB - : ABSTRACTBackground:The impact of age on the development of depression among patients with chronic kidney disease (CKD) at stages before dialysis is not well known. We aimed to explore the incidence of major depression among predialysis CKD patients of successively older ages through midlife. METHODS: We conducted a retrospective cohort study using the longitudinal health insurance database 2005 in Taiwan. This study investigated 17,889 predialysis CKD patients who were further categorized into study (i.e. middle and old-aged) groups and comparison group aged 18-44. The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) was applied for coding diseases. RESULTS: The group aged 75 and over had the lowest (hazard ratio [HR] 0.47; 95% confidence interval [CI] 0.32-0.69) risk of developing major depression, followed by the group aged 65-74 (HR 0.67; 95% CI 0.49-0.92), using the comparison group as reference. The adjusted survival curves showed significant differences in cumulative major depression-free survival between different age groups. We observed that the risk of major depression development decreases with higher age. Females were at a higher risk of major depression than males among predialyasis CKD patients. CONCLUSIONS: The incidence of major depression declines with higher age in predialysis CKD patients over midlife. Among all age groups, patients aged 75 and over have the lowest risk of developing major depression. A female preponderance in major depression development is present. We suggest that depression prevention and therapy should be integrated into the standard care for predialysis CKD patients, especially for those young and female. PMID- 30398135 TI - Acute Post-Streptococcal Glomerulonephritis in the Northern Territory of Australia: A Review of Data from 2009 to 2016 and Comparison with the Literature. AB - Acute post-streptococcal glomerulonephritis (APSGN) is an inflammatory kidney disease following infection with nephritogenic strains of group A Streptococcus. In 1991, APSGN became notifiable in the Northern Territory (NT) of Australia with cases recorded on the NT Notifiable Disease Database (NTNDS). The case definition of a confirmed case requires laboratory definitive evidence or laboratory suggestive evidence in conjunction with a clinically compatible illness. Probable cases require clinical evidence only. Acute post-streptococcal glomerulonephritis notifications from 2009 to 2016 were extracted from the NTNDS. Of the 322 cases, 261 were confirmed and 61 probable. The majority, 304 (94%), were Aboriginal and the median age was 8 years (range: 0-62 years). Incidence for confirmed cases was 13.8/100,000 person-years, with inclusion of probable cases increasing incidence to 17.0/100,000 person-years. Highest incidence of confirmed cases was in Aboriginal children less than 15 years of age at 124.0 cases/100,000 person years. The rate ratio of confirmed cases in Aboriginal to non-Aboriginal Australians was 18.9 (95% confidence interval: 11.4-33.6). Recent trends show a consistently high number of notifications annually with less frequent outbreaks. The Aboriginal population of the NT continues to have high rates of APSGN with recent trends showing higher rates than previously reported. Sustained preventative efforts and continued surveillance strategies are needed. PMID- 30398136 TI - Dengue Virus Infection of Primary Human Smooth Muscle Cells. AB - Dengue virus (DENV) infection of humans is presently the most important arthropod borne viral global threat, for which no suitable or reliable animal model exists. Reports addressing the effect of DENV on vascular components other than endothelial cells are lacking. Dengue virus infection of vascular smooth muscle cells, which play a physiological compensatory response to hypotension in arteries and arterioles, has not been characterized, thus precluding our understanding of the role of these vascular components in dengue pathogenesis. Therefore, we studied the permissiveness of primary human umbilical artery smooth muscle cells (HUASMCs) to DENV 1-4 infection and compared with the infection in the previously reported primary human umbilical vein endothelial cells (HUVECs) and the classically used, non-transformed, and highly permissive LLC-MK2 cells (macaque kidney cells). Our results show that HUASMC are susceptible and productive to infection with the four DENV serotypes, although to a lesser extent when compared with the other cell lines. This is the first report of DENV permissiveness in human smooth muscle cells, which might represent an unexplored pathophysiological contributor to the vascular collapse observed in severe human dengue infection. PMID- 30398137 TI - Growth Status, Inflammation, and Enteropathy in Young Children in Northern Tanzania. AB - Recent evidence suggests that enteropathy of the gut due to environmental conditions (i.e., environmental enteropathy [EE]) in young children is negatively associated with linear growth. Using a case-control study design, we examined the potential determinants of stunting in stunted and non-stunted children 22-28 months of age. Potential determinants included inflammation biomarkers C-reactive protein, alpha-1-acid glycoprotein (AGP), and endotoxin-core antibody (EndoCAb) measured in serum samples; enteropathy markers alpha-1-antitrypsin, neopterin, myeloperoxidase (MPO) measured in stools samples; and demographic, health, feeding, and household characteristics. We also explored the determinants of EE by testing associations of composite EE scores and individual biomarkers with potential risk factors. Fifty-two percent of children (n = 310) were found to be stunted, and mean height-for-age Z scores (HAZ) were -1.22 (SD +/- 0.56) among non-stunted (control) children and -2.82 (SD +/- 0.61) among stunted (case) children. Child HAZ was significantly (P < 0.05) and inversely associated with AGP, and child stunting was significantly associated (P < 0.05) with low dietary diversity, severe household hunger, and absence of soap in the household. Alpha-1 acid glycoprotein and EndoCAb concentrations were also significantly higher (P < 0.05) among children in households with no soap. Our study documented a seemingly localized cultural practice of young children (25%) being fed their dirty bathwater, which was associated with significantly higher concentrations of MPO (P < 0.05). Alpha-1-acid glycoprotein showed the most consistent associations with child growth and hygiene practices, but fecal EE biomarkers were not associated with child growth. The lack of retrospective data in our study may explain the null findings related to fecal EE biomarkers and child growth. PMID- 30398138 TI - Zika Virus and the Safety of Blood Supply in Brazil: A Retrospective Epidemiological Evaluation. AB - The potential for transfusion transmission of dengue virus (DENV), chikungunya virus (CHIKV), and Zika virus (ZIKV) has raised concerns about the safety of the blood supply in endemic areas. In this study, nucleic acid testing (NAT) for ZIKV, DENV, and CHIKV RNA was performed in asymptomatic blood donor samples in the city of Campinas, located in the southeast region of Brazil (1962 in 2015 and 1775 in 2016). The prevalence of reactive NAT was 0.15% in 2015 and 0.62% in 2016 for dengue, 0.05% in 2015 and 0.17% in 2016 for Zika, and 0% in both years for chikungunya. These results demonstrate the weakness of the clinical interview in screening these blood donors. Furthermore, positivity for ZIKV was detected in March 2015, 1 year before the first reported cases in the region. These data attest the feasibility of using donor samples held in library as a tool for retrospective epidemiological evaluation, which is particularly interesting considering emerging pathogens, for which data on their spread and penetrance are initially scarce. PMID- 30398139 TI - Depressive Symptoms Mediate the Associations of Stigma with Medication Adherence and Quality of Life in Tuberculosis Patients in China. AB - Stigma has been associated with health-related outcomes such as medication adherence and quality of life (QOL) in patients with tuberculosis (TB); however, the mechanisms via which TB-related stigma interferes with specific outcomes are unclear. This study aimed to determine whether depressive symptoms were one of the mechanisms that mediated the associations between TB-related stigma and both medication adherence and QOL in patients with TB. A cross-sectional survey was conducted between October 1, 2013, and March 31, 2014, in Hubei Province, central China, and data were collected from 1,342 patients with TB, using a structured questionnaire that measured TB-related stigma, depressive symptoms, medication adherence, and QOL. Multiple imputation was used to account for missing data. Structural equation modeling was performed to assess the mediating effect of depressive symptoms on the associations of TB-related stigma with medication adherence and QOL. Mediation analyses showed that depressive symptoms partially mediated the association between TB-related stigma and medication adherence (standardized indirect effect = -0.16, 95% bias-corrected confidence interval [CI] [-0.19, -0.13], P < 0.01). Moreover, depressive symptoms fully mediated the association between TB-related stigma and QOL (standardized indirect effect = 0.17, 95% bias-corrected CI [-0.21, -0.14], P < 0.01). The results suggest that depressive symptoms played a key role in the relationships among TB-related stigma, medication adherence, and QOL in patients with TB. Therefore, the alleviation of depressive symptoms could be an important strategy for improving medication adherence and QOL in patients with TB. PMID- 30398140 TI - Whatman Protein Saver Cards for Storage and Detection of Parasitic Enteropathogens. AB - Current methods to identify the etiology of diarrhea require laboratory facilities for storage of pathogens, which is often challenging in low-resource settings. This study evaluated the efficacy of a low-cost method for preserving stool specimens for the detection of parasitic enteropathogens using Whatman 903 protein saver cards (Sigma-Aldrich, St. Louis, MO). Stool samples known to be positive by multiplex real-time polymerase chain reaction for Giardia lamblia, Cryptosporidium spp., and Entamoeba histolytica parasites were preserved on 232 Whatman cards. DNA was then extracted from cards using Chelex and Qiagen extraction protocols, and tested for these parasites using multiplex real-time PCR. We included stool samples known to have a higher parasite load (cycle threshold [ct]-value < 30) and those with a lower parasite load (ct values 30 35). Sensitivities and specificities were determined using DNA extracted directly from whole stool samples using Qiagen kits (QIAGEN, Hilden, Germany). For whole stool samples with ct values < 30, preserved directly on Whatman 903 protein saver cards for Giardia analysis, the sensitivity was 100% for both Qiagen and Chelex DNA extraction. For E. histolytica, this was 100% for sensitivity for Qiagen and 80% for Chelex DNA extractions, and for Cryptosporidium, this was 80% for Qiagen and 50% for Chelex DNA extraction. The specificity was 100% for all parasites for all extraction procedures. Given the high sensitivity for stool samples with higher parasite loads, we recommend the use of the Whatman 903 protein saver card for preserving fecal specimens for the analysis of Giardia and E. histolytica using Qiagen DNA extractions in low-resource settings. PMID- 30398141 TI - Handheld Point-of-Care Lactate Measurement at Admission Predicts Mortality in Ugandan Children Hospitalized with Pneumonia: A Prospective Cohort Study. AB - Globally, pneumonia is the leading cause of death among children younger than 5 years old, with most deaths occurring in low-income countries. Rapid bedside tools to assist practitioners to accurately triage and risk-stratify these patients may improve clinical care and patient outcomes. We conducted a prospective cohort study of children with pneumonia admitted to two Ugandan hospitals to examine the predictive value of a single point-of-care lactate measurement using a commercially available handheld device, the Lactate Scout Analyzer. One hundred and fifty-five children were included, 90 (58%) male, with a median (interquartile range [IQR]) age of 11 (1.4-20) months. One hundred and twenty-five (81%) patients had chest indrawing, 133 (86%) were hypoxemic, and 75 (68%) had a CXR abnormality. In-hospital mortality was 22/155 (14%). Median (IQR) admission lactate level was 2.4 (1.8-3.6) mmol/L among children who survived versus 7.2 (2.6-9.7) mmol/L among those who died (P < 0.001). Lactate was a better prognostic marker of mortality (area under receiver operator characteristic 0.76, 95% CI: 0.69-0.87, P <= 0.001), than any single clinical sign or composite clinical risk score. Lactate level at admission of < 2.0, 2.0 4.0, and > 4.0 mmol/L accurately risk-stratified children, with 5-day mortality of 2%, 11% and 26%, respectively (P < 0.001). Slow lactate clearance also predicted subsequent mortality in children with repeated lactate measurements. Hand-held lactate measurement is a clinically informative and convenient tool in low-resource settings for triage and risk stratification of pediatric pneumonia. PMID- 30398142 TI - Use of Real-Time Polymerase Chain Reaction to Differentiate between Pathogenic Entamoeba histolytica and the Nonpathogenic Entamoeba dispar in Ecuador. AB - Microscopic examination of stool samples has been considered to be the "gold standard" for diagnosis of intestinal parasites. Recently, polymerase chain reaction (PCR) has been approved by the World Health Organization as the method of choice for the diagnosis of Entamoeba histolytica. Of the 106 stool samples collected from the Esmeraldas and Pichincha provinces of Ecuador, all (100%) were positive for E. histolytica/Entamoeba dispar by light microscopy, whereas using real-time PCR (RT-PCR) DNA amplification, 74 (69.8%) were positive for E. dispar and only three (2.8%) were positive for E. histolytica. Some 29 (27.4%) samples were negative for the presence of either E. histolytica or E. dispar, this may be due the presence of Entamoeba mosksvskii, which is morphologically identical to E. histolytica/E. dispar and not specifically targeted by the RT-PCR used. These results indicate the necessity of reevaluating the epidemiology of amebiasis in Ecuador as the prominent species found are nonpathogenic. PMID- 30398143 TI - Factors Associated with Dengue Virus Infection and Reinfection in Asymptomatic Children in Two Colombian Municipalities. AB - Dengue is the most important arbovirosis in the world. In this study, we assessed the knowledge, attitudes, and practices (KAP) regarding dengue in parents from two small Colombian municipalities in the Cundinamarca Province. Parents and their healthy children from 4 to 14 years of age were included in some public elementary schools. After a medical examination, blood samples were taken for diagnosis of dengue using enzyme-linked immunosorbent assays (capture IgM and IgG, and indirect IgG and NS1) and detection of viral RNA by reverse transcription polymerase chain reaction. In addition, a KAP survey was applied to the children's parents or tutors. The indirect IgG test determined that of the 347 examined children, 87.9% had a previous infection with the dengue virus (DENV), 12.7% of them were positive for viral RNA (asymptomatic infection), and 32.0% presented reinfections. Risk factors evaluation showed that children aged 8 years and older living in the municipalities for more than 7 years were more likely to be infected or reinfected by DENV. In the same way, poor nutrition, lack of water supply, sewer service, or waste disposal services could raise the likelihood of dengue infections. The surveys indicated that parents have unhealthy practices and a low knowledge about the transmission of the disease, which could result in an increase of mosquito breeding sites, allowing sustained dengue transmission. PMID- 30398144 TI - Accuracy of Urine and Serum Assays for the Diagnosis of Strongyloidiasis by Three Enzyme-Linked Immunosorbent Assay Protocols. AB - To evaluate the accuracy and reliability of urine assay for the diagnosis of strongyloidiasis, three different immunoassays were used to assess the diagnostic accuracy of anti-Strongyloides IgG in urine and compared with those in serum samples. Analyses by InBios enzyme-linked immunosorbent assay (ELISA) kit (NIE recombinant antigen), SciMedx ELISA kit (Strongyloides stercoralis antigen), and our in-house ELISA (S. ratti antigen) yielded comparable diagnostic performances between urine and serum assays. Levels of Strongyloides-specific IgG in urine significantly correlated with those in serum. Tests for diagnostic agreement between urine and serum IgG assays showed substantial to moderate agreement (kappa = 0.207-0.615). The observed quantitative and qualitative concordance between urine and serum assays in strongyloidiasis suggests that urine has similar diagnostic value to that for serum. Because of the ease and noninvasiveness of clinical sample collection, urine assay has a high potential for the initial diagnosis and mass screening of strongyloidiasis. PMID- 30398145 TI - Case Reports: Prolonged Detection of Zika Virus RNA in Vaginal and Endocervical Samples from a Brazilian Woman, 2018. AB - Zika virus (ZIKV) infection is an emerging public health problem, associated with increased risk for Guillain-Barre syndrome and adverse fetal outcomes, including congenital microcephaly. Zika virus sexual transmission is known, but detection of the virus in different parts of the female reproductive tract is not well established. In this case report, we describe prolonged detection of ZIKV RNA in the vaginal secretion and endocervical mucosa from a Brazilian woman convalescent to ZIKV infection. A viral load of 2 * 102 copies/mL was detected up to 31 days after symptom onset in both samples. Other biological fluids, including whole blood, plasma, serum, urine, and saliva samples, were negative for ZIKV RNA. These findings advance the understanding of ZIKV infection and provide data for additional testing strategies. PMID- 30398146 TI - Molecular Evidence for Plasmodium falciparum Resistance to Sulfadoxine Pyrimethamine but Absence of K13 Mutations in Mangaluru, Southwestern India. AB - In most of India, sulfadoxine-pyrimethamine (SP) plus artesunate serves as first line treatment for uncomplicated falciparum malaria. In 112 clinical Plasmodium falciparum isolates from Mangaluru, southwestern India, we sequenced molecular markers associated with resistance to SP, lumefantrine, and artemisinin (pfdhfr, pfdhps, pfmdr1, and K13). The pfdhfr double mutation 59R-108N combined with the dhps 437G mutation occurred in 39.3% and the pfdhfr double mutation plus the pfdhps double mutation 437G-540E in additional 24.1%. As for pfmdr1, the allele combination N86-184F-D1246 dominated (98.2%). K13 variants were absent. PMID- 30398147 TI - Case Report: Survival from Rabies: Case Series from India. AB - Rabies, a zoonotic viral encephalitis, continues to be a serious public health problem in India and several other countries in Asia and Africa. Survival is rarely reported in rabies, which is considered to be almost universally fatal. We report the clinical and radiological findings of eight patients with laboratory confirmed rabies who survived the illness. With the exception of one patient who recovered with mild sequelae, all survivors had poor functional outcomes. The reported survival from rabies in recent years may reflect an increased awareness of the disease and greater access to better critical care facilities in rabies endemic countries. Nonetheless, there is an urgent need to focus on preventive strategies to reduce the burden of this dreadful disease in rabies-endemic countries. PMID- 30398148 TI - A pathway for Parkinson's Disease LRRK2 kinase to block primary cilia and Sonic hedgehog signaling in the brain. AB - : Parkinson's disease-associated LRRK2 kinase phosphorylates multiple Rab GTPases, including Rab8A and Rab10. We show here that LRRK2 kinase interferes with primary cilia formation in cultured cells, human LRRK2 G2019S iPS cells and in the cortex of LRRK2 R1441C mice. Rab10 phosphorylation strengthens its intrinsic ability to block ciliogenesis by enhancing binding to RILPL1. Importantly, the ability of LRRK2 to interfere with ciliogenesis requires both Rab10 and RILPL1 proteins. Pathogenic LRRK2 influences the ability of cells to respond to cilia-dependent, Hedgehog signaling as monitored by Gli1 transcriptional activation. Moreover, cholinergic neurons in the striatum of LRRK2 R1441C mice show decreased ciliation, which will decrease their ability to sense Sonic hedgehog in a neuro-protective circuit that supports dopaminergic neurons. These data reveal a molecular pathway for regulating cilia function that likely contributes to Parkinson's disease-specific pathology. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter). PMID- 30398149 TI - Immune-mediated hookworm clearance and survival of a marine mammal decrease with warmer ocean temperatures. AB - Increases in ocean temperature are associated with changes in the distribution of fish stocks, and the foraging regimes and maternal attendance patterns of marine mammals. However, it is not well understood how these changes affect offspring health and survival. The maternal attendance patterns and immunity of South American fur seals were assessed in a rookery where hookworm disease is the main cause of pup mortality. Pups receiving higher levels of maternal attendance had a positive energy balance and a more reactive immune system. These pups were able to expel hookworms through a specific immune mediated mechanism and survived the infection. Maternal attendance was higher in years with low sea surface temperature, therefore, the mean hookworm burden and mortality increased with sea surface temperature over a 10-year period. We provide a mechanistic explanation regarding how changes in ocean temperature and maternal care affect infectious diseases dynamics in a marine mammal. PMID- 30398150 TI - Everyone wins. AB - Aeromonas bacteria living in the gut of zebrafish produce a specific molecule to pacify the immune system of their host. PMID- 30398152 TI - Animal models of cholestasis: An update on inflammatory cholangiopathies. AB - Cholestasis is a frequent clinical condition initiating or complicating chronic liver diseases, particularly cholangiopathies, where the biliary epithelium is the primary target of the pathogenetic sequence. Until a few decades ago, understanding of cholestasis relied mostly on the experimental model of bile duct ligation in rodents. However, a simple model of biliary obstruction cannot reproduce the complex mechanisms and networks leading to cholestasis in cholangiopathies. These networks are underpinned by an intricate dysregulation of pro-inflammatory and pro-fibrotic signals involving besides cholangiocytes, multiple cell elements of both innate and adaptive immunity. Therefore, in the last years, a wide range of animal models of biliary injury have been developed, mostly in mice, following three main approaches, chemical induction, immunization and genetic manipulation. In this review, we will give an update of the animal models of the two main cholangiopathies, primary sclerosing cholangitis and primary biliary cholangitis, which have provided us with the most relevant insights into the pathogenesis of these still controversial diseases. PMID- 30398151 TI - A bacterial immunomodulatory protein with lipocalin-like domains facilitates host bacteria mutualism in larval zebrafish. AB - Stable mutualism between a host and its resident bacteria requires a moderated immune response to control bacterial population size without eliciting excessive inflammation that could harm both partners. Little is known about the specific molecular mechanisms utilized by bacterial mutualists to temper their hosts' responses and protect themselves from aggressive immune attack. Using a gnotobiotic larval zebrafish model, we identified an Aeromonas secreted immunomodulatory protein, AimA. AimA is required during colonization to prevent intestinal inflammation that simultaneously compromises both bacterial and host survival. Administration of exogenous AimA prevents excessive intestinal neutrophil accumulation and protects against septic shock in models of both bacterially and chemically induced intestinal inflammation. We determined the molecular structure of AimA, which revealed two related calycin-like domains with structural similarity to the mammalian immune modulatory protein, lipocalin-2. As a secreted bacterial protein required by both partners for optimal fitness, AimA is an exemplar bacterial mutualism factor. PMID- 30398153 TI - Ketamine and magnesium common pathway of antidepressant action. AB - Depression is one of the major causes of disability worldwide. A proportion of adults with major depression fail to achieve remission with first-line treatment. Magnesium influences the neurotransmission involved in emotional processes, such as the serotonergic, noradrenergic, dopaminergic, GABAergic and glutamatergic systems. It has been reported that the mechanism of antidepressants' action is involved in the glutamatergic system. Theories about the role of magnesium ions in pathophysiology of major depressive disorder include blocking the glutamatergic N-methyl-D-aspartate receptor (NMDAR). Ketamine, NMDAR antagonist, was found to promote fast-acting antidepressant and antisuicidal effects. Magnesium and ketamine seem to be involved in key mechanisms of the major depression pathophysiology. The evidence in the paper discussed may indicate the synergistic interaction between magnesium and ketamine pharmacodynamic activity being of particular importance in mood disorders. PMID- 30398154 TI - Magnesium deficiency heightens lipopolysaccharide-induced inflammation and enhances monocyte adhesion in human umbilical vein endothelial cells. AB - Given a possible anti-inflammatory role of magnesium in endothelial cells, the aim of this study was to investigate the effects of magnesium on human umbilical vein endothelial cell (HUVEC) viability, gene expression, and the pro inflammatory response caused by a bacterial endotoxin (LPS). HUVECs were cultured at three different concentrations of magnesium sulphate (0.1 mM; control-1 mM; 5 mM) for 72 hours. Exposing the cells to LPS reduced cell viability in culture with low magnesium, but high magnesium protected the HUVECs from LPS-induced cell death. LPS-treated HUVECs cultured in low magnesium showed up-regulation of mRNA expression for pro-inflammatory factors and the expression of cytokine proteins, including IL-2, IL-3, IL-8, IL-15 and MCP-1. This was associated with greater adhesion of monocytes to the cells. In contrast, high magnesium decreased the expression of inflammatory factors and cytokines. The study found that LPS activation of the expression of many pro-inflammatory factors is exacerbated in the presence of low magnesium concentration whilst a high magnesium concentration partly inhibited the inflammatory response to LPS. PMID- 30398155 TI - Fractional excretion of magnesium and kidney function parameters in nondiabetic chronic kidney disease. AB - AIM: Elevated fractional excretion of magnesium (FEMg) is a noninvasive biomarker of kidney damage, but its association with kidney functional parameters in nondiabetic chronic kidney disease (CKD) patients has not been sufficiently explored thus far. METHODS: We enrolled 111 adult patients with nondiabetic CKD and 30 controls. To precisely investigate kidney function, the following parameters were assessed measured glomerular filtration rate (mGFR), effective renal plasma flow (ERPF), Cystatin C, albuminuria, and fractional excretion of magnesium (FEMg). All the CKD patients were divided into two groups according to the values of mGFR (mL/min/1.73m2): the first group consisted of those with GFR>= 60 mL/min/1.73m2, whereas the second group included those with GFR< 60 mL/min/1.73m2. RESULTS: FEMg (%) was significantly higher in the group of nondiabetic patients with CKD compared to the healthy subjects [6.3 vs. 5.3 %, P=0.013]. There was also significant difference in the value of FEMg between the first and second groups of CKD patients. Increased FEMg was significantly correlated with all the investigated kidney function parameters, mGFR, ERPF, Cystatin C and albuminuria (r=-0.62; r=-0.60; r=0.77; r=0.39; p<0.01 for all). In multiple regression analyses based on observed parameters of kidney function, only cystatin C was independently and significantly associated with FEMg (multiple correlation coefficients: 0.738, p < 0.001)). Nondiabetic CKD patients with GFR< 60 mL/min/1.73m2 have increased FEMg above 6.1% with 78.7 % specificity and 83.7% sensitivity. CONCLUSION: Highly significant association between kidney functional parameters and FEMg may indicate significance of this parameter in clinical practice. PMID- 30398156 TI - Differential effect of nanoparticle and standard forms of ZnO on serum zinc and magnesium levels in rats. AB - This study examined the effect of chronic (2 weeks) administration of zinc oxide nanoparticles (NPs-ZnO) and standard zinc oxide (S-ZnO) on the levels of zinc (Zn), magnesium (Mg) and calcium (Ca) in rat serum. S-ZnO and NPs-ZnO were administered either per os (p.o.) or intraperitoneally (i.p.) at doses of 7 mg/kg or 14 mg/kg. Neither form of ZnO administered p.o. altered serum zinc concentration. However, different effects dependent upon either S-ZnO or NPs-ZnO forms were noticed after i.p. administration. Namely, while S-ZnO increased serum zinc concentration (by 136%) only at the higher dose (14 mg/kg), both doses of NPs-ZnO increased zinc concentration (by 97% at 7 mg/kg and by 564% at 14 mg/kg). The form-dependence of the ZnO effect was also demonstrated in the effect on the serum magnesium level. Only the S-ZnO form (at the dose of 14 mg/kg) reduced serum magnesium concentration (by 14% p.o., 6% i.p.). No influence of NPs-ZnO on the serum calcium level was observed. The present study demonstrated effects on the serum Zn and Mg levels, which differed between the standard and nanoparticle forms of ZnO. This may contribute to the different functional effects of these ZnO forms shown previously. PMID- 30398157 TI - Simultaneous Presence of Follicular Lymphoma, Diffuse Large B-cell Lymphoma, and Hodgkin-like Lymphoma PMID- 30398158 TI - Late Effects of Therapy in Childhood Acute Lymphoblastic Leukemia Survivors. AB - Survival rates for children with acute lymphoblastic leukemia (ALL) have increased with remarkable success over the past 50 years. The optimal use of antileukemic agents in cooperative group protocols, central nervous system directed treatment, improvements in supportive care, and recognition of clinical, biological, and treatment response characteristics that identify patients at lower or higher risk of treatment failure have improved 5-year event-free survival rates to more than 85% and 5-year overall survival rates to more than 90%. Consequently characterizing the occurrence of long-term late effects has become increasingly important. Successful treatment of ALL is associated with increased risk of adverse outcomes such as late mortality, second malignancies, neurological, cardiac, endocrine and social/ psychological disorders. In recent decades, cooperative groups in the United States and Europe have provided essential insights into the long-term effects of ALL therapy providing direction for screening recommendations and new approaches for reducing late morbidity and mortality. Current frontline protocols continue to examine ways to decrease amount and intensity of therapy to reduce late effects whereas survivorship studies attempt to predict such adverse effects precisely and develop targeted prevention and treatment strategies. PMID- 30398160 TI - Biocompatibility assessment of up-and down-converting nanoparticles: implications of interferences with in vitro assays. AB - The safety assessment of nanoparticles (NPs) is crucial during their design and development for biomedicine. One of the prerequisite steps during this evaluation is in vitro testing that employs cell-based assays not always validated and well adapted for NPs. Interferences with in vitro assays may arise due to the nano related optical, oxidative, fluorescent, surface and catalytic properties of NPs. Thus, proper validation of each assay system has to be performed for each NP type. This study aimed to evaluate the applicability of the most common in vitro cytotoxicity assays for the safety assessment of up- and down-converting lanthanide-doped NPs. Conventional cell viability tests and fluorescence-based assays for oxidative stress response were selected to determine the biological effects of up- and down-converting NPs to human brain cells. Comparison with known silver and iron oxide NPs was made for verification purposes. Both the plate reader and flow cytometric measurements were examined. The obtained results indicated that both types of Ln-doped NPs interfered to a much lesser extent than metallic NPs. In addition, the great potential of both up- and down-converting NPs for biomedicine was manifested due to their biocompatibility and low toxicity. PMID- 30398159 TI - Sub-gap optical response in the Kitaev spin-liquid candidate alpha-RuCl3. AB - We report detailed optical experiments on the layered compound alpha-RuCl3 focusing on the THz and sub-gap optical response across the structural phase transition from the monoclinic high-temperature to the rhombohedral low temperature structure, where the stacking sequence of the molecular layers is changed. This type of phase transition is characteristic for a variety of tri halides crystallizing in a layered honeycomb-type structure and so far is unique, as the low-temperature phase exhibits the higher symmetry. One motivation is to unravel the microscopic nature of THz and spin-orbital excitations via a study of temperature and symmetry-induced changes. The optical studies are complemented by thermal expansion experiments. We document a number of highly unusual findings: A characteristic two-step hysteresis of the structural phase transition, accompanied by a dramatic change of the reflectivity. A complex dielectric loss spectrum in the THz regime, which could indicate remnants of Kitaev physics. Orbital excitations, which cannot be explained based on recent models, and an electronic excitation, which appears in a narrow temperature range just across the structural phase transition. Despite significant symmetry changes across the monoclinic to rhombohedral phase transition and a change of the stacking sequence, phonon eigenfrequencies and the majority of spin-orbital excitations are not strongly influenced. Obviously, the symmetry of a single molecular layer determines the eigenfrequencies of most of these excitations. Only one mode at THz frequencies, which becomes suppressed in the high-temperature monoclinic phase and one phonon mode experience changes in symmetry and stacking. Finally, from this combined terahertz, far- and mid-infrared study we try to shed some light on the so far unsolved low energy (<1 eV) electronic structure of the ruthenium 4d 5 electrons in alpha-RuCl3. PMID- 30398161 TI - Raman spectra and structural peculiarities of TeO2-TeO3 mixed oxides. AB - Raman spectra of the mixed crystalline oxides of the (1 - x)TeO2 + xTeO3 (x = 0, 1/4, 1/2, 1) series were recorded and simulated by using the DFT calculations. Good agreement between observed and calculated Raman spectra makes it possible to establish unambiguous assignment for all prominent Raman lines. This result gives an insight into relations between structural peculiarities and observed spectral features for the crystals promising as nonlinear optical materials. Highlights * Several mixed TeO2-TeO3 crystals were synthesized by solid-state chemistry * DFT calculations well describe structures and phonon spectra of TeO2-TeO3 oxides * Raman lines can be assigned to internal vibrations of TeO4 and TeO6 polyhedrons * Observed Raman bands can be used as fingerprints of different structural units. PMID- 30398162 TI - Influence of pennation angle on measurement of shear wave elastography: in vivo observation of shear wave propagation in human pennate muscle. AB - OBJECTIVE: To examine the influence of pennation angle on measurement of shear wave elastography, this study utilised the propagation view mode that can reveal shear wave propagation in human pennate muscle in vivo. APPROACH: The validity of the propagation view mode was qualitatively confirmed by observation of shear wave propagation in tissue-mimicking phantoms. Shear wave velocity of the medial gastrocnemius (MG) was evaluated in 15 healthy males. By changing the placement of the ultrasound probe on the skin surface, shear wave propagation in the MG was changed: shear waves propagated along the MG fascicles (horizontal condition) and across the fascicles (oblique condition). MAIN RESULTS: It was observed that shear wave propagation became faster when shear waves passed through stiffer parts of the phantoms and perimysium of the MG, which is concordant with the basic principle of shear wave elastography. Shear wave velocity in the horizontal condition (2.69 +/- 0.71 m s-1) was significantly higher than that in the oblique condition (2.61 +/- 0.73 m s-1) (p < 0.001), but the effect size was small (Cohen's d = 0.11). SIGNIFICANCE: Ultrasound shear wave elastography can evaluate tissue elasticity of pennate muscles along the fascicle direction, even if shear waves propagate across the obliquely arranged fascicles. PMID- 30398163 TI - Prediction of reentering and switching ferromagnet/antiferromagnet exchange bias by antiferromagnetic proximity effect. AB - Exchange bias (EB) in ferromagnet/antiferromagnet (FM/AF) core/shell nanoparticles can be used to beat the superparamagnetic limit, and these core/shell nanoparticles are commonly fabricated by the ferromagnetic cores that are naturally oxidized to form an antiferromagnetic shell. The drawbacks of this method are that the EB effect is weak and hard to be controlled due to the shell passivation effect. Thus a theoretical work is conceived where the FM/AF core/shell nanoparticles are embedded into an antiferromagnetic matrix, and an antiferromagnetic proximity effect is induced to modulate the FM/AF EB effect in a controlled way. The results show that the shell/matrix proximity may enhance the magnetic stabilization of nanoparticles to generate the core/shell EB if the matrix is a hard AF. On the other hand, a rigid core/shell EB can switch its sign through thermal training by using a softly antiferromagnetic matrix. The local magnetization behaviors and energy barrier variations during magnetizing well interpreted the simulation results. It is evidenced that the proximity effect can optimize the magnetic properties of the pinning antiferromagnetic layer at will, ranging from statically magnetic stability to dynamically magnetic relaxation. This work opens fascinating possibilities for engineering of magnetic materials with desired magnetic properties, which has led to a surge in both experimental and theoretical investigations. PMID- 30398164 TI - Terahertz time-domain spectroscopy as a novel metrology tool for liquid-phase exfoliated few-layer graphene. AB - Few-layer graphene (FLG) platelets exfoliated directly from graphite are finding a wide range of potential applications, including composites and printed electronics. However, characterisation of the FLG material following incorporation into polymers, including the quality of the dispersion, remains a challenge. Here, we present the use of terahertz time-domain spectroscopy as a potential solution to this challenge which could form the basis of a rapid characterisation tool. The THz refractive index was found to be highly sensitive to the loading of FLG, opening the route to mapping local FLG concentration within a polymer composite sample. By fitting the measured permittivity of the flakes to the Drude-Smith model of conductivity, we also show that the carrier concentrations of these materials are comparable to un-doped chemical vapour deposition produced materials. The ability to measure electronic properties of FLG following processing is important to ensure that defects have not been introduced or chemical functionalisation removed during processing. PMID- 30398165 TI - Effects of carotid pressure waveforms on the results of wave separation, wave intensity and reservoir pressure analysis. AB - OBJECTIVE: Recently great attention has been paid to innovative cardiovascular biomarkers obtained from wave separation (WS), wave intensity (WI) and reservoir wave (RW) theories. All these approaches share a requirement for pressure information. The aim of this study was to evaluate differences in WS-, WI- and RW derived parameters obtained achieving pressure waveforms in different ways. APPROACH: Twenty-two individuals (49 +/- 17 years, 59% males) were examined. Common carotid blood flow waveforms were obtained from pulsed-wave Doppler images. Carotid pressure waveforms were achieved in four different ways: (1) with applanation tonometry, used as a reference method; (2) linear scaling from an ultrasound (US)-derived diameter curve; (3) exponential scaling from a US-derived diameter curve; and (4) linear scaling from an accelerometric-derived diameter signal. For each case, the reflection magnitude (RM) and index (RI) were obtained from the WS. The amplitude of the first positive peak (W 1), of the second positive peak (W 2) and of the negative peak (W b) were calculated from the WI, while the maximum of the reservoir (maxPr) and the excess (maxPex) pressure were achieved from the RW. MAIN RESULTS: According to the intra-class coefficient values, the agreement between the standard method and all the others was excellent for the RM (linear: 0.82; exponential: 0.83; accelerometric: 0.86), RI (linear: 0.84; exponential: 0.85; accelerometric: 0.87), maxPr (linear: 0.97; exponential: 0.96; accelerometric: 0.97) and maxPex (linear: 0.85; exponential: 0.87; accelerometric: 0.89), while only a fair/good level was reached for W 1 (linear: 0.67; exponential: 0.77; accelerometric: 0.52), W 2 (linear: 0.52; exponential: 0.69; accelerometric: 0.83) and W b (linear: 0.60; exponential: 0.44; accelerometric: 0.50). SIGNIFICANCE: Measuring carotid pressure waveforms with different approaches does not influence the cardiovascular parameters obtained by WS and RW; those derived by WI are affected by the carotid pressure curve employed. PMID- 30398166 TI - Large-scale individual thyroid monitoring following nuclear accidents by means of non-spectrometric devices. AB - In order to properly respond to an emergency caused by an accident in a nuclear power plant with a spread of radionuclides in the atmosphere, we propose a field procedure to perform a large-scale individual thyroid monitoring of internal contamination due to inhalation of 131I, by means of non-spectrometric equipment, in particular dose rate meters. Specific attention is paid to the individual monitoring of children, because of the very high radiosensitivity of the child's thyroid to the carcinogenic effects of ionising radiation. The device performance was evaluated by measuring mock iodine sources provided in the Child and Adult Thyroid Monitoring After Reactor Accident (CAThyMARA) intercomparison and, just for a scintillator dose rate meter, by means of 60 s acquisitions of healthy volunteers' thyroids. All the devices showed a remarkable accuracy in quantification of equivalent 131I activity in the thyroids of persons of all ages. The selected scintillator dose rate meter showed detection limit values resulting in a maximum committed equivalent dose to thyroid HT, assuming an acute 131I inhalation occurred five days before the measurement, equal to 10 mSv (related to five-year-old children). Considering the level of HT values associated with the calculated detection limit activities, the proposed procedure has a significant sensitivity to be used for fast internally thyroid monitoring in nuclear or radiological emergencies, allowing daily monitoring a large amount of individuals. PMID- 30398167 TI - Effect of age-related baseline risk on radiation dose response for coronary heart disease. AB - We attempted to estimate the mortality risk of radiation-associated coronary heart disease (CHD) by using a model in which radiation was assumed to participate in the atherosclerotic process jointly with ageing. Model parameters were determined by fitting the Life Span Study data of atomic bomb survivors. According to the model, the excess relative risk (ERR) varies depending on the baseline risk; when applied to the death statistics of Japan and the USA, the estimated ERR was consistently higher in the Japanese population. The absolute risk showed an opposite trend, such that the estimated lifetime attributable risk was approximately two times higher in the US population. Excess cases were expected to appear in old age almost synchronously with spontaneous cases; in contrast, the risk is practically unnoticeable for those young to middle aged. Our model suggests that the radiation dose-response curve for CHD, as well as the latency in epidemiological studies, could be modified by the baseline risk. PMID- 30398168 TI - A 3D nanoelectrokinetic model for predictive assembly of nanowire arrays using floating electrode dielectrophoresis. AB - Floating electrode dielectrophoresis (FE-DEP) presents a promising avenue for scalable assembly of nanowire (NW) arrays on silicon chips and offers better control in limiting the number of deposited NWs when compared with the conventional, two-electrode DEP process. This article presents a 3D nanoelectrokinetic model, which calculates the imposed electric field and its resultant NW force/velocity maps within the region of influence of an electrode array operating in the FE-DEP configuration. This enables the calculation of NW trajectories and their eventual localization sites on the target electrodes as a function of parameters such as NW starting position, NW size, the applied electric field, suspension concentration, and deposition time. The accuracy of this model has been established through a direct quantitative comparison with the assembly of manganese dioxide NW arrays. Further analysis of the computed data reveals interesting insights into the following aspects: (a) asymmetry in NW localization at electrode sites, and (b) the workspace regions from which NWs are drawn to assemble such that their center-of-mass is located either in the inter electrode gap region (desired) or on top of one of the assembly electrodes (undesired). This analysis is leveraged to outline a strategy, which involves a physical confinement of the NW suspension within lithographically patterned reservoirs during assembly, for single NW deposition across large arrays with high estimated assembly yields on the order of 87%. PMID- 30398169 TI - Crystallographic orientation errors in mechanical exfoliation. AB - We evaluate the effect of mechanical exfoliation of van der Waals materials on crystallographic orientations of the resulting flakes. Flakes originating from a single crystal of graphite, whose orientation is confirmed using STM, are studied using facet orientations and electron back-scatter diffraction (EBSD). While facets exhibit a wide distribution of angles after a single round of exfoliation ([Formula: see text]), EBSD shows that the true crystallographic orientations are more narrowly distributed ([Formula: see text]), and facets have an approximately [Formula: see text] error from the true orientation. Furthermore, we find that the majority of graphite fractures are along armchair lines, and that the cleavage process results in an increase of the zigzag lines portion. Our results place values on the rotation caused by a single round of the exfoliation process, and suggest that when a 1-2 degree precision is necessary, the orientation of a flake can be gauged by the orientation of the macroscopic single crystal from which it was exfoliated. PMID- 30398170 TI - Special issue on Polyoxometalates. PMID- 30398171 TI - Recent advances of polyoxometalate-catalyzed selective oxidation based on structural classification. AB - The structural diversity and tenability observed in POMs has encouraged extensive investigations into their catalytic activity. Based on the structural classification of POMs, this review summarizes recent advances relating to POM catalyzed selective oxidation and places most emphasis on dynamic developments from 2015 onwards. Work which contributes to comparing the catalytic performance of POMs with delicate structural differences (e.g. the same type of POM structure with differences of the heteroatom, addenda, protonated state or counter-ion) and in elucidating the origin/distinction of catalytic activity, as well as reasonable mechanisms, are especially highlighted. PMID- 30398172 TI - Recent advances in isopolyoxotungstates and their derivatives. AB - During the past decade, isopolyoxotungstates (iso-POTs) and their derivatives have been greatly developed due to their unique structures and potential applications in luminescence, magnetism, catalysis etc. This brief review is principally focused on the main research progress on iso-POTs, iso-POT-based transition-metal derivatives, iso-POT-based rare-earth derivatives, iso-POT-based organometallic derivatives and iso-POT-based heterometallic derivatives, and gives a summary of some representative examples of their syntheses, structures and related properties. In addition, an outlook on the future of this area is presented in the final section. We believe that this systematic commentary on iso POTs and their derivatives will not only disclose a rich set of iso-POT structures, but also reveal a more promising direction for the further functionalization of iso-POTs. PMID- 30398173 TI - Single-crystal-to-single-crystal transformations triggered by dehydration in polyoxometalate-based compounds. AB - Single-crystal-to-single-crystal transformations are solid-state phase transitions between different crystalline states in which the crystal integrity and the long-range structural order are retained through the whole transformation process. Such a phenomenon constitutes the structural response that some compounds afford when being exposed to a given external stimulus (temperature, pressure, light, etc.) and, therefore, its study has become a relevant focus of interest within crystal engineering because it allows for monitoring how certain properties (colour, magnetism, luminescence, porosity) of the stimuli-responsive material are modified as the structure evolves into the activated form. A range of organic, inorganic and hybrid systems have been found to undergo such phase transitions, but these examples only include a small number of compounds that incorporate polyoxometalate anions, among which the removal of guest solvent molecules (dehydration) stands out as the most common external stimulus able to induce the occurrence of a single-crystal-to-single-crystal transformation. This feature article compiles the examples of dehydration-triggered single-crystal-to single-crystal transformation studies that have been reported to date for polyoxometalate-based compounds and reviews some of their most relevant structural aspects. PMID- 30398174 TI - A polyoxometalate-based metal-organic polyhedron constructed from a {V5O9Cl} building unit with rhombicuboctahedral geometry. AB - The design and construction of metal-organic polyhedra has received much attention by chemists due to the intriguing diversity of architectures and topologies that can be achieved. There are several crucial factors which should be considered for the construction of metal-organic polyhedra, such as the starting materials, reaction time and temperature, solvent and suitable organic ligands. Recently, polyoxometalates (POMs), serving as secondary building units to construct POM-based metal-organic polyhedra, have been the subject of much interest. The title compound, dodecakis(dimethylammonium) octakis(MU-benzene 1,3,5-tricarboxylato)hexa-MU-chlorido-tetracosa-MU-oxido triacontaoxidotriacontavanadium, (NH2Me2)12[(V5O9Cl)6(C9H3O6)8], was synthesized successfully by self-assembly of VOCl3 and benzene-1,3,5-tricarboxylic acid under solvothermal conditions. The title polyhedron has an rdo topology when the {V5O9Cl} building unit and the benzene-1,3,5-tricarboxylate (BTC3-) ligand were simplified into 4-connected and 3-connected vertices. Interestingly, when the {V5O9Cl} building unit and the BTC3- ligand are considered as quadrangular and triangular faces, the structure displays rhombicuboctahedral geometry with an outer diameter of 21.88 A. The packing of the polyhedra produces a circular channel with a diameter of 8.2 A. The title compound was characterized by single crystal X-ray diffraction, elemental analysis, IR spectroscopy, thermogravimetric analysis and powder X-ray diffraction. PMID- 30398175 TI - Synthesis and structural characterization of a dumbbell-like phenylphosphonate stabilized Ti7-oxide cluster. AB - In recent years, crystalline polyoxotitanium clusters (PTCs) have attracted increasing attention as a new kind of promising crystalline material. In this work, a PTC stabilized by phenylphosphonate ligands, i.e. hexa-MU-isopropanolato hexaisopropanolatodi-MU3-oxido-hexa-MU3-phenylphosphonato-heptatitanium tetrahydrate, [Ti7(MU3-O)2(O3P-Phen)6(OiPr)12].4H2O [PTC-54; H2O3P-Phen is phenylphosphonic acid, C6H5PO(OH)2, and HOiPr is isopropanol, C3H7OH], was obtained successfully through a facile one-step solvothermal reaction. The dumbbell-like core structure of PTC-54 can be described as two trinuclear {Ti3(MU3-O)} building units combined together by six phenylphosphonate ligands and one additional Ti atom, giving rise to a Ti7 cluster. Adjacent molecules of PTC-54 are further connected through pi-pi interactions between the phenyl groups to form a supramolecular one-dimensional chain. PMID- 30398176 TI - Iron(II) and copper(II) paratungstates B: a single-crystal X-ray diffraction study. AB - Paratungstate B is a common isopolytungstate (IPOT) built of the [W12O40(OH)2]10- anion and exhibits a cluster-like construction of 12 W-centred distorted octahedra. Due to a high surface charge density, the paratungstate anion acts as a multidentate ligand forming high-dimensional extended structures, which exhibit unique catalytic and magnetic properties. Two new paradodecatungstate B compounds decorated by iron(II) or copper(II), namely Na5Fe2.5[W12O40(OH)2].36H2O (Na5Fe2.5paraB) and Na4Cu3[W12O40(OH)2].28H2O (Na4Cu3paraB), have been synthesized by a convenient aqueous solution method, and structurally characterized by single-crystal and powder X-ray diffraction, IR spectroscopy, elemental analysis and thermogravimetric analysis. Both compounds crystallize in the triclinic P-1 space group. In both compounds, the [W12O40(OH)2]10- polyanion acts as a multidentate ligand that links transition-metal and sodium cations, forming a three-dimensional framework. PMID- 30398177 TI - Synthesis, structural characterization and fluorescence enhancement of chromophore-modified polyoxometalates. AB - Intramolecular charge transfers between pi-conjugated molecules and polyoxometalate (POM) clusters have been observed in donor-acceptor systems based on organic donors and inorganic POM acceptors, which unfortunately results in a general quenching of the chromophore luminescence. The development of POM chromophore dyads that are capable of tackling the quenching process and enhancing the fluorescence intensity of such systems remains a highly challenging area of study. A family of organic-inorganic polyoxometalate hybrids, {[(n-C4H9)4N]3[(MnMo6O24){(CH2)3CR}2]} [1, R = -NHCH2C14H9, namely (anthracen-9-ylmethyl)amino; 2, R = -NHCH2C13H9, (9H-fluoren-2-ylmethyl)amino; 3, R = -NHCH2C10H7, (naphthalen-2-ylmethyl)amino; 4, R = -NHCH2C16H9, (pyren-2 ylmethyl)amino], were synthesized by covalently tethering pi-conjugated molecules onto an Anderson cluster. The resulting POM-chromophore dyads were fully characterized by various spectroscopic techniques, single-crystal X-ray diffraction analysis and ESI-MS. The fluorescence features of these dyads were studied in detail to verify a dramatic emission enhancement that can be achieved by fine-tuning the microenvironment in solution and suppressing the intrinsic photo-induced electron-transfer process. PMID- 30398178 TI - A novel two-dimensional layered Cu2+ complex based on Dawson-like [H3BiW18O60]6-: synthesis, structure and magnetic properties. AB - A novel complex based on the Dawson-like [H3BiW18O60]6-, i.e. (C2H9N2)2[{Cu(C10H8N2)(C2H8N2)}2(H3BiW18O60)].5.5H2O or (enH)2[{Cu(2,2' bipy)(en)}2(MU4-H3BiW18O60)].5.5H2O, (1), where enH is protonated ethane-1,2 diamine, 2,2'-bipy is 2,2'-bipyridine and en is ethane-1,2-diamine, has been synthesized hydrothermally and characterized by elemental analysis, single crystal X-ray diffraction analysis, IR spectroscopy, powder XRD, and thermogravimetry and differential thermal analysis (TG-DTA). For (1), each [H3BiW18O60]6- anion acts as a tetradentate ligand connecting [Cu(2,2' bipy)(en)]2+ fragments via two terminal and two bridging O atoms, forming a two dimensional network structure. Along the a and c axes, polyoxometalate units are arranged in an AB...AB manner. The electrochemical behaviour of (1)-CPE (CPE is a carbon paste electrode) was investigated in 2 M H2SO4 solution by cyclic voltammetry (CV). The redox process of WVI/V takes place at E1/2 = -0.58 (I-I') and -0.37 V (II-II'), and at -0.04 V (III-III') for CuII/0. The magnetic properties of (1) were investigated in the range 2-300 K and indicated the existence of strong antiferromagnetic exchange interactions between the Cu2+ centres. PMID- 30398179 TI - pH-induced phase transition and crystallization of soft-oxometalates (SOMs) into polyoxometalates (POMs): a study on crystallization from colloids. AB - In this work, we demonstrate a simple approach for growing 1D (one-dimensional) inorganic chains of K(C6H16N)3Mo8O26.H2O polyoxometalates (POMs) from its colloidal soft-oxometalate (SOM) phase through the variation of pH. The structure is composed mainly of a 1D inorganic chain with a beta-Mo8O264- binding node linked using K+ via Mo-O-K linkages, which results in a cuboctahedral geometry for the K+ ions. Crystal structure and Hirshfeld surface studies reveal the role of triethylammonium cations in restricting the growth of the 1D chain into 2D/3D (two-/three-dimensional) structures. During the nucleation process from the heterogeneous SOM phase, some of the intermolecular interactions in the dispersion phase are retained in the crystal structure, which was evidenced from residual O...O interactions. The crystallization of the species from its colloidal form as a function of pH was studied by the use of Raman spectroscopy and it was found that the increase in volume fraction of the beta-Mo8O264- species in the crystallizing colloidal mixture with the decrease in pH is responsible for the nucleation. This was monitored by time-dependent DLS (dynamic light scattering) measurement and zeta-potential studies, revealing the co existence of both the crystal and the colloidal forms at pH 3-2. This brings us to the conclusion that in the crystallization of POMs, the colloidal SOM phase precedes the crystalline POM phase which occurs via a phase transition. This work could open up avenues for the study of POM formation from the stand-point of colloidal chemistry and SOMs. PMID- 30398180 TI - An unprecedented Zr-containing polyoxometalate tetramer with mixed trilacunary/dilacunary Keggin-type polyoxotungstate units. AB - A novel zirconium(IV)-substituted tetramer polyoxotungstate, H6K4Na16[Zr4(beta GeW10O38)2(A-alpha-PW9O34)2].37H2O, was synthesized hydrothermally and characterized by IR spectroscopy, elemental analysis, thermogravimetric analysis, powder X-ray diffraction, energy-dispersive X-ray spectroscopy and single-crystal X-ray diffraction. The compound crystallizes in the monoclinic P2/n space group. The most remarkable feature is that the centrosymmetric Zr-based polyoxotungstate tetramer consists of dilacunary Keggin-type germanotungstate and trilacunary Keggin-type phosphotungstate units that are linked by ZrIV ions. PMID- 30398181 TI - Effect of the ammonium ion on proton conduction in porous ionic crystals based on Keggin-type silicododecatungstate. AB - Proton conduction in crystalline porous materials has received much attention from basic scientific research through to practical applications. Polyoxometalates (POMs) can efficiently transport protons because of their small superficial negative charge density. A simple method for enhancing proton conductivity is to introduce NH4+ into the crystal structure, because NH4+ can form hydrogen bonds and function as a proton carrier. According to these considerations, NH4+ was introduced into the porous structure of A2[Cr3O(OOCH)6(etpy)3]2[alpha-SiW12O40].nH2O (A = Li, Na, K and Cs; etpy = 4 ethylpyridine) (I-A+) via topotactic cation exchange. The resulting compound, diammonium tris(4-ethylpyridine)hexaformatooxidotrichromium alpha silicododecatungstate hexahydrate, (NH4)2[Cr3(CHO2)6O(C7H9N)3]2[alpha SiW12O40].6H2O, showed high proton conductivity and low activation energy under high relative humidity (RH), suggesting that protons migrate efficiently via rearrangement of the hydrogen-bonding network formed by the NH4+ cations and the waters of crystallization (Grotthuss mechanism). The proton conductivity and activation energy greatly decreased and increased, respectively, with the decrease in RH, suggesting that protons migrate as NH4+ and/or H3O+ under low RH (vehicle mechanism). PMID- 30398182 TI - Synthesis and structural characterization of tube-type tetradecavanadates. AB - By the reaction of ammonium perchlorate with anion-incorporated bowl-type dodecavanadates, viz. [V12O32(X)]5- [X = N3- (1), OCN- and NO3-], tube-type tetradecavanadates, viz. (NH4)7[V14O38(X)] [X = N3- (2), OCN- (3) and NO3- (4)] were synthesized. The crystal structures of penta(tetraethylammonium) azidododecavanadate nitromethane monosolvate, (C8H20N)5[V12O32(N3)].CH3NO2, 1, heptaammonium azidotetradecavanadate dimethyl sulfoxide hexasolvate, (NH4)7[V14O38(N3)].6C2H6OS, 2, heptaammonium cyanatotetradecavanadate dimethyl sulfoxide hexasolvate, (NH4)7[V14O38(OCN)].6C2H6OS, 3, and heptaammonium nitratotetradecavanadate dimethyl sulfoxide hexasolvate, (NH4)7[V14O38(NO3)].6C2H6OS, 4, were determined. The tube consists of two layers of V7 rings with a guest anion at the centre. The distances between the incorporated anions and the nearest V atoms are 3.058 (3), 3.039 (6) and 2.811 (9) A for 2, 3 and 4, respectively, showing that the incorporated anions are stabilized via noncovalent interactions. Two ammonium cations cap both ends of the tube to stabilize the structures via hydrogen-bonding interactions. Linear OCN- and N3- anions sit on the twofold rotation axes of the tube frameworks and the triangular plane of the NO3- anion deviates from the equatorial plane of the tube by ca 30 degrees . PMID- 30398183 TI - Surface-grafted lanthanoid complexes of the tungstosilicate polyanion [SiW12O40]4 : a synthetic, structural and computational investigation. AB - As an extension of our continued interest in the preparation of inorganic-organic hybrids, we report the successful hydrothermal synthesis of sodium tris[triaqua(MU-1,10-phenanthroline-2,9-dicarboxylato)dysprosium(III)] silicododecatungstate dodecahydrate, {[DyNa(C14H6N2O4)3(H2O)9(SiW12O40)].12H2O}n or Na[Dy(PDA)(H2O)3]3[SiW12O40].12H2O (1), and sodium aqua tris[tetraaqua(MU-4 hydroxypyridine-2,6-dicarboxylato)praseodymium(III)] silicododecatungstate dodecahydrate, {[NaPr(C7H3NO5)3(H2O)13(SiW12O40)].12H2O}n or Na(H2O)[Pr(pydc OH)(H2O)4]3[SiW12O40].12H2O (2) (in which H2PDA is 1,10-phenanthroline-2,9 dicarboxylic acid and H2pydc-OH is 4-hydroxypyridine-2,6-dicarboxylic acid or chelidamic acid). Both compounds have been characterized using elemental analysis, IR spectroscopy and X-ray diffraction methods. Structural characterization by single-crystal X-ray diffraction reveals that these compounds consist of [SiW12O40]4- Keggin-type polyoxometalates (POMs), where a single {W3O13} triad is decorated with a trinuclear Ln complex. Moreover, the decorated polyanions are involved in a series of intermolecular interactions, such as hydrogen bonds and anion-pi interactions, resulting in three-dimensional supramolecular architectures. Density functional theory (DFT) studies were conducted to support these intermolecular interactions in both 1 and 2, and have been rationalized using molecular electrostatic potential (MEP) surface calculations. PMID- 30398184 TI - Crystal structures of hybrid completely reduced phosphomolybdates and catalytic performance applied as molecular catalysts for the reduction of chromium(VI). AB - The exploration of highly efficient and low-cost catalysts for the treatment of hexavalent chromium CrVI in environmental remediation is currently one of the most challenging topics. Here, three phosphomolybdate hybrid compounds have been successfully isolated by the hydrothermal method and been applied as supramolecular catalysts for the reduction of CrVI. Single-crystal X-ray diffraction revealed their formulae as (H2bpp)2[Fe(H2O)][Sr(H2O)4]2{Fe[Mo6O12(OH)3(H2PO4)(HPO4)(PO4)2]2}.5H2O (1), (H2bpp)2[Na(H2O)(OC2H5)][Fe(H2O)2][Ca(H2O)2]2{Fe[Mo6O12(OH)3(H2PO4)(HPO4)(PO4)2]2 .4H2O (2) and (H2bpe)3{Fe[Mo6O12(OH)3(HPO4)3(H2PO4)]2}.8H2O (3) [bpp is 1,3 bis(pyridin-4-yl)propane (C13H14N2) and bpe is trans-1,2-bis(pyridin-4 yl)ethylene (C12H10N2)]. The three hybrids consist of supramolecular networks built up by noncovalent interactions between {Fe[P4Mo6VO31]2}22- polyanions and protonated organic cations. This kind of hybrid polyoxometalate could be applied as heterogeneous molecular catalysts for the reduction of CrVI. It was found that the organic moiety plays a vital role in influencing the catalytic activity of the polyanions. Organic bpp-containing hybrids 1 and 2 are highly active in the catalytic reduction of heavy metal CrVI ions using HCOOH as reductant, while bpe containing hybrid 3 is inactive to this reaction. This work is significant for the design of new catalysts, as well as the exploration of reaction mechanisms at a molecular level. PMID- 30398185 TI - Supramolecular interaction-induced assemblies of polyanions and 2-aminopyridinium in two polyoxometalate-based hybrids. AB - Organic-inorganic hybrids consisting of organic cations and polyanions are promising functional materials due to their various compositions and structures. An important aspect of these materials is the interactions between the organic and inorganic components, which not only produce the final structures, but also influence the properties. Here, we investigated the interactions between organic cations and polyanions using protonated 2-aminopyridinium (Hap) as the cation, and successfully obtained two polyoxometalate-based hybrids, namely (C5H7N2)4[Mo8O26], (I), and (C5H7N2)2[NiMo6O16(OH)2{CH3C(CH2O)3}2].4H2O, (II). In the crystal structure of (I), every Hap cation links with two polyanions by donating one or two N-H...O hydrogen bonds, and every polyanion is surrounded by eight Hap cations via terminal or bridging O atoms. Conversely, in compound (II), every Hap cation only links with one polyanion decorated by a triol ligand; this organic-inorganic component further assembles via uncoordinated water molecules. In the extended structures, Hap plays a key role, not only providing a counter charge, but also acting as 'glue' linking polyanions in the role of hydrogen-bond donors. In both compounds, as the nodes of the supramolecular network, the polyanions exhibit an ordered two-dimensional arrangement due to strong hydrogen bonds and electrostatic interactions between the organic and inorganic parts. The electrochemistry of compound (I) shows that redox sourcing from polyanions is a surface-controlled process. Conversely, the magnetic behaviour of compound (II) indicates dominant antiferromagnetic properties. PMID- 30398186 TI - Zirconia-supported 11-molybdovanadophosphoric acid catalysts: effect of the preparation method on their catalytic activity and selectivity. AB - The oxidation of adamantane with hydrogen peroxide catalyzed by zirconia supported 11-molybdovanadophosphoric acid is shown to be a suitable green route for the synthesis of adamantanol and adamantanone. This work evaluates how the catalyst activity and selectivity are affected by some of its preparative parameters, such as the method for supporting the catalytically active heteropoly acid over the zirconia matrix or the pretreatments applied to the resulting materials before being used as heterogeneous catalysts. Our results indicate that the most effective catalysts able to maintain their activity after several reaction runs are those prepared by following the sol-gel route, whereas the most selective catalysts are those obtained by impregnation methods. Moreover, the calcination temperature has also been identified as a relevant parameter influencing the performance of catalysts based on supported heteropoly acids. The increasing catalytic activity observed over several consecutive reaction runs has been attributed to the formation of peroxo derivatives of polyoxometalate clusters at the surface of the catalyst and their accumulation after each reaction cycle. PMID- 30398187 TI - Direct observation of the ZrIV interaction with the carboxamide bond in a noncovalent complex between Hen Egg White Lysozyme and a Zr-substituted Keggin polyoxometalate. AB - The successful cocrystallization of the noncovalent complex formed between (Et2NH2)8[{alpha-PW11O39Zr-(MU-OH)(H2O)}2].7H2O Keggin polyoxometalate (2) and Hen Egg White Lysozyme (HEWL) protein is reported. The resulting structural model revealed interaction between monomeric [Zr(PW11O39)]4-(1), which is a postulated catalytically active species, and the protein in two positions in the asymmetric unit. The first position (occupancy 36%) confirms the previously observed binding sites on the protein surface, whereas the second position (occupancy 14%) provides novel insights into the hydrolytic mechanisms of ZrIV-substituted polyoxometalates. The new interaction site occurs at the Asn65 residue, which is directly next to the Asp66-Gly67 peptide bond that was identified recently as a cleavage site in the polyoxometalate-catalysed hydrolysis of HEWL. Furthermore, in this newly discovered binding site, the monomeric polyoxometalate 1 is observed to bind directly to the side chain of the Asn65 residue. This binding of ZrIV as a Lewis-acid metal to the carbonyl O atom of the Asn65 side chain is very similar to the intermediate state proposed in density functional theory (DFT) studies in which ZrIV activates the peptide bond via interaction with its carbonyl O atom, and can be thus regarded as a model for interaction between ZrIV and a peptide bond. PMID- 30398188 TI - Synthesis and characterization of carbonate-encapsulated ytterbium- and yttrium containing polyoxotungstates. AB - A sandwiched-type carbonate-encapsulated yttrium-containing arsenotungstate(III) has been synthesized under mild reaction conditions. The polyanion [NaCH3COO{Y2(H2O)3(B-alpha-AsW9O33)2(W2O5)(CO3)}]12- (1) was isolated as a solid crystalline material by the reaction of a YIII salt with the sodium salt of trilacunary [AsW9O33]9- in sodium acetate solution. The sodium salt of the polyanion, i.e. Na12[Na(CH3COO){Y2(AsW9O33)2(W2O5)(CO3)(H3O)3}].22H2O (1a), was characterized by various analytical techniques, such as FT-IR, single-crystal X ray diffraction (SC-XRD), TGA (thermogravimetric analysis), 13C NMR and ESI-MS (electrospray ionization mass spectrometry). SC-XRD studies revealed that the polyanion crystallizes in the triclinic space group P-1. The structure showed that the polyanion is a carbonate-encapsulated sandwich-type species, consisting of two trilacunary B-alpha-[AsW9O33]9-, with a lone-pair-containing AsIII heteroatom, together with two extra tungsten centres and two yttrium cations at the sandwich position, where CH3COO- and Na+ ions act as linkers between the two polyanion units. In addition, we have also synthesized two carbonate-encapsulated germanotungstates(IV), without lone-pair-containing heteroatoms, with the formula [Ln3(A-beta-GeW9O34)2(CO3)(H2O)3]13- [Ln = YIII (2) and YbIII (3)], i.e. Y2K3Na4[Y3(A-beta-GeW9O34)2(CO3)(H2O)3].19H2O (2a) and YbK8Na2[Yb(A-beta GeW9O34)2(CO3)(H2O)3].16H2O (3a), and characterized them by FT-IR, SC-XRD, TGA and ESI-MS. Here, the lanthanide ions act as linkers, extending the structures into higher dimensions. Sodium and potassium ions also play a key role as linkers, further extending the structure. The packing shows the presence of certain hydrophilic pores within the structure. PMID- 30398189 TI - A new hexamolybdate-based copper-2,2'-biimidazole coordination polymer serving as an acid catalyst and support for enzyme immobilization. AB - The hydrothermal reaction of (NH4)3[CoMo6O24H6].7H2O (CoMo6), CuCl2.2H2O and 2,2' biimidazole (H2biim) led to the formation of a new coordination polymer, namely poly[diaquabis(2,2'-biimidazole)hexa-MU3-oxo-octa-MU2-oxo hexaoxodicopper(II)hexamolybdate(VI)], [Cu2Mo6O20(C6H6N4)2(H2O)2]n (Cu-Mo6O20), at pH 2-3. It is obvious that in the formation of crystalline Cu-Mo6O20, the original Anderson-type skeleton of heteropolymolybdate CoMo6 was broken and the new isopolyhexamolybdate Mo6O20 unit was assembled. In Cu-Mo6O20, one Mo6O20 unit connects four [Cu(H2biim)(H2O)]2+ ions in a pentacoordinate mode via four terminal O atoms, resulting in a tetra-supported structure, and each CuII ion is shared by two adjacent Mo6O20 units. Infinite one-dimensional chains are established by linkage between two adjacent Mo6O20 units and two CuII ions, and these chains are further packed into a three-dimensional framework by hydrogen bonds, pi-pi interactions and electrostatic attractions. The catalytic performance of this crystalline material used as an efficient and reusable heterogeneous acid catalyst for carbonyl-group protection is discussed. In addition, Cu-Mo6O20 was applied as a new support for enzyme (horseradish peroxidase, HRP) immobilization, forming immobilized enzyme HRP/Cu-Mo6O20. HRP/Cu Mo6O20 showed good catalytic activity and could be reused. PMID- 30398190 TI - Two new POM-based compounds modified by lanthanide-Schiff base complexes with interesting NLO properties. AB - Two POM-based lanthanide derivatives, namely {triaqua[2,6-diacetylpyridine bis(semicarbazone)-kappa5O,N,N',N'',O']terbium(III)}-MU-oxido-[tricosa-MU2-oxido dodecaoxido-MU12-phosphato-dodecamolybdenum(VI)] pentahydrate (1), [Tb(C11H15N7O2)(H2O)3][PMo12O40].5H2O, and the dysprosium(III) analogue (2), have been isolated successfully by the reaction of Keggin-POM [PMo12O40]3- (abbreviated as PMo12), the Ln3+ ion and the Schiff base 2,6-diacetylpyridine bis(semicarbazone) (DAPSC) ligand under hydrothermal conditions. [Ln(DAPSC)(H2O)3][PMo12O40].5H2O is a PMo12-supported cluster featuring a lanthanide-Schiff base complex [denoted Ln-L(Schiff base)]. Single-crystal X-ray diffraction analysis reveals that the LnIII ion is in a distorted tricapped trigonal prismatic arrangement, coordinated by six O atoms and three N atoms. Two O atoms and three N atoms are provided by one DAPSC ligand, while the additional O atoms originate from a PMo12 cluster and three water molecules. Hydrogen bonding interactions between adjacent clusters form an interesting three dimensional supramolecular structure. The identities of 1 and 2 were characterized by IR spectroscopy, thermogravimetric analysis and powder X-ray diffraction. Interestingly, both compounds possess excellent two-photon absorption (TPA) responses to the third-order nonlinear optics (NLO) (2264 GM for 1 and 941 GM for 2), suggesting that they have potential applications in the field of nonlinear optics (NLO). To our knowledge, 1 and 2 are the first POM based Ln-L(Schiff base) complexes showing excellent two-photon responses. Meanwhile, the electrochemical properties of both compounds were studied in detail. PMID- 30398191 TI - Synthesis and characterization of hybrid Anderson hexamolybdoaluminates(III) functionalized with indometacin or cinnamic acid. AB - The single-side Al-centred tris-functionalized hybrid organic-inorganic Anderson polyoxomolybdates (C16H36N)3[Al(OH)3Mo6O18(OCH2)3CNH(C10H8O)].C9H7N.4CH3OH.5H2O (AlMo6-NH-Cin; Cin is cinnamic acid, C10H9O2) and (C16H36N)3[Al(OH)3Mo6O18(OCH2)3CNH(C19H15ClNO3)].9H2O (AlMo6-NH-Indo; Indo is indometacin, C19H16ClNO4) have been prepared in a mild three-step synthesis and structurally characterized by single-crystal X-ray diffraction, 1H NMR and IR spectroscopies and elemental analysis. Both AlMo6-NH-Cin and AlMo6-NH-Indo crystallize in the orthorhombic space group Pbca. The antibacterial activities of AlMo6-NH-Cin and AlMo6-NH-Indo against the Gram-negative human mucosal pathogen Moraxella catarrhalis were investigated by determination of the minimum inhibitory concentration, which is 32 ug ml-1 for AlMo6-NH-Cin and 256 ug ml-1 for AlMo6-NH-Indo. PMID- 30398193 TI - The mixed-valent 10-manganese(III/IV)-containing 36-tungsto-4-arsenate(V), [MnIII6MnIV4O4(OH)12(H2O)12(A-beta-AsW9O34)4]22. AB - Interaction of the mixed-valent 12-manganese coordination complex [MnIII8MnIV4O12(CH3COO)16(H2O)4] with the lacunary 9-tungstoarsenate(V) [A-alpha AsW9O34]9- resulted in the 10-manganese(III/IV)-containing 36-tungsto-4 arsenate(V), [MnIII6MnIV4O4(OH)12(H2O)12(A-beta-AsW9O34)4]22- (1). Polyanion 1 was isolated as a hydrated mixed potassium-sodium salt, K14Na8[MnIII6MnIV4O4(OH)12(H2O)12(A-beta-AsW9O34)4].104H2O, which crystallizes in the orthorhombic space group Pbcn and was characterized by FT-IR spectroscopy and single-crystal X-ray diffraction, as well as elemental and thermogravimetric analyses. The title polyanion contains a unique [MnIII6MnIV4O4(OH)12(H2O)12]14+ core stabilized within the 36-tungsto-4-arsenate(V) framework. PMID- 30398192 TI - Targeted synthesis of a polypyridyl polyoxometalate coordination complex using microwave-assisted reaction conditions. AB - In this article, we build upon our recent efforts that have focused on demonstrating the value of microwave-assisted synthesis in polyoxometalate (POM) chemistry. Herein, we report for the first time a microwave-assisted approach that enabled the facile preparation and crystallization of a large POM-containing coordination complex. The judicious selection and reaction of a sparingly water soluble transition-metal-substituted polyanion (TMSP) salt with the tritopic ligand 2,4,6-tris(4-pyridyl)-1,3,5-triazine (TPT) in a mixed solvent system under moderately forcing conditions yields Ba9[(BIIIWVI11O39CoIII)3(C18H12N6)].38H2O in moderate yield. Crystallographic analysis reveals significant intermolecular interactions between the organic ligand and neighbouring polyanions, predominantly C-H...O(water) in nature; meanwhile, the solvated regions of the crystal show significant disorder. To supplement the crystallographic study, combustion analysis, and IR and 1H NMR spectroscopic analyses were conducted, revealing good bulk purity and the stability of the complex in aqueous media. PMID- 30398194 TI - Structures and energetic properties of 4-halobenzamides. AB - The amide bond represents one of the most fundamental functional groups in chemistry. The properties of amides are defined by amidic resonance (nN->pi*C=O conjugation), which enforces planarity of the six atoms comprising the amide bond. Despite the importance of 4-halo-substituted benzamides in organic synthesis, molecular interactions and medicinal chemistry, the effect of 4-halo substitution on the properties of the amide bond in N,N-disubstituted benzamides has not been studied. Herein, we report the crystal structures and energetic properties of a full series of 4-halobenzamides. The structures of four 4 halobenzamides (halo = iodo, bromo, chloro and fluoro) in the N-morpholinyl series have been determined, namely 4-[(4-halophenyl)carbonyl]morpholine, C11H12XNO2, for halo = iodo (X = I), bromo (X = Br), chloro (X = Cl) and fluoro (X = F). Computations have been used to determine the effect of halogen substitution on the structures and resonance energies. 4-Iodo-N morpholinylbenzamide crystallized with a significant distortion of the amide bond (tau + chiN = 33 degrees ). The present study supports the correlation between the Ar-C(O) axis twist angle and the twist angle of the amide N-C(O) bond. Comparison of resonance energies in synthetically valuable N-morpholinyl and N piperidinyl amides demonstrates that the O atom of the morpholinyl ring has a negligible effect on amidic resonance in the series. PMID- 30398195 TI - Unprecedented three-dimensional hydrogen-bonded hex topological chiral lanthanide organic frameworks built from an achiral ligand. AB - The design and preparation of chiral metal-organic frameworks (CMOFs) from achiral ligands are a big challenge. Using 3-nitro-4-(pyridin-4-yl)benzoic acid (HL) as a new linker, a total of eight chiral lanthanide-organic frameworks (LOFs), namely poly[diaquatris[MU2-3-nitro-4-(pyridin-4-yl)benzoato kappa2O:O']lanthanide(III)], L- and D-[Ln(C12H7N2O4)3(H2O)2]n [(1), Ln = Eu; (2), Ln = Gd; (3), Ln = Dy; (4), Ln = Tb], were hydrothermally synthesized without chiral reagents and determined by X-ray crystallography. Crystal structure analyses show that L-(1)-(4) crystallize in the hexagonal P65 space group and are isomorphous and isostructural, while the enantiomers D-(1)-(4) crystallize in the hexagonal P61 space group. All LnIII ions are octacoordinated by six carboxyl O atoms of six 3-nitro-4-(pyridin-4-yl)benzoate ligands and two water molecules in a dodecahedral geometry. A one-dimensional neutral helical [Ln2(CO2)3]n chain is observed in (1)-(4) as a chiral origin. These helical chains are further interconnected via directional hydrogen-bonding interactions between pyridyl groups and water molecules to construct a three-dimensional (3D) homochiral network with hex topology. The present CMOF structure is the first chiral 3D hydrogen-bonded hex-net and shows good water stability. Solid-state circular dichroism (CD) signals revealed that (1)-(4) crystallized through spontaneous resolution. Furthermore, (1) and (4) display a strong red and green photoluminescence at room temperature, respectively, but their intensities reduce to almost half at 200 degrees C. Notably, upon excitation under visible light (463 nm), a circularly polarized luminescence (CPL) of (1) in the solid state is observed for the first time, with a glum value of 2.61 * 10-2. PMID- 30398196 TI - Solid-state structure and antimicrobial and cytotoxicity studies of a cucurbit[6]uril-like Cu6L4 constructed from 3,5-bis[(1H-tetrazol-5-yl)methyl]-4H 1,2,4-triazol-4-amine. AB - 3,5-Bis[(1H-tetrazol-5-yl)methyl]-4H-1,2,4-triazol-4-amine (H2L) associates under deprotonation with CuSO4 in aqueous medium to form a new waisted barrel-shaped M6L4 cluster, namely hexaaquatetrakis{MU4-3,5-bis[(1H-tetrazol-5-yl)methyl]-4H 1,2,4-triazol-4-amine}-MU4-sulfato-hexacopper(II) sulfate hydrate, [Cu6(SO4)(C6H6N12)4(H2O)6]SO4.nH2O (n = ~23) (1). Cluster 1 resembles concave cucurbit[6]uril and has one disordered sulfate anion trapped inside the cage, which additionally stabilizes the Cu6 unit. The CuII ions have either a square pyramidal or a distorted octahedral geometry. The equatorial positions are filled by N atoms from the L2- ligand, while the axial positions are occupied by coordinated water molecules and O atoms of the sulfate counter-ion. In the solid state, the Cu6 clusters are connected through a large number of hydrogen bonds formed by uncoordinated water molecules and an additional sulfate anion. The compound shows good antimicrobial activity against E. coli tested with the Kirby Bauer approach. In addition, the cell viability towards HeLa and L-929 cells was studied. PMID- 30398197 TI - Cocrystals of pyrazine and benzene polycarboxylic acids. AB - The crystal structures of four cocrystals of pyrazine with benzene polycarboxylic acids were determined, namely pyrazine-phthalic (benzene-1,2-dicarboxylic) acid (1/1), C4H4N2.C8H6O4 (1), pyrazine-hemimellitic (benzene-1,2,3-tricarboxylic) acid (1/1), C4H4N2.C9H6O6 (2), pyrazine-hemimellitic acid-water (1/2/2), C4H4N2.2C9H6O6.2H2O (2a), and pyrazine-pyromellitic (benzene-1,2,4,5 tetracarboxylic) acid (3/1), 3C4H4N2.C10H6O8 (3). In all cases, infinite chains of alternating acid and base molecules, bonded by O-H...N hydrogen bonds, are formed. However, the details of the supramolecular structures are different. The additional carboxylic acid groups in the tri- and tetracarboxylic acids participate in hydrogen bonding with neighbouring acid molecules (in 2), water molecules, which makes the structure more complicated (in 2a), or with additional pyrazine molecules (in 3). pi-pi interactions between aromatic rings help organize the crystal architectures in all cases except for hydrate 2a. In that case, the hydrogen-bond-enriched structure enforces a disposition of the rings in which no stacking is observed. The Hirshfeld surface analysis allows better visualization of the differences between the structures by fingerprint plots in particular. PMID- 30398198 TI - Influence of 3-{5-[4-(diethylamino)benzylidene]rhodanine}propionic acid on the conformation of 5-(4-chlorobenzylidene)-2-(4-methylpiperazin-1-yl)-3H-imidazol 4(5H)-one. AB - The arylidene-imidazolone derivatives are a group of compounds of great interest in medicinal chemistry due to their various pharmacological actions. In order to study the possible conformations of an arylidene-imidazolone derivative, two new crystal structures were determined by X-ray diffraction, namely (Z)-5-(4 chlorobenzylidene)-2-(4-methylpiperazin-1-yl)-3H-imidazol-5(4H)-one, C15H17ClN4O, (6), and its salt 4-[5-(4-chlorobenzylidene)-5-oxo-4,5-dihydro-3H-imidazol-2-yl] 1-methylpiperazin-1-ium 3-{5-[4-(diethylamino)benzylidene]-4-oxo-2 thioxothiazolidin-3-yl}propionate, C15H18ClN4O+.C17H19N2O3S2-, (7). Both compounds crystallize in the space group P-1. The basic form (6) crystallizes with two molecules in the asymmetric unit. In the acid form of (6), the N atom of the piperazine ring is protonated by proton transfer from the carboxyl group of the rhodanine acid derivative. The greatest difference in the conformations of (6) and its protonated form, (6c), is observed in the location of the arylidene imidazolone substituent at the N atom. In the case of (6c), the position of this substituent is close to axial, while for (6), the corresponding position is intermediate between equatorial and axial. The crystal packing is dominated by a network of N-H...O hydrogen bonds. Furthermore, the crystal structures are stabilized by numerous intermolecular contacts of types C-H...N and C-H...Cl in (6), and C-H...O and C-H...S in (7). The geometry with respect to the location of the substituents at the N atoms of the piperazine ring was compared with other crystal structures possessing an N-methylpiperazine moiety. PMID- 30398199 TI - A new twofold interpenetrated two-dimensional cadmium(II) coordination polymer constructed from 2,2'-(benzene-1,4-dicarboxamido)dipropionate. AB - In recent years, much initial interest and enthusiasm has focused on the self assembly of coordination polymers due to the aesthetics of their crystalline architectures and their potential applications as new functional materials. As part of an exploration of chiral coordination polymers, a new twofold interpenetrated two-dimensional (2D) coordination polymer, namely, poly[[tetraaquabis[MU3-(2R,2'R)-2,2'-(benzene-1,4-dicarboxamido)dipropionato kappa5O,O':O'',O''':O'']dicadmium(II)] trihydrate], {[Cd2(C14H14N2O6)2(H2O)4].3H2O}n, has been synthesized by the reaction of Cd(CH3COO)2.2H2O with the designed ligand (2R,2'R)-2,2'-(benzene-1,4 dicarboxamido)dipropionic acid (H2L). The compound has been structurally characterized by elemental analysis, IR spectroscopy, powder X-ray diffraction and single-crystal X-ray diffraction analysis. In the crystal structure, each CdII cation binds to three carboxylate groups from two crystallographically independent L2- dianions. Four carboxylate groups link two crystallographically independent cadmium cations into a 4,4-connected secondary building unit (SBU). The resulting SBUs are extended into a two-dimensional folding sheet via the terephthalamide moiety of the ligand as a spacer, which can be simplified as a (4,4)-connected 4,4L15 net with the point symbol (3.53.62)(32.52.62). In the lattice, two independent folding sheets interpenetrate each other to yield a double-sheet layer. The resulting 2D layers pack in parallel arrays through intermolecular hydrogen bonds and interlayer pi-pi interactions. The thermal stability and photoluminescence properties of the title compound have been investigated and it exhibits an enhanced fluorescence emission and a longer lifetime compared with free H2L. PMID- 30398200 TI - Purification, characterization, crystal structure and NO production inhibitory activity of three new sesquiterpenoids from homalomena occulta. AB - Two new isodaucane-type sesquiterpenoids, namely (1R,4S,5S,6R,7S,10R)-isodauc 6,7,10-triol, C15H28O3, (1), and (1R,4S,5S,6S,7S,10R)-isodauc-6,7,10-triol, (2), and a new eudesmane-type sesquiterpenoid, 1beta,4beta,5alpha-trihydroxyeudesmane, (3), were obtained from the rhizomes of homalomena occulta with the aid of column chromatography. Their structures were elucidated based on extensive spectroscopic analyses, including 1D NMR, 2D NMR and HRESIMS. The structure of (1) was confirmed by single-crystal X-ray diffraction and the absolute configuration was assigned with respect to that of the precursor. The single-crystal structure reveals that adjacent molecules of (1) embrace through two groups of intermolecular O-H...O hydrogen bonds to generate a two-dimensional sheet with a 63-net topology. The three compounds were evaluated for their activity against lipopolysaccharide-induced production of nitrogen oxide (NO) in RAW 264.7 cells, and (1) showed an inhibitory effect on NO production, with IC50 values of 5.7+/ 0.22 uM. PMID- 30398201 TI - Studies via X-ray analysis on intermolecular interactions and energy frameworks based on the effects of substituents of three 4-aryl-2-methyl-1H-imidazoles of different electronic nature and their in vitro antifungal evaluation. AB - The crystal structures of 2-methyl-4-phenyl-1H-imidazole, C10H10N2, (3a), 4-(4 chlorophenyl)-2-methyl-1H-imidazole hemihydrate, C10H9ClN2.0.5H2O, (3b), and 4-(4 methoxyphenyl)-2-methyl-1H-imidazole, C11H12N2O, (3c), have been analyzed. It was found that the electron-donating/withdrawing tendency of the substituent groups in the aryl ring influence the acid-base properties of the 2-methylimidazole nucleus, changing the strength of the intermolecular N-H...N interactions. This behaviour not only influences the crystal structure but also seems to have an important effect on the antifungal activity. Considering the substituent groups, that is, H in (3a), Cl in (3b) and OMe in (3c), the formation of strong N-H...N connections has the probability (3a) > (3b) > (3c), while compound (3c) proves to be more active than (3a) and (3b) at all concentrations against C. neoformans. PMID- 30398202 TI - Order and disorder in (E)-[1-(biphenyl-4-yl)ethylidene]hydrazine: a structural, spectroscopic and theoretical study. AB - An unexpected global disorder (co-existing rotational disorder and glide disorder) has been observed during an X-ray investigation of the crystal structure of (E)-[1-(biphenyl-4-yl)ethylidene]hydrazine, C14H14N2, at room temperature. When the temperature decreases to 273 K, the disorder disappears, but the quality of the data set is low. The diffraction data were collected again at 110 K. Differential scanning calorimetry (DSC) analysis and polarizing microscopy experiments, as well as a fourth set of single-crystal data collected at 283 K, proved that the order-disorder transformation occurs continuously. The analyses of these crystal structures and full-range relaxed potential energy surface scans showed that this kind of global disorder is not very difficult to achieve inside the crystal. Experimental and theoretical studies via UV-Vis and fluorescence spectra impart an understanding on the prediction methods of optical properties, which are essential for the rational design of biphenyl-based materials with pre-defined properties. PMID- 30398203 TI - Low-dimensional compounds containing cyanido groups. Part XXXV. Structure, spectral, thermal and magnetic properties of a binuclear CuII-biquinoline complex with bridging and terminal dicyanamide ligands. AB - From the system CuCl2-biq-NaN(CN)2 (biq is 2,2'-biquinoline), the binuclear molecular complex bis(MU-dicyanamido-kappa2N1:N5)bis[(2,2'-biquinoline kappa2N,N')(dicyanamido-kappaN1)copper(II)], [Cu2(C2N3)4(C18H12N2)2] or [Cu2(biq)2(dca)2(MU1,5-dca)2] (1) [dca is dicyanamide, N(CN)2-] was isolated and characterized by crystal structure analysis, and spectral, thermal and magnetic measurements. IR spectroscopy confirmed the presence of the biq and dca ligands in 1. Its solid-state structure consists of discrete centrosymmetric binuclear copper(II) units with double end-to-end dca bridges. Each CuII atom is in a distorted square-pyramidal environment with the equatorial plane formed by two nitrile N atoms from bridging dca groups, one of the two N atoms of the chelate biq molecule and one nitrile N atom from a terminal dca ligand, whereas the second biq N atom occupies the axial position. Thermal decomposition of 1 in an air atmosphere proceeds gradually, with copper(I) cyanide being the final decomposition product. Magnetic measurements revealed the formation of alternating spin chains and a relatively strong exchange interaction within the binuclear units was also confirmed by Broken Symmetry DFT (density functional theory) calculations. PMID- 30398204 TI - Multifunctional arylsulfonamide derivatives with 5-HT6/5-HT7 receptor antagonistic activity: a structural study. AB - Nowadays, a search for antagonists co-acting on serotonin receptor subtypes 6 and 7 (5-HT6R and 5-HT7R, respectively) is of great interest due to the increasing number of patients suffering from dementia and related behavioural and psychological symptoms. The X-ray crystal structures of four promising multifunctional ligands in the hydrochloride forms were determined, namely 4-(6 fluoro-1,2-benzoxazol-3-yl)-1-[3-(3-methylbenzenesulfonamido)propyl]piperidin-1 ium chloride, C22H27FN3O3S+.Cl-, (I), 4-(6-fluoro-1,2-benzoxazol-3-yl)-1-[4-(5 fluoro-3-methylbenzo[b]thiophene-2-sulfonamido)butyl]piperidin-1-ium chloride, C25H28F2N3O3S2+.Cl-, (II), 4-(6-fluoro-1,2-benzoxazol-3-yl)-1-[4-(6 fluorobenzo[b]thiophene-2-sulfonamido)butyl]piperidin-1-ium chloride, C24H26ClFN3O3S2+.Cl-, (III), and 4-(6-fluoro-1,2-benzoxazol-3-yl)-1-[3-(3-chloro 4-fluorobenzenesulfonamido)propyl]piperidin-1-ium chloride, C21H22ClF2N3O3S2+.Cl , (IV). Two pharmacologically important functional groups, i.e. arylsulfonamide and piperidinyl-fluorobenzisoxazole, are linked by three- and four-membered aliphatic chains. These compounds crystallize as hydrochloride salts in monoclinic space groups, i.e. C2/c for (I), P21/c for (II) and (III), and P21/n for (IV). In the asymmetric unit, a charge-assisted hydrogen bond is observed between the cation located at the piperidine N atom and the chloride anion. The protonated piperidine N atom is critical to the pharmacological activity for the compounds, allowing for a strong interaction with monoaminergic receptors in the central nervous system. The sulfonyl group plays the role of a hydrogen-bond acceptor in the pharmacophore model and is involved in several C-H...O interactions. Two aromatic fragments of the presented structures are involved in C-H...pi contacts, which were studied by Hirshfeld structure analysis. The distances between the mentioned functional groups are in agreement with pharmacophore models given in the literature. The studied interactions observed in the crystal structure indicate the main forces responsible for ligand-receptor recognition and binding. PMID- 30398205 TI - Structural and electrochemical comparison of trinuclear ruthenium oxo clusters [Ru3(OAc)6O(L)3]+and [Ru3(OAc)6O(L)2(CO)] (L = imidazole, benzimidazole, and 4 phenylpyridine). AB - The triruthenium oxo clusters [Ru3(OAc)6O(L)3]+ and [Ru3(OAc)6O(L)2(CO)] possess unique electronic characteristics that vary based on the ligands L. Here we report an investigation of the structural, electrochemical, and optical properties of clusters with imidazole, benzimidazole, and 4-phenylpyridine ligands. The complexes [Ru3(OAc)6O(L)3]+ [1+: L = imidazole (im); 2+: L = benzimidazole (benzim); 3+: L = 4-phenylpyridine (4PP)] and [Ru3(OAc)6O(L)2(CO)] (1-CO and 3-CO) were synthesized by reaction of either [Ru3(OAc)6O(MeOH)3]+ or [Ru3(OAc)6O(MeOH)2(CO)], respectively, with the corresponding heterocycle. We further discovered that [3]OAc could be reduced to the mixed-valence neutral state 3 by refluxing the complex under nitrogen in methanol. Single-crystal X-ray structure analysis of hexa-MU2-acetato-MU3-oxido-tris(1H-imidazole)triruthenium hexafluorophosphate acetonitrile hemisolvate, [Ru3(C2H3O2)6O(C3H4N2)3]PF6.0.5CH3CN, [1]PF6, hexa-MU2-acetato-carbonylbis(1H imidazole)-MU3-oxido-triruthenium methanol monosolvate, [Ru3(C2H3O2)6O(C3H4N2)(CO)].CH3OH, 1-CO, hexa-MU2-acetato-MU3-oxido-tris(4 phenylpyridine)triruthenium pentahydrate, [Ru3(C2H3O2)6O(C11H9N)3].5H2O, 3, and hexa-MU2-acetato-carbonyl-MU3-oxido-bis(4-phenylpyridine)triruthenium methanol monosolvate, [Ru3(C2H3O2)6O(C11H9N)2(CO)].CH3OH, 3-CO, show the expected triruthenium MU3-oxo core and N-coordination of the ligands. Cyclic voltammetry revealed quasi-reversible and irreversible redox couples in [1]PF6, 1-CO, and [2]PF6, while [3]PF6 and 3-CO exhibit reversible redox couples. The optical properties of these richly colored species were investigated using UV-Vis spectroscopy. PMID- 30398206 TI - The solid-state conformation of the topical antifungal agent O-naphthalen-2-yl N methyl-N-(3-methylphenyl)carbamothioate. AB - Tolnaftate, a classic antifungal compound, has been found to crystallize from 1:1 (v/v) acetone-water as large flat colorless needles in the centrosymmetric monoclinic space group P21/c. These crystals contain a 50:50 mixture of the (+ap, sp,+ac,-ac) and (-ap,+sp,-ac,+ac) conformers. The bond lengths in the central CNOS unit are 1.3444 (19), 1.3556 (18) and 1.6567 (15) A for C-N, C-O and C-S, respectively, and the CNOS and C3N moieties are flat and nearly coplanar with each other, consistent with the C-N bond possessing partial double-bond character. Tolnaftate and the four most closely related N,N-disubstituted thiocarbamates in the Cambridge Structural Database (CSD) all exist as E conformational isomers in the solid state. Among these five compounds, tolnaftate is the only one in which the N-tolyl moiety is positioned trans to the S atom, i.e. the N-aryl substituent in each of the other compounds is positioned cis to their respective S atom. Notably, and more importantly, our experimental X-ray structure is unlike all prior theoretical models available for tolnaftate. The implication, either directly or indirectly, is that some of those theoretical models used in earlier studies to explain the spectroscopic properties of tolnaftate and to suggest which protein-ligand interactions are responsible for the binding of tolnaftate to squalene epoxidase are either inappropriate or structurally unreasonable, i.e. the results and conclusions from those prior studies are in need of critical reassessment. PMID- 30398207 TI - Investigation of the molecular structure of 4-(3-methyl-3-phenylcyclobutyl)-2-[2 (3-methylbenzylidene)hydrazinyl]thiazole in the gas and solid phases. AB - In this study, the title Shiff base, C22H23N3S, was synthesized and examined by 1H and 13C NMR spectroscopy and X-ray analysis techniques. The crystal structure is stabilized by classical intermolecular N-H...N hydrogen bonding. The crystal packing is additionally stabilized by C-H...pi interactions. It has been observed that the compound can exist in two different tautomeric forms, and experimental and theoretical studies were carried out on these tautomeric structures. For this purpose, the gas phase of the compound was optimized by density functional theory (DFT) using the B3LYP/6-311G(d) method, which allowed for the structural parameters (bond angles, bond lengths and dihedral angles), as well as the frontier molecular orbitals (FMO), to be examined. In addition, stable structures of the two tautomers in the solid phase were obtained using Quantum ESPRESSO under periodic boundary conditions (PBC). PMID- 30398208 TI - The study of interactions with a halogen atom: influence of NH2 group insertion on the crystal structures of meta-bromonitrobenzene derivatives. AB - Halogen atoms in molecular crystals may be involved in various interactions, often playing a very important role in structure stabilization. By introducing electron-donating groups, such as NH2, the electron density of the molecule is changed and thus interactions with the bromine substituent may alter. Herein, the crystal structures of meta-bromonitrobenzene and its NH2-substituted derivatives are analyzed. In all four described structures, namely m-bromonitrobenzene [Charlton & Trotter (1963). Acta Cryst. 16, 313], 4-bromo-2-nitroaniline (C6H5BrN2O2, 1), 2-bromo-6-nitroaniline (2) and 2-bromo-4-nitroaniline [Arshad et al. (2009). Acta Cryst. E65, o480], the Br atom is engaged in different interactions (Br...pi, Br...O, Br...Br and C-H...Br, respectively). The Hirshfeld surface analysis (HS) and Reduced Density Gradient NonCovalent Interaction (RDG NCI) plots are used to prove the relevance, directionality and stabilizing nature of these interactions. Their modifications have been associated with the position of the amino group in the molecular structure and its influence on charge distribution analyzed with electrostatic potential surfaces (EPS). The diversification of the interactions has been correlated with a sigma-hole potential value that enables a switching of the Br-atom character from electrophilic to nucleophilic. PMID- 30398209 TI - Different cationic forms of (-)-cytisine in the crystal structures of its simple inorganic salts. AB - The crystal structures of 13 simple salts of cytisine, an alkaloid isolated from the seeds of Laburnum anagyroides, have been determined, namely cytisinium (6-oxo 7,11-diazatricyclo[7.3.1.02,7]trideca-2,4-dien-11-ium) bromide, C11H15N2O+.Br-, cytisinium iodide, C11H15N2O+.I-, cytisinium perchlorate, C11H15N2O+.ClO4-, cytisinium iodide triiodide, C11H15N2O+.I-.I3-, cytisinium chloride monohydrate, C11H15N2O+.Cl-.H2O, cytisinium iodide monohydrate, C11H15N2O+.I-.H2O, cytisinium nitrate monohydrate, C11H15N2O+.NO3-.H2O, hydrogen dicytisinium tribromide, C22H31N4O23+.3Br-, hydrogen dicytisinium triiodide, C22H31N4O23+.3I-, hydrogen dicytisinium triiodide diiodide, C22H31N4O23+.I3-.2I-, hydrogen dicytisinium bis(triiodide) iodide, C22H31N4O23+.2I3-.I-, cytisinediium (6-oxidaniumylidene 7,11-diazatricyclo[7.3.1.02,7]trideca-2,4-dien-11-ium) bis(perchlorate), C11H16N2O2+.2ClO4-, and cytisinediium dichloride trihydrate, C11H16N2O2+.2Cl .3H2O. Cytisine has two potential protonation sites, i.e. the N atom of the piperidine ring and the carbonyl O atom of the pyridone ring. Three forms of the cytisinium cation were identified, namely the monocation, which is always protonated at the N atom, the dication, which utilizes both protonation sites, and the third form, which contains two cytisine moieties connected by very short and linear O...H...O hydrogen bonds, with an O...O distance of approximately 2.4 A. This third form may therefore be regarded as a 3+ species, or sesqui-cation, and is observed solely in the salts with bromide, iodide or triiodide (heavier halogen) anions. The cation is quite rigid and all 19 cytisinium fragments in the studied series have very similar conformations. The crystal structures are determined mainly by Coulombic interactions and hydrogen bonds, and the latter form is determined by different networks. Additionally, some anion-pi and lone pair...pi secondary interactions are identified in almost all of the crystal structures. Hirshfeld surface analysis generally confirms the role of different interactions in the determination of the crystal architecture. PMID- 30398210 TI - Crystal structures of racemic and enantiopure synephrine correlated with physicochemical properties from IR spectroscopy and thermal analysis. AB - The proto-alkaloid synephrine {SYN; systematic name: 4-[1-hydroxy-2 (methylamino)ethyl]phenol}, C9H13NO2, is found to crystallize as a neutral molecule in the racemate and as a zwitterion in the pure enantiomer, in which the phenolic H atom has been transferred to the amino group. In the racemate crystal, an enantiomeric pair on an inversion centre is weakly linked by alcoholic O-H and N-H groups into an R22(10) ring. The trigonal pyramidal amino group is also linked to the phenolic and alcoholic groups to form a C(6) chain. In the enantiopure crystal, the deprotonated phenolic O atom is involved in trifurcated hydrogen bonding to two quaternary ammonium groups and an alcoholic O-H group to form a fused R24(11) ring and a C(7) chain. From the results of the crystal structure analysis, thermal analyses and DFT calculations validated from FT-IR spectra, a different tautomer was found in the racemic molecule (RS-SYN) versus the enantiopure molecule (R-SYN). PMID- 30398211 TI - Controlled interpenetration of 44 networks: syntheses and structures of two Cu3 cluster coordination polymers. AB - The reaction of copper nitrate and triethanolamine with benzene-1,4-dicarboxylic acid (bdcH2) or 4,4'-[1,4-phenylenebis(oxy)]dibenzoic acid (podaH2) leads to the formation of poly[bis(MU4-benzene-1,4-dicarboxylato-kappa4O1:O1':O4:O4)bis{MU2 [bis(2-hydroxyethyl)amino]ethanolato-kappa4N,O,O',O'':kappaO}tricopper(II)], [Cu3(C8H4O4)2(C6H14NO3)2] or [Cu3(MU4-bdc)2(teaH2)2] (I), and poly[bis{MU4-4,4' [1,4-phenylenebis(oxy)]dibenzoato-kappa4O:O':O'':O''}bis{MU2-[bis(2 hydroxyethyl)amino]ethanolato-kappa4N,O,O',O'':kappaO}tricopper(II)], [Cu3(C20H12O6)2(C6H14NO3)2] or [Cu3(MU4-poda)2(teaH2)2], (II). The two representative compounds contain a well-established Cu3 cluster supporting a given 44 network. The ligand length is the underlying factor that controls the degree of interpenetration. Controlled interpenetration can be facile to realise by elongating protocols. Compound I shows a non-interpenetrating 44 network, whereas II features a threefold interpenetrating network. Furthermore, similar hydrogen-bond interactions extend the different interpenetrating 44 networks into three-dimensional supramolecular topologies. Variable-temperature magnetic studies showed a ferromagnetic coupling behaviour in the two complexes. PMID- 30398212 TI - Ruthenium(II)-carbonyl complexes containing two N-monodentate 1,8-naphthyridine ligands: active catalysis in transfer hydrogenation reactions. AB - The reaction of 2-aminonicotinaldehyde with 2- or 4-methoxyacetophenone in basic media leads to the new ligands 2-(4-methoxyphenyl)-1,8-naphthyridine and 2-(2 methoxyphenyl)-1,8-naphthyridine, respectively, in high yield. The reaction of these naphthyridine derivatives with [RuCl2(CO)2]n leads to the respective complexes cis-dicarbonyldichloridobis[2-(4-methoxyphenyl)-1,8-naphthyridine kappaN8]ruthenium(II) and cis-dicarbonyldichloridobis[2-(2-methoxyphenyl)-1,8 naphthyridine-kappaN8]ruthenium(II), both [RuCl2(C15H12N2O)2(CO)2], in good yield. Both ruthenium(II) complexes display a slightly distorted octahedron with two cis carbonyl, two cis chloride and two cis naphthyridine ligands, the latter coordinated in a monodentate fashion through the N atom in the 8-position. Both complexes exhibit a moderate catalytic activity in the hydrogen-transfer reaction from propan-2-ol to acetophenone in the presence of a base, with 100% selectivity. PMID- 30398214 TI - A Focused Review on the Pathophysiology, Diagnosis, and Management of Cardiac Amyloidosis. AB - Amyloidosis is a systemic disorder that results from abnormal protein metabolism, producing amyloid fibrils that are subsequently deposited within vital organs. Cardiac involvement is typically associated with the specific subtypes of immunoglobulin lightchain, transthyretin, secondary amyloidosis, and dialysis related amyloidosis. The hallmark of cardiac amyloidosis is the development of restrictive cardiomyopathy and heart failure, usually with a preserved left ventricular ejection fraction. The diagnosis is based on the integration of clinical signs and symptoms, echocardiography, cardiac magnetic resonance imaging, nuclear scintigraphy, electrocardiography, and cardiac biomarkers. Traditionally, management of heart failure symptoms and prevention of heart failure exacerbations have been the cornerstones of therapy. However, various treatments are currently under investigation that aim to eliminate or neutralize the underlying amyloidogenic substrate. Herein, we provide a focused review and discussion of the cardiovascular manifestations, epidemiologic and clinical characteristics, diagnostic modalities, and treatment strategies of cardiac amyloidosis. PMID- 30398215 TI - Hyperuricemia and Cardiovascular Disease. AB - Uric acid (UA), the metabolic mediator of gout and urate renal stones, is associated with increased cardiovascular risk burden. Hyperuricemia is a common metabolic disorder, and interaction among UA and cardiovascular diseases has been clearly described. Several illnesses, including hypertension, myocardial infarction, metabolic syndrome, and heart failure, are related to increases in UA levels. In this article, we discuss the pathophysiology of hyperuricemia and describe the biologic plausibility of this metabolite's participation in the pathogenesis of cardiovascular illness. We conclude by discussing the implications of lowering plasma UA concentrations to reduce the risk of cardiovascular events, including myocardial infarction, stroke, heart failure, and cardiovascular death. PMID- 30398213 TI - Comparison of the crystal structures and Hirshfeld surface analysis of five N-(4 methylbenzenesulfonyl)glycine hydrazone derivatives. AB - The crystal structures of N-(4-methylbenzenesulfonyl)glycine hydrazone and four derivatives with four different substituents have been investigated, namely, (E) N-{2-[2-(benzylidene)hydrazinyl]-2-oxoethyl}-4-methylbenzenesulfonamide, C16H17N3O3S, (I), (E)-N-{2-[2-(4-bromobenzylidene)hydrazinyl]-2-oxoethyl}-4 methylbenzenesulfonamide, C16H16BrN3O3S, (II), (E)-N-{2-[2-(4 chlorobenzylidene)hydrazinyl]-2-oxoethyl}-4-methylbenzenesulfonamide, C16H16ClN3O3S, (III), (E)-N-(2-{2-[4-(dimethylamino)benzylidene]hydrazinyl}-2 oxoethyl)-4-methylbenzenesulfonamide, C18H22N4O3S, (IV), and (E)-N-{2-[2-(4 methoxybenzylidene)hydrazinyl]-2-oxoethyl}-4-methylbenzenesulfonamide, C17H19N3O4S, (V). The molecules in all five crystal structures show similar conformations and hydrogen-bonding patterns. The central part of the molecule, i.e. C-C-N-N=C, is almost linear in all the structures, with the C-C-N-N torsion angles ranging from -178.3 (1) to -180.0 (2) degrees and the C-N-N=C torsion angles ranging from -178.5 (4) to -179.8 (3) degrees . The conformation of the N H and C=O bonds in the amide group of the hydrazone part is syn in all the compounds. In all the structures, sulfonamide and hydrazone dimers with R22(8) ring motifs are observed, which are further augmented by C-H...O interactions. A common feature of each of (I)-(V) is the formation of sulfonamide and hydrazone dimers with an R22(8) ring motif. Hirshfeld surface analyses gave fingerprint plots for H...H, O...H/H...O, N...H/H...N, C...H/H...C and other contacts. The H...H contacts show large surfaces, whereas the O...H plots show the presence of O...H/O...H contacts with the two characteristic long sharp spikes. PMID- 30398216 TI - Utility of Dobutamine Stress Echocardiography in Cardiac Risk Stratification of Patients Undergoing Orthotopic Liver Transplantation. AB - Cardiovascular diseases are a major cause of morbidity and mortality in patients after orthotopic liver transplantation (OLT). This review includes major original articles published in the English-language literature of patients who underwent dobutamine stress echocardiography (DSE) before OLT for cardiac risk stratification. Of a total of 10 original articles (total 1699 patients undergoing DSE), 6 studies used DSE to predict major adverse cardiac events (MACE) in patients undergoing OLT and 4 reported the role of DSE in coronary artery disease (CAD) prediction in patients with end-stage liver disease. The composite incidence of MACE was 11.4%. In predicting postoperative MACE, DSE had a composite sensitivity of 0.12 (95% CI, 0.07-0.19), a specificity of 0.96 (95% CI, 0.94-0.97), a positive predictive value (PPV) of 0.26 (95% CI, 0.16-0.38), and a negative predictive value (NPV) of 0.89 (95% CI, 0.88-0.91). The presence of known CAD in a patient was shown to increase the risk of cardiac events after OLT significantly in three of six studies. The average prevalence of CAD was 14.4%. In predicting CAD, DSE had a composite sensitivity of 0.47 (95% CI, 0.32 0.62), specificity of 0.74 (95% CI, 0.68- 0.79), PPV of 0.23 (95% CI, 0.15-0.33), and NPV of 0.89 (95% CI, 0.84-0.93). This review emphasizes the need for standardizing cardiac risk stratification protocol to screen and prevent cardiac morbidity after OLT, standardizing MACE definition to allow more uniform reporting, and the need for safer and efficacious alternatives to DSE in the evaluation of OLT candidates. PMID- 30398217 TI - Diagnostic Value of Assessment of Cervical Involvement in Early-Stage Endometrial Adenocarcinoma: Comparison of Magnetic Resonance Imaging (MRI) Versus Hysteroscopy. AB - BACKGROUND The aim of this study was to compare magnetic resonance imaging (MRI) and hysteroscopy (HS) for assessing cervical involvement in early-stage endometrial adenocarcinoma in order to establish a more reliable screening method to aid in clinical decision-making. MATERIAL AND METHODS A retrospective analysis was performed on the clinicopathological data from 88 patients with stage I or II endometrial adenocarcinoma who underwent MRI and HS prior to surgery in the Sun Yat-sen Memorial Hospital, Sun Yat-sen University, China. Chi-square and Fisher's exact tests were performed to compare the accuracy, sensitivity, specificity, and positive and negative predictive values in the diagnosis of cervical involvement by MRI and HS. The relationship between clinicopathological factors and the deviation of diagnosis by MRI and HS from that by pathology was also analyzed. RESULTS The accuracy of assessing cervical conditions was 93.2% by MRI and 55.7% by HS. Among these variables, the accuracy, specificity, and positive predictive values of MRI were significantly different from those of HS, while the sensitivity and negative predictive values of MRI and HS were not significantly different from each other. Age, tumor size, tumor differentiation, and depth of myometrial invasion were not associated with the differences in cervical assessment between MRI and HS. However, the tumor location may affect assessment by HS. CONCLUSIONS MRI is better than HS for cervical assessment. The negative predictive values of both MRI and HS are high and unsatisfactory. PMID- 30398218 TI - Visceral fat and insulin resistance - what we know? AB - One of the most significant challenges of current medicine is the increasing prevalence of obesity worldwide that is accompanied by a wide range of chronic health complications and increased mortality. White adipose tissue actively contributes to metabolic regulation by production of a variety of hormones and cytokines, commonly referred to as adipokines. The spectrum and quantity of adipokines produced by the adipose tissue of obese patients is directly or indirectly involved in much obesity-related pathology (type 2 diabetes mellitus, cardiovascular disease, inflammatory response). One of the underlying mechanisms linking obesity, diabetes, and cardiovascular complications is subclinical inflammation, primarily arising in visceral adipose tissue. Adipocyte size, number and polarization of lymphocytes and infiltrated macrophages are closely related to metabolic and obesity-related diseases. The storage capacity of hypertrophic adipocytes in obese patients is limited. This results in chronic energy overload and leads to increased apoptosis of adipocytes that in turn stimulates the infiltration of visceral adipose tissue by immune cells, in particular macrophages. These cells produce many proinflammatory factors; while the overall production of anti-inflammatory cytokines and adipokines is decreased. The constant release of proinflammatory factors into the circulation then contributes to a subclinical systemic inflammation, which is directly linked to the metabolic and cardiovascular complications of obesity. PMID- 30398219 TI - Intraoperative intraocular pressure fluctuation during standard phacoemulsification in real human patients. AB - INTRODUCTION: To evaluate the results of the fluctuations of intraocular pressure (IOP) and calculated mean ocular perfusion pressure (MOPP) during the usual steps of standard phacoemulsification. METHODS: Nine human eyes were evaluated. The IOP was measured indirectly by electronic applanation tonometer. The MOPP was calculated using the systolic blood pressure (SBP), the diastolic blood pressure (DBP) and the IOP: MOPP = 2/3x[DBP + 1/3x(SBP - DBP)] - IOP. The operations were performed with the INFINITI(r) Vision System: main incision 2.2 mm, coaxial handpiece, 2 paracenteses 1.1 mm, bimanual irrigation/aspiration, bottle height 100 cm. As ocular viscoelastic device (OVD) Hypromel 2.5% (UNIMED) was used. RESULTS: The initial and final IOPs were 17-30 Torr (median 18) and 6-16 Torr (median 8), respectively. The IOP values oscillated between 4 and 63 Torr during the procedure. The highest values of the IOP were achieved at the beginning of phacoemulsification (from 42 to 63 Torr). The maximum pressure higher than 50 mmHg and 60 mmHg was found in 89% and 30% of cases, respectively. The mean ocular perfusion pressure (MOPP) at the beginning of the procedure was 46.4-67.0 (median 53.3) and 0.4-42.0 (median 19.3) during the maximum intraocular pressure. CONCLUSIONS: Measured IOP as well as MOPP varied in all normal steps of real phacoemulsification. High values of intraoperative IOL induced by irrigation may compromise the intraocular perfusion. These fluctuations may induce impairment of the optic nerve perfusion, as well as retina, or choroid. PMID- 30398220 TI - Selective coronary angiography, percutaneous coronary intervention and asymptomatic peri-procedural myocardial injury. AB - BACKGROUND: While there have been a number of studies reporting the incidence and implications of elevated troponin levels after percutaneous coronary intervention (PCI), the body of information about the incidence, associations, and implications of elevated troponin levels following coronary angiography (CAG) is limited. MATERIALS AND METHODS: A total of 220 consecutive patients with stable coronary artery disease or intermediate or low-risk acute coronary syndrome without persistent ST-segment elevation (NSTE-ACS) were included in our study. High-sensitivity cardiac troponin I (hs-cTnI) levels were measured before and after coronary angiography (CAG) in patients with or without PCI and correlated with a number of clinical variables. RESULTS: Hs-cTnI elevations above the 99th percentile upper reference limit (URL), or above 20% of the initially positive, yet already declining values, were found in 60 (37.2%) patients after CAG and in 45 (76.2%) patients undergoing PCI. Significant correlations of hs-cTnI elevation were found with the following variables: volume of contrast, fluoroscopy time, dose-area product, amount of contrast agent injected directly into the coronary arteries, total time of balloon dilation and the number and total length of implanted stents (P<0.001 for all). CONCLUSION: While an asymptomatic elevation of hs-cTnI is a common finding after PCI, it does occur, quite surprisingly, also after CAG. Despite contradictory views regarding the clinical relevance of asymptomatic post-procedural elevated hs-cTnI levels, it is generally believed that a mild elevation is not associated with an increased risk. Still, it may pose a diagnostic quandary following a successful interventional procedure and even more so after an uncomplicated CAG. TRIAL REGISTRATION: Clinicaltrials.gov - NCT02960321. PMID- 30398221 TI - Patient-controlled epidural analgesia versus conventional epidural analgesia after total hip replacement - a randomized trial. AB - AIMS: Patient-controlled analgesia (PCA) is usually considered a better option for pain management compared to conventional analgesia. The beneficial effect of PCA has been assessed in a number of studies; however, the results are inconsistent. The goal of this study was to compare of patient-controlled epidural analgesia (PCEA) to conventional epidural analgesia after total hip replacement (THR). METHODS: This prospective study was performed at the Department of Anesthesia and Intensive Care Medicine at a tertiary university hospital. After THR, patients were admitted to the intensive care unit (ICU) and randomized to one of two groups (PCEA and non-PCEA). Postoperative pain in the PCEA group was treated using a standardized protocol, while the analgesia in the non-PCEA group was based on physician prescription according to the patient's clinical condition. The total consumption of analgesics, patients' satisfaction, pain intensity, and analgesia-related complications were recorded for 24 h after surgery. RESULTS: The final sample consisted of 111 patients (PCEA group, n=55 and non-PCEA group, n=56). The PCEA group had significantly lower total consumption of analgesic mixtures (0.9+/-0.3 and 1.3+/-0.4 mL/kg per day, P<0.001).There was greater patient satisfaction (P<0.001) in the PCEA group. The mean pain intensity over 24 hours postoperatively was similar for both groups (P=0.14). There was no significant difference in rate of analgesia-related complications between the groups (hypotension, P=0.14; bradypnea, P=0.11). CONCLUSION: Compared to conventional epidural analgesia based on physician prescription, PCEA led to less total analgesic consumption and greater patient satisfaction after THR. PMID- 30398222 TI - Building caregivers' emotional, parental and social support skills to prevent violence against adolescent girls: findings from a cluster randomised controlled trial in Democratic Republic of Congo. AB - Introduction: Parenting programmes are increasingly popular for reducing children's exposure to interpersonal violence in low/middle-income countries, but there is limited evidence on their effectiveness. We investigated the incremental impact of adding a caregiver component to a life skills programme for adolescent girls, assessing girls' exposure to violence (sexual and others) and caregivers' gender attitudes and parenting behaviours. Methods: In this two-arm, single blinded, cluster randomised controlled trial, we recruited 869 adolescent girls aged 10-14 and 764 caregivers in South Kivu, Democratic Republic of Congo. Following a baseline survey, participants were divided into 35 clusters based on age, language and location. Eighteen clusters were randomised to the treatment arm and 17 clusters to the wait-list control arm. Adolescent girls in both arms received 32 life skills sessions; caregivers in the treatment arm received 13 complementary caregiver sessions. The primary outcome was girls' self-reported exposure to sexual violence in the last 12 months; secondary outcomes included self-reports of specific forms of sexual violence, physical and emotional violence, transactional sex, child marriage for girls and parenting behaviours for caregivers. Intent-to-treat and per-protocol analyses were conducted. Results: At 12 months of follow-up, the intervention showed no impact on sexual violence (adjusted OR=0.95; 95% CI 0.65 to 1.37) or any secondary outcomes for girls. The intervention was associated with improved supportive parenting behaviours. Protocol adherence was also associated with improvements in these outcomes. Conclusion: While the caregiver curriculum improved some parenting outcomes, additional programmatic adaptations may be needed to reduce adolescent girls' violence exposure in humanitarian settings. Trial registration number: NCT02384642. PMID- 30398224 TI - Relationship Between Pitching a Complete Game and Spending Time on the Disabled List for Major League Baseball Pitchers: Response. PMID- 30398223 TI - Preventing violence against refugee adolescent girls: findings from a cluster randomised controlled trial in Ethiopia. AB - Introduction: Interpersonal violence is a critical public health concern in humanitarian contexts, but evidence of effective violence prevention programmes targeting adolescent girls is lacking. We investigated the efficacy of a life skills and safe spaces programme to reduce adolescent girls' experiences of interpersonal violence in a refugee setting. Methods: In this two-arm, single blinded, cluster randomised controlled trial, we recruited 919 Sudanese and South Sudanese girls ages 13-19 years residing in refugee camps in Ethiopia. Girls were divided into 31 clusters, with 457 and 462 participants assigned to the intervention and control arms, respectively. Intervention clusters received 30 life skills sessions delivered in safe spaces and 8 complementary sessions for caregivers. The primary outcome was exposure to sexual violence in the previous 12 months. Secondary outcomes included disaggregated forms of sexual violence, physical violence, emotional violence, transactional sex, child marriage, feelings of safety, attitudes around rites of passage and perceptions of social support. Intent-to-treat analysis was used. Results: At 12-month follow-up, the intervention was not significantly associated with reduction in exposure to sexual violence (adjusted OR =0.96, 95% CI 0.59 to 1.57), other forms of violence, transactional sex or feelings of safety. The intervention was associated with improvements in attitudes around rites of passage and identified social supports. Additionally, the intervention showed a decrease in reported child marriage among girls who were married at baseline. Conclusion: While the intervention impacted key markers along the causal pathway to violence reduction, further research and programmatic adaptations are needed to prevent violence towards adolescents in humanitarian contexts. Trial registration: NCT02506543. PMID- 30398225 TI - A high-throughput serum Raman spectroscopy platform and methodology for colorectal cancer diagnostics. AB - Vibrational spectroscopic techniques such as Raman spectroscopy and Fourier transform infrared spectroscopy (FTIR) have huge potential for the analysis of biological specimens. The techniques allow the user to gain label-free, non destructive biochemical information about a given sample. Previous studies using vibrational spectroscopy with the specific application of diagnosing colorectal diseases such as cancer have mainly focused on in vivo or in vitro studies of tissue specimens using microscopy or probe based techniques. There have been few studies of vibrational spectroscopic techniques based on the analysis of blood serum for the advancement of colorectal cancer diagnostics. With growing interest in the field of liquid biopsies, this study presents the development of a high throughput (HT) serum Raman spectroscopy platform and methodology and compares dry and liquid data acquisition of serum samples. This work considers factors contributing to translatability of the methodologies such as HT design, inter user variability and sample handling effects on diagnostic capability. The HT Raman methods were tested on a pilot dataset of serum from 30 cancer patients and 30 matched control patients using statistical analysis via cross-validated PLS-DA with a maximum achieved a sensitivity of 83% and specificity of 83% for detecting colorectal cancer. PMID- 30398226 TI - Characterization of manganese oxide amendments for in situ remediation of mercury contaminated sediments. AB - Addition of Mn(iv)-oxide phases pyrolusite or birnessite was investigated as a remedial amendment for Hg-contaminated sediments. Because inorganic Hg methylation is a byproduct of bacterial sulfate reduction, reaction of Mn(iv) oxide with pore water should poise sediment oxidation potential at a level higher than favorable for Hg methylation. Changes in Mn(iv)-oxide mineralogy and oxidation state over time were investigated in sediment tank mesocosm experiments in which Mn(iv)-oxide amendment was either mixed into Hg-contaminated sediment or applied as a thin-layer sand cap on top of sediment. Mesocosms were sampled between 4 and 15 months of operation and solid phases were characterized by X-ray absorption spectroscopy (XAS). For pyrolusite-amended sediments, Mn(iv) oxide was altered to a mixture of Mn(iii)-oxyhydroxide and Mn, Fe(iii, ii)-oxide phases, with a progressive increase in the Mn(ii)-carbonate fraction over time as mesocosm sediments became more reduced. For birnessite-amended sediments, both Mn(iii) oxyhydroxide and Mn(ii) carbonate were identified at 4 months, indicating a faster rate of Mn reduction compared to pyrolusite. After 15 months of reaction, birnessite was converted completely to Mn(ii) carbonate, whereas residual Mn, Fe(iii, ii)-oxide phases were still present in addition to Mn(ii) carbonate in the pyrolusite mesocosm. In the thin-layer sand cap mesocosms, no changes in either pyrolusite or birnessite XAS spectra were observed after 10 months of reaction. Equilibrium phase relationships support the interpretation of mineral redox buffering by mixed-valent (Mn, Fe)(iii, ii)-oxide phases. Results suggest that amendment longevity for redox buffering can be controlled by adjusting the mass and type of Mn(iv) oxide applied, mineral crystallinity, surface area, and particle size. For a given site, amendment capping versus mixing with sediment should be evaluated to determine the optimum treatment approach, which may vary depending on application constraints, rate of Mn(iv) oxide transformation, and frequency of reapplication to maintain desired oxidation state and pH. PMID- 30398231 TI - Collagen-based materials combined with microRNA for repairing cornea wounds and inhibiting scar formation. AB - The cornea repair materials amniotic membrane, acellular corneal stroma, and natural polymer-based materials have excellent biocompatibility and support epithelization. However, few researchers have focused on corneal stromal wound healing repair with regard to scar formation and transparency improvements. Herein, we introduced nanocomplexes of gold nanoparticles (AuNPs) and microRNA 133b (miR-133b) into collagen-based material to achieve corneal repair and scar inhibition. We evaluated the cytocompatibility of AuNPs and the ability of miRNA 133b to inhibit myofibroblast transformation in vitro. The AuNPs had no cytotoxicity at working concentrations, and AuNP/miR-133b complexes down regulated the expression of myofibroblast transformation genes (alpha-smooth muscle actin and type I collagen) in corneal stromal cells. We then loaded AuNP/miR-133b complexes into collagen using two methods: loading on the surface (Col-AMS) and loading inside (Col-AMI) the collagen membrane. The results showed that AuNP/miR-133b introduction did not affect water content, light transmittance, or the mechanical properties of the collagen membrane. MiR-133b can maintain its integrity during the preparation of materials. In vivo lamellar keratoplasty results showed that the cornea epithelized completely and rapidly. Corneas without transplantation and with the transplantation of a non-modified collagen membrane became cloudy after trauma to different degrees after approximately 14 days. Interestingly, cornea transparency was retained after transplantation with Col-AMS and Col-AMI. Hematoxylin-eosin-stained histologic sections revealed that the corneas transplanted with Col-AMS and Col-AMI were similar to healthy corneas. Immunohistochemical staining revealed lower a-SM and Col-1 expression in corneal stroma after transplantation with collagen combined with AuNP/miR-133b. Our results thus suggest that collagen membranes combined with AuNP/miR-133b complexes can rapidly repair corneas and effectively inhibit scar formation. PMID- 30398232 TI - Conductometric immunoassay of alpha-fetoprotein in sera of liver cancer patients using bienzyme-functionalized nanometer-sized silica beads. AB - A conductometric immunoassay protocol was designed for the sensitive detection of a liver cancer biomarker, alpha-fetoprotein (AFP), in biological fluids by using enzyme-conjugated nanometer-sized enzyme-doped silica beads. Initially, urease molecules were doped into nanosilica particles by using the reverse micelle method. Thereafter, arginase-labeled anti-AFP antibodies were covalently conjugated onto the surface of the synthesized nanoparticles. The immunoreaction was carried out in a monoclonal anti-AFP capture antibody-coated microplate with a sandwich-type assay format by using bienzyme-functionalized silica nanobeads as the recognition elements. Upon l-arginine introduction, the substrate was cleaved into urea and l-ornithine on the basis of the arginase enzymatic reaction, and the as-produced urea was then decomposed into ammonia (NH4+) and bicarbonate (HCO3-) ions by the doped urease, thus causing the variation in the local conductivity of the detection solution on an interdigitated conductometric transducer. Under optimal conditions, the developed immunosensing system exhibited good conductometric responses toward target AFP within a dynamic linear range of 0.01-100 ng mL-1 at a relatively low detection limit of 4.8 pg mL-1 based on the 3sB criterion. Importantly, good reproducibility, high specificity and acceptable method accuracy were acquired for the analysis of human serum specimens in liver cancer patients. PMID- 30398238 TI - Preparation of Ag@zeolitic imidazolate framework-67 at room temperature for electrochemical sensing of hydrogen peroxide. AB - In this work, a novel non-enzymatic hydrogen peroxide sensor, Ag@zeolitic imidazolate framework-67 (Ag@ZIF-67)/glassy carbon electrode (GCE), was fabricated by a simple method at room temperature. The morphology and structure of Ag@ZIF-67 were investigated by scanning electron microscopy, transmission electron microscopy, energy dispersive spectroscopy, Fourier transform infrared spectroscopy, powder X-ray diffraction, atomic absorption spectrophotometry, and N2 absorption isotherms, which indicated that core-shell Ag@ZIF-67 was successfully synthesized with a porous rhombic dodecahedron structure. Electrochemical investigations demonstrated that the Ag@ZIF-67/GCE had strong electrocatalytic activity towards hydrogen peroxide reduction with a low detection limit of 1.5 MUM (S/N = 3), a fast response time of 3 s, and three different linear relationships in the ranges of 5.0 MUM-275 MUM, 775 MUM-2775 MUM, and 4775 MUM-16 775 MUM with sensitivities of 27 MUA mM-1 cm-2, 13 MUA mM-1 cm-2, and 5.3 MUA mM-1 cm-2, respectively. Moreover, the fabricated sensor exhibited an excellent recovery rate in real sample analysis of medical hydrogen peroxide disinfectant. These results proved that Ag@ZIF-67/GCE is an effective electrochemical sensor for detecting hydrogen peroxide. PMID- 30398241 TI - 5-Formyluracil as a cornerstone for aluminum detection in vitro and in vivo: a more natural and sustainable strategy. AB - 5-Formyluracil (5fU) based probes were designed and synthesized to detect Al3+ ions in vitro and in biological systems. These probes were synthesised using furan-2-carbohydrazide (fr) and 5fU derivatives. We also selectively labelled 5 formyluracil in DNA with the help of Al3+. PMID- 30398242 TI - Triplet electron transfer and spin polarization in a palladium porphyrin fullerene conjugate. AB - Transient electron paramagnetic resonance (TREPR) spectroscopy is used to investigate the pathway and dynamics of electron transfer in a palladium porphyrin-fullerene donor-acceptor conjugate. The heavy Pd atom in the porphyrin greatly enhances the rate of intersystem crossing and as a result, electron transfer from the porphyrin to fullerene occurs via the porphyrin triplet state. The sign of the polarization pattern of the radical pair generated by the electron transfer is opposite in benzonitrile and the liquid crystal 5CB. This difference is the result of a change in sign of the spin-spin coupling, which allows the values of the dipolar and exchange couplings between the electrons in the charge-separated state to be estimated. In addition to the radical pair, signals from the fullerene triplet state are also observed. The polarization of the fullerene triplet state inverts with time, while the radical pair signal decays to a multiplet pattern that persists for times longer than the spin lattice relaxation time. A kinetic model, developed to explain these effects, reveals that forward and reverse electron transfer between the charge-separated state and the fullerene takes place. This process, combined with singlet recombination of the radical pair accounts for the inversion of the fullerene triplet state polarization and the long-lived multiplet polarization of the radical pair. PMID- 30398243 TI - Structure and dynamics of high-temperature strontium aluminosilicate melts. AB - We report the study of high-temperature melts (1600-2300 degrees C) and related glasses in the SrO-Al2O3-SiO2 phase diagram considering three series: (i) depolymerized ([SrO]/[Al2O3] = 3); (ii) fully polymerized ([SrO]/[Al2O3] = 1); and (iii) per-aluminous ([SrO]/[Al2O3] < 1). By considering the results from high temperature 27Al NMR and high-temperature neutron diffraction, we demonstrate that the structure of the polymerized melts is controlled by a close-to-random distribution of Al and Si in the tetrahedral sites, while the depolymerized melts show smaller rings with a possible loss of non-bridging oxygens on AlO4 units during cooling for high-silica compositions. A few five-fold coordinated VAl sites are present in all compositions, except per-aluminous ones where high amounts of high-coordinated aluminium are found in glasses and melts with complex temperature dependence. In high-temperature melts, strontium has a coordination number of 8 or less, i.e. less than in the corresponding glasses. The dynamics of high-temperature melts were studied from 27Al NMR relaxation and compared to macroscopic shear viscosity data. These methods provide correlation times in close agreement. At very high temperatures, the NMR correlation times can be related to the oxygen self-diffusion coefficient, and we show a decrease of the latter with increasing Si/(Al + Si) ratios for polymerized melts with no compositional dependence for depolymerized ones. The dominant parameter controlling the temperature dependence of the aluminum environment of all melts is the distribution of Al-(OSi)p(OAl)(4-p) units. PMID- 30398245 TI - Effect of the degree of inversion on optical properties of spinel ZnFe2O4. AB - Spinel ferrites (T[M1-xFex]O[MxFe2-x]O4 with 0 <= x <= 1, where M is a bivalent metal ion and the superscripts denote tetrahedral and octahedral sites) are materials commonly used in electronics due to their outstanding magnetic properties. Thus, the effect of the degree of inversion, x, on these properties is well known. However, its effect on other properties of these materials has rarely been investigated in detail. Since ferrites gained much attention during the last decade as visible light active photocatalysts and photoelectrocatalysts, understanding the effect of the degree of inversion on the optical properties became necessary. Among photocatalytically and photoelectrocatalytically active spinel ferrites, zinc ferrite (ZnFe2O4, ZFO) is one of the most widely studied materials. In this work, five ZFO samples with degrees of inversion varying from 0.07 to 0.20 were prepared by a solid-state reaction employing different annealing temperatures and subsequent quenching. Raman and UV-Vis-NIR spectra were measured and analyzed together with theoretical results obtained from ab initio calculations. Changes in the UV-Vis-NIR spectra associated with electronic transitions of tetrahedrally and octahedrally coordinated Fe3+ ions are distinguished. However, the optical band gap of the material remains unchanged as the degree of inversion varies. Based on the experimental and theoretical results, a new assignment for the Raman active internal modes and the electronic transitions of ZFO is proposed. PMID- 30398246 TI - Partitioning of nanoscale particles on a heterogeneous multicomponent lipid bilayer. AB - Cell membrane-based sorting and trafficking of nanoscale particles (NPs) are fundamental processes in many cellular activities such as endocytosis, signaling and virus infection; however, the regulation mechanism of these behaviors is still poorly understood. In this work, partitioning of NPs into different lipid phases (i.e., liquid-ordered and liquid-disordered phases) on a ternary lipid bilayer, as well as the influence of NP perturbations on the phase separation of the bilayer, is investigated by using coarse-grained molecular dynamics simulations. Interestingly, it is revealed by our simulations that even with the same chemical affinity between the NPs and lipids in different phases, NPs are still able to preferentially locate at the liquid-disordered (Ld) phase domains. The preferential partitioning behavior of NPs is associated with the physical properties of both the membrane and NPs (e.g., the membrane stiffness and the NP size/quantity). Additionally, the preferential partitioning of NPs facilitates growth of the Ld domain and promotes coupling of this domain between the two leaflets. This work provides new insights into the complicated nano-bio interaction mechanism. Moreover, it suggests methods to regulate the mobility of NPs on cellular membranes to modulate important biological processes accordingly. PMID- 30398247 TI - Quantum approaches to vibrational dynamics and spectroscopy: is ease of interpretation sacrificed as rigor increases? AB - The subject of this Perspective is quantum approaches, beyond the harmonic approximation, to vibrational dynamics and IR spectroscopy. We begin with a pedagogical, unifying review of the most widely used quantum approaches. Some of the key details that lead to steep computational scaling of these approaches are reviewed, as well as some effective strategies to overcome or at least mitigate them. Considering in particular the application to IR spectroscopy, we stress the strength and weakness of each approach for spectral features that evolve from "simple" to "complex". We use the 10-atom formic acid dimer as an ideal example of this evolution. The IR spectrum of this dimer and two isotopologs has been obtained computationally using our software, MULTIMODE, and approaches to obtain accurate, ab initio, full-dimensional potential energy and dipole moment surfaces, also developed by our group. The IR spectra obtained with the widely used "ab initio molecular dynamics" approach are also presented and assessed. The extension of quantum approaches to molecular clusters and even condensed phase applications, where molecular dynamics approaches are typically used, is discussed mainly in the context of the local monomer model. This approach is illustrated for a methane clathrate hydrate, where vibrational energies of the symmetric and asymmetric stretches of methane are given for a number of water cages and compared to experiment. The question about interpretation is also addressed throughout the Perspective. PMID- 30398248 TI - Structural and electronic properties of a van der Waals heterostructure based on silicene and gallium selenide: effect of strain and electric field. AB - Combining van der Waals heterostructures by stacking different two-dimensional materials on top of each other layer-by-layer can enhance their desired properties and greatly extend the applications of the parent materials. In this work, by means of first principles calculations, we investigate systematically the structural and electronic properties of six different stacking configurations of a Si/GaSe heterostructure. The effect of biaxial strain and electric field on the electronic properties of the most energetically stable configuration of the Si/GaSe heterostructure has also been discussed. At the equilibrium state, the electronic properties of the Si/GaSe heterostructure in all its stacking configurations are well kept as compared with that of single layers owing to their weak van der Waals interactions. Interestingly, we find that a sizable band gap is opened at the Dirac K point of silicene in the Si/GaSe heterostructure, which could be further controlled by biaxial strain or electric field. These findings open up a possibility for designing silicene-based electronic devices, which exhibit a controllable band gap. Furthermore, the Si/GaSe heterostructure forms an n-type Schottky contact with a small Schottky barrier height of 0.23 eV. A transformation from the n-type Schottky contact to a p-type one, or from the Schottky contact to an ohmic contact may occur in the Si/GaSe heterostructure when strain or an electric field is applied. PMID- 30398249 TI - Optical frequency comb photoacoustic spectroscopy. AB - We report the first photoacoustic detection scheme using an optical frequency comb-optical frequency comb photoacoustic spectroscopy (OFC-PAS). OFC-PAS combines the broad spectral coverage and the high resolution of OFCs with the small sample volume of cantilever-enhanced PA detection. In OFC-PAS, a Fourier transform spectrometer (FTS) is used to modulate the intensity of the exciting comb source at a frequency determined by its scanning speed. One of the FTS outputs is directed to the PA cell and the other is measured simultaneously with a photodiode and used to normalize the PA signal. The cantilever-enhanced PA detector operates in a non-resonant mode, enabling detection of a broadband frequency response. The broadband and the high-resolution capabilities of OFC-PAS are demonstrated by measuring the rovibrational spectra of the fundamental C-H stretch band of CH4, with no instrumental line shape distortions, at total pressures of 1000 mbar, 650 mbar, and 400 mbar. In this first demonstration, a spectral resolution two orders of magnitude better than previously reported with broadband PAS is obtained, limited by the pressure broadening. A limit of detection of 0.8 ppm of methane in N2 is accomplished in a single interferogram measurement (200 s measurement time, 1000 MHz spectral resolution, 1000 mbar total pressure) for an exciting power spectral density of 42 MUW/cm-1. A normalized noise equivalent absorption of 8 * 10-10 W cm-1 Hz-1/2 is obtained, which is only a factor of three higher than the best reported with PAS based on continuous wave lasers. A wide dynamic range of up to four orders of magnitude and a very good linearity (limited by the Beer-Lambert law) over two orders of magnitude are realized. OFC-PAS extends the capability of optical sensors for multispecies trace gas analysis in small sample volumes with high resolution and selectivity. PMID- 30398250 TI - Distinguishing ionic and radical mechanisms of hydroxylamine mediated electrocatalytic alcohol oxidation using NO-H bond dissociation energies. AB - The mechanism of N-oxyl radical catalyzed oxidation is a long-standing scientific problem. In this work, radical or ionic mechanisms in electrocatalytic oxidation of alcohols are discussed on the NO-H bond dissociation energy (BDE) scale. A thermodynamic model was built to outline the range of BDEs for the catalysts that react via the two mechanisms. The N-oxyl radical catalyzed electrocatalytic benzyl alcohol oxidations with NO-H BDEs smaller than 74 kcal mol-1 reacted by an ionic mechanism, and with BDEs greater than 78 kcal mol-1 reacted by a radical mechanism. Oxidizing aliphatic alcohols via a radical mechanism requires catalysts with BDEs even greater than that of N-hydroxyphthalimide (NHPI), and the ionic mechanism requires catalysts with BDEs smaller than 74 kcal mol-1. With either the ionic or radical mechanism, catalysts with larger BDEs correspond to a smaller activation energy of the key step. Future design of N-oxyls with catalytic activity in alcohol oxidation can be streamlined by our efforts. PMID- 30398251 TI - Effect of Cu intercalation on humidity sensing properties of Bi2Se3 topological insulator single crystals. AB - Here we report the self-flux method-based synthesis of CuxBi2Se3 (x = 0, 0.13 and 0.25) topological insulator (TI) single crystals with high phase purity for humidity sensing for the first time. The samples were thoroughly characterized using XRD, FESEM, Raman, etc. The chemi-resistive humidity sensing performance of the obtained Cu0.25Bi2Se3 single crystal exhibits high sensitivity (~849%) with decent response time (24 s) and recovery (25 s) time, negligible hysteresis (<1%) and excellent stability within an 8-97% relative humidity (RH) range at room temperature. The Freundlich isotherm model shows improved adsorption parameters (k and alpha) for CuxBi2Se3 (x = 0.25) over the entire RH region demonstrating the improved sensing performance of Bi2Se3 TIs with Cu intercalation. The effect of Cu intercalation in Bi2Se3 was investigated using the Langmuir adsorption isotherm (LA) model signifying the role of faster conduction of water vapour over the surface with a single active site for the adsorption-desorption process. The current experimental results suggest that CuxBi2Se3 TIs hold immense potential for important applications related to sensing. PMID- 30398252 TI - Configurationally flexible zinc complexes as catalysts for rac-lactide polymerisation. AB - Zn(N(SiMe3)2)2 was reacted with pyridinemethanol and R,R-N,N'-di(methylbenzyl) 2,5-diiminopyrrole (L1H) to afford the dimeric complex (L1)2Zn2(MU-OR)2. The complex showed moderate activity in rac-lactide polymerization to heterotactic polymer (Pr = 0.75). 2,4-Di-tert-butyl-6-aminomethyl-phenol ligands with amino = N,N,N',N'-tetramethyldiethylenetriamine (L2H) or di-(2-picoly)amine (L3H) were reacted with ZnEt2 to form (L2)ZnEt and with Zn(N(SiMe3)2)2 to form the respective amide complexes. All complexes, including (L1)2Zn2(MU-OR)2 were characterised by X-ray diffraction studies. (L2)ZnEt was unreactive toward ethanol, but the amide complexes afforded (L2)ZnOEt and (L3)ZnOEt upon reaction with ethanol, which were used in rac-lactide polymerization without isolation. All complexes racemise readily at room temperature and show apparent Cs-symmetry in their NMR spectra. The ethoxide complexes were highly active in lactide polymerization, with (L3)ZnOEt reaching full conversion in 15 min at 0.5 mM catalyst concentration at room temperature. In both cases, introduction of a second donor arm on the central nitrogen introduced a slight bias for isotactic monomer enchainment (Pm = 0.55-0.60), which for (L3)ZnOEt was dependent on catalyst concentration. PMID- 30398253 TI - Unusual dielectric response of 4-methyl-1,3-dioxolane derivatives. AB - In this paper, we applied broadband dielectric spectroscopy (BDS) to investigate the molecular dynamics of three 4-methyl-1,3-dioxolane derivatives (MD) whose chemical structures differ in the length of non-polar alkyl side chains. We notice that small changes within their chemical structures have a pronounced impact on parameters characterizing the supercooled dynamics of the compounds selected for this study. Our detailed analysis of the dielectric response reveals that in the supercooled-liquid state besides the structural alpha-relaxation a sub-alpha Debye-like relaxation can be clearly distinguished. The observed two relaxation regimes mirror the structural complexity of the investigated MD derivatives. The amphiphilic nature of the investigated compounds and possible interactions between non-polar side chains can rationalize the observed behavior. To follow the molecular arrangement of MD derivatives at low temperatures, we also carried out Raman measurements. Additionally, we performed BDS measurements at elevated pressures which revealed that, as a result of compression, the sub alpha contribution to the dielectric response disappeared. The paper concludes with a discussion of open questions about the possible molecular origin of the observed sub-alpha Debye-like process. These results provide fresh insight into the puzzling nature of the slow supramolecular relaxation modes in low-molecular glass forming liquids. PMID- 30398254 TI - Photo-irradiated E/Z isomerization reaction of star-shaped isomers containing two cyanostilbene arms with charge transfer excited states. AB - The E/Z isomerization reaction of the multi-cyanostilbene molecule is still not clear. Herein, we have designed and synthesized three star-shaped molecular isomers with a triphenylamine core linked to two cyanostilbene groups with E/Z isomerization, Z,Z-TPDCF, Z,E-TPDCF and E,E-TPDCF, possessing three different isomeric molecular configurations, to investigate the specific E/Z isomerization reaction of the cyanostilbene groups in the two molecular arms. The in situ UV, 1H NMR and HPLC spectra under UV-irradiation clearly showed that the E/Z isomerization reactions of both E,E-TPDCF and Z,Z-TPDCF firstly turned them into Z,E-TPDCF, and the Z,E-TPDCF was almost simultaneously turned into more E,E-TPDCF and less Z,Z-TPDCF due to the calculated lowest unoccupied molecular orbitals of Z,E-TPDCF on the cyanostilbene arm with the Z-configuration. In general, Z,E TPDCF exhibited a relatively better configurational stability than Z,Z-TPDCF or E,E-TPDCF under the photo-irradiation conditions. Further research demonstrated that all three isomers exhibited excellent aggregation-induced emission (AIE) properties. PMID- 30398255 TI - Interrogating the effects of ion-implantation-induced defects on the energy storage properties of bulk molybdenum disulphide. AB - The effects of implanted molybdenum and tungsten ions on the energy-storage properties of electrodes made from bulk molybdenum disulphide (MoS2) have been investigated. Six samples of crystalline MoS2 were modified by an ion implantation strategy: three samples with Mo ions and three with W ions, at varying fluences and at an energy of 10 keV. The Stopping and Range of Ions in Matter (SRIM) software was used to determine the simulated defect density in terms of vacancies and the implanted ion-penetration depth. Raman spectroscopy and photoluminescence spectroscopy were used to determine any changes in the material as a result of irradiation. Electrochemistry showed that the ion implanted MoS2 samples exhibited significant energy storage properties (such as capacity, cycling stability, coulombic efficiency, and electron transfer kinetics) compared to the pristine MoS2 samples, confirming the effects of defects induced by ion-implantation. PMID- 30398256 TI - Investigation of dioxygen activation by copper(ii)-iminate/aminate complexes. AB - The activation of dioxygen by metal ions is critical in chemical and bio-chemical processes. A scientific challenge is the elucidation of the activation site of dioxygen in some copper metalloproteins, which is either the metal center or the substrate. In an effort to address this challenge, we prepared a series of new copper(ii) complexes (1.2H2O, 2.CH3OH, 3) with bio-inspired amidate ligands and investigated their activity towards dioxygen activation. The secondary amine group ligated to copper(ii) of the complex 1.2H2O in methyl alcohol is oxidized (2e-) by air dioxygen in a stepwise fashion to an imine group, affording complex 2. The copper(ii) complex 2 in methyl alcohol induces the 4e- oxidation by air dioxygen of the imine functionality ligated to copper(ii) to an azinate group, resulting in the isolation of a dinuclear azinate copper(ii) compound (4). Experimental and computational studies, including X-band c. w. EPR, UV-vis and ESI-MS spectroscopy and density functional theory computations, indicate a direct attack of the dioxygen on the -HC[double bond, length as m-dash]N- group ligated to copper(ii), and a possible mechanism of the oxidation of the -HC[double bond, length as m-dash]N- functionality ligated to copper(ii) to an azinate group is provided. This unprecedented activation of dioxygen by a copper substrate paves the way for further exploration of the O2 activation mechanisms in enzymes and the development of effective catalysts in O2-involved green organic synthesis. PMID- 30398257 TI - The Boolean logic tree of molecular self-assembly system based on cobalt oxyhydroxide nanoflakes for three-state logic computation, sensing and imaging of pyrophosphate in living cells and in vivo. AB - Sensing of pyrophosphate (PPi) is helpful to better understand many life processes and diagnose various early-stage diseases. However, many traditional reported methods based on artificial receptors for sensing of PPi exhibit some disadvantages including difficulties in designing appropriate binding sites and complicated multi-step assembly/functionalization. Thus, it is significantly important and a big challenge to know how to use a simple molecular self-assembly or an interaction system to solve the above-mentioned limits to achieve the quantitative analysis of specific substances in the system. Based on the natural connection and similarity (such as stimulus responsiveness) between sensing and logic computing, in this study, the Boolean logic tree of molecular self-assembly system based on the cobalt oxyhydroxide (CoOOH) nanoplatform is constructed and applied to organize and connect "plug and play" molecular events (fluorescent dye, acridine orange and anion, PPi). By using molecules as inputs and the corresponding fluorescence signal as the output, the CoOOH-based molecular self assembly system can be programmed for three-input fluorescent Boolean logic computation, fluorescent three-state logic computation, detection of PPi (linear range from 50 to 6400 nM with a detection limit of 20 nM) and even for imaging in living cancer cells and in vivo (in systems such as Zebrafish and Carassius auratus). Our approach adds a new dimension for expanding molecular logic computing and sensing systems, which will not only provide more opportunities for developing novel logic computing paradigms, but also be helpful in promoting the development and applications of intelligent molecular computing and sensing systems. PMID- 30398258 TI - Composite cluster-organic frameworks based on polyoxometalates and copper/cobalt oxygen clusters. AB - Two rare mixed-cluster-organic frameworks (CH3NH3)3[Cu4-(MU3 O)2(Lb)4][MnMo6O18(La)2].4NMF.5H2O (1) and [(CH3)2NH2]3[Co5-(MU3-O)2(Lb)6] [MnMo6O18(La)2].5DMF (2) (La = 2-(hydroxymethyl)-2-(pyridin-4-yl)-1,3 propanediol; Lb = 4-(2-(4-pyridyl)ethenyl) benzoic acid; NMF = N-methylformamide; DMF = N,N-dimethylformamide) have been obtained, exhibiting the first two porous materials simultaneously integrating polyoxometalates and transition-metal-oxygen clusters as secondary building units (SBUs). PMID- 30398259 TI - Group 10 metal-thiocatecholate capped magnesium phthalocyanines - coupling chromophore and electron donor/acceptor entities and its impact on sulfur induced red-shifts. AB - A new and facile method of generating thiolate groups at the phthalocyanine (Pc) beta-position is presented as well the unique properties that these groups confer on the Pc ligand upon coordination of group 10 metals Ni, Pd and Pt(dppe) or SnMe3. In particular, the Q-band is shifted to almost 800 nm for all group 10 metals used, and the complexes show panchromatic absorption owing to new absorbance bands that appear between 400 and 650 nm. Enhanced intersystem crossing for all transition metal coordinated Mg(Pc) complexes was demonstrated by the moderate to very high singlet oxygen quantum yields of 0.36, 0.76 and 0.91 for the Ni, Pd and Pt coordinating complexes, respectively, which show that the heavy metals have direct influence on the Pc pi-system and inter-system-crossing (ISC). This was further confirmed by MO calculations, which show mixing of metal and ligand orbitals, as well as suggest that the Q-band transition has both pi -> pi* and ligand-to-metal charge transfer characteristics. Furthermore, the origin of the Q-band red-shift was shown to be due to greater destabilization of the HOMO compared to LUMO/LUMO+1, thus decreasing the HOMO-LUMO band gap. PMID- 30398264 TI - Cloud droplet activation of organic-salt mixtures predicted from two model treatments of the droplet surface. AB - The droplet surface plays important roles in the interaction between organic aerosols with clouds and climate. Surface active organic compounds can partition to the droplet surface, depleting the solute from the droplet bulk or depressing the droplet surface tension. This may in turn affect the shape of the droplet growth curve, threshold of aerosol activation into cloud droplets, activated droplet size distributions, and cloud radiative effects. In this work, a new monolayer model along with a traditional Gibbs adsorption isotherm model was used in conjunction with equilibrium Kohler theory to predict cloud condensation nuclei (CCN) activation of both simple and complex surface active model aerosol systems. For the surface active aerosol considered, the monolayer droplet model produces similar results to the Gibbs model as well as comparable results to CCN measurements from the literature, even for systems where specific molecular identities and aqueous properties are unknown. The monolayer model is self contained and fully prognostic, and provides a versatile, conceptually simple, yet physically based model for understanding the role of organic surfactants in cloud droplet formation. PMID- 30398268 TI - Stabilization of noble metal nanostructures for catalysis and sensing. AB - Noble metal nanocrystals have been widely used as active components in catalysis and chemical/bio-sensing. The sizes, structures, and shapes of noble metal nanocrystals are crucial to their electronic, optical, and catalytic properties. However, metal nanocrystals tend to lose their structural and morphological properties when they are subjected to thermal and chemical treatment. Therefore, stabilization of noble metal nanostructures remains a challenge. In this feature article, we present our recent efforts on the stabilization of noble metal nanocrystals, i.e., using inorganic and non-metal solids as supports and physical barriers, protecting the nanocrystal surface by a metal coating, and forming alloys with other metals. At the end of this review, we provide our perspectives on the future development of effective methods for nanocrystal stabilization. PMID- 30398269 TI - The structural shift of a DNA template between a hairpin and a dimer tunes the emission color of DNA-templated AgNCs. AB - The scaffolding DNA sequence and the size of silver nanoclusters (AgNCs), confined in a DNA template are the key parameters in determining the fluorescent properties of DNA-stabilized silver nanoclusters (DNA/AgNCs). In addition, we suggest here that the structural shift of a DNA hairpin-dimer is as important as the DNA sequence in determining the emission wavelength of DNA/AgNCs. Furthermore, we show that the structural shift post AgNC formation can be triggered by incubation time and pre-AgNC formation under salt conditions. As an important factor in predicting the emission properties of DNA/AgNCs, the modulation of DNA secondary structures with either sequence changes or ionic conditions can be applied for the dual-color detection system of a target molecule. Particularly, the dual-color detection method may increase the reliability of DNA/AgNC sensors for miRNAs. PMID- 30398270 TI - Translocation of DNA and protein through a sequentially polymerized polyurea nanopore. AB - Here, we investigated the translocation of biomolecules, such as DNA and protein, through a sequentially polymerized polyurea nanopore, with a thin (<10 nm) polymer membrane of uniform thickness. The polyurea membrane was synthesized by molecular layer deposition using p-phenylenediisocyanate (PDI) and p phenylenediamine (PDA) as sequential precursors. The membrane exhibited a hydrophobic surface with a highly negative surface charge density (-51 mC m-2 at pH 8). It was particularly noted that the high surface charge density of the membrane resulted in a highly developed electro-osmotic flow which, in turn, strongly influenced the capture probability of biomolecules, depending on the balance between the electro-osmotic and electrophoretic forces. For instance, the capture frequency of negatively charged DNA was demonstrated to be quite low, since these two forces more or less cancelled each other, whereas that of positively charged MDM2 was much higher, since these two forces were additive. We also identified that the mean translocation time of MDM2 through the polyurea nanopore was 26.1 +/- 3.7 MUs while that of the SiN nanopore was 14.2 +/- 2.0 MUs, hence suggesting that the enhanced electrostatic interaction between positively charged MDM2 and the negatively charged pore surface affects the translocation speed. PMID- 30398271 TI - Electrically gated nanoporous membranes for smart molecular flow control. AB - We report a novel conductive nanoporous membrane platform for a smart drug delivery system, which allows low-power electrically controlled delivery of therapeutic drug molecules via field-effect gating. The device was fabricated and tested with two oppositely charged drug molecules for glaucoma treatment. Drug molecules with the same polarity as the channel potential are excluded from the nanochannel by electrostatic repulsion, while molecules with opposite charge are enriched due to electrostatic attraction. Accordingly, the diffusive flow of the charged molecules can be controlled by a single DC gate voltage without the need for any other mechanism. An anodic aluminum oxide (AAO) membrane with 80 nm pore diameter was functionalized by sputtering a chromium (Cr)-gold (Au)-chromium (Cr) stack. The exterior chromium layer was left to oxidize creating the insulation layer for the gate electrode. The resulting pore size was 50 nm in diameter. The +2 V gate voltage increased the transport rate of the ethacrynic acid, which is negatively charged at pH 7.4, by 337% and the -2 V gate voltage decreased the transport rate by 48%. The transport rate of the timolol maleate, which is positively charged in pH 7.4, was decreased by 66% with +2 V gate voltage and increased by 116% with -2 V gate voltage. The transport control was quantified by the on-off ratio (OOR), which is the ratio between the maximum and minimum transport rate. The OOR was altered by surface treatment of the membrane. Removal of the surface charge decreased the OOR of ethacrynic acid from 6.94 to 5.61 and increased the OOR of timolol maleate from 1.36 to 1.99. These measurements were verified by our simulation results. In the simulations, the OOR of ethacrynic acid was decreased from 5.22 to 3.25 and the OOR of timolol maleate was increased from 1.90 to 3.25. PMID- 30398273 TI - Moire-templated strain patterning in transition-metal dichalcogenides and application in twisted bilayer MoS2. AB - To take full advantage of the electronic properties of transition-metal dichalcogenides and their vdW layered structures, it will be necessary to control the local electronic structure, on which the effect of lattice deformation is significant. Nevertheless, a general approach to programming nanoscale morphology in TMD materials, which would permit local strain engineering, has proven elusive. In this work, we propose a general moire-templated nanoscale morphology engineering method based on bilayer TMDs. The moire superlattice plays the key role in enforcing in-plane periodical variations in local interlayer spacing and potential energy. Upon global in-plane compression, the high-energy, large interlayer-separation stacking domains serve as periodic buckling initiation sites. The buckled features can be thus precisely correlated to the moire periodicity. The spatial profile of the buckled morphology and strain field are possible to be pre-determined, providing a bridge to the electronics and optoelectronics design. We take twisted bilayer MoS2 to demonstrate our approach. We further demonstrate how the morphology can modulate band gap and optical absorption of a MoS2 monolayer, envisioned as a potential constituent layer in a Moire-templated, strain-engineered vdW heterostructure of TMDs. The robustness and programmable nature of our approach arise from superlattice symmetry, energetics and mechanics. Our approach provides a new strategy for on-demand design of morphology and local strain in TMDs under mechanical deformation. PMID- 30398274 TI - Charge-separation in panchromatic, vertically positioned bis(donor styryl)BODIPY aluminum(iii) porphyrin-fullerene supramolecular triads. AB - Three, broad band capturing, vertically aligned supramolecular triads, R2-BDP AlPorF3<-Im-C60 [R = H, styryl (C2H2-Ph), C2H2-TPA (TPA = triphenylamine); <- = coordinate bond], have been constructed using BODIPY derivative (BDP, BDP-Ph2 or BDP-TPA2), 5,10,15,20-tetrakis(3,4,5-trifluorophenyl)aluminum(iii) porphyrin (AlPorF3) and fullerene (C60) entities. The C60 and BDP units are bound to the Al center on the opposite faces of the porphyrin: the BDP derivative through a covalent axial bond using a benzoate spacer and the C60 through a coordination bond via an appended imidazole. Owing to the bis-styryl functionality on BDP, the constructed dyads and triads exhibited panchromatic light capture. Due to the diverse absorption and redox properties of the selected entities, it was possible to demonstrate excitation wavelength dependent photochemical events. In the case of the BDP-AlPorF3 dyad, selective excitation of BDP resulted in singlet-singlet energy transfer to AlPorF3 (kEnT = 1.0 * 1010 s-1). On the other hand, excitation of the AlPorF3 entity in the BDP-AlPorF3<-Im-C60 triad revealed charge separation leading to the BDP-(AlPorF3)+-(C60)- charge separated state (kCS = 2.43 * 109 s 1). In the case of the Ph2-BDP-AlPorF3 dyad, energy transfer from 1AlPorF3* to 1(Ph2-BDP)* was witnessed (kEnT = 1.0 * 1010 s-1); however, upon assembling the supramolecular triad, (Ph2-BDP)-AlPorF3<-Im-C60, electron transfer from 1AlPorF3* to C60 (kCS = 3.35 * 109 s-1), followed by hole shift (kHS = 1.00 * 109 s-1) to Ph2-BDP, was witnessed. Finally, in the case of the TPA2-BDP-AlPorF3<-Im-C60 triad, only electron transfer leading to the (TPA2-BDP)+-AlPorF3<-Im-(C60)- charge separated state, and no energy transfer, was observed. The facile oxidation of Ph2-BDP and TPA2-BDP compared to AlPorF3 in the latter two triads facilitated charge separation through either an electron migration or hole transfer mechanism depending on the initial excitation. The charge-separated states in these triads persisted for about 20 ns. PMID- 30398276 TI - Formation and dynamics of the aggregates of cholesteric double-twist cylinders. AB - We succeeded in driving the unidirectional rigid-body rotation of cholesteric (Ch) double-twist cylinder (DTC) droplets under a heat flux along the cylindrical symmetry axis. To directly observe the rigid-body rotation of DTC droplets, in each of which the center of the rotation and the symmetry axis of the structure correspond, we fabricated DTC aggregates that comprise several DTCs with intact structures. Given a steady heat flux, the DTC aggregates metastabilized by the shape and the surface anchoring show a unidirectional rigid-body rotation with a constant angular velocity. The rotational direction is determined by the molecular chirality and the direction of the heat flux, and the rotational velocity increases with the temperature gradient and decreases with the aggregation number N of the DTCs as 1 + 2/sin2(pi/N). The behavior agrees with a simple model based on the linear phenomenological equation. PMID- 30398277 TI - Oxidative cross-dehydrogenative [2 + 3] annulation of alpha-amino ketones with alpha-keto esters: concise synthesis of clausenamide analogues. AB - A one-pot oxidative cross-dehydrogenative [2 + 3] annulation of alpha-amino ketones with alpha-keto esters at room temperature is reported. The protocol features copper/organo cooperative catalysis and provides densely functionalized pyrrolones in high yields. Subsequent reduction furnished multi-substituted pyrrolidinones which represent the core-structure of the natural product clausenamide, a lead molecule for the treatment of Alzheimer's disease. PMID- 30398279 TI - A morphological, enzymatic and metabolic approach to elucidate apoptotic-like cell death in fungi exposed to h- and alpha-molybdenum trioxide nanoparticles. AB - The present study compares for the first time the effects of h-MoO3 and alpha MoO3 against two fungal strains: Aspergillus niger and Aspergillus flavus. The h MoO3 nanoparticles were more toxic to both fungi than alpha-MoO3. The toxic effects of h-MoO3 were more pronounced toward A. flavus, which presented a growth inhibition of 67.4% at 200 mg L-1. The presence of the nanoparticles affected drastically the hyphae morphology by triggering nuclear condensation and compromising the hyphae membrane. Further analysis of the volatile organic compounds (VOCs) produced by both fungi in the presence of the nanomaterials indicated important metabolic changes related to programmed cell death. These nanomaterials induced the production of specific antifungal VOCs, such as beta Elemene and t-Cadinol, by the fungi. The production of essential enzymes involved in fungal metabolism, such as acid phosphatase, naphthol-As-BI-phosphohydrolase, beta-galactosidase, beta-glucosidase and N-acetyl-beta-glucosaminidase, reduced significantly in the presence of the nanomaterials. The changes in enzymatic production and VOCs corroborate the fact that these nanoparticles, especially h MoO3, exert changes in the fungal metabolism, triggering apoptotic-like cell death responses in these fungi. PMID- 30398278 TI - Scope of surface-modified molecular and nanomaterials in gel/liquid forms for developing mechanically flexible DSSCs/QDSSCs. AB - The advanced lifestyle of the human race involves heavy usage of various gadgets which require copious supplies of energy for uninterrupted functioning. Due to the ongoing depletion of fossil fuels and the accelerating demand for other energy resources, renewable energy sources, especially solar cells, are being extensively explored as viable alternatives. Flexible solar cells have recently emerged as an advanced member of the photovoltaic family; the flexibility and pliability of these photovoltaic materials are advantageous from a practical point of view. Conventional flexible solar cell materials, when dispersed in solvents, are usually volatile and create severe stability issues when incorporated in devices. Recently, non-volatile, less viscous functional molecular liquids/gels have been proposed as potential materials for use in foldable device applications. This perspective article discusses the scope of surface-modified non-volatile molecular and nanomaterials in liquid/gel forms in the manufacturing and deployment of flexible photovoltaics. PMID- 30398280 TI - Aromatic identity, electronic substitution, and sequence in amphiphilic tripeptide self-assembly. AB - The phenomenon of self-assembly in short peptides (2-4 amino acids) has been a source of curiosity, in part for its role in helping to better understand and predict how minimal sequences within proteins might contribute to the formation of larger structures or aggregates. Building on previous work in this field, here we investigate a family of amphiphilic tripeptides for their self-assembly and hydrogel formation. From a parent peptide, Ac-FID-NH2, which was previously shown to self-assemble into high aspect-ratio filaments and form hydrogels, we explored the significance of structural features or sequence variations on the observed self-assembly. This process entailed substituting key aromatic residues, altering the electronics of these aromatic drivers of assembly, and screening tripeptide constitutional isomers. This work more clearly elucidates the mechanisms and design parameters that govern the creation of materials from short peptide building blocks, as well as offering greater insight into the interactions between minimal segments of proteins that underlie their structure and aggregation. PMID- 30398281 TI - Cooperative metal-ligand influence on the formation of coordination polymers, and conducting and photophysical properties of Tl(i) beta-oxodithioester complexes. AB - Eight novel Tl(i) beta-oxodithioester complexes, [TlL]n (1-8), with ligands, L = methyl-3-hydroxy-3-(2-furyl)-2-propenedithioate (L1), methyl-3-hydroxy-3-(2 thienyl)-2-propenedithioate (L2), methyl-3-hydroxy-3-(3-pyridyl)-2 propenedithioate (L3), methyl-3-hydroxy-3-(4-pyridyl)-2-propenedithioate (L4), methyl-3-hydroxy-3-(9-anthracenyl)-2-propenedithioate (L5), methyl-3-hydroxy-3-(4 fluorophenyl)-2-propenedithioate (L6), methyl-3-hydroxy-3-(4-chlorophenyl)-2 propenedithioate (L7) and methyl-3-hydroxy-3-(4-bromophenyl)-2-propenedithioate (L8), were synthesized and thoroughly characterized by elemental analysis, and IR, UV-Vis, 1H and 13C{1H} NMR spectroscopy, and their structures were ascertained by X-ray crystallography. Complexes 1 and 2 crystallized in P21 and P212121 chiral space groups, respectively, and were studied using Circular Dichroism (CD) spectra. Solid state structural analyses revealed that the beta oxodithioester ligands are bonded to Tl(i) ions in (O, S) chelating and chelating bridging modes, thereby forming different types of 1D and 2D coordination polymeric structures. By considering the metal-assisted bonding interactions, various coordination numbers of 5-8 and 10 are established around the metal centre. Except for 5 and 7a which have TlTl separations at 3.724(1) and 3.767(1), 3.891(1) A respectively, the remaining complexes have no TlTl distances <4.0 A. This indicates that the majority of structures contain only weak inter- and intramolecular thallophilic interactions. The structures of 1-8 highlight the role played by variations in substituents in the dithioester unit in the structure and properties of the complexes. The multi-dimensional assembly in these complexes rests on important non-covalent C-Hpi (TlOSC3, chelate), C-HX (X = F, Cl, O, N), C-Hpi, HH and rare TlH-C intermolecular anagostic interactions. The TlH-C anagostic interactions together with C-OTl and C-STl interactions formed 7-, 11- and 12-membered chelate rings about the metal centers. The anagostic interactions in 1, 2 and 7b were assessed by theoretical calculations. All the complexes showed bright green luminescent emissions in solution and solid phases. Time-resolved emission spectra revealed a triexponential decay curve and short mean lifetime for fluorescence behavior. PMID- 30398284 TI - Anti-inflammatory fusicoccane-type diterpenoids from the phytopathogenic fungus Alternaria brassicicola. AB - Altering the cultivation conditions, such as temperature, media compositions, illumination, aeration, the shape of the culturing flask, etc., is regarded as a useful strategy for the exploitation of structurally novel and bioactive secondary metabolites, which inspired us to explore the chemical and pharmacological diversities from the genetically powerful fungus Alternaria brassicicola. As a result, twelve fusicoccane-type diterpenoids, including eight new ones, termed brassicicenes Q-X (1-8), were isolated from a modified rice medium. Biosynthetically, all these compounds were derived from the mevalonic acid (MVA) pathway, and their structures incorporating absolute configurations were assigned by the interpretation of spectroscopic (HRESIMS and 1D and 2D NMR) analyses, chemical conversion, a modified Mosher's method, 13C NMR calculation, and single-crystal X-ray diffraction (Cu Kalpha). Structurally, compound 1 was an unusual 16-nor-dicyclopenta[a,d]cyclooctane diterpenoid bearing a fused cyclopent 2-en-1-one moiety. In addition, compound 3 was found to show significant anti inflammatory activity against the production of NO, TNF-alpha, and IL-1beta at 10 MUM. Further western blot and immunofluorescence experiments found the mechanism of action to be that 3 inhibited the NF-kappaB-activated pathway, highlighting it as a promising starting point for the development of new anti-inflammatory agents. PMID- 30398285 TI - Clinical and echocardiographic correlates of pulmonary hypertension among heart failure patients in Lagos, south-western Nigeria. AB - BACKGROUND: Pulmonary hypertension (PH) is very prevalent among heart failure (HF) subjects and is now recognised as an independent predictor of poor prognosis. There is a paucity of data in our environment about the frequency and correlates of PH in HF. We aimed to determine the frequency of PH in HF patients in an academic hospital and assess its correlates using echocardiography. METHODS: A total of 219 heart failure patients in NYHA functional class II to IV, and without co-morbidities that could cause PH, were consecutively recruited. Demographic, clinical and echocardiographic data were obtained from all subjects. RESULTS: The frequency of PH was 38.8%, using an estimated pulmonary artery systolic pressure (PASP) cut-off value of > 36 mmHg. HF subjects with PH tended to be male with a worse NYHA functional class compared with subjects without PH. HF subjects with PH also had significantly higher left ventricular (LV) filling pressures (higher left atrial volume index and E/e' ratio), more severe mitral regurgitation (MR), poorer LV systolic function, and worse parameters of right ventricular (RV) structure and function compared with those without PH. Echocardiographic variables that correlated significantly with PASP include LV filling pressures (p < 0.001 for all), mitral regurgitant volume (r = 0.269, p < 0.001) and LV ejection fraction (r = -0.239, p > 0.001). On multivariate analysis, the left atrial volume index and E/e' ratio were independently associated with PASP. CONCLUSIONS: PH is common among HF subjects in our environment and is associated with higher LV filling pressure, more severe MR, poorer LV systolic function and worse RV remodelling. Routine screening for PH among HF patients is recommended for better risk stratification and management. PMID- 30398286 TI - Ellisras Longitudinal Study 2017: The relationship between waist circumference, waist-to-hip ratio, skinfolds and blood pressure among young adults in Ellisras, South Africa (ELS 14). AB - BACKGROUND: Obesity and hypertension are major risk factors for non-communicable diseases in the world today. The relationship between indicators of obesity and blood pressure needs attention in the rural South African population. AIM: This study examined the relationship between anthropometric parameters and blood pressure (BP) among young adults in the Ellisras rural area of South Africa. METHODS: A total of 742 (365 females and 377 males) young adults aged 22 to 30 years, who were part of the Ellisras Longitudinal Study (ELS), participated in the research. Anthropometric and BP measurements were taken using the protocol of the International Society for the Advancement of Kinanthropometry (ISAK). Linear regression was used to determine the relationship between anthropometric parameters and BP. The risk of developing hypertension among young Elisras adults was evaluated using logistic regression. RESULTS: The results indicted a higher but on-significant prevalence of hypertension in men (2.7%) than women (2.4%). Linear regression showed a significant positive (p < 0.05) association between waist circumference and systolic BP (beta = 0.273, 95% CI: 0.160-0.386), even after being adjusted for age and gender (beta = 253, 95% CI: 0.127-0.343). The risk for developing hypertension was significant ( p < 0.05) for waist circumference (OR = 2.091, 95% CI: 1.129-3.871) after adjustment for age and gender. CONCLUSIONS: Of all anthropometric parameters, waist circumference was most significantly associated with BP ( p < 0.05). Anthropometric indicators of obesity were strong predictors of hypertension among young adults in the Ellisras rural area. PMID- 30398287 TI - Umbilical cord-derived mesenchymal stromal/stem cells enhance recovery of surgically induced skeletal muscle ischemia in a rat model. AB - This study delves into possible mechanisms underlying the stimulating influence of UC-MSCs transplantation on functional and structural recovery of ischemic skeletal muscles. Limb ischemia was created in Sprague-Dawley rats by excision of femoral and popliteal arteries. Allogeneic rat PKH26-labeled UC-MSCs were administered by direct intramuscular injection. Animals of experimental group responded to the transplantation by improvement in their locomotor function as assessed by the rotarod performance test on day 9 and 29 after transplantation. Histomorphometric analysis showed that relative area of the lesions in the experimental group was significantly smaller than in the control group at all time points during the observation. Calculated densities of microcirculation vessels within the lesions were significantly higher in the experimental group than in the control group on day 10 after transplantation. Only a part of the transplanted allogeneic UC-MSCs survived within the ischemic muscle tissue, and a considerable portion of these surviving cells were found alongside the VEGF producing preserved muscle fibers. The PKH26 label was not found within the walls of capillaries or larger blood vessels. The administration of allogeneic UC-MSCs significantly increased the proportion of M2 macrophages, exhibiting proangiogenic and anti-inflammatory properties, for at least 10 days following the transplantation. PMID- 30398288 TI - Mesenchymal stem cell secretome reduces pain and prevents cartilage damage in a murine osteoarthritis model. AB - Mesenchymal stem cells (MSCs) represent a promising biological therapeutic option as an osteoarthritis (OA)-modifying treatment. MSCs secrete factors that can counteract inflammatory and catabolic processes and attract endogenous repair cells. The effects of intra-articular injection of MSC secretome on OA-related pain, cartilage damage, subchondral bone alterations and synovial inflammation were studied in a mouse collagenase-induced OA model. The MSC secretome was generated by stimulating human bone-marrow-derived MSCs with interferon gamma (IFNgamma) and tumour necrosis factor alpha (TNFalpha). 54 mice were randomly assigned to injections with i) MSC secretome from 20,000 MSCs, ii) 20,000 MSCs or iii) medium (control). Pain was assessed by hind limb weight distribution. Cartilage damage, subchondral bone volume and synovial inflammation were evaluated by histology. MSC-secretome- and MSC-injected mice showed pain reduction at day 7 when compared to control mice. Cartilage damage was more abundant in the control group as compared to healthy knees, a difference which was not found in knees treated with MSC secretome or MSCs. No effects were observed regarding synovial inflammation, subchondral bone volume or the presence of different macrophage subtypes. Injection of MSC secretome, similarly to injection of MSCs, resulted in early pain reduction and had a protective effect on the development of cartilage damage in a murine OA model. By using the regenerative capacities of the MSC-secreted factors, it will be possible to greatly enhance the standardisation, affordability and clinical translatability of the approach. This way, this biological therapy could evolve towards a true disease-modifying anti-osteoarthritic drug. PMID- 30398289 TI - Low-level transcutaneous vagus nerve stimulation attenuates cardiac remodelling in a rat model of heart failure with preserved ejection fraction. AB - NEW FINDINGS: What is the central question of this study? What is the effect of chronic intermittent low-level transcutaneous vagus nerve stimulation on cardiac inflammation, fibrosis and diastolic dysfunction in a rat model of heart failure with preserved ejection fraction? What is the main finding and its importance? In salt-sensitive rats fed with high salt diet, low-level transcutaneous vagus nerve stimulation significantly attenuated blood pressure elevation, ameliorated diastolic function, and attenuated left ventricular inflammation and fibrosis compared to the sham group. Further studies to examine the efficacy of this novel treatment in humans are warranted. ABSTRACT: Inflammation and fibrosis play a central role in the development of heart failure with preserved ejection fraction (HFpEF). We previously showed that low-level, transcutaneous stimulation of the vagus nerve at the tragus (LLTS) is anti-inflammatory. We investigated the effect of chronic intermittent LLTS on cardiac inflammation, fibrosis and diastolic dysfunction in a rat model of HFpEF. Dahl salt-sensitive (DS) rats were randomized in three groups: low salt (LS, 0.3% NaCl; n = 12; control group without stimulation) and high salt (HS, 4% NaCl) with either active (n = 18) or sham (n = 18) LLTS at 7 weeks of age. After 6 weeks of diet (baseline), sham or active LLTS (20 Hz, 2 mA, 0.2 ms) was implemented for 30 min daily for 4 weeks. Echocardiography was performed at baseline and 4 weeks after treatment (endpoint). At endpoint, left ventricle (LV) histology and gene expression were examined. After 6 weeks of diets, HS rats developed hypertension and LV hypertrophy compared to LS rats. At endpoint, LLTS significantly attenuated blood pressure elevation, prevented the deterioration of diastolic function and improved LV circumferential strain, compared to the HS sham group. LV inflammatory cell infiltration and fibrosis were attenuated in the HS active compared to the HS sham group. Pro-inflammatory and pro-fibrotic genes (tumour necrosis factor, osteopontin, interleukin (IL)-11, IL-18 and IL-23A) were differentially altered in the two groups. Chronic intermittent LLTS ameliorates diastolic dysfunction, and attenuates cardiac inflammation and fibrosis in a rat model of HFpEF, suggesting that LLTS may be used clinically as a novel non invasive neuromodulation therapy in HFpEF. PMID- 30398290 TI - Is the New Infant Jarvik 2015 Suitable for Patients<8 kg? In Vitro Study Using a Hybrid Simulator. AB - Our aim was to study the feasibility of implanting the Infant Jarvik 2015 in patients weighing less than 8 kg. The Infant Jarvik 2015 left ventricular assist device (LVAD) was tested in a hybrid simulator of the cardiovascular system reproducing specific patients' hemodynamics for different patient weights (2-7 kg). For each weight, the sensitivity of the pump to different circulatory parameters (peripheral resistance, left ventricular elastance, right ventricular elastance, heart rate, and heart filling characteristics) has been tested repeating for each experiment a pump ramp (10 000-18 000 rpm). The increase in the pump speed causes a decrease (increase) in the left (right) atrial pressure, an increase (decrease) in the arterial systemic (pulmonary) pressure, an increase in the right ventricular pressure, a decrease (increase) in the left (right) ventricular volume, a decrease in the left ventricular cardiac output, an increase in the LVAD output and an increase in the right ventricular cardiac output (total cardiac output). Suction was observed for lower weight patients and for higher pump speed in the case of vasodilation, left ventricular recovery, bradycardia, right ventricular failure, and left ventricular hypertrophy. Backflow was observed in the case of left ventricular recovery at lower pump speed. In the hybrid simulator, the Infant Jarvik 2015 could be suitable for the implantation in patients lower than 8 kg because of the stability of the device respect to the cardio/circulatory changes (low frequency of suction and backflow) and because of the capability of the device to maintain adequate patient hemodynamics. PMID- 30398291 TI - Opinions towards physical activity interventions using Facebook or text messaging: Focus group interviews with vocational school-aged adolescents. AB - Feasible and effective interventions to promote physical activity among vocational school-aged adolescents are strongly needed. Text messaging and Facebook are feasible and acceptable delivery modes for PA interventions among youth. However, little is known about the opinion of vocational school-aged adolescents regarding behavioural change techniques that can be applied through Facebook or text messaging. Therefore, our aim was to gain insight into the opinions of vocational school-aged adolescents towards the use of different behaviour change techniques and towards Facebook/text messaging as a delivery mode for PA interventions. Six focus groups were conducted with 41 adolescents from the first grade (12-14 years) of secondary vocational schools in Flanders (Belgium). In total 41 adolescents participated and completed a questionnaire about their text messaging and Facebook use prior to group discussions. Focus group discussions were audio-recorded and analysed using a thematic analysis method in Nvivo. Participants thought that different behaviour change techniques (e.g., providing feedback, goal setting, self-monitoring, social comparison) could be integrated in a PA intervention using text messaging and Facebook and were enthusiastic about participating in such an intervention. They indicated that text messages are an easy way to receive information about PA, and that a group page on Facebook is ideal to share information with others. Participants deemed it very important that the group page on Facebook would only include peers with whom they also share an offline connection. Furthermore, adolescents stressed the importance of having autonomy (e.g., to determine their personal activity goals, to self-monitor their behaviour) and of being active together with friends. This qualitative study revealed that the use of Facebook and text messaging is promising as a delivery method for PA interventions among vocational school-aged adolescents. The adolescents were keen to participate in an intervention that integrates behaviour change techniques using text messaging or Facebook. PMID- 30398292 TI - Ionic Liquid Stabilized Gelatin-Lignin Films: A potential UV Shielding Material with Excellent Mechanical and Antimicrobial Properties. AB - Significant research is going on to develop environmental friendly UV shielding materials. Herein, we have constructed choline citrate (a bio-based ionic liquid, IL) stabilized homogeneous gelatin-lignin UV shielding films with excellent antimicrobial and mechanical properties. Synthesis procedure of films is less energy demanding, one pot and sustainable in nature. Prepared films are characterized for its mechanical and thermal analysis using UTM and TGA respectively. ATR-IR and PXRD is employed to explore the possible formation of H bonding between biopolymers and IL and change in crystallinity in films after addition of IL to gelatin-lignin matrix. Surface morphology of prepared films has been studied using optical microscope, AFM and FE-SEM. Optical properties of prepared films are measured using UV-Visible spectroscopy. Antimicrobial activity of prepared films has been tested against Bacillus subtilis. Prepared bio-films have shown sun protection factor (SPF) up to ~ 45.0, large elongation ~200% and tensile strength ~70 MPa, which are as good as exhibited by organic polymeric films, indicating a promising renewable resources-based material for UV-light blocking. PMID- 30398293 TI - Dehalogenation of Halogenated Nucleobases and Nucleosides by Organoselenium Compounds. AB - Halogenated nucleosides, such as 5-iodo-2'-deoxyuridine and 5-iodo-2' deoxycytidine are incorporated into the DNA of replicating cells to facilitate DNA-strand breaks and intra- or inter-strand crosslinks upon UV irradiation. In this paper, we show that the naphthyl-based organoselenium compounds can mediate the dehalogenation of halogenated pyrimidine-based nucleosides, such as 5-X-2' deoxyuridine, 5-X-2'-deoxycytidine (X = Br or I). The rate of deiodination was found to be several folds higher than that of the debromination for both nucleosides. Furthermore, the deiodination of iodo-cytidines was found to be faster than that of iodo-uridines. The initial rates of the deiodinations of 5 iodocytosine and 5-iodouracil indicate that the nature of the sugar moiety influences the kinetics of the deiodination. For both the nucleobases and nucleosides, the deiodination and debromination reactions follow a halogen bond mediated and addition-elimination pathway, respectively. PMID- 30398294 TI - The comprehensive outcomes of hepatitis C virus infection: A multi-faceted chronic disease. AB - Treatment of hepatitis C virus (HCV) infection has been revolutionized with the introduction of pangenotypic, interferon- and ribavirin-free regimens associated with high cure rates and a low side effect profile. Additionally, there is evidence that HCV cure reduces HCV complications, improves patient-reported outcomes and is cost-saving in most western countries in the long term. This is a review of the comprehensive burden of HCV and the value of eliminating HCV infection. With the introduction of the interferon-free all-oral, once a day pill treatment regimen for the cure of HCV, the potential to eliminate HCV by 2030 has become a possibility for some regions of the world. Nevertheless, there are barriers to screening, linkage to care, and treatment in many countries that must be overcome in order to reach this goal. In conclusion, globally, work must continue to ensure national policies are in place to support screening, linkage to care and affordable treatment in order to eliminate HCV. PMID- 30398296 TI - Religion and psychotic experiences. PMID- 30398295 TI - White Matter Microstructure Correlates with Memory Performance in Healthy Children: A Diffusion Tensor Imaging Study. AB - BACKGROUND AND PURPOSE: The complex function of memory has been linked to both brain gray and white matter (WM). WM abnormalities are associated with memory impairment in pathological conditions. We investigated whether variation in WM microstructure in healthy children also correlates with memory performance. METHODS: Sixty-five 7.5 to 8.5-year-old healthy children had a brain MRI scan using diffusion tensor imaging (DTI). They were also assessed for memory performance using the Children's Memory Scale (CMS). Eight indices that evaluate verbal and visual memory (immediate and delayed) were measured. DTI parameters reflecting WM microstructure, including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD), were calculated and correlated with memory indices. RESULTS: Tract-based spatial statistics analysis showed multiple WM tracts in which DTI parameters correlated with CMS indices. Specifically, FA (a reflection of WM integrity) and RD values (a reflection of myelination) in multiple projecting, association, and commissural WM tracts correlated with verbal delayed index (P < .05, corrected for voxel-wise multiple comparisons). Also, FA values in several WM tracts, including superior longitudinal fasciculus and posterior corona radiata, positively correlated with delayed recognition index (P < .05, corrected). Region of interest analyses showed similar correlations between FA/RD and CMS scores in WM regions involving these tracts and additionally in the cingulum, and detected additional MD-CMS correlations in several regions. CONCLUSIONS: Significant correlations between DTI parameter values and CMS indices in multiple WM tracts in healthy children indicate that neuroimaging can sensitively detect brain WM changes associated with variations of memory function, even for that in the normal range. PMID- 30398297 TI - Should benzodiazepines be avoided? PMID- 30398298 TI - CYP109E1 from Bacillus megaterium acts as 24- and 25-hydroxylase for cholesterol. AB - In this study, the ability of CYP109E1 from Bacillus megaterium DSM319 to metabolize cholesterol was investigated. This steroid was identified as a new substrate to be converted by CYP109E1 using adrenodoxin and adrenodoxin reductase as redox partners in vitro. The biotransformation was successfully reproduced in vivo using Bacillus megaterium cells overexpressing CYP109E1. To enhance the production of cholesterol derivatives, an Escherichia coli based whole-cell system harbouring CYP109E1 was established. This novel system showed a 3.3-fold higher activity compared with the B. megaterium system yielding about 45 mg/L of these products. Finally, the reaction products were isolated and identified as the highly important cholesterol derivatives, 24(S)- and 25-hydroxycholesterol. PMID- 30398299 TI - Affinity Enhancement of Protein Ligands by Reversible Covalent Modification of Neighboring Lysine Residues. AB - The discovery of protein ligands, capable of forming a reversible covalent bond with amino acid residues on a protein target of interest, may represent a general strategy for the discovery of potent small-molecule inhibitors. We analyzed the ability of different aromatic aldehydes to form imines by reaction with lysine using 1 H NMR techniques. 2-Hydroxybenzaldehyde derivatives were found to efficiently form imines in the millimolar concentration range. These benzaldehyde derivatives could increase the binding affinity of protein ligands towards the cognate protein target. Affinity maturation was achieved not only by displaying ligand and aldehyde moieties on two complementary locked nucleic acid strands but also by incorporating the binding fragments in a single small-molecule ligand. The affinity gain was only observed when lysine residues were accessible in the immediate surroundings of the ligand-binding site and could be abrogated by quenching with a molar excess of hydroxylamine. PMID- 30398300 TI - Confined Pt1 1+ Water Clusters in a MOF Catalyze the Low-Temperature Water-Gas Shift Reaction with both CO2 Oxygen Atoms Coming from Water. AB - The synthesis and reactivity of single metal atoms in a low-valence state bound to just water, rather than to organic ligands or surfaces, is a major experimental challenge. Herein, we show a gram-scale wet synthesis of Pt1 1+ stabilized in a confined space by a crystallographically well-defined first water sphere, and with a second coordination sphere linked to a metal-organic framework (MOF) through electrostatic and H-bonding interactions. The role of the water cluster is not only isolating and stabilizing the Pt atoms, but also regulating the charge of the metal and the adsorption of reactants. This is shown for the low-temperature water-gas shift reaction (WGSR: CO + H2 O -> CO2 + H2 ), where both metal coordinated and H-bonded water molecules trigger a double water attack mechanism to CO and give CO2 with both oxygen atoms coming from water. The stabilized Pt1+ single sites allow performing the WGSR at temperatures as low as 50 degrees C. PMID- 30398301 TI - Tin Diselenide Molecular Precursor for Solution-Processable Thermoelectric Materials. AB - In the present work, we detail a fast and simple solution-based method to synthesize hexagonal SnSe2 nanoplates (NPLs) and their use to produce crystallographically textured SnSe2 nanomaterials. We also demonstrate that the same strategy can be used to produce orthorhombic SnSe nanostructures and nanomaterials. NPLs are grown through a screw dislocation-driven mechanism. This mechanism typically results in pyramidal structures, but we demonstrate here that the growth from multiple dislocations results in flower-like structures. Crystallographically textured SnSe2 bulk nanomaterials obtained from the hot pressing of these SnSe2 structures display highly anisotropic charge and heat transport properties and thermoelectric (TE) figures of merit limited by relatively low electrical conductivities. To improve this parameter, SnSe2 NPLs are blended here with metal nanoparticles. The electrical conductivities of the blends are significantly improved with respect to bare SnSe2 NPLs, what translates into a three-fold increase of the TE Figure of merit, reaching unprecedented ZT values up to 0.65. PMID- 30398302 TI - What Threshold Defines Penumbral Brain Tissue in Patients with Symptomatic Anterior Circulation Intracranial Stenosis: An Exploratory Analysis. AB - BACKGROUND AND PURPOSE: Impaired distal perfusion predicts neurological deterioration in large artery atherosclerosis. We aim to determine the optimal threshold of Tmax delay on perfusion imaging that is associated with neurological deterioration in patients with symptomatic proximal anterior circulation large artery stenosis. METHODS: Data were abstracted from a prospective ischemic stroke database of consecutively enrolled patients with symptomatic proximal intracranial stenosis (internal carotid artery or M1 segment of the middle cerebral artery) who underwent magnetic resonance perfusion imaging within 24 hours of symptom onset during a 15-month period. Tissue volumes of perfusion delay Tmax 0-4 seconds, Tmax > 4 seconds, Tmax > 6 seconds, and Tmax > 8 seconds were calculated using an automated approach. A target mismatch (penumbra-core) was defined as >=15mL of brain tissue using each of the Tmax threshold categories. The outcome was neurological deterioration at 30 days defined as new or worsening neurological deficits that are not attributed to a nonvascular etiology. RESULTS: Among 52 patients with symptomatic intracranial stenosis, 26 patients met inclusion criteria. Neurological deterioration was associated with target mismatch profile defined according to Tmax > 6 seconds (66.7% [6/9] vs. 5.9% [1/17], P < .01) and Tmax >8 seconds (57.1% [4/7] vs. 15.8% [3/19], P = .05] but not according to Tmax > 4 seconds (27.3% [6/17] vs. 11.1% [1/9], P = .35]. CONCLUSIONS: A target mismatch profile using Tmax > 6 seconds may define tissue at risk in patients with acute symptomatic proximal anterior circulation intracranial stenosis. More studies are needed to confirm our findings. PMID- 30398303 TI - Enantioselective Organocatalytic Four-Atom Ring Expansion of Cyclobutanones: Synthesis of Benzazocinones. AB - An enantioselective Michael addition- four-atom ring expansion cascade reaction involving cyclobutanones activated by a N-aryl secondary amide group and ortho amino nitrostyrenes has been developed for the preparation of functionalized eight-membered benzolactams using bifunctional aminocatalysts. Taking advantage of the secondary amide activating group, the eight-membered cyclic products could be further rearranged into their six-membered isomers having a glutarimide core under base catalysis conditions without erosion of optical purity, featuring an overall ring expansion- ring contraction strategy. PMID- 30398304 TI - Tuning Confined Nanospace for Preparation of N-doped Hollow Carbon Spheres for High Performance Supercapacitors. AB - The structural parameters and surface functionalities of hollow carbon spheres are critical for their electrochemical performance. Herein, preparation of N doped-hollow carbon spheres (N-HCS) with tunable structural parameters and surface properties is reported by using a confined pyrolysis strategy. Polystyrene/polyaniline (PSPAN) was pyrolyzed in a silica shell, which provided a confined nanospace. PSPAN functioned as both the core and a source of carbon and nitrogen. The surface properties and structural parameters of the obtained N-HCS could be optimized by regulating the pore size of the silica shell. The silica shell coating also prevented agglomeration of the N-HCS, leading to a regular and well-distributed spherical morphology. The N-HCS synthesized in relatively porous conditions had thinner shell, larger mesopore size, higher surface area, and higher nitrogen content and showed excellent electrochemical performance as a supercapacitor with a specific capacitance of 436.5 F g-1 at 0.5 A g-1 . PMID- 30398305 TI - Surface Plasmon Resonance-Enhanced Visible-NIR-Driven Photocatalytic and Photothermal Catalytic Performance by Ag/Mesoporous Black TiO2 Nanotube Heterojunctions. AB - Ag/mesoporous black TiO2 nanotubes heterojunctions (Ag-MBTHs) were fabricated through a surface hydrogenation, wet-impregnation and photoreduction strategy. The as-prepared Ag-MBTHs possess a relatively high specific surface area of ~85 m2 g-1 and an average pore size of ~13.2 nm. The Ag-MBTHs with a narrow band gap of ~2.63 eV extend the photoresponse from UV to the visible-light and near infrared (NIR) region. They exhibit excellent visible-NIR-driven photothermal catalytic and photocatalytic performance for complete conversion of nitro aromatic compounds (100 %) and mineralization of highly toxic phenol (100 %). The enhancement can be attributed to the mesoporous hollow structures increasing the light multi-refraction, the Ti3+ in frameworks and the surface plasmon resonance (SPR) effect of plasmonic Ag nanoparticles favoring light-harvesting and spatial separation of photogenerated electron-hole pairs, which is confirmed by transient fluorescence. The fabrication of this SPR-enhanced visible-NIR-driven Ag-MBTHs catalyst may provide new insights for designing other high-performance heterojunctions as photocatalytic and photothermal catalytic nanomaterials. PMID- 30398307 TI - Foreword. PMID- 30398308 TI - Relational Sociology as a Form of Life: In memoriam Francois Depelteau (1963 2018). PMID- 30398310 TI - When Should I Allow Patients to Bring Dogs into My Office? PMID- 30398309 TI - Guidelines for tuning the macropore structure of monolithic columns for high performance liquid chromatography. AB - The ability to control the external porosity and to tune the dimensions of the macropore size on multiple length scales provides the possibility of tailoring the monolithic support structure towards separation performance. This paper discusses the properties of conventional polymer-monolithic stationary phases and its limitations regarding the effects of morphology on kinetic performance. Furthermore, guidelines to improve the macropore structure are discussed. The optimal monolithic macropore structure is characterized by high external porosity (while maintaining ultra-high-pressure stability), high structure homogeneity, polymer globule clusters in the submicron range, and macropores with a diameter tuned toward speed (small diameter in the 100-500 nm range using short beds) or efficiency (larger macropores in the range of 500 nm-1 MUm allowing the use of longer column formats). Finally, promising approaches to control the morphology are discussed. PMID- 30398312 TI - Specialty Recognition Changes and the ADA Code of Ethics. PMID- 30398311 TI - Is There a Thief Among You? PMID- 30398313 TI - Whatever Happens with Health Care, MDA Insurance Will Have Your Back. PMID- 30398315 TI - Take Care to Avoid these Common Public Health Code Violations. PMID- 30398314 TI - MDA Dentists and Pregnant Patients: A Survey of Attitudes and Practice. AB - Objectives There are dental and medical consensus statements stating oral health care is safe throughout pregnancy. This survey seeks to assess the attitudes and practice of Michigan Dental Association dentists regarding the oral health and treatment of pregnant patients as a preliminary assessment to facilitate state perinatal oral health initiatives. Methods Surveys were sent to all 4,494 Michigan Dental Association (MDA) members via the Michigan Dental Association List Serv between July and September of 2013 using an online survey instrument. There were 347 respondents, a response rate of 7.72 percent. Results Of the respondents, 91 percent strongly agree that oral health care is an important part of prenatal care, but only 37 percent indicate they provide restorative procedures and periodontal scaling and root planning procedures throughout all stages of pregnancy. Conclusions MDA dentists believe oral health care is important for pregnant patients. There is a need to provide continuing education in the management of pregnant patients. PMID- 30398316 TI - Prevalence and Factors Associated with the Use of Denture Adhesives by Older Complete Denture Wearers. AB - This study investigated the prevalence and the factors affecting the use of denture adhesives (DA) by older complete denture wearers. One hundred patients were interviewed and clinically examined for dentures' retention, stability and occlusion. A total of 31% used DA on a regular basis or sometimes; 14% used DA on both dentures, 19% on the maxillary denture and 26% on the mandibular one. DA use on the maxillary denture was significantly associated with younger age (p=0.026) and lower frequency of dentures' use (p?0.005), while their use on the mandibular denture was associated with the lower frequency of dentures' use (p?0.05) and good retention and stability of the maxillary denture (p=0.007). Multiple logistic regression analyses revealed that the DA use on maxillary dentures was significantly associated with younger age (odds ratio=0.938, p=0.026), while their use on the mandibular one was associated with good retention and stability of maxillary denture (odds ratio=1.451, p=0.007). These findings suggested that patient-driven factors, such as patients' age and denture's use habits had more significant effect on DA use than the denture's technical characteristics. Those factors should be further investigated to guide dentists in personalised recommendations on DA use to improve denture patients' quality of life. PMID- 30398318 TI - Challenges of implementing and embedding a programme to improve care for older people with dementia on hospital wards. AB - The authors took part in a national research project that evaluated an intervention to enhance person-centred care for people with dementia in hospital. The Person, Interactions, Environment (PIE) programme involves staff observing care on a ward, focusing on these three areas. Findings from observations form the basis for introducing changes to ward practices. Implementing PIE led to improvements in practice but proved challenging in the context of the NHS. Sustaining the programme after the research required important features to be in place, in particular the presence of a 'driver' to maintain momentum, the support of the ward manager to encourage ward staff to take part and a degree of flexibility and persistence in the implementation of the programme. Staff expressed satisfaction from taking part in PIE, which continues to be used to improve care in this area of practice. PMID- 30398317 TI - Accidental Ingestion of an Implant Screwdriver: A Case Report and Literature Review. AB - Head and neck oncology patients are high risk for ingestion or aspiration of dental instruments during treatment, due to altered anatomy and sensation. This article describes a case report of accidental ingestion of an implant screwdriver during the prosthetic phase of oral rehabilitation of a 79 year old oncology patient. The management protocol is described which included referral to the medical Accident and Emergency department, where the object was safely removed from the stomach via endoscopy. A review of similar cases of ingestion/inhalation in the literature suggests implant screwdrivers should be retrieved as safe passage through the gastrointestinal system is not assured. Awareness of the medical history and risk factors should alert clinicians to be extra cautious, and preventative strategies should be implemented at all times. Preventative measures include ligation of instruments with floss/suture material, treatment in a more vertical position, and use of rubber dam where possible. PMID- 30398319 TI - Assessing and managing the acute complications of diabetes mellitus. AB - Nurses commonly encounter patients with type 1 or type 2 diabetes mellitus in their practice. Management of these conditions requires an in-depth knowledge of blood glucose monitoring. It is essential that nurses are aware of normal blood glucose levels, so that they can respond to complications caused by elevated and reduced blood glucose levels. This article aims to enhance nurses' knowledge of the acute metabolic complications of diabetes, such as diabetic ketoacidosis and hyperosmolar hyperglycaemic state, to assist in their recognition and management in clinical practice. It discusses the causes, pathophysiology and treatment of these complications, which are regarded as potentially life-threatening medical emergencies. PMID- 30398320 TI - "Wrongful Birth" Claims and the Paradox of Parenting a Child with a Disability. AB - "Wrongful birth" is a controversial medical malpractice claim raised by the mother of a child born with a disability against a medical professional whose failure to provide adequate prenatal information denied her the chance to abort. Plaintiff-mothers are required to testify that, but for the defendant's negligence, they would have terminated their pregnancy. Accordingly, alongside pro-life activists, disability rights advocates have opposed "wrongful birth" claims for stigmatizing and discriminating against people with disabilities by framing their very existence as a harm. Despite plaintiff-mothers' need for caretaking resources, scholars have recommended solutions ranging from the wholesale elimination of the wrongful birth claim to the curtailment of damages. To the extent scholars and the media have acknowledged mothers in the wrongful birth discourse at all, often it has been to blame and shame them for allegedly rejecting their children. They have paid little attention to the ways wrongful birth jurisprudence forces mothers to disavow their children in court, and thereby to forfeit the "good mother" ideal, in exchange for the possibility of securing necessary resources for their children. Commentators who question plaintiff-mothers' maternal devotion exacerbate the psychological toll the law already imposes. This Article shifts the blame from mothers to the legal system. While wrongful birth proceedings portray mothers' feelings about their children as categorically negative, real life accounts and social science findings reveal the true paradoxical experiences of all mothers, including plaintiff-mothers raising children with disabilities. To acknowledge this complex reality and mitigate the emotional strain of bringing a wrongful birth claim, this Article proposes several legal reforms: (1) broadening the analysis of emotional distress to reflect and legitimize mothers' paradoxical feelings about their children; (2) reframing the harm to mothers as loss of reproductive choice rather than as the birth of a flawed child and, accordingly, expanding available economic damages to include plaintiff-mothers' unexpected childcare responsibilities; and (3) educating plaintiffs' attorneys to empathize with the emotional aspects of mothers' litigation experiences and to counsel mothers accordingly. Today's approach to "wrongful birth" claims, which both stigmatizes disability and strains caretakers, demands urgent reform. PMID- 30398322 TI - Composite Beads for Reactivation of Functional Appliances PMID- 30398321 TI - Children are Crying and Dying while the Supreme Court is hiding: Why Public Schools Should Have Broad Authority to Regulate Off-Campus Bullying "Speech." AB - Bullying has long been a concern for students, parents, teachers, and school administrators. But technological advances--including the internet, cell phones, and social media--have transformed the nature of bullying and allow "cyberbullies" to extend their reach far beyond the schoolhouse gate. The U.S. Supreme Court established that schools may regulate on-campus speech if the speech creates a substantial disruption of, or material interference with, school activities. However, the Court has yet to rule on a school's ability to regulate students' off-campus bullying speech. This Note examines how various courts have approached the issue, analyzes the current circuit split, and ultimately proposes that schools should have the authority to discipline students for off-campus bullying speech. PMID- 30398323 TI - Medicaid Work Requirements: Will They Help the Unemployed Gain Jobs or Improve Health? AB - Issue: The Centers for Medicare and Medicaid Services approved Medicaid work requirement demonstration projects in four states, and other states also have applied. However, the future of these projects has been clouded by legal and policy challenges. Goal: To assess whether state Medicaid work requirement projects are designed for success in promoting employment among unemployed Medicaid beneficiaries. Methods: To examine the design of new work requirement projects, we reviewed the evidence, analyzed the overlap of Medicaid and Supplemental Nutrition Assistance Program (SNAP) work requirements, and convened a roundtable of seven experts who have research or implementation experience with work programs for Medicaid and public assistance recipients. Findings and Conclusion: Mandatory work programs would be less effective and efficient than well-administered voluntary programs. Far more people will be subject to Medicaid work requirements than are currently subject to them in SNAP. This surge could overwhelm the limited resources of existing employment training and support programs. Medicaid demonstration projects contribute almost no additional funding to train the unemployed or provide necessary social supports. Medicaid work requirement programs are not well designed to help people get jobs or improve health and are more likely to lead to a loss of health insurance coverage. PMID- 30398324 TI - Dual-Site and Dual-Excitation Fluorescent Probe That Can Be Tuned for Discriminative Detection of Cysteine, Homocystein, and Thiophenols. AB - Thiols play a vital role in both the physiological process and organic synthesis field, including aliphatic thiols (e.g., Cys, Hcy, and GSH) and thiophenols. As a result of the similarities of thiols in terms of molecular structure and chemical properties, it is difficult for conventional fluorescent probes to distinguish them, which hinders the progress of biological and pathological research. Keeping this in mind, a dual-site and dual-excitation fluorescent probe (YY) was designed to distinguish among Cys, Hcy, and thiophenols by three different reaction paths. When excited at 470 nm, YY only exhibits a fluorescence OFF-ON response toward thiophenols. However, when excited at 453 nm, YY not only displays a fluorescence OFF-ON response toward Hcy and thiophenols (lambdaem = 499 and 561 nm) but also presents a two-stage fluorescence response toward Cys, which possesses a fluorescence OFF-ON response in the first stage (lambdaem = 501 nm) and then a fluorescence ON-OFF response in the second stage (lambdaem = 556 nm). This specific fluorescence response indicates that YY has ability to overcome the above-mentioned challenge to achieve discriminative detection of Cys, Hcy, and thiophenols qualitatively, which promotes the study of thiols in the fields of physiology and pathology. Furthermore, cell-imaging studies show that YY can be applied to the imaging of exogenous Cys, Hcy, and thiophenols through two different emission channels. PMID- 30398325 TI - Charting an Unexplored Streptococcal Biosynthetic Landscape Reveals a Unique Peptide Cyclization Motif. AB - Peptide natural products are often used as signals or antibiotics and contain unusual structural modifications, thus providing opportunities for expanding our understanding of Nature's therapeutic and biosynthetic repertoires. Herein, we have investigated the under-explored biosynthetic potential of Streptococci, prevalent bacteria in mammalian microbiomes that include mutualistic, commensal, and pathogenic members. Using a new bioinformatic search strategy, in which we linked the versatile radical S-adenosylmethionine (RaS) enzyme superfamily to an emerging class of natural products in the context of quorum sensing control, we identified numerous, uncharted biosynthetic loci. Focusing on one such locus, we identified an unprecedented post-translational modification, consisting of a tetrahydro[5,6]benzindole cyclization motif in which four unactivated positions are linked by two C-C bonds in a regio- and stereo-specific manner by a single RaS enzyme. Our results expand the scope of reactions that microbes have at their disposal in concocting complex ribosomal peptides. PMID- 30398326 TI - Reactions of Folded Molecules in Water. AB - The chemistry of confined molecules is a relatively new undertaking, and this Account describes the effects of certain host container compounds on the behavior of molecules held as guests within. The containers are known as cavitands, which have one open end that allows small molecules to go in and out. The containers are amphiphilic: they feature aromatic surfaces that create a hydrophobic space inside but their peripheries are polar and permit solubility in water. The tension between the inner space of the cavitand and the outer space of the medium is experienced by the guest molecules. Two kinds of cavitand, a cylindrical and a cone-like methylated cavitand, are presented here, and they bind guests in somewhat different depths. The cylindrical cavitand typically has its aromatic panels closer to the guests and when a suitable guest is inside, two cylindrical cavitands can form a capsule through hydrogen bonding between their rims. Halogen bonding may also occur between the aromatic faces of the cavitands and the "sigma hole" of appropriate halides. Long-chain organic compounds of suitable size form host/guest complexes through hydrophobic forces on brief sonication with both cavitands in water. The container's shape acts on flexible guests and deforms them in order to fill the space properly. NMR spectroscopy reveals that many long chain guests assume U- or J-shaped conformations within the cavitands. The J shaped conformations are dynamic and undergo "yo-yo" like motions in the cavitand. An inevitable consequence of a folded chain is that its ends are closer together. Accordingly, these guests are prone to cyclization processes. The cavitands act as templates and were applied as chaperones for the synthesis of several classes of large-ring heterocycles, many of which were previously unknown compounds. Functional groups that are remote in extended, long-chain molecules act independently; when folded in cavitands, the functions are brought into proximity and affect each other's reactivities. Such communication introduces the concept of "entanglement" to chemistry. The concept was applied to the monofunctionalization of symmetrical long chain diesters, diazides, and diisocyanates. For the diisocyanates, macrocyclic urea formation followed the desymmetrization. Folding flexible molecules in a predictable way can also offer new reaction pathways for remote chemical functionalization. Most such processes involving C-H activation proceed through 6-membered transition states; folding promises alternative ring sizes but has yet to be shown. These results should encourage applications using more accessible container molecules such as cyclodextrins, cucurbiturils, and pillarenes. PMID- 30398327 TI - Origin of the Overpotential for the Oxygen Evolution Reaction on a Well-Defined Graphene Electrode Probed by in Situ Sum Frequency Generation Vibrational Spectroscopy. AB - To develop an efficient material for the cathode of the lithium-oxygen (Li-O2) secondary battery, the oxygen reduction and evolution reactions (ORR and OER) on a well-defined graphene electrode have been investigated in a typical organic solvent, dimethyl sulfoxide (DMSO). The adsorption and desorption behaviors of the solvents on the graphene electrode surface were evaluated by an intrinsically surface-selective vibrational spectroscopy of sum frequency generation (SFG) during the ORR and OER. After the initial ORR depositing lithium peroxide (Li2O2) on the graphene electrode surface in a LiClO4/DMSO solution, the SFG spectroscopy revealed that the subsequent OER oxidizing the Li2O2 preferentially proceeds at the interface between the Li2O2 and graphene rather than that between the Li2O2 and bulk solution. Therefore, the OER tends to reduce the electric conductivity between the Li2O2 and graphene by decreasing their contact area before a large part of the deposited Li2O2 was oxidized, which elucidates the origin of the high overpotential for the OER. PMID- 30398328 TI - Colloidal Metal-Organic Framework Hexapods Prepared from Postsynthesis Etching with Enhanced Catalytic Activity and Rollable Packing. AB - Recent studies on the effect of particle shapes have led to extensive applications of anisotropic colloids as complex materials building blocks. Although much research has been devoted to colloids of convex polyhedral shapes, branched colloids remain largely underexplored because of limited synthesis strategies. Here we achieved the preparation of metal-organic framework (MOF) colloids in a hexapod shape, not directly from growth but from postsynthesis etching of truncated rhombic dodecahedron (TRD) parent particles. To understand the branch development, we used in situ optical microscopy to track the local surface curvature evolution of the colloids as well as facet-dependent etching rate. The hexapods show unique properties, such as improved catalytic activity in a model Knoevenagel reaction likely due to enhanced access to active sites, and the assembly into open structures which can be easily integrated with a self rolled-up nanomembrane structure. Both the postsynthesis etching and the hexapod colloids demonstrated here show a new route of engineering micrometer-sized building blocks with exotic shapes and intrinsic functionalities originated from the molecular structure of materials. PMID- 30398329 TI - Ir-Alloyed Ultrathin Ternary PdIrCu Nanosheet-Constructed Flower with Greatly Enhanced Catalytic Performance toward Formic Acid Electrooxidation. AB - Ternary metal-element alloys have been reported as efficient electrocatalysts toward various electrochemical reactions, but a unique three-dimensional (3D) Ir alloyed ternary nanosheet-composed flower (NCF) structure has not been explored yet. Herein, an innovated 1.8 nm Ir-alloyed ultrathin ternary PdIrCu NCF structure is synthesized via one-pot solvothermal reduction without using any surfactant. The as-prepared PdIrCu/C NCF catalyst remarkably improves the stability than commercial Pd/C toward formic acid electrooxidation while resulting in significantly increased mass activity. The improvement of electrocatalytic properties depends on the introduction of Ir and Cu atoms, which greatly prevented poisoning from CO while modifying the electronic structure of Pd for increased reaction active sites and accelerated charge-transfer rate as well as facilitated mass transport by ultrathin NCF 3D structure. Therefore, this catalyst possesses a promising application prospect in electrochemical energy storage/conversion systems. PMID- 30398330 TI - Application of Rubrene Air-Gap Transistors as Sensitive MEMS Physical Sensors. AB - Micro-electromechanical systems (MEMS) made of organic materials have attracted efforts for the development a new generation of physical, chemical, and biological sensors, for which the electromechanical sensitivity is the current major concern. Here, we present an organic MEMS made of a rubrene single-crystal air-gap transistor. Applying mechanical pressure on the semiconductor results in high variations in drain current: an unparalleled gauge factor above 4000 has been measured experimentally. Such a high sensitivity is induced by the modulation of charge injection at the interface between the gold electrode and the rubrene semiconductor as an unusual transducing effect. Applying these devices to the detection of acoustic pressure shows that force down to 230 nN can be measured with a resolution of 40 nN. This study demonstrates that MEMS based on rubrene air-gap transistors constitute a step forward in the development of high-performance flexible sensors. PMID- 30398331 TI - Oxygen-Oxygen Bond Cleavage and Formation in Co(II)-Mediated Stoichiometric O2 Reduction via the Potential Intermediacy of a Co(IV) Oxyl Radical. AB - In reactions of significance to alternative energy schemes, metal catalysts are needed to overcome kinetically and thermodynamically difficult processes. Often, high-oxidation-state, high-energy metal oxo intermediates are proposed as mediators in elementary steps involving O-O bond cleavage and formation, but the mechanisms of these steps are difficult to study because of the fleeting nature of these species. Here we utilized a novel dianionic pentadentate ligand system that enabled a detailed mechanistic investigation of the protonation of a cobalt(III)-cobalt(III) peroxo dimer, a known intermediate in oxygen reduction catalysis to hydrogen peroxide. It was shown that double protonation occurs rapidly and leads to a low-energy O-O bond cleavage step that generates a Co(III) aquo complex and a highly reactive Co(IV) oxyl cation. The latter was probed computationally and experimentally implicated through chemical interception and isotope labeling experiments. In the absence of competing chemical reagents, it dimerizes and eliminates dioxygen in a step highly relevant to O-O bond formation in the oxygen evolution step in water oxidation. Thus, the study demonstrates both facile O-O bond cleavage and formation in the stoichiometric reduction of O2 to H2O with 2 equiv of Co(II) and suggests a new pathway for selective reduction of O2 to water via Co(III)-O-O-Co(III) peroxo intermediates. PMID- 30398332 TI - Tunable Localized Surface Plasmon Resonance and Broadband Visible Photoresponse of Cu Nanoparticles/ZnO Surfaces. AB - Plasmonic Cu nanoparticles (NP) were successfully deposited on ZnO substrates by atomic layer deposition (ALD) owing to the Volmer-Weber island growth mode. An evolution from Cu NP to continuous Cu films was observed with an increasing number of ALD cycles. Real and imaginary parts of the NP dielectric functions, determined by spectroscopic ellipsometry using an effective medium approach, evidence a localized surface plasmon resonance that can be tuned between the visible and near-infrared ranges by controlling the interparticle spacing and size of the NP. The resulting Cu NP/ZnO device shows an enhanced photoresponse under white light illumination with good responsivity values, fast response times, and stability under dark/light cycles. The significant photocurrent detected for this device is related to the hot-electron generation at the NP surface and injection into the conduction band of ZnO. The possibility of tuning the plasmon resonance together with the photoresponsivity of the device is promising in many applications related to photodetection, photonics, and photovoltaics. PMID- 30398333 TI - In Situ Sensing of the Neurotransmitter Acetylcholine in a Dynamic Range of 1 nM to 1 mM. AB - The neurotransmitter acetylcholine (ACh) plays a key role in the pathophysiology of brain disorders such as Alzheimer's disease. Understanding the dynamics of ACh concentration changes and kinetics of ACh degradation in the living brain is crucial to unravel the pathophysiology of such diseases and the rational design of therapeutics. In this work, an electrochemical sensor capable of dynamic, label-free, selective, and in situ detection of ACh in a range of 1 nM to 1 mM (with temporal resolution of less than one second) was developed. The sensor was employed for the direct detection of ACh in artificial cerebrospinal fluid and rat brain homogenate, without any prior separation steps. A potentiometric receptor-doped ion-selective electrode (ISE) with selectivity for ACh was designed by taking advantage of the positive charge of ACh. The dynamic range, limit of detection (LOD), and the selectivity of the sensor were optimized stepwise by (i) screening of hydrophobic biomimetic calixarenes to identify receptors that strongly bind to ACh based on shape-selective multitopic recognition, (ii) doping of the ISE sensing membrane with an ACh-binding hydrophobic calixarene to enable selective detection of ACh in complex matrices, (iii) utilizing a hydrophilic calixarene in the inner filling solution of the ISE to buffer the concentration of ACh and, thereby, lower the LOD of the sensor, and (iv) introducing a surface treatment step prior to the measurement by placing the sensor for ~1 min in a solution of a hydrophilic calixarene to lower the LOD of the sensor even further. PMID- 30398334 TI - Potent Protein Delivery into Mammalian Cells via a Supercharged Polypeptide. AB - The efficient delivery of proteins into cells is needed to fully realize the potential of protein-based therapeutics. Current protein delivery strategies generally suffer from poor endosomal escape and low tolerance for serum. Here, the genetic fusion of a supercharged polypeptide, called SCP, to a protein provides a generic method for intracellular protein delivery. It allows efficient protein endocytosis and endosomal escape and is capable of potently delivering various proteins with a range of charges, sizes, and bioactivities into the nucleus of living cells. SCP is discovered to bind directly to the nuclear import protein importin beta1 and gains access to the nucleus. Furthermore, SCP shows minimal hemolytic activity and stability in serum and lacks toxicity and immunogenicity in vivo. Effective gene editing can be achieved by SCP-mediated delivery of Cas9 protein and guide RNA. This study may provide an efficient and useful tool for the design and development of cell-nuclear-targeted drug delivery. PMID- 30398335 TI - Esterase-Catalyzed Production of Hyperpolarized 13C-Enriched Carbon Dioxide in Tissues for Measuring pH. AB - 13C Magnetic resonance imaging of hyperpolarized (HP) 13C-enriched bicarbonate (H13CO3-) and carbon dioxide (13CO2) is a novel and sensitive technique for tissue pH mapping in vivo. Administration of the HP physiological buffer pair is attractive, but poor polarization and the short T1 of 13C-enriched inorganic bicarbonate salts are major drawbacks for this approach. Here, we report a new class of mixed anhydrides for esterase-catalyzed production of highly polarized 13CO2 and H13CO3- in tissue. A series of precursors with different alkoxy and acyl groups were synthesized and tested for chemical stability and T1. 13C enriched ethyl acetyl carbonate (13C-EAC) was found to be the most suitable candidate due to the relatively long T1 and good chemical stability. Our results showed that 13C-EAC can be efficiently and rapidly polarized using BDPA. HP 13C EAC was rapidly hydrolyzed by esterase to 13C-enriched monoacetyl carbonate (13C MAC), which then decomposed to HP 13CO2. Equilibrium between the newly produced 13CO2 and H13CO3- was quickly established by carbonic anhydrase, producing a physiological buffer pair with 13C NMR signals that can be quantified for pH measurements. Finally, in vivo tissue pH measurements using HP 13C-EAC was successfully demonstrated in the liver of healthy rats. These results suggest that HP 13C-EAC is a novel imaging probe for in vivo pH measurements. PMID- 30398336 TI - Orange-Emitting Li4Sr4[Si4O4N6]O:Eu2+-a Layered Lithium Oxonitridosilicate Oxide. AB - We report on the structure and properties of the lithium oxonitridosilicate oxide Li4Sr4[Si4O4N6]O:Eu2+ obtained from solid-state metathesis. The crystal structure was solved and refined from single-crystal X-ray data in the space group P42/ nmc (No. 137) [ Z = 2, a = 7.4833(6), c = 9.8365(9) A, and R1(obs) = 0.0477]. The structure of Li4Sr4[Si4O4N6]O:Eu2+ is built up from a layered 2D network of SiN3O tetrahedra and exhibits stacking disorder. The results are supported by transmission electron microscopy and energy-dispersive X-ray spectroscopy as well as lattice energy, charge distribution, and density functional theory (DFT) calculations. Optical measurements suggest an indirect band gap of about 3.6 eV, while DFT calculations on a model free of stacking faults yield a theoretical electronic band gap of 4.4 eV. Samples doped with Eu2+ exhibit luminescence in the orange spectral range (lambdaem ~ 625 nm; full width at half-maximum ~ 4164 cm-1; internal quantum efficiency at room temperature = 24%), extending the broad field of phosphor materials research toward the sparsely investigated materials class of lithium oxonitridosilicate oxides. PMID- 30398337 TI - Organic Single-Crystalline p-n Heterojunctions for High-Performance Ambipolar Field-Effect Transistors and Broadband Photodetectors. AB - Organic semiconducting single crystals are ideal building blocks for organic field-effect transistors (OFETs) and organic photodetectors (OPDs) because they can potentially exhibit the best charge transport and photoelectric properties in organic materials. Nevertheless, it is usual for single-crystal OFETs to be built from one kind of organic material in which the dominant transport is either electron or hole; such OFETs show unipolar charge transport. Furthermore, single crystal OPDs present high performance only in restricted regions because of the limited absorption of one-component single crystals. In an ideal situation, devices which comprise both electron- and hole-transporting single crystals with complementary absorptions, such as single-crystalline p-n heterojunctions (SCHJs), can permit broadband photoresponse and ambipolar charge transport. In this paper, a solution-processing crystallization strategy to prepare an SCHJ composed of C60 and 6,13-bis(triisopropylsilylethynyl)pentacene (TIPS-PEN) was shown. These SCHJs demonstrated ambipolar charge-transport characteristics in OFETs with a balanced performance of 2.9 cm2 V-1 s-1 for electron mobility and 2.7 cm2 V-1 s-1 for hole mobility. This demonstration is the first of single crystal OFETs in which both electron and hole mobilities were over 2.5 cm2 V-1 s 1. OPDs fabricated upon as-prepared SCHJs exhibited highly sensitive photoconductive properties ranging from ultraviolet to visible and further to near-infrared regions as a result of complementary absorption between C60 and TIPS-PEN, thereby attaining photoresponsivities that are among the highest reported values within the OPDs. This work would provide valuable references for developing novel SCHJ systems to achieve significant progress in high-performance ambipolar OFETs and broadband OPDs. PMID- 30398338 TI - Indoor exposure to ambient particles and its estimation using fixed site monitors. AB - Ambient PM2.5 concentrations measured at fixed site monitors (FSM) are often biased with respect to exposure concentrations because of spatial variability and infiltration. Based on comparison of ambient concentrations from 14 FSMs and of exposure concentrations measured indoors and outdoors at two schools in Hong Kong for winter and summer seasons, the magnitude and sources of exposure error based on using FSMs as a surrogate for exposure are quantified. An approach for bias correcting surrogate exposure estimates from FSMs is demonstrated. The approach is based on a proximity factor (PF) that accounts for differences in spatial locations, proximity to emissions and deviation from dominant wind direction, and an infiltration factor (IF) that varies by season. The combination of the PF and IF reduce bias in mean school exposure estimates from +/-90% to +/-20%. Bias in exposure estimates from using FSMs as surrogates tend to be smaller for which the exposure site and FSM are aligned with wind direction, have similar sampling height, and are in close proximity. The methodology demonstrated to assess concordance between FSMs and exposure measurement sites can be applied more broadly to help reduce exposure error, which may help to interpret seasonal variations in health estimates. PMID- 30398339 TI - The Role of Ionic Liquid Breakdown in the Electrochemical Metallization of VO2: An NMR Study of Gating Mechanisms and VO2 Reduction. AB - Metallization of initially insulating VO2 via ionic liquid electrolytes, otherwise known as electrolyte gating, has recently been a topic of much interest for possible applications such as Mott transistors and memory devices. It is clear that the metallization takes place electrochemically, and, in particular, there has previously been extensive evidence for the removal of small amounts of oxygen during ionic liquid gating. Hydrogen intercalation has also been proposed, but the source of the hydrogen has remained unclear. In this work, solid-state magic angle spinning NMR spectroscopy (1H, 2H, 17O, and 51V) is used to investigate the thermal metal-insulator transition in VO2, before progressing to catalytically hydrogenated VO2 and electrochemically metallized VO2. In these experiments electrochemical metallization of bulk VO2 particles is shown to be associated with intercalation of hydrogen, the degree of which can be measured with quantitative 1H NMR spectroscopy. Possible sources of the hydrogen are explored, and by using a selectively deuterated ionic liquid, it is revealed that the hydrogenation is due to deprotonation of the ionic liquid; specifically, for the commonly used dialkylimidazolium-based ionic liquids, it is the "carbene" proton that is responsible. Increasing the temperature of the electrochemistry is shown to increase the degree of hydrogenation, forming first a less hydrogenated metallic orthorhombic phase then a more hydrogenated insulating Curie-Weiss paramagnetic orthorhombic phase, both of which were also observed for catalytically hydrogenated VO2. The NMR results are supported by magnetic susceptibility measurements, which corroborate the degree of Pauli and Curie Weiss paramagnetism. Finally, NMR spectroscopy is used to identify the presence of hydrogen in an electrolyte gated thin film of VO2, suggesting that electrolyte breakdown, proton intercalation, and reactions with decomposition products within the electrolyte should not be ignored when interpreting the electronic and structural changes observed in electrochemical gating experiments. PMID- 30398340 TI - Impact of Morphology on Iron Oxide Nanoparticles-Induced Inflammasome Activation in Macrophages. AB - Inflammasomes, a critical component of the innate immune system, mediate much of the inflammatory response manifested by engineered nanomaterials. Iron oxide nanoparticles (IONPs), a type of nanoparticles that have gained widespread acceptance in preclinical and clinical settings, are known to induce inflammasome activation, but how morphology affects the inflammasome-activating property of IONPs has not been addressed. In this report, we have synthesized four morphologically distinct IONPs having the same aspect ratio and similar surface charge, thus offering an ideal system to assess the impact of morphology on nanoparticle-elicited biological effect. We show that morphology was a critical determinant for IONP-induced IL-1beta release and pyroptosis, with the octapod and plate IONPs exhibiting significantly higher activity than the cube and sphere IONPs. The inflammasome-activating capacity of different IONPs correlated with their respective ability to elicit intracellular reactive oxygen species generation, lysosomal damage, and potassium efflux, three well-known mechanisms for nanoparticle-facilitated inflammasome activation. Furthermore, we demonstrate that the release of IL-1beta induced by IONPs was only partly mediated by NLRP3, suggesting that inflammasomes other than NLRP3 are also involved in IONP-induced inflammasome activation. Our results may have implications for designing safer nanoparticles for in vivo applications. PMID- 30398341 TI - Vibrational Properties of Thiolate-Protected Gold Nanoclusters. AB - Over recent years, the field of thiolate-protected gold nanoclusters has made remarkable progress. The successful determination of the structure of some of these clusters by X-ray crystallography was a milestone in this field. X-ray crystallography is arguably the most important technique in the field up to now, and it enabled the study of structure evolution as a function of cluster size. It also shed light on the structure of the Au-S interface. Recently, it has been realized that thiolate-protected gold clusters are very dynamic systems. Metal atoms and ligands can exchange easily between clusters. Furthermore, the adsorbed ligands bear conformational dynamics. Such dynamic effects call for experimental methods that can cope with it. Future efforts in this field will be directed toward applications of thiolate-protected clusters, and many of them will rely on dissolved clusters. Therefore, structure determination in solution is an important issue, though it is very challenging. The structure of the metal core and the Au-S interface is not expected to change in solution with respect to the crystal. However, the structure of the adsorbed ligand itself is sensitive to the environment and may be different in the solid state and in solution, as has been shown in fact in the past. It is this (dynamic) structure of the ligand that determines the interaction between the cluster and its environment, which is crucial, for example, for sensing applications. Vibrational spectroscopy is a promising technique to characterize thiolate-protected clusters in different environments. A vibrational spectrum is sensitive to structure (conformation) although this information is often "hidden" in the spectrum, requiring detailed analysis and support from theory to be deciphered. Compared to other techniques like UV-vis spectroscopy and mass spectrometry, vibrational spectroscopy was not extensively used in the field of thiolate-protected clusters, but we believe that the technique will be very valuable for the future developments in the field. We have used vibrational spectroscopy to investigate thiolate-protected gold clusters for mainly two lines of research. In the first, we studied in detail the low energy region of the vibrational spectrum, in particular the Au-S vibrational modes, in order to understand the structure sensitivity. It emerges that the Au-S vibrational spectrum is indeed sensitive to the structure of the interface but also to other factors, especially the organic part of the thiol, in a complex way. The ability to directly correlate structure, from X-ray crystallography, and vibrational spectra for thiolate-protected clusters, should lead to a database that will help in the future the structure determination of the Au-S interface by vibrational spectroscopy for systems where direct structure determination is not possible, for example, for flat surfaces. A second line of research focused on the determination of the structure of the adsorbed ligands for dissolved clusters. Such information is mostly extracted by the comparison of theoretical and calculated spectra for different conformers. In this respect, vibrational circular dichroism (VCD) is particularly powerful as it strongly depends on the conformation, more than conventional infrared spectroscopy. VCD can be applied to chiral nonracemic compounds, and it is a sensitive probe for chirality. Using this method, it was possible to demonstrate that a cluster can transfer its chirality to achiral thiolate ligands. In this Account, we summarize the possibilities and challenges of vibrational spectroscopy in the field of thiolate protected clusters. PMID- 30398342 TI - A Dual-H-NOX Signaling System in Saccharophagus degradans. AB - Nitric oxide (NO) is a critical signaling molecule involved in the regulation of a wide variety of physiological processes across every domain of life. In most aerobic and facultative anaerobic bacteria, heme-nitric oxide/oxygen binding (H NOX) proteins selectively sense NO and inhibit the activity of a histidine kinase (HK) located on the same operon. This NO-dependent inhibition of the cognate HK alters the phosphorylation of the downstream response regulators. In the marine bacterium Saccharophagus degradans ( Sde), in addition to a typical H-NOX ( Sde 3804)/HK ( Sde 3803) pair, an orphan H-NOX ( Sde 3557) with no associated signaling protein has been identified distant from the H-NOX/HK pair in the genome. The characterization reported here elucidates the function of both H-NOX proteins. Sde 3557 exhibits a weaker binding affinity with the kinase, yet both Sde 3804 and Sde 3557 are functional H-NOXs with proper gas binding properties and kinase inhibition activity. Additionally, Sde 3557 has an NO dissociation rate that is significantly slower than that of Sde 3804, which may confer prolonged kinase inhibition in vivo. While it is still unclear whether Sde 3557 has another signaling partner or shares the histidine kinase with Sde 3804, Sde 3557 is the only orphan H-NOX characterized to date. S. degradans is likely using a dual-H-NOX system to fine-tune the downstream response of NO signaling. PMID- 30398343 TI - High-Resolution Extended X-ray Absorption Fine Structure Analysis Provides Evidence for a Longer Fe...Fe Distance in the Q Intermediate of Methane Monooxygenase. AB - Despite decades of intense research, the core structure of the methane C-H bond breaking diiron(IV) intermediate, Q, of soluble methane monooxygenase remains controversial, with conflicting reports supporting either a "diamond" diiron core structure or an open core structure. Early extended X-ray absorption fine structure (EXAFS) data assigned a short 2.46 A Fe-Fe distance to Q (Shu et al. Science 1997, 275, 515 ) that is inconsistent with several theoretical studies and in conflict with our recent high-resolution Fe K-edge X-ray absorption spectroscopy (XAS) studies (Castillo et al. J. Am. Chem. Soc. 2017, 139, 18024 ). Herein, we revisit the EXAFS of Q using high-energy resolution fluorescence detected extended X-ray absorption fine structure (HERFD-EXAFS) studies. The present data show no evidence for a short Fe-Fe distance, but rather a long 3.4 A diiron distance, as observed in open core synthetic model complexes. The previously reported 2.46 A feature plausibly arises from a background metallic iron contribution from the experimental setup, which is eliminated in HERFD-EXAFS due to the increased selectivity. Herein, we explore the origin of the short diiron feature in partial-fluorescent yield EXAFS measurements and discuss the diagnostic features of background metallic scattering contribution to the EXAFS of dilute biological samples. Lastly, differences in sample preparation and resultant sample inhomogeneity in rapid-freeze quenched samples for EXAFS analysis are discussed. The presented approaches have broad implications for EXAFS studies of all dilute iron-containing samples. PMID- 30398344 TI - Wearable Bioelectronics: Enzyme-Based Body-Worn Electronic Devices. AB - In this Account, we detail recent progress in wearable bioelectronic devices and discuss the future challenges and prospects of on-body noninvasive bioelectronic systems. Bioelectronics is a fast-growing interdisciplinary research field that involves interfacing biomaterials with electronics, covering an array of biodevices, encompassing biofuel cells, biosensors, ingestibles, and implantables. In particular, enzyme-based bioelectronics, built on diverse biocatalytic reactions, offers distinct advantages and represents a centerpiece of wearable biodevices. Such wearable bioelectronic devices predominately rely on oxidoreductase enzymes and have already demonstrated considerable promise for on body applications ranging from highly selective noninvasive biomarker monitoring to epidermal energy harvesting. These systems can thus greatly increase the analytical capability of wearable devices from the ubiquitous monitoring of mobility and vital signs, toward the noninvasive analysis of important chemical biomarkers. Wearable enzyme electrodes offer exciting opportunities to a variety of areas, spanning from healthcare, sport, to the environment or defense. These include real-time noninvasive detection of biomarkers in biofluids (such as sweat, saliva, interstitial fluid and tears), and the monitoring of environmental pollutants and security threats in the immediate surrounding of the wearer. Furthermore, the interface of enzymes with conducting flexible electrode materials can be exploited for developing biofuel cells, which rely on the bioelectrocatalytic oxidation of biological fuels, such as lactate or glucose, for energy harvesting applications. Crucial for such successful application of enzymatic bioelectronics is deep knowledge of enzyme electron-transfer kinetics, enzyme stability, and enzyme immobilization strategies. Such understanding is critical for establishing efficient electrical contacting between the redox enzymes and the conducting electrode supports, which is of fundamental interest for the development of robust and efficient bioelectronic platforms. Furthermore, stretchable and flexible bioelectronic platforms, with mechanical properties similar to those of biological tissues, are essential for handling the rigors of on-body operation. As such, special attention must be given to changes in the behavior of enzymes due to the uncontrolled conditions of on-body operation (including diverse outdoor activities and different biofluids), for maintaining the attractive performance that these bioelectronics devices display in controlled laboratory settings. Therefore, a focus of this Account is on interfacing biocatalytic layers onto wearable electronic devices for creating efficient and stable on-body electrochemical biosensors and biofuel cells. With proper attention to key challenges and by leveraging the advantages of biocatalysis, electrochemistry, and flexible electronics, wearable bioelectronic devices could have a tremendous impact on diverse biomedical, fitness, and defense fields. PMID- 30398345 TI - Protective Epitope Discovery and Design of MUC1-based Vaccine for Effective Tumor Protections in Immunotolerant Mice. AB - Human mucin-1 (MUC1) is a highly attractive antigen for the development of anticancer vaccines. However, in human clinical trials of multiple MUC1 based vaccines, despite the generation of anti-MUC1 antibodies, the antibodies often failed to exhibit much binding to tumor presumably due to the challenges in inducing protective immune responses in the immunotolerant environment. To design effective MUC1 based vaccines functioning in immunotolerant hosts, vaccine constructs were first synthesized by covalently linking the powerful bacteriophage Qbeta carrier with MUC1 glycopeptides containing 20-22 amino acid residues covering one full length of the tandem repeat region of MUC1. However, IgG antibodies elicited by these first generation constructs in tolerant human MUC1 transgenic (Tg) mice did not bind tumor cells strongly. To overcome this, a peptide array has been synthesized. By profiling binding selectivities of antibodies, the long MUC1 glycopeptide was found to contain immunodominant but nonprotective epitopes. Critical insights were obtained into the identity of the key protective epitope. Redesign of the vaccine focusing on the protective epitope led to a new Qbeta-MUC1 construct, which was capable of inducing higher levels of anti-MUC1 IgG antibodies in MUC1.Tg mice to react strongly with and kill a wide range of tumor cells compared to the construct containing the gold standard protein carrier, i.e., keyhole limpet hemocyanin. Vaccination with this new Qbeta-MUC1 conjugate led to significant protection of MUC1.Tg mice in both metastatic and solid tumor models. The antibodies exhibited remarkable selectivities toward human breast cancer tissues, suggesting its high translational potential. PMID- 30398346 TI - Recyclable and Reusable Heteroleptic Nickel Catalyst Immobilized on Metal-Organic Framework for Suzuki-Miyaura Coupling. AB - Metal-organic frameworks (MOFs) provide highly versatile platforms to stabilize molecular catalysts that are not readily accessible under homogeneous conditions, thus enabling access to a new set of catalytic materials. Herein, we describe a recyclable and highly active nickel catalyst immobilized on MOF for Suzuki Miyaura coupling reaction, which operates under mild conditions. This mixed ligand catalyst forms from the combination of 1 equiv of MOF-immobilized ligand, 1 equiv of nickel source, and 1 equiv of PPh3. The nature of the catalyst was verified through a series of analytical tests and catalysis experiments. The immobilized catalyst was reusable for at least up to 7 cycles without decrease in the yield of the coupled product. We also verified that this reaction does not work under homogeneous conditions and that the reaction is truly heterogeneous through "hot filtration" experiments. We identified that the reaction is first order in arylborane concentration and negative order in arylbromide concentration through the effect of substrate concentrations on the initial rate. This informed us to conduct the catalysis under slow addition of the arylbromide and reduce the catalyst loading to 1% from 3%, without detriment to the yield or rate of the reaction. The catalyst gave good to excellent isolated yields with a range of functionalities, including heterocycles on aryl bromide with widely varying electronic properties. PMID- 30398347 TI - Interfacial Interactions of Sucrose during Cryopreservation Detected by Raman Spectroscopy. AB - There is considerable interest in the use of sugars to preserve cells. In this study, low temperature Raman spectroscopy was used to characterize the behaviors of sucrose during freezing. The hydrogen bond network between sucrose and water was investigated at -10 degrees C and -50 degrees C, and the Raman spectra showed strengthened sucrose-water and sucrose-sucrose hydrogen bonds in more concentrated sucrose solution at -50 degrees C. The concentration of sucrose at the ice interface increased as the ice density decreased, and it plateaued across a narrow channel of nonfrozen sucrose solution before it decreased toward the next ice interface. The biophysical environment at interfaces between the cell and nonfrozen sucrose solution and between the cell and extracellular ice was also studied. A thin layer of nonfrozen sucrose solution was observed at the interface between the cell and extracellular ice. The extracellular concentration of sucrose at this interface was generally lower than that of bulk nonfrozen sucrose solution. The variation of sucrose concentration outside different regions of the cell membrane suggests that the chemical environment around the cell during freezing may be more heterogeneous than previously thought. Raman spectra and images also showed colocalization of nonfrozen sucrose solution and the cell, which implied that direct interaction between sucrose and cell membrane might be responsible for protective properties of sucrose. Sucrose was predominantly distributed outside the cell, and the observation of strong partitioning of sucrose across the cell membrane is consistent with substantial cell dehydration detected by the Raman spectra. This work enhances our understanding of the behaviors of sucrose solution and its interactions with cells at low temperature and can improve cryopreservation protocols of cells frozen in a sucrose-based media. PMID- 30398348 TI - Role of Mono- and Divalent Surface Cations on the Structure and Adsorption Behavior of Water on Mica Surface. AB - Understanding solid-water(vapor) interfacial systems is relevant for both industrial and academic scenarios for their presence in wide areas ranging from tribology to geochemistry. Using grand canonical Monte Carlo simulations, we have investigated the role of monovalent (lithium, Li+; sodium, Na+; and potassium, K+) and divalent (magnesium, Mg2+; calcium, Ca2+) cations on the structure and adsorption behavior of water on mica surface. The water density adjacent to the surface exhibits (a) oscillations due to hydration of surface cations (interfacial layer), (b) followed by a thick liquidlike layer. The thickness of the interfacial layer is strongly dependent on the hydration shell size and hydration energy of surface ions. Water molecules immediately next to the surface (contact layers) adsorb on ditrigonal (hexagonal) cavities of mica surface and form an ordered structure. The Li+, Na+, Mg2+, and Ca2+ surface ions are coadsorbed with water molecules on the ditrigonal cavities due to their smaller hydration shell. Majority of water molecules in the second contact layer hydrate the surface ions and, together with the rest of the water molecules, form hydrogen bonds among themselves. The structure of the water molecules in the third and subsequent layer is random and more bulk liquidlike, except those molecules that hydrate the surface ions. The adsorption isotherm of water on all ion-exposed mica surface exhibits three regimes: (a) an initial rapid increase in water loading for relative vapor pressure ( p/ p0) <=0.2 due to hydration of surface ions; (b) followed by a linear increase between p/ p0 = 0.2 and 0.7, where the hydrogen bond formation between the water molecules of the interfacial layer occurs; and (c) exponential growth beyond p/ p0 = 0.7 due to thickening of the liquidlike layer. The water loading on divalent-ion-exposed mica surface is higher compared to the monovalent ions case. Although the divalent ions have higher hydration energy, the fraction of water molecules hydrating the surface ions is less compared to nonhydrating water molecules. We found that ion hydration energy and size of hydration shell play a crucial role in their structure adjacent to mica surface. At lower water loadings, the surface ions form a hydration shell with surface bridging oxygens, whereas at higher water content, the hydration preference is shifted toward mobile water molecules. The detailed understanding obtained from this work will be useful in identifying the role of ions in cloud formation, nanotribological studies, and activities of biological molecules and catalysts. PMID- 30398349 TI - Application of the Systematic Molecular Fragmentation by Annihilation Method to ab Initio NMR Chemical Shift Calculations. AB - NMR is a powerful tool for obtaining information on the structural characterization and dynamics of proteins, and nucleic acids, and their complexes. The complexity of the spectra is such that elucidation through computational simulation is a much desired thing. However, the size of most structures of interest is such that they remain out of reach of accurate quantum chemical techniques. Fragmentation methods have been shown to be a viable means of reducing the cost of ab initio calculations to enable the prediction of molecular properties of large systems to chemical accuracy. We look at the systematic molecular fragmentation by annihilation method for a model peptide system and show that this procedure reproduces the shielding constants of a full calculation at only a fraction of the cost. Discussion of the considerations needed in applying this method is discussed and comparison made with the results of the similar fragment molecular orbital and ONIOM methods. PMID- 30398351 TI - Gold Nanorods/Polypyrrole/m-SiO2 Core/Shell Hybrids as Drug Nanocarriers for Efficient Chemo-Photothermal Therapy. AB - Combination therapy as a novel strategy with the combination of photothermal therapy and chemotherapy (photothermal-chemotherapy) has aroused the tremendously increasing interest owing to the synergistic therapeutic effect on destroying cancer cells because the hyperthermia generated from photothermal therapy can promote drug delivery into tumors, which would highly increase therapeutic efficacy as compared to those sole treatments. Herein, we fabricated a novel nanomaterial-based carrier composed of gold nanorods (GNRs), polypyrrole (PPy), and mesoporous silica to form GNRs/PPy/m-SiO2 core/shell hybrids. After loading the anticancer drug of doxorubicin (DOX), the photothermal effect and the drug release behavior of GNRs/PPy@m-SiO2-DOX hybrids were investigated. The in vitro and in vivo near-infrared (NIR) photothermal-chemotherapy were also revealed. The results indicated that the NIR-induced photothermal effect was beneficial to promote the release of the drug. In addition, combination therapy demonstrated the enhanced synergistic efficacy and excellent treatment efficacy for cancer therapy. PMID- 30398350 TI - Fabrication of Few-Layered Porous Graphite for Removing Fluorosurfactant from Aqueous Solution. AB - Due to the persistence, toxicity, and widespread occurrence of fluorosurfactants in the blood of general population, it is very important to develop recyclable and highly effective adsorbent material for their removal from aqueous solution. Herein, a new type of few-layered porous graphite (FPG) was fabricated as an adsorbent, and the adsorption characteristics of FPG toward potassium perfluorobutane sulfonate (PFBS), potassium perfluorohexane sulfonate (PFHxS), and potassium perfluorooctane sulfonate (PFOS) in environmental cleanup were evaluated under laboratory condition. The results indicated that the as-prepared FPG had sorption capacities of 1.22, 1.52, and 2.48 mmol g-1 for PFBS, PFHxS, and PFOS, respectively, which were the highest adsorption values of PFHxS, PFBS, and PFOS on different kinds of today's carbon materials. The efficiency of FPG remained almost constant during the first five cycles of the adsorption desorption process after heating. The outstanding adsorption performance of FPG was attributed to its unique physical properties, such as high porosity, high hydrophobicity, low density, and excellent heat stability. The findings presented herein indicated that FPG could serve as a promising adsorbent for the removal of fluorosurfactant in waste water. PMID- 30398352 TI - Rhodium-Catalyzed Annulation of alpha-Imino Carbenes with alpha,beta-Unsaturated Ketones: Construction of Multisubstituted 2,3-Dihydropyrrole/pyrrole Rings. AB - An efficient annulation of alpha-imino rhodium carbenes with alpha,beta unsaturated ketones has been developed to generate multisubstituted 2,3 dihydropyrrole derivatives. Using the optimized catalyst, this approach is compatible with both cyclic and normal linear alpha,beta-unsaturated ketones. Further detosylation in the presence of base could produce multisubstituted pyrroles. The new method has the potential to enable the rapid construction of bioactive molecules containing pyrrole rings. PMID- 30398353 TI - Catalytic Asymmetric Hydrophosphination of ortho-Quinone Methides. AB - An efficient catalytic asymmetric hydrophosphination of ortho-quinone methides with H-phosphine oxides is established. A chiral bifunctional squaramide is superior to catalyze this enantioselective carbon-phosphorus bond formation, delivering optically active alpha-arylmethyl phosphine oxides in high yields with high enantioselectivities (up to 94% yield, 99:1 er). Additionally, employing in situ-generated o-QMs for this hydrophosphination step economically provides the corresponding phosphine oxides with comparable yield and enantioselectivity. PMID- 30398354 TI - The Jones-Ray Effect Is Not Caused by Surface-Active Impurities. AB - Pure aqueous electrolyte solutions display a minimum in surface tension at concentrations of 2 +/- 1 mM. This effect has been a source of controversy since it was first reported by Jones and Ray in the 1930s. The Jones-Ray effect has frequently been dismissed as an artifact linked to the presence of surface-active impurities. Herein we systematically consider the effect of surface-active impurities by purposely adding nanomolar concentrations of surfactants to dilute electrolyte solutions. Trace amounts of surfactant are indeed found to decrease the surface tension and influence the surface chemistry. However, surfactants can be removed by repeated aspiration and stirring cycles, which eventually deplete the surfactant from solution, creating a pristine surface. Upon following this cleaning procedure, a reduction in the surface tension by millimolar concentrations of salt is still observed. Consequently, we demonstrate that the Jones-Ray effect is not caused by surface-active impurities. PMID- 30398355 TI - Enhanced Antibacterial and Food Simulant Activities of Silver Nanoparticles/Polypropylene Nanocomposite Films. AB - In this work, we synthesize dodecyl mercaptan-functionalized silver nanoparticles integrated with polypropylene nanocomposite (DM-AgNPs/PP) substrates by a simple in situ melt blending method. The formation and distribution of AgNPs are confirmed by UV-visible spectroscopy, Fourier transform infrared spectroscopy, transmission electron microscopy, and thermogravimetric analysis. The existence of DM-AgNPs in PP film substrate enhances the thermal degradation and crystallization properties. Further, the antimicrobial activity of as-synthesized DM-AgNPs/PP film substrate is studied using Gram-negative ( Escherichia coli) and Gram-positive ( Staphylococcus aureus) bacteria as model microbes, which displayed significantly enhanced bacteriostatic activities under optimized composition and experimental conditions. Interestingly, PP substrate with 0.4% DM AgNPs exhibits drastically improved antibacterial property via the release of oxygen reactive species and Ag ion diffusion processes; thus, the inhibition rates of E. coli and S. aureus are obtained as 100 and 84.6%, respectively, which is higher than the conventional AgNPs. Finally, we demonstrate the migration study of Ag ions from the DM-AgNPs/PP film using different food simulant solutions by inductively coupled plasma-mass spectrometry analysis and the dissolved Ag ion content is estimated, which is a key prospect for the toxicity analysis. The overall Ag ion migration value is estimated between 1.8 and 24.5 MUg/cm2 and displayed a lowest limit of Ag ion migration as 0.36 MUg/cm2. Our work highlights the development of high performance nanocomposites as promising antibacterial and food simulant materials for biomedical and industrial applications. PMID- 30398357 TI - Partially Naked Fluoride in Solvate Ionic Liquids. AB - Truly naked fluoride exists only in the gas phase. Fluoride can be stabilized by a complexing agent and an organic cation, resulting in anhydrous or dehydrated fluoride which is "partially naked." This partially naked fluoride enables fluorination reactions at much lower temperatures than hydrated fluorides. Here we show a simple method for preparing fluoride-based solvate ionic liquids (SILs) by mixing 1-alkyl-3-methylimidazolium (1-ethyl-3-methylimidazolium or 1-butyl-3 methylimidazolium) bromide, silver fluoride (AgF), and EG (1:1:1 in molar ratio) in dry methanol. Removal of the methanol produced anhydrous SILs, [C2C1im]F.EG and [C4C1im]F.EG. This is the first SIL reported that comprises fluoride. 1H NMR and infrared spectroscopy reveal fluoride hydrogen bonds with EG OH groups and cation aromatic H atoms but not cation tail group protons. Fluorination reactions on benzyl bromide show that [C2C1im]F.EG has high reactivity with reasonable yield under mild conditions, confirming the fluoride ion is partially naked. PMID- 30398356 TI - Double-Stranded RNAs High-Efficiently Protect Transgenic Potato from Leptinotarsa decemlineata by Disrupting Juvenile Hormone Biosynthesis. AB - RNA interference (RNAi) has been developed for plant pest control. In this study, hairpin-type double-stranded RNA (dsRNA) targeting the juvenile hormone (JH) acid methyltransferase ( JHAMT) gene ( dsJHAMT) was introduced in potato plants via Agrobacterium-mediated transformation. The results indicated that the transcriptional RNA of dsJHAMT accumulated in the transgenic plants. The transcripts and proteins of the L. decemlineata JHAMT gene were significantly reduced in larvae feeding on dsJHAMT transgenic foliage. The dsJHAMT had a significant negative effect on the growth and development of L. decemlineata, especially resulting in less oviposition. Importantly, in the field trials, transgenic plants are high-efficiently protected from insect damage mainly because surviving insects laid fewer or no eggs. Even full protection from beetle damage can be acquired by continuously lowering insect population size at large scale in the field over the years. Therefore, the transgenic plants expressing dsJHAMT successfully provided an additional option for plant pest control. PMID- 30398358 TI - Self-Assembly of Amphiphilic Schiff Base and Selectively Turn on Circularly Polarized Luminescence by Al3. AB - We designed glutamide-derived amphiphilic Schiff bases containing three different aldehyde moieties for the fabrication of circularly polarized luminescence (CPL) emitting materials. Upon self-assembly in acetonitrile, Schiff bases featuring 4 (dimethylamino)-2-hydroxylbenzaldehyde and 1-hydroxy-2-naphthaldehyde groups form supramolecular gels with twist and fiber structures, respectively, whereas Schiff bases featuring 2-hydroxy-1-naphthaldehyde groups form precipitation with flake structures. Although emission and circular dichroism signals can be detected from the supramolecular gels formed by amphiphilic Schiff bases, none of them exhibits a circularly polarized luminescence (CPL). Although Mg2+, Zn2+, and Al3+ can significantly enhance the fluorescence of the Schiff bases, interestingly, only Al3+ ion is able to turn on the CPL emission. This study on the one hand provides a simple method for the fabrication of CPL-emitting supramolecular materials and on the other hand offers a novel way for the sensing of aluminum ion with supramolecular materials. PMID- 30398359 TI - Synthesis of Quinolines and Pyrido[3,2- g or 2,3- g]quinolines Catalyzed by Heterogeneous Propylphosphonium Tetrachloroindate Ionic Liquid. AB - This report explains an efficient method for synthesis of an array of quinolines via the reaction of 2-aminoaryl ketones with terminal and internal alkynes in the presence of propylphosphonium tetrachloroindate ionic liquid supported on nanosilica (PPInCl-nSiO2) as a heterogeneous and reusable catalyst under solvent free conditions. Inspired by this catalytic system, the first easy one-step synthesis of symmetric and unsymmetric pyrido[3,2- g or 2,3- g]quinolines was investigated through the reaction of diaroylphenylenediamines with one alkyne or two different alkynes. PMID- 30398360 TI - Nanoscale Study of Bubble Nucleation on a Cavity Substrate Using Molecular Dynamics Simulation. AB - In this paper, the molecular dynamics simulation method is utilized to investigate the phase transition behavior of an argon film placed on cavity substrates with different wettability conditions. A simple Lennard-Jones liquid is heated by a metal platinum substrate at different temperatures, and a complete process of bubble nucleation is successfully visualized on the cavity substrate at temperatures of 150 and 160 K. Moreover, the bubble nucleation behavior shows dependence on cavity wettability. A layer of liquid atom is attracted to the strongly hydrophilic cavity and obtains more energy to nucleate first. In contrast, the liquid atom suffers a large repulsive force from the metal atom in the hydrophobic cavity, thus an original small bubble nucleus stably stays inside before the incipient boiling time. With an increase in the heating time, the original bubble nucleus grows up from the hydrophobic cavity. This bubble nucleation behavior on a hydrophobic cavity is in agreement with macro theory, which states that a cavity provides an original nucleus for bubble formation and growth. Besides, cavity wettability plays a crucial role in the incipient boiling temperature of an argon film. The incipient boiling temperature increases with the weakening of the cavity hydrophobicity, and this trend is in accordance with macro experiments, which show that liquid is easier to boil on a more hydrophobic substrate. PMID- 30398362 TI - Two new sesquiterpenoids from the marine-sediment-derived fungus Trichoderma harzianum P1-4. AB - Three cyclonerane sesquiterpenoids, including the known cyclonerodiol (1), together with its new derivatives, (10E)-12-acetoxy-10-cycloneren-3,7 -diol (2) and 12-acetoxycycloneran-3,7-diol (3) were isolated from the cultures of marine sediment-derived fungus Trichoderma harzianum P1-4. The structures of the new compounds (2 and 3) were elucidated based on extensive spectroscopic methods (1D/2D NMR and HR-MS) and optical rotation analysis. PMID- 30398361 TI - Mucosal T helper 17 and T regulatory cell homeostasis correlates with acute SIV viremia and responsiveness to antiretroviral therapy in macaques. AB - Depletion of gut T helper 17 (Th17) cells during HIV infection leads to decreased mucosal integrity and increased disease progression. Conversely T regulatory (Treg) cells may inhibit antiviral responses or immune activation. In HIV elite controllers, a balanced Th17/Treg ratio is maintained in the blood, suggesting a role for these responses in controlling inflammation and viral replication. HIV infected individuals exhibit a range in responsiveness to combination antiretroviral therapy (cART). Given the link between the Th17/Treg ratio and HIV disease, we reasoned these responses may play a role in cART responsiveness. Here, we investigated the relationship between the mucosal Th17/Treg ratio to acute SIV viremia and the response to cART. Nineteen rhesus macaques were infected with highly pathogenic SIVDeltaB670 virus and cART was initiated 6 weeks post-infection. Mucosal CD4 T-cell subsets were assessed by intracellular cytokine staining (ICS) in the colon and mesenteric lymph nodes. Higher baseline Th17/Treg ratios corresponded with increased acute SIV viremia. Th17/Treg ratios decreased during acute SIV infection and were not restored during cART, and this corresponded to increased gut immune activation (Ki67+), markers of microbial translocation (sCD14), and T-cell exhaustion (TIGIT+). Animals that maintained a more balanced mucosal Th17/Treg ratio at the time of cART initiation exhibited a better virological response to cART and maintained higher peripheral CD4 counts. These results suggest mucosal Th17 and Treg homeostasis influences acute viremia and the response to cART, a result that suggests therapeutic interventions that improve the Th17/Treg ratio before or during cART may improve treatment of HIV. PMID- 30398363 TI - A new source of oxygenated monoterpenes with phytotoxic activity: essential oil of Cuminum Cyminum L. from Iran. AB - Chemical constitutes and phytotoxic activity of Cuminum cymiunm L. is investigated in the present study. For this means seeds of C. cyminum L. was harvested from Ilkhchi of Iran. The major components of essential oil (EO) with more than 94% were 3-caren-10-al, cuminal, 2-Caren-10-al, gamma-Terpinene, (-) beta-Pinene and p-Cymene. This study found that cumin EO displayed meaningful inhibitory impacts on germination indices and the growth of the seedlings of Amaranthus retroflexus, Lactuca sativa, and Acroptilon repens. The germination indices showed severely concentration-dependent responses. In the case of A. retroflexus and L. sativa germination indices were controlled in the 500 ppm and in the A. repens were inhibited in the 1500 ppm of EO concentration. Overall, this study suggests that EO derived from C. cyminum L. looks to be a promising candidate for its utilization as a natural herbicide in large scale. PMID- 30398364 TI - A new oleanane triterpene from the leaves of Ficus hirta. AB - Repeated column chromatography of the n-hexane extract of Ficus hirta leaves (Moraceae) led to isolation of a new oleanane triterpene, 3beta-hydroxy-11-oxo olean-12-enyl-3-stearate (1) in addition to three known compounds, taraxerol (2), 3beta-acetoxy-11alpha-methoxy-12-ursene (3) and 3beta-acetoxy-11alpha-hydroxy-12 ursene (4). Their structures were elucidated by spectroscopic methods and by comparison with data reported in the literatures. PMID- 30398365 TI - Chemical constituents, Antibacterial and Acetylcholine esterase inhibitory activity of Cupressus macrocarpa leaves. AB - The chemical constituents of Cupressus macrocarpa were investigated. A new neolignan glycoside (1) in addition to nine known compounds were isolated. The acetylcholinesterase (AChE) inhibitory activity and antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) of different fractions and isolates of C. macrocarpa were evaluated. The light petroleum fraction showed the highest activity in both assays with IC50 value of 88.79 ug/ml and 152.58 ug/ml for the AChE inhibitory activity and MRSA antibacterial activities, respectively. Weak to moderate activity were detected for the isolated compounds. PMID- 30398366 TI - Safety and Efficacy of Retroperitoneoscopic Living Donor Nephrectomy: Comparison of Early Complication, Donor and Recipient Outcome with Hand-Assisted Laparoscopic Living Donor Nephrectomy. AB - INTRODUCTION: Laparoscopic surgery has been a standard procedure of living donor nephrectomy. Transperitoneal hand-assisted laparoscopic living donor nephrectomy (HALDN) has been commonly reported by many centers with excellent outcome. However, there are few studies reporting retroperitoneoscopic living donor nephrectomy (RPLDN). METHODS: Four hundred four consecutive kidney donors (124 men, 280 women) were enrolled in this study. Age of the donors was 55.0 +/- 10.7 years. RPLDN was performed for 294 donors, and HALDN for 110 donors. We compared perioperative donor outcome and early complication rates between RPLDN and HALDN to evaluate the safety and efficacy of RPLDN. RESULTS: Intraoperative blood loss was significantly less in the RPLDN than in HALDN (P<0.05). The conversion rate to open surgery was similar between the two groups. The intraoperative complication rate was 1.0% (2 vascular injury, 1 bowel injury) in RPLDN and 0.9% (1 vascular injury) in HALDN. The postoperative complication rate was 3.4% (6 surgical site infection, 2 postoperative bleeding, 1 ileus, 1 rhabdomyolysis) in RPLDN and 1.8% (2 surgical site infection) in HALDN. Although warm ischemic time was significantly longer in RPLDN than in HALDN (P<0.01), the incidence of delayed graft function was similar between the two groups. Furthermore, there was no difference in 1-year graft survival between the two groups. CONCLUSIONS: Both RPLDN and HALDN procedures were well tolerated with minimal complication rates, and both procedures showed similar impact on recipient graft function. These results suggest that RPLDN could be a feasible option for living donor nephrectomy as well as HALDN. . PMID- 30398368 TI - Forward dynamic optimization of handle path and muscle activity for handle based isokinetic wheelchair propulsion: A simulation study. AB - Push-rim wheelchair propulsion is biomechanically inefficient and physiologically stressful to the musculoskeletal structure of human body. This study focuses to obtain a new, optimized propulsion shape for wheelchair users, which is within the ergonomic ranges of joint motion, thus reducing the probability of injuries. To identify the propulsion movement, forward dynamic optimization was performed on a 3D human musculoskeletal model linked to a handle based propulsion mechanism, having shape and muscle excitations as optimization variables. The optimization resulted in a handle path shape with a circularity ratio of 0.95, and produced a net propulsion power of 34.7 watts for an isokinetic propulsion cycle at 50 rpm. Compared to push-rim propulsion, the compact design of the new propulsion mechanism along with the ergonomically optimized propulsion shape may help to reduce the risk of injuries and thus improve the quality of life for wheelchair users. PMID- 30398367 TI - Effective Connectivity Within the Default Mode Network In Left Temporal Lobe Epilepsy: Findings from the Epilepsy Connectome Project. AB - The Epilepsy Connectome Project examines the differences in connectomes between temporal lobe epilepsy (TLE) patients and healthy controls. Using this data, the effective connectivity of the default mode network in patients with left TLE compared to healthy controls was investigated using spectral dynamic causal modeling of resting state functional magnetic resonance imaging data. Group comparisons were made using two parametric empirical Bayes (PEB) models. The first level of each PEB model consisted of each participant's spectral dynamic causal modeling. Two different second level models were constructed: the first comparing effective connectivity of the groups directly and the second using the Rey Auditory Verbal Learning Test (RAVLT) delayed free recall index as a covariate at the second level in order to assess effective connectivity controlling for the poor memory performance of left TLE patients. After an automated search over the nested parameter space and thresholding parameters at 95% posterior probability, both models revealed numerous connections in the DMN which lead to inhibition of the left hippocampal formation. Left hippocampal formation inhibition may be an inherent result of the left temporal epileptogenic focus as memory differences were controlled for in one model and the same connections remained. An excitatory connection from the posterior cingulate cortex to the medial prefrontal cortex was found to be concomitant with left hippocampal formation inhibition in TLE patients when including RAVLT delayed free recall at the second level. PMID- 30398369 TI - Assessment of residual stone fragments after retrograde intrarenal surgery. AB - OBJECTIVES: To define the most suitable approach to assess residual stone fragments after RIRS. METHODS: Ninety two patients (115 renal units) submitted to RIRS for symptomatic kidney stones > 5 mm and < 20 mm or < 15 mm in the lower calyx diagnosed by noncontrast computed tomography (NCCT) were prospectively studied. Residual fragments were assessed by endoscopic evaluation (END) at the end of the procedure and by NCCT, ultrasound (US) and Kidneys-Ureter-Bladder X ray (KUB) performed at the 90th postoperative-day (POD). NCCT was considered the gold standard for the evaluation of residual fragments after RIRS. RESULTS: 90th POD NCCT resulted stone free in 74.8% (86/115), 0 - 2 mm in 8.7% (10/115) and > 2 mm residual fragments in 16.5% (19/115) renal units. Stone-free status by END at the end of RIRS was coincident to NCCT in 93.0% of the cases (40/43). There were no cases of residual fragments > 2 mm on NCCT if END resulted stone free. In all cases that END resulted residual fragments > 2 mm, US was correct according to NCCT. Neither US nor KUB were able to identify residual fragments between 0 - 2 mm. KUB had only 31.6% (6/19) sensitivity to detect residual fragments > 2 mm and did not add sensitivity or specificity to US. CONCLUSIONS: In the follow-up imaging after RIRS, we suggest that if endoscopic evaluation resulted in residual fragments < 2 mm, a 90th POD NCCT should be performed. Ultrasound may be used if endoscopic evaluation showed fragments > 2 mm. PMID- 30398370 TI - Phytochemical constituents and antimicrobial activity of Allium Eriophyllum Var. Eriophyllum from Iran. AB - The aerial parts of Allium eriophyllum Var. eriophyllum (Syn. A. longisepalum Bertol.) were collected at full flowering stage.The essential oil was isolated by hydro distillation and analyzed by a combination of capillary GC and GC-MS. The main components were carvacrol (71.54%), Methyl (methylthio) methyl disulfide (9.51%), (E)-caryophyllene (8.37%) and beta-bisabolene (4.38%). The in vitro antimicrobial activity of the essential oil of A. eriophyllum were studied against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli and Candida albicans. The results of the bioassays showed that the oil exhibited high antimicrobial activity against all the tested pathogens compared standard antibiotics. PMID- 30398371 TI - Addressing Psychometric Limitations of the Attentional Control Scale via Bifactor Modeling and Item Modification. AB - The purpose of this three-part study was to identify and correct psychometric limitations of the Attentional Control Scale (ACS; Derryberry & Reed, 2002 ) via bifactor modeling and item modification. In Study 1 (N = 956), results from exploratory factor analyses (EFAs) and confirmatory factor analyses (CFAs) suggested that the multidimensionality of the ACS might be a function of a method effect (i.e., reverse coding). In Study 2 (N = 478), reverse-coded items were recoded in a straightforward manner and submitted to EFA. Results supported retention of 15 items and 2 factors. In Study 3 (N = 410), CFA was used to test the model identified in Study 2 and compare it to competing models (i.e., 1 factor, bifactor). The bifactor model exhibited the best fit to the data. However, results from bifactor analysis suggested that the structure of the ACS is more consistent with a unidimensional rather than multidimensional model. Additionally, the second domain-specific factor appears to be redundant with the general factor and both domain-specific factors are poorly defined and might be of little practical value. Taken together, results caution the use of the ACS subscales independent of the total score. Moreover, they support coding ACS items in a straightforward manner. PMID- 30398372 TI - Coumarins and flavones from the fruit and root extracts of Micromelum integerrimum. AB - A phytochemical investigation of the fruit and root extracts of Micromelum integerrimum resulted in the isolation and identification of a new compound, integerravone (1), together with 23 known compounds (2-24). Their structures were characterized by spectroscopic methods as well as comparisons made from the literature. Compounds 2, 3-15, 17-18 and 20-23 were evaluated for their cytotoxicities against the colon cancer cell line, HCT116. All of them were inactive at 50 uM. Most of the phenolic compounds were evaluated for their antioxidant activity using the DPPH assay. Compounds 14 and 22-24 showed antioxidant activity with IC50 values ranging from 24.83-135.05 uM. PMID- 30398373 TI - Test-retest reliability of graph theoretic metrics in adolescent brains. AB - Graph theory analysis of structural brain networks derived from diffusion tensor imaging (DTI) has become a popular analytical method in neuroscience, enabling advanced investigations of neurological and psychiatric disorders. The purpose of this study was to investigate: 1) the effects of edge weighting schemes, and 2) the effects of varying interscan periods on graph metrics' test-retest reliability within the adolescent brain. We compared a binary (B) network definition with three weighting schemes: fractional anisotropy (FA), streamline count (SC), and streamline count with density and length correction (SDL). Two commonly used global and two local graph metrics were examined. The analysis was conducted with two groups of adolescent volunteers who received DTI scans either 12 weeks apart (16.62+/-1.10yrs) or within the same scanning session (30 minutes apart) (16.65+/-1.14yrs). The intraclass correlation coefficient (ICC) was used to assess test-retest reliability and the coefficient of variation (CV) was used to assess precision. On average, each edge scheme produced reliable results at both time intervals. Weighted measures outperformed binary measures, with SDL weights producing the most reliable metrics. All edge schemes except FA displayed high CV values, leaving FA as the only edge scheme that consistently showed high precision while also producing reliable results. Overall findings suggest that FA weights are more suited for DTI connectome studies in adolescents. PMID- 30398374 TI - A computational approach to investigate optimal cutting speed configurations in rotational needle biopsy cutting soft tissue. AB - The rotational cutting method has been used in needle biopsy technologies to sample tough tissues, such as calcifications in the breast. The rotational motion of the needle introduces shear forces to the cutting surface such that the cutting force in the axial direction is reduced. As a result, tissue samples with large volume and better quality can be obtained. In order to comprehensively understand the effect of the needle rotation to the axial cutting force under a wide range of the needle insertion speed, this paper demonstrates a computational approach that incorporates the surface-based cohesive behavior to simulate a rotating needle cutting soft tissue. The computational model is validated by comparing with a cutting test dataset reported in the literature. The validated model is then used to generate response surfaces of the axial cutting force and torque in a large parameter space of needle rotation and insertion speeds. The results provide guidelines for selecting optimal speed configurations under different design situations. PMID- 30398375 TI - Sulfation of hesperetin, naringenin and apigenin by the human cytosolic sulfotransferases: a comprehensive analysis. AB - Previous studies have revealed sulfation as a major pathway for the metabolism of hesperetin, naringenin and apigenin. The current study was designed to identify the human cytosolic sulfotransferase (SULT) enzyme(s) capable of sulfating these flavonoid compounds. Of the thirteen human SULTs, six (1A1, 1A2, 1A3, 1B2, 1C4, 1E1) displayed significant sulfating activity toward hesperetin, five (1A1, 1A2, 1A3, 1B2, 1C4) displayed sulfating activity towards naringenin, and four (1A1, 1A2, 1A3, 1C4) showed sulfating activity towards apigenin. Of the four human organ specimens tested, liver and intestine cytosols displayed much higher hesperetin-, naringenin- and apigenin-sulfating activity than lung and kidney cytosols. Moreover, sulfation of hesperetin, naringenin and apigenin was shown to take place in HepG2 human hepatoma cells and Caco-2 human colon adenocarcinoma cells under cultured conditions. Taken together, these results provided a biochemical basis underlying the metabolism of hesperetin, naringenin and apigenin through sulfation in humans. PMID- 30398376 TI - Commute Time as a Method to Explore Brain Functional Connectomes. AB - Graph theory has been extensively applied to investigate the brain complex networks in current neuroscience research. Many metrics derived from graph theory, such as local and global efficiencies, are based on the path length between nodes. These approaches are commonly used in the analyses of brain networks assessed by resting-state fMRI, though relying on the strong assumption that information flow throughout the network is restricted to the shortest paths. In this study, we propose the utilization of the commute time as a tool to investigate regional centrality on the functional Connectome. Our initial hypothesis was that an alternative approach that considers alternative routes (such as the commute time) could provide further information into the organization of functional networks. However, our empirical findings on the ADHD 200 database suggest that, at the group level, the commute time and shortest path are highly correlated. In contrast, at the subject level, we discovered that the commute time is much less susceptible to head motion artifacts when compared to metric based on shortest paths. Given the overall similarity between the measures, we argue that commute time might be advantageous particularly for connectomic studies in populations where motion artifacts are a major issue. PMID- 30398377 TI - Signaling Events Downstream of AHR Activation That Contribute to Toxic Responses: The Functional Role of an AHR-Dependent Long Noncoding RNA ( slincR) Using the Zebrafish Model. AB - BACKGROUND: A structurally diverse group of chemicals, including dioxins [e.g., 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD)] and polycyclic aromatic hydrocarbons (PAHs), can xenobiotically activate the aryl hydrocarbon receptor (AHR) and contribute to adverse health effects in humans and wildlife. In the zebrafish model, repression of sox9b has a causal role in several AHR-mediated toxic responses, including craniofacial cartilage malformations; however, the mechanism of sox9b repression remains unknown. We previously identified a long noncoding RNA, sox9b long intergenic noncoding RNA ( slincR), which is increased (in an AHR dependent manner) by multiple AHR ligands and is required for the AHR-activated repression of sox9b. OBJECTIVE: Using the zebrafish model, we aimed to enhance our understanding of the signaling events downstream of AHR activation that contribute to toxic responses by identifying: a) whether slincR is enriched on the sox9b locus, b) slincR's functional contributions to TCDD-induced toxicity, c) PAHs that increase slincR expression, and d) mammalian orthologs of slincR. METHODS: We used capture hybridization analysis of RNA targets (CHART), qRT-PCR, RNA sequencing, morphometric analysis of cartilage structures, and hemorrhaging screens. RESULTS: The slincR transcript was enriched at the 5' untranslated region (UTR) of the sox9b locus. Transcriptome profiling and human ortholog analyses identified processes related to skeletal and cartilage development unique to TCDD-exposed controls, and angiogenesis and vasculature development unique to TCDD-exposed zebrafish that were injected with a splice-blocking morpholino targeting slincR. In comparison to TCDD exposed control morphants, slincR morphants exposed to TCDD resulted in abnormal cartilage structures and a smaller percentage of animals displaying the hemorrhaging phenotype. In addition, slincR expression was significantly increased in six out of the sixteen PAHs we screened. CONCLUSION: Our study establishes that in zebrafish, slincR is recruited to the sox9b 5' UTR to repress transcription, can regulate cartilage development, has a causal role in the TCDD-induced hemorrhaging phenotype, and is up-regulated by multiple environmentally relevant PAHs. These findings have important implications for understanding the ligand-specific mechanisms of AHR mediated toxicity. https://doi.org/10.1289/EHP3281. PMID- 30398378 TI - Antioxidant coumarin and pyrone derivatives from the insect-associated fungus Aspergillus Versicolor. AB - Two new compounds, versicolones A and B (1 and 2), and three known pyrone derivatives (3-5) were isolated from the insect-associated fungus Aspergillus versicolor. Their structures were elucidated through a combination of HRESIMS and NMR spectroscopic analysis. Versicolone A (1) was revealed as a coumarin derivative with the rare 5-alkyl side chain substitution. Compound 5 exhibited significant antioxidant activity with EC50 value of 8.0 MUM in the ABTS (2,2 azino-bis-3-ethylbenzothiazoline-6-sulfonic acid) assay, which was more than 2 fold potency of the positive control trolox. PMID- 30398380 TI - A new furan derivative from an endophytic Aspergillus tubingensis of Decaisnea insignis (Griff.) Hook.f. & Thomson. AB - A new furan derivative named 3-(5-oxo-2,5-dihydrofuran-3-yl) propanoic acid (1) was isolated for the first time. Its structure was elucidated by UV, IR, NMR, HR ESI-MS and the single-crystal X-ray diffraction spectroscopic data. Meanwhile, the antifungal and antibacterial activities of compound 1 was tested, it exhibited potent antifungal activity against Fusarium graminearum with MIC value of 16 ug/mL and medium antibacterial activity against Streptococcus lactis with MIC value of 32 ug/mL. PMID- 30398379 TI - Identification of Subclinical Language Deficit using Machine Learning Classification based on Post-stroke Functional Connectivity derived from Low Frequency Oscillations. AB - Post-stroke neuropsychological evaluation can take a long time to assess impairments in subjects without overt clinical deficits. We utilized functional connectivity (FC) from ten-minute non-invasive resting-state functional MRI (rs fMRI) to identify stroke subjects at risk for subclinical language deficit (SLD) using a machine learning classifier. Discriminative ability of FC derived from slow-4 (0.027-0.073 Hz), slow-5 (0.01-0.027 Hz) and low frequency oscillations (LFO; 0.01-0.1 Hz) were compared. Sixty clinically non-aphasic right-handed subjects were categorized into three groups based on stroke status and normalized verbal fluency score (VFS): 20 ischemic stroke subjects at a higher risk of SLD (LD+; mean VFS=-1.77), 20 ischemic stroke subjects with lower risk of SLD (LD-; mean VFS=-0.05), 20 healthy controls (HC; mean VFS=0.29). T1-weighted and rs-fMRI scans were acquired within 30 days of stroke onset. Blood-oxygen-level-dependent signal was extracted from regions in the language network and FC based on Pearson's correlation was evaluated. Selected features were used by a multiclass support vector machine to classify test subject into one of the subgroups. Classifier performance was assessed using a nested leave-one-out cross validation. FC derived from slow-4 (70%) band provided the best accuracy in comparison to LFO (65%) and slow-5 (50%) , reasonably higher than random chance (33.33%). Based on subgroup-specific accuracy, classification was best realized within the slow-4 band for LD+ (81.6%) and LD- (78.3%) and slow-4 and LFO bands for HC (80%), i.e., early stage stroke subjects showed a slow-4 FC dominance whereas HC also indicated the normalized involvement of FC in LFO. While frontal FC differentiated between stroke and healthy, occipital FC differentiated between the two stroke groups. We demonstrated that stroke subjects at risk for SLD can be differentiated from control subjects using rs-fMRI with a classifier with reasonable accuracy in an expedited manner, which otherwise could take longer to identify via neuropsychological assessments. PMID- 30398381 TI - A Novel Semirigid Ureterorenoscope with Vacuum Suctioning System for Management of Single Proximal Ureteral and Renal Pelvis Stones: An Initial Experience. AB - INTRODUCTION: A novel semirigid ureterorenoscope named the Sotn ureterorenoscope was designed with a vacuum suction system. The present study aimed to evaluate the feasibility and safety of using the Sotn ureterorenoscope to manage single proximal ureteral or renal pelvis stones. METHODS: Data were retrospectively collected from consecutive patients treated with a Sotn ureterorenoscope between February 2010 and August 2015 at Sun Yat-sen Memorial Hospital of Sun Yat-sen University and Jiangmen Wuyi Traditional Chinese Medicine Hospital in China. The primary outcome was the primary stone-free rate (SFR) in 1 month. The secondary outcomes were the final SFR and the perioperative complication rate. RESULTS: A total of 386 patients were evaluated, including 240 males and 146 females. The median (interquartile range [IR]) age was 50 (40-59) years. There were 96 and 290 stones located in the renal pelvis and proximal ureter, respectively. The median (IR) operative time and console time for all patients were 40 (30-70) min and 20 (12-38) min, respectively. The primary overall SFR was 86.5%, while the SFRs for stones with a diameter of <= 1 cm, 1-2 cm, and 2-3 cm were 95.7%, 86.9%, and 69.0%, respectively. Complications occurred in 90 patients (23.3%); these complications were classified as Clavien-Dindo grades 1-2 (minor) in 79 (20.5%) patients, and grades 3-4 (major) in 11 (2.8%). CONCLUSIONS: The novel semirigid Sotn ureterorenoscope featuring a vacuum suction system is effective and safe for managing proximal ureteral and renal pelvis stones. PMID- 30398382 TI - Is a drain needed after robotic radical prostatectomy with or without pelvic lymph node dissection? Results of a single center randomized clinical trial. AB - OBJECTIVE: To investigate by means of a randomized clinical trial the safety of no drain in the pelvic cavity after Robot-assisted radical prostatectomy (RARP) with or without extended pelvic lymph node dissection (ePLND). MATERIALS AND METHODS: From May to December 2016, 112 consecutive patients who underwent RARP with or without ePLND were prospectively randomized in a control (CG) and study (SG) group. In the CG, a drain was placed in the pelvic cavity at the end of surgery and removed after 24 hours. The trial was designed to assess non inferiority. The primary end point was evaluated as complication rates graded by Clavien-Dindo score (CDS). Secondary endpoints included length of hospital stay (LOHS) and hospital readmission (RAD). RESULTS AND LIMITATIONS: At final analysis, 56 patients were in the CG and 54 belonged to the SG. The groups were homogenous for all preoperative and perioperative variables and did not show any difference of CDS complication rates (28.9% in the CG and 20.4% in the SG; p = 0,254), LOHS (on average 4 days in each group; p = 0,689), and RAD rates (3.6% in the CG and 3.7% in the SG; p = 0,970). CONCLUSIONS: In a modern cohort of patients who underwent RARP with or without ePLND, a single center RCT showed that no drain policy is equivalent to drain after RARP in terms of CDS complication rate, LOHS and RAD rate. The option of placing a postoperative drain for the first 24 hours could be considered in cases of difficult urethro-vesical anastomosis with uncertain watertightness. PMID- 30398384 TI - Supracostal upper pole endoscopic-guided prone tubeless "Maxi-PCNL": a contemporary evaluation of complications. AB - OBJECTIVE: To develop a contemporary complication profile for supracostal, upper pole endoscopic-guided prone tubeless "maxi-PCNL" in order to evaluate the need for change. MATERIALS/METHODS: We identified patients undergoing supracostal upper pole PCNL by a single surgeon at a high volume, tertiary care stone center between October 2010 and April 2017. Access was obtained with ureteroscopic guidance. The tract was dilated to 30 french via radial balloon dilation. All cases were tubeless with ureteral stent for 5-7 days. Preoperative, operative and postoperative variables were recorded. We recorded need for blood transfusion, angioembolization, thoracentesis and/or chest tube insertion, ICU and 30-day readmission. RESULTS: 375 patients were included. Mean age was 57 years old and 59% were women. Mean BMI was 33 kg/m2. Mean stone burden was 35 mm. The mean operative time was 99 minutes. Median stay was 1 day. There were no complications due to prone position. Postoperative complications included pleural drain (4%), transfusion (6.7%) and angioembolization (0.5%). Transfusion rates were higher in patients with pre-operative hemoglobin <10mg/dL (28% vs 5.1%, p<0.00001). Rate of ICU admission and readmission was 4.5% and 7.5% respectively. Transfusion (p=<0.001), pleural drain (p=0.0002) and readmission (p=0.030) were associated with ICU admission. Male gender was associated with readmission (10.3% vs 5.5%, OR=3.1, p=0.012). CONCLUSIONS: In supracostal upper pole endoscopic-guided prone tubeless Maxi-PCNL, pulmonary complication rate was lower than previously reported and bleeding complications were comparable to mini-PCNL series. Establishing contemporary complication rates will help to assess need for evolution to mini-PCNL or lower pole supine PCNL. PMID- 30398383 TI - Establishment of a High Yield rAAV/HBoV Vector Production System Independent of Bocavirus Non-structural Proteins. AB - The genome of recombinant adeno-associated virus 2 (rAAV2) remains a promising candidate for gene therapy for cystic fibrosis (CF) lung disease, but due to limitations in the packaging capacity and the tropism of this virus with respect to the airways, strategies have evolved for packaging an rAAV2 genome (up to 5.8kb) into the capsid of human bocavirus 1 (HBoV1) to produce a chimeric rAAV2/HBoV1 vector. Although a replication-incompetent HBoV1 genome has been established as a trans helper for capsid complementation, this system remains suboptimal with respect to virion yield. Here we describe a streamlined production system based on knowledge of the involvement of HBoV1 non-structural (NS) proteins NS1, NS2, NS3, NS4 and NP1 in the process of virion production. Our analyses reveal that NS1 and NS2 negatively impact virion production, NP1 is required to prevent premature termination of transcription of the cap mRNA from the native genome, and silent mutations within the polyadenylation sites of the cap coding sequence can eliminate this requirement for NP1. We further show that preventing the expression of all NS proteins significantly increases virion yield. Whereas the expression of capsid proteins VP1, VP2 and VP3 from a codon optimized cap mRNA was highly efficient, optimal virion assembly, and thus potency, required enhanced VP1 expression, entailing a separate VP1 expression cassette. The final NS protein-free (NS-free) production system uses 3-plasmid cotransfection of HEK293 cells, with one trans helper plasmid encoding VP1 and the AAV2 Rep proteins, and another encoding VP2-3 and components from adenovirus. This system yielded >16-fold more virions than the prototypic system, without reducing transduction potency. This increase in virion production is expected to greatly facilitate both research on the biology of rAAV2/HBoV1 and preclinical studies testing the effectiveness of this vector in gene therapy for CF lung disease in large animal models. PMID- 30398385 TI - Laparoscopic Completion Nephrectomy for Local Surgical Bed Recurrence after Partial Nephrectomy: An Analysis of Procedural Complexity and Feasibility. AB - OBJECTIVES: To study the feasibility and perioperative outcomes associated with a laparoscopic approach to completion nephrectomy in patients with locoregional disease recurrence after partial nephrectomy for renal cell carcinoma. PATIENTS AND METHODS: We performed a retrospective review of patients who underwent partial nephrectomy between 2006 and 2016 and developed locoregional recurrence, defined by the presence of new disease within the original surgical bed. Those undergoing planned laparoscopic completion nephrectomy constituted the study cohort. Perioperative outcomes as well as clinical and pathologic parameters associated with ability to successfully perform laparoscopic completion nephrectomy were assessed. RESULTS: Among 1,259 patients who underwent partial nephrectomy during the study period, 45 cases (3.6%) of locoregional disease recurrence were observed. A laparoscopic approach to completion nephrectomy was attempted in 33 patients. Overall, 16 (48.5%) patients experienced a postoperative complication, 9 of whom (27.3%) had a major event (Clavien grade >=3). Intraoperative open conversion was necessary in 12 (36%) patients. Higher R.E.N.A.L score of the original tumor (P<0.001) and clinical evidence of synchronous metastatic relapse (P<0.001) were associated with increased likelihood of open conversion. Blood loss (725 vs 175 ml, P<0.001), operative time (280 vs 160 min, P<0.001), risk of major postoperative complication (58% vs. 9.5%, P=0.005), and hospital length of stay (4.5 vs. 2 days, P=0.026) were significantly higher in individuals requiring open conversion. CONCLUSION: Laparoscopic completion nephrectomy for true locoregional recurrence is a technically demanding procedure associated with significant postoperative morbidity and a high rate of open conversion. Although feasible, careful patient selection may optimize surgical outcomes. PMID- 30398386 TI - Network Functional Architecture and Aberrant Functional Connectivity in Post Traumatic Stress Disorder: A Clinical Application of Network Convergence. AB - Posttraumatic stress disorder (PTSD) is associated with disrupted functional connectivity in multiple neural networks. Multinetwork models of PTSD hypothesize that aberrant regional connectivity emerges from broad network-level disruptions. However, few studies have tested how characteristics of network-level organization influence regional functional connectivity in PTSD. This gap in knowledge impacts both our understanding of the pathophysiology of the disorder and the development of network-targeted PTSD treatments. We acquired resting state imaging from a naturalistic sample of patients with PTSD (n = 42) and healthy controls (n = 42). Group differences in functional connectivity were identified using region of interest analyses and estimations of within- and between neural network activity; PTSD patients demonstrated reduced amygdala orbitofrontal connectivity and increased default mode network (DMN) connectivity compared with controls. We then used convergence-a novel measure representing the capacity for functional integration-to test whether differences in functional architecture underlie connectivity signatures of PTSD. This approach found that reduced frontoparietal network (FPN) convergence was associated with reduced amygdala-orbitofrontal connectivity. Furthermore, in controls only, increased DMN convergence was associated with reduced DMN-to-salience network connectivity, and increased FPN convergence was associated with reduced FPN-to-ventral attention network connectivity. These results suggest that FPN functional architecture may underlie insufficiencies in top-down control in PTSD, with results broadly supporting the notion that networks' functional architecture influences the breakdown of normative functional relationships in PTSD. This work also indicates the potential of convergence to be applied to clinical populations in future research studies. PMID- 30398387 TI - Poly(thioketal urethane) Autograft Extenders in an Intertransverse Process Model of Bone Formation. AB - Iliac crest autograft (AG) is the gold standard for bone grafting. Due to the limited supply of autograft, synthetic materials such as ceramics and polymers have been proposed as AG extenders to minimize the volume of AG required for induction of new bone formation. However, the feasibility of reactive polymers for use as settable AG extenders has not been previously investigated. In this study, a reactive oxygen species (ROS)-degradable poly(thioketal urethane) (PTKUR) was evaluated as a settable AG extender. AG was anticipated to enhance infiltration of cells into the defect and induce new bone formation. Histological analysis of a preliminary study in a rat femoral segmental defect model showed that cells infiltrated PTKUR/AG implants at 4 weeks. In a second experiment, implantation into an intertransverse process model of bone formation showed bone remodeling from the superior and inferior transverse processes. Histological analysis combining data from stains and fluorochrome injections showed lamellar bone formation ongoing near the base of the transverse processes after 8 weeks. Similar findings were observed for a second group in which 35% of the AG was replaced with calcium phosphate (CaP) granules. These observations highlight the potential of PTKUR for use as a settable AG extender. PMID- 30398388 TI - Chemosensitizer and docetaxel-loaded albumin nanoparticle: overcoming drug resistance and improving therapeutic efficacy. AB - AIM: Investigated strategy exploits the utilization of quercetin as a chemosensitizer for docetaxel (DTX), which was incorporated into albumin nanoparticles (NPs; bovine serum albumin NPs [BSA-NPs]). MATERIAL & METHODS: BSA NPs containing both drugs were optimized, extensively characterized for different quality attributes and performance was investigated using series of in vitro and in vivo investigations. RESULTS: Co-encapsulated BSA-NPs exhibited size: 209.26 +/- 9.84 nm, polydispersibility index: 0.184 +/- 0.05 and good entrapment efficiency (~75% for DTX and ~68% for quercetin). Higher in vitro cytotoxicity, cell uptake and apoptosis were achieved in MCF-7 cell line. Similarly, higher P glycoprotein efflux inhibition was observed in MDA-MB-231. About 2.5-fold increase in bioavailability of DTX was achieved with improved antitumor efficacy and reduced in vivo toxicity. CONCLUSION: Developed BSA-NPs provide an effective and safer alternative approach using co-delivery of chemosensitizer. PMID- 30398389 TI - Acute post-traumatic sleep may define vulnerability to a second traumatic brain injury in mice. AB - Chronic neurological impairments can manifest from repetitive traumatic brain injury (rTBI), particularly when subsequent injuries occur before the initial injury completely heals. Herein, we apply post-traumatic sleep as a physiological biomarker of vulnerability, hypothesizing that a second TBI during post-traumatic sleep worsens neurological and histological outcomes compared to one TBI or a second TBI after post-traumatic sleep subsides. Mice received sham or diffuse TBI by midline fluid percussion injury; brain-injured mice received one TBI or rTBIs at 3hr or 9hr intervals. Over 40 hours post-injury, injured mice slept more than shams. Functional assessments indicated lower latencies on rotarod and increased Neurological Severity Scores for mice with rTBIs within 3-hrs. Anxiety-like behaviors in the open field task were increased for mice with rTBIs at 3hrs. Based on pixel density of silver accumulation, neuropathology was greater at 28 days post-injury (DPI) in rTBI groups than sham and single TBI. Cortical microglia morphology was quantified and mice receiving rTBI were de-ramified at 14 DPI compared to shams and mice receiving a single TBI, suggesting robust microglial response in rTBI groups. Orexin-A positive cells were sustained in the lateral hypothalamus with no loss detected, indicating loss of wake-promoting neurons did not contribute to post-traumatic sleep. Thus, the duration of post traumatic sleep is a period of vulnerability that results in exacerbated injury from rTBI. Monitoring individual post-traumatic sleep is a potential clinical tool for personalized TBI management, where regular sleep patterns may inform rehabilitative strategies and return-to-activity guidelines. PMID- 30398390 TI - Walnut (Juglans regia L.) kernel extracts protects against isoproterenol-induced myocardial infarction in rats. AB - Walnuts kernels (Juglans regia L.) have rich antioxidants content and have been used in both cosmetic and pharmaceutical industry. The current study dealt with the protective role of walnut kernels extracts (WK) on isoproterenol (ISO) induced myocardial infarction (MI) in rats. Rats were pretreated with WK extracts (300 mg/kg) daily for 35 days. Then, isoproterenol (100 mg/kg) was injected subcutaneously into rats to induce myocardial infarction. Cardiac diagnostic markers (LDH and CPK), cardiac troponin, heart lipid peroxidation (TBARS and hydroperoxide), antioxidant system (CAT, SOD, GPx, GST, GSH and GSSG) and the levels of lipid profile were evaluated in rats, and the results revealed WK significantly prevented myocardial injury induced by ISO (P<0.05). WK significantly alleviated the oxidative damage and dyslipidemia in isoproterenol induced MI rats (P<0.05). The effect produced by WK was compared with alpha tocopherol. The mechanisms for the protective effects of WK could be attributed to its antilipid peroxidative, antioxidant and antilipidaemic properties. In conclusion, we demonstrated that WK has a significant protective effect against ISO-induced myocardial infarction. PMID- 30398391 TI - Enhancing Retention of Mesenchymal Stem Cells with Pro-survival Factors Promotes Angiogenesis in a Mouse Model of Limb Ischemia. AB - Mesenchymal stem/stromal cells (MSCs) offer great promise in the treatment of ischemic injuries including stroke, heart infarction and limb ischemia. However, poor cell survival after transplantation remains a major obstacle to achieve effective MSC therapies. To improve cell survival and retention, we transplanted human bone marrow MSCs with or without a specific pro-survival factor (PSF) cocktail consisting of IGF1, Bcl-XL, a caspase inhibitor, a mitochondrial pathway inhibitor and matrigel into the limbs of immune deficient mice, after induction of hindlimb ischemia. The PSF markedly prolonged the retention of the MSCs in the ischemic limb muscles as demonstrated by bioluminescence imaging. Using micro computed tomography (micro-CT) to image the limb muscle vasculature in the mice nine weeks after the transplantation, we found that the mice transplanted with MSCs without PSF did not show a significant increase in the blood vessels in the ischemic limb compared to the non-transplanted control mice. In contrast, the mice transplanted with MSCs plus PSF showed a significant increase in the blood vessels, especially the larger and branching vessels, in the ischemic limb as compared to the control mice that did not receive MSCs. Thus, we demonstrated that prolonged retention of MSCs using PSF effectively promoted angiogenesis in ischemic animal limbs. This study highlights the importance of enhancing cell survival in the development of effective MSC therapies to treat vascular diseases. PMID- 30398392 TI - From Stumbling Block to Enabler: The Role of Public Financial Management in Health Service Delivery in Tanzania and Zambia. AB - The way governments manage resources through the budget cycle has important implications for health policy and whether governments achieve societal objectives such as efficiency, equity, quality, and accountability. Studies found a positive association between health service delivery outcomes and good governance of public finance; however, the mechanisms through which public financial management affects service delivery remain underexplored. This article maps the three stages of the budget cycle to common performance criteria used in health service delivery. It applies this approach to experiences in Tanzania and Zambia. The findings point to a number of stumbling blocks, including the lack of flexibility to provide additional resources for unexpected demand for care, misalignment between budgeting and planning, fragmented funding sources, rigid internal controls, insufficient budget provision leading to arrears, and a budget evaluation system that is excessively compliance driven and gives inadequate attention to issues of equity, quality, and efficiency in service delivery. PMID- 30398393 TI - Construction, Validation and Sensitivity Analyses of a Job Exposure Matrix for Early Plutonium Workers at the Sellafield Nuclear Site, United Kingdom. AB - Plutonium is a radiologically significant alpha-particle emitter. The potential for adverse health effects from internal exposures due to plutonium intakes has been recognized since the 1940s. The workforce of the Sellafield nuclear facility (Cumbria, UK), includes one of the world's most important groups of plutonium exposed workers for studying the potential health risks of this internal exposure. However, for several hundred workers employed at the start of plutonium work at the facility (1952-1963), historical monitoring records based on measurements of urinary excretion of plutonium are not sufficiently reliable to provide the accurate and unbiased exposure assessments needed for epidemiological studies. Consequently, these early workers have had to be excluded from such studies, significantly reducing their power. We constructed a population-specific quantitative job exposure matrix (JEM) to estimate the average intakes of "typical plutonium workers" in this period, from 1952-1963, and assessed its validity and sensitivity to exposure assessment decisions. We conducted internal cross-validation using an a priori 10% extracted sample to evaluate reliability of estimates, explored JEM sensitivity to assumptions in the exposure assessment, and assessed the impact of uncertainty in urinalysis measurements on the precision of annual intake estimates using Markov Chain Monte Carlo (MCMC) methodology. Pairwise correlations ( RP) of estimated (JEM) and measured (10% sample) annual intakes were moderate to high ( RP > 0.4) for 10 out of 13 JEM groups, while absolute differences were <20% for 11 out of 13 JEM groups. There was little evidence of a temporal trend in correlations ( P = 0.13) or absolute differences ( P = 0.34). The median JEM-derived cumulative intake of 95.2 (IQR, 55.0-130.0) Bq was comparable to those based on alternative assumptions in the exposure assessment (median range, 95.2-100.0 Bq; 75th percentiles, 130.0-146.0 Bq). Measurement error simulation resulted in a 40-60% reduced median cumulative intake but higher maximum cumulative intakes. The JEM finds a balance between reliability and precision that makes it useful for epidemiological purposes and is relatively insensitive to specific choices in the exposure assessment. This JEM will allow the inclusion of workers with longest follow-up and who could not be included up until now in epidemiological studies without introducing significant bias. PMID- 30398394 TI - Persistence of Gamma-H2AX Foci in Bronchial Cells Correlates with Susceptibility to Radiation Associated Lung Cancer in Mice. AB - The risk of developing radiation-induced lung cancer differs between different strains of mice, but the underlying cause of the strain differences is unknown. Strains of mice also differ in how quickly they repair radiation-induced DNA double-strand breaks (DSBs). We assayed mouse strains from the CcS/Dem recombinant congenic strain set for their efficacy in repairing DNA DSBs during protracted radiation irradiation. We measured unrepaired gamma-H2AX radiation induced foci (RIF), which persisted after chronic 24-h gamma irradiation, as a surrogate marker for repair efficiency in bronchial epithelial cells for 17 of the CcS/Dem strains and the BALB/c founder strain. We observed a very strong correlation (R2 = 79.18%, P < 0.001) between the level of unrepaired RIF and radiogenic lung cancer percentage incidence measured in the same strains. Interestingly, spontaneous levels of foci in nonirradiated mice also showed good correlation with lung cancer incidence when incidence data from male and female mice were combined. These results suggest that genetic differences in DNA repair capacity largely account for differing susceptibilities to radiation-induced lung cancer among CcS/Dem mouse strains, and that high levels of spontaneous DNA damage are also a relatively good marker of cancer predisposition. In a smaller pilot study, we found that the repair capacity measured in peripheral blood leucocytes also correlated well with radiogenic lung cancer susceptibility, raising the possibility that the assay could be used to detect radiogenic lung cancer susceptibility in humans. PMID- 30398395 TI - POINT: podiatry for international diabetic foot teams. AB - FOREWORD: The Point Project is an initiative between the two organisations: D Foot International and the International Federation of Podiatrists (FIP-IFP). Both organisations promote the role of evidence-based foot care for patients with and at risk of diabetes. This collaborative work highlights the podiatric skills needed in order to deliver comprehensive evidence-based care to patients with diabetic foot disease. The statements along with the relevant skills and behaviours are based upon the guidance documents produced by the International Working Group on the Diabetic Foot (IWGDF), thus meaning while this is a consensus document it is also evidence-based. Representatives from both organisations with a multidisciplinary membership met early in 2017 to discuss the different areas of practice and to define which skills and behaviours were required at different levels of practice. Using the TRIEpodD-document (UK) and IWGDF guidance as the basis for discussion, the team identified which knowledge, skills and behaviours could be considered podiatric in nature. Once identified as podiatric, we discussed at which level of podiatric practice they could apply. The members of the team came from a variety of locations which represented practice at the different levels. Following the initial meeting, further discussions took place via email in order to consolidate initial discussions and complete the document. Cognisant of the large volume of guidance in relation to all areas of practice, this document is aimed to assist clinicians by pointing them in the direction in which they need to develop services rather than being a set of rules which must be followed. The POINT team feels that this document supports clinicians globally on three levels: As a benchmarking tool for existing teams to critically reflect upon their practice and identify where quality improvements can be made As a tool for clinicians who wish to establish a diabetic foot team to highlight the skills needed in order to provide care across the breadth of diabetic foot practice highlighting the specific roles in which podiatrists can help For national and local decision makers, to identify which skills can be provided by podiatrists to promote the development of the profession. While this is a consensus relating to podiatric skills, the team is aware that, in the absence of podiatrists, skills will be provided by other health professionals. We support this practice and while such professionals can not be considered podiatrists, they are providing podiatric skills to the diabetic foot team. The delivery of the relevant skill to the patient is the important factor, not the health professional is delivering it. The development of this document is merely the first step to identifying areas where skills need to be developed. Both D-Foot and FIP-IFP are committed to developing podiatric skills further across the globe. The aims and objectives of the two organisations are mutually beneficial to those suffering from diabetic foot disease. People with diabetes deserve the best care that they can receive, irrespective of the resources available. By working together we have been able to identify the podiatric knowledge, skills and behaviours required to provide evidence-based care. The next step is to work together to ensure consistent delivery of these globally for the benefit of those suffering the debilitating consequences of diabetic foot disease. PMID- 30398396 TI - Kenya National Hospital Insurance Fund Reforms: Implications and Lessons for Universal Health Coverage. AB - This article identifies and describes the reforms undertaken by the National Hospital Insurance Fund (NHIF) and examines their implications for Kenya's quest to achieve universal health coverage (UHC). We undertook a review of published and grey literature to identify key reforms that had been implemented by the NHIF since 2010. We examined the reforms undertaken by the NHIF using a health financing evaluation framework that considers the feasibility, equity, efficiency, and sustainability of health financing mechanisms. We found the following NHIF reforms: (1) the introduction of the Civil Servants Scheme (CSS), (2) the introduction of a stepwise quality improvement system, (3) the health insurance subsidy for the poor (HISP), (4) revision of monthly contribution rates and expansion of the benefit package, and (5) the upward revision of provider reimbursement rates. Though there are improvements in several areas, these reforms raise equity, efficiency, feasibility, and sustainability concerns. The article concludes that though NHIF reforms in Kenya are well intentioned and there has been improvement in several areas, design attributes could compromise the extent to which they achieve their intended goal of providing universal financing risk protection to the Kenyan population. PMID- 30398397 TI - Comparison of philosophical concerns between professionals and the public regarding two psychiatric treatments. AB - BACKGROUND: Psychiatric interventions are a contested area in medicine, not only because of their history of abuses, but also because their therapeutic goal is to affect emotions, thoughts, beliefs, and behaviors that are regarded as pathological. Because psychiatric interventions affect characteristics that seem central to who we are, they raise issues regarding identity, autonomy, and personal responsibility for one's own well-being. Our study addresses two questions: (1) Do the public and academic researchers understand the philosophical stakes of these technologies in the same way? Following from this, (2) to what extent does the specific type of psychiatric technology affect the issues these two groups raise? This study compares how ethical issues regarding neurosurgical and pharmaceutical psychiatric interventions are discussed among the public and in the professional community of academic medicine and bioethics. METHODS: We analyzed (1) online public comments and (2) the medical and bioethics literature, comparing the discussions of pharmacological and neurosurgical interventions in psychiatry in each source. RESULTS: Overall, the public discussed philosophical issues less frequently than academics. For the two types of psychiatric interventions, we found differences between the academic literature and public comments among all themes, except for personal responsibility. CONCLUSIONS: These findings reveal some of the similarities and discrepancies in how philosophical issues associated with psychiatric treatments are discussed in professional circles and among the public. Further research into what causes these discrepancies is crucial. PMID- 30398398 TI - SWINE MENISCUS: ARE FEMORAL-TIBIAL SURFACES PROPERLY TUNED TO BEAR THE FORCES EXERTED ON THE TISSUE? AB - Menisci are subjected to different pathologies that affected the knee proper functions and biology. Over the years, different techniques were tried to repair meniscus injury, and, when the reparation was not possible, to replace or regenerate it. These techniques still present a lack of controlled and independent clinical studies that not allow identifying their effective failure rate. This rate could be due to a still incomplete knowledge about meniscal biology, its composition and biomechanical properties. The purpose of this study was to analyse the relationship between the contact forces and the meniscal structures at the level of the femoral and tibial surfaces of the meniscus to improve the knowledge about this tissue, in view of the possible application in tissue engineering, for the production of meniscal scaffolds. Swine meniscal samples were studied for morphological (Safranin-O, Sirius Red and collagen type I and II), biochemical (DNA, GAGs and GAGs/DNA ratio), CT scanning and biomechanical analyses (compression and traction tests) of femoral and tibial meniscal surfaces. Results revealed a biomechanical-dependent characterization of the meniscus. The femoral surface is characterized by a higher quantity of GAGs and a greater amount of cells (p<0.01 for each analysis), with the interposition of radial and oblique fibres. These features are responsible of a higher resistance (p<0.05) to compressive forces like that acted on by the femoral condyles. Oppositely, the tibial surface shows a circumferential arrangement of the fibres and a poorer GAGs presence and cellular spread (p<0.01); these characteristics seem to allow a higher resistance (p<0.05) of the tibial surface to traction forces. Results from this work provide useful information for the design and creation of meniscal substitute and suggest that the features of the meniscus are biomechanical-dependent and that its composition and structure are dependent to the different forces that femur and tibia generate upon its surfaces. The importance of the present study is linked to how the contact forces act on the knee meniscus in particular considering the femoral condyles and tibial plateau: these results can be useful for the tissue-engineering of meniscus, providing information about meniscal biology, its composition and biomechanical properties. PMID- 30398399 TI - Surgical Feasibility of a One-Stage Cell-Based Arthroscopic Procedure for Meniscus Regeneration. AB - PURPOSE: To test the technical aspects and feasibility of seeding a combination of meniscus cells isolated from a rapid digestion protocol and mesenchymal stromal cells (MSCs) (20: 80 ratio) into a meniscus scaffold for the development of a one-stage arthroscopic procedure for meniscus regeneration. METHODS: A cadaveric study was performed using nine fresh frozen human cadaveric knee joints. Two different arthroscopic cell-seeding methods were applied to the Collagen Meniscus Implant (CMI(r)) as carrier scaffold: either 1) seeding before arthroscopic surgical implantation of the scaffold, or 2) after implantation of the scaffold. The cells were injected inside the scaffold, using fast green stained fibrin glue as carrier, to macroscopically visualize the amount of fibrin glue. Macroscopic pictures and confocal microscopy analyses were used to determine cell distribution and viability. In addition, the DNA content in the cell-seeded scaffold was determined. In addition, different concentrations of Liberase were examined to find the optimal concentration for rapid digestion of meniscus tissue. RESULTS: Macroscopically, seeding before implantation showed a better distribution of fast green-stained fibrin glue carrier compared to seeding the scaffold before surgical implantation. In addition, it resulted in significantly more cells and a better cell distribution compared to seeding the scaffold after arthroscopic implantation. Both seeding methods did not affect cell viability. Following rapid digestion, 0.0125% Liberase resulted in the highest cell isolation efficiency. CONCLUSIONS: This study demonstrates that living human meniscus cells can be isolated efficiently, combined with MSCs in 20: 80 ratio, and uniformly delivered into a currently-available meniscus scaffold. This scaffold can then be arthroscopically implanted, creating a one stage solution for partial meniscal deficiency. PMID- 30398400 TI - MRI Evaluation of Cartilage Repair and Iron Particle-Kinetics after Magnetic Delivery of Stem Cells. AB - Magnetic cell delivery system, termed as magnetic targeting, has been developed for minimal invasive cell transplantation. Cells are magnetically labeled with nano-sized iron particles. However, the temporal change in iron particles in vivo has not been clarified. In addition, the influence of magnetic resonance imaging (MRI) after magnetic targeting therapy has never been investigated. In the present study, magnetically labeled bone marrow mesenchymal stem cells (MSCs) were injected into rabbit knee joint with an articular cartilage defect, with or without existence of the magnetic field (m-MSC group, MSC group). PBS was injected as a control. Articular cartilage defects were assessed by MRI using a 4.7 Tesla magnet at 1, 4, and 12 weeks after treatment. Articular cartilage defects were also evaluated using Safranin-O staining, type II collagen immunostaining, and Berlin blue staining at 1, 4, and 12 weeks after treatment. In the assessment using T2 mapping of MRI, the area of repaired tissues with T2 had a value similar to that for articular cartilage. This was significantly larger in the m-MSC group than that in the other groups at 12 weeks after treatment. Histological findings by Safranin-O staining and type II collagen immunostaining also revealed better cartilage repair in the m-MSC group than in the other groups. T2 mapping of MRI was therefore considered to successfully reflect the degree of cartilage repair. On the other hand, T2* images of MRI showed hypointense areas in cartilage defects in the m-MSC group. The T2* hypointense area in the m-MSC group was significantly larger than that in the other groups at 1 and 4 weeks, but not at 12 weeks after treatment. In the histological assessment, iron particles stained with Berlin blue could be detected in repaired tissues at 1 and 4 weeks, but not at 12 weeks after treatment. The T2* hypointense area seems to indicate the existence of iron particles. These findings suggest that MRI can evaluate the regenerative process of cartilage with magnetic targeting and kinetics of ferucarbotran after the magnetic targeting of MSCs. MRI can be used safely without inhibiting the cartilage repair, following magnetic targeting of MSCs. PMID- 30398401 TI - Evaluation of different decellularization protocols on the generation of pancreas derived hydrogels. AB - Different approaches have investigated the effects of the different extracellular matrices (ECMs) and 3D culture on islets function, showing encouraging results. Ideally, the proper scaffold should mimic the biochemical composition of the native tissue as it drives numerous signaling pathways involved in tissue homeostasis and functionality. Tissue-derived decellularized biomaterials can preserve the ECM composition of the native tissue making it an ideal scaffold for 3D tissue engineering applications. However, the decellularization process may affect the retention of specific components, and the choice of the proper detergent is fundamental in preserving the native ECM composition. In this study, we evaluated the effect of different decellularization protocols on the mechanical properties and biochemical composition of pancreas-specific ECM (pECM) hydrogels. Fresh porcine pancreas tissue was harvested, cut in small pieces, rinsed in water and treated with two different detergents (SDS or Triton X-100) for one day followed by 3 days in water. Use of a protease inhibitor was also evaluated. Effective decellularization was confirmed by PicoGreen assay and H&E staining, showing no differences among groups. Triton-treated samples were able to form a firm hydrogel under the appropriate conditions, while the use of SDS had detrimental effects on the gelation properties of the hydrogels. ECM biochemical composition was characterized both in the fresh porcine pancreas and all decellularized pECM hydrogels by quantitative mass spectrometry analysis. Fibrillar collagen was the major ECM component in all groups, with all generated hydrogels having a higher amount compared to the fresh pancreas. This effect was more pronounced in the SDS treated hydrogels when compared with the Triton groups, showing very little retention of other ECM molecules. Conversely, basement membrane and matricellular proteins were better retained when the tissue was pretreated with a protease inhibitor and decellularized in Triton X100 making the hydrogel more similar to the native tissue. In conclusion, we showed that all the protocols evaluated in the study showed effective tissue decellularization, but only when the tissue was pre-treated with a protease inhibitor and decellularized in Triton detergent, the biochemical composition of the hydrogel was closer to the native tissue ECM. PMID- 30398402 TI - Who Needs Big Health Sector Reforms Anyway? Seychelles' Road to UHC Provides Lessons for Sub-Saharan Africa and Island Nations. AB - The road to universal health coverage (UHC) needs not be driven by big reforms that include the initiation of health insurance, provider-funder separation, results-based financing, or other large health sector reforms advocated in many countries in sub-Saharan Africa and elsewhere. The Seychelles experience, documented through a series of analytical products like public expenditure reviews and supporting surveys with assistance from the World Bank and World Health Organization (WHO), shows an alternative, more incremental reform road to UHC, with important lessons to the region and other small-population or island nations. Done well, in some countries, a basic supply-side funded, publicly owned and operated, and integrated health system can produce excellent health outcomes in a cost-effective and sustainable way. The article traces some of the factors that facilitated this success in the Seychelles, including high political commitment, strong voice and a downward accountability culture, strong public health functions, and an impressive investment in primary health care. These factors help explain past successes and also provide a good basis for adaptation of health systems to dramatic shifts in the epidemiological and demographic transitions, disease outbreaks, and rising public expectation and demand for high quality of care. Once again, how the Seychelles responds can show the way for other countries in the region and elsewhere regardless of the types of reforms countries engage in. PMID- 30398403 TI - Utilization of Health Care and Burden of Out-of-Pocket Health Expenditure in Zimbabwe: Results from a National Household Survey. AB - In the last decade, Zimbabwe has undertaken substantial changes and implemented new initiatives to improve health system performance and services delivery, including results-based financing in rural health facilities. This study aims to examine the utilization of health services and level of financial risk protection of Zimbabwe's health system. Using a multistage sampling approach, 7,135 households with a total of 32,294 individuals were surveyed in early 2016 on utilization of health services, out-of-pocket (OOP) health expenditure, and household consumption (as a measure of living standards) in 2015. The study found that the outpatient visits were favorable to the poor but the poorest had less access to inpatient care. In 2015, household OOP expenditure accounted for about one quarter of total health expenditure in Zimbabwe and 7.6% of households incurred catastrophic health expenditure (CHE). The incidence of CHE was 13.4% in the poorest quintile in comparison with 2.8% in the richest. Additionally, 1.29% of households fell into poverty due to health care-related expenditures. The study suggests that there are inequalities in utilization of health services among different population groups. The poor seeking inpatient care are the most vulnerable to CHE. PMID- 30398404 TI - Correlation of IL28B rs12979860 genotype and gender with spontaneous clearance of HCV infection: a Pakistani cross-section study. AB - AIM: There is a strong correlation of IL28B rs12979860 genetic variations and gender with spontaneous clearance of hepatitis C virus (HCV) infection. MATERIALS & METHODS: HCV-infected subjects were categorized into HCV spontaneous clearance (SC) group and chronic hepatitis C (CHC) group on the basis of anti-HCV antibodies and HCV RNA level and follow-up of 6 months. 35 subjects were classified in SC group and 165 subjects were classified in CHC group. IL28B rs12979860 genotypes were determined by allele-specific PCR. RESULTS & CONCLUSION: Multinominal logistic regression analyses revealed that both genders favor IL28B rs12979860 CT genotype (OR: 4.80; CI: 2.22-10.35; p = 0.0005) and (OR: 3.47; CI: 1.63-7.43; p = 0.001) for male and female, respectively, are significant in spontaneous clearance of HCV infection. PMID- 30398405 TI - Body image, personality profiles and alexithymia in patients with polycystic ovary syndrome (PCOS). AB - AIM: Polycystic ovary syndrome (PCOS) is a common endocrine-metabolic disorder. It affects women's physical well-being and leads to great psychological distress. Indeed, women with PCOS show a compromised quality of life as well as impaired emotional well-being. The aim of this study is to assess personality characteristics, body image and alexithymia in women with PCOS. MATERIALS AND METHODS: A total of 59 women with PCOS and 38 healthy controls were administered the Toronto Alexithymia Scale (TAS), the Body Uneasiness Test (BUT) and the Minnesota Multiphasic Personality Inventory-2 (MMPI-2). RESULTS: The PCOS group showed higher values of alexithymia and a higher body uneasiness. They also showed higher values on many clinical, content and supplementary scales of the MMPI-2. DISCUSSION: It seems that physical appearance and bodily function have a central place in the minds of women with PCOS, as well as in their relationships. However, it is a body they find it hard to feel and with which they mostly feel uncomfortable. Their approach to the outside world seems to be characterized by a certain degree of immaturity, anger, hostility and distrust. Low self-esteem also seems to be connected to a certain tendency toward introversion and withdrawal. This leads to problems in social, professional and intimate relationships. PMID- 30398406 TI - Time of admission and mortality after hip fracture: a detailed look at the weekend effect in a nationwide study of 55,211 hip fracture patients in Norway. AB - Background and purpose - There are numerous studies on the weekend effect for hip fracture patients, with conflicting results. We analyzed time of admission and discharge, and the association with mortality and length of hospital stay in more detail. Patients and methods - We used data from 61,211 surgically treated hip fractures in 55,211 patients, admitted to Norwegian hospitals 2008-2014. All patients were aged 50 years or older. Data were analyzed with Cox and Poisson regression. Results - Mortality within 30 days did not differ substantially by day of admission, although admissions on Sundays and holidays had a slightly increased mortality. The hazard ratios were 1.1 (95% confidence interval [CI] 0.97-1.2) for Sundays, and 1.2 (CI 0.98-1.4) for holidays, relative to Mondays. For patients admitted between 6:00 am and 7:00 am the hazard ratio was 1.4 (CI 1.1-1.8) relative to patients admitted between 2:00 pm and 3:00 pm. Discharges during weekends and holidays were associated with a substantial higher mortality than weekday discharges. Patients admitted from Friday to Sunday generally stayed in hospital for a shorter time than patients admitted during other days. Interpretation - Our results indicate that the discussion on weekday versus weekend admission effects might have distracted attention from other important factors, such as time of day of admission, and day of discharge from hospital treatment. PMID- 30398408 TI - Who Believes in Nonlimited Willpower? In Search of Correlates of Implicit Theories of Self-Control. AB - Recently, the most prominent model of self-control, the strength model, was criticized, and other explanations of self-control have been proposed. One of them is a concept of lay, implicit, willpower theories, that is, believing either that willpower is limited (as in the strength model) or nonlimited. Research shows that holding a nonlimited-resource belief prevents individuals from suffering ego depletion and is related to successful self-regulation. The current study explored how personality, time perspective, and intelligence predict willpower theories. Additionally, two aspects of willpower theories, strenuous mental activity and resistance to temptations, were measured separately. The results indicated that the two aspects of willpower theories were not correlated with each other. This supports hypothesis that willpower theories may be domain specific and also suggests that these two aspects should not be aggregated into one, homogenous scale as was done in some previous research. Both aspects of holding a nonlimited-resource theory were related positively to emotional stability and negatively to past negative time perspective. Strenuous mental activity was positively associated with intellect and negatively with present fatalism, whereas resistance to temptations was correlated positively with conscientiousness and future time perspective. There were no relations between willpower theories and intelligence, which posits that similar life outcomes related with these two attributes are based on distinct mechanisms. Regression analyses revealed that only personality traits (emotional stability and conscientiousness) remained significant predictors of willpower beliefs. PMID- 30398407 TI - Decreased Thyroid Peroxidase Antibody Titer in Response to Selenium Supplementation in Autoimmune Thyroiditis and the Influence of a SEPP Gene Polymorphism: A Prospective, Multicenter study in China. AB - Background Recent intervention studies have suggested selenium(Se) as an effective treatment in autoimmune thyroiditis (AIT). However, the exact mechanism is still unclear. The aim of the present study was to explore the effect of Se on thyroid peroxidase antibody (TPOAb) titers in patients with AIT and to analyze a potential impact of the genetic background on the effect of Se supplementation Methods Randomized, placebo-controlled, double-blind trial. 364 patients with elevated TPOAb (>300 IU/mL) were recruited and randomized to receive Se yeast 200 MUg/day supplementation or placebo. Urinary iodine concentration (UIC), serum thyroid-stimulating hormone (TSH), free thyroxine (FT4), TPOAb, Se, malondialdehyde (MDA), and serum glutathione peroxidase (GPX3) activity were measured at baseline and follow-up. 96 patients were genotyped for SNP r25191g/a. Results The median UIC was 182 MUg/L. Serum Se increased significantly (p<0.001) after Se treatment. TPOAb titer decreased by 10.0% at 3 months and by 10.7% at 6 months after se supplementation while there was a moderate increase in TPOAb titer over the follow-up period in patients receiving placebo. GPX3 activity significantly increased (p<0.001), and MDA significantly decreased (p<0.001) after 6 months of Se supplementation. TPOAb titer decreased to different extents in patients with different genotypes of SNP r25191g/a after Se supplementation. Serum TPOAb titer in patients with the AA genotype had a more significant decrease (by 46.2%) than those with the GA and GG genotypes (by 14.5 and 9.8% respectively) at 3 months of Se supplementation (P=0.070). Conclusions Se supplementation significantly reduced TPOAb titer in patients with AIT, and there may be an important genetic component influencing interindividual differences in the decrease in TPOAb titer. PMID- 30398409 TI - The proto CpG island methylator phenotype of sessile serrated adenomas/polyps. AB - Sessile serrated adenomas/polyps (SSA/Ps) are the putative precursors of the ~20% of colon cancers with the CpG island methylator phenotype (CIMP). To investigate the epigenetic phenotype of these precancers, we prospectively collected fresh tissue samples of 17 SSA/Ps and 15 conventional adenomas (cADNs), each with a matched sample of normal mucosa. Their DNA was subjected to bisulfite next generation sequencing to assess methylation levels at ~2.7 million CpGs located predominantly in gene regulatory regions and spanning 80.5Mb; RNA was sequenced to define the samples' transcriptomes. Compared with normal mucosa, SSA/Ps and cADNs exhibited markedly remodeled methylomes. In cADNs, hypomethylated regions were far more numerous (18,417 vs 4288 in SSA/Ps) and rarely affected CpG islands/shores. SSA/Ps seemed to have escaped this wave of demethylation. Cytosine hypermethylation in SSA/Ps was more pervasive (hypermethylated regions: 22,147 vs 15,965 in cADNs; hypermethylated genes: 4938 vs 3443 in cADNs) and more extensive (region for region), and it occurred mainly within CpG islands and shores. Given its resemblance to the CIMP typical of SSA/Ps' putative descendant colon cancers, we refer to the SSA/P methylation phenotype as proto-CIMP. Verification studies of six hypermethylated regions in an independent series of precancers demonstrated DNA methylation markers' high potential for predicting the diagnosis of SSA/Ps and cADNs. Surprisingly, proto-CIMP in SSA/Ps was associated with upregulated gene expression; downregulation was more common in cADNs. In conclusion, the epigenetic landscape of SSA/Ps differs markedly from that of cADNs. These differences are a potentially rich source of novel tissue based and noninvasive biomarkers. PMID- 30398410 TI - Muscle and joint pains in middle-aged women are associated with insomnia and low grip strength: a cross-sectional study. AB - BACKGROUND: Although muscle and joint pains are among the most common symptoms in menopausal transition, their underlying mechanisms are not precisely known. This study aimed to investigate the factors associated with myalgia and arthralgia in middle-aged women. METHODS: We analyzed in a cross-sectional manner the first visit records of 305 Japanese women aged 40-59 years who enrolled in a health and nutrition education program at a menopause clinic. The prevalence of muscle and joint pains was estimated according to the participants' responses to the Menopausal Health-Related Quality of Life Questionnaire. Background characteristics including age, menopause status, body composition, cardiovascular parameters and physical fitness, as well as other menopausal symptoms including vasomotor symptoms, insomnia, depression and anxiety, were assessed for associations with daily myalgia and arthralgia. RESULTS: The percentage of women who were bothered by muscle and joint pains almost every day of the previous week was 56.1%. Characteristics associated with these symptoms were: low stature; high body fat percentage; low grip strength; and high vasomotor, insomnia, depression and anxiety symptom scores. Multivariate logistic regression analysis revealed that independently associated factors (adjusted odds ratio [95% confidence interval]) for daily myalgia/arthralgia were low hand-grip strength (kgf) (0.92 [0.87-0.97]) and insomnia symptom score (1.20 [1.07-1.34]). CONCLUSION: Muscle and joint pains are highly prevalent in Japanese middle-aged women. Low grip strength and insomnia are independently associated with these symptoms. Treatment of insomnia in this population might improve myalgia/arthralgia, and in turn, help restore grip strength, or treatment of hand pain might conversely reduce insomnia in addition to improvement in grip strength. PMID- 30398411 TI - Lysyl Oxidase is a key player in BRAF/MAPK pathway-driven thyroid cancer aggressiveness. AB - BACKGROUND: BRAF mutation is the most common somatic mutation in thyroid cancer. The mechanism associated with BRAF mutant tumor aggressiveness remains unclear. Lysyl oxidase (LOX) is highly expressed in aggressive thyroid cancers, and involved in cancer metastasis. The objective is to determine whether LOX mediates the effect of the activated MAPK pathway in thyroid cancer. METHODS: The prognostic value of LOX and its association with BRAF mutation was analyzed in the TCGA and an independent cohort. Inhibition of mutant BRAF and the MAPK pathway, and overexpression of BRAF mutant and mouse models of BRAFV600E were used to test the effect on LOX expression. RESULTS: In the TCGA cohort, LOX expression was higher in BRAF mutant tumors compared to wild-type tumors (P<0.0001).Patients with BRAF mutant tumors with high LOX expression had a shorter disease-free survival (DFS) (P=0.03) compared to patients with BRAF mutation and low LOX group. In the independent cohort, a significant positive correlation between LOX and percentage of BRAF mutated cells was found. The independent cohort confirmed high LOX expression to be associated with a shorter DFS (P=0.01). Inhibition of BRAFV600E and MEK decreased LOX expression. Conversely overexpression of mutant BRAF increased LOX expression. The mice with thyroid-specific expression of BRAFV600E, showed a strong LOX and p-ERK expressions in tumor tissue. Inhibition of BRAFV600E in transgenic and orthotopic mouse models significantly reduced the tumor burden as well as LOX and p-ERK expressions. CONCLUSIONS: Our data suggests that BRAFV600E tumors with high LOX expression are associated with more aggressive disease. The biological underpinnings of the clinical findings were confirmed by showing that BRAF and the MAPK pathway regulate LOX expression. PMID- 30398413 TI - ECG of the Month. PMID- 30398412 TI - "I want us to be a normal family": Toward an understanding of the functions of anonymity among U.S. oocyte donors and recipients. AB - BACKGROUND: Anonymity remains the more common practice in gamete donations, but legislation prohibiting anonymity with a goal of protecting donor-conceived children's right to know their genetic origins is becoming more common. However, given the dearth of research investigating the function of anonymity for donors and recipients, it is unclear whether these policies will accomplish their goals. The aim of this study was to explore experiences with anonymity among oocyte donors and recipients who participated in an anonymous donor oocyte program and to understand the ways in which anonymity functions for them. METHODS: Semistructured interviews were conducted with 50 women: 28 oocyte donors and 22 recipients who were recruited from an academic center for reproductive medicine in the United States. RESULTS: Donors and recipients view anonymity both as a mechanism to protect the interests of all parties (recipients, donors, and donor conceived children) and as a point of conflict. Specifically, three key areas were identified where both donors and recipients saw anonymity as having an important role: relieving anxieties about family structures and obligations; protecting their interests and those of donor-conceived children (while acknowledging where interests conflict); and managing the future. CONCLUSION: As gamete donation increasingly moves away from the practice of anonymity, examining why anonymity matters to stakeholders will be helpful in devising strategies to successfully implement identity-release options. PMID- 30398414 TI - What Is Your Neurologic Diagnosis? PMID- 30398415 TI - How veterinary biobanking provides opportunities to accelerate research. PMID- 30398416 TI - Pathology in Practice. PMID- 30398417 TI - Effects of the use of silver-coated urinary catheters on the incidence of catheter-associated bacteriuria and urinary tract infection in dogs. AB - OBJECTIVE To determine the effects of silver-coated versus standard silicone urinary catheters on the incidence of catheter-associated bacteriuria (CAB) and catheter-associated urinary tract infection (CAUTI) in dogs. DESIGN Randomized controlled clinical trial. ANIMALS 36 dogs requiring urinary bladder catheterization for >= 24 hours. PROCEDURES Dogs were randomly assigned to receive a silver-coated or non-silver-coated (control) silicone Foley catheter. Urine samples for cytologic examination and bacterial culture were collected at the time of catheter insertion and daily until catheters were removed (>= 24 hours to 7 days later). Results were compared between groups. RESULTS No significant differences were identified between catheter groups in the incidence of CAB or CAUTI. Although the median time to development of cytologically detected bacteriuria, culture-detected bacteriuria, and CAUTI did not differ significantly between groups, median time to CAB development (either method) was significantly longer for dogs that received a control catheter rather than a silver-coated catheter. For both types of catheters combined, older age was a significant predictor of culture-detected bacteriuria, and longer duration of catheterization was a significant predictor of culture-detected bacteriuria and overall CAB. CONCLUSIONS AND CLINICAL RELEVANCE Silver-coated urinary catheters provided no clinical benefit over standard urinary catheters for the dogs of this study and were associated with earlier development of CAB but not CAUTI. A larger prospective study is required to definitively determine whether the use of silver coated urinary catheters should or should not be considered to reduce the risk of CAB or CAUTI in dogs. PMID- 30398418 TI - Theriogenology Question of the Month. PMID- 30398419 TI - Interventional treatment of benign nasopharyngeal stenosis and imperforate nasopharynx in dogs and cats: 46 cases (2005-2013). AB - OBJECTIVE To determine outcome for dogs and cats with benign nasopharyngeal stenosis or an imperforate nasopharynx that underwent balloon dilatation or metallic stent placement. DESIGN Retrospective case series. ANIMALS 15 dogs and 31 cats. PROCEDURES Medical records were retrospectively reviewed, and data on signalment, history, clinical signs, lesion location, treatment, and outcome were obtained. Patients were excluded if < 6 months of follow-up information was available. RESULTS 5 dogs and 22 cats underwent balloon dilatation, and results were successful in 11 (0 dogs and 11 cats) of the 27 (41%). Stents were placed in 34 patients (including 15 in which balloon dilatation had been unsuccessful). Uncovered stents were placed in 30 patients, and results were successful in 20 (67%). Covered stents were placed in 11 patients (including 7 in which uncovered stent placement was unsuccessful), and results were successful in all 11. Twenty three of the 34 (68%) patients in which stents were placed developed complications. The most common complications were tissue ingrowth (n = 10), chronic infection (7), and stent fracture (5) for the 30 patients with uncovered stents and chronic infection (8) and oronasal fistula (3) for the 11 patients with covered stents. Overall, outcome was successful in 36 of the 46 (78%) patients (median follow-up time, 24 months; range, 2 to 109 months). CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that in dogs and cats, nasopharyngeal stenosis and imperforate nasopharynx can be successfully treated with balloon dilatation or stent placement, but that there was a high risk of failure with balloon dilatation alone and a high risk of complications regardless of procedure. PMID- 30398420 TI - Exploration of veterinary shortages in the wake of the Veterinary Feed Directive. AB - OBJECTIVE To identify geographic areas in the United States where food animal veterinary services may be insufficient to meet increased needs associated with the US FDA's Veterinary Feed Directive. DESIGN Cross-sectional study. SAMPLE Data collected between 2010 and 2016 from the US Veterinary Medicine Loan Repayment Program, the National Animal Health Monitoring System Small-Scale US Livestock Operations Study, and the USDA's National Veterinary Accreditation Program. PROCEDURES Each dataset was analyzed separately to identify geographic areas with greatest potential for veterinary shortages. Geographic information systems methods were used to identify co-occurrence among the datasets of counties with veterinary shortages. RESULTS Analysis of the loan repayment program, Small-Scale Livestock Operations Study, and veterinary accreditation datasets revealed veterinary shortages in 314, 346, and 117 counties, respectively. Of the 3,140 counties in the United States during the study period, 728 (23.2%) counties were identified as veterinary shortage areas in at least 1 dataset. Specifically, 680 counties were identified as shortage areas in 1 dataset, 47 as shortage areas in 2 datasets, and 1 Arizona county as a shortage area in all 3 datasets. Arizona, Kentucky, Missouri, South Dakota, and Virginia had >= 3 counties identified as shortage areas in >= 2 datasets. CONCLUSIONS AND CLINICAL RELEVANCE Many geographic areas were identified across the United States where food animal veterinary services may be inadequate to implement the Veterinary Feed Directive and meet other producer needs. This information can be used to assess the impact of federal regulations and programs and help understand the factors that influence access to food animal veterinary services in specific geographic areas. PMID- 30398421 TI - What Is Your Diagnosis? PMID- 30398423 TI - Diagnostic Imaging in Veterinary Dental Practice. PMID- 30398424 TI - Noncardiogenic pulmonary edema associated with ozone exposure in three kittens. AB - CASE DESCRIPTION Three 21-week-old sexually intact female sibling domestic shorthair cats were brought to an emergency clinic because of signs of sudden respiratory distress that were noted by the owner after the cats had been confined for approximately 10 hours in a room with an operating ozone-generating air purifier. No other potential toxicant exposures were reported. CLINICAL FINDINGS On initial examination, the 3 cats were severely dyspneic and tachypneic. Pulmonary crackles were audible on thoracic auscultation. Thoracic radiography revealed a marked peribronchial, unstructured interstitial pulmonary pattern that coalesced to a patchy alveolar pattern, consistent with noncardiogenic pulmonary edema. TREATMENT AND OUTCOME A diuretic (furosemide, 2 mg/kg [0.9 mg/lb], IV) and bronchodilator (terbutaline sulfate, 0.01 mg/kg [0.005 mg/lb], IM) were administered, and supplemental oxygen was provided by placing the cats in an oxygen cage at 80% oxygen saturation. By 24 hours after placement in the oxygen cage, all cats had unremarkable respiratory rates and thoracic auscultation findings. Complete resolution of the respiratory signs and radiographic pulmonary lesions was achieved within 48 to 72 hours after initial evaluation. At a recheck examination performed 3 months after initial evaluation, the cats remained free of respiratory signs, and no radiographic pulmonary lesions were detected. CLINICAL RELEVANCE To the authors' knowledge, this was the first reported case of pulmonary toxicosis believed to have been caused by ozone exposure in cats. Associated respiratory signs were successfully and rapidly reversed following oxygen supplementation and medical treatment. PMID- 30398425 TI - Use of a subcutaneous ureteral bypass device for treatment of benign ureteral obstruction in cats: 174 ureters in 134 cats (2009-2015). AB - OBJECTIVE To determine outcomes of subcutaneous ureteral bypass (SUB) device placement for treatment of benign ureteral obstruction in cats. DESIGN Retrospective case series. ANIMALS 134 cats with SUB devices placed in 174 obstructed ureters during 144 hospitalizations. PROCEDURES Medical records of cats that underwent SUB device placement for treatment of benign ureteral obstruction between 2009 and 2015 were reviewed. The SUB device was placed by use of fluoroscopic and surgical methods. Signalment, history, diagnostic imaging results, postprocedural results, duration of hospitalization, complications, and short- and long-term outcomes were recorded. RESULTS Ureteral obstructions were caused by ureterolithiasis (114/174 [65.5%]), stricture (28/174 [16.1%]), both ureterolithiasis and stricture (29/174 [16.7%]), or pyonephrosis (1/174 [0.6%]); in 2 (1.1%) cats, the cause was not recorded. Fifty-two of the 134 (39%) cats had bilateral ureteral obstruction. At admission, 127 (95%) cats were azotemic. Median serum creatinine concentrations at admission and 3 months after SUB device placement were 6.6 and 2.6 mg/dL, respectively. Median renal pelvis diameters before and after the procedure were 9.2 and 1.5 mm, respectively. Postsurgical complications included device occlusion with blood clots (14/172 [8.1%]), device leakage (6/172 [3.5%]), and kinking of the device tubing (8/174 [4.6%]). Cats survived to hospital discharge after 135 of the 144 (94%) hospital admissions. The most common long-term complication was catheter mineralization (40/165 [24.2%]), which was documented a median of 463 days after device placement. A high postoperative serum ionized calcium concentration was significantly associated with SUB device occlusion. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that SUB device placement may be a viable option for treatment of cats with benign ureteral obstruction. PMID- 30398426 TI - Perceptions of support and policies regarding pregnancy, parenting, and family planning during veterinary training at United States veterinary medical training institutions. AB - OBJECTIVE To gather information about issues associated with pregnancy, lactation, and parenting for US veterinary students and house officers (trainees) and their perception of pregnancy and parenting support services available at US veterinary training institutions. DESIGN Cross-sectional mixed-method survey. SAMPLE 2,088 veterinary students and 312 house officers from 27 US veterinary training institutions. PROCEDURES An email with a link to an online survey was sent to the associate dean for academic affairs at each of the 30 AVMA-accredited US veterinary training institutions with a request that it be forwarded to all veterinary students and house officers (interns and residents). RESULTS Among the 2,400 respondents, 185 (7.7%) reported that they were a parent, were pregnant, or had a significant other who was pregnant. Several significant differences in attitudes and perceptions of pregnancy and parenting support services provided by veterinary training institutions were identified between males and females, veterinary students and house officers, and respondents who were and were not parents. CONCLUSIONS AND CLINICAL RELEVANCE Results provided crucial information about an important facet of well-being for veterinary trainees and suggested that veterinary students and house officers face substantial challenges in becoming parents during their training programs and that perceptions of those challenges differ between males and females. PMID- 30398428 TI - Letters to the Editor. PMID- 30398427 TI - Outcomes of elective gonadectomy procedures performed on dogs and cats by veterinary students and shelter veterinarians in a shelter environment. AB - OBJECTIVE To determine complication rates for elective gonadectomy procedures performed by veterinary students on dogs and cats in an animal shelter, characterize these complications, and compare rates with those for shelter employed veterinarians (SEVs). DESIGN Retrospective cohort study. ANIMALS 10,073 dogs and cats for which gonadectomy was performed by a veterinary student (n = 3,048 surgeries) or SEV (7,025 surgeries) at an urban animal shelter over a 16 month period. PROCEDURES Electronic medical records for included dogs and cats were reviewed and data collected regarding patient signalment, duration of gonadectomy, surgeon type (student or SEV), and types of surgical complications recorded (including death or euthanasia) during the period from anesthetic induction to 72 hours after surgery. Complication and mortality rates were compared between veterinary students and SEVs. RESULTS No significant differences were identified between students and SEVs regarding rates of overall complications for both species, minor complications for both species, major complications for both species, and overall complications for dogs or cats specifically. The most common complications were self-limiting, with no long-term consequences, for both students and SEVs. Differences in mortality rates between students and SEVs could not be definitively determined owing to low numbers of nonsurviving patients. CONCLUSIONS AND CLINICAL RELEVANCE With judicious case selection and as a part of a surgical training program, complication rates for veterinary student-performed gonadectomy procedures for dogs and cats were no different from those for SEV-performed gonadectomy procedures. We believe such information regarding patient outcomes will allow shelter staff to make informed decisions and help them in discussions with stakeholders who may have concerns about student participation. PMID- 30398429 TI - Pathology in Practice. PMID- 30398431 TI - Chest Radiographs in Congestive Heart Failure: Visualizing Neural Network Learning. AB - Purpose To examine Generative Visual Rationales (GVRs) as a tool for visualizing neural network learning of chest radiograph features in congestive heart failure (CHF). Materials and Methods A total of 103 489 frontal chest radiographs in 46 712 patients acquired from January 1, 2007, to December 31, 2016, were divided into a labeled data set (with B-type natriuretic peptide [BNP] result as a marker of CHF) and unlabeled data set (without BNP result). A generative model was trained on the unlabeled data set, and a neural network was trained on the encoded representations of the labeled data set to estimate BNP. The model was used to visualize how a radiograph with high estimated BNP would look without disease (a "healthy" radiograph). An overfitted model was developed for comparison, and 100 GVRs were blindly assessed by two experts for features of CHF. Area under the receiver operating characteristic curve (AUC), kappa coefficient, and mixed-effects logistic regression were used for statistical analyses. Results At a cutoff BNP of 100 ng/L as a marker of CHF, the correctly trained model achieved an AUC of 0.82. Assessment of GVRs revealed that the correctly trained model highlighted conventional radiographic features of CHF as reasons for an elevated BNP prediction more frequently than the overfitted model, including cardiomegaly (153 [76.5%] of 200 vs 64 [32%] of 200, respectively; P < .001) and pleural effusions (47 [23.5%] of 200 vs 16 [8%] of 200, respectively; P = .003). Conclusion Features of congestive heart failure on chest radiographs learned by neural networks can be identified using Generative Visual Rationales, enabling detection of bias and overfitted models. (c) RSNA, 2018 See also the editorial by Ngo in this issue. PMID- 30398430 TI - A Deep Learning Model to Predict a Diagnosis of Alzheimer Disease by Using 18F FDG PET of the Brain. AB - Purpose To develop and validate a deep learning algorithm that predicts the final diagnosis of Alzheimer disease (AD), mild cognitive impairment, or neither at fluorine 18 (18F) fluorodeoxyglucose (FDG) PET of the brain and compare its performance to that of radiologic readers. Materials and Methods Prospective 18F FDG PET brain images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) (2109 imaging studies from 2005 to 2017, 1002 patients) and retrospective independent test set (40 imaging studies from 2006 to 2016, 40 patients) were collected. Final clinical diagnosis at follow-up was recorded. Convolutional neural network of InceptionV3 architecture was trained on 90% of ADNI data set and tested on the remaining 10%, as well as the independent test set, with performance compared to radiologic readers. Model was analyzed with sensitivity, specificity, receiver operating characteristic (ROC), saliency map, and t distributed stochastic neighbor embedding. Results The algorithm achieved area under the ROC curve of 0.98 (95% confidence interval: 0.94, 1.00) when evaluated on predicting the final clinical diagnosis of AD in the independent test set (82% specificity at 100% sensitivity), an average of 75.8 months prior to the final diagnosis, which in ROC space outperformed reader performance (57% [four of seven] sensitivity, 91% [30 of 33] specificity; P < .05). Saliency map demonstrated attention to known areas of interest but with focus on the entire brain. Conclusion By using fluorine 18 fluorodeoxyglucose PET of the brain, a deep learning algorithm developed for early prediction of Alzheimer disease achieved 82% specificity at 100% sensitivity, an average of 75.8 months prior to the final diagnosis. (c) RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Larvie in this issue. PMID- 30398432 TI - Pediatric American Thyroid Association Guidelines Are Not Completely Applicable to Pediatric Nodule Evaluation. PMID- 30398434 TI - Building a Better Online Portal for Patients to Obtain Radiologic Results. PMID- 30398433 TI - Validity of RECIST Version 1.1 for Response Assessment in Metastatic Cancer: A Prospective, Multireader Study. AB - Purpose To determine the relationship between target lesion selection with use of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and classification of therapeutic response in patients with metastatic cancer undergoing systemic cytotoxic and/or targeted therapies. Materials and Methods This prospective multireader study was conducted between July 2015 and July 2017. Three hundred sixteen consecutive participants with metastatic cancer underwent 932 CT examinations to monitor systemic treatment. CT studies were independently read by three radiologists. Readers identified a maximum of five lesions total (and a maximum of two lesions per organ). Dedicated oncology tumor response software was used. The Fleiss kappa statistic was used to analyze interreader agreement in the assignment of individual response classes (complete response, partial response, progressive disease, or stable disease) and in the differentiation between progressive and nonprogressive disease. Results Readers selected the same set of target lesions in 128 of the 316 participants (41%) and selected a different set in 188 (59%). When target lesion selection was concordant, agreement was high (assignment of treatment response category: kappa = 0.97; 95% confidence interval [CI]: 0.91, 1.0; differentiation between progressive and nonprogressive disease: kappa = 0.98; 95% CI: 0.90, 1.0). When target lesion selection was discordant, agreement was significantly reduced (assignment of treatment response category: kappa = 0.58; 95% CI: 0.54, 0.62; differentiation between progressive and nonprogressive disease: kappa = 0.6; 95% CI: 0.59, 0.70). With concordant target lesion selection, readers agreed regarding diagnosis of progression in 97.7% of participants (95% CI: 95.4%, 100.0%); with discordant target lesion selection, readers agreed in only 55.3% (95% CI: 47.9%, 62.6%) (P < .01). Conclusion In patients with metastatic cancer undergoing systemic treatment, different cancer sites may appear similarly suitable and thus likely to be selected as target lesions but may yield inconsistent or even conflicting results with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. This indicates that the current, limited set of target lesions in RECIST 1.1 may not reflect overall tumor load or response to therapy. (c) RSNA, 2018 See also the editorial by Sosna in this issue. PMID- 30398435 TI - Quantification of Macrophages in High-Grade Gliomas by Using Ferumoxytol-enhanced MRI: A Pilot Study. AB - Purpose To investigate ferumoxytol-enhanced MRI as a noninvasive imaging biomarker of macrophages in adults with high-grade gliomas. Materials and Methods In this prospective study, adults with high-grade gliomas were enrolled between July 2015 and July 2017. Each participant was administered intravenous ferumoxytol (5 mg/kg) and underwent 3.0-T MRI 24 hours later. Two sites in each tumor were selected for intraoperative sampling on the basis of the degree of ferumoxytol-induced signal change. Susceptibility and the relaxation rates R2* (1/T2*) and R2 (1/T2) were obtained by region-of-interest analysis by using the respective postprocessed maps. Each sample was stained with Prussian blue, CD68, CD163, and glial fibrillary acidic protein. Pearson correlation and linear mixed models were performed to assess the relationship between imaging measurements and number of 400* magnification high-power fields with iron-containing macrophages. Results Ten adults (four male participants [mean age, 65 years +/- 9 {standard deviation}; age range, 57-74 years] and six female participants [mean age, 53 years +/- 12 years; age range, 32-65 years]; mean age of all participants, 58 years +/- 12 [age range, 32-74 years]) with high-grade gliomas were included. Significant positive correlations were found between susceptibility, R2*, and R2' and the number of high-power fields with CD163-positive (r range, 0.64-0.71; P < .01) and CD68-positive (r range, 0.55-0.57; P value range, .01-.02) iron containing macrophages. No significant correlation was found between R2 and CD163 positive (r = 0.33; P = .16) and CD68-positive (r = 0.24; P = .32) iron containing macrophages. Similar significance results were obtained with linear mixed models. At histopathologic analysis, iron particles were found only in macrophages; none was found in glial fibrillary acidic protein-positive tumor cells. Conclusion MRI measurements of susceptibility, R2*, and R2' (R2* - R2) obtained after ferumoxytol administration correlate with iron-containing macrophage concentration, and this shows their potential as quantitative imaging markers of macrophages in malignant gliomas. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 30398436 TI - Optimizing Electronic Release of Imaging Results through an Online Patient Portal. AB - Purpose To determine an optimal embargo period preceding release of radiologic test results to an online patient portal. Materials and Methods This prospective discrete choice conjoint survey with modified orthogonal design was administered to patients by trained interviewers at four outpatient sites and two institutions from December 2016 to February 2018. Three preferences for receiving imaging results associated with a possible or known cancer diagnosis were evaluated: delay in receipt of results (1, 3, or 14 days), method of receipt (online portal, physician's office, or phone), and condition of receipt (before, at the same time as, or after health care provider). Preferences (hereafter, referred to as utilities) were derived from parameter estimates (beta) of multinomial regression stratified according to study participant and choice set. Results Among 464 screened participants, the response and completion rates were 90.5% (420 of 464) and 99.5% (418 of 420), respectively. Participants preferred faster receipt of results (P < .001) from their physician (P < .001) over the telephone (P < .001). Each day of delay decreased preference by 13 percentage points. Participants preferred immediate receipt of results through an online portal (utility, -.57) if made to wait more than 6 days to get results in the office and more than 11 days to get results by telephone. Compared with receiving results in their physician's office on day 7 (utility, -.60), participants preferred immediate release through the online portal without physician involvement if followed by a telephone call within 6 days (utility, -0.49) or an office visit within 2 days (utility, -.53). Older participants preferred physician-directed communication (P < .001). Conclusion The optimal embargo period preceding release of results through an online portal depends on the timing of traditional telephone- and office-based styles of communication. (c) RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Arenson et al in this issue. PMID- 30398437 TI - Is RECIST Version 1.1 Reliable for Tumor Response Assessment in Metastatic Cancer? PMID- 30398438 TI - Machine Learning in Radiology: Resistance Is Futile. PMID- 30398439 TI - Acute Flaccid Myelitis in a 10-Year-Old Girl. PMID- 30398440 TI - Long-term Graft and Patient Survival after Percutaneous Angioplasty or Arterial Stent Placement for Transplant Renal Artery Stenosis: A 21-Year Matched Cohort Study. AB - Purpose To compare long-term graft and patient survival after percutaneous angioplasty (PTA) or stent placement for transplant renal artery stenosis (TRAS) with a control cohort without TRAS. Materials and Methods This is a retrospective matched cohort study of 41 patients (median age, 49 years; range, 18-72 years), including 27 male patients (median age, 48 years; range, 18-67 years) and 14 female patients (median age, 52 years; range, 24-68 years), with TRAS from December 1995 through 2016. Primary end points were death-censored graft and patient survival, compared by using log-rank test and Cox proportional regression. Secondary outcomes were improvement in renal function, blood pressure (BP), and complications. Results Twenty-four patients underwent PTA and 17 received stent placements. Ten-year graft survival was 92.1% (range, 83.2%-100%) versus 81.4% (range, 67.8%-95.3%) (P = .56), and 10-year patient survival was 89.9% (79.1%-100%) versus 84.7% (72.1%-97.5%) (P = .49), for the study and control groups, respectively. Five patients (12%) resumed dialysis in each group and a total of 17 patients died (eight in the study group and nine in the control group). Most patients died with a functioning graft (seven of eight in the study group and seven of nine in the control group). Posttreatment median systolic and diastolic BP improved by 12% and 7.4%, respectively, and serum creatinine improved by 27%. Normal systolic BP and serum creatinine level at 1 year after treatment were associated with better survival for patients (P = .04; hazard ratio [HR], 1.04; 95% confidence interval [CI]: 1.0, 1.075) and grafts (P < .001; HR, 1.02; 95% CI: 1.0, 1.027). Other covariates, including PTA versus renal stent placement, intra-arterial pressure gradient greater than 10%, diastolic BP, age at transplantation, sex, graft type, rejection, and delayed graft function, were not significant. Five patients (12.2%) had a complication (Society of Interventional Radiology class A, two of 41 [4.9%]; class B, two of 41 [4.9%]; and class D, one of 41 [2.4%]); 30-day graft loss and patient mortality were zero. Conclusion Long-term graft and patient survival after endovascular correction of transplant renal artery stenosis (TRAS) was similar to that without TRAS and most patients avoided returning to dialysis. (c) RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Dickey and Durrani in this issue. PMID- 30398441 TI - Does Endovascular Intervention for Transplant Renal Artery Stenosis Improve Outcomes at 10 Years? PMID- 30398442 TI - Using a Deep Learning Network to Diagnose Congestive Heart Failure. PMID- 30398443 TI - Editor's Note: Publication of AI Research in Radiology. PMID- 30398444 TI - Simplified PI-RADS with Biparametric MRI: A Practical Approach to Improve Management of PI-RADS Version 2 Category 3 Lesions. PMID- 30398445 TI - In this issue - Innovation to build learning health systems. PMID- 30398446 TI - The robot will see you now? PMID- 30398448 TI - Development of a National Core Dataset for the Iranian ICU Patients Outcome Prediction; a Comprehensive Approach. AB - OBJECTIVE: To define a core dataset for ICU Patients Outcome Prediction in Iran. This core data set will lead us to design ICU outcome prediction models with the most effective parameters. METHODS: A combination of literature review, national survey and expert consensus meetings were used. First, a literature review was performed by a general search in PubMed to find the most appropriate models for intensive care mortality prediction and their parameters. Secondly, in a national survey, experts from a couple of medical centers in all parts of Iran were asked to comment on a list of items retrieved from the earlier literature review study. In the next step, a multi-disciplinary committee of experts was installed. In 4 meetings each data item was examined separately and included/excluded by committee consensus. RESULTS: The combination of the literature review findings and experts' consensus resulted in a draft dataset including 26 data items. 92% percent of data items in the draft dataset were retrieved from the literature study and the others were suggested by the experts. The final dataset of 24 data items covers patient history and physical examination, chemistry, vital signs, oxygenations and some more specific parameters. Conclusions: This dataset was designed to develop a nationwide prognostic model for predicting ICU mortality and length of stay. This dataset opens the door for creating standardized approaches in data collection in the Iranian intensive care unit estimation of resource utility. PMID- 30398447 TI - The WHAAM Application: a Tool to Support the Evidence-Based Practice in the Functional Behaviour Assessment. AB - BACKGROUND: The most recent computing technologies can promote the application of evidence-based practice (EBP) in the field of Applied Behavior Analysis (ABA). OBJECTIVE: The study describes how the use of technology can simplify the application of evidence-based practices in applied behaviour analysis. METHODS: The WHAAM application demonstrates this in the following two case studies. We are monitoring dysfunctional behaviours, collecting behavioural data, performing systematic direct observations, creating a visual baseline and intervention charts and evaluating the planned interventions using the TAU-U statistical index. RESULTS: Significant positive changes of children's problem behaviours are observed and recorded. Both the duration of the identified behaviour "to get out of bed in time" (r = -.79, TAU-U = -.58, p < .05) and the frequency of the behaviour "interrupting others" (r= -.96, TAU-U = -.82, p < .01) decreased. CONCLUSION: the WHAAM application is an effective tool to support functional behaviour assessments and it is an example of how technology can support practitioners by facilitating the application of evidence-based practices and increasing the communication among clinical, educational and family environments. PMID- 30398449 TI - The Heimdall Framework for Supporting Characterisation of Learning Health Systems. AB - BACKGROUND: Learning Health Systems (LHS) can focus population medicine and Evidence Based Practice; smart technology delivering the next generation of improved healthcare described as Precision Medicine, and yet researchers in the LHS domain presently lack the ability to recognise their relevant works as falling within this domain. OBJECTIVE: To review LHS literature and develop a framework describing the domain that can be used as a tool to analyse the literature and support researchers to identify health informatics investigations as falling with the domain of LHS. METHOD: A scoping review is used to identify literature on which analysis was performed. This resolved the ontology and framework. The ontology was applied to quantify the distribution of classifications of LHS solutions. The framework was used to analyse and characterise the various works within the body of LHS literature. RESULTS: The ontology and framework developed was shown to be easily applicable to the literature, consistently describing and representing the goals, intentions and solutions of each LHS investigation in the literature. More proposed or potential solutions are described in the literature than implemented LHS. This suggests immaturity in the domain and points to the existence of barriers preventing LHS realisation. CONCLUSION: The lack of an ontology and framework may have been one of the causes for the failure to describe research works as falling within the LHS domain. Using our ontology and framework, LHS research works could be easily classified, demonstrating the comprehensiveness of our approach in contrast to earlier efforts. PMID- 30398450 TI - Understanding optimization processes of electronic health records (EHR) in select leading hospitals: a qualitative study. AB - BACKGROUND: Little is known about optimization of electronic health records (EHR) systems in the hospital setting while adoption of EHR systems continues in the United States. OBJECTIVE: To understand optimization processes of EHR systems undertaken in leading healthcare organizations in the United States. METHODS: Informed by grounded theory approach, a qualitative study was undertaken that involved 11 in-depth interviews and a focus group with the EHR experts from the high performing healthcare organizations across the United States. RESULTS: The study describes EHR optimization processes characterized by prioritizing exponentially increasing requests with predominant focus on improving efficiency of EHR, building optimization teams or advisory groups, and standardization. The study discusses 16 types of optimization that interdependently produced 16 results along with identifying 11 barriers and 20 facilitators to optimization. CONCLUSION: The study describes overall experiences of optimizing electronic health records in select high performing healthcare organizations in the US. The findings highlight the importance of optimizing the EHR after, and even before, go-live and dedicating resources exclusively for optimization. PMID- 30398451 TI - Chief Information Officer team evolution in university hospitals: interaction of the three 'C's (CIO, CCIO, CRIO). AB - BACKGROUND: The Chief Information Officer (CIO) and Chief Clinical Information Officer (CCIO) are now established senior roles in hospital practice. With increasing emphasis on optimising use of routine health data for secondary purposes and research, additional skills are required as part of the senior information officer team, particularly in academic health care institutions. OBJECTIVE: Here we present the role of the Chief Research Information Officer (CRIO), as an emerging, and important, component of the senior information team. Method: We review recent publications describing the composition of the senior information team, including CIO and CCIO roles, and present evidence for development of the CRIO as a distinct component of the team. RESULTS: The CRIO is emerging as an additional senior role in academic healthcare institutions, whose roles include leadership of the informatics strategy and optimisation of routine data collection systems for research data use. Such individuals should be senior clinicians with experience in informatics, in addition to having established research expertise and knowledge of research processes, governance and academic networks. CONCLUSION: The CRIO is emerging as a distinct senior information leadership role in conjunction with the already established positions of CCIO and CIO, who together, can provide optimal oversight of digital activities across the organisation. PMID- 30398452 TI - What to expect from electronic patient record system implementation; lessons learned from published evidence. AB - BACKGROUND: Numerous studies have examined specific factors related to success, failure and implications of Electronic patient record (EPR) system implementations, but usually limited to specific aspects. Objective: To review the published peer-reviewed literature and present findings regarding factors important in relation to successful EPR implementations and likely impact on subsequent clinical activity. METHOD: Literature reviewResults: 312 potential articles were identified on initial search of which 117 were relevant and included in the review. Several factors were related to implementation success, such as good leadership and management, infrastructure support, staff training and focus on workflows and usability. In general, EPR implementation is associated with improvements in documentation, and screening performance, and reduced prescribing errors, whereas there are minimal available data in other areas such as effects on clinical patient outcomes. The peer-reviewed literature appears to under-represent a range of technical factors important for EPR implementations, such as data migration from existing systems and impact of organisational readiness. CONCLUSION: The findings presented here represent synthesis of data from peer-reviewed literature in the field and should be of value to provide the evidence-base for organisations considering how best to implement an EPR system. PMID- 30398453 TI - Can we trust Electronic health records? The Smoking Test for Commission Errors. AB - BACKGROUND: Considerable interest exists on using general practice electronic health records (EHR) for research and other uses. There is also concern on their quality. AIM: We suggest a simple test to assess errors of commission and in consequence overall EHR data quality that can be done on a periodical basis. METHOD: Patient records with simultaneous entries of three different stages on smoking were studied. The codes "Never smoked tobacco", "smoker" and "ex-smoker" should follow this chronological order. It should then be possible to extrapolate the overall level of errors of commission for the organisation. RESULTS: The Smoking Test in our sample found errors in 169 patients, with 60 cases where dual errors were discovered. We express it as an estimated error of commission level of 2.6% related to the total population of the practice. CONCLUSIONS: Considering the constant and regular entries on smoking status (83.59% of the entries were done over last month), we can conclude smoking entries analysis can serve as a simple test to periodically assess the overall EHR data quality, and any trends. PMID- 30398454 TI - Learning health systems need to bridge the 'two cultures' of clinical informatics and data science. AB - Background UK health research policy and plans for population health management are predicated upon transformative knowledge discovery from operational "Big Data". Learning health systems require not only data, but feedback loops of knowledge into changed practice. This depends on knowledge management and application, which in turn depend upon effective system design and implementation. Biomedical informatics is the interdisciplinary field at the intersection of health science, social science and information science and technology that spans this entire scope. Issues In the UK, the separate worlds of health data science (bioinformatics, "Big Data") and effective healthcare system design and implementation (clinical informatics, "Digital Health") have operated as 'two cultures'. Much NHS and social care data is of unusably poor quality. Substantial research funding is wasted on 'data cleansing' or by producing very weak evidence. There is not yet a sufficiently powerful professional community or evidence base of best practice to influence the practitioner community or the digital health industry. Recommendation The UK needs increased clinical informatics research and education capacity and capability at much greater scale and ambition to be able to meet policy expectations, address the fundamental gaps in the discipline's evidence base and mitigate the absence of regulation.Independent evaluation of digital health interventions should be the norm, not the exception. Conclusions Policy makers and research funders need to acknowledge the existing gap between the 'two cultures' and recognise that the full social and economic benefits of digital health and data science can only be realised by accepting the interdisciplinary nature of biomedical informatics and supporting a significant expansion of clinical informatics capacity and capability. PMID- 30398455 TI - In this issue: Digital disparities, complexity and patient safety. AB - In this issue we publish articles about how digital health and the skills needed to use it may increase disparities. PMID- 30398456 TI - Automated conflict resolution between multiple clinical pathways: a technology report. AB - BACKGROUND: The number of people in the UK with three or more long-term conditions continues to grow and the management of patients with co-morbidities is complex. In treating patients with multimorbidities, a fundamental problem is understanding and detecting points of conflict between different guidelines which to date has relied on individual clinicians collating disparate information. OBJECTIVE: We will develop a framework for modelling a diverse set of care pathways, and investigate how conflicts can be detected and resolved automatically. We will use this knowledge to develop a software tool for use by clinicians that can map guidelines, highlight root causes of conflict between these guidelines and suggest ways they might be resolved. METHOD: Our work consists of three phases. First, we will accurately model clinical pathways for six of the most common chronic diseases; second, we will automatically identify and detect sources of conflict across the pathways and howthey might be resolved. Third, we will present a case study to prove the validity of our approach using a team of clinicians to detect and resolve the conflicts in the treatment of a fictional patient with multiple common morbidities and compare their findings and recommendations with those derived automatically using our novel software. DISCUSSION: This paper describes the development of an important software-based method for identifying a conflict between clinical guidelines. Our findings will support clinicians treating patients with multimorbidity in both primary and secondary care settings. PMID- 30398457 TI - Influence of previous work experience and education on Internet use of people in their 60s and 70s. AB - BACKGROUND: Internet use among the elderly is influenced by various demographic backgrounds, social life and health factors. OBJECTIVE: This study aims to identify the impact of several demographic features on 60- to 79-year-old individuals' intention to use the Internet. METHOD: Finland population data (N = 2508) from the 2012 IKIPOSA project was used with two cohorts: 60s group (n = 1515) and 70s group (n = 990). Descriptive statistic and two binomial logistic regressions have been used with the unadjusted effect and Forward LR method to measure each predictor's contribution to the model. In addition, a preliminary analysis to measure the multicollinearity was performed. RESULT: Of the 18 independent variables, only nine predictors, namely, age, education, financial situation, having children, entrepreneurship, a leadership position, a higher level white-collar worker and a lower level white-collar worker, were significant factors in predicting the Internet use. Meanwhile, gender, having grandchildren, living alone, marital status, house location and type, stay-at-home mother or father, blue-collar worker, agricultural entrepreneur and social relations satisfaction were not significant predictors. The most significant predictors were education and age, which contributed 19% and 10%, respectively, to the model. Other significant predictors, lower level white-collar worker, higher level white-collar worker and financial situation, had less impact with only around 6%. CONCLUSION: Education and age were influential factors among elderly to use the Internet in their later life. Certain work experiences affect elderly people's engagement with the Internet after retirement. PMID- 30398458 TI - Who adopts a patient portal?: An application of the diffusion of innovation model. AB - BACKGROUND: Patient portals have emerged as an important tool through which patients can access online health information and engage in their health care. However, we know little about how patients perceive portals and whether patient perceptions might influence portal adoption. OBJECTIVE: Apply the diffusion of innovation (DOI) theory to assess perceptions of adopters and non-adopters of a patient portal. METHODS: We conducted a cross-sectional survey of adopters and non-adopters of the portal. Our survey consisted of perceived attributes from the DOI theory, socio-demographic characteristics and patient perceptions of technology adoption. RESULTS: Three factors representing perceived attributes from DOI theory accounted for 73% of the variance in the data: Factor 1 - Relative Advantage (27%); Factor 2 - Ease of Use (24%) and Factor 3 - Trialability (22%). Adopters perceived greater Relative Advantage [mean (SD)] = 3.8 (0.71) versus 3.2 (0.89), p < 0.001, Ease of Use = 4.1 (0.71) versus 3.3 (0.95), p < 0.001 and Trialability = 4.0 (0.57) versus 3.4 (0.99), p < 0.001 than non-adopters. In multivariate modelling, age [OR = 3.75, 95% CI: (2.17, 6.46), p < 0.001] and income [OR = 1.87, 95% CI: (1.17, 3.00), p < 0.01] predicted adoption of the portal. Among DOI factors, Relative advantage predicted adoption of the portal [OR = 1.48, 95% CI: (1.03, 2.11), p < 0.05]. CONCLUSION: Patients will adopt a patient portal if they perceive it to offer a relative advantage over existing practices such as telephoning or visiting the doctor's office. Organisations seeking to increase the adoption of patient portals should implement strategies to promote the relative advantage of portals as, for example, through posters in waiting and exam rooms. A digital divide in the adoption of patient portals may exist with respect to age and income. PMID- 30398459 TI - Designing health information technology tools for behavioral health clinicians integrated within a primary care team. AB - BACKGROUND: Electronic health records (EHRs) are a key tool for primary care practice. However, EHR functionality is not keeping pace with the evolving informational and decision-support needs of behavioral health clinicians (BHCs) working on integrated teams. OBJECTIVE: Describe workflows and tasks of BHCs working with integrated teams, identify their health information technology needs, and develop EHR tools to address them. METHOD: A mixed-methods, comparative-case study of six community health centers (CHCs) in Oregon, each with at least one BHC integrated in their primary care team. We observed clinical work and conducted interviews to understand workflows and clinical tasks, aiming to identify how effectively current EHRs supported integrated care delivery, including transitions, documentation, information sharing, and decision making. We analyzed these data and employed a user-centered design process to develop EHR tools addressing the identified needs. RESULTS: BHCs used the primary care EHR for documentation and communication with other team members, but the EHR lacked the functionality to fully support integrated care. Needs include the ability to: (1) automate and track paper-based screening; (2) document behavioral health history; (3) access patient social and medical history relevant to behavioral health issues, and (4) rapidly document and track progress on goals. To meet these needs, we engaged users and developed a set of EHR tools called the BH e Suite. CONCLUSION: Integrated primary care teams, and particularly BHCs, have unique information needs, workflows and tasks. These needs can be met and supported by the EHR with a moderate level of modification. PMID- 30398460 TI - Patient-centric implementation of an electronic medication management system at a tertiary hospital in Western Sydney. AB - BACKGROUND: Traditional implementations of electronic medication management (EMM) systems have involved two common formats - a 'big bang' approach on the day of go live, or a phased ward-by-ward approach over months. OBJECTIVE: To describe the patient-centric roll-out, a novel implementation model in converting from paper to EMM. METHOD: This model iteratively converted a large tertiary teaching hospital to electronic from paper medication charts, commencing the roll-out in the emergency department (ED). The tenet of 'one patient, one chart' was maintained with new patients commenced on EMM, while existing inpatients were maintained on paper charts until their discharge. In the second week, all other intake points commenced patients on EMM, and in the third week, all remaining patients were manually converted to EMM. The implementation was assessed with training completion rates, staff satisfaction surveys, focus group interviews and incident logs. RESULTS: At go-live, 79% of doctors, 68% of nurses and 90% of pharmacists were trained in the EMM system. The ED converted to electronic prescribing within 24 hours; by day 20, all patients were on EMM. Two hundred and thirty issues were logged, none critical, of which 22 were escalated. Of the 51,063 medications administered, there were 13 EMM-related clinical incidents including three double dosing errors, none of which led to an adverse event or death. Overall, 77% of staff surveyed were satisfied with the EMM implementation. CONCLUSIONS: The patient-centric roll-out model represents an innovative and safe approach with a single medication chart reducing transcription and improved medication safety for the patient and the organisation. PMID- 30398461 TI - Community-based screening for cardiovascular risk using a novel mHealth tool in rural Kenya. AB - BACKGROUND: An increasing burden of cardiovascular disease (CVD) in low-resource settings demands innovative public health approaches. OBJECTIVES: To design and test a novel mHealth tool for use by community health workers (CHWs) to identify individuals at high CVD risk who would benefit from education and/or pharmacologic interventions. METHODS: We designed and implemented a novel two-way mobile phone application, "AFYACHAT," to rapidly screen for CVD risk in rural Kenya. AFYACHAT collects and stores SMS text message data entered by a CHW on a subject's age, sex, smoking, diabetes, and systolic blood pressure, and returns as SMS text message the category of 10-year CVD risk: "GREEN" (<10% 10 year risk of cardiovascular event), "YELLOW" (10 to <20%), "orange"(20 to <30%), or "RED" (>=30%). CHWs were equipped and trained to use an automated blood pressure device and the mHealth tool. RESULTS: Five CHWs screened 2,865 subjects in remote rural communities in Kenya over a 22 month period (2015-17). The median age of subjects was 50 (IQR 43 to 60) and 1581 (55%) were female. Point prevalence of hypertension (systolic blood pressure>140mmHg), diabetes, and tobacco use were 23%, 3.2%, and 22%, respectively. Overall, the 10-year risk of CVD among patients was <10% in 2778 (97%) patients, 10 to <20% in 65 (2.3%), 20 to <30% in 12 (0.4%), and >=30% in 10 (0.2%). CONCLUSION: We have developed a mHealth tool that can be used by CHWs to screen for CVD risk factors, demonstrating proof-of concept in rural Kenya. PMID- 30398462 TI - SMASH! The Salford medication safety dashboard. AB - BACKGROUND: Patient safety is vital to well-functioning health systems. A key component is safe prescribing, particularly in primary care where most medications are prescribed. Previous research demonstrated that the number of patients exposed to potentially hazardous prescribing can be reduced by interrogating the electronic health record (EHR) database of general practices and providing feedback to general practitioners in a pharmacist-led intervention. We aimed to develop and roll out an online dashboard application that delivers this audit and feedback intervention in a continuous fashion. METHOD: Based on initial system requirements we designed the dashboard's user interface over 3 iterations with 6 general practitioners (GPs), 7 pharmacists and a member of the public. Prescribing safety indicators from previous work were implemented in the dashboard. Pharmacists were trained to use the intervention and deliver it to general practices. RESULTS: A web-based electronic dashboard was developed and linked to shared care records in Salford, UK. The completed dashboard was deployed in all but one (n=43) general practices in the region. By November 2017, 36 pharmacists had been trained in delivering the intervention to practices. There were 135 registered users of the dashboard, with an average of 91 user sessions a week. CONCLUSION: We have developed and successfully rolled out of a complex, pharmacist-led dashboard intervention in Salford, UK. System usage statistics indicate broad and sustained uptake of the intervention. The use of systems that provide regularly updated audit information may be an important contributor towards medication safety in primary care. PMID- 30398463 TI - The Use of Slack for Medical Residency Development and Recruiting. PMID- 30398464 TI - Interoperability in Health and Social Care: Organizational Issues are the Biggest Challenge. AB - A great asset of any healthcare system is "information" which includes, but not limited to patient data, clinical history and treatments. It is no secret that there is a growing demand for healthcare, however, this demand is yet to be achieved due to the challenge in the limitation of resources and the complexity of the problem area. PMID- 30398465 TI - Dominant negative SERPING1 variants cause intracellular retention of C1-inhibitor in hereditary angioedema. AB - Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent edema attacks associated with morbidity and mortality. HAE results from variations in the SERPING1 gene encoding C1 inhibitor (C1INH), a serine protease inhibitor (serpin). Reduced plasma levels of C1INH lead to enhanced activation of the contact system triggering high levels of bradykinin and increased vascular permeability, but the cellular mechanisms leading to low C1INH levels (20-30% of normal) in heterozygous HAE type I patients remain obscure. Here, we showed that C1INH encoded by a subset of HAE-causing SERPING1 alleles affected secretion of normal C1INH protein in a dominant negative fashion by triggering formation of protein-protein interactions between normal and mutant C1INH leading to creation of larger intracellular C1INH aggregates that were trapped in the endoplasmic reticulum (ER). Notably, intracellular aggregation of C1INH and ER abnormality were observed in fibroblasts from a heterozygous carrier of a dominant negative SERPING1 gene variant, but the condition was ameliorated by viral delivery of the SERPING1 gene. Collectively, our data link abnormal accumulation of serpins, a hallmark of serpinopathies, with dominant negative disease mechanisms affecting C1INH plasma levels in HAE type I patients and may pave the way for new treatments of HAE. PMID- 30398466 TI - Autosomal recessive, familial, isolated dilated cardiomyopathy due to compound desmoplakin gene mutations. PMID- 30398467 TI - Current management of acute diarrheal infections in adults. AB - New guidelines on the management of acute diarrhea in adults were promulgated in 2016. The aim of this review was to provide an overview of the context of acute diarrhea and how to generally approach a patient; to present some new areas in the field concerning diagnostics, particularly culture-independent testing, as well as some of the risks and benefits of treatment; and to discuss prevention, particularly in the traveler's diarrhea setting. PMID- 30398468 TI - Evaluation of serotonin and dopamine secretion and metabolism in patients with irritable bowel syndrome. PMID- 30398469 TI - Complete genome sequencing of Comamonas kerstersii 8943, a causative agent for peritonitis. AB - Because of poor differentiation among the members of genus Comamonas using phenotypic methods, human infections caused by C. kerstersii are sporadically reported in the literature. Here, we represent the first complete genome sequence of C. kerstersii 8943, which caused peritonitis in a patient with continuous ambulatory peritoneal dialysis (CAPD). The complete genome with no gaps was obtained using third-generation Pacific Biosciences (PacBio) RSII sequencing system with single-molecule real-time (SMRT) analysis. Protein-coding genes, rRNAs and tRNAs were predicted. Functional annotations of the genome using different databases revealed several genes related to pathogenicity including antibiotic resistance genes and prophages. Our work demonstrates that whole genome sequencing can enhance the resolution of clinical investigations and our data can be used as a reference genome during the rapid diagnosis of C. kerstersii infections in the future. PMID- 30398471 TI - Comprehensive transcriptome analysis of Sarcophaga peregrina, a forensically important fly species. AB - Sarcophaga peregrina (flesh fly) is a frequently found fly species in Palaearctic, Oriental, and Australasian regions that can be used to estimate minimal postmortem intervals important for forensic investigations. Despite its forensic importance, the genome information of S. peregrina has not been fully described. Therefore, we generated a comprehensive gene expression dataset using RNA sequencing and carried out de novo assembly to characterize the S. peregrina transcriptome. We obtained precise sequence information for RNA transcripts using two different methods. Based on primary sequence information, we identified sets of assembled unigenes and predicted coding sequences. Functional annotation of the aligned unigenes was performed using the UniProt, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes databases. As a result, 26,580,352 and 83,221 raw reads were obtained using the Illumina MiSeq and Pacbio RS II Iso-Seq sequencing applications, respectively. From these reads, 55,730 contigs were successfully annotated. The present study provides the resulting genome information of S. peregrina, which is valuable for forensic applications. PMID- 30398470 TI - Enabling precision medicine in neonatology, an integrated repository for preterm birth research. AB - Preterm birth, or the delivery of an infant prior to 37 weeks of gestation, is a significant cause of infant morbidity and mortality. In the last decade, the advent and continued development of molecular profiling technologies has enabled researchers to generate vast amount of 'omics' data, which together with integrative computational approaches, can help refine the current knowledge about disease mechanisms, diagnostics, and therapeutics. Here we describe the March of Dimes' Database for Preterm Birth Research (http://www.immport.org/resources/mod), a unique resource that contains a variety of 'omics' datasets related to preterm birth. The database is open publicly, and as of January 2018, links 13 molecular studies with data across tens of thousands of patients from 6 measurement modalities. The data in the repository are highly diverse and include genomic, transcriptomic, immunological, and microbiome data. Relevant datasets are augmented with additional molecular characterizations of almost 25,000 biological samples from public databases. We believe our data sharing efforts will lead to enhanced research collaborations and coordination accelerating the overall pace of discovery in preterm birth research. PMID- 30398472 TI - Brain metastasis DNA methylomes, a novel resource for the identification of biological and clinical features. AB - Brain metastases (BM) are one the most lethal and poorly managed clinical complications in cancer patients. These secondary tumors represent the most common intracranial neoplasm in adults, most frequently originating from lung cancer, breast cancer, and cutaneous melanoma. In primary brain tumors, such as gliomas, recent advances in DNA methylation profiling have allowed for a comprehensive molecular classification. Such data provide prognostic information, in addition to helping predict patient response to specific systemic therapies. However, epigenetic alterations of metastatic brain tumors with specific biological and translational relevance still require much further exploration. Using the widely employed Illumina Infinium HumanMethylation 450K platform, we have generated a cohort of genome-wide DNA methylomes from ninety-six needle dissected BM specimens from patients with lung cancer, breast cancer, and cutaneous melanoma with clinical, pathological, and demographic annotations. This resource offers an unprecedented and unique opportunity to identify novel DNA methylation features influencing the behavior of brain metastasis, and thus accelerate the discovery of BM-specific theranostic epigenetic alterations. PMID- 30398473 TI - De novo assembly and annotation of three Leptosphaeria genomes using Oxford Nanopore MinION sequencing. AB - Leptosphaeria maculans and Leptosphaeria biglobosa are ascomycete phytopathogens of Brassica napus (oilseed rape, canola). Here we report the complete sequence of three Leptosphaeria genomes (L. maculans JN3, L. maculans Nz-T4 and L. biglobosa G12-14). Nz-T4 and G12-14 genome assemblies were generated de novo and the reference JN3 genome assembly was improved using Oxford Nanopore MinION reads. The new assembly of L. biglobosa showed the existence of AT rich regions and pointed to a genome compartmentalization previously unsuspected following Illumina sequencing. Moreover nanopore sequencing allowed us to generate a chromosome-level assembly for the L. maculans reference isolate, JN3. The genome annotation was supported by integrating conserved proteins and RNA sequencing from Leptosphaeria-infected samples. The newly produced high-quality assemblies and annotations of those three Leptosphaeria genomes will allow further studies, notably focused on the tripartite interaction between L. maculans, L. biglobosa and oilseed rape. The discovery of as yet unknown effectors will notably allow progress in B. napus breeding towards L. maculans resistance. PMID- 30398474 TI - X-ray computed microtomography of Megachirella wachtleri. AB - Understanding the origin and early evolution of squamates has been a considerable challenge given the extremely scarce fossil record of early squamates and their poor degree of preservation. In order to overcome those limitations, we conducted high-resolution X-ray computed tomography (CT) studies on the fossil reptile Megachirella wachtleri (Middle Triassic, northern Italy), which revealed an important set of features indicating this is the oldest known fossil squamate in the world, predating the previous oldest record by ca. 75 million years. We also compiled a new phylogenetic data set comprising a large sample of diapsid reptiles (including morphological and molecular data) to investigate the phylogenetic relationships of early squamates and other reptile groups along with the divergence time of those lineages. The re-description of Megachirella and a new phylogenetic hypothesis of diapsid relationships are presented in a separate study. Here we present the data descriptors for the tomographic scans of Megachirella, which holds fundamental information to our understanding on the early evolution of one of the largest vertebrate groups on Earth today. PMID- 30398475 TI - A global dataset of air temperature derived from satellite remote sensing and weather stations. AB - Air temperature at 2 m above the land surface is a key variable used to assess climate change. However, observations of air temperature are typically only available from a limited number of weather stations distributed mainly in developed countries, which in turn may often report time series with missing values. As a consequence, the record of air temperature observations is patchy in both space and time. Satellites, on the other hand, measure land surface temperature continuously in both space and time. In order to combine the relative strengths of surface and satellite temperature records, we develop a dataset in which monthly air temperature is predicted from monthly land surface temperature for the years 2003 to 2016, using a statistical model that incorporates information on geographic and climatic similarity. We expect this dataset to be useful for various applications involving climate monitoring and land-climate interactions. PMID- 30398476 TI - A high-resolution streamflow and hydrological metrics dataset for ecological modeling using a regression model. AB - Hydrological variables are among the most influential when analyzing or modeling stream ecosystems. However, available hydrological data are often limited in their spatiotemporal scale and resolution for use in ecological applications such as predictive modeling of species distributions. To overcome this limitation, a regression model was applied to a 1 km gridded stream network of Germany to obtain estimated daily stream flow data (m3 s-1) spanning 64 years (1950-2013). The data are used as input to calculate hydrological indices characterizing stream flow regimes. Both temporal and spatial validations were performed. In addition, GLMs using both the calculated and observed hydrological indices were compared, suggesting that the predicted flow data are adequate for use in predictive ecological models. Accordingly, we provide estimated stream flow as well as a set of 53 hydrological metrics at 1 km grid for the stream network of Germany. In addition, we provide an R script where the presented methodology is implemented, that uses globally available data and can be directly applied to any other geographical region. PMID- 30398477 TI - Finding a sensible approach to sensitive data. PMID- 30398479 TI - Apalutamide for the treatment of patients with castration-resistant prostate cancer. AB - Patients with recurrent, nonmetastatic prostate cancer after curative intent therapy can experience a heterogeneous clinical course ranging from indolent disease that can be observed for years to a rapidly progressive disease that is metastatic in a relatively short time. Patients with short prostate-specific antigen (PSA) doubling times are at risk for early development of metastatic disease and are frequently placed on androgen deprivation therapy. Although castration-resistant disease inevitably occurs in these patients, most therapies for castration-resistant disease have shown benefit in the metastatic setting. Apalutamide is a nonsteroidal antiandrogen agent that binds directly to the ligand-binding domain of the androgen receptor, preventing androgen receptor translocation, DNA binding and androgen receptor-mediated transcription. Apalutamide showed improved metastasis-free survival and prolonged time to symptomatic progression in men with nonmetastatic castration-resistant prostate cancer with a short PSA doubling time. PMID- 30398478 TI - Insights on the persistence of pines (Pinus species) in the Late Cretaceous and their increasing dominance in the Anthropocene. AB - Although gymnosperms were nearly swept away by the rise of the angiosperms in the Late Cretaceous, conifers, and pines (Pinus species) in particular, survived and regained their dominance in some habitats. Diversification of pines into fire avoiding (subgenus Haploxylon) and fire-adapted (subgenus Diploxylon) species occurred in response to abiotic and biotic factors in the Late Cretaceous such as competition with emerging angiosperms and changing fire regimes. Adaptations/traits that evolved in response to angiosperm-fuelled fire regimes and stressful environments in the Late Cretaceous were key to pine success and are also contributing to a new "pine rise" in some areas in the Anthropocene. Human-mediated activities exert both positive and negative impacts of range size and expansion and invasions of pines. Large-scale afforestation with pines, human mediated changes to fire regimes, and other ecosystem processes are other contributing factors. We discuss traits that evolved in response to angiosperm mediated fires and stressful environments in the Cretaceous and that continue to contribute to pine persistence and dominance and the numerous ways in which human activities favor pines. PMID- 30398481 TI - Sodium zirconium cyclosilicate: a new potassium binder for the treatment of hyperkalemia. AB - Hyperkalemia is one of the most common electrolyte disturbances, especially among some groups of patients, such as in those with chronic kidney disease, diabetes or heart failure. Hyperkalemia has been associated with increased risks of mortality, arrhythmias, hospitalization and costs, as well as the need to down titrate/discontinue renin-angiotensin-aldosterone system inhibitors (RAASIs), despite their well-known cardiovascular and nephroprotective benefits. Current potassium binders have limitations (slow onset of action, limited selectivity for potassium binding, risk of drug interactions or gastrointestinal intolerance). Sodium zirconium cyclosilicate (SZC) is a new potassium binder recently approved for the treatment of chronic hyperkalemia. It is a nonabsorbable, inorganic crystal which selectively binds potassium and ammonium in exchange of Na+ and H+ in the whole gastrointestinal tract, achieving a rapid correction of serum potassium levels (within 2 days) and maintaining normokalemia in the long term (up to 1 year), with a good safety profile (common adverse reactions include gastrointestinal events and a dose-dependent risk of edema), excellent tolerability and a low potential for drug interactions. Its potassium-lowering efficacy is maintained irrespective of the use of RAASIs. In summary, SZC is a new potassium binder recently approved for the treatment of hyperkalemia. Its differences with respect to currently available potassium binders make SZC an attractive therapeutic option. PMID- 30398480 TI - Emicizumab for routine prophylaxis to prevent bleeding episodes in patients with hemophilia A. AB - Hemophilia A is an X-linked bleeding disorder caused by defects in the gene encoding factor VIII (FVIII). Routine prophylaxis with exogenous FVIII requires frequent intravenous injections. One of the most challenging issues in the treatment of hemophilia A is the development of alloantibodies against infused FVIII. Presence of inhibitors results in an ineffective factor replacement therapy and increases the risk of morbidity and mortality in these patients. Therefore, there is growing interest in the development of new strategies for the prophylaxis and prevention of bleeding in patients with hemophilia to circumvent these drawbacks. Emicizumab (ACE-910; Roche, Genentech and Chugai Pharmaceutical) is a recombinant humanized bispecific antibody that restores the function of missing FVIII by bridging activated FIX and FX, simulating the cofactor function of FVIII. PMID- 30398482 TI - An update of treatments of hepatocellular carcinoma in patients refractory to sorafenib. AB - Hepatocellular carcinoma (HCC) remains among the neoplastic diseases with the most unfavorable prognosis. Historically, systemic treatments for HCC have been scarce. In particular, sorafenib was the only registered drug for the treatment of unresectable HCC until 2017. Last year, regorafenib was approved by the global regulatory agencies as second-line therapy. Since then, further randomized, controlled trials have been successful in this patient population. This paper deals with the most recent data concerning cabozantinib and ramucirumab, the two drugs that have recently demonstrated efficacy in phase III, randomized, controlled trials in HCC patients who failed previous treatment with sorafenib. PMID- 30398483 TI - Life sciences licensing deals in the second quarter of 2018: updates and trends. AB - During the second quarter of 2018, Cortellis Competitive Intelligence registered 985 new deals (excluding mergers and acquisitions) with a total disclosed deal value of USD 19.5 billion as part of its ongoing coverage of licensing activity in the life sciences sector compared to 964 and USD 35.6 billion in the first quarter and 1,104 and USD 13.6 billion in the second quarter of 2017. Total deal value in the second quarter did not quite reach the peak of 2014 (paced by Novartis' USD 16 billion purchase of GlaxoSmithKline's oncology portfolio) but eclipsed the previous quarter primarily due to Allogene's USD 2.8 billion license for Cellectis' chimeric antigen receptor T-cell immunotherapy program for cancer. PMID- 30398484 TI - Understanding gold nanoparticle dissolution in cyanide-containing solution via impact-chemistry. AB - The electrochemical dissolution of citrate-capped gold nanoparticles (AuNPs) was studied in cyanide (CN-) containing solutions. It was found that the gold nanoparticles exhibited different dissolution behaviours as ensembles compared to the single particles. At the single particle level, a nearly complete oxidation of 60 nm AuNPs was achieved at concentrations greater than or equal to 35.0 mM CN and at a potential of 1.0 V. Mechanistic insights and rate data are reported. PMID- 30398485 TI - Ionic conductivity and local structural features in Ce1-xSmxO2-x/2. AB - Sm-Doped ceria is one of the most promising materials to be used as electrolyte in solid oxide fuel cells due to its remarkable ionic conductivity values in the intermediate temperature range. Transport properties and local structural features of Ce1-xSmxO2-x/2 (0.1 <= x <= 0.7) were studied by an impedance/MU Raman spectroscopy coupled approach up to 1073 K. Results suggest that C-based nanosized defect clusters are responsible for the drop in ionic conductivity observed even at x = 0.2, i.e. at a Sm content lower than necessary to allow C domains to reach the percolation threshold through crystallites. Moreover, within the fluorite-type compositional region, with increasing the Sm content, defect clusters undergo a rearrangement resulting in the enlargement of C-based domains rather than in the increase of their number; at higher x, on the contrary, both the size and amount of C domains increase in parallel. PMID- 30398486 TI - Molecular design of high-temperature organic dielectric switches. AB - A design strategy of reducing the molecular symmetry was used to obtain a series of picrate-based high-temperature phase transition compounds. Their dielectric switching behaviours accompanied by phase transitions can be attributed to the order-disorder transitions of the cations and the displacements of both cations and anions. PMID- 30398487 TI - Mechanisms of action of Ru(ii) polypyridyl complexes in living cells upon light irradiation. AB - The unique photophysical properties of Ru(ii) polypyridyl complexes make them very attractive candidates as photosensitisers in Photodynamic Therapy (PDT). However, to date, there are not many studies exploring in detail the mechanism(s) of action of such compounds in living systems upon light irradiation. This feature article provides an overview of the most in-depth biological studies on such compounds. PMID- 30398488 TI - Light-enhanced hypoxia-responsive nanoparticles for deep tumor penetration and combined chemo-photodynamic therapy. AB - Herein, we report a light-enhanced hypoxia-responsive nanoparticle for synergic treatment of solid tumors. The conversion of oxygen in the tumor exterior induced ROS and the continuous consumption of oxygen amplified the hypoxia conditions in the tumor, which enhanced the surface-to-core penetration of nanoparticles into the hypoxia central tissue. PMID- 30398489 TI - An intracellular diamine oxidase triggered hyperpolarized 129Xe magnetic resonance biosensor. AB - Here, a novel method was developed for suppressing 129Xe signals in cucurbit[6]uril (CB6) until the trigger is activated by a specific enzyme. Due to its noncovalent interactions with amino-groups and CB6, putrescine dihydrochloride (Put) was chosen for blocking interactions between 129Xe and CB6. Upon adding diamine oxidase (DAO), Put was released from CB6 and a 129Xe@CB6 Hyper-CEST signal emerged. This proposed 129Xe biosensor was then tested in small intestinal villus epithelial cells. PMID- 30398490 TI - An ultrafine ruthenium nanocrystal with extremely high activity for the hydrogen evolution reaction in both acidic and alkaline media. AB - An ultrafine ruthenium nanocrystal (RuNC) was fabricated via thermal annealing tris(2,2'-bipyridine)ruthenium dichloride with cyanuric acid. The as-obtained RuNC features a small diameter of ~2 nm and high crystallinity. As an electrocatalyst for the hydrogen evolution reaction, the ultrafine RuNC exhibited remarkable performance in both acidic and alkaline media. PMID- 30398491 TI - Role of microstructures in the compression response of three-dimensional foam formed wood fiber networks. AB - High-porosity, three-dimensional wood fiber networks made by foam forming present experimentally accessible instances of hierarchically structured, athermal fiber networks. We investigate the large deformation compression behavior of these networks using fiber-resolved finite element analyses to elucidate the role of microstructures in the mechanical response to compression. Three-dimensional network structures are acquired using micro-computed tomography and subsequent skeletonization into a Euclidean graph representation. By using a fitting procedure to the geometrical graph data, we are able to identify nine independent statistical parameters needed for the regeneration of artificial networks with the observed statistics. The compression response of these artificially generated networks and the physical network is then investigated using implicit finite element analysis. A direct comparison of the simulation results from the reconstructed and artificial network reveals remarkable differences already in the elastic region. These can neither be fully explained by density scaling, the size effect nor the boundary conditions. The only factor which provides the consistent explanation of the observed difference is the density and fiber orientation nonuniformities; these contribute to strain-localization so that the network becomes more compliant than expected for statistically uniform microstructures. We also demonstrate that the experimentally manifested strain stiffening of such networks is due to development of new inter-fiber contacts during compression. PMID- 30398492 TI - Synthesis of nanoporous poly-melamine-formaldehyde (PMF) based on Schiff base chemistry as a highly efficient adsorbent. AB - This study proposes the construction of nanoporous poly-melamine-formaldehyde (PMF) through the Schiff base condensation reaction of paraformaldehyde and melamine. The PMF nanoparticles showed a good adsorption capability to some benzene-ring-containing dyes including acid fuchsine, nigrosine, and methyl orange. Moreover, the as-prepared PMF nanoparticles were employed as the coating adsorbent for the solid-phase microextraction (SPME) of seven volatile fatty acids (VFAs) with high enrichment factors. A PMF-assisted SPME method was established for the enrichment of VFAs from environmental water samples with satisfactory recoveries (88.5%-102.0%) and acceptable precisions (relative standard deviations <10.9%). This contribution might furnish an advanced benchmark for the exploitation of new porous organic polymers as the effective adsorbents for SPME or other fields of utilization. PMID- 30398493 TI - Crosslinked PVA/SSA proton exchange membranes: correlation between physiochemical properties and free volume determined by positron annihilation spectroscopy. AB - Two processes for crosslinking polyvinyl alcohol (PVA) with sulfosuccinic acid (SSA) and thermal crosslinking were used to fabricate a proton exchange membrane (PEM). Such PEMs are used in different fields involving fuel cell applications. The crosslinking reaction between PVA and SSA was confirmed using Fourier transform infrared (FTIR) spectroscopy. The characterization of the prepared membranes, namely, ion exchange capacity (IEC), thermal analyses, water uptake, and ionic conductivity, was carried out. The IEC of the prepared membranes was found to be between 0.084 and 2.086 mmol g-1, resulting in an essential increase in the ionic conductivity. It was observed that the ionic conductivity was in the range of 0.003-0.023 S cm-1, depending on both temperature and SSA content. From the thermogravimetric analysis (TGA) results, it was revealed that the thermal stability of the crosslinked membranes improved. Moreover, water uptake decreased with increasing SSA content. Positron annihilation lifetime spectroscopy (PALS) was used to study the microstructure of the PVA/SSA membranes and their distribution at different ambient temperatures and relative humidity (RH) values. At room temperature, no significant change was observed in the free-volume holes up to 15 wt% SSA; thereafter, the size of the free-volume holes increased with the SSA content. The PALS results show that at different humidity values, the size of the free-volume holes for crosslinked PVA/SSA membranes is lower than those for Nafion membranes, i.e., the gas permeability for the prepared PVA/SSA membranes is less than that for the Nafion membrane. In addition, a strong correlation between the water uptake, ionic conductivity, tensile strength, and free-volume holes was observed. PMID- 30398494 TI - Methylene insertion into an Fe2S2 cluster: formation of a thiolate-bridged diiron complex containing an Fe-CH2-S moiety. AB - Reduction of a thiolate-bridged FeIIFeIII complex leads to the cleavage of an Fe S bond by the insertion of the methylene unit from CH2Cl2 to give a neutral FeIIFeIII complex with a novel Fe-CH2-S fragment. The structural and electrochemical differences of the alkylated and the non-alkylated Fe2S2 complexes are also examined. PMID- 30398495 TI - Vibrational properties and Raman spectra of pristine and fluorinated blue phosphorene. AB - Using density functional theory, we investigated the vibrational properties and Raman spectra of pristine blue phosphorene and fluorinated blue phosphorene. The fluorinated blue phosphorene possesses a Dirac cone at the K point (about 310 cm 1). The shape of the Dirac cone remains unchanged under different tensile strains. The Raman tensor and thus angle-dependent Raman intensities of all Raman active modes are calculated for the polarizations of scattered light parallel and perpendicular to that of the incident light. The characteristics of angle dependent Raman intensities are discussed. Moreover, the polarization direction averaged non-resonant Raman spectra of pristine blue phosphorene and fluorinated blue phosphorene are compared with that of germanene and black phosphorene. PMID- 30398496 TI - Enhancing intracellular microRNA imaging: a new strategy combining double-channel exciting single colour fluorescence with the target cycling amplification reaction. AB - A microRNA (miRNA) fluorescence (FL) nanoprobe based on PDA-UCNPs@FAM-LLD@AuNPs was developed, which exhibited an enhanced signal for imaging intracellular miRNA by combining double-channel exciting single colour FL (DCESCF) with the target cycling amplification reaction. Through this strategy, normal cells and cancer cells could be successfully discriminated. PMID- 30398497 TI - A fluoride activated methylene blue releasing platform for imaging and antimicrobial photodynamic therapy of human dental plaque. AB - We report a F- activated methylene blue (MB) releasing platform for imaging and antimicrobial photodynamic therapy (aPDT). By utilizing this platform, one of the selected probes, FD-F3, displays a remarkable near-infrared fluorescence and absorption increase towards F- with good selectivity and low detection limit. This probe has been successfully applied for visualizing F- and performing F- activated aPDT in naturally grown human plaque biofilms. PMID- 30398498 TI - Water phase transitions from the perspective of hydrogen-bond network analysis. AB - We analyze the water vapour-liquid and solid-liquid phase transitions from the perspective of hydrogen bond networks. Using molecular dynamics simulation data for the TIP4P/2005 and TIP4P/ice water models, we built hydrogen bond networks in the neighbourhood of the transitions. We studied the behaviour of some topological network properties: the average degree, clustering coefficient, and average path length. We found that these properties exhibit a discontinuity while approaching a phase transition region, similar to those that appear for some thermodynamic properties in the same region. This approach can be extended to characterize other water phase transitions. Besides, it can also be applied to study the phase transitions of other hydrogen-bonded substances or to other scenarios whose relevant "interaction" could be identified together with a "proper criterion" defined in an analogous way as in the case of hydrogen bonded systems. PMID- 30398499 TI - Structural characterization of nucleotide 5'-triphosphates by infrared ion spectroscopy and theoretical studies. AB - The molecular family of nucleotide triphosphates (NTPs), with adenosine 5' triphosphate (ATP) as its best-known member, is of high biochemical importance as their phosphodiester bonds form Nature's main means to store and transport energy. Here, gas-phase IR spectroscopic studies and supporting theoretical studies have been performed on adenosine 5'-triphosphate, cytosine 5' triphosphate and guanosine 5'-triphosphate to elucidate the intrinsic structural properties of NTPs, focusing on the influence of the nucleobase and the extent of deprotonation. Mass spectrometric studies involving collision induced dissociation showed similar fragmentation channels for the three studied NTPs within a selected charge state. The doubly charged anions exhibit fragmentation similar to the energy-releasing hydrolysis reaction in nature, while the singly charged anions show different dominant fragmentation channels, suggesting that the charge state plays a significant role in the favorability of the hydrolysis reaction. A combination of infrared ion spectroscopy and quantum-chemical computations indicates that the singly charged anions of all NTPs are preferentially deprotonated at their beta-phosphates, while the doubly-charged anions are dominantly alphabeta-deprotonated. The assigned three-dimensional structure differs for ATP and CTP on the one hand and GTP on the other, in the sense that ATP and CTP show no interaction between nucleobase and phosphate tail, while in GTP they are hydrogen bonded. This can be rationalized by considering the structure and geometry of the NTPs where the final three dimensional structure depends on a subtle balance between hydrogen bond strength, flexibility and steric hindrance. PMID- 30398502 TI - Huge Rashba-type spin-orbit coupling in binary hexagonal PX nanosheets (X = As, Sb, and Bi). AB - We theoretically propose that Rashba-type band splitting can be achieved in binary alloyed hexagonal PX nanosheets (X = As, Sb, and Bi). The lack of inversion symmetry results in an effective electric field perpendicular to the basal plane of PX, hence, leading to Rashba-type spin-orbit coupling (SOC) in the two dimensional PX nanosheets. Since the SOC strength roughly scales quadratically with atomic number, the largest band splitting is found in PBi with a Rashba coefficient of ~1.56 eV A, which is a huge value among two-dimensional materials. Furthermore, tensile biaxial strain can be employed to significantly enhance the strength of SOC, for instance, a Rashba coefficient of 4.41 eV A can be realized at a strain of 10%. The huge and strain-tunable Rashba-type SOC of PBi suggests that it holds great promise for spintronic applications. PMID- 30398501 TI - Recent progress in the self-assembly of block copolymers confined in emulsion droplets. AB - When the self-assembly of block copolymers (BCPs) occurs within a deformable emulsion droplet, BCPs can aggregate into a variety of nanoscaled particles with unique nanostructures and properties since the confinement effect can effectively break the symmetry of a structure. On the other hand, the self-assembled BCP particles can serve as the scaffolds to further direct the spatial arrangement of functional inorganic nanoparticles (NPs) via co-assembly or in situ deposition, thus generating diverse hybrid functional BCP/NP composites with enhanced properties. Here, we summarize the recent progress in the confined self-assembly of BCPs within the emulsion droplet and spatial arrangement of NPs on the resulting BCP scaffolds. This feature article focuses on the influence of multiple factors, including the oil/water interfacial properties, confinement degree, intrinsic properties of BCPs, additives, pH value, and temperature, on the nanostructures of the self-assembled BCP particles as well as the spatial arrangement of NPs on the BCP scaffolds from both experiment and simulation studies. PMID- 30398500 TI - An evaporation induced self-assembly approach to prepare polymorphic carbon dot fluorescent nanoprobes for protein labelling. AB - Herein, we report a novel route to prepare polymorphic carbon dot fluorescent probes via the evaporation-induced self-assembly of glutaraldehyde and carbon dots, which first usually form carbon nanoclusters which then could self-assemble to form carbon nanocrystals, nanospheres or nanofibers in different ionic strength solutions at room temperature. The aldehyde functionalized polymorphic C dot fluorescent probe can easily covalently bond with amino groups on proteins. PMID- 30398503 TI - An adhesion based approach for the detection of esophageal cancer. AB - Esophageal cancer has a 5 year survival rate of ~20%. This dismal prognosis is due, in part, to the fact that esophageal cancer often presents at a late stage. Thus, there is a critical need for assays that enable the early detection of cancerous tissue within the esophagus. The luminal surface of the esophagus expresses signature molecule(s) at sites of transformation providing an avenue for the development of in situ assays that detect neoplastic growth within the esophagus. An attractive approach, receiving increased attention, is the endoscopic administration of particles conjugated with ligands to signature molecules present on transforming tissue. Detection of the particles within the esophagus, post-washing, would indicate the presence of the signature molecule and thus transforming tissue. In this work, we utilized cancerous and normal esophageal cells to provide in vitro proof of principle for this approach utilizing ligand-conjugated microspheres and demonstrate the need, and provide the framework for, engineering this technology. Specifically, the study (i) reveals selective increased expression of signature molecules on cancerous esophageal cells relative to normal cells; (ii) demonstrates selective binding of ligand-conjugated microspheres to cancerous esophageal cells relative to normal cells; (iii) demonstrates that the selective recognition of cancerous, relative to normal esophageal cells, is highly dependent on the biophysical design of the assay; and (iv) advocates utilizing the knowledge from the field of cell adhesion as a guide for the effective development of ligand-conjugated particle-based schemes that seek to detect esophageal oncogenesis in situ. PMID- 30398504 TI - Direct observation of atomic step edges on the rutile TiO2(110)-(1 * 1) surface using atomic force microscopy. AB - Clarifying the atomic configuration of step edges on a rutile TiO2 surface is crucial for understanding its fundamental reactivity, and the direct observation of atomic step edges is still a challenge. AFM is a powerful tool for investigating surface structures with true atomic resolution, and it provides the opportunity to resolve the real structure of step edges with improved techniques. In this work, we successfully imaged the atomic configuration of 001 and 1-11 step edges on the surface of rutile TiO2(110)-(1 * 1), and we present the direct observation of oxygen vacancies along the 1-11 step edges, indicating that one 1 11 step edge site corresponds to one oxygen vacancy using AFM. We also made use of the simultaneous AFM/STM measurements to explore the electronic structure of step edges, which enhanced the evidence of oxygen vacancies existing along the 1 11 step edges and further demonstrated that the 001 step edge was terminated by an O row. The effect of the reduced 1-11 step edges was explored by probing the O2 adsorption and the nucleation behavior of gold clusters. It was found that oxygen vacancies along the 1-11 step edges could contribute to O2 dissociative adsorption and there was no obvious difference compared with the oxygen vacancies on the flat terrace. The reduced step edge and terrace likewise acted as nucleation and growth sites for gold atoms/nanoparticles, in line with previous reports. The present study provides a complete characterization of the atomic configuration of the step edges on the TiO2(110) surface and plays an important role in investigating the surface chemistry of metal oxides. PMID- 30398505 TI - Catalytic and networking effects of carbon black on the kinetics and conversion of sulfur vulcanization in styrene butadiene rubber. AB - The present work discusses the effects of carbon-black (CB) on the kinetics and conversion of sulfur vulcanization in styrene butadiene rubber (SBR) compounds. Kinetic studies revealed that the onset of the vulcanization reaction shortens monotonically by incorporation of CB, but the rate of vulcanization goes through a maximum at a critical loading of CB. It was demonstrated that CB has two roles in the kinetics of vulcanization: a catalytic effect on accelerating the initial reactions among vulcanization agents and a networking effect on retarding the crosslinking of macro-radicals. It was shown that the latter effect dominates the former one at high concentrations of CB where the rubber-mediated network of CB is formed and a large portion of rubber is immobilized as bound rubber. By using two types of CBs with very different specific surface areas, it was discussed that the critical loading at which the retarding effect begins coincides with the rheological percolation threshold of CBs. Moreover, conversion of vulcanization under isothermal conditions was continuously reduced as the concentration of CBs increased. This was correlated to the magnitude of the physical restrictions exerted by CBs, depending on the specific surface area of each CB. However, it was also shown that this restriction could be alleviated at higher temperatures during non-isothermal vulcanization, which enhances the degree of conversion in crosslinking. PMID- 30398506 TI - Calculation of critical nucleation rates by the persistent embryo method: application to quasi hard sphere models. AB - We study the crystal nucleation of the Weeks-Chandler-Andersen (WCA) model, using the recently introduced persistent embryo method (PEM). The method provides detailed characterization of pre-critical, critical and post-critical nuclei, as well as nucleation rates that compare favorably with those obtained using other methods (umbrella sampling, forward flux sampling or seeding). We further map our results to a hard sphere model allowing comparison with other existing predictions. Implications for experiments are also discussed. PMID- 30398507 TI - Analysis of the soybean metallothionein system under free radical stress: protein modification connected to lipid membrane damage. AB - Metallothioneins are small Cys-rich peptides capable of coordinating metal ions, and proposed to be involved in radical stress. The four Zn(ii)-GmMT complexes of soybean (Glycine max) were recombinantly synthesised and exposed to oxidative (HO) and reductive (H atoms and eaq-) stress conditions. Gamma-irradiation was used to simulate the endogenous formation of the reactive species in both aqueous solutions and unsaturated lipid vesicle suspensions, a biomimetic model that showed that tandem protein/lipid damage occurs, in particular under reductive radical stress. This is due to the formation of diffusible sulphur-centred radicals, which migrate from the aqueous phase to the lipid bilayer and are thus able to transform the cis double bond of the oleate moiety into the trans isomer. Among the amino acid residues present in GmMTs, Cys is one of the most sensitive residues towards the attack of free radicals, thus suggesting metal-clusters to be good interceptors of free radicals. Also Met, Tyr and Phe residues are sensitive amino acid sites of attack under both oxidative and reductive conditions. The modification of the Zn(ii)-GmMT complexes, in particular isoform 2, was monitored by Raman spectroscopy and mass spectrometry. Free radical stress on the Zn(ii)-GmMT complexes is able to induce significant structural changes such as partial deconstruction and/or rearrangement of the metal clusters, but not the complete demetallation of the proteins nor breaking of the backbone, thus confirming their capability to act as protectors under free radical stress conditions. PMID- 30398508 TI - Organic and hybrid resistive switching materials and devices. AB - The explosive increase in digital communications in the Big Data and internet of Things era spurs the development of universal memory that can run at high speed with high-density and nonvolatile storage capabilities, as well as demonstrating superior mechanical flexibility for wearable applications. Among various candidates for the next-generation information storage technology, resistive switching memories distinguish themselves with low power consumption, excellent downscaling potential, easy 3D stacking, and high CMOS compatibility, fulfilling key requirements for high-performance data storage. Employing organic and hybrid switching media in addition allows light weight and flexible integration of molecules with tunable device performance via molecular design-cum-synthesis strategy. In this review, we present a timely and comprehensive review of the recent advances in organic and hybrid resistive switching materials and devices, with particular attention on their design principles for electronic property tuning and flexible device performance. The current challenges posed with development of organic and hybrid resistive switching materials and flexible memory devices, together with their future perspectives, are also discussed. PMID- 30398509 TI - Stress-oscillation behaviour of semi-crystalline polymers: the case of poly(butylene succinate). AB - Stress oscillation has been observed in a number of linear thermoplastic polymers during the cold-drawing process, where the polymers exhibit periodic self-excited oscillatory neck propagation. However, the origin of the mechanical stress oscillation process and its relationship with the crystalline morphology of the polymer are still under debate. In this work, we revisit the stress oscillation behavior by studying a semi-crystalline polyester, poly(butylene succinate) (PBS), a biodegradable polymer suitable for biomedical and packaging applications. Stress oscillation of PBS is observed when deformed at a range of elongation rates from 10 to 200 mm min-1, and the fluctuation magnitude decays as the deformation temperature increases from 23 to 100 degrees C. Periodic transparent/opaque bands form during necking of PBS, which consists of alternating regions of highly oriented crystalline zones and microcavities due to crazing and voiding, although the degree of crystallinity did not change significantly in the bands. Simultaneous small- and wide-angle X-ray scattering confirms that the alternating stress increases, as shown in the stress-strain curves, correspond to the appearance of the transparent bands in the sample, and the abrupt drop of the stress is the result of voiding during the neck propagation. The voiding and cavitation are ultimately responsible for the stress oscillation process in PBS. The in-depth analysis of this work is important in understanding and controlling the occurrence of instabilities/cavitation during polymer processing such as film blowing, biaxial stretching and injection moulding of biodegradable polymer materials. PMID- 30398510 TI - Elemental characterisation of the pyramidal neuron layer within the rat and mouse hippocampus. AB - A unique combination of sensitivity, resolution, and penetration make X-ray fluorescence imaging (XFI) ideally suited to investigate trace elemental distributions in the biological context. XFI has gained widespread use as an analytical technique in the biological sciences, and in particular enables exciting new avenues of research in the field of neuroscience. In this study, elemental mapping by XFI was applied to characterise the elemental content within neuronal cell layers of hippocampal sub-regions of mice and rats. Although classical histochemical methods for metal detection exist, such approaches are typically limited to qualitative analysis. Specifically, histochemical methods are not uniformly sensitive to all chemical forms of a metal, often displaying variable sensitivity to specific "pools" or chemical forms of a metal. In addition, histochemical methods require fixation and extensive chemical treatment of samples, creating the strong likelihood for metal redistribution, leaching, or contamination. Direct quantitative elemental mapping of total elemental pools, in situ within ex vivo tissue sections, without the need for chemical fixation or addition of staining reagents is not possible with traditional histochemical methods; however, such a capability, which is provided by XFI, can offer an enormous analytical advantage. The results we report herein demonstrate the analytical advantage of XFI elemental mapping for direct, label-free metal quantification, in situ within ex vivo brain tissue sections. Specifically, we definitively characterise for the first time, the abundance of Fe within the pyramidal cell layers of the hippocampus. Localisation of Fe to this cell layer is not reproducibly achieved with classical Perls histochemical Fe stains. The ability of XFI to directly quantify neuronal elemental (P, S, Cl, K, Ca, Fe, Cu, Zn) distributions, revealed unique profiles of Fe and Zn within anatomical sub regions of the hippocampus i.e., cornu ammonis 1, 2 or 3 (CA1, CA2 or CA3) sub regions. Interestingly, our study reveals a unique Fe gradient across neuron populations within the non-degenerating and pathology free rat hippocampus, which curiously mirrors the pattern of region-specific vulnerability of the hippocampus that has previously been established to occur in various neurodegenerative diseases. PMID- 30398511 TI - Audit of transfusion of blood products in paediatric congenital heart surgery on cardiopulmonary bypass. AB - BACKGROUND: Cardiac surgery is associated with peri-operative bleeding, which may result in the need for blood transfusion, particularly in paediatric congenital cardiac surgery on cardiopulmonary bypass (CPB). There is a necessity for regular auditing in order to improve practices. METHODS: Retrospective, contextual, descriptive data of 105 patients were collected for the period January to December 2014. RESULTS: The median age of patients was four (1-6) years, weight was 13 (8.4-20) kg, and mean lowest CPB haemoglobin level was 8.3 (1.5) g/dl. There was a statistically significant difference in median red packed cell (RPC), platelet and cryoprecipitate units per patient transfused across four RACHS (risk adjusted classification for congenital heart surgery) categories (p = 0.03, p = 0.0013, p = 0.0001, respectively). There was a statistically significant correlation between transfused fresh frozen plasma units with CPB time (r = 0.2634, p = 0.0199) and RPC units (r = -0.4654, p < 0.001). CONCLUSIONS: Although no standardised transfusion guidelines were available, overall transfusion of blood products was comparable to reported practices. PMID- 30398512 TI - Transradial versus transfemoral intervention in non-ST-segment elevation acute coronary syndrome patients undergoing percutaneous coronary intervention: the Korean transradial intervention registry of 1 285 patients. AB - INTRODUCTION: Although the implementation of transradial intervention (TRI) has increased over the last few years, there are limited data on the impact of TRI on efficacy and safety in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). We sought to compare one-year clinical outcomes and bleeding complications of TRI with those of transfemoral intervention (TFI) in patients with NSTE-ACS. METHODS: The Korean TRI registry was a cohort of 20 centres from 2012 to 2015. The primary efficacy endpoint was major adverse cardiovascular events (MACE), defined as a composite of cardiac death (CD), non-fatal myocardial infarction (MI) and repeat revascularisation (RR). Among the 1 319 patients with NSTE-ACS, 1 285 were finally analysed after excluding 34 due to lack of follow-up data. The patients were divided into TRI and TFI groups according to the final access site. RESULTS: At one-year follow up, the TRI group showed a significantly lower rate of MACE, and a marginally significantly lower rate of CD than the TFI group in the crude population. However, in propensity-score matched analysis, the rate of MACE did not differ between the TRI and TFI groups. Regarding bleeding complications, the TRI group was associated with significantly lower rates of major bleeding in both the crude and matched populations. Independent predictors of MACE were chronic kidney disease (CKD) and multi-vessel disease (MVD). CONCLUSIONS: In patients with NSTE-ACS, TRI was associated with favourable one year clinical outcomes and lower bleeding complications compared to TFI. Independent predictors of MACE were clinical and angiographic profiles (CKD, MVD) rather than vascular access sites. PMID- 30398514 TI - How to Make US Health Care More Equitable and Less Costly: Begin by Replacing Employment-Based Insurance. PMID- 30398515 TI - Influenza Vaccine for 2018-2019. PMID- 30398513 TI - Delayed left ventricular pseudo-aneurysm after postinfarction repair of ventricular septal defect. AB - Left ventricular pseudo-aneurysm is a rare complication that usually occurs after myocardial infarction or cardiac surgery. Sometimes it is related to cardiac rupture. We report on surgical management for a left ventricular pseudo-aneurysm that developed four years after surgery for ventricular septal defect in a patient with acute myocardial infarction. PMID- 30398516 TI - Sex hormones and measures of kidney function in the Diabetes Prevention Program Outcomes Study. AB - Context: Despite sex differences in the onset and progression of CKD, it is unclear whether endogenous sex hormones are associated with kidney function among persons without chronic kidney disease (CKD). Research Design and Methods: We conducted a secondary analysis of Diabetes Prevention Program (DPP) and its follow-up observational study, the DPP Outcomes Study (DPPOS), over an 11-year period. Participants included overweight and glucose-intolerant men (n=889) and premenopausal and postmenopausal women (n=1281) not using exogenous sex hormones and who had urine albumin-to-creatinine ratio (ACR) < 30 mg/g and normal estimated glomerular filtration ratio (eGFR)>60 ml/min/1.73 m2 at randomization. We examined the association between sex hormones and incidence of eGFR <60 ml/min/1.73 m2 and/or ACR > 30 mg/g on at least one measurement. Results: At randomization, the mean (SD) of eGFR was 94 (15) ml/min/1.73 m2, and the median (IQR) of ACR was 4.5 (3.3-7.6) mg/g. During follow-up, 187 men (24.6%) and 263 women (24.2%) had incident albuminuria and 136 men (17.9%) and 123 women (11.3%) had incident low eGFR. Among men, higher baseline sex hormone binding globulin (SHBG) was associated with reduced risk of low eGFR (hazard ratio [HR] per SD, 95% confidence interval [CI]: 0.80 [0.57, 0.90]) in adjusted analyses. No significant associations were observed among women. There were significant interactions between sex steroids and low eGFR by randomization arm. Conclusions: Sex steroids were not associated with development of low eGFR or albuminuria. Among men, higher SHBG was associated with reduced risk of low eGFR on at least one measurement. PMID- 30398517 TI - Protocol Deviations, Reanalyses, and Corrections to Derivative Studies of the PREDIMED Trial. PMID- 30398519 TI - Sodium Restriction in Heart Failure: Too Much Uncertainty-Do the Trials. PMID- 30398520 TI - Protocol Deviations and Reanalyses in Derivative Studies of the PREDIMED Trial. PMID- 30398518 TI - Recombinant thyrotropin vs levothyroxine withdrawal in 131I therapy of N1 thyroid cancer: a large matched cohort study (ThyrNod). AB - Context: Recombinant human thyrotropin (rhTSH) has been shown to be an effective stimulation method for radioactive iodine (RAI) therapy in differentiated thyroid cancer including those with nodal metastases (N1 DTC). Objectives: To demonstrate the non-inferiority of rhTSH vs thyroid hormone withdrawal (THW) in preparation to RAI regarding disease status at the first evaluation in the real-life setting in N1 DTC patients. Design, patients: This was a French multicenter retrospective study. Groups were matched according to age (<45/>=45 years), number of N1 (<=5/>5 lymph nodes) and stage (pT1-T2/pT3). Results: The cohort consisted of 404 pT1-T3/N1/M0 DTC, prepared with rhTSH (n=205) or THW (n=199). Pathological characteristics and initial administrated RAI activities (3.27 +/-1.00 GBq) were similar between the two groups. At first evaluation (6-18 months post-RAI), disease-free status was defined by thyroglobulin levels below threshold and a normal ultrasound. Disease-free rate was not inferior in the rhTSH group (75.1%) compared to the THW group (71.9%). The observed difference between the success rates was 3.3 % [-6.6; 13.0]; rhTSH was therefore considered non-inferior to THW as the upper limit of this interval was less than 15%. At the last evaluation (29.7+/- 20.7 for rhTSH and 36.7+/- 23.8 months for THW)), 83.5% (rhTSH) and 81.5% (THW) of patients achieved a complete response. This result was not influenced by any of the known prognostic factors. Conclusions: A preparation for initial RAI treatment with rhTSH was non-inferior to one with THW in our series of pT1-T3/N1/M0-DTC on disease-free status outcomes at the first evaluation and after three years. PMID- 30398521 TI - Association Between Cannabis Use and Risk for Diabetic Ketoacidosis in Adults With Type 1 Diabetes. PMID- 30398523 TI - Error in Figure 1. PMID- 30398522 TI - Natural Progression of Symptom Change and Recovery From Concussion in a Pediatric Population. AB - Importance: The natural progression of symptom change and recovery remains poorly defined in children after concussion. Objectives: To describe the natural progression of symptom change by age group (5-7, 8-12, and 13-18 years) and sex, as well as to develop centile curves to inform families about children after injury recovery. Design, Setting, and Participants: Planned secondary analysis of a prospective multicenter cohort study (Predicting Persistent Postconcussive Problems in Pediatrics). The setting was 9 pediatric emergency departments within the Pediatric Emergency Research Canada (PERC) network. Participants were aged 5 to 18 years with acute concussion, enrolled from August 1, 2013, to May 31, 2015, and data analyses were performed between January 2018 and March 2018. Exposures: Participants had a concussion consistent with the Zurich Consensus Statement on Concussion in Sport diagnostic criteria and 85% completeness of the Postconcussion Symptom Inventory (PCSI) at each time point. Main Outcomes and Measures: The primary outcome was symptom change, defined as current rating minus preinjury rating (delta score), at presentation and 1, 2, 4, 8, and 12 weeks after injury, measured using the PCSI. Symptoms were self-rated for ages 8 to 18 years and rated by the child and parent for ages 5 to 7 years. The secondary outcome was recovery, defined as no change in symptoms relative to current preinjury PCSI ratings (delta score = 0). Mixed-effects models incorporated the total score, adjusting for random effects (site and participant variability), fixed-effects indicators (age, sex, time, age by time interaction, and sex by time interaction), and variables associated with recovery. Recovery centile curves by age and sex were computed. Results: A total of 3063 children (median age, 12.0 years [interquartile range, 9.2-14.6 years]; 60.7% male) completed the primary outcome; 2716 were included in the primary outcome analysis. For the group aged 5 to 7 years, symptom change primarily occurred the first week after injury; by 2 weeks, 75.6% of symptoms had improved (PCSI change between 0 and 2 weeks, -5.3; 95% CI, -5.5 to -5.0). For the groups aged 8 to 12 years and 13 to 18 years, symptom change was prominent the first 2 weeks but flattened between 2 and 4 weeks. By 4 weeks, 83.6% and 86.2% of symptoms, respectively, had improved for the groups aged 8 to 12 years (PCSI change between 0 and 4 weeks, -9.0; 95% CI, -9.6 to -8.4) and 13 to 18 years (PCSI change between 0 and 4 weeks, -28.6; 95% CI, -30.8 to -26.3). Sex by time interaction was significant only for the adolescent group (beta = 0.32; 95% CI, 0.21-0.43; P < .001). Most adolescent girls had not recovered by week 12. Conclusions and Relevance: Symptom improvement primarily occurs in the first 2 weeks after concussion in children and in the first 4 weeks after concussion in preadolescents and male adolescents. Female adolescents appear to have protracted recovery. The derived recovery curves may be useful for evidence-based anticipatory guidance. PMID- 30398524 TI - Error in Corresponding Author and Affiliation. PMID- 30398525 TI - Notice of Duplicate Publication: Performance of the Simplified American Academy of Pediatrics Table to Screen Elevated Blood Pressure in Children. PMID- 30398526 TI - I Am Worried About Gonorrhea: What Do I Need to Know? PMID- 30398527 TI - Alcohol, Cigarette, and Cannabis Use Between 2002 and 2016 in Pregnant Women From a Nationally Representative Sample. PMID- 30398529 TI - Elements of a Comprehensive Public Health Response to the Opioid Crisis. PMID- 30398528 TI - Use of High-Sensitivity Cardiac Troponin for the Exclusion of Inducible Myocardial Ischemia: A Cohort Study. AB - Background: Many patients with coronary artery disease (CAD) are routinely referred for surveillance stress testing despite recommendations against it. Objective: To determine whether low levels of resting high-sensitivity cardiac troponin I (hs-cTnI) can identify persons without inducible myocardial ischemia. Design: Observational study. Setting: A university-affiliated hospital network. Patients: Persons with stable CAD: 589 in the derivation group and 118 in the validation cohort. Measurements: Presence of inducible myocardial ischemia was determined by myocardial perfusion imaging with technetium-99m single-photon emission computed tomography during either treadmill or pharmacologic stress testing. Resting plasma hs-cTnI was measured within 1 week of the stress test, and the negative predictive value (NPV) for inducible ischemia was calculated. The derivation cohort was followed for 3 years for incident cardiovascular death and myocardial infarction. Results: In the derivation cohort, 10 of 101 patients with an hs-cTnI level below 2.5 pg/mL had inducible myocardial ischemia (NPV, 90% [95% CI, 83% to 95%]) and 3 of 101 had inducible ischemia involving at least 10% of the myocardium (NPV, 97% [CI, 92% to 99%]). In the validation cohort, 4 of 32 patients with an hs-cTnI level below 2.5 pg/mL had inducible ischemia (NPV, 88% [CI, 71% to 96%]) and 2 of 32 had ischemia of 10% or greater (NPV, 94% [CI, 79% to 99%]). After a median follow-up of 3 years in the derivation cohort, no adverse events occurred in patients with an hs-cTnI level below 2.5 pg/mL, compared with 33 (7%) cardiovascular deaths or incident myocardial infarctions among those with an hs-cTnI level of 2.5 pg/mL or greater. Limitation: The data may not be applicable to a population without known CAD or to persons with unstable angina, and the modest sample sizes warrant further validation in a larger cohort. Conclusion: Very low hs-cTnI levels may be useful in excluding inducible myocardial ischemia in patients with stable CAD. Primary Funding Source: National Institutes of Health. PMID- 30398530 TI - Human Papillomavirus Vaccination and School Entry Requirements: Politically Challenging, But Not Impossible. PMID- 30398531 TI - A Diagnostically Challenging Infusion Reaction-Kounis, Takotsubo, or the ATAK! PMID- 30398532 TI - Reduced Salt Intake for Heart Failure: A Systematic Review. AB - Importance: Recent estimates suggest that more than 26 million people worldwide have heart failure. The syndrome is associated with major symptoms, significantly increased mortality, and extensive use of health care. Evidence-based treatments influence all these outcomes in a proportion of patients with heart failure. Current management also often includes advice to reduce dietary salt intake, although the benefits are uncertain. Objective: To systematically review randomized clinical trials of reduced dietary salt in adult inpatients or outpatients with heart failure. Evidence Review: Several bibliographic databases were systematically searched, including the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and CINAHL. The methodologic quality of the studies was evaluated, and data associated with primary outcomes of interest (cardiovascular-associated mortality, all-cause mortality, and adverse events, such as stroke and myocardial infarction) and secondary outcomes (hospitalization, length of inpatient stay, change in New York Heart Association [NYHA] functional class, adherence to dietary low-salt intake, and changes in blood pressure) were extracted. Findings: Of 2655 retrieved references, 9 studies involving 479 unique participants were included in the analysis. None of the studies included more than 100 participants. The risks of bias in the 9 studies were variable. None of the included studies provided sufficient data on the primary outcomes of interest. For the secondary outcomes of interest, 2 outpatient-based studies reported that NYHA functional class was not improved by restriction of salt intake, whereas 2 studies reported significant improvements in NYHA functional class. Conclusions and Relevance: Limited evidence of clinical improvement was available among outpatients who reduced dietary salt intake, and evidence was inconclusive for inpatients. Overall, a paucity of robust high quality evidence to support or refute current guidance was available. This review suggests that well-designed, adequately powered studies are needed to reduce uncertainty about the use of this intervention. Protocol Registration: PROSPERO Identifier: CRD42015019504. PMID- 30398533 TI - Characteristics of Patients With Professional Guardians in the Department of Veterans Affairs Health Care System. PMID- 30398534 TI - Clinical Utility of Reinterpreting Previously Reported Genomic Epilepsy Test Results for Pediatric Patients. AB - Importance: Clinical genomic tests that examine the DNA sequence of large numbers of genes are commonly used in the diagnosis and management of epilepsy in pediatric patients. The permanence of genomic test result interpretations is not known. Objective: To investigate the value of reinterpreting previously reported genomic test results. Design, Setting, and Participants: This study retrospectively reviewed and reinterpreted genomic test results from July 1, 2012, to August 31, 2015, for pediatric patients who previously underwent genomic epilepsy testing at a single tertiary care pediatric health care facility. Reinterpretation of previously reported variants was conducted in May 2017. Main Outcomes and Measures: Patient reports from clinical genomic epilepsy tests were reviewed, and all reported genetic variants were reinterpreted using 2015 consensus standards and guidelines for interpreting hereditary genetic variants. Three classification tiers were used in the reinterpretation: pathogenic or likely pathogenic variant, variant of uncertain significance (VUS), or benign or likely benign variant. Results: A total of 309 patients had genomic epilepsy tests performed (mean [SD] age, 5.6 [0.8] years; 163 [52.8%] male), and 185 patients had a genetic variant reported. The reported variants resulted in 61 patients with and 124 patients without a genetic diagnosis (VUS variants only). On reinterpretation of all reported variants, 67 of the 185 patients (36.2%) had a change in variant classification. Of the 67 patients with a genetic variant change in interpretation, 21 (31.3%) experienced a change in diagnosis. During the 5 years of the study, 19 of 61 patients (31.1%) with a genetic diagnosis and 48 of 124 patients (38.7%) with undiagnosed conditions (VUS only) had their results reclassified. Review of genomic reports issued during the final 2 years of the study identified reclassification of variants in 4 of 16 patients (25.0%) with a pathogenic or likely pathogenic variant and 11 of 41 patients (26.8%) with a VUS. Conclusions and Relevance: The identified high rate of reinterpretation in this study suggests that interpretation of genomic test results has rapidly evolved during the past 5 years. These findings suggest that reinterpretation of genomic test results should be performed at least every 2 years. PMID- 30398536 TI - Dialysis for Patients With End-stage Renal Disease Who Are Homeless. PMID- 30398535 TI - Influence of Surgical Procedures and General Anesthesia on Child Development Before Primary School Entry Among Matched Sibling Pairs. AB - Importance: Substantial preclinical evidence suggests that the developing brain is susceptible to injury from anesthetic drugs. Findings from clinical studies of the neurotoxic effects of anesthesia are mixed, but these effects can be influenced by unmeasured confounding from biological and environmental risk and protective factors on child development. Objective: To examine the association between surgical procedures that require general anesthesia before primary school entry and child development in biological siblings. Design, Setting, and Participants: This retrospective sibling-matched cohort study included sibling pairs aged 5 to 6 years with the same birth mother who had Early Development Instrument (EDI) data completed. The EDI is a population-based measure of child development that assesses children's readiness to learn in 5 major domains (physical health and well-being, social knowledge and competence, emotional health and maturity, language and cognitive development, and communication skills and general knowledge). All eligible children in public and Catholic schools in Ontario, Canada, from 2004 through 2012 were included. Data were analyzed from December 13, 2017, through July 27, 2018. Exposures: Surgical procedures that require general anesthesia from the date of birth to EDI completion. Main Outcomes and Measures: Early developmental vulnerability, defined as any major domain of the EDI in the lowest 10th percentile of the Ontario population. Results: Of the 187 226 eligible children for whom the EDI was completed, a total of 10 897 sibling pairs (21 794 children; 53.8% female; mean [SD] age, 5.7 [0.3] years) were subsequently identified, including 2346 with only 1 child exposed to surgery. No significant differences were found between exposed and unexposed children in early developmental vulnerability (697 of 3080 [22.6%] vs 3739 of 18 714 [20.0%]; adjusted odds ratio [aOR], 1.03; 95% CI, 0.98-1.14; P = .58) or for each of the 5 major EDI domains (aOR for language and cognitive development, 0.96 [95% CI, 0.80-1.14]; aOR for physical health and well-being, 1.09 [95% CI, 0.96 1.24]; aOR for social knowledge and competence, 0.98 [95% CI, 0.84-1.14]; aOR for emotional health and maturity, 0.98 [95% CI, 0.84-1.14]; and aOR for communication skills and general knowledge, 0.90 [95% CI, 0.77-1.05]), after adjusting for confounding factors (age at EDI completion, sex, mother's age at birth, and eldest sibling status). Conclusions and Relevance: In this provincial cohort study, children who had surgical procedures that require general anesthesia before primary school entry were not found to be at increased risk of adverse child development outcomes compared with their biological siblings who did not have surgery. These findings further support that anesthesia exposure in early childhood is not associated with detectable adverse child development outcomes. PMID- 30398537 TI - Omitted Mention of and Reference to Related Study. PMID- 30398538 TI - Considerations on Retrospective Identification and Classification of Learning Disabilities. PMID- 30398539 TI - Incorrect Affiliation. PMID- 30398540 TI - Abetalipoproteinemia From Previously Unreported Gene Mutations. PMID- 30398541 TI - Familial Trigeminal Neuralgia Cases Implicate Genetic Factors in Disease Pathogenesis. PMID- 30398543 TI - The Potential for Troponin to Inform Prognosis in Patients With Stable Coronary Artery Disease. PMID- 30398542 TI - Effect of Intensive Patient Education vs Placebo Patient Education on Outcomes in Patients With Acute Low Back Pain: A Randomized Clinical Trial. AB - Importance: Many patients with acute low back pain do not recover with basic first-line care (advice, reassurance, and simple analgesia, if necessary). It is unclear whether intensive patient education improves clinical outcomes for those patients already receiving first-line care. Objective: To determine the effectiveness of intensive patient education for patients with acute low back pain. Design, Setting, and Participants: This randomized, placebo-controlled clinical trial recruited patients from general practices, physiotherapy clinics, and a research center in Sydney, Australia, between September 10, 2013, and December 2, 2015. Trial follow-up was completed in December 17, 2016. Primary care practitioners invited 618 patients presenting with acute low back pain to participate. Researchers excluded 416 potential participants. All of the 202 eligible participants had low back pain of fewer than 6 weeks' duration and a high risk of developing chronic low back pain according to Predicting the Inception of Chronic Pain (PICKUP) Tool, a validated prognostic model. Participants were randomized in a 1:1 ratio to either patient education or placebo patient education. Interventions: All participants received recommended first-line care for acute low back pain from their usual practitioner. Participants received additional 2 * 1-hour sessions of patient education (information on pain and biopsychosocial contributors plus self-management techniques, such as remaining active and pacing) or placebo patient education (active listening, without information or advice). Main Outcomes and Measures: The primary outcome was pain intensity (11-point numeric rating scale) at 3 months. Secondary outcomes included disability (24-point Roland Morris Disability Questionnaire) at 1 week, and at 3, 6, and 12 months. Results: Of 202 participants randomized for the trial, the mean (SD) age of participants was 45 (14.5) years and 103 (51.0%) were female. Retention rates were greater than 90% at all time points. Intensive patient education was not more effective than placebo patient education at reducing pain intensity (3-month mean [SD] pain intensity: 2.1 [2.4] vs 2.4 [2.2]; mean difference at 3 months, -0.3 [95% CI, 1.0 to 0.3]). There was a small effect of intensive patient education on the secondary outcome of disability at 1 week (mean difference, -1.6 points on a 24 point scale [95% CI, -3.1 to -0.1]) and 3 months (mean difference, -1.7 points, [95% CI, -3.2 to -0.2]) but not at 6 or 12 months. Conclusions and Relevance: Adding 2 hours of patient education to recommended first-line care for patients with acute low back pain did not improve pain outcomes. Clinical guideline recommendations to provide complex and intensive support to high-risk patients with acute low back pain may have been premature. Trial Registration: Australian Clinical Trial Registration Number: 12612001180808. PMID- 30398544 TI - Orbital Apex Syndrome in a Patient With Histiocytic Sarcoma. PMID- 30398545 TI - Considerations on Retrospective Identification and Classification of Learning Disabilities-Reply. PMID- 30398546 TI - Current Understanding and Gaps in Research of Carotid Webs in Ischemic Strokes: A Review. AB - Importance: A succession of research has explored the linkage between carotid webs (CaWs) and ischemic strokes. Imaging and pathologic analysis have defined CaW as an intimal variant of fibromuscular dysplasia, which appears as a shelflike lesion on the posterior aspect of the carotid bulb, more specifically at the origin of internal carotid artery. Reported findings of carotid webs in young patients with recurrent ischemic strokes without an otherwise determined cause have raised questions about the mechanism, natural history, and need for intervention. This review addresses the current understanding of CaW and highlights findings that prompt further investigation into this unique vascular entity as a modifiable stroke risk factor. Observations: Imaging analysis demonstrates hemodynamic disturbance in the presence of CaWs. The protuberant shelflike structure creates a pocket therein that may subsequently lead to local thrombosis and cerebral embolism. Computed tomographic angiography is an accurate and often used noninvasive diagnostic modality. Although treatment paradigms have not been systematically evaluated, antiplatelet monotherapy may not be sufficient to reduce recurrent ischemic events in the small series of patients with stroke and symptomatic CaWs. Conclusions and Relevance: The limited clinical data on CaWs, although complicated by selection bias, suggest an increased prevalence of these vascular entities in cerebral ischemic events among patients younger than 60 years. Imaging suggests CaW to be a possible nidus for cerebral thromboembolism. Physicians should consider CaW as a cause of stroke in younger patients with anterior circulation ischemic strokes of an otherwise undetermined cause. Treatment options in CaWs with ischemic strokes have not been extensively investigated. Multicenter observational studies evaluating the natural history of CaW are warranted. PMID- 30398547 TI - Improved inference of intermolecular contacts through protein-protein interaction prediction using coevolutionary analysis. AB - Motivation: Predicting residue-residue contacts between interacting proteins is an important problem in bioinformatics. The growing wealth of sequence data can be used to infer these contacts through correlated mutation analysis on multiple sequence alignments of interacting homologs of the proteins of interest. This requires correct identification of pairs of interacting proteins for many species, in order to avoid introducing noise (i.e. non-interacting sequences) in the analysis that will decrease predictive performance. Results: We have designed Ouroboros, a novel algorithm to reduce such noise in intermolecular contact prediction. Our method iterates between weighting proteins according to how likely they are to interact based on the correlated mutations signal, and predicting correlated mutations based on the weighted sequence alignment. We show that this approach accurately discriminates between protein interaction versus non-interaction and simultaneously improves the prediction of intermolecular contact residues compared to a naive application of correlatedmutation analysis. This requires no training labels concerning interactions nor contacts. Furthermore, the method relaxes the assumption of one-to-one interaction of previous approaches, allowing for the study of many-to-many interactions. Availability: Source code and test data are available at www.bif.wur.nl/. Supplementary information: Supplementary information is available at Bioinformatics online. PMID- 30398548 TI - Computational Modeling of Cellular Structures Using Conditional Deep Generative Networks. AB - Motivation: Cellular function is closely related to the localizations of its substructures. It is, however, challenging to experimentally label all subcellular structures simultaneously in the same cell. This raises the need of building a computational model to learn the relationships among these subcellular structures and use reference structures to infer the localizations of other structures. Results: We formulate such a task as a conditional image generation problem and propose to use conditional generative adversarial networks for tackling it. We employ an encoder-decoder network as the generator and propose to use skip connections between the encoder and decoder to provide spatial information to the decoder. To incorporate the conditional information in a variety of different ways, we develop three different types of skip connections, known as the self-gated connection, encoder-gated connection, and label-gated connection. The proposed skip connections are built based on the conditional information using gating mechanisms. By learning a gating function, the network is able to control what information should be passed through the skip connections from the encoder to the decoder. Since the gate parameters are also learned automatically, we expect that only useful spatial information is transmitted to the decoder to help image generation. We perform both qualitative and quantitative evaluations to assess the effectiveness of our proposed approaches. Experimental results show that our cGAN-based approaches have the ability to generate the desired subcellular structures correctly. Our results also demonstrate that the proposed approaches outperform the existing approach based on adversarial autoencoders, and the new skip connections lead to improved performance. In addition, the localizations of generated subcellular structures by our approaches are consistent with observations in biological experiments. Availability: The source code and more results are available at https://github.com/divelab/cgan/. PMID- 30398549 TI - The Accuracy of Smartphone Sound Level Meter Applications With and Without Calibration. AB - Purpose: The purpose of this study is to determine the accuracy of smartphone sound level meter applications (SLMAs) with calibration features across stimulus levels and for ambient room noise measures in the clinical setting. Method: The accuracy of 3 iOS-based smartphone SLMAs (SLMA1: Analyzer [Version 2.7.2, DSP Mobile], SLMA2: Sound Level Meter Pro [Version 2.2, Mint Muse LLC], and SLMA3: SPL Meter [Version 9.3, Andrew Smith, Studio Six Digital]), using a single smartphone device (iPhone 6S Model A1688, iOS 9.3.4, Apple), was evaluated with and without calibration using a 1000-Hz narrowband noise (NBN) and white noise (WN) stimuli over a range of sound levels (20-100 dB) and in ambient noise measures of 8 speech and hearing room environments. A simultaneous and corresponding SLMA and Type 1 sound level meter (SLM) measure per condition were documented with a photo image; each condition was replicated 5 times. Mean SLMA and SLM measures were compared. SLMA measures were considered accurate if within +/- 2 dB of the SLM. Results: Measures of NBN and WN signals using these SLMAs were accurate at levels above 40-50 dB when calibrated. NBN and WN signals using some SLMAs were significantly (p < .05) more accurate with calibration at levels > 40 to 50 dB. SLMA measures with or without calibration adjustment were inaccurate and overestimated room ambient noise levels < 50 dB. Conclusions: These findings suggest that some SLMAs are accurate for measuring NBN and WN stimuli within the range of 50-100 dB in sound-treated environments when calibrated. However, outcomes indicated that some SLMAs, even with calibration, overestimated low ambient noise levels and may not accurately verify quiet room environments < 50 dB for clinical services. These results should not be generalized for all smartphone types, and continued research on SLMAs using next generation smartphone devices is warranted. PMID- 30398550 TI - Clinical Decision Support in the Era of Artificial Intelligence. PMID- 30398552 TI - Guggenheim Museum, New York City. PMID- 30398553 TI - Meeting the Criteria of Medication Therapy Management. PMID- 30398554 TI - Limited Focus in Evaluation of Vaccine Cost-effectiveness. PMID- 30398555 TI - Re-examining the Association Between "4/20" and Fatal Crashes-Doobie-ous Data? PMID- 30398556 TI - Further Lessons in Pneumocystis Pneumonia Prophylaxis. PMID- 30398557 TI - Mineralocorticoid Receptor Antagonism Treatment for All Patients With ST-Segment Myocardial Infarction? PMID- 30398558 TI - Meeting the Criteria of Medication Therapy Management-Reply. PMID- 30398559 TI - Limited Focus in Evaluation of Vaccine Cost-effectiveness-Reply. PMID- 30398560 TI - Further Lessons in Pneumocystis Pneumonia Prophylaxis-Reply. PMID- 30398561 TI - Mineralocorticoid Receptor Antagonism Treatment for All Patients With ST-Segment Myocardial Infarction?-Reply. PMID- 30398563 TI - Speech Impairment in Boys With Fetal Alcohol Spectrum Disorders. AB - Background: Fetal alcohol spectrum disorders (FASD) are a highly prevalent spectrum of patterns of congenital defects resulting from prenatal exposure to alcohol. Approximately 90% of the cases involve speech impairment. Yet, to date, no detailed symptom profiles nor dedicated treatment plans are available for this population. Purpose: This study set out to chart the speech and speech motor characteristics in boys with FASD to profile the concomitant speech impairment and identify possible underlying mechanisms. Method: Ten boys with FASD (4.5-10.3 years old) and 26 typically developing children (4.1-8.7 years old; 14 boys, 12 girls) participated in the study. Speech production and perception, and oral motor data were collected by standardized tests. Results: The boys with FASD showed reduced scores on all tasks as well as a deviant pattern of correlations between production and perception tasks and intelligibility compared with the typically developing children. Speech motor profiles showed specific problems with nonword repetition and tongue control. Conclusions: Findings indicate that the speech impairment in boys with FASD results from a combination of deficits in multiple subsystems and should be approached as a disorder rather than a developmental delay. The results suggest that reduced speech motor planning/programming, auditory discrimination, and oral motor abilities should be considered in long-term, individually tailored treatment. PMID- 30398564 TI - wgd - simple command line tools for the analysis of ancient whole genome duplications. AB - Motivation: Ancient whole genome duplications (WGDs) have been uncovered in almost all major lineages of life on Earth and the search for traces or remnants of such events has become standard practice in most genome analyses. This is especially true for plants, where ancient WGDs are abundant. Common approaches to find evidence for ancient WGDs include the construction of KS distributions and the analysis of intragenomic co-linearity. Despite the increased interest in WGDs and the acknowledgement of their evolutionary importance, user-friendly and comprehensive tools for their analysis are lacking. Here, we present an easy to use command-line tool for KS distribution construction named wgd. The wgd suite provides commonly used KS and co-linearity analysis workflows together with tools for modeling and visualization, rendering these analyses accessible to genomics researchers in a convenient manner. Availability & implementation: wgd is free and open source software implemented in Python and is available at https://github.com/arzwa/wgd. Supplementary information: Supplementary methods are available at Bioinformatics online. PMID- 30398565 TI - Slowed Dark Adaptation in Early AMD: Dual Stimulus Reveals Scotopic and Photopic Abnormalities. AB - Purpose: The recovery of visual sensitivity after a photobleach in early AMD is slowed in rods but cones also may be abnormal. The purpose of this article was to test different stimulus locations to investigate cone function and its relation to rod abnormalities. Methods: Stimuli were presented at two locations, 3.0 degrees and 5.5 degrees , in the inferior visual field. Post photobleach dark adaptation (DA) curves from 50 early-AMD patients were compared with those from 15 healthy controls of similar age. Curves were characterized in terms of four parameters: ct, cone threshold; alpha, the transition point from cone to rod function; S2, the slope of the second rod-mediated component; and beta, the transition from the second to the third rod-mediated component. Results: There were strong location effects for the healthy group and the AMD group. Cone threshold was higher for the outer compared with the inner stimulus (P = 0.001), S2 was steeper for outer compared with inner (P < 0.001), alpha was shorter for outer (P = 0.004), and beta was shorter for outer than inner (P = 0.002). The high variance in the patient data, particularly for alpha and beta, explained the absence of a group*location interaction in the statistics. Conclusions: The data provide a novel perspective on abnormal cone- and rod-sensitivity recovery in early dry AMD. The comparison of pairs of DA curves from different locations highlights the involvement of cones in the underlying pathology of AMD. Dynamic measures of visual function are particularly sensitive to early AMD. PMID- 30398567 TI - With Gratitude on Veterans Day. PMID- 30398566 TI - Lipopolysaccharide-induced testicular dysfunction and epididymitis in mice: a critical role of tumor necrosis factor alpha. AB - Systemic inflammation may impair male fertility, and its underlying mechanisms remain poorly understood. The present study investigates the effect of lipopolysaccharide (LPS)-induced systemic inflammation on the testis and epididymis in mice. Intraperitoneal injection of LPS significantly impaired testicular functions, including testosterone production, spermatogenesis, and blood-testis barrier permeability. The epididymitis characterized by leukocyte infiltration and fibrosis was observed in the cauda epididymis after LPS injection. LPS-induced testicular dysfunction and epididymitis were abolished in tumor necrosis factor alpha (Tnfa) knockout mice. Pomalidomide, a TNFA inhibitor, blocked the detrimental effects of LPS on the testis and epididymis. The results indicate that LPS-induced systemic inflammation impairs male fertility through TNFA production, suggesting that the intervention on TNFA production would be considered for the prevention and treatment of inflammatory impairment of male fertility. PMID- 30398568 TI - The Other 45: Improving Patients' Chronic Disease Self-Management and Medical Students' Communication Skills. AB - Context: To improve chronic disease self-management among an underserved population and to improve the skills of second-year osteopathic medical students, an educational curriculum, The Other 45, was developed. In addition to a typical 15-minute office visit, this program allows second-year students to provide chronic disease education to patients for 45 minutes in an effort to improve patient disease self-management and associated health outcomes. Objective: To determine whether patients who participate in The Other 45 report improvements in their ability to manage their chronic disease(s) and their health outcomes and whether second-year osteopathic medical students report changes in patient centered care, clinical confidence, and medical/teaching knowledge. Methods: Patients with a previously diagnosed chronic disease participated in 3 visits for The Other 45. Chronic disease self-management and health outcomes were measured using the Health Education Impact Questionnaire, which participants completed at each visit. Students received a formal presentation on teaching skills, and those who participated in The Other 45 completed a pre- and postclinic survey measuring 3 focused domains: patient-centered care, clinical confidence, and medical/teaching knowledge. Results: A total of 47 patients and 69 students participated in the study. As measured by the Health Education Impact Questionnaire, patients' skill and technique acquisition (P=.01), constructive attitudes and approaches (P=.01), and health services navigation (P=.03) showed significant improvement at the 3-week follow-up visit, and self-monitoring and insight showed significant improvement (P=.01) at the 3-month follow-up visit. Patients' positive and active engagement in life (P=.04 and P=.03) and emotional well-being (P=.003 and P=.0007) significantly improved at the 3-week and 3-month follow-up, respectively. The students improved significantly in all 3 domains as a result of participating in the program: patient-centered care (P=.012), clinical confidence (P<.001), and medical/teaching knowledge (P=.002). Conclusions: The Other 45 was effective in improving patients' ability to manage their chronic disease(s), as well as improving second-year osteopathic medical students' ability to educate a patient with chronic disease. Implementing this type of program has the potential to affect patients with chronic disease as well as medical students in a rural underserved setting. PMID- 30398569 TI - Cardiovascular Disease as a Result of the Interactions Between Obesity, Climate Change, and Inflammation: The COCCI Syndemic. AB - Obesity and climate change conspire to create an environment in which subclinical vascular inflammation leads to progressive atherosclerosis, which contributes to the number 1 cause of global mortality: cardiovascular disease. The syndemic model requires 2 or more diseases or contributors to disease (such as obesity and climate change) clustering within a specific population in addition to the associated societal and social factors, ultimately creating an environment supportive of a greater adverse interaction. This article explores the syndemic of obesity and climate change as a driver for cardiovascular disease. PMID- 30398570 TI - Evidence for the Prevention of Type 2 Diabetes Mellitus. AB - Type 2 diabetes mellitus (T2DM) is a common chronic metabolic condition. Before receiving this diagnosis, persons typically have a long period of prediabetes. There is good evidence that T2DM can often be prevented or delayed by means of lifestyle interventions (39%-71%), medications (28%-79%), or metabolic surgery (75%). However, despite consistent data demonstrating their efficacy, these tools are underused, and knowledge about them among primary care physicians is limited. In an effort to engage physicians in addressing this public health crisis more effectively, the authors reviewed the evidence that T2DM can be prevented or delayed in persons at risk. PMID- 30398571 TI - Correlation of Personal Experience and Acquired Knowledge With Intent to Recommend Adjunctive Osteopathic Manipulative Treatment or Yoga for Patients With Chronic Low Back Pain. AB - Context: Osteopathic manipulative treatment (OMT) and yoga are both recommended by systematic reviews in the evidence-based research literature for low back pain management. It is unknown, to the authors' knowledge, what the effect of personal experience with OMT or yoga, reading research articles on OMT or yoga, or both will have on medical students' recommendations for these treatment options to future patients with chronic low back pain. Objective: To evaluate the likelihood of osteopathic medical students recommending OMT or yoga to treat patients with chronic low back pain based on their personal experience or reading research articles that recommend OMT or yoga for patients with chronic low back pain. Methods: In this prospective cohort study, researchers administered an anonymous 18-question online survey for osteopathic medical students. The survey included a patient vignette, 2 evidence-based articles, and multiple choice, yes/no, and Likert-type questions. Participants were recruited via email from all 4 years of medical school. Between-group differences in proportions were assessed with descriptive statistics and chi2 tests; differences within groups were assessed with the McNemar test; and Fischer exact tests were used when expected cell counts were less than 5. Results: A total of 180 participants (100 male, 80 female) completed the study. Personal experience increased the likelihood of osteopathic medical students recommending OMT (P<.018) or yoga (P<.001) to a future patient or to a patient in a case vignette (P<.05) with chronic low back pain. Students who read research articles were more likely to recommend OMT to the case patient and future patients before and after reading the intervention article regardless of their experience (P<.001). Conclusion: Personal experience and reading evidence-based research may increase the likelihood that osteopathic medical students will recommend OMT to future patients with chronic low back pain. PMID- 30398572 TI - An Education in Osteopathic Ultrasonography (AEIOU) Program: One Institution's Approach to Advancing an Ultrasonography Curriculum. AB - Advances in ultrasonography (US) have allowed this technology to play an increasingly important role in numerous fields of medicine. It is important that medical schools incorporate this broadly applicable tool into their curricula. Touro University College of Osteopathic Medicine-CA has implemented a progressive US curriculum that is intended to complement osteopathic education, keep pace with medical advances, and arm future physicians with the most advanced skills and tools to practice medicine. In this article, the authors highlight the importance of US training in medical education and demonstrate the relative ease, cost-effectiveness, and direct benefit to students of implementing such a curriculum. The authors discuss the specifics of the US curriculum in osteopathic undergraduate medical education and describe how a staged rollout helped the college address the need for funding, faculty, and facilities. Plans for continued expansion, the successful and effective use of peer educators, the outcomes measured from this project, and avenues for further study are also discussed. PMID- 30398573 TI - Public Health and Interprofessional Education as Critical Components in the Evolution of Osteopathic Medical Education. AB - Public health and interprofessional education (IPE) are included among the osteopathic core competencies and Entrustable Professional Activities that should be reflected in osteopathic medical curricula. Cognizant of the importance of these 2 areas, Touro University College of Osteopathic Medicine-CA (TUCOM) has developed initiatives to advance them on campus as well as within its academic curriculum. The authors acknowledge the importance of incorporating public health content into osteopathic medicine as well as expanding IPE in the health professions as part of a larger project to impart a unique identity and relevance to osteopathic medical education at TUCOM. The authors describe TUCOM's public health and IPE initiatives and outcomes in the context of current and future relevance for osteopathic medicine. Future directions to assess the quality and impact of these programs that may be of value for other colleges of osteopathic medicine are also discussed. PMID- 30398574 TI - Boerhaave Syndrome. PMID- 30398575 TI - Dry Digital Gangrene. PMID- 30398576 TI - Updated Additional Contributions. PMID- 30398577 TI - Error in End Matter. PMID- 30398578 TI - Transposed Row Labels and Data in Table. PMID- 30398581 TI - Researchers Reprogram Cells In Vivo to Restore Vision in Mice. PMID- 30398582 TI - Ambulatory Blood Pressure Monitoring. PMID- 30398585 TI - Test Detects One in a Million Cancer Cells. PMID- 30398586 TI - Preventive Migraine Drug Approved. PMID- 30398584 TI - Hypertension-A Public Health Challenge of Global Proportions. PMID- 30398583 TI - High Blood Pressure in Young Adulthood and Risk of Premature Cardiovascular Disease: Calibrating Treatment Benefits to Potential Harm. PMID- 30398587 TI - New Treatment for Certain Types of Leukemia and Lymphoma. PMID- 30398589 TI - Out-of-Office Blood Pressure Monitoring in 2018. PMID- 30398590 TI - Public Health Emergency Preparedness: Globalizing Risk, Localizing Threats. PMID- 30398591 TI - Indications of Physical Overexertion. PMID- 30398592 TI - Cumulative Incidence of Autism Into Adulthood for Birth Cohorts in Denmark, 1980 2012. PMID- 30398593 TI - Evaluation of Lowering the P Value Threshold for Statistical Significance From .05 to .005 in Previously Published Randomized Clinical Trials in Major Medical Journals. PMID- 30398594 TI - Medications With Depression as an Adverse Effect. PMID- 30398595 TI - Medications With Depression as an Adverse Effect. PMID- 30398596 TI - Stress-Related Disorders and Autoimmune Disease. PMID- 30398597 TI - Diagnostic vs Management Reasoning. PMID- 30398598 TI - Medications With Depression as an Adverse Effect-Reply. PMID- 30398599 TI - Stress-Related Disorders and Autoimmune Disease-Reply. PMID- 30398600 TI - Diagnostic vs Management Reasoning-Reply. PMID- 30398601 TI - Association of Blood Pressure Classification in Young Adults Using the 2017 American College of Cardiology/American Heart Association Blood Pressure Guideline With Cardiovascular Events Later in Life. AB - Importance: Little is known regarding the association between level of blood pressure (BP) in young adulthood and cardiovascular disease (CVD) events by middle age. Objective: To assess whether young adults who developed hypertension, defined by the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) BP guideline, before age 40 years have higher risk for CVD events compared with those who maintained normal BP. Design, Setting, and Participants: Analyses were conducted in the prospective cohort Coronary Artery Risk Development in Young Adults (CARDIA) study, started in March 1985. CARDIA enrolled 5115 African American and white participants aged 18 to 30 years from 4 US field centers (Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota; and Oakland, California). Outcomes were available through August 2015. Exposures: Using the highest BP measured from the first examination to the examination closest to, but not after, age 40 years, each participant was categorized as having normal BP (untreated systolic BP [SBP] <120 mm Hg and diastolic BP [DBP] <80 mm Hg; n = 2574); elevated BP (untreated SBP 120-129 mm Hg and DBP <80 mm Hg; n = 445); stage 1 hypertension (untreated SBP 130-139 mm Hg or DBP 80-89 mm Hg; n = 1194); or stage 2 hypertension (SBP >=140 mm Hg, DBP >=90 mm Hg, or taking antihypertensive medication; n = 638). Main Outcomes and Measures: CVD events: fatal and nonfatal coronary heart disease (CHD), heart failure, stroke, transient ischemic attack, or intervention for peripheral artery disease (PAD). Results: The final cohort included 4851 adults (mean age when follow-up for outcomes began, 35.7 years [SD, 3.6]; 2657 women [55%]; 2441 African American [50%]; 206 taking antihypertensive medication [4%]). Over a median follow-up of 18.8 years, 228 incident CVD events occurred (CHD, 109; stroke, 63; heart failure, 48; PAD, 8). CVD incidence rates for normal BP, elevated BP, stage 1 hypertension, and stage 2 hypertension were 1.37 (95% CI, 1.07-1.75), 2.74 (95% CI, 1.78-4.20), 3.15 (95% CI, 2.47-4.02), and 8.04 (95% CI, 6.45-10.03) per 1000 person-years, respectively. After multivariable adjustment, hazard ratios for CVD events for elevated BP, stage 1 hypertension, and stage 2 hypertension vs normal BP were 1.67 (95% CI, 1.01-2.77), 1.75 (95% CI, 1.22-2.53), and 3.49 (95% CI, 2.42-5.05), respectively. Conclusions and Relevance: Among young adults, those with elevated blood pressure, stage 1 hypertension, and stage 2 hypertension before age 40 years, as defined by the blood pressure classification in the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines, had significantly higher risk for subsequent cardiovascular disease events compared with those with normal blood pressure before age 40 years. The ACC/AHA blood pressure classification system may help identify young adults at higher risk for cardiovascular disease events. PMID- 30398603 TI - Association of Blood Pressure Classification in Korean Young Adults According to the 2017 American College of Cardiology/American Heart Association Guidelines With Subsequent Cardiovascular Disease Events. AB - Importance: Among young adults, the association of the 2017 American College of Cardiology/American Heart Association (ACC/AHA) High Blood Pressure Clinical Practice Guidelines with risk of cardiovascular disease (CVD) later in life is uncertain. Objective: To determine the association of blood pressure categories before age 40 years with risk of CVD later in life. Design, Setting, and Participants: This population-based cohort study from the Korean National Health Insurance Service consisted of 2 488 101 adults aged 20 through 39 years with blood pressure measurements taken twice from 2002 through 2005. Starting from January 1, 2006, participants were followed up until the date of CVD diagnosis, death, or December 31, 2015. Exposures: Participants were categorized by blood pressure readings: normal (systolic, <120 mm Hg; diastolic, <80 mm Hg), elevated (sytolic, 120-129 mm Hg; diastolic, <80 mm Hg), stage 1 hypertension (systolic, 130-139 mm Hg; diastolic, 80-89 mm Hg), and stage 2 hypertension (systolic, >=140 mm Hg; diastolic, >=90 mm Hg). Main Outcomes and Measures: The primary outcome was CVD defined as 2 or more days of hospitalization due to CVD or death due to CVD. The secondary outcomes were coronary heart disease (CHD) and stroke. Results: The study population consisted of 2 488 101 participants (median age, 31 years [interquartile range, 27-36 years], 789 870 women [31.7%]). A total of 44 813 CVD events were observed during a median follow-up duration of 10 years. Men with baseline stage 1 hypertension compared with those with normal blood pressure had higher risk of CVD (incidence, 215 vs 164 per 100 000 person-years; difference, 51 per 100 000 person-years [95% CI, 48-55]; adjusted hazard ratio [HR], 1.25 [95% CI, 1.21-1.28]), CHD (incidence, 134 vs 103 per 100 000 person years; difference, 31 per 100 000 person-years [95% CI, 28-33]; adjusted HR, 1.23 [95% CI, 1.19-1.27]), and stroke (incidence, 90 vs 67 per 100 000 person-years; difference, 23 per 100 000 person-years [95% CI, 21-26]; adjusted HR, 1.30 [95% CI, 1.25-1.36]). Women with baseline stage 1 hypertension compared with those with normal blood pressure had increased risk of CVD (incidence, 131 vs 91 per 100 000 person-years; difference, 40 per 100 000 person-years [95% CI, 35-45]; adjusted HR, 1.27 [95% CI, 1.21-1.34]), CHD (incidence, 56 vs 42 per 100 000 person-years; difference, 14 per 100 000 person-years [95% CI, 11-18]; adjusted HR, 1.16 [95% CI, 1.08-1.25]), and stroke (incidence, 79 vs 51 per 100 000 person years; difference, 28 per 100 000 person-years [95% CI, 24-32]; adjusted HR [1.37, 95% CI, 1.29-1.46]). Results for state 2 hypertension were consistent. Conclusions and Relevance: Among Korean young adults, stage 1 and stage 2 hypertension, compared with normal blood pressure, were associated with increased risk of subsequent cardiovascular disease events. Young adults with hypertension, defined by the 2017 ACC/AHA criteria, may be at increased risk of cardiovascular disease. PMID- 30398602 TI - Effect of Inorganic Nitrite vs Placebo on Exercise Capacity Among Patients With Heart Failure With Preserved Ejection Fraction: The INDIE-HFpEF Randomized Clinical Trial. AB - Importance: There are few effective treatments for heart failure with preserved ejection fraction (HFpEF). Short-term administration of inorganic nitrite or nitrate preparations has been shown to enhance nitric oxide signaling, which may improve aerobic capacity in HFpEF. Objective: To determine the effect of 4 weeks' administration of inhaled, nebulized inorganic nitrite on exercise capacity in HFpEF. Design, Setting, and Participants: Multicenter, double-blind, placebo controlled, 2-treatment, crossover trial of 105 patients with HFpEF. Participants were enrolled from July 22, 2016, to September 12, 2017, at 17 US sites, with final date of follow-up of January 2, 2018. Interventions: Inorganic nitrite or placebo administered via micronebulizer device. During each 6-week phase of the crossover study, participants received no study drug for 2 weeks (baseline/washout) followed by study drug (nitrite or placebo) at 46 mg 3 times a day for 1 week followed by 80 mg 3 times a day for 3 weeks. Main Outcomes and Measures: The primary end point was peak oxygen consumption (mL/kg/min). Secondary end points included daily activity levels assessed by accelerometry, health status as assessed by the Kansas City Cardiomyopathy Questionnaire (score range, 0-100, with higher scores reflecting better quality of life), functional class, cardiac filling pressures assessed by echocardiography, N-terminal fragment of the prohormone brain natriuretic peptide levels, other exercise indices, adverse events, and tolerability. Outcomes were assessed after treatment for 4 weeks. Results: Among 105 patients who were randomized (median age, 68 years; 56% women), 98 (93%) completed the trial. During the nitrite phase, there was no significant difference in mean peak oxygen consumption as compared with the placebo phase (13.5 vs 13.7 mL/kg/min; difference, -0.20 [95% CI, -0.56 to 0.16]; P = .27). There were no significant between-treatment phase differences in daily activity levels (5497 vs 5503 accelerometry units; difference, -15 [95% CI, -264 to 234]; P = .91), Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (62.6 vs 61.9; difference, 1.1 [95% CI, -1.4 to 3.5]; P = .39), functional class (2.5 vs 2.5; difference, 0.1 [95% CI, -0.1 to 0.2]; P = .43), echocardiographic E/e' ratio (16.4 vs 16.6; difference, 0.1 [95% CI, -1.2 to 1.3]; P = .93), or N-terminal fragment of the prohormone brain natriuretic peptide levels (520 vs 533 pg/mL; difference, 11 [95% CI, -53 to 75]; P = .74). Worsening heart failure occurred in 3 participants (2.9%) during the nitrite phase and 8 (7.6%) during the placebo phase. Conclusions and Relevance: Among patients with HFpEF, administration of inhaled inorganic nitrite for 4 weeks, compared with placebo, did not result in significant improvement in exercise capacity. Trial Registration: ClinicalTrials.gov Identifier: NCT02742129. PMID- 30398605 TI - Monitoring Blood Pressure Outside of the Doctor's Office. PMID- 30398604 TI - Association of Change in Cardiovascular Risk Factors With Incident Cardiovascular Events. AB - Importance: There is consistent evidence of the association between ideal cardiovascular health and lower incident cardiovascular disease (CVD); however, most studies used a single measure of cardiovascular health. Objective: To examine how cardiovascular health changes over time and whether these changes are associated with incident CVD. Design, Setting, and Participants: Prospective cohort study in a UK general community (Whitehall II), with examinations of cardiovascular health from 1985/1988 (baseline) and every 5 years thereafter until 2015/2016 and follow-up for incident CVD until March 2017. Exposures: Using the 7 metrics of the American Heart Association (nonsmoking; and ideal levels of body mass index, physical activity, diet, blood pressure, fasting blood glucose, and total cholesterol), participants with 0 to 2, 3 to 4, and 5 to 7 ideal metrics were categorized as having low, moderate, and high cardiovascular health. Change in cardiovascular health over 10 years between 1985/1988 and 1997/1999 was considered. Main Outcome and Measure: Incident CVD (coronary heart disease and stroke). Results: The study population included 9256 participants without prior CVD (mean [SD] age at baseline, 44.8 [6.0] years; 2941 [32%] women), of whom 6326 had data about cardiovascular health change. Over a median follow-up of 18.9 years after 1997/1999, 1114 incident CVD events occurred. In multivariable analysis and compared with individuals with persistently low cardiovascular health (consistently low group, 13.5% of participants; CVD incident rate per 1000 person-years, 9.6 [95% CI, 8.4-10.9]), there was no significant association with CVD risk in the low to moderate group (6.8% of participants; absolute rate difference per 1000 person-years, -1.9 [95% CI, -3.9 to 0.1]; HR, 0.84 [95% CI, 0.66-1.08]), the low to high group, (0.3% of participants; absolute rate difference per 1000 person-years, -7.7 [95% CI, -11.5 to -3.9]; HR, 0.19 [95% CI, 0.03-1.35]), and the moderate to low group (18.0% of participants; absolute rate difference per 1000 person-years, -1.3 [95% CI, -3.0 to 0.3]; HR, 0.96 [95% CI, 0.80-1.15]). A lower CVD risk was observed in the consistently moderate group (38.9% of participants; absolute rate difference per 1000 person-years, -4.2 [95% CI, -5.5 to -2.8]; HR, 0.62 [95% CI, 0.53-0.74]), the moderate to high group (5.8% of participants; absolute rate difference per 1000 person-years, -6.4 [95% CI, -8.0 to -4.7]; HR, 0.39 [95% CI, 0.27-0.56]), the high to low group (1.9% of participants; absolute rate difference per 1000 person-years, -5.3 [95% CI, -7.8 to -2.8]; HR, 0.49 [95% CI, 0.29-0.83]), the high to moderate group (9.3% of participants; absolute rate difference per 1000 person-years, -4.5 [95% CI, -6.2 to -2.9]; HR, 0.66 [95% CI, 0.51-0.85]), and the consistently high group (5.5% of participants; absolute rate difference per 1000 person-years, -5.6 [95% CI, -7.4 to -3.9]; HR, 0.57 [95% CI, 0.40-0.80]). Conclusions and Relevance: Among a group of participants without CVD who received follow-up over a median 18.9 years, there was no consistent relationship between direction of change in category of a composite metric of cardiovascular health and risk of CVD. PMID- 30398607 TI - A Letter to Our Daughter. PMID- 30398609 TI - Use of Home Blood Pressure Results for Assessing the Quality of Care for Hypertension. PMID- 30398610 TI - Treatment of Hypertension: Addressing a Global Health Problem. PMID- 30398611 TI - The 2018 European Society of Cardiology/European Society of Hypertension and 2017 American College of Cardiology/American Heart Association Blood Pressure Guidelines: More Similar Than Different. PMID- 30398612 TI - Structural Relationship Between Cognitive Processing and Syntactic Sentence Comprehension in Children With and Without Developmental Language Disorder. AB - Purpose: We assessed the potential direct and indirect (mediated) influences of 4 cognitive mechanisms we believe are theoretically relevant to canonical and noncanonical sentence comprehension of school-age children with and without developmental language disorder (DLD). Method: One hundred seventeen children with DLD and 117 propensity-matched typically developing (TD) children participated. Comprehension was indexed by children identifying the agent in implausible sentences. Children completed cognitive tasks indexing the latent predictors of fluid reasoning (FLD-R), controlled attention (CATT), complex working memory (cWM), and long-term memory language knowledge (LTM-LK). Results: Structural equation modeling revealed that the best model fit was an indirect model in which cWM mediated the relationship among FLD-R, CATT, LTM-LK, and sentence comprehension. For TD children, comprehension of both sentence types was indirectly influenced by FLD-R (pattern recognition) and LTM-LK (linguistic chunking). For children with DLD, canonical sentence comprehension was indirectly influenced by LTM-LK and CATT, and noncanonical comprehension was indirectly influenced just by CATT. Conclusions: cWM mediates sentence comprehension in children with DLD and TD children. For TD children, comprehension occurs automatically through pattern recognition and linguistic chunking. For children with DLD, comprehension is cognitively effortful. Whereas canonical comprehension occurs through chunking, noncanonical comprehension develops on a word-by-word basis. Supplemental Material: https://doi.org/10.23641/asha.7178939. PMID- 30398614 TI - Long term antiarrhythmic drug treatment after atrial fibrillation ablation: does too obstinate rhythm control strategy bring serious risk of proarrhythmia to ablated patients? PMID- 30398613 TI - Verb Variability and Morphosyntactic Priming With Typically Developing 2- and 3 Year-Olds. AB - Purpose: This study was specifically designed to examine how verb variability and verb overlap in a morphosyntactic priming task affect typically developing children's use and generalization of auxiliary IS. Method: Forty typically developing 2- to 3-year-old native English-speaking children with inconsistent auxiliary IS production were primed with 24 present progressive auxiliary IS sentences. Half of the children heard auxiliary IS primes with 24 unique verbs (high variability). The other half heard auxiliary IS primes with only 6 verbs, repeated 4 times each (low variability). In addition, half of the children heard prime-target pairs with overlapping verbs (lexical boost), whereas the other half heard prime-target pairs with nonoverlapping verbs (no lexical boost). To assess use and generalization of the targeted structure to untrained verbs, all children described probe items at baseline and 5 min and 24 hr after the priming task. Results: Children in the high variability group demonstrated strong priming effects during the task and increased auxiliary IS production compared with baseline performance 5 min and 24 hr after the priming task, suggesting learning and generalization of the primed structure. Children in the low variability group showed no significant increases in auxiliary IS production and fell significantly below the high variability group in the 24-hr posttest. Verb overlap did not boost priming effects during the priming task or in posttest probes. Conclusions: Typically developing children do indeed make use of lexical variability in their linguistic input to help them extract and generalize abstract grammatical rules. They can do this quite quickly, with relatively stable, robust learning occurring after a single optimally variable input session. With reduced variability, learning does not occur. PMID- 30398615 TI - Protocol Deviations, Reanalyses, and Corrections to PREDIMED Trial Derivative Study on Peripheral Artery Disease. PMID- 30398616 TI - Protocol Deviations and Reanalyses in a Derivative Study of the PREDIMED Trial. PMID- 30398617 TI - Migration-related changes in smoking among non-Western immigrants in France. AB - Background: Migrants make up a growing share of European populations, and very little is known about the impact of migration on their smoking patterns. We develop a longitudinal analysis of smoking prevalence among native-born and immigrants in France based on retrospective data collected in the 2010 national Barometre sante health survey. Methods: Analyses concerned 19 578 individuals aged 18-70 years and born in metropolitan France, in the Maghreb or in sub Saharan Africa. Person-years with and without smoking were reconstructed using migration and smoking histories and analyzed with discrete-time regression models. Results: Prior to migration, immigrants from both the Maghreb and sub Saharan Africa had lower smoking prevalence than the native-born of similar birth cohort, age and education. After migration, the prevalence increased over time among Maghrebin men up to levels beyond those of the native-born (odds ratio: 1.54 [1.09-2.17] for 10 years of residence or more), while it remained much lower throughout among men from sub-Saharan Africa (odds ratio: 0.36 [0.19-0.68] for 10 years of residence or more). Starting at extremely low levels, the prevalence in both groups of women rose considerably after migration. Women from sub-Saharan Africa nearly caught up to the native-born (odds ratio: 0.70 [0.37-1.32] for 10 years of residence or more), but this was not the case for those from the Maghreb (odds ratio: 0.52 [0.33-0.81] for 10 years of residence or more). Conclusion: The findings uncover the low pre-migration prevalence and the diversity of post migration trajectories. Tobacco control programs targeting recently arrived migrants would contribute to prevent unhealthy assimilation. PMID- 30398618 TI - Micafungin-Induced Hypoglycemia in a Type 1 Diabetes Patient: A Case Report and Review of Literature. AB - Objective: Patients with type 1 diabetes mellitus (T1DM) are insulin-dependent. Infection increases insulin resistance and subsequently increases insulin needs. We are reporting the first case of a patient with T1DM and severe infection who has reduced insulin needs after starting micafungin therapy. Methods: A 29-year old Hispanic female with known history of long-standing uncontrolled type 1 diabetes presented for evaluation of worsening dysphagia and dyspnea. She was found to have cervical necrotizing fasciitis extending into the mediastinum and required several debridement surgeries along with broad spectrum antibiotics and antifungal therapy. She had uncontrolled diabetes with a glycosylated hemoglobin (HbA1c) of 13.4% (18.8 mmol/L) on admission. Her insulin requirements progressively increased due to worsening infection, continuous tube feeds, and multiple debridement surgeries. She was started on micafungin, a potent 1,3-beta D glucan synthase inhibitor, to broaden antimicrobial coverage when her insulin requirement decreased to zero for >48 hours. Right after discontinuation of micafungin and switching to a different antifungal, insulin requirements increased back to her baseline needs. Results: This is the first report of decreased insulin requirements in a patient with T1DM correlating with micafungin administration. The mechanism of micafungin-induced hypoglycemia is not yet established. Oral administration of linear 1,3-beta-D glucan has been documented to significantly decrease blood glucose levels by inhibiting expression of sodium glucose transporter-1 (SGLT1) in intestinal mucosa. Conclusion: We hypothesize that micafungin may inhibit SGLT-1 function and decrease insulin requirements in patient with T1DM. PMID- 30398619 TI - Conjugative transposons and their cargo genes vary across natural populations of Rickettsia buchneri infecting the tick Ixodes scapularis. AB - Rickettsia buchneri (formerly Rickettsia endosymbiont of Ixodes scapularis, or REIS) is an obligate intracellular endosymbiont of the black-legged tick, the primary vector of Lyme disease in North America. It is noteworthy among the rickettsiae for its relatively large genome (1.8 Mb) and extraordinary proliferation of mobile genetic elements (MGEs), which comprise nearly 35% of its genome. Previous analysis of the R. buchneri genome identified several integrative conjugative elements named RAGEs (Rickettsiales amplified genomic elements); the composition of these RAGEs suggests that continued genomic invasions by MGEs facilitated the proliferation of rickettsial genes related to an intracellular lifestyle. In this study, we compare the genomic diversity at RAGE loci among sequenced rickettsiae that infect three related Ixodes spp., including two strains of R. buchneri and Rickettsia endosymbiont of Ixodes pacificus strain Humboldt, as well as a closely-related species R. tamurae infecting Amblyomma testudinarium ticks. We further develop a novel multiplex droplet digital PCR assay and use it to quantify copy number ratios of chromosomal R. buchneri RAGE-A and RAGE-B to the single-copy gene gltA within natural populations of I. scapularis. Our results reveal substantial diversity among R. buchneri at these loci, both within individual ticks as well as in the I. scapularis population at large, demonstrating that genomic rearrangement of MGEs is an active process in these intracellular bacteria. PMID- 30398620 TI - Tandem repeats contribute to coding sequence variation in bumblebees (Hymenoptera: Apidae). AB - Tandem repeats (TRs) are highly dynamic regions of the genome. Mutations at these loci represent a significant source of genetic variation and can facilitate rapid adaptation. Bumblebees are important pollinating insects occupying a wide range of habitats. However, to date, molecular mechanisms underlying the potential adaptation of bumblebees to diverse habitats are largely unknown. In the present study, we investigate how TRs contribute to genetic variation in bumblebees, thus potentially facilitating adaptation. We identified 26,595 TRs from the assembled 18 chromosome sequences of the buff-tailed bumblebee (Bombus terrestris), 66.7% of which reside in genic regions. We also compared TRs found in B. terrestris with those present in the assembled genome sequence of a congener, B. impatiens. We found that a total of 1,137 TRs were variable in length between the two sequenced bumblebee species, and further analysis reveals that 101 of them are located within coding regions. These 101 TRs are responsible for coding sequence variation and correspond to protein sequence length variation between the two bumblebee species. The variability of identified TRs in coding regions between bumblebees was confirmed by PCR amplification of a subset of loci. Functional classification of bumblebee genes where coding sequences include variable-length TRs suggests that a majority of genes (87%) that could be assigned to a protein class are related to transcriptional regulation. Our results show that TRs contribute to coding sequence variation in bumblebees, and thus may facilitate the adaptation of bumblebees through diversifying proteins involved in controlling gene expression. PMID- 30398621 TI - How Ocular Dominance and Binocularity Are Reflected by the Population Receptive Field Properties. AB - Purpose: The neural substrate of binocularity and sighting ocular dominance in humans is not clear. By utilizing the population receptive field (pRF) modeling technique, we explored whether these phenomena are associated with amplitude and pRF size differences. Methods: The visual field maps of 13 subjects were scanned (3-T Skyra) while viewing drifting bar stimuli. Both eyes (binocular condition), the dominant eye and the nondominant eye (two monocular conditions) were stimulated in separate sessions. For each condition, pRF size and amplitude were assessed. Binocular summation ratios were calculated by dividing binocular by mean monocular values (amplitude and pRF size). Results: No differences in pRF size were seen between the viewing conditions within each region, that is, either between binocular and monocular or between dominant and nondominant viewing conditions. Binocular amplitudes were higher than the monocular amplitudes, but similar among the dominant and nondominant eyes. Binocular summation ratios derived from amplitudes were significantly higher than one (~1.2), while those ratios derived from pRF size were not. These effects were found in all studied areas along the visual hierarchy, starting in V1. Conclusions: Neither the amplitude nor the pRF size show intereye difference and therefore cannot explain the different roles of the dominant and the nondominant eyes. Binocular, as compared to monocular vision, resulted in higher amplitudes, while receptive fields' sizes were similar, suggesting increased binocular response intensity as the basis for the binocular summation phenomenon. Our results could be applicable in imaging studies of monocular disease and studies that deal with nondisparity binocularity effects. PMID- 30398622 TI - An iTRAQ-Based Quantitative Proteomic Analysis of Plasma Proteins in Preterm Newborns With Retinopathy of Prematurity. AB - Purpose: Retinopathy of prematurity (ROP) is a vision-threatening complication of a premature birth, in which the etiology still remains unclear. Importantly, the molecular processes that govern these effects can be investigated in a perturbed plasma proteome composition. Thus, plasma proteomics may add new insights into a better understanding of the pathogenesis of this disease. Methods: The cord and peripheral blood of neonates (<=30 weeks gestational age) was drawn at birth and at the 36th postmenstrual week (PMA), respectively. Blood samples were retrospectively subdivided into ROP(+) and ROP(-) groups, according to the development of ROP. Results: The quantitative analysis of plasma proteome at both time points revealed 30 protein abundance changes between ROP(+) and ROP(-) groups. After standardization to gestational age, children who developed ROP were characterized by an increased C3 complement component and fibrinogen level at both analyzed time points. Conclusions: Higher levels of the complement C3 component and fibrinogen, present in the cord blood and persistent to 36 PMA, may indicate a chronic low-grade systemic inflammation and hypercoagulable state that may play a role in the development of ROP. PMID- 30398623 TI - In Vivo Prediction of Air-Puff Induced Corneal Deformation Using LASIK, SMILE, and PRK Finite Element Simulations. AB - Purpose: To simulate deformation amplitude after laser-assisted in situ keratomileusis (LASIK), small incision lenticule extraction (SMILE), and photorefractive keratectomy (PRK) with finite element models. Methods: Finite element simulations of air-puff applanation on LASIK, SMILE, and PRK models were performed on a cohort of normal eyes, which had undergone refractive treatments. Short- and long-term wound healing responses were considered for SMILE and LASIK models based on evidence of microdistortions in Bowman's layer and crimping of collagen fibers. First, inverse simulations were performed to derive the preoperative properties of the cornea. Using these properties and planned refractive treatment, postoperative air-puff deformation amplitude was predicted and compared with the in vivo measurements. Results: The predicted postoperative corneal stiffness parameters agreed very well with in vivo values of SMILE, LASIK, and PRK eyes. Intraclass correlations (ICC) were greatest in PRK eyes (ICC > 0.95). This agreement was lower for peak deformation amplitude and peak deflection amplitude in SMILE and LASIK eyes (ICC < 0.9). In PRK eyes, peak deformation and deflection amplitude predictions were the best relative to in vivo magnitudes. Also, linear correlation (r) between in vivo measurement and predicted biomechanical parameters indicated strong agreement between them (SMILE: r >= 0.89, LASIK: r >= 0.83, PRK: r >= 0.87). Conclusions: The is the first study to present predictive simulations of corneal deformation changes after different procedures. Patient-specific preoperative corneal biomechanical properties and finite element models were a significant determinant of accurate postoperative deformation amplitude prediction. PMID- 30398624 TI - The Effect of Aging on Nerve Morphology and Substance P Expression in Mouse and Human Corneas. AB - Purpose: Aging impairs corneal nerve density and sensitivity. Substance P (SP), a neuropeptide secreted by sensory nerves, regulates nerve morphology and nociception. Here, we investigate the relationship between aging, nerve morphology, and SP expression in mouse and human corneas. Methods: SP levels in mouse corneas (wild type and substance P-knockout) and human corneas and tears were quantified with an ELISA assay. Corneal total nerve length (TNL) was measured with whole-mount beta3-tubulin immunofluorescence in mouse and in vivo laser corneal confocal microscopy in humans. SP and beta3-tubulin stained cross sections were used to assess the colocalization of SP and nerves in human and mouse corneas. Ocular surface nociception was assessed with a wiping test in mice. Results: SP colocalizes with sub-basal neurons in mice and humans. In WT mice, SP levels decrease with age (P = 0.0045, 8 vs. 52 weeks; P = 0.004, 26 vs. 52 weeks) as well as TNL (P = 0.018, 8 vs. 26 weeks; P = 0.0001, 8 vs. 52 weeks). Knockout mice show a greater TNL reduction (8 vs. 26 weeks, P = 0.0016) than WT mice. In the oldest WT and age-matched KO mice, nociception is impaired (P = 0.007 and P < 0.0001, respectively), and KO mice sensitivity is restored by topical SP treatment. In humans, SP levels are reduced in old subject corneas and correlate, in tears, with age (P = 0.0368); TNL also decreases in older patients (P = 0.0002). Conclusions: Age-associated corneal nerve loss is paralleled by reduction of SP expression in mice and humans. SP promotes the maintenance of normal nerve morphology in the long term and modulates nociception in the cornea. PMID- 30398626 TI - Possible Causes of Discordance in Refraction in Monozygotic Twins: Nearwork, Time Outdoors and Stochastic Variation. AB - Purpose: To evaluate the impact of differences in nearwork and time spent outdoors on difference in refraction in monozygotic (MZ) twins. Methods: Data on MZ twins aged 7 to 18 years from the Guangzhou Twin Eye Study were used in this analysis. A standard questionnaire was administered by personal interview to estimate time spent on nearwork and time spent outdoors. Spherical equivalent (SE) was measured by autorefraction under cycloplegia. The interaction between age and nearwork or time spent outdoors was also estimated. Results: A total of 490 MZ twin pairs (233 male and 257 female) were eligible in this analysis, the mean age was 13.14 +/- 2.49. In the mixed-effects model, nearwork difference was a risk factor of discordance in myopic SE (beta = -0.11 diopter (D)/h, P = 0.009), the overall association between time outdoors difference and SE discordance was not significant (beta = -0.89 (D)/h, P = 0.120) although an interaction between time spent outdoors difference and age was detected (beta = 0.07 (D)/h, P = 0.002). Furthermore, difference in nearwork and time outdoors explained about 1.8% and 2.5% of the variation in SE discordance, respectively. Conclusions: Given the very marked genetic similarity of MZ twins, and the small effects of known risk factors on SE discordance, we suggest that the SE discordance across MZ twins largely results from stochastic variations at the genomic or epigenetic levels, or from uncollected environmental factors. PMID- 30398627 TI - Lamina Cribrosa and Choroid Features and Their Relationship to Stage of Pseudoexfoliation Glaucoma. AB - Purpose: To better understand the relationship of lamina cribrosa (LC) and choroid features to the severity of pseudoexfoliation glaucoma (PXG). Methods: In this cross-sectional study, 137 eyes of 122 subjects (47 eyes with moderate/advanced PXG [mean deviation (MD), -15.0 +/- 7.7 dB], 34 eyes with mild PXG [MD, -2.7 +/- 1.5 dB], 32 aged-matched pseudoexfoliation syndrome [PXS] eyes, and 24 aged-matched control eyes) were investigated. Optic discs, LC thickness, and anterior LC depth (ALD; midsuperior, center, and midinferior) as well as peripapillary choroidal thickness were determined. Linear mixed modeling was used to adjust for age, sex, and axial length. Results: A progressive decrease in LC thickness was found when comparing controls (271.9 +/- 61.3 MUm), PXS (212.6 +/- 51.5 MUm), mild PXG (180.8 +/- 24.6 MUm), and moderate/advance PXG (138.9 +/- 37.5 MUm) (P < 0.001). ALD was greater (P < 0.001) in moderate/advance glaucoma (306.7 +/- 105.3 MUm) and mild PXG (209.5 +/- 79.7 MUm) compared with PXS (155 +/ 86.7 MUm) and healthy controls (149.2 +/- 103 MUm). Although eyes with moderate/advance PXG had the thinnest choroid (117.2 +/- 36.6 MUm), choroidal thickness was comparable in mild PXG, PXS, and controls (150.0 +/- 46.1, 159.7 +/ 65.5, and 157.5 +/- 51.1 MUm, respectively; P = 0.002). Worse MD was the only factor associated with thinner LC (beta = 2.344, P < 0.001) and choroid (beta = 1.717, P = 0.009 MUm) in PXG eyes. Higher IOP (beta = 4.305, P = 0.013) and worse MD (beta = -6.390, P < 0.001) were associated with deeper ALD in PXG. Conclusions: In pseudoexfoliation, LC thinning is an early sign, and there is progressive thinning with advancing glaucoma. Choroidal thinning is observable only with moderate/advanced glaucoma. In PXG eyes, LC thickness, depth, and peripapillary choroidal thickness are associated with glaucoma severity. PMID- 30398628 TI - Web Exclusive. Annals On Call - Improving Estimation of Cardiovascular Risk. PMID- 30398625 TI - The Henle Fiber Layer in Albinism: Comparison to Normal and Relationship to Outer Nuclear Layer Thickness and Foveal Cone Density. AB - Purpose: Directional optical coherence tomography (D-OCT) allows the visualization of the Henle fiber layer (HFL) in vivo. Here, we used D-OCT to characterize the HFL and outer nuclear layer (ONL) in albinism and examine the relationship between true foveal ONL and peak cone density. Methods: Horizontal D OCT B-scans were acquired, registered, and averaged for 12 subjects with oculocutaneous albinism and 26 control subjects. Averaged images were manually segmented to extract HFL and ONL thickness. Adaptive optics scanning light ophthalmoscopy was used to acquire images of the foveal cone mosaic in 10 subjects with albinism, from which peak cone density was assessed. Results: Across the foveal region, the HFL topography was different between subjects with albinism and normal controls. In particular, foveal HFL thickness was thicker in albinism than in normal controls (P < 0.0001), whereas foveal ONL thickness was thinner in albinism than in normal controls (P < 0.0001). The total HFL and ONL thickness was not significantly different between albinism and controls (P = 0.3169). Foveal ONL thickness was positively correlated with peak cone density in subjects with albinism (r = 0.8061, P = 0.0072). Conclusions: Foveal HFL and ONL topography are significantly altered in albinism relative to normal controls. Our data suggest that increased foveal cone packing drives the formation of Henle fibers, more so than the lateral displacement of inner retinal neurons (which is reduced in albinism). The ability to quantify foveal ONL and HFL may help further stratify grading schemes used to assess foveal hypoplasia. PMID- 30398629 TI - Web Exclusive. Annals Graphic Medicine - Paused. PMID- 30398630 TI - An Unusual Amnestic Syndrome Associated With Combined Fentanyl and Cocaine Use. PMID- 30398631 TI - An Unusual Amnestic Syndrome Associated With Combined Fentanyl and Cocaine Use. PMID- 30398632 TI - Interactions Between Physicians and Skilled Home Health Care Agencies in Certification of Plans of Care. PMID- 30398633 TI - Interactions Between Physicians and Skilled Home Health Care Agencies in Certification of Plans of Care. PMID- 30398634 TI - Correction: Disappearance of the National Guideline Clearinghouse. PMID- 30398635 TI - Long-Term Effectiveness of Sigmoidoscopy Screening in Women and Men. PMID- 30398636 TI - Long-Term Effectiveness of Sigmoidoscopy Screening in Women and Men. PMID- 30398637 TI - Swan, Ganz, and Their Catheter: Its Evolution Over the Past Half Century. AB - Jeremy Swan and William Ganz developed their eponymous pulmonary artery (PA) catheter in the 1970s and, in the process, revolutionized measurement of cardiac output, pressures within the left side of the heart, and resistance in systemic and pulmonary circulations. Their invention enabled diagnostic measurements at the bedside and contributed to the birth of critical care medicine; technologic advances preceding the PA catheter generally could not be used at the bedside and required patients to be stable enough to be taken to the catheterization laboratory. Swan and Ganz worked in the same department but had quite dissimilar backgrounds and personalities. This article describes their lives and careers, the state of intensive care before and after their catheter was introduced, and the natural life cycle the PA catheter faced as new, less invasive technology arrived to replace it. PMID- 30398638 TI - Want Fries With That? PMID- 30398639 TI - Nonalcoholic Fatty Liver Disease. AB - Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease. Most cases are diagnosed incidentally in the primary care or hospital setting on the basis of elevated liver enzyme levels or hepatic steatosis on imaging. NAFLD encompasses a wide spectrum: The vast majority of patients have nonprogressive nonalcoholic fatty liver, and a few of those develop progressive liver injury, inflammation, and fibrosis, a condition termed nonalcoholic steatohepatitis. Cardiovascular disease is the leading cause of death in patients with nonalcoholic fatty liver disease. Persons with nonalcoholic steatohepatitis have increased liver-related mortality. In the absence of regulatory agency approved drugs, lifestyle modification and weight loss remain the cornerstones of NAFLD therapy. PMID- 30398640 TI - Annals for Educators - 6 November 2018. PMID- 30398641 TI - The neurodegenerative diseases ALS and SMA are linked at the molecular level via the ASC-1 complex. AB - Understanding the molecular pathways disrupted in motor neuron diseases is urgently needed. Here, we employed CRISPR knockout (KO) to investigate the functions of four ALS-causative RNA/DNA binding proteins (FUS, EWSR1, TAF15 and MATR3) within the RNAP II/U1 snRNP machinery. We found that each of these structurally related proteins has distinct roles with FUS KO resulting in loss of U1 snRNP and the SMN complex, EWSR1 KO causing dissociation of the tRNA ligase complex, and TAF15 KO resulting in loss of transcription factors P-TEFb and TFIIF. However, all four ALS-causative proteins are required for association of the ASC-1 transcriptional co-activator complex with the RNAP II/U1 snRNP machinery. Remarkably, mutations in the ASC-1 complex are known to cause a severe form of Spinal Muscular Atrophy (SMA), and we show that an SMA-causative mutation in an ASC-1 component or an ALS-causative mutation in FUS disrupts association between the ASC-1 complex and the RNAP II/U1 snRNP machinery. We conclude that ALS and SMA are more intimately tied to one another than previously thought, being linked via the ASC-1 complex. PMID- 30398642 TI - Localizing and classifying adaptive targets with trend filtered regression. AB - Identifying genomic locations of natural selection from sequence data is an ongoing challenge in population genetics. Current methods utilizing information combined from several summary statistics typically assume no correlation of summary statistics regardless of the genomic location from which they are calculated. However, due to linkage disequilibrium, summary statistics calculated at nearby genomic positions are highly correlated. We introduce an approach termed Trendsetter that accounts for the similarity of statistics calculated from adjacent genomic regions through trend filtering, while reducing the effects of multicollinearity through regularization. Our penalized regression framework has high power to detect sweeps, is capable of classifying sweep regions as either hard or soft, and can be applied to other selection scenarios as well. We find that Trendsetter is robust to both extensive missing data and strong background selection, and has comparable power to similar current approaches. Moreover, the model learned by Trendsetter can be viewed as a set of curves modeling the spatial distribution of summary statistics in the genome. Application to human genomic data revealed positively-selectedregions previously discovered such as LCT in Europeans and EDAR in East Asians. We also identified a number of novel candidates and show that populations with greater relatedness share more sweep signals. PMID- 30398643 TI - ChEMBL: towards direct deposition of bioassay data. AB - ChEMBL is a large, open-access bioactivity database (https://www.ebi.ac.uk/chembl), previously described in the 2012, 2014 and 2017 Nucleic Acids Research Database Issues. In the last two years, several important improvements have been made to the database and are described here. These include more robust capture and representation of assay details; a new data deposition system, allowing updating of data sets and deposition of supplementary data; and a completely redesigned web interface, with enhanced search and filtering capabilities. PMID- 30398644 TI - Zinc Finger Artificial Transcription Factor-Mediated Chloroplast Genome Interrogation In Arabidopsis thaliana. AB - The large majority of core photosynthesis proteins in plants are encoded by nuclear genes, but a small portion has been retained in the plastid genome. These plastid-encoded chloroplast proteins fulfill essential roles in the process of photochemistry. Here, we report about the use of nuclear-encoded, chloroplast targeted zinc finger artificial transcription factors (ZF-ATFs) with effector domains of prokaryotic origin to modulate the expression of chloroplast genes, and to enhance the photochemical activity and growth characteristics of Arabidopsis thaliana plants. This technique was named chloroplast genome interrogation. Using this novel approach, we obtained evidence that ZF-ATFs can indeed be translocated to chloroplasts of Arabidopsis plants, can modulate their growth and operating light use efficiency of Photosystem II, and finally can induce statistically significant changes in the expression levels of several chloroplast genes. Our data suggests that the distortion of chloroplast gene expression might be a feasible approach to manipulate the efficiency of photosynthesis in plants. PMID- 30398645 TI - Genomics and development of Lentinus tigrinus, a white-rot wood-decaying mushroom with dimorphic fruiting bodies. AB - Lentinus tigrinus is a species of wood-decaying fungi (Polyporales) that has an agaricoid form (a gilled mushroom) and a secotioid form (puffball-like, with enclosed spore-bearing structures). Previous studies suggested that the secotioid form is conferred by a recessive allele of a single locus. We sequenced the genomes of one agaricoid (Aga) strain and one secotioid (Sec) strain (39.53-39.88 Mb, with 15581-15380 genes, respectively). We mated the Sec and Aga monokaryons, genotyped the progeny, and performed bulked segregant analysis (BSA). We also fruited three Sec/Sec and three Aga/Aga dikaryons, and sampled transcriptomes at four developmental stages. Using BSA, we identified 105 top candidate genes with non-synonymous SNPs that co-segregate with fruiting body phenotype. Transcriptome analyses of Sec/Sec vs. Aga/Aga dikaryons identified 907 differentially expressed genes (DEGs) along four developmental stages. On the basis of BSA and DEGs, the top 25 candidate genes related to fruiting body development span 1.5 Mb (4% of the genome), possibly on a single chromosome, although the precise locus that controls the secotioid phenotype is unresolved. The top candicates include genes encoding a cytochrome P450 and an ATP-dependent RNA helicase, which may play a role in development, based on studies in other fungi. PMID- 30398646 TI - Quercetin, but Not Epicatechin, Decreases Plasma Concentrations of Methylglyoxal in Adults in a Randomized, Double-Blind, Placebo-Controlled, Crossover Trial with Pure Flavonoids. AB - Background: Methylglyoxal (MGO) is the most potent precursor of advanced glycation end products (AGEs). MGO and AGEs have been associated with diabetes, its complications, and other age-related diseases. Experimental studies have shown that the flavonoids quercetin and epicatechin are able to scavenge MGO and lower AGE formation. Objective: Data on the effects of these flavonoids on MGO and AGE concentrations in humans are not yet available. We therefore investigated the effect of quercetin and epicatechin on the concentrations of MGO and AGEs in a post hoc analysis. Methods: Thirty-seven apparently healthy, nonsmoking adults with a systolic blood pressure between 125 and 160 mm Hg at screening were included in a randomized, double-blind, placebo-controlled crossover trial. Participants ingested (-)-epicatechin (100 mg/d), quercetin 3-glucoside (160 mg/d), or placebo capsules for periods of 4 wk separated by 4-wk washout periods. Fasting blood samples were collected at the start and end of each intervention period. Liquid chromatography-tandem mass spectrometry was used to determine plasma concentrations of the dicarbonyl compounds MGO, glyoxal (GO), and 3 deoxyglucosone (3-DG) and free and protein-bound AGEs. Gene expression of glyoxalase 1 (GLO1), the enzyme involved in the degradation of MGO, was determined by either microarray or quantitative reverse transcriptase-polymerase chain reaction. Results: The treatment effect (Deltatreatment - Deltaplacebo) of quercetin on MGO was -40.2 nmol/L (95% CI: -73.6, -6.8 nmol/L; P = 0.019), a decrease of 11% from baseline values, whereas GO, 3-DG, and free and protein bound AGEs did not change significantly. Epicatechin did not affect the concentrations of dicarbonyls and free and protein-bound AGEs. We did not find a significant change in expression of GLO1. Conclusions: In apparently healthy (pre)hypertensive men and women, quercetin but not epicatechin decreased plasma MGO concentrations. Quercetin may potentially form a new treatment strategy for diseases in which MGO plays a pivotal role. This study was registered at clinicaltrials.gov as NCT01691404. PMID- 30398647 TI - Letter: It is Time for Federal Protection Against Surprise Medical Billing. PMID- 30398648 TI - A New Species of the Simulium (Simulium) multistriatum Species-Group (Diptera: Simuliidae) From Thailand and Its Phylogenetic Relationships With Related Species. AB - Simulium undecimum sp. nov. is described from Thailand. This new species is assigned to the Simulium multistriatum species-group, one of the 20 species groups of the subgenus Simulium in the Oriental Region. It is characterized by the female cibarium with minute processes, male ventral plate with a narrow body having two vertical rows of distinct teeth on the posterior surface and without setae on the anterior and lateral surfaces, pupal gill with eight short filaments decreasing in length from dorsal to ventral, and divergent at an angle of around 90 degrees when viewed laterally, spine-combs only on abdominal segments 7 and 8, and cocoon wall-pocket shaped with anterolateral windows. Taxonomic notes to separate this new species from related species in Thailand and other countries are given. This new species is the 11th nominal member of this species-group recorded in Thailand. An analysis of the COI gene sequences shows that it is most closely related with S. malayense Takaoka & Davies (cytoform A) from Thailand but they are distantly separated by 3.01-8.87%. PMID- 30398649 TI - Sun-related risks and risk reduction practices in Irish outdoor workers. AB - Background: Ultraviolet radiation (UVR) is an occupational hazard for outdoor workers. Aims: This descriptive study aimed to describe the solar UVR risk, and explore associations between demographic characteristics and sun-safety knowledge, risks and practices, in golf-course maintenance workers on the island of Ireland. Methods: A survey, designed to collect demographic and occupational information, measures of skin cancer knowledge and sun protection practices, was completed by 154 male outdoor workers in the golf-course maintenance industry. Statistical analysis included tests of association and non-parametric tests. Results: Less than 10% of this mainly male worker group had received education/training on solar UVR risks (sun safety) and two-thirds were more concerned about workplace injury. While a majority used routine precautionary measures, those with greater knowledge of skin cancer, senior grades and workers under 45 years were significantly more likely to use sunscreen and/or sunglasses. Conclusions: Findings indicate that these workers were a high risk group for skin cancer, with good knowledge of the risk, but limited training or education in risk reduction. While the prevalence of sunscreen and sunglasses use is relatively good, it was better among younger workers and those in senior grades, and could be improved if they were routinely provided as a control measure by the employer. PMID- 30398650 TI - Lineage-specific expression divergence in grasses is associated with. AB - Poaceae (grasses) is an agriculturally important and widely distributed family of plants with extraordinary phenotypic diversity, much of which was generated under recent lineage-specific evolution. Yet little is known about the genes and functional modules involved in the lineage-specific divergence of grasses. Here, I address this question on a genome-wide scale by applying a novel branch-based statistic of lineage-specific expression divergence, LED, to RNA-seq data from nine tissues of the wild grass Brachypodium distachyon and its domesticated relatives Oryza sativa japonica (rice) and Sorghum bicolor (sorghum). I find that LED is generally smallest in B. distachyon and largest in O. sativa japonica, which underwent domestication earlier than S. bicolor, supporting the hypothesis that domestication may increase the rate of lineage-specific expression divergence in grasses. Moreover, in all three species, LED is positively correlated with protein-coding sequence divergence and tissue specificity, and negatively correlated with network connectivity. Further analysis reveals that genes with large LED are often primarily expressed in anther, implicating lineage specific expression divergence in the evolution of male reproductive phenotypes. Gene ontology enrichment analysis also identifies an overrepresentation of terms related to male reproduction in the two domesticated grasses, as well as to those involved in host-pathogen defense in all three species. Last, examinations of genes with the largest LED reveal that their lineage-specific expression divergence may have contributed to antimicrobial functions in B. distachyon, to enhanced adaptation and yield during domestication in O. sativa japonica, and to defense against a widespread and devastating fungal pathogen in S. bicolor. Together, these findings suggest that lineage-specific expression divergence in grasses may increase under domestication and preferentially target rapidly evolving genes involved in male reproduction, host-pathogen defense, and the origin of domesticated phenotypes. PMID- 30398651 TI - Presence of an Agrobacterium-type tumor-inducing plasmid in Neorhizobium sp. NCHU2750 and the link to phytopathogenicity. AB - The genus Agrobacterium contains a group of plant-pathogenic bacteria that have been developed into an important tool for genetic transformation of eukaryotes. To further improve this biotechnology application, a better understanding of the natural genetic variation is critical. During the process of isolation and characterization of wild-type strains, we found a novel strain (i.e., NCHU2750) that resembles Agrobacterium phenotypically but exhibits high sequence divergence in several marker genes. For more comprehensive characterization of this strain, we determined its complete genome sequence for comparative analysis and performed pathogenicity assays on plants. The results demonstrated that this strain is closely related to Neorhizobium in chromosomal organization, gene content, and molecular phylogeny. However, unlike the characterized species within Neorhizobium, which all form root nodules with legume hosts and are potentially nitrogen-fixing mutualists, NCHU2750 is a gall-forming pathogen capable of infecting plant hosts across multiple families. Intriguingly, this pathogenicity phenotype could be attributed to the presence of an Agrobacterium-type tumor inducing plasmid in the genome of NCHU2750. These findings suggest that these different lineages within the family Rhizobiaceae are capable of transitioning between ecological niches by having novel combinations of replicons. In summary, this work expanded the genomic resources available within Rhizobiaceae and provided a strong foundation for future studies of this novel lineage. With an infectivity profile that is different from several representative Agrobacterium strains, this strain may be useful for comparative analysis to better investigate the genetic determinants of host range among these bacteria. PMID- 30398652 TI - Overexpression of Orange Carotenoid Protein Protects the Repair of Photosystem II under Strong Light in Synechocystis sp. PCC 6803. AB - Orange carotenoid protein (OCP) plays a vital role in the thermal dissipation of excitation energy in the photosynthetic machinery of the cyanobacterium Synechocystis sp. PCC 6803. To clarify the role of OCP in the protection of photosystem II (PSII) from strong light, we generated an OCP-overexpressing strain of Synechocystis and examined the effects of overexpression on the photoinhibition of PSII. In OCP-overexpressing cells, thermal dissipation of energy was enhanced and the extent of photoinhibition of PSII was reduced. However, photodamage to PSII, as monitored in the presence of lincomycin, was unaffected, suggesting that overexpressed OCP protects the repair of PSII. Furthermore, the synthesis de novo of proteins in thylakoid membranes, such as the D1 protein which is required for the repair of PSII, was enhanced in OCP overexpressing cells under strong light, while the production of singlet oxygen was suppressed. Thus, the enhanced thermal dissipation of energy via overexpressed OCP might support the repair of PSII by protecting protein synthesis from oxidative damage by singlet oxygen under strong light, with the resultant mitigation of photoinhibition of PSII. PMID- 30398653 TI - Longevity of Preserved Germplasm: The Temperature Dependency of Aging Reactions in Glassy Matrices of Dried Fern Spores. AB - This study explores temperature dependency of aging rate in dry cells over a broad temperature range encompassing the fluid to solid transition (Tg) and well below. Spores from diverse species of eight families of ferns were stored at temperatures ranging from +45oC to c. -176oC (vapor phase above liquid nitrogen), and viability was monitored periodically for up to 4300 days (ca. 12 years). Accompanying measurements using differential scanning calorimetry (DSC) provide insights into structural changes that occur such as Tg, between +45 and -20oC (depending on moisture), and triacylglycerol (TAG) crystallization, between -5 and -35oC (depending on species). We detected aging even at cryogenic temperatures, which we consider analogous to unscheduled degradation of pharmaceuticals stored well below Tg caused by a shift in the nature of molecular motions that dominate chemical reactivity. We occasionally observed faster aging of spores stored at -18oC (conventional freezer) compared to 5oC (refrigerator), and linked this with mobility and crystallization within TAG, which likely influences molecular motion of dried cytoplasm in a narrow temperature range. Temperature dependency of longevity was remarkably similar among diverse fern spores, despite widely disparate aging rates; this provides a powerful tool to predict deterioration of germplasm preserved in the solid state. Future work will increase our understanding of molecular organization and composition contributing to differences in longevity. PMID- 30398654 TI - Morphological and Molecular Analyses of Simulium rufibasis (Diptera: Simuliidae) in Thailand. AB - A man-biting black fly species so far regarded as Simulium rufibasis Brunetti in Thailand was morphologically analyzed. It was found to be almost indistinguishable in the female from S. rufibasis sensu stricto but distinguishable in the male by the slender fore basitarsus and abdominal segments 2, 6, and 7 each with a pair of shiny dorsolateral patches, and in the pupa by the absence of spine-combs on abdominal segment 7 and terminal hooks on segment 9. It is described as a new species, Simulium tenebrosum. Taxonomic notes are given to separate it from all 11 known species of the S. rufibasis subgroup of the Simulium (Simulium) tuberosum species-group. An analysis of the COI gene sequences shows that this new species is distantly separated from the closely related species. PMID- 30398655 TI - Erg6 gene is essential for stress adaptation in Kluyveromyces lactis. AB - We investigated the effect of Kluyveromyces lactis ERG6 gene deletion on plasma membrane function and showed increased susceptibility of mutant cells to salt stress, cationic drugs and weak organic acids. Contrary to Saccharomyces cerevisiae, Klerg6 mutant cells exhibited increased tolerance to tunicamycin. The content of cell wall polysacharides did not significantly vary between wild-type and mutant cells. Although the expression of the NAD+-dependent glycerol 3 phosphate dehydrogenase (KlGPD1) in the Klerg6 mutant cells was only half of that in the parental strain, it was induced in the presence of calcofluor white. Also, cells exposed to this drug accumulated glycerol. The absence of KlErg6p led to plasma membrane hyperpolarization but had no statistically significant influence on the plasma membrane fluidity. We propose that the phenotype of Klerg6 mutant cells to a large extent was a result of the reduced activity of specific plasma membrane proteins that require proper lipid composition for full activity. PMID- 30398657 TI - Trichophoromyia iorlandobaratai (Diptera: Psychodidae), a new phlebotomine species from the Brazilian Amazonia. AB - Trichophoromyia iorlandobaratai sp. n. Vasconcelos dos Santos, Santos Neto, Sanchez Uzcategui & Galardo is described and illustrated on the basis of male specimens collected in the municipality of Itaituba, Para State, Brazilian Amazonia. This species can be differentiated from other morphologically similar species within Trichophoromyia by means of the male characters such as the ratio between the aedeagal ducts/sperm pump, shape and distribution of setae in the gonocoxite, and particularly the distinct shape of paramere. PMID- 30398658 TI - Neurofibromatosis type 1. PMID- 30398656 TI - InterPro in 2019: improving coverage, classification and access to protein sequence annotations. AB - The InterPro database (http://www.ebi.ac.uk/interpro/) classifies protein sequences into families and predicts the presence of functionally important domains and sites. Here, we report recent developments with InterPro (version 70.0) and its associated software, including an 18% growth in the size of the database in terms on new InterPro entries, updates to content, the inclusion of an additional entry type, refined modelling of discontinuous domains, and the development of a new programmatic interface and website. These developments extend and enrich the information provided by InterPro, and provide greater flexibility in terms of data access. We also show that InterPro's sequence coverage has kept pace with the growth of UniProtKB, and discuss how our evaluation of residue coverage may help guide future curation activities. PMID- 30398659 TI - MitoMiner v4.0: an updated database of mitochondrial localization evidence, phenotypes and diseases. AB - Increasing numbers of diseases are associated with mitochondrial dysfunction. This is unsurprising given mitochondria have major roles in bioenergy generation, signalling, detoxification, apoptosis and biosynthesis. However, fundamental questions of mitochondrial biology remain, including: which nuclear genes encode mitochondrial proteins; how their expression varies with tissue; and which are associated with disease. But experiments to catalogue the mitochondrial proteome are incomplete and sometimes contradictory. This arises because the mitochondrial proteome has tissue- and stage-specific variability, plus differences among experimental techniques and localization evidence types used. This leads to limitations in each technique's coverage and inevitably conflicting results. To support identification of mitochondrial proteins, we developed MitoMiner (http://mitominer.mrc-mbu.cam.ac.uk/), a database combining evidence of mitochondrial localization with information from public resources. Here we report upgrades to MitoMiner, including its re-engineering to be gene-centric to enable easier sharing of evidence among orthologues and support next generation sequencing, plus new data sources, including expression in different tissues, information on phenotypes and diseases of genetic mutations and a new mitochondrial proteome catalogue. MitoMiner is a powerful platform to investigate mitochondrial localization by providing a unique combination of experimental sub cellular localization datasets, tissue expression, predictions of mitochondrial targeting sequences, gene annotation and links to phenotype and disease. PMID- 30398660 TI - Both Oleanolic Acid and a Mixture of Oleanolic and Ursolic Acids Mimic the Effects of Fructus ligustri lucidi on Bone Properties and Circulating 1,25 Dihydroxycholecalciferol in Ovariectomized Rats. AB - Background: Oleanolic acid (OA) and ursolic acid (UA) are major chemical constituents found in Fructus ligustri lucidi (FLL), a Chinese herb previously shown to increase bone properties and modulate calcium-vitamin D metabolism in rats. OA and UA have been reported to exert osteoprotective effects in vitro. Objective: The present study was designed to determine whether OA or OA + UA mimicked the effects of FLL on bone and calcium homeostasis using ovariectomized rats. Methods: Three-month-old ovariectomized Sprague-Dawley rats were stabilized for 2 mo and randomly assigned to 4 groups offered the same amount (15-17 g/d) of a control diet or experimental diets containing FLL (18.8 g/kg), OA (0.67 g/kg), or OA (0.67 g/kg) + UA (0.22 g/kg) for 6 wk. Serum was obtained for measurement of 1,25-dihydroxycholecalciferol [1,25(OH)2D3] and bones were collected for micro CT analysis. Calcium balance was measured at weeks 1 and 6. A calcium kinetic study using 45Ca was conducted at week 6 and modeled using WinSAAM software. Results: Compared with the control group, rats fed the FLL-, OA-, and OA + UA enriched diets had better bone properties and 51%, 31%, and 27% higher serum 1,25(OH)2D3 concentrations at week 6, respectively. These variables did not differ between the treatments. Calcium balance was not affected by diet at either week 1 or week 6. Kinetic modeling predicted that FLL and OA + UA diet-fed rats had 9% and 15% less endogenous excretion of calcium, respectively, compared with the control group. All 3 treatments resulted in a higher calcium mass of compartment 3 because of changes in transfer rate between compartments 2 and 3, and were positively associated with the serum 1,25(OH)2D3 concentration (R2 = 0.28; P < 0.01). Conclusion: Similar to FLL, OA and OA + UA increase bone properties, serum 1,25(OH)2D3 concentration, and calcium use in ovariectomized rats, suggesting their potential role in management of osteoporosis. PMID- 30398661 TI - Mediastinal ectopic parathyroid adenoma. PMID- 30398662 TI - Autoimmune Thyroid Disease in Islet Transplant Recipients Discontinuing Immunosuppression Late After Lymphodepletion. AB - Context: Clinical islet transplantation (CIT) is an innovative strategy to treat highly selected individuals with type 1 diabetes mellitus (T1DM). Lymphodepletion with alemtuzumab or thymoglobulin is often used for induction therapy in CIT. Alemtuzumab was recently licensed as a treatment for relapsing remitting multiple sclerosis (RRMS). In RRMS, autoimmune thyroid disease (AITD) has developed in up to 40% of individuals treated with alemtuzumab. The appearance of AITD after CIT is not well described. We herein explore factors associated with AITD developing after CIT and any relationship with exposure to lymphodepleting antibodies (alemtuzumab or thymoglobulin). Case Description: Five cases of AITD developing after CIT for T1DM are described. All were female. Four cases had received alemtuzumab (20-40mg) prior to at least 1 islet infusion, and one received thymoglobulin induction. The presentation with AITD was 18-135 months after first transplant and 11-18 months after withdrawal of all maintenance immunosuppression. Four cases presented with clinical and biochemical evidence of hyperthyroidism from Graves' disease. One case presented with biochemical evidence of hypothyroidism and positive TSH receptor antibodies (TRAb). All were treated with conventional therapies for AITD. Conclusions: Despite routine use of alemtuzumab, clinical presentations of AITD seem to be uncommon in CIT patients receiving immunosuppression. However, AITD can develop following withdrawal of immunosuppression, highlighting the need for careful thyroid surveillance in this population. PMID- 30398664 TI - Loss of gene body methylation in Eutrema salsugineum is associated with reduced gene expression. AB - Gene body methylation (gbM) is typically characterized by DNA methylation in the CG context within coding regions, and is associated with constitutive genes that have moderate to high expression levels. A recent study discovered the loss of gbM in two plant species (Eutrema salsugineum and Conringia planisiliqua), illustrating that gbM is not necessary for survival and reproduction. The same paper stated there was no detectable effect of gbM loss on gene expression (GE). Here, we reanalyzed the GE data and accounted for experimental variability in expression level estimates. We show that the loss of gbM in E. salsugineum is associated with a small but highly significant decrease in GE relative to the closely related species Arabidospis thaliana. Our results are consistent with various evolutionary analyses that suggest gbM has a function, perhaps as a homeostatic effect on gene expression. PMID- 30398663 TI - CATH: expanding the horizons of structure-based functional annotations for genome sequences. AB - This article provides an update of the latest data and developments within the CATH protein structure classification database (http://www.cathdb.info). The resource provides two levels of release: CATH-B, a daily snapshot of the latest structural domain boundaries and superfamily assignments, and CATH+, which adds layers of derived data, such as predicted sequence domains, functional annotations and functional clustering (known as Functional Families or FunFams). The most recent CATH+ release (version 4.2) provides a huge update in the coverage of structural data. This release increases the number of fully- classified domains by over 40% (from 308 999 to 434 857 structural domains), corresponding to an almost two- fold increase in sequence data (from 53 million to over 95 million predicted domains) organised into 6119 superfamilies. The coverage of high-resolution, protein PDB chains that contain at least one assigned CATH domain is now 90.2% (increased from 82.3% in the previous release). A number of highly requested features have also been implemented in our web pages: allowing the user to view an alignment between their query sequence and a representative FunFam structure and providing tools that make it easier to view the full structural context (multi-domain architecture) of domains and chains. PMID- 30398665 TI - Recovery from a myocardial infarction is impaired in male C57bl/6N mice acutely exposed to the bisphenols and phthalates that escape from medical devices used in cardiac surgery. AB - Bisphenols and phthalates leach from medical devices, and this exposure is likely to increase in post-cardiac surgery patients. Previous studies suggest that such chemical exposure may impact recovery and wound healing, yet the direct effects of bisphenols and phthalates are unknown in this context. To study the direct effect of clinically based chemical exposures, we measured the metabolites representative of six bisphenols and ten phthalates in men before and after cardiac surgery and then replicated this exposure in a mouse model of cardiac surgery and assessed survival, cardiac function and inflammation. Bisphenol A (BPA), di-ethyl hexyl phthalate (DEHP), butylbenzyl phthalate, di-isodecyl phthalate and di-n-butyl phthalate metabolites were increased after surgery. DEHP exposure predominated, was positively correlated with duration on the cardiopulmonary bypass machine and exceeded its tolerable daily intake limit by 37-fold. In vivo, C57bl/6N male mice treated with BPA+phthalates during recovery from surgery-induced myocardial infarction had reduced survival, greater cardiac dilation, reduced cardiac function and increased infiltration of neutrophils, monocytes and macrophages suggesting impaired recovery. Of interest, genetic ablation or estrogen receptor beta (ERbeta) antagonism did not improve recovery and replacement of DEHP with tri-octyl trimellitate or removal of BPA from the mixture did not ameliorate these effects. To examine the direct effects on inflammation, treatment of human THP-1 macrophages with BPA and phthalates induced a dysfunctional pro-inflammatory macrophage phenotype with increased expression of M1-type macrophage polarization markers and MMP9 secretion, yet reduced phagocytic activity. These results suggest that chemicals escape from medical devices and may impair patient recovery. PMID- 30398667 TI - Intraorganellar Enzyme Partitioning: A Novel Layer of Chlorophyll Biosynthesis Regulation. PMID- 30398669 TI - MYOSITIS, 1st edition, edited by H. Chinoy and R.G. Cooper. PMID- 30398668 TI - Comment on: Should rheumatologists be a core discipline of a chronic pain multi disciplinary team?: reply. PMID- 30398670 TI - Comment on: Should Rheumatology be a core discipline of a chronic pain multi disciplinary team? PMID- 30398666 TI - Functional Diversity of Class XI Myosins in Arabidopsis thaliana. AB - Plant myosin XI acts as a motive force for cytoplasmic streaming through interacting with actin filaments within the cell. Arabidopsis thaliana (At) has 13 genes belonging to the myosin XI family. Previous reverse genetic approaches suggest that At myosin XIs are partially redundant, but are functionally diverse for their specific tasks within the plant. However, the tissue-specific expression and enzymatic properties of myosin XIs have to date been poorly understood, primarily because of the difficulty in cloning and expressing large myosin XI genes and proteins. In this study, we cloned full-length cDNAs and promoter regions for all 13 At myosin XIs and identified tissue-specific expression (using promoter-reporter assays) and motile and enzymatic activities (using in vitro assays). In general, myosins belonging to the same class have similar velocities and ATPase activities. However, the velocities and ATPase activities of the 13 At myosin XIs are significantly different and are classified broadly into three groups based on velocity (high group, medium group and low group). Interestingly, the velocity groups appear roughly correlated with the tissue-specific expression patterns. Generally, ubiquitously expressed At myosin XIs belong to the medium-velocity group, pollen-specific At myosin XIs belong to the high-velocity group and only one At myosin XI (XI-I) is classified as belonging to the low-velocity group. In this study, we demonstrated the diversity of the 13 myosin XIs in Arabidopsis at the molecular and tissue levels. Our results indicate that myosin XIs in higher plants have distinct motile and enzymatic activities adapted for their specific roles. PMID- 30398671 TI - Estimating Prevalence of Hepatitis C Virus Infection in the United States, 2013 2016. AB - Hepatitis C virus (HCV) infection is the most commonly reported bloodborne infection in the United States, causing substantial morbidity and mortality and costing billions of dollars annually. To update the estimated HCV prevalence among all adults aged >=18 years in the United States, we analyzed 2013-2016 data from the National Health and Nutrition Examination Survey (NHANES) to estimate the prevalence of HCV in the noninstitutionalized civilian population and used a combination of literature reviews and population size estimation approaches to estimate the HCV prevalence and population sizes for four additional populations: incarcerated people, unsheltered homeless people, active-duty military personnel, and nursing home residents. We estimated that during 2013-2016 1.7% (95% confidence interval [CI], 1.4-2.0%) of all adults in the United States, approximately 4.1 (3.4-4.9) million persons, were HCV antibody-positive (indicating past or current infection) and that 1.0% (95% CI, 0.8-1.1%) of all adults, approximately 2.4 (2.0-2.8) million persons, were HCV RNA-positive (indicating current infection). This includes 3.7 million noninstitutionalized civilian adults in the United States with HCV antibodies and 2.1 million with HCV RNA and an estimated 0.38 million HCV antibody-positive persons and 0.25 million HCV RNA-positive persons not part of the 2013-2016 NHANES sampling frame. Conclusion: Over 2 million people in the United States had current HCV infection during 2013-2016; compared to past estimates based on similar methodology, HCV antibody prevalence may have increased, while RNA prevalence may have decreased, likely reflecting the combination of the opioid crisis, curative treatment for HCV infection, and mortality among the HCV-infected population; efforts on multiple fronts are needed to combat the evolving HCV epidemic, including increasing capacity for and access to HCV testing, linkage to care, and cure. PMID- 30398672 TI - Insecticide-treated nets for preventing malaria. AB - BACKGROUND: A previous version of this Cochrane Review identified that insecticide-treated nets (ITNs) are effective at reducing child mortality, parasite prevalence, and uncomplicated and severe malaria episodes. Insecticide treated nets have since become a core intervention for malaria control and have contributed greatly to the dramatic decline in disease incidence and malaria related deaths seen since the turn of the millennium. However, this time period has also seen a rise in resistance to pyrethroids (the insecticide used in ITNs), raising questions over whether the evidence from trials conducted before resistance became widespread can be applied to estimate the impact of ITNs on malaria transmission today. OBJECTIVES: The primary objective of this review was to assess the impact of ITNs on mortality and malaria morbidity, incorporating any evidence published since the previous update into new and existing analyses, and assessing the certainty of the resulting evidence using GRADE. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) published in the Cochrane Library, MEDLINE, Embase, LILACS, the World Health Organization (WHO) International Clinical Trials Registry Platform, ClinicalTrials.gov, and the ISRCTN registry for new trials published since 2004 and up to 18 April 2018. SELECTION CRITERIA: We included individual randomized controlled trials (RCTs) and cluster RCTs comparing bed nets or curtains treated with a synthetic pyrethroid insecticide at a minimum target impregnation dose recommended by the WHO with no nets or untreated nets. DATA COLLECTION AND ANALYSIS: One review author assessed the identified trials for eligibility and risk of bias, and extracted data. We compared intervention and control data using risk ratios (RRs), rate ratios, and mean differences, and presented all results with their associated 95% confidence intervals (CIs). We assessed the certainty of evidence using the GRADE approach. We drew on evidence from a meta-analysis of entomological outcomes stratified by insecticide resistance from 2014 to inform the GRADE assessments. MAIN RESULTS: Our updated search identified three new trials. A total of 23 trials met the inclusion criteria, enrolling more than 275,793 adults and children. The included studies were conducted between 1987 and 2001.ITN versus no netsInsecticide-treated nets reduce child mortality from all causes by 17% compared to no nets (rate ratio 0.83, 95% CI 0.77 to 0.89; 5 trials, 200,833 participants, high-certainty evidence). This corresponds to a saving of 5.6 lives (95% CI 3.6 to 7.6) each year for every 1000 children protected with ITNs. Insecticide-treated nets also reduce the incidence of uncomplicated episodes of Plasmodium falciparum malaria by almost a half (rate ratio 0.55, 95% CI 0.48 to 0.64; 5 trials, 35,551 participants, high-certainty evidence) and probably reduce the incidence of uncomplicated episodes of Plasmodium vivax malaria (risk ratio (RR) 0.61, 95% CI 0.48 to 0.77; 2 trials, 10,967 participants, moderate-certainty evidence).Insecticide-treated nets were also shown to reduce the prevalence of P falciparum malaria by 17% compared to no nets (RR 0.83, 95% CI 0.71 to 0.98; 6 trials, 18,809 participants, high-certainty evidence) but may have little or no effect on the prevalence of P vivax malaria (RR 1.00, 95% CI 0.75 to 1.34; 2 trials, 10,967 participants, low-certainty evidence). A 44% reduction in the incidence of severe malaria episodes was seen in the ITN group (rate ratio 0.56, 95% CI 0.38 to 0.82; 2 trials, 31,173 participants, high-certainty evidence), as well as an increase in mean haemoglobin (expressed as mean packed cell volume) compared to the no-net group (mean difference 1.29, 95% CI 0.42 to 2.16; 5 trials, 11,489 participants, high certainty evidence).ITN versus untreated netsInsecticide-treated nets probably reduce child mortality from all causes by a third compared to untreated nets (rate ratio 0.67, 95% CI 0.36 to 1.23; 2 trials, 25,389 participants, moderate certainty evidence). This corresponds to a saving of 3.5 lives (95% CI -2.4 to 6.8) each year for every 1000 children protected with ITNs. Insecticide-treated nets also reduce the incidence of uncomplicated P falciparum malaria episodes (rate ratio 0.58, 95% CI 0.44 to 0.78; 5 trials, 2036 participants, high certainty evidence) and may also reduce the incidence of uncomplicated P vixax malaria episodes (rate ratio 0.73, 95% CI 0.51 to 1.05; 3 trials, 1535 participants, low-certainty evidence).Use of an ITN probably reduces P falciparum prevalence by one-tenth in comparison to use of untreated nets (RR 0.91, 95% CI 0.78 to 1.05; 3 trials, 2,259 participants, moderate-certainty evidence). However, based on the current evidence it is unclear whether or not ITNs impact on P vivax prevalence (1 trial, 350 participants, very low certainty evidence) or mean packed cell volume (2 trials, 1,909 participants, low certainty evidence). AUTHORS' CONCLUSIONS: Although there is some evidence that insecticide resistance frequency has some effects on mosquito mortality, it is unclear how quantitatively important this is. It appeared insufficient to downgrade the strong evidence of benefit on mortality and malaria illness from the trials conducted earlier. PMID- 30398673 TI - Targeting the pedunculopontine nucleus in Parkinson's disease: Time to go back to the drawing board. PMID- 30398674 TI - Mediterranean diets and prodromal Parkinson's disease: A causal line, or a confound circle? PMID- 30398675 TI - PTRHD1 Loss-of-function mutation in an african family with juvenile-onset Parkinsonism and intellectual disability. AB - BACKGROUND: The genetic bases of PD in sub-Saharan African (SSA) populations remain poorly characterized, and analysis of SSA families with PD might lead to the discovery of novel disease-related genes. OBJECTIVES: To investigate the clinical features and identify the disease-causing gene in a black South African family with 3 members affected by juvenile-onset parkinsonism and intellectual disability. METHODS: Clinical evaluation, neuroimaging studies, whole-exome sequencing, homozygosity mapping, two-point linkage analysis, and Sanger sequencing of candidate variants. RESULT: A homozygous 28-nucleotide frameshift deletion in the PTRHD1 coding region was identified in the 3 affected family members and linked to the disease with genome-wide significant evidence. PTRHD1 was recently nominated as the disease-causing gene in two Iranian families, each containing 2 siblings with similar phenotypes and homozygous missense mutations. CONCLUSION: Together with the previous reports, we provide conclusive evidence that loss-of-function mutations in PTRHD1 cause autosomal-recessive juvenile parkinsonism and intellectual disability. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 30398676 TI - Familial ataxia, tremor, and dementia in a polish family with a novel mutation in the CCDC88C gene. PMID- 30398677 TI - Current Controversies in Prenatal Diagnosis 2: NIPT Results Suggesting Maternal Cancer Should Always Be Disclosed. PMID- 30398678 TI - Posttraumatic Stress Disorder in Patients With Borderline Personality Disorder: Treatment Outcomes and Mediators. AB - Posttraumatic stress disorder (PTSD) is highly comorbid with personality disorder (PD). We evaluated whether comorbid PTSD has a negative effect on patients' ability to benefit from evidence-based psychological treatments for PD and tested potential mediators of any effect. The effect of PTSD on self-harm and borderline PD symptoms was evaluated in 90 patients with borderline PD who were receiving dialectical behavior therapy or mentalization-based therapy. Self-report and interview measures were administered every 3 months over a 12-month period. Three quarters of participants met criteria for PTSD. In the 12 months after beginning treatment, participants with PTSD did not engage in self-harm more often or present with more severe borderline PD symptoms. However, a higher level of PTSD symptom severity at baseline was associated with more frequent self-harm during follow-up, incidence rate ratio = 1.03, 95% CI [1.01, 1.06], p = .005. Participants whose PTSD did not improve or worsened were more likely to still self-harm, odds ratio (OR) = 0.91, 95 % CI [0.85, 0.97], p = .004, and report more severe borderline PD symptoms, b = 0.53, 95% CI [0.34, 0.73], p < .001, at the end of 12 months. The negative effects of PTSD symptoms remained significant after adjusting for potential confounders and were partially mediated by high ongoing levels of emotional dysregulation, indirect effect b = 0.32, 95% CI [0.19, 0.50]. These findings identify subgroups at risk of poorer outcomes from evidence-based psychological treatments for PD and support the idea that treating PTSD may improve outcomes. PMID- 30398679 TI - Synthesis of Bis(phosphino)alkane Monosulfides by the Addition of Diphosphine Monosulfides to Alkenes under Light. AB - Bisphosphinated compounds are regarded to be the most ubiquitous privileged ligand structures in transition-metal catalysis. The development of highly atom economical reactions is of great importance for their syntheses because lower atom-economical methods often require complicated purification procedures under inert atmospheres to remove excess amounts of the starting materials and byproducts. Herein, we disclose the photoinduced addition reactions of PV(S)-PIII single-bond-bearing diphosphine monosulfides to alkenes. These reactions require only equimolar amounts of the diphosphine monosulfide relative to the alkene and facilitate the highly selective introductions of two different types of phosphorus groups, such as thiophosphinyl and phosphino groups, to a variety of alkenes without any catalyst, base, or additive. PMID- 30398680 TI - Prevalence of Posttraumatic Stress Disorder and Psychological Comorbidities Among U.S. Active Duty Service Members, 2006-2013. AB - Among active duty service members, posttraumatic stress disorder (PTSD) diagnoses have increased dramatically since 2000. Because psychiatric comorbidity is more common for PTSD than for other mental health disorders, we examined the prevalence estimates of disorders comorbid or trimorbid with PTSD in this study. The medical records of 523,626 female and male active duty Sailors and Marines who entered the U.S. military between 2006 and 2013 were examined for diagnoses of PTSD and 14 potentially comorbid disorders. Results showed that 1.8% of military members had a PTSD diagnosis; among those with PTSD, 83.3% had a comorbid mental health disorder, and 62.2% had a third (i.e., trimorbid) disorder. Most frequently, PTSD co-occurred with depressive disorder (49.0%), adjustment disorder (37.0%), generalized anxiety disorder (36.1%), and alcohol use disorder (26.9%). All disorders we examined were significantly more likely to be diagnosed in service members with PTSD than in those without PTSD, odds ratios = 1.52-29.63. For service members with PTSD, comorbid mental health disorders are the rule rather than the exception. Consequently, it is important that clinicians also assess for other disorders and select treatment options that address both PTSD and comorbid conditions. PMID- 30398681 TI - The Synthesis of Waltherione F and Analogues with Modifications at the 2- and 3 Positions as Potential Antitrypanosomal Agents. AB - Chagas disease also know as American Trypanosomiasis (AT) is a tropical parasitic disease endemic in South America, is caused by Trypanosoma cruzi which is transmitted by the blood-sucking insect vectors called triatomine bugs. Quinoline alkaloids from the root extract of Waltheria indica are known to possess antitrypanosomal activity. Waltherione F 3, one of those alkaloids, was synthesised in 5 steps in 11% overall yield. A key step in the sequence utilised the Conrad-Limpach synthesis for the formation of the quinolin-4(1H)-one ring system. Our synthetic strategy was designed to enable the modification of the 2- and 3-positions of the scaffold, allowing the generation of a diverse library of analogues to support our on-going medicinal chemistry program that is looking for new agents to tackle this devastating disease. PMID- 30398682 TI - Giant Electro-Optical Effect through Electrostriction in a Nanomechanical Metamaterial. AB - Electrostriction is a property of all naturally occurring dielectrics whereby they are mechanically deformed under the application of an electric field. It is demonstrated here that an artificial metamaterial nanostructure comprising arrays of dielectric nanowires, made of silicon and indium tin oxide, is reversibly structurally deformed under the application of an electric field, and that this reconfiguration is accompanied by substantial changes in optical transmission and reflection, thus providing a strong electro-optic effect. Such metamaterials can be used as the functional elements of electro-optic modulators in the visible to near-infrared part of the spectrum. A modulator operating at 1550 nm with effective electrostriction and electro-optic coefficients of order 10-13 m2 V-2 and 10-6 m V-1 , respectively, is demonstrated. Transmission changes of up to 3.5% are obtained with a 500 mV control signal at a modulation frequency of ~6.5 MHz. With a resonant optical response that can be spectrally tuned by design, modulators based on the artificial electrostrictive effect may be used for laser Q-switching and mode-locking among other applications that require modulation at megahertz frequencies. PMID- 30398683 TI - Pyridyl Radical Cation for C-H Amination of Arenes. AB - Electron-transfer photocatalysis provides access to the elusive and unprecedented N-pyridyl radical cation from selected N-substituted pyridinium reagents. The resulting C(sp2)-H functionalization of hetero(arenes) furnishes versatile intermediates for the development of valuable aminated aryl scaffolds. Mechanistic studies that include the first spectroscopic evidence of a spin trapped N-pyridyl radical adduct implicate SET-triggered, pseudo-mesolytic cleavage of the N-X pyridinium reagents triggered by visible light. PMID- 30398684 TI - Sulfinate and Carbene Co-catalyzed Rauhut-Currier Reaction for Enantioselective Access to Azepino[1,2-a]indole. AB - A carbene and sulfinate co-catalyzed intermolecular Rauhut-Currier reaction between enals and nitrovinyl indoles is disclosed. The carbene catalyst activates the enal and the sulfinate co-catalyst activates the nitrovinyl indole. Both activation processes are realized via the formation of covalent bonds between catalysts and substrates to generate the catalyst-bound intermediates. The dual catalytic reaction affords azepino[1,2-a]indole products with excellent stereo selectivities. Our study demonstrates the unique involvement of sulfinate as effective nucleophilic catalyst in activating electron-deficient alkenes for asymmetric reactions. The dual catalytic approach shall also encourage future explorations of both sulfinate and carbene catalysts for new reactions. PMID- 30398686 TI - Women in Science Awards. PMID- 30398685 TI - Men and Women in Immunology: Closing the gap on gender parity? PMID- 30398687 TI - Impressum. PMID- 30398688 TI - Prediction of Major Regio-, Site-, and Diastereoisomers in Diels-Alder Reactions by Using Machine-Learning: The Importance of Physically Meaningful Descriptors. AB - Machine learning can predict the major regio-, site-, and diastereoselective outcomes of Diels-Alder reactions better than standard quantum-mechanical methods and with accuracies exceeding 90 % provided that i) the diene/dienophile substrates are represented by "physical-organic" descriptors reflecting the electronic and steric characteristics of their substituents and ii) the positions of such substituents relative to the reaction core are encoded ("vectorized") in an informative way. PMID- 30398689 TI - Surface modification of chitosan films with a fibronectin fragment-DNA aptamer complex to enhance osteoblastic cell activity: a mass spectrometry approach probing evidence on protein behavior. PMID- 30398690 TI - Recent Progress of Strong Exciton-Photon Coupling in Lead Halide Perovskites. AB - The semiconductor exciton-polariton, arising from the strong coupling between excitons and confined cavity photon modes, is not only of fundamental importance in macroscopic quantum effects but also has wide application prospects in ultralow-threshold polariton lasers, slowing-light devices, and quantum light sources. Very recently, metallic halide perovskites have been considered as a great candidate for exciton-polariton devices owing to their low-cost fabrication, large exciton oscillator strength, and binding energy. Herein, the latest progress in exciton-polaritons and polariton lasers of perovskites are reviewed. Polaritons in planar and nanowires Fabry-Perot microcavities are discussed with particular reference to material and photophysics. Finally, a perspective on the remaining challenges in perovskite polaritons research is given. PMID- 30398692 TI - Colloidal Quantum Dot Arrangement Assisted by Perylene Bisimide Self-Assembly. AB - Colloidal semiconductor nanocrystals, so-called quantum dots (QDs), are attractive as molecular-like smart nanomaterials, and their emission and optoelectronic properties in the dispersed state have been actively studied. The construction of supramolecular structures composed of multiple QDs, however, is still challenging. Here, a new strategy to form supramolecular QD structures via self-assembly of perylene bisimide (PBI) dyes is demonstrated. In a mixed solution, QDs and PBI undergo time-dependent fusion to form an isolated colloidal QD-PBI complex or a unique QD-PBI co-aggregate composed of QDs arranged along a sheet-like PBI nanostructure, and these dramatically different supramolecular structures can be controlled by the solvent polarity. PMID- 30398691 TI - A Conductive and Highly Deformable All-Pseudocapacitive Composite Paper as Supercapacitor Electrode with Improved Areal and Volumetric Capacitance. AB - Flexible energy storage electronics have gained increasing attention in recent years, but the simultaneous acquiring of high volumetric and high areal capacities as well as excellent flexibility in order to truly implement wearable and portable electronics in practice remains challenging. Here, a conductive and highly deformable freestanding all-pseudocapacitive paper electrode (Ti3 C2 Tx /MnO2 NWs) is fabricated by solution processing of hybrid inks based on Ti3 C2 Tx MXene and ultralong MnO2 nanowires. The resulting Ti3 C2 Tx /MnO2 NWs hybrid paper manifests a remarkable areal capacitance of up to 205 mF cm-2 and outstanding volumetric capacitance of 1025 F cm-3 . Both the values are highly comparable with, or in most cases much higher than those of previously reported MXene-based flexible electrodes. The excellent energy storage performance is well maintained with a capacitance retention of 98.38% during 10 000 charge-discharge cycles. In addition, the flexible supercapacitor demonstrates excellent flexibility and electrochemical stability during repeated mechanical bendings of up to 120 degrees , suggesting great potentials for the applications in future flexible and portable electronics. PMID- 30398693 TI - All-Nanoporous Hybrid Membranes: Redefining Upper Limits on Molecular Separation Properties. AB - New membrane-based molecular separation processes are an essential part of the strategy for sustainable chemical production. A large literature on "hybrid" or "mixed-matrix" membranes exists, in which nanoparticles of a higher-performance porous material are dispersed in a polymeric matrix to boost performance. We demonstrate that the hybrid membrane concept can be redefined to achieve much higher performance if the membrane matrix and the dispersed phase are both nanoporous crystalline materials, with no polymeric phase. As the first example of such a system, we find that surface-treated nanoparticles of the zeolite MFI can be incorporated in situ during growth of a polycrystalline membrane of the MOF ZIF-8. The resulting all-nanoporous hybrid membrane shows propylene/propane separation characteristics that exceed known upper-bound performance limits defined for polymers, nanoporous materials, and polymer-based hybrid membranes. This serves as a starting point for a new generation of chemical separation membranes containing interconnected nanoporous crystalline phases. PMID- 30398694 TI - Anabaena sp. strain PCC 7120: Laboratory Maintenance, Cultivation, and Heterocyst Induction. AB - Anabaena sp. strain PCC 7120 is a multicellular, filamentous, freshwater cyanobacterium that is capable of differentiating specialized heterocyst cells for nitrogen fixation. This unit includes protocols for the growth and maintenance of Anabaena appropriate for a research or teaching laboratory. Controlled induction and assessment of heterocyst development is also covered. (c) 2018 by John Wiley & Sons, Inc. PMID- 30398695 TI - A prospective study of alcohol involvement and the dual-systems model of adolescent risk-taking during late adolescence and emerging adulthood. AB - AIMS: To estimate interactions and unique effects of behavioral approach and behavioral control on alcohol involvement hypothesized by dual-systems models, during adolescence and emerging adulthood. DESIGN: In a longitudinal study, behavioral approach and behavioral control were examined in relation to alcohol involvement, cross-sectionally and prospectively. SETTING AND PARTICIPANTS: A total of 846 general population twins born in Colorado, USA were assessed twice (mean = 17.3 and 22.8 years; female = 51.4%; white = 91.8%). MEASUREMENTS: Behavioral approach was measured by self-report questionnaires of sensation seeking and subjective effects of alcohol. Behavioral control was measured by self-reported lack of planning and nine executive functioning (EF) tasks. Interviewers administered semi-structured clinical interviews to assess alcohol use and disorder (AUD). FINDINGS: None of 36 interaction effects was statistically significant (beta = -0.16-0.14, P > 0.06), suggesting that dual systems are additively related to alcohol involvement. In multiple regression models, behavioral approach and behavioral control explained independent variance in alcohol use quantity (beta = 0.09-0.33, P < 0.04) and frequency (beta = -0.11 0.29, P < 0.03) at both waves. During adolescence, only subjective effects (beta = 0.27-0.28, P < 0.001) explained independent variance in AUD. Moreover, measures of the same construct explained independent variance in alcohol involvement: for behavioral control, lack of planning and EF were associated with alcohol frequency in adolescence (beta = -0.11-0.25, P < 0.02) and AUD in emerging adulthood (beta = -0.09-0.16, P < 0.03). For the behavioral approach, subjective effects were associated with all measures at both waves (beta = 0.20-0.33, P < 0.01) and sensation-seeking was associated with all measures in emerging adulthood (beta = 0.09-0.11, P < 0.04). In prospective models, adolescent alcohol involvement was associated with later lack of planning (beta = 0.12-0.18, P < 0.03) and lack of planning in adolescence was associated with later alcohol involvement (beta = 0.12-0.14, P < 0.02). CONCLUSIONS: Both the behavioral approach and behavioral control components of dual-systems models explain alcohol involvement during adolescence and adulthood, and different measures of the same system assess separate risk processes. The relations between alcohol involvement and the dual systems appear to be bidirectional. PMID- 30398696 TI - Enhanced Sensitivity in Nanopore Sensing of Cancer Biomarkers in Human Blood via Click Chemistry. AB - Cancer biomarkers are expected to be indicative of the occurrence of certain cancer diseases before the tumors form and metastasize. However, many biomarkers can only be acquired in extremely low concentrations, which are often beyond the limit of detection (LOD) of current instruments and technologies. A practical strategy for nanopore sensing of cancer biomarkers in raw human blood down to the femtomolar level is developed here. This strategy first converts the detection of cancer biomarkers to the quantification of copper ions by conducting a sandwich assay involving copper oxide nanoparticles. The released Cu2+ is then taken to catalyze the "click" reaction which ligates a host-guest modified DNA probe. Finally, this DNA probe is subjected to single-channel recordings to afford the translocation events that can be used to derive the concentrations of the original biomarkers. Due to the amplification effects of nanoparticle loadings and the "click" reaction, the LOD of this strategy can be as low as the subfemtomolar level. Further, the acid treatment step could effectively eliminate the interferences from plasma proteins in raw human blood and make the strategy highly suitable for the detection of cancer biomarkers in clinical samples. PMID- 30398697 TI - Global Folding of a Na+-Specific DNAzyme Studied by FRET. AB - Recently a few RNA-cleaving DNAzymes have been isolated with excellent specificity for Na+, and some of them contain a Na+ binding aptamer. This metal recognition mechanism is different from most previously reported DNAzymes. Previous studies using 2-aminopurine (2AP) as a probe have indicated interesting local folding by Na+. In this work, fluorescence resonance energy transfer (FRET) was used to probe the global folding of the Ce13d DNAzyme, one of the Na+ specific DNAzymes. FRET pairs were at different locations yielding a total of five constructs to probe its three-way junc-tion structure with a large loop. With end-labelled DNAzymes, the global structure appears quite rigid with little folding by adding up to 200 mM monovalent metal ions, although some minor dif ferences were observed between Li+, Na+ and K+. This lack of large conformational change is also consistent with CD spectroscopy data. The loop was then labelled with an internal TMR fluorophore at the G14 position, and its cleavage activity was partially retained. A clear Na+-dependent folding was observed with spectral crossover. From a biosensing standpoint, global folding based sensors are unlikely to work due to the overall rigid structure of the DNAzyme. Therefore, the best way us-ing this DNAzyme to discriminate Na+ from K+ is based on cleavage activity, followed by probing local folding, while global folding is the least effective for metal discrimination. PMID- 30398698 TI - Programed Assembly of Nucleoprotein Nanoparticles Using DNA and Zinc Fingers for Targeted Protein Delivery. AB - With a growing number of intracellular drug targets and the high efficacy of protein therapeutics, the targeted delivery of active proteins with negligible toxicity is a challenging issue in the field of precision medicine. Herein, a programed assembly of nucleoprotein nanoparticles (NNPs) using DNA and zinc fingers (ZnFs) for targeted protein delivery is presented. Two types of ZnFs with different sequence specificities are genetically fused to a targeting moiety and a protein cargo, respectively. Double-stranded DNA with multiple ZnF-binding sequences is grafted onto inorganic nanoparticles, followed by conjugation with the ZnF-fused proteins, generating the assembly of NNPs with a uniform size distribution and high stability. The approach enables controlled loading of a protein cargo on the NNPs, offering a high cytosolic delivery efficiency and target specificity. The utility and potential of the assembly as a versatile protein delivery vehicle is demonstrated based on their remarkable antitumor activity and target specificity with negligible toxicity in a xenograft mice model. PMID- 30398699 TI - Dose reduction of biologic therapy in inflammatory arthritis: A qualitative study of patients' perceptions and needs. AB - OBJECTIVE: Successful biologic disease-modifying anti-rheumatic drug (bDMARD) dose reduction appears increasingly possible from clinical trials. The present study aimed to understand the patient perspective of bDMARD dose reduction. METHODS: Patients with rheumatoid arthritis, ankylosing spondylitis or psoriatic arthritis who were self-administering subcutaneous bDMARDs therapy at two National Health Service trusts participated in semi-structured interviews. To capture multiple experiences, patients were purposefully sampled for a range of age, gender, disease duration, reducing/not reducing bDMARDs and either within 3 12 months of bDMARD initiation or >=12 months and in remission/low disease activity. Inductive thematic analysis was utilized. RESULTS: Fifteen patients were interviewed (six on dose reduction). Five overarching themes were identified. When thinking about dose reduction, patients reflected on their difficult life before bDMARDs ("Where I was then") compared with their transformative effects ("Where I am now"). All raised concerns that a dose reduction would take them back to where they used to be ("Fears for the future") and most believed it to be a cost-cutting exercise. Most had "Hopes for the future", that a reduction would lower their risk of side effects, and release funds for other patients. They wanted a clear rationale for reduction, collaborative decision making, and control over flexible dosing ("Information needs"). CONCLUSION: Patients were fearful of reducing the dose of their bDMARDs, having previously experienced uncontrollable symptoms. However, most were willing to try, provided that there was a clear rationale and that it was in their best interests, with opportunities for collaboration and dose control. These patient perspectives will inform the provision of patient information to guide clinical discussions. PMID- 30398700 TI - Materials Science and Design Principles of Growth Factor Delivery Systems in Tissue Engineering and Regenerative Medicine. AB - Growth factors (GFs) are signaling molecules that direct cell development by providing biochemical cues for stem cell proliferation, migration, and differentiation. GFs play a key role in tissue regeneration, but one major limitation of GF-based therapies is dosage-related adverse effects. Additionally, the clinical applications and efficacy of GFs are significantly affected by the efficiency of delivery systems and other pharmacokinetic factors. Hence, it is crucial to design delivery systems that provide optimal activity, stability, and tunable delivery for GFs. Understanding the physicochemical properties of the GFs and the biomaterials utilized for the development of biomimetic GF delivery systems is critical for GF-based regeneration. Many different delivery systems have been developed to achieve tunable delivery kinetics for single or multiple GFs. The identification of ideal biomaterials with tunable properties for spatiotemporal delivery of GFs is still challenging. This review characterizes the types, properties, and functions of GFs, the materials science of widely used biomaterials, and various GF loading strategies to comprehensively summarize the current delivery systems for tunable spatiotemporal delivery of GFs aimed for tissue regeneration applications. This review concludes by discussing fundamental design principles for GF delivery vehicles based on the interactive physicochemical properties of the proteins and biomaterials. PMID- 30398702 TI - Nanomechanics of Cells and Biomaterials Studied by Atomic Force Microscopy. PMID- 30398701 TI - Nanoparticle Gradient Materials by Centrifugation. AB - Nanoparticle gradient materials are a unique class of functional materials. They combine the specific properties of nanoparticles with macroscopic materials. A continuous spatial gradient of the nanoparticle concentration leads to diverse physical property profiles. Therefore, these materials have a remarkable potential for applications in optics, electronics, and sensors. A novel approach for the defined and controlled synthesis of this material class is the fabrication in ultracentrifugal fields. The formation of a nanoparticle gradient by sedimentation in a gelatin solution is monitored online with optical systems inside an analytical ultracentrifuge. As soon as the desired nanoparticle concentration gradient is generated, the material is solidified by gelation and the desired gradient is fixed in the material. Application of the established theory of analytical ultracentrifugation allows simulations of the sedimentation process of the nanoparticles in advance. Thus, desired nanoparticle gradient materials can also be tailor-made and fabricated on a preparative scale. This is demonstrated for the example of spherical gold nanoparticles of different sizes, gold nanorods, mixtures thereof, and spherical superparamagnetic iron oxide nanoparticles. PMID- 30398703 TI - Highly Efficient In Vivo Targeting of the Pulmonary Endothelium Using Novel Modifications of Polyethylenimine: An Importance of Charge. AB - Pulmonary vascular disease encompasses a wide range of serious afflictions with important clinical implications. There is critical need for the development of efficient, nonviral gene therapy delivery systems. Here, a promising avenue to overcome critical issues in efficient cell targeting within the lung via a uniquely designed nanosystem is reported. Polyplexes are created by functionalizing hyperbranched polyethylenimine (PEI) with biological fatty acids and carboxylate-terminated poly(ethylene glycol) (PEG) through a one-pot 1-ethyl 3-(3-dimethylaminopropyl)carbodiimide hydrochloride/N-hydroxysuccinimide reaction. Following intravenous injection, polyplexes show an exceptionally high specificity to the pulmonary microvascular endothelium, allowing for the successful delivery of stabilized enhanced green fluorescent protein (eGFP) expressing messenger ribonucleic acid (mRNA). It is further shown, quantitatively, that positive surface charge is the main mechanism behind such high targeting efficiency for these polyplexes. Live in vivo imaging, flow cytometry of single cell suspensions, and confocal microscopy are used to demonstrate that positive polyplexes are enriched in the lung tissue and disseminated in 85-90% of the alveolar capillary endothelium, whilst being sparse in large vessels. Charge modification, achieved through poly(acrylic acid) or heparin coating, drives a highly significant reduction in both targeting percentage and targeting strength, highlighting the importance of specific surface charge, derived from chemical formulation, for efficient targeting of the pulmonary microvascular endothelium. PMID- 30398704 TI - Regulating Fast Anionic Redox for High-Voltage Aqueous Hydrogen-Ion-based Energy Storage. AB - The ionic conductivity and small size of the hydrogen ion make it an ideal charge carrier for hydrogen-ion energy storage (HES); however, high-voltage two electrode configurations are difficult to construct as the result of the lack of efficient cathodic energy storage. Herein, the high potential fast anionic redox at the cathode of reduced graphene oxide (rGO) was applied by introducing redox additive electrolytes. By coupling the storing hydrogen ion in the Ti3 C2 Tx at the anode, a HES with a voltage of 1.8 V and a plateau voltage at 1.2 V was constructed. Compared with 2.2 Wh kg-1 for the low-voltage Ti3 C2 Tx //Ti3 C2 Tx , the specific energy of asymmetric rGO//Ti3 C2 Tx reaches 34.4 Wh kg-1 . Furthermore, it possesses an energy density of 23.7 Wh kg-1 at high power density of 22.5 kW kg-1 . Thus, this study provides a novel guideline for constructing high-voltage fast HES full cells. PMID- 30398705 TI - DNA Origami Templated Silica Growth by Sol-gel Chemistry. AB - Improving the stability of DNA origami structures with respect to thermal, chemical and mechanical influences will be essential to fully explore of the real life applicability of DNA nanotechnology. Here we present a strategy to increase the mechanical resilience of individual DNA origami objects and more advanced 3D DNA origami crystals in solution as well as in the dry state. By encapsulating DNA origami in a protective silica shell using sol-gel chemistry, all objects maintain their structural integrity, which allowed for a detailed structural analysis of the crystals in a dry state, revealing their true 3D shape without lattice deformation and drying-induced collapse. Analysis by energy-dispersive X ray spectroscopy showed a uniform silica coating whose thickness could be controlled via pre-cursor concentrations and reaction time. PMID- 30398706 TI - Shift to paying physicians under MACRA has system CEOs preparing for complications. PMID- 30398707 TI - Hidden danger: dirty medical tools. PMID- 30398709 TI - DESIGN AWARDS GOLD: Humber River Hospital Toronto. PMID- 30398710 TI - DESIGN AWARDS SILVER: Christ Hospital Joint and Spine Center Cincinnati. PMID- 30398708 TI - Winning designs reflect two industry trends. PMID- 30398711 TI - DESIGN AWARDS Cleveland Clinic Abu Dhabi Abu Dhabi, United Arab Emirates. PMID- 30398712 TI - DESIGN AWARDS Swedish Edmonds Ambulatory Care Center Edmonds, Wash. PMID- 30398713 TI - DESIGN AWARDS Kaiser Permanente Antelope Valley Medical Offices Lancaster, Calif. PMID- 30398714 TI - New acadenuc hospital ups the ante in San Diego. PMID- 30398715 TI - Survey dissatisfaction. PMID- 30398716 TI - Time to act on mental health legislation. PMID- 30398717 TI - In the wake of devastating Louisiana floods: A hospital CEO's stories of response, resiliency. PMID- 30398718 TI - Helping ACOs track patients' care. PMID- 30398719 TI - 'Always put the consumer and consumer protection out front and first'. AB - Dr. Karen DeSalvo stepped down last month as chief of the Office of the National Coordinator for Health Information Technology. She retains the title of acting assistant secretary of health, which she has held since the fall of 2014. The former health commissioner of New Orleans recently spoke with Modern Healthcare reporter Joseph Conn about her nearly three years leading the ONC, which made her the longest-serving person in that role. This is an edited transcript. PMID- 30398720 TI - Top 40 Medicare Part D prescription drugs Ranked by total payments in 2014. PMID- 30398721 TI - Precision Medicine in Cancer Prevention: Exploring Applications in Mississippi and Beyond. PMID- 30398722 TI - Top 10 Facts You Need to Know about Carotid Artery Disease. PMID- 30398723 TI - Emergency Physician-Performed Bedside Ultrasound in the Evaluation of Acute Appendicitis in a Pediatric Population. AB - Background/Objective Many pediatric emergency departments in the United States have adopted a staged ultrasound and CT pathway for the diagnosis of acute appendicitis. However, most algorithms only include radiology-performed ultrasound (RUS) and not emergency physician- performed bedside ultrasound (BUS). Our objective was to determine if emergency physician-performed BUS provides sufficient diagnostic accuracy for acute appendicitis in a pediatric population, thereby limiting additional cost and/or delays in disposition. Methods This is a single-center prospective study of pediatric patients with concern for and requiring further work-up for acute appendicitis. Each patient had a focused bedside ultrasound (BUS) performed by an emergency physician with training in BUS. Diagnostic accuracy was compared with surgical pathology standard, as well as radiology- performed ultrasound (RUS), computed tomography (CT), and clinical follow-up. Results Among46 enrolledpatients, 12were diagnosed with acute appendicitis (26%). There were no negative laparotomies in those who had surgery. There was one case of missed appendicitis at 4-week follow-up. BUS had a sensitivity of 100% (95% Cl: 72% to 100%) and. a specificity of 81% (61% to 93%) when the app6ndix'was visualized (37). This resulted in positive likelihood ratio of5.2 and a negative likelihood ratio ofo. In the cases where the appendix was not visualized on BUS (9), 1 patient was diagnosed with appendicitis, and the other 8 patients were negative for appendicitis. In RUS both the sensitivity and specificity was 100% when the appendix was visualized. The sensitivity and specificity of CT in our studywas 90% and 100% respectively. Conclusions Emergency physicians can perform bedside ultrasound with high accuracy for acute appendicitis in a pediatric population. When the appendix is not visualized by ultrasound, a staged ultrasound and CT pathway should be considered. PMID- 30398724 TI - MSMA Supports Immunizations with GiveMeAShot.org. PMID- 30398725 TI - Primordial and Primary Prevention: Addressing Non-communicable Diseases in Mississippi. PMID- 30398726 TI - Rural Hospital Survival Depends on Infusion of Monies, Especially to cover Uncompensated Care: Could Medicaid Expansion Provide Critical Relief? PMID- 30398727 TI - Physicians Should Support Universal Healthcare. PMID- 30398728 TI - Sandbagging Medicaid is a futile Weapon Against the ACA and Short-Changes Mississippians Hundreds of Millions. PMID- 30398729 TI - New findings in acute kidney injury. PMID- 30398730 TI - Life-style habits and nutrition in CKD. PMID- 30398731 TI - Challenges to regenerate the kidney. PMID- 30398732 TI - Annual progress in nephrology: glomerulonephritis and nephrotic syndrome. PMID- 30398733 TI - Recent progress in pediatric nephrology. PMID- 30398734 TI - Renal tubular physiology. PMID- 30398735 TI - Aromaptlege - im Linklang mit dem Menschen. PMID- 30398736 TI - <>. PMID- 30398737 TI - Die Ture einen Spalt geoffnet. PMID- 30398738 TI - Mit geringem Aufwand gutsitzen. PMID- 30398739 TI - Sturze vermeiden - aber wie?. PMID- 30398740 TI - <>. PMID- 30398741 TI - <>. PMID- 30398742 TI - Abwesenheiten reduzieren. PMID- 30398744 TI - Pravention von Gewichtszunahme in der Schwangerschaft. PMID- 30398743 TI - Martha Meier 1930-2016. PMID- 30398745 TI - L'aromatherapie: en harmonie avec la personne. PMID- 30398746 TI - <>. PMID- 30398747 TI - Un probleme de stigmatisation. PMID- 30398748 TI - La consultation d'enseignement therapeutique. PMID- 30398749 TI - Intirmieres de premier recours et patients face au fleau. PMID- 30398750 TI - 2016, annee de <> decision. PMID- 30398751 TI - Vers une pratique transdisciplinaire. PMID- 30398753 TI - Laromaterapia: in armonia con la persona. PMID- 30398752 TI - Le mercure, un ennemi invisible qui fait peur. PMID- 30398755 TI - 2016, I'anno <> decisione. PMID- 30398754 TI - <>. PMID- 30398756 TI - Unire le forze. PMID- 30398757 TI - Overweight and Obesity Prevalence and Trends Among Mississippi Public School Students: A Decade of Data Between 2005 and 2015. AB - This study estimated. the prevalence of overweight and obesity in Mississippi public school students in grades K-12 and examined changes between 2005 and 2015. In 2015, the prevalence of overweight, obesity, and both combined remained higher than national averages, yet the rates have neither increased nor decreased significantly since 2005 (p = 0.6904). In 2015, as with all previous years, there was no difference between boys and girls (p=0.570). As in all previous years, the prevalence of obesity in 2015 was significantly higher among black students (p < 0.001) than among white students. Similar to 2011 and 2013, there was a significant difference by grade level in 2015 (p=0.0029), with the lowest prevalence again among the elementary students. The significant linear decrease in obesity prevalence among elementary school students observed during 2013 continued to 2015 (p = 0.0209). Trends are discussed in the context of state policy and recent research. PMID- 30398758 TI - Teen Pregnancy in Mississippi: A History and Analysis of Recent Legislative and Governmental Attempts to Address Different Aspects of this Issue in Mississippi. AB - Background Mississippi has one of the highest teen pregnancy and birth rates in the nation. From 1991 to 2014 the birthrate to Mississippi teens decreased by 55 percent, which ranks number 35 in the rate of decline (versus 61% nationally). However, in 2014 Mississippi's teen birth rate still kept it at number 48 out of 50 states.' Mississippi has implemented Healthy Teens for a Better Mississippi as a Governor's initiative and best practice programs to reduce teen pregnancy in the state of Mississippi. Several bills have been passed into law that address various aspects of teen pregnancy prevention. Methods Recent legislation implemented from 2011 to 2015 was reviewed and summarized. Results and Conclusions Teen births have decreased 55 percent from 1991 to 2014. It is not possible to point to any one factor that can explain this reduction. It is likely that many factors have affected this change in teen pregnancy and birth rates. It is still too early to be able to assess the effect of the various laws that have been passed to address teen pregnancy. PMID- 30398759 TI - Top 10 Facts You Should Know About Immunizations and Vaccine Exemptions in Mississippi. PMID- 30398761 TI - Neighbor State Sees Swell in Preventable Mumps Cases: Legislature Holds the Key. PMID- 30398760 TI - Top 10 Facts You Should Know About Diagnostic Evaluation of Neonatal Cholestasis. PMID- 30398762 TI - Bariatric Surgery -A Viable Option and the Best Hope for Many Mississippians? AB - [Research shows that diets are ineffective in the treatment of obesity because neuro-hormonal systems to preserve excess weight are stronger than the will to keep it off No magic pill has worked or is on the horizon. Newel; minimally invasive bariatricsurgery procedures do work but may be underutilized. In this Commentaiy, the authors who are affiliated with the UMMC Mississippi Centerfor Obesity Research and one of whom trained at the London School of Economics (ELW), speak to this issue. ---Ed.]. PMID- 30398763 TI - Sell assets or go private? CHS weighs the options as it struggles unde huge debt load. PMID- 30398764 TI - The next administration is already charting its healthcare course HHS short list?. PMID- 30398765 TI - Rapid adoption of bundled payments remains an act of faith. PMID- 30398766 TI - Not-for-profit systems still working on improving community outreach. PMID- 30398768 TI - Thank you for that question, Lester. PMID- 30398767 TI - Today's specia : IT How tech-enabled food service can make patients happier and save money. PMID- 30398769 TI - Rejecting Kentucky Medicaid proposal would reaffirm commitment to full coverage. AB - Kentucky Gov. Matt Bevin, representing a state where the uninsured rate has plummeted from 14.3% to 6% since adopting the Medicaid expansion under the Affordable Care Act, is proposing sweeping Medicaid changes that would make it harder for Kentuckians to keep their coverage. He threatens to cancel the Medicaid expansion if HHS doesn't approve his plan. PMID- 30398770 TI - Frequent violence in the ED doesn't have to be part of the job. PMID- 30398772 TI - Largest professional liability carriers Ranked by direct premiums written for medical professional liability in the U.S., 2015. PMID- 30398771 TI - 'If Mayo was a high-cost provider, we would be cut out of many of these networks'. AB - Mayo Clinic, which has a 150-year history as a medical practice, now operates 22 hospitals and draws patients with complex needs from all over the world to its 1,243-bed flagship facility in Rochester, Minn. The organization has also garnered praise for insulating clinical decisions from financial incentives by paying physicians under a salary model with no productivity bonuses. But even though Mayo is built to let doctors be doctors and has been ahead of the curve in studying how to measure and reward value in healthcare delivery, it isn't immune to challenges such as physician burnout and the mounting pressure to reduce costs and adopt value-based payment models. Bob Herman, Modern Healthcare's Midwest bureau chief, interviewed Mayo President and CEO Dr. John Noseworthy while he was in Chicago as co-chair of a consortium of 12 health system CEOs convened with the American Medical Association to address physician burnout. The following is an edited excerpt. PMID- 30398773 TI - Trump could boost Medicaid expansion by swaying down-ballot state elections. PMID- 30398774 TI - Talking point or real solution? Experts assess Trump's favorite health reform idea. PMID- 30398775 TI - Safety net systems step up care for immigrants barred from coverage under ACA. PMID- 30398776 TI - School clinics are in session. PMID- 30398777 TI - How some Blues made the ACA work while others failed. PMID- 30398778 TI - Lower the volume on quality reporting. PMID- 30398779 TI - Upcoming open enrollment offers opportunity for more Americans to protect health, wealth. PMID- 30398780 TI - Helping track crash cart medications. PMID- 30398782 TI - Most frequently billed DRGs Ranked by 2014 Medicare patient discharges. PMID- 30398781 TI - 'We don't set the price. Pharmaceutical manufacturers set the price'. AB - Pharmacy benefit managers are facing heat for not doing enough to slow down drug price hikes. UnitedHealth Group's subsidiary, OptumRx, recently acquired Catamaran Corp. for almost $13 billion, making it the third-largest PBM in the country by market share. Modern Healthcare Midwest Bureau Chief Bob Herman recently asked OptumRx. CEO Mark Thierer about the controversy swirling around the industry. The following is an edited excerpt. PMID- 30398783 TI - Mental health rises to top of agenda, but has a tough course ahead. PMID- 30398784 TI - ICD-10 one year later: The drama is over, the rewards yet to materialize. PMID- 30398785 TI - So you think you can analyze data?. PMID- 30398786 TI - Payment headaches hinder progress on mental health access. PMID- 30398787 TI - A promising fiddling with health insurance. PMID- 30398788 TI - For a model of efficiency and high-quality care, look at the performance of rural hospitals. PMID- 30398789 TI - Treating dental care as healthcare. PMID- 30398790 TI - Pharmaceutical research and development spending Ranked by percentage of revenue spent on research in 2015 ($ in millions). PMID- 30398791 TI - Two Different Covenants Not to Compete? PMID- 30398793 TI - Inability to Perform at an Acceptable Level. PMID- 30398792 TI - Good Leadership Can't Be Outsourced. PMID- 30398794 TI - Risk Management Q&A: Refund of Professional Fees. PMID- 30398795 TI - The Facts about Michigan's Dental Therapist Proposal. PMID- 30398796 TI - Detection of Monckeberg Medial Sclerosis on Conventional Dental Imaging. AB - Vascular calcification occurs with aging, and several risk factors including diabetes, hyperlipidemia, and disorders of calcium metabolism have been identified. M6nckeberg medial sclerosis (MMS) is the most common variant of medial calcification. M6nckeberg sclerosis can lead to significant adverse cardiovascular outcomes such as arterial stiffness, increased pulse and left ventricular hypertrophy. Here we report two cases of MMS involving facial vasculature, diagnosed incidentally on radiographs during their routine dental evaluation. They appear as convoluted "railroad tracks" patterns of the facial artery calcification. We believe that a better understanding and identification of these calcifications can lead to appropriate patient follow-up with medical providers and interventions to reduce morbidity and mortality by potentially predicting possible cardiovascular events. PMID- 30398797 TI - Associate Buy-Ins: What You Need to Know. Part II. AB - In part two of this article, which began last month, Ted Schumann discusses contract issues to consider, including associate employment agreements, buy-in agreements, operating agreements, and buy-sell agreements. Plus - 10 things to avoid after the buy-in is concluded. PMID- 30398799 TI - Most important best practice? Readers say partnerships targeting readmissions. AB - Hospitals are concluding they have to work very closely with healthcare providers, community organizations, families and patients themselves if they're going to keep people out of hospital beds-the new mandate under Medicare and fast growing models of value-based payment. PMID- 30398798 TI - THE FUTURIST Follow the money. Then follow the trust. PMID- 30398800 TI - THE FUTURIST The long-term prognosis for payment policy in an era of demand for value. AB - The task of forecasting the direction of healthcare finance and payment is difficult enough in just the short term, given the pace and scope of change that characterizes today's strategic environment. PMID- 30398801 TI - Genome sequencing rated top advance of past 40 years. AB - The sequencing of the human genome represents the most significant breakthrough in healthcare over the past 40 years, according to Modern Healthcare readers. That achievement, capping a 13-year, $3 billion international effort funded by the federal government, drew the most votes from the 728 respondents to a survey that listed 60 healthcare milestones achieved since Modern Healthcare was founded in 1976. The survey asked readers to pick their top five choices from each of three categories: science and technology; healthcare delivery; and politics and policy. PMID- 30398802 TI - THE FUTURIST Not one-size-fits-all: Innovative providers creating new healthcare models. AB - Today's fast pace of change might suggest that forecasting the evolution of healthcare professions over the next 25 years is an exercise in futility. PMID- 30398803 TI - THE FUTURIST Toward a personalized, learning healthcare system. AB - The great inversion of medicine, with its roots just starting to take hold now, will have been fully achieved over the next few decades. PMID- 30398804 TI - Future space: Harnessing the power of big data. AB - With the federal government spending tens of billions of dollars to push healthcare providers to install electronic health record systems, health information technology has been at the forefront of innovation in the healthcare industry for most of the past decade. PMID- 30398805 TI - Top 10 Facts You Should Know About Screening for Critical Congenital Heart Disease. PMID- 30398806 TI - Mississippi Perspective: Dermatologic Manifestations of Arsenic Poisoning. AB - A Mississippi perspective on arsenic poisoning is largely related to thousands of asthma patients cared for by one physician, Elmer D. Gay, MD, in the 1950s. The general medical uses of arsenic and its specific use in intractable asthma are reviewed along with the dermatologic manifestations of arsenic poisoning. PMID- 30398807 TI - Working for Cures in the 21st Century. PMID- 30398808 TI - Improper Use of MAPS by Office Personnel. PMID- 30398809 TI - Infghting, Backstabbing and Undermining...0h My! PMID- 30398810 TI - A Big Change - ADA Code Eliminates Specialty Exclusivity. PMID- 30398811 TI - Resolutions Accomplished! PMID- 30398812 TI - SPECIAL FEATURE. PEDIATRIC DENTISTRY. AB - There are approximately 2 million children living in the state of Michigan who will receive dental care with one of more than 5,500 MDA member dentists. Of these 5,500 MDA members, only approximately 100 are pediatric dentists.(1-3) Thus, it's safe to say that most children will find their dental homes in general dental offices. These general dentists will be providing preventive, diagnostic, and restorative care to most children under most circumstances. And with that in mind, it's of great importance that all dentists be comfortable providing high quality care to the majority of children, referring only a select group for care by a pediatric dentist. PMID- 30398813 TI - Antibiotics and Local Anesthetics: Drug Considerations for the Child Patient. AB - A primary concern of dental care for the child patient is patient safety. Antibiotics and local anesthetics are very commonly used in dental care, making it critical that providers take into account the special considerations when these drugs are used with the child patient. Considerations in medication selection, indications for use, appropriate and safe dosing, suitable prescribing and administration, and potential deleterious effects are discussed. An overview is provided to ensure proper use of antibiotics and local anesthetics for the pediatric patient. PMID- 30398814 TI - Supernumerary Teeth: Value-based Guidelines for Management. PMID- 30398815 TI - Associate Buy-Ins: What You Need to Know. PMID- 30398816 TI - Clinical Evaluation of All Ceramic Zirconia Framework Resin Bonded Bridges. AB - OBJECTIVE: To evaluate the clinical longevity of 58 adhesively bonded single unit yttria-stabilized tetragonal zirconia polycrystalline (Y-TZP) ceramic Resin Bonded Bridges (RBB). MATERIALS AND METHODS: Twenty six consecutive patients with at least one congenitally missing tooth in the maxilla or mandible were provided with 58 single unit Y-TZP RBBs. The cantilever RBBs were designed and milled using a CAD-CAM system to produce frameworks which were veneered using a glass ceramic material and cemented with a self-etching dual-cure resin cement. RESULTS: Following a mean follow up period of 36.2 months (maximum 62.3 months, minimum 25.4 months), 48 restorations remain in service with a survival rate of 82.7%. One anterior retainer fracture was encountered and no fractures of the posterior framework or ceramic were noted within the time frame reported. CONCLUSIONS: All ceramic Y-TZP RBBs replacing maxillary and mandibular teeth in the anterior and posterior areas demonstrated an 82.7% Kaplan Meier survival rate over 3 years, which was comparable to previously published survival rates for the non-perforated metal framework RBBs. CLINICAL IMPLICATIONS: Replacement of anterior or posterior teeth using single unit cantilevered RBBs using Y-TZP ceramics should be considered a viable restorative option with a high survival rate. PMID- 30398829 TI - Regulation of Ni-CNT Interaction on Mn-Promoted Nickel Nanocatalysts Supported on Oxygenated CNTs for CO2 Selective Hydrogenation. AB - Mn-promoted Ni nanoparticles (NPs) supported on oxygen-functionalized carbon nanotubes (CNTs) were synthesized for CO2 hydrogenation to methane. This novel metal-carbon catalytic system was characterized by both experimental and computational studies. An anomalous metal-support interaction mode (i.e., a higher temperature would lead to a weakened Ni-CNT interaction) was observed. Deep investigation confirmed that surface oxygen groups (SOGs) on CNTs played a key role in tuning the Ni-CNT interaction. We proposed that high calcination temperature would firstly lead to the decomposition of SOGs (>400 degrees C), then causing a loss of anchoring sites and the anchoring effect of SOGs on Ni NPs, thus cutting off the connection between interfacial Ni atoms and CNT body, resulting in the migration and coalescence of fine flat Ni NPs into larger sphere ones at 550 degrees C (geometric effect). Density functional theory calculation study clarified that this kind of anchoring effect stemmed from the formation of covalent bonding between the interfacial Ni atom and C or O elements of SOGs, causing the electrons to be transferred from Ni atoms to CNT support because of the intrinsic electronegativity of -COOH (electronic effect). Besides, Mn promotion notably boosts the activity compared with unpromoted catalysts, which was irrelevant to the size effect, but enhanced CO2 adsorption and conversion according to the result of CO2-temperature programmed desorption and transient response experiment. The optimized NiMn350 catalyst endowed with Mn promotion and robust Ni-CNT interaction showed both high activity and sintering resistance for more than 140 h. Our findings paved the way to reasonably design the metal-carbon catalyst with both high activity and stability. PMID- 30398830 TI - Structurally Engineered Hyperbranched NiCoP Arrays with Superior Electrocatalytic Activities toward Highly Efficient Overall Water Splitting. AB - Developing inexpensive transition-metal-based nanomaterials with high electrocatalytic activity is of significant necessity for electrochemical water splitting. In this study, we propose a controllable structural engineering strategy of constructing a hyperbranched architecture for highly efficient hydrogen evolution reaction/oxygen evolution reaction (HER/OER). Hyperbranched NiCoP architecture organized by hierarchical nanorod-on-nanosheet arrays is rationally prepared as a demonstration via a facile solvothermal and phosphorization approach. A strong synergistic benefit from the multiscale building blocks is achieved to enable outstanding electrocatalytic properties in an alkaline electrolyzer, including low HER and OER overpotentials of 71 and 268 mV at 10 mA cm-2, respectively, which significantly outperforms the counterparts of individual nanorods and nanosheets. The bifunctional catalysts also show highly efficient and durable overall water electrocatalysis with a small voltage of 1.57 V to drive a current density of 10 mA cm-2. The present study will open a new window to engineering hyperbranched architectures with exceptional electrocatalytic activities toward overall water splitting. PMID- 30398831 TI - Recyclable Polymeric Thin Films for the Selective Detection and Separation of Picric Acid. AB - Thin-film probes have been developed for the reversible detection and separation of picric acid (PA) with extreme sensitivity in aqueous media. The free radical copolymerization of dimethylacrylamide (DMA), benzophenone acrylamide (BPAM), and glycidyl methacrylate (GMA) with a feed ratio of 95:1:4 yielded [p(DMA- co-BPAM- co-GMA)] (P1). P1 was transformed to the final polymeric probe, P2, by a subsequent ring-opening reaction between N-(pyren-1-yl-methyl)propan-1-amine (Py PA) with the epoxide unit of P1. P2 exhibited rapid and selective sensing properties toward PA in aqueous media via turn-off fluorescence emission. The detection sensitivity was tuned precisely by varying the pH of the solution. After the immobilization of P2 on a quartz slide by spin-coating, followed by exposure to UV light, the resulting film exhibited an attogram-level detection limit toward PA. The photoinduced electron transfer together with an energy transfer process between PA and the pyrene units of P2 were maximized by the strong pi-pi stacking of pyrene units of P2, which, in turn, induced rapid exciton energy diffusion. Furthermore, the separation of PA from the mixture of the various nitroaromatic compounds by the P2 film was achieved. Whereas the detection process of PA was reversible and repeatable over multiple cycles, the P2 film could be recycled. PMID- 30398832 TI - Electron Dose-Controlled Formation, Growth, and Assembly of Nanoclusters and Nanoparticles from Aurophilic Au(I)-Thiolate Ensemble on Surfaces. AB - The ability to precisely control electron irradiation-induced formation, growth, and assembly of nanoclusters or nanoparticles on a solid surface is important for design and creation of catalytically or chemically active surface sites and interfaces free from chemical reducing agents. Here, we show the results of an investigation of the electron dose-controlled formation, growth, and assembly of nanoclusters and nanoparticles in a molecularly assembled thin film of Au(I) thiolate motifs on a substrate, highlighting an in situ monitoring of the evolution of morphology under controlled electron dose. With aurophilic motifs of Au(I)-thiolate being confined by electrostatic interactions, the sizes of Au nanoclusters and nanoparticles were shown to increase with electron dose, revealing a propensity of a string alignment of the grown nanoclusters and nanoparticles. This growth preference to one-dimensional assembly is supported by the analysis of the surface reaction kinetics in terms of the surface density of electron dose for the growth of the nanoclusters and nanoparticles. The electron dose-controlled size-focusing and directional assembly of nanoclusters and nanoparticles may be exploited as new strategy for the precise control of nanoclusters or nanoparticles and their assemblies on solid surfaces not only free from chemical reducing agent but also with the ability of visual monitoring of the morphological evolution during growth. PMID- 30398834 TI - 3D Printed Graphene Electrodes' Electrochemical Activation. AB - Three-dimensional (3D) printing technologies are emerging as an important tool for the manufacturing of electrodes for various electrochemistry applications. It has been previously shown that metal 3D electrodes, modified with metal oxides, are excellent catalysts for various electrochemical energy and sensing applications. However, the metal 3D printing process, also known as selective laser melting, is extremely costly. One alternative to metal-based electrodes for the aforementioned electrochemical applications is graphene-based electrodes. Nowadays, the printing of polymer-/graphene-based electrodes can be carried out in a matter of minutes using cheap and readily available 3D printers. Unfortunately, these polymer/graphene electrodes exhibit poor electrochemical activity in their native state. Herein, we report on a simple activation method for graphene/polymer 3D printed electrodes by a combined solvent and electrochemical route. The activated electrodes exhibit a dramatic increase in electrochemical activity with respect to the [Fe(CN)6]4-/3- redox couple and the hydrogen evolution reaction. Such in situ activation can be applied on-demand, thus providing a platform for the further widespread utilization of 3D printed graphene/polymer electrodes for electrochemistry. PMID- 30398833 TI - Solution-Based Property Tuning of Black Phosphorus. AB - The air instability of black phosphorus (BP) severely hinders the development of its electronic and optoelectronic applications. Although a lot of effort has been made to passivate it against degradation in ambient conditions, approaches to further manipulate the properties of passivated BP are still very limited. Herein, we report a simple and low-cost chemical method that can achieve BP passivation and property tailoring simultaneously. The method is conducted by immersing a BP sample in the solution containing both 2,2,6,6 tetramethylpiperidinyl- N-oxyl (TEMPO) and triphenylcarbenium tetrafluorobor in a mixture of water and acetone (v/v = 1:1). After the treatment, the BP sample is functionalized with TEMPO, which not only efficiently passivates BP but also p dopes BP to a degenerated density level of 1013 cm-2. The performance of the BP field effect transistor is improved after functionalization with a high Ion/ Ioff ratio of 106 and carrier mobility of 881.5 cm2/(V.s). The functionalization induced doping also significantly reduces the contact resistance between BP and the Cr/Au electrode to 0.97 kOmega.MUm. Additionally, we observe a great reduction of BP electrical and optical anisotropies after functionalization. This chemical functionalization method provides a viable route to simultaneously passivate and tune the properties of BP. PMID- 30398835 TI - Facile and Large-Area Preparation of Polypyrrole Film for Low-Haze Transparent Supercapacitors. AB - The transparent flexible supercapacitor is considered to be the key energy storage component for the development of wearable and fully transparent electronic devices. However, the current transparent supercapacitor faces the low haze challenge, which is essential for the high-definition visualization in transparent electronics. Herein, we developed a facile interfacial polymerization approach for the large-area preparation of flexible polypyrrole/polyethylene terephthalate (PPy/PET) transparent conductive films in a cost-effective way. The PPy/PET film exhibits a highly uniform morphology and a low haze level of 1.40% (corresponding to high definition) as well as negligible resistance changing under an ultrasmall bending radius. The sandwich-structured, large-area, transparent supercapacitor assembled based on the PPy/PET films also keeps a similar low haze level. A facile N, N-dimethylformamide etchant-written strategy on the PPy/PET film is developed to fabricate the patterned micro-supercapacitors (MSCs) in series in scalable area, which show a low haze level of 1.66% and a high transparency of 70.2%. Significantly, the low-haze MSC possesses high energy storage capacity and presents almost no capacitance loss at an extreme bending state. This work demonstrates a facile preparation of large-area and low-haze transparent flexible supercapacitors and also enlightens broad interests in their potential integrity toward the fully transparent wearable electronics. PMID- 30398836 TI - High-Performance and Multifunctional Colorimetric Humidity Sensors Based on Mesoporous Photonic Crystals and Nanogels. AB - Colorimetric sensors, as a key branch of the application of photonic crystals (PCs), brings enthusiasm to scientists to do research. Here, simple mesoporous and structurally colored one-dimensional photonic crystals (1DPCs) constructed by alternating assembly of poly(acrylamide- N,N'-methylene bis(acrylamide)) (P(AM MBA)) nanogels and TiO2 nanoparticles are reported as high-performance colorimetric humidity sensors. The sensors with bright colors display rapid response to relative humidity (RH) change and reach sensing balance in 0.5 s. By varying RH from 47.0% to 89.3%, stopband of a sensor changes from 426 to 668 nm, almost spanning the whole visible range. Meanwhile, visual sensing of RH possesses good reversibility and repeatability. Moreover, the sensors with delicate patterns are facilely fabricated by partial UV photodegradation of the polymer layers with nano TiO2 as catalyst. The delicate patterns and backgrounds show different colors and change color simultaneously and quickly by varying the ambient humidity. Accurate QR code pattern is also realized on the PC sensor; it is found successful reading of the data is only achieved by increasing RH to realize high color contrast between the code and background. Given their excellent properties, the porous hybrid PCs are promising as high-performance humidity sensors with potential display, decoration, information-storage, and encryption functions. PMID- 30398837 TI - High-Flux Oil/Water Separation with Interfacial Capillary Effect in Switchable Superwetting Cu(OH)2@ZIF-8 Nanowire Membranes. AB - Highly ordered architectures with roughness and porous surface are the key challenges toward developing smart superwetting membranes. We prepared switchable superwetting Cu(OH)2@ZIF-8 core/shell nanowire membranes for high-flux oil/water separation as well as simultaneous heavy-metal ions removal in one step. The well defined Cu(OH)2@ZIF-8 core/shell nanowire grown on copper mesh with average length of ca. 15 MUm and diameter of ca. 162 nm exhibits high water contact angle (CA) of ca. 153 +/- 0.6 degrees . After modified by ethanol, the membrane holds the reverse superwettability with oil (dichloromethane as an example) CA of ca. 155 +/- 0.8 degrees underwater. The separation efficiencies of the membranes are higher than that of 97.2% with a remarkable flux rate higher than 90 000 L m-2 h 1 for the immiscible oil/water mixture. And the removal efficiency for Cr3+ ions at 10 ppb can arrive at 99.2 wt % in the toluene-in-water emulsion. The high performances of the smart superwetting membranes can be attributed to the interfacial capillary effects of the hierarchical Cu(OH)2@ZIF-8 core/shell nanostructures. This work may provide a new insight into the design of smart superwetting surfaces for oil/water separation and target adsorption in one step. PMID- 30398838 TI - Tungsten Carbide and Cobalt Modified Nickel Nanoparticles Supported on Multiwall Carbon Nanotubes as Highly Efficient Electrocatalysts for Urea Oxidation in Alkaline Electrolyte. AB - The tungsten carbide and cobalt-modified Ni-based catalyst [Ni-Co-WC/multiwall carbon nanotubes (MWCNTs)], synthesized through a sequential impregnation method, was evaluated for the urea electrooxidation in alkaline electrolyte to reduce the overpotential and increase the current density simultaneously. The as-prepared Ni Co-WC/MWCNTs catalyst was characterized using scanning electron microscopy-EDX, transmission electron microscopy, X-ray diffraction, and X-ray photoelectron spectroscopy. Characterization results indicate that Ni, Co, and WC nanoparticles are uniformly distributed on the MWCNTs. For the Ni-Co-WC/MWCNT electrode, the maximum current density for urea electrooxidation is more than 4 times higher than that of the Ni/C catalyst, with a reduction of 120 mV in the onset overpotential. In addition, the Ni-Co-WC/MWCNTs catalyst also shows an enhanced catalytic stability with a continuous higher current density under steady-state conditions. PMID- 30398839 TI - Coloration of Liquid-Metal Soft Robots: From Silver-White to Iridescent. AB - Gallium-based room-temperature liquid metals are becoming increasingly attractive and outstanding candidates for designing soft robots because of their remarkable electrical conductivity, superior flexibility, excellent stability, and low toxicity. However, the color of liquid metals is limited to shiny silver-white with high reflectivity, which is not helpful for camouflage, like that found in natural soft animals such as cephalopods. Herein, a biomimetic chromatic liquid metal soft robot with tunable structural colors is reported. Colors ranging from white to gold and black appear on the surface of liquid metal when placed on a graphite substrate and mixed with Al foil in an electrolyte solution. A stable liquid-metal functional material with a rainbow-like appearance is realized under the regulation of an electric field. Further composition and structure characterization reveals that it is a nanoscale Ga2O3 film that displays the multicolor characteristic. The nanostructural film indicates that light scattering of Ga2O3 occurs when the liquid metal is on the graphite surface, and thin-film interference triggers iridescence when the liquid metals are subjected to electrolysis, respectively. These results provide a route to create kaleidoscopic and colorful liquid metals, which are expected to have diverse applications, especially in reinforcing soft robot design with intelligent camouflage function. PMID- 30398840 TI - Liquid Intrusion into Zeolitic Imidazolate Framework-7 Nanocrystals: Exposing the Roles of Phase Transition and Gate Opening to Enable Energy Absorption Applications. AB - Liquid intrusion into zeolitic imidazolate framework 7 (ZIF-7) has been observed for the first time. Among the three typical phases of ZIF-7, we discover that only the guest-free ZIF-7-II structure can be intruded by mechanical pressure, and intriguingly, this pressurized liquid intrusion behavior is detected only in nanocrystals, indicating the crystal size effect. Because of its unique combination of non-outflow property and high intrusion pressure, water intrusion into ZIF-7-II generates a marked energy dissipation capacity of ~2 J/g despite its limited pore volume. We present several strategies that can be easily implemented to tune its intrusion pressure and energy dissipation and accomplish material reusability. Remarkably, we found that the pore cavities of ZIF-7-II can accommodate water molecules without experiencing any phase transition, which is entirely different from other solvents whose incorporation will trigger a spontaneous conversion into ZIF-7-I. Our pressure-vs-volume data further reveal that the process of water infiltration and retainment is controlled by the gate opening/closing mechanism, which has enabled us to probe the viscoelasticity of ZIF-7 via cyclic liquid intrusion experiments. This study has deepened our understanding of the time-dependent mechanical properties of ZIFs and shed new light on the structural flexibility central to the novel applications of metal organic framework materials. PMID- 30398841 TI - Selective Sequestration of Aromatics from Aqueous Mixtures with Sugars by Hydrophobic Molecular Calixarene Cavities Grafted on Silica. AB - The separation of aromatic contaminants from sugar-aromatic aqueous mixtures is required in second-generation biorefineries because aromatic compounds deactivate (bio)catalysts typically involved in upgrading lignocellulosic biomass to fuels and chemicals. This separation remains challenging, however, because of the degree of molecular recognition needed to sequester dilute aromatic impurities from concentrated sugar streams. Herein, we demonstrate that hydrophobic cavities of p- tert-butylcalix[4]arene macrocycles grafted on amorphous silica (calix/SiO2) perform this separation selectively and efficiently by acting as selective molecular hosts that adsorb aromatic compounds (5 hydroxymethylfurfural, vanillin, and vanillic acid) while excluding monomeric sugar (glucose chosen as a prototypical model) in aqueous mixtures. By comparing calix/SiO2 to a range of organically modified SiO2 surfaces and other porous adsorbents, we demonstrate that the organization of hydrophobic functional groups within discrete nests consisting of calixarene cavities is crucial for facilitating the adsorption of aromatics. Density functional theory calculations of the host-guest complex indicate that adsorption is brought about by weak dispersive (van der Waals) interactions between tert-butyl upper-rim substituents in calixarene hosts and aromatic guests. Calix/SiO2 can be repeatedly reused, demonstrating its viability as an adsorbent within a continuous biorefining process. These calix/SiO2 adsorbents expand the palette of materials available for selective sugar-aromatic separations, which until now have been limited to pyrene-based sites of metal-organic framework NU-1000, and demonstrate that sites consisting of relatively simple hydrophobic tert-butyl substituents organized around a hemispherical molecular cavity provide a sufficient degree of molecular recognition for performing this separation selectively. PMID- 30398842 TI - Ligandless Surfactant-Assisted Emulsification Microextraction and Total Reflection X-ray Fluorescence Analysis for Ionic Gold Traces Quantification in Aqueous Samples and Extracts Containing Gold Nanoparticles. AB - Due to the current use of gold nanoparticles (AuNPs) in many fields and their potential dissolution/transformation into ionic gold (Au3+), there is an increasing interest in methods enabling the discrimination of Au3+ from AuNPs in environmental samples. In this contribution, the combination of a novel ligandless surfactant-assisted emulsification microextraction procedure (LL SAEME) with total reflection X-ray fluorescence spectrometry (TXRF) is proposed for the isolation and preconcentration of Au3+ in aqueous extracts containing AuNPs. The method is fast, simple, and involves low operating costs and low consumption of reagents in comparison with other spectroscopic methods. It is based on the formation of a gold hydrophobic compound with the cationic surfactant cetyltrimethylammonium bromide (CTAB) which is extracted in a few microliters of 1,2-dichloroethane. After shaking the solution by hand for 5 s, the mixture is centrifuged for 3 min at 2000 rpm and 5 MUL of the organic phase containing the gold ions are deposited on a quartz reflector to carry out the TXRF analysis. Using this approach, the limit of detection for gold was 0.05 MUg/L and a good linearity ( R2 > 0.99) was assessed in the range of 1-500 MUg/L. Moreover, no matrix effects were observed when ionic gold was extracted from different types of water such as river, mineral, and tap waters as well as in synthetic aqueous solutions containing other ions, AuNPs, and dissolved organic matter. As a study case, the developed LL-SAEME-TXRF method was applied to monitor AuNPs stability in soils in laboratory-controlled experiments by means of Au3+ monitoring over time. PMID- 30398843 TI - All-Poly(ionic liquid) Membrane-Derived Porous Carbon Membranes: Scalable Synthesis and Application for Photothermal Conversion in Seawater Desalination. AB - Herein, we introduce a straightforward, scalable, and technologically relevant strategy to manufacture charged porous polymer membranes (CPMs) in a controllable manner. The pore sizes and porous architectures of CPMs are well-controlled by rational choice of anions in poly(ionic liquid)s (PILs). Continuously, heteroatom doped hierarchically porous carbon membrane (HCMs) can be readily fabricated via morphology-maintaining carbonization of as-prepared CPMs. These HCMs, as photothermal membranes, exhibited excellent performance for solar seawater desalination, representing a promising strategy to construct advanced functional nanomaterials for portable water production technologies. PMID- 30398844 TI - pH-Sensitive Polymers as Dynamic Mediators of Barriers to Nucleic Acid Delivery. AB - The nonviral delivery of exogenous nucleic acids (NA) into cells for therapeutic purposes has rapidly matured into tangible clinical impact. Synthetic polymers are particularly attractive vectors for NA delivery due to their relatively inexpensive production compared to viral alternatives and their highly tailorable chemical properties; indeed, many preclinical investigations have revealed the primary biological barriers to nonviral NA delivery by systematically varying polymeric material properties. This review focuses on applications of pH sensitive chemistries that enable polymeric vectors to serially address multiple biological barriers to NA delivery. In particular, we focus on recent innovations with in vivo evaluation that dynamically enable colloidal stability, cellular uptake, endosomal escape, and nucleic acid release. We conclude with a summary of successes to date and projected areas for impactful future research. PMID- 30398845 TI - Identification and Molecular Characterization of Peroxisome Proliferator Activated Receptor delta as a Novel Target for Covalent Modification by 15-Deoxy Delta12,14-prostaglandin J2. AB - PPARdelta belongs to the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors. Upon activation by an agonist, PPARdelta controls a variety of physiological processes via regulation of its target genes. 15-Deoxy Delta12,14-prostaglandin J2 (15d-PGJ2) is a cyclopentenone prostaglandin that features an electrophilic, alpha,beta-unsaturated ketone (an enone) in the cyclopentenone ring. Many of 15d-PGJ2's biological effects result from covalent interaction between C9 and the thiol group of a catalytic cysteine (Cys) in target proteins. In this study, we investigated whether 15d-PGJ2 activates PPARdelta by forming a covalent adduct. Our data show that 15d-PGJ2 activates PPARdelta's transcriptional activity through formation of a covalent adduct between its endocyclic enone at C9 and Cys249 in the receptor's ligand-binding domain. As expected, no adduct formation was seen following a Cys-to-Ser mutation at residue 249 (C249S) of PPARdelta or with a PGD2/PGJ2 analogue that lacks the electrophilic C9. Furthermore, the PPARdelta C249S mutation weakened induction of the receptor's DNA binding activity by 15d-PGJ2, which highlights the biological significance of our findings. Calculated chemical properties as well as data from molecular orbital calculations, reactive molecular dynamics simulations, and intrinsic reaction coordinate modeling also supported the selectivity of 15d PGJ2's C9 toward PPARdelta's Cys thiol. In summary, our results provide the molecular, chemical, and structural basis of 15d-PGJ2-mediated PPARdelta activation, designating 15d-PGJ2 as the first covalent PPARdelta ligand to be identified. PMID- 30398846 TI - Mechanistic Origin of the High Performance of Yolk@Shell Bi2S3@N-Doped Carbon Nanowire Electrodes. AB - High-performance lithium-ion batteries are commonly built with heterogeneous composite electrodes that combine multiple active components for serving various electrochemical and structural functions. Engineering these heterogeneous composite electrodes toward drastically improved battery performance is hinged on a fundamental understanding of the mechanisms of multiple active components and their synergy or trade-off effects. Herein, we report a rational design, fabrication, and understanding of yolk@shell Bi2S3@N-doped mesoporous carbon (C) composite anode, consisting of a Bi2S3 nanowire (NW) core within a hollow space surrounded by a thin shell of N-doped mesoporous C. This composite anode exhibits desirable rate performance and long cycle stability (700 cycles, 501 mAhg-1 at 1.0 Ag-1, 85% capacity retention). By in situ transmission electron microscopy (TEM), X-ray diffraction, and NMR experiments and computational modeling, we elucidate the dominant mechanisms of the phase transformation, structural evolution, and lithiation kinetics of the Bi2S3 NWs anode. Our combined in situ TEM experiments and finite element simulations reveal that the hollow space between the Bi2S3 NWs core and carbon shell can effectively accommodate the lithiation-induced expansion of Bi2S3 NWs without cracking C shells. This work demonstrates an effective strategy of engineering the yolk@shell-architectured anodes and also sheds light onto harnessing the complex multistep reactions in metal sulfides to enable high-performance lithium-ion batteries. PMID- 30398847 TI - Resonance-Frequency Modulation for Rapid, Point-of-Care Ebola-Glycoprotein Diagnosis with a Graphene-Based Field-Effect Biotransistor. AB - Recent outbreaks of Ebola-virus infections in several countries demand a rapid point-of-care (POC)-detection strategy. This paper reports on an innovative pathway founded on electronic-resonance-frequency modulation to detect Ebola glycoprotein (GP), on the basis of a carrier-injection-trapping-release-transfer mechanism and the standard antibody-antigen-interaction principle within a dielectric-gated reduced graphene oxide (rGO) field-effect transistor (GFET). The sensitivity of Ebola detection can be significantly enhanced by monitoring the device's electronic-resonance frequency, such as its inflection frequency ( fi), where the phase angle reaches a maximum (thetamax). In addition to excellent selectivity, a sensitivity of ~36-160% and ~17-40% for 0.001-3.401 mg/L Ebola GP can be achieved at high and low inflection-resonance frequencies, respectively, which are several orders of magnitude higher than the sensitivity from other electronic parameters (e.g., resistance-based sensitivity). Using equivalent circuit modeling for contributions from channel and contact, analytical equations for resonance shifts have been generalized. When matching with the incoming ac measurement signal, electronic resonance from the phase-angle spectrum evolves from various relaxation processes (e.g., trap and release of injected charges at surface-trap sites of the channel-gate oxide and channel-source or drain interfaces) that are associated with a characteristic emission frequency. Using charge-relaxation dynamics, a high-performance bio-FET sensing platform for healthcare and bioelectronic applications is realized through resonance shifting. PMID- 30398848 TI - Polarity Control in Growing Highly Ga-Doped ZnO Nanowires with the Vapor-Liquid Solid Process. AB - Surface behavior modification by forming surface-transparent conductive nanowires (NWs) is an important technique for many applications, particularly when the polarities of the NWs can be controlled. The polarities of Ga-doped ZnO (GaZnO) NWs grown on templates of different polarities under different growth conditions are studied for exploring a polarity control growth technique. The NWs are formed on Ga- and N-face GaN through the vapor-liquid-solid (VLS) process using Ag nanoparticles as growth catalyst. The NWs grown on templates of different polarities under the Zn- (O-) rich conditions are always Zn (O) polar. During the early stage of NW growth, because the lattice sizes among different nucleation islands formed at the triple-phase line are quite different, high-density planar defects are produced when lateral growths from multiple nucleation islands form a GaZnO double bilayer. In this situation, frequent domain inversions occur, and GaZnO polarity is unstable. Under the Zn- (O-) rich conditions, because the lateral growth rate of GaZnO in the Zn- (O-) polar structure is higher due to more available dangling bonds, the growth of the Zn- (O-) polar structure dominates NW formation such that the NW eventually becomes Zn (O) polar irrespective of the polarity of the growth template. Therefore, the polarity of a doped-ZnO NW can be controlled simply by the relative supply rates of Zn and O during VLS growth. PMID- 30398849 TI - Lipase-Catalyzed Regioselective Synthesis of Dextrin Esters. AB - Four lipase enzymes were investigated as catalysts in the synthesis of regioselectively monosubstituted dextrin esters from dextrin and vinyl acetate. An immobilized lipase enzyme (Lipozyme TL IM) exhibited the highest activity. This enzyme showed regioselective substitution of the dextrin at the primary hydroxyl group (C6 position) under optimal conditions (60 degrees C for 24 h, using a 1:3 molar ratio of glucose unit/vinyl acetate and 2.5 U/mL enzyme dosage in an organic solvent). To compare the reactivity of other vinyl esters, monosubstituted dextrin esters (degrees of substitution [DS] ~ 1) with varying side-chain lengths (C2-C12) were synthesized. With increasing side-chain length, the initial catalytic activity of the lipase enzyme decreased, resulting in lower DS values. However, the final DS values of the monosubstituted dextrin esters with longer side chains were higher than those of the shorter-chain analogues, because of an increase in affinity between the substrate and acyl donor. PMID- 30398850 TI - Atomic-Thick TiO2(B) Nanosheets Decorated with Ultrafine Co3O4 Nanocrystals As a Highly Efficient Catalyst for Lithium-Oxygen Battery. AB - Development of highly efficient catalysts based on transition metal oxides (TMOs) is desirable and remains a big challenge for lithium-oxygen (Li-O2) batteries. In the present work, atomic-thick TiO2(B) nanosheets decorated with ultrafine Co3O4 nanocrystals (Co3O4-TiO2(B)) were synthesized and utilized as cathode catalyst in Li-O2 batteries by designing a hybrid and inducing oxygen vacancies. The XPS characterization results suggested that the introduction of Co3O4 nanocrystals could induce numerous oxygen vacancies in the TiO2(B) nanosheets through Co doping in the hybrid catalyst. The subsequent electrochemical experiments indicated that the Li-O2 batteries with the prepared hybrid catalysts showed high specific capacity (11000 mAhg-1), and good cycling stability (200 cycles at a limited capacity of 1000 mAhg-1) with low polarization (above 2.7 V for discharge medium voltage and below 4.0 V for charge medium voltage within 80 cycles). Furthermore, a possible working mechanism was proposed for a better understanding of the high performance of Co3O4-TiO2(B) catalysts for the Li-O2 batteries. This work also provided new insights into designing efficient catalysts through interface engineering between 2D (two-dimensional) TMOs and 0D (zero-dimensional) TMOs for Li-O2 batteries or other catalysis-related fields. PMID- 30398851 TI - Predictive Model for the Electrical Transport within Nanowire Networks. AB - Thin networks of high aspect ratio conductive nanowires can combine high electrical conductivity with excellent optical transparency, which has led to a widespread use of nanowires in transparent electrodes, transistors, sensors, and flexible and stretchable conductors. Although the material and application aspects of conductive nanowire films have been thoroughly explored, there is still no model which can relate fundamental physical quantities, like wire resistance, contact resistance, and nanowire density, to the sheet resistance of the film. Here, we derive an analytical model for the electrical conduction within nanowire networks based on an analysis of the parallel resistor network. The model captures the transport characteristics and fits a wide range of experimental data, allowing for the determination of physical parameters and performance-limiting factors, in sharp contrast to the commonly employed percolation theory. The model thus constitutes a useful tool with predictive power for the evaluation and optimization of nanowire networks in various applications. PMID- 30398852 TI - Electric Single-Molecule Hybridization Detector for Short DNA Fragments. AB - By combining DNA nanotechnology and high-bandwidth single-molecule detection in nanopipets, we demonstrate an electric, label-free hybridization sensor for short DNA sequences (<100 nucleotides). Such short fragments are known to occur as circulating cell-free DNA in various bodily fluids, such as blood plasma and saliva, and have been identified as disease markers for cancer and infectious diseases. To this end, we use as a model system an 88-mer target from the RV1910c gene in Mycobacterium tuberculosis, which is associated with antibiotic (isoniazid) resistance in TB. Upon binding to short probes attached to long carrier DNA, we show that resistive-pulse sensing in nanopipets is capable of identifying rather subtle structural differences, such as the hybridization state of the probes, in a statistically robust manner. With significant potential toward multiplexing and high-throughput analysis, our study points toward a new, single-molecule DNA-assay technology that is fast, easy to use, and compatible with point-of-care environments. PMID- 30398853 TI - Facile Preparation of Epoxide-Functionalized Surfaces via Photocurable Copolymer Coatings and Subsequent Immobilization of Iminodiacetic Acids. AB - Herein, we report a simple coat/cure preparation of epoxide-functionalized surfaces using a photocurable copolymer technology. The photocurable copolymer, poly(glycidyl methacrylate- co-butyl acrylate- co-4-benzoylphenyl methacrylate) (GBB), was synthesized by single electron transfer-living radical polymerization (SET-LRP). The epoxide content in the copolymer was tuned by controlling the content of glycidyl methacrylate. Three copolymers, GBB(1), GBB(2), and GBB(3), with epoxide contents of 22, 63, and 91 mol %, respectively, were cast onto polypropylene films and photocured by UV-light exposure. Subsequently, iminodiacetic acids (IDA) were immobilized onto the GBB-coated materials via a ring-opening reaction. The IDA-functionalized coatings GBB(1)-IDA, GBB(2)-IDA, and GBB(3)-IDA presented IDA contents of 1.47 +/- 0.08, 18.67 +/- 1.46, and 49.05 +/- 2.88 nmol/cm2, respectively, which increased as the epoxide content increased. The IDA-functionalized GBB coatings exhibited metal chelating capability toward transition metal ions (e.g., iron and copper). The reported photocurable copolymer technology offers a facile and tunable preparation of epoxide-functionalized surfaces, with potential extended applications in biopatterning, active packaging, and nanotechnology. PMID- 30398854 TI - Solid-Phase Epitaxial Growth of an Alumina Layer Having a Stacking-Mismatched Domain Structure of the Intermediate gamma-Phase. AB - Solid-phase epitaxy (SPE), a solid-state phase transition of materials from an amorphous to a crystalline phase, is a convenient crystal growing technique. In particular, SPE can be used to grow alpha-Al2O3 epitaxially with a novel structure that provides an effective substrate for improved performance of light emitting diodes (LEDs). However, the inevitable two-step phase transformation through the gamma-Al2O3 phase hinders the expected improved crystallinity of alpha-Al2O3, and thereby further enhancement of LED performance. Herein, we provide a fundamental understanding of the SPE growth mechanism from amorphous to metastable gamma-Al2O3 using transmission electron microscopy (TEM) and density functional theory (DFT) calculations. The nanobeam precession electron diffraction technique enabled clear visualization of the double-positioning domain distribution in the SPE gamma-Al2O3 film and emphasized the need for careful selection of the viewing directions for any investigation of double positioning domains. Void and stacking fault defects further investigated by high resolution scanning TEM (STEM) analyses revealed how double-positioning domains and other SPE growth behaviors directly influence the crystallinity of SPE films. Additionally, DFT calculations revealed the origins of SPE growth behavior. The double-positioning gamma-Al2O3 domains randomly nucleate from the alpha-Al2O3 substrate regardless of the alpha-Al2O3 termination layer, but the large energy requirement for reversal of the gamma-Al2O3 stacking sequence prevents it from switching the domain type during the crystal growth. We expect that this study will be useful to improve the crystallinity of SPE gamma- and alpha-Al2O3 films. PMID- 30398855 TI - Reductive Cleavage of Sulfoxide and Sulfone by Two Radical S-Adenosyl-l methionine Enzymes. AB - Sulfoxides and sulfones are commonly found in nature as a result of thioether oxidation, whereas only a very few enzymes have been found to metabolize these compounds. Utilizing the strong reduction potential of the [4Fe-4S] cluster of radical S-adenosyl-l-methionine (SAM) enzymes, we herein report the first enzyme catalyzed reductive cleavage of sulfoxide and sulfone. We show two radical SAM enzymes, tryptophan lyase NosL and the class C radical SAM methyltransferase NosN, are able to act on a sulfoxide SAHO and a sulfone SAHO2, both of which are structurally similar to SAM. NosL cleaves all of the three bonds (i.e., S-C(5'), S-C(gamma), and S-O) connecting the sulfur center of SAHO, with a preference for S-C(5') bond cleavage. Similar S-C cleavage activity was also found for SHAO2, but no S-O cleavage was observed. In contrast to NosL, NosN almost exclusively cleaves the S-C(5') bonds of SAHO and SAHO2 with much higher efficiencies. Our study provides valuable insights into the [4Fe-4S] cluster-mediated reduction reactions and highlights the remarkable catalytic promiscuity of radical SAM enzymes. PMID- 30398856 TI - Film-Based Fluorescent Sensor for Monitoring Ethanol-Water-Mixture Composition via Vapor Sampling. AB - In situ, on line, noncontact, and fast monitoring of the compositions of ethanol water mixtures via vapor-phase sampling has remained a challenge for years. In this work, we report for the first time a film-based fluorescent sensor showing unprecedented ability to discriminate the compositions of ethanol-water mixtures. Importantly, ethanol contents in the mixtures can vary from 0 to 100% (v/v), the response time is less than 2 s, and the sensing is fully reversible. More importantly, the monitoring was performed via vapor-phase sampling, avoiding sample contamination. The principle behind it is ascribed to the big difference in the fluorescent quantum yield of the sensing unit, a newly designed and synthesized monosubstituted fluorescent o-carborane derivative (ZPCarb), in the two solvents. In addition, the sensor as developed was successfully used for the determination of ethanol contents in four commercial liquors, suggesting its potential application in the quality control of beverages, in monitoring fermentation processes, and in other processes. PMID- 30398857 TI - Effects of Modified DATEMs with Different Alkyl Chain Lengths on Improving Oxidative and Physical Stability of 70% Fish Oil-in-Water Emulsions. AB - The objective of this study was to produce oxidatively and physically stable 70% fish oil-in-water emulsions by combined use of sodium caseinate (CAS), commercial diacetyl tartaric acid esters of mono- and diglycerides (DATEM), and modified DATEM. First, the optimal formula was determined using DATEM and CAS. Subsequently, modified DATEMs (DATEM C12 and DATEM C14) were designed for investigating both the effects of different alkyl chain lengths and caffeic acid conjugation to the emulsifier on physical and oxidative stability of the emulsions. Emulsions produced with modified DATEMs showed better oxidative stability compared with emulsion using commercial DATEM plus an equivalent amount of free caffeic acid, confirming the advantage of having antioxidant covalently attached to the emulsifier. Results indicated that DATEM_C14 replaced more CAS compared with DATEM_C12 from the interface in 70% fish oil-in-water emulsion. Emulsions produced with DATEM_C14 had significantly decreased amounts of primary and secondary oxidation products compared with emulsions using DATEM_C12. PMID- 30398858 TI - Phytotoxic ent-Isopimarane-Type Diterpenoids from Euphorbia hylonoma. AB - Thirteen new ent-isopimarane-type diterpenoids, 1-10 and 14-16, and seven known diterpenoids, 11-13 and 17-20, were isolated from the roots of Euphorbia hylonoma. Among these compounds, four pairs of C-12 epimers (1 vs 2, 4 vs 5, 12 vs 13, and 14 vs 15) were identified. The structures of the new diterpenoids were elucidated using spectroscopic data analyses, electronic circular dichroism, and single-crystal X-ray diffraction data. The phytotoxic effects of compounds 1-20 on the growth of the roots and shoots of Poa annua and Festuca arundinacea seedlings were evaluated. Among the tested diterpenoids, 18 was the most active for inhibiting the growth of P. annua seedlings, and this compound was as active as glyphosate. PMID- 30398859 TI - Engineering Improved Antiphosphotyrosine Antibodies Based on an Immunoconvergent Binding Motif. AB - Phosphotyrosine (pY) is one of the most highly studied posttranslational modifications that is responsible for tightly regulating many signaling pathways in eukaryotes. Pan-specific pY antibodies have emerged as powerful tools for understanding the role of these modifications. Nevertheless, structures have not been reported for pan-specific pY antibodies, greatly impeding the further development of tools for integrating this ubiquitous posttranslational modification using structure-guided designs. Here, we present the first crystal structures of two widely utilized pan-specific pY antibodies, PY20 and 4G10. The two antibodies, although developed independently from animal immunizations, have surprisingly similar modes of recognition of the phosphate group, implicating a generic binding structure among pan-specific pY antibodies. Sequence alignments revealed that many pY binding residues are predominant in the mouse V germline genes, which consequently led to the convergent antibodies. On the basis of the convergent structure, we designed a phage display library by lengthening the CDR L3 loop with the aid of computational modeling. Panning with this library resulted in a series of 4G10 variants with 4 to 11-fold improvements in pY binding affinities. The crystal structure of one improved variant showed remarkable superposition to the computational model, where the lengthened CDR-L3 loop creates an additional hydrogen bond indirectly bound to the phosphate group via a water molecule. The engineered variants exhibited superior performance in Western blot and immunofluorescence. PMID- 30398860 TI - Probing Antibody Binding to Canine Parvovirus with Charge Detection Mass Spectrometry. AB - There are many techniques for monitoring and measuring the interactions between proteins and ligands. Most of these techniques are ensemble methods that can provide association constants and in some cases stoichiometry. Here we use charge detection mass spectrometry (CDMS), a single particle technique, to probe the interactions of antigen binding fragments (Fabs) from a series of antibodies with the canine parvovirus (CPV) capsid. In addition to providing the average number of bound Fabs as a function of Fab concentration (i.e., the binding curve), CDMS measurements provide information about the distribution of bound Fabs. We show that the distribution of bound ligands is much better at distinguishing between different binding models than the binding curve. The binding of Fab E to CPV is a textbook example. A maximum of 60 Fabs bind and the results are consistent with a model where all sites have the same binding affinity. However, for Fabs B, F, and 14, the distributions can only be fit by a model where there are distinct virus subpopulations with different binding affinities. This behavior can be distinguished from a situation where all CPV particles are identical, and each particle has the same distribution of sites with different binding affinities. The different responses to viral heterogeneity can be traced to the Fab binding sites. A comparison of Fab binding to new and aged CPV capsids reveals that a post-translational modification at the binding site for Fab E (M569) probably reduces the binding affinity. PMID- 30398861 TI - Evolutionary Effects on Bound Substrate pKa in Dihydrofolate Reductase. AB - In the present study, we address the effect of active site structure and dynamics of different dihydrofolate reductase (DHFR) isoforms on the pKa of the bound substrate 7,8-dihydrofolate, in an attempt to understand possible evolutionary trends. We apply a hybrid QM/MM free energy perturbation method to estimate the pKa of the N5 position of the bound substrate. We observe a gradual increase in N5 basicity as we move from primitive to more evolved DHFR isoforms. Structural analysis of these isoforms reveals a gradual sequestering of water molecules from the active site in the more evolved enzymes, thereby modulating the local dielectric environment near the substrate. Furthermore, the present study reveals a clear correlation between active site hydration and the N5 pKa of the substrate. We emphasize the role of the M20 loop in controlling the active site hydration level, via a pre-organized active site with a more hydrophobic environment and reduced loop flexibility as evolution progresses from bacterial to the human enzyme. PMID- 30398862 TI - Understanding Molecular Drivers of Melanin Binding To Support Rational Design of Small Molecule Ophthalmic Drugs. AB - Binding of drugs to ocular melanin is a prominent biological phenomenon that affects the local pharmacokinetics and pharmacodynamics in the eye. In this work, we report on the development of in vitro and in silico tools for an early assessment and prediction of melanin binding properties of small molecules. A robust high-throughput assay has been established to study the binding of large sets of compounds to melanin. The extremely randomized trees approach was used to develop an in silico model able to predict the extent of melanin binding from the molecular properties of the compounds. After the last iteration of the model, strong melanin binders could prospectively be identified with 91% accuracy. On the basis of in vitro data generated for approximately 3400 chemically diverse drug-like small molecules, pronounced correlations were observed between the extent of melanin binding and the basicity, lipophilicity, and aromaticity of the compounds. PMID- 30398863 TI - Preparation of Carbodiimides with One-Handed Axial Chirality. AB - The axial chirality of carbodiimide was proposed in 1932, but the synthesis of carbodiimide with one-handed axial chirality has not been achieved because of the low barrier of racemization. This work presents a strategy to use a conformationally restrained cyclic structure for creating carbodiimides whose biases of the axial chirality (labeled as SNCN/ RNCN) are higher than 100:1, as determined by vibrational circular dichroism spectroscopy and density functional theory calculations. PMID- 30398864 TI - The Extreme Structural Plasticity in the CYP153 Subfamily of P450s Directs Development of Designer Hydroxylases. AB - CYP153s are bacterial class I P450 enzymes traditionally described as alkane hydroxylases with a high terminal regioselectivity. They have been more recently shown to also catalyze hydroxylations at nonactivated carbon atoms of small heterocycles. The aim of our work was to perform an extensive characterization of this subfamily in order to deliver a toolbox of CYP153 enzymes for further development as biocatalysts. Through the screening of recently sequenced bacterial genomes, 20 CYP153s were selected, comprising 17 single monooxygenase domains and three multidomain variants, where the monooxygenase domain is naturally fused to its redox partners in a single polypeptide chain. The 20 novel variants were heterologously expressed, and their activity was screened toward octane and small heterocycles. A more extended substrate characterization was then performed on three representative candidates, and their crystal structures were unveiled and compared with those of the known CYP153A7 and CYP153A33. The tested enzymes displayed a wide range of activities, ranging from Omega and Omega 1 hydroxylations of lauric acid to indigo-generating indole modification. The comparative analysis highlighted a conserved architecture and amino acid composition of the catalytic core close to the heme, while showing a huge degree of structural plasticity and flexibility in those regions hosting the substrate recognition sites. Although dealing with this type of conformational variability adds a layer of complexity and difficulty to structure-based protein engineering, such diversity in substrate acceptance and recognition promotes the investigated CYP153s as a prime choice for tailoring designer hydroxylases. PMID- 30398865 TI - Evolutionary Exploitation of Vertebrate Peroxisome Proliferator-Activated Receptor gamma by Organotins. AB - Globally persistent man-made chemicals display ever-growing ecosystemic consequences, a hallmark of the Anthropocene epoch. In this context, the assessment of how lineage-specific gene repertoires influence organism sensitivity toward endocrine disruptors is a central question in toxicology. A striking example highlights the role of a group of compounds known as obesogens. In mammals, most examples involve the modulation of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma). To address the structural and biological determinants of PPARgamma exploitation by a model obesogen, tributyltin (TBT), in chordates, we employed comparative genomics, transactivation and ligand binding assays, homology modeling, and site-directed mutagenesis. We show that the emergence of multiple PPARs (alpha, beta and gamma) in vertebrate ancestry coincides with the acquisition of TBT agonist affinity, as can be deduced from the conserved transactivation and binding affinity of the chondrichthyan and mammalian PPARgamma. The amphioxus single-copy PPAR is irresponsive to TBT; as well as the investigated teleosts, this is a probable consequence of a specific mutational remodeling of the ligand binding pocket. Our findings endorse the modulatory ability of man-made chemicals and suggest an evolutionarily diverse setting, with impacts for environmental risk assessment. PMID- 30398866 TI - Study of the Effect of Tyrosyl Oleate on Lipid Oxidation in a Typical Italian Bakery Product. AB - Tyrosyl oleate (TO), synthesized using oleic acid and tyrosol, was added to the original receipt of tarallini, to evaluate its antioxidant effectiveness. Lipid oxidation in control sample and samples with 1%, 4%, and 7% of TO at different storage times (0, 15, 30, 37, and 45 days) was evaluated. Accelerated oxidation analysis showed that the control sample took more than four times to complete the oxidation compared tarallini with TO. The control sample and tarallini with 1% of TO exceeded the peroxide value limit after 30 days of storage and the other two final products after 45 days. The control sample registered a oxidized fatty acid concentration higher than all the samples formulated with TO. The concentration of volatile compounds from lipid oxidation in tarallini with TO showed a lower concentration than the control sample. All the determinations carried out confirm, for the first time, that TO can counteract lipid oxidation in a real lipid system. PMID- 30398867 TI - Accuracy of Partial Core Corrections Using Fourier Transforms in Pseudopotential Density Functional Theory. AB - Partial core corrections can be important in obtaining an accurate description of nonlinear exchange-correlation functionals and improving the transferability of pseudopotentials. We show that a widely used procedure, which calculates partial core charge density, rho core partial, in Fourier space and then converts it to real space with fast Fourier transforms, can lead to sizable numerical errors of exchange-correlation potentials in the vacuum region. Such errors occur in modeling low-dimensional materials or surfaces with supercells. The loss of accuracy originates from the slow-decaying feature of core charge density in reciprocal space. Numerical errors on the order of 1 eV in the Kohn-Sham energies of unoccupied states can occur in pseudopotential-density functional calculations. The direct calculation of the partial core charge in real space can avoid the numerical errors caused by Fourier transforms. PMID- 30398868 TI - Tanshinone-IIA-Based Analogues of Imidazole Alkaloid Act as Potent Inhibitors To Block Breast Cancer Invasion and Metastasis in Vivo. AB - Tanshinone-IIA (Tan-IIA), a primary active component extracted from commonly used Chinese herbal, Salvia miltiorrhiza (Danshen), is considered as a potential inhibitor against tumor cell proliferation. However, the potential application of Tan-IIA is hindered by its poor water solubility and low bioavailability. In this work, an imidazole moiety was linked to the skeleton of Tan-IIA to enhance its antitumor activity. A series of Tan-IIA-based analogues TA01-TA12 were synthesized, and their inhibitory activities against the migration and invasion of MDA-MB-231 cells were investigated. All compounds, particularly TA12, markedly inhibited the proliferation, migration, and invasion of MDA-MB-231cells. TA12 also prominently blocked cancer cell metastasis in blood vessels and surrounding tissues in zebrafish xenograft model. Further studies showed that the mechanisms may involve S-phase arrest pathway, which was probably caused by inducing reactive oxygen species production and activating DNA damage. These results indicated that the Tan-IIA-based analogues of imidazole derivates can act as potent antimetastasis agents. PMID- 30398869 TI - Transition from Water Wires to Bifurcated H-Bond Networks in 2-Pyridone.(H2O) n, n = 1-4 Clusters. AB - Mass-selective two-color resonant two-photon ionization (2C-R2PI), UV/UV hole burning, and infrared (IR) depletion spectra of supersonic jet-cooled 2 pyridone.(H2O) n clusters with n = 1-4 have been measured to investigate the local hydration patterns around 2-pyridone (2PY) as a function of cluster size. As shown by others, the IR frequencies of the OH and NH stretches of the n = 1, 2 clusters are characteristic of water wires stretching from the NH to the C?O group of 2PY. We identify two isomers (3A and 3B) of the n = 3 cluster in the 2C R2PI spectrum and separate them by IR/UV and UV/UV hole-burning techniques. Isomer 3A exhibits a three-membered water wire, extending the n = 1, 2 structural motif. Isomer 3B exhibits bifurcated water wires with the first H2O donating to two waters that form H-bonds to the C?O group. This increases the H-bond strength between the NH group of 2PY and the proximal H2O molecule, lowering the NH stretch to ~2800 cm-1. The n = 4 cluster is also bifurcated with two water wires between the bifurcating H2O and the C?O group. The cluster-selective IR spectra are complemented with density-functional calculations using the PW91, B3LYP, B97 D, and M06-2X functionals, where the latter two include long-range dispersive interactions, and with the ab initio correlated SCS-CC2 method. The calculated IR spectra provide firm assignments of the structures of the n = 1-4 cluster structures and allow us to understand the evolution of individual H-bond strengths with increasing cluster size. PMID- 30398870 TI - Annealing CsPbX3 (X = Cl and Br) Perovskite Nanocrystals at High Reaction Temperatures: Phase Change and Its Prevention. AB - Annealing perovskite nanocrystals at high reaction temperature changes their crystal phase, shape, and optical properties. Carrying out reactions between 180 and 250 degrees C, the impact of thermal annealing for CsPbCl3 and CsPbBr3 nanocrystals in a reaction flask was investigated here. At higher temperature, a phase change was observed instantly, which could not be trapped even with ice bath cooling. Interestingly, using a calculated amount of preformed alkylammonium halides as dual passivating agents, the nanocrystals of both CsPbCl3 and CsPbBr3 could even be stabilized for hours of annealing at 250 degrees C. CsPbCl3, which was reported to be a poor emissive nanocrystal in comparison to CsPbBr3, could sustain even more than 5 h of annealing at 250 degrees C and recorded ~51% absolutely quantum yield. Details of the interface chemistry and the role of the used dual passivating agent for providing thermal stability are studied and reported in this Letter. PMID- 30398871 TI - beta-Triketone-Monoterpene Hybrids from the Flowers of the Australian Tree Corymbia intermedia. AB - Four new beta-triketone monoterpene hybrids, intermediones A-D (1-4), have been identified from the flowers of the Australian eucalypt tree Corymbia intermedia. Intermediones A-D are beta-triketones that incorporate a pinene moiety attached via a benzyl group to a syncarpic acid. The structures of 1-4, including relative configurations, were elucidated from the analysis of 1D/2D NMR and MS data. The absolute configurations of intermediones A and B were determined by comparison of experimental and predicted ECD spectra. Intermedione D possesses a tetracyclic ring system that is related to that found in the meroterpenes, guadials B and C. Low to moderate antiplasmodial activity toward the chloroquine-sensitive (3D7) strain of Plasmodium falciparum, with IC50 values ranging from 9.9 to 20.8 MUM, was observed for intermediones A, B, and D. PMID- 30398872 TI - A Dispersion-Corrected Modified Embedded-Atom Method Bond Order Interatomic Potential for Sulfur. AB - An interatomic potential for sulfur has been developed using the bond order addition to the modified embedded-atom method (MEAM-BO). In order to correctly model the interaction between molecules, dispersion forces have been included via the DFT-D3 modification. It is demonstrated that this semi-empirical classical potential correctly reproduces the behavior of the S2 dimer, various cyclic sulfur rings, the molecular solids: alpha-, beta-, and gamma-, sulfur, and a number of theoretical, high symmetry sulfur structures. This potential will serve as a useful tool in the atomistic modeling of sulfur, and, ultimately, in the modeling of sulfur containing organic compounds using this updated MEAM-BO formalism. PMID- 30398873 TI - Why and How Carbon Dioxide Conversion to Methanol Happens on Functionalized Semiconductor Photoelectrodes. AB - Functionalization of semiconductor electrode surfaces with adsorbed 2-pyridinide (2-PyH-*) has been postulated to enable selective CO2 photoelectroreduction to CH3OH. This hypothesis is supported by recent estimates of sufficient 2-PyH-* lifetimes and low barriers for hydride transfer (HT) to CO2. However, the complete mechanism for reducing CO2 to CH3OH remained unidentified. Here, vetted quantum chemistry protocols for modeling GaP reveal a pathway involving HTs to specific CO2 reduction intermediates. Predicted barriers suggest that HT to HCOOH requires adsorbed HCOOH* reacting with 2-PyH-*, a new catalytic role for the surface. HT to HCOOH* produces CH2(OH)2, but subsequent HT to CH2(OH)2 forming CH3OH is hindered. However, CH2O, dehydrated CH2(OH)2, easily reacts with 2-PyH *, producing CH3OH. Further reduction of CH3OH to CH4 via HT from 2-PyH-* encounters a high barrier, consistent with experiment. Our finding that the GaP surface enables HT to HCOOH* explains why the primary CO2 reduction product over CdTe photoelectrodes is HCOOH rather than methanol, as HCOOH does not adsorb on CdTe and so the reaction terminates. The stability of 2-PyH-* (vs its protonation product DHP*), the relative dominance of CH2(OH)2 over CH2O, and the required desorption of CH2(OH)2* are the most likely limiting factors, explaining the low yield of CH3OH observed experimentally. PMID- 30398874 TI - Molecular Basis of Aqueous-like Activity of Lipase Treated with Glucose-Headed Surfactant in Organic Solvent. AB - Lipases are useful as catalysts, particularly for the kinetic resolution of racemic alcohols and esters. However, their industrial applications are limited by their poor activities in organic media. We recently found that a lipoprotein lipase from Burkholderia species displays dramatically enhanced activity in organic solvent if the protein is coated with glucose-headed surfactant (GHS). Here we investigate the molecular basis of this enhanced enzymatic activity in organic solvent by performing molecular dynamics simulations on Burkholderia cepacia lipase as a model enzyme. Our simulation results indicate that the enhanced activity of lipase stems from a dual function of GHSs different in water and organic solvent. GHS molecules maintain the open conformation of lipase by providing lipid-like microenvironment surrounding the active site in water and stabilize its native active conformation by providing water-like microenvironment around the surface of the lipase in the organic solvent. Our data also suggest the role of organic cosolvent that can facilitate closed-to-open conformational changes during the freeze-drying process. The computational approach in this study lays its potential for guiding the design of more effective surfactant molecules to improve the activity of lipases in organic solvent. PMID- 30398875 TI - Tuning the Relaxation of Nanopatterned Polymer Films with Polymer-Grafted Nanoparticles: Observation of Entropy-Enthalpy Compensation. AB - Polymer films provide a versatile platform in which complex functional relief patterns can be thermally imprinted with a resolution down to few nanometers. However, a practical limitation of this method is the tendency for the imprinted patterns to relax ("slump"), leading to loss of pattern fidelity over time. While increasing temperature above glass transition temperature ( Tg) accelerates the slumping kinetics of neat films, we find that the addition of polymer-grafted nanoparticles (PGNP) can greatly enhance the thermal stability of these patterns. Specifically, increasing the concentration of poly(methyl methacrylate) (PMMA) grafted titanium dioxide (TiO2) nanoparticles in the composite films slows down film relaxation dynamics, leading to enhanced pattern stability for the temperature range that we investigated. Interestingly, slumping relaxation time is found to obey an entropy-enthalpy compensation (EEC) relationship with varying PGNP concentration, similar to recently observed relaxation of strain-induced wrinkling in glassy polymer films having variable film thickness. The compensation temperature, Tcomp was found to be in the vicintity of the bulk Tg of PMMA. Our results suggest a common origin of EEC relaxation in patterned polymer thin films and nanocomposites. PMID- 30398876 TI - Nanoscale Nucleic Acid Recognition at the Solid-Liquid Interface Using Xeno Nucleic Acid Probes. AB - Challenges in reliable nucleic acid detection are manifold. The major ones are related to false positive or negative signals due to a lack of target specificity in detection and to low sensitivity, especially when a plethora of background sequences are present that can mask the specific recognition signal. Utilizing designed synthetic nucleic acids that are commonly called xeno nucleic acids could offer potential routes to meeting such challenges. In this article, we present the general framework of nucleic acid detection, especially for nanoscale applications, and discuss how and why the xeno nucleic acids could be truly an alternative to the DNA probes. Two specific cases, locked nucleic acid (LNA) and peptide nucleic acid (PNA), which are nuclease-resistant and can form thermally stable duplexes with DNA, are addressed. It is shown that the relative ease of the conformationally rigid LNA probe to be oriented upright on the substrate surface and of the nonionic PNA probe to result into high probe density assists in their use in nanoscale nucleic acid recognition. It is anticipated that success with these probes may lead to important developments such as PCR independent approaches where the major aim is to detect a small number of target sequences present in the analyte medium. PMID- 30398877 TI - Dialkali-Metal Monochalcogenide Semiconductors with High Mobility and Tunable Magnetism. AB - The discovery of archetypal two-dimensional (2D) materials provides enormous opportunities in both fundamental breakthroughs and device applications, as evident by the research booming in graphene, transition-metal chalcogenides, and black phosphorus. Here, we report a new, large family of semiconducting dialkali metal monochalcogenides (DMMCs) with an inherent A2X monolayer (ML) structure, in which two alkali sub-MLs form hexagonal close packing and sandwich the triangular chalcogen atomic plane. Such a unique lattice leads to extraordinary physical properties, such as good dynamical and thermal stability, visible to near infrared energy gap, and high electron mobility. Most strikingly, DMMC MLs host extended van Hove singularities near the valence band (VB) edge, readily accessible by moderate hole doping within 1.0 * 1013 cm-2. Upon critical doping, DMMC MLs undergo spontaneous ferromagnetic transition when the top VBs become fully spin-polarized by strong exchange interactions. Such 2D gate tunable magnetism are promising for exploring novel device concepts in spintronics, electronics and optoelectronics. PMID- 30398878 TI - Surface Characteristics Control the Attachment and Functionality of (Chimeric) Avidin. AB - The physical adsorption (physisorption) of proteins to surfaces is an important but incompletely understood factor in many biological processes and is of increasing significance in bionanotechnology as well. Avidin is an important protein because of strong avidin-biotin binding, which has been exploited in numerous applications. We have undertaken thorough experimentation on the physisorption of avidin, to chemically different flat surfaces of Si and graphite and also to the curved version of the latter, on multiwalled carbon nanotubes (MWNTs) of different diameters. The difference in the behavior of avidin on Si versus graphite is drastic; on Si, avidin deposits as single globular tetrameric units and maintains functionality, whereas on graphite, it forms irregular networks of two-layer thick filaments, where the first layer has lost its biological activity. On MWNTs, avidin also deposits as one-dimensional formations, or stripes, but these appear to order in a perpendicular arrangement to the MWNT axis. A better understanding of protein-surface interactions is essential for the development of robust and reliable methods for biofunctionalization of materials. This work also provides insights into the importance of the nanoscale surface architecture. PMID- 30398879 TI - Peripherally Restricted, Highly Potent, Selective, Aqueous-Soluble EP2 Antagonist with Anti-Inflammatory Properties. AB - The prostaglandin E2 receptor, EP2, plays an important role in physiology and in a variety of pathological conditions. Studies indicate that EP2 is pro inflammatory in chronic peripheral and central nervous system disease and cancer models. Thus, targeting the EP2 receptor with small molecules could be a therapeutic strategy for treating inflammatory diseases and cancer. We recently reported a novel class of competitive antagonists of the EP2 receptor. However, earlier leads displayed low selectivity against the DP1 prostanoid receptor, moderate plasma half-life, and low aqueous solubility, which renders them suboptimal for testing in animal models of disease. We now report a novel compound TG8-69, which has suitable drug-like properties. We present synthesis, lead-optimization studies, pharmacological characterization, and anti inflammatory properties of this compound that support its use in chronic peripheral inflammatory diseases, including rheumatoid arthritis, endometriosis, and cancer, in which EP2 appears to play a pathogenic role. PMID- 30398880 TI - Access to alpha,gamma-Diamino Diacid Derivatives via Organocatalytic Asymmetric 1,4-Addition of Azlactones and Dehydroalanines. AB - A convenient and functional-group-tolerant organocatalytic asymmetric 1,4 addition of azlactones and dehydroalanine is disclosed. The reaction is used for the first synthesis of chiral alpha,gamma-diamino diacid derivatives with nonadjacent stereogenic centers in moderate to high yields, with excellent diastereo- and enantioselectivities, under the catalysis of a chiral thiourea catalyst. In addition, the reaction could be conducted in gram-scale, and the products of the reaction could be readily converted to various alpha,gamma diamino diacid derivatives, alpha,gamma-diamino dialcohols, and modified peptides with nonproteinogenic amino acid residues. PMID- 30398881 TI - Tandem Oxidative Ring-Opening/Cyclization Reaction in Seconds in Open Atmosphere for the Synthesis of 1-Tetralones in Water-Acetonitrile. AB - A mild and practical tandem oxidative ring-opening/cyclization reaction mediated by Ce4+ for the synthesis of 1-tetralones is presented. This rapid transformation was completed within 30 s and conducted in an open reactor at 0 degrees C in a water-acetonitrile mixture. Various cyclobutanol derivatives are transformed into desired products in good to high yields, and this reaction can be easily scaled up to the gram scale. PMID- 30398882 TI - Intramolecular trans-Carbocarbonation of Internal Alkynes by a Cascade of Formal anti-Carbopalladation/Cyclopropanol Opening. AB - An intramolecular cascade reaction consisting of a formal anti-carbopalladation terminated by the ring-opening of a cyclopropanol unit is presented. The products, which involve tetrasubstituted alkene units embedded in an oligocyclic ring system, are generated in moderate to excellent yield. The opening of the cyclopropanol unit leads to a keto group in the gamma-position to the emerging double bond. PMID- 30398883 TI - Hydrogenation of Nitriles and Ketones Catalyzed by an Air-Stable Bisphosphine Mn(I) Complex. AB - Efficient hydrogenations of nitriles and ketones with molecular hydrogen catalyzed by a well-defined bench-stable bisphosphine Mn(I) complex are described. These reactions are environmentally benign and atomically economic, implementing an inexpensive, earth-abundant nonprecious metal catalyst. A range of aromatic and aliphatic nitriles and ketones were efficiently converted into primary amines and alcohols, respectively, in good to excellent yields. The hydrogenation of nitriles proceeds at 100 degrees C with catalyst loading of 2 mol % and 20 mol % base ( t-BuOK), while the hydrogenation of ketones takes place already at 50 degrees C, with a catalyst loading of 1 mol % and 5 mol % of base. In both cases, a hydrogen pressure of 50 bar was applied. PMID- 30398884 TI - Opto-Mechanics Driven Fast Martensitic Transition in Two-Dimensional Materials. AB - Diffusional phase-change materials, such as Ge-Sb-Te alloys, are used in rewritable nonvolatile memory devices. But the continuous pursuit of readout/write speed and reduced energy consumption in miniaturized devices calls for an optically driven, diffusionless phase change scheme in ultrathin materials. Inspired by optical tweezers, in this work, we illustrate theoretically and computationally that a linearly polarized laser pulse with selected frequency can drive an ultrafast diffusionless martensitic phase transition of two-dimensional ferroelastic materials such as SnO and SnSe monolayers, where the unit-cell strain is tweezed as a generalized coordinate that affects the anisotropic dielectric function and electromagnetic energy density. At laser power of 2.0 * 1010 and 7.7 * 109 W/cm2, the transition potential energy barrier vanishes between two 90 degrees -orientation variants of ferroelastic SnO and SnSe monolayer, respectively, so displacive domain switching can occur within picoseconds. The estimated adiabatic thermal limit of energy input in such optomechanical martensitic transition (OMT) is at least 2 orders of magnitude lower than that in Ge-Sb-Te alloy. PMID- 30398885 TI - The Fate of Water at the Electrochemical Interfaces: Electrochemical Behavior of Free Water Versus Coordinating Water. AB - The water reduction that produces hydrogen is one key reaction for electrochemical energy storage. While it has been widely studied in traditional aqueous electrolytes for water splitting (electrolyzers), it also plays an important role for batteries. Indeed, the reduction of water at relatively high potential prevents the practical realization of high-voltage aqueous batteries, while water contamination is detrimental for organic battery electrolytes. Nevertheless, recent studies pointed toward the positive effect of traces of water for Li-air batteries as well as for the formation of solid-electrolyte interphase. Herein, we provide a detailed understanding of the role of the solvation on water reduction reaction in organic electrolytes. Using electrochemistry, classical molecular dynamics simulations, and nuclear magnetic resonance spectroscopy, we were able to demonstrate that (1) the hydrophilicity/hydrophobicity of the species inside the electrochemical double layer directly controls the reduction of water and (2) water-coordinating strong Lewis acids such as Li+ cation are more reactive than free water (or noncoordinating) water molecules. PMID- 30398886 TI - Effect of Molecular Weight on the Feature Size in Organic Ice Resists. AB - The feature size of patterns obtained by electron-beam lithography (EBL) depends critically on resist properties, beam parameters, development process, and instrument limitations. Frozen layers of simple organic molecules such as n alkanes behave as negative-tone resists for EBL. With the unique advantage of an in situ thermal treatment replacing chemical development, the entire lithographic process can be performed within a single instrument, thus removing the influence of chemical developers on the feature size. By using an environmental transmission electron microscope, we can also minimize the influence of instrumental limitations and explore the fundamental link between resist characteristics and feature size. Our results reveal that the onset dose of organic ice resists correlates with the inverse molecular weight and that in the thermal development the role of change in solubility of polymers is mirrored in a shift in the solid/vapor critical temperature of organic ices. With a 0.4 pA beam current, we obtained 4.5, 5.5, and 8.5 nm lines with frozen octane, undecane, and tetradecane, respectively, consistent with the predictions of a model we developed that links beam profile and feature size. The knowledge acquired on the response of small organic molecules to electron irradiation, combined with the flexibility and operational advantages of using them as qualified EBL resists, provides us with new opportunities for the design and production of nanodevices and broadens the reach of EBL especially toward biological applications. PMID- 30398887 TI - Bromo- or Methoxy-Group-Promoted Umpolung Electron Transfer Enabled, Visible Light-Mediated Synthesis of 2-Substituted Indole-3-glyoxylates. AB - A visible-light-mediated radical tandem cyclization of ortho-isocyano-alpha-bromo cinnamates to 2-substituted indole-3-glyoxylates is achieved by formation of both C-C/C-S and C-O bonds. The reaction proceeds through a hitherto unprecedented bromine- or methoxy-group-promoted umpolung back electron transfer from an alpha carbonyl radical to the photocatalyst. This method allows preparation of diverse 2-arylated or 2-thioarylated indole-3-glyoxylates. The glyoxylate group installed in the products can be utilized for several biologically relevant manipulations. PMID- 30398888 TI - Robust Covalent Coupling Scheme for the Development of FRET Aptasensor based on Amino-Silane-Modified Graphene Oxide. AB - In recent years, numerous aptamers have been physisorbed on graphene oxide (GO) to develop fluorescence resonance energy transfer-based aptasensors using the fluorescence quenching property of GO. However, physisorbed aptasensors show poor signal reversibility and reproducibility as well as nonspecific probe displacement, and thereby are not suitable for many analytical applications. To overcome these problems when working with complex biological samples, we developed a facile and robust covalent surface functionalization technique for GO based fluorescent aptasensors using a well-studied adenosine triphosphate binding aptamer (ABA). In the scheme, GO is first modified with amino-silane, and further with glutaraldehyde to create available carbonyl groups for the covalent attachment of a fluorophore and an amino dual modified ABA. The surface modification method was characterized by zeta-potential, X-ray photoelectron spectroscopy, and Fourier-transform infrared spectroscopy (FTIR). The linearity, sensitivity, selectivity, and reversibility of the resulting GO-based covalent aptasensor was determined and systematically compared with the physisorbed aptasensor. Although both sensors showed similar performance in terms of sensitivity and linearity, better selectivity and higher resistance to nonspecific probe displacement was achieved with the developed covalent ABA sensor. The surface modification technique developed here is independent of the aptamer sequence, and therefore could be used universally for different analytical applications simply by changing the aptamer sequence for the target biomolecule. PMID- 30398889 TI - Vectorial Control of the Spin-Orbit Interaction in Suspended InAs Nanowires. AB - Semiconductor nanowires featuring strong spin-orbit interactions (SOI), represent a promising platform for a broad range of novel technologies, such as spintronic applications or topological quantum computation. However, experimental studies into the nature and the orientation of the SOI vector in these wires remain limited despite being of upmost importance. Typical devices feature the nanowires placed on top of a substrate which modifies the SOI vector and spoils the intrinsic symmetries of the system. In this work, we report experimental results on suspended InAs nanowires, in which the wire symmetries are fully preserved and clearly visible in transport measurements. Using a vectorial magnet, the nontrivial evolution of weak antilocalization (WAL) is tracked through all 3D space, and both the spin-orbit length l SO and coherence length lphi are determined as a function of the magnetic field magnitude and direction. Studying the angular maps of the WAL signal, we demonstrate that the average SOI within the nanowire is isotropic and that our findings are consistent with a semiclassical quasi-1D model of WAL adapted to include the geometrical constraints of the nanostructure. Moreover, by acting on properly designed side gates, we apply an external electric field introducing an additional vectorial Rashba spin-orbit component whose strength can be controlled by external means. These results give important hints on the intrinsic nature of suspended nanowire and can be interesting for the field of spintronics as well as for the manipulation of Majorana bound states in devices based on hybrid semiconductors. PMID- 30398890 TI - Remote Phononic Effects in Epitaxial Ruddlesden-Popper Halide Perovskites. AB - Despite their weak nature, van der Waals (vdW) interactions have been shown to effectively control the optoelectronic and vibrational properties of layered materials. However, how vdW effects exist in Ruddlesden-Popper layered halide perovskites remains unclear. Here we reveal the role of interlayer vdW force in Ruddlesden-Popper perovskite in regulating phase-transition kinetics and carrier dynamics based on high-quality epitaxial single-crystalline (C4H9NH3)2PbI4 flakes with controlled dimensions. Both substrate-perovskite epitaxial interaction and interlayer vdW interaction play significant roles in suppressing the structural phase transition. With reducing flake thickness from ~100 to ~20 nm, electron phonon coupling strength decreases by ~30%, suggesting the ineffectiveness of phonon confinement of the natural quantum wells. Therefore, the conventional understanding that vdW perovskite is equivalent to a multiple quantum well has to be substantially amended due to significant nonlocal phononic effects in the layered crystal, where intralayer interaction is not drastically different from the interlayer force. PMID- 30398892 TI - Reply to: High PEEP: Only a Dam Against Edema Formation? Probably Not (Again). PMID- 30398891 TI - In-Place Modulation of Rectification in Tunneling Junctions Comprising Self Assembled Monolayers. AB - This paper describes tunneling junctions comprising self-assembled monolayers that can be converted between resistor and diode functionality in-place. The rectification ratio is affected by the hydration of densely packed carboxylic acid groups at the interface between the top-contact and the monolayer. We studied this process by treatment with water and a water scavenger using three different top-contacts, eutectic Ga-In (EGaIn), conducting-probe atomic force microscopy (CP-AFM), and reduced graphene oxide (rGO), demonstrating that the phenomena is molecular in nature and is not platform-speciffc. We propose a mechanism in which the tunneling junctions convert to diode behavior through the lowering of the LUMO, which is suffcient to bring it close to resonance at positive bias, potentially assisted by a Stark shift. This shift in energy is supported by calculations and a change in polarization observed by X-ray photoelectron spectroscopy and Kelvin probe measurements. We demonstrate light driven modulation using spiropyran as a photoacid, suggesting that any chemical process that is coupled to the release of small molecules that can tightly bind carboxylic acid groups can be used as an external stimulus to modulate rectification. The ability to convert a tunneling junction reversibly between a diode and a resistor via an effect that is intrinsic to the molecules in the junction extends the possible applications of Molecular Electronics to reconfigurable circuits and other new functionalities that do not have direct analogs in conventional semiconductor devices. PMID- 30398893 TI - Nonoperative Management of Femoroacetabular Impingement: A Prospective Study. AB - BACKGROUND:: The literature has given little attention to the nonoperative management of femoroacetabular impingement (FAI) syndrome despite a rapidly expanding body of research on the topic. PURPOSE:: To perform a prospective study utilizing a nonoperative protocol on a consecutive series of patients presenting to our clinic with FAI syndrome. STUDY DESIGN:: Cohort study; Level of evidence, 2. METHODS:: Between 2013 and 2016, patients meeting the following criteria were prospectively recruited in a nonoperative FAI study: no prior hip surgery, groin based pain, a positive impingement test, and radiographic FAI syndrome. The protocol consisted of an initial trial of rest, physical therapy, and activity modification. Patients who remained symptomatic were then offered an image-guided intra-articular steroid injection. Patients with recurrent symptoms were then offered arthroscopic treatment. Outcome scores were collected at 12 and 24 months. Statistical analysis was performed to identify risk factors for the need for operative treatment and to determine patient outcomes based on FAI type and treatment. RESULTS:: Ninety-three hips (n = 76 patients: mean age, 15.3 years; range, 10.4-21.4 years) were included in this study and followed for a mean +/- SD 26.8 +/- 8.3 months. Sixty-five hips (70%) were managed with physical therapy, rest, and activity modification alone. Eleven hips (12%) required a steroid injection but did not progress to surgery. Seventeen hips (18%) required arthroscopic management. All 3 groups saw similar improvements in modified Harris Hip Score ( P = .961) and nonarthritic hip score ( P = .975) with mean improvements of 20.3 +/- 16.8 and 13.2 +/- 15.5, respectively. Hips with cam impingement and combined cam-pincer impingement were 4.0 times more likely to meet the minimal clinically important difference in modified Harris Hip Score ( P = .004) and 4.4 times more likely to receive surgical intervention ( P = .05) than patients with pincer deformities alone. Participants in team sports were 3.0 times more likely than individual sport athletes to return to competitive activities ( P = .045). CONCLUSION:: A majority (82%) of adolescent patients presenting with FAI syndrome can be managed nonoperatively, with significant improvements in outcome scores at a mean follow-up of 2 years. CLINICAL RELEVANCE:: A nonoperative approach should be the first-line treatment for young active patients with symptomatic FAI syndrome. PMID- 30398894 TI - Long-term Outcomes of Primary Repair of the Anterior Cruciate Ligament Combined With Biologic Healing Augmentation to Treat Incomplete Tears. AB - BACKGROUND:: Surgical treatment to repair partial anterior cruciate ligament (ACL) injury without reconstruction has demonstrated inconsistent clinical success. PURPOSE:: To examine the long-term clinical outcomes of primary ACL repair combined with biologic healing augmentation in patients with symptomatic partial ACL tears. STUDY DESIGN:: Case series; Level of evidence, 4. METHODS:: 50 patients (mean age, 29.5 years) with a partial ACL tear and symptomatic knee instability were treated with primary ligament repair in conjunction with marrow stimulation and followed prospectively for a mean duration of 10.2 years (range, 5.3-14.3 years). Comparative analysis of preinjury, preoperative, and postoperative scores using patient-reported assessment instruments was performed to examine clinical outcomes. Correlation of final outcome scores with patient age, type of ACL tear, side-to-side difference in ligamentous laxity, and body mass index (BMI) was performed through use of Spearman rank analysis. RESULTS:: 44 patients were available for assessment at final follow-up. The median Tegner Activity Scale score of 7 at final follow-up was the same as the preinjury median score of 7 ( P = .128). The mean Marx Activity Scale, International Knee Documentation Committee (IKDC) Subjective, and Lysholm Knee Questionnaire scores were 10.8, 90.4, and 96.2, respectively, at final follow-up. Mean final Knee injury and Osteoarthritis Outcome Score (KOOS) subset assessments of Pain, Symptoms, Activities of Daily Living, Sports, and Quality of Life were 98.6, 97.5, 99.7, 94.3, and 95.6, respectively. Secondary ACL insufficiency occurred in 27% of patients. Clinical outcome scores were similar for all scoring instruments between patients treated for an associated diagnosis of meniscal or articular cartilage injury. No significant correlations of age, BMI, ACL tear type, or laxity and final IKDC Subjective, Lysholm, or KOOS scores were found. Analysis revealed a negative correlation of patient age and Tegner score at preinjury ( rs = -0.333, P = .022) and at final follow-up ( rs = -0.376, P = .013). The mean side-to-side difference in ligamentous laxity of 3.4 mm at short-term follow-up in those patients who developed secondary ACL insufficiency over the duration of follow-up was significantly greater than the mean of 0.9 mm in those who did not ( P = .010). CONCLUSION:: Primary ACL repair combined with biologic healing augmentation to treat select cases of knee instability secondary to incomplete ACL rupture demonstrated good to excellent long-term outcomes in this cohort for those patients who did not experience secondary ACL insufficiency, with high rates of restoration of knee stability and return to preinjury athletic activities. The rate of secondary treatment for recurrent ACL insufficiency over the course of long-term follow-up was greater than would be expected for primary ACL reconstruction. Greater side-to-side differences in objective findings of ligamentous laxity were identified at shorter term follow-up in the patients who later went on to experience symptomatic secondary ACL insufficiency, compared with those who maintained stability long term. PMID- 30398895 TI - The Association between Respiratory Infection and Air Pollution in the Setting of Air Quality Policy and Economic Change. AB - RATIONALE: Fine particulate air pollution (<=2.5um; PM2.5) has been associated with an increased risk of respiratory disease, but assessments of specific respiratory infections in adults are lacking. OBJECTIVE: To estimate the rate of respiratory infection healthcare encounters in adults associated with acute increases in PM2.5 concentrations. METHODS: Using case-crossover methods, we studied 498,118 adult New York State residents with a primary diagnosis of influenza, bacterial pneumonia, or culture negative pneumonia upon hospitalization or emergency department (ED) visit (2005-2016). We estimated the rate of healthcare encounters associated with increases in PM2.5 in the previous 1-7 days and explored differences Before (2005 to 2007), During (2008-2013), and After (2014-2016) implementation of air quality policies and economic changes. RESULTS: Interquartile range increases in PM2.5 over the previous 7 days were associated with increased excess rates of culture negative pneumonia hospitalizations (2.5%; 95% CI 1.7%, 3.2%) and ED visits (2.5%; 95% CI 1.4%, 3.6%), and increased excess rates of influenza ED visits (3.9%; 95% CI 2.1%, 5.6%). Bacterial pneumonia hospitalizations but not ED visits were associated with increases in PM2.5 and though imprecise, were of a similar magnitude to culture negative pneumonia (Lag day 6 ER 2.3%; 95% CI: 0.3, 4.3). Increased relative rates of influenza ED visits and culture negative pneumonia hospitalizations were generally larger in the After period (p< 0.025 for both outcomes), compared to the During period, despite reductions in overall PM2.5 concentrations. CONCLUSION: Increased rates of culture negative pneumonia and influenza were associated with increased PM2.5 concentrations during the previous week, which persisted despite reductions in PM2.5 from air quality policies and economic changes. Though unexplained, this temporal variation may reflect altered toxicity of different PM2.5 mixtures or increased pathogen virulence. PMID- 30398896 TI - Precision Medicine in Acute Kidney Injury - A Promising Future? PMID- 30398897 TI - Video Analysis of Reported Concussion Events in the National Football League During the 2015-2016 and 2016-2017 Seasons. AB - BACKGROUND:: Concussions in American football remain a high priority of sports injury prevention programs. Detailed video review provides important information on causation, the outcomes of rule changes, and guidance on future injury prevention strategies. PURPOSE:: Documentation of concussions sustained in National Football League games played during the 2015-2016 and 2016-2017 seasons, including consideration of video views unavailable to the public. STUDY DESIGN:: Descriptive epidemiology study. METHODS:: All reported concussions were reviewed with all available video footage. Standardized terminology and associated definitions were developed to describe and categorize the details of each concussion. RESULTS:: Cornerbacks sustained the most concussions, followed by wide receivers, then linebackers and offensive linemen. Half (50%) of concussions occurred during a passing play, 28% during a rushing play, and 21% on a punt or kickoff. Tackling was found to be the most common activity of concussed players, with the side of the helmet the most common helmet impact location. The distribution of helmet impact source-the object that contacted the concussed player's helmet-differed from studies of earlier seasons, with a higher proportion of helmet-to-body impacts (particularly shoulder) and helmet-to-ground impacts and with a lower proportion of helmet-to-helmet impacts. Helmet-to-ground concussive impacts were notable for the high prevalence of impacts to the back of the helmet and their frequency during passing plays. CONCLUSION:: Concussion causation scenarios in the National Football League have changed over time. CLINICAL RELEVANCE:: The results of this study suggest the need for expanded evaluation of concussion countermeasures beyond solely helmet-to-helmet test systems, including consideration of impacts with the ground and with the body of the opposing player. It also suggests the possibility of position-specific countermeasures as part of an ongoing effort to improve safety. PMID- 30398898 TI - Medical education dilemma: how best to accommodate basic sciences in a curriculum for the 21st century medical students? AB - Over the years the medical curriculum has been changed to accommodate a variety of evolving disciplines and an exploding scientific knowledge of the basic sciences to prepare "a competent physician" of the 21st century. Therefore, we must be innovative in our approach of curricular development if we wish to continue to incorporate new basic sciences knowledge in the face of decreasing contact hours to satisfy the buzz word, "integration". Certainly, the challenges are phenomenal. The question how best to integrate basic sciences, is not easy to answer as the objectives of the courses and outcome vary from one medical school to another and the fact is, one size does not fit all. However, if we believe that basic sciences are the language of medicine and foundation of clinical knowledge, then we must resolve this ongoing dilemma by introducing basic sciences through a better alignment in a given curriculum. The purpose of this mini review is to evaluate different curricular models for their basic sciences content and address their strength and weakness. In addition, we will introduce a spiral design to integrate basic sciences for senior students. Finally, we will provide some insight as to how learning and retention of basic science content can be sustained. PMID- 30398899 TI - DNA barcoding reveals insect diversity in the mangrove ecosystems of Hainan Island, China. AB - Insect diversity is an indicator of environmental conditions. Frequent outbreaks of mangrove pests have threatened the fragile mangrove ecosystem in China and the sustainable utilization of mangrove resources. The understanding of mangrove pests, as well as a fundamental knowledge of insect diversity, in mangrove forests in China has been hindered by the difficulty of morphological species delimitation because captured insect specimens are either larvae or incompletely preserved adults. DNA barcoding technology uses only a small amount of DNA to conduct species identification. Taking advantage of this, we investigated the entomofauna of mangrove forests on Hainan Island by using a barcode combining cytochrome c oxidase subunit I (COI) and cytochrome-b (Cytb). We collected 627 specimens at six localities around the island, which were identified as 219 insect species belonging to 11 orders and 72 families. Lepidoptera, Coleoptera, and Hymenoptera are the most species-rich and abundant taxa. We also identified 13 mangrove pests, 5 parasitoids, and 12 species of predators. PMID- 30398900 TI - Electromyostimulation with blood flow restriction enhances activation of mTOR and MAPK signaling pathways in rat gastrocnemius muscles. AB - Neuromuscular electrical stimulation (NMES) combined with blood flow restriction (BFR) induces muscle hypertrophy. However, cellular mechanisms underlying the muscle hypertrophy induced by NMES combined with BFR remain unclear. We tested the hypothesis that NMES combined with BFR would enhance the mechanistic target of rapamycin (mTOR) and mitogen activated protein kinase (MAPK) signaling pathways. Age-matched male Wistar rats (6 months old, n=7 per group) were assigned randomly into control, BFR alone (BFR), NMES alone (NMES) and NMES combined with BFR (NMES/BFR) groups. NMES induced 25 isometric contractions lasting 8 s with a 4-s resting period between each contraction in the gastrocnemius muscle. Four sets in total were performed, with 1-min intervals between each set. A latex cuff was placed on the proximal portion of the hind limb and blood flow restriction at 200 mmHg was conducted in four sets (each set 5 min) with 1-min rest intervals between sets. Venous blood was collected from the lateral tail vein to determine pH, H+, and lactate, before and immediately after the treatments. Expression levels of proteins related to muscle hypertrophy were determined by western blot analysis. The application of NMES combined with BFR encouraged muscle fatigue more than NMES alone. NMES/BFR induced greater changes in accumulation of metabolites and increase in the weight of gastrocnemius muscle. The phosphorylation of mTOR and MAPK signaling related proteins was also enhanced following NMES combined with BFR, compared with other conditions. Thus, NMES enhanced the activation of mTOR and MAPK signaling pathways when combined with BFR. PMID- 30398901 TI - Hydrogen cyanide produced by Pseudomonas chlororaphis O6 is a key aphicidal metabolite. AB - A biocontrol bacterium Pseudomonas chlororaphis O6 promotes plant health through multifaceted mechanisms. In this study, we used P. chlororaphis O6 mutants to examine metabolites with aphicidal activity. Direct application of intact P. chlororaphis cells to the surface of second instar nymphs of the green peach aphid resulted in no mortality. However, nymphs died when exposed only to the volatiles produced by the P. chlororaphis O6 wild-type strain when growing on rich media. Mutants lacking in production of two antibiotics, phenazine and pyrrolnitrin, or the insect toxin, FitD, retained the aphicidal potential of the wild type strain. However, the volatiles produced by mutants defective in the lacking production of hydrogen cyanide (HCN) or with a defect in the synthesis of a global regulator, GacS, which regulates HCN synthesis, showed no aphicidal activity. Direct application of potassium cyanide caused mortality of green peach aphid nymphs. These results indicate that HCN production by a plant probiotic is involved in preventing insect growth. PMID- 30398902 TI - Risk of Redislocation After Primary Patellar Dislocation: A Clinical Prediction Model Based on Magnetic Resonance Imaging Variables. AB - BACKGROUND:: First-time lateral patellar dislocations have historically been treated with a nonoperative approach; a clinical tool to predict patients who are most likely to redislocate may have clinical utility. PURPOSE:: (1) To determine if there are discriminating factors present between patients who redislocated their patellas and those who did not after a first-time lateral patellar dislocation and (2) to use this information to develop a model that can predict the recurrence risk of lateral patellar dislocation in this population. STUDY DESIGN:: Case-control study; Level of evidence, 3. METHODS:: The study population included those with first-time lateral patellar dislocation, magnetic resonance imaging within 6 weeks, and 2-year minimum follow-up. Cohort A was from a prospective study with 2-year follow-up. Cohort B was a prospectively identified cohort with retrospective chart review. Follow-up was obtained clinically or via mail for patients without 2-year clinical follow-up. RESULTS:: Sixty-one patients (42%) out of 145 with primary lateral patellar dislocation had recurrent dislocation within 2 years. Stepwise logistic regression analysis demonstrated that skeletal immaturity (odds ratio, 4.05; 95% CI, 1.86-8.82; P = .0004), sulcus angle (odds ratio, 4.87; 95% CI, 2.01-11.80; P = .0005), and Insall-Salvati ratio (odds ratio, 3.0; 95% CI, 1.34-6.70; P = .0074) were significant predictors of redislocation. Receiver operator characteristic curves defined the cut points to be sulcus angle >=154 degrees and Insall-Salvati ratio >=1.3. The probability of redislocation based on the presence of factors was 5.8% with no factors present and 22.7% with any 1 factor present, increasing to 78.5% if all 3 factors were present. CONCLUSION:: This model demonstrates a high risk of lateral patellar redislocation when a patient presents with skeletal immaturity as well as magnetic resonance measurements of sulcus angle >=154 degrees and patellar height as measured by Insall-Salvati ratio >=1.3. A patient will have a low risk of lateral patellar redislocation with the inverse findings. PMID- 30398903 TI - Repression of adipose Vascular Endothelial Growth Factor reduces obesity through adipose browning. AB - Obesity is the results of excessive energy accumulation and associated with many diseases. We previously reported that universal repression of vascular endothelial growth factor (VEGF) leads to brown-like adipocyte development in white adipose tissues and mice are resistant to obesity. Using an adipose specific VEGF repression mouse model (aP2-rtTR-krabtg/+/VEGFtetO/tetO), we show that adipose-specific VEGF repression can repeat the previous phenotypes including adipose browning, increased energy consumption and reduction in body weight. Expression of brown adipose-associated genes are increased and white adipose-associated genes are down regulated. Our study demonstrates that adipose specific VEGF repression can lead to an anti-obesity activity through adipose browning and have potential clinical values. PMID- 30398904 TI - Role of pregnancy and obesity on vitamin D status, transport, and metabolism in baboons. AB - INTRODUCTION: Human studies show that obesity is associated with vitamin D insufficiency, which contributes to obesity-related disorders. Our aim was to elucidate the regulation of vitamin D during pregnancy and obesity in a non-human primate species. METHODS: We studied lean and obese non-pregnant and pregnant baboons. Plasma 25-OH-D and 1alpha,25-(OH)2-D metabolites were analyzed using ELISA. Vitamin D-related gene expression was studied in maternal kidney, liver, subcutaneous fat, and placental tissue using real-time PCR and immunoblotting. RESULTS: Pregnancy was associated with an increase in plasma bioactive vitamin D levels compared to non-pregnant baboons in both lean and obese groups. Pregnant baboons had lower renal 24-hydroxylase CYP24A1 protein and chromatin-bound vitamin D receptor (VDR) than non-pregnant baboons. In contrast, pregnancy upregulated the expression of CYP24A1 and VDR in subcutaneous adipose tissue. Obesity decreased vitamin D status in pregnant baboons (162 +/- 17 vs. 235 +/- 28 nM for 25-OH-D; 671 +/- 12 vs. 710 +/- 10 pM for 1alpha,25-(OH)2-D, obese versus lean pregnant baboons, p<0.05). Lower vitamin D status correlated with decreased maternal renal expression of the vitamin D transporter cubulin and the 1 alpha hydroxylase CYP27B1. Maternal obesity also induced placental downregulation of the transporter megalin (LRP2), CYP27B1, the 25-hydroxylase CYP2J2, and VDR. CONCLUSIONS: Baboons represent a novel species to evaluate vitamin D regulation. Both pregnancy and obesity altered vitamin D status. Obesity-induced downregulation of vitamin D transport and bioactivation genes are novel mechanisms of obesity-induced vitamin D regulation. PMID- 30398905 TI - Skeletal muscle interstitial fluid metabolomics at rest and associated with an exercise bout: application in rats and humans. AB - Blood or biopsies are often applied to characterize metabolites that are modulated by exercising muscle. However, blood has inputs derived from multiple tissues, biopsies cannot discriminate secreted vs. intracellular metabolites and their invasive nature is challenging for frequent collections in sensitive populations (e.g., children, pregnant women). Thus, minimally-invasive approaches to interstitial fluid (IF) metabolomics would be valuable. A catheter was designed to collect gastrocnemius IF from acutely anesthetized adult male rats, at rest or immediately following 20 min. exercise (~60% VO2max). Using non targeted, gas chromatography/time-of-flight mass spectrometry analysis, 299 metabolites were detected, including non-annotated metabolites, sugars, fatty acids, amino acids, purine metabolites and derivatives. Just 43% of all detected metabolites were in common between IF and blood plasma, and only 20% of exercise modified metabolites were shared in both pools, highlighting that the blood does not fully reflect the metabolic outcomes in muscle. Notable exercise patterns included increased IF amino acids (except Leu and Isoleu), increased alpha ketoglutarate and citrate (which may reflect tricarboxylic acid cataplerosis or shifts in non-mitochondrial pathways), and higher concentration of the signaling lipid oleamide. A preliminary study of human muscle IF was conducted using a 20 kDa microdialysis catheter placed in the vastus lateralis of 5 healthy adults at rest and during exercise (60% VO2max, 30 min). Approximately 70% of commonly detected metabolites discriminating rest and exercise in rats were also changed in exercising humans. Interstitium metabolomics may aid in the identification of molecules that signal muscle work (e.g., exertion, fatigue) and muscle health. PMID- 30398906 TI - Developmental origins of myocardial abnormalities in postnatal life. AB - Poor quality and quantity maternal nutrition during the plane of pregnancy exerts permanent and damaging effects on the heart of the developing fetus. The developmental origin of adult heart disease is considered as an important and critical factor in the pathogenesis of myocardial abnormalities in later life. Low birth weight, a marker of intrauterine stress, has been linked to predisposition to heart disease. In this article, our work on the impact of exposure to a low protein diet, in utero, on the developing heart as well as its long term consequences are discussed. Other studies providing some supportive evidence are also described. It is proposed that normal fetal nutrition, growth and development through efficient maternal nutrition (as well as other predisposing factors) before and during pregnancy may serve as a strategy for the primary prevention of heart disease. PMID- 30398907 TI - Colletotrichum orbiculare MTF4 is a key transcription factor downstream of MOR essential for plant signal-dependent appressorium development and pathogenesis. AB - The cucumber anthracnose fungus, Colletotrichum orbiculare, forms a specialized infection structure, called an appressorium. Appressorium differentiation relies on fungal perception of physical and biochemical signals at the plant surface. Our previous report showed that the morphogenesis-related NDR (nuclear Dbf2 related) kinase pathway (MOR) is crucial for translating plant-derived signals for appressorium development. Here, we focused on identifying transcriptional regulators downstream of MOR that are involved in plant signal sensing and transduction for appressorium development. Based on whole-genome transcript profiling, we identified a Zn(II)2Cys6 transcription factor, CoMTF4, as a potential downstream factor of MOR. CoMTF4 was expressed in planta rather than in vitro under the control of the NDR kinase CoCbk1. Phenotypes of comtf4 mutants, strains with constitutively active CoCbk1 and strains with constitutive overexpression of CoMTF4 suggested that CoMtf4 acts downstream of MOR. Furthermore, nuclear localization of CoMtf4 was dependent on the MOR and responsive to plant-derived signals that lead to appressorium morphogenesis. Thus, we conclude that CoMtf4 is a transcription factor downstream of MOR that is essential for appressorium morphogenesis and pathogenesis and is regulated in response to plant-derived signals. This study provides insights into fungal sensing of plant signals and subsequent responses critical for appressorium formation. PMID- 30398908 TI - A toolbox for nodule development studies in chickpea: a hairy-root transformation protocol and an efficient laboratory strain of Mesorhizobium sp. AB - Mesorhizobium sp. produces root nodules in chickpea. Chickpea and model legume Medicago truncatula are members of inverted repeat lacking clade (IRLC). The rhizobia after internalization into the plant cell are called 'bacteroid'. Nodule Specific Cysteine-rich (NCR) peptides in IRLC legumes guide bacteroids to a 'terminally differentiated swollen (TDS)' form. Bacteroids in chickpea are less TDS than those in Medicago. Nodule development in chickpea indicates recent evolutionary diversification and merits further study. A hairy root transformation protocol and an efficient laboratory strain are prerequisites for performing any genetic study on nodulation. We have standardized a protocol for composite plant generation in chickpea with a transformation frequency above 50 %, as shown by fluorescent markers. This protocol also works well in different ecotypes of chickpea. Localization of subcellular markers in these transformed roots is similar to the localization observed in transformed Medicago roots. When checked inside transformed nodules, peroxisomes were concentrated along the periphery of the nodules, while ER and Golgi bodies surrounded the symbiosomes. Different Mesorhizobium strains were evaluated for their ability to initiate nodule development and efficiency of nitrogen fixation. Inoculation with different strains resulted in different shapes of TDS bacteroids with variable nitrogen fixation. Our study provides a toolbox to study nodule development in the crop legume chickpea. PMID- 30398909 TI - The anti-inflammatory and anti-fibrotic effects of tadalafil in thioacetamide induced liver fibrosis in rats. AB - Liver fibrosis is a health concern that leads to organ failure mediated via production of inflammatory cytokines and fibrotic biomarkers. This study aimed to explore the protective effect of tadalafil, a phosphodiesterase-5 inhibitor, against thioacetamide (TAA)-induced liver fibrosis. Fibrosis was induced by administration of TAA (200 mg/kg, i.p.) twice weekly for 6 weeks. Serum transaminases activities, liver inflammatory cytokines, fibrotic biomarkers, and liver histopathology were assessed. TAA induced marked histopathological changes in liver tissues coupled with elevations in serum transaminases activities. Furthermore, hepatic content of nitric oxide and tumor necrosis factor-alpha, interleukin-6, and interleukin-1 beta were elevated, together with a reduction of interleukin-10 in the liver. In addition, TAA increased hepatic contents of transforming growth factor-beta, hydroxyproline, alpha-smooth muscle actin, and gene expression of collagen-1. Pretreatment with tadalafil protected against TAA induced liver fibrosis, in a dose-dependent manner, as proved by the alleviation of inflammatory and fibrotic biomarkers. The effects of tadalafil were comparable with that of silymarin, a natural antioxidant, and could be assigned to its anti inflammatory and anti-fibrotic properties. PMID- 30398910 TI - High PEEP: Only a Dam Against Edema Formation? Probably Not (Again). PMID- 30398911 TI - Combining the Pulmonary Rehabilitation Decisional Score with the Bode Index and Clinical Opinion in Assigning Priority for Pulmonary Rehabilitation. AB - Combining objective tools with clinical decision (CD) may help clinicians identify the priority for pulmonary rehabilitation (PR) in patients with COPD. We aimed to assess the specificity, sensitivity and efficiency of a new tool, the Pulmonary Rehabilitation Decisional Score (PRDS), and its correlation with the BODE index (BI) and CD in assigning PR priority. We retrospectively compared the three methods (CD vs. PRDS vs. BI) in 124 patients. We assigned low priority (LP), high priority (HP) and very high priority (VHP) to PR based on a priori scores of PRDS (LP = 0-10; HP = 11-17; VHP >=18) and BI (LP = 0-2; HP = 3-5; VHP >=6) and compared these with CD. PR priority assigned by the different methods was similar among groups, but did not often refer to the same subjects. PRDS and BI showed very high concordance with CD in defining VHP (97.8% and 95.6% for PRDS and BI, respectively), but were less concordant with CD in assigning LP and HP. Both PRDS and BI differently evaluated 38/124 cases compared to CD (PRDS underprescribed 18 and overprescribed 20; BI underprescribed 19 and overprescribed 19). However, a direct comparison between PRDS and BI showed that the discordance decreased to 8 underprescriptions and 10 overprescriptions (efficiency ~85%). An objective instrument such as the PRDS can enhance CD with additional information on new aspects such as disability and fragility. PRDS and BI are nonetheless equally efficient at detecting discrepancies versus CD alone, especially when the priority for PR is defined as low or very high. PMID- 30398912 TI - The Role of the Pathologist in Population Health. AB - CONTEXT.-: As part of its Value-Based Care initiative, the College of American Pathologists has pursued research to better understand the role pathologists can have in population health. OBJECTIVES.-: To answer the following questions: (1) what is the impact of population health and population health management on pathologists; (2) what roles are pathologists playing in population health management; (3) is population health something that pathologists in both larger and smaller settings can engage in; (4) are pathologists in a position to analyze laboratory data for population health, and, if so, what are the key information sources those pathologists must access; and (5) what steps can a pathologist take to become involved in population health? DESIGN.-: We conducted 10 semistructured interviews with pathologists and other medical laboratory leaders who have been active in population health. These interviews were supplemented with a review of the medical literature. RESULTS.-: Pathologists have demonstrated that laboratory data can provide unique value-added contributions to improving the health of populations. These contributions are not limited to pathologists in large, integrated settings. However, pathologists need to be proactive to contribute to health systems' population health efforts and may need to both enhance their own skills and the quality of their data to maximize the value of their contributions. CONCLUSIONS.-: Although not necessarily a definitive summary of the roles that pathologists are playing in population health, this article identifies some of the promising and innovative activities occurring among pathologists and laboratorians. PMID- 30398913 TI - "Please Help Me See the Dragon I Am Slaying": Implementation of a Novel Patient Pathologist Consultation Program and Survey of Patient Experience. AB - CONTEXT.-: Pathologists evaluate human disease and teach medical students, residents, and clinicians. Historically recognized as the "doctor's doctor," pathologists are well suited to be a direct patient resource of individualized, accurate information. OBJECTIVE.-: To develop and implement a pathology consultation service whereby patients review their tissue slides directly with the pathologists. DESIGN.-: A pathologist conducted patient consultations, reviewing biopsy or surgery findings on a multiheaded microscope or computer screen. The pathologist evaluated patients' understanding of their disease and invited patients to ask specific questions. We recorded patient demographic data and assessed utilization with a short patient satisfaction survey using 6 questions with a 5-point Likert scale and 2 questions for open response. RESULTS. : A total of 31 patients came for consultation; 39% (12 of 31) were accompanied by a friend or family member. Patients' median age was 59 years, with a strong female predominance (90%; 28 of 31). The majority of patients had breast cancer (58%; 18 of 31) or hematologic malignancy (19%; 6 of 31). Of the 31 patients, the survey response rate was 58% (18 of 31). Top-box scoring demonstrated program support, with 89% (16 of 18) of respondents strongly recommending the experience to another patient. Additionally, 78% (14 of 18) strongly agreed that they felt more empowered after seeing their disease. Mean scores for Likert-based questions all were higher than 4.0. CONCLUSIONS.-: To our knowledge, this study is the first report of direct patient-pathologist consultation. Early data suggest that the program may provide effective patient-specific education. The high response rate and favorable assessment of the program suggest that it may be a valuable resource for some patients. PMID- 30398914 TI - Mucinous Cystadenoma of the Urachus and Review of Current Classification of Urachal Mucinous Cystic Neoplasms. AB - Urachal neoplasms are uncommon and represent a minor portion of bladder tumors. According to the recently updated World Health Organization classification (2016), these tumors are classified as adenomas, adenocarcinomas, nonglandular neoplasms, and mixed carcinomas. The mucinous cystic neoplasms represent a small percentage of urachal tumors with morphologic spectrum ranging from benign mucinous cystadenoma to borderline mucinous cystic tumor of low malignant potential and to malignant mucinous cystadenocarcinoma. Benign urachal mucinous cystic adenomas are exceedingly rare, and only a few cases have been reported in literature to date. The goal of this review is to summarize the clinical features, histopathologic characteristics, treatment, and prognosis of urachal mucinous cystadenoma in the light of differentiating them from mucinous cystic tumor of low malignant potential and mucinous cystadenocarcinoma. PMID- 30398915 TI - The effect of the branched-chain amino acids on the in-vitro activity of bovine intestinal alkaline phosphatase. AB - Branched-chain amino acids (BCAA) are used as nutritional support for patients with a range of conditions including liver cirrhosis and in-born errors of amino acid metabolism, and are commonly used "sports"/exercise supplements. The effects of the BCAA on the in-vitro activity of calf intestinal alkaline phosphatase (EC. 3.1.3.1) were studied. All three BCAA were found to be uncompetitive inhibitors of the enzyme with L-leucine being the most potent (Ki' = 24.9mM) and L-valine, the least potent (Ki' = 37mM). Mixed BCAA are able to act in combination to inhibit the enzyme. Given the important role of intestinal alkaline phosphatase in gut homeostasis, these findings have potential implications for those taking high levels of BCAA as supplements. PMID- 30398916 TI - Health Status in Patients with COPD According to GOLD 2017 Classification: Use of the COMCOLD Score in Routine Clinical Practice. AB - The COMCOLD score was developed to quantify the impact of comorbidities on health status in patients with chronic obstructive pulmonary disease (COPD). The objective of this study is to evaluate the association between health status in outpatients with COPD according to COMCOLD score and the GOLD 2017 groups according to symptoms (B and D vs. A and C) and exacerbations (C and D vs. A and B). 439 patients were included. The average score was 2.4 +/- 3. 48% of cases had a COMCOLD score >0. The most symptomatic patients (B and D vs. A and C) had a higher score: 3 +/- 3.3 vs. 1.3 +/- 2.1 (p < 0.001), in contrast with the groups with a higher risk of exacerbation (C and D vs. A and B) in which there was no significant difference: 3 +/- 3.5 vs. 2.2 +/- 3.0 (p = 0.055). The most symptomatic patients (B and D) showed a greater prevalence of depression, peripheral artery disease and heart disease with an adjusted OR of 3.04 [CI95%: 1.36; 6.86], 2.49 [CI95%: 1.17; 5.29], and 4.41 [CI95%: 2.50; 7.75], respectively. Moreover, no relationship was found between the comorbidities defined by the COMCOLD score and the GOLD 2017 groups with the greatest risk of exacerbation (C and D). The greatest effect on health status was found in those patients with COPD belonging to the most symptomatic groups (B and D), with depression, peripheral artery disease, and heart disease being the main comorbidities involved. PMID- 30398917 TI - Caseload profiling in district nursing: a systematic literature review. AB - This systematic literature review aims to identify and appraise current evidence to establish if caseload profiling (CP) provides a strategy to support district nurses to evidence and manage increasingly complex caseloads. A total of 17 studies where thematically synthesised and recurrent themes were identified and summarised under the headings of: defining caseload profiling; caseload profiling in the context of caseload management; workload analysis and its relationship to caseload profiling; potential impact of caseload profiling; and potential barriers to caseload profiling. The literature review showed CP is a robust method of articulating the complexity of care and practitioners could use it to help manage their own caseloads. However, the literature is mainly founded on expert opinion and further research is needed to strengthen the validity of the evidence. PMID- 30398918 TI - Lasting powers of attorney. AB - A key justification for introducing a law that regulates decision-making for those who are unable to make choices because of incapacity, was to allow people to prepare for future incapacity, by choosing people they trust to make those decisions on their behalf. In England and Wales, the Mental Capacity Act 2005 provides the opportunity for adults to do this through the use of a lasting power of attorney (Mental Capacity Act 2005, sections 9-14). In this article, Richard Griffith considers lasting powers of attorney for health and care and their impact on district nurse practice. PMID- 30398920 TI - Is death still a taboo subject in palliative care? PMID- 30398919 TI - Evaluation of a novel night-time compression garment: a prospective observational study. AB - This prospective, single-centre, observational study set out to evaluate the clinical performance and safety of JOBST Relax(r), a custom-made compression garment, when worn by a series of patients with lymphoedema during resting hours and at night. Patients were recruited after undergoing complete decongestive therapy (CDT) and wore the night-time compression garment for 21 days as part of their compression therapy regimen. Questionnaires were used to capture their views on parameters such as the garment's comfort, ease of use, fit, ability to avoid excessive heat and perspiration, its effect on their quality of life and their overall satisfaction with it. Occurrences of erythema, skin rash, skin dryness and pain were also evaluated. Ninety-one patients completed the study. Most perceived the night-time compression garment to be 'very good' or 'good' in terms of its ease of use and comfort, its ability to control their oedema and its effect on their quality of sleep. The prevalence of erythema, skin rash, skin dryness and pain was reduced when compared with baseline. Patients also reported that the night-time garment reduced their dependence on others and improved their quality of life. Overall, most rated their satisfaction with the garment as 'very good' or 'good'. Patients reported a high level of satisfaction with both the garment and the comfort associated with it when wearing it frequently. PMID- 30398921 TI - Silence to voice. PMID- 30398922 TI - Winter and the key infection prevention and control practices. PMID- 30398923 TI - Improving the personalisation of care in a district nursing team: a service improvement project. AB - Service users can benefit in a variety of ways from a personalised approach to care. This service improvement project aimed to improve personalisation for patients being cared for by a community nursing team in the south of England. A plan, study, do, act (PDSA) approach to the project was undertaken with a community nursing team. Both quantitative and qualitative data showed improvement once the focus on personalisation had been improved. Patient and staff satisfaction scores improved and a documentation audit showed the focus on personalisation had increased. Qualitative data suggested that personalisation had also saved staff time, although this measurement was not included in the project. A focus on personalisation can be beneficial for staff and service users. PMID- 30398924 TI - Achieving care integration. PMID- 30398925 TI - Drug adherence and symptom management in older people. AB - There are a number factors that need to be considered when managing frail older people with multiple health problems. Inappropriate polypharmacy and poor adherence, particularly in older adults, is associated with negative health outcomes. In addition to assessing the patient's current symptoms and health status, it is therefore important to consider which medications patients are prescribed, whether they are appropriate and whether they are being taken as prescribed. This case study aims to increase awareness of poor adherence to medication in the older adult population. PMID- 30398926 TI - Coordinated Tcf7l2 regulation in a mouse model implicates Wnt signaling in Fetal Alcohol Spectrum Disorders. AB - Mouse models of fetal alcohol spectrum disorders (FASD) have repeatedly identified genes with long-term changes in expression, DNA methylation, noncoding RNA and histone modifications in response to neurodevelopmental alcohol exposure. Articulation of FASD is achieved via alcohol's effect on gene expression, likely involving epigenetic regulation. The list of genes affected is large and heterogeneous, depending on experimental protocol. We present reanalysis and synthesis of results highlighting Wnt transcription factor 7 like 2 (Tcf7l2) gene as uniquely compatible with hippocampal DNA methylation, histone modifications, and gene expression changes in a coordinated response to neurodevelopmental alcohol exposure. We data-mined literature for Tcf7l2 alterations in response to prenatal alcohol exposure. Four studies identified changes in brain Tcf7l2 expression in different FASD models. Further, we performed an in silico TCF7L2 binding site analysis for FASD mouse model datasets. Seven of these published gene lists were significantly enriched for TCF7L2 binding, indicating potential functional relationships. Finally, TCF7L2 is involved in regulation of hundreds of genes, with a role in brain development, myelination, and neuronal function. Tcf7l2 may be involved in neurological defects associated with alcohol exposure via dysregulation of many genes through Wnt signaling. Further functional work is warranted to validate this model for FASD. PMID- 30398929 TI - School and Community Socioeconomic Status and Access to Athletic Trainer Services in Wisconsin Secondary Schools. AB - CONTEXT: Secondary schools have made significant progress in providing athletic trainer (AT) coverage to their student-athletes, but the levels of access at schools with ATs may vary widely. Socioeconomic disparities in medical coverage and access have been noted in other health care fields, but such disparities in the level of access to AT services have not been thoroughly examined. OBJECTIVE: To determine if (1) access to AT services or (2) the level of access (AT hours per week and athletes per AT hour) differed based on the socioeconomic characteristics of secondary schools. DESIGN: Cross-sectional study. SETTING: Mailed and e-mailed surveys. PATIENTS OR OTHER PARTICIPANTS: High school athletic directors and ATs from 402 Wisconsin high schools. MAIN OUTCOME MEASURE(S): Respondents provided information as to whether their school used the services of an AT and the number of hours per week that their school had an AT on-site. The number of athletes per AT hour was calculated by dividing the total number of athletes at the school by the number of hours of AT coverage per week. The socioeconomic status of each school was determined using the percentage of students with free or reduced-cost lunch and the county median household income (MHI). RESULTS: Schools without an AT on-site were in lower MHI counties ( P < .001) and had more students eligible for a free or reduced-cost lunch ( P < .001). Lower levels of AT access (fewer hours of AT access per week and more athletes per AT hour) were observed at schools in the lowest third of the county MHI and with the highest third of students eligible for a free or reduced-cost lunch ( P < .001). CONCLUSIONS: Socioeconomic disparities were present in access to AT services. New models are needed to focus on providing a high level of AT access for all student-athletes, regardless of socioeconomic status. PMID- 30398930 TI - Cost-Benefit of Hiring Athletic Trainers in Oregon High Schools From 2011-2014. AB - CONTEXT: Hiring athletic trainers (ATs) in high schools may lower medical payments by third-party payers such as Medicaid or commercial insurers by reducing injury risks or may increase medical payments due to more referrals to other health care providers. To date, evidence is lacking on the actual financial effect of high school ATs based on an analysis of medical claims. OBJECTIVE: To assess the overall cost-benefit of hiring ATs in Oregon high schools based on medical claims data across years. DESIGN: Descriptive epidemiology study. SETTING: Oregon public high schools. PATIENTS OR OTHER PARTICIPANTS: Patients aged 14 to 18 years old. MAIN OUTCOME MEASURE(S): We analyzed the 2011-2014 limited dataset from the Oregon Health Authority's All Payer All Claims Database. Paired t tests were used to compare claims payments at the zip code level between periods of having and not having ATs in Oregon high schools. We also used the percentage of AT effort to adjust for AT investment. The main outcome measure was the return on investment associated with hiring ATs in high schools. RESULTS: The presence of ATs in Oregon high schools may have had different effects on medical payments for Medicaid and commercial insurance. With every dollar invested in hiring ATs in Oregon public high schools from 2011 to 2014, Medicaid payments increased by 24 cents per month at the zip code level, while commercial insurance payments decreased by 24 cents, although the changes were not statistically significant. CONCLUSIONS: Hiring ATs in an outreach model for high schools may not necessarily generate medical savings for Medicaid or commercial insurers. Further research is needed to determine if the lack of cost savings in our study was a factor of the employment model, resulted from increased health care utilization, or reflected the need for ATs to deliver more on-site AT services. PMID- 30398927 TI - Multidimensional Assessment of the Host Response in Mechanically Ventilated Patients with Suspected Pneumonia. AB - RATIONALE: The identification of informative elements of the host response to infection may improve the diagnosis and management of bacterial pneumonia. OBJECTIVE: To determine whether the absence of alveolar neutrophilia can exclude bacterial pneumonia in critically ill patients with suspected infection and to test whether signatures of bacterial pneumonia can be identified in the alveolar macrophage transcriptome. METHODS: We determined the test characteristics of alveolar neutrophilia for the diagnosis of bacterial pneumonia in 3 cohorts of mechanically ventilated patients. In one cohort, we also isolated macrophages from alveolar lavage fluid and used the transcriptome to identify signatures of bacterial pneumonia. Finally, we developed a humanized mouse model of Pseudomonas aeruginosa pneumonia to determine if pathogen-specific signatures can be identified in human alveolar macrophages. MEASUREMENTS AND MAIN RESULTS: An alveolar neutrophil percentage < 50% had a negative predictive value of > 90% for bacterial pneumonia in both the retrospective (N = 851) and validation cohorts (N = 76 and N = 79). A transcriptional signature of bacterial pneumonia was present in both resident and recruited macrophages. Gene signatures from both cell types identified patients with bacterial pneumonia with test characteristics similar to alveolar neutrophilia. CONCLUSIONS: The absence of alveolar neutrophilia has a high negative predictive value for bacterial pneumonia in critically ill patients with suspected infection. Macrophages can be isolated from alveolar lavage fluid obtained during routine care and used for RNA-Seq analysis. This novel approach may facilitate a longitudinal and multidimensional assessment of the host response to bacterial pneumonia. PMID- 30398928 TI - Return to Learn After Sport-Related Concussion: A Survey of Secondary School and Collegiate Athletic Trainers. AB - CONTEXT: Recent recommendations have emphasized return-to-learn (RTL) protocols to aid athletes in recovery from sport-related concussion (SRC) but have been based primarily on anecdotal evidence. OBJECTIVE: To investigate the RTL practices of certified athletic trainers (ATs) after an SRC. DESIGN: Cross sectional study. SETTING: Online survey. PATIENTS OR OTHER PARTICIPANTS: A total of 1083 individuals (27%) from a random sample of 4000 ATs in the National Athletic Trainers' Association membership database completed an electronic survey. Participants consisted of 729 self-identified secondary school ATs (SSATs; 67.3%; experience = 14.0 +/- 9.7 years) and 354 self-identified collegiate ATs (CATs; 32.7%; experience = 13.4 +/- 9.7 years). MAIN OUTCOME MEASURE(S): We used chi2 analyses to assess respondent differences related to current knowledge, current practices, and available resources. Independent t tests were used to compare SSATs and CATs on years of certification and annual number of SRCs evaluated. RESULTS: Of our total respondents, 41.2% (n = 446) correctly indicated the absence of evidence-based RTL guidelines. Whereas most (73.9%, n = 800) respondents had an established RTL policy, only 38.1% (n = 413) used such guidelines in their clinical practice. Most (97.1%, n = 708) SSATs and 82.2% (n = 291) of CATs had access to (a) mental health professional(s); however, minorities of SSATs (21.4%, n = 156) and CATs (37.0%, n = 131) never accessed these resources to care for concussed student-athletes. CONCLUSIONS: Our results suggested that, despite the absence of empirical evidence, most surveyed ATs incorporated some form of RTL protocol in their SRC management policy. The varying AT knowledge, clinical practices, and resources highlighted by our results should be considered when creating or refining an RTL protocol. PMID- 30398931 TI - Outcome of subtrochanteric femur resection in patients with spinal cord injuries. AB - OBJECTIVE:: To analyse the clinical outcome of subtrochanteric femur resection in patients with infected hip joints caused by pressure ulcers (PUs) in patients following spinal cord injury (SCI). METHOD:: A retrospective cohort study, carried out between January 2004 and December 2015. Only patients receiving a subtrochanteric femur resection were included. SCI patients were treated for a hip joint infection caused by a PU. Primary outcome measures were to work out the revision rates and the rate of heterotopic ossification occurrence. RESULTS:: At the time of admission, 37 out of the 56 participating patients (66.1%) showed a category IV PU with the ischium being most commonly affected (n=25, 44.6%). The subtrochanteric femur resection was combined either with a direct wound closure (n=29; 51.8%) or a myocutaneous flap (n=27; 48.2%). The mean number of surgeries was 2.6 (1-4; SD=1.6) and 21 patients were successfully treated by a single surgery. Of the patients, 28 had wound healing disorders (50%) and required a revision surgery, and 24 (42.9%) developed a postoperative heterotopic ossification. CONCLUSION:: Hip joint infection caused by PUs can be treated with subtrochanteric femur resection. However, the number of postoperative complications is still high. PMID- 30398932 TI - Preliminary experience of an expert panel using Triangle Wound Assessment for the evaluation of chronic wounds. AB - OBJECTIVE:: Wound assessment is an essential part of wound management and has traditionally focused on the wound bed. The Triangle of Wound Assessment (Triangle) is a new assessment tool that includes a holistic evaluation of the patient with a wound. The aim of this pilot study was to describe the use of the Triangle in our clinical practice in Spain. METHODS:: Prospective, consecutive patients, male and female, over 18 years old, with wounds of any aetiology and duration, who attended the centres involved in the study, were recruited between May and June 2017. The TWA was used during the first presentation, to assess the wound bed, edge and periwound skin. The study's expert panel met to discuss the results collected by the assessment, as well as the advantages and disadvantages of the system. RESULTS:: We recruited 90 patients. Non-viable tissue (necrotic/sloughy) was recorded in 57.8% of the patients, elevated exudate (medium/high) in 52.2%. Approximately 25% of the patients had signs or symptoms of local infection. Maceration was the most prevalent issue recorded on the wound edge and periwound skin assessment, affecting 31.1% and 30.0% of the patients, respectively. The presence of hyperkeratosis was high for the study population as the main aeitologies of the wounds identified here were DFU. CONCLUSIONS:: The implementation of Triangle Wound Assessment could help in the holistic approach to patient care by focusing on more than local wound care, identifying barriers to achieving wound healing and evaluating wound response and patient compliance. PMID- 30398933 TI - Effects of haem oxygenase-1 expression on oxidative injury and biological behaviours of rat dermal fibroblasts. AB - OBJECTIVE:: This study investigated the effects of high haem oxygenase-1 (HO-1) expression on oxidative injury and the biological behaviours of rat dermal fibroblasts, under high glucose conditions. METHOD:: Rat dermal fibroblasts were cultured in normal glucose (1.0g/l), high glucose (4.5g/l) or haemin (5MUm). A bilirubin kit, real-time polymerase chain reaction (RT-PCR) and Western blotting measured the protease activity, mRNA, and protein levels of HO-1, respectively. An enzyme-linked immunosorbent assay (ELISA) kit measured media levels of 8 hydroxydeoxyguanosine (8-OHdG), reactive oxygen species (ROS) and collagen (hydroxyproline) secretion. Cell proliferation was measured using flow cytometry. Cell apoptosis was measured using Hoechst 33258 staining and flow cytometry. The transwell method and scratch test evaluated cell migration. RESULTS:: HO-1 expression exhibited a time-dependent change that was lowest in the high glucose (HG) group at 96 hours compared with the normal glucose (NG) group. In the HG group, the 8-OHdG, ROS and cell apoptosis were increased, and collagen secretion, cell proliferation and cell migration (horizontal and vertical) were decreased compared with the NG group at 96 hours. Haemin treatment sustained high HO-1 expression for at least 96 hours, and the cells exhibited decreased 8-OHdG and ROS, increased collagen synthesis, improved proliferation and migration ability, and decreased apoptosis in the NG and haemin (NH) group/HG and haemin (HH) group compared with the NG/HG groups. These cells recovered from oxidative injury and biological behaviours dysfunction. CONCLUSION:: Haemin induces HO-1 expression in fibroblasts and it may influence the oxidative injury and biological behaviours of fibroblasts. These findings suggest that HO-1 may accelerate the healing of diabetic wounds via alleviation of oxidative injury and improvement of biological behaviours of fibroblasts. PMID- 30398934 TI - Treating mucormycosis using a multimodality approach: a case series. AB - Most fungal infections found in wounds are secondary or superadded, and are generally benign in their clinical course in healthy individuals, with the exception of mucormycosis. This is a life-threatening infection caused by fungi of the order Mucorales. Primary cutaneous disease may occur following traumatic implantation of spores, or use of contaminated bandages, or as a complication of extensive burns, diabetic acidosis and other specific immunocompromised conditions. The clinical spectrum is highly non-specific and is often triggered by seemingly innocuous trauma. The superficial vesicles or patchy erythema rapidly degrade to haemorrhagic necrosis and rapidly progressive gangrenous lesion. The problem with diagnosing mucormycosis remains, therefore, that the condition has poor clinical indicators and requires reliance on microscopy and fungal culture. Management starts with a clinical suspicion, taking into account the risk factors and lack of response to first-line agents, as well as an aggressive clinical course. Treatment is multimodal, with medical correction of the risk factors and optimisation of limiting factors, such as diabetes, neutropenia and immunosuppressants. Treatment generally involves radical and repetitive surgical debridement, intravenous amphotericin B with monitoring of the nephrotoxicity, along with adjuvant modalities, such as hyperbaric oxygen therapy, colony stimulating factor, interferons gamma and white blood cell transfusion. Successful courses of therapy typically last 4-6 weeks and require cumulative doses that are equivalent to >2g of amphotericin B deoxycholate. PMID- 30398935 TI - Uncontrolled gelatin degradation in non-healing chronic wounds. AB - OBJECTIVE:: To compare matrix metalloproteinase (MMP)-9 and the antiproteinase tissue inhibitor of metalloproteinases (TIMP)-1 in wound fluids and sera from patients with chronic non-healing or acute healing wounds. In addition, the functional consequences on MMP-9 activity and general gelatinase activity were assessed. METHOD:: In this observational study, samples were collected from patients with venous leg ulcers (VLUs), patients with type 2 diabetes with neuropathic foot ulcers (DFUs), and from another cohort of VLU patients with sterile split-thickness skin graft donor sites after autologous skin grafting, serving as healing control wounds. MMP-9 and TIMP-1 concentrations were determined by enzyme-linked immunosorbent assays. MMP-9 and gelatinase activities were determined in wound fluids in subsets of the patients. RESULTS:: A total of 24 patients took part in the study. No significant differences in MMP-9 wound fluid levels were found among the three groups. TIMP-1 levels were markedly and significantly lower in the two chronic wound groups resulting in a severely unbalanced MMP-9/TIMP-1 ratio, especially notable in the VLU group and possibly in the elevated endogenous MMP-9 activity (p<0.01) compared with the acute wound fluids. At least 20% of the chronic wound fluids displayed atypical patterns on gelatin zymography and showed high general gelatinase activity that was not inhibited by either TIMP-1 or by a gelatinase inhibitor (AG3340). MMP-9 levels were higher in the sera of the patients with type 2 diabetes. CONCLUSION:: We hypothesise that non-MMP proteinases contribute to matrix destruction in a significant number of chronic wounds. Blocking the excessive MMP-9 activity may be insufficient to normalise wound healing. The reasons and effects of the very low TIMP-1 levels in chronic wounds need further clarification. PMID- 30398936 TI - Topical sucralfate cream treatment for aplasia cutis congenita with dystrophic epidermolysis bullosa: a case study. AB - Bart syndrome consists of aplasia cutis congenita (ACC) and dominant or recessive dystrophic epidermolysis bullosa (DEB), associated with skin fragility and nail dysplasia. ACC in DEB is thought to be caused by trauma, the most cited cause being in utero formation of bullae consequent to friction of the limbs. Epidermolysis bullosa (EB) refers to a hereditary mechanobullous disease following trauma, characterised by formation of blisters on the skin and mucous membranes. There are four categories of the disease, including epidermolysis bullosa simplex, junctional epidermolysis bullosa, dystrophic epidermolysis bullosa and Kindler syndrome. Infection, sepsis and death may occur as a consequence of generalised blistering with complication. We present the case of a newborn diagnosed with DEB and whose lesions became almost fully epithelialised after treatment with 10% topical sucralfate. PMID- 30398937 TI - The need for a timely diagnostic workup for patients with venous leg ulcers. AB - OBJECTIVE:: To explore the need for an extended diagnostic workup in patients with venous leg ulcers (VLUs) and to establish the prevalence of the underlying causes of VLU. METHOD:: This retrospective cohort study analysed data from patients with VLU. The visual analogue scale (VAS) was used for pain assessment. The ankle-brachial index (ABI) was measured to exclude patients with arterial pathology. A duplex was performed. All patients received a wound treatment plan and ambulatory compression therapy. Continuous variables were presented as mean+/ standard deviation (SD) or median and interquartile range (IQR). Mann-Whitney U test and Kruskal-Wallis were used. When normally distributed, an independent sample t-test was used. RESULTS:: A total of 70 patients were recruited. Of these, 18 (25.7%) experienced a VLU once and 52 (74.3%) had a recurrent VLU. Treatment of the underlying lesions was performed in almost 30% of patients. Patients who were treated showed almost two times slower healing rates compared with those who were not treated for an underlying pathology. The mean time in patient referral exceeded two years, and patients who did not see their GP were treated by nurses who did not provide regular feedback the GP; as a result, compression therapy was not always adequate. CONCLUSION:: Patients with a VLU showing no signs of healing after 2 months should be referred to a dedicated wound care centre to avoid delays. PMID- 30398939 TI - Do you know what we did last fall? PMID- 30398938 TI - Antimicrobial assessment of a chitosan microfibre dressing: a natural antimicrobial. AB - OBJECTIVE:: Chitosan is a natural biopolymer and is the main structural component of the cuticles of crustaceans, insects and molluscs and the cell walls of certain fungi. It is abundant in nature and is naturally antimicrobial. A natural fibre has been created with chitosan and is being used as a wound dressing, namely Kytocel. It is an absorbent fibre dressing that is claimed to be biodegradable and biocompatible. This study was undertaken to assess the antimicrobial properties of the microfibre wound dressing using a variety of methods commonly used to assess other antimicrobial dressings. METHOD:: The zone of inhibition (ZOI) assay, challenge test (log reduction), time-to-kill and an in vitro wound model were all used in this report. Representative Gram-positive and Gram-negative bacteria were used and one yeast, Candida albicans. RESULTS:: The ZoI test showed no observable zones around the dressing but killed the organisms underneath the dressing. There was a >3 log reduction of Staphylococcus aureus and Escherichia coli within two hours and >3 log reduction against Pseudomonas aeruginosa and Candida albicans between four and 24 hours in the challenge test. In the wound model, there was a 2 log reduction of Escherichia coli within the wound model and in the sponge and culture medium below the dressing. CONCLUSION:: The chitosan microfibre wound dressing gives wound care an additional dressing to use to help prevent and manage bioburden and wound infection. PMID- 30398940 TI - Skin Integrity and Infection Prevention Las Vegas: don't bust on biofilm, bet on dHACM. AB - The 4th International Skin Integrity and Infection Prevention conference, hosted by the Journal of Wound Care and the University of Huddersfield, was held earlier this year in Las Vegas. A key theme was the impact of biofilm on wound healing. In the second of our sponsored symposia reports, the manner in which delayed healing can be reversed through effective biofilm management, and the introduction of regulatory proteins found in dehydrated human amnion chorion membrane allograft were explained. PMID- 30398942 TI - Skin Integrity and Infection Prevention Las Vegas: the science of biofilm, a multifaceted challenge to healing. AB - At the 4th International Skin Integrity and Infection Prevention conference, hosted by the Journal of Wound Care and the University of Huddersfield, in Las Vegas, one of the main themes was the control and resolution of biofilm. A series of reports will describe the key points of four sponsored symposia at the event. The first of these concentrates on the role of biofilm in chronic wounds and new therapies to aid the healing of these wounds by disrupting biofilm. PMID- 30398941 TI - Evaluation of fluorescence biomodulation in the real-life management of chronic wounds: the EUREKA trial. AB - OBJECTIVE:: Fluorescence biomodulation (FB), a form of photobiomodulation (PBM) that is also known as low energy level light (LELL), has become an increasingly used clinical tool to induce wound healing in wounds that remain recalcitrant to treatment. In a real-life clinical setting, the aim of the EUREKA (EvalUation of Real-lifE use of Klox biophotonic system in chronic wound mAnagement) study was to confirm the efficacy and safety of LumiHeal, a system based on FB, in the treatment of chronic wounds such as venous leg ulcers (VLUs), diabetic foot ulcers (DFUs) and pressure ulcers (PUs). The effects of this FB system on the modulation of wound healing in chronic ulcers through FB induction were previously examined in an interim analysis of this study. METHOD:: A multicenter, prospective, observational, uncontrolled trial in 12 clinical sites in Italy. The wound was cleansed with saline and a 2mm thick layer of a chromophore gel was applied to the affected area in a biweekly regimen. The area was then illuminated with the LED activator for five minutes at a distance of 5cm. Treatment was used in combination with standard of care specific to each type of chronic wound (VLU, DFU, PU). Wound area evaluation was assessed using the Silhouette Imaging System and quality of life (QoL) with the Cardiff Wound Impact Schedule (CWIS). A seven point evaluation of the clinicans' view was also examined. RESULTS:: We enrolled 100 subjects, with the final analysis including 99 patients/ulcers consisting of 52 VLUs, 32 DFUs and 15 PUs. Total wound closure at the end of the study was achieved in 47 patients by aetiology: 26 VLUs (50% of VLUs); 16 DFUs (50% of DFUs); and five PUs (33.3% of PUs). The mean wound area regression at last study assessment was significant for VLUs (41.0%; p<0.001) and DFUs (52.4%; p<0.001). After four weeks of treatment, it was possible to significantly predict if the ulcer would respond (defined as a decrease of wound size) to the study treatment. Adherence was high (95.2%) and no related serious adverse events were reported during the study. QoL significantly improved, with an increase of 15.4% of the total score, using the CWIS (p<0.001). CONCLUSION:: The study confirmed a positive efficacy profile of the FB system in inducing the wound healing process in three different types of hard-to-heal chronic wounds. The treatment was shown to be safe and well tolerated by the patients, with a significant improvement in patient QoL. This approach offers an effective modality for the treatment of hard to-heal chronic ulcers. PMID- 30398943 TI - Ensuring healthy skin as part of wound prevention: an integrative review of health professionals' actions. AB - OBJECTIVE:: To provide a synthesis of the best available, recent primary or secondary research evidence on early preventative activities taken to increase skin health, and reduce the incidence of facility-acquired skin tears and pressure ulcers (PUs) in community, residential and health-care institutions. METHOD:: An integrative review focusing on a 10-year period, 2007-2017. A literature search of health databases was carried out, as well as a search of grey literature in relevant skin, wound care and nursing association journals. A second search was also conducted focused on literature from policy and guideline development organisations. Primary outcomes of interest were reduction in dry skin (xerosis), friable skin, or increases in healthy skin maintenance activities. Secondary outcomes of interest were reductions in PU or skin tear occurrences. Opinion, non-systematic literature reviews and discussion papers were excluded. RESULTS:: Of the 4932 references obtained from the searches, a total of 33 articles were included in the review: 27 peer-reviewed journal articles and six articles from the grey literature search. No guideline was found that focused on maintaining skin health as a person ages. Studies identified the main factors for maintaining skin health as nutrition, hydration and skin care regimen. CONCLUSION:: Skin care regimens, including a focus on good nutrition and pH balance, should start immediately on arrival in institutions such as hospitals or residential aged care, and continue throughout the stay. PMID- 30398944 TI - Hormetic Effects of Thiophanate-Methyl in Multiple Isolates of Sclerotinia homoeocarpa. AB - Twenty-eight isolates of Sclerotinia homoeocarpa, causal agent of dollar spot disease in turf, were assessed for fungicide hormesis at sublethal concentrations of thiophanate-methyl (T-methyl). Each isolate was grown in corn meal agar amended with 11 concentrations of T-methyl (30,500 to 0.047 ug/liter), and the area of mycelial growth was determined relative to the control. Three replicates were used per concentration, and the experiment was repeated three to five times for each isolate. Reference isolates (EC50 > 20 ug/liter), with no prior history of T-methyl exposure, were highly sensitive and not stimulated by low doses. Likewise, no stimulation was observed in two highly sensitive isolates (EC50 > 30 ug/liter) that had been preconditioned by exposure to T-methyl, or in four T methyl-tolerant isolates. Seventeen (81%) preconditioned T-methyl-tolerant isolates (EC50 = 294 to1,550 ug/liter) had statistically significant growth stimulation, in the range of 2.8 to 19.7% relative to the control. These results support that hormesis (low-dose stimulation, high-dose inhibition) is a common dose response in preconditioned S. homoeocarpa, particularly in response to subtoxic doses of T-methyl. PMID- 30398945 TI - Hormetic Effects of Mixtures of Carbendazim and Iprodione on the Virulence of Botrytis cinerea. AB - Hormetic effects of fungicides on mycelial growth and virulence of plant pathogenic fungi have been reported, but the effects of fungicide mixtures on virulence hormesis of plant pathogens remain to be investigated. In this study, hormetic effects of mixtures of carbendazim and iprodione on the virulence of two carbendazim-resistant isolates of Botrytis cinerea were determined. Spraying carbendazim alone at 3 to 800 MUg/ml exhibited hormetic effects on virulence to cucumber leaves, and carbendazim at 10 MUg/ml had the maximum stimulation of 16.7% for isolate HBtom451. Spraying iprodione alone at 0.0001 to 0.0625 MUg/ml exhibited hormetic effects on virulence, and iprodione at 0.025 MUg/ml had the maximum stimulation of 18.7% for isolate HBtom451. However, spraying simultaneously carbendazim at 800 MUg/ml and iprodione at 0.0625 MUg/ml showed inhibitory effects on virulence to cucumber leaves. The mixture of carbendazim at 3 MUg/ml and iprodione at 0.0001 MUg/ml had much higher virulence stimulations than either fungicide at the same concentration alone. The maximum stimulation for the mixtures occurred at 10 and 0.0005 MUg/ml for carbendazim and iprodione, respectively, and these concentrations were much lower than the concentration of their respective fungicide alone eliciting the maximum stimulations. The maximum stimulation amplitude for the mixture was slightly higher than that of each fungicide alone. These results demonstrated that carbendazim and iprodione mainly had dose-additive rather than amplitude-additive interactions when sprayed simultaneously with regard to virulence stimulations. Studies on virulence stimulations for mycelia treated with fungicide in potato dextrose agar showed that the maximum stimulation for the mixtures occurred at concentrations much lower than the concentration of carbendazim alone, indicating a dose-additive interaction when compared with carbendazim hormesis. Studies on potential physiological mechanisms of hormesis showed that increased tolerance to H2O2 may be one of the mechanisms for virulence hormesis for the mixtures of iprodione and carbendazim. These studies will advance our understanding of hormesis of fungicide mixtures. PMID- 30398946 TI - Phytophthora Species Detected in Two Ozark Forests with Unusual Patterns of White Oak Mortality. AB - Widespread decline and mortality of white oaks (Quercus alba) occurred in Missouri Ozark forests between 2011 and 2017. Symptoms included rapid crown death with bronzing of leaves, retention of dead leaves, crown dieback and thinning, and loss of large limbs within one year of death. Decline and mortality were associated with hillside drainages and fit descriptions of European oak forests predisposed to decline by pathogenic Phytophthora species. A survey was performed at two locations in 2014 and 2015 to assess the distribution of dead and declining white oaks, and the occurrence and distribution of Phytophthora species. Multiple Phytophthora species were detected, including P. cinnamomi, P. cactorum, P. europaea, and P. pini. P. cinnamomi was the most common and widely distributed species among plots at both locations. The detection of P. cinnamomi at the base of white oaks was not associated with poor crown vigor. However, more quantitative survey techniques are necessary to clearly evaluate this relationship. P. cinnamomi kills fine roots of white and red oaks in North America and has been associated with the decline of white oaks in the United States (Ohio) and other countries. Further studies are needed to determine the importance of P. cinnamomi in oak decline within the Ozark highlands. PMID- 30398947 TI - Clinical and Pathologic Profiles of Esophageal Cancer in Mozambique: A Study of Consecutive Patients Admitted to Maputo Central Hospital. AB - PURPOSE: Eastern Africa was recently described as a high-incidence geographic area for esophageal cancer. Mozambique is included in this region. This study aimed to characterize this malignant disease at Maputo Central Hospital (MCH) to develop a global program for esophageal cancer management in Mozambique. METHODS: MCH records from between 2012 and 2016 were used to assess the clinical, pathologic, and outcome profiles of esophageal tumors. A descriptive analysis of data collected was performed. Overall survival was evaluated using Kaplan-Meier curves. RESULTS: In the study, 522 consecutive patient cases of esophageal cancer were recorded. The median patient age was 56.1 years (range, 27 to 97 years); 291 (55.7%) patients were women, and 230 (44.1%) were men. Regarding tumor site, 113 patients (21.6%) had a tumor in the lower third, 154 (29.5%) in the middle, and 50 (9.6%) in the upper third of the esophagus; in the remaining 196 (37.5%), tumor site was unknown. Squamous cell carcinoma comprised 94.4% of cases with documented histopathology (74.9% of the sample). Surgical treatment was possible in 32 patients (6.1%). Disease stage was documented only in these 32 surgical patients; 28.1%, 53.1%, and 18.8% had stage I, II, and III disease, respectively. The remaining patient cases seemed to involve clinically advanced tumors. The median follow-up time was of 1.6 months. The median survival time was of 3.5 months for all patients; for patients treated with curative intent, it was of 8.7 months. CONCLUSION: Esophageal carcinoma is a common malignant tumor at MCH and is diagnosed in the advanced stages resulting in poor prognosis. Therefore, implementation of an Esophageal Cancer Program in Mozambique is essential. PMID- 30398948 TI - Task Sharing and Shifting to Provide Pathology Diagnostic Services: The Kenya Fine-Needle Aspiration Biopsy Cytology and Bone Marrow Aspiration and Trephine Biopsy Training Program. AB - PURPOSE: Fine-needle aspiration biopsy (FNAB) cytology is a simple, inexpensive, and accurate diagnostic test for benign, infectious, and malignant lesions of the breast, thyroid, lymph nodes, and other organs. Similarly, bone marrow aspiration and trephine (BMAT) biopsy procedures are relatively simple and inexpensive techniques that are important for diagnosing and monitoring many hematologic diseases including leukemias and lymphomas. However, the scarcity of pathologists in Kenya limits patient access to these simple diagnostic tests. We describe a task sharing and shifting program that sought to improve the provision of FNABs and BMAT biopsies in tertiary public hospitals in Kenya. METHODS: Between January 2016 and February 2017, we trained pathologists, pathology residents, and technologists from the University of Nairobi and Aga Khan University Hospital, Nairobi, in FNAB and BMAT biopsies, who in turn trained pathologists, medical officers (MO), clinical officers (CO), and technologists at five tertiary public hospitals. The program involved curriculum development, training workshops, the establishment of new and strengthening existing FNAB and BMAT biopsy clinics, interim site visits, audits, and stakeholder workshops. RESULTS: Fifty-one medical personnel at the tertiary hospitals were trained. The FNAB numbers increased by 41% to 1,681, with 139 malignant diagnoses (7.1%). BMAT biopsy numbers increased by 268% to 140, with 34 malignant cases. Between 60% and 100% of the FNAB and BMAT biopsy procedures were performed by MO and CO over the project period. One new FNAB and two new BMAT biopsy clinics were established. CONCLUSION: This project demonstrates a successful model of task sharing and shifting from specialist pathologists to MO and CO that improved access to important FNAB and BMAT biopsy services in a low-resource setting. PMID- 30398949 TI - Detection of High-Risk Human Papillomavirus in Oral Cavity Squamous Cell Carcinoma Using Multiple Analytes and Their Role in Patient Survival. AB - PURPOSE: Accurate detection of human papillomavirus (HPV) in oral cavity squamous cell carcinoma (OSCC) is essential to understanding the role of HPV in disease prognosis and management of patients. We used different analytes and methods to understand the true prevalence of HPV in a cohort of patients with OSCC with different molecular backgrounds, and we correlated HPV data with patient survival. METHODS: We integrated data from multiple analytes (HPV DNA, HPV RNA, and p16), assays (immunohistochemistry, polymerase chain reaction [PCR], quantitative PCR [qPCR], and digital PCR), and molecular changes (somatic mutations and DNA methylation) from 153 patients with OSCC to correlate p16 expression, HPV DNA, and HPV RNA with HPV incidence and patient survival. RESULTS: High prevalence (33% to 58%) of HPV16/18 DNA did not correlate with the presence of transcriptionally active viral genomes (15%) in tumors. Eighteen percent of the tumors were p16 positive and only 6% were both HPV DNA and HPV RNA positive. Most tumors with relatively high copy number HPV DNA and/or HPV RNA, but not with HPV DNA alone (irrespective of copy number), were wild-type for TP53 and CASP8 genes. In our study, p16 protein, HPV DNA, and HPV RNA, either alone or in combination, did not correlate with patient survival. Nine HPV-associated genes stratified the virus-positive from the virus-negative tumor group with high confidence ( P < .008) when HPV DNA copy number and/or HPV RNA were considered to define HPV positivity, and not HPV DNA alone, irrespective of copy number ( P < .2). CONCLUSION: In OSCC, the presence of both HPV RNA and p16 is rare. HPV DNA alone is not an accurate measure of HPV positivity and therefore may not be informative. HPV DNA, HPV RNA, and p16 do not correlate with patients' outcome. PMID- 30398950 TI - Feasibility of Patient Navigation to Improve Breast Cancer Care in Malaysia. AB - PURPOSE: Late stage at presentation and poor adherence to treatment remain major contributors to poor survival in low- and middle-income countries (LMICs). Patient navigation (PN) programs in the United States have led to improvement in diagnostic or treatment timeliness, particularly for women in lower socioeconomic classes or minority groups. To date, studies of PN in Asia have been limited. We aimed to assess the feasibility of PN in a state-run hospital in an LMIC and to report the impact on diagnostic and treatment timeliness for patients in its first year of implementation. METHODS: We established PN in a dedicated breast clinic of a Malaysian state-run hospital. We compared diagnostic and treatment timeliness between navigated patients (n = 135) and patients diagnosed in the prior year (n = 148), and described factors associated with timeliness. RESULTS: Women with PN received timely mammography compared with patients in the prior year (96.4% v 74.4%; P < .001), biopsy (92.5% v 76.1%; P = .003), and communication of news (80.0% v 58.5%; P < .001). PN reduced treatment default rates (4.4% v 11.5%; P = .048). Among navigated patients, late stage at presentation was independently associated with having emotional and language barriers ( P = .01). Finally, the main reason reported for delay, default, or refusal of treatment was the preference for alternative therapy. CONCLUSION: PN is feasible for addressing barriers to cancer care when integrated with a state run breast clinic of an LMIC. Its implementation resulted in improved diagnostic timeliness and reduced treatment default. Wider adoption of PN could be a key element of cancer control in LMICs. PMID- 30398951 TI - Missed Opportunities for Engagement in the Prevention Continuum in a Predominantly Black and Latino Community in New York City. AB - Even though over the last 25 years, the Centers for Disease Control and Prevention recommendations for HIV screening have expanded to encompass population-wide screening in all healthcare settings, and despite the availability of pre-exposure prophylaxis (PrEP), a large proportion of individuals at risk of infection are not linked to prevention care. We evaluated missed opportunities for HIV screening and linkage to PrEP from 2006 through 2017 at an urban academic medical center serving a predominantly minority community. A missed opportunity for HIV screening was a provider visit that did not include HIV testing and occurred within the 12 months before the first positive HIV test. A missed opportunity for prevention was a visit after 2012 that included a negative HIV test, no evaluation for PrEP, and was followed by a positive HIV test. Univariate analysis was performed to assess characteristics of individuals with missed opportunities for screening and prevention services. Between 2006 and 2017, 721 patients were newly diagnosed with HIV. Two hundred forty-seven diagnoses were made in the early period (2006-2010), 236 in the middle period (2010-2013), and 238 in the late period (2014-2017). Overall 60% of patients had at least one missed opportunity, 36% for HIV screening, and 42% for PrEP. There was no improvement in the rates of individuals with a missed opportunity for HIV screening over time. Ending the HIV epidemic will require concerted efforts to bolster access to testing and ensure that all individuals are offered screening, counseling, and linkage to prevention and care services. PMID- 30398952 TI - Multi-Site Evaluation of Community-Based Efforts to Improve Engagement in HIV Care Among Populations Disproportionately Affected by HIV in the United States. AB - This study assesses effects of a community-based intervention across seven sites in the United States on HIV care utilization and study retention, among people living with HIV (PLWH). A two-armed study was conducted from 2013 to 2016 in each of seven community-based agencies across the United States. Each site conducted interventions involving community engagement approaches in the form of case management or patient navigation. Control conditions were standard of care involving referral to HIV clinical care. Participants (N = 583) were adults reporting erratic or no HIV care in the past 6 months. Longitudinal survey data on demographics, behavioral risks, and HIV care were collected from participants at baseline, before service delivery, and at 6-month follow-up. Unadjusted and adjusted generalized linear mixed models were used to assess the intervention effects on HIV care utilization and study retention. Participants were majority black (75.5%), cisgender male (55.1%), and heterosexual (55.4%). No significant intervention effect was observed on HIV care utilization, although both groups improved significantly over time [adjusted odds ratio (AOR): 2.09, 95% confidence interval (CI): 1.30-3.37]. Intervention participants were more likely to be retained in the study (AOR: 1.50, 95% CI: 1.03-2.20). Community intervention did not affect HIV care utilization more than standard of care, but intervention participants were more likely to be retained in the study, suggesting that such approaches support relationship building in ways that can facilitate follow-up of socially vulnerable PLWH. More research is needed to understand how such community efforts can support better HIV care utilization in these populations. PMID- 30398953 TI - Stigma and Healthcare-Seeking Practices of Men Who Have Sex with Men in Western Kenya: A Mixed-Methods Approach for Scale Validation. AB - In sub-Saharan Africa, men who have sex with men (MSM) experience high HIV prevalence, in part, due to stigma and discrimination creating barriers to engagement in prevention and care services. We examined the reliability and validity of measures of stigma and satisfaction with healthcare providers, as well as explored whether scores on the factors varied across sociodemographic variables among MSM in western Kenya. A mixed-methods design using a sequential triangulation approach was adopted, involving a survey of 89 MSM and 10 key informant interviews. Reliability and correlation analyses, exploratory factor analyses, t-tests, and ANOVAs (analyses of variances) were conducted to test the scale's psychometric properties and examine differences in mean scores by demographics. Thematic analysis with qualitative data was used to validate the meaning of scales and explore how stigma influences and relates to satisfaction with healthcare providers. Of 89 participants, 50% identified as homosexual, 52% had college degree, 45% were above 25 years, and 72% had ever been married. Three subscales measuring enacted stigma, internalized stigma, and mistrust of healthcare providers showed good reliability (alpha = 0.80, alpha = 0.90, and alpha = 0.90). Men who identified as homosexual reported higher mean scores of enacted stigma and distrust of healthcare providers compared to heterosexual/bisexual identified (p < 0.001). Qualitative data revealed perceptions that healthcare providers were not knowledgeable to handle MSM needs. Study provides preliminary evidence for the reliability and validity of measures of stigma and mistrust of healthcare providers in Kenya. Quantitative and qualitative findings highlight the need for interventions to reduce stigma and create a more inclusive health system. PMID- 30398954 TI - Impact of Alternative Encounter Types on HIV Viral Suppression Rates in an Integrated Health System. AB - Kaiser Permanente Mid-Atlantic States (KPMAS) members are increasingly utilizing electronic encounter types, such as telephone appointments and secure messaging for healthcare purposes, although their impact on health outcomes is unknown. We evaluated whether use of alternative encounters by adult human immunodeficiency virus (HIV)-infected patients affected the likelihood of achieving viral suppression (VS). Our study population of 3114 patients contributed 6520 patient years between 2014 and 2016. We compared VS (HIV RNA <200 copies/mL) by number of in-person visits (1 or >=2), with further stratification for additional phone and/or e-mail encounters (none, phone only, e-mail only, and both phone and e mail). Rate ratios (RRs) for VS by number of in-person visits and encounter types were obtained from Poisson modeling, adjusting for age, sex, race/ethnicity, and HIV risk. Compared to those with >=2 visits, patients with one in-person visit alone were significantly less likely to achieve VS (RR = 0.93; 95% confidence interval, CI: [0.87-1.00]), as were those with one in-person visit plus a telephone encounter (0.93; [0.90-0.97]). We did not find significant differences in VS comparing patients with one in-person visit plus e-mail only (RR = 1.00; 95% CI: [0.97-1.02]) or plus e-mail and telephone (0.99; [0.97-1.01]) to those with >=2 in-person visits. If supplemented by e-mail communications (with or without telephone contact), patients with one in-person visit per year had similar estimated rates of VS compared with >=2 in-person visits. More research is needed to know if these findings apply to other care systems. PMID- 30398955 TI - Preliminary Impact of the weCare Social Media Intervention to Support Health for Young Men Who Have Sex with Men and Transgender Women with HIV. AB - Young racial/ethnic minority men who have sex with men (MSM) and transgender women with HIV often have poor health outcomes. They also utilize a wide array of social media. Accordingly, we developed and implemented weCare, a social media intervention utilizing Facebook, texting, and GPS-based mobile social and sexual networking applications to improve HIV-related care engagement and health outcomes. We compared viral load suppression and clinic appointment attendance among 91 participants during the 12-month period before and after weCare implementation. McNemar's chi-square test analyses were conducted comparing the pre- and postintervention difference using paired data. Since February 2016, intervention staff and 91 intervention participants (79.1% African American and 13.2% Latino, mean age = 25) exchanged 13,830 messages during 3,758 conversations (average: 41.3 conversations per participant) across a variety of topics, including appointment reminders, medication adherence, problem solving, and reducing barriers. There were significant reductions in missed HIV care appointments (68.0% vs. 53.3%, p = 0.04) and increases in viral load suppression (61.3% vs. 88.8%, p < 0.0001) 12 months postimplementation. Our results highlight the initial success of weCare in improving care engagement and viral suppression. Social media is an important tool, especially for young MSM and transgender women, to support individual- (e.g., viral suppression) and community- (e.g., reduced transmission efficiency) level health. It may also be a useful tool for improving engagement with biomedical HIV prevention tools (e.g., PrEP use). PMID- 30398957 TI - Effects of Protein Versus Carbohydrate Supplementation on Markers of Immune Response in Master Triathletes: A Randomized Controlled Trial. AB - OBJECTIVE: This study examines the long-term effects of ingesting hydrolyzed beef protein versus carbohydrate on indirect markers of immunity during 10 weeks of endurance training in master-aged triathletes (n = 16, age 35-60 years). METHODS: Participants were randomly assigned to either a hydrolyzed beef protein (PRO, n = 8) or nonprotein isoenergetic carbohydrate (CHO, n = 8) condition, which consisted of ingesting 20 g of each supplement, mixed with water, once a day immediately post workout, or before breakfast on nontraining days. Salivary human neutrophil peptides (HNP1-3) were measured before and after performing an incremental endurance test to volitional exhaustion at both pre and post intervention. Additionally, baseline levels of platelets, neutrophils, eosinophil basophils, monocytes, and lymphocytes were determined at pre and post intervention. RESULTS: No significant changes in baseline concentration and secretion rate of salivary HNP1-3 were observed for either treatment. The CHO group showed a nonsignificant decrease in resting HNP1-3 concentrations following the intervention (p = 0.052, effect size d = 0.53). Protein supplementation demonstrated a significant reduction in lymphocyte counts pre to post intervention (mean [SD]: 2.30 [0.57] vs. 1.93 [0.45] 103/mm3, p = 0.046, d = 0.77), along with a moderate but not statistically significant increase (d = 0.75, p = 0.051) of the neutrophil-to-lymphocyte ratio. CONCLUSIONS: In master aged triathletes, postworkout ingestion of only protein, with no carbohydrate, may not be as effective as carbohydrate alone to attenuate negative long-term changes of some salivary and cellular immunological markers. Future studies should consider the co-ingestion of both macronutrients. PMID- 30398958 TI - Three Colletotrichum Species, Including a New Species, are Associated to Leaf Anthracnose of Rubber Tree in Hainan, China. AB - Colletotrichum gloeosporioides and C. acutatum have been reported to be causal agents of anthracnose disease of rubber tree. Recent investigations have shown that both C. gloeosporioides and C. acutatum are species complexes. The identities of Colletotrichum species causing anthracnose disease of rubber tree in Hainan, China, are unknown. In this study, 106 isolates obtained from rubber tree with symptoms of anthracnose were collected from 12 counties of Hainan and identified at the species complex level based on the ITS sequences and colony morphologies. Seventy-four isolates were identified as C. gloeosporioides species complex and the other 32 isolates as C. acutatum species complex. Forty-two isolates were selected for further multilocus phylogenetic analyses in order to identify the isolates to the species level. Twenty-six isolates from the C. gloeosporioides species complex were characterized for partial sequences of seven gene regions (ACT, TUB2, CHS-1, GAPDH, ITS, ApMat, and GS), and the other 16 isolates from the C. acutatum species complex for five gene regions (ACT, TUB2, CHS-1, GAPDH, and ITS). Three species were identified: C. siamense and C. fructicola from the C. gloeosporioides species complex, and a new species C. wanningense from the C. acutatum species complex. Artificial inoculation of rubber tree leaves confirmed the pathogenicity of the three species. The present study improves the understanding of species causing anthracnose on rubber tree and provides useful information for the effective control of the disease. PMID- 30398959 TI - Self-Controlled Feedback and Learner Impulsivity in Sequential Motor Learning. AB - Many studies have attributed self-controlled feedback benefits associated with motor learning to learners' greater information processing during practice. However, individual learner characteristics like their impulsivity can also influence how people engage cognitively during learning. We investigated possible dissociations between the types of interaction in self-controlled knowledge of results (KR) and learner impulsivity levels in learning a sequential motor task. Ninety volunteers responded to the self-restraint section of the Barkley deficits in executive functioning scale, and those 60 participants with the highest ( n = 30) and lowest ( n = 30) impulsivity scores practiced a motor task involving sequential pressing of four keys in predetermined absolute and relative times. We further divided participants into four experimental groups by assigning the high- and low-impulsivity groups to two forms of KR-self-controlled absolute and yoked. Study results showed no interaction effect between impulsivity and self controlled KR, and, contrary to expectation, self-controlled KR did not benefit learning, independently of impulsivity. However, low-impulsivity participants performed better than high-impulsivity participants on the absolute dimension of the transfer task, while high-impulsivity learners were better at the relative dimension. Cognitive characteristics of automatic and reflexive processing were expressed by the strategies used to direct attention to relative and absolute task dimensions, respectively. Low-impulsivity learners switched their attention to both dimensions at the end of practice, while high-impulsivity learners did not switch their attention or directed it only to the relative dimension at the end of the practice. These results suggest that the cognitive styles of high- and low-impulsive learners differentially favor learning distinct dimensions of a motor task, regardless of self-controlled KR. PMID- 30398956 TI - Barriers and Facilitators to Seeking HIV Services in Chicago Among Young Men Who Have Sex with Men: Perspectives of HIV Service Providers. AB - Young men who have sex with men (YMSM) are disproportionally impacted by HIV, and continue to lag behind other age groups in the receipt of HIV prevention and care services. To inform the development of interventions to improve pre-exposure prophylaxis and HIV care engagement outcomes among YMSM, a growing number of studies have reported the barriers and facilitators YMSM encounter when accessing HIV services. Few studies, however, have assessed how HIV service providers perceive these facilitators and barriers. In total, 21 interviews were conducted with HIV service providers in Chicago about barriers and facilitators they perceived affected YMSM's engagement in HIV services. Barriers included lack of comprehensive wraparound services, lack of trust of providers, unfamiliarity with seeking HIV services, feelings of invincibility, lack of knowledge of HIV service providers, intersectional and structural concerns (e.g., not thinking the site's services were for YMSM), geography and distance to clinic, and HIV stigma. Facilitators included presence of comprehensive wraparound services, high trust in providers, a clinic's willingness to serve uninsured patients, community engagement, word-of-mouth recommendations from lesbian, gay, bisexual, and transgender (LGBT) friends, intersectionality (e.g., offering LGBT-tailored services), geography and distance, lack of HIV stigma. Axial coding revealed that five conceptual themes cut across multiple barriers and facilitators, including health system characteristics, intersectionality, geography and transportation, community outreach, and stigma. These conceptual themes map closely onto Bronfenbrenner's ecological model. Overall, these findings highlight the importance of a multi-level approach to future intervention development to increase engagement in HIV services among YMSM. PMID- 30398960 TI - Serum and Erythrocyte Biomarkers of Nutrient Status Correlate with Short-Term Alpha-Carotene, Beta-Carotene, Folate, and Vegetable Intakes Estimated by Food Frequency Questionnaire in Military Recruits. AB - OBJECTIVE: Food frequency questionnaires (FFQs) estimate habitual dietary intake and require evaluation in populations of interest in order to determine accuracy. Thus, the purpose of this study was to determine agreement between circulating biomarkers and FFQ estimated dietary intake in a military population consuming all meals in a dining facility over 12 weeks. METHODS: 2014 Block FFQs were administered and fasted blood samples were drawn to assess nutritional biomarkers at the end of a 12-week training period in male (n = 141) and female (n = 125) Marine recruits undergoing initial military training. FFQ estimates of alpha- and beta-carotene, folate, and fruit and vegetable intake and circulating concentrations of serum alpha- and beta-carotene and serum and erythrocyte folate were measured. Partial correlations were used in the full model, and weighted kappa coefficients were used to determine agreement between ranking quartiles of dietary intake estimates with corresponding biomarker status quartiles. RESULTS: Serum and dietary intake of alpha-carotene were positively associated in males (p = 0.009) and females (p < 0.001), as was serum and intake of beta-carotene (males, p = 0.002; females, p < 0.001). Alpha-carotene was positively associated with vegetable intake in males (p = 0.02) and beta-carotene with vegetable intake in females (p = 0.003). Serum folate in males (p = 0.002) and erythrocyte folate in females (p = 0.02) were associated with dietary folate intake. In females, the relationships between biomarker and dietary estimates yielded significant kappa coefficients. In males, a significant kappa coefficient was observed for erythrocyte folate and dietary intake of folate only. The kappa coefficient for serum and estimated intake of beta-carotene was not significant in males. CONCLUSION: Twelve-week habitual intake of alpha-and beta-carotene and folate were correlated with circulating biomarkers in a military training population. The 2014 Block FFQ was able to accurately rank females into quartiles of nutrient status based on intake, while males were ranked less accurately than females. PMID- 30398962 TI - Single Lobe Left Atrial Appendage with Large Ostia Anatomy: Implications for Kissing-Watchman Technology. PMID- 30398961 TI - Early results of surgery for femoroacetabular impingement in patients with osteonecrosis of femoral head. AB - PURPOSE: Femoroacetabular impingement and its surgical treatment have not been described before in osteonecrosis of femoral head. We present here outcomes of 15 patients with femoroacetabular impingement secondary to osteonecrosis of femoral head. This results from partial collapse of femoral head, particularly in the anterosuperior region, secondary to osteonecrosis. With subsequent remodelling, periphery of the femoral head flattens and osteophytes form in this area. All these patients were managed with open/arthroscopic osteochondroplasty of femoral head. METHODS: These patients were symptomatic for hip impingement. Cam deformity was studied using computed tomography and magnetic resonance imaging. In six patients open osteochondroplasty was carried out using surgical hip dislocation. In nine patients arthroscopic femoral head osteochondroplasty was done. All the patients were followed up for hip pain (VAS), Harris hip score (HHS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and hip range of motion. RESULTS: A statistically significant improvement in the VAS for pain, HHS, and WOMAC score was noted. Average HHS improved from 71.3 (SD, 13) to 89.7 (SD, 14.5), p-value 0.0079. Average WOMAC improved from 73.6 (SD, 15.4) to 92.4 (SD, 16), p-value 0.0154. Impingement test became negative in all the patients. A significant improvement in hip ROM was noted. There was no conversion to total hip arthroplasty. All patients could sit on the floor cross-legged and squat. CONCLUSION: Some patients with partial collapse of femoral head due to osteonecrosis present chiefly with symptoms of femoroacetabular impingement. They should be identified as osteochondroplasty gives successful results in these patients. Level of evidence - IV. PMID- 30398963 TI - A self-expanding percutaneous valve for patients with pulmonary regurgitation and an enlarged native right ventricular outflow tract: one-year results. AB - AIMS: To assess the safety and efficacy of the Venus p-valve. METHODS AND RESULTS: Patients who had moderate or severe pulmonary regurgitation after surgical repair of the right ventricular outflow tract (RVOT) with a transannular or RVOT patch were included in the study. Fifty-five patients (67% female; average age 28.7+/-12.4 years) from 6 different hospitals in China were enrolled. The procedure success rate was 98.2%. One patient experienced valve dislodgement two days after the procedure. During the 12-month follow-up, two patients died, one due to infective endocarditis. Three other patients developed infective endocarditis. Two patients developed atrial flutter, and one patient had pulmonary embolism. Echocardiography examinations at 12 months showed that two patients had mild pulmonary regurgitation, and 19 patients had trace pulmonary regurgitation. No paravalvular regurgitation occurred. The mean peak pulmonary gradient was 16.3+/-7.4 (range 4-38) mmHg. Compared with the baseline data, the right ventricle end-diastolic volume index (RVEDVI) was reduced from 137.6+/ 15.8mL/m2 to 83.9+/-16.0mL/m2 (P<0.001), and the New York Heart Association (NYHA) class was significantly improved (P<0.01). CONCLUSIONS: The one-year results of the China Venus p-valve study shown considerable promise for a hither to unmet need in patients with pulmonary regurgitation and an enlarged native RVOT. PMID- 30398964 TI - Impact of the 1-year angioscopic findings on long-term clinical events in 504 patients treated with first-generation or second-generation drug-eluting stents: The DESNOTE-X Study. AB - AIMS: We aimed to test the hypothesis that presence of in-stent yellow plaque (YP) assessed by angioscopy would be a risk of very late stent failure (VLSF) of the cobalt chromium everolimus-eluting stent (CoCr-EES) in comparison with first generation drug-eluting stents (DES). METHODS AND RESULTS: The DESNOTE-X study was a prospective cohort study, an extended study of the DESNOTE (UMIN000013515). All patients who received successful angioscopic examination at planned 1-year follow-up of DES were clinically followed. Primary endpoint was VLSF defined as a composite of cardiac death, target vessel myocardial infarction, and target lesion revascularization. A total of 504 patients with 549 lesions were enrolled during 12.5 years. At 1-year follow-up, the incidence of YP was significantly higher in the first-generation DES than in the CoCr-EES [199/292 (68 %) vs. 80/257 (31 %), p<0.001]. Maximum yellow color grade on coronary angioscopy at 1 year follow-up was an independent predictor of future VLSF in the first generation DES (HR 2.604 [95%CI: 1.265-5.361], p=0.009), whereas it was not in the CoCr-EES (p for interaction = 0.022). CONCLUSIONS: Incidence of in-stent atherosclerosis identified as YP on angioscopy was lower and its impact on late clinical events appeared smaller in the CoCr-EES than in the first-generation DES. PMID- 30398965 TI - How does the failure of Absorb apply to the other bioresorbable scaffolds?: Expert review of first-in-man and pivotal trials. AB - Absorb bioresorbable scaffold (BRS), the most studied device among all BRS, suffered a major setback following the negative results of the ABSORB trials. However, approximately 34 BRSs from 22 companies are currently under development. The potential device specific factors related to increased event rate in Absorb were: 1) weaker mechanical properties, 2) larger strut thickness (less embedment and larger protrusion) and width (larger footprint) predisposing to underexpansion / protrusion of strut, eventually resulting in increased thrombogenicity, and 3) longer bioresorption time combined with failure of encapsulation of struts before dismantling process ensues. Given the diversity of bioresorbable materials (even amongst PLLA), the different mechanical properties and bioresorption profiles of each new BRS, one could expect considerable difference in early and late clinical outcomes. As a matter of fact, data from first-in-man (FIM) and pivotal trials demonstrated variable clinical results. Early clinical evidence from FIM trials indeed does not support class effect. However, the absence of a comparator precludes us from drawing definitive conclusions. Further clinical evidence should confirm the absence (or presence) of a class effect. PMID- 30398966 TI - Impact of Absorb bioresorbable scaffold implantation technique on post-procedural quantitative coronary angiographic endpoints in ST-elevation myocardial infarction: a sub-analysis of the BVS STEMI STRATEGY-IT study. AB - AIMS: To evaluate the impact of bioresorbable vascular scaffold (BRS) implantation technique on post-procedural quantitative coronary angiography (QCA) parameters in ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: We assessed 442 STEMI patients who underwent BRS implantation in the BVS STEMI STRATEGY-IT study. Optimal BRS implantation was assessed using PSP-score, developed and validated in the GHOST-EU registry. We analyzed post-implantation QCA parameters, including minimum lumen diameter (MLD) and maximum footprint, in patients with and without optimal BRS implantation, coded as maximum PSP score. Patients with optimal BRS implantation had higher post-MLD and lower maximum footprint than those without. Multivariate analysis demonstrated that optimal BRS implantation was an independent predictor of high post-MLD, defined as >= 2.4mm for 2.5 or 3.0mm-BRS and >= 2.8mm for 3.5mm-BRS. Thrombectomy before optimal BRS implantation showed a trend towards higher post-MLD and lower maximum footprint. There was no relationship between optimal BRS implantation and device-oriented composite events at 1-year. CONCLUSIONS: Optimal BRS implantation, assessed by PSP-score, was associated with better post-procedural QCA parameters in STEMI. Thrombectomy before optimal BRS implantation might improve angiographic result in STEMI. Long-term follow-up is needed to analyze the relationship between QCA parameters and clinical outcomes after BRS implantation in STEMI. PMID- 30398967 TI - Three-year follow-up of the randomised comparison between an everolimus-eluting bioresorbable scaffold and a durable polymer everolimus-eluting metallic stent in patients with ST-segment elevation myocardial infarction (TROFI II trial). PMID- 30398968 TI - A new practical anatomical classification for left atrial appendage closure (LAAC). PMID- 30398969 TI - Percutaneous Repair of Healed Endocarditis of Mitral Valve Using MitraClip Devices Around a Large Mobile Vegetation. PMID- 30398970 TI - The effects of estradiol and testosterone on renal tissues oxidative after central injection of angiotensin II in female doca - salt treated rats. AB - Background Although numerous studies have proven that estrogen (Est) has a protective effect on the development of hypertension, more research needs to be done to show its detailed mechanism in a variety of hypertension. The important role of active oxygen species in blood pressure is well defined. We examined whether or not sex hormones change the growth of reactive oxygen species (ROS) in kidneys after central microinjection of angiotensin II (Ang II). Materials and methods Female Wistar rats, 8 weeks old (200 +/- 10 g) were used in this study. The animal groups were (1) Sham, (2) Ovariectomy (OVX), (3) Sham-Hypertension (Sham-Hyper), (4) OVX-Hypertension (OVX-Hyper), (5) Sham-Hyper-Est, (6) OVX-Hyper Est; (7) Sham-Hyper-Testosterone (Tst) and (8) OVX-Hyper-Tst. Solutions of 1% NaCl and 0.1 KCl were used and desoxycorticostrone (doca-salt) was injected (45 mg/kg) 3 times a week in Hypertension groups. Estradiol and Tst (2 mg/kg and 5 mg/kg; daily; subcutaneously) for 4 weeks. Ang II (50 MUM, 5 MUL) was microinjected by intracerebroventricular ( i.c.v.) infusion and malondialdehyde (MDA) and thiol in the kidneys were measured. Results MDA in the kidneys was increased by Ang II and doca-salt treatments. Both estradiol and Tst decreased the kidney's MDA. The level of thiol was higher in Hyper groups and reversed after treatment with estradiol and Tst. Conclusions Our findings suggest that central effect of Ang II on blood pressure and kidney disease is accompanied with increased levels of oxidative stress in the kidneys. Indeed sex hormones change the ROS level in the kidneys after central microinjection of Ang II.. PMID- 30398971 TI - Prevalence and associated factors for social phobia among school-going adolescents in a rural area of Puducherry, South India. AB - Background The World Health Organisation has reported that mental disorders are one of the leading causes of disability worldwide. Social phobia is one such mental disorder that can have significant impact on the livelihood of adults if not detected at an early stage. There have been very few studies done on social phobia among adolescents in South India. Hence, this study was done to determine the prevalence of social phobia and factors associated with it among the school going adolescents in rural Puducherry. Methodology A community-based cross sectional study was conducted among 1018 school going adolescents from December 2017 to January 2018 in rural Puducherry. Information on socio-demographic characteristics was collected by a pre-tested semi-structured questionnaire and social phobia was assessed using the validated Social Phobia Inventory (SPIN) questionnaire. Results Among 1018 participants, 738 (72.5%) belonged to early adolescence (10-13 years); 520 (51.1%) were boys; 557 (54.7%) were studying in a middle class; 931 (91.5%) were Hindus; 978 (96.1%) had siblings. The prevalence of social phobia among adolescents was found to be 22.9% (95% CI: 20.4-25.5%). The prevalence of mild social phobia was 18% [95% confidence interval (CI): 15.7 20.4%], moderate social phobia was 4% (95% CI: 2.9-5.4%), severe social phobia was 0.7% (95% CI: 0.3-1.3%) and very severe social phobia was 0.2% (95% CI: 0.03 0.64%). Higher age, female gender, lack of counselling services and specialist visits at school were found to be determinants of social phobia. Conclusion The current study showed that one in every five adolescents was at risk of developing social phobia. Health education for students, teachers and family members needs to be given to make them aware of the importance of social phobia. PMID- 30398972 TI - Prevalence of traumatic injuries to the anterior teeth among 3-17-year-old school children of Indore and correlating it with Kuppuswamy SES, occlusal relationship and ascertaining percentage of those seeking the treatment. AB - Background Orofacial trauma is one of the most prevailing oral health problems among the children. This study aimed to assess the prevalence and distribution of traumatic injuries and to correlate the causes, specific age groups, socio economic status, occlusal relationship and ascertain the percentage of those seeking the treatment among school children in Indore (Madhya Pradesh, India). Materials and methods Five thousand school going children aged between 3 and 17 years belonging to different zones of Indore were randomly selected and divided into three age groups, Group I - 3-5 years; Group II - 6-11 years and Group III - 12-17 years. The study was carried out by a single investigator and assisted by a well-trained cooperative alert assistant. An American Dental Association (ADA) type 3 examination was carried out using a mouth mirror and explorer under sufficient natural light. Traumatic injuries to the anterior teeth were recorded according to the Ellis and Davey classification. Details were noted concerning the gender, age and socio-economic status of patient; cause of trauma, number, type and relationship of teeth, lip competence and the level of unmet treatment needs. Results One thousand and seventeen children had traumatized anterior teeth with a mean prevalence of 20.34%. Prevalence was more in boys than in girls with a ratio of 2:1. Single tooth injury was observed in 81.7%. The prevalence of trauma was highest in the upper socio-economic class (31.4%) and least was seen in lower class (14.8%). The most common cause of trauma was from a fall (36.72%). Maximum prevalence was seen in either class II division 1 malocclusion or distal step terminal plane primary molar relationship. Only 2.95% of the children had undergone treatment for traumatically injured anterior teeth. Conclusion High prevalence of traumatized teeth with the low percentage of children receiving treatment emphasizes the need for education programs about traumatic dental injuries that should be directed towards the children, parents and school teachers. PMID- 30398973 TI - Impaired dynamic thiol/disulfide homeostasis in pubertal gynecomastia. AB - Background The aim of the study was to evaluate the dynamic thiol/disulfide homeostasis (TDH) with a new method in patients with pubertal gynecomastia and also to investigate the relationship between sex hormones. Methods Thiol/disulfide homeostasis, involving native thiol (SH), disulfide (SS) and total thiol (SS + SH), was evaluated between 20 adolescent boys with gynecomastia in mid-puberty and 50 healthy adolescents, who were matched for age, body mass index (BMI) and pubertal stage. The correlations of total serum testosterone (TT) and estradiol (E2) levels with the oxidative parameters were also determined. Results No significant difference was found between the total thiol, native thiol, disulfide/native thiol and disulfide/total thiol ratios of the patient and control groups. The mean disulfide concentrations, disulfide/native thiol and the disulfide/total thiol ratios were statistically significantly higher in the patient group than in the controls. A positive correlation was found between the E2 and native thiol levels, also there was a negative correlation between the E2 and disulfide levels. TT was negatively correlated with both native thiol and disulfide levels. All these did not statistically differ between the patients with unilateral and bilateral gynecomastia. Conclusions There was an impaired thiol/disulfide homeostasis in patients with pubertal gynecomastia. According to this result, we can postulate that oxidative stress may be an etiologic factor that contributes to initiation and/or progression of gynecomastia. PMID- 30398974 TI - AMPKalpha pathway involved in hepatic triglyceride metabolism disorder in diet induced obesity mice following Escherichia coli Infection. AB - To investigate the different effects of acute pulmonary infection induced by Escherichia coli (E. coli) on lipid metabolism between diet-induced obesity (DIO, fed with high-fat diet) mice and lean mice. A total of 180 ICR mice were selected to be challenged intranasally with phosphate-buffered saline or 109 CFUs/mL of E. coli, and the body character indexes, biochemical indexes and expressions of genes and proteins involved in lipid metabolism were examined pre- and post infection. Results revealed that, before infection, DIO mice had significantly higher body weight, adipose and liver indexes, free fatty acid and triglyceride contents than lean mice. After infection, increased free fatty acid and triglyceride contents, increased expressions of resistin, SREBP-1c, ACC1, FAS and SCD-1, and declined PPARalpha, CPT-1alpha expressions and AMPKalpha phosphorylation were detected in the infected group, while the change rates were more serious in the lean mice than the DIO mice. The above-mentioned findings verified that, after being infected with E. coli, hepatic lipid metabolism disorder was aggravated by activating SREBP-1c related lipid synthesis pathway and inhibiting PPARalpha related fatty acid oxidation pathway. However, infection induced lipid metabolic disorders was slighter in the DIO mice than the lean mice through AMPKalpha pathway. PMID- 30398975 TI - BK channel overexpression on plasma membrane of fibroblasts from Hutchinson Gilford progeria syndrome. AB - Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder wherein symptoms resembling aspects of aging are manifested at a very early age. It is a genetic condition that occurs due to a de novo mutation in the LMNA gene encoding for the nuclear structural protein lamin A. The lamin family of proteins are thought to be involved in nuclear stability, chromatin structure and gene expression and this leads to heavy effects on the regulation and functionality of the cell machinery. The functional role of the large-conductance calcium activated potassium channels (BKCa) is still unclear, but has been recently described a strong relationship with their membrane expression, progerin nuclear levels and the ageing process. In this study, we found that: i) the outward potassium membrane current amplitude and the fluorescence intensity of the BKCa channel probe showed higher values in human dermal fibroblast obtained from patients affected by HGPS if compared to that from healthy young subjects; ii) this result appears to correlate with a basic cellular activity such as the replicative boost. We suggest that studying the HGPS also from the electrophysiological point of view might reveal new clues about the normal process of aging. PMID- 30398976 TI - Inactivation of glycogen synthase kinase-3alpha is required for mitochondria mediated apoptotic germ cell phagocytosis in Sertoli cells. AB - The rapid and efficient clearance of apoptotic germ cells (GCs) by Sertoli cells (SCs) is important for spermatogenesis. High mitochondrial activity in phagocytes is critical for continued clearance of apoptotic cells. However, the underlying molecular mechanism is poorly understood. Glycogen synthase kinase-3alpha (GSK3alpha) is a protein kinase that participates in the regulation of mitochondrial activity. Immunohistochemistry evidenced the predominant presence of the Ser21 phosphorylation GSK3alpha (inactivation) signal in SCs. Heat shock induced apoptosis of GCs and dephosphorylation of GSK3alpha in SCs is a perfect model to investigate the role of GSK3alpha in phagocytic action. The number of apoptotic GCs was significantly lower in GSK3alpha inhibitor pre-treated mice with HS compared to normal control. In vitro phagocytosis assays shown that the phagocytic activity in GSK3alpha activated SCs was downregulated, while GSK3alpha inhibitor supplementation restored this process. Moreover, GSK3alpha activation participates in the alteration of the mitochondrial ultrastructure and activity. In particular, GSK3alpha activation inhibits mitochondrial fission via phosphorylation of dynamin related protein 1 at Ser637. Changes of mitochondrial activity resulted in the accumulation of lipid droplets and the alteration of metabolism pattern in SCs. In summary, our results demonstrate that inactivation of GSK3alpha is required for mitochondria-mediated apoptotic GCs phagocytosis in SCs. PMID- 30398977 TI - Incident Diabetes in Survivors of Critical Illness and Mechanisms Underlying Persistent Glucose Intolerance: A Prospective Cohort Study. AB - OBJECTIVES: Stress hyperglycemia occurs in critically ill patients and may be a risk factor for subsequent diabetes. The aims of this study were to determine incident diabetes and prevalent prediabetes in survivors of critical illness experiencing stress hyperglycemia and to explore underlying mechanisms. DESIGN: This was a prospective, single center, cohort study. At admission to ICU, hemoglobin A1c was measured in eligible patients. Participants returned at 3 and 12 months after ICU admission and underwent hemoglobin A1c testing and an oral glucose tolerance test. Blood was also collected for hormone concentrations, whereas gastric emptying was measured via an isotope breath test. beta-cell function was modeled using standard techniques. SETTING: Tertiary-referral, mixed medical-surgical ICU. PATIENTS: Consecutively admitted patients who developed stress hyperglycemia and survived to hospital discharge were eligible. MEASUREMENTS AND MAIN RESULTS: Consent was obtained from 40 patients (mean age, 58 yr [SD, 10], hemoglobin A1c 36.8 mmol/mol [4.9 mmol/mol]) with 35 attending the 3-month and 26 the 12-month visits. At 3 months, 13 (37%) had diabetes and 15 (43%) had prediabetes. At 12 months, seven (27%) participants had diabetes, whereas 11 (42%) had prediabetes. Mean hemoglobin A1c increased from baseline during the study: +0.7 mmol/mol (-1.2 to 2.5 mmol/mol) at 3 months and +3.3 mmol/mol (0.98-5.59 mmol/mol) at 12 months (p = 0.02). Gastric emptying was not significantly different across groups at either 3 or 12 months. CONCLUSIONS: Diabetes and prediabetes occur frequently in survivors of ICU experiencing stress hyperglycemia. Based on the occurrence rate observed in this cohort, structured screening and intervention programs appear warranted. PMID- 30398978 TI - Survival, Quality of Life, and Functional Status Following Prolonged ICU Stay in Cardiac Surgical Patients: A Systematic Review. AB - OBJECTIVES: Compared with noncardiac critical illness, critically ill postoperative cardiac surgical patients have different underlying pathophysiologies, are exposed to different processes of care, and thus may experience different outcome trajectories. Our objective was to systematically review the outcomes of cardiac surgical patients requiring prolonged intensive care with respect to survival, residential status, functional recovery, and quality of life in both hospital and long-term follow-up. DATA SOURCES: MEDLINE, Embase, CINAHL, Web of Science, and Dissertations and Theses Global up to July 21, 2017. STUDY SELECTION: Studies were included if they assessed hospital or long-term survival and/or patient-centered outcomes in adult patients with prolonged ICU stays following major cardiac surgery. After screening 10,159 citations, 114 articles were reviewed in full; a final 34 articles met criteria for data extraction. DATA EXTRACTION: Two reviewers independently extracted data and assessed risk of bias using the National Institutes of Health Quality Assessment Tool for Observational Studies. Extracted data included the used definition of prolonged ICU stay, number and characteristics of prolonged ICU stay patients, and any comparator short stay group, length of follow-up, hospital and long-term survival, residential status, patient-centered outcome measure used, and relevant score. DATA SYNTHESIS: The definition of prolonged ICU stay varied from 2 days to greater than 14 days. Twenty-eight studies observed greater in-hospital mortality among all levels of prolonged ICU stay. Twenty-five studies observed greater long-term mortality among all levels of prolonged ICU stay. Multiple tools were used to assess patient-centered outcomes. Long-term health related quality of life and function was equivalent or worse with prolonged ICU stay. CONCLUSIONS: We found consistent evidence that patients with increases in ICU length of stay beyond 48 hours have significantly increasing risk of hospital and long-term mortality. The significant heterogeneity in exposure and outcome definitions leave us unable to precisely quantify the risk of prolonged ICU stay on mortality and patient-centered outcomes. PMID- 30398979 TI - The Endogenous Opioid System: Role and Dysfunction Caused by Opioid Therapy. AB - The endogenous opioid system is comprised of a wide array of receptors and ligands that are present throughout the central and peripheral nervous system, the gastrointestinal tract, and the immune system. This explains the multitude of physiological functions it is responsible for including analgesia, mood regulation, and modulation of the stress response. It also plays a pivotal role in modulating the brain's reward center with behavioral and social implications on mood disorders and addiction. Exogenous opioid therapy hijacks the endogenous system and alters its functions contributing to an imbalance that is responsible for the pathogenesis of several disease states. PMID- 30398980 TI - Differential cross-tolerance to the effects of nicotinic acetylcholine receptor drugs in C57BL/6J mice following chronic varenicline. AB - Varenicline is a smoking cessation pharmacotherapy with a presumed mechanism of action of partial efficacy at the alpha4beta2 nicotinic acetylcholine receptor (nAChR); however, the extent to which daily varenicline use leads to changes in nAChR sensitivity is unclear. This study examined the consequences of daily varenicline treatment on disruptions in operant responding (i.e. rate-decreasing effects) and hypothermia induced by administration of nicotine, epibatidine, cytisine, and cocaine in C57BL/6J mice. Furthermore, mecamylamine was used to assess the involvement of nAChRs in the effects of varenicline. Mice were trained under a fixed ratio 20 of milk reinforcement, and rectal temperatures were measured after 30 min following drug-administration. Varenicline, nicotine, epibatidine, and cytisine produced dose-dependent decreases in response rate and rectal temperature. Chronic varenicline (30 mg/kg) engendered tolerance to varenicline, but more cross-tolerance to nicotine, for both disruptions in operant responding and hypothermia. Cross-tolerance only developed to the hypothermic effects of epibatidine, and no cross-tolerance developed to any effects of cytisine and cocaine. In varenicline-tolerant mice, mecamylamine did not antagonize the effects of varenicline. The varying magnitudes of tolerance and cross-tolerance among effects and drugs are indicative of a nonuniform nAChR pharmacology in vivo. PMID- 30398981 TI - Large Dual-Lumen Extracorporeal Membrane Oxygenation Cannulas Are Associated with More Intracranial Hemorrhage. AB - Large dual-lumen veno-venous (VV) extracorporeal membrane oxygenation (ECMO) cannulas may increase venous pressure in the brain, contributing to intracranial hemorrhage (ICH). A retrospective cohort study was performed using the extracorporeal life support organization (ELSO) registry. Propensity score matching was used to control for confounding. The rate of ICH and rates of hemolysis, cannula complications, and mortality were compared between patients with a 27 French dual-lumen cannula and patients with a 31 French dual-lumen cannula. Seven hundred forty-four patients were included in the propensity score matched cohort. Patients were well matched except there was some residual imbalance in body weight and sex. Patients with a 31 French cannula had an ICH rate of 4.3% compared with 1.6% in patients with a 27 French cannula (p = 0.03). There were no differences in hemolysis, cannula complications, or mortality between groups. After controlling for body weight and sex in the matched cohort, ICH odds remained higher in patients with a 31 French cannula; odds ratio = 2.74, (95% CI = 1.06-7.09, p = 0.03). Our study data suggest that large dual-lumen VV ECMO cannulas are associated with more ICH, and thus, smaller cannulas may be preferable when feasible. PMID- 30398982 TI - Obesity Is Associated with Driveline Infection of Left Ventricular Assist Devices. AB - In patients with left ventricular assist devices (LVADs), the association of driveline infection (DLI) and body mass index (BMI) remains controversial. The aim of this study was to explore a potential correlation between BMI and DLI in the LVAD patient population. A retrospective, single-center study evaluated patients who underwent LVAD implantation between May 2012 and July 2016. Driveline infection was evaluated per Interagency Registry for Mechanically Assisted Circulatory Support established criteria. Of 222 included patients, 80% were male, the average age was 55 years, and the main underlying heart failure diagnosis was nonischemic cardiomyopathy (56%). The majority of patients (65%) received LVAD as destination therapy and 35% as a bridge to transplantation. Average time-to-first DLI was 296 days after LVAD implantation. In comparison to non-DLI group (80%, N = 177), patients in DLI group (20%, N = 45) had a higher BMI (33.5 +/- 8.3 kg/m in DLI group vs. 28.8 +/- 7.5 kg/m in non-DLI group, p = 0.0003) and were younger (51 +/- 12 years in DLI group vs. 56 +/- 12 years in non DLI group, p = 0.013). There was a significant correlation between BMI and DLI (p < 0.0001), and age was negatively correlated with DLI (p = 0.01). Analysis revealed no correlation between time-to-first DLI and BMI. Our data confirm that higher BMI is associated with increased prevalence of DLI in LVAD population, particularly in younger patients. Addressing excessive body weight in this patient cohort may significantly reduce DLI and thereby improve long-term outcomes. PMID- 30398983 TI - Association between admission lactate levels and mortality in patients with acute coronary syndrome: a retrospective cohort study. AB - OBJECTIVE: Hyperlactatemia at admission is associated with poor outcome in critically ill patients. However, data on the prognostic value of blood lactate level in patients with acute coronary syndrome (ACS) are limited. The present study assessed the prognostic effect of admission lactate level in a large population of patients with ACS. MATERIALS AND METHODS: This was a retrospective observational study including patients with ACS who were admitted to the Coronary Care Unit of the First Affiliated Hospital of Wenzhou Medical University between 2014 and 2017. Patients were divided into tertiles of lactate level (T1: <1.8; T2: 1.8-2.6; T3: >=2.7 mmol/l). The clinical outcomes were 30-day and 180-day mortality from hospital admission. Cox proportional hazards models were used to evaluate the association between lactate level and survival. RESULTS: A total of 1865 consecutive patients with ACS were enrolled. Significant positive associations were observed between admission lactate level and both 180-day and 30-day mortality, with highest risk for lactate greater than or equal to 2.7 mmol/l. The adjusted hazard ratio for 180-day mortality was 2.09 [95% confidence interval (CI): 1.18-3.71, P=0.011] for T3 and 1.53 (95% CI: 0.86-2.72, P=0.147) for T2 compared with T1 (P for trend=0.006), and 1.10 (95% CI: 1.02-1.18, P=0.010) for each unit increase in lactate level. Similar trends were observed for 30-day mortality. The association was highly consistent across all subgroups studied (all P for interaction >0.05). CONCLUSION: In patients with ACS, elevated admission lactate level is an independent predictor of 30-day and 180-day all cause mortality. PMID- 30398984 TI - Multiple Pilomatricomas: A Retrospective Study and Literature Review. AB - Pilomatricoma is usually a single lesion. However, some patients present with more than one, a fact that has been reported in association with several systemic diseases. The aim of this analysis is to determine the prevalence of multiple pilomatricomas (MP) in our institution as well as to describe their clinical features and associated comorbidities. This is a retrospective analysis reviewing patients with a histological diagnosis of pilomatricoma registered in the database of the Pathology Department of our institution, from January 2005 to March 2017. One hundred ninety-five patients with histological criteria for pilomatricoma were registered. Fourteen (0.7%) of those patients suffered from MP. Among them, the most relevant findings were: 9 (64%) patients were women and 5 (36%) were men. The median age at diagnosis was 16 years. Seven (50%) had 2 pilomatricomas and 7 (50%) had more than 2. Two (14%) suffered from Steinert myotonic dystrophy (SMD). Regarding family background, 3 of them had relatives with pilomatricomas, one of them with pancreatic cancer, and another one with SMD. A total of 36 pilomatricomas were excised from those 14 patients with the following characteristics: The mean lesion size was 12 mm. The majority of the lesions (53%) were located on the head and neck. There was no recurrence or malignant transformation in any patient. Articles reporting on MP are scarce. We communicate 2 new familial MP without associated comorbidities. We would like to highlight that 2 of our patients with MP also developed SMD, an association previously reported. Thus, a thorough physical examination and inquiring about family history are of utmost importance for an early diagnosis of possible associated diseases. PMID- 30398985 TI - Syringocystadenoma Papilliferum of the Anogenital Area and Buttocks: A Report of 16 Cases, Including Human Papillomavirus Analysis and HRAS and BRAF V600 Mutation Studies. AB - Syringocystadenoma papilliferum (SCAP) is a benign tumor most commonly located on the head and neck area often associated with nevus sebaceus. In its usual location, the human papillomavirus (HPV) DNA and mutations in the RAS/mitogen activated protein kinase signaling pathway have been detected in SCAP. We studied 16 cases of SCAP in the anogenital areas and buttock where this neoplasm is rare and attempted to find out whether SCAP in these sites have different histopathological and molecular biological features. It seems that there is no significant difference between the morphology of anogenital SCAP and SCAP in other locations. Several tumors in our cohort demonstrated features resembling those seen in warts, but HPV DNA was not found in these lesions. On the contrary, we identified DNA of HPV high-risk types in some tumors without HPV-related morphology. Our study confirms the role of HRAS and BRAF V600 mutations in the pathogenesis of SCAP, including SCAP in the anogenital areas and buttock. PMID- 30398986 TI - Examination of Tar-Induced Verrucous Growths Reveals Absence of Human Papillomavirus. PMID- 30398987 TI - Neutropenic Fever and a Diffuse Hyperpigmented Papular Rash: Challenge. PMID- 30398988 TI - Cytoimmunofluorescence Diagnosis in Surgically Induced Pemphigus Foliaceus. AB - Pemphigus foliaceus is an autoimmune bullous disease with autoantibodies against desmoglein 1. Case reports of pemphigus after surgery have also been described, which may simulate an infection of the surgical wound, a contact dermatitis, or even a tumor recurrence. Cytoimmunofluorescence can help to establish a rapid diagnosis. PMID- 30398989 TI - Possible Sertraline-Induced Hiccups in a Boy With Obsessive-Compulsive Disorder and Attention-Deficit/Hyperactivity Disorder. AB - Hiccup is a sudden-onset repeated involuntary and spasmodic contraction of the diaphragm and intercostal muscle accompanied by laryngeal closure, generating the characteristic inspiratory sound and discomfort. Various factors including drugs may trigger the hiccups. There are some reports regarding the possible links between psychotropic agents that can affect the dopaminergic system and the triggering of hiccup; however, to our knowledge, there are no data regarding sertraline-induced hiccup. We present the case of a boy with obsessive-compulsive disorder and attention-deficit/hyperactivity disorder who displayed hiccup after sertraline therapy. PMID- 30398990 TI - Reconfiguring a One-Way Street: A Position Paper on Why and How to Improve Equity in Global Physician Training. AB - Large numbers of U.S. physicians and medical trainees engage in hands-on clinical global health experiences abroad, where they gain skills working across cultures with limited resources. Increasingly, these experiences are becoming bidirectional, with providers from low- and middle-income countries traveling to experience health care in the United States, yet the same hands-on experiences afforded stateside physicians are rarely available for foreign medical graduates or postgraduate trainees when they arrive. These physicians are typically limited to observership experiences where they cannot interact with patients in most U.S. institutions. In this article, the authors discuss this inequity in global medical education, highlighting the shortcomings of the observership training model and the legal and regulatory barriers prohibiting foreign physicians from engaging in short-term clinical training experiences. They provide concrete recommendations on regulatory modifications that would allow meaningful short term clinical training experiences for foreign medical graduates, including the creation of a new visa category, the designation of a specific temporary licensure category by state medical boards, and guidance for U.S. host institutions supporting such experiences. By proposing this framework, the authors hope to improve equity in global health partnerships via improved access to meaningful and productive educational experiences, particularly for foreign medical graduates with commitment to using their new knowledge and training upon return to their home countries.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30398992 TI - Leading Practices and Future Directions for Technical Standards in Medical Education. AB - The medical profession first addressed the need for technical standards (TS), defining the non-academic requirements deemed essential for participation in an educational program, in guidelines published by the Association of American Medical Colleges in 1979. Despite many changes in the practice of medicine and legal, cultural, and technological advances that afford greater opportunities for people with disabilities, the profession's approach to TS largely has not changed over the ensuing four decades. Although physicians with disabilities bring unique perspectives to medicine and contribute to a diverse physician workforce of culturally-competent practitioners, they remain underrepresented in the profession.As part of an initiative sponsored by the Association of Academic Physiatrists, the authors describe the need for an updated TS framework, outlining interval changes in the legal and regulatory climate, medical practice, and medical education since the initial TS guidelines were put forth. They conclude by offering eight recommendations and two functional approaches to TS that are consistent with now-prevalent competency-based medical education constructs.The profession's commitment to diversity and inclusion should extend explicitly to people with disabilities, and this stance should be clearly communicated through medical schools' TS and procedures for requesting accommodations. To this end, schools should consider the principles of universal design to create policies and assessments that work for all learners, to the greatest extent possible, without the need for after-the-fact accommodations. A thoughtful and concerted effort along these lines is long overdue in medical education. PMID- 30398991 TI - Developing Tomorrow's Leaders: A Medical Student Distinction Track in Health System Transformation and Leadership. AB - PROBLEM: Calls for medical education reform focus on preparing physicians to meet the challenges of today's complex health care system. Despite implementing curricula focused on health systems science (HSS), including quality improvement (QI), patient safety, team-based care, and population health, a significant gap remains in training students to meet the system's evolving needs. APPROACH: Brody School of Medicine redesigned its curriculum to prepare leaders to effect health system change. This included development of a Distinction Track in Health System Transformation and Leadership, known as Leaders in INnovative Care (LINC) Scholars Program. Selected LINC scholars spend eight weeks in a summer immersion experience designed to provide foundational knowledge and practical application. OUTCOMES: Two cohorts (15 LINC scholars) completed the summer immersion in 2015 and 2016. Participants demonstrated significant improvement in knowledge and confidence, and continue to be engaged in ongoing QI projects throughout the health system. All scholars have presented their work at local, regional, or national meetings. Students rated patient navigation experiences, health system leader interviews, QI project application, and interprofessional experiences as most valuable and recommended adoption in the curriculum for all students. NEXT STEPS: A Distinction Track with an immersion component can be an effective method to pilot innovative HSS components for the entire curriculum while preparing a cadre of learners with advanced expertise. To longitudinally measure HSS knowledge change, behavioral impact, and organization-level outcomes, next steps must focus on development of workplace-based assessments, establishment of learner portfolios, and longitudinal tracking of student outcomes, including career trajectory.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30398993 TI - Teaching Critical Thinking: A Case for Instruction in Cognitive Biases to Reduce Diagnostic Errors and Improve Patient Safety. AB - Diagnostic errors account for up to 70% of medical errors. Prevention of diagnostic errors is more complex than building safety checks into health care systems; it requires an understanding of critical thinking, of clinical reasoning, and of the cognitive processes through which diagnoses are made. When a diagnostic error is recognized, it is imperative to identify where and how the mistake in clinical reasoning occurred. Cognitive biases may contribute to errors in clinical reasoning. By understanding how physicians make clinical decisions, and examining how errors due to cognitive biases occur, cognitive bias awareness training and de-biasing strategies may be developed to decrease diagnostic errors and patient harm. Studies of the impact of teaching critical thinking skills have mixed results but are limited by methodological problems.This Perspective explores the role of clinical reasoning and cognitive bias in diagnostic error, as well as the effect of instruction in metacognitive skills on improvement of diagnostic accuracy for both learners and practitioners. Recent literature questioning whether teaching critical thinking skills increases diagnostic accuracy is critically examined, as are studies suggesting metacognitive practices result in better patient care and outcomes. Instruction in metacognition, reflective practice and cognitive bias awareness may help learners move toward adaptive expertise and help clinicians improve diagnostic accuracy. The authors argue that explicit instruction in metacognition in medical education, including awareness of cognitive biases, has the potential to reduce diagnostic errors and thus improve patient safety. PMID- 30398994 TI - Outcomes of Noninvasive Ventilation in Obese Patients With Acute Asthma Exacerbations. AB - BACKGROUND: The role of noninvasive positive pressure ventilation (NIPPV) in acute asthma exacerbation is controversial. However, the outcome of NIPPV in obese patients with asthma during such exacerbation has not been well studied despite well-established relationship between obesity and asthma. STUDY QUESTION: Does body mass index (BMI) play a role in the outcome of NIPPV during an acute exacerbation and does it predict of the success or failure of NIPPV? STUDY DESIGN: The study was a retrospective analysis by design. The purpose of the study was to assess factors predicting the success or failure of NIPPV. The entire cohort was divided into 2 groups: patients who failed NIPPV and patients who did not. Univariate and multivariate regression analysis was used to predict the variables. Stepwise selection method was used to select variables for final regression model. RESULTS: A total 96 patients were included in the study. Of those, 18 patients (18.9%) failed NIPPV and required endotracheal intubation (group 1). Rest (78.1%) did not fail NIPPV (group 2). Mean age of the study population was 48.8 years and 53% of patients were female. In the univariate analysis, the group that did not fail NIPPV (group 2) had significantly higher number of obese patients (47.9% versus 22.2%; P 0.013). Multivariate analysis showed significant association between BMI categories (BMI of 30 or more) and failure of NIPPV (odds ratio 0.26, 95% confidence interval, 0.08-0.85; P-value 0.017). Forced introduction of smoking status as a risk factor did not change the significance of association. CONCLUSION: Despite the limitations of the study design and the sample size, our analysis showed that patients with high BMI (obese) fared well with NIPPV during acute asthma exacerbation. Because there are controversies on use of NIPPV during asthma exacerbation, larger-scale prospective studies are needed to better understand the role of NIPPV in obese patients with asthma during acute exacerbation. PMID- 30398995 TI - Iatrogenic Takotsubo Cardiomyopathy. PMID- 30398997 TI - Case of Erythema Multiforme Drug Eruption Induced by Ledipasvir/Sofosbuvir: Erratum. PMID- 30398996 TI - Hyponatremic Seizures After Polyethylene Glycol Bowel Preparation: The Elderly at Risk. PMID- 30398998 TI - The risk factors, frequency and diagnosis of atypical antipsychotic drug-induced hypothermia: practical advice for doctors. AB - Hypothermia is unpredictable and life-threatening adverse effect of atypical antipsychotic drug (APD) treatment, which has been little described. The aim of this article is to increase the awareness that hypothermia induced by APD drugs is more common than the current published case reports may suggest, and risk factors increase its development. Moreover, valuable guidelines regarding how to detect the early stages of hypothermia in clinical practice are included. A literature search for reports on APD-induced hypothermia in PubMed, Academic Search Complete, Medline Complete and eHealthMe databases was conducted. The literature search apart from eHealthMe database resulted in 524 articles, which included 34 case reports. Hypothermia was mostly induced by olanzapine (14) and risperidone (10). However, the data from Food and Drug Administration reports revealed several dozen more cases of APD-induced hypothermia (591case reports) compared with the published case reports (e.g. olanzapine-262 and risperidone 161). Hypothermia, mostly mild (61% of cases), has developed mainly in men (71%) having schizophrenia, a few hours after commencement of treatment or in the presence of risk factors. Owing to the increased risk of hypothermia development during APD treatment, doctors should routinely measure body temperature of patients, especially during the first days of the therapy. Early diagnosis of hypothermia and appropriate treatment may prevent death. PMID- 30398999 TI - Comparison of Anal Versus Rectal Staging in the Prognostication of Rectal Squamous Cell Carcinoma: A Population-Based Analysis. AB - BACKGROUND: Rectal squamous cell carcinoma is a rare malignancy with limited data regarding management and prognosis. It is also unknown whether a rectal squamous cell cancer staging system should be based on size, as for anal squamous cell carcinoma, or depth of invasion, as for rectal adenocarcinoma. OBJECTIVE: The aims of the current study were to determine the optimal management strategy, prognostic factors, and staging system for rectal squamous cell carcinoma. DESIGN: This was a population-based study. SETTINGS: The Surveillance, Epidemiology, and End Results database was used to identify patents diagnosed between 1988 and 2013. PATIENTS: Patients >=18 years of age undergoing radiation or local excision alone, radiation with local excision, or radiation with radical resection were included. Patients were then staged according to both the American Joint Committee on Cancer classification for rectal adenocarcinoma (American Joint Committee on Cancer-rectum) and anal cancer (American Joint Committee on Cancer-anus). MAIN OUTCOME MEASURES: The main outcome was 5-year, disease specific survival. RESULTS: In both univariate and multivariate survival analyses, the addition of local excision or radical resection to radiation resulted in similar-to-worse outcomes across all of the stages. Among patients staged according to American Joint Committee on Cancer-rectum (n = 1646), although a significant difference in 5-year survival was observed for stage I as compared with higher stages, no difference was noted between stages II and III (80% vs 61% and 62%). However, in the American Joint Committee on Cancer-anus classification (n = 1327), a significant difference was observed across all of the stages (87% vs 72% vs 59%; p < 0.001). In multivariate analysis, the prognostic discrimination based on HRs provided by the American Joint Committee on Cancer-anus was superior to that of the American Joint Committee on Cancer rectum. LIMITATIONS: This study was limited by lack of data on chemotherapy and location of positive nodes. CONCLUSIONS: A treatment approach primarily based on radiation should be considered the optimal management strategy for rectal squamous cell carcinoma. Moreover, a staging system based on size (American Joint Committee on Cancer-anus) rather than on depth of invasion (American Joint Committee on Cancer-rectum) appears to be more accurate in predicting its prognosis. See Video Abstract at http://links.lww.com/DCR/A734. PMID- 30399000 TI - Estimating the effect of treatment duration using observational data in practice. PMID- 30399001 TI - Re: Associations between Childhood Thyroid Cancer and External Radiation Dose after the Fukushima Daiichi Nuclear Power Plant Accident. PMID- 30399002 TI - Association between liver fibrosis and hepatitis E seroprevalence among HIV positive individuals in Nepal. AB - OBJECTIVE: Hepatitis E virus (HEV) seropositivity may confer an increased risk of liver fibrosis in immunosuppressed individuals. We studied this effect in HIV infected individuals in Nepal, a country hyperendemic for HEV. PARTICIPANTS AND METHODS: We prospectively evaluated 200 HIV-positive individuals. Serum samples were tested for components of fibrosis scores and cytokeratin-18. RESULTS: Of 200 patients, 43% were HEV-immunoglobulin G+. The mean fibrosis-4 score was 8.02 in the HEV-positive and 1.17 in the HEV-negative group (P<0.001). The mean nonalcoholic fatty liver disease score was 2.12 in the HEV-positive and -2.53 in the HEV-negative group (P=0.02). The mean aminotransferase-platelet ratio index score was 0.37 in the HEV-positive and 0.38 in the HEV-negative group (P=0.9). The mean cytokeratin-18 levels were 119.9 in the HEV-positive group and 158.6 in the HEV-negative group (P=0.08). CONCLUSION: We found higher fibrosis-4 and nonalcoholic fatty liver disease scores in HEV-HIV-positive individuals, suggesting an increased liver fibrosis profile in this group. Further studies using liver stiffness measurements should be carried out. PMID- 30399004 TI - Nurse Attitudes Related to Accepting Electronic Health Records and Bedside Documentation. PMID- 30399003 TI - The association between obesity and outcomes in acute pancreatitis: an individual patient data meta-analysis. AB - OBJECTIVES: There are data to suggest that obesity is associated with local and systemic complications as well as mortality in acute pancreatitis (AP). Cohort studies to date, however, have shown conflicting results from mostly unadjusted analyses. Therefore, we performed an individual patient data meta-analysis with the primary aim to investigate the association between obesity and mortality in AP. Our secondary aim was to investigate the association between obesity and necrosis, organ failure, multiple organ failure, and invasive intervention. PATIENTS AND METHODS: We systematically searched four electronic databases for prospective studies on obesity and outcomes in AP. Researchers of eligible studies were invited to share individual patient data using a standardized data collection form. All end points were investigated with a one-stage mixed effects Poisson model with random intercepts and forced entry of relevant confounders. RESULTS: We included five databases with 1302 patients, of whom 418 (32%) were obese. In total, 466 (36%) patients had necrosis, 328 (25%) had organ failure, 188 (14%) had multiple organ failure, 210 (16%) had an intervention, and 84 (7%) patients died. We found no significant association between obesity and mortality [relative risk (RR) 1.40, 95% confidence interval (CI): 0.89-2.20], necrosis (RR: 1.08, 95% CI: 0.90-1.31) or invasive intervention (RR: 1.10, 95% CI: 0.83-1.47) after adjustment for confounders. However, obesity was independently associated with the development of organ failure (RR: 1.38, 95% CI: 1.11-1.73) and multiple organ failure (RR: 1.81, 95% CI: 1.35-2.42). CONCLUSION: Obesity is independently associated with the development of organ failure and multiple organ failure in AP. However, there is no association between obesity and mortality, necrosis, and an intervention. PMID- 30399005 TI - Summer Institute in Nursing Informatics 2018 Balancing Digital Demands: Access, Use, Security. PMID- 30399006 TI - Corrigendum to: Designing and Developing a Mobile App for Clinical Decision Support: An Interprofessional Collaboration. PMID- 30399007 TI - Factors Affecting Consumer Acceptance of an Online Health Information Portal Among Young Internet Users. PMID- 30399008 TI - It's not me, it's you: Should we abandon the idea of burnout? PMID- 30399009 TI - PA practice analysis: Multidisciplinary tasks, knowledge, and skills. AB - In conducting its practice analysis, the National Commission on Certification of Physician Assistants incorporated new approaches in 2015. Twelve groups of PAs identified knowledge, tasks, and skills required for practice not only in primary care, but also in 11 practice focus areas (specialties). In addition, a list of diseases and disorders likely to be encountered was identified for each specialty. A representative sample of 15,771 certified PAs completed an online algorithm-driven survey and data were analyzed to determine how practice is the same for all PAs and how it differs depending on the practice focus. Larger differences between PAs in different specialties were seen in the frequency ratings of diseases and disorders encountered than for ratings of task, knowledge, and skill statements. Distinctions between PAs in primary care and those in other specialties were more pronounced, as the specialty was more divergent from primary care. PMID- 30399010 TI - Cochlear Reflectance and Otoacoustic Emission Predictions of Hearing Loss. AB - OBJECTIVES: Cochlear reflectance (CR) is the cochlear contribution to ear-canal reflectance. CR is a type of otoacoustic emission (OAE) that is calculated as a transfer function between forward pressure and reflected pressure. The purpose of this study was to compare wideband CR to distortion-product (DP) OAEs in two ways: (1) in a clinical-screening paradigm where the task is to determine whether an ear is normal or has hearing loss and (2) in the prediction of audiometric thresholds. The goal of the study was to assess the clinical utility of CR. DESIGN: Data were collected from 32 normal-hearing and 124 hearing-impaired participants. A wideband noise stimulus presented at 3 stimulus levels (30, 40, 50 dB sound pressure level) was used to elicit the CR. DPOAEs were elicited using primary tones spanning a wide frequency range (1 to 16 kHz). Predictions of auditory status (i.e., hearing-threshold category) and predictions of audiometric threshold were based on regression analysis. Test performance (identification of normal versus impaired hearing) was evaluated using clinical decision theory. RESULTS: When regressions were based only on physiological measurements near the audiometric frequency, the accuracy of CR predictions of auditory status and audiometric threshold was less than reported in previous studies using DPOAE measurements. CR predictions were improved when regressions were based on measurements obtained at many frequencies. CR predictions were further improved when regressions were performed on males and females separately. CONCLUSIONS: Compared with CR measurements, DPOAE measurements have the advantages in a screening paradigm of better test performance and shorter test time. The full potential of CR measurements to predict audiometric thresholds may require further improvements in signal-processing methods to increase its signal to noise ratio. CR measurements have theoretical significance in revealing the number of cycles of delay at each frequency that is most sensitive to hearing loss. PMID- 30399011 TI - Biomarkers of Systemic Inflammation and Risk of Incident Hearing Loss. AB - BACKGROUND: Chronic inflammation may lead to cochlear damage, and the only longitudinal study that examined biomarkers of systemic inflammation and risk of hearing loss found an association with a single biomarker in individuals <60 years of age. The purpose of our study was to determine whether plasma inflammatory markers are associated with incident hearing loss in two large prospective cohorts, Nurses' Health Studies (NHS) I and II. METHODS: We examined the independent associations between plasma levels of markers of systemic inflammation (C-reactive protein [CRP], interleukin-6 [IL-6], and soluble tumor necrosis factor receptor 2 [TNFR-2]) and self-reported hearing loss. The participants in NHS I (n = 6194 women) were 42 to 69 years of age at the start of the analysis in 1990, while the participants in NHS II (n = 2885 women) were 32 to 53 years in 1995. After excluding women with self-reported hearing loss before the time of blood-draw, incident cases of hearing loss were defined as those women who reported hearing loss on questionnaires administered in 2012 in NHS I and 2009 or 2013 in NHS II. The primary outcome was hearing loss that was reported as moderate or worse in severity, pooled across the NHS I and NHS II cohorts. We also examined the pooled multivariable-adjusted hazard ratios for mild or worse hearing loss. Cox proportional hazards regression was used to adjust for potential confounders. RESULTS: At baseline, women ranged from 42 to 69 years of age in NHS I and 32 to 53 years of age in NHS II. Among the NHS I and II women with measured plasma CRP, there were 628 incident cases of moderate or worse hearing loss during 100,277 person-years of follow-up. There was no significant association between the plasma levels of any of the three inflammatory markers and incident moderate or worse hearing loss (multivariable adjusted pooled p trend for CRP = 0.33; p trend IL-6 = 0.54; p trend TNFR-2 = 0.70). There was also no significant relation between inflammatory marker levels and mild or worse hearing loss. While there was no significant effect modification by age for CRP or IL-6 in NHS I, there was a statistically significant higher risk of moderate or worse hearing loss (p interaction = 0.02) as well as mild or worse hearing loss (p interaction = 0.004) in women >=60 years of age who had higher plasma TNFR-2 levels. CONCLUSIONS: Overall, there was no significant association between plasma markers of inflammation and risk of hearing loss. PMID- 30399012 TI - Refocusing the Lens: Caring and Compassion in an Online Nursing Environment. AB - The concept of compassionate caring in an online nursing education environment is an idea that has limited research. The College of Nursing at Sacred Heart University has adopted a caring model and philosophy to foster an engaged, mutually beneficial environment and guide how faculty and students interact in the online environment. Examples of how faculty engage students in these behaviors are offered. PMID- 30399014 TI - Developments in family planning and abortion care: from the personal to the planetary. PMID- 30399015 TI - Abortion through telemedicine. AB - PURPOSE OF REVIEW: Medical abortion offers a well tolerated and effective method to terminate early pregnancy, but remains underutilized in the United States. Over the last decade, 'telemedicine' has been studied as an option for medical abortion to improve access when patients and providers are not together. A number of studies have explored various practice models and their feasibility as an alternative to in-person service provision. RECENT FINDINGS: A direct-to-clinic model of telemedicine medical abortion has similar efficacy with no increased risk of significant adverse events when compared with in-person abortion. A direct-to-consumer model is currently being studied in the United States. International models of direct-to-consumer medical abortion have shown promising results. SUMMARY: The introduction of telemedicine into abortion care has been met with early success. Currently, there are limitations to the reach of telemedicine because of specific restrictions on mifepristone in the United States as well as laws that specifically prohibit telemedicine for abortion. If these barriers are removed, telemedicine can potentially increase abortion access. PMID- 30399016 TI - Pericoital contraception. AB - PURPOSE OF REVIEW: To evaluate the literature on repeat use of emergency contraception and pericoital approaches to contraception. RECENT FINDINGS: Women are very interested in an oral, on-demand contraceptive option, were one available. Ulipristal acetate and a combination of levonorgestrel (LNG) and meloxicam (a cyclo-oxygenase-2 inhibitor) both appear to be more effective at disrupting ovulation than LNG alone. Recent advisories from the United Kingdom regarding daily dosing of ulipristal for fibroids emphasize the need for more safety data. SUMMARY: Repeat pericoital dosing of 1.5-mg LNG is approximately as effective as other on-demand contraceptive methods and is overall very safe. The most common side effect is irregular bleeding. Repeat on-demand ulipristal acetate or meloxicam/other cyclo-oxygenase-2 inhibitors have potential as an on demand option either alone or in combination but have not been evaluated for contraceptive efficacy in a large-scale study. Given the high unmet need for contraception, even among women with access to available options, there is a distinct need for options that address needs of women who are interested in an on demand option. On-demand oral contraception has the potential to expand the convenience of contraceptive options and overall contraceptive use. PMID- 30399017 TI - Cystoscopy at the time of incontinence and prolapse surgery. AB - PURPOSE OF REVIEW: This article provides an update on the use of cystoscopy at the time of prolapse and incontinence surgery. RECENT FINDINGS: Iatrogenic lower urinary tract injury is a known complication of antiincontinence procedures and surgical repair of pelvic organ prolapse. Intraoperative cystoscopy improves detection of lower urinary tract injuries in women undergoing pelvic floor surgery. The pelvic surgeon has a number of agents available to aid in the cystoscopic visualization of ureteral efflux. When injuries of the urinary tract are identified and treated intraoperatively, there is decreased morbidity, lower healthcare costs, and a lower risk of litigation than when detection is delayed. Therefore, many organizations, including the American College of Obstetricians and Gynecologists (ACOG), the American Urogynecologic Society (AUGS), and the American Urological Association (AUA) recommend cystoscopy at the time of pelvic floor surgery. SUMMARY: Cystoscopy should be universally employed at the time of prolapse and incontinence surgery, except in instances of isolated repair of the posterior compartment. PMID- 30399018 TI - Viral Respiratory Infections Diagnosed After PICU Admission. AB - OBJECTIVES: Reduction of nosocomial infections represents an increasingly recognized aspect of PICU benchmarking. We investigated the prevalence and outcomes of viral respiratory infections acquired during admission to PICU. DESIGN: Multicenter, statewide retrospective linkage study. SETTING: Tertiary PICU. PATIENTS: All children less than 16 years requiring PICU admission for greater than 48 hours from January 1, 2008, until December 31, 2013. INTERVENTION: Testing was performed in symptomatic patients using an extended panel polymerase chain reaction capturing nine respiratory viruses. Duration of intubation and total duration of respiratory support were primary outcomes. MEASUREMENTS AND MAIN RESULTS: Of 3,607 patients admitted to PICU for greater than 48 hours, 102 (2.8%) were diagnosed with a PICU-associated viral infection out of 702 patients (19.4%) undergoing viral testing, reflecting a rate of 2.8 PICU-associated viral infections per 1,000 PICU patient days. Compared with negative/untested patients, those with PICU-associated viral infections had greater intubation duration (median 164 vs 67; p< 0.001), longer respiratory support (204 vs 68 hr; p < 0.001), were more likely to require extracorporeal life support (odds ratio, 5.3; 2.7-10.3; p < 0.001), high-frequency oscillatory ventilation (odds ratio, 3.0; 1.7-5.4; p < 0.001), and inhaled nitric oxide (odds ratio, 2.7; 1.5-5.0; p = 0.001). When comparing patients with PICU-associated viral infection with patients who tested negative for respiratory viruses, no substantial difference in these outcomes was found. CONCLUSIONS: The acquisition of viral infections during PICU admission is less frequent compared with previous reports on bacterial and fungal hospital-acquired infections. We did not observe worse patient-centered outcomes when comparing virus positive versus tested but negative patients. Our findings challenge the clinical value of performing viral respiratory diagnostics in PICU patients evaluated for infection. PMID- 30399019 TI - Early Peritoneal Dialysis and Major Adverse Events After Pediatric Cardiac Surgery: A Propensity Score Analysis. AB - OBJECTIVES: Early peritoneal dialysis may have a role in modulating the inflammatory response after cardiopulmonary bypass. This study sought to test the effect of early peritoneal dialysis on major adverse events after pediatric cardiac surgery involving cardiopulmonary bypass. DESIGN: In this observational study, the outcomes in infants post cardiac surgery who received early peritoneal dialysis (within 6 hr of completing cardiopulmonary bypass) were compared with those who received late peritoneal dialysis. The primary outcome was a composite of one or more of cardiac arrest, emergency chest reopening, requirement for extracorporeal membrane oxygenation, or death. Secondary outcomes included duration of mechanical ventilation, length of intensive care, and hospital stay. A propensity score methodology utilizing inverse probability of treatment weighting was used to minimize selection bias due to timing of peritoneal dialysis. SETTING: Cardiac ICU, The Royal Children's Hospital, Melbourne, VIC, Australia. PATIENTS: From 2012 to 2015, infants who were commenced on peritoneal dialysis after cardiac surgery were included. MEASUREMENTS AND MAIN RESULTS: Among 239 eligible infants, 56 (23%) were commenced on early peritoneal dialysis and 183 (77%) on late peritoneal dialysis. At 90 days, early peritoneal dialysis as compared with late peritoneal dialysis was associated with a decreased risk of primary outcome (relative risk, 0.16; 95% CI, 0.05-0.47; p < 0.001 and absolute risk difference, -18.1%; 95% CI, -25.1 to -11.1; p < 0.001). Early peritoneal dialysis was also associated with a decrease in duration of mechanical ventilation and intensive care stay. Among infants with a cardiopulmonary bypass greater than 150 minutes, early peritoneal dialysis was also associated with a survival advantage (relative risk, 0.14; 95% CI, 0.03-0.84; p = 0.03 and absolute risk difference, -7.8; 95% CI, -13.6 to -2; p = 0.008). CONCLUSIONS: Early peritoneal dialysis in infants post cardiac surgery is associated with a decrease in the rate of major adverse events. The role of early peritoneal dialysis warrants the conduct of randomized trials both in high and low-to-middle income countries; any beneficial effects if confirmed have the potential to strongly influence outcomes for children born with congenital heart disease. PMID- 30399020 TI - Noninvasive Continuous Blood Pressure Monitoring: Are the Intraoperative Episodes of Hypotension in Clear Sight? PMID- 30399021 TI - Serum Concentrations of Lidocaine During Bariatric Surgery. AB - Lidocaine has been shown to be clinically beneficial during bariatric surgery. However, information about lidocaine serum concentrations in this setting is scarce. This prospective clinical trial included 42 obese patients undergoing laparoscopic bariatric surgery. They received lidocaine based on adjusted body weight. Administration began with a 1.5 mg.kg bolus of intravenous lidocaine followed by a continuous infusion of 2 mg.kg.hour. After skin closure, administration was decreased to 1 mg.kg.hour until discharge from the recovery room. No serum concentrations of lidocaine were outside the usual accepted range (1.5-5 ug.mL). PMID- 30399022 TI - Comparison of Invasive and Noninvasive Blood Pressure Measurements for Assessing Signal Complexity and Surgical Risk in Cardiac Surgical Patients. AB - BACKGROUND: Continuous arterial blood pressure (ABP) is typically recorded by placement of an intraarterial catheter. Recently, noninvasive ABP monitors have been shown to be comparable in accuracy to invasive measurements. In a previous study, we showed that the fluctuations in beat-to-beat ABP measurements were not random variations but had a complex dynamical structure, and that ABP dynamical complexity was inversely associated with surgical risk estimated using the Society of Thoracic Surgeons (STS) index. Dynamical complexity is a mathematical construct that reflects the capacity of a physiological system to adapt to stimuli. The objectives of present study were to: (1) determine whether noninvasive beat-to-beat ABP measurements also exhibit a complex temporal structure; (2) compare the complexity of noninvasive versus invasive ABP time series; and (3) quantify the relationship between the complexity of noninvasive ABP time series and the STS risk scores. METHODS: Fifteen adult patients undergoing coronary artery bypass graft, valve, or combined coronary artery bypass graft/valve surgery ;were enrolled in this observational study. Preoperative ABP waveforms were simultaneously recorded for >=15 minutes using a radial artery catheter (invasive) and a continuous noninvasive arterial pressure monitor. Beat-to-beat systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP) time series were extracted from the continuous waveforms. Complexity was assessed using the multiscale entropy method. The Wilcoxon signed-rank test was used to compare the mean ranks of indices derived from invasive versus noninvasive ABP time series. Spearman correlation coefficients were used to quantify the relationship between invasive and noninvasive indices. Linear regression analysis was used to quantify the association between each of the complexity indices and the STS risk scores. RESULTS: Beat-to-beat fluctuations in noninvasive ABP measurements were not random but complex; however, their degree of complexity was lower than that of fluctuations in invasively obtained ABP signals (SBP: 7.05 vs 8.66, P < .001; DBP: 7.40 vs 8.41, P < .001; PP: 6.83 vs 8.82, P < .001; and MAP: 7.17 vs 8.68, P < .005). Invasive and noninvasive indices for MSESigma.slope showed good correlation (rs) (0.53 for SBP, 0.79 for DBP, 0.42 for PP, 0.60 for MAP). The complexity of noninvasive ABP time series (-0.70 [-1.28 to -0.11]; P = .023 for DBP), like that of invasive time series (-0.94 [-1.52 to -0.35]; P = .004 for DBP), was inversely associated with estimated surgical risk in patients undergoing cardiovascular operations. CONCLUSIONS: Our results support the use of noninvasive ABP monitoring in computations of complexity-based indices that correlate with estimated surgical risk. PMID- 30399023 TI - In Response. PMID- 30399024 TI - Effect of High-Dose Vitamin D Supplementation on Upper Respiratory Tract Infection Symptom Severity in Healthy Children. AB - BACKGROUND: Observational studies support the role of vitamin D in reducing viral upper respiratory tract infection (URTI) symptom severity in adults and children. This study assessed whether wintertime high-dose vitamin D supplementation (2000 IU/day) reduces URTI symptom severity compared with standard-dose (400 IU/day) supplementation in preschool children. Secondary objectives were to assess effects of high-dose supplementation on outpatient physician visits, emergency department (ED) visits, and antibiotic prescriptions for URTI. METHODS: This was a secondary analysis of a multisite randomized clinical trial involving 703 healthy 1-5-year-old children in Toronto, Canada. High-dose or standard-dose oral vitamin D was randomly assigned for one winter season. For each URTI, parents completed symptom checklists based on the Canadian Acute Respiratory and Flu Scale. Symptom severity, frequency of outpatient visits, ED visits, and antibiotic prescriptions for URTI between groups were analyzed using negative binomial regression. RESULTS: URTI symptom severity was not reduced in the high dose vs. standard-dose group (incidence rate ratio (IRR)=0.97, 95% CI 0.76-1.23). High-dose vitamin D did not decrease frequency of outpatient visits (IRR=1.16, 95% CI 0.84-1.60), ED visits (IRR=1.17, 95% CI 0.57-2.40), or antibiotic prescriptions (IRR=1.02, 95% CI 0.61-1.72). Serum 25-hydroxyvitamin D was higher in the high-dose group (48.7 ng/mL, 95% CI 46.9-50.5) than the standard-dose group (36.8 ng/mL, 95% CI 35.4-38.2; p<0.001). CONCLUSIONS: High-dose vitamin D supplementation did not reduce URTI symptom severity, outpatient visits, ED visits, or antibiotic prescriptions relative to standard-dose. These results do not support vitamin D supplementation above the standard recommended dose for reducing URTI symptoms in children. PMID- 30399026 TI - Prognostic Value of Vascular Calcifications and Regional Fat Depots Derived From Conventional Chest Computed Tomography. AB - PURPOSE: The prognostic value of vascular calcifications as well as of regional fat depots has been reported separately, in population-based studies, and using gated-computed tomography (CT) examinations. We, therefore, explored the interplay and prognostic value of vascular calcifications and adipose tissue depots assessed during conventional nongated chest CT. MATERIALS AND METHODS: We enrolled a consecutive series of 1250 patients aged between 35 and 74 years who underwent clinically indicated chest CT scans. We measured the extent of coronary artery calcification (CAC) using the segment-involvement score (CACSIS), and aortic and valve calcification. Pericardial fat volume (PFV), hepatic fat, and abdominal subcutaneous adipose tissue were also calculated. Patients were followed-up for all-cause mortality. RESULTS: A total of 577 (46%) patients had presence of CAC in the coronary tree. Over a mean follow-up of 3.7 years, 51 (4%) deaths occurred, 23 (4.1%) in male patients and 28 (4.1%) in female patients. Patients with higher PFV were older (P<0.0001), more frequently male (P<0.0001), had higher abdominal subcutaneous adipose tissue (P<0.0001), hepatic fat (P<0.0001), as well as a larger extent of CAC (P<0.0001), aortic calcium (P<0.0001), and valve calcium (P<0.0001). From a multivariable Cox regression model, age (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.03-1.11), P=0.001, PFV upper tertile (HR, 4.07; 95% CI, 2.09-7.92), P<0.0001, and CACSIS>5 (HR, 2.19; 95% CI, 1.14-4.23; P<0.0001) were independent predictors of all-cause death. CONCLUSIONS: In this relatively large patient cohort undergoing clinically indicated conventional chest CT scans, PFV and coronary calcification were high risk markers associated with worsening survival. PMID- 30399025 TI - Assessment of NAMS members' prescription patterns of hormone therapy before and after the 2016 NAMS Annual Meeting. AB - OBJECTIVE: Hormone therapy (HT) prescription patterns have varied enormously over time and across specialties. The present study attempts to look at practice variation in specific controversial scenarios and to determine if attendance at The North American Menopause Society (NAMS) 2016 Annual Meeting, where the draft of the 2017 NAMS HT Position Statement was presented, had any impact on members' HT prescribing patterns. METHODS: An anonymous survey with 11 case scenarios was sent to all NAMS members before and after the 2016 NAMS Annual Meeting. Pre- and postmeeting responses were pooled into a single cohort. For those who responded to both surveys, only the postmeeting survey responses were included in the cohort. The impact of attendance at the 2016 NAMS Annual Meeting was investigated by comparing paired responses with "controversial questions" between pre- and postmeeting surveys in the matched population who either attended the 2016 NAMS Annual Meeting (intervention arm) or did not (control arm). "Controversial questions" were defined as those where 25% to 75% of responders answered "YES" to a question. McNemar's test was applied to analyze paired responses using SAS statistical software, with P <= 0.05 being considered statistically significant. RESULTS: A total of 1,786 NAMS members were surveyed before and after the 2016 NAMS meeting, 234 (13%) completed the premeeting survey, 166 (9%) completed the postmeeting survey, and 52 completed both surveys. Of the 52, 27 attended the 2016 NAMS Annual Meeting and 25 did not. The pooled cohort contains 348 responses which represents a 20% response rate. Six complex case scenarios with "controversial questions" were identified from the pooled cohort and reexamined in the intervention and control arm, respectively. In the intervention arm, significant changes toward being more likely to prescribe HT in guideline consistent cases were noted in four out of six cases, whereas significant changes in HT use were not seen in any of six complex cases in the control arm. CONCLUSIONS: NAMS members' prescribing patterns of HT vary in complex clinical scenarios. After the 2016 NAMS Annual Meeting where a draft of the 2017 NAMS HT Position Statement was presented and discussed, in four challenging and complex clinical situations a significant number of practitioners changed their prescription patterns toward prescribing HT which was consistent with the new guideline. PMID- 30399027 TI - Axillary Chest Wall Hibernoma With Intrathoracic Extension Presenting as Thoracic Outlet Syndrome. AB - Hibernomas are rare benign soft tissue tumors derived from brown fat. This case report describes an axillary hibernoma with intrathoracic extension, presenting as a thoracic outlet syndrome. A multimodality imaging series illustrates the classic radiologic features of hibernoma as well as its highly unusual pattern of growth. The latter resulted in TOS with vascular displacement and osseous remodeling, features that are generally absent in lipomatous masses. Detailed preoperative imaging allowed to plan a single surgical procedure in which an extrathoracic axillary approach was combined with intrathoracic video-assisted thoracic surgery. PMID- 30399028 TI - Correlation analysis of motor function improvement and brain structure for upper limb paralysis. AB - Intervention with combined low-frequency repetitive transcranial magnetic stimulation and intensive occupational therapy can improve brain function in poststroke patients with motor paralysis. We aimed to evaluate the relationship between brain structure at the time of intervention and the degree of motor function improvement using this combination therapy. Twenty-five patients with upper limb paralysis after stroke were hospitalized for 15 days to receive 12 sessions of low-frequency repetitive transcranial magnetic stimulation over the nonlesional hemisphere and occupational therapy. Imaging analysis was carried out using three-dimensional T1-weighted images. Correlation analysis between cortical thickness and upper limb motor function score was carried out using FreeSurfer. Correlation analysis between cortical thickness and motor function improvement was carried out by atlas-based analysis. FreeSurfer showed that significant positive correlations were found between cortical thickness of the postcentral or supramarginal gyrus of the diseased hemisphere and motor function improvements in nondominant hand paralysis (uncorrected P<0.001). Results using the atlas supported these results (P<0.05). The results of the analysis indicated that the effect of our proposed treatment could be related to the cortical thickness. In particular, it is considered that the cortical thickness of the postcentral gyrus or the supramarginal gyrus of the affected hemisphere plays an important role in such recovery in poststroke hemiparetic patients. PMID- 30399029 TI - Biplane Double-supported Screw Fixation of Femoral Neck Fractures: Surgical Technique and Surgical Notes. AB - Osteosynthesis of femoral neck fractures is still associated with high complication rates. The novel method of biplane double-supported screw fixation offers better osteosynthesis stability by buttressing two of three medially diverging cannulated screws on the inferior neck cortex. Biomechanically, the most effective component of this fixation is the third, inferior obtuse screw, supported along considerable distance on both the inferior and posterior cortices of the femoral neck following its spiral anterior curve. Thus, biplane double supported screw fixation achieves greater inferoposterior cortical support of the implants, allowing immediate full weight bearing for patients older than 55 years. Although the method has been recently communicated, some important surgical aspects still remain to be discussed. This report aims at describing a detailed and modified surgical technique and providing criteria and recommendations for its successful application according to the clinical experience over more than 9 years. LEVEL OF EVIDENCE:: Level V, expert evidenceThis is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30399031 TI - The early-citation trend: an analysis of seven rehabilitation journals concerning the 2015-2017 window. PMID- 30399030 TI - Inappropriate Questions Asked of Female Orthopaedic Surgery Applicants From 1971 to 2015: A Cross-sectional Study. AB - INTRODUCTION: The Civil Rights Act prohibits employers from making employment decisions based on sex, race, color, religion, or national origin. Questions regarding these topics during a residency interview are therefore prohibited. METHODS: A questionnaire was sent to all female orthopaedic surgeons who had an e mail address in the American Academy of Orthopaedic Surgeons directory. Participants were asked to describe what, if any, inappropriate questions they were asked during interviews. RESULTS: Four hundred eighty-eight of 997 invited female orthopaedic surgeons completed the questionnaire (48.9%). Their residency interviews took place from 1971 to 2015. Overall, 61.7% of participants were asked an inappropriate question during an interview. This proportion neither increased nor decreased from 1971 to 2015 (P = 0.315). The most common themes of questions included "raising children during residency" (37.9%), "marital status" (32.4%), and "pregnancy during residency" (29.7%). Of those who were asked an inappropriate question, only 1.4% reported the inappropriate question to authorities. DISCUSSION: The present study suggests that over half of female applicants have been asked inappropriate questions at orthopaedic surgery residency interviews, and that there has been no improvement in that percentage over nearly five decades. It is the responsibility those interviewing to be aware of this issue and to be in compliance with national guidelines. LEVEL OF EVIDENCE: Level IV. PMID- 30399034 TI - Reflexive laboratory-based cryptococcal antigen screening and preemptive fluconazole therapy for cryptococcal antigenemia in HIV-infected individuals with CD4 <100 cells/uL: a stepped-wedge, cluster-randomized trial. AB - BACKGROUND: HIV-infected persons with cryptococcal antigenemia (CrAg) are at high risk for meningitis or death. We evaluated the effect of CrAg screening and pre emptive fluconazole therapy, as an adjunct to antiretroviral therapy (ART), on six-month survival among persons with advanced HIV disease. METHODS: We enrolled HIV-infected, ART-naive eligible participants with <100 CD4 cells/uL, in a stepped-wedge, cluster-randomized trial from July 2012 - December 2014 at 17 Ugandan clinics. Clinics participated in a prospective observational phase, followed by an interventional phase with lab-based, reflexive CrAg screening of residual CD4 count plasma. Asymptomatic CrAg-positive participants received preemptive fluconazole therapy for ten weeks. We assessed six-month survival using Cox-regression, adjusting for nadir CD4, calendar time, and stepped-wedge steps. RESULTS: We included 1,280 observational and 2,108 interventional participants, of whom 9.3% (195/2,108) were CrAg-positive. CD4-, time-, and stepped-wedge-adjusted analyses demonstrated no difference in survival in the observational vs the interventional arms (HR = 1.34; 95% CI, 0.86-2.10; P = 0.20), including when the analysis was limited to persons who started ART (HR=1.11; 95% CI, 0.62 - 1.79, P=0.86) However, six-month mortality of participants with CrAg titers <1:160 and CrAg-negative patients did not differ. Patients with CrAg titers >=1:160 had 2.6-fold higher six-month mortality than patients with titers <1:160. CONCLUSION: We observed no overall survival benefit of the lab-based reflexive CrAg screen-and-treat intervention. However, preemptive antifungal therapy for asymptomatic cryptococcosis appeared to be effective in patients with CrAg titer <1:160. A more aggressive approach may be required for persons with CrAg titer >=1:160.This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. PMID- 30399033 TI - Understanding Quality of Care and Satisfaction With Sexual and Reproductive Healthcare Among Young Men. AB - OBJECTIVE: Sexual and reproductive healthcare (SRHC) guidelines recommend the delivery of quality preventive SRHC to males beginning in adolescence. A quality of care (QOC) framework was used to examine factors associated with young male's perceptions of QOC and satisfaction with care, which can influence their engagement and use of SRHC. METHODS: Cross-sectional surveys were conducted from August 2014 to September 2016 with 385 male patients aged 15-24 years, recruited from primary care and sexually transmitted disease (STD) clinics. Surveys measured QOC received, satisfaction with care, and domains of a QOC framework. Poisson regression analyses examined associations between domains of quality and perceived QOC as well as satisfaction with care. RESULTS: Over half of males reported QOC as excellent (59%) and were very satisfied with the services (56.7%). Excellent QOC and high satisfaction with services was associated with timely care, higher Clinician-Client Centeredness, and being a bisexual male. Excellent QOC was also associated with greater comfort in the clinic, being tested for human immunodeficiency virus/STDs, attending primary care settings, and receipt of higher number of SRHC services. CONCLUSIONS: Using a QOC framework as part of providing SRHC to young males can be important in improving their perceptions of QOC and satisfaction with services. PMID- 30399035 TI - Effectiveness of a lay counsellor-led combination intervention for retention of mothers and infants in HIV care: A randomized trial in Kenya. AB - BACKGROUND: Retention of mothers and infants across the prevention of mother-to child HIV transmission continuum remains challenging. We assessed the effectiveness of a lay worker administered combination intervention compared with the standard of care (SOC) on mother-infant attrition. METHODS: HIV-positive pregnant women starting antenatal care at 10 facilities in western Kenya were randomized using simple randomization to receive individualized health education, retention/adherence support, appointment reminders and missed visit tracking versus routine care per guidelines. The primary endpoint was attrition of mother- infant pairs at six months postpartum. Attrition was defined as the proportion of mother-infant pairs not retained in the clinic at six months postpartum due to mother or infant death or lost to follow-up. Intent-to-treat analysis was used to assess the difference in attrition. This trial is registered with ClinicalTrials.gov; NCT01962220. RESULTS: From September 2013-June 2014, 361 HIV positive pregnant women were screened, 340 were randomized to the intervention (n=170) or SOC (n=170). Median age at enrollment was 26 years (IQR 22-30), median gestational age, 24 weeks (IQR 17-28). Overall attrition of mother-infant pairs was 23.5% at six months postpartum. Attrition was significantly lower in the intervention arm compared to SOC (18.8% vs. 28.2%, RR=0.67, 95% CI 0.45-0.99, p=0.04). Overall the proportion of mothers who were retained and virally suppressed (< 1000 copies/ml) at six months postpartum was 54.4%, with no difference between study arms. CONCLUSIONS: Provision of a combination intervention by lay counselors can decrease attrition along the PMTCT cascade in low resource settings.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30399036 TI - Monocyte-to-lymphocyte ratio is associated with tuberculosis disease and declines with anti-TB treatment in HIV-infected children. AB - BACKGROUND: The blood monocyte-to-lymphocyte ratio (MLR) is associated with active tuberculosis (TB) in adults, but has not been evaluated as a TB diagnostic biomarker in HIV-infected children in whom respiratory sampling is difficult. SETTING: In a cohort of HIV-infected hospitalized Kenyan children initiating antiretroviral therapy, absolute monocyte and lymphocyte counts were determined at enrollment and 4, 12, and 24 weeks thereafter. METHODS: Children were classified as confirmed, unconfirmed, or unlikely pulmonary TB. ROC curves of MLR cutoff values were generated to distinguish children with confirmed TB from those with unconfirmed and unlikely TB. General estimating equations were used to estimate change in MLR over time by TB status. RESULTS: Of 160 children with median age 23 months, 13 (8.1%) had confirmed TB and 67 (41.9%) had unconfirmed TB. Median MLR among children with confirmed TB [0.407 (interquartile range (IQR) 0.378 - 0.675)] was higher than MLR in children with unconfirmed [0.207 (IQR 0.148 - 0.348), p < 0.01] or unlikely [0.212 (IQR 0.138 - 0.391), p = 0.01] TB. MLR above 0.378 identified children with confirmed TB with 77% sensitivity, 78% specificity, 24% positive predictive value, and 97% negative predictive value. After TB treatment, median MLR declined in children with confirmed TB and levels were similar to children with unlikely TB after 12 weeks. CONCLUSION: Blood MLR distinguished HIV-infected children with confirmed TB from those with unlikely TB and declined with TB treatment. MLR may be a useful diagnostic tool for TB in settings where respiratory-based microbiologic. PMID- 30399037 TI - HIV-Related Stigma Affects Cognition in Older Men Living with HIV. AB - BACKGROUND: Stigma remains a reality for many people living with HIV. Stigma bears on mental health, but we hypothesized that it might also affect cognition, in turn affecting function. METHODS: We estimated the impact of HIV-related stigma on brain health and everyday functioning among 512 older Caucasian men living with HIV in Canada, using the International Classification of Functioning, Disability and Health as a comprehensive framework to integrate biopsychosocial perspectives. Experience of HIV-related stigma, as indicated by a single self report item, was related to cognitive test performance, cognitive symptoms and mood. Structural equation modelling was used to estimate the relationships between these variables. FINDINGS: A comprehensive structural equation model was built including personal, environmental, biological factors, and measures of mental and cognitive health, activity limitations, and participation restrictions. HIV-related stigma contributed to lower cognitive test performance and worse mental health. These in turn affected real world function. The paths from stigma to cognition and mood had distinct downstream effects on physical, cognitive and meaningful activities. INTERPRETATION: This provides evidence that HIV-related stigma is a threat to cognitive as well as mental health, with a negative impact on everyday function in men aging with HIV. This argues for direct links between the psychosocial and biological impacts of HIV at the level of the brain. Stigma reduction may be a novel route to addressing cognitive impairment in this population. FUNDING: Operating support was provided by the Canadian Institutes of Health Research (TCO-125272), and by the CIHR HIV Clinical Trials Network (CTN-273). PMID- 30399038 TI - The role of socio-behavioral factors in sub-protective tenofovir diphosphate (TFV DP) levels among YMSM enrolled in two PrEP trials. AB - BACKGROUND: Young men who have sex with men (YMSM) experience disparities in HIV acquisition more than any other group. Daily oral pre-exposure prophylaxis (PrEP) with tenofovir/embricitabine (TDF/FTC) has been shown to effectively prevent HIV transmission in YMSM; however, recent studies suggest that young Black men who have sex with men (YBMSM) experience sub-protective levels of tenofovir diphosphate (TFV-DP) more frequently than other groups. SETTING: Combined data from Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) 110/113, two open label PrEP studies that provided PrEP and evidence-based behavioral interventions to young MSM (YMSM) age 15 to 22 years old. METHODS: Bivariate and logistic regression analysis were used to examine sociodemographic and behavioral factors associated with protective TVF-DP levels (defined as >=700 fmol/punch) in ATN 110/113 data. RESULTS: In bivariate analysis, self-identified Black participants, residential displacement due to sexual orientation, low perceived risk, and stigma with the medication were associated with sub-protective levels. Hispanic ethnicity was associated with protective levels. In the final models, Black males were less likely to have sub-protective levels than non-Black males at 4, 8, 12 weeks. Self-reported displacement due to sexual orientation was associated with sub-protective levels while older age was as associated with protective levels. CONCLUSION: These findings highlight how future behavioral research and biomedical prevention efforts in YMSM will need to address PrEP disparities that may occur in YBMSM, perception of risk and lack of key supportive housing during this period that may be critical factors that contribute to HIV acquisition. PMID- 30399039 TI - Rate of Nicotine Metabolism and Tobacco Use among Persons with HIV: Implications for Treatment and Research. AB - BACKGROUND: The nicotine metabolite ratio (NMR) is a biomarker that represents individual variation in the speed that nicotine is metabolized. The rate of nicotine metabolism alters smoking behavior (e.g., amount) and has been validated for personalizing tobacco dependence medication selection to increase treatment efficacy and reduce treatment side effects in the general population of smokers. While smoking rates are extremely high among those with HIV, the NMR has not been evaluated in this underserved population. METHODS: We used baseline data from a smoking cessation clinical trial for smokers with HIV (N = 131) to examine associations between NMR and demographic, smoking, disease-related, and psychological characteristics. Pearson r and ANOVA were used to identify univariate correlates of NMR, which were then entered into a multiple linear regression model. RESULTS: In univariate analyses, a higher NMR (faster nicotine metabolism) was associated with being Caucasian, and more cigarettes per day, nicotine dependence, exhaled carbon monoxide, and symptoms of depression and anxiety, and using efavirenz. In a multiple regression model, a higher NMR was associated with more cigarettes per day, higher anxiety symptoms, and efavirenz use. CONCLUSIONS: As in other populations, faster nicotine metabolism was associated with use of more cigarettes and higher anxiety symptoms. Notably, efavirenz use was associated with faster metabolism, which might make it harder to quit smoking for people with HIV treated with that medication. These findings could help guide further study and the clinical use of the NMR to personalize nicotine dependence treatment in this underserved population. PMID- 30399040 TI - PD-1 expression in HIV-specific CD8+ T-cells prior to antiretroviral therapy is associated with HIV persistence. AB - BACKGROUND: The persistence of latently infected T-cells remains the principal barrier to HIV cure. Understanding how the early immune responses shape persistence of HIV on antiretroviral therapy (ART) will be fundamental for potential eradication. Here, we aimed to determine the relationship between CD8 T cell function and phenotype prior to therapy and HIV persistence on-ART. METHODS: Blood samples from 29 individuals enrolled during primary HIV infection (at baseline and every 3 months up to 2 years post-ART initiation) were obtained. HIV specific T-cell function and expression of the activation markers were evaluated prior to ART by flow cytometry. Cell associated HIV DNA and unspliced (US)-RNA were quantified in purified CD4 T-cells by real time PCR. Data was analysed using non-parametric statistics. RESULTS: Elevated immune activation, dominance of monofunctional CD8 T-cells and skewed distribution of memory profile was observed prior to ART. After ART initiation, HIV DNA and US-RNA levels rapidly diminished, reaching a plateau by 30 weeks post-ART. The proportion of baseline HIV-specific effector memory and terminal effector CD8 T-cells directly correlated with HIV DNA levels at one year post-ART. A strong positive correlation was observed between the proportion of bulk and HIV-specific PD-1 CD8 T-cells measured prior to ART and HIV DNA at one year post-ART, CONCLUSIONS:: A higher proportion of terminally differentiated CD8 T-cells and increased PD1 expression were associated with HIV persistence on ART following treatment of primary infection. Thus, the quality of the early CD8 T-cell immune response may serve as a predictor of HIV persistence on ART. PMID- 30399041 TI - Increased neutrophil surface PD-L1 expression in tobacco smokers: consequences for anti-PD-1 treatment. PMID- 30399042 TI - Increasing melanoma incidence in the elderly in North-East Hungary: is this a more serious problem than we thought? AB - There is a great need for efficient and cost-effective melanoma screening, but this is not yet solved. Epidemiological studies on trends in melanoma incidence by tumour thickness, anatomical site and demographical data can help to improve public health efforts regarding earlier melanoma diagnosis. We aimed to study the trends in the incidence and characteristics of patients and their melanoma in North-East Hungary from 2000 to 2014. Data were obtained from a university hospital-based registry. A total of 1509 cutaneous invasive melanomas of 1464 patients were included in the study. A moderate but significant increase in incidence was observed in the region [average annual percentage change: 3.04 (0.07; 6.11); P=0.045], with a breakpoint in 2007. From 2001 to 2007, the trend was increasing [APC: 9.84 (3.52; 16.55); P=0.006], but it stalled from 2007 [APC: -2.45 (-5.99; 1.23); P=0.164]. However, in the age groups over the age of 60 years, where the standardised incidence was the highest, the incidence continued to rise. Furthermore, older age, male sex and trunk or lower extremity localization were found to be associated with thicker melanomas. Our results support that regular screening examination for melanoma would be desirable for people over the age of 60 years. PMID- 30399043 TI - Cruciferous vegetable intake and colorectal cancer risk: Japan public health center-based prospective study. AB - We aimed to assess the association between cruciferous vegetable intake and colorectal cancer (CRC) development among Japanese adults aged between 45 and 74 years in the Japan Public Health Center-based Prospective Study. During 1 325 853 person-years of follow-up, 2612 CRC cases were identified. The association of cruciferous vegetable intake with CRC risk was assessed using a Cox proportional hazard regression model to compute hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for potential confounders. No significant association was observed between the highest cruciferous vegetable intake quartile (compared with the lowest) and CRC risk in men (multivariate HRs: 1.08; 95% CI: 0.91, 1.29) and women (multivariate HRs: 0.99; 95% CI: 0.80, 1.22) and its subsites. Women showed a marginal negative association between cruciferous vegetable intake and the risk of colon cancer (CC) after excluding participants who developed CC in the first 3 years of follow-up (P for trend=0.08); a positive association was found with proximal CC in men. Cruciferous vegetable intake does not have a significant association with CRC risk in the Japanese general population. PMID- 30399045 TI - One Step Forward, Two Steps. PMID- 30399044 TI - The association between birth order and childhood brain tumors: a systematic review and meta-analysis. AB - The incidence of childhood brain tumors (CBT) has increased worldwide, likely resulting from the improvements of early diagnostics. We conducted a systematic review and meta-analysis to clarify the association between birth order and CBT. We followed established guidelines to systematically search Ovid Medline, PubMed, and the Cochrane Library for English language studies, published before March 2018. Quality assessment was performed using the Newcastle-Ottawa Scale. Meta analysis provided pooled risk estimates and their 95% confidence intervals (CIs) for birth order and CBT. We identified 16 case-control studies with a total sample of 32 439 cases and 166 144 controls and three prospective cohort studies (i.e. 4515 incident cases of CBTs among 5 281 558 participants). Compared with first birth order, the meta-odds ratio for second birth order in case-control studies was 1.04 (95% CI: 1.01-1.07), that for third birth order was 0.98 (95% CI: 0.90-1.06), and that for fourth order was 0.85 (95% CI: 0.78-0.92). The meta hazard ratio for second or higher birth order compared with first birth order in cohort studies was 1.00 (95% CI: 0.96-1.05). We found no association between birth order and CBT in both case-control and cohort study designs; the small association observed for fourth birth order deserves further consideration. PMID- 30399046 TI - Epidurals and Colorectal Surgery: Have They Had Their Day? PMID- 30399047 TI - Prevention and Management of Colostomy Complications: Retraction and Stenosis. PMID- 30399048 TI - Expert Commentary on the Prevention and Management of Colostomy Complications: Retraction and Stenosis. PMID- 30399049 TI - Treatment of Complicated Anal Fistula by an Endofistular Polyurethane-Sponge Vacuum Therapy: A Pilot Study. AB - BACKGROUND: Treatment of supra- and transsphincteric anal fistulas remains a clinical challenge because current treatment results are variable and potentially endanger sphincter function. OBJECTIVE: Based on positive results of endoluminal polyurethane-sponge vacuum therapy in the upper and lower GI tract, a new system for endofistular vacuum therapy was developed for anal fistulas to utilize vacuum therapy to remove the endofistular pseudoepithelium and to induce granulation in the fistula tract. DESIGN: This study is based on a prospective case series. PATIENTS: Seven patients with complicated anal fistulas (3 associated with Crohn's disease and 4 of cryptoglandular origin) longer than 4 cm were treated. Initially, the fistula was curettaged and the first endofistular vacuum therapy sponge was positioned in the fistula tract. The inner fistula opening was closed by suture. A 125 mm Hg constant vacuum was applied to the sponge, and the endofistular vacuum therapy sponge was changed a median of 3 (3-5) times after each 48 to 72 hours of constant vacuum therapy. After final removal, the fistulas were reevaluated every other week for 3 months. MAIN OUTCOME MEASURE: The main outcome measured was the closure of the fistula. RESULTS: All patients tolerated the therapy well and no adverse events were observed. Fistula tract closure was demonstrated within 4 weeks after the termination of vacuum therapy. One patient with cryptoglandular fistula developed a recurrence within the follow-up of 3 months. LIMITATIONS: This was an observational study that had no control arm. CONCLUSION: In this pilot case series, the results are encouraging. Because endoluminal vacuum therapy would be a new and sphincter-sparing therapy, this concept warrants further investigation in controlled trials. PMID- 30399050 TI - Robotic Posterior Suturepexy for Colonic Prolapse Two Years After Transanal Total Mesorectal Excision for Low Rectal Cancer. PMID- 30399051 TI - Management of Pilonidal Disease Needs Paradigm Shift From More to Less: Enough Evidence and Logic Available. PMID- 30399052 TI - Special Thanks and Appreciation to our Reviewers. PMID- 30399053 TI - Corrigendum. PMID- 30399055 TI - Differences in Perceptions of Incivility Among Disciplines in Higher Education. AB - BACKGROUND: Incivility occurs in various forms in higher education and negatively affects teaching and learning outcomes. It has not been determined if incivility is more prevalent in one discipline than another. PURPOSE: The purpose of this study was to compare faculty and student perceptions of incivility across disciplines at a large public university. METHODS: In this descriptive comparative study, a convenience sample of 156 faculty and 421 students completed the Incivility in Higher Education-Revised survey electronically. RESULTS: The total sample was 577. Nursing reported the highest level of perceived incivility, with all other disciplines also reporting some level of incivility. Faculty perceived more incivility than students. CONCLUSIONS: With a national awareness of incivility in nursing education, this study shows that incivility also exists in other disciplines and is a starting point for addressing its impact on higher education. PMID- 30399056 TI - Boot Up the First Day of Class With "Selfie-Starters". PMID- 30399057 TI - Ready, Set, Communicate. PMID- 30399058 TI - Exploration of Mindfulness Among Ethnic Minority Undergraduate Nursing Students. AB - BACKGROUND: Meeting projected needs for ethnically diverse nurses depends on a strong pipeline of diverse students within nursing programs. Colleges assume students readily navigate the university; however, this may not be the reality especially among ethnic minority students. PURPOSE: The purpose was to explore the concept of mindfulness among ethnic minority nursing students. Exploring mindfulness, and a lack thereof, may provide strategies for overcoming challenges ethnic minority students experience in prelicensure nursing programs. METHODS: A qualitative study using thematic analysis of semistructured in-depth interviews was conducted with 20 ethnic minority undergraduate nursing students. RESULTS: Themes that emerged reveal positive associations of mindfulness and negative implications when there is a lack of mindfulness. CONCLUSION: Based on the findings from this study, using consistent mindfulness techniques could positively influence coping skills for dealing with the stressors of college, resulting in overall success and retention of ethnic minority and first generation students in a nursing program. PMID- 30399059 TI - A Blended Approach to Course Orientation. PMID- 30399060 TI - Resveratrol Mitigates High-Fat Diet-Induced Vascular Dysfunction by Activating the Akt/eNOS/NO and Sirt1/ER Pathway. AB - We investigated whether resveratrol (RSV) can attenuate obesity and diabetes progression and improve diabetes-induced vascular dysfunction, and we attempted to delineate its underlying mechanisms. Male C57Bl/6 mice were administered a high-fat diet (HFD) for 17 weeks. Mice developed type 2 diabetes with increased body weight, hyperglycemia, hyperinsulinemia, and hyperlipidemia. Oral gavage with RSV significantly reversed the symptoms induced by the HFD. Insulin sensitivity likewise improved after the RSV intervention in these mice. Phenylephrine-induced cremaster arteriolar constriction was impaired, whereas RSV treatment significantly mitigated the vessel responsiveness to phenylephrine. The obese diabetic mice exhibited increased leukocyte rolling, adhesion, and transmigration in the postcapillary venules of the cremaster muscle. By contrast, RSV treatment significantly attenuated HFD-induced extravasation. RSV significantly recovered phosphorylated Akt and eNOS expression in the thoracic aorta. In addition, activated adenosine monophosphate-activated protein kinase in the thoracic aorta was involved in the improvement of epithelial function after RSV intervention. RSV considerably upregulated the plasma NO level in HFD mice. Moreover, RSV-enhanced human umbilical vein endothelial cells healing through Sirt1/ER pathway may be involved in the prevention of leukocyte extravasation. Collectively, RSV attenuates diabetes-induced vascular dysfunction by activating Akt/eNOS/NO and Sirt1/ER pathway. Our mechanistic study provides a potential RSV based therapeutic strategy against cardiovascular disease. PMID- 30399061 TI - The number and localization of CD68+ and CD163+ macrophages in different stages of cutaneous melanoma. AB - The role of tumor-associated macrophages (TAMs) in cutaneous melanoma is controversial. TAMs include immunogenic and immunosuppressive subtypes, and have distinct functions according to their microanatomical localization. Our aim was to investigate TAMs in benign, premalignant, and malignant melanocytic lesions to determine possible associations with tumor progression and clinicopathological characteristics. In total, 184 tissue samples, including benign and dysplastic nevi, in-situ melanomas, superficial (Breslow's depth <1 mm), and deep (Breslow's depth >4 mm) invasive melanomas and lymph node metastases, were analyzed for macrophage content. Samples were stained immunohistochemically for CD68 and CD163, representing all TAMs and M2-macrophages, respectively. Macrophages were counted by hotspot analysis, and assessed semiquantitatively from the tumor cell nests and stromal component of malignant cases. CD68+ and CD163+ TAMs were more abundant in invasive melanomas compared with benign nevi. The proportion of TAMs in the tumor nests was higher in deep melanomas and lymph node metastases compared with superficially invasive melanomas. High amounts of CD68+ macrophages in tumor cell nests were associated with recurrence, whereas low CD163+ macrophage proportion in tumor stroma was associated with recurrence and in primary melanomas also with poor overall survival. TAMs seem to promote tumor progression in cutaneous melanoma. In particular, CD68+ TAMs and their abundance in tumor nests were associated with poor prognostic factors. However, the correlation of low stromal CD163+ TAM proportion with a poor prognosis indicates that the role of TAMs depends on their subtype and microanatomical localization.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc nd/4.0/. PMID- 30399062 TI - Role of Hemodialysis in the Management of Cyanide Intoxication From Apricot Kernels in a 3-Year-Old Child. AB - Cyanide (CN) is one among the most potent and rapidly acting lethal poisons, and it may cause death unless immediately diagnosed and treated. We report an unusual case of pediatric CN poisoning after ingestion of apricot kernels containing amygdalin, who survived with antidotal therapy and hemodialysis. A 3-year-old girl presented with respiratory distress and coma following tonic-clonic convulsions after ingestion of 3 apricot kernels. She had severe metabolic acidosis (pH 6.91, bicarbonate [HCO3] 5.6 mEq/L, base excess -26.0 mEq/L). Her blood CN level was measured 3.15 mg/L, 3 hours after ingestion. Hydroxocobalamin could not be administered immediately because it had to be brought from a medical center 4 hours apart. Therefore, a 3-hour hemodialysis session was carried out, following which she showed some clinical improvement. In addition, when hydroxocobalamin was obtained, it was then administered. During follow-up, she was completely asymptomatic with blood pressure, and other hemodynamic parameters normalized. This case presents hemodialysis as a way to correct metabolic derangements from CN poisoning and suggests that it may have a role in select cases of pediatric CN poisoning, especially when CN-scavenging antidotes may be unavailable. PMID- 30399063 TI - A Survey Assessing Pediatric Transport Team Composition and Training. AB - OBJECTIVE: The aim of this study was to assess national pediatric/neonatal specialty transport teams' composition and training requirements to determine if any current standardization exists. METHODS: This was a survey of the transport teams listed with the American Academy of Pediatrics via SurveyMonkey. RESULTS: While most of the teams maintain internal criteria for team competency and training, there is large variation across team compositions. The vast majority of the teams have a nurse-led team with the addition of another nurse, medic, and/or respiratory therapist regardless of mode of transport. Many of the teams report adjusting team composition based on acuity. Fewer than 15% of teams have a physician as a standard team member. More than 80% required a minimum number of supervised intubations prior to independent practice; however, the number varied largely from as little as 3 to as many as 30. Eighty-eight percent of the teams report using simulation as part of their education program, but again there were marked differences between teams as to how it was used. CONCLUSIONS: There is tremendous variability nationally among pediatric/neonatal transport teams regarding training requirements, certifications, and team composition. The lack of standardization regarding team member qualifications or maintenance of competency among specialized transport teams should be looked at more closely, and evidence-based guidelines may help lead to further improved outcomes in the care of critically ill pediatric patients in the prehospital setting. PMID- 30399064 TI - Implementing the 2016 American Academy of Pediatrics Guideline on Brief Resolved Unexplained Events: The Parent's Perspective. AB - OBJECTIVES: A "brief resolved unexplained event" refers to sudden alterations in an infant's breathing, color, tone, or responsiveness that prompt the parent or caregiver to seek emergency medical care. A recently published clinical practice guideline encourages discharging many of these infants home from the emergency department if they have a benign presentation. The goal is to avoid aggressive inpatient investigations of uncertain benefit. The present research explored parents' reactions to the prospect of returning home with their infant following such an event. METHODS: The study used qualitative research methods to analyze semistructured, audio-recorded interviews of parents who had witnessed a brief resolved unexplained event between 2011 and 2015 and taken their infant to the emergency department of an academic teaching hospital. RESULTS: A total of 22 parent interviews were conducted. The infants included 8 boys and 14 girls aged 3.6 +/- 3.5 months (mean +/- SD). Qualitative analysis of interview transcripts revealed a near-universal apprehension about the child's well-being, ambivalence about the best course of action after the evaluation in the emergency department, and need for reassurance about the unlikelihood of a recurrence. Parents did not, however, answer the main research question with a single voice: attitudes toward the return-home scenario ranged from unthinkable to extreme relief. Two-thirds of parents expressed at least some reservations about the idea of returning home. CONCLUSIONS: Successful implementation of the 2016 guideline will require close attention to the parent's point of view. Otherwise, parental resistance is likely to compromise clinicians' best efforts. PMID- 30399065 TI - Confronting Subconscious Bias: Ethics in the Pediatric Emergency Department. AB - Physicians are only human. Upon graduating from medical school, physicians take an oath declaring veracity and fidelity toward our patients. We are told to lay aside negative feelings toward patients in exchange for integrity, truth, honor, and compassion. The idea is simple, but following through on it is quite a challenge. Pediatric emergency medicine physicians generally have rapid focused patient interactions, yet even in these brief encounters, instantaneous and subconscious reactions to difficult patients occur. Difficult patients are those who raise negative feelings within the clinician such as anxiety, frustration, guilt, and dislike. Recognition of these reactions and emotions will help physicians understand more about themselves, and assist in interacting more favorably with challenging patients. It is common for doctors to attempt to suppress their human reactions to maintain clinical objectivity, yet these reactions facilitate a better doctor-patient relationship. Allowing ourselves to yield to our emotions help the patient realize that the physician is a human being. PMID- 30399066 TI - Socioeconomic Status and Analgesia Provision at Discharge Among Children With Long-Bone Fractures Requiring Emergency Care. AB - BACKGROUND: Inadequate treatment of painful conditions in children is a significant and complex problem. The objective of this study was to examine the effect of socioeconomic status on the provision of analgesic medicines at discharge in children treated emergently for a long-bone fracture. METHODS: A retrospective review of all patients during a 1-year period with a long-bone fracture treated in 2 urban pediatric emergency departments (EDs) was performed. RESULTS: Eight hundred seventy-three patients were identified who met our inclusion criteria. Sixty percent of patients received a prescription for an opioid-containing medicine, and 22% received a prescription for an over-the counter analgesic medicine at ED discharge. Socioeconomic status had no effect on opioid analgesic prescriptions at discharge. Patients in the lowest-income group were younger, presented to the ED longer after an injury, were likely nonwhite, and had higher rates of over-the-counter analgesic medicine prescriptions provided at discharge. Higher-income patients were likely white and non-Hispanic, presented to the ED sooner, and were less likely to receive a prescription for a nonopioid analgesic medicine. CONCLUSIONS: Socioeconomic status is associated with different nonopioid analgesic prescription patterns in children treated in the ED for a long-bone fracture, but had no effect on opioid analgesic prescriptions. PMID- 30399067 TI - Paraplegia After Basketball Play: A Case of Spinal Cord Infarction Secondary to Fibrocartilaginous Embolization. AB - Pediatric emergency medicine providers must be astute at generating the differential diagnosis and performing the appropriate evaluation to promptly determine the underlying cause of new onset paraplegia. Spinal cord infarction (SCI) is a potential etiology of paraplegia in children, and fibrocartilaginous embolization is a rare underlying cause of SCI. We present an illustrative case of SCI secondary to fibrocartilaginous embolization in an otherwise healthy adolescent who developed symptoms of spinal cord dysfunction after basketball play. PMID- 30399068 TI - Medical Disimpaction for Children With Organic Esophageal Foreign Body in the Era of Eosinophilic Esophagitis. AB - OBJECTIVE: Esophageal foreign body impaction (EFBI) is a common presentation in pediatric emergency medicine. Interventions (medical or endoscopic) are often required because of the severity of symptoms and risk of complications. Use of medical disimpaction (MD) such as glucagon injections and effervescent agents (eg, carbonated beverages) has been well described in adults; however, there are limited data in the pediatric literature. Eosinophilic esophagitis (EoE) is a relatively "new" clinicopathological entity that may present with EFBI mostly due to food with histological findings of EoE. Our study aim was to determine the efficacy of MD for organic EFBI in the pediatric population especially in children with EoE. METHODS: A retrospective chart review was performed using the International Classification of Diseases codes and the emergency department database of patients presenting with EFBI from January 2010 to December 2014. Response to MD was defined as symptomatic relief of obstruction. Age, object ingested, medical agent used, EoE status, complications, and outcome were recorded. RESULTS: A total of 317 presentations of EFBI were identified during the study period, of which organic EFBI accounted for 101 impactions (31.9%). Medical disimpaction was attempted for 42 (41.6%) with organic EFBI, resulting in resolution of symptoms for 16 (38.1%). One child with EoE responded to MD compared with 15 without EoE (4.8% vs 71.4%, P < 0.0001). CONCLUSIONS: Medical disimpaction was ineffective in children with EoE but may be of help with symptom resolution in approximately 70% of children without EoE. PMID- 30399069 TI - Let's Take Care of Each Other. PMID- 30399071 TI - Standard Short Peripheral Catheters (SPCs) Versus Power Injectable SPCs During Contrast Computed Tomography and Magnetic Resonance Imaging Angiography: A Quality Improvement Study. AB - To perform high-resolution computed tomography and magnetic resonance imaging angiographies, contrast typically is rapidly injected through a 20-gauge or larger short peripheral catheter (SPC). Intravenous access in infants and children can be challenging, and the use of large-gauge catheters is not always feasible. An institutional review board-approved quality improvement study was undertaken at a 250-bed pediatric hospital on Florida's Gulf Coast that compared the use and outcomes of standard SPCs (nonfenestrated) versus a power injectable SPC (fenestrated with 3 side holes distal to the catheter tip). PMID- 30399070 TI - Implementation of Smart Pump Technology With Home Infusion Providers: An Assessment of Clinician Workflow and Patient Satisfaction. AB - While hospitals have adopted smart pump technology (SPT) featuring drug libraries and medication safety software, most home infusion providers (HIPs) continue to use traditional infusion pumps that don't offer drug libraries or medication safety software. As infusion delivery is moving from the hospital to the home, the purpose of this study was to determine whether SPT was a feasible alternative at both a hospital-based and a rural HIP. HIP personnel were trained on an ambulatory infusion pump. Patients requiring home infusion used the pump and recorded daily pump interactions for 5 to 7 days. After the creation of a drug library, clinicians felt comfortable programming pumps after 7 uses. Patients reported 100% overall satisfaction, and the majority of alarms were resolved without contacting the HIP. Ambulatory SPT can be implemented successfully by HIPs and can be used effectively by patients. PMID- 30399072 TI - Short Peripheral Catheter Quality and Economics: The Intravenous Quotient. AB - Peripheral intravenous therapy is an established therapy with known complications and failures. The burden of the cost of unsuccessful short peripheral catheter (SPC) placement and maintenance is not always clearly identified. This often obscured cost of poor quality needs to be defined and addressed. The scope of the problem is defined here, and a metric that can be applied to measure the magnitude of the problem and identify targets for focused improvement initiatives that would improve the quality of infusion therapy using SPCs is proposed. PMID- 30399073 TI - Does the Use of an Infusion Pump for Red Blood Cells Increase Hemolysis? AB - Transfusions of red blood cells (RBCs) are frequently administered for a variety of clinical conditions. The use of an infusion pump has become common practice in nursing. Lack of evidence regarding hemolysis associated with transfusing older RBCs using an infusion pump led one 361-bed acute care suburban medical center to maintain its nursing policy to infuse all blood products by gravity. A combined simulated and clinical study was conducted with 25 units of RBCs. No significant hemolysis was demonstrated as measured by hemolysis index and serum potassium levels. As a result of this study, the nursing policy at the medical center was changed. PMID- 30399074 TI - Improving Vascular Access Outcomes and Enhancing Practice. AB - With most hospitalized patients requiring peripheral intravenous catheters (PIVCs), PIVC-related process improvement may substantially affect the health, safety, and satisfaction of patients and health care workers, in addition to reducing costs. This study examined PIVC practice-related metrics before and after a comprehensive process improvement program, which included a change to closed catheter technology. Data were obtained from observations, clinician interviews, and patient records. Metrics included assessment of risk, especially blood exposure and contamination; measurement of insertion efficiency; and quantification of PIVC failure. A significant improvement in most metrics was achieved after the process improvement program. PMID- 30399075 TI - The Association of Patient Satisfaction with Pain, Anxiety, and Self-Reported Physical Function. AB - BACKGROUND: A complete understanding of the variables that influence patient satisfaction has yet to be reached. The purpose of this study was to determine whether patient-reported physical function, pain, and/or anxiety are associated with patient satisfaction in a hand and upper-extremity outpatient setting. METHODS: This is a cohort study of 1,160 adult patients presenting to an upper extremity (non-shoulder) clinic from January 1, 2014, to December 31, 2016, who completed functional patient-reported outcome measures (PROMIS [Patient-Reported Outcomes Measurement Information System] Physical Function, PROMIS Upper Extremity, and abbreviated Disabilities of the Arm, Shoulder and Hand scale [QuickDASH]) and psychological patient-reported outcome measures (PROMIS Anxiety and PROMIS Pain Interference) immediately prior to their physician encounter. After the clinic visit, included patients filled out the Press Ganey Medical Practice satisfaction survey online. Logistic regression models were used to predict overall patient satisfaction and satisfaction with the care provider among all, new, and return clinic visit types from the patient-reported functional and psychological measures, controlling for age and provider. RESULTS: Among all visit types, there was a significant negative association of both pain and anxiety with patient satisfaction, whereby a 10-point increase in PROMIS Pain Interference (higher self-reported pain symptomatology) was associated with a 17% decrease in the odds of overall satisfaction (odds ratio [OR], 0.83 [95% confidence interval (CI), 0.71 to 0.98]; p = 0.03), and a 10-point increase in PROMIS Anxiety (higher self-reported anxiety) was associated with a 16% decrease in the odds of satisfaction with the care provider (OR, 0.84 [95% CI, 0.72 to 0.97]; p = 0.02). A significant positive association was found between higher levels of self-reported physical function and new-patient satisfaction with their care provider (OR, 1.22 [95% CI, 1.02 to 1.47]; p = 0.03). Among return patient visits, there was a negative association with overall patient satisfaction between both pain interference (OR, 0.76 [95% CI, 0.58 to 0.98]; p = 0.04) and anxiety (OR, 0.69 [95% CI, 0.53 to 0.89]; p < 0.01). CONCLUSIONS: In hand and upper-extremity (non-shoulder) clinic visits, pre-encounter levels of patient reported physical function, anxiety, and pain were significantly associated with patient satisfaction with the care provided. As the U.S. health-care system increasingly utilizes satisfaction scores in payment models and in quality assessment, these associations may influence how such metrics are interpreted and are utilized. PMID- 30399076 TI - The Effectiveness of a Private Orthopaedic Practice-Based Osteoporosis Management Service to Reduce the Risk of Subsequent Fractures. AB - BACKGROUND: Osteoporosis is prevalent in the United States, with an increasing need for management. In this study, we evaluated the effectiveness of a private orthopaedic practice-based osteoporosis management service (OP MS) in reducing subsequent fracture risk and improving other aspects of osteoporosis management of patients who had sustained fractures. METHODS: This was a retrospective cohort study using the 100% Medicare data set for Michigan residents with any vertebral; hip, pelvic or femoral; or other nonvertebral fracture during the period of April 1, 2010 to September 30, 2014. Patients who received OP MS care with a follow-up visit within 90 days of the first fracture, and those who did not seek OP MS care but had a physician visit within 90 days of the first fracture, were considered as exposed and unexposed, respectively (first follow-up visit = index date). Eligible patients with continuous enrollment in Medicare Parts A and B for the 90 day pre-index period were followed until the earliest of death, health-plan disenrollment, or study end (December 31, 2014) to evaluate rates of subsequent fracture, osteoporosis medication prescriptions filled, and bone mineral density (BMD) assessments. Health-care costs were evaluated among patients with 12 months of post-index continuous enrollment. Propensity-score matching was used to balance differences in baseline characteristics. Each exposed patient was matched to an unexposed patient within +/- 0.01 units of the propensity score. After propensity-score matching, Cox regression examined the hazard ratio (HR) of clinical and economic outcomes in the exposed and unexposed cohorts. RESULTS: Two well-matched cohorts of 1,304 patients each were produced. The exposed cohort had a longer median time to subsequent fracture (998 compared with 743 days; log-rank p = 0.001), a lower risk of subsequent fracture (HR = 0.8; 95% confidence interval [CI] = 0.7 to 0.9), and a higher likelihood of having osteoporosis medication prescriptions filled (HR = 1.7; 95% CI = 1.4 to 2.0) and BMD assessments (HR = 4.3; 95% CI = 3.7 to 5.0). The total 12-month costs ($25,306 compared with $22,896 [USD]; p = 0.082) did not differ significantly between the cohorts. CONCLUSIONS: A private orthopaedic practice-based OP MS effectively reduced subsequent fracture risk, likely through coordinated and ongoing comprehensive patient care, without a significant overall higher cost. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 30399077 TI - Effect of Physical Parameters on Outcomes of Total Knee Arthroplasty. AB - BACKGROUND: Increasing body mass index (BMI) has been shown to correlate with increased rates of complications after total knee arthroplasty. To our knowledge, body surface area, body mass, and height have not been investigated in this manner. BMI and body surface area are affected differently by changes in height, and they are affected similarly by changes in weight. The purpose of this study was to quantify revision for any reason, mechanical failure, aseptic loosening, polyethylene wear, reoperation, and any infection after total knee arthroplasty using BMI, body surface area, body mass, and height as continuous variables. METHODS: Prospectively collected data from a single institution's total joint registry were used to analyze 22,243 consecutive knees, in 16,106 patients, treated with a primary total knee arthroplasty from 1985 to 2012. The Kaplan Meier survival method was used to evaluate revision and other common complications, with outcomes assessed using Cox regression analysis. Smoothing spline parameterization was used on physical parameters in these models. RESULTS: Increasing BMI, body surface area, body mass, and height were associated with an increased risk of any revision surgical procedure, mechanical failure, and aseptic loosening after total knee arthroplasty. The risk of a revision surgical procedure was directly associated with each 1 standard deviation increase in BMI (hazard ratio [HR], 1.19; p < 0.01), body surface area (HR, 1.37; p < 0.01), body mass (HR, 1.30; p < 0.01), and height (HR, 1.22; p < 0.01). This association was especially demonstrated with revision for mechanical failure (BMI: HR, 1.15; p < 0.01; body surface area: HR, 1.35; p < 0.01; body mass: HR, 1.27; p < 0.01; and height: HR, 1.23; p < 0.01). The risk of failure in the subgroups of mechanical failure including a revision surgical procedure for aseptic loosening or polyethylene wear was also associated with increasing body surface area, body mass, and height. Increasing BMI (HR, 1.22; p < 0.01), body surface area (HR, 2.56; p < 0.01), and body mass (HR, 2.54; p < 0.01) were also associated with increased risk of any infection. CONCLUSIONS: Increasing BMI, body surface area, body mass, and height were strongly associated with the rates of revision, aseptic loosening, and other common complications following total knee arthroplasty. Body surface area and body mass appear to correlate more strongly with mechanical failure outcomes than BMI or height. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 30399078 TI - Allograft Compared with Autograft in Osteochondral Transplantation for the Treatment of Osteochondral Lesions of the Talus. AB - BACKGROUND: There is a paucity of clinical studies that compare the efficacy of autograft and allograft in osteochondral transplantation for treatment of osteochondral lesions of the talus (OLT). The purpose of the present study was to compare the clinical and radiographic outcomes following osteochondral transplantation with autograft or allograft for OLT. METHODS: A retrospective analysis comparing patients treated with autograft or allograft for OLT was performed. Clinical outcomes were evaluated with use of the Foot and Ankle Outcome Score (FAOS) and the Short Form-12 (SF-12) score. Magnetic resonance imaging (MRI) was evaluated with use of the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score. The rates of cyst occurrence, graft degradation, graft failure, and revision surgeries were also evaluated. RESULTS: Twenty-five nonrandomized patients with autograft and 16 with allograft were included, with a mean follow-up of 26 months in the autograft group and 22 months in the allograft group. There were no significant differences among all demographic variables between the autograft and allograft groups. The mean postoperative FAOS was significantly higher in the autograft group (81.9; 95% confidence interval [CI]: 78.6 to 85.2) than in the allograft group (70.1; 95% CI: 63.7 to 76.5; p = 0.006). Similarly, the mean postoperative SF-12 scores were significantly higher in the autograft group (74.7; 95% CI: 71.0 to 78.4) than in the allograft group (66.1; 95% CI: 61.2 to 71.0; p = 0.021). MOCART scores were significantly better in the autograft group (87.1) than in the allograft group (75.5; p = 0.005). The rate of chondral wear on MRI was higher in the allograft group (53%) than in the autograft group (4%; p < 0.001). Cyst formation in the graft itself was more likely to occur in the allograft group (47%) than in the autograft group (8%; p = 0.017). The rate of secondary procedures for the graft was higher in the allograft group (25%) than in the autograft group (0%; p = 0.009). CONCLUSIONS: In this small nonrandomized cohort study, the procedures performed with use of an autograft provided better clinical and MRI outcomes than the allograft procedures. The rate of chondral wear on MRI was higher with allograft than with autograft, and allograft-treated patients had a higher rate of clinical failure. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 30399079 TI - Late Dislocation Following Total Hip Arthroplasty: Spinopelvic Imbalance as a Causative Factor. AB - BACKGROUND: Late dislocations after total hip arthroplasty (THA) are challenging for the hip surgeon because the cause is often not evident and recurrence is common. Recently, decreased spinopelvic motion has been implicated as a cause of dislocation. The purpose of this study was to assess the mechanical causes of late dislocation, including the influence of spinopelvic motion. METHODS: Twenty consecutive patients were studied to identify the cause of their late dislocation. Cup inclination and anteversion were measured on standard pelvic radiographs. Lateral standing and sitting spine-pelvis-hip radiographs were used to measure pelvic motion, femoral mobility, and sagittal cup position by assessing sacral slope, pelvic-femoral angle, and cup ante-inclination. Spinopelvic motion was defined as the difference between the standing and sitting sacral slopes (Deltasacral slope). A new measurement, the combined sagittal index, which measures the sagittal acetabular and femoral positions, was used to assess the functional motion of the hip joint and risk of impingement. RESULTS: There were 9 anterior dislocations (45%) and 11 posterior dislocations (55%) at a mean of 8.3 years after a primary THA. Eight of the 9 patients with an anterior dislocation had spinopelvic abnormalities such as fixed posterior pelvic tilt when standing, increased standing femoral extension, and an increased standing combined sagittal index. Ten of the 11 patients with a posterior dislocation had abnormal spinopelvic measurements such as decreased spinopelvic motion (average Deltasacral slope [and standard error] = 9.0 degrees +/- 2.4 degrees ), increased femoral flexion, and a decreased sitting combined sagittal index. For every 1 degrees decrease in spinopelvic motion, there was an associated 0.9 degrees increase in femoral motion and, in some patients, this resulted in osseous impingement and dislocation. CONCLUSIONS: Patients with a late dislocation have abnormal spinopelvic motion that precipitates the dislocation, especially when combined with cup malposition or soft-tissue abnormalities. Spinopelvic stiffness is associated with increased age and increased femoral motion, which may lead to impingement and dislocation. Lateral spine-pelvis-hip radiographs may predict the risk and direction of dislocation. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 30399080 TI - Clinical and MRI Outcomes 10 Years After Repair of Massive Posterosuperior Rotator Cuff Tears. AB - BACKGROUND: Massive rotator cuff tears are challenging to treat, with few or no studies on long-term outcomes of repair. The purpose of this study was to report 10-year outcomes following repair of massive posterosuperior rotator cuff tears, with and without extension into the subscapularis, and to determine prognostic factors that could influence clinical scores and retear rates. METHODS: The records of 234 patients who underwent repair of a massive posterosuperior rotator cuff tear at a total of 15 centers were retrieved. Patients were asked to return for evaluation at 10 years; 78 patients could not be contacted, 7 had died, and 19 had undergone a reoperation. A total of 130 patients (68% men) with a mean age (and standard deviation) of 56.1 +/- 7.7 years (range, 26 to 79 years) were evaluated clinically, and 102 of them were also evaluated using magnetic resonance imaging (MRI). The tear was confined to the supraspinatus and infraspinatus tendons in 94 shoulders and also involved the superior portion of the subscapularis in 36 shoulders. Univariable and multivariable regressions were performed to determine whether 10-year total Constant-Murley scores and repair integrity were associated with patient characteristics, tear patterns, or repair techniques. RESULTS: In the study cohort, complications were noted in 14 shoulders (11%) (stiffness in 10 and infection in 4). For the 130 shoulders evaluated clinically, the mean total Constant-Murley score improved from 53.1 +/- 15.9 (range, 14 to 83) preoperatively to 78.5 +/- 11.3 (range, 36 to 98) at 10 years. Of the 102 shoulders evaluated using MRI, 32 had a retear (Sugaya type IV or V). Of the 19 shoulders that underwent a reoperation (excluded from the study cohort), 9 had a retear. The overall prevalence of retears was 34%. Multivariable regression analysis revealed a significant association between the 10-year Constant-Murley score and preoperative retraction of the infraspinatus tendon, but no association between retears and any of the variables. Involvement of the subscapularis had no significant effect on preoperative or postoperative Constant Murley scores or retear rates. CONCLUSIONS: Patients who had repair of a massive posterosuperior rotator cuff tear maintained considerable improvements in clinical and radiographic outcomes at 10 years. Partial concomitant tears of the subscapularis did not affect the total postoperative Constant-Murley scores or retear rates. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 30399081 TI - Effectiveness and Sustainability of a Standardized Care Pathway Developed with Use of Lean Process Mapping for the Treatment of Patients Undergoing Posterior Spinal Fusion for Adolescent Idiopathic Scoliosis. AB - BACKGROUND: Recent changes in health care have begun to shift the industry from a volume-based to a value-based focus. This shift has led to standardized care pathways that decrease care variability, improve outcomes, and decrease cost. Although numerous studies have described standardized pathways for adolescent idiopathic scoliosis (AIS), few have demonstrated sustainability. We report the effectiveness and sustainability of a standardized care pathway for patients undergoing posterior spinal fusion for AIS. METHODS: A standardized care pathway was developed and implemented (in March 2015) at our pediatric hospital for all patients undergoing posterior spinal fusion for AIS. This pathway was developed with use of the Lean process mapping technique to create an evidence-based protocol for preoperative, operative, postoperative, and post-discharge care. The 44 patients managed prior to implementation of the pathway (pre-pathway group) were compared with the 169 patients managed after implementation (post-pathway group). The post-pathway group was divided into 5 cohorts, each representing a 6 month time period. Clinical outcomes (pain scores, medication requirements, transfusions) and efficiency metrics (length of stay) were used to determine pathway sustainability. RESULTS: The pre-pathway group included patients managed in the 8 months prior to implementation (July 2014 to February 2015) and the post pathway group included patients who underwent surgery from March 2015 to July 2017, divided into 5 cohorts representing 6 months each. Patients in the post pathway group had lower postoperative pain scores, and used significantly less opioids at each time interval, compared with the pre-pathway group. Perioperative transfusion requirements and postoperative length of stay were significantly lower across all post-pathway cohorts compared with the pre-pathway group. There were no significant differences in clinical results among the 5 post-pathway cohorts. CONCLUSIONS: Implementation of a standardized care pathway developed with use of Lean process mapping demonstrated effective and sustained improvements to the care of patients with AIS, as well as decreased postoperative length of stay. These outcomes have been maintained over 2.5 years, indicating that high-quality care for patients with AIS undergoing spinal fusion can be achieved and sustained with use of a standardized care pathway. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 30399082 TI - Experimental Validation of the Radiographic Union Score for Tibial Fractures (RUST) Using Micro-Computed Tomography Scanning and Biomechanical Testing in an in-Vivo Rat Model. AB - BACKGROUND: The Radiographic Union Score for Tibial fractures (RUST) and the modified version of the system, mRUST, are popular standards for assessing fracture-healing progress with use of radiographs. To our knowledge, this is the first study to experimentally validate the ability of RUST and mRUST to accurately assess bone-healing progression with use of both micro-computed tomography (micro-CT) scanning and biomechanical testing. METHODS: Adult male rats (n = 29) underwent osteotomy with a midshaft fracture gap repaired with use of a polyetheretherketone plate. Anteroposterior and lateral radiographs were made of the repaired femora prior to rat death at end points of 5, 6, 7, 8, 9, and 17 weeks, and 2 fellowship-trained orthopaedic trauma surgeons independently assigned RUST and mRUST scores to repaired femora. The repaired and intact contralateral femora were then dissected. Bones underwent dissection, micro-CT scanning, and biomechanical torsion testing at the end points. RESULTS: RUST scores ranged from 5 to 12 and mRUST scores ranged from 5 to 16. Intraclass correlation coefficients (ICCs) were 0.89 (95% confidence interval [CI]: 0.78 to 0.94) for RUST and 0.86 (95% CI: 0.74 to 0.93) for mRUST, which fall within the "almost perfect agreement" category for ICCs. Spearman rank correlation coefficients (RS) showed correlation of RUST (RS range, 0.456 to 0.818) and mRUST (RS range, 0.519 to 0.862) with micro-CT measurements of mineralized callus volume (BV), total callus volume (TV), and BV/TV ratio, but less so with bone mineral density (BMD). Additionally, RUST (RS range, 0.524 to 0.863) and mRUST (RS range, 0.434 to 0.850) were correlated with some biomechanical properties. A RUST score of 10 or an mRUST score of 15 may be considered the threshold above which a plated bone is "healed" because, at these scores, 120% or 140% of failure torque, respectively, was achieved by the repaired femora as compared with the intact contralateral femora. CONCLUSIONS: RUST and mRUST both show strong statistical correlations with micro-CT and biomechanical parameters. CLINICAL RELEVANCE: RUST and mRUST scoring systems provide clinicians with validated, reliable, and available tools to assess the progress of fracture-healing. PMID- 30399083 TI - Five to Ten-Year Results of the Birmingham Hip Resurfacing Implant in the U.S.: A Single Institution's Experience. AB - BACKGROUND: International surgeon series and registry data have demonstrated positive outcomes and long-term survival of the Birmingham Hip Resurfacing (BHR) implant. We report the 5 to 10-year results from a single center in the U.S. METHODS: Three hundred and fourteen patients (360 hips) underwent surface replacement arthroplasty with use of the BHR implant and consented to study participation. Patient-reported outcomes and complication and revision data were collected at a minimum of 5 years of follow-up for 93% (324 of 350) of the hips in surviving patients. A matched-cohort analysis was used to compare clinical outcomes between use of the BHR and total hip arthroplasty. RESULTS: Mean modified Harris hip score (mHHS) and University of California, Los Angeles (UCLA) scores significantly improved postoperatively, to 89.9 and 8.0, respectively (p < 0.001). The Kaplan-Meier estimated rate of survival for all-cause revision was 97.2% (95% confidence interval [CI], 94.7% to 98.5%) and 93.8% (95% CI, 88.8% to 96.7%) at 5 and 10 years, respectively. In a subgroup analysis of patients fitting our current BHR inclusion criteria (males <60 years of age with a diagnosis of osteoarthritis and anatomy conducive to a femoral head component of >=48 mm), survival free of aseptic revision was 99.5% (95% CI, 96.6% to 99.9%) at 5 years and 98.2% (95% CI, 94.4% to 99.4%) at 10 years. Fourteen patients (4.3% of all hips) required revision. Postoperative UCLA scores were significantly greater for BHR compared with total hip arthroplasty (mean score of 8.0 +/- 2.0 versus 7.6 +/- 1.8; p = 0.040) in a matched-cohort analysis, with patients matched according to preoperative UCLA score, diagnosis, age, sex, and body mass index. Among matched patients who were highly active preoperatively (UCLA score of 9 to 10), BHR provided a smaller median decrease in the postoperative UCLA score (0.0 versus 1.0; p < 0.001), which was clinically important according to the minimal clinically important difference (MCID, 0.92). Furthermore, BHR provided a greater likelihood of remaining highly active compared with total hip arthroplasty (61% compared with 20%; p < 0.001). CONCLUSIONS: BHR demonstrated excellent survivorship and clinical outcomes at 5 to 10 years in selected patients. As compared with total hip arthroplasty, the use of the BHR may provide highly active patients with clinically important advantages in postoperative activity as well as a greater likelihood of remaining highly active. Continued follow-up is necessary to validate long-term BHR outcomes. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 30399084 TI - Strategies for Weight Reduction Prior to Total Joint Arthroplasty. PMID- 30399085 TI - Predatory Publishing in Orthopaedic Research. AB - BACKGROUND: The open-access model has changed the landscape of academic publishing over the last 20 years. An unfortunate consequence has been the advent of predatory publishing, which exploits the open-access model for monetary gain by collecting publishing fees from authors under the pretense of being a legitimate publication while providing little-to-no peer review. This study aims to investigate the predatory publishing phenomenon in orthopaedic literature. METHODS: We searched Beall's List of Predatory Journals and Publishers and another list of predatory journals for journal titles that are possibly related to orthopaedics. We then searched their web sites for the following information: total number of articles published, journal country of origin, author country of origin, article processing charge (APC), quoted review time, and location of the listed headquarters. We also reported the article quality of a random sample of these journals. We consulted InCites Journal Citation Reports to determine the number of nonpredatory orthopaedic publications that are indexed, and we manually searched a random sample of these legitimate journals for Beall's criteria. Additionally, we searched the Directory of Open Access Journals (DOAJ) and PubMed databases for any possible predatory journal titles. RESULTS: We found 104 suspected predatory publishers, representing 225 possible predatory journals. One journal was indexed in the DOAJ, and 20 were indexed in PubMed. Review time was not identified for 56.2% of the journals, and 36.5% quoted a review time of <1 month. Nearly half of the listed addresses of the publishers were either unsearchable or led to residential or empty lots. Eighty-two legitimate journals were identified. The median APC was $420 for predatory journals and $2,900 for legitimate journals. We found that a random sample of the legitimate journals published studies with higher reporting standards, but a few also contained 1 criterion that is found on Beall's list. CONCLUSIONS: This study highlights the scope of orthopaedic predatory publishing. Possibly predatory journals outnumber legitimate orthopaedic journals. Orthopaedic surgeons should be aware of the suspected predatory journals and consult available online tools to identify them because distinguishing them from legitimate journals can be a challenge. PMID- 30399087 TI - Spinopelvic Stiffness and the Lax Hip Arthroplasty: A Conundrum for the Aging Population: Commentary on an article by Nathanael Heckmann, MD, et al.: "Late Dislocation Following Total Hip Arthroplasty. Spinopelvic Imbalance as a Causative Factor". PMID- 30399086 TI - Trends in the Orthopaedic Surgery Subspecialty Fellowship Match: Assessment of 2010 to 2017 Applicant and Program Data. AB - BACKGROUND: Orthopaedic surgery has become increasingly specialized, and most trainees currently complete subspecialty fellowship training. The purposes of this investigation were to evaluate recent trends in U.S. orthopaedic fellowship matches and to provide relevant analyses for future orthopaedic fellowship applicants and fellowship program directors. METHODS: This study analyzed data from orthopaedic fellowship match programs from 2010 to 2017. For each fellowship, the following variables were analyzed: numbers of positions offered, participating programs, applicant registrations, rank lists submitted by applicants (i.e., completed applications), applicants matched, and filled positions. Applicant-matching success rate and percentage of total fellowship positions filled for each subspecialty were calculated, and trends were evaluated for significance and difference between subspecialties utilizing ordinary least square regressions, with p < 0.05 indicating significance. RESULTS: From 2010 to 2017, the number of fellowship positions that were offered increased in all subspecialties (p < 0.05) except for spine (p = 0.44) and trauma (p = 0.92). Participating fellowship programs increased in all subspecialties (p < 0.05) except spine (p = 0.38) and sports medicine; the latter experienced the only significant decrease (p < 0.05). The largest significant increases (p < 0.05) in both applicant registrations (33.5%) and rank lists submitted by applicants (45.3%) were in adult reconstruction. The subspecialty with the highest applicant matching success rate during the study period of 2010 to 2017 was sports (mean, 93.5%). Spine and trauma had the lowest applicant-matching success rates in 2016 to 2017. The percentage of positions filled across all subspecialties increased from 2011 to 2017 (p < 0.05); hand had the highest mean (96.6% filled), and adult reconstruction had the largest significant increase from 82.0% in 2010 to 95.5% in 2017 (p < 0.05). CONCLUSIONS: This investigation provides data with regard to current trends in the orthopaedic fellowship match. Specifically, adult reconstruction fellowship training has recently gained popularity at a more rapid rate than the other subspecialty fellowship pathways, although hand surgery consistently maintains a very high rate of positions filled. Our results for orthopaedic subspecialty fellowship match trends may assist fellowship directors with program planning and career advising and may also assist current residents with fellowship application expectations and career planning. PMID- 30399088 TI - Durability of Massive Rotator Cuff Repair: Commentary on an article by Philippe Collin, MD, et al.: "Clinical and MRI Outcomes 10 Years After Repair of Massive Posterosuperior Rotator Cuff Tears". PMID- 30399089 TI - Is There a Role for Surface Replacement Arthroplasty in Today's Orthopaedic Practice?: Commentary on an article by Marcus C. Ford, MD, et al.: "Five to Ten Year Results of the Birmingham Hip Resurfacing Implant in the U.S. A Single Institution's Experience". PMID- 30399090 TI - Sacral Nerve Stimulation as a Therapy for Patients With Refractory Voiding and Bowel Dysfunction. AB - Sacral nerve stimulation delivers nonpainful electrical pulses to the sacral nerves that modulate the reflexes that control the bladder, bowels, and pelvic floor musculature. This relatively simple procedure was generated to improve and restore function in patients with a variety of pelvic floor disorders. Currently this therapy is approved for use in patients with urgency urinary incontinence, urinary urgency-frequency, nonobstructive urinary retention, and fecal incontinence. This review includes the history of this treatment modality, explains the mechanism of action, and describes the procedure for implantation of this device. Additionally, advancements in this treatment over the past two decades and landmark literature to date regarding sacral nerve stimulation are reviewed. Current literature regarding off-label uses of this treatment modality for a variety of pelvic floor disorders is also discussed. PMID- 30399091 TI - Home Self-Collection by Mail to Test for Human Papillomavirus and Sexually Transmitted Infections. AB - OBJECTIVE: To evaluate the validity and acceptability of at-home self-collection to test for high-risk human papillomavirus (HPV) and sexually transmitted infections among women overdue for cervical cancer screening by national guidelines. METHODS: Low-income, infrequently screened women were recruited from the general population in North Carolina to participate in an observational study. Participants provided two self-collected cervicovaginal samples (one at home and one in the clinic) and a clinician-collected cervical sample. Samples were tested for high-risk HPV, Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, and Mycoplasma genitalium. Cervical samples were also tested by liquid-based cytology. RESULTS: Overall, 193 women had conclusive high risk HPV results for all three samples and cytology results. Prevalence of high risk HPV within self-home samples (12.4%) was not different from that within clinician samples (11.4%; P=.79) and from that within self clinic samples (15.5%; P=.21). Positivity for high-risk HPV in all sample types increased with increasing grades of cervical abnormality (P<.001). Self-home samples detected high-risk HPV in all identified cases of high-grade squamous intraepithelial lesions and of cervical intraepithelial neoplasia 2 or worse. Detection was comparable across sample types for T vaginalis (range 10.2-10.8%), M genitalium (3.3-5.5%), C trachomatis (1.1-2.1%), and N gonorrhoeae (0-0.5%). Kappa values between sample types ranged from 0.56 to 0.66 for high-risk HPV, 0.86-0.91 for T vaginalis, and 0.65-0.83 for M genitalium. Most participants reported no difficulty understanding self-collection instructions (93.6%) and were willing to use self-collection in the future (96.3%). CONCLUSION: Mail-based, at-home self collection for high-risk HPV and sexually transmitted infection detection was valid and well accepted among infrequently screened women in our study. These findings support the future use of high-risk HPV self-collection to increase cervical cancer screening rates among higher risk women in the United States. PMID- 30399092 TI - Serial Third-Trimester Ultrasonography Compared With Routine Care in Uncomplicated Pregnancies: A Randomized Controlled Trial. AB - OBJECTIVE: Among uncomplicated pregnancies, serial third-trimester ultrasound examinations identified significantly more cases with a composite of fetal growth or amniotic fluid abnormalities (27%) than did routine fundal height measurements (8%). METHODS: Women without complications between 24 0/7 and 30 6/7 weeks of gestation were randomized (NCT0270299) to either routine care (control arm) or ultrasound examination every 4 weeks (intervention arm). The primary outcome was a composite of abnormalities of fluid volume and growth: oligohydramnios or polyhydramnios; fetal growth restriction; or large for gestational age. The secondary outcome was the presence of composite maternal or neonatal morbidity among the two groups. A total of 206 participants was needed to have 80% power to detect an increase in the primary composite outcome from 10% in control to 25% in the intervention group (baseline rate 10%; two-tailed; alpha=0.05; loss to follow up 5%). All women were included in the intent-to-treat analysis. Fisher exact, chi tests, or two-sample t tests were used to assess group differences. RESULTS: From July 11, 2016, to May 24, 2017, 852 women were screened for eligibility and 206 were randomized as follows: 102 in routine care and 104 in serial ultrasound examinations. The two groups were comparable in baseline characteristics. The primary composite outcome was significantly higher among women who were in the ultrasound examination group than the routine care group (27% vs 8%; relative risk 3.43, 95% CI 1.64-7.17); five women (95% CI 3-11) were needed to identify at least one of the composite ultrasound abnormalities. Although we were underpowered to detect a significant difference, the following secondary endpoints occurred with similar frequency in the ultrasound examination group than the routine care group: induction resulting from abnormal ultrasound examination findings (14% vs 6%), cesarean delivery in labor (5% vs 6%), and prespecified composite maternal morbidity (9% in both groups) and composite neonatal morbidity (1% vs 4%). CONCLUSION: Among uncomplicated pregnancies between 24 0/7 and 30 6/7 weeks of gestation, serial third-trimester ultrasound examinations were significantly more likely to identify abnormalities of fetal growth or amniotic fluid than measurements of fundal height and indicated ultrasound examination. No differences in maternal and neonatal outcomes were noted, although we were underpowered for these endpoints. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02702999. PMID- 30399094 TI - Laparoscopic Radical Trachelectomy for Embryonal Rhabdomyosarcoma of the Cervix in a 2-Year-Old Girl. AB - BACKGROUND: Embryonal rhabdomyosarcoma of the cervix is a rare and aggressive malignancy that usually affects children and young adults. CASE: We describe a 2 year-old patient who presented with a mass protruding through the vaginal introitus. Preoperative investigations including vaginoscopy, hysteroscopy, magnetic resonance imaging, and biopsies confirmed embryonal rhabdomyosarcoma, botryoid subtype, arising from the cervix. She was successfully treated with neoadjuvant chemotherapy and interval laparoscopic radical trachelectomy to achieve remission. CONCLUSION: Collaboration between the pediatric and adult surgical and medical oncology teams was critical to implement this fertility sparing treatment strategy in such a young girl having this rare tumor. PMID- 30399093 TI - Cervical Screening by Pap Test and Visual Inspection Enabling Same-Day Biopsy in Low-Resource, High-Risk Communities. AB - OBJECTIVE: To develop an effective, low-cost, single-visit cervical screening strategy incorporating a modified Pap test and visual inspection with acetic acid and Lugol's iodine for low-income settings. METHODS: We conducted a prospective cohort trial. Two low-income Muslim Uyghur communities in China's far western Kashi Prefecture served as pilot and validation study sites, respectively, and 4,049 women (aged 30-59 years) were screened. The conventional Pap test was modified using a cotton swab to collect cervical cells without scraping the cervix using an Ayre spatula, allowing visual inspection with acetic acid (and visual inspection with Lugol's iodine if visual inspection with acetic acid was negative) to be performed in a single visit. Results from both tests were available within 1-2 hours. Women positive for either or both underwent same-day biopsy that was shipped by a courier service to a central pathology laboratory. RESULTS: Single-visit screening incorporating both a modified Pap test and visual inspection achieved a sensitivity of 96.0% (95% CI 91.6-100), which was superior to Pap testing (76%, 95% CI 66.3-85.7; P<.001) or visual inspection with acetic acid-visual inspection with Lugol's iodine (48%, 95% CI 36.7-59.3; P<.001) alone in detecting cervical intraepithelial neoplasia (CIN) 2 or worse lesions. Rapid interpretation of both diagnostic procedures facilitated efficient same-day biopsy that achieved a negative predictive value of 98.2% in detecting CIN 2 or worse lesions. The increased sensitivity and minimized loss of follow-up allowed this approach to identify an extremely high prevalence of CIN 1 (2,741/100,000, 95% CI 2,238-3,245/100,000), CIN 2 or 3 (1,457/100,000, 95% CI 1,088 1,826/100,000), and cervical cancer (395/100,000, 95% CI 202-589/100,000) among these underscreened, at-risk women. CONCLUSION: Single-visit cervical screening with both a modified Pap test and visual inspection has greater sensitivity to detect high-grade CINs, reduces loss of follow-up, and could be an efficient low cost strategy for low-resource settings. PMID- 30399095 TI - Massive Hemorrhage From Suspected Iatrogenic Uterine Rupture. AB - BACKGROUND: Intrauterine balloon tamponade is recommended for refractory postpartum hemorrhage resulting from atony, but few studies have assessed complications associated with placement. CASE: A 39-year-old woman, gravida 4 para 1, with posterior placenta previa and suspected placenta accreta had a postpartum hemorrhage after a scheduled cesarean delivery. An intrauterine balloon tamponade device was easily placed transcervically; however, the patient required additional analgesia for constant severe stabbing pain worsened on examination. Three hours after placement, the balloon was expelled from the cervix, resulting in 1,500 mL of fresh blood and clot. Emergent exploratory laparotomy identified a uterine rupture inferior and lateral to the hysterotomy site. CONCLUSION: Intrauterine balloon tamponade may contribute to iatrogenic uterine rupture and should be considered in patients with refractory hemorrhage, hemodynamic instability, or severe pain despite analgesia. PMID- 30399096 TI - Retroperitoneal Ectopic Pregnancy. AB - BACKGROUND: Retroperitoneal ectopic pregnancies are rare and have a tendency to implant along major vessels of the abdomen and pelvis. Clinical manifestations can vary from no symptoms to hypovolemic shock and death. CASE: A 30-year-old woman presented in hypovolemic shock with left flank and abdominal pain after attempting to medically terminate her first-trimester pregnancy. Intraoperative findings revealed normal pelvic organs with a massive retroperitoneal hematoma containing chorionic villi confirmed on histopathology. CONCLUSIONS: In a woman with a pregnancy of unknown location presenting with worsening flank pain, a retroperitoneal ectopic pregnancy must be considered. Prompt diagnosis and management in a low-resource setting presents additional challenges. PMID- 30399097 TI - Quality of Information Available Online for Abortion Self-Referral. AB - OBJECTIVE: To assess the quality of information available online for abortion self-referral and to determine whether quality varies by region or distance to an abortion provider. METHODS: This was a cross-sectional study. We used a standard protocol to perform internet searches from August 2016 to June 2017 for abortion services in the 25 most populous U.S. cities and the 43 state capitals that were not one of the 25 most populous cities. We classified the first 10 webpage results and the first five map results and advertisements as facilitating abortion referral (local independent abortion provider, local Planned Parenthood facility, national abortion provider or organization, prochoice website, or abortion directory), not facilitating abortion referral (nonproviding physician office, nonmedical website, abortion provider greater than 50 miles from the location, news article, general directory, other), or hindering abortion referral (crisis pregnancy center or antichoice website). We used U.S. Census Bureau subregions to examine geographic differences. We made comparisons using a chi test. RESULTS: Overall, from 612 searches from 68 cities, 52.9% of webpage results, 67.3% of map results, and 34.4% of advertisements facilitated abortion referral, whereas 12.9%, 21.7%, and 29.9%, respectively, hindered abortion referral. The content of the searches differed significantly based on U.S. Census Bureau subregion (all P<=.001) and distance to an abortion provider (all P<=.02). CONCLUSION: Two thirds of map results facilitated abortion self-referral, whereas only half of webpage results did so. Advertisements were the least likely to facilitate and the most likely to hinder self-referral. Quality was lowest in areas that were farthest from abortion providers. PMID- 30399098 TI - A Colposcopy Trainer to Simulate Visualization and Biopsy of the Cervix. AB - BACKGROUND: Colposcopy is a common office procedure providing a magnified view of the cervix for the evaluation of an abnormal cytology result. Traditionally the procedure has been replicated in simulation training by using a sausage or hotdog to represent the cervix and allow for target biopsy. This is neither reusable nor sustainable. METHOD: We developed a cervix model comprised of food coloring and ballistics gel. After cooling, the surface was dotted with gel that can be activated by a black light to mimic acetowhite changes. The cervix was placed into an existing pelvic trainer and then piloted by attending physicians and resident trainees in obstetrics and gynecology and family practice. EXPERIENCE: Sixteen physicians and residents were surveyed after a simulated colposcopy. Twelve had performed colposcopies and of those, eight stated that the model was very comparable with the real procedure; four stated the model was somewhat comparable. Three had never performed a colposcopy but stated that model was very or somewhat comparable with textbook or journal photographs. CONCLUSION: Our colposcopy trainer represents continued innovation in the field of simulation while being sustainable and economic. We continue to work on enhancing our model to be even more sophisticated and offering additional training options. PMID- 30399099 TI - Menopause-Related Cognitive Impairment. AB - BACKGROUND: Identifying the cognitive changes associated with the menopausal transition prevents misattribution of symptoms to more ominous causes such as neurodegenerative disease. CASE: Two women with cognitive loss and objective evidence of menopause-related cognitive impairment are presented, misattributed to Alzheimer disease in one case and frontotemporal dementia in the other. Neurocognitive testing, neuroimaging, and laboratory findings are reviewed. Both women were diagnosed with menopause-related cognitive impairment and were stable in follow-up over 4 or more years. CONCLUSIONS: Recognizing the cognitive changes associated with menopause and distinguishing from cognitive impairment resulting from other etiologies-including neurodegenerative diseases such as Alzheimer disease-has important clinical implications both for treatment and for prognosis. PMID- 30399100 TI - Pregnancy and Childbirth After Sexual Trauma: Patient Perspectives and Care Preferences. AB - OBJECTIVE: To explore the pregnancy and childbirth experiences and preferences of women with a history of sexual trauma in order to identify trauma-informed care practices that health care providers may use to improve obstetric care. METHODS: We conducted a qualitative study consisting of semistructured interviews with women who either self-identified as having a history of sexual trauma or did not. Participants were recruited from a tertiary care ambulatory clinic and had at least one birth experience within the past 3 years. Interviews were audio recorded and transcribed verbatim. Grounded theory was used to derive themes using the participants' own words. RESULTS: From 2015 to 2017, we interviewed 20 women with a history of sexual trauma and 10 without. Women with a history of sexual trauma desired clear communication about their history between prenatal care providers and the labor and delivery team. In the intrapartum period, they desired control over who was present in the labor room at the time of cervical examinations and for health care providers to avoid language that served as a stressing reminder of prior sexual trauma. They wanted control over the exposure of their bodies during labor and to be asked about their preference for a male health care provider. In the postpartum period, some women with a history of sexual trauma found breastfeeding healing and empowering. CONCLUSION: Women with a history of sexual trauma have clear needs, preferences, and recommendations for obstetric care providers regarding disclosure, cervical examinations, health care provider language, body exposure, and male health care providers. They offer insight into unique breastfeeding challenges and benefits. PMID- 30399101 TI - The Residency Interview Season: Time for Commonsense Reform. AB - Residency applicants and residency programs invest significant resources in attempting to match applicants into the best possible programs. However, recent trends have made the process increasingly inefficient. Decisions made by all parties-students, medical schools, and residency programs-have contributed to a system that has become increasingly anxiety-provoking for the students and unnecessarily cumbersome for the programs. Relatively straightforward solutions exist, however, that would improve the process for all parties involved. With improved mentoring of medical students, honest and timely assessment of applicants by programs, and, most importantly, standardizing the interview invitation timeline, candidates and programs would encounter an improved residency interview experience. PMID- 30399102 TI - Induced Abortion in a Population Entitled to Free-of-Charge Long-Acting Reversible Contraception. AB - OBJECTIVE: To study the rate of induced abortion in a population in whom long acting reversible contraceptive (LARC) methods are offered free of charge as part of primary health care services. METHODS: We conducted a register-based cohort study on females aged 15-44 years in the city of Vantaa, Finland. We assessed the rate of abortion among females entitled to LARC methods free of charge by survival analysis in four cohorts: those visiting public family planning clinics and initiating free-of-charge LARC methods during 2013-2014 (LARC cohort, n=2,035); those visiting public family planning clinics not choosing LARC methods (no LARC cohort, n=7,634); and three age-matched control participants for every LARC and no LARC participant from the general population not using the services (nonservice users, n=5,981 and 22,748). The patients were followed up by means of Finnish national registers until February 28, 2016. RESULTS: During the 78,500 woman-years accumulated, altogether 996 patients in Vantaa underwent an abortion (12.3 abortions/1,000 woman-years, 95% CI 11.6-13.1). Of these, 16 abortions occurred in the LARC cohort (3.9/1,000, 95% CI 2.4-6.0), 243 in the no LARC cohort (15.3/1,000, 95% CI 13.5-17.2), and 737 (12.6/1,000, 95% CI 11.7-13.5) among matched nonservice users. The adjusted abortion rate in the LARC cohort was 80% lower than in the no LARC cohort (risk ratio [RR] 0.20, 95% CI 0.11-0.32) and 74% lower than among their matched control participants (RR 0.26, 95% CI 0.15 0.43). In contrast, there was no difference in the abortion rate between the no LARC cohort and the control participants (adjusted RR 1.01, 95% CI 0.87-1.18). CONCLUSION: When providing a population with free-of-charge LARC methods, the abortion rate was markedly lower among patients initiating free-of-charge LARC compared with patients using the services but not initiating a LARC method. Programs of this kind could be of major importance in populations with high rates of unintended pregnancy. PMID- 30399104 TI - Levels of Maternal Care Verification Pilot: Translating Guidance Into Practice. AB - Development of systems for perinatal regionalization and for the provision of risk-appropriate maternal care is a key strategy to decrease maternal morbidity and mortality. Regionalized systems pertaining to neonatal care are broadly implemented in many states, but networks for risk-appropriate maternal care are lacking. In response to increases in maternal morbidity and mortality over the past decade, the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) developed and published the levels of maternal care guidelines in 2015. The guidelines are designed to promote collaboration among maternal facilities and health care providers with the goal that pregnant women receive care at a facility appropriate for their risk. The Centers for Disease Control and Prevention (CDC) developed the Levels of Care Assessment Tool in 2013 to assist states and jurisdictions in assessing maternal and neonatal levels of care in alignment with the national guidelines published by ACOG and SMFM and the American Academy of Pediatrics, respectively. With the goal of promoting levels of maternal care, ACOG and SMFM developed and piloted the levels of maternal care verification program. Fourteen facilities across three states (Georgia, Illinois, and Wyoming) participated in the pilot. A multidisciplinary team representing organizations with expertise in maternal risk appropriate care performed an onsite comprehensive review of the maternal services available in each facility using the results from the CDC Levels of Care Assessment Tool as a previsit screening. A verification program that could be implemented on a local, state, or regional scale is being developed leveraging the lessons learned from the pilot. PMID- 30399103 TI - Neonatal Morbidity After Management of Vaginal Noncephalic Second-Twin Delivery by Residents. AB - OBJECTIVE: To assess neonatal mortality and morbidity according to whether a resident or senior obstetrician initially managed vaginal delivery of noncephalic second twins. METHODS: The JUmeaux MODe d'Accouchement study was a national, prospective, population-based, cohort study of twin deliveries in 176 maternity units in France, where active management of second-twin delivery is recommended. The primary outcome of our study was a composite of neonatal mortality and morbidity. Neonatal outcomes of noncephalic second twins born at or after 32 weeks of gestation after vaginal delivery of the first twin were compared according to the initial managing practitioner-supervised resident or senior obstetrician. Deliveries performed by a senior obstetrician after failure by a resident were classified as resident deliveries. Deliveries in maternity units without residents were excluded. We used multilevel multivariable Poisson regression models and propensity score matching to control for indication bias and potential confounders, including the maternity unit status. We performed subgroup analyses according to gestational age at delivery, before or after 37 weeks of gestation, and to the noncephalic second twin presentation, breech or transverse. RESULTS: Among 1,376 noncephalic second-twin deliveries, 545 (39.6%) were initially managed by a resident and 831 (60.4%) by a senior obstetrician. Residents failed to deliver the second twin in 125 (22.9%) women. Composite neonatal mortality and morbidity did not differ between the resident and senior groups (13/545 [2.4%] vs 29/831 [3.5%]; adjusted relative risk 0.78, 95% CI 0.35 1.74). Subgroup analyses were consistent with the overall analysis. CONCLUSION: Supervised resident and senior staff management of noncephalic second-twin vaginal delivery is associated with similar neonatal morbidity and mortality, which supports continued training of residents in such deliveries. PMID- 30399105 TI - Preconception Coverage Before and After the Affordable Care Act Medicaid Expansions. AB - OBJECTIVE: To estimate the effects of the Affordable Care Act Medicaid expansion provision that was largely implemented in 2014 on preconception insurance coverage among low-income women. METHODS: We used a quasiexperimental, difference in-difference design to compare changes in preconception insurance coverage among low-income women living in expansion compared with nonexpansion states before and after the Medicaid expansions. Women with family incomes 138% the federal poverty level or less who participated in the Pregnancy Risk Assessment Monitoring System from 2009 to 2015 from states that did or did not expand their Medicaid programs on January 1, 2014, were included. The exposure of interest was the state Medicaid expansion. The primary outcome was insurance status 1 month before conception. We conducted additional subgroup and sensitivity analyses to test the assumptions of the model and the robustness of the findings. RESULTS: The study sample included 30,495 women from eight states that expanded Medicaid under the Affordable Care Act and 26,561 patients from seven states in that did not. The rate of preconception Medicaid coverage was 30.8% prepolicy and 35.6% postpolicy in nonexpansion states and 43.2% prepolicy and 56.8% postpolicy in expansion states. There was a significantly greater increase in Medicaid coverage in expansion states after the policy implementation (adjusted difference-in difference estimate +8.6% points, 95% CI 1.1-16.0). Rates of preconception uninsurance were 44.2% prepolicy and 34.3% postpolicy in nonexpansion states and 37.4% prepolicy and 23.5% postpolicy in expansion states. There was no significant difference in the changes in uninsurance between the two groups in the postpolicy period (adjusted difference-in-difference estimate -4.1, 95% CI 11.1 to 2.9). Non-Medicaid insurance coverage was 25.3% prepolicy and 30.5% postpolicy in nonexpansion states and 19.4% prepolicy and 19.7% postpolicy in expansion states. Relative to nonexpansion states, there was a significant decrease in non-Medicaid coverage in the expansion states in the postpolicy period (adjusted difference-in-difference estimate -4.7, 95% CI -8.3 to -1.1). The results were robust to alternate model specifications and study period definitions. CONCLUSION: Medicaid expansion was associated with increased enrollment in Medicaid before pregnancy among low-income women; however, there were no changes in the rates of uninsurance. Additional years of postpolicy data are needed to fully assess the effects of the policy change. PMID- 30399106 TI - Terminal Complement Activation in Preeclampsia. AB - OBJECTIVE: To evaluate whether C5b-9 concentrations in blood and urine are increased in preeclampsia with severe features. METHODS: The Complement and Preeclampsia in the Americas study is a prospective, multicenter case-control study performed at six centers in Colombia from November 2015 to July 2016. The case group included women with preeclampsia with severe features, and the control group included women who were healthy or had chronic hypertension, gestational hypertension, or preeclampsia without severe features. We enrolled two women in the control group for every woman in the case group. Soluble C5b-9 concentrations were measured by enzyme-linked immunosorbent assays in blood and urine. The primary outcome was C5b-9 concentrations in women in the case group compared with all women in the control group, and the secondary outcome was C5b-9 levels in women in the case group compared with individual control subgroups. Differences were assessed by test of medians, and associations were further evaluated by receiver operating characteristic curve analysis and logistic regression with alpha=0.05. RESULTS: Three hundred fifty-two patients were enrolled. Plasma C5b-9 concentrations did not differ significantly between women in the case group and those in the control group, but urine C5b-9 concentrations were higher in women in the case group (median [interquartile range] 9.9 [1.6-43.7] vs 1.8 [0.54-4.1] ng/mL, P<.001). In subgroup analysis, plasma C5b-9 concentrations were increased in women in the case group compared with healthy women in the control group (median [interquartile range] 2,778 [1,633-4,230] vs 1,374 [1,064-2,332] ng/mL, P<.001), and urine C5b-9 concentrations were increased in women in the case group compared with all control subgroups (P<.001). Using receiver operating characteristic analysis, urine C5b-9 concentrations differentiated preeclampsia with severe features from hypertensive women in the control group (area under the receiver operating characteristic curve 0.74, 95% CI 0.68-0.80). Urine C5b-9 22 ng/mL or greater (range 0-158.4 ng/mL) was the optimal cut point for diagnosis of preeclampsia with severe features with adjusted odds ratio of 10.0 (95% CI 3.5 28.8, P<.001). CONCLUSION: Urinary excretion of terminal complement effector C5b 9 is higher in women with preeclampsia with severe features compared with women with other hypertensive disorders of pregnancy and women without hypertension. PMID- 30399107 TI - Chromosomal Microarray Analysis Results From Pregnancies With Various Ultrasonographic Anomalies. AB - OBJECTIVE: To examine chromosomal microarray analysis results in pregnancies with various ultrasonographic anomalies and to characterize the copy number variants in diverse fetal phenotypes. METHODS: We retrospectively examined chromosomal microarray analyses of amniocenteses performed nationwide as a result of fetal ultrasonographic anomalies (structural defects, fetal growth restriction, and polyhydramnios) between January 2013 and September 2017. The rate of abnormal chromosomal microarray findings was compared between the different phenotypes and with a previously described control population of 15,225 pregnancies with normal ultrasonographic findings. RESULTS: Clinically significant chromosomal microarray aberrations were detected in 272 of 5,750 pregnancies (4.7%): 115 (2%) karyotype detectable and 157 (2.7%) submicroscopic. Most commonly detected copy number variants were 22q11.21 deletions (0.4%) followed by 22q11.21 gain of copy number (0.2%). Specific copy number variants detected among pregnancies with abnormal ultrasonographic findings were up to 20-fold more prevalent compared with low risk pregnancies. Some variants were associated with specific phenotypes (eg, 22q11.21 microdeletions with cardiovascular and 17q12 microdeletions with genitourinary defects). CONCLUSION: The rate of abnormal amniotic chromosomal microarray analysis results is twice that of karyotypic abnormalities in pregnancies with various abnormal ultrasonographic findings. PMID- 30399109 TI - Nonsteroidal Antiinflammatory Drug Administration and Postpartum Blood Pressure in Women With Hypertensive Disorders of Pregnancy. AB - OBJECTIVE: To evaluate whether postpartum nonsteroidal antiinflammatory drug (NSAID) administration is associated with increased blood pressure in women with hypertensive disorders of pregnancy and to estimate the association between NSAID administration and use of opioid medication. METHODS: We conducted a retrospective cohort study of women with hypertensive disorders of pregnancy. Patients were analyzed in two groups according to whether they received NSAIDs postpartum. Study participants were women delivered at a tertiary care center from 2008 to 2015. The primary outcome was change in mean arterial pressure during the postpartum period. Secondary outcomes were postpartum pain scores, cumulative postpartum opioid requirement, initiation or dose escalation of antihypertensive agents, and adverse postpartum outcomes including acute renal failure, change in hematocrit, and maternal readmission for hypertensive disorder. RESULTS: Two hundred seventy-six women with hypertensive disorders of pregnancy were included (129 NSAID-unexposed and 147 NSAID-exposed). Postpartum NSAID administration was not associated with a statistically significant change in mean arterial pressure compared with no NSAID administration (-0.7 vs -1.8; mean difference 1.10, 95% CI -1.44 to 3.64). Similarly, no difference was observed between the cohorts in terms of need for initiation or escalation in dose of antihypertensive agents or maternal readmission for hypertensive disorder. The study was underpowered to determine whether NSAID administration was associated with any difference in less frequent secondary outcomes (eg, incidence of acute renal insufficiency, need for postpartum transfusion) or cumulative opioid use. CONCLUSION: Nonsteroidal antiinflammatory drug administration to postpartum patients with hypertensive disorders of pregnancy is not associated with a change in blood pressure or requirement for antihypertensive medication. PMID- 30399108 TI - Child Neurodevelopmental Outcomes by Prepregnancy Body Mass Index and Gestational Weight Gain. AB - OBJECTIVE: To study the association of prepregnancy body mass index (BMI) and gestational weight gain with child neurodevelopmental outcomes. METHODS: We performed a secondary analysis of data from two parallel, multicenter, randomized, double-blind, placebo-controlled thyroxine replacement trials in pregnant women with either hypothyroxinemia or subclinical hypothyroidism who delivered at term. Body mass index was categorized as normal (18.5-24.9), overweight (25.0-29.9), or obese (30 or greater). We also evaluated early (20 weeks of gestation or less), late (greater than 20 weeks of gestation), and total gestational weight gain and categorized gestational weight gain as inadequate, adequate, and excessive per 2009 Institute of Medicine guidelines. Neurodevelopmental outcomes included 5-year Wechsler Preschool and Primary Scale of Intelligence and 3-year Differential Ability Scales-II. Linear and logistic regression analyses were performed and adjusted for maternal age, race-ethnicity, education, insurance status, parity, smoking and alcohol use, thyroid status (subclinical hypothyroidism or hypothyroxinemia), treatment group, gestational age at delivery, and neonatal sex. RESULTS: Of the 948 women included, 380 (40%), 305 (32%), and 263 (28%) had normal, overweight, and obese prepregnancy BMI, respectively. A total of 106 (11%), 212 (22%), and 630 (66%) of women had inadequate, adequate, and excessive total rates of gestational weight gain, respectively. Maternal differences among the BMI categories included race ethnicity, education, insurance type, parity, and thyroid status (all P<.01), whereas the gestational weight gain groups only differed by parity (P<.001). In unadjusted analysis, children of obese (93.2+/-12.8; 88.5+/-13.3) and overweight (94.1+/-15.6; 89.6+/-16.0) women had lower Wechsler Preschool and Primary Scale of Intelligence and Differential Ability Scales-II scores, respectively, than normal-weight women (97.4+/-15.4; 93.9+/-16.0; P<.001 for all comparisons); however, in adjusted analysis, there were no differences in neurodevelopmental outcomes by maternal BMI. The association was primarily accounted for by race ethnicity and education. In unadjusted and adjusted analyses, there were no differences in neurodevelopmental outcomes by adequacy of early, late, or total gestational weight gain. CONCLUSION: In women with either subclinical hypothyroidism or hypothyroxinemia, neither prepregnancy BMI nor gestational weight gain was associated with neurodevelopmental outcomes among children born at term in adjusted analyses. PMID- 30399111 TI - The Patient-Physician Relationship: The Death of Intimacy. PMID- 30399110 TI - Antepartum Testing for the Prevention of Stillbirth: Where Do We Go From Here? AB - Unexpected antepartum fetal demise remains one of the most tragic complications of pregnancy. Various approaches to antepartum fetal assessment have been developed as a means of either reassuring the clinician of fetal well-being or identifying potential fetal jeopardy and the need for delivery. As additional high-risk groups of women are identified, indications for antenatal testing continue to expand despite a paucity of good-quality data linking such testing to improved outcomes for women with these additional risk factors. The expansion of established antepartum testing protocols to include women with conditions such as advanced maternal age or obesity without additional, well-established indications for testing is not warranted, particularly because baseline rates of stillbirth seen with these conditions before 39 weeks of gestation are already lower than stillbirth rates achieved with current antepartum testing protocols. Beyond 39 weeks of gestation, if the established risks of stillbirth are deemed unacceptable, delivery is a more rational and evidence-based approach than antepartum testing. PMID- 30399112 TI - What Is New in Ovarian Cancer?: Best Articles From the Past Year. AB - This month we focus on current research in ovarian cancer. Dr. Wright discusses four recent publications, which are concluded with a "bottom-line" that is the take-home message. A complete reference for each can be found on on this page along with direct links to abstracts. PMID- 30399113 TI - The Menopausal Brain. PMID- 30399114 TI - Connect the Dots-December 2018. PMID- 30399115 TI - Sex Differences in Physical Fitness Characteristics and Match-Play Demands in Adolescent Netball: Should Male and Female Adolescents Co-compete in Netball? AB - Tissera, KM, Naughton, GA, Gabbett, TJ, Krause, LM, Moresi, MP, and Benson, AC. Sex differences in physical fitness characteristics and match-play demands in adolescent netball: Should male and female adolescents co-compete in netball? J Strength Cond Res XX(X): 000-000, 2018-Sports participation offers multifaceted benefits, especially during adolescence. However, policies relating to male and female adolescents co-competing in team sports can be prohibitive and lack an evidence base. This study aimed to strengthen evidence on coparticipation of male and female adolescents playing recreational netball. Off-court fitness characteristics (power, speed, agility, and high-speed intermittent running) and match-play performances from global positioning system (GPS) and video analysis were compared in adolescent males (n = 34, mean +/- SD, age, 15.2 +/- 0.8 years) and females (n = 45, mean +/- SD, age, 14.9 +/- 0.7 years), with previous recreational netball experience. Independent t-tests showed adolescent men outperforming females in all off-court fitness characteristics (p < 0.001). Two way analyses of variance explored sex-based interactions in match-play (GPS accelerometer data and notational analyses) and type of competition (mixed /single-sex formats) in forty-two 7-minute matches. Overall, no differences in match-play performances were found between males and females (p > 0.05). Notational skill-based comparisons showed that male skills were better in mixed- than single-sex matches. Conversely, competition format did not alter skills of females. Despite more netball experience in females and superior off-court fitness characteristics in males, on-court performance differences between males and females were minimal in these recreational adolescent netball players. Coparticipation in netball was not detrimental to the performance of either sex. PMID- 30399116 TI - Acute Effect of Popular High-Intensity Functional Training Exercise on Physiologic Markers of Growth. AB - Kliszczewicz, B, Markert, CD, Bechke, E, Williamson, C, Clemons, KN, Snarr, RL, and McKenzie, MJ. Acute effect of popular high-intensity functional training exercise on physiologic markers of growth. J Strength Cond Res XX(X): 000-000, 2018-Constantly evolving, high-intensity functional training (HIFT) exercise consists of various modalities, orders, weights, and repetition schemes. High intensity functional training has gained popularity among the general population, but lacks empirical evidence regarding acute adaptive responses. The purpose of this study was to describe the acute effects of 2 representative bouts of HIFT on physiologic markers of growth. For convenience, the bouts are designated "short" (<5 minutes) and "long" (~15 minutes), although duration was not the only difference between bouts. Ten apparently healthy men (28.1 +/- 5 years) performed 2 HIFT bouts in a randomized crossover design. Blood was collected at 5 time points (Pre, Post, 1, 3, and 6 hours) to examine growth hormone (GH), insulin like growth factor (IGF-1), insulin-like growth factor binding proteins 1 and 2 (IGFBP-1 and IGFBP-2), and vascular endothelial growth factor (VEGF). Blood lactate concentration ([La]) was analyzed at the Pre and Post time points. A repeated-measures analysis of variance (ANOVA) revealed no trial differences among the markers (IGF-1, IGFBP-1, IGFBP-2, and VEGF) except GH at Post, where the long bout produced a greater effect (p = 0.005). Mean GH levels (pg.ml) in the short bout increased from 68.4 to 106.5, and in the long bout, mean GH levels increased from 38.5 to 286.4. The repeated-measures ANOVA revealed a main time effect in GH (p = 0.037), while a post hoc t-test demonstrated elevated GH at 1 hour (p = 0.018) when compared with Pre. No time-dependent change (p > 0.05) was observed in IGF-1, IGFBP-1, IGFBP-2, or VEGF. Mean blood [lactate] increased more than tenfold in both bouts. The findings of this descriptive study suggest that, other than GH, there are no acute differences in markers of skeletal muscle or vascular growth between these 2 specific HIFT bouts. PMID- 30399117 TI - Comparison of the FitroDyne and GymAware Rotary Encoders for Quantifying Peak and Mean Velocity During Traditional Multijointed Exercises. AB - Fernandes, JFT, Lamb, KL, Clark, CCT, Moran, J, Drury, B, Garcia-Ramos, A, and Twist, C. Comparison of the FitroDyne and GymAware rotary encoders for quantifying peak and mean velocity during traditional multijointed exercises. J Strength Cond Res XX(X): 000-000, 2018-The FitroDyne and GymAware rotary encoders are being increasingly used in resistance training to monitor movement velocity, but how closely their velocity outcomes agree is unknown. Consequently, this study aimed to determine the level of agreement between the FitroDyne and GymAware for the assessment of movement velocity in 3 resistance training exercises. Fifteen men performed 3 repetitions of bench press, back squat, and bent-over-row exercises at 10% 1 repetition maximum increments (from 20 to 80%). For each repetition, the FitroDyne and GymAware recorded peak and mean barbell velocity (cm.s). Although strongly correlated (r = 0.79-1.00), peak velocity values for the GymAware were significantly lower than the FitroDyne for all exercises and loads. Importantly, the random errors between the devices, quantified through Bland and Altman's 95% limits of agreement, were unacceptable, ranging from +/-3.8 to 25.9 cm.s. Differences in mean velocity were smaller (and nonsignificant for most comparisons) and highly correlated (r = 0.86-1.00) between devices. Notwithstanding smaller random errors than for the peak values, mean values still reflected poor agreement (random errors between +/-2.1 and 12.0 cm.s). These findings suggest that the FitroDyne and GymAware cannot record peak or mean velocity with acceptable agreement and should neither be used interchangeably nor their data compared. PMID- 30399118 TI - Whole-Body Vibration as a Warm-up Before Exercise-Induced Muscle Damage on Symptoms of Delayed-Onset Muscle Soreness in Trained Subjects. AB - Magoffin, RD, Parcell, AC, Hyldahl, RD, Fellingham, GW, Hopkins, JT, and Feland, JB. Whole-body vibration as a warm-up before exercise-induced muscle damage on symptoms of delayed-onset muscle soreness in trained subjects. J Strength Cond Res XX(X): 000-000, 2018-There is no clear scientific evidence that whole-body vibration (WBV) used as a warm-up before performing eccentric exercise mitigates delayed-onset muscle soreness (DOMS) and speeds strength loss recovery. These benefits were observed primarily in nonresistance-trained individuals. The aim of this study was to determine whether WBV could mitigate soreness and expedite strength recovery for resistance-trained individuals when used as a warm-up before eccentric exercise. Thirty resistance-trained males completed 300 maximal eccentric contractions of the quadriceps after warming up with (WBV) or without (CON) WBV. Both CON and WBV experienced significant isometric (26.3 and 30.2%, respectively) and dynamic (50.9 and 46.4%, respectively) strength loss immediately after exercise. Isometric strength was significantly depressed after 24 hours in the CON group (8.2% p < 0.02), but not in the WBV group (5.9% p = 0.7). Isometric strength was no longer significantly depressed after 48 hours in the CON group (6.1% p < 0.07) or the WBV group (4.1% p = 0.20). Dynamic strength was significantly decreased in both the CON and WBV groups at 24 hours (17.7% p < 0.001 and 15.5% p < 0.001, respectively) and 48 hours (17.1% p < 0.01 and 13.6% p < 0.002), but only significant for the CON at 1 week after exercise (8.6% p = 0.05). Pain as measured by a visual analog scale was significant in both groups at 24 and 48 hours after exercise, but WBV experienced significantly less soreness than the CON group after 24 hours (28 vs. 46 mm p < 0.01, respectively) and 48 hours (38 vs. 50 mm p < 0.01). Pain pressure threshold increased significantly in both groups, but there was no difference between groups. These results suggest the use of WBV before eccentric exercise mildly mitigates DOMS in trained individuals. Application of WBV can function as a quick mode of warm-up before resistance training and can decrease pain perception from DOMS. This may be beneficial to athletes undergoing a heavy strength training phase where DOMS is likely. PMID- 30399119 TI - Clinical Outcomes and Complications Following Surgical Management of Traumatic Posterior Sternoclavicular Joint Dislocations: A Systematic Review. AB - BACKGROUND: Traumatic posterior sternoclavicular joint dislocations are rare orthopaedic emergencies. Treatment typically consists of closed reduction, with surgical management reserved for unstable cases. Because of the low prevalence of this condition, limited clinical evidence exists for a superior surgical stabilization technique. METHODS: A systematic review of the literature following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was performed. MEDLINE and Embase databases were searched using a comprehensive search strategy. A descriptive and critical analysis of the results was performed. RESULTS: Forty relevant studies (108 cases) were identified. Favorable subjective and objective outcomes were reported for all 5 categories of stabilization described. The overall complication rate was 16%, including 4 cases of recurrent instability. Ligament reconstruction using tendon graft had the lowest recurrent instability and complication rates, and open reduction and internal fixation techniques required a second operation for implant removal in 80% of cases. CONCLUSIONS: A comprehensive review of the surgical management of traumatic posterior sternoclavicular joint dislocations is presented. Results suggest favorable outcomes for all of the methods of stabilization, with a modest complication rate. The trends observed have helped to guide the development of clinical care recommendations that aid in treatment decision-making for these injuries. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 30399120 TI - Postoperative Gait Mechanics After Total Hip Arthroplasty: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Total hip arthroplasty is recommended by clinical practice guidelines for improving pain in patients with severe hip osteoarthritis, yet functional limitations may persist postoperatively. The effects of the surgical approach on postoperative gait biomechanics may influence these limitations after total hip arthroplasty but are currently not well established. The purpose of this study was to investigate the differences in postoperative gait biomechanical differences, at early and late follow-up, in patients with hip osteoarthritis who underwent total hip arthroplasty using different surgical approaches. METHODS: Four electronic databases were searched from their inception to December 2016. Four pairs of reviewers independently determined study eligibility, rated study quality, and extracted data. Pooled estimates for each meta-analysis were obtained using a random-effects model. Mean differences (MDs) and standardized mean differences (SMDs) were calculated for spatiotemporal, kinematic, and kinetic gait variables at early (<=3 months) and late (>=6 months) postoperative follow-up. The posterior, anterior, direct lateral, and anterolateral approaches were compared using the mean postoperative differences between approaches, standard deviations, and sample sizes. RESULTS: Nineteen studies (757 participants) were included. Individual and pooled effect sizes for the differences between approaches were inconsistent, with minimal significant differences at early or late follow-up. A significant increase in step length was observed after the posterior approach compared with the anterolateral approach at early (SMD = 0.68, p = 0.035) and late (SMD = 0.46, p = 0.032) follow-up, as well as a significant increase in hip adduction moment after the posterior approach compared with the lateral approach at early follow-up (SMD = 0.70, p = 0.020). Effect sizes ranged from small to very large, but too few studies comparing similar surgical approaches, as well as inconsistent reporting of outcome measures, limited the ability to pool data. CONCLUSIONS: These findings suggest little early or late postoperative difference in gait biomechanics between surgical approaches. Although some significant differences between surgical approaches exist, determining whether the reported postoperative gait value differences are clinically meaningful remains a substantial challenge for the interpretation of these findings. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 30399121 TI - "Chylous Ascites: Complication of laparoscopic donor nephrectomy. Case Report and review of literature." AB - BACKGROUND: Chylous ascites (CA) is an extremely rare complication after laparoscopic donor nephrectomy (LDN). It can increase the hospital stay, morbidity in postoperative period and thus negating the benefits of laparoscopic surgery. Most of the cases were managed conservatively, but surgical intervention may be occasionally required. This report describes importance of accurate localization of the leaking chyle duct and its repair by endosuturing in a renal donor not responding to conservative treatment. METHODS: A comprehensive review of literature regarding this rare complication after LDN was performed with Pubmed/Medline and Google Scholar using "chyle, complications, laparoscopic donor nephrectomy" as keywords. The demographic profile and management of patients is discussed in detail. The various surgical modalities used to manage these patients are described. RESULTS: Fifty-four cases of Chyle leak/ascites have been reported after LDN in literature till date. Around 77% donors with CA could be successfully managed conservatively with dietary measures and total parentral nutrition. Surgical intervention was required in nearly 23% donors ranging from clip application, use of argon coagulation, endosuturing with application of glue after 36.1+/-19.07 days of failed conservative treatment. Donors with massive ascites or requiring frequent large volume paracentesis on conservative treatment are likely to require surgical therapy. The present case was successfully managed with laparoscopic endosuturing and has no recurrence at 6 month follow-up. CONCLUSIONS: Chylous ascites is a rare complication after donor nephrectomy in experienced centers. While conservative management remains the first line of treatment, early surgical treatment shall be undertaken in cases of massive ascites. PMID- 30399122 TI - A Randomized Controlled Trial of Naloxone for Optimization of Hypoxemia in Lung Donors after Brain Death. AB - BACKGROUND: Persistent hypoxemia is the principal reason lungs from otherwise eligible BD organ donors are not transplanted. Experimental models and retrospective studies have suggested that naloxone attenuates neurogenic pulmonary edema and reverses hypoxemia after brain death. We undertook a multi site randomized placebo-controlled trial to evaluate whether naloxone is able to improve oxygenation in BD donors with hypoxemia. METHODS: BD organ donors at four OPOs were randomized in a blinded manner to naloxone 8-mg or saline placebo if lung were being considered for allocation but exhibited hypoxemia (PFR below 300 mm Hg). The primary outcome was change in PFR from baseline to final ABG. Secondary outcomes included early improvement in PFR and proportion of lungs transplanted. RESULTS: A total of 199 lung-eligible BD donors were randomized to naloxone (n=98) or placebo (n=101). Groups were comparable at baseline. Both groups exhibited similar improvements in oxygenation (median improvement in PFR of 81 with naloxone vs. 80 with saline, p=0.68) with 37 (39%) vs. 38 (40%) exhibiting reversal of hypoxemia. There was no difference in the rate of lungs transplanted (19% in both groups, p=0.97) although it was significantly higher in those with reversal of hypoxemia (32/69 vs. 2/111, p<0.001). CONCLUSIONS: Naloxone does not improve oxygenation more than placebo in hypoxemic organ donors. However, reversal of hypoxemia was a powerful predictor of lung utilization regardless of drug therapy. Further OPO-led research is needed to assess optimal interventions to improve oxygenation in BD donors with hypoxemia. PMID- 30399123 TI - The Continued Need for Clinical Trials in Deceased Organ Donor Management. PMID- 30399124 TI - Liver Transplantation for Nonalcoholic Steatohepatitis: New Evidence of a Profound Increase Across Age Cohorts. PMID- 30399125 TI - 23rd Nantes Actualites Transplantation: "Genomics and Immunogenetics of Kidney and Inflammatory Diseases - Lessons for Transplantation". PMID- 30399126 TI - Rapidly Growing Conjunctival Squamous Cell Carcinoma Following Corneal Transplantation in a Patient with Xeroderma Pigmentosum. PMID- 30399127 TI - Safety and efficacy of PCSK9 inhibitor treatment in heart transplant patients. PMID- 30399128 TI - Effect of case volume on mortality after pediatric liver transplantation in Korea. AB - BACKGROUND: The purpose of this study was to evaluate whether institutional case volume affects clinical outcomes after pediatric liver transplantation. METHODS: We conducted a nationwide retrospective cohort study using the database of Korean National Healthcare Insurance Service. Between January 2007 and December 2016, 521 pediatric liver transplantations were performed at 22 centers in Korea. Centers were categorized according to the average annual number of liver transplantations: >10, 1-10, and <1. RESULTS: In-hospital mortality rates in the high-, medium-, and low-volume centers were 5.8%, 12.5%, and 32.1%, respectively. After adjustment, in-hospital mortality was significantly higher in low-volume centers (adjusted odds ratio, 9.693; 95% CI, 4.636-20.268; P<0.001) and medium volume centers (adjusted odds ratio, 3.393; 95% CI, 1.980-5.813; P<0.001) compared to high-volume centers. Long-term survival for up to 9 years was better in high-volume centers. CONCLUSIONS: centers with higher case volume (>10 pediatric liver transplantations/year) had better outcomes after pediatric liver transplantation, including in-hospital mortality and long-term mortality, compared to centers with lower case volume (<=10 liver transplantations/year). PMID- 30399129 TI - The impact of frailty on acute care general surgery patients: a systematic review. AB - BACKGROUND: Frailty may predict negative health outcomes more accurately than chronological age alone. This review examines evidence for the impact of frailty on adverse outcomes in patients admitted with an acute care general surgery (ACS) diagnosis. METHODS: A systematic literature search for studies reporting frailty and outcomes after admission with an ACS diagnosis was performed. We searched PubMed and SCOPUS from inception until September 2017. RESULTS: A total of 8668 records were screened of which seven studies examined the relationship between frailty and outcomes in ACS patients. Frailty was associated with higher 30-day mortality patients (OR 3.04 95% CI 2.67-3.46 p<0.01), post-operative complications, length of stay, institutional discharge, and critical care admission. CONCLUSION: There is emerging evidence that frailty is associated with worse outcomes in patients with an unplanned admission due to an ACS diagnosis. Further investigation is warranted with regards to how frailty may impact patients with an acute illness more severely.Level of evidenceIII, systematic review. PMID- 30399130 TI - A novel treatment option in the management of traumatic haemothorax. PMID- 30399131 TI - A comparison of cholecystitis grading scales. AB - BACKGROUND: Previously, our group developed the Parkland Grading Scale for Cholecystitis (PGS) to stratify gallbladder (GB) disease severity that can be determined immediately when performing laparoscopic cholecystectomy (LC). In prior studies, PGS demonstrated excellent interrater reliability and was internally validated as an accurate measure of LC outcomes. Here, we compare PGS against a more complex cholecystitis severity score developed by the national trauma society (AAST), which requires clinical, operative, imaging, and pathologic inputs, as a predictor of LC outcomes.Eleven Acute Care Surgeons prospectively graded 179 GBs using PGS and filled out a post-operative questionnaire regarding the difficulty of the surgery. Three independent raters retrospectively graded these GBs using PGS from images stored in the electronic medical record (EMR). Three additional surgeons then assigned separate AAST scores to each GB. The Intraclass Correlation Coefficient (ICC) statistic assessed rater reliability for both PGS and AAST. The PGS score and the median AAST score became predictors in separate linear, logistic, and negative binomial regression models to estimate peri-operative outcomes. RESULTS: The average ICC of PGS and AAST was 0.8647 and 0.8341, respectively. PGS was found to be a superior predictor of increasing operative difficulty (R 0.566 vs 0.202), case length (R 0.217 vs 0.037), open conversion rates (AUC 0.904 vs 0.757), and complication rates (AUC 0.7039 vs 0.6474) defined as retained stone, small bowel obstruction, wound infection, or postoperative biliary leak. PGS performed similar to AAST in predicting partial cholecystectomy, readmission, bile leak rates, and length of stay. CONCLUSION: Both PGS and AAST are accurate predictors of LC outcomes. PGS was found to be a superior predictor of subjective operative difficulty, case length, open conversion rates, and complication rates. PGS has the advantage of being a simpler, operative based scale which can be scored at a single point in time. LEVEL OF EVIDENCE: IV. Single institution, retrospective review. PMID- 30399133 TI - Loop Ileostomy for C. difficile Infection: Important considerations. PMID- 30399132 TI - In reply Trauma pneumonectomy for major thoracic bleeding: when should we consider it? PMID- 30399134 TI - NF-kappaB mediates early blood-brain barrier disruption in a rat model of traumatic shock. AB - BACKGROUND: Blood-brain barrier (BBB) disruption is associated with a large number of central nervous system and systemic disorders. The aim of the present study was to investigate the dynamic change of BBB changes during traumatic shock and resuscitation as well as the mechanisms involved. METHODS: The experiments were carried out on male Sprague Dawley rats anaesthetized with pentobarbital sodium. To produce traumatic shock, the rats were subjected to bilateral femoral traumatic fracture and blood withdrawal from the femoral artery to decrease mean arterial pressure (MAP) to 35 mmHg. Hypovolemic status (at a MAP of 35 to 40 mm Hg)was sustained for 1 h followed by fluid resuscitation with shed blood and 20 ml/kg of lactated Ringer's solution. RESULTS: The rats were sacrificed at 1 h, 2 h or 6 h after fluid resuscitation. BBB permeability studies showed that traumatic shock significantly increased brain water contents and sodium fluorescein leakage, which was aggravated by fluid resuscitation. Real time RT PCR and westerm blot analyses revealed that Na-K-Cl cotransporter-1 (NKCC1) and VEGF expression were up-regulated in cortical brain tissue of traumatic shock rats, and this change was accompanied by down-regulation of occludin and claudin 5. Traumatic shock also significantly increased the protein levels of NF-kappaB p65 subunit. Of note, administration of NF-kappaB inhibitor PDTC effectively attenuated augmentation of the above changes. CONCLUSIONS: Our results suggest that traumatic shock is associated with early BBB disruption, and inhibition of NF-kappaB may be an effective therapeutic strategy in protecting the BBB under traumatic shock conditions. LEVEL OF EVIDENCE: This is a Basic Science paper and, therefore, does not require a level of evidence. PMID- 30399135 TI - Impact of contrast extravasation on computed tomography of the psoas major muscle in patients with blunt torso trauma. AB - BACKGROUND: The clinical significance of contrast extravasation (CE) on computed tomography (CT) of the psoas major muscle after blunt torso trauma and the optimal management of patients requiring transcatheter arterial embolization (TAE) of the lumbar artery have not been well elucidated. The aim of this study was to investigate the impact of CE on CT to determine the need for TAE of the lumbar artery. METHODS: We examined a single-center retrospective cohort of blunt torso trauma patients who underwent contrast-enhanced CT from 2008 through 2017. Basic demographics and clinical data were obtained, including the number of lumbar transverse process fractures (LTPFs) and maximum psoas major muscle hematoma (PMMH) size and ratio. Maximum PMMH size was analyzed by measuring the cross-sectional area of hematoma size at the level of CE. PMMH size ratio was obtained by dividing maximum PMMH size by psoas major muscle size of the unaffected side at the same slice level. RESULTS: A total of 762 patients were included. One hundred seventeen patients had LTPFs and/or PMMH. Of 117 patients, 25 had CE on CT of the psoas major muscle and had significantly higher rates of older age and severe injury compared to those without CE. Of the 25 patients with CE, 13 required TAE of the lumbar artery. Patients who required TAE had a significantly higher number of LTPFs (4 vs. 2, P=0.011) and higher PMMH size ratio (2.10 vs. 1.32, P=0.016). PMMH size ratio revealed moderate accuracy (AUROC=0.782). CONCLUSIONS: Approximately half of the blunt torso trauma patients with CE on CT of the psoas major muscle will require TAE of the lumbar artery. Higher number of LTPFs and larger PMMH size can be a predictor of the need for TAE of the lumbar artery among patients with CE on CT. LEVEL OF EVIDENCE: Level IV, study type: Therapeutic / Care management. PMID- 30399136 TI - Outcomes for Popliteal Artery Injury Repair after Discharge: A Large-scale Population-based Analysis. AB - BACKGROUND: Although short-term outcomes for popliteal artery injury after endovascular versus open repair appear similar, studies on outcomes after discharge are limited. We evaluated popliteal artery injury repair in a population-based dataset. We hypothesized that post-discharge outcomes for open repair are superior to endovascular repair. METHODS: Patients with popliteal artery injury were identified in the California Office of Statewide Health Planning and Development 2007-2014 discharge database. Popliteal artery injury and other lower-extremity injuries were identified using ICD-9-CM diagnosis codes. Procedure codes were evaluated to identify open repair, endovascular repair, fasciotomy, and amputation. Primary outcomes were mortality or amputation. The association between repair method and each outcome was evaluated with logistic regression. Post-discharge amputation and all-cause mortality were evaluated using survival analysis. RESULTS: Among 769 patients with popliteal artery injury, open repair occurred in 456 (59.3%), endovascular repair in 37 (4.3%), combined endovascular and open in 18 (2.3%), and non-operative management in 258 (33.6%). Fasciotomy was performed more frequently in open than endovascular repair (p=0.001) during index admission. Amputation rate was also increased in open repair but this was not significant (p=0.196). Arterial thromboembolus during index admission was more likely after endovascular or combined endovascular and open compared with open (24.3%, 55.6%, 16.7%, respectively, p<0.001). Patients requiring both endovascular and open were more likely to undergo amputation post-discharge (Hazard Ratio [HR]: 4.11, 95% confidence interval [CI] 1.16-14.53). Patients undergoing endovascular repair were more likely to die post-discharge (HR: 4.43, 95%CI 1.06-18.56) compared with patients who had open repair (median 98.5 days post-discharge). CONCLUSIONS: In a large cohort with popliteal artery injury, open repair was associated with lower rates of index admission arterial thromboembolus as well as post-discharge amputation and all-cause mortality. We recommend conducting a prospective multicenter study to examine the appropriate use of endovascular repair for this injury. LEVEL OF EVIDENCE: Level III. Prognostic and Epidemiological. PMID- 30399137 TI - The current status of clinical trials in emergency gastrointestinal surgery. A systematic analysis of contemporary clinical trials. AB - BACKGROUND: Emergency gastrointestinal surgery (EGS) conditions represent a significant healthcare burden globally requiring emergency operations that are associated with mortality rates as high as 80%. EGS is currently focussed on quality improvement and internal audits, which occurs at a national or local level. An appreciation of what EGS trials are being conducted is important to reduce research wastage and develop coordinated research strategies in surgery. The primary aim of this study was to identify and quantify recent and active trials in emergency gastrointestinal surgery. The secondary aim was to identify conditions of interest, and which aspects of care were being modified. METHODS: A systematic search of WHO, UK, US, Australian and Canadian trials databases was undertaken using broad terms to identify studies addressing emergency abdominal surgery and specific high-risk diagnoses. Studies registered between 2013-2018 were eligible for inclusion. Data on study topic, design, and funding body were collected. Interventions were classified into 'peri-operative', 'procedural', 'post-operative', 'non-surgical' and 'other' categories. RESULTS: Searches identified 5603 registered trials. After removal of duplicates, 4492 studies remained and 42 were eligible for inclusion. Almost 50% of trials were located in Europe and 17% (n=7) in the USA. The most common condition addressed was acute appendicitis (n=11), with the most common intervention being procedure based (n=23). Hospital based funding was the most common funder (n=30). CONCLUSION: There is large disparity in the number of surgical trials in emergency surgery, which are primarily focussed on high-volume conditions. More research is needed into high-mortality conditions. EVIDENCE LEVEL: 1a (oxford). PMID- 30399138 TI - Impact of ACA-related Insurance Expansion Policies on Mortality and Access to Post-Discharge Care for Trauma Patients: An Analysis of the National Trauma Data Bank. AB - BACKGROUND: Uninsured trauma patients have worse outcomes and worse access to post-discharge care that is critically important for recovery after injury. Little is known regarding the impact of the insurance coverage expansion policies of the Affordable Care Act (ACA), most notably state-level Medicaid expansion, on trauma patients. In this study, we examine the national impact of these policies on payer-mix, inpatient mortality, and access to post-acute care for trauma patients. METHODS: We used the 2011-2016 National Trauma Data Bank to evaluate for changes in insurance coverage among 18-64 year-old trauma patients. Our pre /post-expansion models defined 2011-2013 as the pre-policy period, 2015-2016 as the post-policy period, and 2014 as a washout year. To evaluate for policy associated changes in inpatient mortality and discharge disposition among the policy-eligible sample, we leveraged multivariable linear regression techniques to adjust for year-to-year variation in patient demographics, injury characteristics, and facility traits. We then examined the relationship between the magnitude of facility-level reductions in uninsured patients and access to post-acute care following policy implementation. RESULTS: We identified 1,656,469 patients meeting inclusion criteria between 2011-2016. The pre-policy uninsured rate of 23.4% fell by 5.9 percentage-points after coverage expansion (p<0.001), with a corresponding 7.5 percentage-point increase in Medicaid coverage (p<0.001). Following policy implementation, there were no significant changes in inpatient mortality. However, there was a >30% relative increase in discharge to a post-acute care facility and a similar increase in discharge with home health services (p<0.001 for both). The greatest gains in access to post-acute services were seen among facilities with the greatest reductions in their uninsured rate (p=0.003). CONCLUSION: ACA-related coverage expansion policies, most notably Medicaid expansion, were associated with a >25% reduction in the uninsured rate among nonelderly adult trauma patients. Although no immediate impact on inpatient mortality was seen, insurance coverage expansion was associated with a higher proportion of patients receiving critically important post-discharge care. LEVEL OF EVIDENCE: Level III, Epidemiological. PMID- 30399139 TI - Isoform 6-selective Histone Deacetylase Inhibition Reduces Lesion Size and Brain Swelling Following Traumatic Brain Injury and Hemorrhagic Shock. AB - BACKGROUND: Non-selective histone deacetylase (pan-HDAC) inhibitors, such as valproic acid (VPA), have demonstrated neuroprotective properties in trauma models. However, isoform-specific HDAC inhibitors may provide opportunity for more effective drug administration with lesser side effects. We investigated HDAC6 inhibition with ACY-1083 in an in vitro and an in vivo large animal model of injury. METHODS: Mouse hippocampal cells were subjected to oxygen-glucose deprivation (0% O2, glucose-free, serum-free medium, 18 hours) and reoxygenation (21% O2, normal culture media, 4 hours) +/- VPA (4mM) or ACY1083 (30nM, 300nM). Cell viability was measured by methylthiazolyl tetrazolium (MTT) assay. Expression of hypoxia-inducible factor-1alpha (HIF1alpha), heat shock protein 70 (HSP70), and effectors in the phosphoinositide-3 kinase (PI3K)/mTOR pathway were measured by Western Blot analysis. Additionally, swine were subjected to combined TBI and HS and randomized to three treatment groups (n=5/group): (i) normal saline (NS; 3x hemorrhage volume); (ii) NS + VPA (NS; 3x hemorrhage volume, VPA; 150 mg/kg), and (iii) NS + ACY-1083 (NS; 3x hemorrhage volume, ACY-1083; 30 mg/kg). After 6 hours, brain tissue was harvested to assess lesion size and brain swelling. RESULTS: Significant improvement in cell viability was seen with both HDAC inhibitors in the in vitro study. ACY-1083 suppressed HIF1alpha expression and upregulated phosphorylated mTOR and HSP70 in a dose-dependent manner. Lesion size and brain swelling in animals treated with pharmacologic agents (VPA and ACY 1083) were both smaller than in the NS group. No differences were observed between the VPA and ACY-1083 treatment groups. CONCLUSIONS: In conclusion, selective inhibition of HDAC6 is as neuroprotective as non-selective HDAC inhibition in large animal models of TBI and hemorrhagic shock. LEVEL OF EVIDENCE: not applicable (preclinical study). PMID- 30399140 TI - Clinical Evaluation of a Polish Translation and Cross-Cultural Adaptation of the Nasal Obstruction Symptom Evaluation (NOSE) Scale. AB - BACKGROUND Nasal obstruction is the most common rhinologic complaint in ear, nose, and throat (ENT) clinical practice and septal deviation is the leading cause. The Nasal Obstruction Symptom Evaluation (NOSE) scale is a brief, self administered questionnaire that has been widely used to assess symptoms and quality of life related to nasal obstruction, and is commonly used in clinical outcome studies. The aim of this study was to undertake a clinical evaluation of a Polish translation and cross-cultural modification of the NOSE scale for nasal obstruction. MATERIAL AND METHODS A controlled clinical validation study was conducted in a tertiary referral center. The Polish version of the NOSE scale was developed according to cross-cultural adaptation guidelines. The psychometric properties of the Polish version of the NOSE scale (internal consistency, reproducibility, validity, responsiveness, interpretability) were assessed in 51 patients with nasal obstruction and 51 controls matched according to gender and age. RESULTS Internal consistency of the Polish version of the NOSE scale was 0.80 as assessed by Cronbach's alpha, and an intraclass correlation of the reproducibility was 0.98. Construct inter-item and item-total correlations confirmed validity. Correlation confirmed appropriate criterion validity with a visual analog scale (VAS) and discriminant validity was confirmed between patients and controls. Responsiveness and interpretability were also confirmed. CONCLUSIONS The Polish version of the NOSE scale is a brief and reproducible clinical evaluation tool for use in clinical practice in Polish-speaking patients with nasal obstruction. PMID- 30399142 TI - Rodent control to fight Lassa fever: Evaluation and lessons learned from a 4-year study in Upper Guinea. AB - Lassa fever is a viral haemorrhagic fever caused by an arenavirus. The disease is endemic in West African countries, including Guinea. The rodents Mastomys natalensis and Mastomys erythroleucus have been identified as Lassa virus reservoirs in Guinea. In the absence of a vaccine, rodent control and human behavioural changes are the only options to prevent Lassa fever in highly endemic areas. We performed a 4 year intervention based on chemical rodent control, utilizing anticoagulant rodenticides in 3 villages and evaluating the rodent abundance before and after treatment. Three additional villages were investigated as controls. Analyses to assess the effectiveness of the intervention, bait consumption and rodent dynamics were performed. Anthropological investigations accompanied the intervention to integrate local understandings of human-rodent cohabitation and rodent control intervention. Patterns of bait consumption showed a peak at days 5-7 and no consumption at days 28-30. There was no difference between Bromadiolone and Difenacoum bait consumption. The main rodent species found in the houses was M. natalensis. The abundance of M. natalensis, as measured by the trapping success, varied between 3.6 and 16.7% before treatment and decreased significantly to 1-2% after treatment. Individuals in treated villages welcomed the intervention and trapping because mice are generally regarded as a nuisance. Immediate benefits from controlling rodents included protection of food and belongings. Before the intervention, local awareness of Lassa fever was non-existent. Despite their appreciation for the intervention, local individuals noted its limits and the need for complementary actions. Our results demonstrate that chemical treatment provides an effective tool to control local rodent populations and can serve as part of an effective, holistic approach combining rodent trapping, use of local rodenticides, environmental hygiene, house repairs and rodent-proof storage. These actions should be developed in collaboration with local stakeholders and communities. PMID- 30399143 TI - A decade of vector control activities: Progress and limitations of Chagas disease prevention in a region of Guatemala with persistent Triatoma dimidiata infestation. AB - INTRODUCTION: Chagas disease, a neglected tropical disease that affects millions of Latin Americans, has been effectively controlled in Guatemala after multiple rounds of indoor residual insecticide spraying (IRS). However, a few foci remain with persistent Triatoma dimidiata infestation. One such area is the municipality of Comapa, Department of Jutiapa, in the southeastern region of Guatemala, where control interventions appear less effective. We carried out three cross sectional entomological and serological surveys in Comapa to evaluate a decade of vector control activities. Baseline serological (1999) and entomological (2001-2) surveys were followed by three rounds of insecticide applications (2003-2005) and intermittent focal spraying of infested houses, until approximately 2012. Household inspections to determine entomological indices and construction materials were conducted in 2001, 2007 and 2011. Seroprevalence surveys were conducted in school-age children in 1999, 2007 and 2015, and in women of child bearing age (15-44 years) only in 2015. After multiple rounds of indoor residual sprayings (IRS), the infestation index decreased significantly from 39% (2001-2) to 27% (2011). Household construction materials alone predicted <10% of infested houses. Chagas seroprevalence in Comapa declined in school-aged children by 10 fold, from 10% (1999) to 1% (2015). However, seroprevalence in women of child bearing age remains >10%. CONCLUSION: After a decade of vector control activities in Comapa, there is evidence of significantly reduced transmission. However, the continued risk for vector-borne and congenital transmission pose a threat to the 2022 Chagas disease elimination goal. Systematic integrated vector control and improved Chagas disease screening and treatment programs for congenital and vector-borne disease are needed to reach the elimination goal in regions with persistent vector infestation. PMID- 30399144 TI - Keratoconus severity identification using unsupervised machine learning. AB - We developed an unsupervised machine learning algorithm and applied it to big corneal parameters to identify and monitor keratoconus stages. A big dataset of corneal swept source optical coherence tomography (OCT) images of 12,242 eyes acquired from SS-1000 CASIA OCT Imaging Systems in multiple centers across Japan was assembled. A total of 3,156 eyes with valid Ectasia Status Index (ESI) between zero and 100% were selected for the downstream analysis. Four hundred and twenty corneal topography, elevation, and pachymetry parameters (excluding ESI Keratoconus indices) were selected. The algorithm included three major steps. 1) Principal component analysis (PCA) was used to linearly reduce the dimensionality of the input data from 420 to eight significant principal components. 2) Manifold learning was used to further reducing the selected principal components nonlinearly to two eigen-parameters. 3) Finally, a density-based clustering was applied to the eigen-parameters to identify eyes with keratoconus. Visualization of clusters in 2-D space was used to validate the quality of learning subjectively and ESI was used to assess the accuracy of the identified clusters objectively. The proposed method identified four clusters; I: a cluster composed of mostly normal eyes (224 eyes with ESI equal to zero, 23 eyes with ESI between five and 29, and nine eyes with ESI greater than 29), II: a cluster composed of mostly healthy eyes and eyes with forme fruste keratoconus (1772 eyes with ESI equal to zero, 698 eyes with ESI between five and 29, and 117 eyes with ESI greater than 29), III: a cluster composed of mostly eyes with mild keratoconus stage (184 eyes with ESI greater than 29, 74 eyes with ESI between five and 29, and 6 eyes with ESI equal to zero), and IV: a cluster composed of eyes with mostly advanced keratoconus stage (80 eyes had ESI greater than 29 and 1 eye had ESI between five and 29). We found that keratoconus status and severity can be well identified using unsupervised machine learning algorithms along with linear and non-linear corneal data transformation. The proposed method can better identify and visualize the keratoconus stages. PMID- 30399146 TI - Correlations of left ventricular systolic function indices with aortic root systolic excursion (ARSE): A cross-sectional echocardiographic study. AB - BACKGROUND: Heart failure (HF), is a major public health issue globally. Echocardiography is cost-effective in the diagnosis in expert hands. This study was conducted to estimate the usefulness of Aortic Root Systolic Excursion (ARSE) as a simple and accurate measure to estimate Left Ventricular (LV) function. METHODS: This was a cross-sectional echocardiographic study among adults aged >= 18 years, with or without heart failure, in sinus rhythm, and with no LV out-let obstruction. We studied the correlations of ARSE with some selected indices of LV Systolic Functions. We determined optimal cut-offs of ARSE in detecting LV dysfunction. We generated a simple regression equation to best estimate LV ejection fraction according to the modified Simpson method. RESULTS: Overall 213 echocardiograms were included from 106 males (49.8%), with mean age of the participants being 52.4 (SD: 18.3) years. The rate of LV systolic dysfunction was highest with Teicholz method (17.4%) and lowest with MAPSE method (5.2%). ARSE correlated with the LV functions. This was highest for the Simpson method (r = 0.619, p<0.001), and lowest for the ITV method (r = 0.319, p<0.001). Optimal cut offs to detect LV systolic dysfunction was ~ 6.6 mm. For an LV ejection fraction < 55%, the sensitivity was 82.9%, and the specificity was 97.2%, with an AUROC of 91.6%.The logarithmic regression equation was best in predicting LV ejection fraction (AUC: 60.2%), followed by the power model (AUC: 56.7%), and the linear model (AUC: 53.6%). CONCLUSION: ARSE correlated well with LV systolic function. The cut-off <= 6.5 mm suggest LV systolic dysfunction. LV Ejection Fraction was best estimated with the generic equation: LVEF (%) = 29 x In [ARSE]. PMID- 30399148 TI - Relationship between the rate of change in lamina cribrosa depth and the rate of retinal nerve fiber layer thinning following glaucoma surgery. AB - PURPOSE: To assess whether lamina cribrosa depth (LCD) reduction and the rate of change in LCD over time (DeltaLCD/Deltat) is associated with retinal nerve fiber layer (RNFL) thickness and the rate of RNFL thinning over time (DeltaRNFL/Deltat) to test the hypothesis that, in a long term, RNFL thinning occurs irrespectively to the displacement of the lamina cribrosa following glaucoma surgery. METHODS: Twenty-nine primary open-angle glaucoma patients underwent glaucoma surgery. Sixteen patients underwent trabeculectomy and 13 patients undertook non penetrating deep sclerectomy. Images of optic nerve head using spectral-domain optical coherence tomography (SD-OCT) with enhanced depth imaging technology were obtained preoperatively, at one-, three-, six-month and follow-up postoperative visit from 12 to 29 months after surgery (1pv, 3pv, 6pv, and FUpv, respectively). Correspondingly, measurements of the circumpapillary RNFL thickness were acquired. RESULTS: Intraocular pressure decreased from 24.0+/-8.9 to 10.9+/ 3.9mmHg at 6pv (P<0.001) and to 12.7+/-4.4mmHg at FUpv (P<0.001). LCD was reduced from 465.3+/-136.4MUm to 402.9+/-126.4MUm at 1pv (P<0.001) and maintained similar position at 6pv (394.3+/-118.4MUm; P = 0.170 with respect to 1pv). A significant decrease in the LCD was noted at FUpv (342.8+/-90.3MUm, P<0.001) with respect to 6pv. RNFL thickness increased significantly to 64.9+/-19.8MUm at 1pv (P = 0.005) and subsequently decreased to baseline level at 3pv. Further statistically significant decrease in RNFL thickness with respect to previous visit was found at 6pv and at FUpv (56.4+/-15.6MUm and 55.0+/-14.0MUm, P = 0.023 and P = 0.045, respectively). A thinner RNFL thickness at FUpv was not related to the LCD at FUpv (P = 0.129) but was correlated with DeltaLCD/Deltat at FUpv (P = 0.003). The DeltaRNFL/Deltat at FUpv was statistically significantly correlated with DeltaLCD/Deltat at FUpv (P<0.001). CONCLUSIONS: This is the first study that considers direct correlation between the rate of change in LCD with the rate of RNFL thinning over time. A thinner RNFL thickness following glaucoma surgery was associated with the rate of LCD reduction, not with position of the lamina cribrosa at the FUpv. PMID- 30399141 TI - Genotype to phenotype: Diet-by-mitochondrial DNA haplotype interactions drive metabolic flexibility and organismal fitness. AB - Diet may be modified seasonally or by biogeographic, demographic or cultural shifts. It can differentially influence mitochondrial bioenergetics, retrograde signalling to the nuclear genome, and anterograde signalling to mitochondria. All these interactions have the potential to alter the frequencies of mtDNA haplotypes (mitotypes) in nature and may impact human health. In a model laboratory system, we fed four diets varying in Protein: Carbohydrate (P:C) ratio (1:2, 1:4, 1:8 and 1:16 P:C) to four homoplasmic Drosophila melanogaster mitotypes (nuclear genome standardised) and assayed their frequency in population cages. When fed a high protein 1:2 P:C diet, the frequency of flies harbouring Alstonville mtDNA increased. In contrast, when fed the high carbohydrate 1:16 P:C food the incidence of flies harbouring Dahomey mtDNA increased. This result, driven by differences in larval development, was generalisable to the replacement of the laboratory diet with fruits having high and low P:C ratios, perturbation of the nuclear genome and changes to the microbiome. Structural modelling and cellular assays suggested a V161L mutation in the ND4 subunit of complex I of Dahomey mtDNA was mildly deleterious, reduced mitochondrial functions, increased oxidative stress and resulted in an increase in larval development time on the 1:2 P:C diet. The 1:16 P:C diet triggered a cascade of changes in both mitotypes. In Dahomey larvae, increased feeding fuelled increased beta-oxidation and the partial bypass of the complex I mutation. Conversely, Alstonville larvae upregulated genes involved with oxidative phosphorylation, increased glycogen metabolism and they were more physically active. We hypothesise that the increased physical activity diverted energy from growth and cell division and thereby slowed development. These data further question the use of mtDNA as an assumed neutral marker in evolutionary and population genetic studies. Moreover, if humans respond similarly, we posit that individuals with specific mtDNA variations may differentially metabolise carbohydrates, which has implications for a variety of diseases including cardiovascular disease, obesity, and perhaps Parkinson's Disease. PMID- 30399149 TI - Machine learning in medicine: Addressing ethical challenges. AB - Effy Vayena and colleagues argue that machine learning in medicine must offer data protection, algorithmic transparency, and accountability to earn the trust of patients and clinicians. PMID- 30399147 TI - Modulation of voltage-dependent K+ conductances in photoreceptors trades off investment in contrast gain for bandwidth. AB - Modulation is essential for adjusting neurons to prevailing conditions and differing demands. Yet understanding how modulators adjust neuronal properties to alter information processing remains unclear, as is the impact of neuromodulation on energy consumption. Here we combine two computational models, one Hodgkin Huxley type and the other analytic, to investigate the effects of neuromodulation upon Drosophila melanogaster photoreceptors. Voltage-dependent K+ conductances in these photoreceptors: (i) activate upon depolarisation to reduce membrane resistance and adjust bandwidth to functional requirements; (ii) produce negative feedback to increase bandwidth in an energy efficient way; (iii) produce shunt peaking thereby increasing the membrane gain bandwidth product; and (iv) inactivate to amplify low frequencies. Through their effects on the voltage dependent K+ conductances, three modulators, serotonin, calmodulin and PIP2, trade-off contrast gain against membrane bandwidth. Serotonin shifts the photoreceptor performance towards higher contrast gains and lower membrane bandwidths, whereas PIP2 and calmodulin shift performance towards lower contrast gains and higher membrane bandwidths. These neuromodulators have little effect upon the overall energy consumed by photoreceptors, instead they redistribute the energy invested in gain versus bandwidth. This demonstrates how modulators can shift neuronal information processing within the limitations of biophysics and energy consumption. PMID- 30399145 TI - Functional equivalence of germ plasm organizers. AB - The proteins Oskar (Osk) in Drosophila and Bucky ball (Buc) in zebrafish act as germ plasm organizers. Both proteins recapitulate germ plasm activities but seem to be unique to their animal groups. Here, we discover that Osk and Buc show similar activities during germ cell specification. Drosophila Osk induces additional PGCs in zebrafish. Surprisingly, Osk and Buc do not show homologous protein motifs that would explain their related function. Nonetheless, we detect that both proteins contain stretches of intrinsically disordered regions (IDRs), which seem to be involved in protein aggregation. IDRs are known to rapidly change their sequence during evolution, which might obscure biochemical interaction motifs. Indeed, we show that Buc binds to the known Oskar interactors Vasa protein and nanos mRNA indicating conserved biochemical activities. These data provide a molecular framework for two proteins with unrelated sequence but with equivalent function to assemble a conserved core-complex nucleating germ plasm. PMID- 30399150 TI - Prediction of myopia development among Chinese school-aged children using refraction data from electronic medical records: A retrospective, multicentre machine learning study. AB - BACKGROUND: Electronic medical records provide large-scale real-world clinical data for use in developing clinical decision systems. However, sophisticated methodology and analytical skills are required to handle the large-scale datasets necessary for the optimisation of prediction accuracy. Myopia is a common cause of vision loss. Current approaches to control myopia progression are effective but have significant side effects. Therefore, identifying those at greatest risk who should undergo targeted therapy is of great clinical importance. The objective of this study was to apply big data and machine learning technology to develop an algorithm that can predict the onset of high myopia, at specific future time points, among Chinese school-aged children. METHODS AND FINDINGS: Real-world clinical refraction data were derived from electronic medical record systems in 8 ophthalmic centres from January 1, 2005, to December 30, 2015. The variables of age, spherical equivalent (SE), and annual progression rate were used to develop an algorithm to predict SE and onset of high myopia (SE <= -6.0 dioptres) up to 10 years in the future. Random forest machine learning was used for algorithm training and validation. Electronic medical records from the Zhongshan Ophthalmic Centre (a major tertiary ophthalmic centre in China) were used as the training set. Ten-fold cross-validation and out-of-bag (OOB) methods were applied for internal validation. The remaining 7 independent datasets were used for external validation. Two population-based datasets, which had no participant overlap with the ophthalmic-centre-based datasets, were used for multi-resource validation testing. The main outcomes and measures were the area under the curve (AUC) values for predicting the onset of high myopia over 10 years and the presence of high myopia at 18 years of age. In total, 687,063 multiple visit records (>=3 records) of 129,242 individuals in the ophthalmic centre-based electronic medical record databases and 17,113 follow-up records of 3,215 participants in population-based cohorts were included in the analysis. Our algorithm accurately predicted the presence of high myopia in internal validation (the AUC ranged from 0.903 to 0.986 for 3 years, 0.875 to 0.901 for 5 years, and 0.852 to 0.888 for 8 years), external validation (the AUC ranged from 0.874 to 0.976 for 3 years, 0.847 to 0.921 for 5 years, and 0.802 to 0.886 for 8 years), and multi-resource testing (the AUC ranged from 0.752 to 0.869 for 4 years). With respect to the prediction of high myopia development by 18 years of age, as a surrogate of high myopia in adulthood, the algorithm provided clinically acceptable accuracy over 3 years (the AUC ranged from 0.940 to 0.985), 5 years (the AUC ranged from 0.856 to 0.901), and even 8 years (the AUC ranged from 0.801 to 0.837). Meanwhile, our algorithm achieved clinically acceptable prediction of the actual refraction values at future time points, which is supported by the regressive performance and calibration curves. Although the algorithm achieved balanced and robust performance, concerns about the compromised quality of real world clinical data and over-fitting issues should be cautiously considered. CONCLUSIONS: To our knowledge, this study, for the first time, used large-scale data collected from electronic health records to demonstrate the contribution of big data and machine learning approaches to improved prediction of myopia prognosis in Chinese school-aged children. This work provides evidence for transforming clinical practice, health policy-making, and precise individualised interventions regarding the practical control of school-aged myopia. PMID- 30399151 TI - Ambient fine particulate pollution and daily morbidity of stroke in Chengdu, China. AB - INTRODUCTION: Association has been reported between ambient fine particulate matter (PM) and adverse outcomes of cerebrovascular events. However, it remains unclear that whether short-term exposure to PM relates to stroke and the lag of health effects. This triggers us to examine the relationship between PM and population stroke morbidity in Chengdu. METHODS: The daily average concentration of atmospheric pollutants and meteorological factors and daily morbidity of stroke in Chengdu (2013-2015) were collected. Based on time series analysis generalized additive models (GAM), single-pollutant, two-pollutant and multi pollutant model were established. The effects of atmospheric PM2.5 (defined as PM less than 2.5MUm in aerodynamic diameter), PMc(defined as PM less than 10MUm and more than 2.5MUm in aerodynamic diameter) and PM10 (defined as PM less than 10MUm in aerodynamic diameter) concentration on the daily mortality of stroke were analyzed, respectively. RESULTS: The three-year mean concentrations of PM2.5, PMc and PM10 for air pollutants were 75.9, 43.9 and 119.7 MUg/m3, respectively. PM2.5 on the current day (lag0) and with a moving average of 0-1 days were significantly associated with the increasing risk of stroke morbidity, and PM2.5 with a lag of 0-1 days had greater association, whereas for PMc and PM10 there were no significant association observed. In our study, every 10MUg/m3 increase of PM2.5 was associated with 0.69% percent change in stroke morbidity (95%CI: 0.01~1.38). For females, every 10MUg/m3 increase of PM2.5 contributes to 0.80% percent change of onset. And for the group of age less than 65, we observed 0.78% higher risk every 10MUg/m3 increase of PM2.5. CONCLUSIONS: These findings suggest that short-term exposure to PM2.5 within 1 day is associated with the onset of stroke, and the younger people (age<65) and females are more sensitive than older people and males. PMID- 30399152 TI - Health-motivated taxes on red and processed meat: A modelling study on optimal tax levels and associated health impacts. AB - BACKGROUND: The consumption of red and processed meat has been associated with increased mortality from chronic diseases, and as a result, it has been classified by the World Health Organization as carcinogenic (processed meat) and probably carcinogenic (red meat) to humans. One policy response is to regulate red and processed meat consumption similar to other carcinogens and foods of public health concerns. Here we describe a market-based approach of taxing red and processed meat according to its health impacts. METHODS: We calculated economically optimal tax levels for 149 world regions that would account for (internalize) the health costs associated with ill-health from red and processed meat consumption, and we used a coupled modelling framework to estimate the impacts of optimal taxation on consumption, health costs, and non-communicable disease mortality. Health impacts were estimated using a global comparative risk assessment framework, and economic responses were estimated using international data on health costs, prices, and price elasticities. FINDINGS: The health related costs to society attributable to red and processed meat consumption in 2020 amounted to USD 285 billion (sensitivity intervals based on epidemiological uncertainty (SI), 93-431), three quarters of which were due to processed meat consumption. Under optimal taxation, prices for processed meat increased by 25% on average, ranging from 1% in low-income countries to over 100% in high-income countries, and prices for red meat increased by 4%, ranging from 0.2% to over 20%. Consumption of processed meat decreased by 16% on average, ranging from 1% to 25%, whilst red meat consumption remained stable as substitution for processed meat compensated price-related reductions. The number of deaths attributable to red and processed meat consumption decreased by 9% (222,000; SI, 38,000-357,000), and attributable health costs decreased by 14% (USD 41 billion; SI, 10-57) globally, in each case with greatest reductions in high and middle-income countries. INTERPRETATION: Including the social health cost of red and processed meat consumption in the price of red and processed meat could lead to significant health and environmental benefits, in particular in high and middle-income countries. The optimal tax levels estimated in this study are context-specific and can complement the simple rules of thumb currently used for setting health motivated tax levels. PMID- 30399154 TI - Genotype-ocular biometry correlation analysis of eight primary angle closure glaucoma susceptibility loci in a cohort from Northern China. AB - PURPOSE: Recent genome-wide association studies (GWAS) have verified eight genetic loci that were significantly associated with primary angle-closure glaucoma (PACG). The present study investigated whether these variants are associated with the ocular biometric parameters of anterior chamber depth (ACD) and axial length (AL) in a northern Chinese population, as well as whether there were differences in the association of genetic markers in our cohort based on ethnicity. METHODS: A case-control association study of 500 patients and 720 controls was undertaken. All individuals were genotyped for eight single nucleotide polymorphisms (SNPs) (rs11024102 in PLEKHA7, rs3753841 in COL11A1, rs1015213 located between PCMTD1 and ST18, rs3816415 in EPDR1, rs1258267 in CHAT, rs736893 in GLIS3, rs7494379 in FERMT2, and rs3739821 mapping between DPM2 and FAM102A) using an improved multiplex ligation detection reaction (iMLDR) technique. Allelic and genotypic frequency differences were evaluated using a logistic regression model. Generalized estimation equation (GEE) analysis was conducted for association testing between genotypes and ocular biometric parameters. False discovery rate (FDR) correction for multiple comparisons was employed, and the statistical power was calculated via power and sample size calculation. RESULTS: Four of the eight SNPs, rs3753841, rs1258267, rs736893 and rs7494379, were associated with PACG (p = 0.007, 0.0016, 0.0045, 0.045, respectively), and only rs3753841, rs1258267 and rs736893 surpassed the FDR correction. For subgroup analysis, only rs1258267 could withstand multiple testing correction in the Han nationality (p = 0.00571). In the GEE tests, rs3753841, rs1258267 and rs736893 were found to be nominally associated with ACD (p = 0.023, 0.016, 0.01, respectively). However, these associations could not survive FDR correction. CONCLUSIONS: The SNP rs3753841 in COL11A1, rs1258267 in CHAT and rs736893 in GLIS3 are associated with PACG in northern Chinese people, and the association of genetic markers manifests a tendency of ethnic diversity. Larger population-based studies are warranted to reveal additional PACG loci and ethnic aspects of PACG. PMID- 30399155 TI - Harmonic voltage measurement error of the capacitor voltage transformer. AB - This paper explores the mechanism for the harmonic voltage measurement error (HVME) of a capacitor voltage transformer (CVT) in a comprehensive way and develops a practical error correction method to improve the harmonic measurement performance of a CVT. The harmonic equivalent circuit (HEC) of CVTs with different types of dampers are established and the parameter value calculation methods of the circuit elements are presented. Characteristics of the individual inherent resonance mode of the HEC, including the resonant frequency, the resonant type and the circuit elements involved, are analyzed systematically. Centered on resonance mode formulation, an universal error correction method for CVTs in measuring harmonic voltage is proposed based on the piecewise fitting of the transformation ratio. A physical experimental platform available for low voltage CVTs is developed in laboratory, which utilizes a 10-kV harmonic generator and a step-up transformer to provide harmonic signals with high voltage level. Moreover, a novel experimental scheme for testing the HVME of high-voltage CVTs is proposed based on alternating current/direct current (AC/DC) filters. Experiments are conducted on these experimental platforms to test the HVME of a 35-kV CVT in laboratory and a 525-kV CVT in a back-to-back DC converter station. The experimental results verify the validity of the built HECs of CVTs, the resonant mode analysis results and the resonant frequency calculation method. Finally, the effectiveness of the proposed harmonic error correction method is proved by several examples. PMID- 30399153 TI - The impact of self-distancing on emotion explosiveness and accumulation: An fMRI study. AB - Emotions unfold over time with episodes differing in explosiveness (i.e., profiles having a steep vs. a gentle start) and accumulation (i.e., profiles increasing over time vs. going back to baseline). In the present fMRI study, we wanted to replicate and extend previous findings on the psychological and neural mechanisms underlying emotion explosiveness and accumulation. Specifically, we aimed to: (a) replicate the finding that different neural mechanisms are associated with emotion explosiveness and accumulation, (b) replicate the finding that adopting a self-distanced (vs. self-immersed) perspective decreases emotion explosiveness and accumulation at the level of self-report, and (c) examine whether adopting a self-distanced (vs. self-immersed) perspective similarly modulates activity in the brain regions associated with emotion explosiveness and accumulation. Participants in an fMRI scanner were asked to adopt a self-immersed or self-distanced perspective while reading and thinking about negative social feedback, and to report on felt changes in negative affect during that period using an emotion intensity profile tracking approach. We replicated previous findings showing that emotion explosiveness and accumulation were related to activity in regions involved in self-referential processing (such as the medial prefrontal cortex) and sustained visceral arousal (such as the posterior insula), respectively. The finding that adopting a self-distanced (vs. self-immersed) perspective lowers emotion explosiveness and accumulation was also replicated at a self-report level. However, perspective taking did not impact activity in the neural correlates of emotion explosiveness and accumulation. PMID- 30399157 TI - Variable generalization performance of a deep learning model to detect pneumonia in chest radiographs: A cross-sectional study. AB - BACKGROUND: There is interest in using convolutional neural networks (CNNs) to analyze medical imaging to provide computer-aided diagnosis (CAD). Recent work has suggested that image classification CNNs may not generalize to new data as well as previously believed. We assessed how well CNNs generalized across three hospital systems for a simulated pneumonia screening task. METHODS AND FINDINGS: A cross-sectional design with multiple model training cohorts was used to evaluate model generalizability to external sites using split-sample validation. A total of 158,323 chest radiographs were drawn from three institutions: National Institutes of Health Clinical Center (NIH; 112,120 from 30,805 patients), Mount Sinai Hospital (MSH; 42,396 from 12,904 patients), and Indiana University Network for Patient Care (IU; 3,807 from 3,683 patients). These patient populations had an age mean (SD) of 46.9 years (16.6), 63.2 years (16.5), and 49.6 years (17) with a female percentage of 43.5%, 44.8%, and 57.3%, respectively. We assessed individual models using the area under the receiver operating characteristic curve (AUC) for radiographic findings consistent with pneumonia and compared performance on different test sets with DeLong's test. The prevalence of pneumonia was high enough at MSH (34.2%) relative to NIH and IU (1.2% and 1.0%) that merely sorting by hospital system achieved an AUC of 0.861 (95% CI 0.855 0.866) on the joint MSH-NIH dataset. Models trained on data from either NIH or MSH had equivalent performance on IU (P values 0.580 and 0.273, respectively) and inferior performance on data from each other relative to an internal test set (i.e., new data from within the hospital system used for training data; P values both <0.001). The highest internal performance was achieved by combining training and test data from MSH and NIH (AUC 0.931, 95% CI 0.927-0.936), but this model demonstrated significantly lower external performance at IU (AUC 0.815, 95% CI 0.745-0.885, P = 0.001). To test the effect of pooling data from sites with disparate pneumonia prevalence, we used stratified subsampling to generate MSH NIH cohorts that only differed in disease prevalence between training data sites. When both training data sites had the same pneumonia prevalence, the model performed consistently on external IU data (P = 0.88). When a 10-fold difference in pneumonia rate was introduced between sites, internal test performance improved compared to the balanced model (10* MSH risk P < 0.001; 10* NIH P = 0.002), but this outperformance failed to generalize to IU (MSH 10* P < 0.001; NIH 10* P = 0.027). CNNs were able to directly detect hospital system of a radiograph for 99.95% NIH (22,050/22,062) and 99.98% MSH (8,386/8,388) radiographs. The primary limitation of our approach and the available public data is that we cannot fully assess what other factors might be contributing to hospital system-specific biases. CONCLUSION: Pneumonia-screening CNNs achieved better internal than external performance in 3 out of 5 natural comparisons. When models were trained on pooled data from sites with different pneumonia prevalence, they performed better on new pooled data from these sites but not on external data. CNNs robustly identified hospital system and department within a hospital, which can have large differences in disease burden and may confound predictions. PMID- 30399159 TI - Visual attention mechanism and support vector machine based automatic image annotation. AB - Automatic image annotation not only has the efficiency of text-based image retrieval but also achieves the accuracy of content-based image retrieval. Users of annotated images can locate images they want to search by providing keywords. Currently most automatic image annotation algorithms do not consider the relative importance of each region in the image, and some algorithms extract the image features as a whole. This makes it difficult for annotation words to reflect salient versus non-salient areas of the image. Users searching for images are usually only interested in the salient areas. We propose an algorithm that integrates a visual attention mechanism with image annotation. A preprocessing step divides the image into two parts, the salient regions and everything else, and the annotation step places a greater weight on the salient region. When the image is annotated, words relating to the salient region are given first. The support vector machine uses particle swarm optimization to annotate the images automatically. Experimental results show the effectiveness of the proposed algorithm. PMID- 30399158 TI - A computational analysis of dynamic, multi-organ inflammatory crosstalk induced by endotoxin in mice. AB - Bacterial lipopolysaccharide (LPS) induces an acute inflammatory response across multiple organs, primarily via Toll-like receptor 4 (TLR4). We sought to define novel aspects of the complex spatiotemporal dynamics of LPS-induced inflammation using computational modeling, with a special focus on the timing of pathological systemic spillover. An analysis of principal drivers of LPS-induced inflammation in the heart, gut, lung, liver, spleen, and kidney to assess organ-specific dynamics, as well as in the plasma (as an assessment of systemic spillover), was carried out using data on 20 protein-level inflammatory mediators measured over 0 48h in both C57BL/6 and TLR4-null mice. Using a suite of computational techniques, including a time-interval variant of Principal Component Analysis, we confirm key roles for cytokines such as tumor necrosis factor-alpha and interleukin-17A, define a temporal hierarchy of organ-localized inflammation, and infer the point at which organ-localized inflammation spills over systemically. Thus, by employing a systems biology approach, we obtain a novel perspective on the time- and organ-specific components in the propagation of acute systemic inflammation. PMID- 30399160 TI - Open reduction and internal fixation of displaced proximal humeral fractures. Does the surgeon's experience have an impact on outcomes? AB - INTRODUCTION: To evaluate outcomes following open reduction and internal fixation of displaced proximal humeral fractures with regards to the surgeon's experience. MATERIAL AND METHODS: Patients were included undergoing ORIF by use of locking plates for displaced two-part surgical neck type proximal humeral fractures. Reduction and functional outcomes were compared between procedures that were conducted by trauma surgeons [TS], senior (>2 years after board certified) trauma surgeons [STS] and trauma surgeons performing >=50 shoulder surgeries per year [SS]. Quality of reduction was measured on postoperative x-rays. Functional outcomes were assessed by gender- and age-related Constant Score (nCS). Secondary outcome measures were complication and revision rates. RESULTS: Between 2002-2014 (12.5 years) n = 278 two-part surgical neck type humeral fractures (AO 11-A2, 11 A3) were included. Open reduction and internal fixation was performed with the following educational levels: [TS](n = 68, 25.7%), [STS](n = 110, 41.5%) and [SS](n = 77, 29.1%). Functional outcome (nCS) increased with each higher level of experience and was significantly superior in [SS] (93.3) vs. [TS] (79.6; p = 0.01) vs. [STS] (83.0; p = 0.05). [SS] (7.8%) had significantly less complications compared with [TS] (11.3%; p = 0.003) and [STS](11.7%; p = 0.01) moreover significantly less revision rates (3.9%) vs. [TS](8.2%) and [STS](7.4%) (p<0.001). Primary revision was necessary in 13 cases (4.7%) due to malreduction of the fracture. CONCLUSION: Quality of reduction and functional outcomes following open reduction and internal fixation of displaced two-part surgical neck fractures are related to the surgeon's experience. In addition, complications and revision rates are less frequent if surgery is conducted by a trauma surgeon performing >=50 shoulder surgeries per year. PMID- 30399156 TI - Predicting CD4 T-cell epitopes based on antigen cleavage, MHCII presentation, and TCR recognition. AB - Accurate predictions of T-cell epitopes would be useful for designing vaccines, immunotherapies for cancer and autoimmune diseases, and improved protein therapies. The humoral immune response involves uptake of antigens by antigen presenting cells (APCs), APC processing and presentation of peptides on MHC class II (pMHCII), and T-cell receptor (TCR) recognition of pMHCII complexes. Most in silico methods predict only peptide-MHCII binding, resulting in significant over prediction of CD4 T-cell epitopes. We present a method, ITCell, for prediction of T-cell epitopes within an input protein antigen sequence for given MHCII and TCR sequences. The method integrates information about three stages of the immune response pathway: antigen cleavage, MHCII presentation, and TCR recognition. First, antigen cleavage sites are predicted based on the cleavage profiles of cathepsins S, B, and H. Second, for each 12-mer peptide in the antigen sequence we predict whether it will bind to a given MHCII, based on the scores of modeled peptide-MHCII complexes. Third, we predict whether or not any of the top scoring peptide-MHCII complexes can bind to a given TCR, based on the scores of modeled ternary peptide-MHCII-TCR complexes and the distribution of predicted cleavage sites. Our benchmarks consist of epitope predictions generated by this algorithm, checked against 20 peptide-MHCII-TCR crystal structures, as well as epitope predictions for four peptide-MHCII-TCR complexes with known epitopes and TCR sequences but without crystal structures. ITCell successfully identified the correct epitopes as one of the 20 top scoring peptides for 22 of 24 benchmark cases. To validate the method using a clinically relevant application, we utilized five factor VIII-specific TCR sequences from hemophilia A subjects who developed an immune response to factor VIII replacement therapy. The known HLA DR1-restricted factor VIII epitope was among the six top-scoring factor VIII peptides predicted by ITCall to bind HLA-DR1 and all five TCRs. Our integrative approach is more accurate than current single-stage epitope prediction algorithms applied to the same benchmarks. It is freely available as a web server (http://salilab.org/itcell). PMID- 30399161 TI - Hydroxychloroquine partially prevents endothelial dysfunction induced by anti beta-2-GPI antibodies in an in vivo mouse model of antiphospholipid syndrome. AB - BACKGROUND: Antiphospholipid syndrome is associated with endothelial dysfunction, which leads to thrombosis and early atheroma. Given that hydroxychloroquine has anti-thrombotic properties in lupus, we hypothesized that it could reduce endothelial dysfunction in an animal model of antiphospholipid syndrome. We evaluated the effect of hydroxychloroquine in preventing endothelial dysfunction in a mouse model of antiphospholipid syndrome. METHODS: Antiphospholipid syndrome was induced by an injection of monoclonal anti-beta-2-GPI antibodies. Vascular reactivity was evaluated in mesenteric resistance arteries isolated from mice 3 weeks (APL3W) after receiving a single injection of anti-beta-2-GPI antibodies and after 3 weeks of daily oral hydroxychloroquine treatment (HCQ3W) compared to control mice (CT3W). We evaluated endothelial dysfunction by measuring acetylcholine-mediated vasodilation. A pharmacological approach was used to evaluate NO synthase uncoupling (tetrahydrobiopterin) and the generation of reactive oxygen species (Tempol). RESULTS: Impaired acetylcholine-mediated dilation was evidenced in mice 3 weeks after anti-beta-2-GPI antibodies injection compared to CT3W, by reduced maximal dilation (p<0.0001) and sensitivity (pKd) (p = 0.01) to acetylcholine. Hydroxychloroquine improved acetylcholine-dependent dilation, on pKd (p = 0.02) but not maximal capacity compared to untreated mice. The addition of tetrahydrobiopterin (p = 0.02) and/or Tempol (p = 0.0008) improved acetylcholine-mediated dilation in APL3W but not in HCQ3W. CONCLUSIONS: We demonstrated that endothelial dysfunction in mouse resistance arteries persisted at 3 weeks after a single injection of monoclonal anti-beta-2-GPI antibodies, and that hydroxychloroquine improved endothelium-dependent dilation at 3 weeks, through improvement of NO synthase coupling and oxidative stress reduction. PMID- 30399162 TI - Assessing a novel way to measure step count while walking using a custom mobile phone application. AB - INTRODUCTION: Walking speed has been associated with many clinical outcomes (e.g., frailty, mortality, joint replacement need, etc.). Accurately measuring walking speed (stride length x step count/time) typically requires significant clinician/staff time or a gait lab with specialized equipment (i.e., electronic timers or motion capture). In the present study, our goal was to measure "step count" via smartphones through novel software and to compare with step tracking software that come standard with iOS and Android smartphones as a first step in walking speed measurement. METHODS: A separate calibration and validation data collection was performed. Individuals in the calibration collection (n = 5) walked 20m at normal and slow speed (<1.0 m/s). Appropriate settings for the novel mobile application were chosen to measure step count. Individuals in the validation (n = 52) collection walked at 6m, 10m, and 20m at normal and slow walking speeds. We compared step difference (absolute difference) from observed step counts to native step tracking software and our novel software derived step counts. We used generalized estimated equation adjusted (participant level) negative binomial regression models of absolute step difference from observed step counts, to determine optimal settings (calibration) and subsequently to gauge performance of the shake algorithm settings and native step tracking software across different distances and speeds (validation). RESULTS: For iOS/iPhone 6, when compared to observed step count, the shake service (software driven approach) significantly outperformed the embedded native step tracking software across all distances at slow speed, and for short distance (6m) at normal speed. On the Android phone, the shake service outperformed the native step tracking software at slow speed at 6 meters and 20 meters, while its performance eclipsed the native step tracking software only at 20 meters at normal speed. DISCUSSION: Our software based approach outperformed native step tracking software across various speeds and distances and carries the advantage of having adjustable measurement parameters that can be further optimized for specific medical conditions. Such software applications will provide an effective way to capture standardized data across multiple commercial smartphone devices, facilitating the future capture of walking speed and other clinically important performance parameters that will influence clinical and home care in the era of value based care. PMID- 30399163 TI - Appraisal of the water footprint of irrigated agriculture in a semi-arid area: The Segura River Basin. AB - Irrigated agriculture is a key activity in water resources management at the river basin level in arid and semi-arid areas, since this sector consumes the largest part of the water resources overall. The current study proposes a methodology to evaluate the water footprint (WF) of the irrigated agriculture sector at the river basin level, through a simulation of the anthropised water cycle combining a hydrological model and a decision support system. The main difference from the approaches that have already been used is that the new methodology includes the limitations of the system for the exploitation of water resources where the irrigated areas are located, and it considers the hydrological principles governed by the law of continuity of mass. Water footprint accounting was carried out for the Segura River Basin (South-eastern Spain), applying the methodology proposed and another that is usually applied. The results of the two methodologies were compared, revealing significant differences in the values of the WF, basically due to the blue component. The methodology that is usually applied overestimated the WF of the agriculture in the basin since supply deficits were not taken into account, providing results that would only be possible if there were no spatial or temporal restrictions to water use. So, in order to make the WF indicator useful in water resources management plans, it is necessary to adapt the computations to the main characteristics of the water exploitation system of the whole basin under study, respecting the hydrological principles of the water cycle: regulation and transport infrastructure, the real water resources available and the priority of access to water between concurrent water uses. PMID- 30399164 TI - Telemonitoring system for patients with chronic kidney disease undergoing peritoneal dialysis: Usability assessment based on a case study. AB - There are two million people with chronic kidney disease (CKD) worldwide. In Mexico, it is estimated that by 2025, there will be 212 thousand CKD cases. Among the renal replacement treatments, peritoneal dialysis (PD) exists either in the continuous ambulatory (CAPD) or automated (APD) mode, which requires continuous monitoring and strict control. Thus, several software systems have been proposed to perform reliable remote monitoring of patients using PD but also to achieve the goal with effectiveness, efficiency and satisfaction; i.e., in software engineering, this is called usability. However, few studies have addressed usability issues using case studies with patients and medical staff in real domains. In this paper, we present a usability assessment of a telemonitoring system for patients with CKD on peritoneal dialysis treatment through a case study with patients and medical staff of the Mexican Institute of Social Security (IMSS). The usability evaluation was carried out through the application of two satisfaction instruments. These instruments evaluated multiple usability criteria, such as navigability, interactivity, motivation, satisfaction, and applicability. The results obtained from the usability evaluation show that, on average, the services offered by the system have 91.3% acceptance by users (patient-doctors), with the APD and CAPD exchange data registration services having the highest acceptance for patients, with a positive perception of 94.5% and 92.3%, respectively. Meanwhile, for the doctors and nurses, the alarm reception for patients in a risk situation was highest with 95% acceptance. Based on the obtained results, the evaluated telemonitoring system holds wide acceptance, satisfaction, and applicability from patients' and doctors' perspectives. It is also noted that the evaluated system considers and satisfies the requirements and suitable parameters that should be monitored in PD treatment according to studies presented in the literature. PMID- 30399165 TI - Clustering-local-unique-enriched-signals (CLUES) promotes identification of novel regulators of ES cell self-renewal and pluripotency. AB - BACKGROUND: Key regulators of developmental processes can be prioritized through integrated analysis of ChIP-Seq data of master transcriptional factors (TFs) such as Nanog and Oct4, active histone modifications (HMs) such as H3K4me3 and H3K27ac, and repressive HMs such as H3K27me3. Recent studies show that broad enrichment signals such as super-enhancers and broad H3K4me3 enrichment signals play more dominant roles than short enrichment signals of the master TFs and H3K4me3 in epigenetic regulatory mechanism. Besides the broad enrichment signals, up to ten thousands of short enrichment signals of these TFs and HMs exist in genome. Prioritization of these broad enrichment signals from ChIP-Seq data is a prerequisite for such integrated analysis. RESULTS: Here, we present a method named Clustering-Local-Unique-Enriched-Signals (CLUES), which uses an adaptive size-windows strategy to identify enriched regions (ERs) and cluster them into broad enrichment signals. Tested on 62 ENCODE ChIP-Seq datasets of Ctcf and Nrsf, CLUES performs equally well as MACS2 regarding prioritization of ERs with the TF's motif. Tested on 165 ENCODE ChIP-Seq datasets of H3K4me3, H3K27me3, and H3K36me3, CLUES performs better than existing algorithms on prioritizing broad enrichment signals implicating cell functions influenced by epigenetic regulatory mechanism in cells. Most importantly, CLUES helps to confirm several novel regulators of mouse ES cell self-renewal and pluripotency through integrated analysis of prioritized broad enrichment signals of H3K4me3, H3K27me3, Nanog and Oct4 with the support of a CRISPR/Cas9 negative selection genetic screen. CONCLUSIONS: CLUES holds promise for prioritizing broad enrichment signals from ChIP-Seq data. The download site for CLUES is https://github.com/Wuchao1984/CLUESv1. PMID- 30399167 TI - Chemical composition and larvicidal activities of Azolla pinnata extracts against Aedes (Diptera:Culicidae). AB - BACKGROUND: The resistance problem of dengue vectors to different classes of insecticides that are used for public health has raised concerns about vector control programmes. Hence, the discovery of alternative compounds that would enhance existing tools is important for overcoming the resistance problem of using insecticides in vectors and ensuring a chemical-free environment. The larvicidal effects of Azolla pinnata extracts by using two different extraction methods with methanol solvent against Aedes in early 4th instar larvae was conducted. METHODS: The fresh Azolla pinnata plant from Kuala Krai, Kelantan, Malaysia was used for crude extraction using Soxhlet and maceration methods. Then, the chemical composition of extracts and its structure were identified using GCMS-QP2010 Ultra (Shimadzu). Next, following the WHO procedures for larval bioassays, the extracts were used to evaluate the early 4th instar larvae of Aedes mosquito vectors. RESULTS: The larvicidal activity of Azolla pinnata plant extracts evidently affected the early 4th instar larvae of Aedes aegypti mosquito vectors. The Soxhlet extraction method had the highest larvicidal effect against Ae. aegypti early 4th instar larvae, with LC50 and LC95 values of 1093 and 1343 mg/L, respectively. Meanwhile, the maceration extraction compounds were recorded with the LC50 and LC95 values of 1280 and 1520 mg/L, respectively. The larvae bioassay test for Ae. albopictus showed closely similar values in its Soxhlet extraction, with LC50 and LC95 values of 1035 and 1524 mg/L, compared with the maceration extraction LC50 and LC95 values of 1037 and 1579 mg/L, respectively. The non-target organism test on guppy fish, Poecilia reticulata, showed no mortalities and posed no toxic effects. The chemical composition of the Azolla pinnata plant extract has been found and characterized as having 18 active compounds for the Soxhlet method and 15 active compounds for the maceration method. CONCLUSIONS: Our findings showed that the crude extract of A. pinnata bioactive molecules are effective and have the potential to be developed as biolarvicides for Aedes mosquito vector control. This study recommends future research on the use of active ingredients isolated from A. pinnata extracts and their evaluation against larvicidal activity of Aedes in small-scale field trials for environmentally safe botanical insecticide invention. PMID- 30399166 TI - Loss of charge mutations in solvent exposed Lys residues of superoxide dismutase 1 do not induce inclusion formation in cultured cell models. AB - Mutations in superoxide dismutase 1 (SOD1) associated with familial amyotrophic lateral sclerosis (fALS) induce the protein to misfold and aggregate. Missense mutations at more than 80 different amino acid positions have been associated with disease. How these mutations heighten the propensity of SOD1 to misfold and aggregate is unclear. With so many mutations, it is possible that more than one mechanism of aggregation may be involved. Of many possible mechanisms to explain heightened aggregation, one that has been suggested is that mutations that eliminate charged amino acids could diminish repulsive forces that would inhibit aberrant protein:protein interactions. Mutations at twenty-one charged residues in SOD1 have been associated with fALS, but of the 11 Lys residues in the protein, only 1 has been identified as mutated in ALS patients. Here, we examined whether loss of positively charged surface Lys residues in SOD1 would induce misfolding and formation of intracellular inclusions. We mutated four different Lys residues (K30, K36, K75, K91) in SOD1 that are not particularly well conserved, and expressed these variants as fusion proteins with yellow fluorescent protein (YFP) to assess inclusion formation. We also assessed whether these mutations induced binding to a conformation-restricted SOD1 antibody, designated C4F6, which recognizes non-natively folded protein. Although we observed some mutations to cause enhanced C4F6 binding, we did not observe that mutations that reduce charge at these positions caused the protein to form intracellular inclusions. Our findings may have implications for the low frequency of mutations at Lys residues SOD1 in ALS patients. PMID- 30399168 TI - Fertility hormones and vitamin E in active and passive adult male smokers in Calabar, Nigeria. AB - Smoking is an extremely lethal act and is associated with many illnesses. Lately, major concerns that passive smokers face the same health risks as (if not higher than) active smokers have been raised. Some studies have shown that active smoking is associated with low serum levels of vitamins and testosterone. Are these facts also valid in passive smokers? This study investigated the levels of cotinine, testosterone, follicle stimulating (FSH), Luteinizing Hormone (LH), prolactin and vitamin E in male active smokers and compare these with male passive smokers. Serum levels of cotinine, testosterone, FSH, LH, prolactin and vitamin E were determined in 60 cigarette smokers, 60 passive smokers and 60 non smokers recruited from Calabar metropolis. The hormones were assayed using ELISA and Vitamin E using high performance liquid chromatography. Socio-demographic and anthropometric indices were obtained and data analyzed using PAWstatistic 18. Cotinine levels were significantly (p<0.05) higher in active smokers than in passive smokers and controls. Vitamin E and testosterone were significantly lower in both active (p<0.05) and passive smokers (p<0.05) when compared to non smokers. The FSH of the active smokers was significantly higher (p = 0.034) than that of the controls while the passive smokers had the highest LH values (p = 0.0001). However, there were no significant variations in the prolactin levels among the three groups. Both passive and active smoking depletes serum vitamins E and lowers testosterone levels. Lower serum vitamin E is pointer to increased oxidative stress which in conjunction with lower testosterone levels may lead to increased incidence of infertility in both active and passive male smokers. PMID- 30399170 TI - Roles of metacognition and achievement goals in mathematical modeling competency: A structural equation modeling analysis. AB - This study investigates the relationship between metacognition and achievement goals which may influence mathematical modeling competency in students of mathematics education programs. The current study employs 538 students of mathematics education program; 483 (89.8%) of whom are male and 55 (10.2%) are aged from 18 years old to 22 years old. The study follows a correlational research design to investigate and measure the degree of relationship amongst mathematical modeling competencies, achievement goals and metacognition. Results indicate that achievement goals and metacognition positively influence mathematical modeling competency. Moreover, four metacognition dimensions including awareness, planning, cognitive strategy and self-checking are positive partial mediators because they increase the association between achievement goals and mathematical modeling competency. In conclusion, metacognition and achievement goals positively affect students' mathematical modeling competency. PMID- 30399169 TI - Identifying and addressing gaps in reproductive health education for adolescent girls with type 1 diabetes. AB - AIMS: Adolescent girls with diabetes are at risk for adverse pregnancy outcomes due to age, risk-taking behavior, poor glycemic control, and lack of knowledge. Our aims were to assess attitudes and behaviors related to reproductive health education (RHE) among diabetes healthcare providers and adolescent girls with diabetes, and to pilot a brief clinic-based RHE intervention. METHODS: We surveyed 29 providers and 50 adolescent girls with type 1 diabetes about RHE experiences, attitudes, and behaviors. We piloted the RHE intervention with 9 adolescent-parent dyads. RESULTS: 50% of providers were very uncomfortable discussing pregnancy or contraception. Most (72%) did not proactively initiate RHE; common barriers included insufficient time and subject knowledge. Fewer than 10% recommended long-acting reversible contraceptives. A minority (10%) of adolescents had discussed pregnancy or contraception with a provider. RHE sessions lasted a median of 16 (range 13-24) minutes, and there were promising trends for changes in adolescents' self-efficacy and intentions to use contraception and seek preconception counseling and in their knowledge of reproductive health. CONCLUSION: Adolescent girls with diabetes rarely receive education on pregnancy and contraception due to provider discomfort, limited knowledge, and limited time. RHE using easily-accessible materials with an educator may help address this gap in care. PMID- 30399171 TI - Linguistic neutrosophic Hamacher aggregation operators and the application in evaluating land reclamation schemes for mines. AB - Land reclamation has become a significant way for the improvement of ecological environment in mining areas. When selecting the optimal land reclamation scheme, LNNs (linguistic neutrosophic numbers) are suitable to describe the complex fuzzy evaluation information through linguistic truth, indeterminacy and falsity membership degrees. Furthermore, the Hamacher aggregation operators are good tools to handle multi-criteria decision making problems. Accordingly, the aim of this paper is to extend Hamacher aggregation operators with LNNs and then build a decision making framework for evaluating land reclamation schemes in mining areas. First, new operational laws of LNNs based on Hamacher t-norm and t-conorm are defined. Then, several linguistic neutrosophic Hamacher aggregation operators, including the linguistic neutrosophic Hamacher weighted mean aggregation operators and linguistic neutrosophic Hamacher hybrid weighted mean aggregation operators are developed. Meanwhile, their desirable properties are proved. Thereafter, a method for decision making with linguistic neutrosophic information based on these operators is proposed to deal with complex decision problems. At last, the validity of this method is confirmed by an illustrative example of evaluating the land reclamation schemes in mining areas. In addition, the impact of the parameter in extended Hamacher aggregation operators is discussed. The merits of the proposed method are also highlighted by comparing with other decision making methods. The results show that the proposed linguistic neutrosophic Hamacher aggregation operators have great flexibility and advantages, and can provide powerful ways for the evaluation of land reclamation schemes. PMID- 30399172 TI - An improved environmental DNA assay for bull trout (Salvelinus confluentus) based on the ribosomal internal transcribed spacer I. AB - The majority of environmental DNA (eDNA) assays for vertebrate species are based on commonly analyzed regions of the mitochondrial genome. However, the high degree of mitochondrial similarity between two species of charr (Salvelinus spp.), southern Dolly Varden (S. malma lordii) and bull trout (Salvelinus confluentus), precludes the development of a mitochondrial eDNA assay to distinguish them. Presented here is an eDNA assay to detect bull trout based on the first ribosomal internal transcribed spacer (ITSI), a nuclear marker. This assay successfully detects bull trout and avoids detecting Dolly Varden as well as brook trout (S. fontinalis), Arctic char (S. alpinus), and lake trout (S. namaycush). In addition, this assay was compared with an extensively used mitochondrial bull trout assay and it was found that the ITSI-based assay produced higher detectability. Our results suggest this assay should out-perform the published mtDNA assay across the range of bull trout, while the added specificity allows reliable bull trout detection in areas where bull trout co occur with other charr such as Dolly Varden. While clearly a superior assay in this instance, basing assays on ITSI is not without problems. For vertebrates, there are fewer ITSI sequences available than commonly sequenced regions of the mitochondrial genome. Thus, the initial in silico screening of candidate assays must be preceded by much more extensive sampling and sequencing of sympatric or closely related taxa. Further, all copies of the internal transcribed spacers within an individual may not be identical, which can lead to complications. Lastly, the copy number for ITSI varies widely across taxa; the greater detectability associated with this assay cannot be assumed for other species. PMID- 30399173 TI - A novel decarboxylating amidohydrolase involved in avoiding metabolic dead ends during cyanuric acid catabolism in Pseudomonas sp. strain ADP. AB - Cyanuric acid is a common environmental contaminant and a metabolic intermediate in the catabolism of s-triazine compounds, including atrazine and other herbicides. Cyanuric acid is catabolized via a number of bacterial pathways, including one first identified in Pseudomonas sp. strain ADP, which is encoded by a single, five-gene operon (atzDGEHF) found on a self-transmissible plasmid. The discovery of two of the five genes (atzG and atzH) was reported in 2018 and although the function of atzG was determined, the role of atzH was unclear. Here, we present the first in vitro reconstruction of the complete, five-protein cyanuric acid catabolism pathway, which indicates that AtzH may be an amidase responsible for converting 1,3-dicarboxyurea (the AtzE product) to allophanate (the AtzF substrate). We have solved the AtzH structure (a DUF3225 protein from the NTF2 superfamily) and used it to predict the substrate-binding pocket. Site directed mutagenesis experiments suggest that two residues (Tyr22 and Arg46) are needed for catalysis. We also show that atzH homologs are commonly found in Proteobacteria associated with homologs of the atzG and atzE genes. The genetic context of these atzG-atzE-atzH clusters imply that they have a role in the catabolism of nitrogenous compounds. Moreover, their presence in many genomes in the absence of homologs of atzD and atzF suggests that the atzG-atzE-atzH cluster may pre-date the evolution of the cyanuric acid catabolism operon. PMID- 30399174 TI - Cancer immunotherapy using PolyPurine Reverse Hoogsteen hairpins targeting the PD 1/PD-L1 pathway in human tumor cells. AB - Immunotherapy approaches stand out as innovative strategies to eradicate tumor cells. Among them, PD-1/PD-L1 immunotherapy is considered one of the most successful advances in the history of cancer immunotherapy. We used our technology of Polypurine reverse Hoogsteen hairpins (PPRHs) for silencing both genes with the aim to provoke the elimination of tumor cells by macrophages in co culture experiments. Incubation of PPRHs against PD-1 and PD-L1 decreased the levels of mRNA and protein in THP-1 monocytes and PC3 prostate cancer cells, respectively. Viability of THP-1 cells and macrophages obtained by PMA differentiation of THP-1 cells was not affected upon incubation with the different PPRHs. On the other hand, PC3 cell survival was partially decreased by PPRHs against PD-L1. The greatest effect in decreasing cell viability was obtained in macrophages/PC3 co-culture experiments by combining PPRHs against PD 1 and PD-L1. This effect was also observed in other cancer cell lines: HeLa, SKBR3 and to a minor extent in M21. Apoptosis was not detected when macrophages were treated with the different PPRHs. However, co-cultures of macrophages with the four cancer cell lines treated with PPRHs showed an increase in apoptosis. The order of fold-increase in apoptosis was HeLa > PC3 > SKBR3 > M21. This study demonstrates that PPRHs could be powerful pharmacological agents to use in immunotherapy approaches for the inhibition of PD-1 and PD-L1. PMID- 30399175 TI - Metformin reveals a mitochondrial copper addiction of mesenchymal cancer cells. AB - The clinically approved drug metformin has been shown to selectively kill persister cancer cells through mechanisms that are not fully understood. To provide further mechanistic insights, we developed a drug surrogate that phenocopies metformin and can be labeled in situ by means of click chemistry. Firstly, we found this molecule to be more potent than metformin in several cancer cell models. Secondly, this technology enabled us to provide visual evidence of mitochondrial targeting with this class of drugs. A combination of fluorescence microscopy and cyclic voltammetry indicated that metformin targets mitochondrial copper, inducing the production of reactive oxygen species in this organelle, mitochondrial dysfunction and apoptosis. Importantly, this study revealed that mitochondrial copper is required for the maintenance of a mesenchymal state of human cancer cells, and that metformin can block the epithelial-to-mesenchymal transition, a biological process that normally accounts for the genesis of persister cancer cells, through direct copper targeting. PMID- 30399176 TI - Extracellular microvesicle microRNAs as predictive biomarkers for targeted therapy in metastastic cutaneous malignant melanoma. AB - BACKGROUND: Mitogen activated-protein kinase pathway inhibitors (MAPKis) improve treatment outcome in patients with disseminated BRAFV600 mutant cutaneous malignant melanoma (CMM) but responses are of limited duration due to emerging resistance. Although extensive research in mechanisms of resistance is being performed, predictive biomarkers for durable responses are still lacking. We used miRNA qPCR to investigate if different levels of extracellular microvesicle microRNA (EV miRNA) in matched plasma samples collected from patients with metastatic IV BRAFV600 mutated CMM before, during and after therapy with MAPKis could serve as predictive biomarkers. MATERIALS AND METHODS: EV miRNAs were extracted from plasma samples from 28 patients collected before and during therapy, measured by quantitative PCR-array and correlated to therapy outcome. RESULTS: Increased levels of EV let-7g-5p during treatment compared to before treatment (EV let-7g-5p_delta) were associated with better disease control with MAPKis (odds ratio 8568.4, 95% CI = 4.8-1.5e+07, P = 0.000036). Elevated levels of EV miR-497-5p during therapy were associated with prolonged progression free survival (PFS) (hazard ratio = 0.27, 95% CI = 0.13-0.52, P <0.000061). CONCLUSIONS: EV miRNAs let-7g-5p and miR-497-5p were identified as putative novel predictive biomarkers of MAPKi treatment benefit in metastatic CMM patients highlighting the potential relevance of assessing EV miRNA during and after treatment to unravel novel mechanisms of resistance. PMID- 30399177 TI - Miransertib (ARQ 092), an orally-available, selective Akt inhibitor is effective against Leishmania. AB - Leishmaniasis is amongst the most important neglected diseases, afflicting more than 12 million people in 88 countries. There is an urgent need for safe orally bioavailable and cost-effective drugs for the treatment of leishmaniasis. It has recently been shown that Leishmania activates host macrophage serine/threonine kinase Akt, to promote survival of both parasites and infected cells. Here, we sought to evaluate a compound, Miransertib (ARQ 092), an orally bioavailable and selective allosteric Akt inhibitor currently in clinical trials for patients with PI3K/Akt-driven tumors or Proteus syndrome. Miransertib was tested against Leishmania donovani and Leishmania amazonensis, causative agents of visceral and cutaneous leishmaniasis, respectively. Cultured promastigotes were susceptible to Miransertib. In addition, Miransertib was markedly effective against intracellular amastigotes of L. donovani or L. amazonensis-infected macrophages. Miransertib also enhanced mTOR dependent autophagy in Leishmania-infected macrophages, which may represent one mechanism of Miransertib-mediated killing of intracellular Leishmania. Whereas parasite clearance in the spleen of mice infected with L. donovani and treated with Miransertib was comparable to that when treated with miltefosine, Miransertib caused a greater reduction in the parasite load in the liver. In the cutaneous leishmaniasis infection model, lesions were reduced by 40% as compared to mock treated mice. Together, these results provide direct evidence to support the conclusion that Miransertib is an excellent lead compound for the development of a new oral drug therapy for visceral and cutaneous leishmaniasis. PMID- 30399178 TI - One-time-pad cryptography scheme based on a three-dimensional DNA self-assembly pyramid structure. AB - The security strength of the traditional one-time-pad encryption system depends on the randomness of the secret key. However, It can hardly to generatea truerandom key by using the existing technologies and methods, and it is also difficult to issue and store the random keywhich is at least as long as the plaintext. Therefore, we pay more attention to the logical operation used in the encryption and decryption but not to how to generate the random key. The calculator, a three-dimensional DNA self-assembly pyramid structure, is designed to construct four common logical operations (AND, OR, NOT, XOR) by programming DNA interactions. And two novel one-time-pad cryptography schemes, a single-bit one-time-pad algorithm and improved double-bit one-time-pad algorithm, are proposed based on the calculator. The security fragments, used to construct the three-dimensional DNA self-assembly pyramid structure, are intercepted from a reference chain which is selected from the DNA database. All of the interception parameters are transmitted to recipient by hiding in DNA sequences. Only the authorized user can get all secret parameters to reconstruct the structure. The secret random key sequences for the two one-time-pad cryptography algorithms are generated by using logistic map. It only needs to share two parameters and thresholding function in sender and recipient without code books. The simulation results and security analysis show that the encryption algorithms are effective and can provide higher computational complexity as well as a reduced cracking probability except for the difficult of biological experiments. PMID- 30399179 TI - Conservation implications for jaguars and other neotropical mammals using highway underpasses. AB - The Nuevo Xcan-Playa del Carmen highway in Quintana Roo, bisects the vegetation corridor connecting two Jaguar Conservation Units (JCUs): Yum Balaam (north) and Sian Ka'an (south). The project's main goal was to describe differential use of available crossing structures (wildlife underpasses and culverts) by mammals present along this highway. We set 28 camera traps along the 54km stretch of the highway covering wildlife underpasses (10), and culverts such as box culverts (9) and pipes (9) from September 2016 until March 2017. A total of 24 jaguar crossings have been recorded exclusively using wildlife underpasses, including four males and two females. At least 18 other mammal species including five of the target priority species (protected by Mexican law) were documented, all of which were native except for two invasive species. In terms of species using the crossing structures, we identified 13 species using wildlife underpasses, nine using concrete box culverts and 10 using concrete pipes. Wildlife underpasses show higher diversity values (Shannon's exponential index = 5.8 and Inverse Simpson's index = 4.66) compared to culverts because they allow bigger species to cross. We recommend more highways along the jaguar's distribution should develop mitigation measures to allow for wildlife connectivity. Wildlife underpasses, along with retrofitted culverts, could help secure not only the permanence of this species by facilitating the functional connectivity between populations but have positive impacts on other neotropical mammalian fauna as well. PMID- 30399180 TI - A qualitative study of women's network social support and facility delivery in rural Ghana. AB - Similar to many sub-Saharan African countries, maternal mortality in Ghana ranks among the highest (39th) globally. Prior research has demonstrated the impact of social network characteristics on health facility delivery in sub-Saharan Africa. However, in-depth examination of the function of all members in a woman's network, in providing various types of support for the woman's pregnancy and related care, is limited. We qualitatively explore how women's network social support influences facility delivery. Qualitative data came from a mixed methods evaluation of a Maternal and Newborn Health Referral project in Ghana. In 2015 we conducted in-depth interviews with mothers (n = 40) and husbands (n = 20), and 4 focus group interviews with mothers-in-law. Data were analyzed using narrative summaries and thematic coding procedures to first examine women's network composition during their pregnancy and childbirth experiences. We then compared those who had homebirths versus facility births on how network social support influenced their place of childbirth. Various network members were involved in providing women with social support. We found differences in how informational and instrumental support impacted women's place of childbirth. Network members of women who had facility delivery mobilized resources to support women's facility delivery. Among women who had homebirth but their network members advocated for them to have facility delivery, members delayed making arrangements for the women's facility delivery. Women who had homebirth, and their network members advocated homebirth, received support to give birth at home. Network support for women's pregnancy-related care affects their place of childbirth. Hence, maternal health interventions must develop strategies to prioritize informational and instrumental support for facility-based pregnancy and delivery care. PMID- 30399181 TI - The lived experience of female genital cutting (FGC) in Somali-Canadian women's daily lives. AB - Many of the Somali women who have immigrated to other countries, including Canada, have experienced Female Genital Circumcision/ Mutilation/ Cutting (FGC). While there is literature on the medical aspects of FGC, we were interested in understanding the daily life experiences and bodily sensations of Somali-Canadian women in the context of FGC. Fourteen women living in the Greater Toronto Area were interviewed. Interview data were analyzed using a phenomenological approach. We found that the memory of the ceremonial cutting was vivid but was frequently described with acceptance and resignation-as something that just is; that was normal given the particular context, familial and cultural, and their young age. Most of the women recounted experiencing pain and discomfort throughout their adult lives but were intent on not noticing or giving the pain any power; they considered themselves healthy. The following themes emerged from our interviews: Every Body Had It: Discussing FGC, I'm Normal Aren't I?, and Feeling in My Body all themes that work at normalizing their bodies in a society that they know views them as different. They dealt with both pain and pleasure in the context of their busy lives suggesting resilience in spite of the day-to-day difficulties of daily life. PMID- 30399182 TI - Combining QTL mapping with transcriptome and metabolome profiling reveals a possible role for ABA signaling in resistance against the cabbage whitefly in cabbage. AB - Whiteflies are among the world's most significant agricultural pests and chemical insecticides are extensively used to reduce crop damage to acceptable levels. However, nearly all insecticides pose a threat to the environment and alternative control methods, such as breeding of crop varieties that are inherently insect resistant, are needed. Previously, a strong source of plant-age dependent resistance to the cabbage whitefly (Aleyrodes proletella) has been identified in the modern white cabbage (Brassica oleracea var. capitata) variety Rivera. However, nothing is known about the molecular mechanisms or the genes involved in this resistance. In the present study, a multidisciplinary approach combining transcriptome and metabolome profiling with genetic mapping was used to identify the molecular players of whitefly resistance in cabbage. Transcriptome profiles of young (susceptible) and older (resistant) Rivera plants were analyzed using RNA sequencing. While many genes involved in general processes were differentially expressed between both ages, several defense-related processes were overrepresented in the transcriptome profile of older plants. Hormone measurements revealed that jasmonic acid (JA) levels decreased upon whitefly infestation at both plant ages. Interestingly, abscisic acid (ABA) levels showed contrasting effects in response to whitefly infestation: ABA levels were reduced in young plants but induced in older plants upon whitefly feeding. Auxin levels were significantly lower in older plants compared with young plants, independent of whitefly presence, while glucosinolate levels were higher. Additionally, whitefly performance was monitored in an F2 population derived from a cross between Rivera and the susceptible white cabbage variety Christmas Drumhead. Significant QTL intervals were mapped on chromosome 2 and 9 for oviposition rate and whitefly adult survival, respectively. Several genes that were higher expressed in older plants and located in the identified QTL intervals were orthologous to Arabidopsis genes that have been related to ABA signaling, suggesting a role for ABA in the regulation of resistance towards whiteflies. Our results show that combining different omics approaches is a useful strategy to identify candidate genes underlying insect resistance. PMID- 30399183 TI - A predictive epilepsy index based on probabilistic classification of interictal spike waveforms. AB - Quantification of interictal spikes in EEG may provide insight on epilepsy disease burden, but manual quantification of spikes is time-consuming and subject to bias. We present a probability-based, automated method for the classification and quantification of interictal events, using EEG data from kainate- and saline injected mice (C57BL/6J background) several weeks post-treatment. We first detected high-amplitude events, then projected event waveforms into Principal Components space and identified clusters of spike morphologies using a Gaussian Mixture Model. We calculated the odds-ratio of events from kainate- versus saline treated mice within each cluster, converted these values to probability scores, P(kainate), and calculated an Hourly Epilepsy Index for each animal by summing the probabilities for events where the cluster P(kainate) > 0.5 and dividing the resultant sum by the record duration. This Index is predictive of whether an animal received an epileptogenic treatment (i.e., kainate), even if a seizure was never observed. We applied this method to an out-of-sample dataset to assess epileptiform spike morphologies in five kainate mice monitored for ~1 month. The magnitude of the Index increased over time in a subset of animals and revealed changes in the prevalence of epileptiform (P(kainate) > 0.5) spike morphologies. Importantly, in both data sets, animals that had electrographic seizures also had a high Index. This analysis is fast, unbiased, and provides information regarding the salience of spike morphologies for disease progression. Future refinement will allow a better understanding of the definition of interictal spikes in quantitative and unambiguous terms. PMID- 30399184 TI - Treatment of personality disorder using a whole of service stepped care approach: A cluster randomized controlled trial. AB - BACKGROUND AND OBJECTIVES: People with personality disorders are prevalent in emergency and inpatient mental health services. We examined whether implementing a stepped care model of psychological therapy reduces demand on hospital units by people with personality disorder, in a cluster randomized controlled trial. METHOD: A total of 642 inpatients (average age 36.8, 50.5% female) with a primary ICD-10 personality disorder were recruited during 18 months baseline, then monitored during an 18 month active trial phase. In the active trial phase two equivalent sites were randomised to either treatment as usual (TAU), or a whole of service intervention that diverted people away from hospital and into stepped care psychological therapy clinics. The study design was cost neutral, with no additional staff or resources deployed between sites. A linear mixed models analysis evaluated outcomes. RESULTS: As predicted, demand on hospital services reduced significantly in the intervention compared to TAU site. The intervention site evidenced shorter bed days, from an average of 13.46 days at baseline to 4.28 days per admission, and patients were 1.3 times less likely to re-present to the emergency department compared to TAU. Direct cost savings for implementing the approach was estimated at USD$2,720 per patient per year. Limitations included not directly comparing individual symptom changes. CONCLUSIONS: Using a whole of service stepped care model of treatment for personality disorder significantly reduced demand on hospital services. PMID- 30399186 TI - Oviparous elasmobranch development inside the egg case in 7 key stages. AB - Embryological stages of oviparous elasmobranch during development can be difficult to identify, requiring magnification and/or fixation of an anaesthetized embryo. These restrictions are poorly suited for monitoring the development of living elasmobranchs inside their egg cases. There are two major aims of this study. The first was to observe elasmobranch embryonic development non-invasively and produce a non-invasive developmental key for identifying the life stages for an elasmobranch inside the egg case. To this end, 7 key developmental stages were identified for the greater spotted catshark, Scyliorhinus stellaris, and are provided here with diagrams from multiple perspectives to demonstrate the key features of each stage. The physiological and ecological relevance of each stage are discussed in terms of structure and function for embryonic survival in the harsh intertidal zone. Also discussed is the importance of the egg case membrane and the protective embryonic jelly. The second aim of the study was to understand the applicability of the 7 developmental stages from S. stellaris to other oviparous elasmobranchs. Thus, changes in embryonic body size and egg yolk volume at each stage were measured and compared with those of the closely related, lesser spotted catshark, Scyliorhinus canicula. We find nearly identical growth patterns and yolk consumption patterns in both species across the 7 developmental stages. Thus, although the 7 developmental stages have been constructed in reference to the greater spotted catshark, we suggest that it can be applied to other oviparous elasmobranch species with only minor modification. PMID- 30399185 TI - Arrhythmia initiation in catecholaminergic polymorphic ventricular tachycardia type 1 depends on both heart rate and sympathetic stimulation. AB - AIMS: Catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) predisposes to ventricular tachyarrhythmias (VTs) during high heart rates due to physical or psychological stress. The essential role of catecholaminergic effects on ventricular cardiomyocytes in this situation is well documented, but the importance of heart rate per se for arrhythmia initiation in CPVT1 is largely unexplored. METHODS AND RESULTS: Sixteen CPVT1 patients performed a bicycle stress-test. Occurrence of VT triggers, i.e. premature ventricular complexes (PVC), depended on high heart rate, with individual thresholds. Atrial pacing above the individual PVC threshold in three patients did not induce PVCs. The underlying mechanism for the clinical observation was explored using cardiomyocytes from mice with the RyR2-R2474S (RyR2-RS) mutation, which exhibit exercise-induced VTs. While rapid pacing increased the number of Ca2+ waves in both RyR2-RS and wild-type (p<0.05), beta-adrenoceptor (betaAR) stimulation induced more Ca2+ waves in RyR2-RS (p<0.05). Notably, Ca2+ waves occurred despite decreased sarcoplasmic reticulum (SR) Ca2+ content in RyR2-RS (p<0.05), suggesting increased cytosolic RyR2 Ca2+ sensitivity. A computational model of mouse ventricular cardiomyocyte electrophysiology reproduced the cellular CPVT1 phenotype when RyR2 Ca2+ sensitivity was increased. Importantly, diastolic fluctuations in phosphorylation of RyR2 and SR Ca2+ content determined Ca2+ wave initiation. These factors were modulated towards increased propensity for arrhythmia initiation by increased pacing rates, but even more by betaAR stimulation. CONCLUSION: In CPVT1, VT propensity depends on individual heart rate thresholds for PVCs. Through converging data from clinical exercise stress testing, cellular studies and computational modelling, we confirm the heart rate independent pro-arrhythmic effects of betaAR stimulation in CPVT1, but also identify an independent and synergistic contribution from effects of high heart rate. PMID- 30399187 TI - Longitudinal analysis of developmental changes in electroencephalography patterns and sleep-wake states of the neonatal mouse. AB - The neonatal brain undergoes rapid maturational changes that facilitate the normal development of the nervous system and also affect the pathological response to brain injury. Electroencephalography (EEG) and analysis of sleep-wake vigilance states provide important insights into the function of the normal and diseased immature brain. While developmental changes in EEG and vigilance states are well-described in people, less is known about the normal maturational properties of rodent EEG, including the emergence and evolution of sleep-awake vigilance states. In particular, a number of developmental EEG studies have been performed in rats, but there is limited comparable research in neonatal mice, especially as it pertains to longitudinal EEG studies performed within the same mouse. In this study, we have attempted to provide a relatively comprehensive assessment of developmental changes in EEG background activity and vigilance states in wild-type mice from postnatal days 9-21. A novel EEG and EMG method allowed serial recording from the same mouse pups. EEG continuity and power and vigilance states were analyzed by quantitative assessment and fast Fourier transforms. During this developmental period, we demonstrate the timing of maturational changes in EEG background continuity, frequencies, and power and the emergence of identifiable wake, NREM, and REM sleep states. These results should serve as important control data for physiological studies of mouse models of normal brain development and neurological disease. PMID- 30399188 TI - Concurrent validity of an isokinetic lift test used for admission to the Swedish Armed Forces. AB - The aim of this study was to assess the concurrent validity of the IsoKai isokinetic lift test peak force (IsoKaiPeak) in comparison to a submaximal 5-10RM deadlift test (5-10RMDL), and to develop an equation for converting the IsoKaiPeak in Newton (N) to an estimated 1RM (1RMest) deadlift load in kilograms (kg). The participants included 28 males and 16 female employees in the Swedish Armed Forces (20-59 years). Each participant conducted the IsoKai lift test, followed by the 5-10RMDL test at one occasion. The Pearson's correlation coefficient, with a 95% confidence interval was calculated to evaluate the validity between the IsoKaiPeak and the 1RMest deadlift load derived from the 5 10RMDL test. Univariate and multivariable linear regressions were used to derive the equation for calculating the 1RMest deadlift load based on the IsoKaiPeak. The IsoKaiPeak showed good- to-excellent correlation with the 1RMest deadlift weight with a correlation coefficient of 0.84 (0.72-0.91) for the total sample, and 0.65 (0.37-0.83) and 0.81 (0.53-0.93) in males and females, respectively. The final equation, 1RMest deadlift weight (kg) = -51.63 + (0.08 x IsoKaiPeak) + (2.28 x BMI), explained 72% (adjusted R2 = 0.72) of the total variance in the 1RMest, and had a standard error of the estimate (SEE) of 16.57 kg. In conclusion, the IsoKai isokinetic lift test could be considered a highly valid measure of maximal dynamic muscular strength in comparison to the 5-10RMDL. The equation can be used to convert the IsoKai lift test (N) results to an 1RMest deadlift load (kg), but with consideration of the relative large SEE. PMID- 30399189 TI - Prevalence of underweight, overweight and obesity and their associated risk factors in Nepalese adults: Data from a Nationwide Survey, 2016. AB - INTRODUCTION: Over the past few decades, the total population of Nepal has increased substantially with rapid urbanization, changing lifestyle and disease patterns. There is anecdotal evidence that non-communicable diseases (NCDs) and associated risk factors are becoming key public health challenges. Using nationally representative survey data, we estimated the prevalence of underweight, overweight and obesity among Nepalese adults and explored socio demographic factors associated with these conditions. MATERIALS AND METHODS: We used the Nepal Demographic Health Survey 2016 data. Sample selection was based on stratified two-stage cluster sampling in rural areas and three stages in urban areas. Weight and height were measured in all adult women and men. Body mass index (BMI) was calculated using Asian specific BMI cut-points. RESULTS: A total of 13,542 adults aged 18 years and above (women 58.19%) had their weight and height measured. The mean (+/-SD) age was 40.63+/-16.82 years (men 42.75+/-17.27, women 39.15+/-16.34); 41.13% had no formal education and 60.97% lived in urban areas. Overall, 17.27% (95% CI: 16.64-17.91) were underweight; 31.16% (95% CI: 30.38-31.94) overweight/obese. The prevalence of both underweight (women 18.30% and men 15.83%, p<0.001) and overweight/obesity (women 32.87% and men 28.77%, p<0.001) was higher among women. The older adults (>=65 years) (aOR: 2.40, 95% CI: 1.92-2.99, p<0.001) and the adults of poorest wealth quintile (aOR: 2.05, 95% CI: 1.62-2.59, p<0.001) were more likely to be underweight. The younger age adults (36-45 years) (aOR: 3.05, 95% CI: 2.61-3.57, p<0.001) and women (aOR: 1.53, 95% CI 1.39-1.68, p<0.001) were more likely to be overweight or obese. Also, all adults were twice likely to overweight/obese (p<0.001). No significant difference was observed for overweight/obesity by ecological regions and place of residence (urban vs. rural). CONCLUSION: These findings confirm co-existence of double burden of underweight and overweight/obesity among Nepalese adults. These conditions are associated with increased risk of developing NCDs. Therefore, effective public health intervention approaches emphasizing improved primary health care systems for NCDs prevention and care and using multi-sectoral approach, is essential. PMID- 30399190 TI - High intensity resistance training causes muscle damage and increases biomarkers of acute kidney injury in healthy individuals. AB - PURPOSE: High-intensity interval resistance training (HIIRT) is an increasingly popular exercise program that provides positive results with short sessions. This study aimed to evaluate whether an HIIRT session causes muscle and kidney damage. METHODS: Fifty-eight healthy volunteers (median age 24 years, 50% women) participated in this study and performed a HIIRT session. The Borg CR10 scale for pain (CR10P) and blood and urine samples were collected before (baseline) and 2 and 24 hours after the HIIRT session. Blood samples were analyzed for serum creatinine (SCr), creatine kinase (CK) and myoglobin. Urine samples were assessed for creatinine, neutrophil gelatinase-associated lipocalin, interleukin 18, calbindin, microalbuminuria, trefoil factor-3 and beta-2 microglobulin. RESULTS: CR10P had a significant increase at 2 and 24 hours post-workout, and CK increased significantly at 2 hours and increased further at 24 hours. Myoglobin increased significantly at 2 hours and remained elevated at 24 hours. SCr increased modestly but significantly at 24 hours only in men. Three men met the KDIGO diagnostic criteria for acute kidney injury. The urinary kidney injury biomarkers increased significantly at 2 hours and returned to the baseline values 24 hours after HIIRT. CONCLUSIONS: A single HIIRT session caused early and significant elevations in CK, myoglobin, SCr, microalbuminuria and urinary biomarkers indicative of kidney tubular injury, suggesting the occurrence of muscle and kidney damage. PMID- 30399191 TI - Amalgam tattoo versus melanocytic neoplasm - Differential diagnosis of dark pigmented oral mucosa lesions using infrared spectroscopy. AB - BACKGROUND: Dark pigmented lesions of the oral mucosa can represent a major diagnostic challenge. A biopsy is usually required to determine the nature of such intraoral discolorations. This study investigates the potential use of infrared spectroscopy for differential diagnosis of amalgam tattoos versus benign or malignant melanocytic neoplasms. MATERIALS AND METHODS: For this retrospective study, formalin-fixed paraffin-embedded tissue (FFPE) specimens of dark pigmented lesions concerning the oral mucosa or the lip were investigated using mid infrared spectroscopy. The samples were chosen from patients who had undergone a mucosal biopsy at the University Hospital Innsbruck (Austria) between the years 2000 and 2017. Principal component analysis was used for data exploration. Evaluation was based on the superimposition of the recorded spectra and the corresponding histologic slides. RESULTS: In total, 22 FFPE specimens were analyzed. Clear differences were found between amalgam and non-amalgam samples. A general weakening of the penetrating infrared radiation allowed for unspecific discrimination between these two classes. An overall accuracy in predicting the correct class of 95.24% was achieved. CONCLUSION: Infrared spectroscopy appears to be a suitable technique to differentiate between amalgam tattoos and melanocytic lesions in FFPE samples. It could potentially be applied in vivo, too, serving as a non-invasive diagnostic tool for intraoral dark pigmented lesions. PMID- 30399194 TI - Placebo acceptability in chronic pain patients: More dependent on application mode and resulting condition than on individual factors. AB - INTRODUCTION: Placebo effects can be very effective in certain pain conditions, but their use is still highly controversial. Several studies show that patients would accept a placebo treatment under certain circumstances, particularly when they are informed prior to the treatment or when there are no effective treatment alternatives. This study examines the question, which factors influence the degree of acceptability of a hypothetical placebo application. METHODS: Patients filled in a questionnaire dealing with placebo applications. Moreover general data, diagnosis, duration of pain, pain ratings and anxiety/depression/stress scores, sleep disorders and opioid intake were collected from the patients' charts. 129 patients (44 men / 85 women, mean age 51.5 years, 18.0-80.9 years) entered the study. All patients had chronic pain syndromes and were treated in an universitary academic interdisciplinary pain center. Mean duration of pain was 14.7 years. RESULTS: The study did not show significant differences in placebo acceptability among patients with different pain diagnoses or accompanying psychological diagnoses or disorders. Hidden placebo application was considered much more unacceptable for the patients than the enhanced placebo or the open placebo application. An improved condition was associated with less feeling of deception, more trust and less negative mood than an unchanged or worsened condition. CONCLUSION: Acceptance of placebo as pain therapy is much more dependent on the way of application (hidden or open) or on the resulting condition (improved, unchanged or worsened) than on factors inherent in the individual patients. PMID- 30399193 TI - Melatonin improves neurological outcomes and preserves hippocampal mitochondrial function in a rat model of cardiac arrest. AB - Cerebral injury after cardiac arrest (CA)/cardiopulmonary resuscitation (CPR) has been implicated in the poor prognosis of CA survivors. This study was designed to evaluate the impact of melatonin on postresuscitation neurological outcomes and to explore the underlying mechanism. Sprague-Dawley rats were randomly assigned to four groups: sham group, CPR group, melatonin pretreatment group (Pre-M) and posttreatment group (Post-M). For the last 2 groups, daily melatonin gavage was performed for 12 consecutive days before or 24 hours after rat survival from CA/CPR. No statistical differences were observed in heart rate (HR), mean arterial blood pressure (MAP), and end-tidal carbon dioxide (ETCO2) at baseline and after restoration of spontaneous circulation (ROSC) among groups. However, melatonin pretreatment or posttreatment significantly improved neurological deficit score and memory and spatial learning ability after CA/CPR. Further studies demonstrated that the complex I- and complex-II supported mitochondrial respiration were greatly increased under melatonin treatment. In addition, melatonin treatment preserved the mitochondrial-binding hexokinase II (HKII) and ATP levels and suppressed the upregulated protein lysine acetylation in hippocampus after CA/CPR. In conclusion, using a rat asphyxial CA model we have demonstrated that treatment with melatonin either before or after CA/CPR provides a promising neuroprotective effect, and this protection was mediated by increasing mitochondrial HKII expression, suppressing protein acetylation and improving mitochondrial function in hippocampus. PMID- 30399195 TI - Discriminatory performance of adiponectin and leptin in the identification of impaired glucose tolerance: The Guangzhou Biobank Cohort Study - Cardiovascular Disease Subcohort. AB - BACKGROUND: To evaluate the additional discriminatory performance of adiponectin, leptin, and their ratio in the identification of impaired glucose tolerance (IGT) in men and women without diabetes on top of conventional risk factors. METHODS & RESULTS: A total of 698 subjects underwent an oral glucose tolerance test (oGTT) and adipocytokine measurements. A comprehensive stepwise selection procedure was performed, followed by c-statistics and integrated discrimination improvement (IDI) analysis. In males, adiponectin levels were significantly lower in the IGT group compared to the non-IGT group (Whitney U test, p < 10-4), whereas leptin levels were significantly higher (p = 0.009) in IGT group. In females, adiponectin and leptin levels were not significantly different between groups (Mann-Whitney U test, p = 0.073 and p = 0.08, respectively). Adjusting for the most informative, sex-specific, clinical and biochemical factors, adiponectin, leptin and their ratio were not found to be significant predictors of the response to the glucose load, when modelled as continuous terms or tertiles. In males, the area-under-the-curve (AUC) for adiponectin was estimated at 0.620 (95% CI: 0.558-0.682) and the addition of adiponectin into the basic model provided a DeltaAUC benefit of 0.004, showing no additional discriminatory benefit on top of conventional risk factors (IDI p-value: 0.27), nor did the addition of leptin or their ratio. The results were similar in females. CONCLUSIONS: In Chinese individuals without diabetes, no significant evidence for the potential discriminatory value of adiponectin, leptin or their ratio in the identification of IGT on top of conventional risk factors was observed. PMID- 30399192 TI - Prevention of lipopolysaccharide-induced preterm labor by the lack of CX3CL1 CX3CR1 interaction in mice. AB - Preterm labor (PTL) is the most common cause of neonatal death and long-term adverse outcome. The pharmacological agents for PTL prevention are palliative and frequently fail to prevent PTL and improve neonatal outcome. It is essential to fully understand the molecular mechanisms of PTL in order to develop novel therapeutic methods against PTL. Several lines of evidence indicate some chemokines are expressed in gestational tissues during labor or PTL. To reveal the pathophysiological roles of the CX3CL1-CX3CR1 axis in PTL, we performed present study using LPS-induced PTL mice model in CX3CR1-deficient (Cx3cr1-/-) mice. We indicated that PTL was suppressed in Cx3cr1-/- mice and immunoneutralization of CX3CL1 in WT mice. From immunohistochemical and the gene expression analyses, the CX3CL1-CX3CR1 axis has detrimental roles in PTL through intrauterine recruitment of macrophages and the enhancement of macrophage-derived inflammatory mediators. Thus, the CX3CL1-CX3CR1 axis may be a good molecular target for preventing PTL. PMID- 30399196 TI - Proteome-scale understanding of relationship between homo-repeat enrichments and protein aggregation properties. AB - Expansion of homo-repeats is a molecular basis for human neurological diseases. We are the first who studied the influence of homo-repeats with lengths larger than four amino acid residues on the aggregation properties of 1449683 proteins across 122 eukaryotic and bacterial proteomes. Only 15% of proteins (215481) include homo-repeats of such length. We demonstrated that RNA-binding proteins with a prion-like domain are enriched with homo-repeats in comparison with other non-redundant protein sequences and those in the PDB. We performed a bioinformatics analysis for these proteins and found that proteins with homo repeats are on average two times longer than those in the whole database. Moreover, we are first to discover that as a rule, homo-repeats appear in proteins not alone but in pairs: hydrophobic and aromatic homo-repeats appear with similar ones, while homo-repeats with small, polar and charged amino acids appear together with different preferences. We elaborated a new complementary approach to demonstrate the influence of homo-repeats on their host protein aggregation properties. We have shown that addition of artificial homo-repeats to natural and random proteins results in intensification of aggregation properties of the proteins. The maximal effect is observed for the insertion of artificial homo-repeats with 5-6 residues, which is consistent with the minimal length of an amyloidogenic region. We have also demonstrated that the ability of proteins with homo-repeats to aggregate cannot be explained only by the presence of long homo repeats in them. There should be other characteristics of proteins intensifying the aggregation property including such as the appearance of homo-repeats in pairs in the same protein. We are the first who elaborated a new approach to study the influence of homo-repeats present in proteins on their aggregation properties and performed an appropriate analysis of the large number of proteomes and proteins. PMID- 30399197 TI - The evolving drug epidemic of prescription opioid injection and its association with HCV transmission among people who inject drugs in Montreal, Canada. AB - AIMS: To examine temporal trends in prescription opioid (PO) injection and to assess its association with hepatitis C virus (HCV) seroconversion among people who inject drugs (PWID). DESIGN: Prospective cohort study spanning 2004 to 2016. SETTING: Montreal, Canada. PARTICIPANTS: PWID reporting injection in the past 6 months. MEASUREMENTS: PWID were recruited between 2004 and 2016. At each 3-6 month follow-up visit, participants completed interview-administered questionnaires and were tested for HCV-Antibody (HCV-Ab). FINDINGS: Among 1524 PWID (83% males, mean age 38 (SD=10), 34% (31-36) PO injection past month) included in trends analyses, PO injection use expanded between 2004-2009, and plateaued between 2010-2016 (trend tests <0.001 and 0.0.335 respectively). Of the 432 HCV-seronegative PWIDs followed at least once (81% males, mean age 34 (sd 9.8), 38% injection PO), 153 became HCV-Ab positive during 1230 years of follow up, for an incidence of 12.4 per 100 person-years (95% CI=10.6, 14.6). PO injectors were 3.9 times more likely to seroconvert to HCV, relative to non PO injectors. In a multivariate analysis, a stronger association between PO injection and HCV seroconversion was found post 2009 (aHR=5.4, 95%CI: 2.7, 10.8) than before (aHR = 1.5 (0.9, 2.4), (p-value for interaction < 0.001). CONCLUSION: Prescription opioid injection increased among people who inject drugs in Montreal Canada from 2004 to 2009, to reach a plateau between 2010 and 2016. The association between prescription opioid injection and HCV seroconversion was stronger during the second period than the first according to the epidemic phase. PMID- 30399198 TI - The interaction between BRAF mutation and microsatellite instability (MSI) status in determining survival outcomes after adjuvant 5FU based chemotherapy in stage III colon cancer. AB - PURPOSE: The predictive role of biomarkers in colon cancer is still being defined. The aim of this study is to determine the interaction between BRAF mutation and microsatellite instability (MSI) status in determining survival benefit after adjuvant 5-FU based chemotherapy in stage III colon cancer. METHODS: We performed a retrospective cohort study including all curatively resected stage III colon cancer cases over a 33-year period. A clinicopathological database was collated (adjuvant chemotherapy, age, gender, obstruction, perforation, tumor location, grade, mucin, nodal stage, extramural vascular, and perineural invasion). BRAF (V600E) mutation testing was performed and MSI status established by immunohistochemistry for mismatch repair proteins and molecular testing for National Cancer Institute panel markers. Patients were categorized into four groups for comparison: MSS and BRAF-ve (termed " traditional"), MSI and BRAF-ve (termed " presumed Lynch"), MSI and BRAF+ve (termed " sporadic MSI"), and MSS and BRAF+ve (termed " other BRAF"). The primary endpoint was cancer specific survival. Interaction testing was conducted to determine whether there were different responses to chemotherapy between groups. RESULTS: A total of 686 unselected cases met inclusion criteria and had tissue available, of which 15.7% had BRAF mutation (BRAF+ve) and 13.8% had MSI. Thirty nine percent received chemotherapy. Overall, adjuvant chemotherapy produced a cancer specific survival benefit (HR 0.66, 95% CI, 0.49-0.88, P < 0.01). On adjusted analysis, neither BRAF nor MSI status were individually predictive of survival benefit. On adjusted analysis specifically of the chemotherapy effect in each subgroup, only patients in the presumed Lynch (HR 0.260, 95% CI, 0.09-0.80, P < 0.01) and other BRAF groups (HR 0.45, 95% CI, 0.23-0.87, P < 0.01) had a significant survival benefit from chemotherapy. On interaction testing of subgroups, adjusting for all the clinicopathological parameters, only patients in the presumed Lynch group (HR 0.277, 95% CI, 0.10-0.75, P < 0.01) gained a differentially greater benefit from chemotherapy than other groups. CONCLUSIONS: In this historical cohort, MSI testing is predictive of response to adjuvant chemotherapy in stage III colon cancer, but only when results are interpreted in combination with BRAF. This supports the role of routine testing for these biomarkers. PMID- 30399199 TI - Tumor cell seeding in the biopsy tract and its clinical significance in osteosarcomas. AB - BACKGROUND AND OBJECTIVES: The reasons behind the removal of the biopsy tract in osteosarcomas are not well known, and studies about tumor seeding in the biopsy tract have generated conflicting results. This study is designed to evaluate the presence and possible clinical significance of tumor cell seeding in the biopsy tract of osteosarcomas. METHODS: We prospectively evaluated 55 cases of osteosarcomas for tumor cell seeding and other clinical and pathologic prognostic parameters. RESULTS: Eleven cases (20%) involved microscopic tumor foci in the biopsy tract. The higher local recurrence rates (P = 0.005) and worse recurrence free survivals ( P = 0.009) were observed in patients with tumor cell foci in the biopsy tract. Mitotic rate, tumor cell pleomorphism, and matrix production in main tumor foci were higher in cases with tumor seeding ( P = 0.047, P = 0.012, and P = 0.005, respectively) CONCLUSIONS: Tumor seeding in the biopsy tract is a fact in osteosarcomas. The higher local recurrence rates are more likely to occur in cases with tumor seeding. PMID- 30399200 TI - The everlasting issue of prolonged air leaks after lobectomy for non-small cell lung cancer: A data-driven prevention planning model in the era of minimally invasive approaches. AB - BACKGROUND AND OBJECTIVES: Prolonged air leaks (PAL) are the most frequent complication after lobectomy for non-small cell lung cancer, even in case of minimally invasive approaches. We developed a novel score to identify high-risk patients for PAL during minimally invasive lobectomy. METHODS: A dedicated database was created. We investigated preoperative candidate features and specific intraoperative variables. Univariate and subsequent logistic regression analysis with bootstrap resampling have been used. Model performance has been assessed by reckoning the area under the receiver operating characteristics curve and the Hosmer-Lemeshow goodness of fit. RESULTS: PAL (>5 days) occurred in 72 (15.69%) patients. Five variables emerged from the model. Each one was assigned a score to provide a cumulative scoring system: forced expiratory volume in 1 second below 86% (P = 0.004, 1.5 points), body mass index <24 ( P = 0.002, 1 point), active smoking ( P = 0.001, 1.5 points), incomplete fissures ( P = 0.004, 1.5 points), and adhesions ( P = 0.0001, 1 point). The new score provided a stratification into four risk classes. CONCLUSIONS: The risk score incorporates either general or more specific variables, providing a risk stratification that could be readily applied intra- and postoperatively. Henceforth, specific technical and management measures could be properly allocated to curb PAL. PMID- 30399201 TI - Reply to: Bariatric Surgery, Physical Activity, and Fracture Risk. PMID- 30399202 TI - Management of locoregional recurrence after radical resection of a primary nonmetastatic retroperitoneal soft tissue sarcoma: The Gustave Roussy experience. AB - BACKGROUND: Despite surgery, many patients experience locoregional recurrence (LR), the optimum treatment of which is still debated. METHODS: All 297 consecutive patients operated for a nonmetastatic primary retroperitoneal soft tissue sarcoma (RPS) between 1994 and 2017 were retrospectively analyzed to report our experience in treating LR. RESULTS: After a median follow-up of 97 months, 55 patients (19%) developed LR. The first site of recurrence was locoregional in 100% with associated peritoneal metastases in 45% and distant metastases in 5%. After LR treatment, the 1-, 3-, and 5-year overall survival (OS) rates were 71%, 46%, and 33%. Low tumor grade, disease-free interval above 24 months, exclusive LR, and well-differentiated liposarcoma were predictive of better OS. The treatment strategy (best supportive care, chemotherapy radiotherapy, and/or surgery) was not statistically significant. Fourteen patients underwent initial surveillance (strategic delay) for low-grade LR and eventually required treatment in 86% after a median delay of 20 months during which no patient developed distant metastases. CONCLUSIONS: The management of LR in RPS is complex. An initial surveillance may not alter survival in asymptomatic low-grade and slow-growing LR. An LR decision scheme is proposed. PMID- 30399203 TI - Growing identification of genetic aetiologies for neonatal-onset epilepsies: lessons from the Neonatal Seizure Registry. PMID- 30399204 TI - Pre-operative predictors of early recurrence/mortality including the role of inflammatory indices in patients undergoing partial hepatectomy for spontaneously ruptured hepatocellular carcinoma. AB - BACKGROUND AND OBJECTIVES: Spontaneous rupture of Hepatocellular Carcinoma (srHCC) is a life-threatening emergency. We sought to identify the pre-operative predictors of early tumor recurrence/mortality including the role of inflammatory indices after partial hepatectomy for srHCC. METHODS: Between 2000-2015, 79 patients with srHCC were identified to have undergone upfront partial hepatectomy following srHCC. Clinicopathologic data were retrospectively analyzed to identify pre-operative predictors of early (<1 year) recurrence and mortality. RESULTS: Seventy-nine patients were identified to have undergone partial hepatectomy for srHCC. The 1-year mortality and 1-year recurrence rate in our series was 30.3% and 41.8% respectively. On multivariate analyses, free tumor rupture and a tumor size > 10 cm were identified to be independent predictors of early recurrence while an alpha fetoprotein (AFP) > 200 ng/mL was an independent predictor of early mortality. Neutrophil-to-lymphocyte ratio > 3 and prognostic nutritional index < 40 were predictors of early recurrence while PLR > 180 was a predictor of early mortality on univariate analyses but not multivariate analyses. CONCLUSIONS: Tumor size > 10 cm, free tumor rupture, and an AFP > 200 ng/mL were useful predictors in avoiding "futile surgery" in patients with srHCC undergoing a partial hepatectomy. Preoperative inflammatory markers appear to be less useful as predictors of early recurrence/mortality in this cohort of patients. PMID- 30399205 TI - Comparative Evaluation of the Antioxidant Capacities and Organic Acid and Volatile Contents of Mango Slurries Fermented with Six Different Probiotic Microorganisms. AB - Mango slurries were fermented with 6 different probiotic microorganisms (Lactobacillus plantarum, Streptococcus thermophilus, Lactobacillus casei, Saccharomyces cerevisiae D254, S. cerevisiae DV10, and S. cerevisiae R2) to develop products with higher bioactivity. Changes in pH, reducing sugars, organic acids, and volatile compounds were determined. In addition, total phenolics and antioxidant capacity during fermentation were monitored. Among the strains used, S. cerevisiae D254 exhibited the fastest utilization of sugar in a mango slurry. Different volatile compounds were produced, mainly consisting of fatty acids, alcohols, and esters. S. cerevisiae DV10 produced higher amounts of esters and alcohols. The antioxidant capacity of the mango slurries improved by different degrees after fermentation with the six probiotic microorganisms. Fermentation with L. plantarum obtained the most organic acids as well as total phenolics and exhibited the highest FRAP and CUPRAC values. The results of this study indicated that fermentation with probiotic microorganisms can enhance the health benefits obtained from mango slurries. PRACTICAL APPLICATION: Probiotic-fermented mango slurry is a fermentation product that combines the nutritional value of mango with the health benefits of probiotics. Probiotic fermentation improves the flavor of a mango slurry and increases the availability and variety of mango products that can be appreciated by consumers. PMID- 30399206 TI - Arylation Chemistry for Bioconjugation. AB - Bioconjugation chemistry has been used to prepare modified biomolecules with functions beyond what nature intended. Central to these techniques is the development of highly efficient and selective bioconjugation reactions that operate under mild, biomolecule compatiable conditions. Methods that form a nucleophile-sp2 carbon bond show promise for creating bioconjugates with new modifications, sometimes resulting in molecules with unparalleled functions. Here we outline and review sulfur, nitrogen, selenium, oxygen, and carbon arylative bioconjugation strategies and their applications to modify peptides, proteins, sugars, and nucleic acids. PMID- 30399207 TI - IL-17 Receptor Signaling in Osteoblasts/Osteocytes Mediates PTH-Induced Bone Loss and Enhances Osteocytic RANKL Production. AB - Primary hyperparathyroidism (PHPT) is a condition where elevated PTH levels lead to bone loss, in part through increased production of the osteoclastogenic factor IL-17A, by bone marrow (BM) T-helper 17 (Th17) cells, a subset of helper CD4+ T cells. In animals, PHPT is modeled by continuous PTH treatment (cPTH). In mice, an additional critical action of cPTH is the capacity to increase the production of RANKL by osteocytes. However, a definitive link between IL-17A and osteocytic expression of RANKL has not been made. Here we show that cPTH fails to induce cortical and trabecular bone loss and causes less intense bone resorption in conditional knock-out (IL-17RADeltaOCY ) male and female mice lacking the expression of IL-17A receptor (IL-17RA) in dentin matrix protein 1 (DMP1)-8kb-Cre expressing cells, which include osteocytes and some osteoblasts. Therefore, direct IL-17RA signaling in osteoblasts/osteocytes is required for cPTH to exert its bone catabolic effects. In addition, in vivo, silencing of IL-17RA signaling in in DMP1-8kb-expressing cells blunts the capacity of cPTH to stimulate osteocytic RANKL production, indicating that cPTH augments osteocytic RANKL expression indirectly, via an IL-17A/IL-17RA-mediated mechanism. Thus, osteocytic production of RANKL and T cell production of IL-17A are both critical for the bone catabolic activity of cPTH. (c) 2018 American Society for Bone and Mineral Research. PMID- 30399209 TI - GOP gears up to transform Medicare. Is U.S. ready for wholesale change? PMID- 30399208 TI - Percutaneous vertebroplasty for osteoporotic vertebral compression fracture. AB - BACKGROUND: Percutaneous vertebroplasty remains widely used to treat osteoporotic vertebral fractures although our 2015 Cochrane review did not support its role in routine practice. OBJECTIVES: To update the available evidence of the benefits and harms of vertebroplasty for treatment of osteoporotic vertebral fractures. SEARCH METHODS: We updated the search of CENTRAL, MEDLINE and Embase and trial registries to 15 November 2017. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials (RCTs) of adults with painful osteoporotic vertebral fractures, comparing vertebroplasty with placebo (sham), usual care, or another intervention. As it is least prone to bias, vertebroplasty compared with placebo was the primary comparison. Major outcomes were mean overall pain, disability, disease-specific and overall health-related quality of life, patient reported treatment success, new symptomatic vertebral fractures and number of other serious adverse events. DATA COLLECTION AND ANALYSIS: We used standard methodologic procedures expected by Cochrane. MAIN RESULTS: Twenty-one trials were included: five compared vertebroplasty with placebo (541 randomised participants), eight with usual care (1136 randomised participants), seven with kyphoplasty (968 randomised participants) and one compared vertebroplasty with facet joint glucocorticoid injection (217 randomised participants). Trial size varied from 46 to 404 participants, most participants were female, mean age ranged between 62.6 and 81 years, and mean symptom duration varied from a week to more than six months.Four placebo-controlled trials were at low risk of bias and one was possibly susceptible to performance and detection bias. Other trials were at risk of bias for several criteria, most notably due to lack of participant and personnel blinding.Compared with placebo, high- to moderate-quality evidence from five trials indicates that vertebroplasty provides no clinically important benefits with respect to pain, disability, disease-specific or overall quality of life or treatment success at one month. Evidence for quality of life and treatment success was downgraded due to possible imprecision. Evidence was not downgraded for potential publication bias as only one placebo-controlled trial remains unreported. Mean pain (on a scale zero to 10, higher scores indicate more pain) was five points with placebo and 0.7 points better (0.3 better to 1.2 better) with vertebroplasty, an absolute pain reduction of 7% (3% better to 12% better, minimal clinical important difference is 15%) and relative reduction of 10% (4% better to 17% better) (five trials, 535 participants). Mean disability measured by the Roland-Morris Disability Questionnaire (scale range zero to 23, higher scores indicate worse disability) was 14.2 points in the placebo group and 1.5 points better (0.4 better to 2.6 better) in the vertebroplasty group, absolute improvement 7% (2% to 11% better), relative improvement 9% better (2% to 15% better) (four trials, 472 participants).Disease-specific quality of life measured by the Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO) (scale zero to 100, higher scores indicating worse quality of life) was 62 points in the placebo group and 2.3 points better (1.4 points worse to 6.7 points better), an absolute imrovement of 2% (1% worse to 6% better); relative improvement 4% better (2% worse to 10% better) (three trials, 351 participants). Overall quality of life (European Quality of Life (EQ5D), zero = death to 1 = perfect health, higher scores indicate greater quality of life) was 0.38 points in the placebo group and 0.05 points better (0.01 better to 0.09 better) in the vertebroplasty group, absolute improvement: 5% (1% to 9% better), relative improvement: 18% (4% to 32% better) (three trials, 285 participants). In one trial (78 participants), 9/40 (or 225 per 1000) people perceived that treatment was successful in the placebo group compared with 12/38 (or 315 per 1000; 95% CI 150 to 664) in the vertebroplasty group, RR 1.40 (95% CI 0.67 to 2.95), absolute difference: 9% more reported success (11% fewer to 29% more); relative change: 40% more reported success (33% fewer to 195% more).Low-quality evidence (downgraded due to imprecision and potential for bias from the usual care controlled trials) indicates uncertainty around the risk estimates of harms with vertebroplasty. The incidence of new symptomatic vertebral fractures (from six trials) was 48/418 (95 per 1000; range 34 to 264)) in the vertebroplasty group compared with 31/422 (73 per 1000) in the control group; RR 1.29 (95% CI 0.46 to 3.62)). The incidence of other serious adverse events (five trials) was 16/408 (34 per 1000, range 18 to 62) in the vertebroplasty group compared with 23/413 (56 per 1000) in the control group; RR 0.61 (95% CI 0.33 to 1.10). Notably, serious adverse events reported with vertebroplasty included osteomyelitis, cord compression, thecal sac injury and respiratory failure.Our subgroup analyses indicate that the effects did not differ according to duration of pain (acute versus subacute). Including data from the eight trials that compared vertebroplasty with usual care in a sensitivity analyses altered the primary results, with all combined analyses displaying considerable heterogeneity. AUTHORS' CONCLUSIONS: We found high- to moderate-quality evidence that vertebroplasty has no important benefit in terms of pain, disability, quality of life or treatment success in the treatment of acute or subacute osteoporotic vertebral fractures in routine practice when compared with a sham procedure. Results were consistent across the studies irrespective of the average duration of pain.Sensitivity analyses confirmed that open trials comparing vertebroplasty with usual care are likely to have overestimated any benefit of vertebroplasty. Correcting for these biases would likely drive any benefits observed with vertebroplasty towards the null, in keeping with findings from the placebo-controlled trials.Numerous serious adverse events have been observed following vertebroplasty. However due to the small number of events, we cannot be certain about whether or not vertebroplasty results in a clinically important increased risk of new symptomatic vertebral fractures and/or other serious adverse events. Patients should be informed about both the high- to moderate quality evidence that shows no important benefit of vertebroplasty and its potential for harm. PMID- 30399210 TI - Why can't devicemakers and insurers get along? PMID- 30399211 TI - Does long-term care deliver? PMID- 30399212 TI - Bringing world-class cancer care closer to home. Links between community hospitals and cancer centers can lead to better care and a better bottom line. PMID- 30399213 TI - Giving thanks for health and healthcare progress this holiday season. AB - Those of us who spend our time thinking about the fate of the nation's health and healthcare system have no shortage of things to be thankful for this holiday season. PMID- 30399214 TI - Hospitals need community conversations to ensure essential services remain available. AB - Our nation is in the midst of unprecedented change, and healthcare is in the thick of it. To better serve the needs of individuals we are placing greater emphasis on improving the patient experience; we are focused like a laser beam on enhancing quality and patient safety; and we are striving to increase value and make care affordable. PMID- 30399216 TI - Quest sees growth through hospital, system partnerships. AB - Quest Diagnostics, with $7.5 billion in sales in 2015, remains the world's largest provider of laboratory testing services. But with growth slowing, CEO Stephen Rusckowski has aggressively moved to Include "esoteric" testing in Its offerings and expand its relationships with major hospital systems and Integrated delivery networks. Modern Healthcare reporter Adam Rubenfire recently asked Rusckowski about the heightened competitive pressure in the laboratory testing market. The following is an edited transcript. PMID- 30399215 TI - Command centers help manage flow. PMID- 30399217 TI - Largest vendors of electronic health record systems Ranked by number of ambulatory-care providers using a vendor's certified system. PMID- 30399218 TI - THE DENTAL FORECAST: A CAUSE FOR CELEBRATION. PMID- 30399219 TI - What if a Patient Files a Complaint Against Me? PMID- 30399220 TI - A Review of Antibiotic Classifications. PMID- 30399221 TI - Oral Pathology Quiz #94. Case Number 1. Hyperplastic candidiasis. PMID- 30399222 TI - Re-Examining Safety Protocols for Tylenol. AB - Acetaminophen is one of the most commonly ingested medications both in the US and throughout the world. While generally considered to be one of the safer drugs on the market, life threatening hepatotoxicity occurs in patients who overdose, either intentionally or unintentionally, and fail to receive diagnosis and treatment in a timely manner. Prevention of overdose through proper patient education, coupled with timely recognition and treatment, is critical in patient management. PMID- 30399223 TI - Giving Back by Giving Smiles. Smile Bangladesh Repairs Cleft Palates and Lives. PMID- 30399224 TI - Five Things to Know About Peri-Implant Mucositis and Peri-Implantitis. AB - This brief manuscript is part of an educational evidence-based series intending to inform clinicians on most recent clinical findings. This article addresses five frequent questions on peri-implant mucositis and peri-implantitis while considering its epidemiology, diagnosis, etiology and management. PMID- 30399226 TI - Appeals court ruling gives FTC merger challenges new life. PMID- 30399225 TI - Now it's personal: Top execs fined for false claims. PMID- 30399227 TI - Why the CMS wants surgeons to code every 10 minutes. PMID- 30399228 TI - Aetna makes large bet on wellness with Apple Watches. PMID- 30399229 TI - No quick fix for Rx price spikes. AB - Patients are complaining their drugs are unaffordable. Insurers are protesting that specialty drug costs are forcing them to jack up premiums. State Medicaid directors say spiking pharmacy costs are forcing them to make painful coverage trade-offs. PMID- 30399230 TI - Building a lifeline for rural addicts. AB - Medication-assisted treatment for opioid abusers is scarce in rural areas, but three projects aim to develop strategies to make it more accessible. PMID- 30399231 TI - A mixed picture on public health. AB - Over the past year, there have been several reports indicating America's health status has taken a turn for the worse. PMID- 30399233 TI - Using genomics to pair patients with best breast cancer treatments. PMID- 30399232 TI - Transformation of healthcare requires physician leaders steeped in business skills. AB - Imagine a business leader. Did you envision a physician? Probably not. Doctors are experts in their chosen medical field but aren't conventionally thought of as possessing management leadership skills. PMID- 30399234 TI - "If one PBM won't give it to them, they'll get it from another PBM". AB - Some drug industry officials have tried to shift blame for rising retail drug prices to pharmacy benefit managers, who are hired by insurers, employers, unions and governments to negotiate prices and establish formularies. Consolidation among PBMs left just a handful of powerful players, and even the Medicare Payment Advisory Commission has lamented there is "a real complexity in how PBMs operate and where they get their revenues." Modern Healthcare Midwest Bureau Chief Bob Herman recently interviewed Mark Merritt, CEO of the Pharmaceutical Care Management Association, the PBM industry trade group, to get his take on the issues. The following is an edited excerpt. PMID- 30399235 TI - Largest healthcare systems: Ranked by total assets in 2015 ($ in millions). PMID- 30399236 TI - Cancer's Risky Business. Educating Your Patients About Cancer Risk Factors. AB - ALTHOUGH IT'S IMPOSSIBLE TO PREDICT what can lead to cancer in any individual, researchers look at data compiled over many years to make confident decisions that certain behaviors, characteristics, and factors increase the risk of developing cancer. By discussing these factors with patients, oncology nurses can potentially reduce or identify their chances of developing future cancers. PMID- 30399237 TI - How Do You Bridge Oncology Nurses and Genetic Counselors? PMID- 30399238 TI - How Nurses Can Help Women Adhere to Oral Adjuvant Breast Cancer Treatment. PMID- 30399239 TI - The Case of the Struggle to Stop Smoking. PMID- 30399240 TI - Balance Perfectionism and Self-Compassion With a Meditation Exercise. PMID- 30399241 TI - Safety Depends on Embracing Our Role as Quality Managers. PMID- 30399242 TI - New Guidelines Suggest Radiation for More Patients With Breast Cancer. PMID- 30399243 TI - Aetna's antitrust defeat may signal the end of health insurance mega-mergers. AB - The Aetna-Humana antitrust ruling will complicate any deal involving health insurers with significant Medicare Advantage holdings. That combined with the uncertain future of the ACA mean the industry is likely to see a wave of smaller tie-ups. PMID- 30399244 TI - Prevention benefits at risk. AB - ACA repeal puts free cancer screenings and other prevention benefits for seniors and many privately insured patients at risk, though political pressure could make paring benefits hard. PMID- 30399245 TI - What ACA repeal could mean for mental health coverage. AB - Rolling back the ACA's coverage expansions and essential benefits could undermine the mental health protections established in other legislation that won bipartisan support. PMID- 30399246 TI - Few healthcare sectors bemoan Trump's rejection of TPP trade deal. AB - The spurned TPP had few supporters in healthcare. Some groups said the intellectual property provisions were too strong, while others contended they weren't strong enough. PMID- 30399247 TI - The next frontier in quality measurement: How patients feel. AB - Performance measures based on patient-reported outcomes could be invaluable in gauging whether medical care actually made life better for patients, but the field is not yet mature enough to drive value-based payments. PMID- 30399248 TI - As for-profits stumble, regional systems pick up the pieces. AB - Some regional not-for-profit systems see acquiring the hospital assets of struggling for-profit operators as a way to gain referrals, expand their provider networks and consolidate their regions. PMID- 30399249 TI - How not to fix Medicare. AB - Donald Trump campaigned on a promise to leave Medicare alone. But in choosing Rep. Mick Mulvaney of South Carolina to head the Office of Management and Budget, he is signaling a huge fight lies ahead over the future of the program. PMID- 30399251 TI - Outpatient providers need to consider better care transitions, too. AB - Consider all care transitions, even those that might seem insignificant, such as the switch from a pediatric to an adult provider. Find a payment system that reimburses and grants flexibility for coordinated care. Put critical providers, such as behavioral health specialists and coordinators, in the same location. PMID- 30399250 TI - Proceed cautiously with Medicaid reforms to protect gains made in caring for our youth. AB - As the discussion about healthcare access and coverage in our nation goes forward, we all must be committed to ensuring that our nation's most precious resource-children and adolescents-are prioritized. PMID- 30399252 TI - 'Too many patients equate costs with quality'. AB - With Dr. Tom Price headed for confirmation to lead HHS, ambulatory surgery centers, often physician-owned, have cause for optimism. Price, an orthopedic surgeon and member of the U.S. House of Representatives, once chaired a chain of ASCs in his home state of Georgia. Recent CMS rules equalizing payments to ASCs and hospital outpatient departments were a start, says William Prentice, CEO of the Ambulatory Surgery Center Association, which represents nearly 3,000 of the 5,600 centers in the U.S. What follows is an edited transcript of his interview last week with Modern Healthcare editor Merrill Goozner. PMID- 30399253 TI - Finance companies with the largest healthcare loan portfolios: Ranked by amount of loans underwritten in 2016. PMID- 30399254 TI - Trump's HHS nominees tee up Obamacare repeal effort. PMID- 30399257 TI - Failure at one Indian Health Service hospital reveals a system in crisis. PMID- 30399256 TI - Advocates cheer mental health reforms in Cures bill. PMID- 30399255 TI - Add-ons ensure Cures Act easy lame-duck passage. PMID- 30399259 TI - We can't retreat from the progress achieved in pursuit of universal access to affordable care. PMID- 30399258 TI - The 21st Century Christmas Tree Act. AB - On the surface, it looks like every healthcare special interest and their 1,400 lobbyists won an early Christmas present courtesy of the 21st Century Cures Act, which passed the House of Representatives by a whopping 392-26 margin last week and appears headed for Senate passage and enactment. PMID- 30399260 TI - Using military-style discipline to enforce hand hygiene standards. PMID- 30399261 TI - 'Everybody feels they have to redo or dust off their strategic plan'. AB - Over the past decade, the top leadership of the nation's hospitals formulated their business plans on the twin premises that more people would have comprehensive health insurance and that the reimbursement system was moving inexorably toward value-based payment. Modern Healthcare reporter Steven Ross Johnson recently asked American Hospital Association CEO Rick Pollack what impact the election will have on those basic assumptions. The following is an edited transcript. PMID- 30399262 TI - Risk-corridor payments Ranked by insurance issuers owed the most for 2015 and 2014 ($ in millions). PMID- 30399263 TI - No repeal without replace, CEOs urge, as Trump readies a new healthcare overhaul. PMID- 30399264 TI - ACA repeal without replacement could spur insurer exodus. PMID- 30399265 TI - With Wellcare deal, future looks bright for Medicare Advantage plans. PMID- 30399266 TI - What to expect when Anthem and Cigna meet the Justice Department in court. PMID- 30399267 TI - How AHRQ's low profile threatens work on healthcare best practices. PMID- 30399268 TI - Faith in unregulated pensions. PMID- 30399269 TI - Where campaign ads mattered. PMID- 30399270 TI - America's pain. AB - Last week's Facing Addiction in America: The Surgeon General's Report on Alcohol, Drugs and Health did a grave disservice to Americans rightfully upset about the rising tide of drug and alcohol dependency in their communities. PMID- 30399271 TI - Need for more diversity in healthcare leadership represents a moral and business imperative. AB - In the turbulent environment known as the U.S. healthcare system, one thing- unfortunately--has remained constant: The absence of true diversity among the leaders who make the key decisions that guide and influence our industry. PMID- 30399272 TI - Integrated provider teams take 24/7 approach to preventing ER visits. PMID- 30399273 TI - Researching the most important questions shaping quality and safety. AB - If you've never heard of AHRQ, you're not alone. But the Agency for Healthcare Research and Quality is quietly fueling research that's shaping the fundamentals. of the U.S. healthcare system. In October, Modern Healthcare reporter Elizabeth Whitman spoke with Dr. Andy Bindman, who became AHRQ's director in May, about the agency's work; its. influence, and the perks and perils of running a little-known federal agency (story, p. 14). A primary-care physician, Bindman spent nearly 30 years at San Francisco General Hospital-the city's safety net provider-and much of his own research has investigated barriers in access to care. The following is.an edited transcript. PMID- 30399274 TI - Health systems with highest ratio of unfunded pension liabilities. Ranked by organizaton's ratio of unfunded pension liabilities in 2015. PMID- 30399276 TI - The Trumping of Obamacare. What will happen to Medicaid? PMID- 30399275 TI - Health care: What's the new path? PMID- 30399277 TI - Replace or...? The future awaits on Trumpcare '17. AB - To provide context to what follows, I wrote this review about a month after the election and after President-elect Trump announced that he will nominate Rep. Tom Price, MD, to be the Secretary of the Department of Health and Human Services (DHHS) and Seema Verma, a Medicaid expert, to be the Administrator of the Centers for Medicare and Medicaid Services (CMS). It will be published about a month after the Inauguration. PMID- 30399278 TI - Putting HAIs, the nephrologist at center stage. PMID- 30399279 TI - Part 1. Applying Lean principles to clinic operations. PMID- 30399280 TI - Water treatment: The largest syringe used in dialysis. PMID- 30399281 TI - The ROI on ultrapure water: A case study. PMID- 30399282 TI - Multidisciplinary focus gives Spring Clinical attendees a broader view of kidney care. PMID- 30399283 TI - Healthcare leaders funnel cash to Hillary Clinton, shun Donald Trump. PMID- 30399284 TI - Scale savings seen in Dignity- CHI merger, but debt issues loom. PMID- 30399285 TI - Should you worry about ACA hikes?. PMID- 30399286 TI - Everyone is fretting about ACA exchange premiums. What about the rest of the individual market? PMID- 30399287 TI - When physicians burn out, solutions are elusive Support groups can't counter the root causes of a crisis. PMID- 30399290 TI - Integrating diabetic eye screenings with primary care. PMID- 30399289 TI - Urban hospitals, an endangered species, still fill a unique role in their communities. AB - As the CEO of a hospital named after Albert Einstein, I'm otten asked which of his quotes is my favorite. My answer is always the same: "Life is like riding a bicycle. To keep your balance, you must keep moving." PMID- 30399288 TI - Drugs and insurance affordability will top the post-election agenda. AB - Healthcare pricing concerns are making a late run for relevance as the presidential campaign heads down the homestretch. PMID- 30399292 TI - Largest patient-satisfaction measurement firms Ranked by total number of clients in 2015. PMID- 30399291 TI - 'If you have a great team, you can figure out just about any complicated problem'. AB - On Oct. 17, Dr. A. Marc Harrison started his run as president and CEO of Intermountain Healthcare. The Salt Lake City-based integrated delivery network which generated $6.1 billion in revenue last year, operates 22 hospitals, employs 1,400 physicians and offers health plans through an insurance subsidiary-is widely recognized as an innovator in technology and care delivery. Harrison worked at Intermountain's Primary Children's Hospital while completing his residency and internship. Before returning to Intermountain to succeed longtime leader Dr. Charles Sorenson, Harrison spent more than a decade with the Cleveland Clinic, including as CEO of its hospital in Abu Dhabi. Modern Healthcare Managing Editor Gregg Blesch recently spoke with Harrison about managing population health, running a hospital in Abu Dhabi and building personal connections in a large health system. This following is an edited transcript. PMID- 30399293 TI - Great job reducing readmissions, hospitals-but it's about to get harder. PMID- 30399294 TI - More Americans gain health coverage, but their cost-sharing keeps rising. PMID- 30399296 TI - The FDA requires UDIs for medical devices. Now hospitals have to catch up. PMID- 30399297 TI - Aiming for happier customers. AB - In an industry saddled with a reputation for poor service, some health insurers are putting a priority on reaching out to solve subscribers problems. PMID- 30399295 TI - Health information exchanges coming of age and proving their worth. PMID- 30399298 TI - Providers shouldn't worry about getting good at MIPS. They should get out of it. AB - Medicare's new payment system for physicians is causing anxiety because of the short stretch of road before their performance is judged for a raise or pay cut. In the long- term, though, Medicare and most everyone else want providers to leave that new system behind. It's value-based training wheels. PMID- 30399299 TI - True care coordination essential to achieve best outcomes in a value-based system. AB - I've been meeting with physicians nationwide about their planned, ongoing and potential transitions from fee-for-service to value-based reimbursement. It's certainly a work in progress. PMID- 30399300 TI - End-of-life concierge service aims to help families cope with details. PMID- 30399302 TI - Uninsured by state: Ranked by percentage of uninsured in 2015. PMID- 30399301 TI - Surescripts CEO sees 'a much more interconnected and digitized healthcare system' ahead. AB - Now that nearly all of the nation's hospitals and the vast majority of Its office based physicians have adopted electronic' health record systems, the focus has shifted to getting these disparate systems to exchange patient Information. Surescripts has been at the center of the push for health data-sharing. The private health information exchange network, formed in 2008 with the merger of two rival e-prescribing networks, is jointly owned by two pharmacy trade groups the National Association of Chain Drug Stores and the National Community Pharmacists Association-and pharmacy benefit management companies CVS Health and Express Scripts. Surescripts recently reported ithandled 9.7 billion electronic transactions in 2015-48% more than the previous year. Modern Healthcare health IT reporter-Joseph Conn interviewed Surescripts CEO Tom Skelton about the role of e prescribing in achieving meaningful interoperability. This is an edited transcript. PMID- 30399303 TI - Taking the initiative in healthcare: Will California voters cap drug prices?. PMID- 30399305 TI - Frontrunners in the race for Hillary Clinton's top health posts. PMID- 30399304 TI - In Colorado, a push for single-payer healthcare. PMID- 30399307 TI - The REIT way to finance growth. PMID- 30399306 TI - Measuring healthcare performance is their business, and business is good. PMID- 30399308 TI - Predicting Medicare spending is hard, especially if it's in the future. AB - The debates are over, but let's not pick on the candidates. Let's take a closer look at the nonsense spouted by Fox News moderator Chris Wallace on the state of our "entitlements," which I prefer to call retirement benefits after a lifetime of hard work and paying taxes. PMID- 30399310 TI - Deploying community health workers to reduce readmission rates. PMID- 30399309 TI - Why Mayo Clinic, despite its five-star rating, believes it's time to rethink how quality is graded. AB - You may have seen the news: Mayo Clinic was one of a small number of hospitals in the country awarded a five-star rating by the CMS on its Hospital Compare website when the ratings were released in July. Mayo was also named the top hospital in the country by U.S. News and World Report in its annual Best Hospitals Honor Roll. PMID- 30399311 TI - 'We don't have enough data, and we don't have it at the right time'. AB - For over a quarter century, the National Committee for Quality Assurance has worked with employers, health plans, providers and patients to develop quality performance measures. But reporting required for its Healthcare Effectiveness Data and Information Set, or HEDIS, and bther quality reporting has triggered a backlash by providers. Modern Healthcare Editor Merrill Goozner recently spoke with NCQA President Margaret O'Kane about recent controversies swirling around quality measurement. The following is an edited transcript. PMID- 30399312 TI - Largest post-acute companies Ranked by net revenue for the organization's fiscal 2015. PMID- 30399313 TI - Reply PMID- 30399314 TI - Design of Y2 Receptor Selective and Proteolytically Stable PYY3-36 Analogues. AB - In recent years peptide YY (PYY) has attracted attention within the area of diabetes and obesity due to its involvement in food intake regulation and glucose homeostasis. It is well-known that PYY1-36 is rapidly cleaved by dipeptidyl peptidase-4 to the more Y2 receptor selective analogue PYY3-36, which is further cleaved to the inactive analogue PYY3-34. In order to improve the selectivity and proteolytic stability of the C-terminus, we synthesized several analogues incorporating N-methyl amino acids or beta-homo amino acids and other non-natural amino acids. These were tested against all four NPY receptors, and highly potent and Y2 receptor selective analogues were identified by combining a tryptophan residue in position 30 with either N-methyl or beta-homo arginine in position 35. We also identified an analogue with a MeGln34 substitution that surprisingly displayed high affinity toward all four receptors. In addition, these analogues displayed improved stability toward C-terminal proteolysis compared to native PYY3-36. PMID- 30399315 TI - FTIR Analysis of Molecular Changes Associated with Warming Injury in Cryopreserved Leukocytes. AB - In this article, we explored the effects of cooling rate, dimethyl sulfoxide (DMSO) concentration, and thawing protocol on the post-thaw viability of frozen human white blood cells (WBCs). Different cooling rates (1, 2, 5, 10, 20, and 50 degrees C/min) at two DMSO concentrations (5 and 10% v/v) were tested as the samples were cooled to -120 degrees C. Frozen samples were thawed following either a fast (100 degrees C/min) or slow (2 degrees C/min) warming protocol applied in either a single stage or in two stages interrupted by a 6 min hold at 40, -50, -60, -70, or -80 degrees C. The highest post-thaw viability was obtained when WBCs were cooled at 2 degrees C/min in a 5% DMSO solution and warmed at the fastest rate (100 degrees C/min) without any interruption. Post thaw viability decreased when the warming rate was reduced or when rapid warming was interrupted by a hold at a temperature below -60 degrees C. To elucidate the mechanisms of warming injury in addition to the biological response, several key interfacial and molecular phenomena require greater understanding; thus, we used Fourier transform infrared (FTIR) spectroscopy to investigate the roles of molecular structure and conformation in damage to cryopreserved WBCs during warming. During warming, FTIR spectra revealed the accumulation of cellular protein and lipid membrane damage below -60 degrees C if the samples were thawed slowly at 2 degrees C/min. The results presented here suggest that irreversible alterations of biomolecular structure are correlated with cell injury during warming; these deleterious effects appeared to be caused by one or more low temperature kinetic processes, consistent with eutectic formation/melting and/or devitrification in the intracellular milieu. PMID- 30399316 TI - Modulating Chirality-Selective Photoluminescence of Single-Walled Carbon Nanotubes by Ionic Liquids. AB - The chirality-selective near-infrared emission of surfactant-stabilized single wall carbon nanotubes could be controlled by simply varying the anion of the commonly used 1-butyl-3-methylimidazolium ionic liquids. This result advances the notion of the designer solvent ability of ionic liquids and provides opportunities for modulating the properties of nanomaterials. PMID- 30399317 TI - Pb2+ Binds to Downstream Regulatory Element Antagonist Modulator (DREAM) and Modulates Its Interactions with Binding Partners: A Link between Neuronal Calcium Sensors and Pb2+ Neurotoxicity. AB - Pb2+ exposure leads to diverse neurological disorders; however, the mechanism of Pb2+-induced neurotoxicity is not clearly understood. Here we demonstrate that Pb2+ binds to EF-hands in apo-DREAM (downstream regulatory element antagonist modulator) with a lower equilibrium dissociation constant ( Kd = 20 +/- 2 nM) than Ca2+ ( Kd = 1 MUM). Based on the Trp169 emission and CD spectra, we report that Pb2+ association triggers changes in the protein secondary and tertiary structures that are analogous to those previously observed for Ca2+-bound protein. The hydrophobic cavity in the C-terminal domain of DREAM is solvent exposed in the presence of Pb2+ as determined using a hydrophobic probe, 1 anilinonaphthalene-8-sulfonic acid (1,8-ANS). Pb2+ association with DREAM also modulates interactions between DREAM and its intracellular partners as evident from the fact that Pb2+-bound DREAM associates with peptide-based model systems, presenilin-1 helix-9 "PS1HL9" KV4.3(70-90) "site-2" and KV4.3(2-22) "site 1". Namely, dissociation constants for Pb2+-bound DREAM interaction with PS1HL9 ( Kd = 2.4 +/- 0.1 MUM), site-2 ( Kd = 11.0 +/- 0.5 MUM) and site 1 ( Kd = 5.0 +/- 0.6 MUM) are nearly identical to those observed for Ca2+ bound DREAM. Isothermal titration calorimetry data reveal that Pb2+ binds to two high-affinity sites in Ca2+ bound DREAM with the overall apparent constant of 4.81 +/- 0.06 MUM and its binding to Ca2+ bound DREAM is entropy-driven. Taking into account the structural and sequence similarity between DREAM and other neuronal calcium sensor (NCS) proteins, these results strongly indicate that DREAM and possibly other NCS proteins bind Pb2+ with a higher affinity than that for Ca2+ and Pb2+ interactions with NCS proteins can contribute to Pb2+-induced neurotoxicity. PMID- 30399318 TI - Azelnidipine Attenuates the Oxidative and NFkappaB Pathways in Amyloid-beta Stimulated Cerebral Endothelial Cells. AB - Cerebral amyloid angiopathy (CAA), a condition depicting cerebrovascular accumulation of amyloid beta-peptide (Abeta), is a common pathological manifestation in Alzheimer's disease (AD). In this study, we investigated the effects of Azelnidipine (ALP), a dihydropyridine calcium channel blocker known for its treatment of hypertension, on oligomeric Abeta (oAbeta)-induced calcium influx and its downstream pathway in immortalized mouse cerebral endothelial cells (bEND3). We found that ALP attenuated oAbeta-induced calcium influx, superoxide anion production, and phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2) and calcium-dependent cytosolic phospholipase A2 (cPLA2). Both ALP and cPLA2 inhibitor, methylarachidonyl fluorophosphate (MAFP), suppressed oAbeta-induced translocation of NFkappaB p65 subunit to nuclei, suggesting that cPLA2 activation and calcium influx are essential for oAbeta induced NFkappaB activation. In sum, our results suggest that calcium channel blocker could be a potential therapeutic strategy for suppressing oxidative stress and inflammatory responses in Abeta-stimulated microvasculature in AD. PMID- 30399319 TI - Two-Dimensional Hybrid Halide Perovskites: Principles and Promises. AB - Hybrid halide perovskites have become the "next big thing" in emerging semiconductor materials, as the past decade witnessed their successful application in high-performance photovoltaics. This resurgence has encompassed enormous and widespread development of the three-dimensional (3D) perovskites, spearheaded by CH3NH3PbI3. The next generation of halide perovskites, however, is characterized by reduced dimensionality perovskites, emphasizing the two dimensional (2D) perovskite derivatives which expand the field into a more diverse subgroup of semiconducting hybrids that possesses even higher tunability and excellent photophysical properties. In this Perspective, we begin with a historical flashback to early reports before the "perovskite fever", and we follow this original work to its fruition in the present day, where 2D halide perovskites are in the spotlight of current research, offering characteristics desirable in high-performance optoelectronics. We approach the evolution of 2D halide perovskites from a structural perspective, providing a way to classify the diverse structure types of the materials, which largely dictate the unusual physical properties observed. We sort the 2D hybrid halide perovskites on the basis of two key components: the inorganic layers and their modification, and the organic cation diversity. As these two heterogeneous components blend, either by synthetic manipulation (shuffling the organic cations or inorganic elements) or by application of external stimuli (temperature and pressure), the modular perovskite structure evolves to construct crystallographically defined quantum wells (QWs). The complex electronic structure that arises is sensitive to the structural features that could be in turn used as a knob to control the dielectric and optical properties the QWs. We conclude this Perspective with the most notable achievements in optoelectronic devices that have been demonstrated to date, with an eye toward future material discovery and potential technological developments. PMID- 30399320 TI - Isolation of a 300 kDa, Au~1400 Gold Compound, the Standard 3.6 nm Capstone to a Series of Plasmonic Nanocrystals Protected by Aliphatic-like Thiolates. AB - Disclosed herein is a method to obtain the ~300 kDa gold-hexanethiolate compound, extracted from the Faradaurate series of smaller (3) and larger (1) homologues, thereby permitting the first measurement of its distinctive properties by methods including mass spectrometry, optical spectroscopy, electron microscopy, X-ray scattering, and diffraction. The results suggest a monocrystalline metallic core (free of twinning planes) of ~3.1 nm minimum dimension, which supports a clear plasmonic optical response, along with a diffuse exterior shell. An idealized model to account for this (and smaller) members of the series is proposed based on the completion of a convex core of regular truncated-octahedral (TO) morphology, that is, the TO (5,5) crystallite comprising 1289 sites. The diffuse layer may comprise the 240 S sites (thiolate sulfur headgroups) and 96 Au-adatom sites, giving a total composition (1385,240) and a molar mass of ~301.0 kDa (90.7% Au). The ~300 and ~400 kDa gold compounds contain Au~1400 and Au~2000 atoms, respectively. PMID- 30399321 TI - Stimulations of the Culture Medium of Activated Microglia and TNF-Alpha on a Scrapie-Infected Cell Line Decrease the Cell Viability and Induce Marked Necroptosis That Also Occurs in the Brains from the Patients of Human Prion Diseases. AB - Activation of microglia and increased expression of TNF-alpha are frequently observed in the brains of human and animal prion diseases. As an important cytokine, TNF-alpha participates in not only pro-inflammatory responses but also in cellular communication, cell differentiation, and cell death. However, the role of TNF-alpha in the pathogenesis of prion disease remains ambiguous. In this study, the activities of a scrapie-infected cell line SMB-S15 and its normal partner SMB-PS exposed to the supernatant of a LPS-activated microglia cell line BV2 were evaluated. After it was exposed to the LPS-stimulated supernatant of BV2 cells, the cell viability of SMB-S15 cells was markedly decreased, whereas that of the SMB-PS cells remained unchanged. The level of TNF-alpha was significantly increased in the LPS-stimulated supernatant of BV2 cells. Further, we found that the recombinant TNF-alpha alone induced the decreased cell viability of SMB-S15 and the neutralizing antibody for TNF-alpha completely antagonized the decreased cell viability caused by the LPS-stimulated supernatant of BV2 cells. Stimulation with TNF-alpha induced the remarkable increases of apoptosis-associated proteins in SMB-PS cells, such as cleaved caspase-3 and RIP1, whereas an obvious increase of necroptosis-associated protein in SMB-S15 cells, such as p-MLKL. Meanwhile, the upregulation of caspase-8 activity in SMB-PS cells was more significant than that of SMB-S15 cells. The decreased cell viability of SMB-S15 and the increased expression of p-MLKL induced by TNF-alpha were completely rescued by Necrostatin 1. Moreover, we verified that removal of PrPSc propagation in SMB-S15 cells by resveratrol partially rescues the cell tolerance to the stimulation of TNF-alpha. These data indicate that the prion-infected cell line SMB-S15 is more vulnerable to the stimulations of activated microglia and TNF-alpha, which is likely due to the outcome of necroptosis rather than apoptosis. Furthermore, significant upregulation of p-MLKL, MLKL, and RIP3 was detected in the post-mortem cortical brains of the patients of various types of human prion diseases, including sporadic Creutzfeldt-Jakob disease (sCJD), G114 V-genetic CJD (gCJD), and fatal familial insomnia (FFI). PMID- 30399322 TI - Bitter Taste Receptors: Taking a Bigger Bite of Airway Smooth Muscle Pathophysiology. PMID- 30399323 TI - NAPE-PLD controls OEA synthesis and fat absorption by regulating lipoprotein synthesis in an in vitro model of intestinal epithelial cells. AB - Oleoylethanolamide (OEA), a fatty acid ethanolamide (FAE), is a lipid mediator that controls food intake and lipid metabolism. Accumulating data imply the importance of intestinal OEA in controlling satiety in addition to gastrointestinal peptide hormones. Although the biochemical pathway of FAE production has been illustrated, the enzymes responsible for the cleavage of OEA from its precursor N-acyl-phosphatidylethanolamine (NAPE) must be identified among reported candidates in the gut. In this study, we assessed the involvement of NAPE-specific phospholipase D (NAPE-PLD), which can directly release FAEs from NAPE, in intestinal OEA synthesis and lipid metabolism. Clustered regularly interspaced short palindromic repeats/caspase 9-mediated deletion of the NAPE-PLD gene in intestinal epithelial-like Caco-2 cells reduced OEA levels, regardless of their differentiation states. Transcriptome analysis revealed that deletion of NAPE-PLD activates a transcriptional program for nutrient transportation, including lipids and lipoproteins, and inactivates cell-cycle or mitosis-related genes in Caco-2 cells. In addition, the basolateral secretion of lipoproteins was increased in NAPE-PLD-deleted cells although lipoprotein size was not affected. By contrast, cellular lipid levels were reduced in NAPE-PLD-deleted cells. Overall, these results indicate that NAPE-PLD plays important roles in OEA synthesis and fat absorption by regulating lipoprotein production in the intestinal epithelial cells.-Igarashi, M., Watanabe, K., Tsuduki, T., Kimura, I., Kubota, N. NAPE-PLD controls OEA synthesis and fat absorption by regulating lipoprotein synthesis in an in vitro model of intestinal epithelial cells. PMID- 30399324 TI - TNF-alpha is upregulated in subacute thyroiditis and stimulates expression of miR 155-5p in thyroid follicle cells. AB - Tumor necrosis factor alpha (TNF-alpha) regulates the expression of proinflammatory cytokines and apoptosis in thyroids. miR-155-5p is upregulated in circulating microvesicles in patients with autoimmune thyroiditis. However, the function and molecular mechanisms of TNF-alpha and miR-155-5p in the initiation and progression of subacute thyroiditis are largely unknown. Herein, we determined serum TNF-alpha levels in subacute thyroiditis patients and normal healthy controls by ELISA assay. Proliferation and apoptosis of rat thyroid follicle FRTL-5 cells were determined by MTT, TUNEL, and annexin V staining assays. Protein levels and phosphorylation status were assessed by immunoblotting. miR-155-5p expression was determined by the real-time quantitative PCR. Serum TNF-alpha was significantly upregulated in patients with subacute thyroiditis compared to that in normal healthy controls. In rat thyroid follicle FRTL-5 cells, TNF-alpha treatment led to a reduction of cell proliferation and an induction of apoptosis. It also increased IL-6 expression and phosphorylation of JAK2 and STAT3. Importantly, we demonstrated that serum miR-155-5p was upregulated in subacute thyroiditis patients and TNF-alpha stimulated the expression of miR-155-5p in FRTL-5 cells. We found that miR-155-5p inhibited the proliferation and induced apoptosis of FRTL-5 cells and increased the expression of IL-6 in FRTL-5 cells. Our results demonstrated that serum TNF alpha and miR-155-5p were upregulated in patients with subacute thyroiditis, and TNF-alpha inhibited proliferation and induced apoptosis of rat thyroid follicle FRTL-5 cells via modulating the IL-6-JAK2/STAT3 pathway and miR-155-5p signaling. Our findings suggest that miR-155-5p might be a novel biomarker of subacute thyroiditis. PMID- 30399325 TI - Hiding in plain sight: time to unlock autoimmune clues in human CD5+ B cells by using nextgen technology. AB - CD5+ B cells expand in many autoimmune diseases, including type 1 diabetes (T1D), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). Furthermore, CD5+ B cells contain important subsets: IL-10-producing B-reg cells, FasL expressing subset, and the majority of pre-naive B cells. In addition, they are major sources of natural autoantibodies, which are polyreactive and autoreactive. Thus, CD5+ B cells are clearly loaded with autoimmune clues that are yet to be unlocked and understood. We hypothesize that human CD5+ B cells are likely to yield enormously important novel information about the role of B cells in autoimmune disease if analyzed using the new technological advances in molecular biology and genomics. Use of high-throughput sequencing of B cell receptors (BCR) of CD5+ B cells could reveal public BCRs associated with autoimmune diseases, whereas transcriptional analysis of CD5+ B cells using single-cell RNA-seq may delineate distinct sublineages and their relationship to conventional B cells. If it turns out that autoimmune repertoires are concentrated in CD5+ B cells, given that CD5+ B cells are clearly identifiable by flow cytometry, therapeutic strategies can be developed to safely remove CD5+ B cells to mitigate ongoing autoimmunity and protect at-risk individuals. PMID- 30399326 TI - Promise and pitfalls of immune checkpoint inhibitors in hepato-pancreato-biliary malignancies. AB - A growing understanding of the immune system and its anti-tumor functions has been imperative for the comprehension of malignant processes and beneficial in the pursuit of effective cancer treatments. To defend the body, immune cells must be able to differentiate between self and foreign cells using checkpoints, allowing the immune cells to attack foreign cells. Among the different types of immune target therapies recently developed, checkpoint inhibitors have come to the forefront in cancer treatment, encouraging their study in numerous different types of cancer, including hepato-pancreato-biliary malignancies (HPB). Traditionally, these malignancies have been treated with standard cytotoxic chemotherapy, but with little benefit in the metastatic setting. However, impressive results with checkpoint inhibitor therapy have been noted in a number of cancers as these agents enable immune cells to kill cancer cells more efficiently. Two classes of checkpoint inhibitors being extensively studied are inhibitors of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) ligand and programmed cell death protein 1 and its ligand (PD-1 and PD-L1). Checkpoint inhibitors have an advantage over other types of immunotherapies, such as cell based therapies, in that they are commercially available and can be given to patients with a range of pathologies and regardless of HLA status. Herein, we will discuss the application of immune checkpoint inhibitors to HPB malignancies as well as the limitations of these medications in these cancers. PMID- 30399327 TI - Resident bacteria in breast cancer tissue: pathogenic agents or harmless commensals? AB - Breast cancer is the second most common cancer in women. Recent evidence identifies a unique microbiome in breast tissue; a site previously thought to be sterile. The identification that this microbiome varies considerably from healthy subjects to cancer patients has prompted investigations into the role of specific bacterial species in oncogenesis. Indeed, certain bacteria have been shown to aid cancer development in vitro by promoting genomic instability, invasion, and chemotherapy resistance. However, the in vivo role of the breast microbiome in cancer appears to be more complex, involving numerous interactions between its constituent species and host cells. As such, reduced abundances of species which exert a protective effect against oncogenesis have come into focus and there is an emerging consensus that states of microbial dysbiosis, in which the normal balance of bacterial species is altered, can contribute to the development of cancer. This review summarizes the findings to date from the available literature pertaining to the microbiome in breast cancer and outlines areas worthy of further investigation. PMID- 30399328 TI - TGF-beta signaling and its targeted therapy in gastrointestinal cancers. AB - The transforming growth factor beta (TGFbeta) signaling pathway governs physiological homeostasis in the gastrointestinal system and its deregulation can lead to a diverse range of human pathologies including juvenile polyposis syndrome and tumor initiation, progression, and metastasis. In gastrointestinal malignancies, tumor cells evade the known tumor suppressive effects of TGFbeta signaling through frequent inactivation of the pathway. Paradoxically, tumor cells utilize TGFbeta-mediated regulation of epithelial-mesenchymal transition and immunomodulation to facilitate the invasive and migratory phenotype of gastrointestinal cancers and avoid immunosurveillance. The dichotomous role of TGFbeta as both a tumor suppressor and tumor promoter has highly challenged research efforts to specifically target TGFbeta signaling as a cancer therapy. The current preclinical approach is to inhibit TGFbeta-mediated generation of a favorable microenvironment for tumor growth, invasion, and metastasis. Here, we overview the alterations of TGFbeta signaling and its fundamental biological relevance in gastrointestinal tumorigenesis. We further discuss future perspectives for efficacious molecular targeted treatment of contextual TGFbeta tumor-promoting effects in gastrointestinal cancers. PMID- 30399330 TI - Reconsidering the Passive Diffusion Model of Steroid Hormone Cellular Entry. AB - Steroid hormones have long been thought to enter target cells via passive diffusion through the plasma membrane. Now, reporting in Developmental Cell, Okamoto et al. (2018) demonstrate that, at least for Drosophila, steroid hormones require a protein transporter for cellular entry. PMID- 30399329 TI - 3-Dimensional Volumetric Analysis of Relationship Between the Orbital Volume Ratio and Enophthalmos in Unoperated Blowout Fractures. AB - PURPOSE: Blowout fractures are common in midfacial trauma and often involve other parts of facial bones. Sometimes, patients have complications caused by inadequate management. Surgical indications, such as clinical symptoms, can be inaccurate owing to post-traumatic swelling or hematoma formation. Previous studies on the prediction of enophthalmos used the orbital volume ratio (OVR) or only the volume of herniated tissue. This study examined which of these values is more predictive of the degree of enophthalmos. In addition, the predictive values for a 2-mm enophthalmos in unoperated blowout fractures were assessed. PATIENTS AND METHODS: A total of 191 patients underwent nonoperative treatment for blowout fractures at our institution; they were divided into 2 groups according to the degree of enophthalmos (>2 mm vs 0 to 2 mm) and were further divided into 3 subgroups according to the location of the fracture (inferior, medial, or inferomedial). Multifactor logistic regression analysis was performed to determine the relationship between the degree of enophthalmos and these values. RESULTS: We observed a correlation between the OVR and the degree of enophthalmos, as well as a correlation between the volume of herniated tissue and the degree of enophthalmos. Regarding the anatomic location of herniation, the orbital floor was found to be more correlated with the amount of enophthalmos. CONCLUSIONS: The OVR is a more reliable predictor than measurement of the volume of herniated tissue. The relationship found between radiologic examination findings and the degree of enophthalmos can be used as a surgical indication in addition to consideration of the anatomic location. PMID- 30399331 TI - Locally Sourced: Auxin Biosynthesis and Transport in the Root Meristem. AB - Localized maxima of the plant hormone auxin are crucial to root development and meristem maintenance. In this issue of Developmental Cell, Brumos et al. used elegant genetic and grafting experiments to distinguish between the contributions of local and distal auxin sources to auxin maxima generation and root meristem maintenance. PMID- 30399332 TI - Rotten to the Core: Why Micronuclei Rupture. AB - A recent study in Nature from Liu et al. (2018) suggests that the rupture of micronuclei and resulting exposure of genomic DNA to the cytosol is driven by microtubule-induced defects in the biochemical composition of their bounding membranes. PMID- 30399333 TI - A Regeneration Toolkit. AB - The ability of animals to replace injured body parts has been a subject of fascination for centuries. The emerging importance of regenerative medicine has reinvigorated investigations of innate tissue regeneration, and the development of powerful genetic tools has fueled discoveries into how tissue regeneration occurs. Here, we present an overview of the armamentarium employed to probe regeneration in vertebrates, highlighting areas where further methodology advancement will deepen mechanistic findings. PMID- 30399335 TI - SoxB1 Activity Regulates Sensory Neuron Regeneration, Maintenance, and Function in Planarians. AB - SoxB1 genes play fundamental roles in neurodevelopmental processes and maintaining stem cell multipotency, but little is known about their function in regeneration. We addressed this question by analyzing the activity of the SoxB1 homolog soxB1-2 in the planarian Schmidtea mediterranea. Expression and functional analysis revealed that soxB1-2 marks ectodermal-lineage progenitors, and its activity is required for differentiation of subsets of ciliated epidermal and neuronal cells. Moreover, we show that inhibiting soxB1-2 or its candidate target genes leads to abnormal sensory neuron regeneration that causes planarians to display seizure-like movements or phenotypes associated with the loss of sensory modalities. Our analyses highlight soxB1-2-regulated genes that are expressed in sensory neurons and are homologous to factors implicated in epileptic disorders in humans and animal models of epilepsy, indicating that planarians can serve as a complementary model to investigate genetic causes of epilepsy. PMID- 30399336 TI - Oxidative Stress Orchestrates Cell Polarity to Promote Embryonic Wound Healing. AB - Embryos have a striking ability to heal wounds rapidly and without scarring. Embryonic wound repair is a conserved process, driven by polarization of cell cell junctions and the actomyosin cytoskeleton in the cells around the wound. However, the upstream signals that trigger cell polarization around wounds are unknown. We used quantitative in vivo microscopy in Drosophila and zebrafish embryos to identify reactive oxygen species (ROS) as a critical signal that orchestrates cell polarity around wounds. ROS promote trafficking of adherens junctions and accumulation of actin and myosin at the wound edge and are necessary for wound closure. We show that, in Drosophila, ROS drive wound healing in part through an ortholog of Src kinase, Src42A, which we identify as a redox sensor that promotes polarization of junctions and the cytoskeleton around wounds. We propose that ROS are a reparative signal that drives rapid embryonic wound healing in vertebrate and invertebrate species. PMID- 30399334 TI - The Lysosomal Transcription Factor TFEB Represses Myelination Downstream of the Rag-Ragulator Complex. AB - Myelin allows for fast and efficient axonal conduction, but much remains to be determined about the mechanisms that regulate myelin formation. To investigate the genetic basis of myelination, we carried out a genetic screen using zebrafish. Here, we show that the lysosomal G protein RagA is essential for CNS myelination. In rraga-/- mutant oligodendrocytes, target genes of the lysosomal transcription factor Tfeb are upregulated, consistent with previous evidence that RagA represses Tfeb activity. Loss of Tfeb function is sufficient to restore myelination in RagA mutants, indicating that hyperactive Tfeb represses myelination. Conversely, tfeb-/- single mutants exhibit ectopic myelin, further indicating that Tfeb represses myelination during development. In a mouse model of de- and remyelination, TFEB expression is increased in oligodendrocytes, but the protein is localized to the cytoplasm, and hence inactive, especially during remyelination. These results define essential regulators of myelination and may advance approaches to therapeutic remyelination. PMID- 30399337 TI - Pericyte ALK5/TIMP3 Axis Contributes to Endothelial Morphogenesis in the Developing Brain. PMID- 30399338 TI - The Polyploid State Plays a Tumor-Suppressive Role in the Liver. PMID- 30399339 TI - Mechanical Force-Driven Adherens Junction Remodeling and Epithelial Dynamics. PMID- 30399341 TI - Sex reversal. AB - Weber and Capel discuss various aspects of sex reversal, including how it happens, why it happens in some species but not others, and whether it is adaptive. PMID- 30399340 TI - A changing climate for seagrass conservation? AB - Tropical coral reefs are threatened and in decline, and their future is highly uncertain. With increasing rates of climate change and rising global temperatures, people looking to coral reefs for food and income may increasingly have to rely on resources from other habitats. Efforts to protect and conserve the coral reefs we have left are critical for a suite of economic, ecological, cultural and intrinsic reasons, but there is also an urgent need to take heed of the future scenarios from coral reefs and broaden the focus of tropical marine conservation. Seagrass meadows in particular are becoming ever more important for people and planet as coral reef health declines, but these systems are also globally under stronger anthropogenic threat. We need to increase and reprioritize our conservation efforts and use our limited conservation resources in a more targeted manner in order to attain sustainable systems. For seagrass, there are practicable conservation opportunities to develop sustainable ways to respond to increased resource use. Targeted action now could restore and protect seagrass meadows to maintain the many ecosystem services they provide. PMID- 30399342 TI - Amphibians. AB - Since the dawn of history, amphibians have been a part of human culture. Western Europeans built fires for cooking and warmth, adding large logs as needed. What occasionally emerged was astounding: large black animals (which had found shelter in the logs) with four legs and a tail, jet black with striking bright yellow spots. These fire salamanders were variously thought to be the product of the fire itself, or, as Aristotle reported, capable of extinguishing fire. Pliny the Elder is said to have tested this idea by throwing a salamander into flames - the salamander died! - nevertheless the association with fire persisted. Pliny perpetuated other fantastical claims, which spread; even Leonardo da Vinci contributed to the legend, and myths from different regions merged - at one point, asbestos was claimed to be salamander wool. Salamanders were attributed great powers; a single salamander upstream was thought to be sufficient to kill an army. King Francis I. of France chose a salamander as his emblem - a powerful symbol, born of fire, filled with poison, immune from burning, and even able to douse flames. Before the emergence of great cities and conurbations, people grew up surrounded by nature. Salamanders and newts, toads and frogs were all part of normal human experience. Myths such as those surrounding the fire salamanders were commonplace. Shakespeare's witches brewed with an eye of newt and tail of frog. As a child, we raised tadpoles and were taught to shudder at the appearance of a tiger salamander in a root cellar. In general, amphibians are seen as benign and harmless, even helpful as creatures that devour harmful insects and serve as an alternative food source. Thus, it came as a shock to most biologists and to the public at large in the 1980s that amphibians around the world were in decline and that they were at greater risk of extinction as a taxon than any other vertebrate group. A study of every amphibian species known in 2004 showed that on the order of 40% were at high risk of extinction, and by 2008, the decline of amphibians was seen as evidence of an impending sixth mass extinction. PMID- 30399343 TI - Orangutan populations are certainly not increasing in the wild. AB - A recent report, published by the Government of Indonesia with support from the Food and Agricultural Organization and Norway's International Climate and Forest Initiative, states that orangutan populations (Pongo spp.) have increased by more than 10% in Indonesia from 2015 to 2017, exceeding the government target of an annual 2% population increase [1]. This assessment is in strong contrast with recent publications that showed that the Bornean orangutan (P. pygmaeus) lost more than 100,000 individuals in the past 16 years [2] and declined by at least 25% over the past 10 years [3]. Furthermore, recent work has also demonstrated that both Sumatran orangutans (P. abelii) and the recently described Tapanuli orangutan (P. tapanuliensis) lost more than 60% of their key habitats between 1985 and 2007, and ongoing land use changes are expected to result in an 11-27% decline in their populations by 2020 [4,5]. Most scientific data indicate that the survival of these species continues to be seriously threatened by deforestation and killing [4,6,7] and thus all three are Critically Endangered under the International Union for Conservation of Nature's Red List. PMID- 30399344 TI - Memory: Theta Rhythm Couples Periodic Reactivation during Memory Retrieval. AB - Memory retrieval involves the reactivation of memory traces distributed throughout the brain. New research suggests that these memory reactivations have an oscillatory nature and that they are coupled to preferential stages of the hippocampal theta cycle. PMID- 30399345 TI - Cell Biology: Functional Conservation, Structural Divergence, and Surprising Convergence in the MICOS Complex of Trypanosomes. AB - The MICOS complex is conserved across eukaryotes, but little is known about it outside the group that comprises animals and fungi. A new study finds that mitochondria of trypanosomatid parasites bear a divergent MICOS with both ancestral and derived subunits, but with conserved functions in crista development and membrane contact-site formation. PMID- 30399346 TI - Neuroscience: Memory Encoding in the Absence of Cell Firing. AB - New research suggests that rats can learn new spatial information in the absence of cell firing. A small enhancement of GABAergic inhibition with a low dose of muscimol blocked cell firing but left long-term potentiation induction intact, while behaviorally it blocked memory retrieval but left memory encoding intact. PMID- 30399347 TI - Cell Division: The Unattached Kinetochore Wears an Expansive RZZ Coat. AB - The Rod-Zw10-Zwilch complex localizes to kinetochores during mitosis. New studies reveal that this complex plays a critical role in driving the expansion of the outer domain of unattached kinetochores, in addition to its known role in the control of the spindle assembly checkpoint. PMID- 30399348 TI - Charles Bonnet Syndrome: Cortical Hyperexcitability and Visual Hallucination. AB - Loss of foveal vision with sparing of peripheral vision, as in macular degeneration, is often associated with visual hallucinations: it has been suggested that these occur because deafferentation of neurons in regions of visual cortex results in local neuronal hyperexcitability, and new evidence supports this hypothesis. PMID- 30399349 TI - Palaeontology: Many Babies or Bigger Brains? AB - A cynodont from the Early Jurassic reveals unexpectedly large litters in these early mammal relatives, supporting the hypothesis that an increase in brain size was connected to smaller litters during the early evolution of mammals. PMID- 30399350 TI - Cognitive Neuroscience: Functional Specialization in Human Cerebellum. AB - A new brain imaging study reveals that the human cerebellum contains a region that represents visual space that is dissociable from a region displaying visual memory-related activity, with both regions exhibiting precise functional coupling with corresponding cerebral cortical areas. PMID- 30399351 TI - Neuroenergetics: Astrocytes Have a Sweet Spot for Glucose. AB - Astrocytes are polarized cells that are known to take up glucose while delivering lactate, not glucose, for neuronal use. A new study suggests how astrocytes could facilitate glucose uptake, storage and funneling at energy-requiring sites through a privileged intracellular route. PMID- 30399352 TI - Plant Development: Adding HAM to Stem Cell Control. AB - The stem cell niche of the shoot meristem is stably maintained despite a rapidly changing cellular context. Recent papers reveal a mechanism controlling the spatial patterning of the stem cell niche that prevents its self-termination. PMID- 30399353 TI - Symbiosis: High-Carb Diet of Reef Corals as Seen from Space. AB - High levels of phytoplankton visible in satellite imagery are correlated with an increased uptake of carbon compounds by corals. This suggests that corals rely less on carbon production by photosynthetic symbionts when other resources are plentiful, and that the changes in the acquisition mode of carbon can be inferred by remote-sensing techniques. PMID- 30399354 TI - Towards a Unified Model of SMC Complex Function. AB - Protein complexes built of structural maintenance of chromosomes (SMC) and kleisin subunits, including cohesin, condensin and the Smc5/6 complex, are master organizers of genome architecture in all kingdoms of life. How these large ring shaped molecular machines use the energy of ATP hydrolysis to change the topology of chromatin fibers has remained a central unresolved question of chromosome biology. A currently emerging concept suggests that the common principle that underlies the essential functions of SMC protein complexes in the control of gene expression, chromosome segregation or DNA damage repair is their ability to expand DNA into large loop structures. Here, we review the current knowledge about the biochemical and structural properties of SMC protein complexes that might enable them to extrude DNA loops and compare their action to other motor proteins and nucleic acid translocases. We evaluate the currently predominant models of active loop extrusion and propose a detailed version of a 'scrunching' model, which reconciles much of the available mechanistic data and provides an elegant explanation for how SMC protein complexes fulfill an array of seemingly diverse tasks during the organization of genomes. PMID- 30399356 TI - Empathy is not in our genes. AB - In academic and public life empathy is seen as a fundamental force of morality - a psychological phenomenon, rooted in biology, with profound effects in law, policy, and international relations. But the roots of empathy are not as firm as we like to think. The matching mechanism that distinguishes empathy from compassion, envy, schadenfreude, and sadism is a product of learning. Here I present a dual system model that distinguishes Empathy1, an automatic process that catches the feelings of others, from Empathy2, controlled processes that interpret those feelings. Research with animals, infants, adults and robots suggests that the mechanism of Empathy1, emotional contagion, is constructed in the course of development through social interaction. Learned Matching implies that empathy is both agile and fragile. It can be enhanced and redirected by novel experience, and broken by social change. PMID- 30399355 TI - Relating constructs of attention and working memory to social withdrawal in Alzheimer's disease and schizophrenia: issues regarding paradigm selection. AB - Central nervous system diseases are not currently diagnosed based on knowledge of biological mechanisms underlying their symptoms. Greater understanding may be offered through an agnostic approach to traditional disease categories, where learning more about shared biological mechanisms across conditions could potentially reclassify sub-groups of patients to allow realisation of more effective treatments. This review represents the output of the collaborative group "PRISM", tasked with considering assay choices for assessment of attention and working memory in a transdiagnostic cohort of Alzheimer's disease and schizophrenia patients exhibiting symptomatic spectra of social withdrawal. A multidimensional analysis of this nature has not been previously attempted. Nominated assays (continuous performance test III, attention network test, digit symbol substitution, N-back, complex span, spatial navigation in a virtual environment) reflected a necessary compromise between the need for broad assessment of the neuropsychological constructs in question with several pragmatic criteria: patient burden, compatibility with neurophysiologic measures and availability of preclinical homologues. PMID- 30399357 TI - Aptamer as capture agent in enzyme-linked apta-sorbent assay (ELASA) for ultrasensitive detection of Aflatoxin B1. AB - Aflatoxin B1 (AFB1), is one of the most toxic mycotoxins found to contaminate various food commodities like cereals, dried fruits, tree nuts, spices and crude vegetable oils. In spite of considerable progress in analytical techniques, there is still a need to develop rapid and highly sensitive detection platforms for AFB1. In this study, AFB1 specific aptamer was used as a capture molecule to develop an enzyme-linked apta-sorbent assay (ELASA) for ultrasensitive detection of AFB1. Under optimized conditions, the assay had a linear detection range from 1 MUg to 1 pg with a limit of detection (LOD) of 1 pg/mL in buffer. Conventional ELISA with AFB1 hapten as the capture agent (LOD = 10 pg/mL) was also carried out to compare the results with the present method. Recovery studies in food samples like dried red chillies, groundnut and pepper using both the methods was found to be in the range of 88.49-106.4% at 10 ng/mL and 87.4% to 95.8% at 5 ng/mL for ELASA and 76.56-127.68% at 10 ng/mL and 82-101.2% at 5 ng/mL for ELISA. Higher detection (10 fold) and better recovery using ELASA suggest that the method could offer an early, ultrasensitive, high-throughput, qualitative and semi quantitative detection of AFB1 in contaminated food samples. PMID- 30399359 TI - Changes in the mitochondrial proteome in human hepatocytes in response to alpha amanitin hepatotoxicity. AB - Amanitin-induced apoptosis is proposed to have a significant effect on the pathogenesis of liver damage. However, few reports have focused on proteome changes induced by alpha-amanitin (alpha-AMA). Here, we evaluated changes in mitochondrial proteins of hepatocytes in response to 2 MUM alpha-AMA, a concentration at which alpha-AMA-induced cell damage could be rescued at cellular level by common clinical drugs. We found 56 proteins were differentially expressed in an alpha-AMA-treated group. Among them, 38 proteins were downregulated and 18 were upregulated. Downregulated functional proteins included importer TOMM40, respiratory chain component cytochrome C, and metabolic enzymes of citrate acid cycle such as malate dehydrogenase, which localize on the mitochondrial outer membrane, inner membrane and matrix respectively. Immunoblot analysis showed that alpha-AMA decreased mitochondrial import receptor subunit TOMM40 and cytochrome c accompanied by an increase in the cytosol although their total protein levels were not affected significantly. The mitochondrial membrane potential was also destroyed by alpha-AMA and was restored by the clinical drug silibinin. Immunofluorescence suggested that mitochondrial morphology did not change. Taken together, our results provide further insights into the toxic mechanism of alpha-AMA on hepatocytes. PMID- 30399358 TI - A lateral flow assay for simultaneous detection of Deoxynivalenol, Fumonisin B1 and Aflatoxin B1. AB - Deoxynivalenol (DON), Fumonisin B1 (FB1) and Aflatoxin B1 (AFB1) have strong toxicity to humans and exist widely in grain and food. It is necessary to screen these mycotoxins to guarantee food safety. In order to develop a rapid, simple, low-cost and simultaneous-detection method, composites of antibody-nano-Au particles, DON-BSA, FB1-BSA, and AFB1-BSA were prepared to establish a lateral flow assay based on competitive inhibition. The results suggested that the visual detection limits for DON, FB1 and AFB1 were 10, 30, and 10 ng mL-1, respectively. On the other hand, it had no reactivity to T-2 toxin, zearalenone, ochratoxin A and nivalenol, which demonstrates good specificity. Besides, the strip had good repeatability and stability. Therefore, DON, FB1 and AFB1 would be screened simultaneously by lateral flow assay for food safety. PMID- 30399360 TI - Dose Optimization of Chloroquine by Pharmacokinetic Modeling During Pregnancy for the Treatment of Zika Virus Infection. AB - The insidious nature of Zika virus (ZIKV) infections can have a devastating consequence for fetal development. Recent reports have highlighted that chloroquine (CQ) is capable of inhibiting ZIKV endocytosis in brain cells. We applied pharmacokinetic modeling to develop a predictive model for CQ exposure to identify an optimal maternal/fetal dosing regimen to prevent ZIKV endocytosis in brain cells. Model validation used 13 nonpregnancy and 3 pregnancy clinical studies, and a therapeutic CQ plasma window of 0.3-2 MUM was derived. Dosing regimens used in rheumatoid arthritis, systemic lupus erythematosus, and malaria were assessed for their ability to target this window. Dosing regimen identified that weekly doses used in malaria were not sufficient to reach the lower therapeutic window; however, daily doses of 150 mg achieved this therapeutic window. The impact of gestational age was further assessed and culminated in a final proposed regimen of 600 mg on day 1, 300 mg on day 2 and 3, and 150 mg thereafter until the end of trimester 2, which resulted in maintaining 65% and 94% of subjects with a trough plasma concentration above the lower therapeutic window on day 6 and at term, respectively. PMID- 30399361 TI - Amyloid-beta1-42 dynamically regulates the migration of neural stem/progenitor cells via MAPK-ERK pathway. AB - Neural stem/progenitor cell (NSPC) based therapy represents an attractive treatment for Alzheimer's disease (AD), the most common neurodegenerative disorder with no effective treatment to date. This can be achieved by stimulating endogenous NSPCs and/or administrating exogenously produced NSPCs. Successful repair requires the migration of NSPCs to the loci where neuronal loss occurs, differentiation and integration into neural networks. However, the progressive loss of neurons in the brain of AD patients suggests that the repair by endogenous NSPCs in the setting of AD may be defective. The production and deposition of amyloid-beta1-42 (Abeta1-42) peptides is thought to be a central event in the pathogenesis of AD. Here we report that Abeta1-42 peptides inhibit the migration of in vitro cultured NSPCs by disturbing the ERK-MAPK signal pathway. We found that the migratory capacity of NSPCs was compromised upon treatment with oligomeric Abeta1-42; the inhibitory effect occurred in a dose dependent manner. Our previous studies have shown that Abeta1-42 triggers the expression of GRK2 by unknown mechanism. Herein we found that the Abeta1-42 evoked upregulation of GRK2 expression was attenuated upon treatment with the ERK inhibitor SCH772984 at 2.5 MUM, but not with inhibitors for p38 or JNK. We detected a dose-dependent increase in levels of phosphorylated ERK1/2 after incubation of cells with oligomeric Abeta1-42 peptides for 3 days. We observed that an increase in the phosphorylation of p38 and JNK coincided with reduced phosphorylation of ERK1/2 upon treatment with Abeta1-42 for 6 and/or 9 days. We hypothesize that the divergence of the activation of the MAPK family of pathways may contribute to the inhibition of NSPCs migration after the long-term incubation with Abeta1-42. Pretreatment with 1 MUM MEK inhibitor U0126 reversed the effects of Abeta1-42 on GRK2 expression of and NSPC migration. Together, our results suggest that Abeta1-42 oligomers compromise the migratory capacity of NSPCs through the MEK-ERK pathway. PMID- 30399362 TI - Pharmacological inhibition of serine palmitoyl transferase and sphingosine kinase 1/-2 inhibits Merkel Cell Carcinoma cell proliferation. AB - The majority of Merkel cell carcinoma (MCC), a highly aggressive neuroendocrine cancer of the skin, is associated with Merkel cell polyomavirus (MCPyV) infection. Polyomavirus binding, internalization and infection is mediated by glycosphingolipids (GSL). Besides receptor function, bioactive sphingolipids (SL) are increasingly recognized as potent regulators of several hallmarks of cancer. MCPyV+ and MCPyV- cells express serine palmitoyltransferase (SPT) subunits and sphingosine kinase (SK)1/2 mRNA. Induced expression of MCPyV-large tumor antigen in human lung fibroblasts resulted in upregulation of SPTLC1-3 and SK1/2 expression. Therefore we exploited pharmacological inhibition of SL metabolism as an option to interfere with proliferation of MCPyV+ MCC cell lines. We used myriocin (a SPT antagonist) and two SK inhibitors (SKI-II and ABC294640). In MKL 1 and WaGa cells myriocin decreased cellular ceramide, sphingomyelin, and sphingosine-1-phosphate (S1P) content. SKI-II increased ceramide species but decreased sphingomyelin and S1P concentrations. Aberrant SL homeostasis was associated with reduced cell viability, increased necrosis, procaspase-3 and PARP processing, caspase-3 activity, and decreased AKTS473 phosphorylation. Myriocin and SKI-II decreased tumor size and Ki-67 staining of xenografted MKL-1 and WaGa tumors on the chorioallantoic membrane. Our data suggest that pharmacological inhibition of SL synthesis could represent a potential therapeutic approach in MCC. PMID- 30399363 TI - Painless local pressure application to test microvascular reactivity to ischemia. AB - BACKGROUND: Forearm cutaneous blood flux (CBF) measurement with post-occlusive reactive hyperemia (PORH) is uncomfortable and may not be devoid of risks. We aimed to investigate post-compression reactive hyperemia (PCRH) with a custom made indenter that was designed to be easily used routinely by inexperienced observers. METHODS: Medical students evaluated PCRH with 1- to 4-min pressure applications of 16 to 34 kPa and PORH with 3-min forearm cuff occlusion using laser speckle contrast imaging in 15 healthy volunteers. Participants were asked to quantify their discomfort with a visual analogue scale (VAS) of 10 cm. Total ischemia (ISCH) was quantified by the product of CBF during ischemia and ischemia duration (min). We subtracted the CBF changes in the skin from a reference ipsilateral (PCRH) or contralateral (PORH) non-stimulated area. RESULTS: The average VAS was 1.0 for PCRH vs. 6.0 for PORH (p < 0.001). A strong linear relationship between ISCH and peak PCRH (r2 = 0.915, p < 0.001) was noted. Peak PORH values (63.9 laser perfusion units (LPU)) were significantly lower than all values of the 3-min PCRH (72.6 LPU), including the one obtained with 16 kPa. CONCLUSION: Inexperienced observers could test microvascular reactivity with PCRH without inducing the discomfort that is typically experienced with PORH. Further, PCRH elicits a higher peak response to ischemia compared with PORH. This extremely simple method could influence a broad spectrum of routine cutaneous microcirculation investigations, especially when a painful approach is particularly inadequate or if the patient is fragile. CLINICAL TRIAL REGISTRATION: NCT02861924. PMID- 30399364 TI - Transgenic lysyl oxidase homolog 1 overexpression in the mouse eye results in the formation and release of protein aggregates. AB - Sequence variants in LOXL1 coding for the secreted enzyme lysyl oxidase homolog 1 (LOXL1) associate with pseudoexfoliation (PEX) syndrome, a condition that is characterized by the deposition of extracellular fibrillar PEX material in the anterior eye and other parts of the body. Since the specific role of LOXL1 in the pathogenesis of PEX is unclear, and an increase in its expression was reported for early stages of PEX syndrome, we generated and studied transgenic mice with ocular overexpression of its mouse ortholog Loxl1. The chicken betaB1-crystallin promoter was used to overexpress Loxl1 in the lenses of betaB1-crystallin-Loxl1 transgenic mice. Transgenic lenses contained high levels of the protein LOXL1 and its mRNA, which were both not detectable in lenses of wildtype littermates. In wildtype mice, immunoreactivity for LOXL1 was mainly seen extracellularly in region of the ciliary zonules. betaB1-crystallin-Loxl1 littermates showed an additional diffuse immunostaining in lens fibers and capsule, and in the inner limiting membrane and retina indicating secretion of soluble LOXL1 from transgenic lenses. In addition, lens fibers of transgenic animals contained multiple distinct spots of very intense LOXL1 immunoreactivity. By transmission electron microscopy, those spots correlated with electron-dense round or oval bodies of 20-50 nm in diameter which were localized in the rough endoplasmic reticulum and not seen in wildtype lenses. Immunogold electron microscopy confirmed that the electron-dense bodies contained LOXL1 indicating aggregation of insoluble LOXL1. Similar structures were seen in the extracellular lens capsule suggesting their secretion from lens fibers. Otherwise, no changes were seen between the eyes of betaB1-crystallin-Loxl1 mice and their wildtype littermates, neither by light microscopy and funduscopy of whole eyes, nor by scanning and quantitative transmission electron microscopy of ciliary epithelium and zonules. At one month of age, intraocular pressure was significantly higher in transgenic mice than in wildtype littermates. No differences in IOP were seen though at 2-5 months of age. We conclude that LOXL1 has a strong tendency to aggregate in the rER when expressed in vivo at high amounts. A similar scenario, involving intracellular aggregation of LOXL1 and secretion of LOXL1 aggregates into the extracellular space, may be involved in the early pathogenetic events in eyes of PEX patients. PMID- 30399366 TI - Comparative transcriptome analysis reveals molecular strategies of ghost moth Thitarodes armoricanus in response to hypoxia and anoxia. AB - Hypoxia or anoxia greatly impact the survival of many animal species. The ghost moth Thitarodes armoricanus is distributed in the Tibetan Plateau at an average elevation of approximate 4 km above sea level and has probably evolved a superior capacity to tolerate low oxygen levels. In this study, transcriptome analysis using high-throughput RNA-seq revealed common and different adaptation strategies of T. armoricanus in response to hypoxia (11% O2) or anoxia. T. armoricanus adopted three common strategies for adaptation to hypoxia or anoxia: Up-regulated signal transduction pathways essential for cellular survival, strengthened cell and organelle structure and activity, and activated immune system. Under hypoxia, T. armoricanus might develop a strategy to adapt to hypoxia by suppressing TCA, oxidative phosphorylation pathways, and hypoxanthine catabolism. T. armoricanus larvae kept active under hypoxia but became coma under anoxia, probably relating to up-regulated or suppressed dopamine synthesis pathway. Furthermore, the HIF system seemed not to be essential for regulating the hypoxic and anoxic responses of this insect in Tibetan Plateau. This study provides a global view of gene expression profiles and suggests common and different adaptation strategies of T. armoricanus under hypoxic and anoxic conditions. The results are helpful for understanding the mechanism responsible for the low oxygen level tolerance of this insect species. PMID- 30399365 TI - Chemical synthesis of 7-oxygenated 12alpha-hydroxy steroid derivatives to enable the biochemical characterization of cytochrome P450 8B1, the oxysterol 12alpha hydroxylase enzyme implicated in cardiovascular health and obesity. AB - Cholic acid is the endogenous 12alpha-hydroxylated bile acid, which possesses enhanced cholesterol absorption properties compared to its 12-desoxy counterpart, chenodeoxycholic acid. The oxysterol 12alpha-hydroxylase enzyme is cytochrome P450 8B1 (P450 8B1), which regioselectively and stereoselectively incorporates the 12alpha-hydroxy group in 7alpha-hydroxycholest-4-en-3-one, the biosynthetic precursor of cholic acid. Despite the vital role of P450 8B1 activity in cardiovascular health, research studies of other 12alpha-hydroxy steroid derivatives are rare. A synthetic route to incorporate a C12alpha-hydroxy group into the C12-methylene (-CH2-) in dehydroepiandrosterone derivatives is disclosed. The incorporation of the C12-oxygen was accomplished through a copper mediated Schonecker oxidation of an imino-pyridine intermediate, introducing the 12beta-hydroxy group. The resulting 12beta-hydroxy steroid derivative was oxidized to the C12-ketone, which was stereoselectively reduced with lithium tri sec-butylborohydride to afford the 12alpha-hydroxy stereochemistry. The C7 position was oxidized to yield the various 7-keto, 7beta-hydroxy, and 7alpha hydroxy derivatives. Furthermore, 7-ketodehydroepiandrosterone and 12 alpha hydroxy-7-ketodehydroepiandrosterone both displayed NMDA receptor antagonistic activities at 10 MUM concentrations. These C12alpha-hydroxy steroids will be used as tools to identify new biochemical properties of the enzymatic products of P450 8B1, the oxysterol 12alpha-hydroxylase. PMID- 30399367 TI - Prosocial effects of an oxytocin metabolite, but not synthetic oxytocin receptor agonists, in a mouse model of autism. AB - Currently, there are no established pharmaceutical strategies that effectively treat social deficits in autism spectrum disorder (ASD). Oxytocin, a neurohormone that plays a role in multiple types of social behaviors, has been proposed as a possible therapeutic against social impairment and other symptoms in ASD. However, from the standpoint of pharmacotherapy, oxytocin has several liabilities as a standard clinical treatment, including rapid metabolism, low brain penetrance, and activity at the vasopressin (antidiuretic hormone) receptors. The present studies describe findings from a preclinical screening program to evaluate oxytocin receptor (OXTR) agonists and oxytocin metabolites for potential clinical use as more optimal treatments. We first investigated two synthetic oxytocin analogs, TC-OT-39 and carbetocin, using in vitro cell-based assays for pharmacological characterization and behavioral tests in the BALB/cByJ mouse model of ASD-like social deficits. Although both TC-OT-39 and carbetocin selectively activate the OXTR, neither synthetic agonist had prosocial efficacy in the BALB/cByJ model. We next evaluated two oxytocin metabolites: OT(4-9) and OT(5-9). While OT(5-9) failed to affect social deficits, the metabolite OT(4-9) led to significant social preference in the BALB/cByJ model, in a dose-dependent manner. The increased sociability was observed at both 24 h and 12 days following the end of a subchronic regimen with OT(4-9) (2.0 mg/kg). Overall, these results suggest that the prosocial effects of oxytocin could be mediated by downstream activity of oxytocin metabolites, raising the possibility of new pathways to target for drug discovery relevant to ASD. PMID- 30399368 TI - Time-varying pharmacodynamics in a simple non-integer HIV infection model. AB - In this paper we study the effect of time-varying drug exposure in the dynamics of a fractional order model for the human immunodeficiency virus infection. We compute the reproduction number of the model and verify the stability of the disease-free equilibrium. The model is simulated for parameters directly modelling the pharmacodynamics of HIV, namely the slope of the dose-response curve, the drug's half-life, and the dosing interval. The later affect in a significant way the infection patterns. The order of the fractional derivative is also a key player of the model, adding more information, which could be useful for a deeper understanding of the pharmacodynamics of HIV, necessary for more accurate therapeutic regimens. PMID- 30399369 TI - A small molecule Hedgehog agonist HhAg1.5 mediated reprogramming breaks the quiescence of noninjured liver stem cells for rescuing liver failure. AB - Liver is the second most transplanted organ according to United network for organ sharing. Due to shortage of compatible donors, surgical difficulties, immunological hindrance, and high postoperative cost, stem cell therapy is an attractive substitute of liver transplant for millions of patients suffering from hepatic failure. Due to several technical limitations such as viral integration, inefficient differentiation, and adult phenotypes and epigenetic memory of fibroblasts, induced pluripotent stem cells, mesenchymal stem cells, or induced hepatocyte may not present a great clinical substitute for liver transplant. We pioneered a novel technology for robust expansion of quiescent liver stem cells (LSCs) from mice via utilizing of Hedgehog agonist HhAg1.5 for 3 weeks. These expanded LSCs retained stem-like properties after multiple passaging and differentiated to hepatocytes and cholangiocytes. Grafting of ex vivo expanded LSCs in Fah-/- Rag2-/- Il2rg-/- knockout mice, significantly increased life span compared to control group (P < 0.001). Thus in this study, we provide a promising viable substitute for primary hepatocytes for regenerative medicine and for life threatening metabolic liver diseases. PMID- 30399370 TI - Knee replacement surgery significantly elevates the urinary inflammatory biomarkers neopterin and 7,8-dihydroneopterin. AB - CONTEXT: Knee arthroplasty surgery is significant trauma, leading to an activated immune system causing inflammation and oxidative stress. Many current biomarkers are invasive, costly, and often slow to analyse, limiting their use for rapid inflammatory measurements. OBJECTIVES: We have examined the use of urinary neopterin and total neopterin in knee arthroplasty patients to non-invasively measure oxidative stress and inflammation from immune system activation. We aim to validate the use of these biomarkers for quick, cost effective and predictive measurements of post-surgical inflammation assessment. METHODOLOGY: 19 Knee arthroplasty patients were analysed pre-operatively and for a defined post operative period to determine the urinary levels of neopterin and total neopterin (neopterin +7,8-dihydroneopterin) using high performance liquid chromatography with fluorescence detection. These results were then compared to a control group of 20 participants with normal knee function. RESULTS: 7,8-Dihydroneopterin was stable in urine over 12 h when refrigerated. Knee arthritis was associated with an increase in pre-operative neopterin (oxidative stress) and total neopterin (inflammation). The subsequent arthroplasty surgery generated a significant increase neopterin and total neopterin. Both biomarkers were reduced immediately post-operatively, before becoming elevated on the following days. There was no clear evidence of an association between initial neopterin and total neopterin levels and a patient's level of inflammation during in-hospital recovery. CONCLUSIONS: The stability of 7,8-dihydroneopterin in urine allows for its use as an inflammatory marker. Urinary neopterin and total neopterin provided a fast, non-invasive, and simple measure of oxidative stress and inflammation after knee arthroplasty. PMID- 30399371 TI - Long noncoding RNA GHET1 in human cancer. AB - LncRNAs are a group of noncoding RNAs that are >200 nucleotides in length. These RNAs have no significant protein-coding potential due to the lack of obvious open reading frames. To date, accumulating evidence has demonstrated that dysregulation of lncRNAs exhibits indispensable roles in the pathological processes of human cancers. These RNAs function as either oncogenes or tumor suppressor genes to regulate proliferation, migration and invasion of cancer cells. GHET1, a prominent oncogenic lncRNA, is highly expressed in diverse malignancies. Furthermore, GHET1 performs key functions in carcinogenesis and progression, suggesting that GHET1 is expected to be a prospective biomarker or therapeutic target for cancers. In this review, we provide a summary of the current evidence concerning the biological functions, underlying mechanisms and clinical significance of GHET1 during tumor development. PMID- 30399372 TI - Diacylglycerol kinase gamma predicts prognosis and functions as a tumor suppressor by negatively regulating glucose transporter 1 in hepatocellular carcinoma. AB - Diacylglycerol kinases (DGK) are a family of enzymes catalyzing the transformation of diacylglycerol into phosphatidic acid, which have been recognized as key regulators in cell signaling pathways. The role of DGKgamma in human malignancies has seldom been studied. In this study, we investigated the role of DGKgamma in hepatocellular carcinoma (HCC). We found that DGKgamma was down-regulated in HCC tumor tissues and cell lines as compared to that in non tumor tissues. The prognostic value of DGKgamma expression was evaluated by Cox regression and Kaplan-Meier analyses. Lower DGKgamma expression in tumor tissues was an independent prognostic factor for poor post-surgical overall survival. By using HDACs inhibitors treatment and ChIP-PCR, we discovered that histone H3 and H4 deacetylation mainly contributed to the downregulation of DGKgamma expression. Functional studies revealed that ectopic expression of DGKgamma inhibited cell proliferation and cell migration in HCC cells. Mechanism studies showed that DGKgamma overexpression led to down regulation of GLUT1 protein level and AMPK activity, which result in glucose uptake suppression as well as lactate and ATP production declination. The decrease of GLUT1 level could be partially rescued by treatments with either DGK inhibitor and lysosome inhibitor, indicating DGKgamma may down-regulate GLUT1 through its kinase activity and lysosome degradation process. Together, this study demonstrated that DGKgamma plays a tumor suppressor role in HCC by negatively regulating GLUT1. DGKgamma could be a novel prognostic indicator and therapeutic target for HCC. PMID- 30399373 TI - Extended live-tracking and quantitative characterization of wound healing and cell migration with SiR-Hoechst. AB - Cell migration is essential to many life processes, including immune response, tissue repair, and cancer progression. A reliable quantitative characterization of the cell migration can therefore aid in the high throughput screening of drug efficacy in wound healing and cancer treatments. In this work, we report what we believe is the first use of SiR-Hoechst for extended live tracking and automated analysis of cell migration and wound healing. We showed through rigorous statistical comparisons that this far-red label does not affect migratory behavior. We observed excellent automated tracking of random cell migration, in which the motility parameters (speed, displacement, path length, directionality ratio, persistence time, and direction autocorrelation) obtained closely match those obtained from manual tracking. We also present an analysis framework to characterize the healing of a scratch wound from the perspective of single cells. The use of SiR-Hoechst is advantageous for the crowded environments in wound healing assays because as long as cell nuclei do not overlap, continuous tracking can be maintained even if there is cell-cell contact. In this paper, we report wound recovery based on the number of cells migrating into the wound over time, normalized by the initial cell count prior to the infliction of the wound. This normalized cell count approach is impervious to operator bias during the arbitration of wound edges and is also robust against variability that arises due to differences in the cell density of different samples. Additional wound healing characteristics were also defined based on the evolution of cell speed and directionality during healing. Not unexpected, the wound healing cells exhibited much higher tendency to maintain the same migratory direction in comparison to the randomly migrating cells. The use of SiR-Hoechst thus greatly simplified the automation of single cell and whole population analysis with high spatial and temporal resolution over extended periods of time. PMID- 30399374 TI - Genetics and epigenetics in obesity. AB - Obesity is among the most threatening health burdens worldwide and its prevalence has markedly increased over the last decades. Obesity maybe considered a heritable trait. Identifications of rare cases of monogenic obesity unveiled that hypothalamic circuits and the brain-adipose axis play an important role in the regulation of energy homeostasis, appetite, hunger and satiety. For example, mutations in the leptin gene cause obesity through almost unsuppressed overeating. Common (multifactorial) obesity, most likely resulting from a concerted interplay of genetic, epigenetic and environmental factors, is clearly linked to genetic predisposition by multiple risk variants, which, however only account for a minor part of the general BMI variability. Although GWAS opened new avenues in elucidating the complex genetics behind common obesity, understanding the biological mechanisms relative to the specific risk contributing to obesity remains poorly understood. Non-genetic factors such as eating behavior or physical activity strongly modulate the individual risk for developing obesity. These factors may interact with genetic predisposition for obesity through epigenetic mechanisms. Thus, here, we review the current knowledge about monogenic and common (multifactorial) obesity highlighting the important recent advances in our knowledge on how epigenetic regulation is involved in the etiology of obesity. PMID- 30399375 TI - Obesity and cardiovascular disease: revisiting an old relationship. AB - A wealth of clinical and epidemiological evidence has linked obesity to a broad spectrum of cardiovascular diseases (CVD) including coronary heart disease, heart failure, hypertension, stroke, atrial fibrillation and sudden cardiac death. Obesity can increase CVD morbidity and mortality directly and indirectly. Direct effects are mediated by obesity-induced structural and functional adaptations of the cardiovascular system to accommodate excess body weight, as well as by adipokine effects on inflammation and vascular homeostasis. Indirect effects are mediated by co-existing CVD risk factors such as insulin resistance, hyperglycemia, hypertension and dyslipidemia. Adipose tissue (AT) quality and functionality are more relevant aspects for cardiometabolic risk than its total amount. The consequences of maladaptive AT expansion in obesity are local and systemic: the local include inflammation, hypoxia, dysregulated adipokine secretion and impaired mitochondrial function; the systemic comprise insulin resistance, abnormal glucose/lipid metabolism, hypertension, a pro-inflammatory and pro-thrombotic state and endothelial dysfunction, all of which provide linking mechanisms for the association between obesity and CVD. The present narrative review summarizes the major pathophysiological links between obesity and CVD (traditional and novel concepts), analyses the heterogeneity of obesity related cardiometabolic consequences, and provides an overview of the cardiovascular impact of weight loss interventions. PMID- 30399376 TI - Paracrine effect of mesenchymal stem cell as a novel therapeutic strategy for diabetic nephropathy. AB - Diabetic nephropathy (DN) is a microvascular complication of diabetes mellitus (DM) and the main reason for end-stage renal diseases (ESRD). Based on the role of mesenchymal stem cells (MSCs) in regenerative medicine, the MSC therapy has been considered a promising strategy to ameliorate the progression of DN. In this article, we review the therapeutic potential of MSCs in DN, mainly involving MSC paracrine mechanism based on trophic factors and extracellular vesicles. Knowledge of mechanism underlying the therapeutic action of MSCs on DN can provide much needed new drug targets for this disease. PMID- 30399378 TI - NF-kappaB signaling and integrin-beta1 inhibition attenuates osteosarcoma metastasis via increased cell apoptosis. AB - Osteosarcoma is a common primary bone malignancy, and distant metastasis limited the cure estimate during last decades. Detailed investigation of osteosarcoma metastasis is valuable for improving therapeutic strategy. Our study indicated increased integrin-beta1 expression and NF-kB signaling activation in metastatic osteosarcoma tissues. Gain-of-function assays showed that integrin-beta1 knockdown significantly inhibited osteosarcoma growth and metastasis, whereas exogenous reintroducing of integrin-beta1 restored cell proliferation and metastasis in vitro and in vivo. NF-kappaB signaling directly modulated integrin beta1 expression, which is an effective target for the treatment of osteosarcoma. Mechanically, integrin-beta1 blockage with AIIB2 antibody increased osteosarcoma cell apoptosis. Immunohistochemistry staining of integrin-beta1 revealed that elevated integrin-beta1 expression was correlated with poor prognosis of osteosarcoma patients and acted as an independent detrimental factor for osteosarcoma. Our data showed that integrin-beta1 and NF-kappaB signaling are promising therapeutic targets to improve the clinical outcome of osteosarcoma patients. The examination of integrin-beta1 expression will also identify patients with high risk of disease progression. PMID- 30399379 TI - Synthesis of Femur extracted hydroxyapatite reinforced nanocomposite and its application for Pb(II) ions abatement from aqueous phase. AB - This research study shows the adsorptive potential of biopolymer based nanocomposite for the removal of Pb(II) ions from aqueous phase. The nanocomposite was synthesized by Femur calcined hydroxyapatite and glutaraldehyde cross-linked chitosan. Characterizations like Fourier Transform Infrared (FTIR) Spectroscopy, X-ray Diffraction (XRD) and Scanning Electron Microscopy (SEM) were performed to investigate the structural modifications, mineral composition and the surface texture of prepared nanocomposite. The adsorption of Pb(II) ions over nanocomposite reveals that the synthesized solid sorbent has promising abatement tendency for heavy metal ions. The adsorption process followed the pseudo-second order kinetics and the equilibrium data of lead ions adsorption was best fitted to Sips isotherm model. The uptake capacity of synthesized nanocomposite increased from 209 mg/g to 354 mg/g with rise in temperature from 18 degrees C to 48 degrees C. The thermodynamic analysis suggested that the Pb(II) ions adsorption was spontaneous and endothermic in nature. Additionally, enthalpy of adsorption (~22.07 KJ/mol) indicated that the heavy metal ions were chemisorbed over nanocomposite surface. Adsorption of Pb2+ increased about ~1.6 times in the observed pH range and highest uptake was obtained at pH 5. PMID- 30399377 TI - Assessment of PKA and PKC inhibitors on force and kinetics of non-failing and failing human myocardium. AB - AIMS: Heart failure (HF) is a prevalent disease that is considered the foremost reason for hospitalization in the United States. Most protein kinases (PK) are activated in heart disease and their inhibition has been shown to improve cardiac function in both animal and human studies. However, little is known about the direct impact of PKA and PKC inhibitors on human cardiac contractile function. MATERIAL AND METHODS: We investigated the ex vivo effect of such inhibitors on force as well as on kinetics of left ventricular (LV) trabeculae dissected from non-failing and failing human hearts. In these experiments, we applied 0.5 MUM of H-89 and GF109203X, which are PKA and PKC inhibitors, respectively, in comparison to their vehicle DMSO (0.05%). KEY FINDINGS AND CONCLUSION: Statistical analyses revealed no significant effect for H-89 and GF109203X on either contractile force or kinetics parameters of both non-failing and failing muscles even though they were used at a concentration higher than the reported IC50s and Kis. Therefore, several factors such as selectivity, concentration, and treatment time, which are related to these PK inhibitors according to previous studies require further exploration. PMID- 30399380 TI - Size controllable one step synthesis of gold nanoparticles using carboxymethyl chitosan. AB - Gold nanoparticles (AuNPs) were synthesized by reducing chloroauric acid with nontoxic and biodegradable carboxymethyl chitosan (CMC) as dual roles of reducing agent and stabilizer. Several CMC with different molecular parameters, i.e., degree of substitution (DS), substitution position, degree of deacetylation (DD) and molecular weight (MW) have been investigated for their reducing and stabilizing ability on the synthesis of AuNPs. The obtained AuNPs were characterized with UV-vis spectroscopy, transmission electron microscopy and Fourier transform infrared spectroscopy. The resulting AuNPs displayed controllable size and shape not only depending on the molecular parameters of CMC but experimental parameters, such as reaction temperature, time, pH, concentration of NaOH, HAuCl4 and CMC in solution. The results indicated the addition of NaOH to a solution containing HAuCl4 and CMC is essential to synthesize individual spherical AuNPs with a rather uniform size distribution. The -OH at C-6 and -NH2 at C-2 of CMC played important roles in the reduction of Au(III) to Au(0) and -COO- groups were accountable for the stabilizing ability of CMC to AuNPs. PMID- 30399381 TI - In vitro and in vivo anticoagulant activity of heparin-like biomacromolecules and the mechanism analysis for heparin-mimicking activity. AB - Heparin-like biomacromolecules (HepLBm), exhibiting similar chemical structure and biological properties to heparin, can be obtained by modifying either synthetic biopolymers or natural biomacromolecules with physical or chemical methods. In this work, a low-cost and biocompatible sodium alginate was chosen as a model biomacromolecule to design anticoagulant HepLBm with a similar sulfation degree to heparin. FTIR, 1H NMR, and element analysis data were used to confirm the chemical structure of HepLBm. Hemolysis tests, clotting time, complement activation, and contact activation tests were carried out to determine the in vitro anticoagulant activity of HepLBm. In addition, systematic studies of blood cell count, coagulation function, and histopathology were performed to demonstrate the in vivo anticoagulant activity and toxicity of HepLBm with SD rat experiments. Furthermore, a series of linear molecules containing carboxyl groups, sulfonic groups, and hydroxyl groups were selected and their clotting time was tested to provide a mechanism analysis for the excellent anticoagulant activity of HepLBm. With the excellent in vitro/in vivo anticoagulant activity, good biocompatibility, and low cost, the HepLBm synthesized in this work would have great potential for substitution of heparin in many application fields, such as the surface modification of biomedical devices, extracorporeal anticoagulants, and other clinical fields. PMID- 30399382 TI - Zebrafish acid ceramidase: Expression in Pichia pastoris GS115and biochemical characterization. AB - Acid ceramidase (N-acylsphingosine deacylase EC 3.5.1.23; AC) catalyzes the hydrolysis of ceramide into sphingosine (SPH) and free fatty acid. Zebrafish acid ceramidase (AC) has 60% homology with the human AC). Mutations in the human AC gene asah1 are known to cause Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy. Zebrafish AC was overexpressed in Pichia pastoris by inserting asah1b gene into the genome. The majority of the overexpressed enzyme was secreted into the culture medium and purified to apparent homogeneity by stepwise chromatography. The recombinant protein was glycosylated precursor, that further undergoes limited autoproteolytic processing into two subunits (alpha and beta) which are visible in SDS-PAGE. The zebrafish AC is heterodimer associated with an inter-subunit disulfide bond. SDS-PAGE estimated the mass of native enzyme to be approximately 50 kDa & size exclusion chromatography estimated the mass of the active enzyme as approximately 100 kDa, suggesting the formation of a dimer of heterodimers. The protein was secreted as a mixture of processed and unprocessed forms in the culture media. A preliminary characterization of purified zebrafish AC was done by an enzyme assay. The zebrafish AC expressed in Pichia pastoris would be used for further structural and functional analysis. PMID- 30399383 TI - A GH family 28 endo-polygalacturonase from the brown-rot fungus Fomitopsis palustris: Purification, gene cloning, enzymatic characterization and effects of oxalate. AB - Brown-rot fungi are the wood-decay basidiomycetes and have ability to break down plant cell wall carbohydrates. It has been suggested that degradation of pectin is important for the initial stages of brown rot. We purified an endo polygalacturonase (FpPG28A) from the brown-rot fungus Fomitopsis palustris, analysis of the predicted amino acid sequence indicated that FpPG28A belongs to GH family 28. The highest activity of purified FpPG28A was observed at 60 degrees C in 50 mM sodium acetate buffer (pH 5.0); this activity was highly specific for polygalacturonic acid chains. However, calcium polygalacturonate gel was not degraded by FpPG28A under those optimal conditions. We observed that calcium polygalacturonate gel was readily degraded by the enzyme in the oxalate buffer. Furthermore, the thermostability of FpPG28A was elevated in oxalate buffer at pH 3.0. These results indicated that oxalate has an important role in the degradation of woody pectin by FpPG28A. PMID- 30399384 TI - Development and characterization novel bio-adhesive for wood using kenaf core (Hibiscus cannabinus) lignin and glyoxal. AB - The recent study focused on lignin-phenol-glyoxal (LPG) as an alternative way to replace toxic formaldehyde used in commercially available wood adhesives. The concern of the uses of carcinogenic formaldehyde in wood adhesive industry has become major problem over human health, environmental and economy issues. In this study, lignin isolated from Kenaf (Hibiscus cannabinus) via soda and Kraft pulping were modified into SLPG (soda lignin-phenol-glyoxal) and KLPG (Kraft lignin-phenol-glyoxal) adhesives and were compared to phenol-formaldehyde (PF). Complementary analyses such as Fourier Transform Infrared (FTIR) spectroscopy, 1H and 13C Nuclear Magnetic Resonance (NMR) spectroscopy, thermal stability; Thermogravimetric analysis (TGA) and Differential Scanning Calorimetry (DSC) were utilized to characterize all isolated lignin samples. The physical properties of the resins were further characterized in term of viscosity, gel time and total solid content. It was found that soda lignin comprised higher phenolic OH content and greater molecular weight compared to Kraft lignin. Various molar ratio of adhesives were applied on plywood and were mechanically tested. The 30% (w/w) SLPG has shown to have higher tensile strength and internal bonding stress at 72.08 MPa and 53.83 N mm-2 respectively to that of PF. PMID- 30399385 TI - Evaluation of a micro-spectrometer for the real-time assessment of liver graft mild-to-moderate macrosteatosis: a proof of concept study. AB - BACKGROUND: Liver macrosteatosis (MS) is a major predictor of graft dysfunction after transplantation. However, frozen section techniques to quantify steatosis are often unavailable in the context of procurements, and the findings of preoperative imaging techniques correlate poorly with those of permanent sections, so that the surgeon is ultimately responsible for the decision. Our aim was to assess the accuracy of a non-invasive pocket spectrometer (PSM) for the extemporaneous estimation of MS. METHODS: We prospectively evaluated a commercial PSM by scanning the liver capsule. A double pathological quantification of MS was performed on permanent sections. Initial calibration (training cohort) was performed on 35 livers (MS<=60%) and an algorithm was created to correlate the estimated (PSM) and known (pathological) MS values. A second assessment (validation cohort) was then performed on 154 grafts. RESULTS: Our algorithm achieved a coefficient of determination R2=0.81. Its validation on the second cohort demonstrated a Lin's concordance coefficient of 0.78. Accuracy reached 0.91%, with reproducibility of 86.3%. The sensitivity, specificity, positive and negative predictive values for MS>=30% were 66.7%, 100%, 100% and 98%, respectively. The PSM could predict the absence (<30%) / presence (>=30%) of MS with a kappa coefficient of 0.79. Neither graft weight nor height, donor body mass index nor the CT-scan liver-to-spleen attenuation ratio could accurately predict MS. CONCLUSION: We demonstrated that a PSM can reliably and reproducibly assess mild-to-moderate MS. Its low cost and the immediacy of results may offer considerable added-value decision support. This tool could avoid the detrimental and prolonged ischaemia required by the pathological examination of (potentially) marginal grafts. This device now needs to be assessed in the context of a large scale multicentre study. LAY SUMMARY: The macro-vacuolar liver steatosis is a major prognostic factor for outcomes after liver transplantation. However, it is often difficult for logistical reasons to get this estimation during a procurement. In this perspective, we developed an algorithm for a commercial, portable and affordable spectrometer to accurately estimate this content in a real-time fashion. This device could be of great interest for clinical decision making to accept or discard a potential human liver graft. PMID- 30399386 TI - Platycodi Radix and its active compounds ameliorate against house dust mite induced allergic airway inflammation and ER stress and ROS by enhancing anti oxidation. AB - Allergic airway inflammation is an increasing global health problem, and novel strategies to prevent or ameliorate the condition are needed. The endoplasmic reticulum (ER) is involved in protein synthesis and maturation, and is a susceptible to sub-organelle stress including inflammation and ROS-amplifying signaling. Here, the effects of Platycodi Radix extracts (PRE) on house dust mite (HDM) extract (Dematophagoides pteronyssius)-induced asthma were investigated. Following 50, 100, or 200 mg/kg-PRE-treatment, the infiltration of inflammatory cells, ER stress, and NF-kappaB signaling were controlled. The expression of inflammatory cytokines and mucin5AC was also inhibited in the presence of PRE. Consistently, in the HDM-exposed human bronchial epithelial cells, ER stress and its associated ROS were significantly increased along with NF-kappaB signaling, which was also attenuated by PRE and its components. This study suggests that PRE might be useful as a therapeutic/preventive agent in HDM-associated allergic airway inflammation. ER stress and its associated ROS signaling involved in inflammation provide additional mechanistic insight into the underlying molecular mechanism. PMID- 30399387 TI - Inflammatory eruptions associated with immune checkpoint inhibitor therapy: A single-institutional, retrospective analysis with stratification of reactions by toxicity and implications for management. AB - BACKGROUND: There is increasing recognition of distinct inflammatory eruptions associated with checkpoint inhibitors. A better understanding of their severity, therapeutic response and impact on cancer treatment is needed. OBJECTIVE: To analyze the different rashes associated with immunotherapy referred to our institution's oncodermatology clinic and inpatient consultative service, and to evaluate their therapeutic response and impact on immunotherapy. METHODS: We retrospectively reviewed patients' medical records referred to the oncodermatology clinic or inpatient dermatology service between 2016-2018 at Yale New Haven Hospital for eruptions that developed during immunotherapy. RESULTS: 98 patients (51 men, 47 women) treated with checkpoint inhibitors developed 103 inflammatory eruptions, with a range of mean latency of 0.2-17.7 months. A minority (25/103; 24.3%) required immunotherapy interruption, most notably immunobullous (7/8; 87.5%), lichenoid (8/26; 30.8%), maculopapular (6/18; 33.3%), and SJS-like (2/2, 100%) reactions. Only 3/16 (18.8%) interrupted cases developed a grade 2 or 3 flare on rechallenge. Most reactions (93/103; 90.3%) responded to dermatologic therapy and/or immunotherapy interruption. LIMITATIONS: This was a retrospective study from a single tertiary care center. CONCLUSION: A variety of inflammatory reactions may occur from immunotherapy with differing degrees of severity. While most rashes responded to topical treatment, immunobullous and exfoliative presentations frequently interrupted immunotherapy. Increased awareness and early recognition may reduce the need for unnecessary immunotherapy interruption. PMID- 30399388 TI - Protein disulfide-isomerase A3 significantly reduces ischemia-induced damage by reducing oxidative and endoplasmic reticulum stress. AB - Ischemia causes oxidative stress in the endoplasmic reticulum (ER), accelerates the accumulation of unfolded and misfolded proteins, and may ultimately lead to neuronal cell apoptosis. In the present study, we investigated the effects of protein disulfide-isomerase A3 (PDIA3), an ER-resident chaperone that catalyzes disulfide-bond formation in a subset of glycoproteins, against oxidative damage in the hypoxic HT22 cell line and against ischemic damage in the gerbil hippocampus. We also confirmed the neuroprotective effects of PDIA3 by using PDIA3-knockout HAP1 cells. The HT22 and HAP1 cell lines showed effective (dose dependent and time-dependent) penetration and stable expression of the Tat-PDIA3 fusion protein 24 h after Tat-PDIA3 treatment compared to that in the control PDIA3-treated group. We observed that the fluorescence for both 2',7' dichlorofluorescein diacetate (DCF-DA) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL), which are markers for the formation of hydrogen peroxide (H2O2)-induced reactive oxygen species and apoptosis, respectively, was higher in HAP1 cells than in HT22 cells. The administration of Tat-PDIA3 significantly reduced the (1) DCF-DA and TUNEL fluorescence in HT22 and HAP1 cells, (2) ischemia-induced hyperactivity that was observed 1 day after ischemia/reperfusion, (3) ischemia-induced neuronal damage and glial (astrocytes and microglia) activation that was observed in the hippocampal CA1 region 4 days after ischemia/reperfusion, and (4) lipid peroxidation and nitric oxide generation in the hippocampal homogenates 3-12 h after ischemia/reperfusion. Transient forebrain ischemia significantly elevated the immunoglobulin-binding protein (BiP) and C/EBP-homologous protein (CHOP) mRNA levels in the hippocampus at 12 h and 4 days after ischemia, relative to those in the time-matched sham operated group. Administration of Tat-PDIA3 ameliorated the ischemia-induced upregulation of BiP mRNA levels versus the Tat peptide- or control-PDIA3-treated groups, and significantly reduced the induction of CHOP mRNA levels, at 12 h or 4 days after ischemia. Collectively, these results suggest that Tat-PDIA3 acts as a neuroprotective agent against ischemia by attenuating oxidative damage and blocking the apoptotic pathway that is related to the unfolded protein response in the ER. PMID- 30399389 TI - Successful control of the first OXA-48 and/or NDM carbapenemase-producing Klebsiella pneumoniae outbreak in Slovenia 2014-2016. AB - BACKGROUND: Carbapenemase-producing Enterobacteriaceae (CPE) occur only sporadically in Slovenia. AIM: To describe the first Slovenian carbapenemase producing (CP) Klebsiella pneumoniae and Escherichia coli outbreak which occurred at the tertiary teaching hospital University Medical Centre Ljubljana from October 2014 to April 2015. METHODS: A CPE-positive case was defined as any patient infected or colonized with CPE. A strict definition of a contact patient was adopted. Measures to prevent cross-transmission included cohorting of all CPE carriers with strict contact precautions and assignment of dedicated healthcare workers, cohorting of all contact patients until obtaining the result of screening cultures, systematic rectal screening of contact patients, and tagging of all CPE-positive cases and their contacts. Educational campaigns on CPEs were implemented. Clinical specimens were processed using standard procedures. Pulsed field gel electrophoresis (PFGE) was used to determine relatedness. Multi-locus sequence typing was performed on CP K. pneumoniae isolates that belonged to different pulsotypes. FINDINGS: Before the outbreak was brought under control, 40 patients were colonized or infected with OXA-48 and/or New Delhi metallo-beta lactamase (NDM)-producing CPE; in 38 patients OXA-48 and/or NDM-producing K. pneumoniae was detected, in seven OXA-48 and/or NDM-producing E. coli was found together with K. pneumoniae, and in two patients only CP E. coli was isolated. The outbreak was oligoclonal with two major CP K. pneumoniae clusters belonging to ST437 and ST147 in epidemiologically linked patients. CONCLUSION: Initial standard control measures failed to prevent the outbreak. Once the problem had been recognized, strict infection control measures and the education of healthcare workers contributed to the successful control of the outbreak. PMID- 30399390 TI - Neuronal mechanisms regulating the critical period of sensory experience dependent song learning. AB - Neuronal circuits are intensively shaped depending on experiences received during developmental critical periods. How neuronal circuits are sculpted can even affect the later development of higher cognitive functions, such as vocal communication skills. Here, we propose songbirds that learn to sing from early auditory experiences as a model for understanding the neuronal mechanisms underlying the development of multistep vocal learning. By applying the principal concepts of neuronal mechanisms for regulating the timing of critical periods, which have been well investigated by using experience-dependent mammalian cortical plasticity, we review our current understanding of the underlying neuronal mechanism of the song-learning critical period. PMID- 30399393 TI - Are glucose profiles well-controlled within the targets recommended by the International diabetes Federation in type 2 diabetes? A meta-analysis of results from continuous glucose monitoring based studies. AB - AIMS: To assess continuous glucose monitoring (CGM) derived intra-day glucose profiles using global guideline for type 2 diabetes recommended by the International Diabetes Federation (IDF). METHODS: The Cochrane Library, MEDLINE, PubMed, CINAHL and Science Direct were searched to identify observational studies reporting intra-day glucose profiles using CGM in people with type 2 diabetes on any anti-diabetes agents. Overall and subgroup analyses were conducted to summarise mean differences between reported glucose profiles (fasting glucose, pre-meal glucose, postprandial glucose and post-meal glucose spike/excursion) and the IDF targets. RESULTS: Twelve observational studies totalling 731 people were included. Pooled fasting glucose (0.81 mmol/L, 95% CI, 0.53-1.09 mmol/L), postprandial glucose after breakfast (1.63 mmol/L, 95% CI, 0.79-2.48 mmol/L) and post-breakfast glucose spike (1.05 mmol/L, 95% CI, 0.13-1.96 mmol/L) were significantly higher than the IDF targets. Pre-lunch glucose, pre-dinner glucose and postprandial glucose after lunch and dinner were above the IDF targets but not significantly. Subgroup analysis showed significantly higher fasting glucose and postprandial glucose after breakfast in all groups: HbA1c <7% and >=7% (53 mmol/mol) and duration of diabetes <10 years and >=10 years. CONCLUSIONS: Independent of HbA1c, fasting glucose and postprandial glucose after breakfast are not well-controlled in type 2 diabetes. PMID- 30399391 TI - Temperature shift activates bloodstream VSG expression site promoters in Trypanosoma brucei. AB - Trypanosoma brucei relies on two types of variant surface glycoprotein (VSG) expression sites (ESs) for RNA polymerase I (Pol I) transcription of VSG pre mRNA. Trypanosomes developing into infectious metacyclic cells in the tsetse vector use metacyclic VSG ESs (MESs) and proliferating parasites in the mammalian host deploy bloodstream VSG ESs (BESs). Unlike the monocistronic MESs, BESs are polycistronic and their highly conserved promoters differ considerably from the MES promoters. The significance of the divergent sequences of MES and BES promoters remains to be determined. We used a reporter system to specifically test the effect of temperature on the activity of MES and BES promoters in procyclic trypanosomes and our results demonstrate that transcription from the MES promoter is largely insensitive to changes in temperature. In contrast, the BES promoter drives rapid activation of transcription upon a change of temperature from 28 degrees C to 37 degrees C. Additionally, endogenous BESs respond similarly to the elevation of temperature and initiate increased production of BES pre-mRNA and mRNA. Our results indicate that the sequence of the BES promoter is a specificity signal which triggers BES activation in vivo upon entry into the mammalian host. PMID- 30399392 TI - Heterozygous huntingtin promotes cadmium neurotoxicity and neurodegeneration in striatal cells via altered metal transport and protein kinase C delta dependent oxidative stress and apoptosis signaling mechanisms. AB - Huntington's disease (HD) is functionally linked to environmental factors including cigarette use and dyshomeostasis in the levels of metals. Interestingly, one of the most abundant heavy metals in cigarettes is cadmium (Cd), which also accumulates in the striatum and causes neurotoxicity upon exposure. Thus, we hypothesized that heterozygous huntingtin (HTT), responsible for the majority of cases of HD in patients, in combination with Cd exposure would cause neurotoxicity and neurodegeneration via increased intracellular accumulation of Cd and activation of oxidative stress signaling mechanisms in a mouse striatal cell line model of HD. We report that heterozygous HTT striatal cells are significantly more susceptible to Cd-induced cytotoxicity as compared to wild-type HTT cells upon exposure for 48 h. The heterozygous HTT and Cd induced cytotoxicity led to a NADPH oxidase (NOX) mediated oxidative stress that was attenuated by exogenous antioxidants and a NOX inhibitor, apocynin. Heterozygous HTT coupled with Cd exposure caused increased expression of protein kinase C delta (PKCdelta) and other key oxidative stress proteins levels, enhanced the activation of caspase-9 and caspase-3 mediated apoptosis, and blocked the overexpression of extracellular signal-regulated kinase (ERK). We observed significantly greater intracellular accumulation of Cd and reduced expression of divalent metal transporter 1 (DMT1) protein in the heterozygous HTT striatal cells upon Cd exposure. Treatment with zinc, manganese, and iron as well as exogenous antioxidants significantly attenuated the Cd-induced cytotoxicity. Collectively, these results demonstrate that heterozygous HTT exhibits greater neurotoxic properties when coupled with Cd exposure to cause cell death via caspase mediated apoptosis, altered metal transport, and modulation of ERK and PKCdelta dependent oxidative signaling mechanisms. PMID- 30399394 TI - Characterization of a quasi-enveloped, fast replicating hepevirus from fish and its use as hepatitis E virus surrogate. AB - Hepatitis E virus (HEV) is an emerging concern for the safety of plasma-derived medicinal products. The lack of an efficient cell culture system hampers the studies on HEV biology as well as validation studies to test the capacity of virus reduction steps to clear HEV. Hence, a surrogate hepevirus that can efficiently replicate in cell culture is needed. Cutthroat trout virus (CTV) is a non-pathogenic fish hepevirus, which can replicate in cell culture to high titers. Under interferon inhibition, CTV replication reached up to 5 * 107 genome equivalents per MUL in 4-5 days. The intracellular CTV progeny was already lipid associated, suggesting that the envelope is acquired from intracellular membranes. Transmission electron microscopy of purified quasi-enveloped virus revealed exosome-like structures with an average size of 40 nm, in contrast to 27 34 nm for the non-enveloped virus. The quasi-enveloped virus was significantly less infectious than the non-enveloped virus. Assays based on quantitative RT PCR, immunofluorescence and immunocytochemistry were established to evaluate virus inactivation. Cold ethanol fractionation removed 3.0 log of CTV and pasteurization of human albumin inactivated more than 3.7 log to below the limit of detection. Similar to HEV, virus replication was promoted in the presence of 17beta-estradiol, an effect that can contribute to the understanding of the exacerbated virulence of HEV in pregnant women. These results together reveal substantial similarities between the human and fish HEV and validate CTV as a practical virus model to use in some applications for evaluating the HEV reduction capacity of biological manufacturing process steps. PMID- 30399395 TI - Varenicline for long term smoking cessation in patients with COPD. AB - BACKGROUND: Quitting smoking is key for patients with Chronic Obstructive Pulmonary Disease (COPD). Standard recommendations for quitting smoking are implemented for COPD as well. Varenicline Tartrate (VT) is the most effective drug to help quit smoking, but few studies have analysed its effectiveness. AIM OF THE STUDY: To determine the Abstinence Rate (AR) at 12 months, in COPD and non COPD smokers. METHODS: Observational study in 31 COPD (post bronchodilator-BD FEV1/FVC <0.70) and in 63 non-COPD smokers, were invited to receive treatment with Varenicline Tartrate (VT). Fourteen subjects with COPD and 46 non-COPD subjects received additionally Cognitive-Behavioral Therapy (CBT). Abstinence rate (AR) was validated by exhaled carbon monoxide CO (COe), in addition to a phone or face-to-face interview. Motivation score was measured with a visual analogue scale (MS). RESULTS: Differences between COPD and non-COPD, mean FEV1/FVC ratio 0.52 +/- 0.10 vs. 0.90 +/- 0.15, age 60 +/- 10 vs. 47 +/- 10 years, smoking pack-years 37 +/- 3.5 vs. 22 +/- 12, and COe 16 +/- 11 vs. 12 +/- 9 ppm were statistically significant (p < 0.05); for MS the score was 93 +/- 11 vs. 93 +/- 11 and for attempts to quit (AQ) 2 +/- 2 vs. 2 +/- 3 were not. AR was not significantly different at 12 months (61.2 vs. 42.8% p = 0.072). Motivation was the only significant one-year AR predictor. CONCLUSIONS: COPD smokers had a similar response (higher tendency) to VT regardless of the presence of airflow obstruction and stronger nicotine addiction. PMID- 30399396 TI - Time-domain exponential energy for epileptic EEG signal classification. AB - Automatic classification and prediction of epileptic electroencephalogram (EEG) signal are of great concern to the research community due to its non-stationary and non-linear properties. Features with minimal computation cost are highly needed for the rapid real-time precise diagnosis and implementation in the EEG scanning devices. Even though energy is a well-known feature for the analysis of signals, it is very rarely used in EEG analysis. An exponential energy feature in the time domain is proposed in this study. The proposed exponential energy feature provides a classification accuracy of 89% in the Bern-Barcelona EEG dataset and 99.5% in the Ralph Andrzejak EEG dataset. The promising results open a wide applicability of exponential energy in biomedical signal analysis. PMID- 30399397 TI - Effects of lidocaine on adult zebrafish behavior and brain acetylcholinesterase following peripheral and systemic administration. AB - Lidocaine is a voltage-gated Na+ channel blocker, commonly used as a fast-acting local and general anesthetic. Lidocaine also has central action, affecting behavior both clinically and in animal models. Adult zebrafish are rapidly becoming a critical novel model organism in translational neuroscience research. Here, we examine the effects of acute peripheral (lateral line application, 4%) and systemic (water immersion, 1, 5 and 10 mg/L) administration of lidocaine on adult zebrafish behavior tested in the novel tank test. Overall, the drug evoked hypolocomotor effect when applied systemically (at 10 mg/L) and peripherally. Peripheral lidocaine also reduced top exploration in the novel tank test (vs. sham), suggesting anxiogenic-like effect of the lateral line blockage, Our findings show the importance of the lateral line system in driving adult zebrafish locomotion, and suggest sedative-like effects of systemic lidocaine in aduld zebrafish. In addition, reflecting the role of central cholinergic contribution in lidocaine action, brain acetylcholinesterase (AChE) activity was lower following peripheral and systemic administration of lidocaine at behaviorally active doses. Collectively, our data support the effects of lidocaine on behavioral responses in zebrafish, and reinforce the growing utility of this aquatic model to screen various CNS drugs. PMID- 30399398 TI - Corticospinal excitability, assessed through stimulus response curves, is phase-, task-, and muscle-dependent during arm cycling. AB - The purpose of the present study was to examine corticospinal excitability to the biceps and triceps brachii during arm cycling and an intensity-matched tonic contraction using stimulus response curves (SRCs) elicited via transcranial magnetic stimulation (TMS). Corticospinal excitability was assessed using TMS elicited motor-evoked potentials (MEPs) at eight different stimulation intensities (85-190% of MEP threshold). MEPs were recorded during arm cycling at two different positions, mid-elbow flexion (6 o'clock relative to a clock face) and mid-elbow extension (12 o'clock relative to a clock face), in addition to an intensity-matched (12 o'clock) tonic contraction. At the 12 o'clock position, the slope of the SRC was significantly lower during arm cycling than the tonic contraction for the biceps brachii (Cycling: 0.64 +/- 0.47, Tonic: 1.02 +/- 0.38, P < 0.05) but was not different for the triceps brachii (Cycling: 1.33 +/- 0.49, Tonic: 1.48 +/- 0.43, P = 0.42). Within arm cycling, the SRC slope was significantly greater at the 6 o'clock position than 12 o'clock position for the biceps brachii (6 o'clock: 1.37 +/- 0.24, 12 o'clock: 0.64 +/- 0.47, P < 0.05) but was not different for the triceps brachii (6 o'clock: 1.11 +/- 0.28, 12 o'clock: 1.33 +/- 0.49, P = 0.34). These findings demonstrate that corticospinal excitability to the biceps brachii is task-dependent during the extension phase of arm cycling. Neither position nor task influenced corticospinal excitability to the triceps brachii, providing further support that the motor control of locomotor outputs is muscle-specific. PMID- 30399399 TI - "Complementary Medicine": Complementary and alternative health approaches in pediatric and adolescent gynecology. AB - Complementary and alternative health care approaches are prevalent in the patients and families served by practitioners in pediatric and adolescent gynecology. This paper addresses gaps in knowledge, including new terminology, prevalence of use, rates of and reasons behind nondisclosure, and potential interactions of herbal products with prescribed medication. It closes with practical complementary health approaches to the adolescent with dysmenorrhea. PMID- 30399400 TI - Oxcarbazepine free or loaded PLGA nanoparticles as effective intranasal approach to control epileptic seizures in rodents. AB - The brain as a target for drug delivery is a challenge in pharmaceutical research. Among the several proposed strategies, the intranasal route represents a good strategy to deliver drugs to the brain. The goal of this study was to investigate the potential use of oxcarbazepine (OXC) to enhance brain targeting efficiency after intranasal (IN) administration. As well as attempting to use as low a dose as possible to obtain therapeutic effect. Our results showed that, after IN administrations, the dose of OXC that was effective in controlling epileptic seizures was 0.5 mg/kg (1 dose, every 20 min for 1 h) in rodents, confirmed by Cerebral Spinal Fluid (CSF) bioavailability. With the aim of reducing the number of administrations, sustaining drug release and increasing brain targeting, OXC was loaded into poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs). The selected nanoformulation for in vivo studies was obtained re-suspending the freeze-dried and cryo-protected OXC loaded PLGA NPs. The translocation of 1-1'-Dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine Iodide loaded PLGA NPs, from nose to the brain, was confirmed by Fluorescence Molecular Tomography, which also evidenced an accumulation of NPs in the brain after repeated IN administrations. IN administrations of OXC loaded PLGA NPs reduced the number of administrations to 1 over 24 h compared to the free drug thus controlling seizures in rats. Immunohistochemical evaluations (anti neurofilament, anti-beta tubulin, and anti-caspase3) demonstrated a neuroprotective effect of OXC PLGA NPs after 16 days of treatment. These encouraging results confirmed the possibility of developing a novel non-invasive nose to brain delivery system of OXC for the treatment of epilepsy. PMID- 30399401 TI - Prenatal alcohol exposure and offspring alcohol use and misuse at 22 years of age: A prospective longitudinal study. AB - Studies have shown that prenatal alcohol exposure (PAE) is related to drinking problems during adulthood, but the level of prenatal exposure associated with young adults' quantity and frequency of alcohol use and drinking problems has not yet been established. The relation between PAE and offspring levels of alcohol use and alcohol abuse/dependency was examined in 608 22-year-olds. Mothers were recruited in early pregnancy and maternal alcohol use data were collected for each trimester of pregnancy. The offspring were assessed at multiple phases from birth to young adulthood. The average daily volume of drinking was calculated based on a self-report questionnaire developed by the Maternal Health Practices and Child Development Project and alcohol abuse/dependence was assessed using the Diagnostic Interview Schedule-IV. Exposure to one or more drinks/day during the first trimester of pregnancy was significantly related to increased levels of drinking at 22 years of age, controlling for other predictors of alcohol use. PAE was also related to two or more symptoms of Alcohol Use Disorder, but not to a full diagnosis of young adult alcohol abuse/dependence. These results indicate that individuals exposed to as little as one drink per day during gestation are at risk of higher levels of drinking and more problems with alcohol by age 22. PMID- 30399402 TI - Cloning, expression prolife, and immune characterization of a novel stat family member (stat5bl) in Chinese tongue sole (Cynoglossus semilaevis). AB - STAT plays important roles in innate immunity during JAK/STAT signaling pathway, and STAT5 is particularly focused due to the existence of duplicated forms in fish and mammal. In Chinese tongue sole, stat5bl was suggested to be a candidate related to Vibrio harveyi resistance based on previous QTL screening. In this study, the full length of stat5bl cDNA was cloned and its expression patterns were analyzed. stat5bl was predominantly expressed in immune tissues, where the highest level was observed in liver, followed by skin and gill. Time course expression patterns were examined in six tissues (liver, skin, gill, kidney, intestine, spleen) after V. harveyi infection. stat5bl could be up-regulated by V. harveyi infection in all tissues except liver, despite the timepoints of peak were different. In contrast, stat5bl was significantly downregulated in liver. To elucidate the role of stat5bl in liver, in vitro RNAi were performed using primary liver cell culture. Knockdown of stat5bl could regulate the expression of genes closely related to JAK/STAT pathway. This study would enlarge our understanding of stat5bl in fish immunity. PMID- 30399403 TI - cDNA cloning, characterization, and expression analysis of the Rac1 and Rac2 genes from Cynoglossus semilaevis. AB - Rac1 and Rac2, belonging to the small Rho GTPase family, play an important role during the immune responses. In this study, a Rac1 homolog (CsRac1) and a Rac2 homolog (CsRac2) were cloned from the Cynoglossus semilaevis. The full-length of CsRac1 and CsRac2 cDNA was 1219 bp and 1047 bp, respectively. Both CsRac1 and CsRac2 contain a 579 bp open reading frame (ORF) which encoding a 192 amino acids putative protein. The predicted molecular weight of CsRac1 and CsRac2 was 21.41 kDa and 21.35 kDa, and their theoretical pI was 8.50 and 7.91, respectively. Sequence analysis showed that the conserved RHO domain was detected both from amino acid of CsRac1 and CsRac2. Homologous analysis showed that CsRac1 and CsRac2 share high conservation with other counterparts from different species. The CsRac1 and CsRac2 transcript showed wide tissue distribution, in which CsRac1 and CsRac2 exhibit the highest expression level in liver and gill, respectively. The expression level of CsRac1 and CsRac2 fluctuated in the liver and gill tissues at different time points after challenged by Vibrio harveyi. Specifically, CsRac1 and CsRac2 were significantly up-regulated at 48 h and 96 h post injection. Moreover, the knocking down of CsRac1 and CsRac2 in cell line (TSHKC) reduced the expression of CsPAK1, CsIL1-beta and CsTNF-alpha. The present data suggests that CsRac1 and CsRac2 might play important roles in the innate immunity of half-smooth tongue sole. PMID- 30399404 TI - Childhood adversity impact on gut microbiota and inflammatory response to stress during pregnancy. AB - BACKGROUND: Adverse childhood experiences (ACEs), such as abuse or chronic stress, program an exaggerated adult inflammatory response to stress. Emerging rodent research suggests that the gut microbiome may be a key mediator in the association between early life stress and dysregulated glucocorticoid-immune response. However, ACE impact on inflammatory response to stress, or on the gut microbiome, have not been studied in human pregnancy, when inflammation increases risk of poor outcomes. The aim of this study was to assess the relationships among ACE, the gut microbiome, and cytokine response to stress in pregnant women. METHODS: Physically and psychiatrically healthy adult pregnant women completed the Adverse Childhood Experiences Questionnaire (ACE-Q) and gave a single stool sample between 20 and 26 weeks gestation. Stool DNA was isolated and 16S sequencing was performed. Three 24-hour food recalls were administered to assess dietary nutrient intake. A subset of women completed the Trier Social Stress Test (TSST) at 22-34 weeks gestation; plasma interleukin-6 (IL-6), interleukin-1beta (IL-1beta), high sensitivity C-reactive protein (hsCRP), tumor necrosis factor alpha (TNF-alpha), and cortisol were measured at four timepoints pre and post stressor, and area under the curve (AUC) was calculated. RESULTS: Forty-eight women completed the ACE-Q and provided stool; 19 women completed the TSST. Women reporting 2 or more ACEs (high ACE) had greater differential abundance of gut Prevotella than low ACE participants (q = 5.7 * 10^-13). Abundance of several gut taxa were significantly associated with cortisol, IL-6, TNF-alpha and CRP AUCs regardless of ACE status. IL-6 response to stress was buffered among high ACE women with high intake of docosahexaenoic acid (DHA) (p = 0.03) and eicosapentaenoic acid (EPA) (p = 0.05). DISCUSSION: Our findings suggest that multiple childhood adversities are associated with changes in gut microbiota composition during pregnancy, and such changes may contribute to altered inflammatory and glucocorticoid response to stress. While preliminary, this is the first study to demonstrate an association between gut microbiota and acute glucocorticoid-immune response to stress in a clinical sample. Finally, exploratory analyses suggested that high ACE women with high dietary intake of omega-3 polyunsaturated fatty acids (PUFAs) had a dampened inflammatory response to acute stress, suggesting potentially protective effects of omega-3s in this high-risk population. Given the adverse effects of inflammation on pregnancy and the developing fetus, mechanisms by which childhood adversity influence the gut brain axis and potential protective factors such as diet should be further explored. PMID- 30399405 TI - Ketamine and depression: A special kase for kynurenic acid? PMID- 30399406 TI - 17beta-estradiol inhibits human umbilical vascular endothelial cell senescence by regulating autophagy via p53. AB - Vascular endothelial cell (VEC) senescence is an initiating factor in numerous cardiovascular diseases. Recent studies showed that 17beta-estradiol (17beta-E2), an estrogen with numerous biological activities such as inhibition of atherosclerosis, protects VECs from senescence. However, the effects of 17beta-E2 on human umbilical VECs (HUVECs) remain unknown. This study investigated the anti senescent effect of 17beta-E2 on HUVECs and explored the underlying mechanism with respect to autophagy and p53 activity. First, rapamycin and 3-methyladenine were used to clarify the relationship between autophagy and senescence in HUVECs, and an inverse relationship was demonstrated. Next, the effect of 17beta-E2 on H2O2-induced senescence of HUVECs was examined. Increased autophagy induced by 17beta-E2 inhibited H2O2-induced senescence of HUVECs, increased cell viability, and maintained HUVEC morphology. 17beta-E2 pre-treatment also decreased cell cycle arrest, decreased the dephosphorylation of Rb, decreased the production of ET-1, and increased the production of NO. Most importantly, 17beta-E2 pre treatment increased autophagy by activating p53 and its downstream effector p53 upregulated modulator of apoptosis (PUMA). Overall, our data indicate the critical role of autophagy in the anti-senescent effect of 17beta-E2 on HUVECs. PMID- 30399407 TI - Central artery stiffness is related to cerebral oxygenation hemodynamics during executive function tasks in healthy middle-aged and older adults. AB - Age-related decreases in cognitive function, cerebral perfusion, and vascular function increase the risk of dementia. However, the effects of central artery stiffness on cerebral oxygenation hemodynamics during executive function tasks and executive function remain unclear. The aim of this cross-sectional study was to investigate the relationships among central artery stiffness, cerebral oxygenation hemodynamics during executive function tasks, and executive function in middle-aged and older adults. Sixty-two middle-aged and older adults (age range: 51-79 years) were recruited for this study. For each participant, we measured the carotid artery beta-stiffness, oxygenated hemoglobin (oxy-Hb) signal change in the prefrontal cortex during the Stroop task, and Stroop interference time. Correlation analyses revealed that the carotid artery beta-stiffness was significantly correlated with the Stroop interference time (r = 0.43, P < 0.001) and with the oxy-Hb signal change in the left (r = -0.38, P = 0.002), but not the right, prefrontal cortex. In addition, the Stroop interference time was significantly correlated with the oxy-Hb signal change in the left (r = -0.42, P = 0.001), but not the right, prefrontal cortex. The participants were divided into the low and high arterial stiffness groups according to the median value. We found that the Stroop interference time was significantly shorter (P = 0.006) and the oxy-Hb signal change in the left prefrontal cortex was significantly larger in the low arterial stiffness group than in the high arterial stiffness group (P = 0.011). In the low, but not the high, arterial stiffness group, the oxy-Hb signal change of the left prefrontal cortex during executive function tasks was significantly larger than the oxy-Hb signal change of the right prefrontal cortex (P = 0.014). These results suggest that increases in central artery stiffness are associated with decreases in oxygenation hemodynamics in the left prefrontal cortex during executive function tasks and reductions in executive function. PMID- 30399408 TI - Congeneric variability in lifespan extension and onset of senescence suggest active regulation of aging in response to low temperature. AB - Lifespan extension under low temperature is well conserved across both endothermic and exothermic taxa, but the mechanism underlying this change in aging is poorly understood. Low temperature is thought to decrease metabolic rate, thus slowing the accumulation of cellular damage from reactive oxygen species, although recent evidence suggests involvement of specific cold-sensing biochemical pathways. We tested the effect of low temperature on aging in 11 strains of Brachionus rotifers, with the hypothesis that if the mechanism of lifespan extension is purely thermodynamic, all strains should have a similar increase in lifespan. We found differences in change in median lifespan ranging from a 6% decrease to a 100% increase, as well as differences in maximum and relative lifespan extension and in mortality rate. Low temperature delays reproductive senescence in most strains, suggesting an extension of healthspan, even in strains with little to no change in lifespan. The combination of low temperature and caloric restriction in one strain resulted in an additive lifespan increase, indicating these interventions may work via non- or partially overlapping pathways. The known low temperature sensor TRPA1 is present in the rotifer genome, but chemical TRPA1 agonists did not affect lifespan, suggesting that this gene may be involved in low temperature sensation but not in chemoreception in rotifers. The congeneric variability in response to low temperature suggests that the mechanism of low temperature lifespan extension is an active genetic process rather than a passive thermodynamic one and is dependent upon genotype. PMID- 30399409 TI - Nitrite treatment downregulates vascular MMP-2 activity and inhibits vascular remodeling in hypertension independently of its antihypertensive effects. AB - Hypertension is associated with cardiovascular remodeling. Given that impaired redox state activates matrix metalloproteinase (MMP)- 2 and promotes vascular remodeling, we hypothesized that nitrite treatment at a non-antihypertensive dose exerts antioxidant effects and attenuates both MMP-2 activation and vascular remodeling of hypertension. We examined the effects of oral sodium nitrite at antihypertensive (15 mg/kg) or non-antihypertensive (1 mg/kg) daily dose in hypertensive rats (two kidney, one clip; 2K1C model). Sham-operated and 2K1C hypertensive rats received vehicle or nitrite by gavage for four weeks. Systolic blood pressure decreased only in hypertensive rats treated with nitrite 15 mg/Kg/day. Both low and high nitrite doses decreased 2K1C-induced vascular remodeling assessed by measuring aortic cross-sectional area, media/lumen ratio, and number of vascular smooth muscle cells/aortic length. Both low and high nitrite doses decreased 2K1C-induced vascular oxidative stress assessed in situ with the fluorescent dye DHE and with the lucigenin chemiluminescence assay. Vascular MMP-2 expression and activity were assessed by gel zymography, Western blot, and in situ zymography increased with hypertension. While MMP-2 levels did not change in response to both doses of nitrite, both doses completely prevented hypertension-induced increases in vascular MMP activity. Moreover, incubation of aortas from hypertensive rats with nitrite at 1-20 MUmol/L reduced gelatinolytic activity by 20-30%. This effect was fully inhibited by the xanthine oxidase (XOR) inhibitor febuxostat, suggesting XOR-mediated generation of nitric oxide (NO) from nitrite as a mechanism explaining the responses to nitrite. In vitro incubation of aortic extracts with nitrite 20 MUmol/L did not affect MMP-2 activity. These results show that nitrite reverses the vascular structural alterations of hypertension, independently of anti-hypertensive effects. This response is mediated, at least in part, by XOR and is attributable to antioxidant effects of nitrite blunting vascular MMP-2 activation. Our findings suggest nitrite therapy to reverse structural alterations of hypertension. PMID- 30399410 TI - The methanolic extract of Thymus praecox subsp. skorpilii var. skorpilii restores glucose homeostasis, ameliorates insulin resistance and improves pancreatic beta cell function on streptozotocin/nicotinamide-induced type 2 diabetic rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Thymus praecox subsp. skorpilii var. skorpilii (syn. Thymus praecox subsp. jankae (Celak.) Jalas) is consumed as a Turkish folk medicine for the treatment of spasm, sore throat and shortness of breath, also having strong antioxidant activity and the leaves of the plant have been utilized for the treatment of diabetes as the decoction in Turkey. AIM OF THE STUDY: In the present study, we aimed to investigate the potential mechanism of antidiabetic action of Thymus praecox subsp. skorpilii var. skorpilii methanolic extract (TPSE) on streptozotocin (STZ)/nicotinamide (NA)-induced type 2 diabetic rats. MATERIALS AND METHODS: Sprague Dawley rats were randomly divided into four groups; control, diabetes, TPSE (100 mg/kg b.w, p.o.) and metformin group (400 mg/kg b.w, p.o.). Diabetes was established in all groups except control group by 55 mg/kg STZ (i.p.) for once 15 min after 100 mg/kg NA injection. 3 days after STZ/NA injection, treatments were administered for three weeks and then rats were decapitated; tissue and blood samples were obtained for measuring the level of glucose transporters (both GLUTs and sodium glucose co-transporters (SGLTs)), enzymes related to glucose (Hexokinase (HK), phosphoenolpyruvate carboxykinase (PEPCK), alpha-glucosidase) and lipid metabolism (Acetyl-coenzyme carboxylase (ACC)), AST, ALT, creatinine, insulin, anti-inflammatory (IL-10) and inflammatory (TNF-alpha, IL-1beta, IL-6) cytokines, AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma (PPAR-gamma) and glucagon like peptide-1 (GLP-1). Histopathological alterations of the pancreas were examined. RESULTS: After three weeks of treatment, TPSE has exhibited a significant reduction of plasma levels of the proinflammatory cytokines. Besides, TPSE treatment elevated plasma insulin levels and normalized blood glucose levels. Moreover, it improved the values of AMPK in liver and GLP-1 in pancreas. Increased alpha-glucosidase, PEPCK, GLUT-2 and SGLTs levels with the induction of diabetes considerably lowered with TPSE treatment. Especially on SGLT-2, TPSE achieved a more prominent decrease. After the atrophy in Langerhans islets due to diabetes induction, treatment was found to prevent the damage of islets. CONCLUSIONS: Based on the findings presented here, it has been concluded that TPSE has marked antidiabetic effects through various pathways on STZ/NA-induced diabetic rats and it may potentially be used as an effective treatment for type 2 diabetes mellitus (T2DM). Further research on isolation of the bioactive components is underway. PMID- 30399411 TI - If You Can't Trust a Bulboventricular Foramen, Whom Can You Trust? PMID- 30399412 TI - Atypical Right Pulmonary Artery Dissection Complicating Severe Blunt Chest Trauma. AB - Pulmonary artery dissection is a rare albeit life-threatening event and it mostly occurs as the spontaneous rupture of pulmonary artery aneurysm complicating chronic pulmonary hypertension. Here, we describe a case of blunt traumatic pulmonary artery dissection. PMID- 30399413 TI - CRISPR-Cpf1-mediated genome editing and gene regulation in human cells. AB - Clustered regularly interspaced short palindromic repeat (CRISPR) system is being championed as a robust and flexible tool for genome editing. Compared with CRISPR associated protein 9 (Cas9), the CRISPR from Prevotella and Francisella 1 (Cpf1) protein has some distinct characteristics, including RNase activity, T-rich protospacer adjacent motif (PAM) preference and generation of sticky cutting ends. The extremely low propensity of off-target effects and relatively high editing efficiency represent prominent advantages of Cpf1 over Cas9. CRISPR-Cpf1, alone or fused with function domains, has broadly expanded the applications such as multiplex gene knockout, transcriptional repression or activation and epigenome editing in a drug controlled way. Meanwhile, the modification of CRISPR RNAs (crRNAs) with aptamer RNA achieves great promotion on genome editing. Moreover, disease-associated gene manipulation in mice, tumor mutation detection in patients with cancers, and more yet to come, represent growing demands of CRISPR-Cpf1 in clinical genome therapy. In this review, we summarized the unique properties of Cpf1 and the molecular mechanisms underlying CRISPR-Cpf1 on gene editing and regulation in human cells. PMID- 30399414 TI - Moderating effects of forgiveness on relationship between empathy and health related quality of life in hemodialysis patients: a structural equation modeling approach. AB - CONTEXT: Health-related quality of life (QOL) is a recommended clinical tool to assess hemodialysis patients and a primary end point to observe the effectiveness of overall disease management. Empathy is associated with positive outcomes such as pain relief and reduced anxiety and distress. Numerous studies have tested the relationships among empathy, forgiveness and QOL; however, a mechanism of forgiveness has not been fully explored in hemodialysis patients. OBJECTIVES: To test the relationship among empathy and health-related QOL, and confirm the moderating effects of forgiveness on relationship between empathy and health related QOL among hemodialysis patients. METHODS: In a descriptive cross sectional study conducted from September to December 2017, 457 hemodialysis patients from 5 hospitals filled out the Heartland Forgiveness Scale, Interpersonal Reactivity Index-C, Kidney Disease Questionnaire, and general information. The data were analyzed using SPSS, and structural equation modeling was used to address the relationships among empathy, forgiveness, and health related QOL. RESULTS: Empathy was significantly positively associated with health related QOL. The proposed model had a good fit to the data. Forgiveness was found to play a partial mediating role between empathy and health-related QOL. CONCLUSION: The results imply that empathy significantly directly and indirectly influences health-related QOL. Empathy among hemodialysis patients should be monitored and effectively managed to improve positive effects on their health related QOL. Nurses should consider implementing empathy interventions with an emphasis on building forgiveness strategies to help hemodialysis patients improve their health-related QOL. PMID- 30399415 TI - Palliative Care Use and Patterns of End-of-Life Care in Hospitalized Patients With Calciphylaxis. PMID- 30399416 TI - Biomarkers for diseases with TDP-43 pathology. AB - The discovery that aggregated transactive response DNA-binding protein 43 kDa (TDP-43) is the major component of pathological ubiquitinated inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) caused seminal progress in the unveiling of the genetic bases and molecular characteristics of these now so-called TDP-43 proteinopathies. Substantial increase in the knowledge of clinic-pathological coherencies, especially for FTLD variants, could be made in the last decade, but also revealed a considerable complexity of TDP-43 pathology and often a poor correlation of clinical and molecular disease characteristics. To date, an underlying TDP-43 pathology can be predicted only for patients with mutations in the genes C9orf72 and GRN, but is dependent on neuropathological verification in patients without family history, which represent the majority of cases. As etiology-specific therapies for neurodegenerative proteinopathies are emerging, methods to forecast TDP-43 pathology at patients' lifetime are highly required. Here, we review the current status of research pursued to identify specific indicators to predict or exclude TDP-43 pathology in the ALS-FTLD spectrum disorders and findings on candidates for prognosis and monitoring of disease progression in TDP-43 proteinopathies with a focus on TDP-43 with its pathological forms, neurochemical and imaging biomarkers. PMID- 30399417 TI - Airway infection with Nontypeable Haemophilus influenzae is more rapidly eradicated in vitamin D deficient mice. AB - Chronic obstructive pulmonary disease (COPD), which is characterized by an excessive inflammatory response of the airways, is often complicated by exacerbations. Vitamin D deficiency has been associated with an increased risk for COPD and may predispose COPD patients to a higher exacerbation rate, particularly during smoking. In the current study, we investigated the effect of vitamin D deficiency and cigarette smoke (CS)-exposure on lung inflammation and bacterial clearance after an acute infection with Nontypeable Haemophilus influenzae (NTHi). Vitamin D deficient or sufficient mice were exposed to nose only CS or ambient air for 6 weeks and oropharyngeally instilled with 106 NTHi. Residual viable NTHi were measured at different time points post-infection. Mechanisms of bacterial clearance (e.g. phagocytosis, pattern recognition receptors, antimicrobial peptides, surfactant proteins and mucin) and lung remodeling (e.g. metalloproteinases, MMP's) were assessed. Although smoking resulted in reduced phagocytosis capacity of macrophages and neutrophils, bacterial clearance was similar to control mice. By contrast and independent of smoking, bacterial clearance was significantly accelerated in vitamin D deficient mice already from 24 h post-infection (p = 0.0087). This faster and complete eradication was associated with a more rapid resolution of cytokines and neutrophils 72 h post-infection and dominated by an upregulation of cathelicidin related antimicrobial peptide (CRAMP) mRNA during infection (p = 0.026). However, vitamin D deficiency also resulted in more MMP12 protein in broncho-alveolar lavage and a shift in mRNA expression of MMP12/TIMP1 (p = 0.038) and MMP9/TIMP1 (p = 0.024) ratio towards more protease activity. Overall, vitamin D deficient mice resolved NTHi infection faster with a faster resolution of local lung inflammation, possibly through upregulation of CRAMP. This was associated with a disruption of the protease/anti-protease balance, which may potentially scale towards a higher extracellular matrix breakdown. PMID- 30399418 TI - How do spatially distinct frequency specific MEG networks emerge from one underlying structural connectome? The role of the structural eigenmodes. AB - Functional networks obtained from magnetoencephalography (MEG) from different frequency bands show distinct spatial patterns. It remains to be elucidated how distinct spatial patterns in MEG networks emerge given a single underlying structural network. Recent work has suggested that the eigenmodes of the structural network might serve as a basis set for functional network patterns in the case of functional MRI. Here, we take this notion further in the context of frequency band specific MEG networks. We show that a selected set of eigenmodes of the structural network can predict different frequency band specific networks in the resting state, ranging from delta (1-4 Hz) to the high gamma band (40-70 Hz). These predictions outperform predictions based from surrogate data, suggesting a genuine relationship between eigenmodes of the structural network and frequency specific MEG networks. We then show that the relevant set of eigenmodes can be excited in a network of neural mass models using linear stability analysis only by including delays. Excitation of an eigenmode in this context refers to a dynamic instability of a network steady state to a spatial pattern with a corresponding coherent temporal oscillation. Simulations verify the results from linear stability analysis and suggest that theta, alpha and beta band networks emerge very near to the bifurcation. The delta and gamma bands in the resting state emerges further away from the bifurcation. These results show for the first time how delayed interactions can excite the relevant set of eigenmodes that give rise to frequency specific functional connectivity patterns. PMID- 30399419 TI - Fiber length profiling: A novel approach to structural brain organization. AB - There has been a recent increased interest in the structural connectivity of the cortex. However, an important feature of connectivity remains relatively unexplored; tract length. In this article, we develop an approach to characterize fiber length distributions across the human cerebral cortex. We used data from 76 participants of the Adult WU-Minn Human Connectome Project using probabilistic tractography. We found that connections of different lengths are not evenly distributed across the cortex. They form patterns where certain areas have a high density of fibers of a specific length while other areas have very low density. To assess the relevance of these new maps in relation to established characteristics, we compared them to structural indices such as cortical myelin content and cortical thickness. Additionally, we assessed their relation to resting state network organization. We noted that areas with very short fibers have relatively more myelin and lower cortical thickness while the pattern is inverted for longer fibers. Furthermore, the cortical fiber length distributions produce specific correlation patterns with functional resting state networks. Specifically, we find evidence that as resting state networks increase in complexity, their length profiles change. The functionally more complex networks correlate with maps of varying lengths while primary networks have more restricted correlations. We posit that these maps are a novel way of differentiating between 'local modules' that have restricted connections to 'neighboring' areas and 'functional integrators' that have more far reaching connectivity. PMID- 30399420 TI - Phase I/II Trial of a Combination of Anti-CD3/CD7 Immunotoxins for Steroid Refractory Acute Graft-versus-Host Disease. AB - Effective therapies for treating patients with steroid-refractory acute graft versus-host-disease (SR-aGVHD), particularly strategies that reduce the duration of immunosuppression following remission, are urgently needed. The investigated immunotoxin combination consists of a mixture of anti-CD3 and anti-CD7 antibodies separately conjugated to recombinant ricin A (CD3/CD7-IT), which induces in vivo depletion of T cells and natural killer (NK) cells and suppresses T cell receptor activation. We conducted a phase I/II trial to examine the safety and efficacy of CD3/CD7-IT in 20 patients with SR-aGVHD; 17 of these patients (85%) had severe SR aGVHD, and all 20 patients had visceral organ involvement, including 18 (90%) with gastrointestinal (GI) involvement and 5 (25%) with liver involvement. A validated 2-biomarker algorithm classified the majority of patients (11 of 20) as high risk. On day 28 after the start of CD3/CD7-IT therapy, the overall response rate was 60% (12 of 20), with 10 patients (50%) achieving a complete response. The 6-month overall survival rate was 60% (12 of 20), including 64% (7 of 11) classified as high risk by biomarkers. The 1-week course of treatment with CD3/CD7-IT caused profound but transient depletion of T cells and NK cells, followed by rapid recovery of the immune system with a diverse TCR Vbeta repertoire, and preservation of Epstein-Barr virus- and cytomegalovirus-specific T cell clones. Furthermore, our results indicate that CD3/CD7-IT appeared to be safe and well tolerated, with a relatively low prevalence of manageable and reversible adverse events, primarily worsening of hypoalbuminemia, microangiopathy, and thrombocytopenia. These encouraging results suggest that CD3/CD7-IT may improve patient outcomes in patients with SR-aGVHD. PMID- 30399421 TI - Artemisinin B Improves Learning and Memory Impairment in AD Dementia Mice by Suppressing Neuroinflammation. AB - Alzheimer's disease is a chronic neurological ailment that seriously threatens human health and imposes a huge burden on families and the society at large. Emerging evidence suggests that neuroinflammation is an important pathological manifestation of neurodegenerative diseases, and currently considered a new research target. We previously found that artemisinin B from Artemisia annua Linn. has strong anti-inflammatory and immunological activities. In the present study, we assessed the anti-neuroinflammatory effects of artemisinin B in vitro and in vivo, exploring the underlying mechanisms. The results demonstrated that artemisinin B inhibited NO secretion from LPS-induced BV2 cells and significantly reduced the expression levels of the inflammatory cytokines IL-1beta, IL-6 and TNF-alpha. This was accompanied by reduced gene expression levels of MyD88 and NF kappaB as well as TLR4 and MyD88 protein levels. These inhibitory effects were further confirmed in AD model mice. This study also showed that artemisinin B improved spatial memory in dementia mice in the water maze and step-through tests, and altered the pathological features and the levels of inflammatory cytokines in the hippocampus and the cortex. These results suggested that artemisinin B might inhibit neuroinflammation and exert neuroprotective effects on cognitive functions by modulating the TLR4-MyD88-NF-kappaB signaling pathway. This study provides direct evidence for the potential application of artemisinin B in the treatment of neuroinflammatory diseases. PMID- 30399422 TI - The combined effect of IL-17F and CCL20 gene polymorphism in susceptibility to multiple sclerosis in Egypt. AB - BACKGROUND: Levels of CCL20 and its CCR6 receptor are elevated in many autoimmune diseases which help in the recruitment of T helper (Th17) cells to site of inflammation. OBJECTIVES: Determine the value of single nucleotide polymorphism of CCL20 (rs6749704) and IL-17F (rs763780) genes and their concomitant effect on the serum CCL20 level and susceptibility to MS in Egyptian patients. SUBJECTS AND METHODS: Blood samples were collected from 83 patients and 95 healthy subjects. Serum levels of CCL20 were measured by ELISA. The DNA was analyzed for rs6749704 and rs763780 using Genotyping Taqman assay. RESULTS: The mean serum levels of CCL20 in the MS group were significantly higher than healthy group (P < 0.001). Frequencies of CT genotype of rs6749704 in CCL20 gene and C allele in MS patients were significantly higher compared to controls. Also significant increase of rs763780 in IL-17F gene was detected in MS patients. Concomitant polymorphism in both genes in MS patients showed an increase risk to MS rather than individual locus. CONCLUSION: CCL20 may play an important role in the pathogenesis of MS. Both allelic variation of (rs6749704) within CCL20 gene and (rs763780) within IL 17F gene can be considered risk factor for development of MS in Egyptian patients. PMID- 30399423 TI - SIRT1 rs12778366, FGFR2 rs2981582, STAT3 rs744166, LIPC rs10468017, rs493258 and LPL rs12678919 genotypes and haplotype evaluation in patients with age-related macular degeneration. AB - OBJECTIVE: Age-related macular degeneration (AMD) is the leading cause of blindness in elderly individuals in the developed countries. The etiology of AMD is thought to be multifactorial, including environmental and genetic factors. Our purpose was to determine the genotype frequencies of six different SNPs in genes that encode proteins involved in AMD-related molecular changes (SIRT1 rs12778366, FGFR2 rs2981582, STAT3 rs744166, LIPC rs10468017, rs493258 and LPL rs12678919) for evaluation of haplotype risk in patients with AMD. METHODS: The study cohort consisted of 652 AMD patients and 829 healthy controls. The genotyping was carried out using the RT-PCR. RESULTS: TT genotype of the LIPC rs493258 polymorphism was associated with decreased odds of early AMD development under the codominant and recessive models (OR = 0.446; 95% CI: 0.258-0.772; p = 0.004 and OR = 0.455; 95% CI: 0.274-0.756; p = 0.002, respectively) after Bonferroni correction, (p > 0.05/6, since we analyzed 6 different SNPs). The haplotype containing the two minor alleles T-T in rs10468017-rs493258 were significantly (p = 0.034) associated with early AMD development decreasing. There were no associations found with atrophic AMD development. CONCLUSION: The study showed that LIPC rs493258 gene and haplotype containing the two minor alleles T-T in rs10468017-rs493258 may decrease AMD development. PMID- 30399424 TI - The V2 protein encoded by a monopartite begomovirus is a suppressor of both post transcriptional and transcriptional gene silencing activity. AB - Papaya leaf curl virus (PaLCuV) is a begomovirus (genus Begomovirus; family Geminiviridae) with a monopartite genome that is usually associated with beta- and alphasatellites in plants. Geminiviruses are DNA viruses with small circular genomes that occur as minichromosomes in the nucleus and are susceptible to post transcriptional gene silencing (PTGS) and transcriptional gene silencing (TGS). Transient expression of the PaLCuV V2 (PV2) protein together with the green fluorescent protein (GFP) in Nicotiana benthamiana resulted in enhanced levels of GFP fluorescence and GFP mRNA, indicative of suppression of PTGS. Expression of PV2 from a Potato virus X vector restored GFP expression in N. benthamiana plants harbouring a transcriptionally silenced GFP transgene, indicative of suppression of TGS. The results show that the PV2 protein encoded by PaLCuV has both suppressor of PTGS and TGS activity and is an important factor in overcoming host RNA-silencing based defenses. PMID- 30399425 TI - Association between duplicated maltase genes and the transcriptional regulation for the carbohydrate changes in Drosophila melanogaster. AB - Gene duplication could promote phenotypic and genetic adaptation to various environments. To understand the effects of gene duplication on transcriptional regulation associated with environmental changes, we focused on the starch hydrolysis pathway, in which amylase enzymes together with maltase enzymes hydrolyze starch into glucose. Drosophila genomes involve ten duplicated Maltase genes. We examined the levels of transcription of the nine of these genes in 36 lines of Drosophila melanogaster collected from a natural population. In the investigated population, the levels of transcription were different between the two dietary carbohydrate sources, glucose and starch. At the transcriptional level, a single Maltase gene, which transcribes the specific Maltase transcripts, worked together with an Amylase gene in the pathway. The three of nine genes responded to carbohydrate changes, and the degree of the response was similar to Amylase gene. Our results suggest that gene duplication could increase capacity of the transcriptional regulation associated with environmental changes. PMID- 30399426 TI - Genomic amplification of BCR-ABL1 fusion gene and its impact on the disease progression mechanism in patients with chronic myelogenous leukemia. AB - Identification of BCR-ABL1 fusion gene amplification status is critically important in the effective management of chronic myelogenous leukemia (CML) patients. Earlier reports suggested that overexpression of BCR-ABL1 either through amplification of BCR-ABL1 fusion gene or by the up regulation of BCR-ABL1 transcript level might be an early phenomenon in the establishment of IM resistance and disease evolution in CML. In the current study, we performed dual color dual fusion locus specific BCR/ABL1 FISH analysis along with karyotype analysis using GTG banding (G-banding using trypsin and Giemsa) technique in 489 patients with different clinical stages of CML at diagnosis or during the course of the disease to unravel the spectrum of BCR-ABL1 fusion gene amplification status. Among the study group analyzed, it was found that prevalence of occurrence of BCR-ABL1 fusion gene amplification was significantly higher in advanced stages of disease and in IM resistant CML-CP patients when compared to initial stage of disease, de novo CML-CP. Cytogenetic and metaphase FISH characterization on our study samples revealed that BCR-ABL1 fusion gene amplification was occurred through the formation of extra copies Ph chromosomes and isoderived Ph chromosomes. Current study suggests that unrestrained activity of BCR-ABL1 played a vital role in resistance to targeted therapy and disease evolution in CML. In our study population, patients in progressive stage CML and in IM resistant CP with multiple copies of BCR-ABL1 fusion gene displayed a poor response to targeted treatment with IM. Hence, the early identification of BCR ABL1 fusion gene amplification using FISH technique will lead to improved interventions and outcome in future CML patients. PMID- 30399427 TI - MEG2 inhibits the growth and metastasis of hepatocellular carcinoma by inhibiting AKT pathway. AB - MEG2 was recently found to have important functions in human cancers. However, the expression status and biological functions of MEG2 in hepatocellular carcinoma (HCC) remain unknown. In this study, we demonstrated that MEG2 expression was reduced in HCC tissues and cell lines using qRT-PCR, western blot and immunohistochemical staining. Decreased MEG2 expression predicted unfavorable clinical features and decreased overall survival and disease-free survival of HCC patients. In vitro functional assays showed that overexpression of MEG2 inhibited the cell viability, migration and invasion of HCCLM3 cells while MEG2 knockdown promoted these biological functions of Hep3B cells. Subcutaneous injection model and tail vein injection model showed that forced expression of MEG2 in HCCLM3 decreased the growth and lung metastasis of HCCLM3 cells in nude mice. Mechanically, MEG2 inhibited the EMT and AKT phosphorylation of HCC cells. The promoting effects of MEG2 knockdown on EMT, cell viability, proliferation, migration and invasion of Hep3B cells was blocked by AKT phosphorylation inhibition. In all, this study demonstrates that MEG2 inhibits the growth and metastasis of hepatocellular carcinoma by inhibiting AKT pathway. PMID- 30399429 TI - Morphology, geographic distribution, and host preferences are poor predictors of phylogenetic relatedness in the mistletoe genus Viscum L. AB - Besides their alleged therapeutic effects, mistletoes of the genus Viscum L. (Viscaceae) are keystone species in many ecosystems across Europe, Africa, Asia and Australia because of their complex faunal interactions. We here reconstructed the evolutionary history of Viscum based on plastid and nuclear DNA sequence data. We obtained a highly resolved phylogenetic tree with ten well-supported clades, which we used to understand the spatio-temporal evolution of these aerial parasites and evaluate the contribution of reproductive switches and shifts in host ranges to their distribution and diversification. The genus Viscum originated in the early Eocene in Africa and appeared to have diversified mainly through geographic isolation, in several cases apparently coinciding with shifts in host preferences. During its evolution, switches in the reproductive mode from ancestral dioecy to monoecy imply an important role in the long-distance dispersal of the parasites from Africa to continental Asia and Australia. We also observed multiple cases of photosynthetic surface reduction (evolution of scale leaves) within the genus, probably indicative of increasing specialization associated with the parasitic lifestyle. Even compared with other parasitic angiosperms, where more host generalists than specialists exist, Viscum species are characterized by extraordinarily broad host ranges. Specialization on only a few hosts from a single family or order occurs rarely and is restricted mostly to very recently evolved lineages. The latter mostly derive from or are closely related to generalist parasites, implying that niche shifting to a new host represents an at least temporary evolutionary advantage in Viscum. PMID- 30399428 TI - Genome-wide association and gene-environment interaction study identifies variants in ALDH2 associated with serum ferritin in a Chinese population. AB - Ferritin is not only a biomarker of total iron status and systemic inflammation but is also associated with metabolic disorders. A number of genetic variations have been identified to affect serum ferritin, but there is limited understanding of the genetic variations in serum ferritin. To evaluate the relationships among genetic variations, metabolism and ferritin, we performed a secondary analysis of our previous genome-wide association study of ferritin. After adjusting for population stratification and age, the rs671 in ALDH2 was significantly associated with ferritin concentrations (P-combined = 2.98 * 10-8). Men carrying the mutated genotype of rs671 had lower serum ferritin levels. BMI was the mediation between rs671 and ferritin (P = 0.003). Moreover, a significant interaction between rs671 and alcohol consumption on ferritin levels was observed (P = 3.02 * 10-4). rs671 genotypes were significantly relevant to serum ferritin in drinkers (P = 2.39 * 10-7). We reported that rs671 was associated with ferritin in a manner of BMI mediation. These findings will provide new insights into the impacts of genetic variations and metabolisms on serum ferritin levels. PMID- 30399430 TI - Mitochondrial phylogenomics of the Hymenoptera. AB - The insect order Hymenoptera presents marvelous morphological and ecological diversity. Higher-level hymenopteran relationships remain controversial, even after recent phylogenomic analyses, as their taxon sampling was limited. To shed light on the origin and diversification of Hymenoptera, in particular the poorly studied Parasitica, we undertook phylogenetic analyses of 40 newly and 43 previously sequenced mitochondrial genomes representing all major clades of Hymenoptera. Various Bayesian inferences using different data partitions and phylogenetic methods recovered similar phylogenetic trees with strong statistical support for almost all nodes. Novel findings of the mitogenomic phylogeny mainly affected the three infraorders Ichneumonomorpha, Proctotrupomorpha and Evaniomorpha, the latter of which was split into three clades. Basal relationships of Parasitica recovered Stephanoidea + (Gasteruptiidae + Aulacidae) as the sister group to Ichneumonomorpha + (Trigonalyoidea + Megalyroidea). This entire clade is sister to Proctotrupomorpha, and Ceraphronoidea + Evaniidae is sister to Aculeata (stinging wasps). Our divergence time analysis indicates that major hymenopteran lineages originated in the Mesozoic. The radiation of early apocritans may have been triggered by the Triassic-Jurassic mass extinction; all extant families were present by the Cretaceous. PMID- 30399431 TI - Distinct molecular evolution of influenza H3N2 strains in the 2016/17 season and its implications for vaccine effectiveness. AB - Influenza virus is a respiratory pathogen that causes seasonal epidemics by resulting in a considerable number of influenza-like illness (ILI) patients. During the 2016/17 season, ILI rates increased unusually earlier and higher than previous seasons in Korea, and most viral isolates were subtyped as H3N2 strains. Notably, the hemagglutinin (HA) of most Korean H3N2 strains retained newly introduced lysine signatures in HA antigenic sites A and D, compared with that of clade 3C.2a vaccine virus, which affected antigenic distances to the standard vaccine antisera in a hemagglutination inhibition assay. The neuraminidase (NA) of Korean H3N2 strains also harbored amino acid mutations. However, neither consistent amino acid mutations nor common phylogenetic clustering patterns were observed. These suggest that Korean H3N2 strains of the 2016/17 season might be distantly related with the vaccine virus both in genotypic and phenotypic classifications, which would adversely affect vaccine effectiveness. PMID- 30399432 TI - CBN: Constructing a Clinical Bayesian Network based on Data from the Electronic Medical Record. AB - The process of learning candidate causal relationships involving diseases and symptoms from electronic medical records (EMRs) is the first step towards learning models that perform diagnostic inference directly from real healthcare data. However, the existing diagnostic inference systems rely on knowledge bases such as ontology that are manually compiled through a labour-intensive process or automatically derived using simple pairwise statistics. We explore CBN, a Clinical Bayesian Network construction for medical ontology probabilistic inference, to learn high-quality Bayesian topology and complete ontology directly from EMRs. Specifically, we first extract medical entity relationships from over 10,000 deidentified patient records and adopt the odds ratio (OR value) calculation and the K2 greedy algorithm to automatically construct a Bayesian topology. Then, Bayesian estimation is used for the probability distribution. Finally, we employ a Bayesian network to complete the causal relationship and probability distribution of ontology to enhance the ontology inference capability. By evaluating the learned topology versus the expert opinions of physicians and entropy calculations and by calculating the ontology-based diagnosis classification, our study demonstrates that the direct and automated construction of a high-quality health topology and ontology from medical records is feasible. Our results are reproducible, and we will release the source code and CN-Stroke knowledge graph of this work after publication1. PMID- 30399433 TI - Evidence that thiol group modification and reactive oxygen species are involved in hydrogen sulfide-induced mitochondrial permeability transition pore opening in rat cerebellum. AB - We report here the effects of hydrogen sulfide (sulfide), that accumulates in ETHE1 deficiency, in rat cerebellum. Sulfide impaired electron transfer and oxidative phosphorylation. Sulfide also induced mitochondrial swelling, and decreased DeltaPsim and calcium retention capacity in cerebellum mitochondria, which were prevented by cyclosporine A (CsA) plus ADP, and ruthenium red, suggesting mitochondrial permeability transition (mPT) induction. Melatonin (MEL) and N-ethylmaleimide also prevented sulfide-induced alterations. Prevention of sulfide-induced decrease of DeltaPsim and viability by CsA and MEL was further verified in cerebellum neurons. The data suggest that sulfide induces mPT pore opening via thiol modification and ROS generation. PMID- 30399434 TI - Oral siRNA delivery using dual transporting systems to efficiently treat colorectal liver metastasis. AB - Oral siRNA delivery is an ideal way to translate siRNA therapeutic effects in the clinic due to its ability to be administered in convenient and multiple dosages. However, an effective oral delivery system requires overcoming both a hostile gastrointestinal (GI) environment and non-specific targeting. Here, an HTsRP-NC system is a new oral siRNA delivery system consisting of a siRNA/protamine (sRP) nano-complex protected by a multi-functional hyaluronic acid-taurocholic acid (HA TCA) conjugate. The HTsRP-NC promotes cell penetration and enhances endosomal escape in cancer cells. Moreover, protection of the sRP by HA-TCA from the hostile GI environment helps the AKT siRNA complex to reach the liver through the utilization of a TCA-mediated enterohepatic bile acid recycling system. AKT siRNA was released by 90% in presence of hyaluronidase in the tumor cells which indicate the potential use of HTsRP-NCs for siRNA delivery to treat tumor. After HA receptor (CD44)-mediated cellular uptake of the HTsRP-NC by the liver cancer cells, functional expression of AKT siRNA leads to the suppression of metastatic liver cancer growth in a colorectal liver metastasis (CLM) murine model. Tumor nodules were reduced by more than 1 mm size compared to control group and tumor cells were suppressed by 50% after HTsRP-NCs treatment with AKT siRNA. Overall, oral administration of the HTsRP-NC supports its potential in therapeutic applications for the effective treatment of CLM. PMID- 30399435 TI - Angelica sinensis polysaccharide encapsulated into PLGA nanoparticles as a vaccine delivery and adjuvant system for ovalbumin to promote immune responses. AB - Nanoparticles (NPs)-based vaccine delivery systems are widely used for their ability to control the release of antigens and promote immune responses against cancer or infectious diseases. In this study, the immunopotentiator Angelica sinensis polysaccharide (ASP) and model protein antigen ovalbumin (OVA) were encapsulated into Poly(lactic-co-glycolic acid) (PLGA) to formulate the novel NPs based vaccine delivery system (ASP-PLGA/OVA). These formulations were subcutaneously administered to mice, then the magnitude and kinetics of antibody and cellular immune responses were assessed. The ASP-PLGA/OVA NPs were pherical in shape with smooth surfaces, approximately 225.2 nm in average size, negatively charged (around -11.27 mV), and the encapsulation efficiency of OVA at around 66.28%, respectively. Furthermore, ASP-PLGA/OVA NPs could keep stable at 4 degrees C over 30 days and provide a sustained and controlled release of OVA from the NPs. The results demonstrated that mice immunized with ASP-PLGA/OVA NPs could significantly enhance lymphocyte proliferation and improve the ratio of CD4+ to CD8+ T cells, thereby ASP-PLGA/OVA NPs could induce a strong cellular immune response. Moreover, the ASP-PLGA/OVA NPs could induce vigorous and long-term IgG immune responses with a mixed Th1 and Th2 responses and up-regulate the levels of Th-associated cytokines. These results suggested that ASP-PLGA/OVA NPs, which stimulated strong and continuous antibody responses and induced cellular immune responses, could potentially serve as an efficient and safe vaccine delivery and adjuvant system against infections and diseases. PMID- 30399436 TI - Preparation and evaluation of trityl-loaded lipid nanocapsules as oxygen sensors for electron paramagnetic resonance oximetry. AB - Oxygen is essential in physiology and pathophysiology. Electron paramagnetic resonance (EPR) oximetry, using oxygen sensitive paramagnetic materials, could be attractive for measuring oxygen in tissues. The aim of the present study was to assess the properties of lipid nanocapsules (LNCs) loaded with the nitroxide tempo-benzoate (TB) or tetrathiatriarylmethyl (TAM) radicals. LNCs loaded with the EPR probes were successfully prepared by the phase inversion process leading to nanocapsules of about 60 nm. LNCs protected the TB radical against reduction in vitro. The calibration of the EPR line width (LW) as a function of the pO2 showed a two-fold increase in sensitivity with TAM-LNC compared to hydrophilic trityl radical. The TAM-LNCs were evaluated in vivo. Contrarily to unencapsulated TAM, for which a rapid decrease in EPR signal was observed, the half-life of TAM LNCs administered in muscles or in tumours exceeded an hour. Carbogen-challenges in mice demonstrated that the TAM-LNCs responded well to changes in oxygen environment. However, the apparent pO2 values acquired were higher than the expected physiological values. These results warrant further investigation in the formulation of stable nano-objects encapsulating EPR oxygen sensitive probes. PMID- 30399437 TI - Bioresponsive peptide-polysaccharide nanogels - A versatile delivery system to augment the utility of bioactive cargo. AB - We report the design, synthesis and efficacy of a new class of gel-like nano carrier, or 'nanogel', prepared via templated electrostatic assembly of anionic hyaluronic acid (HA) polysaccharides with the cationic peptide amphiphile poly-L lysine (PLL). Small molecules and proteins present during nanogel assembly become directly encapsulated within the carrier and are precisely released by tuning the nanogel HA:PLL ratio to control particle swelling. Remarkably, nanogels exhibit versatile and complimentary mechanisms of cargo delivery depending on the biologic context. For example, in mammalian cells, nanogels are rapidly internalized and escape the endosome to both deliver membrane-impermeable protein cargo into the cytoplasm and improve chemotherapeutic potency in drug resistant cancer cells. In bacteria, nanogels permeabilize microbial membranes to sensitize bacterial pathogens to the action of a loaded antibiotic. Thus, peptide nanogels represent a versatile, readily scalable and bio-responsive carrier capable of augmenting and enhancing the utility of a broad range of biomolecular cargoes. PMID- 30399438 TI - A novel and innovative paper-based analytical device for assessing tear lactoferrin of dry eye patients. AB - PURPOSE: To elucidate the correlation between lactoferrin concentration in the tear film and signs and symptoms of severe dry eye disease (DED) using a novel microfluidic paper-based analytical device (MUPAD) and enzyme-linked immunosorbent assay (ELISA). METHODS: Twenty-four patients were recruited at the Keio University Hospital. Using a novel MUPAD, lactoferrin concentrations were measured in 4 patients with GVHD-related DED, 3 patients with other type of dry eye and 2 controls (Group A). For validation by ELISA, 22 patients (7 patients from Group A) comprising 9 patients with GVHD-related DED, 6 patients with other types of DED and 7 controls were examined (Group B). The link between lactoferrin concentration and clinical data about the severity of aqueous tear deficient DED was also investigated by both MUPAD and ELISA. RESULTS: The lactoferrin concentration in tear fluid of the DED patients was positively correlated between MUPAD and ELISA (p = 0.006, r = 0.886). The tear fluid of the GVHD patients showed low or undetectable lactoferrin concentration. Analysis by ELISA demonstrated that lactoferrin concentrations in the tear film from the GVHD patients were significantly lower than those from the non-GVHD patients (p = 0.010576). ELISA revealed lactoferrin concentration correlated with the value of Schirmer test and tear breakup time, whereas it was inversely correlated with OSDI, fluorescein and rose bengal scores. CONCLUSIONS: The novel MUPAD may pave the way for measuring lactoferrin concentration in tear fluid from DED patients. Our results suggested that lactoferrin concentration in tear fluid reflect the severity of DED. PMID- 30399439 TI - Great effect of porin(aha) in bacterial adhesion and virulence regulation in Aeromonas veronii. AB - Aeromous veronii is a serious pathogen which can infect mammals and aquatic organisms and causes irreparable damage to fish aquaculture. It has been demonstrated that adhesion to host surface and cells are the initial steps in bacterial pathogenesis. Previous study found that bacterial weaken motility probably caused by the absence of flagellarr-related genes. In this study, we generated the aha deletion and complementary strains and found that two strains can be stably inherited for more than 50 generations. No significant change was found in the growth of mutant ?aha. But the ability of biofilm formation, the adhesion and invasion to EPC cells significantly decreased for 3.7-folds and 2.3 folds respectively. Due to aha gene deletion, the stability of A. veronii flagellar was severely declined and the mutant ?aha with no mobility. Compared with the wild-type TH0426, the pathogenicity of A. veroniiaha-deleted strain to zebrafish and mice reduced significantly and virulence attenuated severely. Cytotoxicity experiment also proved that mutant ?aha showed much weaker virulence at the same time infection. The consequences declared that the stability of flagellar decreased severely with porin missing and lost the moility. Porin regulated by aha gene is essential for the adhesion and virulence of A. veronii. Thence, the mutant ?aha of A. veronii provides an important tool for further concentration on the pathogenic mechanism of A. veronii. PMID- 30399440 TI - A systematic review of Toxoplasma gondii antigens to find the best vaccine candidates for immunization. AB - At present, there is not any available accepted vaccine for prevention of Toxoplasma gondii (T. gondii) in human and animals. We conducted literature search through English (Google Scholar, PubMed, Science Direct, Scopus, EBSCO, ISI Web of Science) scientific paper databases to find the best vaccine candidates against toxoplasmosis among T. gondii antigens. Articles with information on infective stage, pathogenicity, immunogenicity and characterization of antigens were selected. We considered that the ideal and significant vaccines should include different antigens and been expressed in all infective stages of the parasite with a high pathogenicity and immunogenicity. Evaluation within this systematic review indicates that MIC 3, 4, 13, ROP 2, RON 5, GRA 1, 6, 8, 14 are expressed in all three infective stages and have pathogenicity and immunogenicity. MIC 5, ROM 4, GRA 2, 4, 15, ROP 5, 16, 17, 38, RON 4, MIC 1, GRA 10, 12, 16, SAG 3 are expressed in only tachyzoites and bradyzoites stages of T. gondii with pathogenicity/immunogenicity. Some antigens appeared to be expressed in a single stage (tachyzoites) but have high pathogenicity and induce immune response. They include enolase2 (ENO2), SAG 1, SAG5D, HSP 70, ROM 1, ROM 5, AMA 1, ROP 18, RON2 and GRA 24. In conclusion, current vaccination against T. gondii infection is not satisfactory, and with the increasing number of high-risk individuals, the development of an effective and safe specific vaccine is greatly valuable for toxoplasmosis prevention. This systematic review reveals prepare candidates for immunization studies. PMID- 30399441 TI - Differential expression of TLRs 2, 4, 9, iNOS and TNF-alpha and arginase activity in peripheral blood monocytes from glucantime unresponsive and responsive patients with anthroponotic cutaneous leishmaniasis caused by Leishmania tropica. AB - BACKGROUND: Detection of the mechanism of host/parasite interactions in unresponsive forms of anthroponotic cutaneous leishmaniasis (ACL) caused by Leishmania tropica is helpful for immunotherapy and vaccine development. In the present study, the gene expression of toll-like receptors (TLRs), TNF-alpha, iNOS and also arginase (ARG) activity in monocytes from Glucantime unresponsive in comparison to responsive patients infected with L. tropica was investigated. METHODS: In this case-control study, patients with unresponsive (n = 10) and responsive (n = 10) ACL were recruited. Gene expression of TLR2, TLR4, TLR9, TNF alpha and iNOS was analyzed in L. tropica-exposed monocytes. The level of ARG activity in both isolated promastigotes and the lysates of monocytes was also determined. RESULTS: L. tropica-exposed monocytes represented higher expression of all three TLRs and TNF-alpha and lower expression of iNOS compared to unexposed ones in both groups of patients. Results revealed a significant down regulation of TLR2 and TNF-alpha and up-regulation of TLR9 expression in unresponsive isolates in comparison to responsive ones. Besides, ARG level showed a significant increase in L. tropica-stimulated monocytes and cultured promastigotes from unresponsive isolates versus responsive ones. CONCLUSIONS: The decreased TLR2, TLR4, TNF-alpha and iNOS and the increased level of TLR9 expression in L. tropica-exposed monocytes from unresponsive isolates and also the increment in ARG activity in their promastigotes and monocytes, might possibly be involved in the severity of the disease and leading to Glucantime unresponsiveness. PMID- 30399442 TI - Improving quality of life among latino cancer survivors: Design of a randomized trial of patient navigation. AB - Latino cancer survivors have lower survival rates for most cancers relative to non-Latino whites, including, colorectal, prostate, and breast. In addition, Latinos experience health disparities in both access to care and quality of care. Experts recommend providing psychosocial services as an integral part of quality cancer care; however, there continues to be a paucity of information on the efficacy of Patient Navigators (PNs) in linking Latino cancer survivors to appropriate psychosocial services. Redes En Accion: The National Latino Cancer Research Network partnered with LIVESTRONG Cancer Navigation Services Patient Navigation program (PN-LCNS) to provide an intervention to improve wellness and increase access to psychosocial services among non-metastatic Latino cancer survivors from Texas and Chicago using trained bilingual, bicultural PNs. The study design involved a mixed-methods approach in two phases. Phase I used a Community-Based Participatory Research (CBPR) approach wherein PNs engaged community partners who provide services to breast, colorectal and prostate Latino cancer survivors. Phase II was a randomized controlled trial (RCT) that evaluated the efficacy of combining PN-facilitated interventions with the culturally tailored and CBPR-informed PN-LCNS in 300 breast, prostate and colorectal Latino cancer survivors. Outcomes investigated were improvements in: 1) quality of life (QOL), both general and disease-specific, and; 2) treatment follow-up compliance. While limited work has addressed the psychosocial needs of Latino cancer survivors, culturally-competent interventions using PNs have potential to address these needs and significantly improve Latino cancer survivorship. PMID- 30399443 TI - Evolution of commercially available compounds for HTS. AB - Over recent years, an industry of compound suppliers has grown to provide drug discovery with screening compounds: it is estimated that there are over 16 million compounds available from these sources. Here, we review the chemical space covered by suppliers' compound libraries (SCL) in terms of compound physicochemical properties, novelty, diversity, and quality. We examine the feasibility of compiling high-quality vendor-based libraries avoiding complicated, expensive compound management activity, and compare the resulting libraries to the ChEMBL data set. We also consider how vendors have responded to the evolving requirements for drug discovery. PMID- 30399444 TI - Men who have sex with men: A group of travellers with special needs. PMID- 30399445 TI - Zika virus disease in India - Update October 2018. PMID- 30399446 TI - Development of a Digital Droplet Polymerase Chain Reaction (ddPCR) assay to detect Leishmania DNA in samples from Cutaneous Leishmaniasis patients. AB - AIM: Here, we evaluate the ddPCR platform using an evaluated qPCR-based diagnostic assay for the detection of Leishmania infection in Cutaneous Leishmaniasis patients. METHODS: A standard curve of cultured Leishmania parasite material and clinical samples of CL patients were tested with ddPCR to determine the analytical and diagnostic performance. RESULTS: The limit of detection of the assay on the ddPCR platform was much higher than the published limit of detection of the same assay on the qPCR platform (100 vs 1 parasites/mL, respectively). CONCLUSION: While the performance of this assay in ddPCR format was acceptable for research purposes, it is not sufficient for clinical diagnostic purposes. The assay is more suited to the qPCR platform. PMID- 30399447 TI - Prospective evaluation of lymphocyte subtyping for the diagnosis of invasive candidiasis in non-neutropenic critically ill patients. AB - OBJECTIVES: This study aimed to investigate the distinguishing ability of lymphocyte subtyping for Invasive candidiasis (IC) diagnosis and prognosis in non neutropenic critically ill patients. METHODS: We assessed the quantitative changes in key parameters of lymphocyte subtyping at the onset of clinical signs of infection in non-neutropenic critically ill patients and their potential influence on diagnosis and outcome of IC. The primary outcome was 28-day mortality. RESULTS: Among the 182 consecutive critically ill patients, 22 (12.1%) were in the IC group. The CD28+CD8+ T-cell counts (AUC 0.863, 95%CI 0.804-0.909, P<0.001) had greater diagnostic value for IC than other parameters had. Adding CD28+CD8+ T to Candida score significantly improved the predictive value of Candida score (P=0.039). Multivariate logistic regression analysis identified CD28+CD8+ T-cell counts<=78 cells/mm3 (OR 24.544, 95%CI 6.461-93.236, P<0.001) as an independent predictor for IC diagnosis. CD28+CD8+ T-cell counts could also predict 28-day mortality. Kaplan-Meier survival analysis provided evidence that CD28+CD8+ T-cell count <144cells/mm3 (log-rank test; P=0.03) were associated with lower survival probabilities. CONCLUSIONS: CD28+CD8+ T-cell counts play an important role in early diagnosis of IC. Low counts are associated with early mortality in non-neutropenic critically ill patients. These results suggest the potential usefulness of measuring CD28+CD8+ T-cell lymphocyte levels in the early recognition and diagnosis of IC. TRIAL REGISTRATION: ChiCTR-ROC-17010750. Registered 28 February 2017. PMID- 30399448 TI - Controlled immobilization-traction based on intervertebral stability is conducive to the regeneration or repair of the degenerative disc: An in vivo study on the rat coccygeal model. AB - BACKGROUND CONTEXT: Previous studies have shown the potential for intervertebral disc tissue regeneration is very limited. While in vivo and in vitro studies have shown that traction can restore disc height and internal pressure, in many clinical studies it was shown that axial mechanical traction for the treatment of low back pain is ineffective. PURPOSE: The aim of this study was to identify how the disc could be distracted, how to define the state of traction, and to further examine the feasibility of regenerating or restoring the degenerative disc by means of traction. STUDY DESIGN: A macro- and microlevel structural analysis of degenerative discs of rat tail before and after controlled immobilization traction. METHODS: In this study, 49 6-month-old male Sprague-Dawley rats were randomly assigned to one of seven groups. Group A was the sham control group in which caudal vertebrae were instrumented with K-wires only. In Group B (model group), caudal vertebrae were immobilized using a custom-made external device to fix four caudal vertebrae (Co7-Co10) and Co8-Co9 underwent 4 weeks of compression to induce moderate disc degeneration. In Group C, vertebrae Co8-Co9 underwent 4 weeks of compression to induce moderate disc degeneration, followed by removal of the external apparatus. Rats in the other four groups (Groups D-G), Co8-Co9 underwent 4 weeks of compression to induce moderate disc degeneration followed by 2 weeks, 4 weeks, 6 weeks, and 8 weeks of distraction, respectively. Caudal vertebrae were harvested and disc height, T2 signal intensity of the discs, disc morphology, total glycosaminoglycan content of the nucleus pulposus and the structure of the Co8-Co9 end plate were evaluated. RESULTS: After 4 weeks of compression, the intervertebral height and T2 signal intensity of Co8-Co9 vertebrae of rats in Groups B to G were significantly reduced compared with Group A (sham group, all p<.0001). Histological scores of rats in Group B averaged 10.14 and the total glycosaminoglycan (GAG) of nucleus pulposus averaged 238.21MUg GAG/ng DNA. The bony end plate structure showed significant changes in comparison with the control Group. After 2 weeks to 8 weeks of traction, the disc space and T2 signal intensity of Co8-Co9 vertebrae in Group E were significantly recovered compared to that of rats in Group B (p<.0001), and the intervertebral height of the Co8-Co9 in Group D, Group F, and Group G when compared with Group B (p<.0001). Meanwhile, the T2 signal intensity of Co8-Co9 in Group D, F, and G when compared with Group B (p<.001). Histological scores dropped from an average of 10.14 in Group B to 5.57 in Group E, and 5.86 in Group F (all p<.0001). Furthermore, the total GAG content of the nucleus pulposus increased from an average of 238.21 MUg GAG/ng DNA in Group B to 601.02 MUg GAG/ng DNA in Group E (p<.0001). The number of pores of end plates in rats in Groups D and E both were significantly increased when compared to that of rats in Group B (Groups D vs Groups B, p<.05; Groups E vs Groups B, p<.0001). CONCLUSIONS: A mechanical degenerative model was successfully established by using a custom-made device. We demonstrated that disc degeneration is a cascade of biochemical, mechanical, and structural changes mediated by cells in an abnormal mechanical environment. Not all levels of disc degeneration can be regenerated or repaired. Regeneration or recovery of disc degeneration requires specific conditions. Based on the immobilization-traction mode, the cascade cycle of disc degeneration is interrupted. Traction of 2 to 6 weeks is a sensitive period for regeneration of the degenerative disc. Moreover, the duration and extent of the traction loading must be moderately controllable, and beyond the limits that can lead to significant degeneration. These data may help improve our understanding of the pathogenesis of clinical disc degeneration and how to optimize the use of traction devices for possible regeneration. PMID- 30399449 TI - CD133 as a regulator of cancer metastasis through the cancer stem cells. AB - Cancer stem cells are the cancer cells that have abilities to self-renew, differentiate into defined progenies, and initiate and maintain tumor growth. They also contribute to cancer metastasis and therapeutic resistance, both of which are the major causes of cancer mortality. Among the reported makers of the cancer stem cells, CD133 is the most well-known marker for isolating and studying cancer stem cells in different types of cancer. The CD133high population of cancer cells are not only capable of self-renewal, proliferation, but also highly metastatic and resistant to therapy. Despite very limited information on physiological functions of CD133, many ongoing studies are aimed to reveal the mechanisms that CD133 utilizes to modulate cancer dissemination and drug resistance with a long-term goal for bringing down the number of cancer deaths. In this review, in addition to the regulation of CD133, and its involvement in cancer initiation, and development, the recent updates on how CD133 modulates cancer dissemination, and therapeutic resistance are provided. The key signaling pathways that are upstream or downstream of CD133 during these processes are summarized. A comprehensive understanding of CD133-mediated cancer initiation, development, and dissemination through its pivotal role in cancer stem cells will offer new strategies in cancer therapy. PMID- 30399450 TI - Relationship between Clavien-Dindo classification and long-term survival outcomes after curative resection for gastric cancer: A propensity score-matched analysis. AB - BACKGROUND: The impact of postoperative complications (POCs) on the long-term survival outcomes after curative resection for gastric cancer has seldom been reported. The purpose of this study was to evaluate the relationship between the severity of POCs and long-term survival outcomes after curative resection for gastric cancer. METHODS: The study analyzed 3091 patients who underwent curative resection for gastric cancer in a single center between June 2009 and June 2015. Patients were divided into two groups based on the occurrence or absence of postoperative complications which were recorded using the Clavien-Dindo classification. Long-term survival outcomes were compared between groups after propensity score matching (PSM). RESULTS: A total of 3091 patients were included in the entire cohort. After PSM, no significant difference in baseline data was observed between the complications (C) group (n = 375) and no complications (NC) group (n = 375). With a median follow-up of 51 months, POCs were associated with decreased 5-year overall survival (OS) (51.7% vs. 67.5%, P < 0.001), disease-free survival (DFS) (49.9% vs. 65.6%, P < 0.001), and disease-specific survival (DSS) (53.9% vs. 68.8%, P < 0.001). Increasing Clavien-Dindo grades from II to IV was significantly associated with a corresponding decrease in OS (60, 48.3, 34%, P = 0.010), DFS (58.3, 46.3, 32.1%, P < 0.001) and DSS (62.9, 50.3, 34%, P < 0.001). Multivariate analysis confirmed POCs was an independent prognostic factor for decreased OS, DFS, and DSS (all P < 0.05). CONCLUSIONS: POCs had a negative impact on long-term survival outcomes after curative resection for gastric cancer. The negative effects were also increased with higher Clavien-Dindo grades. PMID- 30399451 TI - National Quality Improvement Initiative in Home Visiting Services Improves Breastfeeding Initiation and Duration. AB - OBJECTIVE: To improve breastfeeding through home visiting. METHODS: From 2013 2016, the Home Visiting Collaborative Improvement and Innovation Network (HV CoIIN) enrolled 15 home visiting agencies serving 1,000 families in seven states. Using the Breakthrough Series Collaborative model (BTS), HV-CoIIN faculty taught a theory of change and continuous quality improvement (CQI) skills and facilitated opportunities for networked learning. RESULTS: HV CoIIN improved home visitors' breastfeeding competencies and use of data to inform practice. Breastfeeding initiation increased from 47% to 61%. Exclusive breastfeeding increased from 10% to 13.5% of 3-month olds and from 5% to 8% of 6 month-olds. CONCLUSIONS: Home visiting programs can improve breastfeeding among participants with very low baseline breastfeeding rates. CQI and BTS can be used to improve home visiting services in ways that advance national public health priorities. PMID- 30399452 TI - One-pot synthesis of glycosyl phenylthiosulfonates from sulfinate, S and glycosyl bromides. AB - Glycosyl phenylthiosulfonates are reagents which are valuable for the S glycosylation decoration of organic compounds and proteins. Here, one-pot multiple-component synthesis of glycosyl phenylthiosulfonates from sulfinate, sulfur powder and glycosyl bromides is reported. The reactions afford glycosyl phenylthiosulfonates in good yields under mild conditions. Further application and exploration of glycosyl phenylthiosulfonates are still on underway in our group. PMID- 30399453 TI - Binding silver to chitooligosaccharides through N-heterocyclic carbenes: Synthesis and antimicrobial activity. PMID- 30399454 TI - Could being chlorhexidine an adequate positive control to antimicrobial photodynamic therapy in in vitro studies? AB - BACKGROUND: Chlorhexidine digluconate (CHX) is commonly applied as positive control of new antimicrobials, because it is considered the gold-standard for chemical plaque control. In this sense, the aim of this study was to compare the effect of treatments with curcumin-mediated aPDT and CHX in relation to the viability of specific microorganism groups in two distinct times (immediately and 24 h later). METHODS: Dentin caries microcosms were grown on bovine dentin discs (37 degrees C, anaerobiosis) for 3 days in the Active Attachment Amsterdam Biofilm Model. The biofilms were treated with 300 MUM curcumin and 75 J.cm-2 LED, or 0.06% and 0.12% CHX. Then, total microorganisms, total streptococci, mutans streptococci, and total lactobacilli counts were determined. The statistical analysis was conducted by Kruskal-Wallis and post-hoc Dunn's tests (P < 0.05). RESULTS: Curcumin-mediated aPDT (C + L+), 0.06% and 0.12% CHX reduced mutans streptococci counts (0.19, 0.10 and 0.07 log10 respectively) in the immediate analysis. After 24 h, it was observed a re-growth of microorganisms treated by curcumin-mediated aPDT, whereas both CHX concentrations demonstrated a decrease of the viable microorganisms. CONCLUSION: This study confirmed the substantive effect of CHX and the immediate effect of aPDT. The use of a neutralizer solution was important to block the substantivity of CHX and permit its fair comparison with aPDT, allowing its use as a positive control in further studies. PMID- 30399455 TI - Efficacy of photodynamic therapy vs ultrasonic scaler for preventing gingival inflammation and white spot lesions during orthodontic treatment. AB - INTRODUCTION: The complex designs of fixed orthodontic appliances hinder proper access for cleaning, favouring the development of gingival inflammation and white spot lesions around brackets. The aim of this study was to evaluate the effectiveness to avoid these undesirable effects by using two prophylactic methods: Photodynamic Therapy (PDT) and conventional ultrasonic scaler (US), in patients during fixed orthodontic treatment. MATERIALS AND METHODS: Twenty patients under orthodontic treatment for at least 15 months were randomly divided into two groups: PDT mediated by methylene blue (MB) and US. Both treatments were applied in repeated doses (four times in intervals of 2 weeks in the beginning of the study (T0), with booster doses at 3, 6 and 9 months, T1, T2 and T3, respectively). Periodontal clinical parameters (full-mouth plaque score (FMPS), full-mouth bleeding score (FMBS) and probing depth (PD)) were recorded as well as the International Caries Detection and Assessment System (ICDAS) index. Samples of subgingival plaque and saliva (for determination of 4 periodontopathogens and mutans streptococci, respectively), were collected at T0 and at the follow-ups of T1, T2 and T3. RESULTS: The evolution of FMPS, FMBS, PD, ICDAS scores as well as the counts of periodontopathogens and salivary mutans streptococci was similar after US or PDT implementation. Greatest periodontal scores reduction took place at T1 for FMBS and PD and at T2 for FMPS. Main microbial reduction took place at T1. ICDAS index began to increase from T2. No statistically significant intergroup differences were observed. CONCLUSIONS: Additional treatment of PDT or US in repeated doses delayed undesired side effects during fixed orthodontic treatment in young patients with low caries risk and signs of gingival inflammation. PMID- 30399456 TI - In vitro photodynamic inactivation (PDI) of pathogenic germs inducing onychomycosis. AB - Onychomycosis is a fungal nail infection caused primarily by the dermatophytes Trichophyton rubrum and Trichophyton interdigitale or, less frequently, by molds like Aspergillus spp. and Scopulariopsis brevicaulis. Photodynamic treatment of onychomycosis is considered a promising future therapy to overcome the frequent failure of currently used antifungals. In this study, we tested the potential of three photosensitizers for photodynamic inactivation of the onychomycosis causing pathogens T. rubrum, T. interdigitale and S. brevicaulis. Photosensitizers used are 10,15,20-Tetrakis(1-methylpyridinium-4-yl) porphyrintetra(p-toluenesulfonate) (TMPyP), 5,10,15-tris-(1-methylpyridinium-2-yl)corrolato-(trans dihydroxo)phosphorus(V) (PCor+) and 2',4',5',7'-tetrabromo-3',6'-dihydroxyspiro[2 benzofuran-3,9'-xanthene]-1-one (Eosin Y). The phototoxic effects caused by the cationic photosensitizers (PCor+ and TMPyP) were tested on suspension cultures of spores as well as on fungi during growth on surfaces where both photosensitizers cause high phototoxicity. The anionic Eosin Y was tested on surface-growing fungi only and induces remarkable phototoxic effects on dermatophytes and molds. In all cases, no spore regrowth was detected after PDI. This study is considered a first step towards successful and cost efficient treatment of onychomycosis. PMID- 30399458 TI - Higher trait reappraisal predicts stronger HPA axis habituation to repeated stress. AB - Undergoing stress can be advantageous when it leads to adaptation and growth; however, failure of the hypothalamic-pituitary-adrenal (HPA) axis to habituate (i.e., nonhabituation) involves continuing to become highly activated in response to repeated exposure of the same stimulus and is considered maladaptive. Although 50-75% of individuals assessed in a laboratory exhibit adaptive habituation to repeated stress, variability in habituation suggests psychological processes used in response to stress may play a role, such as emotion regulation (ER). Nonetheless, no research to date has investigated whether ER strategies affect HPA axis habituation. We investigated whether tendency to use two ER strategies, reappraisal and suppression, influenced HPA axis habituation among 84 healthy young adults (60.7% female; Mage = 24.8 years, SD = 6.0) exposed to a standardized experimental stress paradigm on two consecutive days. HPA axis stress responses were assessed using salivary cortisol concentrations. We also examined whether non-manipulated state ER strategies (i.e., those used by the participant during and following the stressor on the first day) modulated HPA axis habituation over and above trait-use in a subsample (N = 60). Trait, but not state, reappraisal was associated with stronger HPA axis habituation. Neither trait nor state suppression were significantly associated with HPA axis habituation. These findings expand our current understanding of how ER can affect stress-related health outcomes and suggest habitual reappraisal plays an important role in adaption of the HPA axis to stress. PMID- 30399457 TI - Hypericin-glucamine antimicrobial photodynamic therapy in the progression of experimentally induced periodontal disease in rats. AB - OBJECTIVE: To evaluate the effect of antimicrobial photodynamic therapy (aPDT) using the photosensitizer hypericin-glucamine in the progression of experimentally induced periodontal disease (PD) in rats. MATERIAL AND METHODS: Subgingival ligatures were inserted around the upper second molars of 30 rats. After 7 days (Baseline), the animals were randomly distributed into 3 experimental (n = 5) groups: Hypericin-glucamine; LED (amber LED, 700 mA, 590 nm, 90 mW, 34.10 J/cm2); and aPDT (Hypericin-glucamine + LED). The treated hemimaxillae were randomly chosen. The periodontal disease progression was monitored without treatment interference in the opposite hemimaxillaes, which were used as the negative control of each animal. The euthanasia was programmed according to each experimental period, 7 or 15 days after the Baseline. Microtomographic, histometric and Tartrate Resistant Acid Phosphatase (TRAP) immunohistochemistry analyses were carried out. RESULTS: Computerized microtomography analyses indicated that the aPDT group had a significantly higher percentage of bone tissue when compared to the other 7 days experimental groups. This result was corroborated by the histometric evaluations of the furcal area. The LED-treated group presented the highest percentages of bone volume for the 15 days experimental groups, which is remarkably higher than the groups treated with Hy-g and aPDT. The histometric analyses demonstrated the control groups had greater bone loss in the proximal regions when compared to the treated groups. The aPDT led to a lower osteoclast activity at both 7 and 15 days. Thus, we can conclude that aPDT exhibits positive effects in PD treatment by promoting favorable conditions for periodontal repair. PMID- 30399459 TI - Salivary uric acid: Associations with resting and reactive blood pressure response to social evaluative stress in healthy African Americans. AB - High levels of uric acid are associated with greater risk of stress-related cardiovascular illnesses that occur disproportionately among African Americans. Whether hyperuricemia affects biological response to acute stress remains largely unknown, suggesting a need to clarify this potential connection. The current study examined how salivary uric acid (sUA) is associated with resting and reactive blood pressure - two robust predictors of hypertension and related cardiovascular disease and disparity. Healthy African Americans (N = 107; 32% male; M age = 31.74 years), completed the Trier Social Stress Test to induce social-evaluative stress. Systolic and diastolic blood pressure readings were recorded before, during, and after the task to assess resting and reactive change in blood pressure. Participants also provided a saliva sample at baseline that was assayed for sUA. At rest, and controlling for age, sUA was modestly associated with higher systolic (r = .201, p = .044), but not diastolic (r = .100, p = .319) blood pressure. In response to the stressor task, and once again controlling for age, sUA was also associated with higher total activation of both systolic (r = .219, p = .025) and diastolic blood pressure (r = .198, p < .044). A subsequent moderation analysis showed that associations between sUA and BP measures were significant for females, but not for males. Findings suggest that uric acid may be implicated in hypertension and cardiovascular health disparities through associations with elevated blood pressure responses to acute social stress, and that low levels of uric acid might be protective, particularly for females. PMID- 30399460 TI - Rising to the challenge: Epilepsy specialist nurses as leaders of service improvements and change (SENsE study). AB - PURPOSE: To report the leadership role and change activities of epilepsy specialist nurses (ESNs) in Ireland; findings from the SENsE study. METHOD: A mixed methods study design was used, involving 12 epilepsy specialist nurses working in five units in Ireland, 24multidisciplinary team members working with them, and 35 people with epilepsy and their family members. Data were collected using individual and focus group interviews, observation and documentary analysis. RESULTS: Five key areas in which ESNs demonstrated leading on the change agenda were identified. These included: Initiating new clinical practice developments; Building capability within the multidisciplinary team; Developing education programmes and resources for people with epilepsy, family and the public; Exerting influence through membership of committees and lobbying; and Advancing the ESN role. CONCLUSION: Though the epilepsy specialist nurse role was first established in the UK in 1988, much of the literature that discusses or describes the ESN role is founded on anecdotal evidence, or focusses on their clinical expertise. Findings from this study provide empirical evidence that the ESNs were involved as key players in leading changes within the services, in the education of others, and the continuous advancement of epilepsy care. PMID- 30399462 TI - Ocular myasthenia gravis patients following the administration of tacrolimus and steroids. PMID- 30399461 TI - The first-hour-of-the-day sleep EEG reliably identifies interictal epileptiform discharges during long-term video-EEG monitoring. AB - PURPOSE: To determine the usefulness of the first-hour sleep EEG recording in identifying interictal epileptiform discharges (IEDs) during long-term video-EEG monitoring. METHOD: We retrospectively reviewed 255 consecutive patients who underwent continuous long-term video-EEG monitoring in the adult epilepsy monitoring unit (EMU) at the University of Chicago. The complete video-EEG recording was reviewed, and the occurrence of IEDs was determined for each patient. We compared the occurrence of IEDs observed during the first-hour sleep EEG recordings with the occurrence of IEDs observed during the complete video-EEG recordings. RESULTS: Overall, IEDs were observed in 134 (53%) of 255 patients during the full long-term video-EEG recording with a mean duration of 4 days. IEDs were identified in the first-hour sleep EEG in 125 (49%) of 225 patients. Comparing to reviewing full records, the first hour sleep EEG identified IEDs in 125 (93%) of 134 patients. Of the IED subtypes, the first-hour sleep EEG identified 92 (94%) of 98 patients with temporal lobe IEDs, 11 (92%) of 12 patients with frontal lobe IEDs, 3 (100%) of 3 patients with parietal lobe IEDs, 1(50%) of the 2 patients with occipital lobe IEDs, 16 (94%) of 17 patients with generalized IEDs, and 2 (100%) 2 patients with multi-focal IEDs. CONCLUSIONS: The first-hour sleep EEG reliably predicts the occurrence of IEDs during the long term video-EEG recording, and therefore can be a time-efficient tool for identifying patients with IEDs during long-term video-EEG recording in the adult epilepsy monitoring unit. PMID- 30399463 TI - Toll-like receptor 4 contributes to a myofibroblast phenotype in cardiac fibroblasts and is associated with autophagy after myocardial infarction in a mouse model. AB - BACKGROUND AND AIMS: Cardiac fibrosis after myocardial infarction (MI) is involved in fibroblast transforming and differentiating into myofibroblast phenoconversion, however, the underlying mechanisms are poorly understood. Toll like receptor 4 (TLR4)-mediated pathogen-associated molecular patterns are key factors that deteriorate cardiac remodelling after MI. Moreover, autophagy has dual roles in cell survival in myocardial tissues after MI. We evaluated the relationship between TLR4 signalling and cardiac myofibroblast transformation differentiation after MI in vivo and in vitro and analysed the role of autophagy. METHODS: We reproduced a model of MI by the permanent ligation of the left anterior descending coronary artery of Tlr4-knockout (Tlr4-/-) and wild-type (WT) male mice. We evaluated scar formation, myofibroblast phenoconversion, LC3 dot formation, autophagy related proteins and alpha-smooth muscle actin (SMA) in cardiac tissues, 7, 14, and 28 days after myocardial infarction. Cardiac fibroblasts were cultured from Tlr4-/- or WT mice. Vimentin, alpha-SMA, bilayer membrane vesicle structures of autophagosomes, and autophagy related proteins were observed after treatment with lipopolysaccharide (LPS) or 3-methyladenine (3 MA) at 24 h. RESULTS: After MI on 7, 14, and 28 days, Tlr4-/- mice showed that heart tissue fibrosis and expression of alpha-SMA, a marker of myofibroblasts, were decreased compared to WT mice. Additionally, levels of LC3II, Atg5, Atg7, and Beclin-1, which are involved in autophagy, were lower than those in WT mice. Further, p62 expression, which is negatively correlated with autophagy levels, was higher in Tlr4-/- mice. Moreover, LC3-labelled autophagosomes in cardiac tissues were reduced in these animals. In vitro, LPS, a ligand of TLR4, stimulated alpha-SMA expression in cardiac fibroblasts, enhanced autophagic flux, and increased autophagosome numbers. In contrast, these effects were not obvious in Tlr4-/- cardiac fibroblasts. LC3II, Atg5, Atg7, and Beclin-1 were upregulated, and p62 was downregulated in cardiac fibroblasts of WT mice stimulated with LPS. However, these effects were blocked by 3-methyladenine, an inhibitor of autophagy. CONCLUSIONS: These results suggest that TLR4 signalling executes the development of a myofibroblast phenotype after MI via autophagy and could be therapeutically exploited to improve outcome after myocardial injury. PMID- 30399464 TI - Single and combined effects of peripheral artery disease and of type 2 diabetes mellitus on the risk of cardiovascular events: A prospective cohort study. AB - BACKGROUND AND AIMS: The individual and combined effects of type 2 diabetes (T2DM) and peripheral artery disease (PAD) on future cardiovascular events are unknown and are addressed in the present investigation. METHODS: Cardiovascular events were prospectively recorded in 1049 subjects, encompassing 4 groups: 558 with neither PAD nor diabetes, 153 with T2DM but without PAD, 192 with PAD but without T2DM and 146 with the combination of PAD and T2DM. RESULTS: Over a mean follow-up period of 7.2 +/- 2.6 years, the cardiovascular event rate was lowest in patients with neither PAD nor T2DM (16.7%). Compared to this group the event rate was not significantly increased in T2DM patients without PAD (22.2%, p = 0.077) but higher in non-diabetic patients with PAD (52.6%; p < 0.001) and further increased in patients with both PAD and T2DM (71.2%; p < 0.001). Nondiabetic PAD patients were at a higher cardiovascular risk than T2DM patients without PAD (p < 0.001). Compared to those with neither PAD nor T2DM, hazard ratios after multivariate adjustment were 1.26 [0.84-1.91]; p = 0.267, 4.17 [2.97 5.85]; p < 0.001, and 7.82 [5.49-11.12]; p < 0.001 for those with T2DM only, for those with PAD only and for those with the combination of PAD plus diabetes, respectively. CONCLUSIONS: PAD is a stronger risk factor for future cardiovascular events than T2DM, but T2DM in PAD patients accelerates atherothrombotic disease and strongly increases the incidence of cardiovascular events. PMID- 30399465 TI - Design, synthesis and bioevaluation of tricyclic fused ring system as dual binding site acetylcholinesterase inhibitors. AB - Due to recently discovered non-classical acetylcholinesterase (AChE) function, dual binding-site AChE inhibitors have acquired a paramount attention of drug designing researchers. The unique structural arrangements of AChE peripheral anionic site (PAS) and catalytic site (CAS) joined by a narrow gorge, prompted us to design the inhibitors that can interact with dual binding sites of AChE. Eighteen homo- and heterodimers of desloratadine and carbazole (already available tricyclic building blocks) were synthesized and tested for their inhibition potential against electric eel acetylcholinesterase (eeAChE) and equine serum butyrylcholinesterase (eqBChE). We identified a six-carbon tether heterodimer of desloratadine and indanedione based tricyclic dihydropyrimidine (4c) as potent and selective inhibitor of eeAChE with IC50 value of 0.09 +/- 0.003 MUM and 1.04 +/- 0.08 MUM (for eqBChE) with selectivity index of 11.1. Binding pose analysis of potent inhibitors suggest that tricyclic ring is well accommodated into the AChE active site through hydrophobic interactions with Trp84 and Trp279. The indanone ring of most active heterodimer 4b is stabilized into the bottom of the gorge and forms hydrogen bonding interactions with the important catalytic triad residue Ser200. PMID- 30399466 TI - Antileishmanial activity and ultrastructural changes of sesquiterpene lactones isolated from Calea pinnatifida (Asteraceae). AB - Bioactivity-guided fractionation of antileishmanial active CH2Cl2 phase of MeOH extract from leaves of Calea pinnatifida led to isolation of two sesquiterpene lactones calein C (1) and calealactone C (2), which structures were stablished on the basis of spectroscopic analysis. Compounds 1 and 2 displayed potent activity against Leishmania amazonensis promastigotes with EC50 of 1.7 and 4.6 ug mL-1, respectively. Compound 2 presented low cytotoxicity for J774 macrophages and displayed activity against amastigote forms of L. amazonensis similar to miltefosine with CC50 values of 31.73 and 27.18 ug mL-1, respectively. Additionally, compounds 1 and 2 caused ultrastructural changes in promastigotes leading to a loss of their classical structural morphology, as evidenced by electron microscopy. Also compound 2 decreased the mitochondria membrane potential. To the best of our knowledge, this is the first occurrence of 1 and 2 in C. pinnatifida. The results obtained highlighted the importance of studying sesquiterpene lactones isolated from Calea pinnatifida in terms of antileishmanial activity, in order to understand the mechanism of action of the isolated compounds in promastigotes forms of L. amazonensis. PMID- 30399467 TI - Prevalence and risk factors of chronic obstructive pulmonary disease in dairy farmers: AIRBAg study. AB - BACKGROUND: The AIRBAg study was designed to assess the prevalence of chronic obstructive pulmonary disease (COPD) in dairy farmers and to define its associated risk factors. METHODS: Between March 2012 and February 2017 randomly selected dairy farmers in the French region of Brittany were asked to complete a self-administered questionnaire and undergo an occupational health check-up with electronic mini-spirometry and standard spirometry. Those having one or more of the following features: chronic cough, chronic bronchitis, wheezing, dyspnea and/or a ratio FEV1/FEV6 < 80% were then referred to a pulmonologist for further check-up including spirometry with a reversibility test. Each COPD case was matched with three controls (dairy farmers and non-farm employees), for sex and age ( +/- 5 years). Conditional multivariate logistic regression models were used to estimate the odds ratios between COPD occurrence and various risk factors. RESULTS: The 1203 farmers examined included 525 (43.6%) who were "at risk of bronchial obstruction" and 432 (35.9%) of these saw the pulmonologist. This screening identified 16 (1.3%) cases of COPD, including eight non-smokers and five with an FEV1 < 80% of predicted values. Their average age was 54.6 ( +/- 7.7) years and 10 of them were men. None complained of illness before the study. Multivariate analyses revealed no significant occupational risk factors for COPD. CONCLUSIONS: This unexpected result may be because Breton dairy farms began to modernize early (1950s), giving rise to conditions with much lower exposure to airborne contaminants. PMID- 30399468 TI - Living in a multi-stressors environment: An integrated biomarker approach to assess the ecotoxicological response of meagre (Argyrosomus regius) to venlafaxine, warming and acidification. AB - Pharmaceuticals, such as the antidepressant venlafaxine (VFX), have been frequently detected in coastal waters and marine biota, and there is a growing body of evidence that these pollutants can be toxic to non-target marine biota, even at low concentrations. Alongside, climate change effects (e.g. warming and acidification) can also affect marine species' physiological fitness and, consequently, compromising their ability to cope with the presence of pollutants. Yet, information regarding interactive effects between pollutants and climate change-related stressors is still scarce. Within this context, the present study aims to assess the differential ecotoxicological responses (antioxidant activity, heat shock response, protein degradation, endocrine disruption and neurotoxicity) of juvenile fish (Argyrosomus regius) tissues (muscle, gills, liver and brain) exposed to VFX (via water or feed), as well as to the interactive effects of warming (DeltaT degrees C = +5 degrees C) and acidification (DeltapCO2 ~ +1000 uatm, equivalent to DeltapH = -0.4 units), using an integrated multi-biomarker response (IBR) approach. Overall, results showed that VFX toxicity was strongly influenced by the uptake pathway, as well as by warming and acidification. More significant changes (e.g. increases surpassing 100% in lipid peroxidation, LPO, heat shock response protein content, HSP70/HSC70, and total ubiquitin content, Ub,) and higher IBR index values were observed when VFX exposure occurred via water (i.e. average IBR = 19, against 17 in VFX-feed treatment). The co-exposure to climate change-related stressors either enhanced (e.g. glutathione S transferases activity (GST) in fish muscle was further increased by warming) or attenuated the changes elicited by VFX (e.g. vitellogenin, VTG, liver content increased with VFX feed exposure acting alone, but not when co-exposed with acidification). Yet, increased stress severity was observed when the three stressors acted simultaneously, particularly in fish exposed to VFX via water (i.e. average IBR = 21). Hence, the distinct fish tissues responses elicited by the different scenarios emphasized the relevance of performing multi-stressors ecotoxicological studies, as such approach enables a better estimation of the environmental hazards posed by pollutants in a changing ocean and, consequently, the development of strategies to mitigate them. PMID- 30399470 TI - Trigeminocardiac Reflex: Case Report and Literature Review of Intraoperative Asystole in Response to Manipulation of the Temporalis Muscle. AB - BACKGROUND: The trigeminocardiac reflex is a sudden onset of bradycardia, hypotension, apnea or gastric hypermotility in response to stimulation of the trigeminal nerve. CASE DESCRIPTION: A 60 year-old female underwent a left orbitozygomatic craniotomy to debulk a large skull base epidermoid cyst compressing the brainstem and cranial nerves. Intraoperatively, retraction of the temporalis muscle consistently produced asystole. Cessation of retraction resulted in prompt return of sinus rhythm. CONCLUSIONS: Our report describes an unusual and extreme example of the trigeminocardiac reflex and explores possible etiologies. This is the third reported surgical case in which manipulation of the temporalis muscle alone was sufficient to elicit bradycardia and asystole, and the first such case within the context of neurosurgery. We emphasize the importance for surgical teams to be cognizant of such extreme examples of this reflex. PMID- 30399469 TI - Antifibrotic Effect of Boric Acid in Rats with Epidural Fibrosis. AB - BACKGROUND: Epidural fibrosis is a major problem after spine surgery, with some patients having recurrent symptoms secondary to excessive formation of scar tissue resulting in neurologic compression. We used a rat laminectomy model to determine if topical application of boric acid could be helpful in the prevention of epidural fibrosis. METHODS: Rats were randomly assigned to 2 control and 2 experimental groups (n = 8 for each group). The negative control group received no surgery, and the positive control group underwent laminectomy only. Experimental groups were classified according to the study agents applied onto the dura mater after laminectomy at the L3 level: 2.5% boric acid solution and 5% boric acid solution. The extent of epidural fibrosis was assessed 4 weeks later macroscopically and histopathologically. RESULTS: Boric acid reduced epidural fibrosis in rats after laminectomy. The effect of 5% boric acid solution was more pronounced (P < 0.05) compared with the 2.5% solution. CONCLUSIONS: The antifibrotic effect of boric acid solution for the prevention of epidural fibrosis suggests that boric acid should be further evaluated in future studies for the prevention of epidural fibrosis. PMID- 30399471 TI - Neoplastic cerebral aneurysm from metastatic lung adenocarcinoma with neuroendocrine features. AB - BACKGROUND: Neoplastic cerebral aneurysms are exceedingly rare. We describe a case of a ruptured, distal middle cerebral artery aneurysm as the presenting symptom leading to the identification of metastatic lung cancer. CASE DESCRIPTION: The patient underwent an uncomplicated surgical trapping and ligation of the aneurysm. Histopathologic examination of the aneurysm confirmed the neoplastic cerebral aneurysm was due to a metastatic lung adenocarcinoma with neuroendocrine features. The patient subsequently underwent stereotactic radiosurgery to the resection cavity. CONCLUSIONS: NCAs are rare, and there is insufficient data to support specific guidelines for management. This case is novel as the patient received adjuvant stereotactic radiosurgery to the operative bed as well as systemic chemotherapy and has maintained good functional status as of last follow-up at 6 months. PMID- 30399472 TI - Measures of health-related quality of life outcomes in pediatric neurosurgery: literature review. AB - BACKGROUND: Improving value in healthcare means optimizing outcomes while minimizing costs. The emerging pay-for-performance era requires understanding the impact of healthcare services on health-related quality of life (HRQoL). Pediatric and surgical subspecialties have yet to fully integrate HRQoL measures into practice. This study aims to review and characterize the HRQoL outcome measures across various pediatric neurosurgical diagnoses. METHODS: A literature review was performed by searching PubMed and Google Scholar with search terms such as "health-related quality of life" and "pediatric neurosurgery" and then including the specific pathologies for which a HRQoL instrument was found (for example: "health-related quality of life" + "epilepsy"). Each measurement was evaluated based on content and purpose, relative strengths and weaknesses, and validity. RESULTS: 68 articles were reviewed. Epilepsy, brain tumor, cerebral palsy, spina bifida, hydrocephalus, and scoliosis were diagnoses with published studies using disease-specific HRQoL instruments. General HRQoL instruments were also reported. Internal, test-retest, and/or inter-rater reliability varied across instruments, as did face, content, concurrent, and/or construct validity. Few instruments have been tested enough for robust reliability and validity. Significant variability exists in usage of these instruments in clinical studies within pediatric neurosurgery. CONCLUSIONS: HRQoL instruments reported in pediatric neurosurgery are currently without standardized guidelines and thus exhibit high variability in use. Clinicians should support the development and application of these methodologies to optimize these instruments, promote standardization of research, improve performance measures to reflect clinically modifiable and meaningful measures, and ultimately lead the national discussion in healthcare quality and patient-centered care. PMID- 30399473 TI - Stereotactic Radiosurgery for Neurosurgical Patients: A Historical Review and Current Perspectives. AB - Today, stereotactic radiosurgery is an effective therapy for a variety of intracranial pathology that were treated solely with open neurosurgery in the past. The technique was developed from the combination of therapeutic radiation and stereotactic devices for the precise localization of intracranial targets. Although stereotactic radiosurgery was originally performed as a partnership between neurosurgeons and radiation oncologists, this partnership has weakened in recent years, with some procedures being performed without neurosurgeons. At the same time, neurosurgeons across the United States and Canada have found their stereotactic radiosurgery training during residency inadequate. Although neurosurgeons, residency directors, and department chairs agree that stereotactic radiosurgery education and exposure during neurosurgery training could be improved, a limited number of resources exist for this kind of education. This review describes the history of stereotactic radiosurgery, assesses the state of its use and education today, and provides recommendations for the improvement of neurosurgical education in stereotactic radiosurgery for the future. PMID- 30399475 TI - Amphiphilic quaternary ammonium chitosans self-assemble onto bacterial and fungal biofilms and kill adherent microorganisms. AB - Formation of biofilms on solid surfaces is a long-standing challenge to multiple medical and health-related applications. Once formed, biofilms are very difficult to destroy, and microorganisms in biofilms are much more resistant to antimicrobial agents than their free-floating counterparts. The current antimicrobial agents/disinfectants often have low residence time on biofilms, leading to low antimicrobial effect on biofilm microorganisms. We designed and synthesized an amphiphilic quaternary ammonium chitosan (CS612) as biocompatible antimicrobial agents that bind onto preformed biofilms to kill adherent microorganisms. CS612 was synthesized through an external acid-free approach, and showed excellent concentration-dependent cytocompatibility toward mammalian cells. Antimicrobial functions of CS612 were confirmed by minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) tests against Gram-positive bacteria, Gram-negative bacteria, and fungi. CS612 rapidly bound onto preformed bacterial and fungal biofilms, and killed adherent microorganisms living in the biofilms. The biofilm-binding kinetic parameters were determined, pointing to a new strategy to manage microorganisms in biofilms and their accompanying problems. PMID- 30399474 TI - Rationale and design of the randomized prospective ATLAS study: Avoid Transvenous Leads in Appropriate Subjects. AB - BACKGROUND: The defibrillator lead is the weakest part of the transvenous (TV) implantable cardioverter defibrillation (ICD) system and a frequent cause of morbidity. Lead dislodgement, cardiac perforation, insertion-related trauma including pneumothorax and vascular injury, are common early complications of TV ICD implantation. Venous occlusion, tricuspid valve dysfunction, lead fracture and lead insulation failure are additional, later complications. The introduction of a totally sub-cutaneous ICD (S-ICD) may reduce these lead-related issues, patient morbidity, hospitalizations and costs. However, such benefits compared to the TV-ICD have not been demonstrated in a randomized trial. DESIGN: ATLAS (Avoid Transvenous Leads in Appropriate Subjects) is a multi-centered, randomized, open label, parallel group trial. Patients younger than 60 years are eligible. If older than 60 years, patients are eligible if they have an inherited heart rhythm disease, or risk factors for ICD-related complication, such as hemodialysis, a history of ICD or pacemaker infection, heart valve replacement, or severe pulmonary disease. This study will determine if using an S-ICD compared to a TV ICD reduces a primary composite outcome of perioperative complications including pulmonary or pericardial perforation, lead dislodgement or dysfunction, tricuspid regurgitation and ipsilateral venous thrombosis. Five hundred patients will be enrolled from 14 Canadian hospitals, and data collected to both early- (at 6 months) and mid-term complications (at 24 months) as well as mortality and ICD shock efficacy. SUMMARY: The ATLAS randomized trial is comparing early- and mid term vascular and lead-related complications among S-ICD versus TV-ICD recipients who are younger or at higher risk of ICD-related complications. PMID- 30399476 TI - Child sleep problems and adult mental health in those born at term or extremely low birth weight. AB - OBJECTIVES: To examine associations between parent-reported child sleep walking or talking, nightmares, and trouble sleeping at age eight and psychiatric problems in adulthood (age 30-35) in extremely low birth weight (ELBW; <1000 g) survivors and matched normal birth weight (NBW; >2500 g) control participants. METHODS: At age eight, parents of ELBW survivors and NBW control participants completed sleep items on the Child Behavior Checklist assessing the presence of sleep walking/talking, nightmares, or trouble sleeping. At age 30-35, 98 ELBW and 94 NBW individuals completed the Mini International Neuropsychiatric Interview (MINI), Beck Anxiety Inventory (BAI), and Beck Depression Inventory (BDI). Analyses were conducted in each birth weight group independently. RESULTS: In NBW participants, sleep walking/talking in childhood predicted higher BAI and BDI scores, as well as more than three times the odds of having a mood or anxiety disorder (OR = 3.48; 95% CI, 1.26-9.60) at age 30-35. Sex and childhood sleep problem interactions revealed that females who manifested sleep walking/talking as children had higher BAI scores than males. Nightmares in children born at NBW predicted higher BAI scores. These associations persisted despite adjustment for child mental health, sex, socioeconomic status, sexual or physical abuse, and family functioning. Trouble sleeping in childhood did not predict adult mental health problems. Childhood sleep problems did not predict psychopathology in ELBW adults. CONCLUSIONS: Children born at NBW who manifest sleep walking or talking appear to be at increased risk for developing mood or anxiety disorders in adulthood. No associations between child sleep and adult mental illness were noted in those with ELBW surviviors. Childhood sleep walking/talking may be a unique risk factor for mental health problems later in life. PMID- 30399477 TI - Characterization of growth hormone disulfide-linked molecular isoforms during post-exercise release vs nocturnal pulsatile release reveals similar milieu composition. AB - OBJECTIVE: To characterize the influence of mode (aerobic/resistance) and volume of exercise (moderate/high) on circulating GH immediately post-exercise as well as following the onset of sleep. DESIGN: This study used repeated measures in which subjects randomly completed 5 separate conditions: control (no exercise), moderate volume resistance exercise (MR), high-volume resistance exercise (HR), moderate volume aerobic exercise (MA), and high volume aerobic exercise (HA). METHODS: Subjects had two overnight stays on each of the 5 iterations. Serial blood draws began as soon as possible after the completion of the exercise session. Blood was obtained every 20 min for 24-h. GH was measured using a chemiluminescent immunoassay. Pooled samples representing post exercise (PE) and first nocturnal pulse (NP) were divided into two aliquots. One of these aliquots was chemically reduced by adding 10 mM glutathione (GSH) to break down disulfide linked aggregates. RESULTS: No differences were observed when pooling GH response at post-exercise (2.02 +/- 0.21) and nocturnal pulse (2.63 +/- 0.51; p = .32). Pairwise comparisons revealed main effect differences between controls (1.19 +/- 0.29) and both MA (2.86 +/- 0.31; p = .009) and HA (3.73 +/- 0.71; p = .001). Both MA (p = .049) and HA (p = .035) responses were significantly larger than the MR stimulus (1.96 +/- 0.28). With GSH reduction, controls significantly differed from MA (p = .018) and HA (p = .003) during PE, but only differed from HA (p = .003) during NP. CONCLUSIONS: This study demonstrated similar GH responses to exercise and nocturnal pulse, indicating that mode and intensity of exercise does not proportionately affect GH dimeric isoform concentration. PMID- 30399478 TI - Stereotypic behaviours in frontotemporal dementia and progressive supranuclear palsy. AB - INTRODUCTION: The behavioural variant of frontotemporal dementia (bvFTD), and the Richardson variant of progressive supranuclear palsy (PSP-RS) share several clinical signs and symptoms. Since stereotypic behaviours are fairly common in bvFTD, and are also described in other degenerative dementias including Alzheimer's disease, and parkinsonisms with dementia, we aimed to examine the extent to which stereotypies also characterise PSP-RS. METHODS: We compared 53 bvFTD patients with 40 demented PSP-RS patients, seen consecutively as outpatients at four Italian Hospitals. Patients were assessed by the Neuropsychiatric Inventory (NPI); Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) for cognitive functions; Stereotypy Rating Inventory (SRI) for stereotypies; Unified Parkinson's Disease Rating Scale (UPDRS) for motor function; and Activities of Daily Living (ADL) to assess autonomy in daily life. RESULTS: The groups did not differ for age, illness duration, cognitive functions or total NPI score; PSP-RS had significantly more depressive symptoms and greater motor and autonomy compromise than bvFTD. The groups did not differ significantly on total SRI score, but bvFTD had significantly more cooking and eating stereotypies. Twenty-three (57.5%) PSP-RS and 43 (81%) bvFTD patients had at least one stereotypy; 16/23 (69.5%) PSP-RS and 9/43 (20.9%) bvFTD patients appeared aware of their stereotypies. CONCLUSION: Stereotypies were common in our demented PSP-RS patients. Further studies on earlier stage non-demented PSP patients are required to ascertain whether stereotypies are characteristic of PSP in general or are confined to PSP-RS, and whether they may be used to suggest a PSP diagnosis early in disease course. PMID- 30399479 TI - Left-shifting prism adaptation boosts reward-based learning. AB - Visuospatial cognition has an inherent lateralized bias. Individual differences in the direction and magnitude of this bias are associated with asymmetrical D2/3 dopamine binding and dopamine system genotypes. Dopamine level affects feedback based learning and dopamine signaling asymmetry is related to differential learning from reward and punishment. High D2 binding in the left hemisphere is associated with preference for reward. Prism adaptation (PA) is a simple sensorimotor technique, which modulates visuospatial bias according to the direction of the deviation. Left-deviating prism adaptation (LPA) induces rightward bias in healthy subjects. It is therefore possible that the right side of space increases in saliency along with left hemisphere dopaminergic activity. Right-deviating prism adaptation (RPA) has been used mainly as a control condition because it does not modulate behavior in healthy individuals. Since LPA induces a rightward visuospatial bias as a result of left hemisphere modulation, and higher dopaminergic activity in the left hemisphere is associated with preference for rewarding events we hypothesized that LPA would increase the preference for learning with reward. Healthy volunteers performed a computer based probabilistic classification task before and after LPA or RPA. Consistent with our predictions, PA altered the preference for rewarded versus punished learning, with the LPA group exhibiting increased learning from reward. These results suggest that PA modulates dopaminergic activity in a lateralized fashion. PMID- 30399480 TI - The people behind the samples: Biographical features of Past Hunter-Gatherers from KwaZulu-Natal who yielded aDNA. AB - PURPOSE: Skeletons sampled for ancient human DNA analysis are sometimes complete enough to provide information about the lives of the people they represent. We focus on three Later Stone Age skeletons, ca. 2000 B.P., from coastal KwaZulu Natal, South Africa, whose ancient genomes have been sequenced (Schlebusch et al., 2017). METHODS: Bioarchaeological approaches are integrated with aDNA information. RESULTS: All skeletons are male. Dental development shows that the boy, with prominent cribra orbitalia, died at age 6-7 years. Two men show cranial and spinal trauma, extensive tooth wear, plus mild cribra orbitalia in one. CONCLUSIONS: Dental wear and trauma of the adults are consistent with hunter gatherer lives. Even partial aDNA evidence contributes to sex determination. Parasitic infection such as schistosomiasis is the best-fit cause for the child's anemia in this case. CONTRIBUTION TO KNOWLEDGE: The convergence of genomic and bioarchaeological approaches expands our knowledge of the past lives of a boy and two men whose lives as hunter-gatherers included episodes of trauma and disease. LIMITATIONS: The skeletons are incomplete, in variable condition, and from poorly characterized local cultural contexts. SUGGESTIONS FOR FURTHER RESEARCH: Thorough osteobiographic analysis should accompany paleogenomic investigations. Such disciplinary collaboration enriches our understanding of the human past. PMID- 30399481 TI - Investigation on drug-binding in heme pocket of CYP2C19 with UV-visible and resonance Raman spectroscopies. AB - Cytochrome P450 (CYP) is a class of heme-containing enzymes which mainly catalyze a monooxygenation reaction of various chemicals, and hence CYP plays a key role in the drug metabolism. Although CYP2C19 isoform is a minor hepatic CYP, it metabolizes clinically important drugs such as omeprazole and S-mephenytoin. In this work, the interaction of purified CYP2C19 WT (CYP2C19) with seven drugs (phenytoin, S-mephenytoin, omeprazole, lansoprazole, cimetidine, propranolol, and warfarin) was investigated using spectroscopic methods. The binding of each drug and the induced structural change in the heme distal environment were evaluated. Ferric form of CYP2C19 was revealed to contain a six-coordinate low-spin heme with a water molecule as a sixth ligand in a distal site, and the addition of each drug caused varied minor fraction of five-coordinate heme. It was suggested that the ligated water molecule was partly moved away from the heme distal environment and that the degree of water removal was dependent on the type of drugs. The effect on the coordination was varied with the studied drugs with wide variation in the dissociation constants from 2.6 MUM for lansoprazole to 5400 MUM for warfarin. Phenytoin and S-mephenytoin showed that binding to CYP2C19 occurred in a stepwise manner and that the coordination of a water molecule was facilitated in the second binding step. In the ferrous CO-bound state, nu(FeCO) stretching mode was clearly observed at 471 cm-1 in the absence of drugs. The Raman line was greatly up-shifted by omeprazole (487 cm-1) and lansoprazole (477 cm-1) but was minimally affected by propranolol, phenytoin, and S-mephenytoin. These results indicate that slight chemical modification of a drug greatly affects the heme distal environments upon binding. PMID- 30399482 TI - Inhibitory effect of silibinin on Amadori-albumin in diabetes mellitus: A multi spectroscopic and biochemical approach. AB - Due to increased understanding of the damaging effects of glycation process, it is highly desirable to manage this process effectively either by prevention or by managing the consequences of glycation preferentially at early stage. The use of potential naturally occurring compounds as anti-glycating agents may provide an effective approach to control the development and progression of diabetic associated complications. In the present study, human serum albumin (albumin) was co-incubated with glucose and different concentrations of silibinin. Silibinin was demonstrated to possess anti-glycation activity. We found that silibinin inhibits glucoseinduced glycation at an early stage. We analyzed the effect of silibinin on albumin structure and its biochemical properties at early stage of glycation through various biophysical and biochemical techniques. Nitro blue tertazolium assay results showed that fructosamine formation was reduced in the presence of silibinin. UV-visible spectra results showed decrease in the absorbance with increasing concentrations of silibinin towards native albumin absorbance. Fluorescence results showed that the intensity was increased with increasing the silibinin concentrations as compared to Amadori-albumin. In addition, Far-UV CD spectra demonstrated some restoration of alpha-helicity when albumin was incubated with glucose in the presence of silibinin. Moreover, silibinin caused significant reduction in carbonyl contents with concomitant increase in free thiol, lysine and arginine residues. The anti-glycation activity of silibinin was concentration-dependent. From all the observations, we can conclude that silibinin might be acting as an obstacle in the binding of glucose with albumin and thus preventing the glycation induced changes in albumin. Silibinin may be effective in delaying glycation mediated pathologies in diabetic individuals. PMID- 30399483 TI - Ozone and cardiac arrest: The role of previous hospitalizations. AB - BACKGROUND: Several studies have reported associations between exposure to particulate matter and incidence of out-of-hospital cardiac arrest (OHCA) and some have observed associations with ozone (O3). There are no studies investigating susceptibility based on previous disease history to short-term O3 exposure and the risk of OHCA. AIM: To investigate the role of previous cardiovascular-related hospitalizations in modifying the associations between the risk of OHCA and short-term increase in O3 concentrations. METHODS: A time stratified case-crossover analysis of 11,923 OHCA registered in the Swedish Register for Cardiopulmonary Resuscitation from 2006 to 2014 was performed. Using personal identification numbers, OHCA were linked to all previous hospitalizations in Sweden since 1987 to create susceptible groups based on the principal diagnosis code at discharge. Susceptibility was based on hospitalization for i) acute myocardial infarction; ii) heart failure; iii) arrhythmias; iv) diabetes; v) hypertension; and vi) stroke. Moving 2 and 24-h averages for O3, PM2.5, PM10, and NO2 were constructed from hourly averages. RESULTS: A 10 MUg/m3 higher 2-h average O3 concentration was associated with a 2% higher risk of OHCA (95% CI, 0% 3%). Associations were similar for 24-h average O3 and in individuals with or without hospitalizations for AMI, heart failure, diabetes, hypertension or stroke. Individuals with previous hospitalizations for arrhythmias had a lower risk of OHCA with higher O3. No associations were observed for other pollutants. CONCLUSIONS: Short-term exposure to O3 was associated with an elevated risk of OHCA, however, previous hospitalizations for cardiovascular diseases were not associated with additionally augmented risks. PMID- 30399484 TI - Risk of second primary neoplasm and mortality in childhood cancer survivors based on a national registry database. AB - OBJECTIVE: Although overall childhood cancer survival has improved, survivors may still have an elevated risk for second primary neoplasm (SPN) and excess mortality. The aim of the current study was to estimate the risks for SPN and mortality in childhood cancer survivors in Israel as compared to the general population. METHODS: All children aged 0-19 diagnosed with primary neoplasm between 1980-2007 who survived at least 5 years following diagnosis were included in the study. Follow-up continued until December 31st, 2013, or diagnosis of SPN, or death due to any cause (the earliest of these events). Standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) were calculated. Cox proportional hazards regression was employed to assess predictors of SPN and mortality. RESULTS: The cohort consisted of 6637 childhood cancer survivors. A total of 244 all-site SPN cases were observed. Compared to the general population, the risks for SPN and for mortality were significantly increased (SIR = 5.48; 95%CI: 4.82-6.22 and SMR = 13.99; 95%CI = 12.54-15.56, respectively). Factors predicting SPN were sex (female), older age at first diagnosis, and initial cancer diagnosis (lymphomas). Factors predicting mortality were older age at first diagnosis, initial cancer diagnosis (myeloproliferative diseases) and earlier years, according to calendar period of initial diagnosis. CONCLUSIONS: Although 5-year childhood cancer survival is high, survivors are at elevated risk for SPN and mortality, and the risks are associated with baseline characteristics of the patients. The increased risks should be considered when planning treatment, follow-up and surveillance of the survivors. PMID- 30399485 TI - Biochar combined with polyvalent phage therapy to mitigate antibiotic resistance pathogenic bacteria vertical transfer risk in an undisturbed soil column system. AB - The vertical migration of antibiotic resistance pathogenic bacteria (ARPB) and antibiotic resistance genes (ARGs) in the surface soil-vadose soil system has become a new threat to ecological safety and public health; there is an imperative need to develop an efficient technique for targeted control and inactivation of ARPB in these systems. In this work, undisturbed soil columns (0 ~ -5 m) were constructed to investigate the impact of biochar amendment or/and polyvalent bacteriophage (PhiYSZ-KK) therapy on the vertical control and inactivation of tetracycline-resistant Escherichia coli K-12 and chloramphenicol resistant Klebsiella pneumonia K-6. The simultaneous application of polyvalent phage and biochar impeded the vertical migration of ARPB from the top soil to lower soil layers and stimulated the ARPB dissipation in the soil column. After 60-day incubation, levels of ARPB and ARGs decreased significantly in the soil column by magnitudes of 2-6. Additionally, high throughput sequencing indicated that the simultaneous application of biochar and phage clearly maintained the structure and diversity of the soil microbial communities (p < 0.05). This work therefore demonstrates that the application of a biochar/phage combination is an environmentally friendly, efficacious measure for the control and inactivation of ARPB/ARGs in vertical soil column systems. PMID- 30399486 TI - Rapid depressurization and phase transition of CO2 in vertical ducts - Small scale experiments and Rankine-Hugoniot analyses. AB - This study discusses the rapid expansion and phase transition of liquefied carbon dioxide (CO2) in vertical ducts. Results from small-scale experiments in three test setups (A, B, and C) were compared with a Rankine-Hugoniot model that treats the phase transition as an adiabatic evaporation wave of constant thickness. The model calculates the fluid properties behind the evaporation wave. The motivation was to identify hazards and quantify the energy-release in tank explosions such as a boiling liquid expanding vapor explosion. The experimental results corresponded with a Chapman Jouguet (CJ) solution. The contributions include a mapping of CJ solutions calculated from a range of pre-rupture conditions. The puncture of a diaphragm (setup A, and B), or complete test section rupture (setup C) initiated the tests. The three test setups provided a range of pressures for the model. Evaporation waves were observed, propagating with velocities of 35-42 ms-1 (setup A, and B), and ~ 10 ms-1 (setup C) into the superheated liquid. The calculated vapor mass fraction behind of the evaporation wave was in the range 0.21-0.23. The study presents a strategy, which incorporates the calculated vapor mass fraction, to predict the energy released in a tank explosion. PMID- 30399487 TI - Assessment of individual-based perfluoroalkly substances exposure by multiple human exposure sources. AB - Individual exposure of perfluoroalkyl substances (PFASs) was assessed by analyzing serum, food, dust, drinking water, and hand wipes from 50 individuals. The PFASs concentrations in serum were correlated most strongly with exposure to PFASs through the (direct and indirect) ingestion of dust (p < 0.01). Daily PFOA intakes were estimated to be 2.07 ng/kg/day from food, 0.003 ng/kg/day from dust, 0.053 ng/kg/day from hand-to-mouth activity, and 0.020 ng/kg/day from drinking water. Daily perfluorooctanesulfonic acid (PFOS) intakes were estimated to be 0.689 ng/kg/day from food, 0.001 ng/kg/day from dust, 0.018 ng/kg/day from hand to-mouth activity, and 0.005 ng/kg/day from drinking water. The daily PFOA and PFOS intakes calculated for individuals in this study and in group/scenario based exposure assessment of previous studies were compared. The estimated PFOS intake on individual basis (0.695 ng/kg/day) was a little bit higher than the intake on group/scenario basis (0.652 ng/kg/day). However, the estimated daily PFOA intake on individual basis (1.41 ng/kg/day) was about four times higher than the intake on group/scenario basis (0.339 ng/kg/day). Among the exposure pathways, food ingestion was major contributor to the total daily PFOA and PFOS intakes on individuals (99% of total intake) and group/scenario basis (64% of total intake). PMID- 30399488 TI - Flame retardant vinylon/poly(m-phenylene isophthalamide) blended fibers with synergistic flame retardancy for advanced fireproof textiles. AB - Superior flame retardant textiles are urgently needed to address high fire and heat risks. This study provides a simple and effective strategy to improve the flame retardancy of textiles through a synergistic effect between the blended fibers, and a system with synergistic in flame retardant vinylon (FRV)/poly(m phenylene isophthalamide) (PMIA) blended fibers is discovered. The FRV/PMIA 50/50 exhibits a much higher time to ignition and a lower peak heat release rate than those of the neat components, indicating a synergistic flame retardancy between constituents. The corresponding mechanism is explored. The residual char layer formed by blended fibers connects together and keeps the original fiber shape, which acts as a barrier slowing heat transmission and gas diffusion. Concurrently, thermal degradation analysis of blended fibers implies that both components mutually interact with each other, resulting in a higher experimental amount of incombustible gases at an early degradation stage and lower experimental amount of combustible gases at a later degradation stage as compared to the theoretical one. Therefore, the synergistic flame retardancy in FRV/PMIA blended fibers is attributed to the actions in the condensed and gas phases during pyrolysis. This work provides an effective strategy to design fireproof textiles. PMID- 30399489 TI - Sensorimotor characteristics of sign translations modulate EEG when deaf signers read English. AB - Bilingual individuals automatically translate written words from one language to another. While this process is established in spoken-language bilinguals, there is less known about its occurrence in deaf bilinguals who know signed and spoken languages. Since sign language uses motion and space to convey linguistic content, it is possible that action simulation in the brain's sensorimotor system plays a role in this process. We recorded EEG from deaf participants fluent in ASL as they read individual English words and found significant differences in alpha and beta EEG at central electrode sites during the reading of English words whose ASL translations use two hands, compared to English words whose ASL translations use one hand. Hearing non-signers did not show any differences between conditions. These results demonstrate the involvement of the sensorimotor system in cross-linguistic, cross-modal translation, and suggest that covert action simulation processes are involved when deaf signers read. PMID- 30399491 TI - The intricacies of self-lipid antigen presentation by CD1b. AB - The CD1 family of glycoproteins are MHC class I-like molecules that present a wide array of self and foreign lipid antigens to T-cell receptors (TCRs) on T cells. Humans express three classes of CD1 molecules, denoted as Group 1 (CD1a, CD1b, and CD1c), Group 2 (CD1d), and Group 3 (CD1e). Of the CD1 family of molecules, CD1b exhibits the largest and most complex antigen binding groove; allowing it the capabilities to present a broad spectrum of lipid antigens. While its role in foreign-lipid presentation in the context of mycobacterial infection are well characterized, understanding the roles of CD1b in autoreactivity are recently being elucidated. While the mechanisms governing proliferation of CD1b restricted autoreactive T cells, regulation of CD1 gene expression, and the processes controlling CD1+ antigen presenting cell maturation are widely undercharacterized, the exploration of self-lipid antigens in the context of disease have recently come into focus. Furthermore, the recently expanded pool of CD1b crystal structures allow the opportunity to further analyze the molecular mechanisms of T-cell recognition and self-lipid presentation; where the intricacies of the two-compartment system, that accommodate both the presented self-lipid antigen and scaffold lipids, are scrutinized. This review delves into the immunological and molecular mechanisms governing presentation and T-cell recognition of the broad self-lipid repertoire of CD1b; with evidence mounting pointing towards a role in diseases such as microbial infection, autoimmune diseases, and cancer. PMID- 30399490 TI - Identification of a linear B-cell epitope in the catalytic domain of bothropasin, a metalloproteinase from Bothrops jararaca snake venom. AB - Bothropasin is a hemorrhagic snake venom metalloproteinase (SVMP) from Bothrops jararaca venom, the snake responsible for most bites in Southeastern Brazil. SVMPs, such as bothropasin, are involved in the main bothropic envenoming symptoms, which include hemorrhage, inflammation, necrosis and blood coagulation deficiency. B-cell epitope mapping of SVMPs can lead to the identification of peptides capable of inducing neutralizing antibodies without causing toxic effects, therefore improving anti-venom production. Here, using the SPOT synthesis technique, we have identified an epitope located in the catalytic domain of bothropasin (202KARMYELANIVNEILRYLYMH222) which was synthesized and named BotEp1. The peptide was used to immunize Swiss mice and Anti-BotEp1 serum cross-reacted with bothropasin and crude venoms from B. jararaca and B. atrox venoms. Furthermore, Anti-BotEp1 antibodies were able to completely neutralize the hemorrhagic activity of a chromatographic fraction from B. jararaca venom, which contains hemorrhagic SVMPs. In addition, the coagulation activity of the hemorrhagic fraction showed to be diminished when tested in serum from rabbit immunized with BotEp1 (compared to serum from non-immunized animal). Our results show the identification of neutralizing epitopes in bothropasin and provide basis for the use of synthetic peptides to improve the production of immunotherapeutics. PMID- 30399492 TI - Extracellular vimentin modulates human dendritic cell activation. AB - Vimentin is an intermediate filament protein traditionally considered to be an intracellular protein with a structural role. However, recent evidence suggests that vimentin can also be found outside the cell in disease conditions such as cancer, traumatic tissue injury, and inflammation. Extracellular vimentin was previously found to stimulate innate immunity by increasing monocyte and macrophage ability to kill bacteria. However, vimentin has also been previously found to decrease neutrophil infiltration into inflamed tissue. How extracellular vimentin affects the initiation of adaptive immune responses is unknown. Initiation of adaptive immunity involves priming of naive T cells by antigen presenting cells, the most effective of which are dendritic cells (DCs). In this study, we demonstrate how extracellular vimentin modulates lipopolysaccharide (LPS) - induced activation of human DCs. Using cytometric bead arrays, we show that extracellular vimentin decreases LPS-activated DC secretion of pro inflammatory cytokines IL-6 and IL-12 while increasing secretion of the anti inflammatory cytokine IL-10. Using flow cytometry, we show that extracellular vimentin does not significantly affect LPS-induced DC surface expression of MHC I (HLA-ABC) or MHC II (HLA-DR) presentation molecules, costimulatory factors (CD80, CD86), or the DC maturation marker (CD83). Further, LPS-stimulated DCs co cultured with allogeneic naive CD4 + T cells (Th0) induced less secretion of the pro-inflammatory Th1 effector cytokine IFN-gamma in the presence of vimentin than in the presence of LPS alone. This result suggests that vimentin reduces Th1 differentiation. Taken together, our data suggest that extracellular vimentin may inhibit pro-inflammatory adaptive immune responses, by blocking DC secretion of pro-inflammatory cytokines. Thus, extracellular vimentin may play an important role in cancer or trauma-complications by inducing suppression of the adaptive immune response. In a positive sense, the presence of extracellular vimentin may prevent tissue-damage from contributing to the development of autoimmunity. Consequently, extracellular vimentin may become a novel drug target for treatment of a variety of pro- and anti-inflammatory disease conditions. PMID- 30399493 TI - Increase in isoflavonoid content in Glycine max cells transformed by the constitutively active Ca2+ independent form of the AtCPK1 gene. AB - Calcium-dependent protein kinases (CDPKs) represent a class within a multigene family that plays an important role in biotic and abiotic plant stress responses and is involved in the regulation of secondary metabolite biosynthesis. Our previous study showed that overexpression of the mutant constitutively active Ca2+ independent form of the AtCPK1 gene (AtCPK1-Ca) significantly increased the biosynthesis of anthraquinones and stilbenes in Rubia cordifolia L. and Vitis amurensis Rupr. transgenic cell cultures, respectively. Here, we have established transgenic calli of soybean plants Glycine max (L.) Merr. that express the AtCPK1 Ca gene. Heterologous expression of the AtCPK1-Ca gene provoked a 5.2-fold increase in total isoflavone production up to 208.09 mg/L, along with an increase in isoflavone aglycones production up to 6.60 mg/L, which is 3-fold greater than that of the control culture. The production of prenylated isoflavones significantly increased, reaching 3.78 mg/L, 13-fold higher than in the control culture. The expression levels of 4-coumarate:CoA ligases, isoflavone synthases, 2-hydroxyisoflavanone dehydratase, isoflavone dimethylallyltransferase, and coumestrol 4-dimethylallyltransferase genes in transgenic cell cultures significantly increased. Thus, heterologous expression of the AtCPK1-Ca gene can be used to bioengineer plant cell cultures that produce isoflavonoids. PMID- 30399494 TI - A new type 1 ribosome-inactivating protein from the seeds of Gypsophila elegans M.Bieb. AB - Ribosome-inactivating proteins (RIPs) are enzymes with N-glycosylase activity that remove adenine bases from the ribosomal RNA. In theory, one single RIP molecule internalized into a cell is sufficient to induce cell death. For this reason, RIPs are of high potential as toxic payload for anti-tumor therapy. A considerable number of RIPs are synthesized by plants that belong to the carnation family (Caryophyllaceae). Prominent examples are the RIPs saporin from Saponaria officinalis L. or dianthin from Dianthus caryophyllus L. In this study, we have isolated and characterized a novel RIP (termed gypsophilin-S) from the tiny seeds of Gypsophila elegans M. Bieb. (Caryophyllaceae). It is noteworthy that this is the first study presenting the complete amino acid sequence of a RIP from a Gypsophila species. Gypsophilin-S was isolated from the defatted seed material following ammonium sulphate precipitation and HPLC-based ion exchange chromatography. Gypsophilin-S-containing fractions were analysed by SDS-PAGE and mass spectrometry. The full amino acid sequence of gypsophilin-S was assembled by MALDI-TOF-MS-MS and PCR. Gypsophilin-S exhibited strong adenine releasing activity and its cytotoxicity in human glioblastoma cells was investigated using an impedance-based real-time assay in comparison with recombinant saporin and dianthin. PMID- 30399495 TI - A role for 3'-O-beta-D-ribofuranosyladenosine in altering plant immunity. AB - Our understanding of how, and the extent to which, phytopathogens reconfigure host metabolic pathways to enhance virulence is remarkably limited. Here we investigate the dynamics of the natural disaccharide nucleoside, 3'-O-beta-D ribofuranosyladenosine, in leaves of Arabidopsis thaliana infected with virulent Pseudomonas syringae pv. tomato strain DC3000. 3'-O-beta-D-ribofuranosyladenosine is a plant derived molecule that rapidly accumulates following delivery of P. syringae type III effectors to represent a major component of the infected leaf metabolome. We report the first synthesis of 3'-O-beta-D-ribofuranosyladenosine using a method involving the condensation of a small excess of 1-O-acetyl-2,3,5 three-O-benzoyl-beta-ribofuranose activated with tin tetrachloride with 2',5'-di O-tert-butyldimethylsilyladenosine in 1,2-dichloroethane with further removal of silyl and benzoyl protecting groups. Interestingly, application of synthetic 3'-O beta-D-ribofuranosyladenosine did not affect either bacterial multiplication or infection dynamics suggesting a major reconfiguration of metabolism during pathogenesis and a heavy metabolic burden on the infected plant. PMID- 30399496 TI - Genome-wide identification and biochemical characterization of the UGT88F subfamily in Malus x domestica Borkh. AB - The UDP-glycosyltransferase UGT88F subfamily has been described first in Malus x domestica with the characterization of UGT88F1. Up to now UGT88F1 was one of the most active UGT glycosylating dihydrochalcones in vitro. The involvement of UGT88F1 in phloridzin (phloretin 2'-O-glucoside) synthesis, the main apple tree dihydrochalcone, was further confirmed in planta. Since the characterization of UGT88F1, this new UGT subfamily has been poorly studied probably because it seemed restricted to Maloideae. In the present study, we investigate the apple tree genome to identify and biochemically characterize the whole UGT88F subfamily. The apple tree genome contains five full-length UGT88F genes out of which three newly identified members (UGT88F6, UGT88F7 and UGT88F8) and a pseudogene. These genes are organized into two genomic clusters resulting from the recent global genomic duplication event in the apple tree. We show that recombinant UGT88F8 protein specifically glycosylates phloretin in the 2'OH position to synthetize phloridzin in vitro and was therefore named UDP-glucose: phloretin 2'-O-glycosyltransferase. The Km values of UGT88F8 are 7.72 MUM and 10.84 MUM for phloretin and UDP-glucose respectively and are in the same range as UGT88F1 catalytic parameters thus constituting two isoforms. Co-expression patterns of both UGT88F1 and UGT88F8 argue for a redundant function in phloridzin biosynthesis in planta. Contrastingly, recombinant UGT88F6 protein is able to glycosylate in vitro a wide range of flavonoids including flavonols, flavones, flavanones, chalcones and dihydrochalcones, although flavonols are the preferred substrates, e.g. Km value for kaempferol is 2.1 MUM. Depending on the flavonoid, glycosylation occurs at least on the 3-OH and 7-OH positions. Therefore UGT88F6 corresponds to an UDP-glucose: flavonoid 3/7-O-glycosyltransferase. Finally, a molecular modeling study highlights a very high substitution rate of residues in the acceptor binding pocket between UGT88F8 and UGT88F6 which is responsible for the enzymes divergence in substrate and regiospecificity, despite an overall high protein homology. PMID- 30399497 TI - Computationally aided stereochemical assignment of undescribed bisabolenes from Calea urticifolia. AB - Calea urticifolia (Mill.) DC. (Compositae) is a medicinal plant found in El Salvador. Calea is used in folkloric medicine as a psychoactive principle with calming effect, as well as in the treatment of diarrhea and fever. Three undescribed bisabolenes, named caleanolenes A-C, as well as, three known sesquiterpene lactones 2,3-epoxyjuanislamin, calealactone B, calein C, and the flavonoid acacetin, were isolated from the chloroform extract of the leaves of C. urticifolia. The chemical structures of the isolated compounds were determined on the basis of HRMS, IR, CD, and from 1D and 2D NMR spectroscopic studies. The absolute configurations of the caleanolenes have been partly established using GIAO NMR and ECD calculations. The isolated compounds were evaluated for cytotoxicity against the CA46 and Raji lymphoma, and the MCF7 breast cancer cell lines, with 2,3-epoxyjuanislamin showing the best activity in all cell lines (IC50 value range 2.9-12.3 MUM). PMID- 30399498 TI - Young adult dual combusted cigarette and e-cigarette users' anticipated responses to a nicotine reduction policy and menthol ban in combusted cigarettes. AB - BACKGROUND: The aim of the study was to assess young adult dual e-cigarette (EC) and combusted cigarette (CC) users' anticipated responses to a hypothetical very low nicotine content product standard and menthol ban in CC. METHODS: Data came from 240 young adult (18-29 years) dual CC and EC users recruited via Amazon Mechanical Turk between June 20-22, 2017. Descriptive statistics were used to report sample characteristics. McNemar's tests were used to assess differences between product categories in terms of anticipated responses to hypothetical regulations. RESULTS: A hypothetical very low nicotine content product standard in CC resulted in reported intentions to quit or reduce CC use and increase use of EC (p's<0.001). Hypothetical restrictions regarding the availability of menthol CC resulted in marginally significant reported intentions to increase EC use (p = 0.080). Anticipated responses to regulation were associated with baseline EC and CC use characteristics. CONCLUSIONS: This work provides preliminary evidence of the impact that regulations regarding nicotine content and menthol in CC may have on the use of EC among young adult dual users. PMID- 30399499 TI - Prevalence, incidence, recovery, and recurrence of alcohol use disorders from childhood to age 30. AB - BACKGROUND: Little is known about the course of alcohol use disorders (AUDs) in representative samples during high-risk periods of adolescence and early adulthood. The primary objective of this research is to describe the prevalence and course of initial AUD episodes experienced between childhood and age 30 in a regionally representative cohort sample. METHODS: Study data are from an epidemiological study of 816 youth. Participants were initially selected at random from nine high schools in western Oregon, USA. Four waves of data collection were conducted between ages 16 and 30. AUD course milestones are referenced to participants' age. RESULTS: Results indicated that male participants (43%) were significantly more likely to be diagnosed with a lifetime AUD than female participants (28%), OR [CI95] = 1.97 [1.47-2.65], and rate of first incidence was especially high between ages 18 and 24.9, a developmental period that also corresponded to the peak interval in prevalence rates. The rate of first AUD incidence substantially diminished beginning around age 25. Among those with an initial AUD episode, 87% recovered by age 30 and, of these, the average episode length was 23 months. Among recovered cases, 33% went on to experience a second AUD episode (i.e., a recurrence) after a minimum 12-month asymptomatic recovery period. Risk for recurrence remained relatively high within the 5 years following initial AUD offset. CONCLUSIONS: AUDs are common lifetime conditions in representative samples, whereby most affected individuals by age 30 experience a time-limited course rather than a recurring or persistent course. PMID- 30399500 TI - Historical trends in the grade of onset and sequence of cigarette, alcohol, and marijuana use among adolescents from 1976-2016: Implications for "Gateway" patterns in adolescence. AB - INTRODUCTION: In the past decade, marijuana use prevalence among adolescents has remained relatively steady while cigarette and alcohol prevalence has declined. We examined historical trends in: average grade of onset of marijuana, alcohol, and cigarette use by 12th grade; proportion who try alcohol/cigarettes before first marijuana use, among those who use by 12th grade; and conditional probability of marijuana use by 12th grade after trying alcohol/cigarettes. METHODS: Data were drawn from 40 yearly, cross-sectional surveys of 12th grade US adolescents. A subset of students (N = 246,050) were asked when they first used each substance. We reconstructed cohorts of substance use from grade-of-onset to determine sequence of drug use, as well as probability of marijuana use in the same or later grade. RESULTS: Average grade of first alcohol and cigarette use by 12th grade increased across time; e.g., first cigarette increased from grade 7.9 in 1986 to 9.0 by 2016 (beta=0.04, SE = 0.001, p < 0.01). The proportion of 12th grade adolescents who smoke cigarettes before marijuana fell below 50% in 2006. Each one-year increase was associated with 1.11 times increased odds of first cigarette in a grade after first marijuana (95% C.I. 1.11-1.12). Among those who initiate alcohol/cigarettes prior to marijuana by 12th grade, the probability of subsequent marijuana use is increasing. CONCLUSION: Marijuana is increasingly the first substance in the sequence of adolescent drug use. Reducing adolescent smoking has been a remarkable achievement of the past 20 years; those who continue to smoke are at higher risk for progression to marijuana use. PMID- 30399501 TI - A first investigation of tongue, lip, and jaw movements in persons with dysarthria due to multiple sclerosis. AB - BACKGROUND: Multiple sclerosis can affect the speech motor system and result in dysarthria. OBJECTIVES: This pilot study sought to identify tongue, lip, and jaw motor deficits in persons with dysarthria due to multiple sclerosis (PwDMS) to better understand the speech motor mechanisms that underlie their aberrant speech. METHODS: Tongue and jaw movements during "ai" and lower lip and jaw movements during "bob"were examined in eleven PwDMS and fourteen age- and sex matched controls using three-dimensional electromagnetic articulography. Movement duration, maximum displacement, peak speed, stiffness (i.e., peak speed/displacement ratio), and jaw contribution to lower lip and tongue displacements were of particular interest. RESULTS: Whereas most kinematic measures yielded significant between-group differences for tongue and jaw motor performance during "ai", lower lip and jaw motor performance during "bob" were mostly comparable between groups. CONCLUSION: Findings suggest that speech movements of the tongue are differentially more impaired than those of the lower lip in PwDMS. Particularly the ability to move the tongue with adequate speed during speech was significantly impaired in PwDMS, which may explain, in part, their slowed speech rate. Aberrant jaw kinematics during "ai" may be a compensatory strategy to maximize speech clarity in the presence of the impaired tongue motor performance. PMID- 30399503 TI - Rise and shine: A treatment experiment testing a morning routine to decrease subjective sleep inertia in insomnia and bipolar disorder. AB - Sleep inertia involves decreased performance or disorientation upon waking that lasts several hours and impairs functioning. Though sleep inertia is common in insomnia and may interfere with treatment, Cognitive Behavioral Therapy for Insomnia (CBTI) does not routinely include a component to address sleep inertia. The present study evaluates such a component, the RISE-UP routine, in CBTI for insomnia comorbid with bipolar disorder. We hypothesized that the RISE-UP routine would increase physical activity in the morning and reduce the duration and severity of self-reported sleep inertia. Sleep and sleep inertia were monitored in the week prior to and following the intervention with daily sleep diaries, actigraphy, and ecological momentary assessment (EMA). Participants were randomized to a bipolar-specific modification of CBT-I (CBTI-BP) with RISE-UP (N = 20) or a psychoeducation (PE) comparison condition (N = 20). The treatment experiment (RISE-UP vs PE) was completed in the first treatment session. RISE-UP reduced the duration and severity of self-reported sleep inertia, as measured by diary reports and by EMA ratings, and was rated as acceptable and credible. Compliance was high, and increases in morning activity levels were verified via actigraphy. Addressing morning sleep inertia via behavioral modifications upon waking may be a useful addition to CBTI. PMID- 30399502 TI - Surveillance and molecular characterization of human adenovirus in patients with acute gastroenteritis in the era of rotavirus vaccine, Brazil, 2012-2017. AB - BACKGROUND: In Brazil, limited data are available regarding the incidence and molecular epidemiology of Human Adenovirus (HAdV) in diarrheic disease, especially in the post rotavirus (RVA) vaccine era. OBJECTIVE: The aims of the study were to investigate the frequency of HAdV infections in patients with gastroenteritis during a 6-year period (2012-2017); conduct molecular typing of positive strains, and obtain further information on the HAdV seasonality. STUDY DESIGN: A total of 3003 fecal samples negative for both, RVA and Norovirus, were selected and tested for HAdV by PCR. Positive HAdV samples were sequenced to obtain genotype identification. RESULTS: HAdV was detected in 3.9% (117/3003); 76 belong to species F (70 HAdV-F41; 6 HAdVF40), 31 to species C (15 HAdV-C1; 13 HAdV-C2; 3 HAdV-C5), 5 belong to species D (3 HAdVD56 and 2 untyped), 4 belong to species A (2 HAdV-A12; 2 HAdV-A31), and 1 belong to HAdVB3. Detection rate significantly varied according to the year, suggesting that HAdV infections show a tendency to occur in natural oscillatory fluctuation. No consistent seasonal pattern was identified. Children <=5 years exhibited higher positivity rate, reinforcing that HAdV is an important pathogen in childhood diarrhea. Genetic analysis indicated that HAdV strains circulating in Brazil were closely related to worldwide strains, and there is no evidence for the introduction of a particular HAdV variant in the country. CONCLUSIONS: The present investigation does not suggest that HAdV has assumed an epidemiological importance in Brazil after the RVA vaccine introduction and contributed to the definition of the clinical and public health significance of HAdV infections. PMID- 30399504 TI - Prevalence of auditory pseudohallucinations in adult survivors of physical and sexual trauma with chronic post-traumatic stress disorder (PTSD). AB - Auditory Verbal Hallucinations (AVHs) are commonly associated with psychosis but are also reported in post-traumatic stress disorder (PTSD). Hearing voices after the experience of stress has been conceptualised as a dissociative experience. Brewin and Patel's (2010) seminal study reported that hearing voices is relatively common in PTSD, as hearing voices was associated with PTSD in half and two thirds of military veterans and survivors of civilian trauma, respectively. The authors conceptualised these voices as "auditory pseudohallucinations." To build upon this work, we administered Brewin and Patel's' interview to adult survivors (n = 40) of physical and sexual trauma with chronic PTSD, and healthy controls (n = 39). In contrast to previous findings, only 5% (n = 2) of our PTSD sample reported recently hearing a voice that was consistent with an auditory pseudohallucination, with no reports in our control group. Thus, no support was provided for auditory pseudohallucinations as a significant symptom in this population. PMID- 30399505 TI - Cysteine proteases secreted by the pinewood nematode, Bursaphelenchus xylophilus: In silico analysis. AB - The pinewood nematode, Bursaphelenchus xylophilus, is an important plant parasitic nematode responsible for the development of the pine wilt disease and recognised as a major forest pest. Previous studies on the comparison of B. xylophilus and B. mucronatus secretomes obtained under maritime pine, Pinus pinaster, wood extract stimulus revealed that several cysteine proteases were increased in B. xylophilus secretome. In nematodes, proteases are known to play critical roles in parasitic processes like tissue penetration, digestion of host tissues for nutrition and evasion of host immune response. To gain further insight into the possible role of cysteine proteases on B. xylophilus pathogenicity, the molecular characterisation of four secreted cysteine peptidases was performed. BxCP3 and BxCP11 were identified as cathepsin L-like proteins and BxCP7 and BxCP8 as cathepsin B proteins. Only BxCP8 revealed high homology with another B. xylophilus cathepsin B referred on GenBank, all the others differ from the closer proteins deposited in this database. In silico three-dimensional structures of the four BxCP suggest that these proteins are pro enzymes that become active when the pro-peptide is cleaved. BxCP7 and BxCP8 predicted structures revealed the presence of an occluding loop that occludes the active site cleft, typical of cathepsin B proteases. PMID- 30399506 TI - Expression of vitamin D receptor in the porcine uterus and effect of 1,25(OH)2D3 on progesterone and estradiol-17beta secretion by uterine tissues in vitro. AB - Vitamin D3 acting via its nuclear receptor (VDR) was shown to target many reproductive tissues and regulate their function. Nevertheless, little is known about the role of vitamin D3 and VDR in the uterus. We hypothesized that VDR expression profile varies in the porcine uterus throughout the course of the estrous cycle, and 1,25(OH)2D3 influences uterine steroidogenic activity. The aim of this study was to investigate VDR mRNA expression, VDR protein abundance and immunolocalization in the porcine endometrium and myometrium harvested on Days 2 5, 12-13, 15-16 and 18-20 of the estrous cycle. Additionally, in studied pigs, 25OHD concentration in plasma and uterine flushings was determined by RIA. The effect of 1,25(OH)2D3 (10, 50 and 100 ng/mL) in vitro on progesterone (P4) and estradiol-17beta (E2) release by endometrial and myometrial slices obtained on Days 12-13 of the estrous cycle was also examined. Nuclear VDR immunostaining was found in endometrial (luminal and glandular epithelium, stromal cells) and myometrial cells throughout examined days of the estrous cycle. In the endometrium, the highest VDR mRNA expression was observed on Days 12-13 and 18 20, whereas the greatest VDR protein abundance was noted only on Days 12-13 of the estrous cycle. In the myometrium, either VDR transcript or protein level was the greatest on Days 12-13. Interestingly, the highest 25OHD concentration in plasma and uterine flushings was shown also on Days 12-13 of the estrous cycle. 1,25(OH)2D3 did not affect P4 release by uterine slices while myometrial release of E2 was significantly increased in response to 1,25(OH)2D3 (10 and 50 ng/mL). Overall, obtained results indicate that porcine uterus is a target tissue for vitamin D3 throughout the entire estrous cycle. VDR mRNA expression and protein abundance altered within uterine tissues depending on studied days of the estrous cycle with the greatest protein abundance during mid-luteal phase of the estrous cycle in both uterine tissues. In addition, 1,25(OH)2D3 significantly increased myometrial release of E2 on Days 12-13 of the estrous cycle. These results suggest the role of vitamin D3-VDR system in the uterus, especially as a regulator of myometrial estrogenic activity in pigs during mid-luteal phase of the estrous cycle. PMID- 30399507 TI - A collaborative computer aided diagnosis (C-CAD) system with eye-tracking, sparse attentional model, and deep learning. AB - Computer aided diagnosis (CAD) tools help radiologists to reduce diagnostic errors such as missing tumors and misdiagnosis. Vision researchers have been analyzing behaviors of radiologists during screening to understand how and why they miss tumors or misdiagnose. In this regard, eye-trackers have been instrumental in understanding visual search processes of radiologists. However, most relevant studies in this aspect are not compatible with realistic radiology reading rooms. In this study, we aim to develop a paradigm shifting CAD system, called collaborative CAD (C-CAD), that unifies CAD and eye-tracking systems in realistic radiology room settings. We first developed an eye-tracking interface providing radiologists with a real radiology reading room experience. Second, we propose a novel algorithm that unifies eye-tracking data and a CAD system. Specifically, we present a new graph based clustering and sparsification algorithm to transform eye-tracking data (gaze) into a graph model to interpret gaze patterns quantitatively and qualitatively. The proposed C-CAD collaborates with radiologists via eye-tracking technology and helps them to improve their diagnostic decisions. The C-CAD uses radiologists' search efficiency by processing their gaze patterns. Furthermore, the C-CAD incorporates a deep learning algorithm in a newly designed multi-task learning platform to segment and diagnose suspicious areas simultaneously. The proposed C-CAD system has been tested in a lung cancer screening experiment with multiple radiologists, reading low dose chest CTs. Promising results support the efficiency, accuracy and applicability of the proposed C-CAD system in a real radiology room setting. We have also shown that our framework is generalizable to more complex applications such as prostate cancer screening with multi-parametric magnetic resonance imaging (mp-MRI). PMID- 30399508 TI - Salivary biomarkers of inflammation and oxidative stress in healthy adults. AB - OBJECTIVES: Diagnostic value of saliva depends on the reproducibility of data in repeatedly collected samples and predictable correlations between saliva and blood. We aimed to investigate the reliability, blood reflectance, and influence of blood contamination in the analysis of inflammatory and oxidative stress biomarkers in saliva samples. DESIGN: In total, 37 healthy young male participants (26.7 +/- 2.2 years) were included. Unstimulated whole saliva and blood samples were collected on the first visit, and saliva samples were collected again after 2-3 days. The concentrations of total protein and inflammatory [C-reactive protein (CRP), IL-1beta, IL-6, and TNF-alpha] and oxidative stress [8-hydroxy-2'-deoxyguanosine (8-OHdG), malondialdehyde (MDA), and total antioxidant capacity (TAC)] biomarkers in saliva and blood, and as well as blood contamination biomarkers (transferrin and hemoglobin) in saliva were analyzed. RESULTS: The intra-class correlations of all examined biomarkers except TNF-alpha were fair to excellent. Significant positive correlations between CRP and IL-6 and between total protein and TAC were stable in the saliva samples collected on different days. Notably, IL-6 was the only biomarker that showed a significant correlation between saliva and blood. As the concentration of salivary transferrin increased, the saliva/blood ratios of total protein and TAC also increased. The concentration of salivary hemoglobin did not affect the saliva/blood ratios of biomarkers. CONCLUSIONS: The findings of this study are limited to healthy young males. For clinical applications, studies on salivary diagnostics should be performed for individual disease and health conditions, demographic characteristics, and biomarkers. PMID- 30399510 TI - Breastfeeding initiation and duration in France: The importance of intergenerational and previous maternal breastfeeding experiences - results from the nationwide ELFE study. AB - OBJECTIVE: To assess the role of the mother's mother and mothers' previous personal experiences with breastfeeding and childcare in breastfeeding practices. DESIGN AND SETTING: The analysis included 13,774 mother-infant dyads from the French national birth cohort ELFE. Feeding practices were assessed by face-to face interview in maternity wards in 2011, by phone interviews at months 2 and 12 post-partum and by Internet/paper questionnaires monthly from months 3-10. Sociodemographic, maternal and newborn-related factors were collected in the maternity unit and by postnatal phone interview at month 2. Multivariable logistic and linear regression was used to assess the association of mother's mother and mothers' previous personal experiences with breastfeeding initiation and duration. FINDINGS: Previous breastfeeding experience (i.e., whether mothers had breastfed their previous children) was positively associated with both breastfeeding initiation and duration. Mothers who had been breastfed themselves as infants were more likely to initiate and continue breastfeeding than non breastfed mothers. Conversely, non-breastfed mothers who had received care advice from their own mother were less likely to start and maintain breastfeeding. The effect of having been breastfed in infancy was especially important for primiparous mothers and to a lesser extent, multiparous mothers with no previous breastfeeding experience. Also, formal experience in childcare, in a professional context, was associated with breastfeeding initiation but not duration. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Mother's mother and mother's previous breastfeeding experience have a strong influence on breastfeeding practices. Breastfeeding interventions should be tailored to the mother's level of experience and should provide extra support for multiparous mothers with no previous breastfeeding experience. PMID- 30399509 TI - Expression of human and Porphyromonas gingivalis glutaminyl cyclases in periodontitis and rheumatoid arthritis-A pilot study. AB - OBJECTIVES: Human glutaminyl cyclases (QC and isoQC) play an important role in maintaining inflammatory conditions. Meanwhile a glutaminyl cyclase synthesized by Porphyromonas gingivalis (PgQC), a key pathogen in developing periodontitis and a potential link of periodontitis with rheumatoid arthritis (RA), was discovered. This study was aimed to determine the expression of QC, isoQC and PgQC in patients with chronic periodontitis (CP) and RA. DESIGN: Thirty volunteers were enrolled in a pilot study and divided into 3 groups (healthy, CP and RA individuals). Blood samples, biofilm and gingival crevicular fluid (GCF) were analysed for mRNA expression of QC, isoQC and P. gingivalis QC. Major bacteria being associated with periodontal disease were quantified in subgingival biofilm and protein levels for monocyte chemoattractant protein (MCP)-1, MCP-3 and interleukin (IL)-1beta) were determined in the GCF. Expression of PgQC on the mRNA and protein levels was assessed in two P. gingivalis strains. RESULTS: PgQC is expressed in P. gingivalis strains and the protein seems to be located mainly in peri-plasmatic space. mRNA expression of QC was significantly increased in the peripheral blood from RA patients vs. healthy subjects and CP patients (p = 0.013 and p = 0.003, respectively). In GCF of RA patients, QC mRNA was detected more frequently than in healthy controls (p = 0.043). In these samples IL-1beta levels were also elevated compared to GCF from periodontally healthy individuals (p = 0.003). PgQC was detected in eight out of the 13 P. gingivalis positive biofilm samples. CONCLUSION: Activity of QC may play a supportive role in maintaining chronic periodontal inflammation and destruction in RA. PgQC is expressed in vivo but further research is needed to evaluate biological importance of this enzyme and if it constitutes a potential target in periodontal antimicrobial therapy. PMID- 30399511 TI - Castleman disease: Case series of two surgical patients from different ends of the disease spectrum with literature review. AB - Castleman Disease (CD) is a rare, heterogeneous group of hyperimmune lymphoproliferative disorders, not very familiar to surgeons. Unicentric Castleman Disease (UCCD) at one end of the spectrum is a localized disease, with little or no systemic symptoms. It may be an incidental radiological finding or detected while investigating for a symptomatic lymph node mass. Surgery is the primary treatment and has good long term prognosis. Multicentric Castleman Disease (MCCD) is a more serious systemic condition, often associated with constitutional symptoms. Exaggerated systemic inflammatory response secondary to "Cytokine storm" involving Interleukin-6 (IL-6) may cause multi-organ dysfunction. In addition, immunosuppression or malignant transformation can prove lethal. Human Herpes Simplex Virus 8 (HHV8) associated MCCD is a major subgroup occurring in immunocompromised individuals due to the viral trigger. Antiviral therapy is important in its treatment. Idiopathic MCCD (IMCCD) has no known biomarker and is diagnosed after excluding infective, autoimmune and malignant conditions of lymphoid tissue. IMCCD requires systemic therapy. We report a patient of UCCD who presented as a retroperitoneal mass in right iliac fossa causing pressure on femoral nerve. Following successful surgical excision she had good recovery. We report another patient who had large inguinal lymph node mass with constitutional symptoms. IMCCD was diagnosed after excision biopsy and comprehensive work up. Patient was started on corticosteroids followed by CD-20 targeted therapy. These two cases showcase the two ends of the clinical spectrum of CD requiring different management protocols. Awareness among surgeons and diligent work-up is imperative for early diagnosis and best outcome. PMID- 30399512 TI - An Abies procera-derived tetracyclic triterpene containing a steroid-like nucleus core and a lactone side chain attenuates in vitro survival of both Fasciola hepatica and Schistosoma mansoni. AB - Two economically and biomedically important platyhelminth species, Fasciola hepatica (liver fluke) and Schistosoma mansoni (blood fluke), are responsible for the neglected tropical diseases (NTDs) fasciolosis and schistosomiasis. Due to the absence of prophylactic vaccines, these NTDs are principally managed by the single class chemotherapies triclabendazole (F. hepatica) and praziquantel (S. mansoni). Unfortunately, liver fluke resistance to triclabendazole has been widely reported and blood fluke insensitivity/resistance to praziquantel has been observed in both laboratory settings as well as in endemic communities. Therefore, the identification of new anthelmintics is necessary for the sustainable control of these NTDs in both animal and human populations. Here, continuing our work with phytochemicals, we isolated ten triterpenoids from the mature bark of Abies species and assessed their anthelmintic activities against F. hepatica and S. mansoni larval and adult lifecycle stages. Full 1H and 13C NMR mediated structural elucidation of the two most active triterpenoids revealed that a tetracyclic steroid-like nucleus core and a lactone side chain are associated with the observed anthelmintic effects. When compared to representative mammalian cell lines (MDBK and HepG2), the most potent triterpenoid (700015; anthelmintic EC50s range from 0.7 MUM-15.6 MUM) displayed anthelmintic selectivity (selectivity indices for F. hepatica: 13 for newly excysted juveniles, 46 for immature flukes, 2 for mature flukes; selectivity indices for S. mansoni: 14 for schistosomula, 9 for immature flukes, 4 for adult males and 3 for adult females) and induced severe disruption of surface membranes in both liver and blood flukes. S. mansoni egg production, a process responsible for pathology in schistosomiasis, was also severely inhibited by 700015. Together, our results describe the structural elucidation of a novel broad acting anthelmintic triterpenoid and support further investigations developing this compound into more potent analogues for the control of both fasciolosis and schistosomiasis. PMID- 30399514 TI - Factors associated with cannabis use change in youth: Evidence from the COMPASS study. AB - INTRODUCTION: Harmful effects of cannabis use in youth scale with frequency. In the context of approaching legalization in Canada, understanding the distinctions between youth who change and who maintain their cannabis use is essential for designing interventions and policy. A substantial number of characteristics may play a role. This study assessed whether and how youth who change their cannabis use differ from those who do not. METHODS: Cannabis use was reported by 8375 Canadian high school students participating in the COMPASS study. GEE multiple logistic regressions were then used to establish impact of 13 baseline demographic and behavioural exposure variables on the likelihood of membership in four frequency change groups at follow-up a year later: reduction, cessation, escalation, and maintenance. RESULTS: Groups were found to differ in several ways. Cessation group members (19.4% of users) were less likely to binge drink (OR 0.82), vape (OR 0.82), or attend class without completing homework (OR 0.72) than maintainers. Students who reduced their use (14.6% of users) were more likely to binge drink (OR 1.36), smoke (OR 1.20), and skip class (OR 1.21). Those who escalated (29.5% of users) were more likely to be male (OR 1.35) and to vape (OR 1.22). CONCLUSIONS: Students who change their cannabis use differ in several demographic and behavioural characteristics. The results raise further concerns about the impact of e-cigarettes and the role of poly-substance use in high-risk trajectories. Distinct classes of cannabis users, essential for policy and intervention development, can be identified in high school populations. PMID- 30399513 TI - Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania. AB - Previous work from our group showed that tamoxifen, an oral drug that has been in use for the treatment of breast cancer for over 40 years, is active both in vitro and in vivo against several species of Leishmania, the etiological agent of leishmaniasis. Using a combination of metabolic labeling with [3H]-sphingosine and myo-[3H]-inositol, alkaline hydrolysis, HPTLC fractionations and mass spectrometry analyses, we observed a perturbation in the metabolism of inositolphosphorylceramides (IPCs) and phosphatidylinositols (PIs) after treatment of L. amazonensis promastigotes with tamoxifen, with a significant reduction in the biosynthesis of the major IPCs (composed of d16:1/18:0-IPC, t16:0/C18:0-IPC, d18:1/18:0-IPC and t16:0/20:0-IPC) and PIs (sn-1-O-(C18:0)alkyl 2-O-(C18:1)acylglycerol-3-HPO4-inositol and sn-1-O-(C18:0)acyl-2-O (C18:1)acylglycerol-3-HPO4-inositol) species. Substrate saturation kinetics of myo-inositol uptake analyses indicated that inhibition of inositol transport or availability were not the main reasons for the reduced biosynthesis of IPC and PI observed in tamoxifen treated parasites. An in vitro enzymatic assay was used to show that tamoxifen was able to inhibit the Leishmania IPC synthase with an IC50 value of 8.48 MUM (95% CI 7.68-9.37), suggesting that this enzyme is most likely one of the targets for this compound in the parasites. PMID- 30399515 TI - Reduced graphene oxide biosensor platform for the detection of NT-proBNP biomarker in its clinical range. AB - Reduced graphene oxide (rGO) thin films can be exploited as highly sensitive transducer layers and integrated in interdigital micro-electrode systems for biosensing processes. The distinctive bipolar characterisitics of rGO thin films can be modulated by a very low external electric field due to the electrostatic charges of biomolecules. These charges lead to a fast response in the readout signals of rGO based ion sensitive field-effect transistors (ISFETs). The characterisitc changes of rGO ISFETs enable a fast, accurate and reproducible detection of biomolecules. The biosensing mechanism offers a fast and label-free approach for analyte detection in contrast to the classical ELISA method. In this contribution, we introduce a reproducible fabrication process of rGO based field effect transistors on wafer level. The sensors are functionalized as biosensors to measure N-terminal pro-brain natriuretic peptide (NT-proBNP) in human serum within its clinical range. Our optimized rGO sensor shows very promising electrical properties and can be considered as a proof of concept study for the detection of various analytes. The easy and cost-effective fabrication as well as the versatile usability make this new technological platform an auspicious tool for different sensing applications in future. PMID- 30399516 TI - Label-free aptasensor for the detection of cardiac biomarker myoglobin based on gold nanoparticles decorated boron nitride nanosheets. AB - A novel electrochemical aptasensor based on gold nanoparticles decorated on boron nitride nanosheets (AuNPs/BNNSs) for the sensitive and selective detection of myoglobin (Mb) is reported. BNNSs were chemically synthesized by a low-cost and simple hydrothermal method. They were deposited onto the fluorine-doped tin oxide (FTO) electrode by a spin-coating method. Subsequently, AuNPs were chemically deposited onto the BNNS/FTO electrode by a seed-mediated chemical reduction method, with an average particle size of approximately 10 nm. The AuNPs/BNNSs/FTO electrode was used as a transducer to immobilize a thiol-functionalized DNA aptamer (Apt) via the covalent interaction of Au-S for the specific binding of Mb. [Fe(CN)6]3-/4- was used as a redox probe to monitor the oxidation current variation upon the binding of Mb with varying concentrations onto the sensor surface. The Apt/AuNPs/BNNSs/FTO sensor shows a high signal response for Mb with a detection limit of 34.6 ng/mL and a dynamic response range of 0.1-100 ug/mL. It is a promising candidate for point-of-care diagnosis in real samples. This strategy could make possible the application of other 2D materials with wide bandgaps for the development of biosensors. PMID- 30399517 TI - A dual-signal readout enzyme-free immunosensor based on hybridization chain reaction-assisted formation of copper nanoparticles for the detection of microcystin-LR. AB - Enzyme-based electrochemical biosensors are widely used in immunoassays, but the intrinsic disadvantages of enzymes including instability or sensitivity to temperature and pH should be considered. Herein, an enzyme-free and dual-signal readout immunoassay was established to detect microcystin-LR (MC-LR) sensitively and selectively. Firstly, the microplate was modified with gold nanoparticles decorated-carbon nanotubes (AuNP-CNT) to immobilize sufficient antigens by the high surface area of CNT and high affinity of AuNP. Then, silver nanoparticles were decorated on gold nanorods to form corn-like AgNP/AuNR composite and then capture secondary antibody and initiator DNA strand. After hybridization chain reaction, long double helix DNA strands can be formed on AgNP/AuNR to germinate copper nanoparticles. A dual-signal readout from the current responses of both silver and copper ions was obtained by using differential pulse stripping voltammetry with the aid of acid-treatment. By using a competitive immunoreaction, MC-LR can be detected in a linear range from 0.005 MUg/L to 20 MUg/L with a lower detection limit of 2.8 ng/L. The reproducibility, stability and specificity were all acceptable, indicating its promising application in environment monitoring and sensitive electrochemical detection for other analytes. PMID- 30399518 TI - An ultrasensitive photoelectrochemical biosensor for glucose based on bio-derived nitrogen-doped carbon sheets wrapped titanium dioxide nanoparticles. AB - In this work, an ultra-sensing photoelectrochemical (PEC) glucose biosensor has been constructed from the bio-derived nitrogen-doped carbon sheets (NDC) wrapped titanium dioxide nanoparticles (NDC-TiO2 NPs) followed by the covalent immobilization of glucose oxidase (GODx) on them (designated as a GODx/NDC TiO2NPs/ITO biosensor). Initially, the TiO2 NPs was synthesized by sol-gel method and then NDC-TiO2 NPs was synthesized utilizing a green source of Prunus persica (peach fruit) through a simple hydrothermal process. The synthesized NDC-TiO2 NPs composite was characterized by FESEM, HRTEM, Raman spectroscopy, XRD, ATR-FTIR spectroscopy and XPS to determine composition and phase purity. These fabricated GODx/NDC-TiO2NPs/ITO biosensor exhibited a good charge separation, highly enhanced and stable photocurrent responses with switching PEC behavior under the light (lambda > 400 nm). As a result, GODx/NDC-TiO2NPs/ITO PEC glucose sensor exhibits a good photocurrent response to detection of glucose concentrations (0.05-10 MUM) with an ultra-low detection limit of 13 nM under optimized PEC experimental conditions. Also, the PEC glucose sensor revealed a high selectivity, good stability, long time durability, and capability to analyze the glucose levels in real human serum. Also, the further development of this work may provide new insights into preparing other bio-derived carbon nanostructure based photocatalysts for PEC applications. PMID- 30399520 TI - Religious attitudes to gamete donation. AB - Religious teachings encourage fertility. The rapid progress of reproductive science has proved a challenge to interpret and adapt to assisted reproductive techniques which were not even dreamed of in ancient scriptures. The clash between religion and science has produced separate laws for each religion and reproductive practitioners are often at a loss to understand and accept them. Four lay members of different religions have set out the thinking of their religion regarding assisted reproductive techniques, concentrating in particular on gamete donation. Similarities rather than differences seem to dominate in the attitudes of the orthodox Catholic, Hindu, Jewish and Muslim beliefs and doctrines. The knowledge of these various religious beliefs and attitudes, as well as promoting a greater understanding, should help reproductive practitioners to accept and abide by the religious wishes of their patients. PMID- 30399519 TI - Significant enhancement of direct electric communication across enzyme-electrode interface via nano-patterning of synthetic glucose dehydrogenase on spatially tunable gold nanoparticle (AuNP)-modified electrode. AB - In this study, the effect of inter-enzyme steric hindrance that occurs during enzyme immobilization on the electrode, on direct electrical communications of enzyme with electrode was investigated via nano-patterning of enzymes on the electrode. Here, the nano-patterning of enzymes was achieved through the combination of DET-capable enzyme that was produced via fusion of site-specific gold binding peptide (GBP) to catalytic subunit of enzyme and gold nanoparticle (AuNP) array with highly tunable dimensions of AuNPs, resulting in spatially controllable enzyme-electrode. The nano-scale spatial control between immobilized enzymes on the highly tuned AuNPs shows different DET efficiency across the enzyme-electrode interface, showing 18.47% of maximum electron recovery which is 3.2-fold enhanced electron recovery efficiency compared to spatially non controlled enzymes on the electrode where showed 5.7% of electron recovery. The result affirms that inter-enzyme interaction is a significant parameter that decides the enzyme-electrode performance. PMID- 30399521 TI - Optimal recording duration of ambulatory EEG (aEEG). PMID- 30399522 TI - Exploring the utility of Analytic Hierarchy Process (AHP) in ranking livelihood activities for effective and sustainable rural development interventions in developing countries. AB - It is commonly known that most development projects, especially in the global south, tend to achieve unintended results or fail because of lack of due diligence. Project satisfaction and sustainability would only be achieved if consistent with the actual needs of the people intended to benefit. Based on field experiences in the Fantekwa District of Eastern Ghana, this study aims to explore the utility of the Analytic Hierarchy Process (AHP) in prioritizing livelihood activities to aid in effective and sustainable poverty reduction interventions in developing countries. Data from twenty five development stakeholders in the district were used for the assessment. The study demonstrates that with appropriate data, and systematically following all required processes, the AHP approach can effectively show where intervention is most needed. Application of AHP in the current context, the study argues, has the potential to address the issue of wrong development targeting with associated counterproductive and nonstarter outcomes. PMID- 30399524 TI - Validation of the Revised Children's Anxiety and Depression Scales (RCADS) and RCADS short forms adapted for adults. AB - BACKGROUND: The life span nature of anxiety and depression has led to an interest in whether assessments designed for use with children and young people are also valid for adults. The Revised Children's Anxiety and Depression Scales (RCADS) is a commonly used measure and we aimed to explore its structural validity in adults. METHODS: We examined the factorial validity of the original and two short form versions of the (RCADS) adapted for adults, using confirmatory factor analysis with a convenience sample (n = 371) aged 18-67. RESULTS: All versions of the RCADS were found to provide reliable measures of general anxiety and depression in adults and of most subdimensions of anxiety corresponding to the original version of the RCADS. However, anxiety subdimension reliability was primarily driven by the strong general anxiety dimension, due to the high comorbidity between anxiety subtypes. LIMITATIONS: We did not include data for children as well as adults in our analyses and small changes were made to the wording of five RCADS items to make them appropriate for adults. CONCLUSIONS: Results suggest that all versions could be helpful for longitudinal and comparative research and evaluation of clinical outcomes, in situations where the focus is on general anxiety and depression, rather than clinical subtypes. PMID- 30399525 TI - Pedestrian injuries due to collisions with cyclists Melbourne, Australia. AB - Over the past decade in Melbourne the popularity of cycling has increased both as a mode of transport and a recreational activity, while at the same time walking has consistently been the most prevalent form of physical activity. Increasing levels of active transport use and physical activity are seen as important public health issues, particularly as the rate of urbanisation continues to grow throughout the world. To date there has been limited research conducted in Australia looking at the prevalence of pedestrian injuries resulting from collisions with cyclists. However there is a potential for the issues surrounding pedestrian and cyclist conflict to increase, given the growing uptake of these modes of transport, the continued densification of the urban environment and the lack of cycling specific infrastructure in many Australian capital cities. This study investigated the prevalence of pedestrian injuries resulting from collisions with cyclists in Melbourne, Australia. The intention was to quantify the extent of these collisions and identify if the rate of collisions was increasing, which may highlight a growing road safety issue. Furthermore the study sought to identify any unique characteristic and injury outcomes associated with this collision type. Aggregate analyses of two Victorian data sources were undertaken to enhance our understanding of pedestrian injuries resulting from collisions with cyclists, the Victorian Injury Surveillance Unit (VISU) and Victorian Police Report Crash Data (Crash Stats). The analysis demonstrated that over the past ten years there does not appear to have been a substantial increase in the number of pedestrian injuries resulting from collisions with cyclists. Furthermore the prevalence of injuries was small, especially when compared to injuries sustained by pedestrians from collisions with motor vehicles. The findings highlight that efforts to increase active transport participation should be encouraged and there may be situations where is it suitable to increase interaction and sharing of space between pedestrians and cyclists. PMID- 30399523 TI - Corrigendum to An overview of the safety pharmacology society strategic plan [Journal of Pharmacological and Toxicological Methods 93 (2018) 35-45]. PMID- 30399527 TI - Pathological correlates of brain arterial calcifications. AB - BACKGROUND: In clinical practice, calcifications seen on computed tomographic studies within the large brain arteries are often referred to as a surrogate marker for cholesterol-mediated atherosclerosis. However, limited data exist to support the association between calcification and atherosclerosis. In this study, we examined if intracranial arterial calcifications were associated with cholesterol-mediated intracranial large artery atherosclerosis (ILAA) within the arteries of the circle of Willis in an autopsy-based sample. METHODS: We carried out a cross-sectional analysis of histopathological characteristics of brain large arteries obtained from autopsy cases. Brain large arteries were examined for evidences of calcifications, which were rated as macroscopic (coalescent) and microscopic (scattered). In addition to calcification, we also obtained measurement of the arterial wall and the presence of ILAA and nonatherosclerotic arterial fibrosis. We built hierarchical models adjusted for demographic and vascular risk factors to assess the relationship between calcification and ILAA. RESULTS: In univariate analysis, the presence of any arterial calcifications was associated with cerebral infarcts (29% vs. 14%, P<.01). Multivariate analysis revealed that among all calcifications, coalescent calcifications were not associated with ILAA. In contrast, scattered calcifications were associated with ILAA (P<.001), decreased lumen diameter (-1.87 +/- 0.41 mm, P<=.001), and increased luminal stenosis (0.03% +/- 0.01%, P<=.006). These findings were independent of age, sex, or other vascular risk factors. CONCLUSIONS: This study demonstrates that coalescent calcifications in brain large arteries, although associated with morbidity, are not synonymous with cholesterol-driven ILAA. Understanding the precise pathological components of cerebrovascular disease, including nonatherosclerotic arterial calcifications, will help develop individualized therapies beyond amelioration of traditional risk factors such as hyperlipidemia. PMID- 30399526 TI - Thrombus on the inflow cannula of the HeartWare HVAD: an update. AB - BACKGROUND: The HeartWare HVAD (Medtronic, Minneapolis, MN) is a continuous-flow left ventricular assist device (LVAD) approved by the FDA in 2012 as a bridge to transplant in patients with end-stage left ventricular heart failure. The current inflow cannula has a smooth outer surface near the inflow edge and a sintered collar of titanium microspheres near the pump. A previous case series of HVAD patients bridged to transplant revealed thrombus on the outer surface of the inflow cannula in 8 of 8 patients, predominantly at the smooth-sintered interface, that was associated with a clinical stroke rate of 12.5%. DESIGN: Cases of HVAD devices removed at the time of heart transplant were identified in the surgical pathology database. The gross and microscopic findings were reviewed along with clinical data. RESULTS: A total of 22 patients with 24 HVAD implants diagnosed with dilated cardiomyopathy (13 patients), ischemic heart disease (4 patients), lymphocytic myocarditis (2 patients), hypertrophic cardiomyopathy (2 patients), and congenital valvular disease (1 patient) were included. Two patients received two HVADs to provide biventricular support. All patients received post-implantation anti-coagulation with an INR goal of 2 to 3. Gross pathologic examination revealed thrombi on the outer aspect of the HVAD inflow cannula in 23 of 24 devices (96%). The inflow cannula of the one device that did not develop thrombus was positioned such that the smooth-sintered interface was buried in the ventricular myocardium and not in contact with blood in the ventricular chamber. Complications during the period of device support included 9 thromboembolic events (41%) including 6 ischemic strokes (27%), 2 intracoronary thromboembolic events and 1 splenic infarct. Patients suffered strokes 4 to 174 days (mean 82) after HVAD placement and had thrombus on the inflow cannula ranging in size from 0.1-2.5 cm (axial), 0.4-4.5 cm (circumferential) and 0.1-0.5 cm (thickness). Histologic evaluation revealed bland, partially organized thrombi without evidence of infection. Other complications included driveline infections (9%), non-driveline related bacteremia (9%) and hemorrhage (5%). CONCLUSIONS: We report here an extension of our original study to a total of 22 patients with 24 HVAD implants who were all successfully bridged to transplant. We validate the very high prevalence of thrombus around the HVAD inflow cannula, associated with a clinical thromboembolic event in over a third of the patients, the majority of which were strokes. The nidus for thrombus formation appears to be the smooth sintered interface of the HVAD inflow cannula. PMID- 30399528 TI - Design, synthesis, anti-inflammatory, cytotoxic and cell based studies of some novel side chain analogues of myrrhanones A & B isolated from the gum resin of Commiphora mukul. AB - Myrrhanones A (1) and B (2), isolated from the gum resin of Commiphora mukul, were reported to exhibit anticancer and anti-inflammatory activities. In view of their interesting skeletal features and biological activities they have been chemically modified by exploiting their side chain functionalities to synthesise 29 diverse analogues. All the synthesized analogues were screened for their cytotoxic potential against a panel of five human cancer cell lines which include DU145 (Prostate), HT-29 (Colon), MCF-7 (Breast), Hela (Cervical) and U87MG (Glioblastoma) along with a normal cell line (L132). The synthesized analogues were also screened for anti-inflammatory activity against TNF-alpha and IL-1beta using LPS induced inflammation model employing U937 cells. The biological screening results revealed that compounds 4b (piperidine analogue), 9d (linear aliphatic four member amide analogue) and 9i (N-methyl piperazine analogue) displayed significant cytotoxic activity against MCF-7, HT-29 and DU145 [IC50 (MUM): 4.65 +/- 1.28, 5.48 +/- 0.13 and 6.63 +/- 1.39] respectively. These analogues were further taken up for apoptotic assay, which confirmed that compounds 4b, 9d and 9i induced apoptosis in MCF-7, HT-29, DU145 cells and arrested in G0/G1 phase. Further, compounds 9c and 9g found to exhibit good anti inflammatory activity against TNF-alpha with IC50 (MUM) values of 10.02 +/- 2.13 and 10.53 +/- 0.48 respectively, while compound 2 exhibited strong inhibitory activity against both TNF-alpha (IC50: 9.39 +/- 0.44 MUM) and IL-1beta (IC50: 12.15 +/- 1.36 MUM). PMID- 30399529 TI - Lambda interferons come to light: dual function cytokines mediating antiviral immunity and damage control. AB - Lambda interferons (IFNlambdas, type III IFNs or interleukins-28/29) were described fifteen years ago as novel cytokines sharing structural and functional homology with IL-10 and type I IFNs, respectively. IFNlambdas engage a unique receptor complex comprising IFNLR1 and IL10R2, nevertheless they share signaling cascade and many functions with type I IFNs, questioning their possible non redundant roles and overall biological importance. Here, we review the latest evidence establishing the primacy of IFNlambdas in front line protection at anatomical barriers, mediating antiviral immunity before type I IFNs. We also discuss their emerging role in regulating inflammation and limiting host damage, a major difference to type I IFNs. IFNlambdas come thus to light as dual function cytokines mediating antiviral immunity and damage control. PMID- 30399530 TI - Oriented immobilization of a delicate glucose-sensing protein on silica nanoparticles. AB - Silica nanoparticles are widely used platform materials for the immobilization of proteins to realize applications in biomedicine and biotechnology. We here report on the use of a highly delicate protein for the systematic evaluation of routes for the surface modification of multifunctional silica nanoparticles. To investigate how surface immobilization methods affect the functionality of surface-bound proteins, we constructed a novel fusion protein, dubbed FlipHOB, that combines the glucose sensor protein FLIP with a variant of the commercially available self-ligating Halo-tag. As indicated by the spectroscopic properties and sensing capabilities of FlipHOB, the oriented immobilization of this protein through its HOB tag domain or DNA-directed immobilization were superior over the non-directional statistical immobilization via glutardialdehyde-mediated cross coupling. Immobilization through double-stranded DNA bridges also allows for the triggered disassembly of FlipHOB nanosensors and the controlled recovery of the sensor protein. We demonstrate that the nanosensors are functional in in vitro settings and can be used for imaging in vivo. We believe that our results show generic strategies and provide essential guidelines for the development of protein-based nanoparticle sensors for applications in the life sciences. PMID- 30399531 TI - Investigating alexithymia in autism: A systematic review and meta-analysis. AB - BACKGROUND: New research suggests that, rather than representing a core feature of autism spectrum disorder (ASD), emotional processing difficulties reflect co occurring alexithymia. Autistic individuals with alexithymia could therefore represent a specific subgroup of autism who may benefit from tailored interventions. The aim of this systematic review and meta-analysis was to explore the nature and prevalence of alexithymia in autism using the Toronto Alexithymia Scale (TAS). METHODS: Online scientific databases were searched systematically for studies on ASD popu lations using the TAS. Meta-analyses were performed to evaluate differences in scores between the ASD and neurotypical groups, and to determine the prevalence of alexithymia in these populations. RESULTS: 15 articles comparing autistic and neurotypical (NT) groups were identified. Autistic people scored significantly higher on all scores compared to the NT group. There was also a higher prevalence of alexithymia in the ASD group (49.93% compared to 4.89%), with a significantly increased risk of alexithymia in autistic participants. CONCLUSIONS: This review highlights that alexithymia is common, rather than universal, in ASD, supporting a growing body of evidence that co-occurring autism and alexithymia represents a specific subgroup in the ASD population that may have specific clinical needs. More research is needed to understand the nature and implications of co-occurring ASD and alexithymia. PMID- 30399532 TI - Accumulation, metabolite and active defence system responses of fluoxetine in zebrafish embryos: Influence of multiwalled carbon nanotubes with different functional groups. AB - Studies on the bioavailability of organic contaminants adsorbed to nanomaterials are increasing. In this study, we investigated the interaction between fluoxetine (FLX) and three multiwalled carbon nanotubes (MWCNTs) with different functional groups in zebrafish (Danio rerio) embryos, focusing on the FLX accumulation, the formation of the metabolite norfluoxetine (NFLX), and the active defence system responses. The accumulation of FLX in zebrafish was intensified by MWCNTs (46 99%), which simultaneously facilitated the formation of the metabolite NFLX by 23 167%. The consistent enhancement revealed that the absorbed FLX is bioavailable in zebrafish. Moreover, the coexisting MWCNTs further promoted the influences of FLX on the active defence system in zebrafish (e.g. antioxidant and metabolic function), eliciting the defence function. The influences of MWCNTs on the bioavailability of FLX in zebrafish could be ordered as OH-MWCNTs > COOH-MWCNTs > pristine MWCNTs. The release of FLX from MWCNTs in biofluids may partially contribute to these significant alterations. In particular, MWCNTs themselves may also modulate the bioavailability of FLX in zebrafish by downregulating the gene expression of membrane ATP-binding cassette transporter (abcb4). These findings demonstrated that MWCNTs increased the bioavailability of FLX in zebrafish, especially the functionalized MWCNTs. The production of metabolites may be a useful bio-endpoint to evaluate the bioavailability of adsorbed contaminants on nanomaterials. PMID- 30399533 TI - Analysis of bupivacaine enantiomers in plasma as total and unbound concentrations using LC-MS/MS: Application in a pharmacokinetic study of a parturient with placental transfer. AB - Bupivacaine, a drug used in obstetric anesthesia and analgesia, is commercially available as a racemic mixture of the R-bupivacaine and S-bupivacaine enantiomers, which show differences in pharmacokinetics, efficacy and toxicity. Changes in bupivacaine plasma protein binding is of clinical relevance considering its high protein binding (approximately 95%) and its classification as an intermediate hepatic extraction ratio drug (E = 0.38). Furthermore, the plasma protein binding of bupivacaine is also of clinical relevance considering that pregnancy is a physiological condition associated with reduced plasma albumin concentration. Also, different pathological conditions, such as pre eclampsia, can reduce the maternal plasma protein concentrations and consequently increase the bupivacaine placental transfer. This report describes the development and validation of analytical methods for the sequential analysis of the total and unbound concentrations of bupivacaine enantiomers in human plasma using liquid chromatography coupled to mass spectrometry (LC-MS/MS) with a sensitivity compatible with application in pharmacokinetic studies including placental transfer. Aliquots of 200 MUL of plasma or plasma ultra-filtrate were extracted with n-hexane in alkaline medium after the deproteinization of the matrix with acetonitrile and water. The separation of bupivacaine enantiomers was obtained on a Chirex(r) 3020 chiral stationary phase column using as a mobile phase a mixture of 95% n-hexane:ethanol (80:20, v/v) at a flow rate of 0.8 mL/min. The lower limit of quantification was 0.25 ng of each enantiomer/mL of plasma as the total concentration and 0.125 ng of each enantiomer/mL of plasma as the unbound concentration. The methods were applied to study the pharmacokinetics of bupivacaine enantiomers after the administration of 2.5 mg of 0.5% racemic bupivacaine hydrochloride with 1:200,000 epinephrine via the epidural route to an HIV-positive parturient woman undergoing antiretroviral treatment. The parturient showed lower AUC0-infinity (25.42 vs. 30.57 ng.h/mL) and higher volume of distribution (841.96 vs 655.05 L) and total clearance (98.34 vs 81.79 L/h) for the R-bupivacaine enantiomer. The pharmacokinetics of bupivacaine were enantioselective displaying a lower plasma proportion of the enantiomer R bupivacaine (AUC(R)/(S) ratio equal to 0.83). The placental transfer was approximately 60% for both bupivacaine enantiomers. The unbound fraction (Fu) for the R-bupivacaine enantiomer was higher (10.84%) than the eutomer S-bupivacaine (6.29%). PMID- 30399534 TI - Tuning parameter estimation in SCAD-support vector machine using firefly algorithm with application in gene selection and cancer classification. AB - In cancer classification, gene selection is one of the most important bioinformatics related topics. The selection of genes can be considered to be a variable selection problem, which aims to find a small subset of genes that has the most discriminative information for the classification target. The penalized support vector machine (PSVM) has proved its effectiveness at creating a strong classifier that combines the advantages of the support vector machine and penalization. PSVM with a smoothly clipped absolute deviation (SCAD) penalty is the most widely used method. However, the efficiency of PSVM with SCAD depends on choosing the appropriate tuning parameter involved in the SCAD penalty. In this paper, a firefly algorithm, which is a metaheuristic continuous algorithm, is proposed to determine the tuning parameter in PSVM with SCAD penalty. Our proposed algorithm can efficiently help to find the most relevant genes with high classification performance. The experimental results from four benchmark gene expression datasets show the superior performance of the proposed algorithm in terms of classification accuracy and the number of selected genes compared with competing methods. PMID- 30399536 TI - Characterization of lingering hope, a new brachytic mutant in sunflower (Helianthus annuus L.) with altered salicylic acid metabolism. AB - Dwarf mutants are useful to elucidate regulatory mechanisms of plant growth and development. A brachytic mutant, named lingering hope (linho), was recently isolated from sunflower (Helianthus annuus). The aim of this report is the characterization of the mutant through genetic, morphometric, physiological and gene expression analyses. The brachytic trait is controlled by a recessive gene. The reduction of plant height depends on shorter apical internodes. The mutant shows an altered ratio length/width of the leaf blade, chlorosis and defects in inflorescence development. The brachytic trait is not associated to a specific hormonal deficiency, but an increased level of several gibberellins is detected in leaves. Notably, the endogenous salicylic acid (SA) content in young leaves of the mutant is very high despite a low level of SA 2-O-beta-d-glucoside (SAG). The CO2 assimilation rate significantly decreases in the second pair of leaves of linho, due to effects of both stomatal and non-stomatal constraints. In addition, the reduction of both actual and potential photochemical efficiency of photosystem II is associated with a reduced content of chlorophylls and carotenoids, a lower chlorophyll a to chlorophyll b ratio and a higher SA content. In comparison to wild type, linho shows a different pattern of gene expression with respect two pathogenesis-related genes and two genes involved in SA biosynthesis and SA metabolism. linho is the first mutant described in sunflower with altered SA metabolism and this genotype could be useful to improve information about the effects of high endogenous content of SA on plant development, reproductive growth and photosynthesis, in a major crop. PMID- 30399535 TI - DNA transfer in forensic science: A review. AB - Understanding the variables impacting DNA transfer, persistence, prevalence and recovery (DNA-TPPR) has become increasingly relevant in investigations of criminal activities to provide opinion on how the DNA of a person of interest became present within the sample collected. This review considers our current knowledge regarding DNA-TPPR to assist casework investigations of criminal activities. There is a growing amount of information available on DNA-TPPR to inform the relative probabilities of the evidence given alternative scenarios relating to the presence or absence of DNA from a specific person in a collected sample of interest. This information should be used where relevant. However, far more research is still required to better understand the variables impacting DNA TPPR and to generate more accurate probability estimates of generating particular types of profiles in more casework relevant situations. This review explores means of achieving this. It also notes the need for all those interacting with an item of interest to have an awareness of DNA transfer possibilities post criminal activity, to limit the risk of contamination or loss of DNA. Appropriately trained forensic practitioners are best placed to provide opinion and guidance on the interpretation of profiles at the activity level. However, those requested to provide expert opinion on DNA-related activity level issues are often insufficiently trained to do so. We advocate recognition of DNA activity associated expertise to be distinct from expertise associated with the identification of individuals. This is to be supported by dedicated training, competency testing, authorisation, and regular fit for purpose proficiency testing. The possibilities for experts to report on activity-related issues will increase as our knowledge increases through further research, access to relevant data is enhanced, and tools to assist interpretations are better exploited. Improvement opportunities will be achieved sooner, if more laboratories and agencies accept the need to invest in these aspects as well as the training of practitioners. PMID- 30399537 TI - Chemically activated high grade nanoporous carbons from low density renewable biomass (Agave sisalana) for the removal of pharmaceuticals. AB - HYPOTHESIS: Enlarging the range of viable nanoporous carbon precursors, namely by the acid treatment of low density biomass residues, can overcome issues related with the availability and quality of raw materials that have potential impact on cost and quality grade of the final product. EXPERIMENTS: Nanoporous carbons were prepared following a two-step process: H2SO4 digestion/polycondensation of biomass waste (Agave sisalana, sisal) at temperature below 100 degrees C and atmospheric pressure to obtain acid-chars that were further chemically activated with KOH or K2CO3. Selected synthesized nanoporous carbons were tested for the removal of pharmaceutical compounds - ibuprofen and iopamidol - in aqueous solutions. FINDINGS: The structure and density of the acid-chars are highly dependent on the concentration of H2SO4 used in the digestion and polycondensation steps. An adequate choice of the acid-char synthesis conditions, activating agent and contact method allowed to feature nanoporous carbons with specific surface areas ranging from 600 to 2300 m2 g-1 and apparent densities reaching 600 kg m-3. The adsorption capacity of a sample obtained by KOH activation for the removal of micropollutants from water was twice higher than the value attained by a golden activated carbon (Cabot-Norit) commercialized for this specific purpose. PMID- 30399538 TI - Effects of aqueous extracts from the rhizome of Pontederia cordata on the growth and interspecific competition of two algal species. AB - Single and co-culture systems of Microcystis aeruginosa and Scenedesmus obliquus were prepared with different initial algal densities and treated with different concentrations of aqueous extracts from the rhizome of Pontederia cordata to study its inhibitory effect on algal growth and the competitive relationship between these two algal species. The results showed that aqueous extracts could inhibit the growth of M. aeruginosa and S. obliquus, and the inhibition rate of aqueous extracts on the growth of M. aeruginosa was always higher than that of S. obliquus. A Lotka-Volterra competition model revealed that these two algal species can co-exist without the addition of aqueous extracts, and S. obliquus exhibited a stronger ability to compete than that of M. aeruginosa. Meanwhile, the dominant algal species changed with the addition of aqueous extracts regardless of the initial ratios of the two algae. The species ratio of mixed cultures had a strong effect on the interspecific interaction between the two algae. The higher proportion of S. obliquus in the initial proportion of two algae, the stronger competitive ability of S. obliquus when compared with that of M. aeruginosa. PMID- 30399539 TI - Cytotoxicity and genotoxicity of cerium oxide micro and nanoparticles by Allium and Comet tests. AB - Cerium oxide (CeO2) is extensively used in a range of applications like in television tubes, glass/ceramic polishing agent, fuel cells, solar cells, gas sensor andultraviolet absorbents. In current study, Allium ana-telophase and comet assays were employed to evaluate the cytotoxic and genotoxic effects of CeO2 microparticles (CMPs, <5 um, bulk) and CeO2 nanoparticles (CNPs, < 25 nm) on the root meristem cells of Allium cepa by using mitotic phases, mitotic index (MI), chromosomal aberrations (CAs), and DNA damage. A cepa roots were treated with the CMPs and CNPs at four different concentrations (12.5, 25, 50, and 100 ppm) for 4 h. Methyl methane sulphonate (MMS,10 ppm) and distilled water were used as positive and negative control groups, respectively. All the applied doses statistically decreased MIs. MI values of CMPs were found higher than CNPs. CMPs and CNPs significantly increased CAs such as chromosome laggards, disturbed anaphase-telophase, stickiness and bridges and also DNA damage. Characterization of CMPs and CNPs showed the particle size as 4.24 +/- 0.7 um and 20.28 +/- 2.33 nm, respectively. The average diameter of CMPs and CNPs in solution were in the range of 372.75 +/- 70.23 nm and 167.74 +/- 38.7 nm, respectively. These results demonstrated that CMPs and CNPs had cytotoxic and genotoxic effects in A. cepa root meristematic cells. PMID- 30399540 TI - Study on the simultaneous degradation of five pesticides by Paenibacillus polymyxa from Panax ginseng and the characteristics of their products. AB - The quality and safety of ginseng products were seriously affected due to the slow metabolism and long-term residual pesticides in ginseng. Microbial degradation is an effective method to degrade pesticide residues. In this study, ginseng endophytic Paenibacillus polymyxa was used to degrade pesticide residues. A method of simultaneous determination of fluazinam, BHC, PCNB, chlorpyrifos and DDT in ginseng roots and ginseng stems and leaves by GC was established. The sample was extracted with n-hexane and purified by Florisil solid phase extraction column. The limit of quantitation was 0.01 MUg mL-1, the linear relationship was good (r >= 0.9901). 7 days after inoculated with P. polymyxa, the degradation rates of fluazinam, BHC, PCNB, chlorpyrifos, and DDT in the medium were 94.77%, 70.34%, 77.92%, 78.30%, 66.70%, respectively (P < 0.05). The safety of 5 pesticide degradation products was investigated by GC-MS. The results showed that after 7 days degradation, the main degradation products were alkanes, which are non-toxic and can't cause secondary pollution to the environment. The actual degradation results were verified by field experiments. The results indicated that after sprayed 5 times with P. polymyxa, the degradation rates of fluazinam, BHC, PCNB, chlorpyrifos and DDT in the ginseng roots were 66.07%, 46.24%, 21.05%, 72.40%, 54.21%, respectively (P < 0.05). The degradation rates in ginseng stems and leaves were 74.18%, 55.61%, 73.65%, 58.13%, 46.91%, respectively (P < 0.05). The results indicated that Paenibacillus polymyxa was an effective degradation strain of 5 pesticides. PMID- 30399541 TI - Addition of wood sawdust during the co-composting of sewage sludge and wheat straw influences seeds germination. AB - The objective of this study was to investigate the effect of addition of sawdust co-composted with sewage sludge and wheat straw on seeds germination. Two mixtures were piled and composted over 90 days. The first mixture (C1) was composed of sewage sludge and wheat straw, while the second mixture (C2) was composed of sewage sludge, wheat straw and wood sawdust. The results showed that the physicochemical parameters of both composts, i.e., temperature (> 55 degrees C in the thermophilic phase), moisture content (~ 30%). pH (6.73 for C1 and 7.19 for C2) and EC values (1.81 mS cm-1 for C1 and 1.32 mS cm-1 for C2) reached the required maturity standard. The values of C/N were below 12 indicating a high degree of maturity. Also, no bacterial pathogens were detected in the final composts. The concentration of total heavy metals has been reduced allowing the elimination of sewage sludge toxicity, confirmed by the germination index, which reached over 80%. Strong positive correlations were noticed between total Kjeldahl nitrogen of C2 and germination indexes of all the studied species. The obtained results indicate that the addition of wood sawdust increases the nitrogen content leading to slightly alkaline compost which influences seeds germination by reducing the phytotoxicity of sewage sludge. PMID- 30399542 TI - Interspecific differences in the bioaccumulation of arsenic of three Patagonian top predator fish: Organ distribution and arsenic speciation. AB - Interspecific differences in arsenic bioaccumulation and organ distribution (muscle, liver, kidney and gills) in three predator fish (creole perch, rainbow trout and brown trout) from a Patagonian lake impacted by volcanic eruptions were studied. Arsenic in fish organs were compared analyzing: 1) temporal (before and after volcanic eruption) and spatial (near and far from the volcano) influence of Puyehue-Cordon Caulle volcanic complex activity on arsenic concentrations; 2) the influence of growth (as total length), organ type and their interactions over arsenic accumulation; and 3) arsenic speciation and total arsenic relationship with carbon to nitrogen ratios (C:N), as a proxy of lipid presence, in fish muscle. In general, total arsenic concentrations in creole perch organs were 2-7 times higher than those recorded in the corresponding organs of salmonids. Arsenic was preferentially accumulated in liver and kidney in the three fish species. The influence of the volcanic activity over arsenic concentrations was more evident in creole perch: organs from creole perch captured closest to the volcano exhibited higher arsenic concentrations. Temporal variations were not so consistent. No clear relationship between arsenic and fish length was observed. Positive and linear relationship between arsenic in all pair of organs was found in creole perch, while rainbow trout showed a quadratic relationship between muscle and the remaining organs, indicating different arsenic assimilation elimination relationships between organs and fish. The arsenic liver:muscle ratio in the three fish species was greater than 1, suggesting some level of arsenic stress. Arsenobetaine (AB) and dimethylarsinic acid (DMA) were the dominant arsenic species in muscle of these fish, having creole perch 3-4 times higher AB than rainbow trout. A positive relationship between C:N ratio and total arsenic concentrations was found, with higher C:N in creole perchs near the volcano. In terms of food safety, no inorganic arsenic compound were detected, therefore arsenic levels in fish from Lake Nahuel Huapi does not represent any health risk to consumers. PMID- 30399543 TI - Functional characterization of the Wrab17 gene in the interaction process between wheat and Puccinia triticina. AB - In the interaction between wheat and Puccinia triticina, wheat resists the invasion of P. triticina by producing hypersensitive reaction-programmed cell death (HR-PCD). To better understand the mechanism of wheat resistance to P. triticina, it is important to identify the defensive genes involved in wheat resistance to leaf rust. This paper systematically presented the role of Wrab17 in the HR-PCD process in wheat after infection by P. triticina. The subcellular location analysis is performed using the full length of Wrab17 coding sequences and Wrab17 is found to be localized in cell nucleus and cytoplasm. Quantitative RT-PCR (RT-qPCR) and western blot analysis showed that expression of Wrab17 at both mRNA and protein levels increased by P. triticina infection, indicating that the Wrab17 gene participated in the interaction between wheat and P. triticina. Wrab17 knockdown plants were generated by RNA-mediated gene silencing technology (RNA interference, RNAi) and confirmed by southern blot. Further analysis with P. triticina inoculation found that knockdown of Wrab17 exhibited decreased HR expansion area in incompatible combination (L10*260) and significant higher sensitivity to the compatible pathogen P. triticina race 165. In all, this work reports that Wrab17 is a new defensive gene playing a role in wheat resistance to leaf rust. PMID- 30399544 TI - Identification of key genes involved in catechin metabolism in tea seedlings based on transcriptomic and HPLC analysis. AB - Tea is a non-alcoholic beverage with many benefits to human health and thereby widely consumed in the world. It contains plenty of secondary metabolites and tea catechins are the characteristic compounds. To further elucidate the biosynthetic and regulatory mechanisms of catechins in tea, high performance liquid chromatography (HPLC) and transcriptome analysis were performed in tea seedlings of different growth stages. A combined method of differential expression and correlation analysis was then conducted. The results showed that the order of total catechin (TC) contents was leaves > stems > roots, irrespective of growth stages. For transcriptome analysis, a total of 355.81 million clean reads were generated and mapped to the referencing tea genome. Further real time PCR analysis of 18 selected genes confirmed RNA-Seq results. A total of 7 structural genes and 35 transcription factors (TFs) were identified to be significantly correlated with TC changes. Among them, three TFs homologous to ANL2, WRKY44 and AtMYB113 might play key roles in catechin regulation. The de novo transcriptome data of different organs in tea seedlings provided new insights into the biosynthetic and metabolic pathways of catechins. PMID- 30399545 TI - Exogenous myo-inositol alleviates salinity-induced stress in Malus hupehensis Rehd. AB - Myo-inositol mediates various physiological processes and stress responses. Here, we investigated its role in Malus hupehensis Rehd. plants when grown hydroponically under saline conditions. Salt-stressed plants showed reduced growth and marked declines in photosynthetic activity and chlorophyll concentrations. However, pretreatment with 50 MUM myo-inositol significantly alleviated those inhibitions and enabled plants to maintain their photosynthetic capacity. In addition to changing stomatal behavior, exogenous myo-inositol inhibited ROS accumulation and Na+ uptake. In contrast, activities of antioxidant systems were enhanced, and expression was elevated for genes involved in Na+ uptake (e.g., HKT1, NHX1, SOS1, and SOS2). This exogenous application also provoked the accumulation of sugars or sugar alcohols, which partially contributed to the maintenance of osmotic balance, and the scavenging of ROS, either directly or indirectly. In summary, myo-inositol appears to alleviate the salt-induced inhibition of physiological processes for M. hupehensis, not only by supporting the plant's antioxidant defense system but also by mediating Na+ and K+ homeostasis and the osmotic balance. PMID- 30399546 TI - Metabolic changes induced by manganese in chamomile. AB - Manganese (Mn) uptake and toxicity in chamomile (Matricaria chamomilla) and changes of phenolic metabolites in plants grown in the soil (1000 MUM Mn2+) or hydroponic culture (100 or 1000 MUM Mn2+) were studied. Under soil cultivation, Mn excess reduced growth and induced symptoms of oxidative stress (including total ROS, hydroxyl radical and lipid peroxidation as detected by fluorescence microscopy), concomitantly with depletion of non-protein thiols and ascorbic acid. Total soluble phenols and individual phenolic acids were rather depleted (p coumaric, chlorogenic, and protocatechuic acids) or unaltered (vanillic and caffeic acids). Shoot Mn content reached 2806 MUg/g DW with BAF 51.0 in the soil culture. In hydroponics, tetraploid plants contained less Mn in both shoots and roots than diploid ones with bioaccumulation factor and translocation factor (diploid/tetraploid) 57.1/37.9 and 0.39/0.32 in 1000 MUM Mn treatment. Plants cultured in hydroponics revealed stimulation of some phenolic acids, mainly chlorogenic acid in the shoots and p-hydroxybenzoic and vanillic acids in the roots (more extensively in tetraploid ones which contained less Mn). Data indicate that excessive Mn accumulation has negative impact not only on the growth but also on phenolic metabolites in young plants mainly. Detailed comparison of the observed metabolic changes with limited literature focused on Mn physiology is provided as well. PMID- 30399547 TI - Electrographic spikes are common in wildtype mice. AB - High-voltage rhythmic electroencephalographic (EEG) spikes have been recorded in wildtype (WT) rats during periods of light slow-wave sleep and passive wakefulness. The source of this activity is unclear but has been attributed to either an inherent form of absence epilepsy or a normal feature of rodent sleep EEG. In contrast, little is known about epileptiform spikes in WT mice. We thus characterize and quantify epileptiform discharges in WT mice for the first time. Thirty-six male WT C57 mice with 24-h wireless telemetry video-EEG recordings were manually scored by blinded reviewers to mark individual spikes and spike trains. Epileptiform spikes were detected in 100% of the recorded WT mice, and spike trains of at least three spikes were recorded in 90% of mice. The spikes were more frequent during the day than at night and were inversely correlated to each animal's locomotor activity. However, the discharges were not absent during active nighttime periods. These discharges may indicate a baseline tendency toward epileptic seizures or perhaps are benign variants of normal rodent background EEG. Nevertheless, a better understanding of baseline WT EEG activity will aid in differentiating pathological and normal EEG activity in mouse epilepsy models. PMID- 30399548 TI - Strategies to enhance the stability of nanoscale zero-valent iron (NZVI) in continuous BrO3- reduction. AB - The reduction of bromate to bromide was successfully achieved by bimetallic catalysts with NZVI support in continuous-flow reactors. The stability of NZVI supported bimetallic catalysts was enhanced by decelerating the iron corrosion and sequential rapid passivation of the iron-Cu-Pd ensembles under optimized reaction conditions. Thus >99% bromate removal can be continuously achieved for 11 h. The lifetime of the bimetallic catalyst was further enhanced and tested under different hydraulic retention time, catalyst loading, and initial bromate concentrations. At the optimized operation conditions, the catalyst showed a complete bromate reduction by 24 h and then the reactivity slowly decreased to 20% over the next 100 h. X-ray diffraction and X-ray photoelectron spectroscopy showed that the reactive NZVI support was oxidized to Fe(II) and Fe(III) along with Cu(0) oxidation to CuO, while the oxidation state of Pd did not change. Therefore, bromate reduction occurred on the surface of reactive NZVI support and Cu(0) particle, while Pd played a role as a hydrogenation catalyst that prolonged the lifetime of the bimetallic catalyst. PMID- 30399549 TI - Anaerobic co-digestion of the aqueous phase from hydrothermally treated waste activated sludge with primary sewage sludge. A kinetic study. AB - The mesophilic anaerobic co-digestion of the liquid fraction from hydrothermal carbonization (LFHTC) of dewatered waste activated sludge with primary sewage sludge (PSS) has been studied. Mixtures of different composition (25, 50 and 75% of LFHTC on a chemical oxygen demand (COD) basis), as well as the individual substrates, have been tested using two inocula (flocculent (FS) and granular (GS) sludges). Methane production decreased as the LFHTC/PSS ratio increased, which can be related to the presence of recalcitrant compounds in the LFHTC, such as alkenes, phenolics, and other oxygen- and nitrogen-bearing aromatics hard-to degrade through anaerobic digestion. Methane yield reached 248 +/- 11 mL CH4 STP/g CODadded with the GS inoculum and 25% LFHTC. A 74 and a 30% increase of methane production was achieved in the 25% LFHTC runs respect to the obtained in the similar experiments with 100% LFHTC, using the FS and GS inocula, respectively. In those late runs, the COD was reduced more than 86%, with a negligible concentration of total volatile fatty acids. With both inocula, total Kjeldahl nitrogen hydrolysis increased as the LFHTC to PSS mixture ratio decreased, reaching values higher than 79% at the end of the experiments. Methane yield values fitted well the first-order, Cone and Weibull kinetic models for both inocula. Significant differences in the kinetic constant values, ranging from 0.100 to 0.168 d-1 and 0.059-0.068 d-1, were found with the FS and GS inocula, respectively. The results obtained support the potential integration of HTC of dewatered waste activated sludge in wastewater treatment plants. PMID- 30399550 TI - The whole genome insight on condition-specific redox activity and arsenopyrite interaction promoting As-mobilization by strain Lysinibacillus sp. B2A1. AB - A gram-positive spore former, Lysinibacillus sp. B2A1 was isolated from a high arsenic containing groundwater of Beimen2A well, Chianan Plain area, Southwestern Taiwan. Noteworthy, in the subsurface-mimicking anoxic incubation with a Na lactate amendment system, this isolate could interact with arsenic-source mineral arsenopyrite and enhance arsenic mobilization. Further, the isolate showed elevated levels of arsenic resistance, 200 mM and 7.5 mM for arsenate and arsenite, respectively. Lysinibacillus sp. B2A1 demonstrated condition-specific redox activities including salient oxic oxidation of arsenite and anoxic reduction of arsenate. The elevated rate of As(III) oxidation (Vmax = 0.13 MUM min-1 per 106 cells, Km = 15.3 MUM) under oxic conditions was potent. Correlating with stout persistence in an arsenic-rich niche, remarkably, the lesser toxic effects of arsenic ions on bacterial sporulation frequency and germination highlight this strain's ability to thrive under catastrophic conditions. Moreover, the whole genome analysis elucidated diverse metal redox/resistance genes that included a potential arsenite S-adenosylmethyltransferase capable of mitigating arsenite toxicity. Owing to its arsenic resistance, conditional redox activities and ability to interact with arsenic minerals leading to arsenic mobilization, the presence of such spore-forming strains could be a decisive indication towards arsenic mobilization in subsurface aquifers having a high concentration of soluble arsenic or its source minerals. PMID- 30399551 TI - Improved bauxite residue dealkalization by combination of aerated washing and electrodialysis. AB - Bauxite residue, a major by-product of the alumina-producing Bayer process, is a serious environmental pollutant due to its high alkalinity. Here, we reported an operation system designed in our laboratory that included washing and electrodialysis dealkalization systems with aeration pipes. Washing with aeration releases a substantial amount of free alkali and attached alkali into water and increases the dealkalization efficiency. The washing liquid was treated with five steps of batch-mode electrodialysis. The average removal of total dissolved solids (TDS) after the aeration and non-aeration electrodialysis processes were 61.30% and 39.61%, respectively. The average removal of OH- under aeration conditions was 76.62%, a value that was greater than the value produced under non aeration conditions (68.48%). This efficiency was also higher than that of some other reports (64.90-68.50%). Aeration decreased the energy consumption to a greater extent than the non-aeration condition. NaOH was recovered in terms of the concentration chamber, and the NaAl(OH)4 present in the dilution chamber was separated for the electrodialysis treatment. Membrane scaling was generated to a lesser amount under aeration conditions than that of non-aeration conditions, which would improve the dealkalization efficiency. The high repeatability of the experiments was indicated by the intraclass correlation coefficient (P < 0.05). PMID- 30399552 TI - Oxygen vacancy boosted photocatalytic decomposition of ciprofloxacin over Bi2MoO6: Oxygen vacancy engineering, biotoxicity evaluation and mechanism study. AB - Herein, efficient visible light driven photocatalytic degradation of ciprofloxacin was realized over Bi2MoO6 with oxygen vacancies (OVs) which can be tunably introduced through a facile solvothermal method via the modulation of tetramethylethylenediamine (TMEDA). The optimal Bi2MoO6 with OVs possessed the highest CIP degradation rate of 1.799 mg min-1 m-1, about 8.4 times than that of the pristine Bi2MoO6. And more than half of CIP was mineralized in only 2 h. The biotoxicity of ciprofloxacin and its byproducts to E. coli K-12 and saccharomyces cerevisiae was thoroughly eliminated after 6 h's photocatalytic treatment. Characterization methods revealed the rich oxygen vacancies in Bi2MoO6 not only endowed it with broader visible light absorption and faster transfer of photogenerated carriers, but also provided abundant absorption sites of surface oxygen for efficient molecular oxygen activation. Correspondingly, plentiful active species were produced and participated in the photocatalytic process, thereby efficiently promoting the ciprofloxacin degradation. Based on the HPLC-MS analysis, a possible decomposition pathway of CIP was finally proposed with the first decomposition step of pipetazine ring oxidation and breakage. This work might open up new avenues for superior visible light driven photocatalysts design to deal with pharmaceutical compounds contamination via tunable OVs Engineering. PMID- 30399553 TI - Enhancing capacitive deionization performance with charged structural polysaccharide electrode binders. AB - Capacitive deionization (CDI) performance, as measured by salt adsorption capacity (SAC) and energy normalized adsorption of salt (ENAS), is frequently limited by anion repulsion at the positive electrode. In this work, we investigate the ability to prevent co-ion repulsion by increasing complementary fixed charged within the electrode macropores by binding composite CDI electrodes with the ionically charged structural polysaccharides chitosan and carboxymethyl cellulose. When employing asymmetrically charged electrode binders, co-ion repulsion was prevented, resulting in SAC and ENAS values that were three times greater than composite electrodes bound with polyvinylidene fluoride (PVDF) and similar to CDI electrodes composed of chemically modified carbon. Polysaccharide binders did not modify the charge balance in the carbon micropores but did shift the discharge voltage of maximum adsorption, enabling a shift in operating voltage that prolonged cycle lifetime without a significant loss in performance. The mechanism of improved salt accumulation with polysaccharide binders was explored with a one-dimensional model that integrated CDI and ion-exchange membrane covered (MCDI) sub-units. Model simulations indicate that carbon macropores covered with thin layers of charged polysaccharides increase adsorption by a sequential accumulation and release of salt to depleted uncovered pores. PMID- 30399554 TI - Response of chloramphenicol-reducing biocathode resistome to continuous electrical stimulation. AB - Understanding the fate of overall antibiotic resistance genes (ARGs) during the biological treatment of antibiotic containing wastewater is a central issue for the water ecological safety assessment. Although the microbial electrode respiration based biotransformation process could significantly detoxify some antibiotic contaminants, e.g. chloramphenicol (CAP), the response of CAP-reducing biocathode microbiome and resistome to continuous electrical stimulation, especially ARGs network interactions, are poorly understood. Here, using highthroughput functional gene array (GeoChip v4.6) and Illumina 16S rRNA gene MiSeq sequencing, the structure, composition, diversity and network interactions of CAP-reducing biocathode microbiome and resistome in response to continuous electrical stimulation were investigated. Our results indicate that the CAP bioelectroreduction process could significantly accelerate the elimination of antibacterial activity of CAP during CAP-containing wastewater treatment compared to the pure bioreduction process. Continuous electrical stimulation could obviously alter both the microbiome and resistome structures and consistently decrease the phylogenetic, functional and overall ARGs diversity and network complexity within the CAP-reducing biofilms. The relative abundances of overall ARGs and specific CAP resistance related major facilitator superfamily (MFS) transporter genes were significantly negatively correlated with the reduction efficiency of CAP to inactive antibacterial product AMCl (partially dechlorinated aromatic amine), which may reduce the ecological risk associated with the evolution of multidrug-resistant bacteria and ARGs during antibiotic-containing wastewater treatment process. This study offers new insights into the response of an antibiotic reducing biocathode resistome to continuous electrical stimulation and provides useful information on the assessment of overall ARGs risk for the bioelectrochemical treatment of antibiotic contaminants. PMID- 30399555 TI - Overlapping anthropogenic effects on hydrologic and seasonal trends in DOC in a surface water dependent water utility. AB - Drinking water supplies are increasingly affected by overlapping anthropogenic global change processes. As a key currency of ecosystem function in aquatic ecosystems, dissolved organic carbon (DOC) concentration and composition is sensitive to many global change processes. However, DOC must also be removed to avoid the production of harmful disinfection byproducts as water is processed. Thus, understanding the effects of global change processes on the seasonal and long-term dynamics of DOC composition and concentration is critical for ensuring the sustainability of drinking water supplies. To understand these dynamics, we analyzed a novel 11-year time series of stream water DOC concentration and composition using Weighted Regressions on Time Discharge and Season (WRTDS) to understand the influences of co-occurring changes in climate and atmospheric deposition. We also discuss the implications for water supply provision and management. We found that, during our study period, overlapping global change processes in the watershed had the net effect of increasing the DOC aromaticity, as measured by SUVA254, at moderate to high discharge levels during the late spring and early summer and the autumn and early winter. However, changes in DOC concentration were more dynamic and we observed both increasing and decreasing trends depending on season and hydrologic state. During summer, at low to moderate flow levels we observed a significant (p < 0.05) increase in DOC concentration. During autumn, at moderate to high flow levels we observed a significant (p < 0.05) decrease in DOC concentration and an increase in SUVA254. For drinking water providers, our results suggest that close monitoring of source waters must be coupled with the development of plans accounting for season- and hydrology-specific long-term changes. PMID- 30399556 TI - Singlet oxygen-dominated non-radical oxidation process for efficient degradation of bisphenol A under high salinity condition. AB - The degradation of organic contaminants under high salinity condition is still a challenge for environmental remediation due to the inhibiting effect resulted from the side reactions between radicals and anions. Here, we demonstrate the non radical oxidation process via peroxymonosulfate (PMS) activation by metal-free carbon catalyst for efficiently decomposing bisphenol A (BPA) in saline water. The nitrogen-doped graphitic carbon (NGC700) exhibits excellent catalytic activity for depredating BPA at acid and neutral pH. Based on the scavenger experiments and electron paramagnetic resonance (EPR) analyses, the mechanism of catalytic oxidation was elucidated as the non-radical pathway, and singlet oxygen was identified as the primary reactive species. Experiments on the influence of anions (5-500 mM) further show that the inhibiting effect was overcame due to the non-radical process. Interestingly, Cl- markedly facilitated the catalytic performance by generating HOCl in the catalytic process. The results highlight leveraging the non-radical pathway dominated by singlet oxygen to conquer the inhibitory effect of anions in NGC700/PMS system, which represents a crucial step towards environmental remediation under high salinity condition. PMID- 30399557 TI - Comparison between kinetics of autochthonous marine bacteria in activated sludge and granular sludge systems at different salinity and SRTs. AB - Biological nutrient removal performances and kinetics of autochthonous marine biomass in forms of activated sludge and aerobic granular sludge were investigated under different salinity and sludge retention time (SRT). Both the biomasses, cultivated from a fish-canning wastewater, were subjected to stepwise increases in salinity (+2 gNaCl L-1), from 30 gNaCl L-1 up to 50 gNaCl L-1 with the aim to evaluate the maximum potential in withstanding salinity by the autochthonous marine biomass. Microbial marine species belonging to the genus of Cryomorphaceae and of Rhodobacteraceae were found dominant in both the systems at the maximum salinity tested (50 gNaCl L-1). The organic carbon was removed with a yield of approximately 98%, irrespective of the salinity. Similarly, nitrogen removal occurred via nitritation-denitritation and was not affected by salinity. The ammonium utilization rate and the nitrite utilization rate were approximately of 3.60 mgNH4-N gVSS-1h-1 and 10.0 mgNO2-N gVSS-1h-1, respectively, indicating a high activity of nitrifying and denitrifying bacteria. The granulation process did not provide significant improvements in the nutrients removal process likely due to the stepwise salinity increase strategy. Biomass activity and performances resulted affected by long SRT (27 days) due to salt accumulation within the activated sludge flocs and granules. In contrast, a lower SRT (14 days) favoured the discharge of the granules and flocs with higher inert content, thereby enhancing the biomass renewing. The obtained results demonstrated that the use of autochthonous-halophilic bacteria represents a valuable solution for the treatment of high-strength carbon and nitrogen saline wastewater in a wide range of salinity. Besides, the stepwise increase in salinity and the operation at low SRT enabled high metabolic activity and to avoid excessive accumulation of salt within the biomass aggregates, limiting their physical destructuration due to the increase in loosely-bound exopolymers. PMID- 30399558 TI - Spatiotemporal patterns of aerosol optical depth throughout China from 2003 to 2016. AB - With China's rapid economic growth, particle pollution, especially fine particulate matter (PM2.5), which is known to have adverse health impacts, has become an increasingly serious issue. Satellite aerosol optical depth (AOD), an important physical property of aerosol particles, can serve as a proxy for investigating particle pollution because it can provide observations with comprehensive spatial and temporal coverage compared with ground-level measurements. This study used an improved 14-year high-resolution AOD dataset to examine the spatial characteristics and temporal dynamics of the dominant pollutants in China from 2003 to 2016 using advanced statistical methods. The improved AOD dataset combines the Moderate Resolution Imaging Spectroradiometer (MODIS) 3-km dark target AOD and 10-km deep blue AOD datasets, which enables a comparison of aerosol loading between eastern and western China. Pixel-based analysis indicates a significant difference between eastern and western China: high AOD values were generally observed in the east with a notable decrease, while low aerosol loadings were found in western China with no distinct change. The most particle polluted areas were the North China Plain, Hubei-Hunan region, Sichuan Basin, and Guangxi-Guangdong region in eastern China and western Qinghai and Tarim Basin in western China, with changes in the national AOD average center shifting to the northwest from 2013 to 2016. The impact factor analysis based on geographically weighted regression indicates that the effect of topography on the spatial characteristics of AOD is negative and more important in eastern China, which has low elevations. Built-up areas significantly exacerbate air pollution in the areas between eastern and western China, and there is no apparent AOD vegetation relation dominates the country. This study thus provides a comprehensive understanding of the spatiotemporal variations of particle concentrations and can facilitate environmental management, policies to alleviate particle pollution, and health risk assessment studies. PMID- 30399560 TI - Genetic variants of filaggrin are associated with occupational dermal exposure and blood DNA alterations in hairdressers. AB - Hairdressers are exposed to high levels of chemicals, including possible carcinogens. For dermal exposure, the skin protects against the uptake of chemicals and the protein filaggrin (encoded by FLG) has a key role in skin barrier function. This study investigated if variants of FLG previously linked to impaired skin barrier function, i.e. null mutations and copy number variation (CNV) alleles (CNV10), are associated with cancer-related DNA changes. Blood and questionnaire data were collected from hairdressers (n = 295) and controls (n = 92). Exposure to aromatic amines was measured as hemoglobin adducts by gas chromatography tandem mass spectrometry. DNA from peripheral blood was used to test for FLG null mutations and CNV (10, 11, or 12 repeats), telomere length, and methylation of selected cancer-related genes. Hairdressers had a lower frequency of FLG null mutations (4.1 vs. 7.6%, P = 0.18) and CNV10 (43.2 vs. 56%, P = 0.0032) than controls. In hairdressers, CNV10 carriers had a decreased risk of high ortho-toluidine adducts in blood compared with non-carriers (odds ratio, OR = 0.49, 95% CI = 0.30-0.81). Further, telomere length was shorter for carriers of any FLG null allele (beta = -0.18, 95% CI = -0.31 to -0.044) and CNV10 carriers (beta = -0.054, 95% CI = -0.11 to -0.00051, linear regression adjusted for age, passive smoking, residence, and education) compared to non-carriers. Carriers of any FLG null allele showed higher methylation of the cyclin-dependent kinase inhibitor 2A gene CDKN2A (OR = 6.26, CI = 1.13-34.7), but not of the other genes analyzed. These associations were not found among the controls. Our study showed that the frequency of FLG CNV10 was lower among hairdressers than controls, which may indicate a healthy worker selection. Moreover, FLG null and CNV10 were associated with cancer-related DNA changes in hairdressers, which may influence their risk of cancer. PMID- 30399559 TI - Trimethyltin chloride induces reactive oxygen species-mediated apoptosis in retinal cells during zebrafish eye development. AB - Trimethyltin chloride (TMT), one of the most widely used organotin compounds in industrial and agricultural fields, is widespread in soil, aquatic systems, foodstuffs and household items. TMT reportedly has toxic effects on the nervous system; however, there is limited information about its effects on eye development and no clear associated mechanisms have been identified. Therefore, in the present study, we investigated eye morphology, vison-related behavior, reactive oxygen species (ROS) production, apoptosis, histopathology, and gene expression to evaluate the toxicity of TMT during ocular development in zebrafish embryos. Exposure to TMT decreased the axial length and surface area of the eye and impaired the ability of zebrafish to recognize light. 2',7' dichlorofluorescein diacetate and acridine orange assays revealed dose-dependent increases in ROS formation and apoptosis in the eye. Furthermore, pyknosis of retinal cells was confirmed through histopathological analysis. Antioxidative enzyme-related genes were downregulated and apoptosis-inducing genes were upregulated in TMT-treated zebrafish compared to expression in controls. Retinal cell-specific gene expression was suppressed mainly in retinal ganglion cells, bipolar cells, and photoreceptor cells, whereas amacrine cell-, horizontal cell-, and Muller cell-specific gene expression was enhanced. Our results demonstrate for the first time the toxicity of TMT during eye development, which occurs through the induction of ROS-mediated apoptosis in retinal cells during ocular formation. PMID- 30399561 TI - Oxidative stress mediated cytotoxicity and apoptosis response of bismuth oxide (Bi2O3) nanoparticles in human breast cancer (MCF-7) cells. AB - Bismuth oxide nanoparticles (Bi2O3 NPs) have shown great potential for several applications including cosmetics and biomedicine. However, there is paucity of research on toxicity of Bi2O3 NPs. In this study, we first examined dose dependent cytotoxicity and apoptosis response of Bi2O3 NPs in human breast cancer (MCF-7) cells. We further explored the potential mechanisms of cytotoxicity of Bi2O3 NPs through oxidative stress. Physicochemical study demonstrated that Bi2O3 NPs have crystalline structure and spherical shape with mean size of 97 nm. Toxicity studies have shown that Bi2O3 NPs reduce cell viability and induce membrane damage dose-dependently in the concentration range of 50-300 MUg/ml. Bi2O3 NPs also disturbed cell cycle of MCF-7 cells. Oxidative stress response of Bi2O3 NPs was evident by generation of reactive oxygen species (ROS), higher lipid peroxidation, reduction of glutathione (GSH) and low superoxide dismutase (SOD) enzyme activity. Interestingly, supplementation of external antioxidant N acetyl-cysteine almost negated the effect of Bi2O3 NPs induced oxidative stress and cell death. We also found that exposure of Bi2O3 NPs induced apoptotic response in MCF-7 cells suggested by impaired regulation of Bcl-2, Bax and caspase-3 genes. Altogether, we found that Bi2O3 NPs induced cytotoxicity in MCF 7 cells through modulating the redox homeostasis via Bax/Bcl-2 pathway. This study warranted further research to delineate the underlying mechanism of Bi2O3 NPs induced toxicity at in vivo level. PMID- 30399562 TI - Strontium doped hydroxyapatite from Mercenaria clam shells: Synthesis, mechanical and bioactivity study. AB - Synthesis of strontium-doped hydroxyapatite from Mercenaria clam shells has been carried out by hydrothermal method. The doping of bioceramic, processed from biogenic resources is mostly unexplored. The objective is to understand the effect of strontium (Sr) incorporation on phase stability, sintering behaviour, mechanical properties and cytotoxicity of hydroxyapatite (HAp) derived from clam shells. The different molar concentrations of Sr, varies from 10, 30, 50, 70% of Ca, were substituted into the HAp. The synthesized powders were sintered at 1200 degrees C in air. The as synthesized powders and sintered specimens were characterized using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and high resolution transmission electron microscopy. The crystallite size and cell parameters of sintered specimens were analyzed from XRD. The XRD of hydrothermally synthesized powders mostly matched with HAp with slight shifting due to Sr doping. However, some distinct Sr based compounds were also observed where Sr substitution is more that 50% of Ca. The XRD of sintered specimen showed increasing beta-tricalcium phosphate (beta-TCP) phase with Sr substitution. The sintered density of solid samples gradually increased from 3.04 g/cc to 3.50 g/cc and surface energy decreased with increasing Sr substitution. Similarly, microhardness, fracture toughness and nanohardness of solid samples found to be enhanced with Sr substitution. The elastic modulus gradually increased from 130 to 137 GPa for HAp and Sr substituted HAp (70% of Ca). The in vitro cytotoxicity of sintered specimen against mouse osteoblast cell line showed that all the samples were nontoxic. However cell proliferation found low for the solid samples containing more than 50% Sr substitution. PMID- 30399563 TI - Multiscale modelling for the heterogeneous strength of biodegradable polyesters. AB - A heterogeneous method of coupled multiscale strength model is presented in this paper for calculating the strength of medical polyesters such as polylactide (PLA), polyglycolide (PGA) and their copolymers during degradation by bulk erosion. The macroscopic device is discretized into an array of mesoscopic cells. A polymer chain is assumed to stay in one cell. With the polymer chain scission, it is found that the molecular weight, chain recrystallization induced by polymer chain scissions, and the cavities formation due to polymer cell collapse play different roles in the composition of mechanical strength of the polymer. Therefore, three types of strength phases were proposed to display the heterogeneous strength structures and to represent different strength contribution to polymers, which are amorphous phase, crystallinity phase and strength vacancy phase, respectively. The strength of the amorphous phase is related to the molecular weight; strength of the crystallinity phase is related to molecular weight and degree of crystallization; and the strength vacancy phase has negligible strength. The vacancy strength phase includes not only the cells with cavity status but also those with an amorphous status, but a molecular weight value below a threshold molecular weight. This heterogeneous strength model is coupled with micro chain scission, chain recrystallization and a macro oligomer diffusion equation to form a multiscale strength model which can simulate the strength phase evolution, cells status evolution, molecular weight, degree of crystallinity, weight loss and device strength during degradation. Different example cases are used to verify this model. The results demonstrate a good fit to experimental data. PMID- 30399564 TI - Anisotropic freeze-cast collagen scaffolds for tissue regeneration: How processing conditions affect structure and properties in the dry and fully hydrated states. AB - Few systematic structure-property-processing correlations for directionally freeze-cast biopolymer scaffolds are reported. Such correlations are critical to enable scaffold design with attractive structural and mechanical cues in vivo. This study focuses on freeze-cast collagen scaffolds with three different applied cooling rates (10, 1, and 0.1 degrees C/min) and two freezing directions (longitudinal and radial). A semi-automated approach for the structural characterization of fully hydrated scaffolds by confocal microscopy is developed to facilitate an objective quantification and comparison of structural features. Additionally, scanning electron microscopy and compression testing are performed longitudinally and transversely. Structural and mechanical properties are determined on dry and fully hydrated scaffolds. Longitudinally frozen scaffolds have aligned and regular pores while those in radially frozen ones exhibit greater variations in pore geometry and alignment. Lamellar spacing, pore area, and cell wall thickness increase with decreasing cooling rate: in longitudinally frozen scaffolds from 25 um to 83.5 um, from 814 um2 to 8452 um2, and from 4.21 um to 10.4 um, and in radially frozen ones, from 69 um to 116 um, from 7679 um2 to 25,670 um2, and from 6.18 um to13.6 um, respectively. Both longitudinally and radially frozen scaffolds possess higher mechanical property values, when loaded parallel rather than perpendicular to the ice-crystal growth direction. Modulus and yield strength range from 779 kPa to 4700 kPa and from 38 kPa to 137 kPa, respectively, as a function of cooling rate and freezing direction. Collated, the correlations obtained in this study enable the custom-design of freeze-cast collagen scaffolds, which are ideally suited for a large variety of tissue regeneration applications. PMID- 30399565 TI - Modeling of Osteoprobe indentation on bone. AB - Osteoprobe (ActiveLife, Santa Barbara, CA) is a novel handheld microindentation instrument designed to test bone in vivo by measuring a Bone Material Strength index (BMSi). In this paper, the Osteoprobe indentation on a cortical bone is modeled computationally to gain insights into the physical interpretation of the BMSi output. The analysis is conducted using an axisymmetric finite element model with an isotropic viscoelastic-plastic constitutive law with continuum damage. The computational model is validated by comparing it with experimental data from the literature. Experimental factors (indenter tip radius and friction coefficient between the indenter and the bone) and four mechanical properties of bone (Young's modulus, compressive yield stress, and damage and viscosity constants) are varied to study their influence on the BMSi. We find that varying the friction coefficient can proportionally change the BMSi up to 3%. The indenter tip radius is proportional to the BMSi, with a more pronounced proportional relation when it is greater than 30 um. Young's modulus has a proportional relation with the BMSi, where decreasing it by 73% reduces the BMSi by 41%. The damage constant has an inversely proportional relation to the BMSi, where increasing it from 0.5 to 0.96 reduces the BMSi by 29%. The compressive yield stress and the viscosity constant have a close proportional relation to the BMSi, where increasing the compressive yield stress from 50 MPa to 200 MPa increases the Osteoprobe BMSi by 21%. In summary, the friction coefficient and the indenter tip radius (when smaller than 30 um) have a small effect on BMSi. Young's modulus and damage have stronger relations with the BMSi than compressive yield stress and viscosity constant. This fundamental study provides new insights into the BMSi measurement and serves as a basis for further computational and experimental investigations on the Osteoprobe technique. Such research is needed to facilitate the embrace of this technique by the clinical community. PMID- 30399566 TI - Generation of two isogenic iPS cell lines (IRFMNi002-A and IRFMNi002-B) from a patient affected by Focal Segmental Glomerulosclerosis carrying a heterozygous c.565G>A mutation in PAX2 gene. AB - Focal Segmental Glomerulosclerosis (FSGS) is the typical renal histologic lesion in familial steroid-resistant nephrotic syndrome, for which there is currently no treatment. Dysfunction of the glomerular podocyte, a specialized cell that forms the glomerular filtration barrier, is central in the pathogenesis of FSGS. Here, we reported the generation of two isogenic iPS cell lines from a patient affected by FSGS, carrying the c.565G > A mutation in the PAX2 gene. The iPS cell lines we generated expressed pluripotency markers at the mRNA and protein levels and differentiated into all three germ layers. These iPSCs will be instrumental in understanding FSGS pathogenesis. PMID- 30399567 TI - Fungal vaccines, mechanism of actions and immunology: A comprehensive review. AB - Fungal infections include a wide range of opportunistic and invasive diseases. Two of four major fatal diseases in patients with human immunodeficiency virus (HIV) infection are related to the fungal infections, cryptococcosis, and pneumocystosis. Disseminated candidiasis and different clinical forms of aspergillosis annually impose expensive medical costs to governments and hospitalized patients and ultimately lead to high mortality rates. Therefore, urgent implementations are necessary to prevent the expansion of these diseases. Designing an effective vaccine is one of the most important approaches in this field. So far, numerous efforts have been carried out in developing an effective vaccine against fungal infections. Some of these challenges engaged in different stages of clinical trials but none of them could be approved by the United States Food and Drug Administration (FDA). Here, in addition to have a comprehensive overview on the data from studied vaccine programs, we will discuss the immunology response against fungal infections. Moreover, it will be attempted to clarify the underlying immune mechanisms of vaccines targeting different fungal infections that are crucial for designing an effective vaccination strategy. PMID- 30399568 TI - Investigation of the effects of naringin on intestinal ischemia reperfusion model at the ultrastructural and biochemical level. AB - We aimed to evaluate the ultrastructural effect of reversing cellular damage, occurring in rats due to ischemia-reperfusion (I/R) in the intestine, with naringin implementation through biochemical parameters. Rats were divided the sham/control, I/R and the naringin groups (n = 7). For I/R group, 120 min of ischemia and 120 min of reperfusion was applied to the superior mesenteric artery. In the naringin group, after 120 min, 50 mg/kg naringin was implemented, and then 120 min of reperfusion was applied. Morphological evaluation was performed via Chiu score and electron microscopy. The antioxidant parameters were examined. Chiu score in I/R (p < 0.01) and naringin (p < 0.05) groups were higher than the sham/control group. In ultrastructural level some irregularity were observed in I/R group. Although it decreased in the naringin group, the damage was observed to continue. Malondialdehyde (MDA) amount and Superoxide dismutase activity (SOD) in I/R group were higher in comparison to the sham/control group (p < 0.01), while glutathione peroxidase activity (Gpx) was found to be lower (p < 0.01). SOD (p < 0.05) and MDA (p < 0.01) were decreased by naringin group. Gpx was decreased in I/R group compared to sham/control group (p < 0.01) and elevated due to naringin administration (p < 0.05). Catalase activity was observed to decrease in the naringin group compared to control and I/R groups (p < 0.01). It was determined that naringin provided limited healing at the ultrastructural level but also effected recovery within antioxidant parameters. PMID- 30399569 TI - Ascorbic acid therapy: A potential strategy against comorbid depression-like behavior in streptozotocin-nicotinamide-induced diabetic rats. AB - This study examined the potency and efficacy of ascorbic acid (AA) in the management of depression-like behavior in diabetic rats. Diabetes mellitus was induced by single intraperitoneal injections of nicotinamide (120 mg/kg) and streptozotocin (65 mg/kg) administered 15 min apart. Diabetic (blood glucose >=250 mg/dL) rats were subjected to intermittent foot-shocks to induce comorbid depression. Seven groups of diabetes comorbid depressed rats received vehicle (1 mL/kg) or AA (10, 25, 50, 100, 200, or 400 mg/kg) orally for eleven days. Three control groups namely- nondiabetic, diabetic, and depressed rats received the vehicles only. The potency (ED50) and efficacy (Emax) of AA against immobility period, hypercorticosteronemia, adrenal hyperplasia, hyperglycemia, hypoinsulinemia, oxidative stress, and inflammatory response were estimated. AA administration caused a dose-dependent decrease (P < 0.05) in immobility period with maximum inhibition of 69% (efficacy) at 200 mg/kg and ED50 of 14 mg/kg (potency). AA at 200 mg/kg produced the maximal reduction in hypercorticosteronemia (55.1%) and adrenal hyperplasia (52.6%) with ED50 of 9.8 and 14.4 mg/kg, respectively. AA at 400 mg/kg produced the maximal reduction in hyperglycemia (35.5%), hypoinsulinemia (32.7%), and lipid peroxidation (82%) with ED50 of 18.6, 13.7, and 20.7 mg/kg, respectively. Moreover, AA at 400 mg/kg produced the maximal increase in SOD content (83%), CAT activity (77.9%), and IL 10 level (63%) with ED50 of 21.5, 21, and 21 mg/kg, respectively. In conclusion, the present results suggest that AA has therapeutic potential against diabetes comorbid depression but better regulation of hyperglycemia and hypoinsulinemia is required to achieve maximal benefits. PMID- 30399570 TI - Nrf2 activation and down-regulation of HMGB1 and MyD88 expression by amnion membrane extracts in response to the hypoxia-induced injury in cardiac H9c2 cells. AB - BACKGROUND: human Amniotic Membrane (hAM) extracts contain bioactive molecules such as growth factors and cytokines. Studies have confirmed the ability of hAM in reduction of post-operative dysfunction in patients with cardiac surgery. However, the function of Amniotic Membrane Proteins (AMPs), extracted from hAM, against hypoxia-induced H9c2 cells injury have never been investigated. In this study, we aimed to appraise the protective impact of AMPs on H9c2 cells under hypoxia condition. METHODS: Cardiomyocyte cells were pre-incubated with AMPs and subjected to 24 h hypoxia to elucidate its effects on expression of Nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1(HO-1). Furthermore, the high mobility group box-1 (HMGB1) and Myeloid differentiation primary response 88 (MyD88) expressions were detected by qPCR and western blotting. The mitochondrial membrane potential (DeltaPsim) was estimated by JC-1 using fluorescent microscopy and fluorimetry. Moreover, the cell apoptosis and intracellular calcium levels were measured by flow cytometry. RESULTS: Pre treatment of AMPs resulted in significant induction in cell viability and decreased the LDH release under hypoxic condition in H9c2 cells. Accordingly, these protective effects of AMPs were associated with a reduction in apoptosis rates and intracellular Ca2+, meanwhile, DeltaPsim was increased. Pre-treatment with AMPs resulted in degradation of HMGB1 and MyD88 levels and depicted pro survival efficacy of AMPs against hypoxia-induced cell damage through induction of HO-1 and Nrf2. CONCLUSION: The data indicated that AMPs mediated HO-1 regulation by Nrf2 activation and plays critical protective effects in hypoxia induced H9c2 injury in vitro by the inhibition of myocardial HMGB1 and MyD88 inflammatory cascade. PMID- 30399571 TI - Glycoprotein from Mytilus edulis extract inhibits lipid accumulation and improves male reproductive dysfunction in high-fat diet-induced obese rats. PMID- 30399572 TI - Focal selective chemo-ablation of spinal cardiac afferent nerve by resiniferatoxin protects the heart from pressure overload-induced hypertrophy. AB - Resiniferatoxin (RTX), a selective transient receptor potential vanilloid 1 (TRPV1) receptor agonist, can eliminate TRPV1+ primary sensory afferents and blunt cardiac sympathetic afferent reflex for a relatively long period. The present study determined the effects of intrathecal RTX administration on transverse aortic constriction (TAC)-induced cardiac dysfunction and cardiac remodeling in rats. Five days before TAC, RTX (2 MUg/10 MUl) was injected intrathecally into the T2/T3 interspace of rats. Cardiac sympathetic nerve activities (CSNAs) and cardiac structure and function were determined eight weeks after TAC. Intrathecal RTX administration abolished TRPV1 expression in the dorsal horn and reduced over-activated CSNA in the TAC rat model. Hemodynamic analysis revealed that RTX reduced left ventricular end-diastolic pressure, indicating the improvement of cardiac compliance. Histologic analysis, real-time reverse transcription-polymerase chain reaction, and Western blots showed that RTX prevented TAC-induced cardiac hypertrophy, cardiac fibrosis, and cardiac apoptosis and reduced the expression of apoptotic proteins and myocardial mRNAs. In conclusion, these results demonstrate that focal chemo-ablation of TRPV1+ afferents in the spinal cord protects the heart from pressure overload-induced cardiac remodeling and cardiac dysfunction, which suggest a novel promising therapeutic method for cardiac hypertrophy and diastolic dysfunction. PMID- 30399573 TI - Studies examining the synergy between Dihydrotanshinone and Temozolomide against MGMT+ glioblastoma cells in vitro: Predicting interactions with the blood-brain barrier. AB - We showed previously that Dihydrotanshinone (DHT) augments temozolomide (TMZ) efficacy by inducing reactive oxygen species production in an in vitro model. Here, the underlying basis of the synergistic effect and the ability of DHT to potentially pass the blood brain barrier (BBB) is investigated using an in vitro model. Trypan blue exclusion assays were used to determine effects of DHT/TMZ combinatorial treatment on GBM cell viability. ELISA was utilized to determine effects on NFkB levels after singular and combinatorial treatment. An in vitro model of the BBB was constructed to predict the potential of DHT to penetrate the BBB in vivo. DHT and TMZ synergistically reduce cancer cell viability, NFkB activity, and markedly halt cell cycle progression. This regimen was also shown to exert minimal effects on astrocytes. Finally, DHT was shown to have the potential of passing through the BBB to a similar extent as TMZ and that paclitaxel's oncolytic effects are completely ablated in the presence of our in vitro BBB. Our data confirms the synergistic interaction between DHT and TMZ and also highlights the potential of combination treatment to sequester NFkB activity and inhibit cell cycle progression. The encouraging data with the BBB model show that the DHT/TMZ combination may be clinically useful and warrants future in vivo testing. PMID- 30399574 TI - Role of vitamin D and vitamin D receptor (VDR) in oral cancer. AB - Oral cancer is known as one of the most common cancers, with a poor prognosis, related to delayed clinical diagnosis, either due to the lack of particular biomarkers related to the disease or costly therapeutic alternatives. Vitamin D executes its functions by interacting with the vitamin D receptor (VDR), both in healthy and diseased individuals, including oral cancer. This review discusses the role of vitamin D and VDR on tumorigenesis, emphasizing on oral cancer. Furthermore, regulation of VDR expression, mechanisms of anticancer effects of calcitriol, oral cancer chemoresistance and its relation with VDR and polymorphisms of VDR gene will be discussed. The manuscript is prepared mainly using the information collected from PubMed and MEDLINE. PMID- 30399575 TI - Encapsulation of rat cardiomyoblasts with alginate-gelatin microspheres preserves stemness feature in vitro. AB - INTRODUCTION: The emergence of numerous tissue engineering and regenerative medicine techniques cell encapsulation paves a way to heal and restore the function of various injured tissues mainly cardiovascular system. Here, we aimed to investigate the role of alginate-gelatin encapsulation on the dynamic of rat cardiomyoblasts in vitro. MATERIALS AND METHODS: Rat cardiomyoblasts cell line H9C2 were enclosed by using alginate-gelatin microspheres and incubated for 7 days. MTT method was used to examine cell viability. The level of genes associated with cardiomyoblasts maturation MYL7, NPPA, NKX2-5, and GATA4 real time PCR. ELISA was used to measure the protein levels of Bcl-2 and Bax factor post-encapsulation. The level of SOD, GPx, and TAC was detected by biochemical analyses. Western blotting was performed to measure the content of AMP-activated protein kinase. RESULTS: We found that encapsulation was able to increase the viability of rat cardiomyocytes after 7 days. The decreased level of Bcl-2 (p < 0.001) coincided with non-significant differences in the level of Bax (p > 0.05). The transcription level of all genes MYL7, NPPA, NKX2-5, and GATA4 were found to down-regulate compared to the control non-treated cells (p < 0.05). No significant differences were found regarding the level of SOD, GPx, and TAC compared to the control (p>0.05). According to western blotting, revealed a reduced level of AMPK following 7-day incubation of rat cardiomyoblasts (p < 0.05). CONCLUSION: Data confirmed that the encapsulation of rat cardiomyoblasts with alginate-gelatin microspheres maintained the cells multipotentiality. PMID- 30399576 TI - Preeclampsia: A close look at renal dysfunction. AB - Preeclampsia (PE) is a unique pathophysiologic situation that physiologic interests of mother, fetus, and placenta diverge. PE is related to the increased circulating antiangiogenic factors originated from hypoxic placenta. It is simply defined by the new onset of hypertension (>=140/90 mmHg) and proteinuria (>=0.3 g/day) after 20 weeks of gestation. PE is associated with kidney dysfunction due to deficiency in podocyte specific vascular endothelial growth factor (VEGF). Hypoxic placenta in PE patients produces increased levels of fms-like tyrosine kinase 1(sFlt-1), a soluble receptor of VEGF. sFlt-1 abrogates binding of VEGF to its receptor on endothelial cells and podocytes, and ultimately damages the filtration barrier. Glomerular endotheliosis and thrombotic microangiopathy (TMA) are the main features of kidney involvement in PE and can induce clotting and vessel occlusion. This complex pathophysiology is ameliorated after delivery; however, permanent kidney damages may remain and is intensified thereafter. This review aims to highlight the biochemical, genetic, and immunological-involved factors in the initiation of PE and explores the relationship between the kidney and PE. This work mainly discusses the pathologic mechanisms of kidney involvement in PE through the lens of the imbalanced VEGF-VEGF receptor signaling pathway. PMID- 30399577 TI - Dietary composition modulates impact of food-added monosodium glutamate on behaviour, metabolic status and cerebral cortical morphology in mice. AB - Effects of food-added monosodium glutamate (MSG) on neurobehaviour, serum biochemical parameters, malondialdehyde (MDA) levels, and changes in cerebral cortex, liver and kidney morphology were assessed in mice fed standard diet (SD) or high-fat diet (HFD). Animals were assigned to 8 groups [SD control, HFD control, and six groups fed MSG plus SD or HFD at 0.1, 0.2 and 0.4 g/kg of feed]. Animals were fed for 8 weeks, behavioural tests were conducted, and blood was taken for estimation of biochemical parameters and MDA level. Whole brain was homogenised for neurochemical assays, while the cerebrum, liver and kidneys were processed for histology. In groups fed MSG/SD, there was a decrease in weight gain, increase in food-intake, an increase in locomotion, a decrease in rearing/grooming, and a decrease in anxiety-response. Also observed were derangements in biochemical parameters, increased MDA, and alteration of renal morphology. Compared to HFD, MSG/HFD groups had reduction in weight gain, food intake, grooming and anxiety-response, an increase in locomotion, and improved memory. Protection against biochemical derangements and HFD-induced organ injuries were also observed. In conclusion, the findings suggest that possible interactions that may occur between dietary constituents and MSG are determinants of the effects of food-added MSG in mice. PMID- 30399578 TI - Prevention of pentylenetetrazole-induced kindling and behavioral comorbidities in mice by levetiracetam combined with the GLP-1 agonist liraglutide: Involvement of brain antioxidant and BDNF upregulating properties. AB - Kindling is a model for studying epileptogenesis and associated neuropsychiatric conditions. The antiepileptic drug levetiracetam (LEV) presents anti-kindling properties, but some severe neuropsychiatric events, especially depression, have been associated with its use in epileptic patients. The positive modulation of glucagon-like peptide-1 (GLP-1) receptors emerged as a potential target for the treatment of epilepsy and other neurological disorders. Here, we investigated behavioral and neurochemical effects of liraglutide (LIRA), a GLP-1 receptor agonist, alone or combined with LEV in mice subjected to PTZ-induced kindling. Male mice received PTZ on alternate days for 21 days. Before PTZ, the animals received LIRA, LEV (alone or in combination with LIRA) or saline. After seizures staging according to Racine's scale, behavioral evaluations were performed to verify anxiety-, depressive-like and cognitive performance. Brain oxidative alterations and BDNF levels were also measured. LEV showed anti-kindling properties, but aggravated depressive-like behavior in PTZ-kindling. In control conditions, LEV induced a pro-depressant effect and impaired avoidance memory retention. LIRA delayed but did not prevent the full kindling development. LIRA prevented the depressive-like behavior induced by PTZ kindling and PTZ + LEV. LEV + LIRA protected against PTZ-induced anxiety-like alterations and impairments in locomotion and cognition. Furthermore, LEV + LIRA reduced nitrite levels and lipid peroxidation in the hippocampus and prefrontal cortex, while it increased reduced glutathione levels in all evaluated brain areas. LIRA or LEV + LIRA increased hippocampal BDNF levels. In conclusion, our results showed that LIRA can be a promising adjunctive therapy for epilepsy-related neuropsychiatric comorbidities and to improve the management of antiepileptic drug associated behavioral adverse effects. PMID- 30399579 TI - Hyperbaric oxygen therapy: Antimicrobial mechanisms and clinical application for infections. AB - Hyperbaric oxygen therapy (HBOT) is a treatment procedure that involves breathing 100% O2 for a certain time and under a certain pressure. HBOT is commonly administrated as a primary or alternative therapy for different diseases such as infections. In this paper, we reviewed the general aspect of HBOT procedures, the mechanisms of antimicrobial effects and the application in the treatment of infections. Parts of the antimicrobial effects of HBOT are believed to result of reactive from the formation of reactive oxygen species (ROS). It is also said that HBOT enhances the antimicrobial effects of the immune system and has an additive or synergistic effect with certain antimicrobial agents. HBOT has been described as a useful procedure for different infections, particularly in deep and chronic infections such as necrotizing fasciitis, osteomyelitis, chronic soft tissue infections, and infective endocarditis. The anti-inflammation property of HBOT has demonstrated that it may play a significant role in decreasing tissue damage and infection expansion. Patients treated by HBOT need carful pre examination and monitoring. If safety standards are strictly tracked, HBOT can be considered a suitable procedure with an apt rate of complication. PMID- 30399580 TI - Response to "Effect of monacolin K and COQ10 supplementation in hypertensive and hypercholesterolemic subjects with metabolic syndrome". PMID- 30399581 TI - Cardio-protective and antioxidant properties of caffeic acid and chlorogenic acid: Mechanistic role of angiotensin converting enzyme, cholinesterase and arginase activities in cyclosporine induced hypertensive rats. AB - Caffeic acid (CAA) and chlorogenic acid (CHA) are important members of hydroxycinnamic acid with natural antioxidant and cardio-protective properties. The present study aimed to determine the effect of CAA and CHA on systolic blood pressure, heart rates (HR) as well as on the activity of the angiotensin-1 converting enzyme (ACE), acetylcholinesterase (AChE), butrylcholinesterase (BChE) and arginase in cyclosporine-induced hypertensive rats. Experimental rats were distributed into 7 groups (n = 6): normotensive control rats; hypertensive rats (induced rats) as well as hypertensive- treated groups with captopril (10 mg/kg/day), CAA (10 and 15 mg/kg/day) and CHA (10 and 15 mg/kg/day), respectively. The experiment lasted for 7 days and the systolic blood pressure (SBP) and heart rates were recorded using tail-cuff method. Oral administration of captopril, caffeic acid and chlorogenic acid normalized hypertensive effect caused by cyclosporine administration. CAA and CHA significantly (P < 0.05) reduced SBP and HR, activity of ACE, AChE, BChE and arginase in the treated hypertensive rats compared with cyclosporine induced-hypertensive rats. Likewise, CAA and CHA improved nitric oxide (NO) bioavailability, increased catalase activity and reduced glutathione content while malondialdehyde (MDA) level was reduced compared with cyclosporine hypertensive rats. Findings from this study shows that CAA and CHA exhibited blood pressure lowering properties and reduced activities of key enzymes linked to the pathogenesis of hypertension in cyclosporine-induced rats. These might be some of the possible mechanisms of action by which their cardio-protective properties are exhibited. PMID- 30399582 TI - Stress-driven discovery in the natural products: A gateway towards new drugs. AB - Elicitation by chemical means including heavy metals is one of a novel technique for drug discoveries. In this review, the effect of heavy metals on animal, plants and microorganisms for the production of novel compounds with the unique structures has been discussed. The number of parameters such as metal concentration, type, dose, treatment schedule, duration of metal exposure, and nutrient composition are significant factors altering the secondary metabolites production. The detailed illustrated diagram representing the mode of action of metal stress has also been discussed. This is the first article reporting all the novel compounds produced from plants and microorganisms in response to metal stress with their pharmacological potential. This new technique opens the new way for drug discovery from natural products. PMID- 30399583 TI - Teneligliptin protects against hypoxia/reoxygenation-induced endothelial cell injury. AB - Cardiovascular complications are the main causes of mortality in diabetic patients. Teneligliptin is a newly developed anti-diabetic agent. It has been reported that teneligliptin has a vascular protective capacity in preclinical studies and diabetes patients. In this study, we investigated the effect of teneligliptin on hypoxia/reoxygenation (H/R)-induced endothelial cell injury in rat cardiac microvascular endothelial cells (CMECs). We showed that teneligliptin pretreatment suppressed H/R-induced production of reactive oxygen species (ROS), NADPH oxidase 4 (NOX4) expression and promoted glutathione production. Teneligliptin pretreatment reduced H/R-induced LDH release and improved cell viability. Teneligliptin significantly relieved the reduction in mitochondrial membrane potential (MMP) induced by H/R. Moreover, teneligliptin suppressed H/R induced cytokine production and production of vascular adhesion molecules such as IL-1beta, TNF-alpha and ICAM-1. Mechanistically, we showed that teneligliptin inhibited the expression of transcriptional factor Egr-1, which regulates cytokine production and vascular adhesion. Collectively, our data support the notion that teneligliptin is a protective agent in CMECs and has the potential for therapeutic use in the treatments of vascular complications in diabetes patients. PMID- 30399584 TI - Ovarian carcinoma biological nanotherapy: Comparison of the advantages and drawbacks of lipid, polymeric, and hybrid nanoparticles for cisplatin delivery. AB - Ovarian carcinoma is one of the most common cancers among women. The most common type of ovarian cancer is epithelial ovarian cancer and cisplatin (DDP) is one of the most interesting chemotherapeutic drugs in clinical regimens for ovarian cancer. Nanoparticles (NPs) including lipid NPs, polymeric NPs, liposomes, dendrimers, oligomers, and nanotubes were usually used for anti-cancer drug delivery. In this study, DDP loaded nanostructured lipid carriers (DDP-NLC), polymeric NPs (DDP-PNP), and lipid-polymer hybrid nanoparticles (DDP-LPN) were prepared for the evaluation in vitro and in vivo. The efficiency of these three kinds of the NPs was compared in terms of in vitro drug release, cellular uptake, in vitro cell growth inhibition, in vivo pharmacokinetics, biodistribution and in vivo antitumor in mice. The size of DDP-PNP (119.8 nm) was smaller than DDP-NLC (132.4 nm) and DDP-LPN (141.2 nm). The release of DDP from DDP-NLC was faster than DDP-PNP. Cellular uptake efficiency of DDP-NLC and DDP-LPN was significantly higher than DDP-PNP. In vivo pharmacokinetics evaluation showed that plasma concentration - time curves (AUCs) of DDP-NLC, DDP-PNP, DDP-LPN and free DDP are 128, 210, 247, and 16 mg/L h, with T1/2 of 4.4, 5.1, 5.5, and 1.7 mg/L h. DDP-LPN exhibits the highest AUC and the longest T1/2. In vivo antitumor efficacy results investigated on ovarian cancer bearing BALB/c mice model demonstrated that DDP LPN showed the strongest antitumor effect. In vitro and in vivo studies demonstrated that DDP-NLC, DDP-PNP and DDP-LPN have different advantages due to the various evaluations. The in vivo anti-tumor results indicate that DDP-LPN may have the best tumor inhibition ability. DDP-NLC, DDP-PNP, and DDP-LPN developed in this study could be used as promising strategies for the treatment of ovarian cancer according to different demands. PMID- 30399585 TI - Triterpenoids from fruits of Sorbus pohuashanensis inhibit acetaminophen-induced acute liver injury in mice. AB - Drug-related hepatotoxicity has become a serious social issue nowadays. Acetaminophen (APAP) was widely used in clinical treatment, although commonly acknowledged that it is a general material that caused drug-related hepatotoxicity. In this study, triterpenoids (Trds) which are mainly composed of ursolic acid and oleanolic acid, were isolated and prepared from fruits of Sorbus pohuashanensis. Further, the effect of Trds against APAP-induced liver injury and the pharmacological mechanism were investigated. The results showed that Trds treatment significantly restrained the increase of serum aspartate transaminase (AST), alanine aminotransferase (ALT), tumor necrosis factor (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6), and hepatic malondialdehyde (MDA) levels, as well as evidently reversed the decrease of hepatic superoxide dismutase (SOD), glutathione (GSH) and catalase (CAT) levels induced by APAP. There are further evidences provided by liver histopathology which demonstrated Trds treatment observably inhibited hepatic tissues necrosis, hemorrhage and infiltration of inflammatory cell induced by APAP. According to the results of western-blot and RT-PCR, the over-expressions of inducible nitric oxide synthase (iNOS) and Cyclooxygenase-2 (COX-2) were inhibited by Trds. Moreover, Trds also effectively restrained APAP-induced phosphorylation of mitogen-activated protein kinase (MAPK) family signals such as p38, c-Jun N terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). These results demonstrated the liver-protection effects that Trds exhibited were related to its property of anti-oxidantion and anti-inflammation. PMID- 30399587 TI - Bile acids elicited endothelium-dependent vasoconstrictor hypo-activity through TRPV4 channels in the thoracic aorta of bile duct ligation rats. AB - Numerous studies have demonstrated the impaired cardiovascular reactivity in cholestasis patients and bile duct ligated animals. However, the underlying mechanism remains uncertain. Transient receptor potential cation V4 (TRPV4) channels are reported to be naturally expressed in the cardiovascular system, especially on endothelial cells. However, the role of TRPV4 (transient receptor potential vanilloid 4) in regulating vascular reactivity is poorly established. In this study, we first determined that bile acids elicited endothelium-dependent vasoconstrictor hypo-activity via TRPV4 channels, which further activated cyclooxygenase 2 (COX2). Myography results demonstrated that the vascular contractile response was attenuated in BDL rats when exposed to 60 mmol/L KCl. Real time PCR and western blotting results showed that bile duct ligation (BDL) induced a time-dependent increase in TRPV4 expression levels. In addition, bile acids upregulated the expression of TRPV4 protein, which proved to be located on the cell surface of endothelial cells, and induced intracellular Ca2+ events. The relaxation response was increased while the contractile response was decreased in BDL rats, and those effects were reversed by a TRPV4 inhibitor (HC067047). Contractions induced by norepinephrine were primarily inhibited by the COX2 inhibitor, but not the NOS inhibitor, and the expression of COX2 was downregulated after TRPV4 inhibition. These data indicated that TRPV4/COX2 pathways in the endothelium are involved in vasoconstrictor hypo-activity. Our current results suggested that the TRPV4 pathway is involved in the regulation of bile acids in vasoconstrictor hypo-activity in bile duct ligation rats. PMID- 30399586 TI - Baicalein stimulates fibroblast growth factor 21 expression by up-regulating retinoic acid receptor-related orphan receptor alpha in C2C12 myotubes. AB - Retinoic acid receptor-related orphan receptor (ROR) alpha has been implicated in various physiological functions, including the immune system, inflammation, and circadian rhythms. In the present study, the synthetic RORalpha/gamma agonist SR1078 stimulated the production and gene expression of fibroblast growth factor 21 (FGF21) in C2C12 myotubes. FGF21, a member of the FGF family, plays important roles in the regulation of peripheral glucose tolerance and lipid metabolism and improves metabolic health. The mRNA expression and secretion of FGF21 was significantly weaker in Rora-silenced cells than in cells transfected with non targeting control siRNA. SR1078 significantly up-regulated C/EBP homologous protein (CHOP), an established marker of ER stress, in a dose-dependent manner in C2C12 myotubes, while CHOP expression was decreased in Rora-silenced C2C12 cells, suggesting that RORalpha is involved in the regulation of FGF21 expression and stimulates ER stress in C2C12 myotubes. The naturally occurring compound baicalein up-regulated FGF21 expression and secretion in C2C12 myotubes. Additionally, the up-regulation of CHOP mRNA and protein expression was observed in C2C12 myotubes after the baicalein treatment. Furthermore, the knockdown of RORalpha prevented the augmentation of FGF21 and up-regulation of CHOP in response to baicalein in C2C12 cells. Collectively, these results suggest that baicalein stimulates the ER stress response and FGF21 expression through an RORalpha-dependent mechanism in C2C12 myotubes, and indicate the potential of baicalein as an effective anti-obesity therapy via its ability to enhance FGF21 production. PMID- 30399588 TI - Increased expression of LINC01510 predicts poor prognosis and promotes malignant progression in human non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC), the most prevalent type of lung cancer, is one of the most leading causes of cancer-related morbidity and mortality worldwide. Evidence is accumulating that long non-coding RNAs (lncRNAs) play vital regulatory roles in tumor development and progression. LINC01510, a novel tumor-related lncRNA, has been identified as an oncogene in colorectal cancer; however, its role in NSCLC remains poorly understood. This study aimed to characterize the biological role of LINC01510 in NSCLC and illuminate the molecular mechanisms. Here we found that LINC01510 was highly expressed in NSCLC tissues. Besides, Fisher's exact test showed that high expression of LINC01510 was associated with larger tumor size, advanced TNM stage and lymph node metastasis. Kaplan-Meier survival analysis showed that patients with high LINC01510 expression had a much lower overall survival rate. Gain- and loss-of function approaches were employed to investigate the effects of LINC01510 on NSCLC cell phenotypes. Functional studies demonstrated that LINC01510 over expression promoted NSCLC cell proliferation, cell cycle progression, migration and invasion, but shRNA-mediated LINC01510 depletion inhibited NSCLC cell proliferation, cell cycle progression, migration and invasion. Notably, LINC01510 ablation suppressed tumorigenicity of NSCLC cells in a murine xenograft model. Furthermore, mechanistic studies revealed that LINC01510 exerted its oncogenic functions in NSCLC through miR-339-5p-mediated regulation of CDK14. To sum up, our data indicate that increased expression of LINC01510 predicts poor prognosis and promotes tumorigenesis in NSCLC. Collectively, this study may provide a basis for LINC01510 as a candidate therapeutic target in NSCLC. PMID- 30399590 TI - NK cells in cerebral ischemia. AB - As a vital cell type in immune system and infiltrating cells in ischemic brain, NK cells can bridge the crosstalk between immune system and nervous system in stroke setting. The mechanism of action of NK cells is complicated, involving direct and indirect actions. NK cells are closely associated with poststroke inflammation, immunodepression and infections. The excessive inflammatory response in ischemic brain is one of the important causes for aggravating cerebral ischemic injury. Besides the inflammation induced by ischemia itself, thrombolytic drug tissue plasminogen activator (tPA) administration could also induce deteriorative inflammation, which is unfavorable for stroke control and recovery. Regulating NK cells may has the potential to modulate the immune response, limiting the development of ischemic damage and getting better outcome. In addition, post-stroke immunosuppression may lead to infections which contribute to higher severity and mortality of ischemic stroke (IS). Targeting NK cells may help to find novel pathways for IS therapy, which can both ameliorate the infarction itself, but also reduce the infectious complications. NK cells may also link IS and related diseases, suggesting NK cells can be used as a diagnostic or prognostic biomarker for IS prevention and treatment. PMID- 30399589 TI - Possible neuroprotective mechanisms of action involved in the neurobehavioral property of naringin in mice. AB - Flavonoids are naturally occurring bioactive phytochemical metabolites widely known to prevent and suppress several human diseases, and are important sources of therapeutic compounds from plants. Evidence derived from previous studies suggests that naringin, a neuroactive flavonoid possess functional beneficial neurobehavioral effects including anxiolytic, antidepressant and memory enhancing properties. However, literature search revealed that no studies have been carried out to evaluate the possible biochemical mechanisms involved in the neurobehavioral property of naringin alone following repeated treatment. Hence, this study was designed to evaluate the possible neuro-biochemical mechanisms involved in the neurobehavioral property of naringin following repeated administration in mice. The effects of naringin (2.5, 5 and 10 mg/kg), diazepam (2 mg/kg), imipramine (15 mg/kg) and donepezil (1 mg/kg) or vehicle on neurobehavioral and biochemical effects were evaluated in mice following repeated intraperitoneal injection for 7 consecutive days. Neurobehavioral activities consisting of open-field (locomotor), elevated-plus maze (anxiolytic), forced swim and social interaction (antidepressant and social preference), and Y-maze (memory enhancing) tests were assessed. Thereafter, brains levels of biomarkers of oxidative, nitrosative and cholinergic parameters were determined. Repeated treatment with naringin produced increased locomotor activity, and demonstrated antidepressant-like effects evidenced by decreased immobility time in forced swim test and increased % social preference in the social interaction test relative to controls. Also, naringin induced anxiolytic-like effect and increased cognitive performance in mice. Mechanistically, naringin significantly increased the activities of superoxide dismutase and catalase, and glutathione concentration relative to vehicle-controls. However, naringin significantly decreased malondialdehyde and nitrite contents, and reduced brain acetylcholinesterase activity in mice brains in a significant manner relative to controls. Taken together, these findings suggest that treatment with naringin might be useful to produce functional behavioral effects via mechanisms related to enhancement of cholinergic transmission, antioxidant defense systems, inhibition of lipid peroxidation and nitrosative processes. PMID- 30399591 TI - Gambogic acid induces heme oxygenase-1 through Nrf2 signaling pathway and inhibits NF-kappaB and MAPK activation to reduce inflammation in LPS-activated RAW264.7 cells. AB - Gambogic acid (GA), a natural product with a xanthone structure, was previously demonstrated to exert anti-inflammatory effects. The aim of this study was to evaluate the anti-inflammatory activity of GA on LPS-stimulated mouse macrophage RAW264.7 and its anti-inflammatory mechanism. Pretreatment with GA inhibited LPS induced production of nitric oxide (NO) and prostaglandin E2 (PGE2) through reducing the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). GA also decreased the expressions of pro-inflammatory cytokines, including TNF-alpha, IL-6 and IL-1beta. The activation of nuclear factor-kappaB (NF-kappaB) and the Mitogen activated phosphokinases (MAPKs) regulates pro-inflammatory factors. Further experiments demonstrated that the nuclear translocation of NF-kappaB, a promoting regulator in inflammation, was blocked via inhibiting the phosphorylation event of IkappaBalpha by GA. Meanwhile, the Mitogen activated phosphokinase (MAPK) signaling pathways were also suppressed. However, activation of nuclear factor erythroid 2-related factor (Nrf2) can inhibit inflammation. GA could activate the nucleus translocation of Nrf2 and up-regulated the expression of heme oxygenase-1 (HO-1). Taken together, GA exhibited its anti-inflammatory activities through Nrf2 activation and NF kappaB depression, thus could be a candidate for the prevention and treatment of diseases that involve excessive inflammation. PMID- 30399592 TI - Ginkgolide B enhances gemcitabine sensitivity in pancreatic cancer cell lines via inhibiting PAFR/NF-kB pathway. AB - Gemcitabine resistance will occur by time after the initial response in pancreatic cancer. Ginkgolide B (GB), a major terpene lactone component of Ginkgo biloba leaves, is a highly selective and competitive inhibitor for platelet activating factor (PAF) receptor. In the present study, we evaluated the effect of GB on gemcitabine sensitivity in pancreatic cancer cell lines in vitro and in vivo. Cell viability assay, flow cytometry, dual luciferase reporter assay and tumor xenograft model were used to evaluate cell proliferation, apoptosis, nuclear factor kappa b (NF-kB) activity in vitro and tumor growth in vivo. Western blot, immunohistochemistry (IHC) and immunofluorescence were used to shown different protein expression levels. We found the half maximal inhibitory concentration (IC50) of gemcitabine was significantly downregulated by GB in a dose-dependent manner. Furthermore, GB could suppress cell proliferation, increase cell apoptosis and repress tumor growth when combined with gemcitabine, but had no effect when treated alone. Gemcitabine could upregulate PAFR and phosphorylated NF-kB/p65 expression, and increase NF-kB activity, but this was largely suppressed in combination with GB. GB could suppress PAFR expression in a dose-dependent manner. Knockout of PAFR significantly decreased phosphorylated NF kB/p65 expression, inhibited NF-kB activity, increased gemcitabine sensitivity and cell apoptosis. Besides, GB had no influence on gemcitabine IC50 in IkappaBalpha-SR stably expressed BxPC-3 and CAPAN1. Our results suggested that GB could enhance gemcitabine sensitivity in pancreatic cancer cell lines by suppressing PAFR/NF-kB pathway. Thus GB may have therapeutic potential when used in combination with gemcitabine in pancreatic cancer. PMID- 30399593 TI - Combined treatment with Cinnamaldehyde and beta-TCP had an additive effect on bone formation and angiogenesis in critical size calvarial defect in ovariectomized rats. AB - Accumulating evidence suggests that improvements in osteogenesis and angiogenesis play an important role in repairing osteoporotic bone defects. Cinnamomum cassia (C. cassia), a traditional Chinese medicinal herb, is reported to show anabolic effects on osteoblasts. However, whether C. cassia could actually repair bone defects in osteoporotic conditions remains unknown. The purpose of this study was to evaluate the effect of combined treatment with Cinnamaldehyde (main oil isolated from the C. cassia) and beta-tricalcium phosphate (beta-TCP) on bone formation and angiogenesis in critical size calvarial defects in ovariectomized (OVX) rats. Using a previously established OVX model, 5 mm critical size calvarial defect was established in OVX rats. All OVX rats were then randomly divided into OVX group (OVX rats + empty defect), TCP group (OVX rats + beta TCP), and CTCP group (Cinnamaldehyde 75 mg/kg/day for 12 weeks + beta-TCP). Twelve weeks after treatment, according to Micro-CT and HE staining, combination of Cinnamaldehyde and beta-TCP had an additive effect on bone regeneration compared with other groups (p < 0.05). Based on dynamic fluorochrome-labelling analysis, Cinnamaldehyde+beta-TCP continuously promoted new bone mineralization compared with other groups at each time point (p < 0.05). Microfil perfusion suggested that CTCP group showed more neovascularization compared with other groups (p < 0.05). Immunohistochemical assay supported the findings that Cinnamaldehyde+beta-TCP enhanced expression of OCN, VEGF and CD31. The present study demonstrated that combined treatment with Cinnamaldehyde and beta-TCP promoted bone formation and angiogenesis in osteoporotic bone defects, which provides a promising new strategy for repairing bone defects in osteoporotic conditions. PMID- 30399594 TI - Extracellular calcium influx through L-type calcium channels, intracellular calcium currents and extracellular signal-regulated kinase signaling are involved in the abscisic acid-induced precognitive and anti-anxiety effects. AB - Abscisic acid (ABA), a critical phytohormone, is also produced in animal tissues. It has been reported that ABA has pro-cognitive and anti-anxiety effects in rats. However, its detailed mechanism has not yet been clarified. Here, the possible roles of extracellular and intracellular calcium store and ERK signaling were evaluated in pro-cognitive and anti-anxiety effects of ABA. Morris water maze (MWM) and plus maze tests were used to evaluate the learning and memory and anxiety-like behavior, respectively, in rats. The inhibitors of L- (nifedipine) and T-type (amiloride) calcium channels and endoplasmic reticulum Ca2+-ATPase (thapsigargin) were centrally (i.c.v.) injected 15 min before ABA. Hippocampal and prefrontal lobe levels of phosphorylated extracellular signal-regulated Kinase (p-ERK) were assessed by immunoblotting. The data showed that ABA has promoting effect on rat's performance in MWM task and induced anti-anxiety effect. In addition, nifedipine and thapsigargin significantly prevented while, amiloride had no effect on the mentioned effects of ABA. Furthermore, p-ERK levels were significantly increased in ABA-treated rats which were inhibited by nifedipine and thapsigargin pretreatment. It seems that the extracellular calcium influx through L-type calcium channels, intracellular calcium storage and ERK signaling are involved, at least in part, in the pro-cognitive and anti-anxiety effects of ABA. PMID- 30399595 TI - Co-administration of the low dose of orexin and nitrergic antagonists induces an antidepressant-like effect in mice. AB - It is now well-established that orexins (OXs) and their receptors are involved in the pathophysiology of depression. Considering the evidence indicating the importance of nitric oxide (NO) system in the mood modulation, this study investigated the effect of intraperitoneal (i.p.) administration of orexin 1 (OX1) receptor antagonist -SB334867- alone or in combination with NO agents on depression using the forced swimming test (FST), tail suspension test (TST) and the number of crossings in open-field test (OFT) in mice. Our results indicated that administration of SB334867 at the dose of 0.5 mg/kg decreased the immobility time in the FST without effect on locomotor activity, suggesting an antidepressant-like effect of SB334867. Moreover, l-Arginine (a NO precursor; 750 mg/kg) or L-NAME (a non-selective nitric oxide synthase (NOS) inhibitor, 10 mg/kg) administration by itself decreased the immobility time in the FST. Interestingly, co-administration of a sub-threshold dose of L-NAME, but not l Arginine, in combination with an ineffective dose of SB334867 produced an antidepressant-like effect in the FST and TST. It should be noted, none of the drugs elicited significant effects on the locomotor activity in the OFT. Altogether, the present data propose that a combination of the sub-effective dose of OX and NO antagonists can be evaluated as an option for the clinical treatment of depression in humans. PMID- 30399596 TI - Up-regulation of miR-383-5p suppresses proliferation and enhances chemosensitivity in ovarian cancer cells by targeting TRIM27. AB - MicroRNAs are small non-coding RNAs which play important roles in tumor progression. MiR-383-5p has been characterized as a cancer suppressor in several cancers. The aim of theses present study was to explore the role of miR-383-5p in the proliferation and chemosensitivity of ovarian cancer cells. MiR-383-5p expression was down-regulated while the expression of TRIM27 was up-regulated in ovarian cancer tissues and cell lines. We came up with the hypothesis that miR 383-5p might be involved in the tumor progression and chemoresistance of ovarian cancer through targeting TRIM27. Bioinformatics study and Luciferase reporter assay indicated that TRIM27 was a target of miR-383-5p and negatively regulated by miR-383-5p in ovarian cancer cells. Up-regulation of miR-383-5p was found to suppress cell proliferation and decrease Ki67 and PCNA expression in ovarian cancer cells (OVCAR3, A2780), suggesting that overexpressed miR-383-5p inhibited cell proliferation of ovarian cancer cells. In addition, up-regulation of miR-383 5p decreased the IC50 value of ovarian cancer cells to paclitaxel and increased cell apoptosis rate under the treatment of paclitaxel, indicating that overexpressed miR-383-5p enhanced chemosensitivity in ovarian cancer cells. However, overexpressed TRIM27 by pcDNA3.1-TRIM27 transfection counteracted the inhibitory effect of miR-383-5p on cell proliferation and chemoresistance in ovarian cancer cells. In vivo experiments also revealed that tumor growth could be inhibited by miR-383-5p mimic. Taken together, this present study found that miR-383-5p was lowly expressed while TRIM27 was highly expressed in ovarian cancer. Up-regulation of miR-383-5p inhibited cell proliferation, tumor growth and enhanced chemosensitivity of ovarian cancer cells through suppressing TRIM27 expression. Therefore, miR-383-5p/TRIM27 axis may be the potential target for the treatment of ovarian cancer. PMID- 30399597 TI - Atorvastatin alleviates early hypertensive renal damage in spontaneously hypertensive rats. AB - This study aimed to examine the effects of atorvastatin on early hypertensive renal damage and explored the underlying mechanisms. 12-week-old salt-loaded spontaneous hypertensive rats (SHRs) were divided into four groups: atorvastatin (AVT), losartan potassium (LP), atorvastatin combined with peroxisome proliferators-activated receptor gamma (PPAR-gamma) inhibitor (AVT + GW9662), and saline. During 10 weeks administration blood pressure and urea albumin creatinine ratio were determined. We also examined the renal function, pathological changes of kidney, inflammatory cytokines in the serum and the association of the change of inflammatory factors in the kidney tissue. AVT did not reduce the mortality of the SHRs. AVT reduced the blood pressure of SHRs, but the effect was not comparable to that of LP. AVT significantly decreased urine protein. AVT and LP displayed comparable effects by significantly decreasing inflammatory cytokines (hs-CRP, IL-1beta, IL-6, TNF-alpha, and TGF-beta) levels in serum. AVT and LP both apparently improved renal pathological changes and significantly reduced the infiltration of macrophage in renal tubular interstitial. Both mRNA and protein expression levels of TLR4, NFkappaB, MCP-1 were significantly down regulated in AVT and LP groups. There was no significant change in macrophage polarity. The addition of PPAR-gamma inhibitor partially reduced the anti-inflammatory effect of AVT. These results mean that Atorvastatin can alleviates the pathology of hypertensive renal damage. Atorvastatin protects the kidney by reducing the apparent inflammation in salt-loaded SHRs. Atorvastatin alleviates inflammation partially by augmenting expression of PPAR-gamma. PMID- 30399598 TI - Hydroalcoholic extract of Brazilian green propolis modulates inflammatory process in mice submitted to a low protein diet. AB - The occurrence of inflammation and protein malnutrition is an aggravating risk factor for morbidity and mortality in the clinical setting. The green propolis, a natural product made by Apis mellifera bees from Baccharis dracunculifolia resin, has therapeutic potential to modulate chronic inflammation. However, its effect on inflammation in an impaired nutritional status is not known. The aim of this study was to characterize the effects of the administration of the hydroalcoholic extract of the green propolis in the chronic inflammatory process of mice submitted to a low-protein diet. For this, we used the subcutaneous implantation of sponge disks as an inflammatory model and the animals were distributed in the following groups: standard protein diet (12% protein content), control treatment; standard protein diet, propolis treatment; low-protein diet (3% protein content), control treatment; low-protein diet, propolis treatment. Propolis was given daily at a dose of 500 mg/kg (p.o.) during a period of 7 or 15 days. Our main findings show that animals fed with standard protein diet and treated with propolis had low levels of red blood cells, hemoglobin, and hematocrit, with the subsequent reestablishment of these levels, in addition to monocyte count elevation and higher TNF levels after one week of treatment. In the low-protein diet group, the propolis treatment provided a significant recovery in weight and maintenance of total serum protein levels at the end of two weeks of treatment. Histological analysis showed propolis reduced the inflammatory infiltrate in the sponges of both standard and low-protein diet groups. In addition, the propolis extract presented antiangiogenic effect in both groups. Therefore, our data suggests that the hydroalcoholic extract of the green propolis promotes weight recovery and avoid the reduction of protein levels, in addition to inhibit inflammation and angiogenesis in animals fed with a low-protein diet. PMID- 30399599 TI - Aminophenols increase proliferation of thyroid tumor cells by inducing the transcription factor activity of estrogen receptor alpha. AB - Aminophenols, which are widely used as components of hair dye and medicine, may function as environmental endocrine disruptors by regulating the proliferation of endocrine-related cancers. Estrogen receptor alpha (ERalpha) is a key regulator of breast cancer. Recently, it was found that ERalpha may also participate in the transformation and progression of thyroid tumors, but its interaction with aminophenols and its function in thyroid tumors is not clear. In this study, the transcription factor activity of ERalpha in BHP10-3 cells (a thyroid tumor cell line) was examined using luciferase assays. The promoter recruitment of ERalpha was examined using chromatin co-precipitation (ChIP). Additionally, in an in vivo study, BHP10-3 cells were transplanted into nude mice. Upon administration of aminophenols, the transcription factor activity of ERalpha was significantly increased in BHP10-3 cells, and the recruitment of ERalpha to the promoter of its target gene was increased. Aminophenols enhanced the in vitro and in vivo proliferation of BHP10-3 cells. By discovering that aminophenols induce the onco promoting activity of ERalpha, our study extends the understanding of the function of aminophenols and suggests that ERalpha is a potential therapeutic target for the treatment of thyroid tumors. PMID- 30399600 TI - Hyperbaric oxygen and aerobic exercise in the long-term treatment of fibromyalgia: A narrative review. AB - Chronic pain is one of the most common clinical presentations in the primary care settings. In the US, Fibromyalgia (FM) affects about 1-3% of adults and commonly occurs in adults between the ages of 40-50 years. FM causes widespread muscular pain and tenderness with hyperalgesia and allodynia and may be associated with other somatic complaints. Hyperbaric oxygen therapy (HBOT) has been utilized and has recently shown promising effects in the management of FM and other chronic pain disorders. In HBOT, the intermittent breathing of 100% oxygen in a pressurized chamber where the pressure is higher than 1 atmosphere absolute (ATA) has been utilized. HBOT exhibits a significant anti-inflammatory effect through reducing production of glial cells and inflammatory mediators which results in pain alleviation in different chronic pain conditions. HBOT can also influence neuroplasticity and affects the mitochondrial mechanisms resulting in functional brain changes. In addition to that, HBOT stimulates nitric oxide (NO) synthesis which helps in alleviating hyperalgesia and NO-dependent release of endogenous opioids which seemed to be the primary HBOT mechanism of antinociception. Moreover, aerobic exercise and meditative movement therapies (MMT) have gained attention for their role in pain alleviation through different anti-inflammatory and antioxidant mechanisms. In this review, we aim to elucidate the different mechanisms of HBOT and aerobic exercise in attenuating pain as adjuvant therapy in the multidisciplinary treatment strategy of chronic pain, and more particularly fibromyalgia. PMID- 30399601 TI - Prevalence of cervical and lumbosacral compressive radiculopathies in Qena governorate/Egypt: Population-based survey. AB - OBJECTIVES: The aim of the study was to estimate the crude prevalence rate (CPR) of compressive radiculopathies in Qena governorate/Egypt. PATIENTS AND METHODS: 10 areas in Qena governorate were selected by random sampling, involving 9303 inhabitants with 57.3% urban residents and 42.7% rural residence. Patients were diagnosed using a screening questionnaire for the diagnosis of cervical and lumbosacral radiculopathies. All positive cases were referred to Qena University Hospital where they underwent full neurological examination, neuro-imaging, and neurophysiological investigations. RESULTS: Out of 9303 inhabitants included in the study (1057 families), 49 cases were recruited positive on initial survey and 32 cases were confirmed after clinical examination, neuroimaging and neurophysiological examinations, giving a CPR of 10.1/1000 in those aged over 30 years. Compressive radiculopathy was more common in males than females (13 versus 6/1000) and in rural than urban populations (15 versus 7/1000). No cases were recruited below 30 years old. The highest age specific prevalence was at >=60 years with a CPR of 26/1000. 11 cases had cervical radiculopathy while 21 cases had lumbosacral radiculopathy (CPR of 3.7 and 6.6/1000 respectively). The highest age specific CPR for males was earlier than females at 50-59 versus >=60 years. CONCLUSION: The overall CPR of compressive radiculopathy in the general population in Qena governorate/Egypt is similar for cervical radiculopathy but higher for lumbosacral radiculopathy than a previous Egyptian study but mid-way compared to other countries. PMID- 30399602 TI - Utilization of sunglasses: A pilot study to examine a simple test for cognitive dysfunction. AB - OBJECTIVE: Utilization is an executive function disorder and implies an inappropriate response to external stimuli. The sunglasses test is a simple test to examine utilization by offering a pair of sunglasses to a patient without any instruction. PATIENTS AND METHODS: We performed a pilot study to examine the sunglasses test in 100 patients, of which 50 had cognitive symptoms and 50 did not have cognitive symptoms. When the patient put on the sunglasses, the test was considered positive. Cognitive dysfunction was based on the results of the MMSE, results of the clock test and neuropsychological examination (blinded). The final diagnosis was based on all results of the work-up (including MRI). RESULTS: Of the 50 patients with cognitive symptoms 30 had a positive test and 28 of them had cognitive dysfunction. Final diagnosis in most patients was Dementia due to probable Alzheimers disease, followed by Frontotemporal dementia. Seven of the 20 patients with a negative test also had cognitive dysfunction. None of the 50 patients without cognitive symptoms put on the sunglasses. Sensitivity of the sunglasses test to detect cognitive dysfunction was 80% and specificity was 97%, with a positive predictive value of 93%. CONCLUSION: Offering sunglasses is a simple test to screen for utilization. Putting on sunglasses without instruction to do so can be indicative for cognitive dysfunction and further cognitive evaluation should be considered. Future studies are needed in a larger group of patients and to determine the role of this test in different diseases with cognitive decline. PMID- 30399603 TI - A study of the intrinsic variability and the effect of environmental conditions on the formation of a postmortem root band. AB - A postmortem root band (PMRB) is defined as "an opaque ellipsoidal band composed of a collection of parallel elongated air/gas spaces and is approximately 0.5mm above the root bulb and about 2mm below the skin surface" [1]. It is generally accepted that it can appear in the root of hairs attached to remains during decomposition [1]. This study aimed to investigate the underlying cause and mechanism of PMRB formation. This was done (i) by observing the overall frequency and the intrinsic variability in anagen hairs containing a PMRB collected across five regions of a human decedent's scalp at three time points, and (ii) by determining if PMRB-like features can be induced via immersion in in-vitro controlled environments of anagen hairs plucked from the scalp of a human decedent (ex-situ postmortem hairs) not containing a PMRB. The results of the first objective illustrated that as time since death increased, the frequency of hairs containing a PMRB across the scalp sampling regions increased and the intrinsic variability decreased. The results of the second objective demonstrated that both an aqueous environment and microbial activity are essential for the formation of PMRB-like features. This study was the first to statistically analyze the intrinsic variability of PMRB formation, as well as the first to induce PMRB-like features in roots of ex-situ postmortem hairs. PMID- 30399605 TI - The cellular and genetic basis of structural colour in plants. AB - While the pathways that produce plant pigments have been well studied for decades, the use by plants of nanoscale structures to produce colour effects has only recently begun to be studied. A variety of plants from across the plant kingdom have been shown to use different mechanism to generate structural colours in tissues as diverse as leaves, flowers and fruits. In this review we explore the cellular mechanisms by which these nanoscale structures are built and discuss the first insights that have been published into the genetic pathways underpinning these traits. PMID- 30399604 TI - Microcystin-RR: Occurrence, content in water and food and toxicological studies. A review. AB - Microcystins (MCs) are hepatotoxins, produced by various species of cyanobacteria, whose occurrence is increasing worldwide owing to climate change and anthropogenic activities. More than 100 variants have been reported, and among them MC-LR is the most extensively studied, but there are other MC congeners that deserve to be investigated. The need for data to characterize the toxicological profile of MC variants other than MC-LR has been identified in order to improve risk assessment in humans and wildlife. Accordingly, the aim of this study was to evaluate the information available in the scientific literature dealing with MC-RR, as this congener is the second most common cyanotoxin in the environment. The review focuses on aspects such as occurrence in water and food, and toxicity studies both in vitro and in vivo. It reveals that, although MC-RR is a real hazard with a high exposure potential in some countries, little is known yet about its specific toxicological properties that differ from those of MC-LR, and important aspects such as genotoxicity and chronic effects have not yet been sufficiently addressed. PMID- 30399606 TI - The 2D to 3D growth transition in the moss Physcomitrella patens. AB - The colonization of land by plants coincided with and was most likely facilitated by the evolution of 3-dimensional (3D) growth. 3D growth is a pivotal feature of all land plants, but most develop in a way that precludes genetic investigation. In the moss Physcomitrella patens, 3D growth (gametophores) is preceded by an extended 2-dimensional (2D) growth phase (protonemata) that can be propagated indefinitely. Studies using P. patens have thus elucidated some of the molecular mechanisms underlying 3D growth regulation. This review summarizes the known molecular mechanisms underlying both the formation of gametophore initial cells and the development of the 3D growth in gametophores. PMID- 30399607 TI - Positive impact of biochar amendment on thermal balance during swine manure composting at relatively low ambient temperature. AB - In this study, the effects of biochar amendment on swine manure composting performance at temperatures in the -5 degrees C-15 degrees C range was investigated. Monitoring result showed biochar addition significantly prolonged thermophilic stage duration to meet harmless standards of livestock manure compost at 5 degrees C, assisting a seemingly difficult composting to succeed. Additionally, from viewpoint of thermal balance, biochar increased organic matter degradation derived heat from 50.4% to 86.5% and water vaporization heat from 29.6% to 73.5% while decreasing heat exchange by two-fold. Overall, the results presented herein indicated that biochar has potential to play a positive role in amelioration of animal manure composting at relatively low ambient temperature and provide insight into how biochar influences heat generation and flow during composting. PMID- 30399608 TI - Microwave-assisted co-pyrolysis of Chlorella vulgaris and wood sawdust using different additives. AB - The microwave-assisted co-pyrolysis of Chlorella vulgaris (CV), wood sawdust (WS) and their blends with additives were investigated. There was a higher liquid and solid yield with silicon carbide (SiC) than activated carbon (AC) in most of samples. Microwave-assisted pyrolysis with additives behaved a positive effect on deoxygenation and aromatization, but not apparent denitrification. With the increase of CV proportion, aromatic hydrocarbons decreased, but aliphatic hydrocarbons increased using AC. High selectivity of phenols was reached at the sample of WS (relative content as 43.6%) using SiC; High selectivity of alkenes was reached at the sample of CV (relative content as 31.2%) and alkanes at the blend sample of 70% CV and 30% WS (relative content as 9.45%). Bio-oil and biochar from microwave-assisted pyrolysis of WS had higher calorific value than that of CV both with AC and SiC. Calorific value of bio-oil decreased by 33.3% after mixing CV with WS. PMID- 30399609 TI - Performance and microbial protein expression during anaerobic treatment of alkali decrement wastewater using a strengthened circulation anaerobic reactor. AB - Herein, a strengthened circulation anaerobic (SCA) reactor was employed for the treatment of actual alkali-decrement wastewater. The degradation mechanism of polyester oligomers and the relationship between the treatment performance and microbial community structure were systematically investigated using various advanced techniques. Results suggest that the accumulation of volatile fatty acids has an inhibitory effect on methanogenic activity. Molecular weight distributions suggest that only incomplete degradation of oligomers was achieved, due to acetogenic inhibition in the lower part of the SCA reactor. Meta-proteomic approach analysis revealed that the methanogens containing heterodisulfide reductase were the primary species involved in methane metabolism. Based on these findings, a possible degradation mechanism for alkali-decrement wastewater in the SCA reactor is proposed. This high-performance anaerobic reactor could be further scaled-up and optimized to serve as a promising and effective unit for the treatment of other refractory industrial wastewaters. PMID- 30399610 TI - Infants Uniquely Express High Levels of RBM3 and Other Cold-Adaptive Neuroprotectant Proteins in the Human Brain. AB - Neuroprotective cold-shock proteins (CSPs) are abundant in the normothermic neonatal rodent brain but decrease with advancing neurodevelopmental age and are low or absent in the adult brain. It has not been established if neurodevelopmental age alters the baseline expression of CSPs in the human brain. Here, we tested the hypothesis that protein levels of RNA-binding motif 3 (RBM3), reticulon-3 (RTN3), and cold-induced RNA-binding protein (CIRBP) are abundant in the normothermic developing human brain but low-to-absent in adults. We also tested if beta-klotho (KLB) is expressed in the developing brain; KLB functions as a coreceptor that controls tissue-specific binding and activity of the systemically circulating thermogenic hormone fibroblast growth factor 21 (FGF21), and is predominantly expressed in the liver, pancreas, and in adipose cells. Methods: Hippocampi and anterior prefrontal cortices (aPFCs/BA10) from a total of 20 male and 20 female subjects were obtained from the NIH NeuroBioBank. CSP and KLB levels were measured in: infants < 1 year old (n = 8), toddlers aged 1-2 years (n = 8), children aged 3-5 years (n = 7), 18-year-old adolescents (n = 8), and adults aged 31-34 years (n = 8). An equal number of male and female (n = 4 each) samples were pooled into each age group, except in the 3- to 5-year-olds which comprised 3 male and 4 female specimens due to sample availability. In total, 78 whole-brain tissues were dissociated using a bead-based Precellys homogenizer to generate equivalent homogenates, and levels of protein targets subsequently analyzed by Western blotting. Results: Infants had the highest levels of RBM3 and other CSPs in the brain compared to all other ages. In the hippocampus, CSPs were detected predominantly in infants. In the aPFC, CSP levels were highest in infants, moderate-to-low in toddlers/children, and below assay detection limits in adolescents/adults. Germane to the thermogenic FGF21/KLB signaling axis, our results confirm that KLB is absent in the adult hippocampus/aPFC as reported by others. In contrast, we report for the first time that KLB is abundant in the early developing human brain; KLB levels were highest in the infant hippocampus/aPFC and moderately expressed in toddlers. RBM3 is a potent neuroprotective CSP. Thus, the impact of these findings on the observed efficacy of therapeutic hypothermia in neonatal brain injury merits further investigation. PMID- 30399611 TI - Recent Advances in Clinical Allergy and Immunology. AB - Allergic diseases are of great concern because of their high prevalence, which is still rising in several regions, their impact on patients' physical and psychological health, the huge burden they place on patients' quality of life, as well as the socioeconomic consequences that they cause. Recent research has provided new data on both genetic and environmental risk factors of atopic/allergic diseases. The application of new technologies such as "omics" has allowed a better understanding of the pathogenesis and has helped with the identification of therapeutic targets. Immense progress has been made in developing and applying novel, targeted therapies, for example for asthma and urticaria. Intensive efforts are being made to find biomarkers that help to classify patients, to identify their potential responsiveness to specific therapies, and to monitor the disease severity. Based on recent insights in the pathogenesis of food allergy and drug hypersensitivity, novel strategies for diagnostics, allergen avoidance, and induction of tolerance have been developed. Here, we summarize important findings in the field of clinical allergy and immunology with a special focus on asthma, allergic rhinitis, atopic dermatitis, food allergy, urticaria, angioedema, and drug hypersensitivity. PMID- 30399612 TI - Clinicopathologic characteristics and survival of patients with gastroenteropancreatic neuroendocrine neoplasm (GEPNEN) in a multi-ethnic Asian institution





. AB -
Background Epidemiological evidence suggests there are differences in gastroenteropancreatic neuroendocrine neoplasm (GEPNEN) among population groups. We aimed to contribute to the current evidence by evaluating the clinicopathologic characteristics of GEPNEN in a multi-ethnic Asian group. Materials and methods This was a retrospective chart review of patients diagnosed with GEPNEN at a tertiary medical institution at Singhealth Outram Campus, Singapore between 1995 and 2015. Results Two hundred ninety-five patients were included in the evaluation; comprising of Chinese (74.6%), Malay (4.4%), Indian (9.5%) and others (11.5%) ethnic backgrounds. Median age at diagnosis was 59, 52.5% were males. Distribution of disease stage at diagnosis was: localised (42.4%), regional (15.3%) and distant (38.0%). The three most common primary tumour sites were located in the pancreas (38.6%), rectum (19.7%) and stomach (9.5%), which varied significantly with ethnic background and age at diagnosis. Malay patients were younger (median 42 years) at diagnosis than Chinese (60 years). Patients with an appendiceal neuroendocrine neoplasm (NEN) (48 years) were younger compared to esophageal NEN (66 years). Disease stage correlated with primary tumour site and grade (p<0.001). Median overall survival (OS) for all GEPNEN was 10.2 years. Age at diagnosis, disease stage, and grading were prognostic factors of overall survival (OS) in multivariable analyses. Conclusion Our findings correspond with other studies that focus on GEPNEN incidences in Asian countries, with pancreas, rectum and stomach being the most common primary tumour sites. Our findings suggest racial differences in primary tumour site and age of diagnosis. Further prospective population-based registries are required to understand these epidemiological differences.
. PMID- 30399614 TI - Musculoskeletal Radiology Around the Globe: Current Practice and Future Directions. PMID- 30399613 TI - Differential Expression Pattern of Exosome Long Non-Coding RNAs (lncRNAs) and MicroRNAs (miRNAs) in Vascular Endothelial Cells Under Heat Stroke. AB - BACKGROUND Heat stroke is a life-threatening disease which is characterized by a high body temperature and multiple organ dysfunction syndrome. Vascular endothelial cell injury is a main feature of heat stroke. Little is known about the long noncoding RNA (lncRNA) and microRNA (miRNA) expression alternation in endothelial cell exosomes related to heat stroke. The aim of this study was to explore the changes of lncRNAs and miRNAs expression pattern in exosomes derived from vascular endothelial cells under heat stroke temperature conditions. MATERIAL AND METHODS Cultured medium exosomes from HUVECs (human vascular endothelial cells) either under normal temperature or heat stroke temperature conditions were harvested; then RNA was extracted and the lncRNAs and miRNAs were analyzed by high throughput sequencing. RESULTS Ten significantly upregulated and 10 downregulated lncRNAs were identified in exosomes derived from heat stroke temperature treated cells. Furthermore, GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses were used to evaluate the signaling pathway of differential expressions in lncRNAs. Finally, the interaction network of lncRNAs-miRNAs-mRNA was uncovered using ceRNA (competing endogenous RNA) principle via prediction software. CONCLUSIONS These results indicate that the identified lncRNAs and miRNAs in endothelial cell exosomes might serve as non invasive biomarkers for heat stroke. PMID- 30399615 TI - Providing Value-Based Service to a Sprawling Orthopaedics Practice. AB - Health care in the United States is changing, and diagnostic radiology is attempting to adapt to the new norm. A view of the landscape shows mergers, acquisitions, and radiology practices becoming larger. Musculoskeletal (MSK) radiology is trending toward subspecialization, and orthopaedic surgery practices are demanding quality, convenience, and efficiency in imaging services. In other industries, optimization of operations and strategic deployment of resources are standard, but radiology is not quite there yet. This article details our opportunities in MSK imaging to increase market share through service, added value, and improved operational efficiency. PMID- 30399616 TI - Musculoskeletal Radiology Practice Subspecialization in Canada: A Subject of Substance? AB - Scientific and technological advances in medical imaging have had a profound impact on health care around the world including Canada. The cost of imaging, however, continues to rise along with innovation. Building a practical subspecialty musculoskeletal imaging service offers the specialty of radiology an opportunity to show how radiologists can consistently add value and improve outcomes without adding a great cost burden to the health care system. PMID- 30399617 TI - Leveraging Technology to Improve Radiology Workflow. AB - Although advancements in the last decade have automated much of the radiology workflow, there are several areas in the complex imaging process where standardization and innovation can be implemented. We discuss multiple tools and integrations that can help improve operational efficiency, quality, and safety. PMID- 30399618 TI - Artificial Intelligence in Radiology: Current Technology and Future Directions. AB - Artificial intelligence (AI) has been heralded as the next big wave in the computing revolution and touted as a transformative technology for many industries including health care. In radiology, considerable excitement and anxiety are associated with the promise of AI and its potential to disrupt the practice of the radiologist. Radiology has often served as the gateway for medical technological advancements, and AI will likely be no different. We present a brief overview of AI advancements that have driven recent interest, offer a review of the current literature, and examine the most likely ways that AI will change radiology in the coming years. PMID- 30399619 TI - Therapeutic Intervention in Musculoskeletal Radiology: Current Practice and Future Directions. AB - Over the last several decades, the volume and range of therapeutic musculoskeletal (MSK) interventions that radiologists can offer their patients has dramatically increased. With new materials and improving imaging modalities, as well as significant investment in research, the field of MSK interventional radiologic intervention will likely continue to expand. In this article, we summarize the range of interventions currently available to the MSK radiologist. We also seek to explore new and emerging techniques that may become commonplace in the near future while considering the challenges that may lie ahead in the field of MSK radiology. PMID- 30399620 TI - Musculoskeletal Imaging: Current Practice and Future Directions. AB - Musculoskeletal (MSK) radiology plays a crucial role in the diagnosis and management of MSK disorders and has rapidly expanded in tandem with advances in technology and improved access to imaging. Although anatomical imaging remains the mainstay of MSK radiology, significant progress has been made in functional and molecular imaging as well as in hybrid imaging with an expanding armament of technologies becoming available or in development. A vast array of research is occurring in MSK imaging, and this review article highlights some of the most promising current and future clinical applications in development in each of the major imaging modalities. Identifying the clinical utility of these technologies in an era of rising health care costs is an important challenge for MSK radiologists. PMID- 30399621 TI - Role of Musculoskeletal Radiology in Modern Sports Medicine. AB - Musculoskeletal radiology's role in the recent and continued evolution of sports medicine is an exciting and expanding one. In this article we explore a variety of the ways that musculoskeletal radiology contributes to current practices in modern sports medicine, discussing advances across a variety of imaging modalities in the care of both elite athletes and so-called weekend warriors. We describe the technical and ethical factors pertaining to image-guided therapeutic intervention in athletes and speculate on the potential for future developments in the role of imaging in deciding when an athlete may return to participation. We also explore the recent shift to the delivery of imaging facilities at sporting events and in stadiums. PMID- 30399622 TI - Musculoskeletal Radiology in the Middle East: Training Programs, Current Practice, and Future Directions. AB - This article outlines the development of radiology training in the Middle East. It discusses the history of radiology in the region and current available pathways to subspecialize in musculoskeletal (MSK) radiology. Owing to the rapidly changing demographics and health indicators in the region, a major shift has occurred in the government's focus in directing more resources to advance the health care system. This in addition to intraregional initiatives, such as the establishment of many radiologic societies, has provided strong incentives toward developing radiology training programs in the region. There are profound differences in the region regarding the development of radiology, with only few countries offering structured radiology training programs and MSK radiology fellowships. To keep up with the explosion of information in imaging technology and hold clinical ground, current and future MSK radiologists must overcome certain challenges and change their approach to stay clinically relevant. PMID- 30399623 TI - Training in Musculoskeletal Radiology in Europe: Philosophy, Challenges, and Practical Implementation. AB - This article provides an overview of the philosophy, mechanisms, and difficulties involved in the establishment of integrated training programs in medicine, radiology, and specifically musculoskeletal radiology across the European Union. PMID- 30399624 TI - A MSK Radiologist's Early Experience as a Department Chair: Climbing the Horizontal Ladder. AB - A radiologist's training is designed to produce a professional with excellent interpretation skills. However, in today's health care environment, a successful radiologist may not be a successful leader or the opposite may be true. Leadership requires a different set of skills with knowledge of common concepts across all levels of health care delivery. When asked to take on administrative responsibilities, you anticipate constant work with occasional glory, but you may not realize the ladder of success is actually horizontal and the spotlight quite bright.In this personal narrative, I have illustrated my pathway to the chair position in the context of climbing the career ladder and entering the stage of leadership. I discuss common concerns facing radiology today and how we can all use our experience and leadership skills to overcome these challenges with effective solutions. PMID- 30399625 TI - Inter-Rater Reliability of Pain Provocation Tests for Painful Lumbar Facet Joints. A Pilot Study. AB - BACKGROUND: With a life-time prevalence of 39%, low back pain (LBP) is one of the most common musculoskeletal disorders. Correct diagnosis of underlying causes is commonly seen as a prerequisite for successful therapy of LBP. Currently, there is no useful, non-invasive clinical test to diagnose painful lumbar zygapophyseal joints. Clinical tests with high diagnostic accuracy are therefore desirable. Inter-rater reliability is commonly seen as a prerequisite of test validity. The objective of this pilot study was thus to evaluate inter-rater reliability of new clinical pain provocation tests for diagnosing painful lumbar zygapophyseal joints. If a clinically significant level of inter-rater reliability were to be determined, this study could constitute a first step towards establishing the clinical utility of this new set of tests in the structural diagnosis of low back disorders. MATERIAL AND METHODS: Patients participating in this study were recruited in a specialist hospital throughout June 2015 until September 2016. Both female and male patients with current LBP, with or without buttock or lower extremity symptoms were screened for inclusion. Patients had preferably to be 50 years or older in order to be included in this study. The upper age limit was set at 90 years. They also had to be fluent in German to be able to follow verbal instructions. Exclusion criteria comprised the presence of red flags, surgical spinal fusion at any level of the lumbar spine, discectomy within the past 12 months, radiculopathy and/or radicular pain, interventional treatments for the IVD, SIJs or ZAJs within the past three months, psychiatric disorders, current litigation issues concerning back pain, and central nervous system diseases. Three certified manual therapy instructors tested patients independently. Fleiss' kappa values and percent agreements were calculated. RESULTS: Subjects included a sample of 48 patients (15 males and 33 females) with a mean age of 66.48 years (range 33 - 90) presenting at a specialist hospital with low back pain. The new pain provocation tests for lumbar zygapophyseal joints showed moderate reliability (Fleiss' kappa = 0.46) and an overall percent agreement of 68.8%. Separate tests for the zygapophyseal joints of L5-S1 showed fair reliability (Fleiss' kappa = 0.37) and an overall percent agreement of 64.6%. Unidimensional tests that were used in the study to exclude the intervertebral disc as a nociceptive generator showed fair reliability as well (average kappa of 0.28 and 0.39, respectively). Neither drop outs nor adverse events occurred. CONCLUSION: The new pain provocation tests for lumbar zygapophyseal joints showed clinically significant levels of inter-rater reliability. Validation of these tests against fluoroscopy-guided medial branch blocks is warranted. PMID- 30399626 TI - [Systematic Reviews and Meta-analyses - Reading, Understanding, Interpreting]. AB - The rising number of medical publications makes it difficult to keep up-to-date on scientific knowledge. In recent years, reviews in the form of narrative or systematic publications and meta-analyses have increased. These can only be interpreted and evaluated if the reader understands the techniques used. This review article describes the differences between narrative and systematic reviews, together with the characteristics of meta-analysis, and discusses their interpretation. The concept of systematic reviews and meta-analysis includes a systematic literature search and summary, together with an appraisal of the quality of the publications. Systematic reviews are often considered to be original studies due to their structure and ability to reduce bias. PMID- 30399627 TI - Video Comment on Michel Kahaleh et al. PMID- 30399628 TI - Video Comment on Carlos Robles-Medranda et al. PMID- 30399629 TI - Video Comment on Andre Ignee et al. PMID- 30399630 TI - Video Comment on Lobke Desomer et al. PMID- 30399631 TI - Video Comment on Juan E. Corral et al. PMID- 30399632 TI - Third-space endoscopy - can we see light at the end of the tunnel? PMID- 30399633 TI - Cholangioscopic diagnostic classification of bile duct lesions: a worthwhile task, not an easy one. PMID- 30399634 TI - What is the place of pancreatic endoscopic ultrasound elastography in 2018? PMID- 30399635 TI - [French comment on article Gastric peroral endoscopic myotomy for the treatment of refractory gastroparesis: a multicenter international experience]. PMID- 30399636 TI - [French comment on article Reliability and accuracy of a novel classification system using peroral cholangioscopy for the diagnosis of bile duct lesions]. PMID- 30399637 TI - [French comment on article Endoscopic ultrasound elastography of small solid pancreatic lesions: a multicenter study]. PMID- 30399638 TI - [French comment on article The clinical significance and synchronous polyp burden of large (>= 20mm) sessile serrated polyps in patients without serrated polyposis syndrome]. PMID- 30399639 TI - Evaluation of Preeclampsia Results after Use of Metformin in Gestation: Systematic Review and Meta-analysis. AB - OBJECTIVE: Does the use of metformin have an influence on the outcomes of preeclampsia (PE)? SOURCES OF DATA: The descriptors pregnancy, metformin, treatment, and preeclampsia associated with the Boolean operators AND and OR were found in the MEDLINE, LILACS, Embase and Cochrane databases. A flowchart with exclusion criteria and inclusion strategy using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol, and eligibility criteria was used. Data were extracted regarding the type of study, the applied dosage, treatment time, segment, bias risks, and the Patient, Intervention, Comparison and Outcome (PICO) strategy to identify the quality of the study. SELECTION OF STUDIES: Total number of journals in the initial search (n = 824); exclusions from repeated articles on different search engines (n = 253); exclusions after reading the titles, when the title had no correlations with the proposed theme (n = 164); exclusions due to incompatibility with the criteria established in the methodological analysis (n = 185), exclusion of articles with lower correlation with the objective of the present study (n = 187); and final bibliographic selection (n = 35). DATA COLLECTION: At first, a systematic review of the literature was performed. Subsequently, from the main selection, randomized and non-randomized trials with metformin that presented their results in absolute and relative numbers of PE outcomes were selected. The variables were treated statistically in the meta-analysis with the Review Manager software (RevMan), version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration. Denmark in the Hovedistaden region. SYNTHESIS OF DATA: The study showed that metmorfin presented greater preventive effects for pregnancy-induced hypertension and was less effective for PE. CONCLUSION: Metformin may gain place in preventive treatments for PE, once the dosages, the gestational age, and treatment time are particularly evaluated. A methodological strategy with an improved perspective of innovative and/or carefully progressive dosages during pregnancy to avoid side effects and the possibility of maternal-fetal risks is suggested. PMID- 30399640 TI - ? PMID- 30399641 TI - [Long-Term Follow-Up in Childhood Cancer Survivors - Position paper 2018 of the working group "long-term follow-up" of the Society of Pediatric Oncology and Hematology (GPOH) on long-term surveillance, long-term follow-up and late effect evaluation in pediatric oncology patients]. AB - Nowadays, childhood cancer patients survive much more often than they did 40 years ago. Therefore, the cure rates rise over 80%. Approximately 33,000 cured childhood cancer patients are documented by the German Childhood Cancer Registry (GCCR) for long-term follow-up in Germany. But does that mean, they are healthy, too? When compared to the normal population, it can be seen that morbidity and mortality are significantly higher among former childhood cancer patients. In two out of three survivors, the cancer and its treatments can lead to treatment related late complications 30 years later; in about one-third, these late complications are classified as severe. A structured long-term follow-up is needed to detect and to treat new diseases early. The purpose of this position paper is to update the first position paper from 2007. Current developments are described, how appropriate aftercare structures and aftercare facilities should be planned, taking into account existing structures and increasing needs. PMID- 30399642 TI - [Acute Promyelocytic Leukemia: New treatment strategies with ATRA and ATO - AML BFM-Recommendations]. AB - The treatment of acute promyelocytic leukemia (APL) has changed significantly in recent years. Today, APL patients with standard risk (also known as low risk) can be treated chemotherapy-free only with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). For high-risk patients, induction chemotherapy should be added. The curative results are good and comparable to those achieved in the past with chemotherapy plus ATRA. However, toxicities, especially infectious complications, are reduced. The main risk remains early lethal bleeding. Timely diagnosis and early ATRA treatment can reduce this risk. This review presents and discusses current treatment strategies and recommendations for APL in children. PMID- 30399643 TI - [A Short Neonatologic Case Report: Salt Cod and Blue Lips]. PMID- 30399644 TI - ? PMID- 30399645 TI - Evidence for a Role of ACTN3 R577X Polymorphism in Football Player's Career Progression. AB - The aim was to investigate a possible role of the ACTN3 R577X polymorphism in a Brazilian football player's career progression. 2 questions were formulated: 1. Does ACTN3 polymorphism affect the probability of an individual being a professional football player? 2. Does this polymorphism affect the progression of the athlete throughout his career? The study included 353 players from first division Brazilian football clubs in the following categories: under-14 (U-14), U 15, U-17, U-20, and professional (PRO). The control group (CON) was composed of 100 healthy non-athletes. The chi-squared test was used to assess differences between the allele and genotype frequencies. Comparing football categories, the XX genotype was less frequent among professional players than in the U-20 (p<0.05) or the U-15 category (p<0.05). The RX genotype also presented more frequently in the PRO category than the U-14 category (p<0.05). Moreover, a trend towards a higher frequency of the RX genotype and a lower frequency of the XX genotype was observed in the professional category compared to U-20. These results suggest that the genotype in the ACTN3 polymorphism affects the probability of a football player progressing throughout his career and becoming professional, meaning that playing football selects against the ACTN3 XX genotype. PMID- 30399646 TI - Predicted Equation for VO2 Based on a 20-Meter Multistage Shuttle Run Test for Children. AB - This study compared maximum oxygen consumption (VO2max) on a 20-meter multistage shuttle run test (20-Srt) with a cardiopulmonary exercise test (CPET) to determine a VO2max prediction equation for a 20-Srt in children aged 6-10 years. Eighty healthy children performed the CPET on a treadmill, while the 20-Srt took place on a sports court. Heart rate (HR) was measured and the expired gases were continuously measured breath-by-breath using a portable gas analyzer. The VO2max was lower (p<0.05) in CPET than 20-Srt for all, female, and male participants, respectively (46.3+/-7.9 vs. 48.7+/-4.6; 42.7+/-7.8 vs. 46.7+/-4.8; 49.3+/-6.8 vs. 50.4+/-3.9, mL.kg-1.min-1). The standard error estimates were between 3.0 and 3.6 and considered as not clinically relevant if less than 5 mL.kg-1.min-1. The intraclass correlation coefficient between the VO2 in CPET and in 20-Srt was 0.74 (CI95% 0.55-0.84) and considered moderately reliable. The linear multiple regression excluded sex, body mass index and fat-free mass and retained the maximum speed and age in the predictive equation. The 20-Srt estimates the VO2max with moderate reliability and the predictive equation was VO2maxpred=4.302+(maximum speed*5.613)-(age*1.523) for children aged 6-10 years. PMID- 30399647 TI - Fc-gamma receptor expression profile in a North-Indian cohort of pediatric-onset systemic lupus erythematosus: An observational study. AB - BACKGROUND: Polymorphisms in the Fcgamma-receptor (FcgammaR) have been associated with increased susceptibility to systemic lupus erythematosus (SLE). There is a paucity of data on FcgammaR expression pattern in pediatric subjects with SLE. The aim of the study was to assess the expression of various FcgammaRs by flow cytometry in children with pediatric-onset SLE (pSLE). METHODS: Thirty-one children aged 0-15 years fulfilling 2012 Systemic Lupus International Collaborating Clinics Classification Criteria for SLE were enrolled. Disease active (n = 14) and the inactive group were delineated using the SLE Disease Activity Index (SLEDAI). Thirteen age- and sex-matched controls were also enrolled. Blood samples of cases and controls were assessed for CD64, CD32B and CD16 expression on B lymphocytes, neutrophils and monocytes by flow cytometry using standard techniques. Median fluorescence intensity (MFI) and percentage expression were calculated using the FACS DIVA software and Kaluza software. RESULTS: Median fluorescence intensity and percentage expression of CD64 on monocytes (MFI: 1.71 vs 1.51, P = 0.86) and neutrophils (MFI: 0.42 vs 0.64, P = 0.3) were comparable between patients and controls. MFIs of CD16 expression on neutrophils (3.47 vs 11.4, P = 0.05) and monocytes (1.28 vs 3.45, P = 0.07) were lower in patients compared to controls. CD32B expression on lymphocytes (MFI: 0.56 vs 1.37; % expression:18.3% vs 12.32%) was also comparable between cases and controls. Expression of CD64, CD16, and CD32B were also comparable between patients with active and inactive disease. CONCLUSION: No significant differences were observed in FcgammaR expression between patients and controls. However, the overall trends of FcgammaR expression and decreased CD16 on monocytes and neutrophils are in consonance with data from larger cohorts of adult SLE patients. PMID- 30399648 TI - The auxin influx carrier, OsAUX3, regulates rice root development and responses to aluminium stress. AB - In rice, there are five members of the auxin carrier AUXIN1/LIKE AUX1 family; however, the biological functions of the other four members besides OsAUX1 remain unknown. Here, by using CRISPR/Cas9, we constructed two independent OsAUX3 knock down lines, osaux3-1 and osaux3-2, in wild-type rice, Hwayoung (WT/HY) and Dongjin (WT/DJ). osaux3-1 and osaux3-2 have shorter primary roots (PRs), decreased lateral root (LR) density, and longer root hairs (RHs) compared with their WT. OsAUX3 expression in PRs, LRs, and RHs further supports that OsAUX3 plays a critical role in the regulation of root development. OsAUX3 locates at the plasma membrane and functions as an auxin influx carrier affecting acropetal auxin transport. OsAUX3 is up-regulated in the root apex under aluminium (Al) stress, and osaux3-2 is insensitive to Al treatments. Furthermore, 1 naphthylacetic acid accented the sensitivity of WT/DJ and osaux3-2 to respond to Al stress. Auxin concentrations, Al contents, and Al-induced reactive oxygen species-mediated damage in osaux3-2 under Al stress are lower than in WT, indicating that OsAUX3 is involved in Al-induced inhibition of root growth. This study uncovers a novel pathway alleviating Al-induced oxidative damage by inhibition of acropetal auxin transport and provides a new option for engineering Al-tolerant rice species. PMID- 30399649 TI - NO as a multimodal transmitter in the brain: discovery and current status. AB - NO operates throughout the brain as an intercellular messenger, initiating its varied physiological effects by activating specialized GC-coupled receptors, resulting in the formation of cGMP. In line with the widespread expression of this pathway, NO participates in numerous different brain functions. This review gives an account of the discovery of NO as a signalling molecule in the brain, experiments that originated in the search for a mysterious cGMP-stimulating factor released from central neurones when their NMDA receptors were stimulated, and summarizes the subsequent key steps that helped establish its status as a central transmitter. Currently, various modes of operation are viewed to underlie its diverse behaviour, ranging from very local signalling between synaptic partners (in the orthograde or retrograde directions) to a volume-type transmission whereby NO synthesized by multiple synchronous sources summate spatially and temporally to influence intermingled neuronal or non-neuronal cells, irrespective of anatomical connectivity. PMID- 30399650 TI - Electrogenerated Chemiluminescence with Peroxydisulfate as a Coreactant Using Boron Doped Diamond Electrodes. AB - We report on the use of boron doped diamond electrodes for the electrochemiluminescence (ECL) of the coreactant peroxydisulfate and the luminophore ruthenium(II)-tris(2,2'-bipyridine). Compared to common electrode materials (i.e., Pt, Au, glassy carbon), boron doped diamond has a large overpotential for the evolution of hydrogen in aqueous electrolyte solutions. This intrinsic feature enables reductive-oxidation ECL with peroxydisulfate to be obtained without interference from hydrogen evolution and with high reproducible signals and stable emission. We investigated the effects of the peroxydisulfate concentration and the pH on the ECL emission to find the optimal conditions for enhancing the signal. PMID- 30399651 TI - Fringe jump compensation techniques for the time-averaging zero-crossing phase measurement in the KSTAR millimeter-wave interferometer. AB - A fringe jump compensation algorithm has been developed for a phase measurement that measures the phase within a single fringe. The algorithm is extremely useful in the case of the time-averaging zero-crossing phase detector on noisy environments. When the noise level on the measurements is not sufficiently suppressed, the signals near the fringe jump show a negative slope instead of a sharp drop. The slope brings an ambiguity over the compensation process. An algorithm with an additional channel that measures the phase of a half fringe shift has been applied in the millimeter-wave interferometer on the Korea Superconducting Tokamak Advanced Research device. These techniques removed the ambiguity in most cases. The algorithm can provide a most simple, robust, and cost-effective solution for the phase measurement system in various fields. PMID- 30399652 TI - Electrostatic design and conditioning of a triple point junction shield for a 200 kV DC high voltage photogun. AB - Nuclear physics experiments performed at the Continuous Electron Beam Accelerator Facility (CEBAF) at the Jefferson Lab require a DC high voltage photogun to generate polarized electron beams from GaAs photocathodes. The photogun uses a tapered ceramic insulator that extends into the vacuum chamber and mechanically holds the cathode electrode. Increasing the operating voltage from nominal -130 kV to -200 kV will provide lower beam emittance, better transmission through injector apertures, and improved photocathode lifetime. This desire to increase the photogun operating voltage led to the design of a triple-point-junction shield electrode which minimizes the electric field at the delicate insulator metal-vacuum interface and linearizes the potential across the insulator, thus reducing the risk of arcing along the ceramic insulator. This work describes the results obtained using COMSOL(r) electrostatic-field simulation software and presents the high voltage conditioning results of the upgraded -200 kV CEBAF photogun. PMID- 30399653 TI - Turbulence measurements on the high and low magnetic field side of the DIII-D tokamak. AB - In this paper, we address the challenging question of measuring turbulence levels on the high magnetic field side (HFS) of tokamak plasmas. Although turbulence measurements on the HFS can provide a stringent constraint for the turbulence model validation, to date only low magnetic field side (LFS) measured turbulence has been used in validation studies. To address this issue, an eight channel Correlation Electron Cyclotron Emission (CECE) system at DIII-D was modified to probe both LFS and HFS. In contrast to the second harmonic extraordinary mode electron cyclotron resonance emission that is typically used in CECE, we show that it is possible to probe the HFS using fundamental O-mode electron cyclotron resonance emission. The required hardware modifications for the HFS measurements are presented here, and the potential issues in this measurement are discussed. PMID- 30399654 TI - A rotary and reciprocating scintillator based fast-ion loss detector for the MAST U tokamak. AB - The design and unique feature of the first fast-ion loss detector (FILD) for the Mega Amp Spherical Tokamak - Upgrade (MAST-U) is presented here. The MAST-U FILD head is mounted on an axially and angularly actuated mechanism that makes it possible to independently adapt the orientation [0 degrees , 90 degrees ] and radial position [1.40 m, 1.60 m] of the FILD head, i.e., its collimator, thus maximizing the detector velocity-space coverage in a broad range of plasma scenarios with different q95. The 3D geometry of the detector has been optimized to detect fast-ion losses from the neutral beam injectors. Orbit simulations are used to calculate the strike map and predict the expected signals. The results show a velocity-space range of [4 cm, 13 cm] in gyroradius and [30 degrees , 85 degrees ] in pitch angle, covering the entire neutral beam ion energy range. The optical system will provide direct sight of the scintillator and simultaneous detection with two cameras, giving high spatial and temporal resolution. The MAST U FILD will shed light on the dominant fast-ion transport mechanisms in one of the world's two largest spherical tokamaks through absolute measurements of fast ion losses. PMID- 30399655 TI - The high-k poloidal scattering system for NSTX-U. AB - An 8-channel, high-k poloidal far-infrared (FIR) scattering system is under development for the National Spherical Torus eXperiment Upgrade (NSTX-U). The 693 GHz poloidal scattering system replaces a 5-channel, 280 GHz high-k toroidal scattering system to study high-k electron density fluctuations on NSTX-U. The FIR probe beam launched from Bay G is aimed toward Bay L, where large aperture optics collect radiation at 8 simultaneous scattering angles ranging from 2 degrees to 15 degrees . The reduced wavelength in the poloidal system results in less refraction, and coupled with a new poloidal scattering geometry, extends measurement of poloidal wavenumbers from the previous limit of 7 cm-1 up to >40 cm-1. Steerable launch optics coupled with receiver optics that can be remotely translated in 5 axes allow the scattering volume to be placed from r/a = 0.1 out to the pedestal region (r/a ~ 0.99) and allow for both upward and downward scattering to cover different regions of the 2D fluctuation spectrum. PMID- 30399656 TI - Design, development, and testing of an environmental P-T cell for infrared spectroscopy measurements. AB - Water absorption bands due to superficially adsorbed molecules often dominate the near-infrared spectra of particulate minerals and rocks, when measured in the laboratory in the reflectance mode. In order to remove this, the spectral effect is thus necessary to acquire spectra of samples in vacuum and at higher temperatures. With the aim to accomplish this task, we developed an environmental cell to perform infrared spectroscopic measurements at controlled pressure temperature conditions. Currently the cell allows one to measure reflectance spectra in the temperature range from room values up to 300 degrees C (573 K), in the pressure range of 103-10-6 mbar. The acquisition of spectra continuously in two distinct phases, namely, during a preliminary pumping stage (at room T) and subsequently during a heating stage (in vacuum), permits to highlight and characterize separately the effect of pressure and temperature on infrared spectra. PMID- 30399657 TI - Using integrated data analysis to extend measurement capability (invited). AB - The analysis approach called integrated data analysis (IDA) provides a means to exploit all information present in multiple streams of raw data to produce the best inference of a plasma parameter. This contrasts with the typical approach in which information (data) from a single diagnostic is used to measure a given parameter, e.g., visible bremsstrahlung -> Z eff. Data from a given diagnostic usually contain information on many parameters. For example, a Thomson scattering diagnostic is sensitive to bremsstrahlung and line emission in addition to electron temperature. This background light is typically subtracted off and discarded but could be used to improve knowledge of Z eff. IDA encourages explicit awareness of such information and provides the quantitative framework to exploit it. This gives IDA the ability to increase spatial and temporal resolution, increase precision and accuracy of inferences, and measure plasma parameters that are difficult or impossible to measure using single diagnostic techniques. One example is the measurement of Z eff on Madison symmetric torus using IDA since no single diagnostic can provide a robust measurement. As we enter the burning plasma era, application of IDA will be critical to the measurement of certain parameters, as diagnostic access in the harsh fusion environment will be extremely limited. PMID- 30399658 TI - A periodic magnetic field as a special environment for scientific research created by rotating permanent magnet pairs. AB - A magnetic field is an often-encountered physical environment that can affect many processes, including chemical, physical, and biochemical processes. Utilization of magnetic fields is thus very helpful in a wide variety of applications, such as scientific research in various disciplines, materials processing (e.g., crystal growth and separation) in industry, and nuclear fusion. There are many different types of magnetic fields generated by different magnets, such as superconducting magnets, electromagnets, hybrid magnets, pulsed magnets, and permanent magnets. In this paper, we introduce a newly designed periodic magnetic field generated by rotating permanent magnet pairs. Preliminary tests showed that the periodic magnetic field is valuable in water evaporation, silver deposition, and protein crystallization. Apparently, in such a new environment that can generate a periodic magnetic field, a periodic force field will also be simultaneously generated on the sample. Further work shall be carried out to explore the potential applications of this magnetic field. PMID- 30399659 TI - Initial results and designs of dual-filter and plenoptic imaging for high temperature plasmas. AB - Mass injection has found new applications in magnetic fusion including edge localized-mode control. Better understanding of injected-mass-plasma interactions requires spatially and temporally resolved diagnostics that can characterize the dynamics of the mass interactions with plasmas. Fast imaging can be used to characterize the ionization dynamics such as the propagation of the ionization front, which moves at the thermal sound or higher speed, and mixing of the neutral atoms with the ambient plasma. Multi-wavelength spectral imaging is promising since different parts of the plasma give different spectral signatures. Here we describe a dual-spectral imaging technique based on a monochromatic camera sensor and filters with two passing optical wavelengths. The method is shown to improve image contrast, and it compares favorably with alternatives such as color cameras and methods using a filter wheel. Further improvements through relative filter area ratios and plenoptic imaging are possible. The initial results from EAST and plenoptic imaging are also included. PMID- 30399660 TI - Improved design for Heliotron J soft X-ray diagnostic for tomographic reconstruction studies. AB - Identifications of the plasma boundary shape and mode structure are important problems for the studies of the magnetohydrodynamics equilibrium and stability studies. Imaging diagnostics have the possibility to measure the plasma boundary shape and mode structure directly. The soft X-ray (SX) tomography is an imaging diagnostic for offering these direct measurements. However, SX tomography is by nature a limited angle tomography and provides a challenge as an ill-condition inverse problem. The reconstructed profiles depend heavily on the quality of measurements along with the employed inversion algorithm. This paper provides a detailed description of tomographic reconstruction of simulated SX measurements from the current SX diagnostic design of Heliotron J (H-J), which is a medium size heliotron device. Heliotron J has a unique magnetic geometry, and the quantitative identification of the plasma boundary and mode structure is a critical problem. The Phillip-Tikhonov regularization is employed to address the inversion problem. Finally, a new design for Heliotron J soft X-ray diagnostic is discussed which holds enhanced capabilities for tomographic reconstructions especially for the high poloidal number perturbations. PMID- 30399661 TI - Solid-state framing camera operating in interferometric mode. AB - A high speed solid-state framing camera has been developed which can operate in interferometric mode. This camera measures the change in the index of refraction of a semiconductor when x-rays are incident upon it. This instrument uses an x ray transmission grating/mask in front of the semiconductor to induce a corresponding phase grating in the semiconductor which can then be measured by an infrared probe beam. The probe beam scatters off of this grating, enabling a measure of the x-ray signal incident on the semiconductor. In this particular instrument, the zero-order reflected probe beam is attenuated and interfered with the diffracted orders to produce an interferometric image on a charge coupled device camera of the phase change induced inside the semiconductor by the incident x-rays. PMID- 30399662 TI - A portable low-power integrated current and temperature laser controller for high sensitivity gas sensor applications. AB - A low-noise, low power, high modulation-bandwidth design integrated laser current and temperature driver with excellent long-term stability is described. The current driver circuit is based on the Hall-Libbrecht design. A high sensitivity and a stable driver current were obtained using a differential amplifier and an integral amplifier. The set-point voltage for the current driver came from an ultra-compact, ultra-low temperature coefficient voltage reference chip or the digital to analog convertor output of a microcontroller or a modulation signal. An integral temperature chip, referred to as ADN8834, was used to drive the thermoelectric cooler controller of the distributed feedback (DFB) laser. The internal amplifier acquired the feedback current of the temperature sensor. The proportional-integral-derivative parameters such as proportion, integration, and derivative were set by external resistors. The short- and long-term stability and linearity of the developed laser driver were tested using a DFB laser with a central wavelength of 6991 cm-1. The laser driver was validated for high sensitivity gas sensing of CO2 and C2H2 via a laser absorption spectroscopy experiment. The limits of detection were less than 11.5 ppm and 0.124 ppm for CO2 and C2H2, respectively. Direct absorption measurements and the 1-f and 2-f demodulation signals confirmed the capabilities of the proposed laser driver system in high-sensitivity gas sensing applications. The driver unit can readily be accommodated into many portable laser sensing devices for industrial applications. PMID- 30399663 TI - Multipoint vertical-Thomson scattering diagnostic on HL-2A tokamak. AB - Some progress has been made to develop the multipoint Thomson scattering (TS) diagnostic for the HL-2A tokamak physics experiments. Hardware of silicon avalanche photodiode detector electronics is improved, which provides two output signal channels. In one channel, only the rapid TS signal is the output after deducting the influence of the background slow-varying plasma light. In the other, both the rapid TS signal and the plasma background signal are the output. In the latest HL-2A experiment campaign, the newly developed electronics are tested and TS signals can be obtained from each of the two channels, where the signal is digitized by 12-bit transient recorder sampled at 1 GS/s. Laser beam alignment is fulfilled by using motorized stages to control the laser beam passing through ~10 mm-wide narrow throats of the lower and upper closed divertors with small movements and then the stray laser light is reduced. New modules of fast digitizers with more than 100 channels are installed and will be used to record TS pulse signals. On the basis of these achievements, about 15 point measurements of plasma electron temperature and density by Thomson scattering diagnostic will come into operation in the upcoming HL-2A experiment campaign. PMID- 30399664 TI - Steady state magnetic sensors for ITER and beyond: Development and final design (invited). AB - The measurements of the magnetic field in tokamaks such as ITER and DEMO will be challenging due to the long pulse duration, high neutron flux, and elevated temperatures. The long duration of the plasma pulse makes standard techniques, such as inductive coils, prone to errors. At the same time, the hostile environment, with repairs possible only on blanket exchange, if at all, requires a robust magnetic sensor. This contribution presents the final design of novel, steady-state, magnetic sensors for ITER. A poloidal array of 60 sensors mounted on the vacuum vessel outer shell contributes to the measurement of the plasma current, plasma-wall clearance, low-frequency MHD modes and will allow for crosscheck with the outer-vessel inductive coils. Each sensor hosts a pair of bismuth Hall probes, themselves an outcome of extensive R&D, including neutron irradiations (to 1023 n/m2), temperature cycling tests (73-473 K) and tests at high magnetic field (to 12 T). A significant effort has been devoted to optimize the sensor housing by design and prototyping. The production version features an indium-filled cell for in situ recalibration of the onboard thermocouple, vital for the interpretation of the Hall sensor measurement. PMID- 30399665 TI - Distribution of collected target debris using the large area solid debris radiochemistry collector. AB - A large area solid radiochemistry collector was deployed at the National Ignition Facility (NIF) with a collection efficiency for post-shot, solid target debris of approximately 1% of the total 4pi solid angle. The collector consisted of a 20-cm diameter vanadium foil surrounded by an aluminum side-enclosure and was fielded 50 cm from the NIF target. The collector was used on two NIF neutron yield shots, both of which had a monolayer of 238U embedded in the capsule ablator 10 MUm from the inner surface. Fission and activation products produced in the 238U were collected, and subsequent analyses via gamma spectroscopy indicated that the distribution of fission products was not uniform, with peak and valley fission products preferentially collected on the vanadium and low- and high-mass fission products primarily located on the aluminum side-enclosure. The results from these shots will be used to design future nuclear data experiments at NIF. PMID- 30399666 TI - Initial beam emission spectroscopy diagnostic system on HL-2A tokamak. AB - A beam emission spectroscopy system is being developed and deployed on the HL-2A tokamak to measure local low wavenumber (k ? rho i < 1) density fluctuations by measuring the Doppler-shifted emission from a 50 kV deuterium heating neutral beam. High spatial resolution (Deltar <= 1 cm, Deltaz <= 1.5 cm) measurements are achieved with customized in-vacuum optics. High frequency, high-gain preamplifiers sample the light intensity at a Nyquist frequency of 1 MHz and achieve a high S/N ratio via high optical throughput, low-noise preamplifiers, and high quantum efficiency photodiodes. A first set of 16 detector channels [configured in an 8 (radial) * 2 (poloidal) array] has been installed and tested at HL-2A, covering the radial range r/a = 0.8-1.1. The frequency and wavenumber spectra have been measured under different plasma conditions. Initial measurements have demonstrated the capability of measuring edge plasma density fluctuation spectra and the poloidal flow velocity fields with a high S/N ratio. PMID- 30399667 TI - Signal to noise ratio of upgraded imaging bolometer for KSTAR. AB - An InfraRed imaging Video Bolometer (IRVB) was installed on KSTAR in 2012 having a ~2 MUm * 7 cm * 9 cm Pt foil blackened with graphite and a 5 mm * 5 mm aperture located 7.65 cm from the foil with 16 * 12 channels and a time resolution of 10 ms. The IR camera was an Indigo Phoenix (InSb, 320 * 256 pixels, 435 fps, <25 mK). In 2017, the IRVB was upgraded by replacing the IR camera with a FLIR SC7600 (InSb, 640 * 512 pixels, 105 fps, <25 mK). The aperture area was reduced by approximately half to 3.5 mm * 3.5 mm, and the number of channels was quadrupled to 32 * 24. A synthetic image derived using the projection matrix for the upgraded IRVB from a Scrape Off Layer Plasma Simulator (SOLPS) model with 146 kW of total radiated power had a maximum signal of 7.6 W/m2 and a signal to noise ratio (SNR) of 11. Experimental data for a plasma with parameters similar to the SOLPS model (total radiated power of 158 kW) had a maximum signal of 12.6 W/m2 and noise equivalent power density (SNR) of 0.9 W/m2 (14). PMID- 30399668 TI - Magnetic diagnostic suite of the C-2W field-reversed configuration experiment. AB - A fundamental component of any magnetically confined fusion experiment is a firm understanding of the magnetic field. The increased complexity of the C-2W machine warrants an equally enhanced diagnostic capability. C-2W is outfitted with over 700 magnetic field probes of various types. They are both internal and external to the vacuum vessel. Inside, a linear array of innovative in-vacuum annular flux loop/B-dot combination probes provide information about plasma shape, size, pressure, energy, temperature, and trapped flux when coupled with established theoretical interpretations. A linear array of B-dot probes complement the azimuthally averaged measurements. A Mirnov array of 64 3D probes, with both low and high frequency resolution, detail plasma motion and MHD modal content via singular value decomposition analysis. Internal Rogowski probes measure axial currents flowing in the plasma jet. Outside, every feed-through for an internal probe has an external axial field probe. There are many external loops that measure the plasma formation dynamics and the total external magnetic flux. The external measurements are primarily used to characterize eddy currents in the vessel during a plasma shot. Details of these probes and the data derived from their signals are described. PMID- 30399669 TI - X-ray spectrometer throughput model for (selected) flat Bragg crystal spectrometers on laser plasma facilities. AB - At large laser faculties, such as OMEGA and the National Ignition Facility (NIF), x-ray spectrometers are provided by the facility to diagnose plasma conditions or monitor backlighters. Often the calibration of these spectrometers is unknown or out of date. As a remedy to this situation, we present a simple ray trace method to calibrate flat crystal spectrometers using only basic information regarding the optical design of the spectrometer. This model is then used to output photometric throughput estimates, dispersion, solid angle, and spectral resolution estimates. This model is applied to the mono angle crystal spectrometer and Super Snout I at the NIF and the X-Ray Spectrometer at the OMEGA laser facility. PMID- 30399670 TI - Reconstruction and analysis of exploding wire particle trajectories via automatic calibration of stereo images. AB - Quantitative understanding of the physics of dust or granular matter transport significantly impacts several aspects of burning plasma science and technology. This work takes machine vision techniques popular in robotics and self-driving cars and applies them to identification and analysis of microparticles generated from exploding wires. Using only the image frames and knowledge of the intrinsic properties of the cameras, a Python code was written to identify the particles, automatically calibrate the relative image positions, and extract trajectory data. After identifying approximately 50 particles based on the timing of secondary particle explosions, the eight point and random sample consensus algorithms were used to determine the geometric correlation between the cameras. Over 100 particle matches were found between the two camera views. These correlated trajectories were used in subsequent 3D track reconstruction and analysis of the physics behind the particle motion. The 3D reconstruction resulted in accurate positioning of the particles with respect to the experimental setup. The particle motion was consistent with the effects of a 1 g gravitational field modified by drag forces. The methods and analyses presented here can be used in many facets of high temperature plasma diagnostics. PMID- 30399671 TI - On evaluating x-ray imaging crystals with synchrotron radiation. AB - Bent crystals used in diagnostics of plasmas combine x-rays diffracted from across the crystal. Therefore imperfections in the resulting 1-D spectrum or 2-D image are not the best way to find out why one particular crystal may differ in its performance from another and what, if anything, to do about it. Instead, here we want to measure the diffraction locally, with the necessary resolution. Nominally monochromatic and unidirectional radiation from the synchrotron's standard x-ray optics proved to be insufficient for the purpose. Here much better radiation comes from the x-ray topography setup at the x-ray optics testing beamline 1-BM at the Advanced Photon Source, thanks to a specially designed quartz conditioning crystal. Some worrisome features in a bent crystal's diffraction have thereby disappeared, while minor fabrication flaws remain highly visible. PMID- 30399672 TI - Visible spectroscopy diagnostics for tungsten source assessment in the WEST tokamak: First measurements. AB - The present work concerns the measurements obtained with the Tungsten (W) Environment in Steady-state Tokamak (WEST) visible spectroscopy system during the first experimental campaign. This system has been developed in the framework of the WEST project that equipped the existing Tore Supra device with a tungsten divertor in order to test actively cooled tungsten Plasma Facing Components (PFC) in view of preparing for ITER operation. The goal of this diagnostic is to measure the PFC sources and the deuterium recycling with spectral, spatial, and temporal resolution adapted to the predicted power deposition profiles on the objects observed. Three kinds of PFCs are monitored: the Ion Cyclotron Resonance Heating (ICRH) antenna and Low Hybrid Current Drive (LHCD) launcher W limiters; one of the 6 W inner bumpers; and the upper and lower W divertors. Large-aperture in-vessel actively cooled optical systems (f-number ~ 3) were installed for each view and connected to optical fibres. A total of 240 optical fibers can be distributed on various detection systems including a fast response-time, multi channel, filtered photodetector-based "Filterscope" system, developed by Oak Ridge National Laboratory (USA) as well as grating spectrometers optimized for multi-sightline analysis. The first WEST experimental campaign conducted in 2017 has been dedicated to plasma start-up development during which the visible spectroscopy system has provided crucial information related to the impurity content first and then impurity sources. The diagnostic setup for that first experimental campaign was limited to the inner bumper and outer limiters but was sufficient to demonstrate that the optical setup was in accordance with the specifications. The radiance calibration procedure allowed us to estimate fluxes from the main limiter of about 8 * 1018 atoms/(s m2) and to show a first W source radial profile along the outboard limiter. PMID- 30399673 TI - Characterization and calibration of the Thomson scattering diagnostic suite for the C-2W field-reversed configuration experiment. AB - The new C-2W Thomson scattering (TS) diagnostic consists of two individual subsystems for monitoring electron temperature (Te) and density (ne): one system in the central region is currently operational, and the second system is being commissioned to monitor the open field line region. Validating the performance of the TS's custom designed system components and unique calibration of the detection system and diagnostic as a whole is crucial to obtaining high precision Te and ne profiles of C-2W's plasma. The major components include a diode-pumped Nd:YAG laser which produces 35 pulses at up to 20 kHz, uniquely designed collection lenses with a fast numerical aperture, and uniquely designed polychromators with filters sets to optimize a Te ranging from 10 eV to 2 keV. This paper describes the design principles and techniques used to characterize the main components of the TS diagnostic on C-2W, as well as the results of Rayleigh scattering calibrations performed for the whole system response. PMID- 30399674 TI - Applications of thin film plastic scintillator in measurement of soft x rays generated from Z-pinch implosion. AB - A thin film plastic scintillator detector has been developed for the measurement of radiation power and yield of soft x rays produced from Z-pinch implosion. To enable soft x-ray measurements using plastic scintillators, the detector geometry has been specially designed to minimize visible light and alleviate nonlinear behavior. Energy response has been calibrated, and saturation effects have been explored and described in details. The possibility and limitation of its application to such high-density radiation bursts are analyzed. The detector has been fielded on several meters away in vacuum pipes for hundreds of shots at different Z-pinch facilities, and the measured data in these experiments agreed well with the results from other diagnostics, demonstrating the feasibility and reliability of the detector. PMID- 30399675 TI - 2D GEM based imaging detector readout capabilities from perspective of intense soft x-ray plasma radiation. AB - A detecting system based on the Gas Electron Multiplier (GEM) technology is considered for tokamak plasma radiation monitoring. In order to estimate its capabilities in processing and recording intense photon flux (up to ~0.1 MHz/mm2), the imaging effectiveness of GEM detectors was tested with different patterned anode planes (i.e., different signal readouts): a simple hexagonal readout structure and three structures with interconnected electrodes (XY square, XY rectangular, and UXV). It was found that under intense photon flux, all the readouts fail to account for a considerable amount of the incoming signals due to mostly photon position determination ambiguity and overlapped signals. Analysis of the signals that can be used to determine photon position and energy unambiguously showed that the UXV readout structure is more effective among the readouts with interconnected electrodes. Along with similar spatial resolution and accuracy, the UXV based layout could be considered as a quite promising base of the interconnected anode electrodes configuration, keeping in mind that the photon rate capability has to be improved for the final application. PMID- 30399676 TI - Zeeman spectroscopy as a method for determining the magnetic field distribution in self-magnetic-pinch diodes (invited). AB - In the self-magnetic-pinch diode, the electron beam, produced through explosive field emission, focuses on the anode surface due to its own magnetic field. This process results in dense plasma formation on the anode surface, consisting primarily of hydrocarbons. Direct measurements of the beam's current profile are necessary in order to understand the pinch dynamics and to determine x-ray source sizes, which should be minimized in radiographic applications. In this paper, the analysis of the C IV doublet (580.1 and 581.2 nm) line shapes will be discussed. The technique yields estimates of the electron density and electron temperature profiles, and the method can be highly beneficial in providing the current density distribution in such diodes. PMID- 30399677 TI - Development of a backlit-multi-pinhole radiography source. AB - Backlit-pinhole radiography uses a pinhole placed between an x-ray source and a sample. The backlit-multi-pinhole design uses two pinholes on the same substrate, which are separated by a wall, to create two radiographic images projected along similar axes. The wall, a 100-MUm thick titanium foil, prevents x-rays generated near one pinhole from exiting the other pinhole. First results indicate that the multi-pinhole target can create two independent radiographs along similar axes. The images are recorded 2 ns apart. Details of our multi-pinhole design and our first results are discussed. PMID- 30399678 TI - Effect of neutron and gamma -ray on charge-coupled device for vacuum/extreme ultraviolet spectroscopy in deuterium discharges of large helical device. AB - A charge-coupled device (CCD) is widely used as a detector of vacuum spectrometers in fusion devices. Recently, a deuterium plasma experiment has been initiated in a Large Helical Device (LHD). Totally 3.7 * 1018 neutrons have been yielded with energies of 2.45 MeV (D-D) and 14.1 MeV (D-T) during the deuterium experiment over four months. Meanwhile, gamma-rays are radiated from plasma facing components and laboratory structural materials in a wide energy range, i.e., 0.01-12.0 MeV, through the neutron capture. It is well known that these neutrons and gamma-rays bring serious problems to the CCD system. Then, several CCDs of vacuum ultraviolet/extreme ultraviolet/X-ray spectrometers installed at different locations on LHD for measurements of spectra and spatial profiles of impurity emission lines are examined to study the effect of neutrons and gamma rays. An additional CCD placed in a special shielding box made of 10 cm thick polyethylene contained 10% boron and 1.5 cm thick lead is also used for the detailed analysis. As a result, it is found that the CCD has no damage in the present neutron yield of LHD, while the background noise integrated for all pixels of CCD largely increases, i.e., 1-3 * 108 counts/s. The data analysis of CCD in the shielding box shows that the background noise caused by the gamma-ray is smaller than that caused by the neutron, i.e., 41% from gamma-rays and 59% from neutrons. It is also found that the noise can be partly removed by an accumulation of CCD frames or software programming. PMID- 30399680 TI - Design and measurement methods for a lithium vapor box similarity experiment. AB - The lithium vapor box divertor is a concept for handling the extreme divertor heat fluxes in magnetic fusion devices. In a baffled slot divertor, plasma interacts with a dense cloud of Li vapor which radiates and cools the plasma, leading to recombination and detachment. Before testing on a tokamak, the concept should be validated: we plan to study detachment and heat redistribution by a Li vapor cloud in laboratory experiments. Mass changes and temperatures are measured to validate a direct simulation Monte Carlo model of neutral Li. The initial experiment involves a 5 cm diameter steel box containing 10 g of Li held at 650 degrees C as vapor flows out a wide nozzle into a similarly sized box at a lower temperature. Diagnosis is made challenging by the required material compatibility with lithium vapor. Vapor pressure is a steep function of temperature, so to validate mass flow models to within 10%, absolute temperature to within 4.5 K is required. The apparatus is designed to be used with an analytical balance to determine mass transport. Details of the apparatus and methods of temperature and mass flow measurements are presented. PMID- 30399681 TI - Calibration of a neutron time-of-flight detector with a rapid instrument response function for measurements of bulk fluid motion on OMEGA. AB - A newly developed neutron time-of-flight (nTOF) diagnostic with a fast instrument response function has been fielded on the OMEGA laser in a highly collimated line of sight. By using a small plastic scintillator volume, the detector provides a narrow instrument response of 1.7 ns full width at half maximum while maintaining a large signal-to-noise ratio for neutron yields between 1010 and 1014. The OMEGA hardware timing system is used along with an optical fiducial to provide an absolute nTOF measurement to an accuracy of ~56 ps. The fast instrument response enables the accurate measurement of the primary deuterium-tritium neutron peak shape, while the optical fiducial allows for an absolute neutron energy measurement. The new detector measures the neutron mean energy with an uncertainty of ~7 keV, corresponding to a hot-spot velocity projection uncertainty of ~12 km/s. Evidence of bulk fluid motion in cryogenic targets is presented with measurements of the neutron energy spectrum. PMID- 30399682 TI - Development of a three-wave far-infrared laser interferometry and polarimetry diagnostic system for the C-2W field-reversed configuration plasmas. AB - Great advancements in modern field-reversed configuration (FRC) experiments motivated the development of a 14-chord three-wave far infrared (FIR) laser interferometry and polarimetry diagnostic system, which can provide simultaneous high temporal resolution measurements of density and Faraday rotation profiles with high accuracy. The unique challenges facing FIR diagnostics in high beta FRC plasmas are the extremely small (<0.5 degrees ) Faraday rotation angles, and severe laser beam refraction effects due to high density gradient and choice of long wavelength. The diagnostic system design and development are described with methods to overcome the challenges, and initial experimental data are also presented. PMID- 30399683 TI - Design of tangential x-ray crystal spectrometer for Aditya-U tokamak. AB - A tangential soft x-ray crystal spectrometer has been designed to measure the x ray spectrum of He-like argon for the Aditya-U tokamak plasma. The system enables to measure electron temperature using the intensity ratio of the resonance line to the satellite line. For this purpose, an x-ray spectral line at 3.9494 A from He-like argon, Ar16+, is considered. The spectrometer consists of a cylindrically bent silicon (111) crystal and a CCD detector to measure the resonance spectral line and its satellite lines in the wavelength region of 3.94-4.0 A, viewing the plasma tangentially at an angle of 26 degrees with respect to the toroidal direction in the magnetic axis. Considering Aditya-U tokamak plasma parameters and its geometrical constraints, plasma to crystal and crystal to detector distances have been kept at 1.47 m and 0.5 m, respectively, to detect a sufficient signal. The engineering design has been optimized after adequately addressing the issues related to port geometry and machine accessibility. Details on the design of the crystal spectrometer are presented in this paper. PMID- 30399684 TI - System level design of the ITER bolometer port plug cameras. AB - The ITER bolometer diagnostic is planned to have 550 lines of sight (LOS) distributed all over the vessel. 240 channels are provided by cameras mounted in two upper ports and in one equatorial port. This paper describes the current status of the system level design of the port cameras and the solutions proposed on how to implement all required camera components while meeting a multitude of competing requirements. Sensor holders, support structures, and different apertures depending on the camera type (pinhole or collimator), cable connectors, ceramic track plates, and many mineral insulated cables have to be integrated within a restricted space envelope to guarantee functionality. The design of the internal electrical interfaces and the external mechanical mountings will be described as well. Using the example of an upper port camera with 60 LOS, the assembly of the camera components is explained and two currently discussed architecture options for the remote handling maintenance scheme in the hot cell are compared. PMID- 30399685 TI - Measurement of the toroidal radiation asymmetry during massive gas injection triggered disruptions on J-TEXT. AB - Disruptions have the potential to cause severe damage to large tokamaks like ITER. The mitigation of disruption damage is one of the essential issues for the tokamak. Massive gas injection (MGI) is a technique in which large amounts of a noble gas are injected into the plasma in order to safely radiate the plasma energy evenly over the entire plasma-facing wall. However, the radiated energy during the disruption triggered by massive gas injection is found to be toroidally asymmetric. In order to investigate the spatial and temporal structures of the radiation asymmetry, the radiated power diagnostics for the J TEXT tokamak have been upgraded. The multi-channel arrays of absolute extreme ultraviolet photodiodes have been upgraded at four different toroidal positions to investigate the radiation asymmetries during massive gas injection. It is found that the toroidal asymmetry is associated with plasma properties and MGI induced MHD activities. PMID- 30399686 TI - A support vector regression method for efficiently determining neutral profiles from laser induced fluorescence data. AB - A support vector regression (SVR) method is integrated with a collisional radiative (CR) model of helicon plasmas in the Helicon-Cathode (HelCat) linear plasma device to determine Ar i profiles based on metastable-pumped Laser Induced Fluorescence (LIF) measurements. A machine learning approach to the CR model allows for an efficient exploration of the input parameter space and can inherently incorporate probe and LIF measurement errors in profile inputs to which a CR model would normally be sensitive. A training set is created for mapping CR model outputs to Ar i input profiles using radial points as SVR input features and parameters of a sigmoidal-type function as output features. This SVR method may easily be adapted to other LIF pumping schemes and may even be used in conjunction with a CR model to validate electron temperature and density plasma profiles if neutral or ion profiles are already known. PMID- 30399687 TI - Observations of core ion cyclotron emission on ASDEX Upgrade tokamak. AB - The B-dot probe diagnostic suite on the ASDEX Upgrade tokamak has recently been upgraded with a new 125 MHz, 14 bit resolution digitizer to study ion cyclotron emission (ICE). While classic edge emission from the low field side plasma is often observed, we also measure waves originating from the core with fast fusion protons or beam injected deuterons being a possible emission driver. Comparing the measured frequency values with ion cyclotron harmonics present in the plasma places the origin of this emission on the magnetic axis, with the fundamental hydrogen/second deuterium cyclotron harmonic matching the observed values. The actual values range from ~27 MHz at the on-axis toroidal field BT = -1.79 T to ~40 MHz at BT = -2.62 T. When the magnetic axis position evolves during this emission, the measured frequency values track the changes in the estimated on axis cyclotron frequency values. Core ICE is usually a transient event lasting ~100 ms during the neutral beam startup phase. However, in some cases, core emission occurs in steady-state plasmas and lasts for longer than 1 s. These observations suggest an attractive possibility of using a non-perturbing ICE based diagnostic to passively monitor fusion alpha particles at the location of their birth in the plasma core, in deuterium-tritium burning devices such as ITER and DEMO. PMID- 30399688 TI - Motional Stark effect imaging first results on the DIII-D tokamak. AB - A motional Stark effect (MSE) imaging diagnostic was benchmarked against existing conventional MSE polarimeters on the DIII-D tokamak and delivered new capabilities for measuring the magnetic pitch angle from 2 neutral beams and on the high field side of DIII-D. Line integration across flux surfaces was considerable for the radial view utilised; nevertheless, the imaging MSE measurements from both beams were self-consistent and in close agreement with conventional MSE measurements. The ferroelectric liquid crystal waveplate used in the imaging polarimeter was discovered to have spatially non-uniform retardance; hence, it is necessary for the calibration source to replicate the ray paths of the neutral beam emission through the optical system. PMID- 30399689 TI - Velocity-space sensitivity of time-of-flight neutron spectrometer at EAST in deuterium plasma. AB - The Time-Of-Flight Enhanced Diagnostics (TOFED) neutron spectrometer with a double-ring structure has been installed at the Experimental Advanced Superconducting Tokamak (EAST) to perform advanced neutron emission spectroscopy diagnosis for deuterium plasma. In order to reduce the random coincidence from the background neutrons and gamma-rays, TOFED was moved outside the experimental hall and placed in the newly-built nuclear diagnostics laboratory in 2017. In this paper, the instrument-specific weight functions of TOFED are derived by taking the instrument response matrix and the radial line of sight in this new layout into consideration. The results show that the instrument is predominantly sensitive to counter-passing particles in the region where time-of-flights < 69.4 ns, while events at higher time-of-flights (corresponding lower neutron energies) are mostly representative of co-passing ions. The instrument-specific weight functions express the relationship between data in a given channel of the spectrum and the velocity space region that contributes to that. The results can be applied for energetic particle physics studies at EAST, in particular to compare data from different diagnostic techniques. PMID- 30399690 TI - Development of an ultra-fast photomultiplier tube for gamma-ray Cherenkov detectors at the National Ignition Facility (PD-PMT). AB - A new ultra-fast photomultiplier tube and associated drivers have been developed for use in the next generation of gamma-ray high pressure gas Cherenkov detectors for inertial confinement fusion experiments at the National Ignition Facility. Pulse-dilation technology has been applied to a standard micro-channel-plate based photomultiplier tube to improve the temporal response by about 10*. The tube has been packaged suitably for deployment on the National Ignition Facility, and remote electronics have been designed to deliver the required non-linear waveforms to the pulse dilation electrode. This is achieved with an avalanche pulse generator system capable of generating fast arbitrary waveforms over the useful parameter space. The pulse is delivered via fast impedance-matching transformers and isolators, allowing the cathode to be ramped on a sub-nanosecond time scale between two high voltages in a controlled non-linear manner. This results in near linear pulse dilation over several ns. The device has a built-in fiducial system that allows easy calibration and testing with fiber optic laser sources. Results are presented demonstrating the greatly improved response time and other parameters of the device. PMID- 30399691 TI - Imputation of faulty magnetic sensors with coupled Bayesian and Gaussian processes to reconstruct the magnetic equilibrium in real time. AB - A Bayesian with Gaussian process-based numerical method to impute a few missing magnetic signals caused by impaired magnetic probes during tokamak operations is developed such that the real-time reconstruction of magnetic equilibria, whose performance strongly depends on the measured magnetic signals and their intactness, is affected minimally. Likelihood of the Bayesian model constructed with Maxwell's equations, specifically Gauss's law for magnetism and Ampere's law, results in an infinite number of solutions if two or more magnetic signals are missing. This undesirable characteristic of the Bayesian model is remediated by coupling the model with the Gaussian process. Our proposed numerical method infers nine non-consecutive missing magnetic signals correctly in less than 1 ms suitable for the real-time reconstruction of magnetic equilibria during tokamak operations. PMID- 30399692 TI - Note: Biochemical samples centrifuged in-flight on drones. AB - The ability to conduct en-route centrifugation of samples improves quality and timeliness in the pre-analytical phase. This is demonstrated here on a quadcopter whereby the propellers were adapted to house and apply centrifugal forces to sample-containing capillary tubes instead of incorporating a centrifuge. Tests revealed the ability of the method to separate non-homogenized milk into a cream portion and a skim milk portion, and human whole blood into plasma, buffy coat, and red blood cell components. PMID- 30399693 TI - Ambient-pressure atomic force microscope with variable pressure from ultra-high vacuum up to one bar. AB - We present the design and performance of an ambient-pressure atomic force microscope (AP-AFM) that allows AFM measurements using the laser deflection technique in a highly controlled environment from ultra-high vacuum (UHV) up to 1 bar with various gases. While the UHV of the AP-AFM system is obtained by a combination of turbo-molecular and ion pumps, for the higher-pressure studies, the ambient-pressure chamber is isolated from the pumps and high-purity gases are dosed via a leak valve from a gas manifold. The AP-AFM system, therefore, provides versatile AFM techniques, including the measurement of topography, friction and local conductance mapping, and force spectroscopy in a highly controlled environment with pressures ranging from UHV up to atmospheric pressure. Atomically resolved stick-slip images and force spectroscopy of highly ordered pyrolytic graphite (HOPG) at variable pressure conditions are presented to demonstrate the performance of the AP-AFM system. Force spectroscopy results of vacuum-cleaved HOPG, followed by exposure to lab air, oxygen, and methane show that adhesion between the AFM tip and the HOPG depends significantly on the exposed gas and pressure. Our results show that the deposition of airborne hydrocarbon impurities at ambient conditions leads to a significant change in adhesion force, implying that the wettability of the HOPG surface depends on the environment and the pressure. PMID- 30399694 TI - Correlation polarimetry for broadband magnetic fluctuation measurements. AB - Correlation techniques have been successfully utilized for plasma diagnostics like electron cyclotron emission to reduce measurement noise. We present the first application of such a technique to Faraday-effect polarimetry measurements on the Madison Symmetric Torus (MST). The MST far infrared (FIR) interferometer polarimeter diagnostic utilizes 11 vertical chords with a chord separation of 7-8 cm and a heterodyne detection system for fluctuation measurements up to several hundred kHz. The planar-diode mixers viewing each chord represent independent noise sources; modifying the optical setup so that two different mixers view the same chord allows cross correlation between the two independent signals to reduce the noise floor in fluctuation measurements. In this manner, the noise floor in both interferometry and polarimetry measurements in reversed-field pinch discharges has been reduced by a factor of 20-30. The correlation polarimeter provides a sensitive measurement of broadband magnetic fluctuations. PMID- 30399695 TI - Experimental considerations to observe two ionizing fronts in systems with a sharp absorption edge. AB - This paper examines the experimental requirements to observe two shock fronts driven by a single x-ray source in systems with a sharp absorption edge. We consider systems where the peak of the x-ray radiation drive coincides with the K edge of the carbon, which occurs at a photon energy of 284 eV, causing photons to be deposited in two regions. The low-energy photons (E < 284 eV) penetrate further and drive the main shock, while the higher-energy photons (E > 284 eV) are absorbed in the ablated plasma. These higher-energy photons create an ionization front, which then produces a second shock, termed an edge-shock. Using a different radiation-hydrodynamics code and different opacity and equation of state tables, we replicate the previous work and build upon them to explore the conditions required to form the edge shock. We find that having the material K edge coincide with the spectral domain of the radiation source is necessary but not sufficient on its own to drive the edge-shock. PMID- 30399696 TI - JET diagnostic enhancements testing and commissioning in preparation for DT scientific campaigns. AB - In order to optimize the scientific exploitation of JET (Joint European Torus) during the upcoming deuterium-tritium experiments, a set of diagnostic systems is being enhanced. These upgrades focus mainly on the experimental and operational conditions expected during tritium campaigns. It should be stressed that measurements relevant for burning plasmas are specifically targeted. Previously non-available capabilities, such as a current measurement system fully covering all poloidal field circuits, are described in detail. Instrument descriptions, performance prediction, testing, and initial commissioning results of these systems are presented. PMID- 30399697 TI - Sub-nanosecond single line-of-sight (SLOS) x-ray imagers (invited). AB - A new generation of fast-gated x-ray framing cameras have been developed that are capable of capturing multiple frames along a single line-of-sight with 30 ps temporal resolution. The instruments are constructed by integrating pulse dilation electron imaging with burst mode hybrid-complimentary metal-oxide semiconductor sensors. Two such instruments have been developed, characterized, and fielded at the National Ignition Facility and the OMEGA laser. These instruments are particularly suited for advanced x-ray imaging applications in Inertial Confinement Fusion and High energy density experiments. Here, we discuss the system architecture and the techniques required for tuning the instruments to achieve optimal performance. Characterization results are also presented along with planned future improvements to the design. PMID- 30399698 TI - Microwave frequency comb Doppler reflectometer applying fast digital data acquisition system in LHD. AB - We succeeded in increasing the radial observation points of the microwave frequency comb Doppler reflectometer system from 8 to 20 (or especially up to 45) using the high sampling rate of 40 GS/s digital signal processing. For a new acquisition system, the estimation scheme of the Doppler shifted frequency is constructed and compared with the conventional technique. Also, the fine radial profile of perpendicular velocity is obtained, and it is found that the perpendicular velocity profile is consistent with the E * B drift velocity one. PMID- 30399699 TI - Integrated diagnostic and data analysis system of the C-2W advanced beam-driven field-reversed configuration plasma experiment. AB - The new C-2W experiment (also called Norman) at TAE Technologies, Inc. studies the evolution of field-reversed configuration (FRC) plasmas sustained by neutral beam injection. Data on the FRC plasma performance are provided by a comprehensive suite of diagnostics that includes over 700 magnetic sensors, four interferometer systems, multi-chord far-infrared polarimetry, two Thomson scattering systems, ten types of spectroscopic measurements, multiple fast imaging cameras with selectable atomic line filters, bolometry, reflectometry, neutral particle analyzers, and fusion product detectors. Most of these diagnostic systems are newly built using experience and data from the preceding C 2U experiment to guide the design process. A variety of commercial and custom acquisition electronics collect over 4000 raw signals from the C-2W diagnostics. These data are processed into physics results using a large-scale database of diagnostics metadata and analysis software, both built using open-source software tools. PMID- 30399700 TI - The single-line-of-sight, time-resolved x-ray imager diagnostic on OMEGA. AB - The single-line-of-sight, time-resolved x-ray imager (SLOS-TRXI) on OMEGA is one of a new generation of fast-gated x-ray cameras comprising an electron pulse dilation imager and a nanosecond-gated, burst-mode, hybrid complementary metal oxide semiconductor sensor. SLOS-TRXI images the core of imploded cryogenic deuterium-tritium shells in inertial confinement fusion experiments in the ~4- to 9-keV photon energy range with a pinhole imager onto a photocathode. The diagnostic is mounted on a fixed port almost perpendicular to a 16-channel, framing-camera-based, time-resolved Kirkpatrick-Baez microscope, providing a second time-gated line of sight for hot-spot imaging on OMEGA. SLOS-TRXI achieves ~40-ps temporal resolution and better than 10-MUm spatial resolution. Shots with neutron yields of up to 1 * 1014 were taken without observed neutron-induced background signal. The implosion images from SLOS-TRXI show the evolution of the stagnating core. PMID- 30399701 TI - Cavity ring-down spectroscopy to measure negative ion density in a helicon plasma source for fusion neutral beams. AB - Cavity Ring Down Spectroscopy (CRDS) is used to measure the D- absolute density produced in the helicon plasma reactor RAID (Resonant Antenna Ion Device) at the Swiss Plasma Center. The birdcage geometry of the helicon antenna produces a homogeneous, high-density plasma column (n e ? 1.5 * 1018 m-3 in H2 and D2 at 0.3 Pa and 3 kW of input power) 1.4 m long. We present the CRDS experimental setup, its positioning on the RAID reactor, and how the mechanical and thermal effects of the plasma affect the measurement. First results in deuterium plasma confirm the production of negative ions (D-) with a significant density: an average value of 3.0 * 1016 m-3 of D- is obtained at 0.3 Pa and 5 kW of power input in Cs-free plasma. This result is in good agreement with calculations performed with the collisional radiative code YACORA. PMID- 30399702 TI - Beam phase retrieval based on higher order modes in cylindrical superconducting radio frequency cavities. AB - The control of beam phase relative to the accelerating RF field within a superconducting cavity is important in many accelerator applications and is of particular importance for a free electron laser facility. As standard practice, the phase is usually inferred from the beam-induced transient field with respect to a timing reference. We report here on an alternative and novel means of beam phase determination based on beam-excited higher order electromagnetic modes and the accelerating electromagnetic mode, which are conveniently available from the same coupler. The monopole modes are immune to the electron beam offset and therefore are best suited for the task. A coupled circuit model is used to assist the development and to rapidly assess the facility of the method. Simulations based on the circuit model indicate that the resolution of this system depends critically on the signal to noise ratio. Beam-based measurements with a test setup were carried out at the European X-ray Free Electron Laser (XFEL), Germany. Based on this new method, we have routinely obtained a resolution of 0.1 degrees . The best resolution observed with the current setup was 0.03 degrees . These results agree very well with the predictions from those predicted by a circuit model. The system investigated here can be used to provide diagnostic information for the current low level RF system employed in the European XFEL. To this end, the associated electronics are under development. This monitor is the first of its kind that can deliver direct and online measurements of the beam phase with respect to the RF field. PMID- 30399703 TI - Testing of the ITER plasma position reflectometry high-field side in-vessel antenna assembly prototype. AB - The ITER plasma position reflectometry diagnostic aims to provide measurements of the edge plasma to correct or supplement the magnetics for plasma position control. It consists of five reflectometers, two of which have components installed inside the vessel. One of these systems probes the plasma from the high field side using a bistatic array of small pyramidal horns located in the gap between two blankets. Electromagnetic simulations have shown that the blankets shape the radiation pattern and need to be considered as part of the antenna. Full-wave plasma simulations have confirmed these results and have also shown that the first-wall geometry may induce measurement errors above the required margin. To further address these issues, we manufactured a prototype of the high field side antenna, which includes a mock-up of the blanket modules. Here, we present the results of the prototype tests, with and without the blankets, using a metallic mirror as a target. The signals reflected from the mirror are used to derive the mirror distance and assess the precision of the measurements under different arrangements. The sensitivity to the blankets' installation tolerances is also assessed by changing the antennas' position with respect to the blankets' surfaces and cut-outs. PMID- 30399704 TI - Particle and heat flux diagnostics on the C-2W divertor electrodes. AB - A suite of diagnostics was developed to measure particle and heat fluxes arriving at the divertor electrodes of the C-2W experiment at TAE Technologies. The divertor electrodes consist of 4 concentric rings, each equipped with a bolometer, electrostatic energy analyzer, and thermocouple mounted at two opposing azimuthal locations. These probes provide measurements of the power flux to the divertor electrodes as well as measurements of the ion current density, ion energy distribution, and total energy deposition. The thermocouples also provide calibration points for inferring the heat deposition profile via thermographic imaging of the electrodes with a fast infrared camera. The combined measurements enable the calculation of the energy lost per escaping electron/ion pair, which is an important metric for understanding electron heat transport in the open field lines that surround the field-reversed configuration plasma in C 2W. PMID- 30399705 TI - Four-dimensional calibration turntable of the motional Stark effect diagnostic on EAST. AB - The motional Stark effect (MSE) diagnostic is applied to measure the safety factor q and current density profile of a tokamak device, which are important parameters in realizing the high-performance and long-pulse steady state of a tokamak. A single-channel MSE diagnostic based on dual photoelastic modulators, whose sightline meets with the neutral beam injection at a major radius of R = 2.12 m, has been built for the D window of the Experimental Advanced Superconducting Tokamak (EAST). According to the requirements of MSE diagnostic polarimetric calibration, a high-precision four-dimensional calibration turntable, driven by four stepping motors and controlled by software running on the computer, was designed for EAST. The turntable allows us to rapidly calibrate the MSE diagnostic in a series of positions and angles during EAST maintenance. The turntable can move in four dimensions of translation, yaw, pitch, and roll of the polarizer and can create linearly polarized light at any given angle with accuracy of ~0.05 degrees for the MSE system offline calibration. The experimental results of the MSE diagnostic calibration in the laboratory show that the turntable has the advantages of high positioning accuracy, flexible spatial movement, and convenient control and fully meets the calibration requirements of an MSE diagnosis system. PMID- 30399706 TI - Estimating the performance of lithium beam measurements of current density and electron density in an H-mode pedestal. AB - The lithium beam is an effective diagnostic tool for investigation of stability and particle transport in the pedestal. It was used successfully to measure edge current density on DIII-D, achieving qualitative agreement with neoclassical models. Electron density profiles were also measured. Proposed upgrades will continue these measurements with higher reliability as well as explore edge current measurements using spectroscopy. The optics will be redesigned to optimize throughput and aperture broadening and to replace the photomultiplier tubes with avalanche photodiodes. The new system will yield detailed measurements of the pedestal, complementing existing diagnostics for investigating pedestal stability, edge localized mode cycle, and particle transport through the pedestal. PMID- 30399707 TI - Passive bistatic radar using digital video broadcasting-terrestrial receivers as general-purpose software-defined radio receivers. AB - We investigate the use of low-cost digital video broadcasting-terrestrial (DVB-T) receivers as general-purpose software-defined radio (SDR) receivers for passive bistatic radar (PBR) applications. Two DVB-T receivers are synchronized using a common clock to perform coherent measurements. By exploiting the direct-path signal in the surveillance channel, we use the cross-correlation process to estimate the time offset between the data streams of reference and surveillance channels caused by the universal serial bus communication. We demonstrate the detection of static and moving targets as well as short-range targets, including a landing airplane at 8 km, multiple ships with different velocities, and vehicles within 20 m from the receiver acquiring at a 2 MHz bandwidth, by using Japan's Integrated Services Digital Broadcasting Terrestrial digital TeleVision (TV) signal broadcast. We also propose to improve the range resolution of the designed PBR system by combining multiple SDR receivers tuned to different carrier frequencies. The designed system and proposed method can be used for various applications, such as airplane navigation, harbor protection, and traffic density monitoring. PMID- 30399708 TI - Thomson scattering systems on C-2W field-reversed configuration plasma experiment. AB - TAE Technologies' newly constructed C-2W experiment aims to improve the ion and electron temperatures in a sustained field-reversed configuration plasma. A suite of Thomson scattering systems has been designed and constructed for electron temperature and density profile measurements. The systems are designed for electron densities of 1 * 1012 cm-3 to 2 * 1014 cm-3 and temperature ranges from 10 eV to 2 keV. The central system will provide profile measurements of Te and ne at 16 radial locations from r = -9 cm to r = 64 cm with a temporal resolution of 20 kHz for 4 pulses or 1 kHz for 30 pulses. The jet system will provide profile measurements of Te and ne at 5 radial locations in the open field region from r = -5 cm to r = 15 cm with a temporal resolution of 100 Hz. The central system and its components have been characterized, calibrated, installed, and commissioned. A maximum-likelihood algorithm has been applied for data processing and analysis. PMID- 30399709 TI - Using multiple neutron time of flight detectors to determine the hot spot velocity. AB - An important diagnostic value of a shot at the National Ignition Facility is the resultant center-of-mass motion of the imploding capsule. This residual velocity reduces the efficiency of converting laser energy into plasma temperature. A new analysis method extracts the effective hot spot motion by using information from multiple neutron time-of-flight (nToF) lines-of-sight (LoSs). This technique fits a near Gaussian spectrum to the nToF scope traces and overcomes reliance on models to relate the plasma temperature to the mean energy of the emitted neutrons. This method requires having at least four nToF LoSs. The results of this analysis will be compared to an approach where each LoS is analyzed separately and a model is used to infer the mean energy of the emitted neutrons. PMID- 30399710 TI - Design of Langmuir probe diagnostic system for the upgraded lower tungsten divertor in EAST tokamak. AB - In order to achieve long-pulse H-mode plasma scenario over 400 s with high heating power in the Experimental Advanced Superconducting Tokamak (EAST) device, the lower graphite divertor will be upgraded into a tungsten (W) divertor with active water cooling, which consists of the W/Cu monoblock units and the W flat tile units as the divertor plasma facing components. As a fundamental diagnostic tool, the divertor Langmuir probe (Div-LP) diagnostic system will be upgraded accordingly. This paper presents the design of two kinds of new Div-LP systems, which are planned to be utilized on the W/Cu monoblock units and the W flat-tile units for the upgraded lower tungsten divertor, respectively, including their structures and preliminary poloidal and toroidal layouts. The Div-LP diagnostic system can measure the plasma parameters with the schemes of triple-probe, double probe, and single-probe, to obtain the spatial and temporal distribution of plasma behavior on the divertor targets, which is useful for the discharge control and operation in EAST. In addition, the thermal analysis of the two kinds of probe assemblies is also carried out by using the three-dimensional finite element code ANSYS, which is aimed to get the optimal designs to withstand the long-pulse and high-power operation in EAST future experiments. PMID- 30399711 TI - Tracer-Encapsulated Solid Pellet (TESPEL) injection system for Wendelstein 7-X. AB - Impurity confinement in fusion plasmas is mainly determined by transport mechanisms in the core region. For the Wendelstein 7-X stellarator, its island divertor is expected to screen effectively external impurity sources in the scrape-off layer at higher densities. However, the unique feature of Tracer Encapsulated Solid Pellet (TESPEL) injection, releasing impurities at a well localized radial position directly in the core plasma, enables investigating such transport mechanisms. This paper reports on the detailed design of a completely new TESPEL injection system, which has been designed by the National Institute for Fusion Science, Toki, Japan, and is currently being installed at Max-Planck Institut fur Plasmaphysik, Greifswald, Germany, for the Wendelstein 7-X. This injector consists of a storage and injection unit, attached to a system of guiding tubes which run through 3 successive differential pumping stages. A light gate system and an optical observation system are used to determine the location of the deposited tracers. Laboratory tests carried out by shooting TESPELs onto a sample foil showed good performance after careful realignment of the guiding tubes. PMID- 30399712 TI - The dilation aided single-line-of-sight x-ray camera for the National Ignition Facility: Characterization and fielding. AB - Crystal x-ray imaging is frequently used in inertial confinement fusion and laser plasma interaction applications as it has advantages compared to pinhole imaging, such as higher signal throughput, better achievable spatial resolution, and chromatic selection. However, currently used x-ray detectors are only able to obtain a single time resolved image per crystal. The dilation aided single-line of-sight x-ray camera described here was designed for the National Ignition Facility (NIF) and combines two recent diagnostic developments, the pulse dilation principle used in the dilation x-ray imager and a ns-scale multi-frame camera that uses a hold and readout circuit for each pixel. This enables multiple images to be taken from a single-line-of-sight with high spatial and temporal resolution. At the moment, the instrument can record two single-line-of-sight images with spatial and temporal resolution of 35 MUm and down to 35 ps, respectively, with a planned upgrade doubling the number of images to four. Here we present the dilation aided single-line-of-sight camera for the NIF, including the x-ray characterization measurements obtained at the COMET laser, as well as the results from the initial timing shot on the NIF. PMID- 30399713 TI - A simple and versatile machine for creep testing at low loads (6-300 N) and on miniaturized specimens: Application to a Mg-base alloy. AB - High temperature creep testing at a very low load range (<10 N) on miniaturized specimens has always been a challenge due to inherent design limitation (such as significant preload) of the conventional creep testing machines. In the present study, the challenge was overcome by developing a simple and versatile horizontal creep testing machine to conduct creep tests in the loading range of ~6-300 N in tension and in compression. The competence of the in-house-built horizontal creep machine was validated by conducting creep testing on dog-bone shaped sheet specimens of cast Mg-1Sn-1Ca (TX11) Mg-base alloy over a lower stress range of 1.6-5.9 MPa (equivalent load range of 6.4-18.1 N) at 450 degrees C and in the high stress range of 20-80 MPa (equivalent load range of 76-310 N) at 175 degrees C. PMID- 30399714 TI - Variable location channels to improve efficiency and precision for direct ?T e measurements and high spatial resolution T e -profile measurements using electron cyclotron emission. AB - Electron cyclotron emission (ECE) diagnostics that use variable location channels based on yttrium iron garnet (YIG) bandpass filters improve the precision and the efficiency of measurements of electron temperature (T e ) profiles and fluctuations (deltaT e ). These variable frequency filters were substituted for fixed frequency filters in the intermediate frequency section to achieve the required higher resolution over a target radial range, just before the experiment. Here, we present the proof-of-principle for high temporal resolution measurement of the electron temperature gradient, via real-time slewing of a YIG filter for relocation of an ECE channel during a long pulse. The key component is the application of YIG tunable filters with their narrow bandwidth and capability for a high slew rate of their center frequency. This application permits fast relocation of the ECE channels for direct measurement of the gradient and close spacing of channels to investigate the magnetic island's dynamic behavior. PMID- 30399715 TI - Dual-laser wavelength Thomson scattering at Wendelstein 7-X. AB - This paper presents the approach of the dual-laser wavelength Thomson scattering (TS) system for the Wendelstein 7-X stellarator. The dual-laser wavelength TS method is based on two lasers with different wavelengths being fired quasi simultaneously. This method has two advantages compared to a single laser wavelength TS system. First, the dual laser availability allows an in situ spectral calibration, and second, higher electron temperatures can be measured without any change in the spectral filter setup of the polychromators. The W7-X dual-laser wavelength TS concept is based on high power lasers: a set of standard Nd:YAG lasers with lambda = 1064 nm wavelength and a Nd:YAG laser with lambda = 1319 nm wavelength newly developed for this application. This laser uses a different transition line with 34% efficiency compared to the main 1064 nm Nd:YAG line. Simulations of the expected performance of the new dual-laser wavelength system show that electron temperatures up to Te = 15 keV can be measured compared to the original design parameter up to Te = 10 keV. The in situ spectral calibration can be performed using a range of temperatures from 1 keV to 10 keV using TS measurements of the 1064 nm versus 1319 nm TS simultaneously. PMID- 30399716 TI - Using time-resolved penumbral imaging to measure low hot spot x-ray emission signals from capsule implosions at the National Ignition Facility. AB - We have developed and fielded a new x-ray pinhole-imaging snout that exploits time-resolved penumbral imaging of low-emission hot spots in capsule implosion experiments at the National Ignition Facility. We report results for a series of indirectly driven Be capsule implosions that aim at measuring x-ray Thomson scattering (XRTS) spectra at extreme density conditions near stagnation. In these implosions, x-ray emission at stagnation is reduced by 100-1000* compared to standard inertial confinement fusion (ICF) implosions to mitigate undesired continuum background in the XRTS spectra. Our snout design not only enables measurements of peak x-ray emission times, t o , where standard ICF diagnostics would not record any signal, but also allows for inference of hot spot shapes. Measurement of t o is crucial to account for shot-to-shot variations in implosion velocity and therefore to benchmark the achieved plasma conditions between shots and against radiation hydrodynamic simulations. Additionally, we used differential filtering to infer a hot spot temperature of 520 +/- 80 eV, which is in good agreement with predictions from radiation hydrodynamic simulations. We find that, despite fluctuations of the x-ray flash intensity of up to 5*, the emission time history is similar from shot to shot and slightly asymmetric with respect to peak x-ray emission. PMID- 30399717 TI - Superlinearity, saturation, and the PMT-Tailoring and calibration methodology for prompt radiation detectors. AB - This work illustrates predominant measureable nonlinearities in photomultiplier tubes (PMTs) and introduces a controllable one called "Superlinearity," signifying both a positive nonlinear response and the ability to extend linear operation by counteracting gain saturation mechanisms - charge depletion, space charge field limitation, and secondary emission surface effects. Recognizing superlinearity and its effect on the temporal step response leads to a true definition of linearity, free of a small-signal linear assumption. Furthermore, given the prevalent use of glass microchannel-plate (MCP) PMTs in favor of a faster impulse response in spite of a small charge limit, we are motivated to examine their nonlinear amplitude response and deploy tailored gain bias string methods to fully harness the maximum linear gain as is usually done for transmissive metal mesh and reflective metal dynode PMTs. Our characterization methodology applies standard NIST-traceable calibrated laboratory equipment with absolute input-referenced techniques, examining step responses over many orders of magnitude in controlled illumination. By doing so, we quantitatively reveal the superlinearity strength independent of charge depletion, yielding true linear responsivity and effectively doubling the small-signal linear limit; this is very relevant to PMT modeling and charge deconvolution efforts. With further development, the tailoring strategies we introduce could be applied to MCP detectors, extracting all useful capillary charge with a significant improvement in large linear signal quality. PMID- 30399718 TI - A multi-species powder dropper for magnetic fusion applications. AB - We present a device for controlled injection of a variety of materials in powder form. The system implements four independent feeder units, arranged to share a single vertical drop tube. Each unit consists of a 80 ml reservoir, coupled to a horizontal linear trough, where a layer of powder is advanced by piezo-electric agitation at a speed proportional to the applied voltage, until it falls into a drop tube. The dropper has been tested with a number of impurities of low (B, BN, C), intermediate (Si, SiC), and high Z (Sn) and a variety of microscopic structures (flakes, spheres, rocks) and sizes (5-200 MUm). For low Z materials, drop rates ~2-200 mg/s have been obtained showing good repeatability and uniformity. A calibrated light-emitting diode (LED)-based flowmeter allows measuring and monitoring the drop rate during operation. The fast time-response of the four feeders allows combination of steady and pulsed injections, providing a flexible tool for controlled-dose, real-time impurity injection in fusion plasmas. PMID- 30399719 TI - Calibration and applications of visible imaging cameras on the C-2U advanced beam driven field-reversed configuration device. AB - Two filtered, fast-imaging instruments, with radial and axial views, respectively, were used on the C-2U device to visualize line emission from impurities and hydrogenic neutrals. Novel calibration techniques needed to be developed for these instruments because the accelerated pace of C-2U operations precluded access to the interior of the vacuum vessel, targets used in typical calibration methods were not available, and in order to account for effects which have not been sufficiently addressed in the literature. Spatial calibration involved optimizing parameters in a generic camera model: ex situ using a checkerboard target and in situ using the vacuum vessel port geometry. Radiometric calibration was performed ex situ in three stages. First, the camera relative response function was mapped using an algorithm developed for high dynamic-range imaging. Second, the non-uniformity of the optical system was measured using a large LCD monitor with a characterized angular emission pattern. Finally, the absolute photon efficiency of each interference filter was determined using a calibrated uniform radiance source while also accounting for reduction in the filter transmission for off-normal rays. Periodically during the run campaign, line emission from neutral beams fired into a gas target was used as an in situ reference to check for degradation of viewport transmission. One application using calibrated camera data was tomographic reconstruction of passive impurity emission, which provided a sanity check to the excluded-flux radius inferred from wall-mounted magnetic sensors. PMID- 30399720 TI - Using multiple x-ray emission images of inertially confined implosions to identify spatial variations and estimate confinement volumes (invited). AB - We describe two methods to analyze multiple x-ray images of a small, self emitting object, and we apply these methods to the stagnating hotspots in inertial confinement fusion experiments. The first method, the common integrated profile, can be used to assess and quantify spatial variations in opacity. It is both a simple assessment of consistency and a sophisticated measurement of variations in a region that is otherwise difficult to observe. Second, we present a method to estimate volumes of highly asymmetric objects using multiple images of x-ray emission. The method is based on image intensities and does not require any explicit assumption of symmetry. PMID- 30399721 TI - Note: Improved spatial resolution of time-of-flight Thomson scattering of fusion devices. AB - To measure the electron density and temperature of the outer half of the International Thermonuclear Experimental Reactor, it is currently planned to build two conventional Thomson scattering (TS) systems. It was recently shown that given the same new specifications and optimizing the optical design, a Light Detection and Ranging (LIDAR) TS system covering the full chord is feasible, too. In this note, we demonstrate that by deconvolving the data of the individual spectral channels, one can improve the spatial resolution of LIDAR TS to match that of the conventional core plasma system. We demonstrate that the scale length at the edge of an H-mode plasma is determined with reasonable accuracy. PMID- 30399722 TI - An extended depth-of-field imaging system with a non-rotationally symmetric phase mask. AB - Optical imaging system offers best performance across a range of applications such as machine vision, medical examination, security, and quality inspection in a production line. A typical imaging system is commonly sensitive to the defocus variations in the object plane location, which largely loses the transversal information of volume and brings inaccuracy to the comprehensive vision. Therefore, improvement of depth-of-field (DOF) with high resolution imaging remains a challenge for the conventional imaging system. Here we introduce a newly designed optical imaging system, mainly being composed of a standard Tessar lens and a non-absorptive rectangularly separable phase mask, whose corresponding optical point spread function is greatly invariant to defocus. An extended DOF image is restored by using the Tikhonov regularization algorithm and deconvolving the response function of the optical system. The proof-of-the-concept experimental results verify significantly extended DOF exceeding 40 times compared to the common optical imaging counterparts. Future work includes the use of a durable and high-transmittance phase mask to develop various large DOF optical configurations without loss of resolution. PMID- 30399724 TI - Implementation of a Wollaston interferometry diagnostic on OMEGA EP. AB - A Wollaston interferometer is presented for use in measuring the electron density of plasma plumes created in experiments on the OMEGA EP laser system. The diagnostic is installed as an additional arm on the 4omega probe system, a suite of diagnostics that share a 10 ps pulse of 263 nm laser light captured by an imaging system at f/4. The interferometer utilizes a Wollaston prism to create two angularly separated beams from a single input probe beam, split at any angle between 0 degrees and 90 degrees . This configuration is implemented uniquely such that fringe spacing may be altered independently of field of view, magnification, and imaging resolution, from a range of 17 to 76 MUm/fringe. The region of overlap between the two beams forms a total field of view of approximately 1.2 * 1.6 mm at the target chamber center with an imaging resolution of 5 MUm. Using this configuration, here it is shown that plasma density may be accurately characterized over a range of 3 * 1018-1 * 1020 cm-3. PMID- 30399723 TI - Plasma impurities observed by a pulse height analysis diagnostic during the divertor campaign of the Wendelstein 7-X stellarator. AB - The paper reports on the optimization process of the soft X-ray pulse height analyzer installed on the Wendelstein 7-X (W7-X) stellarator. It is a 3-channel system that records X-ray spectra in the range from 0.6 to 19.6 keV. X-ray spectra, with a temporal and spatial resolution of 100 ms and 2.5 cm (depending on selected slit sizes), respectively, are line integrated along a line-of-sight that crosses near to the plasma center. In the second W7-X operation phase with a carbon test divertor unit, light impurities, e.g., carbon and oxygen, were observed as well as mid- to high-Z elements, e.g., sulfur, chlorine, chromium, manganese, iron, and nickel. In addition, X-ray lines from several tracer elements have been observed after the laser blow-off injection of different impurities, e.g., silicon, titanium, and iron, and during discharges with prefill or a gas puff of neon or argon. These measurements were achieved by optimizing light absorber-foil selection, which defines the detected energy range, and remotely controlled pinhole size, which defines photon flux. The identification of X-ray lines was confirmed by other spectroscopic diagnostics, e.g., by the High-Efficiency XUV Overview Spectrometer, HEXOS, and high-resolution X-ray imaging spectrometer, HR-XIS. PMID- 30399725 TI - Secondary electron emission detectors for neutral beam characterization on C-2W. AB - Heating, current drive, and partial fueling from neutral beam injection are essential to sustainment of C-2W field-reversed configuration plasmas. C-2W has eight 2.1 MW neutral beams (16.8 MW of total electrical power), capable of providing a beam of 15 keV hydrogen neutrals for 30 ms. To maximize the effectiveness of neutral beam injection, duct losses must be minimized by maintaining beam alignment and optimizing beam current for minimum divergence. Each beam terminates on a vertical and horizontal array of secondary electron emission detectors (nine in the vertical, seven in the horizontal, and sharing one in the middle). The molybdenum detectors are spatially separated to characterize the beam size and alignment. With knowledge of the geometry of the vacuum ducts and horizontal and vertical beam profiles from test stand measurements, the focal length, divergence, and power loss were calculated. Through characterization, the set of neutral beams are optimized to inject up to 12 MW of power into the confinement vessel throughout the plasma discharge. PMID- 30399726 TI - Performance of fast-ion loss diagnostic on EAST. AB - The scintillator-based detector for fast-ion loss measurements has been installed on EAST. To obtain high temporal resolution for fast-ion loss diagnostics, fast photomultiplier tube systems have been developed which can supply the complementary measurements to the previous image system with good energy and pitch resolution by using a CCD camera. By applying the rotatable platform, the prompt losses of beam-ions can be measured in normal and reverse magnetic field. The thick-target bremsstrahlung occurring in the stainless steel shield with energetic electrons can produce X-rays, which will strike on the scintillator based detector. To understand this interference on fast-ion loss signals, the effects of energetic electrons on the scintillator-based detector are studied, including runaway electrons in the plasma ramping-up phase and fast electrons accelerated by the lower hybrid wave. PMID- 30399727 TI - In-situ frequency calibration of frequency modulated continuous wave reflectometry. AB - Frequency modulated continuous wave reflectometers have been used to measure the plasma density profiles of the KSTAR tokamak. Three reflectometers are operating in an extraordinary polarization mode in the frequency range of Q band (33-50 GHz), V band (50-75 GHz), and W band (75-110 GHz). Each full frequency band is linearly swept in 20 MUs. The accuracy of the density profile measurement is dependent on how precisely the frequency is calibrated. Two new frequency measurement techniques are developed to in situ calibrate the instantaneous frequency during the sweep time of 20 MUs. First the intermediate frequency (IF) of the receiver is analyzed based on wavelet transform as applying a fixed frequency signal from a synthesizer to the local oscillator (LO) port. The frequency of the transmitted microwave is simply obtained by adding or subtracting the measured IF to the given LO frequency. Once the group delay of the whole system is known, the frequency can be calibrated by measuring the IF. By measuring the reflectometer output without plasma with delay lines of different lengths and subtracting them, the frequency can be calibrated by eliminating the unknown group delay of the system except the known group delay of the delay line. These two techniques are described in detail, and the calibrated frequencies conducted by the two techniques are compared. PMID- 30399728 TI - Unabsorbed light beamlets for diagnosing cross-beam energy transfer. AB - A new diagnostic has been fielded on OMEGA to diagnose cross-beam energy transfer (CBET) during direct-drive implosions. Unabsorbed light from each OMEGA laser beam is imaged as a distinct "spot" onto a gated optical imager. Each spot is in essence the endpoint of a beamlet of light that originates from different regions of each beam profile and follows a path determined by refraction. The intensity of light in the beamlet varies along its path as a result of absorption and CBET with other beamlets. This diagnostic allows the investigation of the effects of CBET on laser energy from specific locations of the beam profile. The diagnostic records images in two 200-ps time windows and includes a Wollaston prism to split each beamlet into two orthogonal polarizations recorded on separate images, allowing the absolute polarization of each beamlet to be determined. This diagnostic has provided the first evidence of polarization rotation caused by CBET during direct-drive implosions. PMID- 30399729 TI - Dual laser holography for in situ measurement of plasma facing component erosion (invited). AB - A digital holography (DH) surface erosion/deposition diagnostic is being developed for 3D imaging of plasma facing component surfaces in situ and in real time. Digital holography is a technique that utilizes lasers reflected from a material surface to form an interferogram, which carries information about the topology of the surface when reconstructed. As described in this paper, dual CO2 lasers at 9.271 and 9.250 MUm wavelengths illuminate the interrogated surface (at a distance of ~1 m) in a region of ~1 cm * 1 cm. The surface feature resolution is ~0.1 mm in the plane of the surface, and the depth resolution ranges from ~0.0001 to ~2 mm perpendicular to the surface. The depth resolution lower limit is set by single-laser and detector optical limitations, while the upper limit is determined by 2pi phase ambiguity of the dual-laser synthetic wavelength. Measurements have been made "on the bench" to characterize the single-laser and dual-laser DH configurations utilizing standard resolution targets and material targets that were previously exposed to high flux plasmas in either the Prototype Material Plasma Exposure eXperiment (Proto-MPEX) or the electro-thermal (ET) arc source. Typical DH measurements were made with 0.03 ms integration with an IR camera that can be framed at rates approaching 1.5 kHz. The DH diagnostic system is progressing toward in situ measurements of plasma erosion/deposition either on Proto-MPEX or the ET arc source. PMID- 30399730 TI - Development of a high-speed full digital processing phase detector for interferometry. AB - This study describes the development of a fully digital-type phase detector for plasma interferometry. This detector functions even in situations in which the phase changes rapidly or the input signal is too small to derive the correct phase shift from the intermediate frequency (IF) signal. The detector directly converts the IF signal waveform of the interferometer to the phase shift signal by means of data processing in a logic circuit. Thus, the phase is derived from the whole waveform of the IF signal. The IF signal of the interferometer is converted to in-phase and quadrature-phase signals by Hilbert transformation, processed by a digital low-pass filter, and converted to polar coordinates by a coordinate rotation digital computer algorithm to obtain the phase shift. A simulation of the high-speed full digital processing phase detector shows that a fringe jump does not occur unless the phase change rate exceeds 0.8 * 106 rad/s. This value is sufficiently large compared to the phase change velocity in rapid density increase resulting from a pellet injection. The phase conversion is simulated using a real IF signal from an interferometer measured with a Heliotron J device. The results show that the phase signal is correctly calculated by the full digital processing method from the IF signal, the phase derivation of which is typically difficult to obtain when using a conventional analog phase detector. PMID- 30399731 TI - Pulse dilation gas Cherenkov detector for ultra-fast gamma reaction history at the NIF (invited). AB - The Cherenkov mechanism used in Gas Cherenkov Detectors (GCDs) is exceptionally fast. However, the temporal resolution of GCDs, such as the Gamma Reaction History diagnostic at the National Ignition Facility (NIF), has been limited by the current state-of-the-art photomultiplier tube technology to ~100 ps. The soon to-be deployed Pulse Dilation Photomultiplier Tube (PD-PMT) at NIF will allow for temporal resolution comparable to that of the gas cell or ~10 ps. Enhanced resolution will contribute to the quest for ignition in a crucial way through precision measurements of reaction history and ablator areal density (rhoR) history, leading to better constrained models. Features such as onset of alpha heating, shock reverberations, and burn truncation due to dynamically evolving failure modes may become visible for the first time. Test measurements of the PD PMT at Atomic Weapons Establishment confirmed that design goals have been met. The PD-PMT provides dilation factors of 2 to 40* in 6 increments. The GCD-3 recently deployed at the NIF has been modified for coupling to a PD-PMT and will soon be making ultrafast measurements. PMID- 30399732 TI - Measuring dynamic fast ion spatial profiles with fusion protons in the Madison Symmetric Torus. AB - Neutral beam injected fast ions play a dominant role in both the field reversed configuration (FRC) at TAE Technologies and the Madison Symmetric Torus (MST) reversed field pinch (RFP), making fast ion diagnosis a major pillar of both research programs. And as strongly self-organized plasmas, the FRC and RFP similarly exhibit dynamic relaxation events which can redistribute fast ions. Recently, a collaboration between TAE Technologies and the University of Wisconsin was conducted to develop a method for measuring a fast changing fast ion spatial profile with a fusion proton detector and to investigate commonalities between the two plasmas. The steerable detector was designed and built at TAE and installed on MST. The fusion proton emission profile resulting from injection of a 25 kV deuterium neutral beam is measured with better than 5 cm spatial resolution and 100 MUs temporal resolution over the course of several 10s of shots. The fast ion density profile, forward modeled by tracing the orbits of the 3 MeV protons through a reconstructed magnetic equilibrium, is observed to flatten during global magnetic tearing mode activity, dropping by 30% in the core and increasing by a similar amount at the edge. The equilibrium profile is observed to be consistent with measurements made with a collimated neutron detector. PMID- 30399733 TI - Area and extraction field analysis of the analogue saturation of 40 mm microchannel plate photomultiplier tubes. AB - Microchannel plate (MCP) photomultiplier tubes (PMTs) are a well-established instrument for the inertial confinement fusion (ICF) community, with several detectors installed at NIF, Omega (LLE Rochester), and Orion (AWE). The analog signals produced at these major ICF facilities cover many orders of magnitude and often need multiple detectors operating at different levels of electron gain. As such, understanding the upper saturation limit of MCP-PMTs to large, low rate signals takes on a high importance. A previous study looked at the saturation limit of double and single MCP-PMTs over their full working area with pulse widths between 4 ns and 100 ns. This follow-on analysis will look at the effect of how the illuminated area affects the saturation limit and at the impact of the MCP to anode extraction field on the impulse response and the level of saturation. PMID- 30399734 TI - Nd:YAG laser Thomson scattering diagnostics for a laboratory magnetosphere. AB - A new Nd:YAG laser Thomson scattering (TS) system has been developed to explore the mechanism of high-beta plasma formation in the RT-1 device. The TS system is designed to measure electron temperatures (Te) from 10 eV to 50 keV and electron densities (ne) of more than 1.0 * 1017 m-3. To measure at the low-density limit, the receiving optics views the long scattering length (60 mm) using a bright optical system with both a large collection window (260-mm diameter) and large collection lenses (300-mm diameter, a solid angle of ~68 * 10-3 str). The scattered light of the 1.2-J Nd:YAG laser (repetition frequency: 10 Hz) is detected with a scattering angle of 90 degrees and is transferred via a set of lenses and an optical fiber bundle to a polychromator. After Raman scattering measurement for the optical alignment and an absolute calibration, we successfully measured Te = 72.2 eV and ne = 0.43 * 1016 m-3 for the coil supported case and Te = 79.2 eV and ne = 1.28 * 1016 m-3 for the coil-levitated case near the inner edge in the magnetospheric plasmas. PMID- 30399735 TI - Optimized quasi-optical cross-polarization scattering system for the measurement of magnetic turbulence on the DIII-D tokamak. AB - Simulations and laboratory tests are used to design and optimize a quasi-optical system for cross-polarization scattering (CPS) measurements of magnetic turbulence on the DIII-D tokamak. The CPS technique uses a process where magnetic turbulence scatters electromagnetic radiation into the perpendicular polarization enabling a local measurement of the perturbing magnetic fluctuations. This is a challenging measurement that addresses the contribution of magnetic turbulence to anomalous thermal transport in fusion research relevant plasmas. The goal of the new quasi-optical design is to demonstrate the full spatial and wavenumber capabilities of the CPS diagnostic. The approach used consists of independently controlled and in vacuo aiming systems for the probe and scattered beams (55-75 GHz). PMID- 30399736 TI - An instrumented glove for monitoring hand function. AB - The measurement of hand kinematics is important for the assessment and rehabilitation of the paralysed hand. The traditional method of hand function assessment uses a mechanical or electronic goniometer placed across the joint of interest to measure the range of joint movement. Mechanical goniometers are imprecise and lack the ability to provide a dynamic measurement; electronic goniometers are expensive and cumbersome to use during therapy. An alternative to the goniometric based assessment is to use inertial motion sensors to monitor the hand movement-these can be incorporated in a glove. In this paper, we present the design of an instrumented glove equipped with Magnetic, Angular Rate and Gravity (MARG) sensors for the objective evaluation of hand function. The instrumented glove presented in this paper is designed to assess the range of movement of the hand and also monitor the hand function during the course of hand rehabilitation. Static and dynamic calibrations were performed for the Euler angles calculated from the MARG sensors. The results are also presented for physiological flexion/extension of the wrist (relative roll), flexion/extension of elbow (relative pitch), and internal rotation/external rotation (relative yaw). The static calibration results gave mean absolute errors of 4.1 degrees for roll, 4.0 degrees for pitch, and 4.6 degrees for yaw. From the dynamic calibration, the speed of response to a step change gave a convergence time of 0.4 s; sinusoidally oscillating movement gave good tracking at 0.2 Hz but exhibits overshoot errors at higher frequencies which were tested to be 1 Hz. We present the results of the calibration of the instrumented glove (one sensor pair measuring one joint angle) measuring anatomical joint angles-mean absolute errors during static calibration: 6.3 degrees for a relative roll (wrist flexion/extension), 5.0 degrees for relative pitch (elbow flexion/extension), and 4.5 degrees for relative yaw (shoulder internal rotation/external rotation). The experimental results from the instrumented glove are promising, and it can be used as an alternative to the traditional goniometer based hand function assessments. PMID- 30399737 TI - High resolution magnetic field measurements in hydrogen and helium plasmas using active laser spectroscopy. AB - Passive spectroscopic measurements of Zeeman splitting have been used reliably to measure magnetic fields in plasmas for decades. However, a requirement is that the field magnitude must be sufficiently strong to be resolved over Doppler and instrument broadening (typically >10 000 G). A diagnostic for measuring magnetic fields spectroscopically well below this limit (>20 G) with high sensitivity has been developed at the Oak Ridge National Laboratory. The diagnostic relies on measuring a high resolution spectral profile using Doppler-free saturation spectroscopy (DFSS) and then fitting the spectrum to a quantum mechanical model. DFSS is an active, laser based technique that greatly reduces the influence of Doppler broadening and eliminates instrument broadening. To date, the diagnostic has been successfully employed to measure the magnetic field in magnetized (550 900 G), low-temperature (5-10 eV), low-density (1010-1012 cm-3), hydrogen and helium plasmas in the 5-200 mTorr pressure range using a low power (25 mW) diode laser. Implementing an approximate crossover resonance model, the measurements are shown to be accurate within 5 G for helium and 83 G for hydrogen. The accuracy in hydrogen can be improved to 39 G if the crossover resonances are neglected. A more robust crossover model can decrease this error to <1 G. PMID- 30399738 TI - A three-dimensional steerable optical tweezer system for ultracold atoms. AB - We present a three-dimensional steerable optical tweezer system based on two pairs of acousto-optic deflectors. Radio frequency signals used to steer the optical tweezers are generated by direct digital synthesis, and multiple time averaged cross beam dipole traps can be produced through rapid frequency toggling. We produce arrays of ultracold atomic clouds in both horizontal and vertical planes and use this to demonstrate the three-dimensional nature of this optical tweezer system. PMID- 30399739 TI - Synthetic diagnostic for electron cyclotron emission imaging. AB - Synthetic diagnostics are aimed at simulating the response of diagnostic systems under actual experimental scenarios and are the key to drawing quantitative inferences from experimental data. The synthetic Electron Cyclotron Emission Imaging (ECEI) diagnostic is suitable for evaluation of the improvement arising from the application of Field Curvature Adjustment (FCA) lenses in the design of the upgraded Experimental Advanced Superconducting Tokamak (EAST) tokamak ECEI system. In previous ECEI systems, a curved image plane is inevitable in optics systems comprising only convex lenses, which leads to significant crosstalk between vertically adjacent channels and strongly limits the vertical channel resolution of the imaging system. The synthetic ECEI diagnostic results show that, with FCA lenses applied, the upgraded ECEI system has significant advantages to focus on high poloidal wavenumber structures with the aberrations from the spherical surfaces corrected and the various artifacts related to the field curvature suppressed. Also, the synthetic ECEI diagnostic is used for some quantitative calculations to partially decouple the effect of density fluctuations and temperature fluctuations for a given plasma. PMID- 30399740 TI - Physical modeling of heat and moisture transfer in wet bio-sourced insulating materials. AB - Simultaneous heat and moisture transfers in bio-sourced insulating materials are significant phenomena in thermal metrology. The present study focuses on these phenomena by experimental and numerical approaches based on the asymmetric hot plate method. In this paper, a bio-sourced insulating material based on flax fibers is developed. The thermal and hygric properties of the sample are then investigated in the humid atmosphere. The temperature is maintained at 30 degrees C, and the relative humidity varies between 30% and 90% RH. A physics based model of simultaneous heat and moisture transfer is developed for thermal conductivity estimation. This model is discretized with finite difference methods and implanted in MATLAB(r). With the Levenberg-Marquardt algorithm, the thermal conductivity of the sample in different hygrothermal conditions is estimated and confirmed by experimental results. The reduced sensitivity of the model to estimated parameters is studied. The results confirm and validate the theoretical and the experimental results. PMID- 30399741 TI - Ab initio response functions for Cherenkov-based neutron detectors. AB - Neutron time-of-flight diagnostics at the NIF were recently outfitted with Cherenkov detectors. A fused silica radiator delivers sub-nanosecond response time and is optically coupled to a microchannel plate photomultiplier tube with gain from ~1 to 104. Capitalizing on fast time response and gamma-ray sensitivity, these systems can provide better than 30 ps precision for measuring first moments of neutron distributions. Generation of ab initio instrument response functions (IRFs) is critical to meet the <1% uncertainty needed. A combination of Monte Carlo modeling, benchtop characterization, and in situ comparison is employed. Close agreement is shown between the modeled IRFs and in situ measurements using the NIF's short-pulse advanced radiographic capability beams. First and second moments of neutron spectra calculated using ab initio IRFs agree well with established scintillator measurements. Next-step designs offer increased sensitivity and time-response. PMID- 30399742 TI - Microwave oscillator using piezoelectric thin-film resonator aiming for ultraminiaturization of atomic clock. AB - We developed a microwave oscillator and a micro electromechanical systems-based rubidium cell for the miniaturization of atomic clocks. A thin-film bulk acoustic resonator (FBAR) having a resonant frequency of the fundamental mode in the 3.5 GHz band was employed instead of a crystal resonator. It delivers a clock transition frequency of Rb atoms of 3.417 GHz without the need for a complicated frequency multiplication using a phase-locked loop. This topology considerably reduces the system scale and power consumption. For downsizing the atomic clock system toward the chip level as well as mass production, a microfabricated gas cell containing Rb and N2 gases was also developed. These microcomponents were incorporated into an atomic clock test bench, resulting in a clock operation with a short-term frequency instability of 2.1 * 10-11 at 1 s. To the best of our knowledge, this is the first report of a coherent population trapping clock operation using an FBAR-based microwave oscillator as well as a microfabricated gas cell. PMID- 30399743 TI - Velocity-space sensitivity of the compact neutron emission spectrometers at EAST. AB - Several compact neutron spectrometers are now installed at EAST (Experimental Advanced Superconducting Tokamak) to obtain information on fuel ions produced in the core of the plasma. In this paper, a stilbene crystal neutron spectrometer and an EJ301 liquid scintillator neutron spectrometer with n-gamma discrimination capability will be discussed. Both spectrometers have a horizontal line of sight, while at different positions. In the last few experiment campaigns at EAST, they all proved to be reliable diagnostics for auxiliary heated D-D plasmas. Taking the response function simulated by dedicated Geant4 models into consideration, the velocity-space sensitivities given by the instrument-specific weight function of the beam-thermal part of neutron energy spectra in D-D plasmas are derived for both spectrometers with the Genesis code. This method makes it possible to directly relate the contribution of different deuteron velocity space regions to events in each channel of the neutron spectrum measured by the two instruments: http://rsi-htpd.peerx-press.org/. PMID- 30399744 TI - A free-standing wire scattering technique to monitor calibration variations of the DIII-D density profile reflectometer. AB - Real-time phase calibration of the ITER profile reflectometer is essential due to the long plasma duration and expected waveguide path length changes during a discharge. Progress has been recently made in addressing this issue by employing a phase calibration technique on DIII-D that monitors calibration variations that occur during each plasma discharge. By installing a thin free-standing metallic wire (1 mm diameter) near the end of the overmoded waveguide transmission system (oriented perpendicular to the waveguide axis), the round-trip phase shift from the wire is detected simultaneously with the plasma phase shifts. Variations in the reflectometer round trip path length (~26 m) are then calculated after each DIII-D plasma discharge, allowing the calibration phase to be accurately monitored and updated. The round-trip reflectometer path length is observed to vary by ~3 mm (root mean square value) during a typical DIII-D discharge. Using the variations in calibration phase, the density profile measurement accuracy can be improved. Since the wire retro-reflected power is ~0.01 of the plasma signal, minimal effect is observed on the reflected signal from the plasma. Importantly, through a suitable choice in wire diameter, the calibration signal can be made approximately independent of the V-band reflectometer launch polarization. This is particularly important on DIII-D since orthogonal X- and O-mode polarized beams are coupled into the same transmission waveguide and launch antenna. PMID- 30399745 TI - Time-delayed mass spectrometry of the low-energy electron impact with a liquid beam surface. AB - We set up an experimental apparatus to investigate the low-energy electron impact with a liquid beam surface, in which a cylindrical liquid beam with a diameter of 25 MUm emits as the laminar flow from a microjet and the positively charged ions produced by the electron-impact ionizations are detected with a linear time-of flight mass spectrometer. We propose a time-delayed mass spectrometry for this apparatus to identify the cationic fragments produced on the liquid surface, in which the application of the ion extracting pulse is delayed with different time intervals after the electron beam pulse. Sensitivity and specificity of the present methodology are demonstrated by the combinational experiments of the gas phase and liquid ethanol. In comparison with the gas-phase experiments, the ion peaks become much broader in the mass spectra of the liquid beam, primarily due to the molecular evaporation and diffusion. After delaying with about 2 MUs, we find that the hydrocarbon ions are ultimately the predominant products in the mass spectra of the liquid ethanol and they are proposed to be produced on the liquid surface. Above observations are in line with the widely accepted picture of the molecular orientation on the liquid surface; namely, the ethanol's CH3-CH2 group on the liquid surface prefers to be oriented outside. Therefore, we demonstrate a new mass spectrometry to explore the molecular structures of the liquid surface. PMID- 30399746 TI - Combination Doppler backscattering/cross-polarization scattering diagnostic for the C-2W field-reversed configuration. AB - A versatile combination Doppler backscattering and Cross-Polarization Scattering (CPS) diagnostic for the C-2W beam-driven field-reversed configuration is described. This system is capable of measuring density fluctuations and perpendicular magnetic field fluctuations across a wide wavenumber range (2.5 <= k theta rho s <= 50), with typical resolution Deltak theta/k theta <= 0.4-0.8. Four tunable frequencies (26 GHz <= f <= 60 GHz corresponding to plasma cut-off densities 0.8 * 1019 <= n e <= 4.4 * 1019 m-3) are launched via quasi-optical beam combiners/polarizers and an adjustable parabolic focusing mirror selecting the beam incidence angle. GENRAY ray tracing shows that the incident O-mode and backscattered CPS X-mode beam trajectories for C-2W plasma parameters nearly overlap, allowing simultaneous detection of n and B r or B theta from essentially the same scattering volume. PMID- 30399747 TI - Study of the properties of thin Li films and their relationship with He plasmas using ion beam analysis in the DIONISOS experiment. AB - Plasma facing component (PFC) conditioning dramatically affects plasma performance in magnetic confinement fusion experiments. Lithium (Li) has been used in several machines to condition PFC with subsequent improvements to plasma performance. Multiple studies have investigated the interactions of Li with deuterium (D) and oxygen (O) in order to ascertain the mechanisms behind the enhanced plasma performance. Ion Beam Analysis (IBA) is a useful tool to interrogate PFC surfaces as they interact with plasmas. Dynamics of ion implantation and sputtering of surfaces (DIONISOS) is a linear plasma device, capable of generating discharges with fluxes ~1021 m-2 s-1 and Te ~6 eV, coupled to an ion accelerator. DIONISOS is capable of analyzing samples using Elastic Recoil Detection (ERD) and Rutherford Backscattering Spectroscopy (RBS) during plasma exposures. The facility has been equipped with a Li deposition system for evaporation of thin coatings on different substrates. The evaporator enables real time ERD and RBS measurements of deposition and erosion of Li coatings on different substrates and the interaction of the Li with the vacuum and plasma. Considerations for ERD, e.g., ion species, energy, and data acquisition frequency, are presented. This work is the basis for further investigation of He, H, and D retention in solid and liquid Li. PMID- 30399748 TI - Upgrade of the ECE diagnostic on EAST. AB - The electron cyclotron emission (ECE) diagnostic on the experimental advanced superconducting tokamak (EAST) was upgraded recently to provide electron temperature profile measurement with wider radial coverage and better precision. The lower limit of the ECE detection frequency band was extended from 104 GHz to 97 GHz by adding a new 8-channel heterodyne radiometer, which ensures capability for the measurement of the second harmonic ECE with toroidal magnetic field down to 1.75 T. Also, the existing 32-channel heterodyne radiometer has been upgraded, with the frequency interval for the lower frequency range up to 120 GHz reduced from 2 GHz to 1 GHz by introducing eight channels in the intermediate frequency part. In addition, a plan is presented to incorporate tunable yttrium iron garnet filters into the existing heterodyne radiometer to obtain detailed measurements of the electron temperature gradient scale length as well as finer spatial pinpointing of magnetohydrodynamic modes. Examples from DIII-D are provided where similar ECE diagnostic allowed precise measurement of the center and width of neoclassical tearing modes. PMID- 30399749 TI - Simplified high-current measurement probe based on a single-mode optical fiber. AB - A "fiber optic cable tester" of 658 nm wavelength has been used to launch a linearly polarized light to the twisted single mode optical fiber of the designed mega-ampere current measurement probe. Modulated intensity variation of light has been converted to the corresponding electrical signal using a fast photodetector assembly having 100 nS rise-time. The effect of undesired linear birefringence has been overcome by manually twisting the fiber at a twist rate of 40 twists per meter. The sensitivity of the designed probe is 0.247 degrees polarization rotation/kA current-turn product, for a single optical fiber loop. PMID- 30399750 TI - Using Laser-Induced Rydberg Spectroscopy diagnostic for direct measurements of the local electric field in the edge region of NSTX/NSTX-U: Modeling. AB - We discuss a novel diagnostic allowing direct measurements of the local electric field in the edge region of NSTX/NSTX-U. This laser based diagnostic's principle consists of depleting the naturally populated n = 3 level to a Rydberg state sensitive to electric fields-that will result in a suppression of part of the D alpha emission. We refer to this approach as Laser-Induced Rydberg Spectroscopy. It is shown that the local electric field can be measured through the Stark induced resonances observed as dips in the D alpha emission. Using forward modeling of simulated absorption spectra, we show precisions reaching +/-2 kV m-1 in regions with a local electric field of 15 kV m-1. PMID- 30399751 TI - Scintillating fiber detectors for time evolution measurement of the triton burnup on the Large Helical Device. AB - Two scintillating fiber (Sci-Fi) detectors have been operated in the first deuterium plasma campaign of the Large Helical Device in order to investigate the time evolution of the triton burnup through secondary 14 MeV neutron measurement. Two detectors use scintillating fibers of 1 mm diameter embedded in an aluminum matrix with a length of 10 cm connected to the magnetic field resistant photomultiplier. A detector with 91 fibers was developed in the Los Alamos National Laboratory and has been employed on JT-60U. Another detector with 109 fibers has been developed in the National Institute for Fusion Science. The signals are fed into a discriminator of 300 MHz bandwidth with a pulse counter module for online measurement and a digitizer of 1 GHz sampling with 14 bits to acquire pulse shape information for offline data analysis. The triton burnup ratio has been evaluated shot-by-shot by the 14 MeV neutron measurement of Sci-Fi detectors which are calibrated by using the neutron activation system and the total neutron measurement of the neutron flux monitor using 235U fission chambers. PMID- 30399752 TI - A heterodyne dispersion interferometer for wide bandwidth density measurements on DIII-D. AB - In order to improve both the density and particularly the temporal resolution beyond previous dispersion interferometers (DIs), a heterodyne technique based on an acousto-optic (AO) cell has been added to the DI. A 40 MHz drive frequency for the AO cell allows density fluctuation measurements into the MHz range. A CO2 laser-based heterodyne DI (HDI) installed on DIII-D has demonstrated that the HDI is capable of tracking the density evolution throughout DIII-D discharges, including disruption events and other rapid transient phenomena. The data also show good agreement with independent density measurements obtained with the existing DIII-D two-color interferometer. The HDI line-integrated density resolution sampled over a 1 s interval is ~9 * 1017 m-2. Density fluctuations induced by MHD instabilities are also successfully measured by the HDI. PMID- 30399754 TI - Digital pulse timing with semiconductor gamma-ray detectors using a wavelet transform technique. AB - Obtaining precise timing information from semiconductor gamma-ray detectors is of great interest for a variety of applications such as high-resolution positron emission tomography. However, pulse timing with these detectors through the common constant-fraction discrimination (CFD) method is strongly affected by the time-walk error that results from the inherent variations in the shape of the detectors' pulses. This paper reports on the use of the wavelet transform for minimizing the time-walk error in digital CFD pulse timing with semiconductor gamma-ray detectors. The details of the method are described, and the experimental results with a 1 mm thick CdTe detector are shown. It is demonstrated that, by using the Haar wavelet transform of the digitized preamplifier pulses, the original tailed time spectrum of the detector with a time resolution of 8.22 +/- 0.12 ns at full-width at half-maximum (FWHM) in the energy range of 300-550 keV improves to a symmetric time spectrum with a time resolution of 3.39 +/- 0.02 ns (FWHM). PMID- 30399753 TI - Implementation of a 1-2 keV point-projection x-ray spectrometer on the National Ignition Facility. AB - A point-projection soft X-ray Opacity Spectrometer (OpSpec) has been implemented to measure X-ray spectra from ~1 to 2 keV on the National Ignition Facility (NIF). Measurement of such soft X-rays with open-aperture point-projection detectors is challenging because only very thin filters may be used to shield the detector from the hostile environment. OpSpec diffracts X-rays from 540 to 2100 eV off a potassium (or rubidium) acid phthalate (KAP or RbAP) crystal onto either image plates or, most recently, X-ray films. A "sacrificial front filter" strategy is used to prevent crystal damage, while 2 or 3 rear filters protect the data. Since May 2017, OpSpec has been recording X-ray transmission data for iron magnesium plasmas on the NIF, at "Anchor 1" plasma conditions (temperature ~150 eV, density ~7 * 1021 e -/cm3). Upgrades improved OpSpec's performance on 6 NIF shots in August and December 2017, with reduced backgrounds and 100% data return using filter stacks as thin as 2.9 MUm (total). Photometric noise is beginning to meet requirements, and further work will reduce systematic errors. PMID- 30399755 TI - Synthetic diagnostic for assessing spatial averaging of charge exchange recombination spectroscopy measurements. AB - A synthetic charge exchange recombination spectroscopy diagnostic based on the FIDASIM modeling suite has been created for the DIII-D tokamak. This synthetic diagnostic assumes that the ions have Maxwellian distribution functions on each flux surface and models emission from charge exchange events between the beam neutrals and a fully ionized impurity. This work was motivated by the observation of non-Gaussian spectra that may be caused by spatial averaging, atomic physics, or non-Maxwellian distribution functions. Measurements of non-Gaussian spectra commonly observed in the high confinement mode pedestal and in plasmas with large core gradients are compared to the synthetic diagnostic. Spatial averaging alone cannot account for the observations in these two cases, opening up the possibility of there being other causes such as non-Maxwellian distribution functions. The synthetic diagnostic has also been used to resolve a long-standing issue: it is shown that the lower temperatures measured by using vertical view chords relative to tangential view chords are due to increased spatial averaging for vertical views due to the DIII-D neutral beams being approximately twice as tall as they are wide. PMID- 30399756 TI - Forward projection matrix derivation through Monte-Carlo ray-tracing of KSTAR infra-red imaging video bolometer (IRVB). AB - The infrared imaging video bolometer (IRVB) as a foil bolometry technique can be an alternative solution to the conventional resistive bolometer due to its electro-magnetic immunity and 2D plasma profiles. The plasma profile of the IRVB cannot be directly derived from the foil images due to the difference between the foil pixel number and the plasma pixel number and the line integrated nature of the incident rays on the foil. So, it needs tomography such as the Phillips Thikhonov algorithm. The projection matrix constructing the foil image from the plasma very directly influences the tomography. So, the projection matrix needs to be constructed precisely. For the technique calculating the precise projection matrix, a forward Monte-Carlo ray-tracing method is proposed here, and this technique can provide the detailed descriptions of the foil image. And it can give enhanced performance in the reconstructions of the plasmas with spatially localized power. PMID- 30399757 TI - Zeeman splitting measurements of magnetic fields in iodine plasma. AB - Iodine is an attractive propellant for next generation ion thrusters. Laser induced fluorescence (LIF) is widely used with other propellant species as a non perturbative technique for measuring flow for thruster prediction models. We apply LIF methods recently demonstrated for singly-ionized iodine to a magnetized plasma environment similar to those found in ion thrusters and in magnetically confined laboratory plasmas. We demonstrate the feasibility of remotely determining the local magnetic field from the Zeeman effect-split spectrum of I+. PMID- 30399758 TI - Initial operation results of NE213 scintillation detector for time-resolved measurements on triton burnup in KSTAR. AB - In time-resolved measurement for triton burnup in Korea Superconducting Tokamak Advanced Research (KSTAR) deuterium plasmas, an NE213 liquid scintillation detector was installed and operated during the 2017 KSTAR campaign. The detector is composed of an NE213 scintillator (50 mm in diameter and 10 mm in thickness) and a photomultiplier tube (PMT). The PMT anode signal was processed under a data acquisition system which contains a field programmable gate array circuit and pulse processing software that is capable of discriminating gamma-ray and neutron pulse signals. In order to determine an appropriate threshold level for the 14 MeV neutron signal resulting from triton burnup, the NE213 scintillation detector was calibrated by using d-d and d-t neutron generators at the National Fusion Research Institute and Intense 14 MeV Neutron Source Facility, OKTAVIAN, Osaka University, Japan. The detector was installed on KSTAR with a 10 mm thick soft iron stray magnetic field shield and a radiation shield which consists of 100 mm thick lead blocks and 200 mm thick borated polyethylene blocks. A discrimination range for d-t neutron was determined based on test results from neutron generators and KSTAR. Data points selected from the discrimination range were consistent with the classical triton confinement characteristics. In conclusion, under condition of an input counting rate of 1.9 * 105 counts per second (CPS), the detector is able to measure triton burnup signals up to 500 CPS for various plasma parameters. PMID- 30399759 TI - Development of a time-of-flight low-energy neutral particle analyzer for EAST tokamak. AB - To understand the erosion effect of neutral particles on the first wall, a low energy neutral particle analyzer (LENPA), based on the time-of-flight method, has been developed for the Experimental Advanced Superconducting Tokamak (EAST). The LENPA to be installed in the EAST mid-plane mainly consists of a chopper sub system, a 3 m long flight tube, two sets of detector assemblies, and data acquisition and processing, vacuum, power supply, and control sub-systems. The neutral outflux is gated in bunches of 1 MUs time scale by a slotted rotating disc which is driven by a vacuum compatible motor modified from a turbomolecular pump. A He-Ne laser beam is projected through the disc slit to record the instants of chopper slits opening with an avalanche photodiode module. An on-axis electron multiplier detects chopped neutrals, and a central perforated Cu-Be plate is employed to channel the emitted secondary electrons into an off-axis electron multiplier. The radiation peaks of on-axis electron multiplier caused by UV photons projected through the central hole of the Cu-Be plate provide an alternative way to record the chopper slits' opening time. With an additional 4 TB fast memory card, 1 GS/s sampling rate has been realized by using a GaGe acquisition card continuously. The LENPA data from the EAST together with neutral particle material erosion experiments will be used to benchmark the simulation results for better predictions on future fusion reactors, such as ITER and China Fusion Engineering Test Reactor (CFETR). PMID- 30399760 TI - Application of Jiles-Atherton model in description of temperature characteristics of magnetic core. AB - The Jiles-Atherton (J-A) model is widely used in magnetic characteristic modeling in alternating field. A dynamic J-A model, which is applied under high-frequency condition, is established. A pointwise iterative calculation method is used, and an approximate calculation method of the anhysteretic magnetization intensity and its derivative is proposed. The solving procedure of the J-A model is optimized. The platform for the magnetization and temperature characteristic test is designed and constructed. The hysteresis curves of ferrite cores at different temperatures are measured. The variation of parameters of magnetic properties with temperature is analyzed, including maximum magnetic flux density, remanence, coercivity, and core loss. Based on the particle swarm optimization combined with natural selection, optimized parameters of the J-A model are obtained. Their variation is analyzed, and their fitted curves with temperature are obtained. It is found that J-A model's modification in temperature can be used to guide the modeling analysis of electrical equipment containing magnetic cores working in high-temperature environment and to predict magnetic properties at high temperatures. PMID- 30399761 TI - An optical trapping system for particle probes in plasma diagnostics. AB - We present one of the first experiments for optically trapping of single microparticles as probes for low temperature plasma diagnostics. Based on the dual laser beam, counter-propagating technique, SiO2 microparticles are optically trapped at very large distances in low-temperature, low-pressure rf plasma. External forces on the particle are measured by means of the displacement of the probe particle in the trap. Measurements can be performed during plasma operation as well as without plasma. The paper focuses on the optical setup and the verification of the system and its principle. Three examples for the particle behavior in the trapping system are presented: First, we measured the neutral gas damping as a verification of the technique. Second, an experiment without a plasma studies the changing particle charge by UV light radiation, and third, by moving the probe particle in the vertical direction into the sheath or into the plasma bulk, respectively, the acting forces on the probe particle are measured. PMID- 30399762 TI - Simulation of the beamline thermal measurements to derive particle beam parameters in the ITER neutral beam test facility. AB - Injection of high energy neutral beam particles will be used in the ITER experiment for plasma heating and current drive. In a ITER heating beam injector, a 40 MW electrostatically accelerated negative beam will be neutralised and filtered along the beamline, obtaining a nominal 16.5 MW neutral beam power to be injected in the tokamak plasma or intercepted during conditioning and commissioning. The beam will heat the actively cooled panels of the beamline components with up to 13 MW/m2 surface power density and 18 MW power. These extreme conditions require testing in a ITER full scale neutral beam test facility under construction in Padova where the temperature of the beamline components will be monitored by 610 embedded thermocouples for protection against critical conditions, for recognising beam conditioning, and for deriving beam parameters. Power density maps of the expected beam-component interactions are applied on a parametric non-linear finite element model to simulate fields of expected temperatures. Such thermal maps are analyzed to derive the beam parameters during operation: divergence of 3-7 mrad and misalignment of 0-3 mrad. The sensibility of the temperature measurements is discussed considering a minimum 10% fraction of the nominal beam power. PMID- 30399763 TI - Average neutron time-of-flight instrument response function inferred from single D-T neutron events within a plastic scintillator. AB - The apparent ion temperature and neutron-reaction history are important characteristics of a fusion plasma. Extracting these quantities from a measured neutron-time-of-flight signal requires accurate knowledge of the instrument response function (IRF). This work describes a novel method for obtaining the IRF directly for single DT neutron interactions by utilizing n-alpha coincidence. The t(d,alpha)n nuclear reaction was produced at Sandia National Laboratories' Ion Beam Laboratory using a 300 keV Cockcroft-Walton generator to accelerate a 2.5 MUA beam of 175 keV D+ ions into a stationary ErT2 target. The average neutron IRF was calculated by taking a time-corrected average of individual neutron events within an EJ-228 plastic scintillator. The scintillator was coupled to two independent photo-multiplier tubes operated in the current mode: a Hamamatsu 5946 mod-5 and a Photek PMT240. The experimental setup and results will be discussed. PMID- 30399764 TI - Erratum: "Charge breeding of radioactive isotopes at the CARIBU facility with an electron beam ion source" [Rev. Sci. Instrum. 89, 052402 (2018)]. PMID- 30399765 TI - Contributed Review: Advanced three-dimensional laser radar imaging with the airborne optical systems testbed. AB - We describe the development of a state-of-the-art airborne 3D laser radar system capable of area coverage rates in excess of 150 km2/h. The ladar testbed can operate day and night and uses a low-power, eye-safe, and covert near-IR laser transmitter and a large-pixel-format photon-counting detector array coupled with a precision, fast-scanning, beam pointing mechanism. Mission areas include wide area down-looking high-resolution open terrain and foliage-penetrating imaging, side-looking and up-looking laser ranging and tracking, and sensor fusion with electro-optical infrared cameras and hyperspectral payloads. We describe the airborne optical systems testbed ladar system, present recently collected 3D data, and discuss testbed configurations that can support advanced imaging applications. PMID- 30399766 TI - A new toroidal x-ray crystal spectrometer for the diagnosis of high energy density plasmas at the National Ignition Facility. AB - The here-described spectrometer was developed for the extended x-ray absorption fine structure spectroscopy of high-density plasmas at the National Ignition Facility. It employs as the Bragg reflecting element a new type of toroidally bent crystal with a constant and very large major radius R and a much smaller, locally varying, minor radius r. The focusing properties of this crystal and the experimental arrangement of the source and detector make it possible to (a) fulfill the conditions for a perfect imaging of an ideal point source for each wavelength, (b) obtain a high photon throughput, (c) obtain a high spectral resolution by eliminating the effects of source-size broadening, and (d) obtain a one-dimensional spatial resolution with a high magnification perpendicular to the main dispersion plane. PMID- 30399767 TI - Extracting the turbulent flow-field from beam emission spectroscopy images using velocimetry. AB - The 2D turbulent E * B flow-field is inferred from density fluctuation images obtained with the beam emission spectroscopy diagnostic on DIII-D using the orthogonal dynamic programming velocimetry algorithm. A synthetic turbulence model is used to test the algorithm and optimize it for measuring zonal flows. Zonal flow measurements are found to require a signal-to-noise ratio above ~10 and a zonal flow wavelength longer than ~2 cm. Comparison between the velocimetry estimated flow-field and the E * B flow-field using a nonlinear gyrokinetic GENE simulation finds that the flow-fields have identical spatial structure and differ only by the mean turbulence phase velocity, which is spatially uniform in this flux tube simulation. PMID- 30399768 TI - High-energy differential-filtering photon spectrometer for ultraintense laser matter interactions. AB - Large quantities of ultrahigh-energy x-rays are produced by petawatt-class lasers; however, spectroscopy in this range of 0.1-1 MeV is difficult due to the long photon mean free path. A novel geometry step filter to measure the high energy bremsstrahlung emission tail has been developed for use in high energy density, short-pulse laser-matter interaction experiments. The grid design of the filters allows for the independent determination of a local background, which reduces systematic errors in the reconstructed spectra. This spectrometer was used to measure x-ray spectra for various laser and target conditions at intensities near 1 * 1018 W/cm2 where single-exponential bremsstrahlung spectra were fit to the data and show an increasing photon temperature with pulse duration for a fixed laser intensity. PMID- 30399769 TI - Neutron measurements at the ELISE neutral beam test facility and implications for neutron based diagnostics at SPIDER. AB - Along the route to the development of a neutral beam injector for ITER, the Padua based Source for Production of Ion of Deuterium Extracted from Rf plasma (SPIDER) and megavolt ITER injector and concept advancement facilities will make use of neutron diagnostics to quantify the homogeneity of the neutral beam profile by measuring the map of the neutron emission from the beam dump with the close contact neutron emission surface mapping (CNESM) system. Neutrons are here produced from beam-target reactions between the deuterium beam and the deuterons previously adsorbed in the calorimeter. In order to aid the interpretation of the diagnostic data, a dedicated experiment on neutron emission from beam-target reactions with beam parameters approaching those expected at SPIDER has been performed at the Extraction from a Large Ion Source Experiment (ELISE) neutral beam test facility. The time trace of neutron emission has been measured using a calibrated liquid scintillator detector at increasing power densities on the target. Compared to calculations based on the local mixing model, a systematic discrepancy was observed exceeding the statistical accuracy of the measurements and increasing as a linear function of the power density. The data are used to derive an empirical temperature dependent correction for applications to neutron measurements at SPIDER. PMID- 30399770 TI - Plasma rotation measurement using UV and visible spectroscopy on Aditya-U tokamak. AB - A high resolution spectroscopic diagnostic for the measurement of the spatial profile of toroidal rotation velocity (vt) and temperature (Ti) of carbon ions has been developed and implemented on the Aditya-U tokamak. The diagnostic consists of a high resolution 1 m (f/8.7) spectrometer having an 1800 grooves/mm grating coupled with a charged couple device. The setup allows measurements from 5 toroidal lines-of-sights passing through different minor radii in the horizontal mid-plane of the Aditya-U tokamak. The carbon line emissions at 529 nm in visible and 229.6 and 227.09 nm in the ultra violet spectral range are recorded using the setup. Initial results show that typical Aditya-U plasmas have a maximum carbon ion temperature (Ti) of ~120 eV and a rotation velocity (vt) of ~-14 km/s in the counter plasma-current direction. PMID- 30399771 TI - Calibration of proton dispersion for the NIF electron positron proton spectrometer (NEPPS) for short-pulse laser experiments on the NIF ARC. AB - Experiments using the Advanced Radiographic Capability (ARC) laser at the National Ignition Facility (NIF) aim to characterize short-pulse-driven proton beams for use as both probes and drivers for high-energy-density physics experiments. Measurements of ARC-driven proton beam characteristics, such as energy spectrum and conversion efficiency, rely on the NIF Electron Positron Proton Spectrometer (NEPPS). The NEPPS diagnostic is a version of an existing particle spectrometer which is used for detecting MeV electron and positron spectra via permanent magnetic field dispersion. These spectrometers have not yet been calibrated for protons and instead use an analytical calculation to estimate the dispersion. Small variations in the field uniformity can affect the proton dispersion due to the relatively small resolving power (E/dE) for this diagnostic. A broadband energy, laser-accelerated proton source was produced at the Titan laser to experimentally calibrate the proton dispersion. These experimental data were used to test the theoretical dispersion. Numerical simulations using measurements of the magnetic field variation within the diagnostic were used to obtain a realistic proton dispersion curve for the new NEPPS units. This procedure for obtaining each independent dispersion is applicable to all EPPS and NEPPS diagnostics, given the axial magnetic field profile. PMID- 30399772 TI - Progress on next generation gamma-ray Cherenkov detectors for the National Ignition Facility. AB - Fusion reaction history and ablator areal density measurements for Inertial Confinement Fusion experiments at the National Ignition Facility are currently conducted using the Gamma Reaction History diagnostic (GRH_6m). Future Gas Cherenkov Detectors (GCDs) will ultimately provide ~100x more sensitivity, reduce the effective temporal response from ~100 to ~10 ps, and lower the energy threshold from 2.9 to 1.8 MeV, relative to GRH_6m. The first phase toward next generation GCDs consisted of inserting the existing coaxial GCD-3 detector into a reentrant well which puts it within 4 m of the implosion. Reaction history and ablator gamma measurement results from this Phase I are discussed here. These results demonstrate viability for the follow-on Phases of (II) the use of a revolutionary new pulse-dilation photomultiplier tube to improve the effective measurement bandwidth by >10x relative to current PMT technology; and (III) the design of a NIF-specific "Super" GCD which will be informed by the assessment of the radiation background environment within the well described here. PMID- 30399773 TI - Toward quasi-DC conductivity of warm dense matter measured by single-shot terahertz spectroscopy. AB - We present an experimental setup capable of measuring the near DC conductivity of laser generated warm dense matter using single-shot terahertz time-domain spectroscopy. The setup uses a reflective echelon and balanced detection to record THz waveforms with a minimum detectable signal of 0.2% in a single laser pulse. We describe details of the experimental setup and the data analysis procedure and present single-shot terahertz transmission data on aluminum that has been laser heated to an electron temperature of 0.5 eV. PMID- 30399774 TI - The multi-spectral imaging diagnostic. AB - The Multi-Spectral Imaging system is a new diagnostic that captures simultaneous spectrally filtered images from a common line of sight while maintaining a large etendue and high throughput. Imaging several atomic line intensities simultaneously may enable numerous measurement techniques. By making a novel modification of a polychromator layout, the MSI sequentially filters and focuses images onto commercial CMOS cameras while exhibiting minimal vignetting and aberrations. A four-wavelength system was initially installed and tested on Alcator C-Mod and subsequently moved to TCV. The images are absolutely calibrated and spatially registered enabling 2D mappings of atomic line ratios and absolute line intensities. The spectral transmission of the optical system was calibrated using an integrating sphere of known radiance. The images are inverted by cross referencing points on TCV with a computer-aided design (CAD) model. PMID- 30399775 TI - Modeling the one-dimensional imager of neutrons (ODIN) for neutron response functions at the Sandia Z facility. AB - The one-dimensional imager of neutrons (ODIN) at the Sandia Z facility consists of a 10-cm block of tungsten with rolled edges, creating a slit imager with slit widths of either 250, 500, or 750 MUm. Designed with a 1-m neutron imaging line of sight, we achieve about 4:1 magnification and 500-MUm axial spatial resolution. The baseline inertial confinement fusion concept at Sandia is magnetized liner inertial fusion, which nominally creates a 1-cm line source of neutrons. ODIN was designed to determine the size, shape, and location of the neutron producing region, furthering the understanding of compression quality along the cylindrical axis of magnetized liner implosions. Challenges include discriminating neutrons from hard x-rays and gammas with adequate signal-to-noise in the 2 * 1012 deuterium-deuterium (DD) neutron yield range, as well as understanding the point spread function of the imager to various imaging detectors (namely, CR-39). Modeling efforts were conducted with MCNP6.1 to determine neutron response functions for varying configurations in a clean DD neutron environment (without x-rays or gammas). Configuration alterations that will be shown include rolled-edge slit orientation and slit width, affecting the resolution and response function. Finally, the experiment to determine CR-39 neutron sensitivity, with and without a high density polyethylene (n, p) converter, an edge spread function, and resolution will be discussed. PMID- 30399776 TI - Invited Review Article: Multi-tip scanning tunneling microscopy: Experimental techniques and data analysis. AB - In scanning tunneling microscopy, we witness in recent years a paradigm shift from "just imaging" to detailed spectroscopic measurements at the nanoscale and multi-tip scanning tunneling microscope (STM) is a technique following this trend. It is capable of performing nanoscale charge transport measurements like a "multimeter at the nanoscale." Distance-dependent four-point measurements, the acquisition of nanoscale potential maps at current carrying nanostructures and surfaces, as well as the acquisition of I - V curves of nanoelectronic devices are examples of the capabilities of the multi-tip STM technique. In this review, we focus on two aspects: How to perform the multi-tip STM measurements and how to analyze the acquired data in order to gain insight into nanoscale charge transport processes for a variety of samples. We further discuss specifics of the electronics for multi-tip STM and the properties of tips for multi-tip STM, and present methods for a tip approach to nanostructures on insulating substrates. We introduce methods on how to extract the conductivity/resistivity for mixed 2D/3D systems from four-point measurements, how to measure the conductivity of 2D sheets, and how to introduce scanning tunneling potentiometry measurements with a multi-tip setup. For the example of multi-tip measurements at freestanding vapor liquid solid grown nanowires, we discuss contact resistances as well as the influence of the presence of the probing tips on the four point measurements. PMID- 30399777 TI - Characterization of shaped Bragg crystal assemblies for narrowband x-ray imaging. AB - X-ray imaging using shaped crystals in Bragg reflection is a powerful technique used in high-energy-density physics experiments. The characterization of these crystal assemblies with conventional x-ray sources is very difficult because of the required angular resolution of the order of ~10 MUrad and the narrow bandwidth of the crystal. The 10-J, 1-ps Multi-Terawatt (MTW) laser at the Laboratory for Laser Energetics was used to characterize a set of Bragg crystal assemblies. The small spot size (of the order of 5 MUm) and the high power (>1018 W/cm2) of this laser make it possible to measure the spatial resolution at the intended photon energy. A set of six crystals from two different vendors was checked on MTW, showing an unexpectedly large variation in spatial resolution of up to a factor of 4. PMID- 30399778 TI - Piezoelectric bimorph as a high-sensitivity viscosity resonant sensor to test the anisotropy of magnetorheological fluid. AB - In this paper, we present a device which is very sensitive for small changes in the viscosity of the investigated fluid. The main part of the device is a piezo electric bimorph which consists of the brass shim with two piezo-ceramic layers on the opposite sides. One of them is responsible for generating vibrations, whereas the second one is meant to measure system response which is produced by the damping properties of the surrounding fluid. During the experiment, the cylindrical bar is forced to move by the series of sinusoidal waves with different frequencies and at constant amplitudes. The probe is immersed in the fluid and then the amplitude vs frequency and phase vs frequency curves are obtained. Next, one can determine the viscosity according to a proper mathematical model. The resonant frequency is related to the damping coefficient which depends on the viscosity of the surrender fluid and immersion depth of the probe. The coefficients necessary for calculating viscosity are obtained by fitting the resonance curve to the amplitude vs frequency data obtained from the experiment. The device has been applied to study the anisotropy of magnetorheological fluids. The weak anisotropy of viscosity has been observed. The highest value of viscosity was observed in the case of viscosity measurement in the direction orthogonal to the magnetic field and the lowest in the direction parallel to the magnetic field. PMID- 30399779 TI - Radio frequency measurements of energetic-particle-driven emission using the ion cyclotron emission diagnostic on the DIII-D tokamak. AB - The Ion Cyclotron Emission (ICE) diagnostic on the DIII-D tokamak consists of two outboard midplane systems. In the first system, straps of an ion cyclotron range of frequencies antenna are configured as receiving antennas. For the second system, dedicated magnetic probes incorporated into the outer wall of carbon tiles have recently been restored. These systems collected a large set of radio frequency measurements in the 2015-2018 experimental campaigns by digitizing signals at 200 MSamples/s for ~5 s per discharge. Each shot typically yields 32 GB of data; techniques for successful handling and analysis of this challengingly large dataset are discussed. The raw voltage fluctuations (<0.2 V and <1 mW) are analyzed in frequency space via fast Fourier transforms. Signals can be analyzed between 1 and 200 MHz with appropriate filtering and aliasing; this frequency range is limited by DC breaks used to provide 5 kV DC isolation. These high frequency signals are driven by energetic ions and electrons. In particular, energetic-ion-driven ICE occurs at harmonics of the ion cyclotron frequency, enabling the frequency to be mapped to lab space via equilibrium reconstruction. In many DIII-D plasmas, ICE is emitted from the radial center of the plasma. PMID- 30399780 TI - Thomson scattering measurements on DIII-D using in-vessel laser mirrors and lenses to diagnose a new divertor location. AB - Translatable in-vessel mirrors have enabled the DIII-D Thomson scattering system to diagnose the divertor plasma in high triangularity shaped plasmas. Previous divertor Thomson scattering measurements in DIII-D were restricted to spatial locations along a Nd:YAG laser beam that was directed through a vertical port. This only allowed measurements to be made in low triangularity shaped plasmas. The new mirrors re-route the laser underneath floor tiles to a position of smaller major radius as necessary for high triangularity plasmas. New in-vessel collection optics transmit scattered light from regions inaccessible to external lenses. Damage to mirrors and high stray light levels are challenges that were overcome to successfully make these measurements. Through the careful use of baffles and light shields, stray light leakage into polychromator detector channels was reduced to negligible levels, allowing temperature measurements below 1 eV. The system is described and the initial results presented. PMID- 30399781 TI - Simple imaging for the diamond anvil cell: Applications to hard-to-reach places. AB - The employment of high-pressure gases as a pressure-transmitting medium, sample, or reactant for diamond anvil cell experiments is widespread. As a pressure transmitter, high-pressure gases are crucial to forming quasi-hydrostatic compression atmospheres for samples inside the uniaxially driven cell. We describe an optical design for forming high-resolution images of the gasket and sample chamber of the diamond anvil cell under high gas pressures in a gas loading apparatus. Our design is simple, is of low-cost, and may be easily adapted to suit gas loading apparatus of any design, as well as other common hard to-reach environments in diamond anvil cell experiments, i.e., those with large stand-off distances, such as cryostats. PMID- 30399782 TI - A Faraday-effect polarimeter for fast magnetic dynamics measurement on DIII-D. AB - A Faraday-effect-based radial-interferometer-polarimeter diagnostic has been developed to explore fast magnetic dynamics in high-performance DIII-D plasmas. The instrument measures radial magnetic field perturbations using three chords positioned near the magnetic axis. Newly developed solid-state sources operating at 650 GHz provide phase noise down to 0.01 degrees / kHz and tunable bandwidth up to 10 MHz. Various systematic errors which can contaminate the polarimetric measurement have been investigated in detail. Distortion of circular polarization due to non-ideal optical components is calibrated using a rotating quarter wave plate technique. The impact of perpendicular magnetic field, i.e., the Cotton Mouton effect, is evaluated. The error due to non-collinearity of probe beams is minimized to less than 0.5 degrees for electron density up to 7 * 1019 m-3 by alignment optimization. Optical feedback, due to multiple reflections induced by the double-pass configuration, is identified and reduced. Coherent and broadband high-frequency magnetic fluctuations for DIII-D H-mode plasmas are observed. PMID- 30399783 TI - A computational tool for simulation and design of tangential multi-energy soft x ray pin-hole cameras for tokamak plasmas. AB - A new tool has been developed to calculate the spectral, spatial, and temporal responses of multi-energy soft x-ray (ME-SXR) pinhole cameras for arbitrary plasma densities (n e,D), temperature (T e), and impurity densities (n Z). ME-SXR imaging provides a unique opportunity for obtaining important plasma properties (e.g., T e, n Z, and Z eff) by measuring both continuum and line emission in multiple energy ranges. This technique employs a pixelated x-ray detector in which the lower energy threshold for photon detection can be adjusted independently. Simulations assuming a tangential geometry and DIII-D-like plasmas (e.g., n e,0 ~ 8 * 1019 m-3 and T e,0 ~ 2.8 keV) for various impurity (e.g., C, O, Ar, Ni, and Mo) density profiles have been performed. The computed brightnesses range from few 102 counts pixel-1 ms-1 depending on the cut-off energy thresholds, while the maximum allowable count rate is 104 counts pixel-1 ms-1. The typical spatial resolution in the mid-plane is ~0.5 cm with a photon energy resolution of 500 eV at a 500 Hz frame rate. PMID- 30399784 TI - SIESTA: A high current ion source for erosion and retention studies. AB - Second ion experiment for sputtering and TDS analysis is a high-current ion source for erosion and retention studies with focus on wall materials for fusion devices. The system is composed of a DuoPIGatron type ion source, three consecutive grids for ion extraction, acceleration and beam focusing, a differential pumping stage, a dipole magnet for mass filtering, a quadrupole doublet lens, a target chamber, a load-lock, and a chamber for thermal desorption spectrometry. The acceleration potential of the source can be varied between 500 V and 10 kV. The target chamber has a base pressure of 10-8 mbar and an operating pressure of 5 * 10-7 mbar. The target can be rotated to study angle-dependent effects and can be heated via electron-impact heating up to 1300 K for high temperature erosion and implantation studies. The target chamber is equipped with an in situ magnetic suspension balance. The operating parameters of the ion source were mapped to achieve the maximum ion current at the target for various gas species and accelerating potentials. The beam emittance for a D3 + ion beam was measured after deflection in the dipole magnet. This was used for ion beam simulations, which were instrumental for the design of the quadrupole lenses. If the quadrupole doublet is used, the ion flux to the target is increased by up to a factor of 4. Additionally, the relative population of neutral particles present in the beam at the target was quantified and is equal to 0.8% when averaged over the measurement positions. The typical beam footprint at the target under normal incidence has an area of 0.5 cm2. The ion current reaching the target increases with the accelerating potential. Due to this effect, the ion flux density at the target in the low-ion-impact-energy range can be increased by operating the source at a higher extraction potential and by applying a (decelerating) potential to the target. Ion impact energies as low as 200 eV/D are achieved this way with a D3 + current of 100 MUA when focusing the beam with the quadrupole doublet lens, equating to a D particle flux density of 3.7 * 1019 m-2 s-1. At ion impact energies of 2 keV/D, the maximum achievable flux density with D3 + is 6 * 1019 D m-2 s-1. Experimental determination of sputter yields was performed via ex situ weight loss measurement for bulk Au samples, showing reasonably good agreement with simulations and experimental data from the literature. PMID- 30399785 TI - Bayesian uncertainty calculation in neural network inference of ion and electron temperature profiles at W7-X. AB - We make use of a Bayesian description of the neural network (NN) training for the calculation of the uncertainties in the NN prediction. Having uncertainties on the NN prediction allows having a quantitative measure for trusting the NN outcome and comparing it with other methods. Within the Bayesian framework, the uncertainties can be calculated under different approximations. The NN has been trained with the purpose of inferring ion and electron temperature profile from measurements of a X-ray imaging diagnostic at W7-X. The NN has been trained in such a way that it constitutes an approximation of a full Bayesian model of the diagnostic, implemented within the Minerva framework. The network has been evaluated using measured data and the uncertainties calculated under different approximations have been compared with each other, finding that neglecting the noise on the NN input can lead to an underestimation of the error bar magnitude in the range of 10%-30%. PMID- 30399786 TI - Application of a Hall sensor for pulsed magnetic field measurement in the FAT-CM FRC experiments. AB - Collisional merging experiments of a field-reversed configuration (FRC) plasma at the super-Alfvenic velocity have been conducted in the FAT (FRC Amplification via Translation)-CM (Collisional Merging) device. In the experiments, two FRCs are collided and merged in a confinement section with a quasi-static confinement magnetic field. Therefore, it is necessary to measure the high-frequency pulsed magnetic field superposed on a quasi-stationary signal. The magnetic field is generally measured by a magnetic coil probe in the pulse discharge experiments; however, in such measurements, errors arise in the low-frequency band in the conducted FRC experiments. Therefore, a Hall sensor has been applied for low frequency magnetic field measurements in the FAT-CM experiments. Calibration of the Hall sensor involves confirming that the sensor has a sufficient response speed and linear characteristics for the magnetic field with a rising time of approximately 240 us and that its output voltage does not saturate up to a magnetic field of 0.7 T. Combination of the Hall sensor and the magnetic coil probe ensures a comprehensive measurement of the magnetic field in the range of FAT-CM experiments. In this study, accurate magnetic measurements were performed in a collisional merging experiment in the FAT-CM device by using a combined magnetic diagnostic system. PMID- 30399787 TI - A liquid VI scintillator cell for fast-gated neutron imaging. AB - The design of a new fast-gated neutron imaging system for the National Ignition Facility with much stricter timing constraints than a previous system has prompted the search for a fast scintillator material that can be used in imaging. A novel imaging cell based on Liquid VI has recently been developed with Eljen Technology and characterized at the Special Technologies Laboratory and the Los Alamos Neutron Science Center. The results show superior timing characteristics and spatial resolution, and sufficient light production for the new system compared to fast plastic scintillators previously used in neutron imaging. While the primary application is in inertial confinement fusion diagnostics, the imaging cell can be used in any fast-gated imaging application where timing characteristics and spatial resolution are of concern. PMID- 30399788 TI - Using L-shell x-ray spectra to determine conditions of non-local thermal dynamic equilibrium plasmas. AB - K-shell x-ray spectra of Li- to H-like ions have long been used to determine plasma conditions. The ratio of integrated line intensities is used to determine the temperature. At the density of non-local thermal dynamic equilibrium (NLTE) plasmas (n e ~ 1021 cm-3), the K-shell spectrum is not very sensitive to density. We propose using the L-shell emission of open L-shell ions (C- to Li-like) as an alternative to determine both temperature and density of NLTE plasmas. First, the L-shell models of a mid-Z material need to be verified against the temperatures obtained using a K-shell spectrum of a low-Z material. A buried layer platform is being developed at the OMEGA laser to study the open L-shell spectra of NLTE plasmas of mid-Z materials. Studies have been done using a 250 MUm diameter dot composed of a layer of 1200 A thick Zn between two 600 A thick layers of Ti, in the center of a 1000 MUm diameter, 13 MUm thick beryllium tamper. Lasers heat the target from both sides for up to 3 ns. The size of the emitting volume vs time was measured with x-ray imaging (face-on and side-on) to determine the density. The temperature was measured from the Ti K-shell spectra. The use of this platform for the verification of atomic L-shell models is discussed. PMID- 30399789 TI - Application of the VUV and the soft x-ray systems on JET for the study of intrinsic impurity behavior in neon seeded hybrid discharges. AB - This paper reports on impurity behavior in a set of hybrid discharges with Ne seeding-one of the techniques considered to reduce the power load on reactor walls. A series of experiments carried out with light gas injection on JET with the ITER-Like-Wall (ILW) suggests increased tungsten release and impurity accumulation [C. Challis et al., Europhysics Conference Abstracts 41F, 2.153 (2017)]. The presented method relies mainly on the measurements collected by vacuum-ultra-violet and soft X-ray (SXR) diagnostics including the "SOXMOS" spectrometer and the SXR camera system. Both diagnostics have some limitations. Consequently, only a combination of measurements from these systems is able to provide comprehensive information about high-Z [e.g., tungsten (W)] and mid-Z [nickel (Ni), iron (Fe), copper (Cu), and molybdenum (Mo)] impurities for their further quantitative diagnosis. Moreover, thanks to the large number of the SXR lines of sight, determination of a 2D radiation profile was also possible. Additionally, the experimental results were compared with numerical modeling based on integrated simulations with COREDIV. Detailed analysis confirmed that during seeding experiments, higher tungsten release is observed, which was also found in the past. Additionally, it was noticed that besides W, the contribution of molybdenum to SXR radiation was greater, which can be explained by the place of its origin. PMID- 30399790 TI - A new B-dot probe circuit for magnetic diagnostics of radio frequency discharges. AB - Accurate magnetic measurements in radio frequency capacitively coupled plasmas (CCP) are challenging due to the presence of inherently strong electric fields and relatively weak magnetic fields. In this work, a new B-dot probe circuit is presented, comprising two variable capacitors in a tunable series resonance circuit, with a center-tapped, step-up transformer. The output characteristics of the probe are predicted using two distinct equivalent circuit models, one for the differential mode and the other for the common mode. A Helmholtz coil and a Faraday cup are used for experimental validation of the predicted probe output. By tuning the two variable capacitors in the circuit, the magnetic probe can achieve improved signal-to-noise ratio by amplifying the inductive signal, while suppressing capacitive coupling interference. Using the newly designed probe, magnetic measurements in typical CCP are presented. PMID- 30399791 TI - Demonstration of confocal laser induced fluorescence at long focal lengths. AB - We add a collection path obscuration to a confocal telescope and confirm theoretical predictions of significant improvement in the longitudinal spatial localization. The improvements of spatial localization permitted an extension of the confocal telescope's focal length from 150 mm to 500 mm. At this longer focal length, millimeter-scale spatial localization is confirmed by comparing radial profiles of metastable state density obtained via confocal and conventional optical arrangements in a helicon source. The long focal length arrangement enables the measurement of argon neutral velocity distribution functions in the conventionally inaccessible region under a helicon source antenna. PMID- 30399792 TI - Supersonic gas-jet characterization with interferometry and Thomson scattering on the OMEGA Laser System. AB - A supersonic gas-jet target platform has been activated on the OMEGA Laser System. An analytic model for gas dynamics in a supersonic nozzle was used to predict gas-plume parameters and to design nozzles for use in laser-plasma experiments. The gas-jet system was analyzed with a Mach-Zehnder interferometer to study neutral density and with Thomson scattering to study plasma parameters on the OMEGA Laser System. These initial measurements demonstrate the capabilities of the OMEGA gas jet as a platform for future laser-plasma interaction science. PMID- 30399793 TI - High resolution, high signal-to-noise crystal spectrometer for measurements of line shifts in high-density plasmas. AB - The Orion high-resolution x-ray (OHREX) spectrometer has been a successful tool for measuring the shapes of density-broadened spectral lines produced in short pulse heated plasmas at the Orion laser facility. We have recently outfitted the instrument with a charge-couple device (CCD) camera, which greatly increased the accuracy with which we can perform line-shift measurements. Because OHREX is located on the outside of the Orion target chamber, no provisions for the shielding of electromagnetic pulses are required. With the CCD, we obtained a higher signal-to-noise ratio than we previously obtained with an image-plate detector. This allowed us to observe structure in the image produced by the diffraction from the two OHREX crystals, which was highly reproducible from shot to shot. This structure will ultimately limit the accuracy of our spectroscopic measurements. PMID- 30399794 TI - Bremsstrahlung x-ray generation for high optical depth radiography applications on the National Ignition Facility. AB - We have tested a set of x-ray sources for use as probes of highly attenuating, laser-driven experiments on the National Ignition Facility (NIF). Unlike traditional x-ray sources that optimize for a characteristic atomic transition (often the n = 2 -> n = 1 transition in ionized, He-like atoms), the design presented here maximizes the total photon flux by optimizing for intense, broadband Bremsstrahlung radiation. Three experiments were performed with identical targets, including a uranium x-ray source foil and a tungsten substrate with a narrow (25 MUm wide) collimating slit to produce a quasi-1D x-ray source. Two experiments were performed using 12 beams from the NIF laser, each delivering approximately 46 kJ of laser energy but with different laser spatial profiles. This pair yielded similar temporal x-ray emission profiles, spatial resolution, and inferred hot electron temperature. A third experiment with only 6 beams delivering approximately 25 kJ produced a lower hot electron temperature and significantly lower x-ray flux, as well as poorer spatial resolution. The data suggest that laser pointing jitter may have affected the location and intensity of the emitting plasma, producing an emission volume that was not well centered behind the collimating slit and lower intensity than designed. However, the 12 beam design permits x-ray radiography through highly attenuating samples, where lower energy line-emission x-ray sources would be nearly completely attenuated. PMID- 30399795 TI - Imaging divertor strike point splitting in RMP ELM suppression experiments in the DIII-D tokamak. AB - Fast visible imaging of the lower divertor from above is used to study the structure and dynamics of lobes induced by resonant magnetic perturbations (RMPs) in Edge-Localized Mode (ELM) suppression experiments in DIII-D. The best compromise between the amount of light and sharp imaging was obtained using emission at 601 nm from Fulcher band molecular deuterium. Multiple spatially resolved peaks in the D2 emission, taken as a proxy for the particle flux, are readily resolved during RMPs, in contrast to the heat flux measured by infrared cameras, which shows little spatial structure in ITER-like conditions. The 25 mm objective lens provides high spatial resolution (2-4 mm/pixel) from the centerpost to the outer shelf over 40 degrees toroidally that overlaps the field of view of the IRTV that measures the divertor heat flux, allowing direct comparison in non-axisymmetric discharges. The image is coupled to a Phantom 7.3 camera using a Schott wound fiber bundle, providing high temporal resolution that allows the lobe dynamics to be resolved between ELMs and across ELM suppression onset. These measurements are used to study the heat and particle flux in 3D magnetic fields and to validate models for the plasma response to RMPs. PMID- 30399796 TI - In-plane thermal diffusivity measurement of thin plates by the transient fin method. AB - The transient fin method has mainly been used for the measurement of in-plane thermal diffusivity of rather highly diffusive materials available under the form of thin plates. This paper presents an extension of the method to low diffusivity materials such as plastics. A new analytical model is used in the real space, avoiding to make a Laplace transform of experimental temperatures recordings that may be inaccurate. Experiments carried on two materials under gas pressure varying from 10-2 mbar to 1 bar show the great influence of heat conduction in the air surrounding the sample, leading to estimation errors that can reach 30% at atmospheric pressure. The experimental results also show that accurate measurements can be achieved if the pressure is lower than 10-2 mbar. PMID- 30399797 TI - Laser calibration of the DIII-D coherence imaging system. AB - In this paper, we describe an in situ calibration technique for Coherence Imaging Spectroscopy (CIS) that measures 2-D images of ion flows on DIII-D. A low power CW diode laser that is tuneable in the range 464-468 nm along with a precision wavemeter (10-5 nm resolution) is used to characterize the interferometer phase as a function of wavelength in the region of C iii (465 nm) and He ii (468 nm). The interferometer is stabilized both mechanically and thermally to minimize drift during the calibration. Optical stirring and an integration sphere are used to obtain spatially uniform calibration images. The quality of the calibration data enables a measurement of phase versus wavelength over approximately 10 fringes of the interferometer. These coefficients can also be related to the geometry of the optics and the birefringent crystal of the interferometer. On DIII-D, the integration sphere with the laser light is inserted into the CIS optical system between shots and the laser image and wavelength are automatically recorded, providing a zero velocity reference. PMID- 30399798 TI - Laser-induced fluorescence diagnostic via pulsed lasers in an argon plasma. AB - Laser-induced fluorescence (LIF) using a pulsed laser is successfully applied in an argon plasma. The laser system consists of a pumping pulse laser fixed at 532 nm and a tunable dye laser. Using a homemade Fabry-Perot interferometer, the large linewidth of the original output is reduced by one order from 4 GHz to 340 MHz. The measured ion temperature is 0.15 eV with a velocity resolution about 200 m/s. It provides great possibility for the combination of LIF and planar LIF using the same pulsed laser system. PMID- 30399799 TI - Characterization of a picosecond gated optical intensifier. AB - The development of high speed imaging detectors is crucial for high-temperature plasma characterization and optimization. These detectors must perform within many strict parameters, such as precise timing, high spatial resolution, low noise, high gain, and fast gating. We present test results on a picosecond gated optical intensifier that aims to meet these requirements. The detector was developed by Kentech and is part of a packaged Sydor solution of 1-8 detectors, designed for use in plasma diagnostics. It has low jitter (SD 4 ps) and gate widths less than 80 ps. We use a pulsed laser to test the gate profile and the spatial resolution performance of the intensifier at different points within the gate. PMID- 30399800 TI - Overview of the Wendelstein 7-X phase contrast imaging diagnostic. AB - A phase contrast imaging (PCI) diagnostic has been developed for the Wendelstein 7-X (W7-X) stellarator. This diagnostic, funded by the U.S. Department of Energy through the Office of Fusion Energy Sciences, is a collaboration between the Max Planck Institute for Plasmaphysics, MIT, and SUNY Cortland. The primary motivation for the development of the PCI diagnostic is measurement of turbulent fluctuations, such as the ion temperature gradient, electron temperature gradient, and the trapped electron mode instabilities. Understanding how the magnetic geometry and other externally controllable parameters, such as the fueling method and heating scheme, modify the amplitude and spectrum of turbulence is important for finding operational scenarios that can lead to improved performance at fusion-relevant temperatures and densities. The PCI system is also sensitive to coherent fluctuations, as may arise from Alfven eigenmodes or other MHD activity, for example. The PCI method creates an image of line-integrated variations in the index of refraction. For a plasma, the image created is proportional to the line-integral of electron density fluctuations. This paper provides an overview of some key features of the hardware and the optical system and presents two examples of recent measurements from the W7-X OP1.2a experimental campaign. PMID- 30399801 TI - Calibration methods of X-ray imaging crystal spectrometer on KSTAR. AB - The detailed calibration methods and procedure for the X-ray imaging crystal spectrometer (XICS) in the Korea Superconducting Tokamak Advanced Research device are investigated. A cross comparison from two different diagnostics including the XICS and charge exchange spectrometer is the best option, in particular, when both systems can be operated simultaneously. PMID- 30399802 TI - Soft X-ray backlighter source driven by a short-pulse laser for pump-probe characterization of warm dense matter. AB - Here we propose a pump-probe X-ray absorption spectroscopy temperature measurement technique appropriate for matter having temperature in the range of 10 to a few 100 eV and density up to solid density. Atomic modeling simulations indicate that for various low- to mid-Z materials in this range the energy and optical depth of bound-bound and bound-free absorption features are sensitive to temperature. We discuss sample thickness and tamp layer considerations. A series of experimental investigations was carried out using a range of laser parameters with pulse duration <=5 ps and various pure and alloyed materials to identify backlighter sources suitable for the technique. PMID- 30399803 TI - Development and characterization of liquid argon and methane microjets for high rep-rate laser-plasma experiments. AB - A cryogenic microjet system has been used for delivering micron-scale continuous liquid hydrogen targets for laser-plasma experiments. This technique has been extended to higher-Z, higher boiling-point gases, including argon and methane. High-resolution shadowgraphy has been used to characterize the jet's morphology and pointing stability. A split and delay illumination source has also been developed for direct measurement of jet speeds without relying on assumptions of fluid flow conditions. Under typical conditions, the argon jets freeze solid due to evaporative cooling, but the methane jets remain liquid and break up to a droplet stream. A piezo driver is used to ensure the droplets are of uniform size. This jet has enabled the investigation of methane in planetary core conditions with high-rep-rate laser heating and x-ray laser probing. PMID- 30399804 TI - Design of an imaging Fabry-Perot interferometer for the VEST edge plasma temperature measurement. AB - A new technique for gas temperature determination in fusion plasmas based on time and space-resolved imaging interferometry is presented. The proposed imaging interferometer includes a multi-channel optical fiber bundle, a pair of flat mirrors, collimating lenses, and a fast camera for registration of interferometry fringes. The technique is applied for ion temperature measurements in the Versatile Experiment Spherical Torus (VEST) tokamak located at the Seoul National University. The multi-channel operation regime of the interferometer is studied by simulations. The first experimental two-channel results obtained using the Halpha emission line from the VEST plasma edge are presented and analyzed. The mentioned apparatus is suggested to be especially useful for the multi-point time resolved characterization of the non-repetitive processes in low-temperature regions of fusion plasmas. PMID- 30399805 TI - Developing a long-duration Zn K- alpha source for x-ray scattering experiments. AB - We are developing a long-duration K-alpha x-ray source at the Omega laser facility. Such sources are important for x-ray scattering measurements at small scattering angles where high spectral resolution is required. To date, He-alpha x ray sources are the most common probes in scattering experiments, using ns-class lasers to heat foils to keV temperatures, resulting in K-shell emission from He like charge states. The He-alpha spectrum can be broadened by emission from multiple charge states and lines (e.g., He-like, Li-like, Be-like). Here, we combine the long duration of He-alpha sources with the narrow spectral bandwidth of cold K-alpha emission. A Ge foil is irradiated by the Omega laser, producing principally Ge He-alpha emission, which pumps Zn K-alpha emission at 8.6 keV from a nearby Zn layer. Using this technique, we demonstrate a long-duration Zn K alpha source suitable for scattering measurements. Our experimental results show a 60% reduction in spectral bandwidth compared to a standard Zn He-alpha source, significantly improving the measurement precision of scattering experiments with small inelastic shifts. PMID- 30399806 TI - Neutron emission spectroscopy of D plasmas at JET with a compact liquid scintillating neutron spectrometer. AB - Neutron emission spectroscopy is a diagnostic technique that allows for energy measurements of neutrons born in nuclear reactions. The JET tokamak fusion experiment (Culham, UK) has a special role in this respect as advanced spectrometers for 2.5 MeV and 14 MeV neutrons have been developed here for the first time for measurements of the neutron emission spectrum from D and DT plasmas with unprecedented accuracy. Twin liquid scintillating neutron spectrometers were built and calibrated at the Physikalisch-Technische Bundesanstalt (PTB) (Braunschweig, Germany) and installed on JET in the recent years with tangential-equatorial (KM12) and vertical-radial (KM13) view lines, with the latter only recently operational. This article reports on the performance of KM12 and on the development of the data analysis methods in order to extract physics information upon D ions kinematics in JET auxiliary-heated D plasmas from 2.5 MeV neutron measurements. The comparison of these results with the correspondents from other JET neutron spectrometers is also presented: their agreement allows for JET unique capability of multi-lines of sight neutron spectroscopy and for benchmarking other 14 MeV neutron spectrometers installed on the same lines of sight in preparation for the DT experimental campaign at JET. PMID- 30399807 TI - Characterization and calibration of a multilayer coated Wolter optic for an imager on the Z-machine at Sandia National Laboratories. AB - The need for a time-resolved monochromatic x-ray imaging diagnostic at photon energies >15 keV has motivated the development of a Wolter optic to study x-ray sources on the Z-machine at Sandia National Laboratories. The work is performed in both the LLNL's x-ray calibration facility and SNL's micro-focus x-ray lab. Characterizations and calibrations include alignment, measurement of throughput within the field of view (FOV), the point-spread function within the FOV both in and out of focus, and bandpass in the FOV. These results are compared with ray tracing models, showing reasonable agreement. PMID- 30399808 TI - Reconstruction of radiation profiles near the plasma boundary using an infrared imaging video bolometer in KSTAR. AB - An infrared imaging video bolometer using tomographic inversion can provide the total radiated power and 2-D radiation profiles, which are crucial information for impurity seeding experiments. Because large amounts of impurities exist at the plasma edge, accurate reconstruction of the radiation profiles near the material boundary is an important issue. In this study, two methods of boundary condition treatment are compared. One involves the exclusion of plasma pixels outside the boundary before reconstruction, whereas the other excludes these pixels after reconstruction. Phantom reconstruction tests are performed with D shaped and divertor radiation profiles, and the second method shows an improvement in the boundary-reconstruction results compared with the first method. Using the second method, the radiation profiles of krypton (Kr) seeded H mode plasmas in KSTAR are reconstructed. A significant amount of input power is dissipated through the Kr radiation. The 2-D reconstructed radiation profiles show that Kr mostly accumulates at the plasma core rather than at the edge. PMID- 30399809 TI - Generation of a multifrequency gravitational-gradient excitation and extraction of the gravitational gradient with a rotating accelerometer gravity gradiometer. AB - A moving-base rotating accelerometer gravity gradiometer (RAGG) is an instrument for measuring gravitational gradient signals produced by geological bodies with a certain signal bandwidth. Development and improvement of RAGG requires that they be subjected to testing and calibration; however, the zero-frequency gravitational gradient signals produced by static test masses are not suitable for this purpose. We propose a method in which multiple test masses simultaneously rotating about a RAGG at different angular velocities and in different circular orbits produce the multifrequency gravitational gradient excitation required for testing or calibrating the RAGG. We also present a gravitational gradient extraction method that combines a fore-end circuit design, a multirate filter technique, and a quadrature amplitude modulation demodulation technique. We describe in detail the procedures for gravitational gradient extraction. Multifrequency gravitational gradient excitations are applied to evaluate this extraction method. A RAGG physical simulation system substitutes for an actual RAGG in a multifrequency gravitational gradient extraction experiment. The extracted multifrequency gravitational gradient signal is consistent with theoretical predictions. The gravitational gradient extraction error approximates the noise of the RAGG physical simulation system. These experimental results suggest that the proposed gravitational gradient extraction method is feasible. The research presented in this paper is of great significance for engineering applications. PMID- 30399810 TI - Design of gamma-ray spectrometers optimized for fast particle studies at ITER. AB - A set of gamma ray spectrometers has been designed for ITER within the Radial Gamma Ray Spectrometer (RGRS) project. The aim of this project is designing a system, integrated with the ITER radial neutron camera, which is able to measure the gamma-rays emitted from the plasma with a good energy resolution (about 1.5% at 4.44 MeV) and at high counting rates (in excess of 1 MHz). The RGRS will be able to operate both in the D phase and in the full-power DT phase and will measure gamma rays from (i) reactions between fast ions, such as alpha particles, and light impurities and (ii) bremsstrahlung emission generated by runaway electron interactions with both plasma bulk and tokamak walls. The RGRS detectors are arranged in nine lines of sights (able to cover a radial region with r < a/3), each featuring a large LaBr3 scintillator crystal. Due to the high neutron flux and magnetic field, several solutions have been adopted to guarantee a good signal to background ratio and MHz counting rate capabilities. The RGRS is capable to combine space and energy distribution measurements of alpha particles and runaway electrons, which will help the study of the fast particle physics in a burning plasma. PMID- 30399811 TI - Spatial heterodyne spectroscopy for high speed measurements of Stark split neutral beam emission in a high temperature plasma. AB - Measurement of electrostatic potential, or local electric field, turbulence is a critical missing component in validating nonlinear turbulence and transport simulations of fusion plasmas. A novel diagnostic is being developed for measuring local electric field fluctuations, E(r,t) , via high-speed measurements of the light emitted from a hydrogenic neutral beam. It exploits the proportionality of the spectral line splitting from the Motional Stark Effect to the total electric field experienced by the neutral atom at the excitation site. The measurement is localized by the usual cross-beam geometry of beam spectroscopy measurements. The corner stone of the diagnostic is a high spectral resolution, high etendue spatial heterodyne spectrometer (SHS). A SHS design with high etendue (~5 mm2 sr) and resolution (~0.14 nm) meets the formidable spectrometer requirements. Field tests of the spectrometer at the DIII-D tokamak demonstrate that the beam emission spectrum produced by the SHS agrees with that of a traditional spectrometer and that the measured flux is adequate for turbulence studies. PMID- 30399812 TI - Design of a custom insertable probe platform for measurements of C-2W inner divertor plasma parameters. AB - A custom motor controlled probe system has been designed to make spatially resolved measurements of temperature, density, flow, and plasma potential in the C-2W inner divertors. Measurements in the inner divertors, which have a 1.7 m radius and are located on either end of the confinement vessel, are critical in order to gauge exactly how local settings affect the plasma conditions, confinement, and stability in the field-reversed configuration core. The inner Divertor Insertable Probe Platform (iDIPP) system consists of a custom motor controlled linear rack and pinion transporter that has a 1.9 m travel length in order to reach the center of the divertor. Mounted to the end of the transporter is a 1 m long segmented probe shaft made of individually floating stainless steel rings to prevent shorting out the electrode plates, which are biased up to 5 kV/m. A variety of interchangeable probe tips, including a triple Langmuir probe, a baffled probe, and a Gundestrup probe, can plug into the end of the probe shaft. Custom UHV coiled cabling comprised of 9 shielded conductors expands/retracts with the motion of the transporter in/out of the divertor. The physics motivating plasma parameter measurements in the inner divertors and the details of the design of the iDIPP system will be discussed. PMID- 30399813 TI - A multichannel gated neutron detector with reduced afterpulse for low-yield neutron measurements in intense hard X-ray backgrounds. AB - A design of multichannel gated photomultiplier tube (PMT) is presented for the 960-channel neutron time-of-flight detector at the Institute of Laser Engineering of Osaka University. This is important for the fusion science and the nuclear photonics where intense hard X-rays are generated from the interaction of ultra short laser pulse of petawatt power density with matter. The hard X-rays often overload PMTs and cause signal-induced background noises called afterpulses, making the detection of subsequent neutrons impossible. For this reason, the PMTs are coupled with an electrical time-gating (ETG) system to avoid overloading. The ETG system disables the PMT by modulating the dynode potential during the primary X-ray flash. An after-pulsing suppression technique is demonstrated by applying a reverse bias voltage between the photocathode and the first dynode. The presented multichannel scheme provides a gate response time of 80 ns, a signal cutoff ratio of 2.5 * 102, and requires reasonably low power consumption. PMID- 30399814 TI - Implementing time resolved electron temperature capability at the NIF using a streak camera. AB - A new capability at the National Ignition Facility (NIF) has been implemented to measure the temperature of x-ray emitting sources. Although it is designed primarily for Inertial Confinement Fusion (ICF), it can be used for any hot emitting source that is well modeled. The electron temperature (Te) of the hot spot within the core of imploded ICF capsules is an effective indicator of implosion performance. Currently, there are spatially and temporally integrated Te inferences using image plates. A temporally resolved measurement of Te will help elucidate the mechanisms for hot spot heating and cooling such as conduction to fuel, alpha-heating, mix, and radiative losses. To determine the temporally resolved Te of hot spots, specific filters are added to an existing x-ray streak camera "streaked polar instrumentation for diagnosing energetic radiation" to probe the emission spectrum during the x-ray burn history of implosions at the NIF. One of the difficulties in inferring the hot spot temperature is the attenuation of the emission due to opacity from the shell and fuel. Therefore, a series of increasingly thick titanium filters were implemented to isolate the emission in specific energy regions that are sensitive to temperatures above 3 keV while not significantly influenced by the shell/fuel attenuation. Additionally, a relatively thin zinc filter was used to measure the contribution of colder emission sources. Since the signal levels of the emission through the thicker filters are relatively poor, a dual slit (aperture) was designed to increase the detected signal at the higher end of the spectrum. Herein, the design of the filters and slit is described, an overview of the solving technique is provided, and the initial electron temperature results are reported. PMID- 30399815 TI - X-ray absorption spectrum combined with deep neural network for on-line detection of beverage preservatives. AB - Aiming at the problem that the common preservative detection methods are too cumbersome and costly, a rapid on-line detection method based on X-ray absorption spectrum (XAS) for beverage preservatives is proposed. Benzoic acid, potassium sorbate, sodium dehydrogenate, and propyl p-hydroxybenzoate were selected to form standard concentration and excess concentration solutions. XAS data were collected by an X-ray spectrum detection system, and the leave one out cross validation method was used to divide the data set. Principal component analysis was used to extract the main features of the spectrum. Deep neural network (DNN) and support vector machine were established to classify samples of different powders and different concentrations of solutions. DNN reached 100% and 94.17% recognition rates on preservative powders and potassium sorbate solutions, respectively. The experimental results show that XAS combined with DNN can identify different types of preservative powder and detect whether the preservative content of the beverage exceeds the standard, which provides a new way to achieve fast on-line detection of preservative content in beverages. PMID- 30399816 TI - A fused silica Cherenkov radiator for high precision time-of-flight measurement of DT gamma and neutron spectra (invited). AB - A fused silica Cherenkov radiator has been implemented at the National Ignition Facility to provide a new high precision measurement of the time-of-flight spectrum of 14.1 MeV DT fusion neutrons. This detector enables a high precision (<30 ps) co-registered measurement of both a thresholded gamma-ray and a neutron spectrum on a single record. Other methods typically require gamma and neutron signals to be co-registered via other diagnostics and/or dedicated timing experiments. Analysis of the co-registered gamma and neutron signals allows precise extraction of the mean neutron energy and bulk hot-spot velocity, both of which were not possible with prior scintillator technologies. Initial measurements demonstrate the feasibility of this measurement and indicate that combined detection of neutrons and gamma-rays on multiple lines-of-sight should enable the bulk vector velocity of the implosion hot-spot to be determined to ~5 km/s and reduced uncertainty in the spectral width ~0.1 keV. PMID- 30399817 TI - Determination of the electron-lattice coupling strength of copper with ultrafast MeV electron diffraction. AB - Electron-lattice coupling strength governs the energy transfer between electrons and the lattice and is important for understanding the material behavior under highly non-equilibrium conditions. Here we report the results of employing time resolved electron diffraction at MeV energies to directly study the electron lattice coupling strength in 40-nm-thick polycrystalline copper excited by femtosecond optical lasers. The temporal evolution of lattice temperature at various pump fluence conditions were obtained from the measurements of the Debye Waller decay of multiple diffraction peaks. We observed the temperature dependence of the electron-lattice relaxation time which is a result of the temperature dependence of electron heat capacity. Comparison with two-temperature model simulations reveals an electron-lattice coupling strength of (0.9 +/- 0.1) * 1017 W/m3/K for copper. PMID- 30399818 TI - Active spectroscopy measurements of the deuterium temperature, rotation, and density from the core to scrape off layer on the DIII-D tokamak (invited). AB - Main-ion charge exchange recombination spectroscopy (MICER) uses the neutral beam induced D alpha spectrum to measure the local deuterium ion (D+) temperature, rotation, and density, as well as parameters related to the neutral beams, fast ions, and magnetic field. An edge MICER system consisting of 16 densely packed chords was recently installed on DIII-D, extending the MICER technique from the core to the pedestal and steep gradient region of H-mode plasmas where the D+ and commonly measured impurity ion properties can differ significantly. A combination of iterative collisional radiative modeling techniques and greatly accelerated spectral fitting allowed the extension of this diagnostic technique to the plasma edge where the steep gradients introduce significant diagnostic challenges. The importance of including the fast ion D alpha emission in the fit to the spectrum for the edge system is investigated showing that it is typically not important except for cases which can have significant fast ion fractions near the plasma edge such as QH-mode. Example profiles from an Ohmic L-mode and a high power ITER baseline case show large differences in the toroidal rotation of the two species near the separatrix including a strong co-current D+ edge rotation. The measurements and analysis demonstrate the state of the art in active spectroscopy and integrated modeling for diagnosing fusion plasmas and the importance of direct main ion measurements. PMID- 30399819 TI - Aperture design for the third neutron and first gamma-ray imaging systems for the National Ignition Facility. AB - The current construction of a new nuclear-imaging view at the National Ignition Facility will provide a third line of sight for hotspot and cold fuel imaging and the first dedicated line of sight for 4.4-MeV gamma-ray imaging of the remaining carbon ablator. To minimize the effort required to hold and align apertures inside the vacuum chamber, the apertures for the two lines of sight will be contained in the same array. In this work, we discuss the system requirements for neutron and gamma-ray imaging and the resulting aperture array design. PMID- 30399820 TI - One dimensional imager of neutrons on the Z machine. AB - We recently developed a one-dimensional imager of neutrons on the Z facility. The instrument is designed for Magnetized Liner Inertial Fusion (MagLIF) experiments, which produce D-D neutrons yields of ~3 * 1012. X-ray imaging indicates that the MagLIF stagnation region is a 10-mm long, ~100-MUm diameter column. The small radial extents and present yields precluded useful radial resolution, so a one dimensional imager was developed. The imaging component is a 100-mm thick tungsten slit; a rolled-edge slit limits variations in the acceptance angle along the source. CR39 was chosen as a detector due to its negligible sensitivity to the bright x-ray environment in Z. A layer of high density poly-ethylene is used to enhance the sensitivity of CR39. We present data from fielding the instrument on Z, demonstrating reliable imaging and track densities consistent with diagnosed yields. For yields ~3 * 1012, we obtain resolutions of ~500 MUm. PMID- 30399821 TI - A compact ultra-wideband ridge waveguide to coaxial line transition. AB - A novel compact single-ridge waveguide (SRW) to coaxial line ultra-wideband transition is proposed in this paper. The transition using shorter matching networks between the coaxial port and the SRW port achieves maximum matching bandwidth; meanwhile, a wideband short circuit is also introduced to further broaden bandwidth performance. The whole structure is very simple and can be readily fabricated with a conventional computer numerical control machine. The prototype transitions were designed, manufactured, and measured. The measured results are reasonably consistent with the simulated results. Measurements show that the return loss and insertion loss of the back-to-back transition are better than 18 dB and 0.2 dB, respectively, from 6 to 18 GHz, with 100% fractional bandwidth. Besides, the measured return loss of the single transition is higher than 23 dB in the entire bandwidth. Compared with some other reported SRW transitions, the proposed SRW transition exhibits extreme compactness, lower insertion loss, and more excellent bandwidth performance. The dimensions of the transition structure are only 0.75lambda * 0.7lambda * 0.35lambda (lambda is the wavelength at the center frequency) for the central frequency of 12 GHz. The design's transition is completely scalable to other needed frequency band. PMID- 30399822 TI - Simulation, design, and first test of a multi-energy soft x-ray (SXR) pinhole camera in the Madison Symmetric Torus (MST). AB - A multi-energy soft x-ray pinhole camera has been designed and built for the Madison Symmetric Torus reversed field pinch to aid the study of particle and thermal-transport, as well as MHD stability physics. This novel imaging diagnostic technique combines the best features from both pulse-height-analysis and multi-foil methods employing a PILATUS3 x-ray detector in which the lower energy threshold for photon detection can be adjusted independently on each pixel. Further improvements implemented on the new cooled systems allow a maximum count rate of 10 MHz per pixel and sensitivity to the strong Al and Ar emission between 1.5 and 4 keV. The local x-ray emissivity will be measured in multiple energy ranges simultaneously, from which it is possible to infer 1D and 2D simultaneous profile measurements of core electron temperature and impurity density profiles with no a priori assumptions of plasma profiles, magnetic field reconstruction constraints, high-density limitations, or need of shot-to-shot reproducibility. The expected time and space resolutions will be 2 ms and <1 cm, respectively. PMID- 30399823 TI - Polycapillary x-ray lenses for single-shot, laser-driven powder diffraction. AB - X-ray diffraction measurements to characterize phase transitions of dynamically compressed high-Z matter at Mbar pressures require both sufficient photon energy and fluence to create data with high fidelity in a single shot. Large-scale laser systems can be used to generate x-ray sources above 10 keV utilizing line radiation of mid-Z elements. However, the laser-to-x-ray energy conversion efficiency at these energies is low, and thermal x-rays or hot electrons result in unwanted background. We employ polycapillary x-ray lenses in powder x-ray diffraction measurements using solid target x-ray emission from either the Z Beamlet long-pulse or the Z-Petawatt (ZPW) short-pulse laser systems at Sandia National Laboratories. Polycapillary lenses allow for a 100-fold fluence increase compared to a conventional pinhole aperture while simultaneously reducing the background significantly. This enables diffraction measurements up to 16 keV at the few-photon signal level as well as diffraction experiments with ZPW at full intensity. PMID- 30399824 TI - Measurements of the effective electron density in an electron beam ion trap using extreme ultraviolet spectra and optical imaging. AB - In an electron beam ion trap (EBIT), the ions are not confined to the electron beam, but rather oscillate in and out of the beam. As a result, the ions do not continuously experience the full density of the electron beam. To determine the effective electron density, n e,eff, experienced by the ions, the electron beam size, the nominal electron density n e, and the ion distribution around the beam, i.e., the so-called ion cloud, must be measured. We use imaging techniques in the extreme ultraviolet (EUV) and optical to determine these. The electron beam width is measured using 3d -> 3p emission from Fe xii and xiii between 185 and 205 A. These transitions are fast and the EUV emission occurs only within the electron beam. The measured spatial emission profile and variable electron current yield a nominal electron density range of n e ~ 1011-1013 cm-3. We determine the size of the ion cloud using optical emission from metastable levels of ions with radiative lifetimes longer than the ion orbital periods. The resulting emission maps out the spatial distribution of the ion cloud. We find a typical electron beam radius of ~60 MUm and an ion cloud radius of ~300 MUm. These yield a spatially averaged effective electron density, n e,eff, experienced by the ions in EBIT spanning ~ 5 * 109-5 * 1011 cm-3. PMID- 30399825 TI - Simple and accurate method of diamagnetic flux measurement in Versatile Experimental Spherical Torus (VEST). AB - Diamagnetic flux is measured accurately in the Versatile Experiment Spherical Torus by simply measuring the change in the toroidal field (TF) coil current without additional poloidal loops. Stray couplings mainly with the plasma current (since poloidal field coils are aligned well to the TF coils) are compensated for, resulting in the minimum measurable flux of +/-0.2 mWb determined mainly by the finite sensitivity of the TF coil current sensor, implying that the accuracy of this simple method can be improved by measuring the TF coil current change with a higher sensitivity. The poloidal beta is derived from the measured diamagnetic flux with the consideration of the low aspect ratio geometry. The poloidal beta and the plasma stored energy derived from the measurement are in good agreement with those from the equilibrium reconstruction, and the energy confinement time derived from the measurement is consistent with the L mode scaling. PMID- 30399826 TI - Design and raytrace simulations of a multilayer-coated Wolter x-ray optic for the Z machine at Sandia National Laboratories. AB - Recent breakthroughs in the fabrication of small-radii Wolter optics for astrophysics allow high energy density facilities to consider such optics as novel x-ray diagnostics at photon energies of 15-50 keV. Recently, the Lawrence Livermore National Laboratory, Sandia National Laboratories (SNL), the Smithsonian Astrophysical Observatory, and the NASA Marshall Space Flight Center jointly developed and fabricated the first custom Wolter microscope for implementation in SNL's Z machine with optimized sensitivity at 17.5 keV. To achieve spatial resolution of order 100-200 microns over a field of view of 5 * 5 * 5 mm3 with high throughput and narrow energy bandpass, the geometry of the optic and its multilayer required careful design and optimization. While the geometry mainly influences resolution and the field of view of the diagnostic, the mirror coating determines the spectral response and throughput. Here we outline the details of the design and fabrication process for the first multilayer-coated Wolter I optic for SNL's Z machine (Z Wolter), including its W/Si multilayer, and present results of raytrace simulations completed to predict and verify the performance of the optic. PMID- 30399827 TI - Development of a triple probe array for mode conversion study of electron cyclotron wave. AB - A triple probe array has been designed with a modified triple probe technique and utilized on the Sino-UNIted Spherical Tokamak for mode conversion research from the electron cyclotron wave to the electron Bernstein wave. The probe array is designed to measure the radial profile of the electron density in the edge region. The probe array consists of 36 single molybdenum tips, constituting 12 sets of triple probes with an interval of 6 mm in the radial direction. The three tips in each triple probe are displaced slightly in the radial direction, and thus they are not at the same magnetic surface to avoid shadow effects in the toroidal direction. A modified triple probe technique is used. The radial profile of the electron density of ohmic heated plasmas has been measured by the triple probe array. The temporal evolution of the density profile is presented, and the mode conversion processes are discussed. PMID- 30399828 TI - Forced flow atomic layer deposition of TiO2 on vertically aligned Si wafer and polysulfone fiber: Design and efficacy of conduit plates and soak function. AB - The effectiveness of three different designs of conduit plates was verified for even distribution of precursors in a voluminous forced-flow atomic layer deposition (ALD) chamber designed to hold macroscopic elongated substrates vertically. Furthermore, a new "soak function" was introduced in the controlling software of the ALD instrument. This function enabled increase in residence time of the precursor in the chamber without escalating the dosage. The flow of precursors guided by the conduit plates with and without application of the soak function was simulated using computational fluid dynamics. A conformal coating of TiO2 with good uniformity on Si and porous polysulfone fibers was achieved to evidence the design and efficacy of conduit plates and soak function. PMID- 30399829 TI - Edge toroidal charge exchange spectra analysis in the EAST. AB - An edge toroidal charge exchange recombination spectroscopy (eCXRS) diagnostic has been deployed successfully on the Experimental Advanced Superconducting Tokamak (EAST) recently, providing edge plasma ion temperature and toroidal rotation. Edge CXRS on EAST typically monitors the carbon vi (529.059 nm, n = 8 > 7) spectral line. Spectral lines emitted from other different impurities that appeared in the wavelength ranges of 528 nm-530 nm illustrate the need to revise the edge change exchange spectra analysis in this region. Since the eCXRS sightlines end on the ion cyclotron range of frequencies (ICRF) stainless steel antenna, the passive Fe lines coming from the antenna could be recorded by eCXRS diagnostic when ICRF is used. A revised edge toroidal charge exchange spectra analysis including Fe spectral lines is presented. The accuracy of eCXRS measurement has been improved by the revised spectra analysis. PMID- 30399830 TI - Internal magnetic field measurements of translated and merged field-reversed configuration plasmas in the FAT-CM device. AB - Field-reversed configuration (FRC) Amplification via Translation-Collisional Merging (FAT-CM) experiments have recently commenced to study physics phenomena of colliding and merged FRC plasma states. Two independently formed FRCs are translated into the confinement region of the FAT-CM device, collided near the mid-plane of the device with a relative speed of up to ~400 km/s, and a final merged FRC plasma state is achieved. To measure internal magnetic field profiles of the translated and merged FRC plasmas as well as to understand its collisional merging process, an internal magnetic probe array, developed by TAE Technologies, has been installed in the mid-plane of the FAT-CM device. Initial magnetic field measurements indicate that both the translated and the merged FRC plasma states exhibit a clear field-reversed structure, which is qualitatively in good agreement with 2D MHD simulation. It is found and verified that a sufficient mirror field in the confinement region is required for colliding FRCs to be fully merged into a single FRC plasma state. PMID- 30399831 TI - Flexible and wavelength-independent optical transmission for laser pointing stabilization and assembly error compensation. AB - A flexible light guide was developed for an ITER (International Thermonuclear Experimental Reactor) poloidal polarimeter which is a passive laser beam alignment and stabilization system for free-space propagation of a wide range of wavelengths. The advantages of using a flexible light guide are (1) to compensate the relative movement between the floor of a building and an optical table, (2) to negate assembly error of the optical transmission line, (3) to minimize the time required for assembly of the line and laser position alignment in a radiological environment, and (4) to transmit a wide wavelength range from visible to far-infrared. The authors fabricated a flexible light guide with an inner diameter of 120 mm and with a motion range of 10 cm. Pointing stability of the laser beam passing through the flexible light guide was less than 70 MUrad when the support moved +/-50 mm. A flexible light guide error of 70 MUrad leads to a beam position displacement of 0.98 mm at a beam position steering mirror ITER poloidal polarimeter that is located 14 m from the flexible light guide. The achieved error is stable enough to guide the laser beam to its target in ITER. PMID- 30399832 TI - MIRRORS: A MATLAB (r) GUI for temperature measurement by multispectral imaging radiometry. AB - MultIspectRal imaging RadiOmetRy Software (MIRRORS) is an open source MATLAB based Graphical User Interface (GUI) designed to automatically process images generated from a four colour multispectral imaging radiometry system for the temperature measurement of samples heated in a diamond anvil cell. The GUI can work in either a live mode (during an experiment) or a post-processing mode and performs background subtraction, spatial correlation, and thermal calibration of the data before producing maps of temperature, emissivity, and their associated uncertainties, an image difference map (i.e., the change in the shape of the temperature field), and a variety of other visualisations derived from them. We describe the distribution, system requirements, and required hardware specific code modifications necessary to setup MIRRORS. We also describe the workflow of the software and its underlying methodologies and provide an example output as well as the results of benchmarking against a traditional spectroradiometric system of known accuracy. PMID- 30399833 TI - Measurements of DIII-D poloidal field by fiber-optic pulsed polarimetry. AB - A new technique for measuring the spatial and temporal structure of the poloidal field is presented, whereby the magnetic field causes the polarization of light traveling through an optical fiber to rotate via the Faraday effect by an amount proportional to the strength of the field oriented along the fiber. In fiber optic pulsed polarimetry, changes in the polarization of the backscatter light from the fiber are detected, thereby permitting measurement of the field as a function of position along the fiber. In this proof-of-principle experiment, specially prepared single-mode fibers with weak fiber Bragg gratings were installed in the poloidal direction on the outside of the thermal blanket on DIII D. Light at 532 nm from a mode-locked Nd:YAG laser was injected into the optical fibers. The laser repetition rate was 895 kHz with a pulse length of <10 ps, resulting in ~1 MUs temporal resolution. A photodetector system measured the Stokes polarization components necessary to determine the amount of polarization rotation. For this experiment, bandwidth limitations of the detectors resulted in a spatial resolution of ~2 cm. The measured temporal and spatial distributions of the poloidal field are consistent with inductive probe measurements and Elastodynamic Finite Integration Technique reconstructions of the spatial distribution. This demonstrates the ability of this technique to provide real time detection of the temporal and spatial variations of the poloidal field. Besides revealing more detailed information about the plasma, this new diagnostic capability can also help in detecting instabilities in real time, thereby enabling enhanced machine protection. PMID- 30399834 TI - The Warm Electron Beam Ion Trap (WEBIT): An instrument for ground calibration of space-borne x-ray spectrometers. AB - The warm electron beam ion trap (WEBIT) at Lawrence Livermore National Laboratory is being developed as a pre-launch, ground calibration source for space-borne, high-throughput, high-resolution x-ray spectrometers, such as the x-ray imaging and spectroscopy mission Resolve quantum calorimeter. Historically, calibration sources for calorimeter spectrometers have relied on characteristic line emission from x-ray tubes, fluorescing metals, and radioactive sources. The WEBIT, by contrast, relies on emission from x-ray transitions in highly charged ions, for example, hydrogen-like and helium-like ions, whose energies are well known and whose line shapes are relatively simple. The WEBIT can create astrophysically relevant ions whose x-ray emission falls in the 0.3-12 keV science bandpass of Resolve and has a portable design advantageous for a calibration source. The WEBIT will be used to help calibrate Resolve's instrumental line shape and gain scale as a function of various operational parameters during both detector subsystem level testing and instrumental level testing. PMID- 30399835 TI - Coherence-imaging spectroscopy for 2D distribution of ion temperature and flow velocity in a laboratory magnetosphere. AB - A coherence-imaging spectroscopy (CIS) technique was developed to investigate plasma confinement in a dipole system that imitates a planetary magnetosphere. Optical interference generated using birefringent crystals enables two dimensional Doppler spectroscopy to measure ion temperatures and flow velocities in plasmas. CIS covers the entire dynamics of the pole areas as well as of the core and edge areas on a dipole confinement device. The two-dimensional visualization of these quantities in the magnetospheric-plasma device RT-1 was demonstrated using CIS. PMID- 30399837 TI - Characterizing the modulation transfer function for X-ray radiography in high energy density experiments. AB - The Modulation Transfer Function (MTF) is an established means for characterizing imaging performance of X-ray radiography systems. We report on experiments using high energy, laser-driven X-ray radiography systems that assess performance using MTF values measured with the knife-edge projection method. The broadband, hard X ray systems under study use line-projection imaging produced by narrowing the laser-generated X-ray source with a slit. We find that good contrast resolution can be achieved (the MTF = 0.5 at 75 MUm wavelength) and that this performance is reproduced on different laser facilities. We also find that the MTF is sensitive both to the thickness of the line-projection slit and to the backing material thickness under the knife-edge. Both these sensitivities are due to a common mechanism, namely induced changes in the spectrally-averaged spatial widths of the X-ray source. The same line-projection system is also used on experimental campaigns measuring Rayleigh-Taylor instability growth by dynamically imaging sinusoidal, high Z micro-targets with wavelengths of 100 MUm or less. By applying the measured MTF values to correct the ripple target contrast measurements, we can predict ripple growth to approximately 10% accuracy. PMID- 30399836 TI - The new magnetic diagnostics in the WEST tokamak. AB - The WEST tokamak consists of a major upgrade of the superconducting medium size tokamak Tore Supra aiming at testing ITER divertor components. Such modification has required rebuilding a full set of magnetic diagnostics. The project was started in 2013 and completed in 2016. The diagnostic consists of a set of 469 sensors (421 pick-up coils, 36 flux loops, and 12 Rogowski coils) installed in the WEST vacuum vessel. New analog integrators have been developed in order to obtain the magnetic field and flux from the raw signal of the sensors. During the startup phase of WEST, plasma currents of the order of a few kilo amperes were measured despite much larger current of the order of hundreds of kilo amperes flowing in nearby conducting structures. The diagnostic is now fully operational and exhibits a noise level of about 0.5 mT on the magnetic field, and 2.0 mWb on flux loops allowing identifying the plasma boundary with an accuracy of a few millimeters on a 2 ms time cycle. PMID- 30399838 TI - Considerations of the q-profile control in KSTAR for advanced tokamak operation scenarios. AB - The q-profile control is essential for tokamaks exploring the advanced tokamak scenarios, which is expected to be able to provide a possible route toward a steady-state high performance operation in a fully non-inductive current drive state. This is because the pressure and current profiles must remain optimal for the scenario during the injection of large amounts of heating and current drive. Here, essential tools for the q-profile control are the motional Stark effect diagnostic for measuring the radial magnetic pitch angle profile and a state-of the-art plasma control system. The pulse duration of the H-mode discharge at KSTAR has been extended year by year with improved control performance, and the experiment of internal transport barrier (ITB) formation in a weakly reversed q profile with a marginal neutral beam injection majority heating successfully demonstrated that the ITB is an alternative candidate to achieve a high performance regime in KSTAR. These recent achievements are attributed to reliable profile measurement, which means that profile feedback control has become a necessary step to ensure a robust and reliable approach to advanced scenarios as the next step of research in KSTAR. In this paper, we discuss the technical and conceptual requirements for q-profile control according to the upgrade plan for heating and current drive systems in the coming years. PMID- 30399839 TI - A compact multi-plane broadband (0.5-17 keV) spectrometer using a single acid phthalate crystal. AB - Acid phthalate crystals such as KAP crystals are a method of choice to record x ray spectra in the soft x-ray regime (E ~ 1 keV) using the large (001) 2d = 26.63 A spacing. Reflection from many other planes is possible, and knowledge of the 2d spacing, reflectivity, and resolution for these reflections is necessary to evaluate whether they hinder or help the measurements. Burkhalter et al. [J. Appl. Phys., 52, 4379 (1981)] showed that the (013) reflection has efficiency comparable to the 2nd order reflection (002), and it can overlap the main first order reflection when the crystal bending axis ( b -axis) is contained in the dispersion plane, thus contaminating the main (001) measurement in a convex crystal geometry. We present a novel spectrograph concept that makes these asymmetric reflections helpful by setting the crystal b -axis perpendicular to the dispersion plane. In such a case, asymmetric reflections do not overlap with the main (001) reflection and each reflection can be used as an independent spectrograph. Here we demonstrate an achieved spectral range of 0.8-13 keV with a prototype setup. The detector measurements were reproduced with a 3D ray-tracing code. PMID- 30399840 TI - First step toward a synthetic diagnostic for magnetic fluctuation measurements using cross-polarization scattering on DIII-D. AB - Cross-polarization scattering (CPS) provides localized magnetic fluctuation ( B ) measurements in fusion plasmas based on the process where B scatters electromagnetic radiation into the orthogonal polarization. The CPS system on DIII-D utilizes the probe beam of a Doppler backscattering (DBS) diagnostic combined with a cross-view CPS receiver system, which allows simultaneous density and B measurements with good spatial and wavenumber coverage. The interpretation of the signals is challenging due to the complex plasma propagation of the DBS probe beam and CPS receive beams. A synthetic diagnostic for CPS is therefore essential to interpret data and perform detailed validation tests of non-linear turbulence simulations. This work reports a first step toward a synthetic diagnostic for CPS utilizing GENRAY, a 3-D ray tracing code, to simulate the propagation of the probe and scattered rays. The local B wavenumber is calculated from the local O- and X-mode wavenumbers using the wave vector matching scattering condition. The CPS wavenumber values and spatial locations are determined by a complex consideration that includes the local density and B level, receive antenna pattern and orientation, scattering volume, wavenumber values detected at the various scattering centers, and alignment of the magnetic wave vector with the plane perpendicular to the magnetic field. The issue of a spurious CPS signal due to polarization mismatches for launch and receive is also discussed. It is suggested that simultaneous O- and X-mode DBS measurements should be utilized for better understanding of the CPS signal contamination when the cutoff locations for both polarizations are close. PMID- 30399841 TI - Upgrades to the in-vessel calibration light source on JET. AB - Since 2010, an in-vessel calibration light source (ICLS) has been used periodically on JET to calibrate a range of diagnostics at UV, visible, and IR wavelengths. During shutdowns, the ICLS (which is essentially an integrating sphere) is positioned within the vacuum vessel by the remote handling (RH) system. Following the 2013 calibration runs, several changes were made to improve the efficiency and quality of the calibrations. Among these was the replacement of a 20 m "umbilical" cable which carried power and other electrical signals through a vessel port to/from a control cubicle. A lightweight 2 m cable now plugs directly into a single connector on the RH manipulator system, greatly reducing the time required for deployment and improving operational flexibility; e.g., the vessel access "floor" no longer needs to be installed. This change also means the system would be compatible with calibrations after a high neutron fluence period of operation. An on-board micro-spectrometer now allows for real time verification of the emitted spectrum. Finally, new "baffles" were designed and installed within the integrating sphere itself, greatly improving the spectral radiance uniformity at non-normal viewing angles (necessary due to orientation uncertainties with the RH system). PMID- 30399842 TI - Development of an ordinary mode multi-channel correlation reflectometer on EAST tokamak. AB - An ordinary-mode polarized multi-channel correlation reflectometer has been developed on the Experimental Advanced Superconducting Tokamak (EAST). The system with four different probing frequencies (i.e., 20.4 GHz, 24.8 GHz, 33 GHz, and 40 GHz) and two poloidally spaced receiving antennas can realize both the radial correlation measurement and the poloidal correlation measurement. These diagnostics focus on the measurement of density fluctuation in the pedestal region to investigate the turbulence transport and H-mode physics on EAST. In this article, the system hardware design, the key component tests, and the system performance are shown in detail. PMID- 30399843 TI - Unsupervised learning about 4D features of microparticle motion. AB - Material clusters of different sizes are known to exist in high-temperature plasmas due to plasma-wall interactions. The facts that these clusters, ranging from sub-microns to above mm in size, can move from one location to another quickly and that there are a lot of them make high-speed imaging and tracking one of the best, effective, and sometimes only diagnostic. An unsupervised machine learning technique based on deconvolutional neural networks is developed to analyze two-camera videos of high-temperature microparticles generated from exploding wires. The neural network utilizes a locally competitive algorithm to infer representations and optimize a dictionary composed of kernels, or basis vectors, for image analysis. Our primary goal is to use this method for feature recognition and prediction of the time-dependent three-dimensional (or "4D") microparticle motion. Features equivalent to local velocity vectors have been identified as the dictionary kernels or "building blocks" of the scene. The dictionary elements from the left and right camera views are found to be strongly correlated and satisfy the projection geometrical constraints. The results show that unsupervised machine learning techniques are promising approaches to process large sets of images for high-temperature plasmas and other scientific experiments. Machine learning techniques can be useful to handle the large amount of data and therefore aid the understanding of plasma-wall interaction. PMID- 30399844 TI - Note: Performance estimation of a rotary ultrasonic motor based on two dimensional analytical model. AB - The comprehension of ultrasonic motor performances as a function of input parameters is a key to intelligent motion control of motor. This paper presents a performance estimation model of a novel rotary ultrasonic motor as a function of input parameters. To evaluate performances of the proposed motor, the finite element software is used to derive the vibration displacements of stator surface points. The output displacements of the points in time domain, which determines the contact state and contact time, are analyzed and compared. Then, a two dimensional analytical model is constructed. The performances of stead rotation speed and stall torque are deduced. According to the simulated results, a prototype motor is manufactured and tested. The experimental results agree well with the simulation results, which verifies the effectiveness of the presented model. PMID- 30399845 TI - Velocity correction for neutron activation diagnostics at the NIF. AB - The velocity distribution of the hotspot in an inertial confinement fusion implosion changes the energy spectra of fusion neutrons emitted from the experiment as a function of viewing angle. These velocity-induced spectral changes affect the response of neutron activation diagnostics (NADs) positioned around the experiment and must be accounted for to correctly extract information about areal density (rhoR) asymmetry from the data. Three mechanisms through which average hotspot velocity affects NAD activation are addressed: change in activation cross section due to the Doppler shift of the mean neutron energy, kinematic focusing of neutron fluence, and change in the scattering cross section due to the Doppler shift. Using the hotspot velocity inferred from neutron time of-flight measurements of D-T and D-D fusion neutrons, the hotspot velocity is shown to account for the observed NAD activation asymmetry in a calibration shot with negligible fuel rhoR. A robust method to evaluate uncertainties in spherical harmonic fits to the NAD data due to the velocity correction and detector uncertainty is discussed. PMID- 30399846 TI - A combined phase contrast imaging and heterodyne interferometer system for multiscale fluctuation measurements (invited). AB - In this work, a novel combined diagnostic capable of measuring multiscale density fluctuations that extend from magnetohydrodynamic (MHD) to the lower range of electron temperature gradient turbulence has been designed, installed, and operated at DIII-D. The combined diagnostic was constructed by adding a heterodyne interferometer to the pre-existing phase contrast imaging (PCI) system, both of which measure line-integrated electron density fluctuations. The port-space footprint is minimized via use of a single 10.6 MUm probe beam. With temporal bandwidths in excess of 1 MHz, the PCI measures high-k (1.5 cm-1 < |k R | <= 25 cm-1) fluctuations with sensitivity 3*1013 m-2/kHz , while the interferometer simultaneously measures low-k (|k R | < 5 cm-1) fluctuations with sensitivity 3*1014 m-2/kHz . The intentional mid-k overlap has been empirically verified with sound-wave calibrations and allows quantitative investigation of multiscale effects that are predicted to be significant in the reactor-relevant T e ~ T i regime. Furthermore, via correlation with the primary DIII-D interferometer, the toroidal mode numbers of core-localized MHD can be measured. PMID- 30399847 TI - A time-resolved millimeter wave conductivity (TR-mmWC) apparatus for charge dynamical properties of semiconductors. AB - This article demonstrates a contactless, time-resolved, millimeter wave conductivity apparatus capable of measuring photoconductivity of a diverse range of materials. This cavity-less system determines the time-dependent magnitude of a sample's charge carrier density-mobility product by monitoring the response of a continuous, millimeter-wave probe beam following excitation of the sample by an ultrafast laser pulse. The probe beam is tunable from 110 GHz to 170 GHz and the sample response data can be obtained over the sub-nanosecond to millisecond time interval. This system has been tested on silicon wafers, S-I GaAs, perovskite thin films, SiO2-Ge(nc), and CdSxSe1-x nanowire samples. We demonstrate a minimum detectable photoconductance change of ~1 uS, an estimated time resolution for conductance decay of ~100 ps, and a dynamic range greater than 57 dB. The calibration constant of the system, needed for quantitative calculation of photoconductivity from experimental data, has been determined using silicon wafers. This system has several advantages over currently used microwave and terahertz techniques, such as facile tunability of probe frequency and substantially wider time range for study of decay kinetics, while maintaining an open sample environment that enables characterization of a wide range of sample sizes under controlled environmental conditions. PMID- 30399848 TI - Absolute calibration of a time-resolved high resolution x-ray spectrometer for the National Ignition Facility (invited). AB - A high resolution, Diagnostic Instrument Manipulator (DIM)-based x-ray Bragg crystal spectrometer has been calibrated for and deployed at the National Ignition Facility (NIF) to diagnose plasma conditions in ignition capsules near stagnation times. The spectrometer has two conical crystals in the Hall geometry focusing rays from the Kr Healpha, Lyalpha, and Hebeta complexes onto a streak camera, with the physics objectives of measuring time-resolved electron density and temperature through observing Stark broadening and the relative intensities of dielectronic satellites. A third von Hamos crystal that time-integrates the Kr Healpha, Hebeta and intervening energy range provides in situ calibration for the streak camera signals. The spectrometer has been absolutely calibrated using a microfocus x-ray source, an array of CCD and single-photon-counting detectors, and multiple K- and L-absorption edge filters at the Princeton Plasma Physics Laboratory (PPPL) x-ray laboratory. Measurements of the integrated reflectivity, energy range, and energy resolution for each crystal are discussed. These calibration data provide absolute x-ray signal levels for NIF measurements, enabling precise filter selection and comparisons to simulations. PMID- 30399849 TI - Incorporating magnetic equilibrium information in Gaussian process tomography for soft X-ray spectroscopy at WEST. AB - Gaussian process tomography (GPT) [J. Svensson, JET Internal Report EFDA-JET PR(11)24, 2011 and D. Li, J. Svensson, H. Thomsen, F. Medina, A. Werner, and R. Wolf, Rev. Sci. Instrum. 84, 083506 (2013)] is a recently developed tomography method applied earlier to soft X-ray (SXR) spectroscopy on WEST-Tungsten (W) Environment in Steady-state Tokamak. The short execution time of the algorithm makes GPT an important candidate for providing real-time information on impurity transport and for fast MHD control. In earlier work, GPT has shown its flexibility by providing good reconstruction results without background information about the magnetic equilibrium. On the other hand, information about the magnetic flux surface geometry can in general be useful for additional regularization of the solution. In this paper, we develop a way to take into account the equilibrium information, by constructing a covariance matrix of the prior Gaussian process depending on the flux surface geometry. The GPT method is validated using synthetic SXR emissivity profiles relevant to WEST plasmas and compares favorably with the classical algorithm based on minimization of the Fisher information. PMID- 30399850 TI - Development of new experimental setup focusing on long-pulse magnetic reconnection by using rotating magnetic field technique. AB - A new closed-type experimental setup to achieve a long-pulse magnetic reconnection in weakly ionized plasmas was developed by using a rotating magnetic field (RMF) technique. The experimental setup has a cylindrical vacuum vessel in which two sets of four antennas are equipped to generate RMF which drives steady azimuthal electron current in two torus plasmas. This device provided a quasi steady magnetic reconnection condition in weakly ionized plasmas with ionization fraction of less than 1%. The proposed experimental setup will extend the research area of laboratory reconnection experiments and be helpful to comprehend the reconnection process in weakly ionized plasmas such as solar chromosphere. PMID- 30399851 TI - Real-time adjustable, 11 MUs FWHM, > 5 kHz, piezo electric pulsed atomic beam source. AB - This paper provides a detailed description of how to construct a pulsed atomic beam source [including a fast ionization gauge (FIG) for characterization] with a unique combination of characteristics. We include technical drawings for a real time adjustable piezo electric actuated pulsed valve capable of generating a 11 MUs duration pulse of gas at a repetition rate of >5 KHz, with a shot-to-shot stability of 0.6%, and maximum densities of 1015 particles/cm3. We also include details on how to construct a FIG, with a 4 MUs rise time, to measure the pulse. We report a 3D density map of a supersonic expansion of helium gas with a speed ratio S = 46 and a calculated longitudinal temperature of 0.3 K. Finally, the results of a laser ionization test are provided in order to verify the performance of the pulsed valve in a typical experimental configuration. PMID- 30399852 TI - Instrumentation for the upgrade to the JET core charge-exchange spectrometers. AB - Charge-exchange spectroscopy on JET has become particularly challenging with the introduction of the ITER-like wall. The line intensities are weaker and contaminated by many nuisance lines. We have therefore upgraded the instrumentation to improve throughput and allow the simultaneous measurement of impurity and fuel-ion charge exchange by splitting the light between two pairs of imaging spectrometers using dichroic beam splitters. Imaging instruments allow us to stack 11 * 1 mm diameter fibres on the entrance slits without cross talk. CCD cameras were chosen to have 512 * 512 pixels to allow frame transfer times <0.2 ms which with minimum exposure times of 5 ms give tolerable smearing even without a chopper. The image plane is optically demagnified 2:1 to match the sensor size of these cameras. Because the image plane of the spectrometer is tilted, the CCD must also be tilted to maintain focus over the spectrum (Scheimpflug condition). To avoid transverse keystoning (causing the vertical height of the spectra to change across the sensor), the configuration is furthermore designed to be telecentric by a suitable choice of the lens separation. The lens configuration is built almost entirely from commercial off-the-shelf components, which allowed it to be assembled and aligned relatively rapidly to meet the deadline for in vessel calibration in the JET shutdown. PMID- 30399853 TI - Experimental comparison of spherically bent HAPG and Ge crystals. AB - The Orion high-resolution X-ray (OHREX) imaging spherically bent crystal spectrometer, operated with both image plates and CCD cameras, provides time averaged plasma diagnostics through high-resolution spectroscopy with good signal to-noise at the Orion laser facility. In order to provide time-resolved spectra, the OHREX will be outfitted with a streak camera, and in this case, even higher signal to noise will be desired. Using the OHREX's sister instrument, the EBIT High-resolution X-ray (EBHiX) spectrometer, at the LLNL electron beam ion trap EBIT-I, we therefore compare the efficiency of a high-quality Ge (111) crystal (2d = 6.532 A) with that of a higher integrated reflectivity, but lower resolution highly annealed pyrolytic graphite (HAPG) crystal (2d = 6.708 A) in the energy range 2408-2452 eV. We find that the HAPG provides overall more signal across the entire image; however, because of the much better focusing properties of the Ge crystal, the latter provides more signal within the central 100 MUm of the spatial profile in the cross-dispersion direction and is thus more suitable for the narrow entrance window of the Livermore-built streak camera. PMID- 30399854 TI - Note: Grid cork and septal cork syringe adapters: An effective tool for efficient greasing of 24-well crystallization trays. AB - Applying grease to seal the well surface of the crystallization plate through traditional approaches in the hanging drop vapor diffusion method is a laborious process and known to cause air bubble formation. Here we report a simple design of adapters to the regular syringes for applying grease to the 24-well crystallization tray. This newly developed tool overcomes the difficulties faced with the traditional greasing methods, such as uneven distribution and excess of grease on the wells. The use of new adapters expedites the process of greasing by 4-5 times which is quick and reliable and can be cost effective in terms of time and labor. In addition, this tool reduces the time and effort required for greasing the wells. Here we demonstrate two types of adaptors (grid cork and septal cork), and the effectiveness of both the adaptors was further corroborated by crystallization trials. PMID- 30399856 TI - Methods of improving spatial resolution for IR spectroscopy in atmospheric pressure plasma systems. AB - High-temperature, atmospheric pressure plasma systems operated in molecular gases present complex diagnostic challenges. Infrared spectroscopy has been used to make measurements of the absorbance spectrum of complex molecular gas mixtures and thereby calculate the concentrations and species temperatures in these systems. For atmospheric-pressure systems, high spatial gradients arise and high spatial-resolution measurements are thus desirable. Some systems have achieved increased spatial resolution by reducing the beam diameter. However, this increase in spatial resolution comes at the expense of the optical throughput. Here we propose modifying a commercial Fourier Transform, Infrared spectrometer system with a set of simple optical elements. This design allows for scannable, high spatial resolution absorbance spectrum measurements of a complex molecular gas mix. We analyze the signal-to-noise ratio for this design and compare it with the diameter reduction method. For sufficiently low plasma radiation levels, this design improves the signal-to-noise ratio relative to reducing the beam diameter size while transmitting nearly all of the beam power. However, whether this design can achieve the desired sub-mm spatial resolution depends on the radiating area of the infrared light source in the spectrometer. PMID- 30399855 TI - Simultaneous visualization of wall motion, beam propagation, and implosion symmetry on the National Ignition Facility (invited). AB - Achieving a symmetric implosion in National Ignition Facility indirect drive targets requires understanding and control of dynamic changes to the laser power transport in the hohlraum. We developed a new experimental platform to simultaneously visualize wall-plasma motion and dynamic laser power transport in the hohlraum and are using it to investigate correlations of these measurements with the imploded capsule symmetry. In a series of experiments where we made one single parameter variation, we show the value of this new platform in developing an understanding of laser transport and implosion symmetry. This platform also provides a new way to evaluate dynamic performance of advanced hohlraum designs. PMID- 30399857 TI - Characterization of a two-channel, high resolution hard x-ray microscope using Fresnel zone plates for laser-plasma interaction experiments. AB - New X-ray imaging techniques are currently being developed at the "Commissariat a l'energie atomique et aux energies alternatives" in the context of Inertial Confinement Fusion. Fresnel zone plates (FZPs) are being considered as they can perform high-resolution and high-flux imaging in the X-ray domain. Here we present the characterization of a bi-lens FZPs resolution used in an imager prototype, designed for the LULI2000 laser facility. Characterization was performed on a synchrotron radiation facility and on a femtosecond laser facility. The resolution of the two FZP channels was measured to be between 2.4 MUm and 5.2 MUm and the expected total resolution for the diagnostic was to be 3.3 MUm. PMID- 30399858 TI - Liquid crystal polymer receiver modules for electron cyclotron emission imaging on the DIII-D tokamak. AB - A new generation of millimeter-wave heterodyne imaging receiver arrays has been developed and demonstrated on the DIII-D electron cyclotron emission imaging (ECEI) system. Improved circuit integration, improved noise performance, and enhanced shielding from out-of-band emission are made possible by using advanced liquid crystal polymer (LCP) substrates and monolithic microwave integrated circuit (MMIC) receiver chips. This array exhibits ~15 dB additional gain and >30* reduction in noise temperature compared to previous generation ECEI arrays. Each LCP horn-waveguide module houses a 3 * 3 mm GaAs MMIC receiver chip, which consists of a low noise millimeter-wave preamplifier, balanced mixer, and IF amplifier together with a local oscillator multiplier chain driven at ~12 GHz. A proof-of-principle partial LCP instrument with 5 poloidal channels was installed on DIII-D in 2017, with a full proof-of-principle system (20 poloidal * 8 radial channels) installed and commissioned in early 2018. The enhanced shielding of the LCP modules is seen to greatly reduce the sensitivity of ECEI signals to out-of band microwave noise which has plagued previous ECEI studies on DIII-D. The LCP ECEI system is expected to be a valuable diagnostic tool for pedestal region measurements, focusing particularly on electron temperature evolution during edge localized mode bursting. PMID- 30399859 TI - Formation of field-reversed configuration using an in-vessel odd-parity rotating magnetic field antenna in a linear device. AB - A Field-Reversed Configuration (FRC) is formed by an in-vessel odd-parity rotating magnetic field (RMF) antenna in a tandem mirror device, Keda mirror with axisymmetricity. The 40-cm diameter antenna is fed independently by four IGBT based power units with an output current of 1500 A each at 84 kHz, and their phases are adjustable to launch odd or even parity RMFs. A medium-sized washer gun is utilized to generate a highly ionized seed hydrogen plasma. Driven by RMF, the resultant FRC is formed with a separatrix radius of ~17 cm, external field of ~50 G, and trapped poloidal flux of ~0.15 mWb. The formation process of FRCs is evidenced by the measurement of an array of internal two-dimensional probes; a comparison with the rigid rotor model is presented in this paper. In addition, substantial toroidal electron current is found to be driven, despite the partial RMF penetration. Moreover, the dependence of the driven current on the antenna current is reported and is found to be consistent with the RMF current driving model. PMID- 30399860 TI - Conceptual design of extended magnetic probe set to improve 3D field detection in NSTX-U. AB - Adding toroidal arrays of magnetic probes at the top and bottom of NSTX-U would improve both the detection of the multimodal plasma response to applied magnetic perturbations and the identification of the poloidal structure of unstable plasma modes, as well as contribute to the validation of MHD models, improve the understanding of the plasma response to external fields, and improve the error field correction. In this paper, the linear MHD code MARS-F/K has been used to identify poloidal locations that would improve the capability to measure stationary or near-stationary 3D fields that may result from the plasma response to external sources of non-axisymmetric fields. The study highlighted 6 poloidal positions where new arrays of both poloidal and radial magnetic field sensors would improve the poloidal resolution. The proposed set of new arrays combined with the present ones is shown to be capable of measuring the poloidal structure of perturbations with n <= 6 and of detecting the multimodal plasma response. Assessment of the trade-off in the poloidal length of the probes leads to an ideal length between 10 cm and 30 cm. A method to configure the probes of a toroidal array based on the singular value decomposition condition number is proposed, and an ideal solution and a low-cost one are presented. PMID- 30399861 TI - Using motional Stark splitting of Dalpha emission to constrain MHD equilibrium analysis in DIII-D plasmas. AB - We report tests of an alternate technique for constraining MHD equilibrium analysis in tokamak plasmas using internal magnetic field measurements based on | B | measurements from the motional Stark splitting of Dalpha spectral lines emitted by a neutral heating beam (MSE-LS). We compare results using MSE-LS with those of the standard equilibrium analysis technique based on line polarization of the Dalpha emission (MSE-LP). An alternative to MSE-LP is needed in future devices such as ITER where MSE-LP will be difficult due to a plasma-induced coating of the first optical element. The tests utilized data from 10 DIII-D shots with 7 MSE-LS and 14 MSE-LP views covering a range of radii along the outer midplane of the plasma. Seven MSE-LS measurements can contribute significantly to the equilibrium reconstruction of pressure and q profiles using both synthetic and experimental DIII-D MSE-LS data. For example, 7 MSE-LS plus seven MSE-LP measurements give a fit quality that is as good as the same cases with 14 MSE-LP measurements. Analyzing synthetic data for 14 MSE-LS measurements shows significant improvement in fitting quality over the case with 7 MSE-LS locations. PMID- 30399862 TI - Development of a tracer-containing compact-toroid injection system. AB - The accumulation and behavior of impurities is one of the most important subjects in the development of magnetically confined fusion reactors because impurities can potentially cause cooling and worsen the confinement of the hot core plasma. Tracer-encapsulated solid pellets (TESPELs) have demonstrated some results for impurity injection for fusion-reactor plasma studies [N. Tamura et al., J. Phys. Conf. Ser. 823, 012003 (2017)]. However, the TESPEL technique has several shortcomings, for example, the penetration depth and the amounts of tracer impurities. In the present study, we have developed a tracer-containing, compact toroid (TCCT) injection system that utilizes a magnetized coaxial plasma gun (MCPG). The discharge current through the MCPG sputters and ionizes the electrode material, and the Lorenz self-force accelerates it as a plasmoid. The MCPG easily accelerates a magnetized plasmoid to speeds greater than the ion thermal velocity of several tens of kilometers per second. The accelerated and ejected plasmoid that contains the tracer ions is itself a warm, ionized plasma. Therefore, a TCCT can potentially be injected into the core region of a target plasma with less adverse effect. PMID- 30399863 TI - Pixel-to-pixel variation on a calibrated PILATUS3-based multi-energy soft x-ray detector. AB - A multi-energy soft x-ray pin-hole camera based on the PILATUS3 100 K x-ray detector has recently been installed on the Madison Symmetric Torus. This photon counting detector consists of a two-dimensional array of ~100 000 pixels for which the photon lower-threshold cutoff energy E c can be independently set for each pixel. This capability allows the measurement of plasma x-ray emissivity in multiple energy ranges with a unique combination of spatial and spectral resolution and the inference of a variety of important plasma properties (e.g., T e, n Z, Z eff). The energy dependence of each pixel is calibrated for the 1.6-6 keV range by scanning individual trimbit settings, while the detector is exposed to fluorescence emission from Ag, In, Mo, Ti, V, and Zr targets. The resulting data for each line are then fit to a characteristic "S-curve" which determines the mapping between the 64 possible trimbit settings for each pixel. The statistical variation of this calibration from pixel-to-pixel was explored, and it was found that the discreteness of trimbit settings results in an effective threshold resolution of DeltaE < 100 eV. A separate calibration was performed for the 4-14 keV range, with a resolution of DeltaE < 200 eV. PMID- 30399864 TI - A high-speed data acquisition system based on FPGA for tokamak. AB - The Experimental Advanced Superconducting Tokamak (EAST) device aims to achieve a steady-state and long-pulse discharge over 1000 s. An embedded high-speed data acquisition system based on a field-programmable gate array (FPGA) for EAST is designed in this study. A cyclone FPGA is used as the master chip, and a TI's analog-to-digital conversion (ADC) chip is used to complete ADC. One acquisition system board consists of four ADC chips. The acquired data are compressed and stored into a disk array through a Peripheral Component Interconnect (PCI) Express interface and then uploaded to the data server. One board can collect the signals of eight channels synchronously. A number of such boards can be used to collect additional channel signals. Experimental results show that the system can reach 80 MSps and the sampling precision can reach 12 bits with 1250 s continuous sampling. The system integrates signal conditioning, data acquisition, and data processing into a single board and provides an architecture with high integration and portability levels. PMID- 30399865 TI - Note: A 3D-printed flexure nanostage driven by piezo buzzers. AB - A flexure nanostage capable of being manufactured at home at a low cost is proposed. A prototype of the said stage-fabricated using a three-dimensional (3D) printer-exhibited single degree-of-freedom motion. Limitations with regard to material, fabrication precision, and actuator force were overcome, and cross talk was reduced by designing flexure holes. Fabrication of such holes was exclusively facilitated by the use of 3D-printing technology. Experimental results demonstrate that the proposed stage can perform linear motion over a 10-MUm distance over a voltage range of 30 V. PMID- 30399866 TI - Research on the normal spectral band emissivity of tungsten between 150 and 500 degrees C. AB - Tungsten is the baseline divertor material for a tokamak. Due to the effect of the interaction of plasma and the first wall, the first wall accumulates a large amount of heat flux and suffers irreversible damages. Therefore, the diagnosis of the first wall temperature of the tokamak by using a radiation thermometer is the premise to ensure the safe and stable operation of the whole facility. However, in order to achieve high precision of temperature measurement, the emissivity of tungsten must be measured accurately. In this paper, we built a set of emissivity measurement system and a method for accurate calculation of emissivity is proposed. This method effectively eliminated the interference of background radiation and improves the accuracy of emissivity measurement. By using this method, the author measured the emissivity of tungsten under the conditions of different surface roughness in the range of 150 degrees C-500 degrees C and discussed the uncertainty of the measurement at the end. PMID- 30399867 TI - Ionic-liquid-gating setup for stable measurements and reduced electronic inhomogeneity at low temperatures. AB - The ionic-liquid-gating technique can be applied to the search for novel physical phenomena at low temperatures because of its wide controllability of the charge carrier density. Ionic-liquid-gated field-effect transistors are often fragile upon cooling, however, because of the large difference between the thermal expansion coefficients of frozen ionic liquids and solid target materials. In this paper, we provide a practical technique for setting up ionic-liquid-gated field-effect transistors for low-temperature measurements. It allows stable measurements and reduces the electronic inhomogeneity by reducing the shear strain generated in frozen ionic liquid. PMID- 30399868 TI - Advanced neutral alkali beam diagnostics for applications in fusion research (invited). AB - Diagnosing the density profile at the edge of high temperature fusion plasmas by an accelerated lithium beam is a known technique since decades. By knowledge of the relevant atomic physics rate coefficients, the plasma electron density profile can be calculated from the relatively calibrated light profile along the beam. Several additional possibilities have already been demonstrated: Charge Exchange Resonance Spectroscopy (CXRS) for ion temperature/flow and Zeeman polarimetry for edge plasma current; therefore the Li-beam diagnostic offers a wealth of information at the plasma edge. The weaknesses of the method are the relatively faint light signal, background light, and technical difficulties of the beam injector which usually seriously limit the applicability. In this talk, we present systematic developments in alkali-beam diagnostics (Li, Na) for the injector and the observation system and detectors which resulted in strongly increased capabilities. Advanced systems have been built, and microsecond scale density profile, turbulence, and zonal flow measurement have been demonstrated. A novel edge current measurement technique has also been designed, and components have been tested with potential microsecond-scale time resolution. Additional possibilities of these advanced systems for spectral measurements (CXRS and various Zeeman schemes) are also discussed. PMID- 30399869 TI - The neutron camera upgrade for MAST Upgrade. AB - The Neutron Camera Upgrade (NCU) is a neutron flux monitor consisting of six lines of sight (LoSs) under installation on Mega Ampere Spherical Tokamak (MAST) Upgrade. The NCU is expected to contribute to the study of the confinement of fast ions and on the efficiency of non-inductive current drive in the presence of on-axis and off-axis neutral beam injection by measuring the neutron emissivity profile along the equatorial plane. This paper discusses the NCU main design criteria, the engineering and interfacing issues, and the solutions adopted. In addition, the results from the characterization and performance studies of the neutron detectors using standard gamma-rays sources and a 252Cf source are discussed. The proposed design has a time resolution of 1 ms with a statistical uncertainty of less than 10% for all MAST Upgrade scenarios with a spatial resolution of 10 cm: higher spatial resolution is possible by moving the LoSs in between plasma discharges. The energy resolution of the neutron detector is better than 10% for a light output of 0.8 MeVee, and the measured pulse shape discrimination is satisfactory. PMID- 30399870 TI - Development of a laser amplification system for the multi-pass Thomson scattering system for GAMMA 10/PDX. AB - The multi-pass Thomson scattering (MPTS) system is a useful technique for increasing the Thomson scattering (TS) signal intensities and improving the TS diagnostic time resolution. The MPTS system developed in GAMMA 10/PDX has a polarization-based configuration with an image relaying system. The MPTS system has been constructed for enhancing the Thomson scattered signals for the improvement of measurement accuracy and the megahertz sampling time resolution. However, in the normal MPTS system, the MPTS signal intensities decrease with the pass number because of the damping due to the optical components. Subsequently, we have developed a new MPTS system with the laser amplification system. The laser amplification system can improve the degraded laser power after six passes in the multi-pass system to the initial laser power. For the first time worldwide, we successfully obtained the continued multi-pass signals after the laser amplification system in the gas scattering experiments. PMID- 30399871 TI - Fast-framing camera based observations of spheromak-like plasmoid collision and merging process using two magnetized coaxial plasma guns. AB - We have been conducting compact toroid (CT) collision and merging experiments by using two magnetized coaxial plasma guns. As is well known, an actual CT/plasmoid moves macroscopically in a confining magnetic field. Therefore, three-dimensional measurements are important in understanding the behavior of the CTs. To observe the macroscopic process, we adopted a fast-framing camera (ULTRA Cam HS-106E) developed by NAC Image Technology. The characteristics of this camera are as follows: a CCD color sensor, capable of capturing 120 images during one sequence with a frame rate of up to 1.25 MHz. Using this camera, we captured the global motion of a CT inside the magnetic field and the collision of two CTs at the mid plane of the experimental device. Additionally, by using a color sensor, we captured the global change in the plasma emission of visible light during the CT collision/merging process. As a result of these measurements, we determined the CT's global motion and the changes in the CT's shape and visible emission. The detailed system setup and experimental results are presented and discussed. PMID- 30399872 TI - X-ray streaked refraction enhanced radiography for inferring inflight density gradients in ICF capsule implosions. AB - In the quest for reaching ignition of deuterium-tritium (DT) fuel capsule implosions, experiments on the National Ignition Facility (NIF) have shown lower final fuel areal densities than simulated. Possible explanations for reduced compression are higher preheat that can increase the ablator-DT ice density jump and induce mix at that interface or reverberating shocks. We are hence developing x-ray Refraction Enhanced Radiography (RER) to infer the inflight density profiles in layered fuel capsule implosions. We use a 5 MUm slit backlit by a Ni 7.8 keV He-alpha NIF laser driven x-ray source positioned at 20 mm from the capsule to cast refracted images of the inflight capsule onto a streak camera in a high magnification (M ~ 60*) setup. Our first experiments have validated our setup that recorded a streaked x-ray fringe pattern from an undriven high density carbon (HDC) capsule consistent with ray tracing calculations at the required ~6 MUm and 25 ps resolution. Streaked RER was then applied to inflight layered HDC capsule implosions using a hydrogen-tritium fuel mix rather than DT to reduce neutron yields and associated backgrounds. The first RER of an imploding capsule revealed strong features associated with the ablation front and ice-ablator interface that are not visible in standard absorption radiographs. PMID- 30399873 TI - Measurement of elastoresistivity at finite frequency by amplitude demodulation. AB - Elastoresistivity, the relation between resistivity and strain, can elucidate the subtle properties of the electronic structure of a material and is an increasingly important tool for the study of strongly correlated materials. To date, elastoresistivity measurements have predominantly been performed with quasi static (DC) strain. In this work, we demonstrate a method using AC strain in elastoresistivity measurements. A sample experiencing AC strain has a time dependent resistivity, which modulates the voltage produced by an AC current; this effect produces time-dependent variations in resistivity that are directly proportional to the elastoresistivity, and which can be measured more quickly, with less strain on the sample, and with less stringent requirements for temperature stability than the previous DC technique. Example measurements between 10 Hz and 3 kHz are performed on a material with a large, well characterized and temperature dependent elastoresistivity: the representative iron-based superconductor Ba(Fe0.975Co0.025)2As2. These measurements yield a frequency independent elastoresistivity and reproduce results from previous DC elastoresistivity methods to within experimental accuracy. We emphasize that the dynamic (AC) elastoresistivity is a distinct material-specific property that has not previously been considered. PMID- 30399874 TI - Experimental demonstration of an electromagnetic pulse mitigation concept for a laser driven proton source. AB - The targets that are used to produce high-energy protons with ultra-high intensity lasers generate a strong electromagnetic pulse (EMP). To mitigate that undesired side effect, we developed and tested a concept called the "birdhouse." It consists in confining the EMP field in a finite volume and in dissipating the trapped electromagnetic energy with an electric resistor. A prototype was tested at a 10 TW 50 fs laser facility. The recorded average EMP mitigation ratio is about 20 for frequencies from 100 MHz to 6 GHz. The EMP mitigation ratio attains the level of 50 in the frequency range of 1-2 GHz where microwave emission is maximal. We measured the intensity of proton emission in two directions: along the laser propagation direction and along the edge of the proton beam. We observed that the "birdhouse" induces a two-fold increase of the intensity in the center of the proton beam and a two-fold reduction of the intensity on its edge. We did not observe any modification of the proton beam normalized spectrum. PMID- 30399875 TI - Preface: Proceedings of the 22nd Topical Conference on High-Temperature Plasma Diagnostics, San Diego, California, USA 16-19 April 2018. PMID- 30399876 TI - Measurement of density fluctuation propagation direction via the far-forward collective scattering diagnostic based on polarimeter-interferometer. AB - Previously, the 17-channel three-wave polarimeter-interferometer system (POLARIS) on the J-TEXT tokamak has been implemented to measure far-forward collective scattering (FFCS) from electron density fluctuations. Recently, this system has been exploited to measure the propagation direction of density fluctuation. After considering the refraction of the laser probe beam passing through plasma, the ray tracing result shows that the detector of POLARIS may receive asymmetric far forward scattering beams. Thus, the heterodyne detection of FFCS is available to identify the propagation direction of density fluctuation by resolving the asymmetric scattering spectrum. Experimentally, the transform of the heterodyne scattering spectrum from symmetry to asymmetry has been observed, while the refraction effect becomes strong demonstrating the capacity of measuring the propagation direction of fluctuation. Furthermore, by changing the plasma potential through the use of an applied positive electrode biasing, the reverse of frequency shift for the heterodyne scattering spectrum is identified, confirming the validity of direction discrimination of density fluctuation. PMID- 30399877 TI - Velocity-space tomography using prior information at MAST. AB - Velocity-space tomography provides a way of diagnosing fast ions in a fusion plasma by combining measurements from multiple instruments. We use a toroidally viewing and a vertically viewing fast-ion D-alpha diagnostic installed on the mega-amp spherical tokamak (before the upgrade) to perform velocity-space tomography of the fast-ion distribution function. To make up for the scarce amount of data, prior information is included in the inversions. We impose a non negativity constraint, suppress the distribution in the velocity-space region associated with null-measurements, and encode the belief that the distribution function does not extend to energies significantly higher than those expected neoclassically. This allows us to study the fast-ion velocity distributions and the derived fast-ion densities before and after a sawtooth crash. PMID- 30399878 TI - An x-ray optic calibration facility for high energy density diagnostics. AB - A facility to calibrate x-ray imaging optics was built at Lawrence Livermore National Laboratory to support high energy density (HED) and inertial confinement fusion (ICF) diagnostics such as those at the National Ignition Facility and the Sandia Z-Machine. Calibration of the spectral reflectivity and resolution of these x-ray diagnostics enable absolute determination of the x-ray flux and wavelengths generated in the HED and ICF experiments. Measurement of the optic point spread function is used to determine spatial resolution of the optic. This facility was constructed to measure (1) the x-ray reflectivity to +/-5% over a spectral range from 5 to 60 keV; (2) point spread functions with a resolution of 50 MUm (currently) and 13 MUm (future) in the image plane; and (3) optic distance relative to the x-ray source and detector to within +/-100 MUm in each dimension. This article describes the capabilities of the calibration facility, concept of operations, and initial data from selected x-ray optics. PMID- 30399879 TI - Development of high-speed vacuum ultraviolet spectroscopy using a modified Seya Namioka monochromator and channel electron multiplier detector in the HL-2A tokamak. AB - A high-speed vacuum ultraviolet monochromator is developed for the HL-2A tokamak through the introduction of a novel channel electron multiplier in a modified Seya-Namioka spectrometer. A good signal to noise ratio of above 2000 is attained in the development phase of the system with typical operating parameters for observing routine HL-2A plasmas. The wavelength calibration is performed using characteristic line emissions from a hollow cathode light source with helium and argon discharges. The first measurement result of the monochromator at a sample rate of 60 kHz is presented in comparison with the visible Dalpha signals. PMID- 30399880 TI - Design and implementation of a Thomson parabola for fluence dependent energy-loss measurements at the Neutralized Drift Compression eXperiment. AB - The interaction of ion beams with matter includes the investigation of the basic principles of ion stopping in heated materials. An unsolved question is the effect of different, especially higher, ion beam fluences on ion stopping in solid targets. This is relevant in applications such as in fusion sciences. To address this question, a Thomson parabola was built for the Neutralized Drift Compression eXperiment (NDCX-II) for ion energy-loss measurements at different ion beam fluences. The linear induction accelerator NDCX-II delivers 2 ns short, intense ion pulses, up to several tens of nC/pulse, or 1010-1011 ions, with a peak kinetic energy of ~1.1 MeV and a minimal spot size of 2 mm FWHM. For this particular accelerator, the energy determination with conventional beam diagnostics, for example, time of flight measurements, is imprecise due to the non-trivial longitudinal phase space of the beam. In contrast, a Thomson parabola is well suited to reliably determine the beam energy distribution. The Thomson parabola differentiates charged particles by energy and charge-to-mass ratio, through deflection of charged particles by electric and magnetic fields. During first proof-of-principle experiments, we achieved to reproduce the average initial helium beam energy as predicted by computer simulations with a deviation of only 1.4%. Successful energy-loss measurements with 1 MUm thick silicon nitride foils show the suitability of the accelerator for such experiments. The initial ion energy was determined during a primary measurement without a target, while a second measurement, incorporating the target, was used to determine the transmitted energy. The energy-loss was then determined as the difference between the two energies. PMID- 30399881 TI - Design of a 3D printed compact interferometric system and required phone application for small angular measurements. AB - A 3D printed smartphone based interferometric system is proposed, and its usability has been demonstrated by measuring small angular rotations. All necessary fringe processing and data analysis have been performed within the phone itself using custom designed application developed in an android platform. The main objective of the proposed work is to demonstrate the usability of modern smartphone and 3D printing technology for optical interferometric applications. The smartphone camera has been used to record the interference fringes which has been formed due to the change in the optical path difference (OPD) between light rays reflected from the top and bottom surface of a microscopic glass slide. The angular variation of the slide causes a detectable change in the OPD between the interfering beams which subsequently would cause a variation in the fringe pattern. By evaluating necessary interferometric parameters, small angular rotation can be computed within the smartphone application. With the designed smartphone based interferometric system, angular rotation as small as 0.02 degrees can be measured accurately and reliably having a dynamic range of -3.68 degrees to 3.68 degrees . Due to the involvement of the smartphone as a platform for recording as well as onboard fringe processing, the designed interferometric system can be visualized as a truly field portable tool for different optical metrological applications. PMID- 30399882 TI - Multi-angle multi-pulse time-resolved Thomson scattering on laboratory plasma jets. AB - A single channel sub-nanosecond time-resolved Thomson scattering system used for pulsed power-driven high energy density plasma measurements has been upgraded to give electron temperatures at two different times and from two different angles simultaneously. This system was used to study plasma jets created from a 15 MUm thick radial Al foil load on a 1 MA pulsed power machine. Two laser pulses were generated by splitting the initial 2.3 ns duration, 10 J, 526.5 nm laser beam into two pulses, each with 2.5 J, and delaying one relative to the other by between 3 and 14 ns. Time resolution within each pulse was obtained using a streak camera to record the scattered spectra from the two beams from two scattering angles. Analysis of the scattering profile showed that the electron temperature of the Al jet increased from 20 eV up to as much as 45 eV within about 2 ns by inverse bremsstrahlung for both laser pulses. The Thomson scattering results from jets formed with opposite current polarities showed different laser heating of the electrons, as well as possibly different ion temperatures. The two-angle scattering determined that the electron density of the plasma jet was at least 2 * 1018 cm-3. PMID- 30399883 TI - Testing a Cherenkov neutron time-of-flight detector on OMEGA. AB - A Cherenkov neutron time-of-flight (nTOF) detector developed and constructed at Lawrence Livermore National Laboratory was tested at 13 m from the target in a collimated line of sight (LOS) and at 5.3 m from the target in the open space inside the OMEGA Target Bay. Neutrons interacting with the quartz rod generate gammas, which through Compton scattering produce relativistic electrons that give rise to Cherenkov light. A photomultiplier tube (PMT) transferred the Cherenkov light into an amplified electrical signal. The Cherenkov nTOF detector consists of an 8-mm-diam, 25-cm quartz hexagonal prism coupled with a Hamamatsu gated PMT R5916U-52. The tests were performed with DT direct-drive implosions with cryogenic and room-temperature targets, producing a wide range of neutron yields and ion temperatures. The results of the tests and comparison with other nTOF detectors on OMEGA are presented. In the collimated LOS at 13 m from the target, the Cherenkov nTOF detector demonstrated good precision measurement in both the yield and ion temperature for DT yields above 3 * 1013. PMID- 30399884 TI - Development of a spectroscopic diagnostic tool for electric field measurements in IShTAR (Ion cyclotron Sheath Test ARrangement). AB - IShTAR, Ion cyclotron Sheath Test ARrangement, is a linear device dedicated to the investigation of the edge plasma-ICRF (Ion Cyclotron Range of Frequencies) antenna interactions in tokamak edge-like conditions and serves as a platform for a diagnostic development for measuring the electric fields in the vicinity of ICRF antennas. We present here our progress in the development of an optical emission spectroscopy method for measuring the electric fields which concentrates on the changes in the helium spectral line profiles introduced by the external electrical field, i.e., the Stark effect. To be able to fully control the operating parameters, at the first stage of the study, the measurements are conducted on a planar electrode installed in the centre of the plasma column in IShTAR's helicon plasma source. At the second stage, the measurements are performed in the vicinity of IShTAR's ICRF antenna. PMID- 30399885 TI - Development of wavelength calibration techniques for high-resolution x-ray imaging crystal spectrometers on the EAST tokamak. AB - Newly developed large-area pixelated two-dimensional detector and two-crystal assemblies were deployed for the first time on tokamaks to enable time-resolved Bragg-diffracted x-ray imaging with good framing rate and water-cooling capabilities for in-vacuum long-pulse operations. High-quality helium-like (He like) and hydrogen-like (H-like) argon spectra have been observed simultaneously for the first time on a single detector for a wide range of plasma parameters to infer both ion temperature and rotation profiles and support studies on spontaneous rotation, impurity transport, and RF physics. Since tokamak plasmas rotate in both the poloidal (theta) and toroidal (phi) directions, a reliable wavelength calibration is needed to account for the correct Doppler shift as well as to compute the spectrometer's instrumental function. Lyalpha lines emitted from Cd x-ray tubes are proposed to be used as "markers" to provide an in situ calibration of the EAST's X-ray imaging crystal spectrometer systems measuring He and H-like argon spectra. The first lab test indicated that the X-ray tube can excite strong Lyalpha lines at 15 kV voltage and 1 mA current when the crystal is shined for 10 min. Other indirect calibration methods using locked-mode discharge scenarios were also studied as complementary methods. PMID- 30399886 TI - Upgrade of X-ray crystal spectrometer for high temperature measurement using neon like xenon lines on EAST. AB - A two-crystal X-ray spectrometer system has been implemented in the EAST tokamak to simultaneously diagnose high- and low-temperature plasmas using He- and H-like argon spectra. But for future fusion devices like ITER and Chinese Fusion Engineering Test Reactor (CFETR), argon ions become fully stripped in the core and the intensity of the H-like lines will be significantly at high temperatures (Te > 5 keV). With increasing auxiliary heating power on EAST, the core plasma temperature could also reach 5 keV and higher. In such conditions, the use of a xenon puff becomes an appropriate choice for both ion-temperature and flow velocity measurements. A new two-crystal system using a quartz 110 crystal (2d = 4.913 A) to view He-like argon lines and a quartz 011 crystal (2d = 6.686 A) to view Ne-like xenon spectra has been deployed on a poloidal X-ray crystal spectrometer. While the He-like argon spectra will be used to measure the plasma temperature in the edge plasma region, the Ne-like xenon spectra will be used for measurement in the hot core. The new crystal arrangement allows a wide temperature measurement ranging from 0.5 to 10 keV or even higher, being the first tests for burning plasmas like ITER and CFETR. The preliminary result of lab-tests, Ne-like xenon lines measurement will be presented. PMID- 30399887 TI - Compensation of the pick-up fluxes on the plasma position control system when resonant magnetic perturbations are applied in J-TEXT. AB - In the J-TEXT tokamak the displacement coils, which serve as sensors for feedback control of plasma position, are significantly affected by the resonant magnetic perturbation (RMP) coils. To eliminate the deviation of plasma position caused by the RMP, the responses of the displacement coils to the RMP are studied with a view to compensate for the pick-up fluxes. Both the linear and eddy responses on the displacement coils are taken into account and adjusted accordingly. It was found that positional correction in the vertical direction was required when the RMP was operated in the poloidal mode m = 1 and horizontal positional correction was required when the RMP was operated in the m = 2 mode. When compensation was applied to the position control system, correction of plasma position was successfully achieved, as observed from soft X-ray imaging, as well as from the evolution of the current of the horizontal and vertical fields. PMID- 30399888 TI - Measurement of electron temperature fluctuations on J-TEXT via correlation ECE. AB - The capabilities of the joint-Texas experimental tokamak correlation electron cyclotron emission (CECE) diagnostic have recently been extended with an upgrade. Four new yttrium iron garnet (YIG) filters from 4 GHz to 18 GHz with a bandwidth of 90 ~ 230 MHz are added to the previous 4 channels. Optical optimization of the transmission line has improved the poloidal resolution, which allows k theta < 3.08 cm-1. The improvement of video amplifiers allows the frequency and amplitude gain to be adjusted discretely from 200 kHz to 1 MHz and from 200 to 1000, respectively, for different situations. A controller is designed to remotely adjust the center frequency of the YIG filters. Based on the CECE, the distribution and the effect of magnetohydrodynamic instabilities on electron temperature fluctuations have been observed. The experiment results show good performance of the upgraded CECE diagnostic. PMID- 30399889 TI - Advancing the capability of the gated laser-entrance-hole imager on the National Ignition Facility. AB - A new configuration based on the recent off-line calibrations of the gated laser entrance hole diagnostic on the National Ignition Facility provides 4-8 interleaved frames per experiment using the standard two frame sensor settings. Since its implementation, the new design has greatly increased the data return for hundreds of experiments at the National Ignition Facility. The large quantity of images from a variety of physics campaigns has revealed information on plasma evolution in hohlraums. PMID- 30399890 TI - Prospects of X-ray imaging spectrometers for impurity transport: Recent results from the stellarator Wendelstein 7-X (invited). AB - This paper reports on the design and the performance of the recently upgraded X ray imaging spectrometer systems, X-ray imaging crystal spectrometer and high resolution X-ray imaging spectrometer, installed at the optimized stellarator Wendelstein 7-X. High resolution spectra of highly ionized, He-like Si, Ar, Ti, and Fe as well as H-like Ar have been observed. A cross comparison of ion and electron temperature profiles derived from a spectral fit and tomographic inversion of Ar and Fe spectra shows a reasonable match with both the spectrometers. The also measured impurity density profiles of Ar and Fe have peaked densities at radial positions that are in qualitative agreement with the expectations from the He-like impurity fractional abundances, given the measured temperature profiles. Repeated measurements of impurity decay times have been demonstrated with an accuracy of 1 ms via injection of non-recycling Ti, Fe, and Mo impurities using a laser blow-off system. PMID- 30399892 TI - Optimizing neutron imaging line of sight locations for maximizing sampling of the cold fuel density in inertial confinement fusion implosions at the National Ignition Facility. AB - Neutron imaging provides a ready measurement of the shape of the "hot spot" core of an inertial confinement fusion implosion. The 14-MeV neutrons emitted by deuterium-tritium reactions are imaged at the National Ignition Facility using a pinhole array onto a scintillator, and the images are recorded on a camera. By changing the gate time of the camera, lower energy neutrons, downscattered by the cold fuel surrounding the hot spot, are recorded. The cold fuel density can be reconstructed using the two images. The kinematics of the scattering coupled with the scattering cross sections restrict the angular extent of the cold fuel sampled, with the backside of the implosion not being sampled at all. This work demonstrates the limited region of the cold fuel measured by the current line of sight (40%). At completion of the three planned lines of sight, 79% of the cold fuel will be sampled. PMID- 30399891 TI - A Wolter imager on the Z machine to diagnose warm x-ray sources. AB - A new Wolter x-ray imager has been developed for the Z machine to study the emission of warm (>15 keV) x-ray sources. A Wolter optic has been adapted from observational astronomy and medical imaging, which uses curved x-ray mirrors to form a 2D image of a source with 5 * 5 * 5 mm3 field-of-view and measured 60-300 MUm resolution on-axis. The mirrors consist of a multilayer that create a narrow bandpass around the Mo Kalpha lines at 17.5 keV. We provide an overview of the instrument design and measured imaging performance. In addition, we present the first data from the instrument of a Mo wire array z-pinch on the Z machine, demonstrating improvements in spatial resolution and a 350-4100* increase in the signal over previous pinhole imaging techniques. PMID- 30399893 TI - A spectroscopic electric field vector imaging diagnostic for electron cyclotron heating systems. AB - An experimental measurement of the wave electric field vector provides important data that can be used to directly compare against 3D full-wave simulations. This direct comparison yields the fastest approach toward identifying missing physics in computational models and providing a high fidelity validation platform. In this paper, we present a diagnostic that is capable of imaging the Electron Cyclotron (EC) wave electric field vector by acquiring filtered images of polarized D beta spectral satellites. The diagnostic is designed to have a spatial and temporal resolution on the order of 100 MUm and 100 MUs, respectively. The diagnostic purpose is to provide experimental data for the direct validation of full-wave codes used to predict EC beam propagation and absorption and to provide real-time monitoring of EC waves. PMID- 30399894 TI - Proposal of a femtosecond megahertz repetition-rate electron diffraction instrument based on the Chinese Academy of Engineering Physics terahertz free electron laser beamline. AB - We report the design and optimization of a femtosecond electron diffraction instrument with megahertz repetition-rate. The proposed instrument is mainly based on the photoinjector of the Chinese Academy of Engineering Physics Terahertz free electron laser facility, which merges a 320 kV DC photocathode gun with two 4-cell super-conducting linac operating at 1.3 GHz. Simulations show that high quality electron probes with fC charge, ultralow emittance, and femtosecond scale bunch duration can be generated. Together with the capability of operating at continuous wave mode, this instrument is well matched with the demand of future electron diffraction. PMID- 30399895 TI - Characterization of the Mercury pulsed power x-ray source spectrum using multichannel density aerogel Cherenkov detectors. AB - The Aerogel Cherenkov Detector for Cygnus (ACD/C) is a time-dependent, x-ray spectral detector that uses SiO2 aerogels spanning an index of refraction (n = 1.02-1.07) corresponding to a 1.1-2.3 MeV x-ray energy threshold. The ACD/C was developed for pulsed power x-ray sources like Cygnus located at the Nevada National Site and Mercury located at the Naval Research Laboratory (NRL). Aerogels sit between the measurement capabilities of gas (>2 MeV) and solids such as fused silica (>0.3 MeV). The detector uses an aluminum converter to Compton scatter incoming x-rays and create relativistic electrons, which produce Cherenkov light in an aerogel or a fused silica medium. The ACD/C was fielded at the NRL when Mercury was tuned to produce up to 4.8 MeV endpoint bremsstrahlung. Despite a high radiation and electromagnetic interference background, the ACD/C was able to achieve high signal over noise across five aerogel densities and fused silica, including a signal to noise for a 1.1 MeV aerogel threshold. Previous experiments at Cygnus observed a signal that was comparable to the noise (1*) at the same threshold. The ACD/C observed time-resolved rise and fall times for different energy thresholds of the photon spectrum. Monte Carlo simulations of the ACD/C's aerogel response curves were folded with a simulation of Mercury's photon energy spectrum and agree within the error to the observed result. PMID- 30399896 TI - The charge exchange recombination spectroscopy diagnostic on the upgraded Lithium Tokamak eXperiment (LTX-beta). AB - The Lithium Tokamak eXperiment has undergone an upgrade to LTX-beta, a major part of which is the addition of neutral beam injection (NBI). NBI has allowed for a new charge exchange recombination spectroscopy (CHERS) system to be installed in order to measure impurity concentrations, ion temperature, and toroidal velocity. Previously on LTX measuring these parameters relied on passive spectroscopy and inversion techniques and had large uncertainty. The CHERS system has 52 total views, split into four groups of 13, half facing toward the beam and half symmetrically facing away from the beam, so the background non-beam related emission can be simultaneously subtracted. Both sets of views sample a major radius of 27-59 cm, with resolution through the beam of 1.5-2.5 cm. LTX-beta is expected to have its magnetic axis near 35 cm, with minor radii of 18-23 cm. Three separate spectrometers will be used for the diagnostic, giving the system great flexibility to simultaneously measure emission from multiple impurity lines. The viewing optics are f/1.8, allowing all of the spectrometers to be fully illuminated. Design and calibration of the system as well as the advantages of various configurations of the spectrometers will be highlighted. PMID- 30399897 TI - Magnetic perturbation diagnostics in the high-temperature lithiated environment of LTX-beta. AB - Magnetic perturbation measurements will be invaluable for characterizing Lithium Tokamak Experiment Beta (LTX-beta) plasmas due to the time-evolving 3D nature of the magnetic fields generated by eddy currents in the vessel and copper shell segments, as well as enhanced MHD instability drive due to newly introduced neutral beam heating. The LTX-beta upgrade includes two new arrays of Mirnov coils: a shell eddy sensor array of two-axis coils distributed over the back surface of one shell segment and a toroidal array of poloidal field coils at the low-field side midplane gap. Evaporative lithium wall-coating and the high temperatures required for liquid lithium wall operation both complicate the implementation of in-vessel diagnostics. While the shell array is protected from lithium exposure, the shell segment to which it is mounted will at times exceed 300 degrees C. The toroidal array, however, will experience direct line-of-sight exposure to the lithium evaporator as well as close proximity to the hot shell and may also be subject to poorly confined beam-driven fast ions. We describe how the two new Mirnov coil arrays meet these environmental challenges and enhance the LTX-beta diagnostic suite. PMID- 30399898 TI - Compact and lightweight 1.5 MUm lidar with a multi-mode fiber coupling free running InGaAs/InP single-photon detector. AB - We present a compact and lightweight 1.5 MUm lidar using a free-running single photon detector (SPD) based on a multi-mode fiber (MMF) coupling InGaAs/InP negative feedback avalanche diode. The ultimate light detection sensitivity of SPD highly reduces the power requirement of the laser, whilst the enhanced collection efficiency due to MMF coupling significantly reduces the volume and weight of telescopes. We develop a specific algorithm for the corrections of errors caused by the SPD and erbium-doped fiber amplifier to extract accurate backscattering signals. We also perform a comparison between single-mode fiber (SMF) coupling and MMF coupling in the lidar receiver, and the results show that the collection efficiency with MMF coupling is five times higher than that with SMF coupling. In order to validate the functionality, we use the lidar system for the application of cloud detection. The lidar system exhibits the ability to detect both the cloud base height and the thickness of multi-layer clouds to an altitude of 12 km with a temporal resolution of 1 s and a spatial resolution of 15 m. Due to the advantages of compactness and lightweight, our lidar system can be installed on unmanned aerial vehicles for wide applications in practice. PMID- 30399899 TI - Turbulence level effects on conventional reflectometry using 2D full-wave simulations. AB - Numerical simulations are critical in improving the capabilities of microwave diagnostics. In this work, the 2D finite-difference time-domain full-wave code REFMUL was applied to broadband turbulent plasmas using the conventional reflectometry setup. Simulations were performed with O-mode waves, fixed frequency probing, and I/Q detection. The plasma density, determining O-mode propagation, was modeled as the sum of a slab background plasma with a fluctuating component following a Kolmogorov-like amplitude k-spectrum. The density turbulence level deltan e/n e was scanned over several orders of magnitude for simulated plasma flows of constant plasma velocity in either the radial or the poloidal direction. Simulations show trends, such as spectral broadening of the complex A(t)eiphi(t) signals and increasing fluctuations in A(t) and phi(t) with increasing deltan e/n e, that are similar for both plasma flow directions. These together with possibilities to reconstruct a poloidal wavenumber spectrum are discussed in view of extending the measuring capabilities. The onset of non-linear effects associated with phase runaway, as previously observed with other 1D and 2D codes, as well as radial Doppler effects is also observed and discussed. PMID- 30399900 TI - A reconstruction method based on evolution of partial differential equation for the Laser-driven Ion-beam Trace Probe (LITP). AB - The Laser-driven Ion-beam Trace Probe (LITP) is a new poloidal magnetic field (Bp) diagnostic method in tokamak devices. It measures the ion displacements which are linear integrations of Bp along the ion beam traces, and a proper tomography method is necessary for the Bp reconstruction. A tomography method based on the solution of partial differential equation is used. The diffusion term and perturbation term are used to avoid the divergence and smooth the reconstructed results. Numerical results show that both the diffusion term and the perturbation term obviously improved the reconstruction results of Bp for LITP. PMID- 30399901 TI - Note: Internal diamagnetic flux measurements on ASDEX Upgrade. AB - Internal diamagnetic flux measurements, with measurement loops and compensation magnetic probes inside the vacuum vessel, are now available on the ASDEX Upgrade tokamak. The measured diamagnetic flux is compared to that predicted by simulations and calculated from equilibrium reconstruction. The diamagnetic flux measured at 2 positions separated toroidally by 180 degrees in the vacuum vessel is compared. PMID- 30399902 TI - Hyperbolic lens design of local oscillator optics system for electron cyclotron emission imaging on J-TEXT. AB - An electron cyclotron emission imaging diagnostic system that contains two 16 antenna arrays is being developed on J-TEXT tokamak. In this heterodyne system, the mixers in the front microwave antenna are used to down-convert the electron cyclotron emission to a 2-12 GHz radio frequency. All of the 24 antenna mixers in the individual enclosure box are driven by shining local oscillator (LO) power via launching optics. The previous approach for LO optics was designed with spherical and cylinder lenses, which has limitations such as the inhomogeneity of the energy deposition on different channels and the difficulty of optics alignment. A new generation of LO optics has been designed and applied on J-TEXT with a hyperbolic lens for uniform power deposition across the entire antenna array. The robustness of the optical alignment will be significantly increased with three hyperbolic lenses. Furthermore, the simulation results and robustness analysis of these LO optics are discussed in this paper. PMID- 30399903 TI - Fabrication of gadolinium particle-based absorption gratings for neutron grating interferometry. AB - The imaging performance of a neutron-based Talbot-Lau interferometer depends to a great extent on the absorption characteristics of the source and analyzer gratings. Due to its high neutron attenuation, gadolinium (Gd) is the preferred material for grating fabrication, but suffers from difficulties with deposition time, stability, uniformity, and selectivity into high aspect ratio structures. Here we present a simple alternative method of Gd deposition into grating structures based on metallic particle suspension casting and subsequent doctor blading. Surface analysis by confocal and electron scanning microscopy shows that a nearly clear, particle free silicon interface of the grating structure over a large area could be reached. Additionally, characterization by neutron radiography confirms a high effective Gd height and homogeneity over the whole grating area. In particular, grating trenches well below 10 MUm width could be successfully filled with Gd and deliver excellent absorbing performance down to the sub-2 A wavelength range. The findings confirm that we obtained an effective binary absorption profile for the fabricated gratings which is of great benefit for grating-based neutron imaging. PMID- 30399904 TI - MOKE setup exploiting a nematic liquid crystal modulator. AB - Here we report on the magneto-optical Kerr effect employing a nematic liquid crystal (LC) device as an optical modulator. This device allows performing intensity, phase, and polarization modulated measurements with a huge signal-to noise ratio when compared to those obtained by means of an opto-mechanical chopper and a photo-elastic modulator. The results demonstrate that the optimal performance is achieved modulating the polarization state of the incident light by means of the LCs. PMID- 30399905 TI - Millimeter-wave system-on-chip advancement for fusion plasma diagnostics. AB - Recent advances in radio-frequency system-on-chip technology have provided mm wave fusion plasma diagnostics with the capability to overcome major challenges such as space inefficiency, inflexible installation, sensitivity, susceptibility to EMI, and prohibitively high cost of conventional discrete component assemblies as higher imaging resolution and data accuracy are achieved by increasing the number of channels. Nowadays, shrinking transistor gate lengths on fabrication techniques have enabled hundreds of GHz operation, which is suitable for millimeter-wave diagnostics on current and future tokamaks. The Davis Millimeter Wave Research Center (DMRC) has successfully developed V-band (55-75 GHz) transmitter and receiver chips for Microwave Imaging Reflectometer (MIR) instruments. The transmitter can illuminate 8 different frequencies simultaneously within 55-75 GHz. Moreover, the receiver has the capability to amplify the reflected signal (>30 dB) while offering 10-30* reduction in noise temperature compared to current MIR instruments. Plasma diagnostics requires ultra-wideband (more than 20 GHz) operation which is approximately nine times wider bandwidth than the recent commercial impetus for communication systems. Current efforts are underway for gallium-arsenide monolithic microwave integrated circuit receiver chips at W-band (75-110 GHz) and F-band (90-140 GHz) permitting measurements at higher toroidal magnetic fields. PMID- 30399906 TI - A compact high-voltage pulse forming module with hundreds of nanoseconds quasi squared output pulse. AB - A pulse forming module (PFM) with a multifunction of energy storage and a quasi squared pulse output is developed to meet the challenge of a compact design and square output waveform in a high-power Marx generator. A simplified pulse forming circuit comprising only 2 parallel connected LC sections, in which every section contains an inductor and a capacitor in series, has been proposed and investigated carefully to obtain a quasi-squared waveform. Influences of inductance values in the circuit on its output waveform to a resistive load are investigated. PFMs are designed and fabricated based on the 2 LC section circuit, in which series folded film capacitors are employed to achieve a high energy density of 0.04 J/cm3 at a charging voltage of 120 kV. The as-designed module can output a quasi-squared waveform with FWHM of about 180 ns and the flattop duration greater than 90 ns. It can work at a repetition rate as high as 50 Hz, while the output waveforms show small differences. This research has developed a PFM with a quasi-squared output waveform based on a simplified 2 LC section circuit, which shows potential to reduce the size of the high power generator system that is based on it. PMID- 30399907 TI - Micro-spectrometer for fusion plasma boundary measurements. AB - In situ probes are being developed to make direct, spatially resolved measurements of the ion energy spectra in the edge of tokamak plasmas while being easily replaced and requiring minimal resources. The ion spectrometers will consist of a combined collimator and energy analyzer fabricated from silicon and mated to a detector to yield a form factor of approximately 2.0 cm * 1.5 cm * 0.2 cm. Results of fabrication and testing of the combined collimator and energy analyzer element are presented. PMID- 30399908 TI - X-ray backlighter requirements for refraction-based electron density diagnostics through Talbot-Lau deflectometry. AB - Talbot-Lau x-ray interferometers can map electron density gradients in High Energy Density (HED) samples. In the deflectometer configuration, it can provide refraction, attenuation, elemental composition, and scatter information from a single image. X-ray backlighters in Talbot-Lau deflectometry must meet specific requirements regarding source size and x-ray spectra, amongst others, to accurately diagnose a wide range of HED experiments. 8 keV sources produced in the high-power laser and pulsed power environment were evaluated as x-ray backlighters for Talbot-Lau x-ray deflectometry. In high-power laser experiments, K-shell emission was produced by irradiating copper targets (500 * 500 * 12.5 MUm3 foils, 20 MUm diameter wire, and >10 MUm diameter spheres) with 30 J, 8-30 ps laser pulses and a 25 MUm copper wire with a 60 J, 10 ps laser pulse. In the pulsed power environment, single (2 * 40 MUm) and double (4 * 25 MUm) copper x pinches were driven at ~1 kA/ns. Moire fringe formation was demonstrated for all x-ray sources explored, and detector performance was evaluated for x-ray films, x ray CCDs, and imaging plates in context of spatial resolution, x-ray emission, and fringe contrast. PMID- 30399909 TI - Vertical fast electron bremsstrahlung diagnostic on J-TEXT tokamak. AB - Fast electron bremsstrahlung (FEB) emission during Ohmic discharge experiments on the Joint Texas Experimental Tokamak (J-TEXT) has been measured by a recently developed vertical multi-channel FEB diagnostic based on CdZnTe detectors. There are 5 sight lines to observe the vertical emission of fast electrons at the high field side with a spatial resolution of 5 cm. The FEB emission in the energy range of 30-300 keV can be measured. The generation of fast electrons accelerated by loop voltage has been confirmed during the early phase of discharge by analyzing the signals of FEB emission. The runaway electron beam instabilities have been observed with the FEB diagnostic on J-TEXT. PMID- 30399910 TI - High resolution gamma-ray spectrometer with MHz capabilities for runaway electron studies at ASDEX Upgrade. AB - A new gamma-ray spectrometer with MHz capabilities has been developed to measure the bremsstrahlung emission spectrum in the gamma-ray energy band generated by MeV range runaway electrons in disruption experiments at ASDEX Upgrade. Properties of the runaway electrons are inferred from the measured bremsstrahlung spectrum by a deconvolution technique, particularly with regard to their maximum energy. Changes induced to the runaway electron velocity space are unambiguously observed both in massive gas injection and resonant magnetic perturbation experiments with the detector. PMID- 30399911 TI - Measurement of incandescent microparticle acceleration using stereoscopic imaging. AB - Microparticles ranging from sub-microns to millimeter in size are a common form of matter in magnetic fusion environment, and they are highly mobile due to their small mass. Different forces in addition to gravity can affect their motion both inside and outside the plasmas. Several recent advances open up new diagnostic possibilities to characterize the particles' motion and their forces: high-speed imaging camera technology, microparticle injection techniques developed for fusion, and image processing software. Extending our earlier work on high temperature 4D microparticle tracking using exploding wires [Z. Wang et al. Rev. Sci. Instrum. 87, 11D601 (2016)], we report here the latest results on time resolved microparticle acceleration measurement. New particle tracking algorithm is found to be effective in particle tracking even when there are a large number of particles close to each other. Epipolar constraint is used for track-pairing from two-camera views. The error field based on an epi-geometry model is characterized on the basis of a large set of 2D track data and 3D track reconstructions. Accelerations based on individual reconstructed 3D tracks are obtained. Force sensitivity in the order of ten gravitational acceleration has been achieved. High-speed imaging is a useful diagnostic tool for microparticle physics, computer model validation, and mass injection technology development for magnetic fusion. PMID- 30399912 TI - Development of a LIBS system for in situ surface measurements during plasma exposure in PISCES-A. AB - A laser-induced breakdown spectroscopy (LIBS) system has been developed with a Q switched Nd:YAG laser (wavelength = 1064 nm and pulse width ~5 ns) to conduct in situ surface measurements during plasma exposure in the PISCES-A linear divertor plasma simulator. The LIBS signal enhancement is obtained with both the magnetic field normal to the surface of a target and steady-state background plasma. Migration of sputtered Ta impurities onto the neighboring Cr surface is identified during He plasma exposure, only when cone structures are formed on the Cr surface. D retention in W during D plasma exposure is observed to decrease with increasing the sample temperature. The temporal evolution of D outgassing from W is measured in a time range of ~10-420 s right after D plasma exposure. A power law fit, t -alpha , yields alpha ~ 0.34 +/- 0.09, which is nearly consistent with calculated and measured values. PMID- 30399913 TI - Observation and evaluation of the alignment of Thomson scattering systems. AB - Concerning plasma diagnostics based on Thomson scattering (TS), precise adjustment and proper alignment is of great importance in order to provide reliable and accurate measurements. Any misalignment could result in an incorrectly determined plasma density or prevent the measurement with this type of diagnostic altogether. Suitable means of alignment monitoring should be integrated into each TS diagnostic system. Variations of commonly used methods are discussed in this article. Correlation of results from alignment control with performed measurements of vibrations on the COMPASS tokamak is presented. Various techniques of optimization of alignment monitoring are shown. The optimal technique, which could be accommodated during the construction of TS diagnostic systems in future fusion devices, is proposed. PMID- 30399914 TI - Characterization of photodetector temporal response for neutron time-of-flight (nToF) diagnostics at the National Ignition Facility. AB - The temporal response of a microchannel plate photomultiplier tube used in the suite of neutron time of flight (nToF) diagnostics at the National Ignition Facility has been characterized to reduce uncertainty in, and understanding of, shot parameters obtained from nTOF data. A short pulse laser, neutral density glass filters, and electrical attenuators were used to gather statistically significant samples of photodetector impulse response functions (IRF) in rapid succession. Individual components have been absolutely calibrated to minimize systematic uncertainties. The zeroth (collected charge), first (transit time), and second central moments (transit time spread) of the IRF were calculated as either the bias voltage or the amount of light incident on the detector was varied. Timing reference was provided by a monitor photodiode viewing a pickoff of the incident laser pulse. The primary sources of uncertainty are jitter in the monitor photodiode and the statistical variation across our measurement period. The spreads in the first moment, with respect to the timing photodiode, and the square root of the second central moment were found to be less than 50 ps and 150 ps, respectively. PMID- 30399915 TI - Improvement of infrared imaging video bolometer for application to deuterium experiment on the large helical device. AB - An infrared imaging video bolometer was improved for application to a neutron environment in fusion plasma devices, i.e., the Large Helical Device (LHD). In order to calibrate the thermal characteristics of the activated foil absorber inside the plasma vacuum vessel, the remote-controlled in situ calibration system was improved with high-surface-flatness mirrors. Furthermore, the carbon coating method was improved by introducing a vacuum evaporation technique instead of the conventional spray technique to realize the coating on both sides of the absorber with reproducibility and uniformity. The optimal thickness of the coating was also determined. Owing to these coating improvements, the reproducibility of the effective emissivity on both sides especially was improved. Finally, the variation with the neutron irradiation of the thermal characteristics of the foil absorber was investigated. It was found that the effect was not significant for the total neutron emission of 3.6 * 1018 on LHD. PMID- 30399916 TI - Radially scanning magnetic probes to study local helicity injection dynamics. AB - Two new magnetic probes have been deployed on the Pegasus spherical tokamak to study the dynamics of local helicity injection non-solenoidal plasma start-up and current drive. The magnetic radial array probe consists of 15 pickup coils (~5 * 8 mm each) that measure Bz(R) over a 15 cm linear extent. The coils consist of traces embedded in a printed circuit board. Three coil designs are utilized to balance frequency response and coil sensitivity. Helmholtz coil measurements are used to measure coil and full assembly bandwidths (~2 MHz and ~200 kHz, respectively) and sensitivities (0.18/0.35/0.96 mV T-1 s). The magnetic radial scanning probe is an array of Hall effect sensors that measure field strength ( |B| <= 177 mT) and direction at 8 spatial points (DeltaR = 1.5 cm), supporting the studies of equilibrium field structure and low-frequency (<=5 kHz) current dynamics. It uses commercial surface-mount Hall effect sensors with chip integrated amplifiers and compensators that are mounted in a 3-D printed frame. Helmholtz coil measurements indicate negligible cross-field gain nonlinearity and provide absolute calibration of the diagnostic. Both probes are constructed as an electrostatically shielded insertable air-side assembly that mounts within a radially translatable ultrahigh vacuum assembly from an existing probe. PMID- 30399917 TI - A multiplexer-based multi-channel microwave Doppler backward scattering reflectometer on the HL-2A tokamak. AB - The Doppler backward scattering (DBS) reflectometer has become a well-established and versatile diagnostic technique for the measurement of density fluctuations and flows in magnetically confined fusion experiments. In this work, a novel multiple fixed-frequency array source with a multiplexer technique is developed and applied in the multi-channel DBS system. The details of the system design and laboratory tests are presented. Preliminary results of Doppler shift frequency spectra measured by the multi-channel DBS reflectometer systems are obtained. Characteristics of plasma rotation and turbulence before and after supersonic molecular beam injection are analyzed. PMID- 30399918 TI - Radiation diagnostics for plasma current ramp-up and ramp-down research. AB - The plasma current ramp-up and ramp-down are the basic processes in the tokamak operation. In order to research these processes in SUNIST (Sino-UNIted Spherical Tokamak), some diagnostic systems that detect the plasma radiation ranging from hard X-rays to visible light are developed. CdZnTe and silicon drift detectors measure the energy spectrum of hard X-rays and soft X-rays coming from the plasma. A pinhole camera equipped with absolute extended ultraviolet array photodiodes has been installed on the top of SUNIST to observe the radiation power loss and the magneto-hydrodynamic activities with high temporal and spatial resolution. The spectrum of vacuum ultraviolet is acquired by using a CCD camera, and the intensity of the lines can be measured by using a photomultiplier tube with a scintillator. The full spectrum of the visible light can be acquired in every 3 ms, and the intensity of some lines, such as Halpha, Hgamma, can be measured by filter scopes with high time response. Additionally, a Doppler broadening measurement system is developed to measure the ion temperature of edge plasma. PMID- 30399919 TI - Transverse resonance island buckets for synchrotron-radiation based electron time of-flight spectroscopy. AB - At the Metrology Light Source (MLS), the compact electron storage ring of the Physikalisch-Technische Bundesanstalt (PTB) with a circumference of 48 m, a specific operation mode with two stable closed orbits for stored electrons was realized by transverse resonance island buckets. One of these orbits is closing only after three turns. In combination with single-bunch operation, the new mode was applied for electron time-of-flight spectroscopy with an interval of the synchrotron radiation pulses which is three times the revolution period at the MLS of 160 ns. The achievement is of significant importance for PTB's future programs of angular-resolved electron spectroscopy with synchrotron radiation and similar projects at other compact electron storage rings. The scheme applied here for selecting the photons originating from a particular orbit by optical imaging has been used before in fs slicing applications and may be relevant for the BESSY VSR project of the Helmholtz-Zentrum Berlin. PMID- 30399920 TI - Phase modulation failsafe system for multi-kJ lasers based on optical heterodyne detection. AB - Amplification of the transverse scattered component of stimulated Brillouin scattering (SBS) can contribute to optical damage in the large aperture optics of multi-kJ lasers. Because increased laser bandwidth from optical phase modulation (PM) can suppress SBS, high energy laser amplifiers are injected with PM light. Phase modulation distributes the single-frequency spectrum of a master oscillator laser among individual PM sidebands, so a sufficiently high modulation index beta can maintain the fluence for all spectral components below the SBS threshold. To avoid injection of single frequency light in the event of a PM failure, a high speed PM failsafe system (PMFS) must be employed. Because PM is easily converted to AM, essentially all PM failsafes detect AM, with the one described here employing a novel configuration where optical heterodyne detection converts PM to AM, followed by passive AM power detection. Although the PMFS is currently configured for continuous monitoring, it can also detect PM for pulse durations >=2 ns and could be modified to accommodate shorter pulses. This PMFS was deployed on the Z-Beamlet Laser (ZBL) at Sandia National Laboratories, as required by an energy upgrade to support programs at Sandia's Z Facility such as magnetized liner inertial fusion. Depending on the origin of a PM failure, the PMFS responds in as little as 7 ns. In the event of an instantaneous failure during initiation of a laser shot, this response time translates to a 30-50 ns margin of safety by blocking a pulse from leaving ZBL's regenerative amplifier, which prevents injection of single frequency light into the main amplification chain. The performance of the PMFS, without the need for operator interaction, conforms to the principles of engineered safety. PMID- 30399921 TI - Contributed Review: Instruments for measuring Seebeck coefficient of thin film thermoelectric materials: A mini-review. AB - Thin film thermoelectric materials (TF TEMs) based on organic semiconductors or organic/inorganic composites exhibit unique properties such as low-temperature processability, mechanical flexibility, great freedom of material design, etc. Thus they have attracted a growing research interest. Similar to inorganic bulk thermoelectric materials (IB TEMs), the Seebeck coefficient combined with electrical conductivity and thermal conductivity is a fundamental property to influence the performance of TF TEMs. However, due to the differences in material and sample geometries, the well-established characterization devices for IB TEMs are no longer applicable to TF TEMs. And until now, a universal standard of measuring the Seebeck coefficient of TF TEMs is still lacking. This mini-review presents the development of instruments designed for measuring the Seebeck coefficient of TF TEMs in the last decade. Primary measurement methods and typical apparatus designs will be reviewed, followed by an error analysis induced by instrumentation. Hopefully this mini-review will facilitate better designs for a more accurate characterization of the Seebeck coefficient of thin film thermoelectric materials. PMID- 30399922 TI - Fast ion D-alpha measurements using a bandpass-filtered system on EAST. AB - Based on the charge exchange reaction between fast ions and a neutral beam, fast ion features can be inferred from the spectrum of Doppler-shifted Balmer-alpha light from energetic hydrogenic atoms. In order to study the interaction between instabilities and fast-ion transport, recently we extended the fast ion D-alpha (FIDA) measurements by using a combination of a bandpass filter and a photomultiplier tube (PMT) (f-FIDA). A bandpass filter selects the desired spectral band from 651 nm to 654 nm before detection by the PMT. Preliminary data from the EAST tokamak show that the active signals have been detected from reneutralized beam ions along the vertical and tangential viewing geometries. The details will be presented in this paper to primarily address the specifications and performance of f-FIDA hardware components and preliminary FIDA measurements. PMID- 30399923 TI - The upgraded JET gamma-ray cameras based on high resolution/high count rate compact spectrometers. AB - The JET gamma-ray cameras have been recently upgraded within the gamma-ray camera upgrade project in support of development of JET high performance deuterium plasma scenarios and in preparation of deuterium-tritium experiments. New, dedicated detectors based on a LaBr3 crystal and silicon photo-multipliers have been developed and replaced pre-existing CsI detectors in all 19 channels. The new instrument gives opportunity of making two-dimensional gamma-ray measurements with a counting rate capability exceeding 1 MCounts/s (MCps) and energy resolution better than 5% at 1.1 MeV. The upgrade is of relevance for fast ion and runaway electron physics studies in high performance deuterium discharges and also in plasmas with tritium at neutron yields in the range up to about 5 * 1017 n/s. PMID- 30399924 TI - Measurement of apparent ion temperature using the magnetic recoil spectrometer at the OMEGA laser facility. AB - The Magnetic Recoil neutron Spectrometer (MRS) at the OMEGA laser facility has been routinely used to measure deuterium-tritium (DT) yield and areal density in cryogenically layered implosions since 2008. Recently, operation of the OMEGA MRS in higher-resolution mode with a new smaller, thinner (4 cm2, 57 MUm thick) CD2 conversion foil has also enabled inference of the apparent DT ion temperature (T ion) from MRS data. MRS-inferred T ion compares well with T ion as measured using neutron time-of-flight spectrometers, which is important as it demonstrates good understanding of the very different systematics associated with the two independent measurements. The MRS resolution in this configuration, DeltaE MRS = 0.91 MeV FWHM, is still higher than that required for a high-precision T ion measurement. We show how fielding a smaller foil closer to the target chamber center and redesigning the MRS detector array could bring the resolution to DeltaE MRS = 0.45 MeV, reducing the systematic T ion uncertainty by more than a factor of 4. PMID- 30399925 TI - Development of thermal image plate using ceramic luminescence materials for aligning and stabilizing beam axis of CO2 laser. AB - A thermal image plate (TIP) using ceramic luminescence materials has been developed in order to visualize a beam spot of a CO2 laser which is used as a light source of an interferometer developed in JT-60SA. By using CaAlSiN3:Eu2+ (CASN), the TIP was developed, and its property was assessed. A CASN TIP was able to visualize the invisible CO2 laser beam as a negative image. The beam diameter and the stability of the beam axis measurement obtained with the CASN TIP were approximately the same as that obtained with a commercial TIP. Furthermore, the time response of the CASN TIP at the best was approximately the same as that of the commercial TIP. The CASN TIP which had the highest time response was applied to the beam axis stabilizer, and then the beam axis stabilization was successfully performed in 2 h. PMID- 30399926 TI - Characterization of the lossy dielectric materials using contour mapping. AB - The imaginary part of the complex permittivity of a lossy dielectric material is large and couples with its real part. The resonant frequency of a cavity with the sample depends not only on the real part of the complex permittivity of the sample but also the imaginary part, resulting in serious ambiguity in determining the sample's complex permittivity. This work proposes a contour mapping method to determine the complex permittivity. The full-wave simulation gives us the contours of the resonant frequency and the quality factor, which are functions of the relative dielectric constant and the loss tangent. By mapping the measured resonant frequency and the measured quality factor, one can uniquely determine the complex permittivity of the sample. Five liquids were examined, including three low-loss materials for benchmarking and two lossy materials. The measured complex permittivities of the three low-loss materials agree very well with the other methods. As for the lossy materials, the measured relative dielectric constant and the loss tangent of alcohol are 6.786 and 0.895, respectively. Besides, the measured dielectric constant of glycerin is 6.811, and its loss tangent is 0.562. The proposed contour mapping technique can be employed to measure the complex permittivity of liquids and solids from lossless to lossy materials. PMID- 30399927 TI - Integrated plasma facing component calorimetry for measurement of shot integrated deposited energy in the NSTX-U. AB - The upgrade to the National Spherical Torus eXperiment (NSTX-U) [J. Menard et al., Nucl. Fusion 52, 083015 (2012)] increases the injected neutral beam power up to 12 MW and the plasma current up to Ip = 2 MA for plasma durations up to 5 s. The graphite plasma facing components have been re-designed to handle greater heat and energy fluxes than were seen in NSTX using a castellated design. We present the experimental testing and validation of a castellated graphite target, similar to the prototype tile design, instrumented with thermocouples at various depths in the castellation. During testing, incident heat flux is provided by a programmed electron beam system and surface temperatures are measured via infrared thermography directly viewing the target surface. It was found that the thermocouple response scaled linearly with the measured surface temperature rise regardless of thermocouple depth in the castellation. A sensitivity of 14.3 degrees C/kJ of deposited energy was found when treating individual castellations as a semi-infinite solid. PMID- 30399928 TI - Simultaneous measurements of turbulent Reynolds stresses and particle flux in both parallel and perpendicular directions in a linear magnetized plasma device. AB - We report temporally resolved simultaneous measurements of the turbulent Reynolds stresses in both the parallel and perpendicular directions and the corresponding particle fluxes in the fusion relevant cylindrical magnetized plasma device Controlled Shear Decorrelation eXperiment (CSDX). CSDX simulates the plasma conditions of multiple plasma instabilities that can arise in the scrape-off layer of fusion devices. In this study, we designed and used a 6-tip Langmuir probe in a novel yet simple design to simultaneously measure all the three dimensional components (radial, azimuthal, and axial) of fluctuations in velocity from the floating potentials and plasma densities with high temporal resolution. From these, we calculated the parallel and perpendicular Reynolds stress and the particle fluxes in addition to the density and potential spectra and the cross phase between different quantities. We can obtain radial profiles of all the aforementioned plasma quantities, which are extremely useful for studying plasma turbulence due to multiple instabilities. We have also cross-checked the time averaged velocity profiles from the probe with laser induced fluorescence measurements of the mean plasma velocity for some common plasma source parameters. PMID- 30399929 TI - Design of a shattered pellet injection system on J-TEXT tokamak. AB - Disruptions have the possibility of causing severe wall damage to large tokamaks like ITER. The mitigation of disruption damage is essential to the safe operation of a large-scale tokamak. The shattered pellet injection (SPI) technique, which is regarded as the primary injection method for ITER, presents several advantages relative to massive gas injection, including more rapid particle delivery, higher total particle assimilation, and more centrally peaked particle deposition. A dedicated argon SPI system that focuses on disruption mitigation and runaway current dissipation has been designed for the Joint Texas Experimental Tokamak (J TEXT). A refrigerator is used to form a single argon pellet at around 64 K. The pellet will be shaped with a 5 mm diameter and a 1.5-10 mm length. Helium gas at room temperature will be used as a propellant gas for pellet acceleration. The pellet can be injected with a speed of 150-300 m/s. The time interval between injection cycles is about 8 min. The pellet will be shattered at the edge of the plasma and then injected into the core of plasma. The first experiments of SPI fast shutdown and runaway current dissipation have been performed. PMID- 30399930 TI - Experimental tests of an infrared video bolometer on Alcator C-Mod. AB - A prototype of an infrared imaging bolometer (IRVB) was successfully tested on the Alcator C-Mod tokamak at the end of its 2016 campaign. The IRVB method interprets the power radiated from the plasma by measuring the temperature rise of a thin, ~2 MUm, Pt absorber that is placed in the torus vacuum and exposed, using a pinhole camera, to the full-spectrum of plasma's photon emission. The IRVB installed on C-Mod viewed the poloidal cross section of the core plasma and observed Ohmic and ion cyclotron range of frequency (ICRF)-heated plasmas. Analysis of total radiated power and on-axis emissivity from IRVB is summarized, and quantitative comparisons made to data from both resistive bolometers and AXUV diodes. IRVB results are clearly within a factor of two, but additional effort is needed for it to be used to fully support power exhaust research. The IRVB is shown to be immune to electromagnetic interference from ICRF which strongly impacts C-Mod's resistive bolometers. Results of the bench-top calibration are summarized, including a novel temperature calibration method useful for IRVBs. PMID- 30399931 TI - In situ wavelength calibration system for the X-ray Imaging Crystal Spectrometer (XICS) on W7-X. AB - An in situ wavelength calibration system for the X-ray Imaging Crystal Spectrometer (XICS) on W7-X has been developed to provide routine calibration between plasma shots. XICS is able to determine plasma flow profiles by measuring the Doppler shift of x-ray line emission from highly charged impurity species. A novel design is described that uses an x-ray tube with a cadmium anode placed in front of the diffracting spherically bent crystal. This arrangement provides calibration lines over the full detector extent for both the Ar16+ and Ar17+/Fe24+ spectrometer channels. This calibration system can provide a relative wavelength accuracy of 3 * 10-7 A across the full spatial extent of the detector, which corresponds to 50 m/s in the W7-X system. An absolute wavelength calibration of 1 * 10-5 A is expected, corresponding to 1 km/s, based on the current known accuracy of the calibration wavelength and the achievable measurement of the absolute positioning of the hardware. This calibration system can be used to independently calibrate XICS systems on both stellarators and tokamaks, without the need for special plasma conditions often used for calibration, such as locked modes on tokamaks. Experimental and simulated results are shown along with expected results, and the complete design of the calibration hardware that is to be installed in the W7-X XICS system. PMID- 30399932 TI - Phased array Doppler reflectometry at Wendelstein 7-X. AB - A passive phased array Doppler reflectometry system has recently been installed in the Wendelstein-7X stellarator. In contrast to conventional Doppler reflectometry systems, the microwave beam can be steered on short time scales in the measurement plane perpendicular to the magnetic field in the range of +/-25 degrees without mechanical steering components. This paper characterizes the design and properties of the phased array antenna system and presents the first measurement results from the latest OP1.2a campaign. PMID- 30399933 TI - Realization of an ultra-high precision temperature control in a cryogen-free cryostat. AB - Single-pressure refractive-index gas thermometry (SPRIGT) is a new type primary thermometry jointly developed by TIPC of CAS in China and LNE-Cnam in France. To realize a competitive uncertainty of 0.25 mK for the thermodynamic temperature measurement, a cryogen-free cryostat with high-stability better than 0.2 mK should be designed. This paper presented the first experimental results of temperature control for this cryostat. To realize this objective, multi-layer radiation shields combined with a thermal-resistance method were used to isolate the thermal-noise from surroundings. Besides, a new temperature control method based on a gas-type heat switch and proportional-integral-derivative control method was proposed, which was applicable to different temperature ranges by changing the working modes of the heat switch. After optimizing, the ultra-high precision temperature control in the range of 5-25 K has been fully realized, which was the temperature instability (with standard deviation) of 0.021 mK at 5.0 K, 0.05 mK at 5.7 K, 0.042 mK at 7.4 K, 0.029 mK at 14.3 K, and 0.022 mK at 25 K with the sampling time of 0.8 s. This was almost the best reporting result in the world and showed its great potential in SPRIGT. PMID- 30399935 TI - Effect of multi-ion-source injection on motional Stark effect diagnostic. AB - Many tokamak devices utilize high-power neutral beams for various beam-based active spectroscopic diagnostics such as the motional Stark effect (MSE). For higher heating performance, it is customary for the neutral beam injection to be made with a multiple number of ion sources, which often makes unfavorable conditions for the active spectroscopic diagnostics. This is mainly because the atomic and molecular emissions taking place from the interactions with multiple beams, or from different flux surfaces, are collected through the front optics at the same time, resulting in systematic errors in the measured quantities. In this work, the effect of the multiple ion source injections on the pitch angle measurements by the MSE diagnostic is quantitatively studied based on both numerical modeling and measurements made from the plasma discharges for the Korea Superconducting Tokamak Advanced Research. The sensitivity of the pitch angle against various combinations of the acceleration voltages of the ion sources is evaluated, yielding the optimum configuration of the beam injection that can maximize the heating efficiency with an acceptable level of the systematic offset in the MSE measurements. PMID- 30399934 TI - Single-shot frequency-resolved optical gating for retrieving the pulse shape of high energy picosecond pulses. AB - Accurate characterization of laser pulses used in experiments is a crucial step to the analysis of their results. In this paper, a novel single-shot frequency resolved optical gating (FROG) device is described, one that incorporates a dispersive element which allows it to fully characterize pulses up to 25 ps in duration with a 65 fs per pixel temporal resolution. A newly developed phase retrieval routine based on memetic algorithms is implemented and shown to circumvent the stagnation problem that often occurs with traditional FROG analysis programs when they encounter a local minimum. PMID- 30399936 TI - Tests of a full-scale ITER toroidal interferometer and polarimeter (TIP) prototype on the DIII-D tokamak (invited). AB - A full-scale ITER toroidal interferometer and polarimeter (TIP) prototype, including an active feedback alignment system, has been installed and tested on the DIII-D tokamak. In the TIP prototype, a two-color interferometry measurement of line-integrated density is carried out at 10.59 MUm and 5.22 MUm using a CO2 and quantum cascade laser, respectively, while a separate polarimetry measurement of the plasma-induced Faraday effect is made at 10.59 MUm. The TIP prototype is equipped with a piezo tip/tilt stage active feedback alignment system that minimizes noise in the measurement and keeps the diagnostic aligned throughout DIII-D discharges. The measured phase resolution for the polarimeter and interferometer is 0.05 degrees (100 Hz bandwidth) and 1.9 degrees (1 kHz bandwidth), respectively. The corresponding line-integrated density resolution for the vibration-compensated interferometer is deltanL = 1.5 * 1018 m-2, and the magnetic field-weighted line-integrated density from the polarimeter is deltanBL = 1.5 * 1019 Tm-2. Both interferometer and polarimeter measurements during DIII-D discharges compare well with the expectations based on calculations using Thomson scattering measured density profiles and magnetic equilibrium reconstructions. Additionally, larger bandwidth interferometer measurements show that the diagnostic is a sensitive monitor of core density fluctuations with demonstrated measurements of Alfven eigenmodes and tearing modes. PMID- 30399937 TI - Theory of a cylindrical Langmuir probe parallel to the magnetic field and its calibration with interferometry. AB - A theory for data interpretation is presented for a cylindrical Langmuir probe in plasma parallel to the magnetic field direction. The theory is tested in a linear low-temperature plasma device Aline, in a capacitive radio-frequency (RF) discharge. The probe is placed on a 3D manipulator, and a position scan is performed. To exclude strong RF perturbations, the probe is RF compensated. Using the theory, electron densities are obtained from the current at the plasma potential, where no sheath is present. Results are calibrated by line-integrated density measurements of a 26.5 GHz microwave interferometer. Reasonable agreement is observed for probe and interferometer measurements. Furthermore, preceding, more general probe theory is compared to the one developed in the current work and the application limits are discussed. PMID- 30399938 TI - A platform for x-ray Thomson scattering measurements of radiation hydrodynamics experiments on the NIF. AB - We present an experimental design for a radiation hydrodynamics experiment at the National Ignition Facility that measures the electron temperature of a shocked region using the x-ray Thomson scattering technique. Previous National Ignition Facility experiments indicate a reduction in Rayleigh-Taylor instability growth due to high energy fluxes, compared to the shocked energy flux, from radiation and electron heat conduction. In order to better quantify the effects of these energy fluxes, we modified the previous experiment to allow for non-collective x ray Thomson scattering to measure the electron temperature. Photometric calculations combined with synthetic scattering spectra demonstrate an estimated noise. PMID- 30399939 TI - A combined millimeter wave and CO2 interferometer on the C-2W Jet plasma. AB - A two wavelength tangentially viewing multi-chord interferometer has been built for the Jet plasma of the C-2W experiment at TAE Technologies. A novel 1 mm wavelength interferometer has been developed to be used simultaneously with a CO2 laser interferometer to provide full coverage of the Jet plasma and the translating field-reversed configuration (FRC) plasma before merging. With CO2 and millimeter wave sources, the interferometer proposes to cover a combined dynamic range of line integrated density of more than 1000 although the CO2 interferometer sub-system is not yet operational. Sited at the axial location of the mirror field of C-2W, the interferometer will play a pivotal role in assessing the FRC before merging and the operation of the inner and outer divertors and particle outflow. The performance of the millimeter wave interferometer and recent measurements is discussed. PMID- 30399940 TI - Simultaneous measurement of C VI, Ne X, and Li III charge exchange lines on EAST. AB - The core toroidal charge exchange recombination spectroscopy system on experimental advanced superconducting tokamak (EAST) has been enhanced recently to extend the spectral range. The C VI charge exchange line at 529.059 nm, Ne X line at 524.897 nm, and Li III line at 516.67 nm are observed successfully. The measurements were performed by injecting neon gas and dropping lithium powder simultaneously during the 2016 EAST experimental campaign. One channel connected to a neon lamp is used to perform the real-time wavelength calibration on a shot to-shot basis. The preliminary results indicate that ion temperature profiles from the carbon and neon impurities are in excellent agreement and provide a consistency check of the measurement from different impurities. Toroidal velocity correction associated with the energy-dependent cross section has been performed. Toroidal rotation of neon impurity is obviously faster than C VI across the whole profile. A cumulative and saturated effect of core lithium ions was observed. PMID- 30399941 TI - Utilization of outer-midplane collector probes with isotopically enriched tungsten tracer particles for impurity transport studies in the scrape-off layer of DIII-D (invited). AB - Triplet sets of replaceable graphite rod collector probes (CPs), each with collection surfaces on opposing faces and oriented normal to the magnetic field, were inserted at the outboard mid-plane of DIII-D to study divertor tungsten (W) transport in the Scrape-Off Layer (SOL). Each CP collects particles along field lines with different parallel sampling lengths (determined by the rod diameters and SOL transport) giving radial profiles from the main wall inward to R-R sep ~ 6 cm. The CPs were deployed in a first-of-a-kind experiment using two toroidal rings of distinguishable isotopically enriched, W-coated divertor tiles installed at 2 poloidal locations in the divertor. Post-mortem Rutherford backscatter spectrometry of the surface of the CPs provided areal density profiles of elemental W coverage. Higher W content was measured on the probe side facing along the field lines toward the inner target indicating higher concentration of W in the plasma upstream of the CP, even though the W-coated rings were in the outer target region of the divertor. Inductively coupled plasma mass spectroscopy validates the isotopic tracer technique through analysis of CPs exposed during L mode discharges with the outer strike point on the isotopically enriched W coated tile ring. The contribution from each divertor ring of W to the deposition profiles found on the mid-plane collector probes was able to be de-convoluted using a stable isotope mixing model. The results provided quantitative information on the W source and transport from specific poloidal locations within the lower divertor region. PMID- 30399943 TI - Dual-pass upgrade to the Thomson scattering diagnostic on the Prototype-Material Plasma Exposure eXperiment (Proto-MPEX). AB - The Thomson scattering (TS) diagnostic on the Prototype-Material Plasma Exposure eXperiment has been upgraded to measure electron temperature (T e ) and density (n e ) simultaneously at two axial locations. After the first pass through the vacuum vessel, the exiting laser beamline is re-collimated in the atmosphere and rerouted into the vacuum vessel for the second pass. The upgrade will help diagnose axial T e and n e gradients between the "central chamber" and the target region which are located 1 m and 2.5 m, respectively, downstream from the Helicon radio-frequency source. The TS measurements have given T e ~ 4-15 eV and n e ~ 2 4 * 1019 m-3 at the central chamber and T e ~ 1-2 eV and n e ~ 1-2 * 1019 m-3 at the target region. The upgrade also increases the number of sampling points at the target region from 3 fibers to 5 fibers, measuring 3 cm radially across the plasma column, and 25 fibers in the central chamber, radially spanning 8 cm. The intensified CCD camera is double triggered for each laser pulse in order to measure (1) the TS and laser stray light and (2) the plasma background light that contains nuisance emission lines and bremsstrahlung. Subtracting the background light from the TS photons improves the temperature and density measurements. Details of the diagnostic setup, axial and radial measurements, and areas for further optimization are discussed. PMID- 30399942 TI - Setup for meV-resolution inelastic X-ray scattering measurements and X-ray diffraction at the Matter in Extreme Conditions endstation at the Linac Coherent Light Source. AB - We describe a setup for performing inelastic X-ray scattering and X-ray diffraction measurements at the Matter in Extreme Conditions (MEC) endstation of the Linac Coherent Light Source. This technique is capable of performing high-, meV-resolution measurements of dynamic ion features in both crystalline and non crystalline materials. A four-bounce silicon (533) monochromator was used in conjunction with three silicon (533) diced crystal analyzers to provide an energy resolution of ~50 meV over a range of ~500 meV in single shot measurements. In addition to the instrument resolution function, we demonstrate the measurement of longitudinal acoustic phonon modes in polycrystalline diamond. Furthermore, this setup may be combined with the high intensity laser drivers available at MEC to create warm dense matter and subsequently measure ion acoustic modes. PMID- 30399944 TI - High magnetic field test of the ITER outer vessel steady-state magnetic field Hall sensors at ITER relevant temperature. AB - The ITER outer vessel steady-state magnetic field sensor diagnostics consist of sixty sensor units. Each sensor unit features a pair of ceramic-metal Hall sensors with a sensing layer made of bismuth. The sensors were tested simultaneously in the magnetic field ranging from -12 T to +12 T at the temperature range from 27 to 127 degrees C. The Hall coefficient and magnetoresistance of the bismuth layer related to the sensors were identified. In the sensor operating conditions, the Hall coefficient dependence on temperature was fitted with an exponential function with a relative error of less than 0.08%, and the dependence on the magnetic field was fitted with a Gaussian-like function with a relative error of less than 0.11%. An alternative expression based on the physical understanding of the free charge carrier transport in semimetals was derived to describe the dependence of the Hall coefficient on the magnetic field, and its fitting error of 1.2 mT in terms of the magnetic field measurement has met the ITER measurement accuracy requirements. PMID- 30399945 TI - The surface eroding thermocouple for fast heat flux measurement in DIII-D. AB - A novel type of surface eroding thermocouple (SETC) has been tested and demonstrated in the small angle slot (SAS) divertor of DIII-D for fast local heat flux measurements. The thermojunction of the SETC is formed between two thin (10 MUm) ribbons, which are filed over to create microfiber junctions. These thermocouples are able to be exposed directly to the plasma at surface temperatures exceeding 2000 degrees C and are capable of sub-10 ms time resolution. Before installation in SAS, the SETCs were exposed in the lower DIII D divertor during L-mode and H-mode discharges, from which results are presented. In preliminary tests, SETCs proved to be a qualified diagnostic to accurately measure both the intra-edge localized mode (ELM) and inter-ELM heat flux during H mode shots with high frequency ELMs (hundreds of Hz) and to resolve heat flux profiles during strike point sweeps. The heat fluxes measured by using SETCs are consistent with the heat fluxes measured by using IR cameras and Langmuir probes. These new diagnostic capabilities will complement the existing IR camera measurements and will be of particularly significant value to measure surface heat flux in the SAS divertor or other regions where the IR camera lacks line of sight. PMID- 30399946 TI - Time-tagged coincidence counting unit for large-scale photonic quantum computing. AB - Real-time analysis of single-photon coincidence is critical in photonic quantum computing. The large channel number and high counting rate foreseen in such experiments pose a big challenge for the conventional time tagged method and coincidence instruments. Here we propose a real-time time-tagged coincidence method and a data filtering solution, demonstrated by a 32-channel coincidence counting unit that has been implemented successfully on a field-programmable gate array system. The unit provides high counting rates, a tunable coincidence window, and a timing resolution of 390 ps. Beyond that, it is feasible to be scaled up to 104 channels and is thus ideally suited for channel consuming applications such as boson sampling. Based on the versatility and scalability the unit has shown, we believe that it is the turn-key solution for many single photon coincidence counting applications in photonic quantum computing. PMID- 30399947 TI - Application of portable near-infrared spectrometer to Heliotron J plasma diagnostics. AB - A simple near-infrared (NIR) spectrometer with a wavelength range of 898-2130 nm has recently been applied to diagnose Heliotron J plasmas. It adopts a symmetrical crossed Czerny-Turner mount equipped with a thermoelectrically cooled 512 channel InGaAs linear sensor. Reciprocal linear dispersion was deduced to 96.37 nm/mm at the center of the detector. External filters can be inserted into the path of the collection optics to reject second-order spectra, as needed. Absolute intensity calibration was performed together with a visible spectrometer using a tungsten halogen lamp, and the effect of the transmittance fringe in the visible region of the applied long-pass filter on the NIR calibration was investigated. The intended application of the NIR spectrometer includes extending the wavelength region of a spectral monitor to less contaminated regions for Heliotron J plasma studies. In preliminary measurements, we observed the Paschen series for the hydrogen pellet injection plasma and two atomic helium lines, i.e., 2S-2P singlet and triplet lines, in helium gas puffing experiments. A continuum spectrum in this regime that is attributable to black-body radiation from hot spots on the plasma-facing components was identified. In addition, this may also be used to monitor background radiation in the YAG-Thomson scattering signals near 1064 nm. PMID- 30399948 TI - Millimeter-wave interferometry and far-forward scattering for density fluctuation measurements on LTX-beta. AB - The lambda ~ 1 mm (f = 288 GHz) interferometer for the Lithium Tokamak Experiment beta (LTX-beta) will use a chirped-frequency source and a centerstack-mounted retro-reflector mirror to provide electron line density measurements along a single radial chord at the midplane. The interferometer is unique in the use of a single source (narrow-band chirped-frequency interferometry) and a single beam splitter for separating and recombining the probe and reference beams. The current work provides a documentation of the interferometry hardware and evaluates the capabilities of the system as a far-forward collective scattering diagnostic. As such, the current optical setup is estimated to have a detection range of 0.4 ? k ? ? 1.7 cm-1, while an improved layout will extend the upper k ? limit to ~3 cm-1. Measurements with the diagnostic on LTX are presented, showing interferometry results and scattered signal data. These diagnostics are expected to provide routine measurements on LTX-beta for high frequency coherent density oscillations (e.g., Alfvenic modes during neutral beam injection) as well as for broadband turbulence. PMID- 30399949 TI - A divertor scraper observation system for the Wendelstein 7-X stellarator. AB - Two graphite divertor elements called scrapers have been installed on the Wendelstein 7-X stellarator in the throat of the magnetic island divertor. To diagnose one, we have designed, built, calibrated, and installed a new infrared/visible imaging endoscope system to enable detailed observations of the plasma interactions and heat loads at one of the scrapers and the nearby divertor surfaces. The new system uses a shuttered pinhole-protected pair of 90 degrees off-axis 228 mm focal length aluminum parabolic mirrors, and two flat turning metal mirrors, to send light to a sapphire vacuum window 1.6 meters away, beyond which we have co-located telephoto lens-based infrared and visible cameras. The back-to-back off-axis parabolas serve to cancel out most aberrations, enabling the use of off-the-shelf commercial optics outside of the vessel. For the infrared, we use a 3-5 MUm 1-megapixel FLIR SC8303HD camera and for the visible, a 5-megapixel CMOS PCO 5.5 edge camera. A short 1-m quartz pickoff fiber is used to send 200-1100 nm light to a compact spectrometer, also located in the same iron shield box as the cameras. The camera field of view covers the 700 mm length of the scraper, and includes locations monitored by thermocouples and Langmuir probes embedded in some of the scraper tiles. Predicted and actual optical test performances of the overall system are compared. PMID- 30399950 TI - Fast-ion D-alpha diagnostic development for the C-2W field-reversed configuration plasma. AB - TAE Technologies's advanced beam-driven field-reversed configuration device has a large fast-ion population, allowing for fast-ion D-alpha (FIDA) studies. Development of a FIDA spectrometer for the new C-2W device is underway. Previous measurements were combined with C-2W geometry to inform the design [N. Bolte, Rev. Sci. Instrum. 87, 11E520 (2016)]. Measured signal levels led to the purchase of a Phantom Miro 110 high-speed camera that will be paired with a Holospec f/1.8 spectrograph from Kaiser Optical Systems, Inc. The spectrograph utilizes a custom transmission grating centered at 656.0 nm. Simulations were used to choose available ports with large predicted signals. Eight neutral beams and 354 ports were considered. Experimentally obtained 1D plasma profiles from C-2U were mapped onto Q2D [M. Onofri, Phys. Plasmas 24, 092518 (2017)] simulation flux surfaces. For each point on the vessel wall, many lines-of-sight (LOSs) are created to view the entirety of each neutral beam path. FIDA spectra are simulated for each LOS using the FIDA simulation code FIDASIM [http://d3denergetic.github.io/FIDASIM/; W. Heidbrink, Commun. Comput. Phys. 10, 716 (2011); and B. Geiger, "Fast-ion transport studies using FIDA spectroscopy at the ASDEX Upgrade tokamak," Ph.D. thesis, Ludwig Maximilian University of Munich, 2012]. Integrating over wavelength and beam-space allows individual ports to be chosen for their large prospective signals. PMID- 30399951 TI - Non-inductive vertical position measurements by Faraday-effect polarimetry on EAST tokamak. AB - Vertical instability control in an elongated plasma is highly desirable for a tokamak reactor. A multi-channel 694 GHz far-infrared laser-based polarimeter interferometer system has been used to provide a non-inductive vertical position measurement in the long-pulse EAST tokamak. A detailed comparison of vertical position measurements by polarimetry and external inductive flux loops has been used to validate Faraday-effect polarimetry as an accurate high-time response vertical position sensor. PMID- 30399952 TI - In situ relative self-dependent calibration of electron cyclotron emission imaging via shape matching. AB - Electron Cyclotron Emission Imaging (ECEI) is a diagnostic system which measures 2-D electron temperature profiles with high spatial-temporal resolution. Usually only the normalized electron temperature fluctuations are utilized to investigate the magnetohydrodynamics modes due to the difficulties of ECEI calibration. In this paper, we developed a self-dependent calibration method for 24 * 16 channel high-resolution ECEI on the Experimental Advanced Superconducting Tokamak. The technique of shape matching is applied to solve for the matrix of the calibration coefficients. The calibrated area is further expanded to an occupation ratio of 88% observation area by utilizing the features of sawtooth crash. The result is self-consistent and consistent with calibrated 1D ECE measurement. PMID- 30399953 TI - Helium line ratio spectroscopy for high spatiotemporal resolution plasma edge profile measurements at ASDEX Upgrade (invited). AB - The thermal helium beam edge diagnostic has recently been upgraded at the ASDEX Upgrade (AUG) tokamak experiment. Line ratio spectroscopy on neutral helium is a valuable tool for simultaneous determination of the electron temperature and density of plasmas. The diagnostic now offers a temporal resolution of 900 kHz with a spatial resolution of up to 3 mm at 32 lines of sight (LOS) simultaneously. The LOS covers a radial region of 8.5 cm, starting at the limiter radius and reaching into the confined region beyond the separatrix. Two components are of particular importance for the aforementioned hardware improvements. The first is the optical head, which collects the light from the experiment. Equipped with an innovative clamping system for optical fiber ends, an arbitrary distribution pattern of LOS can be achieved to gain radial and poloidal profiles. The second major development is a new polychromator system that measures the intensity of the 587 nm, 667 nm, 706 nm, and 728 nm helium lines simultaneously for 32 channels with filter-photomultiplier tube arrays. Thus, the thermal helium beam diagnostic supplements the AUG edge diagnostics, offering fast and spatially highly resolved electron temperature and density profile measurements that cover the plasma edge and scrape-off layer region. Plasma fluctuations, edge localized modes, filaments, and other turbulent structures are resolved, allowing analysis of their frequency and localization or their propagation velocity. PMID- 30399954 TI - Cherenkov detector analysis for implosions with multiple nuclear reactions. AB - Nuclear reactions that produce gamma rays occur in inertial fusion implosions and are commonly measured with Cherenkov detectors. Typically a detector is primarily sensitive to a single reaction, but in some implosions, multiple fusion reactions can occur and are combined in the data. We discuss an analysis technique using multiple thresholded detectors to reproduce the individual burn histories from reactions like DT and HT fusion, which is applicable to separated-reactant mix experiments. Requirements for this technique and resulting analysis uncertainties are quantified using synthetic data. PMID- 30399955 TI - Developing a high-flux, high-energy continuum backlighter for extended x-ray absorption fine structure measurements at the National Ignition Facility. AB - Extended X-ray absorption fine structure (EXAFS) spectroscopy is a powerful tool for in situ characterization of matter in the high energy density regime. An EXAFS platform is currently being developed on the National Ignition Facility. Development of a suitable X-ray backlighter involves minimizing the temporal duration and source size while maximizing spectral smoothness and brightness. One approach involves imploding a spherical shell, which generates a high-flux X-ray flash at stagnation. We present results from a series of experiments comparing the X-ray source properties produced by imploded empty and Ar-filled capsules. PMID- 30399956 TI - Development of a multi-channel capacitive probe for electric field measurements with fine spatial and high time resolution. AB - A capacitive probe [Tan et al., Rev. Sci. Instrum. 88, 023502 (2017)] is one of a few diagnostics that is directly sensitive to the plasma potential. Using this diagnostic technique, a Multi-channel Linear Capacitive Probe (MLCP) is developed for turbulence measurements. The MLCP has 10 spatial channels and provides 9 points of radial electric field measurements simultaneously with a spatial step of 7 mm. A new readout circuit and a correction technique for low frequency attenuation are also developed to achieve the required spatial and time resolution. A performance test of the MLCP using a reversed field pinch plasma confirms that the MLCP resolves sub-centimeter structures of the equilibrium radial electric field profile and fluctuations up to 680 kHz. PMID- 30399957 TI - Measurement of water vapor diffusion in nanoscale polymer films by frequency domain probe beam deflection. AB - We developed an optical pump-probe technique, frequency-domain probe beam deflection (FD-PBD) to measure the diffusion of water vapor in nanoscale polymer films with microsecond temporal resolution and micrometer spatial resolution. We describe the quantitative model of beam deflection for multilayer structures, the experimental approach, and the application of FD-PBD to measure the diffusivity (D m) of saturated water vapor in various glassy polymer films including polyimide (PI, D m = 7.0 * 10-13 m2 s-1), poly(methyl methacrylate) (PMMA, D m = 1.2 * 10-12 m2 s-1), poly-(vinylpyrrolidone) (PVP, D m = 1.7 * 10-12 m2 s-1), and cellulose acetate (CA, D m = 2.6 * 10-11 m2 s-1), and the piperazine/trimesoyl chloride (PIP/TMC, D m = 9 * 10-11 m2 s-1) nanofiltration membrane synthesized by interfacial polymerization. The uncertainty of the measurements is typically ~8%. PMID- 30399958 TI - Investigating the relationship between noise transfer inside the x-ray framing cameras and their imaging ability. AB - We apply a cascaded linear model analysis to a micro-channel plate x-ray framing camera. We establish a theoretical expression of the Noise Power Spectrum (NPS) at the detector's output and assess its accuracy by comparing it to the NPS of Monte Carlo simulations of the detector's response to a uniform illumination. We also demonstrate that fitting the NPS of experimental data against a parametric model based on this expression can yield valuable information on the imaging ability of framing cameras, offering an alternative approach to the usual method employed to measure their modulation transfer functions. PMID- 30399959 TI - Tomographic analysis of tangential viewing cameras (invited). AB - Many tokamaks now use visible light cameras to observe plasma-wall interactions and integrated line emission. The DIII-D coherence imaging spectroscopy diagnostic cameras image interferograms that encode line integrated velocity. By modeling the 2D camera image pixels as line of sight integrals through an axisymmetric discrete grid, it is possible to do tomographic analysis to determine the local plasma line emissivity and parallel velocity. Methods to solve the inverse problem posed by these tangential viewing cameras are presented. The inversion begins with calculation of the sparse response matrix that encompasses all the geometry and diagnostic information and reduces the process of image formation to a sparse matrix-vector multiply. This work includes techniques for determining the detailed geometry of the camera views and methods for handling physical quantities that vary spatially. Additionally, the size of the response matrix has driven the development of capability to distribute the coarse parallel calculation across a heterogeneous cluster of computers on the Energy Sciences Network. Iterative techniques are then used to solve the sparse matrix-vector linear system. PMID- 30399960 TI - Electric discharge machine for preparation of diamond anvil cell sample chambers. AB - We have designed and constructed a novel electric discharge machine designed primarily for the preparation of sample chambers in rhenium and stainless steel gaskets for diamond anvil cell experiments. Our design combines automatic stage movement with relatively low voltage (100 V) operation and routinely achieves a drilling/erosion speed of approximately 0.4 MUm s-1. The machine is used for preparing 100 MUm diameter sample chambers for diamond anvil cell experiments with 250 MUm culets and has also been used to prepare 50 MUm diameter sample chambers for diamond anvil cell experiments with 100 MUm culets to access a pressure of 165 GPa. PMID- 30399961 TI - Camera array-based digital image correlation for high-resolution strain measurement. AB - Digital image correlation (DIC) is a well-known technique for non-contact, non destructive, full-field deformation measurement in experimental solid mechanics. Although DIC has been widely used in science and engineering, the resolution of strain measurement with DIC is limited by imaging resolution and is much lower than that obtained with a strain gauge. To achieve a breakthrough in strain measurement using DIC, a camera array-based DIC method is proposed herein for high-resolution strain measurement. Twenty-five industrial cameras were assembled into a plane array, with each camera capturing a part of the specimen. A novel calibration-based image stitching method is proposed and was applied to these images and their corresponding displacement fields. The strain field was then calculated based on the stitched displacement fields. The use of the camera array greatly improved the measurement spatial resolution of DIC and made high resolution strain measurement possible. Both static error analysis and four point bending experiments were performed to demonstrate the feasibility and effectiveness of the proposed method, and a full-field strain resolution of 10 MUepsilon was achieved. PMID- 30399963 TI - Erratum: "Calibration of a rotating accelerometer gravity gradiometer using centrifugal gradients" [Rev. Sci. Instrum. 89, 054502 (2018)]. PMID- 30399962 TI - Uncertainty analysis of response functions and gamma -backgrounds on Tion and t0 measurements from Cherenkov neutron detectors at the National Ignition Facility (NIF). AB - Cherenkov radiators deployed to measure the neutron time-of-flight spectrum have response times associated with the neutron transit across the detector and are free from long time response tails characteristic of scintillation detectors. The Cherenkov radiation results from simple physical processes which makes them amenable to high fidelity Monte Carlo simulation. The instrument response function of neutron time-of-flight systems is a major contributor to both the systematic and statistical uncertainties of the parameters used to describe these spectra; in particular, the first and second moments of these distributions are associated with arrival time, t0, and ion temperature, Tion. We present the results of uncertainty analysis showing the significant reduction of the uncertainty in determining these quantities in the Cherenkov detector system recently deployed at NIF. The increased sensitivity to gamma radiation requires additional consideration of the effect of this background to the uncertainties in both t0 and Tion. PMID- 30399964 TI - A large-aperture high-sensitivity avalanche image intensifier panel. AB - A large-aperture high-sensitivity image intensifier panel that consists of an avalanche photodiode array and a light-emitting diode array is presented. The device has 40% quantum efficiency, over 104 optical gain, and 80-ns time resolution. The aperture size of the device is 20 cm, and with the current manufacturing process, it can be scaled to arbitrarily larger sizes. The device can intensify the light from a single particle scintillation emission to an eye visible bright flash. The image resolution of the device is currently limited by the size of the avalanche photodiode that is 2 mm, although it can be scaled to smaller sizes in the near future. The image intensifier is operated at a small voltage, typically +57 V. The device can be applied to various applications, such as scintillation imaging, night vision cameras, and an image converter from non visible light (such as infrared or ultraviolet) to visible light. PMID- 30399965 TI - Jet outflow and open field line measurements on the C-2W advanced beam-driven field-reversed configuration plasma experiment. AB - Accurate operation and high performance of the open field line plasma surrounding the field reversed configuration is crucial to achieving the goals of successful temperature ramp up and confinement improvement on C-2W. Knowledge and control of the open field line plasma requires extensive diagnostic efforts. A suite of diagnostics, which consists of microwave interferometry, dispersive spectroscopy, and spatial heterodyne spectroscopy, is being developed to measure electron density, ion temperature, and particle outflow velocity at various locations along the open magnetic field lines. A detailed overview of these diagnostics is presented. PMID- 30399966 TI - First measurements of a scintillator based fast-ion loss detector near the ASDEX Upgrade divertor. AB - A new reciprocating scintillator based fast-ion loss detector has been installed a few centimeters above the outer divertor of the ASDEX Upgrade tokamak and between two of its lower Edge Localized Modes (ELM) mitigation coils. The detector head containing the scintillator screen, Faraday cup, calibration lamp, and collimator systems are installed on a motorized reciprocating system that can adjust its position via remote control in between plasma discharges. Orbit simulations are used to optimize the detector geometry and velocity-space coverage. The scintillator image is transferred to the light acquisition systems outside of the vacuum via a lens relay (embedded in a 3D-printed titanium holder) and an in-vacuum image guide. A charge coupled device camera, for high velocity space resolution, and an 8 * 8 channel avalanche photo diode camera, for high temporal resolution (up to 2 MHz), are used as light acquisition systems. Initial results showing velocity-space of neutral beam injection prompt losses and fast ion losses induced by a (2, 1) neoclassical tearing mode are presented. PMID- 30399967 TI - A table-top EUV focusing optical system with high energy density using a modified Schwarzschild objective and a laser-plasma light source. AB - For investigating extreme ultraviolet (EUV) damage on optics, a table-top EUV focusing optical system was developed in the laboratory. Based on a modified Schwarzschild objective with a large numerical aperture and a laser-plasma light source, this optical system can generate a focusing spot with the maximum energy density of 2.27 J/cm2 at the focal plane of the objective at the wavelength of 13.5 nm. The structures and the characterized properties of this optical system are presented in this paper. For testing the performance of this setup, single shot EUV damage tests were carried out on an optical substrate of CaF2 and a gold thin film. The damage thresholds and morphologies of these samples were given and discussed with former research studies. PMID- 30399968 TI - Relative intensity calibration of the DIII-D charge-exchange recombination spectroscopy system using neutral beam injection into gas. AB - A new calibration method for the DIII-D charge-exchange spectroscopy system produces a smoother impurity density profile compared to previous techniques, improving the accuracy of the impurity density profile reconstruction. The relative intensity calibration between the chords of the DIII-D charge-exchange recombination spectroscopy system is performed by firing neutral beams into the evacuated vacuum vessel pre-filled with neutral gas. Relative calibration is required in order to account for uncertainty in the 3D geometry of the neutral beam. Previous methods using helium gas have been improved by using xenon, which emits an emission line close to the commonly used carbon wavelength 5290.5 A, as well as improved timing of the gas injection, inclusion of variations in the vessel pressure, and timing of neutral beam injection. Photoemission spectra recorded by 112 sightlines viewing 6 neutral beams are compared and used to form a relative calibration factor for each sightline. This relative calibration is shown to improve the quality of the measured ion density profile. PMID- 30399969 TI - Time-resolved and multiple-angle Thomson scattering on gas-puff Z-Pinch plasmas at pinch time. AB - A 526.5 nm Thomson scattering diagnostic laser enables probing of the plasma conditions of neon gas-puff z-pinch implosions with temporal resolution. Splitting the laser into two 2.5 J pulses, both 2.3 ns in duration and separated by 4 ns, allows observation of sub-nanosecond time-resolved spectra for a total time of 7 ns. Collection optics were set at 90 degrees and 30 degrees to the laser, observing the same on-axis scattering volume with a radial extent of 0.4 mm. The spectra from both angles were collected by using the same streak camera, using a coupling system that allowed us to obtain temporal, spectral, and angular resolution in the same image. By comparing the ion-acoustic spectra from the two angles, we determined electron temperature and a range of possible electron densities. Measurements made in the 1-3 ns period before pinch time show best fit (determined by a least-squares method) electron densities of around 2 * 1019 cm 3, increasing to 1.5 * 1020 cm-3 in the 3 ns following the start of the x-ray burst (t = 0 ns) from the pinch. The electron temperature increases from 300 eV to 500 eV at t = 0 ns before decreasing to below 300 eV after pinch time. With the present parameters (probe beam, collection angles, and electron temperature and density), this diagnostic method is too insensitive to electron density to provide more than a constraint on that parameter. Plasma regimes in which this technique could determine electron density with some precision are calculated. PMID- 30399970 TI - Design of the collection optics for the Core Plasma Thomson Scattering (CPTS) in ITER. AB - In the ITER Core Plasma Thomson Scattering, the scattered light collection optics system is installed both inside and outside the diagnostic port under vacuum. The length of the optical path (~6 m) and the need to shield the neutron and gamma radiation increased the complexity of the system with the inclusion of multiple dog-legs, forcing the use of many elements with optical power. Multiple rounds of design have been required in order to satisfy iteratively the system requirements in terms of resolution, aberration, and shielding. The adoption of quasi-free form reflective surfaces for several mirrors eventually allowed the correct compromise between all conflicting requirements. PMID- 30399971 TI - Conceptual design for resistive bolometer system with multiple apertures for measurement of total radiated power in JT-60SA. AB - A field of view (FoV) of the resistive bolometer systems specialized for the total radiated power analysis has been designed with bolometer systems having multiple-apertures in JT-60SA. The multi-aperture bolometer system can reduce the required number of bolometer channels for the determination of the total radiated power. The FoV design has been carried out to minimize unobserved and overlapping regions with the following requirements: (i) independent determination of the divertor and the main plasma radiation, (ii) limitation of the use of only three diagnostic ports, and (iii) a redundant FoV design. With the designed FoV, the whole plasma of JT-60SA is viewed by only five bolometers and five replicated bolometers having the same FoV for redundancy. A signal evaluation with the designed FoV with a predetermined radiation profile indicates that even the lowest performing bolometer exhibits a signal to noise (S/N) ratio of 300 or more. The evaluated S/N ratio is high enough for the total radiated power analysis. Using the designed FoV, the total radiated power over the plasma profile can be determined within 5.3% using only five bolometers. PMID- 30399972 TI - High detection efficiency scintillating fiber detector for time-resolved measurement of triton burnup 14 MeV neutron in deuterium plasma experiment. AB - The behavior of the 1 MeV triton has been studied in order to understand the alpha particle confinement property in the deuterium operation of toroidal fusion devices. To obtain time evolution of the deuterium-tritium (D-T) neutron emission rate where the secondary DT neutron emission rate is approximately 1012 n/s, we designed two high detection efficiency scintillating fiber (Sci-Fi) detectors: a 1 mm-diameter scintillation fiber-based detector Sci-Fi1 and a 2 mm-diameter scintillation fiber-based detector Sci-Fi2. The test in an accelerator-based neutron generator was performed. The result shows that the directionality of each detector is 15 degrees and 25 degrees , respectively. It is found that detection efficiency for DT neutrons is around 0.23 counts/n cm2 for the Sci-Fi1 detector and is around 1.0 counts/n cm2 for the Sci-Fi2 detector. PMID- 30399973 TI - Gallium nitride (GaN) devices as a platform technology for radiation hard inertial confinement fusion diagnostics. AB - Inertial Confinement Fusion (ICF) is undergoing more detailed research to increase neutron yield and will require high resolution imaging near the target. Neutron damage to diagnostics remains a serious issue in understanding and achieving ICF. We have demonstrated that Gallium Nitride (GaN) optoelectronic devices have exceptional neutron radiation hardness, by systematic testing of neutron radiation effects in GaN devices and materials with elevated neutron fluence levels and a broad neutron energy spectrum. During the 2013-2017 run cycles at Los Alamos Neutron Science Center (LANSCE), we irradiated various GaN materials and devices with fast and thermal plus resonance neutrons at several beamlines. This paper presents a radiation hardness study for Aluminum Gallium Nitride and Gallium Nitride (AlGaN/GaN) deep UV LEDs irradiated at the LANSCE 4FP60R beamline. The fluence level was up to 2.4 * 1013 neutrons/cm2 for neutrons with energies greater than 0.1 MeV. The device performance was monitored in real time. After three years of irradiation studies, we found that the GaN devices maintained operation in the forward active region. The current and voltage relation (I-V curves) varied insignificantly in the linear region. Our results demonstrate the radiation hardness needed for laser fusion diagnostics at least up to 1017 neutron yield per shot, if the diagnostics is placed 1 m away from the target, where the neutron fluence per shot is approximately 8 * 1011 n/cm2. The GaN devices can operate for multiple shots. PMID- 30399974 TI - First time-resolved electron density measurements in the C-2W advanced field reversed configuration plasmas from long-path compact second-harmonic interferometer. AB - Characterization of the plasma structure and density is critical for the diagnosis and control of C-2W plasma equilibria. To this end, two compact, highly portable, turnkey second harmonic interferometers are used to make measurements with greater flexibility than available from other diagnostics, providing important information in areas otherwise inaccessible to more complicated systems. The systems are based on a fiber-coupled 1064 nm Nd:YAG laser and provide a sensitivity of a few 1018 m-2 with a time resolution of a few microseconds. System upgrades were made to allow for beam paths in excess of 5 m. Initial data from two system configurations are presented, showing plasma translation and merged equilibria. PMID- 30399975 TI - Development of a Z eff diagnostic using visible and near-infrared bremsstrahlung light for the C-2W field-reversed configuration plasma. AB - In C-2W, an elevated impurity concentration can lead to significant degradation of plasma performance and energy losses through radiation. To gauge plasma contamination from impurities, the effective ion charge (Z eff) can be determined from measurements of bremsstrahlung continuum radiation over a small spectral range free from line radiation. To this end, a diagnostic system including visible and near-infrared bremsstrahlung detectors was deployed in C-2W to measure time-dependent radial distributions of Z eff. The system is complemented by an array of survey spectrometers which enable full-range spectroscopic measurements of impurity emission lines from the vacuum ultraviolet to the near infrared, providing a good picture of the plasma composition. Here, the design scheme for this integrated diagnostic system is presented and discussed. PMID- 30399976 TI - Thin foil proton recoil spectrometer performance study for application in DT plasma measurements. AB - The Thin foil Proton Recoil (TPR) technique has previously been used for deuterium-tritium fusion neutron diagnostics [N. P. Hawkes et al., Rev. Sci. Instrum. 70, 1134 (1999)] and is one of the candidates put forward for use in ITER as part of the high resolution neutron spectrometer (HRNS) system [E. A. Sunden et al., Nucl. Instrum. Methods Phys. Res., Sect. A 701, 62 (2013)]. For ITER, the neutron spectrometer's main purposes are to determine the fuel ion density ratio as well as the ion temperature in DT plasma. This work focuses on testing the capability of a proton telescope detector intended for use as part of the TPR spectrometer. The proton telescope has been tested using proton energies in the range of 3-8 MeV. The experimental results cover energy calibration, resolution estimation, and testing the spectrometer's capability to perform background separation using DeltaE - E energy cuts. In addition, spectrometer performance in terms of signal to background ratios for ITER-like DT plasma conditions is estimated using Monte-Carlo simulations. Results show that the TPR spectrometer geometry dominates in determining the energy resolution and the DeltaE - E energy cuts will significantly reduce the background. In addition, the estimated spectrometer count rates in ITER-like conditions fall below 20 kHz per detector segment. PMID- 30399977 TI - A low noise power supply based on buck converter for current regulation in an inductive load. AB - High current regulations are widely required in tokamaks to generate a specific magnetic field for plasma confinement which is challenging for power electronics. For high current regulation, the stray inductance will cause high noise and surge voltage that may damage the power electronics. In addition, it is difficult to ensure both a fast response and a steady evolution. In this paper, a power supply based on a buck converter for high current regulation in an inductive load is described, in which insulated gate bipolar transistors are used as switches and two capacitor banks are used for energy storage. The first stage capacitor bank at a higher voltage ensures the fast current growth rate at the beginning of discharge and plays the role of wave filter later to reduce the noise. The second stage capacitor bank at a lower voltage provides the main energy required during discharge. A microcontroller is used to regulate the current by a feedback mechanism. This power supply can regulate the high current in an inductive load with low noise and fast response, which has been applied to the poloidal field coils and the ultrafast reciprocating probe system in the SUNIST (Sino-UNIted Spherical Tokamak) spherical tokamak. PMID- 30399978 TI - Noise mitigation methods for ion detectors operating with a direct view of high temperature plasmas. AB - We have developed an ion current measurement instrument with a direct view of a plasma that reduces the particle and radiation-induced noise current it detects by over three orders of magnitude, from tens of microamps to tens of nanoamps. This is accomplished using electric fields, magnetic fields, and physical shielding that limit the flux of particles and radiation into the instrument and suppress the secondary electrons produced within it by particle and radiation impact. Operation of this detector in various configurations, without an ion beam, has allowed identification of the sources of noise current. In our experimental setup, the largest noise contributors were found to be plasma ions and photoelectric emission due to UV radiation. PMID- 30399979 TI - Development of a new compact gamma-ray spectrometer optimised for runaway electron measurements. AB - A new compact gamma-ray spectrometer was developed in order to optimise the measurement of bremsstrahlung radiation emitted from runaway electrons in the MeV range. The detector is based on a cerium doped lutetium-yttrium oxyorthosilicate (LYSO:Ce) scintillator coupled to a silicon photomultiplier and is insensitive to magnetic fields. A dedicated electronic board was developed to optimise the signal readout as well as for online control of the device. The detector combines a dynamic range up to 10 MeV with moderate energy non-linearity, counting rate capabilities in excess of 1 MHz, and an energy resolution that extrapolates to a few % in the MeV range, thus meeting the requirements for its application to runaway electron studies by bremsstrahlung measurements in the gamma-ray energy range. PMID- 30399980 TI - Infrared imaging systems for wall protection in the W7-X stellarator (invited). AB - Wendelstein 7-X aims at quasi-steady state operation with up to 10 MW of heating power for 30 min. Power exhaust will be handled predominantly via 10 actively water cooled CFC (carbon-fiber-reinforced carbon) based divertor units designed to withstand power loads of 10 MW/m2 locally in steady state. If local loads exceed this value, a risk of local delamination of the CFC and failure of entire divertor modules arises. Infrared endoscopes to monitor all main plasma facing components are being prepared, and near real time software tools are under development to identify areas of excessive temperature rise, to distinguish them from non-critical events, and to trigger alarms. Tests with different cameras were made in the recent campaign. Long pulse operation enforces additional diagnostic design constraints: for example, the optics need to be thermally decoupled from the endoscope housing. In the upcoming experimental campaign, a graphite scraper element, in front of the island divertor throat, will be tested as a possible means to protect the divertor pumping gap edges during the transient discharge evolution. PMID- 30399981 TI - On the system stability and calibration of the image plate/scanner system for plasma diagnosis at the National Ignition Facility. AB - At the National Ignition Facility (NIF), storage phosphor image plates (IP) are used extensively for recording x-rays, charged particles, and neutrons. For x-ray imaging and spectroscopy, absolute and relative calibrations are important for extracting plasma information from the diagnostics. We use Fuji MS, SR, and TR image plates that have been cut to fit custom diagnostic envelopes. The image plates are scanned on a General Electric FLA 7000 IP flying spot scanner. Calibrations for sensitivity, spatial scale, and temperature dependent fade are applied. During a set of recent calibrations, we noticed large shifts in the absolute calibration of the image plate system. The possible source of these shifts is discussed. We discuss scanner stability and a method for calibration. We discuss the fade and temperature effects of the image plates and how this correction is applied within the NIF environment. We also compare our NIF GE FLA 7000 IP scanner with a new General Electric Amersham Typhoon IP scanner. PMID- 30399982 TI - Small interprosthetic gaps do not increase femoral peri-prosthetic fracture risk. An in vitro biomechanical analysis. AB - It has been hypothesized that the interprosthetic gap between ipsilateral hip and knee replacements acts as a stress riser affecting bone fracture behaviour. The aim of this study was to quantify femoral strength and fracture morphology for a wide range of interprosthetic gaps. Seven interprosthetic gaps (0-20cm) were created in artificial femora (N = 6-9/group). All specimens were loaded to failure following a compressive loading protocol. Fracture load and fracture morphology were recorded. Outcomes were compared to femora with a hip implant only (N = 6; reference group). Fracture load was highest for 0 cm gaps. All other interprosthetic gaps had fracture loads similar to that of the reference group. Fracture occurred most frequently with a medial butterfly fragment located at the tip of the hip stem.We conclude that small gaps do not act as stress risers. The specific fracture morphology may benefit from different treatment than peri prosthetic hip fractures. PMID- 30399983 TI - Management of greater trochanteric pain syndrome : a systematic review. AB - Greater trochanteric pain syndrome is characterized by pain at or around the greater trochanter. Numerous management modalities have been proposed, with varying success. Cochrane and Pubmed database have been searched from 1990 for studies focusing on the management of this syndrome. We only selected studies with a validated outcome measure. 11 studies met our inclusion criteria. Evidence points towards a pain reduction in the first months after a corticosteroid injection, but this effect does not persist with time. Low energy shock wave therapy also has a positive effect in the short term, the longer term results being more controversial. Although surgery is poorly documented, authors agree to reserve this option only for greater trochanteric pain syndrome failing to respond to conservative measures. The complication and re-intervention rate should not be underestimated. PMID- 30399984 TI - Functional outcome following internal fixation of intraarticular fractures of the distal femur. AB - Distal femur fracture with intra-articular extension is a major cause of severe morbidity in patients with lower extremity injuries. The purpose of this study was to evaluate functional outcome, fracture healing, and the complications of distal femoral intra-articular fractures using locking compression plates. A total of 170 patients with intraarticular fractures of the distal femur were recruited from Emergency and Outpatient department and treated with distal femoral locking compression plates. Clinical and functional outcomes were assessed using the Knee Society score. All patients were followed for twelve months. All fractures united in average 3.2 months (range 7-19 weeks). The results were excellent in 66.47% (113/170) patients, and good in 22.35% (38/170) patients. Non-union was not seen in this study. 5.83% (7/170) patients had limb length discrepancy of < 2 cm and no treatment were needed. It is an effective procedure with an excellent or good functional outcome in the majority of the patients. PMID- 30399985 TI - Femur can be lengthened over nail, along its mechanical axis : a modified lengthening over nail technique. AB - The theoretical risk of medialisation of the knee joint and the lateral shift of the lower extremity mechanical axis, due to achievement of lengthening along the anatomical axis is present in the process of lengthening with elongation nails and the "lengthening over nail" technique. With this new technique described in this study we aimed to prove that lengthening over nail can be performed along the mechanical axis of the femur. Six lower-limb models were used to perform three different lengthening techniques. In group 1, lengthening was achieved along the anatomical axis with an external fixator. In group 2, the clamps of the external fixator were adjusted at 6 degrees to achieve lengthening along the mechanical axis. In group 3, eight different sized nails were applied with an external fixator (angle adjustable clamps were at 6 degrees ) to achieve lengthening along the mechanical axis by LON technique. Photographs were taken after each cm of lengthening and the distance from the mechanical axis line were measured. The modified LON technique described in this study provided lengthening along the mechanical axis. One of the main advantages of the procedure described in our study is the chance for reconsideration and revision of unforeseen angulations and malalignments, via the help of the distal angular adjustable clamps; during the time of the surgery for external fixator removal before application of the poller screws. PMID- 30399986 TI - Results of cosmetic lower limb lengthening by the lengthening over nail technique. AB - We conducted a retrospective study by reviewing our results following cosmetic lengthening using the lengthening over nail technique in terms of the importance of the patient selection process, bone and soft tissue complications, and functional and subjective clinical outcomes. The study data were obtained from medical records and radiographs. A total of 32 patients, 24 males and 8 females, with constitutional short stature underwent the lengthening over nail technique for cosmetic purposes between 2000 and 2013. Lengthening was performed in the femora of 15 patients and in the tibiae of 17 patients. All patients who were accepted for cosmetic lengthening underwent a careful selection process that included a psychiatric evaluation. The mean follow-up time was 73 months (range, 12 to 163 months). Thirty-four complications were reported. Cosmetic lengthening is not without complications. Patient selection is of paramount importance. This technique is recommended for cosmetic lengthening because it is minimally invasive and it has documented reproducible results. PMID- 30399987 TI - Evaluation of the Posterior Tibial Slope in Noncontact ACL Injuries Using Magnetic Resonance Imaging. AB - This study investigated whether an increased posterior tibial slope (PTS) was a risk factor for noncontact anterior cruciate ligament (ACL) injuries. We retrospectively evaluated the Magnetic Resonance (MR) images of 60 patients with noncontact complete ruptures of the ACL and 60 age-matched, healthy individuals with normal knee MR images. We measured the medial and lateral PTS on the sagittal T1W images separately in both the patients with complete ACL ruptures and the control group, as described by Hudek et al. Medial and lateral PTS were investigated between two groups .The patients with complete ACL ruptures had a statistically significantly (p<0.01) larger PTS on the lateral tibial condyle than the control group (4.5 degrees and 3.8 degrees , respectively). However, there was no statistically significant differences between the two groups' medial PTS. Also, the lateral PTS was greater in the complete ACL group than the control group in both females and males (p<0.01). PMID- 30399988 TI - The TRAC-PS dual radius total knee arthroplasty : Disappointing medium and long terms results. AB - The TRAC prosthesis is a dual radius, mobile bearing, posterior stabilized prosthesis, to increase stability by optimizing contact area and control wear using a mobile polyethylene. Between February 1995 and January 2000, a single surgeon performed a continuous series of 85 TRAC-PS TKAs in 85 patients at the University Hospital Brussels. A retrospective review on patient charts was performed. Patients available were scored clinically using the Knee Society Score, WOMAC osteoarthritis index, SF 36 and a Visual Analogue Scale for pain. 43 patients had died at time of evaluation, three were unavailable for examination due to bad general health and five were lost to follow up. The remaining 35 patients were examined with a mean follow-up of 13 years. The mean age of the patients at follow up was 83 years. The mean WOMAC score was 78,4(SD 17,9). The mean Knee Society Score was 86.8(SD 8,4) clinical and 42,6(SD 28) functional. The mean range of flexion was 105 degrees . The mean SF-36 score was 59,8(SD 15,4). The VAS for pain was 6(SD 9). With revision (8 cases) as endpoint, survival rate of the prosthesis was estimated to be 92% at 13 years. Twenty-three Serious Adverse Events (28%) in 17 patients, related to the prosthesis were registered in this patient group. Long term results of this prosthesis were satisfying but a large number of serious adverse events led to abandonment of the TRAC-prosthesis. PMID- 30399989 TI - 5 Year Outcomes and Survivorship of the Triathlon Total Knee Replacement: a Cohort Study. AB - The aim of this study was to determine outcomes and survivorship of the Triathlon knee replacement up to 5 years post-operation. A cohort of 266 patients receiving a Triathlon knee replacement were assessed before surgery and at 3 months, 1 year, 2 years, 3 years and 5 years post-operation. Assessments included patient reported outcome measures, American Knee Society Score, complications and survivorship. The largest improvements in pain, function, stiffness and knee related quality of life occurred in the first 3 months post-operation. Further smaller improvements were reported between 3 and 12 months post-operation, and then a plateauing of outcomes was observed up to 5 years. A high percentage of patients (86%) were satisfied with their outcome at 5 years. Survivorship with revision as the endpoint was 96.6% (95% CI 93.2-98.1%) at 5 years post-operation. In conclusion, this study observed good mid-term patient outcomes and survivorship of the Triathlon knee replacement. PMID- 30399990 TI - Surgical treatment of the Anterior Cruciate Ligament Rupture : where do we stand today? AB - The rupture of the anterior cruciate ligament is one of the most common orthopaedic injuries. This review gives an overview of the surgical treatment of the ACL rupture. A correct knowledge of the anatomy of the ACL is crucial in treating this injury. Recent studies describe the ACl as flat rather than divided in distinct structural bundles. Reconstructive and primary repair techniques can be used to approach this native anatomy. Reconstructive surgery of the ACL still is the golden standard in ACL surgery. An individualized approach is key and should be used. However, ACL reconstruction is not always a success. Return to preinjury of sports only reaches 65% and ACL-reconstructed knees are prone to osteoarthritis. Previous attempts at the primary repair of the ACL were archaic and had disappointing results. Modern diagnostics, operative and biological techniques and strict patient selection could initiate a revival of this technique. PMID- 30399991 TI - Comparative study of autograft harvested from contra lateral proximal tibia versus the iliac crest for operative management of depressed tibial plateau fractures. AB - Our study evaluates differences in fracture healing, clinical outcome and donor site morbidity between iliac crest bone graft and contra lateral proximal tibial bone graft utilized for internal fixation of displaced tibial plateau fractures. In 34 patients requiring bone grafting, iliac crest was utilized in 16 cases and proximal tibia in the remaining 18. Fracture union was achieved in all patients in either group at a mean period of 14 weeks with no difference in the functional knee scores between the groups. The iliac crest group showed significantly higher visual analogue pain scores in the immediate post-operative period and greater donor site complications like superficial wound infection, incisional hernia and chronic pain compared to the proximal tibial group. Contra lateral proximal tibia offers a viable alternative to iliac crest as a donor site for bone graft with adequacy of graft quantity, ease of graft harvest and lesser donor site morbidity. PMID- 30399992 TI - Percutaneous hardware free corrective osteotomy for bunionnette deformity. AB - When bunionette deformities are not responding to conservative treatment, several surgical procedures are available. Recently, minimal invasive techniques have been proposed with good results. We present our results of a strictly percutaneous 5th metatarsal osteotomy to correct the deformity with bandage after care. We present a retrospective review on 20 percutaneous distal oblique 5th metatarsal osteotomies for correction of bunionette deformity. Aftercare consisted of 5-6 weeks of corrective taping with full weight bearing using a post op shoe. Patients were evaluated radiographically and clinically by the American Orthopaedic Foot & Ankle Society (AOFAS) Lesser Toe Metatarsophalangeal-Inter phalangeal scale, Visual Analogue scale (VAS) and Coughlin classification. At a mean follow-up of 27.05 months, the AOFAS improved from a mean of 51 points to 91.6 points (max 100). 90% of patients had good or excellent clinical result and a mean pain score on the visual analog scale was 0.7 out of 10. Radiographic evaluation showed a good correction of the intermetatarsal and metatarsophalangeal angle. We did not encounter any complications such as infections, wound breakdown, neurovascular problems, non-union or recurrence. The percutaneous hardware free corrective osteotomy is an effective, reliable and safe procedure concerning the treatment of bunionette deformity. The results are comparable with previously published outcomes of open and minimal invasive procedures with considerable less soft tissue damage, shorter operating time and the lack of internal fixation. PMID- 30399993 TI - Fixation of clavicle alone in floating shoulder injury : functional and radiological outcome. AB - The aim of this study was to evaluate the clinical and radiological results of fixation of clavicle alone in floating shoulder injury. From 2007to 2011 thirteen patients with floating shoulder injury (ipsilateral clavicle and scapular neck fracture ) were treated by isolated fixation of the clavicle by plate osteosynthesis. Assessment of the shoulder function was performed using the university of California at Los Angeles (UCLA) shoulder rating scale .The mean duration of follow up period was 24.3 months .All the fractures were united , fractures of the clavicle united from 11to 16 weeks after surgery and that of scapula from 12to16 weeks . The overall UCLA shoulder rating scale was 32.3 (range from 30-34) . Isolated plate fixation of clavicle fracture in floating shoulder injuries results in high rates of both clavicular and scapular fracture healing provided the integrity of coracocla-vicular ligament and involvement of the coracoids process with the distal scapular fragment . PMID- 30399994 TI - Virtual 3D planning and patient specific surgical guides for corrective osteotomy of the clavicle : report of three cases. AB - Although many clavicular malunions result in minimal functional deficit, in some symptomatic cases a corrective osteotomy might be necessary. Recently, computer assisted surgical planning combined with patient-specific surgical guides was introduced as a powerful technology with the potential to improve the accuracy, efficiency, and consistency of corrective osteotomies, as shown for osteotomies in other anatomical regions. We describe the use of this technique in three cases of clavicular malunion. PMID- 30399995 TI - Late function and complications of hook plate implantation for distal-third clavicle fractures : a retrospective study. AB - In this study, the examined data was analysed from61 patients with Neer type II clavicle fractures treated with hook plate implantation between January 2008 and February 2011. The patients were divided into three groups depending on the removing time of plates after the fractures healing: early removal (<3 months, n=20), delayed removal (3-6 months, n = 35), and retained plate (>6 months, n = 6). All patients underwent clinical and radiographic follow-up in the outpatient department for a median of 18 months and every fracture healed eventually. Shoulder function was evaluated using the Constant shoulder score. The mean Constant shoulder score was greater, indicating better function, in the early removal group than the delayed removal and retained plategroups (96 [range 89 100] vs. 77 [65-89] and 61 [57-78], respectively; p = 0.000). The complication rateswere10%, 22.9%, and 50% in the early, delayed removal and retained plate groups, respectively (p = 0.043). As a conclusion, the removal timing of the hook plate for distal clavicle fractures plays an important role in subsequent shoulder function and complications. PMID- 30399996 TI - Modified anconeus muscle transfer as treatment of failed surgical release of lateral epicondylitis of the elbow. AB - The purpose of this study was to evaluate the safety and the effectiveness of a new modified anconeus transfer technique in revision surgery for refractory lateral epicondylitis of the elbow. A modified anconeus muscle transfer was performed in nine patients with persistent symptoms after previous surgical release of the common extensor origin. The original technique was modified by using only half of the anconeus muscle. Patients were clinically evaluated, including quickDASH score and grip strength measurement. At a mean follow up period of 36 months, 4 patients had an excellent result, 3 a good result and 1 a poor result. All patients rated their clinical situation as better than before surgery. All but one patient said to be happy with the result and they would undergo the procedure again. The mean quickDash score at the follow up was 10.6 (SD 14.4). No complications were observed. The modified Anconeus muscle transfer is a safe and effective procedure in patients with persistent lateral epicondylitis complaints after a previous surgical release. PMID- 30399997 TI - Excision of painful dorsal wrist ganglion by open or arthroscopic approach : a compariso n study. AB - Dorsal wrist ganglion can be removed through open or arthroscopic excision. The better method for relieving pain remains unknown. In this study, we addressed the following questions: (1) does open excision provide better pain relief than arthroscopic? (2) is there any difference in patient satisfaction, functional outcome, and re-operation rate? Forty-five patients with painful dorsal wrist ganglions underwent open or arthroscopic excision. Posterior interosseous neurectomy was performed during open excision. Clinical outcomes were assessed with a focus on pain relief. Patient satisfaction, recurrence, and reoperation due to residual pain were also assessed. The average pain scores improved significantly after both, open and arthroscopic excision. However, five patients who underwent arthroscopic excision reported the same or worse pain, whereas all patients who underwent open excision reported postoperative alleviation of pain. The recurrence rate was comparable. Patient satisfaction was better in those who underwent open excision. Reoperation was performed in four patients who had residual pain after arthroscopic excision. Both, open and arthroscopic methods can alleviate pain in patients with painful dorsal wrist ganglion. However, 20% of the patients who underwent arthroscopic excision reported residual or persistent pain. PMID- 30399998 TI - Fascial flap surgery for recurrent dorsal ganglion. AB - Recurrence after primary resection of a dorsal wrist ganglion may necessitate a reintervention. A technique was introduced in 2004 in which a flap of the extensor retinaculum is used to cover the defect left in the wrist capsule following repeat radical excision. This retrospective study presents the follow up 4.6 years after this surgery in 20 patients. Recurrence, grip strength and possible flexion deficit are measured in 13 patients who attended clinic, as well as pain and satisfaction scores. Disability scores have been evaluated in 18 patients. One refractory patient was ascertained. A flexion deficit <= 10 degrees was observed in 7 patients. Overall, mild pain, very mild disability, a flexion deficit of 14.2 degrees and a loss of grip strength of 3.6 kg was observed. The retinaculum flap for recurrent dorsal wrist ganglion is a reliable procedure with limited risk for flexion deficit after surgery, high satisfaction rate and low recurrence risk. PMID- 30399999 TI - A life-threatening situation due to a spider bite : a non-infectious necrotizing fasciitis. AB - We present the case of a healthy patient who sustained a spiderbite in the elbow and developed a non-infectious necrotizing fasciitis in the affected limb. Female patient aged 24 pain reported a spiderbite received some 72 h previously in Mexico (the spider was identified as a brown recluse spider-Loxosceles reclusa). Under the suspected diagnosis of necrotizing fasciitis urgent surgery was indicated. During her hospital stay, the patient required three additional surgical procedures, and was discharged from hospital 30 days after admission. Spider bites in the limb may be limb-threatening and life-threatening. Emergency doctors should be aware of this possibility, because spiders can be unintentionally transported all over the world. PMID- 30400000 TI - A comparative study of three approaches for the treatment of lumbosacral tuberculosis. AB - The posterior (P), antero-posterior (AP), and anterior approaches (A) with a new complex locking rod system (D-rod system) were performed on 64 patients with lumbosacral tuberculosis respectively and the efficacies of the three approaches were compared in our study. Related data were then collected and compared with an average of 27.0 months follow up. The lumbosacral angles, VAS, ODI, ESR, and Frankel Grade were significantly improved at the post-operation or final follow up when compared to preoperative scores. The average surgical time, blood loss, and hospital stay following anterior and posterior approaches were markedly less than those following antero-posterior approach. Moreover, there was no tuberculosis recurrence in AP and A group. However, P group had a recurrence rate of 11.1% (2/18). None of the patients in P and A group developed intraoperative or postoperative complications, while two cases were found in AP group. Taken together, anterior approach with the D-rod system is an appropriate method for lumbosacral tuberculosis treatment. PMID- 30400001 TI - Retraction notice to "Signalling cross-talk between nitric oxide and active oxygen in Trifolium repens L. plants responses to cadmium stress" [Environ. Pollut. 239 (2018) 53-68]. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editors-in-Chief. The authors have plagiarized part of a paper that had appeared in Plant, Cell & Environment, 29 (2006) 1532-1544. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365 3040.2006.01531.x The images that were reused were: Fig. 1e, 1f, 1g, 1h, 2a, 2b, 2e, 2f. One of the conditions of submission of a paper for publication is that authors declare explicitly that their work is original and has not appeared in a publication elsewhere. Re-use of any data should be appropriately cited. As such this article represents a severe abuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process. PMID- 30400002 TI - KLF14 potentiates oxidative adaptation via modulating HO-1 signaling in castrate resistant prostate cancer. AB - Insights into the mechanisms by which key factors stimulate cell growth under androgen-depleted conditions is a premise to the development of effective treatments with clinically significant activity in patients with castration resistant prostate cancer (CRPC). Herein, we report that, the expression of Kruppel-like factor 14 (KLF14), a master transcription factor in the regulation of lipid metabolism, was significantly induced in castration-insensitive PCa cells and tumor tissues from a mouse xenograft model of CRPC. KLF14 upregulation in PCa cells, which was stimulated upstream by oxidative stress, was dependent on multiple pathways including PI3K/AKT, p42/p44 MAPK, AMPK and PKC pathways. By means of ectopic overexpression and genetic inactivation, we further show that KLF14 promoted cell growth via positive regulation of the antioxidant response under androgen-depleted conditions. Mechanistically, KLF14 coupled to p300 and CBP to enhance the transcriptional activation of HMOX1, the gene encoding the antioxidative enzyme heme oxygenase-1 (HO-1) that is one of the most important mechanisms of cell adaptation to stress. Transient knockdown of HMOX1 is sufficient to overcome KLF14 overexpression-potentiated PCa cell growth under androgen-depleted conditions. From a pharmacological standpoint, in vivo administration of ZnPPIX (a specific inhibitor of HO-1) effectively attenuates castration-resistant progression in the mouse xenograft model, without changing KLF14 level. Together, these results provide comprehensive insight into the KLF14 dependent regulation of antioxidant response and subsequent pathogenesis of castration resistance and indicate that interventions targeting the KLF14/HO-1 adaptive mechanism should be further explored for CRPC treatment. PMID- 30400003 TI - Analysis of the immune landscape of small bowel neuroendocrine tumors. AB - Immune checkpoint inhibitors have shown promising results in different cancers, and correlation between immune infiltration, expression of programmed death ligand 1 (PD-L1) by tumor cells and response to immunotherapy has been reported. There is limited knowledge regarding the immune microenvironment of small bowel (SB) neuroendocrine tumors (NETs). This work was aimed at characterizing the immune landscape of SB NETs. Expression of PD-L1 and programmed death-1 (PD-1) was evaluated by immunohistochemistry in 102 surgically resected, primary NETs of the duodenum, jejunum and ileum. Extent and characteristics of the tumor associated immune infiltrate were also assessed and investigated in their prognostic potential. We detected the expression of PD-L1 in >=1 and >=50% of tumor cells in 40/102 (39%; 95% CI, 30-49%) and 14/102 (14%; 95% CI, 8-22%) cases respectively. Intratumor host immune response was apparently absent in 35/102 cases (34%; 95% CI, 25-44%), mild to moderate in 46/102 samples (45%, 95% CI, 35 55%), intense in 21/102 tumors (21%, 95% CI, 13-30%). Expression of PD-L1 and extent of immune infiltration were significantly higher in duodenal NETs as compared with jejunal/ileal NETs. A marked peritumoral host response was organized as ectopic lymph node-like structures in 18/102 cases (18%; 95% CI, 11 26%). Neither PD-L1 expression nor the degree of immune infiltration showed any prognostic significance. Overall, the immune landscape of SB NETs is heterogeneous, with adaptive immune resistance mechanisms prevailing in duodenal NETs. Clinical trials of immune checkpoint inhibitors should take into account the immune heterogeneity of SB NETs. PMID- 30400004 TI - Inhibition of TAMs improves the response to docetaxel in castration-resistant prostate cancer. AB - For men with castration-resistant prostate cancer (CRPC), androgen-deprivation therapy (ADT) often becomes ineffective requiring the addition of docetaxel, a proven effective chemotherapy option. Tumor-associated macrophages (TAMs) are known to provide protumorigenic influences that contribute to treatment failure. In this study, we examined the contribution of TAMs to docetaxel treatment. An increased infiltration of macrophages in CRPC tumors was observed after treatment with docetaxel. Prostate cancer cells treated with docetaxel released more macrophage colony-stimulating factor (M-CSF-1 or CSF-1), IL-10 and other factors, which can recruit and modulate circulating monocytes to promote their protumorigenic functions. Inhibition of CSF-1 receptor kinase signaling with a small molecule antagonist (PLX3397) in CRPC models significantly reduces the infiltration of TAMs and their influences. As such, the addition of PLX3397 to docetaxel treatment resulted in a more durable tumor growth suppression than docetaxel alone. This study reveals a rational strategy to abrogate the influences of TAMs and extend the treatment response to docetaxel in CRPC. PMID- 30400005 TI - Otubain 1: a non-canonical deubiquitinase with an emerging role in cancer. AB - The ubiquitin system regulates diverse biological processes, many involved in cancer pathogenesis, by altering the ubiquitination state of protein substrates. This is accomplished by ubiquitin ligases and deubiquitinases (DUBs), which respectively add or remove ubiquitin from substrates to alter their stability, activity, localization and interactions. While lack of catalytic activity makes therapeutic targeting of ubiquitin ligases difficult, DUB inhibitors represent an active area of research and the identification of cancer-associated DUBs may lead to the development of novel therapeutics. A growing body of literature demonstrates that the DUB Otubain 1 (OTUB1) regulates many cancer-associated signaling pathways including MAPK, ERa, epithelial-mesenchymal transition (EMT), RHOa, mTORC1, FOXM1 and P53 to promote tumor cell survival, proliferation, invasiveness and therapeutic resistance. In addition, clinical studies have associated elevated OTUB1 expression with high grade, invasiveness and metastasis in several tumor types including lung, breast, ovarian, glioma, colon and gastric. Interestingly, in addition to catalytic DUB activity, OTUB1 displays a catalytic-independent, non-canonical activity where it inhibits the transfer of ubiquitin onto protein substrates by sequestration of E2 ubiquitin-conjugating enzymes. The aim of this review is to describe the canonical and non-canonical activities of OTUB1, summarize roles for OTUB1 in cancer-associated pathways and discuss its potential therapeutic targeting. PMID- 30400007 TI - KAT5 promotes invasion and metastasis through C-MYC stabilization in ATC. AB - Anaplastic thyroid cancer (ATC) is an aggressive cancer with poor clinical prognosis. However, mechanisms driving ATC aggressiveness is not well known. Components of the DNA damage response (DDR) are frequently found mutated or aberrantly expressed in ATC. The goal of this study is to establish the functional link between histone acetyltransferase lysine (K) acetyltransferase 5 (KAT5, a critical DDR protein) and ATC invasiveness using clinical, in vitro and in vivo models. We analyzed the expression of KAT5 by immunohistochemistry and assessed its relationship with metastasis and overall survival in 82 ATC patients. Using cellular models, we established functional connection of KAT5 expression and C-MYC stabilization. We then studied the impact of genetically modified KAT5 expression on ATC metastasis in nude mice. In clinical samples, there is a strong correlation of KAT5 expression with ATC metastasis (P = 0.0009) and overall survival (P = 0.0017). At the cellular level, upregulation of KAT5 significantly promotes thyroid cancer cell proliferation and invasion. We also find that KAT5 enhances the C-MYC protein level by inhibiting ubiquitin-mediated degradation. Further evidence reveals that KAT5 acetylates and stabilizes C-MYC. Finally, we prove that altered KAT5 expression influences ATC lung metastases in vivo. KAT5 promotes ATC invasion and metastases through stabilization of C-MYC, demonstrating it as a new biomarker and therapeutic target for ATC. PMID- 30400006 TI - ATM deficiency promotes progression of CRPC by enhancing Warburg effect. AB - ATM is a well-known master regulator of double strand break (DSB) DNA repair and the defective DNA repair has been therapeutically exploited to develop PARP inhibitors based on the synthetic lethality strategy. ATM mutation is found with increased prevalence in advanced metastatic castration-resistant prostate cancer (mCRPC). However, the molecular mechanisms underlying ATM mutation-driving disease progression are still largely unknown. Here, we report that ATM mutation contributes to the CRPC progression through a metabolic rather than DNA repair mechanism. We showed that ATM deficiency generated by CRISPR/Cas9 editing promoted CRPC cell proliferation and xenograft tumor growth. ATM deficiency altered cellular metabolism and enhanced Warburg effect in CRPC cells. We demonstrated that ATM deficiency shunted the glucose flux to aerobic glycolysis by upregulating LDHA expression, which generated more lactate and produced less mitochondrial ROS to promote CRPC cell growth. Inhibition of LDHA by siRNA or inhibitor FX11 generated less lactate and accumulated more ROS in ATM-deficient CRPC cells and therefore potentiated the cell death of ATM-deficient CRPC cells. These findings suggest a new therapeutic strategy for ATM-mutant CRPC patients by targeting LDHA-mediated glycolysis metabolism, which might be effective for the PARP inhibitor resistant mCRPC tumors. PMID- 30400008 TI - FAM129A regulates autophagy in thyroid carcinomas in an oncogene-dependent manner. AB - We previously proposed that high expression of FAM129A can be used as a thyroid carcinoma biomarker in preoperative diagnostic exams of thyroid nodules. Here, we identify that FAM129A expression is increased under nutrient and growth factor depletion in a normal thyroid cell line (PCCL3), overlapping with increased expression of autophagy-related protein and inhibition of AKT/mTOR/p70S6K. Supplementation of insulin, TSH and serum to the medium was able to reduce the expression of both FAM129A and autophagy-related protein and reestablish the AKT/mTOR/p70S6K axis. To determine the direct role of FAM129A on autophagy, FAM129A was transfected into PCCL3 cells. Its overexpression induced autophagic vesicles formation, evidenced by transmission electron microscopy. Co-expression of FAM129A and mCherry-EGFP-LC3B in PCCL3 showed an increased yellow puncta formation, suggesting that FAM129Ainduces autophagy. To further confirm its role on autophagy, we knockdown FAM129A in two thyroid carcinoma cell lines (TPC1 and FTC-236). Unexpectedly, FAM129A silencing increased autophagic flux, suggesting that FAM129A inhibits autophagy in these models. We next co-transfected PCCL3 cells with FAM129A and RET/PTC1 and tested autophagy in this context. Co expression of FAM129A and RET/PTC1 oncogene in PCCL3 cells, inhibited RET/PTC1 induced autophagy. Together, our data suggest that, in normal cells FAM129A induces autophagy in order to maintain cell homeostasis and provide substrates under starvation conditions. Instead, in cancer cells, decreased autophagy may help the cells to overcome cell death. FAM129A regulates autophagy in a cell- and/or context-dependent manner. Our data reinforce the concept that autophagy can be used as a strategy for cancer treatment. PMID- 30400010 TI - Membrane estrogen receptor alpha is essential for estrogen signaling in the male skeleton. AB - The importance of estrogen receptor alpha (ERalpha) for the regulation of bone mass in males is well established. ERalpha mediates estrogenic effects both via nuclear and membrane-initiated ERalpha (mERalpha) signaling. The role of mERalpha signaling for the effects of estrogen on bone in male mice is unknown. To investigate the role of mERalpha signaling, we have used mice (Nuclear-Only-ER; NOER) with a point mutation (C451A), which results in inhibited trafficking of ERalpha to the plasma membrane. Gonadal-intact male NOER mice had a significantly decreased total body areal bone mineral density (aBMD) compared to WT littermates at 3, 6 and 9 months of age as measured by dual-energy X-ray absorptiometry (DEXA). High-resolution microcomputed tomography (uCT) analysis of tibia in 3 month-old males demonstrated a decrease in cortical and trabecular thickness in NOER mice compared to WT littermates. As expected, estradiol (E2) treatment of orchidectomized (ORX) WT mice increased total body aBMD, trabecular BV/TV and cortical thickness in tibia compared to placebo treatment. E2 treatment increased these skeletal parameters also in ORX NOER mice. However, the estrogenic responses were significantly decreased in ORX NOER mice compared with ORX WT mice. In conclusion, mERalpha is essential for normal estrogen signaling in both trabecular and cortical bone in male mice. Increased knowledge of estrogen signaling mechanisms in the regulation of the male skeleton may aid in the development of new treatment options for male osteoporosis. PMID- 30400009 TI - GnRH antagonist treatment of malignant adrenocortical tumors. AB - Aberrantly expressed G protein-coupled receptors in tumors are considered as potential therapeutic targets. We analyzed the expressions of receptors of gonadotropin-releasing hormone (GNRHR), luteinizing hormone/chorionic gonadotropin (LHCGR) and follicle-stimulating hormone (FSHR) in human adrenocortical carcinomas and assessed their response to GnRH antagonist therapy. We further studied the effects of the GnRH antagonist cetrorelix acetate (CTX) on cultured adrenocortical tumor (ACT) cells (mouse Calpha1 and Y-1, and human H295R), and in vivo in transgenic mice (SV40 T-antigen expression under inhibin alpha promoter) bearing Lhcgr and Gnrhr in ACT. Both models were treated with control (CT), CTX, human chorionic gonadotropin (hCG) or CTX+hCG, and their growth and transcriptional changes were analyzed. In situ hybridization and qPCR analysis of human adrenocortical carcinomas (n = 11-13) showed expression of GNRHR in 54/73%, LHCGR in 77/100% and FSHR in 0%, respectively. CTX treatment in vitro decreased cell viability and proliferation, and increased caspase 3/7 activity in all treated cells. In vivo, CTX and CTX+hCG (but not hCG alone) decreased ACT weights and serum LH and progesterone concentrations. CTX treatment downregulated the tumor markers Lhcgr and Gata4. Upregulated genes included Grb10, Rerg, Nfatc and Gnas, all recently found to be abundantly expressed in healthy adrenal vs ACT. Our data suggest that CTX treatment may improve the therapy of human adrenocortical carcinomas by direct action on GNRHR-positive cancer cells inducing apoptosis and/or reducing gonadotropin release, directing tumor cells towards a healthy adrenal gene expression profile. PMID- 30400012 TI - Transplantation of human mobilized mononuclear cells improved diabetic neuropathy. AB - Rodent stem cells demonstrated regenerative effects in diabetic neuropathy via improvement in nerve perfusion. As a pre-clinical step, we explored if human mobilized mononuclear cells (hMNC) would have the same effects in rats. hMNC were injected into Rt. hind-limb muscles of streptozotocin-induced diabetic nude rats, and the grafts were monitored using with MRI. After 4 weeks, the effects were compared with those in the vehicle-injected Lt. hind limbs. Nerve conduction, muscle perfusion and gene expression of sciatic nerves were assessed. Induction of diabetes decreased nerve function and expression of Mpz and Met in the sciatic nerves, which are related with myelination. hMNC injection significantly improved the amplitude of compound muscle action potentials along with muscle perfusion and sciatic nerve Mpz expression. On MRI, hypointense signals were observed for 4 weeks at the graft site, but their correlation with the presence of hMNC was detectable for only 1 week. To evaluate paracrine effects of hMNC, IMS32 cells were tested with hepatocyte growth factor (HGF), which had been reported as a myelination-related factor from stem cells. We could observe that HGF enhanced Mpz expression in the IMS32 cells. Because hMNC secreted HGF, IMS32 cells were co cultured with hMNC, and the expression of Mpz increased along with morphologic maturation. The hMNC-induced Mpz expression was abrogated by treatment of anti HGF. These results suggest that hMNC could improve diabetic neuropathy, possibly through enhancement of myelination as well as perfusion. According to in vitro studies, HGF was involved in the hMNC-induced myelination activity, at least in part. PMID- 30400011 TI - Epiregulin induces leptin secretion and energy expenditure in high-fat diet-fed mice. AB - Adipokine leptin regulates neuroendocrine circuits that control energy expenditure, thermogenesis and weight loss. However, canonic regulators of leptin secretion, such as insulin and malonyl CoA, do not support these processes. We hypothesize that epiregulin (EREG), a growth factor that is secreted from fibroblasts under thermogenic and cachexia conditions, induces leptin secretion associated with energy dissipation. The effects of EREG on leptin secretion were studied ex vivo, in the intra-abdominal white adipose tissue (iAb WAT) explants, as well as in vivo, in WT mice with diet-induced obesity (DIO) and in ob/ob mice. These mice were pair fed a high-fat diet and treated with intraperitoneal injections of EREG. EREG increased leptin production and secretion in a dose dependent manner in iAb fat explants via the EGFR/MAPK pathway. After 2 weeks, the plasma leptin concentration was increased by 215% in the EREG-treated group compared to the control DIO group. EREG-treated DIO mice had an increased metabolic rate and core temperature during the active dark cycle and displayed cold-induced thermogenesis. EREG treatment reduced iAb fat mass, the major site of leptin protein production and secretion, but did not reduce the mass of the other fat depots. In the iAb fat, expression of genes supporting mitochondrial oxidation and thermogenesis was increased in EREG-treated mice vs control DIO mice. All metabolic and gene regulation effects of EREG treatment were abolished in leptin-deficient ob/ob mice. Our data revealed a new role of EREG in induction of leptin secretion leading to the energy expenditure state. EREG could be a potential target protein to regulate hypo- and hyperleptinemia, underlying metabolic and immune diseases. PMID- 30400013 TI - Fsh stimulates Leydig cell Wnt5a production, enriching zebrafish type A spermatogonia. AB - Follicle-stimulating hormone (Fsh) modulates vertebrate spermatogenesis by regulating somatic cell functions in the testis. We have found previously that zebrafish Fsh stimulated the differentiating proliferation of type A undifferentiated spermatogonia (Aund) in an androgen-independent manner by regulating the production of growth factors and other signaling molecules in both Sertoli (SCs) and Leydig cells (LCs). For example, Fsh triggered the release of Igf3 that subsequently activated beta-catenin signaling to promote the differentiating proliferation of Aund. In the present study, we report that Fsh moreover uses the non-canonical Wnt pathway to promote the proliferation and accumulation of Aund. Initially, we found that the stimulatory effect of Fsh on the proliferation activity of Aund was further strengthened when beta-catenin signaling was inhibited, resulting in an accumulation of Aund. We then showed that this Fsh-induced accumulation of Aund was associated with increased transcript levels of the non-canonical Wnt ligand, wnt5a. In situ hybridization of insl3 mRNA, a gene expressed in LCs, combined with Wnt5a immunocytochemistry identified LCs as the cellular source of Wnt5a in the adult zebrafish testis. Addition of an antagonist of Wnt5a to incubations with Fsh decreased both the proliferation activity and the relative section area occupied by Aund, while an agonist of Wnt5a increased these same parameters for Aund. Taken together, our data suggest that Fsh triggered LCs to release Wnt5a, which then promoted the proliferation and accumulation of Aund. Hence, Fsh uses non-canonical Wnt signaling to ensure the production of Aund, while also triggering beta-catenin signaling via Igf3 to ensure spermatogonial differentiation. PMID- 30400014 TI - Gut carbohydrate inhibits GIP secretion via a microbiota/SCFA/FFAR3 pathway. AB - Mechanisms of carbohydrate-induced secretion of the two incretins namely glucagon like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are considered to be mostly similar. However, we found that mice exhibit opposite secretory responses in response to co-administration of maltose plus an alpha glucosidase inhibitor miglitol (maltose/miglitol), stimulatory for GLP-1, as reported previously, but inhibitory for GIP. Gut microbiota was shown to be involved in maltose/miglitol-induced GIP suppression, as the suppression was attenuated in antibiotics (Abs)-treated mice and abolished in germ-free mice. In addition, maltose/miglitol administration increased plasma levels of short-chain fatty acids (SCFAs), carbohydrate-derived metabolites, in the portal vein. GIP suppression by maltose/miglitol was not observed in mice lacking a SCFA receptor Ffar3, but it was normally seen in Ffar2-deficient mice. Similar to maltose/miglitol administration, co-administration of glucose plus a sodium glucose transporter inhibitor phloridzin (glucose/phloridzin) induced GIP suppression, which was again cancelled by Abs treatment. In conclusion, oral administration of carbohydrates with alpha-glucosidase inhibitors suppresses GIP secretion through a microbiota/SCFA/FFAR3 pathway. PMID- 30400016 TI - Thermoneutral housing does not influence fat mass or glucose homeostasis in C57BL/6 mice. AB - One major factor affecting physiology often overlooked when comparing data from animal models and humans is the effect of ambient temperature. The majority of rodent housing is maintained at ~22 degrees C, the thermoneutral temperature for lightly clothed humans. However, mice have a much higher thermoneutral temperature of ~30 degrees C, consequently data collected at 22 degrees C in mice could be influenced by animals being exposed to a chronic cold stress. The aim of this study was to investigate the effect of housing temperature on glucose homeostasis and energy metabolism of mice fed normal chow or a high-fat, obesogenic diet (HFD). Male C57BL/6J(Arc) mice were housed at standard temperature (22 degrees C) or at thermoneutrality (29 degrees C) and fed either chow or a 60% HFD for 13 weeks. The HFD increased fat mass and produced glucose intolerance as expected but this was not exacerbated in mice housed at thermoneutrality. Changing the ambient temperature, however, did alter energy expenditure, food intake, lipid content and glucose metabolism in skeletal muscle, liver and brown adipose tissue. Collectively, these findings demonstrate that mice regulate energy balance at different housing temperatures to maintain whole-body glucose tolerance and adiposity irrespective of the diet. Despite this, metabolic differences in individual tissues were apparent. In conclusion, dietary intervention in mice has a greater impact on adiposity and glucose metabolism than housing temperature although temperature is still a significant factor in regulating metabolic parameters in individual tissues. PMID- 30400015 TI - Growth hormone controls lipolysis by regulation of FSP27 expression. AB - Growth hormone (GH) has long been known to stimulate lipolysis and insulin resistance; however, the molecular mechanisms underlying these effects are unknown. In the present study, we demonstrate that GH acutely induces lipolysis in cultured adipocytes. This effect is secondary to the reduced expression of a negative regulator of lipolysis, fat-specific protein 27 (FSP27; aka Cidec) at both the mRNA and protein levels. These effects are mimicked in vivo as transgenic overexpression of GH leads to a reduction of FSP27 expression. Mechanistically, we show GH modulation of FSP27 expression is mediated through activation of both MEK/ERK- and STAT5-dependent intracellular signaling. These two molecular pathways interact to differentially manipulate peroxisome proliferator-activated receptor gamma activity (PPARgamma) on the FSP27 promoter. Furthermore, overexpression of FSP27 is sufficient to fully suppress GH-induced lipolysis and insulin resistance in cultured adipocytes. Taken together, these data decipher a molecular mechanism by which GH acutely regulates lipolysis and insulin resistance in adipocytes. PMID- 30400018 TI - MECHANISMS IN ENDOCRINOLOGY: Estrogens in consumer milk: is there a risk to human reproductive health? AB - Possible effects of xenoestrogens on human health, in particular on male reproductive health, have attracted considerable attention in recent years. Cow's milk was suggested in numerous publications as one of possible sources of xenoestrogens that could affect human health. Although milk has undoubtedly many beneficial health effects and could even have a role in reducing incidence of some cancers, concerns were raised about presumably high levels of estrogens in cow's milk. In intensive farming, concentrations of estrogens in milk are higher due to long milking periods that today extend long into the pregnancy, when concentrations of estrogens in the cow's body rise. Numerous studies examined potential effects of milk on reproductive health and endocrine-related cancers in both experimental studies with laboratory animals, and in human epidemiological studies. In the present review article, we compiled a review of recently published literature about the content of estrogens in cow's milk and potential health effects, in particular on reproductive system, in humans. Although results of published studies are not unequivocal, it seems that there is stronger evidence suggesting that amounts of estrogens in cow's milk are too low to cause health effects in humans. PMID- 30400017 TI - Regulation of adipose tissue inflammation by adenosine 2A receptor in obese mice. AB - Adenosine 2A receptor (A2AR) exerts anti-inflammatory effects. However, the role of A2AR in obesity-associated adipose tissue inflammation remains to be elucidated. The present study examined the expression of A2AR in adipose tissue of mice with diet-induced obesity and determined the effect of A2AR disruption on the status of obesity-associated adipose tissue inflammation. WT C57BL/6J mice and A2AR-disrupted mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity and adipose tissue inflammation. In vitro, bone marrow-derived macrophages from A2AR-disrupted mice and WT control mice were treated with palmitate and examined for macrophage proinflammatory activation. Compared with that of low-fat diet (LFD)-fed WT mice, A2AR expression in adipose tissue of HFD fed WT mice was increased significantly and was present predominantly in adipose tissue macrophages. The increase in adipose tissue A2AR expression in HFD-fed mice was accompanied with increased phosphorylation states of c-Jun N-terminal kinase 1 p46 and nuclear factor kappa B p65 and mRNA levels of interleukin (Il) 1beta, Il6 and tumor necrosis factor alpha. In A2AR-disrupted mice, HFD feeding induced significant increases in adipose tissue inflammation, indicated by enhanced proinflammatory signaling and increased proinflammatory cytokine expression, and adipose tissue insulin resistance, indicated by a decrease in insulin-stimulated Akt phosphorylation relative to those in WT mice. Lastly, A2AR disruption enhanced palmitate-induced macrophage proinflammatory activation. Taken together, these results suggest that A2AR plays a protective role in obesity-associated adipose tissue inflammation, which is attributable to, in large part, A2AR suppression of macrophage proinflammatory activation. PMID- 30400020 TI - Differential efatutazone's impact on mammary neoplasia dependent upon Brca1 dose. PMID- 30400019 TI - Association between the metabolically healthy obese phenotype and the risk of myocardial infarction: results from the Kailuan study. AB - Objective This study aimed to determine if the metabolically healthy obese (MHO) is associated with an increased risk of myocardial infarction (MI) in Chinese population. Design The Kailuan study is a community-based prospective cohort study. Methods BMI and metabolic syndrome (MetS) were assessed in 91 866 participants without a history of MI or stroke. Participants were categorised into six mutually exclusive groups according to the BMI-MetS status: normal weight (BMI: <= 18.5to < 24.0 kg/m2) without MetS (MH-NW), normal weight with MetS (MUH-NW), overweight (BMI: <= 24.0to < 28.0 kg/m2) without MetS (MH-OW), overweight with MetS (MUH-OW), obese (BMI >= 28.0 kg/m2) without MetS (MHO) and obese with MetS (MUO). The hazard ratio (HR) with 95% CI was calculated for the incidence of MI using a multivariable Cox model. Results A total of 6745 (7.34%) individuals were classified as MHO. During a median 8-year follow-up, 1167 (1.27%) participants developed MI. The MHO group had an increased risk of MI (HR: 1.76, 95% CI: 1.37-2.25) in comparison with the MH-NW group after adjusting for potential confounding variables. After a similar adjustment, the risk of MI was significantly elevated in the MUH-NW (HR: 1.62, 95% CI: 1.28-2.05), MUH-OW (HR: 1.98, 95% CI: 1.67-2.35) and MUO group (HR: 2.06, 95% CI: 1.70-2.49). Conclusions MHO subjects showed a substantially higher risk of MI in comparison with MH-NW subjects. That said, even without measurable metabolic abnormalities, obesity was associated with a higher risk of MI. PMID- 30400021 TI - Assessing the prognostic value of PAX2 and PTEN in endometrial carcinogenesis. AB - In order to avoid the consequences of over- and under-treatment of endometrial hyperplasia, diagnostic accuracy and progression risk assessment must be improved. The aim of this study was to assess whether PAX2 or PTEN expression could predict progression-free survival in endometrial intraepithelial neoplasia (EIN) and endometrial endometrioid carcinoma (EEC). Immunohistochemistry for detection of PAX2 and PTEN was performed on 348 endometrial samples; 75 proliferative endometrium (PE), 36 EIN and 237 EEC. Cases classified as PTEN null (1 or more glands negatively stained) were more prevalent in EEC than in PE and EIN (64% EEC vs 11% PE/EIN). A progressive decrease in PAX2 expression was observed from PE to EIN to EEC. Long-term clinical follow-up (6-310 months, median: 126) was available for 62 PE cases, all 36 EIN cases and 178 EEC cases. No patients with PE demonstrated progression to EIN or EEC. Progression of disease was observed in 10 (28%) EIN patients. These patients had significantly lower PAX2 expression than those that regressed (P = 0.005). Progression-free survival analysis revealed that EIN patients with a high-risk PAX2 expression score (H-score <=75) had a higher probability of progression of disease in comparison to those with a low-risk score (H-score >75). PAX2 expression was not prognostic in EEC nor was PTEN status of prognostic value in either EIN or EEC. PAX2 expression analysis by means of H-score has prognostic potential for the identification of high-risk progression cases in EIN but needs to be validated in a larger cohort. PMID- 30400022 TI - A comparative analysis of British and American Society of Echocardiography recommendations for the assessment of left ventricular diastolic function. AB - At present there are two recognised guidelines for the echocardiographic assessment of left ventricular diastolic function provided by the British Society of Echocardiography and American Society of Echocardiography/European Association of Cardiovascular Imaging. However, no direct comparison of these guidelines has been performed to establish whether they provide similar diastolic grading. One hundred and eighty-nine consecutive patients in sinus rhythm who underwent transthoracic echocardiography for a primary indication of either heart failure assessment or assessment of left ventricular systolic function were extracted from our database (McKesson Cardiology). Left ventricular diastolic function assessment was performed using both guidelines and the results were compared. Chi square, Kappa score and one-way ANOVA were used to evaluate the data at a level of P < 0.05. The most frequent outcome was unclassifiable diastolic function with significantly more patients being labelled unclassified with the British compared to American guidelines (47.4 vs 20.5%, P < 0.0001). Having excluded all unclassifiable patients, a significant difference still existed between the two guidelines with a higher proportion of grade one outcomes awarded by the ASE/EACVI guidelines. When grading subcategories were individually compared, there was significantly more grade one diastolic gradings awarded by American compared to the British guidelines (40.7 vs 20.1%, P < 0.0001). In 47% of patients it was not possible to grade diastolic function using the British guidelines, compared to 21% using the American guidelines. For those patients where grading was possible, there was a significant difference in patients classified with normal and grade one diastolic function when using British and American guidelines. PMID- 30400023 TI - Current concepts and challenges to unravel the role of iodothyronine deiodinases in human neoplasias. AB - Thyroid hormones (THs) are essential for the regulation of several metabolic processes and the energy consumption of the organism. Their action is exerted primarily through interaction with nuclear receptors controlling the transcription of thyroid hormone-responsive genes. Proper regulation of TH levels in different tissues is extremely important for the equilibrium between normal cellular proliferation and differentiation. The iodothyronine deiodinases types 1, 2 and 3 are key enzymes that perform activation and inactivation of THs, thus controlling TH homeostasis in a cell-specific manner. As THs seem to exert their effects in all hallmarks of the neoplastic process, dysregulation of deiodinases in the tumoral context can be critical to the neoplastic development. Here, we aim at reviewing the deiodinases expression in different neoplasias and exploit the mechanisms by which they play an essential role in human carcinogenesis. TH modulation by deiodinases and other classical pathways may represent important targets with the potential to oppose the neoplastic process. PMID- 30400024 TI - Thyroid hormone negatively regulates tumorigenesis through suppression of BC200. AB - Thyroid hormone (T3) and its receptor (TR) are involved in cancer progression. While deregulation of long non-coding RNA (lncRNA) expression has been detected in many tumor types, the mechanisms underlying specific involvement of lncRNAs in tumorigenicity remain unclear. Experiments from the current study revealed negative regulation of BC200 expression by T3/TR. BC200 was highly expressed in hepatocellular carcinoma (HCC) and effective as an independent prognostic marker. BC200 promoted cell growth and tumor sphere formation, which was mediated via regulation of cell cycle-related genes and stemness markers. Moreover, BC200 protected cyclin E2 mRNA from degradation. Cell growth ability was repressed by T3, but partially enhanced upon BC200 overexpression. Mechanistically, BC200 directly interacted with cyclin E2 and promoted CDK2-cyclin E2 complex formation. Upregulation of cell cycle-related genes in hepatoma samples was positively correlated with BC200 expression. Our collective findings support the utility of a potential therapeutic strategy involving targeting of BC200 for the treatment of HCC. PMID- 30400025 TI - The potential role of miRNAs and exosomes in chemotherapy in ovarian cancer. AB - Chemoresistance is one of the major obstacles in the treatment of cancer patients. It poses a fundamental challenge to the effectiveness of chemotherapy and is often linked to relapse in patients. Chemoresistant cells can be identified in different types of cancers; however, ovarian cancer has one of the highest rates of chemoresistance-related relapse (50% of patients within 5 years). Resistance in cells can either develop through prolonged cycles of treatment or through intrinsic pathways. Mechanistically, the problem of drug resistance is complex mainly because numerous factors are involved, such as overexpression of drug efflux pumps, drug inactivation, DNA repair mechanisms and alterations to and/or mutations in the drug target. Additionally, there is strong evidence that circulating miRNAs participate in the development of chemoresistance. Recently, miRNAs have been identified in exosomes, where they are encapsulated and hence protected from degradation. These miRNAs within exosomes (exo-miRNAs) can regulate the gene expression of target cells both locally and systemically. Exo-miRNAs play an important role in disease progression and can potentially facilitate chemoresistance in cancer cells. In addition, and from a diagnostic perspective, exo-miRNAs profiles may contribute to the development of predictive models to identify responder and non-responder chemotherapy. Such model may also be used for monitoring treatment response and disease progression. Exo-miRNAs may ultimately serve as both a predictive biomarker for cancer response to therapy and as a prognostic marker for the development of chemotherapy resistance. Therefore, this review examines the potential role of exo-miRNAs in chemotherapy in ovarian cancer. PMID- 30400026 TI - Immunotherapy failure in adrenocortical cancer: where next? AB - Excerpt: Adrenocortical carcinoma (ACC) is a rare endocrine neoplasia, characterized by an overall dismal prognosis and its clinical manifestations are the consequence of either steroid excess or tumor mass progression. Surgery is the mainstay of therapy. For patients with locally advanced or metastatic ACC, not amenable to surgery, Mitotane and cytotoxic chemotherapy (with etoposide, doxorubicin and cisplatin - EDP scheme) are the systemic treatments currently in use. PMID- 30400027 TI - Virilising ovarian tumors: a single center experience. AB - AIMS: Literature on virilising ovarian tumors (VOT) is limited to case reports and series reporting single pathological type. We have analyzed the clinical, hormonal, radiological, histological, management and outcome data of VOT. MATERIALS AND METHODS: This retrospective study was conducted at a tertiary health care center from Western India. Consecutive patients with VOT presenting to our endocrine center between 2002 and 2017 were included. RESULTS: Our study included 13 patients of VOT, two of whom were postmenopausal. All patients in the reproductive age group had secondary amenorrhea except one who presented with primary amenorrhea. Modified F and G score (mFG) at presentation was 24+/-4.3 and all patients had severe hirsutism (mFG >= 15). Change in voice (n=11) and clitoromegaly (n=7) were the other most common virilising symptoms. Duration of symptoms varied from 4 to 48 months. Median serum total testosterone level at presentation was 5.6 ng/ml with severe hyperandrogenemia (serum testosterone >= 2 ng/ml) but unsuppressed gonadotropins in all patients. Transabdominal ultrasonography (TAS) detected VOT in all except one. Ten patients underwent unilateral salpingo-oophorectomy whereas three patients (peri- or postmenopausal) underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. Seven patients had Sertoli-Leydig cell tumor, three had steroid cell tumor and two had Leydig cell tumor and one had miscellaneous sex cord stromal tumor. All patients had normalization of serum testosterone after tumor excision. CONCLUSIONS: Virilising ovarian tumors present with severe hyperandrogenism and hyperandrogenemia. Sertoli-Leydig cell tumor is the most common histological subtype. Surgery is the treatment of choice with good outcome. PMID- 30400028 TI - Not the same thing: metastatic PTCs have a different background than ATCs. AB - Anaplastic thyroid cancer (ATC) is a rare but highly aggressive form of thyroid cancer. By contrast, differentiated Papillary Thyroid Cancer (PTC) only rarely behave aggressively and develop distant metastasis. Whether distantly metastatic PTC (DM-PTC) and ATC share a common genetic background is still to be defined. We used a Next Generation Sequencing (NGS) to explore the genetic background of a cohort of ATC and DM-PTC and a group of well-differentiated PTC that did not developed distant metastasis as control (ctrl-PTC). A panel of 128 amplicons within 21 thyroid cancer related genes was analyzed in a set of 151 thyroid cancer samples including 66 ATCs and DM-PTCs. We showed that the ATC/DM-PTC group had an overall mutational load higher than ctrl-PTCs and that ATCs and DM-PTCs are characterized by a different genetic background, with the exception of mutations in the TERT promoter that were overrepresented in both ATCs (61.1%) and DM-PTCs (48.2%) versus non aggressive ctrl-PTCs (7.6%). In ATCs, TERT promoter mutations were frequently associated with p53 mutations, while in the DM-PTCs no significant co-occurrence was observed. No significant association of MED12 mutations with aggressiveness of thyroid cancer was observed in our analysis. Finally, correlation analysis showed that increasing number of mutations negatively impact on patient overall survival also within the ATC and DM-PTC group. Overall our analysis further highlights the relevance of TERT promoter mutations in driving aggressiveness and provides new pieces of information in the definition of aggressiveness evolution of thyroid cancer lesions. PMID- 30400029 TI - Social defeat stimulates local glucocorticoid regeneration in lymphoid organs. AB - Stress is an important risk factors for human diseases. It activates the hypothalamic-pituitary-adrenal (HPA) axis and increases plasma glucocorticoids, which are powerful regulators of immune system. The response of the target cells to glucocorticoids depends not only on the plasma concentrations of cortisol and corticosterone but also on their local metabolism. This metabolism is catalysed by 11beta?-hydroxysteroid dehydrogenases type 1 and 2, which interconvert glucocorticoid hormones cortisol and corticosterone and their 11-oxo metabolites cortisone and 11-dehydrocorticosterone. The goal of this study was to determine whether stress modulates glucocorticoid metabolism within lymphoid organs - the structures where immune cells undergo development and activation. Using the resident-intruder paradigm, we studied the effect of social stress on glucocorticoid metabolism in primary and secondary lymphoid organs of Fisher 344 (F344) and Lewis (LEW) rats, which exhibit marked differences in their HPA axis response to social stressors and inflammation. We show that repeated social defeat increased the regeneration of corticosterone from 11-dehydrocorticosterone in the thymus, spleen and mesenteric lymphatic nodes (MLN). Compared with the F344 strain, LEW rats showed higher corticosterone regeneration in splenocytes of unstressed rats and in thymic and MLN mobile cells after stress but corticosterone regeneration in the stroma of all lymphoid organs was similar in both strains. Inactivation of corticosterone to 11-dehydrocorticosterone was found only in the stroma of lymphoid organs but not in mobile lymphoid cells and was not upregulated by stress. Together, our findings demonstrate the tissue- and strain-dependent regeneration of glucocorticoids following social stress. PMID- 30400030 TI - Chronic estrogen affects TIDA neurons through IL-1beta and NO: effects of aging. AB - Women are chronically exposed to estrogens through oral contraceptives, hormone replacement therapy or environmental estrogens. We hypothesized that chronic exposure to low levels of estradiol-17beta (E2) can induce inflammatory and degenerative changes in the tuberoinfundibular dopaminergic (TIDA) system leading to reduced dopamine synthesis and hyperprolactinemia. Young (Y; 3-4 months) and middle-aged (MA; 10-12 months) Sprague-Dawley rats that were intact or ovariectomized (OVX), were either sham-implanted or implanted with a slow-release E2 pellet (20ng E2/day for 90 days). To get mechanistic insight, adult 3-4-month old wild-type, inducible nitric oxide synthase (iNOS) and IL-1 receptor (IL-1R) knock out mice were subjected to a similar treatment. Hypothalamic areas corresponding to the TIDA system were analyzed. E2 treatment increased IL-1beta protein and nitrate levels in the arcuate nucleus of intact animals (Y and MA). Nitration of tyrosine hydroxylase in the median eminence increased with E2 treatment in both intact and OVX animals. There was no additional effect of age. This was accompanied by a reduction in dopamine levels and an increase in prolactin in intact animals. E2 treatment increased nitrate and reduced dopamine levels in the hypothalamus and increased serum prolactin in wild-type mice. In contrast, the effect of E2 on nitrate levels was blocked in IL-1 receptor KO mice and the effect on dopamine and prolactin were blocked in iNOS KO animals. Taken together, these results show that chronic exposure to low levels of E2 decreases TIDA activity through a cytokine-nitric oxide-mediated pathway leading to hyperprolactinemia and that aging could promote these degenerative changes. PMID- 30400031 TI - Anti-Mullerian hormone and ovarian aging in mares. AB - Anti-Mullerian hormone (AMH) is used as a marker of follicle population numbers and potential fertility in several species including horses but limited data exist across the lifespan. No one has decreased ovarian reserve experimentally to investigate whether a corresponding, quantitative decrease in AMH results. Concentrations of AMH across the lifespan were compiled from 1101 equine females sampled from birth to >33 years of age. Young and old mares (averaging 6 and 19 years) were hemi-ovariectomized and circulating AMH was assessed before and daily thereafter for 15 days. The remaining ovary was removed later and blood drawn again before and after this second surgery for AMH determination. Polynomial regression analysis and analysis of mares grouped by 5 year intervals of age demonstrated AMH concentrations to be higher in mares aged 5-10 and 10-15 years than 0-5 years of age and lower in mares after 20 years of age. There was high variability in AMH concentrations among neonatal fillies, some of which had concentrations typical of males. Hemi-ovariectomy was followed by a decrease of AMH, almost exactly halving concentrations in intact mares. Concentrations of AMH had returned to intact levels in old mares before complete ovariectomy, as if exhibiting ovarian compensatory hypertrophy, but recovery of AMH was not evident in young mares. AMH may reflect ovarian senescence in mares after 20 years of age but is too variable to do so in the first two decades of life. The ovarian endocrine response to hemi-ovariectomy in mares appears to change with age. PMID- 30400032 TI - The ERalpha membrane pool modulates the proliferation of pituitary tumours. AB - The molecular mechanisms underlying the ERalpha nuclear/cytoplasmic pool that modulates pituitary cell proliferation have been widely described, but it is still not clear how ERalpha is targeted to the plasma membrane. The aim of this study was to analyse ERalpha palmitoylation and the plasma membrane ERalpha (mERalpha) pool, and their participation in E2-triggered membrane-initiated signalling in normal and pituitary tumour cell growth. Cell cultures were prepared from anterior pituitaries of female Wistar rats and tumour GH3 cells, and treated with 10nM of estradiol (E2). The basal expression of ERalpha was higher in tumour GH3 than in normal pituitary cells. Full-length palmitoylated ERalpha was observed in normal and pituitary tumour cells, demonstrating that E2 stimulation increased both, ERalpha in plasma membrane and ERalpha and caveolin-1 interaction after short-term-treatment. In addition, the Dhhc7 and Dhhc21 palmitoylases were negatively regulated after sustained stimulation of E2 for 3h. Although the uptake of BrdU into the nucleus in normal pituitary cells was not modified by E2, a significant increase in the GH3 tumoral cell, as well as ERK1/2 activation, with this effect being mimicked by PPT, a selective antagonist of ERalpha. These proliferative effects were blocked by ICI 182780 and the global inhibitor of palmitoylation. These findings indicate that ERalpha palmitoylation modulated the mERalpha pool and consequently the ERK1/2 pathway, thereby contributing to pituitary tumour cell proliferation. These results suggest that the plasma membrane ERalpha pool might be related to the proliferative behaviour of prolactinoma, and may be a marker of pituitary tumour growth. PMID- 30400033 TI - Exhaustive acute exercise-induced ER stress is attenuated in IL-6 knockout mice. AB - The endoplasmic reticulum (ER) stress and inflammation relationship occurs at different levels and is essential for the adequate homeostatic function of cellular systems, becoming harmful when chronically engaged. Intense physical exercise enhances serum levels of interleukin 6 (IL-6). In response to a chronic exhaustive physical exercise protocol, our research group verified an increase of the IL-6 concentration and ER stress proteins in extensor digitorium longus (EDL) and soleus. Based on these results, we hypothesized that IL-6 knockout mice would demonstrate a lower modulation in the ER stress proteins compared to the wild type mice. To clarify the relationship between exercise-induced IL-6 increased and ER stress, we studied the effects of an acute exhaustive physical exercise protocol on the levels of ER stress proteins in the skeletal muscles of IL-6 knockout (KO) mice. The wild-type (WT) group displayed a higher exhaustion time compared to the IL-6 KO group. After 1 hour of the acute exercise protocol, the serum levels of IL-6 and IL-10 were enhanced in the WT group. Independent of the experimental group, the CHOP and cleaved caspase 12/total caspase 12 ratio in EDL as well as ATF6 and CHOP in soleus were sensitive to the acute exercise protocol. Compared to the WT group, the oscillation patterns over time of BiP in EDL and soleus as well as of peIF2-alpha/eIF2-alpha ratio in soleus were attenuated for the IL-6 KO group. In conclusion, IL-6 seems to be related with the ER stress homeostasis, once knockout mice presented attenuation of BiP in EDL and soleus as well as of pEiF2-alpha/EiF2-alpha ratio in soleus after the acute exhaustive physical exercise protocol. PMID- 30400034 TI - Histone demethylase LSD1 and biological sex: impact on blood pressure and aldosterone production. AB - Human risk allele carriers of Lysine-Specific Demethylase 1 (LSD1) and LSD1 deficient mice have salt sensitive hypertension for unclear reasons. We hypothesized that LSD1 deficiency causes dysregulation of aldosterone's response to salt intake resulting in increased cardiovascular risk factors [blood pressure and microalbumin]. Furthermore, we determined the effect of biological sex on these potential abnormalities. To test our hypotheses, LSD1 male and female heterozygote knockout (LSD1+/-) and wild type (WT) mice were assigned to two age groups: 18 weeks and 36 weeks. Plasma aldosterone levels and aldosterone production from zona glomerulosa cells studied ex vivo were greater in both male and female LSD1+/- mice consuming a liberal salt diet as compared to WT mice consuming the same diet. However, salt sensitive blood pressure elevation and increased microalbuminuria were only observed in male LSD1+/- mice. These data suggest that LSD1 interacts with aldosterone's secretory response to salt intake. Lack of LSD1 causes inappropriate aldosterone production on a liberal salt diet; males appear to be more sensitive to this aldosterone increase as males, but not females, develop salt sensitivity of blood pressure and increased microalbuminuria. The mechanism responsible for the cardiovascular protective effect in females is uncertain but may be related to estrogen modulating the effect of mineralocorticoid receptor activation. PMID- 30400035 TI - Decidual expression and regulation of fatty acid desaturase 3 during mouse decidualization. AB - Decidualization is required for the successful establishment of pregnancy in rodents and primates. Fatty acid desaturase 3 (Fads3) belongs to the fatty acid desaturase family, which is a crucial enzyme for highly unsaturated fatty acid biosynthesis. However, the expression, regulation and function of Fads3 during early pregnancy in mice are still unknown. In this study, we examined Fads3 expression, regulation and function during mouse decidualization. The expression of Fads3 is detected in the subluminal stromal cells at implantation site on day 5 of pregnancy, but not at inter-implantation site and in day 5 pseudopregnant uteri. Compared to delayed implantation, Fads3 is strongly expressed after delayed implantation is activated by estrogen treatment. From days 6 to 8, Fads3 mRNA signals are significantly detected in the decidua. In ovariectomized mice, estrogen significantly stimulates Fads3 expression. However, estrogen has no effect on Fads3 expression in ovariectomized ERalpha-deficient mice, suggesting that estrogen regulation on Fads3 expression is ERalpha dependent. When ovariectomized mice were treated with progesterone, Fads3 expression is significantly increased by progesterone. Progesterone stimulation on Fads3 expression is also detected in cultured stromal cells, which is abrogated by RU486 treatment. These data indicate that progesterone upregulation on Fads3 expression is progesterone receptor-dependent. Fads3 knockdown by siRNA reduces in vitro decidualization of mouse stromal cells. Taken together, Fads3 may play an important role during mouse decidualization. PMID- 30400036 TI - Vincamine as a GPR40 agonist improves glucose homeostasis in type 2 diabetic mice. AB - Vincamine, a monoterpenoid indole alkaloid extracted from madagascar periwinkle, is clinically used for the treatment of cardio-cerebrovascular diseases, while also treated as a dietary supplement with nootropic function. Given the neuronal protection of vincamine and the potency of beta-cell amelioration in treating type 2 diabetes mellitus (T2DM), we investigated the potential of vincamine in protecting beta-cells and ameliorating glucose homeostasis in vitro and in vivo. Interestingly, we found that vincamine could protect INS-832/13 cells function by regulating G-protein-coupled receptor 40 (GPR40)/cAMP/Ca2+/IRS2/PI3K/Akt signaling pathway, while increase glucose-stimulated insulin secretion (GSIS) via modulating GPR40/cAMP/Ca2+/CaMKII pathway, which reveals a novel mechanism underlying GPR40-mediated cell protection and GSIS in INS-832/13 cells. Moreover, administration of vincamine effectively ameliorated glucose homeostasis in either HFD/STZ or db/db type 2 diabetic mice. To our knowledge, our current work might be the first report on vincamine targeting GPR40 and its potential in the treatment of T2DM. PMID- 30400037 TI - AAV8-mediated gene transfer of microRNA-132 improves beta-cell function in mice fed a high fat diet. AB - MicroRNAs have emerged as essential regulators of beta-cell function and beta cell proliferation. One of these microRNAs, miR-132, is highly induced in several obesity models and increased expression of miR-132 in vitro modulates glucose stimulated insulin secretion. The aim of this study was to investigate the therapeutic benefits of miR-132 overexpression on beta-cell function in vivo. To overexpress miR-132 specifically in beta-cells, we employed adeno-associated virus (AAV8) mediated gene transfer using the rat insulin promoter in a double stranded, self-complementary AAV vector to overexpress miR-132. Treatment of mice with dsAAV8-RIP-mir132 increased miR-132 expression in beta-cells without impacting expression of miR-212 or miR-375. Surprisingly, overexpression of miR 132 did not impact glucose homeostasis in chow fed animals. Overexpression of miR 132 did improve insulin secretion and hence glucose homeostasis in high-fat diet fed mice. Furthermore, miR-132 overexpression increased beta-cell proliferation in mice fed a high-fat diet. In conclusion, our data show that AAV8-mediated gene transfer of miR-132 to beta-cells improves beta-cell function in mice in response to a high fat diet. This suggests that increased miR-132 expression is beneficial for beta-cell function during hyperglycemia and obesity. PMID- 30400038 TI - Androgens modulate glucocorticoid receptor activity in adipose tissue and liver. AB - Glucocorticoid signaling is context-dependent, and in certain scenarios glucocorticoid receptors (GR) are able to engage with other members of the nuclear receptor subfamily. Glucocorticoid signaling can exert sexually dimorphic effects, suggesting a possible interaction with androgen sex hormones. We therefore set out to determine the crosstalk between glucocorticoids and androgens in metabolic tissues including white adipose tissue, liver and brown adipose tissue. Thereto we exposed male C57BL/6J mice to elevated levels of corticosterone in combination with an androgen receptor (AR) agonist or an AR antagonist. Systemic and local glucocorticoid levels were determined by mass spectrometry, tissue expression of glucocorticoid-responsive genes and protein was measured by RT-qPCR and Western blot, respectively. To evaluate crosstalk in vitro, cultured white and brown adipocytes were exposed to a combination of corticosterone and an androgen agonist. We found that AR agonism potentiated transcriptional response to GR in vitro in white and brown adipocytes and in vivo in white and brown adipose tissue. Conversely, AR antagonism substantially attenuated glucocorticoid signaling in white adipose tissue and liver. In white adipose tissue this effect could partially be attributed to decreased 11B hydroxysteroid dehydrogenase type 1-mediated glucocorticoid regeneration upon AR antagonism. In liver, attenuated GR activity was independent of active glucocorticoid ligand levels. We conclude that androgen signaling modulates GR transcriptional output in a tissue-specific manner. PMID- 30400039 TI - HOPX homeobox methylation in differentiated thyroid cancer and its clinical relevance. AB - BACKGROUND: The inactivation of the tumor-suppressor homeodomain-only protein X (HOPX) usually involves promoter methylation in several cancer types. This study aimed to investigate the HOPX-beta mRNA expression and promoter methylation and their clinical relevance in differentiated thyroid cancer (DTC). PATIENTS AND METHODS: Clinicopathological data and paraffin-embedded thyroid tumor tissues from 21 patients with DTC and 6 with benign tumors (T) and their nontumor parenchyma (NT) were investigated. Tumor cell lines (FTC238, FTC236 and WRO) were treated with demethylating agent. HOPX-beta mRNA expression was assessed by qRT PCR and methylation status by Q-MSP. Thyroid cancer data from Cancer Genome Atlas (TCGA) was also collected. RESULTS: HOPX-beta mRNA re-expression in two cells lines treated with demethylating agent was observed concomitantly with reduced promoter methylation. Reduced mRNA expression in T group compared to their NT was observed, and reduced protein expression in T compared to NT was observed in 3 cases. Low mRNA expression with high methylation status was detected in 6/14 DTC samples. High methylation status was associated with older age at diagnosis, recurrent or progressive disease and with the presence of new neoplasm event post initial therapy while hyper-methylation correlated with worse overall survival, worse disease free status and older age. CONCLUSION: a moderate coupling of downregulation of HOPX-beta mRNA expression in DTC followed by high HOPX-beta promoter methylation was observed however; high HOPX promoter methylation status was associated with the worse prognosis of DTC patients. PMID- 30400040 TI - Diurnal variation of steroid hormones and reference intervals using mass spectrometric analysis. AB - OBJECTIVE: Accurate measurement of steroid hormones remains challenging. Mass spectrometry affords a reliable means for quantitating steroid profiles accurately. Our objective was to establish and define 1. the extent of diurnal fluctuations in steroid concentrations that potentially necessitate strict adherence to time of sample acquisition and 2. time dependent steroid reference intervals. DESIGN: Nine steroid markers were examined in couplets in males and females. METHODS: Using isotope dilution high performance liquid chromatography tandem mass spectrometric (LC-MS/MS) analysis, we developed a multi-steroid profile requiring only a minimal volume of serum (0.1mL). Couplet (AM and PM) measurements of steroid hormones for 120 healthy females (F) and 62 healthy males (M) were obtained. Patients were recruited from several participating centers. RESULTS: The following diurnal values were noted to be significant in both females and males: Cortisone, Cortisol, Corticosterone, 11 Deoxycortisol (11 DOC), Androstenedione, 17a-Hydroxyprogesterone (17 OHP) and Dehydroepiandrosterone (DHEA). Testosterone was only found to have significant diurnal variance in males. Progesterone showed no significant difference in AM and PM values for either groups and thus may provide an internal control. CONCLUSIONS: When diagnosing endocrine disorders, it is imperative to acknowledge the 24-hour diurnal variation of the biochemical steroid markers. We highlight the importance of standardization of collection times and appropriate implementation of reference intervals. PMID- 30400041 TI - SRC1 Deficiency in Hypothalamic Arcuate Nucleus Increases Appetite and Body Weight. AB - Appetite is tightly controlled by neural and hormonal signals in animals. In general, steroid receptor co-activator 1 (SRC1) enhances steroid hormone signalling in energy balance and serves as a common co-activator of several steroid receptors, such as estrogen and glucocorticoid receptors. However, the key roles of SRC1 in energy balance remain largely unknown. We first confirmed that SRC1 is abundantly expressed in the hypothalamic arcuate nucleus (ARC), which is a critical centre for regulating feeding and energy balance; it is further co-localised with agouti-related protein and proopiomelanocortin neurons in the arcuate nucleus. Interestingly, local SRC1 expression changes with the transition between sufficiency and deficiency of food supply. To identify its direct role in appetite regulation, we repressed SRC1 expression in the hypothalamic ARC using lentivirus shRNA and found that SRC1 deficiency significantly promoted food intake and body weight gain, particularly in mice fed with a high-fat diet. We also found the activation of the AMP-activated protein kinase (AMPK) signalling pathway due to SRC1 deficiency. Thus, our results suggest that SRC1 in the ARC regulates appetite and body weight and that AMPK signalling is involved in this process. We believe that our study results have important implications for recognising the overlapping and integrating effects of several steroid hormones/receptors on accurate appetite regulation in future studies. PMID- 30400042 TI - Gremlin, Noggin, Chordin and follistatin differentially modulate BMP induced suppression of androgen secretion by bovine ovarian theca cells. AB - Bone morphogenetic proteins (BMP) are firmly implicated as intra-ovarian regulators of follicle function and steroidogenesis but information is lacking regarding the regulation of BMP signalling by extracellular binding proteins co expressed in the ovary. In this study we compared the abilities of four BMP binding proteins (gremlin, noggin, chordin, follistatin) to antagonize the action of four different BMPs (BMP2 BMP4, BMP6, BMP7) on LH-induced androstenedione secretion by bovine theca cells in primary culture. Expression of the four BMP binding proteins and BMPs investigated here has previously been documented in bovine follicles. All four BMPs suppressed androstenedione secretion by >85%. Co treatment with gremlin antagonized BMP2- and, less potently, BMP4-induced suppression of androgen secretion but did not affect responses to BMP6 and BMP7. Noggin antagonized the effects of three BMPs (rank order: BMP4 > BMP2 > BMP7) but did not affect the response to BMP6. Follistatin partially reversed the suppressive effects of BMP6 on androgen secretion but did not affect BMP2, BMP4 and BMP7 action. Chordin had no effect on the response to any of the four BMPs. BMP6 treatment upregulated thecal expression of GREM1, NOG, CHRD and SMAD6 mRNA whilst inhibiting expression of the four BMPs. Taken together with previous work documenting the intra-ovarian expression of different BMPs, BMP binding proteins and signalling receptors, these observations reinforce the conclusion that extracellular binding proteins selectively modulate BMP-dependent alterations in thecal steroidogenesis. As such they likely constitute an important regulatory component of this, and other intra-ovarian actions of BMPs. PMID- 30400043 TI - Pharmacological modulation of two melanocortin-5 receptors by MRAP2 proteins in zebrafish. AB - Melanocortin receptor accessory protein 2 (MRAP2) plays an important role in regulating melanocortin receptors. In zebrafish, MRAP2a and MRAP2b show distinct pharmacological effects on MC4R activity, but how MRAP2 protein regulates other zebrafish melanocortin receptors is barely studied. Zebrafish have two mc5r genes: mc5ra and mc5rb, it is still vague which one is the homologous isoform to the mammalian paralog. Here we utilize synteny and phylogenetic analysis to demonstrate the evolutionary conservation of zebrafish MC5Ra and MC5Rb among different species. We also show that MRAP2a and MRAP2b could interact and regulate surface expression of two MC5R receptors. Bimolecular fluorescence complementation (BiFC) studies suggest that zebrafish MC5Rs could form homo- and hetero- dimers, which are suppressed by co-expression with MRAP2 proteins. In comparison with mammalian MC5R-MRAP2 system and different pharmacological effects of zMRAP2 protein on MC5Rs, zmc5ra is identified as the evolutionary homologous paralog to the mammals and it is regulated by metabolic state in zebrafish brain region. PMID- 30400044 TI - Increased Cardiovascular Risk in Thyroid Cancer Patients Taking Levothyroxine: a Nationwide Cohort Study in Korea. AB - OBJECTIVE: Many thyroid cancer patients are exposed to long-term thyroid stimulating hormone (TSH) suppression, in many cases as lifetime treatment, and are consequently subjected to risk for cardiovascular disease. We investigated incidence of coronary heart disease (CHD) and ischemic stroke among thyroid cancer patients compared to matched control subjects. DESIGN: Retrospective cohort study Methods: A total of 182,419 subjects who received thyroidectomy for thyroid cancer during 2004-2012 were selected from the Korean National Health Insurance data, which covers approximately 97% of the entire Korean population. Propensity score matching was used to select non-cancer controls. Cox proportional hazards regression analysis was used to determine relative risk of coronary heart disease, and ischemic stroke. Mean follow-up was 4.32 years. RESULTS: Thyroid cancer patients had elevated risk for CHD and ischemic stroke with HR 1.15 (95% CI 1.10-1.22), and 1.15 (1.09-1.22), respectively. This risk was marked in those who took higher dosage of levothyroxine (HR 1.47, 95% CI 1.34 1.60 for CHD and HR 1.56, 95% CI 1.42-1.72 for ischemic stroke among those who took >=170mcg/d). Atrial fibrillation risk was dose-dependently associated with levothyroxine dosage; however, it comprises only a small proportion of ischemic stroke incidence (4.4%, 128/2914). CONCLUSIONS: The risk for CHD and ischemic stroke was higher in thyroid cancer patients who received thyroidectomy, and the dosage of levothyroxine administered appears to play a major role. More caution is suggested for the screening and treatment of thyroid cancer and subsequent TSH suppression therapy, as well as proper management for cardiovascular disease prevention. PMID- 30400045 TI - Influence of AT1 blockers on obesity and stress induced eating of cafeteria diet. AB - Based on findings that treatment with AT1 receptor blocker (ARB) prevents diet induced obesity and that the activity of the hypothalamic-pituitary-adrenal (HPA) axis is stimulated by AngII and blocked by ARBs, we aimed to investigate whether ARB treatment can reduce stress-induced eating of cafeteria diet (CD) , thus contributing to alterations in eating behavior. Sprague Dawley rats were fed with chow or CD and treated with telmisartan (TEL, 8mg/kg/d) or vehicle. At weeks 2 and 12, rats were stressed over 5 consecutive days by restraint stress (RS, 4h) and by additional shaking at d5. Tail blood was sampled during RS to determine hormone levels. During the first period of RS, ACTH and corticosterone responses were diminished at d5 in CD- compared to chow-fed rats. Independently of feeding, TEL did not reduce stress hormones. Compared to food behavior before RS, the stress-induced CD eating increased in controls but remained unchanged in TEL treated rats. After 12 weeks, TEL reduced weight gain and energy intake, particularly in CD-fed rats. Similar to the first RS period, corticosterone response was reduced in CD-fed rats at d5 during the second RS period. TEL did not further reduce stress hormones and did not lessen the CD eating upon RS. We conclude that CD feeding compensates for stress reactions. However, stress induced CD eating was only reduced by TEL after short-term, but not after long term drug treatment. Thus, the potency of ARBs to lower HPA activity only plays a minor role in reducing energy intake to prevent obesity. PMID- 30400046 TI - Role of GPER in the anterior pituitary gland focusing on lactotroph function. AB - Ovarian steroids control a variety of physiological functions. They exert actions through classical nuclear steroid receptors, but rapid non-genomic actions through specific membrane steroid receptors have been also described. In this study, we demonstrate that the G-protein-coupled estrogen receptor (GPER) is expressed in the rat pituitary gland and, at a high level, in the lactotroph population. Our results revealed that ~40% of the anterior pituitary cells are GPER-positive and ~35% of the lactotrophs are GPER-positive. By immunocytochemical and immuno-electron-microscopy studies we demonstrated that GPER is localized in the plasmatic membrane but is also associated to the endoplasmic reticulum in rat lactotrophs. Moreover, we found that local Gper expression is regulated negatively by 17beta-estradiol (E2) and progesterone (P4), and fluctuates during the estrus cycle, being minimal in proestrus. Interestingly, lack of ovarian steroids after an ovariectomy (OVX) significantly increased pituitary GPER expression specifically in the three morphologically different subtypes of lactotrophs. We found a rapid estradiol stimulatory effect on PRL secretion mediated by GPER, both in vitro and ex vivo, using a GPER agonist G1, and this effect was prevented by the GPER antagonist G36, demonstrating a novel role for this receptor. Then, the increased pituitary GPER expression after OVX could lead to alterations in the pituitary function, as all three lactotroph-subtypes are target of GPER ligand, and could be involved in the PRL secretion mediated by GPER. Therefore it should be taken into consideration in the response of the gland to an eventual hormone replacement therapy. PMID- 30400047 TI - Early menopause and premature ovarian insufficiency are associated with increased risk of type 2 diabetes: a systematic review and meta-analysis. AB - OBJECTIVE/DESIGN: Menopausal transition has been associated with a derangement of glucose metabolism. However, it is not known if early menopause (EM, defined as age at menopause <45 years) or premature ovarian insufficiency (POI, defined as age at menopause <40 years) are associated with increased risk of type 2 diabetes mellitus (T2DM). To systematically investigate and meta-analyze the best evidence regarding the association of age at menopause with the risk of T2DM. METHODS: A comprehensive search was conducted in PubMed, CENTRAL and Scopus, up to January 31st, 2018. Data were expressed as odds ratio (OR) with 95% confidence intervals (CI). The I2 index was employed for heterogeneity. RESULTS: Thirteen studies were included in the qualitative and quantitative analysis (191,762 postmenopausal women, 21,664 cases with T2DM). Both women with EM and POI were at higher risk of T2DM compared with those of age at menopause of 45-55 years (OR: 1.15, 95% CI: 1.04-1.26, p=0.003; I2: 61%, p<0.002 and OR: 1.50, 95% CI: 1.03-2.19, p=0.033; I2: 75.2%, p<0.003), respectively). Similar associations emerged when women with EM and POI were compared with those of age at menopause >45 years (OR: 1.12, 95% CI: 1.01-1.20, p<0.02; I2: 78%, p<0.001 and OR: 1.53, 95% CI: 1.03-2.27, p=0.035; I2: 78%, p<0.001), respectively). CONCLUSIONS: Both EM and POI are associated with increased risk of T2DM. PMID- 30400048 TI - Psychological effects of Dopamine Agonist Treatment in Patients with Hyperprolactinemia and Prolactin Secreting Adenomas. AB - BACKGROUND: Dopamine agonists (DAs) are the main treatment for patients with hyperprolactinemia and prolactinomas. Recently, an increasing number of reports emphasized DAs' psychological side effects, either de- novo or as exacerbations of prior psychiatric disease. METHODS: Review of prospective and retrospective studies (PubMed 1976- September 2018) evaluating the psychological profile of DAs treated patients with hyperprolactinemia and prolactinomas. Case -series and case reports of psychiatric complications were also reviewed. RESULTS: Most studies were cross-sectional and had a control group of healthy volunteers or patients with nonfunctioning pituitary adenomas. There were few prospective studies, with/without control group, that included small numbers of patients. Compared with controls, patients with hyperprolactinemia generally had worse quality of life, anxiety, depression and certain personality traits. Patients receiving DAs had higher impulsivity scores than normoprolactinemic controls. Impulse control disorders (ICDs) were reported in both genders, with hypersexuality mostly in men. Multiple ICDs were sometimes reported in the same patient, usually reversible after DA discontinuation. In case reports, DA therapy was temporally associated with severe depression, manic episodes or psychosis, which improved after discontinuation and administration of psychiatric medications. Gender type of DA, dose and duration of therapy didn't correlate with occurrence of psychiatric pathology. CONCLUSION: Patients with hyperprolactinemia receiving DAs may develop changes in mood and behavior regardless of prior psychiatric history. Increased awareness for ICDs, depression, mania and other types of psychosis is needed by all physicians who prescribe DAs. Larger prospective controlled clinical studies are needed to delineate prevalence, risk stratification and management. PMID- 30400049 TI - ONE-STEP NUCLEIC ACID AMPLIFICATION FOR INTRAOPERATIVE ANALYSIS OF SENTINEL LYMPH NODE IN PAPILLARY THYROID CARCINOMA. AB - OBJECTIVE: Lymphadenectomy in papillary thyroid carcinoma (PTC) is controversial. It is indicated whenever metastases have been proven before or during surgery and as a prophylactic treatment in high-risk patients. However, 30-50% of cN0 patients become pN1 postoperatively. In PTC, selective-sentinel-lymph-node-biopsy (SLNB) with conventional intraoperative analysis has 8% false-negative. One-step nucleic acid amplification (OSNA) is a molecular technique which allows real-time detection of mRNA encoding for cytokeratin 19. OSNA has been introduced in intraoperative analysis of several tumors to reduce false-negative rates, and distinguish micrometastasis from macrometastasis. Our objective was to evaluate the impact of the introduction of OSNA in the intraoperative evaluation of the sentinel node (SN) in PTC. DESIGN: We analyzed a series of 35 patients subjected to SLNB. METHODS: All the dissected nodes, SN and non-SN, were evaluated with OSNA and cytology. RESULTS: We obtained a total of 110 SN. SLNB proved positive in 14 patients (40%) with cytology and in 23 (65.7%) with OSNA (p<0.001). In the 29 patients with subsequent lymphadenectomy we obtained 360 lymph nodes [(52 positive in cytology (14.4%) and 107 in OSNA (29.7%)]. Lymphadenectomy proved positive in 16 patients according to cytology (55%) and in 24 according to OSNA (83%) (p=0002). The majority of patients with micrometastasis in SN showed only micrometastasis in lymphadenectomy. CONCLUSIONS: The present study shows selective-sentinel-lymph-node-biopsy with one-step nucleic acid amplification technique to be feasible in papillary thyroid carcinoma. The quantitative nature of one-step nucleic acid amplification paves the way towards a more personalized surgical approach, limiting lymphadenectomy to patients with intraoperative evidence of macrometastasis in the sentinel node. PMID- 30400050 TI - MECHANISMS IN ENDOCRINOLOGY: Anorexia nervosa and endocrinology: A clinical update. AB - Anorexia nervosa is a syndrome, i.e. collections of symptoms, which it is not defined by etiology. The severe cases are intractable. The syndrome is associated with multiple, profound endocrine alterations which may be adaptive, reactive or etiologic. Adaptive changes potentially may be inappropriate in clinical settings such as inpatient intensive re-nutrition or in a setting with somatic comorbidity. Electrolyte levels must be closely monitored during the refeeding process, and the need for weight gain must be balanced against potentially fatal refeeding complications. An important focus of clinical research should be to identify biomarkers associated with different stages of weight loss and re nutrition combined with psychometric data. Besides well-established peripheral endocrine actions, several hormones also are released directly to different brain areas, where they may exert behavioral and psychogenic actions that could offer therapeutic targets. We need reliable biomarkers for predicting outcome and to ensure safe re-nutrition, however, first of all we need them to explore the metabolism in anorexia nervosa to open new avenues with therapeutic targets. A breakthrough in our understanding and treatment of this whimsical disease remains. Considering this, the aim of the present review is to provide an updated overview of the many endocrine changes in a clinical perspective. PMID- 30400051 TI - Hypoglycaemia is associated with increased risk of fractures in patients with type 2 diabetes mellitus: a cohort study. AB - Objective Type 2 diabetes is associated with an increased risk of fracture. Any factor that incrementally increases this risk should be taken into account when individualizing treatment. Hypoglycemia is a common complication of antidiabetes medications and suggested as a risk factor for fractures, yet its real-life clinical impact is unclear. Design A population-based, retrospective open cohort study using routinely collected data between 1st of January 1995 and 1st of May 2016 in The Health Improvement Network. Methods Patients with type 2 diabetes mellitus with documented hypoglycaemic events were compared to randomly matched patients with type 2 diabetes mellitus without documented hypoglycaemic events matched to exposed patients on age, sex, duration of diabetes and BMI. The primary outcome was any incident fracture. Secondary outcome was incident fragility (osteoporotic) fracture. Results A total of 41,163 patients with type 2 diabetes were included: 14,147 patients in the exposed cohort and 27,016 patients in the unexposed cohort. Patients with a documented hypoglycaemic event were significantly more likely to sustain any fracture compared to patients with no record of hypoglycemic events: adjusted IRR 1.20 (95% CI 1.12-1.30; p < 0.0001). Patients who had a documented hypoglycaemic event were significantly more likely to suffer a fragility fracture compared to controls: adjusted IRR 1.24 (95% CI 1.13-1.37; p < 0.0001). Conclusions Hypoglycaemic events are a significant risk factor for fractures in patients with diabetes mellitus. This observation is clinically relevant when individualizing targets for glycaemic control and selecting antidiabetic agents. PMID- 30400052 TI - Prevalence of moderate-to-severe TR suitable for percutaneous intervention in TTE patients. AB - Moderate-to-severe tricuspid regurgitation is associated with higher mortality and morbidity yet remains significantly undertreated. The reasons for this are complex but include a higher operative mortality for patients undergoing isolated tricuspid valve surgery. This study sought to determine the prevalence of patients with moderate-to-severe tricuspid regurgitation and identify those who could be potentially suitable for percutaneous tricuspid valve intervention by screening patients referred for transthoracic echocardiography (ECHO) at a tertiary center. Our results showed that the prevalence of moderate-to-severe tricuspid regurgitation in our total ECHO patient population was 2.8%. Of these, approximately 1 in 8 patients with moderate-to-severe tricuspid regurgitation would be potentially suitable for percutaneous intervention, and suggests a large, unmet clinical need in this population. PMID- 30400053 TI - Artificial intelligence and echocardiography. AB - Echocardiography plays a crucial role in the diagnosis and management of cardiovascular disease. However, interpretation remains largely reliant on the subjective expertise of the operator. As a result inter-operator variability and experience can lead to incorrect diagnoses. Artificial intelligence (AI) technologies provide new possibilities for echocardiography to generate accurate, consistent and automated interpretation of echocardiograms, thus potentially reducing the risk of human error. In this review, we discuss a subfield of AI relevant to image interpretation, called machine learning, and its potential to enhance the diagnostic performance of echocardiography. We discuss recent applications of these methods and future directions for AI-assisted interpretation of echocardiograms. The research suggests it is feasible to apply machine learning models to provide rapid, highly accurate and consistent assessment of echocardiograms, comparable to clinicians. These algorithm are capable of accurately quantifying a wide range of features, such as the severity of valvular heart disease or the ischaemic burden in patients with coronary artery disease. However, the applications and their use are still in their infancy within the field of echocardiography. Research to refine methods and validate their use for automation, quantification and diagnosis are in progress. Widespread adoption of robust AI tools in clinical echocardiography practice should follow and have the potential to deliver significant benefits for patient outcome. PMID- 30400054 TI - Anti-cancer effect of GV1001 for prostate cancer; function as a ligand of GnRHR. AB - GV1001, a 16-amino acid fragment of the human telomerase reverse transcriptase catalytic subunit (hTERT), has been developed as an injectable formulation of cancer vaccine. Here, we revealed for the first time that GV1001 is a novel ligand for gonadotropin-releasing hormone receptor (GnRHR). The docking prediction for GV1001 against GnRHR showed high binding affinity. Binding of GV1001 to GnRHR stimulated the Galphas-coupled cAMP signaling pathway and antagonized Galphaq-coupled Ca2+ release by leuprolide acetate (LA), a GnRHR agonist. Repeated injection of GV1001 attenuated both serum testosterone level and seminal vesicle weight via desensitization of hypothalamic-pituitary-gonadal (HPG) axis. We then tested whether GV1001 has an inhibitory effect on tumor growth of LNCaP cells, androgen receptor-positive human prostate cancer (PCa) cells. GV1001 significantly inhibited tumor growth and induced apoptosis in LNCaP implanted xenografts. Interestingly, mRNA expressions of matrix metalloproteinase2 and matrix metalloproteinase9 were suppressed by GV1001, but not by LA. Moreover, GV1001 significantly inhibited the proliferation and migration of PCa cells and induced apoptosis in a concentration-dependent manner. Our findings suggest that GV1001 functions as a biased GnRHR ligand to selectively stimulate the Galphas/cAMP pathway, with anti-proliferative and anti migratory effects on human PCa. PMID- 30400055 TI - French Endocrine Society Guidance on endocrine side-effects of immunotherapy. AB - The management of cancer patients has changed due to the considerably more frequent use of immune checkpoint inhibitors (ICPI). However, the use of ICPI has a risk of side-effects, particularly endocrine toxicity. Since the indications for ICPI are constantly expanding due to their efficacy, it is important that endocrinologists and oncologists know how to look for this type of toxicity and how to treat it when it arises. In view of this, the French Endocrine Society initiated the formulation of a consensus document on ICPI-related endocrine toxicity. In this paper, we will introduce data on the general pathophysiology of endocrine toxicity, we will then outline expert opinion focusing primarily on methods for screening, management and monitoring for endocrine side-effects in patients treated by ICPI. We will then look in turn at endocrinopathies that are induced by ICPI including dysthyroidism, hypophysitis, primary adrenal insufficiency and fulminant diabetes. In each chapter, expert opinion will be given on the diagnosis, management and monitoring for each complication. These expert opinions will also discuss the methodology for categorizing these side effects in oncology using 'Common terminology criteria for adverse events' (CTCAE) and the difficulties in applying this to endocrine side-effects in the case of these anti-cancer therapies. This is shown in particular by certain recommendations that are used for other side-effects (high-dose corticosteroids, contra-indicated in ICPI for example), and that cannot be considered as appropriate in the management of endocrine toxicity, as it usually does not require ICPI withdrawal or high dose glucocorticoid intake . PMID- 30400056 TI - Kisspeptin and the regulation of the reproductive axis in domestic animals. AB - The control of reproductive processes involves the integration of a number of factors from the internal and external environment, with the final output signal of these processes being the pulsatile secretion of gonadotrophin releasing hormone (GnRH) from the hypothalamus. These factors include the feedback actions of sex steroids, feed intake and nutritional status, season/photoperiod, pheromones, age and stress. Understanding these factors and how they influence GnRH secretion and hence reproduction is important for the management of farm animals. There is evidence that the RF-amide neuropeptide, kisspeptin, may be involved in relaying the effects of these factors to the GnRH neurons. This paper will review the evidence from the common domestic animals (sheep, goats, cattle, horses and pigs), that kisspeptin neurons are i) regulated by the factors listed above, ii) contact GnRH neurons, and iii) involved in the regulation of GnRH/gonadotrophin secretion. PMID- 30400057 TI - Baicalin alleviates hyperglycemia-induced endothelial impairment 1 via Nrf2. AB - Baicalin is the major component found in Scutellaria baicalensis root, a widely used herb in traditional Chinese medicine, which exhibits strong anti inflammatory, anti-viral and anti-tumor activities. The present work was devoted to elucidate the molecular and cellular mechanisms underlying the protective effects of Baicalin against diabetes-induced oxidative damage, inflammation and endothelial dysfunction. Diabetic mice, induced by streptozotocin (STZ), were treated with intraperitoneal Baicalin injections. Human umbilical vein endothelial cells (HUVECs) were cultured either in normal glucose (NG, 5.5 mM) or high glucose (HG, 33 mM) medium in the presence or absence of Baicalin for 72 h. We observed an obvious inhibition of hyperglycemia-triggered oxidative damage and inflammation in HUVECs and diabetic aortal vasculature by Baicalin, along with restoration of hyperglycemia-impaired nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway activity. However, the protective effects of Baicalin almost completely abolished in HUVECs transduced with shRNA against Nrf2, but not with nonsense shRNA. Mechanistic studies demonstrated that HG decreased Akt and GSK3B phosphorylation, restrained nuclear export of Fyn and nuclear localization of Nrf2, blunted Nrf2 downstream target genes, and subsequently induced oxidative stress in HUVECs. However, those destructive cascade, were well prevented by Baicalin in HUVECs. Furthermore, LY294002 and ML385 (inhibitor of PI3K and Nrf2) attenuated Baicalin mediated Nrf2 activation and the ability of facilitates angiogenesis in vivo and ex vivo. Taken together, the endothelial protective effect of Baicalin under hyperglycemia condition could be partly attributed to its role in downregulating reactive oxygen species (ROS) and inflammation via the Akt/GSK3B/Fyn-mediated Nrf2 activation. PMID- 30400058 TI - Mif deficiency promotes adiposity in fructose-fed mice. AB - The macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine involved in inflammation, regulation of energy metabolism and glucocorticoid action. Chronic low-grade inflammation may be caused by fructose intake, contributing to visceral adipose tissue (VAT) dysfunction. Since MIF is a known antagonist of glucocorticoid signaling, and deregulated glucocorticoid signaling can contribute to lipid metabolism disturbances, we hypothesized that altered MIF signaling might underlie fructose-induced adiposity through glucocorticoid action. We analyzed physiological and biochemical parameters, adipose tissue histology, insulin sensitivity and lipid metabolism in wild type and MIF-/- C57Bl/6J mice consuming 20% fructose solution for 9 weeks. Glucocorticoid prereceptor metabolism and glucocorticoid receptor (GR) protein level were examined in VAT, together with the expression of glucocorticoid-target genes involved in lipid metabolism. The expression of adipogenic and lipogenic transcriptional regulators peroxisome proliferator activated receptor gamma (PPARG) and sterol regulatory element-binding protein 1c (SREBP1c) was also assessed. Results showed disturbed insulin sensitivity in all MIF-/- mice, regardless of the diet. Mice on fructose diet had increased energy intake, but increased visceral adiposity and enlarged adipocytes were observed only in fructose-fed MIF-/- mice. Increased VAT corticosterone level and 11 beta hydroxysteroid dehydrogenase type 1, hexose-6-phosphate dehydrogenase and GR protein levels were observed in the same animals, together with induced expression of examined lipogenic genes and accumulation of PPARG and SREBP1c. In conclusion, the results showed that dietary fructose was associated with increased visceral adiposity through activation of GR-regulated lipogenic genes, but only in the absence of MIF, which set the state of hyperinsulinemia and insulin resistance. PMID- 30400060 TI - Nutrient Sensor Signaling Pathways and Cellular Stress in Fetal Growth Restriction. AB - Fetal growth restriction is one of the most common obstetrical complications resulting in significant perinatal morbidity and mortality. The most frequent etiology of human singleton fetal growth restriction is placental insufficiency, which occurs secondary to reduced utero-placental perfusion, abnormal placentation, impaired trophoblast invasion and spiral artery remodeling, resulting in altered nutrient and oxygen transport. Two nutrient-sensing proteins involved in placental development and glucose and amino acid transport are mechanistic target of rapamycin (mTOR) and O-linked N-acetylglucosamine transferase (OGT), which are both regulated by availability of oxygen. Impairment in either of these pathways is associated with fetal growth restriction and accompanied by cellular stress in the forms of hypoxia, oxidative and endoplasmic reticulum (ER) stress, metabolic dysfunction and nutrient starvation in the placenta. Recent evidence has emerged regarding the potential impact of nutrient sensors on fetal stress response, which occurs in a sexual dysmorphic manner, indicating a potential element of genetic gender susceptibility to fetal growth restriction. In this mini review, we focus on the known role of mTOR and OGT in placental development, nutrient regulation and response to cellular stress in human fetal growth restriction with supporting evidence from rodent models. PMID- 30400059 TI - Neuroendocrine differentiation of prostate cancer leads to PSMA suppression. AB - Prostate-specific membrane antigen (PSMA) is overexpressed in most prostate adenocarcinoma (AdPC) cells and acts as a target for molecular imaging. However, some case reports indicate that PSMA-targeted imaging could be ineffectual for delineation of neuroendocrine (NE) prostate cancer (NEPC) lesions due to the suppression of the PSMA gene (FOLH1). These same reports suggest that targeting somatostatin receptor type 2 (SSTR2) could be an alternative diagnostic target for NEPC patients. This study evaluates the correlation between expression of FOLH1, NEPC marker genes and SSTR2. We evaluated the transcript abundance for FOLH1 and SSTR2 genes as well as NE markers across 909 tumors. A significant suppression of FOLH1 in NEPC patient samples and AdPC samples with high expression of NE marker genes was observed. We also investigated protein alterations of PSMA and SSTR2 in an NE-induced cell line derived by hormone depletion and lineage plasticity by loss of p53. PSMA is suppressed following NE induction and cellular plasticity in p53-deficient NEPC model. The PSMA suppressed cells have more colony formation ability and resistance to enzalutamide treatment. Conversely, SSTR2 was only elevated following hormone depletion. In 18 NEPC patient-derived xenograft (PDX) models we find a significant suppression of FOLH1 and amplification of SSTR2 expression. Due to the observed FOLH1-supressed signature of NEPC, this study cautions on the reliability of using PMSA as a target for molecular imaging of NEPC. The observed elevation of SSTR2 in NEPC supports the possible ability of SSTR2-targeted imaging for follow-up imaging of low PSMA patients and monitoring for NEPC development. PMID- 30400061 TI - Species-specific mechanisms of tumor suppression: trouble in paradigm. AB - A here-to-fore unknown tumor suppression mechanism reached its greatest expression in humans, having evolved to protect during the twenty-five-year lifespan of primitive humans. It depends upon high levels of circulating DHEAS and its importation into cells that have experienced inactivation of TP53, whereupon DHEAS is desulfated to DHEA, an uncompetitive inhibitor of Glucose-6 phosphate Dehydrogenase (G6PD). Uncompetitive inhibition of G6PD becomes irreversible in the presence of high levels of inhibitor and substrate (G6P). We reported an anthropoid primate-specific sequence motif in the Glucose-6 phosphatase (G6PC) promoter that enables intercellular G6P to accumulate to concentrations sufficient to induce irreversible uncompetitive inhibition of G6PD. We now conclude that inactivation of Gulonolactone Oxidase (GLO), a primate specific event resulting in vitamin C auxotrophy, also contributed to kill switch evolution by enabling G6P accumulation. Unique mechanisms of tumor suppression appear to distinguish all vertebrate species, preventing 'one vertebrate species from serving as a valid model system for another'. This unrecognized element of speciation undermines decades of cancer research data, using murine species, that presumed universal mechanisms of tumor suppression, independent of species. Despite this setback, the potential for pharmacological reconstitution of the kill switch tumor suppression system that distinguishes our species suggests that "normalization" of human cancer risk, from its current 40% to the 4% of virtually all other large, long-lived species, represents a realistic near-term goal. PMID- 30400062 TI - Declining free thyroxine levels over time in irradiated childhood brain tumor survivors. AB - OBJECTIVE: The incidence of cranial radiotherapy (cRT)-induced central hypothyroidism (TSHD) in childhood brain tumor survivors (CBTS) is reported to be low. However, TSHD may be more frequent than currently suspected, as its diagnosis is challenging due broad reference ranges for free thyroxine (FT4) concentrations. TSHD is more likely to be present when FT4 levels progressively decline over time. Therefore, we determined the incidence and latency time of TSHD, and changes of FT4 levels over time in irradiated CBTS. DESIGN: Nationwide, 10-year retrospective study of irradiated CBTS. METHODS: TSHD was defined as "diagnosed" when FT4 concentrations were below the reference range with low, normal or mildly elevated thyrotropin levels, and as "presumed" when FT4 declined >= 20% within the reference range. Longitudinal FT4 concentrations over time were determined in growth hormone deficient (GHD) CBTS with and without diagnosed TSHD from cRT to last follow-up (Paired t-test). RESULTS: Of 207 included CBTS, the 5 year cumulative incidence of diagnosed TSHD was 20.3%, which occurred in 50% (25/50) of CBTS with GHD by 3.4 years (range, 0.9-9.7) after cRT. Presumed TSHD was present in 20 additional CBTS. The median FT4 decline in GH-deficient CBTS was 41.3% (P<0.01) to diagnosis of TSHD and 12.4% (P=0.02) in GH-deficient CBTS without diagnosed TSHD. CONCLUSIONS: FT4 concentrations in CBTS significantly decline over time after cRT, also in those not diagnosed with TSHD, suggesting that TSHD occurs more frequent and earlier than currently reported. The clinical relevance of cRT-induced FT4 decline over time should be investigated in future studies. PMID- 30400063 TI - Soluble CD163 was linked to galectin-3, diabetic retinopathy and antidepressants in type 1 diabetes. AB - OBJECTIVE: Depression has been associated with diabetic retinopathy and increased plasma levels of galectin-3, a lectin expressed in activated macrophages. Increased levels of sCD163, the soluble form of a macrophage expressed scavenger receptor involved in several inflammatory processes, have been demonstrated in the vitreous of the eye in type 1 diabetes (T1D) patients with severe diabetic retinopathy. The aim was to explore whether circulating sCD163 was associated with diabetic retinopathy, depression, and/or galectin-3 in T1D patients, controlling for gender, metabolic factors, other diabetes complications, life style, and medication. DESIGN: Cross sectional. METHODS: Two hundred and eighty seven T1D patients, men 56%, age 18-59 years, diabetes duration >=1 year, were consecutively recruited from one specialist diabetes clinic. Depression was assessed by Hospital Anxiety and Depression Scale-depression subscale. Blood samples, anthropometrics and blood pressure were collected, supplemented with data from electronic medical records and the Swedish National Diabetes Registry. High plasma sCD163 was defined as >= 0.575 mg/l (corresponding to the 80th percentile) and high plasma galectin-3 as >=4.659 ug/l (corresponding to the 95th percentile). RESULTS: The prevalence of depression was 10%, antidepressant medication 8%, diabetic retinopathy 72%, high sCD163 20%, and high galectin-3 5%. High galectin-3 (AOR 9.7), antidepressants (AOR 3.8), diabetic retinopathy (AOR 2.4), and systolic blood pressure (per mm Hg) (AOR 1.03) were associated with high sCD163. CONCLUSIONS: This is the first study to show that circulating sCD163 was independently associated with galectin-3, the use of antidepressants, and diabetic retinopathy, in patients with T1D. Depression was not associated with sCD163. PMID- 30400065 TI - The Echocardiography Quality Framework: a comprehensive, patient-centered approach to quality assurance and continuous service improvement. AB - The Echocardiography Quality Framework is a cohesive, patient-centered program, combining quality assurance and continuous service improvement, which can be adapted to suit the needs of any echocardiography department. The framework encompasses measures of the quality of care, reproducibility and consistency, education and training, and customer feedback. The EQF is scalable and adaptable to benefit any echocardiography service. A catalogue or library of supporting documents is being developed, drawing on expertise around the UK, to made available to any participating department. A mechanism and online infrastructure for national registration or assessment is being developed, to be used as a standalone adjunct or linked to BSE Departmental Accreditation. The principles that underpin the EQF may be applicable to other imaging disciplines and, ultimately, other medical or surgical specialties. PMID- 30400064 TI - A patient-centred model to quality assure outputs from an echocardiography department: consensus guidance from the British Society of Echocardiography. AB - Background Quality assurance (QA) of echocardiographic studies is vital to ensure that clinicians can act on findings of high quality to deliver excellent patient care. To date, there is a paucity of published guidance on how to perform this QA. The British Society of Echocardiography (BSE) has previously produced an Echocardiography Quality Framework (EQF) to assist departments with their QA processes. This article expands on the EQF with a structured yet versatile approach on how to analyse echocardiographic departments to ensure high-quality standards are met. In addition, a process is detailed for departments that are seeking to demonstrate to external bodies adherence to a robust QA process. Methods The EQF consists of four domains. These include assessment of Echo Quality (including study acquisition and report generation); Reproducibility & Consistency (including analysis of individual variability when compared to the group and focused clinical audit), Education & Training (for all providers and service users) and Customer & Staff Satisfaction (of both service users and patients/their carers). Examples of what could be done in each of these areas are presented. Furthermore, evidence of participation in each domain is categorised against a red, amber or green rating: with an amber or green rating signifying that a quantifiable level of engagement in that aspect of QA has been achieved. Conclusion The proposed EQF is a powerful tool that focuses the limited time available for departmental QA on areas of practice where a change in patient experience or outcome is most likely to occur. PMID- 30400066 TI - HIF 1 inhibits StAR transcription and testosterone synthesis in murine Leydig cells. AB - Hypoxia-inducible factor-1 (HIF1) is a critical transcription factor involved in cell response to hypoxia. Under physiological conditions, its a subunit is rapidly degraded in most tissues except testes. HIF1 is stably expressed in Leydig cells, which are the main source of testosterone for male, and might bind to the promoter region of steroidogenic acute regulatory protein (Star), which is necessary for the testosterone synthesis, according to software analysis. This study aims to identify the binding sites of HIF1 on Star promoter and its transcriptional regulation of Star to affect testosterone synthesis. Testosterone level and steroid synthesis-related proteins were determined in male Balb/C mice exposed to hypoxia (8% O2). While HIF1 was upregulated, the testosterone level was significantly decreased. This was further confirmed by in vitro experiments with rat primary Leydig cells or TM3 cells exposed to hypoxia (1% O2), CoCl2 or DFX to raise HIF1. The decline of testosterone was reversed by pregnenolone but not cAMP, indicating the cholesterol transport disorder as the main cause. In agreement, StAR expression level was decreased in response to HIF1, while 3b hydroxysteroid dehydrogenase, 17b-hydroxysteroid dehydrogenase and p450scc did not exhibit significant changes. By ChIP, EMSA supershift and dual-luciferase reporter assays, HIF1 was found to bind to the Star promoter region and repress the expression of StAR. Mutation assays identified three HIF1-binding sites on mouse Star promoter. These findings indicate that HIF1 represses Star transcription through directly binding to the Star promoter at -2082/-2078, 2064/-2060 and -1910/-1906, leading to the negative regulation of testosterone synthesis. PMID- 30400067 TI - A new p.(Ile66Serfs*93) IGF2 variant is associated with pre- and postnatal growth retardations. AB - OBJECTIVE: The IGF/IGF1R axis is involved in the regulation of human growth. Both IGF1 and IGF2 can bind to the IGF1R in order to promote growth via the downstream PI3K/AKT pathway. Pathogenic mutations in IGF1 and IGF1R determine intrauterine growth restriction and affect postnatal body growth. However, to date there are only few reports of pathogenic IGF2 mutations causing severe prenatal, as well as postnatal growth retardations. RESULTS: Here we describe a de novo c.195delC IGF2 variant [NM_000612, p.(Ile66Serfs*93)] in a 4-year-old patient with severe pre- and postnatal growth retardations in combination with dystrophy, facial dimorphism, finger deformities, as well as a patent ductus. Cloning and sequencing of a long-range PCR product harboring the deletion and a SNP informative site chr11:2153634 (rs680, NC_000011.9:g.2153634T>C) demonstrated that the variant resided on the paternal allele. This finding is consistent with the known maternal imprinting of IGF2. 3D protein structure prediction and overexpression studies demonstrated that the p.(Ile66Serfs*93) IGF2 gene variation resulted in an altered protein structure that impaired ligand/receptor binding and thus prevents IGF1R activation. CONCLUSION: The severity of the phenotype in combination with the dominant mode of transmission provides further evidence for the involvement of IGF2 in growth disorders. PMID- 30400068 TI - Postoperative use of somatostatin analogs and mortality in patients with acromegaly. AB - OBJECTIVE: To assess the effect of somatostatin analogs (SSA) on mortality in relation to disease control of acromegaly after pituitary surgery. DESIGN: A retrospective study in two large tertiary referral centers in The Netherlands. METHODS: 319 patients with acromegaly in whom pituitary surgery was performed as primary therapy between January 1980 and July 2017 were included. Postoperative treatment with SSA was prescribed to 174 (55%) patients because of persistent or recurrent disease. Disease control at last visit was assessed by IGF1 standard deviation score (SDS). Adequate disease control was defined as IGF1 SDS <= 2. Univariate determinants of mortality and standardized mortality ratios (SMR) were calculated for groups with and without SSA at any moment postoperatively and at last visit. RESULTS: In total, 27 deaths were observed. In univariate analysis, determinants of mortality were inadequate disease control (RR 3.41, P=0.005), surgery by craniotomy (RR 3.53, P=0.013) and glucocorticoid substitution (RR 2.11, P=0.047). There was a strong trend towards increased mortality for patients who used SSA (RR 2.01, P=0.067) and/or dopamine agonists (RR 2.54, P=0.052) at last visit. The SMR of patients with adequate disease control who used SSA at any moment postoperatively (1.07, P=0.785) and at last visit (1.19; P=0.600) was not increased. Insufficiently controlled patients had a significantly raised SMR (3.92, P=0.006). CONCLUSIONS: Postoperative use of SSA is not associated with increased mortality in patients with acromegaly who attain adequate disease control. In contrast, inadequate disease control, primary surgery by craniotomy, and glucocorticoid substitution are associated with increased mortality. PMID- 30400069 TI - Endothelial cell mineralocorticoid receptors oppose VEGF-induced gene expression and angiogenesis. AB - Aldosterone is a key factor in adverse cardiovascular remodeling by acting on the mineralocorticoid receptor (MR) in different cell types. Endothelial MR activation mediates hypertrophy, inflammation and fibrosis. Cardiovascular remodeling is often accompanied by impaired angiogenesis, which is a risk factor for the development of heart failure. In this study, we evaluated the impact of MR in endothelial cells on angiogenesis. Deoxycorticosterone acetate (DOCA) induced hypertension was associated with capillary rarefaction in the heart of wildtype mice but not of mice with cell type-specific MR deletion in endothelial cells. Consistently, endothelial MR deletion prevented the inhibitory effect of aldosterone on the capillarization of subcutaneously implanted silicon tubes and on capillary sprouting from aortic ring segments. We examined MR-dependent gene expression in cultured endothelial cells by RNA-seq and identified a cluster of differentially regulated genes related to angiogenesis. We found opposing effects on gene expression when comparing activation of the mineralocorticoid receptor in ECs to treatment with vascular endothelial growth factor (VEGF), a potent activator of angiogenesis. In conclusion, we demonstrate here that activation of endothelial cell MR impaired angiogenic capacity and lead to capillary rarefaction in a mouse model of MR-driven hypertension. MR activation opposed VEGF-induced gene expression leading to the dysregulation of angiogenesis-related gene networks in endothelial cells. Our findings underscore the pivotal role of endothelial cell MR in the pathophysiology of hypertension and related heart disease. PMID- 30400070 TI - Obesity, fertility and pregnancy: Can we intervene to improve outcomes? AB - Rates of obesity among women of reproductive age have risen dramatically in recent decades. Obesity impacts on health of women across their reproductive lifespan with adverse effects on not only fertility and short term complications of pregnancy, but also on longer term health outcomes for both women and their children. This places considerable burden and cost on health services. Here we review the evidence linking maternal obesity to adverse fertility, pregnancy and longer-term health outcomes for women and their children. We discuss the outcomes of recent lifestyle, pharmacological and surgical intervention studies. As many of these studies have not shown a significant improvement in clinical outcomes, we discuss the need for better study design in future trials. PMID- 30400071 TI - Improving the performance of empirical mode decomposition via Tsallis entropy: Application to Alzheimer EEG analysis. AB - Alzheimer is a degenerative disorder that attacks neurons, resulting in loss of memory, thinking, language skills, and behavioral changes. Computer-aided detection methods can uncover crucial information recorded by electroencephalograms. A systematic literature search presents the wavelet transform as a frequently used technique in Alzheimer's detection. However, it requires a defined basis function considered a significant problem. In this work, the concept of empirical mode decomposition is introduced as an alternative to process Alzheimer signals. The performance of empirical mode decomposition heavily relies on a parameter called threshold. In our previous works, we found that the existing thresholding techniques were not able to highlight relevant information. The use of Tsallis entropy as a thresholder is evaluated through the combination of empirical mode decomposition and neural networks. Thanks to the extraction of better features that boost the classification accuracy, the proposed approach outperforms the state-of-the-art in terms of peak signal to noise ratio and root mean square error. Hence, our methodology is more likely to succeed than methods based on other landmarks such as Bayes, Normal and Visu shrink. We finally report an accuracy rate of 80%, while the aforementioned techniques only yield performances of 65%, 60% and 40%, respectively. PMID- 30400072 TI - Biomaterials as cell carriers for augmentation of adipose tissue-derived stromal cell transplantation. AB - Adipose tissue-derived stromal cells (ADSCs) contain lineage-committed progenitor cells that have the ability to differentiate into various cell types that may be useful for autologous cell transplantation to correct defects of skin, adipose, cartilage, bone, tendon, and blood vessels. The multipotent characteristics of ADSCs, as well as their abundance in the human body, make them an attractive potential resource for wound repair and applications to tissue engineering. ADSC transplantation has been used in combination with biomaterials, including cell sheets, hydrogel, and three-dimensional (3D) scaffolds based on chitosan, fibrin, atelocollagen, and decellularized porcine dermis, etc. Furthermore, low molecular weight heparin/protamine nanoparticles (LH/P NPs) have been used as an inducer of ADSC aggregation. The tissue engineering potential of these biomaterials as cell carriers is increased by the synergistic relationship between ADSCs and the biomaterials, resulting in the release of angiogenic cytokines and growth factors. In this review article, we describe the advantages of ADSC transplantation for tissue engineering, focusing on biomaterials as cell carriers which we have studied. PMID- 30400073 TI - Novel smart clothing with dry electrode biosensor for real-time automatic diagnosis of cardiovascular diseases. AB - The incidence of heart disease increases with age. The typical method of monitoring arrhythmia is to use a body patch type sensor with a wet electrode. Even though this sensor is easy to use, it has several disadvantages such as problems caused by wet electrodes in tissues when they are monitored for long periods. Thus, a monitoring sensor integrated into clothes with a dry electrode is proposed. In this study, we developed a smart outdoor shirt equipped with a dry electrode electrocardiogram (ECG) sensor for a cardiac arrhythmia computer aided diagnosis system. The sensor can be inserted in a console close to the chest, charged, used to communicate wirelessly, and can be connected to a smartphone application. According to experiments, the ECG signals measured by the smart shirt indicated that 97.5 +/- 1% of the signals could be measured in an immobile state and at least 85.2 +/- 2% of the signals could be measured during movement. In addition, we propose a computer-aided diagnosis system for detecting cardiac arrhythmia. It was determined through experiments that the system can detect arrhythmia with an accuracy of 98.2 +/- 2%. PMID- 30400074 TI - Effect of orientation and age on the crack propagation in cortical bone. AB - The crack propagation behavior near the initial crack were studied under the compact tension (CT) fracture toughness experiments test on bovine hip bone joint specimens. The bone specimens were prepared according to ASTM E-399 for plain fracture toughness tests. The specimens were cut from the hip joint both in the longitudinal and transverse direction to the collagen fiber orientation in the bone. The precrack or initial crack "a" were produced parallel and vertical to the lontudinal axis of bone in the longitudinal and transverse specimens respectively. The specimens were tested in the universal testing machine for finding fracture toughness and crack propagation behavior due to different orientation of bone fibers. A camera attached to the machine recorded the crack propagation process. The results show a different crack propagation behavior in longitudinal specimens and transverse specimens. The toughness of the bone consistently changes with age both in longitudinal and transverse direction. Our experimental data matched with the previous published research. PMID- 30400075 TI - Static and dynamic analyses of fracture fixation bone-plate systems for different plate materials and dimensions. AB - BACKGROUND: Various techniques have been developed in the treatment of fractures. One of these techniques is the internal fixation, which has an important place in practice. OBJECTIVE: In this study, fractured tibia bone has been treated with implants as numerically to investigate the stress behavior and the effect of plate material, shape and dimensions under pressure load. METHODS: The outer part of the bone is chosen as orthotropic and the inner part is chosen as isotropic material. The plate has been modeled to take the form of the bone surface and the finite element method has been used for numerical analysis. The effect of stress on bones and implants has been examined for 1% healing by changing the plate length, plate width and plate material. RESULTS: It has been observed that the increase in plate length decreases cortical bone stress until a specific length. On the other hand, the increase in plate width has increased the stress on the bone. CONCLUSIONS: It is important to form the appropriate plate surface to the bone surface in terms of compliance with the bones. PMID- 30400076 TI - An evaluation of the contact forces on the fingers when squeezing a spherical rehabilitation ball. AB - The rehabilitation squeeze ball is a popular device to help strengthen the hand, fingers and forearm muscles. The distributions of the contact pressure in the interface between the therapy ball and hand/fingers can affect the joint moment of each of the individual fingers, thereby affecting rehabilitation effects. In the current study, we evaluated the contact force distributions on the fingers when gripping a spherical object. Eight female adults [age 29 (9.1) years, mass 64.6 (7.1) kg, height 163.5 (1.9) cm, hand length 17.2 (0.7) cm] participated in the study. Contact force sensors were attached to the middle of the palmar surfaces of the distal, middle, and proximal phalanges of the four fingers in the longitudinal direction. In order to evaluate the effects of the ball stiffness on the contact force distributions on the fingers, subjects were requested to perform quasi-static gripping on a standard tennis ball and on a rehabilitation ball. The tennis ball is much stiffer and experiences smaller deformation under compression compared to the rehabilitation ball. We analyzed the force share among the distal, middle, and proximal finger segments, when subjects gripping balls of different stiffnesses (tennis ball vs. rehabilitation ball) and at three different grip efforts. Our results indicated that the grip force is contributed about 60% and 40% by the middle/ring fingers and by the index/little fingers, respectively. These characteristics are independent of the grip force levels and stiffness of the contact surface. PMID- 30400077 TI - Loss of anisotropic properties in abdominal aorta aneurysm obtained from the xenograft rat model. AB - BACKGROUND: Cellular treatments using mesenchymal stem cells (MSCs) cultured in 3D conditions constitute a solution to the classical surgery in treating abdominal aortic aneurysm (AAA). The recurrent question is: how this type of biotherapy changes the mechanical behavior of artery? METHODS: Experiments measurements based on xenograft rat model showed that the proposed cellular treatment leads to a decreasing radius and length of the AAA during its growth. An inverse finite element method was used to investigate the mechanical hyperelastic behavior of the AAA in the untreated case compared to the treated one. RESULTS: Although AAA leads a loss anisotropy while the cellular treatment does not restore it, it was shown that the stiffness of the arterial wall was improved. The numerical analysis of the stress distributions permitted to localize the stress concentration through the arterial wall and the probable zone of the rupture of the aneurysm developed from the xenograft rat model. CONCLUSIONS: The treatment of AAA with MSCs cultured in a 3D conditions constitutes a new challenge. Based on xenograft rat model, this study shows the potential of this cellular treatment to reduce the variation of the growth, the stiffness and the stress distributions. PMID- 30400078 TI - Preservation of femoral and tibial coronal alignment to improve biomechanical effects of medial unicompartment knee arthroplasty: Computational study. AB - BACKGROUND: Medial unicompartmental knee arthroplasty (UKA) could be concerned with wear of the cartilage or the wear in the polyethylene (PE) insert. Mechanical alignment determines the biomechanical effect in the long term. However, previous computational studies all found that femoral and tibial components alignment in the UKA were rare, and the results varied. OBJECTIVE: The purpose of this study was to evaluate the biomechanical effect of the femoral and tibial component coronal alignment in varus and valgus conditions through computational simulation. METHODS: A three-dimensional finite element model of the intact knee was constructed from medical image data of one healthy subject. A medial UKA model of neutral position and various coronal components was developed from the intact knee joint model. The tibial varus-femoral valgus and tibial valgus-femoral varus conditions were analyzed with parallel component angles of 3 degrees , 6 degrees and 9 degrees by using validated finite element models. We considered the contact stresses in the PE inserts and articular cartilage and the force on collateral ligament under gait cycle condition. RESULTS: Compared to the contact stress in the neutral position model, the contact stress on the PE insert increased in both tibial varus-femoral valgus and tibial valgus-femoral varus models. These trends were also observed in the case of the articular cartilage in remain compartment. However, the contact stress on the PE insert and articular cartilage increased largely in the tibial valgus-femoral varus model than in the tibial varus-femoral valgus model. The forces on the medial and lateral collateral ligaments increased in the tibial valgus-femoral varus model, whereas in the tibial varus-femoral valgus model, the forces decreased compared to the forces in the neutral position. The force on the anterior lateral ligament and popliteofibular ligament increased in the tibial varus-femoral valgus model as compared to the neutral position. CONCLUSIONS: Our study suggests that neutral alignment or less than 3 degrees tibial varus-femoral valgus alignment in the coronal plane can be recommended in medial UKA to reduce the postoperative complications and to enhance the life expectancy of implants. PMID- 30400079 TI - Scaffolds of bioactive glass-ceramic (Biosilicate(r)) and bone healing: A biological evaluation in an experimental model of tibial bone defect in rats. AB - This study aimed to investigate the in vivo tissue response of the Biosilicate(r) scaffolds in a model of tibial bone defect. Sixty male Wistar rats were distributed into bone defect control group (CG) and Biosilicate(r) scaffold group (BG). Animals were euthanized 15, 30 and 45 days post-surgery. Stereomicroscopy, scanning electron microscopy, histopathological, immunohistochemistry and biomechanical analysis were used. Scaffolds had a total porosity of 44%, macroporosity of 15% with pore diameter of 230 MUm. Higher amount of newly formed bone was observed on days 30 and 45 in BG. Immunohistochemistry analysis showed that the COX-2 expression was significantly higher on days 15 and 30 in BG compared with the CG. RUNX-2 immunoexpression was significantly higher in BG on days 15 and 45. No statistically significant difference was observed in RANKL immunoexpression in all experimental groups. BMP-9 immunoexpression was significantly upregulated in the BG on day 45. Biomechanical analysis showed a decrease in the biomechanical properties of the bone callus on days 30 and 45. The implantation of the Biosilicate(r) scaffolds was effective in stimulating newly bone formation and produced an increased immunoexpression of markers related to the bone repair. PMID- 30400080 TI - Aligned polyvinylpyrrolidone nanofibers with advanced electrospinning for biomedical applications. AB - BACKGROUND: Electrospinning is a highly effective method in order to generate nano-scaled fibers. In conventional electrospinning technique, geometry of nanofibers are mostly random due to the chaotic behavior of polymer jet. OBJECTIVE: Purpose of this study is to produce aligned nanofibers from PVP polymers with advanced electrospinning technique in order to be used in a potential novel sensor applications, tissue regeneration and engineering. METHODS: In this study, by using finite hollow cylinder focusing electrodes, an external electrostatic field is created. With these electrodes, it is aimed to decrease whipping instability of polymer jet. In addition, it is also investigated that the alignment ratio of nanofibers by using conductive parallel electrodes which placed through jet trajectory. RESULTS: In conclusion, with the effect of electrical field created by cylinder electrodes, radius of the fiber dispersion on the collector was able to be reduced and aligned nanofibers were successfully produced by using electrical field generated from the parallel plates. CONCLUSIONS: Radius of the fiber dispersion on the collector is 9.95 mm and fiber diameters varied between 800 nm and 3 MUm. Additionally, alignment ratio of the fibers is determined with ImageJ software. These alignment of nanofibers can be used in tissue engineering applications and sensor applications. PMID- 30400081 TI - First experience of chick chorioallantoic membrane (CAM) assay in the clinical work flow with oral squamous cell carcinoma patients. AB - INTRODUCTION: The oral squamous cell carcinoma (OSCC) is a leading cause of death in human malignancies. The aim of this study is to integrate the CAM Assay as a reliable and good working in vivo model for the evaluation of OSCC tumor samples and its growth into the clinical work flow. MATERIAL AND METHODS: Fresh human Tumor samples (OSCCs) 1*1 cm in size were cut into 350-450MUm thick slices by a Vibratome and put on the prepared CAM model.After growth of the tumor tissue on the CAM, we started with topical induction of proinflammatory cytokines (TNFalpha) and growth factors (TGFbeta). After further growth of the tumor on the assay, we explanted the tumor tissue and first performed microscopic and then immunohistochemical examinations. E-cadherin and vimentin were used as Epithelial to-mesenchymal transition (EMT) -makers and the histologic preparations were evaluated histomorphometrically. The results were correlated with clinical parameters of the patients. RESULTS: Under TNFalpha, the small tumors (T1 / T2) show higher E-cadherin expression than larger tumors (T3 / T4). The vimentin expression under TNFalpha behaved in the opposite direction, at T1 / T2 the expression decreased in T3 / T4 increased. Furthermore, an increased E-cadherin expression in N0 and diminished E-cadherin expression in N1 / N2b patients could be detected depending on the N-stage of the patients. Vimentin, on the other hand, was reduced in the N0 group and expressed more frequently in the N1 / N2b group. TGFbeta induction also led to increased expression of vimentin in the T3 / T4 tumors and N1 / N2b stages. CONCLUSION: By integrating a CAM assay into the clinical workflow, tumors with preserved tumor architecture can be cultured and subjected to histological and molecular biology studies. Effects on biological behavior are recognizable and demonstrable in this model. The key markers E cadherin and vimentin alone are not sufficient to represent the complexity of the EMT in this model. Further molecular biology and signaling pathway analyzes are necessary. PMID- 30400082 TI - Human and equine endothelial cells in a life cell imaging scratch assay in vitro. AB - BACKGROUND: Human and equine patients are known to frequently develop vascular complications, particularly thrombosis both in veins and arteries as well as in the microvasculature. OBJECTIVE: The aim of the present study was to investigate and compare the angiogenic response of human and equine endothelial cells to lesions in an in vitro scratch assay. METHODS: Endothelial cells from human umbilical vein (HUVEC), abdominal aorta (HAAEC) and dermal microvasculature (HDMEC) as well as equine carotid artery (EACEC) and jugular vein (EVJEC) were cultured and an elongated defect was created (scratch or "wound"). Cultures were monitored over a period of 90 hours in a life cell imaging microscope. RESULTS: In the human endothelial cell cultures, there was a uniform and continuous migration of the cells from the scratch fringe into the denuded area, which was closed after 17 (HUVEC), 15 (HAAEC) and 26 (HDMEC) hours. In the equine endothelial cell cultures, a complete closure of the induced defect occurred after 17 (EVJEC) and 35 (EACEC) hours. CONCLUSIONS: In the equine arterial cells, the delay in closure of the denuded area seems to be the results of a disoriented and uncoordinated migration of endothelial tip cells resulting in slow re endothelialization. PMID- 30400083 TI - Effect of acute hypernatremia induced by hypertonic saline administration on endothelial glycocalyx in rabbits. AB - BACKGROUND AND OBJECTIVE: The endothelial glycocalyx (EG) is fragile and sensitive to damage such as exposure to hypernatremia. Our aim was to describe the influence of hypernatremia on the EG in sublingual and brain microcirculation in rabbits. METHODS: Hypernatremia was induced by intravenous administration of 10% NaCl solution. The sublingual and brain microcirculation were evaluated by the Side-stream Dark Field imaging before (T1) and 20 minutes after infusion of 10% saline (T2). Damage to the EG was quantified by automated analysis of Perfused Boundary Region (PBR) indicating the amount of penetration of red blood cells into the EG. Syndecan-1 levels were also measured. RESULTS: Hypernatremia was reached in all 20 animals, the PBR values of the sublingual area raised from 1,98 (0,3) to 2,17 (0,18) MUm (p = 0,05). The levels of syndecan-1 (1,23 (0,36); 1,31 (0,33) ng/l, p = 0,3) did not mirror PBR changes. CONCLUSIONS: Hypernatremia increased the PBR within the sublingual microcirculation in our animal model, probably due to compression of the EG related to temporary intravascular hypervolemia and changes of the EG charge in RBC instead of direct damaging effect on EG, which has been excluded by rather unchanged levels of syndecan-1. PMID- 30400084 TI - A Free Radical-Generating System Regulates Amyloid Oligomers: Involvement of Cathepsin B. AB - Amyloid-beta (Abeta), a major component of senile plaques, is generated via the proteolysis of amyloid-beta protein precursor (AbetaPP). This cleavage also produces AbetaPP fragment-derived oligomers which can be highly neurotoxic. AbetaPP metabolism/processing is affected by many factors, one of which is oxidative stress (OS). Associated with aging, OS is an important risk factor for Alzheimer's disease. In addition, the protein degradation systems, especially those involving cathepsins, are impaired in aging brains. Moreover, cathepsin B (CTSB) is a cysteine protease with potentially specific roles in AbetaPP proteolysis (beta-secretase activity) and Abeta clearance (Abeta degradative activity). The present work examines the effect of OS and the involvement of CTSB in amyloid oligomer formation. The xanthine/xanthine oxidase (X-XOD) free radical generating system induced the partial inhibition of CTSB activity, which was accompanied by an increase in large amyloid oligomers. These were located throughout the cytosol and in endo-lysosomal vesicles. Cells treated with the CTSB inhibitor CA-074Me also showed increased amyloid oligomer levels, whereas those subjected to OS in the presence of the inhibitor showed no such increase. However, CTSB inhibition clearly modulated the AbetaPP metabolism/processing induced by X-XOD, as revealed by the increase in intracellular AbetaPP and secreted alpha-secretase-cleaved soluble AbetaPP. The present results suggest that CTSB participates in the changes of amyloid oligomer induced by mild OS. PMID- 30400085 TI - Changes in Expression Profiles Revealed by Transcriptomic Analysis in Peripheral Blood Mononuclear Cells of Alzheimer's Disease Patients. AB - Alzheimer's disease (AD) is an age-related neurodegenerative pathology associated with accumulation of DNA damage. Inflammation and cell cycle alterations seem to be implicated in the pathogenesis of AD, although the molecular mechanisms have not been thoroughly elucidated to date. The aim of the present study was to evaluate whether peripheral blood mononuclear cells (PBMCs) of AD patients display alterations in gene expression profiles, focusing on finding markers that might improve the diagnosis of AD. Blood samples were collected from 22 AD patients and 13 healthy individuals to perform genome-wide mRNA expression. We found 593 differentially expressed genes in AD compared to controls, from which 428 were upregulated, and 165 were downregulated. By performing a gene set enrichment analysis, we observed pathways involved in inflammation, DNA damage response, cell cycle, and neuronal processes. Moreover, functional annotation analyses indicated that differentially expressed genes are strongly related to pathways associated with the cell cycle and the immune system. The results were compared with those of an independent study on hippocampus samples, and a number of genes in common between both studies were identified as potential peripheral biomarkers for AD, including DUSP1, FOS, SLC7A2, RGS1, GFAP, CCL2, ANGPTL4, and SSPN. Taken together, our results demonstrate that PBMCs of AD patients do present alterations in gene expression profiles, and these results are comparable to those previously reported in the literature for AD neurons, supporting the hypothesis that blood peripheral mononuclear cells express molecular changes that occur in the neurons of AD patients. PMID- 30400086 TI - Alzheimer's Disease, Visual Search, and Instrumental Activities of Daily Living: A Review and a New Perspective on Attention and Eye Movements. AB - Many instrumental activities of daily living (IADLs), like cooking and managing finances and medications, involve finding efficiently and in a timely manner one or several objects within complex environments. They may thus be disrupted by visual search deficits. These deficits, present in Alzheimer's disease (AD) from its early stages, arise from impairments in multiple attentional and memory mechanisms. A growing body of research on visual search in AD has examined several factors underlying search impairments in simple arrays. Little is known about how AD patients search in real-world scenes and in real settings, and about how such impairments affect patients' functional autonomy. Here, we review studies on visuospatial attention and visual search in AD. We then consider why analysis of patients' oculomotor behavior is promising to improve understanding of the specific search deficits in AD, and of their role in impairing IADL performance. We also highlight why paradigms developed in research on real-world scenes and real settings in healthy individuals are valuable to investigate visual search in AD. Finally, we indicate future research directions that may offer new insights to improve visual search abilities and autonomy in AD patients. PMID- 30400087 TI - Phytochemicals from Achillea fragrantissima are Modulators of AbetaPP Metabolism. AB - Plant derivatives offer a novel and natural source of therapeutics. The desert plant Achillea fragrantissima (Forssk) Sch. Bip (Af) is characterized by protective antioxidative and anti-inflammatory properties. Here, we examined the effect of two Af-derived phytochemicals on learning and memory, amyloid-beta protein precursor (AbetaPP) metabolism, and tau phosphorylation in the familial Alzheimer's disease-linked APPswe/PS1DeltaE9 mouse model. We observed that mice that were injected with the phytochemicals showed a trend of improvement, albeit statistically insignificant, in the Novel Object Recognition task. However, we did not observe improvement in contextual fear conditioning, suggesting that the benefits of treatment may be either indirect or task-specific. In addition, we observed an increase in the full-length form of AbetaPP in the brains of mice treated with Af-derived phytochemicals. Interestingly, both in vivo and in vitro, there was no change in levels of soluble Abeta, oligomeric Abeta, or the carboxyl terminus fragments of AbetaPP (APP-CTFs), suggesting that the increase in full length AbetaPP does not exacerbate AbetaPP pathology, but may stabilize the full length form of the molecule. Together, our data suggest that phytochemicals present in Af may have a modest positive impact on the progression of Alzheimer's disease. PMID- 30400089 TI - The Ethyl Acetate Extract of Leaves of Ugni molinae Turcz. Improves Neuropathological Hallmarks of Alzheimer's Disease in Female APPswe/PS1dE9 Mice Fed with a High Fat Diet. AB - The most common type of dementia is Alzheimer's disease (AD), a progressive neurodegenerative disease characterized by impairment in cognitive performance in aged individuals. Currently, there is no effective pharmacological treatment that cures the disease due to the lack of knowledge on the actual mechanisms involved in its pathogenesis. In the last decades, the amyloidogenic hypothesis has been the most studied theory trying to explain the origin of AD, yet it does not address all the concerns relating to its development. In the present study, a possible new preclinical treatment of AD was evaluated using the ethyl acetate extract (EAE) of leaves of Ugni molinae Turcz. (synonym Myrtus ugni Molina Family Myrtacea). The effects were assessed on female transgenic mice from a preclinical model of familial AD (APPswe/PS1dE9) combined with a high fat diet. This preclinical model was selected due to the already available experimental and observational data proving the relationship between obesity, gender, metabolic stress, and cognitive dysfunction; related to characteristics of sporadic AD. According to chemical analyses, EAE would contain polyphenols such as tannins, flavonoid derivatives, and phenolic acids, as well as pentacyclic triterpenoids that exhibit neuroprotective, anti-inflammatory, and antioxidant effects. In addition, the treatment evidenced its capacity to prevent deterioration of memory capacity and reduction of progression speed of AD neuropathology. PMID- 30400088 TI - Two-Year Longitudinal Monitoring of Amnestic Mild Cognitive Impairment Patients with Prodromal Alzheimer's Disease Using Topographical Biomarkers Derived from Functional Magnetic Resonance Imaging and Electroencephalographic Activity. AB - Auditory "oddball" event-related potentials (aoERPs), resting state functional magnetic resonance imaging (rsfMRI) connectivity, and electroencephalographic (rsEEG) rhythms were tested as longitudinal functional biomarkers of prodromal Alzheimer's disease (AD). Data were collected at baseline and four follow-ups at 6, 12, 18, and 24 months in amnesic mild cognitive impairment (aMCI) patients classified in two groups: "positive" (i.e., "prodromal AD"; n = 81) or "negative" (n = 63) based on a diagnostic marker of AD derived from cerebrospinal samples (Abeta42/P-tau ratio). A linear mixed model design was used to test functional biomarkers for Group, Time, and Group*Time effects adjusted by nuisance covariates (only data until conversion to dementia was used). Functional biomarkers that showed significant Group effects ("positive" versus "negative", p < 0.05) regardless of Time were 1) reduced rsfMRI connectivity in both the default mode network (DMN) and the posterior cingulate cortex (PCC), both also giving significant Time effects (connectivity decay regardless of Group); 2) increased rsEEG source activity at delta (<4 Hz) and theta (4-8 Hz) rhythms and decreased source activity at low-frequency alpha (8-10.5 Hz) rhythms; and 3) reduced parietal and posterior cingulate source activities of aoERPs. Time*Group effects showed differential functional biomarker progression between groups: 1) increased rsfMRI connectivity in the left parietal cortex of the DMN nodes, consistent with compensatory effects and 2) increased limbic source activity at theta rhythms. These findings represent the first longitudinal characterization of functional biomarkers of prodromal AD relative to "negative" aMCI patients based on 5 serial recording sessions over 2 years. PMID- 30400090 TI - Association between Hippocampal Shape, Neuroinflammation, and Cognitive Decline in Alzheimer's Disease. AB - BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition characterized by memory impairment and general decrease in cognitive functions and daily living competences, that leads to a complete loss of autonomy. The pathogenesis of AD is characterized by the deposition of amyloid-beta plaques (Abeta plaques) and neurofibrillary tangles, initially involving cortical and hippocampal structures, and neuroinflammation. To date, no studies have investigated the topological association between neuroinflammation and hippocampal shape in AD. OBJECTIVE: The aim of the present study is to assess the association between hippocampal shape, cognitive profile, and neuroinflammation in a group of AD patients in the mild stage of the disease. METHODS: Thirty-one patients with typical onset AD (mild stage) underwent MRI examination (1.5T scanner); hippocampal structures were segmented using a vertex-wise analysis (FSL FIRST). Immune parameters were evaluated on peripheral blood mononuclear cells by flow-cytometry. Correlation analyses were performed between hippocampal shape and both cognitive profile (ADAS-Cog and MMSE scores), and neuro-inflammatory variables (i.e., circulating monocytes, cytokines). RESULTS: Statistically significant correlations (p < 0.05FWE) between right hippocampal shape and cognitive measurements and between left hippocampal shape and inflammatory indices were detected. The hippocampal field mostly involved was the lateral portion of bilateral hippocampi, mainly overlapping with Cornu Ammonis, extending along the entire longitudinal axis. CONCLUSIONS: A topological relationship between hippocampal atrophy and both cognitive profile and neuroinflammation is found; the association with neuroinflammatory indices is in line with the pattern of AD-associated neuronal death, whereas the association with cognitive test might account for residual cognitive functions. PMID- 30400091 TI - Role of the Glyoxalase System in Alzheimer's Disease. AB - Alzheimer's disease (AD) is an insidious and progressive neurodegenerative disease. The main pathological features of AD are the formation of amyloid-beta deposits in the anterior cerebral cortex and hippocampus as well as the formation of intracellular neurofibrillary tangles. Thus far, accumulating evidence shows that glycation is closely related to AD. As a final product resulting from the crosslinking of a reducing sugar or other reactive carbonyls and a protein, the advanced glycation end products have been found to be associated with the formation of amyloid-beta and neurofibrillary tangles in AD. As a saccharification inhibitor, the glyoxalase system and its substrate methylglyoxal (MG) were certified to be associated with AD onset and development. As an active substance of AGEs, MG could cause direct or indirect damage to nerve cells and tissues. MG is converted to D-lactic acid after decomposition by the glyoxalase system. Under normal circumstances, MG metabolism is in a dynamic equilibrium, whereas MG accumulates in cells in the case of aging or pathological states. Studies have shown that increasing glyoxalase activity and reducing the MG level can inhibit the generation of oxidative stress and AGEs, thereby alleviating the symptoms and signs of AD to some extent. This paper focuses on the relevant mechanisms of action of the glyoxalase system and MG in the pathogenesis of AD, as well as the potential of inhibiting the production of advanced glycation end products in the treatment of AD. PMID- 30400092 TI - Degenerative Amnesia for Past Public Events: An Attempt to Measure Storage and Retrieval. AB - A still unsettled issue of amnesia concerns the differential contributions to recall impairment of the underlying retrieval and storage abilities. The aim of the present study was to disentangle and to measure such roles in the recall of past public events comparing patients with degenerative amnesia and healthy elderly. The experiment included 44 healthy elderly and two groups of participants with degenerative amnesia, namely 17 patients with amnestic mild cognitive impairment and 22 mild Alzheimer's disease patients. Recall of famous past public events was assessed by means of a 52-item questionnaire standardized for the Italian population. A latent-variable approach was adopted in order to infer the contributions of retrieval and storage to the recall performances. A stochastic model was adopted, which in a previous study of recall of recent and remote past public events in healthy elderly succeeded to prove reduced retrieval efficiency for more recent events. The results of the present study suggest that retrieval is more fragile than storage in all three experimental groups. A storage impairment turned out only in the Alzheimer's disease group, where it was limited to more recent memories. In view of the combined roles of the hippocampus and cortex in past memory processing, our results are consistent with the hypothesis that the degenerative process primarily impairs the strategic memory search. However, the sufficiency criterion of the adopted Markov model fell short of significance. Due to this statistical shortcoming, our conclusions, though consistent with the clinical predictions, are to be taken as provisional. PMID- 30400094 TI - Psychometric Properties of Apathy Scales in Dementia: A Systematic Review. AB - Apathy is a prevalent and problematic neuropsychiatric symptom in those with dementia that is emerging as a treatment target, necessitating accurate assessment. While many apathy scales are available, not all have been developed for use exclusively in dementia, and psychometric properties may vary across different populations. This systematic review aimed to provide an overview of the psychometric properties of apathy scales used in Alzheimer's disease (AD) and related dementias, as well as rate the methodological quality of supporting studies. In addition, for those scales identified, performance in clinical trials was reviewed. A search was conducted through Medline, Psychinfo, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. Articles that reported psychometric properties of an apathy scale in an AD or mixed dementia population were included. Of 15 articles, the methodological quality ratings of the studies ranged from adequate to excellent. Three clinical trials and two pooled analyses of clinical trials were included that used apathy scales evaluated in this review. Three scales emerged. The Neuropsychiatric Inventory apathy subscale (NPI-apathy) and the Apathy Evaluation Scale (AES) had the greatest number of studies evaluating psychometric properties and were also used in the clinical trials and have shown sensitivity to change. The Dementia Apathy Interview and Rating demonstrated excellent values of internal consistency, validity, and reliability for use in an AD population. Future research should address comparative scale performance and assess ability to distinguish subtypes of apathy. Validation may include evaluation of performance against specific imaging defined deficits. PMID- 30400096 TI - Impact of Untimely Access to Formal Care on Costs and Quality of Life in Community Dwelling People with Dementia. AB - BACKGROUND: Access to formal care is not always timely and a better understanding on the impact of untimely access is needed. OBJECTIVE: To examine, from a societal perspective, the impact of untimely access to formal care in terms of total costs and quality of life over one year in community dwelling people with dementia. METHODS: Within the Actifcare study, needs, resource use, and quality of life were observed for one year in a cohort of 451 community dwelling people with dementia in 8 European countries. Untimely access to care was operationalized as having at least one unmet need for care identified by the Camberwell Assessment of Need for the Elderly (CANE) instrument. Two regression models were built for both total costs and quality of life measured by the EQ-5D 5L, one using sum of unmet needs and one using a predefined selection of need items. RESULTS: Unmet needs were not associated with higher total costs but they were associated with a lower quality of life of people with dementia. Of all CANE items, only an unmet need for "company" was significantly related to lower total costs. CONCLUSION: Total costs did not seem to differ between participants with unmet and met needs. Only few associations between specific unmet needs and costs and quality of life were found. Furthermore, quality of life of people with dementia decreases when multiple unmet needs are experienced, indicating that assessing and meeting needs is important to improve quality of life. PMID- 30400095 TI - Dual Time-Point [18F]Florbetaben PET Delivers Dual Biomarker Information in Mild Cognitive Impairment and Alzheimer's Disease. AB - BACKGROUND: Current research diagnostic criteria for Alzheimer's disease (AD) and mild cognitive impairment (MCI) due to AD include biomarkers to supplement clinical testing. Recently, we demonstrated that dual time-point [18F]FBB PET is able to deliver both blood flow and amyloid-beta (Abeta) load surrogates. OBJECTIVE: The aim of this study was to investigate whether these surrogates can be utilized as AD biomarkers. METHODS: 112 subjects (41 with MCI, 50 with probable/possible AD, 21 with other dementias) underwent dual time-point [18F]FBB PET. Data were visually and relative quantitatively (Herholz scores for the early and composite SUVRs for the late PET data) analyzed. RESULTS: In the early images AD-typical patterns were present in 42% /27% /33% of probable/possible AD/MCI/other dementia cases. In late [18F]FBB PET, 42% /29% /38% of probable/possible AD/ MCI/other dementia cases were Abeta-positive. 17% of the MCIs were categorized as "MCI due to AD-high likelihood", 44% of the probable ADs as "probable AD with high evidence of AD pathophysiological process" and 28% of the possible ADs as "possible AD with evidence of AD pathophysiological process". 27% of all subjects showed a positive diagnostic and progression biomarker. Herholz scores were lower (0.85+/-0.05 versus 0.88+/-0.04, p = 0.015) for probable/possible AD versus MCI. Composite late phase SUVRs were significantly higher (1.65+/-0.23 versus 1.15+/-0.17, p < 0.005) in Abeta-positive versus Abeta negative patients. Herholz and MMSE scores were positively correlated (R = 0.30 p = 0.006). CONCLUSION: Dual time-point [18F]FBB PET provides dual biomarker information which enables to categorize MCI and AD dementia patients according to established diagnostic criteria. Thus, dual time-point [18F]FBB PET has great potential to supplement diagnostic dementia workups. PMID- 30400093 TI - The Association of Mid- and Late-Life Systemic Inflammation with Brain Amyloid Deposition: The ARIC-PET Study. AB - BACKGROUND: Although inflammation has been implicated in the pathogenesis of Alzheimer's disease, the effects of systemic inflammation on brain amyloid deposition remain unclear. OBJECTIVE: We examined the association of midlife and late-life systemic inflammation with late-life brain amyloid levels in a community sample of non-demented older adults from the Atherosclerosis Risk in Communities (ARIC) - PET Study. METHODS: 339 non-demented participants (age: 75 [SD 5]) were recruited from the ARIC Study to undergo florbetapir PET (amyloid) imaging. Blood levels of high sensitivity C-reactive protein (CRP), a marker of systemic inflammation, were measured 22 years (Visit 2), 16 years (Visit 4), and up to 2 years before PET imaging (Visit 5). Elevated brain amyloid deposition (standardized uptake value ratio >1.2) was the primary outcome. RESULTS: Our primary analyses found no association of midlife and late-life CRP with late-life brain amyloid levels. However, in secondary stratified analyses, we found that higher midlife (Visit 2) CRP was associated with elevated amyloid among males (OR 1.65, 95% CI: 1.13-2.42), and among white (OR 1.33, 95% CI: 1.02-1.75), but not African American, participants (p-interactions<0.05). Among male participants, those who maintained high CRP levels (>=3 mg/L) throughout mid- and late-life were most likely to have elevated brain amyloid (OR, 8.81; 95% CI: 1.23, 62.91). CONCLUSIONS: Although our primary analysis does not support an association between systemic inflammation and brain amyloid deposition, we found evidence for sex- and race-dependent associations. However, findings from subgroup analyses should be interpreted with caution. PMID- 30400097 TI - Association between Peripheral Leptin and Adiponectin Levels and Cognitive Decline in Patients with Neurocognitive Disorders >=65 Years. AB - BACKGROUND: There is evidence that adipokines have roles in brain functioning and cognitive decline. OBJECTIVE: Assess the role of leptin and adiponectin levels in predicting changes in neuro-cognitive disorders (NCD). METHODS: The study included 205 patients over 65 years of age presenting for a one-day hospitalization for current assessment of cognitive function. Peripheral blood leptin and adiponectin levels were measured at admission. Demographic variables, body mass index (BMI), and history of hypertension were also recorded. Cognitive function was assessed by the Mini-Mental State Examination (MMSE) at admission and at later scheduled visits over a median follow-up period of 14.5 months. Conventional univariate comparisons were made between diagnosis groups (Alzheimer's disease (AD), mild NCD, vascular/mixed dementia). Changes in MMSE scores over time were examined with regard to the above variables using a linear mixed model. RESULTS: The mean BMI was significantly lower (by 2 kg/m2, p = 0.01) in patients with AD than in patients with either mild-NCD or vascular/mixed dementia. Leptin levels were significantly higher (p = 0.043) and adiponectin levels significantly lower (p = 0.045) in patients with mild-NCD than in patients with major-NCD (AD or vascular/mixed dementia). However, the mixed model suggested no influence of the baseline levels of these two biomarkers on the course of cognitive decline. CONCLUSION: The present study confirms the associations between leptin and adiponectin and AD or AD-related disorders but did not confirm that these peptides may be used as predictive biomarkers of cognitive decline. PMID- 30400098 TI - Depression and Alzheimer's Disease Biomarkers Predict Driving Decline. AB - BACKGROUND: Symptomatic Alzheimer's disease (AD) and depression independently increase crash risk. Additionally, depression is both a risk factor for and a consequence of AD. OBJECTIVE: To examine whether a depression diagnosis, antidepressant use, and preclinical AD are associated with driving decline among cognitively normal older adults. METHODS: Cognitively normal participants, age >=65, were enrolled. Cox proportional hazards models evaluated whether a depression diagnosis, depressive symptoms (Geriatric Depression Scale), antidepressant use, cerebrospinal fluid (amyloid-beta42 [Abeta42], tau, phosphorylated tau181 [ptau181]), and amyloid imaging biomarkers (Pittsburgh Compound B and Florbetapir) were associated with time to receiving a rating of marginal/fail on a road test. Age was adjusted for in all models. RESULTS: Data were available from 131 participants with age ranging from 65.4 to 88.2 years and mean follow up of 2.4 years (SD = 1.0). A depression diagnosis was associated with a faster time to receiving a marginal/fail rating on a road test and antidepressant use (p = 0.024, HR = 2.62). Depression diagnosis and CSF and amyloid PET imaging biomarkers were associated with driving performance on the road test (p<=0.05, HR = 2.51-3.15). In the CSF ptau181 model, depression diagnosis (p = 0.031, HR = 2.51) and antidepressant use (p = 0.037, HR = 2.50) were statistically significant predictors. There were no interaction effects between depression diagnosis, antidepressant use, and biomarker groups. Depressive symptomology was not a statistically significant predictor of driving performance. CONCLUSIONS: While, as previously shown, preclinical AD alone predicts a faster time to receiving a marginal/fail rating, these results suggest that also having a diagnosis of depression accelerates the onset of driving problems in cognitively normal older adults. PMID- 30400099 TI - Distinct White Matter Changes Associated with Cerebrospinal Fluid Amyloid-beta1 42 and Hypertension. AB - BACKGROUND: Alzheimer's disease (AD) pathology and hypertension (HTN) are risk factors for development of white matter (WM) alterations and might be independently associated with these alterations in older adults. OBJECTIVE: To evaluate the independent and synergistic effects of HTN and AD pathology on WM alterations. METHODS: Clinical measures of cerebrovascular disease risk were collected from 62 participants in University of Kentucky Alzheimer's Disease Center studies who also had cerebrospinal fluid (CSF) sampling and MRI brain scans. CSF Abeta1-42 levels were measured as a marker of AD, and fluid-attenuated inversion recovery imaging and diffusion tensor imaging were obtained to assess WM macro- and microstructural properties. Linear regression analyses were used to assess the relationships among WM alterations, cerebrovascular disease risk, and AD pathology. Voxelwise analyses were performed to examine spatial patterns of WM alteration associated with each pathology. RESULTS: HTN and CSF Abeta1-42 levels were each associated with white matter hyperintensities (WMH). Also, CSF Abeta1 42 levels were associated with alterations in normal appearing white matter fractional anisotropy (NAWM-FA), whereas HTN was marginally associated with alterations in NAWM-FA. Linear regression analyses demonstrated significant main effects of HTN and CSF Abeta1-42 on WMH volume, but no significant HTN*CSF Abeta1 42 interaction. Furthermore, voxelwise analyses showed unique patterns of WM alteration associated with hypertension and CSF Abeta1-42. CONCLUSION: Associations of HTN and lower CSF Abeta1-42 with WM alteration were statistically and spatially distinct, suggesting independent rather than synergistic effects. Considering such spatial distributions may improve diagnostic accuracy to address each underlying pathology. PMID- 30400100 TI - Diazepam Toxicity Presenting as a Dementia Disorder. AB - The toxicity associated with long-standing benzodiazepine use in older persons is a critical issue. Several epidemiological reports have studied correlation between benzodiazepine use and risk of dementia development. In this manuscript, we used a case report to demonstrate how chronic diazepam use can cause cognitive deficits that resemble Alzheimer's disease and related conditions. Benzodiazepine use is common in the geriatric population and is often taken for long periods of time in improper doses. In combination with age-related cortical atrophy on the MRI, our patient risked being misdiagnosed with Alzheimer's disease or another dementing disorder if not for the systematic investigation to resolve his symptoms. With elimination of the offending dispensable drug (diazepam), the patient's cognition improved greatly. PMID- 30400102 TI - Tau Immunotherapies for Alzheimer's Disease and Related Tauopathies: Progress and Potential Pitfalls. PMID- 30400101 TI - Genetic Variations in ABCA7 Can Increase Secreted Levels of Amyloid-beta40 and Amyloid-beta42 Peptides and ABCA7 Transcription in Cell Culture Models. PMID- 30400103 TI - Disease Progression in Huntington Disease: An Analysis of Multiple Longitudinal Outcomes. AB - BACKGROUND: Critical to discovering targeted therapies for Huntington disease (HD) are validated methods that more precisely predict when clinical outcomes occur for different patient profiles. OBJECTIVE: To more precisely predict the probability of when motor diagnosis (diagnostic confidence level 4) on the Unified Huntington's Disease Rating Scale (UHDRS), cognitive impairment (two or more neuropsychological scores on the UHDRS were 1.5 standard deviations below normative means) and Stage II Total Functional Capacity (TFC) first occur by accounting for dependencies between these outcomes. METHODS: Adult premanifest participants with >=36 CAG repeats were selected from multi-center, longitudinal, observational studies: Prospective Huntington At Risk Observational Study (PHAROS, n = 346), Neurobiological Predictors of Huntington Disease (PREDICT, n = 909); and Cooperative Huntington Observational Research Trial (COHORT, n = 430). Probabilities were estimated for each study, and pooled using the Joint Progression of Risk Assessment Tool (JPRAT) which accounts for dependencies between outcomes. RESULTS: All studies had similar probabilities of when motor diagnosis, cognitive impairment, and Stage II TFC first occurred. Probability estimates from JPRAT were 43% less variable than from models that ignored dependencies between outcomes. The probability of experiencing motor-diagnosis, cognitive impairment, and Stage II TFC within 5 years was 10%, 18%, and 7%, respectively for 45-year-olds with 42 CAG repeats, and was 4%, 10% and 5%, respectively, for 40 year olds with 42 CAG repeats. CONCLUSIONS: Improved predictions from JPRAT may benefit treatment studies of rare diseases and is an alternative to composite outcomes when the objective is interpreting individual outcomes within the same model. PMID- 30400104 TI - Increased Blood Pressure and Body Mass Index as Potential Modifiable Factors in The Progression of Myocardial Dysfunction in Duchenne Muscular Dystrophy. AB - BACKGROUND: Duchenne muscular dystrophy (DMD) is characterized by progressive cardiomyopathy. Left ventricular (LV) function may worsen by factors increasing LV afterload such as hypertension and obesity. OBJECTIVE: To identify potential modifiable risk factors for progression of cardiomyopathy in Duchenne muscular dystrophy (DMD). METHODS: We retrospectively analysed systolic blood pressures (SBP) and body-mass indexes (BMI) from 273 visits of 65 DMD patients aged 4-18 years between 2003 and 2016, divided in 14 age groups. Values were normalized using Z-scores (Z-SBP and Z-BMI). A linear mixed model was used to analyse correlations between Z-SBP and BMI, steroid use, age, ambulatory status and cardiac medication (CM) use. To study the relationship between SBP and BMI and myocardial deformation prior to the onset of clinical cardiomyopathy, LV deformation, defined by global longitudinal strain (GLS), was quantified in a subset of 36 patients <11 years. Multiple linear regression was used to study the relation between GLS and clinical parameters. RESULTS: Median follow-up was 5 years. SBP was significantly elevated in all age groups under 14 years (p<=0.04) and 15-16 years (p = 0.033) and correlated positively with BMI (p = 0.001) and negatively with CM use over time (p = 0.018). Z-BMI followed a bell-shaped distribution and plotted approximately one standard deviation above the mean in patients between 7 and 15 years. In the subset of younger patients, reduced GLS was associated with higher BMI (beta= 0.348, p = 0.004). CONCLUSIONS: SBP and BMI may be potentially modifiable factors to retard deterioration of LV function in DMD. PMID- 30400105 TI - Interpreting Genetic Variants: Hints from a Family Cluster of Parkinson's Disease. AB - Technological innovation related to the advent and development of the Next Generation Sequencing (NGS) has provided significant advances in the diagnosis of disorders with genetic and phenotypic variability, such as neurodegenerative diseases. However, the interpretation of NGS data often remains challenging, although advanced prediction tools have contributed to primarily assess the impact of some missense variants. Here, we report a patient with Parkinson's disease (PD) and a family history of disease, in which a panel of 29 disease causing or risk genes for PD were analyzed. We identified a new missense variant in the SNCA gene. Although this variant might be associated with PD in this family, it has been currently classified as a "Variant of Unknown Significance" because of the lack of segregation with disease. Indeed, we subsequently found the same mutation in an unaffected sister. Nevertheless, this finding may help clinicians and researchers in questioning the causative role of genetic variants within the daily clinical and diagnostic settings. PMID- 30400106 TI - Conversion of L-dopa to Extended Release L-dopa (Rytary(r)) in Patients with Fluctuating Parkinson's Disease: Predictor's of Dose. AB - BACKGROUND: A new extended release levodopa capsule (C/L ERC), Rytary(r), has demonstrated improved "on" time in fluctuating Parkinson's disease patients, compared to optimally dosed immediate release levodopa. The milligram dosing, however, differs markedly and no empiric ratio or formula for dose conversion currently exists. OBJECTIVE: To determine the most effective conversion strategy from C/L to C/L ERC. METHODS: We reviewed fluctuating PD patients with problematic "off" time who were converted to C/L ERC using a semi-structured dose titration schedule, and collected data regarding basic efficacy, tolerability, and dosing, in order to determine an empirically based dose conversion formula. We collected demographics, PD historic data, and other medication use. RESULTS: Eighty fluctuating PD patients were given C/L ERC samples, 68 took at least one dose [46 male (67.6%), age 66.6+/-10.3 y], and 62 had adequate data for dose convergence calculations. At a mean follow-up of 119+/-101 days, [Range: 24-355 days], 43/68 (63.3%) remained on C/L ERC. CGI-I of "much improved" or "very much improved" was reported by 27/62 (43.5%) and dyskinesia scores from the Movement Disorder Society Unified Parkinson's Disease Rating Scale item 4.1, (0-4 range)) tended to improve from 0.9+/-1.1 to 0.5+/-0.6, P = 0.08. The mean individual daily ratio was 2.0+/-0.6 : 1, [range 1.0-3.5]. A lower number of baseline daily L-dopa doses predicted a higher conversion ratio but pre-conversion dyskinesia did not. CONCLUSIONS: This retrospective study found that C/L ERC was generally well tolerated and preferred by many patients. The mean total daily conversion ratio is 2 : 1. PMID- 30400107 TI - A Proposed Roadmap for Parkinson's Disease Proof of Concept Clinical Trials Investigating Compounds Targeting Alpha-Synuclein. AB - The convergence of human molecular genetics and Lewy pathology of Parkinson's disease (PD) have led to a robust, clinical-stage pipeline of alpha-synuclein (alpha-syn)-targeted therapies that have the potential to slow or stop the progression of PD and other synucleinopathies. To facilitate the development of these and earlier stage investigational molecules, the Michael J. Fox Foundation for Parkinson's Research convened a group of leaders in the field of PD research from academia and industry, the Alpha-Synuclein Clinical Path Working Group. This group set out to develop recommendations on preclinical and clinical research that can de-risk the development of alpha-syn targeting therapies. This consensus white paper provides a translational framework, from the selection of animal models and associated end-points to decision-driving biomarkers as well as considerations for the design of clinical proof-of-concept studies. It also identifies current gaps in our biomarker toolkit and the status of the discovery and validation of alpha-syn-associated biomarkers that could help fill these gaps. Further, it highlights the importance of the emerging digital technology to supplement the capture and monitoring of clinical outcomes. Although the development of disease-modifying therapies targeting alpha-syn face profound challenges, we remain optimistic that meaningful strides will be made soon toward the identification and approval of disease-modifying therapeutics targeting alpha syn. PMID- 30400108 TI - The severity and associated comorbidities of retinopathy of prematurity among micro-premature infants with birth weights less than 750 grams. AB - OBJECTIVES: To evaluate the characteristics and comorbidities associated with ROP in micro-premature infants and their results. METHODS: This is a retrospective chart review involving multiple intensive care units in Central Texas from 2011 to 2016. Infants were included if birth weight (BW) was<=750 g with confirmed ROP by the International Classification of Retinopathy of Prematurity (ICROP). Neonates were examined and treated with laser ablation or intravitreal ranibizumab (IVR) with subsequent laser treatment, guided by fluorescein angiography, if met treatment criteria defined as type 1 ROP by the Early Treatment of Retinopathy of Prematurity standards. Time to regression was defined clinically. Results were analyzed using chi-squared test. RESULTS: 100 neonates were included in the study. Mean BW was 599 grams and mean gestational age was 24.2 weeks. Forty neonates were classified as type 1 ROP and therefore required intervention; of them 21 received laser alone and 19 required IVR with subsequent laser. Only 2 patients received more than one IVR injection. None of the patients progressed to stage 4 or 5 ROP. CONCLUSIONS: Despite such low birth weights, none of these neonates progressed to stage 4 or 5 ROP likely because of prompt examination and treatment with laser or with IVR and subsequent laser. IVR might serve as a bridge to laser in type 1 ROP allowing some retinal vessel development prior to definitive laser treatment. PMID- 30400109 TI - Feasibility and outcome of an individualized Tai Chi program for improving balance and strength in the elderly: A pilot study. AB - BACKGROUND: Traditional Tai Chi is too complex for most elderly individuals. There have been few reports regarding the development of simplified Tai Chi programs to suit the physical needs of elderly adults. However, these programs were not individualized according to the participants' balance control abilities. OBJECTIVE: Purpose of this study is to develop an individualized Tai Chi program and report the feasibility of the program. METHODS: Phase 1: Five Tai Chi masters performed the Tai Chi movements on a force platform. Based on the results of center of pressure displacement and the individual's balance abilities, an individualized program was developed.Phase 2: Ten community-dwelling older adults received 24 half-hour-sessions, using the individualized Tai Chi exercise program. The Berg Balance Scale (BBS) score, Timed Up & Go (TUG) test, forward reach, and strength of the knee extensor were determined before and after intervention. RESULTS: Participants achieved improved performance on balance control as measured with BBS (p<=0.001), TUG (p = 0.004) and forward reach (p = 0.035) as well as knee extensor strength (p = 0.002) after the program. CONCLUSIONS: This preliminary result suggests that the individualized Tai Chi program is potentially effective to improve balance function and knee extensor strength of the elderly. PMID- 30400110 TI - Assessing the sensitivity and specificity of cognitive screening measures for people with parkinson's disease. AB - INTRODUCTION: While cognitive impairment is a recognised feature of Parkinson's disease (PD), few studies have evaluated the validity of brief cognitive screening measures compared to a comprehensive neuropsychological assessment. This studies aim was to evaluate the sensitivity and specificity of the Mini Mental State Examination (MMSE), Modified Mini-Mental State Examination and Dementia Rating Scale (DRS-2) to detect cognitive impairment in individuals with PD. METHOD: Fifty-eight participants were administered the MMSE, 3MS, DRS-2 and a neuropsychological battery. ROC analyses were conducted to assess their effectiveness in classifying cognitive impairment. RESULTS: None of the three measures demonstrated good sensitivity or specificity to detect single domain cognitive impairment. For detecting impairment on two or more cognitive domains, the MMSE and DRS-2 yielded excellent sensitivity (88%) and specificity (78% and 76% respectively), at cut-off scores of 28 and 136 respectively. The 3MS demonstrated excellent sensitivity (88%) and good specificity (60%) at cut off score of 94. CONCLUSION: The MMSE and DRS-2 have excellent discriminant ability to classify multi-domain cognitive impairment in PD, however, their ability to detect more focal cognitive impairment is limited. Given that focal domain may be an indicator that could be useful in early detection of cognitive impairment for people with PD, this finding has implication for the use of these measures as screening tools in clinical practice. PMID- 30400111 TI - Initial severity of somatosensory impairment influences response to upper limb sensory retraining post-stroke. AB - BACKGROUND: Somatosensory loss occurs often following stroke. A proportional recovery model is proposed for spontaneous motor recovery, with implication for treatment planning. It is currently unknown if initial severity of sensory impairment influences stroke survivors' response to treatment to improve sensation. OBJECTIVE: To examine if initial (pre-treatment) severity of upper limb somatosensory impairment is related to sensation outcomes following treatment. METHODS: Regression analysis was used to investigate the relationship between initial and post-treatment sensation performance. Data were pooled from two randomized controlled trials of somatosensory discrimination retraining (N = 80). Upper limb somatosensation was measured using standardized tests of sensory discrimination: Fabric Matching Test, Wrist Position Sense Test, and functional Tactile Object Recognition Test. RESULTS: Post-treatment somatosensory improvement patterns were proportional to the extent of initial pre-treatment somatosensory impairment (Texture discrimination: B = 0.74, 95% CIs [0.52, 0.96]; Proprioception: B = 0.35, 95% CIs [0.24, 0.47]; Object Recognition: B = 0.85, 95% CIs [0.75, 0.95]). CONCLUSIONS: The effect of somatosensory retraining on post treatment sensation was proportional to the extent of upper limb initial somatosensory impairment. Findings suggest sensory retraining can benefit stroke survivors of varying severity of sensory impairment, including those with more severe somatosensory loss. PMID- 30400112 TI - Do trunk exercises improve trunk and upper extremity performance, post stroke? A systematic review and meta-analysis. AB - BACKGROUND: Post-stroke trunk control is reported to be associated with trunk performance and recovery of the upper limb, but the evidence for the influence of trunk exercise on both of these is unclear. OBJECTIVE: To evaluate the effect of trunk exercises on trunk performance post-stroke, and to determine if these exercises result in improved upper limb function. METHODS: A comprehensive search of the literature published between January 1990 and February 2017 was conducted using the following electronic databases; AMED, CINAHL, Cochrane Library, EMBASE, MEDLINE, PsychInfo and SPORTDiscus. Only randomized, controlled trials, published in English, evaluating the effect of trunk exercises on trunk performance and/or upper limb function post-stroke, were included. RESULTS: A total of 17 studies involving 599 participants were analysed. Meta-analysis showed that trunk exercises had large significant effect on trunk performance post-stroke. This effect varied from very large for acute stroke to medium for subacute and chronic stroke. None of the included studies had measured the effect of trunk exercise on upper limb impairment or functional activity. CONCLUSIONS: Trunk exercises improve trunk performance for people with acute, subacute and chronic strokes. As yet there is no evidence to support the effect of trunk exercise on upper limb function. PMID- 30400113 TI - Relationship between the rate of force development in knee extensor muscles and gait speed in patients with chronic stroke: A cross-sectional study. AB - BACKGROUND: The relationship between peak torque of the knee extensor muscles and gait speed was previously investigated in patients with chronic stroke, but whether the rate of force development (RFD), another indicator of muscle strength, affected gait speed remained unknown. OBJECTIVE: To clarify the relationships between the RFD of the knee extensor muscles over multiple time intervals and gait speed in patients with chronic stroke. METHODS: Twenty chronic stroke patients participated in this study. The RFD of affected and unaffected knee extensor muscles was measured. Time intervals of the RFD were set to 0-50 ms, 0-100 ms (100RFD), 0-200 ms (200RFD), and 0-300 ms (300RFD). Gait speed was assessed at comfortable and maximum pace. Pearson correlation coefficient (r) was used to analyze the relationships between RFD and gait speeds. RESULTS: The RFD of affected knee extensor muscles over all intervals was moderately correlated with both comfortable and maximum gait speeds, whereas only limited combinations (100, 200 and 300RFD with maximum gait speed) were correlated on the unaffected side. CONCLUSIONS: The present results suggest that various factors related to the RFD of affected knee extensor muscles, such as neural drive and muscle size, affect gait speed. PMID- 30400114 TI - Cognitive functioning following traumatic brain injury: The first 5 years. AB - OBJECTIVE: This study reports the results from a 5-year longitudinal investigation of the prevalence and severity of cognitive deficits following significant (i.e., ventilation required for > 24 hours) traumatic brain injury. The changes in performance, either improvement or decline, across five domains of cognitive functioning are described. METHOD: A group of 56 adults was assessed at approximately 6 months, 1 year, and 5 years following injury. RESULTS: Impairment was evident on all measures but prevalence and rate of improvement varied. Overall, by 5 years post-injury over 85% of patients were not impaired on measures of general intelligence, simple attention, and visual perception. However, 28% of patients continued to show some degree of impairment on complex attention and verbal fluency, and performance on verbal memory remained impaired for 60% of patients. There was also evidence for deterioration in complex attention and verbal memory between 1 year and 5 years. ANOVAs showed that improvement occurred on most measures between 6 months and 1 year, but there was both improvement and decline on some measures between 1 year and 5 years. CONCLUSIONS: The findings show that there is considerable heterogeneity in cognitive outcome following TBI, with some deterioration evident over the long term. PMID- 30400115 TI - Improving gait and lower-limb muscle strength in children with cerebral palsy following selective percutaneous myofascial lengthening and functional physiotherapy. AB - BACKGROUND: Selective Percutaneous Myofascial lengthening (SPML) is an innovative minimally invasive surgical procedure, using micro incisions often combined with alcohol nerve block, for managing muscle contractures and stiffness in children with cerebral palsy (CP). There is lack of evidence of effects of a combined intervention of SPML and physiotherapy on gait function and muscle strength in CP. OBJECTIVE: This study investigated the change in gait function and muscle strength in children with CP who underwent gait laboratory assessment before and after SPML, combined with obturator nerve blocks, and 9-month post-surgical functional physiotherapy. METHODS: Ten children with bilateral spastic CP, Gross Motor Function Classification System (GMFCS) level II-IV, age 5-7 years, participated in this study. The Global Gait Graph Deviation Index (Global GGDI) and isometric muscle strength (hand-held dynamometry) were the primary outcome measures. Changes in spatiotemporal gait parameters, gross motor function and GMFCS level were secondarily examined. RESULTS: A significant improvement of Global GGDI was found (p < 0.05). The mean strength in hip flexors, extensors and adductors, knee extensors, and ankle dorsiflexors increased significantly (p < 0.05). Children improved significantly their GMFCS level and gross motor capacity (p < 0.05). CONCLUSIONS: SPML procedure combined with functional physiotherapy can improve gait function and lower-limb muscle strength. PMID- 30400116 TI - Dose-response relationship of transcutaneous spinal direct current stimulation in healthy humans: A proof of concept study. AB - BACKGROUND: Non-invasive transcranial direct current stimulation has been shown to modulate cortical excitability in various studies. Similarly, recent preliminary studies suggest that transcutaneous spinal direct current stimulation (tsDCS) may engender a modulation effect on spinal and cortical neurons. OBJECTIVE: The purpose of this study was to evaluate the dose-response effects of tsDCS in healthy subjects and thereby lay groundwork for expanding treatment options for patients with spinal cord injury (SCI). METHODS: Nine healthy subjects received each of the following 2 tsDCS conditions: Anodal and cathodal, in random order with at least 1 week washout period between each session. In order to test safety and dose response, various current intensities were used (2, 2.5 and 3 mA) for 20 minutes. The active electrode was placed vertically over T10 T11, and the reference electrode was placed over the left shoulder. To evaluate corticospinal excitability, motor evoked potentials over soleus muscle elicited by transcranial magnetic stimulation were measured. To assess spinal cord excitability, H- and M- wave over soleus muscle to calculate Hmax/ Mmax ratio were measured. RESULTS: Linear regression showed a dose response with cathodal tsDCS on motor evoked potentials measured from the left leg as well as with anodal tsDCS on Hmax/ Mmax ratio measured from the left leg. CONCLUSIONS: These findings indicate tsDCS effects are dose-dependent. These effects should be investigated in a larger sample. PMID- 30400117 TI - The development and pilot evaluation of virtual reality balance scenarios in people with multiple sclerosis (ms): A feasibility study. AB - BACKGROUND: Balance deficits are considered a risk factor for falls in MS patients. Therefore, developing innovative approaches such as virtual reality (VR) to improve balance in MS is required. OBJECTIVES: The aims of this study were to develop and evaluate feasibility and acceptability of VR scenarios that target balance in MS using a pilot trial. METHODS: Participants were randomly allocated to either a VR training (i.e. intervention group) (n = 20) or a control group (n = 20). Intervention group received VR training for 6 weeks. Control group received home-based traditional balance exercises without the VR. Participants were assessed at baseline and follow-up on Berg Balance Scale (BBS), Timed Up and Go (TUG) and Fall Efficacy Scale- International (FES-I) and the Short Form 36 (SF-36). RESULTS: Six VR scenarios weer developed. Sixteen participants in the intervention and 16 in the control group completed the study. Significant differences between the two groups were observed at on BBS, MFIS and several outcomes of the SF-36 survey (P < 0.05). Participants reported overall level of satisfaction with the developed VR scenarios. CONCLUSIONS: Findings demonstrated the feasibility and acceptability of a VR-based program in MS individuals. Our findings support the implementation of a larger trial of longer term VR program. PMID- 30400118 TI - Treadmill exercise training could attenuate the upregulation of Interleukin-1beta and tumor necrosis factor alpha in the skeletal muscle of mouse model of chronic/progressive Parkinson disease. AB - BACKGROUND: Induction of Parkinson disease (PD) causes IL-1beta and TNF-alpha upregulation in gastrocnemius skeletal muscles. Endurance exercise suppresses iNOS and HSP90 overexpression in PD skeletal muscle. The purpose of this study is to test the impact of treadmill exercise training on PD-associated IL-1beta and TNF-alpha upregulation in the gastrocnemius muscle. METHODS: Thirty normal albino mice were randomly selected and divided into three equal groups: sedentary control (SC), sedentary PD (SPD), and Exercised PD (EPD). Parkinsonism was induced by treating mice in the SPD and EPD groups with 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine and probenecid (MPTP/p). Gastrocnemius muscles were examined for the expression of IL-1beta and TNF-alpha using immunohistochemistry in the three different groups. RESULTS: Endurance exercise training significantly decreased both IL-1beta and TNF-alpha expression in skeletal muscle in EPD (P value < 0.01) compared with that in the SPD. CONCLUSION: Our present data suggest that PD-induced upregulation of IL-1beta and TNF-alpha in the gastrocnemius muscle could be reversed following endurance exercise training. Accordingly, IL-1beta and TNF-alpha might be considered therapeutically to ameliorate skeletal muscle abnormalities characterizing PD. PMID- 30400119 TI - Energetic cost of walking and spasticity in persons with multiple sclerosis with moderate disability. AB - BACKGROUND: The energetic cost of walking (Cw) is elevated in persons with multiple sclerosis (MS). This may be explained by spasticity and spatiotemporal parameters of gait. OBJECTIVE: To examine the associations among Cw, spasticity of ankle plantarflexors, and spatiotemporal gait parameters in persons with MS who had moderate disability. METHODS: The sample included 44 persons with MS who had moderate disability. Cw was measured over-ground during the 6-Minute Walk using indirect calorimetry and was calculated based on net oxygen consumption and walking speed (i.e., expressed ml.kg-1.m-1). Participants underwent the Modified Ashworth Scale as a measurement of spasticity and performed 4 trials of walking on a GAITRite electronic walkway for measurement of spatiotemporal gait parameters. RESULTS: Spasticity was positively correlated with Cw (r = 0.52, p < 0.05) and inversely correlated with cadence (r = -.45, p < 0.05) and step length (r = -0.40, p < 0.05). Cadence (r = -0.59, p < 0.05) and step length (r = 0.56, p < 0.05) were inversely correlated with Cw. The regression analysis indicated that spasticity explained significant variance in Cw, and cadence and step length accounted for the association. CONCLUSIONS: These results suggest that worse spasticity of the ankle plantarflexors and slower cadence and shorter step length, in turn, are responsible for elevated Cw among persons with MS with moderate disability. This supports the development of therapeutic, rehabilitation interventions delivered by clinicians for managing spasticity and the resulting Cw that may interfere with activities of daily living. PMID- 30400120 TI - Self-powered robots to reduce motor slacking during upper-extremity rehabilitation: a proof of concept study. AB - BACKGROUND: Robotic rehabilitation is a highly promising approach to recover lost functions after stroke or other neurological disorders. Unfortunately, robotic rehabilitation currently suffers from "motor slacking", a phenomenon in which the human motor system reduces muscle activation levels and movement excursions, ostensibly to minimize metabolic- and movement-related costs. Consequently, the patient remains passive and is not fully engaged during therapy. To overcome this limitation, we envision a new class of body-powered robots and hypothesize that motor slacking could be reduced if individuals must provide the power to move their impaired limbs via their own body (i.e., through the motion of a healthy limb). OBJECTIVE: To test whether a body-powered exoskeleton (i.e. robot) could reduce motor slacking during robotic training. METHODS: We developed a body powered robot that mechanically coupled the motions of the user's elbow joints. We tested this passive robot in two groups of subjects (stroke and able-bodied) during four exercise conditions in which we controlled whether the robotic device was powered by the subject or by the experimenter, and whether the subject's driven arm was engaged or at rest. Motor slacking was quantified by computing the muscle activation changes of the elbow flexor and extensor muscles using surface electromyography. RESULTS: Subjects had higher levels of muscle activation in their driven arm during self-powered conditions compared to externally-powered conditions. Most notably, subjects unintentionally activated their driven arm even when explicitly told to relax when the device was self-powered. This behavior was persistent throughout the trial and did not wane after the initiation of the trial. CONCLUSIONS: Our findings provide novel evidence indicating that motor slacking can be reduced by self-powered robots; thus demonstrating promise for rehabilitation of impaired subjects using this new class of wearable system. The results also serve as a foundation to develop more sophisticated body-powered robots (e.g., with controllable transmissions) for rehabilitation purposes. PMID- 30400121 TI - Alterations in the spinal cord and ventral root after cerebral infarction in non human primates. AB - BACKGROUNDS: Cerebral infarction does not only cause focal injury in the ischemic site, but also secondary non-ischemic damage at the remote areas of nervous system associated with the primary focus. OBJECTIVE: This study investigated the changes in the spinal cord and ventral root after middle cerebral artery occlusion (MCAO) in cynomolgus monkeys (Macaca fascicularis). METHODS: Adult male cynonolgus monkeys (4-5 years, 5.5-7.5 kg) were subjected to MCAO (n = 6) or sham surgery (n = 4). After 12 weeks, spinal cords and the ventral roots were harvested. Morphometric alterations in the spinal cord were detected at C5 and L5 levels via immunofluorescence. The profiles of C5 and L5 ventral roots were displayed by toluidine blue staining and transmission electron microscopic examination. RESULTS: Significant axonal loss in the contralateral corticospinal tract and abnormally enlarged axons in the ipsilateral were observed in monkeys with MCAO. The number of neurons in the contralateral ventral horn got declined while that in the ipsilateral was almost unaffected after MCAO compared with sham controls. Glial activation post-MCAO was observed in the bilateral corticospinal tract and the ventral horn. Aberrant nerve fibers appeared frequently in the contralateral ventral roots of MCAO monkey but rarely in the ipsilateral. CONCLUSIONS: These results indicate that focal cerebral infarction leads to pathological alterations in the spinal cord and ventral roots in non-human primates. PMID- 30400122 TI - Meditation enhances brain oxygenation, upregulates BDNF and improves quality of life in patients with primary open angle glaucoma: A randomized controlled trial. AB - BACKGROUND: Glaucoma (POAG) is a kind of neurodegenerative disease known to be closely associated with stress and adverse quality of life (QOL). Stress has also been shown to be involved in etiopathogenesis of primary open angle glaucoma (POAG). Complementary treatment in form of Meditation has been reported to improve QOL, brain oxygenation and decrease markers of stress. With this premise, a randomized controlled trial was carried out to assess the effect of Meditation on intraocular pressure, subjective QOL and objective markers of stress and brain oxygenation in patients with POAG. METHODS: Sixty patients were randomized into intervention and control groups. Intervention group underwent 45 minutes of Meditation daily for 6 weeks in addition to standard medical treatment while controls received only standard medical treatment. Inclusion criteria were patients with POAG, age >45 years, best corrected visual acuity >6/60. Patients with other ocular co-morbid conditions contributing to vision loss, systemic diseases, patients already practicing meditation in any form were excluded. An assessment of IOP, brain oxygenation using functional near infrared spectroscopy (fNIRS), QOL (WHO-BREF QOL) and stress markers in serum (cortisol, beta endorphins, interleukin-6, brain derived neurotrophic factor (BDNF), reactive oxygen species) was made at baseline and at 6 weeks. RESULTS: 21 female and 39 male patients were enrolled with a mean age of 57.28+/-9.37 years. All parameters were comparable between two groups at baseline. At 6 weeks mean level of IOP decreased significantly in intervention group (15.9+/-1.8 mmHg to 14.4+/-1.21 mm Hg, p-value 0.0001) as compared to control group (15.7+/-1.4 mmHg to 15.65+/ 1.41, p-value 0.41). fNIRS showed significant improvement in oxygenated hemoglobin change (DeltaHbO) in intervention group in the prefrontal cortex (p value < 0.0001) as compared to control group (p-value 0.52). WHO-BREF QOL score increased significantly in intervention group (86.6+/-6.16 to 93.3+/-5.66, p value 0.0001) as compared to control (89+/-7.25 to 89.07+/-3.24, p-value 0.74).Mean serum cortisol decreased significantly in intervention group (497+/ 46.37 ng/ml to 447+/-53.78 ng/ml, p-value 0.01) as compared to control group (519.75+/-24.5 to 522.58+/-26.63 ng/ml, p-value 0.64). Mean beta-endorphin levels increased significantly (33+/-5.52pg/ml to 43.27pg/ml, p-value < 0.0001) as compared to control group (34.78+/-4.1pg/ml to 36.33pg+/-4.07pg/ml p-value 0.27). Interleukin-6 decreased significantly in intervention group (2.2+/-0.5 ng/ml to 1.35+/-0.32 ng/ml, p-value < 0.0001) as compared to control group (2.03+/-0.37 to 2.17+/-0.34 ng/ml p-value 0.25). BDNF increased significantly in intervention group (52.24+/-6.71 to 63.25+/-13.48 ng/ml p-value 0.004) as compared to control group (53.23+/-5.82 to 54.42+/-5.66 ng/ml p-value 0.54). ROS decreased significantly in intervention group (1596.19+/-179.14 to 1261+/-244.31 RLU/min/104 neutrophils p-value 0.0001) as compared to control group (1577.5+/ 172.02 to 1662.5+/-84.75 RLU/min/104 neutrophils p-value 0.16). CONCLUSIONS: A short term course of Meditation was associated with significant improvement in brain oxygenation and QOL along with a reduction in IOP and stress markers. Meditation may be a useful as an adjunct to standard treatment in patients with POAG and potentially decrease the risk of glaucoma progression. PMID- 30400123 TI - Returning to work after breast cancer: A systematic review of reviews. AB - BACKGROUND: Due to improvements in breast cancer diagnosis and treatment, the healthcare system faces a growing number of cancer survivors. Breast cancer survivors experience many difficulties when returning to work, including discrimination at work and lack of support by employers and colleagues. OBJECTIVE: To point out the knowledge in literature up to date about return to work (RTW) after breast cancer, the factors influencing it and the interventions to facilitate it. METHODS: A literature search was conducted in January 2017 using the databases Medline (PubMed) and Scopus. Studies were included if they analyzed the problem of RTW in women treated for breast cancer. RESULTS: Twenty six articles met the inclusion criteria. The studies were divided into four themes: factors facilitating or impeding RTW; interventions to enhance RTW; lived experiences of RTW; economic aspects related to cancer survivors and RTW. CONCLUSIONS: The heterogeneity of the interventions suggests the need for a better definition of the concept of RTW. To compare interventions, studies should use a rigorous approach and better outcome measures should be identified to evaluate RTW. PMID- 30400124 TI - Work-related musculoskeletal disorders among greek hospital nursing professionals: A cross-sectional observational study. AB - BACKGROUND: The serious shortages of nurses are related to increased risk for musculoskeletal disorders during work. The complexity of patient care places nurses at high-risk for injury and high in the list of occupations with risk for work-related musculoskeletal disorders (WMSD). OBJECTIVE: The current study evaluated the association of personal, professional and health factors with the development of WMSD in the nursing staff of hospitals in the capital of Greece. METHODS: The study was conducted online with 394 nurses (age: 37.85+/-7.48 years (mean+/-SD), 19.54% male and 80.46% female) using a questionnaire based on the Nordic Musculoskeletal Questionnaire, and comparatively examined WMSD across nurses. RESULTS: The prevalence of musculoskeletal disorders in general was 98%, with symptoms reported for the waist (85.3%), neck (71.2%) and back (70.7%). The risk for WMSD was higher for specific RN groups: female nurses had higher risk than males (p-value = 0.000 to 0.022), RNs with 11-20 years of work experience (p value = 0.008) had higher risk than their younger colleagues, RNs that strain their waist, lift loads, etc faced higher risks (p-value = 0.000 to 0.043). Shift work, age and the body mass index also lead to increased risk. CONCLUSIONS: Our study indicated that Greek nurses suffer more frequently from WMSD in comparison to their colleagues internationally and this must alert hospital managers and the Greek National Health System to develop a prevention policy for WMSD in Greek hospitals. PMID- 30400125 TI - Collision-avoiding imaging trajectories for linac mounted cone-beam CT. AB - BACKGROUND: Some patients cannot be imaged with cone-beam CT for image-guided radiation therapy because their size, pose, or fixation devices cause collisions with the machine. OBJECTIVE: To investigate imaging trajectories that avoid such collisions by using virtual isocenter and variable magnification during acquisition while yielding comparable image quality. METHODS: The machine components most likely to collide are the gantry and kV detector. A virtual isocenter trajectory continuously moves the patient during gantry rotation to maintain an increased separation between the two. With dynamic magnification, the kV detector is dynamically moved to increase clearance for an angular range around the potential collision point while acquiring sufficient data to maintain the field-of-view. Both strategies were used independently and jointly with the resultant image quality evaluated against the standard circular acquisition. RESULTS: Collision avoiding trajectories show comparable contrast and resolution to standard techniques. For an anthropomorphic phantom, the RMSE is <7*10- 4, multi-scale structural similarity index is >0.97, and visual image fidelity is >0.96 for all trajectories when compared to a standard circular scan. CONCLUSIONS: The proposed trajectories avoid machine-patient collisions while providing comparable image quality to the current standard thereby enabling CBCT imaging for patients that could not otherwise be scanned. PMID- 30400126 TI - Performance of the sinogram-based iterative reconstruction in sparse view X-ray computed tomography. AB - Performing X-ray computed tomography (CT) examinations with less radiation has recently received increasing interest: in medical imaging this means less (potentially harmful) radiation for the patient; in non-destructive testing of materials/objects such as testing jet engines, the reduction of the number of projection angles (which for large objects is in general high) leads to a substantial decreasing of the experiment time. In the experiment, less radiation is usually achieved by either (1) reducing the radiation dose used at each projection angle or (2) using sparse view X-ray CT, which means significantly less projection angles are used during the examination. In this work, we study the performance of the recently proposed sinogram-based iterative reconstruction algorithm in sparse view X-ray CT and show that it provides, in some cases, reconstruction accuracy better than that obtained by some of the Total Variation regularization techniques. The provided accuracy is obtained with computation times comparable to other techniques. An important feature of the sinogram-based iterative reconstruction algorithm is that it is simpler and without the many parameters specific to other techniques. PMID- 30400127 TI - Genomic Surgery: Through the Translational Looking Glass From Science Fiction to Reality. PMID- 30400128 TI - Revisiting the Many Names of Freeman-Sheldon Syndrome. AB - While officially designated as distal arthrogryposis type 2A, the condition commonly referred to as Freeman-Sheldon syndrome (FSS) also historically has been termed craniocarpotarsal dystrophy, whistling face syndrome, and craniocarpotarsal dysplasia and classified at different times as a skeletal dysplasia, nonprogressive myopathy, craniofacial syndrome, and distal arthrogryposis. Having previously provided evidence for FSS being a complex myopathic craniofacial syndrome with extra-craniofacial features in most patients, the rationale for revising the FSS eponym and supplanting the current official designation with a new one was based on considerations for educational usefulness, historical accuracy, communication fluency, and nosologic clarity underpinned by genetic, pathologic, and operative experience and outcomes. PMID- 30400129 TI - Eating Behaviour Predicts Weight Loss Six Months after Bariatric Surgery: A Longitudinal Study. AB - Bariatric surgery is currently the most durable weight loss solution for patients with morbid obesity. The extent of weight loss achieved, however, is subject to variation due to various factors, including patients' behaviour. In this study, we aimed to identify pre- and post-surgical predictors of weight loss following bariatric surgery. This prospective study included 57 participants who went through bariatric surgery (laparoscopic Roux-en-Y gastric bypass: n = 30; laparoscopic sleeve gastrectomy: n = 23; one anastomosis gastric bypass-mini gastric bypass: n = 4) in two tertiary referral hospitals. Consenting participants were assessed prior to surgery (T0), and three months (T1) and six months (T2) after surgery. The assessment included interview and anthropometric measurements. The interview was done with the aid of instruments, including the Hospital Anxiety and Depression Scale (HADS) for anxiety and depression screening and the Dutch Eating Behaviour Questionnaire (DEBQ) for eating behaviour assessment. Baseline comorbidity status was obtained from medical records. A Generalised Estimating Equation (GEE) was developed to determine predictors of weight loss. Participants in the study were mostly women (n = 37, 65%) with a mean age of 39.4 (SD = 10.01) years. The mean excess BMI loss (EBMIL) and total weight loss (TWL) at the sixth month was 63.31% and 23.83%, respectively. Anxiety, depression, and external eating scores reduced over time. Advancing age, high BMI, and higher scores for emotional and external eating emerged as significant negative predictors for TWL%. It can be concluded that the patients experienced substantial weight loss after surgery. Continuous monitoring of psychological well-being and eating behaviour are essential for optimal weight loss. PMID- 30400130 TI - Evaluation Tool Development for Food Literacy Programs. AB - Food literacy is described as the behaviours involved in planning, purchasing, preparing, and eating food and is critical for achieving healthy dietary intakes. Food literacy programs require valid and reliable evaluation measures. The aim of this paper is to describe the development and validation of a self-administered questionnaire to measure food literacy behaviours targeted by the Food Sensations(r) for Adults program in Western Australia. Validity and reliability tests were applied to questionnaire item development commencing with (a) a deductive approach using Australian empirical evidence on food literacy as a construct along with its components and (b) adapting an extensively-tested food behaviour checklist to generate a pool of items for investigation. Then, an iterative process was applied to develop a specific food literacy behaviour checklist for program evaluation including exploratory factor analysis. Content, face, and construct validity resulted in a 14-item food behaviour checklist. Three factors entitled Plan & Manage, Selection, and Preparation were evident, resulting in Cronbach's alpha 0.79, 0.76, and 0.81, respectively, indicating good reliability of each of these factors. This research has produced a validated questionnaire, is a useful starting point for other food literacy programs, and has applications globally. PMID- 30400133 TI - Factors Attenuating Zinc Deficiency Improvement in Direct-Acting Antiviral Agent Treated Chronic Hepatitis C Virus Infection. AB - Zinc deficiency is frequently observed in chronic liver diseases. However, no studies have focused on the zinc status in chronic hepatitis C (HCV)-infected patients receiving direct-acting antiviral agents (DAAs). In this retrospective study, we assessed the serum zinc status in DAA-treated HCV patients with sustained virologic response for over two years (Zn-2y). Ninety-five patients were enrolled, whose baseline characteristics and blood parameters at DAA therapy initiation were collected. Baseline Zn < 65 ug/dL (odds ratio (OR) = 10.56, p < 0.001) and baseline uric acid (UA) > 5.5 mg/dL (OR = 9.99, p = 0.001) were independent risk factors for Zn-2y deficiency. A decision-tree algorithm classified low-baseline Zn and high-baseline UA as the first two variables, suggesting that baseline hypozincemia and hyperuricemia are prognosticators for long-term zinc deficiency. Baseline Zn was negatively correlated with the Fibrosis-4 (FIB-4) index, while baseline UA was significantly higher in habitual alcohol drinkers. In conclusion, serum zinc levels should be closely monitored, considering that zinc status improvement is related to liver fibrosis regression. Hyperuricemia indicates risks of developing metabolic disorders and subsequent zinc deficiency, for which an adjustment of personal lifestyle or dietary habits should be recommended clinically. PMID- 30400135 TI - Selenium-Binding Protein 1 in Human Health and Disease. AB - Selenium-binding protein 1 (SBP1) is a highly conserved protein that covalently binds selenium. SBP1 may play important roles in several fundamental physiological functions, including protein degradation, intra-Golgi transport, cell differentiation, cellular motility, redox modulation, and the metabolism of sulfur-containing molecules. SBP1 expression is often reduced in many cancer types compared to the corresponding normal tissues and low levels of SBP1 are frequently associated with poor clinical outcome. In this review, the transcriptional regulation of SBP1, the different physiological roles reported for SBP1, as well as the implications of SBP1 function in cancer and other diseases are presented. PMID- 30400134 TI - New Advances in General Biomedical Applications of PAMAM Dendrimers. AB - Dendrimers are nanoscopic compounds, which are monodispersed, and they are generally considered as homogeneous. PAMAM (polyamidoamine) was introduced in 1985, by Donald A. Tomalia, as a new class of polymers, named 'starburst polymers'. This important contribution of Professor Tomalia opened a new research field involving nanotechnological approaches. From then on, many groups have been using PAMAM for diverse applications in many areas, including biomedical applications. The possibility of either linking drugs and bioactive compounds, or entrapping them into the dendrimer frame can improve many relevant biological properties, such as bioavailability, solubility, and selectivity. Directing groups to reach selective delivery in a specific organ is one of the advanced applications of PAMAM. In this review, structural and safety aspects of PAMAM and its derivatives are discussed, and some relevant applications are briefly presented. Emphasis has been given to gene delivery and targeting drugs, as advanced delivery systems using PAMAM and an incentive for its use on neglected diseases are briefly mentioned. PMID- 30400132 TI - Role of Selenoprotein F in Protein Folding and Secretion: Potential Involvement in Human Disease. AB - Selenoproteins form a group of proteins of which its members contain at least one selenocysteine, and most of them serve oxidoreductase functions. Selenoprotein F (SELENOF), one of the 25 currently identified selenoproteins, is located in the endoplasmic reticulum (ER) organelle and is abundantly expressed in many tissues. It is regulated according to its selenium status, as well as by cell stress conditions. SELENOF may be functionally linked to protein folding and the secretion process in the ER. Several studies have reported positive associations between SELENOF genetic variations and several types of cancer. Also, altered expression levels of SELENOF have been found in cancer cases and neurodegenerative diseases. In this review, we summarize the current understanding of the structure, expression, and potential function of SELENOF and discuss its possible relation with various pathological processes. PMID- 30400131 TI - The Immunomodulatory and Anti-Inflammatory Role of Polyphenols. AB - This review offers a systematic understanding about how polyphenols target multiple inflammatory components and lead to anti-inflammatory mechanisms. It provides a clear understanding of the molecular mechanisms of action of phenolic compounds. Polyphenols regulate immunity by interfering with immune cell regulation, proinflammatory cytokines' synthesis, and gene expression. They inactivate NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) and modulate mitogen-activated protein Kinase (MAPk) and arachidonic acids pathways. Polyphenolic compounds inhibit phosphatidylinositide 3-kinases/protein kinase B (PI3K/AkT), inhibitor of kappa kinase/c-Jun amino-terminal kinases (IKK/JNK), mammalian target of rapamycin complex 1 (mTORC1) which is a protein complex that controls protein synthesis, and JAK/STAT. They can suppress toll like receptor (TLR) and pro-inflammatory genes' expression. Their antioxidant activity and ability to inhibit enzymes involved in the production of eicosanoids contribute as well to their anti-inflammation properties. They inhibit certain enzymes involved in reactive oxygen species ROS production like xanthine oxidase and NADPH oxidase (NOX) while they upregulate other endogenous antioxidant enzymes like superoxide dismutase (SOD), catalase, and glutathione (GSH) peroxidase (Px). Furthermore, they inhibit phospholipase A2 (PLA2), cyclooxygenase (COX) and lipoxygenase (LOX) leading to a reduction in the production of prostaglandins (PGs) and leukotrienes (LTs) and inflammation antagonism. The effects of these biologically active compounds on the immune system are associated with extended health benefits for different chronic inflammatory diseases. Studies of plant extracts and compounds show that polyphenols can play a beneficial role in the prevention and the progress of chronic diseases related to inflammation such as diabetes, obesity, neurodegeneration, cancers, and cardiovascular diseases, among other conditions. PMID- 30400136 TI - Docoxahexaenoic Acid Induces Apoptosis of Pancreatic Cancer Cells by Suppressing Activation of STAT3 and NF-kappaB. AB - The omega3-polyunsaturated fatty acid docosahexenoic acid (DHA) is known to induce apoptosis of cancer cells. In this study, DHA was shown to reduce viability of pancreatic cancer cells (PANC-1) by inducing DNA fragmentation, activating caspase-3, and increasing the ratio of Bax/Bcl-2. To determine the DHA mechanism of action, the impact of DHA on the activation of the key signaling proteins epidermal growth factor receptor (EGFR), signal transducer and activator of transcription factor 3 (STAT3), nuclear transcription factor-kappaB (NF kappaB), and IkappaBalpha in PANC-1 cells was probed. The observed DHA suppression of NF-kappaB DNA-binding activity was found to result from reduced IkappaBalpha phosphorylation. The observed DHA-induced suppression of STAT3 activation was found to be the result of suppressed EGFR activation, which derives from the inhibitory effect of DHA on the integrity of localization of EGFR to cell membrane lipid rafts. Since the activation of STAT3 and NF-kappaB mediates the expression of survival genes cyclin D1 and survivin, DHA induced apoptosis by suppressing the STAT3/NF-kappaB-cyclin D1/survivin axis. These results support the proposal that DHA-induced apoptosis of pancreatic cells occurs via disruption of key pro-cell survival signaling pathways. We suggest that the consumption of DHA-enriched foods could decrease the incidence of pancreatic cancer. PMID- 30400137 TI - Effects of PTFE Micro-Particles on the Fiber-Matrix Interface of Polyoxymethylene/Glass Fiber/Polytetrafluoroethylene Composites. AB - Reinforcing polyoxymethylene (POM) with glass fibers (GF) enhances its mechanical properties, but at the expense of tribological performance. Formation of a transfer film to facilitate tribo-contact is compromised due to the abrasiveness of GF. As a solid lubricant, for example, polytetrafluoroethylene (PTFE) significantly improves friction and wear resistance. The effects of chemically etched PTFE micro-particles on the fiber-matrix interface of POM/GF/PTFE composites have not been systematically characterized. The aim of this study is to investigate their tribological performance as a function of micro-PTFE blended by weight percentage. Samples were prepared by different compositions of PTFE (0, 1.7, 4.0, 9.5, 15.0 and 17.3 wt.%). The surface energy of PTFE micro-particles was increased by etching for 10 min using sodium naphthalene salt in tetrahydrofuran. Tribological performance was characterized through simultaneous acquisition of the coefficient of friction and wear loss on a reciprocating test rig in accordance to Procedure A of ASTM G133-95. Friction and wear resistance improved as the micro-PTFE weight ratio was increased. Morphology analysis of worn surfaces showed transfer film formation, encapsulating the abrasive GF. Energy dispersive X-ray spectroscopy (EDS) revealed increasing PTFE concentration from the GF surface interface region (0.5, 1.0, 1.5, 2.0, 2.5 um). PMID- 30400138 TI - Are Raw Brassica Vegetables Healthier Than Cooked Ones? A Randomized, Controlled Crossover Intervention Trial on the Health-Promoting Potential of Ethiopian Kale. AB - The present human intervention trial investigated the health-promoting potential of B. carinata, with a focus on effects of thermal processing on bioactivity. Twenty-two healthy subjects consumed a B. carinata preparation from raw (allyl isothiocyanate-containing) or cooked (no allyl isothiocyanate) leaves for five days in a randomized crossover design. Peripheral blood mononuclear cells were exposed to aflatoxin B1 (AFB1), with or without metabolic activation using human S9 mix, and subsequently analyzed for DNA damage using the comet assay. Plasma was analyzed for total antioxidant capacity and prostaglandin E2 (PGE2) levels. Cooked B. carinata significantly reduced DNA damage induced by AFB1 as compared to baseline levels (+S9 mix: 35%, -S9 mix: 33%, p <= 0.01, respectively). Raw B. carinata only reduced DNA damage by S9-activated AFB1 by 21% (p = 0.08). PGE2 plasma levels were significantly reduced in subjects after consuming raw B. carinata. No changes in plasma antioxidant capacity were detectable. A balanced diet, including raw and cooked Brassica vegetables, might be suited to fully exploit the health-promoting potential. These results also advocate the promotion of B. carinata cultivation in Eastern Africa as a measure to combat effects of unavoidable aflatoxin exposure. PMID- 30400139 TI - The Relationship between Vegetable Intake and Weight Outcomes: A Systematic Review of Cohort Studies. AB - The relationship between vegetable consumption and measures of adiposity was assessed in cohort studies. Seven databases were searched from inception until February 2018. The quality of individual studies was assessed using the Joanna Briggs Institute Critical Appraisal of Cohort Studies tool. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was applied to determine the quality of the body of evidence. Ten studies were included. Six measured change in vegetable intake over time. Two showed that increasing vegetable consumption resulted in weight loss of 0.09-0.1 kg over four years (p < 0.001). Increased vegetable intake was also associated with a reduced risk of weight gain and overweight or obesity (Odds ratios (ORs) ranged from 0.18 to 0.88) in other studies. Four studies measured vegetable intake at the baseline only. One showed that intakes >4 servings/day reduced the risk of weight gain (OR 0.27 (95% confidence interval (CI) 0.08-0.99) and another found an inverse association with waist circumference in women (-0.36 cm per vegetable serving/day). This review provides moderate quality evidence for an inverse association between vegetable intake and weight-related outcomes in adults. When these findings are coupled with no apparent harm from vegetable consumption, the evidence-base can be used with acceptable confidence to guide practice and policy. PMID- 30400140 TI - Crocin Ameliorates Atopic Dermatitis Symptoms by down Regulation of Th2 Response via Blocking of NF-kappaB/STAT6 Signaling Pathways in Mice. AB - Crocin, a major constituent of Gardenia jasminoides, is a natural colorant carotenoid compound that has been reported to have anti-inflammatory effects. This study investigated the therapeutic effects of crocin on mice with atopic dermatitis induced by Dermatophagoides farinae crude extract, which is a common environmental allergen in house dust that causes atopic dermatitis in humans. Crocin application ameliorated Dermatophagoides farinae crude extract-induced atopic dermatitis symptoms by inhibiting the dermatitis severity score, ear thickness, and serum immunoglobulin E levels in NC/Nga mice. The increases in epidermal thickness and dermal inflammatory cells (eosinophil and mast cells) infiltrations observed on the dorsal back skin of atopic dermatitis control mice were inhibited in a dose-dependent manner by topical application of crocin in atopic dermatitis treatment mice. Crocin inhibited the Dermatophagoides farinae crude extract-induced increase of thymus and activation-regulated chemokines, interleukin (IL)-4, and IL-13 on the dorsal skin of mice. Crocin also inhibited Dermatophagoides farinae crude extract-induced activation of nuclear factor kappaB (NF-kappaB) and signal transducer and activator of transcription (STAT) 6. These results show that crocin ameliorates atopic dermatitis symptoms by down regulation of the Th2 cells-mediated immune response via blocking of NF kappaB/STAT6 signaling pathways. PMID- 30400141 TI - Astaxanthin Prevents Human Papillomavirus L1 Protein Binding in Human Sperm Membranes. AB - Astaxanthin (Asta), red pigment of the carotenoid family, is known for its anti oxidant, anti-cancer, anti-diabetic, and anti-inflammatory properties. In this study, we evaluated the effects of Asta on isolated human sperm in the presence of human papillomavirus (HPV) 16 capsid protein, L1. Sperm, purified by gradient separation, were treated with HPV16-L1 in both a dose and time-dependent manner in the absence or presence of 30 min-Asta pre-incubation. Effects of HPV16-L1 alone after Asta pre-incubation were evaluated by rafts (CTB) and Lyn dislocation, Tyr-phosphorylation (Tyr-P) of the head, percentages of acrosome reacted cells (ARC) and endogenous reactive oxygen species (ROS) generation. Sperm membranes were also analyzed for the HPV16-L1 content. Results show that HPV16-L1 drastically reduced membrane rearrangement with percentage of sperm showing head CTB and Lyn displacement decreasing from 72% to 15.8%, and from 63.1% to 13.9%, respectively. Accordingly, both Tyr-P of the head and ARC decreased from 68.4% to 10.2%, and from 65.7% to 14.6%, respectively. Asta pre incubation prevented this drop and restored values of the percentage of ARC up to 40.8%. No alteration was found in either the ROS generation curve or sperm motility. In conclusion, Asta is able to preserve sperm by reducing the amount of HPV16-L1 bound onto membranes. PMID- 30400142 TI - 2-(4-Methylsulfonylphenyl)pyrimidines as Prospective Radioligands for Imaging Cyclooxygenase-2 with PET-Synthesis, Triage, and Radiolabeling. AB - Cyclooxygenase 2 (COX-2) is an inducible enzyme responsible for the conversion of arachidonic acid into the prostaglandins, PGG2 and PGH2. Expression of this enzyme increases in inflammation. Therefore, the development of probes for imaging COX-2 with positron emission tomography (PET) has gained interest because they could be useful for the study of inflammation in vivo, and for aiding anti inflammatory drug development targeting COX-2. Nonetheless, effective PET radioligands are still lacking. We synthesized eleven COX-2 inhibitors based on a 2(4-methylsulfonylphenyl)pyrimidine core from which we selected three as prospective PET radioligands based on desirable factors, such as high inhibitory potency for COX-2, very low inhibitory potency for COX-1, moderate lipophilicity, and amenability to labeling with a positronemitter. These inhibitors, namely 6 methoxy-2-(4-(methylsulfonyl)phenyl-N-(thiophen-2ylmethyl)pyrimidin-4-amine (17), the 6-fluoromethyl analogue (20), and the 6-(2-fluoroethoxy) analogue (27), were labeled in useful yields and with high molar activities by treating the 6-hydroxy analogue (26) with [11C]iodomethane, [18F]2-fluorobromoethane, and [d2 18F]fluorobromomethane, respectively. [11C]17, [18F]20, and [d2-18F]27 were readily purified with HPLC and formulated for intravenous injection. These methods allow these radioligands to be produced for comparative evaluation as PET radioligands for measuring COX-2 in healthy rhesus monkey and for assessing their abilities to detect inflammation. PMID- 30400143 TI - Properties of Love Waves in Functional Graded Saturated Material. AB - In the present study, the propagation of Love waves is investigated in a layered structure with two different homogeneity saturated materials based on Biot's theory. The upper layer is a transversely isotropic functional graded saturated layer, and the substrate is a saturated semi-space. The inhomogeneity of the functional graded layer is taken into account. Furthermore, the gradient coefficient is employed as the representation of the relation with the layer thickness and the material parameters, and the power series method is applied to solve the variable coefficients governing the equations. In this regard, the influence of the gradient coefficients of saturated material on the dispersion relations, and the attenuation of Love waves in this structure are explored, and the results of the present study can provide theoretical guidance for the non destructive evaluation of functional graded saturated material. PMID- 30400144 TI - Oxidative Stress and Cardiovascular-Renal Damage in Fabry Disease: Is There Room for a Pathophysiological Involvement? AB - Fabry disease is an X-linked lysosomal storage disease caused by mutations in the GLA gene that lead to a reduction or an absence of the enzyme alpha-galactosidase A, resulting in the progressive and multisystemic accumulation of globotriaosylceramide. Clinical manifestation varies from mild to severe, depending on the phenotype. The main clinical manifestations are cutaneous (angiokeratomas), neurological (acroparesthesias), gastrointestinal (nausea, diarrhea abdominal pain), renal (proteinuria and kidney failure), cardiovascular (cardiomyopathy and arrhythmias), and cerebrovascular (stroke). A diagnosis of Fabry disease can be made with an enzymatic assay showing absent or reduced alpha galactosidase A in male patients, while in heterozygous female patients, molecular genetic testing is needed. Enzyme replacement therapy (ERT) with recombinant human alpha-galactosidase is nowadays the most-used disease-specific therapeutic option. Despite ERT, cardiocerebrovascular-renal irreversible organ injury occurs, therefore additional knowledge and a deeper understanding of further pathophysiological mechanisms leading to end organ damage in Fabry disease are needed. Recent data point toward oxidative stress, oxidative stress signaling, and inflammation as some such mechanisms. In this short review, the current knowledge on the involvement of oxidative stress in cardiovascular-renal remodeling is summarized and related to the most recent evidence of oxidative stress activation in Fabry disease, and clearly points toward the involvement of oxidative stress in the pathophysiology of the medium- to long-term cardiovascular-renal damage of Fabry disease. PMID- 30400145 TI - Relative Validity and Reproducibility of a Food Frequency Questionnaire to Assess Nutrients and Food Groups of Relevance to the Gut Microbiota in Young Children. AB - Dietary fiber is an important nutrient for the gut microbiota, with different fiber fractions having different effects. The aim of this study was to determine the relative validity and reproducibility of a food frequency questionnaire (EAT5 FFQ) for measuring intake of fiber, and low and high fiber foods, in studies examining diet and gut microbiota in young children. One hundred parents of 5 year old children completed the 123-item EAT5 FFQ on two occasions four weeks apart. A 3-day weighed diet record (WDR) was completed on non-consecutive days between FFQ appointments. Mean correlations between the (randomly chosen) FFQ and WDR were acceptable for nutrient and food group intakes (r = 0.34 and r = 0.41 respectively). Gross misclassification was below chance (12.5%) for quartiles of nutrient (mean 5.7%) and food group (mean 5.1%) intake. 'Absolute values for surrogate categories' suggested the FFQ clearly differentiated between highest and lowest quartiles for all nutrients and food groups tested. Mean correlations between repeat administrations of the FFQ suggested very good reproducibility for nutrients (r = 0.83) and food groups (r = 0.80). The EAT5 FFQ appears to be an appropriate tool for investigating the intake of nutrients and food groups of relevance to the gut microbiota, and is the first FFQ validated to measure total, soluble and insoluble non-starch polysaccharide intakes in young children. PMID- 30400146 TI - The Impact of Front-of-Package Label Design on Consumer Understanding of Nutrient Amounts. AB - A between-groups experiment examined the salience of front-of-package (FOP) symbols. Adults from Canada, the US, Australia, and the UK completed an online survey (n = 11,617). Respondents were randomized to view cereal boxes displaying one of 11 FOP label conditions for 'high' levels of sugar and saturated fat: control (no FOP symbol), red circle, red 'stop sign', magnifying glass, magnifying glass + exclamation mark, and 'caution' triangle + exclamation mark, plus each of these five conditions accompanied by a 'high in' text descriptor. Participants identified the amount of saturated fat and sugar in the product ('low'/'moderate'/'high'). Participants were more likely to correctly identify the product as 'high' in saturated fat or sugar when shown the stop sign, triangle + exclamation mark, red circle, or magnifying glass + exclamation mark symbols incorporating 'high in' text (p < 0.01). The magnifying glass was the least effective symbol. The stop sign (37.7%) and triangle + exclamation mark (22.0%) were most frequently selected as the best symbol for indicating high nutrient amounts. Overall, FOP labels with 'high in' descriptions, red color and intuitive 'warning' symbols (e.g., stop signs, exclamation marks, 'caution' triangles) were more effective at communicating high levels of nutrients of public health concern in a time-limited environment. PMID- 30400147 TI - Effects of Metformin Combined with Lactoferrin on Lipid Accumulation and Metabolism in Mice Fed with High-Fat Diet. AB - Metformin (Met) and lactoferrin (Lf) both exhibit beneficial effects on body weight management and lipid accumulation. However, the synergistical action of Met and Lf remains unclear. In this study, 64 mice were divided into five groups, namely, the control group, high-fat diet (HFD group), HFD with Met (Met group), Lf (Lf group), and a combination of Met and Lf (Met + Lf group). Met (200 mg/kg body weight) and Lf (2 g/100 mL) were administrated in drinking water. The experiment lasted for 12 weeks. Body weight, serum, and hepatic lipids were determined. Histology of the liver and perirenal fat was observed. Protein expression related to hepatic lipid metabolism was also measured. HFD significantly increased body weight, visceral fat weight, and lipid profiles, which lead to obesity and dyslipidemia in mice. Compared with the HFD group, the treatments significantly decreased body weight and Lee's index (body mass index of mice) with the lowest values in the Met + Lf group. The treatments also decreased the weight of visceral fat, and improved circulating lipid profile and the ability for regulating glucose intake. The adipocyte size and serum TC level were significantly lower in the Met + Lf group as compared with those in the Met or Lf group. The treatments alleviated hepatic lipid accumulation, especially in the Met + Lf group. For protein expression, the p-AMPK/AMPK ratio, a key kinase regulating cellular energy homeostasis, was significantly higher in the Met + Lf group than the ratio in the HFD group. Similarly, the treatments significantly downregulated the protein expression of lipogenic enzymes (FAS, ACC, and SREBP-1) and upregulated the protein expression of lipolytic enzyme (ATGL). The protein expression of HMGCoAR, which is an important rate limiting enzyme in cholesterol biosynthesis, was only significantly lower in the Met + Lf group than in the HFD group. In conclusion, Met and Lf, either alone or in combination, prevented HFD induced obesity and improved lipid metabolism. PMID- 30400148 TI - Identification of Soybean Genes Whose Expression is Affected by the Ensifer fredii HH103 Effector Protein NopP. AB - In some legume-rhizobium symbioses, host specificity is influenced by rhizobial nodulation outer proteins (Nops). However, the genes encoding host proteins that interact with Nops remain unknown. We generated an Ensifer fredii HH103 NopP mutant (HH103OmegaNopP), and analyzed the nodule number (NN) and nodule dry weight (NDW) of 10 soybean germplasms inoculated with the wild-type E. fredii HH103 or the mutant strain. An analysis of recombinant inbred lines (RILs) revealed the quantitative trait loci (QTLs) associated with NopP interactions. A soybean genomic region containing two overlapping QTLs was analyzed in greater detail. A transcriptome analysis and qRT-PCR assay were used to identify candidate genes encoding proteins that interact with NopP. In some germplasms, NopP positively and negatively affected the NN and NDW, while NopP had different effects on NN and NDW in other germplasms. The QTL region in chromosome 12 was further analyzed. The expression patterns of candidate genes Glyma.12g031200 and Glyma.12g073000 were determined by qRT-PCR, and were confirmed to be influenced by NopP. PMID- 30400150 TI - Superoxide Dismutases (SODs) and SOD Mimetics. AB - Superoxide dismutase (SOD) is the only known enzyme to directly scavenge a free radical. [...]. PMID- 30400149 TI - Circulating Linoleic Acid is Associated with Improved Glucose Tolerance in Women after Gestational Diabetes. AB - Women with previously diagnosed gestational diabetes mellitus (GDM) are at increased risk of type-2-diabetes mellitus (T2D). We aimed to establish links between glucose tolerance (GT) and serum fatty acid (FA) profile in the transition from GDM to T2D. Six years after GDM, 221 women were grouped as having normal GT (NGT), impaired GT (IGT), or T2D based on oral GT test results. Fasting serum FAs were profiled, anthropometric measures taken, and dietary intake determined. Linoleic acid (LA) was significantly higher in NGT women (p < 0.001) compared with IGT and T2D, and emerged as a strong predictor of low glucose and insulin levels, independently of BMI. Self-reported vegetable oil consumption correlated with LA serum levels and glucose levels. Delta-6-, delta-9-, and stearoyl-CoA-desaturase activities were associated with decreased GT, and delta-5 desaturase activities with increased GT. In a subgroup of women at high risk of diabetes, low LA and high palmitic acid levels were seen in those that developed T2D, with no differences in other FAs or metabolic measurements. Results suggest that proportions of LA and palmitic acid are of particular interest in the transition from GDM to T2D. Interconversions between individual FAs regulated by desaturases appear to be relevant to glucose metabolism. PMID- 30400152 TI - Genetic Resistance to Avian Leukosis Viruses Induced by CRISPR/Cas9 Editing of Specific Receptor Genes in Chicken Cells. AB - Avian leukosis viruses (ALVs), which are pathogens of concern in domestic poultry, utilize specific receptor proteins for cell entry that are both necessary and sufficient for host susceptibility to a given ALV subgroup. This unequivocal relationship offers receptors as suitable targets of selection and biotechnological manipulation with the aim of obtaining virus-resistant poultry. This approach is further supported by the existence of natural knock-outs of receptor genes that segregate in inbred lines of chickens. We used CRISPR/Cas9 genome editing tools to introduce frame-shifting indel mutations into tva, tvc, and tvj loci encoding receptors for the A, C, and J ALV subgroups, respectively. For all three loci, the homozygous frame-shifting indels generating premature stop codons induced phenotypes which were fully resistant to the virus of respective subgroup. In the tvj locus, we also obtained in-frame deletions corroborating the importance of W38 and the four amino-acids preceding it. We demonstrate that CRISPR/Cas9-mediated knock-out or the fine editing of ALV receptor genes might be the first step in the development of virus-resistant chickens. PMID- 30400151 TI - Attenuation of Free Fatty Acid-Induced Muscle Insulin Resistance by Rosemary Extract. AB - Elevated blood free fatty acids (FFAs), as seen in obesity, impair muscle insulin action leading to insulin resistance and Type 2 diabetes mellitus. Serine phosphorylation of the insulin receptor substrate (IRS) is linked to insulin resistance and a number of serine/threonine kinases including JNK, mTOR and p70 S6K have been implicated in this process. Activation of the energy sensor AMP activated protein kinase (AMPK) increases muscle glucose uptake, and in recent years AMPK has been viewed as an important target to counteract insulin resistance. We reported recently that rosemary extract (RE) increased muscle cell glucose uptake and activated AMPK. However, the effect of RE on FFA-induced muscle insulin resistance has never been examined. In the current study, we investigated the effect of RE in palmitate-induced insulin resistant L6 myotubes. Exposure of myotubes to palmitate reduced the insulin-stimulated glucose uptake, increased serine phosphorylation of IRS-1, and decreased the insulin-stimulated phosphorylation of Akt. Importantly, exposure to RE abolished these effects and the insulin-stimulated glucose uptake was restored. Treatment with palmitate increased the phosphorylation/activation of JNK, mTOR and p70 S6K whereas RE completely abolished these effects. RE increased the phosphorylation of AMPK even in the presence of palmitate. Our data indicate that rosemary extract has the potential to counteract the palmitate-induced muscle cell insulin resistance and further studies are required to explore its antidiabetic properties. PMID- 30400154 TI - Wheat Height Estimation Using LiDAR in Comparison to Ultrasonic Sensor and UAS. AB - As one of the key crop traits, plant height is traditionally evaluated manually, which can be slow, laborious and prone to error. Rapid development of remote and proximal sensing technologies in recent years allows plant height to be estimated in more objective and efficient fashions, while research regarding direct comparisons between different height measurement methods seems to be lagging. In this study, a ground-based multi-sensor phenotyping system equipped with ultrasonic sensors and light detection and ranging (LiDAR) was developed. Canopy heights of 100 wheat plots were estimated five times during a season by the ground phenotyping system and an unmanned aircraft system (UAS), and the results were compared to manual measurements. Overall, LiDAR provided the best results, with a root-mean-square error (RMSE) of 0.05 m and an R2 of 0.97. UAS obtained reasonable results with an RMSE of 0.09 m and an R2 of 0.91. Ultrasonic sensors did not perform well due to our static measurement style. In conclusion, we suggest LiDAR and UAS are reliable alternative methods for wheat height evaluation. PMID- 30400153 TI - Influence of Bioactive Nutrients on the Atherosclerotic Process: A Review. AB - The protective effects of a dietary intervention as a useful tool in the prevention of atherosclerosis disease has gained greater attention in recent years. Several epidemiological studies have demonstrated the importance of diet in reducing expensive treatments or possible undesirable side effects. The main aim of this review is to examine the effects of specific nutrients on the development and progression of atherosclerosis in patients with cardiovascular disease. Various mechanisms have been proposed to explain the cardioprotective effect of different nutrients. In this sense, results have shown stabilization of vulnerable atherosclerotic plaques or downregulation of biomarkers related to inflammation through nutrients such as Omega-3 polyunsaturated fatty acids, hydroxytyrosol of extra virgin olive oil, lycopen, phytosterols of plants, or flavonols of fruits and vegetables, among others. The accumulated evidence on the anti-inflammatory effects related to these nutrients is summarized in the present review. PMID- 30400156 TI - Mitochondrial-Directed Antioxidant Reduces Microglial-Induced Inflammation in Murine In Vitro Model of TC-83 Infection. AB - Venezuelan equine encephalitis virus (VEEV) is an arbovirus that is associated with robust inflammation that contributes to neurodegenerative phenotypes. In addition to triggering central nervous system (CNS) inflammation, VEEV will also induce mitochondrial dysfunction, resulting in increased cellular apoptosis. In this study, we utilize the TC-83 strain of VEEV to determine the role of mitochondrial oxidative stress in mediating inflammation elicited by murine brain microglial cells. Using an in vitro model, we show that murine microglia are susceptible to TC-83 infection, and that these cells undergo mitochondrial stress as the result of infection. We also indicate that bystander microglia contribute more significantly to the overall inflammatory load than directly infected microglia. Use of a mitochondrial targeted antioxidant, mitoquinone mesylate, greatly reduced the pro-inflammatory cytokines released by both direct infected and bystander microglia. Our data suggest that release of interleukin-1beta, a key instigator of neuroinflammation during VEEV infection, may be the direct result of accumulating mitochondrial stress. This data improves our understanding inflammation elicited by murine microglia and will aid in the development of more accurate in vitro and in vivo murine model of VEEV-induced neuroinflammation. PMID- 30400157 TI - Competition among Escherichia coli Strains for Space and Resources. AB - Shiga toxin-producing Escherichia coli (STEC) are a subgroup of E. coli causing human diseases. Methods to control STEC in livestock and humans are limited. These and other emerging pathogens are a global concern and novel mitigation strategies are required. Habitats populated by bacteria are subjected to competition pressures due to limited space and resources but they use various strategies to compete in natural environments. Our objective was to evaluate non pathogenic E. coli strains isolated from cattle feces for their ability to out compete STEC. Competitive fitness of non-pathogenic E. coli against STEC were assessed in competitions using liquid, agar, and nutrient limiting assays. Winners were determined by enumeration using O-serogroup specific quantitative PCR or a semi-quantitative grading. Initial liquid competitions identified two strong non-pathogenic competitors (O103F and O26E) capable of eliminating various STEC including O157 and O111. The strain O103F was dominant across permeable physical barriers for all tested E. coli and STEC strains indicating the diffusion of antimicrobial molecules. In direct contact and even with temporal disadvantages, O103F out-competed STEC O157E. The results suggest that O103F or the diffusible molecule(s) it produces have a potential to be used as an alternative STEC mitigation strategy, either in medicine or the food industry. PMID- 30400155 TI - Longitudinal Maternal Vitamin D Status during Pregnancy Is Associated with Neonatal Anthropometric Measures. AB - Findings on maternal 25-hydroxyvitamin D (25[OH]D) and neonatal anthropometry are inconsistent, and may at least be partly due to variations in gestational week (GW) of 25(OH)D measurement and the lack of longitudinal 25(OH)D measurements across gestation. The aim of the current study was to examine the associations of longitudinal measures of maternal 25(OH)D and neonatal anthropometry at birth. This study included 321 mother-offspring pairs enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singletons. This study was a prospective cohort design without supplementation and without data on dietary supplementation. Nevertheless, measurement of plasma 25(OH)D reflects vitamin D from different sources, including supplementation. Maternal concentrations of total 25(OH)D were measured at 10-14, 15-26, 23-31, and 33-39 GW and categorized as <50 nmol/L, 50-75 nmol/L, and >75 nmol/L. Generalized linear models were used to examine associations of 25(OH)D at each time-point with neonate birthweight z-score, length, and sum of skinfolds at birth. At 10-14 GW, 16.8% and 49.2% of women had 25(OH)D <50 nmol/L and between 50-75 nmol/L, respectively. The association of maternal 25(OH)D with neonatal anthropometry differed by GW and women's prepregnancy BMI (normal (<25.0 kg/m2), overweight/obese (25.0-44.9 kg/m2)). All analyses were stratified by prepregnancy BMI status. Among women with an overweight/obese BMI, 25(OH)D <50 nmol/L at 10-14 GW was associated with lower birthweight z-score (0.56; 95% CI: 0.99, -0.13) and length (-1.56 cm; 95% CI: -3.07, -0.06), and at 23-31 GW was associated with shorter length (-2.77 cm; 95% CI: -13.38, -4.98) and lower sum of skinfolds (-9.18 mm; 95% CI: -13.38, -4.98). Among women with a normal BMI, 25(OH)D <50 nmol/L at 10-14 GW was associated with lower sum of skinfolds (-2.64 mm; 95% CI: -5.03, -0.24), at 23-31 GW was associated with larger birthweight z scores (0.64; 95% CI: 0.03, 1.25), and at 33-39 GW with both higher birthweight z score (1.22; 95% CI: 0.71, 1.73) and longer length (1.94 cm; 95% CI: 0.37, 3.52). Maternal 25(OH)D status during pregnancy was associated with neonatal anthropometric measures, and the associations were specific to GW of 25(OH)D measurement and prepregnancy BMI. PMID- 30400158 TI - An Adaptive Parallel Processing Strategy for Complex Event Processing Systems over Data Streams in Wireless Sensor Networks. AB - Efficient matching of incoming events of data streams to persistent queries is fundamental to event stream processing systems in wireless sensor networks. These applications require dealing with high volume and continuous data streams with fast processing time on distributed complex event processing (CEP) systems. Therefore, a well-managed parallel processing technique is needed for improving the performance of the system. However, the specific properties of pattern operators in the CEP systems increase the difficulties of the parallel processing problem. To address these issues, a parallelization model and an adaptive parallel processing strategy are proposed for the complex event processing by introducing a histogram and utilizing the probability and queue theory. The proposed strategy can estimate the optimal event splitting policy, which can suit the most recent workload conditions such that the selected policy has the least expected waiting time for further processing of the arriving events. The proposed strategy can keep the CEP system running fast under the variation of the time window sizes of operators and the input rates of streams. Finally, the utility of our work is demonstrated through the experiments on the StreamBase system. PMID- 30400159 TI - Use of Foaming Disinfectants and Cleaners to Reduce Aerobic Bacteria and Salmonella on Poultry Transport Coops. AB - Transport coops are infrequently washed and have been demonstrated to cross contaminate broiler carcasses. We hypothesized that peracetic acid or a chlorinated cleaner, commonly used within poultry processing plants, can also be used to disinfect transport coops when applied via a compressed air foam system (CAFS). A mixture of fresh layer manure and concentrated Salmonella Typhimurium (ST) was evenly applied to the floors of four pre-cleaned transport coops and allowed to dry for thirty minutes. Treatments consisted of a (1) water rinse only, (2) product application with a water rinse, (3) product application followed by power washing and (4) power washing followed by application of product. Each foaming treatment was applied with a compressed air foam system and allowed 10 min of contact time. Samples were aseptically collected from the transport coops prior to and following treatment using a sterile 2 * 2-inch stainless steel template and a gauze swab pre-enriched with buffered peptone water. The chlorinated cleaner significantly (p < 0.05) reduced aerobic bacteria and ST by 3.18 to 4.84 logs across application methods. The peroxyacetic acid (PAA) disinfectant significantly (p < 0.05) reduced aerobic bacteria and ST by 3.99 to 5.17 logs across application methods. These data indicate that a compressed air foam system may be used in combination with a commercially available cleaner or disinfectant to reduce aerobic bacteria and ST on the surfaces of commercial poultry transport coops. PMID- 30400160 TI - Reproductive Factors and Risk of Spontaneous Abortion in the Jinchang Cohort. AB - The aim of this study was to investigate the association between female reproductive status and risk of spontaneous abortion among female workers in the Jinchang Cohort. This study used data obtained from a baseline survey of the Jinchang Cohort Study of female workers in Jinchang Industry, the largest nickel production company in China. A standardized, structured questionnaire was used to collect the health status of 18,834 female workers employed by the company from 2011 to 2013. Spearman grade correlation analysis and logistic regression models were used to evaluate the association between female reproductive status and risk of spontaneous abortion. The incidence rate of spontaneous abortion was 6.89%, and fatigue was associated with the risk of spontaneous abortion. The number of pregnancies, age at primary birth and age at the last pregnancy were associated with an increased risk of spontaneous abortion (rs = 0.190, p = 0.000; rs = 0.092, p = 0.000; rs = 0.061, p = 0.000; respectively). In addition, there was a negative correlation between the number of artificial abortions and spontaneous abortions (rs = -0.129, p = 0.000). Female reproductive status was associated with an increased risk of spontaneous abortion in this cohort. More studies are needed to confirm this observed association. PMID- 30400161 TI - A Simple Wireless Sensor Node System for Electricity Monitoring Applications: Design, Integration, and Testing with Different Piezoelectric Energy Harvesters. AB - Real time electricity monitoring is critical to enable intelligent and customized energy management for users in residential, educational, and commercial buildings. This paper presents the design, integration, and testing of a simple, self-contained, low-power, non-invasive system at low cost applicable for such purpose. The system is powered by piezoelectric energy harvesters (EHs) based on PZT and includes a microcontroller unit (MCU) and a central hub. Real-time information regarding the electricity consumption is measured and communicated by the system, which ultimately offers a dependable and promising solution as a wireless sensor node. The dynamic power management ensures the system to work with different types of PZT EHs at a wide range of input power. Thus, the system is robust against fluctuation of the current in the electricity grid and requires minimum adjustment if EH unit requires exchange or upgrade. Experimental results demonstrate that this unit is in a position to read and transmit 60 Hz alternating current (AC) sensor signals with a high accuracy no less than 91.4%. The system is able to achieve an operation duty cycle from <1 min up to 18 min when the current in an electric wire varies from 7.6 A to 30 A, depending on the characteristics of different EHs and intensity of current being monitored. PMID- 30400162 TI - Effect of Multidirectional Forging on the Grain Structure and Mechanical Properties of the Al-Mg-Mn Alloy. AB - The effect of isothermal multidirectional forging (IMF) on the microstructure evolution of a conventional Al-Mg-based alloy was studied in the strain range of 1.5 to 6.0, and in the temperature range of 200 to 500 degrees C. A mean grain size in the near-surface layer decreased with increasing cumulative strain after IMF at 400 degrees C and 500 degrees C; the grain structure was inhomogeneous, and consisted of coarse and fine recrystallized grains. There was no evidence of recrystallization when the micro-shear bands were observed after IMF at 200 and 300 degrees C. Thermomechanical treatment, including IMF followed by 50% cold rolling and annealing at 450 degrees C for 30 min, produced a homogeneous equiaxed grain structure with a mean grain size of 5 um. As a result, the fine grained sheets exhibited a yield strength and an elongation to failure 30% higher than that of the sheets processed with simple thermomechanical treatment. The IMF technique can be successfully used to produce fine-grained materials with improved mechanical properties. PMID- 30400163 TI - Exogenous Melatonin Mitigates Methyl Viologen-Triggered Oxidative Stress in Poplar Leaf. AB - As a ubiquitous molecule, melatonin plays a crucial role in tolerance to multiple stresses in plants. In the present work, we report the role of exogenous melatonin in relieving oxidative stress induced by methyl viologen (MV) in poplar (Populus alba * Populus glandulosa) leaf. Leaf discs pretreated with melatonin exhibited increased tolerance to MV-mediated oxidative stress. It was observed that melatonin pretreatment effectively reduced membrane damage and lipid oxidation as demonstrated by decreased relative electrolyte leakage and malonaldehyde content in poplar leaf discs. Exogenous melatonin also stimulated activities of antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and ascorbate peroxidase (APX), and enhanced accumulation of non-enzymatic antioxidants of AsA and GSH in leaf discs exposed to MV. In addition, pretreatment of melatonin prompted expression of genes for those antioxidant enzymes. Notably, exogenous melatonin increased expression of P5CS, a key gene for proline biosynthesis, under MV treatment. It was further observed that pretreatment with melatonin boosted activity of P5CS as well as accumulation of proline in leaf discs under MV-mediated oxidative stress. Collectively, this work provides evidence for the ameliorative effect of melatonin on MV-induced oxidative stress in poplar leaf. PMID- 30400164 TI - Effects of Environmental Factors on Concrete Carbonation Depth and Compressive Strength. AB - The influence of temperature, CO2 concentration and relative humidity on the carbonation depth and compressive strength of concrete was investigated. Meanwhile, phase composition, types of hydration products and microstructure characteristics of samples before and after the carbonation were analyzed by XRD and ESEM. Research results demonstrate that temperature, CO2 concentration and relative humidity influence the carbonation depth and compressive strength of concrete significantly. There is a linear relationship between temperature and carbonation depth, as well as the compressive strength of concrete. CO2 concentration and relative humidity present a power function and a polynomial function with carbonation depth of concrete, respectively. The concrete carbonation depth increases with the increase of relative humidity and reaches the maximum value when the relative humidity is 70%. Significant differences of phase composition, hydration products and microstructure are observed before and after the carbonation. Carbonization products of samples are different with changes of temperatures (10 degrees C, 20 degrees C and 30 degrees C). The result of crystal structure analysis indicates that the carbonation products are mainly polyhedral spherical vaterite and aragonite. PMID- 30400165 TI - Pentafluorosulfanyl-containing Triclocarban Analogs with Potent Antimicrobial Activity. AB - Concerns have been raised about the long-term accumulating effects of triclocarban, a polychlorinated diarylurea widely used as an antibacterial soap additive, in the environment and in human beings. Indeed, the Food and Drug Administration has recently banned it from personal care products. Herein, we report the synthesis, antibacterial activity and cytotoxicity of novel N,N' diarylureas as triclocarban analogs, designed by reducing one or more chlorine atoms of the former and/or replacing them by the novel pentafluorosulfanyl group, a new bioisostere of the trifluoromethyl group, with growing importance in drug discovery. Interestingly, some of these pentafluorosulfanyl-bearing ureas exhibited high potency, broad spectrum of antimicrobial activity against Gram positive bacterial pathogens, and high selectivity index, while displaying a lower spontaneous mutation frequency than triclocarban. Some lines of evidence suggest a bactericidal mode of action for this family of compounds. PMID- 30400166 TI - Evaluation of Environmental Impacts Due to Blue Water Consumption in China from Production and Consumption Perspectives. AB - Current environmental impact analyses are mainly focused on land, soil, energy, and material consumption, while studies regarding blue water consumption are scarce. Based on the water footprint concept, this study evaluates the impacts of blue water consumption on human health, ecosystem quality, and water resources in China from the production and consumption perspective, respectively. The results indicate that environmental impacts due to blue water consumption in China were 15.82 * 106 DALY (disability-adjusted life years), 96.54 * 108 m2?year, and 175.20 * 108 MJ, and provinces such as Xinjiang, Shandong, and Hebei could be targets for achieving smaller environmental impacts in the future. More than 80% of environmental impacts were related to the agricultural sector. In terms of agricultural production, about 70% of the environmental impacts were related to product export. Measures such as the shift of the agricultural production pattern from water-intensive crops and animal products toward less water-intensive ones, the increase of agricultural water use efficiency, and the adoption of water saving technologies could contribute to smaller environmental impacts. In terms of agricultural consumption, more than 95% of the environmental impacts were related to agricultural products produced locally. The focus was on increasing awareness of the importance of saving water and whether products were imported from regions with relatively small environmental impacts. PMID- 30400167 TI - A Comparison of Psychophysical Dose-Response Behaviour across 16 Sweeteners. AB - Reduction or replacement of sucrose while maintaining sweetness in foods is challenging, but today there are many sweeteners with diverse physical and caloric compositions to choose from. The choice of sweetener can be adapted to match reformulation goals whether these are to reduce calories, lower the glycaemic response, provide bulk or meet criteria as a natural ingredient. The current study sought to describe and compare the sweetness intensity dose response, sweetness growth rate, sweetness potency, and potential for calorie reduction across 16 different sweeteners including sucrose. Sweetness growth rate was defined as the rate of change in sweetness intensity per unit of sweetener concentration. Sweetness potency was defined as the ratio of the concentration of a sweetener to that of sucrose at equivalent sweetness intensity, whereas the potential for calorie reduction is the caloric value of a sweetener compared to sucrose at matched sweetness intensities. Sweeteners were drawn from a range of nutritive saccharide (sucrose, dextrose, fructose, allulose (d-psicose), palatinose (isomaltulose), and a sucrose-allulose mixture), nutritive polyol (maltitol, erythritol, mannitol, xylitol, sorbitol), non-nutritive synthetic (aspartame, acesulfame-K, sucralose) and non-nutritive natural sweeteners stevia (rebaudioside A), luo han guo (mogroside V). Sweetness intensities of the 16 sweeteners were compared with a sensory panel of 40 participants (n = 40; 28 females). Participants were asked to rate perceived sweetness intensity for each sweetener series across a range of concentrations using psychophysical ratings taken on a general labelled magnitude scale (gLMS). All sweeteners exhibited sigmoidal dose-response behaviours and matched the 'moderate' sweetness intensity of sucrose (10% w/v). Fructose, xylitol and sucralose had peak sweetness intensities greater than sucrose at the upper concentrations tested, while acesulfame-K and stevia (rebA) were markedly lower. Independent of sweetener concentration, the nutritive sweeteners had similar sweetness growth rates to sucrose and were greater than the non-nutritive sweeteners. Non-nutritive sweeteners on the other hand had higher potencies relative to sucrose, which decreases when matching at higher sweetness intensities. With the exception of dextrose and palatinose, all sweeteners matched the sweetness intensity of sucrose across the measured range (3.8-25% w/v sucrose) with fewer calories. Overall, the sucrose-allulose mixture, maltitol and xylitol sweeteners were most similar to sucrose in terms of dose-response behaviour, growth rate and potency, and showed the most potential for sugar replacement within the range of sweetness intensities tested. PMID- 30400168 TI - Synthetic Methodologies to Gold Nanoshells: An Overview. AB - Gold nanostructures that can be synthetically articulated to adapt diverse morphologies, offer a versatile platform and tunable properties for applications in a variety of areas, including biomedicine and diagnostics. Among several conformational architectures, gold nanoshells provide a highly advantageous combination of properties that can be fine-tuned in designing single or multi purpose nanomaterials, especially for applications in biology. One of the important parameters for evaluating the efficacy of gold nano-architectures is their reproducible synthesis and surface functionalization with desired moieties. A variety of methods now exist that allow fabrication and chemical manipulation of their structure and resulting properties. This review article provides an overview and a discussion of synthetic methodologies to a diverse range of gold nanoshells, and a brief summary of surface functionalization and characterization methods employed to evaluate their overall composition. PMID- 30400169 TI - Smart and Functional Conducting Polymers: Application to Electrorheological Fluids. AB - Electro-responsive smart electrorheological (ER) fluids consist of electrically polarizing organic or inorganic particles and insulating oils in general. In this study, we focus on various conducting polymers of polyaniline and its derivatives and copolymers, along with polypyrrole and poly(ionic liquid), which are adopted as smart and functional materials in ER fluids. Their ER characteristics, including viscoelastic behaviors of shear stress, yield stress, and dynamic moduli, and dielectric properties are expounded and appraised using polarizability measurement, flow curve testing, inductance-capacitance-resistance meter testing, and several rheological equations of state. Furthermore, their potential industrial applications are also covered. PMID- 30400170 TI - Screening the Marker Components in Psoralea corylifolia L. with the Aids of Spectrum-Effect Relationship and Component Knock-Out by UPLC-MS2. AB - Psoralea corylifolia L., (P. corylifolia), which is used for treating vitiligo in clinic, shows inhibitory and activating effects on tyrosinase, a rate-limiting enzyme of melanogenesis. This study aimed to determine the active ingredients in the ethenal extracts of P. corylifolia on tyrosinase activity. The spectrum effect relationship and knock-out method were established to predict the active compounds. Their structures were then identified with the high resolution mass spectra. A high performance liquid chromatography method was established to obtain the specific chromatograms. Tyrosinase activity in vitro was assayed by the method of oxidation rate of levodopa. Partial least squares method was used to test the spectrum-effect relationships. Chromatographic peaks P2, P4, P9, P10, P11, P13, P21, P26, P28, and P30 were positively related to the activating effects on tyrosinase activity in PE, whereas chromatographic peaks P1, P3, P6, P14, P16, P19, P22, and P29 were negatively related to the activating effects on tyrosinase in the P. corylifolia (PEs). When the sample concentration was 0.5 g.mL-1, equal to the amount of raw medicinal herbs, the target components were daidzein (P2), psoralen (P5), neobavaisoflavone (P13), and psoralidin (P20), which were consistent with the results of spectrum-effect relationships. PMID- 30400171 TI - Effect of Electropulsing Treatment on the Fatigue Crack Growth Behavior of Copper. AB - Crack propagation was quantitatively evaluated to investigate the effect of electropulsing treatment (EPT) on fatigue crack growth of copper specimens. Varying fatigue cycles were obtained under six different load levels. The crack lengths were measured under two load levels to examine the effect of cyclic stress. The microhardness was measured around the vicinity of the crack tip. Furthermore, the fracture surface was observed by scanning electron microscopy. Results show that EPT with electric current density of 150 A/mm2 enhances the high-cycle fatigue life, and the effect tends to increase with the decrease in cyclic stress. Vickers microhardness (HV) near the crack tip decreases to normal levels after treatment, and the approaching cracks on two sides can be observed. Local annealing and recrystallization occur around the fatigue crack tip. Accordingly, crack propagation can be delayed, and fatigue life can be prolonged by EPT. PMID- 30400172 TI - Simultaneous Identification and Dynamic Analysis of Saccharides during Steam Processing of Rhizomes of Polygonatum cyrtonema by HPLC-QTOF-MS/MS. AB - The sweet rhizomes of Polygonatum cyrtonema are widely used as a tonic and functional food. A sensitive and rapid analytical method was developed for simultaneous identification and dynamic analysis of saccharides during steam processing in P. cyrtonema using HPLC-QTOF-MS/MS. Fructose, sorbitol, glucose, galactose, sucrose, and 1-kestose were identified, as well as a large number of oligosaccharides constituted of fructose units through beta-(2->1) or beta-(2 >6). Polysaccharides and oligosaccharides were decomposed to monosaccharides during a steaming process, since the contents of glucose, galactose, and fructose were increased, while those of sucrose, 1-kestose, and polysaccharides were decreased. The high content of fructose was revealed to be the main determinant for increasing the level of sweetness after steaming. The samples of different repeated steaming times were shown to be well grouped and gradually shift along the PC1 (72.4%) axis by principal component analysis. The small-molecule saccharides, especially fructose, could be considered as markers for the steaming process of rhizomes of P. cyrtonema. PMID- 30400173 TI - Solid Oxide Electrochemical Systems: Material Degradation Processes and Novel Mitigation Approaches. AB - Solid oxide electrochemical systems, such as solid oxide fuel cells (SOFC), solid oxide electrolysis cells (SOEC), and oxygen transport membranes (OTM) enable clean and reliable production of energy or fuel for a range of applications, including, but not limited to, residential, commercial, industrial, and grid support. These systems utilize solid-state ceramic oxides which offer enhanced stability, fuel flexibility, and high energy conversion efficiency throughout operation. However, the nature of system conditions, such as high temperatures, complex redox atmosphere, and presence of volatile reactive species become taxing on solid oxide materials and limit their viability during long-term operation. Ongoing research efforts to identify the material corrosion and degradation phenomena, as well as discover possible mitigation techniques to extend material efficiency and longevity, is the current focus of the research and industrial community. In this review, degradation processes in select solid oxide electrochemical systems, system components, and comprising materials will be discussed. Overall degradation phenomena are presented and certain degradation mechanisms are discussed. State-of-the-art technologies to mitigate or minimize the above-mentioned degradation processes are presented. PMID- 30400174 TI - Automated Intracellular Calcium Profiles Extraction from Endothelial Cells Using Digital Fluorescence Images. AB - Endothelial cells perform a wide variety of fundamental functions for the cardiovascular system, their proliferation and migration being strongly regulated by their intracellular calcium concentration. Hence it is extremely important to carefully measure endothelial calcium signals under different stimuli. A proposal to automate the intracellular calcium profiles extraction from fluorescence image sequences is presented. Digital image processing techniques were combined with a multi-target tracking approach supported by Kalman estimation. The system was tested with image sequences from two different stimuli. The first one was a chemical stimulus, that is, ATP, which caused small movements in the cells trajectories, thereby suggesting that the bath application of the agonist does not generate significant artifacts. The second one was a mechanical stimulus delivered by a glass microelectrode, which caused major changes in cell trajectories. The importance of the tracking block is evidenced since more accurate profiles were extracted, mainly for cells closest to the stimulated area. Two important contributions of this work are the automatic relocation of the region of interest assigned to the cells and the possibility of data extraction from big image sets in efficient and expedite way. The system may adapt to different kind of cell images and may allow the extraction of other useful features. PMID- 30400175 TI - Habitual Tea Consumption and Risk of Fracture in 0.5 Million Chinese Adults: A Prospective Cohort Study. AB - BACKGROUND: Tea consumption may have favorable effects on risk of fracture. However, little is known about such association in Chinese adults. The aim of this study was to examine the association between tea consumption and risk of hospitalized fracture in Chinese adults. METHODS: The present study included 453,625 participants from the China Kadoorie Biobank (CKB). Tea consumption was self-reported at baseline. Hospitalized fractures were ascertained through linkage with local health insurance claim databases. THE RESULTS: During a median of 10.1 years of follow-up, we documented 12,130 cases of first-time any fracture hospitalizations, including 1376 cases of hip fracture. Compared with never tea consumers, daily tea consumption was associated with lower risk of any fracture (hazard ratio (HR): 0.88; 95% confidence interval (CI): 0.83, 0.93). Statistically significant reduced risk of hip fracture was shown among daily consumers who most commonly drank green tea (HR: 0.80; 95% CI: 0.65, 0.97) and those who had drunk tea for more than 30 years (HR: 0.68; 95% CI: 0.52, 0.87). Our conclusions: Habitual tea consumption was associated with moderately decreased risk of any fracture hospitalizations. Participants with decades of tea consumption and those who preferred green tea were also associated with lower risk of hip fracture. PMID- 30400176 TI - Developmental Expression and Functions of the Small Heat Shock Proteins in Drosophila. AB - Heat shock proteins (Hsps) form a large family of evolutionarily conserved molecular chaperones that help balance protein folding and protect cells from various stress conditions. However, there is growing evidence that Hsps may also play an active role in developmental processes. Here, we take the example of developmental expression and function of one class of Hsps characterized by low molecular weight, the small Hsps (sHsps). We discuss recent reports and genome wide datasets that support vital sHsps functions in the developing nervous system, reproductive system, and muscles. This tissue- and time-specific sHsp expression is developmentally regulated, so that the enhancer sequence of an sHsp gene expressed in developing muscle, in addition to stress-inducible elements, also carries binding sites for myogenic regulatory factors. One possible reason for sHsp genes to switch on during development and in non-stress conditions is to protect vital developing organs from environmental insults. PMID- 30400177 TI - Communication System Design for an Advanced Metering Infrastructure. AB - This paper primarily deals with the design of an Information and Control Technology (ICT) network for an advanced metering infrastructure (AMI) on the IEEE 34 node radial distribution network. The application is comprised of 330 smart meters deployed in the low voltage system and 33 data concentrators in the medium voltage system. A power line carrier (PLC) communication system design is developed and simulated in Network Simulator 3 (NS-3). The simulation result is validated by comparing the communication network performance with the minimum performance requirements for AMI. The network delay of a single data frame is calculated and compared with the simulation delay. The design methodology proposed in this article may be used for other smart grid applications. The secondary goal is to provide AMI network traffic based on the IEC Std. 61968 and a discussion on whether or not AMI could possibly be a source of big data on the future power grid. PMID- 30400178 TI - Werner Syndrome Protein and DNA Replication. AB - Werner Syndrome (WS) is an autosomal recessive disorder characterized by the premature development of aging features. Individuals with WS also have a greater predisposition to rare cancers that are mesenchymal in origin. Werner Syndrome Protein (WRN), the protein mutated in WS, is unique among RecQ family proteins in that it possesses exonuclease and 3' to 5' helicase activities. WRN forms dynamic sub-complexes with different factors involved in DNA replication, recombination and repair. WRN binding partners either facilitate its DNA metabolic activities or utilize it to execute their specific functions. Furthermore, WRN is phosphorylated by multiple kinases, including Ataxia telangiectasia mutated, Ataxia telangiectasia and Rad3 related, c-Abl, Cyclin-dependent kinase 1 and DNA dependent protein kinase catalytic subunit, in response to genotoxic stress. These post-translational modifications are critical for WRN to function properly in DNA repair, replication and recombination. Accumulating evidence suggests that WRN plays a crucial role in one or more genome stability maintenance pathways, through which it suppresses cancer and premature aging. Among its many functions, WRN helps in replication fork progression, facilitates the repair of stalled replication forks and DNA double-strand breaks associated with replication forks, and blocks nuclease-mediated excessive processing of replication forks. In this review, we specifically focus on human WRN's contribution to replication fork processing for maintaining genome stability and suppressing premature aging. Understanding WRN's molecular role in timely and faithful DNA replication will further advance our understanding of the pathophysiology of WS. PMID- 30400179 TI - Effects of Wet-Pressing and Cross-Linking on the Tensile Properties of Carbon Nanotube Fibers. AB - To increase the strength of carbon nanotube (CNT) fibers (CNTFs), the mean size of voids between bundles of CNTs was reduced by wet-pressing, and the CNTs were cross-linked. Separate and simultaneous physical (roller pressing) and chemical methods (cross-linking) were tested to confirm each method's effects on the CNTF strength. By reducing the fraction of pores, roller pressing decreased the cross sectional area from 160 MUm2 to 66 MUm2 and increased the average load-at-break from 2.83 +/- 0.25 cN to 4.41 +/- 0.16 cN. Simultaneous injection of crosslinker and roller pressing augmented the cross-linking effect by increasing the infiltration of the crosslinker solution into the CNTF, so the specific strength increased from 0.40 +/- 0.05 N/tex to 0.67 +/- 0.04 N/tex. To increase the strength by cross-linking, it was necessary that the size of the pores inside the CNTF were reduced, and the infiltration of the solution was increased. These results suggest that combined physical and chemical treatment is effective to increase the strength of CNTFs. PMID- 30400180 TI - Size Limit and Energy Analysis of Nanoparticles during Wrapping Process by Membrane. AB - The wrapping of nanoparticles (NPs) by a membrane is a phenomenon of widespread and generic interest in biology, as well as in a variety of technological applications, such as drug delivery, clinical diagnostics, and biomedical imaging. However, the mechanisms of the interaction between the membrane and NPs are not well understood yet. In this paper, we have presented an analytic thermodynamic model to investigate the wrapping process of NPs by a cell membrane. It is found that the bending energy of the deformed membrane increases nonlinearly with increasing wrapping degree, which leads to a free energy barrier for the wrapping. On the basis of analysis results, the wrapping of NPs can be divided into three types, i.e., impossible wrapping, barrier wrapping, and free wrapping. Furthermore, a phase diagram for the wrapping of NPs has been constructed, which clarifies the interrelated effects of the size and the ligand density of NPs. We hope that this work can provide some help in understanding the physical mechanism of the wrapping of NPs. PMID- 30400181 TI - The Influence of Annealing on the Structural and Soft Magnetic Properties of (Fe0.4Co0.6)79Nb3B18 Nanocrystalline Alloys. AB - The soft magnetic properties of Fe-based nanocrystalline alloys are determined by their grain size. In the present article, the (Fe0.4Co0.6)79Nb3B18 nanocrystalline alloys have been successfully prepared by isothermal annealing. The variation of soft magnetic properties as a function of annealing temperature and incubation time is investigated in detail. Two distinct crystallization behaviors were found for the (Fe0.4Co0.6)79Nb3B18 alloys. The initial nanocrystallization products comprise a mixture of alpha-Fe(Co), Fe2B, and Fe23B6 type crystalline metastable phases, and the final crystallization products are composed of alpha-Fe(Co), Fe2B, and Fe3B crystalline phases. The grain size decreases first and then increases with the increasing annealing temperature in the range of 764-1151 K, and a fine grain size with mean grain size of 12.7 nm can be achieved for alloys annealed at 880 K. As the annealing temperature increases from 764 K to 1151 K, the saturation magnetization increases first and then decreases without a significant increase of the coercivity. The alloys annealed at 880 K exhibit the optimized soft magnetic properties with high Ms of 145 emu g-1 and low Hc of 0.04 Oe. PMID- 30400182 TI - Transcriptomics Reveal Antiviral Gene Induction in the Egyptian Rousette Bat Is Antagonized In Vitro by Marburg Virus Infection. AB - The Egyptian rousette bat (ERB) is the only known Marburg virus (MARV) reservoir host. ERBs develop a productive MARV infection with low viremia and shedding but no overt disease, suggesting this virus is efficiently controlled by ERB antiviral responses. This dynamic would contrast with humans, where MARV-mediated interferon (IFN) antagonism early in infection is thought to contribute to the severe, often fatal disease. The newly-annotated ERB genome and transcriptome have now enabled us to use a custom-designed NanoString nCounter ERB CodeSet in conjunction with RNA-seq to investigate responses in a MARV-infected ERB cell line. Both transcriptomic platforms correlated well and showed that MARV inhibited the antiviral program in ERB cells, while an IFN antagonism-impaired MARV was less efficient at suppressing the response gene induction, phenotypes previously reported for primate cells. Interestingly, and despite the expansion of IFN loci in the ERB genome, neither MARV showed specific induction of almost any IFN gene. However, we detected an upregulation of putative, unannotated ERB antiviral paralogs, as well as an elevated basal expression in uninfected ERB cells of key antiviral genes. PMID- 30400183 TI - Silicon Field Effect Transistor as the Nonlinear Detector for Terahertz Autocorellators. AB - We demonstrate that the rectifying field effect transistor, biased to the subthreshold regime, in a large signal regime exhibits a super-linear response to the incident terahertz (THz) power. This phenomenon can be exploited in a variety of experiments which exploit a nonlinear response, such as nonlinear autocorrelation measurements, for direct assessment of intrinsic response time using a pump-probe configuration or for indirect calibration of the oscillating voltage amplitude, which is delivered to the device. For these purposes, we employ a broadband bow-tie antenna coupled Si CMOS field-effect-transistor-based THz detector (TeraFET) in a nonlinear autocorrelation experiment performed with picoseconds-scale pulsed THz radiation. We have found that, in a wide range of gate bias (above the threshold voltage V th = 445 mV), the detected signal follows linearly to the emitted THz power. For gate bias below the threshold voltage (at 350 mV and below), the detected signal increases in a super-linear manner. A combination of these response regimes allows for performing nonlinear autocorrelation measurements with a single device and avoiding cryogenic cooling. PMID- 30400184 TI - Preparation and Properties Analysis of Chlorinated Butyl Rubber (CIIR)/Organic Diatomite Damping Composites. AB - In this work, a novel type of diatomite was prepared with a limited content of hindered phenol groups grafted on its hydrophobic surface. The obtained samples were characterized for their surface groups, particle morphology, pore structure, and thermal behaviors. Then, modified diatomite (MDT) was used in preparation of reinforced chlorinated butyl rubber (CIIR) composites by mechanical blending method. The powder of MDT can be uniformly dispersed in CIIR matrices and the compatibility was good. In addition, the MDT showed a positive effect on damping performance of CIIR composites. A blending ratio of CIIR/MDT = 100/10 presented the best damping performance and the damping temperature range (tan delta > 0.7) was extended from 60 to 70 degrees C. The variable temperature FTIR spectra showed the presence of hydrogen bonds between the hydroxyl groups and chloride atoms in the CIIR matrices, and a blue shift exhibited when these hydrogen bonds were dissociated. Hence, these CIIR composites provided good damping behaviors and supplied a novel and promising way for preparation of high damping rubber composites with broad temperature ranges. PMID- 30400185 TI - Indoor Positioning Based on Bluetooth Low-Energy Beacons Adopting Graph Optimization. AB - Bluetooth Low-Energy (BLE) beacons-based indoor positioning is a promising method for indoor positioning, especially in applications of position-based services (PbS). It has low deployment cost and it is suitable for a wide range of mobile devices. Existing BLE beacon-based positioning methods can be categorized as range-based methods and fingerprinting-based methods. For range-based methods, the positions of the beacons should be known before positioning. For fingerprinting-based methods, a pre-requisite is the reference fingerprinting map (RFM). Many existing methods focus on how to perform the positioning assuming the beacon positions or RFM are known. However, in practical applications, determining the beacon positions or RFM in the indoor environment is normally a difficult task. This paper proposed an efficient and graph optimization-based way for estimating the beacon positions and the RFM, which combines the range-based method and the fingerprinting-based method. The method exists without need for any dedicated surveying instruments. A user equipped with a BLE-enabled mobile device walks in the region collecting inertial readings and BLE received signal strength indication (RSSI) readings. The inertial measurements are processed through the pedestrian dead reckoning (PDR) method to generate the constraints at adjacent poses. In addition, the BLE fingerprints are adopted to generate constraints between poses (with similar fingerprints) and the RSSIs are adopted to generate distance constraints between the poses and the beacon positions (according to a pre-defined path-loss model). The constraints are then adopted to form a cost function with a least square structure. By minimizing the cost function, the optimal user poses at different times and the beacon positions are estimated. In addition, the RFM can be generated through the pose estimations. Experiments are carried out, which validates that the proposed method for estimating the pre-requisites (including beacon positions and the RFM). These estimated pre-requisites are of sufficient quality for both range-based and fingerprinting-based positioning. PMID- 30400187 TI - In Situ Diagnosis of Scabies Using a Handheld Digital Microscope in Resource-Poor Settings-A Proof-of-Principle Study in the Amazon Lowland of Colombia. AB - Scabies is a neglected tropical disease associated with important morbidity. The disease occurs worldwide and is particularly common in resource-poor communities in the Global South. A validated technique for the diagnosis of scabies in resource-poor settings does not exist. The objective of the study was to determine the practicability and accuracy of handheld digital microscopy in three indigenous communities in the Amazon lowland of Colombia, where scabies is the most common parasitic skin disease. One-hundred-and-eleven children and adults from three indigenous communities with a presumptive diagnosis of scabies were examined clinically by using a handheld digital microscope placed directly on the skin. The microscopical identification of a mite was verified by an "experienced mother", a woman who had acquired the skills to diagnose scabies as part of traditional Amerindian medicine. The "experienced mother" removed the parasite with a fine needle and placed it on a flat surface in order to enable its direct examination with the digital microscope. Using digital microscopy, scabies was diagnosed in 24 out of 111 participants and confirmed by the extraction of a Sarcoptes mites from the acarine eminence. A characteristic tunnel (burrow) with or without mite could be clearly identified irrespective of the degree of pigmentation of the skin. Besides, digital microscopy revealed pathological characteristics of scabies hitherto unknown and impossible to be seen in dermoscopy, such as partially or totally obliterated tunnels, tunnels with multiple entry or exit points, circumscribed hyperpigmentation around obliterated tunnels and mites secluded in a nodule. This proof-of-principle study demonstrated the accurate diagnosis of scabies by handheld digital microscopy in patients with pigmented skin and the feasibility of this technique in resource poor settings. PMID- 30400186 TI - Leukocyte Telomere Length and Chronic Conditions in Older Women of Northeast Brazil: A Cross-Sectional Study. AB - This study assessed whether telomere length is related to chronic conditions, cardiovascular risk factors, and inflammation in women aged 65 to 74 from Northeast Brazil. Participants were selected from two sources, a representative sample of the International Mobility in Aging Study (n = 57) and a convenience sample (n = 49) recruited at senior centers. Leukocyte telomere length was measured by quantitative polymerase chain reaction from blood samples in 83 women. Natural log-transformed telomere/single copy gene ratio was used as the dependent variable in the analysis. Blood analyses included inflammatory markers (high-sensitivity C-reactive protein and interleukin-6), total, low-density lipoprotein and high-density lipoprotein cholesterol, triglycerides, glucose and glycosylated hemoglobin. Self-rated health, chronic conditions, cardiovascular risk factors and inflammatory markers were not associated with telomere length. No significant independent association was found between telomere length and anthropometric measures or blood markers, even after adjusting for age, education and adverse childhood events among these older women in Northeast Brazil. Our results did not confirm the hypothesis that chronic conditions, cardiovascular risk factors or inflammation are associated with shorter telomere length in these women who have exceptional survival relative to the life expectancy of their birth cohort. PMID- 30400188 TI - Human In Situ Study of the effect of Bis(2-Methacryloyloxyethyl) Dimethylammonium Bromide Immobilized in Dental Composite on Controlling Mature Cariogenic Biofilm. AB - Cariogenic oral biofilms cause recurrent dental caries around composite restorations, resulting in unprosperous oral health and expensive restorative treatment. Quaternary ammonium monomers that can be copolymerized with dental resin systems have been explored for the modulation of dental plaque biofilm growth over dental composite surfaces. Here, for the first time, we investigated the effect of bis(2-methacryloyloxyethyl) dimethylammonium bromide (QADM) on human overlying mature oral biofilms grown intra-orally in human participants for 7-14 days. Seventeen volunteers wore palatal devices containing composite specimens containing 10% by mass of QADM or a control composite without QADM. After 7 and 14 days, the adherent biofilms were collected to determine bacterial counts via colony-forming unit (CFU) counts. Biofilm viability, chronological changes, and percentage coverage were also determined through live/dead staining. QADM composites caused a significant inhibition of Streptococcus mutans biofilm formation for up to seven days. No difference in the CFU values were found for the 14-day period. Our findings suggest that: (1) QADM composites were successful in inhibiting 1-3-day biofilms in the oral environment in vivo; (2) QADM significantly reduced the portion of the S. mutans group; and (3) stronger antibiofilm activity is required for the control of mature long-term cariogenic biofilms. Contact-killing strategies using dental materials aimed at preventing or at least reducing high numbers of cariogenic bacteria seem to be a promising approach in patients at high risk of the recurrence of dental caries around composites. PMID- 30400189 TI - Transcriptome Analysis of Gene Expression Patterns Potentially Associated with Premature Senescence in Nicotiana tabacum L. AB - Senescence affects the remobilization of nutrients and adaption of the plant to the environment. Combined stresses can result in premature senescence in plants which exist in the field. In this study, transcriptomic analysis was performed on mature leaves and leaves in three stages of premature senescence to understand the molecular mechanism. With progressive premature senescence, a declining chlorophyll (chl) content and an increasing malonaldehyde (MDA) content were observed, while plasmolysis and cell nucleus pyknosis occurred, mitochondria melted, thylakoid lamellae were dilated, starch grains in chloroplast decreased, and osmiophilic granules increased gradually. Moreover, in total 69 common differentially expressed genes (DEGs) in three stages of premature senescing leaves were found, which were significantly enriched in summarized Gene Ontology (GO) terms of membrane-bounded organelle, regulation of cellular component synthesis and metabolic and biosynthetic processes. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested that the plant hormone signal transduction pathway was significantly enriched. The common DEGs and four senescence-related pathways, including plant hormone signal transduction, porphyrin and chlorophyll metabolism, carotenoid biosynthesis, and regulation of autophagy were selected to be discussed further. This work aimed to provide potential genes signaling and modulating premature senescence as well as the possible dynamic network of gene expression patterns for further study. PMID- 30400190 TI - Modelling and Design of MEMS Piezoresistive Out-of-Plane Shear and Normal Stress Sensors. AB - In this paper, the design of MEMS piezoresistive out-of-plane shear and normal stress sensor is described. To improve the sensor sensitivity, a methodology by the incorporation of stress concentration regions, namely surface trenches in the proximity of sensing elements was explored in detail. The finite element (FE) model, verified by a five-layer analytical model was developed as a tool to model the performance of the sensor and guide the geometric optimization of the surface trenches. Optimum location and dimensions of the surface trenches have been obtained through a comprehensive FE analysis. The microfabrication and packing scheme was introduced to prototype the sensor with optimum geometric characteristics of surface trenches. Signal output from the prototyped sensor was tested and compared with those from FE simulation. Good agreement has been achieved between the simulation and experimental results. Moreover, the results suggest the incorporation of surface trenches can help improve the sensor sensitivity. More specifically, the sum of signal output from the sensor chip with surface trenches are 4.52, 5.06 and 5.72 times higher compared to flat sensor chip for center sensing area, edge sensing areas 1 and 2, respectively. PMID- 30400191 TI - High Thermal Diffusivity in Thermally Treated Filamentous Virus-Based Assemblies with a Smectic Liquid Crystalline Orientation. AB - Polymers are generally considered thermal insulators because the amorphous arrangement of the polymeric chains reduces the mean free path of heat-conducting phonons. Recent studies reveal that individual chains of polymers with oriented structures could have high thermal conductivity, because such stretched polymeric chains effectively conduct phonons through polymeric covalent bonds. Previously, we have found that the liquid crystalline assembly composed of one of the filamentous viruses, M13 bacteriophages (M13 phages), shows high thermal diffusivity even though the assembly is based on non-covalent bonds. Despite such potential applicability of biopolymeric assemblies as thermal conductive materials, stability against heating has rarely been investigated. Herein, we demonstrate the maintenance of high thermal diffusivity in smectic liquid crystalline-oriented M13 phage-based assemblies after high temperature (150 degrees C) treatment. The liquid crystalline orientation of the M13 phage assemblies plays an important role in the stability against heating processes. Our results provide insight into the future use of biomolecular assemblies for reliable thermal conductive materials. PMID- 30400192 TI - Heavy Metal Mixture Exposure and Effects in Developing Nations: An Update. AB - The drive for development and modernization has come at great cost. Various human activities in developed and developing countries, particularly in sub-Saharan Africa (SSA) have given rise to environmental safety concerns. Increased artisanal mining activities, illegal refining, use of leaded petrol, airborne dust, arbitrary discarding and burning of toxic waste, absorption of production industries in inhabited areas, inadequate environmental legislation, and weak implementation of policies, have given rise to the incomparable contamination and pollution associated with heavy metals in recent decades. This review evaluates the public health effects of heavy metals and their mixtures in SSA. This shows the extent and size of the problem posed by exposure to heavy metal mixtures in regard to public health. PMID- 30400193 TI - Single-Electron Redox Chemistry on the [Cp*Rh] Platform Enabled by a Nitrated Bipyridyl Ligand. AB - [Cp*Rh] complexes (Cp* = pentamethylcyclopentadienyl) are attracting renewed interest in coordination chemistry and catalysis, but these useful compounds often undergo net two-electron redox cycling that precludes observation of individual one-electron reduction events. Here, we show that a [Cp*Rh] complex bearing the 4,4'-dinitro-2,2'-bipyridyl ligand (dnbpy) (3) can access a distinctive manifold of five oxidation states in organic electrolytes, contrasting with prior work that found no accessible reductions in aqueous electrolyte. These states are readily generated from a newly isolated and fully characterized rhodium(III) precursor complex 3, formulated as [Cp*Rh(dnbpy)Cl]PF6. Single-crystal X-ray diffraction (XRD) data, previously unavailable for the dnbpy ligand bound to the [Cp*Rh] platform, confirm the presence of both [eta5-Cp*] and [kappa2-dnbpy]. Four individual one-electron reductions of 3 are observed, contrasting sharply with the single two-electron reductions of other [Cp*Rh] complexes. Chemical preparation and the study of the singly reduced species with electronic absorption and electron paramagnetic resonance spectroscopies indicate that the first reduction is predominantly centered on the dnbpy ligand. Comparative cyclic voltammetry studies with [NBu4][PF6] and [NBu4][Cl] as supporting electrolytes indicate that the chloride ligand can be lost from 3 by ligand exchange upon reduction. Spectroelectrochemical studies with ultraviolet (UV)-visible detection reveal isosbestic behavior, confirming the clean interconversion of the reduced forms of 3 inferred from the voltammetry with [NBu4][PF6] as supporting electrolyte. Electrochemical reduction in the presence of triethylammonium results in an irreversible response, but does not give rise to catalytic H2 evolution, contrasting with the reactivity patterns observed in [Cp*Rh] complexes bearing bipyridyl ligands with less electron-withdrawing substituents. PMID- 30400194 TI - SDN Architecture for 6LoWPAN Wireless Sensor Networks. AB - Wireless sensor networks (WSN) are being increasingly used for data acquisition and control of remote devices. However, they present some constraints in critical and large-scale scenarios. The main limitations come from the nature of their components, such as lossy links, and devices with power supply limitations, poor processing power and limited memory. The main feature of software-defined networks (SDN) is the separation between the control plane and the data plane, making available a logically unified view of the topology in the controllers. In this way, it is possible to build network applications that take into account this unified view, which makes the SDN an alternative approach to solve the mentioned limitations. This paper presents the SD6WSN (software-defined 6LoWPAN wireless sensor network) architecture, developed to control the behavior of the data traffic in 6LoWPAN according to the SDN approach. It takes into account the specific characteristics of WSN devices, such as low data transfer rate, high latency, packet loss and low processing power, and takes advantage of the flexibility provided by flow-based forwarding, allowing the development of specific networking applications based on a unified view. We provide a detailed description of how we have implemented SD6WSN in the Contiki operating system. The new architecture is assessed in two experiments. The first considers a typical advanced metering infrastructure (AMI) network and measures the overhead of SD6WSN control messages in configurations involving different path lengths. The results indicate that the overhead introduced is not excessive, given the advantages that the SDN approach can bring. The second considers a grid-topology to evaluate the average latency of the peer-to-peer communication. It was observed that the average latency in the SD6WSN is considerably lower than that obtained with standard 6LoWPAN, showing the potential of the proposed approach. PMID- 30400195 TI - Open-Ring Butenolides from a Marine-Derived Anti-Neuroinflammatory Fungus Aspergillus terreus Y10. AB - To investigate structurally novel and anti-neuroinflammatory natural compounds from marine-derived microorganisms, the secondary metabolites of Aspergillus terreus Y10, a fungus separated from the sediment of the coast in the South China Sea, were studied. Three new compounds (2-4), with novel open-ring butenolide skeletons, were isolated from the ethyl acetate extract of the culture medium. In addition, a typical new butenolide, asperteretal F (1), was found to dose dependently inhibit tumor necrosis factor (TNF-alpha) generation with an IC50 of 7.6 MUg/mL. The present study shows the existence of open-ring butenolides, and suggests that butenolides such as asperteretal F (1) are a promising new anti neuroinflammatroy candidate for neurodegenerative diseases. PMID- 30400196 TI - Accuracy and Validity of Resting Energy Expenditure Predictive Equations in Middle-Aged Adults. AB - Indirect calorimetry (IC) is considered the reference method to determine the resting energy expenditure (REE), but its use in a clinical context is limited. Alternatively, there is a number of REE predictive equations to estimate the REE. However, it has been shown that the available REE predictive equations could either overestimate or underestimate the REE as measured by IC. Moreover, the role of the weight status in the accuracy and validity of the REE predictive equations requires further attention. Therefore, this study aimed to determine the accuracy and validity of REE predictive equations in normal-weight, overweight, and obese sedentary middle-aged adults. A total of 73 sedentary middle-aged adults (53% women, 40-65 years old) participated in the study. We measured REE by indirect calorimetry, strictly following the standard procedures, and we compared it with the values obtained from 33 predictive equations. The most accurate predictive equations in middle-aged sedentary adults were: (i) the equation of FAO/WHO/UNU in normal-weight individuals (50.0% of prediction accuracy), (ii) the equation of Livingston in overweight individuals (46.9% of prediction accuracy), and (iii) the equation of Owen in individuals with obesity (52.9% of prediction accuracy). Our study shows that the weight status plays an important role in the accuracy and validity of different REE predictive equations in middle-aged adults. PMID- 30400198 TI - A Two-Step Approach for the Design and Generation of Nanobodies. AB - Nanobodies, the smallest possible antibody format, have become of considerable interest for biotechnological and immunotherapeutic applications. They show excellent robustness, are non-immunogenic in humans, and can easily be engineered and produced in prokaryotic hosts. Traditionally, nanobodies are selected from camelid immune libraries involving the maintenance and treatment of animals. Recent advances have involved the generation of nanobodies from naive or synthetic libraries. However, such approaches demand large library sizes and sophisticated selection procedures. Here, we propose an alternative, two-step approach for the design and generation of nanobodies. In a first step, complementarity-determining regions (CDRs) are grafted from conventional antibody formats onto nanobody frameworks, generating weak antigen binders. In a second step, the weak binders serve as templates to design focused synthetic phage libraries for affinity maturation. We validated this approach by grafting toxin- and hapten-specific CDRs onto frameworks derived from variable domains of camelid heavy-chain-only antibodies (VHH). We then affinity matured the hapten binder via panning of a synthetic phage library. We suggest that this strategy can complement existing immune, naive, and synthetic library based methods, requiring neither animal experiments, nor large libraries, nor sophisticated selection protocols. PMID- 30400199 TI - The Role of Vitamin D Oral Supplementation in Insulin Resistance in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVE: To evaluate the effect of vitamin D supplementation (alone or with co supplementation) on insulin resistance in patients with polycystic ovary syndrome (PCOS). METHODS: We performed a literature search of databases (Medline, Scopus, Web of Knowledge, Cochrane Library) and identified all reports of randomized controlled trials (RCTs) published prior to April 2018. We compared the effects of supplementation with vitamin D alone (dose from 1000 IU/d to 60,000 IU/week) or with co-supplements to the administration of placebos in women diagnosed with PCOS. The systematic review and meta-analysis protocol was registered in the International Prospective Register of Systematic Reviews (Prospero) as number CRD42018090572. MAIN RESULTS: Eleven of 345 identified studies were included in the analysis; these involved 601women diagnosed with PCOS. Vitamin D as a co supplement was found to significantly decrease fasting glucose concentrations and the HOMA-IR value. HOMA-IR also declined significantly when vitamin D was supplemented with a dose lower than 4000 IU/d. CONCLUSIONS: Evidence from RCTs suggests that the supplementation of PCOS patients with continuous low doses of vitamin D (<4000 IU/d) or supplementation with vitamin D as a co-supplement may improve insulin sensitivity in terms of the fasting glucose concentration (supplementation with vitamin D in combination with other micronutrients) and HOMA-IR (supplementation with vitamin D in continuous low daily doses or as co supplement). PMID- 30400197 TI - Children with Obesity and Asthma: Which Are the Best Options for Their Management? AB - Obesity and asthma are complex disorders related to gene-environment interactions and various lifestyle factors. At present, they represent two of the most significant paediatric health problems worldwide, particularly in industrialized nations. The aim of this narrative review is to evaluate possible therapeutic strategies to manage asthma in children with overweight/obesity. PubMed was used to search for all of the studies published from January 2008 to June 2018 using the following key words: "asthma" and "overweight" or "obesity" or "obese" and "children" or "paediatric". The literature review showed that growing evidence underlines the existence of an "obese asthma" phenotype characterised by difficult-to-control asthma with additional symptoms, worse control, more frequent and severe exacerbations, reduced response to inhaled corticosteroids, and lower quality of life than other phenotypes. Currently, therapeutic strategies centred on prevention are suggested and the development of resources to assist families with weight loss strategies seems useful for effective weight control and optimal asthma management. Studies on vitamin D supplementation and further knowledge are needed to better define the best therapeutic options to manage asthma in children with overweight/obesity and to reduce the onset and severity of this chronic respiratory disease through the design of a multifactorial intervention. PMID- 30400200 TI - Changes in Sport Nutrition Knowledge, Attitudes/Beliefs and Behaviors Following a Two-Year Sport Nutrition Education and Life-Skills Intervention among High School Soccer Players. AB - The purpose of this study was to examine the impact of a sport nutrition education and life-skills intervention on sport nutrition knowledge (SNK), attitudes/beliefs and dietary behaviors relevant to sport nutrition among high school (HS) soccer players. Three assessments were done over the 2-year intervention (baseline = time 1, end year 1 = time 2, end year 2 = time 3). Participants (n = 217; females = 64%; Latino = 47.5%; 14.9 +/- 0.9-year; 46.5% National School Breakfast/Lunch Program) were assigned to an intervention group (IG, n = 153; 9 schools) or comparison group (CG, n = 64; 4 schools) based on geographical location. Differences over time were examined based on group, sex, socioeconomic status (SES) and race/ethnicity. The IG increased SNK scores by ~10% (time 1 = 51.6%; time 3 = 60.9%; p <= 0.001), with the greatest change in the female IG vs. CG and no differences in male IG vs. CG. Daily breakfast consumption was 53.7% in both groups. IG players were 3 times more likely (95%CI = 2.59, 7.77) to report trying to eat for performance (IG = 48.7% vs. CG = 30.2%). By time 3, IG players were less likely to report that 'diet met nutritional requirements' (31.6%) compared to CG (47.6%). For IG, the consumption of lunch (>=5-days/week) did not change (92.2-93.4%), but declined in the CG (90.6%) (p = 0.04). No other differences by sub-population (race/ethnicity, SES) were observed. Our findings indicate that HS athletes are motivated to learn and improve diet behaviors, and benefit from team-based nutrition interventions. Future interventions should consider delivery of curriculum/experiential learning during a defined training period, with messages reinforced with supports at home, school and athletic settings. PMID- 30400201 TI - The Many Ways by Which O-GlcNAcylation May Orchestrate the Diversity of Complex Glycosylations. AB - Unlike complex glycosylations, O-GlcNAcylation consists of the addition of a single N-acetylglucosamine unit to serine and threonine residues of target proteins, and is confined within the nucleocytoplasmic and mitochondrial compartments. Nevertheless, a number of clues tend to show that O-GlcNAcylation is a pivotal regulatory element of its complex counterparts. In this perspective, we gather the evidence reported to date regarding this connection. We propose different levels of regulation that encompass the competition for the nucleotide sugar UDP-GlcNAc, and that control the wide class of glycosylation enzymes via their expression, catalytic activity, and trafficking. We sought to better envision that nutrient fluxes control the elaboration of glycans, not only at the level of their structure composition, but also through sweet regulating actors. PMID- 30400202 TI - Anti-Breast Cancer Activity of Latroeggtoxin-V Mined from the Transcriptome of Spider Latrodectus tredecimguttatus Eggs. AB - As a black widow spider, Latrodectus tredecimguttatus has poisonous components not only in venomous glands but also in eggs. Our previous work had carried out a transcriptome analysis of the spider eggs in an attempt to probe into the molecular basis of the egg toxicity. A proteinaceous toxin, named Latroeggtoxin V, was mined from the identified transcriptome. In this study, the gene of Latroeggtoxin-V was cloned and heterologously expressed, and the anticancer activity of the recombinant Latroeggtoxin-V (rLatroeggtoxin-V) was characterized. Activity assay found that rLatroeggtoxin-V could selectively act on breast cancer line MDA-MB-231 cells, not only arresting their cell cycle, inhibiting their proliferation and migration, but also inducing their apoptosis. Bioinformatics analysis suggested that Latroeggtoxin-V belongs to the ATPase inhibitor protein family and the further activity assay showed that the rLatroeggtoxin-V inhibited the activity of the Na+/K+-ATPase in MDA-MB-231 cells in a concentration dependent manner, suggesting that the anticancer activity of Latroeggtoxin-V is based on its affecting the ion transport and receptor functions of Na+/K+-ATPase. The present work not only laid the foundation for the utilization of Latroeggtoxin-V in the anticancer drug development and the related fields, but also provided a new paradigm for exploration of the proteinaceous toxins under the direction of transcriptomics and bioinformatics. PMID- 30400203 TI - A Reliable Health Indicator for Fault Prognosis of Bearings. AB - Estimation of the remaining useful life (RUL) of bearings is important to avoid abrupt shutdowns in rotary machines. An important task in RUL estimation is the construction of a suitable health indicator (HI) to infer the bearing condition. Conventional health indicators rely on features of the vibration acceleration signal and are predominantly calculated without considering its non-stationary nature. This often results in an HI with a trend that is difficult to model, as well as random fluctuations and poor correlation with bearing degradation. Therefore, this paper presents a method for constructing a bearing's HI by considering the non-stationarity of the vibration acceleration signals. The proposed method employs the discrete wavelet packet transform (DWPT) to decompose the raw signal into different sub-bands. The HI is extracted from each sub-band signal, smoothened using locally weighted regression, and evaluated using a gradient-based method. The HIs showing the best trends among all the sub-bands are iteratively accumulated to construct an HI with the best trend over the entire life of the bearing. The proposed method is tested on two benchmark bearing datasets. The results show that the proposed method yields an HI that correlates well with bearing degradation and is relatively easy to model. PMID- 30400204 TI - A Review of GPS Trajectories Classification Based on Transportation Mode. AB - GPS trajectories generated by moving objects provide researchers with an excellent resource for revealing patterns of human activities. Relevant research based on GPS trajectories includes the fields of location-based services, transportation science, and urban studies among others. Research relating to how to obtain GPS data (e.g., GPS data acquisition, GPS data processing) is receiving significant attention because of the availability of GPS data collecting platforms. One such problem is the GPS data classification based on transportation mode. The challenge of classifying trajectories by transportation mode has approached detecting different modes of movement through the application of several strategies. From a GPS data acquisition point of view, this paper macroscopically classifies the transportation mode of GPS data into single-mode and mixed-mode. That means GPS trajectories collected based on one type of transportation mode are regarded as single-mode data; otherwise it is considered as mixed-mode data. The one big difference of classification strategy between single-mode and mixed-mode GPS data is whether we need to recognize the transition points or activity episodes first. Based on this, we systematically review existing classification methods for single-mode and mixed-mode GPS data and introduce the contributions of these methods as well as discuss their unresolved issues to provide directions for future studies in this field. Based on this review and the transportation application at hand, researchers can select the most appropriate method and endeavor to improve them. PMID- 30400205 TI - Reactive Oxygen Species Induces Lipid Droplet Accumulation in HepG2 Cells by Increasing Perilipin 2 Expression. AB - Non-alcoholic fatty liver disease (NAFLD) has become the world's most common liver disease. The disease can develop liver fibrosis or even carcinomas from the initial hepatic steatosis, and this process is influenced by many factors. Reactive oxygen species (ROS), as potent oxidants in cells, have been reported previously to play an important role in the development of NAFLD progression via promoting neutral lipid accumulation. Here, we found that ROS can promote lipid droplet formation in hepatocytes by promoting perilipin2 (PLIN2) expression. First, we used different concentrations of hydrogen peroxide to treat HepG2 cells and found that the number of lipid droplets in the cells increased, however also that this effect was dose-independent. Then, the mRNA level of several lipid droplet-associated genes was detected with hydrogen peroxide treatment and the expression of PLIN2, PLIN5, and FSP27 genes was significantly up-regulated (p < 0.05). We overexpressed PLIN2 in HepG2 cells and found that the lipid droplets in the cells were markedly increased. Interference with PLIN2 inhibits ROS-induced lipid droplet formation, revealing that PLIN2 is a critical factor in this process. We subsequently analyzed the regulatory pathway and protein interaction network that is involved in PLIN2 and found that PLIN2 can regulate intracellular lipid metabolism through the PPARalpha/RXRA and CREB/CREBBP signaling pathways. The majority of the data indicated the correlation between hydrogen peroxide induced PLIN2 and lipid droplet upregulation. In conclusion, ROS up-regulates the expression of PLIN2 in hepatocytes, whereas PLIN2 promotes the formation of lipid droplets resulting in lipid accumulation in liver tissues. PMID- 30400206 TI - An Augmented Reality Geo-Registration Method for Ground Target Localization from a Low-Cost UAV Platform. AB - This paper presents an augmented reality-based method for geo-registering videos from low-cost multi-rotor Unmanned Aerial Vehicles (UAVs). The goal of the proposed method is to conduct an accurate geo-registration and target localization on a UAV video stream. The geo-registration of video stream requires accurate attitude data. However, the Inertial Measurement Unit (IMU) sensors on most low-cost UAVs are not capable of being directly used for geo-registering the video. The magnetic compasses on UAVs are more vulnerable to the interferences in the working environment than the accelerometers. Thus the camera yaw error is the main sources of the registration error. In this research, to enhance the low accuracy attitude data from the onboard IMU, an extended Kalman Filter (EKF) model is used to merge Real Time Kinematic Global Positioning System (RTK GPS) data with the IMU data. In the merge process, the high accuracy RTK GPS data can be used to promote the accuracy and stability of the 3-axis body attitude data. A method of target localization based on the geo-registration model is proposed to determine the coordinates of the ground targets in the video. The proposed method uses a modified extended Kalman Filter to combine the data from RTK GPS and the IMU to improve the accuracy of the geo-registration and the localization result of the ground targets. The localization results are compared to the reference point coordinates from satellite image. The comparison indicates that the proposed method can provide practical geo-registration and target localization results. PMID- 30400207 TI - Food Allergy Prevalence in Salvadoran Schoolchildren Estimated by Parent-Report. AB - The prevalence of food allergy (FA) has not been estimated at a population level in Central American countries and, consequently, the magnitude and relevance of the problem in the Central American region remains unknown. Thus, our aim was to evaluate the parent-reported prevalence of FA in a population of schoolchildren from the Central American country El Salvador. A Spanish version of a structured questionnaire was utilized. Five hundred and eight (508) parents returned the questionnaire with valid responses (response rate, 32%). The estimated prevalence rates (95% CI) were: adverse food reactions 15.9 (13.0-19.3), "perceived FA, ever" 11.6 (9.1-14.6), "physician-diagnosed FA, ever" 5.7% (4.0-8.0), "immediate type FA, ever" 8.8% (6.6-11.6), "immediate-type FA, current" 5.3% (3.6-7.6), and anaphylaxis 2.5% (1.5-4.3). The most common food allergens were milk (1.7%), shrimp (1.3), chili (0.7%), chocolate (0.7%), and nuts (0.3%). Most of the "food dependent anaphylaxis" cases (60.5%) sought medical attention, but only one case reported the prescription of an epinephrine autoinjector. Mild and severe FA cases are not uncommon among Salvadoran schoolchildren and both the prescription of epinephrine autoinjectors by healthcare personnel and the use of the autoinjectors by anaphylactic individuals should be encouraged. PMID- 30400208 TI - Enhanced Clean-In-Place Monitoring Using Ultraviolet Induced Fluorescence and Neural Networks. AB - Clean-in-place (CIP) processes are extensively used to clean industrial equipment without the need for disassembly. In food manufacturing, cleaning can account for up to 70% of water use and is also a heavy user of energy and chemicals. Due to a current lack of real-time in-process monitoring, the non-optimal control of the cleaning process parameters and durations result in excessive resource consumption and periods of non-productivity. In this paper, an optical monitoring system is designed and realized to assess the amount of fouling material remaining in process tanks, and to predict the required cleaning time. An experimental campaign of CIP tests was carried out utilizing white chocolate as fouling medium. During the experiments, an image acquisition system endowed with a digital camera and ultraviolet light source was employed to collect digital images from the process tank. Diverse image segmentation techniques were considered to develop an image processing procedure with the aim of assessing the area of surface fouling and the fouling volume throughout the cleaning process. An intelligent decision-making support system utilizing nonlinear autoregressive models with exogenous inputs (NARX) Neural Network was configured, trained and tested to predict the cleaning time based on the image processing results. Results are discussed in terms of prediction accuracy and a comparative study on computation time against different image resolutions is reported. The potential benefits of the system for resource and time efficiency in food manufacturing are highlighted. PMID- 30400209 TI - Add-on Immunoadsorption Shortly-after Optimal Medical Treatment Further Significantly and Persistently Improves Cardiac Function and Symptoms in Recent Onset Heart Failure-A Single Center Experience. AB - BACKGROUND: Immunoadsorption and intravenous immunoglobulin (IVIG) administration may have beneficial effects in patients with dilated cardiomyopathy with end stage heart failure. We investigated the effect of immunoadsorption with subsequent IVIG administration on cardiac function and symptoms in patients on optimal medical treatment (OMT) for heart failure (HF) with recent-onset cardiomyopathy during long-term follow-up. METHODS: Thirty-five patients with recent-onset of HF symptoms received intensive guideline-recommended medical HF therapy for 5.2 months. Subsequently, all patients received a single cycle of immunoadsorption for five days followed by IVIG administration. During the 29 month follow-up period, New York Heart Association (NYHA) functional class, left ventricular ejection fraction (LVEF) and N-terminal pro brain natriuretic peptide (NT-proBNP) were evaluated. Changes in quality of life (QoL) were assessed using the Minnesota Living with HF Questionnaire. RESULTS: Three months after immunoadsorption, NYHA functional class improved from 2.0 to 1.5 (p < 0.005) and LVEF significantly increased from 27.0% to 39.0% (p < 0.0001). Long-term follow up of 29 months showed stable NYHA functional class and a further moderate increase in LVEF from 39.0% to 42.0% (p < 0.0001) accompanied by a significant improvement in NT-proBNP and QoL scores. CONCLUSION: Immunoadsorption followed by IVIG administration further enhances LVEF, HF symptoms, QoL and biomarkers in patients with recent-onset HF on OMT. PMID- 30400210 TI - Functional Identification of Salt-Stress-Related Genes Using the FOX Hunting System from Ipomoea pes-caprae. AB - Ipomoea pes-caprae is a seashore halophytic plant and is therefore a good model for studying the molecular mechanisms underlying salt and stress tolerance in plant research. Here, we performed Full-length cDNA Over-eXpressor (FOX) gene hunting with a functional screening of a cDNA library using a salt-sensitive yeast mutant strain to isolate the salt-stress-related genes of I. pes-caprae (IpSR genes). The library was screened for genes that complemented the salt defect of yeast mutant AXT3 and could grow in the presence of 75 mM NaCl. We obtained 38 candidate salt-stress-related full-length cDNA clones from the I. pes caprae cDNA library. The genes are predicted to encode proteins involved in water deficit, reactive oxygen species (ROS) scavenging, cellular vesicle trafficking, metabolic enzymes, and signal transduction factors. When combined with the quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses, several potential functional salt-tolerance-related genes were emphasized. This approach provides a rapid assay system for the large-scale screening of I. pes caprae genes involved in the salt stress response and supports the identification of genes responsible for the molecular mechanisms of salt tolerance. PMID- 30400211 TI - Internet Mindfulness Meditation Intervention (IMMI) Improves Depression Symptoms in Older Adults. AB - Background: Older adults have fewer physiological reserves and are more likely to be affected by stress. Mindfulness meditation has the potential to be an effective treatment for depression, but little research has been conducted on older adults. The primary objective of this study was to evaluate depression symptom changes in older adults (55-80 years old) taking an Internet Mindfulness Meditation Intervention (IMMI) compared to a waitlist control. The secondary aims were to collect data on pain, perceived stress, resilience, mindfulness, sleep quality, and spirituality. Methods: Fifty older adults were randomized to either the Internet Mindfulness Meditation Intervention, a six-week online intervention with daily home practice, or a waitlist control. Measures were collected at baseline, after the six-week intervention period, and again six weeks later after the waitlist participants completed IMMI. Adherence to home practice was objectively measured with iMINDr. Changes in outcomes for the IMMI and waitlist participants were compared. All participants who completed IMMI were then combined for a within-participant analysis. Results: Adherence to the intervention was low, likely due to a traumatic event in the local area of the participants. Compared to the waitlist participants, those in IMMI had improved depression symptoms (p < 0.00005), perceived stress (p = 0.0007), insomnia symptoms ((p = 0.0009), and pain severity (p = 0.05). In the within-participant analysis of all data before and after IMMI (i.e., those initially randomized to IMMI and waitlist participants who took it), we found improvements in depression symptoms (p = 0.0001), perceived stress (p = 0.0001), insomnia symptoms (p < 0.00005), pain interference (p = 0.003), and spirituality (p = 0.018). A seven week follow-up after the original six-week IMMI program showed sustained improvements in the IMMI participants. Conclusions: IMMI improved depression and related symptoms compared to controls despite minimal support from study staff. IMMI offers a low-dose, low-cost, easily accessible mindfulness meditation intervention for older adults with depression symptoms. PMID- 30400212 TI - PGC-1alpha as a Pivotal Factor in Lipid and Metabolic Regulation. AB - Traditionally, peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), a 91 kDa transcription factor, regulates lipid metabolism and long-chain fatty acid oxidation by upregulating the expression of several genes of the tricarboxylic acid cycle and the mitochondrial fatty acid oxidation pathway. In addition, PGC-1alpha regulates the expression of mitochondrial genes to control mitochondria DNA replication and cellular oxidative metabolism. Recently, new insights showed that several myokines such as irisin and myostatin are epigenetically regulated by PGC-1alpha in skeletal muscles, thereby modulating systemic energy balance, with marked expansion of mitochondrial volume density and oxidative capacity in healthy or diseased myocardia. In addition, in our studies evaluating whether PGC-1alpha overexpression in epicardial adipose tissue can act as a paracrine organ to improve or repair cardiac function, we found that overexpression of hepatic PGC-1alpha increased hepatic fatty acid oxidation and decreased triacylglycerol storage and secretion in vivo and in vitro. In this review, we discuss recent studies showing that PGC-1alpha may regulate mitochondrial fusion-fission homeostasis and affect the renal function in acute or chronic kidney injury. Furthermore, PGC-1alpha is an emerging protein with a biphasic role in cancer, acting both as a tumor suppressor and a tumor promoter and thus representing a new and unresolved topic for cancer biology studies. In summary, this review paper demonstrates that PGC-1alpha plays a central role in coordinating the gene expression of key components of mitochondrial biogenesis and as a critical metabolic regulator in many vital organs, including white and brown adipose tissue, skeletal muscle, heart, liver, and kidney. PMID- 30400213 TI - Clinical Features of Varicella-Zoster Virus Infection. AB - Varicella-zoster virus (VZV) is a pathogenic human herpes virus that causes varicella (chickenpox) as a primary infection, following which it becomes latent in peripheral ganglia. Decades later, the virus may reactivate either spontaneously or after a number of triggering factors to cause herpes zoster (shingles). Varicella and its complications are more severe in the immunosuppressed. The most frequent and important complication of VZV reactivation is postherpetic neuralgia, the cause of which is unknown and for which treatment is usually ineffective. Reactivation of VZV may also cause a wide variety of neurological syndromes, the most significant of which is a vasculitis, which is treated with corticosteroids and the antiviral drug acyclovir. Other VZV reactivation complications include an encephalitis, segmental motor weakness and myelopathy, cranial neuropathies, Guillain-Barre syndrome, enteric features, and zoster sine herpete, in which the viral reactivation occurs in the absence of the characteristic dermatomally distributed vesicular rash of herpes zoster. There has also been a recent association of VZV with giant cell arteritis and this interesting finding needs further corroboration. Vaccination is now available for the prevention of both varicella in children and herpes zoster in older individuals. PMID- 30400214 TI - Anaplastic Lymphoma Kinase (ALK) Receptor Tyrosine Kinase: A Catalytic Receptor with Many Faces. AB - The anaplastic lymphoma kinase (ALK) receptor is a membrane-bound tyrosine kinase. The pathogenesis of several cancers is closely related to aberrant forms of ALK or aberrant ALK expression, including ALK fusion proteins, ALK-activated point mutations, and ALK amplification. Clinical applications of different ALK inhibitors represent significant progress in targeted therapy. Knowledge of different aspects of ALK biology can provide significant information to further the understanding of this receptor tyrosine kinase. In this mini-review, we briefly summarize different features of ALK. We also summarize some recent research advances on ALK fusion proteins in cancers. PMID- 30400215 TI - Characterizing Focused Attention and Working Memory Using EEG. AB - Detecting the cognitive profiles of learners is an important step towards personalized and adaptive learning. Electroencephalograms (EEG) have been used to detect the subject's emotional and cognitive states. In this paper, an approach for detecting two cognitive skills, focused attention and working memory, using EEG signals is proposed. The proposed approach consists of the following main steps: first, subjects undergo a scientifically-validated cognitive assessment test that stimulates and measures their full cognitive profile while putting on a 14-channel wearable EEG headset. Second, the scores of focused attention and working memory are extracted and encoded for a classification problem. Third, the collected EEG data are analyzed and a total of 280 time- and frequency-domain features are extracted. Fourth, several classifiers were trained to correctly classify and predict three levels (low, average, and high) of the two cognitive skills. The classification accuracies that were obtained on 86 subjects were 84% and 81% for the focused attention and working memory, respectively. In comparison with similar approaches, the obtained results indicate the generalizability and suitability of the proposed approach for the detection of these two skills. Thus, the presented approach can be used as a step towards adaptive learning where real time adaptation is to be done according to the predicted levels of the measured cognitive skills. PMID- 30400216 TI - Reclamation of Marine Chitinous Materials for Chitosanase Production via Microbial Conversion by Paenibacillus macerans. AB - Chitinous materials from marine byproducts elicit great interest among biotechnologists for their potential biomedical or agricultural applications. In this study, four kinds of marine chitinous materials (squid pens, shrimp heads, demineralized shrimp shells, and demineralized crab shells) were used to screen the best source for producing chitosanase by Paenibacillus macerans TKU029. Among them, the chitosanase activity was found to be highest in the culture using the medium containing squid pens as the sole carbon/nitrogen (C/N) source. A chitosanase which showed molecular weights at 63 kDa was isolated from P. macerans cultured on a squid pens medium. The purified TKU029 chitosanase exhibited optimum activity at 60 degrees C and pH 7, and was stable at temperatures under 50 degrees C and pH 3-8. An analysis by MALDI-TOF MS revealed that the chitosan oligosaccharides (COS) obtained from the hydrolysis of water soluble chitosan by TKU029 crude enzyme showed various degrees of polymerization (DP), varying from 3-6. The obtained COS enhanced the growth of four lactic acid bacteria strains but exhibited no effect on the growth of E. coli. By specialized growth enhancing effects, the COS produced from hydrolyzing water soluble chitosan with TKU029 chitinolytic enzymes could have potential for use in medicine or nutraceuticals. PMID- 30400217 TI - Amide Activation in Ground and Excited States. AB - Not all amide bonds are created equally. The purpose of the present paper is the reinterpretation of the amide group by means of two concepts: amidicity and carbonylicity. These concepts are meant to provide a new viewpoint in defining the stability and reactivity of amides. With the help of simple quantum-chemical calculations, practicing chemists can easily predict the outcome of a desired process. The main benefit of the concepts is their simplicity. They provide intuitive, but quasi-thermodynamic data, making them a practical rule of thumb for routine use. In the current paper we demonstrate the performance of our methods to describe the chemical character of an amide bond strength and the way of its activation methods. Examples include transamidation, acyl transfer and amide reductions. Also, the method is highly capable for simple interpretation of mechanisms for biological processes, such as protein splicing and drug mechanisms. Finally, we demonstrate how these methods can provide information about photo-activation of amides, through the examples of two caged neurotransmitter derivatives. PMID- 30400218 TI - Production of Selenomethionine-Enriched Bifidobacterium bifidum BGN4 via Sodium Selenite Biocatalysis. AB - Selenium is a trace element essential for human health that has received considerable attention due to its nutritional value. Selenium's bioactivity and toxicity are closely related to its chemical form, and several studies have suggested that the organic form of selenium (i.e., selenomethionine) is more bioavailable and less toxic than its inorganic form (i.e., sodium selenite). Probiotics, especially Bifidobacteriium and Lactobacillus spp., have received increasing attention in recent years, due to their intestinal microbial balancing effects and nutraceutical benefits. Recently, the bioconversion (a.k.a biotransformation) of various bioactive molecules (e.g., minerals, primary and secondary metabolites) using probiotics has been investigated to improve substrate biofunctional properties. However, there have been few reports of inorganic selenium conversion into its organic form using Bifidobacterium and Lactobacillus spp. Here we report that the biosynthesis of organic selenium was accomplished using the whole cell bioconversion of sodium selenite under controlled Bifidobacterium bifidum BGN4 culture conditions. The total amount of organic and inorganic selenium was quantified using an inductively coupled plasma atomic emission spectrometer (ICP-AES). The selenium species were separated via anion-exchange chromatography and analyzed with inductively coupled plasma-mass spectrometry (ICP-MS). Our findings indicated that the maximum level of organic selenium was 207.5 ug/g in selenium-enriched B. bifidum BGN4. Selenomethionine was the main organic selenium in selenium-enriched B. bifidum BGN4 (169.6 ug/g). Considering that B. bifidum BGN4 is a commercial probiotic strain used in the functional food industry with clinically proven beneficial effects, selenium enriched B. bifidum BGN4 has the potential to provide dual healthy functions as a daily supplement of selenium and regulator of intestinal bacteria. This is the first report on the production of organic selenium using B. bifidum spp. PMID- 30400219 TI - Transcription Factor Eb Is Required for Macropinocytosis-Mediated Growth Recovery of Nutrient-Deprived Kras-Mutant Cells. AB - Macropinocytosis is a regulated form of endocytosis that mediates the nonselective uptake of nutrients to support growth under nutrient-deprived conditions. KRAS-mutant cancer cells upregulate macropinocytosis to import extracellular proteins, which subsequently undergo proteolytic degradation in the lysosome. Although transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and function, its role in the degradation of extracellular protein from macropinocytosis in KRAS-mutant cells has not previously been elucidated. In this study, we investigated the role of TFEB in the recovery of macropinocytosis-mediated mTORC1 activity and cell growth under nutrient depletion. Mouse embryonic fibroblasts (MEFs) expressing KrasG12D and KRAS-mutant human cancer cells took up markedly higher levels of tetramethylrhodamine (TMR) dextran than the corresponding wild-type cells. siRNA-mediated inhibition of TFEB did not influence extracellular TMR-dextran uptake, but significantly attenuated lysosomal degradation of extracellular protein. Bovine serum albumin (BSA) treatment restored p-S6K levels and cell proliferation suppressed by leucine deprivation, and these effects were blocked by siTFEB. Collectively, our results show that TFEB plays a role in macropinocytosis-mediated KRAS-mutant cell growth under nutrient deprivation by promoting lysosomal degradation of extracellular proteins. PMID- 30400220 TI - Innovative Immunization Strategies for Antivenom Development. AB - Snakes, scorpions, and spiders are venomous animals that pose a threat to human health, and severe envenomings from the bites or stings of these animals must be treated with antivenom. Current antivenoms are based on plasma-derived immunoglobulins or immunoglobulin fragments from hyper-immunized animals. Although these medicines have been life-saving for more than 120 years, opportunities to improve envenoming therapy exist. In the later decades, new biotechnological tools have been applied with the aim of improving the efficacy, safety, and affordability of antivenoms. Within the avenues explored, novel immunization strategies using synthetic peptide epitopes, recombinant toxins (or toxoids), or DNA strings as immunogens have demonstrated potential for generating antivenoms with high therapeutic antibody titers and broad neutralizing capacity. Furthermore, these approaches circumvent the need for venom in the production process of antivenoms, thereby limiting some of the complications associated with animal captivity and venom collection. Finally, an important benefit of innovative immunization approaches is that they are often compatible with existing antivenom manufacturing setups. In this review, we compile all reported studies examining venom-independent innovative immunization strategies for antivenom development. In addition, a brief description of toxin families of medical relevance found in snake, scorpion, and spider venoms is presented, as well as how biochemical, bioinformatic, and omics tools could aid the development of next-generation antivenoms. PMID- 30400221 TI - Effects of 4-Week Creatine Supplementation Combined with Complex Training on Muscle Damage and Sport Performance. AB - Creatine supplementation has an ergogenic effect in an acute complex training bout, but the benefits of chronic creatine supplementation during long-term complex training remain unknown. The study aimed to evaluate the effects of 4 week complex training combined with creatine supplementation on sport performances and muscle damage biomarkers. Thirty explosive athletes were assigned to the creatine or placebo group, which consumed 20 g of creatine or carboxymethyl cellulose, respectively, per day for 6 days followed by 2 g of the supplements until the end of the study. After 6 days of supplementation, subjects performed tests of one repetition maximum (1-RM) strength of half squat and complex training bouts to determine the optimal individual post-activation potentiation time. Thereafter, all subjects performed a complex training programme consisting of six sets of 5-RM half squats and plyometric jumps 3 times per week for 4 weeks. Body composition, 30-m sprint and jump performances were assessed before and after the training period. Moreover, blood creatine kinase (CK) activity was analysed at the first and the last training bout. After the training, the 1-RM strength in the creatine group was significantly greater than in the placebo group (p < 0.05). CK activity after the complex training bout in the creatine group was significantly reduced compared with the placebo group (p < 0.05). No differences were noted for other variables. This study concluded that creatine supplementation combined with complex training improved maximal muscular strength and reduced muscle damage during training. PMID- 30400222 TI - Evaluation of Agraz Consumption on Adipocytokines, Inflammation, and Oxidative Stress Markers in Women with Metabolic Syndrome. AB - Metabolic syndrome (MetS) is characterized by increased oxidative stress and a pro-inflammatory state. Vaccinium meridionale Swartz (known as "agraz") is a berry rich in polyphenolic compounds with demonstrated antioxidant activity and anti-inflammatory effects in preclinical studies. The aim of this study was to evaluate the effects of agraz consumption on inflammatory and oxidative stress markers in women with MetS. Forty women with MetS (47 +/- 9 years) were randomly assigned to consume daily either 200 mL of agraz nectar or placebo over four weeks in a double-blind, cross-over design study, separated by a 4-week washout period. Metabolic and inflammatory markers in serum and antioxidant/oxidative stress markers in serum and urine were assessed at the end of each period. Serum antioxidant capacity measured by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method was significantly higher (p = 0.028), while urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) was lower (p = 0.041) after agraz consumption, compared to placebo. In conclusion, consumption of agraz during four weeks increased serum antioxidant capacity and decreased a marker of DNA oxidative damage in women with MetS, compared to placebo. These results suggest that agraz consumption may play a protective role in patients with MetS. PMID- 30400223 TI - Renal Replacement Therapy in Children in Lithuania: Challenges, Trends, and Outcomes. AB - Background and Objectives: Pediatric renal replacement therapy (RRT) in Lithuania resumed in 1994 after a 12-year pause in renal transplantation. Management of end stage renal disease (ESRD) has changed, and outcomes have improved over decades. Our aim was to evaluate the dynamics of RRT in Lithuania in the period 1994-2015, describe its distinctive features, and compare our results with other countries. Materials and Methods: Data between 1994 and 2015 were collected from patients under the age of 18 years with ESRD receiving RRT. The data included: Hemodialysis (HD), peritoneal dialysis (PD), transplantation incidence and prevalence, transplant waiting time, dialysis modalities before transplantation, causes of ESRD and gender distribution in transplanted patients, and patient and graft survival. Results: RRT incidence and prevalence maintained an increase up until 2009. Sixty-four transplantations were performed. Juvenile nephronophthisis (25.9%) was the primary cause of ESRD in transplanted children. The transplant waiting time median was 8.0 months. The male to female ratio post-transplantation was 1.02. Patient survival after transplantation at 10 years was 90.0%, while graft survival for living (related) was 77.0% and 51.1% for deceased. Twelve patients died while on RRT. Conclusions: RRT numbers are increasing in Lithuania. HD is the primary treatment of choice before transplantation, with continued low numbers of preemptive transplantation. Patient survival post-transplantation is favorable, though graft survival is less satisfactory. PMID- 30400225 TI - Characterization of Hydroxyproline-Containing Hairpin-Like Antimicrobial Peptide EcAMP1-Hyp from Barnyard Grass (Echinochloa crusgalli L.) Seeds: Structural Identification and Comparative Analysis of Antifungal Activity. AB - Herein, we describe a modified form of the antimicrobial hairpin-like peptide EcAMP1, isolated from barnyard grass (E. crusgalli) seeds, which is structurally characterized by a combination of high-pressure liquid chromatography, mass spectrometry, and automated Edman sequencing. This derivate has a single amino acid substitution (Pro19Hyp) in the second alpha-helical region of the molecule, which is critical for the formation of the hydrophobic core and the secondary structure elements. Comparing the antifungal activity of these two peptides, we found that the modified EcAMP1-Hyp had a significantly weaker activity towards the most-sensitive plant pathogenic fungus Fusarium solani. Molecular dynamics simulations and in vitro binding to the commercial polysaccharides allowed us to conclude that the Pro-19 residue is important for binding to carbohydrates located in the spore cell wall and it chiefly exhibits a fungistatic action representing the hyphal growth inhibition. These data are novel and significant for understanding a role of alpha-hairpinins in plant immunity. PMID- 30400224 TI - Adaptive Data Boosting Technique for Robust Personalized Speech Emotion in Emotionally-Imbalanced Small-Sample Environments. AB - Personalized emotion recognition provides an individual training model for each target user in order to mitigate the accuracy problem when using general training models collected from multiple users. Existing personalized speech emotion recognition research has a cold-start problem that requires a large amount of emotionally-balanced data samples from the target user when creating the personalized training model. Such research is difficult to apply in real environments due to the difficulty of collecting numerous target user speech data with emotionally-balanced label samples. Therefore, we propose the Robust Personalized Emotion Recognition Framework with the Adaptive Data Boosting Algorithm to solve the cold-start problem. The proposed framework incrementally provides a customized training model for the target user by reinforcing the dataset by combining the acquired target user speech with speech from other users, followed by applying SMOTE (Synthetic Minority Over-sampling Technique) based data augmentation. The proposed method proved to be adaptive across a small number of target user datasets and emotionally-imbalanced data environments through iterative experiments using the IEMOCAP (Interactive Emotional Dyadic Motion Capture) database. PMID- 30400226 TI - G-Protein Coupled Receptor Protein Synthesis on a Lipid Bilayer Using a Reconstituted Cell-Free Protein Synthesis System. AB - Membrane proteins are important drug targets which play a pivotal role in various cellular activities. However, unlike cytosolic proteins, most of them are difficult-to-express proteins. In this study, to synthesize and produce sufficient quantities of membrane proteins for functional and structural analysis, we used a bottom-up approach in a reconstituted cell-free synthesis system, the PURE system, supplemented with artificial lipid mimetics or micelles. Membrane proteins were synthesized by the cell-free system and integrated into lipid bilayers co-translationally. Membrane proteins such as the G-protein coupled receptors were expressed in the PURE system and a productivity ranging from 0.04 to 0.1 mg per mL of reaction was achieved with a correct secondary structure as predicted by circular dichroism spectrum. In addition, a ligand binding constant of 27.8 nM in lipid nanodisc and 39.4 nM in micelle was obtained by surface plasmon resonance and the membrane protein localization was confirmed by confocal microscopy in giant unilamellar vesicles. We found that our method is a promising approach to study the different classes of membrane proteins in their native-like artificial lipid bilayer environment for functional and structural studies. PMID- 30400228 TI - Gene and Protein Expression Profile of Selected Molecular Targets Mediating Electrophysiological Function in Pgc-1alpha Deficient Murine Atria. AB - Increases in the prevalence of obesity, insulin resistance, and metabolic syndrome has led to the increase of atrial fibrillation (AF) cases in the developed world. These AF risk factors are associated with mitochondrial dysfunction, previously modelled using peroxisome proliferator activated receptor gamma (PPARgamma) coactivator-1 (Pgc-1)-deficient murine cardiac models. We explored gene and protein expression profiles of selected molecular targets related to electrophysiological function in murine Pgc-1alpha-/- atria. qPCR analysis surveyed genes related to Na+-K+-ATPase, K+ conductance, hyperpolarisation-activated cyclic nucleotide-gated (Hcn), Na+ channels, Ca2+ channels, and indicators for adrenergic and cholinergic receptor modulation. Western blot analysis for molecular targets specific to conduction velocity (Nav1.5 channel and gap junctions) was performed. Transcription profiles revealed downregulation of molecules related to Na+-K+-ATPase transport, Hcn-dependent pacemaker function, Na+ channel-dependent action potential activation and propagation, Ca2+ current generation, calsequestrin-2 dependent Ca2+ homeostasis, and adrenergic alpha1D dependent protection from hypertrophic change. Nav1.5 channel protein expression but not gap junction expression was reduced in Pgc 1alpha-/- atria compared to WT. Nav1.5 reduction reflects corresponding reduction in its gene expression profile. These changes, as well as the underlying Pgc 1alpha-/- alteration, suggest potential pharmacological targets directed towards either upstream PGC-1 signalling mechanisms or downstream ion channel changes. PMID- 30400227 TI - Highly Photoluminescent and Stable N-Doped Carbon Dots as Nanoprobes for Hg2+ Detection. AB - We developed a microreactor with porous copper fibers for synthesizing nitrogen doped carbon dots (N-CDs) with a high stability and photoluminescence (PL) quantum yield (QY). By optimizing synthesis conditions, including the reaction temperature, flow rate, ethylenediamine dosage, and porosity of copper fibers, the N-CDs with a high PL QY of 73% were achieved. The PL QY of N-CDs was two times higher with copper fibers than without. The interrelations between the copper fibers with different porosities and the N-CDs were investigated using X ray photoelectron spectroscopy (XPS) and Fourier Transform infrared spectroscopy (FTIR). The results demonstrate that the elemental contents and surface functional groups of N-CDs are significantly influenced by the porosity of copper fibers. The N-CDs can be used to effectively and selectively detect Hg2+ ions with a good linear response in the 0~50 MUM Hg2+ ions concentration range, and the lowest limit of detection (LOD) is 2.54 nM, suggesting that the N-CDs have great potential for applications in the fields of environmental and hazard detection. Further studies reveal that the different d orbital energy levels of Hg2+ compared to those of other metal ions can affect the efficiency of electron transfer and thereby result in their different response in fluorescence quenching towards N-CDs. PMID- 30400229 TI - Accumulation of Dinophysis Toxins in Bivalve Molluscs. AB - Several species of the dinoflagellate genus Dinophysis produce toxins that accumulate in bivalves when they feed on populations of these organisms. The accumulated toxins can lead to intoxication in consumers of the affected bivalves. The risk of intoxication depends on the amount and toxic power of accumulated toxins. In this review, current knowledge on the main processes involved in toxin accumulation were compiled, including the mechanisms and regulation of toxin acquisition, digestion, biotransformation, compartmentalization, and toxin depuration. Finally, accumulation kinetics, some models to describe it, and some implications were also considered. PMID- 30400230 TI - Preparation of Graphite Oxide Containing Different Oxygen-Containing Functional Groups and the Study of Ammonia Gas Sensitivity. AB - A series of graphite oxide samples were prepared using the modified Hummers method. Flake graphite was used as the raw material and the reaction temperature of the aqueous solution was changed (0 degrees C, 30 degrees C, 50 degrees C, 60 degrees C, 70 degrees C, 80 degrees C, and 100 degrees C). X-ray diffraction, Fourier-transform infrared spectroscopy, Raman spectral analysis, X ray photoelectron spectroscopy, and contact angle tests were performed to characterize the structure, chemical bonding, type, and content of oxygen containing functional groups of the graphite oxide samples. The results showed that the type and content of each oxygen-containing functional group could be controlled by changing the reaction temperature with the addition of water. As the temperature of the system increased, the degree of oxidation of the graphite oxide samples first increased and then decreased. Too high a temperature (100 degrees C) of the system led to the formation of epoxy groups by the decomposition of some hydroxyl groups in the samples, causing the reduction of oxygen-containing functional groups between the graphite layers, poor hydrophilic properties, and low moisture content. When the system temperature was 50 degrees C, the interlayer spacing of the graphite oxide samples was at its highest, the graphite was completely oxidized (C/O = 1.85), and the oxygen-containing functional groups were mainly composed of hydroxyl groups (accounting for approximately 28.88% of the total oxygen-containing functional groups). The high content of hydroxyl and carboxyl groups had good hydrophilic ability and showed the highest moisture content. The sample at 50 degrees C had better sensitivity to ammonia because of its high hydroxyl group and carboxyl group content, with the sample showing an excellent profile when the ammonia concentration was 20-60 ppm. PMID- 30400231 TI - Properties of Experimental Dental Composites Containing Antibacterial Silver Releasing Filler. Materials 2018, 11, 1031. AB - In the published article, "Properties of Experimental Dental Composites Containing Antibacterial Silver-Releasing Filler" [...]. PMID- 30400232 TI - Nucleotide Modifications Decrease Innate Immune Response Induced by Synthetic Analogs of snRNAs and snoRNAs. AB - Short nuclear regulatory RNAs play a key role in the main stages of maturation of the precursors of the major RNA species. Small nuclear RNAs (snRNAs) form the core of the spliceosome and are responsible for the splicing of pre-mRNA molecules. Small nucleolar RNAs (snoRNAs) direct post-transcriptional modification of pre-rRNAs. A promising strategy for the development of non-coding RNA (ncRNAs) mimicking molecules is the introduction of modified nucleotides, which are normally present in natural ncRNAs, into the structure of synthetic RNAs. We have created a set of snoRNAs and snRNA analogs and studied the effect of base modifications, specifically, pseudouridine (Psi) and 5-methylcytidine (m5C), on the immune-stimulating and cytotoxic properties of these RNAs. Here, we performed a whole-transcriptome study of the influence of synthetic snoRNA analogs with various modifications on gene expression in human cells. Moreover, we confirmed the role of PKR in the recognition of snoRNA and snRNA analogs using the short hairpin RNA (shRNA) technique. We believe that the data obtained will contribute to the understanding of the role of nucleotide modification in ncRNA functions, and can be useful for creating the agents for gene regulation based on the structure of natural snoRNAs and snRNAs. PMID- 30400233 TI - A Survey of NFC Sensors Based on Energy Harvesting for IoT Applications. AB - In this article, an overview of recent advances in the field of battery-less near field communication (NFC) sensors is provided, along with a brief comparison of other short-range radio-frequency identification (RFID) technologies. After reviewing power transfer using NFC, recommendations are made for the practical design of NFC-based tags and NFC readers. A list of commercial NFC integrated circuits with energy-harvesting capabilities is also provided. Finally, a survey of the state of the art in NFC-based sensors is presented, which demonstrates that a wide range of sensors (both chemical and physical) can be used with this technology. Particular interest arose in wearable sensors and cold-chain traceability applications. The availability of low-cost devices and the incorporation of NFC readers into most current mobile phones make NFC technology key to the development of green Internet of Things (IoT) applications. PMID- 30400236 TI - A Media-Based School Intervention to Reduce Sexual Orientation Prejudice and Its Relationship to Discrimination, Bullying, and the Mental Health of Lesbian, Gay, and Bisexual Adolescents in Western Canada: A Population-Based Evaluation. AB - School interventions to address sexual orientation discrimination can be important tools for fostering inclusive school climate, and improving student wellbeing. In this study, we empirically evaluated a film-based intervention, Out in Schools, designed to reduce sexual orientation prejudice and foster inclusive school attitudes. Our evaluation mapped data about Out in Schools presentations onto student data from the random cluster-stratified, province-wide 2013 British Columbia Adolescent Health Survey (BCAHS) as well as potential confounding variables of Gay-Straight Alliance clubs (GSAs) and inclusive school policies. Outcome measures included past year sexual orientation discrimination, bullying, suicidal ideation, and school connectedness among lesbian, gay, and bisexual (LGB) and heterosexual (HET) students in grades 8 through 12 (ages 13 to 18; unweighted N = 21,075, weighted/scaled N = 184,821). Analyses used complex samples logistic regression, adjusted for sample design, conducted separately by gender and orientation. We found Out in Schools presentations were associated with reduced odds of LGB students experiencing discrimination, and both LGB and HET girl students being bullied or considering suicide, and increased levels of school connectedness, even after controlling for GSAs and policies. Out in Schools appears to have an additive contribution to reducing orientation prejudice and improving LGB and heterosexual student wellbeing within schools. PMID- 30400234 TI - A Recurrent BRCA2 Mutation Explains the Majority of Hereditary Breast and Ovarian Cancer Syndrome Cases in Puerto Rico. AB - Breast cancer is the most common cause of cancer diagnosis in women and is responsible for considerable mortality among the women of Puerto Rico. However, there are few studies in Puerto Rico on the genetic factors influencing risk. To determine the contribution of pathogenic mutations in BRCA1 and BRCA2, we sequenced these genes in 302 cases from two separate medical centers, who were not selected for age of onset or family history. We identified nine cases that are carriers of pathogenic germline mutation. This represents 2.9% of unselected cases and 5.6% of women meeting National Comprehensive Cancer Network (NCCN) criteria for BRCA testing. All of the identified pathogenic mutations were in the BRCA2 gene and the most common mutation is the p.Glu1308Ter (E1308X) mutation in BRCA2 found in eight out of nine cases, representing 89% of the pathogenic carriers. The E1308X mutation has been identified in breast and ovarian cancer families in Spain, and analysis of flanking DNA polymorphisms shows that all E1308X carriers occur on the same haplotype. This is consistent with BRCA2 E1308X being a founder mutation for the Puerto Rican population. These results will contribute to better inform genetic screening and counseling of breast and ovarian cancer cases in Puerto Rico and Puerto Rican populations in mainland United States. PMID- 30400235 TI - Inferring Novel Autophagy Regulators Based on Transcription Factors and Non Coding RNAs Coordinated Regulatory Network. AB - Autophagy is a complex cellular digestion process involving multiple regulators. Compared to post-translational autophagy regulators, limited information is now available about transcriptional and post-transcriptional regulators such as transcription factors (TFs) and non-coding RNAs (ncRNAs). In this study, we proposed a computational method to infer novel autophagy-associated TFs, micro RNAs (miRNAs) and long non-coding RNAs (lncRNAs) based on TFs and ncRNAs coordinated regulatory (TNCR) network. First, we constructed a comprehensive TNCR network, including 155 TFs, 681 miRNAs and 1332 lncRNAs. Next, we gathered the known autophagy-associated factors, including TFs, miRNAs and lncRNAs, from public data resources. Then, the random walk with restart (RWR) algorithm was conducted on the TNCR network by using the known autophagy-associated factors as seeds and novel autophagy regulators were finally prioritized. Leave-one-out cross-validation (LOOCV) produced an area under the curve (AUC) of 0.889. In addition, functional analysis of the top 100 ranked regulators, including 55 TFs, 26 miRNAs and 19 lncRNAs, demonstrated that these regulators were significantly enriched in cell death related functions and had significant semantic similarity with autophagy-related Gene Ontology (GO) terms. Finally, extensive literature surveys demonstrated the credibility of the predicted autophagy regulators. In total, we presented a computational method to infer credible autophagy regulators of transcriptional factors and non-coding RNAs, which would improve the understanding of processes of autophagy and cell death and provide potential pharmacological targets to autophagy-related diseases. PMID- 30400237 TI - Evaluating the Efficiency of Municipal Solid Waste Management in China. AB - Poor public health is always associated with the mismanagement of municipal solid waste (MSW). Many cities are besieged by MSW in the world. It is essential to do a good job in MSW management (MSWM). In order to improve the efficiency of MSWM, the Chinese government has intensively implemented relevant policies. There are still few studies on MSWM efficiency in China. The research aims to comprehensively analyze MSWM efficiency, find high-efficiency MSWM policy implementation routes and the breakthrough on improving MSWM efficiency. To measure Chinese MSWM efficiency accurately, this paper introduced the three-stage data envelopment analysis (DEA) model into the research. According to the results of DEA, Fuzzy c-Means algorithm was used to the cluster analysis of 33 typical cities. After eliminating the interference of the external environment and random disturbance, the mean value of MSWM efficiency declined from 0.575 to 0.544. The mean of pure technical efficiency (PTE) was declined from 0.966 to 0.611, while the mean of scale efficiency (SE) increased from 0.600 to 0.907. The PTE of central and northeastern cities was relatively low. The SE of western cities was comparatively high and the efficiency distribution of the eastern region was relatively scattered. In general, MSWM efficiency is low and expected to be improved. Regional differences in MSWM efficiency have been shown. The management effectiveness of eight pilot cities (MSW classification) is affirmative but not that significant. To improve MSWM efficiency, differential management for four types of cities should be carried out. PMID- 30400239 TI - A Bias Compensation Method for Distributed Moving Source Localization Using TDOA and FDOA with Sensor Location Errors. AB - Current bias compensation methods for distributed localization consider the time difference of arrival (TDOA) and frequency difference of arrival (FDOA) measurements noise, but ignore the negative influence by the sensor location uncertainties on source localization accuracy. Therefore, a new bias compensation method for distributed localization is proposed to improve the localization accuracy in this paper. This paper derives the theoretical bias of maximum likelihood estimation when the sensor location errors and positioning measurements noise both exist. Using the rough estimate result by MLE to subtract the theoretical bias can obtain a more accurate source location estimation. Theoretical analysis and simulation results indicate that the theoretical bias derived in this paper matches well with the actual bias in moderate noise level so that it can prove the correctness of the theoretical derivation. Furthermore, after bias compensation, the estimate accuracy of the proposed method achieves a certain improvement compared with existing methods. PMID- 30400240 TI - Factor Graph-Assisted Distributed Cooperative Positioning Algorithm in the GNSS System. AB - The development of smart cities calls for improved accuracy in navigation and positioning services; due to the effects of satellite orbit error, ionospheric error, poor quality of navigation signals and so on, it is difficult for existing navigation technology to achieve further improvements in positioning accuracy. Distributed cooperative positioning technology can further improve the accuracy of navigation and positioning with existing GNSS (Global Navigation Satellite System) systems. However, the measured range error and the positioning error of the cooperative nodes exhibit larger reductions in positioning accuracy. In response to this question, this paper proposed a factor graph-aided distributed cooperative positioning algorithm. It establishes the confidence function of factor graphs theory with the ranging error and the positioning error of the coordinated nodes and then fuses the positioning information of the coordinated nodes by the confidence function. It can avoid the influence of positioning error and ranging error and improve the positioning accuracy of cooperative nodes. In the simulation part, the proposed algorithm is compared with a mainly coordinated positioning algorithm from four aspects: the measured range error, positioning error, convergence speed, and mutation error. The simulation results show that the proposed algorithm leads to a 30-60% improvement in positioning accuracy compared with other algorithms under the same measured range error and positioning error. The convergence rate and mutation error elimination times are only 1 / 5 to 1 / 3 of the other algorithms. PMID- 30400238 TI - First Insights into the Gut Microbiota of Mexican Patients with Celiac Disease and Non-Celiac Gluten Sensitivity. AB - Gluten-related disorders (GRDs) are common chronic enteropathies and increasing evidence suggests an involvement of the gut microbiota. We examined the gut microbiota in Mexican people afflicted with GRDs. Ultra-high-throughput 16S marker sequencing was used to deeply describe the duodenal and fecal microbiota of patients with celiac disease (CD, n = 6), non-celiac gluten sensitivity (NCGS, n = 12), and healthy subjects (n = 12) from our local area. Additionally, we also investigated the changes in gut microbiota after four weeks on a gluten-free diet (GFD) in a subset of patients from whom paired samples were available. Despite a high inter-individual variability, significant differences in various microbial populations were identified. The linear discriminant analysis (LDA) effect size (LEfSe) method revealed that the genus Actinobacillus and the family Ruminococcaceae were higher in the duodenal and fecal microbiota of NCGS patients, respectively, while Novispirillum was higher in the duodenum of CD patients (p < 0.05, LDA score > 3.5). Interestingly, paired samples from NCGS patients showed a significant difference in duodenal Pseudomonas between the baseline period (median: 1.3%; min/max: 0.47-6.8%) and the period after four weeks on GFD (14.8%; 2.3-38.5%, p < 0.01, Wilcoxon signed-rank test). These results encourage more research on GRDs in Mexico. PMID- 30400241 TI - Transcriptional Landscape of PARs in Epithelial Malignancies. AB - G protein-coupled receptors (GPCRs), the largest family of cell receptors, act as important regulators of diverse signaling pathways. Our understanding of the impact of GPCRs in tumors is emerging, yet there is no therapeutic platform based on GPCR driver genes. As cancer progresses, it disrupts normal epithelial organization and maintains the cells outside their normal niche. The dynamic and flexible microenvironment of a tumor contains both soluble and matrix-immobilized proteases that contribute to the process of cancer advancement. An example is the activation of cell surface protease-activated receptors (PARs). Mammalian PARs are a subgroup of GPCRs that form a family of four members, PAR1-4, which are uniquely activated by proteases found in the microenvironment. PAR1 and PAR2 play central roles in tumor biology, and PAR3 acts as a coreceptor. The significance of PAR4 in neoplasia is just beginning to emerge. PAR1 has been shown to be overexpressed in malignant epithelia, in direct correlation with tumor aggressiveness, but there is no expression in normal epithelium. In this review, the involvement of key transcription factors such as Egr1, p53, Twist, AP2, and Sp1 that control PAR1 expression levels specifically, as well as hormone transcriptional regulation by both estrogen receptors (ER) and androgen receptors (AR) are discussed. The cloning of the human protease-activated receptor 2; Par2 (hPar2) promoter region and transcriptional regulation of estrogen (E2) via binding of the E2-ER complex to estrogen response elements (ERE) are shown. In addition, evidence that TEA domain 4 (TEAD4) motifs are present within the hPar2 promoter is presented since the YAP oncogene, which plays a central part in tumor etiology, acts via the TEAD4 transcription factor. As of now, no information is available on regulation of the hPar3 promoter. With regard to hPar4, only data showing CpG methylation promoter regulation is available. Characterization of the PAR transcriptional landscape may identify powerful targets for cancer therapies. PMID- 30400242 TI - Spectroscopic Studies of Dual Fluorescence in 2-(4-Fluorophenylamino)-5-(2,4 dihydroxybenzeno)-1,3,4-thiadiazole: Effect of Molecular Aggregation in a Micellar System. AB - The article presents the results of spectroscopic studies focused on a selected compound from the 1,3,4-thiadiazole group-2-(4-fluorophenylamino)-5-(2,4 dihydroxybenzeno)-1,3,4-thia-diazole (FABT)-in a micellar system formed by Triton X-100, a non-ionic detergent. Fluorescence measurements revealed the phenomenon of dual fluorescence whose emergence is related to the particular molecular organisation of the compound, which depends both on the concentration of the detergent and, most of all, the concentration of the compound itself. Dual fluorescence of FABT in a micellar system was observed for the compound dissolved in a methanol aqueous system, i.e., an environment wherein the dual fluorescence of the compound had never been reported before. Based on the interpretation of UV Vis electronic absorption, resonance light scattering (RLS), emission and excitation fluorescence spectra, as well as measurements of dynamic light scattering (DLS) and Principal Component Analysis (PCA), we were able to relate the occurrence of this effect to the process of molecular aggregation taking place between FABT molecules in the micellar system in question. Results of fluorescence spectra measurements and time-correlated single photon counting (TCSPC) indicate that dual fluorescence occurs at detergent concentrations necessary to form micellar systems, which in turn facilitate the process of aggregation of FABT molecules. The correlation between the observed fluorescence effects and the previous measurements performed for analogues from this group suggests the possibility of charge transfer (CT) within the range of detergent concentrations wherein the aforementioned fluorescence effects are observed. It ought to be emphasised that this type of fluorescence effects are relatively easy to induce, which predisposes this groups of fluorophores as ideal fluorescence probes in the context of biological samples. PMID- 30400243 TI - Stable Isotope-Labeled Lipidomics to Unravel the Heterogeneous Development Lipotoxicity. AB - Non-alcoholic fatty liver disease (NAFLD) as a global health problem has clinical manifestations ranging from simple non-alcoholic fatty liver (NAFL) to non alcoholic steatohepatitis (NASH), cirrhosis, and cancer. The role of different types of fatty acids in driving the early progression of NAFL to NASH is not understood. Lipid overload causing lipotoxicity and inflammation has been considered as an essential pathogenic factor. To correlate the lipid profiles with cellular lipotoxicity, we utilized palmitic acid (C16:0)- and especially unprecedented palmitoleic acid (C16:1)-induced lipid overload HepG2 cell models coupled with lipidomic technology involving labeling with stable isotopes. C16:0 induced inflammation and cell death, whereas C16:1 induced significant lipid droplet accumulation. Moreover, inhibition of de novo sphingolipid synthesis by myriocin (Myr) aggravated C16:0 induced lipoapoptosis. Lipid profiles are different in C16:0 and C16:1-treated cells. Stable isotope-labeled lipidomics elucidates the roles of specific fatty acids that affect lipid metabolism and cause lipotoxicity or lipid droplet formation. It indicates that not only saturation or monounsaturation of fatty acids plays a role in hepatic lipotoxicity but also Myr inhibition exasperates lipoapoptosis through ceramide in-direct pathway. Using the techniques presented in this study, we can potentially investigate the mechanism of lipid metabolism and the heterogeneous development of NAFLD. PMID- 30400244 TI - Discovery of 3-Amino-2-Hydroxypropoxyisoflavone Derivatives as Potential Anti-HCV Agents. AB - Synthesis and anti-hepatitis C virus (anti-HCV) effects of certain 3-amino-2 hydroxy-propoxy isoflavone derivatives, 6a-i, were described. The known 3-(3,4 dimethoxyphenyl)-7-(oxiran-2-ylmethoxy)-4H-chromen-4-one (5) was reacted with substituted amines to give the desired isoflavone derivatives, 6a-i. Among them, 7-{3-[(3,4-dimethoxy-phenethyl)amino]-2-hydroxypropoxy}-3-(3,4-dimethoxyphenyl) 4H-chromen-4-one (6b) was the most active, exhibiting approximately 2-fold higher anti-HCV effects than standard antiviral drug ribavirin (EC50 of 6.53 vs. 13.16 MUM). In addition, compound 6b was less cytotoxic than ribavirin. The selectivity index (SI) of 6b is approximately 2.6-fold higher than ribavirin. The compounds 6e, 6h, and 6i were also found to possess higher anti-HCV effects than ribavirin. Compound 6b was found to inhibit the HCV RNA expression in Ava5 cells in a dose dependent manner; furthermore, we found that the antiviral mechanism of compounds 6b, 6e, 6h, and 6i gave rise to induction of HO-1 expression. With the HO-1 promoter-based analysis, we found compounds 6b, 6e, 6h, and 6i induced HO-1 expression through increasing Nrf-2 binding activity. Taken together, compound 6b may serve as a potential lead compound for developing novel anti-HCV agents. PMID- 30400245 TI - Intravenous Delivery of piggyBac Transposons as a Useful Tool for Liver-Specific Gene-Switching. AB - Hydrodynamics-based gene delivery (HGD) is an efficient method for transfecting plasmid DNA into hepatocytes in vivo. However, the resulting gene expression is transient, and occurs in a non-tissue specific manner. The piggyBac (PB) transposon system allows chromosomal integration of a transgene in vitro. This study aimed to achieve long-term in vivo expression of a transgene by performing hepatocyte-specific chromosomal integration of the transgene using PB and HGD. Using this approach, we generated a novel mouse model for a hepatic disorder. A distinct signal from the reporter plasmid DNA was discernible in the murine liver approximately two months after the administration of PB transposons carrying a reporter gene. Then, to induce the hepatic disorder, we first administered mice with a PB transposon carrying a CETD unit (loxP-flanked stop cassette, diphtheria toxin-A chain gene, and poly(A) sites), and then with a plasmid expressing the Cre recombinase under the control of a liver-specific promoter. We showed that this system can be used for in situ manipulation and analysis of hepatocyte function in vivo in non-transgenic (Tg) animals. PMID- 30400246 TI - Influence of Benzyladenine on Metabolic Changes in Different Rose Tissues. AB - Two modern rose varieties, Floribunda and Hybrid Tea, were used to analyze and identify metabolic changes after foliar application with benzyladenine (BA). Volatile organic compounds (VOCs) as metabolites were detected. Two pairs of doses of BA, at 11.16 and 17.87 mg/cm2, and 7.17 and 12.26 mg/cm2 were applied to the foliage of Hybrid Tea and Floribunda, respectively. Sampling time was optimized and treatment duration was 4 weeks. After treatment, the volatiles from the treated and untreated control roses were extracted using headspace solid phase microextraction (HS-SPME) technology by three-phase fiber 50/30 um divinylbenzene/carboxen/polydimethylsiloxane (DVB/CAR/PDMS) and analyzed by gas chromatography (GC) coupled with a flame ionization detector (FID), and with mass spectrometry (GC-MS).The results showed that BA and its dose rate led to metabolic changes of treated roses in comparison with untreated controls. The number of VOCs extracted and detected from leaves, stem, rhizosphere and whole plants from the two rose varieties at doses rate of 17.87 and 12.26 mg/cm2 were 43, 65, 40 and 68 compounds for each plant material, respectively, for both rose varieties. Whilst the VOCs extracted and detected from both rose varieties for leaves, stem, rhizosphere and whole plants were 38, 61, 34 and 66 compounds for each plant material, respectively. The results demonstrate that some volatiles, such as 4-Heptyn-2-ol, Phenyl methyl ether and 3-Methyl-apopinene, increased with increasing doses of BA; these compounds are aroma chemicals with a very powerful smell. This study shows that BA treatments can have a significant effect on metabolite changes in different rose tissues. This method could be applied to other floriculture plants. PMID- 30400247 TI - Isolation and Identification of Potent Antidiabetic Compounds from Antrodia cinnamomea-An Edible Taiwanese Mushroom. AB - Antrodia cinnamomea (AC), an edible Taiwanese mushroom, has been recognized as a valuable natural resource with vast biological and medicinal benefits. Recently, the hypoglycemic and anti-diabetic effects of AC were mentioned in several studies. However, no studies have investigated alpha-glucosidase inhibitors from AC fruiting bodies (ACFB) as they relate to type 2 diabetes (T2D) treatment. The purpose of this study was to gain evidence of potent alpha-glucosidase inhibitory effects, as well as isolate, identify and characterize the active compounds of ACFB. The MeOH extract of ACFB demonstrated potent alpha-glucosidase inhibitory activity, and possessed high pH stability (pH 2-11) and thermostable properties at 40-50 degrees C. Further purification led to the isolation of eight constituents from ACFB, identified as: 25S-antcin K (1), 25R-antcin K (2), dehydrosulphurenic acid (3), 25S-antcin I (4), 25S-antcin B (5), 25R-antcin B (6), dehydroeburicoic acid (7) and eburicoic acid (8). Notably, the ACFB extract and its identified compounds, except 1, 4, and 6 demonstrated a greater effect (EC50 = 0.025-0.21 mg/mL) than acarbose (EC50 = 0.278 mg/mL). As such, these active compounds were determined to be new potent mushroom alpha-glucosidase inhibitors. These active compounds were also identified on the HPLC fingerprints of ACFB. PMID- 30400248 TI - CS-FCDA: A Compressed Sensing-Based on Fault-Tolerant Data Aggregation in Sensor Networks. AB - When the nodes in the network are deployed in the target area with an appropriate density, the effective aggregation and transmission of the data gathered in the monitoring area remain to be solved. The existing Compressed Sensing (CS) based on data aggregation schemes are accomplished in a centralized manner and the Sink node achieves the task of data aggregation. However, these existing schemes may suffer from load imbalance and coverage void issues. In order to address these problems, we propose a Compressed Sensing based on Fault-tolerant Correcting Data Aggregation (CS-FCDA) scheme to accurately reconstruct the compressed data. Therefore, the network communication overhead can be greatly reduced while maintaining the quality of the reconstructed data. Meanwhile, we adopt the node clustering mechanism to optimize and balance the network load. It is shown via simulation results, compared with other data aggregation schemes, that the proposed scheme shows obvious improvement in terms of the Fault-tolerant correcting capability and the network energy efficiency of the data reconstruction. PMID- 30400249 TI - Magneto-Electric Effect on Guided Waves in Functionally Graded Piezoelectric Piezomagnetic Fan-Shaped Cylindrical Structures. AB - Functionally graded piezoelectric-piezomagnetic (FGPP) material simultaneously consists of piezomagnetic and piezoelectric phases, which are able to convert energy among mechanical, electric, and magnetic fields. The magneto-electric effect on waves in FGPP fan-shaped cylindrical structures is studied by exploiting the double Legendre orthogonal polynomial method. By means of the Heaviside function, the initial conditions are brought into wave motion equations. Dispersion properties, electric and magnetic potential, and the Poynting vector are calculated. Subsequently, the effect of the graded variation and geometric size on wave characteristics is analyzed. The FGPP fan-shaped cylindrical structures are of complex geometrical shape and material inhomogeneity, so their influences on the magneto-electric effect are the focus of discussion. Results reveal that the cut-off frequencies have a negative relationship with the cross-section area of the structure. The magneto-electric effect could be adjusted via altering the geometric size of the cross-section. These results can be utilized to design and optimize piezoelectric-piezomagnetic fan-shaped transducers. PMID- 30400251 TI - Joint Sparsity Constraint Interferometric ISAR Imaging for 3-D Geometry of Near Field Targets with Sub-Apertures. AB - This paper proposes a new interferometric near-field 3-D imaging approach based on multi-channel joint sparse reconstruction to solve the problems of conventional methods, i.e., the irrespective correlation of different channels in single-channel independent imaging which may lead to deviated positions of scattering points, and the low accuracy of imaging azimuth angle for real anisotropic targets. Firstly, two full-apertures are divided into several sub apertures by the same standard; secondly, the joint sparse metric function is constructed based on scattering characteristics of the target in multi-channel status, and the improved Orthogonal Matching Pursuit (OMP) method is used for imaging solving, so as to obtain high-precision 3-D image of each sub-aperture; thirdly, comprehensive sub-aperture processing is performed using all sub aperture 3-D images to obtain the final 3-D images; finally, validity of the proposed approach is verified by using simulation electromagnetic data and data measured in the anechoic chamber. Experimental results show that, compared with traditional interferometric ISAR imaging approaches, the algorithm proposed in this paper is able to provide a higher accuracy in scattering center reconstruction, and can effectively maintain relative phase information of channels. PMID- 30400250 TI - Influence of Preparation Methods of Chitooligosaccharides on Their Physicochemical Properties and Their Anti-Inflammatory Effects in Mice and in RAW264.7 Macrophages. AB - The methods to obtain chitooligosaccharides are tightly related to the physicochemical properties of the end products. Knowledge of these physicochemical characteristics is crucial to describing the biological functions of chitooligosaccharides. Chitooligosaccharides were prepared either in a single step enzymatic hydrolysis using chitosanase, or in a two-step chemical-enzymatic hydrolysis. The hydrolyzed products obtained in the single-step preparation were composed mainly of 42% fully deacetylated oligomers plus 54% monoacetylated oligomers, and they attenuated the inflammation in lipopolysaccharide-induced mice and in RAW264.7 macrophages. However, chitooligosaccharides from the two step preparation were composed of 50% fully deacetylated oligomers plus 27% monoacetylated oligomers and, conversely, they promoted the inflammatory response in both in vivo and in vitro models. Similar proportions of monoacetylated and deacetylated oligomers is necessary for the mixtures of chitooligosaccharides to achieve anti-inflammatory effects, and it directly depends on the preparation method to which chitosan was submitted. PMID- 30400252 TI - A Design and Simulation of the Opportunistic Computation Offloading with Learning Based Prediction for Unmanned Aerial Vehicle (UAV) Clustering Networks. AB - Drones have recently become extremely popular, especially in military and civilian applications. Examples of drone utilization include reconnaissance, surveillance, and packet delivery. As time has passed, drones' tasks have become larger and more complex. As a result, swarms or clusters of drones are preferred, because they offer more coverage, flexibility, and reliability. However, drone systems have limited computing power and energy resources, which means that sometimes it is difficult for drones to finish their tasks on schedule. A solution to this is required so that drone clusters can complete their work faster. One possible solution is an offloading scheme between drone clusters. In this study, we propose an opportunistic computational offloading system, which allows for a drone cluster with a high intensity task to borrow computing resources opportunistically from other nearby drone clusters. We design an artificial neural network-based response time prediction module for deciding whether it is faster to finish tasks by offloading them to other drone clusters. The offloading scheme is conducted only if the predicted offloading response time is smaller than the local computing time. Through simulation results, we show that our proposed scheme can decrease the response time of drone clusters through an opportunistic offloading process. PMID- 30400253 TI - Blending In Situ Polyurethane-Urea with Different Kinds of Rubber: Performance and Compatibility Aspects. AB - Specific physical and reactive compatibilization strategies are applied to enhance the interfacial adhesion and mechanical properties of heterogeneous polymer blends. Another pertinent challenge is the need of energy-intensive blending methods to blend high-tech polymers such as the blending of a pre-made hard polyurethane (-urea) with rubbers. We developed and investigated a reactive blending method to prepare the outstanding blends based on polyurethane-urea and rubbers at a low blending temperature and without any interfacial compatibilizing agent. In this study, the polyurethane-urea (PUU) was synthesized via the methylene diphenyl diisocyanate end-capped prepolymer and m-phenylene diamine based precursor route during blending at 100 degrees C with polar (carboxylated nitrile rubber (XNBR) and chloroprene rubber (CR)) and non-polar (natural rubber (NR), styrene butadiene rubber (sSBR), and ethylene propylene butadiene rubber (EPDM)) rubbers. We found that the in situ PUU reinforces the tensile response at low strain region and the dynamic-mechanical response up to 150 degrees C in the case of all used rubbers. Scanning electron microscopy reveals a stronger rubber/PUU interface, which promotes an effective stress transfer between the blend phases. Furthermore, energy filtered transmission electron microscopy (EFTEM) based elemental carbon map identifies an interphase region along the interface between the nitrile rubber and in situ PUU phases of this exemplary blend type. PMID- 30400255 TI - Amphiphilic Fluorine-Containing Block Copolymers as Carriers for Hydrophobic PtTFPP for Dissolved Oxygen Sensing, Cell Respiration Monitoring and In Vivo Hypoxia Imaging with High Quantum Efficiency and Long Lifetime. AB - New amphiphilic star or multi-arm block copolymers with different structures were synthesized for enabling the use of hydrophobic oxygen probe of platinum (II) tetrakis (pentafluorophenyl) porphyrin (PtTFPP) for bioanalysis. The amphiphilic star polymers were prepared through the Atom Transfer Radical Polymerization (ATRP) method by using hydrophilic 4-arm polyethylene glycol (4-arm-PEG) as an initiator. Among the five block copolymers, P1 series (P1a, P1b, and P1c) and P3 possess fluorine-containing moieties to improve the oxygen sensitivity with its excellent capacity to dissolve and carry oxygen. A polymer P2 without fluorine units was also synthesized for comparison. The structure-property relationship was investigated. Under nitrogen atmosphere, high quantum efficiency of PtTFPP in fluorine-containing micelles could reach to 22% and long lifetime could reach to 76 MUs. One kind of representative PtTFPP-containing micelles was used to detect the respiration of Escherichia coli (E. coli) JM109 and macrophage cell J774A.1 by a high throughput plate reader. In vivo hypoxic imaging of tumor-bearing mice was also achieved successfully. This study demonstrated that using well-designed fluoropolymers to load PtTFPP could achieve high oxygen sensing properties, and long lifetime, showing the great capability for further in vivo sensing and imaging. PMID- 30400254 TI - Deep Multi-OMICs and Multi-Tissue Characterization in a Pre- and Postprandial State in Human Volunteers: The GEMM Family Study Research Design. AB - Cardiovascular disease (CVD) and type 2 diabetes (T2D) are increasing worldwide. This is mainly due to an unhealthy nutrition, implying that variation in CVD risk may be due to variation in the capacity to manage a nutritional load. We examined the genomic basis of postprandial metabolism. Our main purpose was to introduce the GEMM Family Study (Genetics of Metabolic Diseases in Mexico) as a multi center study carrying out an ongoing recruitment of healthy urban adults. Each participant received a mixed meal challenge and provided a 5-hours' time course series of blood, buffy coat specimens for DNA isolation, and adipose tissue (ADT)/skeletal muscle (SKM) biopsies at fasting and 3 h after the meal. A comprehensive profiling, including metabolomic signatures in blood and transcriptomic and proteomic profiling in SKM and ADT, was performed to describe tendencies for variation in postprandial response. Our data generation methods showed preliminary trends indicating that by characterizing the dynamic properties of biomarkers with metabolic activity and analyzing multi-OMICS data it could be possible, with this methodology and research design, to identify early trends for molecular biology systems and genes involved in the fasted and fed states. PMID- 30400257 TI - Sample Volume Reduction Using the Schwarzschild Objective for a Circular Dichroism Spectrophotometer and an Application to the Structural Analysis of Lysine-36 Trimethylated Histone H3 Protein. AB - With the increasing interest in scarce proteins, reducing the sample volume for circular dichroism (CD) spectroscopy has become desirable. Demagnification of the incident beam size is required to reduce the sample volume for CD spectroscopy detecting transmitted light passed through the sample. In this study, the beam size was demagnified using a focal mirror, and small-capacity sample cells were developed in an attempt to reduce the sample volume. The original beam size was 6 * 6 mm2; we successfully converged it to a size of 25 * 25 MUm2 using the Schwarzschild objective (SO). The new sample cell and SO allowed the required sample volume to be reduced to 1/10 (15 -> 1.5 MUL), when using a 15 MUm path length cell. By adopting a smaller sample cell, further sample reduction could be achieved. By using the SO system, the secondary structural contents of the lysine 36 trimethylated histone H3 protein were analyzed. The trimethylation induced the increment of helix structures and decrement of unordered structures. These structural alterations may play a role in regulating cellular function(s), such as DNA damage repair processes. PMID- 30400256 TI - Whole-Genome and Expression Analyses of Bamboo Aquaporin Genes Reveal Their Functions Involved in Maintaining Diurnal Water Balance in Bamboo Shoots. AB - Water supply is essential for maintaining normal physiological function during the rapid growth of bamboo. Aquaporins (AQPs) play crucial roles in water transport for plant growth and development. Although 26 PeAQPs in bamboo have been reported, the aquaporin-led mechanism of maintaining diurnal water balance in bamboo shoots remains unclear. In this study, a total of 63 PeAQPs were identified, based on the updated genome of moso bamboo (Phyllostachys edulis), including 22 PePIPs, 20 PeTIPs, 17 PeNIPs, and 4 PeSIPs. All of the PeAQPs were differently expressed in 26 different tissues of moso bamboo, based on RNA sequencing (RNA-seq) data. The root pressure in shoots showed circadian rhythm changes, with positive values at night and negative values in the daytime. The quantitative real-time PCR (qRT-PCR) result showed that 25 PeAQPs were detected in the base part of the shoots, and most of them demonstrated diurnal rhythm changes. The expression levels of some PeAQPs were significantly correlated with the root pressure. Of the 86 sugar transport genes, 33 had positive co-expression relationships with 27 PeAQPs. Two root pressure-correlated PeAQPs, PeTIP4;1 and PeTIP4;2, were confirmed to be highly expressed in the parenchyma and epidermal cells of bamboo culm, and in the epidermis, pith, and primary xylem of bamboo roots by in situ hybridization. The authors' findings provide new insights and a possible aquaporin-led mechanism for bamboo fast growth. PMID- 30400259 TI - Mechanical Stretching Simulates Cardiac Physiology and Pathology through Mechanosensor Piezo1. AB - The dynamics of a living body enables organs to experience mechanical stimulation at cellular level. The human cardiomyocytes cell line provides a source for simulating heart dynamics; however, a limited understanding of the mechanical stimulation effect on them has restricted potential applications. Here, we investigated the effect of mechanical stimulation on the cardiac function associated protein expressions in human cardiomyocytes. Human cardiomyocyte cell line AC16 was subjected to different stresses: 5% mild and 25% aggressive, at 1 Hz for 24 h. The stretched cardiomyocytes showed down-regulated Piezo1, phosphorylated-Ak transforming serine473 (P-AKTS473), and phosphorylated-glycogen synthase kinase-3 beta serine9 P-GSK3betaS9 compared to no stretch. In addition, the stretched cardiomyocytes showed increased low-density lipoprotein receptor related protein 6 (LRP6), and phosphorylated-c-Jun N-terminal kinase threonine183/tyrosine185 (P-JNKT183/Y185). When Piezo inhibitor was added to the cells, the LRP6, and P-JNKT183/Y185 were further increased under 25%, but not 5%, suggesting that higher mechanical stress further activated the wingless integrated-(Wnt)-related signaling pathway when Piezo1 was inhibited. Supporting this idea, when Piezo1 was inhibited, the expression of phosphorylated endothelial nitric oxide synthase serine1177 (P-eNOSS1177) and release of calcium ions were reduced under 25% compared to 5%. These studies demonstrate that cyclic mechanical stimulation affects cardiac function-associated protein expressions, and Piezo1 plays a role in the protein regulation. PMID- 30400260 TI - Electrospun Produced 3D Matrices for Covering of Vascular Stents: Paclitaxel Release Depending on Fiber Structure and Composition of the External Environment. AB - Paclitaxel is a natural, highly lipophilic anti proliferative drug widely used in medicine. We have studied the release of tritium-labeled paclitaxel (3H-PTX) from matrices destined for the coating of vascular stents and produced by the electrospinning method from the solutions of polycaprolactone (PCL) with paclitaxel (PTX) in hexafluoisopropanol (HFIP) and/or solutions of PCL with PTX and human serum albumin (HSA) in HFIP or HIFP-dimethyl sulphoxide (DMSO) blend. The release of PTX has been shown to depend on the composition of electrospinning solution, as well as the surrounding medium, particularly the concentration of free PTX and PTX-binding biomolecules present in human serum. It was shown that 3D matrices can completely release PTX without weight loss. Two-phase PTX release from optimized 3D matrices was obtained: ~27% of PTX was released in the first day, another 8% were released over the next 26 days. Wherein ~2.8%, ~2.3%, and ~0.25% of PTX was released on day 3, 9, and 27, respectively. Considering PTX toxicity, the rate of its diffusion through the arterial wall, and the data obtained the minimum cytostatic dose of the drug in the arterial wall will be maintained for at least three months. PMID- 30400258 TI - Dysregulation of the Immune System in HIV/HCV-Coinfected Patients According to Liver Stiffness Status. AB - BACKGROUND: Advanced cirrhosis is related to alterations in immunity. We aimed to evaluate the levels of peripheral CD4+ T cells (Tregs) and plasma cytokine in patients coinfected with human immunodeficiency virus and hepatitis C virus (HIV/HCV) according to liver fibrosis stages [evaluated as liver stiffness measure (LSM)] and their linear relationship. METHODS: We performed a cross sectional study on 238 HIV/HCV-coinfected patients (119 had <12.5 kPa, 73 had 12.5-25 kPa, and 46 had >25 kPa). Peripheral T-cell subsets were phenotyped by flow cytometry, plasma biomarkers were assessed by multiplex immunoassays, and LSM was assessed by transient elastography. Results: We found HIV/HCV-coinfected patients had higher values of CD4+ Tregs (p < 0.001), memory Tregs (p <= 0.001), and plasma cytokine levels [IFN-gamma (p <= 0.05) and IL-10 (p <= 0.01)] compared with healthy donors and HIV-monoinfected patients. In the multivariate analysis, higher LSM values were associated with reduced levels of IL-10 (adjusted arithmetic mean ratio (aAMR) = 0.83; p = 0.019), IL-2 (aAMR = 0.78; p = 0.017), TNF-alpha (aAMR = 0.67; p < 0.001), and IL-17A (aAMR = 0.75; p = 0.006). When we focus on HIV/HCV-coinfected patients analyzed by LSM strata, patients with >=25 kPa had lower values of IL-2 (aAMR = 0.66; p = 0.021), TNF-alpha (aAMR = 0.565; p = 0.003), and IL-17A (aAMR = 0.58; p = 0.003) than patients with <12.5 kPa. CONCLUSION: HIV/HCV-coinfected patients showed an immunosuppressive profile compared to healthy controls and HIV-monoinfected patients. Additionally, HIV/HCV coinfected patients with advanced cirrhosis (LSM >= 25 kPa) had the lowest plasma values of cytokines related to Th1 (IL-2 and TNF-alpha) and Th17 (IL-17A) response. PMID- 30400261 TI - Electroanalytical Determination of Cysteine Using the Electrodes Based on Ternary Silver-Copper Sulfides. AB - The amperometric determination of cysteine, using an electrode based on ternary silver-copper sulfide, is presented. Electrochemical characterizations (using cyclic voltammetry) of three electrode materials revealed that the electrode based on the material that consists of jalpaite (Ag3CuS2), doped with a small amount of metallic silver, has the best electrocatalytical performance for cysteine oxidation. For the amperometric determination, 0.142 V at pH 5 and 0.04 V at pH 7 vs. Ag/AgCl, related to the electrocatalytical oxidation of thiol group, were chosen. Electrochemical impedance spectroscopy together with Fourier transform infrared spectroscopy (FTIR) revealed that oxidation takes place on the electrode surface with fouling effect, which does not affect a wide linear working range between 1 MUM and 100 MUM. Sensitivities, at pH 5 and pH 7, are calculated to be 0.11 MUA MUM-1 and 0.10 MUA MUM-1, respectively. The detection limits were determined to be 0.036 MUM and 0.024 MUM for pH 5 and pH 7, respectively. In the presence of uric acid, folic acid, ascorbic acid, and glucose no interference was noticed. This electrode showed remarkable stability and excellent reproducibility. The electrode was exploited for the determination of cysteine in a dietary supplement with the excellent recoveries. PMID- 30400262 TI - Impact of Circulating Triglycerides Concentration on Atherosclerotic Disease Status in Middle-Aged Saudi Arabian Dwellers. AB - A number of food micronutrients are reported to influence markers of cardio metabolic health. There is an expectation that there may be an optimal endocrine profile, with triglycerides as a key factor, which may help minimise atherosclerotic disease and associated risk factors. This study involved 84 participants aged (mean +/- SD) 48.2 +/- 8.3 years from both sexes segregated into n = 30 controls, n = 25 at-risk, and n = 29 diagnosed with atherosclerosis, including 20 participants using statins. Atherosclerosis status and risk factors were assessed using a combination of clinical records, C-reactive protein (CRP), blood glucose (FBG), lipids profiles, vascular structural and functional characteristics (including carotid-radial pulse wave velocity (CR-PWV), central systolic blood pressure (C-SBP), peripheral systolic blood pressure (P-SBP), peripheral diastolic blood pressure (P-DBP), carotid intima-media thickness (IMT), and carotid artery inter-adventitial diameter (IAD)). There was a significant difference in triglycerides (TG) levels between the clinical groups (p < 0.05) and between the users and non-users of statin (p < 0.001). Significant associations were distinguished between TG and CRP, FBG, high-density lipoprotein (HDL), C-SBP, P-SBP, P-DBP, CR-PWV, heart rate (HR), and body weight in the pooled sample (p < 0.05). In non-users of statin, TG was associated with C-SBP, P SBP, P-DBP, and HR. In sub-clinical groups, TG was also associated with most of the blood markers. After controlling for statin use, composite z-score analysis revealed 48%, 2%, and 0% differences in in vivo vascular phenotype between high and low TG subgroups in controls, at-risk, and diagnosed atherosclerosis groups, respectively. Thus, TG levels seem to be good indicators for incidence and risk factors of atherosclerosis. PMID- 30400263 TI - Automated Knowledge-Based Intensity-Modulated Proton Planning: An International Multicenter Benchmarking Study. AB - Background: Radiotherapy treatment planning is increasingly automated and knowledge-based planning has been shown to match and sometimes improve upon manual clinical plans, with increased consistency and efficiency. In this study, we benchmarked a novel prototype knowledge-based intensity-modulated proton therapy (IMPT) planning solution, against three international proton centers. Methods: A model library was constructed, comprising 50 head and neck cancer (HNC) manual IMPT plans from a single center. Three external-centers each provided seven manual benchmark IMPT plans. A knowledge-based plan (KBP) using a standard beam arrangement for each patient was compared with the benchmark plan on the basis of planning target volume (PTV) coverage and homogeneity and mean organ-at-risk (OAR) dose. Results: PTV coverage and homogeneity of KBPs and benchmark plans were comparable. KBP mean OAR dose was lower in 32/54, 45/48 and 38/53 OARs from center-A, -B and -C, with 23/32, 38/45 and 23/38 being >2 Gy improvements, respectively. In isolated cases the standard beam arrangement or an OAR not being included in the model or being contoured differently, led to higher individual KBP OAR doses. Generating a KBP typically required <10 min. Conclusions: A knowledge-based IMPT planning solution using a single-center model could efficiently generate plans of comparable quality to manual HNC IMPT plans from centers with differing planning aims. Occasional higher KBP OAR doses highlight the need for beam angle optimization and manual review of KBPs. The solution furthermore demonstrated the potential for robust optimization. PMID- 30400264 TI - An Optical Fiber Sensor Based on La2O2S:Eu Scintillator for Detecting Ultraviolet Radiation in Real-Time. AB - A novel ultraviolet (UV) optical fiber sensor (UVOFS) based on the scintillating material La2O2S:Eu has been designed, tested, and its performance compared with other scintillating materials and other conventional UV detectors. The UVOFS is based on PMMA (polymethyl methacrylate) optical fiber which includes a scintillating material. Scintillating materials provide a unique opportunity to measure UV light intensity even in the presence of strong electromagnetic interference. Five scintillating materials were compared in order to select the most appropriate one for the UVOFS. The characteristics of the sensor are reported, including a highly linear response to radiation intensity, reproducibility, temperature response, and response time (to pulsed light) based on emission from a UV source (UV fluorescence tube) centered on a wavelength of 308 nm. A direct comparison with the commercially available semiconductor-based UV sensor proves the UVOFS of this investigation shows superior performance in terms of accuracy, long-term reliability, response time and linearity. PMID- 30400265 TI - PEDOT Coated Thick Film Electrodes for In Situ Detection of Cell Adhesion in Cell Cultures. AB - Low temperature cofired ceramics (LTCC) provide a technology for the 3 dimensional integration of sensor arrays into bioreactors covering dimensions of several hundred micrometers. Since optical control in such assemblies is not possible, the in situ detection of cell adhesion on impedance electrodes with high spatial resolution would deliver crucial information. A current limitation is the increasing impedance of microelectrodes with decreasing diameter. This study evaluates the suitability of thick film gold electrodes, pristine and coated with electropolymerized poly(3,4-ethylenedioxythiophene) (PEDOT), for the detection of cell adhesion on the electrode surface. The impedance as criterion for cell attachment is measured with a recording system for electroactive cells with the aim of improving usability. Two cell cultures with different adhesion characteristic are used for adhesion assessment on planar test chips. The impedance increase measured on individual PEDOT coated electrodes due to tight contact of cells reaches a factor of 6.8 in cultures of well-adherent HepG2 cells. Less adhered NG108-15 cells produce a maximum impedance increase by a factor of 2.6. Since the electrode impedance is significantly reduced by PEDOT coating, a reduction of the electrode diameter to values below 100 um and spatially resolved detection is possible. The results encourage further studies using PEDOT coated thick film electrodes as bio-electronic-interfaces. We presume that such miniaturized electrodes are suitable for 3-dimensional recordings in electroactive cell cultures, providing information of local cell adhesion at the same time. PMID- 30400266 TI - Endovascular Interventions Permit Isolation of Endothelial Colony-Forming Cells from Peripheral Blood. AB - BACKGROUND: Isolation of endothelial colony-forming cells (ECFCs) is difficult due to the extremely low concentration of their precursors in the peripheral blood (PB). We hypothesized that mechanical injury to the arterial wall during percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) may increase the release of circulating ECFC precursors and induce their growth in vitro. METHODS: PB samples from patients with coronary artery disease were collected before, immediately after, and 24 h after the surgery in the CABG group. In the PCI group, PB was isolated before, immediately after the insertion of the catheter, immediately after balloon angioplasty, and 24 h after the PCI. A mononuclear fraction of PB was isolated and differentiated into ECFCs with the following immunophenotyping and evaluation of angiogenic properties. RESULTS: The obtained cultures corresponded to the phenotype and tube forming potential consistent with ECFCs. The isolation of ECFCs in the PCI group was successful in 75% of cases (six out of eight patients) after catheter insertion and in 87.5% (seven out of eight patients) after the balloon inflation and stent deployment. These cultures had high/medium proliferative activity in contrast to those obtained before or 24 h after the intervention. CONCLUSIONS: Mechanical injury during PCI increases the release of ECFC precursors to the PB and, hence, the efficacy of ECFC isolation. PMID- 30400267 TI - Dietary Nitrate from Beetroot Juice for Hypertension: A Systematic Review. AB - According to current therapeutic approaches, a nitrate-dietary supplementation with beetroot juice (BRJ) is postulated as a nutritional strategy that might help to control arterial blood pressure in healthy subjects, pre-hypertensive population, and even patients diagnosed and treated with drugs. In this sense, a systematic review of random clinical trials (RCTs) published from 2008 to 2018 from PubMed/MEDLINE, ScienceDirect, and manual searches was conducted to identify studies examining the relationship between BRJ and blood pressure. The specific inclusion criteria were: (1) RCTs; (2) trials that assessed only the BRJ intake with control group; and (3) trials that reported the effects of this intervention on blood pressure. The search identified 11 studies that met the inclusion criteria. This review was able to demonstrate that BRJ supplementation is a cost effective strategy that might reduce blood pressure in different populations, probably through the nitrate/nitrite/nitric oxide (NO3-/NO2-/NO) pathway and secondary metabolites found in Beta vulgaris. This easily found and cheap dietary intervention could significantly decrease the risk of suffering cardiovascular events and, in doing so, would help to diminish the mortality rate associated to this pathology. Hence, BRJ supplementation should be promoted as a key component of a healthy lifestyle to control blood pressure in healthy and hypertensive individuals. However, several factors related to BRJ intake (e.g., gender, secondary metabolites present in B. vulgaris, etc.) should be studied more deeply. PMID- 30400268 TI - Human Breast Milk Bacteriome in Health and Disease. AB - It is well-known that, beyond nutritional components, human breast milk (HBM) contains a wide variety of non-nutritive bio-factors perfectly suited for the growing infant. In the pre-2000 era, HBM was considered sterile and devoid of micro-organisms. Though HBM was not included as part of the human microbiome project launched in 2007, great strides have been made in studying the bacterial diversity of HBM in both a healthy state and diseased state, and in understanding their role in infant health. HBM provides a vast array of beneficial micro organisms that play a key role in colonizing the infant's mucosal system, including that of the gut. They also have a role in priming the infant's immune system and supporting its maturation. In this review, we provide an in-depth and updated insight into the immunomodulatory, metabolic, and anti-infective role of HBM bacteriome (bacterial community) and its effect on infant health. We also provide key information from the literature by exploring the possible origin of microbial communities in HBM, the bacterial diversity in this niche and the determinants influencing the HBM bacteriome. Lastly, we investigate the role of the HBM bacteriome in maternal infectious disease (human immunodeficiency virus (HIV) and mastitis)), and cancer. Key gaps in HBM bacterial research are also identified. PMID- 30400269 TI - Conditions Associated with Marine Lipid-Induced Milk Fat Depression in Sheep Cause Shifts in the In Vitro Ruminal Metabolism of 1-13C Oleic Acid. AB - Shifts in ruminal oleic acid (OA) metabolism have received little research attention but recent studies have suggested their association with marine lipid induced milk fat depression (MFD) in ewes and cows. Measurement of specific products of OA within the complex mixture of digesta lipids is however challenging. Therefore, this in vitro trial combined the isotopic labelling technique with the use of rumen inoculum from cannulated sheep fed a diet supplemented or not with 2% of fish oil (which has been demonstrated to cause MFD in dairy ruminants) to characterize the metabolism of OA in response to ruminal alterations associated with MFD. The products of 13C-OA after 24 h of incubation were analysed by gas chromatography-combustion isotope ratio mass spectrometry (GC-C-IRMS). Numerous 13C-labeled 18:1 intermediates and oxygenated FA were detected and no elongation or desaturation of 13OA occurred. Diet supplementation with fish oil (i.e., MFD conditions) resulted in no unique metabolites of 13OA but in relevant changes in the relative contribution of specific metabolic pathways. The inhibition of 18:0 saturation caused by this treatment appeared largely attributable to increased oxygenated FA proportion, in particular the candidate milk fat inhibitor 10-oxo-18:0, and warrants further research on the association between MFD and oxygenated FA. Changes in the concentration of 13C labeled trans 18:1 intermediates but not in cis 18:1, were also observed. PMID- 30400271 TI - Essential Oils from Humulus Lupulus scCO2 Extract by Hydrodistillation and Microwave-Assisted Hydrodistillation. AB - Two different extraction methods were used for a comparative study of essential oils obtained from the Humulus lupulus scCO2 (sc-supercritical) extract: microwave-assisted hydrodistillation (MAHD) and conventional hydrodistillation (HD). As a result, the best conditions for the maximum essential oil production were determined for the MAHD method at 335 W microwave power for 30 min at water to raw material ratio of 8:3. The obtained essential oils were enriched in beta myrcene in the amount of 74.13%-89.32% (wt%). Moreover, the first application for determination of the above-mentioned volatile compounds by supercritical fluid chromatography (SFC) with photo-diode array detection (PDA) is presented, which in comparison with gas chromatography coupled with mass spectrometry (GC-MS/MS) resulted in similar values for beta-myrcene and alpha-humulene in obtained samples within less than 1 min. PMID- 30400270 TI - Targeting the DNA Repair Endonuclease ERCC1-XPF with Green Tea Polyphenol Epigallocatechin-3-Gallate (EGCG) and Its Prodrug to Enhance Cisplatin Efficacy in Human Cancer Cells. AB - The 5'-3' structure-specific endonuclease ERCC1/XPF (Excision Repair Cross Complementation Group 1/Xeroderma Pigmentosum group F) plays critical roles in the repair of cisplatin-induced DNA damage. As such, it has been identified as a potential pharmacological target for enhancing clinical response to platinum based chemotherapy. The goal of this study was to follow up on our previous identification of the compound NSC143099 as a potent inhibitor of ERCC1/XPF activity by performing an in silico screen to identify structural analogues that could inhibit ERCC1/XPF activity in vitro and in vivo. Using a fluorescence-based DNA-endonuclease incision assay, we identified the green tea polyphenol (-) epigallocatechin-3-gallate (EGCG) as a potent inhibitor of ERCC1/XPF activity with an IC50 (half maximal inhibitory concentration) in the nanomolar range in biochemical assays. Using DNA repair assays and clonogenic survival assays, we show that EGCG can inhibit DNA repair and enhance cisplatin sensitivity in human cancer cells. Finally, we show that a prodrug of EGCG, Pro-EGCG (EGCG octaacetate), can enhance response to platinum-based chemotherapy in vivo. Together these data support a novel target of EGCG in cancer cells, namely ERCC1/XPF. Our studies also corroborate previous observations that EGCG enhances sensitivity to cisplatin in multiple cancer types. Thus, EGCG or its prodrug makes an ideal candidate for further pharmacological development with the goal of enhancing cisplatin response in human tumors. PMID- 30400273 TI - Circular RNAs in Muscle Function and Disease. AB - Circular RNAs (circRNAs) are a class of RNA produced during pre-mRNA splicing that are emerging as new members of the gene regulatory network. In addition to being spliced in a linear fashion, exons of pre-mRNAs can be circularized by use of the 3' acceptor splice site of upstream exons, leading to the formation of circular RNA species. In this way, genetic information can be re-organized, increasing gene expression potential. Expression of circRNAs is developmentally regulated, tissue and cell-type specific, and shared across eukaryotes. The importance of circRNAs in gene regulation is now beginning to be recognized and some putative functions have been assigned to them, such as the sequestration of microRNAs or proteins, the modulation of transcription, the interference with splicing, and translation of small proteins. In accordance with an important role in normal cell biology, circRNA deregulation has been reported to be associated with diseases. Recent evidence demonstrated that circRNAs are highly expressed in striated muscle tissue, both skeletal and cardiac, that is also one of the body tissue showing the highest levels of alternative splicing. Moreover, initial studies revealed altered circRNA expression in diseases involving striated muscle, suggesting important functions of these molecules in the pathogenetic mechanisms of both heart and skeletal muscle diseases. The recent findings in this field will be described and discussed. PMID- 30400272 TI - Blue Light Induces Down-Regulation of Aquaporin 1, 3, and 9 in Human Keratinocytes. AB - The development in digital screen technology has exponentially increased in the last decades, and many of today's electronic devices use light-emitting diode (LED) technology producing very strong blue light (BL) waves. Long-term exposure at LED-BL seems to have an implication in the dehydration of the epidermis, in the alterations of shape and number of the keratinocytes, and in the aging of the skin. Aquaporins (AQPs) are water membrane channels that permeate both water and glycerol and play an important role in the hydration of epidermis, as well as in proliferation and differentiation of keratinocytes. Thus, we have hypothesized that AQPs could be involved in the aging of the skin exposed to LED-BL. Therefore, we have examined the expression of AQPs in human keratinocytes exposed to LED-BL at dose of 45 J/cm2, used as an in vitro model to produce the general features of photo aging of the skin. The aim was to verify if LED-BL induces changes of the basal levels of AQPs. The keratinocytes exposure to LED-BL produced an increase of reactive oxygen species (ROS), an activation of 8-hydroxy 2'-deoxyguanosine (8-OHdG), an alteration of proliferating cell nuclear antigen (PCNA), and a down-regulation of AQP1, 3 and 9. These findings are preliminary evidences that may be used as starting points for further investigations about the mechanistic involvement of AQP1, 3, and 9 in LED-BL-induced skin aging. PMID- 30400274 TI - Potential Prebiotic Properties of Nuts and Edible Seeds and Their Relationship to Obesity. AB - Obesity is a global epidemic chronic condition and is progressing at a rapid rate. This review focuses on the potential prebiotic properties of nuts and edible seeds and the plausible mechanisms that their consumption may help the prevention and the management of overweight and obesity. The literature review was performed by searching papers about the topic in MEDLINE and SCOPUS databases. The healthy attributes of nuts and edible seeds, especially dietary fibers and polyphenols contents, indicate that their mechanism of weight gain prevention may occur through interaction with the gut microbiota, by means of prebiotic effects. Among the etiological factors associated with obesity, the gut microbiota seems to play a significant role. Dysbiosis causes an imbalance in energy homeostasis that contributes to obesity. Three mechanisms are proposed in this review to explain the potential role of nut and edible seed consumption on intestinal homeostasis and body weight control: maintenance of the enteric barrier integrity, improvement of anti-inflammatory status and enhancement of butyrate synthesis. Further high-quality clinical trials should explore the interaction between oilseed consumption, microbiota, and body adiposity control, particularly investigating the microbiota metabolites and their relation to the prevention and management of obesity. PMID- 30400275 TI - The Dietary Total-Fat Content Affects the In Vivo Circulating C15:0 and C17:0 Fatty Acid Levels Independently. AB - Pentadecanoic acid (C15:0) and heptadecanoic acid (C17:0) have been described as dietary biomarkers of dairy-fat consumption, with varying degrees of reliability between studies. It remains unclear how the total amount of dietary fat, representing one of the main confounding factors in these biomarker investigations, affects C15:0 and C17:0 circulating concentrations independent of their relative intake. Additionally, it is not clear how changes in the dietary total-fat affects other fatty acids in circulation. Through two dietary studies with different total-fat levels but maintaining identical fatty acid compositions, we were able to see how the dietary total-fat affects the fatty acids in circulation. We saw that there was a statistically significant, proportionate, and robust decrease in the endogenous C15:0 levels with an increase in dietary total-fat. However, there was no significant change in the circulating C17:0 concentrations as the total-fat increased. To conclude, the dietary total-fat content and fat-type have a very complex influence on the relative compositions of circulating fatty acids, which are independent of the actual dietary fatty acid composition. Knowing how to manipulate circulating C15:0 and C17:0 concentrations is far-reaching in nutritional/pathological research as they highlight a dietary route to attenuate the development of metabolic disease (both by reducing risk and improving prognosis). PMID- 30400276 TI - Combination Therapy with Oseltamivir and Favipiravir Delays Mortality but Does Not Prevent Oseltamivir Resistance in Immunodeficient Mice Infected with Pandemic A(H1N1) Influenza Virus. AB - Immunosuppressed individuals can shed influenza virus for prolonged periods of time, leading to the frequent emergence of antiviral resistance. We evaluated the benefits of oseltamivir and favipiravir combination therapy compared to single antiviral agents and monitored the emergence of drug-resistant variants in a pharmacologically immunosuppressed mouse model infected with the A(H1N1) pandemic influenza virus. C57BL/6 mice were immunosuppressed with cyclophosphamide and infected with a lethal dose of pandemic influenza A(H1N1) virus. Forty-eight hours post-infection, mice were treated with oseltamivir (20 mg/kg), favipiravir (20 or 50 mg/kg) or both agents BID for 5 or 10 days. Body weight losses, survival rates, lung viral titers, cytokine levels and emergence of resistant viruses were evaluated. Treatment of immunosuppressed mice with high (50 mg/kg) but not low (20 mg/kg) doses of favipiravir in combination with oseltamivir (20 mg/kg) significantly delayed mortality and reduced lung viral titers compared to treatment with a single drug regimen with oseltamivir but did not prevent the emergence of oseltamivir-resistant H275Y neuraminidase variants. Combination therapy with oseltamivir and favipiravir should be considered for evaluation in clinical trials. PMID- 30400278 TI - Iron (II) Citrate Complex as a Food Supplement: Synthesis, Characterization and Complex Stability. AB - Iron deficiency represents a widespread problem for a large part of the population, especially for women, and has received increasing attention in food/supplement research. The contraindications of the iron supplements commercially available (e.g., imbalances in the levels of other essential nutrients, low bioavailability, etc.) led us to search for a possible alternative. In the present work, a rapid and easy method to synthetize a solid iron (II) citrate complex from iron filings and citric acid was developed to serve, eventually, as a food supplement or additive. In order to state its atomic composition and purity, an assortment of analytical techniques was employed (e.g., combustion analysis, thermogravimetry, X-ray diffractometry, UV/Vis spectrophotometry, etc.). Results demonstrate that the synthesized crystalline solid corresponds to the formula FeC6H6O7?H2O and, by consequence, contains exclusively iron (II), which is an advantage with respect to existing commercial products, because iron (II) is better absorbed than iron (III) (high bioavailability of iron). PMID- 30400279 TI - Candida Interactions with the Oral Bacterial Microbiota. AB - The human oral cavity is normally colonized by a wide range of microorganisms, including bacteria, fungi, Archaea, viruses, and protozoa. Within the different oral microenvironments these organisms are often found as part of highly organized microbial communities termed biofilms, which display consortial behavior. Formation and maintenance of these biofilms are highly dependent on the direct interactions between the different members of the microbiota, as well as on the released factors that influence the surrounding microbial populations. These complex biofilm dynamics influence oral health and disease. In the latest years there has been an increased recognition of the important role that interkingdom interactions, in particular those between fungi and bacteria, play within the oral cavity. Candida spp., and in particular C. albicans, are among the most important fungi colonizing the oral cavity of humans and have been found to participate in these complex microbial oral biofilms. C. albicans has been reported to interact with individual members of the oral bacterial microbiota, leading to either synergistic or antagonistic relationships. In this review we describe some of the better characterized interactions between Candida spp. and oral bacteria. PMID- 30400277 TI - The Roles of Endo-Lysosomes in Unconventional Protein Secretion. AB - Protein secretion in general depends on signal sequence (also named leader sequence), a hydrophobic segment located at or close to the NH2-terminus of a secretory or membrane protein. This sequence guides the entry of nascent polypeptides into the lumen or membranes of the endoplasmic reticulum (ER) for folding, assembly, and export. However, evidence accumulated in recent years has suggested the existence of a collection of unconventional protein secretion (UPS) mechanisms that are independent of the canonical vesicular trafficking route between the ER and the plasma membrane (PM). These UPS mechanisms export soluble proteins bearing no signal sequence. The list of UPS cargos is rapidly expanding, along with the implicated biological functions, but molecular mechanisms accountable for the secretion of leaderless proteins are still poorly defined. This review summarizes our current understanding of UPS mechanisms with an emphasis on the emerging role of endo-lysosomes in this process. PMID- 30400281 TI - Endogenous Anti-Inflammatory Very-Long-Chain Dicarboxylic Acids: Potential Chemopreventive Lipids. AB - In a paradigm shift, cancer research efforts are being dedicated to the discovery of chemopreventive agents. The goal of this approach is to delay or prevent the progression of augmented cell division to established cancer. Research has focused on dietary supplements, drugs, and endogenous lipids that possess anti inflammatory properties. We undertook a lipidomics analysis of potential endogenous anti-inflammatory/anti-proliferative lipids in human plasma. We performed high-resolution mass spectrometric lipidomics analyses of plasma samples from controls and patients with colorectal, kidney, pancreatic, glioblastoma, and breast cancers. We present evidence that endogenous very-long chain dicarboxylic acids (VLCDCA) are anti-inflammatory lipids that possess chemopreventative properties. In a family of VLCDCAs, we characterized VLCDCA 28:4, which is decreased in the plasma of patients with colorectal, kidney, and pancreatic cancers. The structure of this biomarker was validated by derivatization strategies, synthesis of the analytical standard, and tandem mass spectrometry. Our data suggest that VLCDCA 28:4 may be a useful blood biomarker for a number of cancers and that resupplying this lipid, via a prodrug for example, may offer a new anti-inflammatory therapeutic strategy for delaying or preventing the progression of cancer and other inflammatory diseases. PMID- 30400280 TI - Environmental Effects on the Electrical Characteristics of Back-Gated WSe2 Field Effect Transistors. AB - We study the effect of polymer coating, pressure, temperature, and light on the electrical characteristics of monolayer WSe 2 back-gated transistors with Ni / Au contacts. Our investigation shows that the removal of a layer of poly(methyl methacrylate) (PMMA) or a decrease of the pressure change the device conductivity from p- to n-type. From the temperature behavior of the transistor transfer characteristics, a gate-tunable Schottky barrier at the contacts is demonstrated and a barrier height of ~ 70 meV in the flat-band condition is measured. We also report and discuss a temperature-driven change in the mobility and the subthreshold swing that is used to estimate the trap density at the WSe 2 / SiO 2 interface. Finally, from studying the spectral photoresponse of the WSe 2 , it is proven that the device can be used as a photodetector with a responsivity of ~ 0.5 AW - 1 at 700 nm and 0.37 mW / cm 2 optical power. PMID- 30400282 TI - Integrable Near-Infrared Photodetectors Based on Hybrid Erbium/Silicon Junctions. AB - This paper presents the design, fabrication, and characterization of Schottky erbium/silicon photodetectors working at 1.55 um. These erbium/silicon junctions are carefully characterized using both electric and optical measurements at room temperature. A Schottky barrier PhiB of ~673 meV is extrapolated; the photodetectors show external responsivity of 0.55 mA/W at room temperature under an applied reverse bias of 8 V. In addition, the device performance is discussed in terms of normalized noise and noise-equivalent power. The proposed devices will pave the way towards the development of Er-based photodetectors and light sources to be monolithically integrated in the same silicon substrate, and both operating at 1.55 um. PMID- 30400283 TI - Synthesis of Acridines through Alkyne Addition to Diarylamines. AB - A new synthesis of substituted acridines is achieved by palladium-catalyzed addition of terminal acetylenes between the aryl rings of bis(2 bromophenyl)amine. By including a diamine base and elevating the temperature, the reaction pathway favors the formation of acridine over a double Sonogashira reaction to form bis(tolan)amine. This method is demonstrated with several aryl alkynes and alkyl-alkynes. PMID- 30400284 TI - Effects of the Number of Seeds per Berry on Fruit Growth Characteristics, Especially on the Duration of Stage II in Blueberry. AB - In present research, differences in the number of seeds per berry (NSB), berry fresh weight (BW), days to ripening from flowering (DRF), and the duration of a slow growth phase (DS II) among pollen sources were investigated in highbush blueberry (Vaccinium corymbosum). NSB, as well as BW and DRF, were significantly different among the pollen sources. Analysis of covariance (ANCOVA) with NSB as the covariate showed significant interaction between the NSB and pollen sources on BW and DRF when self-pollination was included. However, ANCOVA without self pollination showed no significant effect of the pollen source on BW and DRF. On the other hand, DS II was negatively correlated with NSB, and no significant interaction between NSB and pollen sources was found, even though self pollination was included. Although the relationship between NSB and DS II appeared not to be statistically influenced by the different pollen sources, there seemed to be some difference between self- and cross-pollination. DS II shortened as the NSB increased, which may have led to a decrease in DRF. PMID- 30400286 TI - Corrosion of the Welded Aluminium Alloy in 0.5 M NaCl Solution. Part 2: Coating Protection. AB - The high electrochemical activity of the aircraft 1579 aluminium alloy with a welded joint and the necessity of the coating formation to protect this material against corrosion as well as to increase the stability of the weld interface in the corrosive medium has been previously established. In this work, two suggested methods of protective coating formation based on plasma electrolytic oxidation (PEO) in tartrate-fluoride electrolyte significantly increased the protective properties of the welded joint area of the 1579 Al alloy. The electrochemical properties of the formed surface layers have been investigated using SVET (scanning vibrating electrode technique) and SIET (scanning ion-selective electrode technique), EIS (electrochemical impedance spectroscopy), OCP (open circuit potential), and PDP (potentiodynamic polarization) in 0.5 M NaCl. The less expressed character of the local electrochemical processes on the welded 1579 Al alloy with the composite coating in comparison with the base PEO-layer has been established. Polymer-containing coatings obtained using superdispersed polytetrafluoroethylene (SPTFE) treatment are characterized by the best possible protective properties and prevent the material from corrosion destruction. Single SPTFE treatment enables one to increase PEO-layer protection by 5.5 times. The results of this study indicate that SVET and SIET are promising to characterize and to compare corrosion behaviour of coated and uncoated samples with a welded joint in chloride-containing media. PMID- 30400285 TI - Substitution of Fish for Red Meat or Poultry and Risk of Ischemic Stroke. AB - We investigated the risk of ischemic stroke and its subtypes when red meat or poultry was substituted with fish. A total of 57,053 participants aged 50-65 years at baseline were included in the Danish Diet, Cancer and Health study. All participants filled in a food-frequency questionnaire at recruitment. Potential ischemic stroke cases were identified by linkage to the Danish National Patient Register, and all cases were validated and subclassified. Substitutions were investigated as 150 g/week of fish for 150 g/week of red meat or of poultry using multivariable Cox proportional hazard regression models. During 13.5 years of follow-up, 1879 participants developed an ischemic stroke. Replacing red meat or poultry with fish was not associated with the rate of total ischemic stroke, but there was a statistically significant lower rate of large artery atherosclerosis when fish replaced processed (hazard ratio (HR): 0.78; 95% confidence interval (CI): 0.67; 0.90) and unprocessed (HR: 0.87; 95% CI: 0.75; 0.99) red meat. A statistically significant higher rate of cardioembolism was found when poultry was replaced by total fish (HR: 1.42; 95% CI: 1.04; 1.93). When fatty fish replaced unprocessed red meat, a statistically significant lower rate of small vessel occlusion was found (HR: 0.88; 95% CI: 0.77; 0.99). In conclusion, replacing red meat with fish was not associated with risk of total ischemic stroke but was associated with a lower risk of subtypes of ischemic stroke. PMID- 30400287 TI - Development of Inducible CD19-CAR T Cells with a Tet-On System for Controlled Activity and Enhanced Clinical Safety. AB - The tetracycline regulatory system has been widely used to control the transgene expression. With this powerful tool, it might be possible to effectively control the functional activity of chimeric antigen receptor (CAR) T cells and manage the severe side effects after infusion. In this study, we developed novel inducible CD19CAR (iCAR19) T cells by incorporating a one-vector Tet-on system into the CD19CAR construct. The iCAR19 T cells showed dox-dependent cell proliferation, cytokine production, CAR expression, and strong CD19-specific cytotoxicity. After 48 h of dox induction, the relative CAR expression of induced cells was five times greater than that of uninduced cells. Twenty-four hours after dox removal, CAR expression significantly decreased by more than 60%. In cytotoxicity assays, dox-treated cells induced significantly higher specific lysis against target cells. These results suggested that the activity of iCAR19 T cells was successfully controlled by our Tet-on system, offering an enhanced safety profile while maintaining a robust anti-tumor effect. Besides, all manufacture processes of the lentiviral vectors and the T cells were conducted according to the Good Manufacturing Practice (GMP) standards for subsequent clinical translation. PMID- 30400288 TI - Healthy Dietary Changes in Midlife Are Associated with Reduced Dementia Risk Later in Life. AB - Diet is an important modifiable lifestyle factor related to dementia risk. Yet, the role of midlife dietary changes is unclear. The goal is to investigate whether midlife healthy dietary changes are associated with late-life dementia risk. Data were collected within the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) population-based cohort study (n = 2000) (mean baseline age = 56 years). Participants returned for two late-life re-examinations (mean age = 70 and 78 years). Self-reported midlife diet was measured in a sub-sample (n = 341) (mean total follow-up = 16.8 years). Changes in specific dietary components (fats, vegetables, sugar, salt) were measured in midlife. Dementia diagnoses were ascertained with detailed examinations. Analyses adjusted for potential confounders. Total midlife healthy dietary changes (improving quality of fats, increasing vegetables, decreasing sugar and salt) were associated with a reduced risk of dementia (fully adjusted odds ratio (OR) 0.41, 95% confidence interval (CI) = 0.20-0.85). In contrast, when each factor was assessed individually, associations were not significant. This study is the first to show that beneficial midlife dietary changes are associated with a reduced dementia risk later in life. The results highlight the importance of targeting dietary patterns, where various food items may have synergistic effects. PMID- 30400289 TI - Renal Venous Pattern: A New Parameter for Predicting Prognosis in Heart Failure Outpatients. AB - AIM OF THE STUDY: In chronic heart failure (CHF) patients, renal congestion plays a key role in determining the progression of renal dysfunction and a worse prognosis. The aim of this study was to define the role of Doppler venous patterns reflecting renal congestion that predict heart failure progression. METHODS: We enrolled outpatients affected by CHF, in stable clinical conditions and in conventional therapy. All patients underwent a clinical evaluation, routine chemistry, an echocardiogram and a renal echo-Doppler. Pulsed Doppler flow recording was performed at the level of interlobular renal right veins in the tele-expiratory phase. The venous flow patterns were divided into five groups according to the fluctuations of the flow. Type A and B were characterized by a continuous flow, whereas type C was characterized by a short interruption or reversal flow during the end-diastolic or protosystolic phase. Type D and E were characterized by a wide interruption and/or reversal flow. The occurrence of death and/or of heart transplantation and/or of hospitalization due to heart failure worsening was considered an event during follow-up. RESULTS: During a median follow-up of 38 months, 126 patients experienced the considered end-point. Venous pattern C (HR 4.04; 95% CI: 2.14-7.65; p < 0.001), pattern D (HR 7.16; 95% CI: 3.69-13.9; p < 0.001) and pattern E (HR 8.94; 95% CI: 4.65-17.2; p < 0.001) were all associated with events using an univariate Cox regression analysis. Moreover, both the presence of pattern C (HR: 1.79; 95% CI: 1.09-2.97; p: 0) and of pattern D or E (HR: 1.90; 95% CI: 1.16-3.12; p: 0.011) remained significantly associated to events using a multivariate Cox regression analysis after correction for a reference model with an improvement of the overall net reclassification index (0.46; 95% CI 0.24-0.68; p < 0.001). CONCLUSIONS: Our findings demonstrate the independent and incremental role of Doppler venous patterns reflecting renal congestion in predicting HF progression among CHF patients, thus suggesting its possible utility in daily clinical practice to better characterize patients with cardio-renal syndrome. PMID- 30400290 TI - Persistent Head and Neck Cancer Following First-Line Treatment. AB - Background: Following first-line treatment of head and neck cancer (HNC), persistent disease may require second-line treatment. Methods: All patients with HNC treated between 2008 and 2016 were included. Second-line treatment modalities and survival of patients were analyzed. Results: After first-line therapy, 175/741 patients had persistent disease. Of these, 112 were considered eligible for second-line treatment. Second-line treatment resulted in 50% complete response. Median overall survival of patients receiving second-line therapy was 24 (95% CI: 19 to 29) months; otherwise survival was 10 (9 to 11; p < 0.0001) months. Patients receiving second-line surgery had a median overall survival of 45 (28 to 62) months, patients receiving second-line radiotherapy had a median overall survival of 37 (0 to 79; p = 0.17) months, and patients receiving systemic therapy had a median overall survival of 13 (10 to 16; p < 0.001) months. Patients with persistent HNC in the neck had a better median survival (45 months; 16 to 74 months; p = 0.001) than patients with persistence at other sites. Conclusion: Early treatment response evaluation allows early initiation of second-line treatment and offers selected patients with persistent disease a realistic chance to achieve complete response after all. If possible, surgery or radiotherapy are preferable. PMID- 30400291 TI - Opposing Morphogenetic Defects on Dendrites and Mossy Fibers of Dentate Granular Neurons in CRMP3-Deficient Mice. AB - Collapsin response mediator proteins (CRMPs) are highly expressed in the brain during early postnatal development and continue to be present in specific regions into adulthood, especially in areas with extensive neuronal plasticity including the hippocampus. They are found in the axons and dendrites of neurons wherein they contribute to specific signaling mechanisms involved in the regulation of axonal and dendritic development/maintenance. We previously identified CRMP3's role on the morphology of hippocampal CA1 pyramidal dendrites and hippocampus dependent functions. Our focus here was to further analyze its role in the dentate gyrus where it is highly expressed during development and in adults. On the basis of our new findings, it appears that CRMP3 has critical roles both in axonal and dendritic morphogenesis of dentate granular neurons. In CRMP3 deficient mice, the dendrites become dystrophic while the infrapyramidal bundle of the mossy fiber shows aberrant extension into the stratum oriens of CA3. This axonal misguided projection of granular neurons suggests that the mossy fiber-CA3 synaptic transmission, important for the evoked propagation of the activity of the hippocampal trisynaptic circuitry, may be altered, whereas the dystrophic dendrites may impair the dynamic interactions with the entorhinal cortex, both expected to affect hippocampal function. PMID- 30400293 TI - A Numerical Method to Model Non-linear Damping Behaviour of Martensitic Shape Memory Alloys. AB - This article investigates the efficiency of hybridizing composites with thin layers of martensitic shape memory alloys for improvement of damping. The non linear damping behaviour of martensitic shape memory alloys is simulated using a modified version of Masing's rules. The model was implemented in a user subroutine of a finite element code, and validated by a numerical simulation of experimental hysteresis loops at different maximum strain amplitudes. The experimental free decay of hybridized glass fiber reinforced polymer beams was simulated using the finite element model, including the validated model of the investigated materials. The amplitude-dependent damping of the hybrid beams in free decay was reproduced successfully in the numerical analysis and it was proven that the hybridization technique is efficient for improvement of damping. PMID- 30400294 TI - Long-Circulating Hyaluronan-Based Nanohydrogels as Carriers of Hydrophobic Drugs. AB - Nanohydrogels based on natural polymers, such as polysaccharides, are gaining interest as vehicles for therapeutic agents, as they can modify the pharmacokinetics and pharmacodynamics of the carried drugs. In this work, hyaluronan-riboflavin nanohydrogels were tested in vivo in healthy rats highlighting their lack of toxicity, even at high doses, and their different biodistribution with respect to that of native hyaluronan. They were also exploited as carriers of a hydrophobic model drug, the anti-inflammatory piroxicam, that was physically embedded within the nanohydrogels by an autoclave treatment. The nanoformulation was tested by intravenous administration showing an improvement of the pharmacokinetic parameters of the molecule. The obtained results indicate that hyaluronan-based self-assembled nanohydrogels are suitable systems for low-soluble drug administration, by increasing the dose as well as the circulation time of poorly available therapeutic agents. PMID- 30400292 TI - The Role of Fiber in the Treatment of Functional Gastrointestinal Disorders in Children. AB - We reviewed the available evidence on the role of fiber in the treatment of Functional Constipation (FC) and Irritable Bowel Syndrome (IBS) in children. The vast majority of toddlers and preschoolers do not consume enough fiber. Two of the most common reasons for consultation to a pediatric gastroenterology practice include FC and IBS. The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) guidelines state that the evidence does not support the use of fiber supplements in the treatment of FC in children, and the Rome IV criteria do not recommend an increase in fiber consumption, in children with IBS. Despite this, in general practice, it is commonly recommended that children who experience constipation and IBS to increase their fiber intake. We conducted a systematic review of the available evidence on the role of fiber in the treatment of FC and IBS in children. Thirteen full-text articles with a total of seven hundred and twenty-three pediatric participants were included in this review. Three clinical trials found positive effects of dietary fiber for the management of IBS. Nine out of ten trials found fiber to be either more effective than placebo, or just as effective as laxative treatment. Most studies on the use of fiber for the treatment of FC and IBS have shown its benefit. However, due to the heterogeneity in study design, length of treatment, outcome measures, and amount and type of fiber, we were unable to make a definitive recommendation supporting the use of fiber for the treatment of FC and IBS in children. PMID- 30400295 TI - Analogues of Muraymycin Nucleoside Antibiotics with Epimeric Uridine-Derived Core Structures. AB - Nucleoside analogues have found widespread application as antiviral and antitumor agents, but not yet as antibacterials. Naturally occurring uridine-derived 'nucleoside antibiotics' target the bacterial membrane protein MraY, an enzyme involved in peptidoglycan biosynthesis and a promising target for the development of novel antibacterial agents. Muraymycins represent a nucleoside-peptide subgroup of such MraY-inhibiting natural products. As part of detailed structure activity relationship (SAR) studies on muraymycins and their analogues, we now report novel insights into the effects of stereochemical variations in the nucleoside core structure. Using a simplified version of the muraymycin scaffold, it was shown that some formal inversions of stereochemistry led to about one order of magnitude loss in inhibitory potency towards the target enzyme MraY. In contrast, epimers of the core motif with retained inhibitory activity were also identified. These 5',6'-anti-configured analogues might serve as novel chemically tractable variations of the muraymycin scaffold for the future development of uridine-derived drug candidates. PMID- 30400296 TI - Emerging Ergonomics Issues and Opportunities in Mining. AB - Ergonomics is the scientific discipline that investigates the interactions between humans and systems to optimize both human and system performance for worker safety, health, and productivity. Ergonomics is frequently involved either in the design of emerging technologies or in strategies to alleviate unanticipated human performance problems with emerging technologies. This manuscript explores several such emerging issues and opportunities in the context of the mining sector. In mining, the equipment, tools, and procedures have changed considerably and continue to change. Body-worn technology provides a number of opportunities to advance the safety and health of miners, while teleoperation and autonomous mining equipment stand to benefit significantly from ergonomics applications in other sectors. This manuscript focuses on those issues and opportunities that can impact the safety and health of miners in the near term. PMID- 30400298 TI - Fatigue as an Extra-Intestinal Manifestation of Celiac Disease: A Systematic Review. AB - Celiac disease may present with a range of different symptoms, including abdominal problems in a broader sense, iron deficiency and "constant tiredness". All of these symptoms should consequently lead the clinicians to consider celiac disease as a potential etiopathogenetic cause. Although the pathophysiology of celiac disease is well documented, the actual mechanisms for disease presentation(s) are less well understood. We here address the topic of fatigue in celiac disease. A systematic literature search identified 298 papers of which five met the criteria for full evaluation. None of the reviewed papers were of high quality and had several methodological weaknesses. We conclude that there is an unmet need to study the contributing factors and management of fatigue in celiac disease. PMID- 30400300 TI - The Effect of Varying Almond Shell Flour (ASF) Loading in Composites with Poly(Butylene Succinate (PBS) Matrix Compatibilized with Maleinized Linseed Oil (MLO). AB - In this work poly(butylene succinate) (PBS) composites with varying loads of almond shell flour (ASF) in the 10-50 wt % were manufactured by extrusion and subsequent injection molding thus showing the feasibility of these combined manufacturing processes for composites up to 50 wt % ASF. A vegetable oil-derived compatibilizer, maleinized linseed oil (MLO), was used in PBS/ASF composites with a constant ASF to MLO (wt/wt) ratio of 10.0:1.5. Mechanical properties of PBS/ASF/MLO composites were obtained by standard tensile, hardness, and impact tests. The morphology of these composites was studied by field emission scanning electron microscopy-FESEM) and the main thermal properties were obtained by differential scanning calorimetry (DSC), dynamical mechanical-thermal analysis (DMTA), thermomechanical analysis (TMA), and thermogravimetry (TGA). As the ASF loading increased, a decrease in maximum tensile strength could be detected due to the presence of ASF filler and a plasticization effect provided by MLO which also provided a compatibilization effect due to the interaction of succinic anhydride polar groups contained in MLO with hydroxyl groups in both PBS (hydroxyl terminal groups) and ASF (hydroxyl groups in cellulose). FESEM study reveals a positive contribution of MLO to embed ASF particles into the PBS matrix, thus leading to balanced mechanical properties. Varying ASF loading on PBS composites represents an environmentally-friendly solution to broaden PBS uses at the industrial level while the use of MLO contributes to overcome or minimize the lack of interaction between the hydrophobic PBS matrix and the highly hydrophilic ASF filler. PMID- 30400301 TI - Mango Fruit Yield and Critical Quality Parameters Respond to Foliar and Soil Applications of Zinc and Boron. AB - Mango (Mangifera indica L.), the sixth most important fruit crop worldwide, is likely at risk under a climate change scenario of accelerated soil organic matter mineralization and constrained plant nutrient supplies such as zinc (Zn) and boron (B). We identified the optimum nutrient formulation and application method to possibly rectify nutrient deficits in mango plants grown in one of the warmest and driest regions-Multan, Pakistan. We evaluated the yield and physiological (quality) responses of 20-year-old mango trees to seven treatments of foliar and soil applications of Zn and B. Combined soil application of B and Zn resulted in optimum increases in leaf mineral B and Zn and fruit-set, retention, yield, pulp recovery and total soluble solids at ripening (p = 0.021), while reducing titratable acidity and early fruit shedding (p = 0.034). Additionally, this treatment improved fruit quality (taste, flavour, texture, aroma, acceptability; p <= 0.05). Yield was found to be correlated with retention percentage (P <= 0.001; R2 = 0.91), which was in turn related to fruit-set number panicle-1 (P = 0.039; R2 = 0.61). Therefore, we suggest that combined soil application of B and Zn mitigates leaf mineral deficiencies and improves the yield and quality of mango more efficiently than other individual or combined foliar or soil treatments used in this study. PMID- 30400299 TI - Fishing for Targets of Alien Metabolites: A Novel Peroxisome Proliferator Activated Receptor (PPAR) Agonist from a Marine Pest. AB - Although the chemical warfare between invasive and native species has become a central problem in invasion biology, the molecular mechanisms by which bioactive metabolites from invasive pests influence local communities remain poorly characterized. This study demonstrates that the alkaloid caulerpin (CAU)-a bioactive component of the green alga Caulerpa cylindracea that has invaded the entire Mediterranean basin-is an agonist of peroxisome proliferator-activated receptors (PPARs). Our interdisciplinary study started with the in silico prediction of the ligand-protein interaction, which was then validated by in vivo, ex vivo and in vitro assays. On the basis of these results, we candidate CAU as a causal factor of the metabolic and behavioural disorders observed in Diplodus sargus, a native edible fish of high ecological and commercial relevance, feeding on C. cylindracea. Moreover, given the considerable interest in PPAR activators for the treatment of relevant human diseases, our findings are also discussed in terms of a possible nutraceutical/pharmacological valorisation of the invasive algal biomasses, supporting an innovative strategy for conserving biodiversity as an alternative to unrealistic campaigns for the eradication of invasive pests. PMID- 30400302 TI - Resistance Training Volume Load with and without Exercise Displacement. AB - : Monitoring the resistance training volume load (VL) (sets * reps * load) is essential to managing resistance training and the recovery-adaptation process. SUBJECTS: Eight trained weightlifters, seven of which were at national level, participated in the study. METHODS: VL was measured both with (VLwD) and without (VL) the inclusion of barbell displacement, across twenty weeks of training, in order to allow for comparisons to be made of these VL calculating methods. This consisted of recording the load, repetition count, and barbell displacement for every set executed. Comparisons were made between VL and VLwD for individual blocks of training, select training weeks, and select training days. RESULTS: Strong, statistically significant correlations (r >= 0.78, p < 0.001) were observed between VL and VLwD between all training periods analyzed. t-tests revealed statistically significant (p <= 0.018) differences between VL and VLwD in four of the seven training periods analyzed. CONCLUSION: The very strong relationship between VL and VLwD suggest that a coach with time constraints and a large number of athletes can potentially spare the addition of displacement. However, differences in percent change indicate that coaches with ample time should include displacement in VL calculations, in an effort to acquire more precise workload totals. PMID- 30400303 TI - A Two-Stage Approach for Routing Multiple Unmanned Aerial Vehicles with Stochastic Fuel Consumption. AB - The past decade has seen a substantial increase in the use of small unmanned aerial vehicles (UAVs) in both civil and military applications. This article addresses an important aspect of refueling in the context of routing multiple small UAVs to complete a surveillance or data collection mission. Specifically, this article formulates a multiple-UAV routing problem with the refueling constraint of minimizing the overall fuel consumption for all the vehicles as a two-stage stochastic optimization problem with uncertainty associated with the fuel consumption of each vehicle. The two-stage model allows for the application of sample average approximation (SAA). Although the SAA solution asymptotically converges to the optimal solution for the two-stage model, the SAA run time can be prohibitive for medium- and large-scale test instances. Hence, we develop a tabu search-based heuristic that exploits the model structure while considering the uncertainty in fuel consumption. Extensive computational experiments corroborate the benefits of the two-stage model compared to a deterministic model and the effectiveness of the heuristic for obtaining high-quality solutions. PMID- 30400297 TI - Resveratrol, Metabolic Syndrome, and Gut Microbiota. AB - Resveratrol is a polyphenol which has been shown to have beneficial effects on metabolic syndrome-related alterations in experimental animals, including glucose and lipid homeostasis improvement and a reduction in fat mass, blood pressure, low-grade inflammation, and oxidative stress. Clinical trials have been carried out to address its potential; however, results are still inconclusive. Even though resveratrol is partly metabolized by gut microbiota, the relevance of this "forgotten organ" had not been widely considered. However, in the past few years, data has emerged suggesting that the therapeutic potential of this compound may be due to its interaction with gut microbiota, reporting changes in bacterial composition associated with beneficial metabolic outcomes. Even though data is still scarce and for the most part observational, it is promising nevertheless, suggesting that resveratrol supplementation could be a useful tool for the treatment of metabolic syndrome and its associated conditions. PMID- 30400304 TI - Extraction of Astaxanthin and Lutein from Microalga Haematococcus pluvialis in the Red Phase Using CO2 Supercritical Fluid Extraction Technology with Ethanol as Co-Solvent. AB - Astaxanthin and lutein, antioxidants used in nutraceutics and cosmetics, can be extracted from several microalgal species. In this work, investigations on astaxanthin and lutein extraction from Haematococcus pluvialis (H. pluvialis) in the red phase were carried out by means of the supercritical fluid extraction (SFE) technique, in which CO2 supercritical fluid was used as the extracting solvent with ethanol as the co-solvent. The experimental activity was performed using a bench-scale reactor in semi-batch configuration with varying extraction times (20, 40, 60, and 80 min), temperatures (50, 65, and 80 degrees C) and pressures (100, 400, and 550 bar). Moreover, the performance of CO2 SFE with ethanol was compared to that without ethanol. The results show that the highest astaxanthin and lutein recoveries were found at 65 degrees C and 550 bar, with ~18.5 mg/g dry weight (~92%) astaxanthin and ~7.15 mg/g dry weight (~93%) lutein. The highest astaxanthin purity and the highest lutein purity were found at 80 degrees C and 400 bar, and at 65 degrees C and 550 bar, respectively. PMID- 30400305 TI - A Fluidic Biosensor Based on a Phase-Sensitive Low-Coherence Spectral-Domain Interferometer. AB - A phase-sensitive fluidic biosensor based on a spectral-domain low-coherence interferometer is presented in this paper. With a fiber optic probe employing the common-path interferometric configuration, subnanometric changes in thickness of the molecular layers can be detected through phase analysis of the acquired interference signal from the sensor surface. Advantages of this biosensor include its picometer-scale thickness sensitivity, 13.9-ms time response, and tolerance to the fluctuation in concentration of the target solution. The capabilities of this biosensor in monitoring specific molecular binding and recognizing specific molecular was successfully demonstrated by using the reactions between the molecules of protein A and IgG. The calculated minimum detectable concentration of IgG is 0.11 ug/mL. PMID- 30400307 TI - A Location-Aware Waypoint-Based Routing Protocol for Airborne DTNs in Search and Rescue Scenarios. AB - In this paper, we propose GeoSaW, a delay-tolerant routing protocol for Airborne Networks in Search and Rescue scenarios. The protocol exploits the geographical information of UAVs to make appropriate message forwarding decisions. More precisely, the information about the future UAV's motion path is exploited to select the best UAV carrying the message towards the destination. Simulation results show that the proposed solution outperforms the classic DTN routing protocols in terms of several performance metrics. PMID- 30400308 TI - Fabrication and Thermoelectric Characterization of Transition Metal Silicide Based Composite Thermocouples. AB - Metal silicide-based thermocouples were fabricated by screen printing thick films of the powder compositions onto alumina tapes followed by lamination and sintering processes. The legs of the embedded thermocouples were composed of composite compositions consisting of MoSi2, WSi2, ZrSi2, or TaSi2 with an additional 10 vol % Al2O3 to form a silicide-oxide composite. The structural and high-temperature thermoelectric properties of the composite thermocouples were examined using X-ray diffraction, scanning electron microscopy and a typical hot cold junction measurement technique. MoSi2-Al2O3 and WSi2-Al2O3 composites exhibited higher intrinsic Seebeck coefficients (22.2-30.0 uV/K) at high temperature gradients, which were calculated from the thermoelectric data of composite//Pt thermocouples. The composite thermocouples generated a thermoelectric voltage up to 16.0 mV at high-temperature gradients. The MoSi2 Al2O3//TaSi2-Al2O3 thermocouple displayed a better performance at high temperatures. The Seebeck coefficients of composite thermocouples were found to range between 20.9 and 73.0 uV/K at a temperature gradient of 1000 degrees C. There was a significant difference between the calculated and measured Seebeck coefficients of these thermocouples, which indicated the significant influence of secondary silicide phases (e.g., Mo5Si3, Ta5Si3) and possible local compositional changes on the overall thermoelectric response. The thermoelectric performance, high sensitivity, and cost efficiency of metal silicide-alumina ceramic composite thermocouples showed promise for high-temperature and harsh-environment sensing applications. PMID- 30400306 TI - Carotenoid Content in Human Colostrum is Associated to Preterm/Full-Term Birth Condition. AB - Factors such as lactation stage and premature and small-for-gestational conditions could lead to great inter-individual variability in the carotenoid content of human milk. The aim was to analyze the carotenoid content in colostrum and mature milk of preterm (PT) and full-term (FT) mothers to establish whether they are significantly different and, if so, the stage of lactation when the differences are established. Samples of blood, colostrum, and mature milk were collected from Spanish donating mothers who gave birth to PT or FT infants. Carotenoids from serum and milk samples were analyzed by HPLC-atmospheric pressure chemical ionization (APCI)-MS. Quantitatively, colostrum from PT mothers presented lower total carotenoid content when compared to that from FT mothers. The only exception was lutein, where levels were not different. The transition from colostrum to mature milk makes observed differences in the carotenoid content disappear, since there were no variances between PT and FT groups for both individual and total carotenoid content. The premature birth condition affects the quantitative carotenoid composition of the colostrum but has no effect on the lutein content. This fact could be related to the significant role of this xanthophyll in the development of infant retina and feasibly to cognitive function. PMID- 30400309 TI - Influence of Ligand Functionalization of UiO-66-Based Metal-Organic Frameworks When Used as Sorbents in Dispersive Solid-Phase Analytical Microextraction for Different Aqueous Organic Pollutants. AB - Four metal-organic frameworks (MOFs), specifically UiO-66, UiO-66-NH2, UiO-66 NO2, and MIL-53(Al), were synthesized, characterized, and used as sorbents in a dispersive micro-solid phase extraction (D-uSPE) method for the determination of nine pollutants of different nature, including drugs, phenols, polycyclic aromatic hydrocarbons, and personal care products in environmental waters. The D uSPE method, using these MOFs as sorbents and in combination with high performance liquid chromatography (HPLC) and diode-array detection (DAD), was optimized. The optimization study pointed out to UiO-66-NO2 as the best MOF to use in the multi-component determination. Furthermore, the utilization of isoreticular MOFs based on UiO-66 with the same topology but different functional groups, and MIL-53(Al) to compare with, allowed us for the first time to evaluate the influence of such functionalization of the ligand with regards to the efficiency of the D-uSPE-HPLC-DAD method. Optimum conditions included: 20 mg of UiO-66-NO2 MOF in 20 mL of the aqueous sample, 3 min of agitation by vortex and 5 min of centrifugation, followed by the use of only 500 uL of acetonitrile as desorption solvent (once the MOF containing analytes was separated), 5 min of vortex and 5 min of centrifugation. The validation of the D-uSPE-HPLC-DAD method showed limits of detection down to 1.5 ng.L-1, average relative recoveries of 107% for a spiked level of 1.50 ug.L-1, and inter-day precision values with relative standard deviations lower than 14%, for the group of pollutants considered. PMID- 30400310 TI - beta-Cyclodextrin Does not Alter the Bioaccessibility and the Uptake by Caco-2 Cells of Olive By-Product Phenolic Compounds. AB - Alperujo-a two-phase olive mill waste that is composed of olive vegetation water and solid skin, pulp, and seed fragments - is a highly valuable olive by-product due to its high content in phenolic compounds. In this study, we assessed whether beta-cyclodextrin (beta-CD), which is used to extract and protect alpejuro phenolic compounds (hydroxytyrosol-O-glucoside, tyrosol, caffeic, and p-coumaric acids) could impact on their bioaccessibility (i.e., the percentage of molecule found in the aqueous phase of the digesta) and uptake by intestinal cells, by using an in vitro digestion model and Caco-2 TC7 cells in culture, respectively. Our results showed that beta-CD did not change the bioaccessibility of the selected phenols. Hydroxytyrosol-O-glucoside and caffeic did not cross Caco-2 cell monolayers. Conversely ferulic acid, identified as the main caffeic acid intestinal metabolite, was absorbed through intestinal cell monolayers (~20%). Interestingly, beta-CD moderately but significantly improved the local absorption of tyrosol and p-coumaric acid (2.3 + 1.4% and 8.5 +/- 4.2%, respectively, p < 0.05), even if their final bioavailability (expressed as bioaccessibility * absorption by Caco-2 cells) was not modified (16.2 +/- 0.6% vs. 16.8 +/- 0.5% for tyrosol and 32.0 +/- 3.2% vs. 37.2 +/- 3.2% for p-coumaric acid, from pure alperujo and alperujo complexed with beta-CD, respectively). Overall, our results show that beta-CD is an interesting extraction and storage agent for phenolic compounds that does not alter their in vitro bioavailability. PMID- 30400312 TI - InGaAs Diodes for Terahertz Sensing-Effect of Molecular Beam Epitaxy Growth Conditions. AB - InGaAs-based bow-tie diodes for the terahertz (THz) range are found to be well suited for development of compact THz imaging systems. To further optimize design for sensitive and broadband THz detection, one of the major challenges remains: to understand the noise origin, influence of growth conditions and role of defects for device operation. We present a detailed study of photoreflectance, low-frequency noise characteristics and THz sensitivity of InGaAs bow-tie diodes. The diodes are fabricated from InGaAs wafers grown by molecular beam epitaxy (MBE) on semi-insulating InP substrate under different technological conditions. Photoreflectance spectra indicated the presence of strong built-in electric fields reaching up to 49 kV/cm. It was demonstrated that the spectral density of voltage fluctuations at room temperature was found to be proportional to 1/f, while at lower temperatures, 77-200 K, Lorentzian-type spectra dominate due to random telegraph signals caused by individual capture defects. Furthermore, varying bias voltage, we considered optimal conditions for device room temperature operation in the THz range with respect to signal-to-noise ratio. The THz detectors grown with beam equivalent pressure In/Ga ratio equal to 2.04 exhibit the minimal level of the low-frequency noise, while InGaAs layers grown with beam equivalent pressure In/Ga ratio equal to 2.06 are found to be well suited for fabrication of room temperature bow-tie THz detectors enabling sensitivity of 13 V/W and noise equivalent power (NEP) of 200 pW/?Hz at 0.6 THz due to strong built-in electric field effects. PMID- 30400311 TI - Longitudinal Association between n-3 Long-Chain Polyunsaturated Fatty Acid Intake and Depressive Symptoms: A Population-Based Cohort Study in Japan. AB - It remains unclear whether n-3 long-chain polyunsaturated fatty acids (LCPUFA) have a preventive effect on depression in the general population. This study investigated the longitudinal association between n-3 LCPUFA intake and depressive symptoms in community-dwelling Japanese participants. The participants were aged 40-79 years at baseline in the cohort study; wherein examinations; including the assessment of depressive symptoms and nutritional status; were biennially conducted from 1997 to 2012. The subjects (n = 2335) who had a Center for Epidemiologic Studies Depression Scale (CES-D) score < 16 at the first examination and who participated in the follow-up study at least once were included in the analysis. The follow-up end point was the first onset (CES-D >= 16) or the last examination participation. Hazard ratios (95% CIs) for CES-D >= 16 were estimated using the adjusted Cox proportional hazards model. Overall; 22.1% participants showed depressive symptoms during follow-up (average; 8.1 years). Compared with the lowest tertile; the highest HR for EPA was 0.74 (0.60 0.93), and highest and middle HRs for DHA were 0.79 (0.63-0.98) and 0.80 (0.65 0.99) (P for trend = 0.009 and 0.032), respectively. Among populations with high fish consumption; higher n-3 LCPUFA intake may be associated with a low risk of depressive symptoms. PMID- 30400313 TI - Maternal Factors and Utilization of the Antenatal Care Services during Pregnancy Associated with Low Birth Weight in Rural Nepal: Analyses of the Antenatal Care and Birth Weight Records of the MATRI-SUMAN Trial. AB - Low birth weight (LBW) remains a major public health problem in developing countries, including Nepal. This study was undertaken to examine the association between LBW and maternal factors and antenatal care service utilization, in rural Nepal, using data obtained for a capacity-building and text-messaging intervention, designed to enhance maternal and child health service utilization among pregnant women, in rural Nepal ("MATRI-SUMAN"). The study used a clustered randomized controlled design and was conducted during 2015-2016. We investigated maternal and antenatal care service utilization determinants of LBW, using a logistic regression model. Of the four hundred and two singleton babies, included in the present study, seventy-eight (19.4%) had an LBW (mean (SD), 2210.64 (212.47)) grams. It was found that Dalit caste/ethnicity, illiteracy, manual labor, a female baby, and having more than four family members were significantly positively associated with LBW. In addition, mothers who did not visit an antenatal care (ANC) unit, visited an ANC < 4 times, did not take iron and folic acid (IFA), de-worming tablets, and mothers that did not consume additional food, during pregnancy, were more likely to have an LBW baby, than their counterparts. The MATRI-SUMAN intervention and availability of a kitchen garden at home, were found to reduce the risk of LBW. Nepalese child survival policies and programs should pay attention to these maternal and antenatal care service utilization factors, while designating preventive strategies to improve child health outcomes. PMID- 30400314 TI - Biogenesis, Stabilization, and Transport of microRNAs in Kidney Health and Disease. AB - The kidneys play key roles in the maintenance of homeostasis, including fluid balance, blood filtration, erythropoiesis and hormone production. Disease-driven perturbation of renal function therefore has profound pathological effects, and chronic kidney disease is a leading cause of morbidity and mortality worldwide. Successive annual increases in global chronic kidney disease patient numbers in part reflect upward trends for predisposing factors, including diabetes, obesity, hypertension, cardiovascular disease and population age. Each kidney typically possesses more than one million functional units called nephrons, and each nephron is divided into several discrete domains with distinct cellular and functional characteristics. A number of recent analyses have suggested that signaling between these nephron regions may be mediated by microRNAs. For this to be the case, several conditions must be fulfilled: (i) microRNAs must be released by upstream cells into the ultrafiltrate; (ii) these microRNAs must be packaged protectively to reach downstream cells intact; (iii) these packaged microRNAs must be taken up by downstream recipient cells without functional inhibition. This review will examine the evidence for each of these hypotheses and discuss the possibility that this signaling process might mediate pathological effects. PMID- 30400315 TI - What Protects Adolescents with Youth Subculture Affiliation from Excessive Internet Use? AB - Youth subculture affiliation (SA) appears to be an important risk factor with regard to adolescents' problem behavior. Excessive Internet use (EIU) has emerged as a new type of problem behavior; however, it has not yet been studied in adolescents affiliated with youth subcultures. Thus, the aim of this study was to assess the association between SA and EIU and to explore the role of selected protective factors. We used data from the Health Behaviour in School-aged Children (HBSC) study conducted in 2014 in Slovakia. The final sample for this study comprised 532 adolescents (mean age: 15.4; 49.6% boys). Hierarchical linear regression analysis was conducted to examine the associations of EIU with SA. Adolescents with SA were more likely to report EIU. Adjustment for protective factors decreased the association between EIU and SA. From all tested interactions, only the interaction of SA with family support was found to be significant. The relationship between family support and EIU was mediated via Monitoring by the mother only in adolescents without SA. Our findings imply that the risk of EIU is higher in adolescents with SA. There was a difference in how protective factors worked in adolescents with and without SA. PMID- 30400316 TI - Self-Efficacy of People with Chronic Conditions: A Qualitative Directed Content Analysis. AB - BACKGROUND: Given the increasing prevalence of chronic illnesses and their complications, supporting and empowering chronically ill patients seems crucial. Self-efficacy is considered as a predictor for empowerment. The purpose of this study to explore of different aspects of self-efficacy among persons with chronic physical conditions based on the Family-Centered Empowerment Model (FCEM). METHODS: this qualitative study is part of a larger study; sequential exploratory mixed-method for designing an instrument for the FCEM was conducted from May 2015 to March 2016 in two university hospitals. The sample was 22 participants, including chronically ill patients, family caregivers, and nurses. Data were collected through personal semi-structured interviews. Data analysis was performed concurrently with data collection through directed qualitative content analysis. RESULTS: after determining the self-efficacy attributes in the family center empowerment model, a category matrix was developed and the codes are placed in subcategories of the matrix. Most participants were female (58.0%), with a mean age of 49.50 years. The final analysis yielded a total of 247 units of analysis dispersed in eight subcategories belonging to four generic categories. CONCLUSIONS: the findings of this study represent the dimensions of chronically-ill individuals' self-efficacy that can be used to develop and implement programs for empowering chronic ill patients. PMID- 30400317 TI - A Perspective on Reversibility in Controlled Polymerization Systems: Recent Progress and New Opportunities. AB - The field of controlled polymerization is growing and evolving at unprecedented rates, facilitating polymer scientists to engineer the structure and property of polymer materials for a variety of applications. However, the lack of degradability, particularly in vinyl polymers, is a general concern not only for environmental sustainability, but also for biomedical applications. In recent years, there has been a significant effort to develop reversible polymerization approaches in those well-established controlled polymerization systems. Reversible polymerization typically involves two steps, including (i) forward polymerization, which converts small monomers into macromolecule; and (ii) depolymerization, which is capable of regenerating original monomers. Furthermore, recycled monomers can be repolymerized into new polymers. In this perspective, we highlight recent developments of reversible polymerization in those controlled polymerization systems and offer insight into the promise and utility of reversible polymerization systems. More importantly, the current challenges and future directions to solve those problems are discussed. We hope this perspective can serve as an "initiator" to promote continuing innovations in this fairly new area. PMID- 30400318 TI - PARS: Using Augmented 360-Degree Panoramas of Reality for Construction Safety Training. AB - Improving the hazard-identification skills of construction workers is a vital step towards preventing accidents in the increasingly complex working conditions of construction jobsites. Training the construction workforce to recognize hazards therefore plays a central role in preparing workers to actively understand safety-related risks and make assertive safety decisions. Considering the inadequacies of traditional safety-training methods (e.g., passive lectures, videos, demonstrations), researchers have employed advanced visualization techniques such as virtual reality technologies to enable users to actively improve their hazard-identification skills in a safe and controlled environment. However, current virtual reality techniques sacrifice realism and demand high computational costs to reproduce real environments. Augmented 360-degree panoramas of reality offers an innovative alternative that creates low-cost, simple-to-capture, true-to-reality representations of the actual construction jobsite within which trainees may practice identifying hazards. This proof-of concept study developed and evaluated a platform using augmented 360-degree panoramas of reality (PARS) for safety-training applications to enhance trainees' hazard-identification skills for four types of sample hazards. Thirty subjects participated in a usability test that evaluated the PARS training platform and its augmented 360-degree images captured from real construction jobsites. The usability reviews demonstrate that the trainees found the platform and augmentations advantageously to learning hazard identification. The results of this study will foreseeably help researchers in developing engaging training platforms to improve the hazard-identification skills of workers. PMID- 30400319 TI - Organo-Clay Nanomaterials Based on Halloysite and Cyclodextrin as Carriers for Polyphenolic Compounds. AB - Hybrid material based on halloysite covalently linked to a hyper-reticulated cyclodextrin network was investigated as a potential carrier for polyphenolic compounds. The absorption ability of the hybrid system was studied in different pH conditions as well as the kinetic release of curcumin, chosen as a drug model. A preliminary study was performed to assess the antioxidant capacity of the obtained carrier. The obtained results highlighted that the curcumin molecule can have sustained release from the carrier over the time, retaining its antioxidant properties due to the combination of two different host systems that give rise to an hyper-reticulated structure, allowing an increase in the drug loading and stabilization. Therefore, this work puts forward an efficient strategy to prepare organic-inorganic hybrids with three different cavities that could encapsulate two or more drug molecules with different physico-chemical properties. PMID- 30400320 TI - Comparative Chemical Compositions of Fresh and Stored Vesuvian PDO "Pomodorino Del Piennolo" Tomato and the Ciliegino Variety. AB - The Vesuvian Piennolo cherry tomato (Lycopersicon esculentum Miller) (PdP) is an old and typical variety grown in the Campania region (Italy). PdP is referred to as a long-storage tomato due to its thick and coriaceous skin that allows long post-harvest storage and it has been granted Protected Designation of Origin (PDO) status since 2009. In this study, the chemical composition, focusing in particular on organic acids, antioxidant molecules and volatile compounds, were investigated in PdP and compared to another typical variety in Campania, the Ciliegino tomato (CIL). Chemical characterization was evaluated for both the CIL and PdP varieties during storage in the same environmental conditions until deterioration of 50% of the fruits; deterioration occurred in PdP after 6 months and in CIL tomatoes after 1 month. The results demonstrated variation in the chemical profiles of both varieties with storage length. Particularly, the PdP variety appears richer in antioxidants compounds (i.e., chlorogenic acids and lycopene) and organic acids (i.e., glutamic and malic acids) than does CIL. Additionally, both varieties display different profiles of volatile bioactive compounds and they are differently influenced by the storage time. The results indicate a typical chemical composition of this long-storage tomato closely linked to the geographic origin area. PMID- 30400321 TI - Plant Calcium Signaling in Response to Potassium Deficiency. AB - Potassium (K+) is an essential macronutrient of living cells and is the most abundant cation in the cytosol. K+ plays a role in several physiological processes that support plant growth and development. However, soil K+ availability is very low and variable, which leads to severe reductions in plant growth and yield. Various K+ shortage-activated signaling cascades exist. Among these, calcium signaling is the most important signaling system within plant cells. This review is focused on the possible roles of calcium signaling in plant responses to low-K+ stress. In plants, intracellular calcium levels are first altered in response to K+ deficiency, resulting in calcium signatures that exhibit temporal and spatial features. In addition, calcium channels located within the root epidermis and root hair zone can then be activated by hyperpolarization of plasma membrane (PM) in response to low-K+ stress. Afterward, calcium sensors, including calmodulin (CaM), CaM-like protein (CML), calcium-dependent protein kinase (CDPK), and calcineurin B-like protein (CBL), can act in the sensing of K+ deprivation. In particular, the important components regarding CBL/CBL-interacting protein kinase (CBL/CIPK) complexes-involved in plant responses to K+ deficiency are also discussed. PMID- 30400322 TI - Kaempferia parviflora Extract as a Potential Anti-Acne Agent with Anti Inflammatory, Sebostatic and Anti-Propionibacterium acnes Activity. AB - Kaempferia parviflora, referred to as black ginger, has traditionally been used as a health-promoting alternative medicine. In this study, we examined the anti inflammatory, sebostatic, and anti-Propionibacterium acnes activities of K. parviflora extract. The extract significantly down-regulated the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), and pro-inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) level. Moreover, the phosphorylation of IKBalpha and nuclear factor-kappa B (NF-kappaB), and the enhanced nuclear translocation of NF-kappaB p65 in lipopolysaccharide-stimulated murine macrophage-like cell line (RAW 264.7) cells were markedly decreased by the extract. Notably, the main component of K. parviflora, 5,7-dimethoxyflavone, also modulated the expression of iNOS and NF-kappaB signal molecules in P. acnes stimulated human keratinocyte (HaCaT) cells. Additionally, K. parviflora extract inhibited the lipogenesis of sebocytes, as evidenced by a reduced level of triglyceride and lipid accumulation in the sebocytes. The sebostatic effect was also confirmed by a reduced expression of peroxisome proliferation-activating receptors (PPAR-gamma) and oil-red O staining in sebocytes. Taken together, this study suggests for the first time that K. parviflora extract could be developed as a potential natural anti-acne agent with anti-inflammatory, sebostatic, and anti-P. acnes activity. PMID- 30400323 TI - An Evaluation of Birth Outcomes in Overweight and Obese Pregnant Women Who Exercised during Pregnancy. AB - It is well established that exercise has numerous health benefits, especially in regard to weight management for the obese and overweight population. However, there is limited data to support the safety or effects of exercise in the obese and overweight pregnant population despite the fact that exercise and weight management in this demographic is particularly important. In an effort to establish the safety profile of exercise during pregnancy in this population, we tested the hypothesis that exercise would not result in adverse birth outcomes. We surveyed postpartum women with an average BMI of 34.7 regarding their participation in exercise during pregnancy. Our primary outcome of interest was small for gestational age (SGA). Secondary outcomes included gestational age at delivery, mode of delivery, head circumference, length and birthweight as compared to those who did not exercise. SGA occurred in 12.5% of women who exercised in the first trimester compared to 14.9% in those who did not exercise (p = 0.678). Similar results were seen for women who exercised in the second and third trimesters. Intensity of exercise did not alter these findings and the analysis of secondary outcomes also did not demonstrate a difference between the groups. In conclusion, overweight and obese women who reported exercising during pregnancy did not have a higher incidence of SGA infants. Exercise should not be discouraged in pregnant women due to obesity. PMID- 30400324 TI - Membership Function-Weighted Non-Linear Fitting Method for Optical-Sensing Modeling and Reconstruction. AB - Imprecise measurements present universally due to variability in the measurement error. We devised a very simple membership function to evaluate fuzzily the quality of optical sensing with a small dataset, where a normal distribution cannot be assumed. The proposed membership function was further used as a weighting function for non-linear curve fitting under expected mathematical model constraints, namely the membership function-weighted Levenberg-Marquardt (MFW-LM) algorithm. The robustness and effectiveness of the MFW-LM algorithm were demonstrated by an optical-sensing simulation and two practical applications. (1) In laser-absorption spectroscopy, molecular spectral line modeling was greatly improved by the method. The measurement uncertainty of temperature and pressure were reduced dramatically, by 53.3% and 43.5%, respectively, compared with the original method. (2) In imaging, a laser beam-profile reconstruction from heavy distorted observations was improved by the method. As the dynamic range of the infrared camera increased from 256 to 415, the detailed resolution of the laser beam profiles increased by an amazing 360%, achieving high dynamic-range imaging to capture optical signal details. Therefore, the MFW-LM algorithm provides a robust and effective tool for fitting a proper physical model and precision parameters from low-quality data. PMID- 30400325 TI - Investigation of Optimal Afferent Feedback Modality for Inducing Neural Plasticity with A Self-Paced Brain-Computer Interface. AB - Brain-computer interfaces (BCIs) can be used to induce neural plasticity in the human nervous system by pairing motor cortical activity with relevant afferent feedback, which can be used in neurorehabilitation. The aim of this study was to identify the optimal type or combination of afferent feedback modalities to increase cortical excitability in a BCI training intervention. In three experimental sessions, 12 healthy participants imagined a dorsiflexion that was decoded by a BCI which activated relevant afferent feedback: (1) electrical nerve stimulation (ES) (peroneal nerve-innervating tibialis anterior), (2) passive movement (PM) of the ankle joint, or (3) combined electrical stimulation and passive movement (Comb). The cortical excitability was assessed with transcranial magnetic stimulation determining motor evoked potentials (MEPs) in tibialis anterior before, immediately after and 30 min after the BCI training. Linear mixed regression models were used to assess the changes in MEPs. The three interventions led to a significant (p < 0.05) increase in MEP amplitudes immediately and 30 min after the training. The effect sizes of Comb paradigm were larger than ES and PM, although, these differences were not statistically significant (p > 0.05). These results indicate that the timing of movement imagery and afferent feedback is the main determinant of induced cortical plasticity whereas the specific type of feedback has a moderate impact. These findings can be important for the translation of such a BCI protocol to the clinical practice where by combining the BCI with the already available equipment cortical plasticity can be effectively induced. The findings in the current study need to be validated in stroke populations. PMID- 30400327 TI - Frontiers in Computational Chemistry for Drug Discovery. AB - Computational methods pervade almost all aspects of drug discovery [...]. PMID- 30400326 TI - Combining Calcium Phosphates with Polysaccharides: A Bone-Inspired Material Modulating Monocyte/Macrophage Early Inflammatory Response. AB - The use of inorganic calcium/phosphate supplemented with biopolymers has drawn lots of attention in bone regenerative medicine. While inflammation is required for bone healing, its exacerbation alters tissue regeneration/implants integration. Inspired by bone composition, a friendly automated spray-assisted system was used to build bioactive and osteoinductive calcium phosphate/chitosan/hyaluronic acid substrate (CaP-CHI-HA). Exposing monocytes to CaP-CHI-HA resulted in a secretion of pro-healing VEGF and TGF-beta growth factors, TNF-alpha, MCP-1, IL-6 and IL-8 pro-inflammatory mediators but also IL 10 anti-inflammatory cytokine along with an inflammatory index below 1.5 (versus 2.5 and 7.5 following CaP and LPS stimulation, respectively). Although CD44 hyaluronic acid receptor seems not to be involved in the inflammatory regulation, results suggest a potential role of chemical composition and calcium release from build-up substrates, in affecting the intracellular expression of a calcium sensing receptor. Herein, our findings indicate a great potential of CaP-CHI-HA in providing required inflammation-healing balance, favorable for bone healing/regeneration. PMID- 30400328 TI - 0.16 um-BCD Silicon Photomultipliers with Sharp Timing Response and Reduced Correlated Noise. AB - Silicon photomultipliers (SiPMs) have improved significantly over the last years and now are widely employed in many different applications. However, the custom fabrication technologies exploited for commercial SiPMs do not allow the integration of any additional electronics, e.g., on-chip readout and analog (or digital) processing circuitry. In this paper, we present the design and characterization of two microelectronics-compatible SiPMs fabricated in a 0.16 um BCD (Bipolar-CMOS-DMOS) technology, with 0.67 mm * 0.67 mm total area, 10 * 10 square pixels and 53% fill-factor (FF). The photon detection efficiency (PDE) surpasses 33% (FF included), with a dark-count rate (DCR) of 330 kcps. Although DCR density is worse than that of state-of-the-art SiPMs, the proposed fabrication technology enables the development of cost-effective systems-on-chip (SoC) based on SiPM detectors. Furthermore, correlated noise components, i.e., afterpulsing and optical crosstalk, and photon timing response are comparable to those of best-in-class commercial SiPMs. PMID- 30400330 TI - How Can Cities Adapt to a Multi-Disaster Environment? Empirical Research in Guangzhou (China). AB - Urban disaster risk assessment is the most basic and important part of urban safety development. Conducting disaster prevention and mitigation on the basis of urban disaster risk assessment requires an understanding of the relationship between the city and the natural environment. This enhances the city's ability to withstand various types of disasters and achieves the development of a safe city. Based on a review of the existing literature, we propose a fuzzy comprehensive evaluation method for urban multi-disaster risk assessment. The multi-disaster risk assessment method includes the identification and screening of urban disasters, the assessment of individual disaster risk, and integrated urban disaster risks, the division of urban comprehensive disaster risks into several risk levels, and the determination of coping strategies. Taking Guangzhou (China) as an example, we determined the major disaster risks faced by Guangzhou, assessed the risks of individual disasters, and finally obtained the results of the comprehensive disaster risk of Guangzhou. Second, we analyzed the relationship between the disaster risk assessment and urban safety development, and proposed countermeasures and recommendations for the development of different disaster risk levels. PMID- 30400331 TI - Step Rate Thresholds Associated with Moderate and Vigorous Physical Activity in Adults. AB - Adults are recommended to engage in 150 min of moderate (MPA) to vigorous (VPA) aerobic physical activity per week, with the public health message of obtaining 3000 steps in 30 min. There is a paucity of research on step rate thresholds that correspond to absolute MVPA (moderate = 3 METs, vigorous = 6 METs) with no research evaluating adult relative MVPA (moderate = 40% VO2max, vigorous = 60% VO2max). Anthropometric differences also influence intensity-related step rate thresholds. The purpose of this study was to identify step rates across a range of walking intensities so that mathematical models incorporating anthropometric factors could be used to identify individualized MVPA step rate thresholds. Forty three adults (25?; age = 39.4 +/- 15.2 years) completed a staged treadmill walking protocol with pedometers and indirect calorimetry: six-minutes at 2.4, 3.2, 4.0, 5.6, 6.4, 7.2 km/h. Mathematical modelling revealed absolute and relative MPA step rate thresholds of ~100 steps/minute (spm) and ~125 spm, respectively. VPA corresponded to step rates of ~133 spm and ~139 spm for absolute and relative thresholds respectively. The current public message of 3000 steps in 30 min is valid for absolute MPA. However, VPA is achieved at higher thresholds than previously reported, more than 130 spm for healthy adults. PMID- 30400329 TI - Sex Differences in Salivary Oxytocin and Cortisol Concentration Changes during Cooking in a Small Group. AB - Background: Oxytocin (OT), a neuropeptide, has positive effects on social and emotional processes during group activities. Because cooking is an integrated process in the cognitive, physical, and socio-emotional areas, cooking in a group is reported to improve emotion and cognition. However, evidence for efficacy in group cooking has not been well established at the biological level. Methods: To address this shortcoming, we first measured salivary levels of OT and cortisol (CORT), a biomarker of psychological stress, before and after group cooking for approximately 1 h by people who know each other in healthy married or unmarried men and women. We then compared the initial OT and CORT concentrations with those during individual non-cooking activities in isolation. Results: Baseline OT concentrations before group and non-group sessions did not significantly differ and OT levels increased after both types of activity in men and women. In men, however, the percentage changes of OT levels in the first over the second saliva samples were significantly small during cooking compared with those in individual activities. In women, however, such a difference was not observed. In contrast, the mean salivary CORT concentrations after group cooking were significantly decreased from the baseline level in both sexes, though such decreases were not significant after individual activity sessions. The sex-specific differences were marital-status independent. Conclusion: These results indicate that OT and CORT concentrations after two activity sessions by a familiar group changed in opposite directions in a sex-specific manner. This suggests that, because cooking is experience-based, we need to consider the sex-specific features of group cooking if we apply it for intervention. PMID- 30400333 TI - Estimation of Notched Composite Plates Fatigue Life Using Residual Strength Model Calibrated by Step-Wise Tests. AB - The proposed new technique of fatigue life prediction for notched composite plates is based on a residual strength model calibrated with the use of step-wise fatigue tests. It was proposed to calibrate the fatigue model with fatigue tests in which load conditions are in a step-wise fashion. The adopted fatigue model takes into account the most important loading parameters such as testing frequency, stress ratio, layer orientation and maximal fatigue stress. It was demonstrated that with the use of step-wise fatigue tests, it is possible to calibrate the fatigue model for a particular material and structure with the use of fewer samples. In the experimental tensile and fatigue tests TVR 380 M12/26%/R glass/epoxy composite plates [+45 degrees /-45 degrees ]4 with circular and elliptical cut-outs were used. The fatigue tests were performed under different loading conditions. The influence of testing frequency, stress ratio, maximal fatigue load and also geometry of the cut-out on damage growth rate and fatigue life were studied. The predicted fatigue life was in good agreement with the durability determined experimentally in all investigated samples. PMID- 30400332 TI - Vitamin D: Nutrient, Hormone, and Immunomodulator. AB - The classical functions of vitamin D are to regulate calcium-phosphorus homeostasis and control bone metabolism. However, vitamin D deficiency has been reported in several chronic conditions associated with increased inflammation and deregulation of the immune system, such as diabetes, asthma, and rheumatoid arthritis. These observations, together with experimental studies, suggest a critical role for vitamin D in the modulation of immune function. This leads to the hypothesis of a disease-specific alteration of vitamin D metabolism and reinforces the role of vitamin D in maintaining a healthy immune system. Two key observations validate this important non-classical action of vitamin D: first, vitamin D receptor (VDR) is expressed by the majority of immune cells, including B and T lymphocytes, monocytes, macrophages, and dendritic cells; second, there is an active vitamin D metabolism by immune cells that is able to locally convert 25(OH)D3 into 1,25(OH)2D3, its active form. Vitamin D and VDR signaling together have a suppressive role on autoimmunity and an anti-inflammatory effect, promoting dendritic cell and regulatory T-cell differentiation and reducing T helper Th 17 cell response and inflammatory cytokines secretion. This review summarizes experimental data and clinical observations on the potential immunomodulating properties of vitamin D. PMID- 30400335 TI - Adjustable Method for Real-Time Gait Pattern Detection Based on Ground Reaction Forces Using Force Sensitive Resistors and Statistical Analysis of Constant False Alarm Rate. AB - A new approach is proposed to detect the real-time gait patterns adaptively through measuring the ground contact forces (GCFs) by force sensitive resistors (FSRs). Published threshold-based methods detect the gait patterns by means of setting a fixed threshold to divide the GCFs into on-ground and off-ground statuses. However, the threshold-based methods in the literature are neither an adaptive nor a real-time approach. To overcome these drawbacks, this study utilized the constant false alarm rate (CFAR) to analyze the characteristics of GCF signals. Specifically, a sliding window detector is built to record the lasting time of the curvature of the GCF signals and one complete gait cycle could be divided into three areas, such as continuous ascending area, continuous descending area and unstable area. Then, the GCF values in the unstable area are used to compute a threshold through the CFAR. Finally, the new gait pattern detection rules are proposed which include the results of the sliding window detector and the division results through the computed threshold. To verify this idea, a data acquisition board is designed to collect the GCF data from able bodied subjects. Meanwhile, in order to test the reliability of the proposed method, five threshold-based methods in the literature are introduced as reference methods and the reliability is validated by comparing the detection results of the proposed method with those of the reference methods. Experimental results indicated that the proposed method could be used for real-time gait pattern detection, detect the gait patterns adaptively and obtain high reliabilities compared with the reference methods. PMID- 30400334 TI - Inhibitory Effects of Helianthus tuberosus Ethanol Extract on Dermatophagoides farina body-induced Atopic Dermatitis Mouse Model and Human Keratinocytes. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by complex symptoms. To treat AD without adverse effects, alternative therapeutic agents are required. The tubers of Helianthus tuberosus L. (Jerusalem artichoke) have been used in folk remedies for diabetes and rheumatism. However, its effect on AD development remains unknown. Therefore, this study examined the inhibitory effect of H. tuberosus (HT) on AD skin symptoms using an NC/Nga mouse model and HaCaT keratinocytes. The effect of HT and associated molecular mechanisms were evaluated in Dermatophagoides farina body (Dfb)-induced AD mice and tumor necrosis factor (TNF)-alpha/interferon (IFN)-gamma-stimulated HaCaT keratinocytes by ELISA, western blot, and histological analysis. Topical HT administration attenuated AD skin symptoms in Dfb-induced AD mice, with a significant reduction in the dermatitis score and production of inflammatory mediators. HT also decreased epidermal thickness and mast cell infiltration. Moreover, HT restored filaggrin expression and inhibited adhesion molecules in the mice. These effects were confirmed in vitro. Furthermore, HT suppressed the activation of NF-kappaB, Akt, and mitogen-activated protein kinase (MAPK) signaling pathways induced by TNF-alpha/IFN-gamma. These results suggest that HT is a potential therapeutic agent or supplement for skin allergic inflammatory diseases such as AD. PMID- 30400336 TI - Significant Enhancement of Hydrogen-Sensing Properties of ZnO Nanofibers through NiO Loading. AB - Metal oxide p-n heterojunction nanofibers (NFs) are among the most promising approaches to enhancing the efficiency of gas sensors. In this paper, we report the preparation of a series of p-NiO-loaded n-ZnO NFs, namely (1-x)ZnO-xNiO (x = 0.03, 0.05, 0.7, 0.1, and 0.15 wt%), for hydrogen gas sensing experiments. Samples were prepared through the electrospinning technique followed by a calcination process. The sensing experiments showed that the sample with 0.05 wt% NiO loading resulted in the highest sensing performance at an optimal sensing temperature of 200 degrees C. The sensing mechanism is discussed in detail and contributions of the p-n heterojunctions, metallization of ZnO and catalytic effect of NiO on the sensing enhancements of an optimized gas sensor are analyzed. This study demonstrates the possibility of fabricating high-performance H2 sensors through the optimization of p-type metal oxide loading on the surfaces of n-type metal oxides. PMID- 30400337 TI - Potential Impact of Climate Change on Schistosomiasis: A Global Assessment Attempt. AB - Based on an ensemble of global circulation models (GCMs), four representative concentration pathways (RCPs) and several ongoing and planned Coupled Model Intercomparison Projects (CMIPs), the Intergovernmental Panel on Climate Change (IPCC) predicts that global, average temperatures will increase by at least 1.5 degrees C in the near future and more by the end of the century if greenhouse gases (GHGs) emissions are not genuinely tempered. While the RCPs are indicative of various amounts of GHGs in the atmosphere the CMIPs are designed to improve the workings of the GCMs. We chose RCP4.5 which represented a medium GHG emission increase and CMIP5, the most recently completed CMIP phase. Combining this meteorological model with a biological counterpart model accounted for replication and survival of the snail intermediate host as well as maturation of the parasite stage inside the snail at different ambient temperatures. The potential geographical distribution of the three main schistosome species: Schistosoma japonicum, S. mansoni and S. haematobium was investigated with reference to their different transmission capabilities at the monthly mean temperature, the maximum temperature of the warmest month(s) and the minimum temperature of the coldest month(s). The set of six maps representing the predicted situations in 2021-2050 and 2071-2100 for each species mainly showed increased transmission areas for all three species but they also left room for potential shrinkages in certain areas. PMID- 30400338 TI - New Metabolites from Endophytic Fungus Chaetomium globosum CDW7. AB - Five metabolites including two new ones, prochaetoviridin A (1) and chaetoindolin A (2), were isolated from the endophytic fungus Chaetomium globosum CDW7. Compounds 1 and 2 were characterized as an isocoumarin and an indole alkaloid derivative, respectively, with their structures elucidated by comprehensive spectroscopic analyses including high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), NMR, and circular dichroism (CD) comparison. Compounds 3-5 were identified as chaetoviridin A, chaetoglobosin R, and chaetoglobosin T, respectively. Chaetoviridin A (3) exhibited antifungal activity against Sclerotinia sclerotiorum with an EC50 value of 1.97 MUg/mL. In vivo test showed that 3 displayed a protective efficacy of 64.3% against rape Sclerotinia rot at the dosage of 200 MUg/mL, comparable to that of carbendazim (69.2%). PMID- 30400339 TI - Polo-Like Kinase 4 (PLK4) Is Overexpressed in Central Nervous System Neuroblastoma (CNS-NB). AB - Neuroblastoma (NB) is the most common extracranial solid tumor in pediatrics, with rare occurrences of primary and metastatic tumors in the central nervous system (CNS). We previously reported the overexpression of the polo-like kinase 4 (PLK4) in embryonal brain tumors. PLK4 has also been found to be overexpressed in a variety of peripheral adult tumors and recently in peripheral NB. Here, we investigated PLK4 expression in NBs of the CNS (CNS-NB) and validated our findings by performing a multi-platform transcriptomic meta-analysis using publicly available data. We evaluated the PLK4 expression by quantitative real time PCR (qRT-PCR) on the CNS-NB samples and compared the relative expression levels among other embryonal and non-embryonal brain tumors. The relative PLK4 expression levels of the NB samples were found to be significantly higher than the non-embryonal brain tumors (p-value < 0.0001 in both our samples and in public databases). Here, we expand upon our previous work that detected PLK4 overexpression in pediatric embryonal tumors to include CNS-NB. As we previously reported, inhibiting PLK4 in embryonal tumors led to decreased tumor cell proliferation, survival, invasion and migration in vitro and tumor growth in vivo, and therefore PLK4 may be a potential new therapeutic approach to CNS-NB. PMID- 30400340 TI - Carbohydrate Intake Does Not Counter the Post-Exercise Decrease in Natural Killer Cell Cytotoxicity. AB - In a study using a randomized crossover approach, cyclists (n = 20, overnight fasted) engaged in three 75 km time trials while ingesting water (WAT) or carbohydrate (0.2 g/kg every 15 min) from bananas (BAN) or a 6% sugar beverage (SUG). Blood samples were collected pre-exercise and 0 h, 1.5 h, and 21 h post exercise and analyzed for natural killer (NK) cytotoxicity activity (NKCA) using pure NK cell populations. The two carbohydrate trials (BAN, SUG) compared to WAT were associated with higher post-exercise glucose and lower cortisol, total blood leukocyte, neutrophil, and NK cell counts (interaction effects, p < 0.001). The immediate post-exercise increase in NK cell counts was higher in WAT (78%) compared to BAN (32%) and SUG (15%) trials (p <= 0.017). The 1.5 h post-exercise decrease in NK cell counts did not differ after WAT (-46%), BAN (-46%), and SUG ( 51%) trials. The pattern of change in post-exercise NKCA differed between trials (p < 0.001). The 1.5 h post-exercise decreases in NKCA were 23%, 29%, and 33% in the WAT, BAN, and SUG trials, respectively, but trial contrasts did not differ significantly. Carbohydrate ingestion from BAN or SUG attenuated immediate post exercise increases in leukocyte, neutrophil, and NK cell counts, but did not counter the 1.5 h decreases in NK cell counts and NKCA. PMID- 30400341 TI - Insecticidal Activity and Synergistic Combinations of Ten Different Bt Toxins against Mythimna separata (Walker). AB - The oriental armyworm (OAW), Mythimna separata (Walker), is a destructive pest of agricultural crops in Asia and Australia. Commercialized Bt crops have performed very well against their target pests; however, very few studies have been done on the susceptibility of OAW to Bt toxins in either sprays or expressed in Bt crops. In this work, we evaluated the toxicities of Cry1Ab, Cry1Ac, Cry1Ah, Cry1Fa, Cry2Aa, Cry2Ab, Cry1Ie, Vip3Aa19, Vip3Aa16, and Vip3Ca against OAW neonate larvae, as well as the interaction between Cry and Vip toxins. The results from bioassays revealed that LC50 (lethal concentration for 50% mortality) values ranged from 1.6 to 78.6 MUg/g (toxin/diet) for those toxins. Among them, Vip3 proteins, along with Cry1A proteins and Cry2Aa, were the ones with the highest potency, with LC50 values ranging from 1.6 to 7.4 MUg/g. Synergism between Cry and Vip toxins was observed, being high in the combination of Vip3Aa16 with Cry1 toxins, with synergetic factors ranging from 2.2 to 9.2. The Vip3Ca toxin did not show any synergistic effect with any of the toxins tested. These results can help in designing new combinations of pyramiding genes in Bt crops, as well as in recombinant bacteria, for the control of OAW as well as for resistance management programs. PMID- 30400342 TI - Is It Possible to Maintain High Compliance with the Enhanced Recovery after Surgery (ERAS) Protocol?-A Cohort Study of 400 Consecutive Colorectal Cancer Patients. AB - The aim of our study was to evaluate the implementation and degree of adherence to the Enhanced Recovery after Surgery (ERAS) protocol in a group of 400 patients operated laparoscopically for colorectal cancer, and to assess its impact on the short-term results. The prospective study included patients with histologically confirmed colorectal cancer undergoing elective laparoscopic resection from years 2012 to 2017. For the purpose of further analysis, patients were divided into four groups: 100 consecutive patients were in each group. There were no statistically significant differences between groups in demographic parameters. The mean compliance with the ERAS protocol in the entire study group was 84.8%. Median adherence differed between the groups 76.9% vs. 92.3% vs. 84.6% vs. 84.6%, respectively (p < 0.0001). There were statistically significant differences between groups in the tolerance of oral diet (54% vs. 83% vs. 83% vs. 64%) and mobilization (74% vs. 92% vs. 91% vs. 94%) on the first postoperative day. In subsequent groups, time to first flatus decreased (2.5 vs. 2.1 vs. 2.0 vs. 1.7 days, p = 0.0001). There were no statistical differences in the postoperative morbidity rate between groups (p = 0.4649). The median length of hospital stay in groups was 5 vs. 4 vs. 4 vs. 4 days, respectively (p = 0.0025). Maintaining high compliance with the ERAS protocol is possible, despite the slight decrease that occurs within a few years after its implementation. This decrease in compliance does not affect short-term results, which are comparable to those shortly after overcoming the learning curve. PMID- 30400343 TI - Nanoemulsion as a Platform for Iontophoretic Delivery of Lipophilic Drugs in Skin Tumors. AB - Lipophilic drugs do not usually benefit from iontophoresis mainly because they do not solubilize in aqueous formulations suitable for the application of electric current. To explore the influence of iontophoresis on penetration of these drugs, a cationic nanoemulsion was developed to solubilize zinc phthalocyanine (ZnPc), a promising drug for the treatment of skin cancer. To verify the influence of particle size on iontophoresis, an emulsion of nanoemulsion-like composition was also developed. The formulations were characterized and cutaneous and tumor penetration studies were performed in vitro and in vivo, respectively. With particles of about 200 nm, the nanoemulsion solubilized 2.5-fold more ZnPc than the 13-um emulsion. At the same concentration of ZnPc, in vitro passive penetration studies showed that the nanoemulsion increased, after 1 h of treatment, by almost 4 times the penetration of ZnPc into the viable layers of the skin when compared to the emulsion, whereas iontophoresis of nanoemulsion resulted in a 16-fold increase in ZnPc penetration in only 30 min. An in vivo study in a murine model of melanoma showed that ZnPc reached the tumor after iontophoresis of the nanoemulsion. Therefore, iontophoresis of nanoemulsions appears to be a promising strategy for the topical treatment of tumors with lipophilic drugs. PMID- 30400345 TI - Controlling the Amorphous and Crystalline State of Multinary Alloy Nanoparticles in An Ionic Liquid. AB - Controlling the amorphous or crystalline state of multinary Cr-Mn-Fe-Co-Ni alloy nanoparticles with sizes in the range between ~1.7 nm and ~4.8 nm is achieved using three processing routes. Direct current sputtering from an alloy target in the ionic liquid 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide leads to amorphous nanoparticles as observed by high-resolution transmission electron microscopy. Crystalline nanoparticles can be achieved in situ in a transmission electron microscope by exposure to an electron beam, ex situ by heating in vacuum, or directly during synthesis by using a high-power impulse magnetron sputtering process. Growth of the nanoparticles with respect to the amorphous particles was observed. Furthermore, the crystal structure can be manipulated by the processing conditions. For example, a body-centered cubic structure is formed during in situ electron beam crystallization while longer ex situ annealing induces a face-centered cubic structure. PMID- 30400346 TI - Study of Osteocyte Behavior by High-Resolution Intravital Imaging Following Photo Induced Ischemia. AB - Ischemic injuries and local hypoxia can result in osteocytes dysfunction and play a key role in the pathogenesis of avascular osteonecrosis. Conventional imaging techniques including magnetic resonance imaging (MRI) and computed tomography (CT) can reveal structural and functional changes within bony anatomy; however, characterization of osteocyte behavioral dynamics in the setting of osteonecrosis at the single cell resolution is limited. Here, we demonstrate an optical approach to study real-time osteocyte functions in vivo. Using nicotinamide adenine dinucleotide (NADH) as a biomarker for metabolic dynamics in osteocytes, we showed that NADH level within osteocytes transiently increase significantly after local ischemia through non-invasive photo-induced thrombosis of afferent arterioles followed by a steady decline. Our study presents a non-invasive optical approach to study osteocyte behavior through the modulation of local environmental conditions. Thus it provides a powerful toolkit to study cellular processes involved in bone pathologies in vivo. PMID- 30400344 TI - The Antibacterial and Anti-Eukaryotic Type VI Secretion System MIX-Effector Repertoire in Vibrionaceae. AB - Vibrionaceae is a widespread family of aquatic bacteria that includes emerging pathogens and symbionts. Many Vibrionaceae harbor a type VI secretion system (T6SS), which is a secretion apparatus used to deliver toxins, termed effectors, into neighboring cells. T6SSs mediate both antibacterial and anti-eukaryotic activities. Notably, antibacterial effectors are encoded together with a gene that encodes a cognate immunity protein so as to antagonize the toxicity of the effector. The MIX (Marker for type sIX effectors) domain has been previously defined as a marker of T6SS effectors carrying polymorphic C-terminal toxins. Here, we set out to identify the Vibrionaceae MIX-effector repertoire and to analyze the various toxin domains they carry. We used a computational approach to search for the MIX-effectors in the Vibrionaceae genomes, and grouped them into clusters based on the C-terminal toxin domains. We classified MIX-effectors as either antibacterial or anti-eukaryotic, based on the presence or absence of adjacent putative immunity genes, respectively. Antibacterial MIX-effectors carrying pore-forming, phospholipase, nuclease, peptidoglycan hydrolase, and protease activities were found. Furthermore, we uncovered novel virulence MIX effectors. These are encoded by "professional MIXologist" strains that employ a cocktail of antibacterial and anti-eukaryotic MIX-effectors. Our findings suggest that certain Vibrionaceae adapted their antibacterial T6SS to mediate interactions with eukaryotic hosts or predators. PMID- 30400347 TI - Mechanistic Analysis of Physicochemical Cues in Promoting Human Pluripotent Stem Cell Self-Renewal and Metabolism. AB - We have previously reported that a porous membrane of polyethylene terephthalate (PET) enables significant augmentation of human pluripotent stem cell (hPSC) proliferation and differentiation. The interaction between hPSCs and the PET surface induces beta-catenin-mediated wingless/integrated (Wnt) signaling, leading to upregulation of the expression of adhesion molecules in hPSCs. In this study, we sought to unveil mechanisms underlying the role of the PET membrane in hPSC self-renewal and metabolism. We discovered that physicochemical cues of the PET membrane considerably alter hPSC metabolism by increasing the cell yield and suppressing the generation of toxic byproduct, indicating an effective cell self renewal and a less apoptotic culture environment in the membrane culture system. Furthermore, we discovered that a caspase-8 medicated apoptotic pathway plays a profound role in obstructing hPSCs grown on a traditional tissue culture plate (TCP). Treating hPSCs seeded on a TCP surface with a caspase-8 inhibitor significantly suppressed cellular apoptotic pathway and improved cell proliferation and metabolism. Our experimental results provided valuable insights into signal pathways influencing hPSC self-renewal during routine maintenance and expansion, which would shed light on large-scale preparation of hPSCs for clinical applications. PMID- 30400348 TI - Moderating Effect of Insulin Resistance on the Relationship between Gray Matter Volumes and Cognitive Function. AB - BACKGROUND: It is controversial whether exposure to insulin resistance accelerates cognitive deterioration. The present study aimed to investigate the association between insulin resistance and gray matter volume loss to predict the cognitive decline. METHODS: We recruited 160 participants (78 with Alzheimer's disease and 82 without Alzheimer's disease). Insulin resistance, regional gray matter volume, and cognitive function were assessed. A hierarchical moderated multiple regression (MMR) model was used to determine any associations among insulin resistance, structural changes in the brain, and cognitive decline. RESULTS: The volumes of 7 regions in the gray matter were negatively related to insulin resistance in Alzheimer's disease (p =0.032). Hierarchical MMR analysis indicated that insulin resistance did not directly affect the cognitive decline but moderated the cognitive decline through the decrease in gray matter volume in the key brain regions, i.e., inferior orbitofrontal gyrus (left), middle cingulate gyrus (right), hippocampus (right), and precuneus (right) (p < 0.05 in each case). CONCLUSION: Insulin resistance appears to exacerbate the cognitive decline associated with several gray matter volume loss. PMID- 30400350 TI - Exposed Areas Above Sea Level on Earth >3.5 Gyr Ago: Implications for Prebiotic and Primitive Biotic Chemistry. AB - How life began on Earth is still largely shrouded in mystery. One of the central ideas for various origins of life scenarios is Darwin's "warm little pond". In these small bodies of water, simple prebiotic compounds such as amino acids, nucleobases, and so on, were produced from reagents such as hydrogen cyanide and aldehydes/ketones. These simple prebiotic compounds underwent further reactions, producing more complex molecules. The process of chemical evolution would have produced increasingly complex molecules, eventually yielding a molecule with the properties of information storage and replication prone to random mutations, the hallmark of both the origin of life and evolution. However, there is one problematic issue with this scenario: On the Earth >3.5 Gyr ago there would have likely been no exposed continental crust above sea level. The only land areas that protruded out of the oceans would have been associated with hotspot volcanic islands, such as the Hawaiian island chain today. On these long-lived islands, in association with reduced gas-rich eruptions accompanied by intense volcanic lightning, prebiotic reagents would have been produced that accumulated in warm or cool little ponds and lakes on the volcano flanks. During seasonal wet-dry cycles, molecules with increasing complexity could have been produced. These islands would have thus been the most likely places for chemical evolution and the processes associated with the origin of life. The islands would eventually be eroded away and their chemical evolution products would have been released into the oceans where Darwinian evolution ultimately produced the biochemistry associated with all life on Earth today. PMID- 30400349 TI - Limonoids Containing a C1-O-C29 Moiety: Isolation, Structural Modification, and Antiviral Activity. AB - Five new limonoids named thaigranatins A-E (1-5), containing a C1-O-C29 moiety, were isolated from seeds of the Thai Xylocarpus granatum, collected at the mangrove swamp of Trang Province, together with the known limonoid, granatumin L (6). The structures of these compounds were established by HR-ESIMS and extensive NMR spectroscopic data. The absolute configuration of 1 was unequivocally determined by single-crystal X-ray diffraction analysis, conducted with Cu Kalpha radiation; whereas that of 2 or 6 was established to be the same as that of 1 by the similarity of their electronic circular dichroism (ECD) spectra. In view of the marked antiviral activity of 6, its structure was modified via hydrolysis with alkaline KOH, esterification with diazomethane and various organic acids, and oximization with hydroxyamine. Finally, 18 derivatives, viz. 7-10, 8a-8i, 9a 9b, and 10a-10c, were obtained. In vitro antiviral activities of these derivatives against human immunodeficiency virus 1 (HIV-1) and influenza A virus (IAV) were evaluated. Most notably, 8i exhibited marked inhibitory activity against HIV-1 with an IC50 value of 15.98 +/- 6.87 MUM and a CC50 value greater than 100.0 MUM; whereas 10b showed significant inhibitory activity against IAV with an IC50 value of 14.02 +/- 3.54 MUM and a CC50 value greater than 100.0 MUM. PMID- 30400351 TI - Tissular Distribution and Metabolism of trans-epsilon-Viniferin after Intraperitoneal Injection in Rat. AB - BACKGROUND: Recent studies showed that trans-epsilon-viniferin (epsilon viniferin), a trans-resveratrol dehydrodimer, has anti-inflammatory and anti obesity effects in rodents. The main purpose of this work was to assess the tissue distribution study of epsilon-viniferin and its metabolites after intraperitoneal (IP) administration in rat. METHODS: After IP injection of 50 mg/kg, epsilon-viniferin and its metabolites were identified and quantified in plasma, liver, kidneys, adipose tissues, urine, and faeces by Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS). RESULTS: epsilon Viniferin underwent a rapid hepatic metabolism mostly to glucuronides but also to a lesser extent to sulphate derivatives. The highest glucuronide concentrations were found in liver followed by plasma and kidneys whereas only traces amounts were found in adipose tissues. In contrast the highest epsilon-viniferin areas under concentration (AUC) and mean residence times (MRT) values were found in white adipose tissues. Finally, much lower levels of epsilon-viniferin or its metabolites were found in urine than in faeces, suggesting that biliary excretion is the main elimination pathway. CONCLUSION: A rapid and large metabolism of epsilon-viniferin and a high bioaccumulation in white adipose tissues were observed. Thus, these tissues could be a reservoir of the native form of epsilon viniferin that could allow its slow release and a sustained presence within the organism. PMID- 30400352 TI - Preventive Effect of Garlic Oil and Its Organosulfur Component Diallyl-Disulfide on Cigarette Smoke-Induced Airway Inflammation in Mice. AB - Garlic (Allium sativum) has traditionally been used as a medicinal food and exhibits various beneficial activities, such as antitumor, antimicrobial, hypolipidemic, antiarthritic, and hypoglycemic activities. The aim of this study was to explore the preventive effect of garlic oil (GO) and its organosulfur component diallyl disulfide (DADS) on cigarette smoke (CS)-induced airway inflammation. Mice were exposed to CS daily for 1 h (equivalent to eight cigarettes per day) for two weeks, and intranasally instilled with lipopolysaccharide (LPS) on day 12 after the initiation of CS exposure. GO and DADS were administered to mice by oral gavage, both at rates of 20 and 40 mg/kg, for 1 h before CS exposure for two weeks. In the bronchoalveolar lavage fluid, GO and DADS inhibited the elevation in the counts of inflammatory cells, particularly neutrophils, which were induced in the CS and LPS (CS + LPS) group. This was accompanied by the lowered production (relative to the CS + LPS group) of interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha. Histologically, GO and DADS inhibited the CS- and LPS-induced infiltration of inflammatory cells into lung tissues. Additionally, GO and DADS inhibited the phosphorylation of extracellular signal-regulated kinase and the expression of matrix metalloproteinase-9 in the lung tissues. Taken together, these findings indicate that GO and DADS could be a potential preventive agent in CS-induced airway inflammation. PMID- 30400353 TI - iTRAQ-Based Analysis of Proteins Co-Regulated by Brassinosteroids and Gibberellins in Rice Embryos during Seed Germination. AB - Seed germination, a pivotal process in higher plants, is precisely regulated by various external and internal stimuli, including brassinosteroid (BR) and gibberellin (GA) phytohormones. The molecular mechanisms of crosstalk between BRs and GAs in regulating plant growth are well established. However, whether BRs interact with GAs to coordinate seed germination remains unknown, as do their common downstream targets. In the present study, 45 differentially expressed proteins responding to both BR and GA deficiency were identified using isobaric tags for relative and absolute quantification (iTRAQ) proteomic analysis during seed germination. The results indicate that crosstalk between BRs and GAs participates in seed germination, at least in part, by modulating the same set of responsive proteins. Moreover, most targets exhibited concordant changes in response to BR and GA deficiency, and gene ontology (GO) indicated that most possess catalytic activity and are involved in various metabolic processes. Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) analysis was used to construct a regulatory network of downstream proteins mediating BR- and GA-regulated seed germination. The mutation of GRP, one representative target, notably suppressed seed germination. Our findings not only provide critical clues for validating BR-GA crosstalk during rice seed germination, but also help to optimise molecular regulatory networks. PMID- 30400354 TI - Elevated Levels of Serum IL-17A in Community-Dwelling Women with Higher Depressive Symptoms. AB - Recent studies indicate that patients with depression have increased concentrations of serum pro-inflammatory cytokines. However, studies of IL-17 and studies on community-dwellers are few. The purpose of this study was to investigate serum cytokine levels, especially IL-17A, among subjects with high and low depressive symptoms of a general population. The participants comprised 20 female community-dwellers aged 40 years or older who contributed to a Shika study in Ishikawa, Japan. Ten participants who showed higher and ten who showed lower depressive symptoms among 208 females assessed by the Japanese version of the Centre for Epidemiologic Studies Depression Scale (CES-D) were selected for this study. Serum samples were analyzed for TNF-alpha, IL-6, IL-10, IL-12, and IL 17A using a multiplex Luminex analysis. For the comparison between the high and low depressive groups statistically, linear regression analyses were applied. The serum level of IL-17A was significantly higher among the high depressive participants (p < 0.05) even after controlling possible confounders, whereas there were no differences in TNF-alpha, IL-6, IL-10, or IL-12 between the high and low depressive groups. Our findings supported an association between serum IL 17A levels and depressive symptoms. Peripheral IL-17A immune response may be a preventive and treatment target for depression. PMID- 30400356 TI - Preparation of Functional Monomers as Precursors of Bioprobes from a Common Styrene Derivative and Polymer Synthesis. AB - CM-Str (4-(Chloromethyl)styrene) was used as a useful starting material for the construction of a series of functional monomers. Substitution of the chlorine to the corresponding azide was performed, and the reduction of the azide proceeded smoothly to afford an aminostyrene, which was used as a common precursor for the preparation of functional monomers. Condensation of the amine with a fluorophore, biotin and carbohydrate was accomplished. Among the monomers, a carbohydrate monomer was polymerized with or without acrylamide as a model polymerization to yield the corresponding water-soluble glycopolymers, and biological evaluations of the glycopolymers for a lectin, and wheat germ agglutinin (WGA), were carried out on the basis of the fluorescence change of tryptophan in the WGA. PMID- 30400357 TI - Translation and Validation of the Malay Version of the Parents' Satisfaction Scale (PSS-M) for Assessment of Caregivers' Satisfaction with Health Care Services for Children with Autism Spectrum Disorder. AB - BACKGROUND: A Malay version of Parent Satisfaction Scale (PSS-M) is needed to investigate the factors contributing to the Malay caregivers' satisfaction with health care management for children with autism spectrum disorder (ASD). The aim of the study is to translate and validate the questionnaire to assess the caregivers' satisfaction on health care services. METHODS: A cross-sectional study was conducted among 110 caregivers of children with ASD aged between 2 and 17 years old that received treatment at two tertiary care centres in Kelantan. Permission to use the original version of the PSS questionnaire was obtained. The original English version of the PSS was translated into a Malay version following the 10 steps proposed by an established guideline. Pre-testing of the PSS was carried out with 30 caregivers before confirmatory factor analysis (CFA) was established using 110 caregivers. They were asked to assess their understanding of the questionnaire. The one-dimensional questionnaire consists of 11 items, including staff attitudes, availability of staff, supportiveness, and helpfulness. The 5-point Likert scale provided ratings from 1 (strongly disagree) to 5 (strongly agree). Confirmatory factor analysis was performed using a robust maximum likelihood estimator. RESULTS: The analysis showed model fit data with good reliability. CONCLUSION: The PSS-M shows overall model fitness based on specific indices, with good construct validity and excellent absolute reliability to determine the satisfaction level of caregivers of children with ASD with respect to health care services. PMID- 30400358 TI - Graphene-Modulated Removal Performance of Nitrogen and Phosphorus Pollutants in a Sequencing Batch Chlorella Reactor. AB - In this work, the influence of graphene on nitrogen and phosphorus in a batch Chlorella reactor was studied. The impact of graphene on the removal performance of Chlorella was investigated in a home-built sewage treatment system with seven identical sequencing batch Chlorella reactors with graphene contents of 0 mg/L (T1), 0.05 mg/L (T2), 0.1 mg/L (T3), 0.2 mg/L (T4), 0.4 mg/L (T5), 0.8 mg/L (T6) and 10 mg/L (T7). The influence of graphene concentration and reaction time on the pollutant removal performance was studied. The malondialdehyde (MDA) and total superoxide dismutase (SOD) concentrations in each reactor were measured, and optical microscopy and scanning electron microscopy (SEM) characterizations were performed to determine the related mechanism. The results show that after 168 h, the total nitrogen (TN), ammonia nitrogen (AN) and total phosphorus (TP) removal rates of reactors T1-T7 become stable, and the TN, AN and TP removal rates were gradually reduced with increasing graphene concentration. At 96 h, the concentrations of both MDA and SOD in T1-T7 gradually increased as the graphene concentration increased. In optical microscopy and SEM measurements, it was found that graphene was adsorbed on the surface of Chlorella, and entered Chlorella cells, deforming and reducing Chlorella. Through the blood plate count method, we estimated an average Chlorella reduction of 16%. According to the water quality and microscopic experiments, it can be concluded that the addition of graphene causes oxidative damage to microalgae and destruction of the Chlorella cell wall and cell membrane, inhibiting the nitrogen and phosphorus removal in Chlorella reactors. This study provides theoretical and practical support for the safe use of graphene. PMID- 30400359 TI - Estimating Three-Dimensional Body Orientation Based on an Improved Complementary Filter for Human Motion Tracking. AB - Rigid body orientation determined by IMU (Inertial Measurement Unit) is widely applied in robotics, navigation, rehabilitation, and human-computer interaction. In this paper, aiming at dynamically fusing quaternions computed from angular rate integration and FQA algorithm, a quaternion-based complementary filter algorithm is proposed to support a computationally efficient, wearable motion tracking system. Firstly, a gradient descent method is used to determine a function from several sample points. Secondly, this function is used to dynamically estimate the fusion coefficient based on the deviation between measured magnetic field, gravity vectors and their references in Earth-fixed frame. Thirdly, a test machine is designed to evaluate the performance of designed filter. Experimental results validate the filter design and show its potential of real-time human motion tracking. PMID- 30400355 TI - Dietary Intake in Population with Metabolic Syndrome: Is the Prevalence of Inadequate Intake Influenced by Geographical Area? Cross-Sectional Analysis from PREDIMED-Plus Study. AB - Inadequate diet influences chronic diseases such as cardiovascular disease (CVD), the leading cause of death in Spain. CVD figures vary from one geographical region to another; this could be associated with different food choices. Our aim was to analyse the influence of geographical area on nutrient intakes among the Spanish adult population with Metabolic Syndrome (MetS). We analysed cross sectional baseline data from the PREDIMED-Plus study: 6646 Spanish adults, aged 55-75 years, with overweight/obesity and MetS in four geographical areas. A validated 143-item Food Frequency Questionnaire (FFQ) was used to assess energy and nutrient intakes. The prevalence of inadequate nutrient intake was estimated according to Dietary Reference Intakes (DRIs). Multivariable-adjusted logistic regression was used to assess the relationship between geographical area (North, Central, East and South areas) and inadequate nutrient intake. People in the North area consumed significantly lower amounts of vegetables and fish but more sugar and alcohol (p < 0.001) than other areas. Dietary fibre, vitamin A, E, calcium and magnesium intakes were all lower among men of North area than in the other areas (p < 0.001). Sex (women), non-smoker and physical activity were also associated to adequate nutrient intake. Geographical area influences nutrient intakes. Its effect on dietary quality should be taken into account when planning food policies. PMID- 30400361 TI - Heterologous Expression of the Nybomycin Gene Cluster from the Marine Strain Streptomyces albus subsp. chlorinus NRRL B-24108. AB - Streptomycetes represent an important reservoir of active secondary metabolites with potential applications in the pharmaceutical industry. The gene clusters responsible for their production are often cryptic under laboratory growth conditions. Characterization of these clusters is therefore essential for the discovery of new microbial pharmaceutical drugs. Here, we report the identification of the previously uncharacterized nybomycin gene cluster from the marine actinomycete Streptomyces albus subsp. chlorinus through its heterologous expression. Nybomycin has previously been reported to act against quinolone resistant Staphylococcus aureus strains harboring a mutated gyrA gene but not against those with intact gyrA. The nybomycin-resistant mutants generated from quinolone-resistant mutants have been reported to be caused by a back-mutation in the gyrA gene that restores susceptibility to quinolones. On the basis of gene function assignment from bioinformatics analysis, we suggest a model for nybomycin biosynthesis. PMID- 30400362 TI - A Self Regulating and Crowdsourced Indoor Positioning System through Wi-Fi Fingerprinting for Multi Storey Building. AB - Unobtrusive indoor location systems must rely on methods that avoid the deployment of large hardware infrastructures or require information owned by network administrators. Fingerprinting methods can work under these circumstances by comparing the real-time received RSSI values of a smartphone coming from existing Wi-Fi access points with a previous database of stored values with known locations. Under the fingerprinting approach, conventional methods suffer from large indoor scenarios since the number of fingerprints grows with the localization area. To that aim, fingerprinting-based localization systems require fast machine learning algorithms that reduce the computational complexity when comparing real-time and stored values. In this paper, popular machine learning (ML) algorithms have been implemented for the classification of real time RSSI values to predict the user location and propose an intelligent indoor positioning system (I-IPS). The proposed I-IPS has been integrated with multi-agent framework for betterment of context-aware service (CAS). The obtained results have been analyzed and validated through established statistical measurements and superior performance achieved. PMID- 30400360 TI - A Comprehensive Review of Chemistry, Sources and Bioavailability of Omega-3 Fatty Acids. AB - Omega-3 fatty acids, one of the key building blocks of cell membranes, have been of particular interest to scientists for many years. However, only a small group of the most important omega-3 polyunsaturated fatty acids are considered. This full-length review presents a broad and relatively complete cross-section of knowledge about omega-3 monounsaturated fatty acids, polyunsaturates, and an outline of their modifications. This is important because all these subgroups undoubtedly play an important role in the function of organisms. Some monounsaturated omega-3s are pheromone precursors in insects. Polyunsaturates with a very long chain are commonly found in the central nervous system and mammalian testes, in sponge organisms, and are also immunomodulating agents. Numerous modifications of omega-3 acids are plant hormones. Their chemical structure, chemical binding (in triacylglycerols, phospholipids, and ethyl esters) and bioavailability have been widely discussed indicating a correlation between the last two. Particular attention is paid to the effective methods of supplementation, and a detailed list of sources of omega-3 acids is presented, with meticulous reference to the generally available food. Both the oral and parenteral routes of administration are taken into account, and the omega-3 transport through the blood-brain barrier is mentioned. Having different eating habits in mind, the interactions between food fatty acids intake are discussed. Omega-3 acids are very susceptible to oxidation, and storage conditions often lead to a dramatic increase in this exposure. Therefore, the effect of oxidation on their bioavailability is briefly outlined. PMID- 30400364 TI - Sensor Information Fusion by Integrated AI to Control Public Emotion in a Cyber Physical Environment. AB - The cyber-physical system (CPS) is a next-generation smart system that combines computing with physical space. It has been applied in various fields because the uncertainty of the physical world can be ideally controlled using cyber technology. In terms of environmental control, studies have been conducted to enhance the effectiveness of the service by inducing ideal emotions in the service space. This paper proposes a CPS control system for inducing emotion based on multiple sensors. The CPS can expand the constrained environmental sensors of the physical space variously by combining the virtual space with the physical space. The cyber space is constructed in a Unity 3D space that can be experienced through virtual reality devices. We collect the temperature, humidity, dust concentration, and current emotion in the physical space as an environmental control elements, and the control illumination, color temperature, video, sound and volume in the cyber space. The proposed system consists of an emotion prediction module using modular Bayesian networks and an optimal stimulus decision module for deriving the predicted emotion to the target emotion based on utility theory and reinforcement learning. To verify the system, the performance is evaluated using the data collected from real situations. PMID- 30400363 TI - Total and Nonheme Dietary Iron Intake Is Associated with Metabolic Syndrome and Its Components in Chinese Men and Women. AB - The causal relationship between serum ferritin and metabolic syndrome (MetS) remains inconclusive. Dietary iron intake increases serum ferritin. The objective of this study was to evaluate associations of total, heme, and nonheme dietary iron intake with MetS and its components in men and women in metropolitan China. Data from 3099 participants in the Shanghai Diet and Health Survey (SDHS) obtained during 2012-2013 were included in this analysis. Dietary intake was assessed by 24-h diet records from 3 consecutive days. Multivariate generalized linear mixed models were used to evaluate the associations of dietary iron intake with MetS and its components. After adjustment for potential confounders as age, sex, income, physical exercise, smoking status, alcohol use, and energy intake, a positive trend was observed across quartiles of total iron intake and risk of MetS (p for trend = 0.022). Compared with the lowest quartile of total iron intake (<12.72 mg/day), the highest quartile (>=21.88 mg/day) had an odds ratio (95% confidence interval), OR (95% CI), of 1.59 (1.15,2.20). In addition, the highest quartile of nonheme iron intake (>=20.10 mg/day) had a 1.44-fold higher risk of MetS compared with the lowest quartile (<11.62 mg/day), and higher risks of MetS components were associated with the third quartiles of total and nonheme iron intake. There was no association between heme iron intake and risk of MetS (p for trend = 0.895). Associations for total and nonheme iron intake with MetS risk were found in men but not in women. Total and nonheme dietary iron intake was found to be positively associated with MetS and its components in the adult population in metropolitan China. This research also revealed a gender difference in the association between dietary iron intake and MetS. PMID- 30400365 TI - Nonlinear Cellular Mechanical Behavior Adaptation to Substrate Mechanics Identified by Atomic Force Microscope. AB - Cell-substrate interaction plays an important role in intracellular behavior and function. Adherent cell mechanics is directly regulated by the substrate mechanics. However, previous studies on the effect of substrate mechanics only focused on the stiffness relation between the substrate and the cells, and how the substrate stiffness affects the time-scale and length-scale of the cell mechanics has not yet been studied. The absence of this information directly limits the in-depth understanding of the cellular mechanotransduction process. In this study, the effect of substrate mechanics on the nonlinear biomechanical behavior of living cells was investigated using indentation-based atomic force microscopy. The mechanical properties and their nonlinearities of the cells cultured on four substrates with distinct mechanical properties were thoroughly investigated. Furthermore, the actin filament (F-actin) cytoskeleton of the cells was fluorescently stained to investigate the adaptation of F-actin cytoskeleton structure to the substrate mechanics. It was found that living cells sense and adapt to substrate mechanics: the cellular Young's modulus, shear modulus, apparent viscosity, and their nonlinearities (mechanical property vs. measurement depth relation) were adapted to the substrates' nonlinear mechanics. Moreover, the positive correlation between the cellular poroelasticity and the indentation remained the same regardless of the substrate stiffness nonlinearity, but was indeed more pronounced for the cells seeded on the softer substrates. Comparison of the F-actin cytoskeleton morphology confirmed that the substrate affects the cell mechanics by regulating the intracellular structure. PMID- 30400366 TI - Comparison of Microstructure and Properties of In-Situ TiN- and WC-Reinforced NiCrBSi Composite Coatings Prepared by Plasma Spraying. AB - In this study, NiCrBSi-30 wt.% TiN composite (NTC) coating was produced on carbon steel via plasma spraying, with NiCrBSi-30 wt.% WC composite (NWC) coating as the comparison object. The microstructure and phase constituents of the composite coatings were characterized using scanning electron microscopy (SEM) coupled with energy dispersive spectroscopy (EDS) techniques, transmission electron microscopy (TEM) and x-ray diffraction (XRD). Atomic force microscopy (AFM) was used to measure electronic work functions. The microhardness and wear performance of coatings were also investigated. The average microhardness of the NTC and NWC coatings was 1000 HV and 850 HV, respectively. In addition, the NTC coating had a wear volume loss of 0.8118 mm3, less than 1.4772 mm3, the volume loss of the NWC coating. This was due to the presence of TiN in the form of nanograins in the composite coating and tighter binding to the matrix. PMID- 30400367 TI - Dietary Intake of Anti-Oxidant Vitamins A, C, and E Is Inversely Associated with Adverse Cardiovascular Outcomes in Chinese-A 22-Years Population-Based Prospective Study. AB - Background: Conflicting and population-dependent findings have been reported from epidemiological studies on the associations of dietary intake of anti-oxidant vitamins with cardiovascular events. We investigated the prospective relationship between dietary intake of anti-oxidant vitamins and incident adverse cardiovascular outcomes amongst Hong Kong Chinese. Methods: In this prospective population-based study, baseline dietary intake of anti-oxidant vitamins (A, C, and E) were assessed using a food frequency questionnaire in 875 Chinese participants from the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS) in 1995-1996. The adjusted hazard ratio (HR) of incident adverse cardiovascular outcomes, defined as the first recorded diagnosis of cardiovascular deaths, non-fatal myocardial infarction or non-fatal stroke, and coronary or other arterial revascularizations, was calculated per unit intake of each vitamin using multivariable Cox regression. Results: Over a median follow-up of 22 years, 85 participants (9.7%) developed adverse cardiovascular outcomes. Dietary intakes of vitamin A, C, and E were independently and inversely associated with incident adverse cardiovascular outcomes (HR 0.68, 95%CI 0.53 0.88, p = 0.003 for vitamin A; HR 0.66, 95%CI 0.52-0.85, p = 0.001 for vitamin C; and HR 0.57, 95%CI 0.38-0.86, p = 0.017 for vitamin E) after adjustments for conventional cardiovascular risk factors at baseline. Conclusions: Dietary intakes of anti-oxidant vitamins A, C, and E reduced the risk of adverse cardiovascular outcomes in Hong Kong Chinese. PMID- 30400368 TI - An Evaluation of Environmental Governance in Urban China Based on a Hesitant Fuzzy Linguistic Analytic Network Process. AB - The aim of this study is to evaluate the performance of urban environmental governance by developing hesitant fuzzy linguistic analytic network process (HFL ANP). The study bridges the gaps in current knowledge in the following ways: the study methodically develops the HFL-ANP method to evaluate and pick the optimal environmental governance strategy from alternatives; theoretically, network structure of evaluation indicators system on environmental governance is constructed, and the objective and subjective information in the evaluation process of environmental governance is combined. In detail, based on the environmental Kuznets curve (EKC) and the pollution haven hypothesis, the paper constructs the evaluation indexes system of environmental governance and takes observation time length into consideration. Then, we choose three urban cases of environmental governance by exploring the existing literature. Furthermore, we develop the HFL-ANP method and apply it to the cases. The study calculates the initial weights of all indexes by using multiplicative consistency of the HFL preference relation, and derives the decision matrix through combining objective information with subjective information of environmental governance. Finally, we come to the following conclusions: ANP network stricture is close to real-world practical problems and provides the basis for HFL-ANP method; HFL-ANP is a very suitable method of assessing environmental governance; and based on the urban cases of environmental governance, Shanghai is the optimal alternative. In addition, this indicator system can only be applied to cities in China, and the administrative hierarchy of policies has not been considered by this method. Thus, future studies should expand this method and indicator network to contain different countries and different administrative hierarchy. PMID- 30400369 TI - Newly Identified Essential Amino Acids Affecting Chlorella ellipsoidea DGAT1 Function Revealed by Site-Directed Mutagenesis. AB - Diacylglycerol acyltransferase (DGAT) is a rate-limiting enzyme in the synthesis of triacylglycerol (TAG), the most important form of energy storage in plants. Some residues have previously been proven to be crucial for DGAT1 activity. In this study, we used site-directed mutagenesis of the CeDGAT1 gene from Chlorella ellipsoidea to alter 16 amino acids to investigate effects on DGAT1 function. Of the 16 residues (L482R, E542R, Y553A, G577R, R579D, Y582R, R596D, H603D, H609D, A624R, F629R, S632A, W650R, A651R, Q658H, and P660R), we newly identified 5 (L482, R579, H603, A651, and P660) as being essential for DGAT1 function and 7 (E542, G577, R596, H609, A624, S632, and Q658) that significantly affect DGAT1 function to different degrees, as revealed by heterologous expression of the mutants in yeast strain INVSc1. Importantly, compared with CeDGAT1, expression of the mutant CeDGAT1Y553A significantly increased the total fatty acid and TAG contents of INVSc1. Comparison among CeDGAT1Y553A, GmDGAT1Y341A, AtDGAT1Y364A, BnDGAT1Y347A, and BoDGAT1Y352A, in which tyrosine at the position corresponding to the 553rd residue in CeDGAT1 is changed into alanine, indicated that the impact of changing Y to A at position 553 is specific for CeDGAT1. Overall, the results provide novel insight into the structure and function of DGAT1, as well as a mutant gene with high potential for lipid improvement in microalgae and plants. PMID- 30400370 TI - Radiotherapy Advances in Pediatric Neuro-Oncology. AB - Radiation therapy (RT) represents an integral component in the treatment of many pediatric brain tumors. Multiple advances have emerged within pediatric radiation oncology that aim to optimize the therapeutic ratio-improving disease control while limiting RT-related toxicity. These include innovations in treatment planning with magnetic resonance imaging (MRI) simulation, as well as increasingly sophisticated radiation delivery techniques. Advanced RT techniques, including photon-based RT such as intensity-modulated RT (IMRT) and volumetric modulated arc therapy (VMAT), as well as particle beam therapy and stereotactic RT, have afforded an array of options to dramatically reduce radiation exposure of uninvolved normal tissues while treating target volumes. Along with advances in image guidance of radiation treatments, novel RT approaches are being implemented in ongoing and future prospective clinical trials. As the era of molecular risk stratification unfolds, personalization of radiation dose, target, and technique holds the promise to meaningfully improve outcomes for pediatric neuro-oncology patients. PMID- 30400371 TI - Ginseng (Panax ginseng Meyer) Oligopeptides Protect Against Binge Drinking Induced Liver Damage through Inhibiting Oxidative Stress and Inflammation in Rats. AB - Panax ginseng C.A. Meyer (ginseng) is an edible and traditional medicinal herb, which is reported to have a wide range of biological activity and pharmaceutical properties. There were more studies on ginsenoside and polysaccharides, but fewer on ginseng oligopeptides (GOPs), which are small molecule oligopeptides extracted from ginseng. The present study was designed to investigate the effects and underlying mechanism of ginseng oligopeptide (GOPs) on binge drinking-induced alcohol damage in rats. Sprague Dawley rats were randomly assigned to six groups (n = 10), rats in normal control group and alcohol model group was administered distilled water; rats in four GOPs intervention groups (at a dose of 0.0625, 0.125, 0.25, 0.5 g/kg of body weight, respectively) were administered GOPs once a day for 30 days. Experiment rats were intragastrically administered ethanol at a one-time dose of 7 g/kg of body weight after 30 days. The liver injury was measured through traditional liver enzymes, inflammatory cytokines, expression of oxidative stress markers, and histopathological examination. We found that the GOPs treatment could significantly improve serum alanine aminotransferase and aspartate aminotransferase, plasma lipopolysaccharide, and inflammatory cytokine levels, as well as the oxidative stress markers that were altered by alcohol. Moreover, GOPs treatment inhibited the protein expression of toll-like receptor 4, and repressed the inhibitor kappa Balpha and nuclear factor-kappaB p65 in the liver. These findings suggested that GOPs have a significant protective effect on binge drinking-induced liver injury, and the mechanism possibly mediated by the partial inhibition of lipopolysaccharide-toll-like receptor 4-nuclear factor kappaB p65 signaling in the liver. PMID- 30400372 TI - Short-Term Hemodynamic Effects of Modern Wheat Products Substitution in Diet with Ancient Wheat Products: A Cross-Over, Randomized Clinical Trial. AB - Recent evidence suggests that bioactive compounds isolated from cereals and legumes could exert some metabolic and vascular effects in humans. Due to the recent identification of a non-specific lipid transfer protein (nsLTP2) in wheat with antioxidant and anti-inflammatory activity, we aimed to comparatively test the hemodynamic and metabolic effects of ancient wheat foodstuffs (made of organic KAMUT(r) khorasan wheat) or modern wheat ones, made of a mixture of organic modern commercial durum (T. durum) varieties and soft wheat (T. aestivum), with different nsLTP2 content. Thus, we carried out a randomized, cross-over clinical trial on 63 non-diabetic healthy volunteers (aged 40-70 years) with systolic blood pressure (SBP) 130-139 mmHg and/or diastolic blood pressure (DBP) 85-90 mmHg (pre-hypertensive/borderline high pressure subjects). Each treatment period lasted four weeks. After ancient wheat foodstuffs intake, subjects experienced a significant improvement in triglycerides (-9.8% vs. baseline and -14.5% versus modern wheat), fasting plasma glucose (-4.3% versus baseline and -31.6% versus modern wheat), diurnal SBP (-3.1% vs. baseline and 30.2% vs. modern wheat) and nocturnal SBP (-3.2% vs. baseline and -36.8% vs. modern wheat), and pulse volume change (+4.2% vs. baseline and +2.3% vs. modern wheat) (p < 0.05 vs. baseline and versus modern wheat foodstuffs intake). Therefore, our findings show that substituting modern wheat products in diet with ancient wheat ones, might exert a mild improvement in 24-h SBP and endothelial reactivity in pre-hypertensive healthy subjects. PMID- 30400373 TI - Is More Better? Insights on Consumers' Preferences for Nutritional Information on Wine Labelling. AB - BACKGROUND: Nowadays there is a strong debate on the need to introduce mandatory nutritional information on alcoholic beverages labels, and particularly on wine, as a tool to promote more health-conscious drinking patterns in society. In 2018, the European alcoholic beverages industry presented a self-regulatory proposal, now under assessment by the European Commission. The most critical issue is how to convey nutritional information to consumers, as producers should decide to apply information on label or off-label. METHOD: The current study measured, through a non-hypothetical, incentive compatible artefactual field experiment, Italian wine consumers (N = 103) preferences for four different formats of wine nutritional labelling, namely: back label with the indication of kcal for glass of wine, with the nutritional panel referred to 100 mL, without nutritional information (but with a link to an external website) and with the indication of key nutrients for glass of wine. RESULTS: Findings reveal that respondents preferred the nutritional panel on the back label, assigning the lowest preference to the less informative wine label (only with a website recall). Furthermore, results show a low level of respondents' knowledge of wine nutritional properties. CONCLUSION: Findings, while limited in terms of sample representativeness, seem to support the European Consumer Organisation and the European Alcohol Policy Alliance objection to an off-line label and the advocacy for a traditional and complete on label nutritional information on wine. PMID- 30400374 TI - End-User Feedback on a Low-Cost Portable Air Quality Sensor System-Are We There Yet? AB - Low-cost sensors are a current trend in citizen science projects that focus on air quality. Until now, devices incorporating such sensors have been tested primarily for their technical capabilities and limitations, whereas their usability and acceptability amongst the public rarely goes beyond proof of concept, leaving user experience (UX) unstudied. The authors argue that UX should be taken into account to make sure that products and services are fit for purpose. Nineteen volunteers tested and evaluated a prototype device and provided feedback through semi-structured interviews and during focus group sessions. Their UX was then coded using mixed coding methods regarding device functionality and recommendations for future product development. The results indicate that UX can identify potentially problematic design aspects while giving deeper insights into user needs. For example, UX recognized that one of the most important aspects of user involvement and motivation was successful data harvesting, which frequently failed. This study recommends that future developers of low-cost portable air quality sensor systems prioritize reliable data transmission to minimize data loss. This will ensure an efficient and positive UX that supports user engagement in citizen science based research where collecting sensor-based data is the primary objective. PMID- 30400375 TI - Panton-Valentine Leucocidin Proves Direct Neuronal Targeting and Its Early Neuronal and Glial Impacts a Rabbit Retinal Explant Model. AB - : Panton-Valentine leukocidin (PVL) retinal intoxication induces glial activation and inflammatory response via the interaction with retinal neurons. In this study, rabbit retinal explant was used as a model to study neuronal and glial consequences of PVL intoxication. Retinal explants were treated with different concentrations of PVL. PVL location and neuronal and glial changes were examined using immunohistochemistry. Some inflammatory factors were quantified using RT qPCR at 4 and 8 h. These results were compared with those of control explants. PVL co-localized rapidly with retinal ganglion cells and with horizontal cells. PVL induced Muller and microglial cell activation. Retinal structure was altered and some amacrine and microglial cells underwent apoptosis. Glial activation and cell apoptosis increased in a PVL concentration- and time-dependent manner. IL-6 and IL-8 expression increased in PVL-treated explants but less than in control explants, which may indicate that other factors were responsible for glial activation and retinal apoptosis. On retinal explants, PVL co-localized with neuronal cells and induced glial activation together with microglial apoptosis, which confirms previous results observed in in vivo model. Rabbit retinal explant seems to be suitable model to further study the process of PVL leading to glial activation and retinal cells apoptosis. PMID- 30400376 TI - Self-Dissolving Microneedle Arrays for Transdermal Absorption Enhancement of Human Parathyroid Hormone (1-34). AB - Human parathyroid hormone (1-34) (PTH) has been widely used as the subcutaneous injection formulation for the treatment of osteoporosis. In the present study, we developed an efficient transdermal delivery system of PTH by using dissolving microneedle arrays (MNs) composed of hyaluronic acid (HA) for the treatment of osteoporosis. PTH-loaded MNs, with needle length 800 um, were fabricated via a micro-molding method. The stability of PTH in MNs was found to be 6-fold higher than that of PTH solution when stored at room temperature (15-20 degrees C) for one month. Micron-scale pores were clearly visible in rat skin following application of PTH-loaded MNs. PTH-loaded MNs were completely dissolved by 60 min following application to rat skin. The bioavailability (BA) of PTH relative to subcutaneous injection was 100 +/- 4% following application of PTH-loaded MNs in rats. In addition, PTH-loaded MNs were found to effectively suppress decreases in bone density in a rat model of osteoporosis. Furthermore, no skin irritation was observed at the site of application in rats. These findings indicate that our dissolving MNs have a potential use in formulations for the transdermal delivery of PTH and for the treatment of osteoporosis. PMID- 30400377 TI - Improving the Security and QoE in Mobile Devices through an Intelligent and Adaptive Continuous Authentication System. AB - Continuous authentication systems for mobile devices focus on identifying users according to their behaviour patterns when they interact with mobile devices. Among the benefits provided by these systems, we highlight the enhancement of the system security, having permanently authenticated the users; and the improvement of the users' quality of experience, minimising the use of authentication credentials. Despite the benefits of these systems, they also have open challenges such as the authentication accuracy and the adaptability to new users' behaviours. Continuous authentication systems should manage these challenges without forgetting critical aspects of mobile devices such as battery consumption, computational limitations and response time. With the goal of improving these previous challenges, the main contribution of this paper is the design and implementation of an intelligent and adaptive continuous authentication system for mobile devices. The proposed system enables the real time users' authentication by considering statistical information from applications, sensors and Machine Learning techniques based on anomaly detection. Several experiments demonstrated the accuracy, adaptability, and resources consumption of our solution. Finally, its utility is validated through the design and implementation of an online bank application as proof of concept, which allows users to perform different actions according to their authentication level. PMID- 30400378 TI - Development of High-Performance Enamel Coating on Grey Iron by Low-Temperature Sintering. AB - In this study, we report on a low-temperature sintered enamel coating with a high strength bonding and wear-resistance that protected a grey cast iron substrate. The SiO2-Al2O3-B2O3 composited prescription for the enamel coating was modified by the partial substitutions of SiO2 for B2O3 and alkali metals for Li2O. The optimized enamel coating was prepared by sintering at a relatively low temperature (730 degrees C) for seven minutes. Due to the composition of both the amorphous and crystalline phases, the enamel coating presented sufficient hardness and excellent wear resistance. The wear volume loss and the specific wear rate of the enamel coating were obviously lower than that of the metal substrate. The enamel coating can effectively improve the service life of the grey cast iron substrate in a complex frictional environment. PMID- 30400379 TI - Patient and Provider Perspectives on a Decision Aid for Familial Hypercholesterolemia. AB - Familial Hypercholesterolemia (FH) is an inherited disorder associated with increased cardiovascular risk that requires patients to make multiple impactful decisions regarding the management of their condition. Patient decision aids (PDAs) can facilitate shared decision-making (SDM) and enable patients to make choices that are concordant with their goals and values. To inform the development of a PDA for patients with FH, we employed a qualitative inductive approach and focus group discussions with patients, physicians, and genetic counselors. We explored and analyzed the perceptions and understanding of these stakeholders related to a PDA for FH and identified important concepts to include in the PDA. Categories emerging from focus group discussions included: (a) perceptions of a PDA related to FH; (b) discussion about the content of a PDA related to FH; and (c) SDM. In general, stakeholders were in favor of developing tools which can inform and individualize discussion about genetic testing and treatment options for FH. Physicians valued a tool that facilitates knowledge transfer to FH patients. Patients desired a tool to help them understand the genetic aspects of and treatment options related to FH. Genetic counselors emphasized the inclusion of visual aids to support discussion with patients. Potential barriers to and facilitators of PDA implementation were identified. The input of various stakeholders will inform the development of a prototype tool that will be iteratively tested before implementation in the clinical setting. PMID- 30400380 TI - An Epidemiological Analysis of Head Injuries in Taiwan. AB - Traumatic head injuries occur frequently in Taiwan, having catastrophic consequences for the victims, their families, and society as a whole. However, little is known about the risk factors at the population level in Taiwan. The primary aim of this study was to obtain more information on these variables and their relationships. Another aim was to analyze the effects of independent variables such as sex, age, residency, pre-existing conditions, mechanisms of injury, associated injuries, and severity on the probability of in-hospital death. Using the 2007-2008 total admissions claim dataset from Taiwan's National Health Insurance system, total admissions due to acute head injury were selected for further analysis. The obtained data included patient demographics and trauma hospitalization rate. A total of 99,391 patients were admitted with head injury, 48,792 of which had moderate-to-severe head injury. There were 4935 cases recorded as in-hospital mortality and the standardized in-hospital mortality rate was 10.7 deaths per 100,000 person-years. The mortality rate increased with age. After adjustments, male sex, age older than 54 years, living in a rural area, lower monthly income, a Charlson comorbidity index greater than one, being a pedestrian hit by a motor vehicle, fall from a height, and having significant chest, abdominal, or lower extremity injury increased the risk of death during admission. This population-based analysis provides information about the incidence rate and death rate for admissions in Taiwan due to acute head injury and the factors that affect in-hospital mortality. Our results that highlight the risk factors for adverse outcome can help us prevent or improve rural area trauma care of head injury patients in the future. PMID- 30400381 TI - The Crimping and Expanding Performance of Self-Expanding Polymeric Bioresorbable Stents: Experimental and Computational Investigation. AB - Abstract: Polymeric bioresorbable stents (PBRSs) are considered the most promising devices to treat cardiovascular diseases. However, the mechanical weakness still hampers their application. In general, PBRSs are crimped into small sheathes and re-expanded to support narrowed vessels during angioplasty. Accordingly, one of the most significant requirements of PBRSs is to maintain mechanical efficacy after implantation. Although a little research has focused on commercial balloon-expanding PBRSs, a near-total lack has appeared on self expanding PBRSs and their deformation mechanisms. In this work, self-expanding, composite polymeric bioresorbable stents (cPBRSs) incorporating poly(p-dioxanone) (PPDO) and polycaprolactone (PCL) yarns were produced and evaluated for their in vitro crimping and expanding potential. Furthermore, the polymer time-reliable viscoelastic effects of the structural and mechanical behavior of the cPBRSs were analyzed using computational simulations. Our results showed that the crimping process inevitably decreased the mechanical resistance of the cPBRSs, but that this could be offset by balloon dilatation. Moreover, deformation mechanisms at the yarn level were discussed, and yarns bonded in the crossings showed more viscous behavior; this property might help cPBRSs to maintain their structural integrity during implantation. PMID- 30400382 TI - Development of Parvifloron D-loaded Smart Nanoparticles to Target Pancreatic Cancer. AB - Pancreatic cancer is the eighth leading cause of cancer death worldwide. For this reason, the development of more effective therapies is a major concern for the scientific community. Accordingly, plants belonging to Plectranthus genus and their isolated compounds, such as Parvifloron D, were found to have cytotoxic and antiproliferative activities. However, Parvifloron D is a very low water-soluble compound. Thus, nanotechnology can be a promising delivery system to enhance drug solubility and targeted delivery. The extraction of Parvifloron D from P. ecklonii was optimized through an acetone ultrasound-assisted method and isolated by Flash-Dry Column Chromatography. Then, its antiproliferative effect was selectivity evaluated against different tumor cell lines (IC50 of 0.15 +/- 0.05 MUM, 11.9 +/- 0.7 MUM, 21.6 +/- 0.5, 34.3 +/- 4.1 MUM, 35.1 +/- 2.2 MUM and 32.1 +/- 4.3 MUM for BxPC3, PANC-1, Ins1-E, MCF-7, HaCat and Caco-2, respectively). To obtain an optimized stable Parvifloron D pharmaceutical dosage form, albumin nanoparticles were produced through a desolvation method (yield of encapsulation of 91.2%) and characterized in terms of size (165 nm; PI 0.11), zeta potential ( 7.88 mV) and morphology. In conclusion, Parvifloron D can be efficiently obtained from P. ecklonii and it has shown selective cytotoxicity to pancreatic cell lines. Parvifloron D nanoencapsulation can be considered as a possible efficient alternative approach in the treatment of pancreatic cancer. PMID- 30400383 TI - Perceived Environmental, Individual and Social Factors of Long-Distance Collective Walking in Cities. AB - Long-distance collective walking is a popular activity in cities across China. However, related research is limited, creating a research gap to explore participants' dynamic experience and related influential factors. Therapeutic mobilities theory explores the relationships among walking, health, and well being from a qualitative perspective. Based on therapeutic mobilities theory, following a systematic process, this study develops a scale to quantitatively estimate the perceived environmental, personal, and social factors that may influence health and well-being. By applying construal level theory, this paper further hypothesizes that personality traits and familiarity moderate environmental, personal, and social perceptions. Data were collected with a paper survey (n = 926) from the "Shenzhen 100 km Walking" event. The findings highlight that long-distance collective walkers have comparatively greater experiences of health and well-being in three aspects: positive social interaction, individual development, and environmental understanding. Personality traits, familiarity, and gender moderate this well-being experience. Theoretical and managerial implications are discussed. PMID- 30400384 TI - Epidermal Fatty Acid-Binding Protein: A Novel Marker in the Diagnosis of Dry Eye Disease in Sjogren Syndrome. AB - PURPOSE: Sjogren syndrome (SS) is a chronic inflammatory autoimmune disease of the lacrimal and salivary glands. This study compared the concentrations of epidermal fatty-acid binding protein (E-FABP) in the saliva, serum, and tears of SS patients with dry eye and dry mouth, with those of healthy adults to investigate the usefulness of E-FABP as a diagnostic marker for SS. DESIGN: Prospective, observational case series. PARTICIPANTS: The subjects were 11 new patients with untreated Sjogren syndrome and 12 healthy control individuals. METHODS: The diagnosis of SS was in accordance with the Ministry of Health, Labour and Welfare (Japan) Diagnostic Criteria (1999). Saliva, serum, and tear specimens were collected during internal medicine, dental, and ophthalmological examinations. The ophthalmological tests included the Dry Eye-related Quality of life Score (DEQS), tear break-up time (BUT), vital staining with fluorescein (FS) and lissamine green (LG), and the Schirmer test-1. The E-FABP concentration in the tears, saliva, and serum was measured by enzyme-linked immunosorbent assay (ELISA). MAIN OUTCOME MEASURE: The E-FABP concentrations were compared between patients and controls. RESULTS: There were significant differences between the patient and healthy control groups in all ophthalmological test results. There were no significant differences between the groups in the E-FABP concentrations in the saliva (p = 0.1513) or the serum (p = 0.4799), but the E-FABP concentration in the tears significantly differed between groups. The E-FABP concentration in tears tended to be significantly lower in patients with SS (mean, 323.5 +/- 325.6 pg/mL) than healthy control subjects (mean, 4076 pg/mL; p = 0.0136). The E-FABP concentration in tears significantly correlated with the results of dry eye parameters. CONCLUSION: The E-FABP concentration in tears appears to be related to ocular surface epithelial damage and tear stability and may be a promising novel biomarker in the diagnosis of SS. PMID- 30400386 TI - Elucidating the Beneficial Role of PPAR Agonists in Cardiac Diseases. AB - Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that bind to DNA and regulate transcription of genes involved in lipid and glucose metabolism. A growing number of studies provide strong evidence that PPARs are the promising pharmacological targets for therapeutic intervention in various diseases including cardiovascular disorders caused by compromised energy metabolism. PPAR agonists have been widely used for decades as lipid-lowering and anti-inflammatory drugs. Existing studies are mainly focused on the anti atherosclerotic effects of PPAR agonists; however, their role in the maintenance of cellular bioenergetics remains unclear. Recent studies on animal models and patients suggest that PPAR agonists can normalize lipid metabolism by stimulating fatty acid oxidation. These studies indicate the importance of elucidation of PPAR agonists as potential pharmacological agents for protection of the heart from energy deprivation. Here, we summarize and provide a comprehensive analysis of previous studies on the role of PPARs in the heart under normal and pathological conditions. In addition, the review discusses the PPARs as a therapeutic target and the beneficial effects of PPAR agonists, particularly bezafibrate, to attenuate cardiomyopathy and heart failure in patients and animal models. PMID- 30400385 TI - Nutritional Composition and Bioactive Content of Legumes: Characterization of Pulses Frequently Consumed in France and Effect of the Cooking Method. AB - Pulses display nutritional benefits and are recommended in sustainable diets. Indeed, they are rich in proteins and fibers, and can contain variable amounts of micronutrients. However, pulses also contain bioactive compounds such as phytates, saponins, or polyphenols/tannins that can exhibit ambivalent nutritional properties depending on their amount in the diet. We characterized the nutritional composition and bioactive compound content of five types of prepared pulses frequently consumed in France (kidney beans, white beans, chickpeas, brown and green lentils, flageolets), and specifically compared the effects of household cooking vs. canning on the composition of pulses that can be consumed one way or the other. The contents in macro-, micronutrients, and bioactive compounds highly varied from one pulse to another (i.e., 6.9 to 9.7 g/100 g of cooked product for proteins, 4.6 to 818.9 ug/100 g for lutein or 15.0 to 284.3 mg/100 g for polyphenols). The preparation method was a key factor governing pulse final nutritional composition in hydrophilic compounds, depending on pulse species. Canning led to a greater decrease in proteins, total dietary fibers, magnesium or phytate contents compared to household cooking (i.e., -30%, 44%, -33% and -38%, p < 0.05, respectively, in kidney beans). As canned pulses are easy to use for consumers, additional research is needed to improve their transformation process to further optimize their nutritional quality. PMID- 30400387 TI - Biological Potential and Mechanism of Prodigiosin from Serratia marcescens Subsp. lawsoniana in Human Choriocarcinoma and Prostate Cancer Cell Lines. AB - Tripyrrole molecules have received renewed attention due to reports of numerous biological activities, including antifungal, antibacterial, antiprotozoal, antimalarial, immunosuppressive, and anticancer activities. In a screen of bacterial strains with known toxicities to termites, a red pigment-producing strain, HDZK-BYSB107, was isolated from Chamaecyparis lawsoniana, which grows in Oregon, USA. Strain HDZK-BYSB107 was identified as Serratia marcescens subsp. lawsoniana. The red pigment was identified as prodigiosin using ultraviolet absorption, LC-MS, and 1H-NMR spectroscopy. The bacterial prodigiosin had an inhibitory effect on both Gram-negative and Gram-positive bacteria. The main objective of this study was to explore the anticancer activities and mechanism of strain HDZK-BYSB107 prodigiosin by using human choriocarcinoma (JEG3) and prostate cancer cell lines (PC3) in vitro and JEG3 and PC3 tumor-bearing nude mice in vivo. In vitro anticancer activities showed that the bacterial prodigiosin induced apoptosis in JEG3 cells. In vivo anticancer activities indicated that the prodigiosin significantly inhibited the growth of JEG3 and PC3 cells, and the inhibitory activity was dose and time dependent. The anticancer efficacy of the bacterial prodigiosin on JEG3 and PC3 cells, JEG3 and PC3 tumor exhibited a correlation with the down regulation of the inhibitor of IAP family, including XIAP, cIAP-1 and cIAP-2, and the activation of caspase-9 and caspase-3 accompanied by proteolytic degradation of poly (ADP-ribose)-polymerase. The expressions of P53 and Bax/Bcl-2 in JEG3 and PC3 cells were significantly higher than in untreated groups. Our results indicated that the bacterial prodigiosin extracted from C. lawsoniana is a promising molecule due to its potential for therapeutic applications. PMID- 30400388 TI - Analysis of Hydrodynamic Mechanism on Particles Focusing in Micro-Channel Flows. AB - In this paper, the hydrodynamic mechanism of moving particles in laminar micro channel flows was numerically investigated. A hydrodynamic criterion was proposed to determine whether particles in channel flows can form a focusing pattern or not. A simple formula was derived to demonstrate how the focusing position varies with Reynolds number and particle size. Based on this proposed criterion, a possible hydrodynamic mechanism was discussed as to why the particles would not be focused if their sizes were too small or the channel Reynolds number was too low. The Re-lambda curve (Re, lambda respectively represents the channel-based Reynolds number and the particle's diameter scaled by the channel) was obtained using the data fitting with a least square method so as to obtain a parameter range of the focusing pattern. In addition, the importance of the particle rotation to the numerical modeling for the focusing of particles was discussed in view of the hydrodynamics. This research is expected to deepen the understanding of the particle transport phenomena in bounded flow, either in micro or macro fluidic scope. PMID- 30400389 TI - A Viscosity-Based Model for Bubble-Propelled Catalytic Micromotors. AB - Micromotors have shown significant potential for diverse future applications. However, a poor understanding of the propelling mechanism hampers its further applications. In this study, an accurate mechanical model of the micromotor has been proposed by considering the geometric asymmetry and fluid viscosity based on hydrodynamic principles. The results obtained from the proposed model are in a good agreement with the experimental results. The effects of the semi-cone angle on the micromotor are re-analyzed. Furthermore, other geometric parameters, like the length-radius aspect ratio, exert great impact on the velocity. It is also observed that micromotors travel much slower in highly viscous solutions and, hence, viscosity plays an important role. PMID- 30400390 TI - Parametric Study of an Electroosmotic Micromixer with Heterogeneous Charged Surface Patches. AB - A T-shaped micromixer featuring electroosmotic flow with heterogeneous charged surface patches on the channel walls was analyzed, and an improved design was proposed to enhance mixing performance. Numerical analysis was performed using steady Navier-Stokes equations with an additional electrokinetic body force. The numerical results for species concentration were validated with available experimental data. A parametric analysis of the micromixer was performed by varying channel height, channel width, patch width, and externally applied voltage. The effects of these parameters on the flow structure and mixing performance were analyzed in detail. A quantitative measurement based upon the mass variance was employed to quantify the mixing performance. Numerical results of the parametric study were used to propose an improved micromixer design with spacing between adjacent charged patches. The proposed design provided a more favorable flow structure to allow for enhanced mixing performance. PMID- 30400391 TI - A Simple Extraction Method of Young's Modulus for Multilayer Films in MEMS Applications. AB - Based on the first resonance frequency measurement of multilayer beams, a simple extraction method has been developed to extract the Young's modulus of individual layers. To verify this method, the double-layer cantilever, as a typical example, is analyzed to simplify the situation and finite element modeling (FEM) is used in consideration of the buckling and unbuckling situation of cantilevers. The first resonance frequencies, which are obtained by ANSYS (15.0, ANSYS Inc., Pittsburgh, PA, USA) with a group of thirteen setting values of Young's modulus in the polysilicon layer are brought into the theoretical formulas to obtain a new group of Young's modulus in the polysilicon layer. The reliability and feasibility of the theoretical method are confirmed, according to the slight differences between the setting values and the results of the theoretical model. In the experiment, a series of polysilicon-metal double-layer cantilevers were fabricated. Digital holographic microscopy (DHM) (Lyncee Tech, Lausanne, Switzerland) is used to distinguish the buckled from the unbuckled. A scanning laser Doppler vibrometer (LDV) (Polytech GmbH, Berlin, Germany) system is used to measure the first resonance frequencies of them. After applying the measurement results into the theoretical modulus, the average values of Young's modulus in the polysilicon and gold layers are 151.78 GPa and 75.72 GPa, respectively. The extracted parameters are all within the rational ranges, compared with the available results. PMID- 30400392 TI - Electronic Devices That Identify Individuals with Fever in Crowded Places: A Prototype. AB - Most epidemiological surveillance systems for severe infections with epidemic potential are based on accumulated symptomatic cases in defined geographical areas. Eventually, all cases have to be clinically verified to confirm an outbreak. These patients will present high fever at the early stages of the disease. Here, we introduce a non-invasive low-cost electronic device (bracelet) that measures and reports 24/7, year-round information on the temperature, geographical location, and identification of the subject using the device. The data receiver can be installed in a tower (ground) or a drone (air) in densely populated or remote areas. The prototype was made with low-cost electronic components, and it was tested indoors and outdoors. The prototype shows efficient ground and air connectivity. This electronic device will allow health professionals to monitor the prevalence of fever in a geographical area and to reduce the time span between the presentation of the first cases of a potential outbreak and their medical evaluation by giving an early warning. Field tests of the device, programs, and technical diagrams of the prototype are available as Supplementary Materials. PMID- 30400394 TI - Design and Modeling of Polysilicon Electrothermal Actuators for a MEMS Mirror with Low Power Consumption. AB - Endoscopic optical-coherence tomography (OCT) systems require low cost mirrors with small footprint size, out-of-plane deflections and low bias voltage. These requirements can be achieved with electrothermal actuators based on microelectromechanical systems (MEMS). We present the design and modeling of polysilicon electrothermal actuators for a MEMS mirror (100 MUm * 100 MUm * 2.25 MUm). These actuators are composed by two beam types (2.25 MUm thickness) with different cross-section area, which are separated by 2 MUm gap. The mirror and actuators are designed through the Sandia Ultra-planar Multi-level MEMS Technology V (SUMMiT V(r)) process, obtaining a small footprint size (1028 MUm * 1028 um) for actuators of 550 um length. The actuators have out-of-plane displacements caused by low dc voltages and without use material layers with distinct thermal expansion coefficients. The temperature behavior along the actuators is calculated through analytical models that include terms of heat energy generation, heat conduction and heat energy loss. The force method is used to predict the maximum out-of-plane displacements in the actuator tip as function of supplied voltage. Both analytical models, under steady-state conditions, employ the polysilicon resistivity as function of the temperature. The electrothermal-and structural behavior of the actuators is studied considering different beams dimensions (length and width) and dc bias voltages from 0.5 to 2.5 V. For 2.5 V, the actuator of 550 um length reaches a maximum temperature, displacement and electrical power of 115 degrees C, 10.3 um and 6.3 mW, respectively. The designed actuation mechanism can be useful for MEMS mirrors of different sizes with potential application in endoscopic OCT systems that require low power consumption. PMID- 30400395 TI - Potential of Piezoelectric MEMS Resonators for Grape Must Fermentation Monitoring. AB - In this study grape must fermentation is monitored using a self-actuating/self sensing piezoelectric micro-electromechanical system (MEMS) resonator. The sensor element is excited in an advanced roof tile-shaped vibration mode, which ensures high Q-factors in liquids (i.e., Q ~100 in isopropanol), precise resonance frequency analysis, and a fast measurement procedure. Two sets of artificial model solutions are prepared, representing an ordinary and a stuck/sluggish wine fermentation process. The precision and reusability of the sensor are shown using repetitive measurements (10 times), resulting in standard deviations of the measured resonance frequencies of ~0.1%, Q-factor of ~11%, and an electrical conductance peak height of ~12%, respectively. With the applied evaluation procedure, moderate standard deviations of ~1.1% with respect to density values are achieved. Based on these results, the presented sensor concept is capable to distinguish between ordinary and stuck wine fermentation, where the evolution of the wine density associated with the decrease in sugar and the increase in ethanol concentrations during fermentation processes causes a steady increase in the resonance frequency for an ordinary fermentation. Finally, the first test measurements in real grape must are presented, showing a similar trend in the resonance frequency compared to the results of an artificial solutions, thus proving that the presented sensor concept is a reliable and reusable platform for grape must fermentation monitoring. PMID- 30400393 TI - Microfluidic and Nanofluidic Resistive Pulse Sensing: A Review. AB - The resistive pulse sensing (RPS) method based on the Coulter principle is a powerful method for particle counting and sizing in electrolyte solutions. With the advancement of micro- and nano-fabrication technologies, microfluidic and nanofluidic resistive pulse sensing technologies and devices have been developed. Due to the unique advantages of microfluidics and nanofluidics, RPS sensors are enabled with more functions with greatly improved sensitivity and throughput and thus have wide applications in fields of biomedical research, clinical diagnosis, and so on. Firstly, this paper reviews some basic theories of particle sizing and counting. Emphasis is then given to the latest development of microfuidic and nanofluidic RPS technologies within the last 6 years, ranging from some new phenomena, methods of improving the sensitivity and throughput, and their applications, to some popular nanopore or nanochannel fabrication techniques. The future research directions and challenges on microfluidic and nanofluidic RPS are also outlined. PMID- 30400396 TI - Tuneable Liquid Crystal Micro-Lens Array for Image Contrast Enhancement in a Pixelated Thin Film Photo-Transistor Flat Panel Imager. AB - We propose and demonstrate the concept of using a tuneable liquid crystal micro lens (LCML) array to improve the image contrast of a pixelated thin film photo transistor (TFPT) flat panel imager. Such a device can be used to image contents on paper-based media and display a magnified version on a flat panel display for elderly or visually impaired people. Practical aspects including device physical geometry, object scattering profile, LC material, and focusing effect of LCML on an object are considered during the design process with the support of ZEMAX simulations. An optimised effective focal length (EFL) has been calculated for the designed LCML to best relay the objects or contents on a paper to the TFPT pixel plane. The designed LCML devices are fabricated with the optimised EFL, and they have good phase depth profiles which are close to a spherical lens profile. Preliminary test results show that the combination of a TFPT imager with an LCML array can make the image contrast more than two times better than that using the TFPT imager alone. The tuneable EFL of the developed LCMLs are useful in the situation where the LCML is not in direct contact with the imaged object. PMID- 30400397 TI - Flexural Properties and Fracture Behavior of Nanoporous Alumina film by Three Point Bending Test. AB - This study investigated the influence of porosity on the flexural property of a nanoporous alumina film. When the porosity of the alumina film increased, both bending strength and modulus declined. The results from the bending test revealed that the setting of the film during the bending test had significant influence on the flexural property. Fracture only occurred when the porous side of the alumina film suffered tensile stress. The ability to resist fracture in the barrier layer was higher than in the porous side; the magnitude of the bending strength was amplified when the barrier layer sustained tensile stress. When the porous layer suffered a tensile stress, the bending strength decreased from 182.4 MPa to 47.7 Mpa as the porosity increased from 22.7% to 51.7%; meanwhile, the modulus reduced from 82.7 GPa to 17.9 GPa. In this study, the most important finding from fractographic analysis suggested that there were a localized plastic deformations and layered ruptures at the porous side of the alumina film when a load was applied. The fracture behavior of the nanoporous alumina film observed in the present work was notably different from general ceramic materials and might be related to its asymmetric nanostructure. PMID- 30400398 TI - Electroceutical Approach for Impairing the Motility of Pathogenic Bacterium Using a Microfluidic Platform. AB - Electrotaxis, or galvanotaxis, refers to the migration pattern of cells induced in response to electrical potential. Electrotaxis has not been explored in detail in bacterial cells; information regarding the impact of current on pathogenic bacteria is severely lacking. Using microfluidic platforms and optical microscopy, we designed a series of single- and multi-cue experiments to assess the impact of varying electrical currents and acetic acid concentrations on bacterial motility dynamics in pathogenic multi-drug resistant (MDR) strains of Pseudomonas aeruginosa and Escherichia coli. The use of the microfluidic platform allows for single-cue experiments where electrical current is supplied at a range that is biocidal to bacteria and multi-cue experiments where acetic acid is combined with current to enhance disinfection. These strategies may offer substantial therapeutic benefits, specifically for the treatment of biofilm infections, such as those found in the wound environment. Our results showed that an application of current in combination with acetic acid has profound inhibitory effects on MDR strains of P. aeruginosa and E. coli, even with brief applications. Specifically, E. coli motility dynamics and cell survival were significantly impaired starting at a concentration of 0.125 mA of direct current (DC) and 0.31% acetic acid, while P. aeruginosa was impaired at 0.70 mA and 0.31% acetic acid. As these strains are relevant wound pathogens, it is likely that this strategy would be effective against similar strains in vivo and could represent a new approach to hasten wound healing. PMID- 30400399 TI - Research on the Drilling Performance of a Helical Point Micro Drill with Different Geometry Parameters. AB - During the micro-drilling process of stainless steel, the wear, fracture, and breakage of the micro-drill easily occur. Micro-drill geometry parameters have significant influence on the drilling performance of the micro-drill. Nowadays, the helical point micro-drill is proposed and its improved drilling performance is validated by some researchers. In this study, to analyze the effect of geometry parameters of the helical point micro-drill on drilling performance, the mathematical models of the helical flank and ground flute are proposed, and the cutting lip shape, rake angle, and uncut chip thickness are calculated using MATLAB software. Then, based on the orthogonal tests, nine kinds of micro-drills with different point angles, web thicknesses, and helix angles are fabricated using a six-axis CNC tool grinder, and micro-drilling experiments on 1Cr18Ni9Ti stainless steel are carried out. The drilling force, the burr height, and the hole wall quality are measured and observed. The results show that the point angle is the main contributing factor for the thrust force and burr height, and the web thickness is the main contributing factor for the micro hole wall quality. The increased point angle offers a larger thrust force, but gives rise to a smaller exit burr. A larger web thickness leads to a larger thrust force and burr height, and results in a poor surface quality. With the helix angle increased, the thrust force and burr height decreases, and the surface quality of micro-hole improves. The geometry parameters with a point angle 70 degrees , a point angle of 40 degrees , and web thickness ratio of 0.2 can used to improve the drilling performance of the helical point micro-drill. PMID- 30400400 TI - Analysis of the Diffusion Process by pH Indicator in Microfluidic Chips for Liposome Production. AB - In recent years, the development of nano- and micro-particles has attracted considerable interest from researchers and enterprises, because of the potential utility of such particles as drug delivery vehicles. Amongst the different techniques employed for the production of nanoparticles, microfluidic-based methods have proven to be the most effective for controlling particle size and dispersity, and for achieving high encapsulation efficiency of bioactive compounds. In this study, we specifically focus on the production of liposomes, spherical vesicles formed by a lipid bilayer encapsulating an aqueous core. The formation of liposomes in microfluidic devices is often governed by diffusive mass transfer of chemical species at the liquid interface between a solvent (i.e., alcohol) and a non-solvent (i.e., water). In this work, we developed a new approach for the analysis of mixing processes within microfluidic devices. The method relies on the use of a pH indicator, and we demonstrate its utility by characterizing the transfer of ethanol and water within two different microfluidic architectures. Our approach represents an effective route to experimentally characterize diffusion and advection processes governing the formation of vesicular/micellar systems in microfluidics, and can also be employed to validate the results of numerical modelling. PMID- 30400402 TI - DC Microplasma Jet for Local a:C-H Deposition Operated in SEM Chamber. AB - A DC micro plasma jet for local micro deposition of a:C-H film in the ambient vacuum of scanning electron microscope (SEM) chamber is proposed. Acetylene (C2H2) gas was locally fed into the chamber through an orifice shaped gas nozzle (OGN) at 6.6 sccm in flow rate by applying 80 kPa-inlet pressure with an additional direct pumping system equipped on the SEM chamber. As a cathode, a cut of n-type silicon (Si) wafer was placed right in front of the OGN at 200 MUm gap distance. By applying a positive DC voltage to the OGN, C2H2 plasma was generated locally between the electrodes. During discharge, the voltage increased and the current decreased due to deposition of insulating film on the Si wafer with resulting in automatic termination of discharge at the constant source voltage. A symmetric mountain-shaped a:C-H film of 5 MUm height was deposited at the center by operation for 15 s. Films were deposited with variation of gas flow rate, gap distance, voltage and current, and deposition time. The films were directly observed by SEM and analyzed by surface profiler and by Raman spectroscopy. PMID- 30400401 TI - New Endoscopic Imaging Technology Based on MEMS Sensors and Actuators. AB - Over the last decade, optical fiber-based forms of microscopy and endoscopy have extended the realm of applicability for many imaging modalities. Optical fiber based imaging modalities permit the use of remote illumination sources and enable flexible forms supporting the creation of portable and hand-held imaging instrumentations to interrogate within hollow tissue cavities. A common challenge in the development of such devices is the design and integration of miniaturized optical and mechanical components. Until recently, microelectromechanical systems (MEMS) sensors and actuators have been playing a key role in shaping the miniaturization of these components. This is due to the precision mechanics of MEMS, microfabrication techniques, and optical functionality enabling a wide variety of movable and tunable mirrors, lenses, filters, and other optical structures. Many promising results from MEMS based optical fiber endoscopy have demonstrated great potentials for clinical translation. In this article, reviews of MEMS sensors and actuators for various fiber-optical endoscopy such as fluorescence, optical coherence tomography, confocal, photo-acoustic, and two photon imaging modalities will be discussed. This advanced MEMS based optical fiber endoscopy can provide cellular and molecular features with deep tissue penetration enabling guided resections and early cancer assessment to better treatment outcomes. PMID- 30400403 TI - Simulation Analysis of Improving Microfluidic Heterogeneous Immunoassay Using Induced Charge Electroosmosis on a Floating Gate. AB - On-chip immuno-sensors are a hot topic in the microfluidic community, which is usually limited by slow diffusion-dominated transport of analytes in confined microchannels. Specifically, the antigen-antibody binding reaction at a functionalized area cannot be provided with enough antigen source near the reaction surface, since a small diffusion flux cannot match with the quick rate of surface reaction, which influences the response time and sensitivity of on chip heterogeneous immunoassay. In this work, we propose a method to enhance the transportation of biomolecules to the surface of an antibody-immobilized electrode with induce charge electroosmotic (ICEO) convection in a low concentration suspension, so as to improve the binding efficiency of microfluidic heterogeneous immunoassays. The circular stirring fluid motion of ICEO on the surface of a floating gate electrode at the channel bottom accelerates the transport of freely suspended antigen towards the wall-immobilized antibodies. We investigate the dependence of binding efficiency on voltage magnitude and field frequency of the applied alternate current (AC) electrical field. The binding rate yields a factor of 5.4 higher binding for an applied voltage of 4 V at 10 Hz when the Damkohler number is 1000. The proposed microfluidic immuno-sensor technology of a simple electrode structure using ICEO convective fluid flow around floating conductors could offer exciting opportunities for diffusion limited on-chip bio-microfluidic sensors. PMID- 30400404 TI - Influences of Excitation on Dynamic Characteristics of Piezoelectric Micro-Jets. AB - Piezoelectric micro-jets are based on piezoelectric ink-jet technology and can achieve the drop-on demand requirements. A piezoelectric micro-jet which is designed for bearing lubrication is presented in this paper. In order to analyze the fluid dynamic characteristics of the piezoelectric micro-jet so as to obtain good injection performance, a direct coupling simulation method is proposed in this paper. The effects of inlet and viscous losses in the cavity are taken into account, which are close to the actual conditions in the direct coupling method. The effects of the pulse excitation parameters on the pinch-off time, tail length, velocity, and volume of the droplet are analyzed by the proposed direct coupling method. The pressure distribution inside the cavity of the micro-jet and the status of the droplet formation at different times are also given. In addition, the method is proved to be effective in predicting and analyzing the fluid dynamic characteristics of piezoelectric micro-jets by comparing the simulation results with the experimental results. PMID- 30400405 TI - Designing a Tool System for Lowering Friction during the Ejection of In-Die Sintered Micro Gears. AB - The continuous improvements in micro-forging technologies generally involve process, material, and tool design. The field assisted sintering technique (FAST) is a process that makes possible the manufacture of near-net-shape components in a closed-die setup. However, the final part quality is affected by the influence of friction during the ejection phase, caused by radial expansion of the compacted and sintered powder. This paper presents the development of a pre stressed tool system for the manufacture of micro gears made of aluminum. By using the hot isostatic pressing (HIP) sintering process and different combinations of process parameters, the designed tool system was compared to a similar tool system designed without a pre-stressing strategy. The comparison between the two tool systems was based on the ejection force and part fidelity. The ejection force was measured during the tests, while the part fidelity was documented using an optical microscope and computed tomography in order to obtain a multi-scale characterization. The results showed that the use of pre-stress reduced the porosity in the gear by 40% and improved the dimensional fidelity by more than 75% compared to gears produced without pre-stress. PMID- 30400407 TI - Development of the Electric Equivalent Model for the Cytoplasmic Microinjection of Small Adherent Cells. AB - A novel approach utilizing current feedback for the cytoplasmic microinjection of biological cells is proposed. In order to realize the cytoplasmic microinjection on small adherent cells (diameter < 30 MUm and thickness < 10 MUm), an electrical model is built and analyzed according to the electrochemical properties of target cells. In this study, we have verified the effectiveness of the current measurement for monitoring the injection process and the study of ion channel activities for verifying the cell viability of the cells after the microinjection. PMID- 30400406 TI - PZT-Actuated and -Sensed Resonant Micromirrors with Large Scan Angles Applying Mechanical Leverage Amplification for Biaxial Scanning. AB - This article presents design, fabrication and characterization of lead zirconate titanate (PZT)-actuated micromirrors, which enable extremely large scan angle of up to 106 degrees and high frequency of 45 kHz simultaneously. Besides the high driving torque delivered by PZT actuators, mechanical leverage amplification has been applied for the micromirrors in this work to reach large displacements consuming low power. Additionally, fracture strength and failure behavior of poly Si, which is the basic material of the micromirrors, have been studied to optimize the designs and prevent the device from breaking due to high mechanical stress. Since comparing to using biaxial micromirror, realization of biaxial scanning using two independent single-axial micromirrors shows considerable advantages, a setup combining two single-axial micromirrors for biaxial scanning and the results will also be presented in this work. Moreover, integrated piezoelectric position sensors are implemented within the micromirrors, based on which closed-loop control has been developed and studied. PMID- 30400408 TI - Effects of Environmental Gas and Trace Water on the Friction of DLC Sliding with Metals. AB - This paper describes an experimental study on the friction of a-C:H diamond-like carbon (DLC) and ta-C DLC coatings in gas with different concentration of trace water. Pin-on-disk sliding experiments were conducted with DLC coated disks and aluminum pins in hydrogen, nitrogen, and argon. Trace oxygen was eliminated to less than 0.1 ppm, while water in the gas was controlled between 0 and 160 ppm. Fourier transform infrared spectroscopy (FT-IR) and laser Raman spectroscopy were used to analyze the transfer films on the metal surfaces. It was found that trace water slightly increased friction in hydrogen gas, whereas trace water caused a significant decrease in the friction coefficient in nitrogen and argon, particularly with a-C:H DLC. The low friction in hydrogen was brought about by the formation of transfer films with structured amorphous carbon, but no differences in the structure and contents of the films were found in the tests with and without trace water. In nitrogen and argon, the low friction with a-C:H DLC was achieved by the gradual formation of transfer films containing structured amorphous carbon, and FT-IR spectra showed that the films contained CH, OH, C-O C, and C-OH bonds. PMID- 30400409 TI - Large-Area and High-Throughput PDMS Microfluidic Chip Fabrication Assisted by Vacuum Airbag Laminator. AB - One of the key fabrication steps of large-area microfluidic devices is the flexible-to-hard sheet alignment and pre-bonding. In this work, the vacuum airbag laminator (VAL) which is commonly used for liquid crystal display (LCD) production has been applied for large-area microfluidic device fabrication. A straightforward, efficient, and low-cost method has been achieved for 400 * 500 mm2 microfluidic device fabrication. VAL provides the advantages of precise alignment and lamination without bubbles. Thermal treatment has been applied to achieve strong PDMS-glass and PDMS-PDMS bonding with maximum breakup pressure of 739 kPa, which is comparable to interference-assisted thermal bonding method. The fabricated 152 * 152 mm2 microfluidic chip has been successfully applied for droplet generation and splitting. PMID- 30400410 TI - Nearly Aberration-Free Multiphoton Polymerization into Thick Photoresist Layers. AB - In the era of lab-on-chip (LOC) devices, two-photon polymerization (TPP) is gaining more and more interest due to its capability of producing micrometer sized 3D structures. With TPP, one may integrate functional structures into microfluidic systems by polymerizing them directly inside microchannels. When the feature of sub-micrometer size is a requirement, it is necessary to use high numerical aperture (NA) oil-immersion objectives that are optimized to work close to the glass substrate-photoresist interface. Further away from the substrate, that is, a few tens of micrometers into the photoresist, the focused beam undergoes focal spot elongation and focal position shift. These effects may eventually reduce the quality of the polymerized structures; therefore, it is desirable to eliminate them. We introduce a method that can highly improve the quality of structures polymerized tens of micrometers away from the substrate photoresist interface by an oil-immersion, high NA objective. A spatial light modulator is used to pre-compensate the phase-front distortion introduced by the interfacial refractive index jump on the strongly converging beam. PMID- 30400411 TI - Analysis of the Dynamic Characteristics of a Micro-Piezoelectric Bimorph Beam Based on an Admittance Test. AB - A piezoelectric bimorph beam, as an upgraded cantilever beam structure, can be used to detect gas content and build a micro-actuator, among other functions. Thus, this beam is widely applied to microelectromechanical systems (MEMS), transformers, and precision machinery. For example, when photoacoustic spectroscopy is performed to detect oil-soluble gas in transformers, a micro cantilever beam can be used to detect gas content. The dynamic characteristics of piezoelectric bimorph beams, such as resonant frequency, are important indexes in the applications of these beams. The equivalent circuit model for a piezoelectric bimorph beam is examined in this study and an admittance test is performed on the beam to accurately, quickly, and economically measure and analyze its dynamic characteristics. Then, the least squares method is applied to obtain the characteristic curves of the admittance circle, amplitude frequency, and phase frequency; identify the dynamic characteristics of the piezoelectric bimorph beam (e.g., resonant frequency); and determine the parameters of the equivalent circuit. The resonant frequency of the piezoelectric bimorph beam is 207.67 Hz based on the result of the admittance circle test, which is basically consistent with the results of microscope image method (i.e., 207.85 Hz) and the theoretical calculation (i.e., 222.03 Hz). This finding proves the validity of the proposed test method. This method cannot only improve the detection speed of piezoelectric bimorph beams, but can also provide a fast detection strategy for testing the characteristics of such beams during photoacoustic spectroscopy. PMID- 30400412 TI - An Inexpensive Paper-Based Aluminum-Air Battery. AB - Paper-based batteries are an alternative to traditional batteries due to their low cost, portability, and simplicity to operate. In the present work, we demonstrate an improved and inexpensive paper-based aluminum-air battery employing KOH as the electrolyte with sufficient energy to power small devices. The dimensions of the device, electrode size, and electrolyte concentration were optimized with respect to amperage and reproducibility. The maximum amperage of 17.4 mA and maximum power of 3.0 mW was achieved with a 9 cm2 battery with anode and cathode electrode areas of 5.1 cm2 and 3.75 cm2 respectively, using 1.5 M potassium hydroxide (KOH). In a series configuration, the batteries generate sufficient energy to power light-emitting diodes (LEDs), a flashlight, a glucometer, and a pregnancy test. PMID- 30400413 TI - Friction Reduction for a Rotational Gyroscope with Mechanical Support by Fabrication of a Biomimetic Superhydrophobic Surface on a Ball-Disk Shaped Rotor and the Application of a Water Film Bearing. AB - Friction between contacting surfaces of metal materials restricts the application of mechanical support in the high-precision inertial device of a rotational gyroscope. Instead, a disk- or ring-shaped rotor is electrostatically or magnetically suspended. However, stability of the rotor suspension restricts further improvement of the measurement precision. In the developed rotational gyroscope, a stable mechanical rotor supporting scheme with low friction is achieved by fabrication of a superhydrophobic surface with similar nanostructures of the lotus leaf on the carbon steel ball of the ball-disk-shaped rotor and the addition of a water film between the rotor ball and bronze hemispherical supporting bowl, which forms a water film bearing. The special design of the ball disk-shaped rotor makes it possible for the application of a low-friction water bearing in the gyroscope, with rotor tilting motion. With a superhydrophobic surface, friction is further decreased and the rated spinning speed increases 12.4%, resulting in approximately the same proportion of increase in the scale factor. Moreover, superhydrophobic surface reduces mechanical damping torque for precessional motion to one order smaller than electrostatic feedback torque. Thus, through close-loop control, stable damping characteristics for precessional motion are obtained. The gyroscope exhibits excellent performance with the parameters of the measurement range, scale factor, nonlinearity, resolution, bias stability, and dynamic setting time tested to be -30 degrees /s to 30 degrees /s, -0.0985 V/( degrees /s), 0.43%, 0.1 degrees /s, 0.5 degrees /h, 0.1 s, respectively. PMID- 30400414 TI - Investigation of Micro-Bending of Sheet Metal Laminates by Laser-Driven Soft Punch in Warm Conditions. AB - Microscale laser dynamic flexible forming (uLDFF) is a novel ultrahigh strain rate manufacturing technology with high efficiency and low cost. However, the uLDFF is just confined to single-layer foil at present. In this work, sheet metal laminates (Cu/Ni) were selected as the experimental material for its excellent mechanical and functional properties, and a new micro-bending method of sheet metal laminates by laser-driven soft punch was proposed in warm conditions. The micro-mold and warm platform were designed to investigate the effects of temperature and energy on formability, which were characterized by forming accuracy, surface quality, element diffusion, and so on. The experimental results show that the forming accuracy and quality increased first and then decreased with laser energy, but the hardness increased consistently. In warm conditions, the fluidity of material was improved. The forming depth and accuracy increased for the relieved springback, and the surface quality increased first and then decreased. The tensile fracture disappeared with temperature for the decreased hardness and thinning ratio, and the element diffusion occurred. Overall, this study indicates that the formability can be improved in warm conditions and provides a basis for the investigation of micro-bending of sheet metal laminates by uLDFF in warm conditions. PMID- 30400415 TI - Map-Based Indoor Pedestrian Navigation Using an Auxiliary Particle Filter. AB - In this research, a non-infrastructure-based and low-cost indoor navigation method is proposed through the integration of smartphone built-in microelectromechanical systems (MEMS) sensors and indoor map information using an auxiliary particle filter (APF). A cascade structure Kalman particle filter algorithm is designed to reduce the computational burden and improve the estimation speed of the APF by decreasing its update frequency and the number of particles used in this research. In the lower filter (Kalman filter), zero velocity update and non-holonomic constraints are used to correct the error of the inertial navigation-derived solutions. The innovation of the design lies in the combination of upper filter (particle filter) map-matching and map-aiding methods to further constrain the navigation solutions. This proposed navigation method simplifies indoor positioning and makes it accessible to individual and group users, while guaranteeing the system's accuracy. The availability and accuracy of the proposed algorithm are tested and validated through experiments in various practical scenarios. PMID- 30400416 TI - Squeeze Film Air Damping in Tapping Mode Atomic Force Microscopy. AB - In dynamic plowing lithography, the sample surface is indented using a vibrating tip in tapping mode atomic force microscopy. During writing, the gap between the cantilever and the sample surface is very small, usually on the order of micrometers. High vibration frequency and small distance induce squeeze film air damping from the air in the gap. This damping can cause variations in the cantilever's vibrating parameters and affect the accuracy of the nanoscale patterning depth. In this paper, squeeze film air damping was modeled and analyzed considering the inclined angle between the cantilever and the sample surface, and its effects on the resonant amplitude and damping coefficient of the cantilever were discussed. The squeeze film air damping in the approaching curve of cantilever was observed, and its effect on fabricating nanopatterns was discussed. PMID- 30400417 TI - 3D Printing and Bioprinting in MEMS Technology. AB - 3D printing and bioprinting have advanced significantly in printing resolution in recent years, which presents a great potential for fabricating small and complex features suitable for microelectromechanical systems (MEMS) with new functionalities. This special issue aims to give a glimpse into the future of this research field. PMID- 30400418 TI - Karman Vortex Creation Using Cylinder for Flutter Energy Harvester Device. AB - This study presents the creation of a Karman vortex for a fluttering electromagnetic energy harvester device using a cylinder. The effects of two parameters, which are the diameter and the position of the cylinder, were investigated on the Karman vortex profile and the amplitude of the fluttering belt, respectively. A simulation was conducted to determine the effect of the creation of the Karman vortex, and an experiment was performed to identify influence of the position of the cylinder on the fluttering belt amplitude. The results demonstrated that vortex-induced vibration occurred at the frequency of the first natural mode for the belt at 3 cm and 10 cm for the diameter and position of the cylinder, respectively. Under such configuration, an electromagnetic energy harvester was attached and vibrated via the fluttering belt inside the turbulent boundary layers. This vibration provides a measured output voltage and can be used in wireless sensors. PMID- 30400419 TI - Rapid Nucleic Acid Extraction and Purification Using a Miniature Ultrasonic Technique. AB - Miniature ultrasonic lysis for biological sample preparation is a promising technique for efficient and rapid extraction of nucleic acids and proteins from a wide variety of biological sources. Acoustic methods achieve rapid, unbiased, and efficacious disruption of cellular membranes while avoiding the use of harsh chemicals and enzymes, which interfere with detection assays. In this work, a miniature acoustic nucleic acid extraction system is presented. Using a miniature bulk acoustic wave (BAW) transducer array based on 36 degrees Y-cut lithium niobate, acoustic waves were coupled into disposable laminate-based microfluidic cartridges. To verify the lysing effectiveness, the amount of liberated ATP and the cell viability were measured and compared to untreated samples. The relationship between input power, energy dose, flow-rate, and lysing efficiency were determined. DNA was purified on-chip using three approaches implemented in the cartridges: a silica-based sol-gel silica-bead filled microchannel, nucleic acid binding magnetic beads, and Nafion-coated electrodes. Using E. coli, the lysing dose defined as ATP released per joule was 2.2* greater, releasing 6.1* more ATP for the miniature BAW array compared to a bench-top acoustic lysis system. An electric field-based nucleic acid purification approach using Nafion films yielded an extraction efficiency of 69.2% in 10 min for 50 uL samples. PMID- 30400420 TI - Tool Run-Out Measurement in Micro Milling. AB - The interest in micro manufacturing processes is increasing because of the need for components characterized by small dimensions and micro features. As a result, researchers are studying the limitations and advantages of these processes. This paper deals with tool run-out measurement in micro milling. Among the effects of the scale reduction from macro to micro, tool run-out plays an important role, affecting cutting force, tool life, and the surface integrity of the produced part. The aim of this research is to develop an easy and reliable method to measure tool run-out in micro milling. This measuring strategy, from an Industry 4.0 perspective, can be integrated into an adaptive model for controlling cutting force, with the aim of improving the production quality and the process stability, while at the same time reducing tool wear and machining costs. The proposed procedure deduces tool run-out from the actual tool diameter, the channel width, and the cutting edge's phase, which is estimated by analyzing the cutting force signal. In order to automate the cutting edge phase measurement, the suitability of two functions approximating the force signal was evaluated. The developed procedure was tested on data from experimental tests. A Ti6Al4V sample was machined using two coated micro end mill flutes made by SECO setting different run-out values. The results showed that the developed procedure can be used for tool run-out estimation. PMID- 30400421 TI - Digital PCR: Endless Frontier of 'Divide and Conquer'. AB - Digital polymerase chain reaction (PCR) is becoming ever more recognized amid the overwhelming revolution in DNA quantification, genomics, genetics, and diagnostics led by technologies such as next generation sequencing and studies at the single-cell level. The demand to quantify the amount of DNA and RNA has been driven to the molecular level and digital PCR, with its unprecedented quantification capability, is sure to shine in the coming era. Two decades ago, it emerged as a concept; yet one decade ago, integration with microfluidics invigorated this field. Today, many methods have come to public knowledge and applications surrounding digital PCR is mounting. However, to reach wider accessibility and better practicality, efforts are needed to tackle the remaining problems. This perspective looks back at several inspiring and influential digital PCR approaches in the past and tries to provide a futuristic picture of the trends of digital PCR technologies to come. PMID- 30400423 TI - Operation of a MOEMS Deformable Mirror in Cryo: Challenges and Results. AB - Micro-opto-electro-mechanical systems (MOEMS) Deformable Mirrors (DM) are key components for next generation optical instruments implementing innovative adaptive optics systems, both in existing telescopes and in the future ELTs. Characterizing these components well is critical for next generation instruments. This is done by interferometry, including surface quality measurement in static and dynamical modes, at ambient and in vacuum/cryo. We use a compact cryo-vacuum chamber designed for reaching 10-6 mbar and 160 K in front of our custom Michelson interferometer, which is able to measure performance of the DM at actuator/segment level and at the entire mirror level, with a lateral resolution of 2 um and a sub-nanometer z-resolution. We tested the PTT 111 DM from Iris AO: an array of single crystalline silicon hexagonal mirrors with a pitch of 606 um, able to move in tip, tilt, and piston (stroke 5-7 um, tilt +/-5 mrad). The device could be operated successfully from ambient to 160 K. An additional, mainly focus like, 500 nm deformation of the entire mirror is measured at 160 K; we were able to recover the best flat in cryo by correcting the focus and local tip-tilts on all segments, reaching 12 nm rms. Finally, the goal of these studies is to test DMs in cryo and vacuum conditions as well as to improve their architecture for stable operation in harsh environments. PMID- 30400424 TI - Interfacial Electric Effects on a Non-Isothermal Electroosmotic Flow in a Microcapillary Tube Filled by Two Immiscible Fluids. AB - In this work, a non-isothermal electroosmotic flow of two immiscible fluids within a uniform microcapillary is theoretically studied. It is considered that there is an annular layer of a non-Newtonian liquid, whose behavior follows the power-law model, adjacent to the inside wall of the capillary, which in turn surrounds an inner flow of a second conducting liquid that is driven by electroosmosis. The inner fluid flow exerts an interfacial force, dragging the annular fluid due to shear and Maxwell stresses at the interface between the two fluids. Because the Joule heating effect may be present in electroosmotic flow (EOF), temperature gradients can appear along the microcapillary, making the viscosity coefficients of both fluids and the electrical conductivity of the inner fluid temperature dependent. The above makes the variables of the flow field in both fluids, velocity, pressure, temperature and electric fields, coupled. An additional complexity of the mathematical model that describes the electroosmotic flow is the nonlinear character due to the rheological behavior of the surrounding fluid. Therefore, based on the lubrication theory approximation, the governing equations are nondimensionalized and simplified, and an asymptotic solution is determined using a regular perturbation technique by considering that the perturbation parameter is associated with changes in the viscosity by temperature effects. The principal results showed that the parameters that notably influence the flow field are the power-law index, an electrokinetic parameter (the ratio between the radius of the microchannel and the Debye length) and the competition between the consistency index of the non-Newtonian fluid and the viscosity of the conducting fluid. Additionally, the heat that is dissipated trough the external surface of the microchannel and the sensitivity of the viscosity to temperature changes play important roles, which modify the flow field. PMID- 30400422 TI - A Droplet Microfluidics Based Platform for Mining Metagenomic Libraries for Natural Compounds. AB - Historically, microbes from the environment have been a reliable source for novel bio-active compounds. Cloning and expression of metagenomic DNA in heterologous strains of bacteria has broadened the range of potential compounds accessible. However, such metagenomic libraries have been under-exploited for applications in mammalian cells because of a lack of integrated methods. We present an innovative platform to systematically mine natural resources for pro-apoptotic compounds that relies on the combination of bacterial delivery and droplet microfluidics. Using the violacein operon from C. violaceum as a model, we demonstrate that E. coli modified to be invasive can serve as an efficient delivery vehicle of natural compounds. This approach permits the seamless screening of metagenomic libraries with mammalian cell assays and alleviates the need for laborious extraction of natural compounds. In addition, we leverage the unique properties of droplet microfluidics to amplify bacterial clones and perform clonal screening at high-throughput in place of one-compound-per-well assays in multi-well format. We also use droplet microfluidics to establish a cell aggregate strategy that overcomes the issue of background apoptosis. Altogether, this work forms the foundation of a versatile platform to efficiently mine the metagenome for compounds with therapeutic potential. PMID- 30400425 TI - Design of High-Reliability Micro Safety and Arming Devices for a Small Caliber Projectile. AB - With the development of micro technology, the fuse for small-caliber projectiles tends to be miniaturized and intelligent, the traditional fuse no longer meets the requirements. In this paper, we demonstrate a micro safety and arming (S & A) device with small volume and high reliability in small caliber projectile platforms. The working principle of S & A devices is that a centrifugal insurance mechanism could deform under a centrifugal load and thus cause fuse safety arming. The centrifugal insurance mechanism is designed theoretically, verified by simulation and experimental methods. The experimental results show that, when the rotary speed is over 36,000 rpm, the fuse was armed safely. In addition, the experimental, simulation, and theoretical results are basically consistent, and indicate that the centrifugal insurance mechanism meets the expected criteria. PMID- 30400426 TI - Numerical Investigation of Miniature Ejector Refrigeration System Embedded with a Capillary Pump Loop. AB - A miniature steam ejector refrigeration system embedded with a capillary pump loop can result in a compact design which can be used for electronics cooling. In this paper, computational fluid dynamics (CFD) is employed to investigate the effects of the area ratio of the ejector constant-area mixing section to the nozzle throat, the length of the constant-area section, and the nozzle exit position (NXP), on the performance of a miniature steam ejector. Results show that the performance of the miniature steam ejector is very sensitive to the area ratio of the constant-area mixing section to the nozzle. For the needs of practical application, the area ratio of the constant-area mixing section to the nozzle should be smaller than 16 when the temperature of the primary flow is 60 degrees C. The NXP plays an important role in the flow phenomena inside the miniature ejector. The critical back pressure is more sensitive to length of the constant-area mixing section than the entrainment ratio. Results of this investigation provided a good solution to the miniature steam ejector embedded with a capillary pump loop for electronics cooling application. PMID- 30400427 TI - 3D Printing of Artificial Blood Vessel: Study on Multi-Parameter Optimization Design for Vascular Molding Effect in Alginate and Gelatin. AB - 3D printing has emerged as one of the modern tissue engineering techniques that could potentially form scaffolds (with or without cells), which is useful in treating cardiovascular diseases. This technology has attracted extensive attention due to its possibility of curing disease in tissue engineering and organ regeneration. In this paper, we have developed a novel rotary forming device, prepared an alginate-gelatin solution for the fabrication of vessel-like structures, and further proposed a theoretical model to analyze the parameters of motion synchronization. Using this rotary forming device, we firstly establish a theoretical model to analyze the thickness under the different nozzle extrusion speeds, nozzle speeds, and servo motor speeds. Secondly, the experiments with alginate-gelatin solution are carried out to construct the vessel-like structures under all sorts of conditions. The experiment results show that the thickness cannot be adequately predicted by the theoretical model and the thickness can be controlled by changing the parameters. Finally, the optimized parameters of thickness have been adjusted to estimate the real thickness in 3D printing. PMID- 30400428 TI - Three-Dimensional Finite Element Method Simulation of Perforated Graphene Nano Electro-Mechanical (NEM) Switches. AB - The miniaturization trend leads to the development of a graphene based nanoelectromechanical (NEM) switch to fulfill the high demand in low power device applications. In this article, we highlight the finite element (FEM) simulation of the graphene-based NEM switches of fixed-fixed ends design with beam structures which are perforated and intact. Pull-in and pull-out characteristics are analyzed by using the FEM approach provided by IntelliSuite software, version 8.8.5.1. The FEM results are consistent with the published experimental data. This analysis shows the possibility of achieving a low pull-in voltage that is below 2 V for a ratio below 15:0.03:0.7 value for the graphene beam length, thickness, and air gap thickness, respectively. The introduction of perforation in the graphene beam-based NEM switch further achieved the pull-in voltage as low as 1.5 V for a 250 nm hole length, 100 nm distance between each hole, and 12 number of hole column. Then, a von Mises stress analysis is conducted to investigate the mechanical stability of the intact and perforated graphene-based NEM switch. This analysis shows that a longer and thinner graphene beam reduced the von Mises stress. The introduction of perforation concept further reduced the von Mises stress at the graphene beam end and the beam center by approximately ~20-35% and ~10-20%, respectively. These theoretical results, performed by FEM simulation, are expected to expedite improvements in the working parameter and dimension for low voltage and better mechanical stability operation of graphene based NEM switch device fabrication. PMID- 30400430 TI - Development of Piezo-Driven Compliant Bridge Mechanisms: General Analytical Equations and Optimization of Displacement Amplification. AB - Compliant bridge mechanisms are frequently utilized to scale micrometer order motions of piezoelectric actuators to levels suitable for desired applications. Analytical equations have previously been specifically developed for two configurations of bridge mechanisms: parallel and rhombic type. Based on elastic beam theory, a kinematic analysis of compliant bridge mechanisms in general configurations is presented. General equations of input displacement, output displacement, displacement amplification, input stiffness, output stiffness and stress are presented. Using the established equations, a piezo-driven compliant bridge mechanism has been optimized to maximize displacement amplification. The presented equations were verified using both computational finite element analysis and through experimentation. Finally, comparison with previous studies further validates the versatility and accuracy of the proposed models. The formulations of the new analytical method are simplified and efficient, which help to achieve sufficient estimation and optimization of compliant bridge mechanisms for nano-positioning systems. PMID- 30400429 TI - Assessment of Sub-Micron Particles by Exploiting Charge Differences with Dielectrophoresis. AB - The analysis, separation, and enrichment of submicron particles are critical steps in many applications, ranging from bio-sensing to disease diagnostics. Microfluidic electrokinetic techniques, such as dielectrophoresis (DEP) have proved to be excellent platforms for assessment of submicron particles. DEP is the motion of polarizable particles under the presence of a non-uniform electric field. In this work, the polarization and dielectrophoretic behavior of polystyrene particles with diameters ranging for 100 nm to 1 MUm were studied employing microchannels for insulator based DEP (iDEP) and low frequency (<1000 Hz) AC and DC electric potentials. In particular, the effects of particle surface charge, in terms of magnitude and type of functionalization, were examined. It was found that the magnitude of particle surface charge has a significant impact on the polarization and dielectrophoretic response of the particles, allowing for successful particle assessment. Traditionally, charge differences are exploited employing electrophoretic techniques and particle separation is achieved by differential migration. The present study demonstrates that differences in the particle's surface charge can also be exploited by means of iDEP; and that distinct types of nanoparticles can be identified by their polarization and dielectrophoretic behavior. These findings open the possibility for iDEP to be employed as a technique for the analysis of submicron biological particles, where subtle differences in surface charge could allow for rapid particle identification and separation. PMID- 30400431 TI - Scanning Micro-Mirror with an Electrostatic Spring for Compensation of Hard Spring Nonlinearity. AB - A scanning micro-mirror operated at the mechanical resonant frequency often suffer nonlinearity of the torsion-bar spring. The torsion-bar spring becomes harder than the linear spring with the increase of the rotation angle (hard spring effect). The hard-spring effect of the torsion-bar spring generates several problems, such as hysteresis, frequency shift, and instability by oscillation jump. In this paper, a scanning micro-mirror with an electrostatic comb spring is studied for compensation of the hard-spring effect of the torsion bar spring. The hard-spring effect of the torsion-bar spring is compensated with the equivalent soft-spring effect of the electrostatic-comb spring. The oscillation curve becomes symmetric at the resonant frequency although the resonant frequency increases. Theoretical analysis is given for roughly explaining the compensation. A 0.5 mm square scanning micro-mirror having two kinds of combs, i.e., an actuator comb and a compensation comb, is fabricated from a silicon-on-insulator wafer for testing the compensation of the hard-spring in a vacuum and in atmospheric air. The bending of the oscillation curve is compensated by applying a DC voltage to the electrostatic-comb spring in vacuum and atmosphere. The compensation is attributed by theoretical approach to the soft-spring effect of the electrostatic-comb spring. PMID- 30400432 TI - Web-Based Remote Control of a Building's Electrical Power, Green Power Generation and Environmental System Using a Distributive Microcontroller. AB - This article proposes a novel, web-based, remote monitoring and control system design for a building's electrical power, green power generation and environmental system that will save energy. The supervisory control system is based on the use of distributed microcontroller architecture to access programmable logic controllers (PLC) and remote input/output devices through the system hardware framework with uniform Ethernet technology. The programmable logic controller (PLC) can access and control devices directly or through RS-232 and RS-485 serial communication. The distributed microcontroller is the control module designated through an open-source firmware, to transform heterogeneous communication to Modbus transmission control protocol (TCP) communication and to achieve the exchange of information between the host and client controller. The proposed supervisory control and data acquisition (SCADA) system is based on the professional software of InduSoft Web Studio and provides a supervisory control design with a friendly human-machine interface. The system can realize real-time data acquisition and storage, control command transmission, system security and power trend analysis. Finally, the proposed SCADA system can be built directly into the hypertext markup language (HTML) and HTML5 and run on the web server, allowing access from a personal computer or smartphone web browser. Our system goals are to greatly reduce system complexity and maintenance costs with a simple Ethernet architecture. The control system can be easily expanded with the same technology culture outside the restrictive one of the large companies. Hence, this system can easily be used in a smart home system to enhance the quality of its inhabitants. PMID- 30400433 TI - Characterization of Reagent Pencils for Deposition of Reagents onto Paper-Based Microfluidic Devices. AB - Reagent pencils allow for solvent-free deposition of reagents onto paper-based microfluidic devices. The pencils are portable, easy to use, extend the shelf life of reagents, and offer a platform for customizing diagnostic devices at the point of care. In this work, reagent pencils were characterized by measuring the wear resistance of pencil cores made from polyethylene glycols (PEGs) with different molecular weights and incorporating various concentrations of three different reagents using a standard pin abrasion test, as well as by measuring the efficiency of reagent delivery from the pencils to the test zones of paper based microfluidic devices using absorption spectroscopy and digital image colorimetry. The molecular weight of the PEG, concentration of the reagent, and the molecular weight of the reagent were all found to have an inverse correlation with the wear of the pencil cores, but the amount of reagent delivered to the test zone of a device correlated most strongly with the concentration of the reagent in the pencil core. Up to 49% of the total reagent deposited on a device with a pencil was released into the test zone, compared to 58% for reagents deposited from a solution. The results suggest that reagent pencils can be prepared for a variety of reagents using PEGs with molecular weights in the range of 2000 to 6000 g/mol. PMID- 30400434 TI - High Aspect Ratio Nanoimprint Mold-Cavity Filling and Stress Simulation Based on Finite-Element Analysis. AB - High aspect ratio three-dimensional micro- and nanopatterns have important applications in diverse fields. However, fabricating these structures by a nanoimprinting method invites problems like collapse, dislocation, and defects. Finite-element analysis (FEA) is a good approach to help understand the filling process and stress distribution. The FEA method was employed to simulate the nanoimprinting process using positive and negative molds with aspect ratios of 1:1, 3:1, 5:1, and 7:1. During the filling process, the resist adjacent to boundaries has the maximum displacement. The corners of contact areas between the protruding part of the mold and the resist has the maximum Von Mises stress. For both positive and negative molds, the maximum stress in the mold increases with aspect ratio. However, filling up negative molds is more difficult than positive ones. With the same aspect ratio, the maximum stress in a negative mold is approximately twice as large as that in a positive one. PMID- 30400435 TI - Mechanical Vibration Measurement of Solidly Mounted Resonator in Fluid by Atomic Force Microscopy. AB - The very small vibration of a solidly-mounted resonator (SMR) in fluid may trigger a relatively large motion of the covering fluid, which was implied by our protein-related experimental results. Therefore, a series of experimental methods for characterizing the mechanical longitudinal vibration of the SMR and the corresponding out-of-plane dynamic response of the fluid above the SMR surface is described in this paper. A SMR device with theoretical resonance frequency of 2.5 GHz was driven by an amplitude-modulated (AM) signal, in which the amplitude is modulated by a signal of the second resonance frequency of the atomic force microscope (AFM) cantilever. A lock-in amplifier is used to demodulate the vibration response of the AFM cantilever, which is proportional to the amplitude of the sample vibration in contact mode and tapping mode. The amplitude-frequency curve of the SMR surface is obtained in contact mode with a relatively stronger interaction force between the AFM tip and the SMR surface. The amplitude frequency curve of the motion of the liquid above the SMR device and the peak amplitude of the fluid at different distances above the SMR surface are measured in tapping mode with a relatively weak interaction force between the AFM tip and the fluid sample. PMID- 30400436 TI - A Compact 2-DOF Piezoelectric-Driven Platform Based on "Z-Shaped" Flexure Hinges. AB - A compact 2-DOF (two degrees of freedom) piezoelectric-driven platform for 3D cellular bio-assembly systems has been proposed based on "Z-shaped" flexure hinges. Multiple linear motions with high resolution both in x and y directions are achieved. The "Z-shaped" flexure hinges and the parallel-six-connecting-rods structure are utilized to obtain the lowest working stress while compared with other types of flexure hinges. In order to achieve the optimized structure, matrix-based compliance modeling (MCM) method and finite element method (FEM) are used to evaluate both the static and dynamic performances of the proposed 2-DOF piezoelectric-driven platform. Experimental results indicate that the maximum motion displacements for x-stage and y-stage are lx = 17.65 MUm and ly = 15.45 MUm, respectively. The step response time for x-stage and y-stage are tx = 1.7 ms and ty = 1.6 ms, respectively. PMID- 30400437 TI - Universal Micromachining Platform and Basic Technologies for the Manufacture and Marking of Microphysiological Systems. AB - Micro Physiological Systems (MPS), also known as Multi-Organ-Chip, Organ-on-a Chip, or Body-on-a-Chip, are advanced microfluidic systems that allow the cultivation of different types of cells and tissue in just one common circuit. Furthermore, they thus can also adjust the interaction of these different tissues. Perspectival MPS will replace animal testing. For fast and flexible manufacturing and marking of MPS, a concept for a universal micromachining platform has been developed which provides the following latest key technologies: laser micro cutting of polymer foils, laser micro- and sub-micro-structuring of polymer foils, 3D printing of polymer components as well as optical inspection and online process control. The combination of different laser sources, processing optics, inspection systems, and print heads on multiple axes allows the change and exactly positioning to the workpiece during the process. Therewith, the realization of MPS including 3D printed components as well as direct laser interference patterned surfaces for well-defined cell adhesion and product protection is possible. Additional basic technologies for the generation of periodical line-like structures at polycarbonate foils using special Direct Laser Interference Patterning (DLIP) optics as well as for the 3D printing of fluid-tight cell culture reservoirs made of Acrylonitrile Butadiene Styrene directly onto polycarbonate microfluidics were established. A first prototype of the universal micromachining platform combining different lasers with Direct Laser Writing and DLIP is shown. With this laser micro cutting as well as laser micro-structuring of polycarbonate (PC) foils and therewith functionalization for MPS application could be successfully demonstrated. PMID- 30400438 TI - Optimal Control-Based Inverse Determination of Electrode Distribution for Electroosmotic Micromixer. AB - This paper presents an optimal control-based inverse method used to determine the distribution of the electrodes for the electroosmotic micromixers with external driven flow from the inlet. Based on the optimal control method, one Dirichlet boundary control problem is constructed to inversely find the optimal distribution of the electrodes on the sidewalls of electroosmotic micromixers and achieve the acceptable mixing performance. After solving the boundary control problem, results are also provided to demonstrate the effectiveness of the proposed method; the step-shaped distribution of the external electric potential imposed on the sidewalls is obtained, and the electrodes with an interlaced arrangement are inversely derived according to the obtained external electric potential. PMID- 30400439 TI - Uncertainty Quantification of Microstructure-Governed Properties of Polysilicon MEMS. AB - In this paper, we investigate the stochastic effects of the microstructure of polysilicon films on the overall response of microelectromechanical systems (MEMS). A device for on-chip testing has been purposely designed so as to maximize, in compliance with the production process, its sensitivity to fluctuations of the microstructural properties; as a side effect, its sensitivity to geometrical imperfections linked to the etching process has also been enhanced. A reduced-order, coupled electromechanical model of the device is developed and an identification procedure, based on a genetic algorithm, is finally adopted to tune the parameters ruling microstructural and geometrical uncertainties. Besides an initial geometrical imperfection that can be considered specimen-dependent due to its scattering, the proposed procedure has allowed identifying an average value of the effective polysilicon Young's modulus amounting to 140 GPa, and of the over-etch depth with respect to the target geometry layout amounting to O = - 0.09 MU m. The procedure has been therefore shown to be able to assess how the studied stochastic effects are linked to the scattering of the measured input-output transfer function of the device under standard working conditions. With a continuous trend in miniaturization induced by the mass production of MEMS, this study can provide information on how to handle the foreseen growth of such scattering. PMID- 30400440 TI - A Novel On-Chip Impedance Sensor for the Detection of Particle Contamination in Hydraulic Oil. AB - A novel impedance sensor based on a microfluidic chip is presented. The sensor consists of two single-layer coils and a straight micro-channel, and can detect, not only ferromagnetic and non-ferromagnetic particles in oil as an inductive sensor, but also, water droplets and air bubbles in oil as a capacitive sensor. The experiments are carried out at different excitation frequencies, number of coil turns and particle sizes. For the inductance detection, the inductance signals are found to increase with the excitation frequency and the noise is constant; both the inductance signals and the noise increase with the number of coil turns, but because the noise increases at a faster rate than the signal, the signal-to-noise ratio decreases with the number of coil turns. We demonstrate the successful detection of 40 MUm iron particles and 110 MUm copper particles using the coil with 20 turns at the excitation frequency of 2 MHz. For the capacitance detection, capacitance signals decrease with the excitation frequency and the noise is constant; the capacitance signals decrease with the number of coil turns, while the noise increases, thus, the signal-to-noise ratio decreases with the number of coil turns. We can detect 100 MUm water droplets and 180 MUm bubbles successfully using the coil with 20 turns at the excitation frequency of 0.3 MHz. PMID- 30400442 TI - Editorial for the Special Issue on the Insights and Advancements in Microfluidics. AB - We present a total of 19 articles in this special issue of Micromachines entitled, "Insights and Advancements in Microfluidics."[...]. PMID- 30400441 TI - Micromachining on and of Transparent Polymers for Patterning Electrodes and Growing Electrically Active Cells for Biosensor Applications. AB - We report on microfabrication and assembly process development on transparent, biocompatible polymers for patterning electrodes and growing electrically active cells for in vitro cell-based biosensor applications. Such biosensors are typically fabricated on silicon or glass wafers with traditional microelectronic processes that can be cost-prohibitive without imparting necessary biological traits on the devices, such as transparency and compatibility for the measurement of electrical activity of electrogenic cells and other biological functions. We have developed and optimized several methods that utilize traditional micromachining and non-traditional approaches such as printed circuit board (PCB) processing for fabrication of electrodes and growing cells on the transparent polymers polyethylene naphthalate (PEN) and polyethylene terephthalate (PET). PEN based biosensors are fabricated utilizing lithography, metal lift-off, electroplating, wire bonding, inkjet printing, conformal polymer deposition and laser micromachining, while PET-based biosensors are fabricated utilizing post processing technologies on modified PCBs. The PEN-based biosensors demonstrate 85 100% yield of microelectrodes, and 1-kHz impedance of 59.6 kOhms in a manner comparable to other traditional approaches, with excellent biofunctionality established with an ATP assay. Additional process characterization of the microelectrodes depicts expected metal integrity and trace widths and thicknesses. PET-based biosensors are optimized for a membrane bow of 6.9 to 15.75 um and 92% electrode yield on a large area. Additional qualitative optical assay for biomaterial recognition with transmitted light microscopy and growth of rat cortical cells for 7 days in vitro (DIV) targeted at biological functionalities such as electrophysiology measurements are demonstrated in this paper. PMID- 30400443 TI - Cost Index Model for the Process Performance Optimization of Micro-EDM Drilling on Tungsten Carbide. AB - The present work deals with the execution of through micro-holes on tungsten carbide plates using a micro-electrical discharge machining (micro-EDM) machine. The experiments were carried out by varying peak current, voltage and frequency in order to achieve suitable technology windows. Tubular electrodes, made of two different materials (tungsten carbide and brass), were used. The investigation focuses on the influence of variable process parameters on the process performances and their optimization. The performance indicators taken into account were Material Removal Rate (MRR) and Tool Wear Ratio (TWR). A general model based on a cost index was defined for the process performances optimization and the optimal conditions were identified through the minimization of the objective function. PMID- 30400444 TI - Analytical Formulation of the Electric Field Induced by Electrode Arrays: Towards Automated Dielectrophoretic Cell Sorting. AB - Dielectrophoresis is defined as the motion of an electrically polarisable particle in a non-uniform electric field. Current dielectrophoretic devices enabling sorting of cells are mostly controlled in open-loop applying a predefined voltage on micro-electrodes. Closed-loop control of these devices would enable to get advanced functionalities and also more robust behavior. Currently, the numerical models of dielectrophoretic force are too complex to be used in real-time closed-loop control. The aim of this paper is to propose a new type of models usable in this framework. We propose an analytical model of the electric field based on Fourier series to compute the dielectrophoretic force produced by parallel electrode arrays. Indeed, this method provides an analytical expression of the electric potential which decouples the geometrical factors (parameter of our system), the voltages applied on electrodes (input of our system), and the position of the cells (output of our system). Considering the Newton laws on each cell, it enables to generate easily a dynamic model of the cell positions (output) function of the voltages on electrodes (input). This dynamic model of our system is required to design the future closed-loop control law. The predicted dielectrophoretic forces are compared to a numerical simulation based on finite element model using COMSOL software. The model presented in this paper enables to compute the dielectrophoretic force applied to a cell by an electrode array in a few tenths of milliseconds. This model could be consequently used in future works for closed-loop control of dielectrophoretic devices. PMID- 30400446 TI - Interactive Micromanipulation of Picking and Placement of Nonconductive Microsphere in Scanning Electron Microscope. AB - In this paper, classified theoretical models, consisting of contact with and placement of microsphere and picking operations, are simplified and established to depict the interactive behaviors of external and internal forces in pushing manipulations, respectively. Sliding and/or rolling cases, resulting in the acceleration of micromanipulations, are discussed in detail. Effective contact detection is achieved by combining alterations of light-shadow and relative movement displacement between the tip-sphere. Picking operations are investigated by typical interactive positions and different end tilt angles. Placements are realized by adjusting the proper end tilt angles. These were separately conducted to explore the interactive operations of nonconductive glass microspheres in a scanning electron microscope. The experimental results demonstrate that the proposed contact detection method can efficiently protect the end-tip from damage, regardless of operator skills in initial positioning operations. E-beam irradiation onto different interactive positions with end tilt angles can be utilized to pick up microspheres without bending the end-tip. In addition, the results of releasing deviations away from the pre-setting point were utilized to verify the effectiveness of the placement tilt angles. PMID- 30400445 TI - Biomaterials Meet Microfluidics: From Synthesis Technologies to Biological Applications. AB - Microfluidics is characterized by laminar flow at micro-scale dimension, high surface to volume ratio, and markedly improved heat/mass transfer. In addition, together with advantages of large-scale integration and flexible manipulation, microfluidic technology has been rapidly developed as one of the most important platforms in the field of functional biomaterial synthesis. Compared to biomaterials assisted by conventional strategies, functional biomaterials synthesized by microfluidics are with superior properties and performances, due to their controllable morphology and composition, which have shown great advantages and potential in the field of biomedicine, biosensing, and tissue engineering. Take the significance of microfluidic engineered biomaterials into consideration; this review highlights the microfluidic synthesis technologies and biomedical applications of materials. We divide microfluidic based biomaterials into four kinds. According to the material dimensionality, it includes: 0D (particulate materials), 1D (fibrous materials), 2D (sheet materials), and 3D (construct forms of materials). In particular, micro/nano-particles and micro/nano-fibers are introduced respectively. This classification standard could include all of the microfluidic biomaterials, and we envision introducing a comprehensive and overall evaluation and presentation of microfluidic based biomaterials and their applications. PMID- 30400448 TI - Study on the Optimum Cutting Parameters of an Aluminum Mold for Effective Bonding Strength of a PDMS Microfluidic Device. AB - Master mold fabricated using micro milling is an easy way to develop the polydimethylsiloxane (PDMS) based microfluidic device. Achieving high-quality micro-milled surface is important for excellent bonding strength between PDMS and glass slide. The aim of our experiment is to study the optimal cutting parameters for micro milling an aluminum mold insert for the production of a fine resolution microstructure with the minimum surface roughness using conventional computer numerical control (CNC) machine systems; we also aim to measure the bonding strength of PDMS with different surface roughnesses. Response surface methodology was employed to optimize the cutting parameters in order to obtain high surface smoothness. The cutting parameters were demonstrated with the following combinations: 20,000 rpm spindle speed, 50 mm/min feed rate, depth of cut 5 um with tool size 200 um or less; this gives a fine resolution microstructure with the minimum surface roughness and strong bonding strength between PDMS-PDMS and PDMS-glass. PMID- 30400447 TI - An Electromagnetically Actuated Double-Sided Cell-Stretching Device for Mechanobiology Research. AB - Cellular response to mechanical stimuli is an integral part of cell homeostasis. The interaction of the extracellular matrix with the mechanical stress plays an important role in cytoskeleton organisation and cell alignment. Insights from the response can be utilised to develop cell culture methods that achieve predefined cell patterns, which are critical for tissue remodelling and cell therapy. We report the working principle, design, simulation, and characterisation of a novel electromagnetic cell stretching platform based on the double-sided axial stretching approach. The device is capable of introducing a cyclic and static strain pattern on a cell culture. The platform was tested with fibroblasts. The experimental results are consistent with the previously reported cytoskeleton reorganisation and cell reorientation induced by strain. Our observations suggest that the cell orientation is highly influenced by external mechanical cues. Cells reorganise their cytoskeletons to avoid external strain and to maintain intact extracellular matrix arrangements. PMID- 30400449 TI - On-Chip Microplasmas for the Detection of Radioactive Cesium Contamination in Seawater. AB - On-chip microplasmas have previously been used in designing a compact and portable device for identifying pollutants in a water sample. By exciting a liquid sample with a high energy microdischarge and recording the spectral wavelengths emitted, the individual elements in the liquid are distinguishable. In particular, this study focuses on cesium, a contaminant from nuclear incidents such as the collapse of the nuclear power plant in Fukushima, Japan. This article shows that not only can the presence of cesium be clearly determined at concentrations as low as 10 ppb, but the relative concentration contained in the sample can be determined through the discharges' relative spectral intensity. PMID- 30400450 TI - An Integrated Artificial Cilia Based Microfluidic Device for Micropumping and Micromixing Applications. AB - A multi-purpose microfluidic device that can be used for both micromixing and micropropulsion operations has always been in demand, as it would simplify the various process flows associated with the current micro-total analysis systems. In this aspect, we propose a biomimetic artificial cilia-based microfluidic device that can efficiently facilitate both mixing and propulsion sequentially at the micro-scale. A rectangular microfluidic device consists of four straight microchannels that were fabricated using the microfabrication technique. An array of artificial cilia was embedded within one of the channel's confinement through the aforementioned technique. A series of image processing and micro-particle image velocimetry technologies were employed to elucidate the micromixing and micropropulsion phenomena. Experiment results demonstrate that, with this proposed microfluidic device, a maximum micromixing efficiency and flow rate of 0.84 and 0.089 uL/min, respectively, can be achieved. In addition to its primary application as a targeted drug delivery system, where a drug needs to be homogeneously mixed with its carrier prior to its administration into the target body, this microfluidic device can be used as a micro-total analysis system for the handling of other biological specimens. PMID- 30400451 TI - Application of Ultra-Small Micro Grinding and Micro Milling Tools: Possibilities and Limitations. AB - Current demands for flexible, individual microstructures in high quality result in high requirements for micro tools. As the tool size defines the minimum structure size, ultra-small tools are needed. To achieve tool diameters of 50 um and lower, we investigate the complete manufacturing chain of micro machining. From the development of the machine tools and components needed to produce and apply the micro tools, the micro tools themselves, as well as the micro machining processes. Machine tools are developed with the possibility of producing the micro geometry (cutting edge design) of micro tools as well as plating processes to produce super abrasive micro grinding tools. Applying these setups, we are able to produce ultra-small micro grinding and micro milling tools with typical diameters of 50 um and down to 4 um. However, the application of such tools is very challenging. The article presents possibilities and limitations in manufacturing the micro tools themselves as well as microstructures made with these tools. A special emphasis will be on the influence of the tool substrate in micro milling and grain sizes in micro grinding. PMID- 30400453 TI - Nonlinear Robust Adaptive Multi-Modal Vibration Control of Bi-Electrode Micro Switch with Constraints on the Input. AB - Micro functionally graded material (FGM) structures are able to have proper functions in vast environments. In this paper, nonlinear governing equations of the size-dependent micro-switch are derived using modified couple stress theory. Effective external forces including fringing field of electrostatic force and Casimir force are considered. Two electrodes cooperate to track the in-plane motions of the micro continuous system by tuning the supply voltages of the electrostatic force. An adaptive projection law is proposed to compensate for the effect of error in the initial estimates of system parameters. To achieve more reliability, a robust active vibration strategy is presented to withstand external disturbances. At any time, just one electrode is operational, and optimization is performed to decrease the controller gains. The highly nonlinear inputs have a singularity in the dynamics of the system, which are known as pull in instability, so for safety, the controller gains are chosen such that the pull in voltage is avoided. The dynamic response of the system is simulated using a single mode or multiple modes to validate the effectiveness of the presented vibration control approaches. The effects of error of the initial estimate of system parameters, the effect of impulse and the influences of various volume fractions are studied. PMID- 30400452 TI - Stroke Management: An Emerging Role of Nanotechnology. AB - Stroke is among the leading causes of mortality and morbidity worldwide. Stroke incidences and associated mortality are expected to rise to 23 million and 7.8 million, respectively, by 2030. Further, the aging population, imbalanced lifestyles, and environmental factors continue to shift the rate of stroke incidence, particularly in developing countries. There is an urgent need to develop new therapeutic approaches for treating stroke. Nanotechnology is a growing field, offering an encouraging future prospect for medical research in the management of strokes. The world market for nanotechnology derived products is expected to rise manyfold in the coming decades. Different types of nanomaterials such as perfluorocarbon nanoparticles, iron oxide nanoparticles, gold nanoparticles, polymeric nanoparticles, quantum dots, nanospheres, etc. have been developed for the diagnosis as well as therapy of strokes. Today, nanotechnology has also been integrated with stem cell therapy for treating stroke. However several obstacles remain to be overcome when using such nanomaterials for treating stroke and other neurological diseases. PMID- 30400454 TI - Micromachining Microchannels on Cyclic Olefin Copolymer (COC) Substrates with the Taguchi Method. AB - Micromilling is a straightforward approach to the manufacture of polymer microfluidic devices for applications in chemistry and biology. This fabrication process reduces costs, provides a relatively simple user interface, and enables the fabrication of complex structures, which makes it ideal for the development of prototypes. In this study, we investigated the influence of micromilling parameters on the surface roughness of a cyclic olefin copolymer (COC) substrate. We then employed factor analysis to determine the optimal cutting conditions. The parameters used in all experiments were the spindle speed, the feed rate, and the depth of cut. Roughness was measured using a stylus profilometer. The lowest roughness was 0.173 MUm at a spindle speed of 20,000 rpm, feed rate of 300 mm/min, and cut depth of 20 MUm. Factor analysis revealed that the feed rate has the greatest impact on surface quality, whereas the depth of cut has the least impact. PMID- 30400455 TI - How to Make a Fast, Efficient Bubble-Driven Micromotor: A Mechanical View. AB - Micromotors, which can be moved at a micron scale, have special functions and can perform microscopic tasks. They have a wide range of applications in various fields with the advantages of small size and high efficiency. Both high speed and efficiency for micromotors are required in various conditions. However, the dynamical mechanism of bubble-driven micromotors movement is not clear, owing to various factors affecting the movement of micromotors. This paper reviews various factors acting on micromotor movement, and summarizes appropriate methods to improve the velocity and efficiency of bubble-driven micromotors, from a mechanical view. The dynamical factors that have significant influence on the hydrodynamic performance of micromotors could be divided into two categories: environment and geometry. Improving environment temperature and decreasing viscosity of fluid accelerate the velocity of motors. Under certain conditions, raising the concentration of hydrogen peroxide is applied. However, a high concentration of hydrogen peroxide is not applicable. In the environment of low concentration, changing the geometry of micromotors is an effective mean to improve the velocity of micromotors. Increasing semi-cone angle and reducing the ratio of length to radius for tubular and rod micromotors are propitious to increase the speed of micromotors. For Janus micromotors, reducing the mass by changing the shape into capsule and shell, and increasing the surface roughness, is applied. This review could provide references for improving the velocity and efficiency of micromotors. PMID- 30400457 TI - A Single-Use, Self-Powered, Paper-Based Sensor Patch for Detection of Exercise Induced Hypoglycemia. AB - We report a paper-based self-powered sensor patch for prevention and management of exercise-induced hypoglycemia. The article describes the fabrication, in vitro, and in vivo characterization of the sensor for glucose monitoring in human sweat. This wearable, non-invasive, single-use biosensor integrates a vertically stacked, paper-based glucose/oxygen enzymatic fuel cell into a standard Band-Aid adhesive patch. The paper-based device attaches directly to skin, wicks sweat by using capillary forces to a reservoir where chemical energy is converted to electrical energy, and monitors glucose without external power and sophisticated readout instruments. The device utilizes (1) a 3-D paper-based fuel cell configuration, (2) an electrically conducting microfluidic reservoir for a high anode surface area and efficient mass transfer, and (3) a direct electron transfer between glucose oxidase and anodes for enhanced electron discharge properties. The developed sensor shows a high linearity of current at 0.02-1.0 mg/mL glucose centration (R2 = 0.989) with a high sensitivity of 1.35 uA/mM. PMID- 30400458 TI - Visualization Study of Oil-in-Water-in-Oil (O/W/O) Double Emulsion Formation in a Simple and Robust Co-Flowing Microfluidic Device. AB - A simple and robust co-flowing microfluidic device for double emulsion preparation is designed and assembled to visually study the double emulsion formation by the use of a microscope and high-speed camera. Using a visualization system, the transient processes of double emulsion formation in co-flowing stream are observed and recorded for a variety of flow rates. The effects of flow rates of each fluid on flow modes, drop sizes, and polydispersities are examined and analyzed. The results indicate that the detaching of the inner drops accelerates the detaching of the outer drops and speeds up the drop formation process of double emulsions. The manipulation of flow rates is capable to actively control the sizes of the inner and outer drops as well as the number of inner drops encapsulated. Without surface modification, the microfluidic device produces a variety of emulsions, including the single-core and multi-core O/W/O double emulsions as well as binary emulsions of single and double emulsions. The proposed co-flowing microfluidic device is highly desirable in producing double emulsions in an easy and cheap way. PMID- 30400459 TI - Miniaturization of Implantable Micro-Robot Propulsion Using a Wireless Power Transfer System. AB - This paper presents an efficient coil design for a mm-sized micro-robot which generates a propulsion force and torque and receives electrical energy using a wireless power transfer system. To determine the most efficient coil structures and produce propulsion and torque on the micro-robot, both helical and spiral coil modeling was conducted, and analytical formulations of the propulsion force and torque were derived for helical and spiral coil structures. Additionally, the dominant dimensional factors for determining propulsion and coil torque were analyzed in detail. Based on the results, an optimum coil structure for generating maximum force on the micro-robot was developed and is herein presented with dimensional analysis. Simulations and experiments were also conducted to verify the design, and good agreement was achieved. A 3-mm micro-robot that simultaneously generated a propulsion force and torque and received electrical energy via wireless power transfer was successfully fabricated using the proposed method and verified. PMID- 30400460 TI - Encapsulation of Piezoelectric Transducers for Sensory Augmentation and Substitution with Wearable Haptic Devices. AB - The integration of polymeric actuators in haptic displays is widespread nowadays, especially in virtual reality and rehabilitation applications. However, we are still far from optimizing the transducer ability in conveying sensory information. Here, we present a vibrotactile actuator characterized by a piezoelectric disk embedded in a polydimethylsiloxane (PDMS) shell. An original encapsulation technique was performed to provide the stiff active element with a compliant cover as an interface towards the soft human skin. The interface stiffness, together with the new geometry, generated an effective transmission of vibrotactile stimulation and made the encapsulated transducer a performant component for the development of wearable tactile displays. The mechanical behavior of the developed transducer was numerically modeled as a function of the driving voltage and frequency, and the exerted normal forces were experimentally measured with a load cell. The actuator was then tested for the integration in a haptic glove in single-finger and bi-finger condition, in a 2-AFC tactile stimulus recognition test. Psychophysical results across all the tested sensory conditions confirmed that the developed integrated haptic system was effective in delivering vibrotactile information when the frequency applied to the skin is within the 200-700 Hz range and the stimulus variation is larger than 100 Hz. PMID- 30400461 TI - Design, Characterization and Sensitivity Analysis of a Piezoelectric Ceramic/Metal Composite Transducer. AB - This article presents experimental characterization and numerical simulation techniques used to create large amplitude and high frequency surface waves with the help of a metal/ceramic composite transducer array. Four piezoelectric bimorph transducers are cascaded and operated in a nonlinear regime, creating broad band resonant vibrations. The used metallic plate itself resembles a movable wall which can align perfectly with an airfoil surface. A phase-shifted operation of the actuators results in local displacements that generate a surface wave in the boundary layer for an active turbulence control application. The primary focus of this article is actuator design and a systematic parameter variation experiment which helped optimize its nonlinear dynamics. Finite Element Model (FEM) simulations were performed for different design variants, with a primary focus in particular on the minimization of bending stress seen directly on the piezo elements while achieving the highest possible deflection of the vibrating metallic plate. Large output force and a small yield stress (leading to a relatively small output stoke) are characteristics intrinsic to the stiff piezo ceramics. Optimized piezo thickness and its spatial distribution on the bending surface resulted in an efficient stress management within the bimorph design. Thus, our proposed resonant transduction array achieved surface vibrations with a maximum peak-to-peak amplitude of 500 MU m in a frequency range around 1200 Hz. PMID- 30400456 TI - Towards Multiplex Molecular Diagnosis-A Review of Microfluidic Genomics Technologies. AB - Highly sensitive and specific pathogen diagnosis is essential for correct and timely treatment of infectious diseases, especially virulent strains, in people. Point-of-care pathogen diagnosis can be a tremendous help in managing disease outbreaks as well as in routine healthcare settings. Infectious pathogens can be identified with high specificity using molecular methods. A plethora of microfluidic innovations in recent years have now made it increasingly feasible to develop portable, robust, accurate, and sensitive genomic diagnostic devices for deployment at the point of care. However, improving processing time, multiplexed detection, sensitivity and limit of detection, specificity, and ease of deployment in resource-limited settings are ongoing challenges. This review outlines recent techniques in microfluidic genomic diagnosis and devices with a focus on integrating them into a lab on a chip that will lead towards the development of multiplexed point-of-care devices of high sensitivity and specificity. PMID- 30400462 TI - Modeling and Quantitative Analysis of GNSS/INS Deep Integration Tracking Loops in High Dynamics. AB - To meet the requirements of global navigation satellite systems (GNSS) precision applications in high dynamics, this paper describes a study on the carrier phase tracking technology of the GNSS/inertial navigation system (INS) deep integration system. The error propagation models of INS-aided carrier tracking loops are modeled in detail in high dynamics. Additionally, quantitative analysis of carrier phase tracking errors caused by INS error sources is carried out under the uniform high dynamic linear acceleration motion of 100 g. Results show that the major INS error sources, affecting the carrier phase tracking accuracy in high dynamics, include initial attitude errors, accelerometer scale factors, gyro noise and gyro g-sensitivity errors. The initial attitude errors are usually combined with the receiver acceleration to impact the tracking loop performance, which can easily cause the failure of carrier phase tracking. The main INS error factors vary with the vehicle motion direction and the relative position of the receiver and the satellites. The analysis results also indicate that the low-cost micro-electro mechanical system (MEMS) inertial measurement units (IMU) has the ability to maintain GNSS carrier phase tracking in high dynamics. PMID- 30400463 TI - A Novel Method and Mechanism for Micro-Sphere Singularization. AB - The paper presents an innovative mechanism for the singularization of micro spheres, which can be effectively employed in a diverse range of robotized applications in micro-electronics and micro-mechanics. Many miniaturized devices are currently being developed and consist of different micro-components to be precisely assembled. The demanding product and process requirements can be met by automating the assembly phases, which include sorting and feeding the micro components. Therefore, accurate, high-throughput, and modular mechanisms and tools able to supply a number of micro-components, or even a single element for the subsequent operations, play a significant role. In this context, this work focused on the development of a novel strategy for separating a single component from an unstructured stock of identical parts, in particular of micro-spheres with diameters of 0.2-1 mm. Suitable expedients were considered to overcome the adhesive effects that can become significant at the micro-scale due to the very small size and low mass of the micro-spheres. The paper describes the operating principle and the actuation strategies of the mechanism. The design and the development of a prototype for singularizing micro-spheres with a diameter of 0.6 mm are thoroughly discussed. Finally, the results of experimental singularization tests demonstrate the method effectiveness and the mechanism performance. PMID- 30400465 TI - The Rise of Scalable Micro/Nanopatterning. AB - This is the golden age of scalable micro/nanopatterning, as these methods emerge as an answer to produce industrial-scale nano-objects with a focus on economical sustainability and reliability.[...]. PMID- 30400464 TI - A Review on Micromixers. AB - Microfluidic devices have attracted increasing attention in the fields of biomedical diagnostics, food safety control, environmental protection, and animal epidemic prevention. Micromixing has a considerable impact on the efficiency and sensitivity of microfluidic devices. This work reviews recent advances on the passive and active micromixers for the development of various microfluidic chips. Recently reported active micromixers driven by pressure fields, electrical fields, sound fields, magnetic fields, and thermal fields, etc. and passive micromixers, which owned two-dimensional obstacles, unbalanced collisions, spiral and convergence-divergence structures or three-dimensional lamination and spiral structures, were summarized and discussed. The future trends for micromixers to combine with 3D printing and paper channel were brought forth as well. PMID- 30400466 TI - Editorial for the Special Issue on Microdevices and Microsystems for Cell Manipulation. AB - Microfabricated devices and systems capable of micromanipulation are well-suited for the manipulation of cells.[...]. PMID- 30400467 TI - Ultra-Stretchable Interconnects for High-Density Stretchable Electronics. AB - The exciting field of stretchable electronics (SE) promises numerous novel applications, particularly in-body and medical diagnostics devices. However, future advanced SE miniature devices will require high-density, extremely stretchable interconnects with micron-scale footprints, which calls for proven standardized (complementary metal-oxide semiconductor (CMOS)-type) process recipes using bulk integrated circuit (IC) microfabrication tools and fine-pitch photolithography patterning. Here, we address this combined challenge of microfabrication with extreme stretchability for high-density SE devices by introducing CMOS-enabled, free-standing, miniaturized interconnect structures that fully exploit their 3D kinematic freedom through an interplay of buckling, torsion, and bending to maximize stretchability. Integration with standard CMOS type batch processing is assured by utilizing the Flex-to-Rigid (F2R) post processing technology to make the back-end-of-line interconnect structures free standing, thus enabling the routine microfabrication of highly-stretchable interconnects. The performance and reproducibility of these free-standing structures is promising: an elastic stretch beyond 2000% and ultimate (plastic) stretch beyond 3000%, with <0.3% resistance change, and >10 million cycles at 1000% stretch with <1% resistance change. This generic technology provides a new route to exciting highly-stretchable miniature devices. PMID- 30400468 TI - Multi-Objective Topology Optimization of a Compliant Parallel Planar Mechanism under Combined Load Cases and Constraints. AB - This paper focuses on a new type of configuration design of a compliant parallel mechanism (CPM) planar continuum structure and its characteristic analysis of vibration-inherent frequency for planar motion, which can suppress the impact of random vibration in ultra-precision positioning and manufacturing equipment and improve the inherent frequency response of the mechanism. Firstly, a vector mapping isomorphism between the fully CPM and conventional isomorphic parallel mechanism was constructed with a kinematic differential Jacobian matrix. Then, the mathematical model of topology optimization was put forward considering the compromise programming on the static stiffness and mean vibration-inherent frequency of the mechanism as the design variable and the minimization of compliance as the objective function. A constraint of volume fraction was considered and multi-objective micro displacement mechanism topology optimization based on a prismatic-revolute-revolute (3-PRR) planar nano-positioning continuum structure was performed using the solid isotropic material with penalization (SIMP) technique, which combines the criteria of the optimization algorithm and the vector isomorphic mapping method. Multi-objective topology optimization of the continuum structure micro displacement mechanism was investigated and presented by optimizations with different initial rejection rates. The simulation results show that the stiffness and vibration suppression performance of the continuum structure were improved, whereas the positioning of differential kinematics characteristics of the 3-PRR micro displacement planar fully CPM and isomorphic prototype mechanism retain the same. The modal analysis also provides a rational configuration for the micro displacement mechanism dimensional design and its optimal modal parameters. The crossover oscillation in frequency response of the continuum structure was reduced and quickly converged in the optimization iterations. The performance of the optimized mechanism was verified by the experiments on a planar fully compliant micro displacement continuum structure based on Lead Zirconate Titanate (PZT) actuator. PMID- 30400469 TI - Simulation, Fabrication and Analysis of Silver Based Ascending Sinusoidal Microchannel (ASMC) for Implant of Varicose Veins. AB - Bioengineered veins can benefit humans needing bypass surgery, dialysis, and now, in the treatment of varicose veins. The implant of this vein in varicose veins has significant advantages over the conventional treatment methods. Deep vein thrombosis (DVT), vein patch repair, pulmonary embolus, and tissue-damaging problems can be solved with this implant. Here, the authors have proposed biomedical microdevices as an alternative for varicose veins. MATLAB and ANSYS Fluent have been used for simulations of blood flow for bioengineered veins. The silver based microchannel has been fabricated by using a micromachining process. The dimensions of the silver substrates are 51 mm, 25 mm, and 1.1 mm, in length, width, and depth respectively. The dimensions of microchannels grooved in the substrates are 0.9 mm in width and depth. The boundary conditions for pressure and velocity were considered, from 1.0 kPa to 1.50 kPa, and 0.02 m/s to 0.07 m/s, respectively. These are the actual values of pressure and velocity in varicose veins. The flow rate of 5.843 (0.1 nL/s) and velocity of 5.843 cm/s were determined at Reynolds number 164.88 in experimental testing. The graphs and results from simulations and experiments are in close agreement. These microchannels can be inserted into varicose veins as a replacement to maintain the excellent blood flow in human legs. PMID- 30400470 TI - Introduction of a Chemical-Free Metal PDMS Thermal Bonding for Fabrication of Flexible Electrode by Metal Transfer onto PDMS. AB - Polydimethylsiloxane (PDMS) is a flexible and biocompatible material widely used in the fabrication of microfluidic devices, and is often studied for the fabrication of flexible electrodes. The most popular method of fabricating a flexible electrode using PDMS is done by transferring a metal electrode onto said PDMS. However, the transfer process is difficult and the transferred metal layer is easily damaged due to inherently weak adhesion forces between the metal and PDMS, thus requiring a chemical treatment or sacrificial layer between the two. The fabrication process using a chemical treatment or sacrificial layer is complicated and expensive, which is the major limitation of using PDMS in the fabrication of flexible electrodes. This paper discusses the findings of a possible solution to create strong bonding between PDMS and various metals (copper, nickel and silver) using a chemical-free metal to PDMS thermal bonding technique. This method is the same as the PDMS curing process, but with a variation in the curing condition. The condition required to create strong bonding was studied by observing copper transferred by various PDMS curing conditions, including the standard condition. The condition creating the strong bonding was baking PDMS (5:1 = base polymer: curing agent) at 150 degrees C for 20 min. Experimentation showed that the optimum thickness of the transferred metal shows that the optimum thickness is approximately 500 nm, which allows for a higher resistance to stresses. The successful transfer of copper, nickel and silver layers onto PDMS with a stronger adhesion force opens up many new applications dealing with the fabrication of flexible electrodes, sensors, and flexible soft magnets. PMID- 30400471 TI - Numerical Investigation of a Novel Wiring Scheme Enabling Simple and Accurate Impedance Cytometry. AB - Microfluidic impedance cytometry is a label-free approach for high-throughput analysis of particles and cells. It is based on the characterization of the dielectric properties of single particles as they flow through a microchannel with integrated electrodes. However, the measured signal depends not only on the intrinsic particle properties, but also on the particle trajectory through the measuring region, thus challenging the resolution and accuracy of the technique. In this work we show via simulation that this issue can be overcome without resorting to particle focusing, by means of a straightforward modification of the wiring scheme for the most typical and widely used microfluidic impedance chip. PMID- 30400472 TI - Accurate Extraction of the Self-Rotational Speed for Cells in an Electrokinetics Force Field by an Image Matching Algorithm. AB - We present an image-matching-based automated algorithm capable of accurately determining the self-rotational speed of cancer cells in an optically-induced electrokinetics-based microfluidic chip. To automatically track a specific cell in a video featuring more than one cell, a background subtraction technique was used. To determine the rotational speeds of cells, a reference frame was automatically selected and curve fitting was performed to improve the stability and accuracy. Results show that the algorithm was able to accurately calculate the self-rotational speeds of cells up to ~150 rpm. In addition, the algorithm could be used to determine the motion trajectories of the cells. Potential applications for the developed algorithm include the differentiation of cell morphology and characterization of cell electrical properties. PMID- 30400474 TI - PMMA Solution Assisted Room Temperature Bonding for PMMA-PC Hybrid Devices. AB - Recently, thermoplastic polymers have become popular materials for microfluidic chips due to their easy fabrication and low cost. A polymer based microfluidic device can be formed in various fabrication techniques such as laser machining, injection molding, and hot embossing. A new bonding process presented in this paper uses a 2.5% (w/w) polymethyl methacrylate (PMMA) solution as an adhesive layer to bond dissimilar polymers-PMMA to polycarbonate (PC)-to enclose the PMMA microfluidic channels with PC. This technique has been successfully demonstrated to bond PMMA microchip to PC film. This paper presents bonding strength using a shear strength test and a crack opening method in addition to the fluidic leakage inspection. PMID- 30400473 TI - Progress in Research of Flexible MEMS Microelectrodes for Neural Interface. AB - With the rapid development of Micro-electro-mechanical Systems (MEMS) fabrication technologies, many microelectrodes with various structures and functions have been designed and fabricated for applications in biomedical research, diagnosis and treatment through electrical stimulation and electrophysiological signal recording. The flexible MEMS microelectrodes exhibit excellent characteristics in many aspects beyond stiff microelectrodes based on silicon or metal, including: lighter weight, smaller volume, better conforming to neural tissue and lower fabrication cost. In this paper, we reviewed the key technologies in flexible MEMS microelectrodes for neural interface in recent years, including: design and fabrication technology, flexible MEMS microelectrodes with fluidic channels and electrode-tissue interface modification technology for performance improvement. Furthermore, the future directions of flexible MEMS microelectrodes for neural interface were described, including transparent and stretchable microelectrodes integrated with multi-functional aspects and next-generation electrode-tissue interface modifications, which facilitated electrode efficacy and safety during implantation. Finally, we predict that the relationships between micro fabrication techniques, and biomedical engineering and nanotechnology represented by flexible MEMS microelectrodes for neural interface, will open a new gate to better understanding the neural system and brain diseases. PMID- 30400475 TI - Custom-Designed Glassy Carbon Tips for Atomic Force Microscopy. AB - Glassy carbon is a graphenic form of elemental carbon obtained from pyrolysis of carbon-rich precursor polymers that can be patterned using various lithographic techniques. It is electrically and thermally conductive, mechanically strong, light, corrosion resistant and easy to functionalize. These properties render it very suitable for Carbon-microelectromechanical systems (Carbon-MEMS) and nanoelectromechanical systems (Carbon-NEMS) applications. Here we report on the fabrication and characterization of fully operational, microfabricated glassy carbon nano-tips for Atomic Force Microscopy (AFM). These tips are 3D-printed on to micro-machined silicon cantilevers by Two-Photon Polymerization (2PP) of acrylate-based photopolymers (commercially known as IP-series resists), followed by their carbonization employing controlled pyrolysis, which shrinks the patterned structure by >=98% in volume. Tip performance and robustness during contact and dynamic AFM modes are validated by morphology and wear tests. The design and pyrolysis process optimization performed for this work indicate which parameters require special attention when IP-series polymers are used for the fabrication of Carbon-MEMS and NEMS. Microstructural characterization of the resulting material confirms that it features a frozen percolated network of graphene sheets accompanied by disordered carbon and voids, similar to typical glassy carbons. The presented facile fabrication method can be employed for obtaining a variety of 3D glassy carbon nanostructures starting from the stereolithographic designs provided by the user. PMID- 30400476 TI - Research on Design and Simulation of Biaxial Tensile-Bending Complex Mechanical Performance Test Apparatus. AB - In order to realize a micro-mechanic performance test of biaxial tensile-bending combined loading and solve the problem of incompatibility of test apparatus and observation apparatus, novel biaxial-combined tensile-bending micro-mechanical performance test apparatus was designed. The working principle and major functions of key constituent parts of test apparatus, including the servo drive unit, clamping unit and test system, were introduced. Based on the finite element method, biaxial tensile and tension-bending-combined mechanical performances of the test-piece were studied as guidance to learn the distribution of elastic deformation and plastic deformation of all sites of the test-piece and to better plan test regions. Finally, this test apparatus was used to conduct a biaxial tensile test under different pre-bending loading and a tensile test at different rates; the image of the fracture of the test-piece was acquired by a scanning electron microscope and analyzed. It was indicated that as the pre-bending force rises, the elastic deformation phase would gradually shorten and the slope of the elastic deformation phase curve would slightly rise so that a yield limit would appear ahead of time. Bending speed could exert a positive and beneficial influence on tensile strength but weaken fracture elongation. If bending speed is appropriately raised, more ideal anti-tensile strength could be obtained, but fracture elongation would decline. PMID- 30400478 TI - Electromagnetic Linear Vibration Energy Harvester Using Sliding Permanent Magnet Array and Ferrofluid as a Lubricant. AB - We present an electromagnetic linear vibration energy harvester with an array of rectangular permanent magnets as a springless proof mass. Instead of supporting the magnet assembly with spring element, ferrofluid has been used as a lubricating material. When external vibration is applied laterally to the harvester, magnet assembly slides back and forth on the channel with reduced friction and wear due to ferrofluid, which significantly improves the long-term reliability of the device. Electric power is generated across an array of copper windings formed at the bottom of the aluminum housing. A proof-of-concept harvester has been fabricated and tested with a vibration exciter at various input frequencies and accelerations. For the device where 5 MUL of ferrofluid was used for lubrication, maximum output power of 493 MUW has been generated, which was 4.37% higher than that without ferrofluid. Long-term reliability improvement due to ferrofluid lubrication has also been verified. For the device with ferrofluid, 1.02% decrease of output power has been observed, in contrast to 59.73% decrease of output power without ferrofluid after 93,600 cycles. PMID- 30400477 TI - Milling Positive Master for Polydimethylsiloxane Microfluidic Devices: The Microfabrication and Roughness Issues. AB - We provide a facile and low-cost method (F-L) to fabricate a two-dimensional positive master using a milling technique for polydimethylsiloxane (PDMS)-based microchannel molding. This method comprises the following steps: (1) a positive microscale master of the geometry is milled on to an acrylic block; (2) pre-cured PDMS is used to mold the microscale positive master; (3) the PDMS plate is peeled off from the master and punctured with a blunt needle; and (4) the PDMS plate is O2 plasma bonded to a glass slide. Using this technique, we can fabricate microchannels with very simple protocols quickly and inexpensively. This method also avoids breakage of the end mill (phi = 0.4 mm) of the computerized numerical control (CNC) system when fabricating the narrow channels (width < 50 um). The prominent surface roughness of the milled bottom-layer could be overcomed by pre cured PDMS with size trade-off in design. Finally, emulsion formation successfully demonstrates the validity of the proposed fabrication protocol. This work represents an important step toward the use of a milling technique for PDMS based microfabrication. PMID- 30400479 TI - Modelling and Experimental Verification of Step Response Overshoot Removal in Electrothermally-Actuated MEMS Mirrors. AB - Micro-electro-mechanical system (MEMS) mirrors are widely used for optical modulation, attenuation, steering, switching and tracking. In most cases, MEMS mirrors are packaged in air, resulting in overshoot and ringing upon actuation. In this paper, an electrothermal bimorph MEMS mirror that does not generate overshoot in step response, even operating in air, is reported. This is achieved by properly designing the thermal response time and the mechanical resonance without using any open-loop or closed-loop control. Electrothermal and thermomechanical lumped-element models are established. According to the analysis, when setting the product of the thermal response time and the fundamental resonance frequency to be greater than Q/2pi, the mechanical overshoot and oscillation caused by a step signal can be eliminated effectively. This method is verified experimentally with fabricated electrothermal bimorph MEMS mirrors. PMID- 30400480 TI - Acoustic Manipulation of Bio-Particles at High Frequencies: An Analytical and Simulation Approach. AB - Manipulation of micro and nano particles in microfluidic devices with high resolution is a challenge especially in bioengineering applications where bio particles (BPs) are separated or patterned. While acoustic forces have been used to control the position of BPs, its theoretical aspects need further investigation particularly for high-resolution manipulation where the wavelength and particle size are comparable. In this study, we used a finite element method (FEM) to amend analytical calculations of acoustic radiation force (ARF) arising from an imposed standing ultrasound field. First, an acoustic solid interaction (ASI) approach was implemented to calculate the ARF exerted on BPs and resultant deformation induced to them. The results were then used to derive a revised expression for the ARF beyond the small particle assumption. The expression was further assessed in numerical simulations of one- and multi-directional standing acoustic waves (SAWs). Furthermore, a particle tracing scheme was used to investigate the effect of actual ARF on separation and patterning applications under experimentally-relevant conditions. The results demonstrated a significant mismatch between the actual force and previous analytical predictions especially for high frequencies of manipulation. This deviation found to be not only because of the shifted ARF values but also due to the variation in force maps in multidirectional wave propagation. Findings of this work can tackle the simulation limitations for spatiotemporal control of BPs using a high resolution acoustic actuation. PMID- 30400481 TI - A Method to Encapsulate Small Organic Molecules in Calcium Phosphate Nanoparticles Based on the Supramolecular Chemistry of Cyclodextrin. AB - Calcium phosphate nanoparticles (CPNPs) encapsulating small organic molecules, such as imaging agents and drugs, are considered to be ideal devices for cancer diagnosis or therapy. However, it is generally difficult to encapsulate small organic molecules in CPNPs because of the lack of solubility in water or binding affinity to calcium phosphate. To solve these issues, we utilized the carboxymethyl beta-cyclodextrin (CM-beta-CD) to increase the solubility and binding affinity to small organic molecules for the encapsulation into CPNPs in this work. The results indicated that the model molecules, hydrophilic rhodamine B (RB) and hydrophobic docetaxel (Dtxl), are successfully encapsulated into CPNPs with the assistance of CM-beta-CD. We also demonstrated the CPNPs could be remarkably internalized into A549 cells, resulting in the efficient inhibition of tumor cells' growth. PMID- 30400482 TI - Real Time Monitoring of Children, and Adults with Mental Disabilities Using a Low Cost Non-Invasive Electronic Device. AB - There are a growing number of small children-as well as adults-with mental disabilities (including elderly citizens with Alzheimer's disease or other forms of age-related dementia) that are getting lost in rural and urban areas for various reasons. Establishing their location within the first 72 h is crucial because lost people are exposed to all kinds of adverse conditions and in the case of the elderly, this is further aggravated if prescribed medication is needed. Herein we describe a non-invasive, low-cost electronic device that operates constantly, keeping track of time, the geographical location and the identification of the subject using it. The prototype was made using commercial low-cost electronic components. This electronic device shows high connectivity in open and closed areas and identifies the geographical location of a lost subject. We freely provide the software and technical diagrams of the prototypes. PMID- 30400483 TI - Development of a Cantilever-Type Electrostatic Energy Harvester and Its Charging Characteristics on a Highway Viaduct. AB - We have developed a micro-electro-mechanical systems (MEMS) electrostatic vibratory power generator with over 100 MU W RMS of (root-mean-square) output electric power under 0.03 G RMS (G: the acceleration of gravity) accelerations. The device is made of a silicon-on-insulator (SOI) wafer and is fabricated by silicon micromachining technology. An electret built-in potential is given to the device by electrothermal polarization in silicon oxide using potassium ions. The force factor, which is defined by a proportional coefficient of the output current with respect to the vibration velocity, is 2.34 * 10 - 4 C/m; this large value allows the developed vibration power generator to have a very high power efficiency of 80.7%. We have also demonstrated a charging experiment by using an environmental acceleration waveform with an average amplitude of about 0.03 G RMS taken at a viaduct of a highway, and we obtained 4.8 mJ of electric energy stored in a 44 MU F capacitor in 90 min. PMID- 30400484 TI - Microrobotic Platform for Single Motile Microorganism Investigation. AB - We propose a microrobotic platform for single motile microorganism observation and investigation. The platform utilizes a high-speed online vision sensor to realize real-time observation of a microorganism under a microscopic environment with a relatively high magnification ratio. A microfluidic chip was used to limit the vertical movement of the microorganism and reduce the tracking system complexity. We introduce a simple image processing method, which utilizes high speed online vision characteristics and shows robustness against image noise to increase the overall tracking performance with low computational time consumption. The design also considers the future integration of a stimulation system using microtools. Successful long-time tracking of a freely swimming microorganism inside of a microfluidic chip for more than 30 min was achieved notwithstanding the presence of noises in the environment of the cell. The specific design of the platform, particularly the tracking system, is described, and the performance is evaluated and confirmed through basic experiments. The potential of the platform to apply mechanical stimulation to a freely swimming microorganism is demonstrated by using a 50-um-thick microtool. The proposed platform can be used for long-term observation and to achieve different kinds of stimulations, which can induce new behavior of the cells and lead to unprecedented discoveries in biological fields. PMID- 30400485 TI - Stress Distribution Profile Imaging With Spectral Fabry-Perot Interferometry in Thin Layer Substrates for Surface Micromachining. AB - We have used spectral two-layer interferometry (STLI) imaging for estimation of the stress distribution profiles (SDPs) in thin film substrates, enabling fast and reliable all-optical methodology for the evaluation of pre-stress topography profiles in silicon wafers deposited with thin films. Specifically, in polycrystalline silicon (PS) and silicon nitride (SN) thin films, we demonstrate a nondestructive, systematic, and robust capability for consistent stress distribution profile (SDP) evaluation relying on STLI. In particular, for PS and SN devices, the SDP estimation is consistent and is compared with complementary characterization of the films. PMID- 30400486 TI - Structural Analysis of Disk Resonance Gyroscope. AB - In this paper, we present two design methods to improve the performance of disk resonator gyroscope (DRG), including decreasing the frequency split and increasing the quality factor (Q). The structure parameters, which can affect the frequency split and Q value were concluded with the help of the FEM software. Meanwhile, devices with different parameters were designed, fabricated, and tested, and the experimental result was in accordance with the simulation. With the proposed methods, the DRG was selected with a high Q value and a low frequency split to satisfy the demand of high performance. The weakness and future works were pointed at last. PMID- 30400487 TI - Micro/Nano Manufacturing. AB - Micro- and nano-scale manufacturing has been the subject of an increasing amount of interest and research effort worldwide in both academia and industry over the past 10 years.[...]. PMID- 30400488 TI - Biomedical Applications of Nanotechnology and Nanomaterials. AB - The spurring growth and clinical adoption of nanomaterials and nanotechnology in medicine, i.e. "nanomedicine", to shape global health care system is a collective effort that comprises academia research, industrial drive, and political and financial support from government.[...]. PMID- 30400490 TI - Laser-Induced-Plasma-Assisted Ablation and Metallization on C-Plane Single Crystal Sapphire (c-Al2O3). AB - Laser-induced-plasma-assisted ablation (LIPAA) is a promising micro-machining method that can fabricate microstructure on hard and transparent double-polished single crystal sapphire (SCS). While ablating, a nanosecond pulse 1064 nm wavelength laser beam travels through the SCS substrate and bombards the copper target lined up behind the substrate, which excites the ablating plasma. When laser fluence rises and is above the machining threshold of copper but below that of SCS, the kinetic energy of the copper plasma generated from the bombardment is mainly determined by the laser fluence, the repetition rate, and the substrate-to target distance. With a lower repetition rate, SCS becomes metallized and gains conductivity. When micro-machining SCS with a pulsed laser are controlled by properly controlling laser machining parameters, such as laser fluence, repetition rate, and substrate-to-target distance, LIPAA can ablate certain line widths and depths of the microstructure as well as the resistance of SCS. On the contrary, conductivity resistance of metalized sapphire depends on laser parameters and distance in addition to lower repetition rate. PMID- 30400491 TI - AlN-Based Ceramic Patch Antenna-Type Wireless Passive High-Temperature Sensor. AB - An aluminum nitride (AlN) based patch antenna-type high-temperature wireless passive sensor is reported to operate as both a sensor and an antenna, which integrates in situ measurement/sensing with remote wireless communication at the same time. The sensor is small, easy to manufacture, highly sensitive and has a high operating temperature; it can be used in high-temperature, chemically corrosive and other harsh environments. The sensing mechanism of the sensor, the dielectric constant of the AlN ceramic substrate, increases with rising temperature, which reduces the resonant frequency of the sensor. Thus, the temperature can be measured by detecting changes in the sensor's resonant frequency. High-Frequency Simulation Structure (HFSS) software is used to determine the structure and size of the sensor, which is then fabricated using thick-film technology. The substrate of the sensor is AlN ceramic due to its outstanding thermal resistance at high temperature; and its conductors (the radiation patch and the ground under the substrate) are silver-palladium alloy sintered form silver-palladium paste. A vector network analyzer reveals that the sensor's operating range extends to 700 degrees C. Furthermore, its resonant frequency decreases from 2.20 GHz to 2.13 GHz with increasing temperature from room temperature (25 degrees C) to 700 degrees C, with an absolute sensitivity of 104.77 KHz/ degrees C. Our work verifies the feasibility of measuring high temperatures using AlN-based patch antenna wireless passive temperature sensors, and provides a new material and temperature sensitive structure for high temperature measurement in harsh environments. PMID- 30400489 TI - Bio-Inspired Microdevices that Mimic the Human Vasculature. AB - Blood vessels may be found throughout the entire body and their importance to human life is undeniable. This is evident in the fact that a malfunctioning blood vessel can result in mild symptoms such as shortness of breath or chest pain to more severe symptoms such as a heart attack or stroke, to even death in the severest of cases. Furthermore, there are a host of pathologies that have been linked to the human vasculature. As a result many researchers have attempted to unlock the mysteries of the vasculature by performing studies that duplicate the physiological structural, chemical, and mechanical properties known to exist. While the ideal study would consist of utilizing living, blood vessels derived from human tissue, such studies are not always possible since intact human blood vessels are not readily accessible and there are immense technical difficulties associated with such studies. These limitations have opened the door for the development of microdevices modeled after the human vasculature as it is believed by many researchers in the field that such devices can one day replace tissue models. In this review we present an overview of microdevices developed to mimic various types of vasculature found throughout the human body. Although the human body contains a diverse array of vascular systems for this review we limit our discussion to the cardiovascular system and cerebrovascular system and discuss such systems that have been fabricated in both 2D and 3D configurations. PMID- 30400492 TI - The Analysis of Three-Body Contact Temperature under the Different Third Particle Size, Density, and Value of Friction. AB - Recently, many studies have investigated the friction, wear, and temperature characteristics of the interface between two relative movements. Such analyses often set the coefficient of friction as a fixed value and are analyzed in cases of two-body contact; however, the interface is often a three-body contact and the coefficient of friction varies depending on the operating conditions. This is a significant error in the analysis of contact characteristics, therefore, in this study, the actual interface and the change of the coefficient of friction were analyzed based on three-body micro-contact theory where the contact temperature was also analyzed and the difference between the generally assumed values were compared. The results showed that under three-body contact, the coefficient of total friction increased with an increase in particle size; and at a different particle size and area density of particles, the surface contact temperature increased with the plasticity index and load increases, and the particle contact temperature increased with the increasing particle size. The surface temperature rise was mainly affected by the ratio of the average temperature between surface 1 and surface 2 to the multiplication between the 100th root of the area density of particles and the square root of the equivalent surface roughness (Ts1s2_ave*/etaa0.01sigma0.5) and the ratio of the 10th root of the mean particle diameter to the 100th root of the equivalent surface roughness (xa0.1/sigma0.001). Particle temperature was mainly affected by the ratio of the 10th root of the mean particle diameter to the 100th root of the equivalent surface roughness (xa0.1/sigma0.001) and the area density of particles etaa. Our study indicated that when the contact of surface with surface and the contact of the particles with the surface, the resulting heat balance was assigned to the particles and the surface in a three-body contact situation. Under this contact behavior, it could avoid a too high a rise in micro-contact temperature to achieve the material failure temperature. PMID- 30400493 TI - Correction: Li, H. et al. Research on Design and Simulation of Biaxial Tensile Bending Complex Mechanical Performance Test Apparatus. Micromachines, 2017, 8, 286. AB - In the published paper [1], there is an error in Figure 8. The labels in Figure 8 was incorrect, it should be corrected as follows [...]. PMID- 30400494 TI - Design and Performance Testing of a Novel Three-Dimensional Elliptical Vibration Turning Device. AB - A novel three-dimensional (3D) elliptical vibration turning device which is on the basis of the leaf-spring-flexure-hinges-based (LSFH-based) double parallel four-bar linkages (DPFLMs) has been proposed. In order to evaluate the performance of the developed 3D elliptical vibration cutting generator (EVCG), the off-line tests were carried out to investigate the stroke, dynamic performance, resolution, tracking accuracy and hysteresis along the three vibration axes. Experimental results indicate that the maximum stroke of three vibration axes can reach up to 26 MUm. The working bandwidth can reach up to 1889 Hz. The resolution and hysteresis tests show that the developed 3D EVCG has a good tracking accuracy, relative high resolution and low hysteresis, which is appropriate for micro/nano machining. Kinematical modeling is carried out to investigate the tool vibration trajectory. Experimental results shown that the simulation results agree well with the experimental one, which indicate that the developed 3D EVCG can be used as an option for micro/nano machining. PMID- 30400495 TI - A Micro-Force Sensor with Beam-Membrane Structure for Measurement of Friction Torque in Rotating MEMS Machines. AB - In this paper, a beam-membrane (BM) sensor for measuring friction torque in micro electro-mechanical system (MEMS) gas bearings is presented. The proposed sensor measures the force-arm-transformed force using a detecting probe and the piezoresistive effect. This solution incorporates a membrane into a conventional four-beam structure to meet the range requirements for the measurement of both the maximum static friction torque and the kinetic friction torque in rotating MEMS machines, as well as eliminate the problem of low sensitivity with neat membrane structure. A glass wafer is bonded onto the bottom of the sensor chip with a certain gap to protect the sensor when overloaded. The comparisons between the performances of beam-based sensor, membrane-based sensor and BM sensor are conducted by finite element method (FEM), and the final sensor dimensions are also determined. Calibration of the fabricated and packaged device is experimentally performed. The practical verification is also reported in the paper for estimating the friction torque in micro gas bearings by assembling the proposed sensor into a rotary table-based measurement system. The results demonstrate that the proposed force sensor has a potential application in measuring micro friction or force in MEMS machines. PMID- 30400496 TI - Study on Ti-6Al-4V Alloy Machining Applying the Non-Resonant Three-Dimensional Elliptical Vibration Cutting. AB - The poor machinability of Ti-6Al-4V alloy makes it hard to process by conventional processing methods even though it has been widely used in military and civilian enterprise fields. Non-resonant three-dimensional elliptical vibration cutting (3D-EVC) is a novel cutting technique which is a significant development potential for difficult-to-cut materials. However, few studies have been conducted on processing the Ti-6Al-4V alloy using the non-resonant 3D-EVC technique, the effect of surface quality, roughness, topography and freeform surface has not been clearly researched yet. Therefore, the machinability of Ti 6Al-4V alloy using the non-resonant 3D-EVC apparatus is studied in this paper. Firstly, the principle of non-resonant 3D-EVC technique and the model of cutter motion are introduced. Then the tool path is synthesized. The comparison experiments are carried out with traditional continuous cutting (TCC), two dimension elliptical vibration cutting (2D-EVC), and the non-resonant 3D-EVC method. The experimental results shown that the excellent surface and lower roughness (77.3 nm) could be obtained using the non-resonant 3D-EVC method; the shape and dimension of elliptical cutting mark also relates to the cutting speed and vibration frequency, and the concave/convex spherical surface topography are achieved by non-resonant 3D-EVC in the Ti-6Al-4V alloy. This proved that the non resonant 3D-EVC technique has the better machinability compared with the TCC and 2D-EVC methods. PMID- 30400498 TI - Dislocation Dynamics-Based Modeling and Simulations of Subsurface Damages Microstructure of Orthogonal Cutting of Titanium Alloy. AB - In this work, a novel method is put forward to quantitatively simulate the subsurface damages microstructural alteration of titanium alloy components subjected to microscale cutting. A trans-scale numerical framework is conducted with the purpose of revealing the underlying influence mechanism of tool structure parameters on subsurface dislocation configurations using a dislocation dynamics-based model, which considers both dislocation structural transformation and grain refining. Results showed that the developed framework not only captured the essential features of workpiece microstructure, but also predicted the subsurface damages layer states and their modifications. A series of defects were found in the material subsurface during the orthogonal cutting of titanium alloy, such as edge and screw dislocations, junctions, parallel slip lines, intersection dislocation bands, vacancy defects, and refinement grains. Particularly, in the process of micro-cutting, the depth of subsurface damages layer increased significantly with cutting length at the beginning, and then remained unchanged in the stable removal phase. Moreover, smaller edge radius and larger rake angle can greatly weaken the squeezing action and heat diffusion effect between the tool tip and workpiece, which further prevents the formation of subsurface defects and enhances finished surface quality. In addition, although increasing tool clearance angle could drastically lighten the thickness of subsurface damages layer, it is noteworthy that its performance would be decreased significantly when the clearance angle was greater than or equal to 5 degrees . The micro-end-milling experiment was performed to validate the existing simulation results, and the results show very good agreement. PMID- 30400497 TI - A Fluidic Interface with High Flow Uniformity for Reusable Large Area Resonant Biosensors. AB - Resonant biosensors are known for their high accuracy and high level of miniaturization. However, their fabrication costs prevent them from being used as disposable sensors and their effective commercial success will depend on their ability to be reused repeatedly. Accordingly, all the parts of the sensor in contact with the fluid need to tolerate the regenerative process which uses different chemicals (H3PO4, H2SO4 based baths) without degrading the characteristics of the sensor. In this paper, we propose a fluidic interface that can meet these requirements, and control the liquid flow uniformity at the surface of the vibrating area. We study different inlet and outlet channel configurations, estimating their performance using numerical simulations based on finite element method (FEM). The interfaces were fabricated using wet chemical etching on Si, which has all the desirable characteristics for a reusable biosensor circuit. Using a glass cover, we could observe the circulation of liquid near the active surface, and by using micro-particle image velocimetry (MUPIV) on large surface area we could verify experimentally the effectiveness of the different designs and compare with simulation results. PMID- 30400499 TI - Coupling Mechanism Analysis and Fabrication of Triaxial Gyroscopes in Monolithic MIMU. AB - A novel fully decoupled micro inertial measurement unit (MIMU) is presented in this paper. The proposed MIMU structure, mostly focusing on the gyroscope unit, is highly symmetrical and can be limited to an area of 10,000 MUm * 10,000 MUm. Both the tri-axis gyroscope and tri-axis accelerometer structures are fabricated on the same single silicon chip, which can differentially detect three axes' angular velocities and linear accelerated velocities at the same time. By elaborately arranging different decoupling beams, anchors and sensing frames, the drive and sense modes of the tri-axis gyroscope are fully decoupled from each other. Several dynamic models, including decoupling beams with fabrication imperfections, are established for theoretical analysis. The numerical simulation made by MATLAB shows the structural decoupling of three sense modes, and indicates that the key decoupling beams, which affect the quadrature error, can be improved in design. The whole fabrication process, including silicon on glass (SOG) process, dry/wet etching as well as the methods for improving the fabrication quality, is then shown. Experiments for mode frequency and quality factors of four modes (drive, yaw, pitch and roll) have been performed, and are found to be 455 (6950.2 Hz), 66 (7054.4 Hz), 109 (7034.2 Hz) and 107 (7040.5 Hz) respectively. The analysis and experiment both prove that this novel MIMU has the potential value of further intensive investigation. PMID- 30400500 TI - Controlled Solvent-Free Formation of Embedded PDMS-Derived Carbon Nanodomains with Tunable Fluorescence Using Selective Laser Ablation with A Low-Power CD Laser. AB - We present a study of the application of a single-step and solvent-free laser based strategy to control the formation of polymer-derived fluorescent carbon nanodomains embedded in poly-dimethylsiloxane (PDMS) microchannels. A low-power, laser-induced microplasma was used to produce a localised combustion of a PDMS surface and confine nanocarbon byproducts within the exposed microregions. Patterns with on-demand geometries were achieved under dry environmental conditions thanks to a low-cost 3-axis CD-DVD platform motorised in a selective laser ablation fashion. The high temperature required for combustion of PDMS was achieved locally by strongly focusing the laser spot on the desired areas, and the need for high-power laser was bypassed by coating the surface with an absorbing carbon additive layer, hence making the etching of a transparent material possible. The simple and repeatable fabrication process and the spectroscopic characterisation of resulting fluorescent microregions are reported. In situ Raman and fluorescence spectroscopy were used to identify the nature of the nanoclusters left inside the modified areas and their fluorescence spectra as a function of excitation wavelength. Interestingly, the carbon nanodomains left inside the etched micropatterns showed a strong dependency on the additive materials and laser energy that were used to achieve the incandescence and etch microchannels on the surface of the polymer. This dependence on the lasing conditions indicates that our cost-effective laser ablation technique may be used to tune the nature of the polymer-derived nanocarbons, useful for photonics applications in transparent silicones in a rapid-prototyping fashion. PMID- 30400501 TI - Spiral-Shaped Piezoelectric MEMS Cantilever Array for Fully Implantable Hearing Systems. AB - Fully implantable, self-powered hearing aids with no external unit could significantly increase the life quality of patients suffering severe hearing loss. This highly demanding concept, however, requires a strongly miniaturized device which is fully implantable in the middle/inner ear and includes the following components: frequency selective microphone or accelerometer, energy harvesting device, speech processor, and cochlear multielectrode. Here we demonstrate a low volume, piezoelectric micro-electromechanical system (MEMS) cantilever array which is sensitive, even in the lower part of the voice frequency range (300-700 Hz). The test array consisting of 16 cantilevers has been fabricated by standard bulk micromachining using a Si-on-Insulator (SOI) wafer and aluminum nitride (AlN) as a complementary metal-oxide-semiconductor (CMOS) and biocompatible piezoelectric material. The low frequency and low device footprint are ensured by Archimedean spiral geometry and Si seismic mass. Experimentally detected resonance frequencies were validated by an analytical model. The generated open circuit voltage (3-10 mV) is sufficient for the direct analog conversion of the signals for cochlear multielectrode implants. PMID- 30400502 TI - Design and Fabrication of Capacitive Silicon Nanomechanical Resonators with Selective Vibration of a High-Order Mode. AB - This paper reports the design and fabrication of capacitive silicon nanomechanical resonators with the selective vibration of a high-order mode. Fixed-fixed beam capacitive silicon resonators have been successfully produced by the use of electron beam lithography, photolithography, deep reactive ion etching, and anodic bonding methods. All resonators with different vibration modes are designed to have the same resonant frequency for performance comparison. Measurement results show that higher-order mode capacitive silicon resonators can achieve lower insertion loss compared to that of lower-order mode capacitive silicon resonators. The motional resistance of the fourth mode vibration resonator is improved by 83%, 90%, and 93% over the third, second, and first mode vibration resonators, respectively. PMID- 30400503 TI - Transparent Ferroelectric Capacitors on Glass. AB - We deposited transparent ferroelectric lead zirconate titanate thin films on fused silica and contacted them via Al-doped zinc oxide (AZO) transparent electrodes with an interdigitated electrode (IDE) design. These layers, together with a TiO2 buffer layer on the fused silica substrate, are highly transparent (>60% in the visible optical range). Fully crystallized Pb(Zr0.52Ti0.48)O3 (PZT) films are dielectrically functional and exhibit a typical ferroelectric polarization loop with a remanent polarization of 15 MUC/cm2. The permittivity value of 650, obtained with IDE AZO electrodes is equivalent to the one measured with Pt electrodes patterned with the same design, which proves the high quality of the developed transparent structures. PMID- 30400504 TI - Fabrication of Micro-Optics Elements with Arbitrary Surface Profiles Based on One Step Maskless Grayscale Lithography. AB - A maskless lithography method to realize the rapid and cost-effective fabrication of micro-optics elements with arbitrary surface profiles is reported. A digital micro-mirror device (DMD) is applied to flexibly modulate that the exposure dose according to the surface profile of the structure to be fabricated. Due to the fact that not only the relationship between the grayscale levels of the DMD and the exposure dose on the surface of the photoresist, but also the dependence of the exposure depth on the exposure dose, deviate from a linear relationship arising from the DMD and photoresist, respectively, and cannot be systemically eliminated, complicated fabrication art and large fabrication error will results. A method of compensating the two nonlinear effects is proposed that can be used to accurately design the digital grayscale mask and ensure a precise control of the surface profile of the structure to be fabricated. To testify to the reliability of this approach, several typical array elements with a spherical surface, aspherical surface, and conic surface have been fabricated and tested. The root-mean-square (RMS) between the test and design value of the surface height is about 0.1 MUm. The proposed method of compensating the nonlinear effect in maskless lithography can be directly used to control the grayscale levels of the DMD for fabricating the structure with an arbitrary surface profile. PMID- 30400505 TI - The Continuous Concentration of Particles and Cancer Cell Line Using Cell Margination in a Groove-Based Channel. AB - In the capillary venules, blood cells auto-separate with red blood cells aggregating near the centre of vessel and the nucleated cells marginating toward the wall of vessel. In this experiment, we used cell margination to help enrich the Jurkat cells via a groove-based channel which provides a vertical expansion contraction structure, wherein the red blood cells invade the grooves and push the Jurkat cells to the bottom of the channel. The secondary flows induced by the anisotropic grooves bring the Jurkat cells to the right sidewall. Rigid, 13-um diameter polystyrene particles were spiked into the whole blood to verify the operating principle under various working conditions, and then tests were carried out using Jurkat cells (~15 um). The performance of this device was quantified by analysing the cell distribution in a transverse direction at the outlet, and then measuring the cell concentration from the corresponding outlets. The results indicate that Jurkat cells were enriched by 22.3-fold with a recovery rate of 83.4%, thus proving that this microfluidic platform provides a gentle and passive way to isolate intact and viable Jurkat cells. PMID- 30400506 TI - Repetition Rate Effects in Picosecond Laser Microprocessing of Aluminum and Steel in Water. AB - Picosecond laser drilling was studied in the case of industrial steel and aluminum, which are difficult to microprocess by conventional methods. The dependence of hole morphology and dimensions on the pulse repetition rate and number of pulses in water and air were ascertained. For both materials, the diameter of the hole is larger in water than in air. In water, the diameter is larger at higher repetition rates than at lower ones, and increases with the number of pulses. In air, the hole diameter is not affected by the repetition rate, and remains constant from 100 to 100,000 pulses. Overall, material removal is more efficient in water than in air. The shape of the hole is generally more irregular in water, becoming more so as the number of pulses is increased. This is probably due to debris being trapped in the hole, since water flowing over the target surface cannot efficiently remove it. In aluminum, the depth of the hole is smaller at higher repetition rates. By scanning the beam over the aluminum target in water, the laser penetrates a 400-MUm thick workpiece, generating a line with comparable widths at the entrance and exit surfaces. PMID- 30400507 TI - Microfluidical Microwave Reactor for Synthesis of Gold Nanoparticles. AB - Microwave treatment can reduce the time of selected syntheses, for instance of gold nanoparticles (AuNPs), from several hours to a few minutes. We propose a microfluidic structure for enhancing the rate of chemical reactions using microwave energy. This reactor is designed to control microwave energy with much higher accuracy than in standard devices. Thanks to this, the influence of microwave irradiation on the rate of chemical reactions can be investigated. The reactor consists of a transmission line surrounded by ground metallization. In order to deliver microwave energy to the fluid under test efficiently, matching networks are used and optimized by means of numerical methods. The monolithic device is fabricated in the low temperature co-fired ceramics (LTCC) technology. This material exhibits excellent microwave performance and is resistant to many chemical substances as well as high temperatures. Fabrication of the devices is described in detail. Measurements of microwave parameters are performed and differences between simulation and experiment results are discussed. Finally, the usefulness of the proposed device is proved in exemplary synthesis. PMID- 30400508 TI - Topography Measurement of Large-Range Microstructures through Advanced Fourier Transform Method and Phase Stitching in Scanning Broadband Light Interferometry. AB - Scanning broadband light interferometry (SBLI) has been widely utilized in surface metrology due to its non-contact and high-accuracy method. In SBLI, phase evaluation through Fourier Transform (FT) is a prevalent and efficient technique, where the topography measurement can often be achieved through one interferogram. Nevertheless, the accuracy of the FT method would be significantly influenced by intensity modulation depth: "the lower the modulation of the pixel, the higher the error probability of its phase assignment". If the structure has a large enough range along the z-axis, several areas in an individual interferogram would be weakly modulated due to the limited depth of focus (DOF). In this paper, we propose an advanced FT-based method when it comes to large-height structures. Spatial modulation depth is first calculated for each interferogram independently. After that, a binary control mask is reasonably constructed to identify the pixels that are valid for phase unwrapping. Then, a phase stitching method along the z-axis is carried out to conduct the large-height topography measurement within a giving field of view. The theoretical principle, simulation, and experimental validation are elaborated to demonstrate that the method can achieve an improved robustness for the reconstruction of large-range microstructures, the advantages of which include the elimination of stepping errors, the suppression of light fluctuations, and the freedom of a limited DOF. PMID- 30400509 TI - Rethinking the Design of Low-Cost Point-of-Care Diagnostic Devices. AB - Reducing the global diseases burden requires effective diagnosis and treatment. In the developing world, accurate diagnosis can be the most expensive and time consuming aspect of health care. Healthcare cost can, however, be reduced by use of affordable rapid diagnostic tests (RDTs). In the developed world, low-cost RDTs are being developed in many research laboratories; however, they are not being equally adopted in the developing countries. This disconnect points to a gap in the design philosophy, where parameterization of design variables ignores the most critical component of the system, the point-of-use stakeholders (e.g., doctors, nurses and patients). Herein, we demonstrated that a general focus on reducing cost (i.e., "low-cost"), rather than efficiency and reliability is misguided by the assumption that poverty reduces the value individuals place on their well-being. A case study of clinicians in Kenya showed that "zero-cost" is a low-weight parameter for point-of-use stakeholders, while reliability and standardization are crucial. We therefore argue that a user-driven, value addition systems-engineering approach is needed for the design of RDTs to enhance adoption and translation into the field. PMID- 30400510 TI - Acousto-Plasmonic Sensing Assisted by Nonlinear Optical Interactions in Bimetallic Au-Pt Nanoparticles. AB - A strong influence of mechanical action in nonlinear optical transmittance experiments with bimetallic nanoparticles integrated by gold and platinum was observed. The nanostructured samples were synthesized by a sol-gel method and contained in an ethanol suspension. UV-VIS spectroscopy evaluations, Transmission electron microscopy studies and input-output laser experiments were characterized. A two-photon absorption effect was induced by nanosecond pulses at 532 nm wavelength with an important contribution from the plasmonic response of the nanomaterials. All-optical identification of acoustical waves was remarkably improved by optical nonlinearities. High sensitivity for instrumentation of mechano-optical signals sensing particular fluids was demonstrated by using a variable carbon dioxide incorporation to the system. PMID- 30400511 TI - Indoor Pedestrian Navigation Based on Conditional Random Field Algorithm. AB - Foot-mounted micro-electromechanical systems (MEMS) inertial sensors based on pedestrian navigation can be used for indoor localization. We previously developed a novel zero-velocity detection algorithm based on the variation in speed over a gait cycle, which can be used to correct positional errors. However, the accumulation of heading errors cannot be corrected and thus, the system suffers from considerable drift over time. In this paper, we propose a map matching technique based on conditional random fields (CRFs). Observations are chosen as positions from the inertial navigation system (INS), with the length between two consecutive observations being the same. This is different from elsewhere in the literature where observations are chosen based on step length. Thus, only four states are used for each observation and only one feature function is employed based on the heading of the two positions. All these techniques can reduce the complexity of the algorithm. Finally, a feedback structure is employed in a sliding window to increase the accuracy of the algorithm. Experiments were conducted in two sites with a total of over 450 m in travelled distance and the results show that the algorithm can efficiently improve the long-term accuracy. PMID- 30400512 TI - Investigation of Production Limits in Manufacturing Microstructured Surfaces Using Micro Coining. AB - The application of microstructured surfaces is one possible method to reduce friction in lubricated contacts between components with relative movement. Due to this, the energy efficiency and the occurring wear during the operating time of the final products could be decreased. To manufacture structured surfaces economically, a micro coining process was analyzed within this study. This process offers the potential for integration into the established manufacturing processes of different final products, such as tappets used in a valve train. Thus, large-scale production is enabled. To detect the manufacturing limits of the micro coining process, the manufacturing of the coining tools as well as the coining process needs to be investigated. Within this study, the achievable accuracy and the failure of cuboid and cylindrical microstructure elements with selected dimensions were analyzed. For both types of microstructures, the minimal lateral dimensions were detected. Besides the achievable accuracy, correlations between different geometrical dimensions of the micro elements are presented. Additionally, the aspect ratio is detected as the main cause of failure for the micro coining process. In general, the suitability of a coining process for manufacturing microstructured surfaces is proven. PMID- 30400513 TI - Fabrication of Hexagonal Microlens Arrays on Single-Crystal Silicon Using the Tool-Servo Driven Segment Turning Method. AB - Single-crystal silicon microlens arrays are increasingly required in advanced infrared optics. In this study, the authors attempted to fabricate hexagonal microlens arrays, which offer high optical efficiency, on a single-crystal silicon wafer using diamond turning. A tool-servo driven segment turning method was proposed to reduce the dynamic error of the machine tool induced by lenslet edges during lens array cutting. From the results of both cutting experiments and theoretical analysis of the machine tool dynamic error, it was demonstrated that the segment turning method reduced significantly the dynamic errors and led to high form accuracy. As a result, sharp edges among the lenslets were generated precisely and microlens arrays with a form error of ~300 nm peak-to-valley and surface roughness of ~5 nmSa, which meets the requirements of infrared optical systems, were successfully fabricated. The subsurface damage, such as the amorphization of silicon, caused by machining was also reduced. PMID- 30400515 TI - A Numerical Research of Herringbone Passive Mixer at Low Reynold Number Regime. AB - Passive mixing based on microfluidics has won its popularity for its unique advantage, including easier operation, more efficient mixing performance and higher access to high integrity. The time-scale and performance of mixing process are usually characterized by mixing quality, which has been remarkably improved due to the introduction of chaos theory into passive micro mixers. In this paper, we focus on the research of mixing phenomenon at extremely low Reynold number (Re) regime in a chaotic herringbone mixer. Three-dimensional (3D) modeling has been carried out using computational fluid dynamics (CFD) method, to simulate the chaos-enhanced advection diffusion process. Static mixing processes using pressure driven and electric field driven modes are investigated. Based on the simulation results, the effects of flow field and herringbone pattern are theoretically studied and compared. Both in pressure driven flow and electro osmotic flow (EOF), the mixing performance is improved with a lower flow rate. Moreover, it is noted that with a same total flow rate, mixing performance is better in EOF than pressure driven flow, which is mainly due to the difference in flow field distribution of pressure driven flow and EOF. PMID- 30400516 TI - An Enhanced Robust Control Algorithm Based on CNF and ISM for the MEMS Micromirror against Input Saturation and Disturbance. AB - Input saturation is a widespread phenomenon in the field of instrumentation, and is harmful to performance and robustness. In this paper, a control design framework based on composite nonlinear feedback (CNF) and integral sliding mode (ISM) technique is proposed for a MEMS micromirror to improve its performance under input saturation. To make the framework more effective, some essential improvements are supplied. With the application of the proposed design framework, the micromirror under input saturation and time-varying disturbances can achieve precise positioning with satisfactory transient performance compared with the open-loop performance. PMID- 30400514 TI - Cell Migration Research Based on Organ-on-Chip-Related Approaches. AB - Microfluidic devices have been widely used for cell migration research over the last two decades, owing to their attractive features in cellular microenvironment control and quantitative single-cell migration analysis. However, the majority of the microfluidic cell migration studies have focused on single cell types and have configured microenvironments that are greatly simplified compared with the in-vivo conditions they aspire to model. In addition, although cell migration is considered an important target for disease diagnosis and therapeutics, very few microfluidic cell migration studies involved clinical samples from patients. Therefore, more sophisticated microfluidic systems are required to model the complex in-vivo microenvironment at the tissue or organ level for cell migration studies and to explore cell migration-related clinical applications. Research in this direction that employs organ-on-chip-related approaches for cell migration analysis has been increasingly reported in recent years. In this paper, we briefly introduce the general background of cell migration and organ-on-chip research, followed by a detailed review of specific cell migration studies using organ-on-chip-related approaches, and conclude by discussing our perspectives of the challenges, opportunities and future directions. PMID- 30400517 TI - Electrode Cooling Effect on Out-Of-Phase Electrothermal Streaming in Rotating Electric Fields. AB - In this work, we focus on investigating electrothermal flow in rotating electric fields (ROT-ETF), with primary attention paid to the horizontal traveling-wave electrothermal (TWET) vortex induced at the center of the electric field. The frequency-dependent flow profiles in the microdevice are analyzed using different heat transfer models. Accordingly, we address in particular the importance of electrode cooling in ROT-ETF as metal electrodes of high thermal conductivity, while substrate material of low heat dissipation capability is employed to develop such microfluidic chips. Under this circumstance, cooling of electrode array due to external natural convection on millimeter-scale electrode pads for external wire connection occurs and makes the internal temperature maxima shift from the electrode plane to a bit of distance right above the cross-shaped interelectrode gaps, giving rise to reversal of flow rotation from a typical repulsion-type to attraction-type induction vortex, which is in good accordance with our experimental observations of co-field TWET streaming at frequencies in the order of reciprocal charge relaxation time of the bulk fluid. These results point out a way to make a correct interpretation of out-of-phase electrothermal streaming behavior, which holds great potential for handing high-conductivity analytes in modern microfluidic systems. PMID- 30400518 TI - Rapid Prototyping of Plastic Lab-on-a-Chip by Femtosecond Laser Micromachining and Removable Insert Microinjection Molding. AB - We have introduced a new hybrid fabrication method for lab-on-a-chip devices through the combination of femtosecond laser micromachining and removable insert micro-injection molding. This method is particularly suited for the fast prototyping of new devices, while maintaining a competitive low cost. To demonstrate the effectiveness of our approach, we designed, fabricated, and tested a completely integrated flow cytometer coupled to a portable media device. The system operation was tested with fluorescent plastic micro-bead solutions ranging from 100 beads/MUL to 500 beads/MUL. We demonstrated that this hybrid lab on-a-chip fabrication technology is suitable for producing low-cost and portable biological microsystems and for effectively bridging the gap between new device concepts and their mass production. PMID- 30400519 TI - Label-Free Monitoring of Diffusion in Microfluidics. AB - Label-free, real-time detection of concentration gradients is demonstrated in a microfluidic H-filter, using an integrated photonic crystal slab sensor to monitor sample refractive index with spatial resolution. The recorded diffusion profiles reveal root-mean-square diffusion lengths for non-fluorescing and non absorbing molecules, both small (glucose, 180 Da) and large (bovine serum albumin, 67 kDa). PMID- 30400520 TI - Asymmetric Drain Extension Dual-kk Trigate Underlap FinFET Based on RF/Analog Circuit. AB - Among multi-gate field effect transistor (FET) structures, FinFET has better short channel control and ease of manufacturability when compared to other conventional bulk devices. The radio frequency (RF) performance of FinFET is affected by gate-controlled parameters such as transconductance, output conductance, and total gate capacitance. In recent years, high-k spacer dielectric materials for manufacturing nanoscale devices are being widely explored because of their better electrostatic control and being less affected by short channel effects (SCEs). In this paper, we aim to explore the potential benefits of using different Dual-k spacers on source and drain, respectively: (AsymD-kk) trigate FinFET structure to improve the analog/RF figure of merit (FOM) for low-power operation at 14 nm gate length. It has been observed from the results that the AsymD-kk FinFET structure improves the coupling of the gate fringe field to the underlap region towards the source and drain side, improving the transconductance (gm) and output conductance (gds) at the cost of an increase in Miller capacitance. Furthermore, to reduce the drain field influence on the channel region, we also studied the effect of asymmetric drain extension length on a Dual-kk FinFET structure. It can be observed that the new asymmetric drain extension structures significantly improve the cutoff frequency (fT) and maximum oscillation frequency (fmax) given the significant reduction of inner fringe capacitance towards drain side due to the shifting of the drain extension's doping concentration away from the gate edge. Therefore, the asymmetric drain extension Dual-kk trigate FinFET (AsymD-kkDE) is a new structure that combines different Dual-k spacers on the source and drain and asymmetric drain extension on a single silicon on insulator (SOI) platform to enhance the almost all analog/RF FOM. The proposed structure is verified by technology computer-aided design (TCAD) simulations with varying device physical parameters such as fin height, fin width, aspect ratio, spacer width, spacer material, etc. From comprehensive 3D device simulation, we have demonstrated that the proposed device is superior in performance to a conventional trigate FinFET and can be used to design low-power digital circuits. PMID- 30400522 TI - Fabrication and Actuation of an Electrowetting Droplet Array on a Flexible Substrate. AB - Electrowetting-on-dielectric (EWOD) is a fast, well-established actuation method for a variety of applications, from microfluidics to electrowetting displays to electrowetting lenses. We therefore seek to develop a robust, scalable fabrication method for the realization of EWOD on a flexible polydimethylsiloxane (PDMS) substrate in order to increase the range of possible applications. We fabricated a 5 * 5 array of individually controlled electrowetting cells to manipulate silicone oil droplets via EWOD. The fabrication process utilized exclusively flexible materials to improve the robustness of the overall device, and processing methods were adapted to accommodate the particular challenges posed by flexible materials. Simulation of the EWOD devices was conducted using ANSYS Fluent and showed the change in contact angle in response to voltage applied. Fabricated devices were also tested, with actuation of the oil droplet observed with up to 100 V (RMS) AC applied across underlying electrodes. We demonstrated fabrication of a fully flexible array and verified actuation to center droplets over the electrodes. This work may be expanded to address more specific flexible applications for EWOD. PMID- 30400521 TI - Microfluidic Droplet Extraction by Hydrophilic Membrane. AB - Droplet-based microfluidics are capable of transporting very small amounts of fluid over long distances. This characteristic may be applied to conventional fluid delivery using needles if droplets can be reliably expelled from a microfluidic channel. In this paper, we demonstrate a system for the extraction of water droplets from an oil-phase in a polymer microfluidic device. A hydrophilic membrane with a strong preference for water over oil is integrated into a droplet microfluidic system and observed to allow the passage of the transported aqueous phase droplets while blocking the continuous phase. The oil breakthrough pressure of the membrane was observed to be 250 +/- 20 kPa, a much greater pressure than anywhere within the microfluidic channel, thereby eliminating the possibility that oil will leak from the microchannel, a critical parameter if droplet transport is to be used in needle-based drug delivery. PMID- 30400524 TI - A Microfluidic Device for Culturing an Encapsulated Ovarian Follicle. AB - Microfluidic chips have been proved effective in mimicking different organs of human body. Simulating human ovarian follicles by microfluidic device will be useful in exploring the mechanism of folliculogenesis and related diseases. In this paper, a microfluidic chip was designed to culture a single human pre-antral follicle. Ovarian follicles were first encapsulated in 3D calcium alginate hydrogel beads and then cultured on chip and in dish under same conditions. The diameters of cultured ovarian follicles were measured, and the same amount of medium was collected from microfluidic device or dish per two days for measuring the estradiol and androgen concentrations. The results confirmed the successful growth of ovarian follicles on chip with their hormonal trends and diameters increase, which were similar to ovarian follicles cultured in dish. It is concluded that this microfluidic chip can be used to culture a single human ovarian follicle, which provides a useful tool to explore the hormonal changes and their interactions during folliculogenesis. PMID- 30400523 TI - Light-Activated Metal Oxide Gas Sensors: A Review. AB - Conductometric gas sensors facilitated by photons have been investigated for decades. Light illumination may enhance device attributes including operational temperature, sensing sensitivity and selectivity. This paper aims to provide an overview on the progress of light-activated gas sensors, with a specific focus on sensors based on metal oxides. The material systems that have been studied include pure metal oxides, heterostructures of semiconductor-metal oxides and metal-metal oxides, and metal oxides with dopant. Other reported works on the use of different nanostructures such as one-dimensional and porous nanostructures, study of sensing mechanisms and the interplay between various factors are also summarized. Possible directions for further improvement of sensing properties, through optimizing the size of nanomaterials, film thickness, light intensity and wavelength are discussed. Finally, we point out that the main challenge faced by light-activated gas sensors is their low optical response, and we have analyzed the feasibility of using localized surface plasmon resonance to solve this drawback. This article should offer readers some key and instructive insights into the current and future development of light-activated gas sensors. PMID- 30400526 TI - Thin-Walled Double Side Freeform Component Milling Process with Paraffin Filling Method. AB - The machining of thin-walled double side freeform component has many challenges in terms of the geometrical complexity, high-requirement accuracy, and especially low stiffness. This paper surveys the filling method during the milling processes of thin-walled double side freeform component. Firstly, the DEFORM-3D was used to analyze and calculate the surface residual stress which provides a theoretical basis for parameters selection of the rough milling process, and the optimal milling parameters were obtained by the Taguchi method. Residual stress measurements have been carried out to verify the simulation results. The results show the difference between simulation and experimental data is less than 15%. Secondly, semi-finishing parameters and finishing process parameters were determined by equal error step length and step distance method. Thirdly, two machining experiments were conducted with and without paraffin filling, and the accuracy was measured by coordinate measurement machine. The results shown that the PV values are 25.16 MUm and 20.34 MUm for the concave and convex surface, and the corresponding RMS values are 13.75 MUm and 11.93 MUm in the first milling experiment. The PV values have improved to 8.53 MUm and 7.12 MUm, and RMS values have improved to 2.45 MUm and 3.05 MUm by the filled method applied. PMID- 30400525 TI - Coalescence Processes of Droplets and Liquid Marbles. AB - The coalescence process of droplets and, more recently, of liquid marbles, has become one of the most essential manipulation schemes in digital microfluidics. This process is indispensable for realising microfluidic functions such as mixing and reactions at microscale. This paper reviews previous studies on droplet coalescence, paying particular attention to the coalescence of liquid marbles. Four coalescence systems have been reviewed, namely, the coalescence of two droplets freely suspended in a fluid; the coalescence of two sessile droplets on a solid substrate; the coalescence of a falling droplet and a sessile droplet on a solid substrate; and liquid marble coalescence. The review is presented according to the dynamic behaviors, physical mechanisms and experimental parameters of the coalescence process. It also provides a systematic overview of how the coalescence process of droplets and liquid marbles could be induced and manipulated using external energy. In addition, the practical applications of liquid marble coalescence as a novel microreactor are highlighted. Finally, future perspectives on the investigation of the coalescence process of liquid marbles are proposed. This review aims to facilitate better understanding of the coalescence of droplets and of liquid marbles as well as to shed new insight on future studies. PMID- 30400528 TI - Exploiting Stretchable Metallic Springs as Compliant Electrodes for Cylindrical Dielectric Elastomer Actuators (DEAs). AB - In recent years, dielectric elastomer actuators (DEAs) have been widely used in soft robots and artificial bio-medical applications. Most DEAs are composed of a thin dielectric elastomer layer sandwiched between two compliant electrodes. DEAs vary in their design to provide bending, torsional, and stretch/contraction motions under the application of high external voltages. Most compliant electrodes are made of carbon powders or thin metallic films. In situations involving large deformations or improper fabrication, the electrodes are susceptible to breakage and increased resistivity. The worst cases result in a loss of conductivity and functional failure. In this study, we developed a method by which to exploit stretchable metallic springs as compliant electrodes for cylindrical DEAs. This design was inspired by the extensibility of mechanical springs. The main advantage of this approach is the fact that the metallic spring like compliant electrodes remain conductive and do not increase the stiffness as the tube-like DEAs elongate in the axial direction. This can be attributed to a reduction in thickness in the radial direction. The proposed cylindrical structure is composed of highly-stretchable VHB 4905 film folded within a hollow tube and then sandwiched between copper springs (inside and outside) to allow for stretching and contraction in the axial direction under the application of high DC voltages. We fabricated a prototype and evaluated the mechanical and electromechanical properties of the device experimentally using a high-voltage source of 9.9 kV. This device demonstrated a non-linear increase in axial stretching with an increase in applied voltage, reaching a maximum extension of 0.63 mm (axial strain of 2.35%) at applied voltage of 9.9 kV. Further miniaturization and the incorporation of compressive springs are expected to allow the implementation of the proposed method in soft micro-robots and bio mimetic applications. PMID- 30400527 TI - Recent Progress toward Microfluidic Quality Control Testing of Radiopharmaceuticals. AB - Radiopharmaceuticals labeled with short-lived positron-emitting or gamma-emitting isotopes are injected into patients just prior to performing positron emission tomography (PET) or single photon emission tomography (SPECT) scans, respectively. These imaging modalities are widely used in clinical care, as well as in the development and evaluation of new therapies in clinical research. Prior to injection, these radiopharmaceuticals (tracers) must undergo quality control (QC) testing to ensure product purity, identity, and safety for human use. Quality tests can be broadly categorized as (i) pharmaceutical tests, needed to ensure molecular identity, physiological compatibility and that no microbiological, pyrogenic, chemical, or particulate contamination is present in the final preparation; and (ii) radioactive tests, needed to ensure proper dosing and that there are no radiochemical and radionuclidic impurities that could interfere with the biodistribution or imaging. Performing the required QC tests is cumbersome and time-consuming, and requires an array of expensive analytical chemistry equipment and significant dedicated lab space. Calibrations, day of use tests, and documentation create an additional burden. Furthermore, in contrast to ordinary pharmaceuticals, each batch of short-lived radiopharmaceuticals must be manufactured and tested within a short period of time to avoid significant losses due to radioactive decay. To meet these challenges, several efforts are underway to develop integrated QC testing instruments that automatically perform and document all of the required tests. More recently, microfluidic quality control systems have been gaining increasing attention due to vastly reduced sample and reagent consumption, shorter analysis times, higher detection sensitivity, increased multiplexing, and reduced instrumentation size. In this review, we describe each of the required QC tests and conventional testing methods, followed by a discussion of efforts to directly miniaturize the test or examples in the literature that could be implemented for miniaturized QC testing. PMID- 30400529 TI - Research on the Strategy of Motion Constraint-Aided ZUPT for the SINS Positioning System of a Shearer. AB - The accurate measurement of position and orientation for shearers is a key technology in realizing an automated, fully-mechanized, coal mining face. Since Global Positioning System (GPS) signal cannot arrive at the coal mine underground, wireless sensor network positioning system cannot operate stably in the coal mine; thus a strap-down inertial navigation system (SINS) is used to measure the position and orientation of the shearer. Aiming at the problem of the SINS accumulative error, this paper proposes a positioning error correction method based on the motion constraint-aided SINS zero velocity updated (ZUPT) model. First of all, a stationary state detection model of the shearer is built with median filter based on the acceleration and angular rate measured by the SINS. Secondly, the motion of the shearer is analyzed using coal mining technology, then the motion constraint model of the shearer is established. In addition, the alternate action between the motion constraint model and the ZUPT model is analyzed at the process of movement and cessation of the shearer, respectively; hence, the motion constraint-aided SINS ZUPT model is built. Finally, by means of the experimental platform of the SINS for the shearer, the experimental results show that the maximum position error with the positioning model proposed in this paper is 1.6 m in 180 s, and increases by 92.0% and 88.1% compared with the single motion constraint model and single ZUPT model, respectively. It can then restrain the accumulative error of the SINS effectively. PMID- 30400530 TI - An Assay Using Localized Surface Plasmon Resonance and Gold Nanorods Functionalized with Aptamers to Sense the Cytochrome-c Released from Apoptotic Cancer Cells for Anti-Cancer Drug Effect Determination. AB - To determine the degree of cancer cell killing after treatment with chemotherapeutic drugs, we have developed a sensitive platform using localized surface plasmon resonance (LSPR) and aptamers to detect the extracellular cytochrome-c (cyto-c), a mitochondrial protein released from cancer cells for the induction of apoptosis after treatment, to evaluate the effectiveness of cancer therapy. In this assay, a short single-stranded 76-mer DNA aptamer with a unique DNA sequence, which binds towards the cyto-c like an antibody with a high binding affinity and specificity, was conjugated to gold nanorods (AuNR) for LSPR sensing. Practically, cyto-c was first grabbed by a capturing antibody functionalized on the surface of micro-magnetic particles (MMPs). Subsequently, the AuNR-conjugated aptamer was added to form a complex sandwich structure with cyto-c (i.e., (MMP-Ab)-(cyto-c)-(AuNR-aptamer)) after washing away the non-target impurities, such as serum residues and intracellular contents, in a microfluidic chip. The sandwich complex led to formation of AuNR aggregates, which changed the LSPR signals in relation to the amount of cyto-c. With the LSPR signal enhancement effects from the AuNRs, the detection limit of cyto-c, sparked in human serum or culture medium, was found to be 0.1 ng/mL in our platform and the whole sensing process could be completed within two hours. Moreover, we have applied this assay to monitor the apoptosis in leukemia cancer cells induced by a potential anti-cancer agent phenylarsine oxide. PMID- 30400531 TI - Analytical Solution of Electro-Osmotic Peristalsis of Fractional Jeffreys Fluid in a Micro-Channel. AB - The electro-osmotic peristaltic flow of a viscoelastic fluid through a cylindrical micro-channel is studied in this paper. The fractional Jeffreys constitutive model, including the relaxation time and retardation time, is utilized to describe the viscoelasticity of the fluid. Under the assumptions of long wavelength, low Reynolds number, and Debye-Huckel linearization, the analytical solutions of pressure gradient, stream function and axial velocity are explored in terms of Mittag-Leffler function by Laplace transform method. The corresponding solutions of fractional Maxwell fluid and generalized second grade fluid are also obtained as special cases. The numerical analysis of the results are depicted graphically, and the effects of electro-osmotic parameter, external electric field, fractional parameters and viscoelastic parameters on the peristaltic flow are discussed. PMID- 30400533 TI - Multidisciplinary Role of Microfluidics for Biomedical and Diagnostic Applications: Biomedical Microfluidic Devices. AB - Life scientists are closely working with engineers to solve biological and biomedical problems through the application of engineering tools.[...]. PMID- 30400532 TI - Micromachined Resonant Frequency Tuning Unit for Torsional Resonator. AB - Achieving the desired resonant frequency of resonators has been an important issue, since it determines their performance. This paper presents the design and analysis of two concepts for the resonant frequency tuning of resonators. The proposed methods are based on the stiffness alteration of the springs by geometrical modification (shaft-widening) or by mechanical restriction (shaft holding) using micromachined frequency tuning units. Our designs have advantages in (1) reversible and repetitive tuning; (2) decoupled control over the amplitude of the resonator and the tuning ratio; and (3) a wide range of applications including torsional resonators. The ability to tune the frequency by both methods is predicted by finite element analysis (FEA) and experimentally verified on a torsional resonator driven by an electrostatic actuator. The tuning units and resonators are fabricated on a double silicon-on-insulator (DSOI) wafer to electrically insulate the resonator from the tuning units. The shaft-widening type and shaft-holding type exhibit a maximum tuning ratio of 5.29% and 10.7%, respectively. PMID- 30400534 TI - Modeling and Simulation of a Machining Process Chain for the Precision Manufacture of Polar Microstructure. AB - This paper presents a functional microstructured surface, named Polar Microstructure. Polar microstructure is a three dimensional (3D) structured surface possessing a pattern of distribution of latitude and longitude micro topographies with geometrical characteristics, which is similar to that in the Earth's north or south pole. The spacing of its small surface features can achieve form accuracy at the micrometer level. Polar microstructure has great potential for applications in precision measurement of angle displacement based on the characteristics of its surface features. This paper presents the development of a machining process chain system that integrates single point diamond turning (SPDT) and diamond broaching together to fabricate polar microstructure. A framework of a machining process chain system is presented which is composed of input module, design module, simulation module, output module, and metrology module. After that, modeling of the machining process chain composed of SPDT and diamond broaching is built up. The model takes into consideration the initial surface topography of the workpiece. Simulations have been conducted to obtain the optimal machining parameters in each machining process. A series of experiments was conducted for the ultra-precision machining of various types of polar microstructures. The machining results show that the machining process chain system is technically feasible and effective in the precision manufacturing of polar microstructure. The experimental results agree well with the simulated results. PMID- 30400535 TI - The Parametric Study of Electroosmotically Driven Flow of Power-Law Fluid in a Cylindrical Microcapillary at High Zeta Potential. AB - Due to the increasingly wide application of electroosmotic flow in micromachines, this paper investigates the electroosmotic flow of the power-law fluid under high zeta potential in a cylindrical microcapillary for different dimensionless parameters. The electric potential distribution inside a cylindrical microcapillary is presented by the complete Poisson-Boltzmann equation applicable to an arbitrary zeta potential. By solving the Cauchy momentum equation of power law fluids, the velocity profile, the volumetric flow rate, the average velocity, the shear stress distribution and dynamic viscosity of electroosmotic flow of power-law fluids in a cylindrical microcapillary are studied for different low/high zeta potential, flow behavior index, dimensionless electrokinetic width. The velocity profile gradually changes from parabolic to plug-like shape as the flow behavior index decreases or as the dimensionless electrokinetic width increases. For shear thinning fluids, the viscosity is greater in the center of the microchannel than that near the channel wall, the reverse is true for the shear thickening fluids. Greater volumetric rate and average velocity can be achieved by enhancing the dimensionless electrokinetic width, flow behavior index and zeta potential. It is noted that zeta potential and flow behavior index are important parameters to adjust electroosmotic flow behavior in a cylindrical microcapillary. PMID- 30400536 TI - Investigation of CMOS Multiplexer Jet Matrix Addressing and Micro-Droplets within a Printhead Chip. AB - In this study, we demonstrate and investigate a new droplet injection design. We create a thermal inkjet (TIJ) printhead using an application-specific integrated circuit system and bulk micromachining technology (microelectromechanical systems). We design inkjet printhead chips with a new structure and investigate their properties. For the new structure, the integration of complementary metal oxide-semiconductors (MOSs) and enhancement-mode devices, as well as power switches and a TIJ heater transducer, enables logic functions to be executed on chip. This capability is used in the proposed design to address individual jets with even fewer input lines than in matrix addressing. A high number of jets (at least 896) can be addressed with only 11 input lines. E1 (Enable 1) and E2 (Enable 2) are set up dependently, and they have the ability to reverse their signals in relation to each other (i.e., if E1 is disabled, E2 is enabled and vice versa). The E1 and E2 signals each service 448 jets. If one of the MOSs is turned on, then it corresponds to a power line with a similar function. If an addressing gate terminal of the other MOS has a discharge action, then we can control a different heater to generate heating bubbles in the jet inks. The operating frequency for addressing these measurements is 18 kHz in normal mode, 26 kHz in draft mode, and 16 kHz in best mode. PMID- 30400537 TI - Effects of the Manufacturing Process on the Reliability of the Multilayer Structure in MetalMUMPs Actuators: Residual Stresses and Variation of Design Parameters. AB - Potential problems induced by the multilayered manufacturing process pose a serious threat to the long-term reliability of MEMSCAP(r) actuators under in service thermal cycling. Damage would initiate and propagate in different material layers because of a large mismatch of their thermal expansions. In this research, residual stresses and variations of design parameters induced by metal multi-user micro electromechanical system processes (MetalMUMPs) were examined to evaluate their effects on the thermal fatigue lifetime of the multilayer structure and, thus, to improve MEMSCAP(r) design. Since testing in such micro internal structure is difficult to conduct and traditional testing schemes are destructive, a numerical subdomain method based on a finite element technique was employed. Thermomechanical deformation from metal to insulator layers under in service temperature cycling (obtained from the multiphysics model of the entire actuator, which was validated by experimental and specified analytical solutions) was accurately estimated to define failures with a significant efficiency and feasibility. Simulation results showed that critical failure modes included interface delamination, plastic deformation, micro cracking, and thermal fatigue, similarly to what was concluded in the MEMSCAP(r) technical report. PMID- 30400539 TI - Low-Cost High-Speed In-Plane Stroboscopic Micro-Motion Analyzer. AB - Instrumentation for high-speed imaging and laser vibrometry is essential for the understanding and analysis of microstructure dynamics, but commercial instruments are largely unaffordable for most microelectromechanical systems (MEMS) laboratories. We present the implementation of a very low cost in-plane micro motion stroboscopic analyzer that can be directly attached to a conventional probe station. The low-cost analyzer has been used to characterize the harmonic motion of 52.1 kHz resonating comb drive microactuators using ~50 ns pulsed light emitting diode (LED) stroboscope exposure times, producing sharp and high resolution (~0.5 MUm) device images at resonance, which rivals those of several orders of magnitude more expensive systems. This paper details the development of the high-speed stroboscopic imaging system and presents experimental results of motion analysis of example microstructures and a discussion of its operating limits. The system is shown to produce stable stroboscopic LED illumination to freeze device images up to 11 MHz. PMID- 30400540 TI - Wide Linearity Range and Highly Sensitive MEMS-Based Micro-Fluxgate Sensor with Double-Layer Magnetic Core Made of Fe-Co-B Amorphous Alloy. AB - This paper reports a novel micro-fluxgate sensor based on a double-layer magnetic core of a Fe-Co-B-based amorphous ribbon. The melt-spinning technique was carried out to obtain a Fe-Co-B-based amorphous ribbon composite of Fe58.1Co24.9B16Si1, and the obtained amorphous ribbon was then annealed at 595 K for 1 h to benefit soft magnetic properties. The prepared ribbon showed excellent soft magnetic behavior with a high saturated magnetic intensity (Bs) of 1.74 T and a coercivity (Hc) of less than 0.2 Oe. Afterward, a micro-fluxgate sensor based on the prepared amorphous ribbon was fabricated via microelectromechanical systems (MEMS) technology combined with chemical wet etching. The resulting sensor exhibited a sensitivity of 1985 V/T, a wide linearity range of +/-1.05 mT, and a perming error below 0.4 MUT under optimal operating conditions with an excitation current amplitude of 70 mA at 500 kHz frequency. The minimum magnetic field noise was about 36 pT/Hz1/2 at 1 Hz under the same excitation conditions; a superior resolution of 5 nT was also achieved in the fabricated sensor. To the best of our knowledge, a compact micro-fluxgate sensor with such a high-resolution capability has not been reported elsewhere. The microsensor presented here with such improved characteristics may considerably enhance the development of micro fluxgate sensors. PMID- 30400538 TI - Methods of Micropatterning and Manipulation of Cells for Biomedical Applications. AB - Micropatterning and manipulation of mammalian and bacterial cells are important in biomedical studies to perform in vitro assays and to evaluate biochemical processes accurately, establishing the basis for implementing biomedical microelectromechanical systems (bioMEMS), point-of-care (POC) devices, or organs on-chips (OOC), which impact on neurological, oncological, dermatologic, or tissue engineering issues as part of personalized medicine. Cell patterning represents a crucial step in fundamental and applied biological studies in vitro, hence today there are a myriad of materials and techniques that allow one to immobilize and manipulate cells, imitating the 3D in vivo milieu. This review focuses on current physical cell patterning, plus chemical and a combination of them both that utilizes different materials and cutting-edge micro nanofabrication methodologies. PMID- 30400541 TI - Swimming Characteristics of Bioinspired Helical Microswimmers Based on Soft Lotus Root Fibers. AB - Various kinds of helical swimmers inspired by E. coli bacteria have been developed continually in many types of researches, but most of them are proposed by the rigid bodies. For the targeted drug delivery, the rigid body may hurt soft tissues of the working region with organs. Due to this problem, the biomedical applications of helical swimmers may be restricted. However, the helical microswimmers with the soft and deformable body are appropriate and highly adaptive in a confined environment. Thus, this paper presents a lotus-root-based helical microswimmer, which is fabricated by the fibers of lotus-root coated with magnetic nanoparticles to active under the magnetic fields. The helical microstructures are derived from the intrinsic biological structures of the fibers of the lotus-root. This paper aims to study the swimming characteristic of lotus-root-based microswimmers with deformable helical bodies. In the initial step under the uniform magnetic actuation, the helical microswimmers are bent lightly due to the heterogeneous distribution of the internal stress, and then they undergo a swimming motion which is a spindle-like rotation locomotion. Our experiments report that the microswimmers with soft bodies can locomote faster than those with rigid bodies. Moreover, we also find that the curvature of the shape decreases as a function of actuating field frequency which is related to the deformability of lotus-root fibers. PMID- 30400542 TI - Electrical Tweezer for Droplet Transportation, Extraction, Merging and DNA Analysis. AB - Droplets of aqueous solutions distributed in an immiscible oil phase are increasingly used and investigated as a means to handle and assay small volumes of samples. The primary attraction of this method is that surface interactions are kept to a minimum, and changes in sample concentration, especially due to adsorption to the walls, are avoided. Microfluidic methods to generate, transport, merge, split and perform reactions in droplets were developed recently. These methods depend on the continuous flow of the two phases involved inside closed microfluidic channels. Alternatively, an electrowetting phenomenon was also exploited to control the movement of droplets between two solid substrates. However, there are some situations where small volume sample transport and assaying are required in open systems. Here, we demonstrate a simple electromechanical probe (tweezers) that is capable of manipulating a small aqueous droplet in a bi-layer oil phase. The tweezer consists of two needles positioned close to each other and uses polarization of the aqueous droplet in an applied electrical field to confine the droplet between the needles with minimal solid contact. Mechanical motion of the tweezer can be used to transport the droplet to various positions. Operations such as aliquoting, merging and transport are demonstrated. Finally, this method was used to perform a DNA amplification assay where droplets of the sample and the amplification mixture are aliquoted separately, mixed and amplified using an in-situ heater. This electromechanical tweezer is of interest in low-throughput, small-volume biological and chemical assays where the investigator requires direct and open access to the samples. PMID- 30400543 TI - Pick-and-Place Operation of Single Cell Using Optical and Electrical Measurements for Robust Manipulation. AB - A robust pick and placement operation of a single cell is necessary for efficient sample collection. Detection and manipulation of single cells requires minimum invasiveness. We report a less-invasive method for picking up and placing single cells using optical and electrical observations for robust cell manipulation. We measured the ionic current through a glass pipette during a cell capture and release operation to detect its capture. Trapping a cell on the pipette tip by suction decreased the current and allowed the detection of cell capture within 1 s. A time-series ionic current was sensitive to the location of a cell and effective at detecting a single cell. A time-series ionic current had a higher signal-to-noise ratio than time-series microscope images. Cell membrane integrity was analyzed at the different capturing and voltage conditions. Serum protein coating shows improvement of a cell release from a pipette tip. Measurement of trajectory and distance of a cell reveals that the movement depends on an ejection flow and the flow in a dish. We achieved a pick-up and placement operation for single cells that was compatible with an open-top microwell while performing observations using optical microscopy and measurements using an electrical current. PMID- 30400544 TI - Rotating Circular Micro-Platform with Integrated Waveguides and Latching Arm for Reconfigurable Integrated Optics. AB - This work presents a laterally rotating micromachined platform integrated under optical waveguides to control the in-plane propagation direction of light within a die to select one of multiple outputs. The platform is designed to exhibit low constant optical losses throughout the motion range and is actuated electrostatically using an optimized circular comb drive. An angular motion of +/ 9.5 degrees using 180 V is demonstrated. To minimize the optical losses between the moving and fixed parts, a gap-closing mechanism is implemented to reduce the initial air gap to submicron values. A latch structure is implemented to hold the platform in place with a resolution of 0.25 degrees over the entire motion range. The platform was integrated with silicon nitride waveguides to create a crossbar switch and preliminary optical measurements are reported. In the bar state, the loss was measured to be 14.8 dB with the gap closed whereas in the cross state it was 12.2 dB. To the authors' knowledge, this is the first optical switch based on a rotating microelectromechanical device with integrated silicon nitride waveguides reported to date. PMID- 30400545 TI - Analysis of Membrane Behavior of a Normally Closed Microvalve Using a Fluid Structure Interaction Model. AB - In this paper, membrane deflection against fluid flow and opening membrane (threshold) pressure were studied using fluid-structure interaction (FSI) analysis, and compared with experimental data obtained by Jaemin et al. In the current analysis, two different models (I-shaped and V-shaped) were used to perform the FSI simulation. In microvalve modeling, in order to reduce external actuator usage, interconnections are made between two similar microvalves. This typical interconnection creates a pressure distribution in a local environment. Furthermore, to differentiate the volume factor in a microvalve, a length/width (L/W) ratio term was used. Compared with higher- and lower-L/W-ratio models, the higher-L/W model eventually initiates more deflection in a low-pressure regime than the lower-L/W-ratio model. FSI simulations were performed for 4 MUL/min, 6 MUL/min, 8 MUL/min, 10 MUL/min, and 12 MUL/min flow rates against membrane behavior, and performance evaluations of the microvalves were conducted. It was observed during an FSI simulation that the gate pressure applied to the lower surface deflects the membrane upward, thereby making contact with the wall. Two important parameters (material properties of the structural membrane and the inlet region height) were selected for analysis to evaluate changes in microvalve performance. These results are presented in the current study. PMID- 30400546 TI - Arrayed Force Sensors Made of Paper, Elastomer, and Hydrogel Particles. AB - This article presents a sensor for detecting the distribution of forces on a surface. The device with nine buttons consisted of an elastomer-based layer as a touch interface resting on a substrate of patterned metallized paper. The elastomer-based layer included a three-by-three array of deformable, hemispherical elements/reliefs, facing down toward an array of interdigitated capacitive sensing units on patterned metallized paper. Each hemispherical element is 20 mm in diameter and 8 mm in height. When a user applied pressure to the elastomer-based layer, the contact area between the hemispherical elements and the interdigitated capacitive sensing units increased with the deformation of the hemispherical elements. To enhance the sensitivity of the sensors, embedded particles of hydrogel in the elastomer-based layer increased the measured electrical responses. The measured capacitance increased because the effective dielectric permittivity of the hydrogel was greater than that of air. Electromechanical characterization verified that the hydrogel-filled elastomer was more sensitive to force at a low range of loads (23.4 pF/N) than elastomer alone without embedded hydrogel (3.4 pF/N), as the hydrogel reduced the effective elastic modulus of the composite material by a factor of seven. A simple demonstration suggests that the force-sensing array has the potential to contribute to wearable and soft robotic devices. PMID- 30400547 TI - The Multitasking System of Swarm Robot based on Null-Space-Behavioral Control Combined with Fuzzy Logic. AB - A swarm robot is a collection of large numbers of simple robots used to perform complex tasks that a single robot cannot perform or only perform ineffectively. The swarm robot works successfully only when the cooperation mechanism among individual robots is satisfied. The cooperation mechanism studied in this article ensures the formation and the distance between each pair of individual robots while moving to their destination while avoiding obstacles. The solved problems in this article include; controlling the suction/thrust force between each pair of individual robots in the swarm based on the fuzzy logic structure of the Singer-Input-Singer-Output under Mamdani law; demonstrating the stability of the system based on the Lyapunov theory; and applying control to the multitasking system of the swarm robot based on Null-Space-Behavioral control. Finally, the simulation results make certain that all the individual robots assemble after moving and avoid obstacles. PMID- 30400548 TI - Numerical Simulation of the Behavior of Toroidal and Spheroidal Multicellular Aggregates in Microfluidic Devices with Microwell and U-Shaped Barrier. AB - A microfluidic system provides an excellent platform for cellular studies. Most importantly, a three-dimensional (3D) cell culture model reconstructs more accurately the in vivo microenvironment of tissue. Accordingly, microfluidic 3D cell culture devices could be ideal candidates for in vitro cell culture platforms. In this paper, two types of 3D cellular aggregates, i.e., toroid and spheroid, are numerically studied. The studies are carried out for microfluidic systems containing U-shaped barrier as well as microwell structure. For the first time, we obtain oxygen and glucose concentration distributions inside a toroid aggregate as well as the shear stress on its surface and compare its performance with a spheroid aggregate of the same volume. In particular, we obtain the oxygen concentration distributions in three areas, namely, oxygen-permeable layer, multicellular aggregates and culture medium. Further, glucose concentration distributions in two regions of multicellular aggregates and culture medium are investigated. The results show that the levels of oxygen and glucose in the system containing U-shaped barriers are far more than those in the system containing microwells. Therefore, to achieve high levels of oxygen and nutrients, a system with U-shaped barriers is more suited than the conventional traps, but the choice between toroid and spheroid depends on their volume and orientation. The results indicate that higher oxygen and glucose concentrations can be achieved in spheroid with a small volume as well as in horizontal toroid with a large volume. The vertical toroid has the highest levels of oxygen and glucose concentration while the surface shear stress on its surface is also maximum. These findings can be used as guidelines for designing an optimum 3D microfluidic bioreactor based on the desired levels of oxygen, glucose and shear stress distributions. PMID- 30400549 TI - Extending the Limits of Wireless Power Transfer to Miniaturized Implantable Electronic Devices. AB - Implantable electronic devices have been evolving at an astonishing pace, due to the development of fabrication techniques and consequent miniaturization, and a higher efficiency of sensors, actuators, processors and packaging. Implantable devices, with sensing, communication, actuation, and wireless power are of high demand, as they pave the way for new applications and therapies. Long-term and reliable powering of such devices has been a challenge since they were first introduced. This paper presents a review of representative state of the art implantable electronic devices, with wireless power capabilities, ranging from inductive coupling to ultrasounds. The different power transmission mechanisms are compared, to show that, without new methodologies, the power that can be safely transmitted to an implant is reaching its limit. Consequently, a new approach, capable of multiplying the available power inside a brain phantom for the same specific absorption rate (SAR) value, is proposed. In this paper, a setup was implemented to quadruple the power available in the implant, without breaking the SAR limits. A brain phantom was used for concept verification, with both simulation and measurement data. PMID- 30400550 TI - Nano-Scale Positioning Design with Piezoelectric Materials. AB - Piezoelectric materials naturally possess high potential to deliver nano-scale positioning resolution; hence, they are adopted in a variety of engineering applications widely. Unfortunately, unacceptable positioning errors always appear because of the natural hysteresis effect of the piezoelectric materials. This natural property must be mitigated in practical applications. For solving this drawback, a nonlinear positioning design is proposed in this article. This nonlinear positioning design of piezoelectric materials is realized by the following four steps: 1. The famous Bouc-Wen model is utilized to present the input and output behaviors of piezoelectric materials; 2. System parameters of the Bouc-Wen model that describe the characteristics of piezoelectric materials are simultaneously identified with the particle swam optimization method; 3. Stability verification for the identified Bouc-Wen model; 4. A nonlinear feedback linearization control design is derived for the nano-scale positioning design of the piezoelectric material, mathematically. One important contribution of this investigation is that the positioning error between the output displacement of the controlled piezoelectric materials and the desired trajectory in nano-scale level can be proven to converge to zero asymptotically, under the effect of the hysteresis. PMID- 30400551 TI - Laser-Assisted Mist Capillary Self-Alignment. AB - This paper reports a method combining laser die transfer and mist capillary self alignment. The laser die transfer technique is employed to feed selected microchips from a thermal release tape onto a receiving substrate and mist capillary self-alignment is applied to align the microchips to the predefined receptor sites on the substrate in high-accuracy. The parameters for a low-power laser die transfer process have been investigated and experimentally optimized. The acting forces during the mist-induced capillary self-alignment process have been analyzed and the critical volume enabling capillary self-alignment has been estimated theoretically and experimentally. We have demonstrated that microchips can be transferred onto receptor sites in 300-400 ms using a low-power laser (100 mW), and chips can self-align to the corresponding receptor sites in parallel with alignment accuracy of 1.4 +/- 0.8 MUm. The proposed technique has great potential in high-throughput and high-accuracy assembly of micro devices. This paper is extended from an early conference paper (MARSS 2017). PMID- 30400552 TI - Two-Directional Tuning of Distributed Feedback Film Dye Laser Devices. AB - We demonstrate a two-directional tuning method of distributed feedback (DFB) film dye laser devices to achieve high quality lasing and a large tuning range. In this work, we proposed a simple method to fabricate a continuous tunable solid state dye laser on a flexible Polydimethylsiloxane (PDMS) film. In order to obtain stable and tunable output lasing, the stretching property of the gelatine host was improved by mixing with a certain ratio of glycerol to prevent DFB cavity destruction. We employed two different tuning strategies of the DFB film dye lasers, by stretching the PDMS film in two perpendicular directions, and a nearly 40 nm tuning range in each direction was achieved. The laser device maintained single mode lasing with 0.12 nm linewidth during the tuning process. The reported tunable DFB film dye laser devices have huge potential as coherent light sources for sensing and spectroscopy applications. PMID- 30400553 TI - Enabling Droplet Functionality on Anisotropic Ratchet Conveyors. AB - Anisotropic ratchet conveyors (ARCs) are a recently developed microfluidic platform that transports liquid droplets through a passive, microfabricated surface pattern and applied orthogonal vibrations. In this work, three new functionalities are presented for controlling droplet transport on the ARC system. These devices can pause droplet transport (ARC gate), decide between two pathways of droplet transport (ARC switch), and pass droplets between transport tracks (ARC delivery junction). All devices function solely through the modification of pinning forces acting on the transported droplet and are the first reported devices that can selectively control droplet timing and directionality without active (e.g., thermal, electrical, or magnetic) surface components. PMID- 30400554 TI - The Optimal Locomotion of a Self-Propelled Worm Actuated by Two Square Waves. AB - Worm-like locomotion at small scales induced by propagating a series of extensive or contraction waves has exhibited enormous possibilities in reproducing artificial mobile soft robotics. However, the optimal relation between locomotion performance and some important parameters, such as the distance between two adjacent waves, wave width, and body length, is still not clear. To solve this problem, this paper studies the optimal problem of a worm's motion induced by two peristalsis waves in a viscous medium. Inspired by a worm's motion, we consider that its body consists of two segments which can perform the respective shape change. Next, a quasi-static model describing the worm-like locomotion is used to investigate the relationship between its average velocity over the period and these parameters. Through the analysis of the relationship among these parameters, we find that there exist four different cases which should be addressed. Correspondingly, the average velocity in each case can be approximately derived. After that, optimization is carried out on each case to maximize the average velocity according to the Kuhn-Tucker Conditions. As a result, the optimal conditions of all of the cases are obtained. Finally, numerical and experimental verifications are carried out to demonstrate the correctness of the obtained results. PMID- 30400555 TI - A Liquid-Metal Based Spiral Magnetohydrodynamic Micropump. AB - A liquid-metal based spiral magnetohydrodynamic (MHD) micropump is proposed in this work. The micropump was fabricated in a polydimethylsiloxane (PDMS)-glass hybrid microfluidic chip. This pump utilized two parallel liquid-metal-filled channels as electrodes to generate a parallel electrical field across the pumping channel between the two electrodes. To prevent contact and cross contamination between the liquid metal in the electrode channel and the sample fluid in the pumping channel, a PDMS gap was designed between the liquid metal and the sample fluid. To minimize the chip size, the parallel electrode and pumping channels were designed in a spiral shape. To test pumping performance, NaCl aqueous solution containing fluorescent particles (0.5 MUm in diameter) was filled into the pumping channel as the working sample fluid. When a pair of identical magnets (0.4 T) was placed onto both top and bottom surfaces of the chip, the pump was able to drive the sample fluid at a flow velocity of 233.26 MUm/s at 3000 V. The pump has no moving parts, and the electrodes are easily fabricated, making the pump suitable for miniaturization and integration into microfluidic systems. PMID- 30400556 TI - Air Trapping Mechanism in Artificial Salvinia-Like Micro-Hairs Fabricated via Direct Laser Lithography. AB - Salvinia leaves represent an extraordinary example of how nature found a strategy for the long term retainment of air, and thus oxygen, on a surface, the so-called 'Salvinia effect', thanks to the peculiar three-dimensional and hierarchical shape of the hairs covering the leaves. Here, starting from the natural model, we have microfabricated hairs inspired by those present on the Salvinia molesta leaves, by means of direct laser lithography. Artificial hairs, like their natural counterpart, are composed of a stalk and a crown-like head, and have been reproduced in the microscale since this ensures, if using a proper design, an air retaining behavior even if the bulk structural material is hydrophilic. We have investigated the capability of air retainment inside the heads of the hairs that can last up to 100 h, demonstrating the stability of the phenomenon. For a given dimension of the head, the greater the number of filaments, the greater the amount of air that can be trapped inside the heads since the increase in the number of solid-air interfaces able to pin the liquid phase. For this reason, such type of pattern could be used for the fabrication of surfaces for controlled gas retainment and gas release in liquid phases. The range of applications would be quite large, including industrial, medical, and biological fields. PMID- 30400557 TI - Optic Nerve Stimulation System with Adaptive Wireless Powering and Data Telemetry. AB - To treat retinal degenerative diseases, a transcorneal electrical stimulation based system is proposed, which consists of an eye implant and an external component. The eye implant is wirelessly powered and controlled by the external component to generate the required bi-polar current pattern for transcorneal stimulation with an amplitude range of 5 MUA to 320 MUA, a frequency range of 10 Hz to 160 Hz and a duty ratio range of 2.5% to 20%. Power delivery control includes power boosting in preparation for stimulation, and normal power regulation that adapts to both coupling and load variations. Only one pair of coils is used for both the power link and the bi-directional data link. Except for the secondary coil, the eye implant is fully integrated on chip and is fabricated using UMC (United Microelectronics Corporation, Hsinchu, Taiwan) 0.13 MUm complementary metal-oxide-semiconductor (CMOS) process with a size of 1.5 mm * 1.5 mm. The secondary coil is fabricated on a printed circuit board (PCB) with a diameter of only 4.4 mm. After coating with biocompatible silicone, the whole implant has dimensions of 6 mm in diameter with a thickness of less than 1 mm. The whole device can be put onto the sclera and beneath the eye's conjunctiva. System functionality and electrical performance are demonstrated with measurement results. PMID- 30400558 TI - Determination of the Optimal Sensing Temperature in Pt/Ta2O5/MoO3 Schottky Contacted Nanobelt Straddling Heterojunction. AB - Nanostructured Schottky barrier gas sensors have emerged as novel semiconductor devices with large surface areas and unique electronic characteristics. Although it is widely known that operating these gas sensors requires heating to an optimal temperature for the highest sensitivity, the fundamental mechanism that governs the temperature-dependent sensitivity has yet been well understood. In this work, we present new evidence to support that thermionic field emission (TFE) is the dominant transport mechanism for Schottky contacted nanostructured heterojunction gas sensors at their optimal sensing temperature. Through the fabrication and characterization of Pt/MoO3 Schottky contacts, and Pt/Ta2O5/MoO3 heterojunctions, we found a previously unreported connection between TFE transport and optimal gas sensing temperature. This connection enables the description of Schottky barrier gas sensing performance using transport theory, which is a major step towards systematic engineering of gas sensors with nanostructured high-k oxide layers. PMID- 30400560 TI - Effect of Conductive Material Morphology on Spherical Lithium Iron Phosphate. AB - As an integral part of a lithium-ion battery, carbonaceous conductive agents have an important impact on the performance of the battery. Carbon sources (e.g., granular Super-P and KS-15, linear carbon nanotube, layered graphene) with different morphologies were added into the battery as conductive agents, and the effects of their morphologies on the electrochemical performance and processability of spherical lithium iron phosphate were investigated. The results show that the linear carbon nanotube and layered graphene enable conductive agents to efficiently connect to the cathode materials, which contribute to improving the stability of the electrode-slurry and reducing the internal resistance of cells. The batteries using nanotubes and graphene as conductive agents showed weaker battery internal resistance, excellent electrochemical performance and low-temperature dischargeability. The battery using carbon nanotube as the conductive agent had the best overall performance with an internal resistance of 30 mOmega. The battery using a carbon nanotube as the conductive agent exhibited better low-temperature performance, whose discharge capacity at -20 degrees C can reach 343 mAh, corresponding to 65.0% of that at 25 degrees C. PMID- 30400559 TI - Comparison of Measurements of Bone Mineral Density in Young and Middle-Aged Adult Women in Relation to Dietary, Anthropometric and Reproductive Variables. AB - The objective of this study was to compare current measurements of bone mineral density (BMD) of the lumbar spine (LS), femoral neck (FN), and total femur (TF) regions with initial values recorded 12 years ago in women from Northwest Mexico, and evaluate their correlation with dietary, anthropometric, and reproductive variables. BMD was assessed by Dual-energy X-ray absorptiometry. Participants were grouped as follows: Nulliparous (G1); women who were mothers 12 years ago (G2); and women who were nulliparous 12 years ago, but are now mothers (G3). In all three groups, current LS BMD was higher than initial (p <= 0.05) and current TF BMD in G2 was higher than initial values (p <= 0.05). When comparing current FN and TF BMD among the three groups, G2 had higher values than G3 (p <= 0.05). G2 also showed higher LS BMD than G1 and G3 (p = 0.006). Age at menarche was inversely-correlated with FN and TF BMD in G1 (p < 0.01), while the body mass index (BMI) correlated positively with all three bone regions in G2 (p < 0.05). This study shows that in women without and with children, age at menarche, BMI, and age were factors associated to BMD in healthy subjects in reproductive age. PMID- 30400561 TI - The Roles of Autophagy in Cancer. AB - Autophagy is an intracellular degradative process that occurs under several stressful conditions, including organelle damage, the presence of abnormal proteins, and nutrient deprivation. The mechanism of autophagy initiates the formation of autophagosomes that capture degraded components and then fuse with lysosomes to recycle these components. The modulation of autophagy plays dual roles in tumor suppression and promotion in many cancers. In addition, autophagy regulates the properties of cancer stem-cells by contributing to the maintenance of stemness, the induction of recurrence, and the development of resistance to anticancer reagents. Although some autophagy modulators, such as rapamycin and chloroquine, are used to regulate autophagy in anticancer therapy, since this process also plays roles in both tumor suppression and promotion, the precise mechanism of autophagy in cancer requires further study. In this review, we will summarize the mechanism of autophagy under stressful conditions and its roles in tumor suppression and promotion in cancer and in cancer stem-cells. Furthermore, we discuss how autophagy is a promising potential therapeutic target in cancer treatment. PMID- 30400562 TI - Childhood Experiences and Sporting Event Visitors' Preference for Unhealthy versus Healthy Foods: Priming the Route to Obesity? AB - To date, there is little knowledge about how experiences in childhood frame adults' food and drink consumption patterns in the context of attending sporting events as spectators. Therefore, the goal of this study was to explore the childhood memories of adults when they visited sporting events and find out whether and why this particular setting makes individuals indulge in unhealthy food. The study comprises two components: Study 1 and Study 2. In Study 1, 30 individuals recalled their childhood experiences of sport stadium visits at the age of ten years or younger. Inductive coding of the stories revealed that on site enjoyment is an important factor that may lead to unhealthy food consumption. In Study 2 (n = 240), the effect of enjoyment on the intentions to eat unhealthy versus healthy food at sporting events was tested empirically and contrasted with two other leisure-time activities. The results of the experiment revealed that it is not enjoyment, but the visit to sporting or music events (versus a flea market) that increased the preference for unhealthy versus healthy foods. Implications to decrease (increase) the preference for unhealthy (healthy) food in these particular settings against the background of childhood experiences can be drawn. PMID- 30400563 TI - Economic Evaluation of Environmental Interventions: Reflections on Methodological Challenges and Developments. AB - Evaluation of the costs and outcomes associated with environmental policies and interventions is often required to inform public policy and allocate scarce resources. Methods to conduct assessments of cost-effectiveness have been developed in the context of pharmaceuticals, but have more recently been applied in public health, diagnostics, and other more complex interventions. The suitability of existing economic evaluation methodology has been explored in many contexts, however, this is yet to be undertaken for interventions and policies pertaining to the natural environment, such as urban green spaces and strategies to reduce indoor and outdoor air pollution. To make significant inroads into the evaluation of interventions and policies relating to the natural environment requires an understanding of the challenges faced in this context. Many of these challenges may be practical (data-related), however, a number are also methodological, and thus have implications for the appropriate framework for economic evaluation. This paper considers some of the challenges faced when conducting cost-effectiveness analyses in this context and explores what solutions have been proposed thus far. The intention is to help pave the way for consideration of which existing framework is most appropriate for the evaluation of natural environment (NE) interventions, or if a distinct framework is required. Environmental policies and interventions relating to the built environment, for example, housing, are not explicitly included here. PMID- 30400564 TI - Biochemical and Functional Characterization of Anthocyanidin Reductase (ANR) from Mangifera indica L. AB - Mango (Mangifera indica L.) is abundant in proanthocyanidins (PAs) that are important for human health and plant response to abiotic stresses. However, the molecular mechanisms involved in PA biosynthesis still need to be elucidated. Anthocyanidin reductase (ANR) catalyzes a key step in PA biosynthesis. In this study, three ANR cDNAs (MiANR1-1,1-2,1-3) were isolated from mango, and expressed in Escherichia coli. In vitro enzyme assay showed MiANR proteins convert cyanidin to their corresponding flavan-3-ols, such as (-)-catechin and (-)-epicatechin. Despite high amino acid similarity, the recombinant ANR proteins exhibited differences in enzyme kinetics and cosubstrate preference. MiANR1-2 and MiANR1-3 have the same optimum pH of 4.0 in citrate buffer, while the optimum pH for MiANR1-1 is pH 3.0 in phosphate buffer. MiANR1-1 does not use either NADPH or NADH as co-substrate while MiANR1-2/1-3 use only NADPH as co-substrate. MiANR1-2 has the highest Km and Vmax for cyanidin, followed by MiANR1-3 and MiANR1-1. The overexpression of MiANRs in ban mutant reconstructed the biosynthetic pathway of PAs in the seed coat. These data demonstrate MiANRs can form the ANR pathway, leading to the formation of two types of isomeric flavan-3-ols and PAs in mango. PMID- 30400565 TI - Estimated Acute Effects of Ozone on Mortality in a Rural District of Beijing, China, 2005-2013: A Time-Stratified Case-Crossover Study. AB - Studies have shown that ozone (O3) has adverse impacts on human health. In China, O3 levels have continued to increase since 2010. When compared to the large number of studies concerning the health effects of PM2.5 in China, there have been limited explorations of the effects of O3. The Beijing region has one of the highest O3 concentrations in the country, but there appear to be no published studies regarding the health effects of O3 in Beijing. In this study, we applied a time-stratified case-crossover design to explore the effects of O3 on cause specific mortality for a rural location near Beijing over the period 2005-2013. For year-round effects, we found that for all-causes mortality, with a 10-unit increase in O3 concentration, the odds ratios (ORs) were in the range of 1.009 1.020 for different lag days. The ORs for cardiovascular mortality with a 10-unit increase in O3 concentration were in the range of 1.011-1.017 for different lag days. For warm season effects, the ORs with a 10-unit increase in O3 concentration for all-cause mortality were in the range of 1.025-1.031 for different lag days. The ORs for cardiovascular mortality with a 10-unit increase of O3 concentration were in the range of 1.020-1.024 for different lag days. Our findings fill a knowledge gap that has hitherto existed in studies regarding O3 health impacts, and our results will strengthen the rationale for O3 control in China. PMID- 30400566 TI - Maternal beta-Cell Adaptations in Pregnancy and Placental Signalling: Implications for Gestational Diabetes. AB - Rates of gestational diabetes mellitus (GDM) are on the rise worldwide, and the number of pregnancies impacted by GDM and resulting complications are also increasing. Pregnancy is a period of unique metabolic plasticity, during which mild insulin resistance is a physiological adaptation to prioritize fetal growth. To compensate for this, the pancreatic beta-cell utilizes a variety of adaptive mechanisms, including increasing mass, number and insulin-secretory capacity to maintain glucose homeostasis. When insufficient insulin production does not overcome insulin resistance, hyperglycemia can occur. Changes in the maternal system that occur in GDM such as lipotoxicity, inflammation and oxidative stress, as well as impairments in adipokine and placental signalling, are associated with impaired beta-cell adaptation. Understanding these pathways, as well as mechanisms of beta-cell dysfunction in pregnancy, can identify novel therapeutic targets beyond diet and lifestyle interventions, insulin and antihyperglycemic agents currently used for treating GDM. PMID- 30400567 TI - Optimization of Process Parameters for Preparing Metallic Matrix Diamond Tool Bits by Microwave Pressureless Sintering Using Response Surface Methodology. AB - The process of preparing metallic matrix diamond tool bits by microwave pressureless sintering (MPS) was exclusively studied in this paper. The effects of the sintering temperature, the cold pressure, and the holding time on the mechanical properties of the bit were determined by using the response surface methodology (RSM) with Box-Behnken Design (BBD). In addition, with RSM, the second-order polynomial equation of mechanical properties was obtained. The solutions were well matched with the experimental values. This indicates that major variations in mechanical properties of the sintered sample could be predicted by the models, which shows that the applied model is accurate. Conventional pressureless sintering (CPS) experiments were also conducted to make a comparison. The experimental results showed that the MPS can enhance the mechanical properties of sintered samples. A possible MPS mechanism is proposed in this work after analyzing all the experimental results. PMID- 30400568 TI - A Fluorescence Sensor Capable of Real-Time Herbicide Effect Monitoring in Greenhouses and the Field. AB - Herbicide resistant weeds need to be identified early so that yield loss can be avoided by applying proper field management strategies. A novel chlorophyll fluorescence-imaging sensor has been developed to conduct real-time herbicide effect evaluation. In this research, greenhouse and field experiments were conducted to calibrate the capability of the sensor in monitoring herbicide effects on different biotypes of two grass weeds (Alopecurus myosuroides, Apera spica-venti) in southwestern Germany. Herbicides with different modes of action were applied for the effect monitoring. Chlorophyll fluorescence yield of the plants was measured 3-15 days after treatment (DAT) using the new fluorescence sensor. Visual assessment of the weeds was carried out on 21 DAT. The results showed that the maximal PS II quantum yield (Fv/Fm) of herbicide sensitive weeds was significantly lower than the values of resistant populations in 5 DAT. The new technology was capable of quickly identifying the herbicide's effect on plants. It can be used to optimize management strategies to control herbicide resistant weeds. PMID- 30400569 TI - Blackcurrant Supplementation Improves Trabecular Bone Mass in Young but Not Aged Mice. AB - Due to deleterious side effects of currently available medications, the search for novel, safe, and effective preventive agents for improving bone health in aging continues and is urgently needed. This study aimed to determine whether dietary blackcurrants (BC), an anthocyanin-rich berry, can improve bone mass in a mouse model of age-related bone loss. Thirty-five female C57BL/6J mice, 3 months old (n = 20) and 18 months old (n = 15), were randomized to consume either a standard chow diet or a standard chow diet with 1% (w/w) BC for four months. Dual energy X-ray absorptiometry, Micro computed tomography (uCT), and histomorphometric analyses were conducted to assess bone parameters on femurs. Biochemical assays were conducted to determine bone resorption, antioxidant activity, and inflammation in humerus homogenates. Trabecular bone volume (BV/TV) was significantly lower in aged mice compared to young mice (young control, 3.7 +/- 0.4% vs aged control, 1.5 +/- 0.5%, mean +/- SEM (standard error of mean), p < 0.01; young BC, 5.3 +/- 0.6% vs aged BC, 1.1 +/- 0.3%, p < 0.001). uCT analysis revealed that BC supplementation increased trabecular BV/TV in young mice by 43.2% (p < 0.05) compared to controls. Histomorphometric analysis revealed a 50% increase, though this effect was not statistically significant (p = 0.07). The osteoblast surface increased by 82.5% in aged mice with BC compared to controls (p < 0.01). In humerus homogenates of young mice, BC consumption reduced C telopeptide of type I collagen by 12.4% (p < 0.05) and increased glutathione peroxidase by 96.4% (p < 0.05). In humerus homogenates of aged mice, BC consumption increased catalase by 12% (p = 0.09). Aged mice had significantly elevated concentrations of tumor necrosis factor alpha (TNF-alpha), a pro inflammatory cytokine contributing to bone resorption, which was reduced by 43.3% with BC consumption (p = 0.06). These results suggest that early consumption of BC may protect from aging-associated bone loss. PMID- 30400571 TI - A New Role for Vitamin D: The Enhancement of Oncolytic Viral Therapy in Pancreatic Cancer. AB - Oncolytic viruses have emerged as a novel class of anti-cancer therapeutics with one virus already receiving United States Food and Drug Administration (FDA) approval (talimogene laherparepvec) and many others undergoing testing in clinical trials. These viruses have direct lytic effects on tumor cells as well as immunomodulatory functions to increase inflammatory cell infiltrates in the tumor microenvironment. Despite all of the advances in cancer care, pancreatic cancer remains a highly lethal malignancy. One of the main barriers to successful systemic treatment of the disease is the fibrotic tumor stroma, as the unique extracellular matrix creates an environment that promotes tumor growth and is resistant to chemotherapy and other anti-cancer agents. The pleiotropic effects of Vitamin D have been widely studied, but recent research has now demonstrated it to be an effective agent in modulating pancreatic cancer stroma to facilitate the enhanced delivery of cytotoxic chemotherapy and immunogenicity in response to treatment. This review will explore the combination of Vitamin D with oncolytic viruses and how this novel application of Vitamin D's ability to modulate pancreatic tumor stroma may result in a potential mechanism for increasing the efficacy of oncolytic virotherapy in pancreatic cancer. PMID- 30400570 TI - Multispecies Probiotic Supplementation Favorably Affects Vascular Function and Reduces Arterial Stiffness in Obese Postmenopausal Women-A 12-Week Placebo Controlled and Randomized Clinical Study. AB - Obesity in the postmenopausal period is associated with an increased risk of cardiovascular diseases in women. One of the key drivers of cardiovascular risk is endothelial dysfunction; thus, this is also a crucial point for studies on new therapeutic methods of cardioprotective properties. The aim of the current study was to evaluate the effect of two doses of multispecies probiotic Ecologic(r) Barrier supplement on functional (primary endpoint) and biochemical parameters (secondary endpoint) of endothelial dysfunction in obese postmenopausal women in a 12-week randomized, placebo-controlled clinical trial. A total of 81 obese Caucasian women participated in the trial. The subjects were randomly assigned to three groups that received a placebo, a low dose (LD) (2.5 * 108 colony forming units (CFU) per day), or a high dose (HD) (1 * 1010 CFU per day) of lyophilisate powder containing live multispecies probiotic bacteria. The probiotic supplement was administered each day for 12 weeks in two equal portions. A high dose probiotic supplementation for 12 weeks decreased systolic blood pressure, vascular endothelial growth factor, pulse wave analysis systolic pressure, pulse wave analysis pulse pressure, pulse wave analysis augmentation index, pulse wave velocity, interleukin-6, tumor necrosis factor alpha, and thrombomodulin. Low doses of probiotic supplementation decreased the systolic blood pressure and interleukin-6 levels. The mean changes in the estimated parameters, compared among the three groups, revealed significant differences in the vascular endothelial growth factor, the pulse wave analysis systolic pressure, the pulse wave analysis augmentation index, the pulse wave velocity, the tumor necrosis factor alpha, and thrombomodulin. The post hoc tests showed significant differences for all parameters between HD and the placebo group, and HD and LD (besides pulse wave analysis augmentation index). We show for the first time that supplementation with multispecies probiotic Ecologic(r) Barrier favorably modifies both functional and biochemical markers of vascular dysfunction in obese postmenopausal women. PMID- 30400572 TI - Investigation on the I-V Kink Effect in Large Signal Modeling of AlGaN/GaN HEMTs. AB - The effect brought by the I-V kink effect on large signal performance of AlGaN/GaN high electron mobility transistors (HEMTs) was investigated in this paper. An improved compact model was proposed to accurately characterize the I-V kink effect. The bias dependence of the I-V kink effect has also been taken into consideration. AlGaN/GaN HEMTs with different gate width were utilized to validate the proposed model. Built on the proposed model, the effect brought by the I-V kink effect on large signal performance has been studied. Results show that the I-V kink effect will lead to the degradation of characteristics, including output power, gain, and power-added efficiency at the saturation region. Furthermore, the influence of the I-V kink effect was found to be related with the input power and the static bias point in this work. The time domain waveform and AC dynamic load line were used for validation of results based on simulation. The consequences of this paper will be useful for the optimization of practical circuit design. PMID- 30400573 TI - Dietary Diversity and Food Variety in Chinese Children Aged 3-17 Years: Are They Negatively Associated with Dietary Micronutrient Inadequacy? AB - Micronutrient inadequacy remains a nutritional problem in Chinese children. However, the associations between dietary diversity and inadequate micronutrient intake have not been extensively studied. A total of 2012 children aged 3-17 years from the China Health and Nutrition Survey were included for analysis. Dietary diversity score (DDS) and food variety scores (FVS) were assessed based on three 24-h recall periods. The nutrient adequacy ratio (NAR) was used to determine the micronutrient adequacy of the diet. The mean adequacy ratio (MAR, %) was defined as the sum of each NAR divided by the number of involved micronutrients. Overall micronutrient inadequacy (OMI) was defined as having a MAR below 0.75. Micronutrient inadequacy was defined as the proportion of individuals whose nutrient intake was less than the estimated average requirement. After adjustment confounders, DDS and FVSs were positively associated with MAR and NAR of most nutrients except sodium (p < 0.05). A higher DDS was negatively associated with the prevalence of inadequate intake of vitamin A, riboflavin, vitamin C, iron, zinc, selenium, niacin, phosphorus, magnesium and OMI. Similar results were found for FVSs. In conclusion, this study indicates that poor dietary diversity and food variety in Chinese children are directly associated with inadequate micronutrient intake. PMID- 30400574 TI - Messaging for Interventions Aiming to Improve Calcium Intake in Young Adults-A Mixed Methods Study. AB - Social media channels are the preferred communication tools for many young adults and therefore may have applications in health promotion. The framing of messages is important, as an intervention must resonate with the target group. The aim of this study was to determine what type of messaging is preferred by young adults to improve their calcium intake. A cross-sectional web-based survey was conducted and young adults aged 18 to 25 years recruited. A 14-item survey collected information on the participants' demographics, ranking of text messages, mock Facebook posts with images, preferences related to type of posts they find personally relevant, and frequency and likelihood of engagement with posts and polls in social media. In addition, optional responses from participants about factors that motivate them to consume more calcium-rich foods were included and thematically analysed using NVivo. Eighty-one participants (17 males) completed the survey. No significant difference in ranking of the text messages and Facebook posts were found. Participants indicated that recipe demonstrations (n = 71), cost-saving tips (n = 70), and information on recommended daily intake (n = 62) were personally relevant, while meal inspiration (n = 70), awareness-raising posts (n = 41), and messages about obtaining enough calcium from non-dairy sources (n = 38) would encourage them to eat more calcium-rich foods. The qualitative replies indicated the tone (in young adults' language) and length (short) of messages preferred, and the messaging they perceived would motivate young adults. In conclusion, short, aesthetically pleasing and personally relevant messages written in the language of young adults were recommended. PMID- 30400576 TI - Synthetic Evaluation of Standard and Microwave-Assisted Solid Phase Peptide Synthesis of a Long Chimeric Peptide Derived from Four Plasmodium falciparum Proteins. AB - An 82-residue-long chimeric peptide was synthesised by solid phase peptide synthesis (SPPS), following the Fmoc protocol. Microwave (MW) radiation-assisted synthesis was compared to standard synthesis using low loading (0.20 mmol/g) of polyethylene glycol (PEG) resin. Similar synthetic difficulties were found when the chimeric peptide was obtained via these two reaction conditions, indicating that such difficulties were inherent to the sequence and could not be resolved using MW; by contrast, the number of coupling cycles and total reaction time became reduced whilst crude yield and percentage recovery after purification were higher for MW radiation-assisted synthesis. PMID- 30400575 TI - Emotional Stress State Detection Using Genetic Algorithm-Based Feature Selection on EEG Signals. AB - In recent years, stress analysis by using electro-encephalography (EEG) signals incorporating machine learning techniques has emerged as an important area of research. EEG signals are one of the most important means of indirectly measuring the state of the brain. The existing stress algorithms lack efficient feature selection techniques to improve the performance of a subsequent classifier. In this paper, genetic algorithm (GA)-based feature selection and k-nearest neighbor (k-NN) classifier are used to identify stress in human beings by analyzing electro-encephalography (EEG) signals. GA is incorporated in the stress analysis pipeline to effectively select subset of features that are suitable to enhance the performance of the k-NN classifier. The performance of the proposed method is evaluated using the Database for Emotion Analysis using Physiological Signals (DEAP), which is a public EEG dataset. A feature set is extracted in 32 EEG channels, which consists of statistical features, Hjorth parameters, band power, and frontal alpha asymmetry. The selected features through GA are used as input to the k-NN classifier to distinguish whether each EEG datapoint represents a stress state. To further consolidate, the effectiveness of the proposed method is compared with that of a state-of-the-art principle component analysis (PCA) method. Experimental results show that the proposed GA-based method outperforms PCA, with GA demonstrating 71.76% classification accuracy compared with 65.3% for PCA. Thus, it can be concluded that the proposed method can be effectively used for stress analysis with high classification accuracy. PMID- 30400577 TI - A Tailored Thermosensitive PLGA-PEG-PLGA/Emulsomes Composite for Enhanced Oxcarbazepine Brain Delivery via the Nasal Route. AB - The use of nanocarrier delivery systems for direct nose to brain drug delivery shows promise for achieving increased brain drug levels as compared to simple solution systems. An example of such nanocarriers is emulsomes formed from lipid cores surrounded and stabilised by a corona of phospholipids (PC) and a coating of Tween 80, which combines the properties of both liposomes and emulsions. Oxcarbazepine (OX), an antiepileptic drug, was entrapped in emulsomes and then localized in a poly(lactic acid-co-glycolic acid)-poly(ethylene glycol) poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymer thermogel. The incorporation of OX emulsomes in thermogels retarded drug release and increased its residence time (MRT) in rats. The OX-emulsome and the OX-emulsome thermogel formulations showed in vitro sustained drug release of 81.1 and 53.5%, respectively, over a period of 24 h. The pharmacokinetic studies in rats showed transport of OX to the systemic circulation after nasal administration with a higher uptake in the brain tissue in case of OX-emulsomes and highest MRT for OX emulsomal-thermogels as compared to the IN OX-emulsomes, OX-solution and Trileptal(r) suspension. Histopathological examination of nasal tissues showed a mild vascular congestion and moderate inflammatory changes around congested vessels compared to saline control, but lower toxic effect than that reported in case of the drug solution. PMID- 30400578 TI - Agarwood Essential Oil Ameliorates Restrain Stress-Induced Anxiety and Depression by Inhibiting HPA Axis Hyperactivity. AB - In our previous investigation, we found that agarwood essential oil (AEO) has a sedative-hypnotic effect. Sedative-hypnotic drugs usually have an anxiolytic effect, where concomitant anxiety and depression are a common comorbidity. Therefore, this study further investigated the anxiolytic and antidepressant effects of AEO using a series of animal behavior tests on a restraint stress induced mice model. The elevated plus maze (EPM) test, the light dark exploration (LDE) test, and the open field (OF) test demonstrated that AEO has a significant anxiolytic effect. Simultaneously, the tail suspension (TS) test and the forced swimming (FS) test illuminated that AEO has an antidepressant effect with the immobility time decreased. Stress can cause cytokine and nitric oxide (NO) elevation, and further lead to hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. AEO was shown to dose-dependently inhibit the levels of cytokines, including interleukin 1alpha (IL-1alpha), IL-1beta, and IL-6 in serum, significantly decrease the mRNA level of neural nitric oxide synthase (nNOS) in the cerebral cortex and hippocampus, and inhibit the nNOS protein level in the hippocampus. Concomitant measurements of the HPA axis upstream regulator corticotropin releasing factor (CRF) and its receptor CRFR found that AEO significantly decreases the gene expression of CRF, and significantly inhibits the gene transcription and protein expression of CRFR in the cerebral cortex and hippocampus. Additionally, AEO dose-dependently reduces the concentrations of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) downstream of the HPA axis, as measured by ELISA kits. These results together demonstrate that AEO exerts anxiolytic and antidepressant effects which are related to the inhibition of CRF and hyperactivity of the HPA axis. PMID- 30400579 TI - Fabrication, Experiments, and Analysis of an LBM Additive-Manufactured Flexure Parallel Mechanism. AB - Additive manufacturing technology has advantages for realizing complex monolithic structures, providing huge potential for developing advanced flexure mechanisms for precision manipulation. However, the characteristics of flexure hinges fabricated by laser beam melting (LBM) additive manufacturing (AM) are currently little known. In this paper, the fabrication and characterization of a flexure parallel mechanism through the LBM process are reported for the first time to demonstrate the development of this technique. The geometrical accuracy of the additive-manufactured flexure mechanism was evaluated by three-dimensional scanning. The stiffness characteristics of the flexure mechanism were investigated through finite element analysis and experimental tests. The effective hinge thickness was determined based on the parameters study of the flexure parallel mechanism. The presented results highlight the promising outlook of LBM flexure parts for developing novel nanomanipulation platforms, while additional attention is required for material properties and manufacturing errors. PMID- 30400580 TI - A Survey of Sodium Chloride Content in Italian Artisanal and Industrial Bread. AB - A nationwide survey on salt content in both artisanal and industrial bread was undertaken in Italy to establish a baseline for salt reduction initiatives. Excess sodium intake in the diet is associated with high blood pressure and the risk of cardiovascular diseases. Bread has been identified as a major contributor to salt intake in the Italian diet. Most of the bread consumed in Italy comes from artisanal bakeries so 135 artisanal bread were sampled in 56 locations from Northern to Southern Italy together with 19 samples of industrial bread representative of the entire Italian production. Sodium chloride content was analysed according to the Volhardt's method. A salt content between 0.7% and 2.3% g/100 g (as is basis) was found, with a mean value of 1.5% (Standard Deviation, 0.3). However, the majority of samples (58%) had a content below 1.5%, with 12% having a very low salt content (between 0.5% and 1.0%), whereas the remaining 42% had a salt content higher than the mean value with a very high salt content (>2.0%) recorded for 3% of samples. As regards the industrial bread, an average content of 1.6% was found (SD, 0.3). In this group, most of the samples (56%) had a very high content between 2.0% and 2.5%, whereas 5% only had a content between 1.1% and 1.5%. Statistics on salt content are also reported for the different categories of bread. PMID- 30400583 TI - Decreasing Frequency Splits of Hemispherical Resonators by Chemical Etching. AB - The hemispherical resonator gyroscope (HRG) has attracted the interest of the world inertial navigation community because of its exceptional performance, ultra high reliability and its potential to be miniaturized. These devices achieve their best performance when the differences in the frequencies of the two degenerate working modes are eliminated. Mechanical treatment, laser ablation, ion-beams etching, etc., have all been applied for the frequency tuning of resonators, however, they either require costly equipment and procedures, or alter the quality factors of the resonators significantly. In this paper, we experimentally investigated for the first time the use of a chemical etching procedure to decrease the frequency splits of hemispherical resonators. We provide a theoretical analysis of the chemical etching procedure, as well as the relation between frequency splits and mass errors. Then we demonstrate that the frequency split could be decreased to below 0.05 Hz by the proposed chemical etching procedure. Results also showed that the chemical etching method caused no damage to the quality factors. Compared with other tuning methods, the chemical etching method is convenient to implement, requiring less time and labor input. It can be regarded as an effective trimming method for obtaining medium accuracy hemispherical resonator gyroscopes. PMID- 30400582 TI - Complementary Feeding Practices for South Asian Young Children Living in High Income Countries: A Systematic Review. AB - Sub-optimal nutrition among South Asian (SA) children living in high-income countries is a significant problem. High rates of obesity have been observed in this population, and differential complementary feeding practices (CFP) have been highlighted as a key influence. Our aim was to undertake a systematic review of studies assessing CFP in children under two years of age from SA communities living in high-income countries, including dietary diversity, timing, frequency and promotors/barriers. Searches covered January 1990-July 2018 using MEDLINE, EMBASE, Global Health, Web of Science, BanglaJOL, OVID Maternity and Infant Care, CINAHL, Cochrane Library, POPLINE and World Health Organisation (WHO) Global Health Library. Eligible studies were primary research on CFP in SA children aged 0-2 years. Search terms were "children", "feeding" and "South Asian", and derivatives. Quality appraisal used the Evidence for Policy and Practice Information (EPPI) Weight of Evidence scoring. From 50,713 studies, 13 were extracted with ten from the UK, and one each from the USA, Canada and Singapore. Sub-optimal CFP were found in all studies. All ten studies investigating timing reported complementary feeding (CF) being commenced before six months. Promoters/barriers influencing CFP included income, lack of knowledge, and incorrect advice. This is the first systematic review to evaluate CFP in SA children living in high-income countries and these findings should inform the development of effective interventions for SA infants in these settings. PMID- 30400584 TI - Is Vaginal Birth without an Episiotomy a Rarity in the 21st Century? Cross Sectional Studies in Southern Poland. AB - Purpose: The objective of this study was to analyze the birth methods (vaginal, with medical intervention, or by Cesarean Section, CS) predominant in the Malopolska province, to describe the risk factors for non-physiologically normal births, and to characterize the demographics of women who give birth and selected parameters of maternity care. Methods: The retrospective analysis was conducted on data collected in 2013-2014 in the framework of the current activity of the Polish National Health Fund and encompassed 68,894 childbirths from 29 hospitals in 21 towns in the south of Poland. Results: In the study period, 38,366 (56.5%) of the births in Malopolska were vaginal, and only 22,839 (22.9%) of births were considered 'normal', without an episiotomy. The remaining were births by CS (29,551; 43.5%). Factors increasing the chances of having a normal childbirth in comparison with birth by CS were as follows: days free from work, living in a village, woman's age > 35 years, and the hospital's referral level (primary or secondary). Women aged 18-34 years and those living in a village/town were more frequently admitted directly into the birth room without a stay in the maternity units. There was a high level of medicalization of births in Malopolska: natural labour and childbirth were rare. It seems that efforts to increase natural birth rates should be directed toward both reducing the CS rate as well as increasing vaginal birth without an episiotomy. PMID- 30400585 TI - Reporting Characteristics in Sports Nutrition. AB - Purpose: To examine data reporting characteristics in sports nutrition. Methods: We examined 236 papers from ten journals published in 2016. The primary outcome was statistical variance associated with treatment (SD (correct) vs. SEM or CI). Secondary outcomes included the reporting of: (a) effect sizes (Y/N); (b) outcome prioritization (Y/N; primary, secondary, etc.) and (c) statistical variance relative to change from baseline (CI (correct) vs. SD or SEM). As tertiary/exploratory outcome, we examined whether authors stated a directed hypothesis. Statistical evaluation was performed using chi-square analyses. Results: We observed significant trends for all analyses (p < 0.001) and between category comparisons (p < 0.002). For the primary outcome, 128 (59%) articles correctly used SD to denote treatment variance, while 79 (36%) and 11 (5%) used SEM and CI, respectively. For secondary outcomes, 63 articles (29%) reported effect sizes, while 155 (71%) did not. Additionally, 188 articles (86%) did not prioritize outcomes, 134 articles (61%) stated no hypotheses and 40 (19%, out of 100) articles used CI to denote change scores vs. SD (19%, n = 41) and SEM (n = 10, 5%). Eight articles (4%) reported no variance terms. Conclusions: Overall, there are gaps regarding reporting in sports nutrition. Editors, journal publishers, and the field of exercise science alike should consider these outcomes and provide editorial staff, reviewers and authors with more concrete guidelines. PMID- 30400581 TI - Association between Cardiac Remodeling and Metabolic Alteration in an Experimental Model of Obesity Induced by Western Diet. AB - The high consumption of fat and sugar contributes to the development of obesity and co-morbidities, such as dyslipidemia, hypertension, and cardiovascular disease. The aim of this study was to evaluate the association between dyslipidemia and cardiac dysfunction induced by western diet consumption. Wistar rats were randomly divided into two experimental groups and fed ad libitum for 20 weeks with a control diet (Control, n = 12) or a high-sugar and high-fat diet (HSF, n = 12). The HSF group also received water + sucrose (25%). Evaluations included feed and caloric intake; body weight; plasma glucose; insulin; uric acid; HOMA-IR; lipid profile: [total cholesterol (T-chol), high-density lipoprotein (HDL), non-HDL Chol, triglycerides (TG)]; systolic blood pressure, and Doppler echocardiographic. Compared to the control group, animals that consumed the HSF diet presented higher weight gain, caloric intake, feed efficiency, insulin, HOMA-IR, and glucose levels, and lipid profile impairment (higher TG, T-chol, non-HDL chol and lower HDL). HSF diet was also associated with atrial-ventricular structural impairment and systolic-diastolic dysfunction. Positive correlation was also found among the following parameters: insulin versus estimated LV mass (r = 0.90, p = 0.001); non-HDL versus deceleration time (r = 0.46, p = 0.02); TG versus deceleration time (r = 0.50, p = 0.01). In summary, our results suggest cardiac remodeling lead by western diet is associated with metabolic parameters. PMID- 30400587 TI - A Flexible 12-Lead/Holter Device with Compression Capabilities for Low-Bandwidth Mobile-ECG Telemedicine Applications. AB - In recent years, a number of proposals for electrocardiogram (ECG) monitoring based on mobile systems have been delivered. We propose here an STM32F microcontroller-based ECG mobile system providing both long-term (several weeks) Holter monitoring and 12-lead ECG recording, according to the clinical standard requirements for these kinds of recordings, which in addition can yield further digital compression at stages close to the acquisition. The system can be especially useful in rural areas of developing countries, where the lack of specialized medical personnel justifies the introduction of telecardiology services, and the limitations of coverage and bandwidth of cellular networks require the use of efficient signal compression systems. The prototype was implemented using a small architecture, with a 16-bits-per-sample resolution. We also used a low-noise instrumentation amplifier TI ADS1198, which has a multiplexer and an analog-to-digital converter (16 bits and 8 channels) connected to the STM32F processor, the architecture of which incorporates a digital signal processing unit and a floating-point unit. On the one hand, the system portability allows the user to take the prototype in her/his pocket and to perform an ECG examination, either in 12-lead controlled conditions or in Holter monitoring, according to the required clinical scenario. An app in the smartphone is responsible for giving the users a friendly interface to set up the system. On the other hand, electronic health recording of the patients are registered in a web application, which in turn allows them to connect to the Internet from their cellphones, and the ECG signals are then sent though a web server for subsequent and ubiquitous analysis by doctors at any convenient terminal device. In order to determine the quality of the received signals, system testing was performed in the three following scenarios: (1) The prototype was connected to the patient and the signals were subsequently stored; (2) the prototype was connected to the patient and the data were subsequently transferred to the cellphone; (3) the prototype was connected to the patient, and the data were transferred to the cellphone and to the web via the Internet. An additional benchmarking test with expert clinicians showed the clinical quality provided by the system. The proposed ECG system is the first step and paves the way toward mobile cardiac monitors in terms of compatibility with the electrocardiographic practice, including the long-term monitoring, the usability with 12 leads, and the possibility of incorporating signal compression at the early stages of the ECG acquisition. PMID- 30400589 TI - Mortality Risks among Various Primary Renal Diseases in Children and Adolescents on Chronic Dialysis. AB - There is little information available on the association between primary renal disease (PRD) and long-term mortality in the pediatric dialysis population. The objective of this study was to explore mortality risks in children and adolescents on chronic dialysis, specifically focused on the risk of various PRDs. The study cohort included children and adolescents with end-stage renal disease (ESRD) (aged < 20 years) who had received dialysis for at least 90 days between 2000 and 2014 and were identified from Taiwan's National Health Insurance medical claims. A total of 530 children and adolescents were included in the study. The median age of the included patients was 13.6 years and 305 (57.5%) patients were males. One hundred and seven patients died during the follow-up period and the median survival time was 6.0 years. Mortality was highest in the youngest patients. For patients with the following PRDs, mortality was significantly higher than that in patients with primary glomerulonephritis: secondary glomerulonephritis (adjusted hazard ratio (aHR): 2.50; 95% confidence interval (CI): 1.03-6.08), urologic disorder (aHR: 4.77; 95% CI: 1.69-13.46), and metabolic diseases (aHR: 5.57; 95% CI: 1.84-16.85). Several kinds of PRDs appear to have high mortality risks in the pediatric dialysis population. These differences in mortality risk highlight the importance of the focused clinical management of these high-risk subgroups. PMID- 30400588 TI - Efficacy of Lactobacillus Administration in School-Age Children with Asthma: A Randomized, Placebo-Controlled Trial. AB - Probiotics may have immunomodulatory effects. However, these effects in asthma remain unclear and warrant clinical trials. Here, we evaluated the effects of Lactobacillus paracasei (LP), Lactobacillus fermentum (LF), and their combination (LP + LF) on the clinical severity, immune biomarkers, and quality of life in children with asthma. This double-blind, prospective, randomized, placebo controlled trial included 160 children with asthma aged 6-18 years (trial number: NCT01635738), randomized to receive LP, LF, LP + LF, or a placebo for 3 months. Their Global Initiative for Asthma-based asthma severity, Childhood Asthma Control Test (C-ACT) scores, Pediatric Asthma Severity Scores, Pediatric Asthma Quality of Life Questionnaire scores, peak expiratory flow rates (PEFRs), medication use, the levels of immune biomarkers (immunoglobulin E (IgE), interferon gamma, interleukin 4, and tumor necrosis factor alpha) at different visits, and the associated changes were evaluated. Compared with the placebo group by generalized estimating equation model, children receiving LP, LF, and LP + LF had lower asthma severity (p = 0.024, 0.038, and 0.007, respectively) but higher C-ACT scores (p = 0.005, < 0.001, and < 0.001, respectively). The LP + LF group demonstrated increased PEFR (p < 0.01) and decreased IgE levels (p < 0.05). LP, LF, or their combination (LP + LF) can aid clinical improvement in children with asthma. PMID- 30400590 TI - Factors Associated with Perceived Life Chaos among Post-Myocardial Infarction Survivors in a Malaysian Cardiac Care Facility. AB - Background and objectives: Survivors of chronic life-threatening conditions like myocardial infarction (MI) are often confronted with multiple physical and psychological stressors as a consequence of elevated demands of lifestyle adjustments and modifications. Such stressors, collectively known as "life chaos", cause disruption to one's lifestyle equilibrium of having organized, calm, and regular routines. The objective of the current study was to determine the level of life chaos and its associated correlates among post-myocardial infarction (post-MI) survivors in Malaysia. Materials and Methods: An analytical cross-sectional study was conducted among 242 post-MI survivors in a Malaysian cardiac health facility from July to September 2016. A self-administered questionnaire in Malay that consisted of items on socio-demographics, health attributes, validated OSLO-3 Social Support Scale (OSS-3), and the Modified Confusion, Hubbub, and Order Scale (CHAOS-6) was utilized in this study. Descriptive, bivariate, and multivariate analyses were conducted. Results: The sample constituted of 208 (86%) men and 34 (14%) women. The average age was 55 years (SD = 11), and the age ranged between 24 and 96 years. Overall, 128 (52.9%) of the total post-MI survivors had highly chaotic lives. In multivariate analysis, younger age, lower household income, perceived financial insecurity, poor health status, and multiple comorbidities were related to the high chaos score, and these associations were statistically significant (p < 0.05). Conclusions: Highly chaotic lifestyles were prevalent in post-MI survivors. Demographic, health attributes, and socio-economic factors were important correlates of life chaos. PMID- 30400591 TI - High-Resolution Aerial Imagery Semantic Labeling with Dense Pyramid Network. AB - Semantic segmentation of high-resolution aerial images is of great importance in certain fields, but the increasing spatial resolution brings large intra-class variance and small inter-class differences that can lead to classification ambiguities. Based on high-level contextual features, the deep convolutional neural network (DCNN) is an effective method to deal with semantic segmentation of high-resolution aerial imagery. In this work, a novel dense pyramid network (DPN) is proposed for semantic segmentation. The network starts with group convolutions to deal with multi-sensor data in channel wise to extract feature maps of each channel separately; by doing so, more information from each channel can be preserved. This process is followed by the channel shuffle operation to enhance the representation ability of the network. Then, four densely connected convolutional blocks are utilized to both extract and take full advantage of features. The pyramid pooling module combined with two convolutional layers are set to fuse multi-resolution and multi-sensor features through an effective global scenery prior manner, producing the probability graph for each class. Moreover, the median frequency balanced focal loss is proposed to replace the standard cross entropy loss in the training phase to deal with the class imbalance problem. We evaluate the dense pyramid network on the International Society for Photogrammetry and Remote Sensing (ISPRS) Vaihingen and Potsdam 2D semantic labeling dataset, and the results demonstrate that the proposed framework exhibits better performances, compared to the state of the art baseline. PMID- 30400592 TI - Assessments of Secondary Reinforcement of Epoxy Matrix-Glass Fibre Composite Laminates through Nanosilica (SiO2). AB - The principal objective of this research work was to investigate the results of impregnating epoxy matrix-glass fibre composite laminates with nanosilica as secondary reinforcement. 0.5, 0.75, 1 and 3 wt% nanosilica was used and thereafter properties of composites were assessed through tensile, three point bending, quasi static indentation tests and dynamic mechanical analysis. Scanning electron microscope examinations were done on fracture surfaces and failure modes were analyzed. The internal failures of the composite due to quasi-static indentation were evaluated through C-Scan. Among samples of different weight fractions, 0.75 wt% nanosilica reinforced composite laminates exhibited substantial increase of 42% in tensile strength and 39.46% in flexural strength. The reduction in glass transition temperature (Tg), increase in storage modulus (E'), loss modulus (E") and damping factor (tan delta) were also observed. Quasi static indentation assessments revealed that energy absorption property was enhanced significantly by 53.97%. Hence nanosilica up to 0.75 wt% can be used as a potential candidate for secondary reinforcement in epoxy composite laminates. PMID- 30400593 TI - Three-Dimensional Hierarchical Reticular Nanostructure of Fulfora candelaria Wing Decorated by Ag Nanoislands as Practical SERS-Active Substrates. AB - Although surface-enhanced Raman scattering (SERS) technology has been widely explored nowadays in various fields, the fabrication of practical SERS-active substrates with prominent recognition ability for various analyte molecules is still defective. Natural Fulfora candelaria wing (FCW) with three-dimensional (3D) hierarchical reticular nanostructure was selected as a new bioscaffold for rough silver (Ag) nanoislands to be assembled on to prepare a practical SERS substrate (Ag/FCW substrate). By adjusting the sputtering time of metal Ag, the morphology of the substrates could be easily tuned to control the formation and distribution of "hot spots". Three-dimensional finite-difference time-domain (3D FDTD) simulation indicated that the excellent SERS performance under optimal morphology was ascribed to the local enhanced electric field in rough Ag surface and effective "hot spot" areas. The SERS measurement results show that the optimal Ag/FCW substrates had high SERS performance in terms of Raman signal sensitivity, reproducibility, uniformity and recognition ability for various analyte molecules. Coupled with flexibility of the biological substrates and the cost effectiveness, the sensitive SERS detection of varied analytes based on Ag/FCW substrates offered great potential for practical applications. PMID- 30400586 TI - The Role of Diet, Micronutrients and the Gut Microbiota in Age-Related Macular Degeneration: New Perspectives from the Gut-Retina Axis. AB - Age-related macular degeneration (AMD) is a complex multifactorial disease and the primary cause of legal and irreversible blindness among individuals aged >=65 years in developed countries. Globally, it affects 30-50 million individuals, with an estimated increase of approximately 200 million by 2020 and approximately 300 million by 2040. Currently, the neovascular form may be able to be treated with the use of anti-VEGF drugs, while no effective treatments are available for the dry form. Many studies, such as the randomized controlled trials (RCTs) Age Related Eye Disease Study (AREDS) and AREDS 2, have shown a potential role of micronutrient supplementation in lowering the risk of progression of the early stages of AMD. Recently, low-grade inflammation, sustained by dysbiosis and a leaky gut, has been shown to contribute to the development of AMD. Given the ascertained influence of the gut microbiota in systemic low-grade inflammation and its potential modulation by macro- and micro-nutrients, a potential role of diet in AMD has been proposed. This review discusses the role of the gut microbiota in the development of AMD. Using PubMed, Web of Science and Scopus, we searched for recent scientific evidence discussing the impact of dietary habits (high-fat and high-glucose or -fructose diets), micronutrients (vitamins C, E, and D, zinc, beta-carotene, lutein and zeaxanthin) and omega-3 fatty acids on the modulation of the gut microbiota and their relationship with AMD risk and progression. PMID- 30400595 TI - Breast Cancer Estimate Modeling via PDE Thermal Analysis Algorithms. AB - The significance of this study lies in the importance of (1) nondestructive testing in defect studies and (2) securing the reliability of breast cancer prediction through thermal analysis in nondestructive testing. Most nondestructive tests have negative effects on the human body. Moreover, the precision and accuracy of such tests are poor. This study analyzes these drawbacks and increases the reliability of such methods. A theoretical model was constructed, by which simulated inner breast tissue was observed in a nondestructive way through thermal analysis, and the presence and extent of simulated breast cancer were estimated based on the thermal observations. Herein, we studied the medical diagnosis of breast cancer by creating a theoretical environment that simulated breast cancer in a real-world setting; the model used two-dimensional modeling and partial differential equation (PDE) thermal analysis. Our theoretical analysis, based on partial differential equations, allowed us to demonstrate that non-wounding defect detection is possible and, in many ways, preferable. The main contribution of this paper lies in studying long term estimates. In addition, the model in this study can be extended to predict breast cancer through pure heat and can also be used for various other cancer and tumor analyses in the human body. PMID- 30400596 TI - Anti-Leishmanial and Cytotoxic Activities of a Series of Maleimides: Synthesis, Biological Evaluation and Structure-Activity Relationship. AB - In the present study, 45 maleimides have been synthesized and evaluated for anti leishmanial activities against L. donovani in vitro and cytotoxicity toward THP1 cells. All compounds exhibited obvious anti-leishmanial activities. Among the tested compounds, there were 10 maleimides with superior anti-leishmanial activities to standard drug amphotericin B, and 32 maleimides with superior anti leishmanial activities to standard drug pentamidine, especially compounds 16 (IC50 < 0.0128 MUg/mL) and 42 (IC50 < 0.0128 MUg/mL), which showed extraordinary efficacy in an in vitro test and low cytotoxicities (CC50 > 10 MUg/mL). The anti leishmanial activities of 16 and 42 were 10 times better than that of amphotericin B. The structure and activity relationship (SAR) studies revealed that 3,4-non-substituted maleimides displayed the strongest anti-leishmanial activities compared to those for 3-methyl-maleimides and 3,4-dichloro-maleimides. 3,4-dichloro-maleimides were the least cytotoxic compared to 3-methyl-maleimides and 3,4-non-substituted maleimides. The results show that several of the reported compounds are promising leads for potential anti-leishmanial drug development. PMID- 30400597 TI - Identification of Epigenetic Mechanisms Involved in the Anti-Asthmatic Effects of Descurainia sophia Seed Extract Based on a Multi-Omics Approach. AB - Asthma, a heterogeneous disease of the airways, is common around the world, but little is known about the molecular mechanisms underlying the interactions between DNA methylation and gene expression in relation to this disease. The seeds of Descurainia sophia are traditionally used to treat coughs, asthma and edema, but their effects on asthma have not been investigated by multi-omics analysis. We undertook this study to assess the epigenetic effects of ethanol extract of D. sophia seeds (DSE) in an ovalbumin (OVA)-induced mouse model of asthma. We profiled genome-wide DNA methylation by Methyl-seq and characterized the transcriptome by RNA-seq in mouse lung tissue under three conditions: saline control, OVA-induced, and DSE-treated. In total, 1995 differentially methylated regions (DMRs) were identified in association with anti-asthmatic effects, most in promoter and coding regions. Among them, 25 DMRs were negatively correlated with the expression of the corresponding 18 genes. These genes were related to development of the lung, respiratory tube and respiratory system. Our findings provide insights into the anti-asthmatic effects of D. sophia seeds and reveal the epigenetic targets of anti-inflammatory processes in mice. PMID- 30400594 TI - Pregnancy in Chronic Kidney Disease: Need for Higher Awareness. A Pragmatic Review Focused on What Could Be Improved in the Different CKD Stages and Phases. AB - Pregnancy is possible in all phases of chronic kidney disease (CKD), but its management may be difficult and the outcomes are not the same as in the overall population. The prevalence of CKD in pregnancy is estimated at about 3%, as high as that of pre-eclampsia (PE), a better-acknowledged risk for adverse pregnancy outcomes. When CKD is known, pregnancy should be considered as high risk and followed accordingly; furthermore, since CKD is often asymptomatic, pregnant women should be screened for the presence of CKD, allowing better management of pregnancy, and timely treatment after pregnancy. The differential diagnosis between CKD and PE is sometimes difficult, but making it may be important for pregnancy management. Pregnancy is possible, even if at high risk for complications, including preterm delivery and intrauterine growth restriction, superimposed PE, and pregnancy-induced hypertension. Results in all phases are strictly dependent upon the socio-sanitary system and the availability of renal and obstetric care and, especially for preterm children, of intensive care units. Women on dialysis should be aware of the possibility of conceiving and having a successful pregnancy, and intensive dialysis (up to daily, long-hours dialysis) is the clinical choice allowing the best results. Such a choice may, however, need adaptation where access to dialysis is limited or distances are prohibitive. After kidney transplantation, pregnancies should be followed up with great attention, to minimize the risks for mother, child, and for the graft. A research agenda supporting international comparisons is highly needed to ameliorate or provide knowledge on specific kidney diseases and to develop context-adapted treatment strategies to improve pregnancy outcomes in CKD women. PMID- 30400598 TI - CO2 Uptake of Carbonation-Cured Cement Blended with Ground Volcanic Ash. AB - Accelerated carbonation curing (ACC) as well as partial replacement of cement with natural minerals are examples of many previous approaches, which aimed to produce cementitious products with better properties and environmental amicabilities. In this regard, the present study investigates CO2 uptake of carbonation-cured cement blended with ground Saudi Arabian volcanic ash (VA). Paste samples with cement replacement of 20%, 30%, 40%, and 50% by mass were prepared and carbonation-cured after initial curing of 24 h. A compressive strength test, X-ray diffractometry (XRD), and thermogravimetry were performed. Although pozzolanic reaction of VA hardly occurred, unlike other pozzolana in blended cement, the results revealed that incorporation of VA as a supplementary cementitious material significantly enhanced the compressive strength and diffusion of CO2 in the matrix. This increased the CO2 uptake capacity of cement, reducing the net CO2 emission upon carbonation curing. PMID- 30400600 TI - Anti-Obesity Effects of Medicinal and Edible Mushrooms. AB - Obesity is a group of metabolic disorders caused by multiple factors, including heredity, diet, lifestyle, societal determinants, environment, and infectious agents, which can all lead to the enhancement of storage body fat. Excess visceral fat mass in adipose tissue generate several metabolic disorders, including cardiovascular diseases with chronic inflammation based pathophysiology. The objective of the current review is to summarize the cellular mechanisms of obesity that attenuate by antioxidant potentials of medicinal and edible mushrooms. Studies have showed that mushrooms potentially have antioxidant capacities, which increase the antioxidant defense systems in cells. They boost anti-inflammatory actions and thereby protect against obesity-related hypertension and dyslipidemia. The practice of regular consumption of mushrooms is effective in the treatment of metabolic syndrome, including obesity, and thus could be a good candidate for use in future pharmaceutical or nutraceutical applications. PMID- 30400602 TI - An Improved UU-MESFET with High Power Added Efficiency. AB - An improved ultrahigh upper gate 4H-SiC metal semiconductor field effect transistor (IUU-MESFET) is proposed in this paper. The structure is obtained by modifying the ultrahigh upper gate height h of the ultrahigh upper gate 4H-SiC metal semiconductor field effect transistor (UU-MESFET) structure, and the h is 0.1 MUm and 0.2 MUm for the IUU-MESFET and UU-MESFET, respectively. Compared with the UU-MESFET, the IUU-MESFET structure has a greater threshold voltage and trans conductance, and smaller breakdown voltage and saturation drain current, and when the ultrahigh upper gate height h is 0.1 MUm, the relationship between these parameters is balanced, so as to solve the contradictory relationship that these parameters cannot be improved simultaneously. Therefore, the power added efficiency (PAE) of the IUU-MESFET structure is increased from 60.16% to 70.99% compared with the UU-MESFET, and advanced by 18%. PMID- 30400601 TI - Heat and Pressure Treatments on Almond Protein Stability and Change in Immunoreactivity after Simulated Human Digestion. AB - Almond is consumed worldwide and renowned as a valuable healthy food. Despite this, it is also a potent source of allergenic proteins that can trigger several mild to life-threatening immunoreactions. Food processing proved to alter biochemical characteristics of proteins, thus affecting the respective allergenicity. In this paper, we investigated the effect of autoclaving, preceded or not by a hydration step, on the biochemical and immunological properties of almond proteins. Any variation in the stability and immunoreactivity of almond proteins extracted from the treated materials were evaluated by total protein quantification, Enzyme Linked Immunosorbent Assay (ELISA), and protein profiling by electrophoresis-based separation (SDS-PAGE). The sole autoclaving applied was found to weakly affect almond protein stability, despite what was observed when hydration preceded autoclaving, which resulted in a loss of approximately 70% of total protein content compared to untreated samples, and a remarkable reduction of the final immunoreactivity. The final SDS-PAGE protein pattern recorded for hydrated and autoclaved almonds disclosed significant changes. In addition, the same samples were further submitted to human-simulated gastro-intestinal (GI) digestion to evaluate potential changes induced by these processing methods on allergen digestibility. Digestion products were identified by High Pressure Liquid Chromatography-High Resolution Tandem Mass Spectrometry (HPLC-HRMS/MS) analysis followed by software-based data mining, and complementary information was provided by analyzing the proteolytic fragments lower than 6 kDa in size. The autoclave-based treatment was found not to alter the allergen digestibility, whereas an increased susceptibility to proteolytic action of digestive enzymes was observed in almonds subjected to autoclaving of prehydrated almond kernels. Finally, the residual immunoreactivity of the GI-resistant peptides was in-silico investigated by bioinformatic tools. Results obtained confirm that by adopting both approaches, no epitopes associated with known allergens survived, thus demonstrating the potential effectiveness of these treatments to reduce almond allergenicity. PMID- 30400599 TI - Targeting the Hippo Pathway for Breast Cancer Therapy. AB - Breast cancer (BC) is one of the most prominent diseases in the world, and the treatments for BC have many limitations, such as resistance and a lack of reliable biomarkers. Currently the Hippo pathway is emerging as a tumor suppressor pathway with its four core components that regulate downstream transcriptional targets. In this review, we introduce the present targeted therapies of BC, and then discuss the roles of the Hippo pathway in BC. Finally, we summarize the evidence of the small molecule inhibitors that target the Hippo pathway, and then discuss the possibilities and future direction of the Hippo targeted drugs for BC therapy. PMID- 30400603 TI - A Comparison of Preschoolers' Physical Activity Indoors versus Outdoors at Child Care. AB - The aims of this study were to quantify and examine differences in preschoolers' indoor and outdoor sedentary time and physical activity intensity at child care using GPS devices and accelerometers. We conducted an observational study of 46 children (mean age 4.5 years, 30 boys, 16 girls) from five child care centers who wore accelerometers and GPS devices around their waists for five days during regular child care hours. GPS signal-to-noise ratios were used to determine indoor vs. outdoor location. Accelerometer data were categorized by activity intensity. Children spent, on average, 24% of child care time outdoors (range 12 37% by site), averaging 74 min daily outdoors (range 30-119 min), with 54% of children spending >=60 min/day outdoors. Mean accelerometer activity counts were more than twice as high outdoors compared to indoors (345 (95) vs. 159 (38), (p < 0.001)), for girls and boys. Children were significantly less sedentary (51% of time vs. 75%) and engaging in more light (18% vs. 13%) and moderate-to-vigorous (MVPA) (31% vs. 12%) activity when outdoors compared to indoors (p < 0.001). To achieve a minute of MVPA, a preschooler needed to spend 9.1 min indoors vs. 3.8 min outdoors. Every additional 10 min outdoors each day was associated with a 2.9 min increase in MVPA (2.7 min for girls, 3.0 min for boys). Preschool-age children are twice as active and less sedentary when outdoors compared to indoors in child care settings. To help preschoolers achieve MVPA recommendations and likely attain other benefits, one strategy is to increase the amount of time they spend outdoors and further study how best to structure it. PMID- 30400605 TI - Selenate Prevents Adipogenesis through Induction of Selenoprotein S and Attenuation of Endoplasmic Reticulum Stress. AB - The conversion of preadipocytes to adipocytes (adipogenesis) is a potential target to treat or prevent obesity. Selenate, an inorganic form of selenium, elicits diverse health benefits, mainly through its incorporation into selenoproteins. The individual roles of selenium and certain selenoproteins have been reported. However, the effects of selenate treatment on selenoproteins in adipocytes are unclear. In this study, the effects of selenate pretreatment on selenoprotein and endoplasmic reticulum (ER) stress during adipogenesis were examined in vitro. The selenate pretreatment dose-dependently suppressed the adipogenesis of 3T3-L1 preadipocytes. The selenate pretreatment at 50 MUM for 24 h almost completely suppressed adipogenesis without cytotoxic effects. The expression of the adipogenic genes peroxisome proliferator-activated receptor gamma, CCAAT-enhancer binding protein alpha, and leptin was suppressed by selenate. This pretreatment also upregulated selenoprotein S (SEPS1), an ER resident selenoprotein that reduces ER stress, and prevented dexamethasone induced SEPS1 degradation during the early stage of adipogenesis. The selenate inhibited adipogenesis was associated with an attenuation of ER stress. The expression of the ER stress marker genes was upregulated during the early stage of differentiation, whereas the selenate pretreatment suppressed the mRNA expression of the XBP1 and C/EBP homologous protein. The collective data suggest a preventive role of selenate and SEPS1 in adipogenesis, and support a novel dietary approach to prevent obesity. PMID- 30400606 TI - Uridine Diphosphate-Dependent Glycosyltransferases from Bacillus subtilis ATCC 6633 Catalyze the 15-O-Glycosylation of Ganoderic Acid A. AB - Bacillus subtilis ATCC (American type culture collection) 6633 was found to biotransform ganoderic acid A (GAA), which is a major lanostane triterpenoid from the medicinal fungus Ganoderma lucidum. Five glycosyltransferase family 1 (GT1) genes of this bacterium, including two uridine diphosphate-dependent glycosyltransferase (UGT) genes, BsUGT398 and BsUGT489, were cloned and overexpressed in Escherichia coli. Ultra-performance liquid chromatography confirmed the two purified UGT proteins biotransform ganoderic acid A into a metabolite, while the other three purified GT1 proteins cannot biotransform GAA. The optimal enzyme activities of BsUGT398 and BsUGT489 were at pH 8.0 with 10 mM of magnesium or calcium ion. In addition, no candidates showed biotransformation activity toward antcin K, which is a major ergostane triterpenoid from the fruiting bodies of Antrodia cinnamomea. One biotransformed metabolite from each BsUGT enzyme was then isolated with preparative high-performance liquid chromatography. The isolated metabolite from each BsUGT was identified as ganoderic acid A-15-O-beta-glucoside by mass and nuclear magnetic resonance spectroscopy. The two BsUGTs in the present study are the first identified enzymes that catalyze the 15-O-glycosylation of triterpenoids. PMID- 30400607 TI - Micro-Segregated Liquid Crystal Haze Films for Photovoltaic Applications: A Novel Strategy to Fabricate Haze Films Employing Liquid Crystal Technology. AB - Herein, a novel strategy to fabricate haze films employing liquid crystal (LC) technology for photovoltaic (PV) applications is reported. We fabricated a high optical haze film composed of low-molecular LCs and polymer and applied the film to improve the energy conversion efficiency of PV module. The technique utilized to fabricate our haze film is based on spontaneous polymerization-induced phase separation between LCs and polymers. With optimized fabrication conditions, the haze film exhibited an optical haze value over 95% at 550 nm. By simply attaching our haze film onto the front surface of a silicon-based PV module, an overall average enhancement of 2.8% in power conversion efficiency was achieved in comparison with a PV module without our haze film. PMID- 30400608 TI - Conductive Thread-Based Textile Sensor for Continuous Perspiration Level Monitoring. AB - Individual perspiration level indicates a person's physical status as well as their comfort level. Therefore, continuous perspiration level measurement enables people to monitor these conditions for applications including fitness assessment, athlete physical status monitoring, and patient/elderly care. Prior work on perspiration (sweat) sensing required the user either to be static or to wear the adhesive sensor directly on the skin, which limits users' mobility and comfort. In this paper, we present a novel conductive thread-based textile sensor that measures an individual's on-cloth sweat quantity. The sensor consists of three conductive threads. Each conductive thread is surrounded by a braided cotton cover. An additional braided cotton cover is placed outside the three conductive threads, holding them in a position that is stable for measurement. the sensor can be embedded at various locations on a person's clothing. When the person sweats, the cotton braids absorb the sweat and change the conductivity (resistance) between conductive threads. We used a voltage dividing circuit to measure this resistance as the sensor output (DC). We then conducted a sensor calibration to map this measured voltage to the quantity of electrolyte solution (with the same density as sweat) applied to the sensor. We used this sensor to measure individuals' perspiration quantity and infer their perceived perspiration levels. The system is able to limit the average prediction error to 0.4 levels when compared to five pre-defined perceived perspiration levels. PMID- 30400609 TI - Synthesis of Novel Benzazole Derivatives and Evaluation of Their Antidepressant Like Activities with Possible Underlying Mechanisms. AB - Novel benzazole derivative compounds 4a-4h were obtained by the reaction of corresponding 2-(benzazol-2-ylthio)acetohydrazide and appropriate 4-substituted benzaldehydes. The chemical structures of the synthesized compounds were elucidated by FT-IR, 1H-NMR, 13C-NMR and LCMS spectroscopic methods. Antidepressant-like effects of the compounds were evaluated by tail suspension test (TST) and modified forced swimming tests (MFST). Moreover, locomotor activities of the animals were assessed by an activity cage apparatus. In the series, compounds 4a, 4b, 4e and 4f (at 50 mg/kg) significantly decreased the immobility time of mice in both of the TST and MFST. The same compounds prolonged the swimming time of animals in MFST without any change in the climbing duration. These data indicated that compounds 4a, 4b, 4e and 4f possess significant antidepressant-like activities. Moreover, pre-treatments with p-chloro phenylalanine methyl ester (an inhibitor of serotonin synthesis), NAN-190 (a 5 HT1A antagonist), ketanserin (a 5-HT2A/2C antagonist), and ondansetron (a 5-HT3 antagonist) reversed the exhibited pharmacological effects. Results of the mechanistic studies suggested the involvement of serotonergic system and contributions of 5-HT1A, 5-HT2A/2C and 5-HT3 receptors to the antidepressant-like effects of compounds 4a, 4b, 4e and 4f. Furthermore, unchanged locomotor activity of mice following the administrations of these four derivatives confirmed that the presented antidepressant-like effects are specific. PMID- 30400604 TI - Current Status of Direct Acting Antiviral Agents against Hepatitis C Virus Infection in Pakistan. AB - In Pakistan, the burden of the hepatitis C virus (HCV) infection is the second highest in the world with the development of chronic hepatitis. Interferon-based combination therapy with ribavirin was the only available treatment until a few years back, with severe side-effects and high failure rates against different genotypes of HCV. Interferon-free all-oral direct-acting antiviral agents (DAAs) approved by the FDA have revolutionized the HCV therapeutic landscape due to their efficiency in targeting different genotypes in different categories of patients, including treatment naive, treatment failure and relapsing patients, as well as patients with compensated and decompensated cirrhosis. The availability and use of these DAAs is limited in the developing world. Sofosbuvir (SOF), a uridine nucleotide analogue and inhibitor of HCV encoded NS5B polymerase, is now a widely available and in-use DAA in Pakistan; whereas daclatasvir was recently added in the list. According to the documented results, there is hope that this disease can be effectively cured in Pakistan, although a few concerns still remain. The aim of this article is to review the effectiveness of DAAs and the current status of this treatment against HCV genotype 3 infection in Pakistan; various factors associated with SVR; its limitations as an effective treatment regime; and future implications. PMID- 30400610 TI - Global Analysis of WOX Transcription Factor Gene Family in Brassica napus Reveals Their Stress- and Hormone-Responsive Patterns. AB - The plant-specific WUSCHEL-related homeobox (WOX) transcription factor gene family is important for plant growth and development but little studied in oil crops. We identified and characterized 58 putative WOX genes in Brassica napus (BnWOXs), which were divided into three major clades and nine subclades based on the gene structure and conserved motifs. Collinearity analysis revealed that most BnWOXs were the products of allopolyploidization and segmental duplication events. Gene structure analysis indicated that introns/exons and protein motifs were conserved in each subclade and RNA sequencing revealed that BnWOXs had narrow expression profiles in major tissues and/or organs across different developmental stages. The expression pattern of each clade was highly conserved and similar to that of the sister and orthologous pairs from Brassica rapa and Brassica oleracea. Quantitative real-time polymerase chain reaction showed that members of the WOX4 subclade were induced in seedling roots by abiotic and hormone stresses, indicating their contribution to root development and abiotic stress responses. 463 proteins were predicted to interact with BnWOXs, including peptides regulating stem cell homeostasis in meristems. This study provides insights into the evolution and expression of the WOX gene family in B. napus and will be useful in future gene function research. PMID- 30400611 TI - On-Demand CMOS-Compatible Fabrication of Ultrathin Self-Aligned SiC Nanowire Arrays. AB - The field of semiconductor nanowires (NWs) has become one of the most active and mature research areas. However, progress in this field has been limited, due to the difficulty in controlling the density, orientation, and placement of the individual NWs, parameters important for mass producing nanodevices. The work presented herein describes a novel nanosynthesis strategy for ultrathin self aligned silicon carbide (SiC) NW arrays (<= 20 nm width, 130 nm height and 200 600 nm variable periodicity), with high quality (~2 A surface roughness, ~2.4 eV optical bandgap) and reproducibility at predetermined locations, using fabrication protocols compatible with silicon microelectronics. Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, ultraviolet-visible spectroscopic ellipsometry, atomic force microscopy, X-ray diffractometry, and transmission electron microscopy studies show nanosynthesis of high-quality polycrystalline cubic 3C-SiC materials (average 5 nm grain size) with tailored properties. An extension of the nanofabrication process is presented for integrating technologically important erbium ions as emission centers at telecom C-band wavelengths. This integration allows for deterministic positioning of the ions and engineering of the ions' spontaneous emission properties through the resulting NW-based photonic structures, both of which are critical to practical device fabrication for quantum information applications. This holistic approach can enable the development of new scalable SiC nanostructured materials for use in a plethora of emerging applications, such as NW-based sensing, single-photon sources, quantum LEDs, and quantum photonics. PMID- 30400612 TI - Research on the Relationship between Cutting Force and Machined Surface Quality in Micro Ball End-Milling of Potassium Dihydrogen Phosphate Crystal. AB - Potassium dihydrogen phosphate (KDP or KH2PO4) crystal is widely used as terminal frequency converters in inertial confinement fusion (ICF). However, KDP crystal is a typical difficult-to-cut optical crystal with the characteristic of soft brittle. In this work, the relationship between cutting force and processed surface quality in micro ball end-milling of KDP crystal with various depth of cut and spindle speed is studied by carried out the micro-milling experiments. Fast Fourier Transform (FFT) algorithm is used to diagnose the recorded cutting force. The periodic change of cutting force and the cutting force after filtering noises can be got through FFT analysis. Through calculating the correlation coefficients between the static component of thrust force and roughness value Ra of machined grooves, as well as the peak-valley (P-V) value of thrust force and dimensional error of machined grooves, the roughness value Ra and dimensional error of machined grooves would be predicted by monitoring the static component and P-V value of the thrust force, respectively. The relatively large spindle speed helps to reduce the roughness value Ra. The spindle speed with moderate value is recommended to reduce the dimensional error of machined groove because the dimensional error of machined groove will increase when the spindle speed is small enough (causing brittle cutting) or large enough (reducing cutting stability). PMID- 30400613 TI - The Validity of the Push Band 2.0 during Vertical Jump Performance. AB - The Push Band has the potential to provide a cheap and practical method of measuring velocity and power during countermovement vertical jumping (CMJ). However, very little is known about whether it conforms to laboratory-based gold standards. The aim of this study was to assess the agreement between peak and mean velocity and power obtained from the belt-worn Push Band, and derived from three-dimensional motion capture, and vertical force from an in-ground force platform. Twenty-two volunteers performed 3 CMJ on a force platform, while a belt worn Push Band and a motion capture system (a marker affixed to the Push Band) simultaneously recorded data that enabled peak and mean velocity and power to be calculated and then compared using ordinary least products regression. While the Push Band is reliable, it tends to overestimate peak (9-17%) and mean (24-27%) velocity, and when compared to force plate-derived peak and mean power, it tends to underestimate (40-45%) and demonstrates fixed and proportional bias. This suggests that while the Push Band may provide a useful method for measuring peak and mean velocity during the CMJ, researchers and practitioners should be mindful of its tendency to systematically overestimate and that its measures of peak and mean power should not be used. PMID- 30400614 TI - Cognitive Reframing of Intimate Partner Aggression: Social and Contextual Influences. AB - Intimate partner aggression violates U.S. culturally-accepted standards regarding how partners should treat each other. Victims must reconcile the dissonance associated with being in what should be a loving and supportive relationship, while being in the same relationship that is personally and deeply harmful. To manage these clashing cognitions, victims consciously and unconsciously adopt perceptions to reframe their partner's aggression, minimizing and reinterpreting the occurrence or impact of aggressive acts, and justifying remaining in their relationship. The paper examines the multiple and nested influences that shape such perceptions, including individual, partner, relationship, and cultural factors. Each type of influence is discussed by reviewing previous research and including accounts from women who had experienced aggression. Greater awareness of such perceptions may afford greater control in changing harmful relationship patterns. PMID- 30400616 TI - Investigations of the Effects of Geometric Imperfections on the Nonlinear Static and Dynamic Behavior of Capacitive Micomachined Ultrasonic Transducers. AB - In order to investigate the effects of geometric imperfections on the static and dynamic behavior of capacitive micomachined ultrasonic transducers (CMUTs), the governing equations of motion of a circular microplate with initial defection have been derived using the von Karman plate theory while taking into account the mechanical and electrostatic nonlinearities. The partial differential equations are discretized using the differential quadrature method (DQM) and the resulting coupled nonlinear ordinary differential equations (ODEs) are solved using the harmonic balance method (HBM) coupled with the asymptotic numerical method (ANM). It is shown that the initial deflection has an impact on the static behavior of the CMUT by increasing its pull-in voltage up to 45%. Moreover, the dynamic behavior is affected by the initial deflection, enabling an increase in the resonance frequencies and the bistability domain and leading to a change of the frequency response from softening to hardening. This model allows MEMS designers to predict the nonlinear behavior of imperfect CMUT and tune its bifurcation topology in order to enhance its performances in terms of bandwidth and generated acoustic power while driving the microplate up to 80% beyond its critical amplitude. PMID- 30400615 TI - Protective Effects of Dioscorea batatas Flesh and Peel Extracts against Ethanol Induced Gastric Ulcer in Mice. AB - Gastric ulcer is a major digestive disorder and provoked by multifactorial etiologies, including excessive alcohol consumption. In this study, we examined the gastroprotective effect of aqueous and ethanolic extracts of Dioscorea batatas Decne (DBD; commonly called Chinese yam) flesh or peel against acidified ethanol-induced acute gastric damage in mice. Our findings demonstrated that oral supplementation of aqueous or ethanolic extracts of DBD flesh or peel before ulcer induction was significantly effective in macroscopically and histologically alleviating ethanol-induced pathological lesions in gastric mucosa, decreasing the plasma levels of inflammatory mediators, such as nitric oxide and interleukin 6, attenuating the gastric expression of cyclooxygenase-2, and increasing the gastric content of prostaglandin E2. In particular, pretreatment with the flesh extract prepared in 60% ethanol prominently decreased the expression of biomarkers of oxidative stress, including the plasma levels of 8-hydroxy-2 guanosine and malondialdehyde, and restored heme oxygenase-1 expression and superoxide dismutase activity in the stomach. Overall, these findings suggest that the oral supplementation with DBD extract, especially flesh ethanol extract, prior to excessive alcohol consumption, may exert a protective effect against ethanol-induced gastric mucosal damage in vivo, presumably through the activation of the antioxidant system and suppression of the inflammatory response. PMID- 30400617 TI - Preclinical Pharmacokinetics of C118P, a Novel Prodrug of Microtubules Inhibitor and Its Metabolite C118 in Mice, Rats, and Dogs. AB - C118P, a phosphate prodrug of C118, which is a novel microtubule protein inhibitor, is currently under Phase I clinical development in China for treating ovarian cancer and lung cancer. The preclinical pharmacokinetics of prodrug C118P and its metabolite C118 were extensively characterized in vivo in mice, rats, and dogs and in vitro to support the further development of C118P. The preclinical tissue distribution and excretion were investigated in rats. Plasma protein binding in mice, rat, and human, and hepatic microsomal metabolic stability in mice, rat, dog, monkey, and human, were also evaluated. The (AUC0-inf) and C30s of C118P at 50 mg/kg in rats and 6 mg/kg in dogs, and the C2min of C118 at 6 mg/kg in dogs increased less than the dosage increase, suggested nonlinear pharmacokinetic occurred at high dose. As a prodrug, C118P can be quickly hydrolyzed into C118 after an intravenous administration. The unbound C118 in plasma is slightly higher than C118P. C118P can hardly penetrate the tissue, while C118 can distribute widely into tissues. In tumor-bearing nude mice, the concentration of C118 is high in lung, ovary, and tumor, with an extended half life in tumor. C118P is a promising candidate prodrug for further clinical development. PMID- 30400619 TI - Exploration of Nurses' Knowledge, Attitudes, and Perceived Barriers towards Medication Error Reporting in a Tertiary Health Care Facility: A Qualitative Approach. AB - Medication error reporting (MER) is an effective way used to identify the causes of Medication Errors (MEs) and to prevent repeating them in future. The underreporting of MEs is a challenge generally in all MER systems. The current research aimed to explore nurses' knowledge on MER by determining their attitudes towards reporting and studying the implicated barriers and facilitators. A total of 23 nurses were interviewed using a semi-structured interview guide. The saturation point was attained after 21 interviews. All the interviews were tape recorded and transcribed verbatim, and analysed using inductive thematic analysis. Four major themes and 17 sub-themes were identified. Almost all the interviewees were aware about the existence of the MER system. They showed a positive attitude towards MER. The main barriers for MER were the impacts of time and workload, fear of investigation, impacts on the job, and negative reactions from the person in charge. The nurses were knowledgeable about MER but there was uncertainty towards reporting harmless MEs, thus indicating the need for an educational program to highlight the benefits of near-miss reporting. To improve participation strategies, a blameless reporting culture, reporting anonymously, and a simplified MER process should be considered. PMID- 30400618 TI - TGFbeta Imprinting During Activation Promotes Natural Killer Cell Cytokine Hypersecretion. AB - Transforming growth factor-beta (TGFbeta) is a potent immunosuppressive cytokine that inhibits the anti-tumor responses of NK cells and T cells. However, the stimulation of natural killer (NK) cells with pro-inflammatory cytokines decreases NK cell sensitivity to TGFbeta. Herein, we sought to determine if TGFbeta imprinting (TGFbetai) during NK cell activation and expansion would decrease NK cell sensitivity to TGFbeta suppression. To this end, we demonstrate that the activation of NK cells during chronic IL-2 stimulation and TGFbetai potently induces NK cell hypersecretion of interferon-gamma (IFNgamma) and tumor necrosis factor-alpha (TNFalpha) in response to tumor targets which persists for at least one month in vitro after the removal of TGFbeta. TGFbetai NK cell cytokine hypersecretion is induced following both cytokine and tumor activation. Further, TGFbetai NK cells have a marked suppression of SMAD3 and T-bet which is associated with altered chromatin accessibility. In contrast to their heightened cytokine secretion, TGFbetai NK cells downregulate several activating receptors, granzyme and perforin, and upregulate TRAIL, leading to cell-line-specific alterations in cytotoxicity. These findings may impact our understanding of how TGFbeta affects NK cell development and anti-tumor function. PMID- 30400620 TI - Effects of (-)-Epigallocatechin Gallate (EGCG) on Energy Expenditure and Microglia-Mediated Hypothalamic Inflammation in Mice Fed a High-Fat Diet. AB - Obesity is an escalating global epidemic caused by an imbalance between energy intake and expenditure. (-)-Epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, has been reported to be conducive to preventing obesity and alleviating obesity-related chronic diseases. However, the role of EGCG in energy metabolism disorders and central nervous system dysfunction induced by a high-fat diet (HFD) remains to be elucidated. The aim of this study was to evaluate the effects of EGCG on brown adipose tissue (BAT) thermogenesis and neuroinflammation in HFD-induced obese C57BL/6J mice. Mice were randomly divided into four groups with different diets: normal chow diet (NCD), normal chow diet supplemented with 1% EGCG (NCD + EGCG), high-fat diet (HFD), and high-fat diet supplemented with 1% EGCG (HFD + EGCG). Investigations based on a four-week experiment were carried out including the BAT activity, energy consumption, mRNA expression of major inflammatory cytokines in the hypothalamus, nuclear factor kappa B (NF-kappaB) and signal transducer and activator of transcription 3 (STAT3) phosphorylation, and immunofluorescence staining of microglial marker Iba1 in hypothalamic arcuate nucleus (ARC). Experimental results demonstrated that dietary supplementation of EGCG significantly inhibited HFD-induced obesity by enhancing BAT thermogenesis, and attenuated the hypothalamic inflammation and microglia overactivation by regulating the NF-kappaB and STAT3 signaling pathways. PMID- 30400621 TI - Buzz Kill: Function and Proteomic Composition of Venom from the Giant Assassin Fly Dolopus genitalis (Diptera: Asilidae). AB - Assassin flies (Diptera: Asilidae) inject paralysing venom into insect prey during hunting, but their venoms are poorly characterised in comparison to those produced by spiders, scorpions, or hymenopteran insects. Here we investigated the composition of the venom of the giant Australian assassin fly Dolopus genitalis using a combination of insect microinjection assays, calcium imaging assays of mammalian sensory neurons, proteomics and transcriptomics. Injection of venom into blowflies (Lucilia cuprina) produced rapid contractile paralysis (PD50 at 1 min = 3.1 MUg per fly) followed by death, and also caused immediate activation of mouse dorsal root ganglion neurons (at 50 ng/MUL). These results are consistent with venom use for both prey capture and predator deterrence. Paragon searches of tandem mass spectra of venom against a translated thoracic gland RNA-Seq database identified 122 polypeptides present in the venom, including six linear and 21 disulfide-rich peptides. Some of these disulfide-rich peptides display sequence homology to peptide families independently recruited into other animal venoms, including inhibitor cystine knots, cystine-stabilised alpha/beta defensins, Kazal peptides, and von Willebrand factors. Numerous enzymes are present in the venom, including 35 proteases of the S1 family, proteases of the S10, C1A, M12A, M14, and M17 families, and phosphatase, amylase, hydrolase, nuclease, and dehydrogenase-like proteins. These results highlight convergent molecular evolution between the assassin flies and other venomous animals, as well as the unique and rich molecular composition of assassin fly venom. PMID- 30400622 TI - Efficacy of Anamorelin, a Novel Non-Peptide Ghrelin Analogue, in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) and Cachexia-Review and Expert Opinion. AB - Cancer cachexia is a multilayered syndrome consisting of the interaction between tumor cells and the host, at times modulated by the pharmacologic treatments used for tumor control. Key cellular and soluble mediators, activated because of this interaction, induce metabolic and nutritional alterations. This results in mass and functional changes systemically, and can lead to increased morbidity and reduced length and quality of life. For most solid malignancies, a cure remains an unrealistic goal, and targeting the key mediators is ineffective because of their heterogeneity/redundancy. The most beneficial approach is to target underlying systemic mechanisms, an approach where the novel non-peptide ghrelin analogue anamorelin has the advantage of stimulating appetite and possibly food intake, as well as promoting anabolism and significant muscle mass gain. In the ROMANA studies, compared with placebo, anamorelin significantly increased lean body mass in non-small cell lung cancer (NSCLC) patients. Body composition analysis suggested that anamorelin is an active anabolic agent in patients with NSCLC, without the side effects of other anabolic drugs. Anamorelin also induced a significant and meaningful improvement of anorexia/cachexia symptoms. The ROMANA trials have provided unprecedented knowledge, highlighting the therapeutic effects of anamorelin as an initial, but significant, step toward directly managing cancer cachexia. PMID- 30400623 TI - Reductive Mobilization of Iron from Intact Ferritin: Mechanisms and Physiological Implication. AB - Ferritins are highly conserved supramolecular protein nanostructures composed of two different subunit types, H (heavy) and L (light). The two subunits co assemble into a 24-subunit heteropolymer, with tissue specific distributions, to form shell-like protein structures within which thousands of iron atoms are stored as a soluble inorganic ferric iron core. In-vitro (or in cell free systems), the mechanisms of iron(II) oxidation and formation of the mineral core have been extensively investigated, although it is still unclear how iron is loaded into the protein in-vivo. In contrast, there is a wide spread belief that the major pathway of iron mobilization from ferritin involves a lysosomal proteolytic degradation of ferritin, and the dissolution of the iron mineral core. However, it is still unclear whether other auxiliary iron mobilization mechanisms, involving physiological reducing agents and/or cellular reductases, contribute to the release of iron from ferritin. In vitro iron mobilization from ferritin can be achieved using different reducing agents, capable of easily reducing the ferritin iron core, to produce soluble ferrous ions that are subsequently chelated by strong iron(II)-chelating agents. Here, we review our current understanding of iron mobilization from ferritin by various reducing agents, and report on recent results from our laboratory, in support of a mechanism that involves a one-electron transfer through the protein shell to the iron mineral core. The physiological significance of the iron reductive mobilization from ferritin by the non-enzymatic FMN/NAD(P)H system is also discussed. PMID- 30400624 TI - Evolutionary Game Theoretic Analysis of Low Carbon Investment in Supply Chains under Governmental Subsidies. AB - With the rapid development of global industry and economy, excessive carbon dioxide emission has emerged as a critical issue in both developed and developing countries. Using an evolutionary game framework in which game players can adjust their strategies constantly, this paper investigates how to optimize the strategy of low carbon investment for suppliers and manufacturers in supply chains, and discuss the impacts of various factors on evolutionarily stable strategies. Additionally, we examine an incentive mechanism based on governmental subsidies to eliminate free riding and motivate co-investment. Furthermore, a case study and numerical examples are provided for illustration and simulation purposes, leading to several countermeasures and suggestions. Our analytical results show that the strategic choice of low carbon investment is correlated with profit growth coefficients, investment costs and profits from free riding. Investment costs have more significant impacts than other factors on evolutionarily stable strategies, while profit growth coefficients are more important at initial stages in the evolutionary process. The incentive mechanism based on governmental subsidies is an effective solution to motivate co-investment, and governments should take some measures to improve the assess accuracy and supervisory efficiency of investment strategy. PMID- 30400625 TI - Impact of Precision Medicine on Drug Repositioning and Pricing: A Too Small to Thrive Crisis. AB - The pricing of targeted medicines continues to be a major area of contention in healthcare economics. This issue is further complicated by redefining the role of molecular testing in precision medicine. Currently, whilst pricing of clinical laboratory diagnostics is cost-based, drug pricing is value-based. The pricing for molecular testing is under pressure to change the traditional business model, for it has a critical subsidiary role in determining the final value of targeted medicines. The market size for drugs is reduced by molecular testing when patients with the same disease are stratified based on their genetics, it is critical to determine the value of this new enhanced drug specificity to realize its full pricing potential. However, these value-based pricing strategies require a careful understanding of changing market conditions, especially, in the context of stratified patient segments made possible by precision medicine. In this article, we discuss the various factors impacting pricing decisions, and consider evolving economic trends in precision medicine. PMID- 30400626 TI - Application of Fiber Bragg Grating Acoustic Emission Sensors in Thin Polymer Bonded Explosives. AB - Fiber Bragg grating (FBG) acoustic emission (AE) sensors have been used in many applications. In this paper, based on an FBG AE sensor, the sensing principle of the interaction between the AE wave and the sensor is introduced. Then, the directionality of the FBG AE sensor on the surface of a thin polymer-bonded explosive (PBX) material is studied. Finally, the time coefficient location method is proposed to correct the AE time detected by the FBG AE sensor, thereby improving the accuracy of location experiments. PMID- 30400627 TI - Novel GIS Based Machine Learning Algorithms for Shallow Landslide Susceptibility Mapping. AB - The main objective of this research was to introduce a novel machine learning algorithm of alternating decision tree (ADTree) based on the multiboost (MB), bagging (BA), rotation forest (RF) and random subspace (RS) ensemble algorithms under two scenarios of different sample sizes and raster resolutions for spatial prediction of shallow landslides around Bijar City, Kurdistan Province, Iran. The evaluation of modeling process was checked by some statistical measures and area under the receiver operating characteristic curve (AUROC). Results show that, for combination of sample sizes of 60%/40% and 70%/30% with a raster resolution of 10 m, the RS model, while, for 80%/20% and 90%/10% with a raster resolution of 20 m, the MB model obtained a high goodness-of-fit and prediction accuracy. The RS ADTree and MB-ADTree ensemble models outperformed the ADTree model in two scenarios. Overall, MB-ADTree in sample size of 80%/20% with a resolution of 20 m (area under the curve (AUC) = 0.942) and sample size of 60%/40% with a resolution of 10 m (AUC = 0.845) had the highest and lowest prediction accuracy, respectively. The findings confirm that the newly proposed models are very promising alternative tools to assist planners and decision makers in the task of managing landslide prone areas. PMID- 30400628 TI - Studies on the Spatiotemporal Variability of River Water Quality and Its Relationships with Soil and Precipitation: A Case Study of the Mun River Basin in Thailand. AB - Human activities can affect soil nutrients, thereby influencing river water quality. The spatial pattern of precipitation also impacts distributions of water quality. In this paper, we employed a method that combines point survey, soil, and water quality data to analyze the spatial relationships between precipitation, soil nutrient and water quality in the basin on the basis of field surveys and laboratory analysis. The ordinary kriging method was applied to interpolate the precipitation and soil data, and the spatial pattern was analyzed. The water samples on the main stream and soil samples in the field were collected during both the dry and rainy seasons to analyze the water quality and soil nutrients. The results indicate: (1) The water quality in the dry season is better than that in the rainy season, the water quality in the upper reaches is better than that in the lower reaches, and agricultural activity is the direct source of water pollution. (2) The precipitation in the rainy and dry seasons is differente and the dilution effect of precipitation on pollutant concentrations and transport of water flow affect the spatial distribution of water quality. (3) There is a significant difference in the spatial pattern of soil nutrients between the dry and rainy seasons, and the soil nutrient content and the surface runoff directly affect the water quality. Soil nutrients are affected by human activities, and they potentially act as nonpoint source (NPS) pollution in this river basin. To improve the water quality, suitable agriculture measures need to be implemented. PMID- 30400629 TI - New Dark Area Sensitive Tone Mapping for Deep Learning Based Traffic Sign Recognition. AB - In this paper, we propose a new Intelligent Traffic Sign Recognition (ITSR) system with illumination preprocessing capability. Our proposed Dark Area Sensitive Tone Mapping (DASTM) technique can enhance the illumination of only dark regions of an image with little impact on bright regions. We used this technique as a pre-processing module for our new traffic sign recognition system. We combined DASTM with a TS detector, an optimized version of YOLOv3 for the detection of three classes of traffic signs. We trained ITSR on a dataset of Korean traffic signs with prohibitory, mandatory, and danger classes. We achieved Mean Average Precision (MAP) value of 90.07% (previous best result was 86.61%) on challenging Korean Traffic Sign Detection (KTSD) dataset and 100% on German Traffic Sign Detection Benchmark (GTSDB). Result comparisons of ITSR with latest D-Patches, TS detector, and YOLOv3 show that our new ITSR significantly outperforms in recognition performance. PMID- 30400630 TI - Involvement of 5'-Activated Protein Kinase (AMPK) in the Effects of Resveratrol on Liver Steatosis. AB - This review focuses on the role of 5'-activated protein kinase (AMPK) in the effects of resveratrol (RSV) and some RSV derivatives on hepatic steatosis. In vitro studies, performed in different hepatic cell models, have demonstrated that RSV is effective in preventing liver TG accumulation by activating AMPK, due to its phosphorylation. These preventive effects have been confirmed in studies conducted in animal models, such as mice and rats, by administering the phenolic compound at the same time as the diet which induces TG accumulation in liver. The literature also includes studies focused on other type of models, such as animals showing alcohol-induced steatosis or even steatosis induced by administering chemical products. In addition to the preventive effects of RSV on hepatic steatosis, other studies have demonstrated that it can alleviate previously developed liver steatosis, thus its role as a therapeutic tool has been proposed. The implication of AMPK in the delipidating effects of RSV in in vivo models has also been demonstrated. PMID- 30400631 TI - Machine Learning Aided Scheme for Load Balancing in Dense IoT Networks. AB - With the dramatic increase of connected devices, the Internet of things (IoT) paradigm has become an important solution in supporting dense scenarios such as smart cities. The concept of heterogeneous networks (HetNets) has emerged as a viable solution to improving the capacity of cellular networks in such scenarios. However, achieving optimal load balancing is not trivial due to the complexity and dynamics in HetNets. For this reason, we propose a load balancing scheme based on machine learning techniques that uses both unsupervised and supervised methods, as well as a Markov Decision Process (MDP). As a use case, we apply our scheme to enhance the capabilities of an urban IoT network operating under the LoRaWAN standard. The simulation results show that the packet delivery ratio (PDR) is increased when our scheme is utilized in an unbalanced network and, consequently, the energy cost of data delivery is reduced. Furthermore, we demonstrate that better outcomes are attained when some techniques are combined, achieving a PDR improvement of up to about 50% and reducing the energy cost by nearly 20% in a multicell scenario with 5000 devices requesting downlink traffic. PMID- 30400632 TI - Identification and Characterization of NTB451 as a Potential Inhibitor of Necroptosis. AB - Necroptosis, or caspase-independent programmed cell death, is known to be involved in various pathological conditions, such as ischemia/reperfusion injury, myocardial infarction, atherosclerosis, and inflammatory bowel diseases. Although several inhibitors of necroptosis have been identified, none of them are currently in clinical use. In the present study, we identified a new compound, 4 ({[5-(4-aminophenyl)-4-ethyl-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-N-(1,3 thiazol-2-yl) benzamide (NTB451), with significant inhibitory activity on the necroptosis induced by various triggers, such as tumor necrosis factor-alpha (TNF alpha) and toll-like receptor (TLR) agonists. Mechanistic studies revealed that NTB451 inhibited phosphorylation and oligomerization of mixed lineage kinase domain like (MLKL), and this activity was linked to its inhibitory effect on the formation of the receptor interacting serine/threonine-protein kinase 1 (RIPK1) RIPK3 complex. Small interfering RNA (siRNA)-mediated RIPK1 knockdown, drug affinity responsive target stability assay, and molecular dynamics (MD) simulation study illustrated that RIPK1 is a specific target of NTB451. Moreover, MD simulation showed a direct interaction of NTB451 and RIPK1. Further experiments to ensure that the inhibitory effect of NTB451 was restricted to necroptosis and NTB451 had no effect on nuclear factor-kappaB (NF-kappaB) activation or apoptotic cell death upon triggering with TNF-alpha were also performed. Considering the data obtained, our study confirmed the potential of NTB451 as a new necroptosis inhibitor, suggesting its therapeutic implications for pathological conditions induced by necroptotic cell death. PMID- 30400633 TI - Dynamic Collision Behavior Between Osteoblasts and Tumor Cells Regulates the Disordered Arrangement of Collagen Fiber/Apatite Crystals in Metastasized Bone. AB - Bone metastasis is one of the most intractable bone diseases; it is accompanied with a severe mechanical dysfunction of bone tissue. We recently discovered that the disorganized collagen/apatite microstructure in cancer-bearing bone is a dominant determinant of the disruption of bone mechanical function; disordered osteoblast arrangement was found to be one of the principal determinants of the deteriorated collagen/apatite microstructure. However, the precise molecular mechanisms regulating the disordered osteoblast arrangement triggered by cancer invasion are not yet understood. Herein, we demonstrate a significant disorganization of bone tissue anisotropy in metastasized bone in our novel ex vivo metastasis model. Further, we propose a novel mechanism underlying the disorganization of a metastasized bone matrix: A dynamic collision behavior between tumor cells and osteoblasts disturbs the osteoblast arrangement along the collagen substrate. PMID- 30400634 TI - Magnetic Alginate/Chitosan Nanoparticles for Targeted Delivery of Curcumin into Human Breast Cancer Cells. AB - Curcumin is a promising anti-cancer drug, but its applications in cancer therapy are limited, due to its poor solubility, short half-life and low bioavailability. In this study, curcumin loaded magnetic alginate/chitosan nanoparticles were fabricated to improve the bioavailability, uptake efficiency and cytotoxicity of curcumin to Human Caucasian Breast Adenocarcinoma cells (MDA-MB-231). Alginate and chitosan were deposited on Fe3O4 magnetic nanoparticles based on their electrostatic properties. The nanoparticle size ranged from 120-200 nm, within the optimum range for drug delivery. Controllable and sustained release of curcumin was obtained by altering the number of chitosan and alginate layers on the nanoparticles. Confocal fluorescence microscopy results showed that targeted delivery of curcumin with the aid of a magnetic field was achieved. The fluorescence-activated cell sorting (FACS) assay indicated that MDA-MB-231 cells treated with curcumin loaded nanoparticles had a 3-6 fold uptake efficiency to those treated with free curcumin. The 3-(4,5-Dimethylthiazol-2-yl)-2,5 Diphenyltetrazolium Bromide (MTT) assay indicated that the curcumin loaded nanoparticles exhibited significantly higher cytotoxicity towards MDA-MB-231 cells than HDF cells. The sustained release profiles, enhanced uptake efficiency and cytotoxicity to cancer cells, as well as directed targeting make MACPs promising candidates for cancer therapy. PMID- 30400635 TI - Health Benefits of Bioactive Compounds from the Genus Ilex, a Source of Traditional Caffeinated Beverages. AB - Tea and coffee are caffeinated beverages commonly consumed around the world in daily life. Tea from Camellia sinensis is widely available and is a good source of caffeine and other bioactive compounds (e.g., polyphenols and carotenoids). Other tea-like beverages, such as those from the genus Ilex, the large-leaved Kudingcha (Ilex latifolia Thunb and Ilex kudingcha C.J. Tseng), Yerba Mate (Ilex paraguariensis A. St.-Hil), Yaupon Holly (Ilex vomitoria), and Guayusa (Ilex guayusa Loes) are also traditional drinks, with lesser overall usage, but have attracted much recent attention and have been subjected to further study. This review summarizes the distribution, composition, and health benefits of caffeinated beverages from the genus Ilex. Plants of this genus mainly contain polyphenols and alkaloids, and show diverse health benefits, which, as well as supporting their further popularization as beverages, may also lead to potential applications in the pharmaceutical or nutraceutical industries. PMID- 30400636 TI - An Inverse Relationship between Hyperuricemia and Mortality in Patients Undergoing Continuous Ambulatory Peritoneal Dialysis. AB - Background: The results have been inconsistent with regards to the impact of uric acid (UA) on clinical outcomes both in the general population and in patients with chronic kidney disease. The aim of this study was to study the influence of serum UA levels on mortality in patients undergoing continuous ambulatory peritoneal dialysis. Methods: Data on 492 patients from a single peritoneal dialysis unit were retrospectively analyzed. The mean age of the patients was 53.5 +/- 15.3 years, with 52% being female (n = 255). The concomitant comorbidities at the start of continuous ambulatory peritoneal dialysis (CAPD) encompassed diabetes mellitus (n = 179, 34.6%), hypertension (n = 419, 85.2%), and cardiovascular disease (n = 186, 37.9%). The study cohort was divided into sex-specific tertiles according to baseline UA level. A Cox proportional hazard model was used to calculate hazard ratios (HRs) of all-cause, cardiovascular, and infection-associated mortality with adjustments for demographic and laboratory data, medications, and comorbidities. Results: Multivariate Cox regression analysis showed that, using UA tertile 1 as the reference, the adjusted HR of all cause, cardiovascular, and infection-associated mortality for tertile 3 was 0.4 (95% confidence interval (CI) 0.24-0.68, p = 0.001), 0.4 (95% CI 0.2-0.81, p = 0.01), and 0.47 (95% CI 0.19-1.08, p = 0.1). In the fully adjusted model, the adjusted HRs of all-cause, cardiovascular, and infection-associated mortality for each 1-mg/dL increase in UA level were 0.84 (95% CI, 0.69-0.9, p = 0.07), 0.79 (95% CI, 0.61-1.01, p = 0.06), and 0.79 (95% CI, 0.48-1.21, p = 0.32) for men and 0.57 (95% CI, 0.44-0.73, p < 0.001), 0.6 (95% CI, 0.41-0.87, p = 0.006), and 0.41 (95% CI, 0.26-0.6, p < 0.001) for women, respectively. Conclusions: Higher UA levels are associated with lower risks of all-cause, cardiovascular and infection associated mortality in women treated with continuous ambulatory peritoneal dialysis. PMID- 30400637 TI - N-Heterocyclic Carbene-Polyethyleneimine (PEI) Platinum Complexes Inducing Human Cancer Cell Death: Polymer Carrier Impact. AB - The high interest in N-Heterocyclic platinum carbene complexes in cancer research stems from their high cytotoxicity to human cancer cells, their stability, as well as their ease of functionalization. However, the development of these new molecules as anticancer agents still faces multiple challenges, in particular solubility in aqueous media. Here, we synthesized platinum-NHC bioconjugates that combine water-solubility and cytotoxicity by using polyethyleneimine as polymer carrier. We showed on 8 different types of cells that the activity of these conjugates is modulated by the size of the polymer and the overall density of metal ions onto polymer chains. Using HCT116 cells, the conjugates displayed an effective activity after only 45 min of exposure in vitro correlated with a quick uptake by the cells as shown by the use of various fluorescent-tagged derivatives. PMID- 30400638 TI - Orthogonal Functionalization of Nanodiamond Particles after Laser Modification and Treatment with Aromatic Amine Derivatives. AB - A laser system with a wavelength of 1064 nm was used to generate sp2 carbon on the surfaces of nanodiamond particles (NDPs). The modified by microplasma NDPs were analysed using FT-IR and Raman spectroscopy. Raman spectra confirmed that graphitization had occurred on the surfaces of the NDPs. The extent of graphitization depended on the average power used in the laser treatment process. FT-IR analysis revealed that the presence of C=C bonds in all spectra of the laser-modified powder. The characteristic peaks for olefinic bonds were much more intense than in the case of untreated powder and grew in intensity as the average laser power increased. The olefinized nanodiamond powder was further functionalized using aromatic amines via in situ generated diazonium salts. It was also found that isokinetic mixtures of structurally diverse aromatic amines containing different functional groups (acid, amine) could be used to functionalize the surfaces of the laser-modified nanoparticles leading to an amphiphilic carbon nanomaterial. This enables one-step orthogonal functionalization and opens the possibility of selectively incorporating molecules with diverse biological activities on the surfaces of NDPs. Modified NDPs with amphiphilic properties resulting from the presence carboxyl and amine groups were used to incorporate simultaneously folic acid (FA-CONH-(CH2)5-COOH) and 5(6)-carboxyfluorescein (FL-CONH-(CH2)2-NH2) derivatives on the surface of material under biocompatible procedures. PMID- 30400639 TI - The Handbook of Minerals on a Gluten-Free Diet. AB - The importance of a gluten-free diet (GFD) in the treatment of celiac disease and other gluten-related disorders is undisputable. However, strict GFD often lead to nutritional imbalances and, therefore, to deficiencies. One of the most common deficiencies from a GFD are an insufficient amount of Ca, Fe, Mg, and Zn. This is mainly because the most of popular gluten-free (GF) raw materials are poor in minerals. Although the popularity of GFD is constantly growing, the data on minerals in GF products are still limited. More importantly, an access to the data is even more restricted. Therefore, the paper reviews the Ca, Fe, Mg, and Zn contents in hundreds of grain GF products available worldwide. The data for 444 products from categories of flours, mixes for cooking, bakery products, cereals, groats, rice, and pasta are obtained from research papers and nutritional databases. The calculation of the realization of mineral requirements from a portion of each product with its graphical classification as rich/average/poor source of each mineral is given. The review is a handbook of minerals for people on a GFD, dietitians, and food producers. PMID- 30400641 TI - Adipose Stem Cell Translational Applications: From Bench-to-Bedside. AB - During the last five years, there has been a significantly increasing interest in adult adipose stem cells (ASCs) as a suitable tool for translational medicine applications. The abundant and renewable source of ASCs and the relatively simple procedure for cell isolation are only some of the reasons for this success. Here, we document the advances in the biology and in the innovative biotechnological applications of ASCs. We discuss how the multipotential property boosts ASCs toward mesenchymal and non-mesenchymal differentiation cell lineages and how their character is maintained even if they are combined with gene delivery systems and/or biomaterials, both in vitro and in vivo. PMID- 30400642 TI - Crosstalk between PPARgamma Ligands and Inflammatory-Related Pathways in Natural T-Regulatory Cells from Type 1 Diabetes Mouse Model. AB - Immunomodulation, as a means of immunotherapy, has been studied in major research and clinical laboratories for many years. T-Regulatory (Treg) cell therapy is one of the modulators used in immunotherapy approaches. Similarly, nuclear receptor peroxisome proliferator activated receptor gamma (PPARgamma) has extensively been shown to play a role as an immuno-modulator during inflammation. Given their mutual roles in downregulating the immune response, current study examined the influence of PPARgamma ligands i.e., thiazolidinedione (TZD) class of drugs on Forkhead Box P3 (Foxp3) expression and possible crosstalk between PPARgamma and nTreg cells of Non-Obese Diabetes (NOD) and Non-Obese Diabetes Resistant (NOR) mice. Results showed that TZD drug, ciglitazone and natural ligand of PPARgamma 15d-prostaglandin downregulated Foxp3 expression in activated nTreg cells from both NOD and NOR mice. Interestingly, addition of the PPARgamma inhibitor, GW9662 further downregulated Foxp3 expression in these cells from both mice. We also found that PPARgamma ligands negatively regulate Foxp3 expression in activated nTreg cells via PPARgamma-independent mechanism(s). These results demonstrate that both natural and synthetic PPARgamma ligands capable of suppressing Foxp3 expression in activated nTreg cells of NOD and NOR mice. This may suggest that the effect of PPARgamma ligands in modulating Foxp3 expression in activated nTreg cells is different from their reported effects on effector T cells. Given the capability to suppress Foxp3 gene, it is possible to be tested as immunomodulators in cancer-related studies. The co-lateral use of PPARgamma ligands in nTreg cells in inducing tolerance towards pseudo-self antigens as in tumor microenvironment may uphold beneficial outcomes. PMID- 30400640 TI - Isolation and Characterization of Potentially Probiotic Bacterial Strains from Mice: Proof of Concept for Personalized Probiotics. AB - Modulation of the gut microbiota through the use of probiotics has been widely used to treat or prevent several intestinal diseases. However, inconsistent results have compromised the efficacy of this approach, especially in severe conditions such as inflammatory bowel disease (IBD). The purpose of our study was to develop a personalized probiotic strategy and assess its efficacy in a murine model of intestinal inflammation. Commensal bacterial strains were isolated from the feces of healthy mice and then administered back to the host as a personalized treatment in dextran sodium sulfate (DSS)-induced colitis. Colonic tissues were collected for histological analysis and to investigate inflammatory markers such as Il-1beta, Il-6, TGF-beta, and Il-10, and the enzyme myeloperoxidase as a neutrophil marker. The group that received the personalized probiotic showed reduced susceptibility to DSS-colitis as compared to a commercial probiotic. This protection was characterized by a lower disease activity index and reduced histopathological damage in the colon. Moreover, the personalized probiotic was more effective in modulating the host immune response, leading to decreased Il-1beta and Il-6 and increased TGF-beta and Il-10 expression. In conclusion, our study suggests that personalized probiotics may possess an advantage over commercial probiotics in treating dysbiotic-related conditions, possibly because they are derived directly from the host's own microbiota. PMID- 30400643 TI - The Neglect and Fast Spread of Some Arboviruses: A Note for Healthcare Providers in Nigeria. AB - Arboviruses are distributed worldwide and constitute significant health burden globally. Outbreaks of arboviruses have been reported in Africa and beyond. In Nigeria, like in many other countries, arbovirus infections are more often than not neglected. As the early clinical features of arbovirus infections are generally nonspecific, most healthcare providers mistake them for other diseases. Outbreaks have been reported in Africa and beyond. The consequence of missed diagnosis of diseases cannot be overstated. In this review, some epidemiological data, classical syndromes, and risk factors for five human arboviruses (yellow fever YF, dengue DENV, chikungunya CHIKV, Rift Valley fever RVF, and West Nile virus WNV) found in Nigeria are presented. Health practitioners should ensure in depth analysis rather than a superficial diagnosis of diseases before declaring a course of treatment. PMID- 30400644 TI - Empirical Analysis of Carbon Emission Accounting and Influencing Factors of Energy Consumption in China. AB - China is confronting great pressure to reduce carbon emissions. This study focuses on the driving factors of carbon emissions in China using the Logarithmic Mean Divisia Index (LMDI) method. Seven economic factors, including gross domestic product (GDP), investment intensity, research and development (R&D) intensity, energy intensity, research and development (R&D) efficiency, energy structure and province structure are selected and the decomposition model of influencing factors of carbon emissions in China is constructed from a sectoral perspective. The influence of various economic factors on carbon emissions is analyzed quantitatively. Results show that the R&D intensity and energy intensity are the main factors inhibiting the growth of carbon emissions. GDP and investment intensity are the major factors promoting the growth of carbon emissions. The contribution of R&D efficiency to carbon emissions is decreasing. The impacts of energy structure and province structure on carbon emissions are ambiguous through time. Finally, some policy suggestions for strengthening the management of carbon emissions and carbon emission reduction are proposed. PMID- 30400645 TI - A Video Based Fire Smoke Detection Using Robust AdaBoost. AB - This work considers using camera sensors to detect fire smoke. Static features including texture, wavelet, color, edge orientation histogram, irregularity, and dynamic features including motion direction, change of motion direction and motion speed, are extracted from fire smoke to train and test with different combinations. A robust AdaBoost (RAB) classifier is proposed to improve training and classification accuracy. Extensive experiments on well known challenging datasets and application for fire smoke detection demonstrate that the proposed fire smoke detector leads to a satisfactory performance. PMID- 30400646 TI - Oxygen and Glucose Levels in Cell Culture Media Determine Resveratrol's Effects on Growth, Hydrogen Peroxide Production, and Mitochondrial Dynamics. AB - Resveratrol is a plant-derived polyphenol that has been widely studied for its putative health promoting effects. Many of those studies have been conducted in cell culture, in supra-physiological levels of oxygen and glucose. Resveratrol interacts with reactive oxygen species (ROS) as an antioxidant or pro-oxidant. Resveratrol affects the expression and activities of ROS-producing enzymes and organelles. It is therefore important to consider how cell culture conditions might determine the effects of resveratrol on cultured cells. We determined the effects of resveratrol on cell growth, hydrogen peroxide production, and mitochondrial network characteristics in C2C12 mouse myoblasts and PC3 human prostate cancer cells under conditions of physiological (5%) and supra physiological (18%) oxygen, and normo- (5 mM) and hyper-glycemia (25 mM). Interestingly, most effects of resveratrol on the parameters measured here were dependent upon prevailing oxygen and glucose levels during the experiment. Many of the effects of resveratrol on cell growth, hydrogen peroxide production, and mitochondrial network characteristics that were seen in 25 mM glucose and/or 18% oxygen were absent under the physiologically relevant conditions of 5 mM glucose with 5% oxygen. These findings emphasize the importance of using physiologically meaningful starting conditions for cell-culture experiments with resveratrol and indeed any manipulation affecting ROS metabolism and mitochondria. PMID- 30400647 TI - Population Based Testing for Primary Prevention: A Systematic Review. AB - The current clinical model for genetic testing is based on clinical criteria/family-history (FH) and a pre-defined mutation probability threshold. It requires people to develop cancer before identifying unaffected individuals in the family to target prevention. This process is inefficient, resource intensive and misses >50% of individuals or mutation carriers at risk. Population genetic testing can overcome these limitations. It is technically feasible to test populations on a large scale; genetic-testing costs are falling and acceptability and awareness are rising. MEDLINE, EMBASE, Pubmed, CINAHL and PsychINFO databases were searched using free-text and MeSH terms; retrieved reference lists of publications were screened; additionally, web-based platforms, Google, and clinical-trial registries were searched. Quality of studies was evaluated using appropriate check-lists. A number of studies have evaluated population-based BRCA testing in the Jewish population. This has been found to be acceptable, feasible, clinically-effective, safe, associated with high satisfaction rates and extremely cost-effective. Data support change in guidelines for population-based BRCA testing in the Jewish population. Population panel testing for BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 gene mutations is the most cost-effective genetic-testing strategy in general-population women and can prevent thousands more breast and ovarian cancers than current clinical-criteria based approaches. A few ongoing studies are evaluating population-based genetic-testing for multiple cancer susceptibility genes in the general population but more implementation studies are needed. A future population-testing programme could also target other chronic diseases. PMID- 30400648 TI - The Relationship between Generalized and Abdominal Obesity with Diabetic Kidney Disease in Type 2 Diabetes: A Multiethnic Asian Study and Meta-Analysis. AB - This study examined the associations of body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR) and waist-height ratio (WHtR) with diabetic kidney disease (DKD) in a clinical sample of Asian patients with type 2 diabetes (T2DM); substantiated with a meta-analysis of the above associations. We recruited 405 patients with T2DM (mean (standard deviation (SD)) age: 58 (7.5) years; 277 (68.4%) male; 203 (50.1%) with DKD) from a tertiary care centre in Singapore. DKD was defined as urinary albumin-creatinine ratio >3.3 mg/mmoL and/or estimated glomerular filtration rate <60 mL/min/1.73 m2. All exposures were analysed continuously and categorically (World Health Organization cut points for BMI and WC; median for WHR and WHtR) with DKD using stepwise logistic regression models adjusted for traditional risk factors. Additionally, we synthesized the pooled odds ratio of 18 studies (N = 19,755) in a meta-analysis of the above relationships in T2DM. We found that overweight and obese persons (categorized using BMI) were more likely to have DKD compared to under/normal weight individuals, while no associations were found for abdominal obesity exposures. In meta-analyses however, all obesity parameters were associated with increased odds of DKD. The discordance in our abdominal obesity findings compared to the pooled analyses warrants further validation via longitudinal cohorts. PMID- 30400649 TI - Sodium Levels of Processed Meat in Australia: Supermarket Survey Data from 2010 to 2017. AB - High sodium intake increases blood pressure and consequently increases the risk of cardiovascular diseases. In Australia, the best estimate of sodium intake is 3840 mg sodium/day, almost double the World Health Organization (WHO) guideline (2000 mg/day), and processed meats contribute approximately 10% of daily sodium intake to the diet. This study assessed the median sodium levels of 2510 processed meat products, including bacon and sausages, available in major Australian supermarkets in 2010, 2013, 2015 and 2017, and assessed changes over time. The median sodium content of processed meats in 2017 was 775 mg/100 g (interquartile range (IQR) 483-1080). There was an 11% reduction in the median sodium level of processed meats for which targets were set under the government's Food and Health Dialogue (p < 0.001). This includes bacon, ham/cured meat products, sliced luncheon meat and meat with pastry categories. There was no change in processed meats without a target (median difference 6%, p = 0.450). The new targets proposed by the current government's Healthy Food Partnership capture a larger proportion of products than the Food and Health Dialogue (66% compared to 35%) and a lower proportion of products are at or below the target (35% compared to 54%). These results demonstrate that voluntary government targets can drive nutrient reformulation. Future efforts will require strong government leadership and robust monitoring and evaluation systems. PMID- 30400650 TI - Demand and Supply Side Barriers that Limit the Uptake of Nutrition Services among Pregnant Women from Rural Ethiopia: An Exploratory Qualitative Study. AB - Despite poverty reduction and increased promotion of improved nutrition practices in the community, undernutrition in Ethiopia remains a concern. The present study aimed to explore the demand and supply side barriers that limit the uptake of nutrition services among pregnant women from the rural communities of the Tigray Region, Northern Ethiopia. A community-based qualitative study was conducted in December through January 2017. A total of 90 key informant in-depth interviews and 14 focus group discussions were undertaken. Study participants were purposively selected for specific characteristics, along with health professionals deployed at various levels of the health system, including health posts, health centers, woreda health offices, and the regional health bureau. Study participants were asked to identify the barriers and implementation challenges that limit access to nutrition services for pregnant women. Participants' responses were transcribed verbatim, without editing the grammar, to avoid losing meaning. The data were imported to ATLAS.ti 7 (qualitative data analysis software) for coding and analyzed using a thematic content analysis approach. The study findings indicated that the dietary quality of pregnant women in the study area remains poor and in some cases, poorer quality than pre pregnancy. Across study sites, heavy workloads, food taboos and avoidances, low husband support, lack of economic resources, lack of awareness, low educational level of women, poor dietary habits, increased expenditure for cultural and religious festivities, "dependency syndrome", low physical access to health facilities, poorly equipped health facilities, focus on child health and nutrition, poor coordination among nutrition specific and sensitive sectors, and limited sources of nutrition information were identified as the demand and supply side barriers limiting the uptake of nutrition services during pregnancy. In conclusion, the community would benefit from improved social behavior change communication on nutrition during pregnancy and multi-sectoral coordination among nutrition-specific and nutrition-sensitive sectors. PMID- 30400651 TI - High Performance Acetylene Sensor with Heterostructure Based on WO3 Nanolamellae/Reduced Graphene Oxide (rGO) Nanosheets Operating at Low Temperature. AB - The development of functionalized metal oxide/reduced graphene oxide (rGO) hybrid nanocomposites concerning power equipment failure diagnosis is one of the most recent topics. In this work, WO3 nanolamellae/reduced graphene oxide (rGO) nanocomposites with different contents of GO (0.5 wt %, 1 wt %, 2 wt %, 4 wt %) were synthesized via controlled hydrothermal method. X-ray diffraction (XRD), transmission electron microscopy (TEM), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), thermogravimetric analyses-derivative thermogravimetric analysis-differential scanning calorimetry (TG-DTG-DSC), BET, and photoluminescence (PL) spectroscopy were utilized to investigate morphological characterizations of prepared gas sensing materials and indicated that high quality WO3 nanolamellae were widely distributed among graphene sheets. Experimental ceramic planar gas sensors composing of interdigitated alumina substrates, Au electrodes, and RuO2 heating layer were coated with WO3 nanolamellae/reduced graphene oxide (rGO) films by spin-coating technique and then tested for gas sensing towards multi-concentrations of acetylene (C2H2) gases in a carrier gas with operating temperature ranging from 50 degrees C to 400 degrees C. Among four contents of prepared samples, sensing materials with 1 wt % GO nanocomposite exhibited the best C2H2 sensing performance with lower optimal working temperature (150 degrees C), higher sensor response (15.0 toward 50 ppm), faster response-recovery time (52 s and 27 s), lower detection limitation (1.3 ppm), long-term stability, and excellent repeatability. The gas sensing mechanism for enhanced sensing performance of nanocomposite is possibly attributed to the formation of p-n heterojunction and the active interaction between WO3 nanolamellae and rGO sheets. Besides, the introduction of rGO nanosheets leads to the impurity of synthesized materials, which creates more defects and promotes larger specific area for gas adsorption, outstanding conductivity, and faster carrier transport. The superior gas sensing properties of WO3/rGO based gas sensor may contribute to the development of a high performance ppm-level gas sensor for the online monitoring of dissolved C2H2 gas in large-scale transformer oil. PMID- 30400652 TI - Characterization and Corrosion Resistance of Boron-Containing-Austenitic Stainless Steels Produced by Rapid Solidification Techniques. AB - The composition of a commercial duplex stainless steel was modified with boron additions (3.5, 4.5, and 5.5 wt.%) and processed by rapid-quenching techniques: Melt-spinning, copper-mold casting, and high-velocity oxygen fuel (HVOF). Spray deposition was also used to produce alloys as the process may induce rapid solidified-like microstructures. These processing routes led to microstructures with distinguished corrosion resistance. Among the alloys with different boron contents, the 63.5Fe25Cr7Ni4.5B composition enabled the production of fully amorphous ribbons by melt-spinning. The cooling rate experienced during copper mold casting, high-velocity oxygen fuel, and spray deposition did not ensure complete amorphization. The crystalline phases thereby formed were (Fe,Cr)2B and (Fe,Mo)3B2 borides in an austenitic-matrix with morphology and refinement dependent of the cooling rates. Fully amorphous 63.5Fe25Cr7Ni4.5B ribbons exhibited outstanding corrosion resistance in chloride-rich alkaline and acid media with negligible corrosion current densities of about 10-8 A/cm2 and a broad passivation plateau. Although the specimens of the same composition produced by HVOF process and spray deposition exhibited lower corrosion resistance because of intrinsic porosity and crystalline phases, their corrosion behaviors were superior to those of AISI 1045 steel used as substrate with the advantage to be reinforced with hard borides known to be resistant against wear. PMID- 30400653 TI - The Relationship between Family Violence and Self-Control in Adolescence: A Multi Level Meta-Analysis. AB - Theoretical studies propose an association between family violence and low self control in adolescence; however, empirical findings of this association are inconclusive. The aim of the present research was to systematically summarize available findings on the relation between family violence and self-control across adolescence. We included 28 studies with 143 effect sizes, representing more than 25,000 participants of eight countries from early to late adolescence. Applying a three-level meta-analysis, taking dependency between effect sizes into account while retaining statistical power, we examined the magnitude and direction of the overall effect size. Additionally, we investigated whether theoretical moderators (e.g., age, gender, country), and methodological moderators (e.g., time lag between family violence and self-control, informant) influenced the magnitude of the association between family violence and self control. Our results revealed that family violence and self-control have a small to moderate significant negative association (r = -0.191). This association did not vary across gender, country, and informants. The strength of the association, however, decreased with age and in longitudinal studies. This finding provides evidence that researchers and clinicians may expect low self-control in the wake of family violence, especially in early adolescence. Recommendations for future research in the area are discussed. PMID- 30400654 TI - Healthy Diets in Rural Victoria-Cheaper than Unhealthy Alternatives, Yet Unaffordable. AB - Rural communities experience higher rates of obesity and reduced food security compared with urban communities. The perception that healthy foods are expensive contributes to poor dietary choices. Providing an accessible, available, affordable healthy food supply is an equitable way to improve the nutritional quality of the diet for a community, however, local food supply data are rarely available for small rural towns. This study used the Healthy Diets ASAP tool to assess price, price differential and affordability of recommended (healthy) and current diets in a rural Local Government Area (LGA) (pop ~ 7000; 10 towns) in Victoria, Australia. All retail food outlets were surveyed (n = 40). The four most populous towns had supermarkets; remaining towns had one general store each. Seven towns had cafe/take-away outlets, and all towns had at least one hotel/pub. For all towns the current unhealthy diet was more expensive than the recommended healthy diet, with 59.5% of the current food budget spent on discretionary items. Affordability of the healthy diet accounted for 30-32% of disposable income. This study confirms that while a healthy diet is less expensive than the current unhealthier diet, affordability is a challenge for rural communities. Food security is reduced further with restricted geographical access, a limited healthy food supply, and higher food prices. PMID- 30400655 TI - Theoretical Studies on the Engagement of Interleukin 18 in the Immuno Inflammatory Processes Underlying Atherosclerosis. AB - Interleukin 18 (IL-18) is one of the pro-inflammatory cytokines expressed by macrophages, suggesting that it plays important physiological and immunological functions, among the others: stimulation of natural killers (NKs) and T cells to interferon gamma (IFN- gamma ) synthesis. IL-18 was originally identified as interferon gamma inducing factor and now it is recognized as multifunctional cytokine, which has a role in regulation of innate and adaptive immune responses. Therefore, in order to investigate IL-18 contribution to the immuno-inflammatory processes underlying atherosclerosis, a systems approach has been used in our studies. For this purpose, a model of the studied phenomenon, including selected pathways, based on the Petri-net theory, has been created and then analyzed. Two pathways of IL-18 synthesis have been distinguished: caspase 1-dependent pathway and caspase 1-independent pathway. The analysis based on t-invariants allowed for determining interesting dependencies between IL-18 and different types of macrophages: M1 are involved in positive regulation of IL-18, while M2 are involved in negative regulation of IL-18. Moreover, the obtained results showed that IL-18 is produced more often via caspase 1-independent pathway than caspase 1-dependent pathway. Furthermore, we found that this last pathway may be associated with caspase 8 action. PMID- 30400657 TI - Investigating Motor Competence in Association with Sedentary Behavior and Physical Activity in 7- to 11-Year-Old Children. AB - Children's motor competence (MC) has declined in the past decades, while sedentary behavior (SB) has increased. This study examined the association between MC and physical activity (PA) levels among primary schoolchildren. Demographics, body height and weight, MC (Athletic Skills Track), and PA levels (ActiGraph, GT3X+) were assessed among 595 children (291 boys, mean age = 9.1 years, SD = 1.1). MC was standardized into five categories: from very low to very high. PA levels were classified into SB, light PA (LPA), and moderate-to-vigorous PA (MVPA). Mixed-model analyses were conducted with PA levels as dependent variables and MC as the independent variable, while adjusting for age, gender, and body mass index (BMI) z-score on the individual level. A negative association between MC and SB and a positive association between MC and MVPA were found. The strength of both associations increased as children expressed lower or higher levels of MC. MC is an important correlate of both SB and MVPA, particularly for children with very high or low MC. Developing and improving children's MC may contribute to spending less time in SB and more time in MVPA, particularly for high-risk groups, i.e., children with low MC. Moreover, addressing MC development and PA promotion simultaneously might create positive feedback loops for both children's MC and PA levels. PMID- 30400656 TI - Anti-Adenoviral Activity of 2-(3-Chlorotetrahydrofuran-2-yl)-4-Tosyl-5 (Perfluoropropyl)-1,2,3-Triazole. AB - Background and objectives: A considerable increase in the levels of adenoviral diseases among both adults and children necessitate the development of effective methods for its prevention and treatment. The synthesis of the new fluorinated 1,2,3-triazoles, and the study of the mechanisms of their action, are promising for the development of efficient antiviral drugs of our time. Materials and Methods: Antiviral activity and cell cytotoxic effect of 2-(3 chlorotetrahydrofuran-2-yl)-4-tosyl-5-(perfluoropropyl)-1,2,3-triazole (G29) were determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. The influence of the compound on the infectivity of human adenovirus type 5 (HAdV-5) was carried out via the cytomorphology method. The influence of the compound on the cell cycle under a condition of adenovirus infection was studied using flow cytometric analysis of propidium iodide-stained cells. Results: It was found that G29 suppressed HAdV-5 reproduction by 50% in concentrations of 37 MUg/mL. Furthermore, the compound reduced the titer of virus obtained de novo, and inhibited HAdV-5 inclusion bodies formation by 84-90%. The use of fluorinated compounds under the conditions of adenovirus infection decreased the number of apoptotic cells by 11% and the number of cells in S phase by 21-42% compared to the profile of infected cells. Conclusions: The fluorinated compound G29 showed moderate activity against HAdV-5 based on several mechanisms. It led to the normalization of the life cycle of cells infected with adenovirus to the level of non-infected cells and caused the obstruction of HAdV-5 reproduction, inducing the formation of non-infectious virus progeny. PMID- 30400658 TI - Antioxidant Status, Antidiabetic Properties and Effects on Caco-2 Cells of Colored and Non-Colored Enriched Extracts of Sweet Cherry Fruits. AB - This study aimed to compare three different extracts of Saco sweet cherry, namely the non-colored fraction, colored fraction, and total extract concerning phenolic composition, antioxidant and antidiabetic potential, and erythrocytes' protection and effects on Caco-2 cells. Twenty-two phenolic compounds were identified using high-performance liquid chromatography with diode-array detection. Hydroxycinnamic acids were the most predominant in both the non-colored fraction and total extract, while cyanidin-3-O-rutinoside was the main anthocyanin found in the colored fraction. The total extract was the most effective against 1,1 diphenyl-2-picrylhydrazyl, nitric oxide, and superoxide radicals, and in the inhibition of alpha-glucosidase enzyme. The colored fraction revealed the best activity against hemoglobin oxidation and hemolysis. Regarding to Caco-2 cells, the colored extract exhibited the highest cytotoxic effects, while the total extract was the most efficient in protecting these cells against oxidative damage induced by tert-butyl hydroperoxide. PMID- 30400659 TI - Internet Risks: An Overview of Victimization in Cyberbullying, Cyber Dating Abuse, Sexting, Online Grooming and Problematic Internet Use. AB - The advance of digital media has created risks that affect the bio-psycho-social well-being of adolescents. Some of these risks are cyberbullying, cyber dating abuse, sexting, online grooming and problematic Internet use. These risks have been studied individually or through associations of some of them but they have not been explored conjointly. The main objective is to determine the comorbidity between the described Internet risks and to identify the profiles of victimized adolescents. An analytical and cross-sectional study with 3212 participants (46.3% males) from 22 Spanish schools was carried out. Mean age was 13.92 +/- 1.44 years (range 11-21). Assessment tools with adequate standards of reliability and validity were used. The main results indicate that the most prevalent single risk is cyberbullying victimization (30.27%). The most prevalent two-risk associations are cyberbullying-online grooming (12.61%) and cyberbullying-sexting (5.79%). The three-risk combination of cyberbullying-sexting-grooming (7.12%) is highlighted, while 5.49% of the adolescents present all the risks. In addition, four profiles are distinguished, with the profile Sexualized risk behaviour standing out, with high scores in grooming and sexting and low scores in the rest of the risks. Determining the comorbidity of risks is useful for clinical and educational interventions, as it can provide information about additional risks. PMID- 30400660 TI - Energy-Efficient Medium Access Control Protocols for Cognitive Radio Sensor Networks: A Comparative Survey. AB - The increase of application areas in wireless sensor networks demands novel solutions in terms of energy consumption and radio frequency management. Cognitive radio sensor networks (CRSNs) are key for ensuring efficient spectrum management, by making it possible to use the unused licensed frequency spectrum together with the unlicensed frequency spectrum. Sensor nodes powered by energy constrained batteries necessarily require energy-efficient protocols at the routing and medium access control (MAC) layers. In CRSNs, energy efficiency is more important because the sensor nodes consume additional energy for spectrum sensing and management. To the best of authors' knowledge, there is no survey on "energy-efficient" MAC protocols for CRSNs in the literature, even though a conceptual review on MAC protocols for CRSNs was presented at a conference recently. In this paper, energy-efficient MAC protocols for CRSNs are extensively surveyed and qualitatively compared. Open issues, and research challenges in the design of MAC protocols for CRSNs, are also discussed. PMID- 30400661 TI - Catalytic/Protective Properties of Martian Minerals and Implications for Possible Origin of Life on Mars. AB - Minerals might have played critical roles for the origin and evolution of possible life forms on Mars. The study of the interactions between the "building blocks of life" and minerals relevant to Mars mineralogy under conditions mimicking the harsh Martian environment may provide key insight into possible prebiotic processes. Therefore, this contribution aims at reviewing the most important investigations carried out so far about the catalytic/protective properties of Martian minerals toward molecular biosignatures under Martian-like conditions. Overall, it turns out that the fate of molecular biosignatures on Mars depends on a delicate balance between multiple preservation and degradation mechanisms, often regulated by minerals, which may take place simultaneously. Such a complexity requires more efforts in simulating realistically the Martian environment in order to better inspect plausible prebiotic pathways and shed light on the nature of the organic compounds detected both in meteorites and on the surface of Mars through in situ analysis. PMID- 30400662 TI - Elevated Black Carbon Concentrations and Atmospheric Pollution around Singrauli Coal-Fired Thermal Power Plants (India) Using Ground and Satellite Data. AB - The tropospheric NO2 concentration from OMI AURA always shows high concentrations of NO2 at a few locations in India, one of the high concentrations of NO2 hotspots is associated with the locations of seven coal-fired Thermal Power plants (TPPs) in Singrauli. Emissions from TPPs are among the major sources of black carbon (BC) soot in the atmosphere. Knowledge of BC emissions from TPPs is important in characterizing regional carbonaceous particulate emissions, understanding the fog/haze/smog formation, evaluating regional climate forcing, modeling aerosol optical parameters and concentrations of black carbon, and evaluating human health. Furthermore, elevated BC concentrations, over the Indo Gangetic Plain (IGP) and the Himalayan foothills, have emerged as an important subject to estimate the effects of deposition and atmospheric warming of BC on the accelerated melting of snow and glaciers in the Himalaya. For the first time, this study reports BC concentrations and aerosol optical parameters near dense coal-fired power plants and open cast coal mining adjacent to the east IGP. In situ measurements were carried out in Singrauli (located in south-east IGP) at a fixed site about 10 km from power plants and in transit measurements in close proximity to the plants, for few days in the month of January and March 2013. At the fixed site, BC concentration up to the 95 MUgm-3 is observed with strong diurnal variations. BC concentration shows two maxima peaks during early morning and evening hours. High BC concentrations are observed in close proximity to the coal-fired TPPs (>200 MUgm-3), compared to the outside domain of our study region. Co-located ground-based sunphotometer measurements of aerosol optical depth (AOD) show strong spatial variability at the fixed site, with AOD in the range 0.38-0.58, and the highest AOD in the range 0.7-0.95 near the TPPs in transit measurements (similar to the peak of BC concentrations). Additionally, the Angstrom exponent was found to be in the range 0.4-1.0 (maximum in the morning time) and highest in the proximity of TPPs (~1.0), suggesting abundance of fine particulates, whereas there was low Angstrom exponent over the surrounding coal mining areas. Low Angstrom exponent is characterized by dust from the unpaved roads and nearby coal mining areas. MODIS derived daily AOD shows a good match with the MICROTOPS AOD. The CALIPSO derived subtypes of the aerosol plot shows that the aerosols over Singrauli region are mainly dust, polluted dust, and elevated smoke. The preliminary study for few days provides information about the BC concentrations and aerosol optical properties from Singrauli (one of the NO2 hotspot locations in India). This preliminary study suggests that long-term continuous monitoring of BC is needed to understand the BC concentrations and aerosol optical properties for better quantification and the estimation of the emission to evaluate radiative forcing in the region. PMID- 30400663 TI - Proteomic Analysis of Plasma Membrane Proteins of Antler Stem Cells Using Label Free LC-MS/MS. AB - Deer antlers are unusual mammalian organs that can fully regenerate after annual shedding. Stem cells resident in the pedicle periosteum (PPCs) provide the main cell source for antler regeneration. Central to various cellular processes are plasma membrane proteins, but the expression of these proteins has not been well documented in antler regeneration. In the present study, plasma membrane proteins of PPCs and facial periosteal cells (FPCs) were analyzed using label-free liquid chromatography-mass spetrometry (LC-MS/MS). A total of 1739 proteins were identified. Of these proteins, 53 were found solely in the PPCs, 100 solely in the FPCs, and 1576 co-existed in both PPCs and FPCs; and 39 were significantly up regulated in PPCs and 49 up-regulated in FPCs. In total, 226 gene ontology (GO) terms were significantly enriched from the differentially expressed proteins (DEPs). Five clusters of biological processes from these GO terms comprised responses to external stimuli, signal transduction, membrane transport, regulation of tissue regeneration, and protein modification processes. Further studies are required to demonstrate the relevancy of these DEPs in antler stem cell biology and antler regeneration. PMID- 30400664 TI - Optimization of Regioselective alpha-Glucosylation of Hesperetin Catalyzed by Cyclodextrin Glucanotransferase. AB - The regioselective alpha-glucosylation of hesperetin was achieved by a transglycosylation reaction catalyzed by cyclodextrin glucanotransferase (CGTase) from Thermoanaerobacter sp. using soluble starch as glucosyl donor. By combining mass spectrometry (ESI-TOF) and 2D-NMR analysis, the main monoglucosylated derivative was fully characterized (hesperetin 7-O-alpha-d-glucopyranoside). In order to increase the yield of monoglucoside, several reaction parameters were optimized: Nature and percentage of cosolvent, composition of the aqueous phase, glucosyl donor, temperature, and the concentrations of hesperetin and soluble starch. Under the optimal conditions, which included the presence of 30% of bis(2 methoxyethyl) ether as cosolvent, the maximum concentration of monoglucoside was approximately 2 mM, obtained after 24 h of reaction. To our knowledge, this is the first report of direct glucosylation of hesperetin employing free enzymes instead of whole cells. PMID- 30400665 TI - Development of Flexible Robot Skin for Safe and Natural Human-Robot Collaboration. AB - For industrial manufacturing, industrial robots are required to work together with human counterparts on certain special occasions, where human workers share their skills with robots. Intuitive human-robot interaction brings increasing safety challenges, which can be properly addressed by using sensor-based active control technology. In this article, we designed and fabricated a three dimensional flexible robot skin made by the piezoresistive nanocomposite based on the need for enhancement of the security performance of the collaborative robot. The robot skin endowed the YuMi robot with a tactile perception like human skin. The developed sensing unit in the robot skin showed the one-to-one correspondence between force input and resistance output (percentage change in impedance) in the range of 0-6.5 N. Furthermore, the calibration result indicated that the developed sensing unit is capable of offering a maximum force sensitivity (percentage change in impedance per Newton force) of 18.83% N-1 when loaded with an external force of 6.5 N. The fabricated sensing unit showed good reproducibility after loading with cyclic force (0-5.5 N) under a frequency of 0.65 Hz for 3500 cycles. In addition, to suppress the bypass crosstalk in robot skin, we designed a readout circuit for sampling tactile data. Moreover, experiments were conducted to estimate the contact/collision force between the object and the robot in a real-time manner. The experiment results showed that the implemented robot skin can provide an efficient approach for natural and secure human-robot interaction. PMID- 30400666 TI - Rituximab Therapy in Renal Amyloidosis Secondary to Rheumatoid Arthritis. AB - Secondary amyloid A (AA) amyloidosis is a late and serious complication of poorly controlled, chronic inflammatory diseases. Rheumatoid arthritis (RA) patients with poorly controlled, longstanding disease and those with extra-articular manifestations are under risk for the development of AA amyloidosis. Although new drugs have proven to be significantly effective in the treatment of secondary AA amyloidosis, no treatment modality has proven to be ideal. To date, only in small case series preliminary clinical improvement have been shown with rituximab therapy for AA amyloidosis secondary to RA that is refractory to TNF-alpha inhibitors (TNF-i) therapy. In these case series, we assessed the efficacy and safety of rituximab therapy for patients with RA and secondary amyloidosis. Hacettepe University Biologic Registry was developed at 2005. The data of the RA patients who were prescribed a biological drug were recorded regularly. Patients with biopsy proven AA amyloidosis patients were screened. Of 1022 RA patients under biologic therapy, 0.7% patients had clinically apparent histologically confirmed amyloidosis. Four of seven patients who were prescribed rituximab at least one infusion enrolled to those case series. Two of four patients showed significant clinical improvement and one of them also had decrease in proteinuria and the other one had stable renal function and proteinuria. The main goal for the treatment of AA amyloidosis is to control the activity of the underlying disorder. In this study, we showed that rituximab may be an effective treatment in RA patients with amyloidosis who were unresponsive to conventional disease modifying anti-rheumatic drugs (DMARDs) and/or TNFi. PMID- 30400667 TI - Precision Medicine: The Role of the MSIDS Model in Defining, Diagnosing, and Treating Chronic Lyme Disease/Post Treatment Lyme Disease Syndrome and Other Chronic Illness: Part 2. AB - We present a precision medical perspective to assist in the definition, diagnosis, and management of Post Treatment Lyme Disease Syndrome (PTLDS)/chronic Lyme disease. PTLDS represents a small subset of patients treated for an erythema migrans (EM) rash with persistent or recurrent symptoms and functional decline. The larger population with chronic Lyme disease is less understood and well defined. Multiple Systemic Infectious Disease Syndrome (MSIDS) is a multifactorial model for treating chronic disease(s), which identifies up to 16 overlapping sources of inflammation and their downstream effects. A patient symptom survey and a retrospective chart review of 200 patients was therefore performed on those patients with chronic Lyme disease/PTLDS to identify those variables on the MSIDS model with the greatest potential effect on regaining health. Results indicate that dapsone combination therapy decreased the severity of eight major Lyme symptoms, and multiple sources of inflammation (other infections, immune dysfunction, autoimmunity, food allergies/sensitivities, leaky gut, mineral deficiencies, environmental toxins with detoxification problems, and sleep disorders) along with downstream effects of inflammation may all affect chronic symptomatology. In part two of our observational study and review paper, we postulate that the use of this model can represent an important and needed paradigm shift in the diagnosis and treatment of chronic disease. PMID- 30400668 TI - Road Scene Simulation Based on Vehicle Sensors: An Intelligent Framework Using Random Walk Detection and Scene Stage Reconstruction. AB - Road scene model construction is an important aspect of intelligent transportation system research. This paper proposes an intelligent framework that can automatically construct road scene models from image sequences. The road and foreground regions are detected at superpixel level via a new kind of random walk algorithm. The seeds for different regions are initialized by trapezoids that are propagated from adjacent frames using optical flow information. The superpixel level region detection is implemented by the random walk algorithm, which is then refined by a fast two-cycle level set method. After this, scene stages can be specified according to a graph model of traffic elements. These then form the basis of 3D road scene models. Each technical component of the framework was evaluated and the results confirmed the effectiveness of the proposed approach. PMID- 30400669 TI - A Reliability Scheduling Algorithm for the Static Segment of FlexRay on Vehicle Networks. AB - FlexRay is a next-generation in-vehicle communication protocol which works in real time with flexibility. The most common applications in FlexRay are high bandwidth. X-by-wire applications, such as brake by wire and throttle by wire. However, there is no mechanism which can prevent transient faults in the application layer of FlexRay. If a transient fault occurs during driving, this would be very dangerous; therefore, we propose a fast reliability scheduling algorithm (FRSA) to improve the communication reliability of FlexRay. The proposed method reduces the probability of transient faults in one clock cycle by using a retransmission mechanism to recover the transient errors, and further improves computational complexity using the lookup table method to ensure system reliability. In this paper, we analyze a related literature to establish the system reliability constraints needed to evaluate the necessary time and slot usage, and the proposed cost function is used to evaluate the performance and efficiency when the number of messages is increased. Experimental results show that the proposed FRSA reduces execution time by an average 70.76% and cost by an average 13.33% more than the other existing methods. This method can be useful to others, especially regarding research about periodic time-triggered communication systems. PMID- 30400670 TI - Robust Radiation Sources Localization Based on the Peak Suppressed Particle Filter for Mixed Multi-Modal Environments. AB - This paper addresses a detection problem where sparse measurements are utilized to estimate the source parameters in a mixed multi-modal radiation field. As the limitation of dimensional scalability and the unimodal characteristic, most existing algorithms fail to detect the multi-point sources gathered in narrow regions, especially with no prior knowledge about intensity and source number. The proposed Peak Suppressed Particle Filter (PSPF) method utilizes a hybrid scheme of multi-layer particle filter, mean-shift clustering technique and peak suppression correction to solve the major challenges faced by current existing algorithms. Firstly, the algorithm realizes sequential estimation of multi-point sources in a cross-mixed radiation field by using particle filtering and suppressing intensity peak value, while existing algorithms could just identify single point or spatially separated point sources. Secondly, the number of radioactive sources could be determined in a non-parametric manner as the fact that invalid particle swarms would disperse automatically. In contrast, existing algorithms either require prior information or rely on expensive statistic estimation and comparison. Additionally, to improve the prediction stability and convergent performance, distance correction module and configuration maintenance machine are developed to sustain the multimodal prediction stability. Finally, simulations and physical experiments are carried out in aspects such as different noise level, non-parametric property, processing time and large-scale estimation, to validate the effectiveness and robustness of the PSPF algorithm. PMID- 30400672 TI - Determination of Metals Content in Wine Samples by Inductively Coupled Plasma Mass Spectrometry. AB - Knowledge about the metal content of wine is very important, for many reasons. Depending on the element, its quantity varies in wine from ng/L to mg/L. Despite the fact that metals are not directly connected to the taste and aroma of the wine, their content should be determined and controlled, because excess is undesirable, and in some cases prohibited, due to potential toxicity. Several analytical procedures for metal determination are applied. However, due to sensitivity, low limit of detection and speed of analysis, inductively coupled plasma-mass spectrometry (ICP-MS) is one of the most frequently used techniques. The aim of this study was to reveal specific relationships between the wine samples or between the chemical variables in order to classify the wines according to their metal content by application of chemometric analysis. For metals content determination, two techniques, ICP-MS and inductively coupled plasma-optical emission spectrometry (ICP-OES), were applied. Data obtained showed that none of the wine samples surpassed the toxic levels reported for metals in the literature, thus, these wines appeared to be safe as regards the risk associated with the potentially toxic metals intake. However, specific correlations between metals and specific aspects of the wines themselves have been found. PMID- 30400673 TI - BeeKeeper 2.0: Confidential Blockchain-Enabled IoT System with Fully Homomorphic Computation. AB - Blockchain-enabled Internet of Things (IoT) systems have received extensive attention from academia and industry. Most previous constructions face the risk of leaking sensitive information since the servers can obtain plaintext data from the devices. To address this issue, in this paper, we propose a decentralized outsourcing computation (DOC) scheme, where the servers can perform fully homomorphic computations on encrypted data from the data owner according to the request of the data owner. In this process, the servers cannot obtain any plaintext data, and dishonest servers can be detected by the data owner. Then, we apply the DOC scheme in the IoT scenario to achieve a confidential blockchain enabled IoT system, called BeeKeeper 2.0. To the best of our knowledge, this is the first work in which servers of a blockchain-enabled IoT system can perform any-degree homomorphic multiplications and any number of additions on encrypted data from devices according to the requests of the devices without obtaining any plaintext data of the devices. Finally, we provide a detailed performance evaluation for the BeeKeeper 2.0 system by deploying it on Hyperledger Fabric and using Hyperledger Caliper for performance testing. According to our tests, the time consumed between the request stage and recover stage is no more than 3.3 s, which theoretically satisfies the production needs. PMID- 30400671 TI - Possible Role of CYP450 Generated Omega-3/Omega-6 PUFA Metabolites in the Modulation of Blood Pressure and Vascular Function in Obese Children. AB - Obesity is often accompanied by metabolic and haemodynamic disorders such as hypertension, even during childhood. Arachidonic acid (AA) is metabolized by cytochrome P450 (CYP450) enzymes to epoxyeicosatrienoic acids (EETs) and 20 hydroxyeicosatetraenoic acid (20-HETE), vasoactive and natriuretic metabolites that contribute to blood pressure (BP) regulation. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) omega-3 polyunsaturated fatty acids may compete with AA for CYP450-dependent bioactive lipid mediator formation. We aimed at investigating the role of AA, EPA and DHA and their CYP450-dependent metabolites in BP control and vascular function in 66 overweight/obese children. Fatty acid profile moderately correlated with the corresponding CYP450-derived metabolites but their levels did not differ between children with normal BP (NBP) and high BP (HBP), except for higher EPA-derived epoxyeicosatetraenoic acids (EEQs) and their diols in HBP group, in which also the estimated CYP450-epoxygenase activity was higher. In the HBP group, EPA inversely correlated with BP, EEQs inversely correlated both with systolic BP and carotid Intima-Media Thickness (cIMT). The DHA-derived epoxydocosapentaenoic acids (EDPs) were inversely correlated with diastolic BP. Omega-3 derived epoxymetabolites appeared beneficially associated with BP and vascular structure/function only in obese children with HBP. Further investigations are needed to clarify the role of omega-3/omega-6 epoxymetabolites in children's hemodynamics. PMID- 30400674 TI - Performance Assessment of Five Different Soil Moisture Sensors under Irrigated Field Conditions in Oklahoma. AB - Meeting the ever-increasing global food, feed, and fiber demands while conserving the quantity and quality of limited agricultural water resources and maintaining the sustainability of irrigated agriculture requires optimizing irrigation management using advanced technologies such as soil moisture sensors. In this study, the performance of five different soil moisture sensors was evaluated for their accuracy in two irrigated cropping systems, one each in central and southwest Oklahoma, with variable levels of soil salinity and clay content. With factory calibrations, three of the sensors had sufficient accuracies at the site with lower levels of salinity and clay, while none of them performed satisfactorily at the site with higher levels of salinity and clay. The study also investigated the performance of different approaches (laboratory, sensor based, and the Rosetta model) to determine soil moisture thresholds required for irrigation scheduling, i.e., field capacity (FC) and wilting point (WP). The estimated FC and WP by the Rosetta model were closest to the laboratory-measured data using undisturbed soil cores, regardless of the type and number of input parameters used in the Rosetta model. The sensor-based method of ranking the readings resulted in overestimation of FC and WP. Finally, soil moisture depletion, a critical parameter in effective irrigation scheduling, was calculated by combining sensor readings and FC estimates. Ranking-based FC resulted in overestimation of soil moisture depletion, even for accurate sensors at the site with lower levels of salinity and clay. PMID- 30400675 TI - Disordered Regions of Mixed Lineage Leukemia 4 (MLL4) Protein Are Capable of RNA Binding. AB - Long non-coding RNAs (lncRNAs) are emerging as important regulators of cellular processes and are extensively involved in the development of different cancers; including leukemias. As one of the accepted methods of lncRNA function is affecting chromatin structure; lncRNA binding has been shown for different chromatin modifiers. Histone lysine methyltransferases (HKMTs) are also subject of lncRNA regulation as demonstrated for example in the case of Polycomb Repressive Complex 2 (PRC2). Mixed Lineage Leukemia (MLL) proteins that catalyze the methylation of H3K4 have been implicated in several different cancers; yet many details of their regulation and targeting remain elusive. In this work we explored the RNA binding capability of two; so far uncharacterized regions of MLL4; with the aim of shedding light to the existence of possible regulatory lncRNA interactions of the protein. We demonstrated that both regions; one that contains a predicted RNA binding sequence and one that does not; are capable of binding to different RNA constructs in vitro. To our knowledge, these findings are the first to indicate that an MLL protein itself is capable of lncRNA binding. PMID- 30400676 TI - Serum and Lipoprotein Particle miRNA Profile in Uremia Patients. AB - microRNAs (miRNAs) are post-transcriptional regulators of messenger RNA (mRNA), and transported through the whole organism by-but not limited to-lipoprotein particles. Here, we address the miRNA profile in serum and lipoprotein particles of healthy individuals in comparison with patients with uremia. Moreover, we quantitatively determined the cellular lipoprotein-particle-uptake dependence on the density of lipoprotein particle receptors and present a method for enhancement of the transfer efficiency. We observed a significant increase of the cellular miRNA level using reconstituted high-density lipoprotein (HDL) particles artificially loaded with miRNA, whereas incubation with native HDL particles yielded no measurable effect. Thus, we conclude that no relevant effect of lipoprotein-particle-mediated miRNA-transfer exists under in vivo conditions though the miRNA profile of lipoprotein particles can be used as a diagnostic marker. PMID- 30400677 TI - Design and Analysis of a High-Gain and Robust Multi-DOF Electro-thermally Actuated MEMS Gyroscope. AB - This paper presents the design and analysis of a multi degree of freedom (DOF) electro-thermally actuated non-resonant MEMS gyroscope with a 3-DOF drive mode and 1-DOF sense mode system. The 3-DOF drive mode system consists of three masses coupled together using suspension beams. The 1-DOF system consists of a single mass whose motion is decoupled from the drive mode using a decoupling frame. The gyroscope is designed to be operated in the flat region between the first two resonant peaks in drive mode, thus minimizing the effect of environmental and fabrication process variations on device performance. The high gain in the flat operational region is achieved by tuning the suspension beams stiffness. A detailed analytical model, considering the dynamics of both the electro-thermal actuator and multi-mass system, is developed. A parametric optimization is carried out, considering the microfabrication process constraints of the Metal Multi-User MEMS Processes (MetalMUMPs), to achieve high gain. The stiffness of suspension beams is optimized such that the sense mode resonant frequency lies in the flat region between the first two resonant peaks in the drive mode. The results acquired through the developed analytical model are verified with the help of 3D finite element method (FEM)-based simulations. The first three resonant frequencies in the drive mode are designed to be 2.51 kHz, 3.68 kHz, and 5.77 kHz, respectively. The sense mode resonant frequency is designed to be 3.13 kHz. At an actuation voltage of 0.2 V, the dynamically amplified drive mode gain in the sense mass is obtained to be 18.6 um. With this gain, a capacitive change of 28.11 f F and 862.13 f F is achieved corresponding to the sense mode amplitude of 0.15 MU m and 4.5 MU m at atmospheric air pressure and in a vacuum, respectively. PMID- 30400678 TI - Correction: Do We Need Cephalic Spread of Spinal Anaesthesia for Caesarean Section? A Different Approach to CSE-EVE for Reducing Hypotension. PMID- 30400679 TI - Clinical correlation between serum pepsinogen level and gastric atrophy in gastric neoplasm. AB - Background/Aims: The relationship between the serum pepsinogen (sPG) level and changes in gastric mucosa has been well studied. Here, we evaluated the usefulness of sPG (I, II, I/II ratio) and intragastric pH as a biomarker of severe gastric atrophy in gastric neoplastic lesions. Methods: A total of 186 consecutive Korean patients with gastric neoplastic lesions underwent endoscopic submucosal dissection (ESD) in this study. The serologic atrophy group had sPG I level <= 70 ng/mL and an sPG I/II ratio <= 3.0. Before ESD, overnight fasting venous blood and gastric juice samples were collected to measure the sPG level and intragastric pH. The degree of gastric atrophy was estimated by endoscopy, and the rapid urease test was performed to investigate Helicobacter pylori infection. Results: Patients who met the criteria of serologic atrophy showed more severe endoscopic atrophic changes (61% vs. 18%, p = 0.000). Older patients and those with more atrophic changes at the gastric upper body demonstrated both a lower sPG I level and a lower PG I/II ratio and more severe endoscopic atrophy. The sPG I/II ratio was the lowest in low grade dysplasia than in high grade dysplasia and early gastric cancer (EGC) (p = 0.015). In addition, patients who tested negative for serologic atrophy and H. pylori showed the lowest intragastric pH (p = 0.000). Conclusions: A low sPG I level and a low I/II ratio were correlated with the severity of gastric atrophy in gastric neoplastic lesions, thus indicating it to be a sensitive biomarker of gastric precancerous lesions or EGC. PMID- 30400680 TI - [Application of image guided system in minimally invasive surgery of nasal endoscopy]. PMID- 30400681 TI - [Precise diagnosis and treatment of chronic rhinosinusitis in children]. PMID- 30400682 TI - [Progress in endoscopic and topical treatment of refractory chronic rhinosinusitis]. PMID- 30400683 TI - [The role of MAPK signaling pathway in the repair of mucosal epithelium in chronic sinusitis with nasal polyps and without nasal polyps]. AB - Objective:To evaluate the differences between CRS and normal subjects and between chronic rhinosinusitis without nasal polys(CRSsNP) and chronic rhinosinusitis with nasal polys(CRSwNP) in the regulation of EGF pathways and the regulating proliferative position of MAPK pathways.Method: We evaluated the proliferation rates of ethmoidal mucosal cells before and after stimulation with EGF,epidermal growth factor receptor(EGFR) kinase inhibitor AG1478, and extracellular signalregulated kinase1/2(ERK1/2) inhibitorPD98059 using MTT assays.We also analyzed the sinonasal epithelial cells collected from control subjects and patients with CRS subtypes CRSsNP and CRSwNP for the expression of ERK1/2,phosphorylated ERK1/2 using western blot analyses.Result:The proliferation rates of sinonasal epithelial cells before and after EGF stimulation were lower in CRS patients than in the controls.AG1478 or PD98059 inhibitor treatment of control epithelial cells did not result in a significant difference in proliferation.Although,AG1478 and PD98059 inhibited the proliferation of CRS cells, the level of proliferation inhibition was markedly different in CRSsNP.AG1478 suppressed the proliferation of CRSwNP epithelial cells, whereas PD98059 had no effect.The ratio of ERK1/2 phosphorylation in CRS cells was lower than that of the control cells.Conclusion:MAPK classical pathway and other pathways might be active at the same time to stimulate epithelial cell proliferation in CRSsNP. When the classical pathway was blocked in CRSwNP, some other pathway could have completely compensated the proliferation. PMID- 30400684 TI - [Efficacy and safety of immunotherapy in dust mites andalternaria multi sensitized allergic rhinitis patients]. AB - Objective:The aim of this study is to evaluate the efficacy and safety of immunosuppression in patients with allergic rhinitis with multiple sensitization of dust mites and Alternaria.Method:An open, label random parallel controlled clinical study was conducted. Sixty dust mites and alternaria multi-sensitized allergic rhinitis patients were enrolled and randomized into immunotherapy group and medication group.Evaluation indicators included symptom scores, medication scores,symptom medication combined scores,RQLQ and serum allergen-specific IgE.In immunotherapy group, side effects were also observed and recorded.Result:After 24 months of treatment, all the scores were significantly lower than baseline,in both immunotherapy group and medication group.The scores of immunotherapy group were significantly lower than those of the medication group. Only local side effects were observed in immunotherapy group,without any systemic side effects and anaphylaxis.Conclusion: Mixed immunotherapy with dust mites and alternaria was effective and safe in allergic rhinitis patients and it had better curative effect than medication. PMID- 30400685 TI - [Long-term efficacy of house dust mite subcutaneous immunotherapy in allergic rhinitis patients]. AB - Objective:This study was aimed to compare the long-term effects of house dust mite (HDM) subcutaneous immunotherapy (SCIT) in a cohort of Chinese pediatric and adult patients with allergic rhinitis (AR).Method:Total of 48 AR patients received standardized HDM-SCIT for 3 years, and they received 3 years of standardized dust mite-specific subcutaneous immunotherapy, followed by 2 years after treatment. Prior to treatment (baseline) and at the end of the 3-year and 5 year treatment periods, all patients were evaluated for total nasal symptom scores(TNSS),total combined score (TCS;symptoms(nasal+ocular)+daily medication score),and rhinoconjunctivitis quality of life questionnaire(RQLQ).Safety of HDM SCIT was assessed according to adverse events reported.Result:Fifteen pediatric and 33 adult AR patients completed the study.HDM-SCIT significantly improved symptoms and RQLQ scores at the 3 rd year and 5th year in both children and adults. Superior efficacy was observed at the 3-year and 5-year timepoints in children compared to adults. The safety of HDM-SCIT was comparable in children and adults with AR.Conclusion:A 3-year course of HDM-SCIT is an effective, safe and sustainable long-term treatment in both pediatric patients and adults with AR, although children appear to achieve better long-term efficacy compared to the adults. PMID- 30400686 TI - [The effect of PM2.5 on mucus secretion and ultrastructureof nasal mucosa in allergic rhinitis model]. AB - Objective:The aim of this study is to the roles of nasal lavage fluid levels of MUC5AC, goblet cell hyperplasia and ultrastructure of nasal mucosa following ambient PM2.5 exposure in a rat model of allergic rhinitis(AR).Method:Female Sprague-Dawley rats were assigned randomly into 3 groups: a negative control group(NC group),an ovalbumin(OVA)-induced AR model group(AR group), and AR model group(ARE group) inhaled to PM2.5 at 200 MUg/m3, 3 h/d, for 30 days. Nasal symptoms, levels of MUC5AC in nasal lavage fluid(NLF), were measured in each individual rat.Goblet cell hyperplasia were examined histologically with PAS stained. Nasal mucosa tissue ultrastructure were observed by scanning electron microscope.Result:PM2.5 significantly increased the number of sneezes, nasal rubs and the amount of nasal secretion in rats with AR.Statistically significant differences in MUC5AC levels and goblet cell hyperplasia were observed between the AR model exposure to PM2.5 and the AR model group.The nasal mucosa of AR model exposure to PM2.5 was disordered,lodged,assembled and twisted.Conclusion:Our data indicate that an increase MUC5AC level in NLF and the development of nasal goblet cell hyperplasia may provide some clues for determining the pathogenic mechanisms of AR by exposure to PM2.5. PMID- 30400687 TI - [Analysis of allergen spectrum and sensitization factors in children with allergic rhinitis]. AB - Objective:The aim of this study is to analyze the distribution of common allergens in allergic rhinitis patients aged 2-15 in Zhangjiagang area,in order to provide a path to know the epidemic features of children with AR, and supports epidemiological materials to find better prevention, diagnosis and treatment for them.Method:From July.2015 to July.2018,1 320 children aged 2-15 who were suspected with allergic rhinitis by the doctors of ENT clinic in the Zhangjiagang Affiliated Hospital,were enrolled in this project.Using the serum specific IgE detection methods to detect common allergens in those patients,then analyze the relationship among allergens and gender,age and visiting time of every single patient.Result:The total positive rate of 1 320 children was 82.50%,and the total positive rate of 8 common inhaled allergens was 82.50%.The main allergens were dust mites and dogs. The total positive rate of Children aged in 7-12 was the highest,and the positive rate of dust mites of male was higher than female.The common food allergens total positive rate was 9.09%.And the top three food allergens were milk,shrimp,crab.The number of visitors in July and August was the most in a year.The dust mite had the highest positive rate among common inhaled allergen in a year,and the maximum value appeared in July.The rate of patients who were allergic to one inhalant allergen were lower than those who were allergic to two or more inhalant allergens.Conclusion:The dust mite is the major allergen above all.The total positive rate of Children aged in 7-12 was the highest,and the positive rate of dust mites of male was higher than female;the maximum value appeared in July and August.The rate of patients who were allergic to one inhalant allergen were lower than those who were allergic to two or more inhalant allergens. PMID- 30400688 TI - [Epidemiological investigation and analysis of allergic rhinitis among 6-12 years old children in Zaoyang City of Hubei Province]. AB - Objective:The aim of this study is to investigate the epidemiological characteristics of allergic rhinitis(AR) among 6-12 years old children in Zaoyang.Method:All the children aged from 6 to 12 years old from 2 primary schools in Zaoyang in June 2018 were randomly selected as the research objects.The AR questionnaire was designed, and the epidemiological investigation was carried out. The results were analyzed by SPSS 20.0 software.Result:The prevalence rate of children aged 6-12 in Zaoyang was 13.7%,the prevalence rate of girls was 11.9%,and the prevalence rate of boys was 15.3%. The prevalence rate of boys was higher than that of girls,but the difference was not statistically significant(chi2=3.033,P>0.05).Univariate analysis showed that the factors related to AR were age(t=2.729,P<0.01), family history of allergic diseases (chi2=172.067,P<0.01),exposure to smoking or dust environment (chi2=43.091,P<0.01),exposure to smoking environment during pregnancy (chi2=6.09,P<0.05) and pet feeding history (chi2=9.473,P<0.01).Conclusion:The incidence of allergic rhinitis among 6-12 years old children in Zaoyang is high,age,family history of allergic diseasese,exposure to smoking or dust environment,exposure to smoking environment during pregnancy,and pet feeding history are risk factors for the incidence of allergic rhinitis in children. PMID- 30400689 TI - [Effect of sublingual dust mite drops on single or multiple allergens allergic rhinitis in children]. AB - Objective:Evaluation of the efficacy of standardized dust mite drops in sublingual immunotherapy(SLIT) for allergic rhinitis in children.Method:A retrospective analysis of 174 children who received SLIT with standardized dermatophagoides farinae drops for 2 years.These patients had been divided into two groups:monoasensitized group(n=61) and polysensitized group(n=113).The total medication score(TMS),total nasal symptoms score(TNSS) and inflammatory factors were evaluated before and after SLIT treatment.Result:1After SLIT treatment for 2.0 year,the TNSS in the monosensitized group is(11.27+/-1.46) and(3.48+/ 1.50),polyasensitized group is (11.54+/-1.50) and (3.59+/-1.56),there are significant difference of TNSS between two groups(P<0.01).But the improvements of the TNSS between the two groups have no significant difference(P>0.05),the monosensitized group is(7.68+/-3.23); polysensitized group is (8.14+/-2.56). 2Two groups of children with TMS before and after treatment were obviously improved, monosensitized group is (1.67+/-0.43) and (0.52+/-0.40),polysensitized group is(1.64+/-0.44) and (0.55+/-0.41). There are significant difference of TMS between two groups(P<0.01).But the improvements of the TMS between the two groups have no obvious difference(P>0.05),the monsensitized group is(1.16+/-0.61); polysensitized group is(1.28+/-0.55).3Specific IgG4 serum is increased after treatment(P<0.01).4After immunotherapy,the expression of IL4 and IL-17alpha is down?regulated, IL-2 and TGF-beta1 is up-regulated.Conclusion:1Dust mites under the SLIT,can significantly improve the monosensitized and polyasensitized allergic children nasal symptoms,reduce the drug use, and two groups have the equivalent effect.2Dust mite drops SLIT,can be used to the monosensitized and polyasensitized allergic children.3The rise of dust mites specific IgG4 can be used as immunotherapy effective predictors.4After immunotherapy, Thl/Th2 /Thl7 and Treg can be re?balanced. PMID- 30400690 TI - [Psychoacoustic and clinical features of patients with idiopathic tinnitus]. AB - Objective:The aim of this study is to explore the psychoacoustic and clinical features of patients with idiopathic tinnitus, to understand the relationship and regularity between tinnitus frequency, loudness and hearing loss, and to provide a basis for personalized diagnosis and treatment of tinnitus.Method:A total of 110 patients with idiopathic tinnitus underwent systematic otological professional examination,audiological examination, tinnitus refinement examination, medical history inquiry and tinnitus disability scale(THI) survey.Result:Tinnitus more frequently occurred between 20 to 60 years of age(95.45%),a significant decrease in people under the age of 20 and over the age of 60;67 cases(60.9%) of the tinnitus frequency were completely consistent with the maximum frequency of hearing loss, The Pearson test showed that tinnitus frequency was correlated to frequency of hearing loss (r=0.989,P<0.05).Tinnitus loudness pitch results are mostly concentrated between 40-60dBSL, The Pearson test showed that tinnitus loudness was correlated to hearing loss(r=0.932,P<0.05);The total effective rate of sound therapy was 67.3%,There was a correlation between Residual inhibition and sound therapy(r=0.438,P<0.05); No statistic difference was found between THI scores and Tinnitus duration (r= 0.047,P>0.05).Conclusion:There was a correlation between tinnitus pitch and hearing loss.Residual inhibition may indicate the effectiveness of the sound therapy and may affect the patient's THI score. Full Precision Test can provide clinical reference for early detection of hearing loss in tinnitus patients. PMID- 30400691 TI - [Clinical analysis of 42 cases of nasal natural killer/T-cell lymphoma prominently presenting as ocular symptoms]. AB - Objective:To investigate the clinical features and prognosis of nasal natural killer/T-cell lymphoma(NKTL) with obvious ocular symptoms.Method:We retrospectively analyzed the clinical data of 42 patients with nasal NKTL who prominently showed eye symptoms and were treated from January 2011 to December 2017.Result:After treatment,the patients received complete remission(CR) in 19 cases and partial remission(PR) in 9 cases. The total effective rate was 66.67%.Median follow?up time was 39 months and 18 patients died.In this study, there was no correlation between sex and prognosis(P>0.05).Age>60 years was not related to the prognosis of the patients(P>0.05).The 3-year survival rate of patients treated with radiotherapy and chemotherapy was higher than that of patients treated with radiotherapy or chemotherapy alone(73.3%, 16.7%,P<0.01). The 3-year survival rate of patients with B symptoms was 41.7%, which was not related to prognosis(P>0.05).The prognosis of EBV-DNA positive patients was poor(P<0.01). Twenty-six patients with stage I and II had a better prognosis(P<0.01). Patients with international prognostic index(IPI) <=1 had a better prognosis than those with IPI>=2(83.3 %, 37.5%,P<0.01).Conclusion:Nasal NKTL lymphomas with prominent ocular symptoms are difficult to diagnose early and easy to be misdiagnosed. Clinicians should make a definite diagnosis by pathological biopsy and immunohistochemistry as soon as possible, and assist in diagnosis by EBER in situ hybridization if necessary. PMID- 30400692 TI - [Clinical diagnosis and treatment of adenoid cystic carcinoma of the external auditory canal]. AB - Objective:To discuss the clinical diagnosis, therapies and prognosis of adenoid cystic carcinoma of external auditory canal.Method:Eleven patients with adenoid cystic carcinoma of external auditory canal, who had been admitted to West China hospital, Sichuan university from April 2009 to October 2015 were recruited and a retrospective analysis was performed.Result:All the 11 patients were treated with surgery except one elderly with T1 stage who was only treated with radiotherapy(RT),1 of the 10 patients treated with surgery were added on radiotherapy after surgery. Following up for 12-104 months,the patient who was treated with RT alone has survived with carcinoma for 51 months by now,among the remainder stage T1 patients,one was reoperated for local recurrence 95 months after surgery, and therefore survived without recurrence.The other 2 patients all survived with free-disease;in the stage T2 patients,one was lost to follow-up after identified local recurrence with pulmonary masses 12 months after surgery, another one committed suicide because of family problems 56 months after operation,and the other one survived without recurrence for 57 months after surgery; the stage T3 patient survived without recurrence for 26 months at present;in the T4 patients, one died after gamma knife therapy for local recurrent disease with brain metastasis 22 months after surgery, another one died from pulmonary metastasis 17 months after surgery,and the other one survived without recurrence for 56 months.Conclusion:Adenoid cystic carcinoma of external auditory canal is a rare disease with high misdiagnosis rate and progresses slowly.Surgery is the preferred therapy.The prognosis is closely related to disease clinical stage at presentation type of pathology and surgical approaches. Adenoid cystic carcinoma of external auditory canal is characteristically susceptible to local recurrence and distant metastasis,inaddition to routine re exam of ear,the patients should be reviewed carefully to exclude of pulmonary,brain and kidney metastasis during follow-up. PMID- 30400693 TI - [Clinical characteristics of allergic rhinitis allergen spectrum in Gannan area]. AB - Objective:To study the clinical features of common allergens in patients with allergic rhinitis in Gannan area and provide reference for the prevention,diagnosis and treatment of allergic rhinitis with regional character.MethodThe clinical data of 363 patients who were newly diagnosed with allergic rhinitis and given allergen skin prick test(skin prick test,SPT)at our department from August 2012 to May 2016 were analyzed retrospectively.SPSS 18?0 was used to ananlyze the data.Result:Two hundred and fifty-two cases of allergen skin prick test were positive.The positive rates of allergens were 86.90% of house dust mites,86.11% of dust mites,51.19% of cockroach,14.29% of hair fungus,4.76% of crab meat and 3.17% of shrimp.The positive rate of various allergens in the children group was 93.24% for dust mites,91.89% for house dust mites,44.59% for cockroach,8.11% for crab meat,6.76% for shrimp,and 1.35% for hair fungus.The difference in positive rate of allergens among different age groups was statistically significant(P<0.01),among which the highest was 2 to 14 years old,which was 90.24%;the lowest was >44 to 74 years old,which was 31.70%.The difference in positive rates of allergens among different occupations was statistically significant(P<0.01),among which the highest was 86.45% for students,and the lowest was 45.24% for those without employment.There was no significant difference in the positive rate of allergens between different seasons.ConclusionThe most common allergens in Gangnan area are house dust mites,dust mites cockroache and scrab meat.Patients with allergic rhinitis are more common with multiple allergens.Age and occupation are also factors affecting the positive rate of allergens. PMID- 30400694 TI - [The diagnosis and treatment of cervical bronchogenic cysts in children pediatric]. PMID- 30400695 TI - [Acute sinusitis in children with severe intracranial complications: two cases report]. AB - In the past year, two cases of acute rhinosinusitis have been treated in our department. The intracranial complications of acute sinusitis in children are rare in recent years,which is associated with the low immunity of children,and the untimely treatment of acute infection.The combination of CT and MRI examination can determine the type,scope,location of intracranial complications of acute sinusitis in children with acute sinusitis.Imaging examination is the key to diagnosis intracranial complications of acute rhinosinusitis.Surgical removal of lesions,combing with using sensitive antibiotics,can increase the cure rate of patients. PMID- 30400696 TI - [International consensus on the treatment of pediatric otitis media with effusion and current status of treatment in China]. AB - International consensus on the treatment of pediatric otitis media with effusion and current status of treatment in China Summary Otitis media with effusion (OME) is a non-suppurative inflammatory disease of the middle ear characterized by middle ear effusion and hearing loss, which is common in children.The main impact of OME in children is hearing loss and cooccurring recurrent acute otitis media, which would affect speech language development. Thus OME should be highly vigilant and prompt treatment is necessary. There have been many guidelines and evidence-based medicine research on the diagnosis and treatment of OME in children. But there is still no unified conclusion. International Federation of Otorhinolaryngological Societies Congress(IFOS) published an international consensus on the diagnosis and treatment of OME in children in 2017 to promote the standardized diagnosis and treatment of the disease. The guidelines suggest that gastroesophageal reflux and allergy should be routinely evaluated in children with OME. Children should be routinely evaluated by hearing tests. Steroids, antibiotics, and decongestants are not recommended because they have no evidence of definite efficacy and could cause side effects. Patients with ineffective conservative treatment should undergo myringotomy, and children over 4 years old should also consider adenoidectomy. PMID- 30400697 TI - [The role of Th9 and other IL-9 producing cells in allergic asthma]. AB - The incidence of allergic asthma has been increasing year by year. It is estimated that there are more than 300 million illnesses. It is associated with increased IgE, mast cell activation, airway hyperreactivity, excessive mucus production, and airway remodeling. The traditional view is that allergic asthma is associated with allergic reactions involving T helper type 2 (Th2) cells. Recent studies have found that different subsets of CD4+ T cells (Th17, Th9) as well as innately immunized cells such as mast cells and innate lymphocyte type 2 (ILC2s) are able to produce cytokine IL-9, leading to asthma. Th9 cells develop from nave T cells to IL-9 producing cells in the presence of IL-4 and TGF-beta. IRF4, GATA3, a basic leucine zipper transcription factor, several transcription factors downstream of BATF and IL-4 such as signal transduction and STAT6 activated NFAT are activated. In addition, the transcription factor PU.1 downstream of TGF-beta signaling appears to be also critical for the development of Th9 cells. IL-9 is a pleiotropic cytokine that affects the function of different target cells such as T cells, B cells, mast cells and airway epithelial cells by activating STAT1, STAT3 and STAT5. Due to its versatility, IL-9 has been shown to be involved in several diseases such as cancer, autoimmunity and other pathogen?mediated immunomodulatory diseases. This article reviews the role of Th9 and IL-9?producing cells in allergic asthma. PMID- 30400698 TI - [The research progress of laryngotracheal stenosis in children]. AB - Children's laryngotracheal stenosis is the formation of laryngotracheal scar tissue caused by congenital or acquired factors, resulting in a narrow respiratory tract,which affects breathing. With the development of intensive care,tracheal intubation is widely used in premature infants and critically ill children.Therefore,the incidence of laryngotracheal stenosis in children has increased year by year.Children often need multiple steps of operations, poor surgical tolaerance, seriously affecting the quality of life of the whole family. This article summarizes the classification, etiology,clinical manifestations,diagnosis and treatment progress of children with laryngotracheal stenosis. PMID- 30400700 TI - Relationship between Health Behaviors and Marital Adjustment and Marital Intimacy in Multicultural Family Female Immigrants. AB - Background: This study analyzed the relationship between health behaviors and marital adjustment in multicultural couples to evaluate their health status. Methods: Married couples (70 Korean men and their immigrant wives) completed a structured interview on health behaviors and sociodemographic factors, the Revised Dyadic Adjustment Scale (RDAS), and the Marital Intimacy Scale. Based on the cutoff value of the RDAS, respondents were classified into two groups: high or low dyadic adaptation groups. The collected data were compared with health behavior regarding smoking, alcohol consumption, exercise, and weight. Results: The odds ratio (OR) (95% confidence interval [CI]) by logistic regression with adjustment for age, educational level, career, occupation, length of residence in Korea, nationality, religion, age difference between couple, number of children, monthly income, and proficiency in Korean was 1.279 (1.113-1.492) for unhealthy exercise and 1.732 (1.604-1.887) for unhealthy body weight in female immigrants with low marital adjustment. In Korean husbands with low marital adjustment, the OR (95% CI) was 1.625 (1.232-2.142) for smoking and 1.327 (1.174- 1.585) for unhealthy exercise. No significant relationship was found between marital intimacy and health behaviors in female immigrants or Korean husbands. Conclusion: More desirable health behaviors were observed in highly adapted couples. Therefore, family physicians should be concerned with marital adjustment and other associative factors to evaluate and improve multicultural couples' health status. PMID- 30400701 TI - [Current opinions on the diagnosis and intervention of adenoid cystic carcinoma in external auditory canal]. PMID- 30400699 TI - Association of Geriatric Syndromes with Urinary Incontinence according to Sex and Urinary-Incontinence-Related Quality of Life in Older Inpatients: A Cross Sectional Study of an Acute Care Hospital. AB - Background: Geriatric syndromes are associated with morbidity and poor quality of life (QOL). Urinary incontinence (UI) is one of the most prevalent geriatric syndromes. However, there is little research on the association of UI and UI related QOL with other geriatric syndromes. We investigated the relationship between geriatric syndromes and UI according to gender and UI-related QOL among older inpatients. Methods: This study was conducted among 444 older inpatients (aged 65 years and older) between October 2016 and July 2017. We examined geriatric syndromes and related factors involving cognitive impairment, delirium, depression, mobility decline, polypharmacy, undernutrition, pain, and fecal incontinence. UI-related QOL was assessed using the International Consultation on Incontinence Questionnaire-Short Form. Multiple logistic regression analysis was used to evaluate these associations. Results: Geriatric syndromes and related factors were associated with UI. Mobility decline (odds ratio [OR], 4.16; 95% confidence interval [CI], 2.29-7.56), polypharmacy (OR, 3.35; 95% CI, 1.89-5.92), and pain (OR, 6.80; 95% CI, 3.53-13.09) were related to UI in both genders. Especially, delirium (OR, 7.55; 95% CI, 1.61-35.44) and fecal incontinence (OR, 10.15; 95% CI, 2.50-41.17) were associated with UI in men, while cognitive impairment (OR, 4.19; 95% CI, 1.14-15.44) was significantly associated with UI in women. Patients with depression were more likely to have poor UI-related QOL (OR, 8.54; 95% CI, 1.43-51.15). Conclusion: UI was associated with different geriatric syndromes and related factors according to gender. Care for patients with depression, related to poor UI-related QOL, should be considered in primary care to improve the UIrelated QOL of these individuals. PMID- 30400702 TI - [Endoscopic ear surgery: flash in the pan or transformative innovation? (II)]. PMID- 30400703 TI - [A preliminary study of a modified transnasal endoscopic three step vidian neurectomy]. AB - Objective:The aim of this study is to explore an improved trans-nasal endoscopic surgical approach for vidian neurectomy. Method:Ninety-one patients with nasal hyperreactive disease were collected, including 49 cases of allergic rhinitis and 42 cases of non allergic rhinitis. All sufferers enrolled in the study have treated with medicine, but the symptoms were not effectively controlled. Preoperative CT localization of the vidian canal was performed in each candidate. During the surgery a"Three-step" surgical approach were followed under endoscopic guidance in accordance with the operation procedures. Briefly, such a three-step procedure consists of the following, that is, a transnasal endoscopic sphenoidectomy through sphenoethmoidal recess as step one, with enlargement of the sinus ostium along the junction of the anterior wall and the floor of the sinus until the exposure of the vidian nerve canal toward the lateral wall of the sinus as step two. The last step was further exposure of the vidian nerve going through the canal and electric cautery preventing bleeding from the neurovascular bundle in the canal. Result:All patients were completed successfully with 100% preoperative CT location of the vidian canal in the CT scan and 100% intraoperative accurate exposure of the canal and therefore the cut of the vidian nerve. Conclusion:"Three-step" endoscopic resection of the vidian neurectomy is easy to master and repetitive with less injury. PMID- 30400704 TI - [The analysis of serum allergen spectrum in 0-12 years old children with allergic diseases in Liaoning Province]. AB - Objective:To explore the distribution and characteristics of allergens in children aged 0-12 years old in liaoning province. Method:46 620 children with suspected allergic diseases were grouped according to age, sex and detection time. Then allergen detections were conducted. The distribution of allergen in different groups was analyzed. Result:Most children were sensitized to single allergen, followed by a double positive. 98.08% children showed sensitivities to up to five kinds of allergen. The allergen spectrum of patients in different age groups was slightly different. With the increase of age, the rate, degree and number of allergen positive are generally on the rise. The positive rate and degree of each allergen were statistically significant in different age groups, seasons and genders, but not the trend and degree of variation. The onset time in this region is relatively concentrated in July to September, and the incidence of allergen in summer and autumn is higher than that in winter and spring. Conclusion:In Liaoning Province, household dust mites, animal dander, egg white, milk are the main allergens in patients with allergic disease, and the onset time is relatively concentrated in summer and autumn. Clear the main allergens, the region characteristic and changing trend is conducive to the treatment of allergic disease take effective and preventive measures. PMID- 30400705 TI - [Clinicopathological features and treatment outcome of 37 cases of primary thyroid lymphoma]. AB - Objective:The aim of this study is to explore the clinicopathological features and treatment outcome of primary thyroid lymphoma(PTL). Method:Clinicopathological data of 37 cases of PTL were retrospectively reviewed, and analyzed in combined with follow?up data. Result:Of the 37 patients, Hashimoto's disease was diagnosed in 28(75.7%) patients. The diagnostic rate of preoperative fine needle biopsy (75%) was higher than the fine needle aspiration (53%). The pathological types of these patients included diffuse large B cell lymphoma(n=23), extranodal marginal zone lymphoma of mucosa?associated lymphoid tissue type (MALT) (n=10), follicular lymphoma(FL) grade 3 (n=3) and burkitt lymphoma(BL) (n=1). According to Ann Arbor staging system, 12 patients with stage IE, and 25 patients with stage IIE. With a median follow?up period of 37 months (2-93 months), the 3?year overall survival (OS) rate and progression free survival(PFS) was 87.0% and 81.6%, and 5?year overall survival(OS) rate and PFS was 79.8% and 74.8%. Univariate survival analysis found that comprehensive treatment was an important factor affecting prognosis, but there was no statistical difference in the effects of age, gender, lactate dehydrogenase, level, beta2 microglobulin, Ann Arbor staging, international prognostic index, and tissue subtype on survival (P>0.05). Conclusion:PTL mostly affects middle aged and old female and has a favorable prognosis. Core needle biopsy can improve the diagnostic rate when compared with fine needle aspiration. The optimal treatment is combined modality strategy based on chemotherapy and radiotherapy, and supplemented by surgery. PMID- 30400706 TI - [Association between subjective nasal patency and airflow characteristics of nasal cavity on nasal septum deviation]. AB - Objective:To investigate the pre- and post-operative intranasal airflow characteristics on nasal septum deviation and the correlation between subjective nasal patency and airflow characteristics by numerical simulation. Method:Forty two nasal septum deviation cases were enrolled in this study. Pre- and post operative VAS score of subjective nasal patency were recorded. We created computational fluid dynamics (CFD) nasal cavity airway models based on computed tomography and investigated the pre- and post-operative intranasal airflow characteristics. Result:Postoperative subjective nasal patency on patients with septal deviation showed significant improvement than preoperative (P<0.01). The intranasal airflow on deviated side nasal cavity increased from preoperative (34.94+/-14.82)% to postoperative (47.67+/-3.58)% (P<0.01). The parameters of DeltaP(anterior inferior turbinate),DeltaT(anterior inferior turbinate) and DeltaT(posterior end of the septum)decreased significantly from preoperative (7.657+/-4.839)Pa to postoperative (4.500+/-2.403)Pa,preoperative (8.482+/ 1.767)K to postoperative (7.096+/-1.127)K,and preoperative (11.386+/-0.505)K to postoperative (10.895+/-0.736)K respectively ?(P<0.01).? The value of NR1 decreased from (0.043+/-0.021) Pa*s/ml to (0.038 0+/-0.016) Pa*s/ml, showed statistically significant difference (P<0.05), but the value of NR2 decreased from (0.071 0+/-0.035)?Pa*s/ml? to (0.061 5+/-0.048) Pa*s/ml, showed no statistically significant difference (P>0.05). The related degree of subjective nasal patency VAS score on DeltaT(anterior inferior turbinate) and intranasal airflow of deviated side nasal cavity are higher (R2=0.619 6 and ?R2=0.508 7)than DeltaP(anterior inferior turbinate)and NR2(R2=0.326 7 and ?R2=0.298 1).It suggested that there is no correlation between subjective nasal patency VAS score and DeltaT(posterior end of the septum),NR1 (R2=0.0451 and ?R2=0.0721). Conclusion:It showed different pressure and temperature gradient in bilateral nasal cavity of nasal septal deviation. The septoplasty improved the patient's feeling of subjective nasal patency, and recovered the balance of the airflow distribution on bilateral nasal cavity. By correlation analysis, we concluded that nasal resistance could not represent the severity of subjective nasal patency, but the intranasal airflow showed good correlations with subjective nasal patency, especially the temperature drop in mucous membrane at the nasal front end is more sensitive to reflect subjective nasal patency feeling. PMID- 30400707 TI - [Meta-analysis of voice outcomes after steroid injection on benign vocal fold lesions]. AB - Objective:The aim of this study is to perform a meta-analysis of vocal changes after vocal cord steroid injection (VFSI) in the treatment of benign lesions. Method:Pubmed, Embase, CNKI and Wanfang database were searched using the keywords. A total of 7 articles were characterized based on our keyword search. The chi-square-based I2 statistic test was employed to assess the between-study heterogeneity. Additionally, random effects models were used to calculate mean differences with 95% confidence intervals. Result:A total of 344 cases were included in 7 literatures. Meta-analysis demonstrated a significant increase in maximal phonation time(MPT) and decrease Jitter after VFSI.The index and amplitude perturbations were not statistically significant before and after hormone injection. Conclusion:Our results support that VFSI has advantages in terms of voice quality. However, we need more studies with longer follow-up periods to validate our findings. PMID- 30400708 TI - [The relationship between the changes of serum NGF, HO-1, IL-1 beta and cognitive function in patients with severe OSAHS after comprehensive treatment]. AB - Objective:To explore the relationship between the levels of serum nerve growth factor(NGF), hemeoxygenase 1(HO-1),interleukin-1 beta (IL-1beta) and cognitive function in OSAHS patients. Method:the levels of serum NGF, HO-1 and IL-1beta concentrations in 60 severe OSAHS patients were measured before and after treatment, and the Montreal cognitive score (MoCA), AHI and the LSaO2 were also recorded. Result:1OSAHS patients have serum NGF decreased and serum HO-1, IL 1beta increased.2In severe OSAHS patients the AHI was negatively correlated with NGF (r=-0.648), positively correlated with HO-1 (r=0.695), and positively correlated with IL-1beta(r=0.616).3The MoCA value was positively correlated with NGF (r=0.663), negatively correlated with HO-1 (r=-0.614), and negatively correlated with IL-1beta(r=-0.346).4After half a year of follow-up, the AHI and Serum HO-1 and IL-1beta were significantly decreased, while the MoCA values and serum NGF were significantly increased after treatment. Conclusion:1Severe OSAHS patients have cognitive impairment.2The changes of serum NGF, HO-1 and IL-1beta may be related to the changes of cognitive function in OSAHS patients. 3Comprehensive treatment can improve the patient's LSaO2,reduce AHI, and improve the cognitive function.4Regular monitoring the concentration of serum NGF, HO-1, and IL-1beta may be helpful to assess the patient's condition and recovery. PMID- 30400709 TI - [Mutation analysis and early pregnancy prenatal diagnosis for two families affected with non-syndromic hearing loss]. AB - Objective:The aim of this study is to identify the pathogenic genes of two non syndromic hearing loss families, provide accurate genetic counseling and early pregnancy prenatal diagnosis services for second birth families, which determine the genotype of the fetus, early diagnosis and early intervention to prevent the birth of deaf children. Method:Two families with a severe sensorineural hearing loss were enrolled in this study. Genomic DNA was extracted from the peripheral venous blood of the proband and parents. The mutations of the four hearing loss susceptibility genes were analyzed by the hereditary hearing loss gene detection kit (PCR reverse hybridization) and Sanger sequencing. After confirming the genotype of the subject, the genotype of the fetus was examined for the fetus with 10 to 12 weeks of gestation, and the neonates were diagnosed with prenatal diagnosis. Result:In the two families, the No. 1 family proband was the compound heterozygous mutation of SLC26A4 gene c.IVS7?2A>G/c.2177insCTAT, and parents were carriers. The prenatal diagnosis showed that the fetal genotype of No. 1 family was a compound heterozygous mutation, and the fetus was not born. The No. 2 family proband genotype was the compound heterozygous of GJB2 gene c.605ins46/c.512insAACG, and the parents were both carriers. The No. 2 family, the prenatal diagnosis showed the fetal genotype of No. 2 family GJB2 gene sequence was normal, the newborn passed the hearing screening. Conclusion:Genetic testing of hereditary hearing loss combined with prenatal diagnosis plays a significant role in guiding deaf children with re-fertility needs, especially prenatal diagnosis in early pregnancy, which can achieve early diagnosis, early detection and early intervention, effectively reducing the birth rate of children with deafness. PMID- 30400710 TI - [Differentiation of naive T cells into Th2 cells induced by nuocyte cells in mice with allergic rhinitis]. AB - Objective:The aim of this study is to examine whether nuocytes induced differentiation of primary T cells into Th2 cells in AR mice in vitro. Method:A murine model of AR on the background of BALB/c was established using ovalbumin, and nuocytes were sorted and purified from the mouse nasal associated lymphoid tissue (NALT) and cultured in vitro. Then, we assessed the expression of IL-4 in these cells. Mouse peripheral blood mononuclear cells were isolated and Th2 cells and T cells were isolated for in vitro culture, and the percentage of T cells in Th2 cells was detected. Then, NALT-derived nuocyte cells cultured in vitro were added to the above-mentioned mouse T cell culture medium for co-culture. Result:Numbers of sneezing, nasal rubbing and eosinophils in nasal lavage fluid were all enhanced in AR mice compared to normal ones. We used flow cytometry analysis to identify nuocytes from mice NALT as CD3CD4CD8CD19CD11bCD11cFcepsilonR1 (lineage)-ICOS+, and also found that the cells expressed IL-4, and its protein and mRNA were all increased in AR mice versus normal mice. After nuocytes were co-cultured with T-cell cultures, we determined the percentage of Th2 cells in total T cells, and found that the percentage was increased significantly. Conclusion:nuocyte cells may induce the differentiation of primary T cells into Th2 cells in AR mice through IL-4 pathway. PMID- 30400711 TI - [Clinical observation on specific immunotherapy of allergic rhinitis with artemisia pollen]. AB - Objective:The aim of this study is to observe the clinical efficacy of pollen specific immunotherapy with Artemisia in allergic rhinitis. Method:A total of 139 patients with allergic rhinitis who were positive for Artemisia pollen were selected for allergen skin pricking. All of them were treated with Artemisia pollen-specific immunotherapy. The patients were followed-up for 3 months, respectively before treatment (N), after treatment start interval. 3 months (D1, D2, D3) follow?up fill in the total score of nasal symptoms (TNSS), visual analogue scale (VAS) score, olfactory function grading, ocular symptom score (TOSS) and rhinoconjunctivitis quality of life questionnaire (RQLQ) )score. Result:TNSS:N>D1,N>D2,N>D3,D1,D2,D3 two of the three compared to no difference.VAS:N>D1,N>D2,N>D3,among D1,D2,D3, two of the three compared to no difference. Olfactory function classification:N>D1,N>D2,N>D3,among D1,D2,D3, two of the three compared to no difference.TOSS:N>D1,N>D2,N>D3,among D1,D2,D3,D1>D2,the rest had no difference. RQLQ: N>D1, N>D2, N>D3, D1>D2, D3>D1, D3>D2. Conclusion:The specific pollen immunotherapy of artemisia is effective in the treatment of allergic rhinitis, and the symptoms are obviously improved. PMID- 30400712 TI - [The morphplogical and its influencing factors research after supracricoid partial laryngectory with cricohyoidoepiglottopexy]. AB - Objective:The aim of this study for observing laryngeal morphology, and motion characteristics after supracricoid partial laryngectomy with cricohyoidoepiglottopexy(SCPL-CHEP),exploring the relevant factors affecting the morphology of new laryngeal. Method:Choose 46 cases of patients with laryngeal cancer for SCPL-CHEP as the object of study, dynamic laryngoscope were performed in all the patients, to observe the movement of laryngeal pronunciation (neoglottis closure , supraglottic situation) . Combined with the patient's clinical data, the relevant factors that may affect the pronunciation and movement characteristics of the new throat were analyzed. Result:46 patients after SCPL-CHEP were included in the study. The neoglottis completely closed in 31 cases (67.4%), insufficiency closed in 15 cases (32.6%). Supraglottic vibration in 33 cases (71.7%), 13 cases (28.3%) of supraglottic structure vibration free.The Spearman 's analysis showed that, neoglottal closure status was positively correlated with age and subglottic lesions (r=0.313, P=0.034; r=0.592, P=0.000), and negatively correlated with the postoperative time (r= 0.446, P=0.002). The supraglottic vibration was negatively correlated with postoperative radiotherapy. Conclusion:The anatomy of neolarynx changes greatly,the function of neolarynx only depends on the movement of he remaining cricoarytenoid unit and arytenoid mucosa vibration. The age, tumor type, and postoperative time are related factors that affect glottic closure. Postoperative radiotherapy can reduce the occurrence of supraglottic vibration. PMID- 30400713 TI - [Two cases of tracheotomy in children's tracheobronchial foreign body misdiagnosis]. PMID- 30400714 TI - [A case of esophageal tracheal fistula caused by button cell]. AB - Summary Button batteries are a common emergency in children with esophageal foreign bodies, which need to be removed in time,otherwise serious complications will occur. This article reports a case of esophageal tracheal fistula caused by button cell. It is helpful for differential diagnosis and clinical treatment of esophageal foreign bodies in children caused by button cell. PMID- 30400715 TI - [One case of the infratemporal fossa hydatid invading maxillary sinus]. AB - Summary Male, 43 years old, Tibetan. Main reason: left eyesight impaired for one month. Nasal sinus CT: the 47 mm*44 mm cystic low density shadows can be seen in the left infratemporal fossa, the maxillary sinus cavity reduced under the pressurebase. The patient had the internal and external nasal endoscopic sinus resection of the left fossa.The patient's left eye sight recovered after the operation.Two weeks after the operation, the sinus was re-examined for CT, showing that the left inferior fossa was removed, but there was no significant difference in the maxillary sinus structure. Sixteen months after the operation, the CT showed that the left maxillary sinus is back to normal after absorbing the bone tissue. PMID- 30400716 TI - [A contemporary review of the surgical margins in laryngeal carcinoma]. AB - Summary Laryngeal squamous cell carcinoma is a common malignant tumor of the head and neck. Although the treatment methods and concepts have changed, surgery is still an important treatment for laryngeal cancer. Most studies have shown that the state of the margin of laryngeal surgery is closely related to the patient's ?recovery. ?However, in clinical practice, different doctors often have inconsistent grasping of the margin distance in laryngeal cancer surgery. On the one hand, it may be because the surgeon is on the throat. The characteristics of the margin of cancer are not well understood. On the other hand, the confusion of the concept of the margin and the complexity of the margin of laryngeal cancer may be more important reasons. For example, different terms related to margins are used in English literatures. Therefore, this article reviews the concept, acquisition, evaluation and cutting?edge research of laryngeal surgical margins to improve the standardization of clinical laryngeal surgical margin assessment and promote the in-depth development of related research. PMID- 30400717 TI - [The role of zinc finger protein A20 in airway allergic diseases]. AB - Summary Zinc finger protein A20 is a key negative regulator of NF-kappaB, which plays an important role in regulating immune and inflammatory responses. Recent studies have shown that A20 is involved in the development of airway allergic diseases.This article aims to review the structure, biological functions of A20 and its main pathways for inhibiting the activation of NF-kappaB signaling pathway, and the role of A20 in airway allergic diseases. Further studies will provide new strategies for the prevention and treatment of allergic diseases. PMID- 30400718 TI - [The study of the nitric oxide monitoring in airway allergic diseases]. AB - Summary Airway allergic disease is a chronic non?infectious airway disease characterized by allergic airway inflammation and hyperresponsiveness. In recent years, the incidence of allergic diseases has increased year by year, and the pathogenesis is complex and not clear, which seriously affected the quality of life of patients and has become a global health problem that needs to be solved urgently. In recent years, scholars at home and abroad believe that the concentration of nitric oxide (NO) in oral and nasal exhaled can be used as an objective indicator to reflect the severity of upper and lower airway inflammation, and is a novel biomarker for noninvasive airway inflammation. This article reviews the clinical application of NO monitoring in allergic diseases and its research progress. PMID- 30400720 TI - Statistics for Immunologists PMID- 30400721 TI - Insulin Resistance Is Associated with Early Gastric Cancer: A Prospective Multi Center Case Control Study. AB - Background/Aims: Recently, increased body weight has been found to be associated with an increasing risk of several cancers, including gastric cancer. The true pathogenic role of hyperglycemia in the development of gastric cancer remains unclear as hyperglycemia and its associated conditions may work as carcinogenic factors. The goal of the study was to clarify the factors associated with early gastric cancer and evaluate a homeostasis model assessment of the insulin resistance (HOMA-IR) index, fasting glucose, and lipid profile as predictors of early gastric cancer. Methods: A total of 63 patients with early gastric cancer between November 2012 and March 2013 were included. Preoperative serum lipid profile levels and serum fasting glucose were examined prospectively in patients with early gastric cancer. The same number of controls were evaluated and matched to the early gastric cancer group for age and gender. We performed multivariate logistic regression analysis to identify independent risk factors for early gastric cancer. Results: Univariate analysis showed that risk for early gastric cancer was associated with diastolic blood pressure (BP), total cholesterol, fasting glucose, and HOMA-IR. In the multivariate-adjusted model, higher total cholesterol, fasting glucose, body mass index, and diastolic BP were strongly associated with an increased risk of early gastric cancer. Conclusions: Hyperglycemia, a lower high-density lipoprotein cholesterol level, and a low HOMA IR level appear to be associated with early gastric cancer risk. PMID- 30400722 TI - Statin Exposure Is Not Associated with Reduced Prevalence of Colorectal Neoplasia in patients with Inflammatory Bowel Disease. AB - Background/Aims: Statins have been postulated to lower the risk of colorectal neoplasia. No studies have examined any possible chemopreventive effect of statins in patients with inflammatory bowel disease (IBD) undergoing colorectal cancer (CRC) surveillance. This study examined the association of statin exposure with dysplasia and CRC in patients with IBD undergoing dysplasia surveillance colonoscopies. Methods: A cohort of patients with IBD undergoing colonoscopic surveillance for dysplasia and CRC at a single academic medical center were studied. The inclusion criteria were IBD involving the colon for >8 years (or any colitis duration if associated with primary sclerosing cholangitis [PSC]) and at least two colonoscopic surveillance exams. The exclusion criteria were CRC or high-grade dysplasia (HGD) prior to or at enrollment, prior colectomy, or limited (<30%) colonic disease. The primary outcome was the frequency of dysplasia and/or CRC in statin-exposed versus nonexposed patients. Results: A total of 642 patients met the inclusion criteria (57 statin-exposed and 585 nonexposed). The statin-exposed group had a longer IBD duration, longer follow-up period, and more colonoscopies but lower inflammatory scores, less frequent PSC and less use of thiopurines and biologics. There were no differences in low-grade dysplasia, HGD, or CRC development during the follow-up period between the statin-exposed and nonexposed groups (21.1%, 5.3%, and 1.8% vs 19.2%, 2.9% and 2.9%, respectively). Propensity score analysis did not alter the overall findings. Conclusion: In IBD patients undergoing surveillance colonoscopies, statin use was not associated with reduced dysplasia or CRC rates. The role of statins as chemopreventive agents in IBD remains controversial. PMID- 30400719 TI - Multiple myeloma: 2018 update on diagnosis, risk-stratification, and management PMID- 30400723 TI - Treatment Outcome and Renal Safety of 3-Year Tenofovir Disoproxil Fumarate Therapy in Chronic Hepatitis B Patients with Preserved Glomerular Filtration Rate. AB - Background/Aims: To investigate the treatment efficacy and renal safety of long term tenofovir disoproxil fumarate (TDF) therapy in chronic hepatitis B (CHB) patients with preserved renal function. Methods: The medical records of 919 CHB patients who were treated with TDF therapy were reviewed. All patients had preserved renal function with an estimated glomerular filtration rate (eGFR) of at least 60 mL/min/1.73 m2. The therapeutic efficacy and renal safety, in addition to their associated factors, were assessed using clinical and laboratory parameters. Results: A total of 426 patients (184 treatment-naive and 242 treatment-experienced) were included for analysis. A virologic response (VR) was defined as achieving an undetectable serum hepatitis B virus (HBV) DNA level, and the overall VR was 74.9%, 86.7%, and 89.4% at the 1-year, 2-year, and 3-year follow-ups, respectively. The treatment outcome was favorable in both the treatment-naive and treatment-experienced groups, without significant differences between the two groups. Achieving a VR was not influenced by previous treatment experience, TDF combination therapy, or antiviral resistance. In a multivariate analysis, being hepatitis B e antigen positive at baseline and having a serum HBV DNA level >= 2,000 IU/mL at 12 months were associated with lower VR rates during the long-term TDF therapy. The overall renal impairment was 2.9%, 1.8%, and 1.7% at the 1-year, 2-year, and 3-year follow-ups, respectively. With regard to renal safety, underlying diabetes mellitus (DM) and an initial eGFR of 60 to 89 mL/min/1.73 m2 were significant independent predictors of renal impairment. Conclusions: TDF therapy appears to be an effective treatment option for CHB patients with a preserved GFR. However, patients with underlying DM and initial mild renal dysfunction (eGFR, 60 to 89 mL/min/1.73 m2) have an increased risk of renal impairment. PMID- 30400724 TI - Predicting Malignancy Risk in Gastrointestinal Subepithelial Tumors with Contrast Enhanced Harmonic Endoscopic Ultrasonography Using Perfusion Analysis Software. AB - Background/Aims: Contrast-enhanced harmonic endoscopic ultrasonography (CEH-EUS) is a promising imaging modality that can differentiate subepithelial tumors (SETs) by detecting the degree of enhancement. However, whether CEH-EUS alone can predict the malignancy risk of gastrointestinal stromal tumors (GISTs) remains unclear. This study aimed to evaluate the feasibility of CEH-EUS by using perfusion analysis software for distinguishing among SETs and predicting the malignancy risk of GISTs. Methods: We retrospectively included patients with SETs who underwent preoperative CEH-EUS. In this study, 44 patients with histologically proven GISTs and benign SETs were enrolled. Perfusion analysis was performed using perfusion quantification software. Peak enhancement (PE), wash-in rate (WiR), wash-in perfusion index (WiPI), and wash-in and wash-out areas under the time-intensity curve (WiWoAUC) were calculated and compared between the GISTs and benign SETs. Results: When we allocated the enrolled patients into the leiomyoma group and low- and high-grade malignancy GIST groups, significant statistical differences in PE (p<0.001), WiR (p=0.009), WiPI (p<0.001), and WiWoAUC (p<0.001) were identified in the high-grade malignancy group compared with the leiomyoma group. Conclusions: CEH-EUS with perfusion analysis using perfusion analysis software could be a quantitative and independent method for predicting malignancy risk in gastrointestinal SETs. PMID- 30400726 TI - Continuous Infusion Versus Intermittent Dosing with Pantoprazole for Gastric Endoscopic Submucosal Dissection. AB - Background/Aims: Proton pump inhibitors are widely used to prevent gastric endoscopic submucosal dissection (ESD)-related bleeding, but no standard administration regimens have been established. We aimed to prospectively compare the effects of continuous infusion and intermittent dosing with pantoprazole on preventing gastric ESD-related bleeding. Additionally, we analyzed the risk factors for bleeding. Methods: From April 2012 to May 2013, patients with a gastric epithelial neoplasm scheduled for ESD in the Pusan National University Hospital were randomly assigned to one of two groups according to the pantoprazole administration regimen (continuous infusion or intermittent dosing). The primary outcomes measured were intra- and postprocedural bleeding events. Results: The final analysis included 401 patients. The rate of significant intraprocedural bleeding was 25.4% in the C group and 24.0% in the I group, with no significant difference (p=0.419). In addition, there was no significant difference in the postprocedural bleeding rate between the C and I groups (11.7% vs 10.2%, p=0.374) Multivariate analysis showed that intraprocedural bleeding was associated with the proximal tumor location, the presence of fibrosis, and the size of the resected specimen, whereas postprocedural bleeding was associated with the size of the resected specimen and the procedure/coagulation time. Conclusions: Intermittent dosing with pantoprazole is sufficient and cost effective for the prevention of gastric ESD-related bleeding. Operators should consider tumor characteristics when planning ESD to minimize the risk of intraprocedural bleeding, and patients with large iatrogenic ulcers should be carefully monitored for postprocedural bleeding. PMID- 30400727 TI - Assessment of Clinical Outcomes after Peroral Endoscopic Myotomy via Esophageal Distensibility Measurements with the Endoluminal Functional Lumen Imaging Probe. AB - Background/Aims: Endoluminal functional lumen imaging probe (EndoFLIP) is a modality that enables clinicians to measure volume-controlled distension of the esophagus. This study aimed to assess the utility of EndoFLIP in patients who had achalasia treated with peroral endoscopic myotomy (POEM). We hypothesized that improvement in the distensibility index (DI) is correlated with the postoperative clinical outcome of POEM. Methods: Patients who underwent POEM for achalasia at Cha Bundang Medical Center were included. Physiological measurements of the lower esophageal sphincter (LES) pressure before and after POEM were assessed using EndoFLIP. Patients' symptoms were recorded using the Eckardt score. Results: A total of 52 patients with achalasia were included in this study. Patients with a post-POEM DI below 7 (30 or 40 mL) had a significantly higher rate of incomplete response after POEM (p=0.001). Changes in LES pressure or integrated relaxation pressure after POEM were also significantly associated with an incomplete response (p=0.026 and 0.016, respectively). Multivariate analysis showed that post-POEM DI < 7 was the most important predictor of an incomplete response after POEM (p=0.004). Conclusions: Lower post-POEM DI values were associated with an incomplete post-POEM response. Therefore, post-POEM DI at the esophagogastric junction using EndoFLIP is a useful index for predicting the clinical outcome of POEM in patients with achalasia. PMID- 30400725 TI - Safety and Efficacy of Low-Volume Preparation in the Elderly: Oral Sulfate Solution on the Day Before and Split-Dose Regimens (SEE SAFE) Study. AB - Background/Aim: The use of a low-volume bowel cleansing agent is associated with a greater willingness to undergo repeat colonoscopy. Oral sulfate solution (OSS) is a recently approved low-volume agent; however, its efficacy and safety in the elderly population remain unclear. We aimed to evaluate the efficacy, safety, and acceptability of the OSS preparation, in comparison to those of a standard polyethylene glycol (PEG; 4L) preparation, in elderly patients. Methods: A multicenter, randomized, investigator-blinded study was conducted. Participants were randomized to receive OSS or 4L PEG with a split-dose regimen. Bowel cleansing efficacy was assessed using the Boston Bowel Preparation Scale (BBPS). Acceptance, satisfaction, and preparation-related symptoms were recorded. Additionally, blood parameters were analyzed for electrolyte abnormalities and nephrotoxicity. Results: No group differences in overall bowel cleansing efficacy were observed, with "adequate" preparations achieved in 95.9% (93/97) and 94.8% (91/96) of patients in the OSS and 4L PEG groups, respectively (p = 0.747). The severity of clinical adverse events and frequency of acute kidney injury were similarly low, and no clinically meaningful electrolyte changes were identified. Self-reported scores regarding amount (p<0.001) and feeling (p=0.007), as well as overall satisfaction (p=0.001) and willingness to repeat the preparation (92.8% vs 67.7%, p<0.001), were significantly better in the OSS group than in the 4L PEG group. Conclusions: In elderly individuals, OSS with a split-dose regimen has greater acceptability and comparable efficacy in bowel cleansing compared to 4L PEG. (Clinical trials registration number: NCT03112967). PMID- 30400728 TI - Usefulness of Personal Bowel Habits as a Predictive Factor for Inadequate Bowel Preparation for Colonoscopy: A Prospective Questionnaire-Based Observational Study. AB - Background/Aims: The quality of bowel preparation is important for optimal colonoscopy. It is influenced by medical and personal factors. We aimed to evaluate the effect of bowel habit on the quality of bowel preparation and to identify predictors of inadequate bowel preparation among bowel habit factors. Methods: From June 2017 to September 2017, 90 volunteers were enrolled in this study. Each participant answered a questionnaire consisting of multiple questions about personal bowel habits, including stool form, frequency of bowel movements per week, duration, and degree of straining for bowel movement. Then, all volunteers underwent colonoscopic exam. Eleven endoscopists performed colonoscopies and used the Boston Bowel Preparation Scale (BBPS) as the index for bowel preparation. Two expert endoscopists simultaneously reviewed all colonoscopic images to confirm the final BBPS. Univariate and multivariate logistic regression analyses were performed to verify the correlation between bowel preparation adequacy and bowel habit. Results: Among the 90 participants, 20 (22.2%) had inadequate bowel preparation (total BBPS <=6 or any segmental BBPS <=1). In univariate analysis, infrequent bowel movement (0-2/week) (odds ratio [OR], 12.60; 95% confidence interval [CI], 1.22 to 129, p<0.05) and moderate straining (more than one-fourth of defecations) (OR, 4.40; 95% CI, 1.44 to 13.39; p<0.05) were significantly associated with inadequate bowel preparation. However, only moderate straining was significantly associated with inadequate bowel preparation in multivariate analysis (OR, 4.22; 95% CI, 1.25 to 14.30; p<0.05). Conclusion: Straining is a significant predictor for inadequate bowel preparation. For patients with straining during bowel movements, an intensified preparation regimen should be considered. PMID- 30400729 TI - Efficacy and Safety of Daclatasvir and Asunaprevir in Patients with Hepatitis C Virus Genotype 1b Infection on Hemodialysis. AB - Background/Aims: We evaluated the efficacy and safety of daclatasvir (DCV) and asunaprevir (ASV) in patients with chronic hepatitis C virus (HCV) infection on hemodialysis. Methods: We performed a single-arm, multicenter prospective study. Twenty-one chronic hemodialysis patients with HCV infection were prospectively enrolled from February 2016 to April 2017. We evaluated the virological responses at weeks 4, 12, and 24 (end of treatment [EOT]) and the sustained virological response at 12 weeks after the EOT (SVR12). The tolerability and safety of the drugs were also assessed. Results: None of the 20 patients had the NS5A resistance-associated variant (NS5A RAV), and one patient was indeterminate for the NS5A RAV. Seventeen patients (80%) completed the 24 weeks of treatment with DCV and ASV. Four patients discontinued the study prior to week 12. In an intention-to-treat analysis, the SVR12 was 76.1%. In a per-protocol analysis, patients who completed DCV and ASV treatment achieved an SVR12 of 100%. DCV and ASV were well tolerated by the majority of patients. Three patients discontinued treatment due to adverse events (AEs) including dizziness, dyspnea, and neutropenia. The patient with indeterminate NS5A RAV showed viral breakthrough and discontinued treatment. Conclusions: DCV and ASV combination therapy in chronic hemodialysis patients with HCV infection achieved a high SVR12 rate with few AEs. To maximize the SVR12 rate, it is important to identify candidates by baseline RAV testing. Close monitoring of the safety and tolerability of DCV and ASV may be necessary in HCV-infected patients on hemodialysis. (ClinicalTrials.gov ID NCT02580474). PMID- 30400730 TI - Distinction between Chronic Enteropathy Associated with the SLCO2A1 Gene and Crohn's Disease. AB - Background/Aims: We recently identified recessive mutations in the solute carrier organic anion transporter family member 2A1 gene (SLCO2A1) as causative variants of chronic nonspecific multiple ulcers of the small intestine (CEAS). The aim of this study was to investigate the gastroduodenal expression of the SLCO2A1 protein in patients with CEAS and Crohn's disease (CD). Methods: Immunohistochemical staining for SLCO2A1 was performed with a polyclonal antibody, HPA013742, on gastroduodenal tissues obtained by endoscopic biopsy from four patients with CEAS and 29 patients with CD. Results: The expression of SLCO2A1 was observed in one of four patients (25%) with CEAS and in all 29 patients (100%) with CD (p<0.001). The three patients with CEAS without SLCO2A1 expression had a homozygous splice-site mutation in SLCO2A1, c.1461+1G>C (exon 7) or c.940+1G>A (exon 10). The remaining one CEAS patient with positive expression of SLCO2A1 had compound heterozygous c.664G>A and c.1807C>T mutations. Conclusions: Immunohistochemical staining for SLCO2A1 in gastroduodenal tissues obtained by endoscopic biopsy is considered useful for the distinction of CEAS from CD. PMID- 30400731 TI - Efficacy of Nab-Paclitaxel Plus Gemcitabine and Prognostic Value of Peripheral Neuropathy in Patients with Metastatic Pancreatic Cancer. AB - Background/Aims: The combination of nab-paclitaxel and gemcitabine (nab-P/Gem) is widely used for treating metastatic pancreatic cancer (MPC). We aimed to evaluate the therapeutic outcomes and prognostic role of treatment-related peripheral neuropathy in patients with MPC treated with nab-P/Gem in clinical practice. Methods: MPC patients treated with nab-P/Gem as the first-line chemotherapy were included. All 88 Korean patients underwent at least two cycles of nab-P/Gem combination chemotherapy (125 and 1,000 mg/m2, respectively). Treatment-related adverse events were monitored through periodic follow-ups. Overall survival and progression-free survival were estimated by the Kaplan-Meier method, and the Cox proportional hazards regression linear model was applied to assess prognostic factors. To evaluate the prognostic value of treatment-related peripheral neuropathy, the landmark point analysis was used. Results: Patients underwent a mean of 6.7+/-4.2 cycles during 6.3+/-4.4 months. The median overall survival and progression-free survival rates were 14.2 months (95% confidence interval [CI], 11.8 to 20.3 months) and 8.4 months (95% CI, 7.1 to 13.2 months), respectively. The disease control rate was 84.1%; a partial response and stable disease were achieved in 30 (34.1%) and 44 (50.0%) patients, respectively. Treatment-related peripheral neuropathy developed in 52 patients (59.1%), and 13 (14.8%) and 16 (18.2%) patients experienced grades 2 and 3 neuropathy, respectively. In the landmark model, at 6 months, treatment-related peripheral neuropathy did not have a significant correlation with survival (p=0.089). Conclusions: Nab-P/Gem is a reasonable choice for treating MPC, as it shows a considerable disease control rate while the treatment-related peripheral neuropathy was tolerable. The prognostic role of treatment-related neuropathy was limited. PMID- 30400732 TI - Prognostic Value of Biochemical Response Models for Primary Biliary Cholangitis and the Additional Role of the Neutrophil-to-Lymphocyte Ratio. AB - Background/Aims: Recently reported prognostic models for primary biliary cholangitis (PBC) have been shown to be effective in Western populations but have not been well-validated in Asian patients. This study aimed to compare the performance of prognostic models in Korean patients and to investigate whether inflammation-based scores can further help in prognosis prediction. Methods: This study included 271 consecutive patients diagnosed with PBC in Korea. The following prognostic models were evaluated: the Barcelona model, the Paris-I/II model, the Rotterdam criteria, the GLOBE score and the UK-PBC score. The neutrophil-to-lymphocyte ratio (NLR) was analyzed with reference to its association with prognosis. Results: For predicting liver transplant or death at the 5-year and 10-year follow-up examinations, the UK-PBC score (areas under the receiver operating characteristic curve [AUCs], 0.88 and 0.82) and GLOBE score (AUCs, 0.85 and 0.83) were significantly more accurate in predicting prognosis than the other scoring systems (all p<0.05). There was no significant difference between the performance of the UK-PBC and GLOBE scores. In addition to the prognostic models, a high NLR (>2.46) at baseline was an independent predictor of reduced transplant-free survival in the multivariate analysis (adjusted hazard ratio, 3.74; p<0.01). When the NLR was applied to the prognostic models, it significantly differentiated the prognosis of patients. Conclusions: The UK-PBC and GLOBE scores showed good prognostic performance in Korean patients with PBC. In addition, a high NLR was associated with a poorer prognosis. Including the NLR in prognostic models may further help to stratify patients with PBC. PMID- 30400734 TI - Recurrent Clostridium difficile Infection: Risk Factors, Treatment, and Prevention. AB - The most common cause of antibiotic-associated diarrhea is Clostridium difficile infection (CDI). Recurrent C. difficile infection (rCDI) often occurs after successful treatment of CDI. Due to the increased incidence and the difficulty in treating rCDI, it is becoming an important clinical issue. Identifying risk factors is helpful for early detection, treatment, and prevention of rCDI. Advanced age, use of antibiotics, gastric acid suppression, and infection with a hypervirulent strain are currently regarded as the major risk factors for rCDI. Several treatment modalities, including vancomycin, fidaxomicin, and fecal microbiota transplant (FMT), are suggested for rCDI treatment. However, there is currently no definitive treatment method with sufficient evidence for rCDI. Recent studies have focused on FMT and have shown positive results for rCDI. Prevention of rCDI by measures such as hand washing and isolation of patients is very important. However, these preventive measures are often overlooked in clinical practice. Here, we review the risk factors, treatment, and prevention of rCDI. PMID- 30400735 TI - Relationship between Telomere Maintenance and Liver Disease. AB - Previous studies have established a correlation between increasing chronological age and risk of cirrhosis. This pattern raised interest in the role of telomeres and the telomerase complex in the pathogenesis of liver fibrosis and cirrhosis. This review aims to summarize and analyze the current understanding of telomere regulation in hepatocytes and lymphocytes and how this ultimately relates to the development of liver fibrosis. Notably, in chronic viral hepatitis, telomere shortening in hepatocytes and lymphocytes occurs in such a way that may promote further viral replication while also leading to liver damage. However, while telomere shortening occurs in both hepatocytes and lymphocytes and ultimately results in cellular death, the mechanisms of telomere loss appear to be initiated by independent processes. The understanding of telomere maintenance on a hepatic and immune system level in both viral and non-viral etiologies of cirrhosis may open doors to novel therapeutic strategies. PMID- 30400736 TI - Effects of Moderate Alcohol Drinking in Patients with Nonalcoholic Fatty Liver Disease. AB - Whether moderate alcohol intake is beneficial remains an unsolved issue. Recent studies have suggested that moderate alcohol consumption is associated with beneficial effects related to the prevention of cardiovascular diseases. Moderate alcohol consumption leads to a higher risk of hepatocellular carcinoma in patients with chronic viral liver diseases. However, the effects of moderate alcohol intake in patients with nonalcoholic fatty liver disease are unclear. In this review, we analyzed, from various perspectives, the effect of moderate alcohol consumption in patients with nonalcoholic fatty liver disease. We reviewed four cohort studies and seven cross-sectional studies. The results showed that moderate alcohol consumption was negatively related to the incidence of nonalcoholic steatohepatitis and liver fibrosis. However, moderate alcohol consumption was positively associated with the incidence of hepatocellular carcinoma in patients with nonalcoholic fatty liver disease. The results of the analysis of the relationship between moderate alcohol consumption and the levels of triglycerides, total cholesterol, high-density lipoprotein, and hypertension were diverse. More clinical data are needed to draw a conclusion about the effects of moderate alcohol consumption in patients with nonalcoholic fatty liver disease. PMID- 30400737 TI - Multifunctional Hierarchically-Assembled Hydrogel Particles with Pollen Grains via Pickering Suspension Polymerization. AB - Hierarchical assembly of heterogeneous particles is of great importance to interface and colloid science. In this work, a facile but powerful approach for the large-scale production of multifunctional hydrogel particles armored with biological colloidal species is developed by combining Pickering stabilization and photopolymerization. Biocompatible hollow pollen grains extracted from naturally occurring pollen species with an average diameter of ~32 MUm serve as universal solid emulsifiers dispersed in an oil phase and are self-assembled at the interface between an oil phase and a photo-cross-linkable hydrogel to make water-in-oil (W/O) emulsion droplets. While droplets are solidified into hydrogel particles by UV-induced free-radical polymerization, self-assembled hollow pollen grains are transformed to a robust shell on hydrogel particles with supracolloidal structures. The physically adsorbed hollow pollen grains on the hydrogel core can be released by a hydration-induced swelling of hollow pollen grains, leading to a transient floating behavior of core-shell particles. The size of the resultant core-shell particles is easily controlled by tailoring the process parameters such as a liquid volume or a loading mass of hollow pollen grains. The incorporation of magnetic or upconverting luminescent nanoparticles into a hydrogel core successfully expands the functionality of core-shell particles that can provide new design opportunities for floating drug delivery or ecofriendly proppants. PMID- 30400738 TI - Balancing apoptosis and autophagy for Parkinson's disease therapy: targeting BCL 2. AB - Both of apoptosis and autophagy are significant intracelluar processes to maintain organism homeostasis and survival. Autophagy selectively degrades intracellular damaged organelles and protein aggregates, while apoptosis dismantles damaged or aged cells. Autophagy and apoptosis influence each other under difference conditions. The balance between autophagy and apoptosis is essential to cells fate, especially for long-lived cells, such as neurons. On contrary, their imbalance results in some neurodegenerative disease such as Parkinson's disease (PD). PD is a complicated disorder characterized by a progressive loss of dopaminergic neurons in substantia nigra pars compacta, its pathogenesis is strongly linked to the injuries of autophagy and apoptosis. Therefore, rescuing the balance of autophagy and apoptosis is regarded as a potential strategy in the treatment of PD. There are some core proteins functioned in the crosstalk between apoptosis and autophagy, such as BCL-2 family members. This review summarizes the role of BCL-2 members on the regulation of apoptosis and autophagy and point the possible therapeutic target in this balance to provide some clues for PD treatment. PMID- 30400739 TI - Unveiling the Role of tBP-LiTFSI Complexes in Perovskite Solar Cells. AB - Lead halide-based perovskite materials have been applied as an intrinsic layer for next-generation photovoltaic devices. However, the stability and performance reproducibility of perovskite solar cells (PSCs) needs to be further improved to match that of silicon photovoltaic devices before they can be commercialized. One of the major bottlenecks that hinders the improvement of device stability/reproducibility is the additives in the hole-transport layer, lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) and 4- tert-butylpyridine (tBP). Despite the positive effects of these hole-transport layer additives, LiTFSI is hygroscopic and can adsorb moisture to accelerate the perovskite decomposition. On the other hand, tBP, the only liquid component in PSCs, which evaporates easily, is corrosive to perovskite materials. Since 2012, the empirical molar ratio 6:1 tBP:LiTFSI has been wildly applied in PSCs without further concerns. In this study, the formation of tBP-LiTFSI complexes at various molar ratios has been discovered and investigated thoroughly. These complexes in PSCs can alleviate the negative effects (decomposition and corrosion) of individual components tBP and LiTFSI while maintaining their positive effects on perovskite materials. Consequently, a minor change in tBP:LiTFSI ratio results in huge influences on the stability of perovskite. Due to the existence of uncomplexed tBP in the 6:1 tBP:LiTFSI mixture, this empirical tBP-LiTFSI molar ratio has been demonstrated not as the ideal ratio in PSCs. Instead, the 4:1 tBP:LiTFSI mixture, in which all components are complexed, shows all positive effects of the hole transport layer components with dramatically reduced negative effects. It minimizes the hygroscopicity of LiTFSI, while lowering the evaporation speed and corrosive effect of tBP. As a result, the PSCs fabricated with this tBP:LiTFSI ratio have the highest average device efficiency and obviously decreased efficiency variation with enhanced device stability, which is proposed as the golden ratio in PSCs. Our understanding of interactions between hole-transport layer additives and perovskite on a molecular level shows the pathway to further improve the PSCs' stability and performance reproducibility to make them a step closer to large-scale manufacturing. PMID- 30400733 TI - Effects of 17beta-Estradiol on Colonic Permeability and Inflammation in an Azoxymethane/Dextran Sulfate Sodium-Induced Colitis Mouse Model. AB - Background/Aims: Intestinal barrier dysfunction is a hallmark of inflammatory bowel diseases (IBDs) such as ulcerative colitis. This dysfunction is caused by increased permeability and the loss of tight junctions in intestinal epithelial cells. The aim of this study was to investigate whether estradiol treatment reduces colonic permeability, tight junction disruption, and inflammation in an azoxymethane (AOM)/dextran sodium sulfate (DSS) colon cancer mouse model. Methods: The effects of 17beta-estradiol (E2) were evaluated in ICR male mice 4 weeks after AOM/DSS treatment. Histological damage was scored by hematoxylin and eosin staining and the levels of the colonic mucosal cytokine myeloperoxidase (MPO) were assessed by enzyme-linked immunosorbent assay (ELISA). To evaluate the effects of E2 on intestinal permeability, tight junctions, and inflammation, we performed quantitative real-time polymerase chain reaction and Western blot analysis. Furthermore, the expression levels of mucin 2 (MUC2) and mucin 4 (MUC4) were measured as target genes for intestinal permeability, whereas zonula occludens 1 (ZO-1), occludin (OCLN), and claudin 4 (CLDN4) served as target genes for the tight junctions. Results: The colitis-mediated induced damage score and MPO activity were reduced by E2 treatment (p<0.05). In addition, the mRNA expression levels of intestinal barrier-related molecules (i.e., MUC2, ZO-1, OCLN, and CLDN4) were decreased by AOM/DSS-treatment; furthermore, this inhibition was rescued by E2 supplementation. The mRNA and protein expression of inflammation-related genes (i.e., KLF4, NF-kappaB, iNOS, and COX-2) was increased by AOM/DSS-treatment and ameliorated by E2. Conclusions: E2 acts through the estrogen receptor beta signaling pathway to elicit anti-inflammatory effects on intestinal barrier by inducing the expression of MUC2 and tight junction molecules and inhibiting pro-inflammatory cytokines. PMID- 30400740 TI - Catalytic Aerobic Oxidation of Alcohols by Copper Complexes Bearing Redox-Active Ligands with Tunable H-Bonding Groups. AB - In this research article, we describe the structure, spectroscopy, and reactivity of a family of copper complexes bearing bidentate redox-active ligands that contain H-bonding donor groups. Single-crystal X-ray crystallography shows that these tetracoordinate complexes are stabilized by intramolecular H-bonding interactions between the two ligand scaffolds. Interestingly, the Cu complexes undergo multiple reversible oxidation-reduction processes associated with the metal ion (CuI, CuII, CuIII) and/or the o-phenyldiamido ligand (L2-, L*-, L). Moreover, some of the CuII complexes catalyze the aerobic oxidation of alcohols to aldehydes (or ketones) at room temperature. Our extensive mechanistic analysis suggests that the dehydrogenation of alcohols occurs via an unusual reaction pathway for galactose oxidase model systems, in which O2 reduction occurs concurrently with substrate oxidation. PMID- 30400742 TI - Revealing of MicroRNA Involved Regulatory Gene Networks on Terpenoid Biosynthesis in Camellia sinensis in Different Growing Time Points. AB - Tea, made from leaves of Camellia sinensis, has long been consumed worldwide for its unique taste and aroma. Terpenoids play important roles not only in tea beverage aroma formation, but also in the productivity and quality of tea plantation due to their significant contribution to light harvesting pigments and phytohormones. To date, however, the regulation of terpenoid synthase genes remains unclear. Herein, the analyses of metabolomics, sRNAs, degradome, and transcriptomics were performed and integrated for identifying key regulatory miRNA-target circuits on terpenoid biosynthesis in leaf tissues over five different months in which the amount of terpenoids in tea leaves varies greatly. Four classes of miRNA-TF pairs that might play a central role in the regulation of terpenoid biosynthesis were also uncovered. Ultimately, a hypothetical model was proposed that mature miRNAs maintained by light regulator at both the transcriptional and posttranscriptional levels negatively regulate the targets to control terpenoid biosynthesis. PMID- 30400741 TI - Kinetics of Ion-Exchange Reactions in Hybrid Organic-Inorganic Perovskite Thin Films Studied by In Situ Real-Time X-ray Scattering. AB - The exchange of ions in hybrid organic-inorganic perovskites with the general formula APbX3 (A = MA, FA; X = I, Cl, Br) is studied in five different systems using in situ real-time grazing incident X-ray diffraction (GIXD). In systems where the organic cation is exchanged, we find a continuous shift of the lattice parameter. The relative shift compared to the pure materials is used to quantify the exchange. Whether or not a conversion is possible, as well as the amount of exchanged cations, depends on the halide used. In the case of the interconversion of MAPbI3 and MAPbCl3, we observe a decay of the diffraction peaks of the original perovskite and the emergence of new peaks corresponding to the structure with the alternative halide. Moreover, we determined the relevant time scales of the growth and decay of the perovskite structures. PMID- 30400743 TI - Identification of Short- and Long-Wavelength Emitting Chlorophylls in Cyanobacterial Photosystem I by Plasmon-Enhanced Single-Particle Spectroscopy at Room Temperature. AB - A peculiarity of cyanobacterial Photosystem I (PSI) is the presence of so-called red chlorophylls absorbing at wavelengths longer than the reaction center P700. The origin and function of these chlorophylls have been debated in literature, but so far no consensus has been reached on either question. Here, we use plasmon enhanced single-particle fluorescence spectroscopy to elucidate the origin of both short- and long-wavelength emitting species in monomeric PSI from Thermosynechococcus elongatus at room temperature. Polarized fluorescence spectra of single PSI complexes reveal a phase shift in the modulation of the short wavelength (687 nm) and long-wavelength (717 nm) peaks. Numerical simulations show that this phase shift reflects a spatial angle of 15 degrees between the transition dipole moments of the two forms. Quantum chemical calculations, together with reported X-ray structural and spectroscopic data, were used to assign the chlorophyll a monomer A3 as a candidate for the short-wavelength emitter and the B31-B32 chlorophyll dimer as a candidate for the long-wavelength emitter. PMID- 30400745 TI - Age Attenuates the Negativity Bias in Reframing Effects. AB - A growing literature on reframing effects has identified a robust negativity bias: Under many circumstances, people's attitudes change less when framing switches from negative to positive (vs. positive to negative). Like other basic psychological biases, this one is often assumed to reflect a general human tendency, but there are theoretical reasons to expect boundary conditions on when and for whom it operates. In this article, we zero in on age as one important potential moderator, and test competing predictions from different perspectives. Using a large, highly powered data set that synthesizes across multiple past studies ( N = 2,452; aged 18-81 years), we fit multilevel models to test the moderating impact of age on reframing effects, as well as single-shot framing effects. We found that (consistent with socioemotional selectivity theory), the negativity bias in reframing attenuated as age increased. We discuss implications for the aging literature and for understanding valence biases more broadly. PMID- 30400746 TI - The Short and Longer Term Impacts of Hate Crimes Experienced Directly, Indirectly, and Through the Media. AB - A longitudinal study ( N = 774) explored the short and longer term impacts of anti-Lesbian, Gay, Bisexual, and Trans (LGBT) hate crime experienced directly, indirectly, and through the media. In the short term, being a victim (direct) or personally knowing of a hate crime victim (indirect) was positively associated with vulnerability, emotional responses, and behavioral intentions after reading about a hate crime. Direct victims were also less empathic toward other victims and engaged in more victim-blaming. A structural equation model showed direct experiences (via personal vulnerability and empathy) and media experiences (via group-threat and victim-blaming) to be cross-sectionally associated with behavioral intentions. Media experiences also had lasting demobilizing impacts on actual behaviors, again serially mediated by group-threat and victim-blaming. The findings highlight the emotional and behavioral impacts of hate crimes on both direct victims and on the wider LGBT community. They also raise questions about media reporting of hate crimes and the role of victim-blaming. PMID- 30400747 TI - Aftereffects of Self-Control on Positive Emotional Reactivity. AB - According to the process model of ego depletion, exercising self-control causes shifts in motivation and attention that may increase positive emotional reactivity. In an initial study and a preregistered replication, participants exercised self-control (or not) on a writing task before reporting their emotional responses to positive, negative, and neutral images. In Study 1 ( N = 256), we found that exercising (vs. not exercising) self-control increased positive emotional responses to positive images among more extroverted individuals. In Study 2 ( N = 301), we found that exercising self-control increased positive reactivity independent of extroversion. These findings support the process model of ego depletion and suggest that exercising self-control may influence responding that does not entail self-control (i.e., positive emotional reactivity)-an outcome that is not anticipated by the limited resource model of self-control. PMID- 30400748 TI - Predictive Validity of Thin-Slice Nonverbal Behavior from Social Interactions. AB - We present five studies investigating the predictive validity of thin slices of nonverbal behavior (NVB). Predictive validity of thin slices refers to how well behavior slices excerpted from longer video predict other measured variables. Using six NVBs, we compared predictive validity of slices of different lengths with that obtained when coding is based on full-length (5-min) video, investigating the relative predictive validity of 1-min slices as well as of cumulative slices. Results indicate some loss in predictive validity with 1-min slices, but relatively little loss when Slices 1 and 2 were combined for five of the six NVBs. This research establishes an empirical basis on which researchers can decide how much of their recorded corpus needs to be coded for NVB. The results also provide some guidance on effect sizes in power analyses for researchers coding specific behaviors in a thin-slice design. PMID- 30400749 TI - Improving emotion regulation ability in autism: The Emotional Awareness and Skills Enhancement (EASE) program. AB - Emotion regulation impairments are common among individuals with autism spectrum disorder and are believed to often underlie commonly seen problems with aggression, depression, and anxiety. The Emotional Awareness and Skills Enhancement program was developed to reduce emotion regulation impairment and thereby improve behavioral disturbance, via mindfulness. Emotional Awareness and Skills Enhancement consists of a 16-week individual therapy treatment targeting emotion regulation impairments among individuals with autism spectrum disorder. We describe the conceptual framework and development of the program and present data on feasibility and preliminary efficacy from a pilot trial. The Emotional Awareness and Skills Enhancement manual was developed using a participatory action framework, based on emotion regulation research specific to autism spectrum disorder and input from individuals with autism spectrum disorder, therapists, and parents of children with autism spectrum disorder. Emotional Awareness and Skills Enhancement was piloted in a two-site open trial with 20 participants with autism spectrum disorder (12-17 years old, confirmed autism spectrum disorder diagnosis, IQ > 80).Outcome data support program feasibility and acceptability to participants, as well as significant improvement in emotion regulation impairments and related concerns.Findings offer preliminary support for both the feasibility and clinical effectiveness of the Emotional Awareness and Skills Enhancement program. PMID- 30400750 TI - Prognostic factors for survival in patients with metastatic malign melanoma treated with ipilimumab: Turkish Oncology Group study. AB - PURPOSE: Studies in the last decade show survival improvement with checkpoint blocker therapy in patients with metastatic malign melanoma. Our purpose was to define the efficacy of ipilimumab according to the patient's baseline characteristics including absolute lymphocytes count. METHODS: We collected the data of 97 patients with advanced malign melanoma treated with ipilimumab (3 mg/kg, q3w) retrospectively. Log-rank test was used to analyze the univariate effects of patient's characteristics (age, gender, metastatic sites, ECOG PS, type of melanoma, lactic dehydrogenase levels, anemia, lymphocytes (L), neutrophils (N), N/L ratio), c-kit and BRAF status. Survival analyses were estimated with Kaplan-Meier method. Cox regression analysis was used to assess the possible factors identified with log-rank test. RESULTS: The median age was 58, and 58% were male and 90% of patients had at least one prior systemic therapy. The median survival was 9.7 months for all patients; and the 12- and 24 month survival rates were 43% and 19%, respectively. Absolute lymphocytes count, lactic dehydrogenase level, bone metastasis, the number of metastatic sites, and RECIST response were significantly related to survival. After Cox regression analysis, RECIST response (complete or partial response), absolute lymphocytes count (more than 1500/mm3) and the number of metastatic sites (less than three sites) remained as significant independent prognostic factors for longer survival. CONCLUSION: Ipilimumab improved survival of patients with metastatic malign melanoma. However, patients with fewer metastatic sites and higher absolute lymphocytes count have a significantly better benefit. To determine if these markers could be used to direct patient therapy, further validation analysis is needed. PMID- 30400751 TI - Implications of parenteral chemotherapy dose standardisation in a tertiary oncology centre. AB - BACKGROUND: Dose banding parenteral chemotherapy has the potential to optimise aseptic unit capacity and reduce drug expenditure without compromising the service provided. METHODS: Dose banding tables from NHS England were implemented into the electronic chemotherapy prescribing system. Compliance to the dose bands was analysed and submitted quarterly. Analysis of drug expenditure, drug use and cost per milligram data was also collected. RESULTS: Expenditure on the 17 drugs identified in the 2016/17 dose standardisation CQUIN reduced by approximately L100,000 per month over the CQUIN despite an increase in the number of prescribed doses of these drugs. At the beginning of the year, the percentage of work compounded in house was 60%, which was reduced to 51% of total workload at the end of the year due to outsourcing commonly prescribed doses from commercial pharmaceutical aseptic manufacturers. CONCLUSION: Dose banding parenteral chemotherapy is an efficient cost-saving strategy which also can help to increase the capacity of the aseptic unit. PMID- 30400752 TI - Inhibition of Mastermind-like 1 alleviates liver fibrosis induced by carbon tetrachloride in rats. AB - IMPACT STATEMENT: Liver fibrosis is a common wound-healing response to all kinds of liver injuries. Hepatic stellate cells (HSCs) activation is the key event during liver fibrogenesis. Thus, the elucidation of mechanisms for regulating HSCs activation is helpful for identifying novel anti-fibrotic targets and strategies. MAML1, an important component of Notch signal, functions in critical transcriptional coactivation in the Notch and Wnt/beta-catenin signal pathways. In the present study, we investigated the potential function of MAML1 during hepatic fibrogenesis in rats. Our results demonstrated that MAML1 participates in liver fibrosis through modulating HSCs activation via interrupting both the Notch and Wnt/beta-catenin signal transductions. Additionally, the inhibition of MAML1 markedly attenuated CCl4-induced hepatic fibrogenesis in rats. Our results shed a light for the exploitation of a new therapeutic strategy for hepatic fibrosis via targeting MAML1. PMID- 30400753 TI - Development of an accelerated artificial ageing method for the characterization of degradation products of antioxidants in lubricants by mass spectrometry. AB - The understanding of ageing mechanisms of antioxidants in base oils is indispensable for the development of improved lubricants. In this study, a novel artificial ageing method based on the application of peroxide as oxidant is presented for improved monitoring of thermo-oxidative degradation processes in combination with mass spectrometry. Model oils containing aminic and phenolic antioxidants were aged and chemical structures of their oxidation products were elucidated by ultrahigh performance liquid chromatography and electrospray ionization high resolution (Orbitrap) mass spectrometry. Additionally, synergistic mixtures of four antioxidants were investigated, because the formation of condensed molecules from amines and phenols would have a major influence on the antioxidant potential but could not be detected in the bulk lubricant. PMID- 30400754 TI - Fragmentation studies of selected drugs utilized in palliative care. AB - The results of research on selected drugs used in palliative care are presented, including fentanyl, tramadol, metoclopramide, hyoscine butylbromide, midazolam, haloperidol, levomepromazine and clonazepam. Interpretation of their ESI mass spectra obtained by the use of a triple quadrupole linear ion trap mass spectrometer is given. As a result, fragmentation pathways described in the literature are complemented and presented with more details. On their basis, transitions for quantitative analysis are selected and chromatographic conditions for the determination of the palliative care drugs are proposed as well. These results enable future studies on palliative care drugs in elderly patients including both their quantitation in body fluids and easier identification of their metabolites. PMID- 30400756 TI - Protein function prediction from protein-protein interaction network using gene ontology based neighborhood analysis and physico-chemical features. AB - Protein Function Prediction from Protein-Protein Interaction Network (PPIN) and physico-chemical features using the Gene Ontology (GO) classification are indeed very useful for assigning biological or biochemical functions to a protein. They also lead to the identification of those significant proteins which are responsible for the generation of various diseases whose drugs are still yet to be discovered. So, the prediction of GO functional terms from PPIN and sequence is an important field of study. In this work, we have proposed a methodology, Multi Label Protein Function Prediction (ML_PFP) which is based on Neighborhood analysis empowered with physico-chemical features of constituent amino acids to predict the functional group of unannotated protein. A protein does not perform functions in isolation rather it performs functions in a group by interacting with others. So a protein is involved in many functions or, in other words, may be associated with multiple functional groups or labels or GO terms. Though functional group of other known interacting partner protein and its physico chemical features provide useful information, assignment of multiple labels to unannotated protein is a very challenging task. Here, we have taken Homo sapiens or Human PPIN as well as Saccharomyces cerevisiae or yeast PPIN along with their GO terms to predict functional groups or GO terms of unannotated proteins. This work has become very challenging as both Human and Yeast protein dataset are voluminous and complex in nature and multi-label functional groups assignment has also added a new dimension to this challenge. Our algorithm has been observed to achieve a better performance in Cellular Function, Molecular Function and Biological Process of both yeast and human network when compared with the other existing state-of-the-art methodologies which will be discussed in detail in the results section. PMID- 30400755 TI - MicroRNA-23b and microRNA-27b plus flutamide treatment enhances apoptosis rate and decreases CCNG1 expression in a castration-resistant prostate cancer cell line. AB - The acquisition of a castration-resistant prostate cancer phenotype by prostate cancer cells is the alteration that has the worst prognosis for patients. The aim of this study was to evaluate the role of the microRNAs-23b/-27b as well as the possible CCNG1 target gene in tissue samples from patients with localized prostate cancer that progressed to castration-resistant prostate cancer and in a castration-resistant prostate cancer cell line (PC-3). The microRNAs and target gene expression levels of the surgical specimens were analyzed by quantitative real-time polymerase chain reaction. The prostate cancer cell line, PC-3, was transfected with pre-miR-23b, pre-miR-27b, and their respective controls using Lipofectamine RNAiMAX and exposed or not to flutamide. After transfections, expression levels of both the microRNAs and the gene, CCNG1, were analyzed by quantitative real-time polymerase chain reaction. The apoptosis and cell cycle assays were performed on the mini MUSE cytometer. MicroRNAs-23b/-27b were underexpressed in surgical specimens of prostate cancer; however, their target gene, CCNG1, was overexpressed in 69% of the cases. After transfection with the microRNAs-23b/-27b and flutamide, we observed a reduction in gene expression compared with cells that were treated only with microRNAs or only with flutamide. In the apoptosis assay, we demonstrated cell sensitization following transfection with microRNAs-23b/-27b and potentiation when co-administered with flutamide. The number of cells in apoptosis was almost three times higher with the simultaneous treatments (miR + flutamide) compared with the control (p < 0.05). In the cell cycle assay, only flutamide treatment showed better results; a higher number of cells were found in the G0-G1 phase, and a lower percentage of cells completed the final phase of the cycle (p < 0.05). We conclude that microRNAs-23b/-27b are downexpressed in prostate cancer, and their target gene, CCNG1, is overexpressed. We postulated that microRNAs-23b/-27b sensitize the PC-3 cell line and that after the addition of flutamide in the apoptosis assay, we would observe synergism in the treatments between miR and flutamide. In the cell cycle assay, the use of flutamide was sufficient to decrease the number of cells in mitosis. Therefore, we postulate that microRNAs, along with other drugs, may become very useful therapeutic tools in the treatment of castration-resistant prostate cancer. PMID- 30400757 TI - A qualitative study of parents' and facilitators' experiences of Group Stepping Stones Triple P for parents of children with disabilities. AB - In this qualitative study, we evaluated parents' and facilitators' experiences of the Group Stepping Stones Triple P (GSSTP) programme for parents of children with disabilities. The study was embedded in a randomized controlled trial (RCT) of GSSTP and carried out in the Irish public health service. Eight parents and three psychologists participated in the study. We used a semi-structured interview schedule to collect data and conducted a thematic content analysis of interview transcripts to identify particularly useful and less helpful aspects of the programme and ways that its future delivery may be improved. We conducted separate analyses on parent and psychologist data. The main findings were that parents considered the GSSTP to have helped them develop better self-regulation and behaviour management skills, which contributed to improved family relations. Negative aspects of the programme included the use of dated videos, the volume of programme content, the attrition rate and the shortcomings of the programme in meeting the complex needs of vulnerable families. Improvement suggestions included increasing flexibility of manualised content, providing follow-up support to vulnerable parents, incentivizing parents to attend and updating videos. PMID- 30400759 TI - Assessment of micro ribonucleic acids after exercise: Is this the future to detect coronary artery disease at its early stage? PMID- 30400758 TI - 'Interaction structures' between depressed adolescents and their therapists in short-term psychoanalytic psychotherapy and cognitive behavioural therapy. AB - OBJECTIVE:: Identify the core 'interaction structures' between therapists and depressed adolescents within and across two common forms of psychotherapy. METHOD:: A total of 70 audio-recorded psychotherapy sessions representing short term psychoanalytic psychotherapy (STPP) and cognitive behavioural therapy (CBT) with youth aged 12-18 years old were coded with the Adolescent Psychotherapy Q set (APQ), a newly developed instrument. Data included different therapist patient dyads and stages in treatment and were analysed with cluster analysis. RESULTS:: Three distinct interaction structures between therapists and depressed adolescents: two influenced by the therapists' techniques and one more influenced by the young people's attitude to therapy. CONCLUSION:: When there is a collaborative working relationship between therapists and depressed young people, the therapy process is influenced by the therapists' techniques; while when there is a poor working relationship, the techniques used by therapists of different theoretical orientation become more similar with the aim of engaging the young person in the process. PMID- 30400761 TI - How to identify and fill in the gaps in cardiac rehabilitation referral? PMID- 30400760 TI - A systematic overview to quantify the gender imbalance in cardiovascular rehabilitation trials. PMID- 30400762 TI - Omalizumab, the first available antibody for biological treatment of severe asthma: more than a decade of real-life effectiveness. AB - Omalizumab was the first, and for a long time the only available monoclonal antibody for the add-on treatment of severe allergic asthma. In particular, omalizumab selectively targets human immunoglobulin (Ig)E, forming small-size immune complexes that inhibit IgE binding to its high- and low-affinity receptors. Therefore, omalizumab effectively blunts the immune response in atopic asthmatic patients, thus significantly improving the control of asthma symptoms and successfully preventing disease exacerbations. These very positive effects of omalizumab make it possible to drastically decrease both referrals to the emergency room and hospitalizations for asthma exacerbations. Such important therapeutic actions of omalizumab have been documented by several randomized clinical trials, and especially by more than 10 years of real-life experience in daily clinical practice. Omalizumab can also interfere with airway remodelling by inhibiting the activation of IgE receptors located on structural cells such as bronchial epithelial cells and airway smooth muscle cells. Moreover, omalizumab is characterized by a very good safety and tolerability profile. Hence, omalizumab represents a valuable therapeutic option for the add-on biological treatment of severe allergic asthma. PMID- 30400763 TI - Metacognitive Reflection and Insight Therapy for Persons With Severe Negative Symptoms of Schizophrenia. AB - Individuals with schizophrenia possess enduring deficits that limit their capacity for interpersonal connection. Negative symptoms of schizophrenia provide additional barriers to interpersonal relatedness in that they include a range of deficits related to an individual's ability to express and experience emotions basic human capacities that are needed for daily functioning and an acceptable quality of life. Additionally, metacognitive deficits are closely related to the development and maintenance of negative symptoms; previous research has indicated that treatment of negative symptoms should focus on providing interventions that target metacognition. To explore this issue, a case study is presented in which ongoing assessments of metacognition were used to guide the selection of interventions. These interventions were selected to match the client's capacity for metacognition at that time and were aimed toward practicing and increasing development of metacognitive capacity. Improvements in function and metacognitive capacity are reported, and implications for research and theory are discussed. PMID- 30400764 TI - Metacognitive Reflection and Insight Therapy (MERIT): Application to a Long-Term Therapy Case of Borderline Personality Disorder. AB - Impairments in metacognitive capacity-or the processes that enable individuals to access, understand, and integrate their ideas about their own and others' mental states-are a core barrier to recovery for many people with borderline personality disorder. Although therapeutic approaches that focus on metacognitive capacity are emerging, few deal with the concept of recovery at a foundational level. This article describes how a form of metacognitively oriented psychotherapy focused on recovery, metacognitive reflection and insight therapy (MERIT), assisted a patient with borderline personality disorder and initial metacognitive deficits to develop a complex understanding of himself and others and then to use that knowledge to act as an agent in the world and effectively respond to life challenges. The eight elements of MERIT that stimulate and promote metacognitive capacity are presented with an emphasis on how they were implemented to assist the patient in achieving recovery. PMID- 30400765 TI - Recovery in First-Episode Psychosis: A Case Study of Metacognitive Reflection and Insight Therapy (MERIT). AB - Despite historically pessimistic views from both the professional community and lay public, research is emerging that recovery from psychosis is possible. Recovery has evolved to include not only a reduction in symptoms and return to functioning, but a sense of agency and connection to meaningful roles in life. The development of a more comprehensive conceptualization of recovery has particular importance in the treatment of first-episode psychosis, because early intervention may avoid some of the prolonged dysfunction that may make recovery difficult. As the mental health field moves to intervene early in the course of psychosis and to support recovery for individuals with severe mental illness, it is essential to develop and assess interventions that may promote a more comprehensive recovery. This case illustration offers an account of a type of integrative psychotherapy that may assist individuals in achieving recovery: metacognitive reflection and insight therapy (MERIT). PMID- 30400766 TI - Metacognitive Reflection and Insight Therapy for Schizophrenia: Case Study of a Patient With a Co-Occurring Substance Use Disorder. AB - Decrements in metacognitive functioning, or the ability to form complex and integrated representations of oneself and others, have been identified as a core feature of schizophrenia. These deficits have been observed to be largely independent of the severity of psychopathology and neurocognitive functioning and are linked to poor outcomes for those with the disorder. This study is a case illustration of the efficacy of metacognitive reflection and insight therapy (MERIT) in increasing the metacognitive capacity of an individual diagnosed as having co-occurring schizophrenia and a substance use disorder during three years of individual therapy. The eight elements of MERIT, which promote metacognitive growth, are presented as they apply to the present case. Case conceptualization, outcomes, and prognosis are also presented. These eight elements enabled the patient to move from a state of gross disorganization-unable to identify his thoughts or present them in a linear fashion-to one in which he was able to develop increasingly complex ideas about himself and others and integrate this understanding into a richer sense of himself, of his psychological challenges, and of the role that substance use played in his life. Results of the study also illustrate the foundational necessity of self-reflectivity in order to facilitate understanding of the mind of others and the relationship between psychological pain and the emergence of disorganization. PMID- 30400767 TI - NR2B-Tyr phosphorylation regulates synaptic plasticity in central sensitization in a chronic migraine rat model. AB - BACKGROUND: Although the mechanism of chronic migraine (CM) is unclear, it might be related to central sensitization and neuronal persistent hyperexcitability. The tyrosine phosphorylation of NR2B (NR2B-pTyr) reportedly contributes to the development of central sensitization and persistent pain in the spinal cord. Central sensitization is thought to be associated with an increase in synaptic efficiency, but the mechanism through which NR2B-pTyr regulates synaptic participation in CM-related central sensitization is unknown. In this study, we aim to investigate the role of NR2B-pTyr in regulating synaptic plasticity in CM related central sensitization. METHODS: Male Sprague-Dawley rats were subjected to seven inflammatory soup (IS) injections to model recurrent trigeminovascular or dural nociceptor activation, which is assumed to occur in patients with CM. We used the von Frey test to detect changes in mechanical withdrawal thresholds, and western blotting and immunofluorescence staining assays were performed to detect the expression of NR2B-pTyr in the trigeminal nucleus caudalis (TNC). NR2B-pTyr was blocked with the Src family kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t butyl)-pyrazolo [3,4-d] pyrimidine (PP2) and the protein tyrosine kinase inhibitor genistein to detected the changes in calcitonin gene-related peptide (CGRP), substance P (SP), and the synaptic proteins postsynaptic density 95 (PSD95), synaptophysin (Syp), synaptotagmin1 (Syt-1). The synaptic ultrastructures were observed by transmission electron microscopy (TEM), and the dendritic architecture of TNC neurons was observed by Golgi-Cox staining. RESULTS: Statistical analyses revealed that repeated infusions of IS induced mechanical allodynia and significantly increased the expression of NR2B Tyr-1472 phosphorylation (pNR2B-Y1472) and NR2B Tyr-1252 phosphorylation (pNR2B-Y1252) in the TNC. Furthermore, the inhibition of NR2B-pTyr by PP2 and genistein relieved allodynia and reduced the expression of CGRP, SP, PSD95, Syp and Syt-1 and synaptic transmission. CONCLUSIONS: These data indicate that NR2B-pTyr might regulate synaptic plasticity in central sensitization in a CM rat model. The inhibition of NR2B tyrosine phosphorylation has a protective effect on threshold dysfunction and migraine attacks through the regulation of synaptic plasticity in central sensitization. PMID- 30400768 TI - Semi-parametric estimates of population accuracy and bias of predictions of breeding values and future phenotypes using the LR method. AB - BACKGROUND: Cross-validation tools are used increasingly to validate and compare genetic evaluation methods but analytical properties of cross-validation methods are rarely described. There is also a lack of cross-validation tools for complex problems such as prediction of indirect effects (e.g. maternal effects) or for breeding schemes with small progeny group sizes. RESULTS: We derive the expected value of several quadratic forms by comparing genetic evaluations including "partial" and "whole" data. We propose statistics that compare genetic evaluations including "partial" and "whole" data based on differences in means, covariance, and correlation, and term the use of these statistics "method LR" (from linear regression). Contrary to common belief, the regression of true on estimated breeding values is (on expectation) lower than 1 for small or related validation sets, due to family structures. For validation sets that are sufficiently large, we show that these statistics yield estimators of bias, slope or dispersion, and population accuracy for estimated breeding values. Similar results hold for prediction of future phenotypes although we show that estimates of bias, slope or dispersion using prediction of future phenotypes are sensitive to incorrect heritabilities or precorrection for fixed effects. We present an example for a set of 2111 Brahman beef cattle for which, in repeated partitioning of the data into training and validation sets, there is very good agreement of statistics of method LR with prediction of future phenotypes. CONCLUSIONS: Analytical properties of cross-validation measures are presented. We present a new method named LR for cross-validation that is automatic, easy to use, and which yields the quantities of interest. The method compares predictions based on partial and whole data, which results in estimates of accuracy and biases. Prediction of observed records may yield biased results due to precorrection or use of incorrect heritabilities. PMID- 30400770 TI - Accuracy of the painDETECT screening questionnaire for detection of neuropathic components in hospital-based patients with orofacial pain: a prospective cohort study. AB - BACKGROUND: Better tools are required for the earlier identification and management of orofacial pain with different aetiologies. The painDETECT questionnaire is a patient-completed screening tool with utility for identification of neuropathic pain in a range of contexts. 254 patients, referred from primary care for management of orofacial pain and attending a secondary care centre, were prospectively recruited, and completed the painDETECT prior to consultation. The aim of this study was to determine the accuracy of the painDETECT to detect neuropathic components of orofacial pain, when compared to a reference standard of clinical diagnosis by experienced physicians, in a cohort of hospital-based patients. RESULTS: For the 251 patients included in the analysis, the painDETECT had a modest ability to detect neuropathic components of orofacial pain (AUROC, 0.63; 95% CI, 0.58-0.70; p = 0.001). Patients with orofacial pain diagnoses associated with neuropathic components had higher painDETECT scores than those with non-neuropathic components. However, the painDETECT was weaker at distinguishing patients with mixed pain types, and multiple diagnoses were associated with poor accuracy of the painDETECT. CONCLUSION: In secondary care settings, the painDETECT performed modestly at identifying neuropathic components, and underestimates the complexity of orofacial pain in its mixed presentations and with multiple diagnoses. Prior to clinical applications or research use, the painDETECT and other generic screening tools must be adapted and revalidated for orofacial pain patients, and separately in primary care, where orofacial pain is considerably less common. PMID- 30400769 TI - Detection of copy number variations in brown and white layers based on genotyping panels with different densities. AB - BACKGROUND: Copy number variations (CNV) are an important source of genetic variation that has gained increasing attention over the last couple of years. In this study, we performed CNV detection and functional analysis for 18,719 individuals from four pure lines and one commercial cross of layer chickens. Samples were genotyped on four single nucleotide polymorphism (SNP) genotyping platforms, i.e. the Illumina 42K, Affymetrix 600K, and two different customized Affymetrix 50K chips. CNV recovered from the Affymetrix chips were identified by using the Axiom(r) CNV Summary Tools and PennCNV software and those from the Illumina chip were identified by using the cnvPartition in the Genome Studio software. RESULTS: The mean number of CNV per individual varied from 0.50 to 4.87 according to line or cross and size of the SNP genotyping set. The length of the detected CNV across all datasets ranged from 1.2 kb to 3.2 Mb. The number of duplications exceeded the number of deletions for most lines. Between the lines, there were considerable differences in the number of detected CNV and their distribution. Most of the detected CNV had a low frequency, but 19 CNV were identified with a frequency higher than 5% in birds that were genotyped on the 600K panel, with the most common CNV being detected in 734 birds from three lines. CONCLUSIONS: Commonly used SNP genotyping platforms can be used to detect segregating CNV in chicken layer lines. The sample sizes for this study enabled a detailed characterization of the CNV landscape within commercially relevant lines. The size of the SNP panel used affected detection efficiency, with more CNV detected per individual on the higher density 600K panel. In spite of the high level of inter-individual diversity and a large number of CNV observed within individuals, we were able to detect 19 frequent CNV, of which, 57.9% overlapped with annotated genes and 89% overlapped with known quantitative trait loci. PMID- 30400771 TI - Homecare protective and risk factors for early childhood caries in Japan. AB - BACKGROUND: Early childhood caries (ECC) affects children across Japan and throughout the world. Thus, it is important to identify dietary and dental care habits that either promote oral health or cause ECC. The objective of this study was to identify protective and risk factors associated with ECC in Japan. METHODS: In a typical rural Japanese community, we selected children born between 2004 and 2008 who had received checkups at their community health center including oral examinations conducted by dentists. We obtained data from children's records and from a questionnaire filled out by parents. We enrolled only children who at their checkup for 18-month-olds had no caries, and we obtained data about them at their checkup for 3-year-olds. We classified children as either having caries (treated or untreated) or being caries-free. We conducted bivariate analyses using data on child/family demographic characteristics, child's dietary habits, and child/parental oral health habits. We also conducted logistic regression analysis to control for variables and identify predictors of the presence/absence of caries. RESULTS: Five hundred sixty six children (278 boys, 288 girls) were enrolled and followed. After 2 years, 173 children (30.6%) presented with caries. Logistic regression analysis predicting caries at follow up identified the interaction term "bottlefed overnight and brushed irregularly" at 18 months of age as a highly significant predictor of developing caries adjusted odds ratio (AOR) of 14.27, 95% confidence interval (CI) 1.02-199.71. Two variables measured at follow-up were also significant predictors: having low levels of dental plaque (AOR 2.41, 95% CI 1.34-4.35) and having a mother who had untreated caries (AOR 1.84, 95% CI 1.09-3.12). CONCLUSION: Public health efforts should encourage parents to eliminate bottle feeding overnight and promote brushing twice daily as children's teeth begin to erupt. Greater efforts should be made to teach parents and daytime caregivers how to brush effectively to remove all plaque. Health professionals should pay close attention to mothers' oral health status. Mothers with caries should receive prompt treatment and be assisted in developing better dietary and oral health habits that will benefit themselves and their children. Policies and programs should focus more on family oral health rather than just child oral health. PMID- 30400772 TI - Association of hemoglobin concentration with handgrip strength in relation to hepatocyte growth factor levels among elderly Japanese men aged 60-69 years: a cross-sectional study. AB - BACKGROUND: Hemoglobin concentration reportedly is positively associated with muscle strength, for example, handgrip strength. However, hemoglobin cannot repair muscle directly, but is beneficial only in a supportive role. Since hepatocyte growth factor (HGF) regulates muscle satellite cell production and differentiation, which is stimulated by organ injury, the supportive effect of hemoglobin should thus be stronger for participants with high HGF than for those with low HGF. However, the association between hemoglobin concentration and handgrip strength in relation to HGF levels remains unknown. METHODS: We conducted a cross-sectional study of 255 Japanese elderly men aged 60-69 years who participated in annual health check-ups in 2014-2015. The study population was categorized on the basis of a median value of HGF of 300.6 pg/mL. RESULTS: Among present study population, 128 participants showed low HGF. For participants with low HGF, hemoglobin concentration showed no significant association with handgrip strength (standardized parameter estimate (beta) = 0.03, p = 0.767), but for those with high HGF, hemoglobin concentration was significantly positively associated with handgrip strength (beta = 0.23, p = 0.014). CONCLUSIONS: A significant positive association between hemoglobin level and handgrip strength was established for elderly Japanese men aged 60-69 years with high HGF but not for participants with low HGF. Our finding indicates that HGF levels could determine the relationship of hemoglobin concentration with handgrip strength in elderly Japanese men aged 60-69 years. This result can be expected to serve as an effective tool for the clarification of the roles played by HGF and hemoglobin concentration in maintenance of muscle strength. PMID- 30400773 TI - Barriers in general practitioners' dementia diagnostics among people with a migration background in Germany (BaDeMi) - study protocol for a cross-sectional survey. AB - BACKGROUND: Considering the targeted general practitioner-centred healthcare in Germany, general practitioners (GPs) are in the best possible position to increase awareness of all sorts of dementia, an age-related syndrome with rising relevance in the future. In Germany, a doubling of the number of cases from 1.55 million up to 3 million in 2050 is predicted. Diagnostics can be challenging, especially among patients with a migration background. Complicating factors include: Language-based diagnostic tools, cultural differences in handling the syndrome and its underlying diseases as well as a differing use of the healthcare system. Because of missing research in this field in Germany, the type, frequency and intensity of barriers as well as the way GPs cope with them is unknown. That is why it's crucial to focus research on diagnostics in total and especially among this population group. METHODS: A cross-sectional study among a random sample of 1000 general practitioners in Germany is conducted in October 2017. A self-administered standardized questionnaire was developed, evaluated and send to the GP practices. A response rate of 30% is expected with one reminder letter. Descriptive statistics as well as, depending on the results, multivariable analyses will be executed. Based on these results and the stated needs, a cluster randomized intervention study will be constructed to improve healthcare. DISCUSSION: This study is the first in Germany focusing on how dementia diagnostics in general practice is performed, what problems occur, especially because of a migration background of patients, and how GPs cope with them. Depending on the results, it should emphasize the necessity of dementia diagnostics to be adjusted to the needs of the rising amount of people with a migration background (22.5% in Germany, 2016) like concluded from international studies. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00012503 , date of registration: 05.09.2017. Clinical register of the study coordination office of the University hospital of Bonn: ID530 , date of registration: 05.09.2017. PMID- 30400774 TI - Trial of exercise to prevent HypeRtension in young adults (TEPHRA) a randomized controlled trial: study protocol. AB - BACKGROUND: Hypertension prevalence in young adults has increased and is associated with increased incidence of cerebrovascular and cardiovascular events in middle age. However, there is significant debate regards how to effectively manage young adult hypertension with recommendation to target lifestyle intervention. Surprisingly, no trials have investigated whether lifestyle advice developed for blood pressure control in older adults is effective in these younger populations. METHODS/DESIGN: TEPHRA is an open label, parallel arm, randomised controlled trial in young adults with high normal and elevated blood pressure. The study will compare a supervised physical activity intervention consisting of 16 weeks structured exercise, physical activity self-monitoring and motivational coaching with a control group receiving usual care/minimal intervention. Two hundred young adults aged 18-35 years, including a subgroup of preterm born participants will be recruited through open recruitment and direct invitation. Participants will be randomised in a ratio of 1:1 to either the exercise intervention group or control group. Primary outcome will be ambulatory blood pressure monitoring at 16 weeks with measure of sustained effect at 12 months. Study measures include multimodal cardiovascular assessments; peripheral vascular measures, blood sampling, microvascular assessment, echocardiography, objective physical activity monitoring and a subgroup will complete multi-organ magnetic resonance imaging. DISCUSSION: The results of this trial will deliver a novel, randomised control trial that reports the effect of physical activity intervention on blood pressure integrated with detailed cardiovascular phenotyping in young adults. The results will support the development of future research and expand the evidence-based management of blood pressure in young adult populations. TRIAL REGISTRATION: Clinicaltrials.gov registration number NCT02723552 , registered on 30 March, 2016. PMID- 30400775 TI - Reduction in the IL-6 level at 24 h after admission to the intensive care unit is a survival predictor for Vietnamese patients with sepsis and septic shock: a prospective study. AB - BACKGROUND: Sepsis and septic shock are common problems in intensive care units (ICUs). The mortality of patients with sepsis or septic shock is high. We investigated if reduction in the serum concentration of the cytokines tumor necrosis factor alpha, interleukin (IL)-6 and IL-10, and the rate of change in the IL-6 level at 24 h after ICU admission were survival predictors for patients with sepsis and septic shock in a Vietnamese population. METHODS: This was a prospective study conducted at an ICU in Cho Ray Hospital, Vietnam, from October 2014 to October 2016. Patients diagnosed with sepsis or septic shock using validated international guidelines were enrolled. Plasma samples were collected upon (T0) and 24 h after (T24) ICU admission for measurement of cytokine concentrations. Blood tests were done to detect organ dysfunction. The duration of ICU stays, hospital stay, APACHE II and SOFA scores, and the in-hospital mortality were compared between survival and non-survival groups. Univariate logistic regression and multivariate analysis were done to determine the association between survival and IL-6 reduction at 24 h after ICU admission. RESULTS: A total of 123 patients were enrolled. The concentration (in pg/mL) of IL-6 at To was 413.3 in survivors and 530.0 in non- survivors. At T24, the IL-6 level was 65.4 for survivors and 286.9 for non-survivors. The survival rate was 39.0%. At T24, the concentrations of IL-6 and the reduction in IL-6 level were predictors of survival in patients with sepsis and septic shock. We found a significant association between IL-6 reduction and survival at >=86% with Odds Ratio (OR) 5.67, 95% Confidence Interval (CI); 1.27-25.3, compared with an increase in the IL-6 rate of change. CONCLUSIONS: Our findings suggested that a reduction in the IL-6 level of >=86% at 24 h from ICU admission is a survival predictor for patients with sepsis and septic shock in our population. PMID- 30400776 TI - Exploring the impact of public health teams on alcohol premises licensing in England and Scotland (ExILEnS): procotol for a mixed methods natural experiment evaluation. AB - BACKGROUND: Recent regulatory changes in the system by which premises are licensed to sell alcohol, have given health representatives a formal role in the process in England and Scotland. The degree to which local public health teams engage with this process varies by locality in both nations, which have different licensing regimes. This study aims to critically assess the impact on alcohol related harms - and mechanisms - of public health stakeholders' engagement in alcohol premises licensing from 2012 to 2018, comparing local areas with differing types and intensities of engagement, and examining practice in Scotland and England. METHODS: The study will recruit 20 local authority areas where public health stakeholders have actively engaged with the alcohol premises licensing system (the 'intervention') and match them to a group of 20 lower activity areas using genetic matching. Four work packages are included: (1) Structured interviews and documentary analysis will examine the type and level of intervention activity from 2012 to 2018, creating a novel composite measure of the intensity of such activity and will assess the local licensing system and potential confounding activities over the same period. In-depth interviews with public health, licensing, police and others will explore perceived mechanisms of change, acceptability, and impact. (2) Using longitudinal growth models and time series analyses, the study will evaluate the impact of high and low levels of activity on alcohol-related harms using routine data from baseline 2009 to 2018. (3) Intervention costs, estimated National Health Service cost savings and health gains will be evaluated using the Sheffield Alcohol Policy Model to estimate impact on alcohol consumption and health inequalities. (4) The study will engage public health teams to create a new theory of change for public health involvement in the licensing process using our data. We will share findings with local, national and international stakeholders. DISCUSSION: This interdisciplinary study examines, for the first time, whether and how public health stakeholders' involvement in alcohol licensing impacts on alcohol harms. Using mixed methods and drawing on complex systems thinking, it will make an important contribution to an expanding literature evaluating interventions not suited to traditional epidemiological research. PMID- 30400777 TI - Human papillomavirus infection: protocol for a randomised controlled trial of imiquimod cream (5%) versus podophyllotoxin cream (0.15%), in combination with quadrivalent human papillomavirus or control vaccination in the treatment and prevention of recurrence of anogenital warts (HIPvac trial). AB - BACKGROUND: Anogenital warts are the second most common sexually transmitted infection diagnosed in sexual health services in England. About 90% of genital warts are caused by human papillomavirus (HPV) types 6 or 11, and half of episodes diagnosed are recurrences. The best and most cost-effective treatment for patients with anogenital warts is unknown. The commonly used treatments are self-administered topical agents, podophyllotoxin (0.15% cream) or imiquimod (5% cream), or cryotherapy with liquid nitrogen. Quadrivalent HPV (qHPV) vaccination is effective in preventing infection, and disease, but whether it has any therapeutic effect is not known. METHODS AND DESIGN: To investigate the efficacy of clearance and prevention of recurrence of external anogenital warts by topical treatments, podophyllotoxin 0.15% cream or imiquimod 5% cream, in combination with a three-dose regimen of qHPV or control vaccination. 500 adult patients presenting with external anogenital warts with either a first or subsequent episode of anogenital warts will be entered into this randomised, controlled partially blinded 2 * 2 factorial trial. DISCUSSION: The trial is expected to provide the first high-quality evidence of the comparative efficacy and cost effectiveness of the two topical treatments in current use, as well as investigate the potential benefit of HPV vaccination, in the management of anogenital warts. TRIAL REGISTRATION: The trial was registered prior to starting recruitment under the following reference numbers: International Standard Randomized Controlled Trial Number (ISRCTN) Registry - ISRCTN32729817 (registered 25 July 2014); European Union Clinical Trials Register (EudraCT) - 2013-002951-14 (registered 26 June 2013). PMID- 30400778 TI - Time trends in statin use and incidence of recurrent cardiovascular events in secondary prevention between 1999 and 2013: a registry-based study. AB - BACKGROUND: The current study evaluated time trends of statin use and incidence of recurrent CVD in secondary prevention from 1999 to 2013 and investigated which factors were associated with statin use in secondary prevention. METHODS: Intego is a primary care registration network with 111 general practitioners working in 48 practices in Flanders, Belgium. This retrospective registry-based study included patients aged 50 years or older with a history of CVD. The time trends of statin use and incidence of recurrent CVD in secondary prevention were determined by using a joinpoint regression analysis. Multivariable mixed-effect logistic regression analysis was used to assess factors associated with statin use in patients in secondary prevention in 2013. RESULTS: The overall prevalence of statin use increased and showed two trends: a sharp increase from 1999 to 2005 (annual percentage change (APC) 25.4%) and a weaker increase from 2005 to 2013 (APC 3.7%). The average increase in statin use was the highest in patients aged 80 and older. Patients aged 70-79 years received the most statins. Men used more statins than women did, but both genders showed similar time trends. The incidence of CVD decreased by an average APC of 3.9%. There were no differences between men and women and between different age groups. A significant decrease was only observed in older patients without statins prescribed. In 2013, 61% of the patients in secondary prevention did not receive a statin. The absence of other secondary preventive medication was strongly associated with less statin use. Gender, age and comorbidity were associated with statin use to a lesser degree. CONCLUSIONS: The prevalence of statin use in secondary prevention increased strongly from 1999 to 2013. Less than 50% of patients with a history of CVD received a statin in 2013. Especially patients who did not receive other secondary preventive medication were more likely to not receive a statin. Despite the strong increase in statin use, there was only a small decrease in the incidence of recurrent CVD, and this occurred mainly in older patients without statins prescribed. PMID- 30400779 TI - Increased risk of non-AIDS-defining cancers in Asian HIV-infected patients: a long-term cohort study. AB - BACKGROUND: Data on the long-term risks of non-AIDS defining cancers (NADCs) are limited, especially in Asians. The incidence of NADCs may correlate with the epidemiological trend of cancers or oncogenic infection in each country, and thus the target cancers would be different between Western and Asian countries. We aimed to elucidate the incidence of NADCs and its predictive factors in Asian HIV infected patients. METHODS: Subjects were HIV-infected patients (n = 1001) periodically followed-up for 9 years on average. NADCs were diagnosed by histopathology and/ or imaging findings. Standardized incidence ratios (SIR) were calculated as the ratio of the observed to expected number of NADCs for comparison with an age-and sex-matched general population. Cox's proportional hazards model was used to estimate hazard ratios (HR). RESULTS: During the median follow-up of 9 years, the 10-year cumulative incidence of NADCs was 6.4%.At NADC diagnosis, half of patients presented at age 40-59 years and with advanced tumor stage. Compared with the age-and sex-matched general population, HIV-infected patients are at increased risk for liver cancer (SIR, 4.7), colon cancer (SIR, 2.1), and stomach cancer (SIR, 1.8). In multivariate analysis, a predictive model for NADCs was developed that included age group (40-49, 50-59, 60-69, and >= 70 years), smoker, HIV infection through blood transmission, and injection drug use (IDU), and HBV co-infection. The c-statistic for the NADCs predictive model was 0.8 (95%CI, 0.8-0.9, P < 0.001). The higher 10-year incidence rate of NADCs was associated with increasing prediction score. CONCLUSIONS: Liver and colon cancer risk was elevated in Asian HIV-infected individuals, similar to in Western populations, whereas stomach cancer risk was characteristically elevated in Asian populations. Half of Asian NADC patients were aged 40-59 years and had advanced stage disease at diagnosis. Periodic cancer screening may be warranted for high risk subpopulations with smoking habit, HIV infection through blood transmission or IDU, and HBV co-infection, and screening should be started over 40 years of age. PMID- 30400780 TI - Ixazomib in combination with carboplatin in pretreated women with advanced triple negative breast cancer, a phase I/II trial of the AGMT (AGMT MBC-10 trial). AB - BACKGROUND: Triple-negative breast cancer (TNBC) comprises a heterogeneous group of diseases which are generally associated with poor prognosis. Up to now, no targeted treatment beyond anti-VEGF therapy has been approved for TNBC and cytotoxic agents remain the mainstay of treatment. Ixazomib is a selective and reversible inhibitor of the proteasome, which has been mainly investigated in the treatment of multiple myeloma. In a preclinical study TNBC cells were treated with the first-generation proteasome inhibitor bortezomib in combination with cisplatin and synergistic efficacy was demonstrated. Clinical data are available for carboplatin plus bortezomib in metastatic ovarian and lung cancers showing remarkable antitumor activity and good tolerability (Mol Cancer 11:26 2012, J Thorac Oncol 4:87-92 2009, J Thorac Oncol 7:1032-1040, 2012). Based on this evidence, the phase I/II MBC-10 trial will evaluate the toxicity profile and efficacy of the second-generation proteasome inhibitor ixazomib in combination with carboplatin in patients with advanced TNBC. METHODS: Patients with metastatic TNBC pretreated with at least one prior line of chemotherapy for advanced disease with a confirmed disease progression and measurable disease according to RECIST criteria 1.1 are eligible for this study. Patients will receive ixazomib in combination with carboplatin on days 1, 8, and 15 in a 28-day cycle. The phase I part of this study utilizes an alternate dose escalation accelerated titration design. After establishing the maximum tolerated dose (MTD), the efficacy and safety of the combination will be further evaluated (phase II, including 41 evaluable patients). All patients will continue on study drugs until disease progression, unacceptable toxicity or discontinuation for any other reason. Primary endpoint of the phase II is overall response rate, secondary endpoints include progression-free survival, safety, and quality of life. This trial is open for patient enrollment since November 2016 in six Austrian cancer centers. Accrual is planned to be completed within 2 years. DISCUSSION: Based on preclinical and clinical findings an ixazomib and carboplatin combination is thought to be effective in metastatic TNBC patients. The MBC-10 trial is accompanied by a broad biomarker program investigating predictive biomarkers for treatment response and potential resistance mechanisms to the investigational drug combination. TRIAL REGISTRATION: EudraCT Number: 2016 001421-13 received on March 31, 2016, ClinicalTrials.gov Identifier: NCT02993094 first posted on December 15, 2016. This trial was registered prospectively. PMID- 30400781 TI - GPNMB methylation: a new marker of potentially carcinogenic colon lesions. AB - BACKGROUND: Epigenetic plays an important role in colorectal neoplasia process. There is a need to determine sound biomarkers of colorectal cancer (CRC) progression with clinical and therapeutic implications. Therefore, we aimed to examine the role and methylation status of Glyco Protein Non-Metastatic GPNM B (GPNMB) gene in normal, adenoma and CRC in African American (AA) patients. METHODS: The methylation status of 13 CpG sites (chr7: 23287345-23,287,426) in GPNMB gene's promoter, was analyzed by pyrosequencing in human CRC cell lines (HCT116, SW480, and HT29) and microdissected African American paraffin embedded samples (20 normal, 21 non-advanced adenoma (NA), 48 advanced adenoma (AD), and 20 cancer tissues. GPNMB expression was analyzed by immunohistochemistry (IHC) on tissue microarrays (TMA). Correlations between GPNMB methylation and expression with clinicopathological features were analyzed. GPNMB functional analysis was performed in triplicates using cell proliferation, migration and invasion assays in HCT116 colon cell line after stable transfection with a GPNMB-cDNA expression vector. RESULTS: GPNMB methylation was lower in normal mucosa compared to CRC samples (1/20 [5%] vs. 18/20 [90%]; P < 0.001). AD also had a significantly higher GPNMB methylation frequency than normal colon samples (42/48 [88%] vs 1/20 [5%]; P < 0.001). GPNMB was more frequently methylated in AD than in matched normal mucosa from three patients (3/3 [100%] vs 1/3 [33.3%]; P < 0.001). The frequency of GPNMB methylation in NA differed significantly from that in the normal mucosa (16/21 [76%] vs 1/20 [5%]; P = 0.008). There was statistically significant correlation of higher methylation at advanced stages and lower methylation at stage 1 CRCs (P < 0.05). In agreement with these findings, GPNMB protein expression decreased in CRC tissues compared with AD and NA colon mucosa (p < 0.05). GPNMB overexpression in HCT116 colon cancer cell line decreased cell proliferation [(24 h, P = 0.02), (48 h, P < 0.001, 72 h, P = 0.007)], invasion (p < 0.05) and migration (p > 0.05) compared to the mock-transfected cells. CONCLUSION: Our data indicate a high methylation profile leading to a lower GPNMB expression in adenoma and CRC samples. The functional analysis established GPNMB as a potential tumor suppressor gene. As such, GPNMB might be useful as a biomarker of adenomas with high carcinogenic potential. PMID- 30400782 TI - Long-term effects of neoadjuvant radiotherapy, adjuvant radiotherapy, and chemotherapy-only on survival of locally advanced non-small cell lung Cancer undergoing surgery: a propensity-matched analysis. AB - BACKGROUND: The optimal timing of radiotherapy (RT) with respect to surgery remains controversial for locally advanced non-small cell lung cancer (LA NSCLC) undergoing surgery and the long-term effect of neoadjuvant RT, adjuvant RT, and chemotherapy-only on survival is unknown. METHODS: A retrospective study with Greedy 5 -> 1 Digit propensity score matching technique was performed for locally advanced NSCLC patients identified from the Surveillance, Epidemiology, and End Results (SEER) database during 2004 to 2012. Kaplan-Meier and the log-rank test were conducted to compare NSCLC-specific survival. Cox proportional hazards multivariable regression was performed to assess the impact of different treatment regimens on cancer-specific mortality after adjustment for demographic factors, histology type, tumor grade, tumor size, nodal stage, and extent of resection. RESULTS: One thousand, two hundred and seventy-eight locally advanced NSCLC patients undergoing surgery were identified after propensity matching. Cox regression analyses showed the risk of cancer-specific mortality is not significantly different among neoadjuvant RT, adjuvant RT, and chemotherapy-only. Subgroup analyses showed that for patients with T1/2 & N2/3, the surgery plus chemotherapy-only group showed markedly higher mortality risk (HR = 1.42, 95%CI:1.10-1.83) than the neoadjuvant RT group. Other risk factors include older age, higher tumor grade, larger tumor size, and greater lymph node involvement. CONCLUSIONS: The findings of this study suggest that the benefit of additional neoadjuvant or adjuvant RT to chemotherapy may be linked to a proper selection of LA NSCLC patients who undergo surgery. The timing of radiotherapy should be decided on the premise of fully considering patients' condition and the quality of life after treatment. PMID- 30400783 TI - Growth factor genes and change in mammographic density after stopping combined hormone therapy in the California Teachers Study. AB - BACKGROUND: The contribution of genetic polymorphisms to the large inter individual variation in mammographic density (MD) changes following starting and stopping use of estrogen and progestin combined therapy (EPT) has not been well studied. Previous studies have shown that circulating levels of insulin-like growth factors are associated with MD and cross-talk between estrogen signaling and growth factors is necessary for cell proliferation in the breast. We evaluated single nucleotide polymorphisms (SNPs) in growth factor genes in association with MD changes after women stop EPT use. METHODS: We genotyped 191 SNPs in 13 growth factor pathway genes in 284 non-Hispanic white California Teachers Study participants who previously used EPT and collected their mammograms before and after quitting EPT. Percent MD was assessed using a computer-assisted method. Change in percent MD was calculated by subtracting percent MD of an 'off-EPT' mammogram from percent MD of an 'on-EPT' (i.e. baseline) mammogram. We used multivariable linear regression analysis to investigate the association between SNPs and change in percent MD. We calculated P-values corrected for multiple testing within a gene (Padj). RESULTS: Rs1983210 in INHA and rs35539615 in IGFBP1/3 showed the strongest associations. Per minor allele of rs1983210, the absolute change in percent MD after stopping EPT use decreased by 1.80% (a difference in absolute change in percent MD) (Padj= 0.021). For rs35539615, change in percent MD increased by 1.79% per minor allele (Padj= 0.042). However, after applying a Bonferroni correction for the number of genes tested, these associations were no longer statistically significant. CONCLUSIONS: Genetic variation in growth factor pathway genes INHA and IGFBP1/3 may predict longitudinal MD change after women quit EPT. The observed differences in EPT associated changes in percent MD in association with these genetic polymorphisms are modest but may be clinically significant considering that the magnitude of absolute increase in percent MD reported from large clinical trials of EPT ranged from 3% to 7%. PMID- 30400784 TI - (Cost-)effectiveness of an internet-based physical activity support program (with and without physiotherapy counselling) on physical activity levels of breast and prostate cancer survivors: design of the PABLO trial. AB - BACKGROUND: Higher levels of physical activity (PA) after treatment are associated with beneficial effects on physical and psychosocial functioning of cancer survivors. However, survivors often do not meet the recommended levels of PA. In order to promote PA, we developed a closed internet-based program. The aim of the study is to evaluate the (cost-)effectiveness of an internet-based PA promotion program, alone or combined with physiotherapy counselling, compared to usual care, on PA-levels of breast or prostate cancer survivors. In this multicenter randomised controlled trial (RCT), breast or prostate cancer survivors who completed their primary treatment 3-12 months earlier, will be randomised to either 6-months access to a fully-automated internet-based intervention alone, an internet-based intervention plus remote support by a physiotherapist, or a control group. The intervention is based on the Transtheoretical Model and includes personalized feedback, information, video's and assignments. Additionally, in a second arm, physiotherapy counselling is provided through monthly scheduled and on-demand telephone calls. The control group will receive usual care and a leaflet with PA guidelines. METHODS: At baseline, 6 and 12 months, the primary outcome (PA) will be measured during 7 consecutive days by accelerometers. Secondary outcomes are self-reported PA, fatigue, mood, health-related quality of life, and costs. The group differences for primary and secondary outcomes will be analyzed using linear mixed models. DISCUSSION: If proven to be (cost)effective, this internet-based intervention, either alone or in combination with telephone support, will be a welcome addition to previous RCT's. TRIAL REGISTRATION: Netherlands trial register (NTR6911), Date of trial registration: December 21, 2017. PMID- 30400785 TI - Trajectories of work disability and unemployment among young adults with common mental disorders. AB - BACKGROUND: Labour-market marginalisation (LMM) and common mental disorders (CMDs) are serious societal problems. The aims were to describe trajectories of LMM (both work disability and unemployment) among young adults with and without CMDs, and to elucidate the characteristics associated with these trajectories. METHODS: The study was based on Swedish registers and consisted of all individuals 19-30 years with an incident diagnosis of a CMD in year 2007 (n = 7245), and a matched comparison group of individuals without mental disorders during the years 2004-07 (n = 7245). Group-based trajectory models were used to describe patterns of LMM both before, and after the incident diagnosis of a CMD. Multinomial logistic regressions investigated the associations between sociodemographic and medical covariates and the identified trajectories. RESULTS: Twenty-six percent (n = 1859) of young adults with CMDs followed trajectories of increasing or constant high levels of work disability, and 32 % (n = 2302) followed trajectories of increasing or constant high unemployment. In the comparison group, just 9 % (n = 665) followed increasing or constant high levels of work disability and 21 % (n = 1528) followed trajectories of increasing or constant high levels of unemployment. A lower share of young adults with CMDs followed trajectories of constant low levels of work disability (n = 4546, 63%) or unemployment (n = 2745, 38%), compared to the level of constant low work disability (n = 6158, 85%) and unemployment (n = 3385, 50%) in the comparison group. Remaining trajectories were fluctuating or decreasing. Around 50% of young adults with CMDs had persistent levels of LMM at the end of follow-up. The multinomial logistic regression revealed that educational level and comorbid mental disorders discriminated trajectories of work disability, while educational level, living area and age determined differences in trajectories of unemployment (R2difference = 0.02-0.05, p < 0.001). CONCLUSIONS: A large share, nearly 50%, of young adults with CMDs, substantially higher than in the comparison group of individuals without mental disorders, display increasing or high persistent levels of either work disability or unemployment throughout the follow-up period. Low educational level, comorbidity with other mental disorders and living in rural areas were factors that increased the probability for LMM. PMID- 30400786 TI - Organized screening programmes for breast and cervical cancer in 17 EU countries: trajectories of attendance rates. AB - BACKGROUND: The aim was to analyse participation trajectories in organised breast and cervical cancer screening programmes and the association between socioeconomic variables and participation. METHODS: A pooled, cross-sectional, time series analysis was used to evaluate secondary data from 17 European countries in 2004-2014. RESULTS: The results show that the mammographic screening trend decreases after an initial increase (coefficient for the linear term = 0.40; p = 0.210; 95% CI = - 0.25, 1.06; coefficient for the quadratic term = - 0.07; p = 0.027; 95% CI = - 0.14, - 0.01), while the cervical screening trend is essentially stable (coefficient for the linear term = 0.39, p = 0.312, 95% CI = - 0.42, 1.20; coefficient for the quadratic term = 0.02, p = 0.689, 95% CI = - 0.07, 0.10). There is a significant difference among the country-specific slopes for breast and cervical cancer screening (SD = 16.7, p < 0.001; SD = 14.4, p < 0.001, respectively). No association is found between participation rate and educational level, income, type of employment, unemployment and preventive expenditure. However, participation in cervical cancer screening is significantly associated with a higher proportion of younger women (<= 49 years) and a higher Gini index (that is, higher income inequality). CONCLUSIONS: In conclusion three messages: organized cancer screening programmes may reduce the socioeconomic inequalities in younger people's use of preventive services over time; socioeconomic variables are not related to participation rates; these rates do not reach a level of stability in several countries. Therefore, without effective recruitment strategies and tailored organizations, screening participation may not achieve additional gains. PMID- 30400787 TI - A health communication intervention to integrate partner testing with antiretroviral therapy service among men who have sex with men in China: an observational cohort study. AB - BACKGROUND: In China, antiretroviral therapy (ART) clinics focus on treating people living with HIV and are not required to undertake testing of high-risk populations. To improve partner testing among MSM, we implemented a health communication pilot intervention integrating partner testing with ART services. We aimed to assess the feasibility of the partner referral service and identify the predictors of both successful partner referral for HIV testing and HIV positive test results among referred partners. METHODS: This program ran from April 2014 through December 2015 at designated ART clinics in six cities. The index participants, men living with HIV enrolled at an ART clinic, were assigned a case manager who assumed responsibility for routine ART-related counseling and mobilization of HIV-positive index participants for partner referral testing. Case managers were either nurses or contract staff. The successful referral rate was the proportion of index participants who referred a sexual partner for HIV testing. The HIV-positive partner rate was the proportion of the newly referred contacts who tested HIV-positive. Factors associated with the successful referral rate and the HIV-positive partner rate were assessed. RESULTS: Two thousand three hundred eighty-two index participants were enrolled. The median age was 30 years (IQR 26-37). 829index participants (34.80%) successfully referred at least one sexual partner for screening, and 92 (11.10%) referred partners were HIV positive. Having a hospital nurse as case manager was associated with both successful partner referral (AHR = 1.56, 95% CI = 1.36-1.80) and having a HIV positive partner (AHR = 2.35, 95% CI = 1.45-3.92). Index participants who were married (AHR = 1.44, 95% CI = 1.20-1.73) or employed (AHR = 1.29, 95% CI = 1.11 1.49) were more likely to successfully refer a partner for testing. Stable male partner relations were more likely to result in a referred partner testing HIV positive (AHR = 5.50, 95% CI = 1.85-16.39). CONCLUSION: Our findings indicated that integration of MSM partner testing with ART services via health communication was feasible. Nurses as case managers effectively encouraged index participants to refer their sexual partners for HIV testing. PMID- 30400788 TI - A qualitative insight into informal childcare and childhood obesity in children aged 0-5 years in the UK. AB - BACKGROUND: Previous studies in various countries have found that informal childcare (provided by relatives, friends etc.) was associated with an increased risk of obesity in children aged 0-5 years. However, no qualitative research has been done to explore possible reasons for such a relationship and potential interventions to tackle it. We conducted a qualitative study with both parents and informal carers to explore their 1) experiences in receiving or giving informal childcare for British children aged 0-5 years; 2) perceived explanations of the relationship between informal childcare and childhood obesity and 3) preferred intervention ideas and delivery strategies for preventing obesity among those children under informal care. METHODS: Four in-depth focus groups with a total of 14 participants (7 parents, 7 informal caregivers) were conducted in Birmingham and Edinburgh (1 parent group and 1 informal caregiver group in each city). Data were audio recorded, transcribed verbatim and analysed using a thematic approach. RESULTS: The significance of informal care to parents, carers, and society was recognised (theme one). Informal carers were identified to have practical and emotional support roles for the parents (theme two). Informal care was perceived to contribute to childhood obesity in four ways (theme three): cross-generation conflict preventing adoption of healthy practices; the trade-off for parents between receiving childcare and maintaining control; reduced energy capacity of carers; and increased snacking. Potential intervention ideas and delivery strategies (theme four) were identified. Examples of identified ideas included providing carers with up-to-date weaning advice, and suggestions of healthy snacks and ways to increase physical activity level in informal care. The suggestion of utilising existing primary care platforms (e.g. health visitor check-ups) to reach and deliver low-cost information based interventions, to all children aged 0-5 years who receive informal care, was highlighted. CONCLUSIONS: This exploratory qualitative study provided novel insights into potential explanations for the evidenced link between informal care and childhood obesity in children aged 0-5 years, despite a small size and limited participants in each focus group. Our findings support the idea of and inform the development towards an information based and low-cost intervention delivered through existing primary care platforms. PMID- 30400789 TI - Effect of timing of mother's death on child survival in a rural HIV hyper-endemic South African population. AB - BACKGROUND: Maternal mortality remains a tragedy and a key determinant for child survival. There is increasing evidence that the hazard ratio of demising for young children escalates after the death of their mothers, but few studies has been done in rural areas were HIV/AIDS is more prevalent. The aim of this study is to investigate the survival of children who lost their mothers soon or after their births in a rural setup with high HIV prevalence in South Africa. METHODS: This study used a data set from Africa Health Research Institute in rural South Africa.The study population comprised children (0-10 years of age) from 2000 to 2014. We employed a Cox regression modelling approach to estimate greatest temporal hazard of the child after the death of their mothers, accounting for the confounding influence of wealth index of the household and HIV status of the mother. RESULTS: We found 62,600 live births, and that 2191 children died when they were less than or equal to 10 years old. The mortality rates for < 5 and 5-9 years is 882.25 and 117.75 per 1000 live births respectively, with a maternal mortality rate of 447.3 deaths per 100,000 live births from 2000 to 2004. Child mortality risk was very high in less than 6 weeks after their mother's death (HR 3.45 [95%CI: 1.3-6.54]), and decreased drastically after 3 years following her death (HR 0.8 [0.2-6.3]). This increased risk was more pronounced among children aged less than 1 month and living in poor households. CONCLUSIONS: Children (less than 10 years) in rural households are at their highest risk of dying within 6 weeks of mother's death and this risk decreases substantially after the highly vulnerable window. This indicates that the period of mother's death does play a critical role on the survival of her children.Thus, understanding this risk and its timing in relation to a mother's death is critical to guide interventions and stress the relevance of assessing the interaction between clinical care and socio economic programs in addressing the needs of orphans. PMID- 30400790 TI - Promoting influenza prevention for elderly people in Hong Kong using health action process approach: study protocol. AB - BACKGROUND: People 65 years or older are at greater risk of serious complications from the seasonal influenza compared with young. To promote elderly people's behavioral compliance toward influenza prevention, the aim of the current project is to develop, implement, and evaluate a theory-based low-administration-cost intervention building on a leading psychological theory, the Health Action Process Approach (HAPA). METHODS: The target group is Hong Kong Chinese elderly people aged 65 or older who rarely or never adopt any preventive actions. This project will be conducted in three phases over 24 months. In phase 1, intervention program will be developed building on the HAPA theoretical framework which comprises both the initiation and maintenance of influenza prevention behaviors. In phase 2, intervention will be implemented and evaluated using a randomized controlled trial, including: (a) behavior initiation only, (b) behavior initiation + behavior maintenance, and (c) control group. Both the initiation and maintenance components will comprise weekly-delivered telephone based individual intervention sessions in 3 months. In phase 3, outcome evaluation of behavioral and psychological variables and process evaluation will be conducted. The effectiveness of the intervention will be analyzed using a series of linear mixed models on each behavioral and psychological outcome variable. Structural equation modelling will be used to test the hypothesized theoretical sequence in the HAPA model. DISCUSSION: The proposed project is expected to design theory-based intervention materials to promote the influenza prevention behaviors in Hong Kong elderly people and provide information on its effectiveness and the potential changing mechanism of behavior initiation and maintenance. TRIAL REGISTRATION: This randomized controlled trial was funded by the Health and Medical Research Fund (HMRF), Food and Health Bureau of the Government of the Hong Kong Special Administrative Region (Ref: 16151222) and was registered on 13/10/2017 at CCRB Clinical Trials Registry of the Chinese University of Hong Kong, a Partner Registry of a WHO Primary Registry (Ref: CUHK_CCRB00567 ). PMID- 30400791 TI - The arrhythmogenic cardiotoxicity of the quinoline and structurally related antimalarial drugs: a systematic review. AB - BACKGROUND: Several quinoline and structurally related antimalarial drugs are associated with cardiovascular side effects, particularly hypotension and electrocardiographic QT interval prolongation. A prolonged QT interval is a sensitive but not specific risk marker for the development of Torsade de Pointes a potentially lethal polymorphic ventricular tachyarrhythmia. The increasing use of quinoline and structurally related antimalarials in mass treatments to eliminate malaria rapidly highlights the need to review their cardiovascular safety profiles. METHODS: The primary objective of this systematic review was to describe the documented clinical and electrocardiographic cardiovascular side effects of quinine, mefloquine, lumefantrine, piperaquine, halofantrine, chloroquine, sulfadoxine-pyrimethamine, amodiaquine, and primaquine. Trials in healthy subjects or patients with Plasmodium falciparum or P. vivax infection were included if at least two ECGs were conducted during the trial. All trial designs were included except case reports and pooled analyses. Secondary outcomes were the methods adopted by trials for measuring and reporting the QT interval. RESULTS: Data from trials published between 1982 and July 2016 were included. A total of 177 trials met the inclusion criteria. 35,448 participants received quinoline antimalarials in these trials, of which 18,436 participants underwent ECG evaluation. Subjects with co-medication use or comorbidities including cardiovascular disease were excluded from the majority of trials. Dihydroartemisinin-piperaquine was the drug most studied (5083 participants). Despite enormous use over the past 60 years, only 1076, 452, and 150 patients had ECG recordings reported in studies of chloroquine, amodiaquine, and primaquine respectively. Transiently high concentrations of quinine, quinidine, and chloroquine following parenteral administration have all been associated with hypotension, but there were no documented reports of death or syncope attributable to a cardiovascular cause, nor of electrocardiographic recordings of ventricular arrhythmia in these trials. The large volume of missing outcome information and the heterogeneity of ECG interval reporting and measurement methodology did not allow pooled quantitative analysis of QT interval changes. CONCLUSIONS: No serious cardiac adverse effects were recorded in malaria clinical trials of 35,548 participants who received quinoline and structurally related antimalarials with close follow-up including 18,436 individuals who underwent ECG evaluation. While these findings provide further evidence of the rarity of serious cardiovascular events after treatment with these drugs, they also underscore the need for continued strengthening of pharmacovigilance systems for robust detection of rare drug adverse events in real-world populations. A standardised approach to measurement and reporting of ECG data in malaria trials is also needed. TRIAL REGISTRATION: PROSPERO CRD42016036678. PMID- 30400792 TI - Role of miR29c in goose fatty liver is mediated by its target genes that are involved in energy homeostasis and cell growth. AB - BACKGROUND: A short period of overfeeding can lead to severe hepatic steatosis in the goose, which is physiological, suggesting that geese, as a descendent of a migrating ancestor, may have evolutionally developed a unique mechanism that operates in contrast to the mechanism underlying pathological fatty liver in humans or other mammals. In this study, we report that suppression of miR29c and upregulation of its target genes in goose fatty liver vs. normal liver could be part of a unique mechanism that contributes to the regulation of energy homeostasis and cell growth. RESULTS: Our data showed that miR29c expression was comprehensively inhibited in energy homeostasis-related tissues (the liver, fat and muscle) of overfed vs. normally fed geese, which is different from miR29c induction that occurs in tissues of the diabetic rat. To address the function of miR29c, three predicted target genes (i.e., Insig1, Sgk1 and Col3a1) that participate in energy homeostasis or cell growth were validated by a dual fluorescence reporter system and other in vitro assays. Importantly, expression of Insig1, Sgk1 and Col3a1 was upregulated in goose fatty liver. In line with these observations, treatment of goose hepatocytes with high glucose or palmitate suppressed the expression of miR29c but induced the expression of the target genes, suggesting that hyperglycemia and hyperlipidemia, at least partially, contribute to the suppression of miR29c and induction of the target genes in goose fatty liver. In addition, pharmacological assays indicated that RFX1 was a transcription factor involved in the expression of miR29c. CONCLUSIONS: This study suggests that miR29c may play a role in the regulation of energy homeostasis and tissue growth via its target genes, contributing to the tolerance of the goose to severe hepatic steatosis. PMID- 30400793 TI - Comparison of hock- and footpad-injection as a prostate adenocarcinoma model in rats. AB - BACKGROUND: Objective of this study is a feasibility-test comparing hock- and footpad-injection in rats with inoculated MatLyLu - adenocarcinoma tumor model. This study compares the development of an adenocarcinoma model (MatLyLu) in 12 Copenhagen rats. Two groups (n = 6) of animals were inoculated with 1 * 106 MatLyLu tumor cells solved in 0.1 ml NaCl either by footpad or hock injection. All animals were examined before tumor inoculation and before euthanasia using a 3.0 Tesla MRI. Histological evaluation of all organs was performed post mortem. RESULTS: Both types of injection were able to induce the adenocarcinoma model using MatLyLu tumor cells. The primary tumor could be visualized in MRI and confirmed histologically. Comparing the risk of reflux and the maximum injection volume during injection, the hock injection was superior to the footpad injection (less reflux, less anatomical restrictions for larger volumes). The hock injection induces a faster tumor growth compared to the footpad injection. As consequence the maximum level of long term discomfort after hock injection was reached earlier, even if it grew on a not weight bearing structure. Early lymph node tumor metastasis could not be observed macroscopically nor detected histologically. Therefore the reproducibility of the MatLyLu tumor model is questionable. CONCLUSION: Hock injection is a feasible alternative technique compared with footpad-injection in rats. It provides a save and easy injection method for various early-terminated applications with the potential to increase animal welfare during tumor models in rats. PMID- 30400794 TI - Transcriptomics of Haemophilus (Glasserella) parasuis serovar 5 subjected to culture conditions partially mimetic to natural infection for the search of new vaccine antigens. AB - BACKGROUND: Haemophilus (Glasserella) parasuis is the etiological agent of Glasser's disease in pigs. Control of this disorder has been traditionally based on bacterins. The search for alternative vaccines has focused mainly on the study of outer membrane proteins. This study investigates the transcriptome of H. (G.) parasuis serovar 5 subjected to in vitro conditions mimicking to those existing during an infection (high temperature and iron-restriction), with the aim of detecting the overexpression of genes coding proteins exposed on bacterial surface, which could represent good targets as vaccine candidates. RESULTS: The transcriptomic approach identified 13 upregulated genes coding surface proteins: TbpA, TbpB, HxuA, HxuB, HxuC, FhuA, FimD, TolC, an autotransporter, a protein with immunoglobulin folding domains, another large protein with a tetratricopeptide repeat and two small proteins that did not contain any known domains. Of these, the first six genes coded proteins being related to iron extraction. CONCLUSION: Six of the proteins have already been tested as vaccine antigens in murine and/or porcine infection models and showed protection against H. (G.) parasuis. However, the remaining seven have not yet been tested and, consequently, they could become useful as putative antigens in the prevention of Glasser's disease. Anyway, the expression of this seven novel vaccine candidates should be shown in other serovars different from serovar 5. PMID- 30400795 TI - Understanding drivers of domestic public expenditure on reproductive, maternal, neonatal and child health in Peru at district level: an ecological study. AB - BACKGROUND: Peru has increased substantially its domestic public expenditure in maternal and child health. Peruvian departments are heterogeneous in contextual and geographic factors, underlining the importance of disaggregated expenditure analysis up to the district level. We aimed to assess possible district level factors influencing public expenditure on reproductive, maternal, neonatal and child health (RMNCH) in Peru. METHODS: We performed an ecological study in 24 departments, with specific RMNCH expenditure indicators as outcomes, and covariates of different hierarchical dimensions as predictors. To account for the influence of variables included in the different dimensions over time and across departments, we chose a stepwise multilevel mixed-effects regression model, with department-year as the unit of analysis. RESULTS: Public expenditure increased in all departments, particularly for maternal-neonatal and child health activities, with a different pace across departments. The multilevel analysis did not reveal consistently influential factors, except for previous year expenditure on reproductive and maternal-neonatal health. Our findings may be explained by a combination of inertial expenditure, a results-based budgeting approach to increase expenditure efficiency and effectiveness, and by a mixed-effects decentralization process. Sample size, interactions and collinearity cannot be ruled out completely. CONCLUSIONS: Public district-level RMNCH expenditure has increased remarkably in Peru. Evidence on underlying factors influencing such trends warrants further research, most likely through a combination of quantitative and qualitative approaches. PMID- 30400796 TI - A large animal model for standardized testing of bone regeneration strategies. AB - BACKGROUND: The need for bone graft substitutes including those being developed to be applied together with new strategies of bone regeneration such as tissue engineering and cell-based approaches is growing. No large animal model of bone regeneration has been accepted as a standard testing model. Standardization may be the key to moving systematically towards better bone regeneration. This study aimed to establish a model of bone regeneration in the sheep that lends itself to strict standardization and in which a number of substances can be tested within the same animal. To this end the caudal border of the ovine scapula was used as a consistent bed of mineralized tissue that provided sufficient room for a serial alignment of multiple experimental drill holes. RESULTS: The findings show that for the sake of standardization, surgery should be restricted to the middle part of the caudal margin, an area at least 80 mm proximal from the Glenoid cavity, but not more than 140 mm away from it, in the adult female Land Merino sheep. A distance of 5 mm from the caudal margin should also be observed. CONCLUSIONS: This standardized model with defined uniform defects and defect sites results in predictable and reproducible bone regeneration processes. Defects are placed unilaterally in only one limb of the animal, avoiding morbidity in multiple limbs. The fact that five defects per animal can be evaluated is conducive to intra-animal comparisons and reduces the number of animals that have to be subject to experimentation. PMID- 30400797 TI - Periostin involved in the activated hepatic stellate cells-induced progression of residual hepatocellular carcinoma after sublethal heat treatment: its role and potential for therapeutic inhibition. AB - BACKGROUND: Incomplete thermal ablation may induce invasiveness of hepatocellular carcinoma (HCC). Here, we investigated whether activated hepatic stellate cells (HSCs) would accelerate the progression of residual HCC after sublethal heat treatment, and thus sought to identify the potential targets. METHODS: Hepatocellular carcinoma cells were exposed to sublethal heat treatment and then cultured with the conditioned medium from activated HSCs (HSC-CM). The cell proliferation, migration, invasion and parameters of epithelial-mesenchymal transition (EMT) were analyzed. In vivo tumor progression of heat-treated residual HCC cells inoculated with activated HSCs was studied in nude mice. RESULTS: HSC-CM significantly enhanced the proliferation, motility, invasion, prominent EMT activation and decreased apoptosis of heat-exposed residual HCC cells. These increased malignant phenotypes were markedly attenuated by neutralizing periostin (POSTN) in HSC-CM. Furthermore, exogenous POSTN administration exerted the similar effects of HSC-CM on heat-treated residual HCC cells. POSTN induced the prominent activation of p52Shc and ERK1/2 via integrin beta1 in heat-exposed residual HCC cells. Vitamin D analog calcipotriol blocked POSTN secretion from activated HSCs. Calcipotriol plus cisplatin significantly suppressed the activated HSCs-enhanced tumor progression of heat-treated residual HCC cells via the inhibited POSTN expression and the increased apoptosis. CONCLUSIONS: Activated HSCs promote the tumor progression of heat-treated residual HCC through the release of POSTN, which could be inhibited by calcipotriol. Calcipotriol plus cisplatin could be used to thwart the accelerated progression of residual HCC after suboptimal heat treatment. PMID- 30400798 TI - Analysis of longitudinal semicontinuous data using marginalized two-part model. AB - BACKGROUND: Connective tissue growth factor (CTGF), is a secreted matricellular factor that has been linked to increased risk of cardiovascular disease in diabetic subjects. Despite the biological role of CTGF in diabetes, it still remains unclear how CTGF expression is regulated. In this study, we aim to identify the clinical parameters that modulate plasma CTGF levels measured longitudinally in type 1 diabetic patients over a period of 10 years. A number of patients had negligible measured values of plasma CTGF that formed a point mass at zero, whereas others had high positive values of CTGF that were measured on a continuous scale. The observed combination of excessive zero and continuous positively distributed non-zero values in the CTGF outcome is referred to as semicontinuous data. METHODS: We propose a novel application of a marginalized two-part model (mTP) extended to accommodate longitudinal semicontinuous data in which the marginal mean is expressed in terms of the covariates and estimates of their effect on the mean responses are generated. The continuous component is assumed to follow distributions that stem from the generalized gamma family whereas the binary measure is analyzed using logistic model and both have correlated random effects. Other approaches including the one- and two-part with uncorrelated and correlated random effects models were also applied and their estimates were all compared. RESULTS: Our results using the mTP model identified intensive glucose control treatment and smoking as clinical factors that were associated with decreased and increased odds of observing non-zero CTGF values respectively. In addition, hemoglobin A1c, systolic blood pressure, and high density lipoprotein were all shown to be significant risk factors that contribute to increasing CTGF levels. These findings were consistently observed under the mTP model but varied with the distributions for the other models. Accuracy and precision of the mTP model was further validated using simulation studies. CONCLUSION: The mTP model identified new clinical determinants that modulate the levels of CTGF in diabetic subjects. Applicability of this approach can be extended to other biomarkers measured in patient populations that display a combination of negligible zero and non-zero values. PMID- 30400799 TI - Status of programmed death-ligand 1 expression in sarcomas. AB - BACKGROUND: Sarcomas are challenging to study because of their rarity and histomorphological complexity. PD1 and PD-L1 inhibitors showed a promising anti tumor effect in solid tumors, where a relationship between PD-L1 expression and the objective response has been evidenced. METHODS: In this study, we examined PD L1 expression in 16 bone and soft tissue sarcoma cell lines of 11 different subtypes by means of western blot, flow cytometry and immunocytochemistry, and in 230 FFPE patient-derived tumor tissues by means of immunohistochemistry using three different antibody clones. The association between PD-L1 expression and clinicopathological features was evaluated. RESULTS: We demonstrated that PD-L1 protein is highly expressed in pleomorphic rhabdomyosarcoma, fibrosarcoma, and dedifferentiated liposarcoma (DDLPS) cell lines. From the tissue microarray, undifferentiated pleomorphic sarcoma showed >= 1% immunoreactivity in 20%, 17.6%, and 16.3% of the cases with PD-L1 22C3, SP263, and SP142 antibodies, respectively. In whole sections stained with a PD-L1 22C3 antibody, DDLPS showed >= 1% immunoreactivity in 21.9% of the cases. In DDLPS group, cases with >= 1% PD L1 expression showed statistically significantly worse recurrence-free survival (P = 0.027) and overall survival (P = 0.017) rates. Upon interferon-gamma treatment, the mRNA expression levels of PD-L1 were elevated in the HS-RMS-1, LIPO-224B, MLS1765, RH30, and RH41 cell lines. CONCLUSIONS: We found that the expression of PD-L1 in sarcoma differs depending on the histologic subtype and the PD-L1 antibody clones. These results may serve as primary data for the selection of appropriate patients when applying PD1/PD-L1 inhibitor therapy in sarcoma. PMID- 30400800 TI - Protein kinase C-delta inhibition protects blood-brain barrier from sepsis induced vascular damage. AB - BACKGROUND: Neuroinflammation often develops in sepsis leading to activation of cerebral endothelium, increased permeability of the blood-brain barrier (BBB), and neutrophil infiltration. We have identified protein kinase C-delta (PKCdelta) as a critical regulator of the inflammatory response and demonstrated that pharmacologic inhibition of PKCdelta by a peptide inhibitor (PKCdelta-i) protected endothelial cells, decreased sepsis-mediated neutrophil influx into the lung, and prevented tissue damage. The objective of this study was to elucidate the regulation and relative contribution of PKCdelta in the control of individual steps in neuroinflammation during sepsis. METHODS: The role of PKCdelta in mediating human brain microvascular endothelial (HBMVEC) permeability, junctional protein expression, and leukocyte adhesion and migration was investigated in vitro using our novel BBB on-a-chip (B3C) microfluidic assay and in vivo in a rat model of sepsis induced by cecal ligation and puncture (CLP). HBMVEC were cultured under flow in the vascular channels of B3C. Confocal imaging and staining were used to confirm tight junction and lumen formation. Confluent HBMVEC were pretreated with TNF-alpha (10 U/ml) for 4 h in the absence or presence of PKCdelta-i (5 MUM) to quantify neutrophil adhesion and migration in the B3C. Permeability was measured using a 40-kDa fluorescent dextran in vitro and Evans blue dye in vivo. RESULTS: During sepsis, PKCdelta is activated in the rat brain resulting in membrane translocation, a step that is attenuated by treatment with PKCdelta-i. Similarly, TNF-alpha-mediated activation of PKCdelta and its translocation in HBMVEC are attenuated by PKCdelta-i in vitro. PKCdelta inhibition significantly reduced TNF-alpha-mediated hyperpermeability and TEER decrease in vitro in activated HBMVEC and rat brain in vivo 24 h after CLP induced sepsis. TNF-alpha-treated HBMVEC showed interrupted tight junction expression, whereas continuous expression of tight junction protein was observed in non-treated or PKCdelta-i-treated cells. PKCdelta inhibition also reduced TNF alpha-mediated neutrophil adhesion and migration across HBMVEC in B3C. Interestingly, while PKCdelta inhibition decreased the number of adherent neutrophils to baseline (no-treatment group), it significantly reduced the number of migrated neutrophils below the baseline, suggesting a critical role of PKCdelta in regulating neutrophil transmigration. CONCLUSIONS: The BBB on-a-chip (B3C) in vitro assay is suitable for the study of BBB function as well as screening of novel therapeutics in real-time. PKCdelta activation is a key signaling event that alters the structural and functional integrity of BBB leading to vascular damage and inflammation-induced tissue damage. PKCdelta-TAT peptide inhibitor has therapeutic potential for the prevention or reduction of cerebrovascular injury in sepsis-induced vascular damage. PMID- 30400801 TI - Ibuprofen prevents progression of ataxia telangiectasia symptoms in ATM-deficient mice. AB - BACKGROUND: Inflammation plays a critical role in accelerating the progression of neurodegenerative diseases, such as Alzheimer's disease (AD) and ataxia telangiectasia (A-T). In A-T mouse models, LPS-induced neuroinflammation advances the degenerative changes found in cerebellar Purkinje neurons both in vivo and in vitro. In the current study, we ask whether ibuprofen, a non-steroidal anti inflammatory drug (NSAID), can have the opposite effect and delay the symptoms of the disease. METHODS: We tested the beneficial effects of ibuprofen in both in vitro and in vivo models. Conditioned medium from LPS stimulated primary microglia (LM) applied to cultures of dissociated cortical neurons leads to numerous degenerative changes. Pretreatment of the neurons with ibuprofen, however, blocked this damage. Systemic injection of LPS into either adult wild type or adult Atm-/- mice produced an immune challenge that triggered profound behavioral, biochemical, and histological effects. We used a 2-week ibuprofen pretreatment regimen to investigate whether these LPS effects could be blocked. We also treated young presymptomatic Atm-/- mice to determine if ibuprofen could delay the appearance of symptoms. RESULTS: Adding ibuprofen directly to neuronal cultures significantly reduced LM-induced degeneration. Curiously, adding ibuprofen to the microglia cultures before the LPS challenge had little effect, thus implying a direct effect of the NSAID on the neuronal cultures. In vivo administration of ibuprofen to Atm-/- animals before a systemic LPS immune challenge suppressed cytological damage. The ibuprofen effects were widespread as microglial activation, p38 phosphorylation, DNA damage, and neuronal cell cycle reentry were all reduced. Unfortunately, ibuprofen only slightly improved the LPS induced behavioral deficits. Yet, while the behavioral symptoms could not be reversed once they were established in adult Atm-/- animals, administration of ibuprofen to young mutant pups prevented their symptoms from appearing. CONCLUSION: Inflammatory processes impact the normal progression of A-T implying that modulation of the immune system can have therapeutic benefit for both the behavioral and cellular symptoms of this neurodegenerative disease. PMID- 30400802 TI - Fragment size and level of cell-free DNA provide prognostic information in patients with advanced pancreatic cancer. AB - BACKGROUND: It was recently demonstrated that the size of cell-free DNA (cfDNA) fragments that originates from tumor cells are shorter than cfDNA fragments that originates from non-malignant cells. We investigated whether cfDNA fragment size and cfDNA levels might have prognostic value in patients with advanced pancreatic cancer. METHODS: Blood samples were obtained from patients with advanced pancreatic cancer, before (n = 61) initiation of chemotherapy and after the first cycle of chemotherapy (n = 39). Samples were separated with density centrifugation and plasma DNA was isolated. Mode cfDNA fragment size and cfDNA levels were then determined using a 2100 Bioanalyzer. A cohort of partially age matched healthy volunteers (n = 28) constituted the control group. RESULTS: Both a pre-treatment cfDNA fragment size of <= 167 bp (mode) and high pre-treatment cfDNA levels were associated with shorter progression-free survival (PFS) (p = 0.002 and p < 0.001, respectively) and overall survival (OS) (p = 0.001 and p = 0.001, respectively). Furthermore, multivariable Cox regression analyses demonstrated that pre-treatment cfDNA levels could independently predict prognosis for both PFS (HR = 3.049, p = 0.005) and OS (HR = 2.236, p = 0.028). CONCLUSION: This study demonstrates that cfDNA fragment size and cfDNA levels can be used to predict disease outcome in patients with advanced pancreatic cancer. The described approach, using a rapid, economic and simple test to reveal prognostic information, has potential for future treatment stratification and monitoring. PMID- 30400803 TI - Treat me nice! -a cross-sectional study examining support during the first year in the emergency medical services. AB - BACKGROUND: Working in the emergency medical service (EMS) can be extremely varying and sometimes physically and psychologically demanding. Being new in this context can be a great challenge. This study aim to describe what ambulance nurses consider to be important support during the first year in the EMS. METHODS: Three hundred and eighty-nine eligible participants that had graduated from the prehospital emergency care program were identified via university registrations office in Sweden. The eligible participants received a study specific questionnaire via mail consisting of 70 statements about support during the first year. The perceived importance of each statement were graded on a 7 point Likert scale. The gradings were analysed using descriptive statistics and frequencies, mean and SD were calculated. RESULTS: Two hundred and thirty questionnaires were returned fully completed, giving a response rate of 59%. Fourteen statements regarding desirable support were rated with mean values > 6.00 and SD < 1.00 and considered as being the most important during the first year in the EMS. The important supports regarded; colleagues and work environment, management and organisation, experience-based knowledge, introduction period, practical support, and theoretical support. Most statements regarded culture and climate and the way the newcomers wanted to be treated. CONCLUSION: It was concluded that an important way to support newcomers in the EMS is to treat them 'nice'. This can be achieved by creating an open climate and a welcoming culture where the new professionals feel trusted and treated with respect, created ways to work structurally, have applicable medical guidelines, and for newcomers to receive feedback on their actions. PMID- 30400804 TI - Understanding and repurposing CRISPR-mediated alternative splicing. AB - Two new studies refine our understanding of CRISPR-associated exon skipping and redefine its utility in engineering alternative splicing. PMID- 30400805 TI - SIFR annotator: ontology-based semantic annotation of French biomedical text and clinical notes. AB - BACKGROUND: Despite a wide adoption of English in science, a significant amount of biomedical data are produced in other languages, such as French. Yet a majority of natural language processing or semantic tools as well as domain terminologies or ontologies are only available in English, and cannot be readily applied to other languages, due to fundamental linguistic differences. However, semantic resources are required to design semantic indexes and transform biomedical (text)data into knowledge for better information mining and retrieval. RESULTS: We present the SIFR Annotator ( http://bioportal.lirmm.fr/annotator ), a publicly accessible ontology-based annotation web service to process biomedical text data in French. The service, developed during the Semantic Indexing of French Biomedical Data Resources (2013-2019) project is included in the SIFR BioPortal, an open platform to host French biomedical ontologies and terminologies based on the technology developed by the US National Center for Biomedical Ontology. The portal facilitates use and fostering of ontologies by offering a set of services -search, mappings, metadata, versioning, visualization, recommendation- including for annotation purposes. We introduce the adaptations and improvements made in applying the technology to French as well as a number of language independent additional features -implemented by means of a proxy architecture- in particular annotation scoring and clinical context detection. We evaluate the performance of the SIFR Annotator on different biomedical data, using available French corpora -Quaero (titles from French MEDLINE abstracts and EMEA drug labels) and CepiDC (ICD-10 coding of death certificates)- and discuss our results with respect to the CLEF eHealth information extraction tasks. CONCLUSIONS: We show the web service performs comparably to other knowledge-based annotation approaches in recognizing entities in biomedical text and reach state-of-the-art levels in clinical context detection (negation, experiencer, temporality). Additionally, the SIFR Annotator is the first openly web accessible tool to annotate and contextualize French biomedical text with ontology concepts leveraging a dictionary currently made of 28 terminologies and ontologies and 333 K concepts. The code is openly available, and we also provide a Docker packaging for easy local deployment to process sensitive (e.g., clinical) data in-house ( https://github.com/sifrproject ). PMID- 30400806 TI - Determinants of breastfeeding discontinuation in an Italian cohort of mother infant dyads in the first six months of life: a randomized controlled trial. AB - BACKGROUND: Among breastfeeding determinants, the marketing of breast milk substitutes might contribute to suboptimal breastfeeding rates. The aim of this study was to investigate the effect of receiving information on breast milk substitutes on breastfeeding rates. METHODS: We conducted a randomized, single blind, controlled trial from 2012 to 2014 in a northern Italian maternity ward. We enrolled 802 Caucasian mothers who gave birth to healthy, full-term singletons with a birth weight > 2500 g and who were exclusively breastfeeding from delivery to discharge. Mothers who gave birth to infants with congenital diseases, chromosomal abnormalities, perinatal infections and/or cardio-respiratory instability and/or mothers being affected by endocrine and/or metabolic and/or gastrointestinal and/or renal diseases were excluded. Mothers were randomized to either receive (group A, n = 405) or not (group B, n = 397) written information on a breast milk substitute at discharge. Breastfeeding was promoted and supported in all mother-infant pairs equally. The mode of feeding for up to 6 months after delivery was determined by phone interview. To detect a 10% difference between groups in the discontinuation rate of exclusive breastfeeding at three months of age at 5% significance and 80% power, a total of 356 mother infant pairs per group were needed. RESULTS: The exclusive breastfeeding prevalence was 91% and 92% at 7 days, 79% and 70% at 1 month, 75% and 66% at 2 months, 72% and 62% at 3 months, and 3% and 2% at 6 months in groups A and B, respectively. The relative risk (95% confidence interval) of exclusive breastfeeding (group A vs B) at 7 days and at 1, 2, 3 and 6 months was as follows: 0.99 (0.95-1.03), 1.12 (1.03-1.21), 1.13 (1.03-1.24), 1.15 (1.04-1.27), and 1.49 (0.62-3.61). Nutritional, lifestyle and lactational factors were the primary contributing determinants to early breastfeeding discontinuation. CONCLUSIONS: The present findings indicate that receiving written information on breast milk substitutes at hospital discharge, provided that breastfeeding support and education are offered, does not negatively affect breastfeeding rates. TRIAL REGISTRATION: NCT03208114. Registered 5 July 2017. PMID- 30400807 TI - Assessing the impact of exact reads on reducing the error rate of read mapping. AB - BACKGROUND: Nowadays, according to valuable resources of high-quality genome sequences, reference-based assembly methods with high accuracy and efficiency are strongly required. Many different algorithms have been designed for mapping reads onto a genome sequence which try to enhance the accuracy of reconstructed genomes. In this problem, one of the challenges occurs when some reads are aligned to multiple locations due to repetitive regions in the genomes. RESULTS: In this paper, our goal is to decrease the error rate of rebuilt genomes by resolving multi-mapping reads. To achieve this purpose, we reduce the search space for the reads which can be aligned against the genome with mismatches, insertions or deletions to decrease the probability of incorrect read mapping. We propose a pipeline divided to three steps: ExactMapping, InExactMapping, and MergingContigs, where exact and inexact reads are aligned in two separate phases. We test our pipeline on some simulated and real data sets by applying some read mappers. The results show that the two-step mapping of reads onto the contigs generated by a mapper such as Bowtie2, BWA and Yara is effective in improving the contigs in terms of error rate. CONCLUSIONS: Assessment results of our pipeline suggest that reducing the error rate of read mapping, not only can improve the genomes reconstructed by reference-based assembly in a reasonable running time, but can also have an impact on improving the genomes generated by de novo assembly. In fact, our pipeline produces genomes comparable to those of a multi mapping reads resolution tool, namely MMR by decreasing the number of multi mapping reads. Consequently, we introduce EIM as a post-processing step to genomes reconstructed by mappers. PMID- 30400808 TI - Genome-wide identification and analysis of WD40 proteins in wheat (Triticum aestivum L.). AB - BACKGROUND: WD40 domains are abundant in eukaryotes, and they are essential subunits of large multiprotein complexes, which serve as scaffolds. WD40 proteins participate in various cellular processes, such as histone modification, transcription regulation, and signal transduction. WD40 proteins are regarded as crucial regulators of plant development processes. However, the systematic identification and analysis of WD40 proteins have yet to be reported in wheat. RESULTS: In this study, a total of 743 WD40 proteins were identified in wheat, and they were grouped into 5 clusters and 11 subfamilies. Their gene structures, chromosomal locations, and evolutionary relationships were analyzed. Among them, 39 and 46 pairs of TaWD40s were distinguished as tandem duplication and segmental duplication genes. The 123 OsWD40s were identified to exhibit synteny with TaWD40s. TaWD40s showed the specific characteristics at the reproductive developmental stage, and numerous TaWD40s were involved in responses to stresses, including cold, heat, drought, and powdery mildew infection pathogen, based on the result of RNA-seq data analysis. The expression profiles of some TaWD40s in wheat seed development were confirmed through qRT-PCR technique. CONCLUSION: In this study, 743 TaWD40s were identified from the wheat genome. As the main driving force of evolution, duplication events were observed, and homologous recombination was another driving force of evolution. The expression profiles of TaWD40s revealed their importance for the growth and development of wheat and their response to biotic and abiotic stresses. Our study also provided important information for further functional characterization of some WD40 proteins in wheat. PMID- 30400809 TI - Single sample scoring of molecular phenotypes. AB - BACKGROUND: Gene set scoring provides a useful approach for quantifying concordance between sample transcriptomes and selected molecular signatures. Most methods use information from all samples to score an individual sample, leading to unstable scores in small data sets and introducing biases from sample composition (e.g. varying numbers of samples for different cancer subtypes). To address these issues, we have developed a truly single sample scoring method, and associated R/Bioconductor package singscore ( https://bioconductor.org/packages/singscore ). RESULTS: We use multiple cancer data sets to compare singscore against widely-used methods, including GSVA, z score, PLAGE, and ssGSEA. Our approach does not depend upon background samples and scores are thus stable regardless of the composition and number of samples being scored. In contrast, scores obtained by GSVA, z-score, PLAGE and ssGSEA can be unstable when less data are available (NS < 25). The singscore method performs as well as the best performing methods in terms of power, recall, false positive rate and computational time, and provides consistently high and balanced performance across all these criteria. To enhance the impact and utility of our method, we have also included a set of functions implementing visual analysis and diagnostics to support the exploration of molecular phenotypes in single samples and across populations of data. CONCLUSIONS: The singscore method described here functions independent of sample composition in gene expression data and thus it provides stable scores, which are particularly useful for small data sets or data integration. Singscore performs well across all performance criteria, and includes a suite of powerful visualization functions to assist in the interpretation of results. This method performs as well as or better than other scoring approaches in terms of its power to distinguish samples with distinct biology and its ability to call true differential gene sets between two conditions. These scores can be used for dimensional reduction of transcriptomic data and the phenotypic landscapes obtained by scoring samples against multiple molecular signatures may provide insights for sample stratification. PMID- 30400810 TI - Whole genome sequencing analysis of multiple Salmonella serovars provides insights into phylogenetic relatedness, antimicrobial resistance, and virulence markers across humans, food animals and agriculture environmental sources. AB - BACKGROUND: Salmonella enterica is a significant foodborne pathogen, which can be transmitted via several distinct routes, and reports on acquisition of antimicrobial resistance (AMR) are increasing. To better understand the association between human Salmonella clinical isolates and the potential environmental/animal reservoirs, whole genome sequencing (WGS) was used to investigate the epidemiology and AMR patterns within Salmonella isolates from two adjacent US states. RESULTS: WGS data of 200 S. enterica isolates recovered from human (n = 44), swine (n = 32), poultry (n = 22), and farm environment (n = 102) were used for in silico prediction of serovar, distribution of virulence genes, and phylogenetically clustered using core genome single nucleotide polymorphism (SNP) and feature frequency profiling (FFP). Furthermore, AMR was studied both by genotypic prediction using five curated AMR databases, and compared to phenotypic AMR using broth microdilution. Core genome SNP-based and FFP-based phylogenetic trees showed consistent clustering of isolates into the respective serovars, and suggested clustering of isolates based on the source of isolation. The overall correlation of phenotypic and genotypic AMR was 87.61% and 97.13% for sensitivity and specificity, respectively. AMR and virulence genes clustered with the Salmonella serovars, while there were also associations between the presence of virulence genes in both animal/environmental isolates and human clinical samples. CONCLUSIONS: WGS is a helpful tool for Salmonella phylogenetic analysis, AMR and virulence gene predictions. The clinical isolates clustered closely with animal and environmental isolates, suggesting that animals and environment are potential sources for dissemination of AMR and virulence genes between Salmonella serovars. PMID- 30400812 TI - Analysis and correction of compositional bias in sparse sequencing count data. AB - BACKGROUND: Count data derived from high-throughput deoxy-ribonucliec acid (DNA) sequencing is frequently used in quantitative molecular assays. Due to properties inherent to the sequencing process, unnormalized count data is compositional, measuring relative and not absolute abundances of the assayed features. This compositional bias confounds inference of absolute abundances. Commonly used count data normalization approaches like library size scaling/rarefaction/subsampling cannot correct for compositional or any other relevant technical bias that is uncorrelated with library size. RESULTS: We demonstrate that existing techniques for estimating compositional bias fail with sparse metagenomic 16S count data and propose an empirical Bayes normalization approach to overcome this problem. In addition, we clarify the assumptions underlying frequently used scaling normalization methods in light of compositional bias, including scaling methods that were not designed directly to address it. CONCLUSIONS: Compositional bias, induced by the sequencing machine, confounds inferences of absolute abundances. We present a normalization technique for compositional bias correction in sparse sequencing count data, and demonstrate its improved performance in metagenomic 16s survey data. Based on the distribution of technical bias estimates arising from several publicly available large scale 16s count datasets, we argue that detailed experiments specifically addressing the influence of compositional bias in metagenomics are needed. PMID- 30400811 TI - Characterization and expression profiling of microRNAs in response to plant feeding in two host-plant strains of the lepidopteran pest Spodoptera frugiperda. AB - BACKGROUND: A change in the environment may impair development or survival of living organisms leading them to adapt to the change. The resulting adaptation trait may reverse, or become fixed in the population leading to evolution of species. Deciphering the molecular basis of adaptive traits can thus give evolutionary clues. In phytophagous insects, a change in host-plant range can lead to emergence of new species. Among them, Spodoptera frugiperda is a major agricultural lepidopteran pest consisting of two host-plant strains having diverged 3 MA, based on mitochondrial markers. In this paper, we address the role of microRNAs, important gene expression regulators, in response to host-plant change and in adaptive evolution. RESULTS: Using small RNA sequencing, we characterized miRNA repertoires of the corn (C) and rice (R) strains of S. frugiperda, expressed during larval development on two different host-plants, corn and rice, in the frame of reciprocal transplant experiments. We provide evidence for 76 and 68 known miRNAs in C and R strains and 139 and 171 novel miRNAs. Based on read counts analysis, 34 of the microRNAs were differentially expressed in the C strain larvae fed on rice as compared to the C strain larvae fed on corn. Twenty one were differentially expressed on rice compared to corn in R strain. Nine were differentially expressed in the R strain compared to C strain when reared on corn. A similar ratio of microRNAs was differentially expressed between strains on rice. We could validate experimentally by QPCR, variation in expression of the most differentially expressed candidates. We used bioinformatics methods to determine the target mRNAs of known microRNAs. Comparison with the mRNA expression profile during similar reciprocal transplant experiment revealed potential mRNA targets of these host-plant regulated miRNAs. CONCLUSIONS: In the current study, we performed the first systematic analysis of miRNAs in Lepidopteran pests feeding on host-plants. We identified a set of the differentially expressed miRNAs that respond to the plant diet, or differ constitutively between the two host plant strains. Among the latter, the ones that are also deregulated in response to host-plant are molecular candidates underlying a complex adaptive trait. PMID- 30400813 TI - Genome-wide identification and characterization of long non-coding RNAs involved in the early somatic embryogenesis in Dimocarpus longan Lour. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) are involved in variable cleavage, transcriptional interference, regulation of DNA methylation and protein modification. However, the regulation of lncRNAs in plant somatic embryos remains unclear. The longan (Dimocarpus longan) somatic embryogenesis (SE) system is a good system for research on longan embryo development. RESULTS: In this study, 7643 lncRNAs obtained during early SE in D. longan were identified by high throughput sequencing, among which 6005 lncRNAs were expressed. Of the expressed lncRNAs, 4790 were found in all samples and 160 were specifically expressed in embryogenic callus (EC), 154 in incomplete embryogenic compact structures (ICpECs), and 376 in globular embryos (GEs). We annotated the 6005 expressed lncRNAs, and 1404 lncRNAs belonged to 506 noncoding RNA (ncRNA) families and 4682 lncRNAs were predicted to target protein-coding genes. The target genes included 5051 cis-regulated target genes (5712 pairs) and 1605 trans-regulated target genes (3618 pairs). KEGG analysis revealed that most of the differentially expressed target genes (mRNAs) of the lncRNAs were enriched in the "plant pathogen interaction" and "plant hormone signaling" pathways during early longan SE. Real-time quantitative PCR confirmed that 20 selected lncRNAs showed significant differences in expression and that five lncRNAs were related to auxin response factors. Compared with the FPKM expression trends, 16 lncRNA expression trends were the same in qPCR. In lncRNA-miRNA-mRNA relationship prediction, 40 lncRNAs were predicted to function as eTMs for 15 miRNAs and 7 lncRNAs were identified as potential miRNA precursors. In addition, we verified the lncRNA miRNA-mRNA regulatory relationships by transient expression of miRNAs (miR172a, miR159a.1 and miR398a). CONCLUSION: Analyses of lncRNAs during early longan SE showed that differentially expressed lncRNAs were involved in expression regulation at each SE stage, and may form a regulatory network with miRNAs and mRNAs. These findings provide new insights into lncRNAs and lay a foundation for future functional analysis of lncRNAs during early longan SE. PMID- 30400815 TI - Exploring the genetic basis of gene transcript abundance and metabolite levels in loblolly pine (Pinus taeda L.) using association mapping and network construction. AB - BACKGROUND: Identifying genetic variations that shape important complex traits is fundamental to the genetic improvement of important forest tree species, such as loblolly pine (Pinus taeda L.), which is one of the most commonly planted forest tree species in the southern U.S. Gene transcripts and metabolites are important regulatory intermediates that link genetic variations to higher-order complex traits such as wood development and drought response. A few prior studies have associated intermediate phenotypes including mRNA expression and metabolite levels with a limited number of molecular markers, but the identification of genetic variations that regulate intermediate phenotypes needs further investigation. RESULTS: We identified 1841 single nucleotide polymorphisms (SNPs) associated with 191 gene expression mRNA phenotypes and 524 SNPs associated with 53 metabolite level phenotypes using 2.8 million exome-derived SNPs. The identified SNPs reside in genes with a wide variety of functions. We further integrated the identified SNPs and the associated expressed genes and metabolites into networks. We described the SNP-SNP interactions that significantly impacted the gene transcript abundance and metabolite level in the networks. Key loci and genes in the wood development and drought response networks were identified and analyzed. CONCLUSIONS: This work provides new candidate genes for research on the genetic basis of gene expression and metabolism linked to wood development and drought response in loblolly pine and highlights the efficiency of using association-mapping-based networks to discover candidate genes with important roles in complex biological processes. PMID- 30400814 TI - Alterations in exosomal miRNA profile upon epithelial-mesenchymal transition in human lung cancer cell lines. AB - BACKGROUND: Epithelial-mesenchymal transition (EMT) is regarded as a critical event during tumor metastasis. Recent studies have revealed changes and the contributions of proteins in/on exosomes during EMT. Besides proteins, microRNA (miRNA) is another important functional component of exosomes. We hypothesized that the miRNA profile of exosomes may change following EMT and these exosomal miRNAs may in return promote EMT, migration and invasion of cancer cells. RESULTS: The small RNA profile of exosomes was altered following EMT. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the specific miRNAs of M-exosomes have the potential to drive signal transduction networks in EMT and cancer progression. Co-culture experiments confirmed that M exosomes can enter epithelial cells and promote migration, invasion and expression of mesenchymal markers in the recipient cells. CONCLUSION: Our results reveal changes in the function and miRNA profile of exosomes upon EMT. M-exosomes can promote transfer of the malignant (mesenchymal) phenotype to epithelial recipient cells. Further, the miRNAs specifically expressed in M-exosomes are associated with EMT and metastasis, and may serve as new biomarkers for EMT-like processes in lung cancer. PMID- 30400816 TI - Phylogeography of freshwater planorbid snails reveals diversification patterns in Eurasian continental islands. AB - BACKGROUND: Islands have traditionally been the centre of evolutionary biological research, but the dynamics of immigration and differentiation at continental islands have not been well studied. Therefore, we focused on the Japanese archipelago, the continental islands located at the eastern end of the Eurasian continent. While the Japanese archipelago is characterised by high biodiversity and rich freshwater habitats, the origin and formation mechanisms of its freshwater organisms are not clear. In order to clarify the history of the planorbid gastropod fauna, we conducted phylogenetic analysis, divergence time estimation, ancestral state reconstruction, and lineage diversity estimations. RESULTS: Our analyses revealed the formation process of the planorbid fauna in the Japanese archipelago. Most lineages in the Japanese archipelago have closely related lineages on the continent, and the divergence within the Japanese lineages presumably occurred after the late Pliocene. In addition, each lineage is characterised by different phylogeographical patterns, suggesting that immigration routes from the continent to the Japanese archipelago differ among lineages. Furthermore, a regional lineage diversity plot showed that the present diversity in the Japanese archipelago potentially reflects the differentiation of lineages within the islands after the development of the Japanese archipelago. CONCLUSIONS: Although additional taxon sampling and genetic analysis focused on each lineage are needed, our results suggest that immigration from multiple routes just prior to the development of the Japanese archipelago and subsequent diversification within the islands are major causes of the present-day diversity of the Japanese planorbid fauna. PMID- 30400817 TI - SyNDI: synchronous network data integration framework. AB - BACKGROUND: Systems biology takes a holistic approach by handling biomolecules and their interactions as big systems. Network based approach has emerged as a natural way to model these systems with the idea of representing biomolecules as nodes and their interactions as edges. Very often the input data come from various sorts of omics analyses. Those resulting networks sometimes describe a wide range of aspects, for example different experiment conditions, species, tissue types, stimulating factors, mutants, or simply distinct interaction features of the same network produced by different algorithms. For these scenarios, synchronous visualization of more than one distinct network is an excellent mean to explore all the relevant networks efficiently. In addition, complementary analysis methods are needed and they should work in a workflow manner in order to gain maximal biological insights. RESULTS: In order to address the aforementioned needs, we have developed a Synchronous Network Data Integration (SyNDI) framework. This framework contains SyncVis, a Cytoscape application for user-friendly synchronous and simultaneous visualization of multiple biological networks, and it is seamlessly integrated with other bioinformatics tools via the Galaxy platform. We demonstrated the functionality and usability of the framework with three biological examples - we analyzed the distinct connectivity of plasma metabolites in networks associated with high or low latent cardiovascular disease risk; deeper insights were obtained from a few similar inflammatory response pathways in Staphylococcus aureus infection common to human and mouse; and regulatory motifs which have not been reported associated with transcriptional adaptations of Mycobacterium tuberculosis were identified. CONCLUSIONS: Our SyNDI framework couples synchronous network visualization seamlessly with additional bioinformatics tools. The user can easily tailor the framework for his/her needs by adding new tools and datasets to the Galaxy platform. PMID- 30400819 TI - Detection of long non-coding RNA homology, a comparative study on alignment and alignment-free metrics. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) represent a novel class of non-coding RNAs having a crucial role in many biological processes. The identification of long non-coding homologs among different species is essential to investigate such roles in model organisms as homologous genes tend to retain similar molecular and biological functions. Alignment-based metrics are able to effectively capture the conservation of transcribed coding sequences and then the homology of protein coding genes. However, unlike protein coding genes the poor sequence conservation of long non-coding genes makes the identification of their homologs a challenging task. RESULTS: In this study we compare alignment-based and alignment-free string similarity metrics and look at promoter regions as a possible source of conserved information. We show that promoter regions encode relevant information for the conservation of long non-coding genes across species and that such information is better captured by alignment-free metrics. We perform a genome wide test of this hypothesis in human, mouse, and zebrafish. CONCLUSIONS: The obtained results persuaded us to postulate the new hypothesis that, unlike protein coding genes, long non-coding genes tend to preserve their regulatory machinery rather than their transcribed sequence. All datasets, scripts, and the prediction tools adopted in this study are available at https://github.com/bioinformatics sannio/lncrna-homologs . PMID- 30400818 TI - Combining accurate tumor genome simulation with crowdsourcing to benchmark somatic structural variant detection. AB - BACKGROUND: The phenotypes of cancer cells are driven in part by somatic structural variants. Structural variants can initiate tumors, enhance their aggressiveness, and provide unique therapeutic opportunities. Whole-genome sequencing of tumors can allow exhaustive identification of the specific structural variants present in an individual cancer, facilitating both clinical diagnostics and the discovery of novel mutagenic mechanisms. A plethora of somatic structural variant detection algorithms have been created to enable these discoveries; however, there are no systematic benchmarks of them. Rigorous performance evaluation of somatic structural variant detection methods has been challenged by the lack of gold standards, extensive resource requirements, and difficulties arising from the need to share personal genomic information. RESULTS: To facilitate structural variant detection algorithm evaluations, we create a robust simulation framework for somatic structural variants by extending the BAMSurgeon algorithm. We then organize and enable a crowdsourced benchmarking within the ICGC-TCGA DREAM Somatic Mutation Calling Challenge (SMC-DNA). We report here the results of structural variant benchmarking on three different tumors, comprising 204 submissions from 15 teams. In addition to ranking methods, we identify characteristic error profiles of individual algorithms and general trends across them. Surprisingly, we find that ensembles of analysis pipelines do not always outperform the best individual method, indicating a need for new ways to aggregate somatic structural variant detection approaches. CONCLUSIONS: The synthetic tumors and somatic structural variant detection leaderboards remain available as a community benchmarking resource, and BAMSurgeon is available at https://github.com/adamewing/bamsurgeon . PMID- 30400821 TI - Tuberculous coxitis with trochanteric bursitis manifesting a year after immigration to Germany: a case report. AB - BACKGROUND: Osteoarticular tuberculosis is rare in Germany. In particular, trochanteric bursitis is an extremely rare manifestation of osteoarticular tuberculosis. We describe a case of tuberculous coxitis with trochanteric bursitis, successfully treated with a fourfold tuberculostatic therapy. CASE PRESENTATION: We report the case of a 43-year-old human immunodeficiency virus negative Sudanese man with osteoarticular tuberculosis, who was originally admitted with the suspected diagnosis of ankylosing spondylitis. Low grade fever together with the positive result of an interferon-gamma release assay test as well as findings from magnetic resonance imaging provided clues to the diagnosis. A definitive diagnosis could be set after a computed tomography-guided biopsy. CONCLUSIONS: Apart from a rare involvement pattern of osteoarticular tuberculosis, including trochanteric bursitis, this case highlights the increasing importance of osteoarticular tuberculosis as a differential diagnosis of rheumatic disorders. With the growing migration flows from tuberculosis endemic African countries, clinicians in central and northern Europe may be more frequently confronted with atypical involvement patterns of osteoarticular tuberculosis. PMID- 30400820 TI - Sulfatide decreases the resistance to stress-induced apoptosis and increases P selectin-mediated adhesion: a two-edged sword in breast cancer progression. AB - BACKGROUND: We have previously shown that galactosylceramide (GalCer) affects the tumourigenic and metastatic properties of breast cancer cells by acting as an anti-apoptotic molecule. Since GalCer is a precursor molecule in the synthesis of sulfatides, the present study was aimed to define the role of sulfatides in apoptosis and breast cancer progression. METHODS: Expression of GAL3ST1 in breast cancer cell lines and breast cancer tissue specimens was analysed using real-time PCR, western blotting and immunohistochemistry analysis. The amount of sulfatide, GalCer and ceramide was analysed by thin-layer chromatography binding assay and by the modified hydrophilic interaction liquid chromatography coupled with electrospray mass spectrometry methodology. The tumourigenicity of cancer cells was analysed by an in-vivo tumour growth assay. Apoptotic cells were detected based on caspase-3 activation and the TUNEL assay. The interaction of breast cancer cells with P-selectin or E-selectin was analysed using the flow adhesion assay. The ability of sulfatide-expressing cells to activate and aggregate platelets was studied using the flow-cytometry-based aggregation assay. RESULTS: Using two models of breast cancer, T47D cells with blocked synthesis of sulfatide and MDA-MB-231 cells with neosynthesis of this glycosphingolipid, we showed that high sulfatide levels resulted in increased sensitivity of cancer cells to apoptosis induced by hypoxia and doxorubicin in vitro, and decreased their tumourigenicity after transplantation into athymic nu/nu mice. Accordingly, a clinical study on GAL3ST1 expression in invasive ductal carcinoma revealed that its elevated level is associated with better prognosis. Using MDA-MB-231 cells with neosynthesis of sulfatide we also showed that sulfatide is responsible for adhesion of breast cancer cells to P-selectin-expressing cells, including platelets. Sulfatide also acted as an activating molecule, increasing the expression of P-selectin. CONCLUSIONS: This study demonstrates that increased synthesis of sulfatide sensitises cancer cells to microenvironmental stress factors such as hypoxia and anticancer drugs such as doxorubicin. However, sulfatide is probably not directly involved in apoptotic cascades, because its increased synthesis by GAL3ST1 decreased the amounts of its precursor, GalCer, a known anti-apoptotic molecule. On the other hand, our data support the view that sulfatides are malignancy-related adhesive molecules involved in activating and binding P-selectin-expressing platelets to breast cancer cells. PMID- 30400822 TI - 33rd Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2018) : Washington, D.C., USA. 7-11 November 2018. PMID- 30400823 TI - A risk score system to timely manage treatment in Crohn's disease: a cohort study. AB - BACKGROUND: Clinical severity and intestinal lesions of Crohn's disease (CD) usually progress over time and require a step up adjustment of the therapy either to prevent or to treat complications. The aim of the study was to develop a simple risk scoring system to assess in individual CD patients the risk of disease progression and the need for more intensive treatment and monitoring. METHODS: Prospective cohort study (January 2002-September 2014) including 160 CD patients (93 female, median age 31 years; disease behavior (B)1 25%, B2 55.6%, B3 19.4%; location (L)1 61%, L3 31.9%, L2 6%; L4 0.6%; perianal disease 28.8%) seen at 6-12-month interval. Median follow-up 7.9 years (IQR: 4.3-10.5 years). Poisson models were used to evaluate predictors, at each clinical assessment, of having the following outcomes at the subsequent clinical assessment a) use of steroids; b) start of azathioprine; c) start of anti-TNF-alpha drugs; d) need of surgery. For each outcome 32 variables, including demographic and clinical characteristics of patients and assessment of CD intestinal lesions and complications, were evaluated as potential predictors. The predictors included in the model were chosen by a backward selection. Risk scores were calculated taking for each predictor the integer part of the Poisson model parameter. RESULTS: Considering 1464 clinical assessments 12 independent risk factors were identified, CD lesions, age at diagnosis < 40 years, stricturing behavior (B2), specific intestinal symptoms, female gender, BMI < 21, CDAI> 50, presence of inflammatory markers, no previous surgery or presence of termino-terminal anastomosis, current use of corticosteroid, no corticosteroid at first flare-up. Six of these predicted steroids use (score 0-9), three to start azathioprine (score 0-4); three to start anti-TNF-alpha drugs (score 0-4); six need of surgery (score 0 11). The predicted percentage risk to be treated with surgery within one year since the referral assessment varied from 1 to 28%; with azathioprine from 3 to 13%; with anti-TNF-alpha drugs from 2 to 15%. CONCLUSIONS: These scores may provide a useful clinical tool for clinicians in the prognostic assessment and treatment adjustment of Crohn's disease in any individual patient. PMID- 30400824 TI - Noninvasive biomarkers of gut barrier function identify two subtypes of patients suffering from diarrhoea predominant-IBS: a case-control study. AB - BACKGROUND: Alterations of the small-intestinal permeability (s-IP) might play an essential role in both diarrhoea-predominant IBS (D-IBS) and celiac disease (CD) patients. Our aims were to analyse in D-IBS patients the symptom profile along with the levels of urinary sucrose (Su), lactulose (La), mannitol (Ma), and circulating biomarkers (zonulin, intestinal fatty acid binding protein - I-FABP, and diamine oxidase - DAO) of the gastrointestinal (GI) barrier function. The pro inflammatory interleukins 6 and 8 (IL-6 and IL-8), the plasma values of lipopolysaccharide (LPS), and Toll-like receptor 4 (TLR-4) were also investigated. Besides, these biomarkers were compared with those in CD and healthy controls (HC). Finally, comparisons were performed between D-IBS patients with [D-IBS(+)] and without [D-IBS(-)] increased s-IP according to normal or altered La/Ma ratio. METHODS: The study included 39 D-IBS patients, 32 CD patients, and 20 HC. GI permeability was assayed by high-performance liquid chromatography determination in the urine of Su and La/Ma ratio. ELISA kits assayed circulating concentrations of zonulin, I-FABP, DAO, IL-6, IL-8, LPS, and TLR-4. The Mann-Whitney or the Kruskal-Wallis with Dunn's post-test was used to assess differences among the groups. RESULTS: As for the La/Ma ratio, %Su, and I FABP levels, D-IBS patients were significantly different from CD, but not HC. IL 6 levels were significantly higher in CD than HC, whereas IL-8 levels were significantly higher in both D-IBS and CD patients than HC. By opposite, LPS, and TLR-4 concentrations did not differ significantly among the groups. When D-IBS patients were categorised according to normal or altered s-IP, D-IBS(+) patients had %La, %Su, I-FABP, and DAO levels significantly higher than D-IBS(-) ones. The inflammatory parameters and markers of bacterial translocation (namely, IL-6 and LPS) were significantly higher in D-IBS(+) patients than D-IBS(-) ones. CONCLUSIONS: The present study suggests that two distinct D-IBS subtypes could be identified. The investigation of possible s-IP alterations (i.e., considering the La/Ma ratio) might be useful to assess better and categorise this heterogeneous D IBS population. TRIAL REGISTRATION: NCT01574209 . Registered March 2012. First recruitment started in April 2012. PMID- 30400826 TI - Sexually dimorphic metabolic responses mediated by CRF2 receptor during nutritional stress in mice. AB - BACKGROUND: Chronic stress is a major contributor in the development of metabolic syndrome and associated diseases, such as diabetes. High-fat diet (HFD) and sex are known modifiers of metabolic parameters. Peptide hormones corticotropin releasing factor (CRF) and urocortins (UCN) mediate stress responses via activation and feedback to the hypothalamic-pituitary-adrenal (HPA) axis. UCN3 is a marker of pancreatic beta-cell differentiation, and UCN2 is known to ameliorate glucose levels in mice rendered diabetic with HFD. CRF receptor 2 (CRF2) is the only known cognate receptor for UCN2/3. Here, we ascertained the role of CRF2 in glucose clearance, insulin sensitivity, and other parameters associated with metabolic syndrome in a mouse model of nutritional stress. METHODS: Wild-type (WT) and Crhr2-/- (null) mice of both sexes were fed either normal chow diet or HFD. After 8 weeks, blood glucose levels in response to glucose and insulin challenge were determined. Change in body and fat mass, plasma insulin, and lipid profile were assessed. Histological evaluation of liver sections was performed. RESULTS: Here, we show that genotype (Crhr2), sex, and diet were all independent variables in the regulation of blood glucose levels, body and fat mass gain/redistribution, and insulin resistance. Surprisingly, CRF2-deficient mice (Crhr2-/-) male mice showed similarly impaired glucose clearance on HFD and chow. HFD-fed female Crhr2-/- mice redistributed their fat depots that were distinct from wild-type females and male mice on either diet. Blood cholesterol and low density lipoprotein (LDL) levels were elevated significantly in male Crhr2-/- mice; female Crhr2-/- mice were protected. Male, but not female Crhr2-/- mice developed peripheral insulin resistance. HFD, but not chow-fed wild-type male mice developed hepatic macrovesicular steatosis. In contrast, livers of Crhr2-/- male mice showed microvesicular steatosis on either diet, whereas livers of female mice on this 8-week HFD regimen did not develop steatosis. CONCLUSIONS: CRF2 receptor dysregulation is a sexually dimorphic risk factor in development of pre-diabetic and metabolic symptoms. PMID- 30400827 TI - Development and reliability assessment of a new quality appraisal tool for cross sectional studies using biomarker data (BIOCROSS). AB - BACKGROUND: Biomarker-based analyses are commonly reported in observational epidemiological studies; however currently there are no specific study quality assessment tools to assist evaluation of conducted research. Accounting for study design and biomarker measurement would be important for deriving valid conclusions when conducting systematic data evaluation. METHODS: We developed a study quality assessment tool designed specifically to assess biomarker-based cross-sectional studies (BIOCROSS) and evaluated its inter-rater reliability. The tool includes 10-items covering 5 domains: 'Study rational', 'Design/Methods', 'Data analysis', 'Data interpretation' and 'Biomarker measurement', aiming to assess different quality features of biomarker cross-sectional studies. To evaluate the inter-rater reliability, 30 studies were distributed among 5 raters and intraclass correlation coefficients (ICC-s) were derived from respective ratings. RESULTS: The estimated overall ICC between the 5 raters was 0.57 (95% Confidence Interval (CI): 0.38-0.74) indicating a good inter-rater reliability. The ICC-s ranged from 0.11 (95% CI: 0.01-0.27) for the domain 'Study rational' to 0.56 (95% CI: 0.40-0.72) for the domain 'Data interpretation'. CONCLUSION: BIOCROSS is a new study quality assessment tool suitable for evaluation of reporting quality from cross-sectional epidemiological studies employing biomarker data. The tool proved to be reliable for use by biomedical scientists with diverse backgrounds and could facilitate comprehensive review of biomarker studies in human research. PMID- 30400825 TI - Handgrip strength in old and oldest old Swiss adults - a cross-sectional study. AB - BACKGROUND: Handgrip strength is indicative of overall physical health and mobility in the elderly. A reduction in strength below a certain threshold severely increases the risk of mobility limitations and is predictive for adverse outcomes such as dependence in daily activities and mortality. An overview of age and geography- specific handgrip strength values in older adults provide a reference for further investigations and measures in clinical practice to identify people at risk for clinically meaningful weakness. The aim of this study was to evaluate handgrip strength in the Swiss-German population aged 75 and over. METHODS: In a cross-sectional study, maximal isometric handgrip strength of the dominant hand was evaluated in 244 Swiss people aged 75 years and over (62.7% women), with mean age (SD) of 84.5 (5.6) years in men and 83.1 (5.9) years in women. Demographic data and information about comorbidities, medication, fall history, global cognitive function, self-reported physical activity and dependence in activities of daily living were collected, and correlated with grip strength measures. Age- and gender specific grip strength values are reported as means, standard deviations and standard error of mean. RESULTS: Sex-stratified handgrip strength was significantly lower with advancing age in men (p < .01), from 37.7 (6.5) kg to 25.6 (7.6) kg and in women (p < .01) from 22.2 (4.0) kg to 16.5 (4.7) kg. Handgrip strength in our sample was significantly higher than in Southern European countries. Handgrip strength was independently associated with age, height and ADL dependence in men and women. Overall, 44% of men and 53% of women had handgrip strength measures that were below the clinically relevant threshold for mobility limitations. CONCLUSION: This study reports the age- and sex-stratified reference values for handgrip strength in a representative sample of the Swiss population, aged 75-99 years. Although grip strength decreased with advancing age in both sexes; the relative decline was greater in men than women. Nonetheless men had significantly higher grip strength in all age groups. While the Swiss population sampled had greater grip strength than that reported in other European countries, about 50% were still classified as at risk of mobility limitations. PMID- 30400829 TI - Hepatocellular carcinoma is the most common liver-related complication in patients with histopathologically-confirmed NAFLD in Japan. AB - BACKGROUND: The incidence of liver-related events, cardiovascular events and type 2 diabetes mellitus in patients with histopathologically confirmed NAFLD remains unclear. METHODS: We retrospectively investigated the incidence of liver events, cardiovascular events, malignancy, and type 2 diabetes mellitus in 402 Japanese patients with histopathologically confirmed NAFLD for a median follow-up of 4.2 years. We also investigated predictors of the development of hepatocellular carcinoma and type 2 diabetes mellitus in these patients. RESULTS: The rate of liver-related events per 1000 person years was 4.17 (hepatocellular carcinoma, 3.67; hepatic encephalopathy, 1.60; esophago-gastric varices, 2.43; ascites, 0.80; and jaundice, 0.40). The rate of cardiovascular events and type 2 diabetes mellitus was 5.73 and 9.95, respectively. Overall mortality was 3.33 (liver related events, 1.25; cardiovascular events, 0.42; and malignancies other than hepatocellular carcinoma, 0.83), in patients free of previous or current malignancies. Multivariate analyses identified old age (>=70 years) and advanced fibrosis stage 4 as significant determinants of hepatocellular carcinoma development, and hepatocyte steatosis (> 33%), female sex, and serum ferritin (<=80 MUg/l) as significant determinants of type 2 diabetes mellitus development in these patients. CONCLUSIONS: Our results highlighted the importance of cardiovascular and liver-related events in Japanese patients with histopathologically-confirmed NAFLD. Hepatocellular carcinoma was the most common liver-related event, and the incidence of hepatocellular carcinoma was more than half of that of cardiovascular events. PMID- 30400828 TI - Dexmedetomidine is safe and reduces the additional dose of midazolam for sedation during endoscopic retrograde cholangiopancreatography in very elderly patients. AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) often requires deep sedation. Dexmedetomidine, a highly selective alpha2-adrenoceptor agonist with sedative activity and minimal effects on respiration, has recently been widely used among patients in the intensive care unit. However, its use in endoscopic procedures in very elderly patients is unclear. In this study, we retrospectively investigated the safety and efficacy of dexmedetomidine sedation during ERCP. METHODS: The study included 62 very elderly patients (aged over 80 years) who underwent ERCP from January 2014, with sedation involving dexmedetomidine (i.v. infusion at 3.0 MUg/kg/h over 10 min followed by continuous infusion at 0.4 MUg/kg/h) along with midazolam. For comparison, the study included 78 patients who underwent ERCP before January 2014, with midazolam alone. We considered additional administration of midazolam as needed to maintain a sedation level of 3-4, according to the Ramsay sedation scale. The outcome measures were amount of midazolam, adverse events associated with sedation, and hemodynamics. RESULTS: The incidence of decreased SpO2 and median dose of additional midazolam were significantly lower in the dexmedetomidine group than in the conventional group. The minimum systolic blood pressure and minimum heart rate during and after examination was significantly lower in the dexmedetomidine group than in the conventional group. However, serious acute heart failure or arrhythmia was not noted. CONCLUSIONS: Dexmedetomidine can decrease the incidence of respiratory complications and the total dose of other sedative agents. It can be used as an alternative to conventional methods with midazolam for adequate sedation during ERCP in very elderly patients. PMID- 30400830 TI - Serum cystatin C, impaired kidney function, and geriatric depressive symptoms among older people living in a rural area: a population-based study. AB - BACKGROUND: The relationship between kidney function and depressive symptoms among elderly people has been rarely investigated in settings of the general population. The aim of our study was to examine the association of serum cystatin C (cysC) and impaired kidney function with geriatric depressive symptoms among older people living in a rural community in China. METHODS: This population-based cohort study included 1440 individuals (age >= 60 years) who were recruited for the Confucius Hometown Aging Project in 2010-2011; of the 1124 persons who were free of depressive symptoms, 669 (59.5%) were re-examined in 2014-2016. At baseline, data on demographics, lifestyle factors, health conditions, and medical history were collected through interviews, clinical examinations, and laboratory tests. We defined impaired kidney function as the cystatin C-based estimated glomerular filtration rate (eGFRcysC) < 60 ml/min/1.73 m2, and depressive symptoms as a score >= 5 on the 15-item Geriatric Depression Scale. Data were analyzed using multiple logistic and Cox proportional-hazards models. RESULTS: Of the 1440 participants, 316 (21.9%) were defined to have geriatric depressive symptoms at baseline. Serum cysC levels of 1.01-1.25 and > 1.25 mg/L (vs. <=1.00 mg/L) were associated with a multiple-adjusted odds ratio (OR) of 1.41 (95% CI 1.01-1.97) and 3.20 (2.32-4.41), respectively, for having geriatric depressive symptoms (Ptrend < 0.001). Of the 669 people who were free of depressive symptoms at baseline, 157 had incident depressive symptoms at the follow-up examination. The multiple-adjusted hazard ratio (HR) for incident depressive symptoms were 2.16 (95% CI 1.43-3.27) for serum cysC > 1.25 mg/L (vs. < 1.00 mg/L). Impaired kidney function was cross-sectionally (multiple-adjusted OR = 2.95; 95% CI 2.22 3.92) and longitudinally (multiple-adjusted HR 1.54; 95% CI 1.03-2.30) associated with an increased risk of geriatric depressive symptoms. CONCLUSION: Elevated serum cysC levels and impaired kidney function are associated with an increased risk of geriatric depressive symptoms among Chinese older people living in a rural community. PMID- 30400831 TI - Prevalence of frailty, cognitive impairment, and sarcopenia in outpatients with cardiometabolic disease in a frailty clinic. AB - BACKGROUND: Although frailty and cognitive impairment are critical risk factors for disability and mortality in the general population of older inhabitants, the prevalence and incidence of these factors in individuals treated in the specialty outpatient clinics are unknown. METHODS: We recently established a frailty clinic for comprehensive assessments of conditions such as frailty, sarcopenia, and cognition, and planned 3-year prospective observational study to identify the risk factors for progression of these aging-related statuses. To date, we recruited 323 patients who revealed symptoms suggestive of frailty mainly from a specialty outpatient clinic of cardiology and diabetes. Frailty status was diagnosed by the modified Cardiovascular Health Study (mCHS) criteria and some other scales. Cognitive function was assessed by Mini-Mental State Examination (MMSE), Japanese version of the Montreal Cognitive Assessment (MoCA-J), and some other modalities. Sarcopenia was defined by the criteria of the Asian Working Group for Sarcopenia (AWGS). In this report, we outlined our frailty clinic and analyzed the background characteristics of the subjects. RESULTS: Most patients reported hypertension (78%), diabetes mellitus (57%), or dyslipidemia (63%), and cardiovascular disease and probable heart failure also had a higher prevalence. The prevalence of frailty diagnosed according to the mCHS criteria, cognitive impairment defined by MMSE (<=27) and MoCA-J (<=25), and of AWGS-defined sarcopenia were 24, 41, and 84, and 31%, respectively. The prevalence of frailty and cognitive impairment increased with aging, whereas the increase in sarcopenia prevalence plateaued after the age of 80 years. No significant differences were observed in the prevalence of frailty, cognitive impairment, and sarcopenia between the groups with and without diabetes mellitus, hypertension, or dyslipidemia with a few exceptions, presumably due to the high-risk subjects who had multiple cardiovascular comorbidities. A majority of the frail and sarcopenic patients revealed cognitive impairment, whereas the frequency of suspected dementia among these patients were both approximately 20%. CONCLUSIONS: We found a high prevalence of frailty, cognitive impairment, and sarcopenia in patients with cardiometabolic disease in our frailty clinic. Comprehensive assessment of the high-risk patients could be useful to identify the risk factors for progression of frailty and cognitive decline. PMID- 30400832 TI - Comparison of a group-delivered and individually delivered lifestyle-integrated functional exercise (LiFE) program in older persons: a randomized noninferiority trial. AB - BACKGROUND: The Lifestyle-Integrated Functional Exercise (LiFE) program is effective in improving strength, balance, and physical activity (PA) while simultaneously reducing falls in older people by incorporating exercise activities in recurring daily tasks. However, implementing the original LiFE program includes substantial resource requirements. Therefore, as part of the LiFE-is-LiFE project, a group format (gLiFE) of the LiFE program has been developed, which will be tested regarding its noninferiority to the individually delivered LiFE in terms of PA-adjusted fall incidence and overall cost effectiveness. METHODS: In a multi-centre, single-blinded noninferiority trial, an envisaged sample of N = 300 participants (> 70 years; faller and/or confirmed falls risk; community-dwelling) will be randomized in either LiFE or gLiFE. Both groups will undergo the same strength and balance activities as well as PA promotion activities and habitualization strategies as described in the LiFE programme, however, based on different approaches of delivery: During the 6-month intervention phase, LiFE participants will receive seven home visits and two telephone calls; in gLiFE, the program will be delivered in seven group sessions and also two telephone calls. Main outcomes are a) fall incidence per PA and b) incremental cost-effectiveness ratio comparing costs and quality-adjusted life years between the two interventions. Secondary outcomes include PA behaviour, motor performance, health status, psychosocial status, program evaluation, and adherence. Measurements will be conducted at baseline, 6-month and 12-month follow-up; evaluation of intervention sessions and assessment of psychosocial variables related to execution and habitualization of LiFE activities will be made during the intervention period as well. DISCUSSION: Compared to LiFE, we expect gLiFE to (a) reduce falls per PA by a similar rate; (b) be more cost effective; (c) comparably enhance physical performance in terms of strength and balance as well as PA. By investigating the economic and societal benefit, this study will be of high practical relevance as noninferiority of gLiFE would facilitate large-scale implementation due to lower resource usage. This would result in better reach and increased accessibility, which is important for subjects with a history of falls and/or being at risk of falls. TRIAL REGISTRATION: ClinicalTrials.gov NCT03462654 . Registered on March 12, 2018. PMID- 30400833 TI - Higher levels of tumor necrosis factor beta are associated with frailty in socially vulnerable community-dwelling older adults. AB - BACKGROUND: The complex physiology underpinning the frailty syndrome is responsible for the absence of robust biomarkers that can be used for screening, diagnostic and/or prognostic purposes and has made clinical implementation difficult. Considering socially vulnerable populations, who have poor health status and increased morbidity and mortality, this scenario is even more complex. However, to the best of our knowledge, there are no studies available to investigate frailty biomarkers in socially vulnerable populations. Thus, the aim of this cross-sectional study was to identify potential blood-based biomarkers of frailty in a socially vulnerable population. METHODS: A sample consisting of 347 community-dwelling older people living in a context of high social vulnerability was divided into non-frail (robust), pre-frail and frail groups, according to modified Fried frailty phenotype criteria. Blood samples were collected and analyzed for basic metabolic parameters and for inflammatory cytokines. RESULTS: Levels of Interleukin-1alpha (IL-1alpha) and Tumor Necrosis Factor alpha (TNF alpha) were significantly higher in pre-frail subjects, compared to non-frail ones. Tumor Necrosis Factor beta (TNF-beta) levels presented higher values in the frail compared to non-frail individuals. Interleukin-6 (IL-6) levels in pre-frail and frail subjects were significantly higher compared to the levels of non-frail subjects. Using an ordinal regression analysis, we observed that socially vulnerable older people at higher risk of developing frailty were subjects above 80 years old (OR: 2.5; 95% CI: 1.1-5.6) and who presented higher levels of TNF beta (>=0.81 pg/mL, OR: 2.53; 95% CI: 1.3-4.9). CONCLUSION: As vulnerable populations continue to age, it is imperative to have a greater understanding of the frailty condition, identifying novel potential blood-based biomarkers. The results presented here could help to implement preventive healthcare strategies by evaluating frailty and at the same time measuring a set of inflammatory biomarkers, paying special attention to TNF-beta plasmatic levels. PMID- 30400835 TI - 33rd Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2018) : Washington, D.C., USA. 7-11 November 2018. PMID- 30400834 TI - Study of Healthcare Personnel with Influenza and other Respiratory Viruses in Israel (SHIRI): study protocol. AB - BACKGROUND: The Study of Healthcare Personnel with Influenza and other Respiratory Viruses in Israel (SHIRI) prospectively follows a cohort of healthcare personnel (HCP) in two hospitals in Israel. SHIRI will describe the frequency of influenza virus infections among HCP, identify predictors of vaccine acceptance, examine how repeated influenza vaccination may modify immunogenicity, and evaluate influenza vaccine effectiveness in preventing influenza illness and missed work. METHODS: Cohort enrollment began in October, 2016; a second year of the study and a second wave of cohort enrollment began in June 2017. The study will run for at least 3 years and will follow approximately 2000 HCP (who are both employees and members of Clalit Health Services [CHS]) with routine direct patient contact. Eligible HCP are recruited using a stratified sampling strategy. After informed consent, participants complete a brief enrollment survey with questions about occupational responsibilities and knowledge, attitudes, and practices about influenza vaccines. Blood samples are collected at enrollment and at the end of influenza season; HCP who choose to be vaccinated contribute additional blood one month after vaccination. During the influenza season, participants receive twice-weekly short message service (SMS) messages asking them if they have acute respiratory illness or febrile illness (ARFI) symptoms. Ill participants receive follow-up SMS messages to confirm illness symptoms and duration and are asked to self-collect a nasal swab. Information on socio economic characteristics, current and past medical conditions, medical care utilization and vaccination history is extracted from the CHS database. Information about missed work due to illness is obtained by self-report and from employee records. Respiratory specimens from self-collected nasal swabs are tested for influenza A and B viruses, respiratory syncytial virus, human metapneumovirus, and coronaviruses using validated multiplex quantitative real time reverse transcription polymerase chain reaction assays. The hemagglutination inhibition assay will be used to detect the presence of neutralizing influenza antibodies in serum. DISCUSSION: SHIRI will expand our knowledge of the burden of respiratory viral infections among HCP and the effectiveness of current and repeated annual influenza vaccination in preventing influenza illness, medical utilization, and missed workdays among HCP who are in direct contact with patients. TRIAL REGISTRATION: NCT03331991 . Registered on November 6, 2017. PMID- 30400836 TI - Predictors of distant metastasis on exploration in patients with potentially resectable pancreatic cancer. AB - BACKGROUND: Patients with potentially resectable pancreatic ductal adenocarcinoma (PDAC) are frequently found to be unresectable on exploration due to small distant metastasis. This study was to investigate predictors of small distant metastasis in patients with potentially resectable PDAC. METHODS: Patients who underwent surgical exploration for potentially resectable PDAC from 2013 to 2014 were reviewed retrospectively and divided into two groups according to whether distant metastases were encountered on exploration. Then, univariate and multivariate logistic regression analyses were used to identify predictors of distant metastasis. A scoring system to predict distant metastasis of PDAC on exploration was constructed based on the regression coefficient of a multivariate logistic regression model. RESULTS: A total of 235 patients were included in this study. Mean age of the study population was 61.7 +/- 10.4 years old. Upon exploration, distant metastases were found intraoperatively in 62 (26.4%) patients, while the remaining 173 were free of distant metastases. Multivariate logistic regression analysis identified that age <= 62 years old (p < 0.001), male sex (p = 0.011), tumor size >=4.0 cm (p < 0.001), alanine aminotransferase level (ALT) < 125 U/L (p < 0.001), and carbohydrate antigen (CA19-9) level >= 385 U/mL (p < 0.001) were independent risk factors for occult distant metastasis of PDAC. A preoperative scoring system (0-8 points) for distant metastasis on exploration was constructed using these five factors. The receiver operating characteristic curves showed that the area under the curve of this score was 0.85. A score of 6 points was suggested to be the optimal cut-off value, and the sensitivity and specificity were 85% and 69%, respectively. CONCLUSIONS: Distant metastasis is still frequently encountered on exploration for patients with potentially resectable PDAC. Younger age, male sex, larger tumor size, low ALT level and high CA19-9 level are independent predictors of unexpected distant metastasis on exploration. PMID- 30400837 TI - Bayesian variable selection for parametric survival model with applications to cancer omics data. AB - BACKGROUND: Modeling thousands of markers simultaneously has been of great interest in testing association between genetic biomarkers and disease or disease related quantitative traits. Recently, an expectation-maximization (EM) approach to Bayesian variable selection (EMVS) facilitating the Bayesian computation was developed for continuous or binary outcome using a fast EM algorithm. However, it is not suitable to the analyses of time-to-event outcome in many public databases such as The Cancer Genome Atlas (TCGA). RESULTS: We extended the EMVS to high dimensional parametric survival regression framework (SurvEMVS). A variant of cyclic coordinate descent (CCD) algorithm was used for efficient iteration in M step, and the extended Bayesian information criteria (EBIC) was employed to make choice on hyperparameter tuning. We evaluated the performance of SurvEMVS using numeric simulations and illustrated the effectiveness on two real datasets. The results of numerical simulations and two real data analyses show the well performance of SurvEMVS in aspects of accuracy and computation. Some potential markers associated with survival of lung or stomach cancer were identified. CONCLUSIONS: These results suggest that our model is effective and can cope with high-dimensional omics data. PMID- 30400838 TI - Apatinib affect VEGF-mediated cell proliferation, migration, invasion via blocking VEGFR2/RAF/MEK/ERK and PI3K/AKT pathways in cholangiocarcinoma cell. AB - BACKGROUND: Cholangiocarcinoma (CCA) is a form of cancer that easily aggress to contiguous structures. Vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) are increased in majority species of cancers and suppress tumor progression by blocking VEGF/VEGFR2. Apatinib is a highly selective VEGFR2 antagonist which has inhibitive effect on antiapoptotic and cell growth in CCA. While, the effect of apatinib cell migration and invasion in CCA is still unknown. METHODS: CCA cell lines QBC939 and TFK-1 were transfected with siKDR to establish the KDR function loss cell model, and recombined human VEGF (rhVEGF) protein was added into the culture medium to enhance the VEGF expression. RT-qPCR and western bloting were used to detect the mRNA and protein expression levels of VEGFR2 to investigate whether it was effectively repressed or activated with rhVEGF or apatinib treatment. Then, MTT, wound healing assay, and transwell matrix assay were applied to measure the effect of apatinib and rhVEGF on cell viability, migration and invasion, respectively. RESULTS: The mRNA and protein expressions of VEGFR2 were significantly reduced with KDR RNAi in both QBC939 and TFK-1 cells, and rhVEGF treatment increased these expression levels (p < 0.05). Apatinib dramatically suppressed VEGF-mediated cell migration and invasion at the concentration of 100 nM treatment and significantly decreased the expression of metastasis-associated protein such as Slug, snail and MMP9. Moreover, all of these inhibiting effects of apatinib depended on the VEGFR2 existence. In addition, VEGFR2/RAF/MEK/ERK and PI3K/AKT signal pathways were enhanced by the introduction of rhVEGF, but were dramatically suppressed after the apatinib treatment. CONCLUSION: Apatinib inhibit VEGF-mediated cell migration and invasion in CCA cell lines via inhibiting the VEGFR2/RAF/MEK/ERK and PI3K/AKT pathways. It will be a potentially effective targeted drug for CCA. PMID- 30400839 TI - Implantable collamer lens surgery in patients with primary iris and/or ciliary body cysts. AB - BACKGROUND: The prevalence of primary iris and/or ciliary body cysts is common in myopia, though asymptomatic in nearly all cases. It's a very valuable thing to study the clinical safety and reliability of implantable collamer lens (ICL) surgery in patients with primary iris and/or ciliary body cysts. METHODS: A total of 108 patients (201 eyes) were included in this retrospective study. All eyes had been implanted with V4c implantable collamer lens (ICLV4c). According to the eyes with or without primary iris and/or ciliary body cysts, all eyes were divided into two groups. We observed preoperative and postoperative uncorrected distance visual acuity (UDVA), corrected distance visual acuity)(CDVA), intra ocular pressure(IOP), anterior chamber volume(ACV), anterior chamber depth(ACD), trabecular-iris angle (TIA), angle opening distance at 500 MUm (AOD500),vertical central distance between the corneal endothelium and the front surface of ICL(CE ICL), and the central vault. The follow-up periods covered 12 months. RESULTS: Among all the 201 eyes, primary iris and/or ciliary body cysts were detected in 54 eyes (26.87%),but the prevalence was account to 36.11%(18males,21females).There were 30 eyes (55.56%) with unilateral single cyst, 12 eyes (22.22%) with unilateral double cysts, 12 eyes (22.22%) eyes with unilateral multiple and/or multi-quadrants cysts, the mean size of cysts was (0.714 +/- 0.149)mm(range from 0.510 to 1.075 mm).30.4% of the cysts were located at iridociliary sulcus, 65.5% in pars plicata, and 4.1% in midzonal iris, which showed a characteristic distribution pattern, with cysts found predominantly in the inferior and temporal quadrants.The postoperative size and the number of cysts showed nearly no changes. The postoperative ACV, AOD500 and TIA showed a statistical reduction in both two groups (P < 0.05), but with no statistical significant between the two groups (P > 0.05), the parameters of postoperative IOP,CE-ICL and central vault also showed the same results as which. We did not observe serious complication and IOP elevating in the whole follow-up periods. CONCLUSION: Primary iris and/or ciliary body cysts are not absolutely contraindication for ICL surgery. For some single cyst smaller than 1.075 mm or single quadrant cysts located at ciliary body are rare to lead some serious complications. But, for some multiple cysts, especially multi-quadrants cysts located at iridociliary sulcus, we still should remain cautions. PMID- 30400841 TI - Non-communicable diseases surveillance: overview of magnitude and determinants in Kenya from STEPwise approach survey of 2015. PMID- 30400840 TI - Protocol for the "Chemobrain in Motion - study" (CIM - study): a randomized placebo-controlled trial of the impact of a high-intensity interval endurance training on cancer related cognitive impairments in women with breast cancer receiving first-line chemotherapy. AB - BACKGROUND: Up to 80% of breast cancer patients suffer from Cancer Related Cognitive Impairments (CRCI). Exercise is suggested as a potential supportive care option to reduce cognitive decline in cancer patients. This study will investigate the effects of a high-intensity interval endurance training (HIIT) on CRCI in breast cancer patients. Potentially underlying immunological and neurobiological mechanisms, as well as effects on patients' self-perceived cognitive functioning and common cancer related side-effects, will be explored. METHODS: A single-blinded randomized controlled trial will be carried out. The impact of HIIT on CRCI will be compared to that of a placebo-intervention (supervised myofascial release training). Both interventions will be conducted simultaneously with the patients' first-line chemotherapy treatment typically lasting 12-18 weeks. Fifty-nine women with breast cancer will be included in each of the two groups. The study is powered to detect (alpha = .05, beta = .2) a medium effect size difference between the two groups (d = .5) in terms of patients' change in cognitive testing performances, from baseline until the end of the exercise-intervention. The cognitive test battery, recommended by the International Cancer and Cognition Task Force to assess CRCI, will be used as primary measure. This includes the Hopkins Verbal Learning Test (learning/verbal memory), the Controlled Oral Word Association Test (verbal fluency) and the Trail Making-Test A/B (attention/set-switching). The following endpoints will be assessed as secondary measures: Go-/No-Go test performance (response inhibition), self-perceived cognitive functioning, serum levels of pro- and antiinflammatory markers (tumor necrosis factor alpha, Interleukin-6, Interleukin-1 alpha, Interleukin-1 beta, C-reactive protein, Interleukin-1 receptor antagonist and Interleukin-10), serum levels of neurotrophic and growth factors (brain-derived neurotrophic factor, insulin-like growth factor 1 and vascular endothelial growth factor), as well as common cancer-related side effects (decrease in physical capacity, fatigue, anxiety and depression, sleep disturbances, quality of life and chemotherapy compliance). DISCUSSION: This study will provide data on the question whether HIIT is an effective supportive therapy that alleviates CRCI in breast cancer patients. Moreover, the present study will help shed light on the underlying mechanisms of potential CRCI improving effects of exercise in breast cancer patients. TRIAL REGISTRATION: DRKS.de, German Clinical Trials Register (DRKS), ID: DRKS00011390 , Registered on 17 January 2018. PMID- 30400842 TI - The impact of introducing tyrosine kinase inhibitors on chronic myeloid leukemia survival: a population-based study. AB - BACKGROUND: Chronic myeloid leukemia is associated with a BCR/ABL oncoprotein inhibited by imatinib mesylate, the first tyrosine kinase inhibitor. Although experimental studies have clearly demonstrated the efficacy of imatinib, up-to date data on its effectiveness at the population level are limited. Our study aims to assess the change in disease-specific survival for chronic myeloid leukemia after introducing tyrosine kinase inhibitors in first-line treatment. METHODS: This study analyzed data from two population-based cancer registries in Italy. Disease-specific survival for chronic myeloid leukemia cases diagnosed before and after the introduction of tyrosine kinase inhibitors (February 2002) were calculated up to 10 years. Hazard ratios were calculated using Cox regression models adjusted for sex, age at diagnosis and residency. An interrupted time series analysis was also performed. RESULTS: Between 1996 and 2012, 357 new cases of chronic myeloid leukemia were diagnosed (standardized incidence rate of 1.2 per 100,000 residents), quite constant throughout the period. The interrupted time series analysis showed a gain of 40.4% in 5 years of disease-specific survival for chronic myeloid leukemia (from 47.3, 95%CI 38.5 55.5% to 80.8%, 95%CI 74.5-85.8%) after the introduction of tyrosine kinase inhibitors. The hazard ratio was 0.36 (95%CI 0.25-0.52) for cases diagnosed after tyrosine kinase inhibitor introduction, with differences per age at diagnosis: <65yo 0.17 (95%CI 0.08-0.39), >74yo 0.41 (95%CI 0.23-0.73). An improvement in survival (hazard ratio 0.66, 95%CI 0.36-1.20) was also observed in cases diagnosed before, and alive at, tyrosine kinase inhibitors introduction. CONCLUSIONS: Tyrosine kinase inhibitors increased disease-specific survival both for new and prevalent chronic myeloid leukemia cases. The effectiveness was similar to that observed in trials only in patients ages 65 years or younger. PMID- 30400843 TI - Depression and glycaemic control among type 2 diabetes patients: a cross sectional study in a tertiary healthcare facility in Ghana. AB - BACKGROUND: Diabetes and depression are both chronic debilitating conditions, and their coexistence has been associated with adverse outcomes. In this study, we investigated the association between glycaemic control and depression in type 2 diabetes (T2DM) patients attending a tertiary healthcare facility in Ghana. METHODOLOGY: In a cross-sectional study design, Patient Health Questionnare-9 (PHQ-9) was used to assess depression in 400 T2DM, aged 30-65 years. Anthropometric characteristics and blood pressure were measured. Venous blood was collected to measure the levels of glycated haemoglobin (HbA1c). RESULTS: The prevalence of depression was 31.3% among T2DM patients. Female gender, being unmarried, frequent intake of alcohol, previous smoking status and insulin use were associated with increased odds of depression, whereas being educated above basic school level was associated with a decreased odds of depression. In a multivariable logistic regression model, being unmarried and poor glycaemic control were associated with an increase in odds of depression after adjusting for age, gender, and social factors. The association between depression and glycaemic control was attenuated when clinical factors were introduced into the model. CONCLUSION: In our study population, we found that depression is common among Ghanaians with T2DM, and not associated with poor glycaemic control in a fully multivariable-adjusted model. PMID- 30400844 TI - Healthcare workers' views on the use of continuous positive airway pressure (CPAP) in neonates: a qualitative study in Andhra Pradesh, India. AB - BACKGROUND: Continuous Positive Airway Pressure (CPAP) is a form of non-invasive ventilatory support which is increasingly used in low- and middle-income countries to treat neonates with acute respiratory distress. However, it may be harmful if used incorrectly. We aimed to explore the experiences of doctors and nurses using CPAP in neonatal units in India and their views on enablers and barriers to implementation of CPAP. METHODS: Participants from 15 neonatal units across Andhra Pradesh were identified through purposive sampling. Eighteen in depth interviews (IDI) with doctors and eight focus group discussions (FGD) with 51 nurses were conducted. Data were analysed thematically using the framework approach. RESULTS: Common structural factors that limit the use of CPAP include shortages of staff, consumables and equipment, and problems with regard to the organisation of neonatal units in both district hospitals and medical colleges. This meant that CPAP was often not available for babies who were identified to need CPAP, or that CPAP use was not perceived to be of the highest quality. Providing care under constrained circumstances left staff feeling powerless to provide good quality care for neonates with acute respiratory distress. Despite this, staff were enthusiastic about the use of CPAP and its potential to save lives. CPAP use was mostly perceived as technically easier to provide than ventilation and allowed nurses to provide advanced neonatal care, independently of doctors. CONCLUSIONS: Doctors and nurses embraced CPAP use but identified barriers to implementation which will need to be addressed in order not to impact on safety and quality of care. Ensuring a supportive and enabling environment is in place will be crucial if CPAP is to be scaled-up more widely. PMID- 30400845 TI - Mode of delivery and short-term infant health outcomes: a prospective cohort study in a peri-urban Indian population. AB - BACKGROUND: Previous studies have found a relationship between cesarean section delivery and adverse outcomes in the offspring, partially attributing these findings to differential development of immunity in infants delivered by cesarean compared to vaginal delivery. The purpose of this study is to determine whether cesarean section delivery is associated with higher reports of adverse short-term infant health outcomes in a peri-urban Indian population. METHODS: Data from a prospective pregnancy cohort study in a peri-urban region of Telangana State, India, were analyzed to assess the association between mode of delivery, cesarean section or vaginal, and maternal report of recent infant diarrhea and/or respiratory symptoms at a 6 month follow-up visit. Inverse probability weights were applied to log-binomial regression models to account for maternal pre pregnancy, prenatal, and labor and delivery factors. RESULTS: Of the 851 singleton infants delivered between 2010 and 2015, 46.7% were delivered by cesarean. Cesarean delivery was not associated with an increased report of infants having one or more of the outcomes (diarrhea, respiratory infection, or difficulty breathing) at 6 months (adjusted risk ratio 0.89, 95% confidence interval 0.76-1.03), nor was it associated with infants having a more severe outcome of comorbid diarrhea and respiratory infection (adjusted risk ratio 1.08, 95% confidence interval 0.58-2.04). CONCLUSION: Unlike findings in Western populations, in this peri-urban Indian population, cesarean delivery was not associated with higher reports of short-term adverse gastrointestinal or respiratory infant outcomes after accounting for pre-delivery maternal factors. Future research in this cohort could elucidate whether mode of delivery is associated with other adverse outcomes later in childhood. PMID- 30400846 TI - Direct and moderating effects of personality on stigma towards mental illness. AB - BACKGROUND: While many studies have explored the concept and correlates of stigma towards individuals with mental illness, few have investigated the role of personality in this process. In the current study, we firstly examined the relationship between personality and stigma towards mental illness; and then explored the moderating effects of personality traits on the relationship between contact experience/s and stigma. METHODS: Participants were recruited from public medical (N = 502) and nursing schools (N = 500) from April to September 2016 in Singapore for this cross-sectional survey, and they were randomly assigned to a vignette describing one of the following mental disorders: major depressive disorder, obsessive compulsive disorder, alcohol abuse, schizophrenia, and dementia. Stigma was measured by the 'Personal and Perceived scales of the Depression Stigma Scale' and the 'Social Distance Scale'. These scales together had a 3-factor structure based on a previous national study in Singapore, namely 'weak-not-sick', 'dangerous/unpredictable' and 'social distance'. Personality was measured by the 20-item short form of the International Personality Item Pool five factor model measure. RESULTS: Regression suggested agreeableness and openness to experience were negatively associated with all three domains of stigma. 'Weak-not-sick' and extraversion were positively associated; and 'social distance' was positively associated with higher scores on conscientiousness and neuroticism. Both close- and non-close contact were associated with more positive attitudes towards mental illness among the participants. Openness to experience moderated the relationships of close contact experience with 'weak-not-sick' and 'dangerous/unpredictable', but in different directions. The association between close contact and 'social distance' were moderated by agreeableness. CONCLUSIONS: Unlike non-close contact experience, close contact with people with mental illness worked differently on stigma for individuals with different personality traits. Future studies are needed to further explore the underlying mechanisms for such differences. PMID- 30400847 TI - PA28alphabeta overexpression enhances learning and memory of female mice without inducing 20S proteasome activity. AB - BACKGROUND: The proteasome system plays an important role in synaptic plasticity. Induction and maintenance of long term potentiation is directly dependent on selective targeting of proteins for proteasomal degradation. The 20S proteasome activator PA28alphabeta activates hydrolysis of small nonubiquitinated peptides and possesses protective functions upon oxidative stress and proteinopathy. The effect of PA28alphabeta activity on behavior and memory function is, however, not known. We generated a mouse model that overexpresses PA28alpha (PA28alphaOE) to understand PA28alphabeta function during healthy adult homeostasis via assessment of physiological and behavioral profiles, focusing on female mice. RESULTS: PA28alpha and PA28beta protein levels were markedly increased in all PA28alphaOE tissues analyzed. PA28alphaOE displayed reduced depressive-like behavior in the forced swim test and improved memory/learning function assessed by intersession habituation in activity box and shuttle box passive avoidance test, with no significant differences in anxiety or general locomotor activity. Nor were there any differences found when compared to WT for body composition or immuno-profile. The cognitive effects of PA28alphaOE were female specific, but could not be explained by alterations in estrogen serum levels or hippocampal regulation of estrogen receptor beta. Further, there were no differences in hippocampal protein expression of neuronal or synaptic markers between PA28alphaOE and WT. Biochemical analysis of hippocampal extracts demonstrated that PA28alpha overexpression did not increase PA28-20S peptidase activity or decrease K48 polyubiquitin levels. Instead, PA28alphaOE exhibited elevated efficiency in preventing aggregation in the hippocampus. CONCLUSIONS: This study reveals, for the first time, a connection between PA28alphabeta and neuronal function. We found that PA28alpha overexpressing female mice displayed reduced depressive-like behavior and enhanced learning and memory. Since the positive effects of PA28alpha overexpression arose without an activation of 20S proteasome capacity, they are likely independent of PA28alphabeta's role as a 20S proteasome activator and instead depend on a recognized chaperone-like function. These findings suggest that proteostasis in synaptic plasticity is more diverse than previously reported, and demonstrates a novel function of PA28alphabeta in the brain. PMID- 30400848 TI - Correcting palindromes in long reads after whole-genome amplification. AB - BACKGROUND: Next-generation sequencing requires sufficient DNA to be available. If limited, whole-genome amplification is applied to generate additional amounts of DNA. Such amplification often results in many chimeric DNA fragments, in particular artificial palindromic sequences, which limit the usefulness of long sequencing reads. RESULTS: Here, we present Pacasus, a tool for correcting such errors. Two datasets show that it markedly improves read mapping and de novo assembly, yielding results similar to these that would be obtained with non amplified DNA. CONCLUSIONS: With Pacasus long-read technologies become available for sequencing targets with very small amounts of DNA, such as single cells or even single chromosomes. PMID- 30400849 TI - Hemodynamic instability during percutaneous ablation of extra-adrenal metastases of pheochromocytoma and paragangliomas: a case series. AB - BACKGROUND: Surgical manipulation of pheochromocytomas and paragangliomas (PPGLs) may induce large hemodynamic oscillations due to catecholamine release. Little is known regarding hemodynamic instability during percutaneous ablation of PPGLs. We examined intraprocedural hemodynamic variability and postoperative complications related to percutaneous ablation of extra-adrenal metastases of PPGL. METHODS: From institutional PPGL registry we identified patients undergoing ablation of extra-adrenal PPGL metastases from January 1, 2000, through December 31, 2016. We reviewed medical records for clinical characteristics and hospital outcomes. Tumors were categorized as functional or nonfunctional based on preprocedural fractionated catecholamine and metanephrine profiles. RESULTS: Twenty-one patients (14 female [67%]) underwent 38 ablations. Twenty-four ablations were performed in patients with functional metastatic lesions, and 14 were in nonfunctional lesions. Intraprocedural use of potent vasodilators for hypertension was higher for patients with functional tumors (P = 0.02); use of vasopressors for hypotension was similar for functional and nonfunctional tumors (P = 0.74). Mean (+/-SD) intraprocedural blood pressure range (maximum-minimum blood pressure) during 38 procedures was greater for functional than nonfunctional tumors [systolic: 106 (+/-48) vs 64 (+/-30) mm Hg, P = 0.005; diastolic: 58 (+/-22) vs 35 (+/-14) mm Hg, P = 0.002; mean arterial: 84 (+/-43) vs 47 (+/-29) mm Hg, P = 0.007]. Complications included 5 unplanned intensive care unit admissions (3 for precautionary monitoring, 1 for recalcitrant hypotension, and 1 for hypertensive crisis), 1 case of postoperative bleeding, and 1 death. CONCLUSIONS: Substantial hemodynamic instability may develop during ablation of functional and nonfunctional PPGL metastases. When anesthesia is provided for ablation of metastatic PPGLs in radiology suites, preparation for hemodynamic management should match standards used for surgical resection. PMID- 30400850 TI - Is lower-dose sugammadex a cost-saving strategy for reversal of deep neuromuscular block? Facts and fiction. AB - BACKGROUND: Sugammadex, a gamma-cyclodextrin derivative, belongs to a new class of selective relaxant binding agents. Sugammadex was approved 10-years ago by the European medicines agency and today is used in clinical anesthesia and emergency medicine globally. In this review, indications for neuromuscular block, the challenge of neuromuscular monitoring and the practice of under-dosing of sugammadex as a potential cost-saving strategy are discussed. MAIN BODY: Reversal of neuromuscular block is important to accelerate the spontaneous recovery of neuromuscular function. Sugammadex is able to reverse a rocuronium- or vecuronium induced neuromuscular block rapidly and efficiently from every depth of neuromuscular block. However, since sugammadex was introduced in clinical anesthesia, several studies have reported administration of a lower-than recommended dose of sugammadex. The decision to under-dose sugammadex is often motivated by cost reduction concerns, as the price of sugammadex is much higher than that of neostigmine outside the United States. However, under-dosing of sugammadex leads to an increased risk of recurrence of neuromuscular block after an initial successful (but transient) reversal. Similarly, when not using objective neuromuscular monitoring, under-dosing of sugammadex may result in residual neuromuscular block in the postoperative care unit, with its attendant negative pulmonary outcomes. Therefore, an appropriate dose of sugammadex, based on objective determination of the depth of neuromuscular block, should be administered to avoid residual or recurrent neuromuscular block and attendant postoperative complications. Whether the reduction in perioperative recovery time of the patient can be translated into additional procedural cases performed, faster operative turnover times, or improved organizational resource utilization, has yet to be determined in actual clinical practice that includes verification of neuromuscular recovery prior to tracheal extubation. CONCLUSIONS: The current review addresses the indications for neuromuscular block, the challenge of neuromuscular monitoring, the practice of under-dosing of sugammadex as a potential cost-saving strategy in reversal of deep neuromuscular block, the economics of sugammadex administration and the potential healthcare cost-saving strategies. PMID- 30400851 TI - Genome sequence of the potato pathogenic fungus Alternaria solani HWC-168 reveals clues for its conidiation and virulence. AB - BACKGROUND: Alternaria solani is a known air-born deuteromycete fungus with a polycyclic life cycle and is the causal agent of early blight that causes significant yield losses of potato worldwide. However, the molecular mechanisms underlying the conidiation and pathogenicity remain largely unknown. RESULTS: We produced a high-quality genome assembly of A. solani HWC-168 that was isolated from a major potato-producing region of Northern China, which facilitated a comprehensive gene annotation, the accurate prediction of genes encoding secreted proteins and identification of conidiation-related genes. The assembled genome of A. solani HWC-168 has a genome size 32.8 Mb and encodes 10,358 predicted genes that are highly similar with related Alternaria species including Alternaria arborescens and Alternaria brassicicola. We identified conidiation-related genes in the genome of A. solani HWC-168 by searching for sporulation-related homologues identified from Aspergillus nidulans. A total of 975 secreted protein encoding genes, which might act as virulence factors, were identified in the genome of A. solani HWC-168. The predicted secretome of A. solani HWC-168 possesses 261 carbohydrate-active enzymes (CAZy), 119 proteins containing RxLx[EDQ] motif and 27 secreted proteins unique to A. solani. CONCLUSIONS: Our findings will facilitate the identification of conidiation- and virulence-related genes in the genome of A. solani. This will permit new insights into understanding the molecular mechanisms underlying the A. solani-potato pathosystem and will add value to the global fungal genome database. PMID- 30400852 TI - Crystalloid resuscitation in trauma patients: deleterious effect of 5L or more in the first 24h. AB - BACKGROUND: Over-aggressive intravenous fluid therapy with crystalloids has adverse effects in trauma patients. We assessed the role of large-volume (>=5l) administration of crystalloids within 24h of injury as an independent risk-factor for mortality, in-hospital complications, and prolonged mechanical ventilation. METHODS: A retrospective cohort analysis of adult trauma patients admitted to a level 1-trauma center between December 2011 and December 2012. Patient demographics, clinical and laboratory values, and total resuscitation fluid administered within the first 24h of injury were obtained. Outcomes included mortality, in-hospital complications and ventilator-days. Multivariable logistic regression and Poisson regression analyses were performed to investigate any association between the administration of >=5L crystalloids with the aforementioned outcomes while controlling for selected clinical variables. RESULTS: A total of 970 patients were included in the analysis. 264 (27%) received >=5L of crystalloids in the first 24h of injury. 118 (12%) had in hospital complications and 337 (35%) required mechanical ventilation. The median age was 46 years (interquartile range (IQR) 27-65) years and 73% (n = 708) were males. The median injury severity score (ISS) was 17 (IQR 9-25). Overall mortality rate was 7% (n = 67). Multivariable logistic regression analysis showed several variables independently associated with mortality (p < 0.05), including resuscitation with >=5L crystalloid in the first 24h (adjusted odds ratio (aOR) 2.55), older age (aOR 1.03), higher ISS (aOR 1.09), and lower temperature (aOR 0.68). The variables independently associated with in-hospital complications (p < 0.05) were older age, longer ICU stay, and platelet transfusion within 24h of the injury. Need for mechanical ventilation was more common in patients who received >=5L crystalloids (RR 2.31) had higher ISS (RR 1.02), developed in-hospital complications (RR 1.91) and had lower presenting temperature (RR 0.87). CONCLUSION: Large-volume crystalloid resuscitation is associated with increased mortality and longer time ventilated, but not with in-hospital complications such as pneumonia and sepsis. Based on this data, we recommend judicious use of crystalloids in the resuscitation of trauma patients. PMID- 30400855 TI - Case report: primary resistance to osimertinib in erlotinib-pretreated lung adenocarcinoma with EGFR T790 M mutation. AB - BACKGROUND: Among non-small cell lung cancer (NSCLC) patients with acquired T790 M mutation resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), 71% are likely to benefit from osimertinib. There have been several reports about the secondary resistance to osimertinib treatment in T790 M-positive patients, while primary resistance to osimertinib has been rarely reported. CASE PRESENTATION: A 62-year-old Asian male never smoker who presented with stage IV EGFR L858R-positive adenocarcinoma developed EGFR T790 M mutation after 14 months of treatment with erlotinib combined with thoracic radiotherapy as first-line therapy. The patient was initiated on osimertinib treatment with T790 M mutation detected (14.4%), but disease progressed 2 months later. CONCLUSION: The mechanism of primary resistance to osimertinib remains unclear. There may be an association between T790 M mutation disappearance, TP53 mutation and radiotherapy, but further researches are needed to confirm this. PMID- 30400854 TI - Transcriptome profiling of two contrasting ornamental cabbage (Brassica oleracea var. acephala) lines provides insights into purple and white inner leaf pigmentation. AB - BACKGROUND: Ornamental cabbage (Brassica oleracea var. acephala) is an attractive landscape plant that remains colorful at low temperatures during winter. Its key feature is its inner leaf coloration, which can include red, pink, lavender, blue, violet and white. Some ornamental cabbages exhibit variation in leaf color pattern linked to leaf developmental stage. However, little is known about the molecular mechanism underlying changes in leaf pigmentation pattern between developmental stages. RESULTS: The transcriptomes of six ornamental cabbage leaf samples were obtained using Illumina sequencing technology. A total of 339.75 million high-quality clean reads were assembled into 46,744 transcripts and 46,744 unigenes. Furthermore, 12,771 genes differentially expressed across the different lines and stages were identified by pairwise comparison. We identified 74 and 13 unigenes as differentially expressed genes related to the anthocyanin biosynthetic pathway and chlorophyll metabolism, respectively. Among them, three unigenes (BoC4H2, BoUGT9, and BoGST21) and six unigenes (BoHEMA1, BoCRD1, BoPORC1, BoPORC2, BoCAO, and BoCLH1) were found as candidates for the genes encoding enzymes in the anthocyanin biosynthetic pathway and chlorophyll metabolism, respectively. In addition, two unigenes (BoRAX3 and BoTRB1) as MYB candidates, two unigenes (BoMUTE1, and BHLH168-like) as bHLH candidates were identified for purple pigmentation in ornamental cabbage. CONCLUSION: Our results indicate that the purple inner leaves of purple ornamental cabbage result from a high level of anthocyanin biosynthesis, a high level of chlorophyll degradation and an extremely low level of chlorophyll biosynthesis, whereas the bicolor (purple/green) outer leaves are due to a moderate level of anthocyanin biosynthesis, a high level of chlorophyll degradation and a very low level of chlorophyll biosynthesis. In white ornamental cabbage, the white inner leaves are due to an extremely low level or absence of anthocyanin biosynthesis, a high level of chlorophyll degradation and a very low level of chlorophyll biosynthesis, whereas the bicolor (white/green) leaves are due to a high level of chlorophyll degradation and a low level of chlorophyll biosynthesis and absence of anthocyanin biosynthesis. These results provide insight into the molecular mechanisms underlying inner and bicolor leaf pigmentation in ornamental cabbage and offer a platform for assessing related ornamental species. PMID- 30400856 TI - Correlating enzyme annotations with a large set of microbial growth temperatures reveals metabolic adaptations to growth at diverse temperatures. AB - BACKGROUND: The ambient temperature of all habitats is a key physical property that shapes the biology of microbes inhabiting them. The optimal growth temperature (OGT) of a microbe, is therefore a key piece of data needed to understand evolutionary adaptations manifested in their genome sequence. Unfortunately there is no growth temperature database or easily downloadable dataset encompassing the majority of cultured microorganisms. We are thus limited in interpreting genomic data to identify temperature adaptations in microbes. RESULTS: In this work I significantly contribute to closing this gap by mining data from major culture collection centres to obtain growth temperature data for a nonredundant set of 21,498 microbes. The dataset ( https://doi.org/10.5281/zenodo.1175608 ) contains mainly bacteria and archaea and spans psychrophiles, mesophiles, thermophiles and hyperthermophiles. Using this data a full 43% of all protein entries in the UniProt database can be annotated with the growth temperature of the species from which they originate. I validate the dataset by showing a Pearson correlation of up to 0.89 between growth temperature and mean enzyme optima, a physiological property directly influenced by the growth temperature. Using the temperature dataset I correlate the genomic occurance of enzyme functional annotations with growth temperature. I identify 319 enzyme functions that either increase or decrease in occurrence with temperature. Eight metabolic pathways were statistically enriched for these enzyme functions. Furthermore, I establish a correlation between 33 domains of unknown function (DUFs) with growth temperature in microbes, four of which (DUF438, DUF1524, DUF1957 and DUF3458_C) were significant in both archaea and bacteria. CONCLUSIONS: The growth temperature dataset enables large-scale correlation analysis with enzyme function- and domain-level annotations. Growth temperature dependent changes in their occurrence highlight potential evolutionary adaptations. A few of the identified changes are previously known, such as the preference for menaquinone biosynthesis through the futalosine pathway in bacteria growing at high temperatures. Others represent important starting points for future studies, such as DUFs where their occurrence change with temperature. The growth temperature dataset should become a valuable community resource and will find additional, important, uses in correlating genomic, transcriptomic, proteomic, metabolomic, phenotypic or taxonomic properties with temperature in future studies. PMID- 30400853 TI - Identification of the neurotransmitter profile of AmFoxP expressing neurons in the honeybee brain using double-label in situ hybridization. AB - BACKGROUND: FoxP transcription factors play crucial roles for the development and function of vertebrate brains. In humans the neurally expressed FOXPs, FOXP1, FOXP2, and FOXP4 are implicated in cognition, including language. Neural FoxP expression is specific to particular brain regions but FoxP1, FoxP2 and FoxP4 are not limited to a particular neuron or neurotransmitter type. Motor- or sensory activity can regulate FoxP2 expression, e.g. in the striatal nucleus Area X of songbirds and in the auditory thalamus of mice. The DNA-binding domain of FoxP proteins is highly conserved within metazoa, raising the possibility that cellular functions were preserved across deep evolutionary time. We have previously shown in bee brains that FoxP is expressed in eleven specific neuron populations, seven tightly packed clusters and four loosely arranged groups. RESULTS: The present study examined the co-expression of honeybee FoxP (AmFoxP) with markers for glutamatergic, GABAergic, cholinergic and monoaminergic transmission. We found that AmFoxP could co-occur with any one of those markers. Interestingly, AmFoxP clusters and AmFoxP groups differed with respect to homogeneity of marker co-expression; within a cluster, all neurons co-expressed the same neurotransmitter marker, within a group co-expression varied. We also assessed qualitatively whether age or housing conditions providing different sensory and motor experiences affected the AmFoxP neuron populations, but found no differences. CONCLUSIONS: Based on the neurotransmitter homogeneity we conclude that AmFoxP neurons within the clusters might have a common projection and function whereas the AmFoxP groups are more diverse and could be further sub divided. The obtained information about the neurotransmitters co-expressed in the AmFoxP neuron populations facilitated the search of similar neurons described in the literature. These comparisons revealed e.g. a possible function of AmFoxP neurons in the central complex. Our findings provide opportunities to focus future functional studies on invertebrate FoxP expressing neurons. In a broader context, our data will contribute to the ongoing efforts to discern in which cases relationships between molecular and phenotypic signatures are linked evolutionary. PMID- 30400857 TI - An improved suppression subtractive hybridization technique to develop species specific repetitive sequences from Erianthus arundinaceus (Saccharum complex). AB - BACKGROUND: Sugarcane has recently attracted increased attention for its potential as a source of bioethanol and methane. However, a narrow genetic base has limited germplasm enhancement of sugarcane. Erianthus arundinaceus is an important wild genetic resource that has many excellent traits for improving cultivated sugarcane via wide hybridization. Species-specific repetitive sequences are useful for identifying genome components and investigating chromosome inheritance in noblization between sugarcane and E. arundinaceus. Here, suppression subtractive hybridization (SSH) targeting E. arundinaceus specific repetitive sequences was performed. The five critical components of the SSH reaction system, including enzyme digestion of genomic DNA (gDNA), adapters, digested gDNA concentrations, primer concentrations, and LA Taq polymerase concentrations, were improved using a stepwise optimization method to establish a SSH system suitable for obtaining E. arundinaceus-specific gDNA fragments. RESULTS: Specificity of up to 85.42% was confirmed for the SSH method as measured by reverse dot blot (RDB) of an E. arundinaceus subtractive library. Furthermore, various repetitive sequences were obtained from the E. arundinaceus subtractive library via fluorescence in situ hybridization (FISH), including subtelomeric and centromeric regions. EaCEN2-166F/R and EaSUB1-127F/R primers were then designed as species-specific markers to accurately validate E. arundinaceus authenticity. CONCLUSIONS: This is the first report that E. arundinaceus-specific repetitive sequences were obtained via an improved SSH method. These results suggested that this novel SSH system could facilitate screening of species-specific repetitive sequences for species identification and provide a basis for development of similar applications for other plant species. PMID- 30400858 TI - Prevalence, awareness, treatment and control of hypertension and their determinants: results from a national survey in Kenya. AB - BACKGROUND: Hypertension is the most important risk factor for cardiovascular diseases and the leading cause of death worldwide. Despite growing evidence that the prevalence of hypertension is rising in sub-Saharan Africa, national data on hypertension that can guide programming are missing for many countries. In this study, we estimated the prevalence of hypertension, awareness, treatment, and control. We further examined the factors associated with hypertension and awareness. METHOD: We used data from the 2015 Kenya STEPs survey, a national cross-sectional household survey targeting randomly selected people aged 18-69 years. Demographic and behavioral characteristics as well as physical measurements were collected using the World Health Organization's STEPs Survey methodology. Descriptive statistics were used to estimate the prevalence, awareness, treatment and control of hypertension. Multiple logistic regression models were used to identify the determinants of hypertension and awareness. RESULTS: The study surveyed 4485 participants. The overall age-standardized prevalence for hypertension was 24.5% (95% confidence interval (CI) 22.6% to 26.6%). Among individuals with hypertension, only 15.6% (95% CI 12.4% to 18.9%) were aware of their elevated blood pressure. Among those aware only 26.9%; (95% CI 17.1% to 36.4%) were on treatment and 51.7%; (95% CI 33.5% to 69.9%) among those on treatment had achieved blood pressure control. Factors associated with hypertension were older age (p < 0.001), higher body mass index (BMI) (p < 0.001) and harmful use of alcohol (p < 0.001). Similarly, factors associated with awareness were older age (p = 0.013) and being male (p < 0.001). CONCLUSION: This study provides the first nationally-representative estimates for hypertension in Kenya. Prevalence among adults is high, with unacceptably low levels of awareness, treatment and control. The results also reveal that men are less aware of their hypertension status hence special attention should focus on this group. PMID- 30400860 TI - Audio-video recording during laparoscopic surgery reduces irrelevant conversation between surgeons: a cohort study. AB - BACKGROUND: The prevalence of perioperative surgical complications is a worldwide issue: In many cases, these events are preventable. Audio-video recording during laparoscopic surgery provides useful information for the purposes of education and event analyses, and may have an impact on the focus of the surgeons operating. The aim of the present study was to investigate how audio-video recording in the operating room during laparoscopic surgery affects the focus of the surgeon and his/her assistant. METHODS: A group of laparoscopic procedures where video recording only was performed was compared to a group where both audio and video recordings were made. All laparoscopic procedures were performed at Lindesberg Hospital, Sweden, during the period August to September 2017. The primary outcome was conversation not relevant to the ongoing procedure. Secondary outcomes were intra- and postoperative adverse events or complications, operation time and number of times the assistant was corrected by the surgeon. RESULTS: The study included 41 procedures, 20 in the video only group and 21 in the audio video group. The material comprised laparoscopic cholecystectomies, totally extraperitoneal inguinal hernia repairs and bariatric surgical procedures. Irrelevant conversation time fell from 4.2% of surgical time to 1.4% when both audio and video recordings were made (p = 0.002). No differences in perioperative adverse event or complication rates were seen. CONCLUSION: Audio-video recording during laparoscopic abdominal surgery reduces irrelevant conversation time and may improve intraoperative safety and surgical outcome. TRIAL REGISTRATION: Available at FOU Sweden (ID: 232771) and retrospectively at Clinical trials.gov (ID: NCT03425175 ; date of registration 7/2 2018). PMID- 30400859 TI - Exploring how patients understand and assess their diabetes control. AB - BACKGROUND: Poor understanding of diabetes management targets is associated with worse disease outcomes. Patients may use different information than providers to assess their diabetes control. In this study, we identify the information patients use to gauge their current level of diabetes control and explore patient perceived barriers to understanding the hemoglobin A1c value (HbA1c). METHODS: Adults who self-reported a diagnosis of diabetes were recruited from outpatient, academically-affiliated, Internal Medicine clinics. Semi-structured interviews were conducted with participants and collected data were analyzed using thematic analysis. RESULTS: The mean age of the 25 participants was 56.8 years. HbA1c was one of several types of information participants used to assess diabetes control. Other information included perceived self-efficacy and adherence to self-care, the type and amount of medications taken, the presence or absence of symptoms attributed to diabetes, and feedback from self-monitoring of blood glucose. Most participants reported familiarity with the HbA1c (22 of 25), though understanding of the value's meaning varied significantly. Inadequate diabetes education and challenges with patient-provider communication were cited as common barriers to understanding the HbA1c. CONCLUSIONS: In addition to the HbA1c, several categories of information influenced participants' assessments of their diabetes control. Increased provider awareness of the factors that influence patients' perceptions of diabetes control can inform effective, patient-centered approaches for communicating vital diabetes-related information, facilitating behavior change towards improved patient outcomes. PMID- 30400861 TI - Type 1 tympanoplasty in pediatric patients: a review of 102 cases. AB - BACKGROUND: The aim of this study was to investigate the success of type 1 tympanoplasty in pediatric patients with chronic otitis media, and to evaluate the prognostic factors that may influence its success. MATERIALS AND METHODS: Medical records of 102 children aged between 8 and 18 years (46 female, 56 male) who underwent type 1 tympanoplasty for chronic tympanic membrane perforation between January 2010 and July 2017 were reviewed. Age, gender, condition of contralateral ear (unilateral, bilateral), type (central, marginal) and location of perforation (anterior, posterior, inferior), graft material (fascia, cartilage), pre- and post-operative hearing levels, mean air-bone gap (ABG), surgical approach (postauricular, endaural) and length of follow up were recorded. RESULTS: Anatomical and functional success (ABG < 20 dBHL) rates were 86.3% (88 patients) and 74.5% (76 patients) after a mean follow-up of 32 +/- 16.55 months, respectively. The mean hearing improvement was 10.77 +/- 10.45 dBHL. The graft success rates were significantly higher in tragal cartilage group (95.1%) than in temporalis fascia group (80.3%) (p = 0.033). Graft success was negatively affected by contralateral perforation (p = 0.003). All patients with bilateral perforations and graft failure were in temporalis fascia group. Age, type and location of perforation and surgical approach did not influence graft success (p > 0.05). CONCLUSION: Our results showed that type 1 tympanoplasty can be performed effectively in pediatric population regardless of age, location and type of perforation and surgical approach. Bilateral perforations are prone to reperforation, and should be treated with cartilage graft. PMID- 30400862 TI - Development of polymorphic microsatellite markers by using de novo transcriptome assembly of Calanthe masuca and C. sinica (Orchidaceae). AB - BACKGROUND: Calanthe masuca and C. sinica are two genetically closely related species in Orchidaceae. C. masuca is widely distributed in Asia, whereas C. sinica is restricted to Yunnan and Guangxi Provinces in southwest China. Both play important roles in horticulture and are under the pressure of population decline. Understanding their genetic background can greatly help us develop effective conservation strategies for these species. Simple sequence repeats (SSRs) are useful for genetic diversity analysis, presumably providing key information for the study and preservation of the wild populations of the two species we are interested in. RESULTS: In this study, we performed RNA-seq analysis on the leaves of C. masuca and C. sinica, obtaining 40,916 and 71,618 unigenes for each species, respectively. In total, 2,019/3,865 primer pairs were successfully designed from 3,764/7,189 putative SSRs, among which 197 polymorphic SSRs were screened out according to orthologous gene pairs. After mononucleotide exclusion, a subset of 129 SSR primers were analysed, and 13 of them were found to have high polymorphism levels. Further analysis demonstrated that they were feasible and effective against C. masuca and C. sinica as well as transferable to another species in Calanthe. Molecular evolutionary analysis revealed functional pathways commonly enriched in unigenes with similar evolutionary rates in the two species, as well as pathways specific to each species, implicating species specific adaptation. The divergence time between the two closely related species was tentatively determined to be 3.42 +/- 1.86 Mya. CONCLUSIONS: We completed and analysed the transcriptomes of C. masuca and C. sinica, assembling large numbers of unigenes and generating effective polymorphic SSR markers. This is the first report of the development of expressed sequence tag (EST)-SSR markers for Calanthe. In addition, our study could enable further genetic diversity analysis and functional and comparative genomic studies on Calanthe. PMID- 30400863 TI - Global dissection of alternative splicing uncovers transcriptional diversity in tissues and associates with the flavonoid pathway in tea plant (Camellia sinensis). AB - BACKGROUND: Alternative splicing (AS) regulates mRNA at the post-transcriptional level to change gene function in organisms. However, little is known about the AS and its roles in tea plant (Camellia sinensis), widely cultivated for making a popular beverage tea. RESULTS: In our study, the AS landscape and dynamics were characterized in eight tissues (bud, young leaf, summer mature leaf, winter old leaf, stem, root, flower, fruit) of tea plant by Illumina RNA-Seq and confirmed by Iso-Seq. The most abundant AS (~ 20%) was intron retention and involved in RNA processes. The some alternative splicings were found to be tissue specific in stem and root etc. Thirteen co-expressed modules of AS transcripts were identified, which revealed a similar pattern between the bud and young leaves as well as a distinct pattern between seasons. AS events of structural genes including anthocyanidin reductase and MYB transcription factors were involved in biosynthesis of flavonoid, especially in vegetative tissues. The AS isoforms rather than the full-length ones were the major transcripts involved in flavonoid synthesis pathway, and is positively correlated with the catechins content conferring the tea taste. We propose that the AS is an important functional mechanism in regulating flavonoid metabolites. CONCLUSION: Our study provides the insight into the AS events underlying tea plant's uniquely different developmental process and highlights the important contribution and efficacy of alternative splicing regulatory function to biosynthesis of flavonoids. PMID- 30400864 TI - Open-label study of treatment with alendronate sodium plus vitamin D in men and women with osteoporosis in Thailand. AB - BACKGROUND: It is generally believed that Thai people do not suffer from hypovitaminosis D because there is abundant sunlight throughout the year, and that taking vitamin D supplements could result in abnormally high levels of vitamin D. This is a Thai FDA-driven study to investigate this risk over a period of 26 weeks of taking alendronate sodium/vitamin D3 combination tablets. METHODS: Osteoporosis patients in Thailand were recruited to a multicenter, open-label, 6 month trial of oral alendronate sodium 70 mg/vitamin D3 5600 IU. Patients received study medication once a week for 26 weeks. Serum 25-hydroxyvitamin D (25(OH)D) and Beta-CrossLaps (beta-CTx) levels were measured at baseline and 26 weeks. The primary endpoint was the proportion of patients with 25(OH)D >= 50 ng/mL at week 26; it was hypothesized that 26 weeks' treatment would not result in 25(OH)D serum levels >= 50 ng/mL in > 7% of osteoporosis patients. RESULTS: One hundred ninety-eight patients were recruited. At baseline, 67.2% of the patients had 25(OH)D < 30 ng/mL; this declined to 34.4% by week 26. The mean 25(OH)D level improved from 27.8 ng/mL at baseline to 33.6 ng/mL at week 26. Five patients (2.69% of the full analysis set) had 25(OH)D levels >= 50 ng/mL at 26 weeks. The highest 25(OH)D level, 64.3 ng/mL, was observed in a patient whose baseline level was 102.2 ng/mL. The majority (62.9%) of the patients had optimal 25(OH)D levels (30-50 ng/mL). beta-CTx levels were reduced by 57.7% after 26 weeks' treatment. No clinically significant cases of hypercalcemia which could be associated with hypervitaminosis D were identified during physical examination, in vital signs, or in laboratory results. Overall, 73 patients (36.9%) reported at least one adverse event (AE), with 13 (6.6%) reporting drug-related AEs. Four patients discontinued due to AEs, two of which were drug-related. Serious AEs were reported for four patients, of which one was considered drug-related. CONCLUSIONS: Oral alendronate sodium 70 mg plus vitamin D3 5600 IU once weekly had an acceptable safety profile in this study, and increased serum 25(OH)D and reduced beta-CTx levels in osteoporosis patients. This treatment improved 25(OH)D levels, without causing abnormally high levels, after 26 weeks' treatment. TRIAL REGISTRATION: Clinical Trials.gov NCT01437111 , Registered September 19, 2011. PMID- 30400865 TI - Prevalence and factors associated with pre-diabetes and diabetes mellitus in Kenya: results from a national survey. AB - BACKGROUND: Diabetes Mellitus is one of the four major non-communicable diseases causing about 4 million deaths in 2017. By 2040, low income countries are projected to experience 92% increase in mortality due to diabetes. Undiagnosed diabetes poses a public health concern with costly public health implications especially in Africa. It is therefore crucial to examine the burden and risk factors for diabetes at national level to inform policy and national programs. METHODS: Data from the 2015 Kenya national STEPs survey of adults aged 18-69 years were used. Pre-diabetes was defined as impaired fasting blood glucose level (6.1 mmol/l to < 7 mmol/l) while diabetes was defined as impaired fasting blood glucose level >= 7 mmol/l. Descriptive statistics were used to determine the prevalence of pre-diabetes and diabetes and logistic regression was used to identify associated factors. RESULTS: Complete data for 4069 respondents (51% females), with 46% aged 18-29 and 61% in rural areas were analyzed. The age standardized prevalence for pre-diabetes and diabetes were 3.1% (95% CI: 2.2, 4.0) and 2.4% (1.8, 3.0) respectively. Only 43.7% were aware of their glycemic condition, one in five of those who had diabetes had received treatment, and only 7% of those diagnosed with diabetes had their blood glucose under control. Primary education ((both incomplete (0.21, 95%CI 0.10-0.47) and complete (0.40, 95%CI 0.23-0.71)) were associated with lower odds of pre-diabetes. Older age (60 69 years, AOR; 5.6, 95%CI 2.1-15.1) and raised blood pressure (2.8, 95% CI 1.5 5.0) were associated diabetes while overweight/obesity among women was associated with diabetes. CONCLUSION: The overall diabetes prevalence in Kenya is consistent with what has been reported in other sub-Saharan African countries. Of concern is the higher prevalence of pre-diabetes and undiagnosed diabetes that can progress to complications in the absence of interventions and the low diabetes awareness and control. This is the first nationally representative study to identify important groups at risk of pre-diabetes and diabetes that can be targeted for screening, health promotion and treatment. PMID- 30400866 TI - MaMADS2 repression in banana fruits modifies hormone synthesis and signalling pathways prior to climacteric stage. AB - BACKGROUND: While the role of ethylene in fruit ripening has been widely studied, the contributions of additional plant hormones are less clear. Here we examined the interactions between the transcription factor MaMADS2-box which plays a major role in banana fruit ripening and hormonal regulation. Specifically, we used MaMADS2 repressed lines in transcriptome and hormonal analyses throughout ripening and assessed hormone and gene expression perturbations as compared to wild-type (WT) control fruit. RESULTS: Our analyses revealed major differences in hormones levels and in expression of hormone synthesis and signaling genes mediated by MaMADS2 especially in preclimacteric pulp. Genes encoding ethylene biosynthesis enzymes had lower expression in the pulp of the repressed lines, consistent with reduced ethylene production. Generally, the expression of other hormone (auxin, gibberellins, abscisic acid, jasmonic acid and salicylic acid) response pathway genes were down regulated in the WT pulp prior to ripening, but remained high in MaMADS2 repressed lines. Hormone levels of abscisic acid were also higher, however, active gibberellin levels were lower and auxin levels were similar with MaMADS2 repression as compared to WT. Although abscisic level was higher in MaMADS2 repression, exogenous abscisic acid shortened the time to ethylene production and increased MaMADS2 mRNA accumulation in WT. Exogenous ethylene did not influence abscisic acid level. CRE - a cytokinin receptor, increased its expression during maturation in WT and was lower especially at prebreaker in the repressed line and zeatin level was lower at mature green of the repressed line in comparison to WT. CONCLUSIONS: In addition to previously reported effects of MaMADS2 on ethylene, this transcription factor also influences other plant hormones, particularly at the pre-climacteric stage. The cytokinin pathway may play a previously unanticipated role via MaMADS2 in banana ripening. Finally, abscisic acid enhances MaMADS2 expression to promote ripening, but the transcription factor in turn auto inhibits ABA synthesis and signaling. Together, these results demonstrate a complex interaction of plant hormones and banana fruit ripening mediated by MaMADS2. PMID- 30400868 TI - C-Peptide and cardiovascular risk factors among young adults in a southern Brazilian cohort. AB - BACKGROUND: Proinsulin connecting peptide (C-Peptide) is a marker of the beta cell function and has been considered a marker of insulin resistance whose evidence suggests were associated with cardiovascular mortality. Our study aims to evaluate the association of C-Peptide with metabolic cardiovascular risk factors among young adults followed since birth in southern Brazil. METHODS: In 1982, maternity hospital in Pelotas, a southern Brazilian city, were visited daily and all births were identified. Live births whose family lived in the urban area of the city were identified, their mothers interviewed, and these subjects have been prospectively followed. Casual hyperglycemia patients were excluded from analysis. C-Peptide was assessed at 23 years, when transversely analyzed its association with cardiometabolic and hemodynamic risk factors, and longitudinally 30 years of age. RESULTS: At age 23, 4297 individuals were evaluated, and C Peptide was measured in 3.807. In a cross-sectional analysis at 23 years of age, C-Peptide was positively associated with waist circumference, body mass index, glycaemia, triglycerides, and C-reactive protein. The association with HDL cholesterol was negative. In the longitudinal analysis at 30 years, C-Peptide remained associated with BMI, waist circumference, glycated hemoglobin, triglycerides, and C-reactive protein, whereas the association was negative for HDL. CONCLUSION: In the Pelotas birth cohort, the C-Peptide was associated with obesity indicators (waist circumference and BMI) cross-sectional (23 years) and longitudinal (30 years). We also observed cross-sectional and longitudinal associations of C-Peptide with cardiometabolic and inflammatory risk factors. PMID- 30400867 TI - Temperature and photoperiod changes affect cucumber sex expression by different epigenetic regulations. AB - BACKGROUND: Cucumbers (Cucumis sativus) are known for their plasticity in sex expression. DNA methylation status determines gene activity but is susceptible to environmental condition changes. Thus, DNA methylation-based epigenetic regulation may at least partially account for the instability of cucumber sex expression. Do temperature and photoperiod that are the two most important environmental factors have equal effect on cucumber sex expression by similar epigenetic regulation mechanism? To answer this question, we did a two-factor experiment of temperature and photoperiod and generated methylome and transcriptome data from cucumber shoot apices. RESULTS: The seasonal change in the femaleness of a cucumber core germplasm collection was investigated over five consecutive years. As a result, 71.3% of the 359 cucumber accessions significantly decreased their femaleness in early autumn when compared with spring. High temperature and long-day photoperiod treatments, which mimic early autumn conditions, are both unfavorable for female flower formation, and temperature is the predominant factor. High temperatures and long-day treatments both predominantly resulted in hypermethylation compared to demethylation, and temperature effect was decisive. The targeted cytosines shared in high temperature and long-day photoperiod treatment showed the same change in DNA methylation level. Moreover, differentially expressed TEs (DETs) and the predicted epiregulation sites were clustered across chromosomes, and importantly, these sites were reproducible among different treatments. Essentially, the photoperiod treatment preferentially and significantly influenced flower development processes, while temperature treatment produced stronger responses from phytohormone-pathway-related genes. Cucumber AGAMOUS was likely epicontrolled exclusively by photoperiod while CAULIFLOWER A and CsACO3 were likely epicontrolled by both photoperiod and temperature. CONCLUSIONS: Seasonal change of sex expression is a germplasm-wide phenomenon in cucumbers. High temperature and long-day photoperiod might have the same effect on the methylome via the same mechanism of gene-TE interaction but resulted in different epicontrol sites that account for different mechanisms between temperature- and photoperiod-dependent sex expression changes. PMID- 30400869 TI - Fundus images analysis using deep features for detection of exudates, hemorrhages and microaneurysms. AB - BACKGROUND: Convolution neural networks have been considered for automatic analysis of fundus images to detect signs of diabetic retinopathy but suffer from low sensitivity. METHODS: This study has proposed an alternate method using probabilistic output from Convolution neural network to automatically and simultaneously detect exudates, hemorrhages and microaneurysms. The method was evaluated using two approaches: patch and image-based analysis of the fundus images on two public databases: DIARETDB1 and e-Ophtha. The novelty of the proposed method is that the images were analyzed using probability maps generated by score values of the softmax layer instead of the use of the binary output. RESULTS: The sensitivity of the proposed approach was 0.96, 0.84 and 0.85 for detection of exudates, hemorrhages and microaneurysms, respectively when considering patch-based analysis. The results show overall accuracy for DIARETDB1 was 97.3% and 86.6% for e-Ophtha. The error rate for image-based analysis was also significantly reduced when compared with other works. CONCLUSION: The proposed method provides the framework for convolution neural network-based analysis of fundus images to identify exudates, hemorrhages, and microaneurysms. It obtained accuracy and sensitivity which were significantly better than the reported studies and makes it suitable for automatic diabetic retinopathy signs detection. PMID- 30400870 TI - Demographic consequences of reproductive interference in multi-species communities. AB - BACKGROUND: Reproductive interference can mediate interference competition between species through sexual interactions that reduce the fitness of one species by another. Theory shows that the positive frequency-dependent effects of such costly errors in mate recognition can dictate species coexistence or exclusion even with countervailing resource competition differences between species. While usually framed in terms of pre-mating or post-zygotic costs, reproductive interference manifests between individual Caenorhabditis nematodes from negative interspecies gametic interactions: sperm cells from interspecies matings can migrate ectopically to induce female sterility and premature death. The potential for reproductive interference to exert population level effects on Caenorhabditis trait evolution and community structure, however, remains unknown. RESULTS: Here we test whether a species that is superior in individual-level reproductive interference (C. nigoni) can exact negative demographic effects on competitor species that are superior in resource competition (C. briggsae and C. elegans). We observe coexistence over six generations and find evidence of demographic reproductive interference even under conditions unfavorable to its influence. C. briggsae and C. elegans show distinct patterns of reproductive interference in competitive interactions with C. nigoni. CONCLUSIONS: These results affirm that individual level negative effects of reproductive interference mediated by gamete interactions can ramify to population demography, with the potential to influence patterns of species coexistence separately from the effects of direct resource competition. PMID- 30400871 TI - Exploratory study of the reproducibility of the SCore for INtrinsic and EXtrinsic skin aging (SCINEXA) scale in "Ruta Escondida de la Mitad del Mundo", Ecuador, 2017. AB - BACKGROUND: Few studies have been published related to the analysis of different skin aging parameters for whole-body skin using the SCINEXA scale for skin damage. The aim of this study was to evaluate the reproducibility of the SCINEXA scale (SCore for INtrinsic and EXtrinsic skin Aging) in South-Americans non Caucasian population of a region of Ecuador. METHODS: Exploratory observational study. Thirty subjects of both genders, over 40 years old and living in a rural area with particular characteristics regarding sun exposure were included. The SCINEXA scale was applied at three different time points to assess its reproducibility. Repeated measures analysis of variance was used for comparison of mean SCINEXA scores. Intraclass correlation coefficient, 95% CI and "Cronbach's alpha" coefficient were performed to measure reproducibility. RESULTS: Among participants, 86.7% were female; mean age was over 67 years old, with mainly low educational level, and almost half had more than six hours of sun exposure per day. Test-retest reproducibility of this scale demonstrated almost perfect agreement. The SCINEXA score was greater than 2 points in half of the subjects, reflecting aging due to sun exposure. LIMITATIONS: Most participants were women from one town in a particular geographical area, and the sample size was small. Genetic determinants of skin phenotypes were not assessed. CONCLUSIONS: The SCINEXA score is reproducible in South American non-Caucasian subjects of a particular region of the country. Damage from sun exposure was evident in participants. PMID- 30400872 TI - Long-term follow-up in a Chinese child with congenital lipoid adrenal hyperplasia due to a StAR gene mutation. AB - BACKGROUND: Congenital lipoid adrenal hyperplasia (CLAH) is an extremely rare and the most severe form of congenital adrenal hyperplasia. Typical features include disorder of sex development, early-onset adrenal crisis and enlarged adrenal glands with fatty accumulation. CASE PRESENTATION: We report a case of CLAH caused by mutations in the steroidogenic acute regulatory protein (StAR) gene. The patient had typical early-onset adrenal crisis at 2 months of age. She had normal-appearing female genitalia and a karyotype of 46, XY. The serum cortisol and adrenal steroids levels were always nearly undetectable, but the adrenocorticotropic hormone levels were extremely high. Genetic analysis revealed compound heterozygous mutations at c. 229C > T (p.Q77X) in exon 3 and c. 722C > T (p.Q258X) in exon 7 of the StAR gene. The former mutation was previously detected in only two other Chinese CLAH patients. Both mutations cause truncation of the StAR protein. The case reported here appears to be a classic example of CLAH with very small adrenal glands and is the second reported CLAH case with small adrenal glands thus far. In a 15-year follow-up, the patient's height was approximately average for females before age 4 and fell to - 1 SDS at 10 years of age. Her bone age was similar to her chronological age from age 4 to age 15 years. CONCLUSIONS: In conclusion, this is a classic case of CLAH with exceptionally small adrenal glands. Q77X mutation seems to be more common in Chinese CLAH patients. Additionally, this is the first report of the growth pattern associated with CLAH after a 15-year follow-up. PMID- 30400873 TI - Lack of impact of iodinated contrast media on kidney cell-cycle arrest biomarkers in critically ill patients. AB - BACKGROUND: Iodinated contrast media may contribute to acute kidney injury. However, several recent works suggest that this toxicity is minimal in the clinical setting. Recently, urinary G1 cell-cycle arrest proteins tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin like growth factor binding protein 7 (IGFBP-7) were identified as highly sensitive and specific biomarkers for early detection of kidney aggression. The impact of contrast administration on those biomarkers has not been specifically evaluated but could provide clues about the toxicity of contrast media. This study aimed at measuring changes in TIMP-2 and IGFBP-7 urinary concentrations before and after a contrast-enhanced computed tomography in critically ill patients. METHODS: 77 patients were included in a prospective observational cohort study. Urinary [TIMP -2].[IGFBP-7] was measured before, 6 and 24 h after contrast infusion. Urine output and serum creatinine were followed 3 days. RESULTS: Median [TIMP-2].[IGFBP-7] was 0.06 [interquartile range 0.04;0.26], 0.07 [0.03;0.34] and 0.10 [0.04;0.37] (ng/mL)2/1000 respectively before, 6 and 24 h after contrast infusion. Individual changes from baseline were - 0.01 [- 0.11;0.11] and 0.00 [- 0.10;0.09] (ng/ml)2/1000 at 6 and 24 h. These changes were not higher among the patients increasing their Kidney Disease Improving Global Outcome (KDIGO) classification within 3 days after contrast infusion (n = 14 [18%] based on creatinine criterion only, n = 42 [55%] based on creatinine and urine output). CONCLUSIONS: Changes in [TIMP-2].[IGFBP-7] urinary concentration after contrast-enhanced computed tomography were insignificant, suggesting minimal kidney aggression by modern iodinated contrast media. PMID- 30400874 TI - What is the association between the presence of comorbidities and the appropriateness of care for low back pain? A population-based medical record review study. AB - BACKGROUND: Although "non-specific" in 90% of cases, low back pain (LBP) is often treated as an independent entity, even though comorbidities are commonly associated with it. There is evidence that some LBP may be related to chronic conditions or be a symptom of poor health. The purpose of this study was to clarify the extent of comorbidities amongst a cohort of Australian adults with LBP and examine if having concurrent conditions has any association with appropriateness of care for LBP. METHODS: A population-based sample of patients with one or more of 22 common conditions was recruited by telephone; consents were obtained to review their medical records. Trained surveyors extracted information from their medical records to examine the care patients received for their LBP with respect to ten indicators of appropriate care, ratified by LBP experts. Using LBP as the index condition, lists of self-reported comorbidities and those that were documented in medical records were compared. Medical records were reviewed and analysed with respect to appropriateness of care to identify any significant differences in care received between patients with LBP only and those with LBP plus comorbidities. RESULTS: One hundred and sixty four LBP patients were included in the analysis. Over 60% of adults with LBP in Australia had one of 17 comorbidities documented, with females being more likely than males to have comorbid conditions (63% vs 37%, p = 0.012). The more comorbidities, the poorer their reported health status (63% vs 30%, p = 0.006). Patients with comorbidities were significantly less likely to receive appropriate LBP care on nine of the ten LBP indicators (p < 0.05). CONCLUSIONS: This study established that the presence of comorbidities is associated with poorer care for LBP. Understanding why this is so is an important direction for future research. Further studies using a larger cohort are needed to explore the association between comorbidities and appropriateness of care for LBP, to better inform guidelines and practice in this area. PMID- 30400875 TI - Accurate hybrid template-based and MR-based attenuation correction using UTE images for simultaneous PET/MR brain imaging applications. AB - BACKGROUND: Attenuation correction is one of the most crucial correction factors for accurate PET data quantitation in hybrid PET/MR scanners, and computing accurate attenuation coefficient maps from MR brain acquisitions is challenging. Here, we develop a method for accurate bone and air segmentation using MR ultrashort echo time (UTE) images. METHODS: MR UTE images from simultaneous MR and PET imaging of five healthy volunteers was used to generate a whole head, bone and air template image for inclusion into an improved MR derived attenuation correction map, and applied to PET image data for quantitative analysis. Bone, air and soft tissue were segmented based on Gaussian Mixture Models with probabilistic tissue maps as a priori information. We present results for two approaches for bone attenuation coefficient assignments: one using a constant attenuation correction value; and another using an estimated continuous attenuation value based on a calibration fit. Quantitative comparisons were performed to evaluate the accuracy of the reconstructed PET images, with respect to a reference image reconstructed with manually segmented attenuation maps. RESULTS: The DICE coefficient analysis for the air and bone regions in the images demonstrated improvements compared to the UTE approach, and other state-of-the art techniques. The most accurate whole brain and regional brain analyses were obtained using constant bone attenuation coefficient values. CONCLUSIONS: A novel attenuation correction method for PET data reconstruction is proposed. Analyses show improvements in the quantitative accuracy of the reconstructed PET images compared to other state-of-the-art AC methods for simultaneous PET/MR scanners. Further evaluation is needed with radiopharmaceuticals other than FDG, and in larger cohorts of participants. PMID- 30400877 TI - Cancer risk after renal transplantation in South Korea: a nationwide population based study. AB - BACKGROUND: This study aimed to evaluate patterns of posttransplant malignancies among renal transplant recipients (RTRs) in South Korea using nationwide data. METHODS: The nationwide cohort assessed in this study included RTRs from January 1, 2010, to December 31, 2014. We analyzed cancer incidence during the time course after renal transplantation. Additionally, we calculated standardized incidence ratios (SIRs) to evaluate the risk of malignancies in RTRs. RESULTS: A total of 1343 RTRs (871 males and 472 females, mean age 48.5 +/- 11.6 years) were assessed. Among them, 104 (7.7%) developed malignancies after transplantation, most commonly in the thyroid cancer (23.1%). The SIR for all cancers was 3.54; particularly, the SIRs for renal cancer, myeloma, and non-Hodgkin lymphoma were 16.31, 24.02, and 28.64, respectively. Females showed a higher risk of malignancy than males (SIRs: 4.04 for women and 3.26 for men). The median interval between transplantation and malignancy diagnosis was 27.2 months (range 12.3-54.8 months). CONCLUSIONS: RTRs in South Korea demonstrated a high risk of malignancy after transplantation compared with the general population. This indicates that close surveillance and routine screening for cancer in RTRs are needed. PMID- 30400876 TI - Pragmatic trial of multifaceted intervention (STROKE-CARD care) to reduce cardiovascular risk and improve quality-of-life after ischaemic stroke and transient ischaemic attack -study protocol. AB - BACKGROUND: Patients with ischaemic stroke or transient ischaemic attack (TIA) are at high risk of future cardiovascular events. Despite compelling evidence about the efficacy of secondary prevention, a substantial gap exists between risk factor management in real life and that recommended by international guidelines. Moreover, stroke is a leading cause of disability and morbidity which partly emerges from post-stroke complications. METHODS/DESIGN: We designed a block randomised (2:1 ratio) open pragmatic trial [NCT02156778] with blinded outcome assessment comparing STROKE-CARD to usual post-stroke-patient care. STROKE-CARD is a multifaceted post-stroke disease management program with the objective of reducing recurrent cardiovascular events and improving quality of life in ischaemic stroke and TIA-patients. It combines intensified multi-domain secondary prevention, systematic detection and treatment of post-stroke complications, and patient self-empowerment. Enrolment of 2160 patients with acute ischaemic stroke or TIA (ABCD2-Score >= 3) is planned at two study centres in Austria. The co primary efficacy endpoints are (i) the composite of major recurrent cardiovascular events (nonfatal stroke, nonfatal myocardial infarction, and vascular death) occurring within 12 months after the index event and (ii) one year health-related quality-of-life measured with the European Quality of Life-5 Dimensions (EQ-5D-3 L) questionaire. Secondary endpoints include all-cause mortality, functional outcome, and target-level achievement in risk factor management. DISCUSSION: This trial will provide evidence on whether the pragmatic post-stroke intervention program STROKE-CARD can help prevent cardiovascular events and improve quality-of-life within the setting of a high-quality acute stroke care system. In case of success, STROKE-CARD may be implemented in daily clinical routine and serve as a model for other disease management initiatives. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02156778 . (June 5, 2014, retrospectively registered). PMID- 30400878 TI - A pan-cancer analysis of driver gene mutations, DNA methylation and gene expressions reveals that chromatin remodeling is a major mechanism inducing global changes in cancer epigenomes. AB - BACKGROUND: Recent large-scale cancer sequencing studies have discovered many novel cancer driver genes (CDGs) in human cancers. Some studies also suggest that CDG mutations contribute to cancer-associated epigenomic and transcriptomic alterations across many cancer types. Here we aim to improve our understanding of the connections between CDG mutations and altered cancer cell epigenomes and transcriptomes on pan-cancer level and how these connections contribute to the known association between epigenome and transcriptome. METHOD: Using multi-omics data including somatic mutation, DNA methylation, and gene expression data of 20 cancer types from The Cancer Genome Atlas (TCGA) project, we conducted a pan cancer analysis to identify CDGs, when mutated, have strong associations with genome-wide methylation or expression changes across cancer types, which we refer as methylation driver genes (MDGs) or expression driver genes (EDGs), respectively. RESULTS: We identified 32 MDGs, among which, eight are known chromatin modification or remodeling genes. Many of the remaining 24 MDGs are connected to chromatin regulators through either regulating their transcription or physically interacting with them as potential co-factors. We identified 29 EDGs, 26 of which are also MDGs. Further investigation on target genes' promoters methylation and expression alteration patterns of these 26 overlapping driver genes shows that hyper-methylation of target genes' promoters are significantly associated with down-regulation of the same target genes and hypo-methylation of target genes' promoters are significantly associated with up-regulation of the same target genes. CONCLUSION: This finding suggests a pivotal role for genetically driven changes in chromatin remodeling in shaping DNA methylation and gene expression patterns during tumor development. PMID- 30400879 TI - Malaria in Meghalaya: a systematic literature review and analysis of data from the National Vector-Borne Disease Control Programme. AB - BACKGROUND: Meghalaya, one of eight states in the northeastern region of India, has been reported to carry a high malaria burden. However, malaria surveillance, epidemiology, and vector studies are sparse, and no reviews combining these topics with malaria prevention and control strategies have been published in recent years. Furthermore, no analysis of surveillance data has been published documenting the changes in epidemiology following the first distribution of long lasting insecticidal nets (LLINs) statewide in 2016. METHODS: A hybrid approach was used to describe the status of malaria in Meghalaya. First, a literature search was performed using the terms 'malaria' and 'Meghalaya'. Second, data were obtained from the Meghalaya State Malaria Control Programme for 2006-2017 for analysis of trends. Data from 3 years 2015-2017 were analysed further by district and year to assess changes in malaria incidence and distribution following the introduction of LLINs. RESULTS/CONCLUSIONS: Like malaria in mainland India, malaria in Meghalaya is complex, with both Plasmodium falciparum and Plasmodium vivax parasites in circulation, multiple Anopheles vector species, and reports of both unusual and severe malaria syndromes across all age groups. Integrated statewide malaria epidemiology, vector, and prevention and control data for Meghalaya are not readily available, and published studies are largely focused on a single topic or a single district or region of the state. Although malaria prevention and control approaches are available, (e.g. spraying, LLINs, personal repellents), their use and effectiveness is also not well characterized in the literature. Analysis of state malaria control programme data indicates that case incidence and related fatalities in Meghalaya have declined over the last decade. This could be attributed to changes in treatment guidelines and/or statewide distribution of effective prevention methods such as LLINs. Since the distribution of more than 900,000 LLINs in 2016, the malaria caseload has declined significantly in most Meghalaya districts, excluding the remote and geographically isolated South Garo Hills. Additionally, the proportion of adult malaria cases (15+ years of age versus children 0-14 years) in most districts was significantly greater following LLIN distribution, which likely reflects common lifestyle practices in these areas (e.g. adults working during night hours; small children in the households receiving priority for bed net protection). While reduction in malaria case incidence and related deaths is clear, the changes in malaria transmission and clinical manifestation have not been characterized. Routine epidemiology and vector surveillance combined with real-time data reporting are essential for the continued reduction and eventual elimination of malaria in Meghalaya. PMID- 30400880 TI - Foetal weight prediction models at a given gestational age in the absence of ultrasound facilities: application in Indonesia. AB - BACKGROUND: Birth weight is one of the most important indicators of neonatal survival. A reliable estimate of foetal weight at different stages of pregnancy would facilitate intervention plans for medical practitioners to prevent the risk of low birth weight delivery. This study has developed reliable models to more accurately predict estimated foetal weight at a given gestation age in the absence of ultrasound facilities. METHODS: A primary health care centre was involved in collecting retrospective non-identified Indonesian data. The best subset model selection criteria, coefficient of determination, standard deviation, variance inflation factor, Mallows Cp, and diagnostic tests of residuals were deployed to select the most significant independent variables. Simple and multivariate linear regressions were used to develop the proposed models. The efficacy of models for predicting foetal weight at a given gestational age was assessed using multi-prediction accuracy measures. RESULTS: Four weight prediction models based on fundal height and its combinations with gestational age (between 32 and 41 weeks) and ultrasonic estimates of foetal head circumference and foetal abdominal circumference have been developed. Multiple comparison criteria show that the proposed models were more accurate than the existing models (mean prediction errors between - 0.2 and 2.4 g and median absolute percentage errors between 4.1 and 4.2%) in predicting foetal weight at a given gestational age (between 35 and 41 weeks). CONCLUSIONS: This research has developed models to more accurately predict estimated foetal weight at a given gestational age in the absence of ultrasound machines and trained ultra sonographers. The efficacy of the models was assessed using retrospective data. The results show that the proposed models produced less error than the existing clinical and ultrasonic models. This research has resulted in the development of models where ultrasound facilities do not exist, to predict the estimated foetal weight at varying gestational age. This would promote the development of foetal inter growth charts, which are currently unavailable in Indonesian primary health care systems. Consistent monitoring of foetal growth would alleviate the risk of having inter growth abnormalities, such as low birth weight that is the most leading factor of neonatal mortality. PMID- 30400881 TI - Value of flaccid penile ultrasound in screening for arteriogenic impotence: a preliminary prospective study. AB - BACKGROUND: This prospective study is to evaluate the potential value of sonographic measurements in the flaccid penis for the screening of arteriogenic impotence. METHODS: A consecutive series of 260 Chinese males consulting for sexual dysfunction and 54 controls underwent sonographic examination. The sonographic parameters were correlated with the clinical gold standards, including the international index of erectile function (IIEF) and penile erectile hardness grading scale (EHGS). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and area under the receiver operating characteristic curve (AUROC) of flaccid peak systolic velocity (PSV) in predicting patients with normal function were analyzed. RESULTS: The mean cavernous PSV of both sides in the patients with sexual dysfunction ranged from 7.76 to 11.12 cm/sec with a stepwise increase in IIEF and EHGS grading scale (P < .05). The cutoff value of flaccid PSV for the differential diagnosis of grade 4 of IIEF-5 or EHGS was 8.20-8.90 cm/sec, with an AUROC of 0.657-0.724, specificity of 82.96-86.84% and PPV of 95.20-96.60%, respectively. CONCLUSIONS: This simple flaccid PSV measurement is a specific tool for screening arteriogenic impotence. PMID- 30400882 TI - Autologous arteriovenous fistula is associated with superior outcomes in elderly hemodialysis patients. AB - BACKGROUND: The number of elderly patients with end-stage renal disease is increasing rapidly. The higher prevalence of comorbidities and shorter life expectancy in these patients make it difficult to decide on the type of vascular access (VA). We explored the optimal choice for VA in elderly hemodialysis patients. METHODS: We included elderly patients (> 65 years) visiting our VA clinic and divided them into three groups as follows: radiocephalic arteriovenous fistula (AVF), brachiocephalic AVF, and prosthetic arteriovenous graft (AVG). The primary outcomes were VA abandonment and all-cause mortality. The secondary outcome was maturation failure (MF). RESULTS: Of 529 patients, 61.2% were men. The mean age was 73.6 +/- 6.0 years. The VA types were as follows: 49.9% radiocephalic AVF, 31.8% brachiocephalic AVF, and 18.3% AVG. Patients with an AVG tended to be older, female, and have a lower body mass index. More than half of patients (n = 302, 57.1%) started dialysis with central catheters, but the proportion of predialysis central catheter placement was not different among the VA types. Radiocephalic AVF was significantly superior to AVG in terms of VA abandonment (P = 0.005) and all-cause mortality (P < 0.001) in spite of a higher probability of MF. Brachiocephalic AVF was associated with a shorter time to the first needling and fewer interventions before maturation than radiocephalic AVF. CONCLUSIONS: Autologous AVF was suggested as the preferred VA choice in terms of long-term outcomes in elderly patients. PMID- 30400883 TI - A novel SLC6A8 mutation associated with intellectual disabilities in a Chinese family exhibiting creatine transporter deficiency: case report. AB - BACKGROUND: X-linked creatine transporter deficiency (OMIM#300036,CRTR-D) is characterized by cerebral creatine deficiency, intellectual disabilities, severe speech impairment, seizures and behavioral problems. Mutations in the creatine transporter gene SLC6A8, a member of the solute-carrier family 6 mapped to Xq28, have been reported to cause the creatine transporter deficiency. CASE PRESENTATION: The proband presented at 5 yrs. 1 month of age with delays in intellectual and development, seizures and behavioral problems. A novel missense mutation, c.1181C > A (p.Thr394Lys), in the SLC6A8 gene (NM_005629.3) was detected via targeted exome sequencing, and then validated by Sanger sequencing. Multiple in silico variant effect analysis methods, including SIFT, PolyPhen2, PROVEAN, and Mutation Taster predicted that this variant was likely damaging or diseasing-causing. This hemizygous variation was also identified in the affected brother with the same clinical condition and inherited from the heterozygous carrier mother. The diagnosis was suggested by increased urinary creatine/creatinine (Cr:Crn) ratio and markedly reduced creatine content peak by brain proton magnetic resonance spectroscopy (MRS). The proband's mother became pregnant with a 3rd sibling, in whom the Sanger sequencing result of c.1181C > A was negative. CONCLUSION: The novel mutation c.1181C > A in the SLC6A8 gene reported in a Chinese family has expanded the mutation spectrum of CRTR-D. The combination of powerful new technologies such as targeted exome sequencing with thorough systematic clinical evaluation of patients will improve the diagnostic yield, and assist in genetic counselling and prenatal diagnosis for suspected genetic disorders. PMID- 30400884 TI - Seasonal adherence to, and effectiveness of, subcutaneous interferon beta-1a administered by RebiSmart(r) in patients with relapsing multiple sclerosis: results of the 1-year, observational GEPAT-SMART study. AB - BACKGROUND: Little is known about whether tolerability and adherence to treatment can be influenced by weather and temperature conditions. The objective of this study was to assess monthly and seasonal adherence to and safety of sc IFN-beta1a (Rebif(r), Merck) in relapsing-remitting multiple sclerosis (RRMS) patients using the RebiSmart(r) electronic autoinjector. METHODS: A multicentre, prospective observational study in Greece in adult RRMS patients with EDSS < 6, under Rebif(r)/RebiSmart(r) treatment for <=6 weeks before enrollment. The primary endpoint was monthly, seasonal and annual adherence over 12 months (defined in text). Secondary endpoints included number of relapses, disability, adverse events. RESULTS: Sixty four patients enrolled and 47 completed all study visits (Per Protocol Set - PPS). Mean annual adherence was 97.93% +/- 5.704 with no significant monthly or seasonal variations. Mean relapses in the pre- and post- treatment 12-months were 1.1 +/- 0.47 and 0.2 +/- 0.54 (p < 0.0001, PPS). 10 patients (22%) showed 3-month disability progression, 19 (40%) stabilization and 18 (38%) improvement. EDSS was not correlated to pre- (r = 0.024, p = 0.87) or post-treatment relapses (r = 0.022, p = 0.88). CONCLUSION: High adherence with no significant seasonal or weather variation was observed over 12 months. While the efficacy on relapses was consistent with published studies, we could not identify a relationship between relapses and disability. TRIAL REGISTRATION: Greek registry of non-interventional clinical trials ID: 200136 , date of registration: February 18th, 2013. PMID- 30400885 TI - Insecticide resistance in Anopheles gambiae from the northern Democratic Republic of Congo, with extreme knockdown resistance (kdr) mutation frequencies revealed by a new diagnostic assay. AB - BACKGROUND: Mutations in the voltage-gated sodium channel at codon 1014 confer knock-down resistance (kdr) to pyrethroids in a wide range of insects. Anopheles gambiae exhibits two mutant alleles at codon 1014, serine and phenylalanine; and both are now widespread across Africa. Existing screening methods only allow for one resistant allele to be detected per assay. A new locked nucleic acid (LNA) qPCR assay was developed for the simultaneous detection of both mutant alleles and the wild type allele in a single assay. This tri-allelic detection assay was assessed as part of a study of the insecticide resistance in An. gambiae sensu stricto (s.s.) in the previously un-sampled area of Nord Ubangi, Democratic Republic of the Congo. METHODS: Samples from three sites were tested for insecticide susceptibility using WHO bioassays, with and without the synergist PBO preceding pyrethroid exposures, and were subsequently analysed for frequency and resistance-association of the Vgsc-1014 and Vgsc-N1575Y mutations. Results from the LNA-kdr 1014 assay were compared to results from standard TaqMan-kdr assays. RESULTS: Anopheles gambiae sensu lato (s.l.) was by far the predominant vector captured (84%), with only low frequencies of Anopheles funestus s.l. (9%) detected in Nord Ubangi. Molecular identification found An. gambiae s.s. to be the principal vector (99%) although Anopheles coluzzii was detected at very low frequency. Anopheles gambiae were susceptible to the carbamate insecticide bendiocarb, but resistant to DDT and to the pyrethroids permethrin and deltamethrin. Susceptibility to both pyrethroids was partially restored with prior exposure to PBO suggesting likely involvement of metabolic resistance. Anopheles gambiae s.s. was homozygous for kdr resistant alleles with both the L1014F and L1014S mutations present, and the N1575Y polymorphism was present at low frequency. The LNA-kdr assay simultaneously detected both resistant alleles and gave results entirely consistent with those from the two TaqMan-kdr assays. CONCLUSION: This study provides rare data on insecticide resistance and mechanisms in Anopheles from the centre of Africa, with the first detection of N1575Y. Nord Ubangi populations of An. gambiae s.s. show insecticide resistance mediated by both metabolic mechanisms and Vgsc mutations. The LNA-kdr assay is particularly suitable for use in populations in which both 1014S and 1014F kdr alleles co-occur and provides robust results, with higher throughput and at a quarter of the cost of TaqMan assays. PMID- 30400886 TI - Bisphenol A exposure and type 2 diabetes mellitus risk: a meta-analysis. AB - BACKGROUND: This meta-analytic study explored the relationship between the risk of type 2 diabetes mellitus (T2DM) and bisphenol A concentrations. METHODS: The Embase and Medline (PubMed) databases were searched, using relevant keywords, for studies published between 1980 and 2018. A total of 16 studies, twelve cross sectional, two case-control and one prospective, were included in the meta analysis. The odds ratio (OR) and its 95% confidence interval (CI) were determined across the sixteen studies. The OR and its 95% CI of diabetes associated with bisphenol A were estimated using both fixed-effects and random effects models. RESULTS: A total of 41,320 subjects were included. Fourteen of the sixteen studies included in the analysis provided measurements of urine bisphenol A levels and two study provided serum bisphenol A levels. Bisphenol A concentrations in human bio-specimens showed positive associations with T2DM risk (OR 1.28, 95% CI 1.14, 1.44). A sensitivity analysis indicated that urine bisphenol A concentrations were positively associated with T2DM risk (OR 1.20, 95% CI 1.09, 1.31). CONCLUSIONS: This meta-analysis indicated that Bisphenol A exposure is positively associated with T2DM risk in humans. PMID- 30400887 TI - The value of non-invasive measurement of cardiac output and total peripheral resistance to categorize significant changes of intradialytic blood pressure: a prospective study. AB - BACKGROUND: Blood pressure (BP) is currently the main hemodynamic parameter used to assess the influence of fluid removal during hemodialysis session. Since BP is dependent on cardiac output (CO) and total peripheral resistance (TPRI), investigating these parameters may help to better understand the influence of fluid removal on patient's hemodynamics. We used a novel non-invasive whole-body bio-impedance cardiography device, recently validated in hemodialysis patients, to examine mechanisms of intradialytic hemodynamics in a Chinese dialysis population. METHODS: Chronic hemodialysis patients in Sichuan Provincial People's Hospital were enrolled. Demographic data and dialysis prescriptions were collected. Hemodynamic measurements were made pre-treatment, every 20 min during treatment and immediately after treatment in each random dialysis session. These included blood pressure, cardiac index (CI), total peripheral resistance (TPRI) and cardiac power index (CPI). Patients were divided into 5 hemodynamic groups as per their major hemodynamic response to fluid removal: low CPI, low TPRI, high TPRI, High CPI and those with normal hemodynamics. RESULTS: Twenty-seven patients were enrolled, with 12 (44.4%) males. The average age was 65 +/- 12 y. The average body mass index (BMI) was 23.7 +/- 3.9 kg/m2. 12 (44.4%) patients were diabetic. Three hundred twenty-four hemodynamic measurements were made. Weight, BMI, total fluid removal, pretreatment systolic BP, CI, TPRI and CI differed significantly among the 5 hemodynamic groups.11.1% of patients had low CPI, 25.9% had low TPRI, 18.5% had high CPI, 3.7% had high TPRI and 40.7% had normal hemodynamics. Hemodynamic differences among the 5 subgroups were significant. CONCLUSION: This technology provides multi-dimensional insight into intradialytic hemodynamic parameters, which may be more informative than blood pressure only. Using hemodynamic parameters to describe patients' status is more specific and accurate, and could help to work out specific and effective therapeutic actions according to underlying abnormalities. PMID- 30400888 TI - Highly sensitive electrochemical biosensor based on redox - active monolayer for detection of anti-hemagglutinin antibodies against swine-origin influenza virus H1N1 in sera of vaccinated mice. AB - BACKGROUND: In this work, we report an electrochemical biosensor for the detection of anti-hemagglutinin antibodies against the swine virus H1N1 present in mice sera immunized with mixture of His6-H1 HA in monomeric and oligomeric form. The oriented immobilization of the recombinant His-tagged hemagglutinin (His6-H1 HA) consists of: (i) formation of a mixed layer of 4-mercaptobutanol (MBT) and the thiol derivative of dipyrromethene (DPM); (ii) complexation of Cu (II) by DPM; (iii) immobilization of His6-H1 HA via coordination bonds between Cu (II) sites from DPM-Cu (II) complex and imidazole nitrogen atoms of a histidine tag; (iv) filling free spaces with bovine serum albumin. The interactions between recombinant His6- H1 HA covalently attached to the electrode surface and the anti hemagglutinin H1 antibodies present in mice sera were explored with Osteryoung square-wave voltammetry. RESULTS: This analytical device was able to detect the antibodies present in vaccinated mice sera diluted from 1 * 109 to 1 * 108 fold. CONCLUSIONS: The unprecedented sensitivity of described biosensor is much better than widely use ELISA test and other analytical methods for determination of antibodies against the influenza A viruses. It has been proved that redox active DPM-Cu (II) monolayer is a universal platform suitable for stable and oriented immobilization of any His-tagged sensing elements. Thus, this universal layer could be a base of numerous analytical devices suitable for detection of antibodies against different viruses. PMID- 30400889 TI - Assessing the effect of oral activated vitamin D on overall survival in hemodialysis patients: a landmark analysis. AB - BACKGROUND: Patients with end stage renal disease have a high all-cause and cardiovascular mortality. Secondary hyperparathyroidism and vitamin D deficiency are considered part of the mechanism for the excess mortality observed. We aimed to evaluate the relationship between vitamin D use and all-cause mortality. METHODS: In this retrospective cohort study, we included all incident patients who started hemodialysis in Taiwan between 2001 and 2009. Patients were followed from landmark time, i.e., the 360th day from hemodialysis initiation, through the end of 2010 or death. We evaluated the association between activated vitamin D use or not before landmark time and all-cause mortality using conditional landmark analysis with Cox regression. We used group-based trajectory model to categorize high-dose versus average-dose users to evaluate dose-response relationships. RESULTS: During the median follow-up of 1019 days from landmark time, vitamin D users had a lower crude mortality rate than non-users (8.98 versus 12.93 per 100 person-years). Compared with non-users, vitamin D users was associated with a lower risk of death in multivariate Cox model (HR 0.91 [95% CI, 0.87-0.95]) and after propensity score matching (HR 0.94 [95% CI, 0.90-0.98]). High-dose vitamin D users had a lower risk of death than conventional-dose users, HR 0.75 [95% CI, 0.63-0.89]. The association of vitamin D treatment with reduced mortality did not alter when we re-defined landmark time as the 180th day or repeated analyses in patients who underwent hemodialysis in the hospital setting. CONCLUSIONS: Our findings supported the survival benefits of activated vitamin D among incident hemodialysis patients. PMID- 30400891 TI - Transposase mapping identifies the genomic targets of BAP1 in uveal melanoma. AB - BACKGROUND: BAP1 is a histone deubiquitinase that acts as a tumor and metastasis suppressor associated with disease progression in human cancer. We have used the "Calling Card System" of transposase-directed transposon insertion mapping to identify the genomic targets of BAP1 in uveal melanoma (UM). This system was developed to identify the genomic loci visited by transcription factors that bind directly to DNA; our study is the first use of the system with a chromatin remodeling factor that binds to histones but does not interact directly with DNA. METHODS: The transposase piggyBac (PBase) was fused to BAP1 and expressed in OCM 1A UM cells. The insertion of transposons near BAP1 binding sites in UM cells were identified by genomic sequencing. We also examined RNA expression in the same OCM-1A UM cells after BAP1 depletion to identify BAP1 binding sites associated with BAP1-responsive genes. Sets of significant genes were analyzed for common pathways, transcription factor binding sites, and ability to identify molecular tumor classes. RESULTS: We found a strong correlation between multiple calling-card transposon insertions targeted by BAP1-PBase and BAP1-responsive expression of adjacent genes. BAP1-bound genomic loci showed narrow distributions of insertions and were near transcription start sites, consistent with recruitment of BAP1 to these sites by specific DNA-binding proteins. Sequence consensus analysis of BAP1-bound sites showed enrichment of motifs specific for YY1, NRF1 and Ets transcription factors, which have been shown to interact with BAP1 in other cell types. Further, a subset of the BAP1 genomic target genes was able to discriminate aggressive tumors in published gene expression data from primary UM tumors. CONCLUSIONS: The calling card methodology works equally well for chromatin regulatory factors that do not interact directly with DNA as for transcription factors. This technique has generated a new and expanded list of BAP1 targets in UM that provides important insight into metastasis pathways and identifies novel potential therapeutic targets. PMID- 30400890 TI - Urogenital pathogens, associated with Trichomonas vaginalis, among pregnant women in Kilifi, Kenya: a nested case-control study. AB - BACKGROUND: Screening of curable sexually transmitted infections is frequently oriented towards the diagnosis of chlamydia, gonorrhea, syphilis and trichomoniasis, whereas other pathogens, sometimes associated with similar urogenital syndromes, remain undiagnosed and/or untreated. Some of these pathogens are associated with adverse pregnancy outcomes. METHODS: In a nested case-control study, vaginal swabs from 79 pregnant women, i.e., 28 T. vaginalis positive (cases) and 51 T. vaginalis-negative (controls), were screened by quantitative PCR for Adenovirus 1 and 2, Cytomegalovirus, Herpes Simplex Virus 1 and 2, Chlamydia trachomatis, Escherichia coli, Haemophilus ducreyi, Mycoplasma genitalium, M. hominis, candidatus M. girerdii, Neisseria gonorrhoeae, Streptococcus agalactiae, Treponema pallidum, Ureaplasma parvum, U. urealyticum, and Candida albicans. Additionally, we determined whether women with pathogens highly associated with T. vaginalis had distinct clinical signs and symptoms compared to women with T. vaginalis mono-infection. RESULTS: M. hominis was independently associated with T. vaginalis (adjusted odds ratio = 6.8, 95% CI: 2.3-19.8). Moreover, M. genitalium and Ca M. girerdii were exclusively detected in women with T. vaginalis (P = 0.002 and P = 0.001), respectively. Four of the six women co-infected with T. vaginalis and Ca M. girerdii complained of vaginal itching, compared to only 4 out of the 22 women infected with T. vaginalis without Ca M. girerdii (P = 0.020). CONCLUSION: We confirm M. hominis as a correlate of T. vaginalis in our population, and the exclusive association of both M. genitalium and Ca. M. girerdii with T. vaginalis. Screening and treatment of these pathogens should be considered. PMID- 30400892 TI - A new tooth brushing approach supported by an innovative hybrid toothbrush compared reduction of dental plaque after a single use versus an oscillating rotating powered toothbrush. AB - BACKGROUND: An innovative hybrid toothbrush was designed functioning either in manual mode, in powered mode (sonic) or in combined mode (manual and powered). The primary aim of this study was to evaluate and compare the clinical efficacy of this first hybrid toothbrush (Elgydium Clinic/Inava Hybrid) used in combined mode to a marketed oscillating-rotating powered toothbrush (Oral-B Vitality) in the reduction of dental plaque after a single use. The secondary aims were to evaluate the tolerance and acceptability of each device. METHODS: It was a randomized, examiner-blind, single-center study performed on two parallel groups: hybrid toothbrush (n = 33) versus oscillating-rotating toothbrush (n = 33). A brushing exercise was conducted for two minutes on subjects presenting a "Silness and Loe Plaque Index" (PI) between 1.0 and 2.0 and a "Modified Gingival Index" between 1.0 and 2.0. They were not to have ever used an electric toothbrush. To assess the device effect after brushing, a paired t-test was applied on the change outcome (After-Before brushing). An unpaired t-test was used to compare the efficacy of both devices. A global tolerance assessment of each powered toothbrush was done on all the subjects. The number and percentage of reactions related to each toothbrush was collected and the final tolerance assessment was estimated. RESULTS: After a single use, the hybrid toothbrush used in combined mode presented a global anti-plaque efficacy characterized by a significant decrease of the global PI of 45% on average (p < 0.0001; paired t-test). It was as effective as the oscillating rotating toothbrush in plaque removal (p > 0.05; unpaired t-test). The global tolerance of both toothbrushes was judged as "Good" and they were equally appreciated by the users. CONCLUSION: The results of this one-time use trial demonstrate the efficacy of the hybrid toothbrush used in combined mode for plaque removal. The hybrid toothbrush design allows each user to adapt tooth brushing to his preference (manual / sonic / combined), his skills or his mouth condition. We hypothesize that such an individualized approach can favor long term compliance with oral health recommendations and improve global oral wellness. TRIAL REGISTRATION: ISRCTN12394494 , 20/02/2018 - Retrospectively registered. PMID- 30400893 TI - Tafenoquine and primaquine do not exhibit clinical neurologic signs associated with central nervous system lesions in the same manner as earlier 8 aminoquinolines. AB - BACKGROUND: Tafenoquine was recently approved for Plasmodium vivax radical cure (KRINTAFELTM) and malaria prevention (ARAKODATM). METHODS: A review of the non clinical and clinical literature was conducted to assess whether tafenoquine (and primaquine) exhibit the same neurologic lesions and associated clinical signs as earlier 8-aminoquinolines, as has been alleged in recent opinion pieces. RESULTS: Plasmocid, pamaquine and pentaquine damage specific neuro-anatomical structures in Rhesus monkeys and humans leading to corresponding deficits in neurologic function. Neurologic therapeutic indices for these 3 drugs calculated based on monkey data were well correlated with human data. Despite 60 years of use, there is no evidence that primaquine exhibits similar neurotoxicity in humans. DISCUSSION/CONCLUSIONS: Extrapolation of data from Rhesus monkeys to humans, and the available clinical data, suggest that tafenoquine also does not exhibit pamaquine, pentaquine or plasmocid-like clinical neurologic signs in humans. PMID- 30400895 TI - Renal-limited AL amyloidosis - a diagnostic and management dilemma. AB - BACKGROUND: Amyloidosis is a disorder caused by extracellular tissue deposition of insoluble fibrils which may result in a wide spectrum of symptoms depending upon their types, sites and amount of deposition. Amyloidosis can be divided into either systemic or localized disease. CASE PRESENTATION: We present a case of a middle-aged gentleman who presented with persistent nephrotic syndrome with worsening renal function. Repeated renal biopsies showed the presence of renal limited AL amyloidosis. Systemic amyloidosis workup was unremarkable apart from a slightly raised band of IgG lambda level with no associated immunoparesis. The nephrotic syndrome and renal histology did not improve over a 3-year period despite being given two courses of chemotherapies. CONCLUSION: We hope that early recognition of this unusual localised presentation of renal- limited AL Amyloidosis and its poor response to conventional treatment can alert the nephrologist to the potential existence of this rare condition. PMID- 30400894 TI - Association of lung function with cardiovascular risk: a cohort study. AB - BACKGROUND: The potential effects of pulmonary dysfunction on cardiovascular diseases (CVD) are receiving attention. We aimed to investigate and quantify the cross-sectional and longitudinal associations between lung function and overall cardiovascular risk among Chinese general population. METHODS: We studied 4019 participants from the Wuhan-Zhuhai cohort, with a follow-up of 3 years. A multivariable risk algorithm generated from the Framingham study was used to calculate individuals' overall cardiovascular risk i.e. 10-Year CVD Risk, which was further classified into 2 categories: low (< 10%) and high (>=10%) CVD risk. General linear model and logistic regression model were separately used to assess the associations of lung function with continuous and dichotomous 10-Year CVD Risk. RESULTS: Cross-sectionally, each 5% decrease in FEV1/FVC was associated with a 0.47% increase in 10-Year CVD Risk (P < 0.001). The adjusted odds ratio (OR) (95% confidence interval [CI]) for the prevalence of high CVD risk (10-Year CVD Risk>=10%) was 1.12 (1.07, 1.17) corresponding to each 5% decrease in FEV1/FVC. The OR (95% CI) for high CVD risk in the lowest group of FEV1/FVC (< 70% i.e. chronic obstructive pulmonary disease [COPD]) was 2.37 (1.43, 3.91) when compared with the highest group. Longitudinally, the adjusted risk ratio (RR) (95% CI) for the incidence of high CVD risk was 1.14 (1.03, 1.25) with each 5% decrease in baseline FEV1/FVC. Compared with the highest group of FEV1/FVC, the RR (95% CI) for high CVD risk in the lowest group (COPD) was 4.06 (1.46, 11.26). Analyses of 10-Year CVD Risk with FVC or FEV1 showed similar trends and significant associations (all P < 0.05). CONCLUSION: Reduced lung function was cross-sectionally and longitudinally associated with increased cardiovascular risk in Chinese general population. PMID- 30400896 TI - Analysis of erythrocyte dynamics in Rhesus macaque monkeys during infection with Plasmodium cynomolgi. AB - BACKGROUND: Malaria is a major mosquito transmitted, blood-borne parasitic disease that afflicts humans. The disease causes anaemia and other clinical complications, which can lead to death. Plasmodium vivax is known for its reticulocyte host cell specificity, but many gaps in disease details remain. Much less is known about the closely related species, Plasmodium cynomolgi, although it is naturally acquired and causes zoonotic malaria. Here, a computational model is developed based on longitudinal analyses of P. cynomolgi infections in nonhuman primates to investigate the erythrocyte dynamics that is pertinent to understanding both P. cynomolgi and P. vivax malaria in humans. METHODS: A cohort of five P. cynomolgi infected Rhesus macaques (Macaca mulatta) is studied, with individuals exhibiting a plethora of clinical outcomes, including varying levels of anaemia. A discrete recursive model with age structure is developed to replicate the dynamics of P. cynomolgi blood-stage infections. The model allows for parasitic reticulocyte preference and assumes an age preference among the mature RBCs. RBC senescence is modelled using a hazard function, according to which RBCs have a mean lifespan of 98 +/- 21 days. RESULTS: Based on in vivo data from three cohorts of macaques, the computational model is used to characterize the reticulocyte lifespan in circulation as 24 +/- 5 h (n = 15) and the rate of RBC production as 2727 +/- 209 cells/h/uL (n = 15). Analysis of the host responses reveals a pre-patency increase in the number of reticulocytes. It also allows the quantification of RBC removal through the bystander effect. CONCLUSIONS: The evident pre-patency increase in reticulocytes is due to a shift towards the release of younger reticulocytes, which could result from a parasite induced factor meant to increase reticulocyte availability and satisfy the parasite's tropism, which has an average value of 32:1 in this cohort. The number of RBCs lost due to the bystander effect relative to infection-induced RBC losses is 62% for P. cynomolgi infections, which is substantially lower than the value of 95% previously determined for another simian species, Plasmodium coatneyi. PMID- 30400897 TI - Prevalence and predictors of physical inactivity levels among Kenyan adults (18 69 years): an analysis of STEPS survey 2015. AB - BACKGROUND: Physical inactivity accounts for more than 3 million deaths worldwide, and is implicated in causing 6% of coronary heart diseases, 7% of diabetes, and 10% of colon or breast cancer. Globally, research has shown that modifying four commonly shared risky behaviours, including poor nutrition, tobacco use, harmful use of alcohol, and physical inactivity, can reduce occurrence of non-communicable diseases (NCDs). Risk factor surveillance through population-based periodic surveys, has been identified as an effective strategy to inform public health interventions in NCD control. The stepwise approach to surveillance (STEPS) survey is one such initiative, and Kenya carried out its first survey in 2015. This study sought to describe the physical inactivity risk factors from the findings of the Kenya STEPS survey. METHODS: This study employed countrywide representative survey administered between April and June 2015. A three stage cluster sampling design was used to select clusters, households and eligible individuals. All adults between 18 and 69 years in selected households were eligible. Data on demographic, behavioural, and biochemical characteristics were collected. Prevalence of physical inactivity was computed. Logistic regression used to explore factors associated with physical inactivity. RESULTS: A total of 4500 individuals consented to participate from eligible 6000 households. The mean age was 40.5 (39.9-41.1) years, with 51.3% of the respondents being female. Overall 346 (7.7%) of respondents were classified as physically inactive. Physical inactivity was associated with female gender, middle age (30-49 years), and increasing level of education, increasing wealth index and low levels of High Density Lipoproteins (HDL). CONCLUSION: A modest prevalence of physical inactivity slightly higher than in neighbouring countries was found in this study. Gender, age, education level and wealth index are evident areas that predict physical inactivity which can be focused on to develop programs that would work towards reducing physical inactivity among adults in Kenya. PMID- 30400898 TI - Stated and revealed preferences for HIV testing: can oral self-testing help to increase uptake amongst truck drivers in Kenya? AB - BACKGROUND: Long-distance truck drivers in Africa are particularly at risk of HIV acquisition and offering self-testing could help increase testing coverage in this hard-to-reach population. The aims of this study are twofold: (1) to examine the preference structures of truck drivers in Kenya regarding HIV testing service delivery models and what they mean for the roll-out of HIV self-testing, and (2) to compare the preference data collected from a hypothetical discrete choice experiment with the actual choices made by participants in the intervention arm of a randomised controlled trial (RCT) who were offered HIV testing choices. METHODS: Using data from 150 truck drivers, this paper examines whether the stated preferences regarding HIV testing in a discrete choice experiment predict the actual test selected when offered HIV testing choices. Conditional logit models were used for main effects analysis and stratified models were run by HIV testing choices made in the trial to assess if the attributes preferred differed by test chosen. RESULTS: The strongest driver of stated preference among all participants was cost. However, two preferences diverged between those who actually chose self-testing in the RCT and those who chose a provider administered test: the type of test (p < 0.001) and the type of counselling (p = 0.003). Self-testers preferred oral-testing to finger-prick testing (OR 1.26 p = 0.005), while non-self-testers preferred finger-prick testing (OR 0.56 p < 0.001). Non-self-testers preferred in-person counselling to telephonic counselling (OR 0.64 p < 0.001), while self-testers were indifferent to type of counselling. Preferences in both groups regarding who administered the test were not significant. CONCLUSIONS: We found stated preference structures helped explain the actual choices participants made regarding the type of HIV testing they accepted. Offering oral testing may be an effective strategy for increasing willingness to test among certain groups of truck drivers. However, the importance of in-person counselling and support, and concern that an oral test cannot detect HIV infection may mean that continuing to offer finger-prick testing at roadside wellness centres will best align with the preferences of those already attending these facilities. More research is needed to explore whether who administers the HIV test (provider versus self) makes any difference. TRIAL REGISTRATION: This trial is registered with the Registry for International Development Impact Evaluations ( RIDE ID#55847d64a454f ). PMID- 30400899 TI - A study to identify the practices of the buffalo keepers which inadvertently lead to the spread of brucellosis in Delhi. AB - BACKGROUND: India has the largest Buffalo population in the world, with every household in rural India owning buffaloes depending upon daily milk requirement - dairy farmers can own between 10 to 70 buffaloes. The health of Indian buffaloes is of economic importance since India is one of the largest buffalo meat exporters in the world, and Indian Buffalo semen is sold in the USA for breeding purposes. However, National Control Program on brucellosis is only active in South India and in Panjab (a North Indian state with high human brucellosis incidence). Our aim was to assess the knowledge and practices of the buffalo keepers of Delhi that make them susceptible to brucellosis. RESULTS: Amongst all the 11 districts of Delhi, there was 0% awareness about brucellosis and also about the S19 vaccine as the buffalo keepers had never heard of S19 vaccine which is available at minimal cost from Indian Veterinary Research Institute, Bareilly, India. Majority of the respondents drink raw milk, sleep in cattle sheds, do not isolate sick cattle, do not test buffaloes blood for any disease before purchasing them, apply intrauterine medication with bare hands to buffalo after abortion of foetus, never clean their cattle sheds with a disinfectant and believe that they can only acquire skin infections from cattle. All of these habits make them prone to brucellosis. While about 20 to 27% of respondents reported a history of abortions and retained placenta, disposed of the placenta with bare hands, and applied raw milk on cracked lips. It was surprising to note that majority of them never reared small ruminants like sheep and goat with buffaloes or Bos species as they were aware of the rapid spread of disease from small to big ruminants. CONCLUSIONS: We found that buffalo keepers were ignorant of brucellosis, its causative agent, relevant vaccines and that they also involved in high-risk activities. As such, our findings highlight a need for buffalo keepers to be better educated via several awareness camps to minimize human exposure to Brucella in Delhi. PMID- 30400900 TI - Exploring service providers' perspectives on the prevention and management of fetal alcohol spectrum disorders in South Africa: a qualitative study. AB - BACKGROUND: Fetal alcohol spectrum disorder (FASD) is among the leading causes of developmental and intellectual disabilities in individuals. Although efforts are being made toward the prevention and management of FASD in South Africa, the prevalence remains high. The sustained high prevalence could be attributed to several factors, including the lack of policy for a coordinated effort to prevent, diagnose and manage FASD nationally. In this study, our aim was to explore the perspectives of service providers (health and allied professionals, teachers, social workers) on the prevention and management of FASD towards developing a guideline to inform policy. METHOD: Guided by the exploratory qualitative research design, we purposively sampled relevant service providers in the field of FASD prevention and management for focus group discussions. Nine of these discussions were conducted with to eight participants per discussion session. The discussants were asked various questions on the current and required interventions and practices for the prevention and management of FASD. Following the Framework Method, data were transcribed verbatim and analysed using the thematic content analysis approach. RESULTS: Our findings show that aspects of the prevention and management of alcohol-related conditions are present in various policies. However, there is no clear focus on coordinated, multi-sectoral efforts for a more comprehensive approach to the prevention and management of FASD. The participants recognized the need for specific requirements on broad based preventive awareness programs, training and support for parents and caregivers, inclusive education in mainstream schools and training of relevant professionals. CONCLUSION: Comprehensive and coordinated prevention and management programs guided by a specific policy could improve the prevention and management of FASD. Policy formulation demonstrates commitment from the government, highlights the importance of the condition, and elaborates on context specific prevention and management protocols. PMID- 30400901 TI - Patterns of non-communicable disease and injury risk factors in Kenyan adult population: a cluster analysis. AB - BACKGROUND: Non-communicable diseases and unintentional injuries are emerging public health problems in sub-Saharan Africa. These threats have multiple risk factors with complex interactions. Though some studies have explored the magnitude and distribution of those risk factors in many populations in Kenya, an exploration of segmentation of population at a national level by risk profile, which is crucial for a differentiated approach, is currently lacking. The aim of this study was to examine patterns of non-communicable disease and injury risk through the identification of clusters and investigation of correlates of those clusters among Kenyan adult population. METHODS: We used data from the 2015 STEPs survey of non-communicable disease risk factors conducted among 4484 adults aged between 18 and 69 years in Kenya. A total of 12 risk factors for NCDs and 9 factors for injury were used as clustering variables. A K-medians Cluster Analysis was applied. We used matching as the measure of the similarity/dissimilarity among the clustering variables. While clusters were described using the risk factors, the predictors of the clustering were investigated using multinomial logistic regression. RESULTS: We have identified five clusters for NCDs and four clusters for injury based on the risk profile of the population. The NCD risk clusters were labelled as cluster hypertensives, harmful users, the hopefuls, the obese, and the fat lovers. The injury risk clusters were labelled as helmet users, jaywalkers, the defiant and the compliant. Among the possible predictors of clustering, age, gender, education and wealth index came out as strong predictors of the cluster variables. CONCLUSION: This cluster analysis has identified important clusters of adult Kenyan population for non-communicable disease and injury risk profiles. Risk reduction interventions could consider these clusters as potential target in the development and segmentation of a differentiated approach. PMID- 30400902 TI - The revised international technical guidance on sexuality education - a powerful tool at an important crossroads for sexuality education. AB - In January 2018, UNESCO, together with UNAIDS, UNFPA, UNICEF, UN Women, and the WHO, completed the substantial technical and political process of updating the International Technical Guidance on Sexuality Education, thereby unifying a UN position on rationale, evidence, and guidance on designing and delivering comprehensive sexuality education (CSE). The revised Guidance builds on the original Guidance, with improvements and updates based on new evidence and good practice documented from across the globe. User-surveys and structured consultations with representatives from a wide range of fields and interest groups informed and guided the revision process. The revised Guidance presents one, commonly agreed definition of CSE; enhances and expands its key concepts, topics and learning objectives; places a strengthened focus on gender and human rights; provides guidance on building support and planning the implementation of CSE programmes; and reflects the contribution of CSE to the realization of multiple Sustainable Development Goals (SDGs). With its unified voice, progressive position, and attention to key implementation challenges, the revised Guidance is a responsive, timely, and critically needed tool to advance towards a tipping point for the large-scale application of quality CSE. PMID- 30400903 TI - Porcine reproductive and respiratory syndrome virus inhibits MARC-145 proliferation via inducing apoptosis and G2/M arrest by activation of Chk/Cdc25C and p53/p21 pathway. AB - Porcine reproductive and respiratory syndrome virus(PRRSV) is an important immunosuppressive virus which can suppresses infected cells proliferation. In this work, we examined PRRSV ability to manipulate cell cycle progression of MARC 145 cells and explored the potential molecular mechanisms. The results showed that PRRSV infection imposed a growth-inhibitory effect on MARC-145 cells by inducing cell cycle arrest at G2/M phase. This arrest was due to the significant decrease of Cdc2-cyclinB1 complex activity in PRRSV-infected cells and the activity reduction was a result of Cdc2 Tyr15 phosphorylation and the accumulation of Cdc2 and cyclinB1 in the nucleus. Not only elevated Wee1 and Myt1 expression and inactivated Cdc25C, but also increase of p21 and 14-3-3sigma in a p53-dependent manner caused the inhibitory Tyr15 phosphorylation of Cdc2. PRRSV infection also activated Chk1. Our data suggest PRRSV infection induces G2/M arrest via various molecular regulatory mechanisms. These results provide a new insights for PRRSV pathogenesis. PMID- 30400904 TI - Dietary risk factors for non-communicable diseases in Kenya: findings of the STEPS survey, 2015. AB - BACKGROUND: Burden of non-communicable diseases (NCD) is increasing worldwide. Risk factor surveillance informs public health interventions in NCD control. This study describes the dietary risk factors for NCD found in the Kenya STEPS survey, 2015. METHODS: We performed secondary analysis of the STEPS dataset to determine prevalence of dietary NCD risk factors and their determinants. New variables were created; high dietary salt, defined as addition of salt while eating or intake of processed foods high in salt and high dietary sugar, defined as intake of processed foods or drinks high in sugar in most meals or addition of sugar to beverages already with sugar, on a daily basis. We used the World Health Organization definition of minimum required intake of fruits and vegetables as consumption of less than five servings of fruits and vegetables per day. Perceptions of respondents on diet and health were also assessed. Accounting for complex survey sampling, we calculated prevalence of the various dietary modifiable determinants and adjusted odds ratios (AOR) to identify factors independently associated with dietary NCD risk factors. RESULTS: Of the 4484 individuals surveyed; mean age was 40.5 years (39.9-41.1 years), 60% were female. Prevalence of high reported dietary salt intake was 18.3% (95% CI 17.2%, 19.5%) and sugar 13.7% (95% CI 11.7-15.8%). Awareness of health risk from dietary salt was 88% and 91% for dietary sugar. Approximately 56% of the respondents were implementing strategies to reduce dietary salt and 54% were doing the same for dietary sugar. Only 6.0% (95% CI 4.3-7.6%) of the respondents reported intake of a minimum of five servings of both fruits and vegetables daily. Unhealthy diet was associated with being male (AOR 1.33, 95% CI 1.04, 1.70,), age below 46 years (AOR 1.78, 95% CI 1.42, 2.12) and being a student (AOR 15.6, 95% CI 2.44, 99.39). CONCLUSION: Dietary risk communication should be targeted to males and people under 45 years of age, especially students. Further research is necessary to understand the knowledge: practice mismatch on unhealthy diets. PMID- 30400905 TI - Individual and household level factors associated with presence of multiple non communicable disease risk factors in Kenyan adults. AB - BACKGROUND: Non-communicable diseases (NCDs), are increasing globally, causing about 60% of disability-adjusted life years and 39.8 million deaths in 2015. Risk factors often cluster and interact multiplicatively in an individual and this is strongly associated with the development and severity of NCDs. We assessed the sociodemographic factors associated with the presence of multiple NCD risk factors among individuals aged 18 years and older in the Kenyan population. METHODS: We used national representative data from 4066 individuals out of 4500 who participated in the WHO STEPs study in 2015. NCD risk factor counts were derived by summing the risk factors present in an individual and categorising into 1-3, 4-6 and 7+ risk factors in any combination of the 12 assessed NCD risk factors (hypertension, diabetes mellitus, cholesterol, insufficient physical activity, excessive alcohol use, tobacco use and obesity, excess sugar intake, insufficient fruit and vegetables intake, high salt consumption, and use of unhealthy cooking fats and oils). Ordered logistic regression was used to investigate the sociodemographic factors associated with an individual possesing multiple NCD risk factors. RESULTS: Majority (75.8%) of the individuals in the study possesed 4-6 and 10% had >=7 NCDs risk factors. Nearly everyone (99.8%) had insufficient fruits and vegetable intakes, 89.5% consumed high salt in their diet and 80.3% did not engage in sufficient physical activity. Apart from NCD risk count which increased with age among both men and women, associations with other socio-demographic factors differed between men and women. A woman of Akamba ethinicity had lower odds (0.43) while Meru women had higher odds (3.58) of higher NCD risk factor count, compared to the Kalenjin women. Among men, being a Kisii or Luo was associated with lower odds (0.48 and 0.25 respectively) of higher NCD risk factor count. Women in a marital union had higher odds (1.58) of a higher NCD risk factor count. CONCLUSION: Majority of Kenyan adults possess more than four NCD risk factors; a clear indication of an emerging epidemic of NCDs in this population. Effective and multi-sectoral interventions targeting multiple risk factors in individuals are required to mitigate especially the behavioural and modifiable NCD risk factors in Kenya. PMID- 30400906 TI - Prevalence and predictors of injuries in Kenya: findings from the national STEPs survey. AB - BACKGROUND: Injuries are becoming an increasingly important public health challenge globally, and are responsible for 9% of deaths. Beyond their impact on health and well-being, fatal and non-fatal injuries also affect social and economic development for individuals concerned. Kenya has limited data on the magnitude and factors associated with injuries. This study sought to determine the magnitude and risk factors for injuries in Kenya and to identify where the largest burden lies. METHODS: A national population-based household survey was conducted from April-June 2015 among adults age 18-69 years. A three-stage cluster sample design was used to select clusters, households and eligible individuals based on WHO guidelines. We estimated the prevalence of injuries, identified factors associated with injuries and the use of protective devices/practices among road users. Multivariate logistic regression was used to identify potential factors associated with injuries. RESULTS: A total of 4484 adults were included in the study. Approximately 15% had injuries from the past 12 months, 60.3% were males. Four percent of the respondents had been injured in a road traffic crash, 10.9% had experienced unintentional injuries other than road traffic injuries while 3.7% had been injured in violent incidents. Among drivers and passengers 12.5% reported always using a seatbelt and 8.1% of the drivers reported driving while drunk. The leading causes of injuries other than road traffic crashes were falls (47.6%) and cuts (34.0%). Males (p = 0.001), age 18-29 (p < 0.05) and smokers (p = 0.001) were significantly more likely to be injured in a road traffic crash. A higher social economic status (p = 0.001) was protective against other unintentional injuries while students had higher odds for such types of injuries. Heavy episodic drinking (p = 0.001) and smoking (p < 0.05) were associated with increased likelihood of occurrence of a violent injury. CONCLUSIONS: Our study found that male, heavy episodic drinkers, current smokers and students were associated with various injury types. Our study findings highlight the need to scale up interventions for injury prevention for specific injury mechanisms and target groups. There is need for sustained road safety mass media campaigns and strengthened enforcement on helmet wearing, seatbelt use and drink driving. PMID- 30400908 TI - A decade since sulfonamide-based anti-malarial medicines were limited for intermittent preventive treatment of malaria among pregnant women in Tanzania. AB - BACKGROUND: Despite the development of resistance to Plasmodium falciparum malaria, sulfadoxine-pyrimethamine is still effective for intermittent preventive treatment of malaria in pregnancy (IPTp). In Tanzania, more than 10 years have passed since sulfadoxine-pyrimethamine and sulfamethopyrazine-pyrimethamine (SPs) were reserved for IPTp only. However, the retail pharmaceutical outlet dispensers' knowledge and their compliance with the policies have not been recently explored. Therefore, this study was designed to investigate dispensers' knowledge about these medications together with their actual dispensing practices, a decade since they were limited for IPTp use only. METHODS: This descriptive cross-sectional study was conducted between February and July 2017 in all municipalities of Dar-es-Salaam city. Data were collected by direct interviews using a structured questionnaire to assess knowledge and a simulated client approach was used to assess the actual practice of medicine dispensers. Data analysis was done by using SPSS version 20 and Chi square test was used to test significant differences in proportions between different categorical variables. A p-value of less than 0.05 was considered to be statistically significant. RESULTS: A random sample of 422 medicine dispensers participated in this study whereby 185 (43.8%) were from community pharmacies and 237 (56.2%) from accredited drug dispensing outlets. The study revealed that SPs were available in 76% of the community pharmaceutical outlets in Dar es Salaam. In general majority of the dispensers (64%) had moderate to high knowledge about SPs and their indication. About 80% of the dispensers were aware that SP is reserved for IPTp. However, irrespective of the level of knowledge, almost all dispensers (92%) were willing to dispense the medicines for the purpose of treating malaria, contrary to the current Tanzania malaria treatment guideline. CONCLUSION: Majority of the medicine dispensers in the community pharmaceutical outlets were knowledgeable about SPs and their indications. Disappointingly, almost all dispensers irrespective of their levels of knowledge were willing to dispense SPs for treatment of malaria contrary to the available treatment guidelines. PMID- 30400907 TI - Psychopathology is associated with reproductive health risk in European adolescents. AB - BACKGROUND: Reproductive and mental health are key domains of adolescent wellbeing but possible interrelationships are poorly understood. This cross sectional study evaluated the association between psychopathology and reproductive health risk among European adolescents. METHODS: A structured self report questionnaire was delivered to 12,395 pupils of 179 randomly selected schools in 11 European countries within the EU funded "Saving and Empowering Young Lives in Europe" (SEYLE) project. The questionnaire included items about sexual initiation and reproductive health risk factors, such as number of sexual partners, frequency of condom use, and pregnancy involvement. Psychopathology was evaluated with validated instruments and/or ad-hoc questions. RESULTS: Of 11,406 respondents (median age 15; interquartile range [IQR] 14-15; 57% females), 18.8% reported sexual initiation. Sixty percent of them also reported at least one reproductive risk factor. Sexual initiation was significantly more common among pupils older than 15 years (38% versus 13.2% younger pupils) and males (21.3% versus 16.9% females). It was also more common among pupils with depression (age/sex-adjusted odds ratio [aOR] 1.871), anxiety (aOR 2.190), severe suicidal ideation (aOR 2.259), self-injurious behaviour (aOR 2.892), and suicide attempts (aOR 3.091). These associations were particularly strong among pupils <=15 years old and, for overt psychopathology, among pupils with low non-sexual risk behaviour profile and females. Depression (aOR 1.937), anxiety (aOR 2.282), severe suicidal ideation (aOR 2.354), self-injurious behaviour (aOR 3.022), and suicide attempts (aOR 3.284) were associated with higher reproductive health risk, defined by an increasing number of coexisting reproductive risk factors. CONCLUSIONS: These findings suggest an alignment between mental and reproductive health risk and support the value of cross-domain collaboration in adolescent health. The association between psychopathology and reproductive health risk, as well as its variations with age, sex, and associated risk behaviours, should be considered when designing health-promoting or disease-preventing interventions for adolescents. PMID- 30400909 TI - A health facility based case-control study on determinants of low birth weight in Dassie town, Northeast Ethiopia: the role of nutritional factors. AB - BACKGROUND: Low birth weight remains a major public health problem affecting developing countries. Evidence shows that low birth weight has long lasting negative health consequences through its contribution to stunting, mental impairment and non-communicable chronic diseases in later life. Thus, it is worth investigating the role of nutritional factors as determinants of low birth weight to suggest nutritional interventions to curb its negative health outcomes. This study aimed to investigate the determinants of low birth weight with main focus on the role of nutritional factors in Ethiopia. METHODS: A facility-based case control study was conducted from 3 February to 29 April, 2017. The data were collected using structured, pretested interviewer-administered questionnaire in all public health facilities of Dessie Town. Anthropometric measurements were made following standard procedures for both mothers and their newborns. Consecutive live births of < 2500 g and two succeeding normal weight babies were selected as cases and controls, respectively. Data were entered in to Epi-data software version 3.1, and exported to SPSS version 21, and analyzed using frequency, mean and percentage. Factors with p < 0.25 during bivariate analyses were entered into a multivariable logistic regression model to determine significant determinants of LBW. Statistical significance was considered at p < 0.05. Results were reported with odds ratio and 95% CI. RESULTS: Mean +/- SD of birth weight (g) was 2138 +/- 207 for cases and 3145 +/- 415 for controls. After adjusting for potential confounders using multivariable logistic regression analysis, the absence of iron and folate supplementation, receiving no nutritional counseling and consuming no additional meal, maternal undernutrition, maternal anemia and inadequate dietary diversity during the current pregnancy were found to be significant determinants of low birth weight in our study. CONCLUSION: Lack of nutritional counseling, absence of additional meal intake and iron and folate supplementation during pregnancy, and maternal undernutrition, maternal anemia and inadequate maternal dietary diversity were significant determinants of low birth weight. The importance of nutritional counseling, improving iron and folate supplementation during pregnancy, and nutritional status of pregnant women need to be strengthened to reduce the incidence of LBW in Ethiopia. In addition, behavioral change communications targeting pregnant women to improve women dietary diversity and their extra meal intake practice need to be enhanced in Ethiopia. PMID- 30400910 TI - Prevalence and determinants of heavy episodic drinking among adults in Kenya: analysis of the STEPwise survey, 2015. AB - BACKGROUND: Globally, alcohol consumption contributes to 3.3 million deaths and 5.1% of Disability Adjusted Life Years (DALYs), and its use is linked with more than 200 disease and injury conditions. Our study assessed the frequency and patterns of Heavy Episodic Drinking (HED) in Kenya. HED is defined as consumption of 60 or more grams of pure alcohol (6+ standard drinks in most countries) on at least one single occasion per month. Understanding the burden and patterns of heavy episodic drinking will be helpful to inform strategies that would curb the problem in Kenya. METHODS: Using the WHO STEPwise approach to surveillance (STEPS) tool, a nationally representative household survey of 4203 adults aged 18 69 years was conducted in Kenya between April and June 2015. We used logistic regression analysis to assess factors associated with HED among both current and former alcohol drinkers. We included the following socio-demographic variables: age, sex, and marital status, level of education, socio-economic status, residence, and tobacco as an interaction factor. RESULTS: The prevalence of HED was 12.6%. Men were more likely to engage in HED than women (unadjusted OR 9.9 95%, CI 5.5-18.8). The highest proportion of HED was reported in the 18-29-year age group (35.5%). Those currently married/ cohabiting had the highest prevalence of HED (60%). Respondents who were separated had three times higher odds of HED compared to married counterparts (OR 2.7, 95% CI 1.3-5.7). Approximately 16.0% of respondents reported cessation of alcohol use due to health reasons. Nearly two thirds reported drinking home-brewed beers or wines. Tobacco consumption was associated with higher odds of HED (unadjusted OR 6.9, 95% CI 4.4-10.8); those that smoke (34.4%) were more likely to engage in HED compared to their non smoking counterparts. CONCLUSION: Our findings highlight a significant prevalence of HED among alcohol drinkers in Kenya. Young males, those with less education, married people, and tobacco users were more likely to report heavy alcohol use, with male sex as the primary driving factor. These findings are novel to the country and region; they provide guidance to target alcohol control interventions for different groups in Kenya. PMID- 30400911 TI - Manual wheelchair downhill stability: an analysis of factors affecting tip probability. AB - BACKGROUND: For people who use manual wheelchairs, tips and falls can result in serious injuries including bone fractures, concussions, and traumatic brain injury. We aimed to characterize how wheelchair configuration changes (including on-the-fly adjustments), user variables, and usage conditions affected dynamic tip probability while rolling down a slope and contacting a small block. METHODS: Rigid body dynamic models of a manual wheelchair and test dummy were created using multi-body software (Madymo, TASS International, Livonia, MI), and validated with 189 experiments. Dynamic stability was assessed for a range of seat angles (0 to 20 degrees below horizontal), backrest angles (0 to 20 degrees ), rear axle positions (0 to 20 cm from base of backrest), ground slopes (0 to 15 degrees ), bump heights (0 to 4 cm), wheelchair speeds (0 to 20 km/hr), user masses (50 to 115 kg), and user positions (0 to 10 cm from base of backrest). The tip classifications (forward tip, backward tip, rolled over bump, or stopped by bump) were investigated using a nominal logistic regression analysis. RESULTS: Faster wheelchair speeds significantly increased the probability of tipping either forward or backward rather than stopping, but also increased the probability of rolling over the bump (p < 0.001). When the rear axle was positioned forward, this increased the risk of a backward tip compared to all other outcomes (p < 0.001), but also reduced the probability of being stopped by the bump (p < 0.001 compared to forward tip, p < 0.02 compared to rolling over). Reclining the backrest reduced the probability of a forward tip compared to all other outcomes (p < 0.001), and lowering the seat increased the probability of either rolling over the bump or tipping backwards rather than tipping forward (p < 0.001). In general, the wheelchair rolled over bumps < 1.5 cm, and forwards tipping was avoided by reducing the speed to 1 km/hr. CONCLUSIONS: The probability of forward tipping, corresponding to the greatest risk of injury, was significantly reduced for decreased speeds, smaller bumps, a reclined backrest, and a lower rear seat height. For wheelchairs with dynamic seating adjustability, when travelling downhill, on-the-fly adjustments to the seat or backrest can increase the likelihood of safely rolling over a bump. PMID- 30400912 TI - Microglial response to increasing amyloid load saturates with aging: a longitudinal dual tracer in vivo MUPET-study. AB - BACKGROUND: Causal associations between microglia activation and beta-amyloid (Abeta) accumulation during the progression of Alzheimer's disease (AD) remain a matter of controversy. Therefore, we used longitudinal dual tracer in vivo small animal positron emission tomography (MUPET) imaging to resolve the progression of the association between Abeta deposition and microglial responses during aging of an Abeta mouse model. METHODS: APP-SL70 mice (N = 17; baseline age 3.2-8.5 months) and age-matched C57Bl/6 controls (wildtype (wt)) were investigated longitudinally for 6 months using Abeta (18F-florbetaben) and 18 kDa translocator protein (TSPO) MUPET (18F-GE180). Changes in cortical binding were transformed to Z-scores relative to wt mice, and microglial activation relative to amyloidosis was defined as the Z-score difference (TSPO-Abeta). Using 3D immunohistochemistry for activated microglia (Iba-1) and histology for fibrillary Abeta (methoxy-X04), we measure microglial brain fraction relative to plaque size and the distance from plaque margins. RESULTS: Abeta-PET binding increased exponentially as a function of age in APP-SL70 mice, whereas TSPO binding had an inverse U-shape growth function. Longitudinal Z-score differences declined with aging, suggesting that microglial response declined relative to increasing amyloidosis in aging APP SL70 mice. Microglial brain volume fraction was inversely related to adjacent plaque size, while the proximity to Abeta plaques increased with age. CONCLUSIONS: Microglial activity decreases relative to ongoing amyloidosis with aging in APP-SL70 mice. The plaque-associated microglial brain fraction saturated and correlated negatively with increasing plaque size with aging. PMID- 30400913 TI - Impact of moral case deliberation in healthcare settings: a literature review. AB - BACKGROUND: An important and supposedly impactful form of clinical ethics support is moral case deliberation (MCD). Empirical evidence, however, is limited with regard to its actual impact. With this literature review, we aim to investigate the empirical evidence of MCD, thereby a) informing the practice, and b) providing a focus for further research on and development of MCD in healthcare settings. METHODS: A systematic literature search was conducted in the electronic databases PubMed, CINAHL and Web of Science (June 2016). Both the data collection and the qualitative data analysis followed a stepwise approach, including continuous peer review and careful documentation of our decisions. The qualitative analysis was supported by ATLAS.ti. RESULTS: Based on a qualitative analysis of 25 empirical papers, we identified four clusters of themes: 1) facilitators and barriers in the preparation and context of MCD, i.e., a safe and open atmosphere created by a facilitator, a concrete case, commitment of participants, a focus on the moral dimension, and a supportive organization; 2) changes that are brought about on a personal and inter-professional level, with regard to professional's feelings of relief, relatedness and confidence; understanding of the perspectives of colleagues, one's own perspective and the moral issue at stake; and awareness of the moral dimension of one's work and awareness of the importance of reflection; 3) changes that are brought about in caring for patients and families; and 4) changes that are brought about on an organizational level. CONCLUSIONS: This review shows that MCD brings about changes in practice, mostly for the professional in inter-professional interactions. Most reported changes are considered positive, although challenges, frustrations and absence of change were also reported. Empirical evidence of a concrete impact on the quality of patient care is limited and is mostly based on self-reports. With patient-focused and methodologically sound qualitative research, the practice and the value of MCD in healthcare settings can be better understood, thus making a stronger case for this kind of ethics support. PMID- 30400914 TI - Vision-based assessment of parkinsonism and levodopa-induced dyskinesia with pose estimation. AB - BACKGROUND: Despite the effectiveness of levodopa for treatment of Parkinson's disease (PD), prolonged usage leads to development of motor complications, most notably levodopa-induced dyskinesia (LID). Persons with PD and their physicians must regularly modify treatment regimens and timing for optimal relief of symptoms. While standardized clinical rating scales exist for assessing the severity of PD symptoms, they must be administered by a trained medical professional and are inherently subjective. Computer vision is an attractive, non contact, potential solution for automated assessment of PD, made possible by recent advances in computational power and deep learning algorithms. The objective of this paper was to evaluate the feasibility of vision-based assessment of parkinsonism and LID using pose estimation. METHODS: Nine participants with PD and LID completed a levodopa infusion protocol, where symptoms were assessed at regular intervals using the Unified Dyskinesia Rating Scale (UDysRS) and Unified Parkinson's Disease Rating Scale (UPDRS). Movement trajectories of individual joints were extracted from videos of PD assessment using Convolutional Pose Machines, a pose estimation algorithm built with deep learning. Features of the movement trajectories (e.g. kinematic, frequency) were used to train random forests to detect and estimate the severity of parkinsonism and LID. Communication and drinking tasks were used to assess LID, while leg agility and toe tapping tasks were used to assess parkinsonism. Feature sets from tasks were also combined to predict total UDysRS and UPDRS Part III scores. RESULTS: For LID, the communication task yielded the best results (detection: AUC = 0.930, severity estimation: r = 0.661). For parkinsonism, leg agility had better results for severity estimation (r = 0.618), while toe tapping was better for detection (AUC = 0.773). UDysRS and UPDRS Part III scores were predicted with r = 0.741 and 0.530, respectively. CONCLUSION: The proposed system provides insight into the potential of computer vision and deep learning for clinical application in PD and demonstrates promising performance for the future translation of deep learning to PD clinical practices. Convenient and objective assessment of PD symptoms will facilitate more frequent touchpoints between patients and clinicians, leading to better tailoring of treatment and quality of care. PMID- 30400915 TI - Tobacco use and its determinants in the 2015 Kenya WHO STEPS survey. AB - BACKGROUND: According to the World Health Organization (WHO), in 2015, over 1.1 billion people smoked tobacco, which represents around 15% of the global population. In Africa, around one in five adults smoke tobacco. The 2014 Kenya Global Adult Tobacco Survey reported that 2.5 million adults use tobacco products. The objective of our study was to describe patterns and determinants of tobacco use from the 2015 Kenya STEPS survey, including use of "smokeless" tobacco products and the more novel e-cigarettes. METHODS: The WHO STEPwise approach to surveillance (STEPS) was completed in Kenya between April and June 2015. Logistic regression analyses was used to assess factors affecting prevalence and frequency of tobacco use. Sociodemographic variables associated with tobacco use were considered: age, sex, level of education, wealth quintile, and residence. The relationship with alcohol as an intervening risk factor was also assessed. Our main outcomes of interest were current tobacco use, daily tobacco use and use of smokeless tobacco products. RESULTS: Of 4484 respondents, 605 (13.5%) reported being current tobacco users. Most active tobacco users were male (n = 507/605, 83.8%). Three out of four tobacco users (n = 468/605, 77.4%) reported being less than 50 years old, with the average start age being 21 (20.6, 95% CI 19.3-21.8) and the average quit age 27 (27.2, 95% CI 25.8-28.6). Most tobacco users had only ever attended up to primary school (n = 434/605, 71.7%). Men had nearly seven times higher odds of being tobacco users as compared to women (OR 7.63, 95% CI 5.63-10.33). Alcohol use had a positive effect on tobacco use. Finally, less than ten respondents reported having used e-cigarettes. CONCLUSION: The 2015 Kenya WHO STEPS provided primary data on the status of tobacco use in the country and other leading NCD risk factors, such as alcohol, and associated diseases. Our findings highlight key target populations for tobacco cessation efforts: young people, men, those with lower levels of education, and alcohol consumers. Further data is needed on the use of smokeless tobacco, and its impact on smoked tobacco products, as well as on the novel use of e-cigarettes. PMID- 30400916 TI - Predictors of cervical cancer screening among Kenyan women: results of a nested case-control study in a nationally representative survey. AB - BACKGROUND: Cervical cancer is a major public health concern in Kenya. It is the leading cause of cancer morbidity and mortality among women. Although screening is an effective prevention method, uptake is low among eligible women. Little is known about predictors of cervical cancer screening uptake. This study explored relationship between uptake of cervical cancer screening, socio-demographic, behavioral and biological risk factors. METHODS: Nested case-control study within STEPS survey, a population-based cross-sectional household survey conducted between April and June 2015.Cases were women who had undergone cervical cancer screening and controls were unscreened women. Study participants were women eligible for cervical cancer screening (30-49 years). Variables included socio demographic; behavioral risk factors such as physical activity, tobacco and alcohol use diet and biological factors like diabetes and hypertension. Outcome of interest was cervical cancer screening. Data analysis was done using STATA version 14. Logistic regression model was used to assess relationship between cervical cancer screening and socio-demographic, behavioral and biological risk factors. RESULTS: Of 1180 women interviewed, 16.4% (n = 194) had been screened for cervical cancer. Of unscreened women (n = 986), 67.9% were aware of cervical cancer screening. Higher screening rates were observed in more educated women (25.2%), highest income quintile (29.6%) and living in urban areas (23%) than in women with no formal education (3.2%), poorest (3.6%) and living in rural areas (13.8%). Younger women (35-39) and those with low High-density lipoprotein (HDL) were less likely to be screened [OR = 0.56; 95% CI = (0.34, 0.93); p-value = 0.025] and [OR = 0.51; 95% CI = (0.29, 0.91); p = value 0.023] respectively. Self employed women, those in the fourth wealth quintile, binge drinkers, high sugar consumption and insufficient physical activity were more likely to be screened [OR 2.55 (1.12, 5.81) p value 0.026], [OR 3.56 (1.37, 9.28) p value 0.009], [OR 5.94 (1.52, 23.15) p value 0.010], [OR 2.99 (1.51, 5.89) p value 0.002] and [OR 2.79 (1.37, 5.68) p value 0.005] respectively. CONCLUSION: Uptake of cervical cancer screening is low despite high awareness. Strategies to improve cervical cancer screening in Kenya should be implemented with messages targeting persons with both risky and non-risky lifestyles especially younger women with no formal education living in rural areas. PMID- 30400917 TI - Assessment of a markerless motion analysis system for manual wheelchair application. AB - BACKGROUND: Wheelchair biomechanics research advances accessibility and clinical care for manual wheelchair users. Standardized outcome assessments are vital tools for tracking progress, but there is a strong need for more quantitative methods. A system offering kinematic, quantitative detection, with the ease of use of a standardized outcome assessment, would be optimal for repeated, longitudinal assessment of manual wheelchair users' therapeutic progress, but has yet to be offered. RESULTS: This work evaluates a markerless motion analysis system for manual wheelchair mobility in clinical, community, and home settings. This system includes Microsoft(r) Kinect(r) 2.0 sensors, OpenSim musculoskeletal modeling, and an automated detection, processing, and training interface. The system is designed to be cost-effective, easily used by caregivers, and capable of detecting key kinematic metrics involved in manual wheelchair propulsion. The primary technical advancements in this research are the software components necessary to detect and process the upper extremity kinematics during manual wheelchair propulsion, along with integration of the components into a complete system. The study defines and evaluates an adaptable systems methodology for processing kinematic data using motion capture technology and open-source musculoskeletal models to assess wheelchair propulsion pattern and biomechanics, and characterizes its accuracy, sensitivity and repeatability. Inter-trial repeatability of spatiotemporal parameters, joint range of motion, and musculotendon excursion were all found to be significantly correlated (p < 0.05). CONCLUSIONS: The system is recommended for use in clinical settings for frequent wheelchair propulsion assessment, provided the limitations in precision are considered. The motion capture-model software bridge methodology could be applied in the future to any motion-capture system or specific application, broadening access to detailed kinematics while reducing assessment time and cost. PMID- 30400918 TI - Speed-adaptive control of functional electrical stimulation for dropfoot correction. AB - BACKGROUND: Functional electrical stimulation is an important therapy technique for dropfoot correction. In order to achieve natural control, the parameter setting of FES should be associated with the activation of the tibialis anterior. METHODS: This study recruited nine healthy subjects and investigated the relations of walking speed with the onset timing and duration of tibialis anterior activation. Linear models were built for the walking speed with respect to these two parameters. Based on these models, the speed-adaptive onset timing and duration were applied in FES-assisted walking for nine healthy subjects and ten subjects with dropfoot. The kinematic performance of FES-assisted walking triggered by speed-adaptive stimulation were compared with those triggered by the heel-off event, and no-stimulation walking at different walking speeds. RESULTS: Higher ankle dorsiflexion angle was observed in heel-off stimulation and speed adaptive stimulation conditions than that in no-stimulation walking condition at all the speeds. For subjects with stroke, the ankle plantarflexion angle in speed adaptive stimulation condition was similar to that in no-stimulation walking condition, and it was significant larger than that in heel-off stimulation condition at all speeds. CONCLUSIONS: The improvement in ankle dorsiflexion without worsening ankle plantarflexion in speed-adaptive stimulation condition could be attributed to the appropriate stimulation timing and duration. These results provide evidence that the proposed stimulation system with speed-related parameters is more physiologically appropriate in dropfoot correction, and it may have great potential value in future clinical applications. TRIAL REGISTRATION: Medical Ethics Committee of Guangdong Work Injury Rehabilitation Center, AF/SC 07/2016.22 . Registered 26 May 2016. PMID- 30400919 TI - Personality of Belgian physicians in a clinical leadership program. AB - BACKGROUND: Physician and non-physician leadership development programs aim to improve organizational performance. Although a significant, positive relation between physicians' leadership skills and patient outcomes, staff satisfaction and staff retention has been found, physicians are not formally trained in clinical leadership skills during their physician training. A lot of current healthcare leaders were chosen to take on leadership because of their productivity, published research, solid clinical skills, or because they were great educators, Heifetz RA. Leadership Without Easy Answers; 1994 although they often do not have the skills to build a team, resulting in dysfunctional teams and having to deal with conflicts and chaos. The first steps of a Clinical Leadership Program is to gain insight in one's personality, one's personal skills and one's leadership growth potential, because this gives information on one's natural leadership style. The aim of our research is to gain insight in the personality traits of healthcare professionals who are leading teams and to check (a) whether Belgian physicians with leadership ambition, share certain preferences, (b) whether physicians differ from other healthcare staff in terms of personality, (c) whether our sample of Belgian physicians differs from a population of physicians in the United States of America. METHODS: In-hospital physicians and non-physicians enrolled in a Clinical Leadership Program consented to participate. They explored their personal preferences across four dimensions, based on the Myers-Briggs Type Indicator (MBTI). Their most suitable MBTI profile was determined with a self-assessment and a complementary guidance of an MBTI coach. Chi-squared tests and logistic regression were performed to check distributions across different MBTI-dimensions and to assess the relation with profession and location. RESULTS: Among participating physicians significantly more preferences for 'Thinking' then for 'Feeling' were found. Non-physicians were found to be significantly more 'Sensing' and 'Judging' compared with physicians. No significant differences were found between physicians from our (Belgian) and the USA dataset. CONCLUSION: Preferences of physicians proved to be different from those of non-physicians. 'ISTJ' is the most frequent personality profile both in Belgian and USA physicians. PMID- 30400921 TI - A qualitative exploration of early assessment of innovative medical technologies. AB - BACKGROUND: Hospitals increasingly make decisions about early development of and investment in innovative medical technologies (IMTs), but at present often without an early assessment of their potential to ensure selection of the most promising candidates for further development. This paper explores how early assessment is carried out in different health organisations and then discusses relevant learning points for hospitals. METHODS: A qualitative study design with a structured interview guide covering four themes was used. Content analyses of interview notes were performed covering four predetermined themes: context, basis for decision-making, process and structure, and perceptions. A fifth theme, handling cognitive bias, was identified during data analysis. RESULTS: A total of 11 organisations participated; eight from the private health industry and three public hospitals. The interviews identified four areas in which early assessment is performed in similar manner across the studied organisations and four areas where differences exist between public hospitals and private organisations. Public hospitals indicate a lower degree of formalised early assessment and less satisfaction with how early assessment is performed, compared to private organisations. Based on the above findings, two learning points may carry promise for hospitals. First, having dedicated prioritising committees for IMTs making stop/go decisions. This committee is separate from the IMT development processes and involved staff. Secondly, the committee should base decisions on a transparent early assessment decision-support tool, which include a broad set of domains, is iterative, describes uncertainty, and minimise cognitive biases. CONCLUSIONS: Similarities and differences in the way early assessment is done in different health organisations were identified. These findings suggest promising learning points for the development of an early assessment model for hospitals. PMID- 30400920 TI - Distinct gene expression signatures induced by viral transactivators of different HTLV-1 subgroups that confer a different risk of HAM/TSP. AB - BACKGROUND: Among human T cell leukemia virus type 1 (HTLV-1)-infected individuals, there is an association between HTLV-1 tax subgroups (subgroup-A or subgroup-B) and the risk of HAM/TSP in the Japanese population. To investigate the role of HTLV-1 subgroups in viral pathogenesis, we studied the functional difference in the subgroup-specific viral transcriptional regulators Tax and HBZ using microarray analysis, reporter gene assays, and evaluation of viral-host protein-protein interaction. RESULTS: (1) Transcriptional changes in Jurkat Tet On human T-cells that express each subgroup of Tax or HBZ protein under the control of an inducible promoter revealed different target gene profiles; (2) the number of differentially regulated genes induced by HBZ was 2-3 times higher than that induced by Tax; (3) Tax and HBZ induced the expression of different classes of non-coding RNAs (ncRNAs); (4) the chemokine CXCL10, which has been proposed as a prognostic biomarker for HAM/TSP, was more efficiently induced by subgroup-A Tax (Tax-A) than subgroup-B Tax (Tax-B), in vitro as well as in unmanipulated (ex vivo) PBMCs obtained from HAM/TSP patients; (5) reporter gene assays indicated that although transient Tax expression in an HTLV-1-negative human T-cell line activated the CXCL10 gene promoter through the NF-kappaB pathway, there was no difference in the ability of each subgroup of Tax to activate the CXCL10 promoter; however, (6) chromatin immunoprecipitation assays showed that the ternary complex containing Tax-A is more efficiently recruited onto the promoter region of CXCL10, which contains two NF-kappaB binding sites, than that containing Tax-B. CONCLUSIONS: Our results indicate that different HTLV-1 subgroups are characterized by different patterns of host gene expression. Differential expression of pathogenesis-related genes by subgroup-specific Tax or HBZ may be associated with the onset of HAM/TSP. PMID- 30400923 TI - Dog owner flea/tick medication purchases in the USA. AB - BACKGROUND: Veterinary clinic transaction records from the USA were examined to determine dog owner purchase patterns for three prescription ectoparasiticides. In-clinic purchases of formulations of fluralaner (with 12-week duration per dose) were compared with dog owner purchases of afoxolaner and spinosad (both with 4 week duration per dose) in a population of 231,565 dogs over a 12 month period. Prior studies in human and animal medicine have suggested that patients more closely adhere to prescriber dosing recommendations when they receive a longer-duration medication. RESULTS: Veterinary clinic transaction records were examined for the period June 2014 through March 2017 using records from approximately 650 veterinary clinics. Ectoparasiticide purchase patterns were compared for two products (afoxalaner and spinosad) with monthly dosing and one product (fluralaner) with an extended (12 week) dosing interval. The average dog owner who obtained fluralaner purchased significantly more months of flea/tick protection (5.7 months) over the 12-month study period than the average dog owner that selected either afoxolaner (4.6 months) or spinosad (3.3 months). The proportion of dog owners who obtained only one dose of ectoparasiticide per 12 month period was 42% for fluralaner, 30% for afoxolaner and 37% for spinosad. The proportion of dog owners who obtained 2 doses or less per 12-month period was 67% for fluralaner, 52% for afoxoalaner and 67% for spinosad. Owners that obtained fluralaner were significantly more likely to obtain 7.0-12.0 months of flea and tick protection and significantly less likely to purchase 1.0-6.9 months compared with dog owners who purchased afoxolaner or spinosad. CONCLUSIONS: Dog owners who obtained a flea and tick medication with a longer duration of action acquired significantly more months of protection in a year than dog owners who obtained shorter duration (1 month) products. Dog owners were better able to adhere to veterinary recommendations on ectoparasites control with a longer-acting flea/tick medication. PMID- 30400922 TI - Anti-osteoporotic effects of mixed compositions of extracellular polymers isolated from Aureobasidium pullulans and Textoria morbifera in ovariectomized mice. AB - BACKGROUND: Extracellular polymeric substances isolated from Aureobasidium pullulans (EAP), containing specifically 13% beta-1,3/1,6-glucan, have shown various favorable bone-preserving effects. Textoria morbifera Nakai (TM) tree has been used as an ingredient in traditional medicine and tea for various pharmacological purposes. Thus, the present study was aimed to examine the synergistic anti-osteoporotic potential of mixtures containing different proportions of EAP and TM compared with that of the single formulations of each herbal extract using bilateral ovariectomized (OVX) mice, a renowned rodent model for studying human osteoporosis. METHODS: Thirty five days after bilateral-OVX surgery, 9 combinations of EAP:TM (ratios = 1:1, 1:3, 1:5, 1:7, 1:9, 3:1, 5:1, 7:1, 9:1) and single separate formulations of EAP or TM were supplied orally, once a day for 35 days at a final concentration of 200 mg/kg. Variations in body weight gains during the experimental periods, as well as femur weights, bone mineral density (BMD), bone strength (failure load), and mineral content (calcium [Ca] and inorganic phosphorus [IP]) following sacrifice were measured. Furthermore, histomorphometric and histological profile analyses of serum biochemical parameters (osteocalcin content and bone specific alkaline phosphatase [bALP] activity) were conducted following sacrifice. Femurs histomorphometric analyses were also conducted for bone resorption, structure and mass. The results for the mixed formulations of EAP:TM and separate formulations were compared with those of risedronate sodium (RES). RESULTS: The EAP:TM (3:1) formulation synergistically enhanced the anti-osteoporotic potential of individual EAP or TM formulations, possibly due to enhanced variety of the active ingredients. Furthermore, the effects of EAP:TM were comparable to those of RES (2.5 mg/kg) treatment. CONCLUSION: The results of this study suggest that, the EAP:TM (3:1) combination might act as a new pharmaceutical agent and/or health functional food substance for curing osteoporosis in menopausal women. PMID- 30400925 TI - Trio-R: a script for assessing maternity and paternity in trio studies performed on Agilent chromosomal microarrays. AB - BACKGROUND: Trio studies, which involve the testing of samples from a proband and both parents, are often used by clinical laboratories to help with the classification of genetic variants, including copy number variants. In order for the results of the trio study to be valid, the mother and father must be the true biological parents of the proband. As such, non-paternity and sample mix-ups are potential sources of error. To address these potential issues, we developed a computer script to accurately assess maternity and paternity using single nucleotide polymorphism (SNP) data generated by Agilent chromosomal microarrays, a platform-of-choice for clinical copy number testing. RESULTS: We assessed the performance of the script on 10 putative trios tested at our laboratory, and found that the numbers and proportions of discordant SNPs were useful for determining parental relationships. The results of the assessment also confirmed maternity and paternity in the 10 trios tested, and by doing so essentially excluded pre-analytical sample switching in these 30 samples. CONCLUSIONS: Computational analysis of SNP data can be implemented as a quality control measure for trio testing performed on Agilent microarrays. PMID- 30400924 TI - Effects of green tea extract on overweight and obese women with high levels of low density-lipoprotein-cholesterol (LDL-C): a randomised, double-blind, and cross-over placebo-controlled clinical trial. AB - BACKGROUND: This study aims to examine the effects of green tea extract (GTE) supplement on overweight and obese women with high levels of low density lipoprotein-cholesterol (LDL-C). METHODS: The randomized, double-blind, crossover and placebo-controlled clinical trial was conducted from August 2012 to December 2013. Seventy-three out of 90 subjects aged between 18 and 65 years, with body mass index (BMI) >= 27 kg/m2 and LDL-C >= 130 mg/dl were included in the analysis. The subjects were randomly divided into Groups A and B. Group A received GTE supplement treatment for the first 6 weeks, while Group B received placebo daily. After 6 weeks of treatment and 14 days of washout period, Group A switched to placebo and Group B switched to GTE treatment for 6 weeks. The reduction of LDL-C level between treatments was assessed as the outcome. Additionally, anthropometric measurements, plasma lipoproteins and hormone peptides of both groups were measure at the beginning of weeks 6, 8, and 14 after treatment. RESULTS: Subjects treated with GTE (n = 73) for 6 weeks showed significant differences, with 4.8% (p = 0.048) reduction in LDL-C and 25.7% (p = 0.046) increase in leptin. However, there was no statistical difference in the levels of total cholesterol, triglyceride and high density lipoprotein between the GTE and placebo groups after treatments. CONCLUSIONS: This study shows that green tea extract effectively increases leptin and reduces LDL in overweight and obese women after 6 weeks of treatment even though there were no significant changes in other biochemical markers related to overweight. TRIAL REGISTRATION: This clinical trial is registered with ClinicalTrials.gov: NCT02116517 on 17 April 2014. Retrospectively registered. The first patient enrolled in October 2012 and the study was completed December 2013. PMID- 30400928 TI - Genome editing: from tools to biological insights. PMID- 30400927 TI - Disaster preparedness and response capacity of regional hospitals in Tanzania: a descriptive cross-sectional study. AB - BACKGROUND: Tanzania has witnessed several disasters in the past decade, which resulted in substantial mortality, long-term morbidity, and significant socio economic losses. Health care facilities and personnel are critical to disaster response. We assessed the current state of disaster preparedness and response capacity among Tanzanian regional hospitals. METHODS: This descriptive cross sectional survey was conducted in all Tanzanian regional hospitals between May 2012 and December 2012. Data were prospectively collected using a structured questionnaire based on the World Health Organization National Health Sector Emergency Preparedness and Response Tool. Trained medical doctors conducted structured interviews and direct observations in each hospital. RESULTS: We surveyed 25 regional hospitals (100% capture) in mainland Tanzania, in which interviews were conducted with 13-hospital doctors incharge, 9 matrons and 4 heads of casualty. All the hospitals were found to have inadequate numbers of all cadres of health care providers to support effective disaster response. 92% of hospitals reported experiencing a disaster in the past 5 years; with the top three being large motor vehicle accidents 22 (87%), floods 7 (26%) and infectious disease outbreaks 6 (22%). Fifteen hospitals (60%) had a disaster committee, but only five (20%) had a disaster plan. No hospital had all components of surge capacity. Although all had electricity and back-up generators, only 3 (12%) had a back-up communication system. CONCLUSION: This nationwide survey found that hospital disaster preparedness is at an early stage of development in Tanzania, and important opportunities exist to better prepare regional hospitals to respond to disasters. PMID- 30400926 TI - DELTA2 guidance on choosing the target difference and undertaking and reporting the sample size calculation for a randomised controlled trial. AB - BACKGROUND: A key step in the design of a RCT is the estimation of the number of participants needed in the study. The most common approach is to specify a target difference between the treatments for the primary outcome and then calculate the required sample size. The sample size is chosen to ensure that the trial will have a high probability (adequate statistical power) of detecting a target difference between the treatments should one exist. The sample size has many implications for the conduct and interpretation of the study. Despite the critical role that the target difference has in the design of a RCT, the way in which it is determined has received little attention. In this article, we summarise the key considerations and messages from new guidance for researchers and funders on specifying the target difference, and undertaking and reporting a RCT sample size calculation. This article on choosing the target difference for a randomised controlled trial (RCT) and undertaking and reporting the sample size calculation has been dual published in the BMJ and BMC Trials journals METHODS: The DELTA2 (Difference ELicitation in TriAls) project comprised five major components: systematic literature reviews of recent methodological developments (stage 1) and existing funder guidance (stage 2); a Delphi study (stage 3); a two day consensus meeting bringing together researchers, funders and patient representatives (stage 4); and the preparation and dissemination of a guidance document (stage 5). RESULTS AND DISCUSSION: The key messages from the DELTA2 guidance on determining the target difference and sample size calculation for a randomised caontrolled trial are presented. Recommendations for the subsequent reporting of the sample size calculation are also provided. PMID- 30400929 TI - Enhancing soil organic carbon, particulate organic carbon and microbial biomass in semi-arid rangeland using pasture enclosures. AB - BACKGROUND: Rehabilitation of degraded rangelands through the establishment of enclosures (fencing grazing lands) is believed to improve soil quality and livelihoods, and enhance the sustainability of rangelands. Grazing dominated enclosure (GDE) and contractual grazing enclosure (CGE) are the common enclosure management systems in West Pokot County, Kenya. Under CGE, a farmer owning few animals leases the enclosure to households with relatively more livestock, while GDE is where the livestock utilizing the enclosure are purely owned by the farmer. Livestock management in both systems is via the free-range system. This study evaluated the effect of enclosure management on total soil organic carbon (SOC), particulate organic carbon (POC) and microbial biomass carbon (MBC) and nitrogen (MBN) as key indicators of soil degradation at 0-40 cm depth. The two enclosure systems were selected based on three age classes (3-10, 11-20 and > 20 years since establishment) (n = 3). The adjacent open grazing area (OGR) was used as a reference (n = 9). RESULTS: Relative to OGR, the pasture enclosures significantly decreased soil bulk density and increased the concentrations of total organic C, POC, MBC and MBN compared to the degraded OGR (P < 0.001). Significantly higher concentrations of POC and MBC was recorded in GDE than CGE (P = 0.01). The POC accounted for 24.5-29.5% of the total SOC. MBC concentrations ranged from 32.05 +/- 7.25 to 96.63 +/- 5.31 ug C g-1 of soil in all grazing systems, and was positively correlated with total SOC and POC (P < 0.001). The proportional increase in POC and MBC was higher in GDE (56.6 and 30.5% respectively) compared to CGE (39.2 and 13.9% for POC and MBC respectively). CONCLUSIONS: This study demonstrated that controlling livestock grazing through the establishment of pasture enclosures is the key strategy to enhance total SOC, POC, MBC, and MBN in degraded rangelands; a precondition for improving soil quality. Therefore, the establishment of enclosures is an effective restoration approach to restore degraded soils in semi-arid rangelands. PMID- 30400930 TI - Older adults in treatment for alcohol use disorders: service utilisation, patient characteristics and treatment outcomes. AB - BACKGROUND: In western countries demographic changes are leading to an ageing society. Consequently, the number of older adults with alcohol use disorders (AUDs) will rise and the demand of treatment is likely to increase. However, thus far not many older adults with an AUD are seeking treatment and little is known about the efficacy of treatment for older adults. The present study aimed at determining the proportion of older adults with an AUD in addiction treatment, particular characteristics and treatment outcomes of this clientele. METHODS: Using data of 10,860 patients with an AUD aged 60 and over that are documented within the national German addiction care system we conducted exploratory analyses with regard to prevalence, sociodemographic, disorder- and treatment related variables. RESULTS: Overall, we found a low proportion of older patients in treatment due to AUDs, but highly positive treatment outcomes. With regard to sociodemographic and disorder-related characteristics, older females and late onset patients in particular constitute a unique clientele. CONCLUSIONS: The low service utilisation on the one hand but good treatment prognosis on the other emphasise the need to promote treatment seeking among older adults with AUDs. In this context, the special characteristics we found among older patients may contribute to better reach this population and to improve provisions of targeted treatment approaches. PMID- 30400931 TI - Using equitable impact sensitive tool (EQUIST) to promote implementation of evidence informed policymaking to improve maternal and child health outcomes: a focus on six West African Countries. AB - BACKGROUND: United Nations Children's Fund (UNICEF) designed EQUitable Impact Sensitive Tool (EQUIST) to enable global health community address the issue of equity in maternal, newborn and child health (MNCH) and minimize health disparities between the most marginalized population and the better-off. The purpose of this study was to use EQUIST to provide reliable evidence, based on demographic health surveys (DHS) on cost-effectiveness and equitable impact of interventions that can be implemented to improve MNCH outcomes in Benin, Burkina Faso, Ghana, Mali, Nigeria and Senegal. METHODS: Using the latest available DHS data sets, we conducted EQUIST Situation Analysis of maternal and child health outcomes in the six countries by sub-national categorization, wealth and by residence. We then identified the poorest population class within each country with the highest maternal and child mortality and performed EQUIST Scenario Analysis of this population to identify intervention package, bottlenecks and strategies to address them, cost of the intervention and strategies as well as the number of deaths avertible. RESULTS: Under-five mortality was highest in Atlantique (Benin), Sahel (Burkina Faso), Northern (Ghana), Sikasso (Mali), North West (Nigeria), and Diourbel (Senegal). The number of under-five deaths was considerably higher among the poorest and rural population. Neonatal causes, malaria, pneumonia and diarrhoea were responsible for most of the under-five deaths. Ante-partum, intra-partum, and post-partum haemorrhages, and hypertensive disorder, were responsible for highest maternal deaths. The national average for improved water source was highest in Ghana (82%). Insecticide treated nets ownership percentage national average was highest in Benin (73%). Delivery by skilled professional is capable of averting the highest number of under-five and maternal deaths in the six countries. Redeployment/relocation of existing staff was the strategy with highest costs in Burkina Faso, Nigeria and Senegal. Ghana recorded the least cost per capita ($0.39) while the highest cost per capita was recorded in Benin ($4.0). CONCLUSION: EQUIST highlights the most vulnerable and deprived children and women needing urgent health interventions as a matter of priority. It will continue to serve as a tool for maximizing the number of lives saved; decreasing health disparities and improving overall cost effectiveness. PMID- 30400932 TI - Impact of dyslipidemia on 24-h urine composition in adults without urolithiasis. AB - PURPOSES: To evaluate the influence of dyslipidemia on 24-h urine composition in adults who were non-stone formers (NF). METHODS: Samples for 24-h urine composition were analyzed from 584 NF adults without urolithiasis in a national six-city-based epidemiologic study. The samples were divided into groups based on total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL). The groups were compared based on demographic data and each component of 24-h urinalysis. RESULTS: The numbers of participants in high TG, high TC, high LDL, and low HDL were 106, 175, 147, and 59, respectively. The high TG group had increased urinary excretions of oxalate [mean difference (MD) = 0.032 mmol, 95% confidence interval (CI): 0.000-0.065] and potassium (MD = 4.298 mmol, 95%CI: 0.182-8.414). Increased urinary excretion of calcium (MD = 0.531 mmol, 95%CI: 0.061-1.001), sodium (MD = 41.561 mmol, 95%CI: 9.179-73.942), and chloride (MD = 45.209 mmol, 95%CI: 12.118-78.299) were found in the high TC group. Interestingly, the high LDL group had a decreased urinary excretion of calcium (MD = - 0.573 mmol, 95%CI: -1.048 to - 0.097), oxalate (MD = - 0.038 mmol, 95%CI: -0.07 to - 0.006), sodium (MD = - 53.285 mmol, 95%CI: -85.823 to - 20.748), and chloride (MD = - 55.809 mmol, 95%CI: -89.035 to - 22.583). Increased urinary excretions of citrate (MD = 0.455 mmol, 95%CI: 0.076-0.835) and magnesium (MD = 0.697 mmol, 95%CI: 0.244-1.149) were found in the low HDL group. CONCLUSIONS: The present study first investigated the effects of dyslipidemia on 24-h urinalysis in NF adults. Of note, high LDL and low HDL were found to be adversely related to kidney stone formation. However, people with high TG and high TC should be cautious of getting kidney stones. PMID- 30400933 TI - Impact of accelerated, graduate-entry medicine courses: a comparison of profile, success, and specialty destination between graduate entrants to accelerated or standard medicine courses in UK. AB - BACKGROUND: Little research has compared the profile, success, or specialty destinations of graduates entering UK medical schools via accelerated, 4-yr, standard 5-yr and 6-yr programmes. Four research questions directed this investigation:- What are the success rates for graduates entering graduate-entry vs. undergraduate medicine courses? How does the sociodemographic and educational profile differ between these two groups? Is success - in medical school and foundation training - dependent on prior degree, demographic factors, or aptitude test performance at selection? What specialty do graduate entry medicine students subsequently enter? METHODS: The data from two cohorts of graduates entering medical school in 2007 and 2008 (n = 2761) in the UKMED (UK Medical Education Database) database were studied: 1445 taking 4-yr and 1150 taking 5-yr medicine courses, with smaller numbers following other programmes. RESULTS: Completion rates for degree programmes were high at 95%, with no significant difference between programme types. 4-yr entrants were older, less likely to be from Asian communities, had lower HESA (Higher Education Statistics Agency) tariff scores, but higher UKCAT (UK Clinical Aptitude Test) and GAMSAT (Graduate Medical School Admissions Test) scores, than 5-yr entrants. Higher GAMSAT scores, black or minority ethnicity (BME), and younger age were independent predictors of successful completion of medical school. Foundation Programme (FPAS) selection measures (EPM - educational performance measure; SJT - situational judgment test) were positively associated with female sex, but negatively with black or minority ethnicity. Higher aptitude test scores were associated with EPM and SJT, GAMSAT with EPM, UKCAT with SJT. Prior degree subject, class of degree, HESA tariff, and type of medicine programme were not related to success. CONCLUSIONS: The type of medicine programme has little effect on graduate entrant completion, or EPM or SJT scores, despite differences in student profile. Aptitude test score has some predictive validity, as do sex, age and BME, but not prior degree subject or class. Further research is needed to disentangle the influences of BME. PMID- 30400935 TI - Assessment of tegumental damage to Schistosoma mansoni and S. haematobium after in vitro exposure to ferrocenyl, ruthenocenyl and benzyl derivatives of oxamniquine using scanning electron microscopy. AB - BACKGROUND: Schistosomiasis is one of the most harmful parasitic diseases worldwide, praziquantel being the only drug in widespread use to treat it. We recently demonstrated that ferrocenyl, ruthenocenyl and benzyl derivatives of oxamniquine (Fc-OXA, Rc-OXA and Bn-OXA) are promising antischistosomal drug candidates. METHODS: In this study we assessed the tegumental damage of these three derivatives of oxamniquine using scanning electron microscopy. Adult Schistosoma mansoni and S. haematobium were exposed to a concentration of 100 MUM of each drug and incubated for 4-120 h, according to their onset of action and activity. RESULTS: While on S. mansoni the fastest acting compound was Fc-OXA, which revealed high activity after 4 h of incubation, on S. haematobium, Rc-OXA revealed the quickest onset, being lethal on all males within 24 h. In both species studied, the three derivatives showed the same patterns of tegumental damage consisting of blebs, sloughing and tegument rupturing all over the body. Additionally, on S. mansoni distinct patterns of tegumental damage were observed for each of the compounds: tissue ruptures in the gynaecophoric canal for Fc-OXA, loss of spines for Rc-OXA and oral sucker rupture for Bn-OXA. CONCLUSIONS: Our study confirmed that Fc-OXA, Rc-OXA and Bn-OXA are promising broad spectrum antischistosomal drug candidates. All derivatives show fast in vitro activity against S. mansoni and S. haematobium while validating the previous finding that the parent drug oxamniquine is less active in vitro under the conditions described. This work sets the base for further studies on the identification of a lead oxamniquine derivative, with the aim of identifying a molecule with the potential to become a new drug for human use. PMID- 30400934 TI - Malaria chemoprevention with monthly dihydroartemisinin-piperaquine for the post discharge management of severe anaemia in children aged less than 5 years in Uganda and Kenya: study protocol for a multi-centre, two-arm, randomised, placebo controlled, superiority trial. AB - BACKGROUND: Children hospitalised with severe anaemia in malaria endemic areas in Africa are at high risk of readmission or death within 6 months post-discharge. Currently, no strategy specifically addresses this period. In Malawi, 3 months of post-discharge malaria chemoprevention (PMC) with monthly treatment courses of artemether-lumefantrine given at discharge and at 1 and 2 months prevented 30% of all-cause readmissions by 6 months post-discharge. Another efficacy trial is needed before a policy of malaria chemoprevention can be considered for the post discharge management of severe anaemia in children under 5 years of age living in malaria endemic areas. OBJECTIVE: We aim to determine if 3 months of PMC with monthly 3-day treatment courses of dihydroartemisinin-piperaquine is safe and superior to a single 3-day treatment course with artemether-lumefantrine provided as part of standard in-hospital care in reducing all-cause readmissions and deaths (composite primary endpoint) by 6 months in the post-discharge management of children less than 5 years of age admitted with severe anaemia of any or undetermined cause. METHODS/DESIGN: This is a multi-centre, two-arm, placebo controlled, individually randomised trial in children under 5 years of age recently discharged following management for severe anaemia. Children in both arms will receive standard in-hospital care for severe anaemia and a 3-day course of artemether-lumefantrine at discharge. At 2 weeks after discharge, surviving children will be randomised to receive either 3-day courses of dihydroartemisinin piperaquine at 2, 6 and 10 weeks or an identical placebo and followed for 26 weeks through passive case detection. The trial will be conducted in hospitals in malaria endemic areas in Kenya and Uganda. The study is designed to detect a 25% reduction in the incidence of all-cause readmissions or death (composite primary outcome) from 1152 to 864 per 1000 child years (power 80%, alpha = 0.05) and requires 520 children per arm (1040 total children). RESULTS: Participant recruitment started in May 2016 and is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02671175 . Registered on 28 January 2016. PMID- 30400936 TI - Investigate the mechanisms of Chinese medicine Fuzhengkangai towards EGFR mutation-positive lung adenocarcinomas by network pharmacology. AB - BACKGROUND: Chinese traditional herbal medicine Fuzhengkangai (FZKA) formulation combination with gefitinib can overcome drug resistance and improve the prognosis of lung adenocarcinoma patients. However, the pharmacological and molecular mechanisms underlying the active ingredients, potential targets, and overcome drug resistance of the drug are still unclear. Therefore, it is necessary to explore the molecular mechanism of FZKA. METHODS: A systems pharmacology and bioinformatics-based approach was employed to investigate the molecular pathogenesis of EGFR-TKI resistance with clinically effective herb formula. The differential gene expressions between EGFR-TKI sensitive and resistance cell lines were calculated and used to find overlap from targets as core targets. The prognosis of core targets was validated from the cancer genome atlas (TCGA) database by Cox regression. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment is applied to analysis core targets for revealing mechanism in biology. RESULTS: The results showed that 35 active compounds of FZKA can interact with eight core targets proteins (ADRB2, BCL2, CDKN1A, HTR2C, KCNMA1, PLA2G4A, PRKCA and LYZ). The risk score of them were associated with overall survival and relapse free time (HR = 6.604, 95% CI: 2.314-18.850; HR = 5.132, 95% CI: 1.531-17.220). The pathway enrichment suggested that they involved in EGFR TKI resistance and non-small cell lung cancer pathways, which directly affect EGFR-TKI resistance. The molecular docking showed that licochalcone a and beta sitosterol can closely bind two targets (BCL2 and PRKCA) that involved in EGFR TKI resistance pathway. CONCLUSIONS: This study provided a workflow for understanding mechanism of CHM for against drug resistance. PMID- 30400937 TI - Low-dose aspirin in the prevention of pre-eclampsia in China (APPEC study): protocol for a multicentre randomized controlled trial. AB - BACKGROUND: Low-dose aspirin (LDA) has been proposed as a safe and inexpensive prophylactic agent. Studies in European/Western populations have shown promising results indicating that LDA can reduce the occurrence of pre-eclampsia (PE) in women with identifiable risk factors. However, few controlled trials, particularly large randomized controlled trials, have been performed in Asian populations. The aim of this project is to evaluate the effect of LDA for PE prevention on high-risk pregnant women in China, where PE is highly prevalent and the LDA supply status is commonly suboptimal. METHODS/DESIGN: An open-label, multicentre randomized controlled trial is being conducted at 13 tertiary hospitals in 11 provinces in China. A total of 1000 eligible women with high-risk factors for developing PE according to their medical histories are being randomized into two groups: a control group (n = 500) and an intervention group (n = 500). Women with high-risk factors, such as a history of PE, chronic hypertension, type 1 or 2 diabetes, advanced maternal age, obesity, family history of PE or nulliparity are eligible. The control group is advised to undergo routine examinations, whereas the intervention group undergoes the routine examinations and receives LDA. LDA (100 mg/d) should be prescribed at night, initiating from early pregnancy (12-20 weeks of gestation) and lasting until 34 weeks of gestation. Demographic data and clinical endpoint outcomes, as well as biological samples (e.g., maternal blood, cord blood, amniotic fluid and placental samples), will be collected. The primary outcome is the occurrence of PE, and the secondary outcomes include maternal and neonatal outcomes and maternal biomarker levels. DISCUSSION: This is the first and largest multicentre randomized controlled trial to assess the effect of LDA in preventing PE in a Chinese population. The results will potentially influence the prenatal care recommendations in China regarding intervention with LDA for PE. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02797249 . Registered on 7 June 2016. PMID- 30400938 TI - DNA methylation and de-methylation using hybrid site-targeting proteins. AB - DNA methylation plays important roles in determining cellular identity, disease, and environmental responses, but little is known about the mechanisms that drive methylation changes during cellular differentiation and tumorigenesis. Meanwhile, the causal relationship between DNA methylation and transcription remains incompletely understood. Recently developed targeted DNA methylation manipulation tools can address these gaps in knowledge, leading to new insights into how methylation governs gene expression. Here, we summarize technological developments in the DNA methylation editing field and discuss the remaining challenges facing current tools, as well as potential future directions. PMID- 30400940 TI - Choosing a women's health career. AB - BACKGROUND: In 2005, in response to a decline in residency applications in obstetrics and gynecology (OB GYN), the American College of Obstetrics and Gynecology Presidential Task Force outlined strategies for attracting medical students to OB GYN. Application rates have increased since then, but little is known about which interventions are effective. We aimed to identify modifiable and nonmodifiable variables that may contribute to students choosing OB GYN for their careers; this information could be used to inform curriculum design, faculty development, and innovative exposures to women's health. METHODS: This qualitative study received institutional review board approval. Eligible participants were students who applied or recently matched into OB GYN residency programs from the class of 2014-2016 at our institution. Students were interviewed with open-ended questions and a Likert-type survey. Thematic analysis was performed. RESULTS: Ten qualitative interviews were completed and analyzed. Intrinsic themes such as the potential for a meaningful job in women's health, advocacy for women, or empowerment of women were identified as factors contributing to participant career choice. Extrinsic themes such as positive impressions during the clinical clerkship and welcoming teams were also identified. Most students indicated that the clerkship was the most influential experience. CONCLUSIONS: Participants identified important events, including some that even preceded medical school that guided them toward OB GYN. The data guide us to consider the importance of emphasizing the unique combination of characteristics in OB GYN and improving the learning environment in the clerkship as a way to encourage student recruitment. PMID- 30400939 TI - Effects of recombinant human erythropoietin on cognition and neural activity in remitted patients with mood disorders and first-degree relatives of patients with psychiatric disorders: a study protocol for a randomized controlled trial. AB - BACKGROUND: Bipolar disorder (BD) and unipolar disorder (UD) are associated with cognitive deficits and abnormal neural activity in a "cognitive control network." There is an increased prevalence of cognitive dysfunction in psychiatric patients' first-degree relatives, which constitutes a risk factor for psychiatric illness onset. However, there is no treatment with enduring pro-cognitive efficacy. We found preliminary evidence for beneficial effects of eight weekly doses of recombinant human erythropoietin (EPO) on cognition in BD in a recent randomized controlled trial (RCT). The present RCT consists of two sub-studies that extend our previous work by investigating important novel aspects: (1) the effects of 12 weekly doses of EPO on cognition in first-degree relatives of patients with BD, UD, or schizophrenia; and (2) the effects of extending the treatment schedule from 8 to 12 weeks in remitted patients with BD or UD; and (3) assessment of early treatment-associated neural activity changes that may predict cognitive improvement. METHODS: The trial comprises two parallel sub-studies with randomized, controlled, double-blinded, parallel group designs. First-degree relatives (sub-study 1; n = 52) and partially or fully remitted patients with BD or UD (sub-study 2; n = 52) with objectively verified cognitive dysfunction are randomized to receive weekly high-dose EPO (40,000 IU/mL) or placebo (saline) infusions for 12 weeks. Assessments of cognition and mood are conducted at baseline, after two weeks of treatment, after treatment completion, and at six month follow-up. Functional magnetic resonance imaging (fMRI) is conducted at baseline and after two weeks of treatment. Psychosocial function is assessed at baseline, after treatment completion and six-month follow-up. The primary outcome is change in a cognitive composite score of attention, verbal memory, and executive functions. Statistical power of >= 80% is reached to detect a clinically relevant between-group difference by including 52 first-degree relatives and 52 patients with BD or UD, respectively. Behavioral data are analyzed with an intention-to-treat approach using mixed models. fMRI data are analyzed with the FMRIB Software Library. DISCUSSION: If this trial reveals pro cognitive effects of EPO, this may influence future treatment of mood disorders and/or preventive strategies in at-risk populations. The fMRI analyses may unravel key neurobiological targets for pro-cognitive treatment. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03315897. Registered on 20 October 2017. PMID- 30400941 TI - PD-1 and PD-L1 are more highly expressed in high-grade bladder cancer than in low grade cases: PD-L1 might function as a mediator of stage progression in bladder cancer. AB - BACKGROUND: Bladder cancers have been characterized as a tumor group in which the immunological response is relatively well preserved. Programmed death ligand 1 (PD-L1, B7-H1, CD274) has been shown to be expressed in several malignancies, including bladder cancer. However, the clinicopathological impact of this biomarker has not yet been established. In the present study, a quantitative real time polymerase chain reaction (qPCR) was performed using paired normal and cancerous bladder cancer tissue to investigate PD-1/PD-L1 gene expression. METHODS: We examined the mRNA expression of PD-1/PD-L1 by a qPCR using 58 pairs of normal and cancerous human bladder tissue specimens. We also examined the correlation with the expressions of the STAT1 and NFAT genes, which are thought to be upstream and downstream of the PD-L1 pathway, respectively. RESULTS: There were no significant differences between normal and cancerous tissue in the expression of the PD-1 and PD-L1 genes (p = 0.724 and p = 0.102, respectively). However, PD-1 and PD-L1 were both more highly expressed in high-grade bladder cancer than in low-grade bladder cancer (p < 0.050 and p < 0.010). PD-L1 was positively correlated with the expressions of both the STAT1 (r = 0.681, p < 0.001) and the NFATc1 genes (r = 0.444. p < 0.001). CONCLUSIONS: PD-1 and PD-L1 might be a new biomarker that correlates with the pathological grade of bladder cancer. PD-L1 might function as a mediator of stage progression in bladder cancer and STAT1-NFAT pathway might associate this function. PMID- 30400942 TI - Advancing the evaluation of integrated knowledge translation. AB - BACKGROUND: Integrated knowledge translation (IKT) flows from the premise that knowledge co-produced with decision-makers is more likely to inform subsequent decisions. However, evaluations of manager/policy-maker-focused IKT often concentrate on intermediate outcomes, stopping short of assessing whether research findings have contributed to identifiable organisational action. Such hesitancy may reflect the difficulty of tracing the causes of this distal, multifactorial outcome. This paper elucidates how an approach based on realistic evaluation could advance the field. MAIN TEXT: Realistic evaluation views outcomes as a joint product of intervention mechanisms and context. Through identification of context-mechanism-outcome configurations, it enables the systematic testing and refinement of 'mid-range theory' applicable to diverse interventions that share a similar underlying logic of action. The 'context sensitive causal chain' diagram, a tool adapted from the broader theory-based evaluation literature, offers a useful means of visualising the posited chain from activities to outcomes via mechanisms, and the context factors that facilitate or disrupt each linkage (e.g. activity-mechanism, mechanism-outcome). Drawing on relevant literature, this paper proposes a context-sensitive causal chain by which IKT may generate instrumental use of research findings (i.e. direct use to make a concrete decision) and identifies an existing tool to assess this outcome, then adapts the chain to describe a more subtle, indirect pathway of influence. Key mechanisms include capacity- and relationship-building among researchers and decision-makers, changes in the (perceived) credibility and usability of findings, changes in decision-makers' beliefs and attitudes, and incorporation of new knowledge in an actual decision. Project-specific context factors may impinge upon each linkage; equally important is the organisation's absorptive capacity, namely its overall ability to acquire, assimilate and apply knowledge. Given a sufficiently poor decision-making environment, even well implemented IKT that triggers important mechanisms may fall short of its desired outcomes. Further research may identify additional mechanisms and context factors. CONCLUSION: By investigating 'what it is about an intervention that works, for whom, under what conditions', realistic evaluation addresses questions of causality head-on without sacrificing complexity. A realist approach could contribute greatly to our ability to assess - and, ultimately, to increase - the value of IKT. PMID- 30400943 TI - CRISPR/Cas9 offers a new tool for studying the role of chromatin architecture in disease pathogenesis. AB - A recent study used CRISPR/Cas9 to reveal long-range looping between disease related genes and their regulatory elements that is mediated by the CCCTC-binding factor (CTCF) in prostate cancer. PMID- 30400944 TI - A functional description of adult picky eating using latent profile analysis. AB - OBJECTIVE: Research has indicated that adult picky eating (PE) is associated with elevated psychosocial impairment and limited dietary variety and fruit and vegetable intake; however, research operationalizing PE behaviors is limited. Previous research identified a PE profile in children, marked by high food avoidance (satiety responsiveness, fussiness, and slow eating) and low food approach (food enjoyment and responsiveness) appetitive traits. The present study aimed to replicate a similar latent eating behavior profile in an adult sample. METHODS: A sample of 1339 US adults recruited through Amazon's MTurk completed an online survey that included a modified self-report version of the Child Eating Behavior Questionnaire (CEBQ-A). Latent profile analysis was employed to identify eating profiles using the CEBQ-A subscales, ANCOVAs were employed to examine profile differences on various self-report measures, and eating profiles were compared across BMI classifications. RESULTS: Analyses converged on a four profile solution, and a picky eater profile that closely resembled the past child profile emerged. Participants in the picky eater profile (18.1%) scored higher on measures of adult PE and social eating anxiety compared to all other profiles, scored higher on eating-related impairment and depression than moderate eating profiles, and were more likely to be of normal weight. DISCUSSION: A distinct adult PE profile was observed, indicating childhood PE and appetitive behaviors may carry over into adulthood. Research identifying meaningful groups of picky eaters will help to shed light on the conditions under which picky eating is a risk factor for significant psychosocial impairment or distress, or weight related problems. PMID- 30400945 TI - Prevalence of hypobetalipoproteinemia and related psychiatric characteristics in a psychiatric population: results from the retrospective HYPOPSY Study. AB - BACKGROUND: Hypobetalipoproteinemia (HBL) is defined by plasma concentrations of LDL-cholesterol (LDL-C) lower than the fifth percentile for age and sex. Several psychiatric symptoms have been reported in association with HBL. The objective was to assess the prevalence of primary HBL in patients hospitalized in a psychiatric population and to better characterize the related psychiatric disorders. METHODS: HYPOPSY is a retrospective study including 839 adults hospitalized in the Psychiatry department of Nantes University Hospital during the year 2014, except patients with eating disorders. The prevalence of primary HBL was defined by a plasma LDL-C concentration <= 50 mg/dL. Secondary causes of HBL were excluded after a review of medical records (n=2). Related-psychiatric disorders in patients with and without HBL were recorded using the ICD-10 classification. RESULTS: Twenty cases of primary HBL (mean [SD] LDL-C: 42 [7] mg/dL) were diagnosed, leading to a prevalence of 2.39%. In comparison, the prevalence of HBL in a healthy control population was 0.57%. Psychiatric patients with HBL were characterized by a higher frequency of schizophrenia (p=0.044), hetero-aggression (p=0.015) and pervasive and specific developmental disorders (including autism) (p=0.011). CONCLUSIONS: The prevalence of HBL is 4-fold higher in psychiatric than in general population. More specifically, some statistically significant associations were found between low LDL-C concentrations and schizophrenia, autism and hetero-aggression. These data reinforce the hypothesis for a link between genetically low LDL-C levels and psychiatric disorders. PMID- 30400946 TI - Rationale and pre-clinical evidences for the use of autologous cartilage micrografts in cartilage repair. AB - BACKGROUND: The management of cartilage lesions is an open issue in clinical practice, and regenerative medicine represents a promising approach, including the use of autologous micrografts whose efficacy was already tested in different clinical settings. The aim of this study was to characterize in vitro the effect of autologous cartilage micrografts on chondrocyte viability and differentiation and perform an evaluation of their application in racehorses affected by joint diseases. MATERIALS AND METHODS: Matched human chondrocytes and micrografts were obtained from articular cartilage using Rigenera(r) procedure. Chondrocytes were cultured in the presence or absence of micrografts and chondrogenic medium to assess cell viability and cell differentiation. For the pre-clinical evaluation, three racehorses affected by joint diseases were treated with a suspension of autologous micrografts and PRP in arthroscopy interventions. Clinical and radiographic follow-ups were performed up to 4 months after the procedure. RESULTS: Autologous micrografts support the formation of chondrogenic micromasses thanks to their content of matrix and growth factors, such as transforming growth factor beta (TGFbeta) and insulin-like growth factor 1 (IGF-1). On the other hand, no significant differences were observed on the gene expression of type II collagen, aggrecan, and SOX9. Preliminary data in the treatment of racehorses are suggestive of a potential in vivo use of micrografts to treat cartilage lesions. CONCLUSION: The results reported in this study showed the role of articular micrografts in the promoting chondrocyte differentiation suggesting their potential use in the clinical practice to treat articular lesions. PMID- 30400947 TI - Impact of rye-based evening meals on cognitive functions, mood and cardiometabolic risk factors: a randomized controlled study in healthy middle aged subjects. AB - BACKGROUND: Whole grain (WG) intake is associated with reduced risk of obesity, type 2 diabetes and cardiovascular disease, whereas type 2 diabetes increases the risk of cognitive decline and dementia. The purpose of this study was to investigate the effects of short-term intervention with WG rye on cognitive functions, mood and cardiometabolic risk markers in middle-aged test subjects. METHOD: Rye-based breads were provided to 38 healthy test subjects (aged 52-70y) during three consecutive days in a crossover study design, using white wheat flour bread (WWB) as a reference. The rye-based bread consisted of a WG rye kernel/flour mixture (1:1 ratio) supplemented with resistant starch type 2 (RS2) (RB + RS2). The last bread portion was ingested at 2100 h, and cognitive function, mood and cardiometabolic risk markers were determined the following morning, 11 - 14 h post intake. RESULTS: In comparison to WWB, the RB + RS2 product increased ratings of mood parameters (valance, P < 0.001; activation P < 0.05). No differences were seen in the cognitive tests depending on intervention (P > 0.05). RB + RS2 increased insulin sensitivity (P < 0.05), fasting levels of gut hormones (PYY, P < 0.05; GLP-2, P < 0.01) and fasting concentrations of plasma acetate, butyrate and total SCFA (P < 0.001). In contrast, fasting levels of IL - 1beta were decreased (P < 0.05). Insulin sensitivity was positively correlated with working memory test performance (P < 0.05). CONCLUSIONS: This study display novel findings regarding effects of WG rye products on mood, and glucose and appetite regulation in middle-aged subjects, indicating anti-diabetic properties of WG rye. The beneficial effects are suggested to be mediated through gut fermentation of dietary fiber in the RB + RS2 product. TRIAL REGISTRATION: The study was retrospectively registered at ClinicalTrials.gov, register number NCT03275948 . Registered September 8 2017. PMID- 30400949 TI - Modeled exposure to tetrachloroethylene-contaminated drinking water and the occurrence of birth defects: a case-control study from Massachusetts and Rhode Island. AB - BACKGROUND: Residents of Massachusetts and Rhode Island were exposed to tetrachloroethylene-contaminated drinking water from 1968 through the early 1990s when it leached from the vinyl lining of asbestos cement water distribution pipes. While occupational exposure to solvents during pregnancy has consistently been linked to an increased risk of certain birth defects, mixed results have been observed for environmental sources of exposure, including contaminated drinking water. The present case-control study was undertaken to examine further the association between prenatal exposure to tetrachloroethylene-contaminated drinking water and the risk of central nervous system defects, oral clefts and hypospadias. METHODS: Cases were comprised of live- and stillborn infants delivered between 1968 and 1995 to mothers who resided in 28 Massachusetts and Rhode Island cities and towns with some PCE-contaminated water supplies. Infants with central nervous system defects (N = 268), oral clefts (N = 112) and hypospadias (N = 94) were included. Controls were randomly selected live-born, non-malformed infants who were delivered during the same period and geographic area as cases (N = 771). Vital records and self-administered questionnaires were used to gather identifying information, birth defect diagnoses, and other relevant data. PCE exposure during the first trimester was estimated using water distribution system modeling software that incorporated a leaching and transport model. Prenatal PCE exposure was dichotomized as "high" or "low" exposure at the level corresponding to an estimated average concentration of 40 MUg/L, the criterion for remediation when PCE contamination was discovered in 1980. RESULTS: Mothers with "high" levels of exposure to PCE-contaminated drinking water during the first trimester (> 40 MUg/L) had increased odds of having a child with spina bifida (OR: 2.0, 95% CI: 0.8-5.4), cleft lip with or without cleft palate (OR: 3.8, 95% CI: 1.2-12.3) and hypospadias (OR: 2.1, 95% CI:0.5-8.3). No increases in the odds of other defects were observed in relation to "high" exposure levels. CONCLUSIONS: The results of the present study suggest that mothers with "high" PCE exposure levels during the first trimester have increased odds of having a child with spina bifida, cleft lip with or without cleft palate, and hypospadias. These findings support several prior studies that observed an increased risk of selected birth defects following prenatal exposure to solvents in occupational and environmental settings. Even though PCE contamination from vinyl lined pipes was remediated many years ago, it remains a widespread contaminant across the U.S and so environmental regulations must be guided by a precautionary perspective that safeguards pregnant women and their offspring. PMID- 30400950 TI - Quantitative CT analysis using functional imaging is superior in describing disease progression in idiopathic pulmonary fibrosis compared to forced vital capacity. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is chronic fibrosing pneumonia with an unpredictable natural disease history. Functional respiratory imaging (FRI) has potential to better characterize this disease. The aim of this study was to identify FRI parameters, which predict FVC decline in patients with IPF. METHODS: An IPF-cohort (treated with pamrevlumab for 48 weeks) was retrospectively studied using FRI. Serial CT's were compared from 66 subjects. Post-hoc analysis was performed using FRI, FVC and mixed effects models. RESULTS: Lung volumes, determined by FRI, correlated with FVC (lower lung volumes with lower FVC) (R2 = 0.61, p < 0.001). A negative correlation was observed between specific image based airway radius (siRADaw) at total lung capacity (TLC) and FVC (R2 = 0.18, p < 0.001). Changes in FVC correlated significantly with changes in lung volumes (R2 = 0.18, p < 0.001) and siRADaw (R2 = 0.15, p = 0.002) at week 24 and 48, with siRADaw being more sensitive to change than FVC. Loss in lobe volumes (R2 = 0.33, p < 0.001), increasing fibrotic tissue (R2 = 0.33, p < 0.001) and airway radius (R2 = 0.28, p < 0.001) at TLC correlated with changes in FVC but these changes already occur in the lower lobes when FVC is still considered normal. CONCLUSION: This study indicates that FRI is a superior tool than FVC in capturing of early and clinically relevant, disease progression in a regional manner. PMID- 30400951 TI - Study of human rights violations faced by women who use drugs in Estonia. AB - BACKGROUND: Estonia continues to have the highest prevalence of HIV among people who inject drugs, and the highest overdose mortality, in the European Union. In August 2017, the Eurasian Harm Reduction Association (EHRA), the Canadian HIV/AIDS Legal Network (CHALN), and the Estonian Association of People Who Use Psychotropic Substances (LUNEST) conducted a study in Estonia to assess the situation regarding the human rights of women who use drugs and/or living with HIV. METHODS: The research methodology, developed by EHRA and CHALN, comprised in depth interviews with 38 drug-dependent women conducted between August 8 and 14, 2017, in Tallinn and Ida-Viru county. The interviews were transcribed, and 37 were analyzed using thematic content analysis. RESULTS: The study has documented widespread violations of parental rights (removal of children because of their mother's inability to cease drug use and barriers to regaining custody), violations of the right to health (the failure to provide quality drug and HIV treatment, and the disclosure of medical data, including HIV status and opioid substitution treatment (OST) records), the violation of labor rights due to drug use, arbitrary arrest, street drug testing, and violations of the right to a fair trial. A number of women have experienced repeated cases of gender-based violence but have had no access to psychosocial support, shelters, or other protection or rehabilitation measures. CONCLUSIONS: Our findings suggest that punitive drug laws and their enforcement practices, the lack of gender-specific drug treatment facilities, combined with stigma related to drugs and HIV, are the main drivers of systematic and serious violations of the human rights of women who use drugs or who are drug dependent. Stigma and human rights violations undermine Estonia's efforts in HIV prevention, care, and treatment, and its overall efforts to respect, protect, and fulfill the right to health of women who use drugs or who are drug dependent. For these reasons, the Government of Estonia should address a variety of issues related to the protection of human rights of this vulnerable population group. PMID- 30400948 TI - Epidemiology of Taenia saginata taeniosis/cysticercosis: a systematic review of the distribution in southern and eastern Africa. AB - BACKGROUND: The beef tapeworm, Taenia saginata, causing cysticercosis in bovines and taeniosis in humans, is thought to have a global distribution. In eastern and southern Africa, cattle production plays a crucial role in the economy, but a clear overview of the prevalence of T. saginata in the region is still lacking. This review aims to summarize existing knowledge on T. saginata taeniosis and bovine cysticercosis distribution in eastern and southern Africa. METHODS: A systematic review was conducted, that gathered published and grey literature, including OIE reports, concerning T. saginata taeniosis and bovine cysticercosis in eastern and southern Africa published between January 1st, 1990 and December 31st, 2017. RESULTS: A total of 1232 records were initially retrieved, with 78 full text articles retained for inclusion in the database. Unspecified taeniosis cases were reported for Angola, Ethiopia, Kenya, Madagascar, Malawi, South Africa, Tanzania, Uganda and Zambia, whereas T. saginata taeniosis cases were found for Ethiopia, Kenya, South Africa, Tanzania, Zambia and Zimbabwe. The prevalence of taeniosis ranged between 0.2-8.1% based on microscopy, and between 0.12-19.7% based on coproAg-ELISA. In Ethiopia, the percentage of tapeworm self reporting was high (45.0-64.2%), and a substantial number of anthelmintic treatments were reported to be sold in towns. The presence of bovine cysticercosis was reported in all 27 countries/territories included in the study, except for Rwanda and Somalia, Comoros, Madagascar, Mauritius, Mayotte, Seychelles and Socotra. The prevalence of cysticercosis ranged between 0.02-26.3% based on meat inspection, and between 6.1-34.9% based on Ag-ELISA. CONCLUSIONS: Although T. saginata has been reported in the majority of countries/territories of the study area, T. saginata taeniosis/cysticercosis remains a largely ignored condition, probably due to the absence of symptoms in cattle, the lack of data on its economic impact, and the fact that human taeniosis is considered a minor health problem. However, the occurrence of bovine cysticercosis is a clear sign of inadequate sanitation, insufficient meat inspection, and culinary habits that may favour transmission. Measures to reduce transmission of T. saginata are therefore warranted and the infection should be properly monitored. PMID- 30400952 TI - Hemorrhage within the tympanic membrane without perforation. AB - BACKGROUND: Hemotympanum refers to both the presence of blood in the middle ear cavity and to ecchymosis of the tympanic membrane (TM), and a systematic study of intra-TM (iTM) hemorrhage without bleeding in the middle ear cavity has not been conducted. The goals of our study were to analyze the causes of iTM hemorrhage without TM perforation or bleeding in the middle ear cavity, and to demonstrate the clinical characteristics of the disease. METHODS: This Case series study included five patients with iTM hemorrhage between August 2014 and August 2017. An iTM hemorrhage was diagnosed when otoendoscopic examination demonstrated minor bleeding behind the intact TM, a hemorrhage was observed between the TM annulus and the epidermal layer, and temporal bone computed tomography revealed thickening of the TM without soft tissue density within the tympanic cavity or temporal bone fracture. Initial symptoms, and serial findings of otoendoscopy and pure tone audiometry (PTA) were investigated. RESULTS: iTM hemorrhage developed due to blunt head trauma in two patients, descent barotrauma during scuba diving in two patients, and spontaneous epistaxis in one patient. Otalgia and ear fullness were the most common symptoms, but PTA showed no or minimal conductive hearing loss in all patients. CONCLUSIONS: An iTM hemorrhage may develop after blunt head trauma, barotrauma due to scuba diving, or spontaneous epistaxis; otological symptoms included otalgia, tinnitus, and aural fullness. An iTM hemorrhage resolved spontaneously without specific treatment, usually within 1 month. PMID- 30400953 TI - Effect of serum triglyceride level on the prognosis of patients with hepatocellular carcinoma in the absence of cirrhosis. AB - BACKGROUND: The liver plays an important role in the metabolism of lipid and lipoprotein. Dyslipidemia has been demonstrated to be related with several cancers, but the association between serum lipid and hepatocellular carcinoma (HCC) in the absence of cirrhosis remains unclear. METHODS: A total of 2528 patients with HCC at the Beijing Ditan Hospital between February 2008 and December 2017 were retrospectively included in the study. We identified 200 patients with HCC without cirrhosis by histopathology, imaging, endoscopic findings, and laboratory tests. Multivariate regression analysis was performed to determine the independent characteristics associated with HCC without cirrhosis and its prognosis. RESULTS: In the logistics regression analysis, compared to patients with HCC with cirrhosis, patients with HCC without cirrhosis were more likely to have elevated triglyceride (TG) levels (OR = 2.66; 95% CI, 1.18-6.01; P = 0.019). The Kaplan-Meier analysis revealed that a lower TG level was a risk factor regardless of the presence of cirrhosis. The results of the Cox proportional hazard regression analysis showed that a decreased TG level was significantly related to a worse overall survival (HR = 0.51; 95% CI, 0.29-0.89; P = 0.017). CONCLUSION: Serum TG level may be an independent factor to predict the prognosis of patients with HCC in the absence of cirrhosis. PMID- 30400956 TI - Prospective study of the prevalence and co-morbidities of obstructive sleep apnea in active-duty army personnel in the three southernmost provinces of Thailand using questionnaire screening. AB - BACKGROUND: It is crucial for the army to know the prevalence of obstructive sleep apnea (OSA) syndrome in active-duty army personnel. Little information has been reported on the prevalence of OSA and clinical features in active-duty army personnel. This study was aimed to estimate the prevalence of snoring and risk of developing OSA in active-duty army personnel in Thailand and to identify the co morbidities of OSA. In total, 1107 participants who were aged 20-60 years and were deployed to the three southernmost provinces of Thailand were enrolled. All the participants completed the Phramongkutklao (PMK) Hospital OSA Questionnaire that was modified and validated from the Berlin Questionnaire and underwent physical examination. The participants were 1107 active-duty army personnel in the three southernmost provinces of Thailand, both males and females, aged 20-60 years. METHODS: The PMK OSA Questionnaire was used to assess the risk of OSA together with interviewing for snoring, fatigue, falling asleep and day-time sleepiness. Physical examination of the neck, chest and hip circumference, and height was performed. Information concerning physical training, co-morbid diseases, smoking and alcoholic consumption was collected. RESULTS: The prevalence of snoring was 58.5, and 4.8% met the PMK OSA Questionnaire criteria, thus indicating a high risk of OSA. The information obtained indicated that laryngopharyngeal reflux (LPR), current smoking and alcoholic consumption were significantly higher in the high-risk OSA group. CONCLUSION: Early detection and treatment of OSA in active-duty army personnel are imperative. Physical examination and polysomnography can be used to reveal the high-risk group. High body mess index (BMI), laryngopharyngeal reflux, current smoking and alcoholic consumption are modifiable factors for OSA and are avoidable. A policy to decrease the BMI and risk of LPR, as well as to stop smoking and alcoholic consumption, should be applied. PMID- 30400954 TI - Vitexin compound 1, a novel extraction from a Chinese herb, suppresses melanoma cell growth through DNA damage by increasing ROS levels. AB - BACKGROUND: Vitex negundo L (Verbenaceae) is an aromatic shrub that is abundant in Asian countries. A series of compounds from Vitex negundo have been used in traditional Chinese medicine for the treatment of various diseases. Cutaneous melanoma is one of the most aggressive malignancies. A significant feature of melanoma is its resistance to traditional chemotherapy and radiotherapy; therefore, there is an urgent need to develop novel treatments for melanoma. METHODS: We first examined the effects of VB1 (vitexin compound 1) on cell viability by CCK-8 (cell counting kit) and Colony Formation Assay; And then, we analyzed the apoptosis and cell cycle by flow cytometry, verified apoptosis by Immunoblotting. The in vivo effect of VB1 was evaluated in xenograft mouse model. Potential mechanisms of VB1's antitumor effects were explored by RNA sequencing and the key differential expression genes were validated by real-time quantitative PCR. Finally, the intracellular reactive oxygen species (ROS) level was detected by flow cytometry, and the DNA damage was revealed by Immunofluorescence and Immunoblotting. RESULTS: In this study, we show that VB1, which is a compound purified from the seed of the Chinese herb Vitex negundo, blocks melanoma cells growth in vitro and in vivo, arrests the cell cycle in G2/M phase and induces apoptosis in melanoma cell lines, whereas the effects are not significantly observed in normal cells. To study the details of VB1, we analyzed the alteration of gene expression profiles after treatment with VB1 in melanoma cells. The findings showed that VB1 can affect various pathways, including p53, apoptosis and the cell cycle pathway, in a variety of melanoma cell lines. Furthermore, we confirmed that VB1 restored the P53 pathway protein level, and then we demonstrated that VB1 significantly induced the accumulation of ROS, which resulted in DNA damage in melanoma cell lines. Interestingly, our results showed that VB1 also increased the ROS levels in BRAFi (BRAF inhibitor)-resistant melanoma cells, leading to DNA cytotoxicity, which caused G2/M phase arrest and apoptosis. CONCLUSIONS: Taken together, our findings indicate that vitexin compound 1 might be a promising therapeutic Chinese medicine for melanoma treatment regardless of BRAFi resistance. PMID- 30400955 TI - Genetic basis of index patients with familial hypercholesterolemia in Chinese population: mutation spectrum and genotype-phenotype correlation. AB - BACKGROUND: Although there have been many reports in the genetics of familial hypercholesterolemia (FH) worldwide, studies in regard of Chinese population are lacking. In this multi-center study, we aim to characterize the genetic spectrum of FH in Chinese population, and examine the genotype-phenotype correlations in detail. METHODS: A total of 285 unrelated index cases from China with clinical FH were consecutively recruited. Next-generation sequencing and bioinformatics tools were used for mutation detection of LDLR, APOB and PCSK9 genes and genetic analysis. RESULTS: Overall, the detection rate is 51.9% (148/285) in the unrelated index cases with a total of 119 risk variants identified including 84 in the LDLR gene, 31 in APOB and 4 in PCSK9 gene. Twenty-eight variants were found in more than one individual and LDLR c.1448G > A (p. W483X) was most frequent one detected in 9 patients. Besides, we found 8 (7 LDLR and 1 APOB) novel variants referred as "pathogenic (or likely pathogenic) variants" according to in silico analysis. In the phenotype analysis, patients with LDLR null mutation had significantly higher LDL cholesterol level than LDLR defective and APOB/PCSK9 mutation carriers and those with no mutations (p < 0.001). Furthermore, 13 double heterozygotes, 16 compound heterozygotes and 5 true LDLR homozygotes were identified and the true LDLR homozygotes had the most severe phenotypes. CONCLUSIONS: The present study confirmed the heterogeneity of FH genetics in the largest Chinese cohort, which could replenish the knowledge of mutation spectrum and contribute to early screening and disease management. PMID- 30400957 TI - The pervasive effects of recombinant Fasciola gigantica Ras-related protein Rab10 on the functions of goat peripheral blood mononuclear cells. AB - BACKGROUND: Fasciola gigantica-induced immunomodulation is a major hurdle faced by the host for controlling infection. Here, we elucidated the role of F. gigantica Ras-related protein Rab10 (FgRab10) in the modulation of key functions of peripheral blood mononuclear cells (PBMCs) of goats. METHODS: We cloned and expressed recombinant FgRab10 (rFgRab10) protein and examined its effects on several functions of goat PBMCs. Protein interactors of rFgRab10 were predicted in silico by querying the databases Intact, String, BioPlex and BioGrid. In addition, a total energy analysis of each of the identified interactions was also conducted. Gene Ontology (GO) enrichment analysis was carried out using FuncAssociate 3.0. RESULTS: The FgRab10 gene (618 bp), encodes 205-amino-acid residues with a molecular mass of ~23 kDa, had complete nucleotide sequence homology with F. hepatica Ras family protein gene (PIS87503.1). The rFgRab10 protein specifically cross-reacted with anti-Fasciola antibodies as shown by Western blot and immunofluorescence analysis. This protein exhibited multiple effects on goat PBMCs, including increased production of cytokines [interleukin-2 (IL-2), IL-4, IL-10, transforming growth factor beta (TGF-beta) and interferon gamma (IFN-gamma)] and total nitric oxide (NO), enhancing apoptosis and migration of PBMCs, and promoting the phagocytic ability of monocytes. However, it significantly inhibited cell proliferation. Homology modelling revealed 63% identity between rFgRab10 and human Rab10 protein (Uniprot ID: P61026). Protein interaction network analysis revealed more stabilizing interactions between Rab proteins geranylgeranyltransferase component A 1 (CHM) and Rab proteins geranylgeranyltransferase component A 2 (CHML) and rFgRab10 protein. Gene Ontology analysis identified RabGTPase mediated signaling as the most represented pathway. CONCLUSIONS: rFgRab10 protein exerts profound influences on various functions of goat PBMCs. This finding may help explain why F. gigantica is capable of provoking recognition by host immune cells, less capable of destroying this successful parasite. PMID- 30400958 TI - Bitter melon (Momordica charantia) attenuates atherosclerosis in apo-E knock-out mice possibly through reducing triglyceride and anti-inflammation. AB - BACKGROUND: Bitter melon (BM, Momordica charantia) has been accepted as an effective complementary treatment of metabolic disorders such as diabetes, hypertension, dyslipidemia and etc. However it is unclear whether BM can prevent the progression of atherosclerosis. To confirm the effects of BM on atherosclerosis and explore its underlying mechanisms, we design this study. METHODS: Twenty four male apolipoprotein E knock-out (ApoE-/-) mice aged 8 weeks were randomly divided into control group fed with high fat diet (HFD) only and BM group fed with HFD mixed with 1.2%w/w BM. After 16 weeks, body weight, food intake, blood glucose, serum lipids were measured and the atherosclerotic plaque area and its histological composition were analyzed. The expression of vascular cell adhesive molecules and inflammatory cytokines in the aortas were determined using quantitative polymerase chain reaction. RESULTS: Body weight gain and serum triglycerides (TG) significantly decreased in BM group. BM reduced not only the atherosclerotic plaque area and the contents of collagen fibers in atherosclerotic plaques but also the serum soluble vascular cell adhesion molecule (VCAM)-1 and P-selectin levels, as well as the expressions of monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6 in aortas. CONCLUSION: Our study indicates that dietary BM can attenuate the development of atherosclerosis in ApoeE-/- mice possibly through reducing triglyceride and anti-inflammation mechanism. PMID- 30400959 TI - The effectiveness and cost-effectiveness of community-based lay distribution of HIV self-tests in increasing uptake of HIV testing among adults in rural Malawi and rural and peri-urban Zambia: protocol for STAR (self-testing for Africa) cluster randomized evaluations. AB - BACKGROUND: Knowledge of HIV status remains below target in sub-Saharan Africa, especially among men and adolescents. HIV self-testing (HIVST) is a novel approach that enables unique distribution strategies, with potential to be highly decentralised and to provide complementary coverage to facility-based testing approaches. However, substantial gaps in evidence remain on the effectiveness and cost-effectiveness of HIVST, particularly in rural settings, and on approaches to facilitate linkage to confirmatory HIV testing, prevention, and treatment services. This protocol describes two cluster-randomized trials (CRT) included within the UNITAID/PSI HIV Self-Testing Africa (STAR) project. METHODS: Two independent CRTs were designed around existing reproductive health programmes in rural Malawi and rural/peri-urban Zambia. Common features include use of constrained randomisation to allocate health clinic catchment areas to either standard HIV testing (SOC) or SOC plus community-based distribution of OraQuick HIV Self Tests (Bethlehem, PA USA, assembled in Thailand) by trained lay distributors selected by the community. Community-based distribution agents will be trained (3-day curriculum) to provide brief demonstration of kit use and interpretation, information and encouragement to access follow up services, and management of social harm. The primary outcome of both CRTs is the proportion of the population aged 16 years and older who tested for HIV within the 12-month intervention period. Secondary outcomes in both trials include lifetime HIV testing, antiretroviral therapy (ART) initiation and ART use. Circumcision status among males will be a secondary outcome in Zambia and clinic-level demand for ART will be a secondary outcome in Malawi. Outcomes will be measured using cross sectional household surveys, and routine data extraction from participating clinics. Costing studies will be used to evaluate the cost-effectiveness of the intervention arm. Qualitative research will be used to guide distribution and explore reasons for testing and linkage to onward care. DISCUSSION: The STAR Malawi and STAR-Zambia trials will provide rigorous evidence of whether community based lay HIVST distribution is an effective and cost-effective approach to increasing coverage of HIV testing and demand for follow-on HIV services in rural and peri-urban communities in sub-Saharan Africa. TRIAL REGISTRATION: Clinicaltrials.gov, Malawi: NCT02718274 , 18 March 2016; Zambia: NCT02793804 , 3 June 2016. Protocol date: 21 February 2018. PMID- 30400960 TI - MicroRNA-31-5p regulates chemosensitivity by preventing the nuclear location of PARP1 in hepatocellular carcinoma. AB - BACKGROUND: MicroRNAs (miRNAs) posttranscriptionally regulate gene expression and thereby contribute to the modulation of numerous complex and disease-relevant cellular processes, including cell proliferation, cell motility, apoptosis and stress response. miRNA-31-5p is encoded on a genomic fragile site, 9p21.3, which is reportedly lost in many hepatocellular carcinoma (HCC) tumors. Based on previous findings, we hypothesized that miR-31-5p alters chemosensitivity and that miR-31-5p mimics may influence sensitivity to chemotherapeutics in HCC as well as in a variety of other cancers. METHODS: MiR-31-5p and PARP1 in HCC tissues were tested by RT-PCR and histological analysis, respectively. Next, clonogenic assay and western blot were used to detect miR-31-5p and PARP1 to modulate sensitivity to OXA-based chemotherapy. The distribution of OXA in the nuclear and intracellular was detected by ICP-MS. Coimmunoprecipitation was used to characterize the protein-protein interaction between PARP1 and ABCB9. A xenograft nude mouse model was used to examine the in vivo effects of miR-31-5p. RESULTS: Reintroduction of miR-31-5p into miR-31-5p-null Hep3B cells significantly enhanced clonogenic resistance to oxaliplatin. Although miR-31-5p re-expression increased chemoresistance, it paradoxically increased the relative intracellular accumulation of oxaliplatin. This effect was coupled with a significantly decreased intranuclear concentration of oxaliplatin by ICP-MS. miR 31-5p prevents the nuclear location of PARP1 detected by immunofluorescence, histological analysis and Western blotting analysis. We subsequently identified an indirect miR-31-5p-mediated upregulation of ABCB9, which is a transporter associated with drug accumulation in lysosomes, along with an increased uptake of oxaliplatin to lysosomes; these phenomena were associated with a downregulation of PARP1, a bipotential transcriptional regulator with multiple miR-31-5p binding sites. However, the indirect overexpression of ABCB9 promoted cellular chemosensitivity, suggesting that miR-31-5p promotes chemoresistance largely via an ABCB9-independent mechanism. CONCLUSIONS: Overall, our data suggest that the loss of miR-31-5p from HCC tumors promotes chemosensitivity, and this knowledge may be prognostically beneficial in the context of therapeutic sensitivity. PMID- 30400961 TI - The association of 18F-FDG PET/CT and biomarkers in confirming coronary microvascular dysfunction. AB - OBJECTIVE: The purpose of this study is to evaluate the association between PET/CT CFR and biomarkers combined in confirming the diagnosis of coronary microvascular dysfunction. RESULTS: A total of 28 patients (21 males and 7 females) were included in this descriptive observational study (both qualitative and quantitative). The mean patient age was 55.50 +/- 10.21 years (range 27-70 years) and the median was 56.5 years (range 49-63 years). All patients underwent Echo, CAG and PET/CT scan. Chest tightness was the most common symptom in our study. Most patients had normal blood pressure (n = 18, 64.3%) while only (n = 10, 37.5%) had hypertension, and (n = 1, 3.6%) had diabetes mellitus. The mean HDL in CMVD (n = 25) and non-CMVD (n = 3) were 1.30 +/- 0.39 and 1.08 +/- 0.95, respectively, indicating that the difference between the groups was statistically significant (p = 0.04). Similarly, the mean HBA1c- (glycated haemoglobin) in CMVD (n = 25) and non-CMVD (n = 3) were 5.6 +/- 0.53 and 5.0 +/- 0.26, respectively, with (p = 0.03). Our findings managed to show the association between biomarkers and PET/CT CFR in confirming the diagnosis of coronary microvascular dysfunction. PMID- 30400963 TI - From scientific discovery to treatments for rare diseases - the view from the National Center for Advancing Translational Sciences - Office of Rare Diseases Research. AB - We now live in a time of unprecedented opportunities to turn scientific discoveries into better treatments for the estimated 30 million people in the US living with rare diseases. Despite these scientific advances, more than 90% of rare diseases still lack an effective treatment. New data and genetics technologies have resulted in the first transformational new treatments for a handful of rare diseases. This challenges us as a society to accelerate progress so that no disease and no patient is, ultimately, left behind in getting access to safe and effective therapeutics. This article reviews initiatives of the National Center for Advancing Translational Sciences (NCATS) Office of Rare Diseases Research (ORDR) that are aimed at catalyzing rare diseases research. These initiatives fall into two groups: Promoting information sharing; and building multi-disciplinary multi-stakeholder collaborations. Among ORDR's information sharing initiatives are GARD (The Genetics and Rare Diseases Information Center), RaDaR (The Rare Diseases Registries Program) and the NCATS Toolkit for Patient-Focused Therapy Development (Toolkit). Among the collaboration initiatives are the RDCRN (Rare Diseases Clinical Research Network), and the NCATS ORDR support for conferences and workshops. Despite the success of these programs, there remains substantial work to be done to build enhanced collaborations, clinical harmonization and interoperability, and stakeholder engagement so that the recent scientific advances can benefit all patients on the long list of rare diseases waiting for help. PMID- 30400962 TI - Dose escalation of radiation therapy with or without induction chemotherapy for unresectable locally advanced pancreatic cancer. AB - BACKGROUND: Dose escalation of conventionally fractionated radiation therapy (CFRT) above 45-54 Gy has an unclear survival benefit. Prior National Cancer Database (NCDB) analyses have shown improved overall survival with induction chemotherapy (iC) prior to concurrent chemoradiation (CRT) in locally advanced pancreatic cancer. Our study compared dose-escalated CFRT with and without iC. METHODS: The NCDB was queried for primary stage III, cT4 N0-1 M0 LAPC treated with CRT with or without iC (2004-2015). CFRT was stratified by < 55 Gy and >= 55 Gy. Cohort iC + CRT and CRT included those with and without iC, respectively. The primary endpoint was overall survival (OS). Kaplan-Meier analysis, Cox proportional hazards method, and propensity score matching were used. RESULTS: Among 2029 patients, cohort iC + CRT had 738 patients (n = 601 for 45-55 Gy and n = 137 for >=55 Gy) and cohort CRT had 1291 patients (n = 1066 for 45-55 Gy and n = 225 for >=55 Gy). Median follow-up was 24.3 months and 24.6 months for cohorts iC + CRT and CRT, respectively. Dose escalation showed improved survival in the multivariable analysis in cohort iC + CRT (HR 0.77, p = 0.013) but not in cohort CRT (HR 0.91, p = 0.19). Using 2:1 propensity score matching, a total of 387 patients for cohort iC + CRT and 549 patients for cohort CRT were matched. After matching, dose escalation remained significant for improved overall survival in cohort iC + CRT (median OS 16.2 vs 15.2 months; 2-yr OS 33.4% vs 25.4%; p = 0.022) but not in cohort CRT (median OS 11.8 vs 10.6 months; 2-yr OS 13.3% vs 10.1%; p = 0.16). CONCLUSIONS: Patients with locally advanced pancreatic cancer who undergo iC have improved survival with radiation dose escalation above 55 Gy. For patients without iC, there is no clear association between radiation dose escalation and survival. PMID- 30400964 TI - Trends in repeated pregnancy among adolescents in the Philippines from 1993 to 2013. AB - OBJECTIVE: The extent of repeated pregnancy (RP) and repeated birth (RB) among adolescents aged 15-19 is still unknown in the Philippines despite the health and socio-economic consequences. This study aims to investigate the RP and RB prevalence trends in the Philippines from 1993 to 2013. METHODS: A total of 7091 women aged 15-24 who experienced at least one pregnancy were captured in the Philippine demographic health surveys from 1993 to 2013. Annual RP and RB prevalence per age group in three and five categories were calculated and stratified by region, type of residence and wealth index. Cochran-Armitage tests and multivariate logistic regression were applied to determine trend estimates. RESULTS: Compared to women aged 19-21 years and 22-24 years, for which decreasing patterns were found, RP ([Adjusted Odds ratio (AOR =0.96; 95%Confidence interval (CI) =0.82-1.11) and RB (AOR = 0.90; CI = 0.73-1.10) trends among 15-18 year olds showed negligible reduction over the 20 years. From a baseline prevalence of 20.39% in 1993, the prevalence of RP among adolescents had only reduced to 18.06% by 2013. Moreover, the prevalence of RB showed a negligible decline from 8.49% in 1993 to 7.80% in 2013. Although RP and RB prevalence were generally found more elevated in poorer communities, no differences in trends were noted across wealth quintiles. CONCLUSION: For two decades, the Philippines has shown a constant and considerably high RP prevalence. Further investigation, not only in the Philippines but also in other developing countries, is necessary to enable development of secondary prevention programs. PMID- 30400965 TI - Comorbid opioid use is undertreated among forensic patients with schizophrenia. AB - BACKGROUND: Substance use disorders are associated with poorer clinical outcomes in patients with schizophrenia. There is no specific treatment for amphetamine or cannabis use disorder, but methadone and buprenorphine are used as replacement therapy in the treatment of opioid dependence. Our aim was to study whether patients with schizophrenia have received opioid replacement therapy for their opioid use disorder. METHODS: The study sample consisted of 148 individuals diagnosed with schizophrenia who were in involuntary psychiatric treatment as forensic patients in Finland in 2012. The proportion of the study sample with comorbid opioid use disorder having received opioid replacement therapy prior to their forensic psychiatric treatment was compared to the available information of opioid dependent patients in general. The data were collected from forensic examination statements, patient files and other medical registers retrospectively. RESULTS: Of the study sample, 15.6% (23/148) had a history of opioid use disorder, of whom 8.7% (2/23) had received opioid replacement treatment (95% confidence interval (Cl): 1.1-28.0), even though opioid use disorder had been diagnosed in the treatment system. According the available information the corresponding proportion among patients with opioid use disorder and using substance use disorder services was 30.4% (565/1860, 95% Cl: 28.3 32.5). The fraction of patients receiving opioid replacement therapy was significantly lower among patients with schizophrenia (p = 0.022). CONCLUSIONS: Opioid replacement therapy was seldom used among schizophrenia patients who were later ordered to involuntary forensic psychiatric treatment. More attention should be paid to the possible use of opioids when planning treatment for patients with schizophrenia. TRIAL REGISTRATION: Our study is not a randomized controlled trial (but a register-based study); thus the trial registration is not applicable. PMID- 30400966 TI - Cross-cultural adaptation and validation of the Simplified Chinese version of Copenhagen Hip and Groin Outcome Score (HAGOS) for total hip arthroplasty. AB - BACKGROUND: To translate and cross-culturally adapt the Copenhagen Hip and Groin Outcome Score (HAGOS) into a Simplified Chinese version (HAGOS-C) and evaluate the reliability, validity, and responsiveness of the HAGOS-C in total hip arthroplasty (THA) patients. METHODS: The cross-cultural adaptation was performed according to the internationally recognized guidelines of the American Academy of Orthopaedic Surgeons Outcome Committee. A total of 192 participants were recruited in this study. The intra-class correlation coefficient (ICC) was used to determine reliability. Construct validity was analyzed by evaluating the correlations between HAGOS-C and EuroQoL 5-dimension (EQ-5D), as well as the short form (36) health survey (SF-36). Responsiveness of HAGOS-C was evaluated according to standard response means (SRM) and standard effect size (ES) between the first test and the third test (6 months after primary THA). RESULTS: The original version of the HAGOS was well cross-culturally adapted and translated into Simplified Chinese. HAGOS-C was indicated to have excellent reliability (ICC = 0.748-0.936, Cronbach's alpha = 0.787-0.886). Moderate to substantial correlations between subscales of HAGOS-C and EQ-5D (r = 0.544-0.751, p < 0.001), as well as physical function (r = 0.567-0.640, p < 0.001), role physical (r = 0.570-0.613, p < 0.001), bodily pain (r = 0.467-0.604, p < 0.001), and general health (r = 0.387-0.432, p < 0.001) subscales of SF-36, were observed. The ES of 0.805-1.100 and SRM of 1.408-2.067 revealed high responsiveness of HAGOS-C. CONCLUSIONS: HAGOS-C was demonstrated to have excellent acceptability, reliability, validity, and responsiveness in THA, which could be recommended for patients in mainland China. PMID- 30400967 TI - White blood cell count and all-cause and cause-specific mortality in the Guangzhou biobank cohort study. AB - BACKGROUND: Several studies have shown positive associations between higher WBC count and deaths from all-causes, CHD, stroke and cancer among occidental populations or developed countries of Asia. No study on the association of WBC count with all-cause and cause-specific mortality in Chinese populations was reported. We studied this using prospective data from a large Chinese cohort. METHODS: We used prospective data from the Guangzhou Biobank Cohort Study (GBCS), a total of 29,925 participants in present study. A Cox proportional hazards regression model was used to estimate the hazard ratios (HR) and 95% confidence interval (CI). RESULTS: The hazard ratios (HR) for all-cause, CHD, and respiratory disease mortality for the highest decile of WBC count (women > 8.2 * 109/L; men > 8.8 * 109/L) was 1.83 (95% confidence interval (CI) 1.54, 2.17), 3.02 (95% CI 1.84, 4.98) and 2.52 (95% CI 1.49, 4.27), respectively, after adjusting for multiple potential confounders. The associations were similar when deaths during the first 2 years of follow-up were excluded. After further adjusting for pulmonary function, the highest decile of WBC count was associated with 90% higher risk of respiratory disease mortality (HR 1.90, 95% CI 1.08, 3.33). No evidence for an association between higher WBC count and cancer mortality was found. Sub-type analysis showed that only granulocyte count remained significantly predictive of all-cause, CHD, and respiratory disease mortality. CONCLUSIONS: Elevated WBC, specifically granulocyte, count was associated with all-cause, CHD and respiratory mortality in southern Chinese. Further investigation is warranted to clarify whether decreasing inflammation would attenuate WBC count associated mortality. PMID- 30400968 TI - Epigenetic silencing of TMEM176A activates ERK signaling in human hepatocellular carcinoma. AB - BACKGROUND: The role of TMEM176A in human hepatocellular carcinoma (HCC) is unknown. This study explored the epigenetic regulation and function of TMEM176A in human HCC. MATERIALS AND METHODS: Twelve HCC cell lines and 126 cases of primary cancer were analyzed. Methylation-specific PCR, immunohistochemistry, flow cytometry, and xenograft mouse models were employed. RESULTS: TMEM176A was highly expressed in SNU387, SNU182, Huh1, and SNU475 cells; reduced expression was observed in HepG2 and PLC/PRF/5 cells; and no expression was found in SNU449, HBXF344, SMMC7721, Huh7, and LM3 cells. Unmethylation of the TMEM176A promoter was detected in SNU387, SNU182, Huh1, and SNU475 cells; partial methylation was observed in HepG2 and PLC/PRF/5 cells; and complete methylation was found in SNU449, HBXF344, SMMC7721, Huh7, and LM3 cells. Upon treatment with 5-Aza-2 deoxycytidine, re-expression of TMEM176A was detected in SNU449, HBXF344, SMMC7721, Huh7, and LM3 cells; increased expression of TMEM176A was observed in HepG2 and PLC/PRF/5 cells; and no expression changes were found in SNU387, SNU182, Huh1, and SNU475 cells. The TMEM176A promoter region was methylated in 75.4% (95/126) of primary human HCC. Reduced expression of TMEM176A was associated with promoter region methylation (P < 0.05). No association was found between TMEM176A promoter methylation and age, gender, HBV infection, liver cirrhosis, tumor size, lymph node metastasis, vessel cancerous embolus, number of lesions, and TNM stage (all P > 0.05). These results demonstrated that the expression of TMEM176A is regulated by promoter region methylation. Methylation of the TMEM176A promoter was significantly associated with tumor cell differentiation (P < 0.05) and was an independent prognostic factor for poor 3 year overall survival (OS, P < 0.05). TMEM176A expression induced cell apoptosis; inhibited cell proliferation, migration, and invasion; suppressed human HCC cell xenograft growth in mice; and inhibited ERK signaling in HCC cells. CONCLUSION: The promoter region of TMEM176A is frequently methylated in human HCC, and the expression of TMEM176A is regulated by promoter region methylation. Methylation of the TMEM176A promoter may serve as a diagnostic and prognostic marker in HCC. TMEM176A suppresses HCC growth by inhibiting the ERK signaling pathway. PMID- 30400969 TI - Relation of baseline neutrophil-to-lymphocyte ratio to survival and toxicity in head and neck cancer patients treated with (chemo-) radiation. AB - BACKGROUND: A high neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation and together with the platelet-to-lymphocyte ratio (PLR) is associated with worse outcomes in several solid tumors. We investigated the prognostic value of NLR and PLR in patients with head and neck squamous cell carcinoma (HNSCC) treated with primary or adjuvant (chemo)radiotherapy ((C)RT). METHODS: A retrospective chart review of consecutive patients with HNSCC was performed. Neutrophil-to-lymphocyte ratio and PLR were computed using complete blood counts (CBCs) performed within 10 days before treatment start. The prognostic role of NLR and PLR was evaluated with univariable and multivariable Cox regression analyses adjusting for disease-specific prognostic factors. NLR and PLR were assessed as log-transformed continuous variables (log NLR and log PLR). Endpoints of interest were overall survival (OS), locoregional recurrence free survival (LRFS), distant recurrence-free survival (DRFS), and acute toxicity. RESULTS: We analyzed 186 patients treated from 2007 to 2010. Primary sites were oropharynx (45%), oral cavity (28%), hypopharynx (14%), and larynx (13%). Median follow-up was 49 months. Higher NLR was associated with OS (adjusted HR per 1 unit higher log NLR = 1.81 (1.16-2.81), p = 0.012), whereas no association could be shown with LRFS (HR = 1.49 (0,83-2,68), p = 0.182), DRFS (HR = 1.38 (0.65-3.22), p = 0.4), or acute toxicity grade >= 2. PLR was not associated with outcome, nor with toxicity. CONCLUSION: Our data suggest that in HNSCC patients treated with primary or adjuvant (C)RT, NLR is an independent predictor of mortality, but not disease-specific outcomes or toxicity. Neutrophil to-lymphocyte ratio is a readily available biomarker that could improve pre treatment prognostication and may be used for risk-stratification. PMID- 30400970 TI - Recommendations for the design of small population clinical trials. AB - BACKGROUND: Orphan drug development faces numerous challenges, including low disease prevalence, patient population heterogeneity, and strong presence of paediatric patient populations. Consequently, clinical trials for orphan drugs are often smaller than those of non-orphan drugs, and they require the development of efficient trial designs relevant to small populations to gain the most information from the available data. The International Rare Diseases Research Consortium (IRDiRC) is aimed at promoting international collaboration and advance rare diseases research worldwide, and has as one of its goals to contribute to 1000 new therapies for rare diseases. IRDiRC set up a Small Population Clinical Trials (SPCT) Task Force in order to address the shortcomings of our understanding in carrying out clinical trials in rare diseases. RESULTS: The IRDiRC SPCT Task Force met in March 2016 to discuss challenges faced in the design of small studies for rare diseases and present their recommendations, structured around six topics: different study methods/designs and their relation to different characteristics of medical conditions, adequate safety data, multi arm trial designs, decision analytic approaches and rational approaches to adjusting levels of evidence, extrapolation, and patients' engagement in study design. CONCLUSIONS: Recommendations have been issued based on discussions of the Small Population Clinical Trials Task Force that aim to contribute towards successful therapy development and clinical use. While randomised clinical trials are still considered the gold standard, it is recommended to systematically take into consideration alternative trial design options when studying treatments for a rare disease. Combining different sources of safety data is important to give a fuller picture of a therapy's safety profile. Multi-arm trials should be considered an opportunity for rare diseases therapy development, and funders are encouraged to support such trial design via international networks. Patient engagement is critical in trial design and therapy development, a process which sponsors are encouraged to incorporate when conducting trials and clinical studies. Input from multiple regulatory agencies is recommended early and throughout clinical development. Regulators are often supportive of new clinical trial designs, provided they are well thought through and justified, and they also welcome discussions and questions on this topic. Parallel advice for multiregional development programs should also be considered. PMID- 30400972 TI - Knowledge and utilization of family planning methods among people living with HIV in Kathmandu, Nepal. AB - BACKGROUND: Addressing family planning (FP) needs of people living with HIV is an effective response to HIV prevention. Healthy timing and spacing of births help ensure the health and well-being of all women and infants, regardless of their HIV-infection. In addition, preventing unintended pregnancies is an important strategy for prevention of mother to child transmission of HIV. The main purpose of this study was to explore the knowledge of family planning methods and identify factors affecting the utilization of such methods among HIV infected men and women attending two Anti-Retroviral Therapy (ART) sites of Kathmandu, Nepal. METHODS: This was a descriptive cross-sectional study. Two ART sites of Kathmandu were purposively chosen and a sample of 265 respondents (both men and women) was selected based on proportionate probability random sampling. A structured questionnaire was administered face to face to all of the eligible participants. RESULTS: The mean +/- SD age of the participants was 36.62 +/- 7.58 years. Sixty five percent of the respondents' spouses were HIV positive. A majority of the respondents (72%) had heard of seven modern family planning methods. Considerably high number (72%) of the respondents or their spouses were using at least one of the method of family planning. The most common method was condom (83%) and the least common was IUCD (0.50%). The use of short acting (pills, depo-provera) and long acting (implant, IUCD) family planning methods other than condom dropped from 56.6 to 2% after diagnosis. Utilization of family planning methods was significantly associated with gender, education and HIV status of spouse. Males (Adjusted Odds Ratio (AOR) = 2.48, 95% CI = 1.20-5.07, p = 0.01) educated respondents (AOR = 3.27, 95% CI = 1.41-7.54, p = < 0.01) and individuals whose spouse were not infected with HIV (AOR = 4.70, 95% CI = 1.41-15.67, p = 0.01) were more likely to use FP methods. CONCLUSION: The tendency for HIV infected men and women to avoid additional child bearing in Nepal is higher compared to sub Saharan Africa. However, the use of effective methods of family planning is low. Therefore, more effective counselling sessions by service providers regarding the availability and use of alternative family planning methods besides condom is necessary. PMID- 30400971 TI - Progressive resistance training in cachectic head and neck cancer patients undergoing radiotherapy: a randomized controlled pilot feasibility trial. AB - BACKGROUND: Cancer cachexia is a prevalent symptom of head and neck neoplasms. The reduction in skeletal muscle mass is one of the main characteristics which can lead to poor physical functioning. The purposes of this pilot randomized controlled trial were to determine the feasibility of progressive resistance training in cachectic head and neck cancer patients during radiotherapy and to explore possible risks and benefits. METHODS: Twenty cachectic participants with head and neck cancer receiving radiation were randomized to obtain either a machine supported progressive resistance training (n = 10) or usual care (n = 10). The training took place 3 times weekly for 30 min. Intervention included 3 exercises for major muscle groups with 8-12 repetition maximum for 3 sets each. Bioelectrical impedance analysis, hand-held dynamometry, Six-Minute Walk Test and standardized questionnaires for fatigue and quality of life were used for evaluating outcomes at baseline before radiotherapy (t1), after 7 weeks of radiotherapy (t2) and 8 weeks after the end of radiotherapy (t3). RESULTS: All participants (n = 20) completed the trial. No serious adverse events occurred. At the initial assessment the cachectic patients had already lost 7.1 +/- 5.2% of their body weight. General fatigue (score 10.7 +/- 3.3) and reduced quality of life (score 71.3 +/- 20.6) were prevalent in cachectic head and neck cancer patients even before radiotherapy. An average improvement of weight loading for leg press (+ 19.0%), chest press (+ 29.8%) and latissimus pull-down (+ 22.8%) was possible in the intervention group. Participants had at least 13 training sessions. The outcome measures showed nonsignificant changes at t2 and t3, but a trend for a better course of general fatigue and quality of life at t2 in the intervention group. CONCLUSIONS: Despite advanced tumor stage and burdensome treatment the intervention adherence is excellent. Progressive resistance training in cachectic head and neck cancer patients during radiotherapy seems to be safe and feasible and may have beneficial effects of general fatigue and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03524755 . Registered 15 May 2018 - Retrospectively registered. PMID- 30400973 TI - Knee pain as a predictor of structural progression over 4 years: data from the Osteoarthritis Initiative, a prospective cohort study. AB - BACKGROUND: There is evidence that knee pain not only is a consequence of structural deterioration in osteoarthritis (OA) but also contributes to structural progression. Clarifying this is important because targeting the factors related to knee pain may offer a clinical approach for slowing the progression of knee OA. The aim of this study was to examine whether knee pain over 1 year predicted cartilage volume loss, incidence and progression of radiographic osteoarthritis (ROA) over 4 years. METHODS: Osteoarthritis Initiative participants with no ROA (Kellgren-Lawrence grade <= 1) (n = 2120) and with ROA (Kellgren-Lawrence grade > 2) (n = 2249) were examined. Knee pain was assessed at baseline and 1 year using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Knee pain patterns were categorised as no pain (WOMAC pain < 5 at baseline and 1 year), fluctuating pain (WOMAC pain > 5 at either time point) and persistent pain (WOMAC pain > 5 at both time points). Cartilage volume, incidence and progression of ROA were assessed using magnetic resonance imaging and x-rays at baseline and 4-years. RESULTS: In both non-ROA and ROA, greater baseline WOMAC knee pain score was associated with increased medial and lateral cartilage volume loss (p <= 0.001), incidence (OR 1.07, 95% CI 1.01-1.13) and progression (OR 1.07, 95% CI 1.03-1.10) of ROA. Non-ROA and ROA participants with fluctuating and persistent knee pain had increased cartilage volume loss compared with those with no pain (p for trend <= 0.01). Non-ROA participants with fluctuating knee pain had increased risk of incident ROA (OR 1.62, 95% CI 1.04-2.54), corresponding to a number needed to harm of 19.5. In ROA the risk of progressive ROA increased in participants with persistent knee pain (OR 1.82, 95% CI 1.28-2.60), corresponding to a number needed to harm of 9.6. CONCLUSIONS: Knee pain over 1 year predicted accelerated cartilage volume loss and increased risk of incident and progressive ROA. Early management of knee pain and controlling knee pain over time by targeting the underlying mechanisms may be important for preserving knee structure and reducing the burden of knee OA. PMID- 30400974 TI - Measures that increase social equality are effective in improving life satisfaction in times of economic crisis. AB - BACKGROUND: The financial crisis of 2008/2009, for some also in 2011, was accompanied by increasing social inequality and unemployment, which strained the welfare generosity systems in many countries. Welfare generosity redistributes internal resources to decrease poverty and increase equal opportunities. This was used by many countries to combat the crisis. We investigated the effects of increased social inequality, unemployment and welfare generosity on life satisfaction (LS) before and after the crisis. METHODS: A representative sample from the European Social Survey (2002 to 2014) with data from 26 countries was used (N = 301,559). Time from start of crisis (either 2008 or 2010-2012) was determined separately for each case. LS was measured with a single question with 11 response alternatives. Social inequality was measured using the Gini index. Unemployment was measured by a single question (No/Yes). Welfare generosity was measured using expenditure on social protection (PPS) per inhabitant (Eurostat). Data were analyzed by multilevel analysis and multilevel mediation analysis. RESULTS: Welfare generosity was associated with decreased levels of social inequality. The negative relationship between social inequality and LS was weakened when controlling for welfare generosity after the financial crisis. This effect of welfare generosity was not seen for the negative impact of unemployment on LS. CONCLUSION: The financial crisis stimulated the use of welfare generosity in Europe and strengthened the positive relationship between welfare generosity and LS. Social inequality, unemployment and welfare generosity played significant mediator roles between the crisis and LS, with increased welfare generosity far more strongly associated with increased LS. Measures that increase social equality in a country and thereby increase equal opportunity for all social classes, may be assumed to be effective in improving the general LS of the population in a country in times of economic crisis. PMID- 30400975 TI - The inflammatory response in the regression of lumbar disc herniation. AB - Lumbar disc herniation (LDH) is highly associated with inflammation in the context of low back pain. Currently, inflammation is associated with adverse symptoms related to the stimulation of nerve fibers that may lead to pain. However, inflammation has also been indicated as the main factor responsible for LDH regression. This apparent controversy places inflammation as a good prognostic indicator of spontaneous regression of LDH. This review addresses the molecular and cellular mechanisms involved in LDH regression, including matrix remodeling and neovascularization, in the scope of the clinical decision on conservative versus surgical intervention. Based on the evidence, a special focus on the inflammatory response in the LDH context is given, particularly in the monocyte/macrophage role. The phenomenon of spontaneous regression of LDH, extensively reported in the literature, is therefore analyzed here under the perspective of the modulatory role of inflammation. PMID- 30400976 TI - Insights into malaria transmission among Anopheles funestus mosquitoes, Kenya. AB - BACKGROUND: Most malaria vectors belong to species complexes. Sibling species often exhibit divergent behaviors dictating the measures that can be deployed effectively in their control. Despite the importance of the Anopheles funestus complex in malaria transmission in sub-Saharan Africa, sibling species have rarely been identified in the past and their vectoring potential remains understudied. METHODS: We analyzed 1149 wild-caught An. funestus (senso lato) specimens from 21 sites in Kenya, covering the major malaria endemic areas including western, central and coastal areas. Indoor and outdoor collection tools were used targeting host-seeking and resting mosquitoes. The identity of sibling species, infection with malaria Plasmodium parasites, and the host blood meal sources of engorged specimens were analyzed using PCR-based and sequencing methods. RESULTS: The most abundant sibling species collected in all study sites were Anopheles funestus (59.8%) and Anopheles rivulorum (32.4%) among the 1062 successfully amplified specimens of the An. funestus complex. Proportionally, An. funestus dominated in indoor collections whilst An. rivulorum dominated in outdoor collections. Other species identified were Anopheles leesoni (4.6%), Anopheles parensis (2.4%), Anopheles vaneedeni (0.1%) and for the first time in Kenya, Anopheles longipalpis C (0.7%). Anopheles funestus had an overall Plasmodium infection rate of 9.7% (62/636), predominantly Plasmodium falciparum (59), with two infected with Plasmodium ovale and one with Plasmodium malariae. There was no difference in the infection rate between indoor and outdoor collections. Out of 344 An. rivulorum, only one carried P. falciparum. We also detected P. falciparum infection in two non-blood-fed An. longipalpis C (2/7) which is the first record for this species in Kenya. The mean human blood indices for An. funestus and An. rivulorum were 68% (93/136) and 64% (45/70), respectively, with feeding tendencies on a broad host range including humans and domestic animals such as cow, goat, sheep, chicken and pig. CONCLUSIONS: Our findings underscore the importance of active surveillance through application of molecular approaches to unravel novel parasite-vector associations possibly contributed by cryptic species with important implications for effective malaria control and elimination. PMID- 30400977 TI - Safety and efficacy of applying sufficient analgesia combined with a minimal sedation program as an early antihypertensive treatment for spontaneous intracerebral hemorrhage: a randomized controlled trial. AB - BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) is a serious threat to human health. Although early blood pressure (BP) elevation is closely associated with a poor prognosis, the optimal antihypertensive regimen for acute-phase ICH remains controversial. In ICH, pain, sleep deprivation, and stress are usually the main causes of dramatic BP increases. While traditional antihypertensive treatment resolves the increased BP, it does not address the root cause of the disease. Remifentanil relieves pain and, when combined with dexmedetomidine's antisympathetic action, can restore elevated BP to normal levels. Here, we seek to validate the efficacy and safety of applying sufficient analgesia in combination with a minimal sedation program versus antihypertensive drug therapy for the early and rapid stabilization of BP in ICH patients. METHODS/DESIGN: We are conducting a multicenter, prospective, randomized controlled, single-blinded, superiority clinical trial across 15 hospitals. We will enroll 354 subjects in mainland China, and all subjects will be randomized into experimental and control groups in which they will be given remifentanil combined with dexmedetomidine or antihypertensive drugs (urapidil, nicardipine, and labetalol). The primary endpoint will be the systolic BP control rate within 1 h of treatment initiation, and the efficacy and safety of the antihypertensive regimens will be compared between the two groups. Secondary endpoints include the incidence rate of early hemorrhage growth, neurological function, duration of intensive care unit (ICU) stay, and staff satisfaction with the treatment process. DISCUSSION: We hypothesize that applying sufficient analgesia in combination with minimal sedation will act as an effective and safe antihypertensive strategy in ICH and that this treatment strategy could, therefore, be widely used as an ICH acute phase therapy. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03207100 . Registered on 22 July 2017. PMID- 30400978 TI - Advice from the health insurer as a channelling strategy: a natural experiment at a Dutch health insurance company. AB - BACKGROUND: In a health care system based on managed competition it is important that health insurers are able to channel their enrolees to preferred care providers. However, enrolees are often very negative about financial incentives and any limitations in their choice of care provider. Therefore, a Dutch health insurance company conducted an experiment to study the effectiveness of a new method of channelling their enrolees. This method entails giving enrolees advise on which physiotherapists to choose when they call customer service. Offering this advice as an extra service is supposed to improve service quality ratings. Objective of this study is to evaluate this channelling method on effectiveness and the impact on service quality ratings. METHODS: In this experiment, one of the health insurer's customer service call teams (pilot team) began advising enrolees on their choice of physiotherapist. Three data sources were used. Firstly, all enrolees who called customer service received an online questionnaire in order to measure their evaluation of the quality of service. Enrolees who were offered advice received a slightly different questionnaire which, in addition, asked about whether they intended to follow the advice they were offered. Multilevel regression analysis was conducted to analyse the difference in service quality ratings between the pilot team and two comparable customer service teams before and after the implementation of the channelling method. Secondly, employees logged each call, registering, if they offered advice, whether the enrolee accepted it, and if so, which care provider was advised. Thirdly, data from the insurance claims were used to see if enrolees visited the recommended physiotherapist. RESULTS: The results of the questionnaire show that enrolees responded favorably to being offered advice on the choice of physiotherapist. Furthermore, 45% of enrolees who received advice and then went on to visit a care provider, followed the advice. The service quality ratings were higher compared to control groups. However, it could not be determined whether this effect was entirely due to the intervention. CONCLUSIONS: Channelling enrolees towards preferred care providers by offering advice on their choice of care provider when they call customer service is successful. The effect on service quality seems positive, although a causal relationship could not be determined. PMID- 30400980 TI - Prevalence and antimicrobial susceptibility pattern of Enterococcus species isolated from different clinical samples at Black Lion Specialized Teaching Hospital, Addis Ababa, Ethiopia. AB - OBJECTIVE: Enterococci which are parts of the normal intestinal flora are opportunistic human pathogens. Their increasing importance is largely due to their resistance to antimicrobials. So the aim this study was to determine the prevalence and antimicrobial pattern of Enterococcus spp. RESULT: From the total of 422 samples processed, 15 Enterococcus species were isolated. In this study, linezolid were the drug of choice for Enterococcus species, which showed 100% sensitive followed by vancomycin 93.3% sensitive. In contrast, highly resistance (80%) was observed for ampicillin followed by doxycycline (73.3%). All of isolated Enterococci were sensitive to linezolid, however, resistance was observed to common antibiotics. The presence of multidrug resistant Enterococci in our study should be considered as an alarm for Enterococcal infections. PMID- 30400979 TI - Prevalence of nasal colonization by methicillin-resistant Staphylococcus aureus in outpatients living with HIV/AIDS in a Referential Hospital of the Northeast of Brazil. AB - OBJECTIVE: The purpose of this study is to investigate the prevalence of MRSA among people living with HIV/AIDS (PLHA) being monitored in a tertiary outpatient hospital in the state of Pernambuco, in the Brazilian Northeast. RESULTS: Staphylococcus aureus was isolated from a nasal swab and found in 31.4% of the individuals (95% CI 27.3-35.5), of whom 4.4% (95% CI 8.5-19.5) were MRSA, as confirmed by the presence of the mecA gene. For individuals whose S. aureus was recovered, the mean age was 41.5 years; 93.6% were on antiretroviral treatment. This group had CD4 cell counts > 200 (92%) and viral load <= 100 copies (79.1%). Use of antimicrobial agents in the past 12 months was found among 21% of the individuals, and 24.2% reported use of illicit drugs at lease once in their lifetime. Prevalence of nasal colonization by MSSA (26.7%) and MRSA (4.4%) was higher in comparison to other studies of this population; nevertheless, we were unable to establish factors associated with risk. PMID- 30400981 TI - Progress in research on the role of circular RNAs in lung cancer. AB - BACKGROUND: Circular RNA (circRNA), as a covalently closed circular RNA molecule, is widely present, which is recognized as a competing endogenous RNA. A large number of differentially expressed circRNAs have been identified and are recognized as potential biomarkers for the diagnosis of tumors. MAIN BODY: CircRNAs play an important role in the regulation of cell signaling pathways. The main biological functions of circRNAs include acting as miRNA sponges, regulating the transcription of the parental genes, and acting as adapters to regulate the interactions between proteins and encoding proteins. Compared with normal tissues, there are differentially expressed circRNAs in lung cancer tissue, and the expression levels of circRNAs are correlated with clinicopathological features of lung cancer. Their roles in pathway regulation are described, and the diagnostic and prognostic values are further evaluated. CONCLUSION: In lung cancer, circRNAs participate in the proliferation, migration, and invasion, acting as a competitive endogenous RNA. Differentially expressed circRNAs may serve as non-invasive diagnostic markers for lung cancers. Further investigation of the roles of circRNAs in the pathogenesis and regulatory pathways is conducive to the development of novel approaches for the diagnosis and accurate treatment of lung cancers. PMID- 30400982 TI - Intrauterine fetal deaths related to antiphospholipid syndrome: a descriptive study of 65 women. AB - OBJECTIVE: Although one of the three obstetric manifestations of antiphospholipid syndrome (APS) is intrauterine fetal death (IUFD), little is known about it in this context. We report the first large series of patients with APS and IUFD. METHODS: We retrospectively analyzed the history and clinical data of women at four French hospitals. All had (1) APS diagnosis (Sydney criteria) and (2) IUFD at or after 10 weeks of gestation (weeks) between 2000 and 2016. RESULTS: The study included 65 women. Their median age at the index IUFD was 29 years (IQR 26 33); 38 (58%) were primigravidas. The index IUFD was the first APS clinical manifestation in 48 women (74%). Overall, 35% had a triple-positive antibody profile. IUFD occurred at a median gestational age of 24 weeks (IQR 18-27) and was associated with maternal obstetric complications in 16 women (25%), namely, preeclampsia (n = 12), hemolysis, elevated liver enzymes, and low platelet syndrome (HELLP) (n = 6), and/or placental abruption (n = 5). Half of the 50 women with available data had a small-for-gestational-age fetus. Overall, including during the follow-up period of 4 years (IQR 2-9), 28 women (43%) had at least one thrombosis, and 29% were diagnosed with systemic lupus erythematosus (SLE). Ultimately, 54 women (83%) had at least one live birth. Only one woman had three consecutive early miscarriages. CONCLUSION: IUFD was most often the inaugural sign of APS. Of the APS classification criteria, IUFD, preeclampsia, and thromboses were common in this cohort, while the "3 consecutive early miscarriages" criterion was met only once. With treatment, most of the women successfully had at least one live birth. PMID- 30400983 TI - Zoonotic Cryptosporidium species and subtypes in lambs and goat kids in Algeria. AB - BACKGROUND: Little is known on the occurrence and identity of Cryptosporidium species in sheep and goats in Algeria. This study aimed at investigating the occurrence of Cryptosporidium species in lambs and goat kids younger than 4 weeks. METHODS: A total of 154 fecal samples (62 from lambs and 92 from kid goats) were collected from 13 sheep flocks in Medea, Algeria and 18 goat flocks across Algiers and Boumerdes. They were screened for Cryptosporidium spp. by nested-PCR analysis of a fragment of the small subunit (SSU) rRNA gene, followed by restriction fragment length polymorphism and sequence analyses to determine the Cryptosporidium species present. Cryptosporidium parvum and C. ubiquitum were further subtyped by sequence analysis of the 60 kDa glycoprotein gene. RESULTS: Cryptosporidium spp. were detected in 17 fecal samples (11.0%): 9 from lambs (14.5%) and 8 from goat kids (8.7%). The species identified included C. parvum in 3 lambs, C. xiaoi in 6 lambs and 6 goat kids, and C. ubiquitum in 2 goat kids. Cryptosporidium infections were detected mostly in animals during the first two weeks of life (7/8 for goat kids and 7/9 for lambs) and in association with diarrhea occurrence (7/17 or 41.2% goat kids and 7/10 or 70.0% lambs with diarrhea were positive for Cryptosporidium spp.). Subtyping of C. parvum and C. ubiquitum isolates identified the zoonotic IIaA13G2R1 and XIIa subtype families, respectively. Minor differences in the SSU rRNA gene sequences were observed between C. xiaoi from sheep and goats. CONCLUSIONS: Results of this study indicate that three Cryptosporidium species occur in lambs and goat kids in Algeria, including zoonotic C. parvum and C. ubiquitum. They are associated with the occurrence of neonatal diarrhea. PMID- 30400984 TI - Health related quality of life improvement in chronic non-specific neck pain: secondary analysis from a single blinded, randomized clinical trial. AB - BACKGROUND: Chronic non-specific neck pain is related to limited cervical mobility, impaired function, neck muscles myofascial pain syndrome, and stress at work. The aforementioned factors are strongly related and may lead to a negative impact on health-related quality of life. There are some effective conservative Physical therapy interventions for treating chronic non-specific neck pain. Currently, Deep Dry Needling is emerging as an alternative for improving symptoms and consequently, the quality of life in patients with chronic non-specific neck pain. The purpose of the study was to examine the effectiveness of Deep Dry Needling of myofascial trigger points on health-related quality of life improvement, as a secondary analysis, in people with chronic non-specific neck pain. METHODS: A randomized parallel-group blinded controlled clinical trial was conducted at a public Primary Health Care Centre in Madrid, Spain, from January 2011 to September 2014. One hundred thirty subjects with chronic non-specific neck pain and active myofascial trigger points in neck muscles were randomly allocated into two groups. Subjects in the intervention group (n = 65) were treated with Deep Dry Needling in active myofascial trigger points plus stretching in neck muscles; Control group (n = 65) received only stretching. Both interventions lasted 2 weeks, 2 sessions per week. Health-related quality of life was measured with Short Form-36 (SF-36), in 5 assessments: at baseline, after intervention period; and at 1, 3 and 6 months after intervention. RESULTS: For both groups, SF-36 mean values increased in all dimensions in every assessment. Significant differences (p < 0.05) were found in favor of the intervention group for all dimensions at the last assessment. For some dimensions (physical function, physical role, social function and vitality), the evidence was more consistent from the beginning. CONCLUSIONS: Deep Dry Needling plus stretching is more effective than stretching alone for Health-related quality of life improvement, especially for physical function, physical role, social function and vitality dimensions, in people with non-specific neck pain. TRIAL REGISTRATION: Current Controlled Trials ISRCTN22726482 . Registered 9 October 2011. PMID- 30400985 TI - Struggling for a feasible tool - the process of implementing a clinical pathway in intensive care: a grounded theory study. AB - BACKGROUND: Clinical pathways can enhance care quality, promote patient safety and optimize resource utilization. However, they are infrequently utilized in intensive care. This study aimed to explain the implementation process of a clinical pathway based on a bottom-up approach in an intensive care context. METHODS: The setting was an 11-bed general intensive care unit in Sweden. An action research project was conducted to implement a clinical pathway for patients on mechanical ventilation. The project was managed by a local interprofessional core group and was externally facilitated by two researchers. Grounded theory was used by the researchers to explain the implementation process. The sampling in the study was purposeful and theoretical and included registered nurses (n31), assistant nurses (n26), anesthesiologists (n11), a physiotherapist (n1), first- and second-line managers (n2), and health records from patients on mechanical ventilation (n136). Data were collected from 2011 to 2016 through questionnaires, repeated focus groups, individual interviews, logbooks/field notes and health records. Constant comparative analysis was conducted, including both qualitative data and descriptive statistics from the quantitative data. RESULTS: A conceptual model of the clinical pathway implementation process emerged, and a central phenomenon, which was conceptualized as 'Struggling for a feasible tool,' was the core category that linked all categories. The phenomenon evolved from the 'Triggers' ('Perceiving suboptimal practice' and 'Receiving external inspiration and support'), pervaded the 'Implementation process' ('Contextual circumstances,' 'Processual circumstances' and 'Negotiating to achieve progress'), and led to the process 'Output' ('Varying utilization' and 'Improvements in understanding and practice'). The categories included both facilitating and impeding factors that made the implementation process tentative and prolonged but also educational. CONCLUSIONS: The findings provide a novel understanding of a bottom-up implementation of a clinical pathway in an intensive care context. Despite resonating well with existing implementation frameworks/theories, the conceptual model further illuminates the complex interaction between different circumstances and negotiations and how this interplay has consequences for the implementation process and output. The findings advocate a bottom-up approach but also emphasize the need for strategic priority, interprofessional participation, skilled facilitators and further collaboration. PMID- 30400986 TI - Clinical utility of tumor genomic profiling in patients with high plasma circulating tumor DNA burden or metabolically active tumors. AB - BACKGROUND: This retrospective study was undertaken to determine if the plasma circulating tumor DNA (ctDNA) level and tumor biological features in patients with advanced solid tumors affected the detection of genomic alterations (GAs) by a plasma ctDNA assay. METHOD: Cell-free DNA (cfDNA) extracted from frozen plasma (N = 35) or fresh whole blood (N = 90) samples were subjected to a 62-gene hybrid capture-based next-generation sequencing assay FoundationACT. Concordance was analyzed for 51 matched FoundationACT and FoundationOne (tissue) cases. The maximum somatic allele frequency (MSAF) was used to estimate the amount of tumor fraction of cfDNA in each sample. The detection of GAs was correlated with the amount of cfDNA, MSAF, total tumor anatomic burden (dimensional sum), and total tumor metabolic burden (SUVmax sum) of the largest ten tumor lesions on PET/CT scans. RESULTS: FoundationACT detected GAs in 69 of 81 (85%) cases with MSAF > 0. Forty-two of 51 (82%) cases had >= 1 concordance GAs matched with FoundationOne, and 22 (52%) matched to the National Comprehensive Cancer Network (NCCN) recommended molecular targets. FoundationACT also detected 8 unique molecular targets, which changed the therapy in 7 (88%) patients who did not have tumor rebiopsy or sufficient tumor DNA for genomic profiling assay. In all samples (N = 81), GAs were detected in plasma cfDNA from cancer patients with high MSAF quantity (P = 0.0006) or high tumor metabolic burden (P = 0.0006) regardless of cfDNA quantity (P = 0.2362). CONCLUSION: This study supports the utility of using plasma-based genomic assays in cancer patients with high plasma MSAF level or high tumor metabolic burden. PMID- 30400987 TI - First report of natural Wolbachia infection in wild Anopheles funestus population in Senegal. AB - BACKGROUND: Until very recently, Anopheles were considered naturally unable to host Wolbachia, an intracellular bacterium regarded as a potential biological control tool. Their detection in field populations of Anopheles gambiae sensu lato, suggests that they may also be present in many more anopheline species than previously thought. RESULTS: Here, is reported the first discovery of natural Wolbachia infections in Anopheles funestus populations from Senegal, the second main malaria vector in Africa. Molecular phylogeny analysis based on the 16S rRNA gene revealed at least two Wolbachia genotypes which were named wAnfu-A and wAnfu B, according to their close relatedness to the A and B supergroups. Furthermore, both wAnfu genotypes displayed high proximity with wAnga sequences previously described from the An. gambiae complex, with only few nucleotide differences. However, the low prevalence of infection, together with the difficulties encountered for detection, whatever method used, highlights the need to develop an effective and sensitive Wolbachia screening method dedicated to anopheline. CONCLUSIONS: The discovery of natural Wolbachia infection in An. funestus, another major malaria vector, may overcome the main limitation of using a Wolbachia-based approach to control malaria through population suppression and/or replacement. PMID- 30400988 TI - Measurement of single kidney glomerular filtration rate in dogs using dynamic contrast-enhanced magnetic resonance imaging and the Rutland-Patlak plot technique. AB - BACKGROUND: Nephropathies are among the most common diseases in dogs. Regular examination of the kidney function plays an important role for an adequate treatment scheme. The determination of the glomerular filtration rate (GFR) is seen as the gold standard in assessing the kidney status. Most of the tests have the disadvantage that only the complete glomerular filtration rate of both kidneys can be assessed and not the single kidney glomerular filtration rate. Imaging examination techniques like dynamic contrast-enhanced magnetic resonance imaging have the potential to evaluate the single kidney GFR. There are studies in human medicine describing the determination of the single kidney GFR using this technique. To our knowledge there are no such studies for dogs. RESULTS: An exponential fit was found to describe the functional interrelation between signal intensity and contrast medium concentrations. The changes of contrast medium concentrations during the contrast medium bolus propagation were calculated. The extreme values of contrast medium concentrations in the kidneys were reached at nearly the same time in every individual dog (1st maximum aorta 8.5 s, 1st maximum in both kidneys after about 14.5 s; maximum concentration values varied between 17 and 125 umol/mL in the aorta and between 4 and 15 umol/mL in the kidneys). The glomerular filtration rate was calculated from the concentration changes of the contrast medium using a modified Rutland-Patlak plot technique. The GFR was 12.7 +/- 2.9 mL/min m2 BS for the left kidney and 12.0 +/- 2.2 mL/min/m2 BS for the right kidney. The mean values of the coefficient of determination of the regression lines were averagely 0.91 +/- 0.08. CONCLUSIONS: The propagation of contrast medium bolus could be depicted well. The contrast medium proceeded in a similar manner for every individual dog. Additionally, the evaluation of the single kidney function of the individual dogs is possible with this method. A standardized examination procedure would be recommended in order to minimize influencing parameters. PMID- 30400989 TI - Clinically important change in tinnitus sensation after stapedotomy. AB - BACKGROUND: When measuring the treatment effect in tinnitus with multi-item outcome instruments, it is crucial for both clinical and research purposes to take into consideration clinical importance of the outcome scores. The aim of the present study is to determine minimal important change (MIC) in tinnitus which is clinically meaningful to patients with otosclerosis. METHODS: The study population was 95 patients with otosclerosis, suffering from tinnitus. They completed the Tinnitus Functional Index before stapedotomy and 3 months after the surgery. The minimal important change was estimated with the Clinical Global Impression Scale as the external criterion (anchor). The mean change method and the receiver operating characteristic (ROC) method were used to determine minimal important change in tinnitus sensation. RESULTS: The improvement in tinnitus after stapedotomy was reported by 69.4% of the patients with otosclerosis. Minimal important change in tinnitus was estimated as reduction of 8.8 points in the Tinnitus Functional Index. CONCLUSIONS: The anchor-based approach using an external criterion (anchor) allows to determine change in tinnitus sensation which is meaningful to patients after stapedotomy. The value of 8.8 points in Tinnitus Functional Index could be used as benchmark of stapedotomy effectiveness in otosclerosis patients suffering from tinnitus. Hearing difficulties comorbid with tinnitus could affect the perception of tinnitus change. PMID- 30400991 TI - Haemoglobin, magnetic resonance imaging markers and cognition: a subsample of population-based study. AB - BACKGROUND: Low haemoglobin is highly prevalent among the elderly and has been associated with dementia. However, the mechanisms underlying this association with cognitive dysfunction, either through cerebrovascular disease or neurodegeneration, remain poorly understood. We aimed to examine the association of decreased haemoglobin levels with markers of cerebral small vessel disease (CSVD), neurodegeneration and cognitive impairment in an elderly Asian population. METHODS: A total of 796 Chinese, Malay and Indian participants aged 60 years and older from the Epidemiology of Dementia in Singapore study were included in this study. After providing information on demographics, anthropometry and cardiovascular risk factors, participants underwent 3-T brain magnetic resonance imaging (MRI) to measure markers of CSVD, including cerebral microbleeds, cortical cerebral microinfarcts, lacunes, enlarged perivascular spaces and white matter hyperintensities, as well as neurodegenerative markers, including cortical thickness and subcortical structure volumes quantified using FreeSurfer. Cognition was assessed using a detailed neuropsychological assessment. Logistic and linear regression models were constructed, adjusting for age, gender, education, race, body mass index, smoking, hypertension, hyperlipidaemia, diabetes, glomerular filtration rate and other MRI markers, to test the association between haemoglobin levels and the MRI markers and cognition. RESULTS: Decreased haemoglobin levels were associated with cerebral microbleeds, specifically lobar microbleeds (OR, 1.21; 95% CI, 1.04-1.40; p = 0.015). Decreased haemoglobin levels were also associated with occipital cortical thinning (mean difference, - 0.011; 95% CI, - 0.019, - 0.004; p = 0.003) and smaller accumbens volume (mean difference, - 0.01; 95% CI, - 0.02, 0.00; p = 0.005). A significant association was also observed between decreased haemoglobin levels and poorer global cognitive performance (mean difference, - 0.04; 95% CI, 0.09, 0.00; p = 0.048). In cognitive domain analysis, associations were again observed between decreased haemoglobin levels and worse performance on attention (mean difference, - 0.05; 95% CI, - 0.10, - 0.01; p = 0.028) and language (mean difference, - 0.06; 95% CI, - 0.12, 0.00; p = 0.048) domains; however, these associations did not survive multiple comparison. CONCLUSIONS: Decreased haemoglobin levels were associated with lobar microbleeds, neurodegenerative markers and cognitive dysfunction. Future studies should ascertain whether iron, folate or vitamin B12 supplementation is able to ameliorate the onset and progression of cognitive impairment and dementia associated with low haemoglobin. PMID- 30400990 TI - T cell epigenetic remodeling and accelerated epigenetic aging are linked to long term immune alterations in childhood cancer survivors. AB - BACKGROUND: Cancer treatments have substantially improved childhood cancer survival but are accompanied by long-term complications, notably chronic inflammatory diseases. We hypothesize that cancer treatments could lead to long term epigenetic changes in immune cells, resulting in increased prevalence of inflammatory diseases in cancer survivors. RESULTS: To test this hypothesis, we established the epigenetic and transcriptomic profiles of immune cells from 44 childhood cancer survivors (CCS, > 16 years old) on full remission (> 5 years) who had received chemotherapy alone or in combination with total body irradiation (TBI) and hematopoietic stem cell transplant (HSCT). We found that more than 10 years post-treatment, CCS treated with TBI/HSCT showed an altered DNA methylation signature in T cell, particularly at genes controlling immune and inflammatory processes and oxidative stress. DNA methylation remodeling in T cell was partially associated with chronic expression changes of nearby genes, increased frequency of type 1 cytokine-producing T cell, elevated systemic levels of these cytokines, and over-activation of related signaling pathways. Survivors exposed to TBI/HSCT were further characterized by an Epigenetic-Aging-Signature of T cell consistent with accelerated epigenetic aging. To investigate the potential contribution of irradiation to these changes, we established two cell culture models. We identified that radiation partially recapitulated the immune changes observed in survivors through a bystander effect that could be mediated by circulating factors. CONCLUSION: Cancer treatments, in particular TBI/HSCT, are associated with long-term immune disturbances. We propose that epigenetic remodeling of immune cells following cancer therapy augments inflammatory- and age-related diseases, including metabolic complications, in childhood cancer survivors. PMID- 30400992 TI - Assessment of upper limb use in children with typical development and neurodevelopmental disorders by inertial sensors: a systematic review. AB - Understanding development of bimanual upper limb (UL) activities in both typical and atypical conditions in children is important for: i) tailoring rehabilitation programs, ii) monitoring progress, iii) determining outcomes and iv) evaluating effectiveness of treatment/rehabilitation. Recent technological advances, such as wearable sensors, offer possibilities to perform standard medical monitoring. Body-worn motion sensors, mainly accelerometers, have shown very promising results but, so far, these studies have mainly focused on adults. The main aim of this review was to report the evidence of UL activity of both typically developing (TD) children and children with neurodevelopmental disorders (NDDs) that are reliably reported and comparable, using a combination of multiple wearable inertial sensors, both in laboratory and natural settings. Articles were selected from three research databases (PubMed, Web of Science and EBSCO). Included studies reported data on children aged 0-20 years old simultaneously wearing at least two inertial sensors on upper extremities. The collected and reported data were relevant in order to describe the amount of physical activity performed by the two ULs separately. A total of 21 articles were selected: 11 including TD, and 10 regarding NDDs. For each article, a review of both clinical and technical data was performed. We considered inertial sensors used for following aims: (i) to establish activity intensity cut-points; (ii) to investigate validity and reliability of specified markers, placement and/or number of inertial sensors; (iii) to evaluate duration and intensity of natural UL movements, defined motor tasks and tremor; and (iv) to assess efficacy of certain rehabilitation protocols. Our conclusions were that inertial sensors are able to detect differences in use between both hands and that all reviewed studies support use of accelerometers as an objective outcome measure, appropriate in assessing UL activity in young children with NDDs and determining intervention effectiveness. Further research on responsiveness to interventions and consistency with use in real-world settings is needed. This information could be useful in planning UL rehabilitation strategies. PMID- 30400994 TI - The impact of social support on the health-related quality of life of adult patients with tuberculosis in Harare, Zimbabwe: a cross-sectional survey. AB - OBJECTIVE: Tuberculosis (TB) is the second prime cause of mortality in Sub Saharan Africa and remains a major worldwide public health problem. Unfortunately, patients with TB are at risk of poor mental health. However, patients who receive an adequate amount of social support are likely to have improved health outcomes. The study was done to establish how social support influences the health-related quality of life (HRQoL) of patients with TB in Harare, Zimbabwe. Data were collected from 332 TB patients and were analysed through structural equation modelling. RESULTS: The mean age of the participants was 40.1 (SD 12.5) years and most were; males (53%), married (57.8%), educated (97.3%), unemployed (40.7%), stayed with family (74.4%), and reported of less than average levels of income (51.5%). Patients received the most significant amount of social support from the family. Patients also presented with lower HRQoL as they considerably reported of pain, anxiety and depression. The final model accounted for 68.8% of the variance. Despite methodological limitations, the study findings suggest that social support optimises patients' HRQoL. Based on the patients' responses, it was noted that patients presented with lower mental health, therefore, there is a need to develop and implement patient wellness interventions. PMID- 30400996 TI - Predominance of Brucella abortus antibodies among women with spontaneous abortion in the city of Mwanza: unrecognized link or coincidence? AB - OBJECTIVE: This study investigated the association of Brucella seropositivity and spontaneous abortions in human population in the city of Mwanza, Tanzania. RESULTS: A comparative cross sectional study which used 148 sera from women with spontaneous abortion and 250 sera from full-term delivered women was conducted in July 2017. Detection of Brucella abortus and Brucella melitensis antibodies was done using slide agglutination test. Data were analyzed using STATA version 13 software. The median age of the study participants was 25 (interquartile range 21 30) years. The overall seropositivity of Brucella antibodies was significantly higher among sera from women with spontaneous abortion than full term delivered women; (86/148, 58.1%: 95% CI 50-66 vs. 65/250, 26%: 95% CI 18-33, P < 0.001). Seropositivity of B. abortus was significantly higher among sera from women with spontaneous abortion than full-term delivered women (31.8% vs. 10.8%, P < 0.001). Women with abortion had 3.59 odds of being brucella seropositive compared to full term women (OR: 3.59, 95% CI; 2.25-5.74, P < 0.001). Seropositivity of Brucella antibodies is significantly higher among women with spontaneous abortion than full-term delivered women necessitating a need to investigate the relationship between Brucellosis and adverse pregnancy outcomes. PMID- 30400997 TI - Neuroticism and Somatic Complaints: Concomitant Effects of Rumination and Worry. AB - BACKGROUND: Neuroticism is associated with inflated somatic symptom reporting. Worry and rumination are a cognitive concomitant of neuroticism and potentially mediate the neuroticism-somatic complaint relationship. AIMS: The present study examined the degree to which worry and rumination mediated the relationship between neuroticism and somatic complaints. METHOD: A sample of 170 volunteers, recruited via convenience sampling, took part. Participants completed a series of self-report measures: the Eysenck Personality Questionnaire Revised-Short Form, Penn State Worry Questionnaire, the Ruminative Response Scale and the Somatic Symptom Scale-8. RESULTS: Analysis revealed significant positive correlations between neuroticism, rumination and worry. Neuroticism, rumination and worry also correlated positively with somatic complaints. Using structural equation modelling, a mediational model indicated that rumination fully mediated the relationship between neuroticism and somatic complaints. CONCLUSIONS: Findings are consistent with the symptom perception hypothesis and have implications for healthcare in terms of managing individuals who present with multiple somatic complaints. Future research would benefit from adopting a longitudinal approach to test how rumination interacts with neuroticism and somatic complaints over time. PMID- 30400995 TI - Evaluating interventions for informed consent for surgery (ICONS): Protocol for the development of a core outcome set. AB - BACKGROUND: The concept of informed consent is fundamental to medical practice. Shortcomings in the process can lead to patient complaints, litigation, unmet expectations and poor outcomes. Consent research has focused on developing tools to improve patient recall and understanding. However, the definitions, methods of measurement and timing of measurement vary widely across the studies that have been done. Although a Cochrane review has reported that many of these interventions appear to work, the high level of heterogeneity in outcome reporting prevents the identification of those interventions that work best and why they do so. It is also not clear which outcomes are most important to each party involved in the consent process and why. METHODS/DESIGN: This project will develop a core outcome set for assessing the effects of interventions aimed at improving informed consent for surgery and other invasive procedures for adult patients with the capacity to consent for themselves. We will conduct a systematic review of the qualitative and quantitative literature to identify outcomes used to date in consent research and map these into domains. A series of semi-structured key stakeholder interviews will also be used to identify relevant outcomes. These processes will produce a list of potential outcomes for assessing the effects of interventions to improve consent, which will be refined through an international Delphi survey and consensus webinars involving key stakeholders to produce the core outcome set. DISCUSSION: The ICONS study aims to develop a core outcome set for use in trials and reviews of interventions designed to improve the informed consent process for surgery and other invasive procedures. Our aim is that this core outcome set will reduce the level of selection and reporting bias in consent research and help clinicians to compare tools to improve consent. PMID- 30400998 TI - Consumption of non-digestible oligosaccharides elevates colonic alkaline phosphatase activity by up-regulating the expression of IAP-I, with increased mucins and microbial fermentation in rats fed a high-fat diet. AB - We have recently reported that soluble dietary fibre, glucomannan, increased colonic alkaline phosphatase (ALP) activity and the gene expression without affecting the small-intestinal activity and that colonic ALP was correlated with gut mucins (index of intestinal barrier function). We speculated that dietary fermentable carbohydrates including oligosaccharides commonly elevate colonic ALP and gene expression as well as increase mucin secretion and microbial fermentation. To test this hypothesis, male Sprague-Dawley rats were fed a diet containing 30 % lard with or without 4 % fructo-oligosaccharides (FOS), galacto oligosaccharides (GOS), raffinose (RAF) and lactulose (LAC), which are non digestible oligosaccharides or isomalto-oligosaccharides (IMOS; some digestible oligosaccharides) for 2 weeks. Colon ALP activity, the gene expression and gut luminal variables including mucins, organic acids and microbiota were measured. Colonic ALP was significantly elevated in the FOS, RAF and LAC groups, and a similar trend was observed in the GOS group. Colonic expression of intestinal alkaline phosphatase (IAP -I), an ALP gene, was significantly elevated in the FOS, GOS and RAF groups and tended to be increased in the LAC group. Dietary FOS, GOS, RAF and LAC significantly elevated faecal mucins, caecal n-butyrate and faecal ratio of Bifidobacterium spp. Dietary IMOS had no effect on colonic ALP, mucins, organic acids and microbiota. Colon ALP was correlated with mucins, caecal n-butyrate and faecal Bifidobacterium spp. This study demonstrated that non-digestible and fermentable oligosaccharides commonly elevate colonic ALP activity and the expression of IAP-I, with increasing mucins and microbial fermentation, which might be important for protection of gut epithelial homoeostasis. PMID- 30400993 TI - 5-HTR2A and 5-HTR3A but not 5-HTR1A antagonism impairs the cross-modal reactivation of deprived visual cortex in adulthood. AB - Visual cortical areas show enhanced tactile responses in blind individuals, resulting in improved behavioral performance. Induction of unilateral vision loss in adult mice, by monocular enucleation (ME), is a validated model for such cross modal brain plasticity. A delayed whisker-driven take-over of the medial monocular zone of the visual cortex is preceded by so-called unimodal plasticity, involving the potentiation of the spared-eye inputs in the binocular cortical territory. Full reactivation of the sensory-deprived contralateral visual cortex is accomplished by 7 weeks post-injury. Serotonin (5-HT) is known to modulate sensory information processing and integration, but its impact on cortical reorganization after sensory loss, remains largely unexplored. To address this issue, we assessed the involvement of 5-HT in ME-induced cross-modal plasticity and the 5-HT receptor (5-HTR) subtype used. We first focused on establishing the impact of ME on the total 5-HT concentration measured in the visual cortex and in the somatosensory barrel field. Next, the changes in expression as a function of post-ME recovery time of the monoamine transporter 2 (vMAT2), which loads 5-HT into presynaptic vesicles, and of the 5-HTR1A and 5-HTR3A were assessed, in order to link these temporal expression profiles to the different types of cortical plasticity induced by ME. In order to accurately pinpoint which 5-HTR exactly mediates ME-induced cross-modal plasticity, we pharmacologically antagonized the 5-HTR1A, 5-HTR2A and 5-HTR3A subtypes. This study reveals brain region-specific alterations in total 5-HT concentration, time-dependent modulations in vMAT2, 5 HTR1A and 5-HTR3A protein expression and 5-HTR antagonist-specific effects on the post-ME plasticity phenomena. Together, our results confirm a role for 5-HTR1A in the early phase of binocular visual cortex plasticity and suggest an involvement of 5-HTR2A and 5-HTR3A but not 5-HTR1A during the late cross-modal recruitment of the medial monocular visual cortex. These insights contribute to the general understanding of 5-HT function in cortical plasticity and may encourage the search for improved rehabilitation strategies to compensate for sensory loss. PMID- 30400999 TI - Lysozyme-rich milk mitigates effects of malnutrition in a pig model of malnutrition and infection. AB - Malnutrition remains a leading contributor to the morbidity and mortality of children under the age of 5 years and can weaken the immune system and increase the severity of concurrent infections. Livestock milk with the protective properties of human milk is a potential therapeutic to modulate intestinal microbiota and improve outcomes. The aim of this study was to develop an infection model of childhood malnutrition in the pig to investigate the clinical, intestinal and microbiota changes associated with malnutrition and enterotoxigenic Escherichia coli (ETEC) infection and to test the ability of goat milk and milk from genetically engineered goats expressing the antimicrobial human lysozyme (hLZ) milk to mitigate these effects. Pigs were weaned onto a protein-energy-restricted diet and after 3 weeks were supplemented daily with goat, hLZ or no milk for a further 2 weeks and then challenged with ETEC. The restricted diet enriched faecal microbiota in Proteobacteria as seen in stunted children. Before infection, hLZ milk supplementation improved barrier function and villous height to a greater extent than goat milk. Both goat and hLZ milk enriched for taxa (Ruminococcaceae) associated with weight gain. Post-ETEC infection, pigs supplemented with hLZ milk weighed more, had improved Z-scores, longer villi and showed more stable bacterial populations during ETEC challenge than both the goat and no milk groups. This model of childhood disease was developed to test the confounding effects of malnutrition and infection and demonstrated the potential use of hLZ goat milk to mitigate the impacts of malnutrition and infection. PMID- 30401000 TI - Reliability and validity of a Mediterranean diet and culinary index (MediCul) tool in an older population with mild cognitive impairment. AB - Dementia is a leading cause of morbidity and mortality without pharmacologic prevention or cure. Mounting evidence suggests that adherence to a Mediterranean dietary pattern may slow cognitive decline, and is important to characterise in at-risk cohorts. Thus, we determined the reliability and validity of the Mediterranean Diet and Culinary Index (MediCul), a new tool, among community dwelling individuals with mild cognitive impairment (MCI). A total of sixty-eight participants (66 % female) aged 75.9 (sd 6.6) years, from the Study of Mental and Resistance Training study MCI cohort, completed the fifty-item MediCul at two time points, followed by a 3-d food record (FR). MediCul test-retest reliability was assessed using intra-class correlation coefficients (ICC), Bland-Altman plots and kappa agreement within seventeen dietary element categories. Validity was assessed against the FR using the Bland-Altman method and nutrient trends across MediCul score tertiles. The mean MediCul score was 54.6/100.0, with few participants reaching thresholds for key Mediterranean foods. MediCul had very good test-retest reliability (ICC=0.93, 95 % CI 0.884, 0.954, P<0.0001) with fair to-almost-perfect agreement for classifying elements within the same category. Validity was moderate with no systematic bias between methods of measurement, according to the regression coefficient (y=-2.30+0.17x) (95 % CI -0.027, 0.358; P=0.091). MediCul over-estimated the mean FR score by 6 %, with limits of agreement being under- and over-estimated by 11 and 23 %, respectively. Nutrient trends were significantly associated with increased MediCul scoring, consistent with a Mediterranean pattern. MediCul provides reliable and moderately valid information about Mediterranean diet adherence among older individuals with MCI, with potential application in future studies assessing relationships between diet and cognitive function. PMID- 30401001 TI - Effect of long-term low-dose folic acid supplementation on degree of total homocysteine-lowering: major effect modifiers. AB - We sought to examine the potential modifiers in the association between long-term low-dose folic acid supplementation and the reduction of serum total homocysteine (tHcy) among hypertensive patients, using data from the China Stroke Primary Prevention Trial (CSPPT). This analysis included 16 867 participants who had complete data on tHcy measurements at both the baseline and exit visit. After a median treatment period of 4.5 years, folic acid treatment significantly reduced the tHcy levels by 1.6 MUmol/l (95 % CI 1.4, 1.8). More importantly, after adjustment for baseline tHcy and other important covariates, a greater degree of tHcy reduction was observed in certain subgroups: males, the methylenetetrahydrofolate reductase (MTHFR) 677TT genotype, higher baseline tHcy levels (>=12.5 (median) v. <12.5 MUmol/l), lower folate levels (<8.0 (median) v. >=8.0 ng/ml), estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2 (v. 60-<90 and >=90 ml/min per 1.73 m2), ever smokers and concomitant use of diuretics (P for all interactions <0.05). The degree of tHcy reduction associated with long-term folic acid supplementation can be significantly affected by sex, MTHFR C677T genotypes, baseline folate, tHcy, eGFR levels and smoking status. PMID- 30401002 TI - Modulation of aquaporin gene expression by n-3 long-chain PUFA lipid structures in white and brown adipose tissue from hamsters. AB - EPA (20 : 5n-3) and DHA (22 : 6n-3) fatty acids have weight-reducing properties with physiological activity depending on their molecular structure - that is, as TAG or ethyl esters (EE). Aquaporins (AQP) are membrane protein channels recognised as important players in fat metabolism, but their differential expression in white adipose tissue (WAT) and brown adipose tissue (BAT), as well as their modulation by dietary n-3 long-chain PUFA (LCPUFA) such as EPA and DHA, has never been investigated. In this study, the transcriptional profiles of AQP3, AQP5, AQP7 and selected lipid markers of WAT (subcutaneous and visceral) and BAT (interscapular) from hamsters fed diets containing n-3 LCPUFA in different lipid structures such as fish oil (FO, rich in EPA and DHA in the TAG form) and FO-EE (rich in EPA and DHA in the EE form) were used and compared with linseed oil (LSO) as the reference group. A clear effect of fat depot was observed for AQP3 and leptin (LEP), with the lowest values of mRNA found in BAT relative to WAT. The opposite occurred for PPARalpha. AQP7 was affected by diet, with FO-fed hamsters having higher mRNA levels compared with LSO-fed hamsters. The relative gene expression of AQP5, adiponectin (ADIPO), GLUT4 and PPARgamma was influenced by both fat tissue and diet. Taken together, our results revealed a differential expression profile of AQP and some markers of lipid metabolism in both WAT and BAT in response to feeding n-3 LCPUFA in two different structural formats: TAG v. EE. PMID- 30401003 TI - New cancer cases attributable to diet among adults aged 30-84 years in France in 2015. AB - This study aimed to estimate the number of new cancer cases attributable to diet among adults aged 30-84 years in France in 2015, where convincing or probable evidence of a causal association exists, and, in a secondary analysis, where at least limited but suggestive evidence of a causal association exists. Cancer cases attributable to diet were estimated assuming a 10-year latency period. Dietary intake data were obtained from the 2006 French National Nutrition and Health Survey. Counterfactual scenarios of dietary intake were based on dietary guidelines. Corresponding risk relation estimates were obtained from meta analyses, cohort studies and one case-control study. Cancer incidence data were obtained from the French Network of Cancer Registries. Nationally, unfavourable dietary habits led to 16 930 new cancer cases, representing 5.4 % of all new cancer cases. Low intake of fruit and dietary fibre was the largest contributor to this burden, being responsible for 4787 and 4389 new cancer cases, respectively. If this is expanded to dietary component and cancer pairs with at least limited but suggestive evidence of a causal association, 36 049 new cancer cases, representing 11.6 % of all new cancer cases, were estimated to be attributable to diet. These findings suggest that unfavourable dietary habits lead to a substantial number of new cancer cases in France; however, there is a large degree of uncertainty as to the number of cancers attributable to diet, including through indirect mechanisms such as obesity, and therefore additional research is needed to determine how diet affects cancer risk. PMID- 30401004 TI - 24-h severe energy restriction impairs postprandial glycaemic control in young, lean males. AB - Intermittent energy restriction (IER) involves short periods of severe energy restriction interspersed with periods of adequate energy intake, and can induce weight loss. Insulin sensitivity is impaired by short-term, complete energy restriction, but the effects of IER are not well known. In randomised order, fourteen lean men (age: 25 (sd 4) years; BMI: 24 (sd 2) kg/m2; body fat: 17 (4) %) consumed 24-h diets providing 100 % (10 441 (sd 812) kJ; energy balance (EB)) or 25 % (2622 (sd 204) kJ; energy restriction (ER)) of estimated energy requirements, followed by an oral glucose tolerance test (OGTT; 75 g of glucose drink) after fasting overnight. Plasma/serum glucose, insulin, NEFA, glucagon like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and fibroblast growth factor 21 (FGF21) were assessed before and after (0 h) each 24 h dietary intervention, and throughout the 2-h OGTT. Homoeostatic model assessment of insulin resistance (HOMA2-IR) assessed the fasted response and incremental AUC (iAUC) or total AUC (tAUC) were calculated during the OGTT. At 0 h, HOMA2-IR was 23 % lower after ER compared with EB (P<0.05). During the OGTT, serum glucose iAUC (P<0.001), serum insulin iAUC (P<0.05) and plasma NEFA tAUC (P<0.01) were greater during ER, but GLP-1 (P=0.161), GIP (P=0.473) and FGF21 (P=0.497) tAUC were similar between trials. These results demonstrate that severe energy restriction acutely impairs postprandial glycaemic control in lean men, despite reducing HOMA2-IR. Chronic intervention studies are required to elucidate the long-term effects of IER on indices of insulin sensitivity, particularly in the absence of weight loss. PMID- 30401005 TI - Vitamin E intake and risk of stroke: a meta-analysis. AB - Findings from observational studies on the associations between vitamin E intake and stroke risk remain controversial, and the dose-response relationship between vitamin E intake and risk of stroke remains to be determined. We conducted a meta analysis of prospective studies aiming to clarify the relationships between vitamin E intake and risk of stroke. Relevant studies were identified by searching online databases through to June 2018. We computed summary relative risks (RR) with corresponding 95 % CI. Among 3156 articles retrieved from online databases and relevant bibliographies, nine studies involving 3284 events and 220 371 participants were included in the final analyses. High dietary vitamin E intake was inversely associated with the risk of overall stroke (RR=0.83, 95 % CI 0.73, 0.94), and with the risk of stroke for individuals who were followed-up for <10 (RR=0.84, 95 % CI 0.72, 0.91). There was a non-linear association between dietary vitamin E intake and stroke risk (P=0.0249). Omission of any single study did not alter the summary result. In conclusion, this meta-analysis suggests that there is a significant inverse relationship between dietary vitamin E intake and stroke risk. This meta-analysis provides evidence that a higher dietary vitamin E intake is associated with a lower stroke risk. PMID- 30401006 TI - Energy restriction in renal protection. AB - Energy restriction (ER) has been widely studied as a novel intervention, and its ability to prolong life has been fully demonstrated. For example, ER can significantly extend the lifespans of model flies, worms, rodents and other mammals. The role of ER in renal protection has also been elucidated. In preclinical studies, adjusting total energy intake or consumption of specific nutrients has prophylactic or therapeutic effects on ageing-related kidney disease and acute and chronic kidney injury. Amino acid restriction has gradually attracted attention. ER mimetics have also been studied in depth. The protective mechanisms of ER and ER mimetics for renal injury include increasing AMP activated protein kinase and sirtuin type 1 (Sirt1) levels and autophagy and reducing mammalian target of rapamycin, inflammation and oxidative stress. However, the renal protective effect of ER has mostly been investigated in rodent models, and the role of ER in patients cannot be determined due to the lack of large randomised controlled trials. To protect the kidney, the mechanism of ER must be thoroughly researched, and more accurate diet or drug interventions need to be identified. PMID- 30401007 TI - Mediterranean diet and its components in relation to all-cause mortality: meta analysis. AB - The beneficial association of the Mediterranean diet (MedDiet) with longevity has been consistently demonstrated, but the associations of MedDiet components have not been accordingly evaluated. We performed an updated meta-analysis of prospective cohort studies published up to 31 December 2017, to quantify the association of adherence to MedDiet, expressed as an index/score (MDS) and of its components with all-cause mortality. We estimated summary relative risks (SRR) and 95 % CI using random effects models. On the basis of thirty studies (225 600 deaths), SRR for the study-specific highest/lowest and per 1sd MDS increment were 0.79 (95 % CI 0.77, 0.81, Iota 2=42 %, P-heterogeneity 0.02) and 0.92 (95 % CI 0.90, 0.94, Iota 2 56 %, P-heterogeneity <0.01), respectively. Inversely, statistically significant associations were evident in stratified analyses by country, MDS range and publication year, with some evidence for heterogeneity across countries overall (P-heterogeneity 0.011), as well as across European countries (P=0.018). Regarding MDS components, relatively stronger and statistically significant inverse associations were highlighted for moderate/none excessive alcohol consumption (0.86, 95 % CI 0.77, 0.97) and for above/below-the median consumptions of fruit (0.88, 95 % CI 0.83, 0.94) and vegetables (0.94, 95 % CI 0.89, 0.98), whereas a positive association was apparent for above/below-the median intake of meat (1.07, 95 % CI 1.01, 1.13). Our meta-analyses confirm the inverse association of MedDiet with mortality and highlight the dietary components that influence mostly this association. Our results are important for better understanding the role of MedDiet in health and proposing dietary changes to effectively increase adherence to this healthy dietary pattern. PMID- 30401008 TI - The potential anti-inflammatory role of adiponectin in food allergy: a case control study on children. AB - We aimed to assess the possible relationship between food allergy and two key adipokines - leptin and adiponectin - in children with food allergy. A total of forty patients with definite diagnosis of food allergy according to clinical history and specific IgE (sIgE) for food allergens (group I) were enrolled in this pilot study. The control group (group II) included thirty children with no evidence of allergic symptoms. Serum levels of leptin and adiponectin were measured by ELISA. Meanwhile, sIgE was measured for the eight most common food allergens by the immunoblot method in all participants. The median ages in groups I and II were 18.5 and 23.5 months, respectively. The respective Caesarean section rate was 64.9 and 16.7 % in groups I and II (P<0.001). Serum levels of adiponectin were significantly higher in the patient group compared with controls (24.11 (sd 12.14) v. 10.67 (sd 12.23) MUg/ml, P<0.001), whereas no statistically meaningful difference was detected in serum leptin concentrations (P=0.92). There was a significant inverse relationship between age and adiponectin levels in group I (P=0.002, r -0.479) and group II (P=0.04, r -0.365), and it was more significant in group I. The most common allergens in the patient group were wheat (52.5 %), hazelnut (52.5 %), cow's milk (50 %) and egg white (30 %). The results of this study suggest an essential link between adiponectin and food allergy that is probably unlikely to be affected by obesity as a confounding factor. PMID- 30401009 TI - Creating a web-based electronic tool to aid tuberculosis (TB) cluster investigation: data integration in TB surveillance activities in the United Kingdom, 2013 to 2016. AB - Molecular technology to identify relatedness between Mycobacterium tuberculosis complex isolates, representative of possible tuberculosis (TB) transmission between individuals, continues to evolve. At the same time, tools to utilise this information for public health action to improve TB control should also be implemented. Public Health England developed the Strain Typing Module (STM) as an integral part of the web-based surveillance system used in the United Kingdom following the roll-out of prospective 24 loci mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) strain typing. The creation of such a system required data integration and linkage, bringing together laboratory results and patient notification information. The STM facilitated widespread access to patient strain typing and clustering results for the public health community working in TB control. In addition, the system provided a log of cluster review and investigation decision making and results. Automated real-time data linkage between laboratory and notification data are essential to allow routine use of genotyping results in TB surveillance and control. Outputs must be accessible by those working in TB control at a local level to have any impact in ongoing public health activity. PMID- 30401010 TI - Characterisation of HIV-1 transmission clusters and drug-resistant mutations in Denmark, 2004 to 2016. AB - This study describes the prevalence of human immunodeficiency virus (HIV) drug resistance mutations among 1,815 patients in Denmark from 2004 to 2016 and characterises transmission clusters. POL sequences were analysed for subtype, drug resistance mutations and phylogenetic relationship. The prevalence of surveillance drug resistance mutations (SDRM) was 6.7%, while the prevalence of drug resistance mutations (DRM) with a clinical impact was 12.3%. We identified 197 transmission clusters with 706 patients. Patients 40 years or older were less likely to be members of a transmission cluster and patients in transmission clusters were less likely to be infected abroad. The proportion of late presenters (LP) was lower in active compared with inactive clusters. Large active clusters consisted of more men who have sex with men (MSM), had members more frequently infected in Denmark and contained a significantly lower proportion of LP and significantly fewer patients with DRM than small active clusters. Subtyping demonstrated that the Danish HIV epidemic is gradually becoming more composed of non-B subtypes/circulating recombinant forms. This study shows that active HIV-1 transmission has become increasingly MSM-dominated and that the recent increase in SDRM and DRM prevalence is not associated with more sustained transmission within identified transmission networks or clusters. PMID- 30401011 TI - Addendum for Euro Surveill. 2018;23(10). PMID- 30401012 TI - An unusual outbreak of norovirus associated with a Halloween-themed swimming pool party in England, 2016. AB - In October 2016, an outbreak of norovirus occurred among attendees of a Halloween themed party at a public swimming pool in the south-east of England. Norovirus genogroup II was confirmed in 11 cases. In the retrospective cohort study of pool users, 68 individuals (37 female and 31 male), with a median age of 11 years (range: 0-50 years), met the case definition of developing diarrhoea or vomiting between 6 and 72 h after the pool visit. Multivariable analysis showed that increasing age was associated with a reduced risk of illness (odds ratio = 0.91; 95% confidence interval: 0.83-0.99). Pool behaviours (swallowing water) and the timing of visit (attending pool party after automatic dosing system was switched off) were independently associated with increased risk. Environmental investigations revealed that the automatic dosing system was switched off to reduce chlorine levels to an intended range of 0.5-1 parts per million to facilitate the use of a commercial red dye. There was a lack of compliance with the operator's own pool operating procedures, particularly on maintaining effective chlorine levels in pool water, recording of test results and recording of actions undertaken. This outbreak highlights the risks of lowering chlorine levels when using pool water colourants. PMID- 30401013 TI - Upsurge in echovirus 30 detections in five EU/EEA countries, April to September, 2018. AB - An upsurge in Echovirus 30 (E30) infections, associated with meningitis/meningoencephalitis, has been observed in Denmark, Germany, the Netherlands, Norway and Sweden in the period April to September 2018, compared with 2015-2017. In total, 658 E30 infections among 4,537 enterovirus infections were detected in 15 countries between January and September 2018 and affected mainly newborns and 26-45 year-olds. National public health institutes are reminded to remain vigilant and inform clinicians of the ongoing epidemic. PMID- 30401015 TI - Prophylactic Antibiotics in Implant-Based Breast Reconstruction. PMID- 30401014 TI - A Giant Fibroepithelial Polyp of the Small Bowel Associated with High-Grade Obstruction. PMID- 30401018 TI - Temporal Factors Drive Motorcycle Collision-Related Trauma. PMID- 30401025 TI - An Update on the Use of Temporary Intravascular Shunting in the Era of Balanced Blood Product Resuscitation. PMID- 30401019 TI - Neoadjuvant Capecitabine Results in Similar Total Lymph Node Harvests as 5 Fluorouracil but an Increased Number of Lymph Nodes Containing Adenocarcinoma on Resection. PMID- 30401030 TI - Violence Against Women: Facial Fractures Secondary to Assault in the Urban Female Population. PMID- 30401026 TI - Stapled Transanal Rectal Resection Procedure with Two Different Devices: Comparative Results. PMID- 30401034 TI - Multi-Disciplinary Approach after Blunt Polytrauma. PMID- 30401032 TI - The Treatment of Triple Negative Breast Cancer: Does Insurance Status Matter? PMID- 30401035 TI - Psychiatric Comorbidities and Outcomes in Trauma Patients: Is There a Significant Difference? PMID- 30401036 TI - Traumatic Deaths during the Functional Years: Working Toward Sustainable Prevention. PMID- 30401037 TI - The Influence of Breast Density on the Utility of MarginProbe in Partial Mastectomy. PMID- 30401038 TI - Perforated Sigmoid Diverticulitis Resulting in Subcutaneous Abscess. PMID- 30401039 TI - Obstructive Uropathy Secondary to an Indirect Extraperitoneal Ureteral Inguinal Hernia. PMID- 30401041 TI - Predictive Value of the Initial Trauma Survey: Is Our Hunch Good Enough? PMID- 30401043 TI - Resident Accuracy in Performing Extended Focused Assessment with Sonography in Trauma for Trauma: Not as Good as We Think We Are? PMID- 30401046 TI - Repair of Vascular Stretch Injury to Distal Femoral Artery after Femur Fracture. PMID- 30401047 TI - Surgical Management of Traumatic Ballistic Injury to the Breast. PMID- 30401050 TI - Recurrent Small Bowel Obstruction Caused by Metastatic Cervical Cancer with Negative PAP Screening. PMID- 30401051 TI - Mucinous Eccrine Carcinoma of the Sweat Glands: Characteristics, Treatment, and Survival Outcomes of a Rare Malignancy. PMID- 30401052 TI - Reverse Malrotation: An Uncommon Presentation of Abdominal Pain. PMID- 30401066 TI - Validation of an Autoclave Procedure for Sterilization of Mouse (Mus musculus) Carcasses. AB - The sterilization of potentially infectious animal carcasses is an important biologic safety issue in animal facilities operatingas infection or quarantine barriers. However, the literature lacks a validated protocol. Here we describe the validation of anautoclave program suitable for daily use in a small rodent biocontainment unit. We evaluated several procedures for processing mouse carcasses in a standard autoclave. Heat sensors and biologic indicators were implanted inside the peritoneal cavity of dead mice, which were loaded at various densities into IVC cages or metal boxes. Heat sensors revealed broad differencesin temperature inside carcasses compared with the autoclave chamber. Achieving the appropriate sterilization temperaturewas considerably prolonged in carcasses compared with typical laboratory waste material. We show that for 5 cadavers placedwell separated inside an IVC, a modified program for mouse cage sterilization using 134 degrees C for 15 min is suitable. To sterilizeapproximately 1 kg of carcasses in autoclavable boxes, a period of 6 h is required to reach an effective temperature of 121 degrees Cfor 60 min at the center of the waste by using an autoclave program for liquids. In conclusion, we here validated 2 protocolsfor the sterilization of potentially infectious mouse carcasses, to ensure the application of efficacious procedures. PMID- 30401085 TI - Traumatic Epidural Hematoma: Patient Characteristics and Management. PMID- 30401096 TI - Development and Validation of an Affordable, Nonperishable Suturing Simulator. PMID- 30401097 TI - Single-Center Experience with Subvesical Bile Ducts (Ducts of Luschka). PMID- 30401098 TI - Infrarenal Infected Aneurysm of Abdominal Aorta Caused by Clostridium Perfringens. PMID- 30401099 TI - Incidence of and Risk Factors for Incisional Hernia after Liver Surgery Performed with a J-Shaped Right Subcostal Incision. PMID- 30401100 TI - Missile Embolism to the Pulmonary Artery. PMID- 30401102 TI - Asymptomatic Metastatic Carcinoid Tumor Discovered by Routine Screening Mammography. PMID- 30401103 TI - Is Neoadjuvant Radiotherapy Alone a Good Alternative to Neoadjuvant Chemoradiotherapy in Patients with Low Performance Status? PMID- 30401104 TI - Implementation of a Trauma Activation Checklist. PMID- 30401106 TI - Damage Control Vascular Surgery for the General Surgeon. PMID- 30401105 TI - Wound Breakdown with Stratafix versus Monocryl Suture in Aesthetic and Reconstructive Plastic Surgery: Data from a Single Surgeon. PMID- 30401107 TI - Caught in Limbo: The Effect of ICU Boarding Time on Overall Hospital Length of Stay in Trauma Patients. PMID- 30401108 TI - A Surgical "Chimera": The Gallbladder Volvulus in the Spigelian Hernia Sac. PMID- 30401109 TI - Triple Positive Breast Cancer in a Male with Cardiac Disease. PMID- 30401110 TI - The Incidence of Severe Dysphagia after Odontoid Fracture. PMID- 30401111 TI - Needle Break: Complication and Management of Intraosseous Vascular Access. PMID- 30401112 TI - Factors Associated with Treatment Failure after an Index Episode of Acute Diverticulitis. PMID- 30401113 TI - Cardiac Tamponade from Coronary Artery Injury after Laparoscopic Anti-Reflux Surgery. PMID- 30401114 TI - Giant Pseudocysts of the Spleen: A Rare Sequela of Traumatic Splenic Injury. PMID- 30401115 TI - A Radiologically Detected Intraperitoneal Foreign Body in a Patient Without Prior Surgery. PMID- 30401116 TI - Cholecystotomy with Stone Retrieval: A Novel Approach for the Management of Gallstone Ileus. PMID- 30401117 TI - The Management of Patients with Colorectal Cancer and Synchronous Liver Metastases or Indeterminate Liver Lesions: A Community Teaching Hospital Experience. PMID- 30401118 TI - Atypical Vascular Breast Masses. PMID- 30401147 TI - Novel Repair of Grynfeltt Hernia Using Self-Fixating Mesh. PMID- 30401148 TI - Mucormycosis Infection Following Trauma. PMID- 30401150 TI - Acute Extremity Compartment Syndrome Secondary to Statin-Induced Myopathy. PMID- 30401149 TI - Angiosarcoma of the Breast: A Rare and Dismal Complication of Breast Surgery Associated with Radiation. PMID- 30401151 TI - Misplaced Central Venous Catheter or Persistent Left Superior Vena Cava? PMID- 30401152 TI - Classification of Nonocclusive Mesenteric Ischemia Based on the Trigger for the Disease. PMID- 30401153 TI - Increasing Body Mass Index Predicts Wound Complications after Elective Endovascular Abdominal Aortic Aneurysm Repair. PMID- 30401154 TI - Sustainability of NSQIP-Driven Protocol Changes at a Single Institution. PMID- 30401155 TI - Solitary Fibrous Tumors of the Pleura: Current Diagnostic Tools. PMID- 30401156 TI - 10-Year Analysis of Benign Ovarian Teratomas: Outcomes and Follow-Up. PMID- 30401157 TI - Acute Scrotal Edema in Cirrhotic after Laparoscopic Cholecystectomy. PMID- 30401158 TI - Paget's Disease of the Breast: An Institutional Review and Surgical Management. PMID- 30401159 TI - High-Frequency Oscillatory Ventilation (HFOV) as Primary Ventilator Strategy in the Management of Severe Acute Respiratory Distress Syndrome (ARDS) with Pneumothorax in the Setting of Trauma. PMID- 30401160 TI - Renal Function Does Not Deteriorate after Elective Digestive Surgery in Severe Chronic Kidney Disease Patients in the Predialysis State. PMID- 30401161 TI - Postoperative Central Anticholinergic Syndrome: Is it Really that Rare? PMID- 30401216 TI - High-Frequency Oscillatory Ventilation (HFOV) as Primary Ventilator Strategy in the Management of Severe Acute Respiratory Distress Syndrome (ARDS) with Pneumothorax in the Setting of Trauma. PMID- 30401217 TI - Penetrating Traumatic Laceration of Common Hepatic Artery and Portal Vein: A Rare Story of Success. PMID- 30401218 TI - Resident Duty Hours and American Board of Surgery In-Training Examination Performance. PMID- 30401219 TI - Mediastinal Aortopulmonary Paraganglioma. PMID- 30401221 TI - Multisystem Trauma: How Bad Can It Get? PMID- 30401220 TI - Polysubstance-Induced Self-Enucleation after Motor Vehicle Collision. PMID- 30401222 TI - Overreliance on Standardized Protocols: A Pilot Study of Surgical Residents and Fellows. PMID- 30401223 TI - Joint Inguinal and Femoral Hernia Repair by a Preperitoneal Laparoscopic Approach, Using a Femoral Plug and a Supra-Infrafunicular Mesh Fitted to the Spermatic Cord. PMID- 30401224 TI - Pediatric Pedestrians and Bicyclists versus Motor Vehicle Accidents: Comparison of Injury Patterns by Mechanism and Influence of Socioeconomic Status. PMID- 30401227 TI - Use of a Gastroduodenal Tube to Preserve the Common Wall during Excision of a Gastric Duplication. PMID- 30401225 TI - A Metastatic Rectal Gastrointestinal Stromal Tumor to the Small Bowel Mesentery Treated with Neoadjuvant Imatinib and Debulking Surgery Followed by Low Anterior Resection. PMID- 30401226 TI - Howard Atwood Kelly: Man of Science, Man of God. PMID- 30401228 TI - Penetrating Chest Trauma and Pericarditis. PMID- 30401229 TI - Tying Sutures in Single-Port Laparoscopy. PMID- 30401257 TI - The Impact of Gender on Complications and Outcomes of Pelvic Fracture. PMID- 30401258 TI - Native Americans Have an Increased Risk of Major Bile Duct Injury during Laparoscopic Cholecystectomy: Results from a Statewide Analysis. PMID- 30401259 TI - Management of Recurrent Invasive Ductal Carcinoma in Transrectus Abdominis Myocutaneous Flap and Lymphatic Remodeling to the Contralateral Axilla. PMID- 30401260 TI - Upregulation of CA 19-9 in Complicated Cholecystitis. PMID- 30401261 TI - Vicarious Contrast Excretion with Prolonged Retention Causing Biliary Colic. PMID- 30401262 TI - Retroversus Implantation of a Situs Solitus Deceased Donor Liver into a Situs Inversus Totalis Recipient. PMID- 30401263 TI - Continuous Abdominal Irrigation for Treatment of Tertiary Peritonitis in the Immunosuppressed Patient after Solid Organ Transplant: A Novel Approach. PMID- 30401264 TI - Hyponatremia on Initial Presentation Correlates with Suboptimal Outcomes after Traumatic Brain Injury. PMID- 30401265 TI - Damage Control Surgery and the Management of a Cholecystocolic Fistula. PMID- 30401266 TI - Intussusception in the Adult Population: A Challenge to Surgeons. PMID- 30401267 TI - The Changing Epidemiology of Diverticulitis in the United States. PMID- 30401268 TI - Robert Reynolds Macintosh, M.D. (1897-1989): Forefather of Anesthesiology, Advocate for Patient Safety. PMID- 30401269 TI - Gallbladder Polyps in Children: A Painful Inflammatory Process. PMID- 30401271 TI - A Case of Ingested Dental Prosthesis with Sharp Clasps Successfully Removed Through Anus Using Part of a Plastic Glove. PMID- 30401270 TI - Vascular Complications in Pediatric Port Removal. PMID- 30401286 TI - Understanding ACGME Scholarly Activity Requirements for General Surgery Programs in the Era of Single Accreditation and the Next Accreditation System. AB - Becoming compliant with the Accreditation Council for Graduate Medical Education (ACGME) requirements for scholarly activity and remaining compliant over time requires time and attention to the development of an environment of inquiry, which is reflected in detailed documentation submitted in program applications and annual updates. Since the beginning of the next accreditation system, all ACGME programs have been required to submit evidence of scholarly activity of both residents and faculty on an annual basis. Since 2014, American Osteopathic Association-accredited programs have been able to apply for ACGME accreditation under the Single Graduate Medical Education Accreditation initiative. The Residency Program Director, Chair, Designated Institutional Official, Faculty, and coordinator need to work cohesively to ensure compliance with all program requirements, including scholarly activity in order for American Osteopathic Association-accredited programs to receive Initial ACGME Accreditation and for current ACGME-accredited programs to maintain accreditation. Fortunately, there are many ways to show the type of scholarly activity that is required for the training of surgeons. In this article, we will review the ACGME General Surgery Program Requirements and definitions of scholarly activity. We will also offer suggestions for how programs may show evidence of scholarly activity. PMID- 30401315 TI - Response to Letter. PMID- 30401317 TI - Atopic dermatitis: A disease "More common in families that sneeze and wheeze". PMID- 30401318 TI - The burden of atopic dermatitis. AB - Background: Atopic dermatitis (AD) is a dermatologic condition that affects a large percentage of children and adults in the United States. The disease process is not fully understood, and, currently, there is no cure, so today's treatment methodologies focus on the rash and the symptoms, e.g., pruritus. Even though there is no mortality with this condition, there is significant morbidity and burden. Objective: This review concentrated on several areas in which AD influences quality of life. The areas include sleep, interference with daily activities (e.g., school and/or work), psychological stressors, and the impact on parents and caregivers. The direct and indirect costs of AD are also examined. Methods: A medical literature search was conducted that focused on quality of life (QOL), health-related quality of life, and costs in patients with AD. Results: AD caused poor QOL as assessed in both generic and specific QOL questionnaires. Skin pain was frequently experienced in this condition, which worsens QOL. A significant effect on sleep was found in multiple studies. A large amount of school and/or work absenteeism and psychological stressors was seen in patients with AD. Multiple burdens of the caregivers and parents of patients with AD were documented. Medical costs were also significantly higher compared with patients without AD. Conclusion: The impact of AD is likely more significant than previously acknowledged. AD results in significant morbidity as seen through generic and specific QOL questionnaires, sleep studies, and other questionnaires that measure psychological effects. Physicians should consider evaluating patients with AD beyond their rash and symptoms to achieve the best care possible. PMID- 30401319 TI - Severe atopic dermatitis: Therapeutic update. AB - Background: Atopic dermatitis (AD) is a common inflammatory skin disorder with a multitude of highly characterized comorbidities that affect infants, children, and adults worldwide. Despite its high prevalence and health burden, our armamentarium to treat AD in its severe form has remained lacking. For decades, the only Food and Drug Administration approved systemic treatment options for AD had been limited to corticosteroids. Methods: We conducted a nonsystematic review of the new and emerging drugs for the treatment of AD. Results: The recent emergence of dupilumab, a monoclonal antibody that selectively inhibits the type 2 cytokines that are integral to the pathogenesis of AD has provided dermatologists and allergists with a safe and effective targeted therapy to manage patients with moderate-to-severe disease. Numerous other drugs, both topical and systemic, are currently in development for the treatment of AD and have shown promise in their early phase trials. These agents include monoclonal antibodies that target various mediators relevant for a type 2 immune response, small-molecule inhibitors that block signaling through the Janus kinase pathway, and other agents that are aimed at addressing the symptomatology of itch. Conclusion: When anticipating the successful development and release of these drugs in the near future, it will be imperative for providers to review the available data, including the efficacy and adverse effects profile of each agent to determine the best treatment approach for each individual patient with AD. PMID- 30401320 TI - The effect of preoperative penicillin allergy testing on perioperative non-beta lactam antibiotic use: A systematic review and meta-analysis. AB - Background: The majority of patients for elective surgery and with a history of penicillin allergy are placed on alternative prophylactic antibiotic therapies, which have been associated with the emergence of multidrug-resistant pathogens and increased morbidity and mortality rates. However, self-reporting of penicillin allergy alone may overestimate the prevalence of penicillin allergy in the population. Objective: To assess the effects of preoperative antibiotic allergy testing protocols in reducing the use of non-beta-lactam antibiotics. Methods: We searched medical literature data bases through July of 2018. Two reviewers independently extracted data from published studies and assessed the risk of bias in cohort studies by using the Newcastle-Ottawa Scale. We collected information related to study design, methodology, demographics, interventions, and outcomes. We pooled odds ratios for the rate of prescribing non-beta-lactam antibiotics by using a fixed-effects model. Results: Of 905 citations screened for eligibility, nine studies met inclusion criteria for qualitative analysis. Studies reported that the rates of non-beta-lactam use after preoperative skin testing ranged from 6 to 30%. In addition, four of the nine studies had sufficient control data to be included in a meta-analysis. These four studies found that preoperative testing protocols significantly decreased the rates of prescribing non-beta-lactam antibiotics compared with usual care (odds ratio 3.64 [95% confidence interval, 2.67-4.98]; p < 0.0001). Seven studies reported on adverse drug reactions after preoperative skin testing and found that the rate of such reactions was rare. Conclusion: Preoperative antibiotic allergy testing protocols seemed to be a safe and effective tool in reducing the use of non-beta lactam antibiotics during surgery. PMID- 30401321 TI - Assessment of atopic dermatitis as a risk factor for chronic spontaneous urticaria in a pediatric population. AB - Background: Atopic dermatitis (AD) and chronic spontaneous urticaria (CSU) represent two of the most common chronic inflammatory pruritic skin diseases. Any relationship between atopic skin disorders and CSU is controversial, mostly due to the paucity of relevant epidemiologic and pathogenetic data. Objective: To evaluate whether a history of AD in early childhood represents a risk factor for the subsequent occurrence of CSU in a pediatric population. Methods: Retrospective data of new cases of patients who visited the outpatient allergy unit of a tertiary pediatric hospital in Athens, Greece, between June 2014 and August 2016, were analyzed. Diagnoses of CSU and AD were based on diagnostic criteria proposed by the European Academy of Allergy and Clinical Immunology and the Hanifin and Rajka criteria, respectively. The data analyzed included CSU and AD diagnoses and the association with gender and season of birth as well as a personal and family history of allergy-related diseases (e.g., asthma, allergic rhinitis, AD, and food and drug allergies). Results: Records from 2261 children were included in the analysis (1365 boys; mean +/- standard deviation [SD] age, 8.7 +/- 5.8 years). Fifty-one children (31 boys; mean +/- SD age, 9.1 +/- 4.6 years) were diagnosed with CSU, whereas AD was reported in 761 children (466 boys; mean +/- SD age, 5.2 +/- 3.8 years). Multivariate data analysis showed that the children with a history of an early diagnosis of AD were at increased risk for later CSU occurrence (odds ratio 2.923 [95% confidence interval, 1.647 5.189], p < 0.001). No significant associations were observed with respect to other demographic and atopy-associated characteristics of the patients. Conclusion: Results of our study indicated that AD may constitute an important risk factor to the subsequent occurrence of CSU. This notion warrants further study with well-designed prospective cohorts. PMID- 30401322 TI - Challenges in managing patients referred for eosinophilic esophagitis: A telephone survey and retrospective review. AB - Background: Eosinophilic esophagitis (EoE) in patients referred to allergists can be difficult to manage. This is due to multiple factors, including overlaps in presentation with gastroesophageal reflux disease and proton-pump inhibitor responsive eosinophilia, remaining uncertainties regarding the role of different forms of allergy testing, and a variety of patient adherence issues. Objective: To highlight, in an objectively studied fashion, complications that can be faced when managing patients referred for EoE. Methods: We conducted a telephone survey of 78 patients (pediatric and adult) who were referred to our academic allergy clinic for EoE. The survey focused on patients' perspectives regarding their symptoms and treatments. We then conducted a chart review to determine if there had been a proton-pump inhibitor (PPI) trial before diagnosis, and we compared patient responses with documented allergy test results, treatment plans, and biopsy results. Results: Only 22 of 78 patients (28%) had a >=8-week PPI trial before diagnosis and/or referral. There was considerable variability in the type of allergy testing done for patients, and how the results were used to guide therapy. More than one-third of the patients reported being on a different treatment regimen (PPI, swallowed steroid, and/or diet) than planned, and the majority of patients on dietary therapy reported being on a different diet than planned. Also, nearly half of the adult patients did not have follow-up biopsies done despite recommendations for this. Conclusion: We identified several challenges in EoE management, including potential misdiagnosis or overtreatment, lack of standardization in testing and dietary recommendations, and patient adherence issues. We hope this information will prompt increased vigilance for these issues and promote solutions when needed. PMID- 30401323 TI - Correlation of negative skin-prick test results for tree nuts and successful tree nut challenges among children with peanut allergy. AB - Background: Children with peanut allergy are regularly instructed to avoid all tree nuts. However, children with peanut allergy are likely not allergic to all tree nuts. Objective: In our cohort of patients with peanut anaphylaxis and who underwent oral immunotherapy, we sought to determine the correlation of skin prick testing (SPT) results for tree nuts and the likelihood of successfully passing a tree nut challenge. Methods: SPT was performed for peanut and tree nuts (macadamia, pine nut, coconut, hazelnut, brazil nut, cashew, pecan, walnut, pistachio, almond) in 27 patients with known peanut allergy. The probability of a negative SPT result (wheal < 3 mm) for each nut was determined. Results: All the patients demonstrated positive results in peanut allergy diagnostics in SPT, component testing, or food challenge. Only 15.4% of the patients had a positive SPT result to peanut alone. Macadamia, pine nut, and coconut SPT had a probability of negative SPT results of 0.97, 0.97, and 0.91, respectively. The odds ratio for this group having a negative SPT was 46.22. For hazelnut, brazil nut, and cashew, the probability of a negative SPT result was 0.81, 0.77, and 0.73, respectively. Pecan, walnut, and pistachio had odds ratios of 0.68, 0.68, and 0.64, respectively. All the patients with macadamia, pine nut, and coconut negative SPT results subsequently passed 9-g food challenges without oral immunotherapy. Conclusion: Despite current recommendations to avoid all tree nuts for patients with peanut allergy, the majority of patients with peanut allergy had negative SPTs and food challenges to certain tree nuts, especially macadamia, pine nut, and coconut. This pattern was seen despite most patients having multiple nut sensitizations. PMID- 30401324 TI - Pearls and pitfalls in the diagnosis of cough variant asthma. AB - Cough alone may sometimes be the sole presenting symptom of asthma. Patients experience cough without wheeze or shortness of breath and with normal baseline pulmonary function test results. These patients do, however, demonstrate bronchial hyperreactivity. They also respond to specific traditional asthma therapy. These patients are considered to have a specific asthma phenotype: cough variant asthma (CVA).In prospective studies of patients with chronic cough, an average of 25% have CVA. Patients have chronic cough, normal baseline pulmonary function tests, positive bronchial inhalation challenge results, and response to specific asthma therapy. What makes these patients cough is still unknown. The cough reflex is complex. The specific cause of cough in CVA may be similar to cough mechanisms seen in typical bronchial asthma.All therapies for typical bronchial asthma have been successful in controlling cough in patients with CVA. The overall prognosis of CVA is excellent, with most patients requiring chronic inhaled corticosteroid therapy. PMID- 30401325 TI - Generalized rash and pruritus in a 58-year-old woman. AB - Although allergists often evaluate rashes associated with allergic, IgE mediated etiologies, it is important to consider a wide range of differential diagnoses that includes inflammatory, infectious, and autoimmune etiologies. The case of a 58-year-old woman with a 1-year history of progressive pruritic rash that did not improve with topical creams and steroids is presented. The patient did not state any other symptoms, and a physical examination was notable for a widespread rash. After a detailed evaluation of the rash, a differential diagnosis was made, and results of a skin biopsy confirmed a specific diagnosis. Even in the context of a medical history of atopy, one must consider nonallergic causes of rash, including abnormal presentations of systemic conditions. It is important to determine the specific etiology of the rash because this will dictate treatment and prognosis and/or complications of the disease associated with the skin manifestations. PMID- 30401326 TI - For the Patient. PMID- 30401327 TI - Effect of indoor air quality on the development of rhinitis in an urban population in Poland. AB - Background: Indoor air significantly impacts the incidence of rhinitis among residents of urban agglomerations. Objective: To assess the impact of indoor air pollution on rhinitis. Methods: Data were collected by using an European Community Respiratory Health Survey (ECRHS) and International Study of Asthma and Allergies in Childhood (ISAAC) standardized questionnaires (N = 18,617), and medical examinations were carried out (N = 4783) in selected Polish regions. For statistical analysis, the odds ratio (OR) was calculated with a 95% confidence interval to detect factors associated with rhinitis. The Wald test was performed to assess the significance of those factors. A value of p < 0.05 was considered statistically significant. Results: The most important factors associated with allergic rhinitis declared by adults, ages 20-44 years were the following: the age of the buildings (OR 1.34), presence of central heating system (OR 1.19), gas furnace used to heat the house (OR 1.19), solid-fuel stove (OR 1.92), and bottled gas stove (OR 1.66). More frequent declarations of nonallergic rhinitis in the study group were associated with the use of a central heating system (children ages 6-7 years: OR 1.21; children ages 13-14 years: OR 1.22; and adults, ages 20 44 years: OR 1.27), solid-fuel stove (children ages 6-7 years: OR 2.95; children ages 13-14 years: OR 2.86; adults, ages 20-44 years: OR 2.02), and bottled-gas stove (children ages 6-7 years: OR 1.89; children ages 13-14 years: OR 1.88; adults, ages 20-44 years: OR 2.06). Diagnosed seasonal allergic rhinitis in adults, ages 20-44 years was associated with the year when the building was constructed (1970-1990) (OR 1.93) and the presence of a central heating system (OR 1.85). The year of construction of a building (1946-1969) (OR 4.84) as well as the use of central heating (OR 1.79) were causes of allergies to molds in the group of children ages 6-7 years, whereas sensitization to Dermatophagoides. pteronyssinus (OR 1.62) and Dermatophagoides farinae (OR 1.78) in children ages 6 7-years was associated with the presence of a central heating system. In children ages 13-14 years, the use of a solid-fuel stove was a cause of sensitization to D. farinae (OR 1.62). Conclusion: The age of the building, home heating systems, and pollution emitted by cooking appliances have a significant impact on the incidence of rhinitis. The highlights of the study included the following: (1) the age and condition of the building, the use of heating devices, stoves, and also mold allergens and house-dust mites contributed to a higher incidence of rhinitis, mainly among adults, ages 20-44 years; (2) gas-storage tanks and solid fuels contribute to rhinitis in the group of children ages 6-7 years and children ages 13-14 years. PMID- 30401328 TI - Early risk factors for cow's milk allergy in children in the first year of life. AB - Background: Cow's milk allergy (CMA) is a key form of food allergy (FA). It was shown that the frequency of FA seems to have increased during the past 10-20 years, which led to the thought that FA may have different risk factors. Epigenetic regulations and environmental pre- and postnatal factors play a large role in contributing to allergy. Understanding the risk factors that pertain to the development of FA may help to provide reasonable recommendations for prevention of the disease. Objective: To assess the impact of perinatal and environmental risk factors on the incidence of CMA in children in the first year of life. Methods: The study group consisted of 138 infants with CMA and 101 healthy infants without allergy. CMA was confirmed by an elimination test and oral food challenge. To assess infant, parental, and environmental risk factors, we used a validated questionnaire survey. Results: The incidence of CMA was three times higher in infants with a positive family history for allergy (p < 0.001). An analysis revealed that mothers of children with CMA were fourfold more frequently university educated than mothers of children without allergy (p < 0.0001). The ages of the mothers from the study group were significantly higher than the ages of the mothers from the control group. Children from the study group were breast-fed for a significantly shorter time than children from the control group. The risk of CMA was threefold lower in children who had pets at home (p = 0.0002). The risk of IgE-mediated CMA was twofold higher than the risk of non-IgE-mediated CMA if the family had more children (p = 0.04) and as many as ninefold higher if multiorgan symptoms were detected (p = 0.01). Conclusion: A positive family history of allergy and mother's education increased the risk of CMA in children in the first year of life, whereas having pets at home and a longer period of breast-feeding decreased the risk. PMID- 30401329 TI - Extrinsic warming of low-osmolality iodinated contrast media to 37 degrees C reduced the rate of allergic-like reaction. AB - Background: Although there is good evidence that warming of contrast media changes the bolus kinetics and injection pressure of iodinated contrast media, there has been little evidence that it affects clinical adverse event rates in a meaningful way. Objective: To determine whether the extrinsic warming of low osmolality iodinated contrast media to 37 degrees C reduced adverse reactions. Methods: Data on adverse reactions were collected from two cohorts, one of which used contrast media at room temperature and the other in which contrast media were warmed to 37 degrees C before administration. Adverse reactions, including allergic-like and physiological reactions, were reviewed. We compared the incidence rates of adverse reactions between the two cohorts by using the chi2 test. Results: A total of 70,446 injections in cohort 1 and 203,873 injections in cohort 2 were included. Extrinsic warming reduced the rate of allergic-like reactions to iopromide 370, iopamidol 370, and iohexol 350 (0.32% in cohort 1 versus 0.21% in cohort 2, p = 0.003; 0.14% versus 0.10%, p = 0.046; and 0.32% versus 0.13%, p = .003, respectively). However, the physiological reaction rates could not be reduced (p = 0.057, p = 0.107, and p = 0.962, respectively). The extrinsic warming of iopromide 300 could not reduce adverse reaction rates (allergic-like reaction rates: 0.21% versus 0.16%, p = 0.407; physiological reaction rates: 0.17% versus 0.13%, p = 0.504). Conclusion: Extrinsic warming to 37 degrees C before intravenous administration was associated with a reduction in the rate of allergic-like reactions to iopromide 370, iopamidol 370, and iohexol 350. PMID- 30401330 TI - Effect of indoor air quality on the natural history of asthma in an urban population in Poland. AB - Background: Indoor air pollution may have an impact on asthma. Objective: To evaluate the influence of indoor air pollution on the natural history of asthma. Methods: Data collection by using the European Community Respiratory Health Survey and International Study of Asthma and Allergies in Childhood standardized questionnaire (N = 18,617) and medical examinations (N = 4783) in selected Polish regions was used. Statistical analysis was performed by using the chi2 test. A value of p < 0.05 was considered statistically significant. Results: Questionnaire results demonstrated that people who used the central heating system were less likely to declare the occurrence of asthma (odds ratio [OR] 0.84) and were corroborated with clinical findings of moderate asthma (OR 0.35). Symptomatic asthma occurred more frequently in people who used a solid-fuel heating device (OR 1.36) and electric heaters (OR 1.54). The use of cooking appliances with municipal natural gas (OR 1.77) and gas storage tanks (OR 2.03) was correlated with more frequent declarations of asthma. Symptomatic asthma was more common among people who smoked for at least 1 year (OR 2.26) and those who smoked over the course of the preceding month (OR 1.60). Passive exposure to tobacco smoke provided for a 1.5-fold increase in the incidence of symptomatic asthma (OR 1.53), regardless of the time of exposure. Conclusion: Both active and passive tobacco smoke exposure as well as the use of certain types of heating and cooking appliances have a significant impact on the incidence of asthma and the intensification of its symptoms in rooms with limited air exchange. Highlights of the study included the following: (1) central heating had an amelioratory effect on asthma, (2) heating technologies used at home had a significant impact on the incidence of asthma, and (3) devices used for cooking (municipal and cylinder gas stoves) played an important role in the intensification of asthma symptoms. PMID- 30401342 TI - Implementation of a community pharmacy-based pre-exposure prophylaxis service: a novel model for pre-exposure prophylaxis care. AB - : Background National guidelines for the provision of HIV pre-exposure prophylaxis (PrEP) to reduce a person's risk of acquiring HIV were made available in 2014. We created a pharmacist-managed HIV PrEP clinic in a community pharmacy setting at Kelley-Ross Pharmacy in Seattle, WA, USA. METHODS: The clinic operates under a collaborative drug therapy agreement based on these guidelines. This allows pharmacists to initiate and manage tenofovir disoproxil fumarate/emtricitabine under the supervision of a physician medical director. RESULTS: Between March 2015 and February 2018, 714 patients were evaluated and 695 (97.3%) initiated PrEP. Five hundred and thirteen (74%) patients began medication the same day as their initial appointment. Of the prescriptions filled in our pharmacy, 90% of patients had a mean proportion of days covered (PDC) greater than 80%, and 98% had a zero-dollar patient responsibility per month, including uninsured individuals. 19% of patients were lost to follow up, with an effective drop-out rate of 25%. Two hundred and seven diagnoses of sexually transmissible infections were made. There were no HIV seroconversions in the service. CONCLUSION: The pharmacist-managed PrEP clinic proved to be a successful alternative model of PrEP care, with high initiation rates and low drop-out and lost-to-follow-up rates. This may benefit individuals who do not access PrEP in traditional health care settings or where PrEP access is scarce. Financial sustainability of the model was dependent on the ability of pharmacists in the clinic to bill insurance plans for their services in accordance with Washington State legislative changes requiring commercial insurances to recognise pharmacists as providers. PMID- 30401343 TI - Being Reproductive. AB - Women's reproductive health maintenance begins in the early years of growth and development. Routine care is the basis for early detection of menstrual dysfunction and delays or acceleration of physical development. Patients and their families may not address menstruation concerns because of the sensitive nature of the topic, the patient's self-conscious attitudes, and the parent's apprehension. Providers should be able to provide early detection of menstrual abnormalities, which may uncover underlying health concerns and structural abnormalities. Early intervention and treatment may accelerate or decelerate physical growth, preserve fertility, and promote healthy behaviors with decreased psychological stress for patients and families. PMID- 30401344 TI - Providing Abortion Services in the Primary Care Setting. AB - Patients commonly present with unintended pregnancy in the primary care setting, and 1 in 4 women has an abortion in her lifetime. Early abortion services can be safely provided in the primary care setting. Abortion options provided in primary care settings include both medication abortion and early uterine aspiration abortion. Medication abortion, provided up to 10 weeks' gestational age, includes mifepristone (a progestin antagonist) and misoprostol (a prostaglandin). Uterine aspiration can be provided via manual or electronic vacuum in the first trimester. PMID- 30401345 TI - Female Athlete Triad. AB - The female athlete triad is a condition seen in physically active female athletes, consisting of low energy availability, menstrual dysfunction, and low bone mineral density. The condition should be viewed as a metabolic injury. It can have an impact on female athletes at any age or level. Activities at highest risk are those emphasizing leanness, aesthetics, and endurance. The cornerstone of treatment is improving mismatched energy balance. A multidisciplinary team, including health care providers, dieticians, and mental health professionals, is vital in caring for female athlete triad patients. Increased awareness and education are needed for medical as well as athletic communities. PMID- 30401346 TI - Menopause. AB - The menopausal transition is a time when many physical and psychological changes are occurring for women. Women may experience irregular menses, vasomotor symptoms, sleep disruption, mood disorders as well as genitourinary symptoms. Despite irregular menstrual cycles, some women can still conceive. It is important to understand what is within normal physiologic changes and what may represent pathologic changes and how to further evaluate this. There are many options available to manage menopausal symptoms when they are impacting quality of life. PMID- 30401347 TI - Bone Health in Women. AB - Bone health is critical to overall health and quality of life. Although genetic factors play a key role in bone formation, there are several external factors that can be modified to preserve bone health. Diet, exercise, menstrual irregularities, medications, disease states, weight, and environmental factors can all affect fracture risk. Osteoporosis is characterized by decrease in bone mass and microarchitectural changes in the bone that increases fracture risk. Screening for osteoporosis may help facilitate treatment before fractures occur. Preventing fractures needs patient and physician understanding of bone health to improve and requires a team effort. PMID- 30401348 TI - Cancer Survivor Health Needs for Women. AB - As a result of better diagnostics and treatment of cancer, the number of survivors is on the rise. Health care needs for female cancer survivors encompass several domains that include surveillance, prevention, management of short/long term side effects of cancer, and cancer therapy. Primary care health providers (PCHPs) can play an important role in their health care. There is a need for PCHPs to acquire knowledge and understand the complexity involved in caring for this population. They also should be familiar with the guidelines for following cancer survivor patients. PMID- 30401349 TI - Women's Health and the Military. AB - Approximately 1.8 million American women are veterans of the Armed Services, and an additional 200,000 women are currently serving on active duty. With the increasing number of women in the military, there has been an increase in the number of women who have faced prolonged deployment in combat environments. This article discusses reproductive health concerns, family planning and contraceptive considerations, intimate partner violence and military sexual assault, posttraumatic stress disorder, and postdeployment health issues. It concludes with a list of available resources accessible to veterans and their providers. PMID- 30401350 TI - Best Practices in Transgender Health: A Clinician's Guide. AB - Providing culturally competent and medically knowledgeable care to the transgender community is increasingly falling within the realms of practice for primary care providers. The purpose of this article is to provide an overview of best practices as they relate to transgender care. This article is by no means a comprehensive guide, but rather a starting point for clinicians as they provide high-quality care to their transgender patients. PMID- 30401351 TI - Plastic Surgery for Women. AB - Plastic surgery is a broad field, including maxillofacial surgery, reconstruction after injuries, hand surgery, and skin flaps and grafts, but the most common procedures for women are liposuction and body contouring, breast surgery, and facial cosmetic procedures. Techniques of face and brow lifts, blepharoplasty, and rhinoplasty are discussed as well as botulinum toxin and filler injections, and laser and pulsed light techniques that may delay or eliminate the need for surgery. Comparison of the surgeries for breast reconstruction, reduction, augmentation, and mastopexy is discussed. New surgeries for enhancement of female genitalia are also examined. PMID- 30401352 TI - Integrative Health for Women. AB - Integrative Medicine is a model of health care that combines both conventional and unconventional therapies that serve the whole person and focus on prevention and whole health. Women are the highest utilizers of health care and Integrative Medicine for a variety of reasons. Integrative Medicine represents a more "female energy" in the field of medicine, which is needed even more today as health care moves toward value-based care and out of high-cost and high-harm care. Integrative Medicine can be incorporated into medical practice and into health workers' lives for wellness. PMID- 30401354 TI - Emerging Challenges and Opportunities in Women's Health. PMID- 30401353 TI - Medication-Assisted Treatment Considerations for Women with Opiate Addiction Disorders. AB - Opioid addiction rates are at a national high, with significant morbidity and mortality. In women, rates have been steadily increasing to be at par with addiction rates in men. Women tend to have quicker addiction and shorter duration to adverse outcomes. Treatment of women has the best outcomes when it is gender specific, trauma-informed, connected with access to psychiatric services, and integrated into the medical home. Improved outcomes can be achieved with coordinated systems of care based on the harm-reduction model, with integration of medication-assisted therapy in a patient-centered medical home. PMID- 30401355 TI - Optimizing Women's Health in Primary Care. PMID- 30401356 TI - Preface. PMID- 30401358 TI - Long-term Follow-up of Laparoscope-Assisted Living Donor Hepatectomy. AB - BACKGROUND: We have introduced and performed laparoscope-assisted surgery in living donor hepatectomy. The objective of this study was to investigate the long term results of laparoscope-assisted living donor hepatectomy. METHODS: From 2006 to 2016, laparoscope-assisted living donor hepatectomy was performed in 11 patients (laparoscopic group), and conventional open living donor hepatectomy was performed in 40 patients (conventional group). Intraoperative and postoperative complications were evaluated according to the Clavien-Dindo classification and analyzed in the laparoscopic group for comparison with the conventional group. RESULTS: The median postoperative follow-up period was 88 months (range, 58-120 months) in the laparoscopic group. One donor in the conventional group died from a motor vehicle crash 16 months after surgery. All others were alive and returned to their preoperative activity level. Regarding intraoperative and early (<=90 days after surgery) postoperative complications, 1 patient (1/11, 9%) showed biliary fistula (Grade IIIa) in the laparoscopic group. In the conventional group, 6 patients (6/40, 15%) showed surgical complications of Grade I in 2 patients and Grade II in 4 patients. Regarding late (>90 days after surgery) postoperative complications, biliary stricture was observed in 1 patient of the laparoscopic group; this patient developed hepatolithiasis 6 years after surgery, and endoscopic lithotomy and extracorporeal shockwave lithotripsy were performed, resulting in successful treatment. Late complications were not observed in the conventional group. CONCLUSION: One donor in the laparoscopic group showed Grade IIIa late complications. The introduction of laparoscopic surgery to living donor hepatectomy should be performed carefully. PMID- 30401357 TI - Impact of Smoking Cessation in Donor Candidates for Living Donor Liver Transplantation. AB - BACKGROUND: The relationship between smoking cessation and weight gain is well recognized. Examining the link between smoking cessation and weight gain in donor candidates for living donor liver transplantation (LDLT) is an important topic because of the influence of weight gain on the liver. This study assessed body weight (BW) changes after smoking cessation in donor candidates for LDLT. METHODS: The 27 donor candidates were retrospectively analyzed. The smoking status was determined based on questionnaires administered at the initial presentation, and the candidates were divided into 2 groups: recent quitters and nonsmokers. The changes in BW were compared between the groups. RESULTS: The recent quitters group included 10 (37.0%) candidates, and the nonsmokers group included 17 (63.0%). In the nonsmokers group, 1 candidate had gained weight since the initial presentation. In contrast, in the recent quitters group, 70.0% of candidates had gained weight since the initial presentation (P < .01). The change in BW from the initial presentation was greater in recent quitters than in nonsmokers (+1.6 kg [+2.4%] vs -0.5 kg [-0.9%]; P < .01). Two candidates in the recent quitters group gained >= 5 kg [8%] of weight. One of these 2 candidates was judged to be in a donor-inadequate status because of the appearance of fatty liver. CONCLUSIONS: Weight gain due to smoking cessation was observed in donor candidates for LDLT. The amount of weight gain after smoking cessation is highly individualized, so everyone concerned with LDLT must be alert to its potential development. PMID- 30401359 TI - Cost Analysis and Determinants of Living Donor Liver Transplantation in Taiwan. AB - BACKGROUND: Liver transplantation (LT) has become established therapy for end stage liver disease and small-cell hepatocellular carcinoma (HCC), relying mainly on living donor LT (LDLT) in Taiwan. The cost of LDLT varies in different countries depending on the insurance system, the costs of the facility, and staff. In this study we aimed to investigate cost outcomes and determinants of LDLT in Taiwan. METHODS: From January 2014 to December 2015, 184 LDLT patients were enrolled in a study performed at the Kaohsiung Chang Gung Memorial Hospital. Patients' transplantation costs were defined as expense from immediately after surgery to discharge during hospitalization for LDLT. Antiviral therapy and hepatitis B immunoglobulin (HBIG) for prevention of hepatitis B virus (HBV) were included, but direct-acting antiviral (DAA) therapy for hepatitis C (HCV) was excluded. RESULTS: The median total, intensive care unit (ICU), and ward costs of LT were US$64,250, $43,357, and $16,138 (currency ratio 1:30), respectively. HBV significantly increased the total cost of LT, followed by postoperative reintubation and bile duct complications. CONCLUSION: The charges associated with anti-HBV viral therapy and HBIG increase the cost of LDLT. Disease severity of liver cirrhosis showed less importance in predicting cost. Postoperative complications such as reintubation or bile duct complications should be avoided to reduce the cost of LT. PMID- 30401360 TI - Thrombotic Ringed Polytetrafluoroethylene Graft With Infection After Living-Donor Liver Transplantation. AB - BACKGROUND: The safety of the living donor in living-donor liver transplantation (LDLT) is always the first priority, meanwhile, the graft-to-recipient weight ratio (GRWR) and the anatomy of the liver allograft must also not be compromised in order to warrant tranplatation success. When it comes to the allograft of the right lobe of the liver without the middle hepatic vein (R-M), the outflow and adequate drainage for the territory of middle hepatic vein (MHV) is one critical concern. Despite publications in some high-volume transplant centers on the positive results of using expanded polytetrafluoroethylene (ePTFE) grafts to substitute those of autologous veins, complications related to the ePTFE graft have not been well discussed. METHODS: From July 2012 to June 2016, 129 adult patients who underwent living donor liver transplantation in Taipei Veterans General Hospital were analyzed. There were 3 cases of adjacent organ erosion with gas bubbles in the lumen of an ePTFE graft, including gastrointestinal (GI) tract penetration in 2 out of the first 15 cases that used the venous graft of ringed expanded polytetrafluoroethylene (rPTFE). The patient survival rate during this period was compared and radiological findings of rPTFE function and clinical signs of erosion with infection were also examined to raise the concerns of safety as well as early detection of complications of rPTFE. RESULTS: The overall 1-year patient survival rate was 90%, of which the right lobe wih MHV (R+M) group was 93.5% and the R-M group was 91.9%. For the mean of GRWR, the R+M group was 1.05 +/- 0.19 and R-M group was 1.19 +/- 0.27, while those who needed reconstruction with vein grafts was 0.96 +/- 0.11. Among the R-M group, 24 out of 88 cases (27.3%) needed reconstruction of MHV tributaries. Of the 24 cases, 15 cases were done with rPTFE and the 1-year patient survival rate of the rPTFE group was 73%, which is significantly worse (P = .008) than the non-rPTFE (89%) and non-reconstructed (97%) groups. The mean GRWR is significantly higher (P = .001) in the non-reconstructed group (1.19 +/- 0.27) than in the rPTFE (0.99 +/- 0.11) and non-rPTFE (0.94 +/- 0.11) groups. The venous grafts patency rate between the different graft types is no different, and there is also significance in warm ischemic time (P = .009) between the non-reconstructed (49 +/- 15), rPTFE (81 +/- 51), and non-rPTFE (56 +/- 18) groups in the mean minutes. CONCLUSION: In cases of fever of unknown cause in patients receiving LDLT with rPTFE graft, a regular computed tomography (CT) scan with contrast and gas bubbles within the graft lumen is the best way for early detection of graft related infection and suspicious GI tract penetration. To decrease the risks of tissue reaction induced by ePTFE graft in LDLT, omentum patches or other inert agents can be introduced as a buffer between the graft and adjacent organs, especially the GI tracts. However, research in material science shall be explored to solve the problem in the future. PMID- 30401362 TI - Imaging Validation of Drug-Eluting Beads Transarterial Chemoembolization of Hepatocellular Carcinomas in Living Donor Liver Transplantation. AB - OBJECTIVE: The aim of this study is to determine whether post-transarterial chemoembolization imaging (computed tomography or magnetic resonance imaging) could accurately predict the tumors' necrosis on pathologic specimens. BACKGROUND: Transarterial chemoembolization with drug-eluting beads has been proven to be an effective way to bridge patients with hepatocellular carcinomas to liver transplantation. MATERIALS AND METHODS: From September 2012 to June 2017, 59 patients with a total of 78 hepatocellular carcinomas, who received transarterial chemoembolization with drug-eluting beads before liver transplantation in Kaohsiung Chang Gung Memorial Hospital, were included in the study. All patients and hepatocellular carcinomas have pre-transarterial chemoembolization and post-transarterial chemoembolization images (computed tomography or magnetic resonance imaging) and pathological findings for correlation. Tumor response was evaluated according to modified Response Evaluation Criteria in Solid Tumors. The ranges of necrotic percentage are 100%, 91-99%, 51-90%, and <50%. RESULTS: The accuracy rate between the imaging and pathology correlation was 40% for computed tomography and 42% for magnetic resonance imaging. The recurrent rate of the complete respond group is 11.5%, the partial respond group is 16.0%, and the stationary group is 28.6%. CONCLUSION: Computed tomography and magnetic resonance imaging sensitivity is not satisfactory for microscopic evaluation of residual tumors after transarterial chemoembolization with drug-eluting beads. However, survival is good after liver transplantation no matter what the microscopic findings were. PMID- 30401361 TI - Correlation Between Splenectomy and Portal Vein Complications in Living Donor Liver Transplantation. AB - OBJECTIVES: In adults undergoing living donor liver transplantation (LDLT), the transplanted livers are partial grafts, and the portal venous pressure is higher than that observed with whole liver grafts. In patients undergoing LDLT concomitant with splenomegaly, portal venous flow is often diverted to collateral vessels, leading to a high risk of portal vein thrombosis. In such cases, occlusion of the collateral veins is important; however, complete occlusion of all collaterals without blocking the blood flow through the splenic artery causes portal hypertension and liver failure. We aimed to examine the effect of performing a splenectomy concomitant with LDLT to reduce portal vein complications. METHODS: Between 1991 and 2017, we performed 170 LDLT operations, including 83 in adults. For this cohort study, adult cases were divided into 2 groups. Group I was those who underwent LDLT without splenectomy (n = 60); Group II was those who underwent LDLT with splenectomy for the reduction of portal hypertension (n = 23). We investigated the incident rates of complications, including blood loss, lethal portal vein thrombosis (intrahepatic thrombosis), acute rejection, and so on. We also investigated the survival rates in both groups. RESULTS: The incident rate of lethal portal vein thrombosis in Group II was significantly lower than that observed in Group I (4.4% vs 21.7%, respectively, P = .0363). There were no statistically significant differences observed between the groups with respect to blood loss, survival rates, and other such parameters. CONCLUSION: LDLT concomitant with splenectomy might effectively reduce the occurrence of portal vein complications in adults. PMID- 30401363 TI - Quality of Life and Group Psychological Intervention in Patients With Cirrhosis on Liver Transplant Waiting List. AB - BACKGROUND: The patients on the liver transplant (LT) waiting list usually present with deterioration in their quality of life. Previous studies on psychological intervention have shown how the quality of life can be improved. OBJECTIVE: To analyze preliminary results of the influence of group psychotherapy on the quality of life of patients on the LT waiting list. METHOD: Fifteen patients on the LT waiting list who accepted receiving group psychotherapy were selected. The development of each 1 of these sessions was carried out at fortnightly periods for 6 months (12 sessions). Those patients who received a transplant and those patients who did not attend more than 6 group psychotherapy sessions were excluded. The Nottingham Health Profile was used to assess the quality of life. It consists of 38 items belonging to 6 health dimensions: energy, pain, physical mobility, emotional reaction, sleep, and social isolation. The study population was given a questionnaire before starting group psychotherapy and after it was finished. RESULTS: Of the 15 patients selected from the study population, 3 patients were given a transplant before the psychotherapy had finished, and 5 patients were excluded for not having attended more than 50% of the sessions. Therefore, the study was completed on 7 patients (n = 7). Overall, a better assessment can be seen in the second questionnaire. CONCLUSIONS: Group psychotherapy might favorably influence the quality of life of patients on the LT waiting list; therefore, it might be interesting to carry out studies on a larger scale in order to confirm these results. PMID- 30401364 TI - Transabdominal Intrapericardial Approach in Liver Transplantation for Unresectable Primary Hepatic Functioning Paraganglioma With Invasion Into Hepatic Veins and Suprahepatic Vena Cava: A Surgical and Anesthesia Management Challenge. AB - Primary hepatic functional paraganglioma is a rare form of extra-adrenal catecholamine-secreting tumor. Definitive treatment of functioning paraganglioma is challenging because of the critical location of the tumor frequently in close proximity to vital structures and risk of excessive catecholamine release during operative manipulation. We report the multidisciplinary management approach for a case of unresectable primary hepatic functional paraganglioma with invasion into the hepatic veins and suprahepatic vena cava. To our knowledge, this is the first report showing that orthotopic liver transplantation is curative for patients with unresectable primary hepatic paraganglioma. For locally advanced unresectable hepatic paraganglioma that involves the intrapericardial vena cava, a meticulous pre- and intraoperative medical management and transabdominal intrapericardial vascular control of the suprahepatic vena cava during orthotopic liver transplantation allows for complete extirpation of the tumor and achieves optimal outcome. PMID- 30401365 TI - Effect of Middle Hepatic Vein Tributaries Preserving Technique Until Just Before Graft Retrieval on Donors' Surgical Outcomes in Living Donor Liver Transplantation. AB - BACKGROUND: The technique of preserving the major tributaries of the middle hepatic vein (MHV) (V5 and V8) until just before graft retrieval is beneficial to minimize congestion time of the graft. However, it remains unclear whether this technique exerts a burden on donors in terms of operative time, blood loss, and postoperative hepatic dysfunction. In this study we investigated adverse effects of the MHV tributaries preserving technique until immediately before graft retrieval on donors' surgical outcomes. METHODS: Data from 71 donors who underwent right hepatectomy without MHV for a liver transplantation at our hospital from January 2002 to August 2016 were retrospectively reviewed. Donors were divided into 3 groups as follows: group 1 (n = 12), no MHV tributary reconstruction; group 2 (n = 33), single MHV tributary reconstruction; group 3 (n = 26), 2 or 3 MHV tributaries reconstruction. Donor operation time, blood loss, proportion of the remnant liver, maximum postoperative total bilirubin, aspartate aminotransferase, alanine transaminase, minimum platelets, prothrombin time, albumin level, number of days in hospital from surgery to discharge, and surgical complications were compared. RESULTS: Compared with groups 2 and 3, group 1 exhibited shorter average operational time and less average blood loss, but the difference was not significant. Comparisons of all other factors indicated no significant differences. CONCLUSION: The technique of preserving the major tributaries of the MHV until just immediately before graft retrieval does not appear to impose an apparent burden on donors. PMID- 30401366 TI - Feasibility and Outcomes of Direct Dual Portal Vein Anastomosis in Living Donor Liver Transplantation Using the Right Liver Graft With Anatomic Portal Vein Variations. AB - BACKGROUND: Portal vein (PV) reconstruction is a crucial factor in successful living donor liver transplantation (LDLT). In LDLT using the right liver grafts with anatomic PV variations, we sometimes encounter dual PV anastomosis. In this study we describe PV variations of donor liver in detail as well as our experiences with PV reconstruction in right liver grafts with PV variations. METHODS: We performed LDLT in 149 recipients between 2002 and 2016. PV variations of donor liver were classified into 3 major anatomic patterns, and we retrospectively analyzed the procedure and postoperative complications of PV anastomosis. RESULTS: PV variations in donor livers were classified as type A (normal type) in 125 patients, type B (trifurcation type) in 7 (4.7%), and type C (caudal origin of the right posterior branch) in 17 (11.4%). Among 75 right liver grafts, 10 (13.3%) had anatomic PV variations. In 9 of 10 recipients, dual PV of the graft were anastomosed to dual PV branches of the recipient in direct end-to end fashion. In the remaining recipient, the posterior portal branch of the graft was anastomosed to the recipient portal trunk through the interposed venous graft in end-to-end fashion and the anterior portal branch of the graft was anastomosed to the side wall of the interposed venous graft. These 10 recipients did not develop any postoperative complications associated with PV anastomosis, although 3 of the 149 recipients (2.0%) developed complications associated with PV anastomosis, such as thrombosis and necrosis. CONCLUSION: Dual PV anastomosis of the right liver graft is safe and feasible in LDLT, even in anatomic PV variations. PMID- 30401367 TI - Correlation Between Blood Transfusion and Blood Glucose Levels in Adult Living Donor Liver Transplantation. AB - BACKGROUND: To evaluate the effect of dextrose contained in banked blood products on the changes of blood glucose levels in adult living donor liver transplantation patients retrospectively. METHODS: Four hundred seventy-seven patients were divided into a non-blood transfusion (BT) group (G1) and a BT group (G2). The changes in blood glucose levels during the operation were compared using a Mann-Whitney U test, and a P value less than .05 was regarded as significant. RESULTS: No significant changes were detected in blood glucose levels after anesthesia, during dissection phase, in the anhepatic phase, or after reperfusion between the groups. Estimated blood loss for G1 (n = 89) and G2 (n = 388) were 718 +/- 514 and 5804 +/- 877 mL respectively, G1 had no blood transfusion but G2 had received 4350 +/- 6230 mL leukocyte-poor red blood cell transfusion, the pre- and end operation hemoglobin for G1 and G2 were 13.2 +/- 2.0, 10.2 +/- 1.9 and 10.1 +/- 1.6, 10.2 +/- 1.9 mg/dL respectively, indicating that they were not under or over transfused. CONCLUSION: When banked blood products are used to replace ongoing blood loss, the dextrose contained in citrate-phosphate-dextrose-adenine seems to have no effect on the changes in the blood glucose levels of the recipients. PMID- 30401368 TI - Comparison of Core Temperature Changes Between Pediatric Patients Lying on Regular Operating Room Linen Drapes and Water-Repellent Sheepskin Rug in Living Donor Liver Transplantation. AB - OBJECTIVES: The aims of this study were to compare the core temperature changes between pediatric patients lying on regular operating room linen drapes and a water-repellent sheepskin rug during living donor liver transplantation (LDLT) and to evaluate the effectiveness of using a water-repellent sheepskin rug in preventing profound hypothermia due to fluid overflow from the abdominal cavity during LDLT. PATIENTS AND METHODS: The operative records of pediatric patients who underwent LDLT from June 1994-September 2003 were reviewed retrospectively. The nasopharyngeal temperature (NT) changes during the LDLT procedure between patients lying on regular operating room drapes (GI) and water-repellent sheepskin rug (GII) were compared and analyzed using the Mann-Whitney U test. A P value <.05 was regarded as significant. RESULTS: Thirty-two patients were included in GI and 56 in GII. Profound hypothermia was not observed in any recipients lying on a water-repellent sheepskin rug (GII). The NT after induction and the following 4 hours into the LT procedure were significantly higher in GII than GI. CONCLUSION: Pediatric patients lying on water-repellent sheepskin preserved their core temperature better in comparison to patients lying on linen drapes. The use of a water-repellent sheepskin rug seems to be effective in preventing profound hypothermia related to physical contact with abdominal fluid overflow during the LDLT. PMID- 30401369 TI - Eye Protection in Liver Transplantation Patients Under General Anesthesia. AB - BACKGROUND: Opsite (Smith & Nephew, Hull, UK) is widely used in wound care but its use in eye protection against corneal abrasion during major surgery is rarely reported. The purpose of the current study is to compare the effectiveness of using Opsite in eye protection with either wet gauze alone or with wet gauze following application of eye ointment in patients undergoing living donor liver transplantation (LDLT). METHODS: This is a prospective, double-blinded, randomized controlled trial. Forty-one patients undergoing liver transplantation were enrolled. One eye of each patient was protected with sterile gauze soaked with normal saline solution and covered with Opsite. Duratears (ALCON, Fort Worth, Tex, United States) ointment was applied to the other eye before covering it with sterile wet gauze and Opsite (ointment group). The corneal examination was carried out after fluorescein staining before and at the end of surgery by the same doctor. A Student t-test and a chi2 test were used for the statistical analyses. RESULTS: Forty-one patients with 82 eyes were observed in this study. No corneal epithelial defects were found in either the normal saline group or the ointment group. CONCLUSION: Opsite combined with wet gauze with or without additional eye ointment provided 100% protection against corneal abrasion in patients undergoing LDLT. PMID- 30401370 TI - Anesthesia Management and Fluid Therapy in Right and Left Lobe Living Donor Hepatectomy. AB - OBJECTIVE: Right lobe living donor hepatectomy poses a greater risk for the donor in relation to blood loss. The aims of this study were to compare anesthetic and intraoperative fluid management in right and left lateral segment living donor hepatectomy. PATIENTS AND METHODS: The anesthesia records of living donor hepatectomy patients were retrospectively reviewed. Donor age and weight, anesthesia time, central venous pressure, blood loss, blood product transfusion, intravenous fluids used, doses of furosemide, and urine output were compared and analyzed between groups using the Mann Whitney U test. RESULTS: Forty-six patients underwent living donor left lateral segment hepatectomy (Group I); while 31 patients underwent right lobe hepatectomy (Group II). The mean blood loss in Group II was significantly higher compared to Group I (118 +/- 81 mL vs 68 +/- 64 mL), but clinically such amount of blood loss was not high enough to affect the hemodynamics. The fluid management was therefore not meaningfully different between the two groups. No blood transfusions or colloid infusions were required for either group. Urine output, hemoglobin changes, blood urea nitrogen, and serum creatinine pre- and postoperatively were not significantly different between groups. CONCLUSIONS: As long as blood loss is minimal, we found no difference in the anesthetic management and fluid replacements between right and left lateral segment living donor hepatectomy. PMID- 30401371 TI - Weaning of Veno-venous Bypass in Liver Transplantation: A Single Center Experience. AB - BACKGROUND: Veno-venous bypass (VVB) has been used in liver transplantation (LT) to minimize hemodynamic instability during caval anastomosis of anhepatic phase. With the introduction of the piggyback (PB) technique, which is a caval-sparing technique, the use of VVB progressively decreased over the world. The aim of this study was to introduce our experience using VVB with the focus on its weaning process. METHODS: A total of 300 consecutive LT cases from May 1996 to November 2003 were examined. Except for pediatric LT, 242 LT cases were investigated to evaluate the trends in VVB use, surgical technique, the amount of transfusion requirements, and durations of operation and anhepatic phase. RESULTS: For the early 100 LT cases, VVB was used in 97.5% of recipients, especially in all the recipients of deceased donor LT (DDLT). Then, the frequency of VVB use was decreased, and VVB was not used after the 268th recipient. In DDLT, the PB technique was first introduced in the 58th recipient and became a routine procedure of the DDLT since the 191th recipient. Living donor LT was increased, and the amount of transfusion requirement, duration of operation, and duration of anhepatic phase was reduced over time. CONCLUSIONS: The increasing experience and sophisticated surgical and anesthetic techniques were important factors responsible for the weaning of VVB. The advancement of the PB technique used in living donor LT might be a main factor of its weaning. PMID- 30401372 TI - The Correlation Between CVP and SVV and Intraoperative Minimal Blood Loss in Living Donor Hepatectomy. AB - BACKGROUND: Blood loss during liver surgery is found to be correlated with central venous pressure (CVP). The aim of the current retrospective study is to find out the cutoff value of CVP and stroke volume variation (SVV), which may increase the risk of having intraoperative blood loss of more than 100 mL during living liver donor hepatectomies. METHOD AND PATIENTS: Twenty-seven adult living liver donors were divided into 2 groups according to whether they had intraoperative blood loss of less (G1) or more than 100 mL (G2). The mean values of the patients' CVP and SVV at the beginning of the transaction of the liver parenchyma was used as the cutoff point. Its correlation to intraoperative blood loss was evaluated using the chi2 test; P < .001 was regarded as significant. RESULTS: The cutoff points of CVP and SVV were 8 mm Hg and 13% respectively. The odds ratio of having blood loss exceeding 100 mL was 91.25 (P < .001) and 0.36 (P < .001) for CVP and SVV, respectively. CONCLUSION: CVP less than 5 mm Hg, as suggested by most authors, is not always clinical achievable. Our results show that a value of less than 8 mm Hg or SVV 13% is able to achieve a minimal blood loss of 100 mL during parenchyma transaction during a living donor hepatectomy. Measurements used to lower the CVP or increased SVV in our serial were intravenous fluids restriction and the use of a diuretic. PMID- 30401373 TI - Simplified Unification Patch Venoplasty for Anomalous Portal Vein Branching in Living Donor Liver Transplantation With Right Lobe Graft. AB - Double portal vein (PV) branches during living donor liver transplantation (LDLT) with right lobe grafts have been considered challenging both in terms of donor safety and the complexity of vascular reconstruction in the recipient. Herein, we describe our experience with 24 adult LDLT recipients during which we employed unification patch venoplasty to reconstruct right lobe grafts with double PV orifices. We retrospectively reviewed the outcomes of 195 adult LDLT recipients receiving right lobe grafts, including 24 cases of adult LDLT recipients in which unification patch venoplasty was used to treat double PVs from January 2010 to June 2015. The anomalous portal vein branches of the donors were of type II in 7 cases (29.2%), type III in 15 cases (62.5%), and type IV in 2 cases (8.3%). We used propensity score matching analysis to compare the clinical outcomes of these recipients with those of 59 recipients who underwent adult LDLT using right lobe grafts with normal PVs in the same period. Intraoperative PV stenting was necessary in 2 (8.3%) of the 24 recipients undergoing unification patch venoplasty. During the follow-up period, all PVs remained patent until death or censoring. No significant difference in terms of postoperative vascular complications was evident between the 2 groups. Moreover, no major complications requiring reoperation or endoscopic and/or radiologic intervention developed in any of the 24 living donors with double PVs. In conclusion, our simplified unification patch venoplasty could be safe and feasible when used to reconstruct double PV orifices in right lobe LDLT from donors with complex PV anomalies. PMID- 30401374 TI - Early Vs Late Liver Retransplantation: Different Characteristics and Prognostic Factors. AB - BACKGROUND: East Asia is a known endemic area for hepatitis B, and living donor liver transplantation is mainly performed. Liver retransplantation (ReLT) is expected to become an increasing problem because of a shortage of organs. This study aimed to compare early and late ReLT with consideration of specific circumstances and disease background of East Asians. METHODS: Between October 1996 and January 2015, 51 patients underwent ReLT; we performed a retrospective analysis of data obtained from medical records of the patients. Clinical characteristics, indication, causes of death, survival rate, and prognostic factors were investigated. RESULT: The survival rate for early ReLT (n = 18) was 51.5% and that for late ReLT (n = 33) was 50.1% at 1 year postoperatively. Continuous venovenous hemodialysis and the use of mechanical ventilators were more frequent, and pre-retransplant intensive care unit stay and prothrombin time was longer in early ReLT than in late ReLT. Operation time was longer and the amount of intraoperative blood loss was greater in late ReLT than in early ReLT. Multivariate analysis showed that a higher C-reactive protein level increased mortality in early ReLT (P = .045), whereas a higher total bilirubin level increased the risk of death in late ReLT (P = .03). CONCLUSION: Patients with early ReLT are likely to be sicker pre-retransplantation and require adequate treatment of the pretransplant infectious disease. On the other hand, late ReLT is likely to be technically more difficult and should be decided before the total bilirubin level increases substantially. PMID- 30401375 TI - Diffusion-Weighted Magnetic Resonance Imaging in Liver Graft Rejection. AB - OBJECTIVE: The purpose of this study is to evaluate the use of diffusion-weighted magnetic resonance imaging (DWMRI) in the assessment of graft rejection after liver transplantation (LT). METHODS: From June 2017 to January 2018, 32 patients were included in the study with a mean age of 52.3 years. All patients underwent LT. The DWMRI was performed using the apparent diffusion coefficient map and measuring the different b-values (b-400, b-600, b-800, and b-1000). These measurements were compared with the histopathology results. Statistical analysis included t test, analysis of variance, and area under the curve for receiver operating characteristic (ROC). RESULTS: There were 17 patients without rejection and 15 patients with liver graft rejection diagnosed by histopathology. The mean (SD) results between the nonrejection and rejection groups were as follows: b-400 = 1.568 (0.265) vs 1.519 (0.119) (P = .089), b-600 = 1.380 (0.181) vs 1.284 (0.106) (P = .039), b-800 = 1.262 (0.170) vs 1.170 (0.086) (P = .035), b-1000 = 1.109 (0.129) vs 1.098 (0.078) (P = .095); B-values * 10-3 mm2/s. Only b-600 (P = .04) and b-800 (P = .04) values have significant differences between the 2 groups. B-600 showed 90.48% sensitivity and 83.33% specificity (ROC area under the curve = 0.784; P < .001), and b-800 showed 90.38% sensitivity and 83.03% specificity (ROC area under the curve = 0.816; P < .001). The values obtained with the apparent diffusion coefficient in b-800 were clearly differentiated between the mild, moderate, and severe degrees of rejection (P < .001). CONCLUSION: Measurement of b-600 and b-800 values using DWMRI may be used for the diagnosis of graft rejection after LT. PMID- 30401376 TI - Comparison of Posttransplant Outcomes in Living Donor Liver Transplantation for Obese and Nonobese Recipients. AB - BACKGROUND: Although living donor liver transplantation for obese recipients has increased, it has not been determined that posttransplant outcomes in obese recipients are inferior compared with nonobese recipients. METHODS: From January 2001 to December 2016, there was a total of 58 (6%) obese patients (body mass index >=30) in a cohort of 973 adult patients that underwent living donor liver transplantation. Propensity score matching and classification were performed based on the type of obesity, and there were 58 patients in the obese group and 141 patients in the nonobese group. We performed comparative analysis of posttransplant outcomes including Model for Early Allograft Function (MEAF) scoring and early allograft dysfunction (EAD). RESULTS: EAD was found in 11 (19%) and 31 (22%) patients in the obese and nonobese groups, respectively (P = .71). The obese group had a higher MEAF score than the nonobese group (5.2 vs 4.5, P = .007). The mean hospitalization of the obese group was shorter than in the nonobese group (32 vs 42 days, P = .003). Other posttransplant outcomes were similar between the obese and nonobese groups, including acute cellular rejection (8 vs 10 cases, P = .17), early graft failure (8 vs 12 cases, P = .30), index hospital mortality (6 vs 11 cases, P = .58), and comprehensive complication index (26.0 vs 24.6, P = .76). CONCLUSION: Posttransplant outcomes of the obese group were not inferior to the nonobese group. However, obesity can impact the severity of EAD and the incidence of early graft failure, based on significantly higher MEAF scores. PMID- 30401377 TI - Intravenous Administration of Tacrolimus Stabilizes Control of Blood Concentration Regardless of CYP3A5 Polymorphism in Living Donor Liver Transplantation: Comparison of Intravenous Infusion and Oral Administration in Early Postoperative Period. AB - BACKGROUND: We compared achievement rate of sufficient tacrolimus blood concentration in the early postoperative period and incidence of acute cellular rejection within 1 month after living donor liver transplantation (LDLT) between tacrolimus intravenous (IV) and oral administration groups. METHODS: From October 2005 to November 2016, 61 LDLT patients administered tacrolimus, who could be genotyped for CYP3A5*3 and *1, were chosen from the electronic record database. The patients were then divided into the 2 groups (an IV group [n = 38] and an oral group [n = 23]). We defined patients with 1*1 or *1*3 as expressors and those with *3*3 as nonexpressors. Sufficient trough level tacrolimus blood concentration on postoperative day (POD) 3 was defined as 10-20 ng/mL. RESULTS: Comparable concentrations were seen between the 2 groups, with mean blood concentration 13.7 +/- 8.5 ng/mL in the oral group and 15.2 +/- 4.3 ng/mL in the IV group. Achievement rate of sufficient tacrolimus concentration on POD 3 was significantly higher in the IV group than in oral group: 97% (37 of 38) vs 65% (15 of 23), respectively (P = .001). When we focused on achievement rate in the oral group according to CYP3A5 polymorphism, the frequency of expressors (17%) was significantly lower than that of nonexpressors (82%) (P = .016). However, in the IV group this negative influence was totally eliminated, resulting in high achievement rates regardless of CYP3A5 polymorphism. In terms of incidence of acute cellular rejection, there was no significant difference between the 2 groups (IV 32% vs oral 17%, P = .250). CONCLUSION: IV administration of tacrolimus allowed us to obtain more stable control of blood concentration regardless of CYP3A5 genotype. PMID- 30401378 TI - Early Enteral Feeding of Daikenchuto Stimulates Early Bowel Movement With Increased Portal Venous Blood Flow After Living Donor Liver Transplantation. AB - : Daikenchuto (DKT), a Japanese Kampo medicine, had been reported to increase small intestinal blood flow after liver resection. The aim of this study was to evaluate the effects of early enteral feeding of DKT on portal venous flow and early bowel movement after living donor liver transplantation (LDLT) in an attempt to clarify whether these effects on bowel motility can prevent bacterial and/or fungal translocation. MATERIALS AND METHODS: Our prospective study included the consecutive 16 LDLT recipients at Mie University Hospital between June 2006 and September 2009. Sixteen patients were divided into the 2 groups according to enteral feeding starting postoperative day (POD) 1: 8 patients in DKT (15 g/d) administration (DKT group, for 1 week) and 8 patients in tepid water administration (non-DKT group, for 1 week). Portal venous flow, portal venous pressure, presence of fungal infection (serum level of beta-D-glucan and fungal polymerase chain reaction assay), time to first food intake, and time to first defecation were serially examined. RESULTS: Portal venous flow (mean [SD] velocity) was significantly increased in DKT group compared with non-DKT group: 47.5 (12.9) vs 31.8 (15.4) (P = .04) on POD 1, 46.8 (11.5) vs 28.8 (12.5) (P = .03) on POD 3, and 42.3 (17.2) vs 25.2 (9.0) (P = .05) on POD 5. However, mean (SD) portal venous pressures did not significantly change between the 2 groups. Between the 2 groups (DKT vs non-DKT), the day of first oral intake was not significantly different: 6.9 (2.5) vs 11.3 (8.7) (P = .061), but the mean (SD) day of first defecation was significantly shorter in the DKT group: 3.9 (1.1) vs 5.5 (2.6) (P = .02). Although fungal polymerase chain reaction assay was not significantly different between the 2 groups (4 vs 4 positive cases), the mean (SD) serum levels of beta-D-glucan were significantly lower in the DKT group than in the non-DKT group: 9.0 (7.4) vs 18.4 (15.9) pg/mL (P = .04). CONCLUSION: Early enteral feeding of DKT after LDLT increased portal vein blood flow without increasing portal vein pressure and stimulated early bowel movement, which in turn might prevent fungal translocation. PMID- 30401379 TI - Acoustic Radiation Force Impulse Elastography in Post-transplant Recurrent Hepatitis C in Living Donor Liver Transplantation. AB - OBJECTIVE: The aim of the study was to evaluate the efficacy of liver fibrosis (LF) with acoustic radiation force impulse (ARFI) elastography for post transplant (post-LT) HCV recurrence. PATIENTS AND METHODS: We enrolled 89 adult recipients of living donor liver transplantation (LDLT) who had HCV, with or without post-LT HCV recurrence and treated or not treated. The post-LT HCV recurrence was diagnosed on the basis of RNA viral load present. ARFI examination was performed every 3 months for all patients, with shear wave velocity (SWV) obtained quantitatively in m/s and correlated with histopathologic fibrosis scoring of liver biopsy (LB). RESULTS: There were 50 (50 of 89) patients without HCV recurrence and 39 (39 of 89) with post-LT recurrence in the 89 patients studied. The recurrent group had significantly higher median SWVs (1.87 +/- 0.52 vs 1.37 +/- 0.52 m/s, P < .0001), in which 18 (18 of 39) patients had antiviral drug treatment and obtained significant improvement with SWVs from 1.83 +/- 0.49 to 1.68 +/- 0.56 m/s, P = .043. The correlations of LF staging between ARFI elastography and Ishak histopathologic LF scores showed great significance, P = .045. The HCV RNA titer after antiviral treatment decreased from 3,831,750 to 0, P < .0001, but the RNA titer of nontreated patients remained high and the median SWV increased. The Ishak LF staging in the nontreated group progressed from stage 1 to 2, P = .012 and SWV increased from 1.69 +/- 0.54 to 1.91 +/- 0.66 m/s, P = .085 at 1-year follow-up. CONCLUSION: ARFI elastography has efficient quantitative LF monitoring correlated with histopathologic staging for post-LT HCV recurrence. It could be an alternative, noninvasive method for frequent LB in the disease follow-up. PMID- 30401380 TI - De Novo Malignancy Following Adult-to-Adult Living Donor Liver Transplantation Focusing on Posttransplantation Lymphoproliferative Disorder. AB - OBJECTIVE: In patients with living donor liver transplantation (LDLT), late-onset complications sometimes develop because of long-term use of immunosuppressive drugs. One of the immunosuppressive drug-related complications is de novo malignancies resulting in reduced survival. PATIENTS AND METHODS: Among 153 patients undergoing LDLT, we retrospectively reviewed the medical records of 97 adult recipients (February 2002 to May 2017), who had been followed-up at our hospital for more than one year after LDLT. The median age was 52 years old (20 70) and the median observational period was 6.9 years (2.4-15.3). RESULTS: De novo malignancy after adult LDLT developed in 11.3% (11/97) of patients, including posttransplantation lymphoproliferative disorder (PTLD) (n = 4) (2 in the brain and 2 in abdominal lymph nodes), lung cancer (n = 1), pancreatic cancer (n = 1), gastric cancer (n = 1), laryngeal cancer (n = 1), lower gingival cancer (n = 1), bladder cancer (n = 1), and melanoma (n = 1). Age at cancer diagnosis ranged from 36 to 70 years old with an average age of 61 years. The interval from LDLT to cancer diagnosis was 8.3 years (3.9-12.2). Four patients (36.6%) including PTLD (n = 2), lung cancer (n = 1), and pancreatic cancer (n = 1) died of cancer and all of them were diagnosed with cancer within 10 years after LDLT. Six patients were diagnosed with cancer more than 10 years after LDLT and all of them survived after treatment of cancer. CONCLUSION: De novo malignancy was found in 11.3% of LDLT patients, and more than half of this population subset developed tumors 10 years after LDLT. Long-term close follow-up should be performed by taking any kinds of de novo malignancy into consideration. PMID- 30401381 TI - Biliary Complications During and After Donor Hepatectomy in Living Donor Liver Transplantation Focusing on Characteristics of Biliary Leakage and Treatment for Intraoperative Bile Duct Injury. AB - BACKGROUND: Biliary complication is one of the major donor complications during and after hepatectomy in living donor liver transplantation (LDLT). We evaluated risk factors for donor biliary complication in adult-to-adult LDLT. PATIENTS AND METHODS: From March 2002 to November 2016, 126 consecutive patients who underwent donor hepatectomy in adult-to-adult LDLT were divided into 2 groups according to biliary compilations: nonbiliary complication (non-BC) group (n = 114) and biliary complication (BC) group (n = 12). RESULTS: Among 126 donor hepatectomies, 35 patients (28%) experienced perioperative complications, including 10 (7.9%) with Clavien-Dindo classification grade III. Biliary complications occurred in 12 patients (9.5%): bile leakage in 10 and intraoperative bile duct injury in 2. Additional computed tomography- and/or ultrasound-guided drainage or exchange of original drain was required in 7 patients. In comparison between BC and non-BC groups, future remnant liver volume was significantly higher in the BC group than in the non-BC group (63% vs 40%; P = .02). In multivariate analysis, larger future remnant liver volume (P = .005) and shorter operating time (P = .02) were identified as independent risk factors for biliary complications. We had 2 patients with intraoperative bile duct injury: both were successfully treated by duct-to-duct biliary anastomosis with insertion of biliary stent or T-tube. CONCLUSION: Large remnant liver volume was a significant risk factor for biliary complications, especially biliary leakage, after donor hepatectomy. For intraoperative bile duct injury, duct-to-duct anastomosis with biliary stent is a feasible method to recover. PMID- 30401382 TI - Donor-Transmitted Bacterial Infection in Deceased Donor Liver Transplantation: Experience of Southern Taiwan Medical Center. AB - BACKGROUND: Bacterial Infection is the most important source of mortality and morbidity in liver transplantation recipients. Donor transmitted bacterial infection is rare but one of the most important infection sources. This kind of infection is difficult to identify, causing treatment dilemma. PATIENTS AND METHODS: In this article, we retrospectively reviewed our deceased donor liver transplants performed from January 2014 to December 2016. Forty-two recipients in Kaohsiung Chang Gung Memorial Hospital receiving liver grafts from 35 deceased liver donors were evaluated. The demography, donor transmitted infection, and outcomes were evaluated. RESULT: Two patients had probable donor transmitted bacterial infection and 1 patient died of suspected transmitted infection. CONCLUSION: Early identification of donor infection and adequate antibiotic treatment for the donor and recipient are the keys to preventing donor transmitted bacterial infection. Donor infection is not an absolute contraindication for organ donation in the area of organ shortage. Organ procurement organizations or similar authorities may establish the platform for sharing the data about donor and recipient infections. PMID- 30401383 TI - Efficiency of Transluminal Angioplasty of Hepatic Venous Outflow Obstruction in Pediatric Liver Transplantation. AB - BACKGROUND: Our aim in this study was to evaluate long-term efficiency of hepatic venous balloon angioplasty (BA) and stent placement (SP) for hepatic venous outflow obstruction (HVOO) in pediatric liver transplantation (LT). METHODS: From January 1999 to September 2016, 262 pediatric patients underwent LT at our hospital. Ten were diagnosed with HVOO, which included 8 living donor grafts and 2 split liver grafts. BA and SP were used in management of these 10 patients with HVOO. After intervention, Doppler ultrasound (DUS) was the major follow-up modality for comparing efficiency of BA and SP. RESULTS: The incidence of HVOO was 3.8% (10 of 262) in our pediatric LTs. Of the 10 HVOO cases, 5 had SP, 3 had BA once, 1 had BA twice, and 1 had BA twice along with SP. The patent hepatic vein was maintained after a mean follow-up of 7.4 (range, 0.04-17) years. Recurrent rate of HVOO after BA was 42%. Neither recurrent HVOO nor stent migration occurred after SP and throughout long-term follow-up. CONCLUSION: Hepatic venous SP was found to be more effective and safe than BA for treatment of HVOO in pediatric LT for long-term follow-up. PMID- 30401384 TI - Transition of Spleen Volume Long After Pediatric Living Donor Liver Transplantation for Biliary Atresia. AB - PURPOSE: After undergoing the Kasai procedure for biliary atresia (BA), most patients develop severe splenomegaly that tends to be improved by liver transplantation. However, fluctuations in splenic volume long after transplantation remain to be elucidated. PATIENTS AND METHODS: Seventy-one consecutive patients who had undergone pediatric living donor liver transplantation (LDLT) for BA were followed up in our outpatient clinic for 5 years. They were classified into 3 groups according to their clinical outcomes: a good course group (GC, n = 41) who were maintained on only 1 or without an immunosuppressant, a liver dysfunction group (LD, n = 18) who were maintained on 2 or 3 types of immunosuppressants, and a vascular complication group (VC, n = 11). Splenic and hepatic volumes were calculated by computed tomography in 464 examinations and the values compared before and after the treatment, especially in the VC group. RESULTS: Splenic volume decreased exponentially in the GC group, with splenic volume to standard spleen volume ratio (SD) being 1.59 (0.33) 5 years after liver transplantation. Splenic volume to standard spleen volume ratios were greater in the VC and LD groups than in the GC group. Patients in the VC group with portal vein stenosis developed liver atrophy and splenomegaly, whereas those with hepatic vein stenosis developed hepatomegaly and splenomegaly. Interventional radiation therapy tended to improve the associated symptoms. CONCLUSIONS: Fluctuations in splenic volume long after pediatric LDLT for BA may reflect various clinical conditions. Evaluation of both splenic and hepatic volumes can facilitate understanding clinical conditions following pediatric LDLT. PMID- 30401385 TI - Clinical Outcomes of Patients With the HeartMate II Left Ventricular Assist Device: A Single-center Experience From Japan. AB - BACKGROUND: Left ventricular assist device (LVAD) therapy is the "gold standard" alternative therapy for patients with advanced heart failure. However, LVAD therapy is still uncommon in the Asia-Pacific region. Therefore, we aimed to elucidate the clinical outcomes of patients from Japan supported with the HeartMate II (HM-II) LVAD at our institution. METHODS: Ninety-two patients (mean 44.3 +/- 12.1 years, 68 men, average body mass index 1.65 +/- 0.28 m2; 81 with nonischemic cardiomyopathy) who underwent HM-II implantation for bridge to transplantation (n = 91) or for destination therapy in a clinical study (n = 1) at the National Cerebral and Cardiovascular Center between April 2013 and October 2017 were enrolled in this analysis. Preoperatively, most patients (n = 73, 79%) had an INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profile of between level 2 and 4. Postoperatively, the average pump speed was 8602 +/- 258 rpm and the hemodynamics were well compensated. RESULTS: Adverse events consisted of 38 (41.3%) hemolysis, 30 (32.6%) major infection, 27 (29.3%) major bleeding (6 [6.5%] with gastrointestinal bleeding), and 18 (19.6%) neurologic dysfunction events. Eighteen patients underwent heart transplantation (HTx) after an average of 32.9 +/- 8.9 months of VAD support, and overall survival at both 6 months and 3 years was 96.3%. CONCLUSION: Clinical outcome among patients with HM-II at our institution is satisfactory for both survival and adverse events. The HM-II can provide effective hemodynamic support during the extremely long waiting period for HTx in Japan. PMID- 30401386 TI - VE/VCO2 Slope and Functional Capacity in Patients Post-Heart Transplantation. AB - BACKGROUND: The ventilatory efficiency represented cardiovascular, pulmonary, and musculoskeletal performance into an integrate index has been used as long-term and short-term prognostic variables in congestive heart failure. The heart failure patients post heart transplantation, whether the ventilatory efficiency was also normalized is still unknown. METHODS: This was a cross-sectional study. We measured ventilation to carbon dioxide production slope and oxygen consumption in peak exercise (peak VO2) by cardiopulmonary exercise test, which represented ventilatory efficiency and functional capacity respectively. Strength of hand grip, the 30-second chair stand test, and 6-minute walking test were also evaluated. Patients with ventilation to carbon dioxide production slope <30 were defined as the normal group; others were defined as the abnormal group. Independent t tests and paired t tests were used when appropriate. The level of statistical significance was set at .05. RESULTS: There were 51 clinically stable post-heart transplantation patients (age 53 +/- 12.4 years; 86.3% were male) at 65.14 +/- 41.17 months after transplantation. The ventilation to carbon dioxide production slope was 29.2 +/- 5.6, which significantly improved compared to that recorded 1 month after heart transplantation (32.6 +/- 6.4). There were 20 patients in the abnormal group, characterized by lower 6-minute walking test distance (normal vs abnormal, 422.5 +/- 97.8 vs 532.6 +/- 87.6 m) and peak VO2 (normal vs abnormal, 14.9 +/- 5.3 vs 18.8 +/- 5.1 mL/kg/min). The abnormal ventilation to carbon dioxide production slope was significantly correlated with 6-minute walking test distances in multivariate analyses. CONCLUSION: Our findings indicate that the ventilation to carbon dioxide production slope is partially abnormal among patients post-heart transplantation. A ventilation to carbon dioxide production slope above the normal range is characterized by a lower peak VO2 during cardiopulmonary exercise test and lower 6-minute walking test distance. The ventilation to carbon dioxide production slope is also significantly negatively correlated with peak VO2, peak work rate, and 6-minute walking test distance. The prognostic utility of the ventilation to carbon dioxide production slope for patients post-heart transplantation requires further investigation. PMID- 30401387 TI - Outcomes of Heart Transplant Recipients With Preexisting Malignancies. AB - BACKGROUND: Ensuring careful selection of heart transplant recipients with pretransplant malignancies (PTM) has been suggested in several retrospective studies. However, cancer survival rates continue to increase and we still lack outcomes data on PTM patients who have undergone heart transplantation (HT) within the Asian region. Herein we report pretransplant characteristics and outcomes among PTM patients with HT. METHODS: A total of 354 patients underwent HT from January 2004 to January 2016. Eight of these patients had a history malignancy that was being treated before transplantation. Posttransplant outcomes and clinical characteristics were collected and possible prognostic factors analyzed. RESULTS: The median age of the patients with a preexisting malignancy was 60 years. The PTM group included 5 males and 3 females, with a median duration of follow-up of 43 months. In this group there were 2 patients with lymphoma after chemotherapy, 1 with colon cancer postoperatively, and 1 was on chemotherapy. In the other 4 patients, nasopharyngeal cancer, thyroid cancer, breast cancer, and endometrial cancer were identified, and each had undergone treatment. Only 1 premalignancy patient, with nasopharyngeal cancer, had disease recurrence. The 5-year overall survival of these patients was 50.0 +/- 17.7%, but 5-year survival for those without PTM was 68.7 +/- 2.0%. CONCLUSION: PTM was 2.3% in our cohort. PTM is associated with an increased risk of all-cause mortality. Thus, our findings suggest careful consideration when selecting PTM patients for HT. PMID- 30401388 TI - Oxygen Consumption at Anaerobic Threshold Predicts Cardiac Events After Heart Transplantation. AB - OBJECTIVES: The ventilatory efficiency and functional capacity measured by the cardiopulmonary exercise test (CPET) have been used as important prognostic variables in congestive heart failure. This study sought to identify whether these predictors before heart transplantation (HTX) play a key role in predicting adverse events in patients with heart failure after HTX. METHODS: This was a retrospective cohort study design. HTX recipients were included for analysis. Ventilation to carbon dioxide production slope (VE/VCO2 slope) and oxygen consumption (VO2) during exercise were collected by CPET, which represented ventilator efficiency and functional capacity respectively. Cardiac-related events 2 years after HTX were recorded by chart review. We divided patients into 2 groups based on VE/VCO2 slope = 34, peak VO2 = 14 mL/kg/min and VO2 at aerobic threshold (AT) = 11 mL/kg/min. Kaplan-Meier survival curves was used to represent the events rate between groups and Log rank test was used to test significance. RESULTS: A total of 87 patients after HTX were included. Mean (SD) age was 48 (11) years and 73 were male; 28 subjects suffered from events, and 76 cardiac events were recorded. The mean (SD) data of peak VO2, VO2 at AT, and VE/VCO2 slope analyzed from CPET were 17.8 (5.6) mL/kg/min, 15.4 (4.4) mL/kg/min, and 33.1 (8.2) mL/kg/min, respectively. Lower VO2 at AT contributed to increase events rate (P < .05). CONCLUSION: Aerobic capacity may better predict 2-year cardiac events in patients after HTX. Strategies to improve aerobic capacity should be focused on in the cohort. PMID- 30401389 TI - Survival Outcomes of Oversized Cardiac Allografts in Pediatric Patients-A Single Center Experience in Taiwan. AB - OBJECTIVES: An oversized cardiac allograft may have a negative impact on survival outcomes according to previous studies; however, due to the shortage of pediatric donor hearts, the use of oversized cardiac allografts is sometimes inevitable. In this study, we reported the survival outcomes of pediatric patients in relation with the donor-recipient weight ratio. METHODS: Twenty-eight children, aged 3 months to 17 years, with dilated cardiomyopathy underwent primary cardiac transplantation at the National Taiwan University Hospital between 1995 and 2012. We analyzed these patients according to the donor-recipient weight ratio: group 1 (n = 19) with donor-recipient weight ratio <2.5 (median 1.1, interquartile range 1.0-1.6), and group 2 (n = 9) with donor-recipient weight ratio >=2.5 (median 3.0, inter-quartile range 2.87-3.5). RESULTS: The 30-day survival rate was 100% for both group 1 and group 2 (P = 1). The survival rates for group 1 and group 2 were 95% vs 100% at 1 year, 84% vs 89% at 5 years, and 73% vs 61% at 10 years. The median survival was 14.4 years vs 12.9 years (P = .6313). CONCLUSION: In this cohort, the use of oversized cardiac allograft in pediatric patients for dilated cardiomyopathy did not have a negative effect on short-term and long-term survival. PMID- 30401390 TI - Changes in Renal Function After Heart Transplantation. AB - : Renal function after heart transplantation (HTx) typically follows a biphasic pattern and an initial decay within 1 to 2 years. Trajectory of renal function after HTx is less reported, especially in Asia. The aims of this cohort study were to describe the changes in HTx recipients' serum creatinine and estimated glomerular filtration rate (eGFR) levels 5 years following HTx in Taiwan. METHODS: We retrospectively reviewed 5 years of 440 consecutive adult patients (>= 18 years) who underwent first HTx from June 1987 to December 2014 at the National Taiwan University Hospital. RESULTS: Among 422 participants, they received induction therapy consisting of intravenous rabbit antithymocyte globulin. Here, we illustrated the trends over the years by dividing the subjects into 2 groups based on their immunosuppressive regimen of transplantation (1987 2002 and 2003-2014) The pretransplantation median serum creatinine concentration level was 1.2 mg/dL, rose to 1.4 mg/dL at 3 months after surgery, and remained steady over 5 years after HTx. Pretransplant median eGFR was 67 mL/min/1.73 m2.The median serum creatinine concentration level and eGFR at baseline were all significantly difference than pretransplantation (P > .05). This result has showed that an initial steep decline within 3 months after transplant remained stable 5 years after HTx. CONCLUSION: As renal function deteriorates after HTx, we observed a steep decline in serum creatinine level and glomerular filtration rate within the 3 months after HTx, followed by a slow rate of deterioration over the following months. We found a time-related progressive deterioration in renal function during the 5 years after HTx. PMID- 30401391 TI - Renal Function Changes Under Everolimus Plus Cyclosporine or Everolimus Plus Tacrolimus After Heart Transplantation. AB - Everolimus (EVR) can be used with calcineurin inhibitors to reduce the risk of renal dysfunction, with similar immunosuppressive effect. In this study, we compared renal function after heart transplantation (HT) under EVR with cyclosporine (CSA) or tacrolimus (TAC). Between 2004 and 2014, EVR with CSA or TAC was used in 117 HT at the National Taiwan University Hospital. After HT, all patients received corticosteroid, EVR (C0 target 3-8 ng/mL) and CSA (C0 blood level 100-200 ng/mL), or TAC (Co blood level 5-10 ng/mL). Renal function was evaluated before HT, every month after HT for up to 1 year, and then every 3 months for up to 2 years. Blood-drug levels of EVR, CSA, and TAC were also monitored simultaneously with renal function. The estimated mean glomerular filtration rate (eGFR) was 76.5 mL/min/1.73 m2 before HT. After HT, the eGFR was 64 mL/min/1.73 m2 at the third month, and 64 mL/min/1.73 m2 at the end of first year. The difference was significant between pre-HT and post-HT (P = .00) during the first year. No significant differences were noted between the CSA and TAC groups. Careful monitoring of blood-drug level and renal function is crucial after heart transplantation. It is concluded that under close monitoring blood drug level and renal function, it is possible to reach acceptable postoperative renal function with no difference of renal function between EVR plus CSA and EVR plus TAC. PMID- 30401392 TI - First Report of the Korean Lung Transplantation Registry. AB - BACKGROUND: The Korean Organ Transplantation Registry (KOTRY) began to register lung transplants in 2015. This is an initial report on the status of patients receiving lung transplants over the past 2 years. METHODS: We analyzed a total of 69 patients who received lung transplants in 2015 and 2016 and who registered with the KOTRY. RESULTS: The 69 patients were treated in 5 institutions. The average (SD) donor age was 39.2 (12.6) years; there were 40 male patients. The average (SD) recipient age was 55.7 (10.0) years, and the number of male recipients was 46. A total of 66 patients underwent bilateral lung transplantation, 3 underwent single-lung transplantation, and 1 underwent simultaneous heart-lung transplantation. The most frequent indication for lung transplantation was idiopathic pulmonary fibrosis (35 patients), followed by connective tissue disease-related interstitial lung disease (9) and acute respiratory failure (8). Prior to transplantation, 23 patients required ventilator care, and 12 required extracorporeal membrane oxygenation while on the waiting list. Episodes of acute rejection during follow-up were reported in 4, 2, 1, and 1 patients at 3, 6, 9, and 12 months, respectively. Infections requiring hospitalization were reported in 27, 10, 4, and 3 patients at 3, 6, 9, and 12 months, respectively. CONCLUSION: The establishment of KOTRY renders it possible to collect nationwide data on lung transplantation, improving research on the topic and clarifying clinical feasibility. PMID- 30401393 TI - Management of De Novo Mycobacterial Infection After Lung Transplantation Without Rifampicin: Case Series of a Single Institution. AB - BACKGROUND AND OBJECTIVES: To treat organ transplant patients with mycobacterial infection, physicians need to pay attention to interaction between drugs used against mycobacteria and immunosuppressants. The purpose of this report is to describe the clinical features of and treatment for mycobacterial infection in lung transplant (LTx) recipients. METHODS: To investigate the incidence, treatment, and outcome for mycobacterial infection, we retrospectively reviewed 100 LTx recipients in our program since 2000. RESULTS: Four recipients (4.0%) developed mycobacterial infection. Three recipients took tacrolimus, and 1 received cyclosporine with mycophenolate mofetil and a steroid for immunosuppression. Tuberculosis (TB) was isolated from 2 recipients, and non tuberculous mycobacteriosis (NTM) was detected in the other 2. We treated the patients with levofloxacin + isoniazid + pyrazinamide + ethambutol (EB) for TB and clarithromycin (CLM) + EB for NTM to avoid interaction of calcineurin inhibitors (CNI: 8-10 ng/mL in trough level) with rifampicin (RFP). In treating the patients with NTM, we were able to maintain an adequate blood concentration of CNI by decreasing the dosage from one-half to one-quarter. All mycobacterial infections were controlled with treatment. In 1 patient with chronic obstructive pulmonary disease (COPD) infected with TB in the native lung, the forced expiratory volume in 1 second (FEV1) unexpectedly increased from 1890 mL before infection to 2320 mL possibly due to organization of the native lung. CONCLUSIONS: We were able to manage the mycobacterial infections using drugs other than RFP without any cases of acute rejection under adequate immunosuppression. Organization of the native lung with TB infection unexpectedly resulted in improvement of FEV1 in a COPD patient. PMID- 30401394 TI - Sustained-Release Tacrolimus Stabilizes Decline of Forced Expiratory Volume in 1 Second Through Decreasing Fluctuation of Its Trough Blood Level. AB - BACKGROUND: Calcineurin inhibitors are a commonly used immunosuppressive drug and over 80% of lung transplant (LTx) recipients use tacrolimus. Sustained-release tacrolimus (SRT) was developed as a once-daily formulation, resulting in slower release and reduction in peak concentration compared with twice-daily immediate release tacrolimus (IRT). Previous reports indicate that SRT may carry fewer side effects than IRT; however, the impact of SRT in bronchiolitis obliterans syndrome (BOS) after LTx is unclear. OBJECTIVE: Our study objective was to evaluate the effect of SRT in BOS after LTx. MATERIALS AND METHODS: We investigated the effect of SRT for BOS among 75 LTx recipients who were alive in 2017 in our LTx program. All analyses were carried out using student t test or F test. RESULTS: Thirty five recipients took IRT, 32 recipients used SRT, 7 recipients used cyclosporine, and 1 patient who received bone marrow and a lung graft from the same donor did not use a calcineurin inhibitor. The most frequent reason for conversion of IRT to SRT was kidney dysfunction, followed by other IRT complications. Five recipients underwent conversion of IRT to SRT because of decline of forced expiratory volume in 1 second (FEV1) with fluctuation of the tacrolimus trough level. After induction of SRT, the fluctuation of the tacrolimus trough level was significantly reduced in 4 of 5 patients (P < .05). Before drug form conversion, the FEV1 in these 5 patients was significantly decreased; however, this exacerbation of FEV1 was attenuated after SRT induction (P < .05). CONCLUSION: SRT appeared to stabilize decline of FEV1 in patients with BOS possibly due to reducing the fluctuation of tacrolimus trough blood concentration. PMID- 30401395 TI - Zinc Deficiency and Long-Term Outcome in Cases After Isolated Intestinal Transplantation in Taiwan. AB - OBJECTIVES: The small intestine is the primary site for absorption of dietary zinc. Intestinal transplant recipients are at high risk for zinc deficiency because of the long process of posttransplant adaptation. We initiated an intestinal transplant program in Taiwan in 2007. In this study, we aimed to retrospectively investigate the incidence of zinc deficiency in recipients after intestinal transplantation. METHODS: Twenty-one isolated intestinal transplants were performed in 20 patients with 1 retransplantation. The level of serum zinc was monitored periodically, and zinc supplements were administered when zinc level was below 700 ng/mL. Twelve patients with graft above 1-year survival and with available related data were enrolled for the analysis of zinc deficiency. The levels of serum zinc were tracked, and the protocol of zinc supplementation is discussed herein. RESULTS: The survival rates of 20 transplant recipients for 1 year, 3 years, and 5 years were 85%, 75%, and 65%, respectively. In the 12 grafts that survived longer than 1 year, we found that zinc deficiency was highest during the third (41.7%) to sixth (50%) month after transplantation. Sustained supplementation of zinc was required for over 70% of patients throughout the 3-year period to maintain their zinc level around the lower normal limit. CONCLUSION: The outcome of isolated small bowel transplantation is promising. Periodical monitoring and sufficient dosing of zinc supplements should be considered into the posttransplant protocol to prevent zinc deficiency after intestinal transplantation. PMID- 30401396 TI - Impact of Donor Age on Outcome of Intestinal Transplantation in Japan. AB - BACKGROUND: Donor age for intestinal transplantation (ITx) is somewhat younger than that for other solid organs. Clear criteria for adequate donors have not been established. There is a donor scarcity for ITx in Japan due to the shortage of young donors. METHODS: We reviewed outcomes associated with ITx in Japan based on donor age for cadaveric and living donation. RESULTS: Standardized report forms were sent to all known ITx programs, asking for information on ITxs performed between 1996 and 2016. All programs responded. Patient and graft survival estimates were obtained using the Kaplan-Meier method. Five institutions provided data on 27 grafts in 24 patients. There were 14 cadaveric and 13 living donor transplants. Median donor age for ITxs was 40 (range, 17-60) years. Graft survival at 5 years was 66% for patients >40 years old (n = 18) and 47% for those <40 years old (n = 9), not a statistically significant difference (P = .49). Graft survival at 5 years was 60% in those >50 years old (n = 5) and 57% for those <50 years old (n = 22), again not a significant difference (P = .27). CONCLUSION: There is no difference in survival between for those with donor age <40 vs >40 years. Donor age for ITx can be extended from >40 to up to 50 years, which may help to mitigate the donor shortage. It will be necessary to clarify the donor criteria for ITx through accumulation of further data on ITx. PMID- 30401397 TI - Three-Year Prospective Follow-up of Potential Pediatric Candidate for Intestinal Transplantation. AB - Intestinal transplantation (ITx) is a treatment for refractory intestinal failure (IF). However, the indications for and timing of ITx are still controversial because the course of IF is unknown. We performed a prospective multi institutional cohort study to identify the prognostic factors for referral to an ITx facility. Patients under 18 years of age in Japan who suffered from IF and had received parenteral nutrition for longer than 6 months were enrolled in this study. They were followed up for 3 years. Seventy-two patients were followed. The mean age at the beginning of the study was 7.0 years. Diagnoses were short gut syndrome (n = 25), motility disorder (n = 45), and other (n = 2). The overall 3 year survival rate was 95%. The 3-year survival rate was 86% in patients with intestinal-failure-associated liver disease (IFALD) (n = 6) compared to 97% in those without IFALD (n = 66) (P = .0003). Furthermore, the 3-year survival rates of patients who did and did not meet the criteria for ITx were 82% (n = 11) and 97% (n = 62), respectively (P = .034). Six (44%) of 14 patients whose performance status (PS) was >=3 at enrollment were dead or still had a PS >= 3 at 3 years. This study indicates that IFALD is a poor prognostic factor in pediatric patients with IF. Our indication for ITx, namely the presence of IFALD or loss of more than 2 parenteral nutrition access sites, seems to be applicable. PMID- 30401398 TI - Seven Japanese Herbals Prolonged Cardiac Allograft Survival. AB - Japanese herbal medicines have long been used as alternative therapy because of their immunomodulatory effects. In recent years, use herbal medicines is rapidly increasing worldwide. In this study, we investigated the effect of 17 components of traditional Japanese herbal medicines on alloimmune responses in a murine model of cardiac allograft transplantation. Fully vascularized heterotopic hearts from C57BL/6 donors were transplanted into CBA mice by using microsurgical techniques. Artemisiae capillaris herba (Inchinko) was given to CBA recipients at a dosage of 1 g/kg/day from the day of transplantation until 7 days afterward. The other 16 components were given at a dosage of 2 g/kg/day for the same time period. Naive CBA mice rejected C57BL/6 cardiac grafts acutely (median survival time [MST] of 7 days). CBA transplant recipients given 2 g/kg/day of Glycyrrhizae radix (Kanzou), Poria sclerotium (Bukuryo), Pinellia tuber (Hange), Cnidii rhizome (Senkyu), Paeoniae radix (Shakuyaku), and Scutellariae radix (Ogon) had prolonged C57BL/6 allograft survival significantly (MSTs were 18, 18, 17, 14, 12, and 12 days, respectively). Moreover, CBA transplant recipients given 1g/kg/day of Artemisiae capillaris herba had prolonged C57BL/6 allograft survival (MST >100 days); however, none of other 10 components prolonged allograft survival. In conclusion, administration of 7 components of traditional Japanese herbal medicines might induce prolongation of fully major histocompatibility complex mismatched cardiac allografts. PMID- 30401399 TI - Administration of Thrombomodulin (CD141) Could Improve Cardiac Allograft Survival in Mice. AB - Thrombomodulin (TM) is a promising natural anti-coagulant therapeutic protein that is effective in the treatment of disseminated intravascular coagulation. However, the mechanisms by which TM on micro-vessels enable the regulation of intimal hyperplasia remain elusive. We investigated the graft-protective effects of TM in a fully major histocompatibility complex-mismatched murine cardiac allograft transplantation model. CBA recipients transplanted with a C57BL/6 heart received intraperitoneal administration of 0.2, 2.0, and 20.0 MUg/day of TM for 8 days. Histological staining was conducted to assess the degree of inflammation and infiltration in the transplanted cardiac grafts. Untreated CBA recipients rejected C57BL/6 cardiac grafts acutely (median survival time [MST] was 7 days). CBA recipients exposed to the above dosages had significantly prolonged allograft survival (MSTs were 16, 21, and 37.5 days, respectively). Histologic assessments from TM-exposed recipients 2 weeks after grafting showed that the myocardium and vessel structure in their allografts were clearly preserved, and that the infiltration of inflammatory cells around coronary arteries was suppressed. TM can induce the prolongation of fully major histocompatibility complex-mismatched cardiac allograft by exerting graft protective effects within the myocardium and coronary arteries. PMID- 30401400 TI - More Hippocampal Weight and Cells in Cardiac Allograft Transplanted Mice. AB - The hippocampus is a brain structure that plays a fundamental role in memory and learning. Many animal studies have demonstrated that the structure of the hippocampus has evolved through exercise and play. However, little is known on the relationship between the brain and immunological reaction. In this study, we investigated the correlation between the weight of the hippocampus and transplant immunology in a murine heart transplant model. Fully vascularized heterotopic hearts from CBA (H2k, allogeneic group) or C57BL/6 (H2b, syngeneic group) donors were transplanted into C57BL/6 recipients by using microsurgical techniques. The weights of the whole brain and hippocampus from syngeneic and allogeneic groups were recorded 1, 2, and 4 weeks after grafting, and histologic assessments were performed. The syngeneic group maintained beating cardiac grafts for over 30 days, but the allogeneic group rejected CBA cardiac allografts acutely within 8 days. The average weight of whole brain from syngeneic and allogeneic group 1, 2, and 4 weeks had no significant differences. However, the average weight of hippocampus at 2 and 4 weeks was considerably increased in the allogeneic group compared with the syngeneic group. Histologic assessments with hematoxylin-eosin and Kluver-Barrera staining of hippocampus from allogeneic group 1 week after grafting demonstrated a greater number of granule and pyramidal cells in the hippocampus. Alloimmune responses in our model increase the weight of hippocampus. PMID- 30401401 TI - Graft Protective Effect of HMG-CoA Reductase Inhibitor Pravastatin in Murine Cardiac Allograft Transplantation. AB - The HMG-CoA reductase inhibitor (statin), which reduces serum cholesterol, has been demonstrated in the control of immune responses and may potentially play an important role in the regulation of acute and chronic rejection in organ transplantations. We investigated the graft-protective effect of a kind of statin, pravastatin, in the survival of fully major histocompatibility complex- mismatched murine cardiac allograft transplantation. Fully vascularized heterotopic hearts from C57BL/6 donors were transplanted into CBA recipients through microsurgical techniques. CBA recipients transplanted with a C57BL/6 heart received oral administration of 40, 120, or 400 MUg/kg/day of pravastatin from the day of transplantation to 7 days afterward. Immunohistochemical staining studies were performed to determine whether intimal formation of coronary arteries in the transplanted cardiac allografts was preserved and also to conduct morphometric analysis. Untreated CBA recipients rejected C57BL/6 cardiac grafts acutely (median survival time [MST] 7 days). CBA recipients exposed with 40 and 120 MUg/kg/day of pravastatin had a small prolonged allograft survival (MSTs of 10 and 9 days, respectively). However, the MST of CBA recipients exposed to 400 MUg/kg/day of pravastatin was significantly effective for allograft survival (MST 50 days). Immunohistochemical staining assessments on 4 weeks after grafting showed suppression of intimal hyperplasia in allograft coronary arteries. Pravastatin could induce the prolongation of fully major histocompatibility complex--mismatched cardiac allograft through the protection of the coronary artery. PMID- 30401402 TI - Recombinant Human Soluble Thrombomodulin Attenuates Hepatic Ischemia and/or Reperfusion Injury by Inhibiting Leukocyte Accumulation in Mice With Normal and Fatty Liver. AB - : In an attempt to increase the number of donor livers, there has been an increased use of marginal donor livers, such as steatotic (fatty) livers that increase susceptibility to ischemia and reperfusion injury (IRI). Inflammatory cell accumulation has a greater role in IRI in steatotic liver than in normal liver. Although the recombinant human soluble thrombomodulin (rhsTM) attracts attention as a new treatment for disseminated intravascular coagulation, the therapeutic efficacy of rhsTM in hepatic IRI remains uncertain, especially in fatty livers. We aimed to demonstrate the effect of rhsTM on hepatic IRI using well-established in vivo experimental models with steatotic liver. METHODS: C57/BL6 mice were divided into 2 groups: normal liver (NL) group and fatty liver (FL) group, in which the steatotic liver was induced by high-fat diet for 9 weeks. The mice in the NL and FL groups were premedicated with venous injection of rhsTM (TM) or saline (Control) as control groups. All 4 groups (NL-Control vs NL-TM, FL-Control vs FL-TM) were subjected to partial hepatic warm ischemia followed by reperfusion. RESULTS: rhsTM significantly attenuated liver injury in the FL group as well as the NL group, as evidenced by transaminase levels and histologic finding after hepatic IRI. rhsTM remarkably decreased the accumulation of inflammatory cells, such as macrophages and neutrophils, in both NL and FL tissue after IRI. Furthermore, rhsTM depressed mRNA and protein expressions of adhesion molecules such as intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 in both NL and FL groups after IRI. CONCLUSION: Our results demonstrate that rhsTM has a protective effect on fatty liver as well as normal liver after hepatic IRI. They also suggest that rhsTM contributes to attenuation of leukocyte accumulation caused by depressing expressions of adhesion molecules that facilitate accumulation of leukocytes in liver tissue in hepatic IRI. PMID- 30401403 TI - Cytoprotective Effects of Mesenchymal Stem Cells During Liver Transplantation from Donors After Cardiac Death in Rats. AB - BACKGROUND: Liver transplantation from donors after cardiac death (DCD) might increase the pool of available organs. Recently, some investigators reported the potential use of mesenchymal stem cells (MSCs) to improve the outcome of liver transplantation from DCD. The aim of this study was to evaluate the cytoprotective effects and safety of MSC transplantation on liver grafts from DCD. METHODS: Rats were divided into 4 groups (n = 5) as follows: 1. the heart beating group, in which liver grafts were retrieved from heart-beating donors; 2. the DCD group, in which liver grafts were retrieved from DCD that had experienced apnea-induced agonal conditions; 3. the MSC-1 group, and 4. the MSC-2 group, in which liver grafts were retrieved as with the DCD group, but were infused MSCs (2.0 * 105 or 1.0 * 106, respectively). The retrieved livers were perfused with oxygenated Krebs-Henseleit bicarbonate buffer (37 degrees C) through the portal vein for 2 hours after 6 hours of cold preservation. Perfusate, bile, and liver tissues were then investigated. RESULTS: Bile production in the MSC-2 group was significantly improved compared with that in the DCD group. Based on histologic findings, narrowing of the sinusoidal space in the both MSC groups was improved compared with that in the DCD group. CONCLUSIONS: MSCs could protect the function of liver grafts from warm ischemia-reperfusion injury and improve the viability of DCD liver grafts. In addition, we found that the infusion of 1.0 * 106 MSCs does not obstruct the hepatic sinusoids of grafts from DCD. PMID- 30401404 TI - Application of Perfusate With Human-Derived Oxygen Carrier Solution Under Subnormothermic Machine Perfusion for Donation After Cardiac Death Liver Grafts in Pigs. AB - : Oxygenation is necessary for aerobic metabolism, which maintains adenosine triphosphate within the graft organ. In recent years, some studies have demonstrated that subnormothermic machine perfusion (SNMP) with hemoglobin-based oxygen carriers has the potential to improve oxygen metabolism. OBJECTIVE: The aim of this study was to evaluate the effectiveness of perfusate with human derived hemoglobin vesicles (HbV) under SNMP in a pig model of donation after cardiac death. MATERIALS AND METHODS: In this study, pig livers were procured with a warm ischemic time of 60 minutes and were preserved in 3 groups for 240 minutes. The preservation conditions were as follows: 4 degrees C cold storage (Group 1); SNMP with University of Wisconsin perfusate alone (Group 2); and SNMP (21 degrees C) with University of Wisconsin solution and HbV (hemoglobin, 0.6 mg/dL) perfusate (Group 3). All livers were perfused for 120 minutes using pig autologous blood machine perfusion (reperfusion phase). We investigated the aspartate transaminase level and hemodynamics (portal vein resistance and oxygen consumption) in the preservation and reperfusion phases. A histologic study (hematoxylin-eosin staining) was performed after 240 minutes of preservation. RESULTS: The portal vein resistance of Group 3 was not increased in comparison with Group 2. During preservation, the oxygen consumption of Group 3 was higher than that of Group 2. However, the level of aspartate transaminase did not differ between Groups 2 and 3. CONCLUSION: The present study revealed that perfusate with HbV increased the oxygen consumption of the donor liver during SNMP. PMID- 30401405 TI - Ex Vivo Reperfusion Model to Evaluate Utility of Machine Preservation for Porcine Liver Donated After Cardiac Death. AB - BACKGROUND: Machine perfusion (MP) techniques are expected to prove useful for preserving the organ viability and recovering organ function for organ transplantation. Furthermore, an accurate assessment of organ viability using MP is important for expanding the donor criteria. In this study, an ex vivo reperfusion model (ERM) simulating transplantation using diluted autologous blood under normothermic conditions was evaluated for its utility of MP under subnormothermic conditions for livers donated after cardiac death (DCD). METHODS: The liver preservation methods for DCD porcine livers were evaluated using the ERM. This investigation was performed using a novel perfusion system developed by our research group. Porcine livers were procured with a warm ischemia time (WIT) of 60 minutes. The organs were then preserved using subnormothemic machine perfusion (SNMP) or static cold storage (CS) for 4 hours. We also compared these tissues with SNMP livers procured under a WIT of 0 minutes. After the preservation, the livers were reperfused for 2 hours using the ERM with diluted autologous blood oxygenated by a membrane oxygenator under NMP conditions. Reperfusion was evaluated based on perfusion flow dynamics and outflow of deviating enzymes. RESULTS: In the early stages of reperfusion, pressure in the blood vessels increased sharply in the CS group. Furthermore, the amount of aspartate aminotransferase accumulation was lower in the SNMP group than in the other groups. These results suggest ischemia-reperfusion injury is suppressed in SNMP conditions. CONCLUSION: An ERM has use in evaluating the utility of MP for the DCD liver. PMID- 30401406 TI - Optimum Perfusate Volume of Purified Subnormothermic Machine Perfusion for Porcine Liver Donated After Cardiac Death. AB - INTRODUCTION: Subnormothermic machine perfusion (SNMP) shows some advantages for the preservation of grafts donated after cardiac death (DCD) and improvements in machine perfusion (MP) technology are important to enhance organ preservation outcomes for liver transplantation. In this study, we focused on purified subnormothermic machine perfusion (PSNMP) and volumes of perfusate removed to substitute for purification and replaced by modified University of Wisconsin gluconate after the start of perfusion and investigated, in particular, the optimum perfusate purification volume. Several purification volumes under SNMP were compared. In addition, the perfusate purification during MP was indicated as a potential technique to enhance the organ quality of DCD grafts and extended criteria donors. METHODS: The PSNMP at several volumes (0.5 L, 1.5 L, and 3 L) were compared with regular SNMP without any purification treatment (untreated control). In the PSNMP group, all perfusate was removed to substitute for purification of the perfusate by modified University of Wisconsin-gluconate solution after the start of perfusion. After removing the perfusate, new perfusate with the same components was perfused to preserve the porcine livers obtained under warm ischemia for 60 minutes using SNMP at 22 degrees C porcine liver for 4 hours. RESULTS: The concentrations of aspartate aminotransferase and lactate dehydrogenase in the untreated group were significantly higher during perfusion compared to those of the intervention group. There are no significant differences among the volume conditions of the purification groups. CONCLUSIONS: The optimal volume of perfusate purification was confirmed with a simple experimental comparison between untreated and PSNMP conditions. PMID- 30401407 TI - Niacin Pretreatment Attenuates Lung Ischemia and Reperfusion-Induced Pulmonary Barrier Function Impairment by Reducing Oxidative Stress and Activating SIRT1 in an Isolated-Perfused Rat Lung Model. AB - PURPOSE: Alveolar-capillary barrier dysfunction, characterized by alveolar protein leak and lung edema, is a common scenario following cardiopulmonary surgery and thoracic organ transplantation. Reactive oxygen species generated through lung ischemia and reperfusion (I/R) injury during surgery plays a crucial role. Niacin, also known as vitamin B3, has been demonstrated to possess antioxidative and anti-inflammatory capacity. In this study, we examine the pulmonary barrier function via capillary filtration coefficient (Kfc) following lung I/R injury with and without niacin treatment. METHODS: Studies were conducted on male Sprague-Dawley rats in 3 groups: sham-operated, lung I/R injury, and niacin-pretreated lung I/R injury group. Rats were subjected to isolated perfused lung preparation. Lung ischemia was established by continuous perfusion and stopping ventilation for 60 minutes, followed by 60 minutes of ventilation. We assessed the Kfc, lung water content, and protein concentration in the lung lavage; pulmonary oxidative stress and lung inflammation were assessed by leukocyte counts, tissue level of tumor nercrosis factor alpha (TNF alpha), and tissue content of malondialdehyde (MDA), respectively. We also assessed the tissue protein level of sirtuin (silent mating type information regulation 2 homolog) 1 (SIRT1). RESULTS: Lungs subjected to I/R injury significantly increased Kfc, pulmonary oxidative stress, lung water content, and lavage leukocyte count and protein concentration (P < .05). Rats treated with niacin of 100 mg/kg/day for 4 days increased lung SIRT1 (P < .05) and attenuated lung I/R injury-induced pulmonary oxidative stress and inflammation and also improved Kfc. CONCLUSIONS: Niacin pretreatment protects lungs against I/R injury induced barrier function impairment through the activation of SIRT1 and reduced pulmonary oxidative stress and lung inflammation. PMID- 30401408 TI - Immunological Response of Pigs to Human Cells, Including Issues Such as the Production of Natural Antibodies in Newborns. AB - Pigs have recently become very popular for use not only in xenotransplantation field, but in regeneration studies as well, sometimes with pigs being used as the scaffold. We have already presented our findings related to the pig immune system against human cells, including the complement systems, natural antibodies (NAs), and NK cells. In this study, we investigated the pig innate immunological reaction against human cells further. Our investigations included issues such as the production of NAs in newborns, day 0 and day 1, and sow colostrum. The alternative pathway for pig complement reacted with human cells, and pig NK cells and macrophages directly injured human aortic endothelial cells. Pig serum clearly contains the natural antibodies IgG and IgM to human peripheral blood mononuclear cells (PBMCs). Pig plasma from day 1 newborns contained almost the same levels of these natural antibodies to human PBMCs as those of sow plasma. On the other hand, pig plasma from day 0 newborns did not contain IgG and IgM to human PBMCs. In addition, sow colostrum clearly contained both IgG and IgM to human PBMCs. As expected, the pig innate immunity system reacted to human cells, including natural antibodies. However, the NAs of pigs, both IgM and IgG, against human cells do not exist in pig serum at day 0, but at day 1 and in mother's milk, indicating that NAs in newborns did not come from the placenta but from sow colostrum. PMID- 30401409 TI - Presence of Pig IgG and IgM in Sera Samples From Baboons After an Orthotopic Liver Xenotransplantation. AB - INTRODUCTION: The immunorejection in xenotransplantation has mostly been studied from the host's immune system activation point of view and there is very little information about the graft-vs-host reaction. OBJECTIVES: To validate an enzyme linked immunosorbent assay (ELISA) test for porcine IgM and IgG quantitation, the assessment of porcine IgG and IgM in sera samples from baboons after liver orthotopic xenotransplantation or in human plasma after xenotransfusion through pig organs, and to assess the presence of porcine immunoglobulin in a baboon after plasmapheresis to a complete change of plasma after 4 passages through pig liver. MATERIALS AND METHODS: Two commercial ELISA kits for pig IgG and IgM quantitation were evaluated for cross reactivity with samples from baboons, Rhesus monkeys, squirrel monkeys, and humans. Then, samples from 18 baboons after orthotopic liver xenotransplantation were studied for porcine IgG and IgM. To understand the phenomenon, human plasma samples after xenotransfusion 1, 2, 3, or 4 times through liver or kidney were assessed for porcine IgG presence and finally, the porcine IgG were quantified in sera samples obtained during more than 4 years from a baboon after plasmapheresis with baboon plasma after xenotransfusion 4 times through a pig liver. RESULTS: Porcine IgG and IgM were found in samples from xenotransplanted baboon during all survival. The quantity of porcine IgG in plasma after xenotransfusion correlated with the number of passages through the pig liver, and the IgG were completely cleared from the baboon 16 days after plasmapheresis and complete substitution of plasma after 4 xenotransfusions through a pig liver. PMID- 30401410 TI - Tetrahydrocurcumin Enhances Islet Cell Function and Attenuates Apoptosis in Mouse Islets. AB - BACKGROUND: The transplantation of isolated pancreatic islets is a promising treatment for diabetes. Curcumin has been used for its pharmacologic effects, such as antidiabetic and anti-inflammatory activities. Tetrahydrocurcumin (THC), one of the major metabolites of curcumin, has been reported to have antioxidant and anti-inflammatory activities. This study examines the hypothesis that preoperative THC treatment can attenuate ischemic damage and apoptosis before islet transplantation. METHODS: Islets isolated from Balb/c mice were randomly divided into 2 groups and cultured in medium supplemented with or without THC. In vitro islet viability and function were assessed. After treatment with a cytokine cocktail consisting of tumor necrosis factor-alpha, interferon-beta, and interleukin-1beta, islet cell viability, function, and apoptotic status were determined. Proteins related to apoptosis were analyzed using INS-1 cell after streptozocin treatment. RESULTS: There was no difference in cell viability between the 2 groups. Islets cultured in the medium supplemented with THC showed 1.3-fold higher glucose-induced insulin secretion than the islets cultured in the medium without THC. After treatment with a cytokine cocktail, glucose-induced insulin release, and NO of the islets were significantly improved in THC-treated islets compared with islets not treated with THC. Apoptosis was significantly decreased, and B-cell lymphoma-2 was elevated in the THC-treated group. The streptozocin-treated INS-1 cell produced significantly higher levels of and B cell lymphoma-2-associated X protein, caspase-3, and caspase-9 than INS-1 treated with THC. CONCLUSIONS: These results suggest that preoperative THC administration enhances islet function before transplantation and attenuates the cytokine induced damage associated with apoptosis. PMID- 30401411 TI - Tetrahydrocurcumin Ameliorates Tacrolimus-Induced Nephrotoxicity Via Inhibiting Apoptosis. AB - BACKGROUND: Calcineurin inhibitors are effective immunosuppressive agents, but associated adverse effects such as nephrotoxicity may limit efficacy. Tacrolimus (FK506) is an immunosuppressive drug used mainly to lower the risk of organ rejection after allogeneic organ transplant. Adverse effects of FK-506 can prompt patients to end treatment despite the efficacy. In the present study, we investigated the protective effect and mechanism of tetrahydrocurcumin (THC) on FK506-induced renal damage, apoptosis, and oxidative stress to evaluate its possible use for kidney protection. MATERIALS AND METHODS: The effect of THC on FK506-induced kidney cell damage was investigated in LLC-PK1 cells. LLC-PK1 cells were pretreated with THC at concentrations of dose for 2 hours followed by addition of FK506 for 24 hours. LLC-PK1 cells were treated with FK506 and THC, and cell viability and glutathione was measured. The number of apoptotic cells was measured using an annexin V/propidium iodide staining with flow cytometry. The effect of apoptosis by THC in LLC-PK1 cells was determined by measuring the caspase-9, caspase-3, B-cell lymphoma-2 (Bcl-2), and Bcl-2-associated X protein levels using Western blotting analyses. RESULTS: FK506-induced LLC-PK1 renal cell damage was markedly ameliorated by THC treatment. THC protected LLC-PK1 cells by preventing FK506-induced glutathione decrease. THC protects against FK506-induced apoptosis in LLC-PK1 cells. Apoptosis was significantly decreased, and Bcl-2 was elevated in the THC-treated group. Bcl-2-associated X protein, caspase-3, and caspase-9 were decreased in the THC-treated group. CONCLUSION: These results collectively provide therapeutic evidence that THC ameliorates the FK506-induced renal damage via antioxidant effect and apoptosis inhibition. PMID- 30401412 TI - Niacin Pretreatment Attenuates Ischemia and Reperfusion of Pancreas-induced Acute Pancreatitis and Remote Lung Injury Through Suppressing Oxidative Stress and Inflammation and Activation of SIRT1. AB - BACKGROUND: Lung injury subsequent to pancreatic ischemia and reperfusion (PIR) due to shock, revascularization, and pancreas transplantation is a major clinical problem. In addition to proteases, massive production and release of reactive oxygen species (ROS) and induction of inflammatory cytokines have been implicated in remote lung injury. Niacin, also known as vitamin B3, is both antioxidative and anti-inflammatory. In this study, we examined the protective effectiveness of niacin pretreatment against PIR-induced pancreatic and remote lung injury. METHODS: Male Sprague-Dawley rats were divided into a sham-operated group, a PIR group, and a PIR group pretreated with niacin; the niacin (300 mg/kg per day) was given on 4 consecutive days before the study. Pancreatic ischemia was established by occluding both the gastroduodenal and splenic arteries for 120 minutes, followed by 240 minutes of reperfusion. Lung injury was assessed by pulmonary barrier function via pulmonary filtration coefficient, Kfc, using an isolated perfused rat lung preparation. Alveolar protein leakage was assessed by protein concentration in the bronchoalveolar lavage fluid (PCBAL). Lung water content was assessed by both wet-weight/dry-weight ratio (W/D) and lung-weight/body-weight ratio (LW/BW). Lung inflammation was evaluated by the lavage differential neutrophil cell count and tissue tumor necrosis-alpha (TNF-alpha) level. Oxidative stress was assessed by tissue malondialdehyde (MDA) level. Serum lactate dehydrogenase (LDH) and amylase were examined for lung and pancreas injury. We also evaluated lung tissue SIRT1 mRNA expression. RESULTS: Compared with the sham group, the PIR group had increased serum amylase and LDH, and impaired the pulmonary barrier dysfunction with marked increases in Kfc, PCBAL, W/D, and LW/BW, and augumented oxidative stress and inflammation with elevated tissue MDA and TNF-alpha and lavage neutrophil count, which correlated with decreased SIRT1 mRNA expression. Conversely, niacin pretreatment reduced pancreatic and remote lung injury and attenuated pulmonary oxidative stress and inflammation, and also protected against PIR-induced pulmonary barrier dysfunction while restoring SIRT1 mRNA expression. CONCLUSION: Niacin pretreatment reduced PIR-induced pancreatic and lung injury and protected against pulmonary barrier function impairment, which was associated with niacin's antioxidative and anti-inflammatory activity and its capacity to increase SIRT1 mRNA expression. PMID- 30401413 TI - A Multiple-Cell Microenvironment in a 3-Dimensional System Enhances Direct Cellular Reprogramming Into Hepatic Organoids. AB - OBJECTIVES: The difficulty in proliferation and availability and the rapid loss functions of primary human hepatocytes highlight the need to develop an alternative, preferably renewable source of human induced hepatocytes in regenerative medicine. Liver organoids generated on a multiple-cell microenvironment in a 3-dimensional (3D) system can provide a highly efficient solution to this issue. METHODS: Human hepatocytes were induced from fibroblasts by the lentiviral expression of FOXA3, HNF1A, and HNF4A. Together with these induced hepatocytes, human umbilical vein endothelial cells and mesenchymal stem cells in a 3D system were used to produce liver organoids. Liver-related gene and protein expression of liver organoids and induced hepatocytes were tested using a 2-dimensional (2D) system. RESULTS: Liver organoids notably increased the expression of hepatic transcription factors, marker genes, transporter genes, and liver metabolism enzyme genes, while it decreased the specific gene expression of fibroblasts. Liver organoids expressed comparable liver-specific proteins, such as ALB, AAT, and HNF4A in the 3D system. CONCLUSION: Direct reprogramming in multiple-cell microenvironments in 3D systems is more controllable and efficient than cell reprogramming in 2D systems. Liver organoids have the potential for use in disease modeling, pharmaceutical applications, and cellular transplantation. PMID- 30401414 TI - Development of Individualized Induced Pluripotent Stem Cells From Fibroblasts of Keloid Lesions in Patients. AB - OBJECTIVE: Presently, interesting research related to induced pluripotent stem cells (iPSCs) is emerging. However, the development of new therapies and techniques for treatment of refractory diseases is still required in dermatology. We are exploring novel methods to provide stem cell therapy and elucidate research mechanisms underlying troublesome diseases by reprogramming iPSCs from the fibroblasts of keloid lesions from patients in vitro. METHOD: Here, we identified the expression of fibroblastic genes in the fibroblast derived from diseased individuals. Corresponding iPSCs were then produced by transfecting patient fibroblasts with non-modified RNA cocktails, expressing OCT4, SOX2, KLF4, cMYC, NANOG, and LIN28 reprogramming factors. The pluripotency of these patient derived iPSCs was identified by immunocytochemistry, real-time quantitative polymerase chain reaction, and teratoma formation in vivo in non-obese diabetic/severe combined immunodeficiency mice. RESULTS: All iPSCs derived from patients significantly expressed the pluripotent transcription factors and could be expanded in vitro. Furthermore, induction of terminal differentiation in long term culture and the capability of forming embryonic bodies to differentiate into all 3 germ layers in vivo were confirmed in immune-deficient mice. CONCLUSION: Fibroblasts from a keloid patient were successfully reprogrammed to iPSCs in vitro. This reprogramming may provide a basis for the production of individualized modified artificial skin to prevent rejections after xenogeneic skin transplantation and trauma through autologous skin transplantation. These cells can also offer a new platform for research on mechanisms underlying skin diseases and personal medical applications. PMID- 30401415 TI - Successful Treatment of Fibrosing Cholestatic Hepatitis With Daclatasvir and Asunaprevir After Liver Transplantation: A Case Report. AB - BACKGROUND: Fibrosing cholestatic hepatitis (FCH) is an aggressive form of hepatitis C virus (HCV) recurrence after liver transplantation (LT). Most FCH cases are fatal, occurring as a secondary disease following rapidly progressive liver dysfunction and graft failure. We report a case of early-onset FCH after LT that was successfully treated using daclatasvir and asunaprevir. CASE REPORT: A 59-year-old woman underwent living donor LT for HCV-related liver cirrhosis. However, liver function was not improved after LT and gradually worsened. A liver biopsy was performed at 30 and 47 days after the living donor LT to identify the cause of the liver dysfunction. The first biopsy result showed no specific finding. However, combined treatment with pegylated interferon and ribavirin was started because of a high HCV viral load (> 8.0 log IU/mL). Nevertheless, liver function and HCV viral load deteriorated, and the second biopsy performed on postoperative day 47 revealed FCH. We converted the antiviral agents into daclatasvir and asunaprevir and performed plasmapheresis twice. Since then, the liver dysfunction and HCV viral load gradually improved, and HCV RNA clearance occurred at week 11 after treatment. The patient achieved a sustained virologic response at week 24 after completion of the treatment. CONCLUSION: Daclatasvir combined with asunaprevir can be a useful treatment option in potentially fatal FCH after LT. PMID- 30401416 TI - Transplantation After Successful Downstaging by Multimodal Treatments of American Joint Committee on Cancer Stage IIIB Hepatocellular Carcinoma With Portal Vein Thrombi: A Case Report. AB - The effective treatment for hepatocellular carcinoma (HCC) with American Joint Committee on Cancer stage IIIB remains controversial and challenging because of the high recurrence rate after resection and low survival rate. The median survival of those with macroscopic portal vein tumor thrombus (PVTT) is short. We reported such a case which received liver transplantation (LT) after successful consecutive downstaging therapies. A 40-year-old man with alcohol related liver cirrhosis and repeated esophageal varices bleeding had HCC with tumor thrombi in right main portal vein and the second portal branch of segment VI (stage IIIB). The received percutaneous alcohol injection, radiofrequency ablation, 8 sessions of transcatheter hepatic arterial chemoembolization, radiotherapy, and target therapy with sorafenib. Computed tomography (CT) scan and magnetic resonance imaging after treatments showed no viable fragments in the tumor and revealed both the right main portal vein and V1 branch were patent. One month later, the patient received a deceased LT. The perioperative course was rather smooth. After discharge, the interval follow-up CT studies of the chest and liver and whole body bone scan showed no tumor recurrence or metastasis up to 20 months postoperation. PMID- 30401417 TI - Isolated Biliary Fistula After Donor Right Hepatectomy and Its Novel Interventional Treatment: Isolated Liver-Punctured Drainage. AB - Isolated biliary leakage is difficult to manage, and afflicted patients often develop refractory fistula. The present case was a 43-year-old male donor whose wife developed acute fulminant liver failure. Computed tomography (CT) volumetry showed that the estimated remnant liver volume was only 394 mL (31%) if his right lobe would be harvested. Since remnant liver volume was marginal, our proposed cut line for the right hepatectomy was set in order to preserve branches of the middle hepatic vein draining segments 4b+8 and 5. Right hepatectomy was performed, but on postoperative day 14, the donor developed fever and right back pain, and enhanced CT showed a 6 cm intra-abdominal abscess at the site of cutting, and we diagnosed it as an isolated biliary fistula since the isolated segment 5/8 was receiving arterial blood supply and exhibiting regrowth. A transabdominal abscess drainage was performed, after which the patient lost 30 to 50 mL of bile juice per day in drainage until 2 months after the drainage procedure. Ethanol injection, acetic acid injection, and transarterial or portal embolization for the isolated liver were proposed, but these all were impossible to carry out because there were no accessible routes. Thus, re-abscess drainage with a 7-French drainage catheter was performed through the isolated liver on postoperative day 53, and the isolated functional liver was punctured to induce liver atrophy. After this drainage, the isolated liver started to shrink and bile output had been stopped. In conclusion, our punctured-liver drainage could be effective for the treatment of isolated biliary fistula, allowing physicians to avoid an invasive additional liver resection or other invasive percutaneous approach using chemical reagents. PMID- 30401418 TI - Heart Transplantation in a Patient Without a Heart: A Case Report. AB - We report a heart transplantation in a patient with no heart. A 60-year-old man suffered from severe infective endocarditis, and due to extensive involvement of the myocardium, only minimal myocardium was left after debridement of the necrotic myocardium and aortic annulus. We finally excised the entire heart to eradicate the infection source and employed 2 extracorporeal membrane oxygenations for full life support. The infection was controlled with strong antibiotics. The patient underwent successful heart transplantation 16 days following the excision and the patient fully recovered without any complications. PMID- 30401419 TI - Arterial Complication After Simultaneous Pancreas-Kidney Transplantation From an Abdominal Aortic Aneurysm Donor: A Case Report. AB - BACKGROUND: With the current disparity between the donor organ availability and recipient needs, various marginal organs with anatomical variations or concomitant diseases have begun to be used. We present a case of simultaneous pancreas-kidney transplantation (SPKTx) from a marginal donor with a giant abdominal aortic aneurysm who was incidentally found to be an organ donor after brain death. CASE PRESENTATION: The donor was a 66-year-old man who died of brain hemorrhage. We performed cannulation of the aorta from the distal part of left common iliac artery because the aneurysm extended from pararenal aorta to the bilateral common iliac artery. Furthermore, we prepared the left common carotid artery as the backup root of cannulation. Fortunately, we could perfuse the organs from the left common iliac artery. Subsequently, we retrieved the heart, liver, pancreas, and kidney grafts and performed SPKTx. The recipient received anatomically and functionally normal organs. At 19 days after transplantation, a rupture of the renal artery occurred on the graft side. We detected the bleeding point and it was managed quickly. CONCLUSIONS: We safely retrieved the organs from a marginal donor and performed the cooperative donation using a creative approach. We dealt with the complications through cautious postoperative management. PMID- 30401420 TI - [Critically ill patient isolation: risk or protection?] AB - INTRODUCTION: Isolation precautions are an effective measure to prevent the spread of multi-resistant microorganisms (MMR). However, its implementation is complex and can increase some risks to the patient. The aim of this study is to determine whether the implementation of isolation precautions increase the risk of patient safety incidents (PSI) in critically ill patients. MATERIAL AND METHODS: A retrospective observational study was conducted involving patients admitted to the ICU of a University Hospital, and that required isolation for more than 48h. Period of study: two years (from 2013/03/01 to 2015/03/31). Data source was the electronic medical record. The tools for evaluation were the Modular Review Form questionnaires (MRF1 and MRF2). An analysis was made of PSI and adverse events (AEs) during periods with and without isolation precautions, including the PSI type, severity, and preventability. RESULTS: The study included a total of 76 patients, 74 of whom had at least one PSI. A total of 798 PSI were detected (511 during isolation period), 599 were a No harm incident (NHI) and 199 were adverse AEs. The most frequent PSIs were associated with medication (316) and patient health care (279). Most of them were moderately or highly preventable. The incidence of PSI during periods with and without isolation was 27.3 (SD 33.8) and 29 (39.6) per 100 patient-days, respectively. CONCLUSIONS: PSIs in ICU are frequent, and the most of them are preventable. The adoption of isolation precautions does not constitute a risk factor for PSI. Improving patient safety culture is essential for an adequate prevention strategy. PMID- 30401421 TI - [Quality of communication with the caregiver of pediatric patient]. AB - INTRODUCTION: The deficiencies in the communication between the doctor and the patient have an impact on the care process and its therapeutic outcome. The objective of this study was to determine the perception of the information provided by treating physicians by parents or primary caregivers and the deficits observed in their relationship during the hospitalization of pediatric patients in high, medium and low complexity units. MATERIALS AND METHODS: Descriptive study carried out from January to May 2017 at the Foundation Hospital de la Misericordia, Bogota (Colombia), through an anonymous, self-filled survey during the hospital stay, consisting of a first part of open questions, and the second by a survey Likert type with qualitative variables. The qualitative variables evaluated through the survey were summarized in frequencies; in addition, the Kaiser-Meyer-Olkin test was performed with principal component analysis under a Varimax rotation. RESULTS: Three hundred and eighty-seven primary caregivers were surveyed, 68.5% belonged to the general stay area, 20.4% to intermediate care and 11.1% to intensive care. Ninety percent of the respondents agreed on the way in which the patient's evolution was explained, expressing satisfaction with the information delivered, the language in which it was expressed and the interest towards their concerns; despite this, 41% indicated uncertainty regarding the medical evolution of their son. CONCLUSIONS: An adequate warning was received regarding the medical information provided, the language used, the treatment of the patient and teaching the main caregiver about the pathology presented by the patient. The uncertainty regarding the evolution of patients is the factor that contributes the most to dissatisfaction with the quality of the information. PMID- 30401422 TI - [Knowledge and attitudes of health care professionals in advance healthcare directives]. AB - BACKGROUND AND OBJECTIVE: The advanced healthcare directive is a new style of health care relationship, based on the respect of the patients autonomous decisions: as well as a valuable tool that enables a proper management of the decisions made at the end of life. The objective of this study was to explore the knowledge and attitudes of the health care professionals regarding the advance directives, as well as the resources for advanced care planning in a municipality of Madrid during 2016-2017. MATERIAL AND METHODS: A cross-sectional descriptive study was carried out on a population of Health care professionals of Primary and Specialised Care. The knowledge and attitudes questionnaire about the advance directives was used. Sociodemographic and knowledge variables related to resources for the advanced care planning. Statistical-descriptive analysis was performed. RESULTS: A total of 431 professionals were included, with a mean age of 44.55 years (SD: 11.1). As regards knowledge about advance directives, the mean score was 5.08 (SD 2.4), with statistically significant differences being found between professional groups. A small percentage (4.6%) of the professionals had their document of Advance directives ready, and 42% of professionals did not know if they were regulated by the Community of Madrid. Less than half (41.5%) of the professionals knew the palliative resources of their institution. CONCLUSIONS: The health care professional's knowledge about advance directives, as well as the resources for the advanced care planning, show deficiencies at training and information level. Almost half of the professionals did not know if these are regulated in the Community of Madrid. They also believe that it would be useful to plan, and very useful to have the Advance directives document ready. PMID- 30401423 TI - [Assessment of an educational intervention regarding blood cultures as process indicators in an emergency department in Argentina]. AB - OBJECTIVE: The aim of this study was to describe 2 process indicators related to taking blood cultures (BC) in an Adult Emergency Department of a tertiary university hospital in Buenos Aires,and to describe the changes after a series of educational activities for health professionals was implemented during May 2016 as regards the appropriate indication of BC and the proper collection technique. MATERIALS AND METHODS: A retrospective cohort study was designed to assess its effectiveness, which consecutively included all patients admitted during 2015 2016. The BC request rate was used as a process indicator, and the percentage of contaminated BCs and the true positives rate were used as quality indicators. Both were measured monthly and prospectively during the period of study. RESULTS: The annual adjusted rate of BC requests was 4.9% (95% CI 4.8-5) in 2015 and 2.9% (95% CI 2.8-2.9) in 2016. The rate of false positive (contaminated) BCs was 4.5% in 2015 and 4.3% after the educational intervention. The true positive BCs were 8.3% in 2015 and 12% post-intervention. CONCLUSIONS: These findings prove how important and effective the educational interventions are. PMID- 30401424 TI - [EFQM Model in the hospitals of Madrid Regional Health Service: full self assessment cycle]. AB - AIM: To analyse a complete cycle of self-assessment using the European Foundation for Quality Management (EFQM) Model in the hospitals of the Madrid Health Service as regards the fundamental concepts of excellence (FCE). METHOD: Descriptive study of the EFQM self-assessments of the entire public hospital sector identifying the methodology and the information on strengths, weaknesses, evidence, RADAR matrix (Results, Approach, Deployment, Assessment and Review), and the related FCEs in the enabling criteria and in the prioritised action plans. RESULTS: The self-assessment was carried out in 85% of the hospitals (29/34), 86% of them required specific training (25/29), with a total of 329 teaching hours and 833 people in training. Multidisciplinary working groups were required in 83% of the hospitals (24/29), with 123 groups and 857 people involved. There were 3,686 strengths and 3,197 weaknesses identified: strengths and weaknesses were 78% (2,869) and 74% (2,355), respectively, for the enabling criteria and 22% (817) and 26% (842), respectively, for the results criteria. The mean score was 404 points with a median of 399. The main FCEs were managing with agility, developing organisational capability, sustaining outstanding results, creating a sustainable future, succeeding through the talent of people, and adding value for customers, with harnessing creativity/innovation and leading with vision, inspiration and integrity being placed in lower positions. A total of 113 action plans were identified for all the hospitals. CONCLUSION: A complete EFQM self-assessment cycle of the entire public hospital sector of a Regional Health Service is provided, linking the analysis and action plans with the FCE of the EFQM Model. PMID- 30401425 TI - [Respect the privacy of the patient: A strategy of small steps]. PMID- 30401427 TI - Editorial overview: The many facets of protein design: from self-assembled materials to vaccines. PMID- 30401426 TI - [Innovation in the health care through the application of the design thinking]. PMID- 30401428 TI - Editorial overview: Membranes and their embedded molecular machines. PMID- 30401429 TI - Khamapirad radiologic criteria as a predictor of pneumonia's bacterial etiology. PMID- 30401430 TI - Liquid and Hydrogel Phases of PrPC Linked to Conformation Shifts and Triggered by Alzheimer's Amyloid-beta Oligomers. AB - Protein phase separation by low-complexity, intrinsically disordered domains generates membraneless organelles and links to neurodegeneration. Cellular prion protein (PrPC) contains such domains, causes spongiform degeneration, and is a receptor for Alzheimer's amyloid-beta oligomers (Abetao). Here, we show that PrPC separates as a liquid phase, in which alpha-helical Thr become unfolded. At the cell surface, PrPC Lys residues interact with Abetao to create a hydrogel containing immobile Abetao and relatively mobile PrPC. The Abetao/PrP hydrogel has a well-defined stoichiometry and dissociates with excess Abetao. NMR studies of hydrogel PrPC reveal a distinct alpha-helical conformation for natively unfolded amino-terminal Gly and Ala residues. Abetao/PrP hydrogel traps signal transducing mGluR5 on the plasma membrane. Recombinant PrPC extracts endogenous Abetao from human Alzheimer's soluble brain lysates into hydrogel, and a PrPC antagonist releases Abetao from endogenous brain hydrogel. Thus, coupled phase and conformational transitions of PrPC are driven by Abeta species from Alzheimer's disease. PMID- 30401432 TI - Regulation of Neuroregeneration by Long Noncoding RNAs. AB - In mammals, neurons in the peripheral nervous system (PNS) have regenerative capacity following injury, but it is generally absent in the CNS. This difference is attributed, at least in part, to the intrinsic ability of PNS neurons to activate a unique regenerative transcriptional program following injury. Here, we profiled gene expression following sciatic nerve crush in mice and identified long noncoding RNAs (lncRNAs) that act in the regenerating neurons and which are typically not expressed in other contexts. We show that two of these lncRNAs regulate the extent of neuronal outgrowth. We then focus on one of these, Silc1, and show that it regulates neuroregeneration in cultured cells and in vivo, through cis-acting activation of the transcription factor Sox11. PMID- 30401433 TI - Histone Acetylation Inhibits RSC and Stabilizes the +1 Nucleosome. AB - The +1 nucleosome of yeast genes, within which reside transcription start sites, is characterized by histone acetylation, by the displacement of an H2A-H2B dimer, and by a persistent association with the RSC chromatin-remodeling complex. Here we demonstrate the interrelationship of these characteristics and the conversion of a nucleosome to the +1 state in vitro. Contrary to expectation, acetylation performs an inhibitory role, preventing the removal of a nucleosome by RSC. Inhibition is due to both enhanced RSC-histone interaction and diminished histone chaperone interaction. Acetylation does not prevent all RSC activity, because stably bound RSC removes an H2A-H2B dimer on a timescale of seconds in an irreversible manner. PMID- 30401431 TI - UV-Protection Timer Controls Linkage between Stress and Pigmentation Skin Protection Systems. AB - Skin sun exposure induces two protection programs: stress responses and pigmentation, the former within minutes and the latter only hours afterward. Although serving the same physiological purpose, it is not known whether and how these programs are coordinated. Here, we report that UVB exposure every other day induces significantly more skin pigmentation than the higher frequency of daily exposure, without an associated increase in stress responses. Using mathematical modeling and empirical studies, we show that the melanocyte master regulator, MITF, serves to synchronize stress responses and pigmentation and, furthermore, functions as a UV-protection timer via damped oscillatory dynamics, thereby conferring a trade-off between the two programs. MITF oscillations are controlled by multiple negative regulatory loops, one at the transcriptional level involving HIF1alpha and another post-transcriptional loop involving microRNA-148a. These findings support trait linkage between the two skin protection programs, which, we speculate, arose during furless skin evolution to minimize skin damage. PMID- 30401434 TI - Semi-analytical method for matrix diffusion in heterogeneous and fractured systems with parent-daughter reactions. AB - A semi-analytical/numerical method for modeling matrix diffusion in heterogeneous and fractured groundwater systems is developed. This is a significant extension of the Falta and Wang (2017) method that only applied to diffusion in an aquitard of infinite thickness. The current solution allows for the low permeability matrix to be embedded within a numerical gridblock, having finite average thickness, a specified volume fraction and a specified interfacial area with the high permeability domain. The new formulation also allows for coupled parent daughter decay reactions with multiple species that each have independent retardation factors, decay rates, and yield coefficients in both the high and low permeability parts of the system. The method uses a fitting function to approximate the transient concentration profile in the low permeability part of each gridblock so that the matrix diffusion flux into the high permeability part of the gridblock can be computed as a concentration dependent source-sink term. This approach is efficient because the only unknowns in each gridblock are the concentrations in the high permeability domain, so there is practically no increase in computational effort compared to a conventional transport simulation. The method is shown to compare favorably with an analytical solution for matrix diffusion in fractured media with parallel fractures, with an analytical solution for matrix diffusion with parent-daughter decay reactions, with laboratory experiments of matrix diffusion in a layered system, with a laboratory experiment involving lens shaped inclusions, and with fine grid numerical simulations of transport in highly heterogeneous systems. PMID- 30401437 TI - Amyotrophic Lateral Sclerosis: An Update for 2018. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons and other neuronal cells, leading to severe disability and eventually death from ventilatory failure. It has a prevalence of 5 in 100,000, with an incidence of 1.7 per 100,000, reflecting short average survival. The pathogenesis is incompletely understood, but defects of RNA processing and protein clearance may be fundamental. Repeat expansions in the chromosome 9 open reading frame 72 gene (C9orf72) are the most common known genetic cause of ALS and are seen in approximately 40% of patients with a family history and approximately 10% of those without. No environmental risk factors are proved to be causative, but many have been proposed, including military service. The diagnosis of ALS rests on a history of painless progressive weakness coupled with examination findings of upper and lower motor dysfunction. No diagnostic test is yet available, but electromyography and genetic tests can support the diagnosis. Care for patients is best provided by a multidisciplinary team, and most interventions are directed at managing symptoms. Two medications with modest benefits have Food and Drug Administration approval for the treatment of ALS: riluzole, a glutamate receptor antagonist, and, new in 2017, edaravone, a free radical scavenger. Many other encouraging treatment strategies are being explored in clinical trials for ALS; herein we review stem cell and antisense oligonucleotide gene therapies. PMID- 30401435 TI - Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1. AB - Interactions between the gut microbiota, diet, and the host potentially contribute to the development of metabolic diseases. Here, we identify imidazole propionate as a microbially produced histidine-derived metabolite that is present at higher concentrations in subjects with versus without type 2 diabetes. We show that imidazole propionate is produced from histidine in a gut simulator at higher concentrations when using fecal microbiota from subjects with versus without type 2 diabetes and that it impairs glucose tolerance when administered to mice. We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38gamma MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1). We also demonstrate increased activation of p62 and mTORC1 in liver from subjects with type 2 diabetes. Our findings indicate that the microbial metabolite imidazole propionate may contribute to the pathogenesis of type 2 diabetes. PMID- 30401438 TI - Diversity and inclusion: from priority setting to publication. PMID- 30401439 TI - Unbalanced risk-benefit analysis of ADHD drugs. PMID- 30401440 TI - Unbalanced risk-benefit analysis of ADHD drugs. PMID- 30401441 TI - Unbalanced risk-benefit analysis of ADHD drugs - Authors' reply. PMID- 30401442 TI - Unbalanced risk-benefit analysis of ADHD drugs. PMID- 30401443 TI - Treating comorbid depression and personality disorders in DSM-5 and ICD-11. PMID- 30401444 TI - Treating comorbid depression and personality disorders in DSM-5 and ICD-11 - Author's reply. PMID- 30401446 TI - Increase in detentions in the UK under the Mental Health Act. PMID- 30401447 TI - Vanessa Pinfold: expertise for better mental health research. PMID- 30401448 TI - Dial P for psychiatry: two short essays about Alfred Hitchcock. PMID- 30401449 TI - And I feel fine: Melancholia. PMID- 30401450 TI - #SwitchedOn: a call for assessing social media use of adolescents. PMID- 30401451 TI - Overexpression of PkINO1 improves ethanol resistance of Pichia kudriavzevii N77-4 isolated from the Korean traditional fermentation starter nuruk. AB - The yeast Pichia kudriavzevii N77-4 was isolated from the Korean traditional fermentation starter nuruk. In this study, fermentation performance and stress resistance ability of N77-4 was analyzed. N77-4 displayed superior thermotolerance (up to 44 degrees C) in addition to enhanced acetic acid resistance compared to Saccharomyces cerevisiae. Moreover, N77-4 produced 7.4 g/L of ethanol with an overall production yield of 0.37 g/g glucose in 20 g/L glucose medium. However, in 250 g/L glucose medium the growth of N77-4 slowed down when the concentration of ethanol reached 14 g/L or more and ethanol production yield also decreased to 0.30 g/g glucose. An ethanol sensitivity test indicated that N77-4 was sensitive to the presence of 1% ethanol, which was not the case for S. cerevisiae. Furthermore, N77-4 displayed a severe growth defect in the presence of 6% ethanol. Because inositol biosynthesis is critical for ethanol resistance, expression levels of the PkINO1 encoding a key enzyme for inositol biosynthesis was analyzed under ethanol stress conditions. We found that ethanol stress clearly repressed PkINO1 expression in a dose-dependent manner and overexpression of PkINO1 improved the growth of N77-4 by 19% in the presence of 6% ethanol. Furthermore, inositol supplementation also enhanced the growth by 13% under 6% ethanol condition. These findings indicate that preventing downregulation in PkINO1 expression caused by ethanol stress improves ethanol resistance and enhances the utility of P. kudriavzevii N77-4 in brewing and fermentation biotechnology. PMID- 30401452 TI - Evaluation of beta-galactosidase from Lactobacillus acidophilus as biocatalyst for galacto-oligosaccharides synthesis: Product structural characterization and enzyme immobilization. AB - beta-Galactosidase is an important industrial enzyme that catalyzes reaction of lactose hydrolysis and recently more interesting reaction of transgalactosylation, yielding a highly valuable group of prebiotic compounds named galacto-oligosaccharides (GOS). In this paper, parameters for achieving high yields of tailor-made GOS using crude beta-galactosidase obtained from Lactobacillus acidophilus ATCC 4356, probiotic bacteria regarded as safe for human consumption, were optimized. At the same time, detailed structural elucidation of obtained GOS was conducted, and it was concluded that beta galactosidase from L. acidophilus shows a particular specificity towards the formation of beta-(1->6) glycosidic bonds. In order to develop more stable and economically cost-effective preparation, crude enzyme was successfully immobilized on a methacrylic polymer carrier Lifetech ECR8409, leading to its simultaneous 2-fold purification. This immobilized preparation showed unchanged specificity towards the transgalactosylation reaction, thus yielding 86 g/l GOS under the previously optimized conditions (lactose concentration 400 g/l in 0.1 M sodium phosphate buffer, pH 6.8 and temperature 50 degrees C). PMID- 30401453 TI - Combinational biosynthesis and characterization of fusion proteins with tandem repeats of allophycocyanin holo-alpha subunits, and their application as bright fluorescent labels for immunofluorescence assay. AB - Fusion protein of streptavidin and allophycocyanin holo-alpha subunit (ApcA) is fluorescent and is able to bind biotin. This fusion protein (SLA) can be used as fluorescent label in immunofluorescence assay. In this study, one or two repeats of ApcA were fused to the protein SLA, with the aim to improve its brightness. The fusion proteins SLA2 (two repeats of ApcA) and SLA3 (three repeats of ApcA), together with lyase (cpcS) and phycoerythrobilin synthesizing enzymes (Ho1 and PebS), were co-expressed in Escherichia coli. These fusion proteins were purified by affinity chromatography. While SLA2 and SLA3 shared similar absorbance spectra, fluorescence spectra and biotin-binding activities with SLA, their brightness were much higher than that of SLA. When used as fluorescent labels in immunofluorescence assay, SLA2 and SLA3 showed higher detection sensitivity than SLA. These results suggested that SLA2 and SLA3 were the preferable fluorescent labels in immunofluorescence assays. PMID- 30401454 TI - Construction and co-cultivation of two mutant strains harboring key precursor genes to produce prodigiosin. AB - The biosynthesis of prodigiosin (PG) from Serratia marcescens involves the coupling of a bipyrrole, 4-methoxy-2,2'-bipyrrole-5-carboxaldehyde (MBC), with a monopyrrole, 2-methyl-3-n-amyl-pyrrole (MAP), and formation of a linear tripyrrole (PG). We constructed mutant strains in which either the MBC biosynthesis by S. marcescens BMJ816 or the MAP biosynthesis by S. marcescens AMJ817. S. marcescens BMJ816 and AMJ817 confirmed that they lose the ability to synthesize PG when they are cultivated alone. An experiment was also conducted in which cultures of the two mutant strains were grown to the early exponential phase in a semi-defined medium, and one suspension culture was inoculated with the other. This approach yielded 103 mg/L PG. The findings suggest that the addition of precursors may enhance PG production by microorganisms. PMID- 30401455 TI - SUMO Safeguards Somatic and Pluripotent Cell Identities by Enforcing Distinct Chromatin States. AB - Understanding general principles that safeguard cellular identity should reveal critical insights into common mechanisms underlying specification of varied cell types. Here, we show that SUMO modification acts to stabilize cell fate in a variety of contexts. Hyposumoylation enhances pluripotency reprogramming in vitro and in vivo, increases lineage transdifferentiation, and facilitates leukemic cell differentiation. Suppressing sumoylation in embryonic stem cells (ESCs) promotes their conversion into 2-cell-embryo-like (2C-like) cells. During reprogramming to pluripotency, SUMO functions on fibroblastic enhancers to retain somatic transcription factors together with Oct4, Sox2, and Klf4, thus impeding somatic enhancer inactivation. In contrast, in ESCs, SUMO functions on heterochromatin to silence the 2C program, maintaining both proper H3K9me3 levels genome-wide and repression of the Dux locus by triggering recruitment of the sumoylated PRC1.6 and Kap/Setdb1 repressive complexes. Together, these studies show that SUMO acts on chromatin as a glue to stabilize key determinants of somatic and pluripotent states. PMID- 30401456 TI - Leveraging DNA-Methylation Quantitative-Trait Loci to Characterize the Relationship between Methylomic Variation, Gene Expression, and Complex Traits. AB - Characterizing the complex relationship between genetic, epigenetic, and transcriptomic variation has the potential to increase understanding about the mechanisms underpinning health and disease phenotypes. We undertook a comprehensive analysis of common genetic variation on DNA methylation (DNAm) by using the Illumina EPIC array to profile samples from the UK Household Longitudinal study. We identified 12,689,548 significant DNA methylation quantitative trait loci (mQTL) associations (p < 6.52 * 10-14) occurring between 2,907,234 genetic variants and 93,268 DNAm sites, including a large number not identified by previous DNAm-profiling methods. We demonstrate the utility of these data for interpreting the functional consequences of common genetic variation associated with > 60 human traits by using summary-data-based Mendelian randomization (SMR) to identify 1,662 pleiotropic associations between 36 complex traits and 1,246 DNAm sites. We also use SMR to characterize the relationship between DNAm and gene expression and thereby identify 6,798 pleiotropic associations between 5,420 DNAm sites and the transcription of 1,702 genes. Our mQTL database and SMR results are available via a searchable online database as a resource to the research community. PMID- 30401457 TI - FUT2 Variants Confer Susceptibility to Familial Otitis Media. AB - Non-secretor status due to homozygosity for the common FUT2 variant c.461G>A (p.Trp154*) is associated with either risk for autoimmune diseases or protection against viral diarrhea and HIV. We determined the role of FUT2 in otitis media susceptibility by obtaining DNA samples from 609 multi-ethnic families and simplex case subjects with otitis media. Exome and Sanger sequencing, linkage analysis, and Fisher exact and transmission disequilibrium tests (TDT) were performed. The common FUT2 c.604C>T (p.Arg202*) variant co-segregates with otitis media in a Filipino pedigree (LOD = 4.0). Additionally, a rare variant, c.412C>T (p.Arg138Cys), is associated with recurrent/chronic otitis media in European American children (p = 1.2 * 10-5) and US trios (TDT p = 0.01). The c.461G>A (p.Trp154*) variant was also over-transmitted in US trios (TDT p = 0.01) and was associated with shifts in middle ear microbiota composition (PERMANOVA p < 10-7) and increased biodiversity. When all missense and nonsense variants identified in multi-ethnic US trios with CADD > 20 were combined, FUT2 variants were over transmitted in trios (TDT p = 0.001). Fut2 is transiently upregulated in mouse middle ear after inoculation with non-typeable Haemophilus influenzae. Four FUT2 variants-namely p.Ala104Val, p.Arg138Cys, p.Trp154*, and p.Arg202*-reduced A antigen in mutant-transfected COS-7 cells, while the nonsense variants also reduced FUT2 protein levels. Common and rare FUT2 variants confer susceptibility to otitis media, likely by modifying the middle ear microbiome through regulation of A antigen levels in epithelial cells. Our families demonstrate marked intra familial genetic heterogeneity, suggesting that multiple combinations of common and rare variants plus environmental factors influence the individual otitis media phenotype as a complex trait. PMID- 30401459 TI - Bi-allelic Mutations in LSS, Encoding Lanosterol Synthase, Cause Autosomal Recessive Hypotrichosis Simplex. AB - Hypotrichosis simplex (HS) is a rare form of hereditary alopecia characterized by childhood onset of diffuse and progressive scalp and body hair loss. Although research has identified a number of causal genes, genetic etiology in about 50% of HS cases remains unknown. The present report describes the identification via whole-exome sequencing of five different mutations in the gene LSS in three unrelated families with unexplained, potentially autosomal-recessive HS. Affected individuals showed sparse to absent lanugo-like scalp hair, sparse and brittle eyebrows, and sparse eyelashes and body hair. LSS encodes lanosterol synthase (LSS), which is a key enzyme in the cholesterol biosynthetic pathway. This pathway plays an important role in hair follicle biology. After localizing LSS protein expression in the hair shaft and bulb of the hair follicle, the impact of the mutations on keratinocytes was analyzed using immunoblotting and immunofluorescence. Interestingly, wild-type LSS was localized in the endoplasmic reticulum (ER), whereas mutant LSS proteins were localized in part outside of the ER. A plausible hypothesis is that this mislocalization has potential deleterious implications for hair follicle cells. Immunoblotting revealed no differences in the overall level of wild-type and mutant protein. Analyses of blood cholesterol levels revealed no decrease in cholesterol or cholesterol intermediates, thus supporting the previously proposed hypothesis of an alternative cholesterol pathway. The identification of LSS as causal gene for autosomal-recessive HS highlights the importance of the cholesterol pathway in hair follicle biology and may facilitate novel therapeutic approaches for hair loss disorders in general. PMID- 30401462 TI - [Calcific uremic arteriolopathy in hemodialysis patient, review of literature through five cases reports]. AB - Calcific uremic arteriolopathy, also called calciphylaxis, is a rare and severe disorder that presents with skin ischemia and necrosis, sometimes it presents with systemic necrosis, the process is secondary to the obliteration of the arterioles first by sub-intimal calcium deposits and then by thrombosis. These lesions can often lead to death due to infectious complications and comorbidities such as diabetes, obesity, arteritis, diffuse vascular calcifications, heart disease and undernutrition. The diagnosis is suggested by the characteristic ischemic skin lesions and their distribution, often bilateral and painful, associeted with calcific uremic arteriolopathy risk factors (phosphocalcic abnormalities, anti-vitamin K). The presence of radiological vascular calcifications is highly suggesting the diagnosis, but remains not very specific. The indication of skin biopsy is rare and reserved for difficult diagnoses. The goals of treatment are: reduce the extension of calcification and treatment of mineral and bone metabolism disorders of end-stage renal disease, dialysis adequacy, local treatment of skin lesions, tissue oxygenation, pain management, discontinuation and contraindication of medications that may contribute to the disorder. We propose to discuss it from a review of the literature and illustrate it with five clinical cases. PMID- 30401460 TI - Bi-allelic CCDC47 Variants Cause a Disorder Characterized by Woolly Hair, Liver Dysfunction, Dysmorphic Features, and Global Developmental Delay. AB - Ca2+ signaling is vital for various cellular processes including synaptic vesicle exocytosis, muscle contraction, regulation of secretion, gene transcription, and cellular proliferation. The endoplasmic reticulum (ER) is the largest intracellular Ca2+ store, and dysregulation of ER Ca2+ signaling and homeostasis contributes to the pathogenesis of various complex disorders and Mendelian disease traits. We describe four unrelated individuals with a complex multisystem disorder characterized by woolly hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and global developmental delay. Through whole-exome sequencing and family-based genomics, we identified bi-allelic variants in CCDC47 that encodes the Ca2+-binding ER transmembrane protein CCDC47. CCDC47, also known as calumin, has been shown to bind Ca2+ with low affinity and high capacity. In mice, loss of Ccdc47 leads to embryonic lethality, suggesting that Ccdc47 is essential for early development. Characterization of cells from individuals with predicted likely damaging alleles showed decreased CCDC47 mRNA expression and protein levels. In vitro cellular experiments showed decreased total ER Ca2+ storage, impaired Ca2+ signaling mediated by the IP3R Ca2+ release channel, and reduced ER Ca2+ refilling via store-operated Ca2+ entry. These results, together with the previously described role of CCDC47 in Ca2+ signaling and development, suggest that bi-allelic loss-of-function variants in CCDC47 underlie the pathogenesis of this multisystem disorder. PMID- 30401458 TI - Understanding the Hidden Complexity of Latin American Population Isolates. AB - Most population isolates examined to date were founded from a single ancestral population. Consequently, there is limited knowledge about the demographic history of admixed population isolates. Here we investigate genomic diversity of recently admixed population isolates from Costa Rica and Colombia and compare their diversity to a benchmark population isolate, the Finnish. These Latin American isolates originated during the 16th century from admixture between a few hundred European males and Amerindian females, with a limited contribution from African founders. We examine whole-genome sequence data from 449 individuals, ascertained as families to build mutigenerational pedigrees, with a mean sequencing depth of coverage of approximately 36*. We find that Latin American isolates have increased genetic diversity relative to the Finnish. However, there is an increase in the amount of identity by descent (IBD) segments in the Latin American isolates relative to the Finnish. The increase in IBD segments is likely a consequence of a very recent and severe population bottleneck during the founding of the admixed population isolates. Furthermore, the proportion of the genome that falls within a long run of homozygosity (ROH) in Costa Rican and Colombian individuals is significantly greater than that in the Finnish, suggesting more recent consanguinity in the Latin American isolates relative to that seen in the Finnish. Lastly, we find that recent consanguinity increased the number of deleterious variants found in the homozygous state, which is relevant if deleterious variants are recessive. Our study suggests that there is no single genetic signature of a population isolate. PMID- 30401463 TI - [Life-threatening hypercalcemia and acute kidney injury induced by etanercept]. AB - Drug-induced sarcoidosis-like disease is a rare, but not exceptional, side effect of anti-tumor necrosis factor (anti-TNF) agents. The organs most commonly involved are lungs, skin and lymph nodes. Kidney involvement is exceptional. Histology usually reveals non-caseating granulomas. Some of the biological features usually described in sarcoidosis are very infrequent in drug-induced granulomatosis. We report a case of sarcoid-like granulomatosis manifesting as life-threatening hypercalcemia and acute kidney injury in a woman treated with etanercept for a rheumatoid arthritis. Seven days after admission, she developed hypoxemic interstitial pneumonia with negative mycobacterial and fungal analysis. This picture suggested sarcoid-like disease induced by tumor necrosis factor blockers and prompted etanercept cessation. Kidney biopsy performed 30 days after admission revealed significant acute interstitial nephritis and intratubular calcium crystals. Staining for acid-fast bacilli and fungi was negative. Clinical picture improved gradually after etanercept withdrawal and cortisone treatment. Three weeks after admission, serum creatinine and calcium levels were normal. Clinical presentation of sarcoidosis-like disease induced by anti-tumor necrosis factor agents may be extremely variable. Our observation shows that severe, life threatening hypercalcemia may occur. Renal involvement is very unusual. This case highlights this diagnostic difficulty and the importance of a close clinical monitoring in patients treated with these drugs. Cessation of the anti-tumor necrosis factor agent leads to resolution of this condition in most cases. PMID- 30401464 TI - Retrospective analysis of nocardiosis in a general hospital from 1998 to 2017. AB - OBJECTIVES: To describe the epidemiological, clinical, microbiological, and therapeutic characteristics of Nocardiosis patients treated in a general hospital. PATIENTS AND METHODS: Monocentric retrospective analysis of patients presenting with Nocardia-positive biological sample from January 1, 1998 to May 1, 2017. RESULTS: We identified nine cases of Nocardia infections. Risk factors were oral corticosteroid therapy (n=3), solid cancer (n=2), hematological cancer (n=1), COPD (n=1). No risk factor was identified in patients with isolated cutaneous presentation (n=2). Disseminated presentations (n=3) were observed in patients receiving corticosteroid therapy (n=2) and presenting with ENT cancer (n=1). Identified Nocardia species were Nocardia nova (n=4), Nocardia cyriacigeorgica (n=2), Nocardia abscessus (n=1), Nocardia brasiliensis (n=1), and Nocardia asteroides (n=1). The median diagnostic time was 17 days. Antibiotic therapy was prolonged and included trimethoprim-sulfamethoxazole in 6/9 cases. The overall one-year case fatality was high (3/8). No recurrence was observed. We identified two cases of respiratory colonization with N. abscessus and N. cyriacigeorgica in COPD patients. CONCLUSION: Nocardiosis can occur both in immunocompetent and immunocompromised patients. It is a severe infection, with a miscellaneous clinical spectrum and complex treatments. Greater knowledge of nocardiosis is required from physicians for optimal medical care. PMID- 30401465 TI - Epigenetic regulators of programmed death-ligand 1 expression in human cancers. AB - The programmed cell death protein 1-programmed death-ligand 1 (PD-L1) axis has been successfully targeted in clinics and the use of immune check-point inhibitors have shown durable antitumor response in untreated or heavily treated advanced stage cancer. PD-L1 upregulation has been found to correlate with poor prognosis in multiple cancer types and expression of PD-L1 in intratumoral compartment has been suggested to influence immune response and act as a key determinant of checkpoint immunotherapy efficacy. Hence it becomes critical to understand the regulation of PD-L1 expression in cancer. Role of oncogenic signaling pathways and transcription factors such as PI3K-AKT, MEK-ERK, JAK-STAT, MYC, HIF-1alpha, AP-1 and NF-kappaB is well established in inducing PD-L1 expression. Even the structural variations resulting in the truncation of the 3' untranslated region (UTR) of PD-L1 has been shown to upregulate PD-L1 expression in multiple cancer types. Since microRNAs carry out post-transcriptional gene silencing by binding to the 3' UTR of its target messenger RNA, truncation of PD L1 3' UTR can result in alleviation of PD-L1 suppression mediated by microRNA, leading to its overexpression. Other epigenetic modifications, such as promoter DNA methylation and histone modifications can also play crucial role in regulating PD-L1 expression. Here, we review recent findings and evidence on epigenetic mechanisms that regulate PD-L1 expression and the biological and clinical implications of such regulation in cancer. PMID- 30401461 TI - Bi-allelic ADPRHL2 Mutations Cause Neurodegeneration with Developmental Delay, Ataxia, and Axonal Neuropathy. AB - ADP-ribosylation is a reversible posttranslational modification used to regulate protein function. ADP-ribosyltransferases transfer ADP-ribose from NAD+ to the target protein, and ADP-ribosylhydrolases, such as ADPRHL2, reverse the reaction. We used exome sequencing to identify five different bi-allelic pathogenic ADPRHL2 variants in 12 individuals from 8 families affected by a neurodegenerative disorder manifesting in childhood or adolescence with key clinical features including developmental delay or regression, seizures, ataxia, and axonal (sensori-)motor neuropathy. ADPRHL2 was virtually absent in available affected individuals' fibroblasts, and cell viability was reduced upon hydrogen peroxide exposure, although it was rescued by expression of wild-type ADPRHL2 mRNA as well as treatment with a PARP1 inhibitor. Our findings suggest impaired protein ribosylation as another pathway that, if disturbed, causes neurodegenerative diseases. PMID- 30401466 TI - [Analysis of social health factors that determine prenatal abuse in Catalonia. Authors reply]. PMID- 30401467 TI - Foster Caregiver Experience of Pediatric Hospital-to-Home Transitions: A Qualitative Analysis. AB - OBJECTIVE: Children entering foster care after discharge from the hospital are at risk for adverse events associated with the hospital-to-home transition. Education of foster caregivers regarding transitional care needs is key. However, little is known about the unique needs of foster caregivers as they transition from hospital to home with a new foster child or how hospital-based health care teams can better support foster caregivers. We aimed to examine the experiences and preferences of foster caregivers' regarding hospital-to-home transitions of children newly discharged into their care and to identify opportunities for inpatient providers to improve outcomes for these children. METHODS: We conducted semistructured telephone interviews of foster caregivers who newly assumed care of a child at the time of hospital discharge between May 2016 and June 2017. Interviews were continued until thematic saturation was reached. Interviews were audio recorded, transcribed, and analyzed to identify themes using a general inductive approach. RESULTS: Fifteen interviews were completed. All subjects were female, 87% were Caucasian, and 73% were first-time foster caregivers. Thirteen themes were identified and grouped into the following domains: 1) knowing the child, 2) medicolegal issues, 3) complexities of multistakeholder communication, and 4) postdischarge preparation and support. CONCLUSIONS: Caregivers of children newly entering foster care following hospital discharge face unique challenges and may benefit from enhanced care processes to facilitate successful transitions. Hospitalization provides an opportunity for information gathering and sharing, clarification of custodial status, and facilitation of communication among multistakeholders, including child protective services and biological parents. PMID- 30401468 TI - Mechanistic Insights into Autoimmune Pancreatitis and IgG4-Related Disease. AB - Autoimmune pancreatitis (AIP) is a pancreatic manifestation of a recently defined disease form known as IgG4-related disease (AIP/IgG4-RD). AIP/IgG4-RD is characterized by elevated systemic IgG4 antibody concentrations and lesional tissues infiltrated by IgG4-expressing plasmacytes. In addition, recent studies have revealed that, in common with other autoimmune diseases, such as systemic lupus erythematosus (SLE) and psoriasis, AIP/IgG4-RD is associated with increased type I IFN (IFN-I) production by plasmacytoid dendritic cells (pDCs). However, unlike SLE, AIP/IgG4-RD is characterized by elevated IFN-I-dependent IL-33 production, the latter emerging as an important contributor to inflammation and fibrotic responses characterizing this disease. On this basis, we propose that blockade of the IFN-I/IL-33 axis might constitute a successful approach to treating this unique type of autoimmunity. PMID- 30401470 TI - Erratum to 'Concurrent Guillain-Barre syndrome, transverse myelitis and encephalitis post-Zika: A case report and review of the pathogenic role of multiple arboviral immunity', Journal of the Neurological Sciences, Volume 395, 15 December 2018, Pages 47-53. PMID- 30401469 TI - Parkinson disease: A systemic review of pain sensitivities and its association with clinical pain and response to dopaminergic stimulation. AB - Patients with Parkinson disease (PD) experience hyperalgesia on evoked pain sensitivity testing, although the relationship of this with persistent pain in PD is less certain. Studies examining this have generated contradictory findings. Further, the role of dopaminergic deficiency as an underlying substrate for hyperalgesia is controversial. We report the results of meta-analyses of the PD pain sensitivity literature in an attempt to answer these questions. We identified 429 records, of which ten articles compared pain sensitivity between PD patients that experienced clinical pain (PDP) to those who did not (PDNP), and twenty studies that examined the effect of dopaminergic medications on pain sensitivity in PD patients. PDP patients experienced a moderate increase in pain sensitivity, had more severe disease, required higher dosages of medication, and were more likely to be female when compared to those PDNP patients. PD patients also had reduced pain sensitivity when tested on dopaminergic medications compared to when they were not on medications. Overall, the results of this systematic review and meta-analysis supports the hypothesis that hyperalgesia contributes to clinical pain in PD, and that the underlying mechanism may be dopaminergically driven. PMID- 30401471 TI - Determinants of level Ib involvement in oral squamous cell carcinoma and implications for submandibular gland-sparing neck dissection. AB - Traditional neck dissection for oral squamous cell carcinoma (OSCC) involves removal of the submandibular salivary gland. Several studies have cited the low incidence of direct gland invasion by tumours and have recommended gland-sparing neck dissection. In this study, a detailed audit of level Ib involvement in OSCC was performed in order to assess the feasibility of submandibular gland-sparing in neck dissection; the rate of direct involvement by the primary tumours, the involvement of periglandular level Ib nodes, and their determinants were investigated. A total of 586 neck dissection specimens obtained between 2005 and 2014 from patients operated on at the study institution for floor of mouth, tongue, and buccal primaries, were evaluated for direct invasion of the gland and periglandular lymphadenopathy. Of 226 node-positive patients, 21 (9.3%) had direct gland invasion by tumour. Risk factors were tumour diameter >4cm (P=0.002) and depth of invasion >10mm (P=0.003). Determinants of periglandular lymphadenopathy were depth of invasion >10mm (P<0.001), perineural invasion (P=0.02), lymphovascular invasion (P=0.014), and moderate/poor differentiation (P<0.0001). Gland-sparing neck dissection is safe in early tumours (pT1pN0-1), with a good chance of minimizing xerostomia without radiotherapy. Larger tumours without clear evidence of submandibular gland invasion or suspicious level Ib lymphadenopathy may be considered for gland preservation, however the oncological safety is unclear. PMID- 30401472 TI - Anaphylactic shock secondary to oral ofloxacin administration with cross reactivity to levofloxacin and ciprofloxacin. PMID- 30401473 TI - What we Know About the Clinical Course of Nonsegmental Vitiligo: Experience of a Researcher and a Dermatologist. PMID- 30401474 TI - [The relationship between neutrophil to lymphocyte ratio and postoperative pain in total knee and hip arthroplasty]. AB - BACKGROUND AND OBJECTIVES: Neutrophil to lymphocyte ratio is a simple, cost effective and easily applicable inflammation indicator that is being used frequently in mortality, morbidity and prognosis studies in the recent years. We evaluated the relationship between neutrophil to lymphocyte ratio and postoperative pain in patients undergoing total hip arthroplasty and total knee arthroplasty. MATERIAL AND METHODS: We included 101 patients who preferred spinal anesthesia and intravenous patient-controlled analgesia in accordance and divided them into two groups, total hip arthroplasty and total knee arthroplasty. We recorded demographic information, duration of operation, length of hospital stay, analgesics consumption, neutrophil to lymphocyte ratio results and postoperative pain using Visual Analog Scale. RESULTS: The morphine consumption of the patients was as follows in group total hip arthroplasty and total knee arthroplasty: at the 4th hour: 7.38mg, 7.80mg; 8th hour: 12.19mg, 13.29mg; 12th hour: 16.94mg, 19.18mg; 24th hour: 25.97mg, 27.98mg; 48th hour: 36.38mg, 39.59mg. The Visual Analog Scale scores of the patients was as follows in group total hip arthroplasty and total knee arthroplasty: at the 4th hour: 4.10, 4.51; 8th hour: 3.02, 3.43; 12th hour: 2.29, 2.55; 24th hour: 1.90, 1.87; 48th hour: 1.08, 1.13. In group total hip arthroplasty, we found a statistically significant association between postoperative neutrophil to lymphocyte ratio and the Visual Analog Scale values on the 48th hour in a positive direction (r=0.311; P=0.031; P<0.05). CONCLUSION: Neutrophil to lymphocyte ratio can be accepted as a relatively objective method for the diagnosis of postoperative pain. PMID- 30401475 TI - [Preoperative education reduces preoperative anxiety in cancer patients undergoing surgery: Usefulness of the self-reported Beck anxiety inventory]. AB - BACKGROUND AND OBJECTIVES: Preoperative instruction is known to significantly reduce patient anxiety before surgery. The present study aimed to investigate the effects of preoperative education on the level of anxiety of cancer patients undergoing surgery using the self-reported Beck anxiety inventory. METHODS: This study is a short-term observational study, including 72 female patients with a diagnosis of endometrial cancer who were scheduled to undergo surgical treatment under general anesthesia. During the pre-anesthetic consultation 15 days before surgery, one group of patients (Group A, n=36) was given comprehensive information about their scheduled anesthetic and surgical procedures, while the other group of patients (Group B, n=36) did not receive any information pertaining to these variables. The Beck anxiety inventory, blood pressure and heart rate were evaluated before and after the preoperative education in Group A. In Group B, these parameters were evaluated at the beginning and at the end of the consultation. RESULTS: The hemodynamic values were lower in the group that received preoperative education, in comparison with the group that did not receive preoperative education. Educating the patients about the procedure resulted in a reduction in the levels of anxiety from mild to minimum, whereas there was no change in the group that did not receive the preoperative education. This latter group kept the same level of anxiety up to the end of pre-anesthetic consultation. CONCLUSIONS: Patient orientation in the preoperative setting should be the standard of care to minimize patient anxiety prior to surgery, especially for patients with cancer. PMID- 30401476 TI - Temporospatial localization of telocytes during esophageal morphogenesis in rabbit. AB - Telocytes (TCs) are CD34 and Vimentin positive (+) immunoreactive stromal cells with a small-sized body and several extremely long telopodes. TCs have been described to provide a mechanical support throughout the tissue by making cellular connections (homo- or hetero) to form a 3D network. Such network can transmit the intercellular signaling. Recently, TCs have been described in the esophageal wall. However, information concerning the role of these cells in esophageal organization and development is rare. Thus, we aimed to record the temporo-spatial localization pattern of TCs during esophageal morphogenesis in rabbit. Embryos and fetuses of New Zealand White rabbits (10th-30th gestational days) were collected. Using CD34 immunostaining, TCs have not been demonstrated in the wall of the developing esophagus till the end of the second third of pregnancy. On 24th gestational day, CD34+ TCs were organized in the adventitia of the esophageal wall specifically in close association with the endothelial cells lining the micro vessels. Later on 26th gestational day, CD34+TCs were additionally expressed in the sub-mucosa and in lamina propria (sub-epithelial). On 28th gestational day, additional CD34+TCs were detected among the smooth muscle bundles of the muscular layer. Reaching the last gestational day, CD34+TCs formed several sheaths in the esophageal wall namely sub epithelial sheath, sub mucosal, muscular (circular and longitudinal) and inter-muscular sheaths and an outer adventitial one. On the other hand, vimentin immunohistochemistry revealed wider spread TCs positivity in all developmental ages. Presumptively, arrangement of CD34 and vimentin positive TCs in all layers of the developing esophageal wall hypothesizes that TC may play a potential role as a progenitor cell initially in differentiation of the epithelial and muscular precursors and finally in shaping of the various layers of the rabbit esophageal wall during its morphogenesis. TCs are also proposed to be involved in the angiogenesis of the esophageal blood capillaries. PMID- 30401477 TI - Amniotic fluid: Source of valuable mesenchymal stem cells and alternatively used as cryopreserved solution. AB - Mesenchymal stem cells (MSCs), which possess remarkable capabilities, are found in amniotic fluid (AF). The findings of several studies have shown the potential benefits of these cells in applications of regenerative medicine. In clinical applications, an over-period of time is required in a preparation process that makes cell collection become more necessary. Herein, the aim of this study was to preserve and characterize the cell's properties after cell cryopreservation into an appropriate cryogenic medium. The results illustrated that the highest hAF MSCs viability was found when the cells were conserved in a solution of 5% DMSO + 10% FBS in AF. However, no statistical differences were identified in a chromosomal aberration of the post-thawed cells when compared to the non-frozen cells. These cells could also maintain their MSC features through the ability to express cell prolific quality, illustrating the typical MSC markers and immune privilege properties of CD44, CD73, CD90 and HLA-ABC. Additionally, post-thawed cells were able to differentiate into chondrogenic lineage by exhibiting chondrogenic related genes (SOX9, AGC, COL2A1) and proteins (transcription factor SOX9 protein (SOX9), cartilage oligomeric matrix protein (COMP) and aggrecan core protein (AGC)), as well as to present sGAGs accumulation. Interestingly, the use of a transmission electron microscope (TEM) uncovered the enrichment of the rough endoplasmic reticulum (rER) that coincided with euchromatin and the prominent nucleolus in the chondrogenic-induced cells that are normally found in the cells of natural cartilage. All in all, this study manifested that AF can be a major consideration and applied for use as a co-mixture of cryogenic medium. PMID- 30401478 TI - An update on pulmonary and neurodevelopmental outcomes of bronchopulmonary dysplasia. AB - Bronchopulmonary dysplasia (BPD) is a common complication of extreme prematurity, and its rate is not improving, despite advances in perinatal intensive care. Children with BPD diagnosed in the neonatal period have higher risks for hospitalizations for respiratory problems over the first few years of life, and they have more asthma in later childhood. Neonates diagnosed with BPD have substantial airway obstruction on lung function testing in later childhood and early adulthood, and many are destined to develop adult chronic obstructive pulmonary disease. Survivors with neonatal BPD have more adverse motor function, worse cognitive development and poorer academic progress than those without BPD. Long-term outcomes for children born extremely preterm will improve if the rate of BPD can be substantially reduced. PMID- 30401479 TI - Prospective validation of the safety of a laparoscopic cholecystectomy training paradigm featuring incremental autonomy. AB - BACKGROUND: Surgical training is under scrutiny for the effect increased resident autonomy may have on patient outcomes. We hypothesize that as laparoscopic cholecystectomy (LC) difficulty increases, there will be increased involvement by senior residents and attending physicians with no differences in complications. METHODS: Ten acute care surgeons were asked to fill out a postoperative questionnaire regarding surgical difficulty after every LC between 11/9/2016 and 3/30/2017. Either the Jonckheere-Terpstra test, Mantel-Haenzel chi square test, or ANOVA was used to test for the association between perioperative data and surgical difficulty. RESULTS: A total of 190 LCs were analyzed. PGY level, percent of surgery time with attending surgeon involvement, partial cholecystectomy rate, and length of operation all significantly rose with increasing level of difficulty (p < 0.001) with no significant differences in 60 day emergency room bounce-backs, readmission, or complication rates. CONCLUSIONS: We found that as LC difficulty increases, so does attending surgeon and/or senior resident involvement, without increased morbidity. PMID- 30401480 TI - Validation of a novel patient-reported outcome measure for parathyroid and thyroid disease (PROMPT). AB - BACKGROUND: Patient-reported outcome measures are being used increasingly to assess disease severity and response to surgery. The purpose of this study was to create and validate a patient-reported outcome measure for symptoms of thyroid enlargement and hyperparathyroidism, 2 conditions where the presence of preoperative symptoms and response to surgery is often questioned. METHODS: A questionnaire reviewing common symptoms was developed from a literature review and expert opinion. Internal validity, reliability, and initial responsiveness to surgery were evaluated. RESULTS: Patient-Reported Outcome Measure for Parathyroid and Thyroid Disease (PROMPT) consists of 30 items: 10 compressive items and 20 hyperparathyroidism items; we evaluated 302 surveys collected over 10 months. PROMPT showed high internal consistency for compressive and hyperparathyroid constructs (Cronbach's alpha 0.84 and 0.95). Constructs were scored from 0-100, with greater scores corresponding to increased severity of symptoms. Preoperatively, patients with a goiter demonstrated greater compressive scores compared with other thyroid patients and hyperparathyroid patients (goiter, 47.5; nodule/other, 38.4; hyperparathyroid, 29.8; P < .0001). PROMPT demonstrated high test-retest reliability with acceptable intraclass correlation coefficients for both compressive score and hyperparathyroid score (0.840 and 0.646). Hyperparathyroid scores improved 2 weeks after (48.6 postop, 44.0 preop, P = .0470). CONCLUSION: We validated a novel measure for symptoms of hyperparathyroidism and goiter. PROMPT demonstrates high internal consistency, test-retest reliability, and preliminary analysis, which suggests that it is sensitive to change after surgery. PMID- 30401481 TI - Hold the door: hPMCA1/neuroplastin interactions regulate Ca2+-binding site accessibility. AB - In a September 2018 paper published in Nature Communications, Gong et al. identified the domains through which human PMCA1 and neuroplastin (NPTN) interact. Upon binding, hPMCA1 TM domains separate T110 in TM1 and A370 in TM3 to reveal the Ca2+-binding site. Thus, NPTN is able to directly modulate the accessibility of cytosolic Ca2+ to PMCA. PMID- 30401482 TI - Conbercept for Treatment of Neovascular Age-related Macular Degeneration: Results of the Randomized Phase 3 Phoenix Study. PMID- 30401483 TI - Not all artificial structures are created equal: Pilings linked to greater ecological and environmental change in sediment communities than seawalls. AB - Artificial structures are agents of change in marine ecosystems. They add novel habitat for hard-substrate organisms and modify the surrounding environment. Most research to date has focused on the communities living directly on artificial structures, and more research is needed on the potential impacts these structures have on nearby communities and the surrounding environment. We compared the sedimentary habitat surrounding two types of artificial structures (pilings and seawalls) to sediments adjacent to rocky reefs using a combination of traditional sediment analyses, stable isotope analysis, and environmental DNA. Artificial and natural shore sediments were best differentiated by sediment variables strongly associated with flow speed. Pilings sediments had significantly finer grain size, higher organic content, and generally lower C:N ratios than sediments adjacent to the other habitat types, suggesting flow is reduced by pilings. Sedimentary assemblages near pilings were also consistent with those predicted under low-flow conditions, with elevated bacterial colonization and increased relative abundances of small deposit feeders compared with other habitat types. Additionally, lumbrinerid polychaetes in pilings sediments had reduced delta15N values, suggesting different detrital resources and fewer trophic linkages compared with lumbrinerids in other habitats. Woody detritus was greater adjacent to seawalls than to natural rocky shores or pilings. Our findings suggest that artificial structures have the potential to influence adjacent soft sediments through changes to sediment properties that affect infaunal and microbial communities, as well as trophic linkages for some consumers. We hypothesize that this is due to a combination of altered flow, differing detrital subsidies, and differing adjacent land-use among habitat types. Managers should consider the potential for changed sediment properties and ecology when deciding where to build different types of artificial structures. Further manipulative experiments are needed to understand mechanisms of change and help manage the impacts of artificial structures on the seafloor. PMID- 30401484 TI - The role of modifiable health-related behaviors in the association between PTSD and respiratory illness. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) increases risk of future respiratory illness. However, mechanisms that underpin the association between these common and debilitating conditions remain unknown. The aim of this study was to identify modifiable, health-related behaviors they may explain the link between PTSD and respiratory problems. METHODS: World Trade Center responders (N = 452, 89% male, mean age = 55 years) completed baseline PTSD and sleep questionnaires, followed by 2-weeks of daily diaries, actigraphy and ambulatory spirometry to monitor lower respiratory symptoms, pulmonary function, activity levels, stressors, and sleep. Lipid levels were obtained from electronic medical records. RESULTS: Cross-sectional mediation analyses revealed that the association between PTSD and self-reported respiratory symptoms was explained by poor sleep, low activity, and daily stressors. The association between PTSD symptoms and pulmonary function was explained by insomnia and low activity. CONCLUSIONS: A range of health-related daily behaviors and experiences, especially sleep disturbances and inactivity, may explain excess respiratory illness morbidity in PTSD. The findings were generally consistent across daily self-report and spirometry measures of respiratory problems. Targeting these behaviors might enhance prevention of and intervention in respiratory problems in traumatized populations. PMID- 30401485 TI - Endothelin receptor emerges as a potential target of Hoxa9-mediated leukemogenesis. PMID- 30401486 TI - Clinical Impact of Intraventricular Conduction Abnormalities After Transcatheter Aortic Valve Implantation With Balloon-Expandable Valves. AB - Transcatheter aortic valve implantation (TAVI) often causes intraventricular conduction abnormalities (ICA), particularly left bundle branch block (LBBB) and advanced atrioventricular block, requiring pacemaker implantation (PMI). However, the relation between ICA and clinical outcomes after TAVI with balloon-expandable valves remains unclear, particularly in the Asian population. This retrospective study included all patients who underwent TAVI with balloon-expandable valves from October 2013 to September 2016. We defined ICA as new onset of complete LBBB (CLBBB) or PMI within 2 weeks after TAVI. We divided the patients into 2 groups: those with and without ICA (new-ICA and no-ICA groups) and we assessed 1-year outcome. Two hundred one consecutive patients underwent TAVI using balloon expandable valves (mean age, 84.8 +/- 5.7 years; women, 64%). ICA occurred in 47 patients (23%), 37 patients (18%) developed CLBBB, and 34 patients recovered from CLBBB within 1 year after TAVI. Ten patients (5%) who developed symptomatic bradycardia required PMI within 2 weeks after TAVI. At 30 days after PMI, 7 patients already had a very low ventricular pacing rate, and 6 patients who recovered from bradycardia needed pacing at 1 year. Patients with ICA tended to have high 1-year all-cause mortality, but there was no significant difference between the 2 groups (12% vs 7%, p = 0.15). In conclusion, ICA occurred in 23% of patients after TAVI with balloon-expandable valves, and approximately 90% of them recovered from ICA during the follow-up. There was no significant difference in 1 year all-cause mortality between the new-ICA and no-ICA groups. PMID- 30401487 TI - Meta-Analysis of Impact of Anemia and Hemoglobin Level on Survival After Transcatheter Aortic Valve Implantation. AB - To establish evidence whether baseline anemia and decreases in baseline hemoglobin levels affect survival after transcatheter aortic valve implantation (TAVI), we performed a meta-analysis of available studies. Studies considered for inclusion met the following criteria: the design was a comparative study of patients with baseline anemia versus those without baseline anemia or a cohort study investigating baseline anemia (as a dichotomous variable) or baseline hemoglobin levels (as a continuous variable) as one of prognostic factors of mortality; the study population was patients who underwent TAVI; and main outcomes included early (30-day or in-hospital) or late (including early) all cause mortality. Study-specific estimates were combined in the random-effects model. Our search identified 15 eligible studies including a total of 11,657 TAVI patients. Pooled analysis demonstrated that baseline anemia was associated with a statistically significant increase in early (p = 0.003) and midterm mortality (p < 0.0001) and that incremental decreases in baseline hemoglobin levels were associated with a statistically significant increase in midterm mortality (p < 0.00001). Pooled analysis of only adjusted estimates indicated that anemia was independently associated with a statistically significant increase in early (p = 0.02) and midterm mortality (p < 0.0001) and that incremental decreases in baseline hemoglobin levels were independently associated with a statistically significant increase in midterm mortality (p < 0.00001). In conclusion, baseline anemia and lower baseline hemoglobin levels may be associated with increased early and midterm mortality after TAVI. PMID- 30401488 TI - Observer for nonlinear systems using mean value theorem and particle swarm optimization algorithm. AB - A new observer design for nonlinear systems is considered. The main idea consist of the determination of the estimation error and mean value theorem parameters (beta) to introduce them into proposed observer structure. This process is designed on basis of mean value theorem (MVT) and Particle Swarm Optimization algorithm (PSO). This observer does not use Linear Matrix Inequality technique (LMI) for stability study. The stability study relies on the use of a classical quadratic Lyapunov function. The observer's gains are determined systematically. For the validation of theoretical development proposed in this paper. We consider two practical realization that deals the secure communication problem and a statistical performance analysis is realized. PMID- 30401489 TI - Process alarm prediction using deep learning and word embedding methods. AB - Industrial alarm systems play an essential role for the safe management of process operations. With the increase in automation and instrumentation of modern process plants, the number of alarms that the operators manage has also increased significantly. The operators are expected to make critical decisions in the presence of flooding alarms, poorly configured and maintained alarms and many nuisance alarms. In this environment, if the incoming alarms can be correctly predicted before they actually occur, the operators may have a chance to address and possibly avoid abnormal behaviors by taking corrective actions in time. Inspired by the application of deep learning in natural language processing, this paper presents an alarm prediction method based on word embedding and recurrent neural networks to predict the next alarm in a process setting. This represents both a novel approach to alarm management as well as a novel application of natural language processing and deep learning techniques to this problem. The proposed method is applied to an actual case study to demonstrate its performance. PMID- 30401490 TI - Editorial for adult CSF total protein: Higher upper reference limits should be considered worldwide. A web-based survey. PMID- 30401491 TI - Concurrent Guillain-Barre syndrome, transverse myelitis and encephalitis post Zika and multiple arboviral immunity. PMID- 30401492 TI - T2 magnetic resonance mapping: The key to find the 'Brahmastra' against atherosclerosis? PMID- 30401493 TI - Comment on "Mean platelet volume and long-term cardiovascular outcomes in patients with stable coronary artery disease". PMID- 30401494 TI - A dose-response association between serum ferritin and metabolic syndrome? PMID- 30401495 TI - Time for risk assessment without borders. PMID- 30401496 TI - Relationships between hospital and surgeon operative volumes and outcomes of esophageal atresia/tracheoesophageal fistula repair. AB - PURPOSE: Most pediatric surgeons perform <2 esophageal atresia and tracheoesophageal fistula (EA/TEF) repairs annually. We aimed to determine whether higher surgeon and hospital volumes are associated with better outcomes after EA/TEF repair. METHODS: Neonates with a diagnosis and repair of EA/TEF at their index hospital admission in the Pediatric Health Information System from 1/2000 to 9/2015 were included. For each patient, hospital and surgeon operative volumes were defined as the number of EA/TEF cases treated in the previous 365 days. Propensity score weighting was used to estimate relationships between operative volumes and rates of in-hospital mortality, readmission within 30 days, and readmission, reoperation, and dilation within one year. RESULTS: Among 3085 patients, lower birth weight, earlier gestational age, the presence of congenital heart disease, and certain other anomalies were associated with higher mortality. In risk-adjusted analyses, there were no significant differences in mortality or any other outcome based on hospital or surgeon volume alone or when comparing low or high-volume surgeons practicing at low- or high-volume hospitals. CONCLUSIONS: Neither surgeon nor hospital volume significantly impacted outcomes after EA/TEF repair. Our findings imply that selective referral and pediatric surgeon subspecialization in EA/TEF may not translate to improved outcomes. TYPE OF STUDY: Retrospective comparative study LEVEL OF EVIDENCE: Level III. PMID- 30401497 TI - Clinical outcomes following identification of tip appendicitis on ultrasonography and CT scan. AB - BACKGROUND/PURPOSE: With recent improvements in imaging technology, subtler variations in the anatomy of the appendix can be appreciated. We hypothesized that radiographic findings of tip appendicitis may not correlate strongly with a pathologic diagnosis of appendicitis. METHODS: Our radiology database was searched for reports of a diagnosis of tip appendicitis between January 2013 and June 2017 for patients between the ages of 2 and 17. Retrospective chart review was performed for demographic and clinical data, including outcomes. For patients managed operatively, the pathology results were reviewed for evidence of acute appendicitis. Patients managed nonoperatively and those with negative pathology were considered to not have appendicitis. RESULTS: Fifty-five patients met inclusion criteria (31 boys and 24 girls); 46/55 patients with tip appendicitis on imaging ultimately did not have appendicitis. Twenty-one patients underwent appendectomy, and 9/21 had pathologic evidence of appendicitis. One patient had a ruptured appendix. No other pathology was identified in the negative appendectomies. Two patients managed nonoperatively required readmission, but not secondary to missed diagnosis of appendicitis. CONCLUSIONS: Ultrasound and CT findings of tip appendicitis may not accurately associate with a final diagnosis of acute appendicitis. Clinical judgment should ultimately dictate appropriate initial management, follow-up tests, and imaging. TYPE OF STUDY: Diagnostic Study. LEVEL OF EVIDENCE: Level III. PMID- 30401498 TI - Attempting to trace the origins of circumcision. PMID- 30401499 TI - Corrigendum to "Clear evidence for item limits in visual working memory" [Cogn. Psychol. 97 (2017) 79-97]. PMID- 30401500 TI - Universal significance of the principle of Samanya and Vishesha beyond Ayurveda. AB - There is a fundamental principle in Ayurveda, known as the principle of Samanya (similarity) and Vishesha (difference). While the principle was essentially propounded in the context of yuktivyapashraya (rational medicine) in Ayurveda, here we would like to argue that it has universal applicability in Ayurveda and beyond, across systems and domains of knowledge, including science, technology and humanities, as well as scientific, experiential and traditional knowledge systems. Taking examples of some of the most well-known problems of ecology, economy and society, we demonstrated the universal significance of the principle of Samanya and Vishesha. To illustrate our argument, we have discussed three brief cases, as diverse as family, climate governance, and poverty reduction, and discussed in the light of the Samanya and Vishesha. Evidently, these issues also have larger relevance to public health. Bringing an Ayurveda concept out from its premises is a new order of thinking. The path-breaking insights that were provided, have important implication for deciphering other basic principles of Ayurveda from the perspective of their wider applicability, and thus their robustness. We have indicated a way forward for future research in Ayurveda to develop knowledge-base for evidence-based clinical practice in contemporary society. PMID- 30401501 TI - Discovery of a non-toxic [1,2,4]triazolo[1,5-a]pyrimidin-7-one (WS-10) that modulates ABCB1-mediated multidrug resistance (MDR). AB - Multidrug resistance (MDR) has been shown to reduce the effectiveness of chemotherapy. Strategies to overcoming MDR have been widely explored in the last decades, leading to a generation of numerous small molecules targeting ABC and MRP transporters. Among the ABC family, ABCB1 plays key roles in the development of drug resistance and is the most well studied. In this work, we report the discovery of non-toxic [1,2,4]triazolo[1,5-a]pyrimidin-7-one (WS-10) from our structurally diverse in-house compound collection that selectively modulates ABCB1-mediated multidrug resistance. WS-10 enhanced the intracellular accumulation of paclitaxel in SW620/Ad300 cells, but did not affect the expression of ABCB1 Protein and ABCB1 localization. The cellular thermal shift assay (CETSA) showed that WS-10 was able to bind to ABCB1, which could be responsible for the reversal effect of WS-10 toward paclitaxel and doxorubicin in SW620/Ad300 cells. Docking simulations were performed to show the possible binding modes of WS-10 within ABCB1 transporter. To conclude, WS-10 could be used as a template for designing new ABCB1 modulators to overcome ABCB1-mediated multidrug resistance. PMID- 30401502 TI - Synthesis and in vitro evaluation of diverse heterocyclic diphenolic compounds as inhibitors of DYRK1A. AB - Dual-specificity tyrosine phosphorylation-related kinase 1A (DYRK1A) is a dual specificity protein kinase that catalyses phosphorylation and autophosphorylation. Higher DYRK1A expression correlates with cancer, in particular glioblastoma present within the brain. We report here the synthesis and biological evaluation of new heterocyclic diphenolic derivatives designed as novel DYRK1A inhibitors. The generation of these heterocycles such as benzimidazole, imidazole, naphthyridine, pyrazole-pyridines, bipyridine, and triazolopyrazines was made based on the structural modification of the lead DANDY and tested for their ability to inhibit DYRK1A. None of these derivatives showed significant DYRK1A inhibition but provide valuable knowledge around the importance of the 7-azaindole moiety. These data will be of use for developing further structure-activity relationship studies to improve the selective inhibition of DYRK1A. PMID- 30401503 TI - The Battle between TET Proteins and DNA Methylation for the Right Cell. AB - DNA methylation is an important epigenetic barrier during somatic cell reprogramming. Yet, how genome-wide methylation is reprogrammed remains largely unknown. Sardina et al. (Cell Stem Cell 2018:https://doi.org/10.1016/j.stem.2018.08.016) address this question by mapping the DNA methylomes of cells undergoing reprogramming and show that TET proteins and transcription factors cooperate to orchestrate demethylation critical to reprogramming. PMID- 30401504 TI - Novel therapeutic targets in autoimmune hepatitis. AB - Autoimmune hepatitis (AIH) is an orphan disease characterized by an autoimmune attack against hepatocytes. The exact sequence of events that leads to a breach of tolerance is incompletely understood. Current hypotheses suggest that environmental agents such as toxins or infectious agents like viruses cause a tissue damage that initiates autoimmunity in genetically susceptible individuals. The growing knowledge of the multi-facetted immune dysregulation, which involves Th1/Th17 polarization and the suspected inability of regulatory T cells to revert autoimmunity in the otherwise tolerogenic milieu of the liver, offers multiple new therapeutic approaches and targets. Standard of care (SOC) is treatment with corticosteroids with or without azathioprine, which is sufficient to induce remission in the majority of patients. However, it rarely cures AIH or restores intrahepatic immune tolerance. Hence, life-long therapy is required in the majority of patients. In addition, several studies suggest a weakening of immune regulation mediated by intrahepatic T cells under current therapies. Furthermore, second line therapies for non-responders, intolerant or otherwise difficult to treat patients are urgently needed as this is relevant for at least one fifth of all patients with inefficacy or intolerance to SOC. Current second line therapies are mainly based on single center retrospective experiences and none of them have been approved by regulatory authorities for AIH, yet. This article highlights new therapeutic approaches based on our growing knowledge on the pathophysiology of AIH. It focuses on cell-based therapies that strengthen or restore immune tolerance. An additional focus lies on new therapeutic agents showing promising results in non-hepatic autoimmune diseases that have a potential for treating AIH. The dynamics in the whole field of innovative therapies for non-hepatic autoimmune diseases will hopefully improve the therapeutic armamentarium for AIH patients in the future. PMID- 30401505 TI - Reply letter to "Chikungunya in Bolivia: Domestic imported case series in Cochabamba". PMID- 30401506 TI - A combined, totally magnetic technique with a magnetic marker for non-palpable tumour localization and superparamagnetic iron oxide nanoparticles for sentinel lymph node detection in breast cancer surgery. AB - BACKGROUND: Surgery for non-palpable breast cancer may often be a challenging procedure. Recently, a magnetic seed (Magseed(r)) used for tumour localization has been developed. Superparamagnetic iron oxide nanoparticles (SPIO) for sentinel lymph node (SN) detection is a novel tracer that may be injected up to four weeks preoperatively. This study is the first combining the magnetic seed and SPIO. MATERIAL AND METHODS: Patients planned for breast conserving surgery and SN-biopsy (SNB) were recruited from two units in Sweden. Patients underwent lesion localization with Magseed(r) and SPIO injection (MagtraceTM) by the breast radiologist in the preoperative period. Feasibility of successful lesion localization and excision together with a successful SNB detection was evaluated. Seed migration, number of SNs, specimen volume and calculated resection ratio (CRR) were reported.A survey of the physicians' experience was conducted. RESULTS: Localization was performed at a median of three days before surgery (range 0-25). All 32 patients underwent microscopically radical resection with a CRR of 1.49. No seed migration was noticed. SNB was successful in all patients. A median of two SNs was retrieved. Radiologists and surgeons reported the procedure easy to learn and outperformed guidewire localization in terms of localization and excision time. They thought the technique facilitated planning localization and surgery. CONCLUSIONS: The combined magnetic technique provided accuracy in tumour localization and SN detection without excess tissue excision and with promising results for flexibility in delivery of care. Larger studies are needed to confirm these findings. PMID- 30401507 TI - Albumin-bilirubin (ALBI) grade-based nomogram to predict tumor recurrence in patients with hepatocellular carcinoma. AB - BACKGROUND: Tumor recurrence after curative resection is common in hepatocellular carcinoma (HCC), but large-scale long-term prediction on an individual basis has seldom been reported. We aimed to construct an albumin-bilirubin (ALBI) grade based nomogram to predict tumor recurrence in patients with HCC undergoing surgical resection. METHODS: A total 1038 patients with newly diagnosed HCC undergoing curative resection between 2002 and 2016 were enrolled. Baseline characteristics, tumor status and severity of liver functional reserve were collected. The Cox proportional hazards model was used to predict tumor recurrence and construct the nomogram. The performance of the nomogram was evaluated by the discrimination and calibration tests. RESULTS: After a mean follow up time of 30 months, 510 (49%) patients developed tumor recurrence. The cumulative recurrence-free survival at 1, 3, 5, and 10 years were 79%, 51%, 38% and 26%, respectively. In the Cox multivariate model, ALBI grade 2-3, multiple tumors, tumor size equal or large than 2 cm, serum alpha-fetoprotein level equal or greater than 20 ng/ml and total tumor volume equal or larger than 227 cm3 were independent risk factors associated with tumor recurrence. A nomogram was constructed based on these five variables. Internal validation with 10,380 bootstrapped sample sets had a good concordance of 0.607 (95% of confidence interval: 0.587-0.627). The calibration plots for 1-, 3- and 5-year recurrence free survival well matched the idealized 45-degree line. CONCLUSIONS: ALBI is a feasible marker for tumor recurrence. This easy-to-use ALBI grade-based nomogram may predict tumor recurrence for individual HCC patient undergoing surgical resection. PMID- 30401508 TI - Influence of Probe Pressure on Ultrasound-Based Shear Wave Elastography of the Liver Using Comb-Push 2-D Technology. AB - It has been postulated that in the liver, applying increased probe pressure during ultrasound-based shear wave elastography (SWE) might lead to a false increase in the SWE result. We aimed to determine the influence of increased intercostal probe pressure when performing SWE of the liver. We also investigated the number of measurements required to achieve technically successful and reliable SWE examinations. This prospective, clinical study included 112 patients and 2240 SWE measurements of the liver. We applied probe pressure intercostally, to reduce the skin-to-liver capsule distance (SCD), which could stabilize the SWE signal and thus increase the number of technically successful measurements. We performed 10 measurements with maximum probe pressure and 10 with normal pressure in each patient. Thus, two analysis groups were compared for differences. Compared with normal pressure, maximum probe pressure significantly reduced the SCD (p < 0.001) and significantly increased the number of technically successful measurements from 981 to 1098, respectively (p < 0.001). The SWE results with normal and maximum probe pressure were 5.96 kPa (interquartile range: 2.41) and 5.45 kPa (interquartile range: 1.96), respectively (p < 0.001). In obese patients, a large SCD poses a diagnostic challenge for ultrasound SWE. We found that maximum intercostal probe pressure could reduce the SCD and increase the number of technically successful measurements, without falsely increasing the SWE result. Only three measurements were required to achieve technically successful and reliable SWE examinations. PMID- 30401509 TI - Comparative Assessment of Hand Joint Ultrasound Findings in Symptomatic Patients with Systemic Lupus Erythematosus and Sjogren's Syndrome: A Pilot Study. AB - Systemic lupus erythematosus (SLE) and primary Sjogren's syndrome (SS) can be associated with inflammatory arthritis, which is underdiagnosed by clinical examination. The aim of this cross-sectional, observational study was to compare, for the first time, the ultrasound (US)-detected joint abnormalities in these two diseases and to define the role of US in patient management. Participants had SLE (n = 18) and SS (n = 23), symptoms of hand joint pain and no previous diagnosis of arthritis. Data on disease activity, duration, damage scores, inflammatory and serologic markers, treatment and clinical and ultrasound parameters (derived from the assessment of 902 joints) were analysed and correlated using descriptive statistics, correlation tests and regression models. Subclinical synovitis/tenosynovitis was detected in 44.4% of SLE patients and 21.7% of SS patients (p = 0.23). There was no significant correlation between either the total Power Doppler score or the total grey-scale score and disease activity scores (British Isles Lupus Assessment Group index and European League Against Rheumatism Sjogren's syndrome disease activity index). Both damage scores (Systemic Lupus International Collaborating Clinics index and Sjogren's syndrome disease damage index) correlated with the total grey-scale synovitis score. Significant proportions of the participants with SLE and SS had erosions (55.6% and 34.8%, respectively, p = 0.184) and osteophytes (61.1% vs. 60.9%, p = 0.98) in at least one joint. The lack of correlation between disease activity scores and US outcome measures indicated their limitations in diagnosing subclinical synovitis in SLE and SS patients. Future research is needed to determine if the development of erosions could be prevented by early diagnosis and prompt treatment of inflammatory arthritis associated with SLE and SS. PMID- 30401510 TI - Second-look arthroscopy after anatomic anterior cruciate ligament reconstruction: Bone-patellar tendon-bone versus hamstring tendon graft. AB - PURPOSE: The purpose of this study was to compare the morphological and clinical outcomes between anatomic rectangular tunnel (ART) ACL reconstruction with a BTB graft and anatomic triple-bundle (ATB) ACL reconstruction with hamstring tendon (HST) grafts. METHODS: The anatomic ACL reconstructions were performed on 467 patients; 233 patients with ART technique and 234 with ATB procedure. ART procedure was predominantly indicated for athletes with higher motivation to return to sports and aggressiveness for muscle training. A total of 113 patients, with a mean age of 20.7 years, had consented to undergo second-look arthroscopy. The average time from ACL reconstruction to the second-look was 10.0 months. This study included 56 ART techniques and 57 ATB procedures. The grafts underwent meticulous probing, and were evaluated based on tension, graft damage, and synovial coverage. Moreover, the femoral tunnel aperture was also observed in detail to assess the space between the femoral tunnel and the graft. As clinical evaluation, knee effusion, range of motion, Lachman test, pivot shift test, KT side-to-side difference, and Lysholm score were assessed. RESULTS: There was no significant difference in graft tension between two procedures, while HST graft in ATB procedure had more cases with graft damage (p = 0.05). Good synovial coverage was found in 98% in ART procedure and 70% in ATB procedure, showing a significant difference (P < 0.001). At femoral tunnel aperture, there were no cases with the space around BTB graft, while 33% showed the space around HST graft, again showing a significant difference (P < 0.001). There were no significant differences in clinical outcomes. CONCLUSION: BTB graft with the ART procedure was superior to HST graft with the ATB procedure in morphology at second-look arthroscopy, while there was no significant difference in clinical outcomes between two procedures. PMID- 30401511 TI - Predictors of Short Intensive Care Unit Stay for Patients with Diabetic Ketoacidosis Using a Novel Emergency Department-Based Resuscitation and Critical Care Unit. AB - BACKGROUND: The resuscitation and critical care unit is a novel emergency department-intensive care unit designed to provide early critical care to emergency department patients for <=24 h. OBJECTIVES: This study sought to identify clinical variables associated with short intensive care unit (ICU) stays in patients with diabetic ketoacidosis (DKA), who commonly require ICU-level care. METHODS: We conducted a retrospective, single-center, cross-sectional study of DKA patients >=18 years of age who presented to an academic, urban hospital emergency department over 16 months. Patient demographics and clinical variables extracted from medical records were compared between prolonged ICU stay patients of >=24 h versus short ICU stay patients (SSPs) of <24 h. ICU care was defined as treatment in the resuscitation and critical care unit or inpatient ICU. RESULTS: One hundred sixty-eight emergency department visits with a primary diagnosis of DKA were analyzed. There were 53 prolonged ICU stay patients, 58 SSPs, and 57 patients required no ICU time. SSPs had significantly higher initial serum bicarbonate (13.0 vs. 9.0 mEq/L, p = 0.01) and shorter anion gap closure time (9.8 vs. 14.4 hours, p = 0.003). Medication nonadherence was a significantly more frequent precipitant in SSPs (67.2% vs. 47.2%, p = 0.03). Initial anion gap, glucose, beta-hydroxybutyrate, and severity of illness scores were not significantly different between groups. After multivariate logistic regression adjusting for variables significant from univariate analysis, higher initial bicarbonate (p = 0.04) and medication nonadherence (p = 0.03) remained significantly associated with SSPs. CONCLUSIONS: Patients with DKA with short ICU stays have higher initial bicarbonate levels and are more likely to have medication nonadherence than patients requiring prolonged critical care. These variables may identify patients with DKA who are best treated in an emergency department-intensive care unit to potentially reduce inpatient ICU use. PMID- 30401512 TI - Clinical immunotherapeutic approaches for the treatment of head and neck cancer. AB - Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide, accounting for more than 550,000 cases and 380,000 deaths annually. The primary risk factors associated with HNSCC are tobacco use and alcohol consumption; nevertheless genetic predisposition and oncogenic viruses also play important roles in the development of these malignancies. The current treatments for HNSCC patients include surgery, chemotherapy, radiotherapy, and cetuximab, and combinations of these. However, these treatments are associated with significant toxicity, and many patients are either refractory to the treatment or relapse after a short period. Despite improvements in the treatment of patients with HNSCC, the clinical outcomes of those who have been treated with standard therapies have remained unchanged for over three decades and the 5-year overall survival rate in these patients remains around 40-50%. Therefore, more specific and less toxic therapies are needed in order to improve patient outcomes. The tumour microenvironment of HNSCC is immunosuppressive; therefore immunotherapy strategies that can overcome the immunosuppressive environment and produce long term tumour immunosurveillance will have a significant therapeutic impact in these patients. This review focuses on the current immunological treatment options under investigation or available for clinical use in patients with HNSCC. PMID- 30401513 TI - Antifungal susceptibility trend and analysis of resistance mechanism for Candida species isolated from bloodstream at a Japanese university hospital. AB - We compared the susceptibility of six commercially available antifungal agents (fluconazole, itraconazole, voriconazole, caspofungin, micafungin, and amphotericin B) against 133 Candida bloodstream isolates between 2008 and 2013 at Aichi Medical University Hospital. C. albicans was the most common isolate, followed by C. parapsilosis, C. glabrata, and C. tropicalis. MIC90s of voriconazole against C. albicans, C. parapsilosis, and C. tropicalis were the lowest and that of micafungin against C. glabrata was the lowest among the agents tested. Of the 133 isolates, two strains were identified as drug-resistant. One was a fluconazole-resistant C. glabrata strain, in which the ATP-binding cassette (ABC) transporter gene expression was upregulated. The other was a micafungin resistant C. glabrata strain, that had 13 amino acid substitutions in FKS1 and FKS2, including a novel substitution V1342I in FKS1 hotspot 2. We also evaluated the susceptibility of T-2307, a novel class of antifungal agents used in clinical trials, against the fluconazole- and micafungin-resistant C. glabrata strain; the MICs of T-2307 were 0.0039 and 0.0078 MUg/mL, respectively. In conclusion, the incidence of bloodstream infection caused by drug-resistant Candida spp. was rare from 2008 to 2013 at our hospital. Of 133 isolates, only two strains of C. glabrata were resistant to azoles or echinocandins, that upregulated the ABC transporter genes or had novel FKS mutations, respectively. PMID- 30401514 TI - FADD at the Crossroads between Cancer and Inflammation. AB - Initially described as an adaptor molecule for death receptor (DR)-mediated apoptosis, Fas-associated death domain (FADD) was later implicated in nonapoptotic cellular processes. During the last decade, FADD has been shown to participate and regulate most of the signalosome complexes, including necrosome, FADDosome, innateosome, and inflammasome. Given the role of these signaling complexes, FADD has emerged as a new actor in innate immunity, inflammation, and cancer development. Concomitant to these new roles, a surprising number of mechanisms deemed to regulate FADD functions have been identified, including post translational modifications of FADD protein and FADD secretion. This review focuses on recent knowledge of the biological roles of FADD, a pleiotropic molecule having multiple partners, and its impact in cancer, innate immunity, and inflammation. PMID- 30401515 TI - A Stent Graft Visualised Through an Infected Haemodialysis Graft Pseudoaneurysm. PMID- 30401516 TI - Rapid Responses to Abiotic Stress: Priming the Landscape for the Signal Transduction Network. AB - Plants grow and reproduce within a highly dynamic environment that can see abrupt changes in conditions, such as light intensity, temperature, humidity, or interactions with biotic agents. Recent studies revealed that plants can respond within seconds to some of these conditions, engaging many different metabolic and molecular networks, as well as rapidly altering their stomatal aperture. Some of these rapid responses were further shown to propagate throughout the entire plant via waves of reactive oxygen species (ROS) and Ca2+ that are possibly mediated through the plant vascular system. Here, we propose that the integration of these signals is mediated through pulses of gene expression that are coordinated throughout the plant in a systemic manner by the ROS/Ca+2 waves. PMID- 30401517 TI - An update on evidence based diagnostic and confirmatory testing strategies for heparin induced thrombocytopenia using combined immunological and functional assays. AB - This manuscript aims to provide a concise review on current diagnostic/ confirmatory strategies of Heparin Induced Thrombocytopenia (HIT) with the combined use of immunological / functional assays in addition to the clinical probability. Laboratory diagnosis of HIT is of primordial importance as the related complications could become rapidly severe and life-threatening and can provoke limb amputation in some cases. The first action in the presence of HIT suspicion is to withdraw heparin and to initiate an alternative anticoagulant. Whilst vitamin K antagonists are not appropriate, anticoagulant options include Fondaparinux, Sodium Danaparoid, DOACs, Argatroban, and Bivalirudin. However, if HIT is excluded, patients can benefit again from the high therapeutic and antithrombotic efficacy of this drug, which remains superior to all the substitutive anticoagulant treatments. HIT is suspected in the presence of a platelet count drop > 50% on 2 successive counts, or a platelet count < 100 G/L, and of a significant clinical probability (4 Ts score). Testing patients' plasma is required for establishing the diagnosis. Laboratory investigation involves first the immunological measurement of heparin dependent IgG antibodies (mainly targeted to Heparin-Platelet Factor 4 complexes). When positive, a functional assay for platelet activation, performed at a low and high heparin concentration, allows confirming this disease. In any case, if the immuno-assay is negative, HIT can be excluded with a high probability, and heparin can be continued (if clinical examination favors this decision). Conversely, the higher the IgG antibody concentration is (and affinity), the higher is the probability of developing HIT. The functional assay has now become for confirming the platelet activation capacity of antibodies, and therefore confirming the presence of HIT. Up to now, the gold reference method for testing antibody-dependent platelet activation is the C14-Serotonin Release Assay, available only in very few laboratories working with radio-isotopes. A simple, sensitive, and accurate flow cytometry assay becomes now available to all clinical sites, and it can be easily used for testing the capacity of heparin dependent-antibodies to activate platelets, at low heparin concentration. This technique can be performed in any laboratory equipped with a flow cytometer and can make the HIT confirmation diagnosis rapidly available, which introduces a great improvement for management of patients with HIT. We believe that an evidence-based update on this topic is timely and well warranted. PMID- 30401518 TI - Management of acquired von Willebrand syndrome. AB - Acquired von Willebrand syndrome (AVWS) is a rare acquired bleeding disorder that resembles von Willebrand disease by its clinical symptoms and laboratory findings, but differs by its negative personal and family history of bleeding diathesis. AVWS is mostly seen in the elderly, but it has been described in children, often in those with congenital heart disease and Wilms tumor. It is most commonly associated with lymphoproliferative, myeloproliferative, cardio vascular, or autoimmune diseases, solid tumors, and certain drugs. The diagnosis should be suspected in a patient who is known for one of these underlying conditions and who presents with new onset of bleeding or who will be undergoing an invasive procedure. Treatment of the underlying condition, when possible, usually results in correction of AVWS. When acute bleeding occurs or the underlying condition is not treated, emphasis should be put on control and prevention of bleeding. Many options are available. DDAVP is the first line of treatment for bleeding. vWF concentrates are used to treat bleeding that is unresponsive to DDAVP and as prophylaxis before procedures. This review summarises current knowledge and reviews the different management options for bleeding. PMID- 30401519 TI - Impact of indocyanine green-fluorescence imaging on distal pancreatectomy with celiac axis resection combined with reconstruction of the left gastric artery. AB - BACKGROUND: We previously reported the usefulness of distal pancreatectomy with celiac axis resection (DP-CAR) with left gastric artery (LGA) reconstruction to prevent ischemic gastropathy. To evaluate the reconstruction quality, we performed intraoperative angiography with indocyanine green (ICG)-fluorescence imaging. METHODS: 21 consecutive patients planned for DP-CAR with LGA reconstruction were enrolled in this prospective, exploratory single-arm study from 2014 to 2017. After LGA reconstruction, intraoperative angiography revealed continuous arterial flow passing through the anastomotic sites and gradually increasing tissue perfusion in the stomach. RESULTS: Three patients were excluded. Among the remaining 18 patients, we obtained good flow in 11 patients and poor flow in 7 patients after initial LGA reconstruction. Among the seven patients with poor flow, five underwent LGA re-anastomosis, three recovered good flow. The incidence of grade B/C DGE was 14% (2/14) in the finally good flow group and 75% (3/4) in the poor flow group (p = 0.019). Ischemic gastropathy occurred in two patients (50%) in the poor flow group (p = 0.039), including one with a gastric perforation. DISCUSSION: Our data show that intraoperative angiography with ICG-fluorescence imaging can evaluate the reconstruction quality, thus contributing to improvements in the short-term outcome of DP-CAR with LGA reconstruction. PMID- 30401520 TI - 18F-FDG PET/CT predicts microvascular invasion and early recurrence after liver resection for hepatocellular carcinoma: A prospective observational study. AB - BACKGROUND: This study assessed the prognostic value of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) in the prediction of MVI and early recurrence following resection. METHOD: This prospective study (ClinicalTrials.gov ID: NCT02145013) included 78 consecutive HCC patients who underwent 18F-FDG PET/CT before curative-intent resection from 2014 to 2017. Prognostic factors available before surgery for predicting MVI and early recurrence (<=2 years) were identified by univariate and multivariate analyses. RESULTS: The 18F-FDG PET/CT result was positive in 30 (38%) patients. MVI was present in 33% (26/78) of specimens. Early recurrence occurred in 19% (14/74) of surviving patients. PET/CT positivity was the sole independent predictor of MVI (odds ratio [OR] = 3.6, 95% confidence interval [CI] = 1.1-11.2; p = 0.03), with a specificity and sensitivity for predicting MVI of 73% and 62%, respectively. Analysis of variables available before surgery showed that PET/CT positivity (hazard ratio [HR] = 5.8, 95% CI = 1.6-20.4; p = 0.006) and the male sex (HR = 6.6; 95% CI = 1.8-24.2; p = 0.005) were independent predictors of early recurrence. CONCLUSION: 18F-FDG PET/CT predicts MVI and early recurrence after surgery for HCC and could be used to select patients for neoadjuvant treatment. PMID- 30401521 TI - CD34+ chimerism analysis for minimal residual disease monitoring after allogeneic hematopoietic cell transplantation. PMID- 30401522 TI - Incorporating newer agents in the treatment of acute myeloid leukemia. AB - Prognosis for patients with AML remains dismal. Despite multiple clinical trials across several decades, little improvement for the therapy of non-APL AML was noted. However, over the last couple of years, several new therapies have demonstrated efficacy in the therapy of patients with AML. Several of those have been approved by the FDA for AML therapy. These include CPX-351, midostaurin, gemtuzumab ozogamicin, enasidenib and ivosidenib. Our goal in this review is to summarize currently available data on these new therapies and discuss the rapidly evolving treatment landscape of AML. PMID- 30401523 TI - Push your luck! PMID- 30401524 TI - Decision making in thoracic aortic surgery: One size fits all? PMID- 30401525 TI - Ascending to the summit of robotic hybrid revascularization. PMID- 30401526 TI - Left atrial to left ventricular valved conduit for a calcified mitral annulus and ascending aorta. PMID- 30401527 TI - The unintended consequences in clinical research. PMID- 30401528 TI - Aspirin in coronary artery surgery: 1-year results of the Aspirin and Tranexamic Acid for Coronary Artery Surgery trial. AB - BACKGROUND: Aspirin may reduce the risk of vascular graft thrombosis after cardiovascular surgery. We previously reported the 30-day results of a trial evaluating aspirin use before coronary artery surgery. Here we report the 1-year outcomes evaluating late thrombotic events and disability-free survival. METHODS: Using a factorial design, we randomly assigned patients undergoing coronary artery surgery to receive aspirin or placebo and tranexamic acid or placebo. The results of the aspirin comparison are reported here. The primary 1-year outcome was death or severe disability, the latter defined as living with a modified Katz activities of daily living score < 8. Secondary outcomes included a composite of myocardial infarction, stroke and death from any cause through to 1 year after surgery. RESULTS: Patients were randomly assigned to aspirin (1059 patients) or placebo (1068 patients). The rate of death or severe disability was 4.1% in the aspirin group and 3.5% in the placebo group (relative risk, 1.17; 95% confidence interval, 0.76-1.81; P = .48). There was no significant difference in the rates of myocardial infarction (P = .11), stroke (P = .086), or death (P = .24), or a composite of these cardiovascular end points (P = .68). With the exception of those with a low European System for Cardiac Operative Risk Evaluation score (P = .03), there were no interaction effects on these outcomes with tranexamic acid (all tests of interaction P > .10). CONCLUSIONS: In patients undergoing coronary artery surgery, preoperative aspirin did not reduce death or severe disability, or thrombotic events through to 1 year after surgery. PMID- 30401529 TI - The myocardial infarct-exacerbating effect of cell-free DNA is mediated by the high-mobility group box 1-receptor for advanced glycation end products-Toll-like receptor 9 pathway. AB - INTRODUCTION: Damage-associated molecular patterns, such as high-mobility group box 1 (HMGB1) and cell-free DNA (cfDNA), play critical roles in mediating ischemia-reperfusion injury (IRI). HMGB1 activates RAGE to exacerbate IRI, but the mechanism underlying cfDNA-induced myocardial IRI remains unknown. We hypothesized that the infarct-exacerbating effect of cfDNA is mediated by HMGB1 and receptor for advanced glycation end products (RAGE). METHODS: C57BL/6 wild type mice, RAGE knockout (KO), and Toll-like receptor 9 KO mice underwent 20- or 40-minute occlusions of the left coronary artery followed by up to 60 minutes of reperfusion. Cardiac coronary perfusate was acquired from ischemic hearts without reperfusion. Exogenous mitochondrial DNA was acquired from livers of normal C57BL/6 mice. Myocardial infarct size (IS) was reported as percent risk region, as measured by 2,3,5-triphenyltetrazolium chloride and Phthalo blue (Heucotech, Fairless Hill, Pa) staining. cfDNA levels were measured by Sytox Green assay (Thermo Fisher Scientific, Waltham, Mass) and/or spectrophotometer. RESULTS: Free HMGB1 and cfDNA levels were increased in the ischemic myocardium during prolonged ischemia and subsequently in the plasma during reperfusion. In C57BL/6 mice undergoing 40'/60' IRI, deoxyribonuclease I, or anti-HMGB1 monoclonal antibody reduced IS by approximately half to 29.0% +/- 5.2% and 24.3% +/- 3.5% (P < .05 vs control 54.3% +/- 3.4%). However, combined treatment with deoxyribonuclease I + anti-HMGB1 monoclonal antibody did not further attenuate IS (29.3% +/- 4.9%). In C57BL/6 mice undergoing 20'/60' IRI, injection of 40'/5' plasma upon reperfusion increased IS by more than 3-fold (to 19.9 +/- 4.3; P < .05). This IS exacerbation was abolished by pretreating the plasma with deoxyribonuclease I or by depleting the HMGB1 by immunoprecipitation, or by splenectomy. The infarct-exacerbating effect also disappeared in RAGE KO mice and Toll-like receptor 9 KO mice. Injection of 40'/0' coronary perfusate upon reperfusion similarly increased IS. The levels of HMGB1 and cfDNA were significantly elevated in the 40'/0' coronary perfusate and 40'/reperfusion (min) plasma but not in those with 10' ischemia. In C57BL/6 mice without IRI, 40'/5' plasma significantly increased the interleukin 1beta protein and messenger RNA expression in the spleen by 30 minutes after injection. Intravenous bolus injection of recombinant HMGB1 (0.1 MUg/g) or mitochondrial DNA (0.5 MUg/g) 5 minutes before reperfusion did not exacerbate IS (P = not significant vs control). However, combined administration of recombinant HMGB1 + mitochondrial DNA significantly increased IS (P < .05 vs individual treated groups) and this infarct-exacerbating effect disappeared in RAGE KO mice and splenectomized C57BL/6 mice. The accumulation of cfDNA in the spleen after combined recombinant HMGB1 + mitochondrial DNA treatment was significantly more elevated in C57BL/6 mice than in RAGE KO mice. CONCLUSIONS: Both HMGB1 and cfDNA are released from the heart upon reperfusion after prolonged ischemia and both contribute importantly and interdependently to post-IRI by a common RAGE-Toll like receptor 9-dependent mechanism. Depleting either of these 2 damage associated molecular patterns suffices to significantly reduce IS by approximately 50%. PMID- 30401530 TI - Differential outcomes of open and clamp-on distal anastomosis techniques in acute type A aortic dissection. AB - OBJECTIVES: Open-distal anastomosis is the preferred technique over clamp-on technique for surgical repair of acute type A aortic dissection (ATAAD). The aim of this study was to define how outcomes of ATAAD were affected by the use of either technique. METHODS: Nordic Consortium for Acute Type A Aortic Dissection includes 8 academic cardiothoracic hospitals in 4 Nordic countries. The cohort consisted of 1134 patients, 153 clamp-on and 981 open-distal, from 2005 to 2014. RESULTS: Patients who underwent operation with the clamp-on were younger, more frequently had coronary artery disease, bicuspid aortic valve, hypotension/shock or syncope, and a greater PennClass than open-distal patients. Postoperative cerebral vascular accident occurred less frequently in clamp-on (14/153, 10%) compared with the open-distal group (190/981, 20%). Clamp-on had greater 30-day mortality (39/153, 25%) than the open-distal group (158/981, 16%), and 5-year survival was also worse in clamp-on (61.8% +/- 4.4%) compared with the open distal group (73.0% +/- 1.6%). The open-distal technique was used more frequently in greater-volume hospitals but was not independently associated with 30-day mortality. Preoperative condition was an independent risk factor whereas hospital volume and later year of operation were beneficial in regard to short-term outcome. Open-distal was independently associated with improved mid-term survival. CONCLUSIONS: Patients who underwent operation with the clamp-on were sicker on presentation and had worse short- and mid-term survival compared with the open-distal group. Patients in the open-distal group had greater rates of cerebrovascular complications. The results support the routine use of open-distal anastomosis as the primary operative strategy for ATAAD, although clamp-on can be performed successfully in select cases. PMID- 30401531 TI - Outcomes of surgery for functional cardiac paragangliomas: A single-center experience of 17 patients. AB - OBJECTIVE: Cardiac paragangliomas are rare neuroendocrine tumors. Early surgical treatment improves clinical symptoms and prolongs survival. We review our experience in 17 patients who underwent surgical resection for functional cardiac paraganglioma. METHODS: Seventeen patients underwent surgery for functional cardiac paraganglioma from 2004 to 2017 were identified. Clinical data and long term outcomes were extracted and analyzed. RESULTS: All 17 patients with cardiac paraganglioma (11 males) with a median age of 35 years (range, 11 to 51 years) were hormonally functional and underwent operations. A 24-hour urine catecholamine assay documented elevation of norepinephrine, epinephrine, and dopamine. Tumors were determined with octreotide scintiscan in all 17 patients and metaiodoben-zylguanidine scintigraphy in 10 of 15 patients. Tumor sites were right atrioventricular groove in 4 patients, between the main arteries in 10 patients, and interatrial groove in 4 patients. All patients underwent complete resection. Concomitant surgeries were: structural reconstruction in 16 patients (94%) and coronary artery bypass graft in 8 patients (47%). One patient had a history of incomplete resection of an intra-atrial tumor. One patient died postoperatively. Operative mortality is 5.8%. During follow-up (mean, 6.5 years; range, 1.5 to 14.2 years), 16 patients are alive in functional class I or II. Two patients developed tumor recurrence and 14 remained symptom-free with normal urinary catecholamines. CONCLUSIONS: With a multidisciplinary treatment, early diagnosis, complete resection for the tumor along with complex reconstruction is achievable for most patients, and it offers promising long-term survival. PMID- 30401532 TI - The absorption of aspirin is reduced after coronary artery bypass grafting. AB - BACKGROUND: Despite treatment with the antiplatelet drug aspirin, some patients who undergo coronary artery bypass grafting (CABG) experience a thromboembolic event in the early postoperative period. The etiology of a reduced aspirin effect after CABG is still unsolved. Hence, we investigated whether patients who undergo CABG have a reduced absorption of aspirin after surgery, measured as levels of plasma salicylic acid (SA). METHODS: In total, 53 patients were included between October 2015 and May 2018. Blood samples where obtained at the day before surgery, and at the first (day 1) and second (day 2) postoperative day. A subgroup of 10 patients had additional blood samples obtained on day 1. Plasma SA was measured using liquid chromatography-electrospray-ionization tandem-mass spectrometry. Multiplate Analyzer (Roche, Roche Diagnostics, Mannheim, Germany) and VerifyNow Aspirin Test (Accumetrics, San Diego, Calif) were used to assess platelet aggregation as a measurement of the antiplatelet effect of aspirin. RESULTS: A comparison of the difference in change of SA concentration between the day before surgery with day 1 and day 2 showed a significantly reduced increase in SA plasma levels after intake of aspirin at day 1 and day 2 after surgery (P < .0001), including a significantly reduced SA increase in the subgroup at 2, 3, and 4 hours after intake of aspirin. Corresponding with a reduced effect of aspirin, neither Multiplate Analyzer arachidonic acid, nor VerifyNow Aspirin Test showed a significant reduction in platelet aggregation 1 hour after intake of aspirin at day 1 (P < .0001). This also accounted for the subgroup 2, 3, and 4 hours after aspirin intake on day 1. At day 2 the same pattern as preoperatively was detected. CONCLUSIONS: After CABG, the SA level and the effect of aspirin were reduced in the immediate postoperative period. PMID- 30401533 TI - The role of protein tyrosine phosphatases in prostate cancer biology. AB - Prostate cancer (PCa) is the most frequent malignancy in the male population of Western countries. Although earlier detection and more active surveillance have improved survival, it is still a challenge how to treat advanced cases. Since androgen receptor (AR) and AR-related signaling pathways are fundamental in the growth of normal and neoplastic prostate cells, targeting androgen synthesis or AR activity constitutes the basis of the current hormonal therapies in PCa. However, resistance to these treatments develops, both by AR-dependent and independent mechanisms. Thus, alternative therapeutic approaches should be developed to target more efficiently advanced disease. Protein tyrosine phosphatases (PTPs) are direct regulators of the protein- and residue-specific phosphotyrosine (pTyr) content of cells, and dysregulation of the cellular Tyr phosphorylation/dephosphorylation balance is a major driving event in cancer, including PCa. Here, we review the current knowledge on the role of classical PTPs in the growth, differentiation, and survival of epithelial prostate cells, and their potential as important players and therapeutic targets for modulation in PCa. PMID- 30401534 TI - Dual-specificity MAP kinase phosphatases in health and disease. AB - It is well established that a family of dual-specificity MAP kinase phosphatases (MKPs) play key roles in the regulated dephosphorylation and inactivation of MAP kinase isoforms in mammalian cells and tissues. MKPs provide a mechanism of spatiotemporal feedback control of these key signalling pathways, but can also mediate crosstalk between distinct MAP kinase cascades and facilitate interactions between MAP kinase pathways and other key signalling modules. As our knowledge of the regulation, substrate specificity and catalytic mechanisms of MKPs has matured, more recent work using genetic models has revealed key physiological functions for MKPs and also uncovered potentially important roles in regulating the pathophysiological outcome of signalling with relevance to human diseases. These include cancer, diabetes, inflammatory and neurodegenerative disorders. It is hoped that this understanding will reveal novel therapeutic targets and biomarkers for disease, thus contributing to more effective diagnosis and treatment for these debilitating and often fatal conditions. PMID- 30401535 TI - Targeting PP2A in cancer: Combination therapies. AB - The serine/threonine phosphatase PP2A regulates a vast portion of the phosphoproteome including pathways involved in apoptosis, proliferation and DNA damage response and PP2A inactivation is a vital step in malignant transformation. Many groups have explored the therapeutic venue of combining PP2A reactivation with kinase inhibition to counteract the very changes in tumor suppressors and oncogenes that lead to cancer development. Conversely, inhibition of PP2A to complement chemotherapy and radiation-induced cancer cell death is also an area of active investigation. Here we review the studies that utilize PP2A targeted agents as combination therapy in cancer. A potential role for PP2A in tumor immunity is also highlighted. PMID- 30401536 TI - cAMP regulation of protein phosphatases PP1 and PP2A in brain. AB - Normal functioning of the brain is dependent upon a complex web of communication between numerous cell types. Within neuronal networks, the faithful transmission of information between neurons relies on an equally complex organization of inter and intra-cellular signaling systems that act to modulate protein activity. In particular, post-translational modifications (PTMs) are responsible for regulating protein activity in response to neurochemical signaling. The key second messenger, cyclic adenosine 3',5'-monophosphate (cAMP), regulates one of the most ubiquitous and influential PTMs, phosphorylation. While cAMP is canonically viewed as regulating the addition of phosphate groups through its activation of cAMP-dependent protein kinases, it plays an equally critical role in regulating removal of phosphate through indirect control of protein phosphatase activity. This dichotomy of regulation by cAMP places it as one of the key regulators of protein activity in response to neuronal signal transduction throughout the brain. In this review we focus on the role of cAMP in regulation of the serine/threonine phosphatases protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) and the relevance of control of PP1 and PP2A to regulation of brain function and behavior. PMID- 30401537 TI - Serine-threonine protein phosphatases: Lost in translation. AB - Protein synthesis is one of the most complex and energy-consuming processes in eukaryotic cells and therefore is tightly regulated. One of the main mechanisms of translational control is post-translational modifications of the components of translational apparatus. Phosphorylation status of translation factors depends on the balanced action of kinases and phosphatases. While many kinase-dependent events are well defined, phosphatases that counteract phosphorylation are rarely determined. This mini-review focuses on the regulation of activity of translational initiation factors by serine/threonine phosphatases. PMID- 30401538 TI - Application and enantiomeric residue determination of diniconazole in tea and grape and apple by supercritical fluid chromatography coupled with quadrupole time-of-flight mass spectrometry. AB - A chiral separation and residue determination method for diniconazole enantiomers in tea, apple, and grape was developed and validated by supercritical fluid chromatography coupled with quadrupole-time-of-flight mass spectrometry (SFC-Q TOF/MS). The two diniconazole enantiomers were separated on a Chiral CCA column, and the chromatographic conditions (mobile phase proportion and modifier, column temperature, backpressure, and auxiliary solvent) were optimized. The optimal SFC Q-TOF/MS conditions were selected as a mobile phase of CO2/isopropanol (IPA) (v/v, 96/4), flow rate at 2.0 mL/min, automated back pressure regulator (ABPR) at 2000 psi, column temperature at 25 C and under electrospray ionization positive mode with the best auxiliary solvent of 2 mmol/L ammonium acetate in methanol/water (v/v, 1/1) at 0.20 mL/min flow rate. Residues in tea and fruit samples were extracted by acetonitrile/water (v/v, 4/1 for fruit and 2/1 for tea), purified by Cleanert TPT or Pesti-Carb solid phase extraction column, then analyzed by SFC-Q-TOF/MS with matrix-matched external standard quantification method. The elution order of diniconazole enantiomers on CCA column was R-(-) diniconazole at first, and S-(+)-diniconazole at second. The standard curve concentration levels of R-(-)-diniconazole and S-(+)-diniconazole in samples ranged from 0.01 mg/L to 1.00 mg/L with the correlation coefficients greater than 0.99. The spiked recoveries of R-(-)-diniconazole and S-(+)-diniconazole in apple and grape at three levels of 0.005, 0.05 and 0.25 mg/kg were in the range of 69.8% to 102.1%, with relative standard deviations (RSDs) (n = 6) between 3.5% and 10.4%, and the limits of quantitation (LOQs) below 0.005 mg/kg. The spiked recoveries in black tea at three levels of 0.01, 0.10, and 0.50 mg/kg were in the range of 85.6% to 90.6%, with the RSDs (n = 6) ranging from 3.9% to 9.5%, and LOQ of 0.01 mg/kg. This residue analysis and determination method for diniconazole enantiomers in apple, grape and tea samples is convenient, reliable, and meets the residue analysis requirement. Also it is applicatied for the residue fates of R-(-)-diniconazole and S-(+)-diniconazole during the fresh tea leaves growing, green tea processing and black tea processing. The degradation half-times (DT50) between R-(-)-diniconazole and S-(+)-diniconazole in the fresh tea leaves growing were 2.9 d and 3.1 d, respectively. The concentrations of R-(-)-diniconazole and S-(+)-diniconazole decreased gradually with time and on the 14th day after application were lower than 10% of the initial concentration. The average enantiomer fractions (EFs) of R-(-)-diniconazole and S-(+)-diniconazole at 2 h, 2, 5, 7, 10 and 14 d after application in fresh tea leaves were 0.505, 0.526, 0.523, 0.558, 0.453 and 0.489, respectively. This result is similar to the result of our last research for the enantiomers of cis-epoxiconazole-another triazole fungicide residues in fresh tea leaves. And in the whole black tea processing, 37.1%-49.3% and 35.9%-57.9% of R-(-)-diniconazole and S-(+)-diniconazole decreased, respectively. The total processing factors (PFs) of R-(-)-diniconazole and S-(+)-diniconazole for the black tea procedure were 0.507-0.629 and 0.421 0.641, respectively. The EFs of R-(-)-diniconazole and S-(+)-diniconazole in black tea processing ranged from 0.432 to 0.532. However, in the whole green tea processing, 22.3%-32.6% and 21.7%-40.3% of R-(-)-diniconazole and S-(+) diniconazole decreased, respectively. The difference between black tea and green tea is nearly 15%, and in green tea is less decreased than in black tea. The total PFs of R-(-)-diniconazole and S-(+)-diniconazole for the green tea procedure were 0.674-0.777 and 0.597-0.783, respectively. The EFs of R-(-) diniconazole and S-(+)-diniconazole in green tea processing ranged from 0.473 to 0.504. The PFs illustrated that for R-(-)-diniconazole and S-(+)-diniconazole decrease, the rolling and fermentation were the critical steps in black tea processing, and the rolling was the critical step in green tea processing, respectively. PMID- 30401539 TI - Purification of two valepotriates from Centranthus ruber by centrifugal partition chromatography: From analytical to preparative scale. AB - Considering chemical complexity of plant crude extracts, purification of natural products is a rate limiting process to identify new compounds as well as to obtain standard references for quantitative or qualitative purposes. In the present work, a centrifugal partition chromatography (CPC) method was developed to isolate and produce high quality reference standards of valtrate and 7 homovaltrate from Centranthus ruber L. roots. These two compounds are controversial aglycon iridioids regulated by the legislation on plant-based dietary supplements. A new biphasic solvent system suitable for CPC separation of valepotriates was developed. It was composed of methanol/hexane/water (5/5/0.8, v/v/v). It yielded a partition coefficient near 1 and a theoretical selectivity of 1.3 between both targeted compounds. Optimization of CPC experimental parameters at the analytical scale (50 mL- and 100 mL-column capacity) enabled compounds' separation with a flow rate of 8 mL/min at 2500 rpm. Then a scale up from a 100 mL-column capacity to a 1000 mL-column capacity has been studied using the "free-space between peaks" concept. It allowed an injected quantity 16 times higher in comparison to the maximal loading capacity of the 100 mL-column. Both valtrate and 7-homovaltrate were recovered in one single step with a purity over 97%. Further MS and NMR characterization allowed to confirm unambiguously the compounds' structures. The highly efficient CPC separation developed in this work provides valepotriates in amounts suitable for further study and strong bases for future industrial development. PMID- 30401540 TI - Open tibial fractures in major trauma centres: A national prospective cohort study of current practice. AB - AIMS: To assess current national practice in the management of severe open tibial fractures against national standards, using data collected by the Trauma and Audit Research Network. MATERIALS AND METHODS: Demographic, injury-specific, and outcome data were obtained for all grade IIIB/C fractures admitted to Major Trauma Centres in England from October 2014 to January 2016. RESULTS: Data was available for 646 patients with recorded grade IIIB/C fractures. The male to female ratio was 2.3:1, mean age 47 years. 77% received antibiotics within 3 h of admission, 82% were debrided within 24 h. Soft tissue coverage was achieved within 72 h of admission in 71%. The amputation rate was 8.7%. 4.3% of patients required further theatre visits for infection during the index admission. The timing of antibiotics and surgery could not be correlated with returns to theatre for early infection. There were significant differences in the management and outcomes of patients aged 65 and over, with an increase in mortality and amputation rates. CONCLUSIONS: Good outcomes are reported from the management of IIIB/C fractures in Major Trauma Centres in England. Overall compliance with national standards is particularly poor in the elderly. Compliance did not appear to affect rates of returning to theatre or early infection. Appropriately applied patient reported outcome measures are needed to enhance the evidence-base for management of these injuries. PMID- 30401541 TI - Erratum to "Extended lateral column tibial plateau fractures. How do we do it?" [Injury 49 (10) (2018) 1878-1885]. PMID- 30401542 TI - Low risk of nonunion with lateral locked plating of distal femoral fractures-A retrospective study of 191 consecutive patients. AB - INTRODUCTION: The reported rate of nonunion of distal femoral fractures varies in the literature. Several risk factors for nonunion following lateral locked plating (LLP) have been described. We aimed to study the rate of nonunion, and risk factors thereof, in a Swedish population where fragility fractures are common. A secondary aim was to study risk factors for reoperation for any cause. PATIENTS AND METHODS: We retrospectively reviewed the hospital files and radiographs of all adult patients admitted to our institution with a distal femoral fracture, from 2004 through 2013. In cases treated with LLP, medical comorbidities, fracture characteristics and implant characteristics were analysed as potential risk factors for nonunion, defined as any surgical intervention to improve healing. RESULTS: There were 8 cases (4%, 95%CI: 1.8-8.1%) of nonunion in 191 fractures treated with LLP. Patients with nonunion were younger: 62 vs. 81 years (p = 0.009) and more commonly had open fractures: 38% vs. 9% (p = 0.034). No patient 80 years or older had a surgical intervention for nonunion. Lower age was independently associated with reoperation for any cause, but not for nonunion. DISCUSSION: The low rate of nonunion in this study is probably due to the fact that we present data from a complete cohort from a geographic catchment area. Referral centres with a high proportion of young patients with high-energy injuries, may be better suited for studies on risk factors for nonunion, due to higher statistical power. However, results from such institutions may not be generalizable to the more common low-energy fractures. PMID- 30401543 TI - Declining Fertility with Reproductive Aging: How to Protect Your Patient's Fertility by Knowing the Milestones. AB - Protection of fertility shares many of the same concepts as optimization of general health, such as smoking cessation, maintenance of a healthy body weight, and moderation of alcohol intake. Increasing attention has been placed on minimizing exposures to known reproductive toxicants. There are few conclusive data to support specific diet patterns or supplements for fertility. Ovarian reserve testing has been explored as potential diagnostic tests for assessment of reproductive aging with some controversy. Finally, the development of vitrification in the assisted reproduction laboratory has increased the success and, therefore, access to fertility preservation by way of oocyte or embryo cryopreservation. PMID- 30401544 TI - Onset of the Menopause Transition: The Earliest Signs and Symptoms. AB - Although more than 80% of women experience some degree of psychological or physical symptoms around menopause, both women and clinicians have misconceptions about how hormonal changes relate to menopausal symptoms and psychological conditions. Recently, several large-scale, longitudinal studies have been conducted to better characterize symptoms and changes that occur around menopause. This article offers current evidence for symptoms that occur in the early menopause transition, including vasomotor symptoms, mood changes, sleep problems, and changes in sexual functioning. PMID- 30401545 TI - Menstrual Cycle Changes as Women Approach the Final Menses: What Matters? AB - Increased variability in menstrual cycle length marks the onset of the menopausal transition, with the likelihood of long cycles increasing as women approach menopause. This article describes the STRAW+10 bleeding criteria for recognizing onset of the early and late menopausal transition, as well as the specific bleeding changes a woman may experience during this life stage, including how women's bleeding experiences differ. The high probability of episodes of excessive and prolonged bleeding as women approach their final menstrual period is documented, as is the continuing probability of ovulation as women reach their final menstrual period. PMID- 30401546 TI - Menstrual Cycle Hormone Changes Associated with Reproductive Aging and How They May Relate to Symptoms. AB - Key cycle changes occur as women transition from reproductive life to menopause, and they can be roughly linked to menopausal staging. It is important to understand the types of studies that inform the current knowledge. Patterns of symptoms within menstrual cycles (sleep, headache) generally favor worsening in association with the perimenstrual phase of the cycle, and patterns of chronic symptoms, such as hot flashes and adverse mood, appear to be worse when hormones are more variable. PMID- 30401548 TI - Cardiovascular Implications of the Menopause Transition: Endogenous Sex Hormones and Vasomotor Symptoms. AB - The menopause transition (MT) is a critical period of women's lives marked by several physiologic changes and menopause-related symptoms that have implications for health. Risk for cardiovascular disease, the leading cause of death in women, increases after menopause, suggesting a contribution of the MT to its development. This article focuses on the relationship between 2 main features of the MT and women's cardiovascular health: (1) dynamic alterations of sex hormones, particularly endogenous estradiol and follicle-stimulating hormone, and (2) vasomotor symptoms, the cardinal symptom of the menopause. Limitations and future directions are discussed. PMID- 30401547 TI - Vasomotor Symptoms Across the Menopause Transition: Differences Among Women. AB - Vasomotor symptoms (VMS) are the primary menopausal symptoms, occurring in up 80% of women and peaking around the final menstrual period. The average duration is 10 years, longer in women with an earlier onset. Compared with non-Hispanic white women, black and Hispanic women are more likely and Asian women are less likely to report VMS. Risk factors include greater body composition (in the early stage of menopausal transition), smoking, anxiety, depression, sensitivity to symptoms, premenstrual syndrome, lower education, and medical treatments, such as hysterectomy, oophorectomy, and breast cancer-related therapies. VMS patterns over time and within higher-risk subgroups are heterogeneous across women. PMID- 30401550 TI - Sleep, Health, and Metabolism in Midlife Women and Menopause: Food for Thought. AB - Sleep and metabolism are essential components of health. Metabolic health depends largely on individual's lifestyle. Disturbances in sleep health, such as changes in sleep patterns that are associated with menopause/reproductive aging and chronologic aging, may have metabolic health consequences. Sleep restriction and age-related changes in sleep and circadian rhythms may influence changes in appetite and reproductive hormones, energy expenditure, and body adiposity. In this article, the authors describe how menopause-related sleep disturbance may affect eating behavior patterns, immunometabolism, immunometabolic dysfunction, and associations between sleep and metabolic outcomes. PMID- 30401549 TI - Depression During and After the Perimenopause: Impact of Hormones, Genetics, and Environmental Determinants of Disease. AB - Vulnerability to depression is increased across the menopause transition and in the early years after the final menstrual period. Clinicians should systematically screen women in this age group; if depressive symptoms or disorder are present, treatment of depression should be initiated. Potential treatments include antidepressants for moderate to severe symptoms, psychotherapy to target psychological and interpersonal factors, and hormone therapy for women with first onset major depressive disorder or elevated depressive symptoms and at low risk for adverse effects. Behavioral interventions can improve physical activity and sleep patterns. PMID- 30401551 TI - Bone Health During the Menopause Transition and Beyond. AB - The menopause transition is a critical period for bone health, with rapid losses in bone mass and strength occurring in a 3-year window bracketing the date of the final menstrual period. Declines in bone mass are accompanied by deleterious changes in bone macrostructure and microarchitecture, which may be captured by changes in composite strength indices and indices of trabecular thickness and connectivity. The onset of the rapid bone loss phase is preceded by changes in sex steroid hormones and increases in markers of bone resorption, measurements of which may be clinically useful in predicting the onset of the rapid loss phase and in identifying the women who will lose the most bone strength over the menopause transition. PMID- 30401554 TI - Genitourinary Changes with Aging. AB - Both chronologic aging and menopause affect the physical, physiologic, and microbiological characteristics of the genitourinary tract. The genitourinary syndrome of menopause, characterized by vulvovaginal and lower urinary tract signs and symptoms, is prevalent and has a significant negative impact on women's lives. In this article, the authors detail the genitourinary tract changes associated with menopause and/or aging. They also review the 2014 North American Menopause Society's definition of the genitourinary syndrome of menopause and present the epidemiology and impact of genitourinary aging in midlife and older women, namely, vulvovaginal, urinary, and sexual symptoms. PMID- 30401553 TI - Physical Activity and Physical Function: Moving and Aging. AB - Evidence supports that the physical disablement process starts earlier than previously thought, in midlife when women still have many years to live. Physical activity participation and interventions have been successful in preventing disability in older adults and may be promising for maintaining function at younger ages. Changing the conversation to more relevant topics in midlife, like positive changes in body composition, sleep, and improved mood, may move the dial on participation, as midlife women do not meet guidelines for physical activity. Exploring the role of reproductive aging beyond chronologic aging may provide gender-specific insights on both disablement and participation. PMID- 30401552 TI - Female Sexual Function at Midlife and Beyond. AB - Sexual function is an important component of quality of life for women. Midlife poses several challenges to optimal sexual function and intimacy for women. In addition to anatomic factors related to estrogen deficiency, such as genitourinary syndrome of menopause, vulvovaginal atrophy, and pelvic organ prolaps, psychosocial factors, including prior sexual trauma, play an important role in sexual function in women. Several treatments have emerged for female sexual dysfunction; long-term studies and head-to-head comparisons are lacking. PMID- 30401556 TI - A More Complete Picture of Reproductive Aging and the Menopause Transition. PMID- 30401555 TI - Cognitive Changes with Reproductive Aging, Perimenopause, and Menopause. AB - This article reviews the role of endogenous estrogen in neural and cognitive processing, followed by an examination of longitudinal cognitive data captured in various stages of the menopausal transition. The remaining text reviews the contradictory results from major hormone therapy trials to date, evidence for the "timing hypothesis," and closes with recommendations for future research and for practicing clinicians. PMID- 30401557 TI - The Disruptive Changes of Midlife: A Biopsychosocial Adventure. PMID- 30401558 TI - Acceptable Success Rate in Patients With Periprosthetic Knee Joint Infection Treated With Debridement, Antibiotics, and Implant Retention. AB - BACKGROUND: Acute periprosthetic joint infection (PJI) following primary total knee arthroplasty (TKA) surgery can be treated with debridement, antibiotics, and implant retention (DAIR). However, varying results have been reported in the literature and optimal timing of the procedure is still debated. In this retrospective cohort study, we investigate (a) success rate of DAIR for treating PJI following primary TKA surgery and (b) whether time after primary surgery until DAIR and (c) type of isolated microorganism influence outcome. METHODS: Sixty-seven patients with PJI following primary TKA surgery treated with DAIR were identified. Patients with insufficient data and patients who did not fulfill Musculoskeletal Infection Society PJI criteria were excluded, leaving 58 patients for analysis. Minimum follow-up was 2 years. A DAIR was considered a success if the patient was infection free after 2 years. RESULTS: The overall success rate of PJI treated with DAIR was 84%. Median time until DAIR was 21 days (7-1092). Thirty-four patients (59%) were revised within 28 days, 42 patients (72%) within 42 days, while 10 patients (17%) were revised more than 90 days after primary TKA surgery. The success rates were 85%, 88%, and 60%, respectively. In the patients revised within 90 days, our success rate was 90% (43/48) regardless of the involved microorganism. CONCLUSION: We find DAIR to be a viable and safe treatment option for PJI following primary TKA surgery, when performed early after primary surgery and with the addition of a relevant postrevision antibiotic regime. PMID- 30401559 TI - Opioid-Sparing Analgesia and Enhanced Recovery After Total Knee Arthroplasty Using Combined Triple Nerve Blocks With Local Infiltration Analgesia. AB - BACKGROUND: Peripheral nerve block and local infiltration analgesia (LIA) have an increasing role as part of multimodal analgesia for enhanced recovery after total knee arthroplasty (TKA). We hypothesized that the combination of obturator nerve block (ONB) and tibial nerve block (TNB) would reduce pain and opioid consumption more than ONB or TNB alone when combined with continuous adductor canal block and LIA. METHODS: Ninety patients were recruited into the study and received spinal anesthesia, LIA, and continuous adductor canal block. They were further randomized to receive either an ONB (group 1), a TNB (group 2), or both (group 3). The primary outcome was total morphine consumption over the postoperative 24 hours. The secondary outcomes included visual analog scale scores, time to first and total dosage of rescue analgesia, Timed Up and Go test, range of motion, muscle strength test, hospital stay, and patient satisfaction. RESULTS: Eighty nine patients completed analysis. The median total morphine consumption during the first 24 postoperative hours was 2 mg (interquartile range [IQR] 0-4) in group 3, 4 mg (IQR 2-8) in group 2, and 6 mg (IQR 6-14) in group 1 (P < .001). Posterior knee pain during the first 24 hours postoperatively was significantly lower in group 3 than in group 1 (P = .006). The ability to ambulate and quadriceps strength were significantly better in group 3 than in the other groups. CONCLUSION: The combination of triple nerve block was superior to double nerve block in improving analgesia and functional outcomes in the immediate postoperative period after total knee arthroplasty, when combined with LIA. PMID- 30401560 TI - Relationship Between the Patient-Reported Outcome Measurement Information System and Traditional Patient-Reported Outcomes for Osteoarthritis. AB - BACKGROUND: Incorporating patient-reported outcomes (PROs) is paramount to the creation of a value-based healthcare system that prioritizes patient-centered care in total joint arthroplasty. The relationship between global assessment PROs such as Patient-Reported Outcome Measurement Information System (PROMIS) and joint-specific PROs for hip and knee, such as short form variations of Knee Injury and Osteoarthritis Outcome Score (KOOS-JR) and Hip Injury and Osteoarthritis Outcome Score (HOOS-JR), has yet to be assessed. METHODS: A retrospective analysis was conducted to assess PRO measurements for knee-related and hip-related complaints. The KOOS-JR and HOOS-JR were compared to the PROMIS computerized adaptive test (CAT) short forms (physical function, pain interference, and pain intensity) to assess their relationship. RESULTS: A total of 3644 patients completed 4609 questionnaires. A modest to strong correlation was observed between the KOOS-JR and the PROMIS CAT (ranging from r = 0.56 to 0.71, P < .05). A modest to strong correlation was also found between the HOOS-JR and the PROMIS CAT (r = 0.59 to -0.79, P < .05). CONCLUSION: PROMIS CATs demonstrated a modest to strong correlation with KOOS-JR or HOOS-JR. Future studies should further investigate the limitations of global assessment health surveys in capturing disease-specific changes following total joint arthroplasty. PMID- 30401562 TI - Possible involvement of Enterococcus infection in the pathogenesis of chronic pancreatitis and cancer. AB - (Aim) Bacterial infection underlies the pathogenesis of many human diseases, including acute and chronic inflammation. Here, we investigated a possible role for bacterial infection in the progression of chronic pancreatitis. (Materials and Methods) Pancreatic juice was obtained from patients with pancreatic cancer (n = 20) or duodenal cancer/bile duct cancer (n = 16) and subjected to PCR using universal primers for the bacterial 16S ribosomal RNA gene. Bacterial species were identified by PCR using bile samples from four pancreatic cancer patients. PCR products were subcloned into T-vectors, and the sequences were then analyzed. Immunohistochemical and serologic analyses for Enterococcus faecalis infection were performed on a large cohort of healthy volunteers and patients with chronic pancreatitis or pancreatic cancer and on mice with caerulein-induced chronic pancreatitis. The effect of E. faecalis antigens on cytokine secretion by pancreatic cancer cells was also investigated. (Results) We found that 29 of 36 pancreatic juice samples were positive for bacterial DNA. Enterococcus and Enterobacter species were detected primarily in bile, which is thought to be a pathway for bacterial infection of the pancreas. Enterococcus faecalis was also detected in pancreatic tissue from chronic pancreatitis and pancreatic cancer patients; antibodies to E. faecalis capsular polysaccharide were elevated in serum from chronic pancreatitis patients. Enterococcus-specific antibodies and pancreatic tissue-associated E. faecalis were detected in mice with caerulein induced chronic pancreatitis. Addition of Enterococcus lipoteichoic acid and heat killed bacteria induced expression of pro-fibrotic cytokines by pancreatic cancer cells in vitro. (Conclusion) Infection with E. faecalis may be involved in chronic pancreatitis progression, ultimately leading to development of pancreatic cancer. PMID- 30401563 TI - The effect of cyclic tensile force on the actin cytoskeleton organization and morphology of human periodontal ligament cells. AB - To explore Girdin/Akt pathway protein expression and morphology change by cyclic tension in the periodontal ligament cells. Human periodontal ligament cells were exposed to cyclic tension force at 4000 MUstrain and 0.5 Hz for 6 h though a four point bending system. Cyclic tension force upregulated F-actin, Girdin and Akt expression in hPDL. In transmission electron microscope assay showed that there are more and bigger mitochondria, more and longer cynapses, more cellular organisms after tension force stimulation than control. The actin filament was changed to be regular lines and pointed to poles of cells. However, we found that the Girdin-depleted cells are small and there are more micro-organisms including more lysosomes and matrix vesicles than control. These finding suggest that the STAT3/Girdin/Akt pathway in PDL to response to mechanical stimulation as well, and Girdin may play a significant role in triggering cell proliferation and migration during orthodontic treatment. It provided an insight into the molecular basis for development of a vitro cell model in studying orthodontic treatment. PMID- 30401564 TI - Correlation of spatio-temporal characteristics of intestinal inflammation with IL 17 in a rat model of hypoganglionosis. AB - Interleukin 17 expression is increased in children with Hirschsprung disease, which is characterized by intestinal inflammation. This study designed to exploit the characteristics of intestinal inflammation and examine the correlation of interleukin 17 in this process of hypoganglionosis model established by benzalkonium chloride treatment. Colon sections from female rats were treated with benzalkonium chloride to induce hypoganglionosis or with saline alone as a sham control. C-reactive protein and tumor necrosis factor-alpha were used as markers of inflammation. Expression of C-reactive protein, tumor necrosis factor alpha, and interleukin 17 was assessed in colon tissue and blood serum on days 7, 14 and 21 after treatment. The correlation between C-reactive protein, tumor necrosis factor-alpha, and interleukin 17 expression was estimated using the Spearman's rank-correlation coefficient. C-reactive protein, tumor necrosis factor-alpha, and interleukin 17 were strongly expressed in submucosa and mucosa layers and serum from treated animals. The expression of C-reactive protein, tumor necrosis factor-alpha, and interleukin 17 maintained the highest level at Day 21. Only C-reactive protein and tumor necrosis factor-alpha expression was increased in control animals and only on day 7. Spearman's rank correlation coefficient was significant in C-reactive protein, tumor necrosis factor-alpha, and interleukin 17 at Day 7, 14 and 21. Concomitant upregulation of C-reactive protein, tumor necrosis factor-alpha, and interleukin 17 and significant positive correlations between C-reactive protein, tumor necrosis factor-alpha, and interleukin 17 may imply that interleukin 17 is involved in spatio-temporal inflammation induced by benzalkonium chloride. PMID- 30401565 TI - Active immunization using hand-push emulsification method increases the operator's risk of transcutaneous immunization. AB - Setting up an animal model by using active immunization methods is a common means of studying immune-related diseases or producing antibodies with high titer and high activities. However, the security during the process of pathogen emulsification remains unclear. In a physical examination, we unexpectedly noticed high levels of angiotensin II type 1 receptor autoantibody (AT1-AA) specific to the immunizing antigen in the sera of some researchers who had participated in setting up active immunization animal models, and we were puzzled about the cause of AT1-AA production. In this study, we intended to investigate whether the emulsified antigen was the source of infection in these researchers, and if so, how to prevent it from occurring. AT1-AA was detected by advanced ELISA method. The participants presented higher levels of AT1-AA compared with non-participants of the same laboratory. This phenomenon remained that some factors during the process of rat model establishment may contribute to AT1-AA production. Animal and glove penetration studies indicated the emulsified antigen infection was attributed to neither aerosol or fur touch nor penetrating through gloves. However, AT1-AA level was largely decreased in the participants after they used an automatic emulsification device. Because of the strong permeability of the adjuvant, we speculated that emulsified antigen might get access to the unprotected skin of the participants accidentally during the immunization process. These results demonstrated that accidental contacts of emulsified antigens may infect researchers during the process of traditional hand-push emulsification, resulting in high specific autoantibody levels, which can be prevented by using appropriate tools. PMID- 30401566 TI - Granulocyte-colony stimulating factor enhances load-induced muscle hypertrophy in mice. AB - Granulocyte-colony stimulating factor (G-CSF) is a cytokine crucially involved in the regulation of granulopoiesis and the mobilization of hematopoietic stem cells from bone marrow. However, emerging data suggest that G-CSF exhibits more diverse functions than initially expected, such as conferring protection against apoptosis to neural cells and stimulating mitogenesis in cardiomyocytes and skeletal muscle stem cells after injury. In the present study, we sought to investigate the potential contribution of G-CSF to the regulation of muscle volume. We found that the administration of G-CSF significantly enhances muscle hypertrophy in two different muscle overload models. Interestingly, there was a significant increase in the transcripts of both G-CSF and G-CSF receptors in the muscles that were under overload stress. Using mutant mice lacking the G-CSF receptor, we confirmed that the anabolic effect is dependent on the G-CSF receptor signaling. Furthermore, we found that G-CSF increases the diameter of myotubes in vitro and induces the phosphorylation of AKT, mTOR, and ERK1/2 in the myoblast-like cell line C2C12 after differentiation induction. These findings indicate that G-CSF is involved in load-induced muscle hypertrophy and suggest that G-CSF is a potential agent for treating patients with muscle loss and sarcopenia. PMID- 30401567 TI - Abdominal muscle weakness as a presenting symptom in GNE myopathy. PMID- 30401568 TI - Neurocognitive sequela of burn injury in the elderly. AB - Elderly individuals are a fast-rising segment of the US population and are at high risk of permanent disability and premature death secondary to traumatic injuries such as burn injury. The current paper will review the extant literature to understand the prevalence of burn injury in the elderly, the neurocognitive complications unique to the aged that places this cohort at risk, and evidence based recommendations to reduce the early and late neurocognitive effects of burn injury in the aged. The elderly are a high-risk population for burn injury and its neurological sequela. This risk, at least in part, reflects multiple factors: age-related changes in the central and peripheral nervous system; multiple pre existing co-morbidities (such as dementia and COPD); polypharmacy; suboptimal social support; and increased susceptibility to hypothermia, burn-related infections, and electrolyte and metabolic dysregulations. PMID- 30401569 TI - Topical tranexamic acid in spinal surgery: A systematic review and meta-analysis. AB - Tranexamic acid (TXA) is a commonly used antifibrinolytic agent for perioperative blood conservation in several surgical specialties. Although historically administered intravenously, such systemic administration may be accompanied by severe side effects. Thus, the topical usage of TXA has been established in several fields but remains poorly evaluated in spine surgery. In this study, the authors aimed to review the medical literature on topical TXA usage in spine surgery to evaluate its safety and efficacy. We reviewed manuscripts and clinical trials exploring topical TXA usage in spine surgery published by April 1st, 2018. Postoperative blood loss volumes and hospitalization lengths of stay were evaluated with separate meta-analyses. We identified five articles and one unpublished clinical trial that were placebo-controlled and comprised 218 patients receiving topical TXA in spine surgery. Patients receiving topical TXA demonstrated significantly lower postoperative blood loss as compared to the placebo group (Standardized Mean Difference [SMD] 2.21, 95% CI 0.79-3.62, p < 0.001) and had a lower hospitalization duration (MD 0.99, 95% CI 0.49-1.49, p < 0.001). Overall, topical TXA favorably reduced postoperative blood loss and hospitalization duration in patients undergoing spinal surgery. However, further randomized controlled trials will be needed to definitively establish the optimal therapeutic doses needed for hemorrhage management, and the pharmacodynamics of tTXA in spinal surgery. PMID- 30401570 TI - Endoscopic transnasal repair of two cases of spontaneous cerebrospinal fluid fistula in the foramen rotundum. AB - We report two female patients aged 16 and 33 who presented with spontaneous cerebrospinal fluid (CSF) rhinorrhoea. Beta-2 transferrin was positive in both cases. Initial high-resolution CT showed fluid in the maxillary sinus but no obvious bony defect. MR imaging revealed maxillary sinus cysts with high signal on T2 sequences. Endoscopic transnasal surgery with intrathecal fluorescein was undertaken and in both cases a leak was identified from foramen rotundum and repaired. Both patients are symptom free at 6 months. These cases highlight the rare occurrence of spontaneous CSF leak from the foramen rotundum, and how they can be effectively repaired using the endoscopic transnasal approach. PMID- 30401571 TI - Brain volume loss and no evidence of disease activity over 3 years in multiple sclerosis patients under interferon beta 1a subcutaneous treatment. AB - The objective of our study was to evaluate the relationship of percentage of annualized brain volume loss (aBVL) and no evidence of disease activity (NEDA) in multiple sclerosis (MS) patients under interferon beta 1-a subcutaneous treatment (IFN-beta) during 3 years of follow up. Relapsing remitting MS (RRMS) patients, with less than three years from disease onset, expanded disability status scale (EDSS) <=3 and in which IFN beta 1-a 44 mcg was indicated, were included. Demographic, clinical and structural parameters from the magnetic resonance (MR) during the 3 years of follow up were analyzed and compared between patients with and without NEDA (defined as the absence of: (a) three-month confirmed disability progression defined as an increase in EDSS score of 1.0; (b) confirmed relapses; and (c) new or enlarged T2 lesions and/or Gd+ lesions). A total of 87 patients, mean age 33 +/- 6 years were included. NEDA was reached by 39 patients at year 3. Percentage of aBVL from baseline to months 24 in NEDA patients was -1.1% vs. 1.54% in patients without NEDA (p < 0.001) and from baseline to month 36 it was 1.43% vs. -2.1% (p < 0.001) in patients with and without NEDA, respectively. At 3 years follow up, patients who received IFN beta 1a and were disease-free had lower percentage of aBVL compared to patients with disease activity. PMID- 30401572 TI - Diagnosing MELAS requires clinical and genetic information. PMID- 30401573 TI - Efficacy and safety of drug-eluting stent for the intracranial atherosclerotic disease: A systematic review and meta-analysis. AB - Drug-eluting stent (DES) is a potential endovascular treatment for patients with symptomatic intracranial atherosclerotic disease (sICAD). However, evidence regarding the treatment of ICAD with DES is lacking. We systematically searched Pubmed, Embase, Cochrane database (before 2017-12-21) for literature reporting the application of DES in the treatment of sICAD. The main outcomes were as follows: the incidence of any stroke or death within 30 days (perioperative complications), ischemic stroke in the territory of the qualifying artery beyond 30 days (long-term complications), in-stent restenosis rate (ISR) and symptomatic ISR during follow-up. Those studies with mean stenosis rate greater than 70% and less than 70% were defined as severe and moderate stenosis group, respectively. The random effect model was used to pool the data. Of 518 articles, 13 studies were eligible and included in our analysis (N = 336 patients with 364 lesions). After the implantation of DES, perioperative complications (mortality = 0) occurred in 6.0% (95%CI 2.0%-11.9%), long-term complications occurred in 2.2% (95%CI 0.7%-4.5%), ISR rate was 4.1% (95%CI 1.6%-7.7%) and the symptomatic ISR rate was only 0.5% (95%CI 0-2.2%). In addition, subgroup analysis showed that the perioperative complication rate in severe stenosis group [10.6% (95%CI 6.5% 15.7%)] was significantly (p < 0.01) higher than that in moderate stenosis group [1.0% (95%CI 0.3%-3.5%)]. In summary, endovascular DES implantation is a relatively safe and effective method compared with stents or medical management group in SAMMPRIS and VISSIT trials. However, a higher preoperative stenosis rate may imply a higher risk of perioperative complications. Further studies are needed. PMID- 30401575 TI - Characteristics associated with transition from opioid initiation to chronic opioid use among opioid-naive older adults. AB - Our primary objective was to determine the prevalence and characteristics of opioid-naive older adults who initiated opioids and transitioned to chronic use. Study populations included older adults >= 65 years with continuous medical and drug plan enrollment one-year prior to opioid initiation (pre-period) through one year after initiation (post-period). Characteristics were determined using multivariate logistic regression. Among eligible insureds (N = 180,498), 70% used only the initial opioid prescription; 30% continued to use opioids requiring >= 2 prescriptions with >= 15 days' supply. Overall, 6% transitioned to chronic use > 90 days. Characteristics associated with chronic use included: (1) Low income, older, females, in poor health, with new/chronic back pain; (2) opioid initiation with long-acting opioids or tramadol; (3) prescriptions for other pain, sleep or antipsychotic medications; and (4) indications of pre and/or post mental health issues. Careful screening, monitoring and/or alternative non-opioid pain management strategies may be warranted for those at risk for chronic opioid use. PMID- 30401577 TI - Predicting Patient Needs for Interdisciplinary Services in a Voice and Swallowing Center. AB - In a subspecialty interdisciplinary voice and swallowing clinic, patient referrals come from a wide variety of disciplines for various reasons, which can make scheduling their initial evaluations challenging. Depending on the nature of complaints and symptoms, patients may best be evaluated either by a single provider (a laryngologist) or by an interdisciplinary team that includes a speech language pathologist. If not scheduled appropriately, the provider and the patient may lose valuable time, resources, and money. This was a retrospective chart review of 76 patients who received an interdisciplinary evaluation in our Voice and Swallowing Center's first 7 months of operation. Two factors were examined for their predictive values: the most common reasons for referral and the disciplines that commonly refer to the clinic. The goal was to probe for any variables known at the time of referral that could inform us whether an interdisciplinary evaluation would be beneficial or not. This information informs resource planning for space, equipment, scheduling, and staffing. The results showed that the most common reasons for a referral to the Voice and Swallowing Center were dysphonia (34.8%), dyspnea/paradoxical vocal fold motion ("PVFM," 20.2%), and dysphagia (18%). Statistical analysis of the results indicated that certain reasons for referral were more likely to require an interdisciplinary evaluation than others: dysphonia, irritable larynx syndrome/chronic cough, and PVFM. Referrals most commonly came from providers with a background discipline of primary care (26%) and otolaryngology (22%). The discipline of a referring provider alone was not a strong enough indicator to reliably predict the type of evaluation needed. Examining the available data on referral patterns, as this study has done, has the potential to inform providers how to better anticipate their patients' needs and also improve clinic operations. PMID- 30401578 TI - Hepatotoxic effects of Euphol-rich fractions from Euphorbia bivonae-Relevance to cytotoxic and anti-tumor activities. AB - These studies were designed to evaluate the preliminary oral toxicity profile of the crude ethanolic aerial part extract of E. bivonae in the Male albino Wistar rats and its active chemical constituents. The 24-h LD50 was determined using probit analysis method. The single dose LD50was found to be 2568.64 mg/kg bw when administrated orally in mice. Additionally, the Wistar rats were used to evaluate the subchronic toxicity of E. bivonae ethanolic extract. The serum biomarkers, lipid peroxidation and antioxidants status in liver and histopathological analysis were investigated in normal and treated groups. Subchronic toxicity studies in rats with oral doses of 50, 150, 350 and 500 mg/kg body weight showed significant increase in alanine aminotransferase, aspartate aminotransferase and total bilirubin levels. In addition, the administration of this extract significantly (p < 0.05) decreased superoxide dismutase, catalase and glutathione peroxidase and an increment in lipid peroxidation and protein carbonyls. Finally, we suggest that the three compounds of E. bivonae extract (sitosterol, euphol and lupeol) are the mainly responsible of this toxicity. PMID- 30401579 TI - mQC: A post-mapping data exploration tool for ribosome profiling. AB - BACKGROUND AND OBJECTIVE: Ribosome profiling is a recent next generation sequencing technique enabling the genome-wide study of gene expression in biomedical research at the translation level. Too often, researchers precipitously start trying to test their hypotheses after alignment of their data, without checking the quality and the general features of their mapped data. Despite the fact that these checks are essential to prevent errors and ensure valid conclusions afterwards, easy-to-use tools for visualizing the quality and overall outlook of mapped ribosome profiling data are lacking. METHODS: We present mQC, a modular tool implemented as a Bioconda package and also available in the Galaxy tool shed. Herewith both bio-informaticians as well as non-experts can easily perform the indispensable visualization of both the quality and the general features of their mapped P-site corrected ribosome profiling reads. The user manual, the raw code and more information can be found on its GitHub repository (https://github.com/Biobix/mQC). RESULTS: mQC was tested on multiple datasets to assess its general applicability and was compared to other tools that partly perform similar tasks. CONCLUSIONS: Our results demonstrate that mQC can accomplish an unfilled but essential position in the ribosome profiling data analysis procedure by performing a thorough RIBO-Seq-specific exploration of aligned and P-site corrected ribosome profiling data. PMID- 30401580 TI - The pretreatment lymphocyte to monocyte ratio predicts clinical outcome for patients with urological cancers: A meta-analysis. AB - BACKGROUND: The lymphocyte to monocyte ratio (LMR), a novel systematic biomarker of inflammation, has been reported to be associated with the progression and prognosis of many malignant cancers. However, the relationship between LMR and survival outcome of urological cancers (UCs) remains controversial. Herein, we conducted a meta-analysis to identify the prognostic value of pretreatment LMR in patients with UCs. METHODS: A literature search was performed in PubMed, Web of Science, Embase, Cochrane Library, Cochrane Central Register of Controlled Trials, Scopus, and CINAHL databases up to July 2018. The pooled hazard ratios (HRs) and odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated to evaluate the association of LMR with survival outcome and clinicopathological characteristics in UCs. RESULTS: A total of 17 articles containing 5552 patients were included in our study. The synthesized analysis showed that elevated pretreatment LMR level could predict favorable overall survival (OS) of UCs patients (pooled HR = 0.82, 95%CI: 0.77-0.87). Additionally, the decreased LMR level was correlated with tumor stage (OR = 1.72, 95%CI: 1.15 2.55), lymph node metastasis (OR = 1.46, 95%CI:1.06-1.99), grade (OR = 1.79, 95%CI:1.41-2.27), tumor size (OR = 2.21, 95%CI:1.81-2.68) and necrosis (OR = 1.71, 95%CI:1.36-2.16). CONCLUSION: The high pretreatment LMR was associated with favorable prognosis, and could be a potential prognostic biomarker in patients with UCs. PMID- 30401581 TI - Primary aneurysmal bone cyst of the mandibular condyle with USP6-CDH11 fusion. AB - Primary aneurysmal bone cyst (ABC) is a cystic bone neoplasm characterized by disease-defining gene fusions involving the USP6/Tre2 gene. The literature describing gnathic ABC is limited. This case report describes a 27-year-old man presenting with a long-standing left-sided facial asymmetry. Multi-detector computed tomography imaging demonstrated a large expansile lesion positioned within the left condylar head. The lesion was biopsied and resected. The specimen showed a giant cell-rich cystic neoplasm, with fibrous tissue lined by multinucleated giant cells. Next-generation sequencing confirmed the presence of a USP6-CDH11 fusion gene, consistent with classification as a primary ABC, the first reported to be translocation-positive in the head of the mandibular condyle. PMID- 30401582 TI - Loss of BMP-10 is correlated with poor survival in ovarian cancer. AB - INTRODUCTION: The expression of bone morphogenetic protein-10 (BMP-10) is downregulated in some cancer types, but its function and mechanism in ovarian cancer remains unclear. MATERIALS AND METHODS: BMP-10 expression was detected in ovarian cancer tissues and cell lines by using immunochemistry and western blotting. Prognostic value of BMP-10 was evaluated by Kaplan-Meier curve and Cox regression model. Knockdown or overexpression of BMP-10 was conducted by using specific siRNA or pcDNA-BMP-10 in ovarian cancer cell lines. The biological features induced by BMP-10 were observed by MTT assay, wound-healing and transwell assays. RESULTS: BMP-10 expression in ovarian cancer tissues was significantly lower than that in ovarian tissues. Low BMP-10 expression in ovarian cancer tissues was related to advance FIGO stage, higher histologic grade, lymph node metastasis, and peritoneal fluid. Kaplan-Meier analysis revealed that low BMP-10 expression was significantly associated with poor prognosis of patients with ovarian cancer. BMP-10 overexpression or knockdown significantly inhibited or promoted proliferation, migration, and invasion of ovarian cancer cells, respectively. Moreover, administration of neutralizing antibody or human recombinant BMP-10 would reverse these effects on ovarian cancer cells. CONCLUSION: Low BMP-10 expression was associated with poor prognosis and progression of ovarian cancer. PMID- 30401583 TI - A Clinical Risk Scoring Tool to Predict Readmission After Cardiac Surgery: A Methodological Issue. PMID- 30401584 TI - Corrigendum to "Association of metformin use with vitamin B12 deficiency in the institutionalized elderly" [Arch. Gerontol. Geriatrics 79 (November-December) (2018) 57-62]. PMID- 30401576 TI - An international perspective on hospitalized patients with viral community acquired pneumonia. AB - BACKGROUND: Who should be tested for viruses in patients with community acquired pneumonia (CAP), prevalence and risk factors for viral CAP are still debated. We evaluated the frequency of viral testing, virus prevalence, risk factors and treatment coverage with oseltamivir in patients admitted for CAP. METHODS: Secondary analysis of GLIMP, an international, multicenter, point-prevalence study of hospitalized adults with CAP. Testing frequency, prevalence of viral CAP and treatment with oseltamivir were assessed among patients who underwent a viral swab. Univariate and multivariate analysis was used to evaluate risk factors. RESULTS: 553 (14.9%) patients with CAP underwent nasal swab. Viral CAP was diagnosed in 157 (28.4%) patients. Influenza virus was isolated in 80.9% of cases. Testing frequency and viral CAP prevalence were inhomogeneous across the participating centers. Obesity (OR 1.59, 95%CI: 1.01-2.48; p = 0.043) and need for invasive mechanical ventilation (OR 1.62, 95%CI: 1.02-2.56; p = 0.040) were independently associated with viral CAP. Prevalence of empirical treatment with oseltamivir was 5.1%. CONCLUSION: In an international scenario, testing frequency for viruses in CAP is very low. The most common cause of viral CAP is Influenza virus. Obesity and need for invasive ventilation represent independent risk factors for viral CAP. Adherence to recommendations for treatment with oseltamivir is poor. PMID- 30401585 TI - Effect of organic loading rate on thermophilic methane fermentation of stillage eluted from ethanol fermentation of waste paper and kitchen waste. AB - Thermophilic methane fermentation was a valid approach for handling the stillage eluted from ethanol fermentation of waste paper and kitchen waste. The wide organic loading rate (OLR) range (2-14 g VTS/(L d)) for stable performance and relatively high energy recovery efficiency (79.0%) were achieved, and OLR of 8 g VTS/(L d) was optimum for achievement of highest biogas evolution and VTS removal efficiency. Microbial community analysis revealed that hydrolysis of cellulose was the critical step for methane production from the stillage. PMID- 30401586 TI - Prognostic and therapeutic role of CLEC12A in acute myeloid leukemia. AB - CLEC12A has recently been identified as an antigen, expressed on leukemic stem cells and leukemic blasts. Given the fact that this expression profile seems stable throughout diagnosis, treatment and relapse on leukemic blasts and leukemic stem cells, CLEC12A can be considered a highly potent and reliable marker for the detection of measurable residual disease and therefore applicable for risk stratification and prognostication in AML. Low CLEC12A expression on leukemic blasts seems to be independently associated with lower likelihood of achieving complete remission after 1 cycle of induction chemotherapy, shorter event free survival, as well as overall survival, indicating potential prognostic properties of CLEC12A expression itself. Lack of expression on the normal hematopoietic stem and progenitor cells, in contrast to CD123 and CD33, might result in less toxicity regarding cytopenias, making CLEC12A an interesting target for innovating immunotherapies, including monoclonal and bispecific antibodies, antibody-drug conjugates and CAR-T cells therapy. PMID- 30401587 TI - Predicting Human miRNA-like Sequences within Human Papillomavirus Genomes. AB - BACKGROUND: This study presents a prediction of putative miRNA within several Human Papillomavirus (HPV) types by using bioinformatics tools and a strategy based on sequence and structure alignment. Currently, little is known about HPV miRNAs. METHODS: Computational methods have been widely applied in the identification of novel miRNAs when analyzing genome sequences. Here, ten whole genome sequences from HPV-6, -11, -16, -18, -31, -33, -35, -45, -52, and -58 were analyzed. Software based on local contiguous structure-sequence features and support vector machine (SVM), as well as additional bioinformatics tools, were utilized for identification and classification of real and pseudo microRNA precursors. RESULTS: An initial analysis predicted 200 putative pre-miRNAs for all the ten HPV genome variants. To derive a smaller set of pre-miRNAs candidates, stringent validation criteria was conducted by applying <-10 DeltaG value (Gibbs Free Energy). Thus, only pre-miRNAs with total scores above the cut off points of 90% were considered as putative pre-miRNAs. As a result of this strategy, 19 pre-miRNAs were selected (hpv-pre-miRNAs). These novel pre-miRNAs were located in different clusters within HPV genomes and some of them were positioned at splice regions. Additionally, the 19 identified pre-miRNAs sequences varied between HPV genotypes. Interestingly, the newly identified miRNAs, 297, 27b, 500, 501-5, and 509-3-5p, were closely implicated in carcinogenesis participating in cellular longevity, cell cycle, metastasis, apoptosis evasion, tissue invasion and cellular growth pathways. CONCLUSIONS: The novel putative miRNAs candidates could be promising biomarkers of HPV infection and furthermore, could be targeted for potential therapeutic interventions in HPV induced malignancies. PMID- 30401588 TI - Vitamin D supplementation for musculoskeletal health outcomes in adults - The end of the beginning? PMID- 30401589 TI - Type of organ failure and acute insult have important bearings in outcomes of liver transplantation: A pragmatic discourse. PMID- 30401590 TI - Association of race with long-term outcomes in patients undergoing popliteal and infra-popliteal percutaneous peripheral arterial interventions. AB - BACKGROUND: Race-related differences in clinical features, presentation, treatment and outcomes of patients with various cardiovascular diseases have been reported in previous studies. However, the long-term outcomes in black versus white patients with popliteal and/or infra-popliteal peripheral arterial disease (PAD) undergoing percutaneous peripheral vascular interventions (PVI) are not well known. METHODS AND RESULTS: We retrospectively evaluated long-term outcomes in 696 patients (263 blacks and 433 whites) who underwent PVI for popliteal and/or infra-popliteal PAD at our institution between 2007 and 2012. When compared to white patients, black patients were younger (70 +/- 11 vs. 72 +/- 11; P = 0.002) and had more comorbidities: higher creatinine (2.04 +/- 2.08 vs. 1.33 +/- 1.16; P < 0.0001) with more ESRD (19% vs. 6%; P < 0.0001) and more diabetes (64% vs. 55%; P = 0.004). At mean follow-up of 36 +/- 20 months, there was no statistically significant difference between black and white patients either in all-cause mortality (29% vs. 32%; P = 0.38) or in major amputation (4.4% vs. 4.2%; P = 0.88), respectively. In a multi-variate Cox proportional hazard model, repeat ipsilateral percutaneous revascularization or bypass were lower in black patients (HR = 0.64 [95% CI 0.46-0.89]; P = 0.007) and major adverse vascular events (MAVE) were lower in black patients as well (HR = 0.7 [95% CI 0.56-0.89]; P = 0.003). CONCLUSION: Black patients undergoing popliteal or infra-popliteal PVI had similar mortality and major amputation, but lower repeat revascularization and MAVE compared to white patients. These data support the use of PVI in minorities despite higher baseline comorbidities and call for more research to understand the mechanisms underlying the high mortality irrespective of race. PMID- 30401591 TI - Type I AV fistula of the thoracic spinal cord. AB - Type I AV fistulas of the spinal cord are exceedingly rare. The average age at diagnosis is 50. Clinical presentation is often very non-specific, and sensory deficits and sphincter dysfunction may also occur. Neurological deterioration is generally gradual. Thus, failure to diagnosis frequently results in permanent disability. A 22-year-old female complained of a "muscle spasm" in the midline thoracic area with no history of trauma or prior occurrence. She also experienced bilateral lower extremity weakness/numbness and perianal anesthesia. She is a healthy female with no medical problems. Exam revealed lower extremity motor function of 1/5 as well as diminished sensation. A foley catheter was placed for urinary retention. The remainder of the neurological exam was normal. MRI demonstrated a lesion at the fourth thoracic level with significant cord compression. The patient was taken emergently to the operating room by neurosurgery. This case demonstrates a rare disorder occurring in a 22-year old female, far younger than the typical 50-year old patient. Moreover, the lesion was located in the thoracic rather than the typical lumbar cord. Symptoms may be misinterpreted as a peripheral nerve lesion and delay time to diagnosis. Early diagnosis remains critical to prevent permanent neurologic sequelae. AV fistula should remain high on the differential of patients presenting with back pain and focal neurologic complaints. PMID- 30401592 TI - Validity of SMART-COP score in prognosis and severity of community acquired pneumonia in the emergency department. AB - BACKGROUND: Determining prognosis in community acquired pneumonia (CAP), is very important. Many scores are introduced up to now for prediction of pneumonia prognosis like SMART-COP. OBJECTIVE: To evaluate validity of SMART-COP score in prognosis and severity of CAP in emergency department (ED). METHODS: All patients older than 18 years old with clinical suspicion of CAP (meeting the inclusion criteria), were enrolled in our study. In this prospective study, patients were admitted to the ED of a tertiary referral center. Hospital length of stay, rate of intensive care unit (ICU) admission, mortality rate, number of intensive respiratory or vasopressor support (IRVS) use, patients' SMART-COP scores and all demographic data were recorded. Validity of SMART-COP in the prediction of IRVS rate and its correlation with other variables were determined. RESULTS: In this study, 47.6% and 52.4% of patients were females and males respectively. The mean age of patients was 68.13 +/- 16.60 years old. The mean hospital length of stay was 13.49 +/- 5.62 days. Of all patients entered in our study, 55 cases (38.5%) needed ICU admission, 29 cases (20.3%) were expired within 1 month and 44 cases (30.8%) needed IRVS during their treatment. SMART-COP >=5 (high risk CAP) accurately predicted the rate of ICU admission, one-month mortality and IRVS need (p-value = 0.001). CONCLUSIONS: SMART-COP>=5 had a high sensitivity and specificity in the prediction of patients' prognosis with severe CAP in the ED. PMID- 30401593 TI - Characteristics and outcomes of in-hospital cardiac arrest in adults hospitalized with acute coronary syndrome in China. AB - AIMS: This retrospective study aims to analyze and explore the clinical characteristics, risk factors, and in-hospital outcomes - including return of spontaneous circulation (ROSC) and survival to discharge - of hospitalized patients admitted with acute coronary syndrome (ACS) suffering cardiac arrest. METHODS: ACS patients admitted to three tertiary hospitals in Fujian, China, were evaluated retrospectively from January 1, 2012 to December 30, 2016. Data were collected, based on the Utstein Style, for all cases of attempted resuscitation for IHCA. We analyzed patient characteristics, pre-event variables, event variables, and the main outcomes, including ROSC and survival to discharge, and identified the influencing factors on the outcomes. RESULTS: The total number of ACS admissions across the three hospitals during this study period was 21,337. Among these admissions, 320 ACS patients experienced IHCA (incidence: 1.50%); 134 (41.9%) patients experienced ROSC; and 68 (21.2%) survived to discharge. The findings indicated that four factors were associated with ROSC, including age <70 years-old, shockable rhythm, duration of resuscitation (<=15 min and 16-30 min), and PCI. Five factors were associated with survival to discharge, including age <70 years-old, shockable rhythm, the duration of resuscitation (<=15 min and 16 30 min), Killip <= II, and CCI <= 2. CONCLUSION: Younger age, shockable rhythm, and shorter duration of resuscitation were all factors demonstrated to be a predictor of ROSC and survival to hospital discharge. PMID- 30401594 TI - Apneic oxygenation to prevent oxyhemoglobin desaturation during rapid sequence intubation in a pediatric emergency department. AB - BACKGROUND: Apneic oxygenation is the delivery of oxygen to the nasopharynx during intubation. It may mitigate the risk of oxyhemoglobin desaturation but has not been well-studied in children. METHODS: We conducted a retrospective, observational study of patients undergoing rapid sequence intubation (RSI) in a pediatric emergency department. We compared patients who received apneic oxygenation, delivered via simple nasal cannula at age-specific flow rates, to patients who did not receive apneic oxygenation. The main outcome was occurrence of oxyhemoglobin desaturation during RSI, defined as oxyhemoglobin saturation dropping to <90% at any time after the administration of paralytic medication and before the endotracheal tube was secured. Data were analyzed using logistic regression, with groups as a fixed effect and patients' age and number of attempts as covariates. RESULTS: Data were collected for 305 of 323 patients who underwent RSI over a 49 month period. Oxyhemoglobin desaturation occurred for 50 patients when apneic oxygenation was used (22%, 95% CI 17% to 28%) and 11 patients without apneic oxygenation (14%, 95% CI 7% to 24%; p > 0.05). There was no difference in the median duration of desaturation or depth of desaturation for the apneic oxygenation group (52 s, 71%) compared to the group without apneic oxygenation (65 s, 79%; p > 0.05). Controlling for covariates, apneic oxygenation was not associated with a lower risk of oxyhemoglobin desaturation, time to desaturation, or depth/duration of desaturation episodes. CONCLUSIONS: In an observational, video-based study of pediatric patients, apneic oxygenation was not associated with a lower risk of oxyhemoglobin desaturation during RSI. PMID- 30401595 TI - Patient perceptions of EMS provider attire. PMID- 30401596 TI - Can Minocycline Become the Magic Pill of Spinal Cord Protection? PMID- 30401597 TI - Usefulness of Continuous Renal Replacement Therapy During an Intra-Aortic Balloon Occlusion in Patients With Ruptured Abdominal Aortic Aneurysms. PMID- 30401598 TI - "My Wife and My Mother-in-Law": Understanding Differences in the Interpretation of Color-Flow Doppler. PMID- 30401599 TI - Temporal stability of urinary cadmium in samples collected several years apart in a population of older persons. AB - OBJECTIVES: There is growing evidence that urine cadmium is a temporally stable biomarker indicative of long-term cadmium exposure; however questions remain with regard to generalizability to older persons, the impact of changes in smoking behavior, and the degree of temporal stability when repeat sample collection spans years instead of weeks or months. METHODS: Using archived samples from cohorts of older men (Osteoporotic Fractures in Men (MrOS-US)) and women (Study of Osteoporotic Fractures (SOF)) (mean age = 80 at study visit 2), we analyzed two morning urine samples each from 39 men and 18 women with a diverse self reported smoking history. For MrOS, samples were collected approximately 6 years apart, and 4 years apart for SOF. Intra-class correlations were computed to assess temporal stability, and adjusted for age and body mass index. RESULTS: The median creatinine-adjusted urinary cadmium levels (0.39 MUg/g for men, 0.89 MUg/g for women) were similar to levels expected for these age/sex groups in the US according to the National Health and Nutrition Examination Survey. The overall intra-class correlation was high (ICC = 0.85; 95% CI: 0.76-0.91) and similar between cohorts (MrOS: ICC = 0.74; 95% CI: 0.58-0.86; SOF: ICC = 0.81; 95% CI: 0.59-0.93), but slightly lower among those who stopped smoking between visits of sample collection (ICC = 0.64; 95% CI: 0.31-0.87) or among former smokers who quit prior to the first sample collection (ICC = 0.68; 95% CI: 0.25-0.93). CONCLUSIONS: We report good-to-excellent reproducibility of urine cadmium using morning urine samples collected 4-6 years apart from older men and women, but slightly lower correlations among those with a history of smoking. Single measures of urine cadmium are a reliable biomarker in older men and women. PMID- 30401600 TI - Does a serious game increase intrinsic motivation in children receiving urotherapy? AB - INTRODUCTION: Urotherapy is considered the treatment of choice for children suffering daytime urinary incontinence (DUI). Urotherapy intends to improve bladder dysfunction for children with DUI. For children with refractory DUI, an intensive inpatient bladder training program exists, which focuses on relearning, concentration on, and awareness of the bladder. Children's motivation and adherence are key determinants of a successful training outcome. It is hypothesized that motivation endurance throughout the treatment process may be enhanced by a serious game training tool, which could make the training more appealing and rewarding. OBJECTIVE: The study explores intrinsic motivation in children receiving bladder training for DUI and whether using a serious game improves their intrinsic motivation. STUDY DESIGN: In this pragmatic study, 50 children were allowed to choose among receiving bladder training with (intervention group) or without the application of a serious game (control group). At 4, 8, and 12 weeks of training, children and parents were asked to complete the Intrinsic Motivation Inventory (IMI). Children also completed the Pediatric Urinary Incontinence Quality of Life Tool (PinQ) before the start of the training and 6 months thereafter. At 6-month follow-up, patients were ask to participate in two focus groups, wherein the children discussed how they used the serious game and which improvements they would prefer. RESULTS: Children who received standard bladder training with the addition of a serious game did not differ in terms of intrinsic motivation from children who underwent standard bladder training only. Training results were equal in both the groups, with 80% good or improved. Incontinence-related quality of life (QoL) improved accordingly. DISCUSSION: In contrast to the study expectations, this game did not increase intrinsic motivation. Findings on training and QoL results are consistent with those of previous studies in both interventions. Although a randomized design could have yielded more valid results than this preference based approach, the latter is more congruent with clinical practice. In contrast to existing bladder diary apps, this game offers a combination of child-friendly instructions, explanation of bladder (dys)function, and keeping a bladder diary. Mobile devices are playing an increasingly important role in health care; therefore, an urotherapy app can be a complementary therapeutic tool. CONCLUSION: Most children find it attractive to combine bladder training with a serious game. However, no added value was found regarding intrinsic motivation and training results. All children with persistent DUI in this cohort were highly motivated to complete an intensive bladder training program. PMID- 30401601 TI - Implementation of Physiological Scoring to Determine Discharge Readiness for Patients Undergoing Otolaryngology Head and Neck Procedures. AB - PURPOSE: This quality improvement project examined whether the use of a validated physiological scoring protocol to determine discharge readiness for surgical procedures proximal to the airway would decrease the time at which discharge criteria were met and postanesthesia care unit (PACU) length of stay. DESIGN: An observational pre-post design compared preimplementation recovery times to postimplementation recovery times. METHODS: PACU nurses were trained to use two physiological scoring protocols to determine when patients met discharge criteria and to document when discharge criteria were met. FINDINGS: During the postimplementation period, there was a significant decrease in the time it took patients to meet PACU discharge criteria when using the physiological scoring protocols compared with the preimplementation group (P < .001). CONCLUSIONS: These results suggest that physiological scoring protocols are safe and appropriate to determine discharge readiness for patients who have surgery proximal to the airway. PMID- 30401602 TI - The Effect of Preoperative Oral Carbohydrate Administration on Insulin Resistance and Comfort Level in Patients Undergoing Surgery. AB - PURPOSE: The aim of this study was to evaluate the effect of preoperative oral carbohydrate solution (OCS) administration on postoperative insulin resistance and patient comfort in elective laparoscopic cholecystectomy. DESIGN: Randomized controlled clinical study. METHODS: The experimental group received OCS. The control group did not eat or drink before surgery. Glucose and insulin level were measured at baseline, 2 hours before surgery, and at the first and third hour after surgery. Insulin resistance was assessed by the homeostasis model assessment of insulin resistance (HOMA-IR). The visual analogue scale (VAS) and general comfort scale (GCS) were used to assess postoperative comfort level. FINDINGS: A significant increase in the glucose level was observed in both groups (P < 0.05). A change in glucose level was significantly higher in the control group (P = .014). HOMA-IR values did not change significantly in the OCS group (P = .160). In the OCS group VAS scores were significantly lower (P < .0001). The OCS group had significantly higher relief (P = .014), ease (P = .001), and transcendence (P < .0001) scores. CONCLUSIONS: OCS decreases insulin resistance and increases comfort. PMID- 30401603 TI - Mechanism of harm from left bundle branch block. AB - The impact of left bundle branch block (LBBB) on cardiac mechanical function ranges from minimal effect in some patients to marked reduction in left ventricular (LV) systolic function in others. It appears that this variability in part reflects differences in anatomical location of the bundle block. In most patients with LBBB and congestive heart failure, however, there is associated cardiac disease such as cardiomyopathies or coronary artery disease which contributes to LV dysfunction. The mechanism of harmful effect of LBBB on cardiac function is in-coordinated ventricular contractions which result in LV contractile inefficiency. Septal contribution to LV systolic function is lost or attenuated and an excessive workload is placed on the LV free wall which responds with remodeling and in some cases it decompensates. The magnitude of the contractile inefficiency depends on the extent of electrical conduction delay and degree of associated heart disease. Another mechanism, which in many patients contributes to cardiac dysfunction in LBBB, is mitral regurgitation due to in coordinated contractions of the papillary muscles and altered mitral valve function due to LV remodeling. Potentially, reduced LV filling time due to prolonged LV systole may contribute to cardiac dysfunction, but there is limited knowledge about the clinical importance of this mechanism. In LBBB there is typically reduced septal perfusion, probably not as a sign of ischemia, but reflecting physiologic autoregulation of coronary flow in response to reduced septal work that reduces metabolic demand. Future studies should explore how current insights into mechanisms of cardiac mechanical effects of LBBB can be incorporated into decision algorithms for selection of patients for cardiac resynchronization therapy, as well as how to manage patients with LBBB and preserved LV function. PMID- 30401604 TI - Second-line cabozantinib versus nivolumab in advanced renal cell carcinoma: Systematic review and indirect treatment comparison. AB - BACKGROUND: Nivolumab and cabozantinib, two new treatment options for previously treated advanced/metastatic renal cell carcinoma (aRCC), have recently been approved. METHODS: Two independent reviewers performed study selection, data extraction, and risk of bias assessment. Indirect treatment comparisons were carried out by directly assessing HR differences and statistical modeling of Kaplan-Meier curves from these two trials. RESULTS: Publications identified showed that no head-to-head comparisons had been carried out. Two indirect treatment comparisons used agreed that there was no significant difference in OS between cabozantinib and nivolumab and that cabozantinib significantly improved PFS compared to nivolumab. CONCLUSIONS: The field of aRCC treatments is evolving rapidly, creating opportunities for individualized treatments and challenges for clinicians to keep up with the evidence. In lieu of availability of direct comparisons of all options, advanced modeling results presented herein can help to inform and improve personalized treatments. PMID- 30401605 TI - Narcolepsy, co-morbidities and smoking. PMID- 30401606 TI - Density of crystalline lens and cornea in different trimesters of pregnancy. AB - PURPOSE: To evaluate topographic measurements of the anterior segment and densitometric measurements of the cornea and lens by Pentacam HR in different trimesters of pregnancy. METHODS: This prospective study included 150 healthy pregnant women in their first, second, or third trimester (Groups 1, 2 and 3, respectively) and 54 non-pregnant healthy women (Group 0). Topographic measurements, including central corneal thickness (CCT), corneal volume (CV), anterior chamber depth (ACD), corneal densitometry (CD) and lens densitometry (LD), were done with the Pentacam HR (Oculus, Wetzlar, Germany). The measurement results of the healthy pregnant women and non-pregnant healthy women were compared. RESULTS: CD values were found in Group 1 to be 13.19, in Group 2 to be 13.16, in Group 3 to be 13.17 and in Group 0 to be 13.22 (p = 0.811). The mean Group 1, Group 2, Group 3 and Group 0 LD-horizontal was 5.40 +/- 0.5, 5.47 +/- 0.38, 5.53 +/- 0.44, 5.36 +/- 0.43, respectively. The mean Group 1, Group 2, Group 3 and Group 0 LD-vertical was 5.6 +/- 0.43, 5.66 +/- 0.32, 5.71 +/- 0.40 and 5.5 +/- 0.44, respectively. Area LD values were higher in the advanced trimester period, and the only statistically significant difference was between Group 3 and Group 0 (p = 0.025). The difference between three-dimensional (3D) and peak LD values was not statistically significant between the groups (p = 0.89 and p = 0.91, respectively). DISCUSSION: The Pentacam HR seems to be an important option for the evaluation of LD, CD and topographic measurements of the anterior segment in pregnancy. In the present study, CD and LD, including LD-horizontal, LD-vertical, peak and 3D values, were not significantly different between pregnant women and non-pregnant women. PMID- 30401607 TI - Commentary on "High Occurrence of Psychiatric Disorders and Suicidal Behavior Across Dementia Subtypes". PMID- 30401608 TI - Effect of Vitamin D Supplementation on Depressive Symptoms in Patients With Knee Osteoarthritis. AB - OBJECTIVES: To determine the effect of vitamin D supplementation and maintaining sufficient serum vitamin D on depressive symptoms in patients with knee osteoarthritis (OA) and vitamin D deficiency. DESIGN: A prespecified secondary analysis of a multicentre, randomized, double-blind, placebo-controlled trial. Participants were randomly assigned to receive oral vitamin D3 (50,000 IU, n = 209) or placebo (n = 204) monthly for 24 months. In addition, participants who completed the trial were classified into 2 groups according to their serum 25(OH)D levels at month 3 and 24 as follows: not consistently sufficient (serum 25(OH)D <= 50 nmol/L at month 3 and/or 24), and consistently sufficient (serum 25(OH)D > 50 nmol/L at both month 3 and 24). Multilevel mixed-effect models were used to compare differences of change in PHQ-9 scores between groups. SETTING AND PARTICIPANTS: This clinical trial was conducted in participants with symptomatic knee OA and vitamin D deficiency from June 2010 to December 2013 in Tasmania and Victoria, Australia. MEASURES: The primary outcome was the depressive symptoms change over 24 months, which was measured using the Patient Health Questionnaire (PHQ-9, 0-27). RESULTS: Of 599 participants who were screened for eligibility, 413 participants were enrolled (mean age: 63.2 years; 50.3% female) and 340 participants (intervention n = 181, placebo n = 159, 82.3% retention rate) completed the study. The baseline prevalence of depression (PHQ-9 score >=5) was 25.4%. Depressive symptoms improved more in the vitamin D supplementation group compared to the placebo group [beta: -0.66, 95% confidence interval (CI): -1.22 to -0.11, P for difference = .02] and in the participants who maintained vitamin D sufficiency compared to those who did not (beta: -0.73, 95% CI: -1.41 to -0.05, P for difference = .04) over 24 months. CONCLUSIONS/IMPLICATIONS: These findings suggest that vitamin D supplementation and maintaining adequate vitamin D levels over 24 months may be beneficial for depressive symptoms in patients with knee OA. PMID- 30401609 TI - Neighborhood Walkability of Retirement Homes: A Cross-Sectional Cohort Study. PMID- 30401610 TI - Effect of Monthly Vitamin D on Chronic Pain Among Community-Dwelling Seniors: A Randomized, Double-Blind Controlled Trial. AB - OBJECTIVE: With advancing age, the prevalence of vitamin D deficiency and musculoskeletal pain increases. However, published data on the effectiveness of vitamin D supplementation in reducing chronic pain are inconclusive. The purpose of this study was to test the effect of 3 different monthly doses of vitamin D on chronic pain in seniors 70 years and older with a prior fall event. DESIGN: 1 year, double-blind randomized clinical trial. SETTING: The trial was conducted in Zurich, Switzerland. Participants were 200 community-dwelling men and women 70 years and older with a prior fall. INTERVENTION: Three study groups with monthly treatments were randomized to either a low-dose control group of vitamin D (24,000 IU vitamin D3/mo), a high dose of vitamin D3 (60,000 IU vitamin D3/mo), or a combination of calcifediol and vitamin D3 (24,000 IU vitamin D3 plus 300 MUg calcifediol/mo). MEASUREMENTS: The primary endpoint was the change in the mean number of painful areas using the McGill Pain map over 12 months of follow-up. All analyses were adjusted for age, sex, body mass index, 25-hydroxyvitamin (OH)D3 levels, and pain scores at baseline. A predefined subgroup analysis was performed by baseline 25(OH)D status (<20 vs >= 20 ng/mL). RESULTS: The mean age of the participants was 78 years, 67.0% (134 of 200) were female, and 58.0% (116 of 200) were vitamin D deficient (<20 ng/mL) at baseline. Over 12 months of follow-up, the changes in the mean number of painful areas did not differ significantly among treatment groups (P = .46). However, there was a significant interaction effect between baseline vitamin levels (<20 vs >= 20 ng/mL) and treatment (P = .02). Among those who were vitamin D replete at baseline (n = 84), there was a significant difference between treatment groups over time (P = .04), and only seniors in the 24,000-IU vitamin D3 group had a marginally significant decrease in their total mean pain score (-0.77; 95% CI, -1.56 to 0.01, P = .05), whereas there were no changes in the high-dose groups. Among seniors who were vitamin D deficient at baseline (n = 116), chronic pain did not differ by treatment groups over time (P = .33). CONCLUSION: Our results suggest that both starting level of 25(OH)D3 and monthly treatment dose of vitamin D may be important with respect to chronic pain reduction-with the only benefit seen among vitamin D-replete seniors treated with a monthly dose of 24,000 IU vitamin D3. PMID- 30401611 TI - Reduced Doses of Direct Oral Anticoagulants in Ischemic Stroke Patients with Nonvalvular Atrial Fibrillation. AB - BACKGROUND: The choice of standard or reduced doses of direct oral anticoagulants (DOACs) depends on patients' age, body weight, and renal function based on package instructions. Our aim was to conduct a simulation of DOAC dose using patients' data obtained on admission. METHODS: This retrospective study included 314 ischemic stroke patients with nonvalvular atrial fibrillation admitted to our hospital between September 2014 and February 2018. Data on age, body weight, creatinine, and creatinine clearance were collected for each subject, and simulation was conducted for the dose of each DOAC. RESULTS: The mean age of 314 subjects was 77.2 years; those aged 75 years or older accounted for 61.5% (193 patients). It was suggested that a standard dose of rivaroxaban could be used in 67.5% of patients and that of apixaban in 65.9%. By contrast, a standard dose of dabigatran could be used in only 16.9% of patients and that of edoxaban in only 32.5%. The simulation analysis for patients aged 75 years or older showed that a standard dose of rivaroxaban could be used in 54.9% of patients and that of apixaban in 44.6%, while that of edoxaban could be used in only 19.7% of patients. CONCLUSIONS: When DOACs are prescribed for secondary prevention of cerebral infarction in patients with nonvalvular atrial fibrillation, the rate of standard or reduced dose varies depending on the kind of DOAC. Further analysis is required to clarify whether a standard dose of one DOAC or reduced dose of another DOAC yields the best result for each patient. PMID- 30401612 TI - Perceived Susceptibility to Cervical Cancer among African American Women in the Mississippi Delta: Does Adherence to Screening Matter? AB - BACKGROUND: Although preventive measures have greatly decreased the national burden of cervical cancer, racial/ethnic and geographic disparities remain, including the disproportionate incidence and mortality among African American women in the Mississippi Delta. Along with structural barriers, health perceptions and cultural beliefs influence participation in cervical screening. This study examined perceived susceptibility to cervical cancer among African American women in the Delta across three groups: 1) women attending screening appointments (screened), 2) women attending colposcopy clinic following an abnormal Papanicolaou test (colposcopy), and 3) women with no screening in 3 years or longer (unscreened/underscreened). METHODS: Data were collected during a study assessing the feasibility/acceptability of self-collected sampling for human papillomavirus (HPV) testing as a cervical screening modality. A questionnaire assessed demographics, health care access, and cervical cancer knowledge and beliefs (including perceived susceptibility). Participants were asked, "Do you think you are at risk for cervical cancer?", and responses included yes, no, and I don't know. Multinomial logistic regression models compared variables associated with answers among each group. RESULTS: Of 524 participants, one-half did not know if they were at risk of cervical cancer (50%) or HPV exposure (53%). Between the unscreened/underscreened (n = 160), screened (n = 198), and colposcopy (n = 166) groups, age (p < .001), education (p = .02), and perceived risk of HPV exposure (p < .01) differed. Older age and younger age at first intercourse (unscreened/underscreened), family history and screening recommendations (screened), and family history and perceived risk of HPV exposure (colposcopy) were associated with perceived susceptibility to cervical cancer. CONCLUSIONS: Differences in the perceived susceptibility to cervical cancer exist between African American women in the Delta. Understanding these variations can help in developing strategies to promote screening among this population with a high burden of disease. PMID- 30401613 TI - Effects of a finger exercise program on hand function in automobile workers with hand osteoarthritis: A randomized controlled trial. AB - Hand osteoarthritis reduces a person's ability to perform work activities and return to their occupation. We investigated the effects of a finger exercise program on hand grip strength, pain, physical function, and stiffness in automobile manufacturing workers with hand osteoarthritis. This randomized controlled trial was conducted on 29 subjects. Fifteen experimental subjects received a finger exercise program with paraffin baths, while 14 control subjects received only paraffin baths. Hand grip strength, pain, physical function, and stiffness were assessed at baseline and 8 weeks later. In the experimental group, hand grip strength (P < 0.001) and Australian/Canadian osteoarthritis hand index (AUSCAN) scores (pain, P < 0.001; stiffness, P < 0.001; physical function, P < 0.001) were significantly improved by 3.52 +/- 2.03, 21.6 +/- 8.3 (pain), 16.8 +/ 10.21 (stiffness), and 13.86 +/- 4.54 (physical function) compared with preintervention values. In the control group, hand grip strength (P = 0.004) and AUSCAN scores (pain, P < 0.001; stiffness, P = 0.019; physical function, P < 0.001) were significantly improved by 0.57 +/- 0.62, 7.85 +/- 5.46 (pain) 11.42 +/- 7.18 (stiffness), and 10.28 +/- 14.41 (physical function) compared with preintervention values. Significant differences between groups were found for postintervention hand grip strength (P = 0.015) and AUSCAN index subscale scores (pain, P < 0.001; physical function, P = 0.020). A combined finger exercise and paraffin bath program is effective in reducing pain, improving physical function, and increasing hand grip strength in workers with hand osteoarthritis. PMID- 30401614 TI - Black pigmentation of both forearm bones after chronic minocycline antibiotic therapy for septic nonunion. A case report and literature review. AB - We report the case of a 28-year-old man with a septic forearm non-union treated with minocycline for 3 months. At the time of reconstructive surgery, the radius and ulna were entirely black. Surgical debridement until bleeding of both bone extremities resulted in a 5-cm defect that was filled with a cement spacer. Histology confirmed poorly vascularized bone with focal areas of acute inflammatory infiltrate at the non-union sites (highly suggestive of infection) and normal structure of the remaining diaphyseal bones, although black in color. Reconstruction with free vascularized fibula transfer was successful leading to complete bone healing. An incidental finding of minocycline-induced black bone discoloration should not change the surgeon's decision because there is no evidence of adverse effects on bone healing in the literature. Surgery can be performed safely at sites of minocycline-induced black bone pigmentation. PMID- 30401615 TI - Student Factors That Influence Clerkship Grades and Matching Into a Surgical Residency. AB - OBJECTIVE: Evaluate the relationship between medical school factors (including preclinical mentorship, order of clerkships, and clerkship grades) and matching into surgical specialties. DESIGN: Clerkship information, match data, and data on structured preclinical research obtained from 2010 to 2015 for a single institution was obtained and analyzed using multivariate analysis. SETTING: University of Michigan Medical School. PARTICIPANTS: Seven hundred and forty-six students who took both the Internal Medicine and Surgery clerkships between 2010 and 2015 and have since participated in the match. RESULTS: Among 740 students studied, 243 matched into a surgical field. Higher Shelf scores were associated with higher clerkship grades in Surgery and Internal Medicine. Honors or High Pass in Surgery were associated with matching into a surgical field. Structured preclinical research in Surgery and order of clerkship were not associated with matching into a surgical field. CONCLUSIONS: Students who went into surgery were more likely to receive Honors or High Pass. Preclinical choices geared toward a surgical specialty (e.g., order of clerkship and structured research) were not associated with matching into a surgical field. These data may help guide school specific advice for students. PMID- 30401616 TI - Emotional Intelligence and Delivering Bad News: The Jury is Still Out. AB - BACKGROUND: Emotional intelligence (EQ) has been proposed to be a critical competency necessary for complex and interpersonal interactions for healthcare providers. OBJECTIVE: The goal of this study was to examine how EQ impacts surgical residents' ability to deliver bad news. METHOD: Residents participated in a patient death simulation, and instructed to disclose the news to the patient's sister. The encounter was recorded and graded according to a 10-point delivering bad news checklist (1%-100%). Residents also completed an EQ assessment (100 = average). RESULTS: Nineteen PGY-1 general surgery residents participated. Overall average performance on delivering bad news was 62% +/- 22% and resident scores ranged from 20% to 90%. There was no correlation between EQ and delivering bad news. CONCLUSIONS: This study failed to find evidence to support the notion that EQ is associated with trainee ability to deliver bad news, suggesting that more evidence is needed to support EQ's role in curricular and assessment endeavors. PMID- 30401618 TI - The complexities of child poverty and health care in the USA. PMID- 30401617 TI - Clinical assessment of palliative radiotherapy for pancreatic cancer. AB - PURPOSE: To evaluate the feasibility and response to radiotherapy for improving the symptoms and quality of life in patients with pancreatic cancer. PATIENTS AND METHODS: We enrolled 31 eligible patients (20 men, 11 women) with pancreatic cancer who were receiving radiotherapy from February 2012 to February 2014. The prescribed dose was 40 to 42Gy delivered to the planning target volume in seven to ten fractions of 4 to 6Gy. Patients completed Brief Pain Inventory (BPI), Functional Assessment Of Cancer Therapy-Hepatobiliary (FACT-Hep), and European Organisation for Research and Treatment of Cancer Quality Of Life Questionnaire C30 (EORTC QLQ-C30) one week prior to radiotherapy, and one and three months after treatment. The main outcome was the evaluation of the proportion of patients with less pain and reduced clinical symptoms after one month of radiotherapy compared to before treatment according to the BPI, FACT-Hep and EORTC QLQ-C30 scales. RESULTS: Of 31 patients, 28 completed the questionnaires. According to BPI evaluation, symptoms were improved in 57% of patients; the FACT General (FACT-G) and liver function subscales revealed that there was symptom improvement in 89% and 7.1% of patients, respectively. Six items in the EORTC QLQ C30 were improved. CONCLUSIONS: Following treatment, pain and clinical symptoms were improved in a considerable proportion of patients with pancreatic cancer, proving that palliative radiotherapy is feasible for pancreatic cancer. PMID- 30401619 TI - Investigating the function and possible biological role of an acetylcholine-gated chloride channel subunit (ACC-1) from the parasitic nematode Haemonchus contortus. AB - The cys-loop superfamily of ligand-gated ion channels are well recognized as important drug targets for many invertebrate specific compounds. With the rise in resistance seen worldwide to existing anthelmintics, novel drug targets must be identified so new treatments can be developed. The acetylcholine-gated chloride channel (ACC) family is a unique family of cholinergic receptors that have been shown, using Caenorhabditis elegans as a model, to have potential as anti parasitic drug targets. However, there is little known about the function of these receptors in parasitic nematodes. Here, we have identified an acc gene (hco acc-1) from the sheep parasitic nematode Haemonchus contortus. While similar in sequence to the previously characterized C. elegans ACC-1 receptor, Hco-ACC-1 does not form a functional homomeric channel in Xenopus oocytes. Instead, co expression of Hco-ACC-1 with a previously characterized subunit Hco-ACC-2 produced a functional heteromeric channel which was 3x more sensitive to acetylcholine compared to the Hco-ACC-2 homomeric channel. We have also found that Hco-ACC-1 can be functionally expressed in C. elegans. Overexpression of both cel-acc-1 and hco-acc-1 in both C. elegans N2 and acc-1 null mutants decreased the time for worms to initiate reversal avoidance to octanol. Moreover, antibodies were generated against the Hco-ACC-1 protein for use in immunolocalization studies. Hco-ACC-1 consistently localized to the anterior half of the pharynx, specifically in pharyngeal muscle tissue in H. contortus. On the other hand, expression of Hco-ACC-1 in C. elegans was restricted to neuronal tissue. Overall, this research has provided new insight into the potential role of ACC receptors in parasitic nematodes. PMID- 30401620 TI - Influenza and pertussis vaccination in pregnancy: Portrayal in online media articles and perceptions of pregnant women and healthcare professionals. AB - INTRODUCTION: Online media may influence women's decision to undergo vaccination during pregnancy. The aims of this mixed-methods study were to: (1) examine the portrayal of maternal vaccination in online media and (2) establish the perceived target of vaccine protection as viewed by pregnant women and maternity healthcare professionals (HCPs). METHODS: Online media articles on maternal vaccination (published July-December 2012 or November 2015-April 2016) were identified through the London School of Hygiene & Tropical Medicine's Vaccine Confidence Database and thematically analysed. Questionnaires for pregnant women and HCPs were distributed within four English hospitals (July 2017-January 2018). RESULTS: Of 203 articles identified, 60% related to pertussis vaccination, 33% to influenza and 6% both. The majority positively portrayed vaccination in pregnancy (97%), but inaccurate, negative articles persist which criticize pertussis vaccination's safety and efficacy. Positively-worded articles about pertussis tended to focus on infant protection and highlight examples of recent cases, whereas positively-worded articles about influenza focused on maternal protection. These themes were reflected in questionnaire responses from 314 pregnant women and 204 HCPs, who perceived pertussis vaccination as protecting the baby, and influenza vaccination as protecting the mother, or mother and baby equally. A minority of the pregnant women surveyed intended to decline influenza (22%) or pertussis (8%) vaccination. CONCLUSIONS: The majority of online articles support pertussis and influenza vaccination during pregnancy. The portrayal of pertussis vaccination as primarily benefiting the child, using real-examples, may influence its higher uptake compared with influenza. This approach should be considered by HCPs when recommending vaccination. HCPs should be prepared to provide advice to women hesitant about vaccination, including addressing any negative media, and consider educational strategies to counteract inaccurate information. Future studies should directly assess the influence of media on vaccine decision-making and establish which media platforms are typically used by pregnant women to gather information. PMID- 30401622 TI - Mineralization of dinitrotoluenes in aqueous solution by sono-activated persulfate enhanced with electrolytes. AB - Oxidative degradation of dinitrotoluenes (DNTs) in industrial wastewater was conducted by sono-activated persulfate process assisted with electrolytes. Experiments were carried out to elucidate the influence of various operating parameters on the sonolytic behavior, such as species and concentrations of electrolytes, ultrasonic power intensity, reaction temperature, dosage of oxygen and persulfate anions. The outcomes indicate that sulfate radicals serve as main oxidants in the sono-activated persulfate process, wherein MgSO4 electrolyte obviously inhibits microbubble coalescence, leading to enhancement of cavitation strength and DNTs removal percentage. On addition of electrolytes, the increment of DNTs removal percentages was proportional to ionic strength of electrolytes. According to the results obtained from gas chromatograph-mass spectrometer (GC MS), it is postulated that DNTs initially undergo denitration pathway with cleavage of nitro group into o-mononitrotoluene (MNT) or oxidation of methyl group followed with decarboxylation procedure into 1,3-dinitrobenzene (DNB), respectively. Due to electrolytes observed commonly in wastewater, the sono activated persulfate process coupled with electrolytes is potentially applied to dispose wastewater effluent from toluene nitration processes. PMID- 30401621 TI - Investigation of group A Streptococcus immune responses in an endemic setting, with a particular focus on J8. AB - Sustained control of group A Streptococcus (GAS) infections in settings of poverty has proven to be challenging, and an effective vaccine may be the most practical long-term strategy to reduce GAS-related disease burden. Candidate GAS vaccines based on the J8 peptide have demonstrated promising immunogenicity in mice, however, less is known about the role of J8 antibodies in the human immune response to GAS infection. We analysed the stimulation of J8 antibodies in response to infection, and the role of existing J8 antibodies in protection against subsequent infection, using data collected in the Fijian population: (1) cross sectional population serosurvey; (2) paired serum collection for assessment of M-specific and J8 antibody responses; and (3) longitudinal assessment of GAS infection and immunity. Median J8 antibody concentrations peaked in the 5-14 year age group, but there was no sustained increase with age. J8 antibody concentration was neither a significant predictor of time to next infection, nor did it show any relationship to the time since last recorded skin infection. Similarly, J8 antibody fold changes over a defined period were associated neither with the time since last skin infection, nor the number of intervening skin infections. While strong M-specific antibody responses were observed for skin infection, similarly strong J8 antibody responses were not observed. There is no indication that antibodies to the J8 antigen would be useful as either a marker of GAS infection or a measure of population immunity, with J8 antibody responses to infection fleeting, if existent at all. PMID- 30401623 TI - Ultrasonic assisted ultrafiltration process for emulsification of oil field produced water treatment. AB - Ultrafiltration has been proven to be very effective in the treatment of oil-in water emulsions, since no chemical additives are required. However, ultrafiltration has its limitations, the main limits are concentration polarization resulting to permeate flux decline with time. Adsorption, accumulation of oil and particles on the membrane surface which causes fouling of the membrane. Studies have shown that the ultrasonic is effective in cleaning of fouled membrane and enhancing membrane filtration performance. But the effectiveness also, depends on the selection of appropriate membrane material, membrane geometry, ultrasonic module design, operational and processing condition. In this study, a hollow and flat-sheet polyurethane (PU) membranes synthesized with different additives and solvent were used and their performance evaluated with oil-in-water emulsion. The steady-state permeate flux and the rejection of oil in percentage (%) at two different modes were determined. A dry/wet spinning technique was used to fabricate the flat-sheet and hollow fibre membrane (HFMs) using Polyethersulfone (PES) polymer base, Polyvinylpyrrolidone (PVP) additive and N, N-Dimethylacetamide (DMAc) solvent. Ultrasonic assisted cross-flow ultrafiltration module was built to avoid loss of ultrasonic to the surrounding. The polyurethane (PU) was synthesized by polymerization and sulphonation to have an anionic group (-OH; -COOH; and -SO3H) on the membrane surface. Changes in morphological properties of the membrane had a significant effect on the permeate flow rate and oil removal. Generation of cavitation and Brownian motion by the ultrasonic were the dominant mechanisms responsible for ultrafiltration by cracking the cake layers and reducing concentration polarization at the membrane surface. The percentage of oil after ultrafiltration process with ultrasonic is about 90% compared to 49% without ultrasonic. Ultrasonic is effective in enhancing the membrane permeate flux and controlling membrane fouling. PMID- 30401624 TI - Facile photo-ultrasonic assisted reduction for preparation of rGO/Ag2CO3 nanocomposites with enhanced photocatalytic oxidation activity for tetracycline. AB - Various antibiotics in the aquatic systems have threat the aquatic ecosystem balance and the human health. In this study, a degradation treatment method for tetracycline (TC), one of the commonly used antibiotics, was explored by using novel photocatalysts of rGO/Ag2CO3 under simulated sunlight, because conventional treatment methods are not efficient on the removal of TC. rGO/Ag2CO3 nanocomposites were synthesized via a facile photo-ultrasonic assisted reduction method. More than 90% of TC was removed by 1% (weightrGO/weightcomposites) rGO/Ag2CO3 within 60 min at pH = 4, which was about 1.3 times higher than that of pure Ag2CO3. The cycling experiments indicated that 1% rGO/Ag2CO3 was highly stable and could be reused for at least 5 cycles without significant deactivation to its photocatalytic activity. In addition, the effects of pH, temperature, and dosage amount of 1% rGO/Ag2CO3 on photocatalytic degradation were investigated. Meanwhile, the effect of ultrasonic on the degradation of TC was also investigated. This study can provide a new method for the preparation of smaller nanosized materials and photocatalysts with high activity and stability for its environmental or other applications. PMID- 30401625 TI - A detailed analysis of the influence of beta-cyclodextrin derivates on the thermal denaturation of lysozyme. AB - The influence of HPbetaCD on the thermal denaturation of lysozyme was analyzed mainly from microcalorimetry and Raman investigations carried out in the molecular fingerprint and the low-frequency regions. It was shown that Raman spectroscopy investigations performed on a wide spectral range give the opportunity to describe the influence of HPbetaCD on the mechanism of protein denaturation. Using D2O as solvent allowed us to show that HPbetaCD mainly destabilizes the tertiary structure of lysozyme by enhancing the protein flexibility and thus inducing the destabilization of the secondary structure. Principal components analysis (PCA) was used for spectra treatment, providing important information about inclusion complex formation between protein hydrophobic residues and CDs molecules. Combining PCA and classical technics (curve fitting) of data analysis allowed a better understanding of the influence of HPbetaCD on the protein denaturation that seems to be related to the CDs capacity to form inclusion complex. It was observed that these interactions prevent the formation of new strong H-bonds between beta-sheet structures thereby inhibiting protein aggregation. This study reveals that CDs are promising systems for inhibiting protein aggregation without protein denaturation, only if designing derivative CDs is carefully controlled. PMID- 30401627 TI - Diaphanous-1 affects the nanoscale clustering and lateral diffusion of receptor for advanced glycation endproducts (RAGE). AB - The interactions between the cytoplasmic protein diaphanous-1 (Diaph1) and the receptor for advanced glycation endproducts (RAGE) drive the negative consequences of RAGE signaling in several disease processes. Reported in this work is how Diaph1 affects the nanoscale clustering and diffusion of RAGE measured using super-resolution stochastic optical reconstruction microscopy (STORM) and single particle tracking (SPT). Altering the Diaph1 binding site has a different impact on RAGE diffusion compared to when Diaph1 expression is reduced in HEK293 cells. In cells with reduced Diaph1 expression (RAGE-Diaph1-/ ), the average RAGE diffusion coefficient is increased by 35%. RAGE diffusion is known to be influenced by the dynamics of the actin cytoskeleton. Actin labeling shows that a reduced Diaph1 expression leads to cells with reduced filopodia density and length. In contrast, when two RAGE amino acids that interact with Diaph1 are mutated (RAGERQ/AA), the average RAGE diffusion coefficient is decreased by 16%. Since RAGE diffusion is slowed when the interaction between Diaph1 and RAGE is disrupted, the interaction of the two proteins results in faster RAGE diffusion. In both RAGERQ/AA and RAGE-Diaph1-/- cells the number and size of RAGE clusters are decreased compared to cells expressing RAGE and native concentrations of Diaph1. This work shows that Diaph1 has a role in affecting RAGE clusters and diffusion. PMID- 30401626 TI - Reverse chemical ecology-based approach leading to the accidental discovery of repellents for Rhodnius prolixus, a vector of Chagas diseases refractory to DEET. AB - Rhodnius prolixus is one of the most important vectors of Chagas disease in Central and South America for which repellents and attractants are sorely needed. Repellents like DEET, picaridin, and IR3535 are widely used as the first line of defense against mosquitoes and other vectors, but they are ineffective against R. prolixus. Our initial goal was to identify in R. prolixus genome odorant receptors sensitive to putative sex pheromones. We compared gene expression of 21 ORs in the R. prolixus genome, identified 4 ORs enriched in male (compared with female) antennae. Attempts to de-orphanize these ORs using the Xenopus oocyte recording system showed that none of them responded to putative sex pheromone constituents. One of the them, RproOR80, was sensitive to 4 compounds in our panel of 109 odorants, namely, 2-heptanone, gamma-octalactone, acetophenone, and 4-methylcychohexanol. Interestingly, these compounds, particularly 4 methylcyclohexanol, showed strong repellency activity as indicated not only by a significant decrease in residence time close to a host, but also by a remarkable reduction in blood intake. 4-Methylcyclohexanol-elicited repellency activity was abolished in RNAi-treated insects. In summary, our search for pheromone receptors led to the discovery of repellents for R. prolixus. PMID- 30401628 TI - Effects of zamicastat treatment in a genetic model of salt-sensitive hypertension and heart failure. AB - Hyperactivity of sympathetic nervous system plays an important role in the development and progression of cardiovascular diseases. An approach to mitigate the enhanced sympathetic nervous system drive is restricting the biosynthesis of noradrenaline via inhibition of the enzyme dopamine beta-hydroxylase (DbetaH), that catalyzes the hydroxylation of dopamine to noradrenaline in sympathetic nerves. The aim of the present study was to evaluate the effects of zamicastat, a novel DbetaH inhibitor that decreases noradrenaline and increases dopamine levels in peripheral sympathetically innervated tissues, on the hemodynamic and cardiometabolic parameters in salt-induced hypertension and heart failure in the Dahl salt-sensitive (SS) rat. Zamicastat (10, 30 and 100 mg/kg body weight) was tested acutely against salt-induced hypertension in the Dahl SS rat. Chronic zamicastat treatment (30 mg/kg/day) was evaluated against salt-induced cardiac hypertrophy and biomarkers of cardiometabolic risk and inflammation in Dahl SS rats and upon the survival rate in aged Dahl SS rats fed a high-salt diet. The reduction in the sympathetic tone attained with zamicastat shaped a dose- and time-dependent effect on blood pressure. Prolonged treatment with zamicastat ameliorated end-organ damage, metabolic syndrome and inflammation hallmarks in hypertensive Dahl SS rats. Survival rate of Dahl SS rats fed a high-salt diet demonstrated that zamicastat increased median survival of Dahl SS rats fed a high salt diet. The use of DbetaH inhibitors, like zamicastat, is a promising approach to treat hypertension, heart failure and cardiovascular diseases where a reduction in the sympathetic tone has beneficial effects. PMID- 30401629 TI - Cardioprotection and improvement in endothelial-dependent vasodilation during late-phase of whole body hypoxic preconditioning in spontaneously hypertensive rats via VEGF and endothelin-1. AB - The present study was designed to investigate the effect of late phase of whole body hypoxic preconditioning on endothelial-dependent vasorelaxation and cardioprotection from ischemia-reperfusion injury in spontaneously hypertensive rats (SHR). Hypoxic preconditioning was performed by subjecting rats to four episodes of alternate exposure to low O2 (8%) and normal air O2 of 10 min each. After 24 h, the mesenteric arteries and hearts were isolated to determine the vascular function and cardioprotection from ischemia-reperfusion (I/R) injury on the Langendorff apparatus. There was a significant impairment in acetylcholine induced relaxation in norepinephrine precontracted arteries (endothelium dependent function) and increase in I/R-induced myocardial injury in SHR in comparison to Wistar Kyoto rats (WKY). However, hypoxic preconditioning significantly restored endothelium-dependent relaxation in SHR and attenuated I/R injury in both SHR and WKY. Hypoxic preconditioning also led to an increase in the levels of endothelin-1 (not endothelin-2 or -3), vascular endothelial growth factor-A (VEGF-A) and HIF-1alpha levels. Pretreatment with bevacizumab (anti-VEGF A) and bosentan (endothelin receptor blocker) significantly attenuated hypoxic preconditioning-induced restoration of endothelium-dependent relaxation and cardioprotection from I/R injury. These interventions also attenuated the levels of VEGF-A and HIF-1alpha without modulating the endothelin-1 levels. It may be concluded that an increase in the endothelin-1 levels with a subsequent increase in HIF-1alpha and VEGF expression may possibly contribute in improving endothelium-dependent vasorelaxation and protecting hearts from I/R injury in SHR during late phase of whole body hypoxic preconditioning. PMID- 30401630 TI - Anticancer effect of pan-PI3K inhibitor on multiple myeloma cells: Shedding new light on the mechanisms involved in BKM120 resistance. AB - The correlation between the Phosphoinositide 3-kinase (PI3K) axis and crucial mechanisms involved in the maintenance of the neoplastic nature of multiple myeloma (MM) has recently evolved a general agreement that PI3K inhibition-based therapies could construct an exciting perspective for the future treatment strategies. Our results outlined that abrogation of PI3K using pan-PI3K inhibitor BKM120 decreased survival of MM cells through induction of a caspase-3-dependent apoptosis coupled with SIRT1-mediated G2/M arrest in both KMM-1 and RPMI 8226 cell lines; however, the cell responses to the inhibitor was quite different, introducing wild-type PTEN-expressing RPMI 8226 as less sensitive cells. By investigating the sensitivity extent of a panel of hematological cell lines to BKM120, we found no significant association with respect to PTEN status. As far as we are aware, the results of the present study propose for the first time that the inhibitory effect of BKM120 was overshadowed, at least partially, through over-expression of either c-Myc or nuclear factor (NF)-kappaB in less sensitive MM cells. While there was no significant effect of the inhibitor on the expression of c-Myc in RPMI 8226, we found an enhanced cytotoxic effect when BKM120 was used in combination with a small molecule inhibitor of c-Myc. Noteworthy, the results of the synergistic experiments also revealed that BKM120 could produce a synergistic anti-cancer effect with carfilzomib (CFZ) and provided an enhanced therapeutic efficacy in MM cells, highlighting that PI3K inhibition might be a befitting approach in MM both in mono and combined therapy. PMID- 30401632 TI - Mechanosensitive TRPV4 channels stabilize VE-cadherin junctions to regulate tumor vascular integrity and metastasis. AB - The transient receptor potential vanilloid 4 (TRPV4) channel is a mechanosensor in endothelial cells (EC) that regulates cyclic strain-induced reorientation and flow-mediated nitric oxide production. We have recently demonstrated that TRPV4 expression is reduced in tumor EC and tumors grown in TRPV4KO mice exhibited enhanced growth and immature leaky vessels. However, the mechanism by which TRPV4 regulates tumor vascular integrity and metastasis is not known. Here, we demonstrate that VE-cadherin expression at the cell-cell contacts is significantly reduced in TRPV4-deficient tumor EC and TRPV4KO EC. In vivo angiogenesis assays with Matrigel of varying stiffness (700-900 Pa) revealed a significant stiffness-dependent reduction in VE-cadherin-positive vessels in Matrigel plugs from TRPV4KO mice compared with WT mice, despite an increase in vessel growth. Further, syngeneic Lewis Lung Carcinomatumor experiments demonstrated a significant decrease in VE-cadherin positive vessels in TRPV4KO tumors compared with WT. Functionally, enhanced tumor cell metastasis to the lung was observed in TRPV4KO mice. Our findings demonstrate that TRPV4 channels regulate tumor vessel integrity by maintaining VE-cadherin expression at cell cell contacts and identifies TRPV4 as a novel target for metastasis. PMID- 30401633 TI - A comparison of 24 chemicals in the six-well bacterial reverse mutation assay to the standard 100-mm Petri plate bacterial reverse mutation assay in two laboratories. AB - The bacterial reverse mutation assay (Ames) is a fundamental genetic toxicology test, and efforts to miniaturize the regulatory GLP version are essential in assessing genotoxic liabilities earlier in the drug development pipeline. Two versions of the Ames were compared: the six-well (miniaturized) plate and the standard 100-mm plate test at two different laboratories. Of twenty-four chemicals tested, a subset of six chemicals was tested in the six-well test only and the remaining eighteen were evaluated in both versions of the test. The plate incorporation procedure was used with one Escherichia coli and four different Salmonella strains. The six-well test uses the same plating procedure and evaluation methods as the standard Ames assay in 100-mm plates, but the smaller format requires 20% of the test chemical. Additionally, the six-well test uses a limit concentration of 1000 MUg/well versus the standard Petri plate test limit concentration of 5000 MUg/plate. Testing across the two formats resulted in 100% concordance in overall mutagenicity judgement and 94% concordance across all tester strains and conditions. Known mutagenic positive control chemicals were correctly detected as positive in both formats. The overall conclusion is that the six-well assay results are concordant with the standard assay format in this evaluation and could be a reliable alternative. PMID- 30401631 TI - Methods to improve the noninvasive diagnosis and assessment of disease severity in children with suspected nonalcoholic fatty liver disease (NAFLD): Study design. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is strongly associated with obesity and is the most common liver disease in the developed world. In children with suspected NAFLD, present guidelines suggest consideration of alternative diagnoses via extensive blood testing, though the yield of this work up is unknown. Furthermore, the gold standard diagnostic test for NAFLD remains liver biopsy, making the development of non-invasive tests critically important. OBJECTIVES: Our objectives are: 1) to determine the accuracy of elastography and multiple serum biomarkers - each assessed individually and as algorithms (including those previously tested in adults) - for the diagnosis of nonalcoholic steatohepatitis (NASH) and early fibrosis in children and (2) to examine the utility of extensive testing for rare alternative diagnoses in overweight or obese children with elevated alanine aminotransferase (ALT) suspected to have NAFLD. DESIGN: This is an ongoing, cross-sectional study in children 2-18 years of age with up to 2 years of prospective follow up. Eligible patients are asymptomatic, overweight or obese, and have an ALT >=35 U/L upon enrollment. Two forms of elastography are obtained serially along with anthropometric data and routine laboratory tests. Elastography and serum biomarkers are also performed immediately prior to any clinically-indicated biopsy. METHODS: Between April 2015 and April 2018, 193 children have been enrolled in this ongoing study and 71 have undergone liver biopsy. Here we carefully report the rationale, methodology, and preliminary data for this study. PMID- 30401635 TI - Putting telemedicine behind bars. PMID- 30401634 TI - Precluding oscillations in Michaelis-Menten approximations of dual-site phosphorylation systems. AB - Oscillations play a major role in a number of biological systems, from predator prey models of ecology to circadian clocks. In this paper we focus on the question of whether oscillations exist within dual-site phosphorylation systems. Previously, Wang and Sontag showed, using monotone systems theory, that the Michaelis-Menten (MM) approximation of the distributive and sequential dual-site phosphorylation system lacks oscillations. However, biological systems are generally not purely distributive; there is generally some processive behavior as well. Accordingly, this paper focuses on the MM approximation of a general sequential dual-site phosphorylation system that contains both processive and distributive components, termed the composite system. Expanding on the methods of Bozeman and Morales, we preclude oscillations in the MM approximation of the composite system. This implies the lack of oscillations in the MM approximations of the processive and distributive systems, shown previously, as well as in the MM approximation of the partially processive and partially distributive mixed mechanism system. PMID- 30401636 TI - Identification and characterization of Clostridium botulinum strains associated with an infant botulism case in China. AB - Infant botulism was rarely reported in China. The second reported event of the disease including three cases occurred in 2015. In the present study, one (the third case) of the three cases was identified and investigated to trace the sources of transmission. Samples from feces and foodstuffs were used to isolate Clostridium botulinum strains. Each isolate was obtained from the baby's feces and opened powdered infant rice cereal, respectively. In this case, the C. botulinum strains were identified and characterized by combined mouse bioassay, Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and high-throughput sequencing including single nucleotide polymorphisms (SNP). Results showed that the disease was caused by a type B strain of C. botulinum. Strains associated with this case as well as isolates from stored and historical samples were phylogenetically analyzed and compared. C. botulinum type B isolates from the infant feces and from an opened container of infant rice cereal were indistinguishable, suggesting that opened container of infant rice cereal is likely to be the source of transmission of spores to the infant. It is not clear that how the opened container was contaminated and the child was exposed since environmental testing was not performed. This study provides detailed information about usage of the three methods and references for dealing with other associated cases. PMID- 30401637 TI - Diet-induced hepatic steatosis activates Ras to promote hepatocarcinogenesis via CPT1alpha. AB - Aberrant activation of the RAS cascade ubiquitously occurs in human hepatocellular carcinomas (HCC), regardless of rare mutations of RAS. However, the association between the Ras cascade and hepatic steatosis during hepatocarcinogenesis remains under-investigated. Here, the variation in the constitutive activity of Ras signaling and HCC incidence was found in a nonalcoholic fatty liver disease (NAFLD)-HCC mouse model, and Ras activity was induced by hepatic steatosis. Even in hepatocyte-specific expression of KrasG12D (Alb-Cre/KrasG12D, Krashep) mice, mutagenic activation of Ras signaling was still significantly enhanced by NAFLD, with downregulation of negative regulators. Interestingly, hepatic steatosis could be alleviated by persistent activation of Ras, whereas Ras accelerated DNA damage and HCC progression through Carnitine palmitoyltransferase 1A (CPT1alpha). A close correlation between active Ras and CPT1alpha was also shown in clinical steatosis peri-tumor tissues of HCC samples and experimental models. CPT1alpha inhibitor etomoxir (ETO) largely ameliorated active Ras-drived HCC. These findings can provide a novel link between steatosis and Ras activity in liver cancer. PMID- 30401638 TI - Long-term diosbulbin B treatment induced liver fibrosis in mice. AB - Airpotato yam is a traditional Chinese medicine used for treating thyroid disease and cancer in China. Diosbulbin B (DB) is reported to be the main hepatotoxic compound isolated from Airpotato yam. A variety of reports have shown the acute liver injury induced by DB in vivo. However, whether long-term administration of DB will cause liver fibrosis in mice is unknown. This study aims to investigate the liver fibrosis induced by long-term DB treatment in mice. C57BL/6 mice were orally given with DB (25, 50 mg/kg) for 1 or 2 month, respectively. Liver hydroxyproline content, hepatic collagen deposition and immune cells infiltration were increased in mice treated with DB (50 mg/kg) for 2 months. Serum amounts of hyaluronic acid and laminin were increased in mice treated with DB for 1 or 2 months. DB (50 mg/kg) induced hepatic stellate cells (HSCs) activation when mice were treated with DB for 2 months. Liver mRNA expression of Col1a1, Col1a2, Col3a1, fibronectin (Fn1), vimentin (Vim) and fibroblast-specific protein 1 (FSP1) were all increased in DB-treated mice. Hepatic protein expression of Vim, FSP1 and collagen 1 (COL1) were increased in DB-treated mice. Additionally, DB induced nuclear factor kappaB (NFkappaB) activation and increased the expression of pro-inflammatory molecules including tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, intercellular cell adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase (iNOS) in mice. In conclusion, long-term administration of DB induced liver fibrosis in mice. HSCs activation, epithelial-mesenchymal transition (EMT) and liver inflammation contributed to DB-induced liver fibrosis in mice. PMID- 30401639 TI - Risks associated with fat burners: A toxicological perspective. AB - Dietary supplements "fat burners", freely available on the market, are intended to promote weight loss and reduce fat accumulation, either via stimulation of lipolysis or by inhibition of lipogenesis. Proponents claim that fat burners can increase fat metabolism, although their usefulness remains controversial. Fat burners are usually claimed to be of natural origin and viewed as being inherently safe. This review focuses on the most common ingredients of natural origin usually found in the fat burners, their molecular mechanisms of action and the toxicological profiles of these compounds in order to gain an insight into their safety. PMID- 30401641 TI - beta-Glucan from Saccharomyces cerevisiae induces SBD-1 production in ovine ruminal epithelial cells via the Dectin-1-Syk-NF-kappaB signaling pathway. AB - The ruminal mucosal epithelium can secrete defensins, which play a key role in innate and adaptive immunity and are considered potential replacements for antibiotics. Of these, sheep beta-defensin-1 (SBD-1) is one of the most potent molecules produced by ovine ruminal epithelial cells (ORECs). beta-glucan, safe and effective immune activators, can stimulate innate and adaptive immune responses. Here we examined whether beta-glucan from Saccharomyces cerevisiae can induce SBD-1 expression in ORECs, as well as the underlying mechanism. First, ORECs were cultured, and quantitative real-time PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA) were used to study the effects of different beta glucan concentrations. Then western blotting, immunohistochemistry, and immunocytofluorescence were performed to investigate the regulatory mechanism of beta-glucan-induced SBD-1 upregulation. We show that beta-glucan can induce the release of SBD-1 from ORECs; the highest SBD-1 mRNA and protein expression was achieved after treatment with 10 MUg/mL at 2 and 4 h. Moreover, beta-glucan induced SBD-1 production was mediated by the activation of dendritic-cell associated C-type lectin 1 (Dectin-1) receptors, Syk, and nuclear factor kappa light-chain-enhancer of activated B cells (NF-kappaB). These findings highlight the immunomodulatory effects of beta-glucan on ORECs. PMID- 30401640 TI - Single type infection of human papillomavirus as a cause for high-grade cervical intraepithelial neoplasia and invasive cancer in Japan. AB - To elucidate oncogenic human papilloma virus (HPV) types in Japan, HPV genotyping was performed in 1526 cervical intraepithelial neoplasia (CIN) and 371 invasive cervical cancer (ICC) patients with the novel Genosearch-31+5 HPV test. The HPV positive rates were 89.3% and 90.8% in CIN and ICC. Regarding single-type infections, 13 internationally recognized high-risk (13HR) types excluding HPV 35, and probably HR HPV 53, 67, 69, and 70 were identified in ICC, suggesting that all these types may be oncogenic. HPV16 and 18 were identified in both SCC and adenocarcinoma (ADC). HPV HPV52, 31 and 58 (alpha-9) were predominantly detected in SCC, whereas HPV 18, 45, 39 and 59 (alpha-7) were in ADC. The prevalence of HPV 18 in SCC significantly decreased with increasing age of patients, whereas the opposite trend was observed in the other HR types. HPV18 is likely to induce SCC rapidly. All ICC cases aged 20-29 were positive for HPV 16 or 18, suggesting that present HPV 16, 18 vaccines may be quite effective to prevent ICC in young women. PMID- 30401642 TI - Denervated mouse dentate granule cells adjust their excitatory but not inhibitory synapses following in vitro entorhinal cortex lesion. AB - Neurons adjust their synaptic strength in a homeostatic manner following changes in network activity and connectivity. While this form of plasticity has been studied in detail for excitatory synapses, homeostatic plasticity of inhibitory synapses remains not well-understood. In the present study, we employed entorhinal cortex lesion (ECL) of organotypic entorhino-hippocampal tissue cultures to test for homeostatic changes in GABAergic neurotransmission onto partially denervated dentate granule cells. Using single and paired whole-cell patch-clamp recordings, as well as immunostainings for synaptic markers, we find that excitatory synaptic strength is robustly increased 3 days post lesion (dpl), whereas GABAergic neurotransmission is not changed after denervation. Even under conditions of pharmacological inhibition of glutamatergic neurotransmission, which prevents neurons to compensate for the loss of input via excitatory synaptic scaling, down-scaling of GABAergic synapses does not emerge 3 days after denervation. We conclude that granule cells maintain structural and functional properties of GABAergic synapses even in the face of substantial changes in network connectivity. Hence, alterations in inhibitory neurotransmission, as seen in pathological brain states, may not simply reflect a homeostatic response to disconnection. PMID- 30401643 TI - Prevalence of hepatitis C virus NS5A resistance-associated substitutions in chronic infection with genotype 1: A pooled analysis based on deposited sequences in GenBank. AB - INTRODUCTION: Resistance-associated substitutions (RASs) in the NS5A gene of hepatitis C virus (HCV) has been studied as one of the predictors of response to NS5A inhibitor-containing regimens. This study aimed to evaluate the prevalence of pre-treatment naturally-occurring NS5A RASs in HCV isolates from patients with chronic HCV genotype 1 (HCV-1) infection retrieved from GenBank. METHODS: In the search procedure, the studies with published HCV-1 NS5A sequence in GenBank were screened and evaluated for inclusion in the pooled analysis. The sequences of the included studies were retrieved from GenBank and evaluated for substitutions in amino acid positions24, 26, 28, 29, 30, 31, 32, 38, 58, 62, 92 and 93 of HCV NS5A including RASs and RASs conferring >100 resistance fold change (RASs >100X). RESULTS: In the pooled analysis, 2409 isolates from patients with HCV-1 infection were included, consisting 1305 (54.2%) HCV-1a and 1104 (45.8%) HCV-1b isolates. The prevalence of NS5A RASs and RASs >100X were 16.0% (95%CI = 14.6%-17.5%) and 4.7% (95%CI = 3.9%-5.6%), respectively. The NS5A RASs were more frequently observed in HCV-1b isolates than in HCV-1a isolates (P < 0.001). CONCLUSION: The naturally-occurring HCV NS5A RASs especially those with clinical relevance (RASs >100X) are observed in a small (4.7%) number of patients with HCV-1 infection. PMID- 30401644 TI - Molecular characterization and expression analysis of big-belly seahorse (Hippocampus abdominalis) interleukin-10 and analysis of its potent anti inflammatory properties in LPS-induced murine macrophage RAW 264.7 cells. AB - Interleukin-10 (IL-10) is a pleiotropic cytokine involved in the regulation of innate and adaptive immunity. In this study, IL-10 from big-belly seahorse (Hippocampus abdominalis) (HaIL-10) was characterized based on its molecular and functional aspects. The coding sequence of HaIL-10 is 570 bp in length and encodes a 189-amino acid residue protein (calculated molecular weight, 21.89 kDa). The deduced amino acid sequence comprises a typical signal peptide and a mature peptide domain sequence carrying four conserved Cys residues and two additional Cys residues specific to fish. Phylogenetic analysis indicated an evolutionary relationship between HaIL-10 and its counterparts in other vertebrates, with close clustering to the fish-specific homologs. Recombinant HaIL-10 (rHaIL-10) significantly reduced nitric oxide (NO) production by lipopolysaccharide (LPS)-induced murine macrophage RAW 264.7 cells in a concentration-dependent manner but had no effect on cell viability, suggestive of its involvement in immune response. The protein expressions of iNOS and COX-2 were significantly reduced by rHaIL-10 in LPS-induced murine macrophages RAW 264.7 cells. HaIL-10 mRNA expression was observed in all analyzed tissues, with the maximum expression being noted in the kidney and ovary. However, transcriptional levels of HaIL-10 were significantly higher in the blood, gill, and intestine upon in vivo induction with LPS, polyinosinic:polycytidylic acid [poly (I:C)], and Streptococcus iniae. To summarize, our findings help in the improved understanding of the biological functions of HaIL-10 and modulation of HaIL-10 mRNA expression in response to immune stress. PMID- 30401645 TI - Comprehensive analysis of Reverse Phase Protein Array data reveals characteristic unique proteomic signatures for glioblastoma subtypes. AB - The most common and lethal type of intracranial tumors include the astrocytomas. Grade IV astrocytoma or Glioblastoma (GBM) is highly aggressive and treatment refractory with a median survival of only 14 to 16 months. Molecular profiling of GBMs reveals a high degree of intra- and inter-tumoral heterogeneity, and hence it is important to understand the important signalling axes that get deregulated in different GBM subtypes to provide effective tailor-made therapies. In this study, we have carried out extensive analysis of Reverse Phase Protein Array (RPPA) data from TCGA cohort to develop protein signatures that define glioma grades or subtypes. The protein signatures that distinguished Grade II or III from GBM had largely overlapped, and pathway analysis revealed the positive enrichment of extracellular matrix proteins (ECM), MYC pathway, uPAR pathway and G2/M checkpoint genes in GBM. We also identified protein signatures for GBMs with genetic alterations (IDH mutation, p53 mutation, EGFR amplification or mutation, CDKN2A/CDKN2B deletion, and PTEN mutation) that occur at high frequency. G-CIMP positive GBM-specific protein signature showed a large similarity with IDH1 mutant protein signature, thus signifying the importance of IDH1 mutation driving the G-CIMP. Gene expression subtype analysis revealed an association of specific proteins to classical (EGFR and phosphor variants), mesenchymal (SERPINE1, TAZ, and Myosin-IIa_pS1943), neural (TUBA1B), and proneural (GSK3_pS9) types. Univariate Cox regression analysis identified several proteins showing significant correlation with GBM survival. Multivariate analysis revealed that IGFBP2 and RICTOR_pT1135 are independent predictors of survival. Overall, our analyses reveal that specific proteins are regulated in different glioma subtypes underscoring the importance of diverse signalling axes playing important role in the pathogenesis of glioma tumors. PMID- 30401646 TI - Comparative study on neuroprotective activities of fucoidans from Fucus vesiculosus and Undaria pinnatifida. AB - This study investigated the neuroprotective activities of five different fucoidan samples with different chemical compositions prepared from Fucus vesiculosus (FE, FF, and S) and Undaria pinnatifida (UE and UF) to determine if they reduced aggregation or cytotoxicity of Abeta1-42 in neuronal PC-12 cells. Only fucoidans S, UE, and UF showed anti-aggregation effects against Abeta1-42, as determined using Thioflavin T (ThT) fluorometric fibrillisation kinetics and transmission electron microscopy (TEM) of fibril morphology. However, all five fucoidan samples reduced the cytotoxicity of both Abeta1-42 and hydrogen peroxide in neuronal PC-12 cells and demonstrated inhibition of apoptosis induced by Abeta1 42. Three fucoidan samples (FF, UE and UF) showed significant activity in enhancing neurite outgrowth. Fucoidan from different seaweed sources and with varying chemical compositions demonstrate a range of neuroprotective activities that may have potential to alter Abeta1-42 neurotoxicity in Alzheimer's disease. PMID- 30401647 TI - Spiro-acridine inhibiting tyrosinase enzyme: Kinetic, protein-ligand interaction and molecular docking studies. AB - Here, we evaluate spiroacridines as inhibitors of tyrosinase, a key enzyme to melanogenesis. For this purpose, the spiroacridines 3-(acridin-9-yl)-N benzylidene-2-cyanoacrylohydrazide (AMTAC-01) and 3-(acridin-9-yl)-2-cyano-N-(4 metoxybenzylidene)-acrylohydrazide (AMTAC-02) were synthesized and their enzymatic inhibition types and mechanisms were investigated. In addition, the interaction of these compounds with the enzyme were studied by UV-Vis spectroscopy, spectrofluorimetry, 1H NMR titration as well as molecular docking. Spectroscopic results reveals that the acridine derivatives interact strongly (Ka ? 104 - 105 M-1) with the mushroom tyrosinase and the enzyme undergoes small structural modifications due to the interaction with AMTAC-01 compound. The interaction studies support the enzymatic inhibition results, which suggests that AMTAC-01 compounds inhibit the enzyme reversibly and follows a noncompetitive type (AMTAC-01) and mixed type (AMTAC-02) of inhibition. Nevertheless, AMTAC-02 (IC50 = 96.29 MUM) inhibits the enzyme more effectively than AMTAC-01 (IC50 = 189.40 MUM), which suggests a highly relevant role of AMTAC-02's methoxy group to the inhibition activity, which is confirmed by docking studies to mushroom tyrosinase. Docking also indicates this interaction to be absent in human tyrosinase. SIGNIFICANCE: Based on previous results which evidenced the relevant activity of two spiroacridinic compounds for cell growth inhibition against melanoma cells, here we improve our understanding about the spiroacridines in the biological media by exploring the molecular mechanism that govern the activities of these two compounds using mushroom tyrosinase (mTYR) enzyme as molecular target. The paper not only will have a major impact upon molecular mechanism that regulates melanin inhibition by spiroacridinic compounds, but also by guiding the search for enzyme inhibitors and the development of new anti-melanoma prophylaxis. PMID- 30401648 TI - alpha-Glucosidase immobilization on chitosan-modified cellulose filter paper: Preparation, property and application. AB - In the present study, alpha-glucosidase (alpha-Glu) was immobilized on the chitosan-modified cellulose filter paper (CFP/CS). For alpha-Glu immobilization, glutaraldehyde (GA) was used as a coupling agent. CFP, environmentally friendly and commercially available with low cost, will avoid the tedious procedure for synthesizing immobilization carrier. In addition, the CFP/CS-immobilized alpha Glu can be directly taken out from the reaction mixture after an enzymatic reaction. This makes the instantaneous separation of immobilized enzyme comes true and is convenient to the subsequent study. Combined with capillary electrophoresis (CE), the CFP/CS-immobilized alpha-Glu was then used for enzyme kinetic and inhibition study. The CFP/CS-immobilized alpha-Glu exhibited enhanced pH and temperature tolerance. In addition, the performance of the CFP/CS immobilized alpha-Glu was studied. Immobilized alpha-Glu exhibited excellent batch-to-batch reproducibility (RSD = 6.7%, n = 5) and improved reusability (71.0% of its initial activity after 10 repeated cycles). Finally, immobilized alpha-Glu was used to screen enzyme inhibitors from 11 traditional Chinese medicines (TCMs). The results showed that CFP/CS has potential development prospects as a novel enzyme immobilization carrier. PMID- 30401649 TI - Aspirin in retrieving the inactivated catalase to active form: Displacement of one inhibitor with a protective agent. AB - Aspirin as a potential drug is able to bind to different targets and also could affect on the binding process of other ligands. In the present work, aspirin was considered as a protective agent to retrieve the inactivated catalase by farnesiferol C (FC) through displacement manner. The catalytic assessment revealed that aspirin is able to remarkably retrieve the activity of FC-catalase from 4.2 +/- 0.2% to 98 +/- 0.1% compare to the control sample. Furthermore, displacement study and CD spectroscopy indicated that aspirin could reduce the stability of FC-catalase complex. Based on the obtained data, it is shown that the binding of aspirin to catalase led to decrease the affinity of catalase to the inhibitor. The releasing analysis of FC from the complex showed that the dissociation constant (Kd) of FC-catalase was increased, considerably from 8.9 +/ 0.2 MUM to 256 +/- 01 MUM in the presence of aspirin at 298 K. Also, molecular simulation proved the instability of FC-catalase following the binding of aspirin to the complex. PMID- 30401650 TI - Injectable angiogenic and osteogenic carrageenan nanocomposite hydrogel for bone tissue engineering. AB - Functional biomaterials that couple angiogenesis and osteogenesis processes are vital for bone tissue engineering and bone remodeling. Herein we developed an injectable carrageenan nanocomposite hydrogel incorporated with whitlockite nanoparticles and an angiogenic drug, dimethyloxallylglycine. Synthesized whitlockite nanoparticles and nanocomposite hydrogels were characterized using SEM, TEM, EDS and FTIR. Developed hydrogels were injectable, mechanically stable, cytocompatible and has better protein adsorption. Incorporation of dimethyloxallylglycine resulted in initial burst release followed by sustained release for 7 days. Human umbilical vein endothelial cells exposed to dimethyloxallylglycine incorporated nanocomposite hydrogel showed enhanced cell migration and capillary tube-like structure formation. Osteogenic differentiation in rat adipose derived mesenchymal stem cells after 7 and 14 days revealed increased levels of alkaline phosphatase activity in vitro. Furthermore, cells exposed to nanocomposite hydrogel revealed enhanced protein expressions of RUNX2, COL and OPN. Overall, these results suggest that incorporation of whitlockite and dimethyloxallylglycine in carrageenan hydrogel promoted osteogenesis and angiogenesis in vitro. PMID- 30401651 TI - Development and application of a CRISPR/Cas9 system for Bacillus licheniformis genome editing. AB - A highly efficient genome editing system for Bacillus licheniformis was developed based on single-plasmid CRISPR/Cas9. For highly efficient genome editing the shuttle vector pWH1520 was selected to construct the knockout plasmids. A construct harboring a pS promoter driving cas9 endonuclease expression, a strong pLY-2 promoter driving the transcription of a single guide RNA was demonstrated as being the most effective. To verify the feasibility of the method the uprT gene coding uracil phosphoribosyltransferase was selected as the reporter gene. The efficiency of introducing nucleotide point mutations and single gene deletion reached an editing efficiency of up to 99.2% and 97.3%, respectively. After a upp deficient strain was engineered, the system and strain were applied to introduce genomic deletions of another two genes, amyL and chiA (encoding amylase and chitinase, respectively) with about 90% deletion efficiency. As two native extracellular proteins with relatively high secretion in the host, amylase and chitinase can hamper the secretion and expression of alkaline protease. It was demonstrated that the mutant with deletions of the two genes effectively improved the alkaline protease yield by 24.8%. The results illustrated that the establishment of a CRISPR/Cas9 system for Bacillus licheniformis is of significance, and confirmed the system's high efficiency. The system provides support for effective molecular modification and metabolic regulation of Bacillus licheniformis, and offers promise for applications in genetic modification of other industrially relevant Bacillus species. PMID- 30401652 TI - Cyclodextrin modified erlotinib loaded PLGA nanoparticles for improved therapeutic efficacy against non-small cell lung cancer. AB - This study was aimed at developing a nanoparticle strategy to overcome acquired resistance against erlotinib in non-small cell lung cancer (NSCLC). To load erlotinib on biodegradable PLGA nanoparticles, erlotinib-cyclodextrin (Erlo-CD) complex was prepared using beta-cyclodextrin sulfobutyl ether, which was in turn loaded in the core of PLGA nanoparticles using multiple emulsion solvent evaporation. Nanoparticles were characterized for size distribution, entrapment and loading efficiency, in-vitro release, and therapeutic efficacy against different lung cancer cells. Effect of formulation on cell cycle, apoptosis, and other markers was evaluated using flow cytometry and western blotting studies. The efficacy of optimized nanoformulation was evaluated using a clinically relevant in-vitro 3D-spheroid model. Results showed that Erlo-CD loaded nanoparticles (210 +/- 8 nm in size) demonstrated 3-fold higher entrapment (61.5 +/- 3.2% vs 21.9 +/- 3.7% of plain erlotinib loaded nanoparticles) with ~5% loading efficiency and sustained release characteristics. Developed nanoparticles demonstrated significantly improved therapeutic efficacy against NSCLC cells in terms of low IC50 values and suppressed colony forming ability of cancer cells, increased apoptosis, and autophagy inhibition. Interestingly, 3D spheroid study demonstrated better anticancer activity of Erlo-CD nanoparticles compared to plain erlotinib. Present study has shown a premise to improve therapeutic efficacy against erlotinib-resistant lung cancer using modified nanoErlo formulations. PMID- 30401653 TI - Effects of recombinant swollenin on the enzymatic hydrolysis, rumen fermentation, and rumen microbiota during in vitro incubation of agricultural straws. AB - An experiment was conducted to determine the effects of swollenin on the enzymatic hydrolysis and in vitro rumen microbial fermentation of agricultural straws. The swollenin from Trichoderma reesei was produced in Pichia pastoris in current study. The recombinant protein caused an obvious disruption on filter paper and slight increase in reducing sugars release when treating xylan, Avicel, rice straw, wheat straw, and corn straw. Simultaneous incubation of swollenin with fibrolytic enzyme resulted in a significant synergistic activity on disruption of filter paper and hydrolysis of above-mentioned substrates. During in vitro rumen fermentation of three straw diets, the dry matter digestibility, acetate production, microbial protein synthesis, and fibrolytic bacterial population were increased by swollenin. This study demonstrates that swollenin could enhance the enzymatic hydrolysis and in vitro ruminal fermentation of agricultural straws, showing the potential of swollenin for improving the utilization of agricultural straws in ruminants. PMID- 30401654 TI - Learning Deficits in Adult Mitochondria Carrier Homolog 2 Forebrain Knockout Mouse. AB - Mitochondrial Carrier Homolog 2 (MTCH2) acts as a receptor for the BH3 interacting-domain death agonist (BID) in the mitochondrial outer membrane. Loss of MTCH2 affects mitochondria energy metabolism and function. MTCH2 forebrain conditional KO (MTCH2 BKO) display a deficit in hippocampus-dependent cognitive functions. Here we study age-related MTCH2 BKO behavioral and electrophysiological aspects of hippocampal functions. MTCH2 BKO exhibit impaired spatial but not motor learning and an impairment in long-term potentiation (LTP) in hippocampal slices. Moreover, MTCH2 BKO express an increase in activated microglia, in addition to a reduction in neuron density in the hippocampus, but do not express amyloid-beta plaques or neurofibrillary tangles. These results highlight the role of mitochondria in the normal hippocampus-dependent memory formation. PMID- 30401656 TI - Frequent Mutation in the FTL Gene Causing Hyperferritinemia Cataract Syndrome in Turkish Population is c.-160 A>G. PMID- 30401655 TI - Biological and histological changes in reproductive patterns of Biomphalaria glabrata experimentally co-infected by Echinostoma paraensei and Angiostrongylus cantonensis. AB - Investigation of co-infection by different helminths in snails can provide essential information about the biology of parasites co-existence under natural conditions. This study aimed to investigate the reproductive and histological changes of Biomphalaria glabrata experimentally co-infected with Echinostoma paraensei and Angiostrongylus cantonensis. Five groups of snails i.e. uninfected, with single and double infections, either E. paraensei first (E + A) or A. cantonensis first (A + E) were followed; three times a week during four weeks the numbers of egg masses, eggs and hatched snails were counted. Histological analysis of the ovotestis and albumen gland was performed after four weeks. The number of egg masses/snail, eggs/snail and hatched snails showed significative differences comparing the control group to all infected groups, especially in group E + A, with the majority of values of parameters analyzed lower than 50% of those observed for control snails. In addition, the mortality was higher in the group E + A than to control group. The histological analysis showed that presence of both parasites in the reproductive organs was associated with tissue damages. PMID- 30401657 TI - Diagnostic Problems in Chronic Basophilic Leukemia AB - Chronic basophilic leukemia (CBL) is an extremely rare type of leukemia. A literature review revealed six cases reported as primary CBL and five patients with secondary CBL. Patients with primary CBL may present with symptoms not related to leukemia. Dysplastic changes in peripheral blood and bone marrow were described and demonstrated in cases of primary and secondary CBL. The literature review also revealed that differential counts made by automated blood cell counters may not characterize cells as basophils in patients with primary and secondary CBL and may mislead physicians in making a differential diagnosis. For these reasons, laboratory studies for the diagnosis of CBL are required, including metachromatic staining by toluidine blue and antigen expressions by flow cytometric analysis, to detect the nature of the neoplastic cells as basophils for a reliable diagnosis of CBL. The literature review failed to reveal specific cytogenetic findings in patients with primary and secondary types of CBL. PMID- 30401658 TI - Assessment of Health-Related Quality of Life in Pediatric Acute Lymphoblastic Leukemia Survivors: Perceptions of Children, Siblings, and Parents. AB - OBJECTIVE: We investigated the health-related quality of life (HRQL) in survivors of pediatric acute lymphoblastic leukemia (ALL) and evaluated the perceptions of children, siblings, and parents. MATERIALS AND METHODS: Seventy ALL survivors, who were between 7 and 17 years and completed therapy >=2 years were included. The control group consisted of healthy siblings. HRQL was assessed by the age specific KINDLR questionnaire. RESULTS: No significant differences could be found among HRQL scores of ALL survivors with respect to variables such as sex, risk group, and having chronic illness. HRQL scores for physical well-being, emotional well-being, family, and social functioning of the patient and sibling self reports and parent proxy reports were lower than the expected value for healthy and chronically ill children. CONCLUSION: These results demonstrated that both ALL survivors and their families need help for psychologic counseling programs to improve their HRQL even after completion of therapy. PMID- 30401659 TI - Appropriateness of Hospital Admission for Emergency Department Patients with Bronchiolitis: Secondary Analysis. AB - BACKGROUND: Bronchiolitis is the leading cause of hospitalization in children under 2 years of age. Each year in the United States, bronchiolitis results in 287,000 emergency department visits, 32%-40% of which end in hospitalization. Frequently, emergency department disposition decisions (to discharge or hospitalize) are made subjectively because of the lack of evidence and objective criteria for bronchiolitis management, leading to significant practice variation, wasted health care use, and suboptimal outcomes. At present, no operational definition of appropriate hospital admission for emergency department patients with bronchiolitis exists. Yet, such a definition is essential for assessing care quality and building a predictive model to guide and standardize disposition decisions. Our prior work provided a framework of such a definition using 2 concepts, one on safe versus unsafe discharge and another on necessary versus unnecessary hospitalization. OBJECTIVE: The goal of this study was to determine the 2 threshold values used in the 2 concepts, with 1 value per concept. METHODS: Using Intermountain Healthcare data from 2005-2014, we examined distributions of several relevant attributes of emergency department visits by children under 2 years of age for bronchiolitis. Via a data-driven approach, we determined the 2 threshold values. RESULTS: We completed the first operational definition of appropriate hospital admission for emergency department patients with bronchiolitis. Appropriate hospital admissions include actual admissions with exposure to major medical interventions for more than 6 hours, as well as actual emergency department discharges, followed by an emergency department return within 12 hours ending in admission for bronchiolitis. Based on the definition, 0.96% (221/23,125) of the emergency department discharges were deemed unsafe. Moreover, 14.36% (432/3008) of the hospital admissions from the emergency department were deemed unnecessary. CONCLUSIONS: Our operational definition can define the prediction target for building a predictive model to guide and improve emergency department disposition decisions for bronchiolitis in the future. PMID- 30401660 TI - Viral Loads Within 6 Weeks After Diagnosis of HIV Infection in Early and Later Stages: Observational Study Using National Surveillance Data. AB - BACKGROUND: Early (including acute) HIV infection is associated with viral loads higher than those in later stages. OBJECTIVE: This study aimed to examine the association between acute infection and viral loads near the time of diagnosis using data reported to the US National HIV Surveillance System. METHODS: We analyzed data on infections diagnosed in 2012-2016 and reported through December 2017. Diagnosis and staging were based on the 2014 US surveillance case definition for HIV infection. We divided early HIV-1 infection (stage 0) into two subcategories. Subcategory 0alpha: a negative or indeterminate HIV-1 antibody test was <=60 days after the first confirmed positive HIV-1 test or a negative or indeterminate antibody test or qualitative HIV-1 nucleic acid test (NAT) was <=180 days before the first positive test, the latter being a NAT or detectable viral load. Subcategory 0beta: a negative or indeterminate antibody or qualitative NAT was <=180 days before the first positive test, the latter being an HIV antibody or antigen/antibody test. We compared median earliest viral loads for each stage and subcategory in each of the first 6 weeks after diagnosis using only the earliest viral load for each individual. RESULTS: Of 203,392 infections, 56.69% (115,297/203,392) were reported with a quantified earliest viral load within 6 weeks after diagnosis and criteria sufficient to determine the stage at diagnosis. Among 5081 infections at stage 0, the median earliest viral load fell from 694,000 copies/mL in week 1 to 125,022 in week 2 and 43,473 by week 6. Among 30,910 infections in stage 1, the median earliest viral load ranged 15,412 17,495. Among 42,784 infections in stage 2, the median viral load declined from 44,973 in week 1 to 38,497 in week 6. Among 36,522 infections in stage 3 (AIDS), the median viral load dropped from 205,862 in week 1 to 119,000 in week 6. The median earliest viral load in stage 0 subcategory 0alpha fell from 1,344,590 copies/mL in week 1 to 362,467 in week 2 and 47,320 in week 6, while that in subcategory 0beta was 70,114 copies/mL in week 1 and then 32,033 to 44,067 in weeks 2-6. The median viral load in subcategory 0alpha was higher than that in subcategory 0beta in each of the first 6 weeks after diagnosis (P<.001). CONCLUSIONS: In the 1st week after diagnosis, viral loads in early infections are generally several times higher than those in later stages at diagnosis. By the 3rd week, however, most are lower than those in stage 3. High viral loads in early infection are much more common in subcategory 0alpha than in subcategory 0beta, consistent with 0alpha comprising mostly acute infections and 0beta comprising mostly postacute early infections. These findings may inform the prioritization of interventions for prevention. PMID- 30401661 TI - Clinicians' Selection Criteria for Video Visits in Outpatient Care: Qualitative Study. AB - BACKGROUND: Video visits with patients were introduced into outpatient care at a hospital in Sweden. New behaviors and tasks emerged due to changes in roles, work processes, and responsibilities. This study investigates the effects of the digital transformation-in this case, how video visits in outpatient care change work processes and introduce new tasks-to further improve the concept of video visits. The overarching goal was to increase the value of these visits, with a focus on the value of conducting the treatment for the patient. OBJECTIVE: Through the real-time, social interactional features of preparing for and conducting video visits with patients with obesity, this study examines which patients the clinicians considered suitable for video visits and why. The aim was to identify the criteria used by clinicians when selecting patients for video visits to understand what criteria the clinicians used as the grounds for their selection. METHODS: Qualitative methods were used, including 13 observations of video visits at 2 different clinics and 14 follow-up interviews with clinicians. Transcripts of interviews and field notes were thematically analyzed, discussed, and synthesized into themes. RESULTS: From the interviews, 20 different arguments for selecting a specific patient for video visits were identified. Analyzing interviews and field notes also revealed unexpressed arguments that played a part in the selection process. The unexpressed arguments, as well as the implicit reasons, for why a patient was given the option of video visits can be understood as the selection criteria for helping clinicians in their decision about whether to offer video visits or not. The criteria identified in the collected data were divided into 3 themes: practicalities, patient ability, and meeting content. CONCLUSIONS: Not all patients with obesity undergoing treatment programs should be offered video visits. Patients' new responsibilities could influence the content of the meeting and the progress of the treatment program. The selection criteria developed and used by the clinicians could be a tool for finding a balance between what the patient wants and what the clinician thinks the patient can manage and achieving good results in the treatment program. The criteria could also reduce the number and severity of disturbances and limitations during the meeting and could be used to communicate the requirements they represent to the patient. Some of the criteria are based on facts, whereas others are subjective. A method for how and when to involve the patient in the selection process is recommended as it may strengthen the patient's sense of responsibility and the relationship with the clinician. PMID- 30401662 TI - Identifying and Understanding Communities Using Twitter to Connect About Depression: Cross-Sectional Study. AB - BACKGROUND: Depression is the leading cause of diseases globally and is often characterized by a lack of social connection. With the rise of social media, it is seen that Twitter users are seeking Web-based connections for depression. OBJECTIVE: This study aimed to identify communities where Twitter users tweeted using the hashtag #MyDepressionLooksLike to connect about depression. Once identified, we wanted to understand which community characteristics correlated to Twitter users turning to a Web-based community to connect about depression. METHODS: Tweets were collected using NCapture software from May 25 to June 1, 2016 during the Mental Health Month (n=104) in the northeastern United States and Washington DC. After mapping tweets, we used a Poisson multilevel regression model to predict tweets per community (county) offset by the population and adjusted for percent female, percent population aged 15-44 years, percent white, percent below poverty, and percent single-person households. We then compared predicted versus observed counts and calculated tweeting index values (TIVs) to represent undertweeting and overtweeting. Last, we examined trends in community characteristics by TIV using Pearson correlation. RESULTS: We found significant associations between tweet counts and area-level proportions of females, single person households, and population aged 15-44 years. TIVs were lower than expected (TIV 1) in eastern, seaboard areas of the study region. There were communities tweeting as expected in the western, inland areas (TIV 2). Counties tweeting more than expected were generally scattered throughout the study region with a small cluster at the base of Maine. When examining community characteristics and overtweeting and undertweeting by county, we observed a clear upward gradient in several types of nonprofits and TIV values. However, we also observed U-shaped relationships for many community factors, suggesting that the same characteristics were correlated with both overtweeting and undertweeting. CONCLUSIONS: Our findings suggest that Web-based communities, rather than replacing physical connection, may complement or serve as proxies for offline social communities, as seen through the consistent correlations between higher levels of tweeting and abundant nonprofits. Future research could expand the spatiotemporal scope to confirm these findings. PMID- 30401663 TI - Evaluating the Long-Term Effectiveness of School-Based Depression, Anxiety, and Substance Use Prevention Into Young Adulthood: Protocol for the Climate School Combined Study. AB - BACKGROUND: Mental health and substance use disorders are the leading causes of global disability in children and youth. Both tend to first onset or escalate in adolescence and young adulthood, calling for effective prevention during this time. The Climate Schools Combined (CSC) study was the first trial of a Web-based combined universal approach, delivered through school classes, to prevent both mental health and substance use problems in adolescence. There is also limited evidence for the cost-effectiveness of school-based prevention programs. OBJECTIVE: The aim of this protocol paper is to describe the CSC follow-up study, which aims to determine the long-term efficacy and cost-effectiveness of the CSC prevention program for depression, anxiety, and substance use (alcohol and cannabis use) up to 7 years post intervention. METHODS: A cluster randomized controlled trial (the CSC study) was conducted with 6411 participants aged approximately 13.5 years at baseline from 2014 to 2016. Participating schools were randomized to 1 of 4 conditions: (1) control (health education as usual), (2) Climate Substance Use (universal substance use prevention), (3) Climate Mental Health (universal mental health prevention), or (4) CSC (universal substance use and mental health prevention). It was hypothesized that the CSC program would be more effective than conditions (1) to (3) in reducing alcohol and cannabis use (and related harms), anxiety, and depression symptoms as well as increasing knowledge related to alcohol, cannabis, anxiety, and depression. This long-term study will invite follow-up participants to complete 3 additional Web based assessments at approximately 5, 6, and 7 years post baseline using multiple sources of locator information already provided to the research team. The primary outcomes include alcohol and cannabis use (and related harms) and mental health symptoms. An economic evaluation of the program will also be conducted using both data linkage as well as self-report resource use and quality of life measures. Secondary outcomes include self-efficacy, social networks, peer substance use, emotion regulation, and perfectionism. Analyses will be conducted using multilevel mixed-effects models within an intention-to-treat framework. RESULTS: The CSC long-term follow-up study is funded from 2018 to 2022 by the Australian National Health and Medical Research Council (APP1143555). The first follow-up wave commences in August 2018, and the results are expected to be submitted for publication in 2022. CONCLUSIONS: This is the first study to provide a long-term evaluation of combined universal substance use and mental health prevention up to 7 years post intervention. Evidence of sustained benefits into early adulthood would provide a scalable, easy-to-implement prevention strategy with the potential for widespread dissemination to reduce the considerable harms, burden of disease, injury, and social costs associated with youth substance use and mental disorders. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1 10.2196/11372. PMID- 30401664 TI - Assessing the Methods, Tools, and Statistical Approaches in Google Trends Research: Systematic Review. AB - BACKGROUND: In the era of information overload, are big data analytics the answer to access and better manage available knowledge? Over the last decade, the use of Web-based data in public health issues, that is, infodemiology, has been proven useful in assessing various aspects of human behavior. Google Trends is the most popular tool to gather such information, and it has been used in several topics up to this point, with health and medicine being the most focused subject. Web based behavior is monitored and analyzed in order to examine actual human behavior so as to predict, better assess, and even prevent health-related issues that constantly arise in everyday life. OBJECTIVE: This systematic review aimed at reporting and further presenting and analyzing the methods, tools, and statistical approaches for Google Trends (infodemiology) studies in health related topics from 2006 to 2016 to provide an overview of the usefulness of said tool and be a point of reference for future research on the subject. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for selecting studies, we searched for the term "Google Trends" in the Scopus and PubMed databases from 2006 to 2016, applying specific criteria for types of publications and topics. A total of 109 published papers were extracted, excluding duplicates and those that did not fall inside the topics of health and medicine or the selected article types. We then further categorized the published papers according to their methodological approach, namely, visualization, seasonality, correlations, forecasting, and modeling. RESULTS: All the examined papers comprised, by definition, time series analysis, and all but two included data visualization. A total of 23.1% (24/104) studies used Google Trends data for examining seasonality, while 39.4% (41/104) and 32.7% (34/104) of the studies used correlations and modeling, respectively. Only 8.7% (9/104) of the studies used Google Trends data for predictions and forecasting in health-related topics; therefore, it is evident that a gap exists in forecasting using Google Trends data. CONCLUSIONS: The monitoring of online queries can provide insight into human behavior, as this field is significantly and continuously growing and will be proven more than valuable in the future for assessing behavioral changes and providing ground for research using data that could not have been accessed otherwise. PMID- 30401665 TI - Patient Portal Use in Diabetes Management: Literature Review. AB - BACKGROUND: Health information technology tools (eg, patient portals) have the potential to promote engagement, improve patient-provider communication, and enhance clinical outcomes in the management of chronic disorders such as diabetes mellitus (DM). OBJECTIVES: The aim of this study was to report the findings of a literature review of studies reporting patient portal use by individuals with type 1 or type 2 DM. We examined the association of the patient portal use with DM-related outcomes and identified opportunities for further improvement in DM management. METHODS: Electronic literature search was conducted through PubMed and PsycINFO databases. The keywords used were "patient portal*," "web portal," "personal health record," and "diabetes." Inclusion criteria included (1) published in the past 10 years, (2) used English language, (3) restricted to age >=18 years, and (4) available in full text. RESULTS: This review included 6 randomized controlled trials, 16 observational, 4 qualitative, and 4 mixed methods studies. The results of these studies revealed that 29% to 46% of patients with DM have registered for a portal account, with 27% to 76% of these patients actually using the portal at least once during the study period. Portal use was associated with the following factors: personal traits (eg, sociodemographics, clinical characteristics, health literacy), technology (eg, functionality, usability), and provider engagement. Inconsistent findings were observed regarding the association of patient portal use with DM-related clinical and psychological outcomes. CONCLUSIONS: Barriers to use of the patient portal were identified among patients and providers. Future investigations into strategies that engage both physicians and patients in use of a patient portal to improve patient outcomes are needed. PMID- 30401666 TI - Patterns Among 754 Gamification Cases: Content Analysis for Gamification Development. AB - BACKGROUND: Gamification is one of the techniques that applies game elements, such as game mechanics and dynamics, to a nongame context (eg, management, education, marketing, and health care). A variety of methodologies have been published for developing gamification. However, some of these are only usable by people with a certain level of gamification knowledge. People who do not have such knowledge face difficulty in using game mechanics and experiencing enjoyment. To ease their difficulties, a gamification methodology should provide directions for using game mechanics. OBJECTIVE: This study aimed at collecting global gamification cases and determining patterns or differences among the collected cases. METHODS: In total, 754 cases were collected based on 4F process elements, such as play type, playful user experience (PLEX)-based fun factors, and game mechanics. In addition, the collected cases were classified into 6 categories. From the data analysis, basic statistics and correlation analyses (Pearson and Kendall) were conducted. RESULTS: According to the analysis results in PLEX-based fun factors, challenge and completion fun factors formed a large proportion among the 6 categories. In the results of the game mechanics analysis, point, leaderboard, and progress accounted for a large proportion among the 6 categories. The results of the correlation analysis showed no difference or specific patterns in game mechanics (Pearson r>.8, Kendall tau>.5, P<.05) and PLEX-based fun factors (Pearson r>.8, Kendall tau>.7, P<.05). CONCLUSIONS: On the basis of the statistical findings, this study suggests an appropriate number of PLEX-based fun factors and game mechanics. In addition, the results of this study should be used for people who do not have gamification knowledge and face difficulty using game mechanics and PLEX-based fun factors. PMID- 30401667 TI - Improving Shared Decision Making Between Patients and Clinicians: Design and Development of a Virtual Patient Simulation Tool. AB - BACKGROUND: Shared decision making (SDM) involves the formation of a collaborative partnership between the patient and clinician combining both of their expertise in order to benefit decision making. In order for clinicians to be able to carry out this skilled task, they require practice. Virtual reality, in the form of a virtual patient, could offer a potential method of facilitating this. OBJECTIVE: The objective of this study was to create a virtual patient that simulated a primary care consultation, affording the opportunity to practice SDM. A second aim was to involve patients in the design of a virtual patient simulation and report the process of the design. METHODS: We employed a multistep design process drawing on patient and expert involvement. RESULTS: A virtual patient, following a narrative style, was built, which allows a user to practice and receive feedback; both clinical and communication skills are required for the simulation. The patient group provided multiple insights, which the academic team had overlooked. They pertained mostly to issues concerning the patient experience. CONCLUSIONS: It is possible to design a virtual patient that allows a learner to practice their ability to conduct SDM. Patient input into the design of virtual patient simulations can be a worthwhile activity. PMID- 30401669 TI - Lung Function in Users of a Smoke-Free Electronic Device With HeatSticks (iQOS) Versus Smokers of Conventional Cigarettes: Protocol for a Longitudinal Cohort Observational Study. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a global public health problem. It is the third-leading cause of death in the world, the fourth leading cause of death in Kazakhstan, and is strongly associated with smoking. Smoking cessation reduces the severity of respiratory symptoms and COPD exacerbations. Heated tobacco products, such as HeatSticks heated by the iQOS device, a smoke-free electronic device, may serve as less risky alternatives to conventional combustible cigarettes. OBJECTIVE: The purpose of this study is to evaluate frequency of exacerbations, respiratory symptoms, physical exercise intolerance, and abnormal lung functions, as well as other parameters and comorbidities among men and women aged 40-59 residing in Almaty, Kazakhstan, who use iQOS with HeatSticks compared to smokers of conventional cigarettes. METHODS: This is a 5-year single-center cohort observational study. It includes two cohorts of participants consisting of men and women aged 40-59 residing in the city of Almaty, Kazakhstan: (1) smokers of combustible cigarettes (control group) and (2) users of iQOS with HeatSticks (exposure group). The study has baseline and periodic (ie, annual) comprehensive clinical assessments, as well as continuous COPD case-finding activities and registration of acute respiratory exacerbations over the course of the 5-year observation period. Study measures include spirometry, chest computed tomography, electrocardiography, physical exams, laboratory testing of serum for biomarkers of inflammation and metabolic syndrome, anthropometry, and the 6-minute walk test. Information about COPD symptoms will be collected using the COPD Assessment Test. RESULTS: Participant recruitment began December 2017, and enrollment is expected to last until late summer 2018. CONCLUSIONS: This is the first cohort observational study in Kazakhstan to assess differences in lung function between users of the heated tobacco product, iQOS with HeatSticks, and smokers of conventional combustible cigarettes. The study results will add to knowledge on whether switching from combustible cigarettes to iQOS with HeatSticks affects respiratory symptoms and diseases, including the development and progression of COPD. TRIAL REGISTRATION: ClinicalTrials.gov NCT03383601; https://clinicaltrials.gov/ct2/show/NCT03383601 (Archived by WebCite at http://www.webcitation.org/72BYoAKxa). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/10006. PMID- 30401668 TI - Parental Activation and Obesity-Related Health Behaviors Among a Racially and Ethnically Diverse Population of Low-Income Pediatric Patients: Protocol for a Cross-Sectional Survey Study. AB - BACKGROUND: Despite a recent decline in the obesity prevalence among preschool aged children, obesity remains disproportionately high among children from low income racial or ethnic minority families. Promoting healthy lifestyles (eg, obesity-preventative behaviors) in primary care settings is particularly important for young children, given the frequency of preventative health visits and parent-provider interactions. Higher adoption of specific health behaviors is correlated with increased patient activation (ie, skill, confidence, and knowledge to manage their health care) among adults. However, no published study, to date, has examined the relationship between parental activation and obesity related health behaviors among young children. OBJECTIVE: The goal of this study is to measure parental activation in low-income parents of preschoolers in 2 large health systems and to examine the association with diet, screen-time, and physical activity behaviors. METHODS: We will conduct a cross-sectional study of parents of preschool-aged patients (2-5 years) receiving primary care at multiple clinic sites within 2 large health care systems. Study participants, low-income black, Hispanic, and white parents of preschool-aged patients, are being recruited across both health systems to complete orally administered surveys. RESULTS: Recruitment began in December 2017 and is expected to end in May 2018. A total of 267 low-income parents of preschool-aged children have been enrolled across both clinic sites. We are enrolling an additional 33 parents to reach our goal sample size of 300 across both health systems. The data analysis will be completed in June 2018. CONCLUSIONS: This protocol outlines the first study to fully examine parental activation and its relationship with parent-reported diet, physical activity, and screen-time behaviors among low-income preschool-aged patients. It involves recruitment across 2 geographically distinct areas and resulting from a partnership between researchers at 2 different health systems with multiple clinical sites. This study will provide new knowledge about how parental activation can potentially be incorporated as a strategy to address childhood obesity disparities in primary care settings. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/9688. PMID- 30401670 TI - Identifying Patients Who Are Likely to Receive Most of Their Care From a Specific Health Care System: Demonstration via Secondary Analysis. AB - BACKGROUND: In the United States, health care is fragmented in numerous distinct health care systems including private, public, and federal organizations like private physician groups and academic medical centers. Many patients have their complete medical data scattered across these several health care systems, with no particular system having complete data on any of them. Several major data analysis tasks such as predictive modeling using historical data are considered impractical on incomplete data. OBJECTIVE: Our objective was to find a way to enable these analysis tasks for a health care system with incomplete data on many of its patients. METHODS: This study presents, to the best of our knowledge, the first method to use a geographic constraint to identify a reasonably large subset of patients who tend to receive most of their care from a given health care system. A data analysis task needing relatively complete data can be conducted on this subset of patients. We demonstrated our method using data from the University of Washington Medicine (UWM) and PreManage data covering the use of all hospitals in Washington State. We compared 10 candidate constraints to optimize the solution. RESULTS: For UWM, the best constraint is that the patient has a UWM primary care physician and lives within 5 miles of at least one UWM hospital. About 16.01% (55,707/348,054) of UWM patients satisfied this constraint. Around 69.38% (10,501/15,135) of their inpatient stays and emergency department visits occurred within UWM in the following 6 months, more than double the corresponding percentage for all UWM patients. CONCLUSIONS: Our method can identify a reasonably large subset of patients who tend to receive most of their care from UWM. This enables several major analysis tasks on incomplete medical data that were previously deemed infeasible. PMID- 30401671 TI - Calorie Estimation From Pictures of Food: Crowdsourcing Study. AB - BACKGROUND: Software designed to accurately estimate food calories from still images could help users and health professionals identify dietary patterns and food choices associated with health and health risks more effectively. However, calorie estimation from images is difficult, and no publicly available software can do so accurately while minimizing the burden associated with data collection and analysis. OBJECTIVE: The aim of this study was to determine the accuracy of crowdsourced annotations of calorie content in food images and to identify and quantify sources of bias and noise as a function of respondent characteristics and food qualities (eg, energy density). METHODS: We invited adult social media users to provide calorie estimates for 20 food images (for which ground truth calorie data were known) using a custom-built webpage that administers an online quiz. The images were selected to provide a range of food types and energy density. Participants optionally provided age range, gender, and their height and weight. In addition, 5 nutrition experts provided annotations for the same data to form a basis of comparison. We examined estimated accuracy on the basis of expertise, demographic data, and food qualities using linear mixed-effects models with participant and image index as random variables. We also analyzed the advantage of aggregating nonexpert estimates. RESULTS: A total of 2028 respondents agreed to participate in the study (males: 770/2028, 37.97%, mean body mass index: 27.5 kg/m2). Average accuracy was 5 out of 20 correct guesses, where "correct" was defined as a number within 20% of the ground truth. Even a small crowd of 10 individuals achieved an accuracy of 7, exceeding the average individual and expert annotator's accuracy of 5. Women were more accurate than men (P<.001), and younger people were more accurate than older people (P<.001). The calorie content of energy-dense foods was overestimated (P=.02). Participants performed worse when images contained reference objects, such as credit cards, for scale (P=.01). CONCLUSIONS: Our findings provide new information about how calories are estimated from food images, which can inform the design of related software and analyses. PMID- 30401672 TI - Assessing the Impacts of Integrated Decision Support Software on Sexual Orientation Recording, Comprehensive Sexual Health Testing, and Detection of Infections Among Gay and Bisexual Men Attending General Practice: Observational Study. AB - BACKGROUND: Gay and bisexual men are disproportionately affected by HIV and other sexually transmissible infections (STIs), yet opportunities for sexual health testing of this population are often missed or incomplete in general practice settings. Strategies are needed for improving the uptake and completeness of sexual health testing in this setting. OBJECTIVES: The goal of the research was to evaluate the impact of an intervention centered around integrated decision support software and routine data feedback on the collection of sexual orientation data and sexual health testing among gay and bisexual men attending general practice. METHODS: A study using before/after and intervention/comparison methods was undertaken to assess the intervention's impact in 7 purposively sampled Australian general practice clinics located near the urban centers of Sydney and Melbourne. The software was introduced at staggered points between April and August 2012; it used patient records to prompt clinicians to record sexual orientation and accessed pathology testing history to generate prompts when sexual health testing was overdue or incomplete. The software also had a function for querying patient management system databases in order to generate de identified data extracts, which were used to report regularly to participating clinicians. We calculated summary rate ratios (SRRs) based on quarterly trends and used Poisson regression analyses to assess differences between the 12-month preintervention and 24-month intervention periods as well as between the intervention sites and 4 similar comparison sites that did not receive the intervention. RESULTS: Among 32,276 male patients attending intervention clinics, sexual orientation recording increased 19% (from 3213/6909 [46.50%] to 5136/9110 [56.38%]) during the intervention period (SRR 1.10, 95% CI 1.04-1.11, P<.001) while comprehensive sexual health testing increased by 89% (305/1159 [26.32%] to 690/1413 [48.83%]; SRR 1.38, 95% CI 1.28-1.46, P<.001). Comprehensive testing increased slightly among the 7290 gay and bisexual men attending comparison sites, but the increase was comparatively greater in clinics that received the intervention (SRR 1.12, 95% CI 1.10-1.14, P<.001). In clinics that received the intervention, there was also an increase in detection of chlamydia and gonorrhea that was not observed in the comparison sites. CONCLUSIONS: Integrated decision support software and data feedback were associated with modest increases in sexual orientation recording, comprehensive testing among gay and bisexual men, and the detection of STIs. Tests for and detection of chlamydia and gonorrhea were the most dramatically impacted. Decision support software can be used to enhance the delivery of sexual health care in general practice. PMID- 30401673 TI - Medical Correctness and User Friendliness of Available Apps for Cardiopulmonary Resuscitation: Systematic Search Combined With Guideline Adherence and Usability Evaluation. AB - BACKGROUND: In case of a cardiac arrest, start of cardiopulmonary resuscitation by a bystander before the arrival of the emergency personnel increases the probability of survival. However, the steps of high-quality resuscitation are not known by every bystander or might be forgotten in this complex and time-critical situation. Mobile phone apps offering real-time step-by-step instructions might be a valuable source of information. OBJECTIVE: The aim of this study was to examine mobile phone apps offering real-time instructions in German or English in case of a cardiac arrest, to evaluate their adherence to current resuscitation guidelines, and to test their usability. METHODS: Our 3-step approach combines a systematic review of currently available apps guiding a medical layperson through a resuscitation situation, an adherence testing to medical guidelines, and a usability evaluation of the determined apps. The systematic review followed an adapted preferred reporting items for systematic reviews and meta-analyses flow diagram, the guideline adherence was tested by applying a conformity checklist, and the usability was evaluated by a group of mobile phone frequent users and emergency physicians with the system usability scale (SUS) tool. RESULTS: The structured search in Google Play Store and Apple App Store resulted in 3890 hits. After removing redundant ones, 2640 hits were checked for fulfilling the inclusion criteria. As a result, 34 apps meeting all inclusion criteria were identified. These included apps were analyzed to determine medical accuracy as defined by the European Resuscitation Council's guidelines. Only 5 out of 34 apps (15%, 5/34) fulfilled all criteria chosen to determine guideline adherence. All other apps provided no or wrong information on at least one relevant topic. The usability of 3 apps was evaluated by 10 mobile phone frequent users and 9 emergency physicians. Of these 3 apps, solely the app "HELP Notfall" (median=87.5) was ranked with an SUS score above the published average of 68. This app was rated significantly superior to "HAMBURG SCHOCKT" (median=55; asymptotic Wilcoxon test: z=-3.63, P<.01, n=19) and "Mein DRK" (median=32.5; asymptotic Wilcoxon test: z=-3.83, P<.01, n=19). CONCLUSIONS: Implementing a systematic quality control for health-related apps should be enforced to ensure that all products provide medically accurate content and sufficient usability in complex situations. This is of exceptional importance for apps dealing with the treatment of life-threatening events such as cardiac arrest. PMID- 30401674 TI - Transition Education for Young Adults With Type 1 Diabetes: Pilot Feasibility Study for a Group Telehealth Intervention. AB - BACKGROUND: Young adults with type 1 diabetes (T1D) experience a decline in glycemic outcomes and gaps in clinical care. A diabetes education and support program designed for young adults was delivered through group videoconference and mobile Web. OBJECTIVE: The objective of our study was to assess the feasibility, acceptability, and preliminary efficacy of the program as measured by attendance and webpage views, satisfaction, and pre- and postintervention psychosocial outcomes, respectively. METHODS: Young adults aged 18-25 years were recruited to attend five 30-minute group diabetes education videoconferences during an 8-week period. Videoconferences included an expert presentation followed by a moderated group discussion. Within 48 hours of each videoconference, participants were sent a link to more information on the study website. Feasibility was assessed using data on videoconference attendance and webpage views. Acceptability was assessed via a Satisfaction Survey completed at the conclusion of the study. Descriptive statistics were generated. Preliminary efficacy was assessed via a survey to measure changes in diabetes-specific self-efficacy and diabetes distress. Pre- and postintervention data were compared using paired samples t tests. RESULTS: In this study, 20 young adults (mean age 19.2 [SD 1.1] years) attended an average of 5.1 (SD 1.0) videoconferences equivalent to 153 (SD 30.6) minutes of diabetes education per participant during an 8-week period. Average participant satisfaction scores were 62.2 (SD 2.6) out of a possible 65 points. A total of 102 links sent via text message (short message service) or email resulted in 504 webpage views. There was no statistically significant difference between pre- and postintervention diabetes-specific self-efficacy or diabetes-related distress. CONCLUSIONS: Delivery of diabetes education via group videoconference using mobile Web follow-up is feasible and acceptable to young adults with T1D. This model of care delivery has the potential to improve attendance, social support, and patient-reported satisfaction. Nevertheless, further research is required to establish the effect on long-term psychosocial and glycemic outcomes. PMID- 30401675 TI - From reading books to increased smart device screen time. PMID- 30401676 TI - Early life factors for myopia in the British Twins Early Development Study. AB - PURPOSE: Myopia is an increasingly prevalent condition globally. A greater understanding of contemporaneous, early life factors associated with myopia risk is urgently required, particularly in younger onset myopia as this correlates with higher severity and increased complications in adult life. METHODS: Analysis of a subset of the longitudinal, UK-based Twins Early Development Study (n=1991) recruited at birth between 1994 and 1996. Subjective refraction was obtained from the twin's optometrists; mean age 16.3 years (SD 1.7). Myopia was defined as mean spherical equivalent <=-0.75 dioptres. A life course epidemiology approach was used to appropriately weight candidate myopia risk factors during critical periods of eye growth. Adjusted ORs for myopia were estimated using multivariable logistic regression models at each life stage, together with variance explained (r2) and area under the receiver operator characteristic curve (AUROC) statistic of predictive models. RESULTS: Factors significantly associated with myopia included level of maternal education (OR 1.33, 95% CI 1.11 to 1.59), fertility treatment (OR 0.63, 95% CI 0.43 to 0.92), summer birth (OR 1.93, 95% CI 1.28 to 2.90) and hours spent playing computer games (OR 1.03, 95% CI 1.01 to 1.06). The total variance explained by this model was 4.4 % (p<0.001) and the AUROC was 0.68 (95% CI 0.64 to 0.72). Consistent associations were observed with socioeconomic status, educational attainment, reading enjoyment and cognitive variables, particularly verbal cognition, at multiple points over the life course. CONCLUSIONS: This study identifies known and novel associations with myopia during childhood development; associated factors identified in early life reflect sociological and lifestyle trends such as rates of maternal education, fertility treatment, early schooling and computer games. PMID- 30401677 TI - PARP1 Suppresses the Transcription of PD-L1 by Poly(ADP-Ribosyl)ating STAT3. AB - Studies have pointed to a role of PARP1 in regulating gene expression through poly(ADP-ribosyl)ating, sequence-specific, DNA-binding transcription factors. However, few examples exist that link this role of PARP1 to the immunogenicity of cancer cells. Here, we report that PARP1 poly(ADP-ribosyl)ates STAT3 and subsequently promotes STAT3 de-phosphorylation, resulting in reduced transcriptional activity of STAT3 and expression of PD-L1. In this study, we showed that PARP1 silencing or pharmacological inhibition enhanced the transcription of PD-L1 in cancer cells, which was accompanied by the upregulation of PD-L1 protein expression, both in the cytoplasm and on the cell surface. This induction of PD-L1 was attenuated in the absence of the transcription factor STAT3. Cell-based studies indicated that PARP1 interacted directly with STAT3 and caused STAT3 poly(ADP-ribosyl)ation. STAT3's activation of PD-L1 transcription was abolished by the over-expression of wild-type PARP1 but not mutant PARP1, which lacks catalytic activity. PARP1 downregulation or catalytic inhibition enhanced the phosphorylation of STAT3, which was reversed by the ectopic expression of wild-type PARP1 but not by mutated PARP1. An inverse correlation between PARP1 and PD-L1 was also observed in clinical ovarian cancer samples. Overall, our study revealed PARP1-mediated poly(ADP-ribosyl)ation of STAT3 as a key step in inhibiting the transcription of PD-L1, and this mechanism exists in a variety of cancer cells. PMID- 30401678 TI - Calnexin impairs the antitumor immunity of CD4+ and CD8+ T cells. AB - Elucidation of the mechanisms of T cell-mediated antitumor responses will provide information for the rational design and development of cancer immunotherapies. Here, we found that calnexin, an endoplasmic reticulum (ER) chaperone protein, is significantly upregulated in oral squamous cell carcinoma (OSCC). Upregulation of its membranous expression on OSCC cells is associated with inhibited T-cell infiltration in tumor tissues and correlates with poor survival of OSCC patients. We found that calnexin inhibits the proliferation of CD4+ and CD8+ T cells isolated from the whole blood of healthy donors and OSCC patients and inhibits the secretion of IFNgamma, TNFalpha, and IL2 from these cells. Furthermore, in a melanoma model, knockdown of calnexin enhanced the infiltration and effector functions of T cells in the tumor microenvironment and conferred better control of tumor growth, whereas treatment with a recombinant calnexin protein impaired the infiltration and effector functions of T cells and promoted tumor growth. We also found that calnexin enhanced the expression of PD-1 on CD4+ and CD8+ T cells by restraining the DNA methylation status of a CpG island in the PD-1 promoter. Thus, this work uncovers a mechanism by which T-cell antitumor responses are regulated by calnexin in tumor cells and suggests that calnexin might serve as a potential target for the improvement of antitumor immunotherapy. PMID- 30401679 TI - Collapse of the Plasmacytoid Dendritic Cells compartment in advanced cutaneous melanomas by components of the tumor cell secretome. AB - Melanoma is an immunogenic neoplasm infiltrated by T cells, although these adaptive T cells usually fail to eradicate the tumor. Plasmacytoid dendritic cells (PDCs) are potent regulators of the adaptive immune response and can eliminate melanoma cells via TLR-mediated effector functions. The PDC compartment is maintained by progressively restricted bone marrow progenitors. Terminally differentiated PDCs exit the bone marrow into the circulation, then home to lymph nodes and inflamed peripheral tissues. Infiltration by PDCs is documented in various cancers. However, their role within the melanoma immune contexture is not completely known. We found that in loco-regional primary cutaneous melanoma (PCM), PDC infiltration was heterogeneous, occurred early, and was recurrently localized at the invasive margin, the site where PDCs interact with CD8+ T cells. A reduced PDC density was coupled with an increased Breslow thickness and somatic mutations at the NRAS p.Q61 codon. Compared to what was seen in PCM, high numbers of PDCs were found in regional lymph nodes, as also identified by in silico analysis. In contrast, in metastatic melanoma (MM) patients, PDCs were mostly absent in the tumor tissues and were significantly reduced in the circulation, particularly in the advanced M1c group. Exposure of circulating PDCs to melanoma cell supernatant (SN-mel) depleted of extracellular vesicles resulted in significant PDC death. SN-mel exposure also resulted in a defect of PDC differentiation from CD34+ progenitors. These findings indicate that soluble components released by melanoma cells support the collapse of the PDC compartment, with clinical implications for refining TLR-agonist based trials. PMID- 30401680 TI - Long-lasting effects of methocinnamox on heroin self-administration in rhesus monkeys. AB - Opioid abuse remains a serious public health challenge, despite the availability of medications that are effective in some patients (naltrexone, buprenorphine, and methadone). This study explored the potential of a pseudoirreversible mu opioid receptor antagonist (methocinnamox; MCAM) as a treatment for opioid abuse by examining its capacity to attenuate the reinforcing effects of mu opioid receptor agonists in rhesus monkeys. In one experiment, monkeys responded for heroin (n=5) or cocaine (n=4) under a fixed-ratio schedule. Another group (n=3) worked under a choice procedure with one alternative delivering food and the other alternative delivering the mu opioid receptor agonist remifentanil. A third group (n=4) responded for food and physiological parameters were measured via telemetry. Effects of MCAM were determined in all experiments and, in some cases, were compared to those of naltrexone. When given immediately before sessions, naltrexone dose-dependently decreased responding for heroin and decreased choice of remifentanil while increasing choice of food, with responding returning to baseline levels one day after naltrexone injection. MCAM also decreased responding for heroin and decreased choice of remifentanil while increasing choice for food; however, opioid-maintained responding remained decreased for several days following treatment. Doses of MCAM that significantly decreased opioid-maintained responding did not decrease responding for cocaine or food. MCAM did not impact heart rate, blood pressure, body temperature, or activity at doses that decreased opioid self-administration. Because MCAM can selectively attenuate opioid self-administration for prolonged periods, this novel drug could be a safe and effective alternative to currently available treatments for opioid abuse. PMID- 30401682 TI - Data Offer New Insights into AML. AB - A recently released dataset from a large cohort of patients with acute myeloid leukemia integrates genomic information about tumor samples with data on how cancer cells respond to drugs. The dataset, which will inform the Beat AML Master Trial, offers new insights into the disease, while providing information that will drive additional research efforts. PMID- 30401681 TI - Interaction with complement proteins and dendritic cells implicates LCCL domain containing proteins (CCps) of malaria parasites in immunomodulation. AB - The evasion of host immune defense is critical for pathogens to invade, establish infection and perpetuate in the host. The complement system is one of the first lines of innate immune defense in humans that destroys pathogens in the blood circulation. Activation of the complement system through direct encounter with pathogens or some other agents leads to osmolysis of pathogens, clearance of soluble immune complexes and recruitment of lymphocytes at the site of activation. Although malaria parasites are not exposed to the complement system owing to their intracellular development for most part of their life cycle in the human host, the extracellular stages must face the complement system of human or mosquito or both. In a recent issue of the Biochemical Journal, Sharma et al. reported that P lasmodium falciparum LCCL domain-containing protein 1 (PfCCp1) inhibited activation of the classical complement pathway and down-regulated effector responses of dendritic cells, which implicate PfCCp1 and related proteins in immunomodulation of the host that likely benefits the parasite. PfCCp1 belongs to a multi-domain protein family that exists as multimeric protein complexes. It needs to be investigated whether PfCCp1 or its multimeric protein complexes have an immunomodulatory effect in vivo and on the mosquito complement system. PMID- 30401683 TI - Ten awards, 1575 nominations, 436 semi-finalists: BMJ's search for the stars of South Asian healthcare continues. PMID- 30401684 TI - Proteome-wide analysis of protein thermal stability in the model higher plant Arabidopsis thaliana. AB - Modern tandem MS-based sequencing technologies allow for the parallel measurement of concentration and covalent modifications for proteins within a complex sample. Recently, this capability has been extended to probe a proteome's three dimensional structure and conformational state by determining the thermal denaturation profile of thousands of proteins simultaneously. While many animals and their resident microbes exist under a relatively narrow, regulated physiological temperature range, plants take on the often widely ranging temperature of their surroundings, possibly influencing the evolution of protein thermal stability. In this report we present the first in-depth look at the thermal proteome of a plant species, the model organism Arabidopsis thaliana By profiling the melting curves of over 1700 Arabidopsis proteins using six biological replicates, we have observed significant correlation between protein thermostability and a number of known protein characteristics, including molecular weight and the composition ratio of charged to polar amino acids. We also report on a divergence of the thermostability of the core and regulatory domains of the plant 26S proteasome that may reflect a unique property of the manner in which protein turnover is regulated during temperature stress. Lastly, the highly replicated database of Arabidopsis melting temperatures reported herein provides baseline data on the variability of protein behavior in the assay. Unfolding behavior and experiment-to-experiment variability were observed to be protein-specific traits, and thus this data can serve to inform the design and interpretation of future targeted assays to probe the conformational status of proteins from plants exposed to different chemical, environmental and genetic challenges. PMID- 30401685 TI - Redox poise and metabolite changes in bread wheat seeds are advanced by priming with hot steam. AB - Fast and uniform germination is key to agricultural production and can be achieved by seed 'priming' techniques. Here, we characterised the responses of bread wheat (Triticum aestivum L.) seeds to a hot steam treatment ('BioFlash'), which accelerated water uptake, resulting in faster germination and seedling growth, typical traits of primed seed. Before the completion of germination, metabolite profiling of seeds revealed advanced accumulation of several amino acids (especially cysteine and serine), sugars (ribose, glucose), and organic acids (glycerate, succinate) in hot steam-treated seeds, whereas sugar alcohols (e.g. arabitol, mannitol) and trehalose decreased in all seeds. Tocochromanols (the 'vitamin E family') rose independently of the hot steam treatment. We further assessed shifts in the half-cell reduction potentials of low-molecular weight (LMW) thiol-disulfide redox couples [i.e. glutathione disulfide (GSSG)/glutathione (GSH) and cystine/cysteine], alongside the activities of the reactive oxygen species (ROS)-processing enzyme superoxide dismutase, catalase, ascorbate peroxidase, and glutathione reductase. Upon the first 4 h of imbibition, a rapid conversion of LMW disulfides to thiols occurred. Completion of germination was associated with a re-oxidation of the LMW thiol-disulfide cellular redox environment, before more reducing conditions were re-established during seedling growth, accompanied by an increase in all ROS-processing enzyme activities. Furthermore, changes in the thiol-disulfide cellular redox state were associated to specific stages of wheat seed germination. In conclusion, the priming effect of the hot steam treatment advanced the onset of seed metabolism, including redox shifts associated with germination and seedling growth. PMID- 30401686 TI - Polyamines stimulate the CHSY1 synthesis through the unfolding of the RNA G quadruplex at the 5'-untraslated region. AB - Glycosaminoglycans (GAGs), a group of structurally related acidic polysaccharides, are primarily found as glycan moieties of proteoglycans (PGs). Among these, chondroitin sulfate (CS) and dermatan sulfate, side chains of PGs, are widely distributed in animal kingdom and show structural variations, such as sulfation patterns and degree of epimerization, which are responsible for their physiological functions through interactions with growth factors, chemokines and adhesion molecules. However, structural changes in CS, particularly the ratio of 4-O-sulfation to 6-O-sulfation (4S/6S) and CS chain length that occur during the aging process, are not fully understood. We found that 4S/6S ratio and molecular weight of CS were decreased in polyamine-depleted cells. In addition, decreased levels of chondroitin synthase 1 (CHSY1) and chondroitin 4-O-sulfotransferase 2 proteins were also observed on polyamine depletion. Interestingly, the translation initiation of CHSY1 was suppressed by a highly structured sequence (positions -202 to -117 relative to the initiation codon) containing RNA G quadruplex (G4) structures in 5'-untranslated region. The formation of the G4s was influenced by the neighboring sequences to the G4s and polyamine stimulation of CHSY1 synthesis disappeared when the formation of the G4s was inhibited by site-directed mutagenesis. These results suggest that the destabilization of G4 structures by polyamines stimulates CHSY1 synthesis and, at least in part, contribute to the maturation of CS chains. PMID- 30401687 TI - Preclinical development and first-in-human imaging of the integrin alphavbeta6 with [18F]alphavbeta6-Binding Peptide in metastatic carcinoma. AB - PURPOSE: The study was undertaken to develop and evaluate the potential of an integrin alphavbeta6-binding peptide (alphavbeta6-BP) for noninvasive imaging of a diverse range of malignancies with positron emission tomography (PET). EXPERIMENTAL DESIGN: The peptide alphavbeta6-BP was prepared on solid phase and radiolabeled with 4-[18F]fluorobenzoic acid. In vitro testing included ELISA, serum stability, and cell binding studies using a paired alphavbeta6-expressing and alphavbeta6-null cell lines. In vivo evaluation (PET/CT, biodistribution and autoradiography) was performed in a mouse model bearing the same paired alphavbeta6-expressing and alphavbeta6-null cell xenografts. A first-in-human PET/CT imaging study was performed in patients with metastatic lung, colon, breast or pancreatic cancer. RESULTS: [18F]alphavbeta6-BP displayed excellent affinity and selectivity for the integrin in vitro (IC50(alphavbeta6) = 1.2 nM vsIC50(alpha beta3) >10 MUM) in addition to rapid target-specific cell binding and internalization (72.5+/-0.9% binding and 52.5+/-1.8% respectively). Favorable tumor affinity and selectivity were retained in the mouse model and excretion of unbound [18F]alphavbeta6-BP was rapid, primarily via the kidneys. In patients, [18F]alphavbeta6-BP was well tolerated without noticeable adverse side effects. PET images showed significant uptake of [18F]alphavbeta6-BP in both the primary lesion and metastases, including metastasis to brain, bone, liver and lung. CONCLUSIONS: The clinical impact of [18F]alphavbeta6-BP PET imaging demonstrated in this first-in-human study is immediate for a broad spectrum of malignancies. PMID- 30401688 TI - Phase III Trial of Adjuvant Sunitinib in Patients With High-Risk Renal Cell Carcinoma: Exploratory Pharmacogenomic Analysis. AB - PURPOSE: In the S-TRAC trial, adjuvant sunitinib prolonged disease-free survival (DFS) versus placebo in patients with loco-regional renal cell carcinoma at high risk of recurrence after nephrectomy. An exploratory analysis evaluated associations between single nucleotide polymorphisms (SNPs) in several angiogenesis- or hypoxia-related genes and clinical outcomes in S-TRAC. EXPERIMENTAL DESIGN: Blood samples were genotyped for 10 SNPs and one insertion/deletion mutation using TaqMan assays. DFS was compared using log-rank tests for each genotype in sunitinib versus placebo groups and between genotypes within each of three (sunitinib, placebo, and combined sunitinib plus placebo) treatment groups. P-values were unadjusted. RESULTS: In all, 286 patients (sunitinib, n=142; placebo, n=144) were genotyped. Longer DFS (HR [95% confidence interval]) was observed with sunitinib versus placebo for VEGFR1 rs9554320 C/C (0.44 [0.21-0.91]; P=0.023), VEGFR2 rs2071559 T/T (0.46 [0.23-0.90]; P=0.020), and eNOS rs2070744 T/T (0.53 [0.30-0.94]; P=0.028). Shorter DFS was observed for VEGFR1 rs9582036 C/A versus C/C with sunitinib, placebo, and combined therapies (P<=0.05), and A/A vs C/C with sunitinib (P=0.022). VEGFR1 rs9554320 A/C versus A/A was associated with shorter DFS in the placebo (P=0.038) and combined (P=0.006) groups. CONCLUSIONS: Correlations between VEGFR1 and VEGFR2 SNPs and longer DFS with sunitinib suggest germline SNPs are predictive of improved outcomes with adjuvant sunitinib in patients with renal cell carcinoma. Independent validation studies are needed to confirm these findings. PMID- 30401689 TI - Blood-based bioenergetic profiling is related to differences in brain morphology in African Americans with Type 2 diabetes. AB - Blood-based bioenergetic profiling has promising applications as a minimally invasive biomarker of systemic bioenergetic capacity. In the present study, we examined peripheral blood mononuclear cell (PBMC) mitochondrial function and brain morphology in a cohort of African Americans with long-standing Type 2 diabetes. Key parameters of PBMC respiration were correlated with white matter, gray matter, and total intracranial volumes. Our analyses indicate that these relationships are primarily driven by the relationship of systemic bioenergetic capacity with total intracranial volume, suggesting that systemic differences in mitochondrial function may play a role in overall brain morphology. PMID- 30401691 TI - Adverse drug reactions. PMID- 30401690 TI - Inhibitory effects of vasostatin-1 against atherogenesis. AB - Vasostatin-1, a chromogranin A (CgA)-derived peptide (76 amino acids), is known to suppress vasoconstriction and angiogenesis. A recent study has shown that vasostatin-1 suppresses the adhesion of human U937 monocytes to human endothelial cells (HECs) via adhesion molecule down-regulation. The present study evaluated the expression of vasostatin-1 in human atherosclerotic lesions and its effects on inflammatory responses in HECs and human THP-1 monocyte-derived macrophages, macrophage foam cell formation, migration and proliferation of human aortic smooth muscle cells (HASMCs) and extracellular matrix (ECM) production by HASMCs, and atherogenesis in apolipoprotein E-deficient (ApoE-/-) mice. Vasostatin-1 was expressed around Monckeberg's medial calcific sclerosis in human radial arteries. Vasostatin-1 suppressed lipopolysaccharide (LPS)-induced up-regulation of monocyte chemotactic protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM 1), and E-selectin in HECs. Vasostatin-1 suppressed inflammatory M1 phenotype and LPS-induced interleukin-6 (IL-6) secretion via nuclear factor-kappaB (NF-kappaB) down-regulation in macrophages. Vasostatin-1 suppressed oxidized low-density lipoprotein (oxLDL)-induced foam cell formation associated with acyl CoA:cholesterol acyltransferase-1 (ACAT-1) and CD36 down-regulation and ATP binding cassette transporter A1 (ABCA1) up-regulation in macrophages. In HASMCs, vasostatin-1 suppressed angiotensin II (AngII)-induced migration and collagen-3 and fibronectin expression via decreasing ERK1/2 and p38 phosphorylation, but increased elastin expression and matrix metalloproteinase (MMP)-2 and MMP-9 activities via increasing Akt and JNK phosphorylation. Vasostatin-1 did not affect the proliferation and apoptosis in HASMCs. Four-week infusion of vasostatin-1 suppressed the development of aortic atherosclerotic lesions with reductions in intra-plaque inflammation, macrophage infiltration, and SMC content, and plasma glucose level in ApoE-/- mice. These results indicate the inhibitory effects of vasostatin-1 against atherogenesis. The present study provided the first evidence that vasostatin-1 may serve as a novel therapeutic target for atherosclerosis. PMID- 30401692 TI - Public spending must improve health, not just healthcare. PMID- 30401693 TI - Necuparanib, a multi-targeting heparan sulfate mimetic, targets tumor and stromal compartments in pancreatic cancer. AB - Pancreatic cancer has an abysmal five year survival rate of 8 %, making it a deadly disease with a need for novel therapies. Here we describe a multi targeting heparin-based mimetic, necuparanib, and its anti-tumor activity in both in vitro and in vivo models of pancreatic cancer. Necuparanib reduced tumor cell proliferation and invasion in a 3-dimensional (3D) culture model; in vivo it extended survival and reduced metastasis. Furthermore, proteomic analysis demonstrated that necuparanib altered the expression levels of multiple proteins involved in cancer-driving pathways including organ development, angiogenesis, proliferation, genomic stability, cellular energetics, and invasion & metastasis. One protein family known to be involved in invasion & metastasis and altered by necuparanib treatment was the matrix metalloprotease (MMP) family. Necuparanib reduced metalloproteinase 1 (MMP1) and increased tissue inhibitor of metalloproteinase 3 (TIMP3) protein levels and was found to increase RNA expression of TIMP3. MMP enzymatic activity was also found to be reduced in the 3D model. Finally, we confirmed necuparanib's in vivo activity by analyzing plasma samples of patients enrolled in a Phase I/II study in patients with metastatic pancreatic cancer; treatment with necuparanib plus standard of care significantly increased TIMP3 plasma protein levels. Together, these results demonstrate necuparanib acts as a broad multi-targeting therapeutic with in vitro and in vivo anti-invasive and anti-metastatic activity. PMID- 30401694 TI - INTESTINAL TOXICITY IN RATS FOLLOWING ADMINISTRATION OF CDK4/6 INHIBITORS IS INDEPENDENT OF PRIMARY PHARMACOLOGY. AB - Recently three different cyclin-dependent kinase 4 and 6 (CDK4/6) dual inhibitors were approved for the treatment of breast cancer (palbociclib, ribociclib and abemaciclib), all of which offer comparable therapeutic benefits. Their safety profiles however are different. For example, neutropenia is observed at varying incidences in patients treated with these drugs; however it is the most common adverse event for palbociclib and ribociclib, whereas diarrhea is the most common adverse event observed in patients treated with abemaciclib. In order to understand the mechanism of diarrhea observed with these drugs and in an effort to guide the development of safer drugs, we compared the effects of oral administration of palbociclib, ribociclib and abemaciclib on the gastrointestinal tract of rats using doses intended to produce comparable CDK4/6 inhibition. Rats administered abemaciclib, but not palbociclib or ribociclib, had fecal alterations, unique histopathological findings and distinctive changes in intestinal gene expression. Morphologic changes in the intestine were characterized by proliferation of crypt cells, loss of goblet cells, poorly differentiated and degenerating enterocytes with loss of microvilli and mucosal inflammation. In the jejunum of abemaciclib-treated rats, down-regulation of enterocyte membrane transporters and up-regulation of genes associated with cell proliferation were observed, consistent with activation of the Wnt pathway and downstream transcriptional regulation. Among these CDK4/6 inhibitors, intestinal toxicity was unique to rats treated with abemaciclib, suggesting a mechanism of toxicity not due to primary pharmacology (CDK4/6 inhibition), but to activity at secondary pharmacological targets. PMID- 30401695 TI - Combining DNA vaccine and AIM2 in H1 nanoparticles exert anti-renal carcinoma effects via enhancing tumor-specific multi-functional CD8+ T cell responses. AB - Renal carcinoma presents a rapid progression in patients with high metastasis with no effective therapeutic strategy. In this study, we designed a folate grafted PEI600-CyD (H1) nanoparticle-mediated DNA vaccine containing an adjuvant of absent in melanoma 2 (AIM2) and a tumor-specific antigen of carbonic anhydrase IX (CAIX) for renal carcinoma therapy. Mice bearing subcutaneous human CAIX (hCAIX)-Renca tumor were intramuscularly immunized with H1-pAIM2/pCAIX, H1-pCAIX, H1-pAIM2, or Mock vaccine, respectively. The tumor growth of hCAIX-Renca was significantly inhibited in H1-pAIM2/pCAIX vaccine group compared with control group. The vaccine activated CAIX-specific CD8+ T cell proliferation and cytotoxic T lymphocyte (CTL) responses, and enhanced the induction of multi functional CD8+ T cells (expressing TNF-alpha, IL-2, and IFN-gamma). CD8+ T cell depletion resulted in the loss of anti-tumor activity of H1-pAIM2/pCAIX vaccine, suggesting that the efficacy of the vaccine was dependent on CD8+ T cell responses. Lung metastasis of renal carcinoma was also suppressed by H1 pAIM2/pCAIX vaccine treatment accompanied with the increased percentages of CAIX specific multi-functional CD8+ T cells in the spleen, tumor, and bronchoalveolar lavage as compared with H1-pCAIX vaccine. Similarly, the vaccine enhanced CAIX specific CD8+ T cell proliferation and CTL responses. Therefore, these results indicated that H1-pAIM2/pCAIX vaccine exhibits the therapeutic efficacy of anti renal carcinoma by enhancing tumor-specific multi-functional CD8+ T cell responses. This vaccine strategy could be a potential and promising approach for the therapy of primary solid or metastasis tumors. PMID- 30401696 TI - Circulating tumor cells with stemness and epithelial-to-mesenchymal transition features are chemoresistant and predictive of poor outcome in metastatic breast cancer. AB - Circulating tumor cells (CTCs) bearing stemness and epithelial-to-mesenchymal transition (EMT) characteristics have been identified in breast cancer, however their clinical significance is not clear. In the current study we investigated the prognostic relevance of single CSC+/partial-EMT+ CTCs in patients with metastatic breast cancer and the effect of first-line chemotherapy on their incidence. For this purpose, triple immunofluorescence against Cytokeratin, ALDH1 and TWIST1 was performed in peripheral blood mononuclear cell (PBMC) cytospins from 130 patients before and after first-line chemotherapy. CSC+/partial-EMT+ CTCs were characterized as cells co-expressing Cytokeratin, high levels of ALDH1 and nuclear TWIST1. CSC+/partial-EMT+ CTCs were evident in 27.7% of patients at baseline and were correlated to lung metastases (p=0.010) and decreased progression-free survival (PFS) [median 10.2 (8.9-11.6) vs. 13.5 (11.3-15.7) months; p=0.024]. Their detection was an independent factor predicting for increased risk of relapse [multivariate analysis; Hazard ratio (HR) (95% CI): 1.785 (1.171- 2.720); p=0.007]. In HER-2 negative patients, CSC+/partial-EMT+ CTCs were additionally associated with reduced overall survival (OS) [median 39 (26.2-51.9) vs. 51 (15.7-86.4) months; p=0.020] and increased risk of death [multivariate analysis; HR (95% CI): 2.228 (1.066-4.655); p=0.033]. Chemotherapy resulted in a significant increase in the incidence of CSC+/partial-EMT+ CTCs (mean CTC% per patient: 59.4% post vs. 39.5% pre; p=0.018), which was subsequently confirmed only in HER2-negative patients (p=0.040) and in non responders at the end of treatment (p=0.020). In conclusion, CSC+/partial-EMT+ CTCs represent a chemoresistant subpopulation, which independently predicts for unfavorable outcome in metastatic breast cancer. Efficient targeting of these CTCs could potentially increase patient survival. PMID- 30401697 TI - Patterns of Transmission Ratio Distortion in Interspecific Lettuce Hybrids Reveal a Sex-Independent Gametophytic Barrier. AB - Interspecific crosses can result in progeny with reduced vitality or fertility due to genetic incompatibilities between species, a phenomenon known as hybrid incompatibility (HI). HI is often caused by a bias against deleterious allele combinations, which results in transmission ratio distortion (TRD). Here, we determined the genome-wide distribution of HI between wild lettuce, Lactuca saligna, and cultivated lettuce, L. sativa, in a set of backcross inbred lines (BILs) with single introgression segments from L. saligna introgressed into a L. sativa genetic background. Almost all BILs contained an introgression segment in a homozygous state except a few BILs, for which we were only able to obtain a single heterozygous introgression. Their inbred progenies displayed severe TRD with a bias toward the L. sativa allele and complete non-transmission of the homozygous L. saligna introgression, i.e. absolute HI. These HI might be caused by deleterious heterospecific allele combinations at two loci. We used an multi locus segregating interspecific F2 population to identify candidate conspecific loci that can nullify the HI in BILs. Segregation analysis of developed double introgression progenies showed nullification of three HI and proved that these HI are explained by nuclear pairwise incompatibilities. One of these digenic HI showed 29% reduced seed set and its pattern of TRD pointed to a sex-independent gametophytic barrier. Namely, this HI was caused by complete non-transmission of one heterospecific allele combination at the haploid stage, surprisingly in both male and female gametophytes. Our study shows that two-locus incompatibility systems contribute to reproductive barriers among Lactuca species. PMID- 30401699 TI - Processive flow by biased polymerization mediates the slow axonal transport of actin. AB - Classic pulse-chase studies have shown that actin is conveyed in slow axonal transport, but the mechanistic basis for this movement is unknown. Recently, we reported that axonal actin was surprisingly dynamic, with focal assembly/disassembly events ("actin hotspots") and elongating polymers along the axon shaft ("actin trails"). Using a combination of live imaging, superresolution microscopy, and modeling, in this study, we explore how these dynamic structures can lead to processive transport of actin. We found relatively more actin trails elongated anterogradely as well as an overall slow, anterogradely biased flow of actin in axon shafts. Starting with first principles of monomer/filament assembly and incorporating imaging data, we generated a quantitative model simulating axonal hotspots and trails. Our simulations predict that the axonal actin dynamics indeed lead to a slow anterogradely biased flow of the population. Collectively, the data point to a surprising scenario where local assembly and biased polymerization generate the slow axonal transport of actin without involvement of microtubules (MTs) or MT-based motors. Mechanistically distinct from polymer sliding, this might be a general strategy to convey highly dynamic cytoskeletal cargoes. PMID- 30401698 TI - Dissecting human disease with single-cell omics: application in model systems and in the clinic. AB - Probing cellular population diversity at single-cell resolution became possible only in recent years. The popularity of single-cell 'omic' approaches, which allow researchers to dissect sample heterogeneity and cell-to-cell variation, continues to grow. With continuous technological improvements, single-cell omics are becoming increasingly prevalent and contribute to the discovery of new and rare cell types, and to the deciphering of disease pathogenesis and outcome. Animal models of human diseases have significantly facilitated our understanding of the mechanisms driving pathologies and resulted in the development of more efficient therapies. The application of single-cell omics to animal models improves the precision of the obtained insights, and brings single-cell technology closer to the clinical field. This Review focuses on the use of single cell omics in cellular and animal models of diseases, as well as in samples from human patients. It also highlights the potential of these approaches to further improve the diagnosis and treatment of various pathologies, and includes a discussion of the advantages and remaining challenges in implementing these technologies into clinical practice. PMID- 30401701 TI - Nearly half of older patients stop taking statins within a year, study finds. PMID- 30401700 TI - Triple therapy in the management of chronic obstructive pulmonary disease: systematic review and meta-analysis. AB - OBJECTIVE: To compare the rate of moderate to severe exacerbations between triple therapy and dual therapy or monotherapy in patients with chronic obstructive pulmonary disease (COPD). DESIGN: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: PubMed, Embase, Cochrane databases, and clinical trial registries searched from inception to April 2018. ELIGIBILITY CRITERIA: Randomised controlled trials comparing triple therapy with dual therapy or monotherapy in patients with COPD were eligible. Efficacy and safety outcomes of interest were also available. DATA EXTRACTION AND SYNTHESIS: Data were collected independently. Meta-analyses were conducted to calculate rate ratios, hazard ratios, risk ratios, and mean differences with 95% confidence intervals. Quality of evidence was summarised in accordance with GRADE methodology (grading of recommendations assessment, development, and evaluation). RESULTS: 21 trials (19 publications) were included. Triple therapy consisted of a long acting muscarinic antagonist (LAMA), long acting beta agonist (LABA), and inhaled corticosteroid (ICS). Triple therapy was associated with a significantly reduced rate of moderate or severe exacerbations compared with LAMA monotherapy (rate ratio 0.71, 95% confidence interval 0.60 to 0.85), LAMA and LABA (0.78, 0.70 to 0.88), and ICS and LABA (0.77, 0.66 to 0.91). Trough forced expiratory volume in 1 second (FEV1) and quality of life were favourable with triple therapy. The overall safety profile of triple therapy is reassuring, but pneumonia was significantly higher with triple therapy than with dual therapy of LAMA and LABA (relative risk 1.53, 95% confidence interval 1.25 to 1.87). CONCLUSIONS: Use of triple therapy resulted in a lower rate of moderate or severe exacerbations of COPD, better lung function, and better health related quality of life than dual therapy or monotherapy in patients with advanced COPD. STUDY REGISTRATION: Prospero CRD42018077033. PMID- 30401702 TI - A simplified mechanism for anisotropic constriction in Drosophila mesoderm. AB - Understanding how forces and material properties give rise to tissue shapes is a fundamental question in developmental biology. Although Drosophila gastrulation is a major system for investigating tissue morphogenesis, there does not exist a consensus mechanical model that explains all the key features of this process. One key feature of Drosophila gastrulation is its anisotropy - the mesoderm constricts much more along one axis than along the other. Previous explanations have involved graded stress, anisotropic stresses or material properties, or mechanosensitive feedback. Here we show that these mechanisms are not required to explain the anisotropy of constriction. In- stead, constriction can be anisotropic if only two conditions are met: the tissue is elastic, as was demonstrated in our recent study, and the contractile domain is asymmetric. This conclusion is general and does not depend on the values of model parameters. This model can explain classical tissue grafting experiments and more recent laser ablation studies. Furthermore, this model may provide alternative explanations for experiments in other developmental systems, including C. elegans and zebrafish. PMID- 30401704 TI - Iron deficiency. AB - Iron deficiency anemia affects >1.2 billions individuals worldwide and iron deficiency in the absence of anemia is even more frequent. Total body (absolute) iron deficiency is caused by physiologically increased iron requirements in children, adolescents, young and pregnant women, by reduced iron intake or by pathological defective absorption or chronic blood loss. Adaptation to iron deficiency at tissue level is controlled by Iron Regulatory Proteins to increase iron uptake and retention; at systemic level suppression of the iron hormone hepcidin increases iron release to plasma by absorptive enterocytes and recycling macrophages. The diagnosis of absolute iron deficiency is easy unless masked by inflammatory conditions. All cases of iron deficiency should be assessed for treatment and for the underlying cause. Special attention is needed in areas endemic for malaria and other infections to avoid infection worsening by iron treatment. Ongoing efforts aim at optimizing the iron salts-based therapy by protocols of administration based on the physiology of hepcidin control and at reducing the common side effects of oral iron. Intravenous iron, especially last generation compounds administered at high dose in single infusions, is becoming an effective alternative in an increasing number of conditions, because of a more rapid and persistent hematological response, and an acceptable safety profile. Risks/benefits of the different treatments should be weighted in a personalized therapeutic approach to iron deficiency. PMID- 30401703 TI - Acute myeloid leukemia induces pro-tumoral p16INK4a driven senescence in the bone marrow microenvironment. AB - Acute myeloid leukemia (AML) is an age-related disease that is highly dependent on the bone marrow microenvironment. With increasing age, tissues accumulate senescent cells, characterized by an irreversible arrest of cell proliferation and the secretion of a set of pro-inflammatory cytokines, chemokines and growth factors, collectively known as the senescence-associated secretory phenotype (SASP). Here, we report that AML blasts induce a senescent phenotype in the stromal cells within the bone marrow microenvironment. We report that the bone marrow stromal cell senescence is driven by p16INK4a expression. The p16INK4a expressing senescent stromal cells then feedback to promote AML blast survival and proliferation via the SASP. Importantly, selective elimination of p16INK4a positive senescent bone marrow stromal cells in vivo improved the survival of mice with leukemia. Next, we find that the leukemia-driven senescent tumor microenvironment is caused by AML induced NOX2-derived superoxide. Finally, using the p16-3MR mouse model we show that by targeting NOX2 we reduced bone marrow stromal cell senescence and consequently reduced AML proliferation. Together, these data identify leukemia generated NOX2 derived superoxide as a driver of pro tumoral p16INK4a-dependent senescence in bone marrow stromal cells. Our findings reveal the importance of a senescent microenvironment for the pathophysiology of leukemia. These data now open the door to investigate drugs which specifically target the 'benign' senescent cells that surround and support AML. PMID- 30401705 TI - Anemia of inflammation. AB - Anemia of inflammation (AI) also known as anemia of chronic disease (ACD) is regarded as the most frequent anemia in hospitalized and chronically ill patients. It is prevalent in patients with diseases that cause prolonged immune activation including infection, auto-immune diseases and cancer. More recently, the list has grown to include chronic kidney disease, congestive heart failure, chronic pulmonary diseases and obesity. Inflammation-inducible cytokines and the master regulator of iron homeostasis, hepcidin, block intestinal iron absorption and cause iron retention in reticuloendothelial cells resulting in iron restricted erythropoiesis. In addition, shortened erythrocyte half-life, suppressed erythropoietin response to anemia and inhibition of erythroid cell differentiation by inflammatory mediators, further contribute to AI, in a disease specific pattern. While the diagnosis of AI is a diagnosis of exclusion and is supported by characteristic alterations of iron homeostasis, hypoferremia and hyperferritinemia, the diagnosis of AI patients with coexisting iron deficiency is more difficult. Apart from treatment of the disease underlying AI, the combination of iron therapy and erythropoiesis-stimulating agents can improve anemia in many patients. In the future, emerging therapeutics which antagonize hepcidin function and re-distribute endogenous iron for erythropoiesis may offer additional options. However, based on experience with anemia treatment in chronic kidney disease, critical illness and cancer, finding the appropriate indications for the specific treatment of AI will require improved understanding and a balanced consideration of the contribution of anemia to each patient's morbidity and the impact of anemia treatment on the patient's prognosis in a variety of disease settings. PMID- 30401706 TI - The molecular genetics of sideroblastic anemia. AB - The sideroblastic anemias (SAs) are a group of inherited and acquired bone marrow disorders defined by pathological iron accumulation in the mitochondria of erythroid precursors. Like most hematological diseases, the molecular genetic basis of the SAs has ridden the wave of technology advancement. Within the last twenty years, with the advent of positional cloning, the human genome project, solid-state genotyping technologies, and next generation sequencing (NGS) has evolved to the point where more than two-thirds of congenital cases (CSAs), and an even greater proportion of cases of acquired clonal disease, can be attributed to mutations in a specific gene or genes. This review focuses on an analysis of the genetics of these diseases and how understanding these defects may contribute to the design and implementation of rational therapies. PMID- 30401707 TI - Iron metabolism under conditions of ineffective erythropoiesis in beta thalassemia. AB - Beta-thalassemia is inherited genetic disorder characterized by ineffective erythropoiesis (IE), leading to anemia and abnormal iron metabolism. IE is as an abnormal expansion of the number of erythroid progenitor cells with unproductive synthesis of enucleated erythrocytes, leading to anemia and hypoxia. Anemic patients affected by beta-thalassemia (BT) suffer from iron overload, even in the absence of chronic blood transfusion, suggesting the presence of one or more erythroid factors with the ability to modulate iron metabolism and dietary iron absorption. Recent studies suggest that decreased erythroid cell differentiation and survival also contributes to IE, aggravating the anemia in BT. Furthermore, hypoxia can also affect and increase iron absorption. To understand the relationship between iron metabolism and IE could provide important insights into the BT condition and help to develop novel treatments. In fact, genetic or pharmacological manipulations of iron metabolism or erythroid cell differentiation and survival have been shown to improve IE, iron overload, and anemia in animal models of BT. Based on those findings, new therapeutic approaches and drugs have been proposed, and clinical trials are currently underway that have the potential to improve erythrocyte production as well as reduce the iron overload and organ toxicity in BT and in other disorders characterized by IE. PMID- 30401708 TI - Liver iron sensing and body iron homeostasis. AB - The liver orchestrates systemic iron balance by producing and secreting hepcidin. Known as the iron hormone, hepcidin induces degradation of the iron exporter ferroportin to control iron entry into the bloodstream from dietary sources, iron recycling macrophages, and body stores. Under physiologic conditions, hepcidin production is reduced by iron deficiency and erythropoietic drive to increase the iron supply when needed to support red blood cell production and other essential functions. Conversely, hepcidin production is induced by iron loading and inflammation to prevent the toxicity of iron excess and limit its availability to pathogens. Inability to appropriately regulate hepcidin production in response to these physiologic cues underlies genetic disorders of iron overload and deficiency, including hereditary hemochromatosis and iron refractory iron deficiency anemia. Moreover, excess hepcidin suppression in the setting of ineffective erythropoiesis contributes to iron loading anemias such as beta thalassemia, whereas excess hepcidin induction contributes to iron restricted erythropoiesis and anemia in chronic inflammatory diseases. These diseases have provided key insights into understanding the mechanisms by which the liver senses plasma and tissue iron levels, the iron demand of erythrocyte precursors, and the presence of potential pathogens, and importantly, how these various signals are integrated to appropriately regulate hepcidin production. This review will focus on recent insights into how the liver senses body iron levels and coordinates this with other signals to regulate hepcidin production and systemic iron homeostasis. PMID- 30401709 TI - Salmonella-induced thrombi in mice develop asynchronously in the spleen and liver and are not effective bacterial traps. AB - Thrombosis is a frequent, life-threatening complication of systemic infection, associated with multiple organ damage. We have previously described a novel mechanism of inflammation-driven thrombosis induced by Salmonella Typhimurium infection of mice. Thrombosis in the liver develops 7 days post-infection persisting after the infection resolves, and is monocytic cell-dependent. Unexpectedly, thrombosis was not prominent in the spleen at this time, despite carrying a similar bacterial burden as the liver. In this study, we show that thrombosis does occur in the spleen but with strikingly accelerated kinetics compared to the liver, being evident by 24 h and resolving rapidly thereafter. The distinct kinetics of thrombosis and bacterial burden provide a test of the hypothesis that thrombi form in healthy vessels to trap or remove bacteria from the circulation, often termed immunothrombosis. Remarkably, despite bacteria being detected throughout infected spleens and livers in the early days of infection, immunohistological analysis of tissue sections show that thrombi contain very low numbers of bacteria. In contrast, bacteria are present throughout platelet aggregates induced by Salmonella in vitro. Therefore, we show that thrombosis develops with organ-specific kinetics and challenge the universality of immunothrombosis as a mechanism to capture bacteria in vivo. PMID- 30401710 TI - CREBBP gene mutations are frequently detected in in situ follicular neoplasia. PMID- 30401711 TI - M2 macrophage-derived exosomes promote cell migration and invasion in colon cancer. AB - Clinical and experimental evidence has shown that tumor-associated macrophages promote cancer initiation and progression. However, the macrophage-derived molecular determinants that regulate colorectal cancer (CRC) metastasis have not been fully characterized. Here we demonstrate that M2 macrophage-regulated CRC cells migration and invasion is dependent upon M2 macrophage-derived exosomes (MDE). MDE displayed a high expression level of miR-21-5p and miR-155-5p, and MDE mediated CRC cells migration and invasion depended on these two miRNAs. Mechanistically, miR-21-5p and miR-155-5p were transferred to CRC cells by MDE and bound to the BRG1 coding sequence, downregulating expression of BRG1, which has been identified as a key factor promoting CRC metastasis, yet is downregulated in metastatic CRC cells. Collectively, these findings show that M2 macrophages induce CRC cells migration and invasion and provide significant plasticity of BRG1 expression in response to tumor microenvironments during malignant progression. This dynamic and reciprocal cross-talk between CRC cells and M2 macrophages provides a new opportunity for the treatment of metastatic CRC. PMID- 30401712 TI - Mammary precancerous stem and non-stem cells evolve into cancers of distinct subtypes. AB - There are distinct cell subpopulations in normal epithelial tissue, including stem cells, progenitor cells, and more differentiated cells, all of which have been extensively studied for their susceptibility to tumorigenesis. However, normal cells usually have to progress through a precancerous lesion state before becoming a full-blown tumor. Precancerous early lesions are heterogeneous, and the cell subset that is the primary source of the eventual tumor remains largely unknown. By using mouse models that are tailored to address this question, we identified a keratin 6a-expressing precancerous stem cell (PcSC) subset and a more differentiated whey acidic protein-positive (WAP+) cell subset in mammary precancerous lesions initiated by the Wnt1 oncogene. Both cell subsets rapidly progressed to cancer upon introduction of constitutively active versions of either HRAS or BRAF. However, the resulting tumors were dramatically different in protein profiles and histopathology: keratin 6a+ precancerous cells gave rise to adenocarcinoma while WAP+ cells yielded metaplastic carcinoma with severe squamous differentiation and more robust activation of MEK/ERK signaling. Therefore, both stem and non-stem cells in mammary precancerous lesions can contribute to the eventual cancers, but their differentiation status determines the resulting cancer phenotype. This work identifies a previously unknown player in cancer heterogeneity and suggests that cancer prevention should target precancerous cells broadly and not be limited to PcSC. PMID- 30401713 TI - Antifibrotic therapy disrupts stromal barriers and modulates the immune landscape in pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDA) remains one of the deadliest forms of cancer, in part, because it is largely refractory to current therapies. The failure of most standard therapies in PDA, as well as promising immune therapies, may be largely ascribed to highly unique and protective stromal microenvironments that present significant biophysical barriers to effective drug delivery, that are immunosuppressive, and that can limit the distribution and function of anti tumor immune cells. Here, we utilized stromal re-engineering to disrupt these barriers and move the stroma toward normalization using a potent antifibrotic agent, halofuginone. In an autochthonous genetically engineered mouse model of PDA, halofuginone disrupted physical barriers to effective drug distribution by decreasing fibroblast activation and reducing key extracellular matrix elements that drive stromal resistance. Concomitantly, halofuginone treatment altered the immune landscape in PDA, with greater immune infiltrate into regions of low hylauronan, which resulted in increased number and distribution of both classically activated inflammatory macrophages and cytotoxic T cells. In concert with a direct effect on carcinoma cells, this led to widespread intratumoral necrosis and reduced tumor volume. These data point to the multifunctional and critical role of the stroma in tumor protection and survival and demonstrate how compromising tumor integrity to move toward a more normal physiologic state through stroma-targeting therapy will likely be an instrumental component in treating PDA. PMID- 30401714 TI - Inhibition of thioredoxin/thioredoxin reductase induces synthetic lethality in lung cancers with compromised glutathione homeostasis. AB - Glutathione (GSH)/GSH reductase (GSR) and thioredoxin/thioredoxin reductase (TXNRD) are two major compensating thiol-dependent antioxidant pathways that maintain protein dithiol/disulfide balance. We hypothesized that functional deficiency in one of these systems would render cells dependent on compensation by the other system for survival, providing a mechanism-based synthetic lethality approach for treatment of cancers. The human GSR gene is located on chromosome 8p12, a region frequently lost in human cancers. GSR deletion was detected in about 6% of lung adenocarcinomas in The Cancer Genome Atlas database. To test whether loss of GSR sensitizes cancer cells to TXNRD inhibition, we knocked out or knocked down the GSR gene in human lung cancer cells and evaluated their response to the TXNRD inhibitor auranofin. GSR deficiency sensitized lung cancer cells to this agent. Analysis of a panel of 129 NSCLC cell lines revealed that auranofin sensitivity correlated with the expression levels of the GSR, glutamate cysteine ligase catalytic subunit (GCLC), and NAD(P)H quinone dehydrogenase 1 (NQO1) genes. In NSCLC patient-derived xenografts with reduced expression of GSR and/or GCLC, growth was significantly suppressed by treatment with auranofin. Together these results provide a proof of concept that cancers with compromised expression of enzymes required for GSH homeostasis or with chromosome 8p deletions that include the GSR gene may be targeted by a synthetic lethality strategy with inhibitors of TXNRD. PMID- 30401715 TI - Assessment of tumor redox status through (S)-4-(3-[18F]fluoropropyl)-L-glutamic acid positron emission tomography imaging of system xc- activity. AB - The cell's endogenous antioxidant system is vital to maintenance of redox homeostasis. Despite its central role in normal and pathophysiology, no non invasive tools exist to measure this system in patients. The cystine/glutamate antiporter system xc- maintains the balance between intracellular reactive oxygen species and antioxidant production through the provision of cystine, a key precursor in glutathione biosynthesis. Here we show that tumor cell retention of a system xc--specific positron emission tomography radiotracer, (S)-4-(3 [18F]fluoropropyl)-L-glutamic acid ([18F]FSPG), decreases in proportion to levels of oxidative stress following treatment with a range of redox-active compounds. The decrease in [18F]FSPG retention correlated with a depletion of intracellular cystine resulting from increased de novo glutathione biosynthesis, shown through [U-13C6, U-15N2]cystine isotopic tracing. In vivo, treatment with the chemotherapeutic doxorubicin decreased [18F]FSPG tumor uptake in a mouse model of ovarian cancer, coinciding with markers of oxidative stress but preceding tumor shrinkage and decreased glucose utilization. Having already been used in pilot clinical trials, [18F]FSPG PET could be rapidly translated to the clinic as an early redox indicator of tumor response to treatment. PMID- 30401716 TI - EGFR cooperates with EGFRvIII to recruit macrophages in glioblastoma. AB - Amplification of the EGFR gene and its truncation mutant EGFRvIII are hallmarks of glioblastoma. Although co-expression of EGFR and EGFRvIII confers a growth advantage, how EGFR and EGFRvIII influence the tumor microenvironment remains incompletely understood. Here we show that EGFR and EGFRvIII cooperate to induce macrophage infiltration via upregulation of the chemokine CCL2. EGFRvIII was significantly enriched in glioblastoma patient samples with high CCL2, and knockout of CCL2 in tumors co-expressing EGFR and EGFRvIII led to decreased infiltration of macrophages. KRAS was a critical signaling intermediate for EGFR and EGFRvIII-induced expression of CCL2. Our results illustrate how EGFR and EGFRvIII direct the microenvironment in glioblastoma. PMID- 30401717 TI - Molecular correlates of metastasis by systematic pan-cancer analysis across The Cancer Genome Atlas. AB - Tumor metastasis is a major contributor to cancer patient mortality, but the process remains poorly understood. Molecular comparisons between primary tumors and metastases can provide insights into the pathways and processes involved. Here, we systematically analyzed and cataloged molecular correlates of metastasis using The Cancer Genome Atlas (TCGA) datasets across 11 different cancer types, these data involving 4,473 primary tumor samples and 395 tumor metastasis samples (including 369 from melanoma). For each cancer type, widespread differences in gene transcription between primary and metastasis samples were observed. For several cancer types, metastasis-associated genes from TCGA comparisons were found to overlap extensively with external results from independent profiling datasets of metastatic tumors. While some differential expression patterns associated with metastasis were found to be shared across multiple cancer types, by and large each cancer type showed a metastasis signature that was distinctive from those of the other cancer types. Functional categories of genes enriched in multiple cancer type-specific metastasis over-expression signatures included cellular response to stress, DNA repair, oxidation-reduction process, protein deubiquitination, and receptor activity. The TCGA-derived prostate cancer metastasis signature in particular could define a subset of aggressive primary prostate cancer. Transglutaminase 2 protein and mRNA were both elevated in metastases from breast and melanoma cancers. Alterations in microRNAs and in DNA methylation were also identified. Implications: Our findings suggest that there are different molecular pathways to metastasis involved in different cancers. Our catalog of alterations provides a resource for future studies investigating the role of specific genes in metastasis. PMID- 30401718 TI - PARP inhibition induces enrichment of DNA repair proficient CD133 and CD117 positive ovarian cancer stem cells. AB - Poly (ADP-ribose) polymerase inhibitors (PARPi) are FDA approved monotherapy agents for the treatment of recurrent ovarian cancer (OvCa) in patients with and without a BRCA mutation. Despite promising response rates, not all patients derive benefit and the majority develop resistance. PARPi treatment in vitro and in vivo induced an enrichment of CD133+ and CD117+ ovarian cancer stem cells (CSCs). This effect was not impacted by BRCA mutation status. In the CSC fractions, PARPi induced cell cycle arrest in G2/M with a consequent accumulation of yH2AX, RAD51 and uniquely DMC1 foci. DNA damage and repair monitoring assays demonstrated that CSCs display more efficient DNA repair due, in part, to activation of embryonic repair mechanisms which involved the RAD51 homologue, DMC1 recombinase. Preserved and induced homologous repair (HR) could be a mechanism of an inherent resistance of CSCs to the synthetic lethality of PARPi that likely promotes disease recurrence. Implications: Treatment with PARPi fails to significantly impact OvCa CSC populations, likely contributing to recurrent disease. OvCa CSCs stabilize genomic integrity post PARPi treatment, due to a more efficient inherent DNA-repair capacity. PARPi induced DMC1 recombinase and HR-proficiency provide CSCs the opportunity to repair DNA damage more efficiently. PMID- 30401719 TI - High Prevalence of a Hotspot of Noncoding Somatic Mutations in Intron 6 of GPR126 in Bladder Cancer. AB - Numerous pangenomic studies identified protein-coding genes and signaling pathways involved in bladder carcinogenesis. However, noncoding somatic alterations remain unexplored. A recent study revealed a mutational hotspot in intron 6 of GPR126 gene in 2.7% of a large breast cancer series. As GPR126 is highly expressed in bladder tissues, we investigated here the prevalence and the prognostic significance of these mutations in bladder cancer. We analyzed a cohort of 103 bladder cancers including 44 nonmuscle-invasive bladder cancers (NMIBC) and 59 muscle-invasive bladder cancers (MIBC). GPR126 mutations were analyzed by high-resolution melting and Sanger sequencing, and GPR126 expression levels were assessed using real-time quantitative RT-PCR. In NMIBC, somatic GPR126 noncoding mutations occurred in 47.7% of samples and were negatively associated with GPR126 mRNA levels. GPR126 mutations had higher frequencies in nonsmoker patients and were associated with a prior history of NMIBC. GPR126 overexpression was detected in 70.5% of samples. GPR126 mutation and overexpression status were not associated with outcome. In MIBC, somatic GPR126 mutations occurred in 44.1% of samples. Mutations were more frequent in females. GPR126 overexpression was detected in 27.1% of the sample. A trend toward significance was observed between GPR126 overexpression and better outcome. We identified the second most frequent mutational hotspot after TERT promoter (~70%) in bladder cancer, with a mutation rate of approximately 50%.Implications: The GPR126 intronic mutational hotspot could be a promising clinical biomarker candidate to monitor tumor burden using circulating tumor DNA in bladder cancer. Mol Cancer Res; 1-7. (c)2018 AACR. PMID- 30401720 TI - Nuclear E-cadherin acetylation promotes colorectal tumorigenesis via enhancing beta-catenin activity. AB - The E-cadherin/beta-catenin signaling pathway plays a critical role in the maintenance of epithelial architecture and regulation of tumor progression. Normally, E-cadherin locates on the cell surface with its cytosolic domain linking to the actin cytoskeleton through interaction with catenins. Although the nuclear localization of E-cadherin has been frequently observed in various types of cancers, little is known regarding the functional consequences of its nuclear translocation. Here, we showed that in colorectal cancer samples and cell lines, E-cadherin localized in the nucleus; and the nuclear localization was mediated through protein interaction with CTNND1. In the nucleus, E-cadherin was acetylated by CBP at Lysine870 and Lysine871 in its beta-catenin binding domain, and the acetylation can be reversed by SIRT2. Acetylation of nuclear E-cadherin attenuated its interaction with beta-catenin, which therefore released beta catenin from the complex, resulting in increased expression of its downstream genes and accelerated tumor growth and migration. Further study showed that acetylation level of nuclear E-cadherin had high prognostic significance in clinical colorectal samples. Taken together, our findings reveal a novel mechanism of tumor progression through post-translational modification of E cadherin, which may serve as a potential drug target of tumor therapy. Implications: This finding that acetylation of nuclear E-cadherin regulates beta catenin activity expands our understanding of the acetylation of E-cadherin promotes colorectal cancer cell growth and suggests novel therapeutic approaches of targeting acetylation in tumors. PMID- 30401721 TI - Erratum. SRY-Box Containing Gene 4 Promotes Liver Steatosis by Upregulation of SREBP-1c. Diabetes 2018;67:2227-2238. PMID- 30401722 TI - Long Read Annotation (LoReAn): automated eukaryotic genome annotation based on long-read cDNA sequencing. AB - Single-molecule full-length cDNA sequencing can aid genome annotation by revealing transcript structure and alternative splice forms, yet current annotation pipelines do not incorporate such information. Here we present Long Read Annotation (LoReAn) software, an automated annotation pipeline utilizing short- and long-read cDNA sequencing, protein evidence, and ab initio prediction to generate accurate genome annotations. Based on annotations of two fungal genomes (Verticillium dahliae and Plicaturopsis crispa) and two plant genomes (Arabidopsis thaliana and Oryza sativa), we show that LoReAn outperforms popular annotation pipelines by integrating single-molecule cDNA sequencing data generated from either the Pacific Biosciences (PacBio) or MinION sequencing platforms, correctly predicting gene structure, and capturing genes missed by other annotation pipelines. PMID- 30401723 TI - Elongator is required for root stem cell maintenance by regulating SHORT ROOT transcription. AB - SHORTROOT (SHR) is essential for stem cell maintenance and radial patterning in Arabidopsis (Arabidopsis thaliana) roots, but how its expression is regulated is unknown. Here, we report that the Elongator complex, which consists of six subunits (Elongator1-6), regulates the transcription of SHR. Depletion of Elongator drastically reduced SHR expression and led to defective root stem cell maintenance and radial patterning. The importance of the nuclear localization of Elongator for its functioning, together with the insensitivity of the elp1 mutant to the transcription elongation inhibitor 6-azauracil, and the direct interaction of the ELP4 subunit with the C-terminal domain of RNA polymerase II (RNAPII CTD), support the notion that Elongator plays important roles in transcription elongation. Indeed, we found that ELP3 associates with the pre-mRNA of SHR and that mutation of Elongator reduces the enrichment of RNAPII on the SHR gene body. Moreover, Elongator interacted in vivo with SUPPRESSOR OF Ty4 (SPT4), a well established transcription elongation factor that is recruited to the SHR locus. Together, these results demonstrate that Elongator acts in concert with SPT4 to regulate the transcription of SHR. PMID- 30401724 TI - Dispatches from the editor: how can we responsibly harness social media to improve our military health journal? PMID- 30401725 TI - Does perception of drug-related harm change with age? A cross-sectional online survey of young and older people. AB - OBJECTIVES: To investigate how young and older people perceive the harms associated with legal and illegal drugs. DESIGN: Cross-sectional study: adults aged 18-24 years versus 45+ completed an online survey ranking the perceived harms associated with 11 drugs on 16 drug-related harm criteria. SETTING: Online survey. PARTICIPANTS: 184 participants aged 18-24 years (113 female: mean age 21: SD 1.3) and 91 participants aged 45+ (51 female: mean age 60: SD 8.5). MAIN OUTCOME MEASURES: 'Perception of drug-related harms': This was measured using a rating scale ranging from 1 (no risk of harm) to 4 (high risk of harm). Participants were also asked about sources which informed their perception on drug-related harms as well as their own personal self-reported drug experiences. RESULTS: Of the illegal drugs, heroin, methamphetamine and cocaine were rated as the most harmful and cannabis was rated as the least harmful. Alcohol and tobacco were also rated as less harmful. The results showed that perceptions of drug related harms were inconsistent with current knowledge from research on drugs. Furthermore, perceptions on drug harms were more conservative in the 45+ group for a number of illegal drugs and tobacco. However, the 45+ age group did not perceive alcohol as any more harmful than the younger group. CONCLUSIONS: This survey demonstrates that the greatest misperception was in relation to alcohol related harms which did not change with age. In order to minimise harms, this misperception needs to be addressed through education and policies that legislate drug use. PMID- 30401727 TI - Detection of cell-free DNA fragmentation and copy number alterations in cerebrospinal fluid from glioma patients. AB - Glioma is difficult to detect or characterize using current liquid biopsy approaches. Detection of cell-free tumor DNA (cftDNA) in cerebrospinal fluid (CSF) has been proposed as an alternative to detection in plasma. We used shallow whole-genome sequencing (sWGS, at a coverage of < 0.4*) of cell-free DNA from the CSF of 13 patients with primary glioma to determine somatic copy number alterations and DNA fragmentation patterns. This allowed us to determine the presence of cftDNA in CSF without any prior knowledge of point mutations present in the tumor. We also showed that the fragmentation pattern of cell-free DNA in CSF is different from that in plasma. This low-cost screening method provides information on the tumor genome and can be used to target those patients with high levels of cftDNA for further larger-scale sequencing, such as by whole-exome and whole-genome sequencing. PMID- 30401726 TI - Temporal and geographic patterns of stab injuries in young people: a retrospective cohort study from a UK major trauma centre. AB - OBJECTIVES: To describe the epidemiology of assaults resulting in stab injuries among young people. We hypothesised that there are specific patterns and risk factors for injury in different age groups. DESIGN: Eleven-year retrospective cohort study. SETTING: Urban major trauma centre in the UK. PARTICIPANTS: 1824 patients under the age of 25 years presenting to hospital after a stab injury resulting from assault. OUTCOMES: Incident timings and locations were obtained from ambulance service records and triangulated with prospectively collected demographic and injury characteristics recorded in our hospital trauma registry. We used geospatial mapping of individual incidents to investigate the relationships between demographic characteristics and incident timing and location. RESULTS: The majority of stabbings occurred in males from deprived communities, with a sharp increase in incidence between the ages of 14 and 18 years. With increasing age, injuries occurred progressively later in the day (r2=0.66, p<0.01) and were less frequent within 5 km of home (r2=0.59, p<0.01). Among children (age <16), a significant peak in injuries occurred between 16:00 and 18:00 hours, accounting for 22% (38/172) of injuries in this group compared with 11% (182/1652) of injuries in young adults. In children, stabbings occurred earlier on school days (hours from 08:00: 11.1 vs non-school day 13.7, p<0.01) and a greater proportion were within 5 km of home (90% vs non-school day 74%, p=0.02). Mapping individual incidents demonstrated that the spike in frequency in the late afternoon and early evening was attributable to incidents occurring on school days and close to home. CONCLUSIONS: Age, gender and deprivation status are potent influences on the risk of violent injury in young people. Stab injuries occur in characteristic temporal and geographical patterns according to age group, with the immediate after-school period associated with a spike in incident frequency in children. This represents an opportunity for targeted prevention strategies in this population. PMID- 30401728 TI - Biopsy-free screening for glioma. PMID- 30401729 TI - Casticin inhibits breast cancer cell migration and invasion by down-regulation of PI3K/Akt signaling pathway. AB - Casticin is one of the major active components isolated from Fructus viticis Increasing studies have revealed that casticin has potential anticancer activity in various cancer cells, but its effects on breast cancer cell migration and invasion are still not well known. Therefore, the ability of cell migration and invasion in the breast cancer MDA-MB-231 and 4T1 cells treated by casticin was investigated. The results indicated that casticin significantly inhibited cell migration and invasion in the cells exposed to 0.25 and 0.50 uM of casticin for 24 h. Casticin treatment reduced matrix metalloproteinase (MMP) 9 (MMP-9) activity and down-regulated MMP-9 mRNA and protein expression, but not MMP-2. Casticin treatment suppressed the nuclear translocation of transcription factors c-Jun and c-Fos, but not nuclear factor-kappaB (NF-kappaB), and decreased the phosphorylated level of Akt (p-Akt). Additionally, the transfection of Akt overexpression vector to MDA-MB-231 and 4T1 cells could up-regulate MMP-9 expression concomitantly with a marked increase in cell invasion, but casticin treatment reduced Akt, p-Akt, and MMP-9 protein levels and inhibited the ability of cell invasion in breast cancer cells. Additionally, casticin attenuated lung metastasis of mouse 4T1 breast cancer cells in the mice and down-regulated MMP-9 expression in the lung tissues of mice treated by casticin. These findings suggest that MMP-9 expression suppression by casticin may act through inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, which in turn results in the inhibitory effects of casticin on cell migration and invasion in breast cancer cells. Therefore, casticin may have potential for use in the treatment of breast cancer invasion and metastasis. PMID- 30401730 TI - Dietary protein intake and risk of ovarian cancer: Evidence from a meta-analysis of observational studies. AB - The association between dietary protein intake and ovarian cancer had been inconsistent in the previous epidemiological studies. The aim of this study was to identify and synthesize all citations evaluating the relationship on ovarian cancer with protein intake. The search included PubMed, Embase, and Web of Science from inception to June 2018. Two authors independently selected studies, extracted data and assessed risk of bias. RR and 95%CI were calculated for relationship between the dietary protein intake and ovarian cancer risk using a random-effects model. Publication bias was evaluated using Egger's test and Begg's funnel plots. At the end, ten citations with 2354 patients were included in meta-analysis. Summarized relative risk (RR) with 95% confidence interval (95%CI) on ovarian cancer was 0.915 (95%CI= 0.821-1.021), with no between-study heterogeneity ( I 2= 0.0%, P = 0.708). The results were consistent both in animal protein intake and in vegetable intake on ovarian cancer. Subgroup analysis by study design did not find positive association either in cohort studies or in case-control studies. Egger's test ( P = 0.230) and Funnel plot suggested no publication bias. Based on the obtained results, we conclude that high dietary protein intake had no significant association on ovarian cancer risk. Besides that, it is necessary to develop high-quality, large scale studies with detailed amount of dietary protein intake for verifying our results. PMID- 30401731 TI - Combination of Transcriptome sequencing and iTRAQ proteome reveal the molecular mechanisms determining petal shape in Herbaceous Peony (Paeonia lactiflora Pall.). AB - The molecular mechanisms controlling petal shape in a herbaceous peony, Paeonia lactiflora Pall., a popular high-grade cut flower worldwide, remain unclear. Here, we selected inner and outer petals from P. lactiflora 'ZiFengyu' with an anemone type as the study object. Using transcriptome sequencing and isobaric tags for relative and absolute quantitation (iTRAQ) proteome, 979 differentially expressed genes and 266 differentially expressed proteins were detected within the inner and outer petals. Of these, the present study identified a key gene APETALA2 that regulates flower shape development. In addition, we obtained a 1935 bp full-length cDNA sequence of APETALA2 by rapid amplification of cDNA ends amplification (RACE). Through further validation using quantitative real time polymerase chain reaction (qRT-PCR) and western blot analysis, APETALA2 showed a markedly higher expression in outer than that in inner petals. Therefore, the present study indicates that the increased expression of APETALA2 contributes to the formation of petals in P. lactiflora. PMID- 30401732 TI - Commentary on Ivancic et al.: Enzyme kinetics from circular dichroism of insulin reveals mechanistic insights into the regulation of insulin-degrading enzyme. AB - Despite the enormous number of therapeutic advances in medicine, nowadays many diseases are still incurable, mainly due to the lack of knowledge of the pathological biochemical pathways triggering those diseases. For this reason, it is compulsory for the scientific community to investigate and unveil the biomolecular mechanisms responsible for the development of those diseases, such as Alzheimer's disease and diabetes, which are widespread all over the world. In this scenario, it is of paramount importance to develop new analytical techniques and experimental procedures that are capable to make the above-mentioned investigations feasible. These new methods should allow easy performable analysis carried out in a label-free environment, in order to give reliable answers to specific biochemical questions. A recent paper published on Bioscience Reports by Ivancic et al. (https://doi.org/10.1042/BSR20181416) proposes a new analytical technique capable to reveal some mechanistic insights into the regulation of insulin-degrading enzyme (IDE), a protein involved in the above-mentioned diseases. IDE is a multifaceted enzyme having different and not well-defined roles in the cell, but it is primarily a proteolytic enzyme capable to degrade several different amyloidogenic substrates involved in different diseases. Moreover, many molecules are responsible for IDE activity modulation so that understanding how IDE activity is regulated represents a very challenging analytical task. The new analytical approach proposed by Ivancic et al. reports on the possibility to study IDE activity in an unbiased and label-free manner, representing a valid alternative assay for the investigation of any proteases degradative activity. PMID- 30401733 TI - Long-read sequencing technology indicates genome-wide effects of non-B DNA on polymerization speed and error rate. AB - DNA conformation may deviate from the classical B-form in ~13% of the human genome. Non-B DNA regulates many cellular processes; however, its effects on DNA polymerization speed and accuracy have not been investigated genome-wide. Such an inquiry is critical for understanding neurological diseases and cancer genome instability. Here, we present the first simultaneous examination of DNA polymerization kinetics and errors in the human genome sequenced with Single Molecule Real-Time (SMRT) technology. We show that polymerization speed differs between non-B and B-DNA: It decelerates at G-quadruplexes and fluctuates periodically at disease-causing tandem repeats. Analyzing polymerization kinetics profiles, we predict and validate experimentally non-B DNA formation for a novel motif. We demonstrate that several non-B motifs affect sequencing errors (e.g., G quadruplexes increase error rates), and that sequencing errors are positively associated with polymerase slowdown. Finally, we show that highly divergent G4 motifs have pronounced polymerization slowdown and high sequencing error rates, suggesting similar mechanisms for sequencing errors and germline mutations. PMID- 30401734 TI - Noncoding transcription influences the replication initiation program through chromatin regulation. AB - In eukaryotic organisms, replication initiation follows a temporal program. Among the parameters that regulate this program in Saccharomyces cerevisiae, chromatin structure has been at the center of attention without considering the contribution of transcription. Here, we revisit the replication initiation program in the light of widespread genomic noncoding transcription. We find that noncoding RNA transcription termination in the vicinity of autonomously replicating sequences (ARSs) shields replication initiation from transcriptional readthrough. Consistently, high natural nascent transcription correlates with low ARS efficiency and late replication timing. High readthrough transcription is also linked to increased nucleosome occupancy and high levels of H3K36me3. Moreover, forcing ARS readthrough transcription promotes these chromatin features. Finally, replication initiation defects induced by increased transcriptional readthrough are partially rescued in the absence of H3K36 methylation. Altogether, these observations indicate that natural noncoding transcription into ARSs influences replication initiation through chromatin regulation. PMID- 30401735 TI - Intravenous Fluids: Finding the Right Balance. PMID- 30401736 TI - Polypyrimidine tract-binding protein blocks miRNA-124 biogenesis to enforce its neuronal-specific expression in the mouse. AB - MicroRNA (miRNA)-124 is expressed in neurons, where it represses genes inhibitory for neuronal differentiation, including the RNA binding protein PTBP1. PTBP1 maintains nonneuronal splicing patterns of mRNAs that switch to neuronal isoforms upon neuronal differentiation. We find that primary (pri)-miR-124-1 is expressed in mouse embryonic stem cells where mature miR-124 is absent. PTBP1 binds to this precursor RNA upstream of the miRNA stem-loop to inhibit mature miR-124 expression in vivo and DROSHA cleavage of pri-miR-124-1 in vitro. This function for PTBP1 in repressing miR-124 biogenesis defines an additional regulatory loop in the already intricate interplay between these two molecules. Applying mathematical modeling to examine the dynamics of this regulation, we find that the pool of pri-miR-124 whose maturation is blocked by PTBP1 creates a robust and self-reinforcing transition in gene expression as PTBP1 is depleted during early neuronal differentiation. While interlocking regulatory loops are often found between miRNAs and transcriptional regulators, our results indicate that miRNA targeting of posttranscriptional regulators also reinforces developmental decisions. Notably, induction of neuronal differentiation observed upon PTBP1 knockdown likely results from direct derepression of miR-124, in addition to indirect effects previously described. PMID- 30401737 TI - Acoustic phonon lifetimes limit thermal transport in methylammonium lead iodide. AB - Hybrid organic-inorganic perovskites (HOIPs) have become an important class of semiconductors for solar cells and other optoelectronic applications. Electron phonon coupling plays a critical role in all optoelectronic devices, and although the lattice dynamics and phonon frequencies of HOIPs have been well studied, little attention has been given to phonon lifetimes. We report high-precision momentum-resolved measurements of acoustic phonon lifetimes in the hybrid perovskite methylammonium lead iodide (MAPI), using inelastic neutron spectroscopy to provide high-energy resolution and fully deuterated single crystals to reduce incoherent scattering from hydrogen. Our measurements reveal extremely short lifetimes on the order of picoseconds, corresponding to nanometer mean free paths and demonstrating that acoustic phonons are unable to dissipate heat efficiently. Lattice-dynamics calculations using ab initio third-order perturbation theory indicate that the short lifetimes stem from strong three phonon interactions and a high density of low-energy optical phonon modes related to the degrees of freedom of the organic cation. Such short lifetimes have significant implications for electron-phonon coupling in MAPI and other HOIPs, with direct impacts on optoelectronic devices both in the cooling of hot carriers and in the transport and recombination of band edge carriers. These findings illustrate a fundamental difference between HOIPs and conventional photovoltaic semiconductors and demonstrate the importance of understanding lattice dynamics in the effort to develop metal halide perovskite optoelectronic devices. PMID- 30401738 TI - Acyl-CoA synthetase 6 enriches the neuroprotective omega-3 fatty acid DHA in the brain. AB - Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is highly abundant in the brain and confers protection against numerous neurological diseases, yet the fundamental mechanisms regulating the enrichment of DHA in the brain remain unknown. Here, we have discovered that a member of the long-chain acyl-CoA synthetase family, Acsl6, is required for the enrichment of DHA in the brain by generating an Acsl6-deficient mouse (Acsl6-/-). Acsl6 is highly enriched in the brain and lipid profiling of Acsl6-/- tissues reveals consistent reductions in DHA-containing lipids in tissues highly abundant with Acsl6. Acsl6-/- mice demonstrate motor impairments, altered glutamate metabolism, and increased astrogliosis and microglia activation. In response to a neuroinflammatory lipopolysaccharide injection, Acsl6-/- brains show similar increases in molecular and pathological indices of astrogliosis compared with controls. These data demonstrate that Acsl6 is a key mediator of neuroprotective DHA enrichment in the brain. PMID- 30401739 TI - C4 photosynthesis and climate through the lens of optimality. AB - CO2, temperature, water availability, and light intensity were all potential selective pressures that determined the competitive advantage and expansion of the C4 photosynthetic carbon-concentrating mechanism over the last ~30 My. To tease apart how selective pressures varied along the ecological trajectory of C4 expansion and dominance, we coupled hydraulics to photosynthesis models while optimizing photosynthesis over stomatal resistance and leaf/fine-root allocation. We further examined the importance of nitrogen reallocation from the dark to the light reactions. We show here that the primary selective pressures favoring C4 dominance changed through the course of C4 evolution. The higher stomatal resistance and leaf-to-root ratios enabled by C4 led to an advantage without any initial difference in hydraulic properties. We further predict a reorganization of the hydraulic system leading to higher turgor-loss points and possibly lower hydraulic conductance. Selection on nitrogen reallocation varied with CO2 concentration. Through paleoclimate model simulations, we find that water limitation was the primary driver for a C4 advantage, with atmospheric CO2 as high as 600 ppm, thus confirming molecular-based estimates for C4 evolution in the Oligocene. Under these high-CO2 conditions, nitrogen reallocation was necessary. Low CO2 and high light, but not nitrogen reallocation, were the primary drivers for the mid- to late-Miocene global expansion of C4 We also predicted the timing and spatial distribution for origins of C4 ecological dominance. The predicted origins are broadly consistent with prior estimates, but expand upon them to include a center of origin in northwest Africa and a Miocene long origin in Australia. PMID- 30401740 TI - Reply to Rogers and Gurau: Definitions of ionic liquids and deep eutectic solvents. PMID- 30401741 TI - Is "choline and geranate" an ionic liquid or deep eutectic solvent system? PMID- 30401742 TI - Reply to Engelhardt et al.: Inclusive fitness does maintain a heritable altruism polymorphism in Tibetan ground tits. PMID- 30401743 TI - No evidence for a heritable altruism polymorphism in Tibetan ground tits. PMID- 30401745 TI - Hsp90 and Hsp70 chaperones: Collaborators in protein remodeling. AB - Heat shock protein 90 (Hsp90) and 70 (Hsp70) are two families of highly conserved ATP-dependent molecular chaperones that fold and remodel proteins. Both are important components of the cellular machinery involved in protein homeostasis and participate in nearly every cellular process. Although Hsp90 and Hsp70 each carry out some chaperone activities independently, they collaborate in other cellular remodeling reactions. In eukaryotes, both Hsp90 and Hsp70 function with numerous Hsp90 and Hsp70 co-chaperones. In contrast, bacterial Hsp90 and Hsp70 are less complex; Hsp90 acts independently of co-chaperones, and Hsp70 uses two co-chaperones. In this review, we focus on recent progress toward understanding the basic mechanisms of Hsp90-mediated protein remodeling and the collaboration between Hsp90 and Hsp70, with an emphasis on bacterial chaperones. We describe the structure and conformational dynamics of these chaperones and their interactions with each other and with client proteins. The physiological roles of Hsp90 in Escherichia coli and other bacteria are also discussed. We anticipate that the information gained from exploring the mechanism of the bacterial chaperone system will provide the groundwork for understanding the more complex eukaryotic Hsp90 system and its modulation by Hsp90 co-chaperones. PMID- 30401744 TI - Structural analysis reveals a pyruvate-binding activator site in the Agrobacterium tumefaciens ADP-glucose pyrophosphorylase. AB - The pathways for biosynthesis of glycogen in bacteria and starch in plants are evolutionarily and biochemically related. They are regulated primarily by ADP glucose pyrophosphorylase, which evolved to satisfy metabolic requirements of a particular organism. Despite the importance of these two pathways, little is known about the mechanism that controls pyrophosphorylase activity or the location of its allosteric sites. Here, we report pyruvate-bound crystal structures of ADP-glucose pyrophosphorylase from the bacterium Agrobacterium tumefaciens, identifying a previously elusive activator site for the enzyme. We found that the tetrameric enzyme binds two molecules of pyruvate in a planar conformation. Each binding site is located in a crevice between the C-terminal domains of two subunits where they stack via a distinct beta-helix region. Pyruvate interacts with the side chain of Lys-43 and with the peptide backbone of Ser-328 and Gly-329 from both subunits. These structural insights led to the design of two variants with altered regulatory properties. In one variant (K43A), the allosteric effect was absent, whereas in the other (G329D), the introduced Asp mimicked the presence of pyruvate. The latter generated an enzyme that was pre-activated and insensitive to further activation by pyruvate. Our study furnishes a deeper understanding of how glycogen biosynthesis is regulated in bacteria and the mechanism by which transgenic plants increased their starch production. These insights will facilitate rational approaches to enzyme engineering for starch production in crops of agricultural interest and will promote further study of allosteric signal transmission and molecular evolution in this important enzyme family. PMID- 30401746 TI - Regulation of Connexin32 by ephrin receptors and T-cell protein tyrosine phosphatase. AB - Gap junctions are intercellular conduits that permit the passage of ions, small metabolites, and signaling molecules between cells. Connexin32 (Cx32) is a major gap junction protein in the liver and brain. Phosphorylation is integral to regulating connexin assembly, degradation, and electrical and metabolic coupling, as well as to interactions with molecular partners. Cx32 contains two intracellular tyrosine residues, and tyrosine phosphorylation of Cx32 has been detected after activation of the epidermal growth factor receptor; however, the specific tyrosine residue and the functional implication of this phosphorylation remain unknown. To address the limited available information of Cx32 regulation by tyrosine kinases, here we used the Cx32 C-terminal (CT) domain in an in vitro kinase-screening assay, which identified ephrin (Eph) receptor family members as tyrosine kinases that phosphorylate Cx32. We found that EphB1 and EphA1 phosphorylate the Cx32CT domain residue Tyr-243. Unlike for Cx43, the tyrosine phosphorylation of the Cx32CT increased gap junction intercellular communication. We also demonstrated that T-cell protein tyrosine phosphatase dephosphorylates pTyr-243. The data presented above along with additional examples throughout the literature of gap junction regulation by kinases, indicate that one cannot extrapolate the effect of a kinase on one connexin to another. PMID- 30401747 TI - Trafficking of the human ether-a-go-go-related gene (hERG) potassium channel is regulated by the ubiquitin ligase rififylin (RFFL). AB - The QT interval is an important diagnostic feature on surface electrocardiograms because it reflects the duration of the ventricular action potential. A previous genome-wide association study has reported a significant linkage between a SNP approximately 11.7 kb downstream of the gene encoding the RING finger ubiquitin ligase rififylin (RFFL) and variability in the QT interval. This, along with results in animal studies, suggests that RFFL may have effects on cardiac repolarization. Here, we sought to determine the role of RFFL in cardiac electrophysiology. Adult rabbit cardiomyocytes with adenovirus-expressed RFFL exhibited reduced rapid delayed rectifier current (I Kr). Neonatal rabbit cardiomyocytes transduced with RFFL-expressing adenovirus exhibited reduced total expression of the potassium channel ether-a-go-go-related gene (rbERG). Using transfections of 293A cells and western blot experiments, we observed that RFFL and the core-glycosylated form of the human ether-a-go-go-related gene (hERG) potassium channel interact. Furthermore, RFFL overexpression led to increased polyubiquitination and proteasomal degradation of hERG protein and to an almost complete disappearance of I Kr, which was dependent on the intact RING domain of RFFL. Blocking the ER-associated degradation (ERAD) pathway with a dominant negative form of the ERAD core component, valosin-containing protein (VCP), in 293A cells partially abolished RFFL-mediated hERG degradation. We further substantiated the link between RFFL and ERAD by showing an interaction between RFFL and VCP in vitro We conclude that RFFL is an important regulator of voltage gated hERG potassium channel activity and therefore cardiac repolarization and that this ubiquitination-mediated regulation requires parts of the ERAD pathway. PMID- 30401748 TI - Live-cell super-resolution microscopy reveals a primary role for diffusion in polyglutamine-driven aggresome assembly. AB - The mechanisms leading to self-assembly of misfolded proteins into amyloid aggregates have been studied extensively in the test tube under well-controlled conditions. However, to what extent these processes are representative of those in the cellular environment remains unclear. Using super-resolution imaging of live cells, we show here that an amyloidogenic polyglutamine-containing protein first forms small, amorphous aggregate clusters in the cytosol, chiefly by diffusion. Dynamic interactions among these clusters limited their elongation and led to structures with a branched morphology, differing from the predominantly linear fibrils observed in vitro. Some of these clusters then assembled via active transport at the microtubule-organizing center and thereby initiated the formation of perinuclear aggresomes. Although it is widely believed that aggresome formation is entirely governed by active transport along microtubules, here we demonstrate, using a combined approach of advanced imaging and mathematical modeling, that diffusion is the principal mechanism driving aggresome expansion. We found that the increasing surface area of the expanding aggresome increases the rate of accretion due to diffusion of cytosolic aggregates and that this pathway soon dominates aggresome assembly. Our findings lead to a different view of aggresome formation than that proposed previously. We also show that aggresomes mature over time, becoming more compacted as the structure grows. The presence of large perinuclear aggregates profoundly affects the behavior and health of the cell, and our super-resolution imaging results indicate that aggresome formation and development are governed by highly dynamic processes that could be important for the design of potential therapeutic strategies. PMID- 30401749 TI - Activation of hepatocyte growth factor/MET signaling initiates oncogenic transformation and enhances tumoraggressiveness in the murine prostate. AB - Emerging evidence has shown that the hepatocyte growth factor (HGF) and its receptor, MET proto-oncogene, receptor tyrosine kinase (MET), promote cell proliferation, motility, morphogenesis, and angiogenesis. While up-regulation of MET expression has been observed in aggressive and metastatic prostate cancer, a clear understanding of MET function in prostate tumorigenesis remains elusive. Here, we developed a conditional Met transgenic mouse strain, H11Met/+:PB-Cre4, to mimic human prostate cancer cells with increased MET expression in the prostatic luminal epithelium. We found that these mice develop prostatic intraepithelial neoplasia after HGF administration. To further assess the biological role of MET in prostate cancer progression, we bred H11Met/+/PtenLoxP/LoxP:PBCre4 compound mice, in which transgenic Met expression and deletion of the tumor suppressor gene Pten occurred simultaneously only in prostatic epithelial cells. These compound mice exhibited accelerated prostate tumor formation and invasion as well as increased metastasis compared with PtenLoxP/LoxP:PB-Cre4 mice. Moreover, prostatic sarcomatoid carcinomas and lesions resembling the epithelial-to-mesenchymal transition developed in tumor lesions of the compound mice. RNA-Seq and qRT-PCR analyses revealed a robust enrichment of known tumor progression and metastasis-promoting genes in samples isolated from H11Met/+/PtenLoxP/LoxP:PB-Cre4 compound mice compared with those from PtenLoxP/LoxP:PB-Cre4 littermate controls. HGF-induced cell proliferation and migration also increased in mouse embryonic fibroblasts (MEFs) from animals with both Met transgene expression and Pten deletion compared with Pten-null MEFs. The results from these newly developed mouse models indicate a role for MET in hastening tumorigenesis and metastasis when combined with the loss of tumor suppressors. PMID- 30401750 TI - An improbable journey: Creativity helped me make the transition from art to curing malaria. AB - I was recently awarded the Alice and CC Wang Award in Molecular Parasitology for my contributions to antimalarial drug development, including laying the groundbreaking work that has led to two new molecular methods for curing malaria. This award means a great deal to me because I have spent much of my scientific career feeling like an imposter-one with the wrong sort of background and poor credentials. I am grateful for the recognition, and I am beginning to recognize that having an atypical background can be an advantage because it gives you a different perspective on a challenge. More generally, diversity in educational and cultural backgrounds is important because it can stimulate new ways of thinking and discovery. PMID- 30401753 TI - Post-Hospitalization Short-Term Oxygen Therapy: Use of a Clinical Management Pathway and Long-Term Follow-Up. AB - BACKGROUND: Home oxygen therapy is commonly prescribed for patients who remain hypoxemic at hospital discharge, although evidence supporting this practice is lacking. This study aimed to evaluate oxygen prescription and follow-up for patients who were prescribed post-discharge short-term oxygen therapy (STOT) and to assess their long-term outcome. METHODS: A retrospective audit was undertaken of subjects prescribed STOT following hospitalization at a single site in Melbourne, Australia, between January 2011 and December 2015. During the study period, a designated clinical pathway for STOT prescription and follow-up after hospital discharge was in place. Chart review was performed to collect subject demographics and comorbidities, results of oxygen assessment (arterial blood gas and 6-min walk tests) and prescription, and results at follow-up re-assessment and mortality. RESULTS: Over five 5 years, 205 subjects were prescribed STOT upon hospital discharge. Common indications for oxygen treatment were chronic lung disease (54%) and dyspnea palliation (26%). Of the 152 subjects who were discharged with non-palliative oxygen therapy, 28% did not fulfil the recommended prescribing criteria or did not have recommended assessments. Among the 118 subjects who attended for re-assessment 4 weeks after initial oxygen provision, 47 (40%) did not fulfill criteria for long-term oxygen therapy. The 1-y cumulative survival rate for the study population was 56%. CONCLUSIONS: A significant proportion of subjects who were prescribed post-discharge STOT did not fulfill the recommended prescribing criteria. The long-term prognosis for subjects who were prescribed post-discharge STOT was poor. PMID- 30401752 TI - SNARE-dependent membrane fusion initiates alpha-granule matrix decondensation in mouse platelets. AB - Platelet alpha-granule cargo release is fundamental to both hemostasis and thrombosis. Granule matrix hydration is a key regulated step in this process, yet its mechanism is poorly understood. In endothelial cells, there is evidence for 2 modes of cargo release: a jack-in-the-box mechanism of hydration-dependent protein phase transitions and an actin-driven granule constriction/extrusion mechanism. The third alternative considered is a prefusion, channel-mediated granule swelling, analogous to the membrane "ballooning" seen in procoagulant platelets. Using thrombin-stimulated platelets from a set of secretion-deficient, soluble N-ethylmaleimide factor attachment protein receptor (SNARE) mutant mice and various ultrastructural approaches, we tested predictions of these mechanisms to distinguish which best explains the alpha-granule release process. We found that the granule decondensation/hydration required for cargo expulsion was (1) blocked in fusion-protein-deficient platelets; (2) characterized by a fusion dependent transition in granule size in contrast to a preswollen intermediate; (3) determined spatially with alpha-granules located close to the plasma membrane (PM) decondensing more readily; (4) propagated from the site of granule fusion; and (5) traced, in 3-dimensional space, to individual granule fusion events at the PM or less commonly at the canalicular system. In sum, the properties of alpha-granule decondensation/matrix hydration strongly indicate that alpha granule cargo expulsion is likely by a jack-in-the-box mechanism rather than by gradual channel-regulated water influx or by a granule-constriction mechanism. These experiments, in providing a structural and mechanistic basis for cargo expulsion, should be informative in understanding the alpha-granule release reaction in the context of hemostasis and thrombosis. PMID- 30401751 TI - Insights into the genomic landscape of MYD88 wild-type Waldenstrom macroglobulinemia. AB - Activating MYD88 mutations are present in 95% of Waldenstrom macroglobulinemia (WM) patients, and trigger NF-kappaB through BTK and IRAK. The BTK inhibitor ibrutinib is active in MYD88-mutated (MYD88 MUT ) WM patients, but shows lower activity in MYD88 wild-type (MYD88 WT ) disease. MYD88 WT patients also show shorter overall survival, and increased risk of disease transformation in some series. The genomic basis for these findings remains to be clarified. We performed whole exome and transcriptome sequencing of sorted tumor samples from 18 MYD88 WT patients and compared findings with WM patients with MYD88 MUT disease. We identified somatic mutations predicted to activate NF-kappaB (TBL1XR1, PTPN13, MALT1, BCL10, NFKB2, NFKBIB, NFKBIZ, and UDRL1F), impart epigenomic dysregulation (KMT2D, KMT2C, and KDM6A), or impair DNA damage repair (TP53, ATM, and TRRAP). Predicted NF-kappaB activating mutations were downstream of BTK and IRAK, and many overlapped with somatic mutations found in diffuse large B-cell lymphoma. A distinctive transcriptional profile in MYD88 WT WM was identified, although most differentially expressed genes overlapped with MYD88 MUT WM consistent with the many clinical and morphological characteristics that are shared by these WM subgroups. Overall survival was adversely affected by mutations in DNA damage response in MYD88 WT WM patients. The findings depict genomic and transcriptional events associated with MYD88 WT WM and provide mechanistic insights for disease transformation, decreased ibrutinib activity, and novel drug approaches for this population. PMID- 30401754 TI - Effect of Noninvasive Ventilation After Unplanned Extubation. AB - BACKGROUND: Our study set out to test the effect of noninvasive ventilation (NIV) performed after unplanned extubation. METHODS: Retrospective analysis of prospectively collected data in a university-affiliated mixed ICU of 12 beds during a 5-y period (January 2013 to December 2017). Unplanned extubation was defined as the occurrence of an unplanned removal of the endotracheal tube, whether deliberate or accidental. NIV after an unplanned extubation was not protocolized and was decided by the physician in charge on an individual basis. RESULTS: A total of 121 subjects (median [25th-75th percentile] age, 62.1 [43.3 73.6] y; median [25th-75th percentile] Simplified Acute Physiology Score II, 45 [36-54]) experienced 131 unplanned extubation episodes. Re-intubation was deemed necessary in 35 subjects (28.9%). NIV was used in 24 subjects (19.8%) (prophylactic NIV, n = 10; rescue NIV, n = 14). The re-intubation rates were 25.8%, 10%, and 64.3% in the no NIV, prophylactic, and rescue NIV subgroups, respectively. The median (25th-75th percentile) time to re-intubation was longer for subjects on NIV (9.1 [3.5-49.2] vs 0.46 [0.25-1] h, P = .001). The median (25th-75th percentile) ICU length of stay and duration of mechanical ventilation were longer in the subjects who underwent NIV (14.5 [7-24.5] vs 6 [3-14] d, respectively, P = .004; and 9 [3-22] vs 3 [1-7.3] d, respectively, P = .003). CONCLUSIONS: NIV after unplanned extubation had uncertain efficacy, especially when provided as rescue management of postextubation respiratory failure. PMID- 30401755 TI - Factors Influencing Activities of Daily Living in Subjects with COPD. AB - BACKGROUND: Activities of daily living (ADL) are important for an independent life. As COPD progresses, the ability to complete ADL is usually reduced. Knowing the possible factors that influence the ability to perform ADL may allow better targeting of appropriate rehabilitation programs to increase the independence levels and/or to prevent further decreases in patients with COPD. Therefore, the aim of this study was to investigate ADL performance as measured by the London Chest Activity of Daily Living scale, which is a commonly used measure in patients with COPD. METHODS: This cross-sectional study included 44 clinically stable subjects who were not taking antibiotics and had not made any changes in their medications for at least three weeks with a COPD diagnosis based on Global Initiative for Chronic Obstructive Lung Disease. Demographic characteristics, pulmonary function, ADL measured by the London Chest Activity of Daily Living scale, functional exercise capacity via the 6-min walk distance, disease-related symptoms measured by the COPD Assessment Test, and peripheral and respiratory muscle strength were evaluated. A multiple linear regression (stepwise) analysis was used to determine the variables that have the greatest influence on ADL (ie, the London Chest Activity of Daily Living scale score). RESULTS: The London Chest Activity of Daily Living scale score had moderate correlations with the COPD Assessment Test score (r = 0.31, P = .041), maximum expiratory pressure value (r = -0.37, P = .01), 6-min walk distance (r = -0.48, P = .001), knee extensor muscle strength (r = -0.47, P = .001), handgrip strength (r = -0.44, P = .003). The 6-min walk distance, COPD Assessment Test score and maximal expiratory pressure values were significant and independent determinants of the London Chest Activity of Daily Living scale, with 40.1% of the variance in subjects with COPD. CONCLUSIONS: Functional exercise capacity, disease-related symptoms, and expiratory muscle strength have the greatest influence on ADL in the subjects with COPD. The level of independence to perform ADL can be increased by improving functional exercise capacity, reducing symptoms, and increasing expiratory muscle strength in subjects with COPD. PMID- 30401756 TI - Impact of Electronic Cigarettes on Various Organ Systems. AB - The electronic cigarette (e-cigarette) has been regarded by many as a healthier alternative to the combustible cigarette, yet there is a lack of consensus concerning the health consequences and the health benefits associated with e cigarette use. We review the research on the effects of e-cigarettes on multiple physiological systems, examine the association between e-cigarette use and combustible cigarette uptake and cessation, and highlight research necessary to build consensus. Although the levels of known toxicants and carcinogens tend to be significantly lower in e-cigarettes than in combustible cigarette smoke, toxicants in e-cigarette e-liquid and those that form as part of the vaporization process may produce adverse health consequences in their own right. Acute effects have been noted in the pulmonary, cardiovascular, and immune systems, which highlight the need for research on long-term exposure. The specific chemical constituents and the levels of those constituents that pose harm remain largely uncharacterized. In addition, the efficacy of e-cigarettes for smoking cessation has yet to be established. As the e-cigarette has evolved rapidly, so has the methodology across studies, making cross-study comparisons more difficult to synthesize. The latest generation of e-cigarette devices deliver nicotine and toxicants at higher levels than earlier devices, especially in experienced users. E-cigarettes pose a risk for nicotine exposure, dependence, and combustible cigarette uptake. E-cigarettes and their delivered toxicants appear harmful to multiple organ systems, although the current body of evidence is limited, especially in terms of long-term effects. Further research is warranted with a focus on individual devices, e-liquid constituents, user characteristics, and patterns of use. Any potential benefit of e-cigarettes for smoking cessation must be weighed against the risks. Given the potential longer-term effects, efforts to prevent e-cigarette use in youth are critical. PMID- 30401757 TI - Ventilation Efficiency and Respiratory Muscle Function at Different Levels of CPAP in Intubated Prematurely Born Infants. AB - BACKGROUND: CPAP improves respiratory function in prematurely born infants by establishing and maintaining functional residual capacity, but the level of CPAP that optimizes respiratory function has not been adequately described. We compared ventilation efficiency and respiratory muscle function at different levels of CPAP. METHODS: We studied spontaneously breathing, intubated convalescent premature infants at King's College Hospital NHS Foundation Trust and calculated the ventilation efficiency index and the respiratory muscle time constant of relaxation (tau) at the end of 3 consecutive 5-min periods at 4, 6, and 8 cm H2O of CPAP delivered in random order. RESULTS: Between February 2016 and August 2016, 38 infants with a median gestational age of 27 (interquartile range [IQR], 25-30) weeks and a median birthweight of 0.88 (IQR, 0.73-1.02) kg were studied. At a CPAP level of 6 cm H2O, the median ventilation efficiency index was higher (1.52 [IQR, 1.02-2.27]) and median tau was lower (15.6 [IQR, 10.1-21.3]) s/cm H2O] compared with the median ventilation efficiency index (0.75 [IQR, 0.56-1.03]) and median tau (23.3 [IQR, 15.4-35.2] sec/cm H2O) at CPAP of 4 cm H2O (P < .001 for both). At a CPAP level of 8 cm H2O, median ventilation efficiency index was significantly lower (1.27 [IQR, 1.04-1.91]) and median tau was not significantly different (11.2 [IQR, 8.3-18.9] s/cm H2O) compared with ventilation efficiency index and tau at CPAP of 6 cm H2O (P < .001 and P = .12, respectively). After multiple logistic regression, the level of CPAP was independently associated with the ventilation efficiency index (adjusted P < .001) and tau (adjusted P = .003). CONCLUSIONS: Increasing the level of CPAP from 4 to 6 cm H2O was associated with enhanced ventilation efficiency and respiratory muscle function in convalescent premature infants on ventilation, but there was no further benefit from increasing the pressure >6 cm H2O. PMID- 30401758 TI - Inner Workings: Hunting for microbial life throughout the solar system. PMID- 30401760 TI - Job Dekker: 2018 Edward Novitski Prize. AB - The Genetics Society of America's (GSA) Edward Novitski Prize is awarded to researchers who have solved challenging problems in genetics through experiments that demonstrate exceptional creativity and ingenuity. Job Dekker of the University of Massachusetts Medical School has been selected for the 2018 award in recognition of his innovative approach to understanding chromosome interactions and nuclear organization. Among Dekker's contributions are the development of the now-ubiquitous approach of chromosome conformation capture and the discovery of topologically associating domains. PMID- 30401761 TI - Caution, Overload: The Troubled Past of Genetic Load. PMID- 30401763 TI - Detecting Adaptation with Genome-Scale Molecule Evolutionary Analysis: An Educational Primer for Use with "RNA Interference Pathways Display High Rates of Adaptive Protein Evolution in Multiple Invertebrates". AB - Hosts and pathogens impose coevolutionary pressure on each other as pathogens strive to establish themselves and hosts seek to suppress infection. RNA interference (RNAi) is a mechanism by which cells repress viruses and transposable elements, thereby serving as a form of immune defense. Previous studies have shown that antiviral RNAi genes evolve extraordinarily quickly in the fruit fly Drosophila melanogaster, suggesting that they may adaptively coevolve with viruses and transposable elements. An article by Palmer and colleagues extends this observation to nematodes and multiple insects. Their article can be combined with this Primer to demonstrate the use of comparative genomics and molecular evolutionary analyses in the measurement of natural selection. PMID- 30401762 TI - The Drosophila Dot Chromosome: Where Genes Flourish Amidst Repeats. AB - The F element of the Drosophila karyotype (the fourth chromosome in Drosophila melanogaster) is often referred to as the "dot chromosome" because of its appearance in a metaphase chromosome spread. This chromosome is distinct from other Drosophila autosomes in possessing both a high level of repetitious sequences (in particular, remnants of transposable elements) and a gene density similar to that found in the other chromosome arms, ~80 genes distributed throughout its 1.3-Mb "long arm." The dot chromosome is notorious for its lack of recombination and is often neglected as a consequence. This and other features suggest that the F element is packaged as heterochromatin throughout. F element genes have distinct characteristics (e.g, low codon bias, and larger size due both to larger introns and an increased number of exons), but exhibit expression levels comparable to genes found in euchromatin. Mapping experiments show the presence of appropriate chromatin modifications for the formation of DNaseI hypersensitive sites and transcript initiation at the 5' ends of active genes, but, in most cases, high levels of heterochromatin proteins are observed over the body of these genes. These various features raise many interesting questions about the relationships of chromatin structures with gene and chromosome function. The apparent evolution of the F element as an autosome from an ancestral sex chromosome also raises intriguing questions. The findings argue that the F element is a unique chromosome that occupies its own space in the nucleus. Further study of the F element should provide new insights into chromosome structure and function. PMID- 30401764 TI - Sentryn and SAD Kinase Link the Guided Transport and Capture of Dense Core Vesicles in Caenorhabditis elegans. AB - Dense core vesicles (DCVs) can transmit signals by releasing neuropeptides from specialized synaptic regions called active zones. DCVs reach the active zone by motorized transport through a long axon. A reverse motor frequently interrupts progress by taking DCVs in the opposite direction. "Guided transport" refers to the mechanism by which outward movements ultimately dominate to bring DCVs to the synaptic region. After guided transport, DCVs alter their interactions with motors and enter a "captured" state. The mechanisms of guided transport and capture of DCVs are unknown. Here, we discovered two proteins that contribute to both processes in Caenorhabditis elegans SAD kinase and a novel conserved protein we named Sentryn are the first proteins found to promote DCV capture. By imaging DCVs moving in various regions of single identified neurons in living animals, we found that DCV guided transport and capture are linked through SAD kinase, Sentryn, and Liprin-alpha. These proteins act together to regulate DCV motorized transport in a region-specific manner. Between the cell body and the synaptic region, they promote forward transport. In the synaptic region, where all three proteins are highly enriched at active zones, they promote DCV pausing by inhibiting transport in both directions. These three proteins appear to be part of a special subset of active zone-enriched proteins because other active zone proteins do not share their unique functions. PMID- 30401765 TI - Sentryn Acts with a Subset of Active Zone Proteins To Optimize the Localization of Synaptic Vesicles in Caenorhabditis elegans. AB - Synaptic vesicles (SVs) transmit signals by releasing neurotransmitters from specialized synaptic regions of neurons. In the synaptic region, SVs are tightly clustered around small structures called active zones. The motor KIF1A transports SVs outward through axons until they are captured in the synaptic region. This transport must be guided in the forward direction because it is opposed by the dynein motor, which causes SVs to reverse direction multiple times en route. The core synapse stability (CSS) system contributes to both guided transport and capture of SVs. We identified Sentryn as a CSS protein that contributes to the synaptic localization of SVs in Caenorhabditis elegans Like the CSS proteins SAD Kinase and SYD-2 (Liprin-alpha), Sentryn also prevents dynein-dependent accumulation of lysosomes in dendrites in strains lacking JIP3. Genetic analysis showed that Sentryn and SAD Kinase each have at least one nonoverlapping function for the stable accumulation of SVs at synapses that, when combined with their shared functions, enables most of the functions of SYD-2 (Liprin-alpha) for capturing SVs. Also like other CSS proteins, Sentryn appears enriched at active zones and contributes to active zone structure, suggesting that it is a novel, conserved active zone protein. Sentryn is recruited to active zones by a process dependent on the active zone-enriched CSS protein SYD-2 (Liprin-alpha). Our results define a specialized group of active zone enriched proteins that can affect motorized transport throughout the neuron and that have roles in both guided transport and capture of SVs. PMID- 30401766 TI - Estimates of the Heritability of Human Longevity Are Substantially Inflated due to Assortative Mating. AB - Human life span is a phenotype that integrates many aspects of health and environment into a single ultimate quantity: the elapsed time between birth and death. Though it is widely believed that long life runs in families for genetic reasons, estimates of life span "heritability" are consistently low (~15-30%). Here, we used pedigree data from Ancestry public trees, including hundreds of millions of historical persons, to estimate the heritability of human longevity. Although "nominal heritability" estimates based on correlations among genetic relatives agreed with prior literature, the majority of that correlation was also captured by correlations among nongenetic (in-law) relatives, suggestive of highly assortative mating around life span-influencing factors (genetic and/or environmental). We used structural equation modeling to account for assortative mating, and concluded that the true heritability of human longevity for birth cohorts across the 1800s and early 1900s was well below 10%, and that it has been generally overestimated due to the effect of assortative mating. PMID- 30401768 TI - A Genome-Wide Screen Identifies Genes in Rhizosphere-Associated Pseudomonas Required to Evade Plant Defenses. AB - Pseudomonas fluorescens and related plant root ("rhizosphere")-associated species contribute to plant health by modulating defenses and facilitating nutrient uptake. To identify bacterial fitness determinants in the rhizosphere of the model plant Arabidopsis thaliana, we performed a high-throughput transposon sequencing (Tn-Seq) screen using the biocontrol and growth-promoting strain Pseudomonas sp. WCS365. The screen, which was performed in parallel on wild-type and immunocompromised Arabidopsis plants, identified 231 genes that increased fitness in the rhizosphere of wild-type plants. A subset of these genes decreased fitness in the rhizosphere of immunocompromised plants. We hypothesized that these genes might be involved in avoiding plant defenses and verified 7 Pseudomonas sp. WCS365 candidate genes by generating clean deletions. We found that two of these deletion mutants, DeltamorA (encoding a putative diguanylate cyclase/phosphodiesterase) and DeltaspuC (encoding a putrescine aminotransferase), formed enhanced biofilms and inhibited plant growth. We found that mutants DeltaspuC and DeltamorA induced pattern-triggered immunity (PTI) as measured by induction of an Arabidopsis PTI reporter and FLS2/BAK1-dependent inhibition of plant growth. We show that MorA acts as a phosphodiesterase to inhibit biofilm formation, suggesting a possible role in biofilm dispersal. We found that both putrescine and its precursor arginine promote biofilm formation that is enhanced in the DeltaspuC mutant, which cannot break down putrescine, suggesting that putrescine might serve as a signaling molecule in the rhizosphere. Collectively, this work identified novel bacterial factors required to evade plant defenses in the rhizosphere.IMPORTANCE While rhizosphere bacteria hold the potential to improve plant health and fitness, little is known about the bacterial genes required to evade host immunity. Using a model system consisting of Arabidopsis and a beneficial Pseudomonas sp. isolate, we identified bacterial genes required for both rhizosphere fitness and for evading host immune responses. This work advances our understanding of how evasion of host defenses contributes to survival in the rhizosphere. PMID- 30401769 TI - Matrix Polysaccharides and SiaD Diguanylate Cyclase Alter Community Structure and Competitiveness of Pseudomonas aeruginosa during Dual-Species Biofilm Development with Staphylococcus aureus. AB - Mixed-species biofilms display a number of emergent properties, including enhanced antimicrobial tolerance and communal metabolism. These properties may depend on interspecies relationships and the structure of the biofilm. However, the contribution of specific matrix components to emergent properties of mixed species biofilms remains poorly understood. Using a dual-species biofilm community formed by the opportunistic pathogens Pseudomonas aeruginosa and Staphylococcus aureus, we found that whilst neither Pel nor Psl polysaccharides, produced by P. aeruginosa, affect relative species abundance in mature P. aeruginosa and S. aureus biofilms, Psl production is associated with increased P. aeruginosa abundance and reduced S. aureus aggregation in the early stages of biofilm formation. Our data suggest that the competitive effect of Psl is not associated with its structural role in cross-linking the matrix and adhering to P. aeruginosa cells but is instead mediated through the activation of the diguanylate cyclase SiaD. This regulatory control was also found to be independent of the siderophore pyoverdine and Pseudomonas quinolone signal, which have previously been proposed to reduce S. aureus viability by inducing lactic acid fermentation-based growth. In contrast to the effect mediated by Psl, Pel reduced the effective crosslinking of the biofilm matrix and facilitated superdiffusivity in microcolony regions. These changes in matrix cross-linking enhance biofilm surface spreading and expansion of microcolonies in the later stages of biofilm development, improving overall dual-species biofilm growth and increasing biovolume severalfold. Thus, the biofilm matrix and regulators associated with matrix production play essential roles in mixed-species biofilm interactions.IMPORTANCE Bacteria in natural and engineered environments form biofilms that include many different species. Microorganisms rely on a number of different strategies to manage social interactions with other species and to access resources, build biofilm consortia, and optimize growth. For example, Pseudomonas aeruginosa and Staphylococcus aureus are biofilm-forming bacteria that coinfect the lungs of cystic fibrosis patients and diabetic and chronic wounds. P. aeruginosa is known to antagonize S. aureus growth. However, many of the factors responsible for mixed-species interactions and outcomes such as infections are poorly understood. Biofilm bacteria are encased in a self-produced extracellular matrix that facilitates interspecies behavior and biofilm development. In this study, we examined the poorly understood roles of the major matrix biopolymers and their regulators in mixed-species biofilm interactions and development. PMID- 30401770 TI - Members of the Genus Methylobacter Are Inferred To Account for the Majority of Aerobic Methane Oxidation in Oxic Soils from a Freshwater Wetland. AB - Microbial carbon degradation and methanogenesis in wetland soils generate a large proportion of atmospheric methane, a highly potent greenhouse gas. Despite their potential to mitigate greenhouse gas emissions, knowledge about methane-consuming methanotrophs is often limited to lower-resolution single-gene surveys that fail to capture the taxonomic and metabolic diversity of these microorganisms in soils. Here our objective was to use genome-enabled approaches to investigate methanotroph membership, distribution, and in situ activity across spatial and seasonal gradients in a freshwater wetland near Lake Erie. 16S rRNA gene analyses demonstrated that members of the methanotrophic Methylococcales were dominant, with the dominance largely driven by the relative abundance of four taxa, and enriched in oxic surface soils. Three methanotroph genomes from assembled soil metagenomes were assigned to the genus Methylobacter and represented the most abundant methanotrophs across the wetland. Paired metatranscriptomes confirmed that these Old Woman Creek (OWC) Methylobacter members accounted for nearly all the aerobic methanotrophic activity across two seasons. In addition to having the capacity to couple methane oxidation to aerobic respiration, these new genomes encoded denitrification potential that may sustain energy generation in soils with lower dissolved oxygen concentrations. We further show that Methylobacter members that were closely related to the OWC members were present in many other high-methane-emitting freshwater and soil sites, suggesting that this lineage could participate in methane consumption in analogous ecosystems. This work contributes to the growing body of research suggesting that Methylobacter may represent critical mediators of methane fluxes in freshwater saturated sediments and soils worldwide.IMPORTANCE Here we used soil metagenomics and metatranscriptomics to uncover novel members within the genus Methylobacter We denote these closely related genomes as members of the lineage OWC Methylobacter Despite the incredibly high microbial diversity in soils, here we present findings that unexpectedly showed that methane cycling was primarily mediated by a single genus for both methane production ("Candidatus Methanothrix paradoxum") and methane consumption (OWC Methylobacter). Metatranscriptomic analyses revealed that decreased methanotrophic activity rather than increased methanogenic activity possibly contributed to the greater methane emissions that we had previously observed in summer months, findings important for biogeochemical methane models. Although members of this Methylococcales order have been cultivated for decades, multi-omic approaches continue to illuminate the methanotroph phylogenetic and metabolic diversity harbored in terrestrial and marine ecosystems. PMID- 30401771 TI - Coordinated Assembly of the Bacillus anthracis Coat and Exosporium during Bacterial Spore Outer Layer Formation. AB - Bacterial spores produced by the Bacillales are composed of concentric shells, each of which contributes to spore function. Spores from all species possess a cortex and coat, but spores from many species possess additional outer layers. The outermost layer of Bacillus anthracis spores, the exosporium, is separated from the coat by a gap known as the interspace. Exosporium and interspace assembly remains largely mysterious. As a result, we have a poor understanding of the overarching mechanisms driving the assembly of one of the most ubiquitous cell types in nature. To elucidate the mechanisms directing exosporium assembly, we generated strains bearing mutations in candidate exosporium-controlling genes and analyzed the effect on exosporium formation. Biochemical and cell biological analyses argue that CotE directs the assembly of CotO into the spore and that CotO might be located at or close to the interior side of the cap. Taken together with data showing that CotE and CotO interact directly in vitro, we propose a model in which CotE and CotO are important components of a protein interaction network that connects the exosporium to the forespore during cap formation and exosporium elongation. Our data also suggest that the cap interferes with coat assembly at one pole of the spore, altering the pattern of coat deposition compared to the model organism Bacillus subtilis We propose that the difference in coat assembly patterns between these two species is due to an inherent flexibility in coat assembly, which may facilitate the evolution of spore outer layer complexity.IMPORTANCE This work dramatically improves our understanding of the assembly of the outermost layer of the B. anthracis spore, the exosporium, a layer that encases spores from many bacterial species and likely plays important roles in the spore's interactions with the environment, including host tissues. Nonetheless, the mechanisms directing exosporium assembly into a shell surrounding the spore are still very poorly understood. In this study, we clarify these mechanisms by the identification of a novel protein interaction network that directs assembly to initiate at a specific subcellular location in the developing cell. Our results further suggest that the presence or absence of an exosporium has a major impact on the assembly of other more interior spore layers, thereby potentially explaining long-noted differences in spore assembly between B. anthracis and the model organism B. subtilis. PMID- 30401772 TI - The Transferable Resistome of Produce. AB - Produce is increasingly recognized as a reservoir of human pathogens and transferable antibiotic resistance genes. This study aimed to explore methods to characterize the transferable resistome of bacteria associated with produce. Mixed salad, arugula, and cilantro purchased from supermarkets in Germany were analyzed by means of cultivation- and DNA-based methods. Before and after a nonselective enrichment step, tetracycline (TET)-resistant Escherichia coli were isolated and plasmids conferring TET resistance were captured by exogenous plasmid isolation. TET-resistant E. coli isolates, transconjugants, and total community DNA (TC-DNA) from the microbial fraction detached from leaves or after enrichment were analyzed for the presence of resistance genes, class 1 integrons, and various plasmids by real-time PCR and PCR-Southern blot hybridization. Real time PCR primers were developed for IncI and IncF plasmids. TET-resistant E. coli isolated from arugula and cilantro carried IncF, IncI1, IncN, IncHI1, IncU, and IncX1 plasmids. Three isolates from cilantro were positive for IncN plasmids and bla CTX-M-1 From mixed salad and cilantro, IncF, IncI1, and IncP-1beta plasmids were captured exogenously. Importantly, whereas direct detection of IncI and IncF plasmids in TC-DNA failed, these plasmids became detectable in DNA extracted from enrichment cultures. This confirms that cultivation-independent DNA-based methods are not always sufficiently sensitive to detect the transferable resistome in the rare microbiome. In summary, this study showed that an impressive diversity of self-transmissible multiple resistance plasmids was detected in bacteria associated with produce that is consumed raw, and exogenous capturing into E. coli suggests that they could transfer to gut bacteria as well.IMPORTANCE Produce is one of the most popular food commodities. Unfortunately, leafy greens can be a reservoir of transferable antibiotic resistance genes. We found that IncF and IncI plasmids were the most prevalent plasmid types in E. coli isolates from produce. This study highlights the importance of the rare microbiome associated with produce as a source of antibiotic resistance genes that might escape cultivation-independent detection, yet may be transferred to human pathogens or commensals. PMID- 30401774 TI - Maintenance of Mitochondrial Morphology in Cryptococcus neoformans Is Critical for Stress Resistance and Virulence. AB - Mitochondria are essential organelles that act in pathways including ATP production, beta-oxidation, and clearance of reactive oxygen species. They occur as a complex reticular network that constantly undergoes fusion and fission, mediated by dynamin-related proteins (DRPs). DRPs include Fzo1, which mediates fusion, and Dnm1, Mdv1, and Fis1, which mediate fission. Mitochondrial morphology has been implicated in virulence in multiple fungi, as with the association between virulence and increased mitochondrial fusion in Cryptococcus gattii This relationship, however, has not been studied in Cryptococcus neoformans, a related opportunistic pathogen. C. neoformans is an environmental yeast that can adapt to the human host environment, overcome the innate immune system, and eventually disseminate and cause lethal meningoencephalitis. We used gene deletion of key DRPs to study their role in mitochondrial morphology and pathogenesis of this yeast. Interestingly, increasing mitochondrial fusion did not increase resistance to oxidative stress, unlike in model yeast. Blocking mitochondrial fusion, however, yielded increased susceptibility to oxidative and nitrosative stresses as well as complete avirulence. This lack of virulence was not mediated by any effects of altered mitochondrial function on two major virulence factors, capsule and melanin. Instead, it was due to decreased survival within macrophages, which in turn was a consequence of increased susceptibility to oxidative and nitrosative stress. Supporting this conclusion, reactive oxygen species (ROS) scavengers rescued the ability of fusion mutants to survive intracellularly. These findings increase our understanding of cryptococcal biology and virulence and shed light on an important group of proteins and cellular processes in this pathogen.IMPORTANCE C. neoformans is a yeast that causes fatal brain infection in close to 200,000 people worldwide every year, mainly afflicting individuals with AIDS or others who are severely immunocompromised. One feature of this microbe that helps it cause disease is that it is able to withstand toxic molecules it encounters when host cells engulf it in their efforts to control the infection. Mitochondria are important organelles responsible for energy production and other key cellular processes. They typically exist in a complex network that changes morphology by fusing and dividing; these alterations also influence mitochondrial function. Using genetic approaches, we found that changes in mitochondrial morphology dramatically influence cryptococcal virulence. We showed that this occurs because the altered mitochondria are less able to eliminate the harmful molecules that host cells produce to kill invading microbes. These findings are important because they elucidate fundamental biology and virulence and may suggest avenues for therapy. PMID- 30401773 TI - Hypoxia Promotes Immune Evasion by Triggering beta-Glucan Masking on the Candida albicans Cell Surface via Mitochondrial and cAMP-Protein Kinase A Signaling. AB - Organisms must adapt to changes in oxygen tension if they are to exploit the energetic benefits of reducing oxygen while minimizing the potentially damaging effects of oxidation. Consequently, organisms in all eukaryotic kingdoms display robust adaptation to hypoxia (low oxygen levels). This is particularly important for fungal pathogens that colonize hypoxic niches in the host. We show that adaptation to hypoxia in the major fungal pathogen of humans Candida albicans includes changes in cell wall structure and reduced exposure, at the cell surface, of beta-glucan, a key pathogen-associated molecular pattern (PAMP). This leads to reduced phagocytosis by murine bone marrow-derived macrophages and decreased production of IL-10, RANTES, and TNF-alpha by peripheral blood mononuclear cells, suggesting that hypoxia-induced beta-glucan masking has a significant effect upon C. albicans-host interactions. We show that hypoxia induced beta-glucan masking is dependent upon both mitochondrial and cAMP-protein kinase A (PKA) signaling. The decrease in beta-glucan exposure is blocked by mutations that affect mitochondrial functionality (goa1Delta and upc2Delta) or that decrease production of hydrogen peroxide in the inner membrane space (sod1Delta). Furthermore, beta-glucan masking is enhanced by mutations that elevate mitochondrial reactive oxygen species (aox1Delta). The beta-glucan masking defects displayed by goa1Delta and upc2Delta cells are suppressed by exogenous dibutyryl-cAMP. Also, mutations that inactivate cAMP synthesis (cyr1Delta) or PKA (tpk1Delta tpk2Delta) block the masking phenotype. Our data suggest that C. albicans responds to hypoxic niches by inducing beta-glucan masking via a mitochondrial cAMP-PKA signaling pathway, thereby modulating local immune responses and promoting fungal colonization.IMPORTANCE Animal, plant, and fungal cells occupy environments that impose changes in oxygen tension. Consequently, many species have evolved mechanisms that permit robust adaptation to these changes. The fungal pathogen Candida albicans can colonize hypoxic (low oxygen) niches in its human host, such as the lower gastrointestinal tract and inflamed tissues, but to colonize its host, the fungus must also evade local immune defenses. We reveal, for the first time, a defined link between hypoxic adaptation and immune evasion in C. albicans As this pathogen adapts to hypoxia, it undergoes changes in cell wall structure that include masking of beta-glucan at its cell surface, and it becomes better able to evade phagocytosis by innate immune cells. We also define the signaling mechanisms that mediate hypoxia induced beta-glucan masking, showing that they are dependent on mitochondrial signaling and the cAMP-protein kinase pathway. Therefore, hypoxia appears to trigger immune evasion in this fungal pathogen. PMID- 30401775 TI - Leishmania Genome Dynamics during Environmental Adaptation Reveal Strain-Specific Differences in Gene Copy Number Variation, Karyotype Instability, and Telomeric Amplification. AB - Protozoan parasites of the genus Leishmania adapt to environmental change through chromosome and gene copy number variations. Only little is known about external or intrinsic factors that govern Leishmania genomic adaptation. Here, by conducting longitudinal genome analyses of 10 new Leishmania clinical isolates, we uncovered important differences in gene copy number among genetically highly related strains and revealed gain and loss of gene copies as potential drivers of long-term environmental adaptation in the field. In contrast, chromosome rather than gene amplification was associated with short-term environmental adaptation to in vitro culture. Karyotypic solutions were highly reproducible but unique for a given strain, suggesting that chromosome amplification is under positive selection and dependent on species- and strain-specific intrinsic factors. We revealed a progressive increase in read depth towards the chromosome ends for various Leishmania isolates, which may represent a nonclassical mechanism of telomere maintenance that can preserve integrity of chromosome ends during selection for fast in vitro growth. Together our data draw a complex picture of Leishmania genomic adaptation in the field and in culture, which is driven by a combination of intrinsic genetic factors that generate strain-specific phenotypic variations, which are under environmental selection and allow for fitness gain.IMPORTANCE Protozoan parasites of the genus Leishmania cause severe human and veterinary diseases worldwide, termed leishmaniases. A hallmark of Leishmania biology is its capacity to adapt to a variety of unpredictable fluctuations inside its human host, notably pharmacological interventions, thus, causing drug resistance. Here we investigated mechanisms of environmental adaptation using a comparative genomics approach by sequencing 10 new clinical isolates of the L. donovani, L. major, and L. tropica complexes that were sampled across eight distinct geographical regions. Our data provide new evidence that parasites adapt to environmental change in the field and in culture through a combination of chromosome and gene amplification that likely causes phenotypic variation and drives parasite fitness gains in response to environmental constraints. This novel form of gene expression regulation through genomic change compensates for the absence of classical transcriptional control in these early-branching eukaryotes and opens new venues for biomarker discovery. PMID- 30401777 TI - Chlamydia trachomatis Inhibits Homologous Recombination Repair of DNA Breaks by Interfering with PP2A Signaling. AB - Cervical and ovarian cancers exhibit characteristic mutational signatures that are reminiscent of mutational processes, including defective homologous recombination (HR) repair. How these mutational processes are initiated during carcinogenesis is largely unclear. Chlamydia trachomatis infections are epidemiologically associated with cervical and ovarian cancers. Previously, we showed that C. trachomatis induces DNA double-strand breaks (DSBs) but suppresses Ataxia-telangiectasia mutated (ATM) activation and cell cycle checkpoints. The mechanisms by which ATM regulation is modulated and its consequences for the repair pathway in C. trachomatis-infected cells remain unknown. Here, we found that Chlamydia bacteria interfere with the usual response of PP2A to DSBs. As a result, PP2A activity remains high, as the level of inhibitory phosphorylation at Y307 remains unchanged following C. trachomatis-induced DSBs. Protein-protein interaction analysis revealed that C. trachomatis facilitates persistent interactions of PP2A with ATM, thus suppressing ATM activation. This correlated with a remarkable lack of homologous recombination (HR) repair in C. trachomatis infected cells. Chemical inhibition of PP2A activity in infected cells released ATM from PP2A, resulting in ATM phosphorylation. Activated ATM was then recruited to DSBs and initiated downstream signaling, including phosphorylation of MRE11 and NBS1 and checkpoint kinase 2 (Chk2)-mediated activation of the G2/M cell cycle checkpoint in C. trachomatis-infected cells. Further, PP2A inhibition led to the restoration of C. trachomatis-suppressed HR DNA repair function. Taking the data together, this study revealed that C. trachomatis modulates PP2A signaling to suppress ATM activation to prevent cell cycle arrest, thus contributing to a deficient high-fidelity HR pathway and a conducive environment for mutagenesis.IMPORTANCE Chlamydia trachomatis induces DNA double-strand breaks in host cells but simultaneously inhibits proper DNA damage response and repair mechanisms. This may render host cells prone to loss of genetic integrity and transformation. Here we show that C. trachomatis prevents activation of the key DNA damage response mediator ATM by preventing the release from PP2A, leading to a complete absence of homologous recombination repair in host cells. PMID- 30401776 TI - Splicing Factor 3B Subunit 1 Interacts with HIV Tat and Plays a Role in Viral Transcription and Reactivation from Latency. AB - The main obstacle to an HIV cure is the transcriptionally inert proviruses that persist in resting CD4 T cells and other reservoirs. None of the current approaches has significantly reduced the size of the viral reservoir. Hence, alternative approaches, such as permanent blocking of viral transcription, to achieve a sustained remission, need urgent attention. To identify cellular factors that may be important for this approach, we sought for host targets that when altered could block HIV transcription and reactivation. Here, we identified splicing factor 3B subunit 1 (SF3B1) as a critical HIV dependency factor required for viral replication. SF3B1 is a splicing factor involved in directing chromatin and nascent gene transcripts to appropriate splice sites. Inhibitors of SF3B1 are currently in development for cancer and have been found to be nontoxic to normal cells compared to malignant cells. Knockdown of SF3B1 abrogated HIV replication in all cell types tested. SF3B1 interacted with viral protein Tat in vitro and in vivo Genetic or pharmacologic inhibition of SF3B1 prevented Tat-mediated HIV transcription and RNA polymerase II association with the HIV promoter. In addition, an inhibitor of SF3B1 prevented HIV reactivation from latency irrespective of the latency-reversing agent used. The data show that SF3B1 is involved in viral transcription and reactivation from latency and may serve as a therapeutic target in the HIV cure efforts.IMPORTANCE The reason why HIV cannot be cured by current therapy is because of viral persistence in resting T cells. One approach to permanent HIV remission that has received less attention is the so-called "block and lock" approach. The idea behind this approach is that the virus could be permanently disabled in patients if viral genome or surrounding chromatin could be altered to silence the virus, thus enabling patients to stop therapy. In this work, we have identified splicing factor 3B subunit 1 (SF3B1) as a potential target for this approach. SF3B1 interacts with the viral protein Tat, which is critical for viral transcription. Inhibition of SF3B1 prevents HIV transcription and reactivation from latency. Since there are preclinical inhibitors for this protein, our findings could pave the way to silence HIV transcription, potentially leading to prolonged or permanent remission. PMID- 30401778 TI - Genomic Surveillance of Enterococcus faecium Reveals Limited Sharing of Strains and Resistance Genes between Livestock and Humans in the United Kingdom. AB - Vancomycin-resistant Enterococcus faecium (VREfm) is a major cause of nosocomial infection and is categorized as high priority by the World Health Organization global priority list of antibiotic-resistant bacteria. In the past, livestock have been proposed as a putative reservoir for drug-resistant E. faecium strains that infect humans, and isolates of the same lineage have been found in both reservoirs. We undertook cross-sectional surveys to isolate E. faecium (including VREfm) from livestock farms, retail meat, and wastewater treatment plants in the United Kingdom. More than 600 isolates from these sources were sequenced, and their relatedness and antibiotic resistance genes were compared with genomes of almost 800 E. faecium isolates from patients with bloodstream infection in the United Kingdom and Ireland. E. faecium was isolated from 28/29 farms; none of these isolates were VREfm, suggesting a decrease in VREfm prevalence since the last UK livestock survey in 2003. However, VREfm was isolated from 1% to 2% of retail meat products and was ubiquitous in wastewater treatment plants. Phylogenetic comparison demonstrated that the majority of human and livestock related isolates were genetically distinct, although pig isolates from three farms were more genetically related to human isolates from 2001 to 2004 (minimum of 50 single-nucleotide polymorphisms [SNPs]). Analysis of accessory (variable) genes added further evidence for distinct niche adaptation. An analysis of acquired antibiotic resistance genes and their variants revealed limited sharing between humans and livestock. Our findings indicate that the majority of E. faecium strains infecting patients are largely distinct from those from livestock in this setting, with limited sharing of strains and resistance genes.IMPORTANCE The rise in rates of human infection caused by vancomycin-resistant Enterococcus faecium (VREfm) strains between 1988 to the 2000s in Europe was suggested to be associated with acquisition from livestock. As a result, the European Union banned the use of the glycopeptide drug avoparcin as a growth promoter in livestock feed. While some studies reported a decrease in VREfm in livestock, others reported no reduction. Here, we report the first livestock VREfm prevalence survey in the UK since 2003 and the first large-scale study using whole-genome sequencing to investigate the relationship between E. faecium strains in livestock and humans. We found a low prevalence of VREfm in retail meat and limited evidence for recent sharing of strains between livestock and humans with bloodstream infection. There was evidence for limited sharing of genes encoding antibiotic resistance between these reservoirs, a finding which requires further research. PMID- 30401780 TI - Petrobactin Protects against Oxidative Stress and Enhances Sporulation Efficiency in Bacillus anthracis Sterne. AB - Bacillus anthracis is a Gram-positive bacillus that under conditions of environmental stress, such as low nutrients, can convert from a vegetative bacillus to a highly durable spore that enables long-term survival. The sporulation process is regulated by a sequential cascade of dedicated transcription factors but requires key nutrients to complete, one of which is iron. Iron acquisition by the iron-scavenging siderophore petrobactin is required for vegetative growth of B. anthracis under iron-depleted conditions and in the host. However, the extent to which petrobactin is involved in spore formation is unknown. This work shows that efficient in vitro sporulation of B. anthracis requires petrobactin, that the petrobactin biosynthesis operon (asbA to -F) is induced prior to sporulation, and that the siderophore itself associates with spores. Petrobactin is also required for oxidative stress protection during late stage growth and for wild-type levels of sporulation in sporulation medium. Sporulation in bovine blood was found to be petrobactin dependent. Collectively, the in vitro contributions of petrobactin to sporulation as well as growth imply that petrobactin may be required for B. anthracis transmission via the spore during natural infections, in addition to its key known functions during active anthrax infections.IMPORTANCE Bacillus anthracis causes the disease anthrax, which is transmitted via its dormant, spore phase. However, conversion from bacillus to spore is a complex, energetically costly process that requires many nutrients, including iron. B. anthracis requires the siderophore petrobactin to scavenge iron from host environments. We show that, in the Sterne strain, petrobactin is required for efficient sporulation, even when ample iron is available. The petrobactin biosynthesis operon is expressed during sporulation, and petrobactin is biosynthesized during growth in high-iron sporulation medium, but instead of being exported, the petrobactin remains intracellular to protect against oxidative stress and improve sporulation. It is also required for full growth and sporulation in blood (bovine), an essential step for anthrax transmission between mammalian hosts. PMID- 30401781 TI - Evasion of Immune Surveillance in Low Oxygen Environments Enhances Candida albicans Virulence. AB - Microbial colonizers of humans have evolved to adapt to environmental cues and to sense nutrient availability. Oxygen is a constantly changing environmental parameter in different host tissues and in different types of infection. We describe how Candida albicans, an opportunistic fungal pathogen, can modulate the host response under hypoxia and anoxia. We found that high infiltration of polymorphonuclear leukocytes (PMNs) to the site of infection contributes to a low oxygen milieu in a murine subdermal abscess. A persistent hypoxic environment did not affect viability or metabolism of PMNs. Under oxygen deprivation, however, infection with C. albicans disturbed specific PMN responses. PMNs were not able to efficiently phagocytose, produce ROS, or release extracellular DNA traps. Failure to launch an adequate response was caused by C. albicans cell wall masking of beta-glucan upon exposure to low oxygen levels which hindered PAMP sensing by Dectin-1 on the surfaces of PMNs. This in turn contributed to immune evasion and enhanced fungal survival. The cell wall masking effect is prolonged by the accumulation of lactate produced by PMNs under low oxygen conditions. Finally, adaptation to oxygen deprivation increased virulence of C. albicans which we demonstrated using a Caenorhabditis elegans infection model.IMPORTANCE Successful human colonizers have evolved mechanisms to bypass immune surveillance. Infiltration of PMNs to the site of infection led to the generation of a low oxygen niche. Exposure to low oxygen levels induced fungal cell wall masking, which in turn hindered pathogen sensing and antifungal responses by PMNs. The cell wall masking effect was prolonged by increasing lactate amounts produced by neutrophil metabolism under oxygen deprivation. In an invertebrate infection model, C. albicans was able to kill infected C. elegans nematodes within 2 days under low oxygen conditions, whereas the majority of uninfected controls and infected worms under normoxic conditions survived. These results suggest that C. albicans benefited from low oxygen niches to increase virulence. The interplay of C. albicans with innate immune cells under these conditions contributed to the overall outcome of infection. Adaption to low oxygen levels was in addition beneficial for C. albicans by reducing susceptibility to selected antifungal drugs. Hence, immunomodulation of host cells under low oxygen conditions could provide a valuable approach to improve current antifungal therapies. PMID- 30401779 TI - Gut Microbial and Metabolic Responses to Salmonella enterica Serovar Typhimurium and Candida albicans. AB - The gut microbiota confers resistance to pathogens of the intestinal ecosystem, yet the dynamics of pathogen-microbiome interactions and the metabolites involved in this process remain largely unknown. Here, we use gnotobiotic mice infected with the virulent pathogen Salmonella enterica serovar Typhimurium or the opportunistic pathogen Candida albicans in combination with metagenomics and discovery metabolomics to identify changes in the community and metabolome during infection. To isolate the role of the microbiota in response to pathogens, we compared mice monocolonized with the pathogen, uninfected mice "humanized" with a synthetic human microbiome, or infected humanized mice. In Salmonella-infected mice, by 3 days into infection, microbiome community structure and function changed substantially, with a rise in Enterobacteriaceae strains and a reduction in biosynthetic gene cluster potential. In contrast, Candida-infected mice had few microbiome changes. The LC-MS metabolomic fingerprint of the cecum differed between mice monocolonized with either pathogen and humanized infected mice. Specifically, we identified an increase in glutathione disulfide, glutathione cysteine disulfide, inosine 5'-monophosphate, and hydroxybutyrylcarnitine in mice infected with Salmonella in contrast to uninfected mice and mice monocolonized with Salmonella These metabolites potentially play a role in pathogen-induced oxidative stress. These results provide insight into how the microbiota community members interact with each other and with pathogens on a metabolic level.IMPORTANCE The gut microbiota is increasingly recognized for playing a critical role in human health and disease, especially in conferring resistance to both virulent pathogens such as Salmonella, which infects 1.2 million people in the United States every year (E. Scallan, R. M. Hoekstra, F. J. Angulo, R. V. Tauxe, et al., Emerg Infect Dis 17:7-15, 2011, https://doi.org/10.3201/eid1701.P11101), and opportunistic pathogens like Candida, which causes an estimated 46,000 cases of invasive candidiasis each year in the United States (Centers for Disease Control and Prevention, Antibiotic Resistance Threats in the United States, 2013, 2013). Using a gnotobiotic mouse model, we investigate potential changes in gut microbial community structure and function during infection using metagenomics and metabolomics. We observe that changes in the community and in biosynthetic gene cluster potential occur within 3 days for the virulent Salmonella enterica serovar Typhimurium, but there are minimal changes with a poorly colonizing Candida albicans In addition, the metabolome shifts depending on infection status, including changes in glutathione metabolites in response to Salmonella infection, potentially in response to host oxidative stress. PMID- 30401783 TI - The Joys and Frustrations of Breastfeeding and Rooming-In Among Mothers With Opioid Use Disorder: A Qualitative Study. AB - OBJECTIVES: To investigate perspectives of mothers with opioid use disorder regarding breastfeeding and rooming-in during the birth hospitalization and identify facilitators and barriers. METHODS: We conducted in-depth qualitative interviews with 25 mothers with opioid use disorder 1-12 weeks after delivery. Grounded theory analysis was used until thematic saturation was reached. Findings were triangulated, with experts in the field and a subset of informants themselves, to ensure data reliability. RESULTS: Among 25 infant-mother dyads, 36% of infants required pharmacologic treatment, 72% of mothers initiated breastfeeding, and 40% continued until discharge. We identified the following themes: (1) information drives maternal feeding choice; (2) the hospital environment is both a source of support and tension for mothers exerting autonomy in the care of their infants; (3) opioid withdrawal symptoms negatively impact breastfeeding; (4) internal and external stigma negatively impact mothers' self efficacy; (5) mothers' histories of abuse and trauma affect their feeding choice and bonding; (6) mothers' recovery makes caring for their infants emotionally and logistically challenging; and (7) having an infant is a source of resilience and provides a sense of purpose for mothers on their path of recovery. CONCLUSIONS: Future interventions aimed at increasing breastfeeding and rooming-in during the birth hospitalization should focus on education regarding the benefits of breastfeeding and rooming-in, supporting mothers' autonomy in caring for their infants, minimizing stigma, and maximizing resilience. PMID- 30401782 TI - The Cellular NMD Pathway Restricts Zika Virus Infection and Is Targeted by the Viral Capsid Protein. AB - Zika virus (ZIKV) infection of neural progenitor cells (NPCs) in utero is associated with neurological disorders, such as microcephaly, but a detailed molecular understanding of ZIKV-induced pathogenesis is lacking. Here we show that in vitro ZIKV infection of human cells, including NPCs, causes disruption of the nonsense-mediated mRNA decay (NMD) pathway. NMD is a cellular mRNA surveillance mechanism that is required for normal brain size in mice. Using affinity purification-mass spectrometry, we identified multiple cellular NMD factors that bind to the viral capsid protein, including the central NMD regulator up-frameshift protein 1 (UPF1). Endogenous UPF1 interacted with the ZIKV capsid protein in coimmunoprecipitation experiments, and capsid expression posttranscriptionally downregulated UPF1 protein levels, a process that we confirmed occurs during ZIKV infection. Cellular fractionation studies show that the ZIKV capsid protein specifically targets nuclear UPF1 for degradation via the proteasome. A further decrease in UPF1 levels by RNAi significantly enhanced ZIKV infection in NPC cultures, consistent with a model in which NMD restricts ZIKV infection in the fetal brain. We propose that ZIKV, via the capsid protein, has evolved a strategy to lower UPF1 levels and dampen antiviral activities of NMD, which in turn contributes to neuropathology in vivo IMPORTANCE Zika virus (ZIKV) is a significant global health threat, as infection has been linked to serious neurological complications, including microcephaly. Using a human stem cell derived neural progenitor model system, we find that a critical cellular quality control process called the nonsense-mediated mRNA decay (NMD) pathway is disrupted during ZIKV infection. Importantly, disruption of the NMD pathway is a known cause of microcephaly and other neurological disorders. We further identify an interaction between the capsid protein of ZIKV and up-frameshift protein 1 (UPF1), the master regulator of NMD, and show that ZIKV capsid targets UPF1 for degradation. Together, these results offer a new mechanism for how ZIKV infection can cause neuropathology in the developing brain. PMID- 30401785 TI - Medical conflicts of interest: when a declaration isn't enough. PMID- 30401784 TI - A centrosomal view of CNS growth. AB - Embryonic development of the central nervous system (CNS) requires the proliferation of neural progenitor cells to be tightly regulated, allowing the formation of an organ with the right size and shape. This includes regulation of both the spatial distribution of mitosis and the mode of cell division. The centrosome, which is the main microtubule-organizing centre of animal cells, contributes to both of these processes. Here, we discuss the impact that centrosome-mediated control of cell division has on the shape of the overall growing CNS. We also review the intrinsic properties of the centrosome, both in terms of its molecular composition and its signalling capabilities, and discuss the fascinating notion that intrinsic centrosomal asymmetries in dividing neural progenitor cells are instructive for neurogenesis. Finally, we discuss the genetic links between centrosome dysfunction during development and the aetiology of microcephaly. PMID- 30401786 TI - Biased agonists of the chemokine receptor CXCR3 differentially control chemotaxis and inflammation. AB - The chemokine receptor CXCR3 plays a central role in inflammation by mediating effector/memory T cell migration in various diseases; however, drugs targeting CXCR3 and other chemokine receptors are largely ineffective in treating inflammation. Chemokines, the endogenous peptide ligands of chemokine receptors, can exhibit so-called biased agonism by selectively activating either G protein- or beta-arrestin-mediated signaling after receptor binding. Biased agonists might be used as more targeted therapeutics to differentially regulate physiological responses, such as immune cell migration. To test whether CXCR3-mediated physiological responses could be segregated by G protein- and beta-arrestin mediated signaling, we identified and characterized small-molecule biased agonists of the receptor. In a mouse model of T cell-mediated allergic contact hypersensitivity (CHS), topical application of a beta-arrestin-biased, but not a G protein-biased, agonist potentiated inflammation. T cell recruitment was increased by the beta-arrestin-biased agonist, and biopsies of patients with allergic CHS demonstrated coexpression of CXCR3 and beta-arrestin in T cells. In mouse and human T cells, the beta-arrestin-biased agonist was the most efficient at stimulating chemotaxis. Analysis of phosphorylated proteins in human lymphocytes showed that beta-arrestin-biased signaling activated the kinase Akt, which promoted T cell migration. This study demonstrates that biased agonists of CXCR3 produce distinct physiological effects, suggesting discrete roles for different endogenous CXCR3 ligands and providing evidence that biased signaling can affect the clinical utility of drugs targeting CXCR3 and other chemokine receptors. PMID- 30401787 TI - Engineering allosteric regulation in protein kinases. AB - Phosphoregulation, in which the addition of a negatively charged phosphate group modulates protein activity, enables dynamic cellular responses. To understand how new phosphoregulation might be acquired, we mutationally scanned the surface of a prototypical yeast kinase (Kss1) to identify potential regulatory sites. The data revealed a set of spatially distributed "hotspots" that might have coevolved with the active site and preferentially modulated kinase activity. By engineering simple consensus phosphorylation sites at these hotspots, we rewired cell signaling in yeast. Using the same approach with a homolog yeast mitogen activated protein kinase, Hog1, we introduced new phosphoregulation that modified its localization and signaling dynamics. Beyond revealing potential use in synthetic biology, our findings suggest that the identified hotspots contribute to the diversity of natural allosteric regulatory mechanisms in the eukaryotic kinome and, given that some are mutated in cancers, understanding these hotspots may have clinical relevance to human disease. PMID- 30401788 TI - Mammalian pigmentation is regulated by a distinct cAMP-dependent mechanism that controls melanosome pH. AB - The production of melanin increases skin pigmentation and reduces the risk of skin cancer. Melanin production depends on the pH of melanosomes, which are more acidic in lighter-skinned than in darker-skinned people. We showed that inhibition of soluble adenylyl cyclase (sAC) controlled pigmentation by increasing the pH of melanosomes both in cells and in vivo. Distinct from the canonical melanocortin 1 receptor (MC1R)-dependent cAMP pathway that controls pigmentation by altering gene expression, we found that inhibition of sAC increased pigmentation by increasing the activity of tyrosinase, the rate limiting enzyme in melanin synthesis, which is more active at basic pH. We demonstrated that the effect of sAC activity on pH and melanin production in human melanocytes depended on the skin color of the donor. Last, we identified sAC inhibitors as a new class of drugs that increase melanosome pH and pigmentation in vivo, suggesting that pharmacologic inhibition of this pathway may affect skin cancer risk or pigmentation conditions. PMID- 30401790 TI - Maternal Intellectual or Developmental Disability and Newborn Discharge to Protective Services. AB - BACKGROUND: Approximately half of women with intellectual and developmental disabilities (IDDs) lose custody of their children at some point in their child's development, but their rates of and risk factors for newborn discharge to child protective services from the birth hospitalization are relatively unknown. METHODS: We conducted a population-based study of newborns of 3845 women with IDDs and 379 834 women without IDDs in Ontario, Canada (2002-2012). We used modified Poisson regression to estimate adjusted relative risks (aRRs) and 95% confidence intervals (CIs) for discharge to child protective services directly from the birth hospitalization (1) comparing newborns of women with and without IDDs and (2) among newborns of women with IDDs according to sociodemographic, health, service, and perinatal characteristics. RESULTS: Approximately 5.7% of newborns of women with IDDs, compared with 0.2% of newborns of women without IDDs, were discharged to child protective services (aRR 8.10; 95% CI 6.51-10.09). Among newborns of women with IDDs, risk factors were maternal psychotic disorder (aRR 2.58; 95% CI 1.90-3.50), social assistance receipt (aRR 2.55; 95% CI 1.87 3.47), failure to receive an ultrasound by 20 weeks' gestation (aRR 1.76; 95% CI 1.32-2.34), and receipt of <4 prenatal visits by 36 weeks' gestation (aRR 1.71; 95% CI 1.05-2.78). CONCLUSIONS: Although women with IDDs are at risk for custody loss immediately postdelivery, certain subgroups are at higher risk than others. Women with vulnerabilities related to comorbid psychotic disorders, poverty, and inadequate prenatal care may benefit from tailored, behavior-based parenting interventions before and during pregnancy to prevent maternal-newborn separations. PMID- 30401791 TI - Filamin A modulates platelet function. PMID- 30401789 TI - Ethical Issues in Gender-Affirming Care for Youth. AB - Transgender and gender-nonconforming (TGNC) youth who suffer from gender dysphoria are at a substantially elevated risk of numerous adverse physical and psychosocial outcomes compared with their cisgender peers. Innovative treatment options used to support and affirm an individual's preferred gender identity can help resolve gender dysphoria and avoid many negative sequelae of nontreatment. Yet, despite advances in these relatively novel treatment options, which appear to be highly effective in addressing gender dysphoria and mitigating associated adverse outcomes, ethical challenges abound in ensuring that young patients receive appropriate, safe, affordable treatment and that access to this treatment is fair and equitable. Ethical considerations in gender-affirming care for TGNC youth span concerns about meeting the obligations to maximize treatment benefit to patients (beneficence), minimizing harm (nonmaleficence), supporting autonomy for pediatric patients during a time of rapid development, and addressing justice, including equitable access to care for TGNC youth. Moreover, although available data describing the use of gender-affirming treatment options are encouraging, and the risks of not treating TGNC youth with gender dysphoria are evident, little is known about the long-term effects of both hormonal and surgical interventions in this population. To support ethical decision-making about treatment options, we encourage the development of a comprehensive registry in the United States to track long-term patient outcomes. In the meantime, providers who work with TGNC youth and their families should endeavor to offer ethically sound, patient-centered, gender-affirming care based on the best currently available evidence. PMID- 30401792 TI - Do platelets LINE up for aging? PMID- 30401793 TI - Correlations of Inflammatory Factors with Intestinal Flora and Gastrointestinal Incommensurate Symptoms in Children with Asthma. AB - BACKGROUND Bronchial asthma is a common pediatric disease, the pathogenesis of which is complicated. The correlations of the levels of inflammatory factors in peripheral serum with intestinal flora and gastrointestinal incommensurate symptoms in children with asthma remain to be further elucidated. MATERIAL AND METHODS A total of 70 children diagnosed with asthma in the Pediatric Department of our hospital from February 2016 to March 2017 were enrolled as an observation group, and another 25 healthy children in the same age range were selected as a control group. The levels of inflammatory factors [C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6)], the total load of intestinal flora, and the main strains were detected among all included patients. Moreover, incommensurate symptoms of patients in the observation group were recorded and gastrointestinal symptom rating scale (GSRS) scores were calculated. The differences in indexes between the observation group and the control group were compared. RESULTS The levels of CRP, TNF-alpha, and IL-6 in peripheral serum in the observation group were significantly higher than those in the control group (p<0.05). The analysis of the correlations of inflammatory factors in peripheral serum with intestinal flora and GSRS scores showed that C reactive protein (CRP) was positively correlated with GSRS scores (r=0.696, p<0.001) and the total load of intestinal bacteria (r=0.813, p<0.001). CONCLUSIONS The inflammatory factors in peripheral serum of children with asthma are closely correlated with intestinal flora and gastrointestinal function. With the increasingly high levels of inflammatory factors in peripheral serum, the probability of intestinal flora disturbance and gastrointestinal incommensurate symptoms will be increased. PMID- 30401794 TI - The Stuck Song Syndrome: A Case of Musical Obsessions. AB - BACKGROUND Historically, clinical researchers have underestimated the prevalence and importance of musical obsessions, which are defined as intrusive, repetitive, persistent sounds or tunes, not controlled by the will, that cause clinically significant anxiety and distress. Musical obsessions have also been described as the "stuck song syndrome" and their prevalence is not clearly established, because few cases have been reported. CASE REPORT This study reports a case of a 32-year-old female with a history of musical obsessions over the course of 12 years. She suffered episodes in which she heard repetitive musical fragments in her head, such as the chorus lines or portions of known or unknown songs, that caused high levels of anxiety in her daily life. The symptoms led her to introduce compulsive behaviors such as listening to the song that matched with the obsessive song. Treatment with fluoxetine 60 mg/day for 12 weeks reduced obsessive symptoms by 60%, improving her quality of life. CONCLUSIONS This case allowed us to explore the semiological spectrum that encompasses musical imagery, in which concepts that belong to normality are involved, such as musical imagination, involuntary musical imagery, and sticky songs, and other concepts that deal with psychopathological aspects such as musical obsessions, musical hallucinations, and palinacousis. Additionally, the case showed us an atypical form of compulsion that accompanied musical obsession, in which the patient sought to complete the obsessive content with real music. Treatment with fluoxetine 60 mg/day generated a symptomatic response but not remission of symptoms. PMID- 30401795 TI - [Inequities in mental health: admissions for psychosis in public hospitals of the Comunitat Valenciana (2008-2015)]. AB - OBJECTIVE: The prevalence of mental health problems is increasing throughout the world. Certain population groups have more probability to suffer mental disorders, which may generate inequities in health. The main of this paper is analyze the differences in the frecuency of hospital admissions according to different inequities dimensions (age, sex and country of birth) of the populaion between 15 and 49 years old between 2008 and 2015 in the Comunitat Valenciana (Spain). METHODS: Transversal study based on all admissions for Diagnosis-related group "Psychosis" in public centers in the Comunitat Valenciana. Sources of information were Minimum Basic Data Set and Population Information System. Descriptive analysis of clinical and social variables was conducted, and differences among subgroups were analyzed by t-Student test for the comparison of a quantitative variable and chi2 test for the comparison of a qualitative variable, as well as the exact Wilcoxon and the Fisher test when application conditions were not satisfied. RESULTS: there were studied 23869 admissions for psychosis generated by 11265 patients. Most of these admissions were because of schizophrenia disorders (39.44%). When comparing by sex, differences in diagnosis were observed, being more frequent psychotic mood disorders in women (39.3%). There also observed differences when comparing by country of birth, being more frequent "Other non-organic psychosis" in foreign people (40.5%). Differences were found regarding mortality during admission, being higher in men (5.1% vs. 4%) and in foreign people (5.3% vs. 3.8%). CONCLUSIONS: There have been detected inequities in the frequency of psychosis admissions in the Comunitat Valenciana. These differences are observed around different dimensions such as age, gender and country of origin. PMID- 30401796 TI - Dynamic laminar rerouting of inter-areal mnemonic signal by cognitive operations in primate temporal cortex. AB - Execution of cognitive functions is orchestrated by a brain-wide network comprising multiple regions. However, it remains elusive whether the cortical laminar pattern of inter-areal interactions exhibits dynamic routings, depending on cognitive operations. We address this issue by simultaneously recording neuronal activities from area 36 and area TE of the temporal cortex while monkeys performed a visual cued-recall task. We identify dynamic laminar routing of the inter-areal interaction: during visual processing of a presented cue, spiking activities of area 36 neurons are preferentially coherent with local field potentials at the supragranular layer of area TE, while the signal from the same neurons switches to target the infragranular layer of area TE during memory retrieval. This layer-dependent signal represents the to-be-recalled object, and has an impact on the local processing at the supragranular layer in both cognitive operations. Thus, cortical layers form a key structural basis for dynamic switching of cognitive operations. PMID- 30401797 TI - Single molecule tracking reveals spatio-temporal dynamics of bacterial DNA repair centres. AB - Single-particle (molecule) tracking (SPT/SMT) is a powerful method to study dynamic processes in living bacterial cells at high spatial and temporal resolution. We have performed single-molecule imaging of early DNA double-strand break (DSB) repair events during homologous recombination in the model bacterium Bacillus subtilis. Our findings reveal that DNA repair centres arise at all sites on the chromosome and that RecN, RecO and RecJ perform fast, enzyme-like functions during detection and procession of DNA double strand breaks, respectively. Interestingly, RecN changes its diffusion behavior upon induction of DNA damage, from a largely diffusive to a DNA-scanning mode, which increases efficiency of finding all sites of DNA breaks within a frame of few seconds. RecJ continues being bound to replication forks, but also assembles at many sites on the nucleoid upon DNA damage induction. RecO shows a similar change in its mobility as RecN, and also remains bound to sites of damage for few hundred milliseconds. Like RecN, it enters the nucleoid in damaged cells. Our data show that presynaptic preparation of DSBs including loading of RecA onto ssDNA is highly rapid and dynamic, and occurs throughout the chromosome, and not only at replication forks or only at distinct sites where many breaks are processes in analogy to eukaryotic DNA repair centres. PMID- 30401799 TI - First Precambrian palaeomagnetic data from the Mawson Craton (East Antarctica) and tectonic implications. AB - A pilot palaeomagnetic study was conducted on the recently dated with in situ SHRIMP U-Pb method at 1134 +/- 9 Ma (U-Pb, zircon and baddeleyite) Bunger Hills dykes of the Mawson Craton (East Antarctica). Of the six dykes sampled, three revealed meaningful results providing the first well-dated Mesoproterozoic palaeopole at 40.5 degrees S, 150.1 degrees E (A95 = 20 degrees ) for the Mawson Craton. Discordance between this new pole and two roughly coeval poles from Dronning Maud Land and Coats Land (East Antarctica) demonstrates that these two terranes were not rigidly connected to the Mawson Craton ca. 1134 Ma. Comparison between the new pole and that of the broadly coeval Lakeview dolerite from the North Australian Craton supports the putative ~40 degrees late Neoproterozoic relative rotation between the North Australian Craton and the combined South and West Australian cratons. A mean ca. 1134 Ma pole for the Proto-Australia Craton is calculated by combining our new pole and that of the Lakeview dolerite after restoring the 40 degrees intracontinental rotation. A comparison of this mean pole with the roughly coeval Abitibi dykes pole from Laurentia confirms that the SWEAT reconstruction of Australia and Laurentia was not viable for ca. 1134 Ma. PMID- 30401798 TI - Gene set enrichment analysis of the bronchial epithelium implicates contribution of cell cycle and tissue repair processes in equine asthma. AB - Severe equine asthma is a chronic inflammatory condition of the lower airways similar to adult-onset asthma in humans. Exacerbations are characterized by bronchial and bronchiolar neutrophilic inflammation, mucus hypersecretion and airway constriction. In this study we analyzed the gene expression response of the bronchial epithelium within groups of asthmatic and non-asthmatic animals following exposure to a dusty hay challenge. After challenge we identified 2341 and 120 differentially expressed genes in asthmatic and non-asthmatic horses, respectively. Gene set enrichment analysis of changes in gene expression after challenge identified 587 and 171 significantly enriched gene sets in asthmatic and non-asthmatic horses, respectively. Gene sets in asthmatic animals pertained, but were not limited, to cell cycle, neutrophil migration and chemotaxis, wound healing, hemostasis, coagulation, regulation of body fluid levels, and the hedgehog pathway. Furthermore, transcription factor target enrichment analysis in the asthmatic group showed that transcription factor motifs with the highest enrichment scores for up-regulated genes belonged to the E2F transcription factor family. It is postulated that engagement of hedgehog and E2F pathways in asthmatic horses promotes dysregulated cell proliferation and abnormal epithelial repair. These fundamental lesions may prevent re-establishment of homeostasis and perpetuate inflammation. PMID- 30401800 TI - Controlling Fano resonances in multilayer dielectric gratings towards optical bistable devices. AB - The spectral properties of Fano resonance generated in multilayer dielectric gratings (MDGs) are reported and numerically investigated in this paper. We examine the MDG consisting of numerous identically alternative chalcogenide glass (As2S3) and silica (SiO2) multilayers with several grating widths inscribed through the structure, emphasizing quality (Q) and asymmetric (q) factors. Manipulation of Fano lineshape and its linear characteristics can be achieved by tailoring the layers' amount and grating widths so that the proposed structure can be applicable for several optical applications. Moreover, we demonstrate the switching/bistability behaviors of the MDG at Fano resonance which provide a significant switching intensity reduction compared to the established Lorentzian resonant structures. PMID- 30401802 TI - Versatile control of synaptic circuits by astrocytes: where, when and how? AB - Close structural and functional interactions of astrocytes with synapses play an important role in brain function. The repertoire of ways in which astrocytes can regulate synaptic transmission is complex so that they can both promote and dampen synaptic efficacy. Such contrasting effects raise questions regarding the determinants of these divergent astroglial functions. Recent findings provide insights into where, when and how astroglial regulation of synapses takes place by revealing major molecular and functional intrinsic heterogeneity as well as switches in astrocytes occurring during development or specific patterns of neuronal activity. Astrocytes may therefore be seen as boosters or gatekeepers of synaptic circuits depending on their intrinsic and transformative properties throughout life. PMID- 30401801 TI - Circulating FABP4 is eliminated by the kidney via glomerular filtration followed by megalin-mediated reabsorption. AB - Circulating fatty acid binding protein 4 (FABP4), secreted from adipocytes, is a potential biomarker for metabolic and cardiovascular diseases. Circulating FABP4 levels are positively associated with adiposity and adrenergic stimulation, but negatively with renal function. In this study, we addressed the issue of how the kidney regulates clearance of circulating FABP4. Tracing study revealed remarkable accumulation of 125I-labeled FABP4 in the kidney. Exogenous FABP4 was exclusively detected in the apical membrane of proximal tubule epithelial cells (PTECs). Bilateral nephrectomy resulted in marked elevation of circulating FABP4 levels. Accelerated lipolysis by beta-3 adrenergic stimulation led to a marked elevation in circulating FABP4 in mice with severe renal dysfunction. Megalin, an endocytic receptor expressed in PTECs, plays a major role in reabsorption of proteins filtered through glomeruli. Quartz-crystal microbalance study revealed that FABP4 binds to megalin. In kidney-specific megalin knockout mice, a large amount of FABP4 was excreted in urine while circulating FABP4 levels were significantly reduced. Our data suggest that circulating FABP4 is processed by the kidney via the glomerular filtration followed by megalin-mediated reabsorption. Thus, it is likely that circulating FABP4 levels are determined mainly by balance between secretion rate of FABP4 from adipocytes and clearance rate of the kidney. PMID- 30401803 TI - Roll-to-roll fabrication of touch-responsive cellulose photonic laminates. AB - Hydroxypropyl-cellulose (HPC), a derivative of naturally abundant cellulose, can self-assemble into helical nanostructures that lead to striking colouration from Bragg reflections. The helical periodicity is very sensitive to pressure, rendering HPC a responsive photonic material. Recent advances in elucidating these HPC mechano-chromic properties have so-far delivered few real-world applications, which require both up-scaling fabrication and digital translation of their colour changes. Here we present roll-to-roll manufactured metre-scale HPC laminates using continuous coating and encapsulation. We quantify the pressure response of the encapsulated HPC using optical analyses of the pressure induced hue change as perceived by the human eye and digital imaging. Finally, we show the ability to capture real-time pressure distributions and temporal evolution of a human foot-print on our HPC laminates. This is the first demonstration of a large area and cost-effective method for fabricating HPC stimuli-responsive photonic films, which can generate pressure maps that can be read out with standard cameras. PMID- 30401805 TI - Conversion of an amide to a high-energy thioester by Staphylococcus aureus sortase A is powered by variable binding affinity for calcium. AB - Thioesters are key intermediates in biology, which often are generated from less energy-rich amide precursors. Staphylococcus aureus sortase A (SrtA) is an enzyme widely used in biotechnology for peptide ligation. The reaction proceeds in two steps, where the first step involves the conversion of an amide bond of substrate peptide into a thioester intermediate with the enzyme. Here we show that the free energy required for this step is matched by an about 30-fold increase in binding affinity of a calcium ion at the calcium binding site of SrtA, which is remote from the thioester bond. The magnitude of this allosteric effect highlights the importance of calcium for the activity of SrtA. The increase in calcium binding affinity upon binding of substrate not only achieves catalytic formation of an energy-rich intermediate in the absence of nucleotide triphosphates or any tight non-covalent enzyme-substrate interactions, but is also accompanied by accumulation of the labile thioester intermediate, which makes it directly observable in nuclear magnetic resonance (NMR) spectra. PMID- 30401804 TI - VGF nerve growth factor inducible is involved in retinal ganglion cells death induced by optic nerve crush. AB - VGF nerve growth factor inducible (VGF) is a polypeptide that is induced by neurotrophic factors and is involved in neurite growth and neuroprotection. The mRNA of the Vgf gene has been detected in the adult rat retina, however the roles played by VGF in the retina are still undetermined. Thus, the purpose of this study was to determine the effects of VGF on the retinal ganglion cells (RGCs) of mice in the optic nerve crush (ONC) model, rat-derived primary cultured RGCs and human induced pluripotent stem cells (iPSCs)-derived RGCs. The mRNA and protein of Vgf were upregulated after the ONC. Immunostaining showed that the VGF was located in glial cells including Muller glia and astrocytes but not in the retinal neurons and their axons. AQEE-30, a VGF peptide, suppressed the loss of RGCs induced by the ONC, and it increased survival rat-derived RGCs and promoted the outgrowth of neurites of rat and human iPSCs derived RGCs in vitro. These findings indicate that VGF plays important roles in neuronal degeneration and has protective effects against the ONC on RGCs. Thus, VGF should be considered as a treatment of RGCs degeneration. PMID- 30401807 TI - Learning from history. AB - The ways historians assemble primary material from which to learn how industry has failed to protect workers and the environment is changing dramatically. Increasingly, historians focus concern on the evolution of the internet and the demise of paper records. The authors of "Monsanto, PCBs," and the Creation of a "World-Wide Ecological Problem" (2018) are also founders of ToxicDocs.org. This web-based resource provides an entirely new degree of transparency. Readers of their article may look at any document they cite by clicking on the reference. Those with or without expertise in science can now judge these authors' analysis, and much more: entertain new lines of inquiry, ask new questions, obtain new insights, and publish well-documented pieces that offer new knowledge and insight to enrich our understanding, not only of the PCB story, but also industry's general behavior when using or marketing toxic substances. PMID- 30401806 TI - In Silico Study Reveals How E64 Approaches, Binds to, and Inhibits Falcipain-2 of Plasmodium falciparum that Causes Malaria in Humans. AB - Plasmodium falciparum malaria, which degrades haemoglobin through falcipain-2 (FP2), is a serious disease killing 445 thousand people annually. Since the P. falciparum's survival in humans depends on its ability to degrade human's haemoglobin, stoppage or hindrance of FP2 has antimalarial effects. Therefore, we studied the atomic details of how E64 approaches, binds to, and inhibits FP2. We found that E64 (1) gradually approaches FP2 by first interacting with FP2's D170 and Q171 or N81, N77, and K76; (2) binds FP2 tightly (DeltaGbinding = -12.2 +/- 1.1 kJ/mol); and (3) persistently blocks access to FP2's catalytic residues regardless of whether or not E64 has already been able to form a covalent bond with FP2's C42. Furthermore, the results suggest that S41, D234, D170, N38, N173, and L172 (which are located in or near the FP2's catalytic site's binding pocket) contribute the most towards the favourable binding of E64 to FP2. Their in silico mutations adversely affect E64-FP2 binding affinity with D234L/A, N173L/A, W43F/A, D234L/A, H174F/A, and N38L/A having the most significant adverse effects on E64-FP2 binding and interactions. The findings presented in this article, which has antimalarial implications, suggest that hydrogen bonding and electrostatic interactions play important roles in E64-FP2 binding, and that a potential FP2-blocking E64-based/E64-like antimalarial drug should be capable of being both hydrogen-bond donor and acceptor, and/or have the ability to favourably interact with polar amino acids (such as S41, S149, N38, N173, N77, Q171) and with charged amino acids (such as D234, D170, H174) of FP2. The abilities to favourably interact with ASN, ASP, and SER appears to be important characteristics that such potential drug should have. PMID- 30401808 TI - Monsanto, PCBs, and the creation of a "world-wide ecological problem". AB - For the past three decades, we have written on the history of occupational and environmental health, authoring books and articles on lead poisoning, silicosis, asbestosis, and angiosarcoma of the liver, among other diseases. One book, Deceit and Denial, focused specifically on the chemical and lead industries. Because of the rarity of historians who study this history, we have been asked to testify on behalf of workers who allege harm from these industrial materials and by state, county, and local governments who seek redress for environmental damages and funds to prevent future harm to children. In about 2010, we began testifying in law suits brought by individuals who claimed that they had suffered from cancers, specifically non-Hodgkin's lymphoma, because of polychlorinated biphenyls (PCBs) in their bodies. At that time, we wrote a Report to the Court about industry knowledge of the dangers of PCBs to workers and the environment. More recently, we have been approached by attorneys representing government agencies on the West Coast of the United States which are seeking funds to abate PCB pollution in their ports, bays, and waterways. The focus of these lawsuits is the Monsanto Corporation, the sole producer of PCBs in the United States from the 1930s through 1977. Through these law suits, an enormous trove of previously private Monsanto reports, papers, memos, letters, and studies have been made available to us and this paper is the result of our examination of these hundreds of thousands of pages. The documents from this collection (with the exception of privileged materials that Monsanto has not made public, and upon which we have not relied) are available on www.ToxicDocs.org , the website we have developed with Professor Merlin Chowkwanyun of Columbia's Mailman School of Public Health. (Almost all of the references that are from this collection can be accessed by readers by clicking on the reference hyperlink.) This monograph is adapted from a report to the court that was originally produced for litigation on behalf of plaintiffs in PCB lawsuits. We are grateful to the Journal of Public Health Policy for publishing this detailed examination of these documents and we hope it will stimulate further research into this important, and now public, archive of industry records. PMID- 30401810 TI - Publisher Correction: Principles of nucleosome organization revealed by single cell micrococcal nuclease sequencing. AB - Change history: In Fig. 1c of this Letter, the two graphs were duplicates. The right panel of Fig. 1c has been corrected online. PMID- 30401809 TI - Applicability of Dynamic Energy Budget (DEB) models across steep environmental gradients. AB - Robust ecological forecasting requires accurate predictions of physiological responses to environmental drivers. Energy budget models facilitate this by mechanistically linking biology to abiotic drivers, but are usually ground truthed under relatively stable physical conditions, omitting temporal/spatial environmental variability. Dynamic Energy Budget (DEB) theory is a powerful framework capable of linking individual fitness to environmental drivers and we tested its ability to accommodate variability by examining model predictions across the rocky shore, a steep ecotone characterized by wide fluctuations in temperature and food availability. We parameterized DEB models for co-existing mid/high-shore (Mytilus galloprovincialis) and mid/low-shore (Perna perna) mussels on the south coast of South Africa. First, we assumed permanently submerged conditions, and then incorporated metabolic depression under low tide conditions, using detailed data of tidal cycles, body temperature and variability in food over 12 months at three sites. Models provided good estimates of shell length for both species across the shore, but predictions of gonadosomatic index were consistently lower than observed. Model disagreement could reflect the effects of details of biology and/or difficulties in capturing environmental variability, emphasising the need to incorporate both. Our approach provides guidelines for incorporating environmental variability and long-term change into mechanistic models to improve ecological predictions. PMID- 30401811 TI - Reversal of proliferation deficits caused by chromosome 16p13.11 microduplication through targeting NFkappaB signaling: an integrated study of patient-derived neuronal precursor cells, cerebral organoids and in vivo brain imaging. AB - The molecular basis of how chromosome 16p13.11 microduplication leads to major psychiatric disorders is unknown. Here we have undertaken brain imaging of patients carrying microduplications in chromosome 16p13.11 and unaffected family controls, in parallel with iPS cell-derived cerebral organoid studies of the same patients. Patient MRI revealed reduced cortical volume, and corresponding iPSC studies showed neural precursor cell (NPC) proliferation abnormalities and reduced organoid size, with the NPCs therein displaying altered planes of cell division. Transcriptomic analyses of NPCs uncovered a deficit in the NFkappaB p65 pathway, confirmed by proteomics. Moreover, both pharmacological and genetic correction of this deficit rescued the proliferation abnormality. Thus, chromosome 16p13.11 microduplication disturbs the normal programme of NPC proliferation to reduce cortical thickness due to a correctable deficit in the NFkappaB signalling pathway. This is the first study demonstrating a biologically relevant, potentially ameliorable, signalling pathway underlying chromosome 16p13.11 microduplication syndrome in patient-derived neuronal precursor cells. PMID- 30401813 TI - Electronic chirality inversion of lanthanide complex induced by achiral molecules. AB - A novel mechanism for chiroptical activity inversion based on the electronic structure of metal complexes without Lambda- or Delta-type structure change was demonstrated spectroscopically and theoretically. To demonstrate the mechanism, a europium (Eu(III)) complex with chiral (+)-3-(trifluoroacetyl)camphor (+tfc) and achiral triphenylphosphine oxide (tppo) was prepared. The steric and electronic structures of the Eu(III) complex were adjusted by additional achiral tppo and coordinating acetone molecules, and were characterised by 1H NMR, photoluminescence, and emission lifetime measurements. The optical activity of the Eu(III) complex in solution was evaluated by circularly polarized luminescence (CPL) measurements. CPL sign inversion, which was independent of Lambda- or Delta-type structure changes from the spectroscopic viewpoint, and a drastic CPL intensity enhancement were observed depending on the external achiral molecules around Eu(III) ion. These phenomena provide the first clarification of optical activity change associated with electronic structure rather than chiral coordination structure-type (Lambda or Delta) under external environments. PMID- 30401812 TI - A bacteria-derived tail anchor localizes to peroxisomes in yeast and mammalian cells. AB - Prokaryotes can provide new genetic information to eukaryotes by horizontal gene transfer (HGT), and such transfers are likely to have been particularly consequential in the era of eukaryogenesis. Since eukaryotes are highly compartmentalized, it is worthwhile to consider the mechanisms by which newly transferred proteins might reach diverse organellar destinations. Toward this goal, we have focused our attention upon the behavior of bacteria-derived tail anchors (TAs) expressed in the eukaryote Saccharomyces cerevisiae. In this study, we report that a predicted membrane-associated domain of the Escherichia coli YgiM protein is specifically trafficked to peroxisomes in budding yeast, can be found at a pre-peroxisomal compartment (PPC) upon disruption of peroxisomal biogenesis, and can functionally replace an endogenous, peroxisome-directed TA. Furthermore, the YgiM(TA) can localize to peroxisomes in mammalian cells. Since the YgiM(TA) plays no endogenous role in peroxisomal function or assembly, this domain is likely to serve as an excellent tool allowing further illumination of the mechanisms by which TAs can travel to peroxisomes. Moreover, our findings emphasize the ease with which bacteria-derived sequences might target to organelles in eukaryotic cells following HGT, and we discuss the importance of flexible recognition of organelle targeting information during and after eukaryogenesis. PMID- 30401814 TI - Intestinal helminth infection promotes IL-5- and CD4+ T cell-dependent immunity in the lung against migrating parasites. AB - The ability of helminths to manipulate the immune system of their hosts to ensure their own survival is often credited with affecting responses to other pathogens. We undertook co-infection experiments in mice to determine how infection with the intestinal helminth Heligmosomoides polygyrus affected the parasitological, immunological and physiological outcomes of a primary infection with a distinct species of helminth; the lung migratory parasite Nippostrongylus brasiliensis. We found that migrating N. brasiliensis larvae were killed in the lungs of H. polygyrus-infected mice by a process involving IL-33-activated CD4+ T cells that released IL-5 and recruited activated eosinophils. The lung pathology normally associated with N. brasiliensis larval migration was also reduced. Importantly, lung immunity remained intact in mice cleared of prior H. polygyrus infection and also occurred during infection with another entirely enteric helminth, Trichuris muris. This study identifies a cross-mucosal immune mechanism by which intestinal helminths may protect their hosts against co-infection by a different parasite at a distal site, via circulation of activated CD4+ T cells that can be triggered to release effector cytokines and mount inflammatory responses by tissue damage associated alarmins, such as IL-33. PMID- 30401815 TI - Author Correction: Larger mammals have longer faces because of size-related constraints on skull form. AB - In Table 1 of this article, the descriptions of landmarks 14, 15, and 36 are incorrect. Landmarks 14 and 36 should read "Posterior extremity of occipital condyle along margin of foramen magnum" and landmark 15 should read "Opisthion". A correct version of Table 2 appears in the Author Correction associated with this article; the error has not been fixed in the original article. PMID- 30401817 TI - Seismic Detection of a Magma Reservoir beneath Turtle Island of Taiwan by S-Wave Shadows and Reflections. AB - Although surface geology, eruption information and clustering seismicity all suggest Turtle Island (Kueishantao) of northern Taiwan is an active volcano, there was no direct evidence to conclude that magma reservoirs exist beneath it. Even less evidence is available to determine their spatial configuration. If the magma reservoirs are filled by liquids and melt, S-waves are totally reflected and leave behind a shadow, like when passing through the Earth's outer core. We detect both these S-wave shadows and strong reflections from the surface using earthquakes at different depths and azimuths. These observations identify a km scale molten-filled volume located beneath Turtle Island. The magmatic nature of the reservoir is supported by the onset of non-double-couple earthquakes with strong CLVD (Compensated Linear Vector Dipole) and ISO (Isotropic) components, which show a tensor crack compatible with some volume changes within the reservoir. Combining these results with two independent 3-D velocity models and aeromagnetic anomalies recorded in Taiwan, a partially-molten ~19% low-velocity volume is estimated in the mid-crust (13-23 km), with spatial uncertainties of ~3 km. The elongated direction approximately follows the strike of the Okinawa trough, indicating that the source of the magma reservoir might be a back-arc opening. PMID- 30401816 TI - Multi-parametric functional ultrasound imaging of cerebral hemodynamics in a cardiopulmonary resuscitation model. AB - Patient mortality at one year reaches 90% after out-of-hospital cardiac arrest and resuscitation. Temperature management is one of the main strategies proposed to improve patient outcome after resuscitation and preclinical studies have shown neuroprotective effects when hypothermia is achieved rapidly, although the underlying mechanisms have not yet been elucidated. State-of-the-art brain imaging technologies can bring new insights into the early cerebral events taking place post cardiac arrest and resuscitation. In this paper, we characterized cerebral hemodynamics in a post-cardiac arrest rabbit model using functional ultrasound imaging. Ultrasound datasets were processed to map the dynamic changes in cerebral blood flow and cerebral vascular resistivity with a 10 second repetition rate while animals underwent cardiac arrest and a cardiopulmonary resuscitation. We report that a severe transient hyperemia takes place in the brain within the first twenty minutes post resuscitation, emphasizing the need for fast post-cardiac arrest care. Furthermore, we observed that this early hyperemic event is not spatially homogeneous and that maximal cerebral hyperemia happens in the hippocampus. Finally, we show that rapid cooling induced by total liquid ventilation reduces early cerebral hyperemia, which could explain the improved neurological outcome reported in preclinical studies. PMID- 30401818 TI - beta-Glucuronidases of opportunistic bacteria are the major contributors to xenobiotic-induced toxicity in the gut. AB - Gut bacterial beta-D-glucuronidases (GUSs) catalyze the removal of glucuronic acid from liver-produced beta-D-glucuronides. These reactions can have deleterious consequences when they reverse xenobiotic metabolism. The human gut contains hundreds of GUSs of variable sequences and structures. To understand how any particular bacterial GUS(s) contributes to global GUS activity and affects human health, the individual substrate preference(s) must be known. Herein, we report that representative GUSs vary in their ability to produce various xenobiotics from their respective glucuronides. To attempt to explain the distinct substrate preference, we solved the structure of a bacterial GUS complexed with coumarin-3-beta-D-glucuronide. Comparisons of this structure with other GUS structures identified differences in loop 3 (or the alpha2-helix loop) and loop 5 at the aglycone-binding site, where differences in their conformations, hydrophobicities and flexibilities appear to underlie the distinct substrate preference(s) of the GUSs. Additional sequence, structural and functional analysis indicated that several groups of functionally related gut bacterial GUSs exist. Our results pinpoint opportunistic gut bacterial GUSs as those that cause xenobiotic-induced toxicity. We propose a structure-activity relationship that should allow both the prediction of the functional roles of GUSs and the design of selective inhibitors. PMID- 30401819 TI - Integrative bioinformatics identifies postnatal lead (Pb) exposure disrupts developmental cortical plasticity. AB - Given that thousands of chemicals released into the environment have the potential capacity to harm neurodevelopment, there is an urgent need to systematically evaluate their toxicity. Neurodevelopment is marked by critical periods of plasticity wherein neural circuits are refined by the environment to optimize behavior and function. If chemicals perturb these critical periods, neurodevelopment can be permanently altered. Focusing on 214 human neurotoxicants, we applied an integrative bioinformatics approach using publically available data to identify dozens of neurotoxicant signatures that disrupt a transcriptional signature of a critical period for brain plasticity. This identified lead (Pb) as a critical period neurotoxicant and we confirmed in vivo that Pb partially suppresses critical period plasticity at a time point analogous to exposure associated with autism. This work demonstrates the utility of a novel informatics approach to systematically identify neurotoxicants that disrupt childhood neurodevelopment and can be extended to assess other environmental chemicals. PMID- 30401821 TI - Ultrafast soliton and stretched-pulse switchable mode-locked fiber laser with hybrid structure of multimode fiber based saturable absorber. AB - We demonstrate an all-fiber mode locked laser based on hybrid structure of multimode fiber saturable absorber (SA) that can realize both conventional soliton and stretched-pulse states. Stable 16.44 MHz conventional soliton pulses are achieved by injecting 80 mW threshold pump power. By increasing the incident pump power to 420 mW, the laser evolves from soliton operation into stretched pulse mode locking state. 310 fs stretched-pulse are obtained with the same repetition rate as the soliton pulses. The center wavelength and its 3 dB spectrum bandwidth are 1603 nm and 14.2 nm, respectively. For the first time, we experimentally confirm transition between conventional soliton and stretched pulse in 1.5 MUm mode-locked fiber laser by introducing multimode optical fiber SA. Moreover, the maximum single pulse energy of nearly 1 nJ is achieved. Such all-fiber mode-locked lasers based on hybrid structure of multimode fiber are attractive for practical applications without damage and the limitation of life time. PMID- 30401820 TI - Comparing effects of CDK inhibition and E2F1/2 ablation on neuronal cell death pathways in vitro and after traumatic brain injury. AB - Traumatic brain injury (TBI) activates multiple neuronal cell death mechanisms, leading to post-traumatic neuronal loss and neurological deficits. TBI-induced cell cycle activation (CCA) in post-mitotic neurons causes regulated cell death involving cyclin-dependent kinase (CDK) activation and initiation of an E2F transcription factor-mediated pro-apoptotic program. Here we examine the mechanisms of CCA-dependent neuronal apoptosis in primary neurons in vitro and in mice exposed to controlled cortical impact (CCI). In contrast to our prior work demonstrating robust neuroprotective effects by CDK inhibitors after TBI, examination of neuronal apoptotic mechanisms in E2F1-/-/E2F2-/- or E2F2-/- transgenic mice following CCI suggests that E2F1 and/or E2F2 likely play only a modest role in neuronal cell loss after brain trauma. To elucidate more critical CCA molecular pathways involved in post-traumatic neuronal cell death, we investigated the neuroprotective effects and mechanisms of the potent CDK inhibitor CR8 in a DNA damage model of cell death in primary cortical neurons. CR8 treatment significantly reduced caspase activation and cleavage of caspase substrates, attenuating neuronal cell death. CR8 neuroprotective effects appeared to reflect inhibition of multiple pathways converging on the mitochondrion, including injury-induced elevation of pro-apoptotic Bcl-2 homology region 3 (BH3) only proteins Puma and Noxa, thereby attenuating mitochondrial permeabilization and release of cytochrome c and AIF, with reduction of both caspase-dependent and -independent apoptosis. CR8 administration also limited injury-induced deficits in mitochondrial respiration. These neuroprotective effects may be explained by CR8-mediated inhibition of key upstream injury responses, including attenuation of c-Jun phosphorylation/activation as well as inhibition of p53 transactivation of BH3-only targets. PMID- 30401822 TI - Untargeted metabolomics reveals transformation pathways and metabolic response of the earthworm Perionyx excavatus after exposure to triphenyl phosphate. AB - Triphenyl phosphate (TPHP) is one of the most highly utilized organophosphorus flame retardants, and has been frequently detected in various environmental matrices, including soil. So far, limited information is known regarding the potential toxicity of TPHP to the earthworm-soil ecosystem. We investigated the metabolism of TPHP and the perturbation of the endogenous metabolome in the earthworm, Perionyx excavatus, using gas chromatography mass spectrometry (GC-MS) and liquid chromatography quadrupole time-of-flight (LC-QTOF)-based untargeted metabolomics approach after acute exposure to TPHP for one and two days through a filter paper contact test, as well as after chronic exposure for 28 days in a soil microcosm experiment. TPHP showed low bioaccumulation potential in the earthworm-soil ecosystem at concentrations of 10 mg/kg and 50 mg/kg. Identified phase I metabolites include diphenyl phosphate, mono-hydroxylated and di hydroxylated TPHP. Two groups of phase II metabolites, thiol conjugates (including mercaptolactic acid, cysteine, cysteinylglycine, and mercaptoethanol conjugates) and glucoside conjugates (including glucoside, glucoside-phosphate, and C14H19O10P conjugates), were putatively identified. Only acute TPHP exposure caused significant perturbations of the endogenous metabolome in earthworms, featuring fluctuations in amino acids, glucose, inosine and phospholipids. These results reveal novel phase II metabolism and toxicity of TPHP in P. excavatus. PMID- 30401823 TI - Epigenetic profiling for the molecular classification of metastatic brain tumors. AB - Optimal treatment of brain metastases is often hindered by limitations in diagnostic capabilities. To meet this challenge, here we profile DNA methylomes of the three most frequent types of brain metastases: melanoma, breast, and lung cancers (n = 96). Using supervised machine learning and integration of DNA methylomes from normal, primary, and metastatic tumor specimens (n = 1860), we unravel epigenetic signatures specific to each type of metastatic brain tumor and constructed a three-step DNA methylation-based classifier (BrainMETH) that categorizes brain metastases according to the tissue of origin and therapeutically relevant subtypes. BrainMETH predictions are supported by routine histopathologic evaluation. We further characterize and validate the most predictive genomic regions in a large cohort of brain tumors (n = 165) using quantitative-methylation-specific PCR. Our study highlights the importance of brain tumor-defining epigenetic alterations, which can be utilized to further develop DNA methylation profiling as a critical tool in the histomolecular stratification of patients with brain metastases. PMID- 30401824 TI - Aggregated SOD1 causes selective death of cultured human motor neurons. AB - Most human neurodegenerative diseases share a phenotype of neuronal protein aggregation. In Amyotrophic Lateral Sclerosis (ALS), the abundant protein superoxide dismutase (SOD1) or the TAR-DNA binding protein TDP-43 can aggregate in motor neurons. Recently, numerous studies have highlighted the ability of aggregates to spread from neuron to neuron in a prion-like fashion. These studies have typically focused on the use of neuron-like cell lines or neurons that are not normally affected by the specific aggregated protein being studied. Here, we have investigated the uptake of pre-formed SOD1 aggregates by cultures containing pluripotent stem cell-derived human motor neurons. We found that all cells take up aggregates by a process resembling fluid-phase endocytosis, just as found in earlier studies. However, motor neurons, despite taking up smaller amounts of SOD1, were much more vulnerable to the accumulating aggregates. Thus, the propagation of disease pathology depends less on selective uptake than on selective response to intracellular aggregates. We further demonstrate that anti SOD1 antibodies, being considered as ALS therapeutics, can act by blocking the uptake of SOD1, but also by blocking the toxic effects of intracellular SOD1. This work demonstrates the importance of using disease relevant cells even in studying phenomena such as aggregate propagation. PMID- 30401825 TI - Similarity of introduced plant species to native ones facilitates naturalization, but differences enhance invasion success. AB - The search for traits associated with plant invasiveness has yielded contradictory results, in part because most previous studies have failed to recognize that different traits are important at different stages along the introduction-naturalization-invasion continuum. Here we show that across six different habitat types in temperate Central Europe, naturalized non-invasive species are functionally similar to native species occurring in the same habitat type, but invasive species are different as they occupy the edge of the plant functional trait space represented in each habitat. This pattern was driven mainly by the greater average height of invasive species. These results suggest that the primary determinant of successful establishment of alien species in resident plant communities is environmental filtering, which is expressed in similar trait distributions. However, to become invasive, established alien species need to be different enough to occupy novel niche space, i.e. the edge of trait space. PMID- 30401826 TI - The molecular basis of antigenic variation among A(H9N2) avian influenza viruses. AB - Avian influenza A(H9N2) viruses are an increasing threat to global poultry production and, through zoonotic infection, to human health where they are considered viruses with pandemic potential. Vaccination of poultry is a key element of disease control in endemic countries, but vaccine effectiveness is persistently challenged by the emergence of antigenic variants. Here we employed a combination of techniques to investigate the genetic basis of H9N2 antigenic variability and evaluate the role of different molecular mechanisms of immune escape. We systematically tested the influence of published H9N2 monoclonal antibody escape mutants on chicken antisera binding, determining that many have no significant effect. Substitutions introducing additional glycosylation sites were a notable exception, though these are relatively rare among circulating viruses. To identify substitutions responsible for antigenic variation in circulating viruses, we performed an integrated meta-analysis of all published H9 haemagglutinin sequences and antigenic data. We validated this statistical analysis experimentally and allocated several new residues to H9N2 antigenic sites, providing molecular markers that will help explain vaccine breakdown in the field and inform vaccine selection decisions. We find evidence for the importance of alternative mechanisms of immune escape, beyond simple modulation of epitope structure, with substitutions increasing glycosylation or receptor binding avidity, exhibiting the largest impacts on chicken antisera binding. Of these, meta-analysis indicates avidity regulation to be more relevant to the evolution of circulating viruses, suggesting that a specific focus on avidity regulation is required to fully understand the molecular basis of immune escape by influenza, and potentially other viruses. PMID- 30401827 TI - Effect of C60 fullerene nanoparticles on the diet-induced obesity in rats. AB - BACKGROUND: Obesity is a growing global health problem. Since increased oxidative stress is one of the key pathological mechanisms underpinning overweight and strongly correlates with progression of obesity-related complications we hypothesized that C60 fullerene nanoparticles, due to their strong antioxidant capacity, could be the promising therapeutic agent in the treatment of this disease. Here we investigated whether the C60 fullerenes can alleviate diet induced obesity (DIO) and metabolic impairments associated with it. METHODS: To determine the effect of C60 fullerenes on some nutritional and metabolic parameters, rats were fed either a normal diet (6.7% fat, 15.27 kJ.g-1) or a high fat diet (38.8% fat, 28.71 kJ.g-1) for 70 days and were simultaneously treated per os with pristine C60 fullerene aqueous solution (C60FAS; 0.3 mg.kg-1 every other day) since the 28th day from the start of the experiment. RESULTS: Rats fed with high fat diet had significantly increased body mass index (BMI), levels of insulin, glucose, glycosilated hemoglobin (HbA1c) and serum pro-inflammatory cytokines compared with control rats fed with low-fat chow. C60 fullerenes normalized the metabolic parameters and partially reduced BMI in DIO animals. Pro inflammatory cytokines (IL-1b, IL-12, INFgamma) were also decreased in serum of DIO rats treated with C60 fullerenes while anti-inflammatory cytokines (IL-4, IL 10) were at the control levels. High fat diet caused the increased level of oxidative stress products, and this was accompanied by decreased activity both the superoxide dismutase and catalase, whereas the administration of C60 fullerenes markedly decreased level of oxidative stress and enhanced antioxidant enzyme activities. CONCLUSION: These data indicate that water-soluble pristine C60 fullerenes reduce chronic inflammation, restore glucose homeostasis as well as positively affects on prooxidant-antioxidant homeostasis. C60 fullerenes could be represented as a promising therapeutic agent in the treatment of obesity and its related complications. PMID- 30401828 TI - A diverse suite of pharmaceuticals contaminates stream and riparian food webs. AB - A multitude of biologically active pharmaceuticals contaminate surface waters globally, yet their presence in aquatic food webs remain largely unknown. Here, we show that over 60 pharmaceutical compounds can be detected in aquatic invertebrates and riparian spiders in six streams near Melbourne, Australia. Similar concentrations in aquatic invertebrate larvae and riparian predators suggest direct trophic transfer via emerging adult insects to riparian predators that consume them. As representative vertebrate predators feeding on aquatic invertebrates, platypus and brown trout could consume some drug classes such as antidepressants at as much as one-half of a recommended therapeutic dose for humans based on their estimated prey consumption rates, yet the consequences for fish and wildlife of this chronic exposure are unknown. Overall, this work highlights the potential exposure of aquatic and riparian biota to a diverse array of pharmaceuticals, resulting in exposures to some drugs that are comparable to human dosages. PMID- 30401829 TI - Chromium-catalyzed para-selective formation of quaternary carbon centers by alkylation of benzamide derivatives. AB - Selective creation of quaternary carbon centers has been a long-standing challenge in synthetic chemistry. We report here the chromium-catalyzed, para selective formation of arylated quaternary carbon centers by alkylative reactions of benzamide derivatives with tertiary alkylmagnesium bromides at room temperature. The reaction, which was enabled by a low-cost chromium(III) salt combined with trimethylsilyl bromide, introduces a sterically bulky tertiary alkyl scaffold on the para-position of benzamide derivatives in a highly selective fashion without either isomerization of the tertiary alkyl group or formation of ortho-alkylated byproducts. Forming low-valent Cr species in situ by reaction of CrCl3 with t-BuMgBr accompanied by evolution of hydrogen can be considered, which serves as reactive species to promote the reaction. The para alkylation likely occurs via a radical-type nucleophilic substitution of imino coordination benzimidate intermediate. PMID- 30401830 TI - Onsite GTP fuelling via DYNAMO1 drives division of mitochondria and peroxisomes. AB - Mitochondria and peroxisomes proliferate by division. During division, a part of their membrane is pinched off by constriction of the ring-shaped mitochondrial division (MD) and peroxisome-dividing (POD) machinery. This constriction is mediated by a dynamin-like GTPase Dnm1 that requires a large amount of GTP as an energy source. Here, via proteomics of the isolated division machinery, we show that the 17-kDa nucleoside diphosphate kinase-like protein, dynamin-based ring motive-force organizer 1 (DYNAMO1), locally generates GTP in MD and POD machineries. DYNAMO1 is widely conserved among eukaryotes and colocalizes with Dnm1 on the division machineries. DYNAMO1 converts ATP to GTP, and disruption of its activity impairs mitochondrial and peroxisomal fissions. DYNAMO1 forms a ring shaped complex with Dnm1 and increases the magnitude of the constricting force. Our results identify DYNAMO1 as an essential component of MD and POD machineries, suggesting that local GTP generation in Dnm1-based machinery regulates motive force for membrane severance. PMID- 30401831 TI - IMP2ART systematic review of education for healthcare professionals implementing supported self-management for asthma. AB - Despite a robust evidence base for its effectiveness, implementation of supported self-management for asthma is suboptimal. Professional education is an implementation strategy with proven effectiveness, though the specific features linked with effectiveness are often unclear. We performed a systematic review of randomised controlled trials and controlled clinical trials (published from 1990 and updated to May 2017 using forward citation searching) to determine the effectiveness of professional education on asthma self-management support and identify features of effective initiatives. Primary outcomes reflected professional behaviour change (provision of asthma action plans) and patient outcomes (asthma control; unscheduled care). Data were coded using the Effective Practice and Organisation of Care Taxonomy, the Theoretical Domains Framework (TDF), and Bloom's Taxonomy and synthesised narratively. Of 15,637 articles identified, 18 (reporting 15 studies including 21 educational initiatives) met inclusion criteria. Risk of bias was high for five studies, and unclear for 10. Three of 6 initiatives improved action plan provision; 1/2 improved asthma control; and 2/7 reduced unscheduled care. Compared to ineffective initiatives, effective initiatives were more often coded as being guideline-based; involving local opinion leaders; including inter-professional education; and addressing the TDF domains 'social influences'; 'environmental context and resources'; 'behavioural regulation'; 'beliefs about consequences'; and 'social/professional role and identity'. Findings should be interpreted cautiously as many strategies were specified infrequently. However, identified features warrant further investigation as part of implementation strategies aiming to improve the provision of supported self-management for asthma. PMID- 30401832 TI - Directed Supramolecular Organization of N-BAR Proteins through Regulation of H0 Membrane Immersion Depth. AB - Many membrane remodeling events rely on the ability of curvature-generating N-BAR membrane proteins to organize into distinctive supramolecular configurations. Experiments have revealed a conformational switch in N-BAR proteins resulting in vesicular or tubular membrane shapes, with shallow membrane immersion of the H0 amphipathic helices of N-BAR proteins on vesicles but deep H0 immersion on tubes. We develop here a minimal elastic model of the local thinning of the lipid bilayer resulting from H0 immersion. Our model predicts that the observed conformational switch in N-BAR proteins produces a corresponding switch in the bilayer-mediated N-BAR interactions due to the H0 helices. In agreement with experiments, we find that bilayer-mediated H0 interactions oppose N-BAR multimerization for the shallow H0 membrane immersion depths measured on vesicles, but promote self-assembly of supramolecular N-BAR chains for the increased H0 membrane immersion depths measured on tubes. Finally, we consider the possibility that bilayer-mediated H0 interactions might contribute to the concerted structural reorganization of N-BAR proteins suggested by experiments. Our results indicate that the membrane immersion depth of amphipathic protein helices may provide a general molecular control parameter for membrane organization. PMID- 30401833 TI - Transposable Element Expression in Acute Myeloid Leukemia Transcriptome and Prognosis. AB - Over half of the human genome is comprised of transposable elements (TE). Despite large-scale studies of the transcriptome in cancer, a comprehensive look at TE expression and its relationship to various mutations or prognosis has not been performed. We characterized the expression of TE in 178 adult acute myeloid leukemia (AML) patients using transcriptome data from The Cancer Genome Atlas. We characterized mutation specific dysregulation of TE expression using a multivariate linear model. We identified distinct patterns of TE expression associated with specific mutations and transcriptional networks. Genes regulating methylation was not associated with significant change in TE expression. Using an unpenalized cox regression analysis we identified a TE expression signature that predicted prognosis in AML. We identified 14 candidate prognostic TE transcripts (TEP) that classified AML as high/low-risk and this was independent of mutation based and coding-gene expression based risk-stratification. TEP was able to predict prognosis in independent cohorts of 284 pediatric AML patients and 19 relapsed adult AML patients. This first comprehensive study of TE expression in AML demonstrates that TE expression can serve as a biomarker for prognosis in AML, and provides novel insights into the biology of AML. Studies characterizing its role in other cancers are warranted. PMID- 30401834 TI - Resting zone of the growth plate houses a unique class of skeletal stem cells. AB - Skeletal stem cells regulate bone growth and homeostasis by generating diverse cell types, including chondrocytes, osteoblasts and marrow stromal cells. The emerging concept postulates that there exists a distinct type of skeletal stem cell that is closely associated with the growth plate1-4, which is a type of cartilaginous tissue that has critical roles in bone elongation5. The resting zone maintains the growth plate by expressing parathyroid hormone-related protein (PTHrP), which interacts with Indian hedgehog (Ihh) that is released from the hypertrophic zone6-10, and provides a source of other chondrocytes11. However, the identity of skeletal stem cells and how they are maintained in the growth plate are unknown. Here we show, in a mouse model, that skeletal stem cells are formed among PTHrP-positive chondrocytes within the resting zone of the postnatal growth plate. PTHrP-positive chondrocytes expressed a panel of markers for skeletal stem and progenitor cells, and uniquely possessed the properties of skeletal stem cells in cultured conditions. Cell-lineage analysis revealed that PTHrP-positive chondrocytes in the resting zone continued to form columnar chondrocytes in the long term; these chondrocytes underwent hypertrophy, and became osteoblasts and marrow stromal cells beneath the growth plate. Transit amplifying chondrocytes in the proliferating zone-which was concertedly maintained by a forward signal from undifferentiated cells (PTHrP) and a reverse signal from hypertrophic cells (Ihh)-provided instructive cues to maintain the cell fates of PTHrP-positive chondrocytes in the resting zone. Our findings unravel a type of somatic stem cell that is initially unipotent and acquires multipotency at the post-mitotic stage, underscoring the malleable nature of the skeletal cell lineage. This system provides a model in which functionally dedicated stem cells and their niches are specified postnatally, and maintained throughout tissue growth by a tight feedback regulation system. PMID- 30401836 TI - Active superelasticity in three-dimensional epithelia of controlled shape. AB - Fundamental biological processes are carried out by curved epithelial sheets that enclose a pressurized lumen. How these sheets develop and withstand three dimensional deformations has remained unclear. Here we combine measurements of epithelial tension and shape with theoretical modelling to show that epithelial sheets are active superelastic materials. We produce arrays of epithelial domes with controlled geometry. Quantification of luminal pressure and epithelial tension reveals a tensional plateau over several-fold areal strains. These extreme strains in the tissue are accommodated by highly heterogeneous strains at a cellular level, in seeming contradiction to the measured tensional uniformity. This phenomenon is reminiscent of superelasticity, a behaviour that is generally attributed to microscopic material instabilities in metal alloys. We show that in epithelial cells this instability is triggered by a stretch-induced dilution of the actin cortex, and is rescued by the intermediate filament network. Our study reveals a type of mechanical behaviour-which we term active superelasticity-that enables epithelial sheets to sustain extreme stretching under constant tension. PMID- 30401835 TI - m6A facilitates hippocampus-dependent learning and memory through YTHDF1. AB - N6-methyladenosine (m6A), the most prevalent internal RNA modification on mammalian messenger RNAs, regulates the fates and functions of modified transcripts through m6A-specific binding proteins1-5. In the nervous system, m6A is abundant and modulates various neural functions6-11. Whereas m6A marks groups of mRNAs for coordinated degradation in various physiological processes12-15, the relevance of m6A for mRNA translation in vivo remains largely unknown. Here we show that, through its binding protein YTHDF1, m6A promotes protein translation of target transcripts in response to neuronal stimuli in the adult mouse hippocampus, thereby facilitating learning and memory. Mice with genetic deletion of Ythdf1 show learning and memory defects as well as impaired hippocampal synaptic transmission and long-term potentiation. Re-expression of YTHDF1 in the hippocampus of adult Ythdf1-knockout mice rescues the behavioural and synaptic defects, whereas hippocampus-specific acute knockdown of Ythdf1 or Mettl3, which encodes the catalytic component of the m6A methyltransferase complex, recapitulates the hippocampal deficiency. Transcriptome-wide mapping of YTHDF1 binding sites and m6A sites on hippocampal mRNAs identified key neuronal genes. Nascent protein labelling and tether reporter assays in hippocampal neurons showed that YTHDF1 enhances protein synthesis in a neuronal-stimulus-dependent manner. In summary, YTHDF1 facilitates translation of m6A-methylated neuronal mRNAs in response to neuronal stimulation, and this process contributes to learning and memory. PMID- 30401838 TI - The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ. AB - Inactivation of ARID1A and other components of the nuclear SWI/SNF protein complex occurs at very high frequencies in a variety of human malignancies, suggesting a widespread role for the SWI/SNF complex in tumour suppression1. However, the underlying mechanisms remain poorly understood. Here we show that ARID1A-containing SWI/SNF complex (ARID1A-SWI/SNF) operates as an inhibitor of the pro-oncogenic transcriptional coactivators YAP and TAZ2. Using a combination of gain- and loss-of-function approaches in several cellular contexts, we show that YAP/TAZ are necessary to induce the effects of the inactivation of the SWI/SNF complex, such as cell proliferation, acquisition of stem cell-like traits and liver tumorigenesis. We found that YAP/TAZ form a complex with SWI/SNF; this interaction is mediated by ARID1A and is alternative to the association of YAP/TAZ with the DNA-binding platform TEAD. Cellular mechanotransduction regulates the association between ARID1A-SWI/SNF and YAP/TAZ. The inhibitory interaction of ARID1A-SWI/SNF and YAP/TAZ is predominant in cells that experience low mechanical signalling, in which loss of ARID1A rescues the association between YAP/TAZ and TEAD. At high mechanical stress, nuclear F-actin binds to ARID1A-SWI/SNF, thereby preventing the formation of the ARID1A-SWI/SNF-YAP/TAZ complex, in favour of an association between TEAD and YAP/TAZ. We propose that a dual requirement must be met to fully enable the YAP/TAZ responses: promotion of nuclear accumulation of YAP/TAZ, for example, by loss of Hippo signalling, and inhibition of ARID1A-SWI/SNF, which can occur either through genetic inactivation or because of increased cell mechanics. This study offers a molecular framework in which mechanical signals that emerge at the tissue level together with genetic lesions activate YAP/TAZ to induce cell plasticity and tumorigenesis. PMID- 30401837 TI - Cryo-EM reveals two distinct serotonin-bound conformations of full-length 5-HT3A receptor. AB - The 5-HT3A serotonin receptor1, a cationic pentameric ligand-gated ion channel (pLGIC), is the clinical target for management of nausea and vomiting associated with radiation and chemotherapies2. Upon binding, serotonin induces a global conformational change that encompasses the ligand-binding extracellular domain (ECD), the transmembrane domain (TMD) and the intracellular domain (ICD), the molecular details of which are unclear. Here we present two serotonin-bound structures of the full-length 5-HT3A receptor in distinct conformations at 3.32 A and 3.89 A resolution that reveal the mechanism underlying channel activation. In comparison to the apo 5-HT3A receptor, serotonin-bound states underwent a large twisting motion in the ECD and TMD, leading to the opening of a 165 A permeation pathway. Notably, this motion results in the creation of lateral portals for ion permeation at the interface of the TMD and ICD. Combined with molecular dynamics simulations, these structures provide novel insights into conformational coupling across domains and functional modulation. PMID- 30401839 TI - Conformational transitions of the serotonin 5-HT3 receptor. AB - The serotonin 5-HT3 receptor is a pentameric ligand-gated ion channel (pLGIC). It belongs to a large family of receptors that function as allosteric signal transducers across the plasma membrane1,2; upon binding of neurotransmitter molecules to extracellular sites, the receptors undergo complex conformational transitions that result in transient opening of a pore permeable to ions. 5-HT3 receptors are therapeutic targets for emesis and nausea, irritable bowel syndrome and depression3. In spite of several reported pLGIC structures4-8, no clear unifying view has emerged on the conformational transitions involved in channel gating. Here we report four cryo-electron microscopy structures of the full length mouse 5-HT3 receptor in complex with the anti-emetic drug tropisetron, with serotonin, and with serotonin and a positive allosteric modulator, at resolutions ranging from 3.2 A to 4.5 A. The tropisetron-bound structure resembles those obtained with an inhibitory nanobody5 or without ligand9. The other structures include an 'open' state and two ligand-bound states. We present computational insights into the dynamics of the structures, their pore hydration and free-energy profiles, and characterize movements at the gate level and cation accessibility in the pore. Together, these data deepen our understanding of the gating mechanism of pLGICs and capture ligand binding in unprecedented detail. PMID- 30401840 TI - Slot machine jingles encourage gamblers to raise the stakes. PMID- 30401842 TI - Embattled Thirty Meter Telescope scores big win in Hawaii's highest court. PMID- 30401841 TI - A once-lush country on the verge of total deforestation. PMID- 30401843 TI - Machine learning spots natural selection at work in human genome. PMID- 30401844 TI - Life in a distant land triggers upheaval in immigrants' microbiomes. PMID- 30401845 TI - Randy pandas utter come-hither bleats. PMID- 30401846 TI - Humans indulged a taste for chocolate a millennium earlier than realized. PMID- 30401847 TI - Holy Cow! Astronomers agog at mysterious new supernova. PMID- 30401848 TI - South Africa's invasive species guzzle precious water and cost US$450 million a year. PMID- 30401849 TI - Dark space cloud caught donning halo of hydrogen molecules. PMID- 30401850 TI - Argentina's mega-storms attract army of meteorologists. PMID- 30401851 TI - US Supreme Court allows historic kids' climate lawsuit to go forward. PMID- 30401852 TI - Coral scientists decry loss of funding for leading Australian reef institute. PMID- 30401853 TI - Swarm of microscopic corkscrews speeds through the eyeball. PMID- 30401854 TI - Cell parts to complex processes, from the bottom up. PMID- 30401856 TI - How to design a winning fellowship proposal. PMID- 30401855 TI - Which biological systems should be engineered? PMID- 30401857 TI - Lessons from the Ebola front lines. PMID- 30401858 TI - What I learnt pulling a straw out of a turtle's nose. PMID- 30401859 TI - Life on Earth to have its DNA analysed in the name of conservation. PMID- 30401860 TI - Why the Bank of England should put a female scientist on its next L50 note. PMID- 30401861 TI - Biomarkers for checkpoint blockade. PMID- 30401863 TI - Human skeletal stem cells identified. PMID- 30401862 TI - A vaccine for tuberculosis. PMID- 30401864 TI - Personalized tracking of exposure to airborne organisms and chemicals. PMID- 30401865 TI - Analyzing the drug overdose epidemic in the United States. PMID- 30401866 TI - Confronting conflict of interest. PMID- 30401867 TI - Is earlier better for melanoma checkpoint blockade? AB - A neoadjuvant approach relying on the administration of combined anti-CTLA-4-anti PD-1 treatment before lymph node surgery is evaluated in two phase 1 trials. Encouraging clinical, pathological and immunological responses to neoadjuvant therapy were observed, suggesting that this concept warrants further exploration; however, any future approach must address the unacceptably high toxicity of the regimens evaluated in these trials. PMID- 30401868 TI - A stratified approach to tuberculosis treatment. PMID- 30401869 TI - Rules of engagement in the gut microbiome. PMID- 30401870 TI - Estimating the risk of Dengue, Chikungunya and Zika outbreaks in a large European city. AB - Outbreaks of arbovirus infections vectored by invasive Aedes albopictus have already occurred and are predicted to become increasingly frequent in Southern Europe. We present a probabilistic model to assess risk of arbovirus outbreaks based on incident cases worldwide, on the probability of arrival of infected travelers, and on the abundance of the vector species. Our results show a significant risk of Chikungunya outbreak in Rome from mid June to October in simulations with high human biting rates (i.e. when >=50% of the population is bitten every day). The outbreak risk is predicted to be highest for Chikungunya and null for Zika. Simulated increase of incident cases in selected endemic countries has no major impact on the outbreak risk. The model correctly estimated the number of imported cases and can be easily adapted to other urban areas where Ae. albopictus is the only potential vector present. PMID- 30401872 TI - Publisher Correction: Diverse populations of local interneurons integrate into the Drosophila adult olfactory circuit. AB - The original version of this Article contained errors in Figs. 4 and 6. In Fig. 4, panel a, text labels UAS-FLP and LexAop2>stop>myr::smGdP-HA were shifted upwards during typesetting of the figure, and in Fig. 6, panel h, the number 15 was incorrectly placed on the heat map scale. These have now been corrected in both the PDF and HTML versions of the Article. PMID- 30401871 TI - Integration of visual and whisker signals in rat superior colliculus. AB - Multisensory integration is a process by which signals from different sensory modalities are combined to facilitate detection and localization of external events. One substrate for multisensory integration is the midbrain superior colliculus (SC) which plays an important role in orienting behavior. In rodent SC, visual and somatosensory (whisker) representations are in approximate registration, but whether and how these signals interact is unclear. We measured spiking activity in SC of anesthetized hooded rats, during presentation of visual and whisker stimuli that were tested simultaneously or in isolation. Visual responses were found in all layers, but were primarily located in superficial layers. Whisker responsive sites were primarily found in intermediate layers. In single- and multi-unit recording sites, spiking activity was usually only sensitive to one modality, when stimuli were presented in isolation. By contrast, we observed robust and primarily suppressive interactions when stimuli were presented simultaneously to both modalities. We conclude that while visual and whisker representations in SC of rat are partially overlapping, there is limited excitatory convergence onto individual sites. Multimodal integration may instead rely on suppressive interactions between modalities. PMID- 30401873 TI - Metabolic pathways synthesis based on ant colony optimization. AB - One of the current challenges in bioinformatics is to discover new ways to transform a set of compounds into specific products. The usual approach is finding the reactions to synthesize a particular product, from a given substrate, by means of classical searching algorithms. However, they have three main limitations: difficulty in handling large amounts of reactions and compounds; absence of a step that verifies the availability of substrates; and inability to find branched pathways. We present here a novel bio-inspired algorithm for synthesizing linear and branched metabolic pathways. It allows relating several compounds simultaneously, ensuring the availability of substrates for every reaction in the solution. Comparisons with classical searching algorithms and other recent metaheuristic approaches show clear advantages of this proposal, fully recovering well-known pathways. Furthermore, solutions found can be analyzed in a simple way through graphical representations on the web. PMID- 30401874 TI - A deadly dance: the choreography of host-pathogen interactions, as revealed by single-cell technologies. AB - Pathogens have numerous mechanisms by which they replicate within a host, who in turn responds by developing innate and adaptive immune countermeasures to limit disease. The advent of high-content single-cell technologies has facilitated a greater understanding of the properties of host cells harboring infection, the host's pathogen-specific immune responses, and the mechanisms pathogens have evolved to escape host control. Here we review these advances and argue for greater inclusion of higher resolution single-cell technologies into approaches for defining immune evasion mechanisms by pathogens. PMID- 30401877 TI - Abundance of molecular triple ionization by double Auger decay. AB - Systematic measurements of electron emission following formation of single 1s or 2p core holes in molecules with C, O, F, Si, S and Cl atoms show that overall triple ionization can make up as much as 20% of the decay. The proportion of triple ionization is observed to follow a linear trend correlated to the number of available valence electrons on the atom bearing the initial core hole and on closest neighbouring atoms, where the interatomic distance is assumed to play a large role. The amounts of triple ionization (double Auger decay) after 1s or 2p core hole formation follow the same linear trend, which indicates that the hole identity is not a crucial determining factor in the number of electrons emitted. The observed linear trend for the percentage of double Auger decay follows a predictive line equation of the form DA = 0.415 . Nve + 5.46. PMID- 30401875 TI - Multilocus sequence typing of Candida albicans isolates from the oral cavities of patients undergoing haemodialysis. AB - This study evaluates the prevalence, diversity, and genetic profiles of Candida albicans isolates recovered from the oral cavities of haemodialysis patients. Oral swab samples were obtained from haemodialysis patients (n = 126) and healthy control subjects (n = 233) and Candida species were characterised. There was no significant difference between the haemodialysis and control groups in the prevalence of yeast carriers (23.6% vs. 31.0%, respectively) or C. albicans carriers (19.8% vs. 21.0%, respectively). C. albicans was the most populous species in both cohorts, followed by C. parapsilosis. C. parapsilosis and C. glabrata were more prevalent in the haemodialysis group than in the control group (C. parapsilosis 5.6% vs. 0.9% and C. glabrata 3.2% vs. 0.4%, respectively; P < 0.05). C. albicans isolates were analysed by multilocus sequence typing and the results were used to construct a phylogenetic tree. Most haemodialysis isolates were placed into Clade 4 (20.0%) and Clade 19 (16.0%) and most control isolates into Clade 8 (17%) and Clade 4 (14.9%). Differences in the strain abundance in each clade were not statistically significant between the two groups. Moreover, there was no significant association between the health status or diagnosis and either the sequence types or clades. PMID- 30401876 TI - Direct quantitative material decomposition employing grating-based X-ray phase contrast CT. AB - Dual-energy CT has opened up a new level of quantitative X-ray imaging for many diagnostic applications. The energy dependence of the X-ray attenuation is the key to quantitative material decomposition of the volume under investigation. This material decomposition allows the calculation of virtual native images in contrast enhanced angiography, virtual monoenergetic images for beam-hardening artifact reduction and quantitative material maps, among others. These visualizations have been proven beneficial for various diagnostic questions. Here, we demonstrate a new method of 'virtual dual-energy CT' employing grating based phase-contrast for quantitative material decomposition. Analogue to the measurement at two different energies, the applied phase-contrast measurement approach yields dual information in form of a phase-shift and an attenuation image. Based on these two image channels, all known dual-energy applications can be demonstrated with our technique. While still in a preclinical state, the method features the important advantages of direct access to the electron density via the phase image, simultaneous availability of the conventional attenuation image at the full energy spectrum and therefore inherently registered image channels. The transfer of this signal extraction approach to phase-contrast data multiplies the diagnostic information gained within a single CT acquisition. The method is demonstrated with a phantom consisting of exemplary solid and fluid materials as well as a chicken heart with an iodine filled tube simulating a vessel. For this first demonstration all measurements have been conducted at a compact laser-undulator synchrotron X-ray source with a tunable X-ray energy and a narrow spectral bandwidth, to validate the quantitativeness of the processing approach. PMID- 30401878 TI - Emergence of a cholecystokinin/sulfakinin signalling system in Lophotrochozoa. AB - Chordate gastrin/cholecystokinin (G/CCK) and ecdysozoan sulfakinin (SK) signalling systems represent divergent evolutionary scenarios of a common ancestral signalling system. The present article investigates for the first time the evolution of the CCK/SK signalling system in a member of the Lophotrochozoa, the second clade of protostome animals. We identified two G protein-coupled receptors (GPCR) in the oyster Crassostrea gigas (Mollusca), phylogenetically related to chordate CCK receptors (CCKR) and to ecdysozoan sulfakinin receptors (SKR). These receptors, Cragi-CCKR1 and Cragi-CCKR2, were characterised functionally using a cell-based assay. We identified di- and mono-sulphated forms of oyster Cragi-CCK1 (pEGAWDY(SO3H)DY(SO3H)GLGGGRF-NH2) as the potent endogenous agonists for these receptors. The Cragi-CCK genes were expressed in the visceral ganglia of the nervous system. The Cragi-CCKR1 gene was expressed in a variety of tissues, while Cragi-CCKR2 gene expression was more restricted to nervous tissues. An in vitro bioassay revealed that different forms of Cragi-CCK1 decreased the frequency of the spontaneous contractions of oyster hindgut. Expression analyses in oysters with contrasted nutritional statuses or in the course of their reproductive cycle highlighted the plausible role of Cragi-CCK signalling in the regulation of feeding and its possible involvement in the coordination of nutrition and energy storage in the gonad. This study confirms the early origin of the CCK/SK signalling system from the common bilaterian ancestor and delivers new insights into its structural and functional evolution in the lophotrochozoan lineage. PMID- 30401879 TI - Pelvic and hypogastric nerves are injured in a rat prostatectomy model, contributing to development of stress urinary incontinence. AB - Urinary incontinence affects 40% of elderly men, is common in diabetic patients and in men treated for prostate cancer, with a prevalence of up to 44%. Seventy two percent of prostatectomy patients develop stress urinary incontinence (SUI) in the first week after surgery and individuals who do not recover within 6 months generally do no regain function without intervention. Incontinence has a profound impact on patient quality of life and a critical unmet need exists to develop novel and less invasive SUI treatments. During prostatectomy, the cavernous nerve (CN), which provides innervation to the penis, undergoes crush, tension, and resection injury, resulting in downstream penile remodeling and erectile dysfunction in up to 85% of patients. There are other nerves that form part of the major pelvic ganglion (MPG), including the hypogastric (HYG, sympathetic) and pelvic (PN, parasympathetic) nerves, which provide innervation to the bladder and urethra. We examine if HYG and PNs are injured during prostatectomy contributing to SUI, and if Sonic hedgehog (SHH) regulatory mechanisms are active in the PN and HYG nerves. CN, PN, HYG and ancillary (ANC) of uninjured, sham and CN crush/MPG tension injured (prostatectomy model) adult Sprague Dawley rats (n = 37) were examined for apoptosis, sonic hedgehog (SHH) pathway, and intrinsic and extrinsic apoptotic mechanisms. Fluorogold tracing from the urethra/bladder was performed. PN and HYG response to SHH protein was examined in organ culture. TUNEL, immunohistochemical analysis for caspase-3 cleaved, -8, -9, SHH, Patched and Smoothened (SHH receptors), and neurite formation, were examined. Florogold positive neurons in the MPG were reduced with CN crush. Apoptosis increased in glial cells of the PN and HYG after CN crush. Caspase 9 was abundant in glial cells (intrinsic), while caspase-8 was not observed. SHH and its receptors were abundant in neurons and glia of the PN and HYG. SHH treatment increased neurite formation. PN and HYG injury occur concomitant with CN injury during prostatectomy, likely contributing to SUI. PN and HYG response to SHH treatment indicates an avenue for intervention to promote regeneration and prevent SUI. PMID- 30401880 TI - The Arabidopsis-Trichoderma interaction reveals that the fungal growth medium is an important factor in plant growth induction. AB - Trichoderma spp colonizes the plant rhizosphere and provides pathogen resistance, abiotic stress tolerance, and enhance growth and development. We evaluated the Arabidopsis-Trichoderma interaction using a split system in which Trichoderma atroviride and Trichoderma virens were grown on PDA or MS medium. Arabidopsis growth was significantly increased at 3 and 5 days post-inoculation with both Trichoderma species, when the fungal strains were grown on PDA in split interaction. The analysis of DR5:uidA reporter line revealed a greater auxin accumulation in root tips when the fungi were grown on PDA in a split interaction. The root hair-defective phenotype of Arabidopsis rhd6 mutant was reverted with both Trichoderma species, even in split interactions. At 12 degrees C, Trichoderma species in split interactions were able to mitigate the effects of cold stress on the plant, and also Trichoderma induced the AtERD14 expression, a cold related gene. Volatile organic compounds analysis revealed that Trichoderma strains produce mainly sesquiterpenes, and that the type and abundance of these compounds was dependent on the fungal strain and the culture medium. Our results show that fungal nutrition is an important factor in plant growth in a split interaction. PMID- 30401881 TI - Super-resolution imaging using nano-bells. AB - In this paper we demonstrate a new scheme for optical super-resolution, inspired, in-part, by PALM and STORM. In this scheme each object in the field of view is tagged with a signal that allows them to be detected separately. By doing this we can identify and locate each object separately with significantly higher resolution than the diffraction limit. We demonstrate this by imaging nanoparticles significantly smaller than the optical resolution limit. In this case the "tag" we have used is the frequency of vibration of nanoscale "bells" made of metallic nanoparticles whose acoustic vibrational frequency is in the multi-GHz range. Since the vibration of the particles can be easily excited and detected and the frequency is directly related to the particle size, we can separate the signals from many particles of sufficiently different sizes even though they are smaller than, and separated by less than, the optical resolution limit. Using this scheme we have been able to localise the nanoparticle position with a precision of ~3 nm. This has many potential advantages - such nanoparticles are easily inserted into cells and well tolerated, the particles do not bleach and can be produced easily with very dispersed sizes. We estimate that 50 or more different particles (or frequency channels) can be accessed in each optical point spread function using the vibrational frequencies of gold nanospheres. However, many more channels may be accessed using more complex structures (such as nanorods) and detection techniques (for instance using polarization or wavelength selective detection) opening up this technique as a generalized method of achieving super-optical resolution imaging. PMID- 30401882 TI - Six-transmembrane epithelial antigen of the prostate 1 protects against increased oxidative stress via a nuclear erythroid 2-related factor pathway in colorectal cancer. AB - The over-expression of six-transmembrane epithelial antigen of the prostate 1 (STEAP1) underlies the pathogenesis of a large subset of human cancers. Expressed on the cancer cell surface, STEAP1 is an attractive target for antibody-based therapy or immunotherapy. However, its role in modulating the pathophysiology of colorectal cancer (CRC) remains relatively unexplored. In this study, we first demonstrated that the STEAP1 transcript level was significantly higher in CRC tissues than in normal colonic tissues. Of note, STEAP1 expression negatively correlated with overall survival as determined from a publicly accessible gene expression profile data set. A loss-of-function approach in cultured CRC cell lines revealed that STEAP1 silencing suppressed cell growth and increased reactive oxygen species (ROS) production, followed by apoptosis, through an intrinsic pathway. Mechanistically, the inhibition of STEAP1 was associated with decreased expression of antioxidant molecules regulated by the transcription factor, nuclear erythroid 2-related factor (NRF2), in CRC cells. Taken together, we identified high STEAP1 transcript levels leading to reduced ROS production that prevented apoptosis via the NRF2 pathway in CRC cells as a pathological mechanism in CRC. This study highlights the STEAP1-NRF2 axis as a therapeutic target for CRC and its manipulation as a novel strategy to conquer CRC. PMID- 30401883 TI - Self-implantable double-layered micro-drug-reservoirs for efficient and controlled ocular drug delivery. AB - Eye diseases and injuries impose a significant clinical problem worldwide. Safe and effective ocular drug delivery is, however, challenging due to the presence of ocular barriers. Here we report a strategy using an eye patch equipped with an array of detachable microneedles. These microneedles can penetrate the ocular surface tissue, and serve as implanted micro-reservoirs for controlled drug delivery. The biphasic drug release kinetics enabled by the double-layered micro reservoirs largely enhances therapeutic efficacy. Using corneal neovascularization as the disease model, we show that delivery of an anti angiogenic monoclonal antibody (DC101) by such eye patch produces ~90% reduction of neovascular area. Furthermore, quick release of an anti-inflammatory compound (diclofenac) followed by a sustained release of DC101 provides synergistic therapeutic outcome. The eye patch application is easy and minimally invasive to ensure good patient compliance. Such intraocular drug delivery strategy promises effective home-based treatment of many eye diseases. PMID- 30401884 TI - Evaluation of Microclimatic Detection by a Wireless Sensor Network in Forest Ecosystems. AB - Timely and accurate detection of microclimates is extremely valuable for monitoring and stimulating exchanges of mass and energy in forest ecosystems under climate change. Recently, the rapid growth of wireless sensor networks (WSNs) has provided a new approach for detecting microclimates in a complex environment at multiple temporal and spatial scales. However, applications of wireless sensors in forest microclimate monitoring have rarely been studied, and the corresponding observation accuracy, error sources and correction methods are not well understood. In this study, through field experiments in two typical subtropical forest ecosystems in Zhejiang Province, China, the accuracy of the temperature and humidity observed by the wireless sensors was evaluated against standard meteorological data. Furthermore, the observation error sources were analyzed and corresponding correction models were established. The results showed that the wireless sensor-based temperature and humidity values performed well within the total observation accuracy. However, the observation errors varied with season, daily periodicity and weather conditions. For temperature, the wireless sensor observations were overestimated during the daytime while they were underestimated during the nighttime. For humidity, the data observed by the wireless sensors generally appeared as overestimates. Adopting humidity as the corrected factor, correction models were established and effectively improved the accuracy of the microclimatic data observed by the wireless sensors. Notably, our error analysis demonstrated that the observation errors may be associated with the shell material of the wireless sensor, suggesting that shading measures for the wireless sensors should be considered for outdoor work. PMID- 30401885 TI - Advanced high resolution x-ray diagnostic for HEDP experiments. AB - High resolution X-ray imaging is crucial for many high energy density physics (HEDP) experiments. Recently developed techniques to improve resolution have, however, come at the cost of a decreased field of view. In this paper, an innovative experimental detector for X-ray imaging in the context of HEDP experiments with high spatial resolution, as well as a large field of view, is presented. The platform is based on coupling an X-ray backligther source with a Lithium Fluoride detector, characterized by its large dynamic range. A spatial resolution of 2 um over a field of view greater than 2 mm2 is reported. The platform was benchmarked with both an X-ray free electron laser (XFEL) and an X ray source produced by a short pulse laser. First, using a non-coherent short pulse laser-produced backlighter, reduced penumbra blurring, as a result of the large size of the X-ray source, is shown. Secondly, we demonstrate phase contrast imaging with a fully coherent monochromatic XFEL beam. Modeling of the absorption and phase contrast transmission of X-ray radiation passing through various targets is presented. PMID- 30401886 TI - Transcriptome analysis for phosphorus starvation-induced lipid accumulation in Scenedesmus sp. AB - Phosphorus stress was applied to enhance the lipid production in Scenedesmus sp. The highest lipid production (350 mg L-1) and lipid content (approximately 41.0% of dry weight) were obtained by addition of 2 mg L-1 NaH2PO4.2H2O every 2 days, which were higher than those in replete phosphorus. Correspondingly, carbohydrate content decreased significantly. We speculated that phosphorus limitation could block starch biosynthesis, and photosynthate flow tended to fatty acid biosynthesis to cope with stress. To investigate the mechanism that phosphorus stress triggers the carbon fixation to lipid biosynthesis, the transcriptome analysis was carried out by the Illumina RNA-seq platform. A total of 2897 genes were identified as differentially expressed genes. The observed overexpression of lipid production under phosphorus stress was bolstered by up-regulation of genes encoding for DGAT and pyruvate kinase, activation of carbohydrate metabolism pathway and fatty acid biosynthesis, and repression of carbohydrate synthesis presumably to shunt the carbon flux toward TAG biosynthesis. The transcriptome will be useful to understand the lipid metabolism pathway and obtain the engineering economic algae species aimed at biodiesel production. PMID- 30401887 TI - PIWI proteins contribute to apoptosis during the UPR in human airway epithelial cells. AB - Small noncoding microRNAs (miRNAs) post-transcriptionally regulate a large portion of the human transcriptome. miRNAs have been shown to play an important role in the unfolded protein response (UPR), a cellular adaptive mechanism that is important in alleviating endoplasmic reticulum (ER) stress and promoting cell recovery. Another class of small noncoding RNAs, the Piwi-interacting RNAs (piRNAs) together with PIWI proteins, was originally shown to play a role as repressors of germline transposable elements. More recent studies, however, indicate that P-element induced WImpy proteins (PIWI proteins) and piRNAs also regulate mRNA levels in somatic tissues. Using genome-wide small RNA next generation sequencing, cell viability assays, and caspase activity assays in human airway epithelial cells, we demonstrate that ER stress specifically up regulates total piRNA expression profiles, and these changes correlate with UPR induced apoptosis as shown by up-regulation of two pro-apoptotic factor mRNAs, CHOP and NOXA. Furthermore, siRNA knockdown of PIWIL2 and PIWIL4, two proteins involved in piRNA function, attenuates UPR-related cell death, inhibits piRNA expression, and inhibits the up-regulation of CHOP and NOXA mRNA expression. Hence, we provide evidence that PIWIL2 and PIWIL4 proteins, and potentially the up-regulated piRNAs, constitute a novel epigenetic mechanism that control cellular fate during the UPR. PMID- 30401888 TI - Classification of marine microdebris: A review and case study on fish from the Great Barrier Reef, Australia. AB - Marine debris, and in particular plastic pollution, is ubiquitous throughout global marine environments. Here, we present a classification of marine microdebris (i.e. debris between 0.1 MUm and <5 mm) tailored to represent synthetic, semi-synthetic and naturally-derived items. The specific aim of this classification is to introduce a level of consistency in the higher-level characterisation of marine microdebris, thereby improving the overall reporting on marine microdebris contamination. We first conducted an extensive literature review on the accumulation of ingested debris in fish to identify discrepancies in marine microdebris reporting as a basis for the new classification. The review reveals the diverse nature of ingested marine microdebris, including items that are non-plastic but often incorrectly reported on as microplastics. We then applied our classification to a case study on wild-caught juvenile coral trout, Plectropomus spp., from the Great Barrier Reef World Heritage Area, Australia. This first report on accumulation of ingested marine debris in commercial fish on the reef demonstrates a high frequency of occurrence and a prevalence of semi synthetic and naturally-derived fibres. Based on our findings, we offer recommendations on potential improvements for the classification presented, ultimately contributing to a more realistic assessment of the ecological risks of marine microdebris. PMID- 30401889 TI - Type 2 diabetes and risk of colorectal cancer in two large U.S. prospective cohorts. AB - BACKGROUND: Previous studies have shown a positive association between type 2 diabetes (T2D) and colorectal cancer (CRC) risk. However, it is uncertain whether this association differs by duration of T2D or sex. We thus investigated the associations of T2D and its duration with the risk of incident CRC. METHODS: We followed 87,523 women from the Nurses' Health Study (1980-2012) and 47,240 men from the Health Professionals Follow-up Study (1986-2012). Data on physician diagnosed T2D was collected at baseline with a questionnaire and updated biennially. Cox regression models were used to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We documented 3000 CRC cases during up to 32 years of follow-up. Among men, T2D was associated with increased risk of CRC compared to those without T2D (HR: 1.42; 95% CI: 1.12 1.81). This positive association persisted in sensitivity analyses by excluding CRC identified within 1 year of diabetes diagnosis and patients with T2D who used hypoglycaemic medications. Among women, T2D was positively, but not statistically significantly, associated with CRC risk (HR: 1.17; 95% CI: 0.98-1.39). CONCLUSIONS: Our findings support that T2D was associated with a moderately higher risk of developing CRC in men; a weaker, nonsignificant positive association was observed in women. PMID- 30401890 TI - Association of symptoms and interval breast cancers in the mammography-screening programme: population-based matched cohort study. AB - BACKGROUND: We assessed the association between symptoms reported at breast cancer screening visits and interval cancers (ICs) in a prospective manner. METHODS: This population-based matched cohort study uses data of the Finnish National Breast Cancer Screening Programme that invites women aged 50-69 years old during 1992-2012. Subjects who attended screening with symptoms were matched with asymptomatic reference cohorts based on age at screening visit, year of invitation, number of invited visits and municipality of invitation. The primary outcome was ICs. RESULTS: Women with a lump had a threefold (hazard ratio 3.7, 95% confidence interval (CI) 3.0-4.6) risk of ICs and a higher risk (hazard ratio 1.7, 95% CI 1.4 to 2.0) at the subsequent visit compared with those without a lump. The fatal interval cancer risk increased by 0.39 per 1000 screens with a lump. The cumulative incidences of interval cancer increased within a month of a mammography-negative visit with a lump and after about 6 months of the visit with retraction or nipple discharge. CONCLUSION: Women with breast symptoms have a clearly increased risk of interval breast cancer after the screening visit. Our findings indicate the need for different screening strategies in symptomatic women. PMID- 30401892 TI - A quantile regression approach to explain the relationship of Fatigue and Cortisol, Cytokine among Koreans with Hepatitis B. AB - Fatigue is a major symptom among patients with Hepatitis B virus (HBV). However, the physiological mechanisms regarding mediate fatigue and the relationships between fatigue, cortisol and cytokines are unclear in patients with HBV. The purpose of this study was to examine the relationships between perceived fatigue, cortisol, and cytokines in Korean patients with HBV. The mean score for overall fatigue was moderate. In linear regression analyses, TNF-alpha was only significant as a predictor of fatigue. In quantile regression analyses, the cortisol level was significant in the 70th, 80th, 90th quantiles in the cognitive/mood fatigue subdimension, which correspond to severe levels of fatigue. IL-6 levels were significant in 90th quantile in overall fatigue and in the cognitive/mood fatigue subdimension. Cortisol, IL-6, and TNF- alpha were related to perceived fatigue in patients with HBV, particularly in the cognitive/mood dimension. This suggests that the fatigue patterns of patients with HBV are related to their mental and mood states and physical responses, such as cortisol and cytokine levels, are correlated with the nature of the fatigue. In the clinic, interventions to manage fatigue in patients with HBV should be developed based on the characteristics of the fatigue. PMID- 30401891 TI - Droplet digital PCR quantification of miR-1290 as a circulating biomarker for pancreatic cancer. AB - Droplet digital PCR was used to validate miR-1290 as circulating biomarker for pancreatic cancer (PC). The diagnostic performance of miR-1290 was evaluate in 167 PC patients and 267 healthy subjects at clinical risk of developing the disease (HS). MiR-1290 plasma levels were compared to CA 19-9 determinations, and the combination of the two biomarkers was also taken into account. Plasma levels of miR-1290 were higher in PC patients compared to HS (p = 2.55 * 10-16). A similar trend was observed for CA 19-9 determinations (p = 1.03 * 10-47). ROC curve analysis revealed that miR-1290 in combination with CA 19-9 was effective for discriminating between PC patients and HS (AUC = 0.956, 95% CI = 0.933-0.979) than the two biomarkers tested alone (miR-1290: AUC = 0.734, 0.678-0.789; CA 19 9: AUC = 0.914, 0.877-0.951). The discriminating ability was higher when only PC patients with low or slightly increased CA 19-9 levels were compared with HS. MiR 1290 concentrations were not able to differentiate between PC patients with single or multiple risk factors for developing PC. Our data suggest that the absolute quantification of circulating miR-1290 levels does not allow to select patients at clinical risk of PC for entry into a surveillance program, and underline the methodological challenges still existing in utilizing circulating miRNAs as new promising biomarkers for PC. PMID- 30401893 TI - Influence of irrigation conditions in the germination of plasma treated Nasturtium seeds. AB - Plasma treatments had emerged as a useful technique to improve seed germination. In this work we investigate the influence of different irrigation conditions and plasma treatments on the germination of nasturtium seeds. During plasma treatment, seeds experience a progressive weight loss as a function of treatment time that has been associated to water release, a process that is more pronounced after longer plasma treatment times. Seeds treated for short times (<30 s) are able to germinate more efficiently than untreated specimen under hydric stress (drought conditions), while plasma treatments for longer times (up to 300 s) impaired germination independently on irrigation conditions. Characterization analysis of plasma treated seeds by FTIR-ATR, SEM/EDX and XPS showed that plasma treatment affected the chemical state of pericarp while, simultaneously, induced a considerable increase in the seeds water uptake capacity. The decrease in germination efficiency found after plasma treatment for long times, or for short times under optimum irrigation conditions, has been attributed to that the excess of water accumulated in the pericarp hampers the diffusion up to the embryo of other agents like oxygen which are deemed essential for germination. PMID- 30401894 TI - Machine learning predicts individual cancer patient responses to therapeutic drugs with high accuracy. AB - Precision or personalized cancer medicine is a clinical approach that strives to customize therapies based upon the genomic profiles of individual patient tumors. Machine learning (ML) is a computational method particularly suited to the establishment of predictive models of drug response based on genomic profiles of targeted cells. We report here on the application of our previously established open-source support vector machine (SVM)-based algorithm to predict the responses of 175 individual cancer patients to a variety of standard-of-care chemotherapeutic drugs from the gene-expression profiles (RNA-seq or microarray) of individual patient tumors. The models were found to predict patient responses with >80% accuracy. The high PPV of our algorithms across multiple drugs suggests a potential clinical utility of our approach, particularly with respect to the identification of promising second-line treatments for patients failing standard of-care first-line therapies. PMID- 30401895 TI - Experimental evidence characterizing pressure fluctuations at the seafloor-water interface induced by an earthquake. AB - An unusual combination of a laboratory experiment and in situ measurement of pressure fluctuations during an earthquake allows us to resolve some uncertainties in bottom pressure recorders (BPRs). In situ BPRs are usually contaminated by seismic waves during earthquakes; thus uncertainty still remains in the data obtained from BPRs. We examine in situ BPR data together with pressure variations produced by a dead weight (a pressure standard) in a laboratory experiment during an earthquake. The features recorded by the in situ BPRs are analysed as part of the overall experiment. We demonstrated that a 10-kg dead weight on a piston-cylinder across an area of 10 mm2 is capable of reproducing pressure fluctuations at a depth of 1000 m in the water column. The experiment also indicates that the internal mechanics of BPRs are isolated from incident seismic waves, suggesting that BPRs measure true in situ pressures without instrumentally induced disturbances. This constitutes the first instance in which pressure fluctuations recorded by in situ BPRs during an earthquake were reproduced using a pressure standard in the laboratory. PMID- 30401896 TI - Kyasanur Forest disease virus infection activates human vascular endothelial cells and monocyte-derived dendritic cells. AB - Kyasanur Forest disease virus (KFDV) is a highly pathogenic tick-borne flavivirus enzootic to India. In humans, KFDV causes a severe febrile disease. In some infected individuals, hemorrhagic manifestations, such as bleeding from the nose and gums and gastrointestinal bleeding with hematemesis and/or blood in the stool, have been reported. However, the mechanisms underlying these hemorrhagic complications remain unknown, and there is no information about the specific target cells for KFDV. We investigated the interaction of KFDV with vascular endothelial cells (ECs) and monocyte-derived dendritic cells (moDCs), which are key targets for several other hemorrhagic viruses. Here, we report that ECs are permissive to KFDV infection, which leads to their activation, as demonstrated by the upregulation of E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 at the mRNA and protein levels. Increased expression of these adhesive molecules correlated with increased leukocyte adhesion. Infected ECs upregulated the expression of interleukin (IL)-6 but not IL-8. Additionally, moDCs were permissive to KFDV infection, leading to increased release of IL-6 and tumor necrosis factor-alpha. Supernatants from KFDV-infected moDCs caused EC activation, as measured by leukocyte adhesion. The results indicate that ECs and moDCs can be targets for KFDV and that both direct and indirect mechanisms can contribute to EC activation. PMID- 30401898 TI - Time-dependent changes in hypoxia- and gliosis-related factors in experimental diabetic retinopathy. AB - Diabetes causes various biochemical changes in the retina; long-term changes in the factors associated with hypoxia and gliosis have rarely been reported. The present study was conducted to explore the changes in these factors in a time dependent manner in experimental diabetic retinopathy (DR). Diabetes was induced in Sprague-Dawley rats by intraperitoneal injection of streptozotocin. The expression of the following factors was examined using immunofluorescence and western blot analysis at 0.5, 1, 2, 4 and 6 months after diabetes onset: hypoxia inducible factor-1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), erythropoietin (EPO), erythropoietin receptor (EPOR), glial fibrillary acidic protein (GFAP), vimentin, glutamate-aspartate transporter (GLAST) and glutamine synthase (GS). The expression of factors such as HIF-1alpha, VEGF, EPO, EPOR, GFAP and vimentin, was up-regulated with the progression of diabetes in the diabetic rat retinas compared to the expression in normal control retinas, whereas the expression of GS and GLAST was down-regulated. Changes in EPO and EPOR appeared 2 weeks after diabetes onset. HIF-1alpha, VEGF and GFAP started to increase at 1 month and vimentin at 4 months after diabetes onset. GS and GLAST started to decrease at 1 month after diabetes onset. The expression of these factors, which are involved in the processes of hypoxia and gliosis, varied at different stages of DR. The time-course change may be helpful in the evaluation of the progression of DR, and it may indicate the optimal intervention time points for DR. PMID- 30401899 TI - Fundus photograph-based deep learning algorithms in detecting diabetic retinopathy. AB - Remarkable advances in biomedical research have led to the generation of large amounts of data. Using artificial intelligence, it has become possible to extract meaningful information from large volumes of data, in a shorter frame of time, with very less human interference. In effect, convolutional neural networks (a deep learning method) have been taught to recognize pathological lesions from images. Diabetes has high morbidity, with millions of people who need to be screened for diabetic retinopathy (DR). Deep neural networks offer a great advantage of screening for DR from retinal images, in improved identification of DR lesions and risk factors for diseases, with high accuracy and reliability. This review aims to compare the current evidences on various deep learning models for diagnosis of diabetic retinopathy (DR). PMID- 30401900 TI - Serial TSH-receptor antibody levels to guide the management of thyroid eye disease: the impact of smoking, immunosuppression, radio-iodine, and thyroidectomy. AB - The Thyrotropin receptor antibody (TRAb) is the main driver of Graves' disease (GD) and its most common extra-thyroidal manifestation: thyroid eye disease (TED). Though key to diagnosis, it has not been used routinely as a marker of disease activity or to guide treatment. Here we demonstrate, through a retrospective review of 105 patients with TED, that serial TRAb levels vary with time, correlate with disease activity and are affected by smoking and endocrine control. Such serial measurements can guide the modern management of thyroid eye disease, helping to prevent the more serious manifestations. We show that surgical thyroidectomy is associated with a reduction in antibody levels and a reduced rate of TED reactivation when compared to radio-iodine ablation where the stimulating antigen is not removed. This provides a molecular explanation for epidemiological studies showing radio-ablation being associated with an increased risk of orbitopathy. To demonstrate the effect of our clinical approach on a patient population, we then compared the incidence and severity of TED in a clinic in a period before and after the introduction of serial TRAb measurements. Despite an increase in disease incidence and severity at presentation over the two-decade study period, our approach saw a significant reduction in the need for surgical intervention for this orbital disorder. PMID- 30401897 TI - Palm Fruit Bioactives modulate human astrocyte activity in vitro altering the cytokine secretome reducing levels of TNFalpha, RANTES and IP-10. AB - Neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, are becoming more prevalent and an increasing burden on society. Neurodegenerative diseases often arise in the milieu of neuro-inflammation of the brain. Reactive astrocytes are key regulators in the development of neuro inflammation. This study describes the effects of Palm Fruit Bioactives (PFB) on the behavior of human astrocytes which have been activated by IL-1beta. When activated, the astrocytes proliferate, release numerous cytokines/chemokines including TNFalpha, RANTES (CCL5), IP-10 (CXCL10), generate reactive oxygen species (ROS), and express specific cell surface biomarkers such as the Intercellular Adhesion Molecule (ICAM), Vascular Cellular Adhesion Molecule (VCAM) and the Neuronal Cellular Adhesion Molecule (NCAM). Interleukin 1-beta (IL 1beta) causes activation of human astrocytes with marked upregulation of pro inflammatory genes. We show significant inhibition of these pro-inflammatory processes when IL-1beta-activated astrocytes are exposed to PFB. PFB causes a dose-dependent and time-dependent reduction in specific cytokines: TNFalpha, RANTES, and IP-10. We also show that PFB significantly reduces ROS production by IL-1beta-activated astrocytes. Furthermore, PFB also reduces the expression of ICAM and VCAM, both in activated and naive human astrocytes in vitro. Since reactive astrocytes play an essential role in the neuroinflammatory state preceding neurodegenerative diseases, this study suggests that PFB may have a potential role in their prevention and/or treatment. PMID- 30401901 TI - Structural basis of Gip1 for cytosolic sequestration of G protein in wide-range chemotaxis. AB - G protein interacting protein 1 (Gip1) binds and sequesters heterotrimeric G proteins in the cytosolic pool, thus regulating G protein-coupled receptor (GPCR) signalling for eukaryotic chemotaxis. Here, we report the underlying structural basis of Gip1 function. The crystal structure reveals that the region of Gip1 that binds to the G protein has a cylinder-like fold with a central hydrophobic cavity composed of six alpha-helices. Mutagenesis and biochemical analyses indicate that the hydrophobic cavity and the hydrogen bond network at the entrance of the cavity are essential for complex formation with the geranylgeranyl modification on the Ggamma subunit. Mutations of the cavity impair G protein sequestration and translocation to the membrane from the cytosol upon receptor stimulation, leading to defects in chemotaxis at higher chemoattractant concentrations. These results demonstrate that the Gip1-dependent regulation of G protein shuttling ensures wide-range gradient sensing in eukaryotic chemotaxis. PMID- 30401902 TI - A chemical genetic screen reveals that iminosugar inhibitors of plant glucosylceramide synthase inhibit root growth in Arabidopsis and cereals. AB - Iminosugars are carbohydrate mimics that are useful as molecular probes to dissect metabolism in plants. To analyse the effects of iminosugar derivatives on germination and seedling growth, we screened a library of 390 N-substituted iminosugar analogues against Arabidopsis and the small cereal Eragrostis tef (Tef). The most potent compound identified in both systems, N-5-(adamantane-1-yl ethoxy)pentyl- L-ido-deoxynojirimycin (L-ido-AEP-DNJ), inhibited root growth in agar plate assays by 92% and 96% in Arabidopsis and Tef respectively, at 10 uM concentration. Phenocopying the effect of L-ido-AEP-DNJ with the commercial inhibitor (PDMP) implicated glucosylceramide synthase as the target responsible for root growth inhibition. L-ido-AEP-DNJ was twenty-fold more potent than PDMP. Liquid chromatography-mass spectrometry (LC-MS) analysis of ceramide:glucosylceramide ratios in inhibitor-treated Arabidopsis seedlings showed a decrease in the relative quantity of the latter, confirming that glucosylceramide synthesis is perturbed in inhibitor-treated plants. Bioinformatic analysis of glucosylceramide synthase indicates gene conservation across higher plants. Previous T-DNA insertional inactivation of glucosylceramide synthase in Arabidopsis caused seedling lethality, indicating a role in growth and development. The compounds identified herein represent chemical alternatives that can overcome issues caused by genetic intervention. These inhibitors offer the potential to dissect the roles of glucosylceramides in polyploid crop species. PMID- 30401904 TI - High-precision gas refractometer by comb-mode-resolved spectral interferometry. AB - High-accuracy knowledge of gas refractivity is typically crucial for optical interferometry, precise optical systems, and calculable pressure standard development. Here, we demonstrate an absolute gas refractometer by spectral interferometry and a high-resolution spectrometer. The spectral interferometry relies on a comb with fiber Fabry-Perot filtering cavity, and a double-spaced vacuum cell. The spectrometer employs a virtually imaged phased array, diffraction grating and near-infrared camera to fully resolve the comb modes. Finally, by means of fast-Fourier-transform, the group refractivity can be derived from the spectrally resolved interferograms of the two beams propagating in the inside and outside of the vacuum cell. To confirm the feasibility and performance of the gas refractometer, the measurement of ambient air was conducted. The proposed scheme has a combined uncertainty of 1.3 * 10-9 for air and a single measurement only takes 10 ms, which is applicable for gas refractivity monitoring and compensating in real time. PMID- 30401903 TI - High precision FRET studies reveal reversible transitions in nucleosomes between microseconds and minutes. AB - Nucleosomes play a dual role in compacting the genome and regulating the access to DNA. To unravel the underlying mechanism, we study fluorescently labeled mononucleosomes by multi-parameter FRET measurements and characterize their structural and dynamic heterogeneity upon NaCl-induced destabilization. Species selective fluorescence lifetime analysis and dynamic photon distribution analysis reveal intermediates during nucleosome opening and lead to a coherent structural and kinetic model. In dynamic octasomes and hexasomes the interface between the H2A-H2B dimers and the (H3-H4)2 tetramer opens asymmetrically by an angle of ~20 degrees on a 50 and 15 us time scale, respectively. This is followed by a slower stepwise release of the dimers coupled with DNA unwrapping. A mutation (H2A-R81A) at the interface between H2A and H3 facilitates initial opening, confirming the central role of the dimer:tetramer interface for nucleosome stability. Partially opened states such as those described here might serve as convenient nucleation sites for DNA-recognizing proteins. PMID- 30401905 TI - Strategic single point mutation yields a solvent- and salt-stable transaminase from Virgibacillus sp. in soluble form. AB - A new transaminase (VbTA) was identified from the genome of the halotolerant marine bacterium Virgibacillus 21D. Following heterologous expression in Escherichia coli, it was located entirely in the insoluble fraction. After a single mutation, identified via sequence homology analyses, the VbTA T16F mutant was successfully expressed in soluble form and characterised. VbTA T16F showed high stability towards polar organic solvents and salt exposure, accepting mainly hydrophobic aromatic amine and carbonyl substrates. The 2.0 A resolution crystal structure of VbTA T16F is here reported, and together with computational calculations, revealed that this mutation is crucial for correct dimerisation and thus correct folding, leading to soluble protein expression. PMID- 30401908 TI - Stroke risk due to partial white-coat or masked hypertension based on the ACC/AHA guideline's blood pressure threshold: the Ohasama study. PMID- 30401910 TI - Simplifying adrenal vein sampling for cardiologists "In the New Era of Catheter Treatment for Hypertension". PMID- 30401907 TI - Association between alcohol consumption during pregnancy and hypertensive disorders of pregnancy in Japan: the Japan Environment and Children's Study. AB - This study examined the association between maternal alcohol consumption during pregnancy and hypertensive disorders of pregnancy in the Japan Environment and Children's Study, a nationwide birth cohort study. A total of 76 940 pregnant women were included in the analysis. Information about alcohol consumption during pregnancy was obtained using two questionnaires: T1 and T2. The mean (standard deviation) gestational age in the T1 and T2 questionnaires were 16.5 (5.8) and 27.9 (3.7) weeks, respectively. Alcohol consumption was considered as an exposure, hypertensive disorders of pregnancy as an outcome, and possible confounding factors were included in a generalized linear mixed-effects model with a logit link function. Among the study subjects, 2 348 (3.1%) women developed hypertensive disorders of pregnancy. Compared with 25 300 women who never drank alcohol, 43 women who drank alcohol according to the T1 questionnaire and continued to drink >=150 g ethanol/week according to the T2 questionnaire had significantly higher odds of hypertensive disorders of pregnancy. The adjusted odds ratio was 3.98 (95% confidence interval [CI], 1.33-11.9). In conclusion, alcohol consumption of >=150 g ethanol/week during pregnancy is better avoided because of the high odds of developing hypertensive disorders of pregnancy. It may be meaningful that healthcare providers confirm information about alcohol consumption during pregnancy. Moreover, discontinuation of alcohol consumption is recommended to prevent the onset of hypertensive disorders of pregnancy in Japan. PMID- 30401906 TI - Thin Film Multi-Electrode Softening Cuffs for Selective Neuromodulation. AB - Silicone nerve cuff electrodes are commonly implanted on relatively large and accessible somatic nerves as peripheral neural interfaces. While these cuff electrodes are soft (1-50 MPa), their self-closing mechanism requires of thick walls (200-600 um), which in turn contribute to fibrotic tissue growth around and inside the device, compromising the neural interface. We report the use of thiol ene/acrylate shape memory polymer (SMP) for the fabrication of thin film multi electrode softening cuffs (MSC). We fabricated multi-size MSC with eight titanium nitride (TiN) electrodes ranging from 1.35 to 13.95 * 10-4 cm2 (1-3 kOmega) and eight smaller gold (Au) electrodes (3.3 * 10-5 cm2; 750 kOmega), that soften at physiological conditions to a modulus of 550 MPa. While the SMP material is not as soft as silicone, the flexural forces of the SMP cuff are about 70-700 times lower in the MSC devices due to the 30 MUm thick film compared to the 600 MUm thick walls of the silicone cuffs. We demonstrated the efficacy of the MSC to record neural signals from rat sciatic and pelvic nerves (1000 um and 200 um diameter, respectively), and the selective fascicular stimulation by current steering. When implanted side-by-side and histologically compared 30 days thereafter, the MSC devices showed significantly less inflammation, indicated by a 70-80% reduction in ED1 positive macrophages, and 54-56% less fibrotic vimentin immunoreactivity. Together, the data supports the use of MSC as compliant and adaptable technology for the interfacing of somatic and autonomic peripheral nerves. PMID- 30401909 TI - Predictors of confirmatory test results for the diagnosis of primary hyperaldosteronism in hypertensive patients with an aldosterone-to-renin ratio greater than 20. The SHRIMP study. AB - It remains unknown which surrogate markers can predict diagnostic test results for primary hyperaldosteronism (PA). The Secondary Hypertension Registry Investigation in Mie Prefecture (SHRIMP) study has sequentially and prospectively recruited 128 patients with hypertension with an aldosterone-to-renin ratio (ARR) greater than 20, evaluated the differences among essential hypertension (EHT), idiopathic hyperaldosteronism (IHA), and aldosterone-producing adenoma (APA), and analyzed the predictors for the confirmatory tests. The patients underwent saline loading, captopril-challenge, and upright furosemide-loading tests. Carotid, renovascular, and cardiac echography, brachial ankle pulse wave velocity (baPWV), endothelial function, nocturnal blood pressure decline, and the apnea hypopnea index were evaluated. Multivariate regression analyses showed that the plasma aldosterone concentration (PAC) at screening was a strong predictor of the saline and captopril test results. The plasma renin activity (PRA) at screening, urine beta2-microglobulin, and left ventricular mass index (LVMI) were independent predictors for the captopril test. The estimated saline PAC and captopril 60 and 90 min ARRs predicted by the equations were highly correlated with the real values. The ROC curve analysis showed PAC at screening among each of predictors for the diagnostic tests and PAC after the saline-loading test had the highest diagnostic abilities of APA. Patients with IHA were older and had glucose intolerance and increased U-Alb/gCre and resistive indices. In patients with APA, the levels of U-Alb/gCre and urine beta2-microglobulin were increased, and levels of insulin and the HOMA-IR were decreased. In conclusion, our proposed equations may be useful for estimating saline PAC and captopril ARR. Diagnostic predictors may differ for each confirmatory test. PMID- 30401911 TI - Impaired nocturnal blood pressure dipping in patients with type 2 diabetes mellitus. AB - Hypertension is a common comorbidity of type 2 diabetes mellitus (T2DM). Both conditions are associated with an increased cardiovascular risk, which is reduced by tight blood pressure (BP) and glycemic control. However, nondipping BP status continues to be an enduring cardiovascular risk factor in T2DM. Cardiovascular autonomic neuropathy and endothelial dysfunction have been proposed as potential mechanisms. This study tested the hypothesis that microvascular disease rather than cardiovascular autonomic neuropathy interferes with the physiological nocturnal BP reduction. Cardiovascular autonomic function and baroreflex sensitivity were determined in 22 type 2 diabetic patients with (DM+) and 23 diabetic patients without (DM-) manifest microvascular disease. BP dipping status was assessed from 24-hour ambulatory BP measurements. Sixteen nondiabetic subjects served as controls (CTRL). Cardiovascular autonomic function was normal in all subjects. Baroreflex sensitivity was lower in DM- compared with CTRL (7.7 +/- 3.3 vs. 12.3 +/- 8.3 ms.mm Hg-1; P < 0.05) and was further reduced in DM + (4.6 +/- 2.0 ms.mm Hg-1; P < 0.01 vs. DM- and CTRL). The nocturnal decline in systolic and diastolic BP was blunted in DM- (12% and 14% vs. 17% and 19% in CTRL; P < 0.05) and even more so in DM+ (8% and 11%; P < 0.05 vs. DM- and P < 0.001 vs. CTRL). A nocturnal reduction in pulse pressure was observed in CTRL and DM- but not in DM+ (P < 0.05 vs. DM- and P < 0.01 vs. CTRL). In T2DM, progression of microvascular disease interferes with the normal nocturnal BP decline and coincides with a persistently increased pulse pressure and reduced baroreflex sensitivity, contributing to their increased cardiovascular risk. PMID- 30401913 TI - Quasi-phase-matched third harmonic generation in organic multilayers. AB - We report the first realization of quasi-phase-matched (QPM) third harmonic generation in isotropic polymer films. Spin-coated thin films of ethyl-violet molecules dispersed in a polymer host (EV) were used as cubic nonlinear optical media because of their transparency at both the fundamental (1230 nm) and the third harmonic (410 nm) wavelengths. A passive layer of a UV-curable material was formed to compensate the phase shift between the two light waves after propagating through each EV layer. We fabricated a series of samples with 1~4 EV layers (0~3 alternatingly coated passive layers). The third harmonic output power showed a quadratic increase with the number of layers, providing a strong evidence for successful quasi-phase-matching. A conversion efficiency of 0.15% was observed with a 190 fs pulse input. PMID- 30401912 TI - Ectopic beats arise from micro-reentries near infarct regions in simulations of a patient-specific heart model. AB - Ectopic beats are known to be involved in the initiation of a variety of cardiac arrhythmias. Although their location may vary, ectopic excitations have been found to originate from infarct areas, regions of micro-fibrosis and other heterogeneous tissues. However, the underlying mechanisms that link ectopic foci to heterogeneous tissues have yet to be fully understood. In this work, we investigate the mechanism of micro-reentry that leads to the generation of ectopic beats near infarct areas using a patient-specific heart model. The patient-specific geometrical model of the heart, including scar and peri-infarct zones, is obtained through magnetic resonance imaging (MRI). The infarct region is composed of ischemic myocytes and non-conducting cells (fibrosis, for instance). Electrophysiology is captured using an established cardiac myocyte model of the human ventricle modified to describe ischemia. The simulation results clearly reveal that ectopic beats emerge from micro-reentries that are sustained by the heterogeneous structure of the infarct regions. Because microscopic information about the heterogeneous structure of the infarct regions is not available, Monte-Carlo simulations are used to identify the probabilities of an infarct region to behave as an ectopic focus for different levels of ischemia and different percentages of non-conducting cells. From the proposed model, it is observed that ectopic beats are generated when a percentage of non conducting cells is near a topological metric known as the percolation threshold. Although the mechanism for micro-reentries was proposed half a century ago to be a source of ectopic beats or premature ventricular contractions during myocardial infarction, the present study is the first to reproduce this mechanism in-silico using patient-specific data. PMID- 30401914 TI - A genome-scale metabolic network alignment method within a hypergraph-based framework using a rotational tensor-vector product. AB - Biological network alignment aims to discover important similarities and differences and thus find a mapping between topological and/or functional components of different biological molecular networks. Then, the mapped components can be considered to correspond to both their places in the network topology and their biological attributes. Development and evolution of biological network alignment methods has been accelerated by the rapidly increasing availability of such biological networks, yielding a repertoire of tens of methods based upon graph theory. However, most biological processes, especially the metabolic reactions, are more sophisticated than simple pairwise interactions and contain three or more participating components. Such multi-lateral relations are not captured by graphs, and computational methods to overcome this limitation are currently lacking. This paper introduces hypergraphs and association hypergraphs to describe metabolic networks and their potential alignments, respectively. Within this framework, metabolic networks are aligned by identifying the maximal Z-eigenvalue of a symmetric tensor. A shifted higher order power method was utilized to identify a solution. A rotational strategy has been introduced to accelerate the tensor-vector product by 250-fold on average and reduce the storage cost by up to 1,000-fold. The algorithm was implemented on a spark-based distributed computation cluster to significantly increase the convergence rate further by 50- to 80-fold. The parameters have been explored to understand their impact on alignment accuracy and speed. In particular, the influence of initial value selection on the stationary point has been simulated to ensure an accurate approximation of the global optimum. This framework was demonstrated by alignments among the genome-wide metabolic networks of Escherichia coli MG-1655 and Halophilic archaeon DL31. To our knowledge, this is the first genome-wide metabolic network alignment at both the metabolite level and the enzyme level. These results demonstrate that it can supply quite a few valuable insights into metabolic networks. First, this method can access the driving force of organic reactions through the chemical evolution of metabolic network. Second, this method can incorporate the chemical information of enzymes and structural changes of compounds to offer new way defining reaction class and module, such as those in KEGG. Third, as a vertex-focused treatment, this method can supply novel structural and functional annotation for ill-defined molecules. The related source code is available on request. PMID- 30401916 TI - Garnet peridotites reveal spatial and temporal changes in the oxidation potential of subduction. AB - Changes in the oxygen fugacity (fO2) of the Earth's mantle have been proposed to control the spatial and temporal distribution of arc-related ore deposits, and possibly reflect the evolution of the atmosphere over billions of years. Thermodynamic calculations and natural evidence indicate that fluids released from subducting slabs can oxidise the mantle, but whether their oxidation potential varied in space and time remains controversial. Here, we use garnet peridotites from western Norway to show that there is a linear decrease in maximum fO2 with increasing depth in the mantle wedge. We ascribe this relation to changes in the speciation of sulfur released in slab fluids, with sulfate, controlling maximum oxidation, preferentially released at shallow depths. Even though the amount of sulfate in the Precambrian oceans, and thus in subducted lithologies, is thought to have been dramatically lower than during the Phanerozoic, garnet peridotites metasomatised during these two periods have a comparable fO2 range. This opens to the possibility that an oxidised mantle with fO2 similar to modern-day values has existed since the Proterozoic and possibly earlier. Consequently, early magmas derived from partial melting of metasomatised mantle may have had suitable fO2 to generate porphyry Cu-Au and iron-oxide Cu-Au deposits. PMID- 30401915 TI - Temporal changes of Sall4 lineage contribution in developing embryos and the contribution of Sall4-lineages to postnatal germ cells in mice. AB - Mutations in the SALL4 gene cause human syndromes with defects in multiple organs. Sall4 expression declines rapidly in post-gastrulation mouse embryos, and our understanding of the requirement of Sall4 in animal development is still limited. To assess the contributions of Sall4 expressing cells to developing mouse embryos, we monitored temporal changes of the contribution of Sall4 lineages using a Sall4 GFP-CreERT2 knock-in mouse line and recombination dependent reporter lines. By administering tamoxifen at various time points we observed that the contributions of Sall4 lineages to the axial level were rapidly restricted from the entire body to the posterior part of the body. The contribution to forelimbs, hindlimbs, craniofacial structures and external genitalia also declined after gastrulation with different temporal dynamics. We also detected Sall4 lineage contributions to the extra-embryonic tissues, such as the yolk sac and umbilical cord, in a temporal manner. These Sall4 lineage contributions provide insights into potential roles of Sall4 during mammalian embryonic development. In postnatal males, long-term lineage tracing detected Sall4 lineage contributions to the spermatogonial stem cell pool during spermatogenesis. The Sall4 GFP-CreERT2 line can serve as a tool to monitor spatial-temporal contributions of Sall4 lineages as well as to perform gene manipulations in Sall4-expressing lineages. PMID- 30401917 TI - Clinical spectrum of male patients with OFD1 mutations. AB - Oral-facial-digital syndrome type 1 (OFD1) is a ciliopathy characterized by oral, facial, and digital malformations that are often accompanied by polycystic lesion of the kidney and central nervous involvement. OFD1 shows an X-linked recessive inheritance caused by mutation in the OFD1 gene (Xp22.2). The disease is generally considered embryonic lethal for hemizygous males. However, males with OFD1 mutations were recently reported. Here, we report four additional Japanese male patients with OFD1 variants and describe the variable clinical manifestation and disease severity among the four patients. Patient 1 with pathogenic indels including a 19-bp deletion and 4-bp insertion (c.2600-18_2600delinsACCT) had end stage renal disease (ESRD) with bilateral cystic kidneys and sensory hearing loss. He showed neither intellectual disability nor facial or digital dysmorphism. Patient 2 with a missense variant in exon 7 (c.539 A > T, p.Asp180Val) presented head circumference enlargement, brachydactyly, high-arched palate, micropenis, severe global developmental delay, and ESRD. Patient 3 had a single base substitution at the splice donor site of intron 16 (c.2260 + 2 T > G) causing a 513-bp deletion at the transcript level. The patient had chronic kidney disease and speech delay, but no oral, facial, or digital dysmorphism. His uncle (patient 4) carried the same OFD1 variant and showed ESRD with extra-renal malformations including obesity and micropenis, which was previously diagnosed as Bardet-Biedl syndrome. The OFD1 mutations were not lethal in these four male patients, likely because the three mutations were in-frame or missense. This report provided insights into the onset mechanism and phenotype-genotype association in patients with OFD1 mutations. PMID- 30401918 TI - Management and diagnosis of mitochondrial fatty acid oxidation disorders: focus on very-long-chain acyl-CoA dehydrogenase deficiency. AB - Mitochondrial fatty acid oxidation disorders (FAODs) are caused by defects in beta-oxidation enzymes, including very long-chain acyl-CoA dehydrogenase (VLCAD), trifunctional protein (TFP), carnitine palmitoyltransferase-2 (CPT2), carnitine acylcarnitine translocase (CACT) and others. During prolonged fasting, infection, or exercise, patients with FAODs present with hypoglycemia, rhabdomyolysis, cardiomyopathy, liver dysfunction, and occasionally sudden death. This article describes the diagnosis, newborn screening, and treatment of long-chain FAODs with a focus on VLCAD deficiency. VLCAD deficiency is generally classified into three phenotypes based on onset time, but the classification should be comprehensively determined based on genotype, residual enzyme activity, and clinical course, due to a lack of apparent genotype-phenotype correlation. With the expansion of newborn screening for FAODs, several issues have arisen, such as missed detection, overdiagnosis (including detection of benign/asymptomatic type), and poor prognosis of the neonatal-onset form. Meanwhile, dietary management and restriction of exercise have been unnecessary for patients with the benign/asymptomatic type of VLCAD deficiency with a high fatty acid oxidation flux score. Although L-carnitine therapy for VLCAD/TFP deficiency has been controversial, supplementation with L-carnitine may be accepted for CPT2/CACT and multiple acyl-CoA dehydrogenase deficiencies. Recently, a double-blind, randomized controlled trial of triheptanoin (seven-carbon fatty acid triglyceride) versus trioctanoin (regular medium-chain triglyceride) was conducted and demonstrated improvement of cardiac functions on triheptanoin. Additionally, although the clinical efficacy of bezafibrate remains controversial, a recent open-label clinical trial showed efficacy of this drug in improving quality of life. These drugs may be promising for the treatment of FAODs, though further studies are required. PMID- 30401920 TI - Accuracy-Precision Trade-off in Human Sound Localisation. AB - Sensory representations are typically endowed with intrinsic noise, leading to variability and inaccuracies in perceptual responses. The Bayesian framework accounts for an optimal strategy to deal with sensory-motor uncertainty, by combining the noisy sensory input with prior information regarding the distribution of stimulus properties. The maximum-a-posteriori (MAP) estimate selects the perceptual response from the peak (mode) of the resulting posterior distribution that ensure optimal accuracy-precision trade-off when the underlying distributions are Gaussians (minimal mean-squared error, with minimum response variability). We tested this model on human eye- movement responses toward broadband sounds, masked by various levels of background noise, and for head movements to sounds with poor spectral content. We report that the response gain (accuracy) and variability (precision) of the elevation response components changed systematically with the signal-to-noise ratio of the target sound: gains were high for high SNRs and decreased for low SNRs. In contrast, the azimuth response components maintained high gains for all conditions, as predicted by maximum-likelihood estimation. However, we found that the elevation data did not follow the MAP prediction. Instead, results were better described by an alternative decision strategy, in which the response results from taking a random sample from the posterior in each trial. We discuss two potential implementations of a simple posterior sampling scheme in the auditory system that account for the results and argue that although the observed response strategies for azimuth and elevation are sub-optimal with respect to their variability, it allows the auditory system to actively explore the environment in the absence of adequate sensory evidence. PMID- 30401919 TI - Identification of candidate genes for leaf scorch in Populus deltoids by the whole genome resequencing analysis. AB - Leaf scorch exists as a common phenomenon in the development of plant, especially when plants encounter various adversities, which leads to great losses in agricultural production. Both Jinhong poplar (JHP) and Caihong poplar (CHP) (Populus deltoids) are obtained from a bud sport on Zhonghong poplar. Compared with CHP, JHP always exhibits leaf scorch, poor growth, premature leaf discoloration, and even death. In this study, the candidate genes associated with leaf scorch between JHP and CHP were identified by the whole genome resequencing using Illumina HiSeqTM. There were 218,880 polymorphic SNPs and 46,933 indels between JHP and CHP, respectively. Among these, the candidate genes carrying non synonymous SNPs in coding regions were classified into 6 groups. The expression pattern of these candidate genes was also explored in JHP and CHP among different sampling stages. Combined with the qRT-PCR analysis, the results showed that genes associated with transport of various nutritional elements, senescence and MYB transcription factor might play important roles during the process of leaf scorch in Populus deltoids. Four genes belonging to these three groups carried more than three SNPs in their coding sequence, which might play important roles in leaf scorch. The above results provided candidate genes involved in leaf scorch in Populus deltoids, and made us better understand the molecular regulation mechanism of leaf scorch in Populus deltoids. PMID- 30401921 TI - Compensatory conservation measures for an endangered caribou population under climate change. AB - Future human land use and climate change may disrupt movement behaviors of terrestrial animals, thereby altering the ability of individuals to move across a landscape. Some of the expected changes result from processes whose effects will be difficult to alter, such as global climate change. We present a novel framework in which we use models to (1) identify the ecological changes from these difficult-to-alter processes, as well as (2) the potential conservation measures that are best able to compensate for these changes. We illustrated this framework with the case of an endangered caribou population in Quebec, Canada. We coupled a spatially explicit individual-based movement model with a range of landscape scenarios to assess the impacts of varying degrees of climate change, and the ability of conservation actions to compensate for such impacts on caribou movement behaviors. We found that (1) climate change impacts reduced movement potential, and that (2) the complete restoration of secondary roads inside protected areas was able to fully offset this reduction, suggesting that road restoration would be an effective compensatory conservation action. By evaluating conservation actions via landscape use simulated by an individual-based model, we were able to identify compensatory conservation options for an endangered species facing climate change. PMID- 30401922 TI - AII amacrine cells in the primate fovea contribute to photopic vision. AB - The AII amacrine cell is known as a key interneuron in the scotopic (night vision) pathway in the retina. Under scotopic conditions, rod signals are transmitted via rod bipolar cells to AII amacrine cells, which split the rod signal into the OFF (via glycinergic synapses) and the ON pathway (via gap junctions). But the AII amacrine cell also has a "day job": at high light levels when cones are active, AII connections with ON cone bipolar cells provide crossover inhibition to extend the response range of OFF cone bipolar cells. The question whether AII cells contribute to crossover inhibition in primate fovea (where rods and rod bipolar cells are rare or absent) has not been answered. Here, immunohistochemistry and three-dimensional reconstruction show that calretinin positive cells in the fovea of macaque monkeys and humans have AII morphology and connect to cone bipolar cells. The pattern of AII connections to cone bipolar cells is quantitatively similar to that of AII cells outside the fovea. Our results support the view that in mammalian retina AII cells first evolved to serve cone circuits, then later were co-opted to process scotopic signals subsequent to the evolution of rod bipolar cells. PMID- 30401923 TI - Touchscreen testing reveals clinically relevant cognitive abnormalities in a mouse model of schizophrenia lacking metabotropic glutamate receptor 5. AB - Metabotropic glutamate receptor 5 (mGlu5) has been implicated in certain forms of synaptic plasticity and cognitive function. mGlu5 knockout (KO) mice and mGlu5 antagonists have been previously used to study the pathophysiology of schizophrenia as they have been shown respectively to display or induce endophenotypes relevant to schizophrenia. While schizophrenia presents with generalized cognitive impairments, the cognitive phenotype of mice lacking mGlu5 has so far only been explored using largely hippocampal-dependent spatial and contextual memory tasks. To address this, we used a touchscreen system to assess mGlu5 KO mice for pairwise visual discrimination, reversal learning, and extinction of an instrumental response requiring no discrimination. Furthermore, we tested the role of mGlu5 in working memory using the Trial-Unique Non-Matching to Location (TUNL) task utilizing pharmacological ablation. mGlu5 KO mice were impaired on discrimination learning, taking longer to reach criterion and requiring more correction learning trials. Performance on reversal learning was also impaired, with mGlu5 KO mice demonstrating a perseverative phenotype. The mGlu5 KO mice responded at a higher rate during extinction, consistent with this perseverative profile. In contrast, wildtype mice treated acutely with an mGlu5 antagonist (MTEP) showed no deficits in a touchscreen task assessing working memory. The present study demonstrates learning and memory deficits as well as an increased perseverative phenotype following constitutive loss of mGlu5 in this mouse model of schizophrenia. These findings will inform translational approaches using this preclinical model and the pursuit of mGlu5 as therapeutic target for schizophrenia and other brain disorders. PMID- 30401924 TI - Dissection of differential vanadate sensitivity in two Ogataea species links protein glycosylation and phosphate transport regulation. AB - The closely related yeasts Ogataea polymorpha and O. parapolymorpha differ drastically from each other by sensitivity to the toxic phosphate analog vanadate. Search for genes underlying this difference revealed two genes, one designated as ABV1 (Alcian Blue staining, Vanadate resistance), which encodes a homologue of Saccharomyces cerevisiae Mnn4 responsible for attachment of mannosylphosphate to glycoside chains of secretory proteins, and the other designated as its S. cerevisiae homologue PHO87, encoding the plasma membrane low affinity phosphate sensor/transporter. The effect of Pho87 on vanadate resistance was bidirectional, since it decreased the resistance on phosphate-depleted medium, but was required for pronounced protection against vanadate by external phosphate. This highlights the dual function of this protein as a low affinity phosphate transporter and an external phosphate sensor. Involvement of Pho87 in phosphate sensing was confirmed by its effects on regulation of the promoter of the PHO84 gene, encoding a high affinity phosphate transporter. The effect of Abv1 was also complex, since it influenced Pho87 level and enhanced repression of the PHO84 promoter via a Pho87-independent pathway. Role of the identified genes in the difference in vanadate resistance between O. polymorpha and O. parapolymorpha is discussed. PMID- 30401925 TI - DArTseq-based analysis of genomic relationships among species of tribe Triticeae. AB - Precise utilization of wild genetic resources to improve the resistance of their cultivated relatives to environmental growth limiting factors, such as salinity stress and diseases, requires a clear understanding of their genomic relationships. Although seriously criticized, analyzing these relationships in tribe Triticeae has largely been based on meiotic chromosome pairing in hybrids of wide crosses, a specialized and labourious strategy. In this study, DArTseq, an efficient genotyping-by-sequencing platform, was applied to analyze the genomes of 34 Triticeae species. We reconstructed the phylogenetic relationships among diploid and polyploid Aegilops and Triticum species, including hexaploid wheat. Tentatively, we have identified the diploid genomes that are likely to have been involved in the evolution of five polyploid species of Aegilops, which have remained unresolved for decades. Explanations which cast light on the progenitor of the A genomes and the complex genomic status of the B/G genomes of polyploid Triticum species in the Emmer and Timopheevi lineages of wheat have also been provided. This study has, therefore, demonstrated that DArTseq genotyping can be effectively applied to analyze the genomes of plants, especially where their genome sequence information are not available. PMID- 30401927 TI - Laminar profile of task-related plasticity in ferret primary auditory cortex. AB - Rapid task-related plasticity is a neural correlate of selective attention in primary auditory cortex (A1). Top-down feedback from higher-order cortex may drive task-related plasticity in A1, characterized by enhanced neural representation of behaviorally meaningful sounds during auditory task performance. Since intracortical connectivity is greater within A1 layers 2/3 (L2/3) than in layers 4-6 (L4-6), we hypothesized that enhanced representation of behaviorally meaningful sounds might be greater in A1 L2/3 than L4-6. To test this hypothesis and study the laminar profile of task-related plasticity, we trained 2 ferrets to detect pure tones while we recorded laminar activity across a 1.8 mm depth in A1. In each experiment we analyzed high-gamma local field potentials (LFPs) and multi-unit spiking in response to identical acoustic stimuli during both passive listening and active task performance. We found that neural responses to auditory targets were enhanced during task performance, and target enhancement was greater in L2/3 than in L4-6. Spectrotemporal receptive fields (STRFs) computed from both high-gamma LFPs and multi-unit spiking showed similar increases in auditory target selectivity, also greatest in L2/3. Our results suggest that activity within intracortical networks plays a key role in the underlying neural mechanisms of selective attention. PMID- 30401928 TI - Unveiling a magnetized jet from a low-mass protostar. AB - Protostellar jets are one of the most intriguing signposts in star formation. Recent detection of a jet rotation indicates that they can carry away angular momenta from the innermost edges of the disks, allowing the disks to feed the central protostars. In current jet-launching models, magnetic fields are required to launch and collimate the jets, however, observationally, it is still uncertain if magnetic fields are really present in the jets. Here we report a clear detection of SiO line polarization in the HH 211 protostellar jet. Since this line polarization has been attributed to the Goldreich-Kylafis effect in the presence of magnetic field, our observations show convincingly the presence of magnetic field in a jet from a low-mass protostar. The implied magnetic field could be mainly toroidal, as suggested in current jet-launching models, in order to collimate the jet at large distances. PMID- 30401926 TI - Enhanced food-related responses in the ventral medial prefrontal cortex in narcolepsy type 1. AB - Narcolepsy type 1 is a chronic sleep disorder caused by a deficiency of the orexin (hypocretin) neuropeptides. In addition to sleep regulation, orexin is important for motivated control processes. Weight gain and obesity are common in narcolepsy. However, the neurocognitive processes associated with food-related control and overeating in narcolepsy are unknown. We explored the neural correlates of general and food-related attentional control in narcolepsy-type-1 patients (n = 23) and healthy BMI-matched controls (n = 20). We measured attentional bias to food words with a Food Stroop task and general executive control with a Classic Stroop task during fMRI. Moreover, using multiple linear regression, we assessed the relative contribution of neural responses during Food Stroop and Classic Stroop to spontaneous snack intake. Relative to healthy controls, narcolepsy patients showed enhanced ventral medial prefrontal cortex responses and connectivity with motor cortex during the Food Stroop task, but attenuated dorsal medial prefrontal cortex responses during the Classic Stroop task. Moreover, the former activity but not the latter, was a significant predictor of spontaneous snack intake. These findings demonstrate that narcolepsy, characterized by orexin deficiency, is associated with decreased dorsal medial prefrontal cortex responses during general executive control and enhanced ventral medial prefrontal cortex responses during food-driven attention. PMID- 30401929 TI - On the detection of carbon fibre storage contamination and its effect on the fibre-matrix interface. AB - Contamination caused by inappropriate carbon fibre (CF) storage may have an impact on their end use in reinforced composite materials. Due to the chemical complexity of CFs it is not easy to detect potential contaminants, especially at the early stage during manufacturing and handling. In this paper, X-ray Photoelectron Spectroscopy (XPS), Fourier Transform Infrared (FTIR) spectroscopy and Surface Energy Analysis (IGC-SEA) were used to assess the surfaces of CFs stored in polyolefin zip-lock bags for possible contamination. Only after over 2 months in-bag storage, was XPS capable of detecting a minor increase in nitrogen on the CF surface while FTIR revealed the presence of fatty acid amides and fatty acids, both associated with the storage media. However neither of these techniques were sensitive enough to show significant evolution of the amount of contamination as a function of storage time. In contrast, IGC-SEA distinguished surface energy differences between CFs before and after storage. These differences were found to change as a function of storage time, which were attributed to increases in contamination amounts. Single fibre fragmentation tests indicated that the surface contamination had potential to disrupt the fibre matrix interface. These findings provide a new method for assessing the surface contamination of CFs with potential application to other materials. PMID- 30401930 TI - Microinjection to deliver protein, mRNA, and DNA into zygotes of the cnidarian endosymbiosis model Aiptasia sp. AB - Reef-building corals depend on an intracellular symbiosis with photosynthetic dinoflagellates for their survival in nutrient-poor oceans. Symbionts are phagocytosed by coral larvae from the environment and transfer essential nutrients to their hosts. Aiptasia, a small tropical marine sea anemone, is emerging as a tractable model system for coral symbiosis; however, to date functional tools and genetic transformation are lacking. Here we have established an efficient workflow to collect Aiptasia eggs for in vitro fertilization and microinjection as the basis for experimental manipulations in the developing embryo and larvae. We demonstrate that protein, mRNA, and DNA can successfully be injected into live Aiptasia zygotes to label actin with recombinant Lifeact-eGFP protein; to label nuclei and cell membranes with NLS-eGFP and farnesylated mCherry translated from injected mRNA; and to transiently drive transgene expression from an Aiptasia-specific promoter, respectively, in embryos and larvae. These proof-of-concept approaches pave the way for future functional studies of development and symbiosis establishment in Aiptasia, a powerful model to unravel the molecular mechanisms underlying intracellular coral-algal symbiosis. PMID- 30401932 TI - Benefit with VR-CAP in mantle cell lymphoma. PMID- 30401933 TI - Interferon enhances immune-checkpoint inhibition. PMID- 30401931 TI - Progressive hearing loss in vitamin A-deficient mice which may be protected by the activation of cochlear melanocyte. AB - Vitamin A deficiency (VAD) produces various pathologic phenotypes in humans and animals. However, evidence regarding the effect of VAD on hearing function has been inconsistent. In this study, we evaluated the effect of VAD on hearing function in two mouse models of VAD. Hearing ability was evaluated on the basis of auditory brainstem response from 3 to 20 weeks after birth in C57BL/6 (pigmented) and imprinting control region (albino) mice. The two mice strains were divided into the VAD (purified vitamin A-free diet from 7 days after pregnancy) and control (normal diet) groups. Albino VAD mice exhibited hearing loss after 6 weeks and became deaf at 18 weeks. Histological findings revealed degenerative changes in outer hair cells and neuronal loss in the spiral ganglion in albino VAD mice. In contrast, pigmented VAD mice, except those with middle-ear infection, showed no significant hearing loss. Interestingly, pigmented VAD mice exhibited melanocyte activation in the stria vascularis and upregulation of tyrosinase. Recovery of hearing after noise exposure was poorer in pigmented VAD mice than in control mice. In conclusion, complete VAD might be related to age related or noise-induced hearing loss in mice, protection against which might involve melanocyte activation. PMID- 30401934 TI - Outcomes depend on tumour histology. PMID- 30401935 TI - Benefit in patients with PD-L1-positive TNBC. PMID- 30401936 TI - Time to abandon single-site irradiation for inducing abscopal effects. AB - Considerable interest is being directed toward combining immune-checkpoint inhibition (ICI) with radiotherapy to improve response rates to ICI, which have been disappointingly low at around 15-30% among patients with advanced-stage cancers other than melanoma. Since a case report published in 2012, in which authors described the resolution of metastatic disease after irradiation of a single lesion in a patient who had been receiving ICI, hundreds of clinical trials have been launched with the aim of testing the safety and/or efficacy of radiotherapy in combination with immunotherapy, nearly all of which use this single-site irradiation, or 'abscopal', approach. However, emerging preclinical and clinical evidence suggests that this approach likely produces suboptimal results. In this Perspective, we describe this evidence and provide a biological rationale supporting the abandonment of the single-site abscopal approach. We instead advocate exploring comprehensive irradiation of multiple/all lesions in order to enhance the likelihood of obtaining meaningful clinical outcomes - if such a clinical synergy between radiation and ICI does exist - before the failure of the current, single-site approach leads to the potential premature and inappropriate abandonment of radiotherapy in combination with ICI altogether. PMID- 30401939 TI - High volume fly ash mortar containing nano-calcium carbonate as a sustainable cementitious material: microstructure and strength development. AB - The mechanisms underlying the effects of nano-calcium carbonate (NC) on the strength of high volume fly ash (FA) mortar are discussed. Two NCs are used as 2%, 4%, 6%, and 8% by weight of cementitious materials. Hydrated products of fly ash mortar containing NC was investigated using X-ray diffraction (XRD), scanning electron microscopy (SEM), thermogravimetric analysis (TG) and differential thermal gravity (DTG) analysis. Results indicate that NC could improve strength of FA mortar due to the more rapid growth of hydrated products induced by NC through additional nucleation sites. Corresponding to the highest measured strength of FA mortar, the optimal contents of NC are around 2%. In addition, the presence of 2% NC improved the microstructure of FA mortar after 180 days due to the formation of calcium carbonaluminate hydrate. PMID- 30401938 TI - Drought-induced susceptibility for Cenangium ferruginosum leads to progression of Cenangium-dieback disease in Pinus koraiensis. AB - Recently, the occurrence of "Cenangium-dieback" has been frequent and devastating. Cenangium-dieback is caused by an endophytic fungus Cenangium ferruginosum in stressed pine trees. Progression of the disease in terms of molecular interaction between host and pathogen is not well studied and there is a need to develop preventive strategies. Thus, we simulated disease conditions and studied the associated transcriptomics, metabolomics, and hormonal changes. Pinus koraiensis seedlings inoculated with C. ferruginosum were analyzed both under drought and well-watered conditions. Transcriptomic analysis suggested decreased expression of defense-related genes in C. ferruginosum-infected seedlings experiencing water-deficit. Further, metabolomic analysis indicated a decrease in the key antimicrobial terpenoids, flavonoids, and phenolic acids. Hormonal analysis revealed a drought-induced accumulation of abscisic acid and a corresponding decline in the defense-associated jasmonic acid levels. Pathogen associated changes were also studied by treating C. ferruginosum with metabolic extracts from pine seedlings (with and without drought) and polyethylene glycol to simulate the effects of direct drought. From RNA sequencing and metabolomic analysis it was determined that drought did not directly induce pathogenicity of C. ferruginosum. Collectively, we propose that drought weakens pine immunity, which facilitates increased C. ferruginosum growth and results in conversion of the endophyte into the phytopathogen causing dieback. PMID- 30401937 TI - Proteomics as a new tool to study fingermark ageing in forensics. AB - Fingermarks are trace evidence of great forensic importance, and their omnipresence makes them pivotal in crime investigation. Police and law enforcement authorities have exploited fingermarks primarily for personal identification, but crucial knowledge on when fingermarks were deposited is often lacking, thereby hindering crime reconstruction. Biomolecular constituents of fingermark residue, such as amino acids, lipids and proteins, may provide excellent means for fingermark age determination, however robust methodologies or detailed knowledge on molecular mechanisms in time are currently not available. Here, we address fingermark age assessment by: (i) drafting a first protein map of fingermark residue, (ii) differential studies of fresh and aged fingermarks and (iii), to mimic real-world scenarios, estimating the effects of donor contact with bodily fluids on the identification of potential age biomarkers. Using a high-resolution mass spectrometry-based proteomics approach, we drafted a characteristic fingermark proteome, of which five proteins were identified as promising candidates for fingermark age estimation. This study additionally demonstrates successful identification of both endogenous and contaminant proteins from donors that have been in contact with various bodily fluids. In summary, we introduce state-of-the-art proteomics as a sensitive tool to monitor fingermark aging on the protein level with sufficient selectivity to differentiate potential age markers from body fluid contaminants. PMID- 30401940 TI - The arrangement of lateral veins along the midvein of leaves is not related to leaf phyllotaxis. AB - Positions of leaves along a stem usually adhere to a genetically determined, species-specific pattern known as a leaf phyllotaxis. We investigated whether the arrangement of lateral secondary veins along primary midveins adhered to a species-specific pattern that resembled an alternate or opposite phyllotaxis. We analyzed the venation of temperate dicotyledonous species from different taxonomic groups and chose 18 woody and 12 herbaceous species that have reticulated leaf venation. The arrangement of the lateral veins was neither alternate nor opposite for any of the species. Lateral vein arrangements were instead mixtures of symmetric and asymmetric patterns. Our results show that lateral vein arrangements are related neither to stem-level leaf phyllotaxis (alternate vs. opposite) nor to life form (woody vs. herbaceous). Our results are therefore generally consistent with the canalization hypothesis that the locations of lateral veins are not completely specified genetically prior to leaf formation. PMID- 30401941 TI - Radiation-induced late dysphagia after intensity-modulated radiotherapy in nasopharyngeal carcinoma patients: a dose-volume effect analysis. AB - Dysphagia is a side effect of nasopharyngeal carcinoma chemo-radiotherapy (CRT) which greatly influences the quality of life of the patients. We analyzed late dysphagia in 134 patients with nasopharyngeal cancer undergoing radical radiotherapy (RT), and correlated these findings with dose-volume histogram (DVH) parameters of the swallowing organs at risk (SWOARs). DVH parameters of SWOARs were correlated with late dysphagia, and with RTOG/EORTC scale score and the M. D. Anderson dysphagia inventory (MDADI) score. The mean dose (Dmean) to the superior and inferior constrictor muscles (SCM and ICM) and age were associated with grade 2 late dysphagia. Receiver operating characteristic (ROC) curves showed that the threshold values for grade 2 late dysphagia were: Dmean to SCM >= 67 Gy, partial volume receiving specified dose of 60 Gy (V60) of SCM >= 95%, Dmean to ICM >= 47 Gy, and V50 of ICM >= 23%. The areas under the ROC curve were 0.681 (p = 0.02), 0.677 (p = 0.002), 0.71 (p < 0.001) and 0.726 (p < 0.001) respectively. Our study demonstrates a significant relationship between late dysphagia and the radiation doses delivered to the SCM and ICM. Our findings suggest that physicians should be cautious in reducing the RT dose to SWOARs in order to avoid severe dysphagia. Further prospective trials are necessary to recommend this as part of routine clinical practice. PMID- 30401942 TI - Correction: Chronic clozapine treatment restrains via HDAC2 the performance of mGlu2 receptor agonism in a rodent model of antipsychotic activity. AB - Following the publication of this article Figs. 3b, c were published incorrectly. Also in sub-panel c of Fig. 4, 'Chronic cloza ine' should read 'Chronic clozapine'. PMID- 30401944 TI - Design the magnetic microencapsulated phase change materials with poly(MMA-MAA) @ n-octadecane modified by Fe3O4. AB - Magnetic microencapsulated phase change materials (magnetic MicroPCMs) are hotly researched for their dual-functions with phase change and magnetic properties, which provided the new applications in fields of maneuverable phase change materials and infrared electromagnetic dual shield. A series of magnetic MicroPCMs samples are synthesized by polymerization and coprecipitation method and the chemical composition contained poly(MMA-MAA) @ n-octadecane modified by Fe3O4. In addition, the characterizations exhibit the excellent magnetic and phase change properties. The magnetic MicroPCMs samples present 20 emu.g-1 saturation magnetization with still high enthalpy of 132 J.g-1, which fully illustrates that the magnetic MicroPCMs fulfill both application on thermal energy storage and magnetic control. PMID- 30401943 TI - Biological interactions of biocompatible and water-dispersed MoS2 nanosheets with bacteria and human cells. AB - Two dimensional materials beyond graphene such as MoS2 and WS2 are novel and interesting class of materials whose unique physico-chemical properties can be exploited in applications ranging from leading edge nanoelectronics to the frontiers between biomedicine and biotechnology. To unravel the potential of TMD crystals in biomedicine, control over their production through green and scalable routes in biocompatible solvents is critically important. Furthermore, considering multiple applications of eco-friendly 2D dispersions and their potential impact onto live matter, their toxicity and antimicrobial activity still remain an open issue. Herein, we focus on the current demands of 2D TMDs and produce high-quality, few-layered and defect-free MoS2 nanosheets, exfoliated and dispersed in pure water, stabilized up to three weeks. Hence, we studied the impact of this material on human cells by investigating its interactions with three cell lines: two tumoral, MCF7 (breast cancer) and U937 (leukemia), and one normal, HaCaT (epithelium). We observed novel and intriguing results, exhibiting evident cytotoxic effect induced in the tumor cell lines, absent in the normal cells in the tested conditions. The antibacterial action of MoS2 nanosheets is then investigated against a very dangerous gram negative bacterium, such as two types of Salmonellas: ATCC 14028 and wild-type Salmonella typhimurium. Additionally, concentration and layer-dependent modulation of cytotoxic effect is found both on human cells and Salmonellas. PMID- 30401945 TI - A pattern-based approach to the interpretation of skeletal muscle biopsies. AB - The interpretation of muscle biopsies is complex and provides the most useful information when integrated with the clinical presentation of the patient. These biopsies are performed for workup of a wide range of diseases including dystrophies, metabolic diseases, and inflammatory processes. Recent insights have led to changes in the classification of inflammatory myopathies and have changed the role that muscle biopsies have in the workup of inherited diseases. These changes will be reviewed. This review follows a morphology-driven approach by discussing diseases of skeletal muscle based on a few basic patterns that include cases with (1) active myopathic damage and inflammation, (2) active myopathic damage without associated inflammation, (3) chronic myopathic changes, (4) myopathies with distinctive inclusions or vacuoles, (5) biopsies mainly showing atrophic changes, and (6) biopsies that appear normal on routine preparations. Each of these categories goes along with certain diagnostic considerations and pitfalls. Individual biopsy features are only rarely pathognomonic. Establishing a firm diagnosis therefore typically requires integration of all of the biopsy findings and relevant clinical information. With this approach, a muscle biopsy can often provide helpful information in the diagnostic workup of patients presenting with neuromuscular problems. PMID- 30401946 TI - Revisiting the role of the pathological grading in pediatric adrenal cortical tumors: results from a national cohort study with pathological review. AB - The prognosis of malignant pediatric adrenocortical tumors is closely related to disease stage, which is used to guide perioperative treatment recommendations. However, current scoring systems are inadequate to distinguish between benign and malignant adrenocortical tumors. Robust microscopic prognostic features that could help determine perioperative therapy are also lacking. The aim of this national study was to review the prognostic value of the Wieneke scoring criteria and Ki67 labeling index in unselected pediatric adrenocortical tumors. Using strict definitions previously defined by expert pathologists, a Wieneke score was re-attributed to each tumor after an independent and centralized review. In addition, Ki67 proliferation index was performed and reviewed for each case. A total of 95 cases were selected; all were treated between 2000 and 2018 and had histopathologic material and sufficient outcome-related information available. Localized disease was found in 88% of patients. Among those with advanced disease, 6% had tumor extension into adjacent organs and 5% had metastases at diagnosis. Median follow-up was 5 years and 3 months. The 5-year PFS was 82%, 95% CI [73%-91%]. Tumor stage significantly correlated with PFS (p < 0.0001). Tumor weight up to 200 g, extra-adrenal extension and initial non-complete surgical resection were statistically associated with worse outcomes. No recurrences nor metastases occurred when the Ki67 index was < 15%. Up to two of the following five factors including tumor necrosis, adrenal capsular invasion, venous invasion, mitotic count > 15/20 high-power fields, and Ki67 index > 15%, significantly correlated with worse outcomes. We propose a pathological scoring system incorporating the Ki67 index as part of a two-step approach after disease staging to guide adjuvant treatment in pediatric adrenocortical tumors, especially after incomplete resection. These results should be validated in an independent cohort. PMID- 30401947 TI - Programmed death ligand-1 expression in non-small cell lung cancer in a Western Australian population and correlation with clinicopathologic features. AB - Immune checkpoint inhibition is an important therapeutic option in patients with non-small cell lung cancer. Programmed cell death ligand-1 (PD-L1) expression may serve as a predictive marker for anti-PD-1/PD-L1 therapies. The relationship between non-small cell lung cancer PD-L1 expression and clinicopathological characteristics remains unclear and there is no population level Australian data. We report the results of PD-L1 testing in patients with non-small cell lung cancer diagnosed at major Western Australian public hospitals served by a single state Pathology provider. We analyzed PD-L1 expression by immunohistochemistry in 241 non-small cell lung cancer specimens using the 22C3 clone on a Dako autostainer platform. Tumor cell PD-L1 expression was scored as Tumor Proportion Score and categorized using pre-specified subsets of 1%, 1-49% and >= 50% for correlation with clinicopathologic features. PD-L1 Tumor Proportion Score was 1% in 65 (27%) cases, 1-49% in 100 (41%) cases and >= 50% in 76 (32%) cases. PD-L1 positive rate was 92% in squamous cell carcinomas and 67% in adenocarcinomas. PD L1 Tumor Proportion Score was higher in squamous cell carcinomas (p = 0.004) and lower in adenocarcinomas (p = 0.003). Of the 196 non-squamous carcinomas, 35% had rat sarcoma viral oncogene homolog (RAS) mutations, 13% had epidermal growth factor receptor (EGFR) mutations, 2% had anaplastic lymphoma kinase (ALK) translocations and 2% had ROS1 translocations. Tumor Proportion Score >= 50% was seen in 34% (23/68), 28% (7/25) and 25% (1/4) of RAS, EGFR mutant, and ALK translocated carcinomas, respectively. There was no significant correlation between PD-L1 expression and molecular or genetic abnormalities, or other parameters including age, gender, stage, and smoking status. In our patient cohort, PD-L1 Tumor Proportion Score was significantly higher in squamous cell carcinomas and lower in adenocarcinomas. The overall prevalence of Tumor Proportion Score >= 50% is consistent with that reported in clinical trials. PMID- 30401948 TI - Hematopoietic neoplasms with 9p24/JAK2 rearrangement: a multicenter study. AB - The purpose of this study is to examine hematopoietic neoplasms with 9p24/JAK2 rearrangement including neoplasms associated with t(8;9)(p22;p24)/PCM1-JAK2 fusion neoplasm as well as cases with translocations involving 9p24/JAK2 and other partner genes. From seven large medical centers, we identified ten patients with t(8;9)(p22;p24) /PCM1-JAK2 and 3 with t(9p24;v)/JAK2 at diagnosis. Majority of the cases showed myeloproliferative neoplasm (MPN) associated features (n = 7) characterized by variable degrees of eosinophilia, myelofibrosis, frequent proliferations of early erythroblasts in bone marrow and extramedullary sites, and infrequent/absent somatic mutations. Other less common presentations included myelodysplastic syndromes (MDS) or MDS/MPN (one each). Four patients presented with B-lymphoblastic leukemia (B-ALL), and of them, two patients with t(8;9)(p22;p24.1) were proven to be B-lymphoblastic crisis of MPN; and the other two cases with t(9p24;v) both were de novo B-ALL, BCR-ABL1-like (Ph-like). We show that the hematopoietic neoplasms with 9p24/JAK2 rearrangement are extremely rare, and most of them are associated with t(8;9)(p22;p24)/PCM1-JAK2, a recent provisional World Health Organization entity under "myeloid/lymphoid neoplasm with a specific gene rearrangement". Cases of t(8;9)(p22;p24)/PCM1-JAK2, though heterogeneous, do exhibit some common clinicopathological characteristic features. Cases with t(9p24;v)/JAK2 are extremely rare; while such cases with a MPN presentation may resemble t(8;9)(p22;p24.1)/PCM1-JAK2, B-ALL cases presenting de novo B-ALL might belong to Ph-like B-ALL. PMID- 30401949 TI - T cell-inflamed phenotype and increased Foxp3 expression in infiltrating T-cells of mismatch-repair deficient endometrial cancers. AB - Mismatch repair-deficient endometrial cancers have a high somatic mutation burden, suggesting that patients with these tumors may benefit from immunotherapy. Elucidating the immune suppressive mechanisms of mismatch repair deficient endometrial cancers is fundamental to developing future immune-based interventions. This study aimed to determine the immune cell populations associated with mismatch repair-deficient endometrial cancers, especially focusing on targetable regulatory pathways of the immune response. A total of 76 endometrial cancer hysterectomy specimens were evaluated for tumor-infiltrating immune cells by immunohistochemistry. Immune specific markers were used to evaluate each specimen for the number of CD8 + cytotoxic T lymphocytes, forkhead box P3 (FoxP3) + regulatory T cells, CD68 + tumor-associated macrophages, as well as programmed death-1 (PD-1) + immune cells, and the percentage of programmed death ligand-1 (PD-L1) + immune cells. Mismatch repair-deficient tumors exhibited a significantly higher number of CD8 + cytotoxic T lymphocytes (p = 0.0006), FoxP3 + regulatory T cells (p = 0.0003), PD-1 + immune cells (p = 0.0069), and a higher percentage of PD-L1 + immune cells (p = 0.0007) occupying the tumor compared to mismatch repair-proficient endometrial cancers. There was no significant difference in CD68 + tumor-associated macrophages infiltration between the two groups. Endometrial cancers with tumor PD-L1 expression also showed significantly increased infiltration of CD8 + cytotoxic T lymphocytes (p = 0.0002), FoxP3 + regulatory T cells (p = 0.0003), PD-1 + immune cells (p < 0.0001), and PD-L1 + immune cells (p < 0.0001). Endometrial cancers showing mismatch repair-deficiency and PD-L1 expression in tumor cells exhibit a prominent T cell-inflamed phenotype. More importantly, the increased number of FoxP3 + regulatory T cells in mismatch repair-deficient endometrial cancers suggests that combination therapy by targeting both regulatory T cells and immune checkpoints may be warranted to improve clinical efficacy. PMID- 30401950 TI - Linking Structure to Dynamics in Protic Ionic Liquids: A Neutron Scattering Study of Correlated and Single-Particle Motions. AB - Coupling between dynamical heterogeneity of ionic liquids and their structural periodicity on different length-scales can be directly probed by quasielastic neutron scattering with polarization analysis. The technique provides the tools to investigate single-particle and cooperative ion motions separately and, thus, dynamics of ion associations affecting the net charge transport can be experimentally explored. The focus of this study is the structure-dynamic relationship in the protic ionic liquid, triethylammonium triflate, characterized by strong hydrogen bonds between cations and anions. The site-selective deuterium/hydrogen-isotope substitution was applied to modulate the relative contributions of different atom groups to the total coherent and incoherent scattering signal. This approach in combination with molecular dynamics simulations allowed us to obtain a sophisticated description of cation self diffusion and confined ion pair dynamics from the incoherent spectral component by using the acidic proton as a tagged particle. The coherent contribution of the neutron spectra demonstrated substantial ion association leading to collective ion migration that preserves charge alteration on picosecond time scale, as well as correlation of the localized dynamics occurring between adjacent ions. PMID- 30401951 TI - Unravelling the Role of O-glycans in Influenza A Virus Infection. AB - The initial stage of host cell infection by influenza A viruses (IAV) is mediated through interaction of the viral haemagglutinin (HA) with cell surface glycans. The binding requirement of IAVs for Galbeta(1,4)Glc/ GlcNAc (lactose/lactosamine) glycans with a terminal alpha(2,6)-linked (human receptors) or alpha(2,3)-linked (avian receptors) N-acetylneuraminic residue commonly found on N-glycans, is well established. However the role and significance of sialylated Galbeta(1,3)GalNAc (core 1) epitopes that are typical O-glycoforms in influenza virus pathogenesis remains poorly detailed. Here we report a multidisciplinary study using NMR spectroscopy, virus neutralization assays and molecular modelling, into the potential for IAV to engage sialyl-Galbeta(1,3)GalNAc O-glycoforms for cell attachment. H5 containing virus like particles (VLPs) derived from an H5N1 avian IAV strain show a significant involvement of the O-glycan-specific GalNAc residue, coordinated by a EQTKLY motif conserved in highly pathogenic avian influenza (HPAI) strains. Notably, human pandemic H1N1 influenza viruses shift the preference from 'human-like' alpha(2,6)-linkages in sialylated Galbeta(1,4)Glc/GlcNAc fragments to 'avian-like' alpha(2,3)-linkages in sialylated Galbeta(1,3)GalNAc without involvement of the GalNAc residue. Overall, our study suggests that sialylated Galbeta(1,3)GalNAc as O-glycan core 1 glycoforms are involved in the influenza A virus life cycle and play a particularly crucial role during infection of HPAI strains. PMID- 30401952 TI - A Novel Design of a Plate for Posterolateral Tibial Plateau Fractures Through Traditional Anterolateral Approach. AB - Biomechanical performance of a newly designed plate for treating posterolateral tibial plateau fractures was compared with three traditional internal fixation devices using finite element analysis (FEA) and biomechanical experiments. Forty synthetic tibias were used to create posterolateral shearing tibial fracture models, which were randomly assigned to groups A-D. The fragments were fixed with two 6.5-mm lag screws (group A), the newly designed plate (group B), a 3.5-mm lateral locking plate (group C), and a posterolateral buttress plate (group D). In the biomechanical experiment, vertical displacement of the posterolateral fragments was measured under axial loads of 500-1500 N. In the FEA, vertical displacement of the posterolateral fragments and stress distribution and maximum stress of each internal fixation were measured under axial loads of 250-750 N. Biomechanically, collective ranges of vertical displacements in the four groups were 0.356 +/- 0.089-1.055 +/- 0.023 mm at 500 N axial load, 0.651 +/- 0.062 1.525 +/- 0.03 mm at 1000 N, and 0.903 +/- 0.077-1.796 +/- 0.04 mm at 1500 N. Differences between the four groups were statistically significant (P < 0.05), except for groups B and C at 1500 N. FEA showed that collective ranges of vertical displacements in the four groups were 0.290-1.425 mm at of 250 N axial load, 0.580-1.680 mm at 500 N, 1.067-1.818 mm at 750 N. Maximum stress of groups A-D were, respectively, 321.940, 132.660, 100.383, and 321.940 MPa under 250 N axial load. Maximum stress of all four internal fixations increased, and the overall trends at 500 and 750 N were consistent with that at 250 N. Posterior, straight fixation was the most reliable. Fixation with the lag screw was least reliable. The new plate and 3.5-mm lateral locking plate exhibited similar control over fragment displacement. The newly designed plate was stable and reliable, indicating its suitability for clinical application. PMID- 30401953 TI - Chelating agent-assisted in situ LDH growth on the surface of magnesium alloy. AB - In situ formation of layered double hydroxides (LDH) on metallic surfaces has recently been considered a promising approach for protective conversion surface treatments for Al and Mg alloys. In the case of Mg-based substrates, the formation of LDH on the metal surface is normally performed in autoclave at high temperature (between 130 and 170 degrees C) and elevated pressure conditions. This hampers the industrial application of MgAl LDH to magnesium substrates. In this paper, the growth of MgAl LDH conversion coating directly on magnesium alloy AZ91 at ambient conditions (25 degrees C) or elevated temperatures is reported in carbonate free electrolyte for the first time. The direct LDH synthesis on Mg alloys is enabled by the presence of organic chelating agents (NTA and EDTA), which control the amount of free and/or hydroxyl bound Mg2+ and Al3+ in the solution. The application of the chelating agents help overcoming the typical technological limitations of direct LDH synthesis on Mg alloys. The selection of chelators and the optimization of the LDH treatment process are supported by the analysis of the thermodynamic chemical equilibria. PMID- 30401954 TI - Prediction of LncRNA Subcellular Localization with Deep Learning from Sequence Features. AB - Long non-coding RNAs are involved in biological processes throughout the cell including the nucleus, chromatin and cytosol. However, most lncRNAs remain unannotated and functional annotation of lncRNAs is difficult due to their low conservation and their tissue and developmentally specific expression. LncRNA subcellular localization is highly informative regarding its biological function, although it is difficult to discover because few prediction methods currently exist. While protein subcellular localization prediction is a well-established research field, lncRNA localization prediction is a novel research problem. We developed DeepLncRNA, a deep learning algorithm which predicts lncRNA subcellular localization directly from lncRNA transcript sequences. We analyzed 93 strand specific RNA-seq samples of nuclear and cytosolic fractions from multiple cell types to identify differentially localized lncRNAs. We then extracted sequence based features from the lncRNAs to construct our DeepLncRNA model, which achieved an accuracy of 72.4%, sensitivity of 83%, specificity of 62.4% and area under the receiver operating characteristic curve of 0.787. Our results suggest that primary sequence motifs are a major driving force in the subcellular localization of lncRNAs. PMID- 30401955 TI - Retraction Note: The Role of Scleraxis in Fate Determination of Mesenchymal Stem Cells for Tenocyte Differentiation. AB - This paper has been retracted. PMID- 30401956 TI - ZNF326 promotes proliferation of non-small cell lung cancer cells by regulating ERCC1 expression. AB - The roles and downstream target genes of the transcription factor ZNF326 in malignant tumors are unclear. Out of 146 lung cancer tissue samples, we found that high expression of ZNF326 in 82 samples was closely related to low differentiation and a high pTNM stage of non-small cell lung cancer (NSCLC) cells. In vitro and in vivo analyses showed that ZNF326 significantly promoted cell cycle progression, colony formation, and proliferation as well as the growth of NSCLC transplanted tumors. Chromatin immunoprecipitation sequencing, dual luciferase assay, and electrophoretic mobility shift assay confirmed that the C2H2 structure of ZNF326 binds to the -833 to -875 bp region of the ERCC1 promoter to initiate transcriptional activity. This binding promoted CyclinB1 synthesis and cell cycle progression. These results show that the ZNF326 transcription factor is highly expressed in lung cancer and promotes the proliferation of NSCLC cells by regulating the expression of ERCC1. PMID- 30401957 TI - Live imaging of collagen deposition during experimental hepatic schistosomiasis and recovery: a view on a dynamic process. AB - Hepatic fibrosis is the central cause of chronic clinical pathology resulting from infection by the blood flukes Schistosoma japonicum or S. mansoni. Much has been elucidated regarding the molecular, cellular and immunological responses that correspond to the formation of the granulomatous response to trapped schistosome eggs. A central feature of this Th2 response is the deposition of collagen around the periphery of the granuloma. To date, traditional histology and transcriptional methods have been used to quantify the deposition of collagen and to monitor the formation of the hepatic granuloma during experimental animal models of schistosomiasis. We have investigated the dynamic nature of granuloma formation through the use of a transgenic mouse model (B6.Collagen 1(A) luciferase mice (B6.Coll 1A-luc+)). With this model and whole-animal bioluminescence imaging, we followed the deposition of collagen during an active schistosome infection with Chinese and Philippines geographical strains of S. japonicum and after clearance of the adult parasites by the drug praziquantel. Individual mice were re-imaged over the time course to provide robust real-time quantitation of the development of chronic fibrotic disease. This model provides an improved method to follow the course of hepatic schistosomiasis-induced hepatic pathology and effectively supports the current dogma of the formation of hepatic fibrosis, originally elucidated from static traditional histology. This study demonstrates the first use of the B6.Coll 1A-luc+ mouse to monitor the dynamics of disease development and the treatment of pathogen-induced infection with the underlying pathology of fibrosis. PMID- 30401958 TI - Membrane protein CD9 is repositioned and released to enhance uterine function. AB - Tetraspanin CD9 is essential for sperm-egg fusion and also contributes to uterine repair through microexosome formation. Microexosomes share CD9 with exosomes and are released from eggs and uterine epithelial cells. However, the mechanism for the formation of microexosomes remains unknown. To address this issue, we examined membrane localization and extracellular release of CD9 proteins using uterine epithelial cells and secretions in mice and humans. In mice, CD9 localized predominantly on the basal region of the plasma membrane and relocated to the apical region upon embryo implantation. Furthermore, extracellular CD9 proteins were detected in uterine secretions of mice and women undergoing infertility treatment, but were below detectable levels in supernatants of pluripotent stem cells. Ultrastructural analysis demonstrated that membrane projections were shortened and the number of mitochondria was reduced in uterine epithelial cells lacking Cd9 genes. Our results suggest that CD9 repositioning and release affect both membrane structures and mitochondrial state in the uterus, and contribute to female fertility. PMID- 30401959 TI - Nondestructive, multiplex three-dimensional mapping of immune infiltrates in core needle biopsy. AB - Enumeration of tumor-infiltrating lymphocytes (TILs) in H&E stained tissue sections has demonstrated limited value in predicting immune responses to cancer immunotherapy, likely reflecting the diversity of cell types and immune activation states among tumor infiltrates. Multiparametric flow cytometry enables robust phenotypic and functional analysis to distinguish suppression from activation, but tissue dissociation eliminates spatial context. Multiplex methods for immunohistochemistry (IHC) are emerging, but these interrogate only a single tissue section at a time. Here, we report transparent tissue tomography (T3) as a tool for three-dimensional (3D) imaging cytometry in the complex architecture of the tumor microenvironment, demonstrating multiplexed immunofluorescent analysis in core needle biopsies. Using T3 imaging, image processing and machine learning to map CD3+CD8+ cytotoxic T cells (CTLs) in whole core needle biopsies from Her2+ murine mammary tumors and human head and neck surgical specimens revealed marked inhomogeneity within single needle cores, confirmed by serial section IHC. Applying T3 imaging cytometry, we discovered a strong spatial correlation between CD3+CD8+ CTLs and microvasculature in the EGFR+ parenchyma, revealing significant differences among head and neck cancer patients. These results show that T3 offers simple and rapid access to three-dimensional and quantitative maps of the tumor microenvironment and immune infiltrate, offering a new diagnostic tool for personalized cancer immunotherapy. PMID- 30401960 TI - Comparative perspectives: regulating insurer use of genetic information. AB - Fear of genetic discrimination has led individuals worldwide to avoid medically recommended genetic testing and participation in genomics research, causing potential health effects as research and clinical care are stymied. In response, many countries have adopted policies that regulate how insurers, such as life, disability, or critical illness insurers, can underwrite using genetic test results. This article presents a comparison of policies in the United Kingdom, Canada, and Australia, through analysis of interviews with 59 key stakeholders representing insurance, government, advocacy, academia, and genetics. While the ultimate policy of each country is different, the policy motivations and issues raised share commonalities across the countries, particularly around themes of fairness, usefulness of genetic information, and the determination of actuarial fairness. PMID- 30401961 TI - Establishing grading indices of available soil potassium on paddy soils in Hubei province, China. AB - Soil testing is an important diagnostic tool for assessing crop-available soil potassium (K) and hence making appropriate fertilizer recommendation. This study was aimed at correlating grain yield response data to soil-test K extracted with ammonium acetate (NH4OAc), cold nitric acid (HNO3), sodium tetraphenylboron (NaTPB) and boiling HNO3 solution, based on 54 field trials conducted during 2011 to 2015 across 15 counties in Hubei province, China. The specific objectives were to establish abundance and deficiency indices of available soil-K (ASK) for rice (Oryza sativa L.) and make accurate K fertilizer recommendations. Potassium extracted with NaTPB and boiling HNO3 was 1.47 times and 3.61 times higher respectively than that extracted with cold HNO3, while K extracted with cold HNO3 was 1.32 times higher than that extracted with NH4OAc. There were significant logarithmic relationships between crop response and soil-test K. The R2 values for cold HNO3-K and NaTPB-K methods were much higher than for NH4OAc-K method. In order to calibrate the application, the abundance and deficiency indices of ASK categorized by cold HNO3-K in low, medium, high and very high ranges were <50 mg kg-1, 50 to 100 mg kg-1, 100 to 200 mg kg-1 and >200 mg kg-1 respectively, and that defined by NaTPB-K were <60 mg kg-1, 60 to 150 mg kg-1, 150 to 330 mg kg-1 and >330 mg kg-1, respectively. These values could be used to evaluate soil K supplying capacity and make appropriate K fertilizer recommendations for rice. PMID- 30401962 TI - Rice straw biochar as a novel niche for improved alterations to the cecal microbial community in rats. AB - Biochar as additive has been shown positive effect in animal production, which may be linked to the role of gastrointestinal microbial modulation. This study aimed to assess the effects of biochar on the gut microbial communities in terms of their structure and diversity. Illumina high-throughput technology was utilized to evaluate the cecal microbial community in Wistar rats received oral rice straw biochar (RSB) at 1120 mg/kg of body weight for 5 weeks. RSB improved the gut mucosal structure and epithelial integrity. More importantly, principal coordinate analysis of UniFrac distances based on a 97% operational taxonomic unit composition and abundance indicated that the bacterial community was ameliorated after RSB addition (P < 0.05). Firmicutes and Bacteroidetes were found to be the prevalent phyla accounting for approximately 90% of the sequences and their ratio of relative abundance was increased by RSB addition (P < 0.05). Improved bacterial proportion of unclassified Lachnospiraceae (P < 0.001), Oscillibacter (P = 0.02), and Clostridium IV (P = 0.02) and XIVa (P = 0.02) as well as decreased abundances of Prevotella (P < 0.001) and Bacteroides (P = 0.03) were also detected at genus level following RSB treatment. These results revealed that RSB altered and improved the cecal microbial community, which may contribute to the affected growth and gut status in rats. PMID- 30401963 TI - Polydisperse Microparticle Transport and Deposition to the Terminal Bronchioles in a Heterogeneous Vasculature Tree. AB - The atmospheric particles from different sources, and the therapeutic particles from various drug delivery devices, exhibit a complex size distribution, and the particles are mostly polydisperse. The limited available in vitro, and the wide range of in silico models have improved understanding of the relationship between monodisperse particle deposition and therapeutic aerosol transport. However, comprehensive polydisperse transport and deposition (TD) data for the terminal airways is still unavailable. Therefore, to benefit future drug therapeutics, the present numerical model illustrates detailed polydisperse particle TD in the terminal bronchioles for the first time. Euler-Lagrange approach and Rosin Rammler diameter distribution is used for polydisperse particles. The numerical results show higher deposition efficiency (DE) in the right lung. Specifically, the larger the particle diameter (dp > 5 MUm), the higher the DE at the bifurcation area of the upper airways is, whereas for the smaller particle (dp < 5 MUm), the DE is higher at the bifurcation wall. The overall deposition pattern shows a different deposition hot spot for different diameter particle. These comprehensive lobe-specific polydisperse particle deposition studies will increase understanding of actual inhalation for particle TD, which could potentially increase the efficiency of pharmaceutical aerosol delivery at the targeted position of the terminal airways. PMID- 30401964 TI - Non-invasive diagnosis of acute intestinal graft-versus-host disease by a new scoring system using ultrasound morphology, compound elastography, and contrast enhanced ultrasound. AB - Acute gastrointestinal (GI) graft-versus-host disease (GvHD) is a life-threating complication in patients after allogeneic stem cell transplantation (ASCT). In 60 sonographic analyses, a novel scoring system for non-invasive diagnosis of severe GI GvHD was developed. The score comprised morphological and vascular changes using B-mode and color-coded Doppler sonography, changes of mural stiffness using compound elastography, and dynamic microvascularisation using contrast-enhanced ultrasound (CEUS). Furthermore, inflammatory parameters such as CRP, Calprotectin, and regenerating islet-derived protein 3alpha (Reg3alpha) were obtained. ROC curve analysis of our novel GvHD sum score revealed an area under the curve of 1.0 (95% CI: 0.99-1.00) in diagnosing GI GvHD and 0.88 (95% CI: 0.79 0.96) for severe GI GvHD. A sum score above 5 correlated with GI GvHD with a sensitivity of 97.6% (41/42) and a specificity of 94.4% (17/18) and score values above 10 with severe GI GvHD with a sensitivity of 91.7% (11/12) and specificity of 79.2% (38/48). The additional use of inflammatory parameters did not improve the predictive power. CEUS is a promising, non-invasive tool for the diagnosis of acute GI GvHD. Together with further descriptive parameters for inflammatory processes, it gains significant diagnostic accuracy in identifying patients with severe stages of acute intestinal GvHD. PMID- 30401966 TI - Breakthrough cytomegalovirus pneumonia in hematopoietic stem cell transplant recipient on letermovir prophylaxis. PMID- 30401965 TI - Effects of HLA mismatch on cytomegalovirus reactivation in cord blood transplantation. AB - Although human leukocyte antigen (HLA) mismatch is often thought to be associated with a high incidence of cytomegalovirus (CMV) reactivation, it is not clear whether this process is mediated by HLA mismatch or other factors, such as acute graft-versus-host disease (aGVHD). Here we focused on cord blood transplantation (CBT) and examined the effects of HLA mismatch on the incidence of CMV reactivation while minimizing the effects of aGVHD. In a multivariate analysis considering aGVHD as a time-dependent covariate, a significant effect on the incidence of CMV reactivation was noted for HLA disparity (hazard ratio [HR]: 0.54 for 8/8 match compared with 3-allele mismatch) and development of aGVHD (HR: 1.26). Next, in an analysis excluding cases that developed aGVHD, the incidences of CMV reactivation for 8/8 match and 1-allele mismatch were low compared with those for other mismatches. These findings were supported by the multivariate analysis (HR: 0.49 for 8/8 match and 0.64 for 1-allele mismatch compared with 3 allele mismatch). Together, these results suggested that HLA mismatch was involved in CMV reactivation and was associated with high morbidity of opportunistic infection after CBT. PMID- 30401967 TI - Vitamin D: is it important in haematopoietic stem cell transplantation? A review. AB - Vitamin D has effects on several body systems, from well-established role in bone metabolism to emerging effects on the immune system. Increasing evidence supports an immunomodulatory effect including inhibition of the pro-inflammatory lymphocyte subsets while enhancing their anti-inflammatory counterpart, in favour of a more tolerogenic status. Vitamin D deficiency is increasingly recognised in association with autoimmune and inflammatory diseases, also with evidence from the field of asthma where vitamin D supplementation may overcome steroid resistance. In the HSCT setting, vitamin D deficiency has been variably associated with increased complications, including graft-versus-host disease (GvHD), with a potential impact on survival outcomes. In this review we provide an overview and critical appraisal of the current literature of the role of vitamin D (and its deficiency) in relation to immunity in both allogeneic and autologous HSCT settings. We conclude that the evidence base is mixed, but a greater understanding of the role of vitamin D in relation to immune reconstitution following HSCT is warranted. Given its potential benefits, its inexpensive cost and favourable side effect profile, consideration of vitamin D levels and its supplementation could be easily incorporated into prospective studies in GvHD, including clinical trials of novel therapeutics, supportive care and biomarkers. PMID- 30401968 TI - No post-transplant pure red cell aplasia development in 106 major ABO incompatible cord blood transplantation. PMID- 30401969 TI - Late relapse after stopping sorafenib in allogeneic hematopoietic stem cell transplant recipients. PMID- 30401970 TI - Post-transplantation cyclophosphamide-based haploidentical versus Atg-based unrelated donor allogeneic stem cell transplantation for patients younger than 60 years with hematological malignancies: a single-center experience of 209 patients. AB - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is limited by availability of HLA-matched sibling donors (MSDs). The alternative use of unrelated donors (UDs) is currently challenged by haploidentical-related donors (HRDs). We retrospectively analyzed 209 consecutive patients younger than 60 years undergoing allo-HSCT from UDs (n = 128) or HRDs (n = 81). Cumulative incidences of grade 3-4 acute (17 vs. 2%, p = 0.003) and 2-year moderate and severe chronic (20 vs. 2%, p < 0.001) GVHD were significantly higher with UD. Progression-free survival (PFS) was significantly better with HRD (51 vs. 69%, p = 0.019), without significant difference in the cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and overall survival (OS). Multivariate analyses confirmed the lower risk of acute and chronic GVHD (grade 2-4, HR = 0.43, p = 0.005; grade 3-4, HR = 0.20, p = 0.017; all grades, HR = 0.43, p = 0.012; moderate or severe, HR = 0.12, p = 0.004), better PFS (HR = 0.61, p = 0.046), and GRFS (HR = 0.47, p = 0.001) with HRD. This was confirmed in match paired analysis. In the absence of MSDs, HRD could be considered as a suitable alternative for patients younger than 60 years. PMID- 30401971 TI - Chirality and Wine. PMID- 30401973 TI - Diversity of copy number variation in the worldwide goat population. AB - Goats (Capra hircus) are an important farm animal species. Copy number variation (CNV) represents a major source of genomic structural variation. We investigated the diversity of CNV distribution in goats using CaprineSNP50 genotyping data generated by the ADAPTmap Project. We identified 6286 putative CNVs in 1023 samples from 50 goat breeds using PennCNV. These CNVs were merged into 978 CNV regions, spanning ~262 Mb of total length and corresponding to ~8.96% of the goat genome. We then divided the samples into six subgroups per geographic distribution and constructed a comparative CNV map. Our results revealed a population differentiation in CNV across different geographical areas, including Western Asia, Eastern Mediterranean, Alpine & Northern Europe, Madagascar, Northwestern Africa, and Southeastern Africa groups. The results of a cluster heatmap analysis based on the CNV count per individual across different groups was generally consistent with the one generated from the SNP data, likely reflecting the population history of different goat breeds. We sought to determine the gene content of these CNV events and found several important CNV overlapping genes (e.g. EDNRA, ADAMTS20, ASIP, KDM5B, ADAM8, DGAT1, CHRNB1, CLCN7, and EXOSC4), which are involved in local adaptations such as coat color, muscle development, metabolic processes, osteopetrosis, and embryonic development. Therefore, this research generated an extensive CNV map in the worldwide population of goat, which offers novel insight into the goat genome and its functional annotation. PMID- 30401974 TI - An Electroencephalography Bioassay for Preclinical Testing of Analgesic Efficacy. AB - We present a multimodal method combining quantitative electroencephalography (EEG), behavior and pharmacology for pre-clinical screening of analgesic efficacy in vivo. The method consists of an objective and non-invasive approach for realtime assessment of spontaneous nociceptive states based on EEG recordings of theta power over primary somatosensory cortex in awake rats. Three drugs were chosen: (1) pregabalin, a CNS-acting calcium channel inhibitor; (2) EMA 401, a PNS-acting angiotensin II type 2 receptor inhibitor; and (3) minocycline, a CNS acting glial inhibitor. Optimal doses were determined based on pharmacokinetic studies and/or published data. The effects of these drugs at single or multiple doses were tested on the attenuation of theta power and paw withdrawal latency (PWL) in a rat model of neuropathic pain. We report mostly parallel trends in the reversal of theta power and PWL in response to administration of pregabalin and EMA 401, but not minocycline. We also note divergent trends at non-optimal doses and following prolonged drug administration, suggesting that EEG theta power can be used to detect false positive and false negative outcomes of the withdrawal reflex behavior, and yielding novel insights into the analgesic effects of these drugs on spontaneous nociceptive states in rats. PMID- 30401972 TI - Involvement of the capsular GalXM-induced IL-17 cytokine in the control of Cryptococcus neoformans infection. AB - Cryptococcus neoformans is an opportunistic fungus that can cause lethal brain infections in immunosuppressed individuals. Infection usually occurs via the inhalation of a spore or desiccated yeast which can then disseminate from the lung to the brain and other tissues. Dissemination and disease is largely influence by the production of copious amounts of cryptococcal polysaccharides, both which are secreted to the extracellular environment or assembled into a thick capsule surrounding the cell body. There are two important polysaccharides: glucuronoxylomannan (GXM) and galactoxylomannan, also called as glucuronoxylomanogalactan (GXMGal or GalXM). Although GXM is more abundant, GalXM has a more potent modulatory effect. In the present study, we show that GalXM is a potent activator of murine dendritic cells, and when co-cultured with T cells, induces a Th17 cytokine response. We also demonstrated that treating mice with GalXM prior to infection with C. neoformans protects from infection, and this phenomenon is dependent on IL-6 and IL-17. These findings help us understand the immune biology of capsular polysaccharides in fungal pathogenesis. PMID- 30401975 TI - Fingolimod-induced decrease in heart rate may predict subsequent decreasing degree of lymphocytes. AB - Here, we determined whether degree of decreased heart rate due to fingolimod treatment correlates with decreasing degree of lymphocytes in relapse-remitting multiple sclerosis (RRMS). In total, 30 patients with RRMS were treated with 0.5 mg fingolimod and their heart rate recorded every 30 minutes for 24 hours. Time trends of heart rate were characterised as three individual amplitudes and phase angles from three cosine curves using a mixed-effect model. Spearman's correlation coefficient and regression analysis were used to determine the effect of heart rate information on change in lymphocyte count pre- and post-fingolimod treatment. Moreover, the degree of decreased lymphocytes induced by fingolimod treatment on heart rate was compared between low and high influence groups. Positive correlation between amplitude from the second curve and difference in lymphocyte number (p = 0.006) was observed. Regression analysis was also significant (p = 0.002). Moreover, the second curve derived from the high amplitude group exhibited a greater decrease in lymphocyte number after fingolimod treatment than the low amplitude group (p < 0.001). We suggest that the degree of decreased lymphocytes after fingolimod treatment (main effect) may be predicted by estimating the influence of degree in heart rate (side effect). PMID- 30401976 TI - The effects of in ovo administration of encapsulated Toll-like receptor 21 ligand as an adjuvant with Marek's disease vaccine. AB - Marek's Disease Virus (MDV) is the causative agent of a lymphoproliferative disease, Marek's disease (MD) in chickens. MD is only controlled by mass vaccination; however, immunity induced by MD vaccines is unable to prevent MDV replication and transmission. The herpesvirus of turkey (HVT) vaccine is one of the most widely used MD vaccines in poultry industry. Vaccines can be adjuvanted with Toll-like receptor ligands (TLR-Ls) to enhance their efficacy. In this study, we examined whether combining TLR-Ls with HVT can boost host immunity against MD and improve its efficacy. Results demonstrated that HVT alone or HVT combined with encapsulated CpG-ODN partially protected chickens from tumor incidence and reduced virus replication compared to the control group. However, encapsulated CpG-ODN only moderately, but not significantly, improved HVT efficacy and reduced tumor incidence from 53% to 33%. Further investigation of cytokine gene profiles in spleen and bursa of Fabricius revealed an inverse association between interleukin (IL)-10 and IL-18 expression and protection conferred by different treatments. In addition, the results of this study raise the possibility that interferon (IFN)-beta and IFN-gamma induced by the treatments may exert anti-viral responses against MDV replication in the bursa of Fabricius at early stage of MDV infection in chickens. PMID- 30401977 TI - Metabolite and lipoprotein responses and prediction of weight gain during breast cancer treatment. AB - BACKGROUND: Breast cancer treatment has metabolic side effects, potentially affecting risk of cardiovascular disease (CVD) and recurrence. We aimed to compare alterations in serum metabolites and lipoproteins during treatment between recipients and non-recipients of chemotherapy, and describe metabolite profiles associated with treatment-related weight gain. METHODS: This pilot study includes 60 stage I/II breast cancer patients who underwent surgery and were treated according to national guidelines. Serum sampled pre-surgery and after 6 and 12 months was analysed by MR spectroscopy and mass spectrometry. In all, 170 metabolites and 105 lipoprotein subfractions were quantified. RESULTS: The metabolite and lipoprotein profiles of chemotherapy recipients and non-recipients changed significantly 6 months after surgery (p < 0.001). Kynurenine, the lipid signal at 1.55-1.60 ppm, ADMA, 2 phosphatidylcholines (PC aa C38:3, PC ae C42:1), alpha-aminoadipic acid, hexoses and sphingolipids were increased in chemotherapy recipients after 6 months. VLDL and small dense LDL increased after 6 months, while HDL decreased, with triglyceride enrichment in HDL and LDL. At baseline, weight gainers had less acylcarnitines, phosphatidylcholines, lyso phosphatidylcholines and sphingolipids, and showed an inflammatory lipid profile. CONCLUSION: Chemotherapy recipients exhibit metabolic changes associated with inflammation, altered immune response and increased risk of CVD. Altered lipid metabolism may predispose for treatment-related weight gain. PMID- 30401978 TI - Statins attenuate outgrowth of breast cancer metastases. AB - BACKGROUND: Metastasis in breast cancer foreshadows mortality, as clinically evident disease is aggressive and generally chemoresistant. Disseminated breast cancer cells often enter a period of dormancy for years to decades before they emerge as detectable cancers. Harboring of these dormant cells is not individually predictable, and available information suggests that these micrometastatic foci cannot be effectively targeted by existing therapies. As such, long-term, relatively non-toxic interventions that prevent metastatic outgrowth would be an advance in treatment. Epidemiological studies have found that statins reduce breast cancer specific mortality but not the incidence of primary cancer. However, the means by which statins reduce mortality without affecting primary tumor development remains unclear. METHODS: We examine statin efficacy against two breast cancer cell lines in models of breast cancer metastasis: a 2D in vitro co-culture model of breast cancer cell interaction with the liver, a 3D ex vivo microphysiological system model of breast cancer metastasis, and two independent mouse models of spontaneous breast cancer metastasis to the lung and liver, respectively. RESULTS: We demonstrate that statins can directly affect the proliferation of breast cancer cells, specifically at the metastatic site. In a 2D co-culture model of breast cancer cell interaction with the liver, we demonstrate that atorvastatin can directly suppress proliferation of mesenchymal but not epithelial breast cancer cells. Further, in an ex vivo 3D liver microphysiological system of breast cancer metastasis, we found that atorvastatin can block stimulated emergence of dormant breast cancer cells. In two independent models of spontaneous breast cancer metastasis to the liver and to the lung, we find that statins significantly reduce proliferation of the metastatic but not primary tumor cells. CONCLUSIONS: As statins can block metastatic tumor outgrowth, they should be considered for use as long-term adjuvant drugs to delay clinical emergence and decrease mortality in breast cancer patients. PMID- 30401979 TI - Hydroxychloroquine retinopathy - implications of research advances for rheumatology care. AB - Despite advances in therapy for rheumatic diseases, hydroxychloroquine remains almost universally recommended for the treatment of systemic lupus erythematosus (SLE), and is often used in the management of other rheumatic diseases such as rheumatoid arthritis (RA). However, the major dose-limiting toxicity of hydroxychloroquine is retinopathy that can lead to loss of vision. New highly sensitive screening methods can identify early stages of retinopathy, and studies that include these modalities have indicated a substantially higher prevalence of hydroxychloroquine retinopathy than was previously recognized, resulting in revisions to ophthalmology guidelines and the recommendation of a low dose of hydroxychloroquine for many patients. However, the efficacy of low-dose hydroxychloroquine for treating SLE and other rheumatic diseases is unknown. Further studies are required to establish the effectiveness and retinal safety of the latest hydroxychloroquine treatment recommendations. PMID- 30401980 TI - A simple table based on height to assess elevated and high blood pressure in children. AB - The 2017 American Academy of Pediatrics (AAP) guideline for assessing "elevated blood pressure (BP) (90th BP percentile)" and "high BP (95th BP percentile)" includes a large number of BP cut-offs based on sex, age and height, which makes it cumbersome to use in clinical practice. We developed and evaluated the performance of a simple table based on a child's height only to assess elevated and high BP in children compared to the reference AAP guideline based on sex, age and height. Data came from 6816 children aged 8-12 years from the U.S. National Health and Nutrition Examination Survey (NHANES) 1999-2016 and 3145 participants aged 5-12 years from NHANES III (1988-1994). Compared to the reference AAP guideline, the simple table had high values of AUC (0.96/0.91), sensitivity (92.7%/83.2%), specificity (99.0%/99.4%), PPV (92.6%/89.3%), NPV (99.0%/99.0%), and Kappa coefficient (0.92/0.85) for screening elevated/high BP when applied to NHANES, and values were similarly high when applied to NHANES III. These findings show that the simple table based on height only performed nearly as well as the reference 2017 AAP guideline based on sex, age and height for assessing elevated and high BP in U.S. children. This simple table may be a useful screening tool to assess high BP in children aged 5-12 years, particularly in a context of mass screening programs. PMID- 30401981 TI - TAZ activation by Hippo pathway dysregulation induces cytokine gene expression and promotes mesothelial cell transformation. AB - Malignant mesothelioma (MM) constitutes a very aggressive tumor that is caused by asbestos exposure after long latency. The NF2 tumor suppressor gene is mutated in 40-50% of MM; moreover, one of its downstream signaling cascades, the Hippo signaling pathway, is also frequently inactivated in MM cells. Although the YAP transcriptional coactivator, which is regulated by the Hippo pathway, can function as a pro-oncogenic protein, the role of TAZ, a paralog of YAP, in MM cells has not yet been clarified. Here, we show that TAZ is expressed and underphosphorylated (activated) in the majority of MM cells compared to immortalized mesothelial cells. ShRNA-mediated TAZ knockdown highly suppressed cell proliferation, anchorage-independent growth, cell motility, and invasion in MM cells harboring activated TAZ. Conversely, transduction of an activated form of TAZ in immortalized mesothelial cells enhanced these in vitro phenotypes and conferred tumorigenicity in vivo. Microarray analysis determined that activated TAZ most significantly enhanced the transcription of genes related to "cytokine cytokine receptor interaction." Among selected cytokines, we found that IL-1 signaling activation plays a major role in proliferation in TAZ-activated MM cells. Both IL1B knockdown and an IL-1 receptor antagonist significantly suppressed malignant phenotypes of immortalized mesothelial cells and MM cells with activated TAZ. Overall, these results indicate an oncogenic role for TAZ in MMs via transcriptional induction of distinct pro-oncogenic genes including cytokines. Among these, IL-1 signaling appears as one of the most important cascades, thus potentially serving as a target pathway in MM cells harboring Hippo pathway inactivation. PMID- 30401982 TI - Unbalanced YAP-SOX9 circuit drives stemness and malignant progression in esophageal squamous cell carcinoma. AB - Yes-associated protein (YAP) has been identified as a key regulator of tissue homeostasis. However, the precise role and regulatory mechanism of YAP in esophageal squamous cell carcinoma (ESCC) remains unclear. Here we report that the genetic or pharmacological inhibition of YAP repressed cancer stem cell (CSC) like properties, including tumorsphere-forming potential, cell motility, and chemoresistance in vitro, and was sufficient to attenuate tumor growth and CSC marker expression in ESCC xenografts. Mechanistically, YAP transcriptionally activated its downstream target SOX9 via TEAD1-mediated binding. We also observed a positive correlation between YAP signaling and SOX9 expression in two independent clinical cohorts. Intriguingly, YAP-targeting microRNAs, including miR-506-3p, which were induced by SOX9, post-transcriptionally repressed YAP expression, contributing to a negative feedback mechanism. Dual inhibition of YAP and SOX9 robustly suppressed malignant phenotypes. Notably, ESCC samples from The Cancer Genome Atlas (TCGA) dataset had frequent (44%) instances of YAP gene amplification and genetic inactivation of Hippo pathway regulators. Nuclear YAP expression was elevated in 197 ESCC tissues from a Chinese cohort. Together, our findings provide evidence that genetic hyperactivation of YAP unbalances the YAP SOX9 feedback loop and confers CSC-like features in ESCC, suggesting that this YAP-SOX9 circuit represents a potential therapeutic target. PMID- 30401983 TI - ACVR1C/SMAD2 signaling promotes invasion and growth in retinoblastoma. AB - Retinoblastoma is the most common intraocular cancer in children. While the primary tumor can often be treated by local or systemic chemotherapy, metastatic dissemination is generally resistant to therapy and remains a leading cause of pediatric cancer death in much of the world. In order to identify new therapeutic targets in aggressive tumors, we sequenced RNA transcripts in five snap frozen retinoblastomas which invaded the optic nerve and five which did not. A three fold increase was noted in mRNA levels of ACVR1C/ALK7, a type I receptor of the TGF-beta family, in invasive retinoblastomas, while downregulation of DACT2 and LEFTY2, negative modulators of the ACVR1C signaling, was observed in most invasive tumors. A two- to three-fold increase in ACVR1C mRNA was also found in invasive WERI Rb1 and Y79 cells as compared to non-invasive cells in vitro. Transcripts of ACVR1C receptor and its ligands (Nodal, Activin A/B, and GDF3) were expressed in six retinoblastoma lines, and evidence of downstream SMAD2 signaling was present in all these lines. Pharmacological inhibition of ACVR1C signaling using SB505124, or genetic downregulation of the receptor using shRNA potently suppressed invasion, growth, survival, and reduced the protein levels of the mesenchymal markers ZEB1 and Snail. The inhibitory effects on invasion, growth, and proliferation were recapitulated by knocking down SMAD2, but not SMAD3. Finally, in an orthotopic zebrafish model of retinoblastoma, a 55% decrease in tumor spread was noted (p = 0.0026) when larvae were treated with 3 uM of SB505124, as compared to DMSO. Similarly, knockdown of ACVR1C in injected tumor cells using shRNA also resulted in a 54% reduction in tumor dissemination in the zebrafish eye as compared to scrambled shRNA control (p = 0.0005). Our data support a role for the ACVR1C/SMAD2 pathway in promoting invasion and growth of retinoblastoma. PMID- 30401985 TI - [Surgical site infection in colon surgery]. PMID- 30401984 TI - Author Correction: Distinguishing genetic correlation from causation across 52 diseases and complex traits. AB - In the version of this article originally published, there were errors in equations. In the HTML and PDF, the initial term of equation 10 was estimated GCP but should have been estimated standard error, while a 'hat' was missing from the first alpha in the second term of the expression at the end of the paragraph following equation (6) in the Methods. In addition, in the abstract in the PDF, a subscript 1 was used instead of a subscript 2 for the final term of the first fourth-moment expression. These errors have been corrected in the HTML, PDF and print versions of the paper. PMID- 30401986 TI - [Ceasing to do what shouldn't be done]. PMID- 30401987 TI - [Evolution of ethylic intoxication in the paediatric population of Navarre in the last 10 years (2007-2016)]. PMID- 30401988 TI - [Surgical site infection in colon surgery]. PMID- 30401989 TI - The prevalence of maternal hypothyroidism in first trimester screening from 11 to 14 weeks of gestation. AB - AIM: The aim of this study was to determine the prevalence of maternal hypothyroidism in the first trimester from 11 to 14 weeks of gestation according to the American Thyroid Association (ATA) guidelines from 2017 and to compare the rates for singleton and twin pregnancies. METHODS: A total of 4965 consecutive Caucasian singleton pregnancies and 109 Caucasian twin pregnancies were included in the investigation. Patients with a history of thyroid gland disorder were excluded. Subclinical maternal hypothyroidism was defined as a thyroid stimulating hormone (TSH) concentration above the 97.5th percentile and free thyroxine (fT4) within the range of a reference population of women at 11-14 weeks of gestation. Overt maternal hypothyroidism was defined as a TSH concentration above the 97.5th percentile and an fT4 below the 2.5th percentile of the reference population.TSH, fT4, and anti thyroid peroxidase antibody (TPOAb) were measured by immunochemiluminescent assays on an 16200 Abbott Architect analyzer. RESULTS: The prevalence of hypothyroidism for twin pregnancies was no higher than that for singleton pregnancies; 6.42% (7/109) vs. 5.32% (264/4965), respectively; P=0.61. All twin pregnancies were subclinical. Singleton hypothyroid pregnancies included 4.91% (244 cases) of subclinical and 0.41% (20 cases) of overt hypothyroidism. The prevalence of TPOAb positive hypothyroid women for twin pregnancies and singleton pregnancies was 71% (5/7) vs. 52% (137/264 cases), respectively but the differences were not statistically significant; P=0.31. CONCLUSION: Each first trimester screening center should establish its TSH and fT4 reference ranges. Our center had higher upper reference limits of TSH than that of the universally fixed limit of 2.5 mU/L, which led to a lower measured prevalence of maternal hypothyroidism. A large number of hypothyroid women were TPOAb positive. PMID- 30401990 TI - Late diagnosis of complete androgen insensitivity syndrome and transmission/carriers of the disease in a family with mutation c.2495G>T p.(Arg832Leu) in exon 7 of the androgen receptor gene: genetic, clinical and ethical aspects. AB - BACKGROUND: The complete androgen insensitivity syndrome (CAIS) is a rare genetic disorder causing insensitivity to androgens in a person with female phenotype and 46,XY karyotype due to a mutation in the androgen receptor gene located on chromosome X. These children are born with female external genitalia, and females are transmitters. CASE REPORT: We illustrate an unexpected diagnosis of CAIS in two siblings during examination for short stature, and describe transmission/carriers in the family along with ethical aspects. CONCLUSION: A genetic examination could have earlier revealed the transmission of c.2495G>Tp.(Arg832Leu) mutation in exon 7. Our experience highlights the possibility of prenatal testing for the management of pregnancy in a family with a history of CAIS. The implications of prenatal testing in relation to CAIS with clearer explication of ethical and clinical issues warrant further investigation. PMID- 30401991 TI - Orthogonal cameras system for tracking of laparoscopic instruments in training environments. AB - Introduction: Motion analysis is a valuable tool for assessment of psychomotor skills in laparoscopy. Nonetheless, it requires technologies for tracking the activity of the laparoscopic instruments during training. This paper presents a sensor-free system to track the movements of laparoscopic instruments based on an orthogonal camera system and video image processing. Methods: The movements of the laparoscopic instruments are tracked with two webcams placed in an orthogonal configuration. The position and orientation in the three-dimensional workspace are obtained using color markers placed on the tip of the instruments. Results: Accuracy tests show a resolution of 0.14 mm for displacement, with 1694 cm3 of total workspace, and 0.54 degrees in the angular movements. Mean relative errors of the tracking system were <1%. The orthogonal cameras show high precision, linearity, and repeatability of motion recording of the laparoscopic instruments. Conclusion: The proposed system offers unconstrained manipulation of the instruments and a low-cost alternative for traditional tracking technologies. PMID- 30401993 TI - Erratum: Successful Treatment of Stevens-Johnson Syndrome with Cyclosporine and Corticosteroid: Correction. AB - [This corrects the article on p. 272 in vol. 71, PMID: 30186001.]. PMID- 30401992 TI - Deprescribing Proton Pump Inhibitors. PMID- 30401994 TI - ? PMID- 30401995 TI - Is There a Reason for the Proton Pump Inhibitor? An Assessment of Prescribing for Residential Care Patients in British Columbia. AB - Background: The use of proton pump inhibitors (PPIs) may cause significant harm to patients in the residential care setting, as these patients are often frail with multiple morbidities. The extent of non-evidence-based use of PPIs in residential care sites of the Fraser Health Authority in British Columbia is unknown. Objective: To determine the proportion of non-evidence-based use of PPI therapy for residential care patients of the Fraser Health Authority. Methods: This retrospective cross-sectional study was conducted in 6 Fraser Health residential care facilities in British Columbia between April 1, 2015, and March 31, 2016. Two definitions of "evidence-based indications" were used. The first definition encompassed broad evidence-based indications for PPI use, specifically gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), gastritis, esophagitis, Barrett esophagus, and gastrointestinal protection from concurrent oral steroids, oral nonsteroidal anti-inflammatory drugs, antiplatelet agents, and anticoagulants. The second definition involved common evidence-based indications for PPI use, specifically GERD or PUD. Descriptive statistics were used to evaluate the primary outcome: the proportion of PPI orders without a documented broad or common evidence-based indication for PPI treatment. Results: A total of 331 residential care patients and 407 PPI orders were assessed. The proportion of PPI orders without a documented broad evidence-based indication was 16.2% (66/407). The proportion of PPI orders without a documented common evidence based indication was 43.7% (178/407). The most frequently documented reason for a PPI order was GERD (214/407 or 52.6%). PPI orders for patients with GERD and gastrointestinal bleeding had the longest duration of therapy during residential care admission, averaging 205.1 and 218.1 days, respectively. Conclusion: About 1 in 6 PPI orders for Fraser Health residential care patients did not have a documented broad evidence-based indication, and about 2 in 5 PPI orders did not have a documented common evidence-based indication. These results indicate a need to assess the appropriateness of therapy for every patient with an active PPI order in residential care facilities. PMID- 30401996 TI - Quantifying Candidacy for Deprescribing of Proton Pump Inhibitors among Long-Term Care Residents. AB - Background: Proton pump inhibitors (PPIs) are a commonly prescribed drug class used to inhibit gastric acid secretion. They are prescribed for both treatment and prophylaxis of several gastrointestinal conditions. Although PPIs can be used safely in the short term, several serious adverse effects have been reported following long-term use, including increased risk of falls and fragility fractures. Long-term care home (LTCH) residents represent a population in which the long-term adverse effects of PPIs can be significant and PPI deprescribing should be considered when appropriate. Objectives: To determine the proportion of LTCH residents with PPI prescriptions who were eligible for PPI deprescribing, and to examine vitamin B12 deficiencies and fall risk in the study population. Methods: This cross-sectional, multisite chart review involved LTCH residents who had an active PPI prescription during October 2016. A convenience sample of 150 charts was randomly selected, and the appropriateness of PPI deprescribing was determined using Canadian guidelines. Descriptive statistics were used to examine demographic characteristics, PPI dosing and indication, vitamin B12 supplementation, fall history, and fall risk. Results: Three of the selected charts were excluded because of missing information. Of the 147 residents included in the chart review, 93 (63%) were candidates for deprescribing. PPI use for gastroesophageal reflux disease for more than 8 weeks without a deprescribing attempt in the past year was the most frequently observed opportunity for deprescribing (49/93 [53%]). Twenty-nine residents (20%) had no documented indication for PPI use. Thirteen residents (9%) had had a fall within the past 30 days, and 53 (36%) had a prescription for vitamin B12 supplements and/or had low serum vitamin B12 levels. Conclusions: A majority of the residents whose charts were reviewed were candidates for PPI deprescribing. This finding suggests an opportunity for clinicians who care for LTCH residents to increase their deprescribing efforts. PMID- 30401997 TI - Evaluation of Prescribing Appropriateness and Initiatives to Improve Prescribing of Proton Pump Inhibitors at Vancouver General Hospital. AB - Background: Proton pump inhibitors (PPIs) have proven clinical efficacy for a variety of indications. However, there is emerging evidence of adverse events associated with their long-term use. The emergence of these adverse events has reinforced the need to regularly evaluate the appropriateness of continuing PPI therapy, and to use only the lowest effective dose for the minimally indicated duration. Objectives: To characterize the appropriateness of PPI orders continued or initiated in the internal medicine and family practice units of Vancouver General Hospital, to detect adverse events associated with PPI use, and to explore the impact of multidisciplinary teaching and provision of educational resources on health care practitioners' views about PPI use. Methods: A chart review was conducted for patients admitted (for at least 24 hours) between January 1 and December 31, 2015, for whom a hospital formulary PPI was prescribed. An educational initiative, which included interprofessional in service sessions, a PPI prescribing infographic, a PPI prescribing card, and a patient counselling sheet, was implemented. The impact of these interventions was assessed using a qualitative survey of health care practitioners. Results: Of the 258 patients whose charts were reviewed, 175 had a PPI prescription before hospital admission, and 83 were initiated on PPI therapy during their hospital stay. Overall, 94 (36%) of the patients were receiving PPIs without an appropriate indication. Community-acquired pneumonia and Clostridium difficile infections were the most common adverse events potentially associated with PPI use. In-service sessions and educational resources on PPI prescribing were reported to affect the clinical practice of 24 (52%) of the 46 survey respondents. Conclusions: The results of this study emphasize the need for ongoing re-evaluation of long-term PPI therapy at the time of admission, during the hospital stay, and upon discharge. Implementing multidisciplinary teaching and providing educational resources may encourage more appropriate prescribing. PMID- 30401998 TI - Characterization of Serious Adverse Drug Reactions in Hospital to Determine Potential Implications of Mandatory Reporting. AB - Background: The Protecting Canadians from Unsafe Drugs Act will eventually require institutions to report all serious adverse drug reactions (ADRs), although the proposed regulations do not yet define what will need to be reported and by whom. Knowledge about the occurrence of serious ADRs in the hospital setting is needed to optimize the effectiveness of reporting and to determine the potential implications of mandatory reporting. Objectives: To quantify and characterize suspected serious ADRs in patients admitted to a general medicine service, to assess the likelihood of causality, and to determine inter-rater agreement for identification of ADRs and assessment of their likelihood. Methods: This prospective observational study involved 60 consecutive patients admitted to a general medicine service at a tertiary care teaching centre starting on March 28, 2016. The primary outcome was the number of serious ADRs, defined by Health Canada as ADRs that result in hospital admission, congenital malformation, persistent or significant disability or incapacity, or death; that are life threatening; or that require significant intervention to prevent one of these outcomes. Medical records were reviewed independently by pairs of pharmacists for serious ADRs, and the likelihood of causality was assessed using the World Health Organization-Uppsala Monitoring Centre system. Inter-rater agreement was calculated using the kappa score, and disagreements were resolved by discussion and consensus. Results: Twenty-three serious ADRs occurred in the sample of 60 patients. The proportion of patients experiencing a serious ADR that contributed to the original hospital admission was 19/60 (32%, 95% confidence interval [CI] 20%-43%), and 4 patients (7%, 95% CI 0%-13%) experienced a serious ADR during their hospital stay. Inter-rater agreement for occurrence of serious ADRs was moderate (kappa 0.58, 95% CI 0.35-0.76). Conclusion: Reportable serious ADRs were common among patients admitted to a general medicine service. Canadian hospitals would face difficulties reporting all serious ADRs because of the frequency of their occurrence and the subjectivity of their identification. PMID- 30402000 TI - Is It Necessary for Pharmacists to Evaluate Other Health Professionals' Satisfaction with Pharmacist Services? PMID- 30402001 TI - ? PMID- 30401999 TI - Roles and Impacts of the Transplant Pharmacist: A Systematic Review. AB - Background: Pharmacists have been involved in the care of transplant recipients for several decades, and a growing body of literature shows the beneficial effects of clinical pharmacist care on important outcomes for these patients. Objectives: The primary objective was to describe the roles and impacts of pharmacists in a solid organ transplant setting. The secondary objective was to describe and rate the pharmacists' interventions. Data Sources: Three databases PubMed, Embase, and Evidence-Based Medicine Reviews-were searched from January 1, 1990, to June 16, 2015. Study Selection and Data Extraction: All studies addressing the roles of pharmacists and the impacts of clinical pharmacy services on the care of solid organ transplant recipients were considered. Only studies providing a statistical analysis were included. Design, setting, sample size, patient characteristics, pharmacists' interventions, study bias, and outcomes were extracted for analysis. Data Synthesis: Four randomized controlled trials, 4 cohort studies, 3 pre-post studies, and 1 quasi-randomized controlled trial were included in the review, representing a total of 1837 patients. Of the 12 studies included, 8 specifically focused on renal transplant, and 1 each focused on liver, lung, abdominal organ, and general solid organ transplant. The pivotal pharmacist activities leading to the main patient outcomes were medication counselling (n = 8 studies), medication reconciliation (n = 5), and reviewing and optimizing drug therapy (n = 3). Improvements to medication adherence (n = 6 studies), morbidity (n = 4), costs (n = 2), and medication errors (n = 2) were reported. Conclusion: Currently available evidence suggests that pharmacists can improve patient outcomes in the solid organ transplant setting. Adherence, morbidity, costs, and medication errors were identified as the main outcomes that were improved by pharmaceutical interventions. Transplant programs need to invest more in this resource. PMID- 30402002 TI - Evaluating Priorities and Resources: A Balancing Act. PMID- 30402003 TI - Bone and Soft-Tissue Biopsies: What You Need to Know. AB - Percutaneous, image-guided musculoskeletal biopsy, due to its minimal invasive nature, when compared with open surgical biopsy, is a safe and effective technique which is widely used in many institutions as the primary method to acquire tissue and bone samples. Indications include histopathologic and molecular assessment of a musculoskeletal lesion, exclusion of malignancy in a bone/vertebral fracture, examination of bone marrow, and infection investigation. Preprocedural workup should include both imaging (for lesion assessment and staging) and laboratory (including coagulation tests and platelet count) studies. In selected cases, antibiotic prophylaxis should be administered before the biopsy. Core needle biopsy of musculoskeletal lesions has a diagnostic accuracy that ranges from 66 to 98% with higher diagnostic yield for lytic, large-size, malignant lesions and when multiple and long specimens are obtained. Reported complication rates range between 0 and 10% and usually do not exceed 5%, with a suggested threshold of 2%. The purpose of this review article is to illustrate the technical aspects, the indications, and the methodology of percutaneous image guided bone biopsy that will assist the interventional radiologist to perform these minimal invasive techniques. PMID- 30402004 TI - Image-Guided Bone Consolidation in Oncology. AB - Occurrence of bone metastases is a common event in oncology. Bone metastases are associated with pain, functional impairment, and fractures, particularly when weight-bearing bones are involved. Management of bone metastases has been improved by the development of various interventional radiology consolidation techniques. Cementoplasty is based on injection of acrylic cement into a weakened bone to reinforce it and to control pain. This minimally invasive technique has proven its efficacy for flat bone submitted to compression forces. However, resistance to torsion forces is limited and, thus, treatment of long bones should be considered with caution. In recent years, variant techniques of percutaneous bone consolidation have emerged, including expansion devices for vertebral augmentation and percutaneous screw fixation for pelvic bone and proximal femur tumors. Research projects are ongoing to develop drug-loaded cements to use them as therapeutic vectors. However, release of drugs is still poorly controlled and conventional polymethylmethacrylate cement remains the gold standard in oncology. Image-guided consolidation techniques enhance the array of treatments in bone oncology. Multidisciplinary approach is mandatory to select the best indications. PMID- 30402005 TI - Integrated CT-Fluoroscopy Equipment: Improving the Interventional Radiology Approach and Patient Experience for Treatment of Musculoskeletal Malignancies. AB - Integrated CT-fluoroscopy equipment augments the comprehensive approach to the treatment of musculoskeletal (MSK) malignancy by interventional radiology techniques. As the role of minimally invasive treatment expands to meet the highly variable presentation of MSK malignancy, creative solutions to treatment challenges are required to improve locoregional tumor control and durability of pain palliation. Challenges to effective treatment can often be attributed to a combination of aggressive tumor biology, large size, forbidding location, and adverse vascularity. In these cases, a tailored treatment approach may necessitate the application of multiple interventional radiology (IR) techniques that require different image guidance capabilities. Integrated CT-fluoroscopy equipment provides the means to leverage both imaging modalities within the same procedural setting to facilitate the simultaneous application of multiple synergistic treatments and protective measures. This article examines the potential role of hybrid units in the IR treatment of challenging MSK malignancies as a means to empower a paradigm transition for a more comprehensive and patient-tailored approach. PMID- 30402006 TI - Percutaneous Fixation by Internal Cemented Screw for the Treatment of Unstable Osseous Disease in Cancer Patients. AB - Interventional radiology expertise in image guidance has expanded the treatment options for cancer patients with unstable osseous disease. Percutaneous fixation by internal cemented screw (FICS) describes the technique by which the interventional radiologist stabilizes a fracture or impending fracture with the percutaneous placement of a cannulated screw that is locked in position by polymethyl methacrylate cement. The durable metallic screws provide added resistance to torque and tension stresses that complement the axial compression resistance of cement. Compared with cementoplasty alone, the procedure has been advanced as a more durable and precise technique for stabilization of osseous disease for certain disease presentations in cancer patients. The application of advanced image guidance techniques improves upon existing percutaneous surgical techniques to facilitate approaches that would otherwise prove quite challenging, particularly with stabilization of the pelvic flat bones. This article examines the applications of percutaneous FICS procedures for the treatment of unstable osseous disease in cancer patients. Indications, techniques, and follow-up care are reviewed. Case examples in which FICS can be performed in unstable pathology are detailed. PMID- 30402007 TI - Ultrasound-Guided Surgery for Carpal Tunnel Syndrome: A New Interventional Procedure. AB - Carpal tunnel syndrome (CTS) may be treated surgically if medical treatment fails. The classical approach involves release of the flexor retinaculum by endoscopic or open surgery. Meta-analyses have shown that the risk of nerve injury may be higher with endoscopic treatment. The recent contribution of ultrasound to the diagnosis and therapeutic management of CTS opens new perspectives. Ultrasound-guided carpal tunnel release via a minimally invasive approach enables the whole operation to be performed as a percutaneous radiological procedure. The advantages are a smaller incision compared with classical techniques; great safety during the procedure by visualization of anatomic structures, particularly variations in the median nerve; and realization of the procedure under local anesthesia. These advantages lead to a reduction in postsurgical sequelae and more rapid resumption of daily activities and work. Dressings are removed by the third day postsurgery. Recent studies seem to confirm the medical, economic, and aesthetic benefits of this new approach. PMID- 30402008 TI - Contained Herniated Lumbar Disc: CT- and Fluoroscopy-Guided Automated Percutaneous Discectomy-A Revival. AB - The combination of a new device and dual guidance (computed tomography [CT] and fluoroscopy) is similar to other percutaneous devices in achieving a mechanical decompression of the disc. The difference, however, is that the target of the decompression with the current technique is the herniated disc itself. The goal of this combined technique is to create a space, an "olive" around the probe, allowing a decrease in pressure inside the hernia. Percutaneous discectomy under combined CT and fluoroscopic guidance is a minimally invasive spine surgery that should be considered as an alternative to surgery in properly selected patients. PMID- 30402009 TI - HIFU for Bone Metastases and other Musculoskeletal Applications. AB - High-intensity focused ultrasound (HIFU) is a totally noninvasive procedure that has shown promising results in the management of numerous malignant and nonmalignant conditions. Under magnetic resonance or ultrasound guidance, high intensity ultrasound waves are focused on a small, well-defined target region, inducing biologic tissue heating and coagulative necrosis, thus resulting in a precise and localized ablation. This treatment has shown both great safety and efficacy profiles, and may offer a multimodal approach to different diseases, providing pain palliation, potential local tumor control, and, in some cases, remineralization of trabecular bone. In musculoskeletal field, HIFU received FDA approval for treating bone metastasis, but its application has also been extended to other conditions, such as osteoid osteoma, desmoid tumor, low-flow vascular malformation, and facet joint osteoarthritis. This article illustrates the basic principles of HIFU and its main effects on biologic tissues with particular attention on bone, provides a step-by-step description of the HIFU procedure, and discusses the commonly treated conditions, in particular bone metastases. PMID- 30402011 TI - Musculoskeletal Metastases Management: The Interventional Radiologist's Toolbox. AB - The prevalence of patients with painful bone metastases is constantly increasing. This is related to the rising incidence of cancer and increasing life expectancy of patients with metastatic stage. Advances in imaging and development of percutaneous techniques have gradually allowed offering minimally invasive acts on these metastases: cementing, vertebral augmentation, osteosynthesis, percutaneous thermal ablation, neurolysis, embolization. The purpose of this article is to present the main tools available to date for the interventional radiologist so that each participant can understand their functioning, indications, and limits. PMID- 30402010 TI - Percutaneous Cement Injection for the Palliative Treatment of Osseous Metastases: A Technical Review. AB - The technical art to percutaneous injection of polymethyl methacrylate (PMMA) cement for the palliative treatment of osseous metastases is not without pitfalls. Pathologic fracture, cortical bone erosion, large lytic tumor, aggressive tumor biology, and tumor vascularity may increase the risk of cement leakage or limit complete consolidation. A calculated and determined approach is often necessary to achieve satisfactory patient-tailored results. This article reviews the challenges and potential complications during the consolidation of osseous metastases. Case examples are presented to facilitate early detection of impending cement leakage, minimize procedural risks, and provide management suggestions for complications. Technical pearls are provided to refine consolidative techniques and improve the comprehensive treatment of painful osseous metastases. PMID- 30402012 TI - Steroids Spinal Injections. AB - Spinal pain is a common condition leading to significant disability and high cost. Spinal injections have been demonstrated to be effective short-term treatments with cost-utility superior to numerous other treatments, including surgical procedures. Appropriate patient selection-based on clinical and imaging finding-and the use of image guidance associated with technical precautions improve the safety and effectiveness of spinal injection and overall patient outcomes. PMID- 30402013 TI - Thermal Ablation of Bone Metastases. AB - Image-guided, minimally invasive, percutaneous thermal ablation of bone metastases has unique advantages compared with surgery or radiation therapy. Thermal ablation of osseous metastases may result in significant pain palliation, prevention of skeletal-related events, and durable local tumor control. This article will describe current thermal ablation techniques utilized to treat bone metastases, summarize contemporary evidence supporting such thermal ablation treatments, and outline an approach to percutaneous ablative treatment. PMID- 30402014 TI - Percutaneous Vertebral Augmentation Techniques in Osteoporotic and Traumatic Fractures. AB - Percutaneous vertebral augmentation/consolidation techniques are varied. These are vertebroplasty, kyphoplasty, and several methods with percutaneous introduction of an implant (associated or not with cement injection). They are proposed in painful osteoporotic vertebral fractures and traumatic fractures. The objectives are to consolidate the fracture and, if possible, to restore the height of the vertebral body to reduce vertebral and regional kyphosis. Stabilization of the fracture leads to a reduction in pain and thus restores the spinal support function as quickly as possible, which is particularly important in the elderly. The effectiveness of these interventions on fracture pain was challenged once by two randomized trials comparing vertebroplasty to a sham intervention. Since then, many other randomized studies in support of vertebroplasty efficacy have been published. International recommendations reserve vertebroplasty for medical treatment failures on pain, but earlier positioning may be debatable if the objective is to limit kyphotic deformity or even reexpand the vertebral body. Recent data suggest that in osteoporotic fracture, the degree of kyphosis reduction achieved by kyphoplasty and percutaneous implant techniques, compared with vertebroplasty, is not sufficient to justify the additional cost and the use of a somewhat longer and traumatic procedure. In young patients with acute traumatic fractures and a significant kyphotic angle, kyphoplasty and percutaneous implant techniques are preferred to vertebroplasty, as in these cases a deformity reduction has a significant positive impact on the clinical outcome. PMID- 30402015 TI - Percutaneous Treatments of Benign Bone Tumors. AB - Benign bone tumors consist of a wide variety of neoplasms that do not metastasize but can still cause local complications. Historical management of these tumors has included surgical treatment for lesion resection and possible mechanical stabilization. Initial percutaneous ablation techniques were described for osteoid osteoma management. The successful experience from these resulted in further percutaneous image-guided techniques being attempted, and in other benign bone tumor types. In this article, we present the most common benign bone tumors and describe the available results for the percutaneous treatment of these lesions. PMID- 30402016 TI - Endovascular Therapy for Lower Extremity Chronic Deep Venous Occlusive Disease: State of Practice. PMID- 30402017 TI - Global Approach to the Patient with Pain in Interventional Radiology. PMID- 30402018 TI - Treatment of Liver Tumors with Transarterial Chemoembolization. PMID- 30402019 TI - A Complication of Ultrasound-Guided Inferior Vena Cava Filter Placement. PMID- 30402020 TI - Pulmonary Complication following Drug-Eluting Bead Hepatic Chemoembolization. PMID- 30402021 TI - The effect of melatonin on cardio fibrosis in juvenile rats with pressure overload and deregulation of HDACs. AB - The effect of melatonin on juveniles with cardio fibrosis is poorly understood. We investigated whether HDACs participate in the anti-fibrotic processes regulated by melatonin during hypertrophic remodeling. Abdominal aortic constriction (AAC) was employed in juvenile rats resulting in pressure overload induced ventricular hypertrophy and melatonin was subsequently decreased via continuous light exposure for 5 weeks after surgery. AAC rats displayed an increased cross-sectional area of myocardial fibers and significantly elevated collagen deposition compared to sham-operated rats, as measured by HE and Masson Trichrome staining. Continuous light exposure following surgery exacerbated the increase in the cross-sectional area of myocardial fibers. The expression of HDAC1, HDAC2, HDAC3, HDAC4 and HDAC6 genes were all significantly enhanced in AAC rats with light exposure relative to the other rats. Moreover, the protein level of TNF-alpha was also upregulated in the AAC light exposure groups when compared with the sham. However, Smad4 protein expression was unchanged in the juveniles' hearts. In contrast, beginning 5 weeks after the operation, the AAC rats were treated with melatonin (10 mg/kg, intraperitoneal injection every evening) or vehicle 4 weeks, and sham rats were given vehicle. The changes in the histological measures of cardio fibrosis and the gene expressions of HDAC1, HDAC2, HDAC3, HDAC4 and HDAC6 were attenuated by melatonin administration. The results reveal that melatonin plays a role in the development of cardio fibrosis and the expression of HDAC1, HDAC2, HDAC3, HDAC4 and HDAC6 in cardiomyocytes. PMID- 30402022 TI - The Nedd8-activating enzyme inhibitor MLN4924 suppresses colon cancer cell growth via triggering autophagy. AB - Neddylation is a post-translational protein modification process. MLN4924 is a newly discovered pharmaceutical neddylation inhibitor that suppresses cancer growth with several cancer types. In our study, we first investigated the effect of MLN4924 on colon cancer cells (HCT116 and HT29). MLN4924 significantly inhibited the neddylation of cullin-1 and colon cancer cell growth in a time and dose-dependent manner. MLN4924 induced G2/M cell cycle arrest and apoptosis in HCT116 and HT29 cells. Moreover, MLN4924 also triggered autophagy in HCT116 and HT29 cells via suppressing the PI3K/AKT/mTOR pathway. Inhibiting autophagy by autophagy inhibitor 3-MA or ATG5 knockdown reversed the function of MLN4924 in suppressing colon cancer cell growth and cell death. Interestingly, MLN4924 suppresses colon cell growth in a xenograft model. Together, our finding revealed that blocking neddylation is an attractive colon cancer therapy strategy, and autophagy might act as a novel anti-cancer mechanism for the treatment of colon cancer by MLN4924. PMID- 30402023 TI - 6-Shogaol reduces progression of experimental endometriosis in vivo and in vitro via regulation of VGEF and inhibition of COX-2 and PGE2-mediated inflammatory responses. AB - Endometriosis (EM) is one of the most common gynaecological disorder affecting women in their reproductive age. Mechanisms involved in the pathogenesis of EM remains poorly understood, however inflammatory responses have been reported to be significantly involved. The efficacy of 6-shogaol on proliferation of endometriotic lesions and inflammatory pathways in experimentally-induced EM model was explored in this study. EM was stimulated in Sprague-Dawley rats by implantation of autologous endometrium onto the peritoneum abdominal wall. Separate groups were treated with 6-shogaol (50, 100 or 150 mg/kg b.wt/day) via oral gavage for one month period. Gestrinone (GTN) group received GTN (0.5 mg/kg/day) as positive control. Five weeks after implantation, the spherical volume of ecto-uterine tissues was determined. Treatment with 6-shogaol significantly reduced the implant size. Histological analysis reported atrophy and regression of the lesions. 6-shogaol administration effectively down regulated NF-kappaB signaling, VEGF and VEGFR-2 (Flk-1) expression in the endometriotic lesions. Excess production of IL-1beta and IL-6 (pro-inflammatory cytokines), PGE2 and nitric oxide (NO) were reduced. Overall, the results of the study reveal the efficacy of 6-shogaol against endometriosis via effectively suppressing proliferation of the lesions and modulating angiogenesis and COX-2/NF kappaB-mediated inflammatory cascades. PMID- 30402024 TI - The treatment effect of novel hGHRH homodimer to male infertility hamster. AB - Extra-hypothalamic growth hormone-releasing hormone (GHRH) plays an important role in reproduction. To study the treatment effect of Grin (a novel hGHRH homodimer), the infertility models of 85 male Chinese hamsters were established by intraperitoneally injecting 20 mg/kg of cyclophosphamide once in a week for 5 weeks and the treatment with Grin or human menopausal gonadotropin (hMG) as positive control was evaluated by performing a 3-week mating experiment. 2-8 mg/kg of Grin and 200 U/kg of hMG showed similar effect and different pathological characteristics. Compared to the single cyclophosphamide group (0%), the pregnancy rates (H-, M-, L-Grin 26.7, 30.8, 31.3%, and hMG 31.3%) showed significant difference, but there was no difference between the hMG and Grin groups. The single cyclophosphamide group presented loose tubules with pathologic vacuoles and significant TUNEL positive cells. Grin induced less weight of body or testis, compactly aligned tubules with little intra-lumens, whereas hMG caused more weight of body or testis, enlarging tubules with annular clearance. Grin presented a dose-dependent manner or cell differentiation-dependentincrease in testicular GHRH receptor, and did not impact the levels of blood and testicular GH, testosterone. Grin promotes fertility by proliferating and differentiating primitive cells through up-regulating testicular GHRH receptor without triggering GH secretion, which might solve the etiology of oligoasthenozoospermia. PMID- 30402026 TI - Fimasartan attenuates renal ischemia-reperfusion injury by modulating inflammation-related apoptosis. AB - Fimasartan, a new angiotensin II receptor antagonist, reduces myocyte damage and stabilizes atherosclerotic plaque through its anti-inflammatory effect in animal studies. We investigated the protective effects of pretreatment with fimasartan on ischemia-reperfusion injury (IRI) in a mouse model of ischemic renal damage. C57BL/6 mice were pretreated with or without 5 (IR-F5) or 10 (IR-F10) mg/kg/day fimasartan for 3 days. Renal ischemia was induced by clamping bilateral renal vascular pedicles for 30 min. Histology, pro-inflammatory cytokines, and apoptosis assays were evaluated 24 h after IRI. Compared to the untreated group, blood urea nitrogen and serum creatinine levels were significantly lower in the IR-F10 group. IR-F10 kidneys showed less tubular necrosis and interstitial fibrosis than untreated kidneys. The expression of F4/80, a macrophage infiltration marker, and tumor necrosis factor (TNF)-alpha, decreased in the IR F10 group. High-dose fimasartan treatment attenuated the upregulation of TNF alpha, interleukin (IL)-1beta, and IL-6 in ischemic kidneys. Fewer TUNEL positive cells were observed in IR-F10 compared to control mice. Fimasartan caused a significant decrease in caspase-3 activity and the level of Bax, and increased the Bcl-2 level. Fimasartan preserved renal function and tubular architecture from IRI in a mouse ischemic renal injury model. Fimasartan also attenuated upregulation of inflammatory cytokines and decreased apoptosis of renal tubular cells. Our results suggest that fimasartan inhibited the process of tubular injury by preventing apoptosis induced by the inflammatory pathway. PMID- 30402025 TI - Effect of carbamazepine on tetrodotoxin-resistant Na+ channels in trigeminal ganglion neurons innervating to the dura. AB - Migraine is a neurological disorder characterized by recurrent and disabling severe headaches. Although several anticonvulsant drugs that block voltage dependent Na+ channels are widely used for migraine, far less is known about the therapeutic actions of carbamazepine on migraine. In the present study, therefore, we characterized the effects of carbamazepine on tetrodotoxin resistant (TTX-R) Na+ channels in acutely isolated rat dural afferent neurons, which were identified by the fluorescent dye DiI. The TTX-R Na+ currents were measured in medium-sized DiIpositive neurons using the whole-cell patch clamp technique in the voltage-clamp mode. While carbamazepine had little effect on the peak amplitude of transient Na+ currents, it strongly inhibited steady-state currents of transient as well as persistent Na+ currents in a concentration dependent manner. Carbamazepine had only minor effects on the voltage-activation relationship, the voltage-inactivation relationship, and the use-dependent inhibition of TTX-R Na+ channels. However, carbamazepine changed the inactivation kinetics of TTX-R Na+ channels, significantly accelerating the development of inactivation and delaying the recovery from inactivation. In the current-clamp mode, carbamazepine decreased the number of action potentials without changing the action potential threshold. Given that the sensitization of dural afferent neurons by inflammatory mediators triggers acute migraine headaches and that inflammatory mediators potentiate TTX-R Na+ currents, the present results suggest that carbamazepine may be useful for the treatment of migraine headaches. PMID- 30402027 TI - Tussilagone suppressed the production and gene expression of MUC5AC mucin via regulating nuclear factor-kappa B signaling pathway in airway epithelial cells. AB - In the present study, we investigated whether tussilagone, a natural product derived from Tussilago farfara, significantly affects the production and gene expression of airway MUC5AC mucin. Confluent NCI-H292 cells were pretreated with tussilagone for 30 min and then stimulated with EGF (epidermal growth factor) or PMA (phorbol 12-myristate 13-acetate) for 24 h or the indicated periods. The MUC5AC mucin gene expression was measured by RT-PCR. Production of MUC5AC mucin protein was measured by ELISA. To elucidate the action mechanism of tussilagone, effect of tussilagone on PMA-induced NF-kappaB signaling pathway was investigated by western blot analysis. Tussilagone significantly inhibited the production of MUC5AC mucin protein and down-regulated the expression of MUC5AC mucin gene, induced by EGF or PMA. Tussilagone inhibited PMA-induced activation (phosphorylation) of inhibitory kappa B kinase (IKK), and thus phosphorylation and degradation of inhibitory kappa Ba (IkappaBalpha). Tussilagone inhibited PMA induced phosphorylation and nuclear translocation of nuclear factor kappa B (NF kappaB) p65. This, in turn, led to the down-regulation of MUC5AC protein production in NCI-H292 cells. These results suggest that tussilagone can regulate the production and gene expression of mucin by acting on airway epithelial cells through regulation of NF-kappaB signaling pathway. PMID- 30402029 TI - Cyanidin-3-glucoside inhibits amyloid beta25-35-induced neuronal cell death in cultured rat hippocampal neurons. AB - Increasing evidence implicates changes in [Ca2+]i and oxidative stress as causative factors in amyloid beta (Abeta)-induced neuronal cell death. Cyanidin-3 glucoside (C3G), a component of anthocyanin, has been reported to protect against glutamate-induced neuronal cell death by inhibiting Ca2+ and Zn2+ signaling. The present study aimed to determine whether C3G exerts a protective effect against Abeta25-35-induced neuronal cell death in cultured rat hippocampal neurons from embryonic day 17 fetal Sprague-Dawley rats using MTT assay for cell survival, and caspase-3 assay and digital imaging methods for Ca2+, Zn2+, MMP and ROS. Treatment with Abeta25-35 (20 uM) for 48 h induced neuronal cell death in cultured rat pure hippocampal neurons. Treatment with C3G for 48 h significantly increased cell survival. Pretreatment with C3G for 30 min significantly inhibited Abeta25-35-induced [Zn2+]i increases as well as [Ca2+]i increases in the cultured rat hippocampal neurons. C3G also significantly inhibited Abeta25-35-induced mitochondrial depolarization. C3G also blocked the Abeta25-35-induced formation of ROS. In addition, C3G significantly inhibited the Abeta25-35-induced activation of caspase-3. These results suggest that cyanidin-3-glucoside protects against amyloid beta-induced neuronal cell death by reducing multiple apoptotic signals. PMID- 30402028 TI - Dual mechanisms for the regulation of brain-derived neurotrophic factor by valproic acid in neural progenitor cells. AB - Autism spectrum disorders (ASDs) are neurodevelopmental disorders that share behavioral features, the results of numerous studies have suggested that the underlying causes of ASDs are multifactorial. Behavioral and/or neurobiological analyses of ASDs have been performed extensively using a valid model of prenatal exposure to valproic acid (VPA). Abnormal synapse formation resulting from altered neurite outgrowth in neural progenitor cells (NPCs) during embryonic brain development has been observed in both the VPA model and ASD subjects. Although several mechanisms have been suggested, the actual mechanism underlying enhanced neurite outgrowth remains unclear. In this study, we found that VPA enhanced the expression of brain-derived neurotrophic factor (BDNF), particularly mature BDNF (mBDNF), through dual mechanisms. VPA increased the mRNA and protein expression of BDNF by suppressing the nuclear expression of methyl-CpG-binding protein 2 (MeCP2), which is a transcriptional repressor of BDNF. In addition, VPA promoted the expression and activity of the tissue plasminogen activator (tPA), which induces BDNF maturation through proteolytic cleavage. Trichostatin A and sodium butyrate also enhanced tPA activity, but tPA activity was not induced by valpromide, which is a VPA analog that does not induce histone acetylation, indicating that histone acetylation activity was required for tPA regulation. VPA mediated regulation of BDNF, MeCP2, and tPA was not observed in astrocytes or neurons. Therefore, these results suggested that VPA-induced mBDNF upregulation was associated with the dysregulation of MeCP2 and tPA in developing cortical NPCs. PMID- 30402030 TI - Mitochondrial dysfunction reduces the activity of KIR2.1 K+ channel in myoblasts via impaired oxidative phosphorylation. AB - Myoblast fusion depends on mitochondrial integrity and intracellular Ca2+ signaling regulated by various ion channels. In this study, we investigated the ionic currents associated with [Ca2+]i regulation in normal and mitochondrial DNA depleted (rho0) L6 myoblasts. The rho0 myoblasts showed impaired myotube formation. The inwardly rectifying K+ current (IKir) was largely decreased with reduced expression of KIR2.1, whereas the voltage-operated Ca2+ channel and Ca2+ activated K+ channel currents were intact. Sustained inhibition of mitochondrial electron transport by antimycin A treatment (24 h) also decreased the IKir. The rho0 myoblasts showed depolarized resting membrane potential and higher basal [Ca2+]i. Our results demonstrated the specific downregulation of IKir by dysfunctional mitochondria. The resultant depolarization and altered Ca2+ signaling might be associated with impaired myoblast fusion in rho0 myoblasts. PMID- 30402031 TI - Advanced tube formation assay using human endothelial colony forming cells for in vitro evaluation of angiogenesis. AB - The tube formation assay is a widely used in vitro experiment model to evaluate angiogenic properties by measuring the formation of tubular structures from vascular endothelial cells (ECs). in vitro experimental results are crucial when considered the advisability of moving forward to in vivo studies. Thus, the additional attentions to the in vitro assay is necessary to improve the quality of the pre-clinical data, leading to better decision-making for successful drug discovery. In this study, we improved the tube formation assay system in three aspects. First, we used human endothelial colony forming cells (ECFCs), which are endothelial precursors that have a robust proliferative capacity and more defined angiogenic characteristics compared to mature ECs. Second, we utilized a real time cell recorder to track the progression of tube formation for 48 hours. Third, to minimize analysis error due to the limited observation area, we used image-stitching software to increase the microscope field of view to a 2*2 stitched area from the 4* object lens. Our advanced tube formation assay system successfully demonstrated the time-dependent dynamic progression of tube formation in the presence and absence of VEGF and FGF-2. Vatalanib, VEGF inhibitor, was tested by our assay system. Of note, IC50 values of vatalanib was different at each observation time point. Collectively, these results indicate that our advanced tube formation assay system replicates the dynamic progression of tube formation in response to angiogenic modulators. Therefore, this new system provides a sensitive and versatile assay model for evaluating pro- or anti angiogenic drugs. PMID- 30402032 TI - Potentiation of endothelium-dependent vasorelaxation of mesenteric arteries from spontaneously hypertensive rats by gemigliptin, a dipeptidyl peptidase-4 inhibitor class of anti-diabetic drug. AB - Dipeptidyl peptidase4 (DPP4) inhibitors such as gemigliptin are anti-diabetic drugs elevating plasma concentration of incretins such as GLP-1. In addition to the DPP4 inhibition, gemigliptin might directly improve the functions of vessels under pathological conditions. To test this hypothesis, we investigated whether the acetylcholine-induced endothelium dependent relaxation (ACh-EDR) of mesenteric arteries (MA) are altered by gemigliptin pretreatment in Spontaneous Hypertensive Rats (SHR) and in Wistar-Kyoto rats (WKY) under hyperglycemia-like conditions (HG; 2 hr incubation with 50 mM glucose). ACh-EDR of WKY was reduced by the HG condition, which was significantly recovered by 1 uM gemigliptin while not by saxagliptin and sitagliptin up to 10 uM. The ACh-EDR of SHR MA was also improved by 1 uM gemigliptin while similar recovery was observed with higher concentration (10 uM) of saxagliptin and sitagliptin. The facilitation of ACh-EDR by gemigliptin in SHR was not observed under pretreatment with NOS inhibitor, L NAME. In the endotheliumdenuded MA of SHR, sodium nitroprusside induced dose dependent relaxation was not affected by gemigliptin. The ACh-EDR in WKY was decreased by treatment with 30 uM pyrogallol, a superoxide generator, which was not prevented by gemigliptin. Exendin-4, a GLP-1 analogue, could not enhance the ACh-EDR in SHR MA. The present results of ex vivo study suggest that gemigliptin enhances the NOS-mediated EDR of the HG-treated MA as well as the MA from SHR via GLP-1 receptor independent mechanism. PMID- 30402033 TI - Regional difference in spontaneous firing inhibition by GABAA and GABAB receptors in nigral dopamine neurons. AB - GABAergic control over dopamine (DA) neurons in the substantia nigra is crucial for determining firing rates and patterns. Although GABA activates both GABAA and GABAB receptors distributed throughout the somatodendritic tree, it is currently unclear how regional GABA receptors in the soma and dendritic compartments regulate spontaneous firing. Therefore, the objective of this study was to determine actions of regional GABA receptors on spontaneous firing in acutely dissociated DA neurons from the rat using patch-clamp and local GABA-uncaging techniques. Agonists and antagonists experiments showed that activation of either GABAA receptors or GABAB receptors in DA neurons is enough to completely abolish spontaneous firing. Local GABA-uncaging along the somatodendritic tree revealed that activation of regional GABA receptors limited within the soma, proximal, or distal dendritic region, can completely suppress spontaneous firing. However, activation of either GABAA or GABAB receptor equally suppressed spontaneous firing in the soma, whereas GABAB receptor inhibited spontaneous firing more strongly than GABAA receptor in the proximal and distal dendrites. These regional differences of GABA signals between the soma and dendritic compartments could contribute to our understanding of many diverse and complex actions of GABA in midbrain DA neurons. PMID- 30402035 TI - Novitates neocaledonicae X: A very rare and threatened new microendemic species of Acropogon (Malvaceae, Sterculioideae) from New Caledonia. AB - A new species, Acropogonhorarius Gateble & Munzinger, sp. nov. (Malvaceae, Sterculioideae), is described from New Caledonia. It is known only from two very small subpopulations in the rainforests of the Petchecara Pass between Thio and Canala, in the southeast of Grande-Terre, New Caledonia's main island. This shrub to small tree has hastate leaves and minute sessile tubular whitish-yellowish flowers and is strikingly different from all other members of the genus. The type locality is geologically complex and located within one of only four amphibolite lenses known in New Caledonia. A line drawing and colour photos are provided for the new species, along with a preliminary risk of extinction assessment, which indicates that the species is Critically Endangered. PMID- 30402034 TI - Conservation priorities for terrestrial mammals in Dobrogea Region, Romania. AB - Based on species occurrence records of museum collections, published literature, and unpublished records shared by mammalian experts, we compiled a distribution database for 59 terrestrial mammals populating the extensively protected Dobrogea Region of Romania. The spatial patterns of mammal distribution and diversity was evaluated and systematic conservation planning applied to identify priority areas for their conservation. The spatial analyses revealed that intensive sampling was not directly correlated to mammal diversity but rather to accessibility for inventory. The spatial prioritisation analysis indicated a relatively aggregated pattern of areas with a high or low conservation value with virtually no connecting corridors between them. The significant overlap between Natura 2000 sites and national protected areas induced an over-optimistic vision of the effectiveness and representativeness of existing Natura 2000 network for species found in Annexes II and IV of the Habitats Directive. These results represent a key step in identifying core areas for the protection of mammal diversity and dispersal corridors for improved connectivity, and to guide future conservation efforts in increasing the effectiveness of the existing protected areas in the context of environmental changes. PMID- 30402036 TI - A Linnaeus NG interactive key to the species of Glomera (Orchidaceae, Coelogyninae) from Southeast Asia. AB - We present a multilingual interactive key available online (http://glomera.linnaeus.naturalis.nl) that can be used on any web browser without the need for installing additional software. The key includes 169 species of Glomera, a genus within the necklace orchids (Coelogyninae) not yet comprehensively treated in any recent field guide or web-based survey. With this key, plants can be identified using a combination of vegetative and floristic characters in addition to distribution and ecology as a first step to further taxonomic revisions. We urge anyone with an interest in wild orchids in Southeast Asia to contribute new observations to update current information on the distribution of these overlooked plants as a first step for a taxonomic revision and to gain more insight into their conservation status. PMID- 30402037 TI - Three new species of Phanerochaete (Polyporales, Basidiomycota). AB - Phanerochaetecanobrunnea, P.cystidiata and P.fusca are presented as new species, supported by morphological studies and two sets of phylogenetic analyses. The 5.8S+nuc 28S+rpb1 dataset shows the generic placement of the three species within the phlebioid clade of Polyporales. The ITS+nuc 28S dataset displays relationships for the new taxa within Phanerochaete s.s. Phanerochaetecanobrunnea grew on angiosperm branches in subtropical Taiwan and is characterised by greyish brown hymenial surface, brown generative hyphae and skeletal hyphae and absence of cystidia. Phanerochaetecystidiata grew on angiosperm branches above 1000 m in montane Taiwan and SW Yunnan Province of China and is characterised by cream to yellowish hymenial surface and more or less encrusted leptocystidia. Phanerochaetefusca grew on angiosperm branches at 1700 m in Hubei Province of China and is characterised by dark brown hymenial surface, leptocystidia, brown subicular hyphae and colourless to brownish basidiospores. PMID- 30402038 TI - Placental Ras Regulates Inflammation Associated with Maternal Obesity. AB - Heightened placental inflammation and dysfunction are commonly associated in pregnant obese women compared to their pregnant lean counterparts. The small GTPase superfamily members known as the rat sarcoma viral oncogene homolog (Ras) proteins, in particular, the K-Ras and H-Ras isoforms, have been implicated to regulate inflammation. The aims were to determine the placental Ras expression and activity with maternal obesity and its role in regulating placental inflammation. Human placenta was obtained at term Caesarean section from lean and obese pregnant women to determine the effect of maternal obesity on Ras protein expression and activity. To determine the effect of Ras on inflammation induced by bacterial endotoxin LPS and proinflammatory cytokines TNF-alpha or IL-1beta, the chemical inhibitor lonafarnib (total Ras inhibitor) and siRNA (siKRAS and siHRAS) were used. Total Ras protein expression together with combined K-Ras and H-Ras activity was significantly increased in the placenta of obese pregnant women and when stimulated with LPS, IL-1beta, or TNF-alpha. Lonafarnib significantly suppressed LPS-, IL-1beta-, or TNF-alpha-induced IL-6, IL-8, MCP-1, and GRO-alpha expression and secretion in placental tissue. Primary trophoblast cells transfected with siKRAS or siHRAS demonstrated only K-Ras silencing significantly decreased IL-1beta-, TNF-alpha-, or LPS-induced IL-6, IL-8, and MCP 1 expression and secretion. Furthermore, siKRAS significantly reduced downstream ERK-1/2 activation induced by LPS. In trophoblast cells, ERK-1/2 signalling is required for IL-6, IL-8, MCP-1, and GRO-alpha secretion. These studies implicate a role for K-Ras in regulating inflammation in human placenta. Suppressing overactive placental K-Ras function may prevent adverse fetal outcomes complicated by maternal obesity. PMID- 30402039 TI - Sevoflurane Exacerbates Cognitive Impairment Induced by Abeta 1-40 in Rats through Initiating Neurotoxicity, Neuroinflammation, and Neuronal Apoptosis in Rat Hippocampus. AB - Objective: This study was aimed at investigating whether sevoflurane inhalation induced cognitive impairment in rats with a possible mechanism involved in the event. Methods: Thirty-two rats were randomly divided into four groups of normal saline (NS) + O2, NS + sevoflurane (sevo), amyloid-beta peptide (Abeta) + O2, and Abeta + sevo. The rats in the four groups received bilateral intrahippocampus injections of NS or Abeta. The treated hippocampus was harvested after inhaling 30% O2 or 2.5% sevoflurane. Evaluation of cognitive function was performed by Morris water maze (MWZ) and an Abeta 1-42 level was determined by ELISA. Protein and mRNA expressions were executed by immunohistochemical (IHC) staining, Western blotting, and qRT-PCR. Results: Compared with the NS-treated group, sevoflurane only caused cognitive impairment and increased the level of Abeta 1-42 of the brain in the Abeta-treated group. Sevoflurane inhalation but not O2 significantly increased glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule (IBA)1 expression in Abeta-treated hippocampus of rats. Expression levels for Bcl-xL, caspase-9, receptor for advanced glycation end products (RAGE) and brain-derived neurotrophic factor (BDNF) were significantly different in quantification of band intensity between the rats that inhaled O2 and sevoflurane in Abeta-treated groups (all P < 0.05). Interleukin- (IL-) 1beta, nuclear factor-kappaB (NF-kappaB), and inducible nitric oxide synthase (iNOS) mRNA expression increased after the rats inhaled sevoflurane in the Abeta-treated group (both P < 0.01). There were no significant differences in the change of GFAP, IBA1, Bcl-xL, caspase-9, RAGE, BDNF, IL-1beta, NF-kappaB, and iNOS in the NS + O2 and NS + sevo group (all P > 0.05). Conclusion: Sevoflurane exacerbates cognitive impairment induced by Abeta 1-40 in rats through initiating neurotoxicity, neuroinflammation, and neuronal apoptosis in rat hippocampus. PMID- 30402040 TI - sST2 as a New Biomarker of Chronic Kidney Disease-Induced Cardiac Remodeling: Impact on Risk Prediction. AB - Heart failure is the most frequent cardiac complication of chronic kidney disease (CKD). Biomarkers help identify high-risk patients. Natriuretic peptides (BNP and NT-proBNP) are largely used for monitoring patients with cardiac failure but are highly dependent on glomerular filtration rate (GFR). Soluble suppression of tumorigenicity 2 (sST2) biomarker is well identified in risk stratification of cardiovascular (CV) events in heart failure. Furthermore, sST2 is included in a bioclinical score to stratify mortality risk. The aims of this study were to evaluate (i) the interest of circulating sST2 level in heart dysfunction and (ii) the bioclinical score (Barcelona Bio-Heart Failure risk calculator) to predict the risk of composite outcome (major adverse coronary events) and mortality in the CKD population. A retrospective study was carried out on 218 CKD patients enrolled from 2004 to 2015 at Montpellier University Hospital. sST2 was measured by ELISA (Presage ST2(r) kit). GFR was estimated by the CKD-EPI equation (eGFR). Indices of cardiac parameters were performed by cardiac echography. No patient had reduced ejection fraction. 112 patients had left ventricular hypertrophy, and 184 presented cardiac dysfunction, with structural, functional abnormalities or both. sST2 was independent of age and eGFR (rho = 0.05, p = 0.44, and rho = 0.07, p = 0.3, respectively). Regarding echocardiogram data, sST2 was correlated with left ventricular mass index (rho = 0.16, p = 0.02), left atrial diameter (rho = 0.14, p = 0.04), and volume index (rho = 0.13, p = 0.05). sST2 alone did not change risk prediction of death and/or CV events compared to natriuretic peptides. Included in the Barcelona Bio-Heart Failure (BCN Bio-HF) score, sST2 added value and better stratified the risk of CV events and/or death in CKD patients (p < 0.0001). To conclude, sST2 was associated with cardiac remodeling independently of eGFR, unlike other cardiac biomarkers. Added to the BCN Bio-HF score, the risk stratification of death and/or CV events in nondialyzed CKD patients was highly improved. PMID- 30402042 TI - Overexpression of CD44 Variant 9: A Novel Cancer Stem Cell Marker in Human Cholangiocarcinoma in Relation to Inflammation. AB - Various CD44 isoforms are expressed in several cancer stem cells during tumor progression and metastasis. In particular, CD44 variant 9 (CD44v9) is highly expressed in chronic inflammation-induced cancer. We investigated the expression of CD44v9 and assessed whether CD44v9 is a selective biomarker of human cholangiocarcinoma (CCA). The expression profile of CD44v9 was evaluated in human liver fluke Opisthorchis viverrini-related CCA (OV-CCA) tissues, human CCA (independent of OV infection, non-OV-CCA) tissues, and normal liver tissues. CD44v9 overexpression was detected by immunohistochemistry (IHC) in CCA tissues. There was a higher level of CD44v9 expression and IHC score in OV-CCA tissues than in non-OV-CCA tissues, and there was no CD44v9 staining in the bile duct cells of normal liver tissues. In addition, we observed significantly higher expression of inflammation-related markers, such as S100P and COX-2, in OV-CCA tissues compared to that in non-OV and normal liver tissues. Thus, these findings suggest that CD44v9 may be a novel candidate CCA stem cell marker and may be related to inflammation-associated cancer development. PMID- 30402041 TI - Upregulation of Plasminogen Activator Inhibitor-1 in Irradiated Recipient Arteries and Veins from Free Tissue Transfer Reconstruction in Cancer Patients. AB - Background: Clinical studies have shown that radiotherapy can induce vascular disease at the site of exposure but is usually not clinically evident until years after treatment. We have studied irradiated human arteries and veins to better understand the underlying biology in search of future treatments. The aim was to investigate whether radiotherapy contributed to a sustained expression of plasminogen activator inhibitor-1 (PAI-1) in human arteries and veins. Methods: Irradiated arteries and veins were harvested, together with unirradiated control vessels, from patients undergoing free tissue transfer reconstruction at a median time of 90 weeks [5-650] following radiation exposure. Differential gene expression of PAI-1 was analysed, together with immunohistochemistry (IHC) and immunofluorescence (IF). Results: PAI-1 gene expression was increased in both arteries (p = 0.012) and veins (p < 0.001) in irradiated compared to unirradiated control vessels. IHC and IF indicated that cells expressing PAI-1 were located in the adventitia of both arteries and veins and colocalized with cells positive for CD68, CD45, and alpha-SMA in arteries and with CD45 and alpha-SMA in veins. Conclusion: The current study shows a sustained upregulation of PAI-1 in both arteries and veins after exposure to ionizing radiation, indicating a chronic inflammation mainly in the adventitia. We believe that the results contribute to further understanding of radiation-induced vascular disease, where targeting PAI 1 may be a potential treatment. PMID- 30402043 TI - PICK1 Deficiency Induces Autophagy Dysfunction via Lysosomal Impairment and Amplifies Sepsis-Induced Acute Lung Injury. AB - Sepsis is a systemic inflammatory reaction caused by infection. Multiple organ failure ultimately leads to high morbidity and mortality. Unfortunately, therapies against these responses have been unsuccessful due to the insufficient underlying pathophysiological evidence. Protein interacting with C-kinase 1 (PICK1) has received considerable attention because of its important physiological functions in many tissues. However, its role in sepsis-induced acute lung injury (ALI) is unclear. In this study, we used cecal ligation and puncture (CLP) to establish a septic model and found that decreased microtubule associated protein-1light chain 3 (LC3)-II/LC3-I in PICK1-/- septic mice was caused by autophagy dysfunction. Consistently, the transmission electron microscopy (TEM) of bone marrow-derived macrophages (BMDMs) from PICK1-/- mice showed the accumulation of autophagosomes as well. However, more serious damage was caused by PICK1 deficiency indicating that the disrupted autophagic flux was harmful to sepsis-induced ALI. We also observed that it was the impaired lysosomal function that mediated autophagic flux blockade, and the autophagy progress was relevant to PI3K-Akt-mTOR pathway. These findings will aid in the potential development of PICK1 with novel evidence of autophagy in sepsis treatment and prevention. PMID- 30402044 TI - Neostigmine Attenuates Proinflammatory Cytokine Expression in Preoptic Area but Not Choroid Plexus during Lipopolysaccharide-Induced Systemic Inflammation. AB - The study was designed to examine whether the administration of neostigmine (0.5 mg/animal), a peripheral inhibitor of acetylcholinesterase (AChE), during an immune/inflammatory challenge provoked by intravenous injection of bacterial endotoxin-lipopolysaccharide (LPS; 400 ng/kg)-attenuates the synthesis of proinflammatory cytokines in the ovine preoptic area (POA), the hypothalamic structure playing an essential role in the control of the reproduction process, and in the choroid plexus (CP), a multifunctional organ sited at the interface between the blood and cerebrospinal fluid in the ewe. Neostigmine suppressed (p < 0.05) LPS-stimulated synthesis of cytokines such as interleukin- (IL-) 1beta, IL 6, and tumor necrosis factor (TNF) alpha in the POA, and this effect was similar to that induced by the treatment with systemic AChE inhibitor-donepezil (2.5 mg/animal). On the other hand, both AChE inhibitors did not influence the gene expression of these cytokines and their corresponding receptors in the CP. It was found that this structure seems to not express the neuronal acetylcholine (ACh) receptor subunit alpha-7, required for anti-inflammatory action of ACh. The mechanism of action involves inhibition of the proinflammatory cytokine synthesis on the periphery as well as inhibition of their de novo synthesis rather in brain microvessels and not in the CP. In conclusion, it is suggested that the AChE inhibitors incapable of reaching brain parenchyma might be used in the treatment of neuroinflammatory processes induced by peripheral inflammation. PMID- 30402045 TI - Multiparametric FDG-PET/MRI of Hepatocellular Carcinoma: Initial Experience. AB - Purpose: To compare multiparametric (mp)FDG-PET/MRI metrics between hepatocellular carcinoma (HCC) and liver parenchyma and to assess the correlation between mpMRI and FDG-PET standard uptake values (SUVs) in liver parenchyma and HCC. Methods: This prospective, institutional review board-approved study enrolled 15 patients (M/F 12/3; mean age 61 y) with HCC. mpMRI including blood oxygen-level-dependent (BOLD) MRI, intravoxel incoherent motion diffusion weighted imaging (IVIM-DWI), and dynamic contrast-enhanced-(DCE-) MRI was performed simultaneously with 18F-FDG-PET on a 3T PET/MRI hybrid system. Quantitative BOLD, IVIM and DCE-MRI parameters (Tofts model (TM) and shutter speed model (SSM)), and PET parameters (SUVmean and SUVmax) were quantified and compared between HCC lesions and liver parenchyma using Wilcoxon signed-rank tests. SUV ratios between HCCs and liver were also calculated (SUVmean T/L and SUVmax T/L). Diagnostic performance of (combined) mp-PET/MRI parameters for characterization of HCC was assessed using ROC analysis. Spearman correlations between PET and mpMRI parameters in HCC tumors and liver parenchyma were evaluated. Results: 21 HCC lesions (mean size 4.0 +/- 2.4 cm; range 2-13 cm) were analyzed. HCCs exhibited significantly higher arterial fraction (from DCE-MRI) and lower R 2 * pre-O2 and post-O2 (from BOLD-MRI) versus liver parenchyma (P < 0.032). The highest diagnostic performance for differentiation between HCC and liver parenchyma was achieved for combined ART SSM and R 2 * post-O2 (AUC = 0.91). SUVmax showed reasonable performance for differentiation of HCC versus liver (AUC = 0.75). In HCC, DCE-MRI parameters K trans (TM and SSM) and v e TM exhibited significant negative correlations with SUVmax T/L (r ranges from -0.624 to -0.566; FDR-adjusted P < 0.050). Conclusions: Despite the observed reasonable diagnostic performance of FDG-PET SUVmax for HCC detection and several significant correlations between FDG-PET SUV and DCE-MRI parameters, FDG-PET did not provide clear additional value for HCC characterization compared to mpMRI in this pilot study. PMID- 30402046 TI - Microvascular Invasion in HCC: The Molecular Imaging Perspective. AB - Hepatocellular carcinoma represents the most frequent primary liver tumor; curative options are only surgical resection and liver transplantation. From 1996, Milan Criteria are applied in consideration of patients with cirrhosis and hepatocellular for liver transplantation; nonetheless, more recently, Milan Criteria have been criticized because they appear over conservative. Apart from number and size of lesions and biomarker levels, which already have been associated with poorer prognosis, overall survival and recurrence rates after transplantation are affected also by the presence of vascular invasion. Microvascular invasion suggests a poor prognosis but it is often hard to detect before transplant. Diagnostic imaging and tumor markers may play an important role and become the main tools to define microvascular invasion. In particular, a possible role could be found for computed tomography, magnetic resonance imaging, and positron emission tomography. In this paper, we analyze the possible role of positron emission tomography as a preoperative imaging biomarker capable of predicting microvascular invasion in patients with hepatocellular carcinoma and thus selecting optimal candidates for liver transplantation. PMID- 30402047 TI - Two-Year Hospital-Wide Surveillance of Central Line-Associated Bloodstream Infections in a Korean Hospital. AB - Background: Surveillance and interventions of central line-associated bloodstream infections (CLABSIs) had mainly been targeted in intensive care units (ICUs). Central lines are increasingly used outside ICUs. Therefore, we performed a hospital-wide survey of CLABSIs to evaluate the current status and develop strategies to reduce CLBASI rates. Methods: All hospitalized patients with central venous catheters (CVCs) were screened for CLABSIs from January 2014 through December 2015 at a 1,328 bed tertiary care teaching hospital in Korea using an electronic data-collecting system. Clinical information including type of CVC was collected. CLABSI rates were calculated using the definitions of the National Health and Safety Network after excluding mucosal barrier injury laboratory-confirmed bloodstream infection (BSI). Results: A total of 154 CLABSIs were identified, of which 72 (46.8%) occurred in general wards and 82 (53.2%) in ICUs (0.81 and 2.71 per 1,000 catheter days), respectively. Non-tunneled CVCs were most common (68.6%) among 70 CLABSI events diagnosed within one week of their maintenance. On the other hand, tunneled CVCs and peripherally inserted central catheters (PICCs) were more common (60.5%) among 114 CLABSI events diagnosed more than a week after maintenance. Whereas the majority (72.2%) of CLABSIs in ICUs were associated with non-tunneled CVCs, tunneled CVCs (38.9%) and PICCs (36.8%) were more common in general wards. Conclusion: CLABSIs are less common in general wards than in ICUs, but they are more often associated with long-term indwelling catheters. Therefore, interventions to prevent CLABSIs should be tailored according to the type of ward and type of catheter. PMID- 30402049 TI - Mediating Role of Anxiety and Depression in the Relationship between Posttraumatic Stress Symptoms and Illness Intrusiveness. AB - Background: Posttraumatic stress symptoms (PTSS) in patients with psychological trauma lead to poor health-related quality of life. Understanding of the relationships among PTSS, anxiety, depression, and illness intrusiveness will guide the development of efficient approaches to enhance subjective well-being in patients with psychological trauma. This study investigated whether anxiety and depression mediate the relationship between PTSS and illness intrusiveness in the hope of providing more comprehensive and effective trauma treatment. Methods: Psychiatric outpatients who visited the trauma clinic of a university hospital (n = 260) participated in this study. Assessments were conducted for PTSS, anxiety, depression, and illness intrusiveness. Structural equation modeling and path analysis were performed to analyze the mediating effects of anxiety and depression on the relationship between PTSS and illness intrusiveness. Results: PTSS had both direct and indirect exacerbating effects on illness intrusiveness. Anxiety exhibited the largest direct exacerbating effect on illness intrusiveness. The indirect effects of PTSS on illness intrusiveness through anxiety alone and through a depression-to-anxiety pathway were significant, but the indirect effect through depression alone was not. Conclusion: The findings demonstrate that anxiety, both independently and as part of an interrelated pathway with depression, partially mediates the relationship between PTSS and illness intrusiveness. Appropriate interventions and a comprehensive approach to alleviate anxiety and depression could mitigate the negative effects of PTSS on illness intrusiveness in patients with psychological trauma. PMID- 30402048 TI - Efficacy of Sorafenib for the Treatment of Post-Transplant Hepatocellular Carcinoma Recurrence. AB - Background: The role of sorafenib in patients with hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) has been rarely studied. The aim of this study was to evaluate the efficacy of sorafenib in post-LT era. Methods: Consecutive patients with post-transplant HCC recurrence not eligible to resection or locoregional therapy were included. Patients receiving best supportive care (BSC) until 2007 were compared with those treated by sorafenib thereafter. Results: Of a total of 65 patients, 20 patients received BSC and 45 received sorafenib. Clinical characteristics were similar between two groups except that sorafenib group received tacrolimus and mammalian target-of-rapamycin inhibitors more frequently than BSC group. Treatment with sorafenib conferred a survival advantage as compared with BSC for survival after recurrence (median, 14.2 vs. 6.8 months; P = 0.01). In multivariate analyses, high serum alpha fetoprotein level, synchronous intrahepatic recurrence and distant metastasis at the time of recurrence, and BSC were independently associated with poorer survival after recurrence. Sorafenib treatment was associated with better survival after recurrence as compared with BSC (hazard ratio, 0.25; 95% confidence interval, 0.10-0.62; P = 0.002). In addition, sorafenib group showed tolerable toxicity in the post-transplant setting. Conclusion: Sorafenib may be beneficial in patients with post-transplant HCC recurrence. PMID- 30402050 TI - Time to Disease Recurrence Is a Predictor of Metastasis and Mortality in Patients with High-risk Prostate Cancer Who Achieved Undetectable Prostate-specific Antigen Following Robot-assisted Radical Prostatectomy. AB - Background: Robot-assisted radical prostatectomy (RARP) is a feasible treatment option for high-risk prostate cancer (PCa). While patients may achieve undetectable prostate-specific antigen (PSA) levels after RARP, the risk of disease progression is relatively high. We investigated metastasis-free survival, cancer-specific survival (CSS), and overall survival (OS) outcomes and prognosticators in such patients. Methods: In a single-center cohort of 342 patients with high-risk PCa (clinical stage >= T3, biopsy Gleason score >= 8, and/or PSA levels >= 20 ng/mL) treated with RARP and pelvic lymph node dissection between August 2005 and June 2011, we identified 251 (73.4%) patients (median age, 66.5 years; interquartile range [IQR], 63.0-71.0 years) who achieved undetectable PSA levels (< 0.01 ng/mL) postoperatively. Survival outcomes were evaluated for the entire study sample and in groups stratified according to the time to biochemical recurrence dichotomized at 60 months. Results: During the median follow-up of 75.9 months (IQR, 59.4-85.8 months), metastasis occurred in 38 (15.1%) patients, most often to the bones, followed by the lymph nodes, lungs, and liver. The 5-year metastasis-free, cancer-specific, and OS rates were 87.1%, 94.8%, and 94.3%, respectively. Multivariate Cox-regression analysis revealed time to recurrence as an independent predictor of metastasis (P < 0.001). Time to metastasis was an independent predictor of OS (P = 0.003). Metastasis-free and CSS rates were significantly lower among patients with recurrence within 60 months of RARP (log-rank P < 0.001). Conclusion: RARP confers acceptable oncological outcomes for high-risk PCa. Close monitoring beyond 5 years is warranted for early detection of disease progression and for timely adjuvant therapy. PMID- 30402051 TI - Sorafenib for Recurrent Hepatocellular Carcinoma after Liver Transplantation. PMID- 30402052 TI - Corrigendum: Relative Level of Bacteriophage Multiplication in vitro or in Phyllosphere May Not Predict in planta Efficacy for Controlling Bacterial Leaf Spot on Tomato Caused by Xanthomonas perforans. AB - [This corrects the article DOI: 10.3389/fmicb.2018.02176.]. PMID- 30402053 TI - Corrigendum: Phytoplasmas-The "Crouching Tiger" Threat of Australian Plant Pathology. AB - [This corrects the article DOI: 10.3389/fpls.2017.00599.]. PMID- 30402054 TI - Niche segregation, competition, and urbanization. AB - Urbanization of species is an ongoing process where successful urban colonizers usually obtain large fitness benefits. Mechanisms proposed to explain associations between urbanization and life-history traits are based on behavioral flexibility in food and habitat use and reduced fear responses. We test the novel hypothesis that interspecific competition for proximity to humans is driving urbanization. We recorded the distance during the breeding season to human habitation for 50 pairs of closely related bird species, where one was closely associated with humans while the other species was not. The degree of urbanization was larger as was range size and abundance in the species more closely associated to humans. Flight initiation distance was shorter, and species closely associated with humans were more abundant in ancestral rural habitats. Likewise, species more closely associated with humans reproduced earlier and during longer periods. These results are consistent with the hypothesis that urbanization is promoted by interspecific competition. Resulting isolation by urban habitat may further facilitate contemporary adaptation to urban environments. PMID- 30402056 TI - Predicting the effect of climate change on a range-restricted lizard in southeastern Australia. AB - Climate change is ranked as one of the most severe threats to global biodiversity. This global phenomenon is particularly true for reptiles whose biology and ecology are closely linked to climate. In this study, we used over 1,300 independent occurrence points and different climate change emission scenarios to evaluate the potential risk of changing climatic conditions on the current and future potential distribution of a rock-dwelling lizard; the velvet gecko. Furthermore, we investigated if the current extent of protected area networks in Australia captures the full range distribution of this species currently and in the future. Our results show that climate change projections for the year 2075 have the potential to alter the distribution of the velvet gecko in southeastern Australia. Specifically, climate change may favor the range expansion of this species to encompass more suitable habitats. The trend of range expansion was qualitatively similar across the different climate change scenarios used. Additionally, we observed that the current network of protected areas in southeast Australia does not fully account for the full range distribution of this species currently and in the future. Ongoing climate change may profoundly affect the potential range distribution of the velvet gecko population. Therefore, the restricted habitat of the velvet geckos should be the focus of intensive pre-emptive management efforts. This management prioritization should be extended to encompass the increases in suitable habitats observed in this study in order to maximize the microhabitats available for the survival of this species. PMID- 30402057 TI - Factors affecting the spatial distribution and breeding habitat of an insular cliff-nesting raptor community. AB - The specific spatial distribution and habitat association-strongly influenced by environmental factors or competitive interactions-are major issues in ecology and conservation. We located and georeferenced nesting sites of five cliff-nesting raptors (Egyptian vulture Neophron percnopterus [a locally extinct species], common buzzard Buteo buteo, osprey Pandion haliaetus, common kestrel Falco tinnunculus, Barbary falcon Falco peregrinus pelegrinoides), and common raven Corvus corax on one of the most biodiverse hotspot within the Canary Islands (Teno, Tenerife). We used generalized linear models to evaluate the factors affecting abundance, richness, and intra- and interspecific interactions. Raptor abundance increased with slope, shrub-covered area, and habitat diversity, and decreased with altitude, and forested and grassed areas. Richness increased with slope and decreased with altitude. Threatened species (osprey, Barbary falcon, and raven) occupied cliffs farther away from houses and roads, and more rugged areas than the non-threatened species. The models suggested that the probability of cliff occupation by buzzards, falcons, and ravens depended only on inter specific interactions. Buzzard occupation increased with the distance to the nearest raven and kestrel nests, whereas falcons and ravens seek proximity to each other. Teno holds between 75% and 100% of the insular breeding populations of the most endangered species (osprey and raven), indicating the high conservation value of this area. Our study suggests that the preservation of rugged terrains and areas of low human pressure are key factors for raptor conservation and provide basic knowledge on the community structure and habitat associations to develop appropriated management actions for these fragile island populations. PMID- 30402055 TI - Like mother, like daughter: heritability of female Richardson's ground squirrel Urocitellus richardsonii cortisol stress responses. AB - Activation of the hypothalamic-pituitary-adrenal (HPA) axis liberates glucocorticoids, which provides an acute indication of an individual's response to stressors. The heritability of the stress response in wild mammals, however, remains poorly documented. We quantified the cortisol stress response of female Richardson's ground squirrels (RGSs) to handling and physical restraint, testing for: (1) the effects of individual age, time of day, and sample latency; (2) repeatability within individuals; (3) narrow-sense heritability; and (4) differences among individuals owing to potential genetic and/or environmental effects. We detected a positive linear relationship between baseline plasma cortisol (BL-cortisol) concentration and stress-induced plasma cortisol (SI cortisol) concentration that defined each individual's cortisol stress response. BL-cortisol, SI-cortisol, and stress response did not differ according to the time the sample was taken, or by subject age. Cortisol stress response was highly repeatable within individuals, had a mother-offspring heritability of h 2 = 0.40 +/- 0.24 (mean +/- SE), full-sibling heritability of hFS2 = 0.37 +/- 0.71 , and half-sibling heritability of hHS2= 0.75 +/- 1.41 . Stress responses of sibling groups, immediate-family groups, and squirrels within a given area did not differ, whereas those of individuals from more distantly related matrilines did. Our results highlight the natural variability in HPA axis reactivity among individuals by quantifying both BL- and SI-cortisol levels, demonstrate partial heritability of the stress response that is not attributable to environmental variation, and suggest that at least part of an individual's stress response can be accounted for by differences in matrilineal history. PMID- 30402058 TI - The ecology of sexual dimorphism in size and shape of the freshwater blenny Salaria fluviatilis. AB - Sexual selection is considered the major cause of sexual dimorphism, but recent observations suggest that natural selection may play a more important role in the evolution of sex differentiation than previously recognized. Therefore, studying the trade-offs between natural selection and sexual selection is crucial to a better understanding of the ecology underlying the evolution of sexual dimorphism. The freshwater blenny Salaria fluviatilis, a fish inhabiting lakes and rivers around the Mediterranean Sea, displays strong sexual dimorphism in size, shape, and behavior (i.e., larger body and head size for males and higher swimming requirements for females during the reproductive period). We tested for differences in sexual dimorphism in size and shape between the populations from lake and river habitats with the goal of identifying the trade-offs between natural and sexual selection that underlie variations in sexual dimorphism in this species. Our results show i) differences in sexual size dimorphism (SSizeD) in accordance to Rensch's rule (i.e., larger individuals in rivers associated with higher SSizeD), and ii) a decrease in shape differentiation between males and females in lake populations. Together, this suggests that the different environmental conditions between lake and river habitats (e.g., resource limitations, predation pressure, water velocity) affect the relative importance of sexual selection in the display of sexual dimorphism within the species. This study highlights the importance of considering the environmental conditions to which populations are exposed to better understand the ecology underlying the evolution of sexual dimorphism. PMID- 30402059 TI - Ecology and evolution along environmental gradients. PMID- 30402060 TI - Opposed elevational variation in prevalence and intensity of endoparasites and their vectors in a lizard. AB - Studying the causes of parasite geographic distribution is relevant to understand ecological and evolutionary processes that affect host populations as well as for species conservation. Temperature is one of the most important environmental variables affecting parasite distribution, as raising temperatures positively affect development, reproduction, and rate of transmission of both endo- and ectoparasites. In this context, it is generally accepted that, in mountains, parasite abundance decreases with elevation. However, empirical evidence on this topic is limited. In the present study, we analyzed the elevational variation of hemoparasites and ectoparasites of a lizard, Psammodromus algirus, along a 2,200 m elevational gradient in Sierra Nevada (SE Spain). As predicted, ectoparasite (mites, ticks, mosquitoes, and sandflies) abundance decreased with elevation. However, hemoparasite prevalence and intensity in the lizard augmented with altitude, showing a pattern contrary to their vectors (mites). We suggest that tolerance to hemoparasites may increase with elevation as a consequence of lizards at high altitudes taking advantage of increased body condition and food availability, and reduced oxidative stress. Moreover, lizards could have been selected for higher resistance against hemoparasites at lowlands (where higher rates of replication are expected), thus reducing hemoparasite prevalence and load. Our findings imply that, in a scenario of climate warming, populations of lizards at high elevation may face increased abundance of ectoparasites, accompanied with strong negative effects. PMID- 30402061 TI - Sperm priming response to perceived mating opportunities is reduced in male guppies with high baseline sperm production. AB - Producing sperm is costly and males have been selected to strategically adjust their sperm production and/or expenditure according to the fitness return associated with a specific mating. For example, males respond to fluctuations in the mating opportunities by adjusting the number of "ready" sperm. This phenomenon is known as "sperm priming" and is interpreted as a strategy to economize the investment in sperm. The cost and benefits of the sperm priming response, however, are expected to depend on a male's baseline sperm production (BSP) in the absence of females, because of the different risk of sperm depletion and the nonlinearly increasing costs of sperm production. We tested this prediction in 2 replicated lines of male guppies Poecilia reticulata that were artificially selected for high and low BSP. BSP has a large genetic variance and a high sire heritability in guppies, and males respond to the perceived mating opportunities by increasing the number of "ready" sperm. We investigated whether males with a different BSP differed in their sperm priming response. We found that when the perceived mating opportunities increased, males from low-sperm lines had a stronger sperm priming response than those from high-sperm lines. This result suggests that adaptive plasticity in sperm priming has the potential to evolve in response to different levels of BSP. The comparison between guppy populations with different levels of sperm production would allow to test whether the pattern reported here is also observed at the interpopulation level. PMID- 30402062 TI - Gradients in predation risk in a tropical river system. AB - The importance of predation risk as a key driver of evolutionary change is exemplified by the Northern Range in Trinidad, where research on guppies living in multiple parallel streams has provided invaluable insights into the process of evolution by natural selection. Although Trinidadian guppies are now a textbook example of evolution in action, studies have generally categorized predation as a dichotomous variable, representing high or low risk. Yet, ecologists appreciate that community structure and the attendant predation risk vary substantially over space and time. Here, we use data from a longitudinal study of fish assemblages at 16 different sites in the Northern Range to quantify temporal and spatial variation in predation risk. Specifically we ask: 1) Is there evidence for a gradient in predation risk? 2) Does the ranking of sites (by risk) change with the definition of the predator community (in terms of species composition and abundance currency), and 3) Are site rankings consistent over time? We find compelling evidence that sites lie along a continuum of risk. However, site rankings along this gradient depend on how predation is quantified in terms of the species considered to be predators and the abundance currency is used. Nonetheless, for a given categorization and currency, rankings are relatively consistent over time. Our study suggests that consideration of predation gradients will lead to a more nuanced understanding of the role of predation risk in behavioral and evolutionary ecology. It also emphasizes the need to justify and report the definition of predation risk being used. PMID- 30402063 TI - The Janus of macrophysiology: stronger effects of evolutionary history, but weaker effects of climate on upper thermal limits are reversed for lower thermal limits in ants. AB - Species may exhibit similar traits via different mechanisms: environmental filtering and local adaptation (geography) and shared evolutionary history (phylogeny) can each contribute to the resemblance of traits among species. Parsing trait variation into geographic and phylogenetic sources is important, as each suggests different constraints on trait evolution. Here, we explore how phylogenetic distance, geographic distance, and geographic variation in climate shape physiological tolerance of high and low temperatures using a global dataset of ant thermal tolerances. We found generally strong roles for evolutionary history and geographic variation in temperature, but essentially no detectable effects of spatial proximity per se on either upper or lower thermal tolerance. When we compared the relative importance of the factors shaping upper and lower tolerances, we found a much stronger role for evolutionary history in shaping upper versus lower tolerance, and a moderately weaker role for geographic variation in temperature in shaping upper tolerance when compared with lower tolerance. Our results demonstrate how geographic variation in climate and evolutionary history may have differential effects on the upper and lower endpoints of physiological tolerance. This Janus effect, where the relative contributions of geographic variation in climate and evolutionary history are reversed for lower versus upper physiological tolerances, has gained some support in the literature, and our results for ant physiological tolerances provide further evidence of this pattern. As the climate continues to change, the high phylogenetic conservatism of upper tolerance may suggest potential constraints on the evolution of tolerance of high temperatures. PMID- 30402064 TI - Changes in feeding selectivity of freshwater invertebrates across a natural thermal gradient. AB - Environmental warming places physiological constraints on organisms, which may be mitigated by their feeding behavior. Theory predicts that consumers should increase their feeding selectivity for more energetically valuable resources in warmer environments to offset the disproportionate increase in metabolic demand relative to ingestion rate. This may also result in a change in feeding strategy or a shift towards a more specialist diet. This study used a natural warming experiment to investigate temperature effects on the feeding selectivity of three freshwater invertebrate grazers: the snail Radix balthica, the blackfly larva Simulium aureum, and the midgefly larva Eukiefferiella minor. Chesson's Selectivity Index was used to compare the proportional abundance of diatom species in the guts of each invertebrate species with corresponding rock biofilms sampled from streams of different temperature. The snails became more selective in warmer streams, choosing high profile epilithic diatoms over other guilds and feeding on a lower diversity of diatom species. The blackfly larvae appeared to switch from active collector gathering of sessile high profile diatoms to more passive filter feeding of motile diatoms in warmer streams. No changes in selectivity were observed for the midgefly larvae, whose diet was representative of resource availability in the environment. These results suggest that key primary consumers in freshwater streams, which constitute a major portion of invertebrate biomass, can change their feeding behavior in warmer waters in a range of different ways. These patterns could potentially lead to fundamental changes in the flow of energy through freshwater food webs. PMID- 30402065 TI - Brain differences in ecologically differentiated sticklebacks. AB - Populations that have recently diverged offer a powerful model for studying evolution. Ecological differences are expected to generate divergent selection on multiple traits, including neurobiological ones. Animals must detect, process, and act on information from their surroundings and the form of this information can be highly dependent on the environment. We might expect different environments to generate divergent selection not only on the sensory organs, but also on the brain regions responsible for processing sensory information. Here, we test this hypothesis using recently evolved reproductively isolated species pairs of threespine stickleback fish Gasterosteus aculeatus that have well described differences in many morphological and behavioral traits correlating with ecological differences. We use a state-of-the-art method, magnetic resonance imaging, to get accurate volumetric data for 2 sensory processing regions, the olfactory bulbs and optic tecta. We found a tight correlation between ecology and the size of these brain regions relative to total brain size in 2 lakes with intact species pairs. Limnetic fish, which rely heavily on vision, had relatively larger optic tecta and smaller olfactory bulbs compared with benthic fish, which utilize olfaction to a greater extent. Benthic fish also had larger total brain volumes relative to their body size compared with limnetic fish. These differences were erased in a collapsed species pair in Enos Lake where anthropogenic disturbance has led to intense hybridization. Together these data indicate that evolution of sensory processing regions can occur rapidly and independently. PMID- 30402066 TI - Effects of a sex ratio gradient on female mate-copying and choosiness in Drosophila melanogaster. AB - In many sexually reproducing species, individuals can gather information about potential mates by observing their mating success. This behavioral pattern, that we call mate-copying, was reported in the fruit fly Drosophila melanogaster where females choosing between 2 males of contrasting phenotypes can build a preference for males of the phenotype they previously saw being chosen by a demonstrator female. As sex ratio is known to affect mate choice, our goal was to test whether mate-copying is also affected by encountered sex ratios. Thus, we created a gradient of sex ratio during demonstrations of mate-copying experiments by changing the number of females observing from a central arena 6 simultaneous demonstrations unfolding in 6 peripheral compartments of a hexagonal device. We also tested whether the sex ratio experienced by females during demonstrations affected their choosiness (male courtship duration and double courtship rate) in subsequent mate-choice tests. Experimental male:female sex ratio during demonstrations did not affect mate-copying indices, but positively affected the proportion of both males courting the female during mate-choice tests, as well as male courtship duration, the latter potentially explaining the former relationship. As expected, the sex ratio affected female choosiness positively, and Drosophila females seem to have evolved a mate-copying ability independently of sex ratio, and a capacity to adapt their choosiness to male availability. This suggests that, as in many animal species, individuals, especially females, can adapt their mate choice depending on the current sex ratio. PMID- 30402068 TI - Recapture probability, flight morphology, and microorganisms. AB - Microorganisms on and within organisms are ubiquitous and interactions with their hosts range from mutualistic over commensal, to pathogenic. We hypothesized that microorganisms might affect the ability of barn swallows Hirundo rustica to escape from potential predators, with positive associations between the abundance of microorganisms and escape ability implying mutualistic effects, while negative associations would imply antagonistic effects. We quantified escape behavior as the ability to avoid capture in a mist net and hence as a small number of recaptures. Because recapture probability may also depend on timing of reproduction and reproductive success, we also tested whether the association between recapture and microorganisms was mediated by an association between recapture and life history. We found intermediate to strong positive relationships between recapture probability and abundance of Bacillus megaterium, but not abundance of other bacteria or fungi. The abundance of B. megaterium was associated with an advance in laying date and an increase in reproductive success. However, these effects were independent of the number of recaptures. This interpretation is supported by the fact that there was no direct correlation between laying date and reproductive success on one hand and the number of recaptures on the other. These findings have implications not only for predator prey interactions, but also for capture-mark-recapture analyses of vital rates such as survival and dispersal. PMID- 30402067 TI - Ecological variation along the salinity gradient in the Baltic Sea Area and its consequences for reproduction in the common goby. AB - Although it has become clear that sexual selection may shape mating systems and drive speciation, the potential constraints of environmental factors on processes and outcomes of sexual selection are largely unexplored. Here, we investigate the geographic variation of such environmental factors, more precisely the quality and quantity of nest resources (bivalve shells) along a salinity gradient in the Baltic Sea Area (Baltic Sea, Sounds and Belts, and Kattegat). We further test whether we find any salinity-associated morphological differences in body size between populations of common gobies Pomatoschistus microps, a small marine fish with a resource-based mating system. In a geographically expansive field study, we sampled 5 populations of P. microps occurring along the salinity gradient (decreasing from West to East) in the Baltic Sea Area over 3 consecutive years. Nest resource quantity and quality decreased from West to East, and a correlation between mussel size and male body size was detected. Population density, sex ratios, mating- and reproductive success as well as brood characteristics also differed between populations but with a less clear relation to salinity. With this field study we shed light on geographic variation of distinct environmental parameters possibly acting on population differentiation. We provide insights on relevant ecological variation, and draw attention to its importance in the framework of context-dependent plasticity of sexual selection. PMID- 30402069 TI - Yolk vitamin E positively affects prenatal growth but not oxidative status in yellow-legged gull embryos. AB - Parental effects occur whenever the phenotype of parents or the environment that they experience influences the phenotype and fitness of their offspring. In birds, parental effects are often mediated by the size and biochemical quality of the eggs in terms of maternally transferred components. Exogenous antioxidants are key egg components that accomplish crucial physiological functions during early life. Among these, vitamin E plays a vital role during prenatal development when the intense metabolism accompanying rapid embryo growth results in overproduction of pro-oxidant molecules. Studies of captive birds have demonstrated the positive effect of vitamin E supplementation on diverse phenotypic traits of hatchling and adult individuals, but its effects on embryo phenotype has never been investigated neither in captivity nor under a natural selection regime. In the present study, we experimentally tested the effect of the in ovo supplementation of vitamin E on morphological traits and oxidative status of yellow-legged gull (Larus michahellis) embryos. The supplementation of vitamin E promoted somatic growth in embryos soon before hatching, but did not affect their oxidative status. Our results suggest that maternally transferred vitamin E concentrations are optimized to prevent imbalances of oxidative status and the consequent raise of oxidative damage in yellow-legged gull embryos during prenatal development. PMID- 30402071 TI - The small-island effect in amphibian assemblages on subtropical land-bridge islands of an inundated lake. AB - The small-island effect (SIE) has become more and more part of the theoretical framework of island biogeography and biodiversity research. However, previous methods for the detection of SIEs are often flawed in one way or another, including not accounting for model complexity, not comparing all relevant models, and not including islands with no species. Therefore, the existence and the prevalence of the SIE may be dubious. In this study, after controlling for all these methodological shortcomings, we tested for the existence of the SIE in amphibian assemblages on subtropical land-bridge islands created by the inundation of the Thousand Island Lake, China. We used the line transect method to determine the distribution of amphibian assemblages on 23 study islands during 3 breeding seasons from 2009 to 2011. To evaluate whether an SIE exists in amphibian assemblages, we compared the fit of a simple linearized power model with two most widely used breakpoint regression models. The information-theoretic multimodel inference approach based on Akaike's information criterion identified the left-horizontal SIE model as the best single model. Thus, we found strong evidence for the existence of an SIE in our system. The upper limit of the SIE for amphibian assemblages was 39.95 ha. Below this threshold area, amphibian richness varied independently of island size. The SIE in amphibian assemblages may be due to episodic disturbances, stochastic events, and nutrient subsidies from the lake. Our results indicate that all the islands >39.95 ha should be protected for the effective conservation of amphibian assemblages in our system. PMID- 30402072 TI - Does urbanization influence the diet of a large snake? AB - Urbanization facilitates synanthropic species such as rodents, which benefit the diets of many predators in cities. We investigated how urbanization affects the feeding ecology of dugites Pseudonaja affinis, a common elapid snake in south west Western Australia. We predicted that urban snakes: 1) more frequently contain prey and eat larger meals, 2) eat proportionally more non-native prey, 3) eat a lower diversity of prey species, and 4) are relatively heavier, than non urban dugites. We analyzed the diet of 453 specimens obtained from the Western Australian Museum and opportunistic road-kill collections. Correcting for size, sex, season, and temporal biases, we tested whether location influenced diet for our 4 predictions. Body size was a strong predictor of diet (larger snakes had larger prey present, a greater number of prey items, and a greater diversity of prey). We identified potential collection biases: urban dugites were relatively smaller (snout-vent length) than non-urban specimens, and females were relatively lighter than males. Accounting for these effects, urban snakes were less likely to have prey present in their stomachs and were relatively lighter than non-urban snakes. Other urban-adapted carnivores appear to benefit from urbanization through increased food supplementation, but we found the opposite of this: urban dugites were less likely to contain a meal, and their meals were smaller, indicating they did not make greater use of synanthropic species than was evident for non-urban snakes. In contrast to other carnivores, snakes do not appear to fit a consistent directional pattern for size differences between urban and non urban populations. PMID- 30402070 TI - Manipulation of parasite load induces significant changes in the structural-based throat color of male iberian green lizards. AB - The honesty of structural-based ornaments is controversial. Sexual selection theory predicts that the honesty of a sexual signal relies on its cost of production or maintenance. Therefore, environmental factors with negative impact on individuals could generate high costs and affect the expression of these sexual signals. In this sense, parasites are a main cost for their hosts. To probe the effect of parasites on the structural-based coloration of a lacertid species Lacerta schreiberi, we have experimentally removed ticks from a group of male Iberian green lizards using an acaricide treatment (i.e., the broad-use insecticide fipronil). All individuals were radio-tracked and recaptured after 15 days to study changes in coloration in both the ultraviolet (UV)-blue (structural based) and UV-yellow (structural and pigment-based) ornamentations after manipulation, as well as changes in endo- and ectoparasitic load and body condition. Additionally, after the experiment, we measured the skin inflammatory response to a mitogen. The fipronil treatment was effective in reducing ticks and it was associated with a significant reduction of hemoparasite load. Throughout the season, individuals treated with fipronil tended to maintain the brightness of the UV-blue throat coloration while control lizards tended to increase it. However, individuals treated with fipronil that were not infected with hemoparasites significantly reduced the brightness of the UV-blue throat coloration. Individuals with a higher initial tick load exhibited a lower UV saturation increment (UV-blue) and a higher brightness increment (UV-yellow) during the experiment. Overall these results experimentally support the idea that parasites adversely influence the expression of the structural-based coloration of male Iberian green lizards. This adds evidence to the hypothesis that sexual ornaments in lizards function as honest signals. PMID- 30402073 TI - Field observations of putative bone-based fluorescence in a gecko. PMID- 30402074 TI - Male mate choice, female competition, and female ornaments as components of sexual selection. PMID- 30402075 TI - The evolution of male mate choice and female ornamentation: a review of mathematical models. AB - The evolution of male preferences and of female ornaments in species with traditional sex roles (i.e., polygyny) have been highlighted as areas in need of more active research by an accumulation of recent findings. The theoretical literature on these topics is relatively small and has centered on the evolution of male choice. Mathematical models have emphasized that, under polygyny, the evolution of male preferences faces much greater competition costs than does the evolution of female preferences. We discuss ways in which costly male choice can nonetheless evolve, via (1) direct selection that favors preferences, primarily through mating with highly fecund females, (2) mechanisms that rely on indirect selection, which weakly counters competitive costs of male preferences, and (3) genetic constraints, primarily in the form of pleiotropy of male and female preferences and traits. We also review a variety of mathematical models that have elucidated how costs to male preferences can be avoided. Finally, we turn our attention to the relatively scant theoretical literature on the effects of male mate choice on the evolution of female traits. We emphasize the finding that the presence of male preferences cannot be assumed to lead to the evolution of female ornaments during polygyny, and point out situations where models have elucidated ways in which female ornaments can nevertheless evolve. PMID- 30402076 TI - Male mate choice as differential investment in contest competition is affected by female ornament expression. AB - High male mating effort and high variation in female quality select for male mate choice, which may be expressed as differential investment of reproductive effort based on female value. Male reproductive effort includes investment in direct contest competition with rival males for access to females, yet variation in male male contest behavior is rarely examined in the context of male mate choice. We examine such male response to variation in female body size, reproductive state, and female-specific ornamentation in the striped plateau lizard, Sceloporus virgatus. We housed lizards in trios of 2 size-matched males and one female for 5 days, such that all 3 lizards were physically isolated and the males could see the female but not each other. We then placed males simultaneously into the female's cage and scored the interaction. Male-male aggression was not significantly affected by female body size, reproductive state, nor ornament color, but was influenced by ornament size which reliably signals the phenotypic quality of the female and her offspring. In the presence of larger-ornamented females, males engaged in more male-male aggressive display behavior more quickly, and performed fewer high-intensity contact behaviors but were equally likely to escalate to this riskier level of fighting. Our data suggest that males adjust their energetic investment during intrasexual competitive interactions in response to variation in the contested female which, assuming males gain direct or indirect benefits from their strategic allocation of reproductive effort, fits the modern understanding of male mate choice. PMID- 30402077 TI - Variation in female aggression in 2 three-spined stickleback populations with female throat and spine coloration. AB - Despite growing interest in female ornament evolution, we still have a rudimentary understanding of female display traits relative to similar traits in males. Under one popular adaptive scenario, female ornaments are hypothesized to function in female-female competition and serve as badges of status, such that their expression is linked with elevated aggression in some cases. In this study, we investigated the relationship between 2 female ornaments-male-like red throat color and red spine coloration-and female aggression in 2 independently derived stream-resident populations of three-spined stickleback Gasterosteus aculeatus. Using simulated intrusions, we tested whether females with redder ornaments were generally more aggressive, and for variation in aggressive and social behaviors between the 2 populations. We found that the red intensity of the throat and spine did not predict aggression levels in either population, suggesting a limited role for both female ornaments during female-female interaction. The 2 populations exhibited different levels of aggressive behaviors, unrelated to the color patches. Our results suggest that variation in selective pressures between populations may promote interpopulation variance in aggressive behavior but not the correlation between female ornamentation and aggression, and raise the possibility that red coloration may have evolved through different mechanisms or processes in the 2 populations. PMID- 30402078 TI - Female mating competition alters female mating preferences in common gobies. AB - Mating decisions can be affected by intrasexual competition and sensitive to operational sex-ratio (OSR) changes in the population. Conceptually, it is assumed that both male and female mate-competition may interfere with female reproductive decisions. Experimentally, however, the focus has been on the effect of male competition on mate choice. In many species with paternal care as in the common goby Pomatoschistus microps, the OSR is often female-biased and female mate-competition for access to available nesting males occurs. Using the same protocol for 3 experiments testing the effect of a perceived risk of female mate competition, I studied female preferences for nest-holding males differing in its nest size (large/small), body size (large/small), and nest status (with/without eggs already in nest) and measured mating decisions, spawning latencies, and clutch size. Regardless of the social context, females preferred males with larger nests. A preference for large males was only expressed in presence of additional females. For nest status, there was a tendency for females to prefer mating with males with an empty nest. Here, female-female competition increased the propensity to mate. The results of this study show that females are sensitive to a female competitive social environment and suggest that in choice situations, females respond to the social context mainly by mating decisions per se rather than by adjusting the clutch size or spawning latency. Females base their mating decisions not only on a male's nest size but also on male size as an additional cue of mate quality in the presence of additional females. PMID- 30402080 TI - Male mate choice in livebearing fishes: an overview. AB - Although the majority of studies on mate choice focus on female mate choice, there is growing recognition of the role of male mate choice too. Male mate choice is tightly linked to 2 other phenomena: female competition for males and ornamentation in females. In the current article, I review the existing literature on this in a group of fishes, Poeciliidae. In this group, male mate choice appears to be based on differences in female quality, especially female size, which is a proxy for fecundity. Some males also have to choose between heterospecific and conspecific females in the unusual mating system of the Amazon molly. In this case, they typically show a preference for conspecific females. Whereas male mate choice is relatively well documented for this family, female ornamentation and female competition are not. PMID- 30402081 TI - Erratum: Invasive house geckos (hemidactylus spp.): their current, potential and future distribution. AB - [This corrects the article DOI: 10.1093/cz/zox052.][This corrects the article DOI: 10.1093/cz/zox052.]. PMID- 30402079 TI - Sex roles and sexual selection: lessons from a dynamic model system. AB - Our understanding of sexual selection has greatly improved during the last decades. The focus is no longer solely on males, but also on how female competition and male mate choice shape ornamentation and other sexually selected traits in females. At the same time, the focus has shifted from documenting sexual selection to exploring variation and spatiotemporal dynamics of sexual selection, and their evolutionary consequences. Here, I review insights from a model system with exceptionally dynamic sexual selection, the two-spotted goby fish Gobiusculus flavescens. The species displays a complete reversal of sex roles over a 3-month breeding season. The reversal is driven by a dramatic change in the operational sex ratio, which is heavily male-biased at the start of the season and heavily female-biased late in the season. Early in the season, breeding-ready males outnumber mature females, causing males to be highly competitive, and leading to sexual selection on males. Late in the season, mating ready females are in excess, engage more in courtship and aggression than males, and rarely reject mating opportunities. With typically many females simultaneously courting available males late in the season, males become selective and prefer more colorful females. This variable sexual selection regime likely explains why both male and female G. flavescens have ornamental colors. The G. flavescens model system reveals that sexual behavior and sexual selection can be astonishingly dynamic in response to short-term fluctuations in mating competition. Future work should explore whether sexual selection is equally dynamic on a spatial scale, and related spatiotemporal dynamics. PMID- 30402083 TI - The Mobile Charging Vehicle Routing Problem with Time Windows and Recharging Services. AB - For the environmental friendliness of the technology on battery electric vehicles, there is growing attention on it. However, the market share of battery electric vehicles remains low due to the range anxiety. As a remedy, the mobile charging services could offer charging service at any time or locations requested. For profitability of the services, the operator should route the charging vehicles in a more efficient manner. For this consideration, we formulate the mobile charging vehicle routing problem as a mixed integer linear program based on the classical vehicle routing problem with time windows. To demonstrate the model, test instances are designed and computational results are presented. In order to examine the change of the number of mobile charging vehicles and travel distance, sensitivity analyses, such as battery capacity and recharging rate, are performed. The results show that larger battery capacity, quicker charging rate, or higher service efficiency could decrease the number of mobile charging vehicles and total traveled distances, respectively. PMID- 30402084 TI - Forecasting Short-Term Traffic Flow by Fuzzy Wavelet Neural Network with Parameters Optimized by Biogeography-Based Optimization Algorithm. AB - Forecasting short-term traffic flow is a key task of intelligent transportation systems, which can influence the traveler behaviors and reduce traffic congestion, fuel consumption, and accident risks. This paper proposes a fuzzy wavelet neural network (FWNN) trained by improved biogeography-based optimization (BBO) algorithm for forecasting short-term traffic flow using past traffic data. The original BBO is enhanced by the ring topology and Powell's method to advance the exploration capability and increase the convergence speed. Our presented approach combines the strengths of fuzzy logic, wavelet transform, neural network, and the heuristic algorithm to detect the trends and patterns of transportation data and thus has been successfully applied to transport forecasting. Other different forecasting methods, including ANN-based model, FWNN based model, and WNN-based model, are also developed to validate the proposed approach. In order to make the comparisons across different methods, the performance evaluation is based on root-mean-squared error (RMSE), mean absolute percentage error (MAPE), and correlation coefficient (R). The performance indexes show that the FWNN model achieves lower RMSE and MAPE, as well as higher R, indicating that the FWNN model is a better predictor. PMID- 30402082 TI - Current Developments in Pt(IV) Prodrugs Conjugated with Bioactive Ligands. AB - To overcome the side effects of and resistance to cisplatin, a variety of Pt(IV) prodrugs were designed and synthesized via different modifications including combination with lipid chains to increase hydrophobicity, conjugation with short peptide chains or nanoparticles to improve drug delivery, or addition of bioactive ligands to the axial positions of Pt(IV) complexes to exert dual function effects. This review summarizes the recent progress in the development of Pt(IV) prodrugs conjugated with bioactive-targeting ligands, including histone deacetylase inhibitors, p53 agonists, alkylating agents, and nonsteroidal anti inflammatory agents. Although Pt(IV) complexes that conjugated with bioactive ligands show satisfactory anticancer effects, none has been approved for clinical use. Therefore, we hope that this review will contribute to further study and development of Pt(IV) complexes conjugated with bioactive and other ligands. PMID- 30402085 TI - Social Touch Gesture Recognition Using Convolutional Neural Network. AB - Recently, social touch gesture recognition has been considered an important topic for touch modality, which can lead to highly efficient and realistic human-robot interaction. In this paper, a deep convolutional neural network is selected to implement a social touch recognition system for raw input samples (sensor data) only. The touch gesture recognition is performed using a dataset previously measured with numerous subjects that perform varying social gestures. This dataset is dubbed as the corpus of social touch, where touch was performed on a mannequin arm. A leave-one-subject-out cross-validation method is used to evaluate system performance. The proposed method can recognize gestures in nearly real time after acquiring a minimum number of frames (the average range of frame length was from 0.2% to 4.19% from the original frame lengths) with a classification accuracy of 63.7%. The achieved classification accuracy is competitive in terms of the performance of existing algorithms. Furthermore, the proposed system outperforms other classification algorithms in terms of classification ratio and touch recognition time without data preprocessing for the same dataset. PMID- 30402086 TI - Impaired Ability to Suppress Excitability of Antagonist Motoneurons at Onset of Dorsiflexion in Adults with Cerebral Palsy. AB - We recently showed that impaired gait function in adults with cerebral palsy (CP) is associated with reduced rate of force development in ankle dorsiflexors. Here, we explore potential mechanisms. We investigated the suppression of antagonist excitability, calculated as the amount of soleus H-reflex depression at the onset of ankle dorsiflexion compared to rest, in 24 adults with CP (34.3 years, range 18-57; GMFCS 1.95, range 1-3) and 15 healthy, age-matched controls. Furthermore, the central common drive to dorsiflexor motoneurons during a static contraction in the two groups was examined by coherence analyses. The H-reflex was significantly reduced by 37% at the onset of dorsiflexion compared to rest in healthy adults (P < 0.001) but unchanged in adults with CP (P = 0.91). Also, the adults with CP had significantly less coherence. These findings suggest that the ability to suppress antagonist motoneuronal excitability at movement onset is impaired and that the central common drive during static contractions is reduced in adults with CP. PMID- 30402087 TI - Cerebellar Theta-Burst Stimulation Impairs Memory Consolidation in Eyeblink Classical Conditioning. AB - Associative learning of sensorimotor contingences, as it occurs in eyeblink classical conditioning (EBCC), is known to involve the cerebellum, but its mechanism remains controversial. EBCC involves a sequence of learning processes which are thought to occur in the cerebellar cortex and deep cerebellar nuclei. Recently, the extinction phase of EBCC has been shown to be modulated after one week by cerebellar continuous theta-burst stimulation (cTBS). Here, we asked whether cerebellar cTBS could affect retention and reacquisition of conditioned responses (CRs) tested immediately after conditioning. We also investigated a possible lateralized cerebellar control of EBCC by applying cTBS on both the right and left cerebellar hemispheres. Both right and left cerebellar cTBSs induced a statistically significant impairment in retention and new acquisition of conditioned responses (CRs), the disruption effect being marginally more effective when the left cerebellar hemisphere was stimulated. These data support a model in which cTBS impairs retention and reacquisition of CR in the cerebellum, possibly by interfering with the transfer of memory to the deep cerebellar nuclei. PMID- 30402088 TI - Impaired GABA Neural Circuits Are Critical for Fragile X Syndrome. AB - Fragile X syndrome (FXS) is an inheritable neuropsychological disease caused by silence of the fmr1 gene and the deficiency of Fragile X mental retardation protein (FMRP). Patients present neuronal alterations that lead to severe intellectual disability and altered sleep rhythms. However, the neural circuit mechanisms underlying FXS remain unclear. Previous studies have suggested that metabolic glutamate and gamma-aminobutyric acid (GABA) receptors/circuits are two counter-balanced factors involved in FXS pathophysiology. More and more studies demonstrated that attenuated GABAergic circuits in the absence of FMRP are critical for abnormal progression of FXS. Here, we reviewed the changes of GABA neural circuits that were attributed to intellectual-deficient FXS, from several aspects including deregulated GABA metabolism, decreased expressions of GABA receptor subunits, and impaired GABAergic neural circuits. Furthermore, the activities of GABA neural circuits are modulated by circadian rhythm of FMRP metabolism and reviewed the abnormal condition of FXS mice or patients. PMID- 30402089 TI - Dermatophytosis: Prevalence of Dermatophytes and Non-Dermatophyte Fungi from Patients Attending Arsho Advanced Medical Laboratory, Addis Ababa, Ethiopia. AB - Background: Dermatophytosis is a disease of major public health problem around the globe causing a considerable morbidity. Objective: To study the prevalence of dermatophytosis and the spectrum of fungi implicated in causing the infection. Methods: Nail, skin, and scalp scrapings were collected from 318 patients and were used for microscopy and culture study. Fungal pathogens were identified by studying the macroscopic and microscopic characteristics of their colonies. Result: Tinea capitis was the predominant clinical manifestation consisting of 48.1% of the cases. Among 153 patients with tinea capitis, 73.2% were in the age group of 1-14 years. Of 318 study participants, 213 (67.98%) were found to be positive for dermatophytosis microbiologically. Out of 164 fungal isolates, 86 were dermatophytes and 78 were non-dermatophyte fungi. Among 86 dermatophytes, T. violaceum represented 38.4% of dermatophyte isolates and 89.7% of the isolates were recovered from tinea capitis. Of 76 non-dermatophyte molds, Aspergillus spp., Scytalidium dimidiatum, and Cladosporium spp. were the most common isolates, respectively. Conclusions: Failure to detect or isolate fungal pathogens in a large number of clinical samples revealed the limitation of clinical diagnosis in differentiating dermatophytosis from other skin infections demonstrating that clinical diagnosis should be coupled with laboratory methods. Recovery of large number of non-dermatophyte fungi along with dermatophytes in our study showed that non-dermatophyte fungi are emerging as important causes of dermatophytosis, warranting the implementation of intensive epidemiological studies of dermatophytosis across the country. PMID- 30402090 TI - Sustained Clinical Efficacy and Mucosal Healing of Thiopurine Maintenance Treatment in Ulcerative Colitis: A Real-Life Study. AB - Background and Aims: Thiopurines are commonly used for treating ulcerative colitis (UC), despite the fact that controlled evidence supporting their efficacy is limited. The aim of this study was to evaluate the long-term outcome of thiopurines as maintenance therapy in a large cohort of UC patients. Methods: All UC patients receiving thiopurine monotherapy at three tertiary IBD centers from 1995 to 2015 were identified. The primary endpoint was steroid-free clinical remission. Secondary endpoints were mucosal healing (MH), defined as Mayo endoscopic subscore 0, long-term safety, and predictors of sustained clinical remission. Results: We identified 192 patients, contributing a total of 747 person-years of follow-up (median follow-up 36 months, range 1-210 months). Steroid dependency was the most common indication for thiopurine treatment (58%). Steroid-free remission occurred in 45.3% of patients; 36.3% stopped thiopurines because of treatment failure and 18.2% for adverse events or intolerance. The cumulative probability of maintaining steroid-free remission while on thiopurine treatment was 87%, 76%, 67.6%, and 53.4% at 12, 24, 36, and 60 months, respectively. MH occurred in 57.9% of patients after a median of 18 months (range 5-96). No independent predictors of sustained clinical remission could be identified. Conclusions: Thiopurines represent an effective and safe long-term maintenance therapy for UC patients. PMID- 30402091 TI - Helicobacter pylori Eradication in Idiopathic Thrombocytopenic Purpura: A Meta Analysis of Randomized Trials. AB - Objective: Several recent reviews of published studies have shown that the eradication of H. pylori infection in patients with ITP improved thrombocytopenia in about half of the cases. However, most included studies were observational case series. We performed the first meta-analysis of randomized trials to gain a better insight into the effect of H. pylori eradication in ITP patients. Methods: A systematic computerized search of the electronic databases including PubMed, EMBASE, Google Scholar, and Cochrane Library (up to December 2017) was conducted. Results: From six studies, a total of 241 patients (125 in eradication group and 116 in control group) were included in the meta-analysis. Patients in the eradication group showed significantly higher overall platelet response rate than those in the control group (odds ratio = 1.93, 95% confidence interval: 1.01 3.71, P = 0.05). In the subgroup analysis, however, children in the eradication group failed to show statistically better response rate than those in the noneradication group (odds ratio = 1.80, 95% confidence interval: 0.88-3.65, P = 0.11). Conclusions: This meta-analysis indicates that H. pylori eradication has a significant therapeutic effect in patients with ITP. Considering the intrinsic limits in the design and sample size of the included studies, however, large randomized controlled trials are warranted to validate the therapeutic impact of H. pylori eradication in adults as well as children with ITP. PMID- 30402093 TI - Crude Polysaccharides from Okra Pods (Abelmoschus esculentus) Grown in Indonesia Enhance the Immune Response due to Bacterial Infection. AB - Okra pods were widely consumed by Indonesians to maintain health. The aim of this study was at investigating the potential of crude polysaccharides from okra pods on immune response in mice infected with Staphylococcus aureus. Thirty male Balb/C mice were divided into six groups: normal control, negative control, and treatment groups (administration of crude polysaccharides at doses of 25, 50, 75, and 100 mg/kg). Crude polysaccharides were administrated for fourteen days. Furthermore, mice were exposed to S. aureus at the fifteenth day. Two weeks after the end of treatment, the parameters were measured. This study showed that crude polysaccharides at a dose of 75 and 100 mg/kg improved phagocytic activity, spleen index, and splenocytes proliferation. Rising of TNF-alpha levels was shown in groups treated with crude polysaccharides at doses of 25, 50, and 100 mg/kg. All treatment groups showed a decreasing level of IL-17. Crude okra polysaccharides also showed a slight increase in NK cells activity and IFN-gamma level. Thus, crude okra polysaccharides could act as an effective material to enhance immune response including phagocytic activity, spleen index, splenocytes proliferation, and control immune responses through cytokine production. PMID- 30402092 TI - Diverse Expression of IL-32 in Diffuse and Intestinal Types of Gastric Cancer. AB - Introduction: Gastric cancer (GC) represents one of the most common cancers worldwide, frequently diagnosed at advanced stages with poor prognosis, indicating on need for new diagnostic and prognostic markers. The aim of the study was to determine the expression of IL-32, proinflammatory and angiogenic mediators, in patients with diffuse and intestinal gastric cancer and the relationship with clinicopathological aspects. Material and Methods: The tissue samples of diffuse and intestinal types of tumor of 70 patients with gastric cancer were analyzed. Expression of IL-32, VEGF, IL-17, and CD31 was measured by immunohistochemistry. Results: IL-32 expression was significantly lower in tissue samples from patients with diffuse type of gastric cancer that is also a severe and more progressive form (TNM stages III and IV, poor histological differentiation, and higher nuclear grade III). Expression of IL-17 was also decreased in patients with diffuse type of gastric cancer. Microvascular density was diminished in diffuse type of gastric cancer. Conclusions: Downregulated expression of IL-32 in tumor tissue of patients with diffuse type of gastric cancer may implicate on its role in limiting ongoing proinflammatory and proangiogenic processes. This emphasizes on unrecognized role of IL-32 in biology of diffuse type of gastric cancer. PMID- 30402094 TI - Effect of Essential Oils from Ginger (Zingiber officinale) and Turmeric (Curcuma longa) Rhizomes on Some Inflammatory Biomarkers in Cadmium Induced Neurotoxicity in Rats. AB - Studies have revealed that anti-inflammatory agents could provide beneficial effect in lowering the incidence/progression of neurological diseases. Hence, this study sought to investigate the effect of essential oils from Nigeria ginger and turmeric rhizomes on some cytokines in cadmium induced neurotoxicity. The result revealed that essential oil from ginger and turmeric rhizomes exerts anti inflammatory effect by preventing alterations of some cytokines/inflammatory biomarkers (IL-6, IL-10 and TNF-Alpha) levels and inhibits both hippocampus and prefrontal cortex acetylcholinesterase (AChE) and adenosine deaminase (ADA) activities (important enzymes relevant in the management/prevention of neurodegenerative diseases) in Cd treated rats. In conclusion, essential oil from ginger and turmeric rhizomes exerts anti-inflammatory properties in Cd induced neurotoxicity. The observed effect could be due to the volatile compounds as revealed by GC-MS analysis. PMID- 30402095 TI - Combination of Maximum Shear Wave Elasticity Modulus and TIRADS Improves the Diagnostic Specificity in Characterizing Thyroid Nodules: A Retrospective Study. AB - Objectives: The present study is aimed at evaluating the diagnostic value of combining shear wave elastography (SWE) parameters and the thyroid imaging reporting and data system (TIRADS) for differentiating between benign and malignant thyroid nodules. Methods: Patients who underwent conventional ultrasonography (US) and SWE before surgery were enrolled in the current study. Each nodule was given a TIRADS risk score. The effectiveness of the SWE parameters was assessed by odds ratios (ORs). The SWE scoring risk stratification was proposed beyond 95% probability, and the desired values were obtained according to the log-normal distribution. The area under the receiver-operating characteristic (AUC) was used to compare the diagnostic performance between TIRADS-alone and TIRADS + SWE. Results: A total of 262 patients with 298 thyroid nodules were enrolled in our study. The pathological analyses were conducted on 121 benign and 177 malignant nodules. The AUC values for TIRADS-alone and TIRADS + SWE were 0.896 (accuracy 83.2%) and 0.917 (accuracy 84.2%), respectively. However, the TIRADS + SWE scores showed a higher specificity (88.4%) and positive predictive value (91.2%) as compared with the TIRADS-alone of 73.6% and 83.2%, respectively. Conclusions: Combining SWE and TIRADS improves the specificity of TIRADS-alone in differentiating between benign and malignant thyroid nodules. PMID- 30402096 TI - Breg Cells in Celiac Disease Isolated or Associated to Hashimoto's Thyroiditis. AB - Hashimoto's thyroiditis (HT) may occur associated with celiac disease (CD). Regulatory B cells (Breg) subsets have been shown to play a significant role in autoimmune processes. Therefore, we have characterized their distribution in the peripheral blood obtained from 10 patients with isolated HT, 10 patients with HT + CD, 9 patients with isolated CD, and 9 healthy donors (HD). Th17 cells were significantly increased in patients with HT and in patients bearing both HT and CD, while patients with isolated CD exhibited a lower percentage of Th17, as compared with healthy donors. CD24hiCD38hi Breg cells were significantly higher in patients with HT + CD and in patients with isolated CD as compared to both HD patients and patients with isolated HT (p = 0.0010). On the contrary, Breg memory phenotypes (CD24hiCD38- and CD24hiCD27+) significantly decreased in patients with HT + CD as compared with the isolated disorders. Following CpG oligodeoxynucleotide stimulation, IL-10+ CD24hiCD38hi Breg cells were similar in all groups of patients, despite these cells would have been higher in CD patients. In conclusion, celiac disease, isolated and even more when associated with HT, determines a peculiar behavior of Breg cells which are increased in number but possibly functionally defective. Furthermore, the association CD + HT was characterized by a reduction of Breg memory subsets as compared with the isolated disorders. The behavior of Th17 subset in patients with celiac disease associated with HT might have been sensitive to the effect of long-lasting GFD, and it is essentially determined by the presence of thyroid autoimmunity. PMID- 30402097 TI - Irisin a Novel Metabolic Biomarker: Present Knowledge and Future Directions. AB - The rising prevalence of chronic diseases such as type 2 diabetes and cardiovascular diseases owing to fat mass excess has been described. In recent years, muscle function/dysfunction has become relevant in metabolic homeostasis. Irisin was described as an exercise-induced myokine. It is the product of type I membrane protein cleavage encoded by the fibronectin type III domain containing 5 (FNDC5) gene. The main beneficial function attributable to irisin is the change of subcutaneous and visceral adipose tissue into brown adipose tissue, with a consequential increase in thermogenesis. Irisin has also been described as a hormone that may have a key role in glucose homeostasis. The way the association of type 2 diabetes with obesity occurs is not fully understood. In recent years, the possible pathways through which irisin could interact with other organs such as the brain or bone have been described. The present paper intends to review the new findings and possible new directions in irisin research. PMID- 30402098 TI - Support Needs of Patients with Cushing's Disease and Cushing's Syndrome: Results of a Survey Conducted in Germany and the USA. AB - Background: Cushing's disease (CD) and Cushing's syndrome (CS) are chronic illnesses, characterized by symptoms of prolonged hypercortisolism, which often changes to hypocortisolism after successful treatment. In view of the high disease burden of CD/CS patients and long-term impaired quality of life, the present survey was conducted to gain information about subjective illness distress and patients' specific needs in terms of supportive measures beyond medical interventions. Patients and Methods: Cross-sectional questionnaire study including patients with CD treated in 2 German neurosurgical tertiary referral centers and CD/CS patient members of a US-based patient support group completed a survey inquiring about disease burden, coping strategies, and support needs. Additionally, the degree of interest in different offers, e.g., internet-based programs and seminars, was assessed. Results: 84 US and 71 German patients answered the questionnaire. Patients in both countries indicated to suffer from Cushing-related symptoms, reduced performance, and psychological problems. 48.8% US patients and 44.4% German patients stated that good medical care and competent doctors helped them the most in coping with the illness. US patients were more interested in support groups (p = 0.035) and in courses on illness coping (p = 0.008) than the German patients, who stated to prefer brochures (p = 0.001). 89.3% of US patients would attend internet-based programs compared to 75.4% of German patients (p = 0.040). There were no differences between groups for the preferred duration of and the willingness to pay for such a program, but US patients would travel longer distances to attend a support meeting (p = 0.027). Conclusion: Patients in both countries need skilled physicians and long-term medical care in dealing with the effects of CD/CS, whereas other support needs differ between patients of both countries. The latter implies that not only disease-specific but also culture-specific training programs would need to be considered to satisfy the needs of patients in different countries. PMID- 30402100 TI - Treatment-Related Adverse Effects in Lung Cancer Patients after Stereotactic Ablative Radiation Therapy. AB - Introduction: Lung cancer is a disease which, despite the advancements in treatment, still has a very poor 5-year survival rate. Stereotactic ablative radiation therapy (SABR) is a highly advanced, sophisticated, and safe treatment which allows patients with early stage lung cancer to be treated effectively without invasive procedures and with excellent clinical outcomes. Avoiding surgery minimises morbidity and recovery time, bettering patients' quality of life. Furthermore, SABR allows patients unsuitable for surgery to still undergo curative treatment. Methods: We aimed to review SABR-related normal tissue toxicities reported in the literature. While many studies assess safety, clinical efficacy, and disease control of SABR for lung cancer, the number of comprehensive reviews that analyse SABR-related side-effects is scarce. This integrative review summarises the toxicities reported in literature based on published clinical trials and tumour location (central or peripheral tumours) for available SABR techniques. Given that the majority of the clinical studies did not report on the statistical significance (e.g., p-values and confidence intervals) of the toxicities experienced by patients, statistical analyses cannot be performed. As a result, adverse events are compiled from clinical reports; however, due to various techniques and nonstandard toxicity reports, no meta analysis is possible at the current stage of reported data. Results: When comparing lobectomy and SABR in phase III trials, surgery resulted in increased procedure-related morbidity. In phase II trials, very few studies showed high grade toxicities/fatalities as a result of SABR for lung cancer. Gross target volume size was a significant predictor of toxicity. An ipsilateral mean lung dose larger than 9 Gy was significantly associated with radiation pneumonitis. Conclusions: Based on the studies reviewed SABR is a safe treatment technique for lung cancer; however, further well-designed phase III randomised clinical trials are required to produce timely conclusive results and to enable their comparison and statistical analysis. PMID- 30402101 TI - Sox Genes Show Spatiotemporal Expression during Murine Tongue and Eyelid Development. AB - The tongue is a critical organ, involved in functions such as speaking, swallowing, mastication, and degustation. Although Sox genes are known to play critical roles in many biological processes, including organogenesis, the expression of the Sox family members during tongue development remains unclear. We therefore performed a comparative in situ hybridization analysis of 17 Sox genes (Sox1-14, 17, 18, and 21) during murine tongue development. Sox2, 4, 6, 8, 9, 10, 11, 12, and 21 were found to be expressed in the tongue epithelium, whereas Sox2, 4-6, 8-11, 13, and 21 showed expression in the mesenchyme of the developing tongue. Expression of Sox1, 4, 6, 8-12, and 21 were observed in the developing tongue muscle. Sox5 and 13 showed expression only at E12, while Sox1 expression was observed only on E18. Sox6, 8, 9, and 12 showed expression at several stages. Although the expression of Sox2, 4, 10, 11, and 21 was detected during all the four stages of tongue development, their expression patterns differed among the stages. We thus identified a dynamic spatiotemporal expression pattern of the Sox genes during murine tongue development. To understand whether Sox genes are involved in the development of other craniofacial organs through similar roles to those in tongue development, we also examined the expression of Sox genes in eyelid primordia, which also contain epithelium, mesenchyme, and muscle. However, expression patterns and timing of Sox genes differed between tongue and eyelid development. Sox genes are thus related to organogenesis through different functions in each craniofacial organ. PMID- 30402099 TI - Translational Significance of Selective Estrogen Receptor Modulators in Psychiatric Disorders. AB - Accumulating data from various clinical trial studies suggests that adjuvant therapy with ovarian hormones (estrogens) could be effective in reducing cognitive deficit and psychopathological symptoms in women with psychiatric disorders. However, estrogen therapy poses serious limitations and health issues including feminization in men and increased risks of thromboembolism, hot flashes, breast hyperplasia, and endometrium hyperplasia when used for longer duration in older women (aged >= 60 years) or in women who have genetic predispositions. On the other hand, selective estrogen receptor modulators (SERMs), which may (or may not) carry some risks of hot flashes, thromboembolism, breast hyperplasia, and endometrial hyperplasia, are generally devoid of feminization effect. In clinical trial studies, adjuvant therapy with tamoxifen, a triphenylethylene class of SERM, has been found to reduce the frequency of manic episodes in patients with bipolar disorder, whereas addition of raloxifene, a benzothiophene class of SERM, to regular doses of antipsychotic drugs has been found to reduce cognitive deficit and psychological symptoms in men and women with schizophrenia, including women with treatment refractory psychosis. These outcomes together with potent neurocognitive, neuroprotective, and cardiometabolic properties suggest that SERMs could be the potential targets for designing effective and safer therapies for psychiatric disorders. PMID- 30402102 TI - Inexpensive Bismuth-Film Electrode Supported on Pencil-Lead Graphite for Determination of Pb(II) and Cd(II) Ions by Anodic Stripping Voltammetry. AB - The present work reports the development and application of bismuth-film electrode (BiFE), obtained by in situ method on the pencil-lead graphite surface, for simultaneous Cd(II) and Pb(II) determination at trace levels, as alternative to replace the mercury-film electrodes. Experimental factors, deposition time (t d ), deposition potential (E d ), and Bi(III) concentration (C Bi ), were investigated by applying a 23 factorial design using 0.10 mol/L acetate buffer solution (pH 4.5) as supporting electrolyte. The analysis conditions of the differential pulse technique were t d = 250 s, E d = -1.40 V, and C Bi = 250 mg L 1. The validation of the method employing BiFE was accomplished by determination of merit figures. The detection limits were of 11.0 MUg L-1 for Cd(II) and 11.5 MUg L-1 for Pb(II), confirming that proposed method is attractive and suitable for heavy metals determination. Additionally, the BiFE developed was successfully applied for the Cd(II) and Pb(II) determination in wastewater sample of battery industry. PMID- 30402104 TI - Bacterioplankton Activity in a Meso-eutrophic Subtropical Coastal Lagoon. AB - The aim of this study was to investigate whether the bacterioplankton activity in the meso-eutrophic Conceicao Lagoon would increase significantly under allochthonous inputs of inorganic nutrients and organic carbon. Abundance and biomass of bacterioplankton were evaluated under three treatments: light (14 h light/10 h dark), complete darkness (dark-control), and nutrient (C + N + P-dark, 100 : 10 : 1) enrichments during 72 h. Nutrient enrichments promoted a significant increase in abundance (maximum of 19.0 *109 cells.L-1 in the first 32 hours) and biomass of the heterotrophic bacterioplankton, which induced the formation of large clusters. Bacterial biomass remained constant in the non enriched incubations (dark-control and light). Bacterial growth rates were significantly higher after nutrient additions (1.35 d-1), followed by control (0.79 d-1), and light (0.63 d-1) treatments, which were statistically equal (p > 0.05). Bacterial production rates were also significantly higher under nutrient additions (1.28 d-1), compared to the control and light (0.50 d-1 and 0.44 d-1, respectively), demonstrating that bacterial growth and production in this meso eutrophic lagoon are under an immediate "bottom-up" regulation, followed by a potential top-down effect. These facts reinforce the urgency on improving the local wastewater management plan in order to prevent further expansion of anoxic waters. PMID- 30402105 TI - Evaluation of Bacillus Strains for Plant Growth Promotion and Predictability of Efficacy by In Vitro Physiological Traits. AB - Bacilli are commonly used as plant growth-promoting agents but can be limited in effectiveness to certain crop and soil environments. The objectives of this study were to (1) identify Bacillus strains that can be consistent in promoting the growth of corn, wheat, and soybean and (2) determine whether physiological traits expressed in vitro can be predictive of growth promotion efficacy/consistency and be used for selecting effective strains. Twelve Bacillus strains isolated from wheat rhizospheres were evaluated in greenhouse pot tests with nonsterile soil for their effects on the growth of corn, soybean, and wheat. The strains also were assessed in vitro for multiple physiological traits. All 12 strains increased corn growth significantly compared to the controls. The four most efficacious strains on corn-Bacillus megaterium R181, B. safensis R173, B. simplex R180, and Paenibacillus graminis R200-also increased the growth of soybean and wheat. No set of traits was a predictor of growth promotion efficacy. The number of traits expressed by a strain also was not an indicator of efficacy as strain R200 that was positive for only one trait showed high growth promotion efficacy. Effective strains can be identified through pot tests on multiple crop plants, but in vitro physiological assays are unreliable for strain selection. PMID- 30402106 TI - Assessment of Diagnostic Values among CA-125, RMI, HE4, and ROMA for Cancer Prediction in Women with Nonfunctional Ovarian Cysts. AB - Objectives: To evaluate the diagnostic performance among CA-125, RMI, HE4, and ROMA for cancer detection in women with nonfunctional ovarian cysts at King Chulalongkorn Memorial Hospital (KCMH). Secondary objective is to reconsider the proper cutoff value of HE4. Methods: This is a prospective analytic study in women with nonfunctional ovarian cysts larger than 3 cm who scheduled for surgery at KCMH during 3rd June 2015 to 31st May 2016. Ultrasonogram and blood sample collection were completed before the operation. Patients' demographic information and pathologic results were obtained. SPSS software version 17 was used for statistical evaluation. Results: A total of 281 participants were evaluated. 19.9% of them were malignant. Compared with CA-125, HE4 had lower sensitivity (53.4% vs. 87.9%) and NPV (89% vs. 93.6%) but higher specificity (97.8% vs. 46.2%) and PPV (86.1% vs. 29.8%). ROMA had slightly lower sensitivity (79.3% vs. 87.9%) and similar NPV (93.7% vs. 93.6%), but higher specificity (79.8% vs. 46.2%) and PPV (50.5% vs. 29.8%) compared with CA-125. The model that achieves the highest area under the ROC curve in differentiating benign versus malignant ovarian tumor was ROMA. Cutoff value of HE4 at 70 pMol/L (from 150 pMol/L) would give sensitivity 74.1% and specificity 86.5% that are comparable with ROMA. Conclusions: HE4 and ROMA had better performance (higher specificity, PPV) compared to CA-125 and RMI. HE4 at 70 pMol/L could be the new cutoff value for Thai women with ovarian cysts, giving higher sensitivity and specificity. PMID- 30402103 TI - Exploring Seipin: From Biochemistry to Bioinformatics Predictions. AB - Seipin is a nonenzymatic protein encoded by the BSCL2 gene. It is involved in lipodystrophy and seipinopathy diseases. Named in 2001, all seipin functions are still far from being understood. Therefore, we reviewed much of the research, trying to find a pattern that could explain commonly observed features of seipin expression disorders. Likewise, this review shows how this protein seems to have tissue-specific functions. In an integrative view, we conclude by proposing a theoretical model to explain how seipin might be involved in the triacylglycerol synthesis pathway. PMID- 30402107 TI - Effect of Compression Loading on Human Nucleus Pulposus-Derived Mesenchymal Stem Cells. AB - Purpose: Mechanical loading plays a vital role in the progression of intervertebral disc (IVD) degeneration, but little is known about the effect of compression loading on human nucleus pulposus-derived mesenchymal stem cells (NP MSCs). Thus, this study is aimed at investigating the effect of compression on the biological behavior of NP-MSCs in vitro. Methods: Human NP-MSCs were isolated from patients undergoing lumbar discectomy for IVD degeneration and were identified by immunophenotypes and multilineage differentiation. Then, cells were cultured in the compression apparatus at 1.0 MPa for different times (0 h, 24 h, 36 h, and 48 h). The viability-, differentiation-, and differentiation-related genes (Runx2, APP, and Col2) and colony formation-, migration-, and stem cell related proteins (Sox2 and Oct4) were evaluated. Results: The results showed that the isolated cells fulfilled the criteria of MSC stated by the International Society for Cellular Therapy (ISCT). And our results also indicated that compression loading significantly inhibited cell viability, differentiation, colony formation, and migration. Furthermore, gene expression suggested that compression loading could downregulate the expression of stem cell-related proteins and lead to NP-MSC stemness losses. Conclusions: Our results suggested that the biological behavior of NP-MSCs could be inhibited by compression loading and therefore enhanced our understanding on the compression-induced endogenous repair failure of NP-MSCs during IVDD. PMID- 30402109 TI - Transfection of Peripheral Blood Monocytes with SOX2 Enhances Multipotency, Proliferation, and Redifferentiation into Neohepatocytes and Insulin-Producing Cells. AB - Following a several-day incubation in medium containing IL-3 and M-CSF to generate a more plastic intermediate "reprogrammed multipotent cells of monocytic origin (RMCMO)," peripheral blood mononuclear cells (PBMCs) can be efficiently converted to hepatocyte-like cells (neohepatocytes) and insulin-producing cells. However, continuous efforts are devoted to enhancing the proliferative capacity of these multipotent cells while maintaining or further increasing their redifferentiation potential. In the present work, PBMCs were transfected with one pluripotency gene (SOX2) and the resulting RMCMO compared to standard RMCMO with respect to cell viability, proliferative activity, and redifferentiation potential. Ectopic SOX2 expression increased the number of viable RMCMO, activated cell cycle genes, and enhanced proliferation as shown by quantitative RT-PCR and Ki67 immunofluorescent staining, respectively. Redifferentiation of RMCMO derived from SOX2-transfected PBMCs to neohepatocytes was more complete in comparison to control cells as revealed by higher urea and glucose secretion, increased activity of cytochrome P450 isoforms, and a phase II enzyme, while the same was true for insulin-producing cells as assessed by the expression of INS, PDX1, and GLUT2 and glucose-stimulated insulin secretion. Our results indicate that SOX2 transfection increases both multipotency and proliferation of RMCMO, eventually allowing production of neohepatocytes and insulin-producing cells of higher quality and quantity for transplantation purposes. PMID- 30402108 TI - The Mechanobiology of the Actin Cytoskeleton in Stem Cells during Differentiation and Interaction with Biomaterials. AB - An understanding of the cytoskeleton's importance in stem cells is essential for their manipulation and further clinical application. The cytoskeleton is crucial in stem cell biology and depends on physical and chemicals signals to define its structure. Additionally, cell culture conditions will be important in the proper maintenance of stemness, lineage commitment, and differentiation. This review focuses on the following areas: the role of the actin cytoskeleton of stem cells during differentiation, the significance of cellular morphology, signaling pathways involved in cytoskeletal rearrangement in stem cells, and the mechanobiology and mechanotransduction processes implicated in the interactions of stem cells with different surfaces of biomaterials, such as nanotopography, which is a physical cue influencing the differentiation of stem cells. Also, cancer stem cells are included since it is necessary to understand the role of their mechanical properties to develop new strategies to treat cancer. In this context, to study the stem cells requires integrated disciplines, including molecular and cellular biology, chemistry, physics, and immunology, as well as mechanobiology. Finally, since one of the purposes of studying stem cells is for their application in regenerative medicine, the deepest understanding is necessary in order to establish safety protocols and effective cell-based therapies. PMID- 30402110 TI - Conditioned Medium from Human Amnion-Derived Mesenchymal Stem Cells Regulates Activation of Primary Hepatic Stellate Cells. AB - Mesenchymal stem cells (MSCs), or multipotent mesenchymal stromal cells, are present in almost all organs and tissues, including the amnion. Human amnion derived mesenchymal stem cell (hAMSC) transplantation has been reported to ameliorate liver fibrosis in animal models. However, the mechanism for the prevention of liver fibrosis is poorly understood. In this study, we investigated the effects, and underlying mechanisms, of a conditioned medium obtained from hAMSC cultures (hAMSC-CM) on a primary culture of rat hepatic stellate cells (HSCs). We observed that in routine culture, hAMSC-CM in HSCs significantly inhibited the expression of alpha-smooth muscle actin (alpha-SMA), an activation marker of HSCs, and the production of collagen type 1 (COL1), a dominant component of the extracellular matrix (ECM) in the culture medium. In addition, hAMSC-CM upregulated the expression of ECM degradation-related genes, such as metalloproteinase- (Mmp-) 2, Mmp-9, Mmp-13, and tissue inhibitor of metalloproteinase- (Timp-) 1; however, it did not affect the expression of collagen type 1alpha1 (Col1a1). These regulatory effects on HSCs were concentration-dependent. A cell proliferation assay indicated that hAMSC-CM significantly suppressed HSC proliferation and downregulated the expression of cyclin B (Ccnb), a proliferation-related gene. Transforming growth factor-beta (TGF-beta) treatment further activated HSCs and hAMSC-CM significantly inhibited the upregulation of alpha-Sma and Col1a1 induced by TGF-beta. These findings demonstrated that hAMSC-CM can modulate HSC function via secretory factors and provide a plausible explanation for the protective role of hAMSCs in liver fibrosis. PMID- 30402111 TI - In Vitro Expansion and Characterization of Mesenchymal Stromal Cells from Peritoneal Dialysis Effluent in a Human Protein Medium. AB - The therapeutic potential of mesenchymal stromal cells (MSCs) from various tissue origins have extensively been explored in both experimental and clinical studies, and peritoneal dialysis effluent-derived MSC (pMSC) may be an easily obtainable MSC source for clinical applications. In this study, we expanded and characterized the pMSCs after expansion in a human protein culture medium. The pMSCs were expanded in plastic dishes with the human protein medium. MSC marker expression was examined by flow cytometry. Spherical formation was tested by hanging drop method, and osteogenic, adipogenic, and chondrogenic differentiation capacities were confirmed by positive staining with Alizarin red, Oil red O, and Alcian blue, respectively. Here, we showed that after four passages of culturing in plastic dishes, pMSCs in the human protein medium displayed a homogeneous pattern of classical MSC markers (positive: CD29, CD44, CD73, CD90, and CD166; negative: CD14, CD34, CD45, CD79a, CD105, CD146, CD271, HLA-DR, SSEA-4, and Stro 1), while in the standard medium, pMSCs from some donors were CD45 or HLA-DR positive. For nonclassical MSC markers, pMSCs were CD200 positive from all the donors, negative for CD163, CD271, CD36, and CD248, and either positive or negative for CD274 and CD140b. Further, pMSCs from the human protein medium had the spherical formation capacity and multipotent differentiation capacity in vitro. In conclusion, upon expansion in a human protein medium, pMSCs showed a differential MSC marker expression profile from those of bone marrow or adipose tissue-derived MSCs and could maintain the multipotency. The therapeutic potential of the pMSCs requires further investigation. PMID- 30402113 TI - Trends for Diarrhea Morbidity in the Jasikan District of Ghana: Estimates from District Level Diarrhea Surveillance Data, 2012-2016. AB - About 22% of childhood deaths in developing countries are attributable to diarrhea. In poor resource settings, diarrhea morbidities are correlated with poverty and socio-contextual factors. Diarrhea rates in Ghana are reported to be high, with cases estimated at 113,786 among children under-five years in 2011. This study analyzed the trends of diarrhea morbidity outcomes in the Jasikan District of Ghana. A retrospective analysis of records on diarrhea data for a five years' period (January 2012 to December 2016) was undertaken. There was a total of 17740 diarrhea case reports extracted from District Health Information Management System (DHIMS) II database in an Excel format which was then exported to Stata version 14 for data cleaning, verification, and analysis. Excel version 2016 was used to plot the actual observed cases by years to assess trends and seasonality. There was a period incidence rate of 272.02 per 1000 persons with a decreasing annual growth rate of 1.85%. Declines for diarrhea generally occurred from November to December and increased from January upwards, evidence that most cases of diarrhea in this study were reported in the harmattan season. High incidence of diarrhea was found to be common among under-five children and among females. Decreasing trend of diarrhea incidence which was identified in this research within the five years' period understudied shows that, by the year 2020, there will be a sharp decline in the incidence rate of diarrhea reported cases in Jasikan District, given improvements in the external environmental conditions in the district, all things being equal. PMID- 30402114 TI - A Novel Computer-Assisted Method of Bite Mark Analysis for Gender Determination. AB - Background: Bite mark analysis is an imperative area of forensic odontology and considered the commonest form of dental evidence presented in the criminal court. The process of comparing bite marks with a suspect's dentition includes analysis and measurement of shape, size, and position of an individual's teeth. The present study was aimed to evaluate the bite marks of males and females using a novel indirect computer-assisted method and explicate its application in forensic odontology. Materials and methods: 60 subjects (30 males and 30 females) with normal occlusion were included in the present study. Bite registrations were obtained with help of modelling waxes, and positive replicas were prepared with dental stone and barium powder. Intraoral periapical radiographs were taken for the same. The radiographs obtained were scanned and analyzed by measuring tools using Sidexis Next Generation software. Intercanine distance (ICD), line AB, angle ABX, and angle ABY were measured. The Kruskal-Wallis test was performed to compare the bite marks of males and females. Results: The mean ICD of males and females was found to be 32.95 mm and 29.84 mm, respectively, and was statistically highly significant with a p value <0.001. The mean ICD, line AB, and angle ABX were found to be higher in males when compared to females. Conclusion: Analysis of bite marks using this novel computer-assisted method is a simple, reliable, easily reproducible, and economical technique with confidentiality of the identity of the participants involved. PMID- 30402112 TI - Mesenchymal Stem Cell Therapy for Ischemic Tissues. AB - Ischemic diseases such as myocardial infarction, ischemic stroke, and critical limb ischemia are immense public health challenges. Current pharmacotherapy and surgical approaches are insufficient to completely heal ischemic diseases and are associated with a considerable risk of adverse effects. Alternatively, human mesenchymal stem cells (hMSCs) have been shown to exhibit immunomodulation, angiogenesis, and paracrine secretion of bioactive factors that can attenuate inflammation and promote tissue regeneration, making them a promising cell source for ischemic disease therapy. This review summarizes the pathogenesis of ischemic diseases, discusses the potential therapeutic effects and mechanisms of hMSCs for these diseases, and provides an overview of challenges of using hMSCs clinically for treating ischemic diseases. PMID- 30402115 TI - Investigation of the Antidiarrheal and Antimicrobial Activities of 80% Methanolic Leaf Extract of Discopodium Penninervum (Hochst.). AB - Diarrhea is a major health problem throughout the world and it has become more problematic in developing countries like Ethiopia. People, in several parts of the world, use different traditional medicines for treating diarrhea and it has been reported that the roots, leaves, and flowers of various species are used for the same purpose. In Ethiopia, for instance, Discopodium Penninervum is used for the treatment of diarrhea and also to control infection. The aim of the present study was, therefore, to evaluate the in vivo antidiarrheal and in vitro antimicrobial effect of Discopodium Penninervum in mice. For the antimicrobial activity test, four standard bacteria and disc diffusion method were used, while for antidiarrheal experiment, animals had been used, which were divided into 5 groups. The first group served as negative control and was administered with vehicle (0.2-0.3ml of distilled water). Groups two (D100), three (D200), and four (D400) were administered 100, 200, and 400 mg/kg of the extract, respectively. Group five served as positive control group and was administered with either loperamide (3mg/kg) for castor oil induced diarrhea and castor oil induced enteropooling diarrhea models or atropine (1mg/kg) for charcoal meal test. Safety study was performed using a standard acute toxicity study procedure. The effect of the extract on castor oil induced diarrheal drops, onset of diarrhea, weight of faeces, small intestinal fluid accumulation, and intestinal motility was measured and analyzed using one-way ANOVA. Preliminary phytochemical screening of the leaves powder of the plant indicated the presence of various components. Inhibition of castor oil induced diarrhea was observed at all tested doses. It can be concluded that crude extracts of Discopodium Penninervum showed strong activities against diarrhea indicating that it contains some chemical constituents that possibly lead to antidiarrheal drug development. PMID- 30402116 TI - Inhibitory Effects of Prunella vulgaris L. Extract on 11beta-HSD1 in Human Skin Cells. AB - Glucocorticoids are a risk factor for age-induced skin structure and function defects, and the glucocorticoid-activating enzyme, 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1), represents a promising therapeutic target. Prunella vulgaris L. (PV) is a perennial and an edible herbaceous plant normally cultivated in Asia and Europe. A recent study demonstrated a broad range of biological activities of PV including immune modulatory, antiviral, antiallergic, anti-inflammatory, antioxidant, and antidiabetic. However, little is known about the inhibitory effect of PV on 11beta-HSD1. In this study, we investigated the inhibitory effect of Prunella vulgaris L. extract (PVE) and the underlying mechanism of 11beta-HSD11 inhibition. Consistent with these results, cortisol levels were also reduced by PVE in vitro. The cortisone-induced translocation of glucocorticoids receptor (GR) was also attenuated. In addition, PVE inhibited a cortisone-mediated decrease in collagen content in skin. Collectively, these results suggest the beneficial effects of PVE in maintaining skin integrity. PMID- 30402117 TI - An Ethanolic Extract of Allium hookeri Root Alleviates Reflux Esophagitis and Modulates NF-kappaB Signaling. AB - Reflux esophagitis (RE) is a kind of gastroesophageal reflux disease, of which an esophageal inflammatory lesion is caused by the contents of the stomach and duodenum flowing back into the esophagus. Allium hookeri is a plant possessing both nutritional and medicinal properties. In our study, we investigated the inhibition effect of inflammation of A. hookeri root extract (AHE) on inflammatory RAW264.7 macrophage cells induced by lipopolysaccharide and rat models of RE. The results showed that AHE significantly reduced the production of nitric oxide (NO) and the protein expression levels of various mediators related to inflammation including inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), and inflammatory cytokines such as interleukin-1 beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). Furthermore, AHE also inhibited the nuclear translocation of nuclear factor kappa B (NF-kappaB) by inhibiting the phosphorylation IkappaBalpha. In addition, AHE administration significantly ameliorated esophageal mucosal damage upon histological evaluation of RE in rats. AHE was also found to downregulate the expression levels of proteins such as COX 2, TNF-alpha, and IL-1beta in the rat esophagus. AHE markedly attenuated activation of NF-kappaB and phosphorylation of IkappaBalpha at the same time. These results indicated that AHE suppressed LPS-induced inflammatory responses in RAW264.7 cells and may help reduce the development of esophagitis through the modulation of inflammation by regulating NF-kappaB activation. PMID- 30402118 TI - Bushenhuoxue Formula Facilitates Articular Cartilage Repair and Attenuates Matrix Degradation by Activation of TGF-beta Signaling Pathway. AB - Objective: To investigate the effect and underlying mechanism of Bushenhuoxue (BSHX) formula on articular cartilage repair. Methods: Twenty-four full-thickness cartilage defect rats were divided into two groups: model group and BSHX group (treated with BSHX formula). Macroscopic observation and histopathological study were conducted after 4- and 8-week treatment. Additionally, we also evaluated chondrocyte proliferation, extracellular matrix (ECM) deposition, cartilage degradation, and chondrocyte hypertrophy-related genes expression in chondrogenic ATDC5 cells cultured in BSHX formula-mediated serum. Moreover, we assessed aforementioned genes expression and pSMAD2/3 protein level in Tgfbetar2 siRNA transfected chondrogenic ATDC5 cells in order to address whether BSHX formula exerts cartilage repairing effect through TGF-beta signaling. Results: Neocartilage regeneration promotion effect was observed in cartilage defect rats after BSHX formula treatment, with increases in Col2 and pSMAD2 and decreases in Mmp13 and Runx2. Moreover, cell proliferation, the elevated Col2a1, Aggrecan and pSMAD2/3, reduced Mmp13, Adamts5, Col10a1, and Runx2 expression were also observed in chondrogenic ATDC5 cells cultured in BSHX formula-mediated serum. Besides, the expression alteration of ECM deposition, cartilage degradation, chondrocyte hypertrophy-related genes, and pSMAD2/3 protein levels presented in Tgfbetar2 downregulated chondrogenic ATDC5 cells couldn't be adjusted by BSHX formula treatment. Conclusion: By activation of TGF-beta signaling, BSHX formula can promote articular cartilage repair by accelerating chondrocyte proliferation and maintaining chondrocyte phenotype, upregulate ECM accumulation, and inhibit matrix degradation. PMID- 30402119 TI - Association of Cold-Heat Patterns with Tongue Features, Body Composition, Anthropometric Indices, and Blood Parameters in Tae-Eum Type. AB - Introduction: The purpose of this study was to elucidate the relationship between cold-heat patterns and body composition, anthropometric indices, blood parameters, and tongue features in Tae-Eum type subjects. We also sought to determine whether significant indicators could be used as risk factors for predicting cold-heat patterns in a clinic. Methods: This prospective, case control pilot study was conducted at a single center. The subjects were males and females aged 19 years or older who had been analyzed as the Tae-Eum type. After screening, subject allocation was performed. The body composition, 11 anthropometric indices, blood parameters, and tongue features of the subjects were measured by well-trained practitioners. An independent t-test was conducted to compare the cold- and heat-pattern groups. Binary logistic regression was performed to determine significant differences between the two groups after adjusting for age, sex, and systolic blood pressure, with a focus on identifying significant indicators. Results: Eighty-nine participants were recruited, 39 of whom were excluded from the analysis. Ultimately, 20 cold-pattern and 30 heat pattern subjects were included in the final analysis. We found that alanine aminotransferase and all anthropometric indices, except for neck and forehead circumference, were significant predictive factors in both groups according to the binary regression analysis. Additionally, the tongue body color in the cold pattern group was significantly paler than that in the heat-pattern group. Conclusions: This study found that cold and heat patterns were significantly associated with body composition, anthropometric indices, blood parameters, and tongue features. We suggest that these factors could thus be used as objective indicators and predictors of cold-heat patterns. Our findings provide fundamental but also applicable data that will be useful for diagnosing and monitoring cold heat patterns in Tae-Eum type patients. PMID- 30402121 TI - Hyperthermic Effect of Ginger (Zingiber officinale) Extract-Containing Beverage on Peripheral Skin Surface Temperature in Women. AB - Ginger is known to warm the body. Therefore, we conducted a placebo-controlled crossover trial to investigate the hyperthermic effect of a palatable ginger containing beverage in healthy women with cold-sensitive extremities. Six women drank 280 mL of 0.07% ginger extract-containing or placebo beverage in a temperature-controlled room (21 degrees C). Their palm temperatures were measured as measure of surface body temperature using a thermographic camera before intake and every 10 min after intake for 60 min. Palm temperature increased immediately following intake of the ginger and placebo beverages. However, palm temperature following intake of the ginger beverage increased for 20 min, while palm temperature following placebo intake decreased again after 10 min. The increased palm temperature following ginger intake was maintained significantly longer than after placebo intake (p < 0.05). In response to a questionnaire, some subjects answered that their increased body temperature was maintained after drinking the ginger beverage. Ginger extract-containing beverage may thus improve cold sensitivity. PMID- 30402120 TI - Investigation on the Antibacterial and Anti-T3SS Activity of Traditional Myanmar Medicinal Plants. AB - Myanmar has a rich pool of, but less known, medicinal plants with traditional knowledge. In this study, we aimed to investigate the inhibitory activity of traditional Myanmar medicinal plants against the type III secretion system (T3SS) of Salmonella enterica serovar Typhimurium UK-1 chi8956 and the intestinal disease-caused by microbes including S. enterica serovar Typhimurium UK-1 chi8956, Proteusbacillus vulgaris CPCC 160013, Escherichia coli CICC 10003, and Staphylococcus aureus ATCC 25923. The EtOH extracts of 93 samples were used to screen the inhibitory activities against the secretion of T3SS effector proteins SipA/B/C/D of S. enterica and the antibacterial activity against S. enterica, P. vulgaris, E. coli, and S. aureus. Out of 71 crude drugs traditionally used, 18 were proofed to be effective either on the growth inhibition of tested bacteria and/or as inhibitors for the T3SS. The EtOH extracts of five plants, Luvunga scandens (Roxb.) Buch.-Ham. ex Wight & Arn. (My7), Myrica nagi Thunb. (My11), Terminalia citrina Roxb. ex Fleming (My21), Thymus vulgaris L. (My49), and Cinnamomum bejolghota (Buch.-Ham.) Sweet (My104), showed potent inhibitory activities against the secretion of T3SS proteins SipA/B/C/D of S. enterica serovar Typhimurium UK-1 chi 8956. Mansonia gagei J.R.Drumm (My3) and Mesua ferrea (Roxb.) L. (My10) showed strong antibacterial activities against P. vulgaris and S. aureus. This study provided the first scientific evidence of T3SS prohibiting and antibacterial properties for the traditional knowledge in Myanmar of using plants as medicines for treating infections and gastrointestinal disease. Further researches are proposed to discover the active chemical compounds and mechanism of L. scandens (Roxb.) Buch.-Ham. ex Wight & Arn, M. nagi Thunb., T. citrina Roxb. ex Fleming, T. vulgaris L., and C. bejolghota (Buch. Ham.) Sweet as antivirulence drugs and the potential of M. gagei J.R.Drumm and M. ferrea L. as new broad spectrum plant antibiotics. PMID- 30402123 TI - Traditional Chinese Medicine Injections in the Treatment of Diabetic Foot: A Systematic Review and Meta-Analysis. AB - Context: The role of traditional Chinese medicine injections (TCMIs) in diabetic foot (DF) has not been well estimated. Objective: To evaluate the clinical effective rate, safety, and the financial cost of TCMIs in treating DF and ulcer wound healing. Methods: We searched PubMed, Embase, CENTRAL, China National Knowledge Infrastructure (CNKI), VIP database, and Wanfang database from inception to May 2018 to find all randomized control trials (RCTs) related to TCMIs in DF treatment. The search items were "Traditional Chinese Medicine Injection" AND "Diabetic foot or Diabetic foot ulcer" AND "random". Study Selection and Synthesis: Only RCTs of TCMIs combined conventional therapies versus conventional therapies and that can be quantitatively synthesized were included. Finally, 17 studies and 1294 participants were included after extraction. Two investigators independently extracted and analyzed the data using RevMan5.3 software. Results: The overall clinical effective rate of TCMI groups is higher than that of control groups [RR=1.27, 95CI % (1.20, 1.34), P<0.00001] based on fixed effect model analysis. Regarding motor nerve conduction velocity of median nerve and peroneal nerve, TCMI group showed a significant improvement (MD=3.84[2.28, 5.41], P<0.00001; MD=2.89[0.63, 5.15], P=0.01). Regarding plasma viscosity TCMI group showed a statistically difference (MD=0.27[0.04, 0.49], P=0.02). In terms of blood viscosity at high shear rate, there was an improvement of TCMI group (MD=0.36[0.05, 0.67], P=0.02). However, sensory nerve conduction velocity of peroneal nerve and median nerve showed a contradiction to motor nerve conduction velocity, respectively (MD=2.59[-1.69, 6.87], p=0.24; MD=2.73[-0.96, 6.43], P=0.15). Conclusion: The data of this study shows that TCMIs can bring benefits to patients with diabetic foot. However, due to low methodological quality of included RCTs, more rigorous designed RCTs with large sample size are recommended to provide more high-quality evidence. PMID- 30402124 TI - Electrochemically Reduced Water Delays Mammary Tumors Growth in Mice and Inhibits Breast Cancer Cells Survival In Vitro. AB - Electrochemical reduced water (ERW) has been proposed to have beneficial effects on human health due to its rich content of H2 and the presence of platinum nanoparticles with antioxidant effects. Many studies have demonstrated that ERW scavenging properties are able to reduce the damage caused by oxidative stress in different experimental models. Although few in vivo studies have been reported, it has been demonstrated that ERW may display anticancer effects by induction of tumor cells apoptosis and reduction of both angiogenesis and inflammation. In this study, we show that ERW treatment of MCF-7, MDA-MB-453, and mouse (TUBO) breast cancer cells inhibited cell survival in a time-dependent fashion. ERW decreased ErbB2/neu expression and impaired pERK1/ERK2 and AKT phosphorylation in breast cancer cells. In addition, ERW treatment induced apoptosis of breast cancer cell lines independently of the status of p53 and ER and PR receptors. Our in vivo results showed that ERW treatment of transgenic BALB-neuT mice delayed the development of mammary tumors compared to the control. In addition, ERW induced a significant prolongation of tumor-free survival and a reduction in tumor multiplicity. Overall, these results suggest a potential beneficial role of ERW in inhibiting cancer cells growth. PMID- 30402122 TI - Anti-Angiogenic Alternative and Complementary Medicines for the Treatment of Endometriosis: A Review of Potential Molecular Mechanisms. AB - Endometriosis is caused by the growth or infiltration of endometrial tissues outside of the endometrium and myometrium. Symptoms include pain and infertility. Surgery and hormonal therapy are widely used in Western medicine for the treatment of endometriosis; however, the side effects associated with this practice include disease recurrence and menopause, which can severely influence quality of life. Angiogenesis is the main biological mechanism underlying the development of endometriosis. Numerous natural products and Chinese medicines with potent anti-angiogenic effects have been investigated, and the molecular basis underlying their therapeutic effects in endometriosis has been explored. This review aims to describe natural products and compounds that suppress angiogenesis associated with endometriosis and to assess their diverse molecular mechanisms of action. Furthermore, this review provides a source of information relating to alternative and complementary therapeutic products that mediate anti angiogenesis. An extensive review of the literature and electronic databases, such as the China National Knowledge Infrastructure, PubMed, and Embase, was conducted using the keywords 'endometriosis,' 'traditional Chinese medicine,' 'Chinese herbal medicine,' 'natural compounds,' and 'anti-angiogenic' therapy. Anti-angiogenic therapy is an emerging strategy for the treatment of endometriosis. Natural anti-angiogenic products and Chinese medicines provide several beneficial clinical effects, including pain relief. In this review, we summarize clinical trials and experimental studies of endometriosis using natural products and Chinese medicines. In particular, we focus on anti-angiogenic products and alternative and complementary medicines for the treatment of endometriosis and additionally examine their therapeutic efficacy and mechanisms of action. Anti-angiogenic natural products and/or compounds provide a new approach for the treatment of endometriosis. Future work will require randomized trials with larger numbers of subjects, as well as long-term follow-up to confirm the findings described here. PMID- 30402125 TI - Protective Effects of Chinese Traditional Medicine Longhu Rendan against Atherosclerosis via Negative Regulation of LOX-1. AB - Longhu Rendan (LHRD), a Chinese traditional compound medicine, has a remarkable treatment effect on motion sickness for about half a century. However, the role of LHRD in atherosclerosis treatment is still unclear. In this study, LHRD treatment significantly diminished total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) levels in apolipoprotein E gene knockout (ApoE-/-) mice fed with high fat and high cholesterol diet (western diet). Besides, LHRD treatment significantly reduced atherosclerotic lesion and plaques formation in both aortic roots and aortic trees. Furthermore, immunofluorescence staining in aortic roots demonstrated that LHRD treatment inhibited lectin-like oxidized low-density-lipoprotein receptor-1 (LOX-1) expression in atherosclerotic plaques. These results indicated that LHRD ameliorated atherosclerosis via reducing serum levels of TC, TG, and LDL-C as well as LOX-1 expression, subsequently attenuating atherosclerotic lesion and lipid deposition. In conclusion, LHRD could significantly attenuate experimental atherosclerosis and might be a novel potential drug for the prevention and treatment of atherosclerosis. PMID- 30402126 TI - Erchen Decoction Ameliorates Lipid Metabolism by the Regulation of the Protein CAV-1 and the Receptors VLDLR, LDLR, ABCA1, and SRB1 in a High-Fat Diet Rat Model. AB - Lipid metabolism disorder is a common metabolic disorder characterized by abnormal lipid levels in blood. Erchen decoction (ECD) is a traditional Chinese medicine prescription, which is used for the treatment of diseases caused by retention of phlegm dampness. It has been reported to ameliorate the disorder of lipid metabolism. The aim of the present study was to investigate the effects and underlying mechanisms of ECD in lipid metabolism disorder induced by a high-fat diet (HFD) in rats. ECD (4.35g/kg/d) and atorvastatin (10mg/kg/d, positive control) were orally administered to HFD-fed rats for four weeks. The parameters, food, water consumption, body weight, body length, liver, and visceral fat weight and the content of serum lipids and lipid transporters were assessed. The effects of ECD on the mRNA and protein expression levels of lipid transport factors were measured by real-time PCR and western blotting. The present study demonstrated that ECD improved the disorders of serum lipid and lipid transporters in HFD-fed rats, TG (0.70+/-0.08 mmol/L, p<0.01), LDL-C (1.50+/-0.19 mmol/L, p<0.01), LDL (1.38+/-0.21 mmol/L, p<0.05), and oxLDL (1.77+/-0.39 ng/mL, p<0.05) were downregulated, while HDL-C (0.87+/-0.13 mmol/L, p<0.01), FFA (0.62+/-0.13 mmol/L, p<0.05), HDL (38.8+/-4.0 mg/dL, p<0.05), and CETP (903.6+/-120.0 ng/mL, p<0.05) were upregulated. But ECD obviously had no effects on the indices food/water/energy intake, body/tissue (liver and fat) weight, and BMI (p>0.05). Concomitantly, ECD reversed the abnormal expressions of those lipid transport factors in the liver and visceral fat. PMID- 30402127 TI - Yellow Laser Stimulation at GV2 Acupoint Mitigates Apoptosis, Oxidative Stress, Inflammation, and Motor Deficit in Spinal Cord Injury Rats. AB - Currently, the suppression of oxidative stress and inflammation is considered as the treatment targets of spinal cord injury due to their roles on the hindrance of recovery process. Since laser acupuncture decreased oxidative stress and enhanced the survival of neurons from oxidative stress damage and GV2 stimulation was selected as one stimulated acupoint in order to enhance the recovery of spinal cord injury, we hypothesized that laser acupuncture at GV2 should enhance the recovery of spinal cord injury. To test this hypothesis, male Wistar rats were induced spinal cord injury at T10 level and they were exposed to a 10 minute stimulation at GV2 by yellow laser. Laser acupuncture was performed at 0.25 and 1, 2, 6, and 12 hours after spinal cord injury. Then, the stimulation was performed once daily for 7 days. Locomotor assessment was carried out on days 3 and 7 after injury. At the end of study period, the densities of polymorphonuclear of leukocyte, Bax, Caspase-3, Bcl-2, and BDNF positive stained cells in ventral horn of spinal cord were determined. Cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and oxidative stress status was also assessed. The results showed that laser acupuncture at GV2 increased BBB score, gross motor score, and densities of Bcl-2 and BDNF positive stained cells but decreased density with polymorphonuclear leukocyte, the densities of Bax and Caspase-3 positive stained cells, COX-2 level, and oxidative stress status in ventral horn of the lesion spinal cord. The reduction of serum COX-2 was also decreased. Therefore, GV2 stimulation by yellow laser might enhance the recovery of spinal cord via the increase in BDNF and the decrease in inflammation, apoptosis, and oxidative stress status in the lesion spinal cord. PMID- 30402128 TI - Genotoxicity Evaluation of an Ethanol Extract Mixture of Astragali Radix and Salviae miltiorrhizae Radix. AB - Myelophil, a combination of Astragali Radix and Salviae Radix, is one of the most commonly used remedies for disorders of Qi and blood in traditional Chinese medicine. Based on the clinical applications of these plants, in particular to pregnant woman, this study aimed to evaluate the genotoxic potential of an ethanol extract mixture of the above two herbs, called Myelophil. Following the Organization for Economic Cooperation and Development (OECD) Guideline methods, a genotoxicity test was conducted using a bacterial reverse mutation test with Salmonella typhimurium (TA98, TA100, TA1535, and TA1537) and Escherichia coli (WP2MUvrA), an in vitro mammalian chromosome aberration test using a Chinese hamster ovary cell line (CHO-K1), and an in vivo mammalian erythrocyte micronucleus test using ICR mouse bone marrow. In the Ames test, for both types of mutations (base substitution and frameshift) under conditions with/without an S9 mix up to 5,000 MUg/plate, Myelophil did not increase the number of revertant colonies of all S. typhimurium strains as well as E. coli strain. For both short (6 h) and long tests with/without S9 mix, the chromosome aberration test did not show any significant increase in the number of structural or numerical chromosome aberrations by Myelophil. In addition, no significant change in the number of micronucleated polychromatic erythrocytes or polychromatic erythrocytes was observed in the bone marrow of an ICR mouse administered Myelophil orally at 2,000 mg/kg/day for 2 days, respectively. These results are the first to provide experimental evidence that Myelophil, an ethanol extract mixture of Astragali Radix and Salviae Radix, has no risk of genotoxicity. PMID- 30402129 TI - Effects of Cinnamaldehyde on the Cell Wall of A. fumigatus and Its Application in Treating Mice with Invasive Pulmonary Aspergillosis. AB - Background: The invasive pulmonary aspergillosis is a kind of high incidence of disease with difficulties in treatment, poor prognosis, and high mortality. Objectives: The study aimed to reveal the effect of cinnamaldehyde on the fungal cell wall and verify its efficacy on invasive pulmonary aspergillosis on immunosuppressed Institute of Cancer Research mice (ICR mice). Methods: ICR mice were given cyclophosphamide 200 mg.kg-1. d-1 by intraperitoneal injection for 2 days. On the 4th day, the mice were given 50 MUL of Aspergillosis fumigatus spore (107colony form unit CFU/mL) by intranasal injection to establish immunosuppressive animal models with invasive Aspergillosis fumigatus infection. Then the mice in treatment group orally administered cinnamaldehyde for 14 consecutive days, while voriconazole was given to the mice in the positive control group. Results: The clearance rate of pulmonary fungi, cure rate, and reduction of 1,3-beta-D-glucans in treatment group were 80.00%, 80.00%, and 81.00%, respectively while in positive control group they were 67.00%, 60.00%, and 62.00%, respectively. There were significant differences in the results between two groups as mentioned above (P<0.05). Electron microscopy showed that, in treatment group, the cell wall of Aspergillus fumigatus was dissolved and detached and the cell surface was incomplete. There were edema, degeneration, and necrosis in nucleus and organelle, which lead to cellular necrocytosis. The cytomembrane of Aspergillus fumigatus was intact, clear, and complete, whereas the cytomembrane in the positive control group disappeared. The hyphal morphology of Aspergillus fumigatus was deformed, but the cell wall was intact. Conclusion: Cinnamaldehyde has a good curative effect in the treatment of invasive pulmonary aspergillus infection in immunodeficient mice. It mainly affects the synthesis of 1,3-beta-D-glucans from the cytoderm of Aspergillus fumigatus but does not affect cell wall. It would potentially be an effective and novel drug for targeted treatment of Aspergillus fumigatus deep infection. PMID- 30402130 TI - Sheng-Jiang Powder Ameliorates High Fat Diet Induced Nonalcoholic Fatty Liver Disease via Inhibiting Activation of Akt/mTOR/S6 Pathway in Rats. AB - Background and Aims: Nonalcoholic fatty liver disease (NAFLD) is an alarming public health problem that directly contributes to increased prevalence of liver cirrhosis and hepatic cell cancer, but without any specific pharmacological option. Sheng-jiang powder (SJP), an empirical Chinese medicine formula to treat NAFLD, showed great efficacy but the specific mechanisms have never been reported. Therefore, we performed this study to explore the effect of SJP on NAFLD and the potential mechanism. Methods: NAFLD was induced by high fat diet (HFD) feeding. Rats were treated with SJP/normal saline daily for 10 weeks and all rats were euthanized after 12 weeks' feeding. Liver tissue samples were obtained for biochemistry test and pathological evaluation. Additionally, oleic acid induced LO2 cells were employed to simulate a cell model of NAFLD. Cells were subjected to western blotting for Akt, mTOR, S6, SREBP1-c, and FASN detection after coincubated with SJP, LY294002 (a selective PI3K inhibitor), or the combination for 24h. Results: HFD significantly induced hepatic steatosis. Plenty of lipid droplets were observed under transmission electron microscope. The ultrastructure of liver cells showed distinct changes with obvious endoplasmic reticulum expansion, mitochondrial contraction, and cell matrix solidification. Although no difference was detected in serum hepatic enzymes and tissue proinflammatory cytokines, the tissue level of SOD and GSH-px was much lower and the pathologic injuries were much severe in HFD feeding rats. However, SJP treatment significantly attenuated the ultrastructure changes and protected rat liver against inflammatory injury. Abundant of lipid droplets and high expression of pAkt, pmTOR, pS6, and FASN were observed in oleic acid treated LO2 cells, while these changes were restored by SJP treatment. Conclusions: SJP is efficient in attenuating HFD induced NAFLD in rats and this effect might be partly related to the inhibition of Akt/mTOR/S6 pathway. PMID- 30402132 TI - Protective Effect of Electroacupuncture at Zusanli on Myocardial Injury in Septic Rats. AB - The protective effect of electroacupuncture (EA) at Zusanli points (ST36) on myocardial injury in a model of sepsis was observed. Forty-eight male Sprague Daley rats were subjected to sepsis by cecal ligation and puncture (CLP) and randomly divided into 4 groups (n=12; A: sepsis + EA; B: sepsis + sham acupuncture; C: sepsis + vagotomy; D: sepsis + vagotomy + EA). Bilateral points were stimulated (2mA, 2-100 Hz) for 1 hour. Abdominal vagotomy was performed in groups C and D. At 6h after CLP, the plasma activity of creatine kinase-MB (CK MB) was determined. A part of cardiac muscle was harvested for evaluating levels of tumor necrosis factor (TNF-alpha), nitric oxide (NO), myeloperoxidase (MPO), and the rate of water content. The activities of CK-MB, TNF-alpha, NO, and MPO and the rate of water content in group A were significantly lower than those of the other groups 6h after CLP. EA after vagotomy showed less anti-inflammatory and protective effects. The results indicated that EA obviously reduced the increased levels of the proinflammatory factors at 6h after CLP, and vagotomy could weaken or eliminate the effects of EA. Cholinergic anti-inflammatory pathway is one of the main mechanisms of cardioprotective effect of EA. PMID- 30402131 TI - Plants Used as Anticancer Agents in the Ethiopian Traditional Medical Practices: A Systematic Review. AB - Background: This systematic review aimed at examining the use patterns of Ethiopian anticancer traditional medicinal plants (MPs) in view of recommending further validation studies. Methods: The information was retrieved from PubMed according to the PRISMA guideline. The electronic library of Addis Ababa University and relevant church-based religious books were also inspected for additional data. Results: From 34 studies meeting specific inclusion/exclusion criteria, 119 anticancer MP species distributed in 98 genera and 57 families were recorded. Fabaceae (10.92 %) and Euphorbiaceae (10.08 %) were the most widely used families. Plumbago zeylanica (Plumbaginaceae) was the most frequently used anticancer MP species. Shrubs (42.02 %) and herbs (35.29 %) were dominant growth forms. About 89.08 % of the MPs were collected from wild habitats. Leaves (33.73 %) and roots (27.11 %) were the most frequently harvested parts. The most favored routes were dermal (33.33 %) and oral (29.25 %). About 87.07 % preparations were made from fresh plant materials. Breast cancer and skin cancer were treated with 14 % and 10.76 % of anticancer MPs, respectively. Conclusion: The review showed that anticancer MPs are widely used across the regions of Ethiopia. Most of the MPs are not scientifically experimented and yet are at a higher vulnerability to loss mainly by human activities. Calling for conservation measures, we recommend experimental validation of the frequently used anticancer MPs. This augments global anticancer drug researches. PMID- 30402133 TI - Baicalin Exerts Anti-Airway Inflammation and Anti-Remodelling Effects in Severe Stage Rat Model of Chronic Obstructive Pulmonary Disease. AB - Chronic obstructive pulmonary disease (COPD) is a worldwide epidemic. Current approaches are disappointing due to limited improvement of the disease development. The present study established 36-week side stream cigarette smoke induced rat model of COPD with advanced stage feature and evaluted the effects of baicalin on the model. Fifty-four Sprague-Dawley rats were randomly divided into six groups including room air control, cigarette smoke exposure, baicalin (40 mg/kg, 80 mg/kg, and 160 mg/kg), and budesonide used as a positive control. Rats were exposed to cigarette smoke from 3R4F research cigarettes. Pulmonary function was evaluated and pathological changes were also observed. Cytokine level related to airway inflammation and remodelling in blood serum, bronchoalveolar lavage fluid, and lung tissue was determined. Blood gases and HPA axis function were also examined, and antioxidant levels were quantified. Results showed that, after treatment with baicalin, lung function was improved and histopathological changes were ameliorated. Baicalin also regulated proinflammatory and anti-inflammatory balance and also airway remodelling and anti-airway remodelling factors in blood serum, bronchoalveolar lavage fluid, and lung tissue. Antioxidant capacity was also increased after treatment with baicalin in COPD rat model. HPA axis function was improved in baicalin treated groups as compared to model group. Therefore, baicalin exerts lung function protection, proinflammatory and anti-inflammatory cytokine regulation, anti-airway remodelling, and antioxidant role in long term CS induced COPD model. PMID- 30402135 TI - Bu Shen Yang Xue Prescription Has Treating Effect on Endometrial Cancer through FSH/PI3K/AKT/Gankyrin/HIF-alpha/cyclinD 1 Pathway in Ishikawa Cells. AB - Background. The formulation of Bu Shen Yang Xue (BSYX) has been clinically used in treating gynecologic disease in China, especially for the development of the endometrium. Endometrial carcinoma is the most common malignant tumor of the female genital tract in developed countries. And few studies have been reported on the antitumor activity of BSYX. Therefore, this study aimed to investigate the effect of BSYX on endometrial cancer and make an initial discussion of the underlining mechanisms in Ishikawa cells. Methods and Results. Firstly, 60 SPF female nude mice were randomly divided into control group, model group, BSYX group, and positive group. The models of subcutaneous tumor xenograft of nude mice were established by injection of human endometrial carcinoma cell line Ishikawa tumor cell suspension. Compared with model group, BSYX reduced effectively tumor volume and changed pathological feature in mice tumor issue. Meanwhile, proteins from tumor issues were detected by western blot analysis. The protein levels of follicle-stimulating hormone receptor (FSHR), p-Akt/Akt, Gankyrin, and cyclinD1 in the model group were higher than those in control group but the expression in BSYX group was lower than that in the model group. The hypoxia inducible factor alpha (HIF-alpha) protein level in the model group was lower than those in control group and upregulated in BSYX group. In addition, Ishikawa cells were cultured and then exposed to follicle-stimulating hormone (FSH), LY294002, a highly selective PI3K inhibitor and serum containing BSYX, respectively. LY294002 and BSYX markedly decreased the cancer cell viability and migration ability and increased the apoptosis rate. FSH promoted the cancer cell ability and migration ability. LY294002 and BSYX evidently downregulated the proteins levels of FSHR, p-Akt/Akt, Gankyrin, and cyclinD1 and upregulated the expression of HIF-alpha protein, and FSH was on the opposite. Conclusions. Taken together, our results showed that the formulation of BSYX had antitumor effect on endometrial cancer in vivo and in vitro and was related with FSH/PI3K/AKT/Gankyrin/HIF-alpha/cyclinD1 transduction pathway. PMID- 30402134 TI - Immunostimulatory Effect of Zanthoxylum schinifolium-Based Complex Oil Prepared by Supercritical Fluid Extraction in Splenocytes and Cyclophosphamide-Induced Immunosuppressed Rats. AB - Complex oil of Zanthoxylum schinifolium and Perilla frutescens seed (ZPCO) is used as a traditional medicine due to its pharmacological activities. The aim of this study was to investigate the immunostimulatory effect of ZPCO in isolated splenocytes as well as in an immunosuppressed rat model, which was generated via oral administration of cyclophosphamide. Notably, our results showed that ZPCO exerted an immunity-enhancing effect both in vitro and in vivo. Specifically, ZPCO treatment enhanced the viability and inflammatory cytokine production of splenocytes and NK cell activity in vitro. Moreover, this product improved host defense under immunosuppressive conditions by increasing the number of immune cells and promoting the expression of cytokines involved in immune responses. Our results suggest that complex oil including Z. schinifolium should be explored as a novel immunostimulatory agent that could potentially be used for therapeutic purposes or as an ingredient in functional foods. PMID- 30402136 TI - Does Electroacupuncture Treatment Reduce Pain and Change Quantitative Sensory Testing Responses in Patients with Chronic Nonspecific Low Back Pain? A Randomized Controlled Clinical Trial. AB - Chronic nonspecific low back pain is common and one of the most disabling conditions in the world. There is moderate evidence that chronic low back pain patients present altered functional connectivity in areas related to pain processing. Quantitative sensory testing is a way of clinical measure of these alterations. Although there is not enough evidence, there are some reports that electroacupuncture is supposedly more effective in relieving pain than acupuncture because the addition of electric current could optimize the effects of traditional technique. Thus, the objective of this randomized clinical trial was to verify if electroacupuncture treatment reduces pain and changes quantitative sensory testing responses in patients with chronic nonspecific low back pain. Patients were evaluated before and after 10 sessions regarding pain (11-point numerical rating pain scale) and quantitative sensory testing (pressure pain threshold, temporal summation, and conditioned pain modulation). There were 1 treatment group (electroacupuncture (EA)) and three different control groups (CTR 1, CTR 2, and CTR 3). A total of 69 patients participated in the study. No significant differences were found in pain intensity or quantitative sensory testing responses when comparing electroacupuncture group to the three control groups. There was a significant reduction in both resting and movement pain intensity in groups EA, CTR 1, and CTR3. Although ten sessions of electroacupuncture have diminished pain intensity in both resting and movement, it could not change significantly quantitative sensory testing and diminish central sensitization in patients with chronic nonspecific low back pain. The implications of this study involve the fact that, maybe, in chronic nonspecific low back pain, electroacupuncture should be associated with other treatments that target central sensitization. PMID- 30402138 TI - Maximin Efficiencies under Treatment-Dependent Costs and Outcome Variances for Parallel, AA/BB, and AB/BA Designs. AB - If there are no carryover effects, AB/BA crossover designs are more efficient than parallel (A/B) and extended parallel (AA/BB) group designs. This study extends these results in that (a) optimal instead of equal treatment allocation is examined, (b) allowance for treatment-dependent outcome variances is made, and (c) next to treatment effects, also treatment by period interaction effects are examined. Starting from a linear mixed model analysis, the optimal allocation requires knowledge on intraclass correlations in A and B, which typically is rather vague. To solve this, maximin versions of the designs are derived, which guarantee a power level across plausible ranges of the intraclass correlations at the lowest research costs. For the treatment effect, an extensive numerical evaluation shows that if the treatment costs of A and B are equal, or if the sum of the costs of one treatment and measurement per person is less than the remaining subject-specific costs (e.g., recruitment costs), the maximin crossover design is most efficient for ranges of intraclass correlations starting at 0.15 or higher. For other cost scenarios, the maximin parallel or extended parallel design can also become most efficient. For the treatment by period interaction, the maximin AA/BB design can be proven to be the most efficient. A simulation study supports these asymptotic results for small samples. PMID- 30402137 TI - Exploring Pharmacological Mechanisms of Xuefu Zhuyu Decoction in the Treatment of Traumatic Brain Injury via a Network Pharmacology Approach. AB - Objectives: Xuefu Zhuyu decoction (XFZYD), a traditional Chinese medicine (TCM) formula, has been demonstrated to be effective for the treatment of traumatic brain injury (TBI). However, the underlying pharmacological mechanisms remain unclear. This study aims to explore the potential action mechanisms of XFZYD in the treatment of TBI and to elucidate the combination principle of this herbal formula. Methods: A network pharmacology approach including ADME (absorption, distribution, metabolism, and excretion) evaluation, target prediction, known therapeutic targets collection, network construction, and molecule docking was used in this study. Results: A total of 119 bioactive ingredients from XFZYD were predicted to act on 47 TBI associated specific proteins which intervened in several crucial pathological processes including apoptosis, inflammation, antioxidant, and axon genesis. Almost each of the bioactive ingredients targeted more than one protein. The molecular docking simulation showed that 91 pairs of chemical components and candidate targets had strong binding efficiencies. The "Jun", "Chen", and "Zuo-Shi" herbs from XFZYD triggered their specific targets regulation, respectively. Conclusion: Our work successfully illuminates the "multicompounds, multitargets" therapeutic action of XFZYD in the treatment of TBI by network pharmacology with molecule docking method. The present work may provide valuable evidence for further clinical application of XFZYD as therapeutic strategy for TBI treatment. PMID- 30402140 TI - Injury Analysis and Prevention in Vehicle Safety. PMID- 30402139 TI - The Effects of Selective Muscle Weakness on Muscle Coordination in the Human Arm. AB - Despite the fundamental importance of muscle coordination in daily life, it is currently unclear how muscle coordination adapts when the musculoskeletal system is perturbed. In this study, we quantified the impact of selective muscle weakness on several metrics of muscle coordination. Seven healthy subjects performed 2D and 3D isometric force target matches, while electromyographic (EMG) signals were recorded from 13 elbow and shoulder muscles. Subsequently, muscle weakness was induced by a motor point block of brachialis muscle. Postblock subjects repeated the force generation tasks. We quantified muscle coordination pre- and postblock using three metrics: tuning curve preferred direction, tuning curve area, and motor modules analysis via nonnegative matrix factorization. For most muscles, the tuning direction for the 2D protocol was not substantially altered postblock, while tuning areas changed more drastically. Typically, five motor modules were identified from the 3D task, and four motor modules were identified in the 2D task; this result held across both pre- and postblock conditions. The composition of one or two motor modules, ones that involved mainly the activation of shoulder muscles, was altered postblock. Our results demonstrate that selective muscle weakness can induce nonintuitive alternations in muscle coordination in the mechanically redundant human arm. PMID- 30402141 TI - Cancer antigen-125 and outcomes in acute heart failure: a systematic review and meta-analysis. AB - Background: Carbohydrate antigen-125 (CA125) is an ovarian cancer marker, but recent work has examined its role in risk stratification in heart failure. A recent meta-analysis examined its prognostic value in heart failure generally. However, there has been no systematic evaluation of its role specifically in acute heart failure (AHF). Methods: PubMed and EMBASE databases were searched until 11 May 2018 for studies that evaluated the prognostic value of CA125 in AHF. Results: A total of 129 and 179 entries were retrieved from PubMed and EMBASE. Sixteen studies (15 cohort studies, 1 randomised trial) including 8401 subjects with AHF (mean age 71 years old, 52% male, mean follow-up 13 months, range of patients 525.1+/-598.2) were included. High CA125 levels were associated with a 68% increase in all-cause mortality (8 studies, HRs: 1.68, 95% CI 1.36 to 2.07; p<0.0001; I2: 74%) and 77% increase in heart failure-related readmissions (5 studies, HRs: 1.77, 95% CI 1.22 to 2.59; p<0.01; I2: 73%). CA125 levels were higher in patients with fluid overload symptoms and signs compared with those without them, with a mean difference of 54.8 U/mL (5 studies, SE: 13.2 U/mL; p<0.0001; I2: 78%). Conclusion: Our meta-analysis found that high CA125 levels are associated with AHF symptoms, heart failure-related hospital readmissions and all-cause mortality. Therefore, CA125 emerges as a useful risk stratification tool for identifying high-risk patients with more severe fluid overload, as well as for monitoring following an AHF episode. PMID- 30402143 TI - High FNDC1 expression correlates with poor prognosis in gastric cancer. AB - Gastric cancer is a common human cancer worldwide. Fibronectin is an important extracellular matrix protein that has been implicated in many cancers and is known to be associated with proliferation and migration. Fibronectin type III domain containing 1 (FNDC1) contains a major component of the structural domain of fibronectin. The objectives of the present study were to measure FNDC1 expression in gastric cancer tissues and evaluate its value as a potential prognostic marker for gastric cancer. FNDC1 protein expression was analyzed by immunohistochemistry in 98 samples of gastric cancer tissue and 25 adjacent normal tissues. The associations between FNDC1 level and various clinicopathological characteristics were assessed, and the correlation between FNDC1 expression levels and prognosis of patients with gastric cancer was analyzed using a Kaplan-Meier analysis. It was demonstrated that FNDC1 expression in gastric cancer tissues and adjacent tissues was significantly different. FNDC1 expression levels were significantly higher in gastric cancer tissues compared with normal gastric tissues (P<0.001). Among the clinicopathological characteristics evaluated, clinical stage (P<0.001), T classification (P<0.001), N classification (P<0.001) and pathological differentiation (P=0.044) were significantly associated with high FNDC1 expression. Higher FNDC1 expression level was significantly correlated with poorer survival. The present findings suggest that FNDC1 expression levels may be a promising prognostic biomarker for gastric cancer. PMID- 30402142 TI - How pH is regulated during amelogenesis in dental fluorosis. AB - Amelogenesis is a complicated process that concerns the interaction between growing hydroxyapatite crystals and extracellular proteins, which requires the tight regulation of pH. In dental fluorosis, the balance of pH regulation is broken, leading to abnormal mineralization. The current review focuses on the electrolyte transport processes associated with pH homeostasis, particularly regarding the changes in ion transporters that occur during amelogenesis, following exposure to excessive fluoride. Furthermore, the possible mechanism of fluorosis is discussed on the basis of acid hypothesis. There are two main methods by which F- accelerates crystal formation in ameloblasts. Firstly, it induces the release of protons, lowering the pH of the cell microenvironment. The decreased pH stimulates the upregulation of ion transporters, which attenuates further declines in the pH. Secondly, F- triggers an unknown signaling pathway, causing changes in the transcription of ion transporters and upregulating the expression of bicarbonate transporters. This results in the release of a large amount of bicarbonate from ameloblasts, which may neutralize the pH to form a microenvironment that favors crystal nucleation. The decreased pH stimulates the diffusion of F- into the cytoplasm of amelobalsts along the concentration gradient formed by the release of protons. The retention of F- causes a series of pathological changes, including oxidative and endoplasmic reticulum stress. If the buffering capacity of ameloblasts facing F- toxicity holds, normal mineralization occurs; however, if F- levels are high enough to overwhelm the buffering capacity of ameloblasts, abnormal mineralization occurs, leading to dental fluorosis. PMID- 30402144 TI - Efficacy of second-look endoscopy in preventing delayed bleeding after endoscopic submucosal dissection of early gastric cancer. AB - The present study aimed to evaluate whether second-look endoscopy (SLE) is able to prevent delayed bleeding after endoscopic submucosal dissection (ESD) of gastric carcinoma and to identify which types of lesion require SLE. ESD of gastric cancer at the early stage was performed on 210 patients between October 2014 and September 2016. Mucosal damage-associated bleeding within 24 h after ESD was considered as delayed bleeding. The association of the characteristics of patients and lesions, as well as surgical factors, with the incidence of bleeding as a measure of outcome was analyzed. A total of 110 patients with melena and/or hematemesis underwent SLE on the second day following gastric ESD. Within the entire cohort (n=210), late delayed bleeding (LDB) was defined as hematemesis or melena occurring following second-look endoscopy. Early delayed bleeding (EDB) was defined as hematemesis or melena occurring from the end of ESD to second-look endoscopy, or as active or possible bleeding at the time of the second-look endoscopy was reported in 17 (8.1%) and 20 patients(9.5%), respectively. The median interval between late delayed bleeding and ESD was one day (range, 1-10 days). The incidence of late delayed bleeding was significantly decreased in the SLE group compared with that in the non-SLE group (4.5 vs. 12%, P=0.028). Multivariate analyses revealed that ulcer, flat gross type, lesion diameter (>2 cm), the resected tumor size of >40 mm and Helicobacter pylori infection were independently associated with late delayed bleeding after ESD, while flat gross type, ulcer, the resected tumor size of >40 mm and artificial ulcer diameter >3 cm were independently associated with early delayed bleeding. Thus, the data of the present study indicates that second-look endoscopy following gastric ESD may be useful in preventing post-ESD delayed bleeding and should be performed on the second day. PMID- 30402145 TI - A study on the prevention and treatment of murine calvarial inflammatory osteolysis induced by ultra-high-molecular-weight polyethylene particles with neomangiferin. AB - The present study aimed to examine the influence of neomangiferin on murine calvarial inflammatory osteolysis induced by ultra-high-molecular-weight polyethylene (UHMWPE) particles. Eight-week-old male C57BL/J6 mice served as an inflammatory osteolysis model, in which UHMWPE particles were implanted into the calvarial subperiosteal space. The mice were randomly distributed into four groups and treated with different interventions; namely, a sham group [phosphate buffered saline (PBS) injection and no UHMWPE particles], model group (PBS injection and implantation of UHMWPE particles), low-dose neomangiferin group (UHMWPE particles +2.5 mg/kg neomangiferin), and high-dose neomangiferin group (UHMWPE particles +5 mg/kg neomangiferin). Following 3 weeks of feeding according to the above regimens, celiac artery blood samples were collected for an enzyme linked immunosorbent assay (ELISA) to determine the expression of receptor activator of nuclear factor-kappaB ligand (RANKL), osteoclast-related receptor (OSCAR), cross-linked C-telopeptide of type I collagen (CTX-1); osteoprotegerin (OPG), tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta. Subsequently, the mice were sacrificed by cervical dislocation following ether inhalation anesthesia, and the skull was separated for osteolysis analysis by micro-computed tomography (micro-CT). Following hematoxylin and eosin staining, tartrate-resistant acid phosphatase (TRAP) staining was performed to observe the dissolution and destruction of the skull. The micro-CT results suggested that neomangiferin significantly inhibited the murine calvarial osteolysis and bone resorption induced by UHMWPE particles. In addition, the ELISA results showed that neomangiferin decreased the expression levels of osteoclast markers RANKL, OSCAR, CTX-1, TNF-alpha and IL-1beta. By contrast, the levels of OPG increased with the neomangiferin dose. Histopathological examination revealed that the TRAP positive cell count was significantly reduced in the neomangiferin-treated animals compared with that in the positive control group, and the degree of bone resorption was also markedly reduced. Neomangiferin was found to have significant anti-inflammatory effects and to inhibit osteoclastogenesis. Therefore, it has the potential to prevent the aseptic loosening of a prosthesis following artificial joint replacement. PMID- 30402146 TI - Improved expression of recombinant fusion defensin gene plasmids packed with chitosan-derived nanoparticles and effect on antibacteria and mouse immunity. AB - In order to develop a secure and competent technique to express the human immune gene for fighting infections, we cloned and expressed the BD2/3 using VR1020 (a eukaryotic expression plasmid). BD2/3 contains human beta-defensin 2 (BD2) and human BD3. To explore safe and effective DNA delivery molecules in vitro and in vivo, the fusion genes of BD2/3 were used as an immune-labelled gene to verify transfection effectivness of modified chitosan (CS). Plasmid of VR1020-BD2/3 was packed with biomaterials: CS, average molecular weight: 25000D; polyethylene glycol-O-chitosan-polyethylenimine (PEG-O-CS-PEI); liposomes (LP); polyamine cationic liposomes (PCL); polyamine cationic liposomes of protamine (PCL protamine) by ionotropic gelation. We observed that BD2/3 fusion gene showed high bioactivity in vitro and in vivo. The BD2/3 fusion protein inhibited the proliferation of bacteria (S. aureus, S. pneumoniae, P. aeruginosa and E. coli). The Kunming mice were immune to these nanoparticles and we analyzed their delivery efficiency and gene expression effect. BD2/3 results in multiple changes of innate and required immune system of mice. BD2/3 increases expression of IgG, IgG1, IgG2a, IL-2, IL-6, IFN-gamma, as well as of lymphocytes and monocytes. Following challenge with virulent E. coli, CD4+ and CD8+ positive T-cell counts were highly elevated in the BD2/3 immunized mice, resulting in higher survival rates of mice. These results indicate that nanoparticles containing modified CS and BD2/3 are potentially safe and effective drugs in vivo to improve the immunity against bacterial infection and enhance innate immunity and adaptive immunity against infectious diseases. PMID- 30402147 TI - Role of miR-520b in non-small cell lung cancer. AB - The aim of the present study was to investigate the expression of microRNA (miR) 520b in non-small cell lung cancer (NSCLC) and its biological functions. Reverse transcription-quantitative polymerase chain reaction was used to detect the expression of miR-520b in 52 cases of NSCLC tissues, and its associations with tumor clinical staging and lymph node metastasis were analyzed. miR-520b mimics was transfected into A549 and Calu-3 cells. Cell proliferation, cell cycle, and cell invasion and migration abilities were assessed via cell counting kit-8 assay, flow cytometry and Transwell chamber assay, respectively. Western blot analysis was performed to detected protein expression levels, and dual luciferase reporter assay was used to detect the gene interaction. miR-520b expression was significantly downregulated in NSCLC. The expression of miR-520b in tumor tissues at N1 stage was lower than that at the N0 stage. miR-520b expression was negatively associated with clinical TNM staging. Furthermore, miR-520b mimic transfection inhibited the proliferation and invasion and metastasis abilities of A549 and Calu-3 cells. The expression of Rab22A was downregulated in the miR-520b mimics-transfected cells, whereas E-cadherin expression was increased, and vimentin expression was downregulated. Dual luciferase reporter assay demonstrated that miR-520b directly targeted the expression of Rab22A. Furthermore, Rab22A reversal downregulated the inhibitory effect of miR-520b. miR 520b expression was downregulated in NSCLC, which was negatively correlated with lymph node metastasis and TNM staging. miR-520b targeted on Rab22A to work as a tumor suppressor, inhibiting tumor proliferation and metastasis. PMID- 30402148 TI - Enhancement of osteogenesis of rabbit bone marrow derived mesenchymal stem cells by transfection of human BMP-2 and EGFP recombinant adenovirus via Wnt signaling pathway. AB - Bone marrow mesenchymal stem cells (BMSCs) are considered the most important seed cells in bone tissue engineering. The present study aimed to investigate the potential of rabbit BMSCs in osteogenesis after the transfection of human BMP-2 and EGFP recombinant adenovirus. Rabbit BMSCs were isolated and the surface stem cell makers, including CD29, CD44 and CD45 were detected by flow cytometry. The expression of BMP-2 mRNA and protein in BMSCs were detected by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. After an induction with osteogenic medium, the alkaline phosphatase (ALK) activity at 7 days, the type I collagen at 14 days, and the calcium nodules at 21 days were performed using an ALK activity kit, immunohistochemical staining and alizarin red S staining, respectively. The expression levels of proteins related to the Wnt signaling pathway were detected by western blot analysis. The positive rates of CD29, CD44 and CD45 were 62.92+/-1.99, 93.55+/-0.99 and 0.21+/ 0.12%. The expression of BMP-2 mRNA and protein was significantly upregulated in Ad-BMP-2/EGFP transfected BMSCs. Furthermore, Ad-BMP-2/EGFP induced ALP activity, promoted the production of type I collagen and calcium nodule formation in rabbit BMSCs. The levels of beta-catenin, cyclin D1, Runx2 and c-myc were upregulated in Ad-hBMP-2/EGFP transfected BMSCs, while the level of GSK3beta was significantly decreased. Results also indicated that the overexpression of BMP-2 by Ad-hBMP 2/EGFP enhanced the osteogenic differentiation ability of cultured rabbit BMSCs via stimulating the Wnt signaling pathway with the accumulation of beta-catenin and suppression of GSK3beta. The Ad-hBMP-2/EGFP transfected rabbit BMSCs are expected to be a good seed cell in bone tissue engineering. PMID- 30402149 TI - Protective effect of dexpanthenol against cisplatin-induced hepatotoxicity. AB - The aim of the present study was to investigate the protective effect of dexpanthenol (Dexp) against cisplatin (Cis)-induced hepatotoxicity. Thirty-two Sprague Dawley rats were divided into four groups: Control group (n=8), Dexp group (n=8, 500 mg/kg/ip/daily single dose/3 days Dexp), Cis group (n=8, 7 mg/kg/ip/single dose Cis) and Cis+Dexp group (n=8, 500 mg/kg/ip/daily single dose/3 days Dexp +7 mg/kg/ip/single dose Cis). MDA, CAT, GSH, GSH-Px, TOS, TAS, OSI, Total Nitrit, IL-1beta, IL-6 and TNF-alpha levels were analyzed in liver tissue samples. After paraffinization of liver tissue samples, histopathological (congestion, loss of glycogen, number of Kupffer cells) and immunohistochemical (caspase-3 expression) parameters were assessed on the paraffinized liver sections. GSH, TAS, TOS, OSI, Tot Nit, L-Arginine, ADMA and SDMA levels were measured in the serum samples. Statistically significant differences were found between the groups in terms of all liver tissue biochemical parameters, with the exception of IL-1beta and TNF-alpha levels. GSH, CAT, GSH-Px, TAS and Tot Nit levels were significantly higher in the Cis+Dexp group compared to the Cis group, whereas MDA, TOS, OSI and IL-6 levels were higher in the Cis group. Similarly, serum GSH, TAS, Tot Nit levels were higher in the Cis+Dexp group whereas TOS, L Arginine, ADMA and SDMA levels were higher in Cis group. There were statistically significant differences between Control and Cis groups in terms of congestion increase, increase of glycogen loss, increase of Kupffer cell number and increase of caspase-3 expression (P<0.001). There was a statistically significant difference between the Cis and the Cis+Dexp groups in terms of histopathologic parameters, with the exception of congestion (P<0.001). To conclude, histopathological, immunohistochemical, and biochemical results of this study demonstrated that Dexp has a protective effect against Cis-induced hepatotoxicity. PMID- 30402150 TI - Intraoperative and postoperative infusion of dexmedetomidine combined with intravenous butorphanol patient-controlled analgesia following total hysterectomy under laparoscopy. AB - The present prospective, randomized, double-blinded, controlled study aimed to investigate the efficacy and safety of dexmedetomidine (DEX) combined with butorphanol for patient-controlled intravenous analgesia (PCIA) following total laparoscopic hysterectomy. A total of 88 patients undergoing total laparoscopic hysterectomy and receiving postoperative PCIA were divided into two groups following surgery. Patients received DEX 0.5 ug/kg intravenously in the DEX group or 0.9% normal saline in the control (CON) group following anesthesia induction. Postoperatively, the PCIA (10 mg butorphanol with 300 ug dexmedetomidine in the DEX group or without DEX in the CON group) was delivered as a 0.5 ml bolus (lockout interval of 15 min) with a continuous background infusion of 2 ml/h. Cardiovascular and respiratory variables, cumulative butorphanol consumption, pain scores, level of sedation, concerning adverse events and the degree of patient satisfaction were recorded for 24 h post-surgery. A total of 81 patients completed the study. Blood pressure and heart rate exhibited no significant difference between the two groups during surgery and for 24 h post-surgery. Compared with the CON group, patients in the DEX group required ~19% less butorphanol (P<0.05). During the first 24 h post-surgery, patients from the DEX group had a significantly lower visual analogue scale score at rest and movement states compared with the CON group (P<0.05). There was no significant difference in sedation score between the groups. The satisfaction scores were significantly higher in the DEX group compared with those in the CON group (P<0.05). Compared with the CON group, the DEX group exhibited a lower rate of postoperative nausea and vomiting (P<0.05). There was no occurrence of serious adverse events, including respiratory depression, hypotension, bradycardia and somnolence. In conclusion, following total laparoscopic hysterectomy, the loading dose of DEX (0.5 ug/kg) followed by a continuous infusion as an adjunct to butorphanol PCIA resulted in effective analgesia, significant butorphanol sparing and less butorphanol-induced nausea and vomiting without excessive sedation or adverse effects. The trial registration number was ChiCTR1800015675 at the Chinese Clinical Trial Registry (chictr.org.cn) and the date of registration was 4th April 2018. PMID- 30402151 TI - Expression of tissue factor in human cervical carcinoma tissue. AB - The present study aimed to investigate tissue factor (TF) expression in cervical cancer and explore its association with disease progression. A total of 258 cervical cancer tissues and their adjacent normal tissues were collected between September 2014 and September 2016. TF expression was detected in the tissue samples by immunohistochemistry and western blot analysis. Associations between the expression of TF and clinical stage, differentiation status and metastasis of cancer cells were examined. The mean immunohistochemistry score of TF expression in cervical cancer tissues was 2.86+/-1.76, which was significantly increased compared with the adjacent normal tissues (0.28+/-0.45). The expression of TF was also significantly associated with the clinical stage, lymph node metastasis and distant metastasis of cancer cells. Immunohistochemistry staining and western blot analysis demonstrated that TF expression in cervical cancer tissues significantly increased as the clinical stage increased. TF expression in tumor tissues from patients with lymph node metastasis was significantly increased compared with samples from patients without lymph node metastasis. TF expression was also significantly increased in patients with distant metastasis compared with those without. In conclusion, TF is highly expressed in cervical cancer tissues and high expression of TF may enhance the invasion and metastasis of cervical cancer cells. PMID- 30402152 TI - Calcimimetic R568 reduced the blood pressure and improved aortic remodeling in spontaneously hypertensive rats by inhibiting local renin-angiotensin system activity. AB - Hypertension is a cardiovascular disease that seriously affects human health. Activation of the calcium-sensing receptor (CaSR) inhibits cyclic adenosine monophosphate (cAMP) formation by increasing [Ca2+]i and subsequently inhibiting renin release. The renin-angiotensin system (RAS) plays an important role in the development of essential hypertension (EH). The purpose of this study was to determine the effects of NPSR568 (R568)-activated CaSR on blood pressure (BP), proliferation, and remodeling of vascular smooth muscle cells, and the activity of the RAS in spontaneously hypertensive rats (SHRs). In this study, we treated SHR and Wistar-Kyoto rats with R568 for 8 weeks. The tail-cuff method was used to assess rat BP weekly. Morphological changes in the thoracic aorta were evaluated with hematoxylin-eosin and Masson staining. Western blotting and immunohistochemistry were used to detect the expression of RAS-related proteins and proliferative remodeling proteins in the thoracic aorta. An enzyme-linked immunosorbent assay was used to detect the content of cAMP, the RAS, and the CaSR in plasma and the thoracic aorta. Finally, we found that treatment with R568 for 8 weeks reduced the BP and inhibited arterial vascular proliferation remodeling in SHRs. R568 administration significantly suppressed the activity of local RAS in the thoracic aortas of SHRs. Moreover, R568 treatment reversed the low expression of CaSR in SHRs. R568 may serve as an effective strategy against EH. PMID- 30402153 TI - Ginsenoside Rg1 attenuates liver injury induced by D-galactose in mice. AB - The present study investigated the effect and underlying mechanisms of ginsenoside Rg1 (Rg1) in attenuating subacute liver injury induced by D-galactose (D-gal) in mice. Specific Pathogen Free (SPF) male C57BL/6J mice were randomly divided into 3 groups: i) D-gal-administration group (D-gal group), where the mice were intraperitoneally administrated with D-gal (120 mg/kg/day for 42 days); ii) D-gal + Rg1 group where the mice were treated with 120 mg/kg/day D-gal for 42 days and with Rg1 at a dose of 20 mg/kg/day for 35 days. The first dose of Rg1 was administered on the 8th day of treatment with D-gal; and iii) the normal control group, where the mice were injected with an equal volume of saline for 42 days. The day following the final injections in all groups, peripheral blood was collected and serum was prepared to measure the contents of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBiL), advanced glycation end products (AGEs) and 8-hydroxy-2 deoxyguanosine (8-OH-dG). Liver tissue homogenates were prepared to measure the contents of malondialdehyde (MDA) and glutathione (GSH), and the activities of glutathione peroxidase (GSH Px) and superoxide dismutase (SOD). Paraffin section were prepared to observe the microscopic structure of the liver. Transmission electron microscopy was used to observe the ultrastructure of hepatocytes. Frozen section were prepared and stained with senescence-associated beta-galactosidase to detect the relative optical density value of senescence-associated markers. Compared with the D-gal group, the contents of AST, ALT, TBiL, AGEs and MDA significantly decreased in the D-gal + Rg1 group, while the activities of SOD and GSH-Px markedly increased, and liver injury and degenerative alterations of hepatocytes were reduced. Administration of Rg1 induced a protective effect on D-gal-induced liver injury in mice by inhibiting the oxidative stress, reducing DNA damage and decreasing the AGE content. PMID- 30402154 TI - Therapeutic effect of irbesartan combined with atorvastatin calcium in the treatment of rats with coronary heart disease. AB - This study aimed to investigate the therapeutic effect of irbesartan combined with atorvastatin calcium in the treatment of rats with coronary heart disease. One hundred sixty Wistar rats were selected to establish coronary heart disease model. Rats with coronary heart disease were randomly divided into 4 groups: Model, irbesartan, atorvastatin calcium and combination groups (irbesartan combined with atorvastatin calcium group). Rats in irbesartan group were treated with 50 mg/(kg.day) irbesartan; rats in atorvastatin calcium group were given atorvastatin calcium at a dose of 10 mg/(kg.day); rats in combination group were subjected to atorvastatin calcium at a dose of 10 mg/(kg.day) and irbesartan at a dose of 50 mg/(kg.day), while rats in model groups were given intragastric administration of normal saline at a dose of 2 ml/day. Serum lipids, including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and TC/HDL-C, were measured by automatic biochemical analyzer. Expression of sPLA2-V in myocardium and aortic trunk of rats was detected by reverse transcription-PCR (RT-PCR) and western blot analysis. After treatment, levels of serum TC, TG, LDL-C, HDL-C and TC/HDL-C in rats of each treatment group were better than those in model group (p<0.05). Expression level of sPLA2-V in myocardium and aortic trunk in model group was significantly higher than that in other groups (p<0.05). Expression level of sPLA2-V in combination group was significantly lower than that in irbesartan and atorvastatin calcium groups (p<0.05). Combination of irbesartan and atorvastatin calcium is superior to irbesartan or atorvastatin calcium alone in the treatment of rats with coronary heart disease. The possible explanation is that the two drugs can reduce the expression of sPLA2-V in myocardium and aortic trunk, which in turn relieved atherosclerosis and achieved better therapeutic effect. PMID- 30402155 TI - Comparison of the predictive value of four-dimensional speckle tracking imaging risk classification and the TIMI system after STEMI reperfusion therapy. AB - The predictive value of four-dimensional speckle tracking imaging (4D-STI) risk classification and TIMI risk scores for the prognosis of patients with ST-segment elevation myocardial infarction (STEMI) after reperfusion therapy were investigated. One hundred and twenty patients with STEMI after reperfusion therapy were involved. At 12 h after reperfusion therapy, 2nd and 3rd day, the three-dimensional longitudinal strain (LS), circumferential strain (CS) and radial strain (RS), area strain (AS), as well as other 4D-STI detection indicators, were collected. The patients were followed up for one year, and were divided into good prognosis group and poor prognosis group. LS, CS, RS and AS indicators were analyzed between these two groups. The ROC curve was drawn to establish the 4D-STI risk classification and its predictive value for poor prognosis and mortality were compared with TIMI risk scores. AS, LS and RS at 12 h after reperfusion treatment, and AS and RS at 2nd and 3rd day had a certain degree of prediction accuracy in STEMI patients in the poor prognosis group. In the 4D-STI and TIMI risk scores, the risk of death and adverse prognosis significantly increased as the risk scores increased (P<0.01). The 4D-STI risk score for predicting poor prognosis and mortality was greater than the TIMI risk score. 4D-STI risk scores are superior to TIMI risk scores in predicting poor prognosis and mortality in patients with STEMI after reperfusion therapy. PMID- 30402156 TI - Outcomes of endovascular interventional therapy for primary Budd-Chiari syndrome caused by hepatic venous obstruction. AB - To date, interventional therapy for patients with Budd-Chiari syndrome (BCS) due to hepatic vein obstruction (HVO) has not been standardized in China. In Western countries, BCS primarily occurs due to thrombosis and the majority of patients receive thrombolysis. In China, BCS is mostly caused by the membranous occlusion of the HV or IVC. The present retrospective study evaluated the efficacy of recanalization techniques in patients with primary BCS due to HVO. The data of 69 patients with BCS due to HVO, who underwent endovascular therapy at 2 centers in China between December 2010 and December 2012, were analyzed. All of the patients underwent balloon angioplasty. In addition, 14, 6 and 5 patients received thrombolysis, endovascular stent and thrombolysis + endovascular stent, respectively. The overall technical success rate was 95.7% (66/69), and was comparable among the treatments. The HV pressure after the treatments was significantly lower compared with that prior to the procedures (23.3+/-6.9 vs. 46.5+/-8.6 cmH2O; P<0.001). The mean follow-up duration was 75 months (range, 60 84 months). During the 5-year follow-up, 10 patients (15.2%) had developed a recurrence of BCS-associated symptoms, of which 7 were successfully treated. The cumulative survival rates at 12, 36 and 60 months after endovascular interventional therapy (balloon angioplasty or combined treatment) were 98.5, 98.5 and 93.9%, respectively. After treatment by endovascular therapy, the patients with BCS caused by HVO had high survival rates and low recurrence rates in the short- and mid-term. PMID- 30402157 TI - Correlation of vascular endothelial function and coagulation factors with renal function and inflammatory factors in patients with diabetic nephropathy. AB - Correlation of vascular endothelial function and coagulation factors with renal function and inflammatory factors in patients with diabetic nephropathy was analyzed. A total of 86 patients diagnosed with diabetes mellitus (DM) and admitted to the 89th Hospital of the People's Liberation Army (Weifang, China) from March 2014 to May 2017 were selected. Among them, 38 patients complicated with nephropathy were divided into the observation group and 48 patients without nephropathy into the control group. The general data of patients were collected, and the relevant biochemical indexes, vascular endothelial function, coagulation factors and renal function indicators and the levels of inflammatory factors were determined. In the observation group, the duration of DM was longer than that in the control group, and the levels of glycated hemoglobin (HbA1c), fasting plasma glucose (FPG) and fasting insulin (FINS), level of fibrinogen (FIB) were higher than those in the control group (p<0.05). Homocysteine (Hcy) and brachial artery blood flow in the observation group were higher than those in the control group. The levels of nitric oxide (NO) and flow-mediated dilation (FMD) were lower than those in the control group (p<0.05). Activated partial thromboplastin time (APTT) in the observation group was shorter than that in the control group (p<0.05). The levels of cystatin-C (Cys-C), serum creatinine (SCr), urea and beta2 microglobulin, levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in peripheral serum in the observation group were greatly higher than those in the control group (p<0.05). It was concluded via the correlation analysis of vascular endothelial function and coagulation factor with renal function and inflammatory factors that SCr and CRP were negatively correlated with NO, and SCr and CRP were positively correlated with FIB. Serum inflammatory factors, coagulation function and vascular endothelial function are closely related to diabetic nephropathy, which are good reference indexes for the assessment of diabetic nephropathy. PMID- 30402158 TI - Human nasopharyngeal carcinoma can be radiosensitized by trichosanthin via inhibition of the PI3K pathway. AB - Nasopharyngeal carcinoma (NPC) is a prevalent tumor that affects the head and neck. Radiation therapy is typically used to treat NPC; however, poor prognoses and distant metastases are common due to radiation resistance. The antitumor activities of trichosanthin (TCS) have been reported in several types of tumors. The aim of the present study was to investigate whether TCS may serve as a potential radiosensitizer in the treatment of NPC tumors. In the present study, NPC cells were treated with radiation alone or together with TCS and radiosensitivity was compared. Clonogenic assay, flow cytometry and an animal study were performed to assess cell death in NPC. The clonogenic assay demonstrated that TCS had a significant radiosensitizing effect on NPC cells. Western blotting indicated that phosphorylated protein kinase B and signal regulated kinase [phosphoinositide 3-kinase (PI3K) pathway] were downregulated, and that cleaved caspase-3 was upregulated by combined treatment with TCS and radiation. Furthermore, TCS potently radiosensitized NPC xenografts in vivo. In conclusion, TCS radiosensitized NPC in vitro and in vivo via downregulation of PI3K pathways and the upregulation of cleaved caspase-3. PMID- 30402159 TI - IMB-6G induces endoplasmic reticulum stress-mediated apoptosis in human nasopharyngeal carcinoma cells. AB - IMB-6G is a novel N-substituted sophoridine acid that has been reported to have anticancer effects. The purpose of the present study was to investigate the effect and underlying mechanism of IMB-6G on human nasopharyngeal carcinoma (NPC) cells. The NPC cell line C666-1 was used in the present study and treated with different concentrations of IMB-6G (0, 1, 2 and 5 uM) for 24 h. Subsequently, cell viability was determined using the Cell Counting kit-8 assay and cell apoptosis was analyzed by performing flow cytometry. The expression levels of genes and proteins in the current study were determined using reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. Results indicated that IMB-6G dose-dependently inhibited C666-1 cell viability and induced apoptosis. It was also revealed that IMB-6G induced apoptosis via inducing endoplasmic reticulum (ER) stress activation. Notably, IMB 6G administration enhanced the expression levels of Binding immunoglobulin protein and CCAAT-enhancer-binding protein homologous protein in C666-1 cells. Further analysis suggested that IMB-6G treatment activated inositol-requiring enzyme 1alpha (IRE1alpha) and PKR-like ER kinase (PERK) signaling pathways in C666-1 cells. In addition, silencing of IRE1alpha and PERK significantly reversed IMB-6G-induced cell growth inhibition and apoptosis. In conclusion, the present findings indicated that IMB-6G induced ER stress-mediated apoptosis through activating IRE1alpha and PERK signaling pathways. The present study suggests that IMB-6G may be a promising agent for NPC treatment. PMID- 30402160 TI - Distinguishing the dominant species of pathogen in ethmoidal sinusitis by sequencing DNA dataset analysis. AB - Identifying the predominant microbial species in patients with ethmoidal sinusitis is conducive to its successful treatment. The aim of the present study was to determine the microbial composition and the predominant fungal and bacterial species in patients with ethmoidal sinusitis. A sample was obtained from 3 patients with ethmoidal sinusitis and from the ethmoid sinus of 2 healthy volunteers. Those samples were sequenced using an Illumina/Solexa sequencing platform for mapping to human, fungal, and bacterial genomes. Fungal and bacterial expressions in those samples were analyzed through bioinformatics and statistical methods. The sequencing data revealed that the dominant fungal strains in the ethmoidal sinusitis samples compared with the healthy controls (8_S33 and 10_S9) were Aspergillus oryzae and Aspergillus flavus, and the dominant bacterial strains were Haemophilus influenzae and Haemophilus parainfluenzae. Together, these findings indicate that the development of ethmoidal sinusitis is associated with the presence of fungi and bacteria, which may benefit the successful diagnosis and treatment for patients with ethmoidal sinusitis. PMID- 30402161 TI - miR-365b-3p inhibits the cell proliferation and migration of human coronary artery smooth muscle cells by directly targeting ADAMTS1 in coronary atherosclerosis. AB - Abnormal proliferation and migration of vascular smooth muscle cells serves a crucial role in the development of atherosclerosis. Previous studies have suggested that some microRNAs (miRs) are involved in this process; however, the associated underlying molecular mechanism is unclear. In present study, human coronary artery smooth muscle cells (HCASMCs) were used to explore the function of miR-365b-3p in the coronary atherosclerosis. It was indicated that platelet derived growth factor-BB (PDGF-BB) treatment inhibited miR-365b-3p expression and upregulated the expression of a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1) in HCASMCs. Subsequently, miR-365b-3p mimic was transfected in HCASMCs to explore the function of this miR. The results of reverse transcription-quantitative polymerase chain reaction and western blot analysis indicated that overexpression of miR-365b-3p significantly downregulated ADAMTS1 expression. Functional assay results revealed that overexpression of miR 365b-3p significantly attenuated PDGF-BB-induced proliferation and migration of HCASMCs. Furthermore, the dual-luciferase reporter assay results confirmed that ADAMTS1 is a direct target gene of miR-365b-3p. This discovery proposed a novel channel of communication between ADAMTS1 and HCASMCs, and suggests a potential therapeutic approach for coronary atherosclerosis. PMID- 30402162 TI - Down-regulated G protein-coupled receptor kinase 6 leads to apoptosis in multiple myeloma MM1R cells. AB - G protein-coupled receptor kinase 6 (GRK6) is highly expressed in multiple myeloma (MM) cell lines, but absent or only weakly expressed in most primary human somatic cells. In the present study, GRK6 expression was assessed in MM patients and healthy individuals by quantitative polymerase chain reaction. Flow cytometry were performed to measure the apoptosis of lentivial-transfected MM1R cells. Western blot analysis was performed to assess the apoptosis and signal transducer and activator of transcription 3 pathway-related factors. The results demonstrated that GRK6 was differentially expressed in individuals who suffered from MM and healthy individuals. Previous studies have shown that downregulating GRK6 has anti-cancer effects in the MM cell line, MM1R. The present study demonstrated that RNA interference-mediated GRK6 knockdown promoted apoptosis in the MM1R cell line. Therefore, we hypothesized that GRK6 plays a significant role in determining the course of MM. PMID- 30402163 TI - Electrocardiography-gated dual-source computed tomography in the detection of atrial septal aneurysm. AB - The aim of the current study was to investigate the atrial septal aneurysm (ASA) incidence rate and describe its morphologic features by dual-source computed tomography (DSCT). A total of 8,626 patients (4,284 men and 4,342 women) who underwent DSCT examinations were enrolled. The presence of ASA was defined as the protrusion of the complete or partial interatrial septum with a maximum vertical distance (MVD) from the atrial septum plane of >10 mm during a cardiac cycle and a diameter of the aneurysm base of >15 mm. The MVD and direction of the protrusion, as well as other abnormalities, were recorded. The ASA patients were classified by both gender and directions of protrusion into four groups, including the right atrium (RA) and left atrium (LA) groups in males and females, respectively. Values across groups were compared using the independent-sample t test and differences in qualitative variables were assessed with the chi2 test. Of the 8,626 patients, 51 (0.6%) were diagnosed with ASA (mean age, 62+/-10 years), including 23 (0.5%) males and 28 (0.6%) females. There were no significant differences in the age (t=-1.37, P>0.05) and incidence rate (chi2=0.43, P>0.05) between the male and female groups. However, there were significant differences in the mean ages (t=-2.20, P<0.05) and the gender proportions (chi2=7.39, P<0.05) of patients in the RA and LA groups. In the two male groups, no significant differences were observed in the diameters of the ASA bases and MVD in the RA and LA groups. In the female groups, the differences in the MVD of protrusion in RA and LA groups were non-significant, whereas the diameters of the base of ASA demonstrated significant differences (t=2.27, P<0.05). In conclusion, the ASA incidence rate was 0.6%, and electrocardiography gated DSCT scan served as an alternative diagnostic technique for the detection of ASA. It is essential for radiologists to recognize this clinical entity and to minimize misdiagnoses and missed diagnoses. PMID- 30402164 TI - Optimal sampling time-point for cyclosporin A concentration monitoring in heart transplant recipients. AB - The present study was performed to determine an optimal time-point for monitoring the concentration of the immunosuppressive drug cyclosporin A (CsA) in heart transplant patients and its efficacy in the prevention of transplant rejection. A total of 32 transplant recipients were randomly assigned for three treatment approaches. Recipients in groups A (n=11), B (n=13) and C (n=8) received oral administration of CsA at doses of 3.2, 3.5 and 4.4 mg/kg, respectively. The plasma CsA concentrations were examined at 2 h intervals over 12 h. Furthermore, their correlation with the 4 h pharmacokinetic profiles as the area under the plasma CsA concentration vs. time curve (AUC0-4 h) were calculated The efficacy of CsA in inhibiting cardiac allograft rejection was assessed at 2 h after oral CsA intake (C2) and adverse events of the drug were examined in the C2-monitored recipients. The plasma CsA concentration rapidly increased in most recipients with a peak level detected at ~2 h after dosing. Regression analysis revealed that among all time-points assessed, the CsA had the highest correlation with the AUC0-4 h at C2. At C2, increasing CsA doses exhibited a positive association with the measure of AUC0-4 h. The efficacy of increasing CsA target levels at C2 in preventing heart transplant rejection was comparable, as the survival rate was 100% in all of the treatment groups. However, the proportion of recipients with side effects in group A was obviously lower than that in the other two groups. In conclusion, C2 is an ideal time-point for monitoring plasma CsA levels with a utility for individualising the next scheduled dose for each patient to ensure that target levels are maintained and achieve a high efficacy and safety of CsA therapy in heart transplant recipients (clinical trial no. 12002610). PMID- 30402165 TI - Anti-inflammatory effect of Resolvin D1 on LPS-treated MG-63 cells. AB - Inflammation reaction plays an important role in the pathogenesis of ankle fracture. The aim of the present study was to investigate the effect of RvD1 on the inflammatory response and underlying molecular mechanisms in MG-63 cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and ELISA were used to determine the mRNA and protein expression of cytokines extracted from peripheral blood in children with or without ankle fracture, respectively. MG-63 cells were pre-treated with/without RvD1 and stimulated with 1 ug/ml LPS. The cell viability was detected by MTT assay. The production of cytokines from MG 63 cells was assessed by RT-qPCR and western blot, respectively. The expression of p-p38, NF-kappaB (p50) and cyclooxygenase-2 (COX-2) mRNA and protein were detected by western blot and/or RT-qPCR. The levels of NLRP3, associated recruitment domain (ASC), cleaved caspase1, caspase-1 were measured by RT-qPCR and/or western blot. The levels of interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF-alpha) mRNA and protein were up-regulated in children with ankle fracture compared with healthy children. RvD1 treatment did not induce cytotoxicity in MG-63 cells, but it can inhibit LPS induced MG-63 cell proliferation inhibition. RvD1 was able to dose-dependently reverse LPS induced up-regulation of TNF-alpha, IL-1beta, IL-6 mRNA and protein expression. Furthermore, the LPS induced up-regulation of p-p38, NF-kappaB (p50), and NLRP3, ASC, cleaved caspase-1/caspase-1, and COX-2 was dose-dependently reversed by RvD1. In conclusion, The present study demonstrated that RvD1 inhibited inflammation though inhibiting MAPKp38/NF-kappaB pathway and NLRP3 inflammasome expression in MG-63 cells, indicating that it may be an effective drug for the treatment of ankle fracture. PMID- 30402167 TI - Cognitive-Enhancing Effect of a Hydroethanolic Extract of Crinum macowanii against Memory Impairment Induced by Aluminum Chloride in BALB/c Mice. AB - Crinum macowanii is a bulbous plant indigenous to many parts of Southern Africa. Extracts of C. macowanii have gained interest since the discovery of various alkaloids, few of which possess acetylcholinesterase inhibitory activity. The present study was performed to evaluate the effect of a crude hydroethanolic extract of C. macowanii against aluminum chloride-induced memory impairment in mice using the Morris water maze and the novel object recognition task. C. macowanii (10, 20, and 40 mg/kg p.o) was administered daily for five weeks, while donepezil (3 mg/kg p.o) was used as the positive control. C. macowanii at a dosage of 40 mg/kg showed a significantly lower escape latency than the negative control (P < 0.0001) and was found to be comparable to donepezil 3 mg/kg in the Morris water maze test. C. macowanii at 40 mg/kg exhibited a significantly higher discrimination index than aluminum chloride-treated mice in the novel object recognition task. The results may support the usefulness of C. macowanii in the management of dementia and related illnesses. PMID- 30402166 TI - Stroke Survivor and Caregiver Perspectives on Post-Stroke Visual Concerns and Long-Term Consequences. AB - Approximately 800,000 people in the United States have a stroke annually. Up to two thirds of stroke survivors have some visual problems, which result in disability and can affect survivors' overall rehabilitation outcomes. Although some post-stroke visual impairments can be corrected and respond well to intervention, ocular signs can be subtle and may not be recognized or reported by the stroke survivor but rather by a vigilant caregiver. The purpose of this study was to explore the post-stroke visual concerns and consequences expressed by stroke survivors and caregivers. This study employed a qualitative design using semistructured interviews conducted with a convenience sample of stroke survivors and caregivers recruited from either a community support group or skilled nursing and long-term care facilities. Interviews were recorded and transcribed verbatim. Comparative content analysis was used to identify vision-related themes by two independent coders. All research team members completed quality checking of coding. Twenty participants (11 stroke survivors and 9 caregivers) expressed visual concerns or consequences following stroke: (1) eye movement problems, (2) perceptual issues, and (3) consequences of vision problems or issues, which affected their daily life/quality of life. Stroke survivors and caregivers reported receiving vision care from (1) eye doctors, (2) occupational therapists, and (3) other healthcare professionals. All vision care providers need to be observant of potential post-stroke visual concerns. Stroke survivors should have a thorough vision evaluation to optimize their independence in everyday activities and quality of life. PMID- 30402169 TI - Adipokines as Biomarkers in Health and Disease. PMID- 30402168 TI - Predictive Role of Urinary Metabolic Profile for Abnormal MRI Score in Preterm Neonates. AB - Background and Objective: Early identification of neonates at risk for brain injury is important to start appropriate intervention. Urinary metabolomics is a source of potential, noninvasive biomarkers of brain disease. We studied the urinary metabolic profile at 2 and 10 days in preterm neonates with normal/mild and moderate/severe MRI abnormalities at term equivalent age. Methods: Urine samples were collected at two and 10 days after birth in 30 extremely preterm infants and analyzed using proton magnetic resonance spectroscopy. A 3 T MRI was performed at term equivalent age, and images were scored for white matter (WM), cortical grey matter (cGM), deep GM, and cerebellar abnormalities. Infants were divided in two groups: normal/mild and moderately/severely abnormal MRI scores. Results: No significant clustering was seen between normal/mild and moderate/severe MRI scores for all regions at both time points. The ROC curves distinguished neonates at 2 and 10 days who later developed a markedly less mature cGM score from the others (2 d: area under the curve (AUC) = 0.72, specificity (SP) = 65%, sensitivity (SE) = 75% and 10 d: AUC = 0.80, SP = 78%, SE = 80%) and a moderately to severely abnormal WM score (2 d: AUC = 0.71, specificity (SP) = 80%, sensitivity (SE) = 72% and 10 d: AUC = 0.69, SP = 64%, SE = 89%). Conclusions: Early urinary spectra of preterm infants were able to discriminate metabolic profiles in patients with moderately/severely abnormal cGM and WM scores at term equivalent age. Urine spectra are promising for early identification of neonates at risk of brain damage and allow understanding of the pathogenesis of altered brain development. PMID- 30402170 TI - Evaluation of Serum Des-Gamma-Carboxy Prothrombin for the Diagnosis of Hepatitis B Virus-Related Hepatocellular Carcinoma: A Meta-Analysis. AB - Aim: To explore the diagnostic efficacy of des-gamma-carboxy prothrombin (DCP) in hepatitis B virus- (HBV-) related hepatocellular carcinoma (HCC). Methods: A retrospective study of 459 cases from June 2016 to March 2018 was undertaken, and records of the DCP levels were extracted. The sensitivity, specificity, and cutoff points were calculated using SPSS 17.0 software. A systematic search in PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials was performed for articles published in English from 1997 to 2017, focusing on serum DCP for HBV-related HCC. Data on sensitivity, specificity, the positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were extracted from five studies by systematic search and one study of our own. The summary receiver operating characteristic (sROC) curve was obtained, and the area under the receiver operating characteristic (AUROC) curve was calculated. Results: The pooled sensitivity, specificity, PLR, NLR, and DOR were 0.71 (95% CI: 0.59, 0.80), 0.93 (95% CI: 0.87, 0.96), 9.5 (95% CI: 5.2, 17.5), 0.32 (95% CI: 0.22, 0.46), and 30 (95% CI: 13, 72), respectively. The AUROC curve was 0.91 (95% CI: 0.88, 0.93). Conclusions: In the diagnosis of HBV related hepatocellular carcinoma (HCC), DCP is an ideal marker that should be considered for surveillance purposes. PMID- 30402171 TI - Association between Serum Copeptin and Stroke in Rural Areas of Northern China: A Matched Case-Control Study. AB - Background: Copeptin has been implicated as an effective prognostic biomarker of stroke outcome; however, few studies have investigated whether copeptin could be used as an etiological factor for stroke or not. The aim of our study was to evaluate the association of serum copeptin with stroke. Methods: In total, 238 participants including 119 cases (87 ischemic stroke and 32 hemorrhagic stroke) and 119 controls were included in this 1 : 1 matched case-control study. Conditional multivariate logistic regression was conducted to assess the Odds Ratios (ORs) and 95% confidence intervals (CI); restricted cubic spline in logistic regression model was used to evaluate the dose-response association between serum copeptin and total stroke, ischemic stroke, and hemorrhagic stroke. Results: The median serum copeptin was 20.90 pmol/L, 20.90 pmol/L, 6.53 pmol/L, and 8.42 pmol/L for total stroke, ischemic stroke, hemorrhagic stroke, and healthy subjects, respectively. The corresponding ORs (95% CIs) for the highest compared with the lowest quartile were 1.23 (0.62-2.44) for total stroke, 4.01 (1.47-10.96) for ischemic stroke, and 0.13 (0.22-0.69) for hemorrhagic stroke. No nonlinear dose-response relationship was found between serum copeptin and total stroke (P nonlinear = 0.278), ischemic stroke (P nonlinear = 0.362), and hemorrhagic stroke (P nonlinear = 0.314). Compared with the reference copeptin level, a significantly increasing trend was found between serum copeptin and ischemic stroke (P overall = 0.002), and a decreasing trend was found between serum copeptin and hemorrhagic stroke (P overall = 0.007). Conclusions: Elevated serum copeptin levels were positively associated with ischemic stroke and adversely associated with hemorrhagic stroke. Additional prospective studies with larger sample size are needed to confirm the present findings. PMID- 30402172 TI - Role of Hyperglycemia-Induced Advanced Glycation End Product (AGE) Accumulation in Atherosclerosis. AB - There is a growing body of evidence that cumulative hyperglycemic exposure plays a central role in the development and progression of atherosclerotic cardiovascular disease in diabetic patients. Monosaccharides, such as glucose, fructose, and glyceraldehyde can react non-enzymatically with amino groups of proteins, lipids, nucleic acids to form senescent macromolecules termed advanced glycation end products (AGEs), whose formation and accumulation has been known to progress in diabetic patients, especially in those with a long history of disease. The sustained accumulation of AGEs could contribute to the phenomenon of metabolic memory or legacy effects observed in long-term follow-up clinical studies of diabetic patients. AGE modification alters the structural integrity and function of various types of macromolecules, and interaction of AGEs with a receptor for AGEs (RAGE) has been shown to evoke inflammatory and thrombotic reactions. Therefore, the AGE-RAGE axis is a novel therapeutic target of atherosclerotic cardiovascular disease in diabetic patients. In this paper, we briefly review the pathological role of AGEs and their receptor RAGE system in atherosclerotic cardiovascular disease, including peripheral artery disease and discuss the clinical utility of measuring AGEs in evaluating the severity of atherosclerosis in patients with diabetes. PMID- 30402173 TI - Effectiveness of Embolization of Inferior Mesenteric Artery to Prevent Type II Endoleak Following Endovascular Aneurysm Repair: A Review of the Literature. AB - Type II endoleak is a common complication that develops after endovascular aneurysm repair. Patients with type II endoleak, which has persisted for 6 months, have a significantly higher rate of aneurysmal sac enlargement, reintervention, and rupture. To date, several studies have examined the effectiveness of preoperative embolization of branch vessels for the prevention of type II endoleak. Particularly, the embolization of the large inferior mesenteric artery (IMA) seems to be a precise, safe, and effective method. IMA is a significant risk factor for type II endoleak. However, there is currently no strong evidence to prove which patients would benefit from preventive IMA embolization. In addition, considering the incidence of type II endoleak and the adverse event rate, routine embolization seems to be unreliable and time consuming. Moreover, previous reports of preoperative IMA embolization were retrospective. Thus, prospective and randomized studies are necessary so that the usefulness of IMA embolization can be proved and the potential benefits can be assessed. To establish preventive IMA embolization as one of the effective therapeutic strategies to prevent type II endoleak and to maximize its therapeutic effect, we should provide a wide range of therapeutic strategies to suit the state of the patient. PMID- 30402175 TI - Countermeasures against Infection in Critical Limb Ischemia Treatments. AB - The preoperative and postoperative infection control measures for critical limb ischemia treatments were described. The treatment strategies for severe ischemic limbs were showed according to the presence and extent of infection. If the treatment strategy for a severe ischemic limb with infection is mistaken, infection will spread and make worse the situation of the ischemic limb, and eventually it can result not only in limb loss but also life threatening. A surgical strategy is very important in the bypass material, the selection of anastomotic site, the use of postoperative antibacterial drugs, and the wound treatment. Infection troubles are the most familiar and indispensable problem for surgeons, the countermeasures against infection especially in critical limb ischemia is the key point along with revascularization. (This is a translation of Jpn J Vasc Surg 2018; 27: 129-132.). PMID- 30402174 TI - Pulmonary Embolism: Contemporary Medical Management and Future Perspectives. AB - Pulmonary embolism (PE) contributes substantially to the global disease burden. A key determinant of early adverse outcomes is the presence (and severity) of right ventricular dysfunction. Consequently, risk-adapted management strategies continue to evolve, tailoring acute treatment to the patients' clinical presentation, hemodynamic status, imaging and biochemical markers, and comorbidity. For subjects with hemodynamic instability or 'high-risk' PE, immediate systemic reperfusion treatment with intravenous thrombolysis is indicated; emerging approaches such as catheter-directed pharmacomechanical reperfusion might help to minimize the bleeding risk. Currently, direct, non vitamin K-dependent oral anticoagulants are the mainstay of treatment for acute PE. They have been shown to simplify initial and extended anticoagulation regimens while reducing the bleeding risk compared to vitamin K antagonists. (This is a review article based on the invited lecture of the 37th Annual Meeting of Japanese Society of Phlebology.). PMID- 30402176 TI - Prevalence and Characteristic Features of Deep Venous Thrombosis in Patients with Severe Motor and Intellectual Disabilities. AB - Sudden death associated with patients with severe motor and intellectual disabilities (SMID) have been thought to be caused in part by venous thromboembolism (VTE), but actual situation of VTE in SMID is not clear. We examined the prevalence and location of deep venous thrombosis (DVT), and the relation of the development of crural veins in 16 patients with SMID, using ultrasonography. The maximum diameter of soleal vein was 1.6+/-0.5 mm. In most cases, DVT was found in the femoral veins. We could not detect thrombus in the soleal veins. In the present study, the detection ratio of DVT was high in patients with SMID who had restricted mobility capability and were bedridden, and we found the veins centrally from popliteal veins in DVT in SMID, not soleal veins, as the initial sites of the DVT. In the literature, the mean diameter of soleal veins, in healthy adults is 6.7+/-1.8 mm, that in contrast in SMID being smaller. Underdevelopment of intramuscular veins is possibly related to the mechanism of DVT in SMID. In the current guidelines for the management of VTE, there is limited in scope of ambulatory adults and no application cases who exhibit to SMID restricted mobility of the lower extremities and are bedridden associated with cerebral palsy and developmental motor disabilities, and such patients have associated high risk of the complications of DVT. According to our present study, it is necessary to provide appropriate guidelines for DVT in SMID considering characteristic features. (This is a translation of Jpn J Phlebol 2017; 28: 29-34.). PMID- 30402177 TI - New Method of Flush Saphenofemoral Ligation that is Expected to Inhibit Varicose Vein Recurrence in the Groin: Flush Ligation Using the Avulsion Technique Method. AB - : Recently, with the spread of laser ablation therapy, it has been called into question whether flush ligation of the great saphenous vein (GSV) reduces varicose vein recurrence after surgery. Because we thought such recurrence was caused by a narrow branch resection area, we developed a new method of flush ligation (the avulsion technique method). MATERIALS AND METHODS: A total of 214 limbs in 180 patients whose GSV had become varicose were studied. In our procedure, we dissect the GSV, lift its proximal stump, and expose the tributaries. We pull out the distal side of the tributaries without ligature as far as possible. We evaluate the area of subcutaneous ecchymosis within a 15-cm radius of the inguinal incision visually on the third post-operative day. RESULTS: We were able to pull out over 10 cm per branch by this method. The area of subcutaneous ecchymosis was mostly less than 10%. No hematoma or pain was observed after the operation. CONCLUSION: This method was safe, with subcutaneous ecchymosis occurring only rarely. We expect this method to reduce saphenofemoral junction recurrence after the operation. (This is a translation of Jpn J Phlebol 2017; 28: 11-16.). PMID- 30402178 TI - Outcomes of Central Venoplasty in Haemodialysis Patients. AB - Objective: To review the outcomes of central venoplasty in the treatment of symptomatic central vein stenosis in patients undergoing haemodialysis via an ipsilateral arteriovenous fistula (AVF). Methods: Data were collected retrospectively, and included all the consecutive cases of central venoplasty between January 2008 and December 2015. Results: A total of 132 central venoplasties in 76 patients were performed, with incidence of symptomatic central vein stenosis at 7.4%. Of the patients, 66% were male and the mean age was 61 years. The most frequent indication was decreased dialysis access flow rates (58%) and 52% of all the patients had symptoms of upper limb swelling. The patients who had previous ipsilateral tunneled internal jugular vein dialysis catheters made up 58% of the patients. The mean time from AVF creation to first central venoplasty was 24 months, and 74% of the cases required a second central venoplasty and the mean time to second venoplasty was 7 months. The overall post intervention assisted primary patency rate was 87%, 74%, 63%, and 42% at 6, 12, 18, and 24 months respectively. Statistically significant differences were found in primary assisted patency (p=0.025) and time to second procedure (p=0.039) comparing those with and without a history of ipsilateral tunneled dialysis catheter. Conclusion: Central venoplasty is technically feasible with low procedural risk. The maintenance of the AVF patency usually requires multiple procedures at average interval of 7 months. Patients with a history of upper limb tunneled dialysis catheter ipsilateral to the side of central vein stenosis or AVF have a less favorable outcome compared to those without. PMID- 30402179 TI - Predictors of Acute Kidney Injury Following Elective Open and Endovascular Aortic Repair for Abdominal Aortic Aneurysm. AB - Objective: To investigate the predictors of acute kidney injury (AKI) following surgery for abdominal aortic aneurysm. Materials and Methods: Subjects were 642 non-hemodialysis patients (open aortic repair [OAR] group, n=453; endovascular aortic repair [EVAR] group, n=189) who underwent elective surgery between 2009 and 2015. AKI was assessed according to the Kidney Disease Improving Global Outcomes criteria. In-hospital mortality and incidence of AKI were compared between the OAR and EVAR groups. The effect of AKI on outcomes and predictors of AKI were examined in both groups. Results: In-hospital mortalities were 0.7% (3/453) in the OAR group and 0.5% (1/189) in the EVAR group. The incidence of AKI increased in the OAR group (14.1% vs. 3.7%, P<0.01). In the OAR group, in hospital mortality (0% vs. 4.7%, P<0.01) increased in patients with AKI. In the OAR group, hemoglobin level <10 g/dL, estimated glomerular filtration rate <60 mL/min/1.73 m2, operation time >300 min, history of ischemic heart disease, and amount of bleeding >1,000 mL were predictors of AKI. In the EVAR group, amount of transfusion>1,000 mL was a predictor of AKI, but AKI was not found to worsen outcomes. Conclusion: AKI affected outcomes of OAR. Knowledge of predictors may optimize perioperative care. PMID- 30402180 TI - Long-Term Results of Femorotibial Polytetrafluoroethylene Bypass with a Distal Vein Cuff for Critical Limb Ischemia. AB - Objective: Although autologous veins are the first-choice conduit for femorotibial artery bypass, if there are no appropriate autologous veins, we perform femorotibial artery bypass using polytetrafluoroethylene (PTFE) with a distal vein cuff for patients with critical limb ischemia (CLI). This study examined the long-term outcomes of femorotibial artery bypass using PTFE with a Miller's cuff. Materials and Methods: Using prospectively collected data for 444 distal bypasses, a retrospective analysis was conducted for 32 femorotibial PTFE bypasses with a Miller's cuff (PTFE-Miller's cuff) performed for patients with CLI from April 1994 to December 2016. Results: Primary and secondary patency rates of PTFE-Miller's cuff at 3 years were 35.8% and 51.2%, respectively. Limb salvage rate of PTFE-Miller's cuff at 3 years was 71.0%. Conclusion: Although the patency rate was low and failed to yield satisfactory results, the limb salvage rate remained relatively high. Femorotibial PTFE bypass with a Miller's cuff was a useful technique of limb salvage for patients with CLI in whom an appropriate autologous vein could not be used. PMID- 30402181 TI - Evaluation, Surgical Management and Outcome of Traumatic Extremity Vascular Injuries: A 5-year Level-1 Trauma Centres Experience. AB - Objective: We aim to share our experience regarding the surgical management and outcome of extremity vascular trauma in level-1 trauma centres in Pakistan. Patients and methods: All consecutive patients with traumatic extremity vascular injury (TEVI) fulfilling the inclusion criteria; between June 2012 and June 2017 were included. The demographics, clinical presentation, management, and outcome measures were recorded. Results: The study included 81 patients. The mean age+/ standard deviation was 28.6+/-14.5 years and 81.5% (n=66) of the patients were males. Blunt TEVI was found in 65.4% (n=53) of the cases. Partial laceration was the most common type of arterial injury (64.2%, n=52) and autologous interposition venous grafting was the most common repair performed (60.5%, n=49). Fasciotomy was performed in 67.9% (n=55) of the patients. The limb salvage rate was 82.7%. The amputation rate was higher in the blunt trauma group when compared with that of the penetrating trauma group. The length of the intensive care unit stay and the use of polytetrafluoroethylene as interposition graft were two independent predictors of limb loss. The mortality rate in this series was 8.6%. Conclusion: Blunt TEVI is associated with higher morbidity and limb loss. The use of synthetic graft should be discouraged. The liberal use of autologous interposition venous graft and the judicious use of fasciotomies are helpful to achieve favorable outcomes. PMID- 30402182 TI - Review of Patency Rates between One-Stage and Two-Stage Brachial-Basilic Transposition Arteriovenous Fistulae Creation in an Asian Population. AB - Objective: To compare patency rates between one- and two-stage (first-stage arteriovenous anastomosis followed by second-stage superficialization) creation of brachial-basilic transposition arteriovenous fistula (BBT-AVF) in an Asian population. Methods: A retrospective review of BBT-AVFs was conducted between July 2008 and March 2015. Kaplan-Meier survival analysis and log-rank test were used to evaluate patency. Results: In total, 103 BBT-AVFs were created in 86 patients (mean age, 61 years; men, 57%). The overall primary, assisted primary, and secondary patency rates at 12, 24, 36, and 48 months were 70%, 48%, 38%, and 35%; 86%, 70%, 62%, and 59%; and 90%, 77%, 70%, and 63%, respectively. There was no significant difference in demographics and preoperative vessel caliber between the groups. The primary failure rate was 24% in the one-stage group, compared with 21% in the two-stage group (p=0.803). There were no statistically significant differences in primary, assisted primary, and secondary patency rates between the groups. Conclusion: There was no significant difference in primary failure and patency rates between the two groups. Both one-stage and two-stage procedures conferred good outcomes with overall 12-month primary patency, secondary patency, and primary failure rates of 70%, 90%, and 23%, respectively. PMID- 30402183 TI - Nitinol Self-Expanding Stents for the Treatment of Obstructive Superficial Femoral Artery Disease: Three-Year Results of the RELIABLE Japanese Multicenter Study. AB - Objective: To assess the use of a nitinol stent to treat symptomatic stenoses or occlusions of the native superficial femoral artery (SFA). Materials and Methods: Seventy-four patients were treated at 12 Japanese sites. The primary endpoint, freedom from target-limb failure (TLF), was a composite of device- or procedure related death, target-limb amputation, target-vessel revascularization (TVR), or restenosis compared to an objective performance goal (OPG) at 12 months. Secondary endpoints, including primary patency, freedom from TVR/target-lesion revascularization (TLR), improvements in clinical parameters, and major adverse events (MAEs) were evaluated through 36 months. Results: The mean overall lesion length was 80.7+/-38.9 mm (mean stented length: 98.8+/-46.1 mm). Freedom from TLF was 81.2% (p<0.001 compared to OPG) with a Kaplan-Meier estimate of 84.2% [95% confidence interval (95%CI) 73.3%, 90.9%] at 12 months. Primary patency was 71.0% at 12 months and 67.8% at 36 months. A total of 94.7% of patients improved by at least one Rutherford category and 70.2% of patients improved ankle-brachial indices ?0.10 from baseline to 36 months. Freedom from TVR/TLR (Kaplan-Meier) was 90% at 12 months and 79.5% at 36 months. Four MAEs were reported; none were found to be device or procedure related. Conclusion: A self-expanding stent was used safely to treat stenotic and occlusive lesions of the SFA in a Japanese patient population. The composite endpoint, freedom from TLF, was superior to an historical control at one year, with low rates of revascularization and good functional and clinical outcomes through three years. PMID- 30402184 TI - Distal Bypass to the Palmar Arch to Rescue Digital Ischemia Due to Peripheral Artery Disease. AB - Digital ischemia is a serious problem in peripheral artery diseases (PAD) patients. Case 1: A 60-year-old woman with large arteriovenous fistula (AVF) complained of digital ischemia symptoms. The patient underwent dissection of AVF and distal bypass to the palmar arch with successful repair. Case 2: A 47-year old female, diagnosed with renal failure, and scleroderma, complained of a digital gangrene. A bypass was performed from the left brachial artery to the superficial palmar arch. The digital gangrene showed a complete recovery within 2 months after surgery. Distal bypass to the palmar arch thus appears to be a useful procedure to re-establish digital circulation in PAD patients. PMID- 30402185 TI - Fistula between the Thoracic Duct and an Unusual Vessel Aneurysm Branching Off the Abdominal Aorta Revealed by Aneurysm Rupture: A Case Report. AB - Fistulas between an aneurysm branching off the abdominal aorta and the thoracic duct are rare. We report a case of aneurysmal-thoracic duct fistula diagnosed by angiography when aneurysm ruptured, and we successfully treated by catheter embolization. A 42-year-old man was referred to our hospital with a chief complaint of sudden back and chest pain. Computed tomography showed both post mediastinal and retroperitoneal hematomas, with the aneurysm from the aorta being connected to the thoracic duct. After confirming the aneurysmal-thoracic duct fistula by angiography, we performed embolization of the aneurysm. The patient has remained well for 3 postoperative months, to date. PMID- 30402186 TI - Single-Stage Surgical Repair of Kommerell Diverticulum with Annuloaortic Ectasia via a Median Sternotomy: Frozen Elephant Trunk Technique with an Antler-Like Shape Reconstruction of Arch Branches. AB - We present here a case of Kommerell diverticulum (KD) with annuloaortic ectasia, in which single-stage surgical repair was performed via a median sternotomy using frozen elephant trunk (FET) technique. We used this technique for the following reasons: firstly, we could perform surgery only via a median sternotomy without thoracotomy; secondly, we were able to deliver the FET using a guidewire through the severely angulated aortic arch. We here investigate this technique as it could potentially be a good treatment option of KD. PMID- 30402187 TI - In Situ Graft Replacement for a Ruptured Abdominal Aortic Aneurysm Infected with Listeria monocytogenes after Endovascular Aneurysm Repair. AB - Listeria monocytogenes infection and rupture of the aneurysm sac, after endovascular aneurysm repair (EVAR), are both rare. We report the case of an 82 year-old man who presented with a ruptured aneurysm by infection with L. monocytogenes after EVAR. We successfully treated him by in situ reconstruction with a bifurcated expanded polytetrafluoroethylene (ePTFE) graft, with partial removal of the infected stent graft. At 30 months from the reoperation, the patient was in good health at home, with no symptoms of infection, and the gallium-67-citrate single-photon emission computed tomography/computed tomography (SPECT/CT) fusion images confirmed no fluid accumulation. PMID- 30402188 TI - Is TEVAR with Full Petticoat Technique Effective for Complicated Acute Type B Dissection Cases? AB - Treatment by thoracic endovascular aortic repair (TEVAR) for type B dissection has improved outcomes. We tried the procedure named "Full Petticoat technique" in which the proximal entry tear was excluded with a covered stent and extended bare metal stents were placed to the aortic bifurcation for three complicated type B dissection cases with dynamic obstruction of the common iliac artery. Follow-up computed tomography revealed favorable aortic remodeling in which the true lumen was expanded. The short-term result of this procedure has shown acceptable aortic remodeling. The significance of this procedure is still unknown in the long term; hence long-term follow-up is necessary to completely understand the usefulness of this technique. PMID- 30402189 TI - Phlegmasia Cerulea Dolens with Compartment Syndrome. AB - Venous thromboembolism (VTE) is a major healthcare problem that results in significant mortality, morbidity, and expenditure of resources. It compounds with pulmonary embolism (PE) and deep vein thrombosis (DVT). Phlegmasia cerulea dolens (PCD) is an uncommon but potentially life-threatening complication of acute DVT characterized by marked swelling of the extremities with pain and cyanosis, which in turn may lead to arterial ischemia and ultimately gangrene with high amputation and mortality rates. The key in treating such patients is to provide quick and effective treatment to save the limbs and the patient. PMID- 30402190 TI - A Case of Upper Limb Arterial Embolization from Aortic Arch Intimal Sarcoma. AB - We report a case with aortic intimal sarcoma who presented with left upper limb arterial embolization from tumor. A 79-year-old female patient presented with paleness and left upper limb paralysis. A transesophageal echocardiogram revealed a mobile and fragile mass attached in the aortic arch. Contrast-enhanced computed tomography showed a massive irregular tumor in the aortic arch with left common carotid and subclavian artery occlusion. Total arch replacement was performed, and tumor was resected en bloc. Although the postoperative course was uneventful, multiple metastasis to the limbs was observed. The patient died 6 months postoperatively. PMID- 30402191 TI - Successful Simultaneous Revascularization for Acute Limb Ischemia and Concomitant Acute Myocardial Infarction. AB - Acute limb ischemia (ALI) is associated with high morbidity and mortality rates, even with the advent of technical advances. Although myocardial infarction is one of the causes of ALI along with intraventricular thrombus formation and subsequent embolism, ALI with concomitant acute myocardial infarction (AMI) is extremely rare. Here, we report a complicated ALI case with concurrent AMI and prolonged limb ischemic duration. The cause may be attributed to thrombosis with atherosclerotic disease of the coronary and peripheral arteries triggered by dehydration. We successfully treated the patient using simultaneous revascularization in a hybrid operating room with the aid of intraoperative hemodialysis for preventing life-threatening reperfusion syndrome. PMID- 30402192 TI - Abdominal Aortic Aneurysm Caused by Aortic Fibromuscular Dysplasia: A Case Report. AB - Fibromuscular dysplasia (FMD) mainly develops in medium-sized arteries, including renal, extracranial, and extremity arteries, but it rarely causes abdominal aortic aneurysm (AAA). A 69-year-old woman with AAA diagnosed on ultrasonography by a home doctor visited our hospital. Contrast-enhanced computed tomography revealed a saccular aneurysm of terminal abdominal aorta. We performed abdominal aortic replacement and resected the section with aneurysm. Pathological examination of the wall tissue of the resected aneurysm revealed findings that are consistent with FMD. We report this case of AAA caused by aortic FMD because of its rarity. PMID- 30402193 TI - Fatal Vasospasm of the Coronary Arteries in a Patient Undergoing Distal Bypass Surgery and Endovascular Therapy for Threatened Lower Limbs Due to Acute Exacerbation of Peripheral Arterial Disease. AB - A 79-year-old man with a heavy smoking history presented with threatened lower limbs due to acute exacerbation of peripheral artery disease (PAD). He underwent emergent distal bypass surgery for the right leg and external iliac stenting for the left leg. Fatal coronary artery spasm (CAS) with ST segment changes on electrocardiography was observed 28 h after the procedures, resulting in cardiac arrest. Coronary angiography showed widespread CAS with improvement after intra arterial nitroglycerin infusion. We should keep in mind that CAS may occur more frequently than expected in PAD patients, especially those who have not stopped smoking prior to revascularization. PMID- 30402194 TI - Refractory Vascular Wall Healing after Paclitaxel-Coated Nitinol Stent Implantation in the Femoropopliteal Artery: A High-Resolution Angioscopic Assessment. AB - It is unclear whether arterial healing occurs beyond 1 year following paclitaxel coated stent implantation in peripheral artery disease. An 81-year-old woman with superficial femoral artery disease underwent endovascular therapy with a paclitaxel-coated stent. An angiography 21 months later revealed peri-stent contrast staining in the superficial femoral artery, and optical frequency domain imaging demonstrated incomplete stent apposition with significant positive vascular remodeling. High-resolution angioscopy detected positive vascular wall remodeling and in-stent yellow plaque more clearly than conventional angioscopy. Refractory superficial femoral arterial wall healing was apparent more than 20 months after paclitaxel-coated stent implantation. PMID- 30402195 TI - Vascular Surgery in Japan: 2011 Annual Report by the Japanese Society for Vascular Surgery. AB - This is an annual report indicating the number and early clinical results of annual vascular treatments performed by vascular surgeons in Japan during 2011, as analyzed by database management committee (DBC) members of the Japanese Society for Vascular Surgery (JSVS). Materials and Methods: To survey the current status of vascular treatments performed by vascular surgeons in Japan, the DBC members of the JSVS analyzed the vascular treatment data provided from National Clinical Database (NCD), including the number of treatments and early clinical results such as operative and in-hospital mortality. Given that NCD data were prospectively built by a nationwide registration, this annual report reports prospective clinical data. Results: In total 71,707 vascular treatments including open repairs and endovascular treatments were registered by 992 institutions in 2011. This database is composed of 7 fields including treatment of aneurysms, chronic arterial occlusive disease, acute arterial occlusive disease, vascular injury, complication of vascular reconstruction, venous diseases, and other vascular treatments. The number of vascular treatments in each field was 17,524, 11,278, 3,799, 1,030, 1,615, 19,371, and 17,510, respectively. In the field of aneurysm treatment, 13,218 cases with abdominal aortic aneurysms (AAA) including iliac aneurysms were registered, including 1,253 ruptured cases. Forty-five percent of AAA cases were treated by stent graft. The operative mortality of ruptured and non-ruptured AAA was 18.8% and 0.8%, respectively. Regarding chronic arterial occlusive disease, open repair was performed in 7,115 cases including 984 distal bypasses to the crural or pedal artery, whereas endovascular procedures were performed in 4,163 cases. For acute arterial occlusive disease, more than 90% of cases were treated with open repair. Vascular injury treatment included 81 venous injury cases and 949 arterial injury cases, and 60% of arterial injuries were iatrogenic. Treatment for complication of previous vascular treatment included 445 cases of graft infections, 240 cases of anastomotic aneurysms, and 811 cases of graft revision operations. The venous treatment included 18,864 varicose vein treatments, 343 cases with lower limb deep venous thrombosis, and 67 cases with vena cava reconstructions. Regarding other vascular operations, 16,296 cases of vascular access operations and 1,037 amputation surgeries are included. Conclusions: This vascular surgery database indicates not only the number of vascular treatments but also the early clinical outcomes for each treatment procedure, thereby representing a useful source for researching the clinical background of poor outcomes and for finding improvements in the quality of treatment. Continuing this work will provide information regarding changing the treatment modality in response to the changing structure of disease and societal needs. (This is a translation of Jpn J Vasc Surg 2017; 26: 45-64.). PMID- 30402196 TI - 2015 JAPAN Critical Limb Ischemia Database (JCLIMB) Annual Report. AB - Since 2013, the Japanese Society for Vascular Surgery has started the project of nationwide registration and tracking database for patients with critical limb ischemia (CLI) who are treated by vascular surgeons. The purpose of this project is to clarify the current status of the medical practice for the patients with CLI to contribute to the improvement of the quality of medical care. This database, called JAPAN Critical Limb Ischemia Database (JCLIMB), was created on the National Clinical Database and collects data of patients' background, therapeutic measures, early results, and long term prognosis as long as five years after the initial treatment. The limbs managed conservatively are also registered in JCLIMB, together with those treated by surgery and/or endovascular treatment. In 2015, 1138 CLI limbs (male, 796 limbs [70%]) were registered by 92 facilities. Arteriosclerosis obliterans has accounted for 98% of the pathogenesis of these limbs. In this manuscript, the background data and the early prognosis of the registered limbs are reported. (This is a translation of Jpn J Vasc Surg 2018; 27: 155-185.). PMID- 30402197 TI - 9th Asian PAD Workshop. PMID- 30402198 TI - Effects of Comorbidities on Asthma Hospitalization and Mortality Rates: A Systematic Review. AB - Background: Recent studies have shown that patients diagnosed with asthma who have other chronic comorbidities have severely worse medical outcomes. However, the number of available published studies in this field is lacking. The aim of this study was to determine the effects of comorbidities in asthmatic patients based on hospitalization and mortality rates. Methods: A systematic review was conducted. Data were obtained from the electronic databases PubMed, CINAHL, and Cochrane until June 15, 2018. The primary objective of this study was to determine the effects of comorbidities on asthma hospitalization and mortality. The secondary objective was to analyze the effects of asthma comorbidity with certain chronic diseases, including COPD, obesity, obstructive sleep apnea, mental illness (anxiety and depression), diabetes mellitus, hypertension, myocardial ischemia, rhinitis, and sinusitis on asthma hospitalization and mortality. Results: From potential 687 articles, only 9 were chosen based on our study inclusion criteria. Almost half of these articles were related to asthma/COPD comorbidity. There were no articles found for hypertension, myocardial ischemia, rhinitis, or sinusitis based on our inclusion/exclusion factors. Each of these 9 published articles had shown an increase in rates of hospitalization, length of stay, and/or mortality, due to asthma-related symptoms, compared to asthma-only patients. Conclusion: There was determined to be a large discrepancy between the available research for various types of comorbid conditions presenting with asthma that focus on hospitalization and mortality rates. The current available literature suggests a large impact that these comorbid diseases can have on asthma-related symptoms when present together, severely affecting a patient's quality of life. We propose that further research on the effects of these comorbidities on asthma mortality and hospitalization can yield beneficial results to improve the management of asthmatic patients. PMID- 30402199 TI - Effects of Physical-Agent Pain Relief Modalities for Fibromyalgia Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - Purpose: We conducted a systematic review and meta-analysis to investigate the effects of the following physical-agent modalities for pain relief in fibromyalgia (FM) patients. Methods: We identified randomized controlled studies of adults with FM in the MEDLINE, CINAHL, and PEDro databases. The primary outcome measure was pain relief measured by a visual analogue scale (VAS), and the secondary outcome measures of interest were subjective improvements in the number of tender points, Fibromyalgia Impact Questionnaire (FIQ), and quality of life (QOL) scores. Results: Eleven studies were included in our review. The studies' physical-agent modalities were low-level laser therapy (LLLT), thermal therapy, electromagnetic field therapy, and transcutaneous electrical nerve stimulation (TENS). LLLT did not reduce VAS scores, but it significantly reduced both the number of tender points and FIQ score. Thermal therapy was associated with significantly reduced VAS scores, tender points, and FIQ scores. Electromagnetic field therapy was associated with significantly reduced VAS score and FIQ score. TENS significantly reduced VAS scores. Conclusion: Our analyses revealed that thermal therapy and LLLT had a partial effect on pain relief in FM patients, and this beneficial effect may have a positive influence on FM patients' health status. PMID- 30402200 TI - [Evaluation of patients' satisfaction in the department of cardiology at the University Hospital Yalgado Ouedraogo]. AB - Introduction: Patients' satisfaction is an important component of health care quality evaluation. Patients and physicians are now care partners. This new relationship deserves to be evaluated. Our study aimed to evaluate the satisfaction of patients hospitalized in the Department of Cardiology at the University Hospital Yalgado Ouedraogo. Methods: We conducted a cross-sectional descriptive study with a single data collection phase of all the patients hospitalized from 1 January to 30 June 2014. We administered SAPHORA questionnaire adapted to suit our context. The scores and the satisfaction rates were calculated according to the studied parameters. Results: During the study period we collected data from 230 patients. The mean hospitalization time was approximately 10 days. 125 (53.2%) men were enrolled in the study, sex ratio was 1.1. 32% (n = 75) of patients were unschooled. Public servants accounted for 24.3% (n = 57) of our study population. The average age of our sample was 50.7 years. Patients over the age of 65 years accounted for 25.6% of the study population. 113 (48.1%) patients had been admitted as medical emergencies. 21 patients (8.9%) had a history of hospitalization in the Depatment of Cardiology. Dilated cardiomyopathy was the diagnosis made during hospitalization in 75 (32%) cases. The overall score of satisfaction of the patients treated in the Department of Cardiology was 78.3%. Satisfaction score on hospital admission was 68.1% and on patients' comfort was 65.8%. Satisfaction score on health care quality and on hospital discharge planning was 84.7% and 84.5% respectively. Patients' suggestions for improvement were based on comfort during hospital stay in 99 (42.1%) cases and on staff identification in 176 (74.9%) cases. Conclusion: The evaluation of the satisfaction is infrequent in our country. It is becoming increasingly frequent in western countries using common and validated tools. It is an important aspect that our hospitals should include in order to increase quality approach to accreditation. PMID- 30402201 TI - [Primary tuberculous abscess and pyogenic psoas abscess: an uncommon association]. AB - Psoas abscesses account for 5-10% of abdominal suppurations. They can be primary or secondary. Primary polymicrobic abscesses of the psoas muscle including, in particular, tuberculous abscesses and pyogenic abscesses, have never been reported in the literature. We report the case of a 35-year old patient, with no particular past medical history, admitted with pain in the right lumbar fossa associated with a fever of 40 degrees C. Onset of symptoms had occurred 5 months before, but without fever. Abdominal CT scan showed an abscess of the right external transverse and oblique psoas muscles extended to the retroperitoneum and infiltrating the thoracoabdominal wall. Cytobacteriological examination of pus showed fast-growth monomorphic wild-type Escherichia coli strains. Systematically performed Real-time PCR test for the detection of Complex Mycobaterium tuberculosis was positive while direct examination after Ziehl-nelseen staining was negative. The culture on a solid Lowenstein Jensen medium was positive after one-month of incubation. The outcome of our patient was favorable under antibacillar quadritherapy and ceftriaxone. This study highlights that a tuberculous origin should be systematically suspected in patients living in endemic areas with chronic, recurrent psoas abscess not responding to antibiotics. PMID- 30402202 TI - Effects of concurrent chloroquine and ethanol administration on the rat kidney morphology. AB - Introduction: The use of antimalarial chloroquine in malaria-endemic regions of Africa is rampant and it is not uncommon to find individuals taken the drug concurrent with alcohol. Effects of anti-malarial drug chloroquine (Chq) and ethanol (Et) combination on kidney volume and function using rat model was investigated. Methods: 32 adult male rats were randomly distributed into four groups of 8 rats each. Group C serve as control and received vehicle only, while Q is Chq treated only, E is Et treated and QE is Et and Chq treated. Chq was administered intraperitoneally at 1mg/100g body weight weekly and 6% Et in drinking water provided ad libitum. Urine volume was collected before the treatment began and after the treatment. After eight weeks, all animals were euthanized; kidneys were harvested and fixed in 10% neutral formalin. The fixed left kidneys were scanned with computed tomography and the scan slices were used to estimate 3-dimensional kidney volume on ImageJ. Results: Total kidney volume was none significantly increased in Q, E and QE treated compared to control groups (p = 0.5150). Also, microscopic analysis showed increased proximal tubule diameter (p = 0.1426) and epithelial hypertrophy (p = 0.2530) and significant urinary space shrinkage (p = 0.00001). The initial urine volume was not significantly different between the control and treated groups (p = 0.9864) however, following treatment urine volume was significantly reduced in QE rats group (p = 0.0029). Conclusion: The results suggest chloroquine and ethanol combination as potential cause of kidney injury through structural damage and function derangement. PMID- 30402204 TI - The Effect of Whole-Body Cryotherapy at Different Temperatures on Proinflammatory Cytokines, Oxidative Stress Parameters, and Disease Activity in Patients with Ankylosing Spondylitis. AB - Purpose: Patients with ankylosing spondylitis (AS) have increased production of proinflammatory cytokines, increased oxidants, and decreased antioxidant capacity. The aim of this study was to determine the effect of whole-body cryotherapy (WBC) at -110 degrees C and -60 degrees C, on disease activity, selected proinflammatory cytokines, and oxidative stress in patients with AS. Methods: Sixty-five patients with AS were recruited to one of three study procedures: WBC at -110 degrees C, -60 degrees C, or exercise therapy (non-WBC). The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Ankylosing Spondylitis Disease Activity Score (ASDAS-CRP), concentration of C-reactive protein (CRP), and the concentrations of interleukin 8 and 17 (IL-8, IL-17) were measured at the beginning of the study and at the end of the intervention. The concentration of thiobarbituric acid reactive substances (TBARS), as a lipid peroxidation result, and total antioxidant status, an antioxidant organism potential, were measured. Results: All the studied groups showed significantly decreased posttherapy disease activity expressed as a function of the BASDAI, ASDAS-CRP, and the IL-8 concentration. We found that the TBARS concentration after therapy was significantly increased in the WBC at -110 degrees C group. A comparison of the therapeutic effects between the treatment groups showed a significantly lower BASDAI after therapy in the WBC at -110 degrees C group compared to the non-WBC group. Conclusion: WBC at -110 degrees C had a positive effect on lowering AS clinical activity as measured by the BASDAI. PMID- 30402203 TI - Connection between Systemic Inflammation and Neuroinflammation Underlies Neuroprotective Mechanism of Several Phytochemicals in Neurodegenerative Diseases. AB - Oxidative damage, mitochondrial dysfunction, and neuroinflammation are strongly implicated in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD), and a substantial portion of elderly population at risk of these diseases requires nutritional intervention to benefit health due to lack of clinically relevant drugs. To this end, anti inflammatory mechanisms of several phytochemicals such as curcumin, resveratrol, propolis, polyunsaturated fatty acids (PUFAs), and ginsenosides have been extensively studied. However, correlation of the phytochemicals with neuroinflammation or brain nutrition is not fully considered, especially in their therapeutic mechanism for neuronal damage or dysfunction. In this article, we review the advance in antioxidative and anti-inflammatory effects of phytochemicals and discuss the potential communication with brain microenvironment by improved gastrointestinal function, enhanced systemic immunity, and neuroprotective outcomes. These data show that phytochemicals may modulate and suppress neuroinflammation of the brain by several approaches: (1) reducing systemic inflammation and infiltration via the blood-brain barrier (BBB), (2) direct permeation into the brain parenchyma leading to neuroprotection, (3) enhancing integrity of disrupted BBB, and (4) vagal reflex mediated nutrition and protection by gastrointestinal function signaling to the brain. Therefore, many phytochemicals have multiple potential neuroprotective approaches contributing to therapeutic benefit for pathogenesis of neurodegenerative diseases, and development of strategies for preventing these diseases represents a considerable public health concern and socioeconomic burden. PMID- 30402206 TI - Effects of High Consumption of Vegetables on Clinical, Immunological, and Antioxidant Markers in Subjects at Risk of Cardiovascular Diseases. AB - High intakes of vegetables have been associated with a lower incidence of cardiovascular diseases (CVD). However, the effect of vegetables on immune function and antioxidant status in human studies have provided contrasting results. In the present study, after a week of run-in period, 38 subjects at risk of CVD were randomly assigned to one of the following 4-week interventions: low vegetable consumption (800 g of vegetables/week) or high vegetable consumption (4200 g of vegetables/week). Vegetables included carrots, topinambur (Jerusalem artichoke, Helianthus tuberosus), tomatoes, red cabbage, and sweet peppers. Blood and salivary samples were collected before and after intervention periods. In addition to clinical, immunological, and antioxidant markers, leukocyte and lymphocyte expression of the gut-homing beta7 integrin was evaluated. No significant changes were detected in clinical, immunological, and antioxidant markers in biological samples, except for an increase in white blood cell count for the low vegetable consumption group (p < 0.05). The study provides additional evidence about the uncertainty of providing a clear evidence for vegetables in modulating markers of immune function and antioxidant status. Further studies are needed in order to unravel the mechanism of effect of vegetable consumption in cardiovascular prevention. PMID- 30402205 TI - Inhibitory Effects of Momordicine I on High-Glucose-Induced Cell Proliferation and Collagen Synthesis in Rat Cardiac Fibroblasts. AB - Diabetes-associated cardiac fibrosis is a severe cardiovascular complication. Momordicine I, a bioactive triterpenoid isolated from bitter melon, has been demonstrated to have antidiabetic properties. This study investigated the effects of momordicine I on high-glucose-induced cardiac fibroblast activation. Rat cardiac fibroblasts were cultured in a high-glucose (25 mM) medium in the absence or presence of momordicine I, and the changes in collagen synthesis, transforming growth factor-beta1 (TGF-beta1) production, and related signaling molecules were assessed. Increased oxidative stress plays a critical role in the development of high-glucose-induced cardiac fibrosis; we further explored momordicine I's antioxidant activity and its effect on fibroblasts. Our data revealed that a high glucose condition promoted fibroblast proliferation and collagen synthesis and these effects were abolished by momordicine I (0.3 and 1 MUM) pretreatment. Furthermore, the inhibitory effect of momordicine I on high-glucose-induced fibroblast activation may be associated with its activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the inhibition of reactive oxygen species formation, TGF-beta1 production, and Smad2/3 phosphorylation. The addition of brusatol (a selective inhibitor of Nrf2) or Nrf2 siRNA significantly abolished the inhibitory effect of momordicine I on fibroblast activation. Our findings revealed that the antifibrotic effect of momordicine I was mediated, at least partially, by the inhibition of the TGF-beta1/Smad pathway, fibroblast proliferation, and collagen synthesis through Nrf2 activation. Thus, this work provides crucial insights into the molecular pathways for the clinical application of momordicine I for treating diabetes-associated cardiac fibrosis. PMID- 30402207 TI - miR-26a Potentially Contributes to the Regulation of Fatty Acid and Sterol Metabolism In Vitro Human HepG2 Cell Model of Nonalcoholic Fatty Liver Disease. AB - Nonalcoholic fatty liver disease (NAFLD) is a metabolic-related disorder ranging from steatosis to steatohepatitis, which may progress to cirrhosis and hepatocellular carcinoma (HCC). This study aimed at assessing the regulatory and protective role of miR-26a on lipid metabolism and progression of NAFLD in human HepG2 cells loaded with free fatty acids (FFA). Lentivirus expressing miR-26a or negative control miR was used to transduce HepG2 cells and to establish stable cell lines. Gain or loss of function using an miR-26a inhibitor was used to compare triglyceride content (TG), total cholesterol level (CL), total antioxidant capacity (TAC), malondialdehyde (MDA) and the level of apoptosis. In addition, quantitative reverse transcription polymerase chain reaction (qPCR) was used to assess the mRNA levels of lipogenesis, TG synthesis, storage genes, inflammatory and fibrogenic markers, and autophagic besides endoplasmic reticulum (ER) stress markers after gaining or losing the function of miR-26a. miR-26a levels decreased in response to FFA in human HepG2 cells. After the establishment of a stable cell line, the upregulation of miR-26a resulted in the downregulation of TG, CL, and MDA levels, through regulating mRNA levels of genes involved in lipid homeostasis, ER stress marker, inflammatory and fibrogenic markers. Nevertheless, there was a marked increment in the mRNA expression of autophagic marker genes. Moreover, miR-26a overexpression protects the cells from apoptosis, whereas inhibition of miR-26a, using an anti-miR-26a oligonucleotide, decreased the expression of miR-26a which potentially contributes to altered lipid metabolism in HepG2 cells loaded with FFA. In conclusion, these findings suggested that miR-26a has a crucial role in regulating fatty acid and cholesterol homeostasis in HepG2 cells, along with the offered protection against the progression of NAFLD in vitro. Hence, miRNAs could receive growing attention as useful noninvasive diagnostic markers to follow the progression of NAFLD and to identify novel therapeutic targets. PMID- 30402208 TI - Insight into novel clinical mutants of RpsA-S324F, E325K, and G341R of Mycobacterium tuberculosis associated with pyrazinamide resistance. AB - Pyrazinamide (PZA) is an important component of first-line anti-tuberculosis drugs which is converted into active form, pyrazinoic acid (POA), by Mycobacterium tuberculosis (MTB) pncA gene encoded, pyrazinamidase (PZase). Mutations in pncA are detected in >70% of PZA resistant isolates but, noticeably, not in all. In this study, we selected 18 PZA-resistant but wild type pncA (pncAWT) MTB isolates. Drug susceptibility testing (DST) of all the isolates were repeated at the critical concentration of PZA drug. All these PZA-resistance but pncAWT isolates were subjected to RpsA sequencing. Fifteen different mutations were identified in eleven isolates, where seven were present in a conserved region including, Ser324Phe, Glu325Lys, Gly341Arg. As the molecular mechanism of resistance behind these variants has not been reported earlier, we have performed multiple analysis to unveil the mechanisms of resistance behind mutations S324F, E325K, and G341R. The mutant and wild type RpsA structures were subjected to comprehensive computational molecular dynamic simulations at 50 ns. Root mean square deviation (RMSD), Root mean square fluctuation (RMSF), and Gibbs free energy of mutants were analyzed in comparison with wild type. Docking score of wild type-RpsA has been found to be maximum, showing a strong binding affinity in comparison with mutants. Pocket volume, RMSD and RMSF have also been found to be altered, whereas total energy, folding effect (radius of gyration) and shape complimentarily analysis showed that variants S324F, E325K, and G341R have been playing a significant role behind PZA-resistance. The study offers valuable information for better management of drug resistance tuberculosis. PMID- 30402210 TI - Smart Wearables in Healthcare: Signal Processing, Device Development, and Clinical Applications. PMID- 30402209 TI - The "Real World"? Effects of Online Communication about Prostate Cancer on Offline Communication. AB - Introduction: Online peer-to-peer social support programs are based on the premise that support from others who have been through a similar experience can help reduce the negative impacts of disease. Such support programs are increasingly found online, but how these conversations translate into real world interactions about health concerns is currently not well understood. Methods: Grounded in social network theory, this formative study explored how participants in an online prostate cancer community comprised of patients and their families translate their online conversations into offline ones. A survey was designed and fielded, and received 157 complete responses. Results: Results support prior research findings that these offline conversations are primarily information oriented (n = 105) and extend them by the finding that members of online prostate cancer social support communities do, in fact, share information obtained online with others offline (n = 103). Family members appear to be primary receivers of this information (n = 121) while health care providers are not, which may impact treatment and care. Conclusions: The opportunity to tie more concretely online messages with offline conversations is of critical importance and interest. Recommendations are presented for future research. PMID- 30402211 TI - 3D Printed Anatomy-Specific Fixture for Consistent Glenoid Cavity Position in Shoulder Simulator. AB - Purpose: Fixation methods for consistent anatomical structure positioning in biomechanical testing can be challenging. Image-based 3D printing is an attractive method for fabrication of biomechanical supports of anatomical structure due to its ability to precisely locate anatomical features with respect to the loading system. Method: A case study is presented to provide a design guide for fixation block fabrication. The anatomy of interest was CT scanned and reconstructed in 3D. The model was imported into commercially available CAD software and modified into a solid object and to create the fixture block. The CAD fixture block is standardized such that anatomical features are always in the same position for the testing system by subtracting the anatomy from a base fixture block. Results: This method allowed a strong immobilization of anatomical specimens and a controlled and consistent positioning feature with respect to the testing system. Furthermore, the fixture block can be easily modified and adapted to anatomical structures of interest using CAD software. Conclusion: This approach allows preservation of the bony anatomy integrity and provides a repeatable and consistent anatomical positioning with respect to the testing system. It can be adapted for other anatomical structures in various other biomechanical settings. PMID- 30402212 TI - A Numerical Model of Blood Flow Velocity Measurement Based on Finger Ring. AB - Aiming to measure the blood flow velocity in a finger, a novel noninvasive method, i.e., a ring with a heat source chip and a temperature sensor, is designed in this paper. The heat source chip is used to heat the finger and generate heat diffusion between the chip and the temperature sensor. And the temperature sensor is designed to measure the temperature difference. Since the blood flow is the main medium of heat diffusion in bodies, part from the heat energy in the tissue will be taken away by the flowing blood. Therefore, the blood flow velocity can be acquired via its relationship with the temperature difference. Compared to the ultrasound Doppler method and the laser Doppler method, the proposed method guarantees a more convenient operation in more flexible work sites. We also analyze the theory between heat transfer and laminar flow. Finally, several simulations are conducted, and the influence of the relevant factors (i.e., the number of blood vessels, the radius, etc.) corresponding to the simulation results is also discussed. PMID- 30402213 TI - Analysis for the Influence of ABR Sensitivity on PTT-Based Cuff-Less Blood Pressure Estimation before and after Exercise. AB - An accurate and continuous measurement of blood pressure (BP) is of great importance for the prognosis of some cardiovascular diseases in out-of-hospital settings. Pulse transit time (PTT) is a well-known cardiovascular parameter which is highly correlated with BP and has been widely applied in the estimation of continuous BP. However, due to the complexity of cardiovascular system, the accuracy of PTT-based BP estimation is still unsatisfactory. Recent studies indicate that, for the subjects before and after exercise, PTT can track the high frequency BP oscillation (HF-BP) well, but is inadequate to follow the low frequency BP variance (LF-BP). Unfortunately, the cause for this failure of PTT in LF-BP estimation is still unclear. Based on these previous researches, we investigated the cause behind this failure of PTT in LF-BP estimation. The heart rate- (HR-) related arterial baroreflex (ABR) model was introduced to analyze the failure of PTT in LF-BP estimation. Data from 42 healthy volunteers before and after exercise were collected to evaluate the correlation between the ABR sensitivity and the estimation error of PTT-based BP in LF and HF components. In the correlation plot, an obvious difference was observed between the LF and HF groups. The correlation coefficient r for the ABR sensitivity with the estimation error of systolic BP (SBP) and diastolic BP (DBP) in LF was 0.817 +/- 0.038 and 0.757 +/- 0.069, respectively. However, those correlation coefficient r for the ABR sensitivity with the estimation error of SBP and DBP in HF was only 0.403 +/- 0.145 and 0.274 +/- 0.154, respectively. These results indicated that there is an ABR-related complex LF autonomic regulation mechanism on BP, PTT, and HR, which influences the effect of PTT in LF-BP estimation. PMID- 30402214 TI - When Collective Knowledge Meets Crowd Knowledge in a Smart City: A Prediction Method Combining Open Data Keyword Analysis and Case-Based Reasoning. AB - One of the significant issues in a smart city is maintaining a healthy environment. To improve the environment, huge amounts of data are gathered, manipulated, analyzed, and utilized, and these data might include noise, uncertainty, or unexpected mistreatment of the data. In some datasets, the class imbalance problem skews the learning performance of the classification algorithms. In this paper, we propose a case-based reasoning method that combines the use of crowd knowledge from open source data and collective knowledge. This method mitigates the class imbalance issues resulting from datasets, which diagnose wellness levels in patients suffering from stress or depression. We investigate effective ways to mitigate class imbalance issues in which the datasets have a higher proportion of one class over another. The results of this proposed hybrid reasoning method, using a combination of crowd knowledge extracted from open source data (i.e., a Google search, or other publicly accessible source) and collective knowledge (i.e., case-based reasoning), were that it performs better than other traditional methods (e.g., SMO, BayesNet, IBk, Logistic, C4.5, and crowd reasoning). We also demonstrate that the use of open source and big data improves the classification performance when used in addition to conventional classification algorithms. PMID- 30402215 TI - Osmophores and floral fragrance in Anacardium humile and Mangifera indica (Anacardiaceae): an overlooked secretory structure in Sapindales. AB - Flowers of Anacardiaceae and other Sapindales typically produce nectar, but scent, often associated with a reward for pollinators, has surprisingly been mentioned only rarely for members of the family and order. However, flowers of Anacardium humile and Mangifera indica produce a strong sweet scent. The origin and composition of these floral scents is the subject of this study. Screening of potential osmophores on the petals and investigations of their anatomy were carried out by light, scanning and transmission electron microscopy. The composition of the floral fragrance was characterized by gas chromatography-mass spectrometry. In both species, the base of the adaxial side of each petal revealed specialized secretory epidermal cells which are essentially similar in structure and distinct from all other neighbouring cells. These cells also showed evidence of granulocrine secretory mechanisms and slight specific variations in their subcellular apparatus coinciding with the respective composition of the floral fragrance, predominantly composed of sesquiterpenes in A. humile and monoterpenes in M. indica. This study reports the presence of osmophores for the first time in flowers of Anacardiaceae and confirms the link between the ultrastructural features of their secretory cells and the volatiles produced by the flowers. The flowers of most Sapindales, including Anacardiaceae, are nectariferous. However, the presence of osmophores has only been described for very few genera of Rutaceae and Sapindaceae. Both the occurrence of osmophores and fragrance may have largely been overlooked in Anacardiaceae and Sapindales until now. Further studies are needed to better understand the nature and diversity of the interactions of their nectariferous flowers with their pollinators. PMID- 30402217 TI - Familial Mediterranean Gene (MEFV) Mutation in Parents of Children with Familial Mediterranean Fever: What Are the Exceptions? AB - Objectives: Familial Mediterranean Fever (FMF) is one of the most prevalent periodic fever syndromes; MEFV, the responsible gene for the disease, is in the short arm of chromosome16. In the considerable count of the FMF patients, only one mutation is found in the MEFV and parents, who were the obligatory carriers for that mutation, were asymptomatic. The aim of this study was to evaluate these asymptomatic parents in regard to mutation in MEFV gene and similarity between parents and offspring patients. Methods: In this cross-sectional study, asymptomatic parents of FMF patients enrolled the study were referred to periodic fever clinic or pediatric rheumatology clinic of Tehran University of Medical Sciences. The patients should have at least one mutation in MEFV gene and none of them had any family history of autoinflammatory disease. Twelve mutations in MEFV gene were assessed in the parents by Vienna Lab FMF Strip Assay kit by MAS PCR/Reverse hybridization. Results: Forty-three patients and their parents participated in the study. Sixty-three percent (27) of patients were male. Onset of disease symptoms in 31 patients (72%) was before 4 years of old. Nine (21%) of the patients had homozygote, 16 (37%) compound heterozygote, and 17(40%) heterozygote for MEFV mutation; there was a case of complex alleles mutations (2%). M694V/M694V in 4 patients (9%) was the most homozygote genotype, and M694V/R761H in 4 (9%) and E148Q in 7 (16%) were the most compound heterozygote and heterozygote genotype, respectively. M694V, M680I, and E148Q were the most mutation in the parents. Overall, 41 patients had mutations similar to their parents' mutation, except 2 whose parents had no mutation, but a patient did. Conclusion: It seems that occurrence of new mutations in offspring is not prevalent among FMF patients and there are other reasons for different clinical presentation in similar mutation carriers. On the other hand, in ethnicities with high prevalence of FMF, new mutation in descendant may occur, infrequently. PMID- 30402216 TI - Longitudinal Study on Low-Dose Aspirin versus Placebo Administration in Silent Brain Infarcts: The Silence Study. AB - Background: We investigated low-dose aspirin (ASA) efficacy and safety in subjects with silent brain infarcts (SBIs) in preventing new cerebrovascular (CVD) events as well as cognitive impairment. Methods: We included subjects aged >=45 years, with at least one SBI and no previous CVD. Subjects were followed up to 4 years assessing CVD and SBI incidence as primary endpoint and as secondary endpoints: (a) cardiovascular and adverse events and (b) cognitive impairment. Results: Thirty-six subjects received ASA while 47 were untreated. Primary endpoint occurred in 9 controls (19.1%) versus 2 (5.6%) in the ASA group (p=0.10). Secondary endpoints did not differ in the two groups. Only baseline leukoaraiosis predicts primary [OR 5.4 (95%CI 1.3-22.9, p=0.022)] and secondary endpoint-a [3.2 (95%CI 1.1-9.6, p=0.040)] occurrence. Conclusions: These data show an increase of new CVD events in the untreated group. Despite the study limitations, SBI seems to be a negative prognostic factor and ASA preventive treatment might improve SBI prognosis. EU Clinical trial is registered with EudraCT Number: 2005-000996-16; Sponsor Protocol Number: 694/30.06.04. PMID- 30402219 TI - A solitary presentation of panniculitis in a patient with a history of breast cancer. AB - Introduction: Panniculits presents as an inflammation of the subcutaneous adipose tissue of the skin. In breast, panniculitis is very rare and is usually a manifestation of underlying inflammatory conditions. The typical presentation is palpable tender nodules, which in cases of breast panniculitis, triggers an extensive work up to exclude a malignancy. Herein we present a case of septal and lobar panniculitis in a female with clinical history of invasive ductal carcinoma. Presentation of the case: A 52-year old female with past medical history of invasive breast carcinoma 5 years prior to the presentation. The patient's chief complaint was a 1-year history of a subcutaneous nodular lesion on her left breast. A core biopsy of the firm nodule showed marked inflammation of the breast. A second skin biopsy showed an abundant chronic inflammatory infiltrate, with lymphocytic vasculitis and neuritis, suggestive of an underlying autoimmune process. Discussion: Subcutaneous panniculitis with or without vasculitis is a rare condition when presenting in the breast. Panniculitis can mimic malignancy and thus, it is important to differentially diagnose it from breast carcinoma. Histologically, it is classified in lobular and septal lymphocytic panniculitis depending on specific diagnostic characteristics. Conclusion: Panniculitis of the breast is a rare condition that needs to be included in the differential diagnosis of subcutaneous breast masses. In all cases, but specifically in females with history of breast cancer, panniculitis still should be thought of as a possibility, and imaging as well as other diagnostic techniques can aid in making the correct diagnosis. PMID- 30402218 TI - Assessment of the nutrition environment in rural counties in the Deep South. AB - The nutrition environment, including food store type, may influence dietary choices, which in turn can affect risk of obesity and related chronic diseases such as CHD, diabetes and cancer. The objective of the present study was to elucidate the extent to which healthy foods are available and affordable in various rural food outlets. A subset of the nutrition environment was assessed using the Nutrition Environment Measures Survey in Stores (NEMS-S). The NEMS-S instrument assessed the availability and price of healthy foods (e.g. low-fat/non fat milk, lean meats and reduced-fat dinner entrees) compared with less healthy counterparts (e.g. whole milk, non-lean meats and regular dinner entrees). The NEMS-S also assessed the quality of fresh fruits and vegetables. Availability, prices and quality of healthy foods were compared between grocery stores (n 24) and convenience stores (n 67) in nine rural counties in Alabama. Mean availability subscale score (possible range 0 to 30; higher score indicates a greater number of healthier foods were available) for grocery stores was 22.6 (sd 8.1), compared with 6.6 (sd 5.2) in convenience stores (P < 0.0001); and mean price subscale score (possible range -9 to 18; higher score indicates that healthier options were less expensive than the less healthy options) for grocery stores was 2.4 (sd 2.7), compared with 0.7 (sd 1.2) in convenience stores (P = 0.0080). Mean total NEMS-S score (possible range -9 to 54) in grocery stores was 29.8 (sd 10.9) compared with 7.3 (sd 7.1) in convenience stores (P < 0.0001). Both grocery and convenience stores could be strategic points of intervention to improve the nutrition environment in the counties that were surveyed. PMID- 30402220 TI - Laparoscopic treatment of obstructed internal supravesical hernia: A cases series and rewiev of the literature. AB - Introduction: internal supravesical hernia (ISH) is an exceptional subtype of internal hernia often presenting with small bowel obstruction (SBO). Its rarity makes preoperative suspicion and diagnosis very difficult in an emergency setting. Methods: we retrospectively analyzed the database of patients admitted in a single center emergency unit for small bowel occlusion (SBO) in virgin abdomen and treated by surgery from August 2013 to October 2018. The patients with intraoperative diagnosis of ISH were included in this study. Results: from 29 patients with virgin abdomen submitted to surgery for SBO, two cases of ISH were recorded. In both cases preoperative diagnosis was made by CT scan and urgent treatment was successfully performed by laparoscopy, reducing the entrapped small bowel and closing the hernia's ring by continuous suture. No intestinal resection was needed. Discussion: urgent laparotomic repair of obstructive ISH is the standard treatment although laparoscopic approach has also been described in a small number of cases. We reported our experience on two cases in which totally laparoscopic treatment was successfully performed in patients with stable hemodynamic parameters thanks to early diagnosis and limited intestinal distension. By an extensive analysis of the international literature, clinical, diagnostic and therapeutic aspects of this form of internal hernia were discussed. Conclusion: CT scan facilitates early ISH preoperative diagnosis, reducing the risk of small bowel resection and increasing the chances of minimally invasive laparoscopic treatment. PMID- 30402221 TI - The first case of hand infection caused by Dermabacter jinjuensis in a symmetrical peripheral gangrene patient. AB - Introduction: Strains of the genus Dermabacter is a recently established species, recognized as relatively rare opportunistic human pathogen, and is infrequently isolated from clinical specimens, including blood cultures, abscesses, wounds, bone, eye, and skin. Presentation of case: We present a 78-year old female with chronic symmetrical peripheral gangrene and hand infection. The patient underwent surgical debridement with amputation on gangrene with infection of both fingers. At 2 weeks postoperatively, pus discharge was newly observed and the patient underwent reoperation. In the subsequent reinfection, unknown organism has been repeatedly identified, may be the most likely causative agent. On the basis of phenotypic and genotypic distinctness and DNA-DNA hybridization results, new strain should be placed in the genus Dermabacter as representing a novel species, for which the name Dermabacter jinjuensis sp. nov. is proposed. Discussion: We judged the novel species as the causative bacteria. Because of, a novel species called D. jinjuensis was repeatedly identified more than common bacteria. It can be considered as a postoperative nosocomial infection or opportunistic infection. It is not clear how the infection of D. jinjensis occurred. Conclusion: This is the first reported case of a human D. jinjuensis infection. We were able to treat patients without any complications by operative treatment and administering appropriate antimicrobial agents according to antibiotics susceptibility test. PMID- 30402222 TI - Stop the bleed campaign: A qualitative study from our experience from the middle east. AB - Background: Bleeding due to unintentional injuries are a leading cause of death in the younger population. The immediate involvement of lay bystanders has been proven to be imperative in outcomes, however, there still is less than 30% of out of-hospital resuscitation attempts initiated by them. Study design: The Stop the Bleed campaign was initiated in Kuwait in September-2017, with the aim to raise awareness and train the general public on emergency situations. A survey questionnaire was distributed to a sample of 150 participants to assess their comprehension. Results: A total of 1531 participants were trained by the campaign. More than half of the participants have had no previous training of any sort for emergency situations, with the majority (86%) of those queered expressing desire to learn about how to deal with trauma and bleeding cases. After training, most participants were able to demonstrate knowledge of how to deal with unstoppable bleeding, know where and when to place a tourniquet, knew how to respond to epistaxis, and the ability to recognize signs of internal bleeding, with 89% expressing that the 'Stop the Bleed' campaign was useful for promoting health and raising awareness on safety of individuals. Conclusion: With the appropriate first-aid training and skill retention, lay members of the public can potentially contribute to a positive and important post-trauma medical response. PMID- 30402223 TI - Understanding psoriasis: Role of miRNAs. AB - Psoriasis is a chronic, immune-mediated inflammatory skin disease, with a multifactorial etiology and important immunologic, genetic and environmental components. Psoriasis vulgaris represents its most common form, with a variable prevalence across the globe. Although its pathogenesis remains to be fully elucidated, a lack of balance in the epigenetic network has been shown to trigger certain elements of this disease, possibly altering its outcome. MicroRNAs are small non-coding RNA molecules involved in RNA-silencing and the post transcriptional regulation of gene expression, which also appear to mediate the immune dysfunction in psoriasis. Although microRNA research is a new field in dermatology and psoriasis, there is rapidly accumulating evidence for its major contribution in the pathogenesis of chronic inflammatory conditions, including psoriasis and other dermatological disorders. Furthermore, circulating miRNAs identified in patients' blood samples have been identified as promising biomarkers of diagnosis, prognosis or treatment response. Extended investigations in this field are required, as until now, the exact involvement of miRNAs in psoriasis have remained to be entirely elucidated. This short review highlights a number of the roles of miRNAs found in different stages of psoriasis. PMID- 30402224 TI - Identification of 26 novel loci that confer susceptibility to early-onset coronary artery disease in a Japanese population. AB - Early-onset coronary artery disease (CAD) has a strong genetic component. Although genome-wide association studies have identified various genes and loci significantly associated with CAD mainly in European populations, genetic variants that contribute toward susceptibility to this condition in Japanese patients remain to be definitively identified. In the present study, exome-wide association studies (EWASs) were performed to identify genetic variants that confer susceptibility to early-onset CAD in Japanese. A total of 7,256 individuals aged <=65 years were enrolled in the present study. EWAS were conducted on 1,482 patients with CAD and 5,774 healthy controls. Genotyping of single nucleotide polymorphisms (SNPs) was performed using Illumina Human Exome 12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The association between allele frequencies for 31,465 SNPs that passed quality control and CAD was examined using Fisher's exact test. To compensate for multiple comparisons of allele frequencies with CAD, a false discovery rate (FDR) of <0.05 was applied for statistically significant associations. The association between allele frequencies for 31,465 SNPs and CAD, as determined by Fisher's exact test, demonstrated that 170 SNPs were significantly (FDR <0.05) associated with CAD. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of hypertension, diabetes mellitus and dyslipidemia revealed that 162 SNPs were significantly (P<0.05) associated with CAD. A stepwise forward selection procedure was performed to examine the effects of genotypes for the 162 SNPs on CAD. The 54 SNPs were significant (P<0.05) and independent [coefficient of determination (R2), 0.0008 to 0.0297] determinants of CAD. These SNPs together accounted for 15.5% of the cause of CAD. Following examination of results from previous genome-wide association studies and linkage disequilibrium of the identified SNPs, 21 genes (RNF2, YEATS2, USP45, ITGB8, TNS3, FAM170B-AS1, PRKG1, BTRC, MKI67, STIM1, OR52E4, KIAA1551, MON2, PLUT, LINC00354, TRPM1, ADAT1, KRT27, LIPE, GFY and EIF3L) and five chromosomal regions (2p13, 4q31.2, 5q12, 13q34 and 20q13.2) that were significantly associated with CAD were newly identified in the present study. Gene ontology analysis demonstrated that various biological functions were predicted in the 18 genes identified in the present study. The network analysis revealed that the 18 genes had potential direct or indirect interactions with the 30 genes previously revealed to be associated with CAD or with the 228 genes identified in previous genome-wide association studies. The present study newly identified 26 loci that confer susceptibility to CAD. Determination of genotypes for the SNPs at these loci may prove informative for assessment of the genetic risk for CAD in Japanese patients. PMID- 30402225 TI - Alleviation effects of natural volatile organic compounds from Pinus densiflora and Chamaecyparis obtusa on systemic and pulmonary inflammation. AB - Chamaecyparis obtusa (C. obtusa) and Pinus densiflora (P. densiflora) have been traditionally used as antibiotic, antinociceptive and anti-inflammatory agents in Asian folk medicine. Recent studies have demonstrated antioxidant, antiproliferative and anti-inflammatory effects of C. obtusa and P. densiflora extracts. In the present study, volatile organic compounds (VOCs) of C. obtusa and P. densiflora were examined to determine whether they have anti-inflammatory capabilities. To evaluate the anti-inflammatory effects of VOCs of C. obtusa and P. densiflora, lipopolysaccharide (LPS) was administered to the lung by nasal injection and to the whole body by intraperitoneal injection. Alterations in serum immunoglobulin E (IgE) levels and prostaglandin E2 (PgE2) were examined using ELISA. LPS-increased serum IgE and PgE2 levels were recovered by administration of dexamethasone and VOCs of C. obtusa and P. densiflora. Levels of mRNA expression of inflammatory cytokines were determined in an LPS-induced inflammation mouse model. Reverse transcription-quantitative polymerase chain reaction was used to determine the mRNA expression levels of cyclooxygenase 2, interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and IL-13 in peripheral blood mononuclear cells. The expression of all examined cytokine mRNAs increased by LPS was suppressed by dexamethasone and VOCs of C. obtusa and P. densiflora. Similar tendencies were observed in lung tissues and cells obtained via bronchoalveolar lavage. The results of the present study suggested that VOCs of C. obtusa and P. densiflora, through their immunosuppressive activities, may have therapeutic potential in the treatment or prevention of inflammation. PMID- 30402226 TI - Increased intestinal ethanol following consumption of fructooligosaccharides in rats. AB - Previous studies have suggested that ethanol is a fermentation product of microflora. However, it is unknown whether this ethanol production is elevated by intake of prebiotics. Prebiotics are considered to enhance the production of short-chain fatty acids (SCFAs) as a fermentation product of beneficial bacteria. In the present study, the effect of fructooligosaccharides (FOS) consumption on intestinal ethanol levels was investigated. Rats were fed a diet with or without 10% FOS for two weeks. Consequently, FOS intake significantly increased ethanol levels per gram of ileum and cecum digesta of the rats (3.5-fold and 1.9-fold, respectively, P<0.01). The numbers of cecum Bifidobacterium (producer of ethanol and lactate) were significantly increased by FOS intake (P<0.05) and correlated with the cecum ethanol levels per gram of cecum (r=0.626, P<0.05). FOS intake also led to a significant increase in the cecum levels of SCFAs, namely lactate, propionate and n-butyrate (P<0.05). Furthermore, ethanol levels were significantly correlated with lactate levels (r=0.691, P<0.01), but not with propionate or n-butyrate levels (r=0.449 and 0.493, respectively, P>0.05). The current study, to the best of our knowledge, is the first to indicate that FOS intake significantly increases the level of intestinal ethanol. Therefore, dietary FOS may affect the intestinal health status of animals by elevating their ethanol levels, without direct ethanol consumption. PMID- 30402227 TI - A method for extracting DNA from hard tissues for use in forensic identification. AB - With deceased and decayed bodies, personal identification is performed using hard tissue DNA, commonly extracted from bone. The quantity and quality of DNA used in the polymerase chain reaction (PCR) amplification step is critical for a successful outcome. Since enamel is the strongest tissue in the human body, it was hypothesized that teeth may preserve DNA better than bones. In the present study, porcine teeth and bone samples were exposed to a variety of environments that imitated personal identification conditions, and DNA extracted from the teeth and bone samples was compared, using a PCR amplification method. The porcine teeth and bones were exposed to 11 different conditions for 5 different time periods to imitate a series of common crime scenes. DNA was extracted by a standard phenol-chloroform method. To test DNA quality, PCR was performed with primers designed to amplify porcine beta-actin (ACTB) and mitochondrial DNA (mtDNA) sequences. The results demonstrated that the quality of DNA extracted from teeth was greater than that extracted from bone in the following environments: Buried in sand, soaked in caustic soda and burnt with rubber. By contrast, the quality of DNA extracted from bone was greater than that extracted from teeth when samples were buried in soil or submerged in water. There was no discernable difference in the quality of DNA extracted from bones and teeth in several environments, including being submerged in seawater, soaked in sulfuric acid, left in open air, and stored at 4, -20 and -80 degrees C. Additionally, the results suggested that PCR using mtDNA primers performed better than that using ACTB primers. Finally, it was indicated that components of seawater may inhibit PCR amplification. The preliminary data reported here may provide basic guidelines for selecting the optimum source of DNA in each case. PMID- 30402228 TI - Serum homocysteine is associated with polycystic ovarian syndrome in Jordan. AB - Polycystic ovarian syndrome (PCOS) is a prevalent endocrinopathy among women of a reproductive age. Although not included in the diagnostic criteria, insulin resistance (IR) is a major characteristic of PCOS and may contribute to its development. The exact cause of IR remains unknown but appears to be multifactorial. Changes in the levels of leptin, adiponectin, branched-chain amino acids (BCAAs) and/or homocysteine have been reported in women with PCOS. However, the relative contribution of the aforementioned metabolites to PCOS has not been tested in Jordan. In the present study, 154 women diagnosed with PCOS and 151 normally menstruating women matched by age and body mass index (BMI) were recruited. The levels of leptin, adiponectin, BCAAs, homocysteine and 5 methyltetrahydrofolate (5-MTHF) were measured in the serum of the recruited participants. It was revealed that homocysteine levels were significantly elevated in women with PCOS compared with normally menstruating women (P<0.0001), while 5-MTHF (P=0.024), leptin (P=0.027) and adiponectin (P=0.010) levels were significantly lower. In multivariate analysis, serum homocysteine had the strongest association with PCOS and significantly increased its risk [P<0.0001; odds ratio 1.217; 95% confidence interval (CI) 1.157-1.280]. With an area under the curve of 0.855 (95% CI 0.811-0.898) in receiver operating characteristic analysis, serum homocysteine was determined to be a good predictor for PCOS diagnosis based on Rotterdam guidelines. It was concluded that serum levels of homocysteine are elevated in women with PCOS in Jordan independent of age, BMI, or leptin, adiponectin and BCAAs levels. PMID- 30402229 TI - D-dimer as a potential clinical marker for predicting metastasis and progression in cancer. AB - D-dimer is a widely used biomarker for indicating the activation of coagulation and fibrinolysis, and is reported to serve important roles in cancer progression. The aim of the current retrospective study was to investigate the association of D-dimer plasma level with the development of various cancers. Patients with breast (n=86), gastric (n=317), pancreatic (n=37), colon (n=153) and rectal (n=137) cancers and 92 healthy volunteers were assessed in the present study. Plasma levels of D-dimer in the patients and healthy controls were measured by immunoturbidimetric assays. The association of D-dimer levels with the clinicopathological features of patients were also determined. The plasma levels of D-dimer were significantly higher in patients with breast cancer (P=0.0022), gastric cancer (P<0.0001), pancreatic cancer (P=0.0003), colon cancer (P=0.0001) and rectal cancer (P=0.0028), compared with the healthy controls. It was also determined that the plasma D-dimer levels were positively associated with clinical cancer stage (P<0.05) and metastasis (P<0.05). These findings suggested that the plasma D-dimer level may be used as marker for predicting cancer metastasis and progression. PMID- 30402230 TI - Synchronous endometrial and ovarian cancer in Lynch syndrome with a MSH2 germline mutation: A case report. AB - Synchronous endometrial and ovarian cancer (SEOC) is a rare entity among gynecological cancers, which exhibits endometrioid histology in its early stages and generally has a good prognosis. However, diagnosis is difficult and recent reports have demonstrated that most clinically diagnosed cases of SEOC have clonally related cancers, indicating metastatic cancer. The association of SEOC with Lynch syndrome is also not clearly understood. We herein present the case of a 41-year-old SEOC patient with MSH2 mutation. The endometrial cancer was an endometrioid adenocarcinoma and the ovarian cancer was mainly endometrioid, but also included a clear cell carcinoma with a borderline clear cell adenofibromatous component, indicating primary ovarian cancer. Both tumors exhibited microsatellite instability (MSI) and loss of expression of MSH2 and MSH6. The patient had a family history of colorectal and gastric cancers. Genetic analysis revealed a germline mutation in exon 6 of MSH2 (c.1042C>T, p.Gln348*) and the patient was diagnosed with Lynch syndrome. This MSH2 mutation has only been registered in one case in the InSiGHT variant databases and has not been reported in a gynecological tumor or SEOC to date. This case is a rare example of a patient with genetically diagnosed Lynch syndrome who also developed SEOC. This synchronous cancer is not common, but it may be caused by Lynch syndrome. Testing for MSI and immunohistochemistry for mismatch repair deficiency is necessary in cases with suspected SEOC. PMID- 30402231 TI - Invasive Paget's disease of the vulva treated with a combination of surgery and concurrent chemoradiotherapy: A case report. AB - Invasive Paget's disease of the vulva (IP) is rare among patients with vulvar cancer. Radiation therapy and chemotherapy are not considered as radical, whereas surgical resection of the tumor with abdominal lymphadenectomy is highly invasive. Thus, more effective and less invasive treatments for IP are required. The present study reports a case of a 64-year-old woman with IP, who was treated with a combination of surgery and concurrent chemoradiotherapy (CCRT). The patient was diagnosed with IP with suspected lymph node metastases to the inguinal and pelvic lymph nodes, after having suffered from pruritus vulvae for 7 years. Following mapping biopsy, wide local excision, bilateral inguinal lymph node resection and laparoscopic pelvic lymphadenectomy were successfully performed. The vulva was reconstructed with a local fat flap. Postoperative pathological examination revealed metastases to the bilateral superficial inguinal and the left obturator and lateral suprainguinal lymph nodes. Adjuvant CCRT (whole pelvic irradiation, 50.4 Gy with weekly cisplatin, 40 mg/m2) was completed without notable complications. Therefore, laparoscopic pelvic lymphadenectomy may be useful in determining the irradiation field for adjuvant CCRT in patients with advanced IP. PMID- 30402232 TI - Ataxia-telangiectasia with a novel ATM gene mutation and Burkitt leukemia: A case report. AB - Ataxia-telangiectasia (A-T) is an infrequent autosomal recessive disorder that involves multiple systems and is characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, radiosensitivity, immune deficiency with recurrent respiratory infections, and a tendency to develop lymphoid malignancies. A-T is caused by mutations in the ATM gene, with >1,000 mutations reported to date and gradually increasing in number. Patients with A-T have an increased incidence of cancers. The aim of the present study was to retrospectively review the case of a patient who presented at the age of 5 years with cerebellar ataxia without telangiectasia, and was diagnosed with Burkitt leukemia by bone marrow biopsy and molecular testing at the age of 7 years at the Xiangya Hospital of Central South University (Changsha, China). The patient received chemotherapy with the pediatric CCCG-BNHL-2015 regimen (R4 group) and achieved a complete remission after 2 courses. However, recurrent respiratory infections and thrombosis occurred during chemotherapy. The diagnosis of A-T was confirmed by uncovering two variants of the ATM gene, including c.742C>T (p.R248X; rs730881336) in exon 7 and c.6067-c.6068 ins GAGGGAAGAT in exon 41 by whole-exome sequencing. Unfortunately, the patient's parents refused follow-up treatment and he succumbed to recurrent severe infections 4 months after the diagnosis of Burkitt leukemia. The diagnosis of A-T may be challenging, as its phenotype can be incomplete early in the course of the disease. Detailed medical history, characteristic clinical manifestations and increasingly developed exome sequencing techniques may be helpful in diagnosing this rare disease. Management should be based on multidisciplinary guidance and other treatment options must be investigated in the future. PMID- 30402233 TI - Challenges in the management of neuroendocrine cervical cancer during pregnancy: A case report. AB - Large-cell neuroendocrine carcinoma (LCNEC) is an uncommon histological subtype of cervical cancer that is associated with poor survival and its occurrence during pregnancy is particularly rare. We herein present the case of a female patient who was diagnosed with cervical LCNEC during pregnancy. The patient declined pregnancy termination and was treated with neoadjuvant chemotherapy with cisplatin and etoposide, without associated toxicity and with good fetal development. At 31.4 weeks of gestation, the fetus was delivered by caesarean section, and the patient underwent radical nerve-sparing hysterectomy with bilateral adnexectomy, along with pelvic and inframesenteric para-aortic lymphadenectomy. The patient received adjuvant chemoradiotherapy and there was no evidence of recurrence or metastasis at 38 months postoperatively. The baby has also been followed up, without any signs of neurodevelopmental disorders. To the best of our knowledge, the present report describes the first case of LCNEC with pregnancy-preserving management in the literature to date. PMID- 30402234 TI - Gastric outlet obstruction caused by metastatic tumor of the stomach originating from primary breast cancer: A case report. AB - The most common sites of breast cancer metastasis are the bone, liver, lung and brain, while gastrointestinal metastasis from breast cancer is rare. We herein present the case of a 68-year-old woman who was admitted to our department with nausea and appetite loss. The patient's medical history included right mastectomy with sentinel lymph node biopsy 5 years earlier for invasive lobular carcinoma, measuring 6.2 cm in greatest diameter, without lymphovascular invasion. Two years after the surgery, the patient developed brain metastasis and underwent metastasectomy to control the neurological symptoms, including unsteadiness and asthenia. After the second surgery, the patient received systemic chemotherapy using S-1, followed by bevacizumab plus paclitaxel. However, due to bevacizumab related cardiotoxicity, the treatment was switched to eribulin. On esophagogastroduodenoscopy, an elevated lesion was identified in the antrum, causing severe narrowing of the gastric outlet. Biopsy and histological examination of the tumor revealed infiltration of the gastric wall by undifferentiated neoplastic cells with poor adhesion, morphologically similar to invasive lobular carcinoma, and immunohistochemical staining was positive for estrogen receptor, mammaglobin and GATA3. Finally, 18F-2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography combined with computed tomography imaging revealed FDG uptake across the thickness of the antral wall. The patient was diagnosed with gastric metastasis from the original breast cancer and subsequently underwent endoscopic self-expandable metallic stent (SEMS) placement. There were no procedure-related adverse events, and the patient remained alive under best supportive care 4 months after SEMS placement. To the best of our knowledge, this is the first reported case of gastric outlet obstruction caused by metastatic breast carcinoma managed by SEMS placement. While such a diagnosis is rare, clinicians treating patients with gastric metastases should be aware of possible gastric outlet obstruction and SEMS placement as an effective palliative intervention. PMID- 30402235 TI - Bone metastasis from cholangiocarcinoma mimicking osteosarcoma: A case report and review literature. AB - Cholangiocarcinoma is an aggressive tumor of the hepatic biliary system and it commonly spreads to the regional lymph nodes, liver and lungs. However, bone metastasis from cholangiocarcinoma is rare compared with other tumors. We herein present the case of a 61-year-old Asian woman who presented with pain in the right scapular area. Magnetic resonance imaging revealed bone destruction and an adjacent soft tissue mass at the right scapula. The findings on computed tomography imaging were compatible with cholangiocarcinoma. Bone biopsy was performed and the diagnosis of cholangiocarcinoma with bone metastasis was confirmed. The survival time was 10 months, despite administration of palliative radiotherapy and chemotherapy. Therefore, bone metastasis from cholangiocarcinoma should be considered as a differential diagnosis in patients who present with an osteolytic bone lesion and a liver mass. PMID- 30402237 TI - Two thousand years of epidemics in Marseille and the Mediterranean Basin. AB - Marseille has been exposed to epidemics for two millennia, including plague, cholera and yellow fever. This long-standing exposure to epidemics has given the people of Marseilles a particular expertise in fighting epidemics. Lazarets and other quarantine measures were implemented as a response to preventing the further spread of the disease in the community. The Institut Hospitalier Universitaire Mediterranee Infection is paving the way today, with its responses built on the region's long history and knowledge of epidemics, infectious diseases and medical microbiology. PMID- 30402236 TI - Lymph node metastasis and high serum CEA are important prognostic factors in hormone receptor positive and HER2 negative breast cancer. AB - In recent years, treatment options for breast cancer have increased, and prognosis has improved since the 1990s. The present study examined the prognosis for recurrence of breast cancer between 2006 and 2009, in comparison with the results of past treatments, and sought to guide future treatment strategies by elucidating present prognostic factors. A total of 662 patients with breast cancer stage 0-III who underwent surgery at Kitasato University Hospital between January 2006 and March 2009 were included. Cases were classified into four subtypes, based on the presence or absence of hormone receptors and human epidermal growth factor receptor 2 (HER2). Factors associated with recurrence and prognosis were then examined. The 5-year recurrence-free survival (RFS) was 94.9% and the 5-year disease-specific survival (DSS) was 98.4%. Factors related to RFS were pathological lymph node (pN) positive [hazard ratio (HR)=2.85, P=0.001], clinical lymph node (cN) positive (HR=2.28, P<0.01), and hormone receptor negative (HR=1.83, P<0.05). Factors associated with DSS were cN positive (HR=4.55, P<0.01), pN positive (HR=3.40, P<0.05), higher preoperative serum carcinoembryonic antigen (CEA) (HR=3.04, P<0.05), and hormone receptor negative (HR=2.32, P<0.05). In the hormone receptor positive HER2 negative, cN-positive/pN positive breast cancer group, RFS and DSS were poorer compared with the other groups. In this group, preoperative high CEA level was a poor prognostic factor. The prognosis for hormone receptor positive HER2-negative breast cancer has improved significantly since the 1990s. On the other hand, the prognosis for cN positive/pN-positive breast cancer was poor. Pre-treatment serum CEA positive cases exhibited a particularly poor prognosis. PMID- 30402238 TI - Emerging infectious diseases in Africa in the 21st century. AB - Many infectious diseases have emerged or reemerged in Africa in the 21st century. Some of them are associated with newly discovered microorganisms such as Rickettsia felis and Tropheryma whipplei; others are known, historical diseases such as plague and cholera. In addition are diseases related to previously known microorganisms which recently have been involved for the first time in massive outbreaks with worldwide impacts (such as Ebola virus, Zika virus and Chikungunya virus). Research on emerging infectious diseases needs to be identified as a priority. PMID- 30402239 TI - Mansonellosis, the most neglected human filariasis. AB - Human mansonellosis is caused by M. perstans, M. ozzardi and M. streptocerca, the three main filarial species in the genus Mansonella. Despite accumulating evidence of a high prevalence in endemic areas, there is currently no filariasis control programme targeting mansonellosis. The health-related impact on people living with these filariae remains unknown, and evidences regarding treatment strategies are scarce. Like other neglected diseases, it mainly affects poor populations living in tropical and subtropical climates. Mansonellosis can be considered one of the most neglected tropical infectious diseases. The objective of this literature review was to draw attention to the gap of knowledge regarding Mansonella spp. taxonomy, the transmission of these arthropod-borne filariasis and the health outcomes of people living with mansonellosis. PMID- 30402241 TI - Neglected vector-borne bacterial diseases and arboviruses in the Mediterranean area. AB - Arthropod vectors can transmit pathogenic microorganisms from one vertebrate to another during their blood meal. Although some vector-borne diseases have been eradicated in the Mediterranean area, such as malaria and dengue, recent endemic microorganisms (Toscana virus, Rickettsia spp.) remain neglected even though they cause many more cases. New diagnostic tools and innovative tools for the identification and characterization of vector species and microorganisms have been developed at IHU Mediterranee Infection, either internally or through collaborative and integrated projects. We have detected Rickettsia slovaca as a human pathogen and have described the disease; we have shown that Rickettsia felis can be transmitted by Anopheles mosquitoes; we have emphasized the increasing importance of bedbug (Cimex lectularius) as a potential vector of Bartonella quintana; and we have described the Toscana virus, a major agent of meningitis and meningoencephalitis which was disseminated in North Africa and Central and Eastern Europe, where it frequently cocirculates with a large number of newly described phleboviruses transmitted by sand flies. PMID- 30402240 TI - Malaria, tuberculosis and HIV: what's new? Contribution of the Institut Hospitalo Universitaire Mediterranee Infection in updated data. AB - The Institut Hospitalo-Universitaire Mediterranee Infection is positioned for the diagnosis, prevention and treatment of the 'big three' killer diseases: malaria, tuberculosis and HIV. We implemented the use of new diagnostic samples such as stools and new diagnostic tests such as mass spectrometry for the dual identification of vectors and pathogens. Furthermore, advances in the prevention and treatment of malaria and tuberculosis are reviewed, along with advances in the understanding of the role of microbiota in the resistance to HIV infection. These achievements represent a major step towards a better management of the 'big three' diseases worldwide. PMID- 30402242 TI - Investigations by the Institut Hospitalo-Universitaire Mediterranee Infection of food and food-borne infections in the Mediterranean Basin and in sub-Saharan Africa. AB - Food-borne infections are major causes of public health concern in developing and developed countries. During the past decade, the Institut Hospitalo-Universitaire Mediterranee Infection has conducted or been involved in multiple investigations that aimed at identifying the sources and strains responsible for food-borne diseases and therefore at improving the understanding, diagnosis, prevention and control of these infections. Investigations were conducted in the Mediterranean area and in sub-Saharan Africa on more than 15 food-borne agents, 17 food products and 14 antibiotic resistance-associated genes. Multiple sources, including unexpected ones, and pathogens, including emerging ones, were involved. Travelling in developing countries and zoonoses are major contributors to food borne infections, while food-borne transmission of resistance-associated genes is increasingly reported. However, risk factors and pathogens associated with food borne infections likely remain untapped and must be more extensively investigated, monitored and regularly reassessed. Diagnostic tests based on new technologies and real-time surveillance tools based on microbiology laboratory data are promising approaches to detect known food-borne infections and decipher new ones. Studies of the microbiota and its relationships with dietary patterns are also worth being conducted. PMID- 30402246 TI - Installing biosafety level 3 containment laboratories in low- and middle-income countries: challenges and prospects from Mali's experience. AB - In Mali, the incidence of tuberculosis (TB) is estimated at 56 cases per 100 000 people, with a prevalence of multidrug-resistant TB in new cases of 1.7% (range, 0.3-3.1%) and in retreatment cases of 17% (range, 4.4-30%). Appropriate biosafety conditions for performing routine TB culture and antimicrobial susceptibility testing have been lacking. In 2015, a biosafety level 3 (BSL3) laboratory set up in a shipping container was donated to the Malian Ministry of Health and Public Hygiene to provide capacity for TB testing. This laboratory is now managed by Malian laboratory staff and is processing samples at the national level. We explain the necessary steps for establishing and running a BSL3 laboratory. Despite the acute need for functioning and sustainable BSL3 laboratories, low- and middle-income countries are faced with a complex process and must overcome many challenges. PMID- 30402244 TI - Role of Institut Hospitalo-Universitaire Mediterranee Infection in the surveillance of resistance to antibiotics and training of students in the Mediterranean basin and in African countries. AB - Surveillance of antibiotic resistance has become a public global concern after the rapid worldwide dissemination of several antibiotic resistance genes. Here we report the role of the Institut Hospitalo-Universitaire Mediterranee Infection created in 2011 in the identification and description of multidrug-resistant bacteria thanks to collaborations and training of students from the Mediterranean basin and from African countries. Since the creation of the institute, 95 students and researchers have come from 19 different countries from these areas to characterize 6359 bacterial isolates from 7280 samples from humans (64%), animals (28%) and the environment (8%). Most bacterial isolates studied were Gram negative bacteria (n = 5588; 87.9%), mostly from Algeria (n = 4190), Lebanon (n = 946), Greece (n = 610), Saudi Arabia (n = 299) and Senegal (n = 278). Antibiotic resistance was diversified with the detection and characterization of extended spectrum beta-lactamases, carbapenemases and resistance to colistin, vancomycin and methicillin. All those studies led to 97 indexed international scientific papers. Over the last 6 years, our institute has created a huge network of collaborations by training students that plays a major role in the surveillance of resistance to antibiotics in these countries. PMID- 30402243 TI - Endocarditis in the Mediterranean Basin. AB - Infective endocarditis is a severe disease with high mortality. Despite a global trend towards an increase in staphylococcal aetiologies, in older patients and a decrease in viridans streptococci, we have observed in recent studies great epidemiologic disparities between countries. In order to evaluate these differences among Mediterranean countries, we performed a PubMed search of infective endocarditis case series for each country. Data were available for 13 of the 18 Mediterranean countries. Despite great differences in diagnostic strategies, we could classify countries into three groups. In northern countries, patients are older (>50 years old), have a high rate of prosthetic valves or cardiac electronic implantable devices and the main causative agent is Staphylococcus aureus. In southern countries, patients are younger (<40 years old), rheumatic heart disease remains a major risk factor (45-93%), viridans streptococci are the main pathogens, zoonotic and arthropod-borne agents are frequent and blood culture-negative endocarditis remains highly prevalent. Eastern Mediterranean countries exhibit an intermediate situation: patients are 45 to 60 years old, the incidence of rheumatic heart disease ranges from 8% to 66%, viridans streptococci play a predominant role and zoonotic and arthropod borne diseases, in particular brucellosis, are identified in up to 12% of cases. PMID- 30402245 TI - Highly infectious diseases in the Mediterranean Sea area: Inventory of isolation capabilities and recommendations for appropriate isolation. AB - Epidemics such as viral haemorrhagic fevers, severe acute respiratory syndrome, Middle East respiratory syndrome coronavirus or yet unknown ones have few chances of disappearing. Globalization, worldwide travel, climate change, social conflicts and wars, among others, are likely to favor the emergence of epidemics. Preparedness of hospitals to prevent the spread of these outbreaks is among the prioritized political programmes of many countries. The EuroNHID network has in the past drawn a map of features and equipment of hospitals across Europe to take care of highly contagious patients. We update the data regarding isolation capabilities and recommendations, with an emphasis on Mediterranean countries. PMID- 30402247 TI - Contribution of the French army health service in support of expertise and research in infectiology in Africa. AB - Historically, infectious diseases have caused more casualties than battle. The French military health service therefore developed a range of research on vector borne diseases such as malaria and arboviruses, antibiotic resistance, infectious agents that can be used as biological weapons and vaccines. The main objective is to control naturally acquired or provoked infectious diseases and limit their impact on armed forces as well as on civilian populations in France or abroad, particularly in Africa and anywhere French armies may be deployed. The expertise of the military health service teams in manipulating agents requiring high level of biosafety precautions and in organizing and providing medical care in unnatural conditions, including the battlefield, associated with complementarity staff experience (physicians, biologists, epidemiologists, researchers, pharmacists, logisticians), has been used in the management of the Ebola outbreak in Guinea. PMID- 30402248 TI - MALDI-TOF MS and point of care are disruptive diagnostic tools in Africa. AB - We review reviewing our experience of point-of-care and mass spectrometry in Senegal as two disruptive technologies promoting the rapid diagnosis of infection, permitting better medical management of patients. PMID- 30402249 TI - Naming microorganisms: the contribution of the IHU Mediterranee Infection, Marseille, France. AB - The number of isolated new microorganisms has dramatically increased after the readaption of culture using the culturomics approach. Each of these microorganisms is deposited in an international strain collection institute, with its name being attributed and published by the scientist who isolated it. The attributed name is of Latin or Latinized origin and chosen on the basis of the geographical location of the sample collection, the institute or geographical region where the project was being performed, the name of a concerned scientist, and characteristics of the sample or the microorganism. Our institution has played an important role in the isolation of new microorganisms, with the first effort reporting 468 new bacterial species (3% of the bacterial species isolated at least once worldwide) and 327 species isolated for the first time from human beings, which in turn resulted in an increase of 30% of the total number of microorganisms isolated. Additionally, more than 100 giant viruses, including seven new species, have been isolated at our institute. In the present work, after recalling the rules of nomenclature, we detail the naming of the new microorganisms chosen at our laboratory. The most common species name was massiliensis, attributed 161 times. We consider it imperative for the cultivators, who have frequently made considerable efforts in the field of microbial culture, to be the ones who name the newly isolated microorganisms, taking into consideration the Latinized nomenclature standards. PMID- 30402250 TI - Mobile populations across the Mediterranean Sea and beyond: travel medicine, mass gathering medicine and homeless health. AB - The Mediterranee Infection institute is internationally recognized for its expertise in infectious diseases and tropical medicine, and is one of the most active research centres for infectious diseases in Europe. Surveillance and research addressing infectious diseases in globally mobile populations is one of the strong components of the research conducted at the institute. A significant amount of clinical, microbiologic and epidemiologic works have been conducted in international travellers, pilgrims participating in large international religious gatherings, economic migrants and homeless migrant people over the last decades by our group. Our strong anchoring in several countries around the Mediterranean Sea and beyond, as well as the pivotal role of Marseille in the EuroTravNet and GeoSentinel international networks that monitor travel-associated diseases, reinforce our leading position in the fields of travel and tropical medicine, mass gathering medicine and homeless health. PMID- 30402251 TI - Sex and bacterial infectious diseases. AB - Most infectious diseases are unequally distributed between male and female subjects. This sex dimorphism is confirmed by epidemiologic studies which suggest an increased number of male septic patients, while, due to the class age of septic patients, an overrepresentation of female patients would be expected. Lifestyle, recreational activities, professional exposition and access to care are plausible reasons for this dimorphism. However, biological differences should be carefully considered, particularly the weight of X-linked variability and the role of sex hormones. Animal models clearly show that clinical response to infection is more exuberant in males than in females. This is partly explained by an attenuation of the inflammatory response by female sex hormones. However, the translation from experimental studies to the bedside remains challenging as a result of confounding factors like age, hormone changes and response to treatment. PMID- 30402253 TI - Higher education at the Institut Hospitalo-Universitaire Mediterranee Infection. AB - Since its creation in 2011, the Institut Hospitalo-Universitaire Mediterranee Infection (IHU MI) has devoted a major part of its funding to support higher education programs. In 2017, on a recurrent budget of 5.8 million Euros per year, 2.9 (50%) were spent on infrastructure, mostly for maintenance and equipment of our new building. Among the remaining 2.9 million Euros, 2.3 (80%) have been dedicated to support higher education programs. PMID- 30402252 TI - Studies of nonhuman primates: key sources of data on zoonoses and microbiota. AB - The genetic and morphologic similarities between primates and humans means that much information obtained from primates may be applied to humans, and vice versa. However, habitat loss, hunting and the continued presence of humans have a negative effect on the biology and behaviour of almost all nonhuman primates. Noninvasive methods such as stool collection are among the safest alternative ways to study the multiple aspects of the biology of primates. Many epidemiologic issues (e.g. pathogen detection, microbiota studies) may be easily studied using stool samples from primates. Primates are undoubtedly among the first candidates suspected of becoming the source of one of the next emerging epidemic of zoonotic origin, as has already been observed with HIV, malaria and monkeypox. The Institut Hospitalo-Universitaire Mediterranee Infection in Marseille actively participates in the study, mostly epidemiologic, of nonhuman primates, using mostly stool samples. PMID- 30402254 TI - Influence of previous medical treatments on social rank in dairy cows. AB - Animal health can present economic and animal welfare concerns for dairy farmers. However, it is unknown whether changes in behaviour as a result of sickness have long-term effects, and whether there is a relationship between the social rank of cows in the herd at a moment in time and the medical treatment history of these cows. The behaviour of 100 high-yielding cows in the waiting area (collecting yard) before the milking parlour was studied for five milking sessions to assess the interactions between the cows, as the cows waited to be milked. The cows were filmed, and the interactions between cows were recorded using an ethogram. The summated social rank score of each cow was compared with its medical treatment history. In our analysis, a positive relationship was found between medical treatment history and social rank, however this association was discounted when age was accounted for. When a subsample of cows older than 4.0 years was analysed to examine the relationship between social rank and medical treatment history in older cows, no significant correlation existed. These results suggest that the relationship between social rank and medical treatment history identified in the analysis is predominately an effect of age. This finding is contradictory to the hypothesis that 'a higher historical level of medical treatments, and the disruption and setbacks associated with these disease conditions, would result in a lower position in the social rank.' This preliminary study reports the findings from one particular herd, and across one relatively short time span, and because associations between treatment history and behaviour may be of interest in management decisions for producers, it is recommended that further investigation of this subject is carried out. PMID- 30402255 TI - Early coronary angiography and survival after out-of-hospital cardiac arrest: a systematic review and meta-analysis. AB - Background: Although acute myocardial infarction is a common cause of out-of hospital cardiac arrest (OHCA), the role of early coronary angiography in OHCA remains uncertain. We conducted a meta-analysis of observational studies to determine the association of early coronary angiography with survival in OHCA. Methods: We searched multiple electronic databases for published studies on early coronary angiography in OHCA between 1 January 1990 and 18 January 2017. Studies were included if (1) restricted to only OHCA, (2) included an exposure group that underwent early coronary angiography within 1 day of arrest onset and a concurrent control group that did not undergo early coronary angiography, and (3) reported survival outcomes. We used a random-effects model to obtain pooled OR. I2 statistics and Cochran's Q test were used to determine between-study heterogeneity. Results: A total of 17 studies with 14 972 patients were included, of whom 6424 (44%) received early coronary angiography. Early coronary angiography was associated with higher odds of survival (pooled OR 2.54 (95% CI 1.94 to 3.33)) and survival with favourable neurological outcome (pooled OR 2.37 (95% CI 1.71 to 3.28)). However, there was substantial heterogeneity in our pooled estimate (I2=88% and p value for Cochran's test <0.0001 for both outcomes). The large heterogeneity in pooled estimates was reduced after including adjusted estimates when available, and was explained by differences in methodological rigour and characteristics of included studies. Conclusion: Among patients resuscitated from OHCA, early coronary angiography is associated with increased survival to discharge and favourable neurological outcome. PMID- 30402256 TI - Childhood and adult exposure to secondhand tobacco smoke and cardiac structure and function: results from Echo-SOL. AB - Objective: To describe the relationship of household secondhand smoke (SHS) exposure and cardiac structure and function. Methods: Participants (n=1069; 68 % female; age 45-74 years) without history of tobacco use, coronary artery disease or severe valvular disease were included. Past childhood (starting at age <13 years), adolescent/adult and current exposure to household SHS was assessed. Survey linear regression analyses were used to model the relationship of SHS exposure and echocardiographic measures of cardiac structure and function, adjusting for covariates (age, sex, study site, alcohol use, physical activity and education). Results: SHS exposure in childhood only was associated with reduced E/A velocity ratio (beta=-0.06 (SE 0.02), p=0.008). SHS exposure in adolescence/adult only was associated with increased left ventricular ejection fraction (LVEF) (1.2 (0.6), p=0.04), left atrial volume index (1.7 (0.8), p=0.04) and decreased isovolumic relaxation time (-0.003 (0.002), p=0.03). SHS exposure in childhood and adolescence/adult was associated with worse left ventricular global longitudinal strain (LVGLS) (two-chamber) (0.8 (0.4), p= 0.049). Compared with individuals who do not live with a tobacco smoker, individuals who currently live with at least one tobacco smoker had reduced LVEF (-1.4 (0.6), p=0.02), LVGLS (average) (0.9 (0.40), p=0.03), medial E' velocity (-0.5 (0.2), p=0.01), E/A ratio (-0.09 (0.03), p=0.003) and right ventricular fractional area change ( 0.02 (0.01), p=0.01) with increased isovolumic relaxation time (0.006 (0.003), p=0.04). Conclusions: Past and current household exposure to SHS was associated with abnormalities in cardiac systolic and diastolic function. Reducing household SHS exposure may be an opportunity for cardiac dysfunction prevention to reduce the risk of future clinical heart failure. PMID- 30402257 TI - Assessing the risk of preterm birth for newborns with congenital heart defects conceived following infertility treatments: a population-based study. AB - Objectives: To quantify the risk of preterm birth (PTB) for newborns with congenital heart defects (CHDs) conceived following infertility treatments, and to examine the role of multiple pregnancies in the association between infertility treatments and PTB for newborns with CHD. Methods: We used data from a population-based, prospective cohort study (EPICARD EPIdemiologie des CARDiopathies congenitales) including 2190 newborns with CHD and excluding cases with atrial septal defects born to women living in the Greater Paris area between May 2005 and April 2008. Statistical analysis included logistic regression to take into account potential confounders (maternal characteristics, invasive prenatal testing, CHD prenatal diagnosis, medically induced labour/caesarean section before labour, birth year). The role of multiple pregnancies was assessed using a path-analysis approach, allowing decomposition of the total effect of infertility treatments on the risk of PTB into its indirect (mediated by the association between infertility treatments and multiple pregnancies) and direct (mediated by mechanisms other than multiple pregnancies) effects. Results: PTB occurred for 40.6% (95% CI 28.7 to 52.5) of newborns with CHD conceived following infertility treatments vs 12.7% (95% CI 11.3 to 14.2) for spontaneously conceived newborns (p<0.001). After taking into account potentially confounding factors, infertility treatments were associated with a 5.0-fold higher odds of PTB (adjusted OR=5.0, 95% CI 2.9 to 8.6). Approximately two-thirds of this higher risk of PTB associated with infertility treatments was an indirect effect (ie, due to multiple pregnancies) and one-third was a direct effect (ie, not mediated by multiple pregnancies). Conclusion: Newborns with CHD conceived following infertility treatments are at a particularly high risk of PTB, exposing over 40% of them to the 'double jeopardy' of CHD and PTB. PMID- 30402258 TI - High prevalence of undiagnosed COPD among patients evaluated for suspected myocardial ischaemia. AB - Objective: Chronic obstructive pulmonary disease (COPD) and coronary artery disease (CAD) are leading causes of global morbidity and mortality. Despite the well-known comorbidity between COPD and CAD, the presence of COPD may be overlooked in patients undergoing coronary evaluation. We aimed to assess the prevalence of undiagnosed COPD among outpatients evaluated due to suspected myocardial ischemia. Methods: Among 500 outpatients who were referred to myocardial perfusion imaging due to suspected stable myocardial ischaemia, 433 patients performed spirometry. Of these, a total of 400 subjects (age 66 years; 45% women) had no previous COPD diagnosis and were included in the current study. We compared the prevalence of previously undiagnosed COPD according to spirometry criteria from The Global Initiative for Chronic Obstructive Lung Disease (GOLD) or lower limit of normal (LLN) and reversible myocardial ischaemia according to symptoms and clinical factors. Results: A total of 134 (GOLD criteria; 33.5 %) or 46 patients (LLN criteria; 11.5%) had previously undiagnosed COPD, whereas 55 patients (13.8 %) had reversible myocardial ischaemia. The presenting symptoms (chest discomfort, dyspnoea) did not differ between COPD, myocardial ischaemia and normal findings. Except for smoking, no clinical factors were consistently associated with previously undiagnosed COPD. Conclusions: Among middle-aged outpatients evaluated due to suspected myocardial ischaemia, previously undiagnosed COPD is at least as common as reversible myocardial ischaemia and the presenting symptoms do not differentiate between these entities. Patients going through a coronary ischaemia evaluation should be additionally tested for COPD, especially if there is a positive history of smoking. PMID- 30402259 TI - Mapping the potential of community first responders to increase cardiac arrest survival. AB - Objective: Resuscitation from out-of-hospital cardiac arrest (OHCA) is largely determined by the availability of cardiopulmonary resuscitation (CPR) and defibrillation within 5-10 min of collapse. The potential contribution of organised groups of volunteers to delivery of CPR and defibrillation in their communities has been little studied. Ireland has extensive networks of such volunteers; this study develops and tests a model to examine the potential impact at national level of these networks on early delivery of care. Methods: A geographical information systems study considering all statutory ambulance resource locations and all centre point locations for community first responder (CFR) schemes that operate in Ireland were undertaken. ESRI ArcGIS Desktop 10.4 was used to map CFR and ambulance base locations. ArcGIS Online proximity analysis function was used to model 5-10 min drive time response areas under sample peak and off-peak conditions. Response areas were linked to Irish population census data so as to establish the proportion of the population that have the potential to receive a timely cardiac arrest emergency response. Results: This study found that CFRs are present in many communities throughout Ireland and have the potential to reach a million additional citizens before the ambulance service and within a timeframe where CPR and defibrillation are likely to be effective treatments. Conclusion: CFRs have significant potential to contribute to survival following OHCA in Ireland. Further research that examines the processes, experiences and outcomes of CFR involvement in OHCA resuscitation should be a scientific priority. PMID- 30402260 TI - Lamin mutation location predicts cardiac phenotype severity: combined analysis of the published literature. AB - Objective: Two LMNA genotype-phenotype cardiac correlations are reported: first, that cardiac involvement in multisystem laminopathies prevails with mutations upstream of the nuclear localisation signal (NLS); second, that worse outcomes occur with non-missense (compared with missense) mutations. We tested whether LMNA mutation DNA location and mutation subtype can predict phenotype severity in patients with lamin heart disease. Methods: We used a semantic workflow platform and manual electronic literature search to identify published LMNA mutations with cardiac-predominant phenotype. Hierarchical cluster analysis (HCA) assembled lamin heart disease into classes based on phenotype severity. 176 reported causative mutations were classified and any relationships to mutation location/subtype assessed by contingency analysis. Results: More adverse phenotype was associated with mutation location upstream of the NLS (p=0.014, OR 2.38, 95% CI 1.19 to 4.80) but not with non-missense mutations (p=0.337, OR 1.36, 95% CI 0.72 to 2.57), although an association with non-missense mutations was identified in a subcluster with malignant ventricular arrhythmia (p=0.005, OR 2.64, 95% CI 0.76 to 9.21). HCA limited to the 65 mutations described on ClinVar as pathogenic/likely pathogenic showed similar findings (upstream of NLS, p=0.030, OR 4.78, 95% CI 1.28 to 17.83; non-missense, p=0.121, OR 2.64, 95% CI 0.76 to 9.21) as did analysis limited to pathogenic/likely pathogenic variants according to the American College of Medical Genetics and Genomics standards. Conclusion: Cardiac patients with an LMNA mutation located upstream versus downstream of the NLS have a more adverse cardiac phenotype, and some missense mutations can be as harmful as non-missense ones. PMID- 30402261 TI - Vision loss in glioblastoma: Disease mimicking presumed therapeutic toxicity. AB - Glioblastoma is the most common and lethal form of primary brain cancer. In the recurrent setting, bevacizumab is a common choice for salvage therapy. Loss of vision in patients initially treated with radiation at the time of diagnosis and later treated with bevacizumab at time of recurrence has been reported, and presumed to be a treatment-related optic neuropathy. Strikingly, only 1 case report described a postmortem biopsy to rule out tumor involvement of the optic tracts. We report the first case of recurrent glioblastoma infiltrating the prechiasmatic and chiasmatic optic nerve, which at the time of vision loss was presumed to be secondary to bevacizumab. It is noteworthy that the MRI findings in the previously reported bevacizumab/radiation-induced optic neuropathy cases (without pathology follow-up) are comparable to our patient. PMID- 30402262 TI - Early detection of recurrent medulloblastoma: the critical role of diffusion weighted imaging. AB - Background: Imaging diagnosis of medulloblastoma recurrence relies heavily on identifying new contrast-enhancing lesions on surveillance imaging, with diffusion-weighted imaging (DWI) being used primarily for detection of complications. We propose that DWI is more sensitive in detecting distal and leptomeningeal recurrent medulloblastoma than T1-weighted postgadolinium imaging. Methods: We identified 53 pediatric patients with medulloblastoma, 21 of whom developed definitive disease recurrence within the brain. MRI at diagnosis of recurrence and 6 months prior was evaluated for new lesions with reduced diffusion on DWI, contrast enhancement, size, and recurrence location. Results: All recurrent medulloblastoma lesions demonstrated reduced diffusion. Apparent diffusion coefficient (ADC) measurements were statistically significantly lower (P = .00001) in recurrent lesions (mean=0.658, SD=0.072) as compared to contralateral normal region of interest (mean=0.923, SD=0.146). Sixteen patients (76.2%) with disease recurrence demonstrated contrast enhancement within the recurrent lesions. All 5 patients with nonenhancing recurrence demonstrated reduced diffusion, with a mean ADC of 0.695 +/- 0.101 (normal=0.893 +/- 0.100, P = .0027). While group 3 and group 4 molecular subtypes demonstrated distal recurrence more frequently, nonenhancing metastatic disease was found in all molecular subtypes. Conclusion: Recurrent medulloblastoma lesions do not uniformly demonstrate contrast enhancement on MRI, but all demonstrate reduced diffusion. Our findings support that DWI is more sensitive than contrast enhancement for detection of medulloblastoma recurrence, particularly in cases of leptomeningeal nonenhancing disease and distal nonenhancing focal disease. As such, recurrent medulloblastoma can present as a reduced diffusion lesion in a patient with normal postgadolinium contrast MRI. PMID- 30402263 TI - Late toxicity in long-term survivors from a phase 2 study of concurrent radiation therapy, temozolomide and valproic acid for newly diagnosed glioblastoma. AB - Background: Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor activity shown to enhance overall survival and progression free survival in patients with newly diagnosed glioblastoma (GBM). This reports on the late toxicity of the VPA/radiotherapy (RT)/temozolomide (TMZ) combination in the long-term survivors of a phase 2 study evaluating this regimen. Methods: 37 patients with newly diagnosed GBM were initially enrolled on this trial and received combination therapy. VPA/RT/TMZ related late toxicities were evaluated in the 6 patients that lived greater than 3 years using the Cancer Therapy and Evaluation Program Common Toxicity Criteria (CTC) Version 4.0 for toxicity and adverse event reporting as well as the RTOG/EORTC Radiation Morbidity Scoring Scheme. Results: The median duration of follow-up for these 6 patients was 69.5m. In this cohort, the median OS was 73.8m (60.8-103.8m) and median PFS was 53.1m (37.3 - 103.8m). The most common late toxicity of VPA in conjunction with RT/TMZ were the CTC classifications of neurological, pain, and blood/ bone marrow toxicity and most were grade 1/2. There were only two grade 3/4 toxicities. Conclusions: The addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated with little late toxicity. Additionally, VPA may result in improved outcomes as compared to historical data and merits further study. PMID- 30402264 TI - Multidimensional minimal clinically important differences in knee osteoarthritis after comprehensive rehabilitation: a prospective evaluation from the Bad Zurzach Osteoarthritis Study. AB - Objective: To determine minimal clinically important differences (MCIDs) for improvement and worsening in various health dimensions in knee osteoarthritis under conservative therapy. Methods: Health, symptoms and function were assessed by the generic Short Form 36 and the condition-specific Western Ontario and McMaster Universities Osteoarthritis Index in n=190 patients with knee osteoarthritis before and after comprehensive rehabilitation intervention (3 month follow-up). By means of construct-specific transition questions, MCIDs were defined as the difference between the 'slightly better/worse' and the 'almost equal' transition response categories according to the 'mean change method'. The bivariate MCIDs were adjusted for sex, age and baseline score to obtain adjusted MCIDs by multivariate linear regression. They were further standardised as (baseline) effect sizes (ESs), standardised response means (SRMs) and standardised mean differences (SMDs) and compared with the minimal detectable change with 95% confidence (MDC95). Results: Multivariate, adjusted MCIDs for improvement ranged from 2.89 to 16.24 score points (scale 0-100), corresponding to ES=0.14 to 0.63, SRM=0.17 to 0.61 and SMD=0.18 to 0.72. The matching results for worsening were -5.80 to -12.68 score points, ES=-0.30 to -0.56, SRM=-0.35 to 0.52 and SMD=-0.35 to -0.58. Almost all MCIDs were larger than the corresponding MDC95s. Conclusions: This study presents MCIDs quantified according to different methods over a comprehensive range of health dimensions. In most health dimensions, multivariate adjustment led to higher symmetry between the MCID levels of improvement and worsening. MCIDs expressed as standardised effect sizes (ES, SRM, SMD) and adjusted by potential confounders facilitate generalisation to the results of other studies. PMID- 30402265 TI - Effect of high-intensity interval training on cardiovascular disease risk factors and body composition in psoriatic arthritis: a randomised controlled trial. AB - Background: Psoriatic arthritis (PsA) is associated with an accumulation of cardiovascular disease (CVD) risk factors. The aim of this study was to evaluate the effect of high-intensity interval training (HIIT) on CVD risk factors in patients with PsA. Methods: We randomly assigned 61 patients with PsA (41 women and 20 men) to an intervention group performing HIIT for 11 weeks or a control group who were instructed to not change their physical exercise habits. Outcomes were assessed at 3 and 9 months with measures on maximal oxygen uptake (VO2max), fat percentage and Body Mass Index (BMI). We used linear mixed models to calculate mean difference with 95% CI between the groups according to the intention-to-treat principle. Results: At 3 months, the HIIT group had a 3.72 mL/kg/min (95% CI 2.38 to 5.06) higher VO2max and a 1.28 (95% CI -2.51 to -0.05) lower truncal fat percentage than controls. There was also some evidence that the HIIT group had lower total fat percentage (-0.80; 95% CI -1.71 to 0.10) and slightly lower BMI (-0.31; 95% CI -0.78 to 0.17) than the control group. At 9 months, the HIIT group had still a higher VO2max (3.08; 95% CI 1.63 to 4.53) than the control group, whereas the difference in other factors were small. Conclusion: In patients with PsA, 3 months with HIIT was associated with a substantial increase in VO2max and a reduction in truncal fat percentage compared with controls. The beneficial effect on VO2max was also sustained through 9 months. Trial registration number: NCT02995460. PMID- 30402267 TI - Neutropaenia in early rheumatoid arthritis: frequency, predicting factors, natural history and outcome. AB - Objectives: To determine the frequency, severity and natural history of neutropaenia in early rheumatoid arthritis (RA), explore its associations with clinical features and assess its impact on clinical management. Methods: The Scottish Early Rheumatoid Arthritis inception cohort prospectively recruited patients with newly diagnosed RA and followed them up every 6 months. Patients with RA who developed at least one episode of neutropaenia (grade 1: <2.0*10^9/L; grade 2: <1.5*10^9/L; grade 3: <1.0*10^9/L; grade 4: <0.5*10^9/L) were compared with those who did not. Comparisons were also made between patients who experienced one or more episodes of neutropaenia and between patients with different neutropaenia grades. Results: 77 neutropaenia episodes were recorded in 58 of 771 (7.5%) patients with RA, who were followed up for a median (range) of 18 (6-48) months. Neutropaenia occurred at a median (range) of 12 (0-120) months after RA diagnosis. The majority had mild neutropaenia (grade 1: n=42; grade 2: n=14; grade 3: n=1; grade 4: n=1). Neutropaenia was transient (single episode) in the majority (44; 75.8%) of cases but led to treatment discontinuation in 14 (24.1%) patients. Patients who developed neutropaenia were more likely to be female (p=0.01) and non-smokers (p=0.007) and had lower baseline neutrophil levels (p<0.0001). Binomial regression analysis confirmed the latter (p<0.0001, B: -0.491) as neutropaenia predictor. The rate of infections did not differ between patients who developed neutropaenia and those who did not (p=0.878). Conclusion: Neutropaenia was a common finding in this cohort. It was usually mild, transient and not associated with increased infection rates. Neutropaenia occurrence was associated with non-smoking, female gender and lower baseline neutrophil levels. PMID- 30402266 TI - Efficacy and safety of non-pharmacological, pharmacological and surgical treatment for hand osteoarthritis: a systematic literature review informing the 2018 update of the EULAR recommendations for the management of hand osteoarthritis. AB - To update the evidence on efficacy and safety of non-pharmacological, pharmacological and surgical interventions for hand osteoarthritis (OA), a systematic literature review was performed up to June 2017, including (randomised) controlled trials or Cochrane systematic reviews. Main efficacy outcomes were pain, function and hand strength. Risk of bias was assessed. Meta analysis was performed when advisable. Of 7036 records, 127 references were included, of which 50 studies concerned non-pharmacological, 64 pharmacological and 12 surgical interventions. Many studies had high risk of bias, mainly due to inadequate randomisation or blinding. Beneficial non-pharmacological treatments included hand exercise and prolonged thumb base splinting, while single trials showed positive results for joint protection and using assistive devices. Topical and oral non-steroidal anti-inflammatory drugs (NSAIDs) proved equally effective, while topical NSAIDs led to less adverse events. Single trials demonstrated positive results for chondroitin sulfate and intra-articular glucocorticoid injections in interphalangeal joints. Pharmacological treatments for which no clear beneficial effect was shown include paracetamol, intra-articular thumb base injections of glucocorticoids or hyaluronic acid, low-dose oral glucocorticoids, hydroxychloroquine and anti-tumour necrosis factor. No trials compared surgery to sham or non-operative treatment. No surgical intervention for thumb base OA appeared more effective than another, although in general more complex procedures led to more complications. No interventions slowed radiographic progression. In conclusion, an overview of the evidence on efficacy and safety of treatment options for hand OA was presented and informed the task force for the updated European League Against Rheumatism management recommendations for hand OA. PMID- 30402268 TI - Haploinsufficiency of A20 impairs protein-protein interactome and leads into caspase-8-dependent enhancement of NLRP3 inflammasome activation. AB - Objectives: TNFAIP3 encodes A20 that negatively regulates nuclear factor kappa light chain enhancer of activated B cells (NF-kappaB), the major transcription factor coordinating inflammatory gene expression. TNFAIP3 polymorphisms have been linked with a spectrum of inflammatory and autoimmune diseases and, recently, loss-of-function mutations in A20 were found to cause a novel inflammatory disease 'haploinsufficiency of A20' (HA20). Here we describe a family with HA20 caused by a novel TNFAIP3 loss-of-function mutation and elucidate the upstream molecular mechanisms linking HA20 to dysregulation of NF-kappaB and the related inflammasome pathway. Methods: NF-kappaB activation was studied in a mutation expressing cell line using luciferase reporter assay. Physical and close proximity protein-protein interactions of wild-type and TNFAIP3 p.(Lys91*) mutant A20 were analysed using mass spectrometry. NF-kappaB -dependent transcription, cytokine secretion and inflammasome activation were compared in immune cells of the HA20 patients and control subjects. Results: The protein-protein interactome of p.(Lys91*) mutant A20 was severely impaired, including interactions with proteins regulating NF-kappaB activation, DNA repair responses and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. The p.(Lys91*) mutant A20 failed to suppress NF-kappaB signalling, which led to increased NF-kappaB -dependent proinflammatory cytokine transcription. Functional experiments in the HA20 patients' immune cells uncovered a novel caspase-8-dependent mechanism of NLRP3 inflammasome hyperresponsiveness that mediated the excessive secretion of interleukin-1beta and interleukin-18. Conclusions: The current findings significantly deepen our understanding of the molecular mechanisms underlying HA20 and other diseases associated with reduced A20 expression or function, paving the way for future therapeutic targeting of the pathway. PMID- 30402269 TI - Impact of extra-articular spondyloarthritis manifestations and comorbidities on drug retention of a first TNF-inhibitor in ankylosing spondylitis: a population based nationwide study. AB - Objectives: To assess the impact of extra-articular spondyloarthritis (SpA) manifestations (anterior uveitis, psoriasis and inflammatory bowel disease (IBD)), and of comorbidities, on tumour necrosis factor alpha inhibitor (TNFi) drug retention in ankylosing spondylitis (AS). Methods: We identified all bio naive patients with AS starting a first ever TNFi July 2006 to December 2015 from the Swedish Rheumatology Quality register and followed these from treatment start through December 2015. We determined the presence of extra-articular SpA manifestations, comorbidities (cardiovascular disease, affective disease, diabetes, malignancies, chronic lung disease and kidney disease) and socioeconomic status before TNFi start, through linkage to five other national registers, and calculated, for each factor, crude and adjusted HRs for discontinuing the TNFi. Results: 2577 patients with AS (71% men) started a first TNFi during the study period. 27% had a history of anterior uveitis, 6% psoriasis and 7% IBD. Anterior uveitis was associated with a superior TNFi drug retention (HR 0.72; 0.62 to 0.83), psoriasis with an inferior (HR 1.48; 1.18 to 1.86), whereas IBD did not affect TNFi drug retention. The effect of the SpA manifestations on TNFi drug retention was of a similar magnitude to that of the comorbidities. Conclusions: In AS, anterior uveitis and psoriasis, but not IBD, affect TNFi drug retention. Possible explanations include differential effects of TNFi on these extra-articular SpA manifestations, or inherent differences in AS, associated with the inflammatory phenotype. Further, comorbidities and socioeconomy affect TNFi drug retention to a similar magnitude as the SpA manifestations, and should, as such, receive due attention in clinical practice. PMID- 30402271 TI - Mixed connective tissue disease: state of the art on clinical practice guidelines. AB - Mixed connective tissue disease (MCTD) is a complex overlap disease with features of different autoimmune connective tissue diseases (CTDs) namely systemic sclerosis, poly/dermatomyositis and systemic lupus erythematous in patients with antibodies targeting the U1 small nuclear ribonucleoprotein particle. In this narrative review, we summarise the results of a systematic literature research which was performed as part of the European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases project, aimed at evaluating existing clinical practice guidelines (CPGs) or recommendations. Since no specific CPGs on MCTD were found, other CPGs developed for other CTDs were taken into consideration in order to discuss what can be applied to MCTD even if designed for other diseases. Three major objectives were proposed for the future development of CPGs: MCTD diagnosis (diagnostic criteria), MCTD initial and follow-up evaluations, MCTD treatment. Early diagnosis, epidemiological data, assessment of burden of disease and QOL aspects are among the unmet needs identified by patients. PMID- 30402270 TI - Systemic sclerosis: state of the art on clinical practice guidelines. AB - Systemic sclerosis (SSc) is an orphan disease characterised by autoimmunity, fibrosis of the skin and internal organs, and vasculopathy. SSc may be associated with high morbidity and mortality. In this narrative review we summarise the results of a systematic literature research, which was performed as part of the European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases project, aimed at evaluating existing clinical practice guidelines or recommendations. Only in the domains 'Vascular & Ulcers' (ie, non pharmacological approach to digital ulcer), 'PAH' (ie, screening and treatment), 'Treatment' and 'Juveniles' (ie, evaluation of juveniles with Raynaud's phenomenon) evidence-based and consensus-based guidelines could be included. Hence there is a preponderance of unmet needs in SSc referring to the diagnosis and (non-)pharmacological treatment of several SSc-specific complications. Patients with SSc experience significant uncertainty concerning SSc-related taxonomy, management (both pharmacological and non-pharmacological) and education. Day-to-day impact of the disease (loss of self-esteem, fatigue, sexual dysfunction, and occupational, nutritional and relational problems) is underestimated and needs evaluation. PMID- 30402272 TI - Antiphospholipid syndrome: state of the art on clinical practice guidelines. AB - Antiphospholipid syndrome (APS) is a rare disease characterised by venous and/or arterial thrombosis, pregnancy complications and the presence of specific autoantibodies called antiphospholipid antibodies. This review aims to identify existing clinical practice guidelines (CPG) as part of the ERN ReCONNET project, aimed at evaluating existing CPGs or recommendations in rare and complex diseases. Seventeen papers providing important data were identified; however, the literature search highlighted the scarceness of reliable clinical data to develop CPGs. With no formal clinical guidelines in place, diagnosis and treatment of APS is largely based on consensus and expert opinion. Patients' unmet need refers to the understanding of the disease and its clinical picture and implications, the need of education for patients, family members and healthcare providers, as well as to the development of monitoring pathways involving multiple healthcare providers. PMID- 30402273 TI - Relapsing polychondritis: state of the art on clinical practice guidelines. AB - Due to the rarity of relapsing polychondritis (RP), many unmet needs remain in the management of RP. Here, we present a systematic review of clinical practice guidelines (CPGs) published for RP, as well as a list of the most striking unmet needs for this rare disease. We carried out a systematic search in PubMed and Embase based on controlled terms (medical subject headings and Emtree) and keywords of the disease and publication type (CPGs). The systematic literature review identified 20 citations, among which no CPGs could be identified. We identified 11 main areas with unmet needs in the field of RP: the diagnosis strategy for RP; the therapeutic management of RP; the management of pregnancy in RP; the management of the disease in specific age groups (for instance in paediatric-onset RP); the evaluation of adherence to treatment; the follow-up of patients with RP, including the frequency of screening for the potential complications and the optimal imaging tools for each involved region; perioperative and anaesthetic management (due to tracheal involvement); risk of neoplasms in RP, including haematological malignancies; the prevention and management of infections; tools for assessment of disease activity and damage; and patient-reported outcomes and quality of life indicators. Patients and physicians should work together within the frame of the ReCONNET network to derive valuable evidence for obtaining literature-informed CPGs. PMID- 30402274 TI - Sjogren's syndrome: state of the art on clinical practice guidelines. AB - Sjogren's syndrome (SS) is a complex autoimmune rheumatic disease that specifically targets salivary and lachrymal glands. As such, patients typically had ocular and oral dryness and salivary gland swelling. Moreover, skin, nasal and vaginal dryness are frequently present. In addition to dryness, musculoskeletal pain and fatigue are the hallmarks of this disease and constitute the classic symptom triad presented by the vast majority of patients. Up to 30% to 50 % of patients with SS may present systemic disease; moreover, there is an increased risk for the development of non-Hodgkin's lymphoma that occurs in a minority of patients. The present work was developed in the framework of the European Reference Network (ERN) dedicated to Rare and Complex Connective Tissue and Musculoskeletal Diseases (ReCONNET). In line with its goals of aiming to improve early diagnosis, treatment and care of rare connective and musculoskeletal diseases, ERN-ReCONNET set to review the current state of clinical practice guidelines (CPGs) in the rare and complex connective tissue diseases of interest of the network. Therefore, the present work was aimed at providing a state of the art of CPGs for SS. PMID- 30402276 TI - Clinical practice guidelines: the first year of activity of the European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ERN ReCONNET). PMID- 30402275 TI - Ehlers-Danlos syndromes: state of the art on clinical practice guidelines. AB - Objective: To report the effort of the European Reference Network for Rare and Complex CONnective tissue and musculoskeletal diseases NETwork working group on Ehlers-Danlos syndromes (EDS) and related disorders to assess current available clinical practice guidelines (CPGs) specifically addressed to EDS, in order to identify potential clinician and patient unmet needs. Methods: Systematic literature search in PUBMED and EMBASE based on controlled terms (MeSH and Emtree) and keywords of the disease and publication type (CPGs). All the published articles were revised in order to identify existing CPGs on diagnosis, monitoring and treatment of EDS. Results: Literature revision detected the absence of papers reporting good quality CPGs to optimise EDS patient care. The current evidence-based literature regarding clinical guidelines for the EDS was limited in size and quality, and there is insufficient research exploring the clinical features and interventions, and clinical decision-making are currently based on theoretical and limited research evidences. Conclusions: Many clinician and patient unmet needs have been identified. PMID- 30402278 TI - Spectral Domain Optical Coherence Tomography Assessment of Macular and Optic Nerve Alterations in Patients with Glaucoma and Correlation with Visual Field Index. AB - Introduction: To evaluate the sectorial thickness of single retinal layers and optic nerve using spectral domain optic coherence tomography (SD-OCT) and highlight the parameters with the best diagnostic accuracy in distinguishing between normal and glaucoma subjects at different stages of the disease. Material and Methods: For this cross-sectional study, 25 glaucomatous (49 eyes) and 18 age matched healthy subjects (35 eyes) underwent a complete ophthalmologic examination including visual field testing. Sectorial thickness values of each retinal layer and of the optic nerve were measured using SD-OCT Glaucoma Module Premium Edition (GMPE) software. Each parameter was compared between the groups, and the layers and sectors with the best area under the receiver operating characteristic curve (AUC) were identified. Correlation of visual field index with the most relevant structural parameters was also evaluated. Results and Discussion: All subjects were grouped according to stage as follows: Controls (CTRL); Early Stage Group (EG) (Stage 1 + Stage 2); Advanced Stage Group (AG) (Stage 3 + Stage 4 + Stage 5). mGCL TI, mGCL TO, mIPL TO, mean mGCL, cpRNFLt NS, and cpRNFLt TI showed the best results in terms of AUC according classification proposed by Swets (0.9 < AUC < 1.0). These parameters also showed significantly different values among group when CTRL vs EG, CTRL vs AG, and EG vs AG were compared. SD-OCT examination showed significant sectorial thickness differences in most of the macular layers when glaucomatous patients at different stages of the disease were compared each other and to the controls. PMID- 30402277 TI - Association between Visual Acuity and Retinal Layer Metrics in Diabetics with and without Macular Edema. AB - Purpose: Diabetes is known to cause alterations in retinal microvasculature and tissue that progressively lead to visual impairment. Optical coherence tomography (OCT) is useful for assessment of total retinal thickening due to diabetic macular edema (DME). In the current study, we determined associations between visual acuity (VA) and retinal layer thickness, reflectance, and interface disruption derived from enface OCT images in subjects with and without DME. Materials and Methods: Best corrected VA was measured and high-density OCT volume scans were acquired in 149 diabetic subjects. A previously established image segmentation method identified retinal layer interfaces and locations of visually indiscernible (disrupted) interfaces. Enface thickness maps and reflectance images of the nerve fiber layer (NFL), combined ganglion cell and inner plexiform layer (GCLIPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), photoreceptor outer segment layer (OSL), and retinal pigment epithelium (RPE) were generated in the central macular subfield. The associations among VA and retinal layer metrics were determined by multivariate linear regressions after adjusting for covariates (age, sex, race, HbA1c, diabetes type, and duration) and correcting for multiple comparisons. Results: In DME subjects, increased GCLIPL and OPL thickness and decreased OSL thickness were associated with reduced VA. Furthermore, increased NFL reflectance and decreased OSL reflectance were associated with reduced VA. Additionally, increased areas of INL and ONL interface disruptions were associated with reduced VA. In subjects without DME, increased INL thickness was associated with reduced VA, whereas in subjects without DME but with previous antivascular endothelium growth factor treatment, thickening of OPL was associated with reduced VA. Conclusions: Alterations in retinal layer thickness and reflectance metrics derived from enface OCT images were associated with reduced VA with and without presence of DME, suggestive of their potential for monitoring development, progression, and treatment of DME. PMID- 30402279 TI - Effect of Collagen Cross-Linking on Alkali Burn-Induced Corneal Neovascularization in Rabbits. AB - Objective: This study aims at investigating the effects and molecular mechanism of riboflavin-ultraviolet-A-induced cross-linking (corneal collagen cross linking, CXL) on corneal neovascularization (CNV) in a rabbit alkali burn model. Methods: A total of 60 rabbits were injured with alkali burns to induce CNV in the right eye and were randomly divided into six groups: Group A-injury and no treatment; Groups B, C, and D-CXL treatment for 30 min, 15 min, and 45 min administered immediately after injury, respectively; and Groups E and F-CXL treatment for 30 min administered 1 day and 3 days after injury, respectively. CNV area, corneal edema, and corneal epithelial defects were observed on days 4, 7, 10, and 14 after injury. Western blot was used to detect expression of the vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-2 (MMP-9), and tissue inhibitor of metalloproteinases 1 (TIMP-1) at 7 and 14 days after injury. Results: CXL treatment decreased CNV and corneal edema in all groups compared to Group A. On day 7, MMP-9 expression was significantly increased in all CXL treatment groups, and TIMP-1 was upregulated in Groups D and F compared to Group A. In addition, VEGF, MMP-2, MMP-9, and TIMP 1 expression were increased in Group A on day 14 after injury. Conclusions: Our results indicate that riboflavin-ultraviolet-A-induced cross-linking (corneal collagen cross-linking, CXL) significantly inhibits alkali burn-induced CNV in rabbits, possibly through downregulating VEGF, MMP-2, MMP-9, and TIMP-1 expression. PMID- 30402280 TI - Pulse Pressure Relationships with Demographics and Kidney Function in Ashanti, Ghana. AB - Introduction: Hypertension, particularly pulse pressure [PP] is a major risk factor for end-stage renal disease. However, the effect of individual components of hypertension namely PP, systolic [SBP] and diastolic blood pressure [DBP] on kidney function, in the general African population is unknown. Methods: Data were collected on 944 participants [aged 40-75 y], living in villages in the area around the city of Kumasi, Ghana, on demographics, medications, height, weight, BP and 24-hour creatinine clearance (CrCl). Results: The demographic and clinical characteristics were: age 55(11) [mean (SD)] years, females 62%, rural village dwellers 52%, diabetes 1.5%, BMI 21(4) kg/m2, 24-hourCrCl as a measure of glomerular filtration rate (GFR) 84(23) ml/min/1.73 m2. 29% had BP >140/90 mmHg; SBP and DBP were 125/74(26/14) mmHg, PP was 51(17) mmHg. PP increased with age by 0.55(95% CI: 0.46,0.64) mmHg/year. PP was higher (53(17) v 49(15) mmHg; p < 0.001) in the semiurban participants. GFR decreased both with increasing PP [ 0.19 (-0.27,-0.10 ml/min/1.73 m2/mmHg; p < 0.001] and SBP [-0.09 (-0.14,-0.03) ml/min/1.73 m2/mmHg; p < 0.001] but there was no significant relationship with DBP [-0.04 (-0.15,0.06)]. After adjusting for SBP, the relationship between GFR and PP became steeper [-0.31 (-0.50,-0.12) ml/min/1.73 m2/mmHg; p < 0.001]. Using multivariate regression analysis that included PP, age, gender, BMI, only increasing age [-0.75 (-0.88,-0.62)] and decreasing BMI [0.49 (0.16,0.81)] were associated with decreased kidney function. Conclusions: In this homogeneous West African population, PP increased with age and had a steeper relationship with declining kidney function than SBP or DBP. PMID- 30402282 TI - School Engagement in Relation to Body Mass Index and School Achievement in a High School Age Sample. AB - Purpose: Research has documented an inverse relationship between body mass index (BMI) and school achievement but has failed to empirically explain it. We tested whether this association among adolescents can be explained in part by student engagement. Methods: A self-report survey about health and school behaviors was completed by 196 high school students; BMI and achievement data were obtained from school records. Three forms of engagement were assessed: behavioral, presenteeism, and affective. Associations of engagement with BMI and achievement were examined, and mediation analyses were conducted. Results: The simple relationship between BMI and achievement was confirmed and demonstrated that BMI was negatively related to academic achievement. Higher BMI was also significantly correlated with lower classroom participation. Mediation tests showed the significant relationship between BMI and achievement was reduced after accounting for behavioral engagement but not affective engagement. Conclusions: These novel findings shed light on why heavier students often experience lower academic achievement. Intervention studies targeting barriers to classroom engagement among overweight and obese youth are needed so that their academic potential is not compromised. PMID- 30402281 TI - Laparoscopic Gastric Plication versus Laparoscopic Sleeve Gastrectomy: An Up-to Date Systematic Review and Meta-Analysis. AB - Introduction: A meta-analysis was conducted in order to provide an up-to-date comparison of laparoscopic sleeve gastrectomy (LSG) and laparoscopic gastric plication (LGP) for morbid obesity. Materials and Methods: The PRISMA guidelines and the Cochrane Handbook for Systematic Reviews of Interventions were used for the conduction of this study. A systematic literature search was performed in the electronic databases (MEDLINE, CENTRAL, and Web of Science and Scopus). The fixed effects or random effects model was used according to the Cochran Q test. Results: Totally, 12 eligible studies were extracted. LSG displayed a statistically significant lower rate of overall complications (OR: 0.35; 95% CI: 0.17, 0.68; p=0.002) and a sustainable higher %EWL through all time endpoints (OR: 4.86, p=0.04; OR: 7.57, p < 0.00001; and OR: 13.74; p < 0.00001). There was no difference between the two techniques in terms of length of hospital stay (p=0.16), operative duration (p=0.81), reoperation rate (p=0.51), and cost (p=0.06). Conclusions: LSG was demonstrated to have a lower overall complications and a higher weight loss rate, when compared to LGP. Further RCTs of a higher methodological quality level, with a larger sample size, are required in order to validate these findings. PMID- 30402284 TI - The Frequency of Resurgery after Percutaneous Lumbar Surgery Using Dekompressor in a Ten-Year Period. AB - To prevent open surgical procedures, minimally invasive techniques, like Dekompressor (PLDD), have been developed. The absence of reherniation is an important factor correlating with clinical success after lumbar surgery. In this retrospective, observational study, the frequency of additional open surgery after PLDD in a long time retrospective was examined. The correlation between clinical symptoms and outcome was assessed, and the time between PLDD and open surgery was analyzed. Consecutive patients after PLDD between 2005 and 2007 were included. MacNab's outcome criteria were used to evaluate patient satisfaction. The need for additional open surgery of the lumbar spine, the period between Dekompressor and resurgery, and the treated levels were analyzed. In total, 73 patients were included in this study. The patients were seen one month after PLDD. The majority of patients (76.7%) had additional radicular pain. The most common level treated was L4-5 (58.9%). The follow-up time was longer than 5 years in 30.1% of the patients and longer than 10 years in 6.82%. The short-term success rate was 67.1%. Additional surgery was performed in 26.0% of patients, with 78.9% of the reoperations undertaken during the first year after PLDD. These patients had a statistically significant worse outcome (P = 0.025). Radicular pain was present in all patients with an early subsequent surgery, but only in 50% of patients with late surgery (P = 0.035). Significantly more patients with poor pain relief had radicular pain (P = 0.04). The short-term success rate was worsened by a resurgery rate of 26.0%. Subsequent surgery, a short time after PLDD, suggests that PLDD is not a replacement for open discectomy. Because patients with radicular pain had a worse outcome and more frequent resurgeries, whether radicular pain is an ideal indication for PLDD should be discussed. PMID- 30402283 TI - Anemia among Women Attending Antenatal Care at the University of Gondar Comprehensive Specialized Referral Hospital, Northwest Ethiopia, 2017. AB - Background: In Ethiopia, prenatal anemia is a major public health concern affecting both the health of the woman and babies. The World Health Organization recommends to conduct repeated prevalence studies concerning prenatal anemia . However, there is no recent evidence on the magnitude of the prenatal anemia. Therefore, the aim of this study was to determine the prevalence and the associated factors of prenatal anemia among women attending the Antenatal Care Clinic at the University of Gondar Referral Hospital. Methods: A facility-based cross-sectional quantitative study was conducted among 362 participants from June 03-July 08, 2017, at the University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia. The systematic random sampling technique was employed. Structured interviewer administered questionnaire was used. Human Immunodeficiency Virus (HIV) screening was conducted. Nutritional status of the participants was assessed. Blood sample was collected by capillary tube . Intestinal parasite was examined by stool wet mount test. HIV serostatus was detected. Anemia was defined as hemoglobin concentration below 11 g/dl. The multivariable logistic regression model was employed to identify associated factors and to control the possible effects of confounders. Result: The prevalence of anemia was 22.2% (95% CI: 18.11, 27.1%). The highest odds of anemia were observed among pregnant women with family size of >five [AOR = 3 (95% CI: 1.03, 8.65)], unprotected water source users, [AOR = 4.09 (95% CI: 1.75, 9.55)], HIV infected [AOR = 2.94(95% CI: 1.37, 6.35)], and multigravida women [AOR = 3.5 (95% CI: 1.35, 9.17)]. Conclusion and Recommendations: The prevalence of anemia among pregnant women attending the University of Gondar Referral Hospital was a moderate public health problem. Unprotected water source, large family size, Human Immunodeficiency Virus infection, and repeated pregnancies were factors that predicted anemia. Thus, prevention of Human Immunodeficiency Virus infection, family planning utilization, and accessing pure water are recommended. PMID- 30402286 TI - Evaluation of Potential Drug-Drug Interactions with Medications Prescribed to Geriatric Patients in a Tertiary Care Hospital. AB - Background and Objectives: The drugs most commonly implicated in major potential interactions are those used in the day-to-day clinical management of elderly patients with chronic diseases. This study is planned to evaluate the profile of drug-drug interactions in the medications prescribed to elderly population and also to identify the possible predictors for potential drug-drug interactions in the elderly. Methods: This cross-sectional study included patients aged above 60 years with a minimum of two drugs in the prescriptions. Data were collected from medical prescriptions and patients' medical records. The data collected included demographic characteristics such as age, gender, height, weight, educational status, socioeconomic status, medical history, and medications prescribed. The prescriptions were analyzed for the potential drug interactions using Lexi InteractTM Online, an online software to check drug-drug interactions. Results: A total of 209 patients were included in the study, among them 104 (49.8%) were males and 105 (50.2%) were females. The mean number of medications received was 6.53 +/- 2.15 per prescription. Around 138 (66%) patients received more than six medications. The mean number of potential drug interactions seen in the prescription of these patients was 3.17 +/- 2.78. Around 18.2% patients had more than five drug interactions. Major drug interactions were observed in 21.42% of cases. Around 3.02% of drug interactions belonged to risk category X, i.e., to be avoided. Logistic regression analysis showed that age above 70 years was associated with the presence of drug interactions. Increased number of medication was independently associated with the occurrence of drug interactions. The presence of drug interactions was not associated with increased number of comorbidities. Conclusion: A significant number of potential drug-drug interactions were seen in the prescriptions of elderly patients. Increasing age and polypharmacy were identified as the predictors of potential drug interactions. PMID- 30402285 TI - The Effect of Hyperbaric Oxygen Therapy on Functional Impairments Caused by Ischemic Stroke. AB - Background: While research suggests a benefit of hyperbaric oxygen therapy (HBOT) for neurologic injury, controlled clinical trials have not been able to clearly define the benefits. Objective: To investigate the effects of HBOT on physical and cognitive impairments resulting from an ischemic stroke. Methods: Using a within-subject design a baseline for current functional abilities was established over a 3-month period for all subjects (n=7). Each subject then received two 4 week periods of HBOT for a total of 40 90-minute treatments over a 12-week period. Subjects completed a battery of assessments and had blood drawn six times over the 9-month total duration of the study. Results: We found improvements in cognition and executive function as well as physical abilities, specifically, improved gait. Participants reported improved sleep and quality of life following HBOT treatment. We also saw changes in serum levels of biomarkers for inflammation and neural recovery. In the functional domains where improvement was observed following HBOT treatment, the improvements were maintained up to 3 months following the last treatment. However, the physiological biomarkers showed a pattern of more transient changes following HBOT treatment. Conclusions: Findings from this study support the idea of HBOT as a potential intervention following stroke. PMID- 30402287 TI - Danish Sonographers' Experiences of the Introduction of "Moderate Risk" in Prenatal Screening for Down Syndrome. AB - Objective: The aim of the study was to determine sonographers' experiences with the introduction of an offer of noninvasive prenatal testing (NIPT) to a new moderate-risk (MR) group at the combined first-trimester prenatal screening (cFTS). Study Design: A qualitative approach consisting of seven semistructured interviews with five sonographers (midwives and nurses). Data was analyzed using thematic analysis. Main Outcome Measures: Sonographers' perception of offering NIPT to women in MR. Results: The sonographers understood NIPT as a positive development in prenatal screening due to a safe procedure and high detection rates for trisomies 13, 18, and 21. Prior to the introduction of MR, the sonographers were concerned about inducing worry in pregnant women in this new risk group. However, the pregnant women responded very positively, which the sonographers attributed to several factors such as the women's overall reason for participating in prenatal screening, the simplicity of the NIPT procedure, and the communicative strategies used by the sonographers. The strategies included all sonographers using the same words and explanations, emphasizing that statistics were in the women's favor, initiating the presentation of MR with a positive message, and downplaying the MR category. Conclusion: Sonographers' communicative strategies succeeded in limiting worry in pregnant women in MR. As such, the findings are valuable for health professionals, who are responsible for communicating about prenatal screening results and diagnostic options. PMID- 30402288 TI - Risk Factors for Neonatal Sepsis in Pregnant Women with Premature Rupture of the Membrane. AB - Background: Premature rupture of the membrane (PROM) is associated with high maternal as well as perinatal morbidity and mortality risks. It occurs in 5 to 10% of all pregnancy while incidence of amniotic membrane infection varies from 6 to 10%. This study aimed to determine the incidence of neonatal sepsis in Cipto Mangunkusumo Hospital and the risk factors. Methods: A cross-sectional study was done in Cipto Mangunkusumo Hospital, Jakarta, from December 2016 to June 2017. The study used total sampling method including all pregnant women with gestational age of 20 weeks or more experiencing PROM, who came to the hospital at that time. Samples with existing comorbidities such as diabetes mellitus or other serious systemic illnesses such as heart disease or autoimmune condition were excluded from the analysis. Results: A total of 405 pregnant women with PROM were included in this study. There were 21 cases (5.2%) of neonatal sepsis. The analysis showed that risk of neonatal sepsis was higher in pregnant women with prolonged rupture of membrane for >= 18 hours before hospital admission (OR 3.08), prolonged rupture of membrane for >= 15 hours during hospitalization (OR 7.32), and prolonged rupture of membrane for >= 48 hours until birth (OR 5.77). The risk of neonatal sepsis was higher in preterm pregnancy with gestational age of <37 weeks (OR 18.59). Conclusion: Risk of neonatal sepsis is higher in longer duration of prolonged rupture of membrane as well as preterm pregnancy. PMID- 30402289 TI - Clinical Effects of Activated Charcoal Unavailability on Treatment Outcomes for Oral Drug Poisoned Patients. AB - Background: Activated charcoal is the most frequently and widely used oral decontaminating agent in emergency departments (EDs). However, there is some debate about its clinical benefits and risks. In Korea, activated charcoal with sorbitol was unavailable as of the mid-2015, and our hospital had been unable to use it from September 2015. This study examined the differences of clinical features and outcomes of patients during the periods charcoal was and was not available. Methods: We retrospectively reviewed the electronic medical records of patients who had visited an urban tertiary academic ED for oral drug poisoning between January 2013 and January 2017. Results: For the charcoal-available period, 413 patients were identified and for the charcoal-unavailable period, 221. Activated charcoal was used in the treatment of 141 patients (34%) during the available period. The mortality rates during the available and unavailable periods were 1.9 and 0.9%, respectively (p = 0.507). There was also no interperiod difference in the development of aspiration pneumonia (9.9 versus 9.5%, p = 0.864), the endotracheal intubation rate (8.4 versus 7.2%, p = 0.586), and vasopressor use (5.3 versus 5.0%, p = 0.85). Intensive care unit (ICU) admission was higher in the unavailable period (5.8 versus 13.6%, p = 0.001). ICU days were lower in the unavailable period (10 [4.5-19] versus 4 [3-9], p = 0.01). Hospital admission (43.3 versus 29.9%, p = 0.001) was lower in the unavailable period. Conclusions: In this single center study, there appeared to be no difference in mortality, intubation rates, or vasopressor use between the charcoal-available and charcoal-unavailable periods. PMID- 30402290 TI - Effect of Dual-Task Conditions on Gait Performance during Timed Up and Go Test in Children with Traumatic Brain Injury. AB - Background: Tasks requiring simultaneous mobility and cognition (dual tasks) have been associated with incidence of falls. Although these deficits have been documented in individuals with neurologic disorder, the effect of dual task in children with traumatic brain injury has not been fully explored. Objective: To investigate the effect of dual-task (dual-motor and dual-cognitive task) conditions on spatiotemporal gait parameters during timed up and go test in children with traumatic brain injury. Methods and Material: A total of 14 children with traumatic brain injury and 21 typically developing children participated in this case-control study. Functional balance was assessed before the actual testing to predict the risk of falls. Timed up and go test was performed under single-task and dual-task (dual-motor and dual-cognitive task) conditions. Spatiotemporal gait parameters were determined using the APDM Mobility Lab system. The descriptive statistics and t-test were used to analyze demographic characteristics and repeated measure ANOVA test was used to analyze the gait parameters. Results: Under dual-task (dual-motor and dual-cognitive task) conditions during the timed up and go test, gait performance significantly deteriorated. Furthermore, the total time to complete the timed up and go test, stride velocity, cadence, and step time during turning were significantly different between children with traumatic brain injury and typically developing children. Conclusions: These findings suggest that gait parameters were compromised under dual-task conditions in children with traumatic brain injury. Dual-task conditions may become a component of gait training to ensure a complete and comprehensive rehabilitation program. PMID- 30402291 TI - Potential of Cocoa Pod Husk Pectin-Based Modified Release Capsules as a Carrier for Chronodelivery of Hydrocortisone in Sprague-Dawley Rats. AB - The potential of cocoa pod husk (CPH) pectin-based modified release (MR) capsules as a carrier for chronodelivery of hydrocortisone in Sprague-Dawley rats was assessed. Extemporaneously formulated CPH pectin-based hydrocortisone (10 mg) capsules crosslinked with calcium chloride (Formulation A) or zinc (Formulation B) and a commercial immediate release hydrocortisone formulation were administered orally to Sprague-Dawley rats and the pharmacokinetic parameters were evaluated using noncompartmental analysis. Formulation A had a 2 h lag phase followed by an increase in serum drug concentration in the treated rats. Peak concentrations (Cmax) of 21.799 +/- 1.993 ng/ml and 20.844 +/- 2.661 ng/ml were achieved after 6 +/- 0.23 h and 6 +/- 0.35 h (Tmax), respectively, for capsules A and B. The immediate release formulation had a peak concentration of 15.322 +/- 0.313 ng/ml within 1 +/- 0.2 h. The relative bioavailability of the CPH pectin based capsules A and B was 213% and 274%, respectively. Formulations A and B had half-lives more than three times that of the immediate release formulation. The MR capsules exhibited a higher exposure, greater bioavailability, and versatility in release of cortisol than the commercial immediate release formulation. Additionally, the MR capsules exhibited an extended drug release with overnight cortisol rise and early morning cortisol peak and hold promise in the management of adrenal insufficiency. PMID- 30402292 TI - Stability of the Subaxial Spine after Penetrating Trauma: Do Classification Systems Apply? AB - Objective: Blunt spinal trauma classification systems are well established and provide reliable treatment algorithms. To date, stability of the spine after civilian gunshot wounds (CGSWS) is poorly understood. Herein, we investigate the validity of trauma classification systems including the Thoracolumbar Injury Classification and Severity Score (TLICS), Subaxial Cervical Spine Injury Classification and Severity Score (SLIC), and Denis' three-column model when applied to spinal penetrating trauma from gunshots, while secondarily evaluating stability of these injuries. Methods: Gunshot injuries to the spine were identified from an institutional database from ICD-nine codes. Trauma scorings systems were applied using traditional criteria. Neurologic compromise and spinal stability were evaluated using follow-up clinic notes and radiographs. Results: Thirty-one patients with CSGSW were evaluated. There was an equal distribution of injuries amongst the spinal levels and spinal columns. Twenty patients had neurological deficits at presentation. Eight patient had a TLICS score >4. Three patients had a SLIC score >4. One patient had surgical treatment. Nonoperative treatment did not lead to spinal instability or adverse outcomes in any cases. The posterior column had a high correlation with neurologic compromise, though not statistically significant (p=.118). Conclusions: The TLICS, SLIC, and three column classification systems cannot be applied to CSGSW to quantify injury severity, predict outcomes, or guide treatment decision-making. Despite significant neurologic injuries and disruption of multiple spinal columns, CSGSW do not appear to result in unstable injuries requiring operative intervention. Further research is needed to identify the rare spinal gunshot injury that would benefit from immediate surgical intervention. PMID- 30402293 TI - Rasterstereographic Analysis of Lateral Shift in Patients with Lumbar Disc Herniation: A Case Control Study. AB - Objective: Detection of a lateral shift (LS) in patients with diagnosed disc herniation compared to healthy controls. Summary of Background Data: A specific lateral shift (LS) pattern is observed in patients with disc herniation and low back pain, as shown in earlier studies. Methods: Rasterstereography (RS) was used to investigate the LS. Thirty-nine patients with lumbar disc herniation diagnosed by radiological assessment and low back pain and/or leg pain (mean age 48.2 years, mean BMI 28.5, 28 males and 11 females) and 36 healthy controls (mean age 47.4 years, mean BMI 25.7, 25 males and 11 females) were analysed. LS, pelvic tilt, pelvic inclination, lordotic angle, and trunk torsion were assessed. Results: The patient group showed a nonsignificant increase in LS, that is, 5.6 mm compared to the healthy controls with 5.0 mm (p = 0.693). However, significant differences were found between groups regarding pelvic tilt in degrees (patients 5.9 degrees , healthy controls 2.0 degrees ; p = 0.016), trunk torsion (patients 7.5 degrees , controls 4.5 degrees ; p = 0.017), and lordotic angle (patients 27.5 degrees , healthy controls 32.7 degrees ; p = 0.022). The correlation between pain intensity and the FFbH-R amounted 0.804 (p = < 0.01), and that between pain intensity and the pain disability index was 0.785 (p < 0.01). Discussion: Although some studies have illustrated LS with disc herniation and low back pain, the present findings demonstrate no significant increase in LS in the patient group compared to healthy controls. Conclusion: The patients with lumbar disc herniation did not demonstrate an increased LS compared to healthy controls. Other parameters like pelvic tilt and inclination seemed to be more suitable to identify changes in posture measured by RS in patients with low back pain or disc herniation. PMID- 30402294 TI - Effects of Bright Light with Reduced Blue Light on Sleepiness on Rising: A Small Exploratory Study. AB - Bright light therapy is a treatment modality for seasonal affective disorder and circadian rhythm disorders in which artificial light of 2,500 lux or higher at the eye is effective. Although short-wavelength visible light is more effective than long-wavelength visible light, it may be hazardous to the retina. Recently, light-emitting diodes (LEDs) have been used as the light source in bright light therapy apparatuses. We developed goggles for bright light therapy equipped with LEDs as the light source. The aim of this study was to examine the efficacy and safety of our goggles when emitting 10,000-lux light with its short-wavelength light content reduced by 30% or 50% (denoted as 30%-cut and 50%-cut light, respectively, henceforth). Six healthy young males participated in this study. They were administered no light, 50%-cut light, and 30%-cut light for 30 min early in the morning for 4 days each. Subjective sleepiness and sleep quality were evaluated by the Stanford Sleepiness Scale (SSS) and the Oguri-Shirakawa Azumi sleep inventory MA version (OSA-MA), respectively. Subjective sleepiness evaluated by the SSS and the subscale of the OSA-MA significantly decreased with 30%-cut light compared with no light. Psychomotor performance evaluated by a calculation task improved with the 30%-cut light, although not significant after multiple comparisons were considered. No abnormality was found by ophthalmoscopy and the vision test. In conclusion, our goggles with 30%-cut light may be safe and have an awakening effect. PMID- 30402296 TI - Electromagnetic Interference from Left Ventricular Assist Device (LVAD) Inhibiting the Pacing Function of an Implantable Cardioverter-Defibrillator (ICD) Device. AB - There is an increasing prevalence of patients with concomitant implantable cardioverter-defibrillators (ICDs) and left ventricular devices (LVADs). The potential for negative interactions between these continually evolving technologies is a valid concern. Previously reported interactions include inappropriate ICD therapy and interference with ICD telemetry function. Understanding the nature of such interactions and developing a comprehensive strategy to approach such situations are important. In this report, we describe a case of electromagnetic interference from LVAD inhibiting the pacing function of an ICD that was corrected by reprograming the device. We would encourage investigators to review patients with ICD and LVAD in their institutions in order to help assess the frequency and nature of these and other interactions. PMID- 30402295 TI - The Association of Unreported Sleep Disturbances and Systemic Inflammation: Findings from the 2005-2008 NHANES. AB - Background/Objective: Sleep apnea is associated with elevated inflammatory markers. A subgroup of patients never report sleep disturbances to their physician. The inflammatory status of this subgroup is not known. The present study aims to evaluate two inflammatory markers, C-reactive protein (CRP) and red cell distribution width (RDW), in those with unreported sleep disturbances and compares these findings to those with and without reported sleep disorders. We also investigate the utility of RDW as an inflammatory marker in sleep disorders. Methods: Sample includes 9,901 noninstitutionalized, civilian, nonpregnant adults from the 2005-2008 National Health and Nutrition Examination Survey, a nationally representative, cross-sectional U.S. study. Sleep questionnaire and laboratory data were used to compare inflammatory markers (CRP and RDW) in five subgroups of individuals: reporting physician-diagnosed sleep apnea, reporting another physician-diagnosed sleep disorder, reported sleep disturbance to physician with no resulting diagnosis, unreported sleep disturbance (poor sleep quality not reported to physician), and no diagnosed sleep disorder or sleep disturbance. Results: Individuals with unreported sleep disturbance had significantly higher odds of elevated RDW (>13.6%) when compared to those without a sleep disturbance in adjusted models (OR=1.33). Those with unreported sleep disturbance had significantly higher odds of elevated CRP levels (>1 mg/L) than those without sleep disturbances (OR 1.34), although the association was not significant when adjusted for obesity and other controls. Conclusion: Self-identified unreported sleep disturbances are associated with significantly higher odds of elevated RDW than those without sleep disturbances. RDW may serve as a valuable indicator in identifying individuals at higher risk for sleep apnea and other sleep disorders. PMID- 30402297 TI - Inspiratory Muscle Training with Isokinetic Device to Help Ventilatory Weaning in a Patient with Guillain-Barre Syndrome by Zika Virus. AB - Zika is an arbovirus infection mainly transmitted by the mosquito Aedes aegypti. In 2016, the burden of Zika epidemic in Brazil was significant. Patients affected by Zika virus can develop Guillain-Barre syndrome, evolving to muscle respiratory failure requiring mechanical ventilation. In this setting, delayed recovery of the muscle weakness can result in prolonged weaning, a condition that by itself is related to a high mortality rate. The study is reporting a case of a patient with Zika and Guillain-Barre syndrome who underwent an inspiratory muscle training program starting after twenty-five days of mechanical ventilation and guided by serial measurements of the timed inspiratory effort (TIE) index. The patient was successfully weaned in two weeks and discharged from the hospital 30 days after extubation. PMID- 30402298 TI - Endodontic Management of a Severely Dilacerated Mandibular Third Molar: Case Report and Clinical Considerations. AB - This article aims at providing an insight to the clinical modifications required for the endodontic management of severely dilacerated mandibular third molar. A 35-year-old patient was referred for the root canal treatment of the mandibular left third molar. An intraoral periapical radiograph revealed a severe curvature in both the canals. A wide trapezoidal access was prepared following the use of intermediate-sized files for apical preparation. Owing to increased flexibility, Hero Shaper NITI files were used for the biomechanical preparation and single cone obturation was carried out. Third molars owing to their most posterior location-limited access coupled with a severe curvature pose utmost clinical challenges require meticulous skill, advanced technology, and patience to achieve success. PMID- 30402300 TI - First Reported Case of Endoscopic Ultrasound-Guided Core Biopsy Yielding Diagnosis of Primary Adrenal Leiomyosarcoma. AB - Primary adrenal leiomyosarcoma (PAL) is an extremely rare mesenchymal tumor with only a few isolated case reports in the medical literature. Endoscopic ultrasound guided fine-needle aspiration (EUS-FNA) or endoscopic ultrasound-guided core biopsy (EUS-CB) is a safe, effective modality for sampling lesions in the gastrointestinal tract and adjacent organs, including the adrenal glands. We describe the case of a 50-year-old male presenting with abdominal pain and unintentional weight loss over the course of one year. CT imaging revealed an 8.1 cm heterogeneous left adrenal mass with PET-confirmed metastases to the liver and lung. Pheochromocytoma was ruled out. Adrenal cortical carcinoma was the other critical differential diagnosis. As the patient was not a candidate for surgery, an EUS-FNA and CB were performed on this left adrenal mass revealing a spindle cell neoplasm with extensive necrosis confirming the diagnosis of primary leiomyosarcoma. The patient was treated with chemotherapy with palliative radiation. This case demonstrates the utility of EUS-FNA or CB as modalities that can aid in the diagnosis of adrenal lesions in specific circumstances. PMID- 30402299 TI - Point-of-Care Ultrasound Identifies Decompensated Heart Failure in a Young Male with Methamphetamine-Associated Cardiomyopathy Presenting in Severe Sepsis to the Emergency Department. AB - We describe a case of a young male who presents to the emergency department with severe sepsis and decompensated heart failure with underlying Methamphetamine Associated Cardiomyopathy that was previously undiagnosed. This presentation is unique because Methamphetamine-Associated Cardiomyopathy is an uncommonly reported condition that presented in a complex clinical scenario of severe sepsis and decompensated congestive heart failure. We discuss how we used point-of-care ultrasound (POCUS) in this case to identify an unsuspected disease process and how it changed our initial resuscitation strategy and management. Emergency physicians can utilize point-of-care ultrasound (POCUS) to help identify these high-risk patients in the emergency department and guide appropriate resuscitation. Methamphetamine-Associated Cardiomyopathy (MAC) is an infrequently described complication of methamphetamine abuse, most commonly presented as a nonischemic dilated cardiomyopathy. With the rise in methamphetamine abuse in the United States, complications from methamphetamine use are more commonly presenting to the emergency department. Proper education and rehabilitation, with a goal of abstinence from amphetamine use, may allow patients to potentially regain normal cardiac function. Since the majority of patients present late with severe cardiac dysfunction, early detection is essential amongst critically ill patients since recognition may significantly influence ED management. PMID- 30402301 TI - Pulmonary Intravascular B-Cell Lymphoma with Angiotropism/Angioinvasion Mimicking Interstitial Lung Disease: A Clinical Dilemma and Potential Diagnostic Challenge. AB - Intravascular large B cell lymphoma (IVLBCL) is a rare type of extranodal diffuse large B-cell lymphoma. Patients typically present with nonspecific findings, particularly bizarre neurologic symptoms, fever, and skin lesions. IVLBCL with primary lung presentation is very rare and difficult to diagnose. The authors report a case of a 75-year-old male who presented with neurological symptoms and showed diffuse pulmonary ground glass opacities on computed tomography scan (CT scan). Surgical lung biopsy was performed. Light microscopic examination of the specimen showed diffuse alveolar septal widening caused by neoplastic lymphocytes, which were positive for CD20. These atypical lymphoid cells also demonstrated angiotropism/angioinvasion of the medium sized pulmonary vessels. The patient was diagnosed with IVLBCL and underwent chemotherapy. The patient is still alive 12 months after diagnosis. PMID- 30402302 TI - Pure Red Cell Aplasia Associated with Thymolipoma: Complete Anaemia Resolution following Thymectomy. AB - Pure red cell aplasia is an uncommon cause of anaemia rarely associated with thymoma. A combination of immunosuppressive therapy and thymectomy offers a potential cure. Thymectomy alone rarely results in anaemia resolution. A seventy three-year-old male with Klinefelter syndrome presented with progressively increasing shortness of breath and anaemia. Serological testing supported primary bone marrow pathology, and a bone marrow biopsy was performed. A pure red cell aplasia was seen on bone marrow examination, and computed tomography of the chest demonstrated a thymoma. Thymectomy was performed, and histology revealed a thymolipoma. Complete anaemia resolution was achieved following thymectomy alone. This suggests that thymomas may directly mediate immune dysregulation resulting in erythroid precursor destruction. PMID- 30402303 TI - Hepatic Sclerosing Hemangioma with Predominance of the Sclerosed Area Mimicking a Biliary Cystadenocarcinoma. AB - We report here an extremely rare case of hepatic sclerosing hemangioma mimicking a biliary cystadenocarcinoma. A previously healthy 39-year-old woman was referred to our hospital because of a large tumor in the liver. Abdominal computed tomography revealed early peripheral ring enhancement in the arterial phase and slight internal heterogeneous enhancement in the delayed phase. Magnetic resonance imaging revealed a tumor with low intensity in the T1-weighted image and very high intensity in the fat-saturated T2-weighted image. The patient underwent hepatectomy for a possible malignant liver tumor. Grossly, the tumor appeared as a white, solid, and cystic mass (weighted 1.1 kg and measured 170*100*80 mm) that was elastic, soft, and homogeneous with a yellowish area. Histological examination showed that the tumor mostly consisted of fibrotic areas with hyalinization. The typical histology of cavernous hemangioma was confirmed in part, and the tumor was diagnosed as a sclerosing hemangioma with predominancy of the sclerosed area. A review of 20 cases reported previously revealed that only 2 (10%) patients were diagnosed as having sclerosing hemangioma preoperatively. PMID- 30402304 TI - Acute Streptococcus mitis Sacroiliitis in a Teenager with Unclear Source of Bacteremia: A Case Report and Literature Review. AB - Septic arthritis is an orthopedic emergency that is commonly caused by Staphylococcus aureus. Old age, diabetes mellitus, rheumatoid arthritis, prosthetic joint, and recent surgery are the main predisposing risk factors. Most cases of septic arthritis are caused by hematogenous spread of infection. Infectious sacroiliitis is a rare form of septic arthritis which is often clinically challenging to diagnose due its various and nonspecific presentations. Streptococcus mitis belongs to viridans group streptococci (VGS) bacteria, which is a component of body flora that is commonly involved in bacterial endocarditis. VGS in general and S. mitis specifically is an uncommon cause of osteoarticular infections. Here, we report a case of spontaneous Streptococcus mitis bacteremia complicated by septic sacroiliitis in a healthy teenager in the absence of infective endocarditis or a clear source of bacteremia. PMID- 30402305 TI - Vertebral Osteomyelitis Secondary to Pneumococcal Infection. AB - Vertebral osteomyelitis secondary to pneumococcal infection is an uncommon condition caused by Streptococcus pneumoniae. Fever, back pain, and raised ESR are common features in the clinical setting. We report a 62-year-old female patient who presented with an unusual presentation. Later on, vertebral osteomyelitis secondary to pneumococcal infection was confirmed at T8, 9 by CT scan, MRI, and cytology. The patient was treated successfully with high-dose ceftriaxone. PMID- 30402306 TI - Disseminated Tuberculosis Presenting as Chronic Orchiepididymitis in a Military Trainee: A Case Report and Review of the Literature. AB - Orchiepididymitis is a clinical diagnosis. The acute form secondary to sexually transmitted or enteric pathogens is well known to primary care providers. However, chronic orchiepididymitis may be secondary to genitourinary tuberculosis (TB), and physicians in countries with a low prevalence of TB might not consider it in their differential diagnosis. Indeed, cognitive errors, such as anchoring or availability bias, may contribute to a delayed diagnosis of genitourinary TB. We present a case of chronic orchiepididymitis as a result of disseminated TB in a Cameroonian male who was visiting the United States for military training. He experienced diagnostic delay and was ultimately diagnosed by orchiectomy. Early consideration of a diagnosis of TB for chronic or recurrent orchiepididymitis in a patient with epidemiologic risk factors is of utmost importance because delayed diagnosis could lead to organ loss. PMID- 30402307 TI - Cloudy Dialysate as the Initial Presentation for Lymphoma. AB - Turbid dialysate in a patient on peritoneal dialysis is usually due to peritonitis and almost all these patients are started on empirical antibiotics pending cultures. However, in few of them with culture negative fluid, this could represent other etiologies like chyle, which requires more intensive investigations, and analysis of fluid itself reveals some rare diagnosis. We present one such report of chylous ascites with prompt investigation leading to a diagnosis of malignancy in a peritoneal dialysis patient. PMID- 30402308 TI - Relapsing Polychondritis with Meningoencephalitis Refractory to Immunosuppressant Therapy. AB - Meningoencephalitis is a rare complication of relapsing polychondritis. We report a case of a 25-year-old male who presented with visual hallucinations and symptoms of depression and anxiety, white matter changes on MRI, and CSF lymphocytosis, along with inflammatory chondritis seen in his auricle cartilage biopsy. Eventually he was given the diagnosis of RP presenting with meningoencephalitis based on CSF analysis, brain MRI findings, negative serologies, and neurologic exam findings. The patient's clinical state did not improve despite being on IV methylprednisolone for a period of 7 days; afterwards he was switched to oral prednisone with no clinical improvement. As a result, he was given cyclophosphamide and rituximab, respectively, without benefit. He also underwent craniectomy with VP shunt due to worsening hydrocephalus and a brain biopsy was done to confirm the diagnosis. He is currently on methotrexate and steroid dependent with a goal to taper down. Even though all 19 reported cases of meningoencephalitis with RP in the literature did respond to immunosuppressive therapy, in our case, however the patient did not respond to immunosuppressive treatment and currently is in mute dementia status after three years of treatment. PMID- 30402309 TI - Impact of Methamphetamine Abuse: A Rare Case of Rapid Cerebral Aneurysm Growth with Review of Literature. AB - Methamphetamine or "meth" is a sympathomimetic amine of the amphetamine-type substances (ATS) class with an extremely high potential for abuse. Illicitly abused neurostimulants like cocaine and meth predispose patients to the aneurysmal formation with reported rupture at a younger age and in much smaller sized aneurysms. However, very rapid growth of aneurysm within less than 2 weeks with methamphetamine abuse is very rarely observed or reported. In this report, we present a patient with repeated and recurrent meth abuse who demonstrated rapid growth of a pericallosal aneurysm over the period of less than two weeks. The pathophysiology of stroke related to meth and ATS abuse is multifactorial with hypertension, tachycardia, and vascular disease postulated as major mechanisms. The rapid growth of an aneurysm has a high risk of aneurysmal rupture and SAH, which is a neurosurgical emergency and therefore warrants careful consideration and close monitoring. This case confirms the dynamic temporal effects of methamphetamine use on intracranial vessels and this specific neurostimulants association to rapid aneurysmal formation. In light of vascular pathologies the possibility of drug-induced pseudoaneurysm should also be considered in young patients with history of meth abuse. PMID- 30402310 TI - Late Recovery from Severe Streptococcus pneumoniae Comatose Meningitis with Concomitant Diffuse Subcortical Cytotoxic Edema and Cortical Hypometabolism. AB - A 75-year-old woman was admitted to ICU with coma following Streptococcus pneumoniae meningitis with bacteremia. Her Glasgow Coma Scale (GCS) score fluctuated around 4 to 6 over the next four weeks. There was no evidence of increased intracranial pressure (ICP). Electroencephalogram (EEG) showed only diffuse aspecific slowing. Impaired cerebral blood flow (CBF) autoregulation was suggested at transcranial Doppler (TCD). Repeated brain magnetic resonance imaging (MRI) examination failed to demonstrate venous thrombosis, arterial ischemic stroke, or brain abscesses but revealed diffuse but reversible cortical cytotoxic edema at diffusion-weighted (DW) sequences. The brain FDG-positron emission tomography (FDG-PET) showed diffuse cortical hypometabolism. The patient unexpectedly experienced a complete neuropsychological recovery the next few weeks. The suggested hypothesis to explain this unusual disease course could be a transient alteration of CBF autoregulation due to some degree of diffuse subcortical microangiopathy. A concomitant reduction of brain metabolism probably prevented the progression towards cortical irreversible ischemic damage. PMID- 30402311 TI - Thrombophlebitis of the Right Renal Capsular Vein during the Early Postpartum Period. AB - Venous thrombophlebitis is an uncommon cause of fever and lower abdominal pain during the early postpartum period. It mostly occurs in the right ovarian vein, and computed tomography (CT) is useful for diagnosis. We present a case of thrombophlebitis of the renal capsular vein. A 27-year-old postpartum woman presented with right lower abdominal pain and fever unresponsive to antibiotics. Contrast CT showed a ring-enhancing mass in the right retroperitoneum, which was distinct from the right ovarian vein. Exploratory laparoscopy revealed a retroperitoneal hematoma and normal appendix. Reconstruction of CT images revealed that the mass was connected to the right renal capsular vein. Anticoagulation therapy improved the patient's symptoms. Postpartum thrombophlebitis can occur at locations other than the ovarian vein, such as the renal capsular vein. If a retroperitoneal mass is discovered during puerperium, a thorough investigation of the mass's continuity with surrounding vessels is essential to avoid unnecessary surgery. PMID- 30402312 TI - Spontaneous Massive Vulvar Edema in Pregnancy: A Case Report. AB - Spontaneous massive vulvar edema in pregnancy is unusual and a cause for concern. This condition should be taken seriously since it might be caused by some conditions such as preeclampsia, diabetes, vulvovaginitis, severe anemia, and neoplasms. We report a case of massive vulvar edema in a 15-year-old primigravida following tocolysis therapy at 33 weeks of gestation. Other causes of vulvar edema were excluded. The vulvar edema appeared spontaneously after tocolysis and rapidly increased in size, associated with severe vulvar pains. The vulvar edema resolved progressively with antibiotics, corticoids, and analgesics. The patient delivered by spontaneous vaginal delivery a term live newborn with an unremarkable postpartum period. The aim of this report is to alert clinicians that conservative attempts could be considered for vulvar edema complicating tocolysis. PMID- 30402313 TI - Malignant Spinal Cord Compression Syndrome as an Initial Presentation of Testicular Cancer. AB - Malignant spinal cord compression syndrome (MSCCS) occurs in 2.5 to 5% of all oncological patients. In 20% of the cases, it is the initial manifestation. This syndrome is a rare event among germ cell tumors (GCT), occurring in only 1.7% of the patients. We present the case of a 24-year-old man who arrived at the emergency department with dysesthesia and paraparesis as well as urinary incontinence. Imaging studies showed an infiltrative lesion in the left testicle, pulmonary and hepatic metastatic disease, and a large retroperitoneal ganglionar conglomerate that infiltrated the spinal cord through the intervertebral foramina of the vertebra level T11 with displacement of the L1 vertebral body. A postoperative biopsy showed a pure embryonal carcinoma. In the initial approach of a young man who presents spinal cord compression, the presence of MSCCS associated with GCT should be considered as a possible cause. A high level of suspicion is required to achieve a timely diagnosis, to grant the patient the best possible outcome. PMID- 30402314 TI - A Case of Lenvatinib-Induced Focal Segmental Glomerulosclerosis (FSGS) in Metastatic Medullary Thyroid Cancer. AB - We describe a case of lenvatinib (E7080) associated focal segmental glomerulosclerosis (FSGS) encountered during the treatment of metastatic medullary thyroid cancer. Proteinuria is a relatively common side effect of VEGF targeted treatments and can occasionally result in treatment discontinuation. Here, we describe a patient who developed secondary FSGS necessitating discontinuation of treatment at first but who was subsequently rechallenged with anti-VEGF-targeted treatment without recurrence of proteinuria. Lenvatinib was a novel experimental agent at the time the treatment took place; however, its recent licensing for the treatment of thyroid malignancies in the UK makes reporting of these adverse effects all the more important now. PMID- 30402315 TI - Malignant Transformation of Testicular Teratoma to PNET, Adenocarcinoma, and Osteosarcoma with Complete Remission after Surgery and Combination Chemotherapy in a Young Adult Male. AB - Mixed germ cell tumors (GCT) with teratoma components can transform into somatic malignancies which can include histologies outside of traditional germ cell lineages. We describe a case of an 18-year-old man with a metastatic testicular GCT with both mature and immature teratoma components containing malignant transformation into multiple histologies including PNET in the primary testicular tumor and osteosarcoma in a separate pulmonary metastatic lesion. Management with targeted chemotherapy resulted in a durable remission. This is the first reported case that we know of a patient with primary PNET malignant transformation with subsequent metastatic transformation to osteosarcoma. PMID- 30402316 TI - Management of Congenital Clinical Anophthalmos with Orbital Cyst: A Kinshasa Case Report. AB - An early developmental lack of the optic vesicle can result in congenital anophthalmia, defined as a complete absence of the eye, which can be distinguished from congenital microphthalmos, where ocular rudiments are present. Here, a rare pediatric case of congenital clinical anophthalmos with orbital cyst in the left orbit is reported. The patient was a 14-month-old girl with no other congenital defects who underwent surgical and prothetic management in St. Joseph's Hospital Kinshasa, Democratic Republic of the Congo (DRC). Surgery was carried out under general anesthesia. The cyst was punctured and its wall fully excised. Near the orbital apex pigmented elements representing iris, ciliary body, and choroidal or retinal remnants were found. The specimens were fixed in formalin for histological examination. Surgical cyst removal including socket deepening for an artificial eye was performed. Postoperative wound healing was uneventful and a satisfactory cosmetic outcome was achieved in all follow-up examinations. Histological examination revealed rudimentary ocular structures similar to degenerated lens tissue with a typical, PAS-positive capsule. Additionally, pigmented epithelial structures, which seem to be of ciliary body, iris, and choroidal or retinal-type epithelium origin, could be detected, prompting the final diagnosis, microphthalmia with dominant cyst formation. PMID- 30402317 TI - Endoprosthetic Reconstruction for a Displaced Atypical Femoral Fracture in a Cancer Patient with Poor Prognosis. AB - Zoledronate or denosumab treatment is beneficial for cancer patients with bone metastasis. However, each agent may trigger atypical femoral fractures. Incomplete atypical femoral fractures can be successfully treated with prophylactic intramedullary nailing. On the other hand, intramedullary nailing for displaced atypical femoral fractures occasionally causes problems with regard to bone healing, resulting in long-term treatment. In cancer patients with poor prognosis who experience atypical femoral fractures, improvement in activities of daily living should be the priority. Thus, we performed endoprosthetic reconstruction for a displaced atypical femoral fracture in a breast cancer patient with poor prognosis to enable walking in the early stage after the operation. Two weeks after the operation, she could successfully walk. The postoperative Musculoskeletal Tumor Society score was 47%, and it had improved to almost the preoperative level before injury (50%). In conclusion, endoprosthetic reconstruction for displaced atypical femoral fractures may be a first-line treatment approach to acquire early postoperative walking ability for improving activities of daily living in cancer patients with poor prognosis. PMID- 30402318 TI - Torticollis as Presentation for Atypical Kawasaki Disease Complicated by Giant Coronary Artery Aneurysms. AB - Kawasaki disease (KD) is an acute systemic vasculitis of childhood. The diagnosis can be made in a patient who presents with a prolonged high fever and meeting at least four of five criteria including polymorphous rash, mucosal changes, extremity changes (including swelling and/or palmar and plantar erythema), bilateral nonsuppurative conjunctivitis, and unilateral cervical lymphadenopathy. Atypical KD refers to patients who have not met the full criteria and in whom atypical features may be present. We discuss a case of a 6-year-old male who presented to the Emergency Department with torticollis. A series of investigations for elevated inflammatory markers revealed dilated coronary artery aneurysms on echocardiogram, and thus he was diagnosed with atypical KD. His only other criteria were bilateral nonsuppurative conjunctivitis and a prior brief febrile illness. He was treated with high-dose intravenous immune globulin (IVIG) and low-dose aspirin. Low-molecular-weight heparin and atenolol were added due to the presence of giant aneurysms. PMID- 30402319 TI - Use of Noninvasive Ventilation with Volume-Assured Pressure Support to Avoid Tracheostomy in Severe Obstructive Sleep Apnea. AB - Obstructive sleep apnea (OSA) is a common disorder in children but can occasionally present with life-threatening hypoxemia. Obesity is a significant risk factor for poor outcomes of OSA treatment. Continuous positive airway pressure (CPAP) is indicated in children who are not candidates for or have an unsatisfactory response to adenotonsillectomy. Children acutely at risk for significant morbidity with other therapies are candidates for a tracheostomy. An eight-year-old patient with morbid obesity and severe OSA refractory to CPAP therapy was treated successfully with a novel noninvasive ventilation (NIV) mode with volume-assured pressure support (VAPS) and avoided tracheostomy. PMID- 30402320 TI - Successful Management of Blue Rubber Bleb Nevus Syndrome (BRBNS) with Sirolimus. AB - Blue rubber bleb nevus syndrome (BRBNS) is a rare disease with vascular malformations in several systems of the body, most commonly the skin and gastrointestinal tract. Bleeding from the gastrointestinal (GI) tract is a major complication, which may lead to chronic iron deficiency anemia and the need for frequent blood transfusions due to ongoing gastrointestinal blood loss. In this case report, we describe a now 19-year-old female with BRBNS who required six blood transfusions per year and after starting sirolimus is symptom- and transfusion-free. PMID- 30402321 TI - Laparoscopic Resection of an Appendix Mucocele in a Breast Cancer Patient. AB - Background: Acute appendicitis may be treated with antibiotics, but most surgeons offer laparoscopic appendectomy (LA). Appendiceal mucocele (AMC) is a rare disorder. Surgical removal is recommended due to the risk of pseudomyxoma peritonei. LA has been suggested for this condition. Although rare, breast cancer (BC) may metastasize to the appendix. An appendiceal mass in a breast cancer patient should be approached as a possible metastatic focus until proven otherwise. Case Presentation: A 45-year-old Caucasian woman with invasive lobular BC underwent bilateral mastectomy. An AMC was found on CT scan. LA was done with a strict minimal touch technique. The appendix was resected with a 1 cm margin of the cecal pole, and the specimen was removed from the abdomen in a retrieval bag. Pathology showed benign cystadenoma. The patient had an uneventful postoperative course. Conclusion: This case highlights the diagnostic challenge of an appendiceal mass in a BC patient. BC patients with AMC should undergo appendectomy to rule out metastatic disease and to prevent pseudomyxoma peritonei. LA can be performed safely in patients with AMC. PMID- 30402322 TI - Total Mandibular Subapical Alveolar Osteotomy to Correct Class II Division I Dentofacial Deformity. AB - Introduction: Class II division I malocclusions are the most common dentofacial deformities seen in clinical practice. Severe cases or cases in which growth has ceased may require full correction combining orthodontic and surgical treatment. We report a case of a total mandibular subapical alveolar osteotomy, performed to correct a class II division I dentofacial deformity. Case Report: A 19-year-old female patient was referred to the oral and maxillofacial surgery department at the Federal University of Parana with chin aesthetic complaints as well as class II malocclusion. The proposed treatment was total mandibular subapical alveolar osteotomy, retaining the chin position and eliminating the need for genioplasty, since, although the patient presented with a class II dentofacial deformity, the chin was well positioned. Under general anesthesia, a "V-shaped" incision was conducted from the right retromolar region to the left retromolar region. A ring of cortical bone was removed around the mental foramen, with the aim to create a space around the mental nerve. Fixation was conducted with plates and screws of the 2.0 system. The patient on six-year follow-up showed osteotomy stability, a better overall occlusion, and outcome satisfaction. PMID- 30402323 TI - Dry Gangrene in Children with Typhoid Intestinal Perforation: A Report of Two Cases. AB - Intestinal perforation is a life-threatening complication of typhoid fever commonly seen in developing countries, but extraintestinal complications are infrequently reported. We report herein two cases of gangrene seen in children managed for typhoid intestinal perforation, highlighting the challenges faced in their management. PMID- 30402325 TI - Advances in MS-Based Analytical Methods: Innovations and Future Trends. PMID- 30402324 TI - Injectable Chemotherapy Downstaged Oral Squamous Cell Carcinoma from Nonresectable to Resectable in a Rescue Dog: Diagnosis, Treatment, and Outcome. AB - This case report documents the diagnosis, treatment, and outcome of a nonresectable oral squamous cell carcinoma in a dog with initial poor prognosis. An approximately 4-year-old female Staffordshire Bull Terrier presented with a large mass on the front of lower jaw which was diagnosed as oral papillary squamous cell carcinoma by histopathology. CT scans revealed invasion of the cancer to the frenulum of the tongue. The mass was inoperable due to location, expansiveness, and metastatic lymph nodes. The dog received 4 treatments of intralesional hyaluronan-platinum conjugates (HylaPlatTM, HylaPharm LLC, Lawrence, Kansas) at 3-week intervals. Clinical chemistry and complete blood count were performed one week after each treatment and results were within normal limits. Complications included bleeding due to tumor tissue sloughing, as well as a single seizure due to unknown causes. Upon completion of chemotherapy, CT showed that the mass had regressed and was no longer invading the lingual frenulum, and multiple lymph nodes were free of metastasis. The mass thus became resectable and the dog successfully underwent rostral bilateral mandibulectomy. Over one year after chemotherapy and surgery, the cancer remains in complete remission. PMID- 30402326 TI - Improvement in Analytical Methods for Determination of Sugars in Fermented Alcoholic Beverages. AB - The main objective of this study was to improve the performance of analytical methods for the determination of sugars in fermented alcoholic beverages based on mid-infrared-partial least squares (MIR-PLS), high-performance liquid chromatography with the ultraviolet detector (HPLC-UV), high-performance liquid chromatography with the refractive index detector (HPLC-RI), and sulfuric acid methods. The MIR-PLS method was found to give good prediction of individual sugars: glucose, fructose, sucrose, and maltose in the alcoholic beverages with less than 4% error. The HPLC-UV method can be used for the determination of glucose in alcoholic beverages after derivatization with p-aminobenzoic acid ethyl ester. The HPLC-RI method was found to be applicable for the determination of individual sugars: glucose, fructose, sucrose, and maltose in the alcoholic beverages. The limit of detection (%, w/w) and recovery (%) of the individual sugars by the HPLC-RI method were fructose 0.001, 89.4-106; glucose 0.002, 92.4 109; and sucrose 0.002, 94.2-95.1. The sulfuric acid method was found to be useful for the determination of total sugar in the alcoholic beverages. The limit of detection (%, w/w) and recovery (%) of the total sugar by the sulfuric acid method were found to be 0.009, 98.2-109. The HPLC-RI method was applied to determine the level of individual sugars, while the sulfuric acid method was used to determine total sugar in Ethiopian traditional fermented alcoholic beverages: Tella, Netch Tella, Filter Tella, Borde, Tej, Korefe, Keribo, and Birz. The sugar contents in the real samples were found in the ranges (%): glucose 0.07-5.60, fructose 0.09-8.50, sucrose and maltose 0.08-3.00, and total sugar 12.0-64.5. The levels of sugars in Ethiopian traditional fermented alcoholic beverages were found to be comparable with literature data. PMID- 30402327 TI - Determination of Fluoroquinolones in Pharmaceutical Formulations by Extractive Spectrophotometric Methods Using Ion-Pair Complex Formation with Bromothymol Blue. AB - In this paper, we reported a new, simple, accurate, and precise extractive spectrophotometric method for the determination of fluoroquinolones (FQs) including ciprofloxacin (CFX), levofloxacin (LFX), and ofloxacin (OFX) in pharmaceutical formulations. The proposed method is based on the ion-pair formation complexes between FQs and an anionic dye, bromothymol blue (BTB), in acidic medium. The yellow-colored complexes which were extracted into chloroform were measured at the wavelengths of 420, 415, and 418 nm for CFX, LFX, and OFX, respectively. Some effective conditions such as pH, dye concentration, shaking time, and organic solvents were also systematically studied. Very good limit of detection (LOD) of 0.084 ug/mL, 0.101 ug/mL, and 0.105 ug/mL were found for CFX, LFX, and OFX, respectively. The stoichiometry of the complexes formed between FQs and BTB determined by Job's method of continuous variation was 1 : 1. No interference was observed from common excipients occurred in pharmaceutical formulations. The proposed method has been successfully applied to determine the FQs in some pharmaceutical products. A good agreement between extractive spectrophotometric method with high-performance liquid chromatography mass spectrometry (HPLC-MS) for the determination of FQs in some real samples demonstrates that the proposed method is suitable to quantify FQs in pharmaceutical formulations. PMID- 30402328 TI - Direct Antiviral Mechanisms of Interferon-Gamma. AB - Interferon-gamma (IFNG) is a pleiotropic cytokine that modulates both innate and adaptive immune networks; it is the most potent activator of macrophages and a signature cytokine of activated T lymphocytes. Though IFNG is now appreciated to have a multitude of roles in immune modulation and broad-spectrum pathogen defense, it was originally discovered, and named, as a secretory factor that interferes with viral replication. In contrast to the prototypical type I interferons produced by any cells upon viral infection, only specific subsets of immune cells can produce IFNG upon infection or stimulation with antigen or mitogen. Still, virtually all cells can respond to both types of interferons. This makes IFNG a versatile anti-microbial cytokine and also gives it a unique position in the antiviral defense system. The goal of this review is to highlight the direct antiviral mechanisms of IFNG, thereby clarifying its antiviral function in the effective control of viral infections. PMID- 30402330 TI - Aryl Hydrocarbon Receptor Ligands Indoxyl 3-sulfate and Indole-3-carbinol Inhibit FMS-like Tyrosine Kinase 3 Ligand-induced Bone Marrow-derived plasmacytoid Dendritic Cell Differentiation. AB - Aryl hydrocarbon receptor (AhR) regulates both innate and adaptive immune responses by sensing a variety of small synthetic and natural chemicals, which act as its ligands. AhR, which is expressed in dendritic cells (DCs), regulates the differentiation of DCs. However, effects of AhR on the differentiation of DCs are variable due to the heterogeneity of DCs in cell surface marker expression, anatomical location, and functional responses. The plasmacytoid DCs (pDCs), one of DC subsets, not only induce innate as well as adaptive immune responses by secreting type I interferons and pro-inflammatory cytokines, but also induce IL 10 producing regulatory T cell or anergy or deletion of antigen-specific T cells. We showed here that AhR ligands indoxyl 3-sulfate (I3S) and indole-3-carbinol (I3C) inhibited the development of pDCs derived from bone marrow (BM) precursors induced by FMS-like tyrosine kinase 3 ligand (Flt3L). I3S and I3C downregulated the expression of signal transducer and activator of transcription 3 (STAT3) and E2-2 (Tcf4). In mice orally treated with I3S and I3C, oral tolerance to dinitrofluorobenzene was impaired and the proportion of CD11c+B220+ cells in mesenteric lymph nodes was reduced. These data demonstrate that AhR negatively regulates the development of pDCs from BM precursors induced by Flt3L, probably via repressing the expression of STAT3. PMID- 30402329 TI - Expansion and Sub-Classification of T Cell-Dependent Antibody Responses to Encompass the Role of Innate-Like T Cells in Antibody Responses. AB - In addition to T cell-dependent (TD) Ab responses, T cells can also regulate T cell-independent (TI) B cell responses in the absence of a specific major histocompatibility complex (MHC) class II and antigenic peptide-based interaction between T and B cells. The elucidation of T cells capable of supporting TI Ab responses is important for understanding the cellular mechanism of different types of TI Ab responses. Natural killer T (NKT) cells represent 1 type of helper T cells involved in TI Ab responses and more candidate helper T cells responsible for TI Ab responses may also include gammadelta T cells and recently reported B-1 helper CD4+ T cells. Marginal zone (MZ) B and B-1 cells, 2 major innate-like B cell subsets considered to function independently of T cells, interact with innate-like T cells. Whereas MZ B and NKT cells interact mutually for a rapid response to blood-borne infection, peritoneal memory phenotype CD49dhighCD4+ T cells support natural Ab secretion by B-1 cells. Here the role of innate-like T cells in the so-called TI Ab response is discussed. To accommodate the involvement of T cells in the TI Ab responses, we suggest an expanded classification of TD Ab responses that incorporate cognate and non-cognate B cell help by innate-like T cells. PMID- 30402331 TI - Validation Study of an Operational Tolerance Signature in Korean Kidney Transplant Recipients. AB - Operational tolerance (OT), defined as maintaining stable graft function without immunosuppression after transplant surgery, is an ideal goal for kidney transplant recipients (KTRs). Recent investigations have demonstrated the distinctive features of B cells, T cells, and dendritic cell-related gene signatures and the distributions of circulating lymphocytes in these patients; nonetheless, substantial heterogeneities exist across studies. This study was conducted to determine whether previously reported candidate gene biomarkers and the profiles of lymphocyte subsets of OT could be applied in Korean KTRs. Peripheral blood samples were collected from 153 patients, including 7 operationally tolerant patients. Quantitative real-time PCR and flow cytometry were performed to evaluate gene expression and lymphocyte subsets, respectively. Patients with OT showed significantly higher levels of B cell-related gene signatures (IGKV1D-13 and IGKV4-1), while T cell-related genes (TOAG-1) and dendritic cell-related genes (BNC2, KLF6, and CYP1B1) were not differentially expressed across groups. Lymphocyte subset analyses also revealed a higher proportion of immature B cells in this group. In contrast, the distributions of CD4+ T cells, CD8+ T cells, mature B cells, and memory B cells showed no differences across diagnostic groups. An OT signature, generated by the integration of IGKV1D-13, IGKV4-1, and immature B cells, effectively discriminated patients with OT from those in other diagnostic groups. Finally, the OT signature was observed among 5.6% of patients who had stable graft function for more than 10 years while on immunosuppression. In conclusion, we validated an association of B cells and their related signature with OT in Korean KTRs. PMID- 30402332 TI - Oral Administration of Silk Peptide Enhances the Maturation and Cytolytic Activity of Natural Killer Cells. AB - Silk peptide, the hydrolysate of silk protein derived from cocoons, has been employed as a biomedical material and is believed to be safe for human use. Silk peptide display various bioactivities, including anti-inflammatory, immune regulatory, anti-tumor, anti-viral, and anti-bacterial. Although earlier investigations demonstrated that silk peptide stimulates macrophages and the production of pro-inflammatory cytokines, its effect on natural killer (NK) cell function has not yet been explored. In this study, we initially confirmed that silk peptide enhances NK cell activity in vitro and ex vivo. To assess the modulatory activity of silk peptide on NK cells, mice were fed various amounts of a silk peptide-supplemented diet for 2 months and the effects on immune stimulation, including NK cell activation, were evaluated. Oral administration of silk peptide significantly enhanced the proliferation of mitogen- or IL-2 stimulated splenocytes. In addition, oral silk peptide treatment enhanced the frequency and degree of maturation of NK cells in splenocytes. The same treatment also significantly enhanced the target cell cytolytic activity of NK cells, which was determined by cell surface CD107a expression and intracellular interferon gamma expression. Finally, oral administration of silk peptide stimulated T helper 1-type cytokine expression from splenic lymphocytes. Collectively, our results suggest that silk peptide potentiates NK cell activity in vivo and could be used as a compound for immune-modulating anti-tumor treatment. PMID- 30402333 TI - Herpes Zoster DNA Vaccines with IL-7 and IL-33 Molecular Adjuvants Elicit Protective T Cell Immunity. AB - Herpes zoster (HZ), or shingles, is caused by the reactivation of latent varicella-zoster virus (VZV) from the sensory ganglia when VZV-specific T-cell immunity is decreased because of aging or immunosuppression. In the present study, we developed HZ DNA vaccine candidates encoding VZV proteins and cytokine adjuvants, such as IL-7 and IL-33. We immunized C57BL/6 mice with DNA plasmids encoding VZV glycoprotein E (gE), immediate early (IE) 63, or IE62 proteins and found that robust VZV protein-specific T-cell responses were elicited by HZ DNA vaccination. Co-administration of DNA plasmids encoding IL-7 or IL-33 in HZ DNA vaccination significantly enhanced the magnitude of VZV protein-specific T-cell responses. Protective immunity elicited by HZ DNA vaccination was proven by challenge experiments with a surrogate virus, vaccinia virus expressing gE (VV gE). A single dose of HZ DNA vaccine strongly boosted gE-specific T-cell responses in mice with a history of previous infection by VV-gE. Thus, HZ DNA vaccines with IL-7 and IL-33 adjuvants strongly elicit protective immunity. PMID- 30402334 TI - Decreased Expression of Sphingosine-1-Phosphate Receptor 1 in the Blood Leukocyte of Rheumatoid Arthritis Patients. AB - Sphingosine-1-phosphate (S1P) plays an important role in trafficking leukocytes and developing immune disorders including autoimmunity. In the synovium of rheumatoid arthritis (RA) patients, increased expression of S1P was reported, and the interaction between S1P and S1P receptor 1 (S1P1) has been suggested to regulate the expression of inflammatory genes and the proliferation of synovial cells. In this study, we investigated the level of S1P1 mRNA expression in the blood leukocytes of RA patients. In contrast to the previous reports, the expression level of this gene was not correlated to their clinical scores, disease durations and ages. However, S1P1 was transcribed at a significantly lower level in the circulating leukocytes of RA patients when compared to age-, and sex-matched healthy controls. Since these data may suggest the participation of S1P1, further studies are needed to determine the role of this receptor in the pathogenesis of RA. PMID- 30402335 TI - Erratum: Immune Disorders and Its Correlation with Gut Microbiome. AB - [This corrects the article on p. 129 in vol. 12, PMID: 23091436.]. PMID- 30402336 TI - Globus Pallidum DBS for Task-Specific Dystonia in a Professional Golfer. PMID- 30402337 TI - Primary Writing Tremor. AB - Background: Primary writing tremor (PWT) is a rare condition; tremor occurs primarily while writing rather than during other tasks. Phenomenology Shown: We illustrate the phenomenology of PWT and point out associated subtle dystonic posturing on neurological examination. Educational Value: PWT is a tremor disorder that shares clinical features with both dystonia and essential tremor. PMID- 30402339 TI - Transient Generalized Chorea in Influenza A Encephalopathy. AB - Background: Influenza A infections are a rare cause of movement disorders. Previously described patients have suffered from acute-onset myoclonus and/or dystonia or post-viral parkinsonism. Case Report: We present the case of a 74 year-old female patient with transient generalized chorea due to influenza A mediated encephalopathy. Discussion: We discuss whether the clinical presentation and the magnetic resonance imaging changes may be attributable to cytokine mediated encephalopathy or to direct cytotoxic effects of the virus. Additionally, we would like to make clinicians aware of this clinical sign in the context of viral encephalopathy. PMID- 30402341 TI - Assessing Trends in Functional and Structural Characteristics: A Survey of Statistical Methods With an Example From Ophthalmology. AB - Purpose: Clinical decisions on treatment are usually based on short-term records of consecutive measurements of structure and function. Useful models for analyzing average trends and a description of statistical methods for classifying individual subjects on the basis of subject-specific trend progressions are presented. Methods: Random effects trend models allow intercepts and slopes of the trend regression to vary across subjects around group-specific mean intercepts and mean slopes. Model results assess whether average intercepts and slopes and subject variability in intercepts and slopes are the same across groups. Fisher's discriminant functions are used for classification. Results: Methods are presented and illustrated on structural visual data from a multiyear perimetry study. Average thickness of the ganglion cell layer from the optical coherence tomography macula scan and of the retinal nerve fiber layer from the optic disc scan for both glaucoma patients on optimal treatment and normal subjects are analyzed. The random effects trend model shows that average intercepts of glaucoma patients and normal subjects are quite different, but that average slopes are the same, and that the subject variability in both intercepts and slopes is larger for the glaucoma group. These findings explain why the subject-specific trend progression is not a good classifier; it is the level of the measurement (intercept or baseline value) that carries useful information in this particular cohort example. Translational Relevance: Clinicians base decisions on short-term records of consecutive measurements and need simple statistical tools to analyze the information. This paper discusses useful methods for analyzing short time series data. Model results assess whether there exist significant trends and whether average trends are different across groups. The paper discusses whether clinical measures classify patients reliably into disease groups, given their variability. With ever more available data, classification plays a central role of personalized medicine. PMID- 30402338 TI - Animal Models of Tremor: Relevance to Human Tremor Disorders. AB - Background: Tremor is the most common movement disorder; however, the pathophysiology of tremor remains elusive. While several neuropathological alterations in tremor disorders have been observed in post-mortem studies of human brains, a full understanding of the relationship between brain circuitry alterations and tremor requires testing in animal models. Additionally, tremor animal models are critical for our understanding of tremor pathophysiology, and/or to serve as a platform for therapy development. Methods: A PubMed search was conducted in May 2018 to identify published papers for review. Results: The methodology used in most studies on animal models of tremor lacks standardized measurement of tremor frequency and amplitude; instead, these studies are based on the visual inspection of phenotypes, which may fail to delineate tremor from other movement disorders such as ataxia. Of the animal models with extensive tremor characterization, harmaline-induced rodent tremor models provide an important framework showing that rhythmic and synchronous neuronal activities within the olivocerebellar circuit can drive action tremor. In addition, dopamine depleted monkey and mouse models may develop rest tremor, highlighting the role of dopamine in rest tremor generation. Finally, other animal models of tremor have involvement of the cerebellar circuitry, leading to altered Purkinje cell physiology. Discussion: Both the cerebellum and the basal ganglia are likely to play a role in tremor generation. While the cerebellar circuitry can generate rhythmic movements, the nigrostriatal system is likely to modulate the tremor circuit. Tremor disorders are heterogeneous in nature. Therefore, each animal model may represent a subset of tremor disorders, which collectively can advance our understanding of tremor. PMID- 30402340 TI - Retinotopic Responses in the Visual Cortex Elicited by Epiretinal Electrical Stimulation in Normal and Retinal Degenerate Rats. AB - Purpose: Electronic retinal prostheses restore vision in people with outer retinal degeneration by electrically stimulating the inner retina. We characterized visual cortex electrophysiologic response elicited by electrical stimulation of retina in normally sighted and retinal degenerate rats. Methods: Nine normally sighted Long Evans and 11 S334ter line 3 retinal degenerate (rd) rats were used to map cortical responses elicited by epiretinal electrical stimulation in four quadrants of the retina. Six normal and six rd rats were used to compare the dendritic spine density of neurons in the visual cortex. Results: The rd rats required higher stimulus amplitudes to elicit responses in the visual cortex. The cortical electrically evoked responses (EERs) for both healthy and rd rats show a dose-response characteristic with respect to the stimulus amplitude. The EER maps in healthy rats show retinotopic organization. For rd rats, cortical retinotopy is not well preserved. The neurons in the visual cortex of rd rats show a 10% higher dendritic spine density than in the healthy rats. Conclusions: Cortical activity maps, produced when epiretinal stimulation is applied to quadrants of the retina, exhibit retinotopy in normal but not rd rats. This is likely due to a combination of degeneration of the retina and increased stimulus thresholds in rd, which broadens the activated area of the retina. Translational Relevance: Loss of retinotopy is evident in rd rats. If a similar loss of retinotopy is present in humans, retinal prostheses design must include flexibility to account for patient specific variability. PMID- 30402342 TI - Improving Spatial Resolution and Test Times of Visual Field Testing Using ARREST. AB - Purpose: Correctly classifying progression in moderate to advanced glaucoma is difficult. Pointwise visual field test-retest variability is high for sensitivities below approximately 20 dB; hence, reliably detecting progression requires many test repeats. We developed a testing approach that does not attempt to threshold accurately in areas with high variability, but instead expends presentations increasing spatial fidelity. Methods: Our visual field procedure Australian Reduced Range Extended Spatial Test (ARREST; a variant of the Bayesian procedure Zippy Estimation by Sequential Testing [ZEST]) applies the following approach: once a location has an estimated sensitivity of <17 dB (a "defect"), it is checked that it is not an absolute defect (<0 dB, "blind"). Saved presentations are used to test extra locations that are located near the defect. Visual field deterioration events are either: (1) decreasing in the range of 40 to 17 dB, (2) decreasing from >17 dB to "defect", or (3) "defect" to blind. To test this approach we used an empirical database of progressing moderate-advanced 24-2 visual fields (121 eyes) that we "reverse engineered" to create visual field series that progressed from normal to the end observed field. ARREST and ZEST were run on these fields with test accuracy, presentation time, and ability to detect progression compared. Results: With specificity for detecting progression matched at 95%, ZEST and ARREST showed similar sensitivity for detecting progression. However, ARREST used approximately 25% to 40% fewer test presentations to achieve this result in advanced visual field damage. ARREST spatially defined the visual field deficit with greater precision than ZEST due to the addition of non-24-2 locations. Conclusions: Spending time trying to accurately measure visual field locations that have high variability is not productive. Our simulations indicate that giving up attempting to quantify size III white-on-white sensitivities below 17 dB and using the presentations saved to test extra locations should better describe progression in moderate-to-advanced glaucoma in shorter time. Translational Relevance: ARREST is a new visual field test algorithm that provides better spatial definition of visual field defects in faster test time than current procedures. This outcome is achieved by substituting inaccurate quantification of sensitivities <17 dB with new spatial locations. PMID- 30402343 TI - Effect of seasonality on chemical profile and antifungal activity of essential oil isolated from leaves Psidium salutare (Kunth) O. Berg. AB - Medicinal plants play a crucial role in the search for components that are capable of neutralizing the multiple mechanisms of fungal resistance. Psidium salutare (Kunth) O. Berg is a plant native to Brazil used as both food and traditional medicine to treat diseases and symptoms such as stomach ache and diarrhea, whose symptoms could be related to fungal infections from the genus Candida. The objective of this study was to investigate the influence of seasonal variability on the chemical composition of the Psidium salutare essential oil, its antifungal potential and its effect on the Candida albicans morphogenesis. The essential oils were collected in three different seasonal collection periods and isolated by the hydrodistillation process in a modified Clevenger apparatus with identification of the chemical composition determined by gas chromatography coupled to mass spectrometry (GC/MS). The antifungal assays were performed against Candida strains through the broth microdilution method to determine the minimum fungicidal concentration (MFC). Fungal growth was assessed by optical density reading and the Candida albicans dimorphic effect was evaluated by optical microscopy in microculture chambers. The chemical profile of the essential oils identified 40 substances in the different collection periods with gamma-terpinene being the predominant constituent. The antifungal activity revealed an action against the C. albicans, C. krusei and C. tropicalis strains with an IC50 ranging from 345.5 to 2,754.2 ug/mL and a MFC higher than 1,024 ug/mL. When combined with essential oils at sub-inhibitory concentrations (MIC/16), fluconazole had its potentiated effect, i.e. a synergistic effect was observed in the combination of fluconazole with P.salutare oil against all Candida strains; however, for C. albicans, its effect was reinforced by the natural product in all the collection periods. The results show that the Psidium salutare oil affected the dimorphic transition capacity, significantly reducing the formation of hyphae and pseudohyphae in increasing concentrations. The results show that P. salutare oil exhibits a significant antifungal activity against three Candida species and that it can act in synergy with fluconazole. These results support the notion that this plant may have a potential use in pharmaceutical and preservative products. PMID- 30402344 TI - Testing the heat dissipation limitation hypothesis: basal metabolic rates of endotherms decrease with increasing upper and lower critical temperatures. AB - Metabolic critical temperatures define the range of ambient temperatures where endotherms are able to minimize energy allocation to thermogenesis. Examining the relationship between metabolic critical temperatures and basal metabolic rates (BMR) provides a unique opportunity to gain a better understanding of how animals respond to varying ambient climatic conditions, especially in times of ongoing and projected future climate change. We make use of this opportunity by testing the heat dissipation limit (HDL) theory, which hypothesizes that the maximum amount of heat a species can dissipate constrains its energetics. Specifically, we test the theory's implicit prediction that BMR should be lower under higher metabolic critical temperatures. We analysed the relationship of BMR with upper and lower critical temperatures for a large dataset of 146 endotherm species using regression analyses, carefully accounting for phylogenetic relationships and body mass. We show that metabolic critical temperatures are negatively related with BMR in both birds and mammals. Our results confirm the predictions of the HDL theory, suggesting that metabolic critical temperatures and basal metabolic rates respond in concert to ambient climatic conditions. This implies that heat dissipation capacities of endotherms may be an important factor to take into account in assessments of species' vulnerability to climate change. PMID- 30402345 TI - Soil respiration of a Moso bamboo forest significantly affected by gross ecosystem productivity and leaf area index in an extreme drought event. AB - Moso bamboo has large potential to alleviate global warming through carbon sequestration. Since soil respiration (R s ) is a major source of CO2 emissions, we analyzed the dynamics of soil respiration (R s ) and its relation to environmental factors in a Moso bamboo (Phllostachys heterocycla cv. pubescens) forest to identify the relative importance of biotic and abiotic drivers of respiration. Annual average R s was 44.07 t CO2 ha-1 a-1. R s correlated significantly with soil temperature (P < 0.01), which explained 69.7% of the variation in R s at a diurnal scale. Soil moisture was correlated significantly with R s on a daily scale except not during winter, indicating it affected R s . A model including both soil temperature and soil moisture explained 93.6% of seasonal variations in R s . The relationship between R s and soil temperature during a day showed a clear hysteresis. R s was significantly and positively (P < 0.01) related to gross ecosystem productivity and leaf area index, demonstrating the significance of biotic factors as crucial drivers of R s . PMID- 30402346 TI - Cancellous bone and theropod dinosaur locomotion. Part III-Inferring posture and locomotor biomechanics in extinct theropods, and its evolution on the line to birds. AB - This paper is the last of a three-part series that investigates the architecture of cancellous bone in the main hindlimb bones of theropod dinosaurs, and uses cancellous bone architectural patterns to infer locomotor biomechanics in extinct non-avian species. Cancellous bone is highly sensitive to its prevailing mechanical environment, and may therefore help further understanding of locomotor biomechanics in extinct tetrapod vertebrates such as dinosaurs. Here in Part III, the biomechanical modelling approach derived previously was applied to two species of extinct, non-avian theropods, Daspletosaurus torosus and Troodon formosus. Observed cancellous bone architectural patterns were linked with quasi static, three-dimensional musculoskeletal and finite element models of the hindlimb of both species, and used to derive characteristic postures that best aligned continuum-level principal stresses with cancellous bone fabric. The posture identified for Daspletosaurus was largely upright, with a subvertical femoral orientation, whilst that identified for Troodon was more crouched, but not to the degree observed in extant birds. In addition to providing new insight on posture and limb articulation, this study also tested previous hypotheses of limb bone loading mechanics and muscular control strategies in non-avian theropods, and how these aspects evolved on the line to birds. The results support the hypothesis that an upright femoral posture is correlated with bending dominant bone loading and abduction-based muscular support of the hip, whereas a crouched femoral posture is correlated with torsion-dominant bone loading and long-axis rotation-based muscular support. Moreover, the results of this study also support the inference that hindlimb posture, bone loading mechanics and muscular support strategies evolved in a gradual fashion along the line to extant birds. PMID- 30402349 TI - Do subterranean mammals use the Earth's magnetic field as a heading indicator to dig straight tunnels? AB - Subterranean rodents are able to dig long straight tunnels. Keeping the course of such "runways" is important in the context of optimal foraging strategies and natal or mating dispersal. These tunnels are built in the course of a long time, and in social species, by several animals. Although the ability to keep the course of digging has already been described in the 1950s, its proximate mechanism could still not be satisfactorily explained. Here, we analyzed the directional orientation of 68 burrow systems in five subterranean rodent species (Fukomys anselli, F. mechowii, Heliophobius argenteocinereus, Spalax galili, and Ctenomys talarum) on the base of detailed maps of burrow systems charted within the framework of other studies and provided to us. The directional orientation of the vast majority of all evaluated burrow systems on the individual level (94%) showed a significant deviation from a random distribution. The second order statistics (averaging mean vectors of all the studied burrow systems of a respective species) revealed significant deviations from random distribution with a prevalence of north-south (H. argenteocinereus), NNW-SSE (C. talarum), and NE SW (Fukomys mole-rats) oriented tunnels. Burrow systems of S. galili were randomly oriented. We suggest that the Earth's magnetic field acts as a common heading indicator, facilitating to keep the course of digging. This study provides a field test and further evidence for magnetoreception and its biological meaning in subterranean mammals. Furthermore, it lays the foundation for future field experiments. PMID- 30402350 TI - BioInstaller: a comprehensive R package to construct interactive and reproducible biological data analysis applications based on the R platform. AB - The increase in bioinformatics resources such as tools/scripts and databases poses a great challenge for users seeking to construct interactive and reproducible biological data analysis applications. Here, we propose an open source, comprehensive, flexible R package named BioInstaller that consists of the R functions, Shiny application, the HTTP representational state transfer application programming interfaces, and a docker image. BioInstaller can be used to collect, manage and share various types of bioinformatics resources and perform interactive and reproducible data analyses based on the extendible Shiny application with Tom's Obvious, Minimal Language and SQLite format databases. The source code of BioInstaller is freely available at our lab website, http://bioinfo.rjh.com.cn/labs/jhuang/tools/bioinstaller, the popular package host GitHub, https://github.com/JhuangLab/BioInstaller, and the Comprehensive R Archive Network, https://CRAN.R-project.org/package=BioInstaller. In addition, a docker image can be downloaded from DockerHub (https://hub.docker.com/r/bioinstaller/bioinstaller). PMID- 30402347 TI - Cancellous bone and theropod dinosaur locomotion. Part I-an examination of cancellous bone architecture in the hindlimb bones of theropods. AB - This paper is the first of a three-part series that investigates the architecture of cancellous ('spongy') bone in the main hindlimb bones of theropod dinosaurs, and uses cancellous bone architectural patterns to infer locomotor biomechanics in extinct non-avian species. Cancellous bone is widely known to be highly sensitive to its mechanical environment, and has previously been used to infer locomotor biomechanics in extinct tetrapod vertebrates, especially primates. Despite great promise, cancellous bone architecture has remained little utilized for investigating locomotion in many other extinct vertebrate groups, such as dinosaurs. Documentation and quantification of architectural patterns across a whole bone, and across multiple bones, can provide much information on cancellous bone architectural patterns and variation across species. Additionally, this also lends itself to analysis of the musculoskeletal biomechanical factors involved in a direct, mechanistic fashion. On this premise, computed tomographic and image analysis techniques were used to describe and analyse the three-dimensional architecture of cancellous bone in the main hindlimb bones of theropod dinosaurs for the first time. A comprehensive survey across many extant and extinct species is produced, identifying several patterns of similarity and contrast between groups. For instance, more stemward non-avian theropods (e.g. ceratosaurs and tyrannosaurids) exhibit cancellous bone architectures more comparable to that present in humans, whereas species more closely related to birds (e.g. paravians) exhibit architectural patterns bearing greater similarity to those of extant birds. Many of the observed patterns may be linked to particular aspects of locomotor biomechanics, such as the degree of hip or knee flexion during stance and gait. A further important observation is the abundance of markedly oblique trabeculae in the diaphyses of the femur and tibia of birds, which in large species produces spiralling patterns along the endosteal surface. Not only do these observations provide new insight into theropod anatomy and behaviour, they also provide the foundation for mechanistic testing of locomotor hypotheses via musculoskeletal biomechanical modelling. PMID- 30402348 TI - Cancellous bone and theropod dinosaur locomotion. Part II-a new approach to inferring posture and locomotor biomechanics in extinct tetrapod vertebrates. AB - This paper is the second of a three-part series that investigates the architecture of cancellous bone in the main hindlimb bones of theropod dinosaurs, and uses cancellous bone architectural patterns to infer locomotor biomechanics in extinct non-avian species. Cancellous bone is widely known to be highly sensitive to its mechanical environment, and therefore has the potential to provide insight into locomotor biomechanics in extinct tetrapod vertebrates such as dinosaurs. Here in Part II, a new biomechanical modelling approach is outlined, one which mechanistically links cancellous bone architectural patterns with three-dimensional musculoskeletal and finite element modelling of the hindlimb. In particular, the architecture of cancellous bone is used to derive a single 'characteristic posture' for a given species-one in which bone continuum level principal stresses best align with cancellous bone fabric-and thereby clarify hindlimb locomotor biomechanics. The quasi-static approach was validated for an extant theropod, the chicken, and is shown to provide a good estimate of limb posture at around mid-stance. It also provides reasonable predictions of bone loading mechanics, especially for the proximal hindlimb, and also provides a broadly accurate assessment of muscle recruitment insofar as limb stabilization is concerned. In addition to being useful for better understanding locomotor biomechanics in extant species, the approach hence provides a new avenue by which to analyse, test and refine palaeobiomechanical hypotheses, not just for extinct theropods, but potentially many other extinct tetrapod groups as well. PMID- 30402351 TI - Uncovering hidden specific diversity of Andean glassfrogs of the Centrolene buckleyi species complex (Anura: Centrolenidae). AB - The glassfrog Centrolene buckleyi has been recognized as a species complex. Herein, using coalescence-based species delimitation methods, we evaluate the specific diversity within this taxon. Four coalescence approaches (generalized mixed Yule coalescents, Bayesian general mixed Yule-coalescent, Poisson tree processes, and Bayesian Poisson tree processes) were consistent with the delimitation results, identifying four lineages within what is currently recognized as C. buckleyi. We propose three new candidate species that should be tested with nuclear markers, morphological, and behavioral data. In the meantime, for conservation purposes, candidate species should be considered evolutionary significant units, in light of observed population crashes in the C. buckleyi species complex. Finally, our results support the validity of C. venezuelense, formerly considered as a subspecies of C. buckleyi. PMID- 30402352 TI - SLiM-Enrich: computational assessment of protein-protein interaction data as a source of domain-motif interactions. AB - Many important cellular processes involve protein-protein interactions (PPIs) mediated by a Short Linear Motif (SLiM) in one protein interacting with a globular domain in another. Despite their significance, these domain-motif interactions (DMIs) are typically low affinity, which makes them challenging to identify by classical experimental approaches, such as affinity pulldown mass spectrometry (AP-MS) and yeast two-hybrid (Y2H). DMIs are generally underrepresented in PPI networks as a result. A number of computational methods now exist to predict SLiMs and/or DMIs from experimental interaction data but it is yet to be established how effective different PPI detection methods are for capturing these low affinity SLiM-mediated interactions. Here, we introduce a new computational pipeline (SLiM-Enrich) to assess how well a given source of PPI data captures DMIs and thus, by inference, how useful that data should be for SLiM discovery. SLiM-Enrich interrogates a PPI network for pairs of interacting proteins in which the first protein is known or predicted to interact with the second protein via a DMI. Permutation tests compare the number of known/predicted DMIs to the expected distribution if the two sets of proteins are randomly associated. This provides an estimate of DMI enrichment within the data and the false positive rate for individual DMIs. As a case study, we detect significant DMI enrichment in a high-throughput Y2H human PPI study. SLiM-Enrich analysis supports Y2H data as a source of DMIs and highlights the high false positive rates associated with naive DMI prediction. SLiM-Enrich is available as an R Shiny app. The code is open source and available via a GNU GPL v3 license at: https://github.com/slimsuite/SLiMEnrich. A web server is available at: http://shiny.slimsuite.unsw.edu.au/SLiMEnrich/. PMID- 30402353 TI - Iberian pig adaptation to acorn consumption: I. Net portal appearance of metabolites. AB - Most valuable cured products from Iberian pigs come from pure bred animals raised for a final grazing-fattening period where pigs eat mainly acorns, a low protein energy rich fruit. This is a nutritional challenge for animals fed equilibrated diets from weaning. The aim of the study was to determine net portal appearance (NPA) of metabolites in gilts fed acorns and evaluate adaptational changes after one week of feeding. Two sampling periods were carried out (after one day and after one week of acorn feeding) with six gilts (34 kg average BW) set up with three catheters: in carotid artery and portal vein for blood sampling, and ileal vein for para-aminohippuric acid (PAH) infusion to measure portal plasma flow (PPF). Pigs were fed at 2.5 * ME for maintenance a standard diet in two portions, at 09:00 (0.25) and 15:00 h (the remaining 0.75). On the day prior to the first sampling period, pigs were fed 2.4 kg of oak acorns. After feeding 0.25 of ration a 6 h serial blood collection was initiated. Following an identical protocol, a second sampling session was performed 1 week later. Adaptation to acorn consumption decreased NPA of ammonia (47%, P < 0.001). Although there was a transfer of urea from the gastrointestinal tract to the circulation in both sampling periods, no differences in NPA of urea was found (P > 0.05). NPA of glucose was not influenced by sampling period (P > 0.05), but NPA of lactate was greatly increased (231%, P < 0.001). There was a negative NPA of albumin although adaptation to acorn feeding did not alter it. Although NPA of triglycerides and cholesterol were unchanged, a subtle increase in arterial and portal cholesterol was noticed (9.6%, P < 0.01). Pigs fed a protein deficient diet for one week adapted decreasing NPA of ammonia for saving metabolic energy as less ammonia would become available for conversion to urea. PMID- 30402354 TI - High-level expression and molecular characterization of a recombinant prolidase from Escherichia coli NovaBlue. AB - Long-term use of organophosphorus (OP) compounds has become an increasing global problem and a major threat to sustainability and human health. Prolidase is a proline-specific metallopeptidase that can offer an efficient option for the degradation of OP compounds. In this study, a full-length gene from Escherichia coli NovaBlue encoding a prolidase (EcPepQ) was amplified and cloned into the commercially-available vector pQE-30 to yield pQE-EcPepQ. The overexpressed enzyme was purified from the cell-free extract of isopropyl thio-beta-D galactoside IPTG-induced E. coli M15 (pQE-EcPepQ) cells by nickel-chelate chromatography. The molecular mass of EcPepQ was determined to be about 57 kDa by 12% sodium dodecyl sulfate-polyacrylamide gel electrophoresis and the result of size-exclusion chromatography demonstrated that the enzyme was mainly present in 25 mM Tris-HCl buffer (pH 8.0) as a dimeric form. The optimal conditions for EcPepQ activity were 60 degrees C, pH 8.0, and 0.1 mM Mn2+ ion. Kinetic analysis with Ala-Pro as the substrate showed that the K m and k cat values of EcPepQ were 8.8 mM and 926.5 +/- 2.0 s-1, respectively. The thermal unfolding of EcPepQ followed a two-state process with one well-defined unfolding transition of 64.2 degrees C. Analysis of guanidine hydrochloride (GdnHCl)-induced denaturation by tryptophan emission fluorescence spectroscopy revealed that the enzyme had a [GdnHCl]0.5,N-U value of 1.98 M. The purified enzyme also exhibited some degree of tolerance to various water/organic co-solvents. Isopropanol and tetrahydrofuran were very detrimental to the enzymatic activity of EcPepQ; however, other more hydrophilic co-solvents, such as formamide, methanol, and ethylene glycol, were better tolerated. Eventually, the non-negative influence of some co-solvents on both catalytic activity and structural stability of EcPepQ allows to adjust the reaction conditions more suitable for EcPepQ-catalyzed bioprocess. PMID- 30402356 TI - Prionochelys matutina Zangerl, 1953 (Testudines: Pan-Cheloniidae) from the Late Cretaceous of the United States and the evolution of epithecal ossifications in marine turtles. AB - Background: Many neritic to nearshore species of marine adapted turtle from the Late Cretaceous of North America are thought to represent the stem lineage of Cheloniidae but due to fragmentary holotypes, low total specimen counts, and resultantly incomplete morphological character suites, are routinely placed either within or outside of crown group Chelonioidea leaving their precise cladistic affinities uncertain. Despite this systematic ambiguity, the referral of these species to either the stem of Cheloniidae or Chelonioidea belies the critical importance of these taxa in any investigation into the origins of extant marine turtles. The adequate incorporation of these species into phylogenetic studies requires the formal description of relatively complete specimens, particularly those possessing associated cranial and post-cranial material. Methods: Remarkably complete fossil specimens of several adult and juvenile marine turtles from the Mooreville Chalk and Eutaw Formations (Alabama, USA) are formally described and assigned to Prionochelys matutina. This material provides new information into the anatomy, ontogeny, and cladistic affinities of the species. A phylogenetic hypothesis for Late Cretaceous marine turtles is then generated through the consilience of stratigraphic, morphological, and molecular data. Results: Phylogenetic analysis places Prionochelys matutina on the stem of Cheloniidae as a member of a monophyletic clade with other putative pan cheloniids, including Ctenochelys stenoporus, Ctenochelys acris, Peritresius martini, and Peritresius ornatus. The members of this clade possess incipient secondary palates, pronounced carapacial and plastral fontanelles at all stages of development, and are characterized by the presence of superficial ossifications at the apices of the neural keel elevations along the dorsal midline of the carapace. Discussion: The epithecal osteoderms dorsal to the neural series (epineurals) found in Ctenochelyidae are unique among turtles. The presence of epineurals in ctenochelyid turtles shows that epithecal ossifications arose independently in both leatherback (Dermochelyidae) and hard-shelled (Cheloniidae) marine turtles. Whether or not the epineurals of Ctenochelyidae are homologous with the dermal ossicles comprising the carapace of Dermochelys coriacea remains untested however, histological thin sectioning of dermochelyid and ctenochelyd epithecal elements may reveal meaningful information in future studies. PMID- 30402355 TI - Heterologous expression of a Glyoxalase I gene from sugarcane confers tolerance to several environmental stresses in bacteria. AB - Glyoxalase I belongs to the glyoxalase system that detoxifies methylglyoxal (MG), a cytotoxic by-product produced mainly from triose phosphates. The concentration of MG increases rapidly under stress conditions. In this study, a novel glyoxalase I gene, designated as SoGloI was identified from sugarcane. SoGloI had a size of 1,091 bp with one open reading frame (ORF) of 885 bp encoding a protein of 294 amino acids. SoGloI was predicted as a Ni2+-dependent GLOI protein with two typical glyoxalase domains at positions 28-149 and 159-283, respectively. SoGloI was cloned into an expression plasmid vector, and the Trx-His-S-tag SoGloI protein produced in Escherichia coli was about 51 kDa. The recombinant E. coli cells expressing SoGloI compared to the control grew faster and tolerated higher concentrations of NaCl, CuCl2, CdCl2, or ZnSO4. SoGloI ubiquitously expressed in various sugarcane tissues. The expression was up-regulated under the treatments of NaCl, CuCl2, CdCl2, ZnSO4 and abscisic acid (ABA), or under simulated biotic stress conditions upon exposure to salicylic acid (SA) and methyl jasmonate (MeJA). SoGloI activity steadily increased when sugarcane was subjected to NaCl, CuCl2, CdCl2, or ZnSO4 treatments. Sub-cellular observations indicated that the SoGloI protein was located in both cytosol and nucleus. These results suggest that the SoGloI gene may play an important role in sugarcane's response to various biotic and abiotic stresses. PMID- 30402357 TI - A large-scale survey on finger counting routines, their temporal stability and flexibility in educated adults. AB - A strong link between bodily activity and number processing has been established in recent years. Although numerous observations indicate that adults use finger counting (FC) in various contexts of everyday life for different purposes, existing knowledge of FC routines and their use is still limited. In particular, it remains unknown how stable the (default) FC habits are over time and how flexible they can be. To investigate these questions, 380 Polish participants completed a questionnaire on their FC routines, the stability of these routines, and the context of FC usage, preceded by the request to count on their fingers from 1 to 10. Next, the test-retest stability of FC habits was examined in 84 participants 2 months following the first session. To the best of our knowledge, such a study design has been adopted for the first time. The results indicate that default FC routines of the majority of participants (75%) are relatively stable over time. At the same time, FC routines can flexibly adapt according to the situation (e.g., when holding an object). As regards prevalence, almost all participants, in line with previous findings on Western individuals, declared starting from the closed palm and extending consecutive fingers. Furthermore, we observed relations between FC preferences and handedness (more left-handers start from the left hand) and that actual finger use is still widespread in healthy adults for a variety of activities (the most prevalent uses of FC are listing elements, presenting arguments and plans, and calendar calculations). In sum, the results show the practical relevance of FC in adulthood, the relative stability of preferences over time along with flexible adaptation to a current situation, as well as an association of FC routines with handedness. Taken together our results suggest that FC is the phenomenon, which is moderated or mediated by multiple embodied factors. PMID- 30402358 TI - Plant defense elicitors: plant fitness versus wheat stem sawfly. AB - The wheat stem sawfly (WSS), Cephus cinctus Norton, is an important wheat pest in the Northern Great Plains of the USA. No single control measure effectively suppresses WSS damage. This study provides information on the effects on the WSS adult settling preference behavior on wheat plants under laboratory conditions from treatment with both synthetic plant defense elicitors (Actigard(r) and cis jasmone) and a botanical insecticide (Azadirachtin(r)). In addition, field experiments were performed to determine whether these chemicals impact the WSS fitness (larval mortality and larval body weight), winter wheat plant fitness (infestation, stem lodging, yield, and quality), adult population of WSS and Bracon spp., and larval parasitism levels. Our lab results showed that there were no significant differences in adult settling behavior on plants exposed separately to each chemical and control. In contrast, when adults were exposed simultaneously to treated and untreated plants, there was a significant reduction in the percentage of adults settling on Actigard(r) and Azadirachtin(r) treated plants compared to plants sprayed with water in the same cage. However, in field situations, regardless of application timing and field location, none of the chemicals significantly reduced adult population or stems damage. The exception was two times applications of Actigard(r) had significantly lower WSS infested stem damage levels at 30 days after initial treatment applications at Knees and 50 days at Choteau locations compared to control, but without effect at the Conrad location. The field study indicated that two times applications of Actigard(r) significantly increased diapausing larval mortality percentages and lowered stem lodging levels compared to untreated controls at Knees and Choteau locations, while no effects at Conrad location. Larval body weight was significantly lower in plots treated with Actigard(r) at Knees and Conrad, but no effects at Choteau. No significant differences were found in wheat yield and quality in plots treated with chemicals and controls at any location. Bracon spp. adult population and parasitism levels were not negatively affected by the use of chemicals. In conclusion, this study offers insights on what treatments should be emphasized in more detail despite variable findings. PMID- 30402359 TI - Ave Maria and Visions of Children: Atypical Charles Bonnet Syndrome or Two Coexisting Deafferentation Phenomena? AB - Charles Bonnet syndrome (CBS) refers to the experience of visual hallucinations in the context of visual impairment. The underlying pathology may be localized anywhere along the visual pathway from the eye itself to visual cortical centers. It is sometimes compared to phantom limb syndrome; both involve decreased sensory input, as in loss of a limb or declining vision, resulting in overactivity in areas of the brain controlling sensory perception. Definitive diagnostic criteria are still lacking and may vary by discipline. However, the following features are generally agreed upon: visual hallucinations, impaired vision, and intact cognition and insight. Psychiatric symptoms, cognitive decline, and hallucinations of other sensory modalities are often excluded, although this remains an area of debate. Certain non-classic cases of CBS have inspired the designation of atypical CBS, which encompasses a wide spectrum of sensory experiences and associated symptoms. Auditory hallucinations in the hearing impaired, a well-described phenomenon thought to have a similar pathogenesis, share with CBS the important risk factor of increased age. In patients experiencing both types of hallucinations with deterioration in both sensory domains, the distinction between a CBS variant and two independent processes may not be straightforward. In addition to the ongoing diagnostic dilemma posed by multimodal hallucinations, these phenomena tend to be underreported by patients likely due to concern that they will be diagnosed with mental illness. Although many patients with this condition are indifferent to it, some suffer distress from their hallucinations and would benefit from recognition, reassurance, and in some cases correction of the underlying cause or pharmacologic treatment. Here we present the case of an elderly woman with a history of macular degeneration and chronic hearing loss who experienced complex auditory and visual hallucinations surrounding an episode of severe anxiety. We postulate that her anxiety acted as a precipitant to her hallucinatory experiences and may partially explain their abrupt onset in the absence of other clear pathologic processes. This case serves to reinforce CBS as a possible etiology of visual hallucinations in the elderly population, while also generating discussion of how to classify her particular set of symptoms. PMID- 30402360 TI - Four-dimensional Plan Optimization for the Treatment of Lung Tumors Using Pencil beam Scanning Proton Radiotherapy. AB - Purpose This study aimed to evaluate the effectiveness of four-dimensional (4D) robust optimization for proton pencil-beam scanning (PBS) treatment of lung tumors. Patients and methods In seven patients with lung cancer, proton beam therapy was planned using 4D robust optimization over 4D computed tomography (CT) data sets. The gross target volume (GTV) was contoured based on individual breathing phases, and a 5-mm expansion was used to generate the clinical target volume (CTV) for each phase. The 4D optimization was conducted directly on the 4D CT data set. The robust optimization settings included a CT Hounsfield unit (HU) uncertainty of 4% and a setup uncertainty of 5 mm to obtain the CTV. Additional target dose objectives such as those for the internal target volume (ITV) as well as the organ-at-risk (OAR) dose requirements were placed on the average CT. For comparison, three-dimensional (3D) robust optimization was also performed on the average CT. An additional verification 4D CT was performed to verify plan robustness against inter-fractional variations. Results Target coverages were generally higher for 4D optimized plans. The difference was most pronounced for ITV V70Gy when evaluating individual breathing phases. The 4D optimized plans were shown to be able to maintain the ITV coverage at full prescription, while 3D optimized plans could not. More importantly, this difference in ITV V70Gy between the 4D and 3D optimized plans was also consistently observed when evaluating the verification 4D CT, indicating that the 4D optimized plans were more robust against inter-fractional variations. Less difference was seen between the 4D and 3D optimized plans in the lungs criteria: V5Gy and V20Gy. Conclusion The proton PBS treatment plans optimized directly on the 4D CT were shown to be more robust when compared to those optimized on a regular 3D CT. Robust 4D optimization can improve the target coverage for the proton PBS lung treatments. PMID- 30402361 TI - Comorbidities and Consequences in Hospitalized Heart Failure Patients with Depression. AB - Objective To evaluate the demographic predictors of major depressive disorder (MDD) in hospitalized congestive heart failure (CHF) patients and measure the differences in hospital stay and cost per comorbidities and the associated risk of in-hospital mortality. Methods This retrospective cross-sectional study used nationwide inpatient data from the healthcare cost and utilization project (HCUP). We identified patients with CHF as the primary diagnosis and MDD as the secondary diagnosis using ICD-9-CM codes and compared with the CHF patient without MDD. The differences in comorbidities were quantified using chi-square tests and the logistic regression model was used to evaluate mortality risk among comorbidities using odds ratio (OR). Results Elder CHF patients, 36-50-year-old (OR: 1.324) and whites (OR: 1.673), have a higher likelihood of a co-diagnosis of MDD. Females with heart failure have two-fold higher odds of MDD (OR: 2.332). Majority of the medical comorbidities were seen in a higher proportion of CHF patients without MDD. Hypothyroidism (10.2%) and drug abuse (15.2%) were seen more in depressed patients comparatively. Among substance use disorder, patients with drug abuse stayed longer and had a higher hospitalization total cost ($51,828). And, hypothyroidism was associated with longer inpatient stay (5.6 days) and cost ($64,726), and four-fold higher odds of in-hospital mortality (OR: 4.405). Though alcohol abuse was seen only in 7.4% of CHF patients with MDD, it was associated with the three-fold higher likelihood of deaths during hospitalization (OR: 3.195). Conclusion A middle-aged, white female with comorbid depression has a higher risk of hospitalization for heart failure. Depressed CHF patients with comorbid hypothyroidism were hospitalized for a longer duration with higher inpatient cost and four times higher risk of mortality during hospitalization stay. Further studies are required to evaluate the underlying cause of worse hospital outcomes in depressed CHF patients with alcohol abuse and hypothyroidism. An integrated healthcare model is required for early diagnosis and treatment of depression and associated comorbidities in CHF patients to reduce mortality and improve post-CHF outcomes. PMID- 30402362 TI - Traumatic Pneumothorax Secondary to Acupuncture Needling. AB - Acupuncture is a common form of therapy involving insertion of fine needles to alleviate nausea and various forms of pain. We describe a case of pneumothorax secondary to acupuncture. A 50-year-old woman presented to the emergency department with right-sided pleuritic chest pain. This was following a history of acupuncture and cupping treatment an hour earlier at a traditional practitioner for long-standing neck pain. On physical examination, the respiratory rate was 22 breaths per minute and her oxygen saturation was 100% on room air. Breath sounds were decreased on the right hemithorax with hyper resonance to percussion. Inspection of her back revealed multiple needling and cupping marks. A chest radiograph revealed a right-sided pneumothorax with an apex-cupola distance of 3.6 cm. She was put on high flow oxygen and a chest tube was inserted into the right chest wall. The patient was admitted. She had radiographic resolution of the pneumothorax four days later and was discharged uneventfully. Follow-up one week later in the clinic showed no radiographic recurrence of the pneumothorax. PMID- 30402363 TI - Primary Causes of Hospitalizations and Procedures, Predictors of In-hospital Mortality, and Trends in Cardiovascular and Cerebrovascular Events Among Recreational Marijuana Users: A Five-year Nationwide Inpatient Assessment in the United States. AB - Background Recent trends in the legalization of marijuana in many states are increasing the popularity of recreational marijuana use. Since current data on hospitalizations in marijuana users is sparse, we evaluated the primary reasons for admissions, procedures and associated healthcare burden in hospitalized recreational marijuana users. Methods The National Inpatient Sample (NIS) for the years 2010-2014 was queried for the hospitalizations with a history of recreational marijuana usage using applicable ICD-9 CM codes. Descriptive statistics were used to report frequency (N) and percentage (%). Discharge weights were applied to achieve national estimates. The predictors of in-hospital mortality in recreational marijuana users were assessed using a two-way hierarchical multivariate regression after adjusting for the confounders. Results We analyzed 465,959 (weighted n=2,317,343) hospitalizations with a history of recreational marijuana use. Among psychiatric disorders, most prominent primary discharge diagnoses were mood disorders (20.6%), schizophrenia/other psychotic disorders (10.6%), and substance/alcohol-related disorders (10.4%). Suicide and intentional self-inflicted injury (3.6%) was the leading cause of emergency admission. The most common non-psychiatric primary discharge diagnoses were diabetes mellitus with chronic complications (2.2%), acute myocardial infarction (AMI) (1.2%), nonspecific chest pain (1.1%), congestive cardiac failure (CHF) (1%), arrhythmia (0.8%), and hypertension (0.8%). Acute cerebrovascular diseases were noted in 1.1% and epilepsy in 1.8% of patients. Alcohol/drug rehabilitation and detoxification (6.9%) and psychiatric evaluation/therapy (3.9%) were the most evident psychiatric procedures whereas most frequent non-psychiatric procedures were diagnostic coronary arteriography (1%), percutaneous transluminal coronary angioplasty (0.7%), and echocardiogram (0.7%). Top independent predictors of in hospital mortality were coagulopathy (OR 5.94), AMI (OR 4.59), pulmonary circulation disorder (OR 2.95), CHF (OR 2.02), renal failure (OR 1.91), coronary atherosclerosis (OR 1.34) and peripheral vascular disorder (OR 1.31). Major cardiovascular and cerebrovascular events also showed increasing trends among users. Conclusion We established the most frequent psychiatric and non psychiatric causes of admissions and procedures in recreational marijuana users, which may pose a significant healthcare burden and increase the odds of in hospital mortality. PMID- 30402364 TI - Sporotrichoid Keratoacanthomas: Case Report and Review of Neoplasms Presenting in a Sporotrichoid Pattern. AB - Sporotrichosis is a fungal infection known for its distinct pattern of infectious skin nodules. Several conditions can present with lesions that appear in a sporotrichoid pattern. An 82-year-old man that presented with three cutaneous nodules on his right leg in a sporotrichoid manner is described; biopsy of each lesion revealed a keratoacanthoma. In addition to keratoacanthomas, other neoplasms-albeit rarely-may be observed to occur in a sporotrichoid manner. These included squamous cell carcinoma (three patients), lymphoma (two patients), and one patient with each of the following: epithelioid sarcoma, Langerhans cell histiocytosis, melanoma, and peripheral nerve sheath tumor. The 10 patients whose cancer had cutaneous lesions that presented in a sporotrichoid distribution ranged from 28 to 83 years old. The tumors equally appeared on either the upper extremity (five patients) or the lower extremity (five patients). Treatments included systemic chemotherapy, surgical intervention, and radiation. Three of the patients died secondary to their tumors. In conclusion, various infections and some miscellaneous disorders can present in a sporotrichoid pattern. Keratoacanthomas can be added to the list of cancers (which include squamous cell carcinoma, lymphoma, epithelioid sarcoma, Langerhans cell histiocytosis, melanoma, and peripheral nerve sheath tumor) whose skin lesions have appeared in a sporotrichoid distribution. When cutaneous lesions appear in a sporotrichoid manner, biopsy of the tissue-for not only microscopic examination but also bacterial, fungal, and mycobacterial cultures-should be considered. PMID- 30402365 TI - Characterization of mineral phosphate solubilizing and plant growth promoting bacteria from termite soil of arid region. AB - Five highly efficient phosphate solubilizing bacteria, viz., Pantoea sp. A3, Pantoea sp. A34, Kosakonia sp. A37, Kosakonia sp. B7 and Bacillus sp. AH9 were isolated from termitorial soils of Sanjivani island of southern Maharashtra, India. These isolates were characterized and explored for phosphate solubilization and plant growth promotion. Among these, Bacillus sp. AH9 showed highest phosphate solubilization index (3.5) and solubilization efficiency (250%) on Pikovskaya agar. Interestingly, Pantoea sp. A34 displayed maximum mineral phosphate solubilization (1072.35 mg/L) in liquid medium and during this period the pH dropped to 3.13. All five isolates had highest P solubilization at 48 h after inoculation. During mineral phosphate solubilization, both gluconic acid and 2-keto gluconic acid were produced by Kosakonia and Bacillus isolates, while only 2-keto gluconic acid was detected in Pantoea isolates. Highest organic acid (39.07 +/- 0.04 g/L) production was envisaged in Bacillus sp. AH9, while Pantoea sp. A34 produced the least amount (13.00 +/- 0.01 g/L) of organic acid. Seed bacterization with Pantoea sp. A3 and Kosakonia sp. A37 resulted in ~ 37% and ~ 53% increase in root length of tomato seedlings, respectively, while Pantoea sp. A34 and Kosakonia sp. B7 had deleterious effects on root length as well as overall growth of the seedlings. To our knowledge, this is the first report of plant growth promoting potential of microorganisms isolated from termitorial soil of Sanjivani island, which is a drought-prone area. Therefore, such efficient growth promoting P solubilizers can offer an effective solution for sustainable agriculture in arid, dryland farming and drought-prone regions. PMID- 30402367 TI - Complete genome sequence of Bacillus velezensis ZY-1-1 reveals the genetic basis for its hemicellulosic/cellulosic substrate-inducible xylanase and cellulase activities. AB - Bacillus velezensis ZY-1-1 was isolated from the larval gut of the lignocellulose rich diet-fed scarab beetle, Holotrichia parallela, and confirmed to possess extremely high xylanase (48153.8 +/- 412.1 U/L) and relatively moderate cellulase activity (610.1 +/- 8.2 U/L). Notably, these xylanase and cellulase activities were enhanced by xylan (1.4 and 5.8-fold, respectively) and cellulose (1.1 and 3.5-fold, respectively), which indicated the hemicellulosic/cellulosic substrate inducible lignocellulolytic activities of this strain. The complete genome of B. velezensis ZY-1-1 comprises of 3,899,251 bp in a circular chromosome with a G + C content of 46.6%. Among the predicted 3688 protein-coding genes, 24 genes are involved in the degradation of lignocellulose and other polysaccharides, including 8, 7 and 2 critical genes for the degradation of xylan, cellulose and lignin, respectively. This genome-based analysis will facilitate our understanding of the mechanism underlying the biodegradation of lignocellulose and the biotechnological application of this novel lignocellulolytic bacteria or related enzymes. PMID- 30402366 TI - Global challenges faced by engineered Bacillus thuringiensis Cry genes in soybean (Glycine max L.) in the twenty-first century. AB - The most important insect pests causing severe economic damages to soybean (Glycine max L.) production worldwide are Chrysodeixis includens (Walker, Noctuidae), Anticarsia gemmatalis (Hubner, Erebidae), Helicoverpa gelotopoeon (Dyar, Noctuidae), Crocidosema aporema (Walsingham; Tortricidae), Spodoptera albula (Walker, Noctuidae), S. cosmiodes (Walker, Noctuidae), S. eridania (Stoll, Noctuidae), S. frugiperda (Smith; Noctuidae), Helicoverpa armigera (Hubner, Noctuidae), H. zea (Boddie; Noctuidae) and Telenomus podisi (Hymenoptera,Platygastidae). Despite the success of biotech Bacillus thuringiensis (Bt)/herbicide tolerance (HT)-soybean in the past decade in terms of output, unforeseen mitigated performances have been observed due to changes in climatic events that favors the emergence of insect resistance. Thus, there is a need to develop hybrids with elaborated gene stacking to avert the upsurge in insect field tolerance to crystal (Cry) toxins in Bt-soybean. This study covers the performance of important commercial transgenic soybean developed to outwit destructive insects. New gene stacking soybean events such as Cry1Ac-, Cry1AF- and PAT-soybean (DAS-81419-2(r), ConkestaTM technology), and MON-87751-7 * MON 87701-2 * MON 87708 * MON 89788 (bearing Cry1A.105 [Cry1Ab, Cry1F, Cry1Ac], Cry2Ab, Cry1Ac) are being approved and deployed in fields. Following this deployment trend, we recommend herein that plant-mediated RNA interference into Bt-soybean, and the application of RNA-based pesticides that is complemented by other best agricultural practices such as refuge compliance, and periodic application of low-level insecticides could maximize trait durability in Bt soybean production in the twenty-first century. PMID- 30402369 TI - Primer design and amplification efficiencies are crucial for reliability of quantitative PCR studies of caffeine biosynthetic N-methyltransferases in coffee. AB - Primers having suboptimal amplification efficiencies were shown to falsely represent fold change expression of the N-methyltransferases gene family involved in caffeine biosynthesis in Coffea canephora. To study this phenomenon, the role of stability of the internal reference gene, as well as the amplification efficiency correction of the primers was investigated. GAPDH and Ubiquitin exhibited a good stability for studying the ontogeny of endosperm tissue, as well as the leaf transcriptome during stress from salicylic acid, methyl jasmonate, PEG-mediated drought and sudden exposure to light. Ubiquitin manifested low variation in Cq under all these stress regimes and in endosperm ontogeny with 30.1-30.9 in the best dataset and 28.8-30.9 in the most deviating dataset. It was observed that problems arising due to improper amplification efficiency of the target or reference genes or both could lead to misinterpretation of gene expression levels. Quantitative RT-PCR performed at a sub-optimal efficiency of GAPDH reference gene at 1.68 led to the faulty interpretation of 2.007 folds upregulation by the 2-DeltaDeltaCt method and 1.705 folds upregulation by Efficiency method for the first NMT (Xanthosine methyltransferase), which actually is repressed during dark acclimatization of coffee plants. Efficiency correction improved the reliability of the expression data and also indicated a downregulation of this gene by 0.485 folds and 0.474 folds using 2-DeltaDeltaCt and E method, respectively, in concordance to earlier reports. Hence, efficiency correction of the primers having suboptimal efficiencies is an absolute prerequisite for the accurate calculation of fold change using quantitative RT PCR. PMID- 30402368 TI - In silico approach to identify non-synonymous SNPs with highest predicted deleterious effect on protein function in human obesity related gene, neuronal growth regulator 1 (NEGR1). AB - Neuronal growth regulator 1 (NEGR1) is a candidate gene for human obesity, which encodes the neural cell adhesion and growth molecule. The aim of the current study was to recognize the non-synonymous SNPs (nsSNPs) with the highest predicted deleterious effect on protein function of the NEGR1 gene. We have used five computational tools, namely, PolyPhen, SIFT, PROVEAN, MutPred and M-CAP, to predict the deleterious and pathogenic nsSNPs of the NEGR1 gene. Homology modeling approach was used to model the native and mutant NEGR1 protein models. Furthermore, structural validation was performed by the PROCHECK server to interpret the stability of the predicted models. We have predicted four potential deleterious nsSNPs, i.e., rs145524630 (Ala70Thr), rs267598710 (Pro168Leu), rs373419972 (Arg239Cys) and rs375352213 (Leu158Phe), which might be involved in causing obesity phenotypes. The predicted mutant models showed higher root mean square deviation and free energy values under the PyMoL and SWISS-PDB viewer, respectively. Additionally, the FTSite server predicted one nsSNP, i.e., rs145524630 (Ala70Thr) out of four identified nsSNPs found in the NEGR1 protein binding site. There were four potential deleterious and pathogenic nsSNPs, i.e., rs145524630, rs267598710, rs373419972 and rs375352213, identified from the above mentioned tools. In future, further functional in vitro and in vivo analysis could lead to better knowledge about these nsSNPs on the influence of the NEGR1 gene in causing human obesity. Hence, the present computational examination suggest that predicated nsSNPs may feasibly be a drug target and play an important role in contributing to human obesity. PMID- 30402370 TI - Effect of ionized calcium on bacteria contamination in chicken carcass under slaughter process. AB - The purpose of this study was to determine the effect of ionized calcium on bacteria cross contamination on chicken carcass and meat during the slaughter process. Compared to the control group, colony of E. coli was not observed on medium containing 0.5% ionized calcium. Cross contamination of bacteria on carcass surface of fresh chicken was increased as the number of scalding was increased. Cross contamination of bacteria on carcass surface of fresh chicken was lower in the 0.5% ionized calcium scalding treatment group than that in the control group. Bacteria colony count on chicken meat surface after cooling water treatment was increased as the storage period was increased. Bacteria colony count was lower in the 0.5% ionized calcium treatment group than that in the control group. PMID- 30402372 TI - Direct Observation of Bacterial Growth in Giant Unilamellar Vesicles: A Novel Tool for Bacterial Cultures. AB - Invited for this month's cover picture are Dr. Masamune Morita, Dr. Kaoru Katoh and Dr. Naohiro Noda from the Biomedical Research Institute at the National Institute of Advanced Industrial Science and Technology (AIST, Japan). The cover picture shows direct monitoring of real-time activity of bacterial growth at the single-cell level inside giant unilamellar vesicles (GUVs); entrapped single bacterial cells are actively increasing to a great number of cells inside GUVs. This study shows new applications for GUVs, and can offer a novel tool for culturing bacteria in bacterial studies. Read the full text of their Communication at https://doi.org/10.1002/open.201800126. PMID- 30402371 TI - Agro-morphological description, genetic diversity and population structure of sugarcane varieties from sub-tropical India. AB - Genetic diversity in 92 sugarcane varieties of sub-tropical India was assessed using 30 morphological descriptors and 643 simple sequence repeat (SSR) marker loci. Out of the 30 morphological descriptors, 14 were found polymorphic, and significant variability was recorded for plant height, cane diameter and number of millable canes. Grouping traits like plant growth habit, leaf blade curvature and leaf sheath adherence were found to be predominantly monomorphic. There were a few pairs of varieties (e.g., CoP 9702 and CoP 9302, CoP 9301 and CoSe 01424, UP 05 and Co 1336, CoS 96258 and CoH 110) that showed similar DUS profiles except differing for a few descriptors. The STRUCTURE profile suggest that all the 92 sugarcane varieties had admixtures and no sub-group had a pure unblemished structure profile. An average Nei's genetic distance of 0.49 was found to be a better measure of diversity, whereas, the average band informativeness (Ibav) value of all the 80 SSR primers was 0.434. Although, the mean Ibav values for EST SSR and genomic-SSR primers were same (0.43), the range of Ibav of EST-SSR (0.04 0.85) was more compared to genomic-SSR (0.12-0.63) primers. The segregation of the varieties based on morphological traits was not in accordance with their geographical distribution or maturity groups, but principal component analysis was able to group the sugarcane varieties that had similar pedigree together. Results indicate that the SSRs have a potential use in the DNA fingerprinting of varieties to prevent any malpractice like unauthorised re-registration of a previously registered sugarcane variety under PPV&FR Act. The marker profiles could also be utilised for variety identification and release, since at present, it has been made mandatory to include it in addition to the morphological descriptors. PMID- 30402373 TI - Direct Observation of Bacterial Growth in Giant Unilamellar Vesicles: A Novel Tool for Bacterial Cultures. AB - Bacterial cultivation techniques are classic, basic, and common processes used to characterize the physiological activity of bacteria in their environment. Owing to recent advances in bacterial cultivation techniques, the physiological activity of bacteria can be elucidated at the single-cell culture level. Here, we report a novel method to monitor the real-time activity of bacterial growth at the single-cell level inside giant unilamellar vesicles (GUVs). This method consists of two steps: 1) encapsulation of single bacteria in 1-33 pL scale GUVs and 2) immobilization of the GUVs on a planar lipid bilayer membrane on a glass surface. We directly observed single E. coli cells actively growing to a great number of cells inside GUVs. GUVs also protected the bacteria from external antibiotic compounds during prolonged cultivation for more than 24 h. This approach can be applied widely in the fields of biochemistry, biotechnology, microbiology, and synthetic biology. PMID- 30402374 TI - Precursors for Atmospheric Plasma-Enhanced Sintering: Low-Temperature Inkjet Printing of Conductive Copper. AB - Bidentate diamine and amino-alcohol ligands have been used to form solid, water soluble, and air-stable monomeric copper complexes of the type [Cu(NH2CH2CH(R)Y)2(NO3)2] (1, R=H, Y=NH2; 2, R=H, Y=OH; 3, R=Me, Y=OH). The complexes were characterized by elemental analysis, mass spectrometry, infrared spectroscopy, thermal gravimetric analysis, and single-crystal X-ray diffraction. Irrespective of their decomposition temperature, precursors 1-3 yield highly conductive copper features [1.5*10-6 Omega m (+/-5*10-7 Omega m)] upon atmospheric-pressure plasma-enhanced sintering. PMID- 30402375 TI - Towards a Smoke-Free Society. PMID- 30402376 TI - Relationships between Virulence Factors and Antimicrobial Resistance among Escherichia coli Isolated from Urinary Tract Infections and Commensal Isolates in Tehran, Iran. AB - Objectives: Uropathogenic Escherichia coli (UPEC) are the major cause of urinary tract infections (UTIs). Here, we determined whether sensitivity to antibiotics was related to the prevalence of iron scavenging genes, or to biofilm and hemolysis formation. Methods: A total of 110 UPEC and 30 E coli isolates were collected from the urine of UTI patients and feces of healthy individuals without UTI, respectively. The presence of iron receptor genes and phenotypic properties were evaluated by polymerase chain reaction and phenotypic methods, respectively. Susceptibility to routine antibiotics was evaluated using the disc diffusion method. Results: The prevalence of iron scavenging genes ranged from 21.8% (ireA) to 84.5% (chuA) in the UPEC. Resistance to ceftazidime and cefotaxime was significantly correlated with the presence of fyuA and iutA iron genes. Biofilm production was significantly associated with the prevalence of fyuA and hma iron genes. A higher degree of antibiotic resistance was exhibited by isolates that produced biofilms than by their non-biofilm producing counterparts. Conclusion: Our study clearly indicates that biofilm production is associated with antibiotic resistance, and that iron receptors and hemolysin production also contribute to reduced antibiotic sensitivity. These results further our understanding of the role that these virulence factors play during UPEC pathogenesis, which in turn may be valuable for the development of novel treatment strategies against UTIs. PMID- 30402377 TI - The Effects of Task-Oriented Circuit Training Using Rehabilitation Tools on the Upper-Extremity Functions and Daily Activities of Patients with Acute Stroke: A Randomized Controlled Pilot Trial. AB - Objectives: The purpose of this study was to investigate the effect of task oriented circuit training (TOCT) using the rehabilitation tools for upper extremity function upon the daily life of patients with acute stroke. Methods: Eighteen patients with acute stroke were randomly allocated into either the experimental group or the control group. The experimental group performed the TOCT program using rehabilitation tools, whilst the control group had neuro developmental treatment. Both groups received 30 minutes of treatment per session, 5~6 times per week, for 4 weeks. The assessments conducted were the Fugl Meyer assessment, motor activity log and stroke impact scale to compare the upper extremity function and activities of daily living. Results: The results showed a significant improvement in the TOCT group compared with the neuro-developmental treatment group in the amount of motor activity use and high stroke impact score, indicating recovery (p < 0.05). Conclusion: The TOCT program using rehabilitation tools could have a positive impact on acute stroke patients use of their upper extremity. PMID- 30402378 TI - Developing the High-Risk Drinking Scorecard Model in Korea. AB - Objectives: This study aimed to develop a high-risk drinking scorecard using cross-sectional data from the 2014 Korea Community Health Survey. Methods: Data were collected from records for 149,592 subjects who had participated in the Korea Community Health Survey conducted from 2014. The scorecard model was developed using data mining, a scorecard and points to double the odds approach for weighted multiple logistic regression. Results: This study found that there were many major influencing factors for high-risk drinkers which included gender, age, educational level, occupation, whether they received health check-ups, depressive symptoms, over-moderate physical activity, mental stress, smoking status, obese status, and regular breakfast. Men in their thirties to fifties had a high risk of being a drinker and the risks in office workers and sales workers were high. Those individuals who were current smokers had a higher risk of drinking. In the scorecard results, the highest score range was observed for gender, age, educational level, and smoking status, suggesting that these were the most important risk factors. Conclusion: A credit risk scorecard system can be applied to quantify the scoring method, not only to help the medical service provider to understand the meaning, but also to help the general public to understand the danger of high-risk drinking more easily. PMID- 30402379 TI - Factors Affecting Smoking Cessation Success of Heavy Smokers Registered in the Intensive Care Smoking Cessation Camp (Data from the National Tobacco Control Center). AB - Objectives: The purpose of this study was to investigate the factors involved in the success of smoking cessation in heavy smokers enrolled in an intensive care smoking cessation camp program. Methods: Heavy smokers enrolled in the program were classified into a success (n = 69) or failure (n = 29) group, according to whether they maintained smoking cessation for 6 months after the end of the program. Demographics, smoking behaviors, and smoking cessation-related characteristics were analyzed. Results: Statistically significantly more participants in the success group had a spouse (98.6%; p = 0.008) compared with participants in the failure group (82.8%). However, multivariate logistic regression analysis indicated that having a spouse was not an independent factor in smoking cessation (p = 0.349). A significant difference in the frequency of counseling between the success and failure groups was observed (p = 0.001), with 72.5% of those who received counseling on 3-5 occasions for 6 months after the end of program successfully quit smoking, indicating that those who received more counseling had a higher likelihood of smoking cessation success. This was confirmed as an independent factor by multivariate logistic regression (p < 0.005). Furthermore, a graduate school level of education or higher, indicated a statistically greater success rate compared to those that were less well educated (p = 0.043). This was also observed as a significant independent factor using multivariate logistic regression (p = 0.046). Conclusion: Education level, marital status, and the number of counseling sessions were significant factors contributing to smoking cessation success. PMID- 30402380 TI - Changing Disease Trends in the Northern Gyeonggi-do Province of South Korea from 2002 to 2013: A Big Data Study Using National Health Information Database Cohort. AB - Objectives: To investigate the chronological patterns of diseases in Northern Gyeonggi-do province, South Korea, and compare these with national data. Methods: A National Health Insurance cohort based on the National Health Information Database (NHID Cohort 2002-2013) was used to perform a retrospective, population based study (46,605,433 of the target population, of which 1,025,340 were randomly sampled) to identify disease patterns from 2002 to 2013. Common diseases including malaria, cancer (uterine cervix, urinary bladder, colon), diabetes mellitus, psychiatric disorders, hypertension, intracranial hemorrhage, bronchitis/bronchiolitis, peptic ulcer, and end stage renal disease were evaluated. Results: Uterine cervix cancer, urinary bladder cancer and colon cancer had the greatest rate of increase in Northern Gyeonggi-do province compared with the rest of the country, but by 2013 the incidence of these cancers had dropped dramatically. Acute myocardial infarction and end stage renal disease also increased over the study period. Psychiatric disorders, diabetes mellitus, hypertension and peptic ulcers showed a gradual increase over time. No obvious differences were found for intracranial hemorrhage or bronchitis/bronchiolitis between the Northern Gyeonggi-do province and the remaining South Korean provinces. Malaria showed a unique time trend, only observed in the Northern Gyeonggi province, peaking in 2004, 2007 and 2009 to 2010. Conclusion: This study showed that the Northern Gyeonggi-do province population had a different disease profile over time, compared with collated data for the remaining provinces in South Korea. "Big data" studies using the National Health Insurance cohort database can provide insight into the healthcare environment for healthcare providers, stakeholders and policymakers. PMID- 30402381 TI - Epidemiological Characterization of Imported Systemic Mycoses Occurred in Korea. AB - Objectives: Imported systemic mycoses is a severe fungal infection that can cause diseases in healthy people. However, there is a serious lack of epidemiological data about imported systemic mycoses. Therefore, an epidemiological characterization of imported systemic mycoses in Korea was performed. Methods: We collected health insurance data between 2008 and 2012 from the Health Insurance Corporation and analyzed the data to determine the prevalence and treatment management of imported systemic mycoses. Results: The prevalence of imported systemic mycoses between 2008 and 2012 increased slowly by 0.49/100,000 to 0.53/100,000 persons. The prevalence of coccidioidomycosis increased from 0.28/100,000 in 2008 to 0.36/100,000 persons in 2012. A mean of 229.6 cases occurred each year. Children and the elderly showed higher prevalence than adults in the 20- to 59-year-old age group. The rate of infection according to region ranged from 0.18/100,000 persons in Ulsan, to 0.59/100,000 persons in Gyeonggi. The prevalence in females was higher than that in males. Inpatient treatment was 3.3% (38 cases), with 96.7% treated as outpatients. Hospitalizations cost 272.7 million won and outpatient treatments cost 111.7 million won. The treatment cost for coccidioidomycosis from 2008 to 2012 was 330.9 million won, with personal charges of 79.2 million won and insurance charges of 251.7 million won. Most of the expenses for the coccidioidomycosis treatment were for inpatient treatment. Conclusion: The results in this study may be a useful resource for determining the changes in the trend of imported systemic mycoses. PMID- 30402382 TI - Public Awareness of Early and Late Complications of Type 2 Diabetes - Application of Latent Profile Analysis in Determining Questionnaire Cut-Off Points. AB - Objectives: A questionnaire was designed to determine public understanding of early and late complications of Type 2 diabetes mellitus (T2DM). Methods: A cross sectional study was performed in participants who were selected using a multi stage sampling method and a standard questionnaire of 67 questions was proposed. An expert panel selected 53 closed-ended questions for content validity to be included in the questionnaire. The reliability of the questionnaire was tested using Cronbach's alpha coefficient giving a score of 0.84. Results: Of the 825 participants, 443 (57.6%) were male, and 322 (41.87%) were 40 years or more. The proportion of low-, moderate- and high- awareness about T2DM and its complications was 29.26%, 62.68%, and 8.06%, respectively. Friends (56.31%) and internet and social networks (20.55%) were the 2 major sources of awareness, respectively. The medical staff (e.g., physicians) had the lowest share in the level of public awareness (3.64%) compared to other sources. Conclusion: These results present data that shows the general population awareness of T2DM is low. Healthcare policymakers need to be effective at raising awarenes of diabetes and it should be through improved education. PMID- 30402383 TI - Army Soldiers' Knowledge of, Attitude Towards, and Preventive Behavior Towards Tuberculosis in Korea. AB - Objectives: The aim of this study was to gather information about Korean Army soldiers' attitude towards tuberculosis to enable the development of an informed educational program and potential intervention plans. Methods: There were 500 male soldiers serving in the Korean Army who responded to questionnaires regarding knowledge of, attitudes towards, and preventive behavior towards tuberculosis. The questionnaires were collected between September 10 until October 1, 2014. Participants' characteristic that influenced differences in knowledge, attitudes, and preventive behavior towards tuberculosis were compared by t test. Variables that influenced preventive behavior were identified by multiple regression analysis. Results: The mean scores assessing knowledge of, attitude, and preventive behavior towards tuberculosis were 11.64 (+/- 4.03) out of 20 points, 3.21 (+/- 0.38) out of 4 points, and 2.88 (+/- 0.42) out of 4 points, respectively. Non-smokers were more knowledgeable about tuberculosis than smokers. Participants who had family or friends with tuberculosis had better knowledge and a more productive attitude to tuberculosis. Participants who were educated or obtained information about tuberculosis, received better scores in all areas of knowledge, attitude and preventive behavior compared to other participants. Non-smoking, family or friends who have had tuberculosis, obtaining information about tuberculosis, and positive attitudes towards treatment and preventive education had an explanatory power of 24.6% with regard to preventive behavior against tuberculosis. Conclusion: More relatable, systemized education should be provided regularly to improve soldiers' knowledge of, attitudes towards, and prevention against tuberculosis in the Republic of Korea Army. PMID- 30402384 TI - Evaluation of Potency on Diphtheria and Tetanus Toxoid for Adult Vaccines by In Vivo Toxin Neutralization Assay Using National Reference Standards. AB - Objectives: Vaccinations against diphtheria and tetanus are essential in providing immunity against these bacterial infections. The potency of diphtheria and tetanus toxoid vaccines can be measured using the in vivo toxin neutralization assay. The limit of potency of this assay was determined only for children. Therefore, we assessed the potency of adult vaccines using this assay to identify the feasibility of limit for adult vaccines. Methods: Fifteen lots of tetanus-reduced diphtheria and tetanus-diphtheria-acellular pertussis vaccines were used. In vivo toxin neutralization and lethal challenge assays were conducted on each vaccine to calculate the potencies of the toxoids. National reference standards for toxins and antitoxins were used for in vivo toxin neutralization assay. Results: All 15 lots satisfied the limits of potency for lethal challenge assay. The potency of diphtheria and tetanus toxoids exceeded 1 and 8 units/mL, respectively, for in vivo toxin neutralization assay. Conclusion: Although additional studies are required for new assays and limits, the current level of potency for adult vaccines as determined by in vivo toxin neutralization assay, was demonstrated in this study. Such efforts to improve assays are expected to promote the development of diphtheria and tetanus vaccines for adults and to contribute to vaccine self-sufficiency. PMID- 30402385 TI - Corrigendum to "Associations between Social and Physical Environments, and Physical Activity in Adults from Urban and Rural Regions"[Osong Public Health Res Perspect 2018;9(1):16-24]. AB - [This corrects the article on p. 16 in vol. 9, PMID: 29503801.]. PMID- 30402386 TI - An unusual case of chylothorax. AB - Pleural effusions occur in up to 70% of cases of malignant pleural mesothelioma (MPM). However, MPM rarely presents as a chylous effusion making it a diagnostic challenge. There are only six reported cases to date. Most cases of chylothoraces due to malignancy are due to lymphoma or bronchogenic carcinoma. We report an interesting case of MPM in a 75-year-old man who presented with recurrent chylothorax. He reported a four-month history of dyspnea and chest discomfort. Chest x-ray revealed a pleural effusion. Pleural fluid analysis was consistent with a chylothorax. Pleural fluid cytology was negative for malignancy. Computed tomography of the chest showed pleural calcifications, mediastinal adenopathy and left lung infiltrate. A fine needle aspirate of the lymph node and transbronchial biopsy specimen (TBBX) of the left lung infiltrate showed extensive reactive appearing mesothelial cells but none that appeared malignant. A video assisted thoracoscopic surgery was suggested but the patient declined. He returned 3 months later with recurrent pleural effusion and worsening airspace disease. Thoracentesis revealed a chylothorax again. Repeat analysis of TBBX and lymph node specimens showed extensive reactive appearing mesothelial cells. Due to concern for MPM, ancillary testing was obtained - loss of BRCA1 associated protein (BAP-1) and CDKN2A/p16 gene deletion. BAP1 staining was lost in the mesothelial cells supporting MPM. This case highlights a rare cause of MPM presenting as a chylous effusion. In a patient with an unknown etiology of chylothorax, MPM must remain in the differential. PMID- 30402387 TI - A new method for acquiring images of meiobenthic images using the FlowCAM. AB - The purpose of this study was to develop a new method for investigating sediment inhabiting meiobenthos using the Flow Cytometer And Microscope (FlowCAM). Meiobenthos are widely recognized as a useful indicator for assessing the effects of anthropogenic and natural disturbances in both shallow and deep ocean ecosystems. These small benthic invertebrates are traditionally investigated by individually counting and identifying specimens under a microscope, which is labor intensive and time consuming. However, FlowCAM, which was originally developed to semiautomatically analyze microplankton, has the potential to resolve these challenges. Meiobenthic specimens were extracted from sediment using the centrifugal separation method and were then pipetted into the FlowCAM system and imaged. The images were then used to classify and count the specimens at high taxonomic levels to verify the effectiveness of this method compared with traditional methods. We found that FlowCAM system: *Enabled sufficient meiobenthic images to be obtained to allow the identification and classification of specimens at high taxonomic levels.*Obtained comparable numbers of individuals to traditional methods.*Has the potential to rapidly process large the volumes of meiobenthos samples that are required when monitoring seasonal and spatial variation in ocean ecosystems and conducting long-term environmental impact assessments. PMID- 30402388 TI - Essentials of Physiotherapy after Thoracic Surgery: What Physiotherapists Need to Know. A Narrative Review. AB - Physiotherapy has recently become an essential part of enhanced recovery protocols after thoracic surgery. The evidence-based practice of physiotherapy is essential for the effective management of postoperative patients. Unfortunately, only a small body of literature has discussed the rationale of the physiotherapy interventions that are routinely implemented following thoracic surgery. Nonetheless, we can integrate the available knowledge into our practice until new evidence emerges. Therefore, in this review, the principles of physiotherapy after thoracic surgery are presented, along with a detailed description of physiotherapy interventions, with the goals of enhancing the knowledge and practical skills of physiotherapists in postoperative care units and helping them to re-evaluate and justify their traditional practices. PMID- 30402389 TI - Reconstruction of Chest Wall Defects Using a Technique Involving Mesh, Titanium Plates, and a Pedunculated Muscle Flap. AB - We herein present a new surgical reconstruction technique for large chest wall defects after resection of advanced chest wall tumors. PMID- 30402390 TI - Comparison of Surgical Outcomes and Survival between Octogenarians and Younger Patients after Pulmonary Resection for Stage I Lung Cancer. AB - Background: Treatment strategies for octogenarians with lung cancer remain controversial. The purpose of this study was to compare surgical outcomes and survival between octogenarians and younger patients with stage IA and IB lung cancer. Methods: We reviewed the medical records of 34 consecutive octogenarians and 457 younger patients (<70 years) with stage I lung cancer who underwent surgical resection from January 2007 to December 2015. We analyzed the survival and surgical outcomes of the 2 groups according to the lung cancer stage (IA and IB). Results: The only significant differences in the clinicopathological features between the groups were the higher proportion of sublobar resection (56.3% vs. 18.9%) and the smaller number of dissected lymph nodes (LNs) in octogenarians. There was no significant difference in hospital stay (11 days vs. 9 days), pneumonia (5.8% vs 1.9%), or operative mortality (0% vs 0.6%) between the 2 groups. Among patients with stage IA lung cancer, 5-year recurrence-free survival was not significantly different between the octogenarians (n=16) and younger patients (n=318) (86.2% vs. 89.1%, p=0.548). However, 5-year overall survival was significantly lower in octogenarians than in younger patients (79.4% vs. 93.4%, p=0.009). Among patients with stage IB lung cancer, there was no significant difference in 5-year recurrence-free survival (62.1% vs. 73.5%, p=0.55) or overall survival (77.0% vs 85.0%, p=0.75) between octogenarians (n=18) and younger patients (n=139). In multivariable analysis, male sex, the number of dissected LNs, and tumor size were factors related to survival (hazard ratio [HR], 5.795; p=0.017; HR, 0.346, p=0.025; and HR, 1.699; p=0.035, respectively). Conclusion: Surgical outcomes and survival after pulmonary resection for stage I lung cancer were comparable in octogenarians and younger patients. Continued careful selection of octogenarians for pulmonary resection is important to achieve good results. PMID- 30402391 TI - Aortic Valve Replacement for Aortic Stenosis in Elderly Patients (75 Years or Older). AB - Background: This study evaluated the early and long-term outcomes of surgical aortic valve replacement (AVR) in elderly patients in the era of transcatheter aortic valve implantation. Methods: Between 2001 and 2018, 94 patients aged >=75 years underwent isolated AVR with stented bioprosthetic valves for aortic valve stenosis (AS). The main etiologies of AS were degenerative (n=63) and bicuspid (n=21). The median follow-up duration was 40.7 months (range, 0.6-174 months). Results: Operative mortality occurred in 2 patients (2.1%) and paravalvular leak occurred in 1 patient. No patients required permanent pacemaker insertion after surgery. Late death occurred in 11 patients. The overall survival rates at 5 and 10 years were 87.2% and 65.1%, respectively. The rates of freedom from valve related events at 5 and 10 years were 94.5% and 88.6%, respectively. The Society of Thoracic Surgeons (STS) score (p=0.013) and chronic kidney disease (p=0.030) were significant factors affecting long-term survival. The minimal p-value approach demonstrated that an STS score of 3.5% was the most suitable cut-off value for predicting long-term survival. Conclusion: Surgical AVR for elderly AS patients may be feasible in terms of early mortality and postoperative complications, particularly paravalvular leak and permanent pacemaker insertion. The STS score and chronic kidney disease were associated with long-term outcomes after AVR in the elderly. PMID- 30402392 TI - Extracorporeal Life Support in Organ Transplant Donors. AB - Background: Extracorporeal life support (ECLS) can be applied in brain-dead donors for organ perfusion before donation, thereby expanding the donor pool. The aim of this study was to examine the benefits and early clinical outcomes of ECLS for organ preservation. Methods: Between June 2012 and April 2017, 9 patients received ECLS with therapeutic intent or for organ preservation. The following data were collected: demographics, purpose and duration of ECLS, cause of death, dose of vasoactive drugs, and need for temporary dialysis before organ retrieval. The early clinical outcomes of recipients were studied, as well as survival and graft function at 1 month. Results: ECLS was initiated for extracorporeal cardiopulmonary resuscitation in 5 patients. The other patients needed ECLS due to hemodynamic deterioration during the assessment of brain death. We successfully retrieved 18 kidneys, 7 livers, and 1 heart from 9 donors. All organs were transplanted and none were discarded. Only 1 case of delayed kidney graft function was noted, and all 26 recipients were discharged without any significant complications. Conclusion: The benefits of protecting the vital organs of donors is significant, and ECLS for organ preservation can be widely used in the transplantation field. PMID- 30402393 TI - Pinch-Off Syndrome, a Rare Complication of Totally Implantable Venous Access Device Implantation: A Case Series and Literature Review. AB - Background: Pinch-off syndrome (POS) is a rare complication after totally implantable venous access device (TIVAD) implantation. In cancer patients, it is important to prevent this rare complication and to recognize it early if it does occur. We present a case series of POS after TIVAD implantation and the results of a literature search about this complication. Methods: From July 2006 to December 2015, 924 permanent implantable central venous catheter implantation procedures were performed. The most common indication was vascular access for chemotherapy. Results: POS occurred in 5 patients in our clinic. Two patients experienced POS within 2 weeks, and the other 3 patients were admitted to department of surgery, Istanbul Faculty of Medicine at 6 to 14 months following implantation. The catheters were found to be occluded during medication administration, and all patients complained of serious pain. The transected fragments of the catheters had migrated to the heart. They were successfully removed under angiography with a single-loop snare. Conclusion: POS is a serious complication after TIVAD implantation. It is important to be aware of this possibility and to make an early diagnosis in order to prevent complications such as drug extravasation and occlusion events. PMID- 30402394 TI - The Effect of Saphenous Vein Ablation on Combined Segmental Popliteal Vein Reflux. AB - Background: This study examined the role of superficial vein surgery in patients with combined superficial venous reflux and segmental popliteal vein reflux. Methods: We retrospectively reviewed 42 limbs in 38 patients with combined superficial venous reflux and segmental popliteal vein reflux who underwent saphenous vein ablation between January 2014 and February 2017. Patients underwent outpatient follow-up duplex ultrasonography at 3, 6, and 12 months postoperatively. Resolution of deep vein reflux was defined as reversed blood flow in a popliteal segment for less than 1.0 second and a decrease in the reflux time of more than 20% of the preoperative reflux time. Results: The mean follow up period was 9 months (range, 3-23 months). Saphenous vein ablations were performed by stripping in 24 limbs and radiofrequency ablation in 18 limbs. Preoperative segmental popliteal vein reflux resolved in 21 of the 42 limbs (50%). Conclusion: This study demonstrated that superficial venous surgery corrected segmental popliteal vein reflux in 50% of limbs with combined superficial venous reflux and segmental popliteal vein reflux. Other prospective studies are necessary to elucidate the etiology of the non-reversible cases. PMID- 30402395 TI - Nonintubated Uniportal Video-Assisted Thoracoscopic Surgery: A Single-Center Experience. AB - Background: We report our surgical technique for nonintubated uniportal video assisted thoracoscopic surgery (VATS) pulmonary resection and early postoperative outcomes at a single center. Methods: Between January and July 2017, 40 consecutive patients underwent nonintubated uniportal VATS pulmonary resection. Multilevel intercostal nerve block was performed using local anesthesia in all patients, and an intrathoracic vagal blockade was performed in 35 patients (87.5%). Results: Twenty-nine procedures (72.5%) were performed in patients with lung cancer (21 lobectomies, 6 segmentectomies, and 2 wedge resections), and 11 (27.5%) in patients with pulmonary metastases, benign lung disease, or pleural disease. The mean anesthesia time was 166.8 minutes, and the mean operative duration was 125.9 minutes. The mean postoperative chest tube duration was 3.2 days, and the mean hospital stay was 5.8 days. There were 3 conversions (7.5%) to intubation due to intraoperative hypoxemia and 1 conversion (2.5%) to multiportal VATS due to injury of the segmental artery. There were 7 complications (17.5%), including 3 cases of prolonged air leak, 2 cases of chylothorax, 1 case of pleural effusion, and 1 case of pneumonia. There was no in-hospital mortality. Conclusion: Nonintubated uniportal VATS appears to be a feasible and valid surgical option, depending on the surgeon's experience, for appropriately selected patients. PMID- 30402396 TI - Surgery for Pulmonary Fungal Infections Complicating Hematological Malignancies. AB - Background: The complication rate of fungal disease is higher among patients with hematological malignancies. We investigated the clinicobacteriological outcomes of resected pulmonary fungal infections complicating hematological malignancies. Methods: Between 2001 and 2017, 21 patients with pulmonary fungal infections complicating hematological malignancies underwent resection, and their clinical records and survival were retrospectively reviewed. Results: The median age of the patients was 47 years, and 13 were male. The histological diagnoses were pulmonary aspergillosis (19 cases), mucormycosis (1 case), and cryptococcosis (1 case). The indications for surgery were resistance to antifungal therapy and the necessity of surgery before hematopoietic stem cell transplantation in 13 and 8 cases, respectively. The diagnoses of the hematological malignancies were acute myelogenous leukemia (10 cases), acute lymphocytic leukemia (5 cases), myelodysplastic syndrome (3 cases), and chronic myelogenous leukemia, malignant lymphoma, and extramedullary plasmacytoma (1 case each). The surgical procedures were partial resection (11 cases), segmentectomy (5 cases), lobectomy (4 cases), and cavernostomy (1 case). The size of the lesions was 0.9-8.5 cm. Fourteen cases had cavitation. There were no surgical-related deaths or fungal progression. Conclusion: Pulmonary fungal infections are resistant to treatments for hematological malignancies. Since the treatment of the underlying disease is extended and these infections often recur and are exacerbated, surgery should be considered when possible. PMID- 30402397 TI - Staged Repair of Truncus Arteriosus Associated with Complete Atrioventricular Septal Defect. AB - We report a case of successful repair of truncus arteriosus (TA) associated with complete atrioventricular septal defect (c-AVSD) using a staged approach. TA associated with c-AVSD is a very rare congenital cardiac anomaly. No report of successful staged repair in South Korea has yet been published. We performed bilateral pulmonary artery banding when the patient was 33 days old, and total correction using an extracardiac conduit was performed at the age of 18 months. The patient recovered uneventfully and is doing well. PMID- 30402398 TI - A Rare Case of Tetralogy of Fallot Associated with Pulmonary Artery Sling. AB - Pulmonary artery sling is a rare congenital cardiac anomaly, in which the left pulmonary artery originates from the right pulmonary artery and courses leftward between the trachea and the esophagus. Tetralogy of Fallot associated with pulmonary artery sling is even rarer, and only a few cases have been reported in the literature. We present a case of tetralogy of Fallot associated with pulmonary artery sling that was repaired successfully. PMID- 30402399 TI - Thoracoscopic Patch Insulation for Phrenic Nerve Stimulation after Permanent Pacemaker Implantation. AB - One of the complications of permanent pacemaker implantation is unintended phrenic nerve stimulation. A 15-year-old boy with a permanent pacemaker presented with chest discomfort due to synchronous chest wall contraction with pacing beats. Even after reprogramming of the pacemaker, diaphragmatic stimulation persisted. Therefore, we performed thoracoscopic phrenic nerve insulation using a Gore-Tex patch to insulate the phrenic nerve from the wire. A minimally invasive approach using a thoracoscope is a feasible option for retractable phrenic nerve stimulation after pacemaker implantation. PMID- 30402400 TI - Residential NO2 exposure is associated with urgent healthcare use in a thunderstorm asthma cohort. AB - Background: There is increasing interest in the role of traffic-related air pollution (TRAP) in allergic airway diseases. Few studies investigate the relationship between TRAP exposure and acute exacerbations of asthma. Objective: The 2016 Melbourne thunderstorm asthma epidemic provided an opportunity to investigate the relationship between proxies of TRAP exposure and asthma exacerbation requiring urgent healthcare in the previous 12 months. Methods: Current asthmatics who presented to the 3 Emergency Departments of Melbourne's second-largest health service with epidemic thunderstorm asthma in November 2016 were identified and completed a standard questionnaire. Their residential addresses were geocoded and the annual average nitrogen dioxide (NO2) exposure for each patient was assigned using a validated satellite-based land use regression model. Residential distance to the nearest major road was calculated using ArcGIS. Multivariate logistic regression was used to investigate the relationship between each TRAP proxy and healthcare use, adjusting for potential confounders. Results: From 263 thunderstorm asthma patients, 88 patients identified with current asthma were analysed. Those with higher mean annual residential NO2 exposure had greater odds of urgent healthcare use in the previous year (odds ratio [OR], 3.45 per one interquartile-range increase; 95% confidence interval [CI], 1.31-9.10; p = 0.01), however distance from major road (OR, 0.95 per 100-m increase; 95% CI, 0.80-1.13; p = 0.57) and living <200 m from a major road (OR, 1.47; 95% CI, 0.29-7.45; p = 0.64) were not significantly associated. Conclusion: In current asthmatics who presented during an epidemic thunderstorm asthma event, greater exposure to residential NO2 was significantly associated with greater odds of asthma exacerbations requiring urgent healthcare in the previous 12 months. PMID- 30402401 TI - Growth of children with food allergies in Singapore. AB - Background: Although it is known that children with food allergies are at risk of impaired growth, this has not been well studied in South-East Asia. Objective: The aim of this cross-sectional study is to survey the growth of children with food allergies in Singapore and the factors impacting it. Methods: Anthropometric data, demographic data, type of food allergy, foods eliminated, and atopic comorbidities were recorded. Malnutrition was defined using World Health Organization standards (<=-2 z-score for weight-for-height [WH], weight-for-age [WA], and height-for-age [HA]). Results: Seventy-four patients (51% male) were recruited over 1 month, with median age at diagnosis of 8 months (interquartile range [IQR], 4-13 months) and at data collection of 25 months (IQR, 14-48 months). Sixty-two (84%) had IgE-mediated allergy, 8 (11%) mixed IgE and non-IgE, and 4 (5%) non-IgE-mediated allergy. Food exclusions: 55% one food, 27% two foods, 8% three to four foods, and 10% >=5 foods. Only 1% were underweight (WA <= -2 z-score) and 3% had WA >= +2 z-score. Having a mixed type food allergy significantly reduced WA (p = 0.023). WA was significantly lower for those referred to the dietitian (p = 0.027). 5.4% were stunted (HA <= -2 z-score). Factors significantly associated with stunting were underlying eczema (p = 0.03) and having an IgE-mediated (p = 0.03) or mixed type food allergy (p = 0.002). One point four percent (1.4%) were undernourished (WH <= -2 z-score) and 1.4% were overweight (WH >= +2 z-score). Multivariate regression analysis found that children with mixed type food allergies were significantly shorter (z-score -1 lower). Children had a lower WA if they had skin involvement as part of their symptom presentation. Conclusion: This is the first survey documenting growth in children with food allergy in Singapore. Eczema, IgE-mediated and mixed type allergies are associated with poorer growth rates in these children. Early, individualised nutritional intervention is recommended for all children with food allergy. PMID- 30402402 TI - Food consumption and the risk of childhood allergy. AB - Background: The prevalence of allergic conditions is increasing in most countries. One possible explanation may be childhood nutrition. Objective: The aim of the study was to investigate the relationship between consumption of pre specified types of food in school-aged children and presence of respiratory and allergic symptoms. Methods: A total of 191 students aged 9-11 years were recruited from 5 schools to geographically cover all of Malta. Data was collected between October 2011 and February 2012. This was part of a bigger study which included clinical and environmental tests besides standardized health questionnaires. For the purposes of this part of the study only the health questionnaires were used. These standardized health questionnaires based on the International Study of Asthma and Allergies in Childhood (ISAAC) were used to identify the presence of respiratory and allergic symptoms and to identify the types of foods and the frequency of consumption of various types of foods. Results: We found that milk, meat, butter, olive oil, and yoghurt consumption had a negative association with allergic symptoms in children, whilst fish consumption had a detrimental effect. These relationships remained significant after correction for paternal level of education. Conclusion: The study highlights the fact that nutrition in early childhood may have a significant effect on the risk of allergic conditions. Our results, taken together with data in the literature, suggest that different types of fish might have had different effects. This is probably related to their different fatty acid constitution thus warranting further studies. PMID- 30402403 TI - Cow's Milk-related Symptom Score as a predictive tool for cow's milk allergy in Indian children aged 0-24 months. AB - Background: Cow's milk protein causes an unfavorable and unwanted reaction in some individuals called cow's milk protein allergy (CMPA). It is more often imprecise and easily missed in primary care settings. Cow's Milk-related Symptom Score (CoMiSS) was developed as a screening and awareness tool to suggest the presence of CMPA using general, dermatological, gastrointestinal, and respiratory symptoms. Objective: Assess the utility of CoMiSS in the diagnosis of CMPA in Indian children aged between 0 and 24 months. Methods: A pilot multicentric, observational, longitudinal study was conducted over a period of 4 months among infants aged 0-24 months with symptoms suggestive of CMPA to measure the positive and negative predictive value of CoMiSS. A predesigned questionnaire was used to record the information via CoMiSS. The patients were confirmed of having CMPA via oral food challenge/skin prick test or ImmunoCAP test. Results: A total of 83 children were enrolled in the study and majority of them had gastrointestinal complaints (61%, 51 of 83) followed by respiratory (41%, 34 of 83) and skin complaints (33%, 27 of 83). CoMiSS was >12 in 72.3% of the infants and amongst them 84.3% were confirmed via oral food challenge/ImmunoCAP test. The positive and negative predictive values for CoMiSS were 93% and 33% respectively. Conclusion: CoMiSS can help predict CMPA in children aged less than 2 years in the Indian primary care setting, aiding in early diagnosis. Prospective randomized studies are needed to evaluate the use of CoMiSS further. PMID- 30402404 TI - A pediatric case of anaphylactic shock induced by tipepidine hibenzate (Asverin). AB - Tipepidine hibenzate (Asverin) is commonly used as an antitussive drug for acute and chronic cough in various age groups and is generally safe and well-tolerated. However, we experienced a case of tipepidine hibenzate-induced anaphylactic shock in a 1-year-old boy. After ingesting cold medication including tipepidine hibenzate, the patient presented with generalized erythema and urticaria, swollen face, coughing, wheezing and vomiting, together with hypotension and a decreased level of consciousness. To identify the culprit drug, we performed skin prick tests (SPTs) and oral drug provocation tests (DPTs). SPTs revealed a negative reaction for all drugs, but DPTs caused a positive reaction only for a full therapeutic dose of tipepidine hibenzate. Physicians need to consider tipepidine hibezate as a culprit drug when anaphylaxis occurs after taking anticough or common cold medication. PMID- 30402405 TI - Nonsteroidal anti-inflammatory drug hypersensitivity in the Asia-Pacific. AB - Nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity reactions (HSRs) are often nonimmunologically mediated reactions which present with immediate HSR type manifestations. These are mediated by cyclooxygenase inhibition resulting in shunting towards the excessive production of leukotrienes. Important disease associations include asthma, nasal polyposis, and chronic spontaneous urticaria, especially among adults. The European Network on Drug Allergy/Global Allergy and Asthma European Network 2013 classification of NSAID HSR comprises nonselective HSR i.e., NSAID exacerbated respiratory disease (NERD), NSAIDs exacerbated cutaneous disease (NECD), NSAIDs induced urticarial-angioedema (NIUA); and selective (allergic) HSR i.e., single NSAID induced urticaria/angioedema or anaphylaxis, NSAIDs-induced delayed HSR. Much of the literature on genetic associations with NSAID HSR originate from Korea and Japan; where genetic polymorphisms have been described in genes involved in arachidonic acid metabolism, basophil/mast cell/eosinophil activation, various inflammatory mediators/cytokines, and different HLA genotypes. The Asian phenotype for NSAID HSR appears to be predominantly NIUA with overlapping features in some adults and children. NECD also appears to be more common than NERD, although both are not common in the Asian paediatric population. Between adults and children, children seem to be more atopic, although over time when these children grow up, it is likely that the prevalence of atopic adults with NSAID HSR will increase. Low dose aspirin desensitization has been shown to be effective in the treatment of coronary artery disease, especially following percutaneous coronary intervention. PMID- 30402406 TI - Evaluation of skin prick test to screen dust mite sensitization in chronic respiratory diseases in Southern Vietnam. AB - Background: In the view of the epidemic growth of sensitization to indoor allergens in Southern Vietnam, there is a requirement to screen large population. Objective: To evaluate skin prick tests (SPTs) as predictors of positive specific IgE (sIgE) to dust allergens, among patients with chronic respiratory diseases (CRDs). Methods: The sensitization to Blomia tropicalis (Blo t), Dermatophagoides pteronissinus (Der p), and Blattella germanica allergens (Bla g) were evaluated among 610 CRD, both SPT (>=4 mm) and sIgE by immuno-CAP (>=0.7 kUA/L). Results: Based on sIgE, 45%, 32%, and 33% of patients with CRD were sensitized to Blo t, Der p, and Bla g, respectively, compared to 19%, 18%, and 13% by SPT. The association between SPT and sIgE was statistically significant, though the Kappa factor was fair (i.e., 0.39 to 0.23). While the specificity of SPT to detect sensitization (compared to sIgE) was >90% among the whole population, the sensitivity was only 34%, 41%, and 24% for Bo t, Der p, and Bla g, suggesting that SPT was not enough sensitive to screen the indoor allergen sensitization. Though, among the <10 pack-year (PY) smokers, the sensitivity was 43% for Blo t, 52% for Der p, and 61% for Blo t and/or Der p, compared to 27%, 30%, and 35% among the >=10 PY smokers. The sensitivity/specificity was not associated with the diagnosis of asthma compared to chronic obstructive pulmonary disease. Conclusion: In the present circumstance, SPT to dust mites allergens can be used to detect a sensitization among CRD population in Southern Vietnam. PMID- 30402407 TI - Evaluation of the left venticular systolic function with the measurement of global longitudinal strain by Speckle tracking echocardiography in anaphylaxis. AB - Background: It is not known how cardiac functions are affected during anaphylaxis. Objective: Our aim was to measure the cardiac functions shortly after an anaphylaxis attack using a new technique that detects subclinical left ventricular dysfunction. Methods: Patients in our hospital who experienced anaphylaxis and urticaria (control group) due to any cause were included in the study. Tryptase levels were measured on the third hour of the reaction and 6 weeks later. Left ventricular systolic functions were evaluated with global strain measurement using echocardiography, approximately 4 hours and 6-week post reaction. Results: Twelve patients were included in the anaphylaxis group (83.3% female; mean age, 43.25 +/- 9.9 years). The causes of anaphylaxis were drug ingestion (n = 11) and venom immunotherapy. Eight of the anaphylactic reactions (66.7%) were severe and in 9 reactions (75%) tryptase levels increased. In the anaphylaxis group, strain values measured shortly after anaphylaxis were significantly lower than those calculated 6 weeks later (p < 0.001) and tryptase levels significantly increased (p = 0.002). The strain values measured both shortly after anaphylaxis and 6 weeks later did not differ according to severity of anaphylaxis. In severe anaphylaxis, tryptase levels during anaphylaxis and 6 weeks later were significantly higher (p = 0.019, p = 0.035). The control group evidenced no differences regarding strain and tryptase levels measured at reaction and 6 weeks later. At reaction, in the anaphylaxis group, the tryptase levels were higher and the strain values were lower than those in the urticaria group (p = 0.007, p = 0.003). Conclusion: Cardiac dysfunction may develop during an anaphylaxis independent of severity of reaction. PMID- 30402409 TI - Asia Pacific Allergy: A great platform for allergy. PMID- 30402410 TI - The Fourth Industrial Revolution and oral and maxillofacial surgery. PMID- 30402408 TI - A clinician's reference guide for the management of atopic dermatitis in Asians. AB - Background: Atopic dermatitis (AD) is a common skin condition among Asians. Recent studies have shown that Asian AD has a unique clinical and immunologic phenotype compared with European/American AD. Objective: The Asian Academy of Dermatology and Venereology Expert Panel on Atopic Dermatitis developed this reference guide to provide a holistic and evidence-based approach in managing AD among Asians. Methods: Electronic searches were performed to retrieve relevant systematic reviews and guidelines on AD. Recommendations were appraised for level of evidence and strength of recommendation based on the U.K. National Institute for Health and Care Excellence and Scottish Intercollegiate Guidelines Network guidelines. These practice points were based on the consensus recommendations discussed during the Asia Pacific Meeting of Experts in Dermatology held in Bali, Indonesia in October 2016 and April 2017. Results: The Expert Panel recommends an approach to treatment based on disease severity. The use of moisturizers is recommended across all levels of AD severity, while topical steroids are recommended only for flares not controlled by conventional skin care and moisturizers. Causes of waning efficacy must be explored before using topical corticosteroids of higher potency. Topical calcineurin inhibitors are recommended for patients who have become recalcitrant to steroid, in chronic uninterrupted use, and when there is steroid atrophy, or when there is a need to treat sensitive areas and pediatric patients. Systemic steroids have a limited role in AD treatment and should be avoided if possible. Educational programs that allow a patient-centered approach in AD management are recommended as an adjunct to conventional therapies. Recommendations on the use of phototherapy, systemic drugs, and emerging treatments are also included. Conclusion: The management of AD among Asians requires a holistic approach, integrating evidence-based treatments while considering accessibility and cultural acceptability. PMID- 30402411 TI - Complications after craniofacial reconstruction with calcium phosphate cements: a case report and review of the literature. AB - Among different graft materials for craniofacial reconstruction, calcium phosphate cements have the advantages of alloplastic grafts and wide use. The authors report a case of foreign body reaction following frontal reconstruction with JectOS (an injectable calcium orthophosphate cement; Kasios) and reviewed the literature on complications of this material after craniofacial reconstruction from 2002 to 2017. Complications were categorized into two groups: immunologic reactions (consisting of seroma collection, chronic sinus mucosa swelling, and foreign body reaction) and non-immune events (infection, fragmentation, and ejection). It is wise to use calcium phosphate-based material only in selected cases with small defects, and long-term follow-up is needed to observe their consequences. PMID- 30402412 TI - Subcutaneous emphysema related to dental procedures. AB - Objectives: The objective of this study was to analyze 11 cases of subcutaneous emphysema associated with dental procedures from a single hospital and discuss approaches for accurate diagnosis and treatment of the condition. Materials and Methods: The medical records of 11 patients who were treated for subcutaneous emphysema related to dental procedures between January 2009 and April 2017 were analyzed retrospectively. Patients with subcutaneous emphysema within the facial area or that spread to the neck and beyond, including the facial region, were assigned to two groups and compared in terms of age, sex, and durations of antibiotic use, hospitalization, and follow-up until improvement. The correlation between location of the origin tooth and range of emphysema spread was analyzed. Results: The average durations of antibiotic use during conservative treatment and follow-up until improvement were 8.55 days (standard deviation [SD], 4.46 days) and 1.82 weeks (SD, 1.19 weeks), respectively. There was no intergroup difference in duration of antibiotic use (P=0.329) or follow-up (P=0.931). Subcutaneous emphysema was more common after dental procedures involving the maxilla or posterior region than after those involving the mandible or anterior region. There was no significant difference in air distribution according to location of the air orifice (maxilla, mandible, or both; P=0.106). Conclusion: Upon adequate conservative treatment accompanied by prophylactic antibiotic treatment considering the risk of infection, patients showed signs of improvement within a few days or weeks. There was no significant difference in treatment period between patients with subcutaneous emphysema localized to the facial region and those with subcutaneous emphysema spreading to the neck or beyond. These findings need to be confirmed by analysis of additional cases. PMID- 30402413 TI - Metachronous second primary malignancy in head and neck cancer patients: is five years of follow-up sufficient? AB - Objectives: The aim of this study was to determine the incidence and characteristics of second primary malignancy (SPM) in patients with head and neck squamous cell carcinoma treated at a tertiary care hospital. Materials and Methods: We retrospectively reviewed the medical records of 221 patients who underwent surgery with or without adjuvant treatment for head and neck cancer from 2000 to 2002. Data of age, sex, risk factors, sites of primary and SPM, TNM stage of primary tumor, incidence of SPM, and survival were collected from medical charts. Results: Eighteen patients developed SPM during a median follow up of 67 months, with an overall incidence of 8.14%. In addition, 77.7% of SPMs occurred in the oral cavity, followed by 11% in the lungs. The 5-year overall survival after the diagnosis of SPM in the head or neck was 70%, compared to 30% for SPM in other body regions. Conclusion: Considering a high incidence of SPM, i.e., 8.14%, in a mean follow-up period of 67 months suggests the need for long term follow-up. Since treatment of SPM has shown an acceptable survival rate, early detection and curative therapy should be emphasized. PMID- 30402414 TI - Clinical characteristics and recurrence-related factors of medication-related osteonecrosis of the jaw. AB - Objectives: The purpose of this study was to investigate the demographic and clinical characteristics of patients with medication-related osteonecrosis of the jaw (MRONJ) and to elucidate factors affecting recurrence in surgical treatment. Materials and Methods: A total of 51 patients who were diagnosed with MRONJ were analyzed according to demographic and clinical features and treatment results through a retrospective chart review from 2013 to 2017 in the Department of Oral and Maxillofacial Surgery, Korea University Anam Hospital, Seoul in Korea. Results: Alendronate composed the majority of medication doses (55.6%), followed by ibandronate (20.0%), risedronate (15.6%), and zoledronate (6.7%). Forty patients (88.9%) were given oral medication, and five patients (11.1%) were intravenously treated, and the mean duration of medication use was 61.1+/-42.9 months. A total of 10 patients (22.2%) had a drug holiday before MRONJ-induced dental treatment lasting an average of 6.8+/-7.0 months. MRONJ occurred 2.7 times more in the mandible, with 41 cases (73.2%) occurring in the mandible and 15 cases (26.8%) occurring in the maxilla, and the prevalence of affected posterior parts (premolar-molar) was six times greater than that of the anterior parts (incisor-canine) (48 cases vs 8 cases, 85.7% vs 14.3%). The most common dental cause of MRONJ was tooth extraction (69.6%). Regarding recurrence, there was no statistical difference in recurrence rate according to either site or stage. However, recurrence occurred in 4 out of 34 cases (11.8%) in the primary closure group and 9 out of 20 cases (45.0%) in the secondary healing group, and there was a statistical difference with respect to closure technique. Conclusion: The identified risk factors in patients taking bone resorption inhibitors can aid dental clinicians in ensuring prevention and proper treatment of MRONJ. PMID- 30402415 TI - Comparison of temporomandibular disorders between menopausal and non-menopausal women. AB - Objectives: Hormonal changes during menopause alter a woman's susceptibility to some disorders. Information regarding the prevalence of temporomandibular disorder (TMD) in menopausal women is limited in the literature. In this study, the prevalence and severity of TMDs were compared between menopausal and non menopausal women. Materials and Methods: The study included 140 women (69 premenopausal and 71 postmenopausal) 45 to 55 years of age that were examined in Shiraz Dental School, Shiraz in Iran. The Helkimo clinical dysfunction index (Di) was used to evaluate temporomandibular joint (TMJ) dysfunction. The data were analyzed using chi-square and Fisher's exact tests. Results: Occurrence of TMD was significantly higher in menopausal than non-menopausal women (P<0.001). All the TMD criteria based on Helkimo Di except range of mandibular movement were significantly more common in menopausal women. The range of mandibular movement was not significantly different between menopausal and non-menopausal women (P=0.178). Conclusion: The results from this study show that TMD can be considered more common and severe in menopausal than non-menopausal women. This finding indicates that, similar to other conditions in menopausal women such as arthritis and osteoporosis, TMD should be taken into consideration by dental and medical professionals. PMID- 30402416 TI - Fate of abstracts presented at the Turkish Association of Oral and Maxillofacial Surgeons (TAOMS) meetings between 2007 and 2009. AB - Objectives: The aim of this study was to determine the rate of peer-reviewed publication of abstracts presented at the annual meetings of the Turkish Association of Oral and Maxillofacial Surgeons (TAOMS) and to identify the time to publication, subspecialty, and study design. Materials and Methods: All abstracts accepted for presentation at a TAOMS meeting between 2007 and 2009 were identified from a book of abstracts and were searched for publication using PubMed and Google Scholar. The following variables were evaluated: publication rate, type of presentation (oral or poster), time to publication, subspecialty, study design, and name of the journal in which the article was published. Results: A total of 478 abstracts were presented at the TAOMS meetings between 2007 and 2009. Of these, 140 abstracts (29.3%) were subsequently published in peer-reviewed journals, including 38.2% of oral presentations and 26.6% of poster presentations. The mean time from presentation to publication was 22 months. Regarding publication fields, research and emerging technologies presentations had the highest publication rate (100%). With regard to study type, animal study (70.0%) and basic research (55.0%) had the highest publication rates. Conclusion: Only 29.3% of abstracts presented at the TAOMS meeting were subsequently published as full-text articles. This rate was found to be similar to the previously reported publication rates in the field of oral and maxillofacial surgery. PMID- 30402417 TI - Conservative surgical treatment for ameloblastoma: a report of three cases. AB - Ameloblastoma treatment varies based on the clinical, histopathologic, and radiographic characteristics. Aggressive surgical treatments, such as marginal or segmental resection, have traditionally been implemented, but some conservative surgical methods are also being introduced, including decompression, enucleation, or curettage. The aim of the present study was to evaluate the possibility of applying these conservative surgical treatments to ameloblastoma and to analyze the prognosis of the procedures and their healing aspects. Among all patients who visited our clinic (Department of Oral and Maxillofacial Surgery, Kyung Hee University Dental Hospital at Gangdong) from 2009 to 2017, three who had undergone conservative surgery were recruited. One of these three patients underwent both excision of the lesion and an iliac bone graft during the same procedure. In the other two patients, due to the size of the lesion, decompression was performed to reduce the size of the lesion, and then conservative surgical treatments followed. As shown in the cases of this study, patients were only treated with conservative surgical methods, such as decompression or enucleation. During the follow-up period, there were no recurrences. In conclusion, the use of conservative surgical treatment in ameloblastoma can be a reliable, safe, and successful method. PMID- 30402418 TI - Revisit Spinal Shock: Pattern of Reflex Evolution during Spinal Shock. AB - When the spinal cord is suddenly severed, all the fundamental functions of the spinal cord below the level of injury including the spinal cord reflexes are immediately depressed, which is referred to as spinal shock. The resolution of spinal shock occurs over a period of days to months, and spinal shock slowly transitions to spasticity. The definition of spinal shock and the pattern of reflex recovery or evolution remains as an issue of debate and controversy. The identification of clinical signs that determine the duration of spinal shock is controversial. The underlying mechanisms of spinal shock are also not clearly defined. Various authors have defined the termination of spinal shock as the appearance of the bulbocavernosus reflex, the recovery of deep tendon reflexes, or the return of reflexic detrusor activity. However, many questions remain to be answered, such as: When should we define spinal shock as the end? What types of reflexes appear first among polysynaptic cutaneous reflexes, monosynaptic deep tendon reflexes, and pathological reflexes? Should it include changes in autonomic reflexes such as a detrusor reflex? PMID- 30402419 TI - Surgical Treatment for Traumatic Optic Neuropathy. AB - Traumatic optic neuropathy (TON) is an important cause of severe visual loss after blunt or penetrating head and facial trauma. High-dose steroids and surgical interventions have been applied in the indirect TON. However, there is no convincing evidence that results of the treatment have any strong benefits in terms of improvement of visual acuity. Nevertheless, surgical decompression should be considered in the case of a direct bony compression to the optic nerve and a progressive visual loss in indirect TON. Neurosurgeon should be aware the surgical indication, optimal timing and relevant technique for the optic canal (OC) decompression. In this review article, we will focus on the surgical approaches to the OC and how to decompress it. PMID- 30402420 TI - Causes and Trauma Apportionment Score of Chronic Subdural Hematoma. AB - Objective: The pathophysiology of chronic subdural hematoma (CSH) is not yet clear. Trauma alone is not sufficient to result in CSH in young individuals, while a trivial injury can result in CSH in older adults. Although the causality and apportionment of trauma are important issues in CSH, especially in terms of insurance, it is too obscure to solve all struggles. Methods: There are three key factors for producing CSH. First, CSH necessitates a potential subdural reservoir. Other important precipitating factors are trauma and coagulopathy. However, these factors are not sufficient to cause CSH development. The trauma apportionment score (TAS) can be used to compare the relative importance of these three factors. Here, we applied the TAS to 239 consecutive cases of CSH. We retrospectively obtained the patients' history and laboratory results from their medical records. Results: The TAS ranged from -5 to 5. The most common score was 0. If we defined the cause of CSH as being combined when the TAS was 0, then the cause was combined in 30 cases (12.6%). If we extended the criteria for a combined cause from 0 to -1 to 1, the cause was combined in 107 cases (44.8%). Regardless of the criteria used, traumatic CSHs were more common than were spontaneous CSHs. Spontaneous CSHs were more common in older than in younger patients (p<0.01, Fisher's exact test). Conclusion: The TAS is a useful tool for differentiating the causality of CSH. PMID- 30402421 TI - Complications Following Burr Hole Craniostomy and Closed-System Drainage for Subdural Lesions. AB - Objective: Burr hole craniostomy and closed-system drainage (BCD) is a common surgical procedure in the field of neurosurgery. However, complications following BCD have seldom been reported. The purpose of this study was to report our experiences regarding complications following BCD for subdural lesions. Methods: A retrospective study of all consecutive patients who underwent BCD for presumed subdural lesions at one institute since the opening of the hospital was performed. Results: Of the 395 patients who underwent BCD for presumed subdural lesions, 117 experienced surgical or nonsurgical complications. Acute intracranial hemorrhagic complications developed in 14 patients (3.5%). Among these, 1 patient died and 5 patients had major morbidities. Malposition of the drainage catheter in the brain parenchyma occurred in 4 patients, and opposite side surgery occurred in 2 patients. Newly developed seizures after BCD occurred in 8 patients (2.0%), five of whom developed the seizures in relation to new brain lesions. Eighty-eight patients (22.3%) suffered from nonsurgical complications after BCD. Pulmonary problems (7.3%) were the most common nonsurgical complications, followed by urinary problems (5.8%), psychologic problems (4.3%), and cognitive impairments (3.8%). Conclusion: The incidence of complications after BCD for subdural lesions is higher than previously believed. In particular, catastrophic complications such as acute intracranial hematomas and surgical or management errors occur at rates that cannot be ignored, possibly causing medico-legal problems. Great caution must be taken during surgery and the postoperative period, and these complications should be listed on the informed consent form before surgery. PMID- 30402422 TI - Expanding Subdural Hematomas in the Subacute Stage and Treatment via Catheter Drainage. AB - Objective: Rapid expansion of subacute subdural hematomas (saSDHs) is an uncommon complication in the course of acute subdural hematomas (SDHs). The current study evaluated relevant factors and treatment methods for saSDHs with neurologic deterioration and mass effect. Methods: A saSDHs was chronologically defined as an SDH occurring 4 to 21 days after head trauma. All cases of surgically treated SDHs were retrieved from the head trauma bank at our institution. Twenty-three patients with expanding saSDHs who met the following criteria were enrolled in the study: defined age of the hematoma, clinical deterioration, and radiological expansion of the hematoma. Cases were analyzed according to demographic factors, trauma mechanism, medical co-morbidity, and surgical method. Results: Expanding saSDHs occurred more often in older (>=60 years old) than in younger patients (69.6% vs. 30.4%, respectively); they also occurred more often in men than in women (64% vs. 36%, respectively). Antiplatelet or anticoagulant therapy was used in 52% of patients. The Glasgow Coma Scale score was 13 at the time of the trauma and deteriorated to 11 at the time of surgery. The mean time from the trauma to development of the expanding saSDH from an SDH was 13.3 days. Regarding surgical methods, closed-system drainage was performed in 22 patients, and only one patient underwent craniotomy with hematoma removal. All patients exhibited neurological improvements after surgery. Conclusion: An expanding saSDH usually occurs around 13 days after trauma in older adults. Minimal trephination with closed-system drainage can be used to manage an expanding saSDHs. PMID- 30402423 TI - Neurodevelopmental Prognostic Factors in 73 Neonates with the Birth Head Injury. AB - Objective: The objective of this study was to reinterpret the neurodevelopmental prognostic factors that are associated with birth head injury by performing a long-term follow-up. Methods: Seventy-three neonates with head injuries were retrospectively analyzed after a duration of 10.0+/-7.3 years to determine the correlations between perinatal factors, including gender, head circumference, gestational age, body weight, and mode of delivery, and head injury factors from radiologic imaging with social, fine motor, language, and motor developmental quotients. Results: There was a statistically significant difference between perinatal factors and head injury factors with respect to head circumference, body weight, gestational age, mode of delivery, Apgar scores at 1 min, cephalohematoma, subdural hemorrhage, subarachnoid hemorrhage, and hypoxic injury, but no direct correlation by regression analysis was observed between perinatal factors and developmental quotients. Of the head injury factors, falx hemorrhage showed a significant indirect relationship with the language and motor developmental quotients. Mode of delivery, subgaleal hematoma, cephalohematoma, greenstick skull fracture, epidural hemorrhage (EDH), tentorial hemorrhage, brain swelling, and hypoxic injury showed an indirect relationship with social development. Conclusion: In terms of perinatal factors and head injury factors, mode of delivery, subgaleal hematoma, cephalohematoma, greenstick skull fracture, EDH, tentorial hemorrhage, falx hemorrhage, brain swelling, and hypoxic injury displayed an indirect relationship with long-term development, and therefore these factors require particular attention for perinatal care. PMID- 30402424 TI - Clinical Feature and Outcomes of Secondary Hydrocephalus Caused by Head Trauma. AB - Objective: Post-traumatic hydrocephalus (PTH) is a frequent and serious complication following brain injury. The incidence of PTH varies greatly among studies. The purpose of this study was to investigate the incidence and treatment of PTH in patients with head trauma. Methods: We examined 956 patients with head trauma who visited our center from January 2012 to December 2015. The hydrocephalus diagnosis was based on radiologic findings and clinical features, and patients were classified into the mild (Group 1, Glasgow Coma Scale score [GCS] 13-15), moderate (Group 2, GCS 9-12), or severe (Group 3, GCS 3-8) brain injury group according to their GCS at admission. To compare these groups, we used age, gender, radiologic findings, PTH developmental period, and postoperative results (Glasgow Outcome Scale). Results: Of the 956 patients, 24 (2.5%) developed PTH. PTH occurred in 11 (1.4%), 3 (5.6%), and 10 (7.0%) patients in Groups 1, 2, and 3, respectively. Of the 24 patients with PTH, 22 (91.7%) developed PTH within 12 weeks post-trauma; the higher the GCS, the later the onset, and the lower the GCS, the earlier the onset (p=0.019). Twenty-one patients underwent ventriculoperitoneal shunting, and 13 had improved symptoms. Conclusion: The incidence of PTH cannot be ignored. The possibility of PTH needs to be considered in patients with head trauma and appropriate follow-up should be undertaken. PTH is a treatable complication and patients' quality of life and neurological status can be improved if the appropriate treatment is selected and applied. PMID- 30402425 TI - The Risk Factors of Subdural Hygroma after Decompressive Craniectomy. AB - Objective: Subdural effusion, also known as subdural hygroma (SDG), is a secondary complication that can occur after decompressive craniectomy (DC). However, the pathogenesis of SDG is not fully understood. It is unclear whether SDG occurrence is related to preoperative patient status or surgical technique. The purpose of this study is to identify risk factors for SDG after DC. Methods: Fifty-nine patients who underwent DC from January 2016 to December 2016 at the same institution were analyzed. We retrospectively reviewed the clinical and radiological features of the patients. We divided the patients into two groups based on the occurrence of SDG after DC. The risk factors for SDG were analyzed. Results: The overall SDG rate after DC was 39% (23 patients). A statistically significant association was observed between preoperative diagnosis, e.g., subdural hemorrhage (SDH; odds ratio [OR], 4.99; 95% confidence interval [CI], 1.36-18.34) or subarachnoid hemorrhage (SAH; OR, 4.18; 95% CI, 1.07-16.32), and the occurrence of SDG after DC. Traumatic brain injury (OR, 4.91; 95% CI, 1.35 17.91) and preoperative cortical opening (OR, 4.77; 95% CI, 1.39-16.32) were important risk factors for SDG. Several surgical techniques did not show a statistically significant association with SDG. The occurrence of SDG after DC was related to the length of hospital stay (p=0.012), but not to prognosis. Conclusion: After DC, SDG is not related to patients' prognosis but to the length of hospital stay. Therefore, it is necessary to study the occurrence of postoperative SDG by confirming the presence of preoperative SDH, SAH, and cortical opening. PMID- 30402426 TI - Relationship between Clinical Outcomes and Superior Sagittal Sinus to Bone Flap Distance during Unilateral Decompressive Craniectomy in Patients with Traumatic Brain Injury: Experience at a Single Trauma Center. AB - Objective: This retrospective study was conducted to investigate the relationship between the superior sagittal sinus (SSS) to bone flap distance and clinical outcome in patients with traumatic brain injury (TBI) who underwent decompressive craniectomy (DC). Methods: A retrospective review of medical records identified 255 adult patients who underwent DC with hematoma removal to treat TBI at our hospital from 2016 through 2017; of these, 68 patients met the inclusion criteria and underwent unilateral DC. The nearest SSS to bone flap distances were measured on postoperative brain computed tomography images, and patients were divided into groups A (distance >=20 mm) and B (distance <20 mm). The estimated blood loss (EBL) and operation time were evaluated using anesthesia records, and the time spent in an intensive care unit (ICU) was obtained by chart review. The clinical outcome was rated using the extended Glasgow Outcome Scale (GOS-E) at 3 and 6 months postoperatively. Results: The male to female ratio was 15:2 and the mean subject age was 55.12 years (range, 18-79 years). The mean EBL and operation times were significantly different between groups A and B (EBL: 655.26 vs. 1803.33 mL, p<0.001; operation time: 125.92 vs. 144.83 min, p<0.001). The time spent in the ICU and GOS-E scores did not differ significantly between the groups. Conclusion: We recommend that when DC is indicated due to TBI, an SSS to bone flap distance of at least 20 mm should be maintained, considering the EBL, operation time, and other outcomes. PMID- 30402427 TI - Initial Dead Space and Multiplicity of Bone Flap as Strong Risk Factors for Bone Flap Resorption after Cranioplasty for Traumatic Brain Injury. AB - Objective: Bone flap resorption (BFR) is a complication of cranioplasty (CP) that increases the risk of brain damage and can cause cosmetic defects. In this study, the risk factors for BFR were examined to improve the prognosis of patients after CP for traumatic brain injury (TBI). Methods: This study was conducted in 80 patients with TBI who underwent decompressive craniectomy and CP with an autologous bone graft between August 2006 and August 2017. BFR was defined as a >0.1 ratio of the difference between the initial bone flap area and the last bone flap area to the craniectomy size and a <0.5 ratio of the last bone flap thickness to the bone thickness of the contralateral region on computed tomography scans and plain skull radiographs. The patients were divided into the BFR and non-BFR groups, and medical data were compared between the two groups. Results: Among the 80 patients, 22 (27.5%) were diagnosed as having BFR after CP. The earliest cases of BFR occurred at 57 days after CP, and the latest BFR cases occurred at 3,677 days after CP. Using multivariate logistic regression analyses, the initial dead space size (odds ratio [OR], 1.002; 95% confidence interval [CI], 1.001-1.004; p=0.006) and multiplicity of the bone flap (OR, 3.058; 95% CI, 1.021-9.164; p=0.046) were found to be risk factors for BFR. Conclusion: The risk factors for BFR in this study were the initial dead space size and multiplicity of the bone flap. PMID- 30402428 TI - Risk Factors of Delayed Intracranial Hemorrhage Following Ventriculoperitoneal Shunt. AB - Objective: Placement of a ventriculoperitoneal (VP) shunt is a common neurosurgical procedure for cerebrospinal fluid diversion. A rare complication is delayed intracranial hemorrhage (ICH) secondary to VP shunting, and only a few patients with this complication have been reported. We investigate the incidence and risk factors of delayed ICH development following VP shunt placement. Methods: Over an 11-year period, 167 patients received a VP shunt for hydrocephalus, and of these, 138 patients were eligible for this study. All medical records and computed tomography scans obtained within 48 h after the operation and at postoperative day 7 were reviewed. The risk factors of developing delayed ICH (>=48 hr after VP shunt placement) were analyzed according to the demographic data, including sex and age, original intracranial lesions, co morbid diseases, and laboratory findings. Results: Delayed ICH following VP shunt placement developed in 34 (24.6%) of the 138 patients. Risk factors for developing delayed ICH were age (p=0.037) and the partial thromboplastin time (PTT) (p=0.032). Intraventricular hemorrhage after VP shunting was the most common complication, occurring in 16 cases. Hemorrhagic volume was <1 mL in 28 cases and >1 mL in 6 cases. Conclusion: This study suggests that old age and delayed PTT are major risk factors for developing delayed ICH following VP shunting. Additionally, delayed ICH after VP shunting commonly occurs even when most patients are asymptomatic. Therefore, extra care should be taken to observe and follow-up with patients who have undergone VP shunt placement. PMID- 30402429 TI - Risk Factors for Hinge Fracture Associated with Surgery Following Cervical Open Door Laminoplasty. AB - Objective: The purpose of this study was to analyze the risk factors for hinge fracture (HF) and non-union during cervical open-door laminoplasty (CODL). Methods: We included 25 patients who underwent CODL with available serial computed tomography scans acquired at 2 days and 1 year postoperatively. Patients' medical records and radiographic data were reviewed. Risk factors related to the surgical procedures were evaluated including the lamina angle, spinous angle, difference in the lamina angle, outer cortex location (OCL), and inner cortex location. Results: There were a total of 76 hinges. Of these, 44 laminae were classified as deformed hinges, and 32 were classified as fragmented hinges. Additionally, 66 laminae were healed completely, and 10 laminae were not healed by 12 months postoperatively. The OCL (odds ratio, 70.45; 95% confidence interval, 7.73-641.76) was identified as a predictor of HFs immediately following CODL. However, none of the factors we evaluated was related to hinge non-union. Conclusion: A medially located hinge gutter ( >1.9 mm from the pedicle on the outer cortex) seems to be an important risk factor for HFs following CODL. However, the hinge healing status was not related to the surgical technique. PMID- 30402430 TI - Outcomes of Anterior Cervical Fusion Using Polyetheretherketone Cage with Demineralized Bone Matrix and Plate for Management of Subaxial Cervical Spine Injuries. AB - Objective: We evaluated the usefulness of a polyetheretherketone (PEEK) cage filled with demineralized bone matrix (DBM) and plate fixation in anterior interbody fusions for subaxial cervical spine injuries. Methods: A retrospective review of 98 patients (58 women, 40 men; mean age, 49.7 years; range, 17-78 years) who underwent single-level anterior cervical discectomy and fusion (ACDF) using a PEEK cage filled with DBM and plate fixation for subaxial cervical spine injuries from March 2005 to June 2018 was conducted. Bone fusion, interbody height (IBH), segmental lordosis, and adjacent segment degeneration (ASD) development were assessed with plain radiographs and computed tomography. Clinical outcomes were assessed using a visual analog scale (VAS) for pain and the Frankel grade for neurologic function. Results: The mean follow-up period was 27.6 months (range, 6-142 months). Twenty-one patients (21.4%) had an improvement of at least one Frankel grade. The mean preoperative and final follow-up neck pain VAS scores were 8.3+/-0.9 and 2.6+/-1.5 (p<0.05). All patients showed solid fusion at the final follow-up. The mean preoperative and final Cobb's angles were -3.7+/-7.9 degrees and 1.9+/-5.1 degrees (p<0.05). The mean preoperative and final IBHs were 36.9+/-1.7 mm and 38.2+/-1.8 mm (p<0.05). Five patients (5%) showed ASD. Conclusion: ACDF using a PEEK cage filled with DBM and plate fixation yielded high fusion rates and satisfactory clinical outcomes without donor-site morbidity. This procedure is safe and effective for single-level subaxial cervical spine injuries. PMID- 30402431 TI - Delayed Trochlear Nerve Palsy Following Traumatic Subarachnoid Hemorrhage: Usefulness of High-Resolution Three Dimensional Magnetic Resonance Imaging and Unusual Course of the Nerve. AB - Cranial nerve palsies are relatively common after trauma, but trochlear nerve palsy is relatively uncommon. Although traumatic trochlear nerve palsy is easy to diagnose clinically because of extraocular movement disturbances, radiologic evaluations of this condition are difficult to perform because of the nerve's small size. Here, we report the case of a patient with delayed traumatic trochlear nerve palsy associated with a traumatic subarachnoid hemorrhage (SAH) and the related radiological findings, as obtained with high-resolution three dimensional (3D) magnetic resonance imaging (MRI). A 63-year-old woman was brought to the emergency room after a minor head trauma. Neurologic examinations did not reveal any focal neurologic deficits. Brain computed tomography showed a traumatic SAH at the left ambient cistern. The patient complained of vertical diplopia at 3 days post-trauma. Ophthalmologic evaluations revealed trochlear nerve palsy on the left side. High-resolution 3D MRI, performed 20 days post trauma, revealed continuity of the trochlear nerve and its abutted course by the posterior cerebral artery branch at the brain stem. Chemical irritation due to the SAH and the abutting nerve course were considered causative factors. The trochlear nerve palsy completely resolved during follow-up. This case shows the usefulness of high-resolution 3D MRI for evaluating trochlear nerve palsy. PMID- 30402432 TI - Craniotomy and Membranectomy for Treatment of Organized Chronic Subdural Hematoma. AB - We report the case of a patient with organized chronic subdural hematoma (OCSH) that was treated with craniotomy. A 72-year-old man was admitted with a complaint of a drowsy mental status after a generalized tonic-clonic seizure. A brain computed tomography scan acquired at a local hospital revealed a large chronic subdural hematoma (CSDH) in the left frontoparietal lobe. The patient had not experienced head trauma and had been taking clopidogrel due to angina. A neurosurgeon at the local hospital performed single burr hole trephination in the left frontal bone and drained some of the hematoma. Brain magnetic resonance imaging performed upon transfer to our hospital showed a large OCSH with a midline shift to the right side, revealing a low, heterogeneous signal on T2 weighted images (WI) and an isodense signal on T1-WI. We performed craniotomy and membranectomy to achieve adequate decompression and expansion of the brain. Following this, the patient recovered completely. Our findings support that neurosurgeons should consider the possibility of organization of a CSDH when selecting a diagnosis and treatment plan. PMID- 30402433 TI - Rapid Redistribution of an Acute Traumatic Epidural Hematoma in a Patient with Invasive Skull Cancer. AB - The rapid spontaneous resolution of an acute epidural hematoma (EDH) has rarely been reported. A possible mechanism of spontaneous resolution is egress of the hematoma into the subgaleal space through a skull fracture. We report a case of rapid redistribution of an acute EDH in a 37-year-old man who had a malignant peripheral nerve sheath tumor of the skull and who slipped and fell when going to the bathroom. A huge EDH without a skull fracture developed in the left parieto occipital area. The acute EDH was completely alleviated and a newly developed intracerebral hematoma was found on a brain computed tomography scan that was acquired the day after the trauma. Given these findings, a fractured skull and increased pressure in the intradural area may have been the mechanisms underlying the redistribution of the hematoma. PMID- 30402434 TI - Burr Hole Drainage with Urokinase Irrigation for the Treatment of Acute Subdural Hematoma: A Case Report. AB - We describe the case of a patient with an acute subdural hematoma (SDH) that was removed using urokinase irrigation after burr hole trephination in a limited situation where craniotomy was not possible. A 90-year-old woman was admitted to our hospital with a stuporous mental status. Computed tomography (CT) scans revealed a chronic SDH, and a burr hole procedure was performed. The patient's postoperative progression was good until the third day after surgery when we found that the acute SDH had increased on CT scans. The patient's guardian refused further surgery, and thus we drained the blood from the hematoma by injecting urokinase through a drainage catheter. We used urokinase for two days, and removed the catheter after confirming via CT scans that the hematoma was almost alleviated. The patient recovered gradually; she was discharged with few neurological deficits. PMID- 30402435 TI - Postpartum Superior Sagittal Sinus Thrombosis: A Case Report. AB - Cerebral venous sinus thrombosis (CVST) is a rare disease. Early diagnosis and treatment are important, as CVST is potentially fatal. Pregnancy and puerperium are known risk factors for CVST. Here, we report the case of a patient who developed superior sagittal sinus thrombosis after a normal vaginal delivery. A 20-year-old woman presented with a headache and seizures two days after a normal vaginal delivery. Initially, brain computed tomography (CT) showed a subarachnoid hemorrhage in the right parietal lobe and sylvian fissure, together with mild cerebral edema. CT angiography revealed superior sagittal sinus thrombosis. Multiple micro-infarctions were seen on diffusion-weighted magnetic resonance images. An intravenous infusion of heparin and mannitol was administered immediately. Two days after treatment initiation, the patient showed sudden neurological deterioration, with left-sided hemiplegia. Brain CT showed moderate brain edema and hemorrhagic densities. Emergency decompressive craniectomy was performed, and heparin was re-administered on post-operative day (POD) 1. On POD 9, the patient's mental state improved from stupor to drowsy, but the left-sided hemiplegia persisted. CT angiography showed that the superior sinus thrombosis had decreased. Superior sagittal sinus thrombosis is an uncommon complication, with an unfavorable outcome, after delivery. Timely diagnosis and treatment are important for preventing neurological deterioration. PMID- 30402436 TI - Endovascular Treatment Following Gauze Packing for the Control of Massive Bleeding from Traumatic Transverse Sinus Lesion. AB - Posterior fossa epidural hematoma (EDH) is uncommon, but the related clinical deterioration can occur suddenly. Accompanying venous sinus injury and lacerations are associated with 40% to 80% mortality. The authors present one clinical case of a patient with posterior fossa EDH from transverse sinus bleeding. A 57-year-old male was injured after falling while working. He was taken to the hospital, where computed tomography scans of his brain revealed a right posterior temporal and cerebellar EDH with a right temporo-occipital fracture. He underwent a right parieto-occipital craniotomy, incorporating the fracture line. Longitudinal laceration of the right transverse sinus extending to the sigmoid sinus with profuse bleeding was identified. Four gauzes were inserted in the epidural space for tamponade of the injured sinus. Conventional angiography and coil embolization for the injured sinus were immediately performed. Subsequently, the patient was transferred to the operating room, wherein staff members removed the gauzes and remnant hematoma. Based on this experience, the authors recommend that for posterior fossa EDH from transverse sinus bleeding, bleeding control should be performed by gauze packing and endovascular treatment. PMID- 30402437 TI - Tracheal Infection Resulting from High Endotracheal Tube Cuff Pressure in an Unconscious Patient with Brain Trauma. AB - Deep neck infections (DNIs) are mainly caused by dental caries, tonsillitis, and pharyngitis; however, DNIs can also occur after head and neck trauma. A 79-year old male patient underwent a craniectomy due to an acute subdural hematoma. The patient was unconscious and continued to have a fever, but no clear cause was found. On postoperative day 9, he suddenly showed redness and swelling on the anterior neck. Enhanced computed tomography of the pharynx revealed tracheal necrosis and an abscess in the surrounding area. An incision and drainage were performed and Enterobacter aerogenes and E. faecalis were identified. The infection was controlled after antibiotic treatment. High endotracheal tube cuff pressure was suspected as the cause of the tracheal infection. Although DNIs are difficult to predict in patients who cannot report their symptoms due to unconsciousness, prevention and rapid diagnosis are important, as DNIs have serious side effects. PMID- 30402438 TI - A Case of Posterior Inferior Cerebellar Artery Infarction after Cervical Chiropractic Manipulation. AB - We describe the case of a patient who had infarction of the posterior inferior cerebellar artery (PICA) after a chiropractic cervical manipulation. A 39-year old man visited the emergency room with signs of cerebellar dysfunction, presenting with a 6-hour history of vertigo and imbalance. Two weeks ago, he was treated by a chiropractor for intermittent neck pain. At the time of admission, brain computed tomography, magnetic resonance imaging, and angiography revealed an acute infarction in the left PICA territory and occlusion of the extracranial vertebral artery (VA; V1/2 junction) as a result of the dissection of the VA. Angiography revealed complete occlusion of the left PICA and arterial dissection was shown in the extracranial portion of the VA. He was treated with antiplatelet therapy. Three weeks later, he was discharged without any sequelae. The possibility of VA dissection should be considered at least once in patients presenting with cerebellar dysfunctions with a recent history of chiropractic cervical manipulation. PMID- 30402439 TI - Investigation of Symptomatic Unstable Changes of Non-Fused Component in the Mixed Type Cervical Ossification of Posterior Longitudinal Ligament Using Dynamic Magnetic Resonance Imaging: A Case Report. AB - A 43-year-old man was transferred to our hospital with recurring myelopathic symptoms after previous anterior and posterior surgical decompressions for mixed type cervical ossification of the posterior longitudinal ligament (OPLL). Conventional magnetic resonance imaging (MRI) showed a preserved cervical curve and the achievement of successful decompression after the previous surgeries. The patient's symptoms were aggravated when he was in the extended neck posture. Dynamic MRI performed with the patient in an extended neck position revealed cord compression by OPLL from C3 to C4 with newly developed retrolisthesis of the C4-5 segment. We recommend the use of dynamic MRI to investigate motion-dependent cord compression caused by instability of the non-fused OPLL component. PMID- 30402440 TI - Rapid Healing and Remodeling Process of Pediatric Seat-Belt Fracture without Surgical Treatment. AB - Pediatric seat-belt fracture is a rare condition, and its management has not been well defined. The authors report a case of pediatric Chance fracture that was managed conservatively and that demonstrated rapid bone healing. A 7-year-old boy presented with back pain after a motor vehicle accident. Plain lumbar spine radiography, three-dimensional computed tomography (CT), and magnetic resonance imaging revealed a seat-belt fracture type C (classified by Rumball and Jarvis), and the patient's condition was managed conservatively. The patient started to ambulate with a brace 2 weeks after the injury. Spine CT performed 100 days after the injury revealed a remodeled fracture, and dynamic radiography did not show any evidence of instability or kyphotic deformity. We suggest that if there are no neurological deficits or severe deformities, then a pediatric seat-belt fracture should be managed conservatively, because the bone healing process is far more rapid in children than it is in adults and because of possible growth problems after surgery. PMID- 30402441 TI - Comparative study of the operative experience of surgical residents before and after 80-hour work week restrictions. AB - Purpose: In Korea, the working-hour limitation regulation has been implemented in December 2017. We aimed to define the difference in operative experience of surgical residents before and after implementing this policy in 2 hospitals among 8 affiliated hospitals of the Catholic Medical Center where implemented the 80 working-hour limitation policy since March 2015. Methods: All the operation records were reviewed, and the number of resident-participated surgeries between March and August in 2002 and 2017 were compared. Operations performed or participated in by residents as first assistants were defined as resident participated surgery. Results: After 2 years from the initiation of the resident work-hour limitations, the number of resident participated surgery has slightly decreased in both hospitals (Yeouido St. Mary's Hospital [YSM]: 317 to 302, St. Paul Hospital [SPH]: 635 to 461). For each resident, changes were like followings: 0 -> 21 cases for R1, 65 -> 72 cases for R2, 83 -> 192 cases for R3, and 169 -> 17 cases for R4 in YSM. In SPH, number of resident participating surgery was changed like followings: 4 -> 32 cases for R1, 222 -> 100 cases for R2, 317 -> 300 cases for R3, and 92 -> 29 cases for R4. In both hospital, while, total number of resident participating oncologic surgery has been decreased, number of resident participating appendectomy has been far increased. Activity of each grade resident is different according to hospital. Conclusion: Although total number of resident participating surgery decreased, variable changes were observed in each grade of resident according to each type of surgery and different hospitals. It is believed that comparisons of experiences from more hospitals in the future would be helpful in establishing the guidelines for surgical experience requirement of residents in Korea. PMID- 30402442 TI - ABT-737 ameliorates docetaxel resistance in triple negative breast cancer cell line. AB - Purpose: This study aimed to validate the synergistic effect of ABT-737 on docetaxel using MDA-MB-231, a triple negative breast cancer (TNBC) cell line overexpressing B-cell lymphoma-2 (Bcl-2). Methods: Western blot analysis was performed to assess expression levels of Bcl-2 family proteins and caspase related molecules. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay. Cell cycle distribution was determined by flow cytometry analysis. Benzyloxycarbonyl-Val-Ala-Asp(OMe) fluoromethylketone (z-VAD-fmk) was used for pretreatment to assess the role of caspases. Results: Cell viability of MDA-MB-231 after combination treatment with ABT-737 and docetaxel was significantly lower than that after docetaxel or ABT 737 monotherapy based on MTT assay (both P < 0.001), with a combination index of 0.41. The proportion of sub-G1 population after combination treatment was significantly higher than that after docetaxel or ABT-737 monotherapy (P = 0.001, P = 0.003, respectively). Pretreatment with z-VAD-fmk completely restored cell viability of MDA-MB-231 from apoptotic cell death induced by combination therapy (P = 0.001). Although pro-caspase-8 or Bid did not show significant change in expression level, pro-casepase-9 showed significantly decreased expression after combination treatment. Cleaved caspase-3 showed increased expression while poly (ADP-ribose) polymerase cleavage was induced after combination treatment. However, hypoxia-inducible factor 1-alpha and aldehyde dehydrogenase 1 totally lost their expression after combination treatment. Conclusion: Combination of ABT 737 with docetaxel elicits synergistic therapeutic effect on MDA-MB-231, a TNBC cell line overexpressing Bcl-2, mainly by activating the intrinsic pathway of apoptosis. Therefore, adjunct of ABT-737 to docetaxel might be a new therapeutic option to overcome docetaxel resistance of TNBCs overexpressing Bcl-2. PMID- 30402443 TI - Alteration of MRP2 expression and the graft outcome after liver transplantation. AB - Purpose: Multidrug resistance-associated protein (MRP) 2 is a glutathione conjugate in the canalicular membrane of hepatocytes. Early graft damage after liver transplantation (LT) can result in alteration of MRP2 expression. The purpose of this study was to evaluate the relationship between the pattern of MRP2 alteration and graft outcome. Methods: Forty-one paraffin-embedded liver graft tissues obtained by protocol biopsy within 2 months after LT; these were stained using monoclonal antibodies of MRP2. We selected 15 live donor biopsy samples as a control, that showed homogenous canalicular staining for MRP2. The pattern of canalicular MRP2 staining of graft was classified into 3 types: homogenous (type C0), focal (type C1), and no (type C2,) staining of the canaliculi. Results: In total, 17.1% graft tissues were type C0, 36.6% were type C1, and 46.3% were type C2. The median operation time was longer in patients with type C2 (562.6 minutes) than in patients with type C0 (393.8 minutes) (P = 0.038). The rates of posttransplant complications were higher in patients with type C2 (100%) than in patients with type C0 (42.9%) and C1 (73.3%) (P < 0.001). Conclusion: MRP2 expression pattern was altered in 82.9% after LT. The pattern of MRP2 alteration was associated with longer operation time and higher rates of post-LT complications. PMID- 30402444 TI - Laparoscopy of hepatocellular carcinoma is helpful in minimizing intra-abdominal adhesion during salvage transplantation. AB - Purpose: This study analyzes the impact of laparoscopic liver resection on intra abdominal adhesion. Methods: Patients who underwent salvage liver transplantation after liver resection for hepatocellular carcinoma from January 2012 to October 2017 at our institution were included. Information about the severity of intra abdominal adhesions was collected from a prospectively maintained database. Intra abdominal adhesions were graded after the agreement of 2 surgeons who participated in the salvage liver transplantation based on predetermined criteria. Adhesion severity and demographic, operative, and postoperative data were compared between the laparoscopic group and the open group. Multivariate logistic regression was performed to consider potential factors related to severe adhesion during salvage transplantation. Results: Sixty-two patients who underwent salvage liver transplantation after liver resection were included in this study. Among them, 52 patients underwent open surgery, and 10 patients underwent laparoscopy. Adhesion was significantly more severe in the open group than in the laparoscopy group (P = 0.029). A multivariate logistic regression model including potential factors related to severe adhesion showed that laparoscopy (odds ratio, 0.168; 95% confidence interval, 0.029-0.970; P = 0.048) was the only significant factor. Conclusion: Laparoscopic liver resection for hepatocellular carcinoma can minimize intra-abdominal adhesion during salvage liver transplantation. PMID- 30402445 TI - Clinical outcome of 1,000 consecutive cases of liver transplantation: a single center experience. AB - Purpose: The aim of this study was to analyze survival outcomes in 1,000 consecutive liver transplantations (LTs) performed at a single institution from 1993 to April 2017. Methods: The study population was divided into 2 groups based on donor type: deceased donor LT (DDLT; n = 181, 18.1%) and living donor LT (LDLT; n = 819; 81.9%), and into 3 periods based on the number of cases (first 300 cases, middle 300 cases, last 400 cases). Results: Infection was the most common cause of death, accounting for 34.8% (95 of 273). Mortality due to hepatocellular carcinoma recurrence occurred most frequently between 1 and 5 years after transplantation. Mortality rate by graft rejection was highest between 5 and 10 years after transplantation. And mortality by de novo malignancy occurred most frequently after 10 years after transplantation. The patient survival rates for the entire population at 5 and 10 years were 74.7%, and 68.6%, respectively. There was no difference in survival rate between the LDLT and DDLT groups (P = 0.188). Cause of disease, disease severity, case period, and retransplantation had a significant association with patient survival (P = 0.002, P = 0.031, P = 0.003, and P = 0.024, respectively). Conclusion: Surgical techniques and perioperative management for transplant patients have improved and undergone standardization. Controlling perioperative infection and managing patients with HCC as LT candidates will result in better outcomes. PMID- 30402446 TI - Kidney transplantation using expanded criteria deceased donors with terminal acute kidney injury: a single center experience in Korea. AB - Purpose: We investigated the clinical outcomes of deceased donor kidney transplantation (KT) using kidneys with terminal acute kidney injury (AKI). Methods: Between February 2000 and December 2013, we performed 202 deceased donor renal transplants from 159 brain dead donors. According to the expanded criteria donor (ECD) and AKI network criteria, we divided 202 recipients into 4 groups: Group I: Non-AKI & standard criteria donor (SCD) (n = 97); group II: Non-AKI & ECD (n = 15); group III: AKI & SCD (n = 52); and group IV: AKI & ECD (n = 38). Results: The incidence of delayed graft function (DFG) was significantly higher in patients with AKI than it was in the non-AKI group (P = 0.008). There were no significant differences among the 4 groups in graft survival (P = 0.074) or patient survival (P = 0.090). However, the long-term allograft survival rate was significantly lower in group IV than it was in other groups (P = 0.024). Conclusion: Allografts from deceased donors with terminal AKI had a higher incidence of DGF than did those from donors without AKI. However, there is no significant difference in graft and patient survival rates among the groups. So, the utilization of renal grafts from ECDs with terminal AKI is a feasible approach to address the critical organ shortage. PMID- 30402447 TI - The long-term prognostic impact of sentinel lymph node biopsy in patients with primary cutaneous melanoma: a prospective study with 10-year follow-up. AB - Purpose: Sentinel lymph node (SLN) biopsy (SLNB) is widely accepted for staging of melanoma patients. It has been shown that clinico-pathological features such as Breslow thickness, ulceration, age, and sex are better predictors of relapse and survival than SLN status alone. The aims of this study were to evaluate the long-term (10-year) prognostic impact of SLNB and to determine predictive factors associated with SLN metastasis, relapse, and melanoma specific mortality (MSM). Methods: This was a prospective observational study on 289 consecutive patients with primary cutaneous melanoma who underwent SLNB from January 2000 to December 2007, and followed until January 2014, at an Italian academic hospital. Results: SLN was positive in 64 patients (22.1%). The median follow-up was 116 months (79 147 months). Ten-year disease-free survival and melanoma specific survival were poor in patients with positive SLN (58.7% and 66.4%, respectively). Only the increasing Breslow thickness resulted independently associated to an increased risk of SLN metastasis. Cox regression analysis showed that a Breslow thickness >2 mm was an independent predictor of relapse, and male sex and Breslow thickness >2 mm was a predictor of MSM. At 10 years, SLN metastasis was not significantly associated to either relapse or MSM. Conclusion: After the fifth year of follow up, SLN metastasis is not an independent predictive factor of relapse or mortality which are mainly influenced by the characteristics of the primary tumor and of the patient. Patients with a Breslow thickness >2 mm regardless of the SLN status should be considered at high risk for 10-year relapse and mortality. PMID- 30402448 TI - Increased CCR7loPD-1hiCXCR5+CD4+ T Cells in Peripheral Blood Mononuclear Cells Are Correlated with Immune Activation in Patients with Chronic HBV Infection. AB - T follicular helper cells (Tfh cells) affect essential immune pathogenesis in chronic hepatitis B virus (HBV) infection. The CCR7loPD-1hi Tfh subset has a partial Tfh effector phenotype and is associated with active Tfh differentiation, whereas the CCR7hiPD-1lo Tfh subset is a resting phenotype. We recruited 20 healthy volunteers and 77 patients with chronic HBV infection, including those in the immune tolerant (IT) phase (n=19), immune clearance (IC) phase (n=20), low replicative (LR) phase (n=18), and reactivation (RA) phase (n=20). The expression of CD4, CXCR5, PD-1, and CCR7 was detected in T cells from peripheral blood by flow cytometry. The frequency of the CCR7loPD-1hi T subset was significantly higher in the patients than in the healthy controls (14.92+/-4.87% vs 12.23+/ 2.95%, p=0.018). The frequency of this Tfh subset in the IC group (18.42%+/-3.08) was increased compared with the IT group (11.94+/-2.87%, p=0.001) and LR group (13.65+/-4.93%, p=0.031) and was higher in the RA group than in the IT group (16.03+/-5.37% vs 11.94+/-2.87%, p=0.030). We observed a weak positive correlation between the CCR7loPD-1hi Tfh subset population and the alanine transaminase (ALT) level (r=0.370, p=0.001). The CCR7loPD-1h Tfh subset in the chronic HBV-infected patients was elevated to various degrees among the different immune phases. CCR7loPD-1hiCXCR5+CD4+ T cells are correlated with the immune status of chronic HBV infection patients and may be developed as a potential indicator for antiviral treatment. PMID- 30402449 TI - Acute-on-Chronic Liver Failure: From Basic Research to Clinical Applications. PMID- 30402450 TI - Glucose Metabolism Changes in Patients with Chronic Hepatitis C Treated with Direct Acting Antivirals. AB - Background and Aims: Chronic hepatitis C is a systemic disease and type 2 diabetes mellitus (T2DM) belongs to more common extrahepatic. The aim of this study was to (i) explore the prevalence of impaired fasting glucose (IFG) and T2DM in patients with chronic hepatitis C, (ii) explore the effect of direct acting antivirals (DAA) treatment on the glycemia, and (iii) explore the factors that modulate the effect of DAA treatment on glycemia in patients with chronic hepatitis C. Methods: We performed a longitudinal retrospective observational study focused on the patients undergoing DAA treatment of chronic hepatitis C. Data about glycemia, history of diabetes, hepatitis C virus, treatment, and liver status, including elastography, were obtained at baseline (before treatment start), at the end of treatment and 12 weeks after the end of treatment. Patients were treated with various regimens of direct acting antivirals. Results: We included 370 patients; 45.9% had F4 fibrosis. At baseline, the prevalence of T2DM increased with the degree of fibrosis (F0-F2 14.4%, F3 21.3%, and F4 31.8%, p=0.004). Fasting glycemia also increased with the degree of fibrosis (F0-F2 5.75+/-0.18 F3 5.84+/-0.17, and F4 6.69+/-0.2 mmol/L, p=0.001). We saw significant decrease of glycemia after treatment in all patients, but patients without T2DM or IFG from 6.21+/-0.12 to 6.08+/-0.15 mmol/L (p=0.002). The decrease was also visible in treatment experienced patients and patients with Child-Pugh A cirrhosis. Conclusion: We confirmed that the prevalence of either T2DM or IFG increases in chronic hepatitis C patients with the degree of fibrosis. The predictive factors for T2DM were, besides F4, fibrosis also higher age and BMI. Significant decrease of fasting glycemia after the DAA treatment was observed in the whole cohort and in subgroups of patients with T2DM, IFG, cirrhotic, and treatment experienced patients. PMID- 30402451 TI - Hospital-based antibiotic use in patients with Mycobacterium avium complex. AB - Treatment guidelines exist for pulmonary Mycobacterium avium complex (MAC) infection, although studies suggest poor concordance in clinician practice. Using a national database including hospital encounters of laboratory-confirmed MAC patients, we sought to characterise US treatment practices. We assessed patients in the Premier Healthcare Database from 2009 to 2013 with two or more MAC positive cultures or one MAC-positive culture and the International Classification of Diseases (9th revision) code for pulmonary nontuberculous mycobacteria (PNTM). Treatment was characterised by patient-, provider- and facility-level factors; significant differences were assessed (p<0.05). Multilevel Poisson regression estimated adjusted relative risks (aRR) of receiving guidelines-based or macrolide resistance-promoting regimens. Of 1326 MAC patients, 645 (49%) received treatment: 10% received guidelines-based treatment and 18% resistance-associated therapy. Patients were more likely to receive guidelines-based therapy if they had multiple hospital encounters (aRR 1.5), codes for PNTM (aRR 5.7) or tuberculosis (aRR 4.5) or radiological procedures (aRR 10.9); multiple hospital encounters (aRR 0.8) or a tuberculosis code (aRR 0.1) were less likely to be associated with receiving resistance promoting regimens. In hospital-based MAC patients, half received antibiotics active against MAC, a low proportion received therapy based on MAC guidelines and many received antibiotics that promote macrolide resistance. Improved implementation of guidelines-based treatment is needed to decrease use of regimens associated with macrolide resistance. PMID- 30402452 TI - Survey on accessibility and real-life application of noninvasive ventilation. AB - Noninvasive mechanical ventilation (NIV) is an accepted method of respiratory failure treatment; however, at present, little is known about the global factors limiting NIV application. A survey designed to determine NIV accessibility and limiting factors in world economies and regions was developed. The questionnaire was sent to members of the European Respiratory Society (ERS) Respiratory Intensive Care Assembly and all ERS National Delegates. Replies to the survey were collected from 161 respondents from 46 countries. NIV was found to be provided most frequently by pulmonologists and intensivists. In high-income economies (HIEs), NIV reimbursement in chronic respiratory failure treatment was found to be independent of the underlying disease and supplementary insurance (p<0.0001), whereas in upper-middle-income economies (UMIEs) it was found to be dependent on the underlying disease (p<0.0001). In chronic respiratory failure, NIV was not reimbursed in lower-middle-income economies (LMIEs) (p<0.0001). In LMIEs and UMIEs, the lack of financial resources was the main limiting factor in acute (p=0.007) and chronic respiratory failure (p<0.0001). In the income-level based assessment, financing was recognised as relevant in LMIEs and UMIEs (p<0.0001), equipment in LMIEs and UMIEs (p=0.03), medical staff in all economies (p=0.02), and legal regulations in LMIEs (p=0.0005). It was confirmed that NIV in acute and chronic respiratory failure is reimbursed based on government regulations in UMIEs and HIEs (p<0.0001), and is not reimbursed and probably will not be reimbursed in the near future in LMIEs (p<0.0001). We conclude that financial constraints are still considered a major limiting factor for NIV use. PMID- 30402453 TI - The Temporal Relationship between Selected Mental Disorders and Substance-Related Disorders: A Nationwide Population-Based Cohort Study. AB - Introduction. Previous studies have examined the association between specific mental disorders, particularly mood and anxiety disorders, and substance-related disorders; but the temporal link between them remains unclear. This study aimed to examine whether individuals with specific mental disorders, including affective psychoses, neurotic disorders, schizophrenia, personality disorders, and adjustment reaction, have higher risks for subsequently developing substance related disorders compared to those without. Methods. A large-scale study with longitudinal data was conducted using the Taiwan National Health Insurance Research Database (NHIRD) consisting of 2,000,118 patients' medical records from 2000 to 2009. A total of 124,423 people diagnosed with selected mental disorders and the same number of people without the diagnoses of the selected disorders were identified between January 1, 2001, and December 31, 2006, and followed up for the diagnoses of substance-related disorders till the end of 2009. We estimated the risk for subsequently developing substance-related disorders among patients with the selected mental disorders compared to those without by using Cox proportional hazard models. The cumulative incidence of substance-related disorders was calculated using the Kaplan-Meier method. Results. The risk for developing substance-related disorders in patients with selected mental disorders is about 5 times (HR=5.09, 95% CI: 4.74-5.48) higher than those without after adjusting for potential confounding variables. From the multivariate analyses of subsamples stratified by age, sex, and urban and income levels, we found all adjusted hazard ratios were significantly higher than 1.0, ranging from 2.12 (95% CI: 1.72-2.62) to 14.55 (95% CI: 7.89-26.83). For children and adolescents aged 10-19 years, those with specific mental disorders had 14.55-fold higher risk for developing substance-related disorders in later life compared to their counterparts. Furthermore, patients with personality disorders had the highest risk (HR=25.05). Conclusions. The earlier onset of the selected mental disorders is a potential risk for developing substance-related disorders in later life, particularly for personality disorders. Health professionals should pay more attention to this at-risk population, especially to adolescents with mental disorders. PMID- 30402455 TI - Noncoding RNAs and Base Modifications: Epigenomic Players Implicated in Neurological Disorders and Tumorigenesis. PMID- 30402454 TI - Revisiting Key Entry Routes of Human Epidemic Arboviruses into the Mainland Americas through Large-Scale Phylogenomics. AB - The rapid worldwide spread of chikungunya (CHIKV), dengue (DENV), and Zika (ZIKV) viruses have raised great international concern. Knowledge about the entry routes and geographic expansion of these arboviruses to the mainland Americas remain incomplete and controversial. Epidemics caused by arboviruses continue to cause socioeconomic burden globally, particularly in countries where vector control is difficult due to climatic or infrastructure factors. Understanding how the virus circulates and moves from one country to another is of paramount importance to assist government and health officials in anticipating future epidemics, as well as to take steps to help control or mitigate the spread of the virus. Through the analyses of the sequences of arbovirus genomes collected at different locations over time, we identified patterns of accumulated mutations, being able to trace routes of dispersion of these viruses. Here, we applied robust phylogenomic methods to trace the evolutionary dynamics of these arboviruses with special focus on Brazil, the epicenter of these triple epidemics. Our results show that CHIKV, DENV-1-4, and ZIKV followed a similar path prior to their first introductions into the mainland Americas, underscoring the need for systematic arboviral surveillance at major entry points of human population movement between countries such as airports and seaports. PMID- 30402456 TI - Multiple Regression Analysis Reveals MicroRNA Regulatory Networks in Oryza sativa under Drought Stress. AB - Drought is a major abiotic stress that reduces rice development and yield. miRNAs (microRNAs) are known to mediate posttranscriptional regulation under drought stress. Although the importance of individual miRNAs has been established, the crosstalks between miRNAs and mRNAs remain unearthed. Here we performed microarray analysis of miRNAs and matched mRNA expression profiles of drought treated rice cultivar Nipponbare. Drought-responsive miRNA-mRNA regulations were identified by a combination of a partial least square (PLS) regression approach and sequence-based target prediction. A drought-induced network with 13 miRNAs and 58 target mRNAs was constructed, and four miRNA coregulatory modules were revealed. Functional analysis suggested that drought-response miRNA targets are enriched in hormone signaling, lipid and carbohydrate metabolism, and antioxidant defense. 13 candidate miRNAs and target genes were validated by RT-qPCR, hierarchical clustering, and ROC analysis. Two target genes (DWARF-3 and P0651G05.2) of miRNA coregulatory modules were further verified by RLM-5' RACE. Together, our integrative study of miRNA-mRNA interaction provided attractive candidates that will help elucidate the drought-response mechanisms in Oryza sativa. PMID- 30402457 TI - Clinical Pharmacology of Hormonal Emergency Contraceptive Pills. AB - Emergency contraceptives play a major role in preventing unwanted pregnancy. The use of emergency contraceptives is characterized by myths and lack of knowledge by both health professionals and users. The main objective of this paper is to summarize the clinical pharmacology of hormonal methods of emergency contraception. A literature review was done to describe in detail the mechanism of action, efficacy, pharmacokinetics, safety profile, and drug interactions of hormonal emergency contraceptive pills. This information is useful to healthcare professionals and users to fully understand how hormonal emergency contraceptive methods work. PMID- 30402458 TI - Effect of Starter Culture and Low Concentrations of Sodium Nitrite on Fatty Acids, Color, and Escherichia coli Behavior during Salami Processing. AB - The reduction of NaNO2 and safety in meat products have been a concern to the meat industry for the last years. This research evaluated the changes in total fatty acids (TFAs) and myoglobin forms by adding starter culture (Lactobacillus sakei/Staphylococcus carnosus) and 50 ppm of NaNO2 during salami processing. In the postripening stage, the starter culture influenced the concentration of the palmitic, oleic, vaccenic, and gamma-linolenic TFAs, whereas the metmyoglobin concentration was lower (which could be related to the antioxidant effect of the starter culture). In this stage, an increase in enthalpy, specific heat, and onset temperature was found when adding starter culture and NaNO2, which is directly related to polyunsaturated TFA. However, when adding just the starter culture without 50 ppm NaNO2, the E. coli population was reduced in 4 log CFU/g. This study proposes the analysis of changes in meat product processing like salami in a holistic form, where the application of starter culture with low nitrite concentrations could be in the meat industry an upward trend for reducing this additive. PMID- 30402459 TI - Viability of Molds and Bacteria in Tempeh Processed with Supercritical Carbon Dioxides during Storage. AB - Application of supercritical carbon dioxide for processing of food products has an impact on microbial inactivation and food quality. This technique is used to preserve tempeh due to no heat involved. The quality of tempeh is highly influenced by mold growth because of its role in forming a compact texture, white color, and functional properties as well as consumer acceptance. This study aims to observe viability of molds and bacteria in tempeh after processed with supercritical CO2 and to determine the best processing conditions which can maintain mold growth and reduce the number of bacteria in tempeh. For that purpose, tempeh was treated using high pressure CO2 at 7.6 MPa (supercritical CO2) and at 6.3 MPa (sub/near supercritical CO2) with incubation period of 5, 10, 15, and 20 min. The best treatment obtained was used to process tempeh for storage study. The results showed that there was a significant interaction between pressure and incubation period for bacterial and mold viability at rho>0.05. Reduction of bacteria and molds increased with longer incubation period. Molds were undetectable after treatment for 20 min with either supercritical CO2 or sub-supercritical, and bacteria significantly reduced up to 2.40 log CFU/g. On the other hand, sub-supercritical CO2 for 10 min was the best processing method because molds survived 4.3x104 CFU/gram after treatment and were able to grow during storage at 30 degrees C, producing white mycelium as indicated by increasing the L* color value and tempeh acceptability. The inactivation of mold was reversible causing it to grow back during storage under suitable conditions. Tempeh matrix composition can provide protection against the destructive effects of supercritical CO2. Gram-positive bacteria were more resistant than Gram-negative. In conclusion, sub-supercritical CO2 can act as a method of cold pasteurization of tempeh and can be used as an alternative method to preserve tempeh. PMID- 30402460 TI - Mice Selected for Acute Inflammation Present Altered Immune Response during Pristane-Induced Arthritis Progression. AB - Mouse lines selected for maximal (AIRmax) or minimal acute inflammatory reaction (AIRmin) were used to characterize the immune response and the influence of genetic background during pristane-induced arthritis (PIA). Susceptible AIRmax mice demonstrated exacerbated cellular profiles during PIA, with intense infiltration of lymphocytes, as well as monocytes/macrophages and neutrophils, producing higher levels of IL-1beta, IFN-gamma, TNF-alpha, IL-10, total IgG3, and chemokines. Resistant AIRmin mice controlled cell activation more efficiently than the AIRmax during arthritis progression. The weight alterations of the spleen and thymus in the course of PIA were observed. Our data suggest that selected AIRmax cellular and genetic immune mechanisms contribute to cartilage damage and arthritis severity, evidencing many targets for therapeutic actions. PMID- 30402461 TI - Duration of Heat Stress Effect on Invasiveness of L. monocytogenes Strains. AB - During food production and food conservation, as well as the passage through the human gastrointestinal (GI) tract, L. monocytogenes is exposed to many adverse conditions which may elicit a stress response. As a result the pathogen may become more resistant to other unpropitious factors and may change its virulence. It has been shown that low and high temperature, salt, low pH, and high pressure affect the invasion capacity of L. monocytogenes. However, there is a scarcity of data on the duration of the stress effect on bacterial biology, including invasiveness. The aim of this work was to determine the period during which L. monocytogenes invasiveness remains altered under optimal conditions following exposure of bacteria to mild heat shock stress. Ten L. monocytogenes strains were exposed to heat shock at 54 degrees C for 20 minutes. Then both heat-treated and nontreated control bacteria were incubated under optimal growth conditions, 37 degrees C, for up to 72 hours and the invasion capacity was tested. Additionally, the expression of virulence and stress response genes was investigated in 2 strains. We found that heat stress exposure significantly decreases the invasiveness of all tested strains. However, during incubation at 37 degrees C the invasion capacity of heat-treated strains recovered to the level of nontreated controls. The observed effect was strain-dependent and lasted from less than 24 hours to 72 hours. The invasiveness of 6 out of the 10 nontreated strains decreased during incubation at 37 degrees C. The expression of inlAB correlated with the increase of invasiveness but the decrease of invasiveness did not correlate with changes of the level of these transcripts. Conclusions. The effect of heat stress on L. monocytogenes invasiveness is strain-dependent and was transient, lasting up to 72 hours. PMID- 30402462 TI - Intermittent Hypoxia Enhances THP-1 Monocyte Adhesion and Chemotaxis and Promotes M1 Macrophage Polarization via RAGE. AB - Intermittent hypoxia (IH) that resulted from obstructive sleep apnea (OSA) has been found to be a risk factor of coronary artery disease. IH and the receptor for advanced glycation end products (RAGE) expression are known to activate monocyte/macrophage and associated with atherosclerosis development, while their effects on monocyte adhesion, chemotaxis to the endothelium, and macrophage polarization remain unknown. In the present study, RAGE in THP-1 monocytes was inhibited by shRNA lentiviral particles, followed by exposure to IH. Cell adhesion assay, transwell migration assay, and macrophage polarization assays were performed to study the effects of IH and RAGE. The mRNA and protein expression levels were investigated by RT/real-time PCR and western blot analysis, respectively. We found that IH increased RAGE expression and activated NF-kB signalling in THP-1 monocytes. The results also revealed that IH enhanced the MCP-1-mediated THP-1 monocyte adhesion and chemotaxis and promoted macrophage polarization toward a proinflammatory phenotype, which was mediated by RAGE activity. Additionally, inhibition of chemokine receptor type 2 (CCR2) suppressed the IH-induced monocyte adhesion and chemotaxis. These results demonstrated a potential role of monocyte adhesion, chemotaxis, and macrophage polarization in the development cardiovascular diseases induced by IH and identified that RAGE could be a promising therapeutic target to prevent atherosclerosis in patients with OSA. PMID- 30402463 TI - Dependence of Anterior Active Rhinomanometry Indices on Nasal Obstructive Disorders in Children with Atopic Bronchial Asthma Complicated by Nasal Symptoms. AB - Background: Atopic bronchial asthma (BA) in children is associated with upper airways pathology (UAP). Among them, a combination of allergic rhinitis (AR) and nasal obstructive disorders (NOD), including hypertrophy of the pharyngeal tonsil (HPT) and anomalies of the intranasal structures (AINS), is abundant. In such patients, anterior active rhinomanometry (AARM) is an important method of examining nasal patency. However, NOD can influence the AARM parameters in children with BA and nasal symptoms, and this effect must be taken into account in clinical practice. Study goal was to elucidate the effect of NOD on rhinomanometric parameters in this group of patients. Methods: Total of 66 children with BA and AR were examined with AARM, rhinovideoendoscopy, spirometry, and standard clinical tests allowing revealing the structure of comorbid pathologies. In order to avoid the influence of anthropometric parameters of children and their age on AARM parameters, a special index of reduced total nasal airflow was used. Results: It has been established that NOD, especially HPT, have a significant negative impact on the indices of anterior active rhinomanometry during the periods of both AR remission and AR exacerbation. The effect of AINS is much weaker and was remarkable only in combination with HPT. PMID- 30402464 TI - Analysis of In Vitro Cyto- and Genotoxicity of Barbatimao Extract on Human Keratinocytes and Fibroblasts. AB - Barbatimao (Stryphnodendron adstringens, Mart.) is a native Brazilian species used in traditional medicine and some commercial preparations owing to its strong wound-healing activity. However, controversy regarding its use due to safety concerns over the potential genotoxic effect of this plant remains. In order to clarify this issue, the effect of hydroalcoholic extract of barbatimao in vitro on cell viability, DNA damage, and induction of apoptosis in two commercial cell lines of keratinocytes (HaCaT) and fibroblasts (HFF-1) was evaluated. Barbatimao stem bark hydroalcoholic extract (70% ethanol) was obtained and lyophilized for subsequent use in all experiments. The main bioactive molecules quantified by HPLC were gallic acid, caffeic acid, quercetin, catechin, and epigallocatechin gallate (EGCG). Barbatimao (0.024 to 1.99 mg/mL) was found to decrease cellular mortality as compared to the control group. GEMO assay, a noncellular DNA protocol that uses H2O2-exposed calf thymus DNA, revealed not only a genotoxic effect of barbatimao, but also a potential genoprotective action against H2O2 triggered DNA fragmentation. These results indicated that barbatimao at concentrations of 0.49 and 0.99 mg/mL, which are near to the levels found in commercial preparations, exerted an in vitro genoprotective effect on cells by decreasing the levels of DNA oxidation quantified by 8-hydroxy-2'-deoxyguanosine (8-OHdG) and reactive oxygen species (ROS) levels. Gene and protein apoptotic markers, quantified by qRT-PCR (BAX/Bcl-2 genes) and immunoassays (Caspases 3 and 8), respectively, also indicated a decrease in apoptotic events in comparison with control cells. Collectively, the results suggest that barbatimao could exert genoprotective and antiapoptotic effects on human keratinocytes and fibroblasts. PMID- 30402465 TI - Status of Artemisinin Resistance in Malaria Parasite Plasmodium falciparum from Molecular Analyses of the Kelch13 Gene in Southwestern Nigeria. AB - Evolution and spread of malaria parasite Plasmodium falciparum capable of evading antimalarials are the prime concern to malaria control. The currently effective drug, artemisinin (ART), is under threat due to detection of ART-resistant P. falciparum parasites in the Southeast Asian countries. It has been shown that amino acid (AA) mutations at the P. falciparum Kelch13 (Pfk13) gene provide resistance to ART. Nigeria, a part of the Sub-Saharan Africa, is highly endemic to malaria, contributing quite significantly to malaria, and resistance to chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) combination drugs has already been reported. Since artemisinin combined therapy (ACT) is the first-line drug for treatment of uncomplicated malaria in Nigeria and five amino acid mutations have been validated in the Pfk13 gene alongside with candidate mutations for ART resistance, we performed molecular surveillance for mutations (following PCR and DNA sequence analyses) in this gene from two southwestern states of Nigeria. Statistical analyses of DNA sequences were also performed following different evolutionary models. None of the different validated and candidate AA mutations of Pfk13 gene conferring resistance to ART could be detected in P. falciparum sampled in the two southwestern states of Nigeria. In addition, DNA sequencing and sequence analyses indicated neither evolutionary selection pressure on the Pfk13 gene nor association of mutations in Pfk13 gene with mutations of other three genes conferring resistance to CQ and SP. Therefore, based on the monomorphism at the Pfk13 gene and nonassociation of mutations of this gene with mutations in three other drug-resistant genes in malaria parasite P. falciparum, it can be proposed that malaria public health is not under immediate threat in southwestern Nigeria concerning ART resistance. PMID- 30402466 TI - Biocompatible Carbon-Based Coating as Potential Endovascular Material for Stent Surface. AB - Stainless steel 316L is a material commonly used in cardiovascular medicine. Despite the various methods applied in stent production, the rates of in-stent restenosis and thrombosis remain high. In this study graphene was used to coat the surface of 316L substrate for enhanced bio- and hemocompatibility of the substrate. The presence of graphene layers applied to the substrate was investigated using cutting-edge imaging technology: energy-filtered low-voltage FE-SEM approach, scanning electron microscopy (SEM), Raman spectroscopy, and atomic force microscopy (AFM). The potential of G-316L surface to influence endothelial cells phenotype and endothelial-to-mesenchymal transition (EndoMT) has been determined. Our results show that the bio- and hemocompatible properties of graphene coatings along with known radial force of 316L make G-316L a promising candidate for intracoronary implants. PMID- 30402467 TI - Insecticides Resistance Status of An. gambiae in Areas of Varying Agrochemical Use in Cote D'Ivoire. AB - Background: Insecticide resistance monitoring of the malaria vectors to different classes of insecticides is necessary for resistance management. Malaria vector control management approaches are essentially based on IRS and LLINs. However, insecticide resistance is caused by several sources of selection and in case the selection pressure is from agricultural practices, then measures need to be taken to avoid a failure of the control methods put in place. The current study was undertaken to monitor the susceptibility of vectors to different classes of insecticides in areas of varying agrochemical use patterns. Methods: A survey to determine the agricultural chemical use pattern was undertaken in ten localities across Cote d'Ivoire. In addition, WHO susceptibility tests were carried out on adults Anopheles gambiae s.l. mosquitoes emerging from collected larvae from the sites surveyed. Four insecticides from each class of the four classes of insecticides were evaluated using the standard susceptibility test methods. Furthermore, the target site mutations involved in resistance mechanisms were identified following the Taqman assay protocols and mosquito species were identified using SINE-PCR. Results: The mortalities of all the An. gambiae s.l populations were similar regardless of the pesticide use pattern. The vectors were resistant to DDT, deltamethrin, and bendiocarb in all localities. In contrast, mosquitoes showed high susceptibility to malathion. High frequency of the Kdr-West gene allele was observed (70-100%). A single Kdr-East mutation was identified in a mosquito that harboured both Ace-1 and Kdr-West genes. Conclusion: Cultivated marshlands representing good habitats for mosquito development may deeply contribute to the selection of resistance genes given the intensive use of agrochemical for crop protection. In view of these, special attention must be given to them to mitigate mosquito resistance to insecticides. PMID- 30402469 TI - Prevalence of Gastrointestinal Parasitic Infections and Assessment of Deworming Program among Cattle and Buffaloes in Gampaha District, Sri Lanka. AB - Gastrointestinal (GI) parasitic infection is a serious issue in cattle management. The effects of GI parasites may vary with age, sex of cattle, nutritional condition, and severity of infection. Prevalence of GI parasites among cattle population in Gampaha District has not been studied and there is no published study available. A total of 45 farms rearing cattle were selected randomly in three areas, namely, Kelaniya, Ganemulla, and Welisara, under three Veterinary Surgeon Divisions (VSD) in Gampaha District (Mahara, Gampaha, and Welisara). Freshly voided cattle fecal samples were collected randomly from the selected farms during March 2017-December 2017. Out of 163 cattle and buffaloes examined, 13.39% (n=22) were positive for eggs of one or more species of GI parasites. The prevalence of parasitic infection was higher in buffaloes (31.25%, 5/16) as compared to that of cows (11.56%, 21/147), but the difference was not significant (P >0.05). Hookworms (Bunostomum spp.), whipworms (Trichuris spp.), digenetic trematodes (Paramphistomum spp.), cestodes (Moniezia spp.), and oocysts of protozoans (coccidians) were found during the study. The nontreated animals indicated the highest percentage of parasitic infections accounting for 46.67% (n= 14), followed by partially treated individuals (15.15%, n= 5). GI parasite prevalence in males was higher when compared to that of females, but the difference was nonsignificant (P >0.05). General Linear Modelling (GLM) revealed that the effect of treatment status was significantly associated with the prevalence of GI parasites. The calves and yearlings had the highest rate of GI parasitic infections. The highest infection rate was observed at Kelaniya, followed by Welisara. Future investigations are necessary to evaluate the economic impact of GI parasites in the study areas. PMID- 30402468 TI - Prevalence and Genotype Distribution of Human Papillomavirus in Invasive Cervical Cancer, Cervical Intraepithelial Neoplasia, and Asymptomatic Women in Southeast China. AB - Cervical cancer is one of the leading causes of cancer-related deaths among women and it is caused by the human papillomavirus (HPV). High variation has been reported in the attribution of specific HPV genotypes to cervical neoplasia among various geographic regions. For effective control of cervical cancer through HPV vaccination, it is essential to estimate the cost-effectiveness of vaccination, to monitor the potential transition into other HPV genotypes, and to understand the distribution of specific HPV genotypes across a specific geographic region. In this study, the distribution of HPV genotypes was investigated in southeast China, from 2011 to 2016. The 12,816 cervical swabs collected from women (age 18 78 years, median 43.6 years) outpatients were analyzed. HPV prevalence among 12,816 cervical swabs analyzed was 22.3% (2,856/12,816). Among these positive cases, 2,216 had only one HPV genotype while 640 had multiple HPV genotypes. The cases with multiple types revealed 23 different HPV genotypes with the five most prevalent being HPV18 (18.2%), HPV52 (14.1%), HPV16 (11.9%), HPV58 (10.6%), and HPV33 (5.5%). The rates of HPV infection in patients with cervical inflammation, CIN-1, CIN-2, CIN-3, squamous carcinoma, and adenocarcinoma were 38.4%, 80.5%, 82.6%, 92.3%, 97.5%, and 93.4%, respectively. Four HPV genotypes, HPV18, HPV16, HPV52, and HPV58, were more prevalent in patients with CIN-2-CIN-3 and invasive cervical cancer. A comparison of HPV genotypes attribution to cervical cancer between southeast China and global incidences revealed distinct differences. Due to this unique prevalence, it is essential to streamline the vaccination development protocol prior to administering vaccines based on global data. PMID- 30402470 TI - Impact of Radiofrequency Ablation and Antiarrhythmic Medications on the Quality of Life of Patients with Supraventricular Tachycardias: Preliminary Validation of the Greek Version of the Umea22 (U22) Questionnaire. AB - Objective: This study aims to (i) translate, culturally adapt, and preliminarily validate the arrhythmia-specific Umea22 (U22) questionnaire and (ii) assess the impact of radiofrequency (RF) ablation and medical treatment on the quality of life of patients with supraventricular tachycardias (SVTs). Methods: A total of 140 patients with atrioventricular nodal re-entry tachycardia (AVNRT) and atrioventricular re-entry tachycardia (AVRT) were enrolled in the study. Of these, 100 patients underwent RF ablation (group A) and 40 patients were managed with antiarrhythmic medications (group B). Health-related quality of life (HRQoL) was assessed for both groups using the Short Form-36 Health Survey (SF-36) and the arrhythmia-specific Umea22 (U22) questionnaire at baseline and 3-month follow up. Exploratory and confirmatory factor analyses were performed to assess the validity of the U22 questionnaire. Univariate comparisons of HRQoL scores between study timepoints and multivariate regression analyses adjusting for baseline confounders were conducted. Results: The factor analysis of the U22 questionnaire yielded a six-factor model ("burden of spells"; "heart contractility"; "character of spells"; "general/non-specific feeling"; "other specific somatic symptoms"; "fear") with acceptable fit results. Patients of group A showed significant improvement in all SF-36 and U22 scores at 3 months' follow-up compared to baseline (all p<0.05). Patients of group B presented deterioration of the total SF-36 score (p=0.001) and improvement of certain U22 measures, namely, well-being (p=0.004), heartbeat speed, and intensity during arrhythmia spells (p<0.0001 for both measures) at 3 months' follow-up, compared to baseline. Employment status, male sex, and urban residence emerged as important predictors. Conclusion: The Greek version of the U22 questionnaire is a valid tool to assess SVT-related symptoms. RF ablation appears to exert more pronounced beneficial outcomes on HRQoL of patients with SVTs compared to medical treatment. Prompt referral of patients with SVTs to specialist centers may favorably affect their quality of life and should be encouraged. PMID- 30402471 TI - Value of Transvaginal Two-Dimensional Contrast-Enhanced Ultrasonography in Diagnosing Atypical Ovarian Corpus Luteum Hematoma. AB - Objective: To evaluate the value of transvaginal two-dimensional contrast enhanced ultrasonography (2D-CEUS) in the diagnosis of atypical ovarian corpus luteum hematoma (AT-OCLH). Methods: A prospective study was performed on 53 consecutive patients with suspected AT-OCLH, and the diagnostic results by transvaginal 2D-CEUS were statistically compared with the gold standard. The gold standard results were confirmed by surgical pathology or long-term follow-up. Results: The characteristic perfusion patterns of AT-OCLH in 2D-CEUS showed no contrast agent perfusion within the tumor mass, and the capsule wall showed rapid, annular, high enhancement perfusion; perfusion patterns could be classified into type Ia and type IIa. AT-OCLH can be distinguished from ovarian tumors based on perfusion characteristics and perfusion pattern type, which can be diagnosed based on the significantly stronger cystic wall perfusion intensity, earlier arrival time, and thicker cystic wall than nonluteal cystic foci (P<0.05). The sensitivity of 2D-CEUS for diagnosing AT-OCLH was 95.7%, with a specificity of 96.6%. A 2D-CEUS scoring system for AT-OCLH was established. Lesions with scores >17.5 were diagnosed as AT-OCLH. Conclusion: 2D-CEUS is an effective method for diagnosing AT-OCLH. PMID- 30402472 TI - Biochanin A Induces S Phase Arrest and Apoptosis in Lung Cancer Cells. AB - Lung cancer is among the most common malignancies with a poor 5-year survival rate reaching only 16%. Thus, new effective treatment modalities and drugs are urgently needed for the treatment of this malignancy. In this study, we conducted the first investigation of the effects of Biochanin A on lung cancer and revealed the mechanisms underlying its potential anticancer effects. Biochanin A decreased cell viability in a time-dependent and dose-dependent manner and suppressed colony formation in A549 and 95D cells. In addition, Biochanin A induced S phase arrest and apoptosis and decreased mitochondrial membrane potential (DeltaPsim) in A549 and 95D cells in a dose-dependent manner. Our results of subcutaneous xenograft models showed that the growth of Biochanin A group was significantly inhibited compared with that of control groups. Finally, P21, Caspase-3, and Bcl 2 were activated in Biochanin A-treated cells and Biochanin A-treated xenografts which also demonstrated that Biochanin A induced cell cycle arrest and apoptosis in lung cancer cells by regulating expression of cell cycle-related proteins and apoptosis-related proteins. In conclusion, this study suggests that Biochanin A inhibits the proliferation of lung cancer cells and induces cell cycle arrest and apoptosis mainly by regulating cell cycle-related protein expression and activating the Bcl-2 and Caspase-3 pathways, thus suggesting that Biochanin A may be a promising drug to treat lung cancer. PMID- 30402473 TI - Zearalenone Changes the Diversity and Composition of Caecum Microbiota in Weaned Rabbit. AB - Mycotoxins exhibit several severe effects on intestinal health, but few studies have assessed mycotoxins effect on the intestinal microflora and its repercussions to humans and animals. In this study, we evaluated the effect of zearalenone (ZEA), one of the most harmful mycotoxins on the structure of caecal microbiota in rabbits. Twenty-eight male weaned rabbits were randomly divided into four groups and orally given different concentrations of ZEA (400, 800, and 1600 MUg/kg.b.w). Microbial communities in caecum samples of rabbits were analyzed for 16S rRNA by Illumina sequencing through Illumina Miseq platform after being fed for 28 days. The results showed that increasing ZEA doses increased the species richness but did not significantly increased the species diversity of the caecum microbiota in the rabbits. In addition, the caecum microbiota from the samples in different ZEA-treated groups was clustered according to their dosing regimens. At the phylum level, ZEA decreased the abundance of Actinobacteria and significantly increased the abundance of Cyanobacteria, Synergistetes, and Proteobacteria. At the genus level, there were declines in the abundance of Adlercreutzia, Blautia, Desulfitobacter, Lactobacillus, Oxalobacter, and p-75-a5. The decrease of abundance in Lactobacillus, Desulfitobacter, and p-75-a5 was particularly noticeable. In conclusion, zearalenone could increase alpha-diversity but significantly decrease the abundance of some bacteria with the important metabolic functions. These findings suggested that ZEA could modify the caecum microbiota. PMID- 30402475 TI - Plasma Nucleotide Dynamics during Exercise and Recovery in Highly Trained Athletes and Recreationally Active Individuals. AB - Circulating plasma ATP is able to regulate local skeletal muscle blood flow and 02 delivery causing considerable vasodilatation during exercise. We hypothesized that sport specialization and specific long-term training stimuli have an impact on venous plasma [ATP] and other nucleotides concentration. Four athletic groups consisting of sprinters (n=11; age range 21-30 yr), endurance-trained athletes (n=16; age range 18-31 yr), futsal players (n=14; age range 18-30 yr), and recreationally active individuals (n=12; age range 22-33 yr) were studied. Venous blood samples were collected at rest, during an incremental treadmill test, and during recovery. Baseline [ATP] was 759+/-80 nmol.l-1 in competitive athletes and 680+/-73 nmol.l-1 in controls and increased during exercise by ~61% in competitive athletes and by ~31% in recreationally active participants. We demonstrated a rapid increase in plasma [ATP] at exercise intensities of 83-87% of VO2max in competitive athletes and 94% in controls. Concentrations reported after 30 minutes of recovery were distinct from those obtained preexercise in competitive athletes (P < 0.001) but not in controls (P = 0.61). We found a correlation between total-body skeletal muscle mass and resting and maximal plasma [ATP] in competitive athletes (r=0.81 and r=0.75, respectively). In conclusion, sport specialization is significantly related to plasma [ATP] at rest, during exercise, and during maximal effort. Intensified exercise-induced plasma [ATP] increases may contribute to more effective vessel dilatation during exercise in highly trained athletes than in recreational runners. The most rapid increase in ATP concentration was associated with the respiratory compensation point. No differences between groups of competitive athletes were observed during the recovery period suggesting a similar pattern of response after exercise. Total-body skeletal muscle mass is indirectly related to plasma [ATP] in highly trained athletes. PMID- 30402477 TI - An Evaluation of Clinical and Histopathological Aspects of Patients with Oral Submucous Fibrosis in the Background of Oral Squamous Cell Carcinoma. AB - Background: The behavior and prognosis of oral squamous cell carcinoma (OSCC) is presumably different in patients with oral submucous fibrosis (OSF). The objective of this study was to assess the effects of demographic features, habits, and histopathological features in the transformation of OSF to OSCC. Methods: Data were extracted from the archives and histopathological evaluation and presence of nodal metastasis were recorded. Results: OSF was detected in 130 (48%) out of 273 OSCC patients. The mean age of presentation among OSF-positive patients was 57.7 years, while patients diagnosed only with OSCC had a comparatively higher age, 59.5 years. In the below 50 years of age group, presence of OSF with OSCC was less (40%). In the OSF-positive group, male to female ratio was 3.2:1. The common primary sites were buccal mucosa and tongue in both groups. Betel quid chewing was present in more than 95% of the sample. Betel chewing, smoking, and alcohol consumption were present in 26.15% of OSF-positive patients. Degree of fibrosis was neither associated with the level of histological differentiation of the tumor (p= 0.195) nor associated with the malignant transformation (p =0.373). Lymph node metastasis was not seen in 76.63% and 68.54% of the patients with and without OSF, respectively. Conclusions: High degree of prevalence of OSF was observed among the OSCC patients. There were also a male predilection and younger age at presentation in these patients. However, a significant association was not observed in the degree of fibrosis with malignant transformation or the level of histopathological differentiation of the tumor. Lymph node metastasis also failed to express a significant relationship with the presence of OSF. PMID- 30402476 TI - Effects of a Short-Term Recreational Team Handball-Based Programme on Physical Fitness and Cardiovascular and Metabolic Health of 33-55-Year-Old Men: A Pilot Study. AB - Recreational team handball is an intermittent high-intensity exercise mode with physiological demands in the range of those found to enhance health and physical fitness of sedentary adults. We examined the effects of a short-term team handball-based training programme on physical fitness and metabolic and cardiovascular health of sedentary 33-55-year-old former male team handball players. Twenty-four participants were divided into team handball (THG; n=15) and control groups (CG; n=9) and evaluated at baseline and postintervention. During 12 weeks, THG performed 2-3 60-min recreational team handball matches weekly (average: 2.2 +/- 0.7), and CG maintained an inactive lifestyle. Average heart rate (HR) during matches was 80 +/- 7%HRmax, with peak values of 91 +/- 6%HRmax. A time-by-group interaction was shown in aerobic performance (p=0.016), postural balance (p=0.019), maximum oxygen uptake (VO2max) (p=0.023), resting HR (p<0.001), high-density lipoprotein (HDL) cholesterol (p=0.048), and fasting blood glucose (p=0.052) in favor of THG. THG improved aerobic performance (80%, p<0.001), VO2max (14%, p<0.001), and postural balance (27%, p=0.018). Decreases in resting HR (16%, p<0.001) and fasting blood glucose (7%, p=0.015) and increases in HDL cholesterol (11%, p=0.002) were found in THG. Recreational team handball practice shows positive physical fitness and health-related adaptations, with high attendance, which may contribute to the reduction of the risk of developing lifestyle diseases. PMID- 30402474 TI - Natural Antispasmodics: Source, Stereochemical Configuration, and Biological Activity. AB - Natural products with antispasmodic activity have been used in traditional medicine to alleviate different illnesses since the remote past. We searched the literature and compiled the antispasmodic activity of 248 natural compounds isolated from terrestrial plants. In this review, we summarized all the natural products reported with antispasmodic activity until the end of 2017. We also provided chemical information about their extraction as well as the model used to test their activities. Results showed that members of the Lamiaceae and Asteraceae families had the highest number of isolated compounds with antispasmodic activity. Moreover, monoterpenoids, flavonoids, triterpenes, and alkaloids were the chemical groups with the highest number of antispasmodic compounds. Lastly, a structural comparison of natural versus synthetic compounds was discussed. PMID- 30402478 TI - Application of Machine Learning Techniques for Clinical Predictive Modeling: A Cross-Sectional Study on Nonalcoholic Fatty Liver Disease in China. AB - Background: Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases. Machine learning techniques were introduced to evaluate the optimal predictive clinical model of NAFLD. Methods: A cross-sectional study was performed with subjects who attended a health examination at the First Affiliated Hospital, Zhejiang University. Questionnaires, laboratory tests, physical examinations, and liver ultrasonography were employed. Machine learning techniques were then implemented using the open source software Weka. The tasks included feature selection and classification. Feature selection techniques built a screening model by removing the redundant features. Classification was used to build a prediction model, which was evaluated by the F-measure. 11 state-of-the art machine learning techniques were investigated. Results: Among the 10,508 enrolled subjects, 2,522 (24%) met the diagnostic criteria of NAFLD. By leveraging a set of statistical testing techniques, BMI, triglycerides, gamma glutamyl transpeptidase (gammaGT), the serum alanine aminotransferase (ALT), and uric acid were the top 5 features contributing to NAFLD. A 10-fold cross validation was used in the classification. According to the results, the Bayesian network model demonstrated the best performance from among the 11 different techniques. It achieved accuracy, specificity, sensitivity, and F-measure scores of up to 83%, 0.878, 0.675, and 0.655, respectively. Compared with logistic regression, the Bayesian network model improves the F-measure score by 9.17%. Conclusion: Novel machine learning techniques may have screening and predictive value for NAFLD. PMID- 30402479 TI - Association of Exercise Capacity, Cardiac Function, and Coronary Artery Calcification with Components for Metabolic Syndrome. AB - Purpose: The purpose of this study was to investigate the association of exercise capacity, cardiac function, and coronary artery calcification (CAC) with components of metabolic syndrome in Korean adults. Method: Medical records of healthy adults who underwent exercise tolerance test (ETT), coronary CT angiography (CTA), and echocardiography of the heart for cardiac health check-up were retrospectively reviewed. Patients who had a history of severe cardiovascular disease or could not perform ETT due to other musculoskeletal problems were excluded. Subjects were classified into groups based on the number of components for metabolic syndrome: no component (Group 1, n=90), 1, 2 components (Group 2, n=321), and 3 or more components (Group 3, n=154). Exercise capacity was assessed using the symptom-limited ETT, and CAC score was obtained using the coronary CTA and Agatston score. Cardiac structure and function were assessed using echocardiography. Results: A total of 565 patients (mean (SD) age 59.5 (9.1), 340 men, 225 women) were selected. Exercise capacity was significantly lower in Group 3 than in the other groups (p<0.05). The CAC score was significantly higher in Group 3 than in the other groups (p<0.05). Compared to the other groups, echocardiography findings in Group 3 showed a greater hypertrophy of the left ventricle and reduction in the diastolic function (p<0.05). Exercise capacity, CAC score, cardiac structure, and function were different between the 3 groups, where a tendency to worsen was observed from Group 1 to Group 3. Conclusion: Metabolic syndrome decreases exercise capacity of the patient and contributes to CAC, thereby increasing the risk for cardiovascular diseases and deterioration in cardiac structure and function. Therefore, early detection of metabolic syndrome and subsequently the prevention and management of heart disease are necessary. PMID- 30402480 TI - Potassium Channel Activation Is Involved in the Cardiovascular Effects Induced by Freeze Dried Syzygium jambolanum (Lam.) DC Fruit Juice. AB - This work aimed to explore the cardiovascular effects induced by freeze-dried juice from Syzygium jambolanum (Lam.) DC fruits (JSJ). JSJ presented high polyphenol content and steroids. HPLC analysis revealed that 2,5-dihydroxybenzoic and caffeic acid were present in higher amounts in the JSJ extract. In rat, JSJ induces hypotension and vasodilatation in mesenteric arteries, with or without vascular endothelium. JSJ-mediated vasodilation response against contractions induced with KCl (60 mM) depolarizing solution was significantly lower than the responses induced by JSJ when evaluated against phenylephrine-induced contractions. To investigate the involvement of potassium channels we used Tyrode's solution with KCl (20 mM) or tetraethylammonium (1.0, 3.0, or 5.0 mM). In these conditions JSJ-induced effects were significantly attenuated. To investigate the potassium channel subtypes involved in the response, we used 4 aminopyridine, glibenclamide, BaCl2, and iberiotoxin. In the presence (simultaneous) of different potassium channel blockers we observed a significant attenuation of JSJ-induced effect. Inhibition was also observed when using BaCl2, glibenclamide, or 4-aminopyridine, separately. However, incubation with iberiotoxin did not promote changes in either maximum effect, or potency. We also evidenced a discrete participation of CaV channels in the JSJ-induced vasorelaxant effect. In addition, patch-clamp studies demonstrated that JSJ could activate potassium channels. In conclusion, JSJ promotes hypotension and vasorelaxation in rats, involving, at least, the activation of potassium channels. PMID- 30402481 TI - The Native Monomer of Bacillus Pumilus Ribonuclease Does Not Exist Extracellularly. AB - Supported by crystallography studies, secreted ribonuclease of Bacillus pumilus (binase) has long been considered to be monomeric in form. Recent evidence obtained using native polyacrylamide gel electrophoresis and size-exclusion chromatography suggests that binase is in fact dimeric. To eliminate ambiguity and contradictions in the data we have measured conformational changes, hypochromic effect, and hydrodynamic radius of binase. The immutability of binase secondary structure upon transition from low to high protein concentration was registered, suggesting the binase dimerization immediately after translocation through the cell membrane and leading to detection of binase dimers only in the culture fluid regardless of ribonuclease concentration. Our results made it necessary to take a fresh look at the binase stability and cytotoxicity towards virus-infected or tumor cells. PMID- 30402482 TI - Food-Origin Lactic Acid Bacteria May Exhibit Probiotic Properties: Review. AB - One of the most promising areas of development in the human nutritional field over the last two decades has been the use of probiotics and recognition of their role in human health and disease. Lactic acid-producing bacteria are the most commonly used probiotics in foods. It is well known that probiotics have a number of beneficial health effects in humans and animals. They play an important role in the protection of the host against harmful microorganisms and also strengthen the immune system. Some probiotics have also been found to improve feed digestibility and reduce metabolic disorders. They must be safe, acid and bile tolerant, and able to adhere and colonize the intestinal tract. The means by which probiotic bacteria elicit their health effects are not understood fully, but may include competitive exclusion of enteric pathogens, neutralization of dietary carcinogens, production of antimicrobial metabolites, and modulation of mucosal and systemic immune function. So far, lactic acid bacteria isolated only from the human gastrointestinal tract are recommended by the Food and Agriculture Organization (FAO) and World Health Organization (WHO) for use as probiotics by humans. However, more and more studies suggest that strains considered to be probiotics could be isolated from fermented products of animal origin, as well as from non-dairy fermented products. Traditional fermented products are a rich source of microorganisms, some of which may exhibit probiotic properties. They conform to the FAO/WHO recommendation, with one exception; they have not been isolated from human gastrointestinal tract. In light of extensive new scientific evidence, should the possibility of changing the current FAO/WHO requirements for the definition of probiotic bacteria be considered? PMID- 30402483 TI - Excess Hydrocortisone Hampers Placental Nutrient Uptake Disrupting Cellular Metabolism. AB - Low birth weight increases neonatal morbidity and mortality, and surviving infants have increased risk of metabolic and cardiovascular disturbances later in life, as well as other neurological, psychiatric, and immune complications. A gestational excess of glucocorticoids (GCs) is a well-known cause for fetal growth retardation, but the biological basis for this association remains elusive. Placental growth is closely related to fetal growth. The placenta is the main regulator of nutrient transport to the fetus, resulting from the difference between placental nutrient uptake and the placenta's own metabolism. The aim of this study was to analyze how excess hydrocortisone affects placental glucose and lipid metabolism. Human placenta explants from term physiological pregnancies were cultured for 18 hours under different hydrocortisone concentrations (2.75, 5.5, and 55 mM; 1, 2, and 20 mg/ml). Placental glucose and lipid uptake and the metabolic partitioning of fatty acids were quantified by isotopic techniques, and expression of specific glucose transporter GLUT1 was quantified by western blot. Cell viability was assessed by MTT, immunohistochemistry and caspase activity. We found that excess hydrocortisone impairs glucose uptake and lipoprotein lipase (LPL) activity, coincident with a GC-dose dependent inhibition of fatty acid oxidation and esterification. None of the experimental conditions showed an increased cell death. In conclusion, our results show that GC overexposure exerts a dysfunctional effect on lipid transport and metabolism and glucose uptake in human placental explants. These findings could well be directly related to a reduced placental growth and possibly to a reduced supply of nutrients to the fetus and the consequent fetal growth retardation and metabolic programming. PMID- 30402485 TI - Evidence of Insecticide Resistance to Pyrethroids and Bendiocarb in Anopheles funestus from Tsararano, Marovoay District, Madagascar. AB - Introduction: In Madagascar, malaria control relies on the countrywide use of long lasting insecticide treated bed nets (LLINs) and on indoor residual spraying (IRS) in the central highland area as well as a small area on the eastern coast. We tested insecticide resistance mechanisms of Anopheles funestus from Tsararano, a malaria endemic village in the coastal health district of Marovoay. Methods: Insecticide susceptibility bioassays were done in July 2017 on first-generation Anopheles funestus (F1) to assess (i) the susceptibility to permethrin (0.05%), deltamethrin (0.05%), DDT (4%), malathion (5%), fenitrothion (1%), and bendiocarb (0.1%); (ii) the effect of preexposure to the piperonyl butoxide (PBO) synergist; and (iii) the enzymatic activities of cytochrome P450, esterases, and glutathione S-transferases (GST). Results: Our results demonstrated that An. funestus was phenotypically resistant to pyrethroids and bendiocarb, with a mortality rate (MR) of 33.6% (95%CI: 24.5-43.7%) and 86% (95%CI: 77.6-92.1%), respectively. In contrast, An. funestus were 100% susceptible to DDT and organophosphates (malathion and fenitrothion). Preexposure of An. funestus to PBO synergist significantly restored the susceptibility to bendiocarb (MR=100%) and increased the MR in the pyrethroid group, from 96% (95%CI: 90.0-98.9%) to 100% for deltamethrin and permethrin, respectively (chi 2 = 43, df = 3, P< 0.0001). Enzymatic activities of cytochrome P450 and alpha-esterases were significantly elevated among An. funestus compared with the IPM reference strain (Mann-Whitney U= 30, P<0.0001; U = 145.5, P <0.0001, respectively). No significant differences of beta-esterases activities compared to the IPM reference strain were observed (Mann-Whitney U = 392.5, P = 0.08). Conclusion: In Tsararano, despite the absence of an IRS programme, there is evidence of high levels of insecticide resistance to pyrethroids and bendiocarb in An. PMID- 30402484 TI - Weaning from Mechanical Ventilation in ARDS: Aspects to Think about for Better Understanding, Evaluation, and Management. AB - Acute respiratory distress syndrome (ARDS) is characterized by severe inflammatory response and hypoxemia. The use of mechanical ventilation (MV) for correction of gas exchange can cause worsening of this inflammatory response, called "ventilator-induced lung injury" (VILI). The process of withdrawing mechanical ventilation, referred to as weaning from MV, may cause worsening of lung injury by spontaneous ventilation. Currently, there are few specific studies in patients with ARDS. Herein, we reviewed the main aspects of spontaneous ventilation and also discussed potential methods to predict the failure of weaning in this patient category. We also reviewed new treatments (modes of mechanical ventilation, neuromuscular blocker use, and extracorporeal membrane oxygenation) that could be considered in weaning ARDS patients from MV. PMID- 30402486 TI - A New Challenge for Radiologists: Radiomics in Breast Cancer. AB - Introduction: Over the last decade, the field of medical imaging experienced an exponential growth, leading to the development of radiomics, with which innumerable quantitative features are obtained from digital medical images, providing a comprehensive characterization of the tumor. This review aims to assess the role of this emerging diagnostic tool in breast cancer, focusing on the ability of radiomics to predict malignancy, response to neoadjuvant chemotherapy, prognostic factors, molecular subtypes, and risk of recurrence. Evidence Acquisition: A literature search on PubMed and on Cochrane database websites to retrieve English-written systematic reviews, review articles, meta analyses, and randomized clinical trials published from August 2013 up to July 2018 was carried out. Results: Twenty papers (19 retrospective and 1 prospective studies) conducted with different conventional imaging modalities were included. Discussion: The integration of quantitative information with clinical, histological, and genomic data could enable clinicians to provide personalized treatments for breast cancer patients. Current limitations of a routinely application of radiomics are represented by the limited knowledge of its basics concepts among radiologists and by the lack of efficient and standardized systems of feature extraction and data sharing. PMID- 30402487 TI - Insecticide Resistance and Fitness: The Case of Four Aedes aegypti Populations from Different Brazilian Regions. AB - Background: Chemical control is still a major strategy to constrain vector density and mitigate pathogen transmission. However, insecticide overuse poses a high selective pressure, favouring the spread of resistance alleles in natural populations. In an insecticide-free environment, a fitness cost is expected in resistant insects when compared to susceptible counterparts. This study investigates whether insecticide resistance to an organophosphate (temephos) and a pyrethroid (deltamethrin) is associated with fitness traits in four Aedes aegypti wild populations sampled every three months over one year. Findings: We measured development time from larvae to adult, female survival, wing length, fecundity, and adult resistance to starvation in field insecticide resistant Ae. aegypti populations four times over a year. These results were confronted with resistance levels to temephos and deltamethrin and with potentially related mechanisms, including a kdr mutation in the pyrethroid target site. No differences in fitness cost were found after contrasting mosquitoes from the same population collected throughout a year, irrespective of differences in insecticide resistance levels. Additionally, significant differences were not observed among field populations. However, compared to the reference strain Rockefeller, field females survived significantly less. Moreover, larval development was equal or slower in three out of four field populations. In no case differences were evidenced in starvation tolerance, wing length, and fecundity. Conclusions: Overall, field resistant mosquitoes seemed to have a slight fitness disadvantage when compared with the Rockefeller susceptible strain which might represent a potential fitness cost of insecticide resistance. However, after comparing Ae. aegypti from the same population but sampled at different moments, or from different field populations, mosquito life-history traits varied independently of resistance ratios. The metabolic deviations necessary to overcome the adverse effects of insecticides may cause an energy trade-off that affects energy allocation and ultimately basic demands of insect biology. The extent of fitness cost due to insecticide resistance is critical information to delay the evolution of resistance in wild vector populations. PMID- 30402488 TI - Automatic Global Level Set Approach for Lumbar Vertebrae CT Image Segmentation. AB - Vertebrae computed tomography (CT) image automatic segmentation is an essential step for Image-guided minimally invasive spine surgery. However, most of state-of the-art methods still require human intervention due to the inherent limitations of vertebrae CT image, such as topological variation, irregular boundaries (double boundary, weak boundary), and image noise. Therefore, this paper intentionally designed an automatic global level set approach (AGLSA), which is capable of dealing with these issues for lumbar vertebrae CT image segmentation. Unlike the traditional level set methods, we firstly propose an automatically initialized level set function (AILSF) that comprises hybrid morphological filter (HMF) and Gaussian mixture model (GMM) to automatically generate a smooth initial contour which is precisely adjacent to the object boundary. Secondly, a regularized level set formulation is introduced to overcome the weak boundary leaking problem, which utilizes the region correlation of histograms inside and outside the level set contour as a global term. Ultimately, a gradient vector flow (GVF) based edge-stopping function is employed to guarantee a fast convergence rate of the level set evolution and to avoid level set function oversegmentation at the same time. Our proposed approach has been tested on 115 vertebrae CT volumes of various patients. Quantitative comparisons validate that our proposed AGLSA is more accurate in segmenting lumbar vertebrae CT images with irregular boundaries and more robust to various levels of salt-and-pepper noise. PMID- 30402489 TI - Simvastatin Effects on Inflammation and Platelet Activation Markers in Hypercholesterolemia. AB - Background: Beside the lipid-lowering effect, statins slow the progression of atherosclerosis by exerting anti-inflammatory and platelet inhibiting effects. We investigated whether platelet inhibition by simvastatin correlates with the statin effects on lipid lowering, inflammation, oxidative stress, and endothelial and platelet activation. Methods: In hypercholesterolemic patients allocated to diet (n=20) or a 2-month treatment with diet plus 40 mg simvastatin (n=25), we evaluated platelet aggregating responses to ADP, collagen, and arachidonic acid (AA), the effect of aspirin on AA-induced aggregation, pro- and anti-inflammatory and atherogenic mediators (IL-1beta, -5, -6, -7, -8, -9, -10, -12, and -13, IFN gamma, IP-10, Eotaxin, and sRAGE), markers of endothelium (sE-selectin, VEGF, and MCP-1) and platelet activation (sP-selectin, sCD-40L, RANTES, and PDGF-bb), and oxidative stress (8-OH-2'-deoxyguanosine). Results: After treatment, beside the improvement of lipid profile, we observed the following: a reduction of platelet aggregation to ADP (p=0.0001), collagen (p=0.0001), AA (p=0.003); an increased antiaggregating effect of aspirin in the presence of AA (p=0.0001); a reduction of circulating levels of IL-6 (p=0.0034), IL-13 (p<0.0001), IFN-gamma (p<0.0001), VEGF (p<0.0001), sE-selectin (p<0.0001), sCD-40L (p<0.0001), sP-selectin (p=0.003), and 8-OH-2'-deoxyguanosine (p<0.0001); an increase of IL-10 and sRAGEs (p=0.0001 for both). LDL-cholesterol levels (i) positively correlated with IL-6, IFN-gamma, E-selectin, sCD-40L, 8-OH-2'-deoxyguanosine, platelet aggregation to ADP, collagen, AA, and aspirin IC-50 and (ii) negatively correlated with IL-10 and sRAGE. In multiple regression analyses, LDL-cholesterol was the strongest predictor for most parameters of platelet reactivity. Conclusion: In primary hypercholesterolemia, simvastatin treatment reduced platelet activation and subclinical inflammation and improved endothelial dysfunction. LDL-cholesterol levels were the major correlate of platelet reactivity; however, other effects of statins may contribute to reducing the progression of atherosclerosis. PMID- 30402490 TI - Gene Expression Profile Signature of Aggressive Waldenstrom Macroglobulinemia with Chromosome 6q Deletion. AB - Background: Waldenstrom macroglobulinemia (WM) is a rare, indolent B-cell lymphoma. Clinically, chromosome 6q deletion (6q del) including loss of the B lymphocyte-induced maturation protein 1 gene (BLIMP-1) is reported to be associated with poor prognosis. However, it remains unclear how the underlying biological mechanism contributes to the aggressiveness of WM with 6q del. Methods: Here, we conducted oligonucleotide microarray analysis to clarify the differences in gene expression between WM with and without 6q del. Gene ontology (GO) analysis was performed to identify the main pathways underlying differences in gene expression. Eight bone marrow formalin-fixed paraffin-embedded samples of WM were processed for interphase fluorescence in situ hybridization analysis, and three were shown to have 6q del. Results: GO analysis revealed significant terms including "lymphocyte activation" (corrected p value=6.68E-11), which included 31 probes. Moreover, IL21R and JAK3 expression upregulation and activation of the B cell receptor signaling (BCR) pathway including CD79a, SYK, BLNK, PLCgamma2, and CARD11 were detected in WM with 6q del compared with WM without 6q del. Conclusion: The present study suggested that the BCR signaling pathway and IL21R expression are activated in WM with 6q del. Moreover, FOXP1 and CBLB appear to act as positive regulators of the BCR signaling pathway. These findings might be attributed to the aggressiveness of the WM with 6q del expression signature. PMID- 30402492 TI - Prevalence and Risk Factors of Hypertension in Two Communes in the Vietnam Northern Mountainous, 2017. AB - Background: The aims were to characterize the prevalence of hypertension (HTN) and explore its associations in the northern mountainous. Methods: We carried out a cross-sectional study in two communes in Chiem Hoa district, Tuyen Quang province, between June and November 2017. All subjects at the age of 18 years and over currently living in two communes. The usage of the descriptive statistics was to characterize the HTN prevalence. We used the univariate and multivariate models of logistic regression to determine the prevalence and related factors of HTN. Results: There were 319 people with overall HTN in the total of 675 participants. Among people with HTN, there were 101 ones with isolated systolic hypertension (ISH). The proportion of HTN among the Tay ethnic group was 47.6%. The factors related to HTN included group, body mass index (BMI), low physical fitness, and waist-hip ratio (WHR). These factors as well as the ethnicity were significantly associated with ISH. Conclusions: Two communes of Chiem Hoa district in Tuyen Quang province had a high prevalence of HTN. Age, BMI, WHR, and physical activity were the risk factors of overall HTN and ISH. In particular, ISH was affected by ethnicity. PMID- 30402491 TI - A Retrospective Study on the Risk of Respiratory Distress Syndrome in Singleton Pregnancies with Preterm Premature Rupture of Membranes between 24+0 and 36+6 Weeks, Using Regression Analysis for Various Factors. AB - Aim: This study aimed to investigate the cause of respiratory distress syndrome (RDS) in neonates from singleton pregnancies with preterm premature rupture of membranes (pPROM) between 24+0 and 36+6 weeks by using regression analysis for various factors. Methods: In 175 singleton pregnancies with pPROM, 95 cases of RDS (54,29%) were diagnosed. In all cases the following information was collected: latency period of PROM, gestational age at birth, Umbilical Artery Pulsatility Index (UA PI), Middle Cerebral Artery Pulsatility Index (MCA PI), fetal distress, antenatal steroids use, delivery type, pregnancy hypertension disease, gestational glucose intolerance or diabetes, neonatal laboratory parameters, gender, weight, Apgar score, and other neonatal complications. Logistic regression analysis was used to investigate the effect of variables on RDS. Results: The results of logistic regression analysis showed that the following variables are closely correlated with RDS: female gender (OR=0.52; 95%CI:0.28-0,97), antenatal steroids use (OR=0,46; 95%CI:0,34-0,64), abnormal UA PI and MCA PI (OR=2.96; 95%CI:1,43-6,12) (OR=2.05; 95%CI:1,07-3,95), fetal distress (OR=2.33; 95%CI:1,16-4,71), maternal HGB (OR=0.69; 95%CI:0,5-0,96), and neonatal RBC, HGB (OR=0.32; 95%CI:0,19-0,55) (OR=0.75; 95%CI:0,65-0,88). Conclusions: The main RDS risk factors in premature neonates are gender, abnormal fetoplacental circulation, and fetal distress. The laboratory parameters such as lower RBC and HGB count are observed in infants with RDS. PMID- 30402493 TI - Cerebrovascular Regulation in Neurological Disorders. PMID- 30402494 TI - Modelling of Running Performances: Comparisons of Power-Law, Hyperbolic, Logarithmic, and Exponential Models in Elite Endurance Runners. AB - Many empirical and descriptive models have been proposed since the beginning of the 20th century. In the present study, the power-law (Kennelly) and logarithmic (Peronnet-Thibault) models were compared with asymptotic models such as 2 parameter hyperbolic models (Hill and Scherrer), 3-parameter hyperbolic model (Morton), and exponential model (Hopkins). These empirical models were compared from the performance of 6 elite endurance runners (P. Nurmi, E. Zatopek, J. Vaatainen, L. Viren, S. Aouita, and H. Gebrselassie) who were world-record holders and/or Olympic winners and/or world or European champions. These elite runners were chosen because they participated several times in international competitions over a large range of distances (1500, 3000, 5000, and 10000 m) and three also participated in a marathon. The parameters of these models were compared and correlated. The less accurate models were the asymptotic 2-parameter hyperbolic models but the most accurate model was the asymptotic 3-parameter hyperbolic model proposed by Morton. The predictions of long-distance performances (maximal running speeds for 30 and 60 min and marathon) by extrapolation of the logarithmic and power-law models were more accurate than the predictions by extrapolation in all the asymptotic models. The overestimations of these long-distance performances by Morton's model were less important than the overestimations by the other asymptotic models. PMID- 30402496 TI - Emerging Technologies and Methods for Musculoskeletal Tissue Repair and Regeneration. PMID- 30402495 TI - Psychiatric Comorbidities among People Who Inject Drugs in Hai Phong, Vietnam: The Need for Screening and Innovative Interventions. AB - The objective of this study is to describe psychiatric comorbidities, associated factors, and access to psychiatric assessment and care in a cohort of people who inject drugs (PWID) in Hai Phong, Vietnam. Mental health was assessed after 12 months' follow-up using the Mini International Neuropsychiatric Interview questionnaire (MINI 5.0.0). PWID medical history, drug use, and sociodemographic and clinical characteristics were also collected. Among 188 PWID who participated in the assessment, 48 (25.5%) had at least one psychiatric disorder and 19 (10.1%) had 2 or more psychiatric disorders. The most common current psychiatric disorders were major depressive episode (12.2%) and psychotic disorder (4.8%), reaching 10.1% for the latter when lifetime prevalence was considered. Females were more likely than males to have at least one psychiatric disorder, a major depressive disorder, or an anxiety disorder. Methamphetamine use was associated with an increased risk of presenting a lifetime psychotic syndrome. Problematic alcohol consumption was associated with an increased risk of having at least one psychiatric disorder. Psychiatric comorbidities are frequent among PWID in Vietnam. These results highlight the need for routine assessment and innovative interventions to address mental health needs among PWID. Community-based interventions targeting mental health prevention and care should be strongly supported. PMID- 30402497 TI - Towards Ultra Low-Cost Myoactivated Prostheses. AB - In developing countries, due to the high cost involved, amputees have limited access to prosthetic limbs. This constitutes a barrier for this people to live a normal life. To break this barrier, we are developing ultra-low-cost closed-loop myoactivated prostheses that are easy to maintain manufacture and that do not require electrodes in contact with the skin to work effectively. In this paper, we present the implementation for a simple but functional hand prosthesis. Our simple design consists of a low-cost embedded microcontroller (Arduino), a wearable stretch sensor (adapted from electroresistive bands normally used for "insulation of gaskets" against EM fields), to detect residual muscle contraction as direct muscle volumetric shifts and a handful of common, not critical electronic components. The physical prosthesis is a 3D printed claw-style two fingered hand (PLA plastic) directly geared to an inexpensive servomotor. To make our design easier to maintain, the gears and mechanical parts can be crafted from recovered materials. To implement a closed loop, the amount of closure of prosthesis is fed back to the user via a second stretch sensor directly connected to claw under the form of haptic feedback. Our concept design comprised of all the parts has an overall cost below AUD 30 and can be easily scaled up to more complicated devices suitable for other uses, i.e., multiple individual fingers and wrist rotation. PMID- 30402498 TI - Onco-Multi-OMICS Approach: A New Frontier in Cancer Research. AB - The acquisition of cancer hallmarks requires molecular alterations at multiple levels including genome, epigenome, transcriptome, proteome, and metabolome. In the past decade, numerous attempts have been made to untangle the molecular mechanisms of carcinogenesis involving single OMICS approaches such as scanning the genome for cancer-specific mutations and identifying altered epigenetic landscapes within cancer cells or by exploring the differential expression of mRNA and protein through transcriptomics and proteomics techniques, respectively. While these single-level OMICS approaches have contributed towards the identification of cancer-specific mutations, epigenetic alterations, and molecular subtyping of tumors based on gene/protein-expression, they lack the resolving-power to establish the casual relationship between molecular signatures and the phenotypic manifestation of cancer hallmarks. In contrast, the multi OMICS approaches involving the interrogation of the cancer cells/tissues in multiple dimensions have the potential to uncover the intricate molecular mechanism underlying different phenotypic manifestations of cancer hallmarks such as metastasis and angiogenesis. Moreover, multi-OMICS approaches can be used to dissect the cellular response to chemo- or immunotherapy as well as discover molecular candidates with diagnostic/prognostic value. In this review, we focused on the applications of different multi-OMICS approaches in the field of cancer research and discussed how these approaches are shaping the field of personalized oncomedicine. We have highlighted pioneering studies from "The Cancer Genome Atlas (TCGA)" consortium encompassing integrated OMICS analysis of over 11,000 tumors from 33 most prevalent forms of cancer. Accumulation of huge cancer specific multi-OMICS data in repositories like TCGA provides a unique opportunity for the systems biology approach to tackle the complexity of cancer cells through the unification of experimental data and computational/mathematical models. In future, systems biology based approach is likely to predict the phenotypic changes of cancer cells upon chemo-/immunotherapy treatment. This review is sought to encourage investigators to bring these different approaches together for interrogating cancer at molecular, cellular, and systems levels. PMID- 30402499 TI - The Effects of Passive Simulated Jogging on Short-Term Heart Rate Variability in a Heterogeneous Group of Human Subjects. AB - Background: Heart rate variability (HRV) reflects neural balance between sympathetic and parasympathetic autonomic nervous systems (ANS). Reduced HRV occurs in several chronic diseases and physical inactivity. External addition of pulses to the circulation restores HRV. A new method to add pulses to the circulation can be accomplished with a passive simulated jogging device (JD). We hypothesized that application of JD might increase HRV in seated and supine postures in a heterogeneous group of volunteer subjects. Methods: Twenty ambulatory persons (age range 31-88) were recruited. The physical activity intervention (JD) moved the feet in a repetitive and alternating manner; upward movement of the pedal is followed by a downward movement of the forefoot tapping against a semirigid bumper to simulate tapping of feet against the ground during jogging. Each subject underwent four, 30 min sessions in seated and supine postures with the active JD and same with Sham. HRV was assessed at baseline (BL), and Recovery (REC) from analysis of an electrocardiogram. Time domain variables were computed, namely, standard deviation of all normal RR intervals (SDNN) and square root of the mean of the sum of the squares of differences between adjacent RR intervals (RMSSD). Frequency domain measures were determined using a standard Fast Fourier spectral analysis, as well as parameters of Poincare plots. Results: Thirty minutes of JD significantly increased time domain measures and Poincare parameters of HRV in both seated and supine postures. Frequency domain parameters showed no change. The effects of JD on HRV measures were not affected by age, gender, or posture. Conclusion: The passive simulated jogging device increased HRV in both seated and supine postures. This intervention that provided effortless physical activity is a novel method to harness the beneficial effects of increasing HRV. PMID- 30402501 TI - Effects of Dexmedetomidine Postconditioning on Myocardial Ischemia/Reperfusion Injury in Diabetic Rats: Role of the PI3K/Akt-Dependent Signaling Pathway. AB - Objective: The present study was designed to determine whether dexmedetomidine (DEX) exerts cardioprotection against myocardial I/R injury in diabetic hearts and the mechanisms involved. Methods: A total of 30 diabetic rats induced by high glucose-fat diet and streptozotocin (STZ) were randomly assigned to five groups: diabetic sham-operated group (DM-S), diabetic I/R group (DM-I/R), diabetic DEX group (DM-D), diabetic DEX + Wort group (DM-DW), and diabetic Wort group (DM-W). Another 12 age-matched male normal SD rats were randomly divided into two groups: sham-operated group (S) and I/R group (I/R). All rats were subjected to 30 min myocardial ischemia followed by 120 min reperfusion except sham groups. Plasmas were collected to measure the malondialdehyde (MDA), creatine kinase isoenzymes (CK-MB), and lactate dehydrogenase (LDH) levels and superoxide dismutase (SOD) activity at the end of reperfusion. Pathologic changes in myocardial tissues were observed by H-E staining. The total and phosphorylated form of Akt and GSK-3beta protein expressions were measured by western blot. The ratio of Bcl-2/Bax at mRNA level was detected by reverse transcription-polymerase chain reaction (RT-PCR). Results: DEX significantly reduced plasma CK-MB, MDA concentration, and LDH level and increased SOD activity caused by I/R. The phosphorylation of Akt and GSK 3beta was increased, Bcl-2 mRNA and the Bcl-2/Bax ratio was increased, and Bax mRNA was decreased in the DEX group as compared to the I/R group, while posttreatment with Wort attenuated the effects induced by DEX. Conclusion: The results of this study suggest that DEX postconditioning may increase the phosphorylation of GSK-3beta by activating the PI3K/Akt signaling pathway and may inhibit apoptosis and oxidative stress of the myocardium, thus exerting protective effects in diabetic rat hearts suffering from I/R injury. PMID- 30402500 TI - Bidirectional Relationship between Gastric Emptying and Plasma Glucose Control in Normoglycemic Individuals and Diabetic Patients. AB - Gastric emptying and glycemic control pathways are closely interrelated processes. Gastric chyme is transferred into the duodenum with velocities depending on its solid or liquid state, as well as on its caloric and nutritional composition. Once nutrients enter the intestine, the secretion of incretins (hormonal products of intestinal cells) is stimulated. Among incretins, glucagon like peptide-1 (GLP-1) has multiple glycemic-regulatory effects that include delayed gastric emptying, thus triggering a feedback loop lowering postprandial serum glucose levels. Glycemic values also influence gastric emptying; hyperglycemia slows it down, and hypoglycemia accelerates it, both limiting glycemic fluctuations. Disordered gastric emptying in diabetes mellitus is understood today as a complex pathophysiological condition, with both irreversible and reversible components and high intra- and interindividual variability of time span and clinical features. While limited delays may be useful for reducing postprandial hyperglycemias, severely hindered gastric emptying may be associated with higher glycemic variability and worsened long term glycemic control. Therapeutic approaches for both gastric emptying and glycemic control include dietary modifications of meal structure or content and drugs acting as GLP-1 receptor agonists. In the foreseeable future, we will probably witness a wider range of dietary interventions and more incretin-based medications used for restoring both gastric emptying and glycemic levels to nearly physiological levels. PMID- 30402502 TI - Role of Tight Glycemic Control during Acute Coronary Syndrome on CV Outcome in Type 2 Diabetes. AB - Both incidence and mortality of acute coronary syndrome (ACS) among diabetic patients are much higher than those among nondiabetics. Actually, there are many studies that addressed glycemic control and CV risk, whilst the literature on the role of tight glycemic control during ACS is currently poor. Therefore, in this review, we critically discussed the studies that investigated this specific topic. Hyperglycemia is implicated in vascular damage and cardiac myocyte death through different molecular mechanisms as advanced glycation end products, protein kinase C, polyol pathway flux, and the hexosamine pathway. Moreover, high FFA concentrations may be toxic in acute ischemic myocardium due to several mechanisms, thus leading to endothelial dysfunction. A reduction in free fatty acid plasma levels and an increased availability of glucose can be achieved by using a glucose-insulin-potassium infusion (GIKi) during AMI. The GIKi is associated with an improvement of either long-term prognosis or left ventricular mechanical performance. DIGAMI studies suggested blood glucose level as a significant and independent mortality predictor among diabetic patients with recent ACS, enhancing the important role of glucose control in their management. Several mechanisms supporting the protective role of tight glycemic control during ACS, as well as position statements of Scientific Societies, were highlighted. PMID- 30402505 TI - Autoimmunity and Otolaryngology Diseases. PMID- 30402503 TI - Association between Early Neuroretinal Dysfunction and Peripheral Motor Unit Loss in Patients with Type 1 Diabetes Mellitus. AB - Objectives: It has been already confirmed that retinal neurodegeneration has a predictive value in the development of microvascular alterations in diabetic retinopathy. However, no data are available on the association between neuroretinal dysfunction and peripheral motor unit loss. Our study, therefore, was aimed at investigating the hypothesis that retinal neurodegeneration could be considered an early marker of diabetic peripheral neuropathy (DPN). Methods: 20 T1DM patients with no symptoms/signs of peripheral polyneuropathy, without DR or with very mild nonproliferative DR, and 14 healthy controls (C) age- and gender matched were enrolled. The following electrophysiological tests were performed: standard nerve conduction studies (NCS) and incremental motor unit number estimation (MUNE) from the abductor hallux (AH) and abductor digiti minimi (ADM). Neuroretinal function was studied by multifocal electroretinogram (MfERG) recordings, measuring response amplitude density (RAD) and implicit time (IT) from rings and sectors of superior (S)/inferior (I)/temporal (T)/nasal (N) macular sectors up to 10 degrees of foveal eccentricity. Results: MfERG RADs from rings and sectors were significantly reduced in T1DM (p < 0.05) vs. C. ADM MUNE and AH MUNE were significantly decreased in T1DM (p = 0.039 and p < 0.0001, respectively) vs. C. A positive correlation between mean MfERG RADs from the central 5 degrees of the four (S, I, T, and N) macular sectors and lower limb motor unit number (r = 0.50, p = 0.041; r = 0.64, p = 0.005; r = 0.64, p = 0.006; and r = 0.61, p = 0.010, respectively) was observed in T1DM patients. No abnormalities of NCS were found in any subject. Conclusions: The motor unit loss on the one hand and neuroretinal dysfunction on the other hand are already present in T1DM patients without DPN. The relationship between neuroretinal dysfunction and motor unit decline supports the hypothesis that neuroretina may represent a potential "window" to track the early neurogenic damage in diabetes. PMID- 30402504 TI - OK-432 Acts as Adjuvant to Modulate T Helper 2 Inflammatory Responses in a Murine Model of Asthma. AB - Enhanced type 2 helper T (Th2) cell responses to inhaled harmless allergens are strongly associated with the development of allergic diseases. Antigen formulated with an appropriate adjuvant can elicit suitable systemic immunity to protect individuals from disease. Although much has been learned about Th1-favored immunomodulation of OK-432, a streptococcal preparation with antineoplastic activity, little is known about its adjuvant effect for allergic diseases. Herein, we demonstrate that OK-432 acts as an adjuvant to favor a systemic Th1 polarization with an elevation in interferon- (IFN-) gamma and ovalbumin- (OVA-) immunoglobulin (Ig) G2a. Prior vaccination with OK-432 formulated against OVA attenuated lung eosinophilic inflammation and Th2 cytokine responses that were caused by challenging with OVA through the airway. This vaccination with OK-432 augmented the ratios of IFN-gamma/interleukin- (IL-) 4 cytokine and IgG2a/IgG1 antibody compared to the formulation with Th2 adjuvant aluminum hydroxide (Alum) or antigen only. The results obtained in this study lead us to propose a potential novel adjuvant for clinical use such as prophylactic vaccination for pathogens and immunotherapy in atopic diseases. PMID- 30402507 TI - Downregulation of Interleukin- (IL-) 17 through Enhanced Indoleamine 2,3 Dioxygenase (IDO) Induction by Curcumin: A Potential Mechanism of Tolerance towards Helicobacter pylori. AB - The anti-inflammatory and antimicrobial properties of curcumin suggest its use as an anti-Helicobacter pylori (H. pylori) agent, but mechanisms underlying its helpful activity are still not clear. Indoleamine 2,3-dioxygenase (IDO) promotes the effector T cell apoptosis by catalyzing the rate-limiting first step in tryptophan catabolism, and its high expression in H. pylori-infected human gastric mucosa attenuates Th1 and Th17 immune response. The aim of this study was to investigate the role of curcumin in modulating the expression of IL-17 and IDO in H. pylori-infected human gastric mucosa. In an organ culture chamber, gastric biopsies from 35 patients were treated with and without 200 MUM curcumin. In H. pylori-infected patients (n = 21), IL-17 was significantly lower, both in gastric biopsies (p = 0.0003) and culture supernatant (p = 0.0001) while IDO significantly increased (p < 0.00001) in curcumin-treated sample compared with untreated samples. In a subgroup of H. pylori-infected patients (n = 15), samples treated with curcumin in addition to IDO inhibitor 1-methyl-L-tryptophan (1-MT) showed a higher expression of IL-17 compared with untreated samples and curcumin treated alone (p < 0.00001). Curcumin downregulates IL-17 production through the induction of IDO in H. pylori-infected human gastric mucosa, suggesting its role in dampening H. pylori-induced immune-mediated inflammatory changes. PMID- 30402506 TI - TNIP1 in Autoimmune Diseases: Regulation of Toll-like Receptor Signaling. AB - TNIP1 protein is increasingly being recognized as a key repressor of inflammatory signaling and a potential factor in multiple autoimmune diseases. In addition to earlier foundational reports of TNIP1 SNPs in human autoimmune diseases and TNIP1 protein-protein interaction with receptor regulating proteins, more recent studies have identified new potential interaction partners and signaling pathways likely modulated by TNIP1. Subdomains within the TNIP1 protein as well as how they interact with ubiquitin have not only been mapped but inflammatory cell- and tissue-specific consequences subsequent to their defective function are being recognized and related to human disease states such as lupus, scleroderma, and psoriasis. In this review, we emphasize receptor signaling complexes and regulation of cytoplasmic signaling steps downstream of TLR given their association with some of the same autoimmune diseases where TNIP1 has been implicated. TNIP1 dysfunction or deficiency may predispose healthy cells to the inflammatory response to otherwise innocuous TLR ligand exposure. The recognition of the anti-inflammatory roles of TNIP1 and improved integrated understanding of its physical and functional association with other signaling pathway proteins may position TNIP1 as a candidate target for the design and/or testing of next generation anti-inflammatory therapeutics. PMID- 30402508 TI - Complement System as a Target for Therapies to Control Liver Regeneration/Damage in Acute Liver Failure Induced by Viral Hepatitis. AB - The complement system plays an important role in innate immunity inducing liver diseases as well as signaling immune cell activation in local inflammation regulating immunomodulatory effects such as liver damage and/or liver regeneration. Our aim is to evaluate the role of complement components in acute liver failure (ALF) caused by viral hepatitis, involving virus-induced ALF in human subjects using peripheral blood, samples of liver tissues, and ex vivo assays. Our findings displayed low levels of C3a in plasma samples with high frequency of C3a, C5a, and C5b/9 deposition in liver parenchyma. Meanwhile, laboratory assays using HepG2 (hepatocyte cell line) showed susceptibility to plasma samples from ALF patients impairing in vitro cell proliferation and an increase in apoptotic events submitting plasma samples to heat inactivation. In summary, our data suggest that the complement system may be involved in liver dysfunction in viral-induced acute liver failure cases using ex vivo assays. In extension to our findings, we provide insights into future studies using animal models for viral-induced ALF, as well as other associated soluble components, which need further investigation. PMID- 30402509 TI - Acer palmatum thumb. Ethanol Extract Alleviates Interleukin-6-Induced Barrier Dysfunction and Dextran Sodium Sulfate-Induced Colitis by Improving Intestinal Barrier Function and Reducing Inflammation. AB - Ulcerative colitis is one inflammatory bowel disease (IBD) and is caused by diverse factors, including the extent and duration of intestinal inflammation. We investigated the effect of Acer palmatum thumb. ethanol extract (KIOM-2015E) on the expression of tight junction proteins and the levels of inflammation in the cell model induced with interleukin-6- (IL-6-) and mouse model of dextran sodium sulfate (DSS) induced with acute colitis. KIOM-2015E (100 mg/kg) was orally administered once per day to BALB/C mice with colitis induced by administration of 5% DSS in drinking water. KIOM-2015E did not affect viability in Caco-2 cells. Also, KIOM-2015E repaired the IL-6-induced intestinal barrier dysfunction in Caco 2 cells. Furthermore, KIOM-2015E recovered the loss of body weight and the abnormally short colon lengths in the DSS-induced model of acute colitis. Moreover, KIOM-2015E significantly inhibited the decrease of zonula occluden-1 and occludin in colonic tissue relative to the DSS-treated control group. KIOM 2015E also significantly inhibited the expression of IL-6 and tumor necrosis factor-alpha in the level of serum relative to the control group. Collectively, these data suggest that KIOM-2015E protects colitis principally by improving intestinal barrier function and promoting anti-inflammatory responses. In turn, these effects inhibit macrophage infiltration into the colon and thus may be a candidate treatment for IBD. PMID- 30402510 TI - Immunoinformatics Approach for Epitope-Based Peptide Vaccine Design and Active Site Prediction against Polyprotein of Emerging Oropouche Virus. AB - Oropouche virus (OROV) is an emerging pathogen which causes Oropouche fever and meningitis in humans. Several outbreaks of OROV in South America, especially in Brazil, have changed its status as an emerging disease, but no vaccine or specific drug target is available yet. Our approach was to identify the epitope based vaccine candidates as well as the ligand-binding pockets through the use of immunoinformatics. In this report, we identified both T-cell and B-cell epitopes of the most antigenic OROV polyprotein with the potential to induce both humoral and cell-mediated immunity. Eighteen highly antigenic and immunogenic CD8+ T-cell epitopes were identified, including three 100% conserved epitopes (TSSWGCEEY, CSMCGLIHY, and LAIDTGCLY) as the potential vaccine candidates. The selected epitopes showed 95.77% coverage for the mixed Brazilian population. The docking simulation ensured the binding interaction with high affinity. A total of five highly conserved and nontoxic linear B-cell epitopes "NQKIDLSQL," "HPLSTSQIGDRC," "SHCNLEFTAITADKIMSL," "PEKIPAKEGWLTFSKEHTSSW," and "HHYKPTKNLPHVVPRYH" were selected as potential vaccine candidates. The predicted eight conformational B cell epitopes represent the accessibility for the entered virus. In the posttherapeutic strategy, ten ligand-binding pockets were identified for effective inhibitor design against emerging OROV infection. Collectively, this research provides novel candidates for epitope-based peptide vaccine design against OROV. PMID- 30402513 TI - Exclusive versus Inclusive Trauma System Model in High Volume Trauma Regions. PMID- 30402511 TI - Lipid and Bile Acid Dysmetabolism in Crohn's Disease. AB - Crohn's disease is one of the systemic autoimmune diseases. It commonly affects the small intestine and colon but may involve any portion of the gastrointestinal tract from the mouth to the anus. The most affected area by Crohn's disease is the distal part of the small intestine, in which the bile acid molecules are most efficiently reabsorbed. Bile acids form mixed micelles together with fatty acids, which function as a transport vehicle to deliver fatty acids to the apical membrane of enterocytes for absorption. Therefore, if the terminal ileum is impaired, bile acid malabsorption may occur, which may cause congenital diarrhoea in Crohn's disease. Similarly, the impairment of the terminal ileum also induces fatty acid malabsorption, which may influence the role of fatty acids in Crohn's disease. In contrast, a recent study reported that multidrug resistance protein 1 (MDR1) regulated effector T-cell function in the ileum from bile acid-driven oxidative stress and MDR1 loss of function in a subset of patients with Crohn's disease. However, the role of consumption of fatty acids in Crohn's disease remains to be fully elucidated. This review is aimed at providing an overview of some recent developments in research of Crohn's disease from comprehensive perspective with a focus on the connection between disease location and behaviour, lipid diets, and bile acid malabsorption. PMID- 30402512 TI - Reduced Activity of HDAC3 and Increased Acetylation of Histones H3 in Peripheral Blood Mononuclear Cells of Patients with Rheumatoid Arthritis. AB - Aberrant histone acetylation and deacetylation are increasingly thought to play important roles in the pathogenesis of rheumatoid arthritis (RA). However, limited data from studies about the activity of histone deacetylases (HDACs) and histone acetyltransferase (HAT) in RA are controversial. Those conflicting results may be caused by sample size, medication, and age- and sex-matched controls. The aim of this study is to investigate the expression and activity of class I HDACs (1-3.8) and their effects on histone acetylation in peripheral blood mononuclear cells (PBMCs) from RA patients. The expression of class I HDACs in PBMCs from RA patients was decreased in both mRNA and protein levels in comparison with HCs. The nuclear HAT activities were dramatically increased. Further, we found HDAC3 activity to be the most significantly reduced in overall reduction of HDACs in the RA group. The extent of total histone H3, but not H4, acetylation in PBMCs from RA patients was increased compared to that in healthy controls (HCs) (p < 0.01). In RA PBMCs, the activity and expression of class I HDACs are decreased, which is accompanied with enhanced HAT activity. An altered balance between HDAC and HAT activity was found in RA PBMCs. PMID- 30402514 TI - Diagnostic Accuracy of Rapid Ultrasound in Shock (RUSH) Exam; A Systematic Review and Meta-analysis. AB - Objective: To perform a diagnostic accuracy of the rapid ultrasound in shock (RUSH) to diagnose the etiology of undifferentiated shock in patients presenting to the emergency department (ED). Methods: We searched the Medline via PubMed, Scopus, and ISI Web of Knowledge till July 2017. Two independent reviewers screened studies for eligibility. Our study analysis is planned in accordance with the guidelines for meta-analysis of diagnostic studies. In the systematic search, of 397 references, 295 were excluded on the basis of the title and abstract. For the remaining 102 articles, the full text was retrieved and critically reviewed. After the selection process, five papers were included. Results: The pooled estimate of all data showed that the RUSH protocol exhibited high sensitivity (0.87, 95% Confidence Interval (CI): 0.80-0.92, I2 = 46.7%) and specificity (0.98, 95% C. I.: 0.96-0.99, I2 = 30.8%). The AUC for SROC, a global measure of the RUSH protocol performance, was 0.98 +/- 0.01, indicates the high accuracy of the test. Positive and negative likelihood ratios reported from the studies ranged from 9.83 to 51.32 and 0.04 to 0.33, respectively. The pooled estimate of all data showed that the RUSH protocol exhibited high positive likelihood ratio (19.19, 95% C. I.: 11.49-32.06, I2 = 14.1%) and low negative likelihood ratio (0.23, 95% C. I.: 0.15-0.34, I2 = 18.4%). Conclusion: This meta analysis suggests that RUSH protocol has generally good role to distinguish the states of shock in patients with undifferentiated shock referred to the emergency department. PMID- 30402516 TI - Effect of Intramuscular Ketamine versus Haloperidol on Short-Term Control of Severe Agitated Patients in Emergency Department; A Randomized Clinical Trial. AB - Objective: To evaluate the efficacy and safety of intramuscular ketamine and haloperidol in sedation of severely agitated patients in emergency department (ED). Methods: This randomized, double-blind clinical trial study was performed on agitated patients referring to two university educational hospitals. Patients were randomly assigned to receive intramuscular (IM) haloperidol (5 mg) or IM ketamine (4 mg/kg). The primary outcome was time to adequate sedation (AMSS <= +1). Secondary outcomes included the need for additional sedatives, required intubation, duration of hospitalization, and side effects. Results: The 90 agitated patients were enrolled. The mean age was 30.37+/-7.36 years (range 18 56); 74% (67/90) were men. The mean time to adequate sedation in ketamine group (7.73 +/- 4.71 minutes) was significantly lower than haloperidol group (11.42 +/- 7.20 minutes) (p= 0.005). 15 minutes after intervention, the sedation score did not differ significantly in both groups (Ketamine:0.14 +/- 0.59 vs. Haloperidol: 0.30 +/- 0.60; p=0.167). The incidence of complications was not significantly different between groups. The physician's satisfaction from the patients' aggression control was significantly higher in ketamine group. Conclusion: These data suggest ketamine may be used for short-term control of agitated patients, additional studies are needed to confirm if ketamine is safe in this patient population. Given rapid effective sedation and the higher physician satisfaction of ketamine in comparison to haloperidol, it may be considered as a safe and appropriate alternative to haloperidol.IRCT Code: IRCT20180129038549N5. PMID- 30402515 TI - Epidemiology of Road Traffic Injuries among Elderly People; A Systematic Review and Meta-Analysis. AB - Objective: To systematically review the epidemiological patterns and interventions for prevention of road traffic injuries (RTIs) among elderly. Methods: Searching keywords including: accident, trauma, road injury, road traffic injuries, aging, old, elder, strategy, intervention, road traffic crash prevention and traffic accident in databases including, Google scholar, SID, IranMedex, PubMed and Scopus. English and non-Persian articles, articles presented in congresses, articles that considered elderly people to have age under than 60 years were excluded. The reporting quality of articles was assessed by two experts using Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) check list. Results: RTIs compromised 23.6% of total injuries among elderly. The most frequent injuries were about car accidents (51.4%). Pedestrian injuries composed 48.1% of the RTIs. Head and neck (32.1%) were most injured body parts. There was a significant difference between elderly and non-elderly people in terms of RTIs associated mortality (Odd=2.57 [1.2-5.4 CI 95%]). Overall 25 main domains of intervention and 73 subordinate domains were extracted in five categories (human, road and environment, tools and cars, medical, legal and political issues). Conclusion: According to the notable prevalence and fatality of RTIs, lack of sufficient studies and valid evidence of the present study can provide an appropriate evidence for better interventions for RTIs prevention among elderly. PMID- 30402517 TI - The Effect of Hyoscine on Pain, Tenderness, and Rebound Tenderness in Patients with Appendicitis: Quasi-Interventional Study. AB - Objective: To evaluate the effect of hyoscine on pain and tenderness, rebound tenderness and appendicitis patients before surgery and this study can be considered as the first study investigated the efficacy of hyoscine on pain, tenderness, and rebound tenderness in patients with appendicitis. Methods: In this single-group, prospective interventional study (before-after) according to inclusion and exclusion criteria, 70 patients with pain in the right lower abdomen and typical symptoms of appendicitis were evaluated and after surgery, diagnostic accuracy was examined by pathologic results. The pain was evaluated before and after administration of hyoscine by numerical and verbal examination. Tenderness and rebound tenderness were also determined. Results: The mean age of patients was 26.81+/-7.66. Totally, 42 patients (60%) had reduction in pain, 50 patients (71% percent) had reduction in tenderness, and 39 (55%) had reduction in rebound tenderness after treatment with the drug. A statistically significant reduction of pain and tenderness, rebound tenderness was observed in all of men after administration of hyoscine (p<0.001) but in women, the reduction of severity of tender results was only significant (p=0.002). Data analysis in women and men together showed the significant reduction of pain, tenderness, and rebound tenderness (p<0.001). Conclusion: According to the results, hyoscine can reduce pain, tenderness, and rebound tenderness. So, it seems that hyoscine is a good candidate for patients with appendicitis. IRCT registration number: IRCT2015111825123N1. PMID- 30402518 TI - Outcome of Extra-Articular Distal Humerus Fractures Fixed by Single Column Extra Articular Distal Humerus Locking Compression Plate Using Triceps Sparing Postero Lateral Approach. AB - Objective: To determine the time to radiological union and final functional outcome of fixation of extra-articular distal humeral fractures with extra artricular distal humerus locking plate. Methods: This prospective study was conducted from March 2014 to February 2018 and included extra-articular distal humeral fractures managed by operative fixation using extra-articular distal humerus locking plate. All the fractures were approached using lateral para tricepetal approach of Gervin, and stabilized with extra-articular distal humerus locking plate with or without lag screws. Time to radiological union was assessed in the follow up and at the final follow up functional outcome was evaluated using Mayo Performance Elbow Score (MEPS). Complications and need for any additional procedures was also recorded. Results: A total of 20 patients with mean age of 36.5 years and an average follow up of 17 months were included. The mean time to radiological union was 17.4 weeks (12 to 36 weeks) which included one delayed union that required bone grafting. The mean flexion at elbow was 127o with only one patient having flexion extension arc movement of less than 100o at the final follow up. The average MEPS at final follow up was 94.7+/-8 with 19 patients having excellent and good results. Conclusion: Use of extra-articular distal humeral locking plate using lateral para-tricepetal approach in extra articular distal humeral fractures allows stable fixation of the fracture to allow early return to function with minimal soft tissue dissection and excellent final functional results and minimum complications. PMID- 30402519 TI - Pattern and Distribution of Shock Index and Age Shock Index Score Among Trauma Patients in Towards Improved Trauma Care Outcomes (TITCO) Dataset. AB - Objective: To compare the shock index (SI - which is the ratio of heart rate to systolic blood pressure) and Age SI (Age in years multiplied by SI) with survival outcome of the patients across multicenter trauma registry in India. Methods: Study is based on Towards Improved Trauma Care Outcomes (TITCO) project. Records with valid details of age, heart rate, systolic blood pressure, Injury Severity Scale (ISS) and Glasgow Coma Scale (GCS) score was considered. SI was categorized into four groups; Group I (SI<0.6) as no shock, group II (SI >=0.6 to <1.0) as mild shock, group III (SI >=1.0 to <1.4) as moderate shock and group IV (SI >=1.4) as severe shock. Age SI was categorized decade wise into six groups. Mortality was dependent variable. GCS and ISS were considered as secondary variables. Results: 10843 participants from TITCO registry satisfying inclusion exclusion criteria were considered for study. Mean SI score in group I to IV was increasing with 0.53 to 1.72 respectively. Age SI was seen to be increasing across its six groups. Gender wise no difference was found among SI group. For severe ISS and critical ISS, mortality in SI group IV was 50% and 56 % respectively. Mortality was increasing across mild to severe GCS among all SI groups. Conclusion: The categorized SI and Age SI had shown increase in death percentages from mild to severe severity of injuries. Similar to GCS and ISS, SI and Age SI should also be calculated and categorized in all health care and further plan for management aspects. PMID- 30402520 TI - Prognostic Value of Arterial Blood Gas Indices Regarding the Severity of Traumatic Injury and Fractures of the Femur and Pelvis. AB - Objective: To evaluate the prognostic value of arterial blood gas (ABG) indices, especially base excess (BE), regarding the severity of traumatic injury. Methods: A total number of 96 trauma patients with fractures of femur and pelvis were included in this study. Demographic characteristics and clinical information of samples were recorded. The results of ABG test and hemoglobin (Hb) were evaluated at two time intervals (on admission and 6 hours later). The outcome of the patients was evaluated at the end of the study (dead or alive). The ABG indices included O2 saturation (O2Sat), PH, PO2, PCO2, bicarbonate (HCO3) and base excess (BE). The mean of the hemodynamic and ABG indices were compared between those who were discharged and mortality cases. The confounders were compensated using a multivariate logistic regression model. Results: Overall 94 trauma patients with long and pelvic fractures were included. There were 69 (73.4%) men and 25 (26.6%) women among the patients with mean age of 37.43 +/- 20.07 years. The mortality rate was 10 (10.6%). The most common mechanism of injury was motorcycle accident in 41 (43.6%) and car collision in 43 (45.7%) patients. We found that mortality was significantly associated with amount of FFP transfusion (p=0.005), but was not associated with amount of transfused packed cells (p=0.113). We also found that mortality was associated with lower BP after 6 hours of admission (p=0.001), higher HR on admission (p=0.036), lower HR after 6 hours (p=0.017), lower O2Sat on admission (p<0.001), higher PCO2 after 6 hours and lower BE on admission (p=0.025). Conclusion: The ABG indices including O2Sat, BE and PCO2 are considered prognostic determinants of outcome in trauma patients with long and pelvic fractures. These findings can be considered as fundamental studies to achieve new diagnostic methods. PMID- 30402521 TI - Effects of Body Mass Index on Outcome Measures of the Patients with Penetrating Injuries; A Single Center Experience. AB - Objective: To determine if there was any decrease in measures of injury severity or outcome with obese patients (body mass index greater than or equal to 30 kg/m2) as compared to non-obese patients (body mass index less than 30 kg/m2). Methods: We conducted a retrospective review of the trauma database maintained by Natividad Medical Center's Level 2-Trauma program. From July 1st, 2014 to July 1st, 2017 there were 371 cases of penetrating trauma in adults between the ages of 18-80 years old. Overall 311 patients had BMI data recorded. We divided these 311 patients into two groups: penetrating injury due to firearm (n= 198) and penetrating injury due to stabbing or piercing (n=113). We compared non-obese patients against obese patients for age, gender, Injury Severity Score (ISS), length of stay (LOS), Intensive Care Unit LOS, units of blood given, direct transfer from ED to operating room, and mortality. Results: A total of 311 patients were included in the study, 198 (63.6%) patients suffered from gunshot wounds and 113 (36.4) from stab or piercing wounds. The mean age was 33.6 +/- 12.8 and there were 283 (91%) men among the victims. Overall 87 (28%) required emergent surgery and a 19 (6.1%) mortality rate was recorded. In the gunshot wound group there was no significant difference between non-obese and obese patients for age (p=0.400), gender (p=0.900), ISS (p=0.544), LOS (p=0.273), Intensive Care Unit LOS (p=0.729), units of blood given (p=0.300), or mortality (p=0.855). We found that in the stab or piercing group there was no significant difference between non-obese and obese patients for age (p=0.900), gender (p=0.900), ISS (p=0.580), LOS (p=0.839), Intensive Care Unit LOS (p=0.305), units of blood given (p=0.431), or mortality (p=0.321). Conclusion: Our findings indicate that in our patient population, there was no significant difference in markers of injury severity, morbidity, or mortality in adult non-obese patients as comparted with obese patients. Furthermore, there was no significant difference between the two groups in operative rates, suggesting that obesity may not confer a protective effect in penetrating trauma. PMID- 30402522 TI - Validity and Reliability of the Emergency Severity Index and Australasian Triage System in Pediatric Emergency Care of Mofid Children's Hospital in Iran. AB - Objective: To evaluate the validity, reliability, sensitivity, and specificity of the Emergency Severity Index (ESI) and Australasian Triage System (ATS) for children visiting admitted to the emergency department (ED). Methods: This was a prospective study occurred in the Mofid children's Hospital in Iran from August 2017 to November 2018 and children had aged <=14 years and presented at the ED with a medical symptom were considered eligible for participation. This study was divided into two phases: in the first phase, we determined the inter-rater reliability of ESI version 4 and ATS by triage nurses and pediatric residents. In the second phase, to analyze the validity, sensitivity, and specificity of each triage system. Reliability and agreement rates were measured using kappa statistics. Results: ESI showed inter-rater reliability with kappa of 0.65-0.92 (P<0.001) and ATS showed inter-rater reliability with kappa of 0.51-0.87 ESI had sensitivity ranged from 81% to 95% and specificity ranged from 73% to 86%. In addition, sensitivity ranged of the ATS were 80% to 95% and specificity ranged from 74% to 87%. Under triage and over triage occurred in 12% and 15% of patients respectively in ESI and 13% and 15% of patients respectively in ATS. Conclusion: The ESI and ATS both valid to triage children in the ED section of Mofid children's Hospital paediatric. Reliability of the ESI is good, moderate to good for the ATS. PMID- 30402523 TI - Assessment of Care and its Associated Factors in Traumatic Patients in North of Iran. AB - Objective: To determine the status of pre-hospital emergency care and its associated factors in traumatic patients. Methods: In across-sectional study, 577 traumatic patients who were transferred to Poursina hospital by EMS (Emergency Medical Services) personnel were selected by simple random sampling method. Pre hospital emergency services were observed. Then the mean of taken measures scores for each domain was determined in percent and evaluated in terms of associated factors (age, working experience of staff and number of missions per day) and compared using Spearman's test. Results: Out of 577 patients, 454 were men (78.7%) and 123 women (21.3%). Their mean age was 35.1 years old. Accident (82.7%) was the most common mechanism of injury. Most vehicles involved in the accident were light -weight cars (48.5%) and motorcycles (32.2%). A significant relationship was found between age, general domain (p=0.039) and hemodynamic (p=0.019) as well as between work experience and general domain (p=0.018). Conclusion: Given that pre-hospital emergency services provided in most of the domains are relatively far from world standard, results of this research can provide information for managers to improve strategic planning on care and medical services, appropriation of budget, knowledge of personnel and necessary equipment. PMID- 30402524 TI - Analysis and Forecasting the Accident Mortality Trends in the Islamic Republic of Iran Applying Lee-Carter Model During the Years 2006 to 2035. AB - Objective: To predict the accident mortality trend in next two decades in Iran. Methods: The study population comprised all deaths recorded in the system of registration and classification of causes of death of Ministry of Health and Medical Education of Iran during the years 2006 to 2015. The information was collected via death certificate, burial permit, and reporting forms. To forecast the trends of causes-of-death, Lee Carter model was employed in a demographic package 18.1 of R software version 3.3.1. Results: Based on the results, the highest percentage of all causes of death from accidents (in unintentional accidents) goes to transport accidents, and most top intentional accidents belonged to intentional self-harm. The trends of unintentional accidents in the whole population and both sexes have reduced from 2006 to 2035, such that the rate has reduced from 62.2 in 2006 to 12.1 per 100 thousand populations in 2035. It is anticipated that the causes of death due to intentional accidents with the rate of 8.86 in 2006, will be 1.89 (per 100,000 population) in the year 2035. Conclusion: Accident mortalities have a significant role in the deaths of Iranian population; therefore, to reduce the impact of accident mortality on society, a precise approach is needed to monitor the trends as well as preventing measures and increasing the safety standards. PMID- 30402525 TI - Analysis of Risk Factors with Hospital Mortality in Pedestrian Injured Patients; A Dataset Analysis of a Level-I Trauma Center in Southern Iran. AB - Objective: To determine the indicators predicting the hospital mortality in pedestrian injured patients admitted to a level I trauma center in Southern Iran. Methods: This case control study was conducted in a Level-I trauma hospital in Shiraz. We selected all survived pedestrians who were admitted in the hospital with duration of admission more than 24 hours in one year from March 2016 to February 2017 as control group and compared with all non-survived pedestrian patients who expired in the hospital according to clinical from March 2012 to February 2017. Multiple logistic regression was performed to identify factors of hospital effect on pedestrian mortality and results expressed by Odds Ratios and their confidence intervals (CI) of 95%. Results: A total of 424 survived pedestrian injured patients were compare to 117 non-survived one. Their mean of survived and non-survived patients were 43.79 +/- 19.37 and 56.76 +/- 18.55 years respectively of which 361 (66.7%) and 180 (33.3%) were men and women, respectively. We found that the gender does not have any relation with hospital mortality (p=0.275). Followed by, age is in relevance with mortality. Glasgow Coma Scale(GCS), Injury Severity Score (ISS), blood urea nitrogen (BUN), platelet (PLT), potassium (K) and hemoglobin (Hb) are significant factor which are associated with mortality. According to logistic analysis GCS <=8 (p<0.001), low hemoglobin level <9 (p=0.030), BUN >24 (p<0.001), thrombocytopenia <150,000 (p<0.001), and hypokalemia <3.5 (p=0.01) were independently associated with hospital mortality. Among them, GCS<=8 was 72.237 times more likely to be associated with hospital mortality (OR =72.24, CI95% =23.19- 225.05). Conclusion: The results suggest that GCS score, ISS, hemoglobin level, platelet count, BUN and potassium level might be independent factors associated with hospital mortality in pedestrian injured patients. PMID- 30402527 TI - Spontaneous Bacterial Peritonitis in Afebrile Cirrhotic Patients; Report from a Referral Transplantation Center. AB - Spontaneous bacterial peritonitis (SBP) is a complication of liver cirrhosis with adverse effect on patient prognosis. Early diagnosis and treatment is highly important, especially in patients without remarkable manifestations. We designed this study to determine the prevalence of SBP among afebrile cirrhotic patients and identify high-risk subgroups in a referral center in southern Iran. This cross-sectional study evaluated all afebrile cirrhotic patients, admitted to the gastroenterology ward of Namazi hospital (affiliated with Shiraz University of Medical Sciences, Shiraz, Iran) over a 6-month period in 2017, for the presence and correlates of SBP. Demographic data, clinical findings, and comorbidities were recorded. Ascitic fluid white blood cells (WBC) count >500 and neutrophil count >250 indicated bacterial peritonitis. In total, 97 afebrile cirrhotic patients comprising of 63 (64.9%) men and 34 (35.1%) women were included. All patients had ascites and 89 (91.8%) had abdominal tenderness. Accordingly, abdominal distension was the top presentation. Confirmed etiologies or comorbidities such as HBS, HCV, and liver cancer or metastasis existed in 46 patients. Thirteen (13.4%) had SBP. The correlations of gender (p=0.331), decreased level of consciousness (p=0.145), tenderness (p=0.315). With regards to the type of presentations, only DLOC showed to be significantly higher in SBP negative patients (p=0.022, OR=0.09. 95%CI=0.01-0.62). Also, using binary logistic regression, the correlation of age with SBP was statistically non significant (coefficient= ?0.013, p=0.595). Our findings indicated that routine paracentesis in all cirrhotic patients regardless of fever can help diagnose a number of potentially neglected patients and improve their outcome. PMID- 30402526 TI - Antimicrobial Survey of Local Herbal Drugs against Acinetobacter baumannii Isolated from Patients Admitted to a Level-I Trauma Center. AB - Objective: To determine the antimicrobial activity and entity of several local herbal plants against Acintobacters isolated from trauma patients admitted to a Level-I trauma center. Methods: The antibacterial activities of the Satureja bachtiarica oil and someselected Iranian medicinal plants (Artemisia sieberi and Tanacetum dumosum belonging to the Asteraceae/Compositae; Salvia mirzayanii and Mentha mozaffarianii belonging to the Lamiaceae/Labiatae) were assayed on A. baumannii by microdilution and agar disc diffusion methods. Having obtained the acceptable antibacterial data, the shade-dried aerial parts of the plants were extracted by hydrodistillation method using Clevenger apparatus according to European pharmacopeia for 3 h. The analysis of S. bachtiarica essential oil accompanied by other herbal drug oils were performed by using GC/FID and GC/MS methods. Results: Outcomes revealed that the S. bachtiarica essential oil exhibited the potent antibacterial capability against Acinetobacter strains in comparison with Colistin, as a positive control. For S. bachtiarica,the growth inhibition zone and minimum inhibitory concentration (MIC) values were 21 mm and 0.5 mg/ml, while, for Colistin, the data were in order: 8 mm and 0.016 mg/ml. Consequently, GC/MS outcomes demonstrated that the major components of the essence were carvacrol (48.6%), followed by p-Cymene (16.6%), gamma-terpinene (6.9%) and linalool (5.3%). Conclusion: Based on the considerable inhibitory activity against nosocomial infections by essential oil of S. bachtiarica, it could be considered as the suitable candidate in the food industry and pharmaceutical uses. PMID- 30402528 TI - Surgical Management of Adult Traumatic Atlantoaxial Rotatory Subluxation with Unilateral Locked Facet; Case Report and Literature Review. AB - Atlantoaxial rotatory subluxation (AARS) is rarely occurred in adults with trauma as the most common cause. In type A and B it is usually managed with close reduction and external brace; however, in nonresponsive cases, surgical interventions might be needed. Our patient is a 21-year-old man with neck pain and torticollis after a car turn- over. There was C1-C2 rotatory subluxation with left side locked facet and C1 rotation about 40 degrees relative to C2 on computed tomography without evident of ligamentous injury in magnetic resonance imaging (MRI). However, during the first 48 hours, two tries of close reduction using Gardner cervical traction under fluoroscopy were failed. Thus, the patient underwent open reduction of the subluxation and atlantoaxial fixation (Harm's technique) with subsequent relief of pain and torticollis. This a rare case of traumatic AARS type A with unilateral locked facet joint in an adult patient which needed surgical manipulation for reduction. The management of the AARS in adults should be individualized in each patient. PMID- 30402529 TI - Intrauterine Fetal Traumatic Brain Injury Following Motor Vehicle Accident; A Case Report and Review of the Literature. AB - Trauma, especially traumatic injuries due to car accidents are one of the causes of maternal and fetal mortality and morbidity during pregnancy. Fetus brain injuries are usually caused fetus death. We herein report a pregnant woman in 28 weeks of gestation. The fetus was found to be normal during in-hospital. At birth, the female neonate demonstrated developmental delay and neurological deficits (hypotonicity). Neuroimaging after birth revealed extreme dilatation of lateral ventricles, hypoplasia and aplasia of the brain. In 4 months, she had multiple morbidities including developmental delay, hypotonia, blindness, oropharyngeal dysphagia and simple partial seizure. Motor and response to stimulation was normal. Appropriate seatbelt usage can protect the fetus from sustaining severe intracranial injuries. PMID- 30402530 TI - Isolated Mesenteric Injury causing Ileal Devascularisation with Uterine Perforation following Termination of Pregnancy; A Case Report and Literature Review. AB - Surgical abortion is one of the leading causes of maternal mortality, constituting up to 20% of maternal deaths. Uterine perforation is a rare complication, accounting for4% of all the abortion related complications. Intestinal injury with uterine perforation following termination of pregnancy is even rare and is a potentially fatal complication with mortality of up to 10%. A 27-year-old G3P2L2 woman with 12 weeks of gestation referred to our hospital in hemorrhagic shock with a suspicion of uterine perforation following dilatation and curettage for termination of pregnancy. Patient underwent emergency laparotomy. She was found to have uterine perforation with mesenteric and ileal injuries intraoperatively. Perforation closure with ileoileal resection and anastomosis was done. Postoperatively the patient recovered completely. Prompt reporting/recognition of uterine perforation, preoperative resuscitation and early intervention are the most important steps in the management of patients with intestinal injury. Trauma surgeon should never hesitate or delay in considering an Emergency Laparotomy/laparoscopy in cases of suspected intestinal injury with uterine perforation. Emergency exploration decreases the morbidity and mortality to a great extent in patients with intestinal injury. PMID- 30402531 TI - Post-Surgical Transitory Inferior Subluxation of Shoulder. PMID- 30402532 TI - Epidemiology of Diabetic Foot Infection in the Metro-Detroit Area With a Focus on Independent Predictors for Pathogens Resistant to Recommended Empiric Antimicrobial Therapy. AB - Background: The polymicrobial nature of diabetic foot infection (DFI) and the emergence of antimicrobial resistance have complicated DFI treatment. Current treatment guidelines for deep DFI recommend coverage of methicillin-resistant Staphylococcus aureus (MRSA) and susceptible Enterobacteriaceae. This study aimed to describe the epidemiology of DFI and to identify predictors for DFI associated with multidrug-resistant organisms (MDROs) and pathogens resistant to recommended treatment (PRRT). Methods: Adult patients admitted to Detroit Medical Center from January 2012 to December 2015 with DFI and positive cultures were included. Demographics, comorbidities, microbiological history, sepsis severity, and antimicrobial use within 3 months before DFI were obtained retrospectively. DFI PRRT was defined as a DFI associated with a pathogen resistant to both vancomycin and ceftriaxone. DFI-MDRO pathogens included MRSA in addition to PRRT. Results: Six-hundred forty-eight unique patients were included, with a mean age of 58.4 +/ 13.7 years. DFI-MDRO accounted for 364 (56%) of the cohort, and 194 (30%) patients had DFI-PRRT. Independent predictors for DFI-PRRT included history of PRRT in a diabetic foot ulcer, antimicrobial exposure in the prior 90 days, peripheral vascular disease, and chronic kidney disease. Long-term care facility residence was independently associated with DFI due to ceftriaxone-resistant Enterobacteriaceae, and recent hospitalization was an independent predictor of DFI due to vancomycin-resistant Enterococcus. Conclusions: An unexpectedly high prevalence of DFI-PRRT pathogens was identified. History of the same pathogen in a prior diabetic foot ulcer and recent antimicrobial exposure were independent predictors of DFI-PRRT and should be considered when selecting empiric DFI therapy. PMID- 30402533 TI - Cardiologist and Diabetologist crosstalk in the era of cardiovascular outcome trials of novel glucose-lowering drugs. AB - The prevalence of type 2 diabetes continues to increase and cardiovascular (CV) diseases remain the leading cause of death in diabetic patients. Diabetologists and Cardiologists have to work together in order to provide the best management to these patients. After years of disappointing studies showing no reduction of CV events with strict glycaemic control, some of the novel glucose-lowering drugs (GLDs) seem to offer a new approach to tackle the problem, since the CV outcome trials (CVOTs-D) of liraglutide, semaglutide, empagliflozin and canagliflozin have demonstrated not only their CV safety but also their efficacy in the reduction of CV morbidity and mortality. Along with the initial enthusiasm, concerns have been raised about the economical sustainability of long-term therapies considering higher costs of new molecules relative to the traditional ones. As expenses in the medical field are on the rise, healthcare systems need to balance the positive impact of an intervention and its overall cost. This review is meant to offer the Cardiologists a different point of view on the positive influence of GLDs, in the light of the main trials in the CV fields they are familiar with. The purpose of this article is to critically review the magnitude of the CVOTs-D results by the analysis of their statistical determinants, to establish the extent of the GLDs positive impact on patients with both diabetes and CV disease. The analysis has been performed taking into account models and statistical determinants used in the main landmark cardiology trials. It is fundamental to translate the result of CVOTs-D in clinical practice: the interdisciplinary crosstalk between the Cardiologist and Diabetologist is of paramount importance in order to fully exploit the power of the new available pharmacological strategies. PMID- 30402534 TI - Primary PCI versus pharmacoinvasive strategy for ST elevation myocardial infarction. AB - Background: The rationale for pharmacoinvasive strategy is that many patients have a persistent reduction in flow in the infarct-related artery. The aim of the present study is to assess safety and efficacy of pharmacoinvasive strategy using streptokinase compared to primary PCI and ischemia driven PCI on degree of myocardial salvage and outcomes. Methods and results: Sixty patients with 1st attack of acute STEMI within 12 h were randomized to 4 groups: primary PCI for patients presented to PPCI-capable centers (group I), transfer to PCI if presented to non-PCI capable center (group II), pharmacoinvasive strategy "Streptokinase followed by PCI within 3-24 h" (group III) and fibrinolytic followed by ischemia driven PCI (group IV). The primary endpoint is the infarction size and microvascular obstruction (MVO) measured by cardiac MRI (CMR) 3-5 days post-MI. Pharmacoinvasive strategy led to a significant reduction in infarction size, MVO and major adverse cardiac and cerebrovascular event (MACCE) compared to group IV but minor bleeding was significantly higher compared to other groups. Conclusions: Pharmacoinvasive strategy resulted in effective reperfusion and smaller infarction size in patients with early STEMI who could not undergo primary PCI within 2 h after the first medical contact. This can provide a wide time window for PCI when the application of primary PCI within the optimal time limit is not possible. However, it was associated with a slightly increased risk of minor bleeding. PMID- 30402535 TI - Climate change stimulated agricultural innovation and exchange across Asia. AB - Ancient farmers experienced climate change at the local level through variations in the yields of their staple crops. However, archaeologists have had difficulty in determining where, when, and how changes in climate affected ancient farmers. We model how several key transitions in temperature affected the productivity of six grain crops across Eurasia. Cooling events between 3750 and 3000 cal. BP lead humans in parts of the Tibetan Plateau and in Central Asia to diversify their crops. A second event at 2000 cal. BP leads farmers in central China to also diversify their cropping systems and to develop systems that allowed transport of grains from southern to northern China. In other areas where crop returns fared even worse, humans reduced their risk by increasing investment in nomadic pastoralism and developing long-distance networks of trade. By translating changes in climatic variables into factors that mattered to ancient farmers, we situate the adaptive strategies they developed to deal with variance in crop returns in the context of environmental and climatic changes. PMID- 30402536 TI - A new mathematical model to explore microbial processes and their constraints in phytoplankton colonies and sinking marine aggregates. AB - N2-fixing colonies of cyanobacteria and aggregates of phytoplankton and detritus sinking hundreds of meters per day are instrumental for the ocean's sequestration of CO2 from the atmosphere. Understanding of small-scale microbial processes associated with phytoplankton colonies and aggregates is therefore crucial for understanding large-scale biogeochemical processes in the ocean. Phytoplankton colonies and sinking aggregates are characterized by steep concentration gradients of gases and nutrients in their interior. Here, we present a mechanistic mathematical model designed to perform modeling of small-scale fluxes and evaluate the physical, chemical, and biological constraints of processes that co-occur in phytoplankton colonies and sinking porous aggregates. The model accurately reproduced empirical measurements of O2 concentrations and fluxes measured in sinking aggregates. Common theoretical assumptions of either constant concentration or constant flux over the entire surface did not apply to sinking aggregates. Consequently, previous theoretical models overestimate O2 flux in these aggregates by as high as 15-fold. PMID- 30402537 TI - Projected changes in persistent extreme summer weather events: The role of quasi resonant amplification. AB - Persistent episodes of extreme weather in the Northern Hemisphere summer have been associated with high-amplitude quasi-stationary atmospheric Rossby waves, with zonal wave numbers 6 to 8 resulting from the phenomenon of quasi-resonant amplification (QRA). A fingerprint for the occurrence of QRA can be defined in terms of the zonally averaged surface temperature field. Examining state-of-the art [Coupled Model Intercomparison Project Phase 5 (CMIP5)] climate model projections, we find that QRA events are likely to increase by ~50% this century under business-as-usual carbon emissions, but there is considerable variation among climate models. Some predict a near tripling of QRA events by the end of the century, while others predict a potential decrease. Models with amplified Arctic warming yield the most pronounced increase in QRA events. The projections are strongly dependent on assumptions regarding the nature of changes in radiative forcing associated with anthropogenic aerosols over the next century. One implication of our findings is that a reduction in midlatitude aerosol loading could actually lead to Arctic de-amplification this century, ameliorating potential increases in persistent extreme weather events. PMID- 30402538 TI - Organic synthesis on Mars by electrochemical reduction of CO2. AB - The sources and nature of organic carbon on Mars have been a subject of intense research. Steele et al. (2012) showed that 10 martian meteorites contain macromolecular carbon phases contained within pyroxene- and olivine-hosted melt inclusions. Here, we show that martian meteorites Tissint, Nakhla, and NWA 1950 have an inventory of organic carbon species associated with fluid-mineral reactions that are remarkably consistent with those detected by the Mars Science Laboratory (MSL) mission. We advance the hypothesis that interactions among spinel-group minerals, sulfides, and a brine enable the electrochemical reduction of aqueous CO2 to organic molecules. Although documented here in martian samples, a similar process likely occurs wherever igneous rocks containing spinel-group minerals and/or sulfides encounter brines. PMID- 30402540 TI - Do slow slip events trigger large and great megathrust earthquakes? AB - Slow slip events have been suggested to trigger subduction earthquakes. However, examples to date have been poorly recorded, occurring offshore, where data are sparse. Better understanding of slow slip events and their influence on subsequent earthquakes is critical for hazard forecasts. We analyze a well recorded event beginning 6 months before the 2012 M w (moment magnitude) 7.6 earthquake in Costa Rica. The event migrates to the eventual megathrust rupture. Peak slip rate reached a maximum of 5 mm/day, 43 days before the earthquake, remaining high until the earthquake. However, changes in Mohr-Coulomb failure stress at the hypocenter were small (0.1 bar). Our data contradict models of earthquake nucleation that involve power law acceleration of slip and foreshocks. Slow slip events may prove useful for short-term earthquake forecasts. PMID- 30402539 TI - Universal intracellular biomolecule delivery with precise dosage control. AB - Intracellular delivery of mRNA, DNA, and other large macromolecules into cells plays an essential role in an array of biological research and clinical therapies. However, current methods yield a wide variation in the amount of material delivered, as well as limitations on the cell types and cargoes possible. Here, we demonstrate quantitatively controlled delivery into a range of primary cells and cell lines with a tight dosage distribution using a nanostraw electroporation system (NES). In NES, cells are cultured onto track-etched membranes with protruding nanostraws that connect to the fluidic environment beneath the membrane. The tight cell-nanostraw interface focuses applied electric fields to the cell membrane, enabling low-voltage and nondamaging local poration of the cell membrane. Concurrently, the field electrophoretically injects biomolecular cargoes through the nanostraws and into the cell at the same location. We show that the amount of material delivered is precisely controlled by the applied voltage, delivery duration, and reagent concentration. NES is highly effective even for primary cell types or different cell densities, is largely cargo agnostic, and can simultaneously deliver specific ratios of different molecules. Using a simple cell culture well format, the NES delivers into >100,000 cells within 20 s with >95% cell viability, enabling facile, dosage controlled intracellular delivery for a wide variety of biological applications. PMID- 30402541 TI - Mass spectrometry imaging of the in situ drug release from nanocarriers. AB - It is crucial but of a great challenge to study in vivo and in situ drug release of nanocarriers when developing a nanomaterial-based drug delivery platform. We developed a new label-free laser desorption/ionization mass spectrometry (MS) imaging strategy that enabled visualization and quantification of the in situ drug release in tissues by monitoring intrinsic MS signal intensity ratio of loaded drug over the nanocarriers. The proof of concept was demonstrated by investigating the doxorubicin (DOX)/polyethylene glycol-MoS2 nanosheets drug delivery system in tumor mouse models. The results revealed a tissue-dependent release behavior of DOX during circulation with the highest dissociation in tumor and lowest dissociation in liver tissues. The drug-loaded MoS2 nanocarriers are predominantly distributed in lung, spleen, and liver tissues, whereas the accumulation in the tumor was unexpectedly lower than in normal tissues. This new strategy could also be extended to other drug-carrier systems, such as carbon nanotubes and black phosphorus nanosheets, and opened a new path to evaluate the drug release of nanocarriers in the suborgan level. PMID- 30402542 TI - A single-cell survey of the human first-trimester placenta and decidua. AB - The placenta and decidua interact dynamically to enable embryonic and fetal development. Here, we report single-cell RNA sequencing of 14,341 and 6754 cells from first-trimester human placental villous and decidual tissues, respectively. Bioinformatic analysis identified major cell types, many known and some subtypes previously unknown in placental villi and decidual context. Further detailed analysis revealed proliferating subpopulations, enrichment of cell type-specific transcription factors, and putative intercellular communication in the fetomaternal microenvironment. This study provides a blueprint to further the understanding of the roles of these cells in the placenta and decidua for maintenance of early gestation as well as pathogenesis in pregnancy-related disorders. PMID- 30402544 TI - Wintertime stress, nursing, and lead exposure in Neanderthal children. AB - Scholars endeavor to understand the relationship between human evolution and climate change. This is particularly germane for Neanderthals, who survived extreme Eurasian environmental variation and glaciations, mysteriously going extinct during a cool interglacial stage. Here, we integrate weekly records of climate, tooth growth, and metal exposure in two Neanderthals and one modern human from southeastern France. The Neanderthals inhabited cooler and more seasonal periods than the modern human, evincing childhood developmental stress during wintertime. In one instance, this stress may have included skeletal mobilization of elemental stores and weight loss; this individual was born in the spring and appears to have weaned 2.5 years later. Both Neanderthals were exposed to lead at least twice during the deep winter and/or early spring. This multidisciplinary approach elucidates direct relationships between ancient environments and hominin paleobiology. PMID- 30402543 TI - Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma. AB - A methionine substitution at lysine-27 on histone H3 variants (H3K27M) characterizes ~80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits polycomb repressive complex 2 (PRC2) in a dominant-negative fashion. Yet, the mechanisms for this inhibition and abnormal epigenomic landscape have not been resolved. Using quantitative proteomics, we discovered that robust PRC2 inhibition requires levels of H3K27M greatly exceeding those of PRC2, seen in DIPG. While PRC2 inhibition requires interaction with H3K27M, we found that this interaction on chromatin is transient, with PRC2 largely being released from H3K27M. Unexpectedly, inhibition persisted even after PRC2 dissociated from H3K27M-containing chromatin, suggesting a lasting impact on PRC2. Furthermore, allosterically activated PRC2 is particularly sensitive to H3K27M, leading to the failure to spread H3K27me from PRC2 recruitment sites and consequently abrogating PRC2's ability to establish H3K27me2-3 repressive chromatin domains. In turn, levels of polycomb antagonists such as H3K36me2 are elevated, suggesting a more global, downstream effect on the epigenome. Together, these findings reveal the conditions required for H3K27M-mediated PRC2 inhibition and reconcile seemingly paradoxical effects of H3K27M on PRC2 recruitment and activity. PMID- 30402546 TI - Case Series about the Changed Antiplatelet Protocol for Carotid Endarterectomy in a Teaching Hospital: More Patients with Complications? AB - Introduction In the Netherlands, clopidogrel monotherapy increasingly replaces acetylsalicylic acid and extended release dipyridamole as the first-choice antiplatelet therapy after ischemic stroke. It is unknown whether the risk of peri- and postoperative hemorrhage in carotid artery surgery is higher in patients using clopidogrel monotherapy compared with acetylsalicylic acid and extended release dipyridamole. We therefore retrospectively compared occurrence of perioperative major and (clinical relevant) minor bleedings during and after carotid endarterectomy of two groups using different types of platelet aggregation inhibition after changing our daily practice protocol in our center. Material and Methods A consecutive series of the most recent 80 carotid endarterectomy patients (November 2015-August 2017) treated with the new regime (clopidogrel monotherapy) were compared with the last 80 (January 2012-November 2015) consecutive patients treated according to the old protocol (acetylsalicylic acid and dipyridamole). The primary endpoint was any major bleeding during surgery or in the first 24 to 72 hours postoperatively. Secondary outcomes within 30 days after surgery included minor (re)bleeding postoperative stroke with persistent or transient neurological deficit, persisting or transient neuropraxia, asymptomatic restenosis or occlusion, (transient) headache. Reporting of this study is in line with the 'Strengthening the Reporting of Observational Studies in Epidemiology' statement. Results Although statistical differences were observed, from a clinical perspective both patients groups were comparable. Postoperative hemorrhage requiring reexploration for hemostasis occurred in none of the 80 patients in the group of the clopidogrel monotherapy (new protocol) and it occurred in one of the 80 patients (1%) who was using acetylsalicylic acid and dipyridamole (old protocol). In three patients (4%) in the clopidogrel monotherapy and one patient (1%) in the acetylsalicylic acid and extended release dipyridamole protocol an ipsilateral stroke was diagnosed. Conclusion In this retrospective consecutive series the incidence of postoperative ischemic complications and perioperative hemorrhage after carotid endarterectomy (CEA) seemed to be comparable in patients using clopidogrel monotherapy versus acetylsalicylic acid and extended release dipyridamole for secondary prevention after a cerebrovascular event. This study fuels the hypothesis that short- and midterm complications of clopidogrel and the combination acetylsalicylic acid and extended release dipyridamole are comparable. PMID- 30402545 TI - High-throughput screening for selective appetite modulators: A multibehavioral and translational drug discovery strategy. AB - How appetite is modulated by physiological, contextual, or pharmacological influence is still unclear. Specifically, the discovery of appetite modulators is compromised by the abundance of side effects that usually limit in vivo drug action. We set out to identify neuroactive drugs that trigger only their intended single behavioral change, which would provide great therapeutic advantages. To identify these ideal bioactive small molecules, we quantified the impact of more than 10,000 compounds on an extended series of different larval zebrafish behaviors using an in vivo imaging strategy. Known appetite-modulating drugs altered feeding and a pleiotropy of behaviors. Using this multibehavioral strategy as an active filter for behavioral side effects, we identified previously unidentified compounds that selectively increased or reduced food intake by more than 50%. The general applicability of this strategy is shown by validation in mice. Mechanistically, most candidate compounds were independent of the main neurotransmitter systems. In addition, we identified compounds with multibehavioral impact, and correlational comparison of these profiles with those of known drugs allowed for the prediction of their mechanism of action. Our results illustrate an unbiased and translational drug discovery strategy for ideal psychoactive compounds and identified selective appetite modulators in two vertebrate species. PMID- 30402547 TI - New treatment method for pain and reduction of local anesthesia use in deep caries. AB - Chemo-mechanical caries removal methods are known to be more effective compared with conventional methods in pain reduction. Carie-careTM, a chemo-mechanical caries removal agent, was introduced in 2010 but a systematic review of its efficacy has not yet been performed. The purpose of this study was to investigate the effectiveness of Carie-careTM on the outcomes of treatment of caries in children and adolescents. The primary outcome was pain while the secondary outcomes included complete caries removal (CCR), time, need for local anesthesia and behavioral response changes. A Comprehensive literature search was performed in PubMed, EMBASE, and the Cochrane Library up to 30 September 2018. The following keywords were used in the search: 'chemo-mechanical caries removal agent', 'dental caries', 'Carie-care', 'chemo-mechanical caries removal', 'chemo mechanical caries excavation', other related keywords, and their combinations. From 942 studies identified, 16 were analyzed. Finally, 4 studies met the eligibility criteria and 260 teeth in 120 children and adolescents were included in this review. This review showed that Carie-careTM reduces pain during caries treatment but requires a longer time for effective treatment than conventional methods. Local anesthesia was not required in the Chemo-mechanical caries removal (CMCR) group. In addition, dental anxiety decreased compared to the control group, and co-operation was more positive. Therefore, it may be a useful alternative to conventional methods in children and adolescents, but further verification through additional studies is needed. PMID- 30402548 TI - Local anesthesia for mandibular third molar extraction. AB - Mandibular third molar extraction is commonly performed in dental clinics. However, the optimal method of anesthesia has not been established for this procedure. The conventional inferior alveolar nerve block is the most widely used method. However, its success rate is not high and it may lead to complications, such as aspiration and nerve injury. Therefore, various anesthesia methods are being investigated. Articaine has been proven to be efficacious in a number of studies and is being used with increasing frequency in clinical practice. In this review article, we will briefly review various local anesthesia techniques, anesthetics, and a computer-controlled local anesthetic delivery (CCLAD) system, which reduces pain by controlling the speed of drug injection, for mandibular third molar extraction. PMID- 30402549 TI - Optimal effective-site concentration of remifentanil for sedation during plate removal of maxilla. AB - Background: Removal of the plate following Le Fort I osteotomy and BSSO (bilateral sagittal split osteotomy) is a common procedure. However, patients who undergo plate removal experience intense pain and discomfort. This study investigated the half-maximal effective concentration (Ce50 ) of remifentanil in the prevention of plate removal pain under sedation using dexmedetomidine. Methods: The study evaluated 18 patients, between 18 and 35 years of age, scheduled for elective surgery. Remifentanil infusion was initiated after sedation using dexmedetomidine, and started at a dose of 1.5 ng/mL on the first patient via target-controlled infusion (TCI). Patients received a loading dose of 1.0 ug/kg dexmedetomidine over 10 min, followed by a maintenance dose of 0.7 ug/kg/h. When the surgeon removed the plate, the patient Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score was observed. Results: The Ce of remifentanil ranged from 0.9 to 2.1 ng/mL for the patients evaluated. The estimated effect-site concentrations of remifentanil associated with a 50% and 95% probability of reaching MOAA/S score of 3 were 1.28 and 2.51 ng/mL, respectively. Conclusions: Plate removal of maxilla can be successfully performed without any pain or adverse effects by using the optimal remifentanil effect-site concentration (Ce50 , 1.28 ng/mL; Ce95 , 2.51 ng/mL) combined with sedation using dexmedetomidine. PMID- 30402550 TI - Awake fiberoptic nasotracheal intubation for patients with difficult airway. AB - Awake fiberoptic nasotracheal intubation is a useful technique, especially in patients with airway obstruction. It must not only provide sufficient anesthesia, but also maintain spontaneous breathing. We introduce a method to achieve this using a small dose of fentanyl and midazolam in combination with topical anesthesia. The cases of 2 patients (1 male, 1 female) who underwent oral maxillofacial surgery are reported. They received 50 ug of fentanyl 2-3 times (total 2.2-2.3 ug/kg) at intervals of approximately 2 min. Oxygen was administered via a mask at 6 L/min, and 0.5 mg of midazolam was administered 1-4 times (total 0.02-0.05 mg/kg) at intervals of approximately 2 min. A tracheal tube was inserted through the nasal cavity after topical anesthesia was applied to the epiglottis, vocal cords, and into the trachea through the fiberscope channel. All patients were successfully intubated. This is a useful and safe method for awake fiberoptic nasotracheal intubation. PMID- 30402551 TI - Medical adhesive related skin injury after dental surgery. AB - An 87-year-old woman was referred for the extraction of residual teeth and removal of tori prior to prosthetic treatment. After surgery under general anesthesia, the surgical tape was removed to detach the bispectral index sensor and the hair cover. After the surgical tape was removed, skin injury occurred on the left side of her face. After epidermis repositioning and ointment application, a dressing was placed over the injury. Her wound was found to have healed completely on follow-up examination. Medical adhesive related skin injury (MARSI) is a complication that can occur after surgery and subjects at the extremes of age with fragile skin are at a higher risk for such injuries. Careful assessment of the risk factors associated with MARSI is an absolute necessity. PMID- 30402552 TI - Airway management in pediatric tongue flap division for oronasal fistula closure: A case report. AB - Oronasal fistulae (ONF) could remain after surgery in some patients with cleft palate. ONF ultimately requires intraoral surgery, which may lead to perioperative airway obstruction. Tongue flap surgery is a technique used to repair ONF. During the second surgery for performing tongue flap division, the flap transplanted from the tongue dorsum to the palate of the patient acts as an obstacle to airway management, which poses a great challenge for anesthesiologists. In particular, anesthesiologists may face difficulty in airway evaluation and patient cooperation during general anesthesia for tongue flap division surgery in pediatric patients. The authors report a case of airway management using a flexible fiberoptic bronchoscope during general anesthesia for tongue flap division surgery in a 6-year-old child. PMID- 30402553 TI - Revisiting the awake retrograde nasal intubation technique. PMID- 30402554 TI - History and significance of the trauma resuscitation flow sheet. AB - There is little to no written information in the literature regarding the origin of the trauma flow sheet. This vital document allows programs to evaluate initial processes of trauma care. This information populates the trauma registry and is reviewed in nearly every Trauma Process Improvement and Patient Safety conference when discerning the course of patient care. It is so vital, a scribe is assigned to complete this documentation task for all trauma resuscitations, and there are continual process improvement efforts in trauma centers across the nation to ensure complete and accurate data collection. Indeed, it is the single most important document reviewed by the verification committee when evaluating processes of care at site visits. Trauma surgeons often overlook its importance during resuscitation, as recording remains the domain of the trauma scribe. Yet it is the first document scrutinized when the outcome is less than what is expected. The development of the flow sheet is not a result of any consensus statement, expert work group, or mandate, but a result of organic evolution due to the need for relevant and better data. The purpose of this review is to outline the origin, importance, and critical utility of the trauma flow sheet. PMID- 30402555 TI - Joint management format at the mixed-surgical intermediate care unit: an interrupted time series analysis. AB - Background: The management format of the mixed-surgical intermediate care unit (IMCU) affects its performance. A format of combined supervision of surgeons with additional critical care certifications and admitting specialists, named the "joint format", may herein be a promising new model of specialized critical care. This study aims to assess the performance of the joint management format. Methods: This observational cohort study compared three IMCU management formats at the stand-alone, mixed-surgical IMCU of a tertiary referral hospital using interrupted time series analyses. All admissions from 2001 until 2015 were included. Predetermined criteria for performance (utilization, efficiency, and safety) were applied to three different management format periods: open (2001 2006), closed (2006-2011), and joint (2011-2015) formats. Results: A total of 8894 admissions were analyzed. In terms of case load (utilization), there was an overall increase in the number of surgical patients (0.25%/year) (p<0.001), age (0.38/year) (p<0.001), and readmissions from the ward (0.16%/year) (p<0.001) and from the intensive care unit (ICU) (0.17%/year) (p=0.014). In terms of efficiency, the admission duration decreased (1.58 hours/year) (p<0.001). Transfer to the ICU within 24 hours, readmission within 24 hours from the ward, and unplanned mortality (eg, safety) did not change over time. Discussion: At a time of increasingly complex case load, the joint format at the mixed-surgical IMCU is an efficient and safe management format in which the admitting specialist continues to provide specialized care. Specialty-specific supervision at IMCUs is a safe option which should be considered in healthcare policy decisions. Level of evidence: Level IV. PMID- 30402556 TI - Experience with uncrossmatched blood refrigerator in emergency department. AB - Background: Uncrossmatched packed red blood cell (PRBC) transfusion is fundamental in resuscitation of hemorrhagic shock. Ready availability of uncrossmatched blood can be achieved by storing uncrossmatched blood in a blood bank refrigerator in the emergency department (ED), but could theoretically lead to inappropriate uncrossmatched use. Methods: This retrospective study was performed at a level I trauma center from January 2013 to March 2014. Possibly inappropriate transfusion was defined as patients who received at least one unit of blood from the ED refrigerator and no more than two units of PRBC in the first 24 hours. Deaths within the first 24 hours were excluded. Patients who received blood from the ED refrigerator who received <=2 units total in 24 hours were compared with those who received >2 units. Results: 158 adults received blood from the ED refrigerator. 140 (88.6%) were trauma patients. 37 (23.4%) received massive transfusion (MT). 42 (26.6%) deaths were excluded. 29 patients received <=2 units and 87 received >2 units in the first 24 hours. The <=2 units group had a higher systolic blood pressure (116 mm Hg vs. 102 mm Hg, p=0.042), lower base deficit (6.4 mEq/L vs. 9.4 mEq/L, p=0.032), higher hematocrit (34% vs. 30%, p=0.024), lower rate of MT protocol activation (27.6% vs. 58.6%, p=0.005), and lower rates of transfusion of fresh frozen plasma (17.2% vs. 54.0%, p=0.001) and platelets (13.8% vs. 39.1%, p=0.012). Appropriately transfused patients were more likely to have evidence of shock with active, non-compressible hemorrhage. Potentially inappropriate uses were more likely in patients either without evidence of hemorrhage or without signs of shock. Discussion: Storing uncrossmatched blood in the ED is an effective way to get PRBCs transfused quickly in hemorrhaging patients and is associated with a low rate of unnecessary uncrossmatched transfusion. Provider education and good clinical judgment are imperative to prevent unnecessary use. Level of evidence: Level III, therapeutic. PMID- 30402557 TI - Evaluation of the Georgia trauma system using the American College of Surgeons Needs Based Assessment of Trauma Systems tool. AB - Background: The American College of Surgeons Needs Based Assessment of Trauma Systems (NBATS) tool was developed to help determine the optimal regional distribution of designated trauma centers (DTC). The objectives of our current study were to compare the current distribution of DTCs in Georgia with the recommended allocation as calculated by the NBATS tool and to see if the NBATS tool identified similar areas of need as defined by our previous analysis using the International Classification of Diseases, Ninth Revision, Clinical Modification Injury Severity Score (ICISS). Methods: Population counts were acquired from US Census publications. Transportation times were estimated using digitized roadmaps and patient zip codes. The number of severely injured patients was obtained from the Georgia Discharge Data System for 2010 to 2014. Severely injured patients were identified using two measures: ICISS<0.85 and Injury Severity Score >15. Results: The Georgia trauma system includes 19 level I, II, or III adult DTCs. The NBATS guidelines recommend 21; however, the distribution differs from what exists in the state. The existing DTCs exactly matched the NBATS recommended number of level I, II, or III DTCs in 2 of 10 trauma service areas (TSAs), exceeded the number recommended in 3 of 10 TSAs, and was below the number recommended in 5 of 10 TSAs. Densely populated, or urban, areas tend to be associated with a higher number of existing centers compared with the NBATS recommendation. Other less densely populated TSAs are characterized by large rural expanses with a single urban core where a DTC is located. The identified areas of need were similar to the ones identified in the previous gap analysis of the state using the ICISS methodology. Discussion: The tool appears to underestimate the number of centers needed in extensive and densely populated areas, but recommends additional centers in geographically expansive rural areas. The tool signifies a preliminary step in assessing the need for state-wide inpatient trauma center services. Level of evidence: Economic, level IV. PMID- 30402558 TI - Banning open carry of unloaded handguns decreases firearm-related fatalities and hospital utilization. AB - Background: Since 1967, in California it has been illegal to openly carry a loaded firearm in public except when engaged in hunting or law enforcement. However, beginning January 1, 2012, public open carry of unloaded handguns also became illegal. Fatal and non-fatal (NF) firearm injuries were examined before and after adoption of the 2012 ban to quantify the effect of the new law on public health. Methods: State-level data were obtained directly from California and nine other US state inpatient and emergency department (ED) discharge databases, and the Centers for Disease Control Web-Based Injury Statistics Query and Reporting System. Case numbers of firearm fatalities, NF hospitalizations, NF ED visits, and state-level population estimates were extracted. Each incident was classified as unintentional, self-inflicted, or assault. Crude incidence rates were calculated. The strength of gun laws was quantified using the Brady grade. There were no changes to open carry in these nine states during the study. Using a difference-in-difference technique, the rate trends 3 years preban and postban were compared. Results: The 2012 open carry ban resulted in a significantly lower incident rate of both firearm-related fatalities and NF hospitalizations (p<0.001). The effect of the law remained significant when controlling for baseline state gun laws (p<0.001). Firearm incident rate drops in California were significant for male homicide (p=0.023), hospitalization for NF assault (p=0.021 male; p=0.025 female), and ED NF assault visits (p=0.04). No significant decreases were observed by sex for suicides or unintentional injury. Changing the law saved an estimated 337 lives (3.6% fewer deaths) and 1285 NF visits in California during the postban period. Discussion: Open carry ban decreases fatalities and healthcare utilization even in a state with baseline strict gun laws. The most significant impact is from decreasing firearm-related fatal and NF assaults. Level of evidence: III, epidemiology. PMID- 30402560 TI - AAST statement on firearm injury. PMID- 30402559 TI - Improving survival after an emergency resuscitative thoracotomy: a 5-year review of the Trauma Quality Improvement Program. AB - Background: Advancement in trauma care has led to the evolution of emergency resuscitative thoracotomy (ERT) for the revival of trauma patients. We now have more precise understanding of selecting suitable patients for achieving optimal outcomes. The aim of our study was to analyze the utilization and survival trends during the past 5 years, as well as factors that influence survival after ERT. Methods: A 5-year (2010-2014) analysis of all trauma patients >=18 years who underwent ERT in the American College of Surgeons Trauma Quality Improvement Program. Outcome measures were utilization rates and survival trends after ERT during the 5-year period. Regression analysis was performed. Results: 2229 patients underwent ERT, mean age was 37+/-17 years, 81% were male. Overall 56% patients had penetrating mechanism, location of major injury was thorax in 48, and 71% had signs of life (SOL) on arrival. The overall survival rate was 9.6%. From 2010-2014 ERT utilization has decreased from 331/100 000 to 243/100 000 trauma admissions (p=0.002) and the survival rate has improved from 7.9% to 11.3% (p<0.001). On regression, the independent predictors of survival were penetrating mechanism, age<60 years, SOL on arrival, no prehospital CPR and ISS. No patient aged >60 years with a blunt mechanism of injury (MOI) survived, and there were no survivors above the age of 70 years, regardless of injury mechanism. Discussion: Utilization of ERT has been decreased during the study period along with improved survival rates. The results of our study demonstrate that performing ERT on patients aged >60 years with a blunt MOI or on any patient aged >=70 years, regardless of MOI, is futile and should be avoided. Level of evidence: Level III, prognostic studies. PMID- 30402561 TI - Mass casualty events: what to do as the dust settles? AB - Care during mass casualty events (MCE) has improved during the last 15 years. Military and civilian collaboration has led to partnerships which augment the response to MCE. Much has been written about strategies to deliver care during an MCE, but there is little about how to transition back to normal operations after an event. A panel discussion entitled The Day(s) After: Lessons Learned from Trauma Team Management in the Aftermath of an Unexpected Mass Casualty Event at the 76th Annual American Association for the Surgery of Trauma meeting on September 13, 2017 brought together a cadre of military and civilian surgeons with experience in MCEs. The events described were the First Battle of Mogadishu (1993), the Second Battle of Fallujah (2004), the Bagram Detention Center Rocket Attack (2014), the Boston Marathon Bombing (2013), the Asiana Flight 214 Plane Crash (2013), the Baltimore Riots (2015), and the Orlando Pulse Night Club Shooting (2016). This article focuses on the lessons learned from military and civilian surgeons in the days after MCEs. PMID- 30402562 TI - Early and late complications of bariatric operation. AB - Weight loss surgery is one of the fastest growing segments of the surgical discipline. As with all medical procedures, postoperative complications will occur. Acute care surgeons need to be familiar with the common problems and their management. Although general surgical principles generally apply, diagnoses specific to the various bariatric operations must be considered. There are anatomic considerations which alter management priorities and options for these patients in many instances. These problems present both early or late in the postoperative course. Bariatric operations, in many instances, result in permanent alteration of a patient's anatomy, which can lead to complications at any time during the course of a patient's life. Acute care surgeons diagnosing surgical emergencies in postbariatric operation patients must be familiar with the type of surgery performed, as well as the common postbariatric surgical emergencies. In addition, surgeons must not overlook the common causes of an acute surgical abdomen-acute appendicitis, acute diverticulitis, acute pancreatitis, and gallstone disease-for these are still among the most common etiologies of abdominal pathology in these patients. PMID- 30402563 TI - Optimizing critical care of the trauma patient at the intermediate care unit: a cost-efficient approach. AB - Background: The aim of this study was to describe the case load, safety, and cost savings of critical care of the trauma patient provided at the surgical intermediate care unit (IMCU). Methods: This cohort study included all trauma admissions between January 1, 2011 and January 7, 2015 at the general intensive care unit (ICU), stand-alone neuro(surgical) IMCU, and stand-alone (trauma) surgical IMCU. Trauma mechanism, Abbreviated Injury Scale score and Injury Severity Score (ISS), vital signs, laboratory parameters, admission duration, intubation duration, ICU transfer, and in-hospital mortality were prospectively collected. Hypothetical cost savings were calculated using the fixed cost price per IMCU (US$1500) and ICU (US$2500) admission day. Results: A total of 1320 admissions were included, 675 (51.1%) at the IMCU and 645 (48.9%) at the ICU. Patients admitted at the IMCU had a median ISS of 17 (11, 22). Their median duration of admission was 32.8 hours (18.8, 62.5). At the IMCU, one patient died due to aneurogenic shock. A subsequent ICU transfer was required in 38 (5.6%) IMCU admissions. Of these transfers, four patients died due to neurological deterioration. At the ICU, the median ISS was 22 (14, 30). Nearly all (n=620, 96.3%) ICU trauma patients required mechanical ventilation. Expected total cost savings due to the presence of the IMCU were US$1 772 785. Discussion: A substantial amount of trauma patients in need of critical care can safely be admitted at the IMCU, without the need for further mechanical ventilation. Thereby, the IMCU could fulfill an essential cost-saving role in the management of severely injured trauma patients. Level of evidence: Level IV. PMID- 30402566 TI - Taking a giant step forward to become a premier journal in urology. PMID- 30402564 TI - Laboratory measures of coagulation among trauma patients on NOAs: results of the AAST-MIT. AB - Background: Warfarin is associated with poor outcomes after trauma, an effect correlated with elevations in the international normalized ratio (INR). In contrast, the novel oral anticoagulants (NOAs) have no validated laboratory measure to quantify coagulopathy. We sought to determine if use of NOAs was associated with elevated activated partial thromboplastin time (aPTT) or INR levels among trauma patients or increased clotting times on thromboelastography (TEG). Methods: This was a post-hoc analysis of a prospective observational study across 16 trauma centers. Patients on dabigatran, rivaroxaban, or apixaban were included. Laboratory data were collected at admission and after reversal. Admission labs were compared between medication groups. Traditional measures of coagulopathy were compared with TEG results using Spearman's rank coefficient for correlation. Labs before and after reversal were also analyzed between medication groups. Results: 182 patients were enrolled between June 2013 and July 2015: 50 on dabigatran, 123 on rivaroxaban, and 34 apixaban. INR values were mildly elevated among patients on dabigatran (median 1.3, IQR 1.1-1.4) and rivaroxaban (median 1.3, IQR 1.1-1.6) compared with apixaban (median 1.1, IQR 1.0-1.2). Patients on dabigatran had slightly higher than normal aPTT values (median 35, IQR 29.8-46.3), whereas those on rivaroxaban and apixaban did not. Fifty patients had TEG results. The median values for R, alpha, MA and lysis were normal for all groups. Prothrombin time (PT) and aPTT had a high correlation in all groups (dabigatran p=0.0005, rivaroxaban p<0.0001, and apixaban p<0.0001). aPTT correlated with the R value on TEG in patients on dabigatran (p=0.0094) and rivaroxaban (p=0.0028) but not apixaban (p=0.2532). Reversal occurred in 14%, 25%, and 18% of dabigatran, rivaroxaban, and apixaban patients, respectively. Both traditional measures of coagulopathy and TEG remained within normal limits after reversal. Discussion: Neither traditional measures of coagulation nor TEG were able to detect coagulopathy in patients on NOAs. Level of evidence: Level IV. PMID- 30402565 TI - Randomized controlled trial to evaluate locally sourced two-component compression bandages for HIV-associated Kaposi sarcoma leg lymphedema in western Kenya: The Kenyan Improvised Compression for Kaposi Sarcoma (KICKS) study protocol. AB - Background: HIV-associated Kaposi sarcoma (KS), among the most frequent cancers seen in sub-Saharan Africa, is associated with a high prevalence of lymphedema. Lymphedema causes progressive functional impairment marked by swelling, physical discomfort, disfiguring changes, skin hardening from fibrosis, poor wound healing, and recurrent skin infection. While compression therapy is considered a major component of lymphedema management, this intervention has never been evaluated in HIV-associated KS lymphedema. Methods/design: The Kenyan Improvised Compression for Kaposi Sarcoma (KICKS) study is a randomized, controlled trial. Due to variable lymphedema stage, we will use block randomization with a 1:1 allocation to assign participants to one of two groups: "Immediate compression" or "Delayed compression." Those randomized to "Immediate compression" intervention arm will receive weekly two-component compression bandages while receiving chemotherapy, whereas those in the "Delayed compression" control arm will be followed during chemotherapy and then receive compression after chemotherapy is completed. The primary outcome is change in Lower Extremity Lymphedema Index from enrollment at Week 0 to blinded outcome assessment at Week 14 between intervention and control arms. Secondary outcomes are change in leg lymphedema-specific quality of life (LYMQOL) and change in overall health quality of life in cancer (EORTC QLQ C30). Discussion: This represents the first study in sub-Saharan Africa to assess a lymphedema-directed intervention for KS, and the intervention-locally sourced two-component compression bandages-is affordable and available. Thus, the KICKS study is an important step towards developing an evidence-based path for regionally relevant management of HIV-associated KS lymphedema. Trial registration: This trial was registered at ClinicalTrials.gov on January 19, 2018: identifier NCT03404297. PMID- 30402567 TI - Does epithelioid angiomyolipoma have poorer prognosis, compared with classic angiomyolipoma? AB - Purpose: Classic angiomyolipoma (AML) is common benign kidney tumor. However, some studies have claimed that epithelioid angiomyolipoma (EAML) has malignant potential. We compared the patient characteristics and prognosis of EAML and classic AML to demonstrate predicting factors and poorer prognosis of EAML. Materials and Methods: The medical records of 231 patients who were diagnosed with EAML (n=27, 11.7%) or classic AML (n=204, 88.3%), were reviewed. All patients underwent computed tomography (CT) scans before operation or needle biopsy. We assessed the age, sex, tumor size, body mass index, comorbidities, and Hounsfield unit (HU) according to each CT phase. We defined the unfavorable group as patients with recurrence, metastasis and death due to tumor progression. Logistic regression analysis was used to predict EAML. Results: EAML patients were younger (41.2 years vs. 49.1 years, p=0.001), predominantly male (55.6% vs. 28.4%, p=0.005), and had a larger tumor (7.5 cm vs. 4.2 cm, p<0.001). The median pre-contrast HU was not significantly different between EAML and classic AML (29.9+/-23.7 vs. 14.7+/-41.0, p=0.071). In multivariable analysis, younger age (odds ratio [OR], 0.96; p=0.032), male sex (OR, 3.33; p=0.013), and tumor larger than 4 cm (OR, 3.8; p=0.009) were significant predictive factors. Five patients (18.5%) had unfavorable outcomes, two patients had lymph node metastasis, and three patients had lung metastasis. Conclusions: Patient and tumor characteristics can be helpful in determining the type of AML preoperatively. Younger age, male sex, and larger tumor mass may increase the possibility of diagnosing EAML. EAML has malignant potential and requires careful follow-up. PMID- 30402569 TI - Are there any predictive risk factors for failure of ureteric stent in patients with obstructive urolithiasis with sepsis? AB - Purpose: To compare patients with sepsis due to obstructive urolithiasis (Sep-OU) and underwent drainage by percutaneous nephrostomy (PCN) or a double-J (DJ) ureteral stent and to identify predictive risk factors of DJ stent failure in these patients. Materials and Methods: We reviewed our records from January 2013 to July 2018 and identified 286 adult patients with Sep-OU out of which 36 had bilateral involvement, thus total 322 renal units were studied. Urologic residents in training carried out both ureteral stenting and PCN tube placement. Demographic data and stone characteristics were recorded along with Charlson comorbidity index. For predicting risk factors of DJ stent failure, those variables that had a p-value <0.1 in univariate analysis were combined in a multinomial regression analysis model. Results: The patients with PCN placement were significantly older than those with DJ stent placement (p=0.001) and also had significant number of units with multiple calculi (p=0.018). PCN was also placed more frequently in those patients with a upper ureteric calculi (p<0.05). On multinomial regression analysis multiple calculi (p=0.014; odds ratio [OR], 4.878; 95% confidence interval [CI], 1.377-17.276) and larger calculi size (p=0.040; OR, 0.974; 95% CI, 0.950-0.999) were the significant predictors of DJ stent failure. Conclusions: In patients with sepsis from obstructive urolithiasis due to larger and multiple calculi a PCN placement might be better suited although this data requires further prospective randomized studies to be extrapolated. PMID- 30402570 TI - Renal function is associated with prognosis in stent-change therapy for malignant ureteral obstruction. AB - Purpose: The authors performed this study to investigate the risk factors for predicting stent failure and to evaluate its impact on prognosis. Materials and Methods: Between January 2002 and March 2017, we retrospectively reviewed 117 consecutive patients who underwent retrograde ureteral stenting and exchanging at least once every 3 months for malignant ureteral obstruction. The patients were classified according to their pre-stenting chronic kidney disease (CKD) stage. The factors affecting stent failure were analyzed using a logistic regression model. Overall survival (OS) was estimated, and the prognostic significance of each variable was estimated using Cox proportional-hazards regression modeling. Results: Before stenting, 91 patients were CKD stages 1-3 and 26 patients were CKD stages 4-5. These two groups differed significantly only in pre-stenting estimated glomerular filtration rate (eGFR), bilateral obstruction, and pre stenting pyuria. Among the 117 patients, stent failure occurred in 30 patients (25.6%), and there were no differences between the groups. Pre-stenting pyuria and post-stenting complications were significant predictors of stent failure. There were 79 deaths in total, including 56 in the CKD stages 1-3 group and 23 in the CKD stages 4-5 group. In the multivariate analysis predicting patient OS, pre stenting eGFR and post-stenting disease progression were significant factors. Conclusions: Internal ureteral stenting was effective for maintaining renal function in malignant ureteral obstruction. However, it did not restore renal function, which is related to the prognosis of the patients. Therefore, to improve patients' renal function and prognosis, patients who require stenting must be quickly recognized and treated. PMID- 30402568 TI - Initial experience of magnetic resonance imaging/ultrasonography fusion transperineal biopsy: Biopsy techniques and results for 75 patients. AB - Purpose: The aim of this study is to describe the technique and to report early results of transperineal magnetic resonance imaging and ultrasonography (MRI-US) fusion biopsy. Materials and Methods: A total of 75 patients underwent MRI-US fusion transperineal biopsy. Targeted biopsy via MRI-US fusion imaging was carried out for cancer-suspicious lesions with additional systematic biopsy. Detection rates for overall and clinically significant prostate cancer (csPCa) were evaluated and compared between systematic and targeted biopsy. In addition, further investigation into the detection rate according to prostate imaging reporting and data system (PI-RADS) score was done. Results of repeat biopsies were also evaluated. Results: Overall cancer detection rate was 61.3% (46 patients) and the detection rate for csPCa was 42.7% (32 patients). Overall detection rates for systematic and targeted biopsy were 41.3% and 57.3% (p<0.05), respectively. Detection rates for csPCa were 26.7% and 41.3%, respectively (p<0.05). The cancer detection rates via MRI fusion target biopsy were 30.8% in PI-RADS 3, 62.1% in PI-RADS 4 and 89.4% in PI-RADS 5. Rates of csPCa missed by targeted biopsy and systematic biopsy were 0.0% and 25.0%, respectively. The cancer detection rate in repeat biopsies was 61.1% (11 among 18 patients) in which 55.5% of cancer suspected lesions were located in the anterior portion. Conclusions: Transperineal MRI-US fusion biopsy is useful for improving overall cancer detection rate and especially detection of csPCa. Transperineal MRI-US targeted biopsy show potential benefits to improve cancer detection rate in patients with high PI-RADS score, tumor located at the anterior portion and in repeat biopsies. PMID- 30402571 TI - Study on the prevalence and incidence of urolithiasis in Korea over the last 10 years: An analysis of National Health Insurance Data. AB - Purpose: We aimed to analyze the incidence and prevalence of urolithiasis in Korea over the last decade using the National Health Insurance (NHI) sample cohort data. Materials and Methods: From January 2002 to December 2013, we enrolled sample cohort data from the NHI. Patients diagnosed with international classification of diseases code N20 or N13.2 were included. The incidence and prevalence rate was counted from the same period and patients previously diagnosed with urolithiasis were excluded. We compared the incidence and prevalence of urolithiasis by region, age, and sex, and identified the changes. Results: Total 1,111,828 subjects were included. Of these subjects, 36,857 had urolithiasis. The male-to-female ratio was 1.57:1, and total incidence rate was 3.27 per 1,000 person-years (1,000p-yrs). The annual incidence was lowest in 2013 (3,138 patients) and highest in 2005 (3,751 patients). Incidence rate by diagnostic code was highest in ureter stone only (2.49 per 1,000p-yrs) and was lowest in kidney and ureter stone both (0.17 per 1,000p-yrs). Prevalence gradually increased from 3,172 in 2002 and 5,758 in 2013. Jeollanam-do had the highest incidence rate of 3.70 persons per 1,000p-yrs, and Jeju had the lowest rate of 2.84 persons per 1,000p-yrs. In gender analysis, Daegu had the highest incidence (4.56) in males, Jeollanam-do had the highest incidence (3.20) in females. Conclusions: Annual incidence remained stable, whereas prevalence gradually increased. The incidence in male was 1.57 times higher than female, and the peak incidence age was 45-49 years, with the highest incidence occurring in Jeollanam-do and the lowest in Jeju. PMID- 30402572 TI - Outcome of 980 nm diode laser vaporization for benign prostatic hyperplasia: A prospective study. AB - Purpose: To evaluate the initial experience and outcome of photo-selective vaporization of the prostate (PVP) for benign prostatic hyperplasia (BPH) in Pakistan with the use of a 980 nm diode laser. Materials and Methods: A prospective study was performed from November 2016 to December 2017. A total of 100 patients diagnosed with bladder outlet obstruction secondary to BPH who planned for PVP were enrolled in the study. PVP was carried out with a diode laser at 980 nm (Biolitec Diode 180W laser) in a continuous wave with a 600 nm (twister) fiber. Baseline characteristics and perioperative data were compared. Postoperative outcomes were evaluated by International Prostate Symptom Score (IPSS), post void residual (PVR) and maximum urinary flow rate (Qmax) at 3 and 6 months after surgery. Results: The mean age was 65.82+/-10.42, mean prostate size was 67.35+/-16.42, operative time was 55.85+/-18.01 and total energy was 198.68+/ 49.12 kJ. At 3 months and 6 months, significant improvements were noted (p<0.001) in IPSS 7.04+/-1.69 (-18.92), Qmax 19.22+/-4.75 mL/s (+13.09) and and PVR 18.89+/ 5.39 mL (-112.80). Most frequent problems were burning micturition (35%) and terminal dysuria (29%). No significant difference in postoperative hemoglobin was seen in patients who were on anti-platelet drugs. Conclusions: PVP with a diode laser is a safe and effective procedure for the treatment of BPH and is also safe in patients who are on anti-platelet agents. PMID- 30402573 TI - Hypogonadal men with moderate-to-severe lower urinary tract symptoms have a more severe cardiometabolic risk profile and benefit more from testosterone therapy than men with mild lower urinary tract symptoms. AB - Purpose: To analyze data from an observational, prospective, cumulative registry study in 805 hypogonadal men stratified by mild or moderate-to-severe lower urinary tract symptoms (LUTS) according to International Prostate Symptom Score. Materials and Methods: A total of 412 men underwent testosterone therapy (TTh) with injectable testosterone undecanoate, 393 men served as untreated controls. Measures of urinary function, anthropometric and metabolic parameters were performed at least twice per year. Results: Data from 615 men with mild LUTS (253 treated, 362 untreated) and 190 with moderate-to-severe LUTS (159 treated, 31 untreated) were available. During a follow-up period of 8 years a significant improvement of LUTS was noted for all TTh-patients whereas the control-groups showed deterioration or fluctuation around initial values. Despite advancing age, TTh fully prevented worsening of symptoms. In parallel, a considerable improvement of anthropometric parameters, lipids and glycemic control, blood pressure, C-reactive protein, and quality of life was found. Moderate-to-severe LUTS was associated with worse cardiometabolic risk profile at baseline as well as worse cardiovascular outcomes during follow-up in comparison to mild LUTS. Effect size of TTh was more pronounced in men with moderate-to-severe than with mild LUTS. Conclusions: Correcting hypogonadism by TTh is highly effective and safe for improving LUTS in hypogonadal men. TTh may also improve cardiometabolic risk and major adverse cardiovascular events. PMID- 30402574 TI - Routine double-J stenting for live related donor kidney transplant recipients: It doesn't serve the purpose, but does it serve a better purpose? AB - Purpose: Despite meticulous techniques, surgical complications continue to be problematic in kidney transplant recipients. Role of routine stenting to reduce complications is controversial. In this study, we compare incidence of early urological complications, lymphoceles, urinary tract infections (UTI) and graft function; with or without double-J stenting. Materials and Methods: All patients who underwent live related donor renal transplantation from February 2014 to February 2016 were included. Transplants prior to February 2015 were without routine stenting; subsequent transplants were with routine stenting. Patients with neurogenic bladder, previously operated bladder and delayed or low urinary output were excluded. Follow-up was for at least three months. Descriptive statistics was performed for all parameters. Chi square test and Fisher's Exact test were used for qualitative variables. For quantitative variables, Mann Whitney test was used to test median difference and independent samples t-test for mean difference. The p-value <=0.05 was considered significant. Results: We analysed 74 patients (34 stented and 40 non-stented). There was no difference in the incidence of urinary leak, anastomotic obstruction, lymphoceles or UTI (p>0.4 for all comparisons). However, mean estimated glomerular filtration rate at sixth day, 14th day, one month and two months were 76.1 vs. 61.5 (p=0.025), 72.1 vs. 56.6 (p=0.005), 79.4 vs. 63.1 (p=0.002) and 82.0 vs. 63.3 (p=0.001) in the stented versus non-stented groups. Conclusions: Placement of ureteral stent in renal transplant does not significantly affect the incidence of early urinary complications or UTI. However, graft function is significantly better in stented recipients, at least in the short term. PMID- 30402575 TI - Hydrocelectomy via scrotal incision is a valuable alternative to the traditional inguinal approach for hydrocele treatment in boys. AB - Purpose: Few studies have explored the treatment of isolated communicating hydroceles via scrotal incision. We prospectively evaluated the surgical outcomes of such treatment in boys with hydroceles compared with that using traditional, inguinal incision hydrocelectomy. Materials and Methods: Of 347 boys aged 0-12 years who were diagnosed as hydrocele on ultrasonography, 173 boys were assigned to the scrotal incision hydrocelectomy group (group I, n=173) and 172 boys were assigned to the traditional inguinal incision hydrocelectomy group (group II, n=172), and finally 156 boys in group I and 156 boys in group II were included in this study. Surgical outcomes, including postoperative complications and hydrocele relapse rates, were compared between groups. Results: The overall success rates were similar in both groups (group I, 96.8%; group II, 89.1%; p=0.740). The operation time and hospital stay were significantly shorter in group I (30.94+/-3.95 minutes and 3.94+/-0.30 days) than in group II (38.02+/ 7.12 minutes and 4.24+/-0.99 days; p<0.001 and p=0.009, respectively). The postoperative complication rate was lower in group I than in group II (3.2% vs. 10.9%, p=0.740). Conclusions: Scrotal incision hydrocelectomy in boys was associated with shorter operative time and hospital stay, and a lower postoperative complication rate, than was the inguinal incision approach. The scrotal incision technique might be an easy and effective alternative treatment when used to treat hydroceles in boys as well as inguinal incision approach. PMID- 30402577 TI - In vivo diagnosis of intraductal papillary mucinous neoplasm with per-oral pancreatoscopy-guided confocal laser endomicroscopy. PMID- 30402578 TI - Endoscopic esophageal septotomy. PMID- 30402579 TI - Endoscopic resection of a giant solitary fibrous tumor of the esophagus. PMID- 30402576 TI - Biliary and pancreatic lithotripsy devices. AB - Background and Aims: Lithotripsy is a procedure for fragmentation or destruction of stones to facilitate their removal or passage from the biliary or pancreatic ducts. Although most stones may be removed endoscopically using conventional techniques such as endoscopic sphincterotomy in combination with balloon or basket extraction, lithotripsy may be required for clearance of large, impacted, or irregularly shaped stones. Several modalities have been described, including intracorporeal techniques such as mechanical lithotripsy (ML), electrohydraulic lithotripsy (EHL), and laser lithotripsy, as well as extracorporeal shock-wave lithotripsy (ESWL). Methods: In this document, we review devices and methods for biliary and pancreatic lithotripsy and the evidence regarding efficacy, safety, and financial considerations. Results: Although many difficult stones can be safely removed using ML, endoscopic papillary balloon dilation (EPBD) has emerged as an alternative that may lessen the need for ML and also reduce the rate of adverse events. EHL and laser lithotripsy are effective at ductal clearance when conventional techniques are unsuccessful, although they usually require direct visualization of the stone by the use of cholangiopancreatoscopy and are often limited to referral centers. ESWL is effective but often requires coordination with urologists and the placement of stents or drains with subsequent procedures for extracting stone fragments and, thus, may be associated with increased costs. Conclusions: Several lithotripsy techniques have been described that vary with respect to ease of use, generalizability, and cost. Overall, lithotripsy is a safe and effective treatment for difficult biliary and pancreatic duct stones. PMID- 30402580 TI - Endoscopic vacuum therapy for a large esophageal perforation after bariatric stent placement. PMID- 30402581 TI - Cholangioscopic forceps-assisted retrieval of a forgotten biliary stent through a distal biliary stricture. PMID- 30402582 TI - EUS-guided hepaticojejunostomy with transjejunal per-oral cholangioscopy and electrohydraulic lithotripsy in a patient with complicated choledocholithiasis after Roux-en-Y gastric bypass. PMID- 30402583 TI - Pancreatic necrosectomy using an automated mechanical endoscopic tissue extraction device. PMID- 30402584 TI - Insulated-tip knife: an alternative method of marsupializing a symptomatic duodenal duplication cyst in a 3-year-old child. PMID- 30402585 TI - Pulley traction-assisted colonic endoscopic submucosal dissection affords good visibility of submucosal layer. PMID- 30402586 TI - EUS-guided portal pressure gradient measurement with a simple novel device: a human pilot study. AB - Background and Aims: Portal hypertension is a serious adverse event of liver cirrhosis. Recently, we developed a simple novel technique for EUS-guided portal pressure gradient (PPG) measurement (PPGM). Our animal studies showed excellent correlation between EUS-PPGM and interventional radiology-acquired PPGM. In this video we demonstrate the results of the first human pilot study of EUS-PPGM in patients with liver disease. Methods: EUS-PPGM was performed by experienced endosonographers using a linear echoendoscope, a 25-gauge FNA needle, and a novel compact manometer. The portal vein and hepatic vein (or inferior vena cava) were targeted by use of a transgastric or transduodenal approach. Feasibility was defined as successful PPGM in each patient. Safety was based on adverse events captured in a postprocedural interview. Results: Twenty-eight patients underwent EUS-PPGM with 100% technical success and no adverse events. PPG ranged from 1.5 to 19 mm Hg and had excellent correlation with clinical parameters of portal hypertension, including the presence of varices (P = .0002), PH gastropathy (P = .007), and thrombocytopenia (P = .036). Conclusion: This novel technique of EUS PPGM using a 25-gauge needle and compact manometer is feasible and appears safe. Given the availability of EUS and the simplicity of the manometry setup, EUS guided PPG may represent a promising breakthrough for procuring indispensable information in the management of patients with liver disease. PMID- 30402587 TI - Endoscopic gallbladder drainage in high-risk surgical patients. PMID- 30402588 TI - Severe Mitral Regurgitation As a Result of Rupture of Mitral Valve Chordae Tendineae in a Patient With Graves Disease. AB - Mitral valve prolapse is a common disorder, but severe mitral regurgitation (MR) as a result of rupture of mitral valve chordae tendineae is a rare manifestation of thyrotoxic heart disease. There are limited reports with respect to the onset of severe MR as a complication of Graves disease. We report a case of a 60-year old woman with Graves disease and thyroid-associated ophthalmopathy as her past history. She had signs of congestive heart failure, a loud murmur as a result of MR, clinical cardiomegaly, and peripheral edema. Echocardiographic and angiographic data were consistent with moderate to severe MR. She also had thyrotoxicosis caused by the recurrence of Graves disease. She was taking methiamazole, a beta-blocker, hydrocortisone, and potassium iodide. Ultimately, thyroidectomy was performed to improve her hyperthyroid state. After normalization of her thyroid status, she continued to have moderate to severe MR, and mitral valve repair was performed. The present case had severe MR as a result of rupture of mitral valve chordae tendineae, which is considered rare in a patient with Graves disease. PMID- 30402589 TI - Olfactory Receptor OR51E1 Mediates GLP-1 Secretion in Human and Rodent Enteroendocrine L Cells. AB - Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), produced by intestinal enteroendocrine L cells, are important gut hormones that coordinate gastrointestinal physiology, metabolism, and appetite. We aimed to investigate the role of olfactory receptor (OR) OR51E1 in GLP-1 and PYY secretion. We analyzed the expression of olfactory marker protein (OMP), an indicator of OR mediated events in nonolfactory systems, in human intestinal L cells. Furthermore, we analyzed OMP and OR51E1 expression in the L cell line NCI-H716. To investigate whether odorant-activated OR signaling stimulates GLP-1 and PYY secretion, we used nonanoic acid, a known OR51E1 ligand. Treatment with 100 MUM nonanoic acid increased GLP-1 secretion by 2.32 +/- 0.41-fold and PYY secretion by 1.44 +/- 0.10-fold; however, this effect was attenuated on small interfering RNA-mediated OR51E1 knockdown. Oral administration of nonanoic acid to rats resulted in a 2.89 +/- 0.53-fold increase in GLP-1 levels and reductions in blood glucose levels compared with the control group. Nonanoic acid stimulates GLP-1 and PYY secretion via OR51E1 signaling in L cells, thereby indicating a potential role of OR-mediated events in GLP-1 and PYY secretion; this could be translated into a therapeutic approach in treating diabetes. PMID- 30402591 TI - U500 Disposable Patch Insulin Pump: Results and Discussion of a Veterans Affairs Pilot Study. AB - We present a Veterans Affairs-sponsored pilot study of U500 concentrated insulin administered via disposable patch insulin pump (DPIP) vs twice-daily (BID) injections with an insulin pen in a case series format. We conducted a prospective, single-center, randomized, intent-to-treat pilot study. Ten participants were enrolled with poorly controlled diabetes, defined as hemoglobin A1C >8.0 and severe insulin resistance defined as total daily dose >200 units. Participants were randomized in a 1:1 ratio to either U500 DPIP or U500 BID insulin titration protocols for 14 weeks. A clinical pattern emerged where four participants randomized to the DPIP treatment arm were withdrawn early as the DPIP did not work well for the purpose studied. There was not a statistically significant difference in the rate of hypoglycemia between treatment arms. Based on our clinical experience and results, we argue against the general use of U500 DPIP in clinical practice. PMID- 30402590 TI - Therapeutic Targets for Adrenocortical Carcinoma in the Genomics Era. AB - Adrenocortical carcinoma (ACC) is a rare and often fatal cancer, affecting ~1 person per million per year worldwide. Approximately 75% of patients with ACC eventually develop metastases and progress on the few available standard-of-care medical therapies, highlighting an incredible need for an improved understanding of the molecular biology of this disease. Although it has long been known that ACC is characterized by certain histological and genetic features (e.g., high mitotic activity, chromosomal instability, and overexpression of IGF2), only in the last two decades of genomics has the molecular landscape of ACC been more thoroughly characterized. In this review, we describe the findings of historical genetics and recent genomics studies on ACC and discuss how underlying concepts emerging from these studies contribute to the current model of critical pathways for adrenocortical carcinogenesis. Integrative synthesis across these studies reveals that ACC consists of three distinct molecular subtypes with divergent clinical outcomes and implicates differential regulation of Wnt signaling, cell cycle, DNA methylation, immune biology, and steroidogenesis in ACC biology. These cellular programs are pharmacologically targetable and may enable the development of therapeutic strategies to improve outcomes for patients facing this devastating disease. PMID- 30402592 TI - An Evidence Map of Research Linking Dietary Sugars to Potentially Related Health Outcomes. AB - Background: Evidence mapping is an emerging tool used to systematically identify, organize, and summarize the quantity, distribution, and characteristics of published studies with the goal of identifying knowledge gaps and future research needs. Objective: The aim of the study was to present an evidence-map database of all published studies that investigated dietary sugars and to select health outcomes for explicating research trends and gaps. Methods: To update an evidence map database previously published in 2013, we performed a literature search in MEDLINE to identify English-language, peer-reviewed human intervention and prospective cohort studies published from January 2013 to December 2016. Abstracts and full-text articles were dual screened on the basis of predefined eligibility criteria. We classified outcomes into 7 health outcome categories that are potentially affected by dietary sugar. Data from the updated evidence map database were merged with those from the previous database for analysis and charting. Results: There were 918 sugar and control intervention arms from a total of 298 intervention studies from 1966 to December 2016. A variety of sugar interventions were investigated across the included intervention studies, and it appears that the research interest across all outcome categories (cardiovascular disease risks, diabetes risks, body weight, body composition, appetite, dietary intake, and liver health-related outcomes) sharply increased from 2006. Bubble plots showed research gaps in long-term intervention studies and in intervention studies in patients with diabetes. In contrast, all 25 included cohort studies had long-term follow-up durations and much larger sample sizes than did intervention studies. None of the cohort studies evaluated dietary intake outcomes, and only one cohort study each examined appetite- and liver health related outcomes. Conclusions: The research trends and research gaps have not changed since 2013 when the original evidence-map database was updated. With continuous updating, evidence mapping can facilitate the process of knowledge translation and possibly reduce research waste. PMID- 30402593 TI - Integrating Calcium Supplementation into Facility-Based Antenatal Care Services in Western Kenya: A Qualitative Process Evaluation to Identify Implementation Barriers and Facilitators. AB - Background: In countries with low calcium intake, the WHO recommends integrating calcium supplementation into antenatal care (ANC) to reduce the risk of preeclampsia, a leading cause of maternal mortality. Current WHO guidelines recommend women take 3-4 calcium supplements plus 1 iron-folic acid supplement at separate times daily. There is limited evidence about implementing these guidelines through routine ANC. Through the Micronutrient Initiative-Cornell University Calcium (MICa) trial, we examined the effect of regimen on supplement consumption among ANC clients in western Kenya. A nested process evaluation examined factors that influence calcium supplementation delivery and uptake. Objectives: This process evaluation assessed ANC providers', pregnant women's, and family members' experiences with calcium supplementation, and investigated the feasibility and acceptability of engaging family members to support adherence. Methods: We conducted semistructured interviews with 7 ANC providers, 32 pregnant women, and 20 adherence partners (family members who provide reminders and support), and 200 observations of ANC consultations. Interviews were transcribed, translated, and analyzed thematically. Observational data were summarized. Results: ANC providers reported positive feelings about calcium supplementation, the training received, and counseling materials, but reported increased workloads. Women reported that providers counseled them on supplement benefits and managing side effects, offered reminder strategies, and provided supplements and behavior change materials. Women explained that reminder materials and adherence partners improved adherence. Most adherence partners reported providing reminders and other instrumental support to help with pill taking, which women confirmed and appreciated. Some women reported that comorbidities, concerns about being perceived as HIV positive, pill burden, unfavorable organoleptic properties, and lack of food were adherence barriers. Conclusions: Although integrating calcium into antenatal iron-folic acid supplementation was generally acceptable to ANC providers, pregnant women, and their families, calcium supplementation presents unique challenges that must be considered to successfully implement these guidelines.This trial was registered at clinicaltrials.gov as NCT02238704. PMID- 30402594 TI - Breakfast Consumption Augments Appetite, Eating Behavior, and Exploratory Markers of Sleep Quality Compared with Skipping Breakfast in Healthy Young Adults. AB - Background: Observational studies show associations between breakfast skipping, reduced satiety, and poor sleep quality; however, intervention studies are lacking. Objective: The purpose of this study was to examine the effects of consuming breakfast compared with breakfast skipping on appetitive, hormonal, and neural markers of appetite and satiety; ad libitum food intake; and exploratory measures of sleep health in young adults. Methods: Thirteen adults [aged 23.5 +/- 0.9 y (mean +/- SEMs); body mass index (kg/m2): 23.6 +/- 0.6] completed the following randomized crossover-design study. Participants consumed a high-protein breakfast ("Breakfast"; 340 kcal, 30 g protein, 36 g carbohydrate, 9 g fat) or skipped breakfast ("Skip") for 7 d/treatment. On day 7, an 8-h clinical testing day was completed including assessments of hunger, fullness, desire to eat, prospective food consumption (PFC), related hormones, food cue-stimulated functional magnetic resonance imaging brain scans, and ad libitum evening food intake. Sleep quantity and quality were assessed with 7-d actigraphy, 7-d sleep diaries, and sleep-related hormones. Results: Morning and daily hunger, desire to eat, PFC, and ghrelin decreased, whereas fullness increased after the Breakfast pattern compared with after the Skip pattern (all, P < 0.05). No difference in peptide YY (PYY) concentrations were detected. Hippocampal, parahippocampal, and middle frontal gyrus activations were reduced after the Breakfast pattern compared with the Skip pattern (all, P < 0.01). Although no differences in daily food intake were observed, the Breakfast pattern reduced evening intake of high carbohydrate and high-fat foods (P < 0.05), whereas evening sugar intake tended to be reduced compared with the Skip pattern (P = 0.085). Although Breakfast led to shorter total sleep time (TST) compared with Skip (P < 0.05), no difference in sleep efficiency (TST/sleep period) was detected. Perceived sleep quality and sleep onset tended to improve after Breakfast compared with after Skip (P = 0.060 and P = 0.07, respectively). Conclusion: Breakfast consumption improved appetite, satiety, and diet quality and may support some aspects of sleep health in healthy young adults. This trial was registered at clinicaltrials.gov as NCT03031132. PMID- 30402596 TI - Ethylene oxide as an occupational contact allergen - an underestimated problem? AB - BACKGROUND: Ethylene oxide (EtO) is a volatile epoxy compound which is used to sterilize medical devices. EtO may cause irritant contact dermatitis, but only few cases of allergic contact dermatitis have been reported yet. OBJECTIVES: About 20 employees of a department for surgery developed eczematous skin reactions at the contact areas to wrist bands of surgical gowns which had been sterilized with EtO. Patch tests were performed to exclude contact allergy. METHODS: Due to the volatility of EtO, patch tests were done with epichlorohydrin (0.1% pet., 1% pet.) which is an epoxy compound chemically related to EtO. RESULTS: 7/8 patients and 4 healthy control persons showed non-allergic irritant reactions to 1.0% epichlorohydrin. 1.0% epichlorohydrin may have induced an iatrogenic sensitization in one of the control persons. None of the control persons reacted to 0.1% epichlorohydrin. Allergic contact dermatitis to EtO and a cross sensitization to epichlorohydrin was diagnosed in a nurse who showed an allergic crescendo patch test reaction to 0.1% epichlorohydrin. CONCLUSIONS: EtO can act as an occupational contact allergen in health personnel, a problem that may have been underestimated in the past due to methodological difficulties in patch testing. When allergic contact dermatitis to EtO is suspected, a patch test to 0.1% epichlorohydrin should be performed. PMID- 30402595 TI - Systemic therapy of atopic dermatitis. AB - Therapy of severe atopic dermatitis, which is refractory to consistent treatment with topical steroids and topical calcineurin inhibitors is still a problem in many cases. The use of cyclosporine, which is the only approved systemic drug for the therapy of severe atopic dermatitis, is often limited by contraindications or adverse reactions. In this context, results from controlled and open-label studies with novel therapeutic approaches such as methotrexate, omalizumab or rituximab, which are in part very promising, are of great interest. In this work we would like to provide an overview of established and new therapeutic options for the treatment of severe atopic dermatitis. PMID- 30402597 TI - Elicitors of severe allergic reactions - reports from allergists and emergency doctors. AB - Data from the anaphylaxis registry of German-speaking countries indicate that food is the most frequent elicitor of severe allergic reactions in children, insect venom is the most frequent elicitor in adults. The anaphylaxis registry considers data from patients of allergy centers. The aim of the present study was to collect data regarding elicitors, cofactors and the medical care of patients with severe allergic reactions seen by private practice allergists but also patients seen by emergency doctors. From June 2008 to December 2009 70 cases of severe allergic reactions from private practice allergists and 154 from emergency doctors in Berlin were registered. Our data show that the profile of elicitors differs among the reporting groups. The reported causes from allergists were severe reactions to food, insect venom and subcutaneous immunotherapy, the emergency doctors reported insect venom as the most frequent elicitor. Our data show that a systematic evaluation of severe allergic reactions can provide important data about elicitors and circumstances of anaphylaxis. Through a comparison with data from the anaphylaxis registry the analysis of the data from the emergency doctors will allow to determine how many patients with severe allergic reactions are seen by an allergist for further diagnostic work-up and subsequent therapy. PMID- 30402599 TI - The German Infant Nutritional Intervention Study (GINI) for the preventive effect of hydrolyzed infant formulas in infants at high risk for allergic diseases. Design and selected results. AB - In the complex interaction between certain environmental factors and genetic disposition, the early allergen exposure plays a major role in the development of allergic diseases. In aiming to reduce the allergen burden for the infant at risk during early infancy, cow's milk protein hydrolysate infant formulas (hypoallergenic infant formulas) are appropriate alternatives to breastfeeding for primary allergy prevention. The German Infant Nutritional Intervention Program (GINI) was supported for the first 3 years by the German Ministry for Education and Research (BMBF) (FKZ 01 EE 9401-4). It is a birth cohort which was primarily scheduled until the children were 3 years old. The aim of the prospective, randomized, double-blind intervention study was to investigate the impact of different cow's milk protein hydrolysate infant formulas in the first 4 - 6 months on the development of allergic diseases in children at risk due to at least one parent or biological sibling with a history of allergic disease. The allocation to one of the 4 intervention formulas (partial whey hydrolysate, extensive whey hydrolysate, extensive casein hydrolysate or standard cow's milk formula) was randomised and stratified by family history (single/biparental) and the respective obstetric clinic. Recruitment was carried out by the three clinical centers (Research Institute Marien-Hospital Wesel, Children's Department, Ludwigs-Maximilians-University Munich and Children's Department Technical University Munich) in 18 obstetric clinics between 01.09.1995 and 30.06.1998. Along with the intervention study a non-interventional, complementary observational cohort of children with or without allergy risk was recruited and followed by annual self-reporting parental questionnaires. The GINI intervention study (GINI-I, N = 2.252) and the non-interventional observation study (GINI-NI, N = 3.739) are combined in the population-based GINIplus study (see article J. Heinrich et al. in this journal). The results of the GINI intervention study confirm that, cow's milk protein hydrolysate infant formulas have a preventive effect on allergic manifestation compared with a standard cow's milk formula, until school age. However, the dimension of the effect is different between the formulas. This effect, which is mainly driven by the effect on atopic eczema, develops in the first months of life and persists without rebound. In the formula groups the cumulative incidence of atopic eczema until school age is reduced between 26% and 45% compared with standard cow's milk formula. A beneficial effect of the hydrolysate formulas on the respiratory manifestations asthma and rhinoconjunctivitis, however, could not be shown. By comparing the GINI intervention and non-intervention arm of the GINIplus study it was demonstrated, that a family history for allergy doubles the risk for eczema in the offspring. Early intervention with cow's milk protein hydrolysate infant formulas is able to substantially compensate this risk for eczema until the age of 6 years. In contrast, by randomization to standard cow's milk formula this risk showed a trend towards a higher incidence compared with children at risk from the non intervention group. Thus, the results of the GINIplus study have contributed to answer some of the controversially discussed questions. PMID- 30402600 TI - The role of the innate immune system in allergic contact dermatitis. AB - . Allergic contact dermatitis is a Tcell mediated inflammatory skin disease that is caused by low molecular weight chemicals and metal ions. These contact allergens induce skin inflammation, an essential element of the sensitization process. Our understanding of the molecular mechanisms that underlie chemical induced inflammation has improved significantly over the last years. The emerging picture shows that contact allergens activate known innate immune and stress responses that play a role in immune responses to infections. Contact allergens use innate immune receptors such as the Toll-like receptors TLR2 and TLR4 and the NOD-like receptor NLRP3 as part of the inflammasome as well as the induction of oxidative stress to induce skin inflammation. The detailed identification of the relevant signaling pathways and the mechanisms of their activation by contact allergens will most likely lead to more targeted therapeutic approaches by interference with these pathways. Moreover, this will help to refine existing, and to develop new in vitro assays for the identification of contact allergens, an important step to replace animal testing e.g. for ingredients of cosmetics which has been prohibited now by EU legislation. PMID- 30402601 TI - Complementary and alternative medicine (CAM) and atopic eczema. AB - . There is a substantial and growing interest in complementary and alternative medicine (CAM) in the general population. This paper aims to answer in how far patients with atopic eczema use CAM and which techniques. Furthermore the evidence basis on the efficacy of CAM in the use for atopic eczema should be reviewed. For that purpose randomized controlled trials (RCT) were searched systematically. In Germany about 46% of the general population and up to 51% of inpatients with eczema use CAM. Acupuncture, homeopathy, diets and supplements comprise the most popular techniques. Better educated, middle-aged women use CAM more frequently. In general the evidence basis concerning studies on the efficacy (and safety) of CAM for atopic eczema with appropriate size and quality is limited. Most studies were found on essential fatty acids and Chinese herbs, whereby the results remain conflicting. There was not enough evidence to assess the efficacy of acupuncture, homeopathy and salt baths. A single study on bioresonance did not show superiority compared to a sham procedure. Single studies indicated beneficial effects for topical hypericum, autologous blood injection, massage therapy, Vitamin E and D, and topical Viatmin B12. These results must be confirmed by future studies. CAM are frequently used in atopic eczema, the evidence basis for that, however, is limited. PMID- 30402598 TI - Food-induced anaphylaxis and cofactors - data from the anaphylaxis registry. AB - Food allergens are frequent causes of anaphylaxis. In particular in children and adolescents they are the most frequent elicitors of severe allergic reactions, and in adults food allergens rank third behind insect venom and drugs. Since July 2006 severe allergic reactions from Germany, Austria, and Switzerland are collected in the anaphylaxis registry. Currently 78 hospitals and private practises are connected. From July 2006 until February 2009 1,156 severe allergic reactions were registered. Among children and adolescents (n = 187, age range from 3 months to 17 years) food allergens were the most frequent triggers, comprising 58% of cases. In the adult group (n = 968, 18 - 85 years) food allergens were in the third position (16.3%) behind insect venom and drugs. In children legumes (31%) and in particular peanuts were frequently responsible food allergens, followed by tree nuts (25%) with hazelnut being the most frequent elicitor. In adults fruits (13.4%) most often induced severe food-dependent anaphylaxis, but also animal products (12.2%); among these most frequently crustaceans and molluscs. Cofactors were often suspected in food-dependent anaphylaxis, namely in 39% of the adult group and in 14% of the pediatric group. In adults drugs (22%) and physical activity (10%) were reported to be the most frequent cofactors, in children physical activity was suspected in 8.7% and drugs in 2.6%. Concomitant diseases like atopic dermatitis, allergic asthma, or allergic rhinoconjunctivitis were reported in 78% of children and adolescents and in 67% of the adults. In conclusion, food-induced anaphylaxis, its cofactors and concomitant diseases are age-dependent. The data offers to identify risk factors of anaphylaxis. PMID- 30402602 TI - Risk factors in Hymenoptera venom allergy. AB - . Risk factors should be part of the decision, of which patient should be offered venom immunotherapy (VIT) and how VIT should be performed. Risk factors for a severe systemic anaphylactic reaction (SAR) after a Hymenoptera field sting include a preceding less severe sting reaction, a wasp sting, an increased baseline serum tryptase concentration (BSTC), mastocytosis, older age, ACE inhibitor medication, and male gender. During VIT, treatment with honey bee venom is the most important risk factor for a SAR. Further risk factors include a high BSTC (for vespid VIT only), presence of venom specific IgE in serum, any antihypertensive medication during therapy, and an ultra-rush protocol for build up. Treatment failure is more common in patients suffering from honey bee venom allergy, high BSTC (for vespid VIT only) or mastocytosis, and in those who had experienced side effects during VIT. Besides discontinuing antihypertensive medication or switching to a moderate type of dose increase during build-up, little can be done to minimize the risks associated with VIT. Increasing the maintenance dose may improve the efficacy of VIT. In patients with a particularly high risk for treatment failure, or in case of treatment failure, VIT should include an increased maintenance dose right from the beginning. Usually, 200 ug will be sufficient. PMID- 30402603 TI - Implant allergy. AB - Osteosynthesis materials or artificial joint replacement make part of clinical routine. In case of complaints mostly mechanical causes or infections are found. Metals like nickel, chromium and cobalt or bone cement components like acrylates and gentamicine may however potentially cause intolerance reactions to implants. Correspondingly, eczema, delayed wound/bone healing, recurrent effusion, pain or implant loosening have been described as manifestation of implant allergy. In contrast to the high incidence of cutaneous metal allergy, allergies associated with implants are rare. Diagnosis of metal implant allergy is based on excluding differential diagnoses - in particular infection - and on a combined approach of allergological diagnostics by patch test and histopathology of periimplant tissue. Risk factors for allergic sensitization to implants or triggering periimplant allergic reactions in the case of preexisting cutaneous metal allergy are unknown. Despite the risk of developing complications being unclear, titanium based osteosynthesis materials are recommended for metal-allergic patients and the use of metal-metal couplings in arthroplasty is rather not recommended for such patients. If a regular, potentially applicable CoCr-polyethylene articulation is preferred, the patient has to be well informed and has to give his written consent. PMID- 30402604 TI - Rare and new occupational inhalant allergens. AB - Occupational airway diseases induced by the inhalation of allergens at workplaces have become common, but the inducing substances are diverse and their pathomechanisms are not always clear. Only few allergens were studied in detail (like wheat flour dust and natural rubber latex) and most of the occupational airway sensitizers were documented only as case reports. In this review rare and exotic occupational Type I-aeroallergens according to their workplace application area (e.g., production of dough and bakery products, handling with decorative and economic plants, wood processing, fish-, shellfish-processing and fish breeding) are described. PMID- 30402605 TI - Novel key cytokines in allergy: IL-17, IL-22. AB - The biology of the T cell cytokines Interleukin (IL-)17 and IL-22 has been a main focus in the field of clinical immunology in the last decade. This intensive interest in both cytokines has resulted in almost 5,000 scientific publications (www.pubmed.com) dealing with the molecular structure, extra- and intracellular signaling pathways, specific transcription factors and the function of IL-17 and IL-22. This review article highlights the main findings concerning IL-17 and IL 22 in the last years. PMID- 30402606 TI - Avoiding contact allergens: from basic research to the in vitro identification of contact allergens. AB - Allergic contact dermatitis (ACD) is a chemical-induced inflammatory skin disease. Contact allergens are low-molecular-weight chemicals that must react with proteins in order to become immunogenic. This interaction leads to the activation of innate immune and stress responses and to the formation of antigenic epitopes for T cells which are the effector cells of ACD. Due to the multitude of chemicals that surround us in our daily life and their potential sensitizing capacity, it is crucial to identify contact sensitizers before these chemicals are used in consumer products. Appropriate in vitro assays for hazard identification are urgently needed to replace animal-based assays. The EU-wide ban on sensitization testing of cosmetic ingredients in animals is in effect since March 2009 and the necessity to test more than 30,000 already marketed chemicals for their sensitizing potential under the EU regulation REACh has intensified the worldwide efforts to replace animal testing. We summarize here the current strategies to develop a battery of assays which allows the identification of contact allergens by in vitro alternatives to animal testing. Our main focus lies on the test systems recently developed within the EU project Sens-it-iv in which we participate. PMID- 30402608 TI - Epidemiology of cutaneous adverse drug reactions. AB - Epidemiologic investigation of cutaneous adverse drug reactions (cADRs) is important in order to evaluate their impact on dermatology and health care in general as well as their burden on affected patients. Few epidemiologic studies have been performed on frequent non-life-threatening cADR, including reactions of both delayed and immediate hypersensitivity, such as maculopapular exanthema (MPE), fixed drug eruption, and urticaria. Concerning rare but life-threatening severe cutaneous adverse reactions, e.g., toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS), several epidemiologic studies have been performed to date, some of which are still ongoing. Such studies enable the calculation of reliable incidence rates and demographic data, and also allow researchers to perform risk estimation for drugs. The spectrum of drugs causing cADR differs substantially when separating the various clinical conditions. Whereas antibiotics are by far the most frequent inducers of milder cADRs, like MPE, they have a much lower risk of inducing SJS/TEN, for which "high-risk" drugs are anti-infective sulfonamides, allopurinol, certain anti-epileptic drugs, nevirapine, and non-steroidal anti inflammatory drugs (NSAIDs) of the oxicam-type. In contrast, AGEP is predominantly caused by the antibiotics pristinamycin and aminopenicillins, followed by quinolones, (hydroxy-)chloroquine, and sulfonamides. DRESS can be induced by a number of drugs known to cause SJS/TEN, such as certain antiepileptics and allopurinol, but also other medications (e.g., minocyclin). PMID- 30402610 TI - Protein and DNA-based assays as complementary tools for fish allergen detection. AB - BACKGROUND: Fish is one of the most important, allergenic foods worldwide. Parvalbumin is the well characterized, major allergen in fish muscle. In this study, we developed a protein- and a DNA-based method for the sensitive detection and authentication of eight commonly consumed fishes in food and compared their applicability. METHODS: Fish parvalbumins were purified. Polyclonal, anti parvalbumin antibodies were raised in rabbits and mice. Protein extracts from food were analyzed by quantitative ELISA. Parvalbumin genes were cloned and sequenced for the design of parvalbumin gene-specific PCR-primers. DNA extracted from food was subjected to specific PCR. RESULTS: Increasing parvalbumin contents were quantified by ELISA in fresh fish, in the order of tuna < mackerel < cod < salmon/trout < redfish < carp < herring. The parvalbumin content of processed fish was up to 67% lower than in fresh fish. In spiked food samples, 1 to 15 ppm fresh fish and 30 to 170 ppm processed fish were still detectable by ELISA. The eight fishes were identified by specific PCR using 0.2 to 10 ng fish DNA. PCRs detected still 3 ppm fresh fish and 30 to 150 ppm processed fish in spiked samples. CONCLUSIONS: Both the protein- and the DNA-based method have sufficient sensitivity to protect fish-allergic consumers. The ELISA allows allergen quantification, while the PCR identifies the fish present in the food. The detection limits of both methods vary depending on different factors. Both methods need to be carefully validated for each fish and fish product when used in detection assays. PMID- 30402607 TI - GINIplus and LISAplus - Design and selected results of two German birth cohorts about natural course of atopic diseases and their determinants. AB - The increasing prevalence of asthma, hay fever, and allergic sensitization in Western Germany after east-west division in 1949 and their rapid increase in East German children after re-unification in 1990 are strong indications for the role of life-style and/or environmental factors in the development of atopic diseases. Obviously, the perinatal period is crucial for priming the immune system. Therefore, explorations of determinants of atopic diseases need pregnancy or birth cohorts as the most appropriate epidemiological study designs. This review presents the design and selected results of the two German birth cohorts GINIplus and LISAplus. GINIplus and LISAplus recruited 5.991 and 3.097 healthy, term newborns, respectively, from Munich, Wesel, Leipzig, and Bad Honnef. Approximately 55% could be followed for the first 10 years. We analyzed the natural course of atopic diseases and the role of life-style, environmental, and genetic factors for disease onset, intermediate phenotypes, and genes involved in detoxification and oxidative stress. The results of these two large birth cohorts contributed substantially to the understanding of atopic diseases and their determinants. PMID- 30402609 TI - Quantification of protein and latex allergen content of various natural rubber latex products. AB - INTRODUCTION: The use of natural rubber latex (NRL) products can cause IgE mediated allergic reactions in exposed people. The aim of this study was to quantify the content of protein and latex allergens of currently available NRL products to estimate the allergenic potential of these products. METHODS: 14 household articles (pacifiers, baby bottle nipples, condoms, household and disposable gloves, toy balloons, and Band-Aids) as well as 18 NRL examination gloves currently used by healthcare workers were investigated. Extracts of the examination gloves were prepared according to the standard method DIN EN 455-3, which contains requirements and testing for biological evaluation of single use medical gloves. The protein content was determined with a modified Lowry method. Latex allergen content was measured using an IgE-inhibition immunoassay with a mix of serum-sensitized patients as detection antibody sources and the latex ImmunoCAP as solid phase. The allergens Hev b 1, 3, 5, and 6.02 were determined using available immunoassays. RESULTS: In 5 out of 18 examination gloves, the protein content was under the detection limit. The other 13 gloves contained protein between 7.1 and 92.3 ug protein/g material. Five glove brands contained protein concentrations above the recommended reference value of 30 ug protein/g material. Latex allergen could be measured in 12 out of 18 NRL gloves. In only 3 gloves could none of the allergens Hev b 1, 3, 5, and 6.02 be detected. Protein and Hev b 1 could be measured in the examined childcare products, while the concentrations of the latex allergens Hev b 3, 5, and 6.02 were mostly under the detection limit. Boiling of childcare products led to a reduction of protein and allergen content. In some of the other daily-used NRL articles, the protein and allergen contents were even higher than in gloves. CONCLUSION: Our study demonstrated that protein, and particularly latex allergens, were detectable in currently available examination gloves as well as in household articles whereby a risk for sensitization and/or induction of allergic symptoms could not be excluded. PMID- 30402611 TI - Occupational contact allergy in bricklayers, tile setters etc. - Current spectrum of sensitization and recent time trends. AB - BACKGROUND: Occupational exposure of bricklayers, construction workers, tile setters etc. has changed during the last years. For some years now, all manually handled cement in the European Union and in Switzerland is chromate-reduced. Epoxy resin systems are being used in more and more fields of application. Improved worker's protection, especially wearing protective gloves, is promoted. These changes influence the spectrum of occupational contact sensitization. OBJECTIVE: Description of the current allergen spectrum in patients working in the building trade who suffer from occupational contact dermatitis. MATERIAL AND METHODS: Retrospective analysis of data of the Information Network of Departments of Dermatology (IVDK), 2009 - 2011. RESULTS: During the study period, 245 bricklayers, construction workers, tile setters etc. with occupational dermatitis have been patch tested. Potassium dichromate was the most frequent allergen, yielding 15.1% positive reactions, followed by epoxy resin with 13.7% positive reactions. Beyond that, there were 8 additional components of epoxy resin systems (5 reactive diluents and 3 amine hardeners), as well as 9 rubber ingredients, mainly thiurams, among the 30 most frequent allergens. In the course of time, a decline of chromate sensitization could be noted, paralleled by a decline of cobalt sensitization. In contrast, sensitization to epoxy resin has increased. CONCLUSION: Thanks to the usage of chromate-reduced cement, chromate sensitization continues to decline in the building trade. The increase of epoxy resin sensitization must prompt intensified prevention efforts. When recommending protective gloves, thiuram-free products should be preferred. The most important allergens are covered by the following test series recommended by the German Contact Dermatitis Research Group (DKG): DKG baseline series, DKG test series "building trade", DKG rubber series. PMID- 30402612 TI - Inhibition of cross-reactive carbohydrate determinants (CCDs) enhances the accuracy of in vitro allergy diagnosis. AB - BACKGROUND: Cross-reactive carbohydrate determinants (CCDs) as they occur on natural allergens from plants and insects influence the measurement of antigen specific IgE-antibodies in the context of in vitro allergy diagnosis. When positive results are based solely on the reaction of CCDs with anti-CCD IgE, results must be rated as false-positive. A generally applicable solution to this problem has not yet been presented. METHODS/PATIENTS: Sera of patients for whom an assumed allergy should be verified or ruled out were tested with three methods for specific IgE determination (a multiallergen teststrip format, a single allergen test and an allergen-component array) in the absence and presence of a novel, semi-synthetic CCD-blocker. The study was not prospective and for many patients unequivocal clinical data were missing; the data section thus focusses on few, well-defined patient sera. RESULTS: More than 20% of all patients were tested positive for IgE-anti-CCD antibodies and hence against a multitude of similarly glycosylated allergen extracts in a strip-based multiallergen test. Incubation of these positive sera with the CCD-blocker led to significant reductions of read-out values and in many cases to negative test results. The inhibitory efficiency was highest for the allergen strip test and for the component array. Results remained positive for relevant allergens for which a true sensitization had been indicated by skin tests or other means. The CCD blocker did not alter the read-outs for unglycosylated allergens or - with CCD negative sera - for all allergens. CONCLUSION: Elimination of CCD-specific IgE antibodies by means of a synthetic CCD-blocker drastically reduced the number of false-positive in vitro test results without compromising the sensitivity for relevant IgE interactions. Thus, the herein described CCD-blocker constitutes a valuable tool for increasing the test specificity of routine in vitro allergy diagnosis. PMID- 30402613 TI - In-vitro diagnostic in atopic dermatitis: Options and limitations. AB - Atopic dermatitis is a chronic inflammatory skin disease with a complex pathogenesis and different exogenous and endogenous trigger factors. One important factor is the sensitization to inhalant and/or food allergens. The detection of total IgE and specific IgE antibodies to inhalant and/or food allergens is one central aspect in diagnosing atopic dermatitis, especially if skin prick tests are not feasible. Many patients are polysensitized, but not all sensitizations are of clinical relevance. The challenge is to identify the sensitizations with clinical relevance and to initiate suitable therapeutic options. In this article we go into detail for the allergens house dust mite, pollen, food, and Malassezia sympodialis. Furthermore, the authors comment on the impact of the detection of specific IgG/IgG4 antibodies in the diagnosis of food allergy in atopic dermatitis. Moreover, new options in the in-vitro diagnostic will be explained briefly and their actual diagnostic significance in patients with atopic dermatitis will be highlighted. These options are the detection of specific IgE antibodies to recombinant allergens and the allergen chip. PMID- 30402614 TI - Rare drug allergies: Review on prevalence and test procedures. AB - This paper gives a review on rare hypersensitivity reactions (including allergies) to drugs. Pathogenesis, allergy tests and possible therapeutic options are discussed by presenting examples out of the following group of drugs: antiinfectious (i.e. chinolones, telaprevir), oncological (i.e. platin-based cytostatics), immunologic (i.e. cetuximab, omalizumab), others (i.e. glucocorticosteroids). Usually there is no standardized allergologcial work-up procedure. Testing must therefore take into consideration previous experiences from other authors and on general recommendations. PMID- 30402615 TI - Molecular allergy diagnostic tests: development and relevance in clinical practice. AB - Molecular allergy is based on identification, characterization and subsequent use of single allergens, being components of complex allergen sources like pollen, mites, furred animals, foods or insect venoms. Only few protein families contain relevant allergens of similar sequence and structure, carrying common IgE epitopes as the basis of cross reactivity. Used as purified or recombinant (glyco)proteins single allergens can potentially improve in-vitro diagnostics, particularly allergen-specific IgE assays through a) increased sensitivity, b) use of risk and marker allergens, c) component-resolved diagnostics (CRD). CRD can differentiate primary, species-specific from secondary, cross-reactive sensitizations to single allergens. Allergen components facilitate an increased analytical sensitivity, particularly if they are underrepresented or missing in conventional allergen extracts. They are mainly used in single assays (singleplex) for the detection of IgE, but also in a microarray format (multiplex) with 112 components from 50 allergen sources with slightly decreased analytical sensitivity. Concepts of molecular allergy can only be separately defined and utilized for each allergen source (pollen, mites, foods or insect venoms). As soon as essential singe allergens are available, their specific role in diagnostics should be defined. This requires well characterized patient cohorts from various countries, since exposure, allergic immune response and clinical relevance can vary substantially between individual subjects and geographical regions. The patient's clinical information is essential for proper interpretation of molecular allergology results. The history and/or challenge test results will finally provide evidence, in how far a sensitization to single allergens might be clinically relevant or not. PMID- 30402616 TI - Contact allergy to fragrances: current clinical and regulatory trends. AB - . Several fragrances are important contact allergens. Compared to the immense multitude of more than 2,500 fragrances used in cosmetics, the spectrum of single substances and natural extracts used for patch testing appears limited, albeit comprising the supposedly most important contact allergens. The present review summarizes the most important results of the opinion of the Scientific Committee on Consumer Safety on fragrance allergens in cosmetic products from July 2012. Clinical results beyond abovementioned screening allergens, animal results in terms of the LLNA and structure activity considerations point to 100 single substances and extracts, respectively, which, in addition to those 26 already identified, must be considered contact allergens, and the presence of which should be declared in cosmetics. In case of the most commonly used fragrance terpenes limonene and linalool hydroperoxides resulting from autoxidation constitute the major allergens. These have become available as patch test material recently. Altogether 12 single substances have caused a (very) high number of published cases of sensitization. Thus their use concentration should be (further) reduced or, in case of hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC, e.g., Lyral(r)), use should be abandoned altogether. This is also recommended in case of oak moss and tree moss due to their content of the strong sensitizers atranol and chloroatranol. As generic maximum dose for the remaining 11 single substances 0.8 ug/cm2 are suggested, which corresponds, under conservative assumptions, a maximum concentration of 100 ppm in the finished product. PMID- 30402619 TI - Hyperresponsiveness to antihistamines in spontaneous urticaria and heat urticaria. AB - : . BACKGROUND: H1 antihistamines are important drugs for the treatment of urticaria and are commonly well tolerated. Cases of hypersensitivity reactions to antihistamines have rarely been reported, the underlying pathomechanism is unknown yet. CASE REPORT: We report the case of a 28-year-old female patient suffering from chronic spontaneous urticaria who experienced severe episodes of wheals and flares induced by different H1 antihistamines. METHODS: We performed skin prick tests (SPT) with a diversity of H1 antihistamines and CAST and FlowCAST analyses. Moreover, a placebo controlled oral challenge test to mizolastin was done. RESULTS: We saw positive SPT reactions to nearly all H1 antihistamines tested with the exception of mizolastin. We observed neither a release of sulfidoleukotrienes nor an upregulation of basophil activation markers in the CAST and FlowCAST analyses. The oral challenge test with mizolastine resulted in the development of generalized wheals and flares. CONCLUSION: H1 antihistamines are effective drugs for the treatment of urticaria, but they may lead to hypersensitivity reactions in rare cases. Because of the negative CAST and FlowCAST results, an IgE-mediated pathomechanism is improbable. We propose that hypersensitivity reactions to H1 antihistamines may be induced by a paradox H1 receptor activation. PMID- 30402620 TI - Exploiting nanoscale effects in phase change memories. AB - The market launch of Intel's 3D XPointTM proves phase change technology has grown mature. Besides storing information in a fast and non-volatile way, phase change memories (PCMs) may facilitate neuromorphic and in-memory computing. In order to establish PCM as a lasting element of the electronics ecosystem, scalability to future technology nodes needs to be assured. Continued miniaturization of PCM devices is not only prescribed in order to achieve memories with higher data density and neuromorphic hardware capable of processing larger amounts of information. Smaller PCM elements are also incentivized by the prospect of increased power efficiency per operation as less material needs to be heated up for switching. For this reason, a good understanding of the effects of confinement on phase change materials is crucial. Here we describe how miniaturization increases the importance of interface effects and we show how in consequence the crystallization kinetics of phase change materials, when confined into nanometer sized structures, can change significantly. Based on this analysis, the implications of such nanoscale effects are discussed and possible ways of exploiting them proposed. PMID- 30402618 TI - Allergy to pets and new allergies to uncommon pets. AB - . Animal dander is an important source of respiratory allergens, and sensitization to allergens from cat and/or dog during childhood represents a risk factor for the development of asthma and rhinitis later in life. The identification and characterization of allergenic components is crucial to improve diagnosis and therapy in patients with allergy to pets. Allergens from furry animals belong to a restricted number of protein families, a large majority are lipocalins or albumins, some are secretoglobins or latherins. Animal dander contains cross-reactive molecules and current efforts aim at defining species specific allergens that have a high diagnostic sensitivity. Component-resolved diagnosis allows to discriminate genuine sensitization from cross-sensitization. This review contains a detailed description of allergenic components of cat, dog, horse, and small mammalian pets. Sensitizations to exotic pets, a newly emerging issue, are also discussed. PMID- 30402617 TI - Prevention of allergies in childhood - where are we now? AB - Allergic diseases represent an increasing health problem for children worldwide. Along with allergic airway diseases, food allergy comes to the fore and herewith closely intertwined the hypothesis that an early allergic sensitization might occur via skin barrier defect(s). The importance of the skin barrier has been documented by several studies meanwhile. Not only genetic studies screen the associations between Filaggrin loss-of-function mutations, atopic dermatitis, allergic sensitization, food allergy and even airway diseases, but also epidemiological studies cast new light on the hypothesis of the atopic march. As another focus in context of the development of an allergic phenotype, the specific microbial exposure with all its diversities has been crystallized as it shapes the immune system in (early) infancy. Studies explored both, the role of human intestinal microbiota as well as the external microbial diversity. Unfortunately suitable markers for atopic predictors are still rare. New studies point out that specific IgE antibodies (e.g., IgE to Phl p 1) in children without allergic symptoms so far, might function as a pre-clinical biomarker, which may help to identify candidates for primary (allergen non-specific) or secondary (allergen-specific) prevention in terms of specific immunoprophylaxis. These manifold research activities document a complex increase in knowledge. Nevertheless new assumptions need to be substantively confirmed in order to finally generate the urgently needed preventive strategies for allergic diseases in childhood. PMID- 30402621 TI - Dendritic silica@aqueous miscible organic-layered double hydroxide hybrids. AB - We present the synthesis of a series of hierarchical Silica@Layered Double Hydroxide (SiO2@LDH) core@shell hybrid materials that have been post-treated using the Aqueous Miscible Organic Solvent Treatment (AMOST) method. The Silica@Aqueous Miscible Organic-Layered Double Hydroxide (SiO2@AMO-LDH) hybrids exhibit composition flexibility with radially oriented AMO-MgyAl-CO3-LDH nanosheets resulting in a new dendritic morphology. PMID- 30402622 TI - A sensitive and fast responsive fluorescent probe for imaging hypoxic tumors. AB - Nitroreductase activities are positively associated with the hypoxic level of tumors, making it an attractive target for tumor detection. Herein, we have developed a 2,5-bis(methylsulfinyl)-1,4-diaminobenzene based probe (BBP), which is a nitroreductase (NTR) responsive fluorescent probe and can rapidly detect NTRs with high sensitivity and specificity. The BBP showed not only a selective response to NTRs over other biological reductants, but also high sensitivity to NTRs and could detect as low as 20 ng mL-1 NTRs. Furthermore, the BBP responded rapidly to NTRs in as fast as 10 minutes, enabling real-time monitoring of the production levels of NTRs. Most importantly, the BBP could identify NTR activities in 2D cell monolayers, 3D tumor spheroids, and even solid tumors in mice. Particularly, the BBP could monitor the early tumor formation and treatment response via measuring NTR activities. Overall, the BBP appears to be an ideal imaging probe for the detection of solid tumors, and possesses great potential in a broad range of diagnostic and therapeutic applications in the clinic. PMID- 30402623 TI - Genistein and daidzein decrease food intake and body weight gain in mice, and alter LXR signaling in vivo and in vitro. AB - The study is designed to determine whether consumption of the soy isoflavones, genistein and daidzein, differentially influence metabolic syndrome, and to further investigate the involvement of Liver X Receptor (LXR) regulation. C57BL/6J mice were fed diets as follows: low fat diet (LF), western-style diet (WD), and WD containing 0.16% (w/w) of genistein (WD + G) or daidzein (WD + D) for 10 weeks. Intake of WD + G and WD + D produced a robust decrease in body weight gain by 40% and 19%, respectively (p < 0.05). Genistein reduced energy intake by 26%, and daidzein decreased energy intake by 8% (p < 0.05). A glucose tolerance test indicated that genistein consumption significantly decreased the incremental areas under the curve (AUC) from 60-120 min, compared to WD-fed mice. Gene array profiling of hepatic mRNA, and cell studies utilizing transiently transfected HepG2 cells and mouse embryonic fibroblast cells devoid of or expressing LXRalpha, indicate that genistein and daidzein induce LXR-mediated pathways. In summary, addition of genistein, compared to daidzein, to a western style diet, more profoundly decreased food intake, body weight gain, while both appear to regulate LXR-mediated pathways. PMID- 30402624 TI - Low temperature aqueous synthesis of size-controlled nanocrystals through size focusing: a quantum dot biomineralization case study. AB - Traditional quantum dot synthesis techniques rely on the separation of nucleation and growth to control nanocrystal size. However, the same goal can be achieved through slow and continuous introduction of reactive precursors to keep the growth mechanism in the size focusing regime throughout synthesis. In this work, we demonstrate the efficacy of this approach within the framework of functional material biomineralization where, despite simultaneous nucleation and growth of particles, this growth mechanism enables size-controlled nanocrystal synthesis. Herein, the single enzyme cystathionine gamma-lyase (CSE) is utilized to biomineralize CdS nanocrystals via the slow, but continuous turnover of the amino acid l-cysteine to produce H2S. Nanocrystal nucleation and growth theories confirm that consistent addition of monomers will result in a high supersaturation term, driving the nanocrystal growth mechanism into the size focusing regime. We further confirm this theory by mimicking biomineralization via chemical routes and demonstrate the influence of varying supersaturation, to further control the average nanocrystal size. Finally, altering the chelation strength of the capping agent l-cysteine is found to play a key role in balancing nanocrystal growth in solution and long-term stability. PMID- 30402627 TI - High selectivity of sulfur-doped SnO2 in NO2 detection at lower operating temperatures. AB - Resistive gas sensors based on metal oxides have aroused great interest in the sensing of NO2 gas due to their low cost, good stability, and easy fabrication. However, drawbacks such as low sensitivity and a lack of selectivity, which originate from the limited kinds of intrinsic active centers on the surface of the metal oxides that could be involved in the gas-sensing reaction, remain great challenges to overcome. To solve these problems, surface modification of SnO2 by S-doping was carried out by the sintering of flower-like SnS2. Gas-sensing tests revealed that the S-doped SnO2 showed ultra-high sensitivity to NO2 (Rg/Ra = 600 toward 5 ppm) with low optimal operating temperature (50 degrees C). The detection limit of the sensor was as low as 50 ppb (Rg/Ra = 11). Notably, the S doped SnO2 showed negligible cross-responses to alcohol, acetone, HCHO, SO2, H2S, and xylene. The ultra-high sensitivity and selectivity toward NO2 were closely related to the content of the S-dopant. This phenomenon is attributed to the active role of S-dopant during the surface reactions with NO2, which was substantiated by in situ Raman characterization and DFT-based calculations. This study offers an important guide for surface modification by doping to improve the sensitivity and selectivity of metal oxides and sheds new light on material design to develop resistive gas sensors for NO2 detection. PMID- 30402628 TI - Discovery of a novel spin-polarized nodal ring in a two-dimensional HK lattice. AB - Nodal-ring materials with a spin-polarized feature have attracted intensive interest recently due to their exotic properties and potential applications in spintronics. However, such a type of two-dimensional (2D) lattice is rather rare and difficult to realize experimentally. Here, we identify the first 2D Honeycomb Kagome (HK) lattice, Mn-Cyanogen, as a new single-spin nodal-ring material by using first-principles calculations. Mn-Cyanogen shows gapless and semiconducting properties in spin-up and spin-down orientations, respectively, indicating a spin gapless semiconductor nature. Remarkably, a spin-polarized nodal ring induced by px,y/pz band inversion is captured from the 3D band structure, which is irrelevant to spin-orbit coupling. The origin of the single-spin nodal-ring can be further clarified by the effective tight-binding (TB) model. These results open a new avenue to achieving spin-polarized nodal-ring materials with promising applications in spintronic devices. PMID- 30402629 TI - High rate and stable symmetric potassium ion batteries fabricated with flexible electrodes and solid-state electrolytes. AB - Aqueous batteries designed with K-ions have outstanding potential for future energy storage applications. When coupled with cathode and anode materials both operating with the intercalation mechanism, K-ion batteries could have kinetics and stability similar to Li-ion batteries in principle but with a much lower cost. However, the electrode materials developed so far still suffer from poor stability and limited activity, especially from the anode side. Herein, a new concept of symmetric K-ion batteries was developed by using potassium Prussian blue (KPB) as a bipolar material. The KPB particles were grown on flexible and strong wiper cloth substrates that were pre-coated with polypyrrole (PPy). The use of PPy as an interlayer not only boosted electrical conductivity but also ensured uniform growth of KPB particles. The synthesized KPB@PPy@wiper electrodes have superior flexibility and stability, and exhibited two redox pairs both with remarkable kinetics. When used as bipolar electrodes in combination with a gel solid-state electrolyte, they delivered a well-defined discharge voltage plateau at ~0.6 V with superior rate capability and cycling stability. This work could provide new insights into the design of K-ion batteries, and give new options for developing flexible solid-state devices. PMID- 30402630 TI - Electrospun nanofibers facilitate better alignment, differentiation, and long term culture in an in vitro model of the neuromuscular junction (NMJ). AB - The neuromuscular junction (NMJ) is a specialized synapse between motor neurons and the muscle fibers they innervate. Due to the complexity of various signalling molecules and pathways, in vivo NMJs are difficult to study. Therefore, in vitro motor neuron-muscle co-culture plays a pivotal role in studying the mechanisms of NMJ formation associated with neurodegenerative diseases. There is a growing need to develop novel methodologies that can be used to develop long-term cultures of NMJs. To date, there have been few studies on NMJ development and long-term maintenance of the system, which is also the main challenge for the current in vitro models of NMJs. In this study, we demonstrate a long-term co-culture system of primary embryonic motor neurons from Sprague-Dawley rats and C2C12 cells on both random and aligned electrospun polylactic acid (PLA) nanofibrous scaffolds. This is the first study to explore the role of electrospun nanofibers in the long term maintenance of NMJs. PLA nanofibrous scaffolds provide better contact guidance for C2C12 cells aligning along the fibers, thus guiding myotube formation. We can only maintain the co-culture system on a conventional glass substrate for 2 weeks, whilst 55% and 70% of the cells still survived on random and aligned PLA substrates after 7 weeks. Our nanofiber-based long-term co culture system is used as an important tool for the fundamental research of NMJs. PMID- 30402631 TI - Two-dimensional beta-lead oxide quantum dots. AB - In recent years, black-phosphorus-analogue (BPA) two-dimensional (2D) materials have been explored to demonstrate promising optoelectronic performances and distinguished ambient stabilities, holding great promise in practical applications. Here, one new kind of BPA material, orthorhombic beta-PbO quantum dots (QDs), is successfully fabricated by a facile liquid phase exfoliation (LPE) technique. The as-prepared beta-PbO QDs show a homogeneous distribution of the lateral size (3.2 +/- 0.9 nm) and thickness (2.5 +/- 0.5 nm), corresponding to 4 +/- 1 layers. The carrier dynamics of beta-PbO QDs was systematically investigated via a femtosecond resolution transient absorption approach in the visible wavelength regime and it was clarified that two decay components were resolved with a decay time of tau1 = 2.3 +/- 0.3 ps and tau2 = 87.9 +/- 6.0 ps, respectively, providing important insights into their potential applications in the field of ultrafast optics, nanomechanics and optoelectronics. As a proof-of concept, beta-PbO QDs were, for the first time to our knowledge, fabricated as a working electrode in a photoelectrochemical (PEC)-typed photodetector that exhibits significantly high photocurrent density and excellent stability under ambient conditions. PMID- 30402632 TI - Digital polymerase chain reaction technology - recent advances and future perspectives. AB - Digital polymerase chain reaction (dPCR) technology has remained a "hot topic" in the last two decades due to its potential applications in cell biology, genetic engineering, and medical diagnostics. Various advanced techniques have been reported on sample dispersion, thermal cycling and output monitoring of digital PCR. However, a fully automated, low-cost and handheld digital PCR platform has not been reported in the literature. This paper attempts to critically evaluate the recent developments in techniques for sample dispersion, thermal cycling and output evaluation for dPCR. The techniques are discussed in terms of hardware simplicity, portability, cost-effectiveness and suitability for automation. The present paper also discusses the research gaps observed in each step of dPCR and concludes with possible improvements toward portable, low-cost and automatic digital PCR systems. PMID- 30402633 TI - A review of sorting, separation and isolation of cells and microbeads for biomedical applications: microfluidic approaches. AB - Several biomedical analyses are performed on particular types of cells present in body samples or using functionalized microparticles. Success in such analyses depends on the ability to separate or isolate the target cells or microparticles from the rest of the sample. In conventional procedures, multiple pieces of equipment, such as centrifuges, magnets, and macroscale filters, are used for such purposes, which are time-consuming, associated with human error, and require several operational steps. In the past two decades, there has been a tendency to develop microfluidic techniques, so-called lab-on-a-chip, to miniaturize and automate these procedures. The processes used for the separation and isolation of the cells and microparticles are scaled down into a small microfluidic chip, requiring very small amounts of sample. Differences in the physical and biological properties of the target cells from the other components present in the sample are the key to the development of such microfluidic techniques. These techniques are categorized as filtration-, hydrodynamic-, dielectrophoretic-, acoustic- and magnetic-based methods. Here we review the microfluidic techniques developed for sorting, separation, and isolation of cells and microparticles for biomedical applications. The mechanisms behind such techniques are thoroughly explained and the applications in which these techniques have been adopted are reviewed. PMID- 30402635 TI - In situ paper-based 3D cell culture for rapid screening of the anti-melanogenic activity. AB - Recently, paper has gained traction in the biotechnology research field due to its ability to be a substrate for 3D cell culture. In this work, we demonstrate the application of paper-based 3D cell culture for rapid and easy screening of the effect of natural compounds on melanin production. Whatman No. 1 filter paper was used as the substrate for B16F10 melanoma cell culture. The use of paper is beneficial for supporting the 3D structure of cells, which makes the result more reliable due to the similarity to in vivo conditions. Furthermore, paper is beneficial for melanin observation due to melanin's black color, which is easily in situ visualized after it is cultured on white paper. Matrigel was used to encapsulate cells before being pipetted onto the paper to prevent the passing of cells through paper pores. The intensity of melanin can then be observed with the naked eye and analyzed by scanning the paper. The analysis process took only 20 minutes, which is faster than that of the conventional absorbance spectroscopy, owing to the elimination of centrifugation, melanin solubilization, and the absorbance measurement step. The color intensity on the paper showed a direct proportion with increased alpha-MSH concentrations, confirming that the color on the paper was melanin. The 3D structure of cells was confirmed by using a scanning electron microscope. To demonstrate the application of the paper-based scaffold, paper-based 3D cell culture was used for screening the effects of Kojic acid and Arbutin on melanin production, which showed increased anti-melanogenesis effects with increased concentrations of natural compounds. High cell viability was observed over 120 hours. In conclusion, the developed paper-based scaffold can be used for screening the effect of natural compounds on melanin production, as a rapid and simple method with low cost. PMID- 30402637 TI - Inhibition of perilipin 2 expression reduces pro-inflammatory gene expression and increases lipid droplet size. AB - Our lab previously demonstrated that triglyceride-rich lipoprotein (TGRL) lipolysis products induce lipid droplet formation and pro-inflammatory gene expression in monocytes. We hypothesized that the inhibition of perilipin 2 expression in THP-1 monocytes would reduce lipid droplet formation and suppress pro-inflammatory gene expression induced by TGRL lipolysis products. In the current study, we use microarray analysis to identify gene expression altered by TGRL lipolysis products in THP-1 monocytes. We confirmed the expression of selected genes by quantitative reverse transcription PCR and characterized lipid droplet formation in these cells after exposure to TGRL lipolysis products. Using siRNA inhibition of perilipin 2 expression, we examined the role of perilipin 2 in the response of THP-1 monocytes to TGRL lipolysis products. We found that perilipin 2 siRNA increased the intracellular triglyceride content, increased the size of lipid droplets, and reduced pro-atherogenic and pro-inflammatory gene expression. We saw a reduction of serum/glucocorticoid kinase 1, v-maf musculoaponeurotic fibrosarcoma oncogene homolog F (avian), chemokine (C-C motif) ligand 3, and interleukin 8 gene expression induced by TGRL lipolysis products. This study supports previous findings that reduction of perilipin 2 expression is protective against atherogenesis, while finding an unexpected increase in lipid droplet size with reduced perilipin 2 expression. PMID- 30402638 TI - Low intake of digestible carbohydrates ameliorates the duodenal absorption of carbohydrates in mice with glucose metabolic disorders induced by sucralose. AB - In the current study, the protective effects of diets with low digestible carbohydrates (LDCs) on plasma glucose, plasma fasting insulin, sweet taste receptors, glucose transporters and absorption of carbohydrates in mice that consume sucralose were evaluated. Sucralose (0.4 g L-1) was administered to mice to induce glucose metabolic disorders. The experimental groups were treated with different LDC contents but with the same energy as the normal-chow group. A pair group fed the highest digestible carbohydrate content was designed to illustrate the effect of digestible carbohydrate content on glucose metabolic disorders. Prolonged administration of sucralose led to metabolic dysfunction that was characterized by a significant increase in plasma glucose, insulin resistance, sweet taste receptors, glucose transporters and absorption of carbohydrates. Treatment with LDC feed positively modulated the altered parameters in a dose dependent manner, suggesting the overall beneficial effects of LDC feed on sucralose associated detrimental changes. PMID- 30402639 TI - Silver nano-needles: focused optical field induced solution synthesis and application in remote-excitation nanofocusing SERS. AB - Tapered metallic nanostructures that harbor surface plasmons are highly interesting for nanophotonic applications because of their waveguiding and field focusing properties. Here, we developed a focused optical field induced solution synthesis for unique crystallized silver nano-needles. Under the focused laser spot, inhomogeneous Ag monomer concentration is created, which triggers the uniaxial growth of silver nanostructures along the radial direction with decreasing rate, forming nano-needle structures. These nano-needles are several micrometers long, with diameter attenuating from hundreds to tens of nanometers, and terminated by a sharp apex only a few nanometers in diameter. Moreover, nano needles with atomically smooth surfaces show excellent performance for plasmonic waveguiding and unique near-field compression abilities. This nano-needle structure can be used for effective remote-excitation detection/sensing. We also demonstrate the assembling and picking up of nano-needles, which indicate potential applications in intracellular endoscopy, high resolution scanning tips, on-chip nanophotonic devices, etc. PMID- 30402640 TI - Synthesis and reactivity of aza-dipyrrin alkali metal salts. AB - We report the lithium, sodium and potassium salts of aza-dipyrrins and detail their use as anionic aza-dipyrrinato ligand sources in complexation. Of the three types of alkali salts studied, those of lithium are found to be most useful as synthetic precursors. For example, they selectively afford heteroleptic aza dipyrrinato zinc complexes which can be further modified via ligand exchange. PMID- 30402641 TI - Defect-free SnTe topological crystalline insulator nanowires grown by molecular beam epitaxy on graphene. AB - SnTe topological crystalline insulator nanowires have been grown by molecular beam epitaxy on graphene/SiC substrates. The nanowires have a cubic rock-salt structure, they grow along the [001] crystallographic direction and have four sidewalls consisting of {100} crystal planes known to host metallic surface states with a Dirac dispersion. Thorough high resolution transmission electron microscopy investigations show that the nanowires grow on graphene in the van der Waals epitaxy mode induced when the catalyzing Au nanoparticles mix with Sn delivered from a SnTe flux, providing a liquid Au-Sn alloy. The nanowires are totally free from structural defects, but their {001} sidewalls are prone to oxidation, which points out the necessity of depositing a protective capping layer in view of exploiting the magneto-electric transport phenomena involving charge carriers occupying topologically protected states. PMID- 30402642 TI - Improving the phase stability and cycling performance of Ce2Ni7-type RE-Mg-Ni alloy electrodes by high electronegativity element substitution. AB - In the present work, a high electronegativity element substitution strategy was employed to obtain a better corrosion resistance and cycling performance of Ce2Ni7-type La0.83-xYxMg0.17Ni3.1Co0.3Al0.1 (x = 0.0-0.6) alloys. The abundance of the Ce2Ni7-type phase increased as x increased from 0 to 0.2 but it decreased with a further increase in x up to 0.6. The alloy with x = 0.2 further showed a superior discharge capacity (400.6 mA h g-1) and high cycling stability (S320 = 75%). We found that the Y (electronegativity value chiY = 1.22 > chiLa = 1.10) element could play an essential role in enhancing the anti-corrosion of alloys based on a theoretical framework of the electronegativity of rare earth elements, thus leading to an excellent cycle lifetime of the alloys. The new alloying designs are expected to provide viable La-Mg-Ni-based intermetallic compounds as anode materials for commercial Ni-MH batteries. PMID- 30402643 TI - Cobalt-catalyzed regioselective syntheses of indeno[2,1-c]pyridines from nitriles and diynes bearing propargyl fragments. AB - A highly efficient CoI2/o-phenanthroline catalyzed cycloaddition reaction of diynes bearing TBS protected propargylic alcohol fragments with nitriles has been developed. This methodology offers regioselective access, with good functional group tolerance, to various indeno[2,1-c]pyridine derivatives in moderate to excellent yields. It was found that o-phenanthroline as a bidentate nitrogen ligand showed high efficacy in this cycloaddition reaction. PMID- 30402644 TI - A new 3-D coordination polymer as a precursor for CuI-based thermoelectric composites. AB - Two complexes, [Cu6I6(L1)3]n (I) and [Cu4I4(L2)2]n (II) (L1 = 1,4 bis(phenylthio)but-2-yne; L2 = 1,4-bis(phenylthio)butane), as precursors for thermoelectric composites were prepared using a literature procedure. During the preparation of I, an unexpected 3-D polymorph [Cu4I4(L1)2]n (1) with a triclinic space group and an infinite [CuI]n staircase structure was obtained. This new polymorph (1) exhibited the same structure at both room temperature and 173 K. Complexes 1 and II were therefore pyrolysed to composites 2 and 3, respectively, at 400 degrees C under a nitrogen gas flow. Composite 3 was pale in color with a low carbon content (0.05 wt%) and easily disassembled during handling. By comparison, the high carbon containing (10.2 wt%) composite 2 can be compressed into a robust, light pellet (density 3.58 g cm-3), which showed a moderate to high Seebeck coefficient (543-1308 MUV K-1) over the temperature range 70-240 degrees C. PMID- 30402645 TI - Nanoflower-like N-doped C/CoS2 as high-performance anode materials for Na-ion batteries. AB - Novel nanoflower-like N-doped C/CoS2 spheres assembled from 2D wrinkled CoS2 nanosheets were synthesized through a facile one-pot solvothermal method followed by sulfurization. Ascribed to the optimized 3D nanostructure and rational surface engineering, the unique hierarchical structure of the nanoflower-like C/CoS2 composites showed an excellent sodium ion storage capacity accompanied by high specific capacity, superior rate performance and long-term cycling stability. Specifically, the conductive interconnected wrinkled nanosheets create a number of mesoporous structures and thus can greatly release the mechanical stress caused by Na+ insertion/extraction. Besides, it was observed from the experiments that many extra defect vacancies and Na+ storage sites are introduced by the nitrogen doping process. It was also observed that the crosslinked 2D nanosheets can effectively reduce the diffusion lengths of sodium ions and electrons, resulting in an outstanding rate performance (>700 mA h g-1 at 1 A g-1 and 458 mA h g-1 at even 10 A g-1) and extraordinary cycling stability (698 mA h g-1 at 1 A g-1 after 500 cycles). The results provide a facile approach to fabricate promising anode materials for high-performance sodium-ion batteries (SIBs). PMID- 30402646 TI - Fabrication of sub-20 nm patterns using dopamine chemistry in self-aligned double patterning. AB - A self-aligned double patterning approach using a dopamine chemistry-inspired coating technique has been developed for the fabrication of sub-20 nm patterns. Poly(methyl methacrylate) (PMMA) films were patterned by nanoimprint lithography to form relief features. A thin layer of polydopamine (PDA) was conformally deposited on the surface of the PMMA pattern sidewalls to form a spacer layer. After etching the surface of the PDA layer from the horizontal surfaces and subsequently removing the PMMA template, free-standing PDA sidewall patterns remained that essentially doubled the original PMMA pattern density with decreased feature dimensions as compared to the initial PMMA template structures. The critical dimension of the PDA patterns can be tuned to ~20 nm by controlling the PDA deposition conditions and further reduced to ~13 nm by thermal carbonization of the PDA. Both simple lines and more complex rhombic ring features were fabricated by this technique to demonstrate its capacity for replicating arbitrary patterns. This work represents a simple and scalable strategy for preparing well-defined nanostructures with feature sizes usually only accessible via complex leading edge lithographic methods. PMID- 30402647 TI - Revisiting the intense NIR active bronzaphyrin, a 26-pi aromatic expanded porphyrin: synthesis and structural analysis. AB - Dithiabronzaphyrin, with intense absorption and fluorescence in the NIR region, was synthesized as its beta-octaethyl analogue via a thiophene bridged terpyrrole. Solid state structural characterization obtained for the first time revealed inversion of the thiophene rings. Studies showed that there is no effect from protonation or temperature on the structural rigidity of the macrocycle. Crystal packing revealed four open dimeric trifluoroacetate [(CF3COO)2H]- moieties binding to the macrocycle in the protonated form via H bonding. PMID- 30402648 TI - Self-assembly of supramolecular nanotubes/microtubes from 3,5-dimethyl-4 iodopyrazole for plasmonic nanoparticle organization. AB - Hierarchical super-architectures from small molecule self-assembly have interesting properties and play an indispensable role in many fields. In most cases, a self-assembly process refers to multiple intermolecular interactions among intricately designed building blocks. Here, a supramolecular assembly with a tubular morphology with dimensions ranging from nanometers to micrometers was prepared through self-assembly of 3,5-dimethyl-4-iodopyrazole (DMIP), a molecule with an unprecedented simple structure. As predicted by density functional theory (DFT) calculations, the hydrogen bond and halogen bond interaction energy between DMIP molecules can be up to 32.81 kJ mol-1, which effectively drives DMIP molecules to assemble into fibrils, sheets, and finally, tubular architectures. Intriguingly, the formed tubular structure can be easily removed by heating at 100 degrees C, enabling the material to function as a disposable template to guide linear organization of nanostructures. As a proof of concept, ordered Au or Ag nanochains with diameters ranging from 18 to 120 nm were facilely prepared in high yield. PMID- 30402649 TI - Ultrasensitive and simple fluorescence biosensor for detection of the mecA gene of Staphylococcus aureus by using an exonuclease III-assisted cascade signal amplification strategy. AB - In this work, a label-free fluorescence biosensor for ultrasensitive and simple detection of the mecA gene of Staphylococcus aureus was proposed by using an exonuclease III (Exo III)-assisted cascade signal amplification strategy. The 3' end-extruding hairpin probe (HP) acted as the target recognition element and the caged G-quadruplex was used as the signal reporter. Without the mecA gene, the HP probe cannot be digested by Exo III, as the G-rich sequences are blocked in the stem of the HP probe. In the presence of the mecA gene, the hybridization of the mecA gene with the 3' end-extruding HP probe triggers the digestion reaction of Exo III, liberating the mecA gene and the mecA gene analogue. Both the released mecA gene and the mecA gene analogue can hybridize with other HP probes and activate another round of the cleavage reaction. Consequently, the released free G-quadruplex is "lit up" by N-methylmesoporphyrin IX (NMM), displaying a dramatically enhanced fluorescence intensity. This sensing platform showed a high sensitivity towards the mecA gene with a detection limit as low as 2.4 fM without any labelling, immobilization, or washing steps. The designed sensing system also exhibits excellent selectivity for the mecA gene in the presence of other interfering DNA sequences. Furthermore, the presented biosensor is robust and has been successfully applied for the detection of the mecA gene in a real food sample with satisfactory results. Owing to its simplicity, cost-effectiveness and ultrasensitivity, our proposed sensing strategy provides a promising platform for the detection of other genes by substituting the target-recognition element. PMID- 30402650 TI - Encapsulation and solubilization of ultrastable quantum dots with multidentate bilayer ligands and rheological behaviour. AB - Quantum dots with unique optical and chemical properties show great potential applications in biology and chemical and medical science. Nevertheless, their practical applications in various fields are greatly limited due to the presence of hydrophobic organic surfaces. In this paper, we report a simple and effective method based on ligand exchange and proton donor-receptor reaction to prepare ultrastable and amphiphilic quantum dots having bilayer ligands with ultidentate structure, which provide active sites for subsequent functional conjugation. Our results show that these quantum dots exhibit monodispersity, excellent stability and solvent-free fluidity. In addition, they maintain their optical properties in a chemical environment due to the large amount of amphiphilic amine salts as ligands, which also endow quantum dots with lower cytotoxicity and higher antibacterial activity. The synthesis strategy in this study provides a new insight into the design and fabrication of promising multifunctional materials for biology, medicine, and energy and display technologies. PMID- 30402651 TI - Acoustic impedance-based size-independent isolation of circulating tumour cells from blood using acoustophoresis. AB - Label-free isolation of CTCs from blood is critical for the development of diagnostic and prognostic tools for cancer. Here, we report a label-free method based on acoustic impedance contrast for the isolation of CTCs from peripheral blood mononuclear cells (PBMCs) in a microchannel using acoustophoresis. We describe a method in which the acoustophoretic migration of PBMCs is arrested by matching their acoustic impedance with that of the sample medium, and CTCs that have different acoustic impedance compared to PBMCs migrate toward the pressure node or antinode and thus become isolated. We show that acoustic streaming which can adversely affect the CTC isolation is suppressed owing to the inhomogeneous liquid flow configuration. We establish a method for isolation of CTCs that have higher or lower acoustic impedance compared to PBMCs by controlling the acoustic impedance contrast of the liquids across the channel. Applying this method, we demonstrate label-free isolation of HeLa and MDA-MB-231 cells from PBMCs (collected from 2.0 mL of blood) within one hour yielding a recovery of >86% and >50-fold enrichment. Combined impedance and size-based sorting is proposed as a promising tool for the effective isolation of CTCs from blood. PMID- 30402654 TI - Rapamycin reduces mortality in acute-stage paraquat-induced toxicity in zebrafish. AB - INTRODUCTION: Paraquat (PQ) intoxication is frequently associated with a high mortality rate. No specific treatment has been shown to reduce mortality in victims within the first 72 hours. We investigated the protective effects of rapamycin (Rapa) against PQ-induced toxicity in a zebrafish model. METHODS: To determine the maximum nonlethal concentration (MNLC) and lethal concentration 50 (LC50) of Rapa, zebrafish were treated at 2-5 days post fertilisation (dpf) and their mortality was recorded every 24 hours. At 5 dpf, the zebrafish were treated with PQ 100 MUg/mL or PQ+Rapa (MNLC, 1/3 MNLC or 1/9 MNLC) for 72 hours, and the rate of survival was recorded every 24 hours. Reverse transcription-polymerase chain reaction was used to test the signalling pathway of mTOR (mammalian target of rapamycin). RESULTS: MNLC and LC50 of Rapa were determined to be 6.7 MUg/mL and 28.9 MUg/mL, respectively. At 48 hours, the PQ+Rapa groups had much lower mortality than the PQ group. The rates of survival of the PQ+Rapa groups were 43.33% (MNLC), 53.89% (1/3 MNLC) and 44.45% (1/9 MLNC), as compared to 19.45% in the PQ group, with the 1/3 MNLC group showing the highest rate of survival (p < 0.001). atg1 was slightly activated in the PQ group. In the PQ+Rapa groups, the expression of atg1 was markedly increased, suggesting strengthening of the autophagy process. CONCLUSION: Rapa can increase the rate of survival of PQ intoxicated zebrafish by inhibiting mTOR complex 1 and activating autophagy. Rapa could be an alternative first-line drug in the treatment of PQ poisoning. PMID- 30402653 TI - Metabolic and endocrine effects of epidural glucocorticoid injections. AB - INTRODUCTION: Epidural steroid injections are an integral part of nonsurgical management of radicular pain from lumbar spine disorders. We studied the effect of dexamethasone 8 mg epidural injections on the hypothalamic-pituitary-adrenal axis and serum glucose control of Asian patients. METHODS: 18 patients were recruited: six diabetics and 12 non-diabetics. Each patient received a total of dexamethasone 8 mg mixed with a local anaesthetic solution of lignocaine or bupivacaine, delivered into the epidural space. Levels of plasma cortisol, adrenocorticotropic hormone (ACTH), serum glucose after an overnight fast and two hour postprandial glucose, as well as weight, body mass index, blood pressure and heart rate were measured within one week prior to the procedure (baseline) and at one, seven and 21 days after the procedure. RESULTS: Median fasting blood glucose levels were significantly higher on post-procedure Day 1 than at baseline. However, there was no significant change in median two-hour postprandial blood glucose from baseline levels. At seven and 21 days, there was no significant difference in fasting or two-hour postprandial glucose levels. Both ACTH and serum cortisol were significantly reduced on Day 1 compared to baseline in all patients. There was no significant difference in ACTH and serum cortisol levels from baseline at Days 7 and 21. CONCLUSION: Our study shows that epidural steroid injections with dexamethasone have a real, albeit limited, side effect on glucose and cortisol homeostasis in an Asian population presenting with lower back pain or sciatica. PMID- 30402656 TI - Plasmodium genomics: an approach for learning about and ending human malaria. AB - Malaria causes high levels of morbidity and mortality in human beings worldwide. According to the World Health Organization (WHO), about half a million people die of this disease each year. Malaria is caused by six species of parasites belonging to the Plasmodium genus: P. falciparum, P. knowlesi, P. vivax, P. malariae, P. ovale curtisi, and P. ovale wallikeri. Currently, malaria is being kept under control with varying levels of elimination success in different countries. The development of new molecular tools as well as the use of next generation sequencing (NGS) technologies and novel bioinformatic approaches has improved our knowledge of malarial epidemiology, diagnosis, treatment, vaccine development, and surveillance strategies. In this work, the genetics and genomics of human malarias have been analyzed. Since the first P. falciparum genome was sequenced in 2002, various population-level genetic and genomic surveys, together with transcriptomic and proteomic studies, have shown the importance of molecular approaches in supporting malaria elimination. PMID- 30402655 TI - Clinical use of sodium-glucose co-transporter-2 inhibitors in Chinese patients with type 2 diabetes mellitus. AB - INTRODUCTION: Type 2 diabetes mellitus (T2DM), the tenth leading cause of death in Hong Kong, has a prevalence of approximately 10%. Sodium-glucose co transporter-2 (SGLT2) inhibitors lower glycated haemoglobin A1c (HbA1c) levels in patients with T2DM via a non-insulin-dependent mechanism of action, but real world data, particularly for Chinese patients, is limited. METHODS: A retrospective, single-centre study was performed among Chinese patients with T2DM who were prescribed SGLT2 inhibitor therapy in Hong Kong. Changes in HbA1c, body weight, and systolic and diastolic blood pressures, estimated glomerular filtration rate (eGFR), lipid profiles and adverse events were observed for patients who completed at least one follow-up visit during the study period. RESULTS: Overall, 100 patients were included, and 53 patients attended an additional final visit. By the final visit, SGLT2 inhibitor therapy significantly decreased HbA1c levels (change 0.31%; 95% confidence interval [CI]: -0.11% to 0.51%; p < 0.001), body weight (change -4.59 kg; 95% CI: -3.75 to -5.54 kg; p < 0.001) and systolic blood pressure (change -5.72 mmHg; 95% CI: -1.72 to -9.72 mmHg; p < 0.001) from baseline. No significant change in eGFR or lipid profiles, except for a significant reduction in high-density lipoprotein cholesterol (change -0.09 mmol/L; 95% CI: -0.16 to -0.02 mmol/L; p = 0.014), was observed. Adverse events were consistent with previous reports for SGLT2 inhibitors, except appetite loss associated with canagliflozin. CONCLUSION: The real-world efficacy and safety profile of SGLT2 inhibitors in Chinese patients was comparable to that reported in Phase III clinical trials, with the exception of appetite loss among patients administered canagliflozin. PMID- 30402657 TI - Correction to: Practical approach to diastolic dysfunction in light of the new guidelines and clinical applications in the operating room and in the intensive care. AB - In the original article [1], the authors noticed a typographical error in Figure 2. The top left box should have included "E/A <0.8 and E <50 cm/s". Please see below the corrected figure. PMID- 30402658 TI - DFT study of the dual catalytic role of L-proline in the aldol reaction and the effect of water on it. AB - The aldol reaction in the presence of L-proline acting as an organocatalyst is a well-known example of asymmetric synthesis. Many theoretical and experimental studies have been carried out to probe the mechanism of this reaction. In this work, two levels of density functional theory in the gas phase and DMSO were used to elucidate the best pathways for this reaction, with the enamine and enol considered intermediates and L-proline considered either a reactant or a facilitator. The calculations indicated that both intermediates are formed simultaneously in the reaction medium. Interestingly, the formation of the enamine intermediate predominates in DMSO at room temperature, whereas the enol becomes the predominant intermediate upon the addition of water. Graphical Abstract The dual role of L-proline leads to single stereoisomeric aldol product via two completely different pathways. PMID- 30402660 TI - Levosimendan in Acute and Advanced Heart Failure: an Expert Perspective on Posology and Therapeutic Application. AB - Levosimendan, a calcium sensitizer and potassium channel-opener, is widely appreciated by many specialist heart failure practitioners for its effects on systemic and pulmonary hemodynamics and for the relief of symptoms of acute heart failure. The drug's impact on mortality in large randomized controlled trials has been inconsistent or inconclusive but, in contrast to conventional inotropes, there have been no indications of worsened survival and some signals of improved heart failure-related quality of life. For this reason, levosimendan has been proposed as a safer inodilator option than traditional agents in settings, such as advanced heart failure. Positive effects of levosimendan on renal function have also been described. At the HEART FAILURE 2018 congress of the Heart Failure Association of the European Society of Cardiology, safe and effective use levosimendan in acute and advanced heart failure was examined in a series of expert tutorials. The proceedings of those tutorials are summarized in this review, with special reference to advanced heart failure and heart failure with concomitant renal dysfunction. Meta-analysis of clinical trials data is supportive of a renal-protective effect of levosimendan, while physiological observations suggest that this effect is exerted at least in part via organ specific effects that may include selective vasodilation of glomerular afferent arterioles and increased renal blood flow, with no compromise of renal oxygenation. These lines of evidence require further investigation and their clinical significance needs to be evaluated in specifically designed prospective trials. PMID- 30402659 TI - Depression, Anxiety, and Cognitive Impairment : Comorbid Mental Health Disorders in Heart Failure. AB - PURPOSE OF REVIEW: Depression, anxiety, and cognitive impairment constitute established risk markers for incident cardiovascular disease (CVD) and are associated with impaired life expectancy and quality of life and high hospitalization rates and healthcare expenditure. This review summarizes current knowledge about mental health disorders in patients with CVD and heart failure (HF). RECENT FINDINGS: Emerging evidence suggests various shared pathophysiological mechanisms between psychological comorbidities and CVD (e.g., systemic inflammation and autonomic dysfunction). Bi-directional interactions involving the central nervous and cardiovascular systems may help explain the rising prevalence of comorbid mood disorders with increasing CVD severity and support the concept of alternative pathophysiological mechanisms in the presence of severe somatic illness, making symptoms less responsive or unresponsive to psychotropic pharmacotherapy. Considering high prevalence and negative impact of psychological comorbidities in CVD and HF, routine care should integrate screening for these conditions. Multidisciplinary treatment approaches with active patient participation in disease management were shown to improve outcomes. However, better understanding of factors mediating the adverse prognostic effects of mood disorders is needed. This might enable more targeted treatment and possibly also facilitate better understanding of the pathophysiological mechanisms driving CVD. PMID- 30402661 TI - The emergence of modern muscle names: the contribution to the foundation of systematic terminology of Vesalius, Sylvius, and Bauhin. AB - Although its history is complicated, today's anatomical nomenclature, including muscle terminology, has acquired a system of naming using epithets. The objective of this literary research paper was to ascertain the founder of modern muscle terminology. The texts of four anatomists, Galen, Andreas Vesalius, Jacobus Sylvius, and Gaspard Bauhin, who have all been identified as being influential in the establishment of early modern anatomy and its nomenclature, were analyzed. Particular emphasis was given to the naming method, and to the consistency of that method. The analysis shows that each of these four anatomists had a different conception of muscle naming, and that three early modern anatomists, Vesalius, Sylvius, and Bauhin, contributed to the development of modern muscle terminology. This investigation revealed the types of contributions they made: Vesalius was an originator of rule-governed muscle terminology with a univocal naming method, Sylvius was an inventor of epithet naming, and Bauhin applied Sylvius's epithet naming method to Vesalius's concept of rule-governed terminology with a univocal naming method. PMID- 30402662 TI - Medial soft tissue contracture does not always exist in varus osteoarthritis knees in total knee arthroplasty. AB - PURPOSE: To evaluate preoperative soft tissue balance for total knee arthroplasty (TKA), varus/valgus stress radiographs has been used in previous studies. While the joint line of femur and tibia is almost parallel in healthy and postoperative knees, osteoarthritis (OA) knees exhibit articular cartilage wear that causes the joint line tilting even in a non-stress condition. Therefore, the exact angle of the joint line might mislead to understand the joint laxity in OA knees. The purpose of this study was to evaluate soft tissue balance in varus OA knees using preoperative stress radiographs under three different constant loads, taking the articular cartilage wear into consideration. METHODS: One hundred and eighteen varus-deformed OA knees in 102 patients were investigated before primary TKA. Preoperative knee radiographs were obtained in the anteroposterior view with no stress (defined as the neutral condition) and with varus and valgus stresses (5, 10, and 15 kg) in extension. Two different types of joint line angle (JLA), the absolute JLA (an exact angle of joint line) and the relative JLA (the absolute JLA minus the JLA in the neutral condition), were compared for the same load with the paired t test. RESULTS: The absolute JLA was 7.9 +/- 1.2 degrees /- 1.5 +/- 2.2 degrees under varus/valgus 15 kg stress, 6.7 +/- 2.4 degrees /- 0.3 +/- 2.1 degrees under varus/valgus 10 kg stress, and 4.7 +/- 2.4 degrees /1.1 +/- 2.2 degrees under varus/valgus 5 kg stress. Significant differences in the numerical values of the absolute JLA were observed between varus and valgus stresses for each load. The neutral JLA was 3.2 +/- 2.0 degrees . The relative JLA was 4.8 +/- 2.1 degrees /- 4.7 +/- 1.8 degrees under varus/valgus 15 kg stress, 3.5 +/- 2.0 degrees /- 3.5 +/- 1.8 degrees under varus/valgus 10 kg stress, and 1.5 +/- 1.9 degrees /- 2.1 +/- 1.8 degrees under varus/valgus 5 kg stress. No significant differences in the numerical values of the relative JLA were observed between varus and valgus stresses for each load. CONCLUSIONS: Consideration of cartilage wear allowed knee laxity to be evaluated more precisely in this study than in previous reports. It was shown that medial soft tissue contracture did not always exist, even in varus OA knees. Regarding clinical relevance, surgeons should be aware that underestimating medial soft tissue laxity due to reliance on the absolute JLA might lead to excessive medial tissue release and result in postoperative instability and lower patient satisfaction. LEVEL OF EVIDENCE: IV. PMID- 30402663 TI - ? PMID- 30402665 TI - Graphene nanosheets modified with curcumin-decorated manganese dioxide for ultrasensitive potentiometric sensing of mercury(II), fluoride and cyanide. AB - A glassy carbon electrode (GCE) was modified by electropolymerization of curcumin on MnO2-Gr nanosheets to obtain a detection method for Hg(II) and for the anions fluoride and cyanide. The complexation by curcumin can be monitored by potentiometry. The results revealed a cathodic shift for the simultaneous detection of fluoride and cyanide and an anodic shift for the mercury(II) sensing, with peak potentials of -0.24, 0.12 and 0.82 V, respectively (vs. Ag/AgCl). The modified GCE is fairly selective, reproducible and repeatable. The detection limits are 19.2 nM for Hg(II), 17.2 nM for fluoride, and 28.3 nM for cyanide (LOD, S/N = 3). The method was successfully applied to the analysis of spiked samples of tap water, river water and petrochemical refinery wastewater. Graphical abstract Schematic of an electrochemical curcumin-MnO2-graphene nanosheet platform for the simultaneous assay of fluoride, cyanide and mercury(II) in the ppb concentration range in various natural and wastewater samples. PMID- 30402666 TI - Craniofacial resection of malignant tumors of the anterior skull base: a case series and a systematic review. AB - BACKGROUND: Craniofacial resection (CFR) is still considered as the gold standard for managing sinonasal malignancies of the anterior skull base (ASB), while endoscopic approaches are gaining credibility. The goal of this study was to evaluate outcomes of patients who underwent CFR at our institution and to compare our results to international literature. METHOD: Retrospective analysis of all patients undergoing CFR between 1995 and 2017, and systematic literature review according to the PRISMA statement. RESULTS: Forty-one patients with sinonasal malignancy (81% with stage T4) of the ASB were included. There was no operative mortality. Complications were observed in 9 cases. We obtained 100% follow-up with mean observation of 100 months. Disease-specific survival rates were 90%, 74%, and 62% and recurrence-free survival was 85% at two, 72% at five, and 10 years follow-up, respectively. CFR as primary treatment, en bloc resection, and resection with negative margins correlated to better survival. Recursive partition analysis identified the latter as the most important prognostic factor, regardless of surgical technique. The relative risk of non-radicality was significantly higher after piecemeal resection compared to en bloc resection. Compared to 15 original articles, totaling 2603 patients, eligible for review, the present study has the longest follow-up time, the second highest 5-year OS, and the third highest 5-year DSS, despite having a higher proportion of patients with high-stage disease. CONCLUSION: CFR in true en bloc fashion can still be considered as the treatment of choice in cases of advanced-stage sinonasal malignancies invading the ASB. PMID- 30402667 TI - Integrating Wikipedia Articles and Images into an Information Resource for Radiology Patients. AB - Wikipedia-an open-access online encyclopedia-contains a large number of medically relevant articles and images that may help supplement glossaries of radiology terms. We sought to determine the extent to which concepts from a large online radiology glossary developed as part of the Patient-Oriented Radiology Reporter (PORTER) initiative could be mapped to relevant Wikipedia web pages and images using automated or semi-automated approaches. The glossary included 4090 concepts with their definitions; the concept's preferred name and lexical variants, such as plurals, adjectival forms, synonyms, and abbreviations, yielded a total of 13,030 terms. Of the 4090 concepts, 3063 (74.9%) had a corresponding English language Wikipedia page identified by automated search with subsequent manual review. We applied the MediaWiki application programming interface (API) to generate web-service calls to identify the images from each concept's corresponding Wikipedia page; three reviewers selected relevant images to associate with the glossary's concepts. Licensing terms for the images were reviewed. For 800 randomly sampled concepts that had associated Wikipedia pages, 362 distinct images were identified from the MediaWiki library and matched to 404 concepts (51%). Three images (1%) had unspecified licensing terms; the rest were in the public domain or available via a Creative Commons license. Wikipedia and the MediaWiki library offer a large collection of medical articles and images that can be incorporated into an online lay-language glossary of radiology terms though a semi-automated approach. PMID- 30402668 TI - Integrating Active Learning and Transfer Learning for Carotid Intima-Media Thickness Video Interpretation. AB - Cardiovascular disease (CVD) is the number one killer in the USA, yet it is largely preventable (World Health Organization 2011). To prevent CVD, carotid intima-media thickness (CIMT) imaging, a noninvasive ultrasonography method, has proven to be clinically valuable in identifying at-risk persons before adverse events. Researchers are developing systems to automate CIMT video interpretation based on deep learning, but such efforts are impeded by the lack of large annotated CIMT video datasets. CIMT video annotation is not only tedious, laborious, and time consuming, but also demanding of costly, specialty-oriented knowledge and skills, which are not easily accessible. To dramatically reduce the cost of CIMT video annotation, this paper makes three main contributions. Our first contribution is a new concept, called Annotation Unit (AU), which simplifies the entire CIMT video annotation process down to six simple mouse clicks. Our second contribution is a new algorithm, called AFT (active fine tuning), which naturally integrates active learning and transfer learning (fine tuning) into a single framework. AFT starts directly with a pre-trained convolutional neural network (CNN), focuses on selecting the most informative and representative AU s from the unannotated pool for annotation, and then fine-tunes the CNN by incorporating newly annotated AU s in each iteration to enhance the CNN's performance gradually. Our third contribution is a systematic evaluation, which shows that, in comparison with the state-of-the-art method (Tajbakhsh et al., IEEE Trans Med Imaging 35(5):1299-1312, 2016), our method can cut the annotation cost by >81% relative to their training from scratch and >50% relative to their random selection. This performance is attributed to the several advantages derived from the advanced active, continuous learning capability of our AFT method. PMID- 30402669 TI - Multi-objective Parameter Auto-tuning for Tissue Image Segmentation Workflows. AB - We propose a software platform that integrates methods and tools for multi objective parameter auto-tuning in tissue image segmentation workflows. The goal of our work is to provide an approach for improving the accuracy of nucleus/cell segmentation pipelines by tuning their input parameters. The shape, size, and texture features of nuclei in tissue are important biomarkers for disease prognosis, and accurate computation of these features depends on accurate delineation of boundaries of nuclei. Input parameters in many nucleus segmentation workflows affect segmentation accuracy and have to be tuned for optimal performance. This is a time-consuming and computationally expensive process; automating this step facilitates more robust image segmentation workflows and enables more efficient application of image analysis in large image datasets. Our software platform adjusts the parameters of a nuclear segmentation algorithm to maximize the quality of image segmentation results while minimizing the execution time. It implements several optimization methods to search the parameter space efficiently. In addition, the methodology is developed to execute on high-performance computing systems to reduce the execution time of the parameter tuning phase. These capabilities are packaged in a Docker container for easy deployment and can be used through a friendly interface extension in 3D Slicer. Our results using three real-world image segmentation workflows demonstrate that the proposed solution is able to (1) search a small fraction (about 100 points) of the parameter space, which contains billions to trillions of points, and improve the quality of segmentation output by * 1.20, * 1.29, and * 1.29, on average; (2) decrease the execution time of a segmentation workflow by up to 11.79* while improving output quality; and (3) effectively use parallel systems to accelerate parameter tuning and segmentation phases. PMID- 30402670 TI - Full-Dose PET Image Estimation from Low-Dose PET Image Using Deep Learning: a Pilot Study. AB - Positron emission tomography (PET) imaging is an effective tool used in determining disease stage and lesion malignancy; however, radiation exposure to patients and technicians during PET scans continues to draw concern. One way to minimize radiation exposure is to reduce the dose of radioactive tracer administered in order to obtain the scan. Yet, low-dose images are inherently noisy and have poor image quality making them difficult to read. This paper proposes the use of a deep learning model that takes specific image features into account in the loss function to denoise low-dose PET image slices and estimate their full-dose image quality equivalent. Testing on low-dose image slices indicates a significant improvement in image quality that is comparable to the ground truth full-dose image slices. Additionally, this approach can lower the cost of conducting a PET scan since less radioactive material is required per scan, which may promote the usage of PET scans for medical diagnosis. PMID- 30402671 TI - Suspicious Lesion Segmentation on Brain, Mammograms and Breast MR Images Using New Optimized Spatial Feature Based Super-Pixel Fuzzy C-Means Clustering. AB - Suspicious lesion or organ segmentation is a challenging task to be solved in most of the medical image analyses, medical diagnoses and computer diagnosis systems. Nevertheless, various image segmentation methods were proposed in the previous studies with varying success levels. But, the image segmentation problems such as lack of versatility, low robustness, high complexity and low accuracy in up-to-date image segmentation practices still remain unsolved. Fuzzy c-means clustering (FCM) methods are very well suited for segmenting the regions. The noise-free images are effectively segmented using the traditional FCM method. However, the segmentation result generated is highly sensitive to noise due to the negligence of spatial information. To solve this issue, super-pixel-based FCM (SPOFCM) is implemented in this paper, in which the influence of spatially neighbouring and similar super-pixels is incorporated. Also, a crow search algorithm is adopted for optimizing the influential degree; thereby, the segmentation performance is improved. In clinical applications, the SPOFCM feasibility is verified using the multi-spectral MRIs, mammograms and actual single spectrum on performing tumour segmentation tests for SPOFCM. Ultimately, the competitive, renowned segmentation techniques such as k-means, entropy thresholding (ET), FCM, FCM with spatial constraints (FCM_S) and kernel FCM (KFCM) are used to compare the results of proposed SPOFCM. Experimental results on multi-spectral MRIs and actual single-spectrum mammograms indicate that the proposed algorithm can provide a better performance for suspicious lesion or organ segmentation in computer-assisted clinical applications. PMID- 30402673 TI - Num1 versus NuMA: insights from two functionally homologous proteins. AB - In both animals and fungi, spindle positioning is dependent upon pulling forces generated by cortically anchored dynein. In animals, cortical anchoring is accomplished by a ternary complex containing the dynein-binding protein NuMA and its cortical attachment machinery. The same function is accomplished by Num1 in budding yeast. While not homologous in primary sequence, NuMA and Num1 appear to share striking similarities in their mechanism of function. Here, we discuss evidence supporting that Num1 in fungi is a functional homolog of NuMA due to their similarity in domain organization and role in the generation of cortical pulling forces. PMID- 30402672 TI - Improving Wellness for LGB Collegiate Student-Athletes Through Sports Medicine: A Narrative Review. AB - In comparison to their heterosexual peers, lesbian, gay, and bisexual (LGB) student-athletes encounter substantial challenges during their intercollegiate and professional athletic careers including detrimental stereotypes, harassment, and discrimination. Such non-inclusive environments promoted throughout the current Western culture of sport are notably associated with higher incidences of mental health and substance use disorders among LGB athletes across youth, collegiate, and professional sports. There have been significant gains at the collegiate level to address LGB-inclusive practices aimed towards administrators, educators, coaches, and student-athletes; however, there is currently no literature that addresses the unique role of the sports medicine team. As first line healthcare providers for student-athletes, sports medicine physicians and athletic trainers are uniquely positioned to support collegiate LGB athletes through affirming sexual identity, recognizing distinctive health risks, and advocating inclusivity within the athletic training room. By examining major themes of concern among current LGB student-athlete experiences across the unique setting of US colleges and universities, this review article aims to further identify opportunities for sports medicine providers to promote positive health outcomes and improve the overall wellness of collegiate LGB student-athletes. PMID- 30402674 TI - Assessing the predictive accuracy of oral glucose effectiveness index using a calibration model. AB - PURPOSE: Current reference methods for measuring glucose effectiveness (GE) are the somatostatin pancreatic glucose clamp and minimal model analysis of frequently sampled intravenous glucose tolerance test (FSIVGTT), both of which are laborious and not feasible in large epidemiological studies. Consequently, surrogate indices derived from an oral glucose tolerance test (OGTT) to measure GE (oGE) have been proposed and used in many studies. However, the predictive accuracy of these surrogates has not been formally validated. In this study, we used a calibration model analysis to evaluate the accuracy of surrogate indices to predict GE from the reference FSIVGTT (SgMM). METHODS: Subjects (n = 123, mean age 48 +/- 11 years; BMI 35.9 +/- 7.3 kg/m2) with varying glucose tolerance (NGT, n = 37; IFG/IGT, n = 78; and T2DM, n = 8) underwent FSIVGTT and OGTT on two separate days. Predictive accuracy was assessed by both root mean squared error (RMSE) of prediction and leave-one-out cross-validation-type RMSE of prediction (CVPE). RESULTS: As expected, insulin sensitivity, SgMM, and oGE were reduced in subjects with T2DM and IFG/IGT when compared with NGT. Simple linear regression analyses revealed a modest but significant relationship between oGE and SgMM (r = 0.25, p < 0.001). However, using calibration model, measured SgMM and predicted SgMM derived from oGE were modestly correlated (r = 0.21, p < 0.05) with the best fit line suggesting poor predictive accuracy. There were no significant differences in CVPE and RMSE among the surrogates, suggesting similar predictive ability. CONCLUSIONS: Although OGTT-derived surrogate indices of GE are convenient and feasible, they have limited ability to robustly predict GE. PMID- 30402675 TI - A methodological inter-comparison study on the detection of surface contaminant sodium dodecyl sulfate applying ambient- and vacuum-based techniques. AB - Biomedical devices are complex products requiring numerous assembly steps along the industrial process chain, which can carry the potential of surface contamination. Cleanliness has to be analytically assessed with respect to ensuring safety and efficacy. Although several analytical techniques are routinely employed for such evaluation, a reliable analysis chain that guarantees metrological traceability and quantification capability is desirable. This calls for analytical tools that are cascaded in a sensible way to immediately identify and localize possible contamination, both qualitatively and quantitatively. In this systematic inter-comparative approach, we produced and characterized sodium dodecyl sulfate (SDS) films mimicking contamination on inorganic and organic substrates, with potential use as reference materials for ambient techniques, i.e., ambient mass spectrometry (AMS), infrared and Raman spectroscopy, to reliably determine amounts of contamination. Non-invasive and complementary vibrational spectroscopy techniques offer a priori chemical identification with integrated chemical imaging tools to follow the contaminant distribution, even on devices with complex geometry. AMS also provides fingerprint outputs for a fast qualitative identification of surface contaminations to be used at the end of the traceability chain due to its ablative effect on the sample. To absolutely determine the mass of SDS, the vacuum-based reference-free technique X-ray fluorescence was employed for calibration. Convex hip liners were deliberately contaminated with SDS to emulate real biomedical devices with an industrially relevant substance. Implementation of the aforementioned analytical techniques is discussed with respect to combining multimodal technical setups to decrease uncertainties that may arise if a single technique approach is adopted. Graphical abstract ?. PMID- 30402676 TI - New analytical approach to determine organophosphorus insecticides in blood by dried matrix spots sampling and GC-MS/MS. AB - This work describes the optimization of a new method for the determination of five organophosphorus insecticides in whole blood. The analytes were extracted from the matrix (50 MUL) using the dried blood spot (DBS) approach and were analyzed by gas chromatography (GC) coupled to tandem mass spectrometry (MS/MS). The studied compounds (diazinon, chlorpyrifos, parathion-ethyl, chlorfenvinphos and quinalphos) were chosen based on the statistics of intoxications in Portugal, and ethion was used as internal standard. The method was fully validated, taking into account international guidelines for bioanalytical method validation, such as those of the Food and Drug Administration (FDA), International Conference on Harmonization (ICH) and Scientific Working Group for Forensic Toxicology (SWGTOX). A linear range of 0.1-25 MUg/mL was obtained for all compounds, except for diazinon and quinalphos (0.05-25 MUg/mL and 0.25-25 MUg/mL, respectively), presenting determination coefficients above 0.99. Concerning precision, the coefficients of variation (CVs) were lower than 14% for all compounds. Those compounds were found to be stable in the samples. Although the values obtained for recovery were low (between 1 and 12%), the method proved to be sensitive, since detection limits between 0.05 and 0.1 MUg/mL were obtained. The novelty is the use of the DBS approach in the extraction of these compounds, and this is the first paper reporting it: DBS is a recent technique of bioanalysis in the field of toxicology, and in addition to its simplicity and sensitivity, it is applicable routinely in both clinical and forensic toxicology situations. Graphical abstract ?. PMID- 30402678 TI - Phase I/II study evaluating the safety and clinical efficacy of temsirolimus and bevacizumab in patients with chemotherapy refractory metastatic castration resistant prostate cancer. AB - Background Mammalian target of rapamycin (mTOR) pathway and angiogenesis through vascular endothelial growth factor (VEGF) have been shown to play important roles in prostate cancer progression. Preclinical data in prostate cancer has suggested the potential additive effect dual inhibition of VEGF and mTOR pathways. In this phase I/II trial we assessed the safety and efficacy of bevacizumab in combination with temsirolimus for the treatment of men with metastatic castration resistant prostate cancer (mCRPC). Methods In the phase I portion, eligible patients received temsirolimus (20 mg or 25 mg IV weekly) in combination with a fixed dose of IV bevacizumab (10 mg/kg every 2 weeks). The primary endpoint for the phase II portion was objective response measured by either PSA or RECIST criteria. Exploratory endpoints included changes in circulating tumor cells (CTC) and their correlation with PSA response to treatment. Results Twenty-one patients, median age 64 (53-82), with pre-treatment PSA of 205.3 (11.1-1801.0), previously treated with a median of 2 (0-5) lines of therapy for mCRPC received the combination of temsirolimus weekly at 20 mg (n = 4) or 25 mg (n = 17) with bevacizumab 10 mg/kg every 2 weeks (n = 21). Median time to progression was 2.6 months (95% CI, 1.2-3.9) and the median best PSA change from baseline to 12 weeks was a 32% increase (-40-632%) which met the predefined futility rule and led to early termination of the study. Nine patients (43%) had >= grade 3 toxicity that included fatigue (24%), anorexia (10%), nausea/vomiting (5%) and lymphopenia (5%). In exploratory analysis, a decrease in CTC levels was observed in 9 out of 11 patients. No association between PSA levels and CTC levels was detected. Conclusions The combination of temsirolimus and bevacizumab showed limited clinical activity in mCRPC patients previously treated with chemotherapy and was associated with significant adverse events (AEs). Transient decrease in CTC levels was independent from PSA response. NCT01083368. PMID- 30402677 TI - An Occam's razor approach to chemical hardness: lex parsimoniae. AB - The term "chemical hardness" refers to the resistance to deformation of the electronic density of a system; the greater this resistance, the "harder" the system. Polarizability, a physical property, is an inverse measure of resistance to deformation and thus should be inversely related to hardness. This is indeed generally accepted. Hardness has been postulated to be the second derivative of a system's energy with respect to its number of electrons, despite the fact that this involves the differentiation of a noncontinuous function. This second derivative is typically approximated as the difference between the ionization energy I and the electron affinity A of the ground-state system, which results in ambiguity in that many molecules do not form stable negative ions. For atoms, the quantity I - A does vary approximately inversely with polarizability, but this is only because the electron affinity is usually relatively low and ionization energy is known to be inversely related to polarizability for atoms. However, molecular polarizability depends primarily upon volume, and so does not show an acceptable inverse correlation with I - A. Since both hardness and polarizability refer to the same property of a system-its resistance to deformation of the electronic density, we propose that the reciprocal of polarizability be taken to be a measure of hardness. We show that polarizabilities that are not known can be estimated quite accurately in terms of the average local ionization energies on the atomic or molecular surfaces and, for molecules, their volumes. PMID- 30402679 TI - Basal lower esophageal sphincter pressure in gastroesophageal reflux disease: An ignored metric in high-resolution esophageal manometry. AB - Manometry and 24-h pH interpretation have seldom been studied. Our aim was to study these parameters as gold standard in reflux disease and to identify predictors of pathological acid reflux. Retrospective case record review of all patients with reflux disease evaluated using endoscopy, manometry, and 24-h pH testing from 2010 to 2016. Patients were categorized using Johnson-DeMeester score into two groups-group I (score > 14.7, normal study) and group II (< 14.7, normal study). These groups were compared for the above-mentioned parameters. Appropriate statistical tests were applied. P-value < 0.05 was considered significant. The study group includes 94 patients (median age 44 years, 63.8% males). Sixty (63.8%) and 34 patients belonged to groups I and II, respectively, 76.6% patients had normal endoscopy while the remaining had mild esophagitis. Peristalsis was normal in 66%, followed by ineffective esophageal motility (19.1%) and fragmented peristalsis (14.9%). Demography, symptoms, endoscopy findings, and peristalsis characteristics were similar between the two groups. Group II patients had significantly lower basal lower esophageal sphincter (LES) pressure (11.9 vs. 16.6; p < 0.02), lower integrated relaxation pressure (5.7 vs. 7.4; p < 0.01), and larger separation between LES and crural diaphragm (1.7 vs. 1.4 cm; p < 0.003). Basal LES pressure < 10 mmHg had the highest likelihood ratio (2.2) to predict an abnormal pH study. Basal LES pressure, integrated relaxation pressure, and hiatus size correlated with pathological acid reflux. Hypotensive basal lower esophageal sphincter pressure was the best predictor of an abnormal pH study but with negative linear correlation. PMID- 30402681 TI - Bowel management program in patients with spina bifida. AB - PURPOSE: Our center has been successfully implementing a bowel management program (BMP) for fecal incontinence consecutive to anorectal malformation and Hirschsprung disease. Recently, the number of patients with spina bifida requiring management for fecal incontinence has increased. The purpose of this study was to review the results of bowel management in patients with spina bifida and the challenges unique to this population. METHODS: A retrospective chart review was performed including all patients with spina bifida who attended our BMP from February 2016 until April 2018. Data collection included: prenatal intervention, gender, age, characteristics of contrast enema, success rateand challenges faced. RESULTS: Twenty-two patients met inclusion criteria 13 of which were females. Three patients had their myelomeningocele repaired prenatally, the remaining were repaired postnatally. Patient ages ranged from 2 to 24 years. Only nine patients were referred to BMP at proper toilet training age. Three patients came to BMP status post an antegrade enema procedure with reported "accidents" on their current regimen. The colon in the contrast enema was non-dilated in all patients and two behaved as hypermotile requiring loperamide. Seventeen patients (77%) were clean of stool and considered successful. Solution leakage during enema administration was the most common challenge and was corrected by increasing the Foley balloon fill volume. CONCLUSIONS: Our bowel management program with enemas is effective for patients with a history of spina bifida. The data support specific considerations for this population including frequent adjustments, close follow-up and specific administration techniques. PMID- 30402680 TI - A novel treatment for patients with constipation: Dawn of a new age for translational microbiome research? PMID- 30402682 TI - Developmental outcome at 3 years of age of infants following surgery for infantile hypertrophic pyloric stenosis. AB - PURPOSE: The study compared neurodevelopmental outcome at 3 years of age of infants with infantile hypertrophic pyloric stenosis (IHPS) who underwent pyloromyotomy with healthy control infants in New South Wales, Australia. METHODS: Infants with IHPS as well as controls were recruited between August 2006 and July 2008. Developmental assessments were performed using the Bayley scales of infant and toddler development (version III) (BSITD-III) at 1 and 3 years of age. RESULTS: Of the 43 infants originally assessed at 1 year, 39 returned for assessment at 3 years (90%). The majority were term infants (77%). Assessments were also performed on 156 control infants. Infants with IHPS scored significantly lower on four of the five Bayley subsets (cognitive, receptive and expressive language and fine motor) compared to control infants. Analysis of co variance showed statistically significant results in favour of the control group for these four subsets. CONCLUSION: Compared with the outcomes at 1 year, infants with IHPS at 3 years of age continue to score below controls in four of the BSITD III subscales. This suggests they should have developmental follow-up with targeted clinical intervention. There is a need for further studies into functional impact and longer term outcomes. PMID- 30402683 TI - A Review of the Neurobiological Basis of Trauma-Related Dissociation and Its Relation to Cannabinoid- and Opioid-Mediated Stress Response: a Transdiagnostic, Translational Approach. AB - Dissociative experiences have been associated with increased disease severity, chronicity, and, in some cases, reduced treatment response across trauma-related and other psychiatric disorders. A better understanding of the neurobiological mechanisms through which dissociative experiences occur may assist in identifying novel pharmacological and non-pharmacological treatment approaches. Here, we review emerging work on the dissociative subtype of posttraumatic stress disorder (PTSD), and other trauma-related disorders providing evidence for two related overarching neurobiological models of dissociation, the defense cascade model of dissociation and Mobb's threat detection model. In particular, we review neuroimaging studies highlighting alterations in functional connectivity of key brain regions associated with these models, including connectivity between the prefrontal cortex, the amygdala and its complexes, the insula, and the periaqueductal gray. Work implicating the kappa-opioid and endocannabinoid systems in trauma-related dissociative experiences is also reviewed. Finally, we hypothesize mechanisms by which pharmacological modulation of these neurochemical systems may serve as promising transdiagnostic treatment modalities for individuals experiencing clinically significant levels of dissociation. Specifically, whereas kappa-opioid receptor antagonists may serve as a pharmacological vehicle for the selective targeting of dissociative symptoms and associated emotion overmodulation in the dissociative subtype of posttraumatic stress disorder and transdiagnostically, modulation of the endocannabinoid system may reduce symptoms associated with emotional undermodulation of the fight or flight components of the defense cascade model. PMID- 30402684 TI - [Complicated syphilis therapy by permanent fillers]. AB - The number of patients suffering from a sexually transmitted disease (STD) in Germany is rising steadily. Mostly MSM (men who have sex with men) are affected. We report the case of an HIV-positive patient with syphilis, in whom the implantation of permanent fillers into the buttocks and thighs, for cosmetic purposes, prevented standard therapy of syphilis by intramuscular penicillin administration. According to current guidelines intravenous ceftriaxone (2 g once daily) was administered instead. PMID- 30402685 TI - [Progressive lower leg ulceration with necrosis]. PMID- 30402687 TI - [Differential diagnostics of lipedema and lymphedema : A practical guideline]. AB - Lipedema is a symmetrical disorder of the subcutaneous adipose tissue that affects almost exclusively women in postpubescent age. The trinity of disfiguring hyperplastic adipose tissue of the proximal extremities, increasing pain over time and bruising is characteristic. Lymphedema can occur in both sexes and is differentiated into primary and secondary subtypes. Symmetry is not a prerequisite for diagnosis. Characteristic for lymphedema is the disproportion between lymphatic fluid and the capacity of lymphatic vessels. The most distal body parts are always more severely affected than proximal parts. In the initial phases lymphedema is painless but in advanced stages tension pain can occur. The combination of both disorders has been described; however, lipedema is not responsible for subsequent lymphedema in contrast to central obesity, which significantly increases the risk of lymphedema. The differential diagnosis is of utmost importance for a meaningful management. PMID- 30402688 TI - [Definitions and explanations on the topic of fracture reduction]. AB - The process of reduction is a key step for successful fracture treatment. The goal of fracture reduction is the realignment of the displaced fractured fragments caused by muscle tension or impaction back into the original anatomic relationship. The reduction process includes not only the application of force at or remote from the fracture site to reverse the deforming forces but also the preoperative planning where to apply these forces and by what means. Furthermore, consideration should be preoperatively given on how to position the patient and the C-arm and how to temporarily maintain reduction for intraoperative x-ray control of the axis, rotation and lengths before definitive fixation. PMID- 30402686 TI - [Impact of lifestyle and environmental factors on male reproductive health]. AB - The identification of potential environmental hazards may be clinically relevant in the diagnosis of male infertility. Knowledge about these factors will improve prevention of fertility disorders. Apart from drugs or factors related to lifestyle such as alcohol and tobacco smoke, various environmental and occupational agents, both chemical and physical, may impair male reproductive function. Reproductive toxicity may evolve at the hypothalamic-pituitary, testicular, or post-testicular level; endpoints comprise deterioration of spermatogenesis and sperm function as well as endocrine disorders and sexual dysfunction. With regard to the complex regulation of the male reproductive system, the available information concerning single exogenous factors and their mechanisms of action in humans is limited. This is also due to the fact that extrapolation of results obtained from experimental animal or in vitro studies remains difficult. Nevertheless, the assessment of relevant exposure to reproductive toxicants should be carefully evaluated during diagnostic procedures of andrological patients. PMID- 30402689 TI - [Outcome after surgical treatment of calcaneal fractures]. AB - BACKGROUND: After controversial discussions in the literature about therapy regimens for calcaneal fractures, a retrospective study of patients operatively treated in a maximum care trauma center was conducted. OBJECTIVE: Investigation of the influencing factors on the treatment quality of operatively treated patients with calcaneal fractures. MATERIAL AND METHODS: Between 2005 and 2013 a total of 90 patients with calcaneal fractures were surgically treated in this hospital with locking plate osteosynthesis. A total of 48 patients with 55 fractures were retrospectively investigated. The assessment with respect to posttraumatic arthrosis was made radiologically and Bohler's and Gissane's angles were also determined. Clinically AOFAS and SF-36 scores were documented. The results were statistically tested with respect to possible risk factors. RESULTS: A total of 9 patients (18.8%) were found with complications necessitating operative revision, with 8 patients requiring subtalar arthrodesis and 1 patient with a deep wound infection. Nicotine abuse and a long interval between trauma and reconstructive surgery were identified as factors that influenced the development of wound healing problems. The average AOFAS score was 68 points and the SF-36 was 58.86 points. A poor result in the scores was caused by the development of symptomatic arthritis and the type of insurance. In this cohort factors, such as age and complexity of fractures were not correlated with a poor result. CONCLUSION: In this patient collective nicotine abuse and a long interval between trauma and surgery were risk factors for development of wound infections. Other factors with an influence on the outcome were the postoperative development of arthritis and the type of health insurance; however, patient age had no impact on the outcome. PMID- 30402690 TI - [Osteosynthesis of bicondylar tibial plateau fracture in a prone position : Video article]. AB - OBJECTIVE: The aim of the surgical treatment of intra-articular bicondylar tibial plateau fractures is the anatomical reconstruction and direct biomechanical optimal fixation of the fractured articular surface and the leg axis, taking the frequently associated soft tissue damage into account. INDICATIONS: This article presents a cadaver model of a simulated complex bicondylar tibial plateau fracture 41C3 according to the AO classification with fracture involvement of all 10 segments and indications for surgery due to a posteromedial shearing fracture and lateral articular destruction with posterolaterocentral impaction. CONTRAINDICATIONS: Pronounced soft tissue damage with acute or incompletely healed infections in the area of the surgical approach. SURGICAL TECHNIQUE: In the presented video of the operation, which is available online, the direct treatment of an intra-articular complex tibial plateau fracture from dorsal in a prone position is shown in detail: posterolateral ca. 13 cm long skin incision immediately above the fibular head with subsequent gentle preparation of the peroneal nerve at the medial border of the biceps femoris muscle. Retraction of the lateral head of the gastrocnemius muscle medially. Proximal detachment of the soleus muscle from the fibular head and retraction of the popliteus muscle medially. Horizontal capsule incision for fracture visualization. Opening of the lateral window ventral to the lateral collateral ligament. If necessary, osteotomy of the lateral femoral epicondyle for improved posterolaterocentral fracture visualization. Angular stable osteosynthetic fixation. Posteromedial approach medial to the medial gastrocnemius head. Retraction of the medial head of the gastrocnemius muscle laterally, horizontal capsular incision with sparing of the semimembranosus muscle medially and posterior cruciate ligaments laterally, fracture reduction, fixation with posteromedial support plate, image converter control, wound closure. FOLLOW-UP: Postoperative cooling and elevation of the operated limb. Depending on the fracture 6-10 weeks partial loading of maximum 20 kg. Prior to full load bearing clinical radiological follow-up checks to determine the bony consolidation and material positioning. RESULTS: This is an established and safe delivery strategy for complex fracture patterns with dorsally running fractures. The risk of intraoperative malreduction is low. Postoperative reduction losses depend on fracture, operation and especially patient-specific characteristics. PMID- 30402691 TI - [Simple elbow dislocations in children : Systematic review and meta-analysis]. AB - BACKGROUND: Simple elbow dislocations in childhood are rare. Nevertheless, they have a high relevance because they can result in subsequent damage and limitations in range of motion. The treatment options are controversially discussed. AIM: The purpose of the study was to review the literature and to derive a recommendation for the best treatment concept. MATERIAL AND METHODS: A systematic literature search was performed via Ovid Medline, whereby 1645 publications were identified (initially nonspecific for age) and evaluated in a stepwise approach. Of these publications four met the inclusion criteria of the authors. The analysis was carried out descriptively and in a meta-analysis. RESULTS: The 4 publications included described simple elbow dislocations in 81 children (<=16 years). The weighted average age was 9.9 years with a gender ratio of 3.8 (boys:girls). The median follow-up was 49 months. Posterior and posterolateral dislocations were the most common with 73%. In 69 children the treatment was conservative and of these 66 were immobilized for longer than 2 weeks after closed reduction. The 12 children who had surgical treatment suffered dislocations that had not been reduced for longer than 3 weeks. The success rate of the conservatively treated immobilized group was 88%, of the conservatively treated non-immobilized group 70% and of the surgical group 42%. The differences between the success rates of the treatment methods was significant (p = 0.032). CONCLUSION: Simple elbow dislocations in children are rare. They most commonly occur in posterior and posterolateral directions. The prognosis is favorable; however a timely diagnosis and correct reduction are relevant for a good outcome. PMID- 30402692 TI - [Importance of trauma and emergency surgery for German metropolitan emergency departments-an analysis of 524,716 emergency patients]. AB - BACKGROUND: The future of emergency departments in Germany is influenced by increasing numbers of patients, demographic changes, new therapeutic concepts, current legislation and expert opinions. There is a lack of reliable data concerning the quantity and the type of injuries and diseases presenting in emergency departments. MATERIAL AND METHODS: This descriptive, epidemiological study included 14 emergency departments in Munich (1.41 million inhabitants in 2014), where 524,716 patients were treated from 1 July 2013 to 30 June 2014. 393,587 were included in this prospectively planned subgroup analysis. Patients presenting in special departments, such as gynecology or ophthalmology (59,523) or cases without a documented diagnosis (71,606) were excluded. Cases were assigned to the discipline trauma surgery or orthopedics according to the ICD-10 diagnosis chapters "injuries, poisoning and certain other consequences of external causes" and "diseases of the musculoskeletal system and connective tissue". RESULTS: Of the 393,587 cases included, 169,208 were treated due to trauma or orthopedic diseases (43%). 134,507 underwent outpatient treatment (79%) and 34,701 were admitted on the same day (21%). 29,920 patients suffered from head injuries (18%), 31,143 fractures (20%) and 24,367 deep wounds (14%) were recorded. On workdays between 8am and 10am, up to 47 patients per hour were treated and between 1pm and 3pm, up to 36 patients per hour. On weekends, most patients presented between 11am and 7pm. CONCLUSION: The present study analyzed the frequency of major diagnoses corresponding to the various medical disciplines including more than 500,000 patients. Of the emergency cases included, 43% were allocated to trauma surgery or orthopedics. These patients presented in the emergency departments around the clock and necessitate the permanent attendance of a trauma and emergency surgeon. Thereby, timely surgical care and decisions regarding indications for surgery and admission are ensured. Competence in trauma and emergency surgery is therefore essential for emergency departments. PMID- 30402693 TI - Comparison of the contents of selected elements and pesticides in honey bees with regard to their habitat. AB - The inspiration for this study was the anxiety of Warsaw beekeepers, who raised the question whether location of hives in large urban agglomerations results in changes in concentrations of xenobiotics, toxic elements, and micronutrients in honey bees. Preliminary studies required elaboration of the research methodology, as the studied object is characterized by a low degree of homogeneity and the method of sample preparation affects obtained results. From many tested approaches, the use of washed and milled abdomens of the bees is recommended. Results obtained for such prepared samples are slightly lower than for whole bees, but their repeatability is higher, which enables easier interpretation of the trends and comparison of different locations. The contents of selected elements (As, Al, Cd, Co, Cr, Cu, Mn, Pb, and Zn) were compared in bees from urban and rural areas. The studies were supported by pesticides analysis. Also, it was checked whether these substances are accumulated on the surface or inside the bee's body. The research indicates the markers of contamination: Al, As, and Cr on the surface and Cd inside the bodies of honey bees. The location of the hives does not influence significantly the content of "toxic," nutrient metals and metalloids in bees (slightly higher levels of As, Al, Pb, and Cd were found in bees from urban areas). In terms of exposure to these elements and pesticides, the large city environment is not harmful for honey bees. PMID- 30402694 TI - Hydro-electric power in the Panjkora basin at the expense of environmental deterioration and biodiversity loss-immediate action required for mitigation. PMID- 30402695 TI - Lead uptake by the symbiotic Daucus carota L.-Glomus intraradices system and its effect on the morphology of extra- and intraradical fungal microstructures. AB - This work examines the strategies adopted by an arbuscular mycorrhizal symbiotic system to ameliorate environmental Pb stress by examining the concentrations of P, Fe, and Pb in the fungal microstructures and the host's root. In vitro cultures of Ri-T DNA-transformed carrot (Daucus carota L.) roots were inoculated with Glomus intraradices and treated with Pb(NO3)2 solution and the extraradical spores and mycelia (S/M) and the root with the vesicles, mycelia, and root cells were subsequently analyzed by polarized energy dispersive x-ray fluorescence (PEDXRF) spectrometry. Upon Pb treatment, within the root, the percentages of mycorrhizal colonization, the vesicles, and mycelia increased as well as the areas of the vesicles and the (extraradical) spores, although the number of spores and arbuscules decreased. The S/M and the mycorrhizal root showed enhanced concentrations of Pb, Fe, and P. These were particularly marked for Fe in the Pb treated cultures. This indicates a synergistic relationship between the arbuscular mycorrhizal fungus and the host that confers a higher Pb tolerance to the latter by the induction of higher Fe absorption in the host. The intraradical vesicle, mycelia, and arbuscule numbers are interpreted as a "tactic to divert" the intraradical Pb traffic away from the root cells to the higher affinity cell walls of the arbuscular mycorrhizal fungi (AMF) microstructures in the apoplast. The results of this work show that the symbiosis between the AMF G. intraradices and the host plant D. carota distinctly improves the latter's Pb tolerance, and imply that the appropriate metal tolerant host-AMF combinations could be employed in process designs for the phytoremediation of Pb. PMID- 30402696 TI - Analysis of swale factors implicated in pollutant removal efficiency using a swale database. AB - Swales are traditional basic open-drainage systems which are able to remove stormwater-borne pollutants. In spite of numerous case studies devoted to their performances, parameters influencing the reduction of pollutant concentrations by swales remain elusive. In order to better characterize them, a database was set up by collecting performance results and design characteristics from 59 swales reported in the literature. Investigations on correlations among pollutant efficiency ratios (ERs) indicated that total trace metals (copper (Cu), zinc (Zn), cadmium (Cd), and lead (Pb)), total suspended solids (TSS), total phosphorus (TP), and total Kjeldahl nitrogen (TKN) exhibited many cross correlated ERs. High ERs were observed for pollutants including a particulate form such as TSS (median ERs = 56%) and total trace metals (median ERs >= 62%), suggesting that these pollutants are efficiently trapped by sedimentation in swale bed and/or filtered within swale soil. Medium to high ERs were found for dissolved trace metals (median ERs >= 44%), whereas ERs for nutrient species were lower (median ERs <= 30%). The inflow concentration was identified as a major factor correlated to ER for most pollutants. For some pollutants, there is also a trend to get higher ER when the geometrical design of the swale increases the hydraulic residence time. Overall, this database may help to better understand swale systems and to optimize their design for improving pollutant removal. PMID- 30402697 TI - A lysosome-targeting nanosensor for simultaneous fluorometric imaging of intracellular pH values and temperature. AB - Lysosomal pH and temperature are two crucial physiological parameters that are involved in regulating intracellular homeostasis, and their precise measurements are extremely important in understanding this process and diseases diagnosis. A lysosome-targeting nanosensor has been designed for simultaneous imaging of pH values and temperature in HeLa cells. Three dyes were covalently immobilized either inside or on silica nanoparticles. The nanosensors have an average diameter of 95 nm. The large surface area of these nanomaterials provides abundant sites for multi-functionality. The surface of nanosensors has been modified with positively-charged amino groups in order to facilitate endocytosis and targeting lysosome. Fluorescein is used as the indicator probe for pH measurement, rhodamine B is the probe for temperature, and a europium complex acts as the reference dye. The dual nanosensor responds to pH values in the range from 3.0 to 9.0, and to temperature in the range from 20 to 60 degrees C. Owing to its good biocompatibility and good sensitivity, the dual nanosensor has been used to monitor changes in local pH values and temperature in the lysosome of HeLa cells. Graphical abstract A dual nanosensor for simultaneously imaging of pH values and temperature inside the lysosome of HeLa cells was constructed by labelling three luminophores in/on silica nanoparticles. It shows high sensitivity and selectivity, good photostability, and good biocompatibility. PMID- 30402698 TI - The effect of methotrexate versus other disease-modifying anti-rheumatic drugs on serum drug levels and clinical response in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors. AB - To investigate the effect of concomitant conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) with adalimumab or infliximab on maintaining serum drug and clinical outcomes after the first year of treatment in patients with rheumatoid arthritis (RA). Second, to assess the influence of methotrexate (MTX) dose on these outcomes. Ninety-two patients with RA starting infliximab (n = 67) or adalimumab (n = 25) tumor necrosis factor inhibitor (TNFi) with available drug levels and clinical improvement assessment (European League Against Rheumatism [EULAR] response) after 12 months were included. Patients were grouped according to concomitant csDMARD use: (i) TNFi monotherapy; (ii) TNFi+MTX; (iii) TNFi with csDMARDs other than MTX (TNFi+OD). Patients receiving MTX were also classified by dose as < 15 mg/week (TNFi+MTX<15) and >= 15 mg/week (TNFi+MTX>=15). Logistic regression analyses were employed. More TNFi+MTX patients had circulating serum TNFi at 12 months (71% TNFi+MTX vs. 20% TNFi+OD vs. 9% TNFi monotherapy). Of these, the probability of maintaining serum TNFi levels was twice (OR 2.3; p = 0.06) than that of patients without MTX. However, statistically significant results were observed only for the highest MTX dose (OR 4.9; p = 0.02). Most patients achieving good EULAR response were treated with TNFi+MTX (81%). The probability of achieving this response was three times higher in patients within the TNFi+MTX group (OR 3.4; p = 0.03); however, no differences were found with regard to MTX dose. The persistence of serum TNFi and the probability of achieving clinical response are influenced by MTX but not by OD in patients with RA treated with infliximab or adalimumab. PMID- 30402699 TI - Histological and inflammatory analysis to diagnostic method of proximal gingivitis by flossing. AB - OBJECTIVES: The aim of this study was to assess with histological and inflammatory analysis the use of flossing as a diagnostic method for detecting proximal gingivitis. MATERIAL AND METHODS: This is a diagnostic accuracy paper composed of two different studies. In the first study, three groups were identified based on papilla status: bleeding (+) with both methods (N = 26); bleeding (+) with dental floss, but no bleeding (-) with probing (N = 26); and no bleeding (-) with either method (N = 26). One papilla from all 78 participants was biopsied and analyzed for the determination of inflammatory infiltrate and percentage of collagen fibers. Sensibility, specificity, positive and negative predictive, and accuracy values were analyzed. In the second study, the volume of gingival crevicular fluid (GCF) was analyzed in 49 participants with flossing+/probing- and flossing-/probing- at contralateral proximal sites. The GCF volume was compared between these sites (n = 172). RESULTS: Significantly greater frequencies of moderate/intense inflammation were found in the flossing+/probing+ (100%) and flossing+/probing- (92.3%) groups compared to those in the flossing-/probing- (0%) group. Significantly different percentages of collagen fibers were found among the three groups (flossing+/probing+ (40.90 +/- 3.68); flossing+/probing- (45.78 +/- 4.55); flossing-/probing- (60.01 +/- 36.66)) (P < 0.001). Dental floss increased the balance between sensitivity and specificity values and showed highest positive predictive (100%) and accuracy (97%) values. Among the 172 sites evaluated, positive bleeding sites had a significantly greater volume of GCF (38 (27-68)) than negative sites (25 (16-51)) (P < 0.001). CONCLUSIONS: The findings suggest that flossing can be used as a diagnostic method for proximal gingivitis in subjects with no history of periodontitis. CLINICAL RELEVANCE: Dental floss can be used as a complementary diagnostic method for proximal gingivitis in adults without clinical attachment loss in clinical practice as well as epidemiology studies. PMID- 30402700 TI - In vivo Raman spectroscopic characteristics of different sites of the oral mucosa in healthy volunteers. AB - OBJECTIVES: Investigate the biochemistry of in vivo healthy oral tissues through Raman spectroscopy. We aimed to characterize the biochemical features of healthy condition in oral subsites (buccal mucosa, lip, tongue, and gingiva) of healthy subjects. More specifically, we investigated Raman spectral characteristics and biochemical content of in vivo healthy tissues on Brazilian population. This characterization can be used to better define normal tissue and improve the detection of oral premalignant conditions in future studies. MATERIALS AND METHODS: For spectroscopic analysis a Raman spectrometer (Kaiser Optical Systems imaging spectrograph Holospec, f / 1.8i-NIR) coupled with a laser 785 nm, 60 mW was used. Raman measurements were obtained by means of an optical fiber (EMVision fiber optic probe) coupled between the laser and the spectrometer. Three spectra per site were acquired from the lip, buccal mucosa, tongue, and gingiva of ten healthy volunteers. This resulted in 30 spectra per oral sub-site and in total 120 spectra. RESULTS: We report detailed biochemical information on these subsites and their relative composition based on deconvolution studies of their spectra. Finally, we also report classification efficiency of 61, 83, 41, and 93% for buccal, gingiva, lip, and tongue respectively after applying multivariate statistical tools. CONCLUSIONS: We quantitated the contribution of various biochemicals in terms of percentage, and this will enable comparison not only across anatomical sites but also across studies. Raman spectroscopy can rapidly probe tissue biochemistry of healthy oral regions. Moreover, the study suggests the possibility of using Raman spectroscopy combined with signal processing and multivariate analysis methods to differentiate the oral sites in healthy conditions and compare with pathological conditions in future studies. CLINICAL RELEVANCE: The spectral characterization of the healthy condition of oral tissues by a noninvasive, label-free, and real-time analytical techniques is important to create a spectral reference for future diagnosis of pathological conditions. PMID- 30402701 TI - Automated assessment of paraspinal muscle fat composition based on the segmentation of chemical shift encoding-based water/fat-separated images. AB - Proton-density fat fraction (PDFF) of the paraspinal muscles, derived from chemical shift encoding-based water-fat magnetic resonance imaging, has emerged as an important surrogate biomarker in individuals with intervertebral disc disease, osteoporosis, sarcopenia and neuromuscular disorders. However, quantification of paraspinal muscle PDFF is currently limited in clinical routine due to the required time-consuming manual segmentation procedure. The present study aimed to develop an automatic segmentation algorithm of the lumbar paraspinal muscles based on water-fat sequences and compare the performance of this algorithm to ground truth data based on manual segmentation. The algorithm comprised an average shape model, a dual feature model, associating each surface point with a fat and water image appearance feature, and a detection model. Right and left psoas, quadratus lumborum and erector spinae muscles were automatically segmented. Dice coefficients averaged over all six muscle compartments amounted to 0.83 (range 0.75-0.90). PMID- 30402702 TI - Left atrial epicardial adipose tissue radiodensity is associated with electrophysiological properties of atrial myocardium in patients with atrial fibrillation. AB - OBJECTIVE: To evaluate whether the epicardial adipose tissue (EAT) phenotype is associated with the electrophysiological properties of adjacent atrial myocardium in patients with atrial fibrillation (AF). METHODS: Between January and May 2017, 30 consecutive patients referred for a first AF catheter ablation were prospectively included. For each patient, a pre-procedural computed tomography scan was performed to assess total and left atrial (LA) EAT amount and radiodensity. A detailed point-by-point voltage mapping using an electroanatomic mapping system was realized to assess the presence of LA low-voltage zone (LVZ). RESULTS: Ten patients (33.3%) presented at least one LVZ. Older age (65 +/- 7 vs. 58 +/- 10 years, p = 0.05) was the only clinical parameter associated with LVZ. Despite no greater LA-EAT thickness by CT scan (3.0 [2.6-3.5] mm vs. 2.8 [2.2 3.1] mm, p = 0.354), patients with LA-LVZ presented significantly lower LA-EAT radiodensity than patients with no LA-LVZ (- 101.8 +/- 12.5 HU vs. - 90.4 +/- 6.3 HU, p = 0.004). No difference between total-EAT volume (131 +/- 61 cm3 vs.107 +/- 58 cm3, p = 0.361) and total-EAT radiodensity (- 106.8 +/- 4.3 HU vs. - 102.4 +/- 6.9 HU, p = 0.119) was found. CONCLUSION: Low LA-EAT radiodensity is associated with the presence of LVZ in patients with medical history of AF. KEY POINTS: * Cardiovascular risk factors are associated with low adipose tissue computed tomography attenuation. * Epicardial adipose tissue (EAT) has emerged as an important factor in the pathogenesis of metabolic-related cardiac diseases such as atrial fibrillation. * We showed that low left atrial EAT attenuation is associated with the presence of low-voltage zone, a surrogate for atrial fibrosis, within the adjacent myocardium. PMID- 30402703 TI - Forensic age estimation for pelvic X-ray images using deep learning. AB - PURPOSE: To develop a deep learning bone age assessment model based on pelvic radiographs for forensic age estimation and compare its performance to that of the existing cubic regression model. MATERIALS AND METHOD: A retrospective collection data of 1875 clinical pelvic radiographs between 10 and 25 years of age was obtained to develop the model. Model performance was assessed by comparing the testing results to estimated ages calculated directly using the existing cubic regression model based on ossification staging methods. The mean absolute error (MAE) and root-mean-squared error (RMSE) between the estimated ages and chronological age were calculated for both models. RESULTS: For all test samples (between 10 and 25 years old), the mean MAE and RMSE between the automatic estimates using the proposed deep learning model and the reference standard were 0.94 and 1.30 years, respectively. For the test samples comparable to those of the existing cubic regression model (between 14 and 22 years old), the mean MAE and RMSE for the deep learning model were 0.89 and 1.21 years, respectively. For the existing cubic regression model, the mean MAE and RMSE were 1.05 and 1.61 years, respectively. CONCLUSION: The deep learning convolutional neural network model achieves performance on par with the existing cubic regression model, demonstrating predictive ability capable of automated skeletal bone assessment based on pelvic radiographic images. KEY POINTS: * The pelvis has considerable value in determining the bone age. * Deep learning can be used to create an automated bone age assessment model based on pelvic radiographs. * The deep learning convolutional neural network model achieves performance on par with the existing cubic regression model. PMID- 30402704 TI - Differentiation of triple-negative breast cancer from other subtypes through whole-tumor histogram analysis on multiparametric MR imaging. AB - PURPOSE: To identify triple-negative (TN) breast cancer imaging biomarkers in comparison to other molecular subtypes using multiparametric MR imaging maps and whole-tumor histogram analysis. MATERIALS AND METHODS: This retrospective study included 134 patients with invasive ductal carcinoma. Whole-tumor histogram-based texture features were extracted from a quantitative ADC map and DCE semi quantitative maps (washin and washout). Univariate analysis using the Student's t test or Mann-Whitney U test was performed to identify significant variables for differentiating TN cancer from other subtypes. The ROC curves were generated based on the significant variables identified from the univariate analysis. The AUC, sensitivity, and specificity for subtype differentiation were reported. RESULTS: The significant parameters on the univariate analysis achieved an AUC of 0.710 (95% confidence interval [CI] 0.562, 0.858) with a sensitivity of 63.6% and a specificity of 73.1% at the best cutoff point for differentiating TN cancers from Luminal A cancers. An AUC of 0.763 (95% CI 0.608, 0.917) with a sensitivity of 86.4% and a specificity of 72.2% was achieved for differentiating TN cancers from human epidermal growth factor receptor 2 (HER2) positive cancers. Also, an AUC of 0.683 (95% CI 0.556, 0.809) with a sensitivity of 54.5% and a specificity of 83.9% was achieved for differentiating TN cancers from non-TN cancers. There was no significant feature on the univariate analysis for TN cancers versus Luminal B cancers. CONCLUSIONS: Whole-tumor histogram-based imaging features derived from ADC, along with washin and washout maps, provide a non-invasive analytical approach for discriminating TN cancers from other subtypes. KEY POINTS: * Whole-tumor histogram-based features on MR multiparametric maps can help to assess biological characterization of breast cancer. * Histogram-based texture analysis may predict the molecular subtypes of breast cancer. * Combined DWI and DCE evaluation helps to identify triple-negative breast cancer. PMID- 30402705 TI - Patients' experience of screening CT colonography with reduced and full bowel preparation in a randomised trial. AB - OBJECTIVES: To assess patients' experience of bowel preparation and procedure for screening CT colonography with reduced (r-CTC) and full cathartic preparation (f CTC) that showed similar detection rate for advanced neoplasia in a randomised trial. METHODS: Six hundred seventy-four subjects undergoing r-CTC and 612 undergoing f-CTC in the SAVE trial were asked to complete two pre-examination questionnaires-(1) Life Orientation Test - Revised (LOT-R) assessing optimism and (2) bowel preparation questionnaire-and a post-examination questionnaire evaluating overall experience of CTC screening test. Items were analysed with chi square and t test separately and pooled. RESULTS: LOT-R was completed by 529 (78%) of r-CTC and by 462 (75%) of f-CTC participants and bowel preparation questionnaire by 531 (79%) subjects in the r-CTC group and by 465 (76%) in the f CTC group. Post-examination questionnaire was completed by 525 (78%) subjects in the r-CTC group and by 453 (74%) in the f-CTC group. LOT-R average score was not different between r-CTC (14.27 +/- 3.66) and f-CTC (14.54 +/- 3.35) (p = 0.22). In bowel preparation questionnaire, 88% of r-CTC subjects reported no preparation related symptoms as compared to 70% of f-CTC subjects (p < 0.001). No interference of bowel preparation with daily activities was reported in 80% of subjects in the r-CTC group as compared to 53% of subjects in the f-CTC group (p < 0.001). In post-examination questionnaire, average scores for discomfort of the procedure were not significantly different between r-CTC (3.53 +/- 0.04) and f CTC (3.59 +/- 0.04) groups (p = 0.84). CONCLUSIONS: Reduced bowel preparation is better tolerated than full preparation for screening CT colonography. KEY POINTS: * Reduced bowel preparation is better tolerated than full preparation for screening CT colonography. * Procedure-related discomfort of screening CT colonography is not influenced by bowel preparation. * Males tolerate bowel preparation and CT colonography screening procedure better than females. PMID- 30402707 TI - Fe3+ Facilitates Endocytic Internalization of Extracellular Abeta1-42 and Enhances Abeta1-42-Induced Caspase-3/Caspase-4 Activation and Neuronal Cell Death. AB - Amyloid beta (Abeta) peptide is a critical causative factor in Alzheimer's disease (AD) and of a variety of fragmented Abeta peptides Abeta1-42 thought to exhibit the most neurotoxic effect. The present study investigated the effects of Fe3+ on Abeta1-42 internalization and Abeta1-42-induced caspase activation and neurotoxicity using mouse hippocampal slices and cultured PC-12 cells. Extracellularly applied Abeta1-42 increased the cell-associated Abeta1-42 levels in a concentration-dependent manner, and the effect was enhanced by adding Fe3+. Fe3+-induced enhancement of the cell-associated Abeta1-42 levels was significantly inhibited by the endocytosis inhibitors dynasore and methyl-beta cyclodextrin. Abeta1-42 reduced PC-12 cell viability in a concentration-dependent manner, and further reduction of the cell viability was obtained with Fe3+. Abeta1-42-induced reduction of cell viability was not affected by A187, an antagonist of amylin-3 receptor. Abeta1-42 activated caspase-3, caspase-4, and caspase-8 to a variety of degrees and Fe3+ further enhanced Abeta1-42-induced activation of caspase-3 and caspase-4. Taken together, these results indicate that Fe3+ accelerates endocytic internalization of extracellular Abeta1-42, enhances Abeta1-42-induced caspase-3/caspase-4 activation, and promotes Abeta1-42 induced neuronal cell death, regardless of amylin receptor. PMID- 30402706 TI - Volumetric 3D assessment of ablation zones after thermal ablation of colorectal liver metastases to improve prediction of local tumor progression. AB - PURPOSE: The goal of this study was to develop and evaluate a volumetric three dimensional (3D) approach to improve the accuracy of ablation margin assessment following thermal ablation of hepatic tumors. METHODS: The 3D margin assessment technique was developed to generate the new 3D assessment metrics: volumes of insufficient coverage (VICs) measuring volume of tissue at risk post-ablation. VICs were computed for the tumor and tumor plus theoretical 5- and 10-mm margins. The diagnostic accuracy of the 3D assessment to predict 2-year local tumor progression (LTP) was compared to that of manual 2D assessment using retrospective analysis of a patient cohort that has previously been reported as a part of an outcome-centered study. Eighty-six consecutive patients with 108 colorectal cancer liver metastases treated with radiofrequency ablation (2002 2012) were used for evaluation. The 2-year LTP discrimination power was assessed using receiver operating characteristic area under the curve (AUC) analysis. RESULTS: A 3D assessment of margins was successfully completed for 93 out of 108 tumors. The minimum margin size measured using the 3D method had higher discrimination power compared with the 2D method, with an AUC value of 0.893 vs. 0.790 (p = 0.01). The new 5-mm VIC metric had the highest 2-year LTP discrimination power with an AUC value of 0.923 (p = 0.004). CONCLUSIONS: Volumetric semi-automated 3D assessment of the ablation zone in the liver is feasible and can improve accuracy of 2-year LTP prediction following thermal ablation of hepatic tumors. KEY POINTS: * More accurate prediction of local tumor progression risk using volumetric 3D ablation zone assessment can help improve the efficacy of image-guided percutaneous thermal ablation of hepatic tumors. * The accuracy of evaluation of ablation zone margins after thermal ablation of colorectal liver metastases can be improved using a volumetric 3D semi-automated assessment approach and the volume of insufficient coverage assessment metric. * The new 5-mm volume-of-insufficient-coverage metric, indicating the volume of tumor plus 5-mm margin that remained untreated, had the highest 2-year local tumor progression discrimination power. PMID- 30402708 TI - Prenatal Exposure to Benzophenone-3 Impairs Autophagy, Disrupts RXRs/PPARgamma Signaling, and Alters Epigenetic and Post-Translational Statuses in Brain Neurons. AB - The UV absorber benzophenone-3 (BP-3) is the most extensively used chemical substance in various personal care products. Despite that BP-3 exposure is widespread, knowledge about the impact of BP-3 on the brain development is negligible. The present study aimed to explore the mechanisms of prenatal exposure to BP-3 in neuronal cells, with particular emphasis on autophagy and nuclear receptors signaling as well as the epigenetic and post-translational modifications occurring in response to BP-3. To observe the impact of prenatal exposure to BP-3, we administered BP-3 to pregnant mice, and next, we isolated brain tissue from pretreated embryos for primary cell neocortical culture. Our study revealed that prenatal exposure to BP-3 (used in environmentally relevant doses) impairs autophagy in terms of BECLIN-1, MAP1LC3B, autophagosomes, and autophagy-related factors; disrupts the levels of retinoid X receptors (RXRs) and peroxisome proliferator-activated receptor gamma (PPARgamma); alters epigenetic status (i.e., attenuates HDAC and sirtuin activities); inhibits post translational modifications in terms of global sumoylation; and dysregulates expression of neurogenesis- and neurotransmitter-related genes as well as miRNAs involved in pathologies of the nervous system. Our study also showed that BP-3 has good permeability through the BBB. We strongly suggest that BP-3-evoked effects may substantiate a fetal basis of the adult onset of neurological diseases, particularly schizophrenia and Alzheimer's disease. PMID- 30402709 TI - A Novel Mecp2Y120D Knock-in Model Displays Similar Behavioral Traits But Distinct Molecular Features Compared to the Mecp2-Null Mouse Implying Precision Medicine for the Treatment of Rett Syndrome. AB - MeCP2 is a fundamental protein associated with several neurological disorders, including Rett syndrome. It is considered a multifunctional factor with a prominent role in regulating chromatin structure; however, a full comprehension of the consequences of its deficiency is still lacking. Here, we characterize a novel mouse model of Mecp2 bearing the human mutation Y120D, which is localized in the methyl-binding domain. As most models of Mecp2, the Mecp2Y120D mouse develops a severe Rett-like phenotype. This mutation alters the interaction of the protein with chromatin, but surprisingly, it also impairs its association with corepressors independently on the involved interacting domains. These features, which become overt mainly in the mature brain, cause a more accessible and transcriptionally active chromatin structure; conversely, in the Mecp2-null brain, we find a less accessible and transcriptionally inactive chromatin. By demonstrating that different MECP2 mutations can produce concordant neurological phenotypes but discordant molecular features, we highlight the importance of considering personalized approaches for the treatment of Rett syndrome. PMID- 30402710 TI - Interleukin 28A.rs12980602 and interleukin 28B.rs8103142 genotypes could be protective against HCV infection among Egyptians. AB - Previous studies showed that interleukin (IL)-28B gene polymorphisms were associated with hepatitis C Virus (HCV) infection and treatment outcomes. We tested whether single-nucleotide polymorphisms (SNPs) in IL-28A and IL-28B are associated with HCV infection among Egyptians with HCV genotype 4 infections. We enrolled 144 chronic HCV patients, 72 spontaneously resolved HCV subjects, and 69 healthy controls. Four SNPs in IL-28A and IL-28B genes (IL-28A.rs12980602, IL 28B.rs12979860, IL-28B.rs8099917, and IL-28B.rs8103142) were genotyped. The most frequent IL-28B haplotype "TCT" was significantly more frequent in HCV-infected subjects than in HCV negative subjects (62.2% vs. 48.6%, respectively; p = 0.005). The frequency of IL-28A.rs12980602 "T" allele was significantly higher than the "C" allele in healthy controls compared to HCV-infected subjects (p < 0.001) with the "TT" genotype significantly higher in healthy controls compared to HCV-infected subjects (p < 0.001) with no association with viral load (p = 0.11) among chronically infected subjects. The results, also, confirmed the previous role of IL-28B SNPs in predicting HCV infection outcome. Importantly, IL 28B.rs8099917 "TT" genotype was significantly associated with low viral load in HCV-infected subjects, while the remaining three SNPs did not. The three IL-28B SNPs were in linkage disequilibrium (D' > 0.68; r2 > 0.43) for all comparisons in HCV patients, while there was no linkage disequilibrium of IL-28A polymorphisms and the three IL-28B SNPs. In conclusion, IL-28A.rs12980602 and IL-28B.rs8103142 TT genotype could be protective against HCV infection. Also, IL-28B.rs12979860, IL-28B.rs8099917, and IL-28B.rs8103142 SNPs predicted the outcome of HCV infection among genotype-4-infected Egyptians. Moreover, IL-28B.rs8099917 SNP affected the viral load in chronic HCV patients. PMID- 30402711 TI - Adult presentation of asymptomatic right lung agenesis: a rare anatomical variation. AB - Pulmonary agenesis is a very rare congenital anomaly characterized by the absence of pulmonary parenchyma and its vasculature. The diagnosis is usually during childhood. Herein, we report a case of incidental discover right pulmonary agenesis in adulthood male. A 30-year-old male presented with pre-operative medical evaluation for varicocele. There was no complaining from respiratory symptoms. He underwent plain chest X-ray and post-contrast CT scanning was performed using 64 multi-detector CT scanner. Chest Plain X-ray revealed cardiac and mediastinal shift to right side with hyper-inflated left lung crosses to right side. Multi-detector computed tomography examination revealed total absence of right lung with compensatory hyperinflation and increase volume of left lung. Hyper-inflated left lung extended to right hemithorax. Mediastinal structures including heart and great vessels were displaced to middle and lower parts of right hemithorax. Descending aorta located to anterior to thoracic vertebrae. Right pulmonary artery was absent. Right main bronchus was rudimentary. No detected other organ anomalies. No detected bony thoracic cage abnormalities. PMID- 30402712 TI - The effect of differences in the number of fiber bundles of the anterior tibial ligament on ankle braking function: a simulation study. AB - PURPOSE: The aim was to clarify the effect of differences in the number of fiber bundles of the anterior tibial ligament (ATFL) on ankle braking function. METHODS: The study sample included 81Japanese cadavers. ATFLs were categorized as: Type I with one fiber bundle; Type II with two fiber bundles that were completely separated; and Type III with three fiber bundles. Three-dimensional reconstructions of a single specimen from each category were then created. These were used to simulate and calculate ATFL strain during dorsiflexion (20 degrees ) and plantarflexion (30 degrees ) on the talocrural joint axis and inversion (20 degrees ) on the subtalar joint axis. RESULTS: Almost all types of superior fiber lines were stretched with dorsiflexion and plantarflexion. Regardless of Type, the inferior fiber line was shortened with plantarflexion and stretched with dorsiflexion. The inferior fiber bundle of Type III was shortened only at plantarflexion 30 degrees and inversion 20 degrees , but in all others it was stretched. CONCLUSIONS: The results suggest that Type III was weaker than Type I and Type II in terms of ankle plantarflexion and inversion braking function. PMID- 30402713 TI - An Expandable Mechanopharmaceutical Device (3): a Versatile Raman Spectral Cytometry Approach to Study the Drug Cargo Capacity of Individual Macrophages. AB - PURPOSE: To improve cytometric phenotyping abilities and better understand cell populations with high interindividual variability, a novel Raman-based microanalysis was developed to characterize macrophages on the basis of chemical composition, specifically to measure and characterize intracellular drug distribution and phase separation in relation to endogenous cellular biomolecules. METHODS: The microanalysis was developed for the commercially available WiTec alpha300R confocal Raman microscope. Alveolar macrophages were isolated and incubated in the presence of pharmaceutical compounds nilotinib, chloroquine, or etravirine. A Raman data processing algorithm was specifically developed to acquire the Raman signals emitted from single-cells and calculate the signal contributions from each of the major molecular components present in cell samples. RESULTS: Our methodology enabled analysis of the most abundant biochemicals present in typical eukaryotic cells and clearly identified "foamy" lipid-laden macrophages throughout cell populations, indicating feasibility for cellular lipid content analysis in the context of different diseases. Single-cell imaging revealed differences in intracellular distribution behavior for each drug; nilotinib underwent phase separation and self-aggregation while chloroquine and etravirine accumulated primarily via lipid partitioning. CONCLUSIONS: This methodology establishes a versatile cytometric analysis of drug cargo loading in macrophages requiring small numbers of cells with foreseeable applications in toxicology, disease pathology, and drug discovery. PMID- 30402715 TI - Correction to: Prognostic value of estimated plasma volume in acute heart failure in three cohort studies. AB - Unfortunately, an error occurred in the methods section of the abstract. PMID- 30402714 TI - Evaluation of a Potential Clinical Significant Drug-Drug Interaction between Digoxin and Bupropion in Cynomolgus Monkeys. AB - PURPOSE: A three-period digoxin-bupropion drug-drug interaction study was performed in cynomolgus monkeys to assess the effect of bupropion and its metabolites on digoxin disposition. METHODS: Monkeys were administered either an i.v. infusion (0.1 mg/kg) or an oral dose of digoxin (0.2 mg/kg) as control. In single-dosing period, monkeys received an i.v. infusion of bupropion at 1.5 mg/kg together with an infusion or oral dosing of digoxin, respectively. During multiple-dosing period, bupropion was orally administered q.d. at 7.72 mg/kg for 12-day. Then it was co-administered with an i.v. infusion or oral dosing of digoxin, respectively. Renal expression of OATP4C1 and P-gp was examined. RESULTS: Bupropion significantly increased i.v. digoxin CLrenal0-48h by 1 fold in single-dosing period. But it had no effect on the systemic disposition of digoxin. In multiple-dosing period, bupropion significantly increased oral digoxin CLrenal0-48h, CLtotal0-48h, CLnon-renal0-48h and decreased its plasma exposure. Bupropion and its metabolites did not alter creatinine clearance. OATP4C1 was located at the basolateral membrane of proximal tubule cells, while P gp was on the apical membrane. CONCLUSIONS: The effect of multiple dosing with bupropion on the pharmacokinetics of digoxin is more pronounced. The magnitude of increase in digoxin CLrenal0-48h contributed to the decrease in AUC of digoxin in some extent, but certainly is not the major driving force. The lack of systemic exposure after a single dose but a significant decrease in exposure mediated by an increase in the digoxin CLnon-renal0-48h with repeated dosing is likely to be the more clinically relevant. PMID- 30402716 TI - Optimised isolation method for RNA extraction suitable for RNA sequencing from feline teeth collected in a clinical setting and at post mortem. AB - Advanced next generation sequencing approaches have started to reveal the cellular and molecular complexity of the microenvironment in many tissues. It is challenging to obtain high quality RNA from mineralised tissues. We developed an optimised method of RNA extraction from feline teeth collected in a clinical setting and at post mortem. Teeth were homogenised in phenol-guanidinium solution at near-freezing temperatures and followed by solid-phase nucleic acid extraction utilising a commercially available kit. This method produced good RNA yields and improved RNA quality based on RNA integrity numbers equivalent (RINe) from an average of 3.6 to 5.6. No correlation was found between RNA purity parameters measured by A260:280 or A230:260 ratios and degree of RNA degradation. This implies that RNA purity indicators cannot be reliably used as parameters of RNA integrity. Two reference genes (GAPDH, RPS19) showed significant changes in expression levels by qPCR at low and moderate RINe values, while RPL17 was stable at all RINe values tested. Furthermore, we investigated the effect of quantity and quality of RNA on the quality of the resultant RNA sequencing (RNA-Seq) data. Thirteen RNA-seq data showed similar duplication and mapping rates (94 to 95%) against the feline genome regardless of RINe values. However one low yield sample with a high RINe value showed a high duplication rate and it was an outlier on the RNA-seq multidimensional scaling plot. We conclude that the overall yield of RNA was more important than quality of RNA for RNA-seq quality control. These results will guide researchers who wish to perform RNA extractions from mineralised tissues, especially if collecting in a clinical setting with the recognised restraints that this imposes. PMID- 30402717 TI - Exposure to and use of mobile devices in children aged 1-60 months. AB - The present study was conducted to determine young children's (aged 1-60 months) exposure to and use of mobile devices. The study included 422 parents of children aged 1-60 months admitted to pediatric outpatient clinics. A questionnaire was administered to the parents via face-to-face interview. Children's overall exposure to mobile devices was 75.6% (n = 319). Of the children, 24.4% (n = 103) had never used a mobile device. Among the children that had used a mobile device, 20.6% (n = 66) were aged between 1 and 12 months; 24.5% (n = 78) were aged between 13 and 24 months. The median age at the first time use of a mobile device was 12 months. The youngest child that used a mobile device was 6 months old. Tablets had a significant difference in the age at first use compared with other mobile media types (P < 0.01). Children's overall mobile device ownership was 30.7% (98/319) in frequency. There was a positive relationship between mobile device ownership and age (p < 0.001). The most commonly owned mobile device was a "tablet" at a frequency of 68.4% (67/98). The frequency of tablet ownership was inversely associated with household income (P < 0.01). Of the children that used mobile devices, 25.7% (82/319) used multiple mobile devices simultaneously. Among 422 children, 15.9% (n = 67) had a tablet in their room. The frequency of tablet use and ownership was inversely related to the mother's educational level (P < 0.01). The parents reported that 22.3% (n = 71) never received help while navigating the mobile device. The most frequent activity with mobile devices was watching videos (70.8%, n = 226). Of the parents, 59.6% (190/319) let their children use mobile devices while they are doing daily tasks or domestic chores. Of the parents, 91.5% (n = 386) reported not having been informed by a doctor about the effects of mobile devices on their children.Conclusion: This study demonstrates a high prevalence of exposure to mobile devices in young children. The frequency of tablet use and ownership of offspring was inversely related with maternal educational level and household income. What is Known: * Mobile phones and other similar mobile devices are now embedded in the daily lives of children. * There are limited data about mobile media use in early childhood, and few guidelines on which clinicians can base their recommendations. What is New: * The exposure to mobile devices is high in young children aged 1-60 months. * The frequency of tablet use and ownership of offspring was inversely related to household income and maternal educational level. PMID- 30402718 TI - Urine can speed up the re-epithelialization process of prostatic urethra wounds by promoting the proliferation and migration of prostate epithelial cells. AB - OBJECTIVES: The present study aimed to investigate the influence of urine on re epithelialization in canine prostatic urethra after prostatectomy and explore possible causes. METHOD: We established two groups of prostatic canine models. The first group contained urine that canines underwent the surgery by two-micron laser resection of the prostate-tangerine technique (TmLRP-TT), and no transurethral catheter was required. The second group was without urine that canines accepted the surgery by TmLRP-TT add ureter skin ostomy urine bypass. Histopathology of re-epithelialization of repair in trauma in canine prostatic urethra was observed by hematoxylin and eosin (HE) staining, and immunochemistry was used to determine the expression of transforming growth factor-beta1 (TGF beta1). Human prostate epithelial line (BPH-1) cells were cultured with or without urine and the abilities of proliferation and migration were tested by CCK 8 and transwell assays, respectively. RESULTS: The histology displayed that there was distinct proliferation of prostatic cell under the wound after 3 days, re epithelialization began after 9 days, and finished after 28 days at urine group. The TGF-beta1 like-IR in prostatic epithelium cells and fibroblast cells under the wound at urine group were strikingly increased as compared with the cells at no urine group after 3, 9, and 11 days, respectively (p < 0.05). In CCK-8 and Transwell assays, an increase of cells' proliferation and migration was detected in urine culture group compared with no urine culture group (p < 0.05). CONCLUSION: Urine may speed up the re-epithelialization process for prostatic urethra wounds by promoting proliferation and migration of prostate epithelial cells. PMID- 30402720 TI - Clinical Pharmacology of Fast-Acting Insulin Aspart Versus Insulin Aspart Measured as Free or Total Insulin Aspart and the Relation to Anti-Insulin Aspart Antibody Levels in Subjects with Type 1 Diabetes Mellitus. AB - BACKGROUND: Fast-acting insulin aspart (faster aspart) is an ultra-fast-acting formulation of insulin aspart (IAsp). This post hoc analysis investigated the pharmacokinetics of faster aspart versus IAsp, measured as free or total IAsp, and the relationship between anti-IAsp antibodies and the pharmacokinetics/pharmacodynamics of faster aspart and IAsp. METHODS: Free and total IAsp concentrations and anti-IAsp antibodies were determined in adults with type 1 diabetes mellitus receiving subcutaneous faster aspart and/or IAsp in four single-dose clinical pharmacology trials (n = 175) and a 26-week phase IIIa trial (n = 1040). Pharmacodynamics were assessed by euglycaemic clamp or meal test, respectively. RESULTS: The pharmacokinetic profile was left-shifted and early exposure was greater with faster aspart versus IAsp independent of free or total IAsp assay. The faster aspart-IAsp difference in the time to 50% of maximum IAsp concentration in the early part of the pharmacokinetic profile (tEarly 50 % Cmax) [95% confidence interval (CI)] was - 8.8 [- 10.0 to - 7.5] and - 7.6 [- 8.8 to - 6.4] min for free and total IAsp, respectively. The faster aspart/IAsp ratio for the area under the concentration-time curve (AUC) for IAsp from time zero to 30 min (AUCIAsp,0-30 min) [95% CI] was 1.88 [1.74-2.04] and 1.77 [1.64-1.90] for free and total IAsp. Higher anti-IAsp antibody levels were associated with a lower ratio of free/total IAsp for the total AUC for IAsp (AUCIAsp,0-t). Early glucose-lowering effect (AUC for the glucose infusion rate [GIR] from time zero to 60 min [AUCGIR,0-60 min]) was greater by 25-44% for faster aspart versus IAsp independent of anti-IAsp antibody levels. Total glucose-lowering effect (total AUC for GIR [AUCGIR,0-t]) in a clamp and 1-h postprandial glucose increment in a meal test appeared essentially unaffected by anti-IAsp antibodies. CONCLUSIONS: Faster aspart provides accelerated pharmacokinetics versus IAsp regardless if based on free or total IAsp assay. Higher anti-IAsp antibodies increase total IAsp concentrations but do not influence faster aspart nor IAsp pharmacodynamics. CLINICALTRIALS. GOV IDENTIFIERS: NCT01618188, NCT02003677, NCT01934712, NCT02568280, NCT01831765. PMID- 30402719 TI - Zirconia Nanoparticles-Induced Toxic Effects in Osteoblast-Like 3T3-E1 Cells. AB - Zirconia (ZrO2) is one of the widely used metal oxides for potential bio applications such as biosensors, cancer therapy, implants, and dentistry due to its high mechanical strength and less toxicity. Because of their widespread applications, the potential exposure to these nanoparticles (NPs) has increased, which has attracted extensive attention. Thus, it is urgent to investigate the toxicological profile of ZrO2 NPs. Titanium dioxide (TiO2) is another extensively used nanomaterials which are known to be weakly toxic. In this study, TiO2 NPs were served as control to evaluate the biocompatibility of ZrO2 NPs. We detected the cytotoxicity of TiO2 and ZrO2 NPs in osteoblast-like 3T3-E1 cells and found that reactive oxygen species (ROS) played a crucial role in the TiO2 and ZrO2 NP induced cytotoxicity with concentration-dependent manner. We also showed TiO2 and ZrO2 NPs could induce apoptosis and morphology changes after culturing with 3T3 E1 cells at high concentrations. Moreover, TiO2 and ZrO2 NPs at high concentrations could inhibit cell osteogenic differentiation, compared to those at low concentrations. In conclusion, TiO2 and ZrO2 NPs could induce cytotoxic responses in vitro in a concentration-dependent manner, which may also affect osteogenesis; ZrO2 NPs showed more potent toxic effects than TiO2 NPs. PMID- 30402721 TI - New mechanisms of phenytoin in calcium homeostasis: competitive inhibition of CD38 in hippocampal cells. AB - PURPOSE: Phenytoin is a major anticonvulsant drug that is effective to improve arrhythmia and neuropathic pain. According to early works, phenytoin affected cell membrane depolarization by sodium channel blocking, guanylyl and adenylyl cyclase suppression that cause to intracellular Na+ and Ca2+ downregulation. This study was aimed to clarify some ambiguities in pathophysiological action of phenytoin by in vitro and molecular docking analyses. METHODS: In this study intracellular free Ca2+ of primary culture of embryonic mouse hippocampus evaluated via Fura 2 as fluorescent probe. The effects of phenytoin on ADP ribosyl cyclase activity was assessed by recently developed fluorometric assay. Molecular docking simulation was also implemented to investigate the possible interaction between phenytoin and CD38. RESULTS: Our results confirmed phenytoin competitively inhibits cyclase activity of CD38 (IC50 = 8.1 MUM) and reduces cADPR content. cADPR is a Ca2+-mobilising second messenger which binds to L-type calcium channel and ryanodine receptors in cell and ER membrane and increases cytosolic free Ca2+. Ca2+ content of cells decreased significantly in the presence of phenytoin in a dose dependent manner (IC50 = 12.74 uM). Based on molecular docking analysis, phenytoin binds to deeper site of CD38 active site, mainly via hydrophobic interactions and consequently inhibits proper contact of substrate with catalytic residues specially Glu 226, Trp 186, Thr221. CONCLUSION: Taken together, one of the anticonvulsant mechanisms of phenytoin is Ca2+ inhibition from CD38 pathway, therefore could be used in disorders that accompanied by CD38 over production or activation such as heart disease, depression, brain sepsis, airway disease, oxidative stress and inflammation. Graphical abstract ?. PMID- 30402722 TI - A New Era of Bile Duct Repair: Robotic-Assisted Versus Laparoscopic Hepaticojejunostomy. AB - BACKGROUND: Despite scientific evidence of the safety, efficacy, and in some cases superiority of minimally invasive surgery in hepato-pancreato-biliary procedures, there are scarce publications about bile duct repairs. The aim of this study was to compare the outcomes of robotic-assisted surgery versus laparoscopic surgery on bile duct repair in patients with post-cholecystectomy bile duct injury. METHODS: This is a retrospective comparative study of our prospectively collected database of patients with bile duct injury who underwent robotic or laparoscopic hepaticojejunostomy. RESULTS: Seventy-five bile duct repairs (40 by laparoscopic and 35 by robotic-assisted surgery) were treated from 2012 to 2018. Injury types were as follows: E1 (7.5% vs. 14.3%), E2 (22.5% vs. 14.3%), E3 (40% vs. 42.9%), E4 (22.5% vs. 28.6%), and E5 (7.5% vs. 0), for laparoscopic hepaticojejunostomy (LHJ) and robotic-assisted hepaticojejunostomy (RHJ) respectively. The overall morbidity rate was similar (LHJ 27.5% vs. RHJ 22.8%, P = 0.644), during an overall median follow-up of 28 (14-50) months. In the LHJ group, the actuarial primary patency rate was 92.5% during a median follow-up of 49 (43.2-56.8) months. While in the RHJ group, the actuarial primary patency rate was 100%, during a median follow-up of 16 (12-22) months. The overall primary patency rate was 96% (LHJ 92.5% vs. RHJ 100%, log-rank P = 0.617). CONCLUSION: Our results showed that the robotic approach is similar to the laparoscopic regarding safety and efficacy in attaining primary patency for bile duct repair. PMID- 30402723 TI - Management of Segmental Bile Duct Injuries After Cholecystectomy: a Systematic Review. AB - BACKGROUND: Injuries to segmental or aberrant bile ducts are encountered less commonly than their major bile duct counterparts and present a unique diagnostic and therapeutic challenge, since the nature of this injury involves a transected bile duct that loses its communication with the main ductal system. In this systematic review, we aim to pool available data on this particular type of biliary injury in an effort to outline available diagnostic and therapeutic modalities and evaluate their efficacy. MATERIALS AND METHODS: An extensive literature search was performed on MEDLINE, Scopus, and Web of Science to identify isolated segmental or aberrant bile duct injuries. RESULTS: A total of 21 studies were included in this systematic report. Ten studies reported non operative management of patients, while 12 reported operative management of included patients. Outcomes of interest were the choice of treatment interventions and their success. Overall, 23 patients were managed non operatively with a 91% success rate and 30 patients were managed operatively with a 90% success rate. CONCLUSION: Non-operative management might be a viable alternative to surgery. Hepatobiliary surgeons should be encouraged to publish their results in treating these rare injuries to further elucidate the role and efficacy of such an approach. PMID- 30402724 TI - Arbuscular Mycorrhizal Fungi Alter the Community Structure of Ammonia Oxidizers at High Fertility via Competition for Soil NH4. AB - Nitrification represents a central process in the cycling of nitrogen (N) which in high-fertility habitats can occasionally be undesirable. Here, we explore how arbuscular mycorrhiza (AM) impacts nitrification when N availability is not limiting to plant growth. We wanted to test which of the mechanisms that have been proposed in the literature best describes how AM influences nitrification. We manipulated the growth settings of Plantago lanceolata so that we could control the mycorrhizal state of our plants. AM induced no changes in the potential nitrification rates or the estimates of ammonium oxidizing (AO) bacteria. However, we could observe a moderate shift in the community of ammonia oxidizers, which matched the shift we saw when comparing hyphosphere to rhizosphere soil samples and mirrored well changes in the availability of ammonium in soil. We interpret our results as support that it is competition for N that drives the interaction between AM and AO. Our experiment sheds light on an understudied interaction which is pertinent to typical management practices in agricultural systems. PMID- 30402725 TI - [Toxic changes of the central nervous system]. AB - CLINICAL ISSUES: Various toxic agents can cause changes to the white matter of the brain leading to leukoencephalopathies. These changes often lead to signal alterations of the white matter with or without a diffusion restriction signal. White matter lesions can be reversible or irreversible. There are many differential diagnoses of toxic leukoencephalopathies. PRACTICAL RECOMMENDATIONS: For the radiologist it is necessary to be familiar with the causes, the clinical and the imaging presentation of toxic leukoencephalopathies because early treatment often leads to improved prognosis. PMID- 30402726 TI - Magnetic-assisted robotic surgery: initial case series of reduced-port robotic prostatectomy. AB - Minimally invasive radical prostatectomy has rapidly been adopted as the primary means of surgical intervention for prostate cancer. Intraoperative tissue retraction relies on either gravity (via positioning) or use of additional ports and instrumentation. We report the use of a novel trocar-less magnetic retractor system to aid with tissue retraction. Three patients underwent robotic-assisted radical prostatectomy in the treatment of prostatic adenocarcinoma at a single tertiary care institution. All surgeries utilized the LevitaTM Magnetic Surgical System (San Mateo, CA) without the use of a fourth robotic arm. The magnetic grasper was used to manipulate the bowel, peritoneum, seminal vesicles, and prostatic capsule. Demographic, pre-operative, and perioperative information were collected. No cases required placement of any additional ports. No intraoperative or immediate post-operative complications occurred. No tissue tearing or subjective tissue damage was noted by placement or removal of the magnetic retractor. Mean operative time was 216 +/- 17 min and mean blood loss was 333 +/- 57 mL. All patients were discharged to home on post-operative day 1. Robotic prostatectomy utilizing a magnetically anchored tissue grasper appears to be safe and effective while reducing the number of ports (fourth robotic arm) needed. Further investigation is warranted. PMID- 30402727 TI - Assessment of the effectiveness of wetland protection in improving waterbird diversity in a Moroccan wetland system. AB - Assessment of the effectiveness of nature conservation measures is a crucial step to ensure that the actions undertaken have achieved the expected results. Depending on the results of such evaluations, managers may need to reframe or even change their approaches. In this analysis, the effectiveness of establishing strictly protected areas was assessed in three important Moroccan Atlantic sites, namely Ad-Dakhla bay, Khnifiss lagoon, and Souss estuary. In particular, we investigated whether protection of these sites was followed by significant changes in the direction and/or strength of change in waterbird species richness and density over time. Our results showed that during the pre-protection period, waterbird species richness has been declining over time, while total waterbird density and the diversity of wading and open-water birds had been maintained at low levels. However, shortly after site protection, a rapid increase in these measures was observed, while there was no significant change in waterfowl species richness and density. Overall, these results suggest that the protection of these wetlands has been a watershed in the recent history of their birds, reversing the trends of a continuing decline towards rapid regeneration. This is one obvious signs of the success of the programme undertaken by the Moroccan authorities to conserve the biodiversity of these wetlands. Further investigations of the effects of protection at all wetlands throughout Morocco are needed to more profoundly understand the role of such conservation measures on shaping wintering waterbird communities. PMID- 30402728 TI - Fluorometric determination of morphine via its effect on the quenching of fluorescein by gold nanoparticles through a surface energy transfer process. AB - A method is described for sensitive and selective fluorometric determination of morphine. It is based on the effect of morphine on quenching of the fluorescence of fluorescein by gold nanoparticles (AuNPs) via surface energy transfer. When fluorescein is added to solutions of colloidal AuNPs, its fluorescence becomes quenched due to nanometal surface energy transfer (NSET) because the absorption of AuNPs strongly overlaps the emission spectrum of fluorescein. In the presence of morphine, which contains both a tertiary nitrogen ring atom and a phenolic hydroxy group, it will coordinate to the AuNPs, and this causes recovery of fluorescence. The presence of a tertiary nitrogen ring atom and a phenolic hydroxy group (both required for the effect to occur) in morphine make the probe highly selective and sensitive for morphine. A paper strip assay also was developed by utilizing this detection scheme. The turn-on fluorescent probe was successfully applied to the determination of morphine in spiked serum and urine samples. The method has a 53 pM limit of detection. The paper strip was applied to the determination of morphine in sweat, urine and other biological fluids. It is perceived to be useful for early detection of drug abuse by adolescent. Graphical abstract Schematic of the mechanism of fluorescence turn on detection of morphine using Au NPs (gold nanoparticles) acting asquencher of the fluorescence of fluorescein. PMID- 30402729 TI - Zigzag Hollow Cracks of Silver Nanoparticle Film Regulated by Its Drying Micro environment. AB - We first verify the critical impact of evaporation on the formation of zigzag hollow cracks by regulating the drying micro-environment of silver nanoparticle film. Uneven evaporation and component segregation contributes to the flows along the surface and inside of droplets. Asymmetric vapor concentration distribution is capable of weakening the surface flow of droplets, thus suppressing the inner compressive stress of nanoparticles and leading to a surface morphology with less cracks. Although defect-free and surface smooth nanoparticle film deposited by a solution-based method remains a big challenge, our work has referential significance to optimize high-quality nanoparticle film with appropriate deposition and curing processes. Moreover, an optimization possibility through the drying micro-environment should be considered in high-end applications due to its enhanced effect on high-resolution patterns. PMID- 30402730 TI - The effect of repeated biopsy on pre-implantation genetic testing for monogenic diseases (PGT-M) treatment outcome. AB - PURPOSE: To study the outcome of repeated biopsy for pre-implantation genetic testing in case of failed genetic diagnosis in the first biopsy. METHODS: The study group included 81 cycles where embryos underwent re-biopsy because there were no transferable embryos after the first biopsy: in 55 cycles, the first procedure was polar body biopsy (PBs) and the second cleavage-stage (BB); in 26 cycles, the first was BB and the second trophectoderm (BLAST) biopsy. The control group included 77 cycles where embryos underwent successful genetic diagnosis following the first biopsy, matched by maternal age, egg number, genetic inheritance type, and embryonic stage at the first biopsy. We measured genetic diagnosis rate, clinical pregnancy rates (PRs), live-birth rates (LBRs), gestational age, and birth weight. RESULTS: For repeated biopsy, genetic diagnosis was received in 67/81 cycles (82.7%); at a higher rate in PB + BB than in BB + BLAST (49/55, 89.1% and 18/26, 69.2% respectively, p = 0.055). Transferable embryos were found in 47 and 68 cycles in the study and the control groups. PRs/ET were 20/47 (42.6%) and 36/68 (52.9%) (p = 0.27), 16/36 (44.4%) following PB + BB, and 4/11 (36.4%) following BB + BLAST (p = 0.74). LBRs/ET were 13/47 (27.7%) in study group, and 28/68 (41.2%) in the controls (p = 0.14), 10/36 (27.8%) following PB + BB group, and 3/11 (27.3%) following BB + BLAST (p > 0.99). Gestational age and birth weight were similar in all groups. CONCLUSIONS: Re-biopsy of embryos when no genetic diagnosis could be reached following the first biopsy, achieved high rates of genetic diagnosis, pregnancies, and live births. PMID- 30402731 TI - [Mechanical circulatory support in cardiogenic shock]. AB - Acute revascularization is of utmost importance in acute heart failure and infarct-related cardiogenic shock. Besides this therapy of the underlying disease, methods for rapid restoration of arterial blood pressure and sufficient organ perfusion are at the forefront. If conventional means such as volume management, inotropic support, or infusion of vasopressors fail in this situation, mechanical circulatory support may be indicated in selected cases. Noninvasive systems for automatic thorax compression are used for extended cardiopulmonary resuscitation. Intra-aortic balloon counter pulsation (IABP) and axial turbine pumps provide circulatory support and left ventricular unloading. Extracorporeal membrane oxygenation (ECMO) devices consisting of a membrane oxygenator in combination with a centrifugal pump also support the gas exchange in cases of acute pulmonary failure. Using mechanical circulatory support allows lifesaving further diagnostic and therapeutic measures in selected cases, despite limited evidence. They help to restore sufficient arterial blood pressure and therefore organ perfusion in acute heart failure and cardiogenic shock. PMID- 30402732 TI - Task-specific focal chin tremor in idiopathic Parkinson's disease: is it an isolated phenomenon or a part of parkinsonism? PMID- 30402733 TI - The emerging neuroscience of appetitive and drug cue extinction in humans. AB - Fear extinction has been extensively studied in both humans and non-human animals, and this work has contributed greatly to our understanding and treatment of anxiety disorders. Yet other psychopathologies like addiction might be associated with impairments selectively in extinction of non-fear based, appetitive and drug cue associations, and these processes have been underexplored in clinical translational neuroscience. Important questions regarding similarities and differences in the neurobiological mechanisms underlying aversive and appetitive extinction remain unanswered, particularly those pertaining to cross-species evidence for the role of the ventromedial prefrontal cortex and, to some extent, the striatum. Here, we aim to draw attention to the paucity of studies investigating non-fear based extinction in humans, summarize emerging findings from the available literature, and highlight important directions for future research. We argue that closing these gaps in our understanding could help inform the development of more targeted, and perhaps more durable, forms of extinction-based treatments for addiction and related psychopathologies characterized by abnormally persistent appetitive and drug cue associations. PMID- 30402734 TI - Vulnerability, Harm, and Compromised Ethics Revealed by the Experiences of Queer Birthing Women in Rural Healthcare. AB - Phenomenological interviews with queer women in rural Nova Scotia reveal significant forms of trauma experienced during labour and birth. Situating the accounts of participants within both phenomenological and intersectional analyses reveals harms enabled by structurally embedded heteronormative and homophobic healthcare practices and policies. Our account illustrates the breadth and depth of harm experienced and outlines how these violate core ethical principles and values in healthcare. PMID- 30402735 TI - We can guide search by a set of colors, but are reluctant to do it. AB - For some real-world color searches, the target colors are not precisely known, and any item within a range of color values should be attended. Thus, a target representation that captures multiple similar colors would be advantageous. If such a multicolor search is possible, then search for two targets (e.g., Stroud, Menneer, Cave, and Donnelly, Journal of Experimental Psychology: Human Perception and Performance, 38(1): 113-122, 2012) might be guided by a target representation that included the target colors as well as the continuum of colors that fall between the targets within a contiguous region in color space. Results from Stroud, Menneer, Cave, and Donnelly, Journal of Experimental Psychology: Human Perception and Performance, 38(1): 113-122, (2012) suggest otherwise, however. The current set of experiments show that guidance for a set of colors that are all from a single region of color space can be reasonably effective if targets are depicted as specific discrete colors. Specifically, Experiments 1-3 demonstrate that a search can be guided by four and even eight colors given the appropriate conditions. However, Experiment 5 gives evidence that guidance is sometimes sensitive to how informative the target preview is to search. Experiments 6 and 7 show that a stimulus showing a continuous range of target colors is not translated into a search target representation. Thus, search can be guided by multiple discrete colors that are from a single region in color space, but this approach was not adopted in a search for two targets with intervening distractor colors. PMID- 30402736 TI - Comparative anatomical properties of some Epidendroideae and Orchidoideae species distributed in NE Turkey. AB - In this research, anatomical, leaf micromorphological features of the samples belonging to 25 taxa (Anacamptis Rich., Cephalanthera Rich., Dactylorhiza Necker ex Nevski, Gymnadenia R.Br., Himantoglossum Spreng., Limodorum Boehm., Ophrys L., Orchis L., Platanthera Rich., Serapias L., Spiranthes Rich. and Steveniella Schltr.) spread in the Karadeniz Region have been evaluated comparatively. In anatomical studies, the transverse section from root, stem and leaf, and surface section from leaves of plants were examined. In addition, micromorphological properties of leaf were determined by electron microscopy. Morphometrical analyses were carried out using the anatomical and leaf micromophological characters of each taxa. The data matrices were obtained by examining the results of at least three samples collected from different localities. The data were evaluated using Statistical Package for the Social Sciences (SPSS) and PAleontological STatistics (PAST) statistical programs with PCA, linear discriminant analysis (LDA), and unweighted pair group method with arithmetic mean analysis. Anatomical characteristics of plants such as root epidermis cell length, cortex diameter and pith cell diameter, leaf upper epidermis length-width and bulliform cell length-width were determined to be important characteristics. It was concluded that these characters are especially important in grouping at the genus level. PMID- 30402737 TI - Electroic and optical properties of germanene/MoS2 heterobilayers: first principles study. AB - First principles calculations have been performed to investigate the structural, electronic, and optical properties of germanene/MoS2 heterostructures. The results show that a weak van der Waals coupling between germanene and MoS2 layers can lead to a considerable band-gap opening (53 meV) as well as the preserved Dirac cone with a linear band dispersion of germanene. The applied external electric filed can not only enhance the interaction strength between two layers, but also linearly control the charge transfer between germanene and MoS2 layers, and consequently lead to a tunable band gap. Furthermore, the reduction in the optical absorption intensity of the heterostructures with respect to the separated monolayers has been predicted. These findings suggest that the Ge/MoS2 hybrid can be designed as the device where both finite band gap and high carrier mobility are required. PMID- 30402739 TI - [Nurses' perspectives on outpatient palliative care in Vorarlberg, Austria]. AB - BACKGROUND: Due to the demographic development the need for palliative care in the outpatient setting will increase and challenge general practitioners and community nurses. AIM: This study investigated the state of outpatient palliative care in Vorarlberg, Austria from the perspective of outpatient community nurses. The key points of the survey covered the burden of symptoms suffered by palliative patients. Another key focus was the cooperation and communication between community nurses and general practitioners. METHODS: Between 8 February and 7 March 2016 all 50 community-based nursing services in Vorarlberg were invited to participate in an online survey designed to estimate outpatient palliative care. The survey collected quantitative and descriptive data and 38 nursing services returned the questionnaire (76 %). RESULTS: According to community-based nurses, the proportion of patients in need of palliative care was 5.7 %. This assessment of needs correlates well with the proportion of personnel qualified in palliative care (p = 0.02). Nursing personnel estimated a high prevalence of symptom burden (76 %). Communication between outpatient nursing personnel and general practitioners relied primarily on telephone calls (79-90 %), less on joint rounds (13-21 %) and case reviews (26-45 %). According to 63 % of the nursing personnel the rate of hospitalization could be reduced with better interprofessional cooperation. DISCUSSION: Symptom burden in the outpatient setting was similar to that of patients being cared for in hospitals. Healthcare personnel in general palliative care should be adequately qualified. The quality of communication via telephone calls should be critically examined in further studies. PMID- 30402738 TI - [Arterial hypertension in old age with the focus on 80]. AB - Untreated high blood pressure in old age increases the risk of secondary diseases, especially stroke, coronary heart disease, myocardial infarction and heart failure and should be treated according to the guidelines. For slightly frail people up to the age of 80 years, a systolic blood pressure of 130-139 mm Hg (measured in the doctors surgery) should be the aim. According to the current European guidelines the same values are recommended for those over the age of 80 years but treatment should start at a systolic blood pressure of >=160 mm Hg. In physically disabled and very frail older people an individually tailored approach is recommended, regardless of age. The authors recommend a target systolic value <150 mm Hg but not below 130/70 mm Hg. In the event of poor tolerance the treatment should be adapted further as necessary. Antihypertensive medication should be selected under the aspects of polypharmacy. In many cases arterial hypertension in old age can be treated in accordance with the guidelines, taking multimorbidity and the interaction of medications into consideration. PMID- 30402741 TI - The role of EP3-receptor expression in cervical dysplasia. AB - PURPOSE: Prostaglandin-mediated inflammatory reactions play a major role in different cancers. Prostaglandin E2-receptor 3 (EP3) expression correlates with FIGO stages in cervical cancer and has been shown to be an independent prognostic factor for overall survival. EP3 expression levels in cervical intraepithelial neoplasia (CIN) as the precursor lesion of cervical cancer are currently unknown. METHODS: EP3 expression was analyzed by immunohistochemistry in 124 patient samples (CIN 1-3 and healthy controls) using the IR-scoring system. Expression levels were correlated with clinical outcome to assess for prognostic relevance in patients with CIN 2. Data analysis was performed using Kruskal-Wallis and Mann Whitney U test. RESULTS: EP3 expression levels significantly correlated with different grades of cervical dysplasia. Median EP3-IRS in healthy cervical tissue was 12 (n = 13) compared to 9 in CIN 1 (n = 38; p = 0.031 vs. healthy control), 6 in CIN 2 (n = 45; p < 0.001 vs. CIN 1) and 4 in CIN 3 (n = 28, p = 0.008 vs. CIN 2). The percentage of EP3 expressing cells in CIN 2 lesions was significantly lower in progressive than in regressive cases (mean percentage of EP3 positive cells in progress: 3.8%, n = 18; in regress: 9.3%, n = 20; p = 0.040). CONCLUSION: EP3 expression significantly decreases with higher grades of cervical intraepithelial neoplasia-which is in line with published IR scores in cervical cancer patients-and seems to be a prognostic marker for regression or progression of CIN 2 lesions. Our findings support the importance of the prostanoid pathway in cervical cancer and could help to identify targets for future therapies. PMID- 30402742 TI - [Pathogenesis and diagnostic evaluation of Fuchs' endothelial corneal dystrophy]. AB - BACKGROUND: Following new treatment options for Fuchs' endothelial corneal dystrophy, our understanding of optical and structural changes in the patient's cornea is also starting to improve. OBJECTIVE: To provide an update on clinical evaluation of Fuchs' dystrophy. MATERIAL AND METHODS: Standardized approaches to evaluate patients with Fuchs dystrophy in routine practice and research are discussed, accounting for the progressive and partially irreversible structural changes in all corneal layers. RESULTS: Early structural changes in the cornea can be detected before clinical edema becomes visible on slit-lamp exam. Optical limitations resulting from these structural changes can be quantified not only with high-contrast acuity but also with glare or contrast sensitivity tests. Characteristic vision-related limitations of patients with Fuchs dystrophy can, e.g., be assessed with V-FUCHS, a Fuchs dystrophy-specific "Visual Function and Corneal Health Status" instrument for patient-reported outcomes. CONCLUSION: Clinical grading of Fuchs dystrophy in an edematous and a non-edematous stage is outdated. Better therapy options and our improved understanding of progressive changes in the entire cornea require a standardized assessment of optical and structural changes and patient-reported limitations. PMID- 30402740 TI - Emphysema quantification using chest CT: influence of radiation dose reduction and reconstruction technique. AB - BACKGROUND: Computed tomography (CT) emphysema quantification is affected by both radiation dose (i.e. image noise) and reconstruction technique. At reduced dose, filtered back projection (FBP) results in an overestimation of the amount of emphysema due to higher noise levels, while the use of iterative reconstruction (IR) can result in an underestimation due to reduced noise. The objective of this study was to determine the influence of dose reduction and hybrid IR (HIR) or model-based IR (MIR) on CT emphysema quantification. METHODS: Twenty-two patients underwent inspiratory chest CT scan at routine radiation dose and at 45%, 60% and 75% reduced radiation dose. Acquisitions were reconstructed with FBP, HIR and MIR. Emphysema was quantified using the 15th percentile of the attenuation curve and the percentage of voxels below -950 HU. To determine whether the use of a different percentile or HU threshold is more accurate at reduced dose levels and with IR, additional measurements were performed using different percentiles and HU thresholds to determine the optimal combination. RESULTS: Dose reduction resulted in a significant overestimation of emphysema, while HIR and MIR resulted in an underestimation. Lower HU thresholds with FBP at reduced dose and higher HU thresholds with HIR and MIR resulted in emphysema percentages comparable to the reference. The 15th percentile quantification method showed similar results as the HU threshold method. CONCLUSIONS: This within-patients study showed that CT emphysema quantification is significantly affected by dose reduction and IR. This can potentially be solved by adapting commonly used thresholds. PMID- 30402743 TI - U.S. Medical Examiner/Coroner capability to handle highly infectious decedents. AB - In the United States of America, Medical Examiners and Coroners (ME/Cs) investigate approximately 20% of all deaths. Unexpected deaths, such as those occurring due to a deceased person under investigation for a highly infectious disease, are likely to fall under ME/C jurisdiction, thereby placing the ME/C and other morgue personnel at increased risk of contracting an occupationally acquired infection. This survey of U.S. ME/Cs' capabilities to address highly infectious decedents aimed to determine opportunities for improvement at ME/C facilities serving a state or metropolitan area. Data for this study was gathered via an electronic survey. Of the 177 electronic surveys that were distributed, the overall response rate was N = 108 (61%), with 99 of those 108 respondents completing all the questions within the survey. At least one ME/C responded from 47 of 50 states, and the District of Columbia. Select results were: less than half of respondents (44%) stated that their office had been involved in handling a suspected or confirmed highly infectious remains case and responses indicated medical examiners. Additionally, ME/C altered their personal protective equipment based on suspected versus confirmed highly infectious remains rather than taking an all-hazards approach. Standard operating procedures or guidelines should be updated to take an all-hazards approach, best-practices on handling highly infectious remains could be integrated into a standardized education, and evidence-based information on appropriate personal protective equipment selection could be incorporated into a widely disseminated learning module for addressing suspected or confirmed highly infectious remains, as those areas were revealed to be currently lacking. PMID- 30402744 TI - T1-MPRAGE and T2-FLAIR segmentation of cortical and subcortical brain regions-an MRI evaluation study. AB - PURPOSE: Development of a warp-based automated brain segmentation approach of 3D fluid-attenuated inversion recovery (FLAIR) images and comparison to 3D T1-based segmentation. METHODS: 3D FLAIR and 3D T1-weighted sequences of 30 healthy subjects (mean age 29.9 +/- 8.3 years, 8 female) were acquired on the same 3T MR scanner. Warp-based segmentation was applied for volumetry of total gray matter (GM), white matter (WM), and 116 atlas regions. Segmentation results of both sequences were compared using Pearson correlation (r). RESULTS: Correlation of GM segmentation results based on FLAIR and T1 was overall good for cortical structures (mean r across all cortical structures = 0.76). Comparatively weaker results were found in the occipital lobe (r = 0.77), central region (mean r = 0.58), basal ganglia (mean r = 0.59), thalamus (r = 0.30), and cerebellum (r = 0.73). FLAIR segmentation underestimated volume of the central region compared to T1, but showed a better anatomic concordance with the occipital lobe on visual review and subcortical structures, when also compared to manual segmentation. Visual analysis of FLAIR-based WM segmentation revealed frequent misclassification of regions of high signal intensity as GM. CONCLUSION: Warp based FLAIR segmentation yields comparable results to T1 segmentation for most cortical GM structures and may provide anatomically more congruent segmentation of subcortical GM structures. Selected cortical regions, especially the central region and total WM, seem to be underestimated on FLAIR segmentation. PMID- 30402745 TI - Impact of isolated basal ganglia infarction at pretreatment DWI on outcomes after endovascular thrombectomy in acute anterior circulation stroke. AB - PURPOSE: Acute infarction confined to the basal ganglia (BG) is occasionally observed on baseline imaging before endovascular thrombectomy. This study aimed to investigate the impact of isolated BG infarction revealed on pretreatment DWI in a large cohort of patients with acute anterior circulation stroke who underwent thrombectomy. METHODS: We retrospectively analyzed clinical and DWI data from 328 patients who underwent thrombectomy for emergent occlusions of the intracranial internal carotid artery or the middle cerebral artery. Characteristics and treatment outcomes were compared between patients with isolated BG infarction and those with non-isolated BG infarction. Binary logistic regression analyses were performed to identify independent predictors of good outcome (90-day mRS 0-2). RESULTS: Isolated BG infarction was found in 57 patients (17.4%). Patients with isolated BG infarction had a higher incidence of underlying severe intracranial atherosclerotic stenosis (21.1% vs. 10.7%, P = 0.032) than those with non-isolated BG infarction. Successful reperfusion occurred more frequently in patients with isolated BG infarction than those with non-isolated BG infarction (93% vs. 79%, odds ratio 3.529, 95% confidence interval 1.226-10.161, P = 0.014). On multivariate logistic regression analysis, independent predictors of good outcome were age, DWI-ASPECTS, and admission NIHSS score. There was no significant difference in the rate of good outcome between the two groups (54.4% vs. 42.8%, P = 0.110). CONCLUSION: Isolated BG infarction on pretreatment DWI may predict successful reperfusion after endovascular thrombectomy in patients with acute anterior circulation stroke. In addition, our study suggested a novel finding that isolated BG infarction was more frequently associated with underlying severe ICAS than non-isolated BG infarction. PMID- 30402746 TI - Proximal internal carotid artery stenosis associates with diffuse wall thickening in petrous arterial segment of moyamoya disease patients: a three-dimensional magnetic resonance vessel wall imaging study. AB - PURPOSE: To investigate the association between proximal internal carotid artery (ICA) luminal narrowing and diffuse wall thickening (DWT) in ipsilateral petrous ICA in moyamoya disease (MMD) patients. METHODS: Forty-one MMD (mean age 42.8 +/- 11.0 years, 19 males) and 36 atherosclerotic patients (mean age 61.5 +/- 7.1 years, 31 males) and 41 healthy controls were recruited and underwent carotid MR vessel wall imaging. The luminal narrowing of proximal ICA was evaluated by the diameter ratio of ICA to common carotid artery (DRICA/CCA). The wall thickness of petrous ICA was measured on T1-VISTA images. The enhancement degree of petrous ICA was recorded and graded into four grades (none to marked) on the CE-T1-VISTA images. The correlation between wall thickness in petrous ICA and DRICA/CCA was analyzed. RESULTS: In total, 81 arteries of MMD patients and 64 arteries of atherosclerotic patients were included for analysis. The DRICA/CCA was significantly correlated with the wall thickness in petrous ICA in MMD (r = - 0.434, P < 0.001) and atherosclerotic groups (r = - 0.604, P < 0.001). Logistic regression analysis revealed that odds ratio (OR) of DRICA/CCA was 4.433 (95% CI 1.980-9.925, P < 0.001) and 2.212 (95% CI 1.253-3.905, P = 0.006) in MMD and atherosclerotic groups in discriminating petrous ICA DWT after adjusting for confounding factors. An increasing trend was found in prevalence of DWT and wall thickness with enhancement grades in petrous ICA in MMD (P = 0.02 and P = 0.01) and atherosclerotic groups (P < 0.001 and P < 0.001), respectively. CONCLUSIONS: The proximal ICA luminal narrowing is significantly associated with wall thickness and diffuse wall thickening in ipsilateral petrous ICA in patients with carotid steno-occlusive diseases regardless of MMD or atherosclerosis. PMID- 30402747 TI - A multinational survey on the infrastructural quality of paediatric intensive care units. AB - BACKGROUND: The aim of the present study was to assess whether paediatric intensive care units (PICUs) in three central European countries comply with guidelines concerning infrastructure provided by the European Society of Intensive Care Medicine (ESICM). Between July 2016 and May 2017, a survey was conducted based on the ESICM guidelines. The questionnaire was structured into four categories: structural quality, diagnostic/therapeutic equipment, personnel and organization. All PICUs treating paediatric patients in the D-A-CH region [Germany (D), Austria (A) and Switzerland (CH)] were researched through the national societies. A total of 126 PICUs were contacted (D: 106; A: 12; and CH: 8). RESULTS: Eighty-five of 126 PICUs responded (D: 67%; A: 61%; and CH: 100%). A median of 500 patients was treated annually (D: 500; A: 350; and CH: 600) with a median of 12 beds (D: 12; A: 8; and CH: 12). Recommendations regarding infrastructure were met as follows: structural quality 62% in D, 71% in A and 75% in CH; diagnostic/therapeutic equipment: 87% in D, 91% in A and 89% in CH; personnel: 65% in D, 87% in A and 85% in CH; and organization: 75% in D, 73% in A and 88% in CH. CONCLUSIONS: This survey reveals deficits concerning structural quality in all countries. Furthermore, shortcomings regarding personnel were found in Germany and for organization in Germany and Austria. These issues need to be addressed urgently to further improve treatment quality and patient safety in the future. PMID- 30402748 TI - Eculizumab in atypical hemolytic uremic syndrome: strategies toward restrictive use. AB - With the introduction of the complement C5-inhibitor eculizumab, a new era was entered for patients with atypical hemolytic uremic syndrome (aHUS). Eculizumab therapy very effectively reversed thrombotic microangiopathy and reduced mortality and morbidity. Initial guidelines suggested lifelong treatment and recommended prophylactic use of eculizumab in aHUS patients receiving a kidney transplant. However, there is little evidence to support lifelong therapy or prophylactic treatment in kidney transplant recipients. Worldwide, there is an ongoing debate regarding the optimal dose and duration of treatment, particularly in view of the high costs and potential side effects of eculizumab. An increasing but still limited number of case reports and small cohort studies suggest that a restrictive treatment regimen is feasible. We review the current literature and focus on the safety and efficacy of restrictive use of eculizumab. Our current treatment protocol is based on restrictive use of eculizumab. Prospective monitoring will provide more definite proof of the feasibility of such restrictive treatment. PMID- 30402749 TI - Rearrangement of the Prefrontal Cortex Neural Activity in Both Hemispheres during Learning. AB - Neuronal activity of both right and left hemispheres of the rat prefrontal brain cortex was recorded in the two-ring maze during animal learning to operate in response to signals. At the beginning of learning, pairwise comparison of neural activity that accompanied correct and incorrect choice of the right and left sides showed significant differences in the left hemisphere and the lack of differences in the right one. With increasing percentage of correct choices during a session of learning, the differences in neuronal responses appeared in the right hemispheres and were reduced in the left one. The opposite trends in rearrangement of the total impulse activity are believed to be related to different roles of hemispheres in the construction of the internal behavioral model. PMID- 30402750 TI - Working Memory for Low-Level Visual Features: Sensory Mechanisms for Detecting the Mismatch between the Current Orientations and Those Stored in Memory. AB - The amplitudes of the P100 and N150 early components of evoked potentials in the visual cortex have been analyzed on 33 volunteers with normal vision during matching between the current orientation and that stored in memory. An increase in the P100 response in the occipital and parietal cortical areas was identified as an informative indicator of mismatch between the current and stored-in-memory orientations. This effect was not found for more complex stimuli, namely, spatial patterns. The N150 component demonstrated a similar effect, but in contrast to P100 it was not stimulus specific. Thus, in the first 100 ms, a signal of mismatch between the current and stored-in-memory orientations arises in the early visual areas that represents a mechanism for early implicit response to changes in the basic characteristics of the visual space. PMID- 30402751 TI - Evolutionary Changes in the Content of Dehydrogenase System Metabolites as a Mechanism of Adaptation to Cold in Higher Vertebrates. AB - It has been found that the optimal body balance control under the conditions of the adaptation to cold is mostly determined by the ratio of the blood concentrations of endogenous ethanol and acetaldehyde related to the activities of liver alcohol dehydrogenase and aldehyde dehydrogenase in the order of increasing level of adaptation: higher vertebrates unadapted to cold, including human -> small animals adapted to cold -> large animals adapted to cold native to the North -> hibernators, regardless of the species specificity and the environment. PMID- 30402752 TI - Morphological Study of Myelinated Fibers of the Sciatic Nerve in Mice after Space Flight and Readaptation to the Conditions of Earth Gravity. AB - We revealed a decrease in the thickness of the myelin sheath and myelin delamination in the tibial nerve of C57BL/6N mice after a 30-day flight aboard the biosatellite Bion-M1. The processes of myelin degeneration continued for seven days after return of the animals to Earth and adaptation to the conditions of natural gravity. Our data add to hypothesis on the role of neurogenic component in pathogenesis of hypogravity motor syndrome. PMID- 30402753 TI - Differences in the Postural Responses to Approaching and Receding Sound Images in Subjects with Different Perceptual Styles. AB - A hypothesis on the universal character of perceptual style for analyzing the surrounding space during sensory interactions has been tested. The indices of postural responses to moving and stationary auditory images in the groups of field-dependent and field-independent subjects, i.e., those who perceive spatial information about the object considering or ignoring the background, respectively, have been investigated. The differences in the sway parameters in both groups were revealed only in the case of moving auditory images. Body sway was more prominent in the group of field-independent subjects, whereas in the subjects from the field-dependent group, backward body displacement was observed during listening to approaching auditory images. Therefore, the perceptual style is reflected in the vertical postural responses to auditory information about the motion in the acoustic space. PMID- 30402754 TI - Morphological and Taxonomic Interpretation of Orestovia and Schuguria, Enigmatic Devonian Plants from Russia. AB - A detailed study of the external and internal surfaces of the cuticle of Orestovia and Schuguria using scanning electron microscopy and confocal laser microscopy has shown that the structures formerly interpreted as stomata or reproductive organs are most likely to be gland cells producing mucilage. Each structure represents a single large cell with a complex aperture on the external wall. In addition, a reproductive organ similar to multilocular sporangia known in brown algae of the order Ectocarpales has been found in attachment to a compression fossil of Orestovia. These data suggest similarity of the genera studied with brown algae. PMID- 30402755 TI - Activity of the Enzymes of the Energy and Carbohydrate Metabolism in the Organs of the Three-Spined Stickleback Gasterosteus aculeatus from Different Biotopes of the White Sea. AB - The activity of the key enzymes of the energy and carbohydrate metabolism (cytochrome c oxidase, lactate dehydrogenase, aldolase, and glucose-6-phosphate dehydrogenase) have been studied in the three-spined stickleback Gasterosteus aculeatus spawning in different biotopes of the White Sea (Sel'dyanaya Bay, Sukhaya Salma Strait, and Kolyushkovaya Lagoon). It was found that individuals of stickleback from different spawning grounds differed mainly in the level of anaerobic metabolism and in the degree of utilization of carbohydrates during glycolysis. The results testify to the existence of adaptive mechanisms for the restructuring of the metabolic pathways of the energy metabolism depending on habitat conditions in different biotopes during the spawning period. PMID- 30402756 TI - Dynamics of Estradiol Level during Metamorphosis in the Daubed Shanny (Leptoclinus maculatus, Fries, 1838) from Spitsbergen Island. AB - The estradiol content of muscles during metamorphosis in the daubed shanny (Leptoclinus maculatus) from different fjords of Spitsbergen Island, Svalbard, have been studied using mass spectrometry. The level of estradiol at the L4 larval stage of development is significantly lower than at the L2 stage. Values of this parameter in adults are significantly higher than in post-larvae (stage L5). Variations in the estradiol level during metamorphosis can be associated with the growth stimulation and regulation of the process. PMID- 30402757 TI - A Mass Burial of Fossil Lions (Carnivora, Felidae, Panthera (Leo) ex gr. fossilis spelaea) from Eurasia. AB - The vertebrate fauna from the cave deposits in Imanai Cave in the Southern Urals (53 degrees 02' N, 56 degrees 26'E) has been studied. It contains 715 bones that belonged to at least 11 individuals of fossil lion (Panthera (Leo) ex gr. fossilis-spelaea). It has been established that this is one of the largest Eurasian burial sites of fossil lions. The bones were accumulated due to the natural death of animals inside the cave. The age and sex estimations have shown that at least six adult males and five adult females died there. According to the accompanying fauna, radiocarbon, geochemical, and mineralogical analyses and archaeological finds, the interval of the lion bone accumulation is determined as the first half to middle of Late Pleistocene (OIS 5-3). PMID- 30402758 TI - The Results of Sable (Martes zibellina) Reintroduction Demonstrate the Founder Effect. AB - The relative abundance of intrapopulation groups with different parameters of skull size, coat color, and expression of an epigenetic cranial trait was compared in autochthonous, reintroduced, and donor populations of sable. Recovery of the species resources and broad variability of the phenotypic trait complex in the newly fomned populations were observed. A large proportion of the animals had the phenotype that included large size, dark coat color, and pronounced expression of a specific phene trait (foramen in the condylar fossa) and was not characteristic of the neighboring autochthonous populations. It is reasonable to attribute the presence of individuals with an unusual morphology in the newly formed populations of animals to a manifestation of the founder principle, because the effect of this principle was promoted by spatial isolation of the primary foci of translocated animals. PMID- 30402759 TI - The Natural Abundance of Heavy Nitrogen Isotope (15N) in Plants Increases near a Large Copper Smelter. AB - The ratio of stable isotopes of nitrogen (15N and 14N) has been assessed in leaves of the forest plants from different functional groups (with ectomycorrhiza, ericoid, and arbuscular mycorrhiza; in a nitrogen-fixing symbiosis) under the conditions of strong transformation of ecosystems by the Karabashsky Copper-Smelting Plant effluents in the Southern Urals. The abundance of 15N in the plants generally increases in polluted habitats. The abundance of the heavy isotope 15N increases significantly with pollution in ericaceous dwarf shrubs (by 3.30/00) and herbs with arbuscular mycorrhizae (by 2.80/00). This indicates a strong alteration in conditions or modes of plant mineral nutrition under the influence of heavy metal pollution of forest ecosystems. PMID- 30402760 TI - Evaluation of the Applicability of the Comparatory Method for Species Diagnosis of Unionidae (Bivalvia) by Genetic Analysis. AB - Five genetically distant groups of mussels possessing high intragroup homogeneity were identified among 65 specimens of 14 East European Unionidae "comparatory species" by genetic analysis of nuclear and mitochondrial markers. By shell morphology other than the shape of the convex contour of the shell, the identified groups correspond to five "taxonomic species" according to Zhadin's classification. The use of the comparatory method for Unionidae species identification is unjustified. PMID- 30402761 TI - New Data on Dinosaurs of the Crimean Peninsula. AB - Reexamination of the holotype of Riabininohadros weberae from the Upper Cretaceous (upper Maastrichtian) of the Crimean Peninsula (Besh-Kosh) allowed determination of previously unknown elements of the femur, astragalus, and calcaneus. This taxon shows a set of primitive characters observed in iguanodontids and basal ornithischians and is referred to as Styracosterna indet. The second dinosaur specimen from Crimea (Aleshino) is a fragmentary skeleton, including cervical and dorsal vertebrae. It possibly belongs to advanced iguanodontids or primitive hadrosauroids. Thus, in the Maastrichtian of the Crimean Peninsula, at least two dinosaur species coexisted. PMID- 30402762 TI - alpha-Fetoprotein Influence on the Conversion of Naive T-Helpers into Memory T Cell Effector Subpopulations. AB - The effect of native alpha-fetoprotein (AFP) on the conversion of naive T-helpers into central memory T-cells (TCM) and effector subpopulations of the preterminally differentiated (TEM) and terminally differentiated (TEMRA) memory T cells was studied. AFP was found to prevent the conversion of naive T-helpers into effector subpopulations of memory T cells (TEM and TEMRA) while reducing the total production of IL-4 and IFN-gamma by the studied cell populations. The data reveal a new role of AFP in the immune tolerance formation during pregnancy. PMID- 30402763 TI - Tannosomes in the Pericarp Cells of Maloideae (Rosaceae). AB - Data on the presence of structural units termed tannosomes in the pericarp cells of Maloideae has been obtained for the first time. Tannosomes merge in the vacuoles to form "tannoglobules." PMID- 30402765 TI - Inhibitory effect of luminal saccharides on glucose absorption from an adjacent jejunal site in rats: a newly described intestinal neural reflex. AB - Nutrients in the lumen of the small intestine are sensed by special cells in the epithelial lining. The ensuing neurohumoral reflexes affect gastrointestinal absorption/secretion, motility, and vascular perfusion. To study in vivo the effect of a monosaccharide (glucose) or polysaccharide (starch) present in the jejunum on glucose absorption from an adjacent part of the intestine and investigate the possible underlying mechanisms. Using the single pass intraluminal perfusion technique, a segment of jejunum (perfusion segment) was continuously perfused with 20 mM glucose to determine glucose absorption. One hour later, a bolus of a saccharide was instilled in an isolated adjacent jejunal segment and the change in glucose absorption was monitored for a further 2 h. The contribution of neural mechanisms in this process was investigated. Instillation of glucose (20 mM or 40 mM) in either distal or proximal jejunal pouch elicited immediate and sustained inhibition of glucose absorption (a decrease by 25%; P < 0.01) from the perfused jejunal segment. Comparable inhibition was obtained with instillation of other monosaccharides or starch in the jejunal pouch. This inhibition was abolished by adding tetrodotoxin to the pouch or to the perfused jejunal segment and also by pretreatment with sympathetic blockers (guanethidine or hexamethonium) and by chemical ablation of capsaicin-sensitive primary afferent fibers. Glucose absorption within the jejunum is auto-regulated through backward and forward mechanisms. This regulation is mediated by neural reflexes involving capsaicin-sensitive afferent and sympathetic efferent fibers. These reflexes might serve to protect against hyperglycemia. PMID- 30402764 TI - Minimal Residual Disease in Indolent Lymphomas: A Critical Assessment. AB - OPINION STATEMENT: Indolent non-Hodgkin lymphomas (iNHL) are a heterogeneous group of pathologies characterized by a prolonged natural history and good response to treatment. They also have a tendency to relapse, in some cases with a worse prognosis. One of the main objectives in the newest clinical trials is to identify patients at high risk of relapse. This cannot be accomplished using only clinical prognostic scores. Detection of minimal residual disease (MRD) is effective in evaluating long-term disease response, with a strong and independent predictive value that was demonstrated in large cohorts of patients. Analysis of MRD allows patient stratification based on the risk for relapse; therefore, different therapeutic programs can be designed based on the response characteristics. This tailored therapy is already happening in current clinical trials. Limits imposed by traditional PCR-based tools are being overcome due to new molecular biology techniques like droplet digital PCR and next generation sequencing. Although these techniques are not yet standardized, they will likely increase the reliability and ensure broad applicability of MRD detection in future years. PMID- 30402766 TI - Microfluidic dielectrophoretic cell manipulation towards stable cell contact assemblies. AB - Cell contact formation, which is the process by which cells are brought into close proximity is an important biotechnological process in cell and molecular biology. Such manipulation is achieved by various means, among which dielectrophoresis (DEP) is widely used due to its simplicity. Here, we show the advantages in the judicious choice of the DEP microelectrode configuration in terms of limiting undesirable effects of dielectric heating on the cells, which could lead to their inactivation or death, as well as the possibility for cell clustering, which is particularly advantageous over the linear cell chain arrangement typically achieved to date with DEP. This study comprises of experimental work as well as mathematical modeling using COMSOL. In particular, we establish the parameters in a capillary-based microfluidic system giving rise to these optimum cell-cell contact configurations, together with the possibility for facilitating other cell manipulations such as spinning and rotation, thus providing useful protocols for application into microfluidic bioparticle manipulation systems for diagnostics, therapeutics or for furthering research in cellular bioelectricity and intercellular interactions. PMID- 30402767 TI - Short- and long-term outcomes after transverse versus extended colectomy for transverse colon cancer. A systematic review and meta-analysis. AB - BACKGROUND: Provide the surgeon with a tool to decide the best surgical approach to transverse colon cancer. OBJECTIVE: To compare the surgical and oncological outcomes between transverse colectomy and extended hemicolectomy for patients with tumours of the transverse colon. DATA SOURCES: A systematic search was performed in the electronic databases (PubMed, Web of Science, Scopus, EMBASE), using the following search terms and/or MeSH terms in all possible combinations: transverse, transversus, colectomy, hemicolectomy, segmental resection, transverse colon cancer. The last search was performed on 10 May 2018. STUDY SELECTION: Two independent authors (Mi.M. and N.V.) analysed each article and performed the data extraction independently. In case of disagreement, a third investigator was consulted (Ma.M.). Discrepancies were resolved by consensus. DATA EXTRACTION AND SYNTHESIS: Data regarding sample size, major clinical and demographic variables, oncologic outcomes and postoperative recovery and complications were extracted. MAIN OUTCOME MEASURES: Main outcomes analysed were anastomotic leakage, early mortality, hospital stay, operative time, overall complications rate, wound infection, harvested nodes and disease-free survival. RESULTS: No statistical differences were found between transverse colectomy and extended hemicolectomy in short- and long-term outcomes; our results revealed no differences in disease-free survival between the two surgical approaches. As expected, a statistically significant difference was found in favour of extended hemicolectomy in terms of number of harvested lymph nodes. CONCLUSIONS: This systematic review with meta-analysis focus on the two major approaches to transverse colon cancer. The reviewed evidence suggests that a conservative approach to transverse colon cancer is feasible and safe and oncological outcomes are comparable between a conservative and an extended surgical procedure. PMID- 30402768 TI - Infectious proctitis: a necessary differential diagnosis in ulcerative colitis. AB - INTRODUCTION: In the last years, there was a rising in the incidence of sexually transmitted infections, including proctitis. Infectious proctitis (IP), mainly caused by agents like Neisseria gonorrhea and Chlamydia trachomatis, is an entity that should be considered when patients with suspected inflammatory bowel disease (IBD) are approached, mainly if they have risk factors such as anal intercourse. CLINICAL CASES/DISCUSSION: The symptoms of IP, like rectal blood, mucous discharge, and anorectal pain, may appear in other causes of proctitis, like IBD. Therefore, to establish the diagnosis, it is crucial to take a detailed history and perform a physical examination, with the diagnosis being supported by complementary tests such as rectosigmoidoscopy, histology, serology, and culture. Depending on the etiology, treatment of IP is based in antibiotics or antivirals, which may be empirically initiated. Co-infections, mainly those that are sexually transmitted, and HIV should be tested and sexual partners should be treated, accordingly. In this article, the authors report three cases of IP, referent to three different patients, and review the initial approach required in cases where there is a clinical and/or endoscopic suspicion of this pathology. PMID- 30402769 TI - Nutritional deficiency among vulnerable elderly patients on acute wards in hospitals. PMID- 30402772 TI - Characterization of a Bacillus sp. isolated from fermented food and its synbiotic effect with barley beta-glucan as a biocontrol agent in the aquaculture industry. AB - The purpose of this study was to evaluate Bacillus sp. SJ-10, isolated from traditional Korean seafood, as a probiotic. Strain SJ-10 was demonstrated to be safe, on the basis of in vitro tests confirming the absence of cytotoxicity, hemolysis, and genes with toxigenic potential, and was susceptible to antibiotics. It met the probiotic prerequisites of a spore count that remained almost constant, acid and bile tolerance under simulated gastrointestinal conditions, and significant adhesion to Caco-2 cells. Moreover, SJ-10 demonstrated beneficial properties as a probiotic: broad-spectrum antimicrobial activity, hydroxyl radical, antioxidant activity, production of functional enzymes such as beta-galactosidase and phytase, and selective growth via beta glucan fermentation. The fish-feeding trial demonstrated that olive flounder fed diets containing SJ-10 alone or in combination with beta-glucan exhibited significantly higher growth performance and pathogenic disease resistance compared with those fed diets containing beta-glucan alone, indicating that SJ-10 diets exerted a beneficial effect as an antibiotic replacer in terms of growth performance and disease resistance in olive flounder. PMID- 30402771 TI - Prospects for the use of spherical gold nanoparticles in immunization. AB - Recent years have seen extremely fast development of new viral nanovaccines and diagnostic agents using nanostructures prepared by biological and chemical synthesis. We used spherical gold nanoparticles (average diameter, 15 nm) as a platform for the antigen for swine transmissible gastroenteritis virus (TGEV). The literature data demonstrate that immunization of animals with the TGEV antigen coupled to gold nanoparticles (GNPs) not only activates antigen presenting cells but also increases the proliferative activity of splenic lymphoid (antibody-forming) cells. The contents of gamma-IFN, IL-1beta, and IL-6 in animals immunized with GNP-antigen conjugates were found to be higher than those in intact animals or in animals given the antigen alone. The increased concentration of IL-1beta in the immunized animals directly correlated with the activity of macrophages and stimulated B cells, which produce this cytokine when activated. The increased concentration of IL-6 indicates that the injected preparations are stimulatory to cellular immunity. Immunization with the TGEV antigen conjugated to GNPs as a carrier activates the respiratory activity of lymphoid cells and peritoneal macrophages, which is directly related to their transforming activity and to the activation of antibody generation. Furthermore, the use of this conjugate allows marked improvement of the structure of the animals' immune organs and restores the morphological-functional state of these organs. The microanatomical changes (increased number of follicles) indicate the activation of the B-dependent zone of the spleen and, consequently, the development of a humoral-type immunological reaction. The degradative processes observed in the animals immunized with TGEV antigen alone are evidence of weak resistance to pathogen attack. These results can be used to develop vaccines against this infection by employing TGEV antigen coupled to gold nanoparticles as a carrier. PMID- 30402773 TI - Carbenoxolone Reverses the Amyloid Beta 1-42 Oligomer-Induced Oxidative Damage and Anxiety-Related Behavior in Rats. AB - The characteristic feature of Alzheimer's disease (AD) is the deposition of amyloid beta inside the brain mainly consisting of Abeta 40 and 42 aggregates. Soluble aggregates of Abeta 42 are reported to be more toxic and exert their neurotoxicity by the induction of oxidative damage and cognitive deficits such as anxiety-like behavior. These alterations emerge due to the induction of gap junction communication through increased activity and expression of connexins such as connexin43 (Cx43) leading to the release of small neurotoxic molecules. In the present study, single intracerebroventricular (icv) injection of Abeta 42 oligomers (10 MUl/rat) was used to induce oxidative damage and anxiety-related behavior in rats. Carbenoxolone (Cbx), a gap junction blocker, was tested (20 mg/kg body weight, i.p., for 6 weeks) against these alterations. Cbx supplementation reversed the Abeta 42 oligomer-induced alterations in the antioxidant defense system. The levels ROS, lipid peroxidation, and protein carbonyls were normalized with Cbx co-treatment leading to the decreased DNA fragmentation and pyknosis in different regions of the rat brain. Cbx induced the anxiolytic behavior and ameliorated the cognitive decline in rats post Abeta 42 oligomer injection. The increased expression of Cx43 post Abeta 42 oligomer injection was also reduced with Cbx supplementation, which might have inhibited the release of small neurotoxic molecules. Our results showed that Cbx prevents the Abeta 42 oligomer-induced oxidative damage and anxiety-like behavior partly by blocking the gap junction communication, which suggests that the therapeutic potential of Cbx may be explored in the progression of AD. PMID- 30402770 TI - Development and clinical assessment of new objective adherence markers for four microbicide delivery systems used in HIV prevention studies. AB - BACKGROUND: Adherence is critical for successful topical, vaginally delivered anti-retroviral (ARV)-based HIV pre-exposure prophylaxis (PrEP). Quantitating systemic or tissue ARV levels through LC-MS/MS is currently viewed as the most reliable measure of adherence. However, for placebo-controlled trials, this is a high cost analysis that measures adherence only in the drug treatment group. A desirable marker of adherence is one that is measured in both placebo and drug treatment groups using a simple on-site clinical laboratory test, which allows necessary interventions for supporting participant adherence. Our objective was to develop adherence markers for four vaginal placebo products currently used as microbicide delivery systems: gel, film, insert, and intravaginal ring. Excipient and spectroscopy-based approaches were used for preclinical development of the placebo markers and subsequently validated by the CONRAD 135 study. The study collected vaginal swabs collected each day for 1 week post vaginal application of gel, film, or insert in the clinic with or without sex. Intravaginal rings were collected after 1 day, 7, and 30 days of use. RESULTS: Placebo gel, film, and insert in vaginal swabs were successfully detected by specific excipient colorimetric or probe-based assays for hydroxyethylcellulose, glycerin, and sorbitol respectively, as well as spectroscopy-based prediction models. The range of detection for gel, film, and insert in swabs collected up to 16 h post vaginal application was 70-100% of the total swabs per time point, with some markers showing potential for longer duration. Decreasing residual glycerin levels and increasing bioanalyte penetration of vaginally used intravaginal rings showed significant changes between 1 and 30 days of use. CONCLUSIONS: We demonstrated clinical proof-of-concept that adherence markers for placebo product can be measured using simple, lower cost approaches. Measuring adherence in both placebo and drug arms of a HIV PrEP study would better inform future trial designs. PMID- 30402775 TI - Comment on 'Exercise training decreases pancreatic fat content and improves beta cell function regardless of baseline glucose tolerance: a randomised controlled trial'. PMID- 30402774 TI - Neoepitopes: a new take on beta cell autoimmunity in type 1 diabetes. AB - Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of pancreatic insulin-producing beta cells. The epitopes recognised by pathogenic T cells in human type 1 diabetes are poorly defined; however, a growing body of evidence suggests that T cell responses against neoepitopes contribute to beta cell destruction in type 1 diabetes. Neoepitopes are formed when self-proteins undergo post-translational modification to create a new epitope that is recognised by T- or B cells. Here we review the role of human T cell responses against neoepitopes in the immune pathogenesis of type 1 diabetes. Specifically, we review the different approaches to identifying neoepitopes relevant to human type 1 diabetes and outline several advances in this field that have occurred over the past few years. We also discuss the application of neoepitopes to the development of antigen-specific therapies for type 1 diabetes and the unresolved challenges that need to be overcome before the full repertoire of neoepitopes recognised by pathogenic human T cells in type 1 diabetes can be determined. This information may then be used to develop antigen-specific therapies for type 1 diabetes and assays to monitor changes in pathogenic, beta cell-specific T cell responses. PMID- 30402776 TI - Type 2 diabetes and the risk of incident hearing loss. AB - AIMS/HYPOTHESIS: Type 2 diabetes mellitus has been implicated as a risk factor for hearing loss, with possible mechanisms including microvascular disease, acoustic neuropathy or oxidative stress. A few small studies have examined the longitudinal association between type 2 diabetes and hearing loss, but larger studies are needed. Our objective was to examine whether type 2 diabetes (including diabetes duration) is associated with incident hearing loss in two prospective cohorts: Nurses' Health Studies (NHS) I and II. METHODS: We conducted a longitudinal study of 139,909 women to examine the relationship between type 2 diabetes and the risk of self-reported incident hearing loss. A physician diagnosis of diabetes was ascertained from biennial questionnaires. The primary outcome was hearing loss reported as moderate or worse in severity (categorised as a 'moderate or severe' hearing problem, or 'moderate hearing trouble or deaf') on questionnaires administered in 2012 in NHS I and 2009 or 2013 in NHS II. Cox proportional hazards regression was used to adjust for potential confounders. RESULTS: During >2.4 million person-years of follow-up, 664 cases of moderate or worse hearing loss were reported among those with type 2 diabetes and 10,022 cases among those without type 2 diabetes. Compared with women who did not have type 2 diabetes, those with type 2 diabetes were at higher risk for incident moderate or worse hearing loss (pooled multivariable-adjusted HR 1.16 [95% CI 1.07, 1.27]). Participants who had type 2 diabetes for >=8 years had a higher risk of moderate or worse hearing loss compared with those without type 2 diabetes (pooled multivariable-adjusted HR 1.24 [95% CI 1.10, 1.40]). CONCLUSIONS/INTERPRETATION: In this large longitudinal study, type 2 diabetes was associated with a modestly higher risk of moderate or worse hearing loss. Furthermore, longer duration diabetes was associated with a higher risk of moderate or worse hearing loss. PMID- 30402777 TI - Associations between objectively assessed physical fitness levels and sleep quality in community-dwelling elderly people in South China. AB - PURPOSE: The aim of this study was to explore associations between objectively assessed physical fitness levels and sleep quality in community-dwelling elderly people in South China. METHODS: One thousand one hundred thirty-six (504 males and 632 females) community-dwelling adults aged >= 50 years old in Dongguan City, South China, were included in the cross-sectional study. All the participants were asked to complete all prepared multi-instrument questionnaire, including the Pittsburgh Sleep Quality Index (Chinese version), for the assessment of the sleep quality and information regarding socio-demographic characteristics, lifestyle, and physical health data. Physical fitness was measured by grip strength, one-leg standing test (OLST) with eyes open, back scratch test, and the forced vital capacity (FVC). RESULTS: The percentage of poor sleep quality among elderly people (>= 50 years old) was up to 18.2%. Lower FVC was associated with the poorer sleep quality (adjusted OR = 0.74 per SD increase; P = 0.009), and participants with lower performance in back scratch test were more likely to suffer poor sleep quality (adjusted OR = 1.17 per SD increase; P = 0.035). The independent contribution of physical fitness tests results on the risk of poor sleep quality was 22.1%. CONCLUSIONS: Our results indicated that sleep quality was strongly associated with physical fitness among community-dwelling elderly people; the lower of the physical fitness predicted poorer sleep quality. PMID- 30402778 TI - The Unfinished Synthesis?: Paleontology and Evolutionary Biology in the 20th Century. AB - In the received view of the history of the Modern Evolutionary Synthesis, paleontology was given a prominent role in evolutionary biology thanks to the significant influence of paleontologist George Gaylord Simpson on both the institutional and conceptual development of the Synthesis. Simpson's 1944 Tempo and Mode in Evolution is considered a classic of Synthesis-era biology, and Simpson often remarked on the influence of other major Synthesis figures-such as Ernst Mayr and Theodosius Dobzhansky-on his developing thought. Why, then, did paleontologists of the 1970s and 1980s-Stephen Jay Gould, Niles Eldredge, David M. Raup, Steven Stanley, and others-so frequently complain that paleontology remained marginalized within evolutionary biology? This essay considers three linked questions: first, were paleontologists genuinely welcomed into the Synthetic project during its initial stages? Second, was the initial promise of the role for paleontology realized during the decades between 1950 and 1980, when the Synthesis supposedly "hardened" to an "orthodoxy"? And third, did the period of organized dissent and opposition to this orthodoxy by paleontologists during the 1970s and 1980s bring about a long-delayed completion to the Modern Synthesis, or rather does it highlight the wider failure of any such unified Darwinian evolutionary consensus? PMID- 30402780 TI - Anaerobic Co-Digestion of Vegetable and Fruit Market Waste in LBR + CSTR Two Stage Process for Waste Reduction and Biogas Production. AB - Vegetable and fruit waste (VFW) is becoming a heavy burden of municipal waste disposal because of its huge amount, but it is a potentially valuable resource that can be developed into high value products such as methane. Conventional anaerobic digestion processes are not suitable for solving the problem of easy acidification of VFW. Thus, a two-stage laboratory-scale anaerobic digestion system was assembled for waste reduction and biogas production of VFW in the mesophilic temperatures. The biphasic system consists of a 70-L leach bed reactor (LBR) and a 35-L continuous stirred tank reactor (CSTR). Water is sprinkled over the material to enhance the extraction process of acidification phase. The leachate was then transferred to the CSTR for biogas production. Batch digestion was lasted 120 h until no biogas was produced. Leachate with a volatile fatty acid (VFA) concentration of 7.6 g/L was obtained within 10 h. The results showed that overall 70.9% of the volatile solids (VS) was removed in the solid-phase system. Over 90% of VFAs were reduced in the methanogenic reactor, and it has been observed that the maximum biogas production rate was 51.26 mL/(d gVS). The maximum methane concentration in the produced biogas was 71%. PMID- 30402779 TI - Performance evaluation of the next generation solid-state digital photon counting PET/CT system. AB - BACKGROUND: The first solid-state silicon photomultiplier (SiPM) digital photon counting (DPC) clinical PET/CT system was introduced by Philips in recent years. The system differs from other SiPM-based PET/CT systems and uses lutetiumyttrium oxyorthosilicate (LYSO) scintillators directly coupled with their own individual SiPM DPC detectors eliminating the need for Anger-logic positioning decoding. We evaluated the system performance, characteristics, and stability of the next generation DPC clinical PET/CT based on NEMA NU2-2012 tests, NEMA NU2-2018 test (timing resolution) and human studies. RESULTS: An energy resolution of 11.2% was measured. NEMA NU2-2012 tests revealed a spatial resolution (mm in FWHM) from (3.96, 4.01, 4.01) at 1 cm to (5.81, 5.83, 4.95) at 20 cm for (axial, radial, tangential). A 5.7 cps/kBq system sensitivity was measured. Peak noise equivalent count rate (NECR) and peak true count rate could not be determined as each exhibited increasing values up to the maximum activity measured (~ 1100 MBq). The maximum NECR was 171 kcps @ 50.5 kBq/mL, with corresponding scatter fraction of 30.8% and maximum trues of 681 kcps. NEMA hot sphere contrast ranged from 62% (10 mm) to 88% (22 mm), cold sphere contrast of 86% (28 mm) and 89% (37 mm). A timing resolution of 322 ps (22Na point source based) and 332 ps (NEMA NU2-2018) was obtained. It revealed < 1% change in TOF timing and +/- 0.4% change in energy resolution during 31-month stability monitoring. CQIE assessment found < 3% axial variance in SUV. 100-60% recovery coefficients of activity concentration at various sphere sizes and contrast levels were measured. CONCLUSIONS: This scanner represents the first solid-state DPC PET/CT, a technologic leap beyond photomultipliers tubes and anger logic. It presents considerable improvements in system performance and characteristics with excellent time-of-flight capability compared to conventional photomultiplier tube (PMT) PET/CT systems. The DPC system leads to promising clinical opportunities with excellent image quality, lesion detectability, and diagnostic confidence. PMID- 30402781 TI - Patient Satisfaction with Mobile Health (mHealth) Application for Exercise Intervention in Breast Cancer Survivors. AB - This study aimed to assess user satisfaction with mobile health (mHealth) application in breast cancer survivors after a 12-week exercise program and provide developers with reference points for mHealth applications from the perspective of patients and physicians. This is a retrospective review of prospectively collected multicenter data of 88 breast cancer survivors who carried out a 12-week exercise program via smartphone application with pedometer. Personalized programs including aerobic and resistance exercise were prescribed by physiatrists. Also, telephone counseling was performed at the 3rd and 9th week. All patients completed the user satisfaction questionnaire at the end of the intervention. The mean achievement rates of aerobic and resistance exercise for 12 weeks were 78.8 and 71.3%, respectively. The mean score of overall satisfaction rated on the 5-point Likert scale was 4.22 +/- 0.73. When the patients were grouped according to age, the overall satisfaction score increased significantly with age (P = 0.040). Also, the satisfaction scores of patients with radiotherapy were significantly higher than patients without radiotherapy (P = 0.001). In terms of system characteristics, the most satisfying was data transmission accuracy (4.32 +/- 0.74). In addition, patients were very satisfied with telephone counseling (4.55 +/- 0.62). The results suggest the direction of mHealth should go to meet the detailed requirements of the specific user group as a more targeted approach. In addition, if a mutual feedback platform can be implanted in mHealth applications, it will increase user loyalty and make mHealth a more available motivational technology in our lives. PMID- 30402782 TI - Ozone-induction coupled with plasma assistance to enhance cataluminescence for monitoring of volatile organic compounds. AB - The authors describe a strategy for ozone-induction coupling with plasma assistance (O3-I/PA) to enhance cataluminescence (CTL) based sensing of volatile organic compounds (VOCs). A homemade O3-I/PA CTL sensor system was constructed based on this strategy. O3-I/PA can significantly enhance the CTL response to many compounds that were hardly detectable previously with adequate sensitivity. Without any preconcentration, the limits of detection (for S/N = 3) are 20 MUg.m 3 (= 5 ppbv) for toluene and 8 MUg.m-3 (6.4 ppbv) for formaldehyde. VOCs including benzene, alkanes, halohydrocarbons, alkenes alcohols, aldehydes, ketones and ethers are found to produce a strong response when using this sensor system. Mechanistic studies showed that the synergistic effect of ozone-induction and plasma assistance promote the oxidation of the VOCs under formation of CO2. This strongly favors CTL emission. The sensor system can be used as a direct reading detector for on-line and real-time monitoring of total VOCs. It also can be used as a detector in gas chromatography for the identification of individual VOCs. It is perceived that this work paves the way to both a new kind of vapor sensor and to a detection scheme in gas chromatography. Graphical abstract The synergistic effect of ozone-induction and plasma assistance promote the deep oxidation of the VOCs into CO2, which strongly favors cataluminescence emission. PMID- 30402784 TI - ? PMID- 30402783 TI - [Imaging diagnostics of the elbow]. PMID- 30402785 TI - Enhanced Desorption Electrospray Ionization Mass Spectrometry via Synchronizing Ion Generation and Ion Injection. AB - A modified version of desorption electrospray ionization mass spectrometry was developed for (i) better utilization of analyte ions and (ii) larger sampling area via synchronization the pulsed nebulizer gas with ion injection. To synchronize the sheath gas, gas flow was paused for 50 ms within each cycle, leading to solvent accumulation at the end of emitter tip. That solvent accumulation enlarged the desorption areas. As a result, the amount of analytes increased. Thus, the improved signal intensity (~ 2-5-folds for various substrates) was benefit from both better analyte ion utilization and larger desorption areas. Finally, the enhanced signal intensity was confirmed with both garlic homogenate and brain homogenate. Graphical Abstract ?. PMID- 30402786 TI - Freiburg Neuropathology Case Conference : Subacute Paraparesis in an Octogenarian. PMID- 30402787 TI - Reversal of Cortical Venous Reflux in Dural Arteriovenous Fistula with Change in Blood Pressure. PMID- 30402788 TI - Complexity reduction in human atrial modeling using extended Kalman filter. AB - Human atrial tissue electrophysiology is modeled upon biophysical details obtained from cellular level measurements. Data collected for this purpose typically represent a unique state of the tissue. As reproducing dynamic cases such as subject-varied and/or disorder-varied electrophysiological properties is in question, such complex models are typically hard to use. Hence, there is a need for simpler yet biophysically accurate and mathematically tractable models to be used for case-specific reproductions and simulations. In this study, a scheme for parameter estimation of a phenomenological cardiac model to match a targeted behavior generated from a complex model is used. Specifically, an algorithm incorporating extended Kalman filter (EKF) into the scheme is proposed. Its performance is then compared to that of particle swarm optimization (PSO) and sequential quadratic programming (SQP), algorithms that have been widely used for parameter optimization. Both robustness and adaptability performance of the algorithms are tested through various designs. For this, reproducing action potential (AP) waveforms of varying remodeling states of atrial fibrillation (AF) at different stimulus protocols was targeted. Also, randomly generated initial parameter sets are included in the tests. In addition, AP duration (APD) restitution curve (RC) is used for a multiscale evaluation of fitting performance. Finally, wavefront propagation on 2D of a selected AF remodeling state using parameter solutions from each of the algorithms is simulated for a qualitative evaluation. In general, PSO yielded superior performances than EKF and SQP with respect to fitting AP waveforms. Considering both AP and APD RC, however, EKF yielded the best accuracies. Also, more accurate spiral wave reentry is obtained with EKF. Overall, EKF algorithm yielded the best performance in robustness and adaptability. Graphical Abstract ?. PMID- 30402789 TI - A novel technique with reduced computed tomography exposure to predict vertebral compression fracture: a finite element study based on rat vertebrae. AB - Vertebral compression fractures are a significant clinical issue with an annual incidence of approximately 750,000 cases in the USA alone. Mechanical properties of vertebrae are successfully evaluated through finite element (FE) models based on vertebrae CT. However, clinical drawbacks associated to radiation transmission encouraged to explore the possibility to use selected or reduced portions of the vertebra. The objective of our study was to develop a new procedure to predict vertebral compression fracture from sub-volumes. We reconstructed rat vertebras from micro-CT of thoracic and lumbar groups. Each vertebra was partitioned into three sub-volumes of different axial thickness. FE simulating compression tests were performed on each model to evaluate their failure load and stiffness. Using a power function, a high correlation was found for stiffness and strength. The sub-volume with three fifths thickness had a failure load of 180.7 +/- 19.2 N for thoracic and of 209.5 +/- 27.4 N for the lumbar vertebra. These values were not significantly different from the values found for the entire vertebra (p > 0.05). Based on our findings, failure loads and stiffnesses obtained with reduced CT scans can be successfully used to predict full vertebral failure. This sub-region analysis and power relationship suggests that one can limit radiation exposure to patients when bone characterization is needed. Graphical abstract Estimated mechanical properties in relation to the extent of the computed tomography reconstruction. PMID- 30402790 TI - Long-term performance of right ventricular pacing leads: risk factors associated with permanent right ventricular pacing threshold increase. AB - PURPOSE: Right ventricular pacing threshold (RVPT) may rise over time accompanied by the increased use of implantable cardiac pacemakers. However, risk factors for permanent RVPT increase are not fully clarified in patients without definite lead fracture and dislodgment. We aimed to evaluate the long-term performance of RV pacing leads and identify risk factors associated with the occurrence of permanent RVPT increase in this population. METHODS: Patients with first implantation of cardiac pacemakers from January 2008 to June 2016 were consecutively enrolled. Follow-up for RVPT increase was until December 2017. The clinical data, specific data on the pacemaker implantation, and routine follow-up were retrieved. RESULTS: During a follow-up duration of 5.4 +/- 2.1 years, permanent RVPT increase (except lead fracture and dislodgment) was found in 8.4% (87/1033) patients. Patients with permanent RVPT increase had higher prevalence of myocardial infarction (MI), diabetes, and the use of amiodarone. The risk factors independently associated with permanent RVPT increase were MI (HR = 1.094, 95% CI 1.014-1.180, p = 0.031), diabetes (HR = 2.804, 95% CI 1.064-3.775, p = 0.003). MI patients with RVPT increase had higher prevalence of multivessel disease and atrioventricular block. Diabetic patients with RVPT increase exhibited higher serum fasting blood glucose (FBG) and hemoglobin A1c (HbA1c) levels, which were correlated with the maximum RVPT (p < 0.001). CONCLUSIONS: Our data showed that permanent RVPT increases (except lead fracture and dislodgement) during long-term follow-up after pacemaker implantation. The likely risk factors predisposing to chronic permanent RVPT increase are MI and diabetes with higher FBG and HbA1c levels. PMID- 30402792 TI - Why should we be concerned about a "g"? PMID- 30402791 TI - Amplified photoelectrochemical immunoassay for the tumor marker carbohydrate antigen 724 based on dye sensitization of the semiconductor composite C3N4-MoS2. AB - The authors describe an amplified photoelectrochemical immunoassay for the tumor marker carbohydrate antigen 724 (CA724). The method employs a C3N4-MoS2 semiconductor as the photoelectric conversion layer. The nanocomposite was characterized by transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray powder diffraction, and UV-vis diffuse reflectometry. The dye eosin Y was encapsulated into CaCO3 nanospheres which then were used as labels for antibody against CA724. In addition, Fe3O4 nanospheres were employed as magnetic platform for constructing photoelectrochemical sandwich immunoassay. The CaCO3 nanospheres can be dissolved with aid of ethylene diamine tetraacetic acid (EDTA) and the carried eosin Y in CaCO3 is released. The released dyes sensitizes the C3N4-MoS2 semiconductor, which induces photocurrent amplification. Under optimal conditions and at a typical working voltage of 0 V (vs. SCE), the photocurrent increases linearly in the range of 0.05 mU mL-1 to 500 mU mL-1 of CA724, with a 0.02 mU mL-1 detection limit. Graphical abstract The C3N4-MoS2 complex, with high efficiency of electron transport, was synthesized to construct a photoelectrochemical analytical platform. A sandwich-type immunoassay was established on the surface of magnetic beads. Carbohydrate antigen 724 in sample was detected sensitively by using sensitization of released eosin Y as signal amplifiery. PMID- 30402793 TI - Tranexamic acid and post-tonsillectomy hemorrhage: propensity score and instrumental variable analyses. AB - PURPOSE: Although post-tonsillectomy hemorrhage occurs rarely, it can be life threatening. Previous studies showed that tranexamic acid (TXA) had insignificant association with the rate of post-tonsillectomy hemorrhage, but those findings were limited by small sample sizes. The purpose of this study was to examine the effectiveness of TXA in preventing post-tonsillectomy hemorrhage using nationwide database. METHODS: Data of a retrospective cohort of 117,598 patients from 750 hospitals, who had undergone tonsillectomy between 2010 and 2016, were drawn from the Diagnosis Procedure Combination database in Japan and studied. RESULTS: Propensity score-matched analysis showed no significant differences in proportions of reoperation or blood transfusion after tonsillectomy between the treatment (TXA from the day of tonsillectomy) and control groups (1.50% vs. 1.47%, p = 0.64). Instrumental variable analysis also showed no significant differences (odds ratio, 0.98; 95% confidence interval, 0.86-1.13; p = 0.82). Higher proportions of reoperation or blood transfusion were significantly associated with male sex, older age, emergency hospitalization, prolonged anesthesia, and medium hospital volume (annual number of tonsillectomies). CONCLUSIONS: Administration of TXA from the day of tonsillectomy is not associated with reduction in reoperation or blood transfusion rates. PMID- 30402794 TI - Impact of age on elderly patients with oral cancer. AB - INTRODUCTION: In this study we have tried to analyze the impact of age on various clinico-pathological parameters, treatment completion and subsequent survival in older patients. MATERIALS AND METHODS: This is a retrospective analysis of 140 elderly (> 65 years) patients of oral cancer operated between January 2012 and December 2013. The patients were divided into two groups based upon their age that <= 70 years and > 70 years.Association of distribution of various clinico pathological factors between different groups was assessed by using Chi-square test. Survival analysis was done using Kaplan Meir analysis. Univariate and multivariate analysis were performed. RESULTS: The two groups had similar distribution of various clinico-pathological factors. Disease free survival for the group <= 70 and > 70 years was 37.6 months and 36.4 months (p < 0.594). 13.5% and 7.8% patients > 70 years and <= 70 years were either advised or received sub optimal adjuvant therapy (p < 0.002). CONCLUSION: There is no difference distribution of various clinico-pathological factors and survival in patients of oral cancer <= 70 and > 70 years of age. Age did not affect survival. Majority of patients could complete the adjuvant therapy advised. Still, significantly more number of patients > 70 years could not receive/complete appropriate adjuvant therapy. Thus treatment needs to be tailored keeping in mind the individual's performance status and the co-morbidities. PMID- 30402795 TI - Microscopic approach for repairing nasal septal perforations using bilateral advancement flaps. AB - BACKGROUND: Septal perforations consist in an anatomic defect of the mucosal, cartilaginous and/or bone tissues of the nasal septum. A huge variety of approaches and techniques for nasal perforation repair have been reported. METHODOLOGY/PRINCIPAL: Between January 2008 and January 2017, 38 patients were treated for nasal septal perforation in Department of Otorhinolaryngology Head and Neck Surgery, Fundacion Jimenez Diaz University Hospital, Madrid, Spain. A novel approach is presented based on microscope. Septal perforation closure was performed with endonasal bilateral advancement flaps-established technique and autologous cartilage and muscle temporal fascia grafts. We performed a retrospective review of closure rates and complications. RESULTS: A postoperative follow-up of at least 12 months was performed in 37 patients. The mean size of perforation was 1.33 cm. After the withdrawal of the silicone splints, perforations were completely closed in all cases. However, during the follow-up, four patients resulted in a reperforation, so our closure rate was 89.19%. For all cases, symptoms related to septal defect were solved. Only one case was reported of local infections that was resolved with antibiotics in a few days. CONCLUSIONS: Microscopic approach of septal perforation closure using bilateral advancement flaps can be an affordable technique with a high percent of success and low rate of complications. PMID- 30402796 TI - Anschluss 1938: Aftermath on Medicine and Society. PMID- 30402797 TI - Capture of attention by target-similar cues during dual-color search reflects reactive control among top-down selected attentional control settings. AB - We investigated the origin of attention capture in the contingent-capture protocol during a search for two colors. When searching for the target color, cues similar to the target capture attention but cues dissimilar to the target do not capture attention. The results are typically explained by top-down contingent capture, a form of proactive control where participants set up attentional control settings (ACSs) for the target and cues matching the ACSs capture attention. However, based on recent research, we hypothesized that the situation could be more complicated during search for several features. Here, reactive control in the form of (cue) color-elicited selection of one of several separate pre-activated ACSs, one for each single searched-for feature, could contribute to performance. With the help of mixing and switch costs, we demonstrated that participants searched for two colors by separate pre-activated ACSs, and a closer inspection of the capture effects of the cues confirmed that reactive control contributed to ACS selection. PMID- 30402798 TI - Is there a measure for low power laser dose? AB - Low power lasers have been used successfully for treatment of many diseases in soft and bone tissues. Basic and clinical researches have developed quickly being the scientific basis to therapeutic protocols based on these lasers. However, there are difficulties to compare experimental and clinical results obtained from different researchers because a complicated and intricate list of physical and biological parameters should be checked before the irradiation procedures as well as part of these parameters are omitted or inaccurately reported. This review focuses on the physical and biological parameters proposed to make experimental and clinical protocols accurate and reproducible as well as suggests dose parameters based on biological effects induced by low power lasers. A variety of parameters are reported by different authors and the number of parameter suggested could overcome three dozens. Thus, laser dose and laser dose equivalent are defined based on laser-induced biological effects and suggested as simplified dose parameters for low power lasers. These parameters could simplify and be useful to researchers and clinicians, permitting comparisons and decreasing mistakes and inaccuracies when laser-induced effects are evaluated and compared with those obtained in previous studies. The laser dose and laser dose equivalent could contribute significantly to improve accuracy, effectiveness, and safety of clinical protocols based on low power lasers. PMID- 30402799 TI - Is there a definition of low lean mass that captures the associated low bone mineral density? A cross-sectional study of 80 men with hip fracture. AB - BACKGROUND AND AIMS: Subjects with osteosarcopenia, the concurrent presence of sarcopenia and osteoporosis, have prognostic disadvantages and can benefit from treatments targeted at both the conditions. Our aim was to elucidate whether the available definitions of low appendicular lean mass (aLM) capture or not the men with associated low bone mineral density (BMD) following a hip fracture. METHODS: 80 men admitted to our rehabilitation hospital underwent a dual-energy X-ray absorptiometry scan 19.1 +/- 4.1 (mean +/- SD) days after hip fracture occurrence. Low aLM was identified according to either Baumgartner's definition (aLM/height2 < 7.26 kg/m2) or the criteria from the Foundation for the National Institutes of Health (FNIH): aLM < 19.75 kg, or aLM adjusted for body mass index (BMI) < 0.789. Low BMD was diagnosed with a T-score < - 2.5 at the unfractured femur. RESULTS: We found a significant positive correlation between aLM and BMD assessed at either femoral neck (r = 0.44; p < 0.001) or total hip (r = 0.50; p < 0.001). After categorization according to the FNIH threshold for aLM, we found a significant association between low aLM and low BMD: chi2(1, n = 80) = 5.4 (p = 0.020), which persisted after adjustment for age and fat mass. Conversely, categorization according to neither Baumgartner's threshold for aLM/height2 nor to the FNIH threshold for aLM/BMI was associated with low BMD. CONCLUSIONS: The association between low aLM and low BMD in men with hip fracture dramatically depends on the adopted definition of low aLM. FNIH threshold for aLM (< 19.75 kg) emerges as a useful tool to capture men with damage to both the components of the muscle-bone unit. PMID- 30402800 TI - Aging leads to dysfunctional innate immune responses to TLR2 and TLR4 agonists. AB - BACKGROUND: Sepsis is more common in the elderly. TNF? is recognized as an important mediator in sepsis and Toll-like receptors (TLRs) play an important role in initiating signaling cascades to produce TNF?. Little is known about how innate immunity is altered in healthy human aging that predisposes to sepsis. AIMS AND METHODS: We tested the hypothesis that aging dysregulates the innate immune response to TLR 2 and 4 ligands. We performed whole blood assays on 554 healthy subjects aged 40-80 years. TNFalpha production was measured at baseline and after stimulation with the TLR2 agonists: peptidoglycan, lipoteichoic acid, Pam3CysK, Zymosan A and the TLR4 agonist lipopolysaccharide (LPS). In a subset of subjects (n = 250), we measured Toll-like receptor (TLR) 2, 4 and MyD88 expression using real-time PCR. RESULTS AND DISCUSSION: We measured a 2.5% increase per year in basal secretion of TNFalpha with aging (n = 554 p = 0.02). Likewise, TNFalpha secretion was increased with aging after stimulation with peptidoglycan (1.3% increase/year; p = 0.0005) and zymosan A (1.1% increase/year p = 0.03). We also examined the difference between baseline and stimulated TNFalpha for each individual. We found that the increase was driven by the elevated baseline levels. In fact, there was a diminished stimulated response to LPS (1.9% decrease/year; p = 0.05), lipoteichoic acid (2.1% decrease/year p = 0.03), and Pam3CysK (2.6% decrease/year p = 0.0007). There were no differences in TLR or MyD88 mRNA expression with aging, however, there was an inverse relationship between TLR expression and stimulated TNFalpha production. CONCLUSIONS: With aging, circulating leukocytes produce high levels of TNFalpha at baseline and have inadequate responses to TLR2 and TLR4 agonists. These defects likely contribute to the increased susceptibility to sepsis in older adults. PMID- 30402801 TI - An Automatic Channel Selection Approach for ICA-Based Motor Imagery Brain Computer Interface. AB - Independent component analysis (ICA) is a potential spatial filtering method for the implementation of motor imagery brain-computer interface (MIBCI). However, ICA-based MIBCI (ICA-MIBCI) is sensitive to electroencephalogram (EEG) channels and the quality of the training data, which are two crucial factors affecting the stability and classification performance of ICA-MIBCI. To address these problems, this paper is mainly focused on the investigation of EEG channel optimization. As a reference, we constructed a single-trial-based ICA-MIBCI system with commonly used channels and common spatial pattern-based MIBCI (CSP-MIBCI). To minimize the impact of artifacts on EEG channel optimization, a data-quality evaluation method, named "self-testing" in this paper, was used in a single-trial-based ICA MIBCI system to evaluate the quality of single trials in each dataset; the resulting self-testing accuracies were used for the selection of high-quality trials. Given several candidate channel configurations, ICA filters were calculated using selected high-quality trials and applied to the corresponding ICA-MIBCI implementation. Optimal channels for each dataset were assessed and selected according to the self-testing results related to various candidate configurations. Forty-eight MI datasets of six subjects were employed in this study to validate the proposed methods. Experimental results revealed that the average classification accuracy of the optimal channels yielded a relative increment of 2.8% and 8.5% during self-testing, 14.4% and 9.5% during session-to session transfer, and 36.2% and 26.7% during subject-to-subject transfer compared to CSP-MIBCI and ICA-MIBCI with fixed the channel configuration. This work indicates that the proposed methods can efficiently improve the practical feasibility of ICA-MIBCI. PMID- 30402802 TI - Secondary-Transferring Graphene Electrode for Stable FOLED. AB - In this work, sharp wrinkles on graphene films, caused by graphene duplicating the grain boundary cracks of copper foil during the preparation process, were carefully explored. A secondary-transferring graphene film process was proposed to re-transform the "Peak" morphology of graphene surface into "Valley" form. The process we have developed is highly effective and almost nondestructive to the graphene through testing the surface morphology and photo-electric properties before and after the secondary-transferring process. Flexible organic light emitting device (FOLED) with PEDOT:PSS/SLG/NOA63 framework as a targeted application was fabricated to illustrate the value of our proposed method in fabricating stable devices, the maximum luminance can reach about 35000 cd/m2, and the maximum current efficiency was 16.19 cd/A. This method can also be applied to the roll-to-roll preparation of large area high-quality graphene. PMID- 30402803 TI - Laparoscopic Adjustable Gastric Banding: an Underestimated Risk Factor for the Development of Esophageal Cancer?-a Nationwide Survey. AB - BACKGROUND: Approximately 14% of Austria's 8.5 million inhabitants have a body mass index (BMI) > 30 kg/m2. The laparoscopic adjustable gastric banding (LAGB) was introduced in Austria in 1994, where about 10.300 patients have received it so far. One of our LAGB patients developed an adenocarcinoma of the distal esophagus 13 years after implantation. OBJECTIVES: In order to calculate whether after LAGB patients are at higher risk for carcinoma of the esophagus, we performed a nationwide survey. METHODS: A questionnaire was sent to all surgical departments in Austria, primarily in order to detect cases with esophageal carcinoma after LAGB, but also to evaluate the policy in Austria concerning preoperative work-up, operation, and follow-up in LAGB patients. RESULTS: Since 1994, 37 of the 119 surgical departments in Austria have performed a total of about 10.300 LAGB implantations. Six patients have been identified with esophageal cancer following LAGB. The WHO statistical report on esophageal cancer shows an incidence of 2.8/100.000 per year in Austria, about 1/3 of which cases are adenocarcinoma of the distal esophagus. CONCLUSION: Following LAGB, the incidence of esophageal cancer might be up to fivefold higher than the aged standardized overall population of Austria. PMID- 30402804 TI - Outcomes of Bariatric Surgery Versus Medical Management for Type 2 Diabetes Mellitus: a Meta-Analysis of Randomized Controlled Trials. AB - INTRODUCTION: Bariatric surgery improves type 2 diabetes (T2D) in obese patients. The sustainability of these effects and the long-term results have been under question. OBJECTIVE: To compare bariatric surgery versus medical management (MM) for T2D based on a meta-analysis of randomized controlled trials (RCTs) with 2 years of follow-up. MATERIAL AND METHODS: Seven RCTs with at least 2-year follow up were identified. The primary endpoint was remission of T2D (full or partial). Four hundred sixty-three patients with T2D and body mass index > 25 kg/m2 were evaluated. RESULTS: After 2 years, T2D remission was observed in 138 of 263 patients (52.5%) with bariatric surgery compared to seven of 200 patients (3.5%) with MM (risk ratio (RR) = 10, 95% CI 5.5-17.9, p < 0.001). Subgroup analysis of the Roux-en-Y gastric bypass (RYGB) showed a significant effect size at 2 years in favor of RYGB over MM for a higher decrease of HbA1C (0.9 percentage points, 95% CI 0.6-1.1, p < 0.001), decrease of fasting blood glucose (35.3 mg/dl, 95% CI 13.3-57.3, p = 0.002), increase of high-density lipoprotein (HDL) (12.2 mg/dl, 95% CI 7.6-16.8, p < 0.001), and decrease of triglycerides (32.4 mg/dl, 95% CI 4.5-60.3, p = 0.02). Four studies followed patients up to 5 years and showed 62 of 225 patients (27.5%) with remission after surgery, compared to six of 156 patients (3.8%) with MM (RR = 6, 95% CI 2.7-13, p < 0.001). CONCLUSION: This meta analysis shows a superior and persistent effect of bariatric surgery versus MM for inducement of remission of T2D. This benefit of bariatric surgery was significant at 2 years and superior to MM even after 5 years. Compared with MM, patients with RYGB had better glycemic control and improved levels of HDL and triglycerides. PMID- 30402805 TI - Gastric Emptying and Food Tolerance Following Banded and Non-banded Roux-en-Y Gastric Bypass. AB - INTRODUCTION: Gastric emptying (GE) and food tolerance (FT) can be altered after Roux-en-Y gastric bypass (RYGB) has been performed, especially when it involved the use of a restrictive mechanism (such as a silastic ring). AIM: To assess GE and FT in patients who underwent banded (BRYGB) or non-banded Roux-en-Y gastric bypass (RYGB). METHODS: Forty-seven BRYGB patients and 47 RYGB patients underwent gastric emptying scintigraphy (GES) and FT assessment (by means of a questionnaire) between 6 months and 2 years postoperatively. RESULTS: GES was performed on average 11.7 +/- 5.0 months (6 to 24) postoperatively. T1/2 medians (time taken for the gastric radioactivity to decrease to half of the original value in the gastric pouch) in the RYGB and BRYGB groups were 48.7 min (40.6 183.0 min) and 56.3 min (41.1-390.9 min), respectively (p = 0.031). The median of total questionnaire scores was 24 points (18-27) in the RYGB group and 20 points (13-27) in the BRYBG group (p < 0.001). CONCLUSIONS: The band (silastic ring) delays GE time and does not affect patient satisfaction or food tolerance to vegetables, bread, or rice, but does affect tolerance to the intake of meat, salad, and pasta. The best tolerated foods are vegetables, salad, and fish. Banded patients are more likely to regurgitate and vomit. Gastric emptying does not affect FT. PMID- 30402808 TI - Prognostic and Clinic-Pathological Significances of SCF and COX-2 Expression in Inflammatory and Malignant Prostatic Lesions. AB - The initiation of prostatic malignancy has been linked to chronic inflammation. Stem cell factor (SCF) is an inflammatory cytokine that is specific to the c-KIT receptor which is type III receptor tyrosine kinase (RTK). Cyclooxygenases (COXs) are the main enzymes which are responsible for prostaglandins production from arachidonic acid. COX2 is an enzyme which is produced under different pathological conditions. The aim of our study; is to investigate the clinicopathological and the prognostic significance of SCF and COX-2 expression in prostatic adenocarcinoma (PC), chronic prostatitis and nodular prostatic hyperplasia (NPH) in a trial to clarify the role of inflammation as a risk factor for prostatic carcinogenesis and cancer progression. SCF and COX-2 tissue protein expression were evaluated in 50 cases of PC, 20 cases of chronic prostatitis and 10 cases of NPH using immunohistochemistry, patients were followed up for 5 years. The relationship between their levels of expressions, clinicopathological, and prognostic criteria were studied. SCF expression in PC was positively correlated with advanced patient age (p = <0.001), high level of PSA (p = 0.010), higher Gleason score (p = 0.011). COX-2 expression in PC was positively correlated with advanced patient age (p = <0.001), high level of PSA (p = 0.016), advanced D'Amico risk group (p = 0.038). High levels of expression of both SCF& COX-2 are associated with higher incidence of tumor relapse, worse disease overall survival and free survival (p < 0.001). SCF and COX-2 are associated with PC progression and associated with poor prognosis in PC patients. PMID- 30402807 TI - Cerebral oxygen metabolism during and after therapeutic hypothermia in neonatal hypoxic-ischemic encephalopathy: a feasibility study using magnetic resonance imaging. AB - BACKGROUND: Therapeutic hypothermia is the standard-of-care treatment for infants diagnosed with moderate-to-severe hypoxic-ischemic encephalopathy (HIE). MRI for assessing brain injury is usually performed after hypothermia because of logistical challenges in bringing acutely sick infants receiving hypothermia from the neonatal intensive care unit (NICU) to the MRI suite. Perhaps examining and comparing early cerebral oxygen metabolism disturbances to those after rewarming will lead to a better understanding of the mechanisms of brain injury in HIE and the effects of therapeutic hypothermia. OBJECTIVE: The objectives were to assess the feasibility of performing a novel T2-relaxation under spin tagging (TRUST) MRI technique to measure venous oxygen saturation very early in the time course of treatment, 18-24 h after the initiation of therapeutic hypothermia, to provide a framework to measure neonatal cerebral oxygen metabolism noninvasively, and to compare parameters between early and post-hypothermia MRIs. MATERIALS AND METHODS: Early (18-24 h after initiating hypothermia) MRIs were performed during hypothermia treatment in nine infants with HIE (six with moderate and three with severe HIE). Six infants subsequently had an MRI after hypothermia. Mean values of cerebral blood flow, oxygen extraction fraction, and cerebral metabolic rate of oxygen from MRIs during hypothermia were compared between infants with moderate and severe HIE; and in those with moderate HIE, we compared cerebral oxygen metabolism parameters between MRIs performed during and after hypothermia. RESULTS: During the initial hypothermia MRI at 23.5+/-5.2 h after birth, infants with severe HIE had lower oxygen extraction fraction (P=0.04) and cerebral metabolic rate of oxygen (P=0.03) and a trend toward lower cerebral blood flow (P=0.33) compared to infants with moderate HIE. In infants with moderate HIE, cerebral blood flow decreased and oxygen extraction fraction increased between MRIs during and after hypothermia (although not significantly); cerebral metabolic rate of oxygen (P=0.93) was not different. CONCLUSION: Early MRIs were technically feasible while maintaining hypothermic goal temperatures in infants with HIE. Cerebral oxygen metabolism early during hypothermia is more disturbed in severe HIE. In infants with moderate HIE, cerebral blood flow decreased and oxygen extraction fraction increased between early and post-hypothermia scans. A comparison of cerebral oxygen metabolism parameters between early and post hypothermia MRIs might improve our understanding of the evolution of HIE and the benefits of hypothermia. This approach could guide the use of adjunctive neuroprotective strategies in affected infants. PMID- 30402809 TI - Safranal protects against beta-amyloid peptide-induced cell toxicity in PC12 cells via MAPK and PI3 K pathways. AB - Alzheimer's disease is a type of cerebrovascular problem with progressive mental disabilities for the patient. This study aimed to investigate the protective effect of safranal on toxicity and oxidative damage induced by beta-amyloid (Abeta) and hydrogen peroxide (H2O2) in PC12 cells as an appropriate model of Alzheimer's cell damage. PC12 cells pretreated with saffron extract (2.5-40 MUg/ml), essential oil (2.5-40 MUg/ml), safranal (2.5-5-40 MUM) and donepezil (5, 10 and 20 MUM) for 120 min. Then exposed to either Abeta (25 MUM) for 48 h or H2O2 (150 MUM) for 24 h. In the end, the cell survival and intracellular reactive oxygen species (ROS) production analyzed. The anti-apoptotic effects of safranal in PC12 cells were studied using flow cytometry after PI staining. Also, western blot analysis of Cyt c, survivin, p44/42 MAPK (ERK1/2), Phospho-p44/42 MAPK (ERK1/2), PI3 Kinase P85, Phospho-PI3 Kinase P85, phospho SAPK/JNK, SAPK/JNK and caspase 3 performed for detection of apoptosis. Safranal (2.5 and 5 MUM) and donepezil (10 and 20 MUM) significantly decreased the Abeta toxicity. The ROS significantly attenuated when cells pretreated with essential oil, saffron extract, safranal, and donepezil. Cell apoptosis significantly increased after treatment with Abeta (25-35) (25 MUM) compared to control. However, after pretreatment with safranal (2.5 MUM) apoptosis was significantly reduced. Western blot analysis of PC12 cells showed that 25 MUM Abeta (25-35) could increase proteins involved in apoptosis signaling and pretreatment with safranal (2.5 MUM) could decrease the apoptosis. According to the results, safranal showed anti apoptotic and antioxidant effects and may exert promising potential for the prevention of Alzheimer's disease. PMID- 30402810 TI - The microfabrication of mold for polymer microfluidic devices with Zr-based metallic glass. AB - Polymer microfluidic devices are used for many purposes such as microarrays and biochips. The key tool for manufacturing these chips in bulk is an appropriate mold. However, the popular material for making molds is nickel or nickel alloys, which have low stiffness and wear out easily. Zr-based metallic glass is a promising material for micro- or nanomolds because it has good mechanical properties and can be easily formed with high precision. In this paper, Zr-based metallic glass is proposed for use as micromold insert to make poly-(methyl methacrylate) (PMMA) microfluidic devices. Our experiments show that they have good feature integrity and replication quality. Microchannels we fabricated using these replicas did not leak and had good flow performance. Zr-based metallic glass can greatly ease the manufacture of plastic microfluidic devices for research and commercial applications. PMID- 30402806 TI - Chemotherapy and the pediatric brain. AB - Survival rates of children with cancer are steadily increasing. This urges our attention to neurocognitive and psychiatric outcomes, as these can markedly influence the quality of life of these children. Neurobehavioral morbidity in childhood cancer survivors affects diverse aspects of cognitive function, which can include attention, memory, processing speed, intellect, academic achievement, and emotional health. Reasons for neurobehavioral morbidity are multiple with one major contributor being chemotherapy-induced central nervous system (CNS) toxicity. Clinical studies investigating the effects of chemotherapy on the CNS in children with cancer have reported causative associations with the development of leukoencephalopathies as well as smaller regional grey and white matter volumes, which have been found to correlate with neurocognitive deficits.Preclinical work has provided compelling evidence that chemotherapy drugs are potent neuro- and gliotoxins in vitro and in vivo and can cause brain injury via excitotoxic and apoptotic mechanisms. Furthermore, chemotherapy triggers DNA (deoxyribonucleic acid) damage directly or through increased oxidative stress. It can shorten telomeres and accelerate cell aging, cause cytokine deregulation, inhibit hippocampal neurogenesis, and reduce brain vascularization and blood flow. These mechanisms, when allowed to operate on the developing brain of a child, have high potential to not only cause brain injury, but also alter crucial developmental events, such as myelination, synaptogenesis, neurogenesis, cortical thinning, and formation of neuronal networks.This short review summarizes key publications describing neurotoxicity of chemotherapy in pediatric cancers and potential underlying pathomechanisms. PMID- 30402811 TI - [Sonographic analysis of swallowing in the cervical section of the esophagus]. AB - BACKGROUND: Dysphagia is a common symptom reported by patients in various medical fields, raising the question of diagnosis. In addition to otorhinolaryngologic examination with a mirror, the current gold standards videofluoroscopy and fiber optic endoscopic evaluation of swallowing (FEES) are available. Ultrasound is frequently used in everyday clinical practice, although its application for swallowing diagnostics needs addressing. MATERIALS AND METHODS: Between April 2012 and February 2014, 81 subjects (age 19-66 years) with no indication of a swallowing disorder were sonographically examined. The anatomic representation of swallowing structures was evaluated and videos of the cervical part of the esophagus during swallowing of different consistencies (saliva, water, jelly) were recorded and analyzed. In a pilot study, the examination was tested on 3 dysphagia patients. RESULTS: The base of the tongue, the intralaryngeal structures, the cervical spine, and the thyroid glands were well visualized. Sonographic representation of the cervical esophagus section was particularly successful. Its length could be detected at 5.78 +/- 1.66 cm, the diameter measured at 0.88 +/- 0.10 cm. Sonographic inspection of the sinus piriformis was most difficult; it could not be seen in 39.5% of cases. Visualization of the sinus piriformis was better in cases of normal weight and age <25 years (odds ratios 5.6 and 11.3, respectively). In the examination of patients with a swallowing disorder, three different pathologies (Forestier's disease, esophageal stenosis, and motor neuron disease) were identified as the cause of complaints. CONCLUSION: Sonography enables very good visualization of swallowing and evaluation of the cervical esophagus. Where available, the otorhinolaryngologist should consider ultrasound as a diagnostic option, as it enables repeated evaluation of swallowing and can complement previously available diagnostic tools. PMID- 30402812 TI - [New aspects in thyroid cancer treatment : Highlights of the ASCO Annual Meeting 2018]. AB - Whereas surgical treatment of thyroid carcinoma plays an important role especially in the early stages, a multimodal approach is pursued in the palliative setting, which, in addition to classical chemotherapy primarily involves treatment with tyrosine kinase inhibitors. An analysis of clinical trials and studies presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2018 is presented. In particular, studies on the treatment of radioiodine-refractory differentiated thyroid cancer, anaplastic thyroid cancer and immunotherapy were selected and analyzed. Clinically and preclinically relevant studies are presented and critically interpreted in this review. PMID- 30402814 TI - Using restricted factor analysis to select anchor items and detect differential item functioning. AB - Restricted factor analysis (RFA) is a powerful method to test for uniform differential item functioning (DIF), but it may require empirically selecting anchor items to prevent inflated Type I error rates. We conducted a simulation study to compare two empirical anchor-selection strategies: a one-step rank-based strategy and an iterative selection procedure. Unlike the iterative procedure, the rank-based strategy had a low risk and degree of contamination within the empirically selected anchor set, even with small samples. To detect nonuniform DIF, RFA requires an interaction effect with the latent factor. The latent moderated structural equations (LMS) method has been applied to RFA and has revealed inflated Type I error rates. We propose using product indicators (PI) as a more widely available alternative to measure the latent interaction. A simulation study, involving several sample-size conditions and magnitudes of uniform and nonuniform DIF, revealed that PI obtained similar power but lower Type I error rates, as compared to LMS. PMID- 30402815 TI - Improving confidence intervals for normed test scores: Include uncertainty due to sampling variability. AB - Test publishers usually provide confidence intervals (CIs) for normed test scores that reflect the uncertainty due to the unreliability of the tests. The uncertainty due to sampling variability in the norming phase is ignored. To express uncertainty due to norming, we propose a flexible method that is applicable in continuous norming and allows for a variety of score distributions, using Generalized Additive Models for Location, Scale, and Shape (GAMLSS; Rigby & Stasinopoulos, 2005). We assessed the performance of this method in a simulation study, by examining the quality of the resulting CIs. We varied the population model, procedure of estimating the CI, confidence level, sample size, value of the predictor, extremity of the test score, and type of variance-covariance matrix. The results showed that good quality of the CIs could be achieved in most conditions. The method is illustrated using normative data of the SON-R 6-40 test. We recommend test developers to use this approach to arrive at CIs, and thus properly express the uncertainty due to norm sampling fluctuations, in the context of continuous norming. Adopting this approach will help (e.g., clinical) practitioners to obtain a fair picture of the person assessed. PMID- 30402813 TI - [Immunotherapy highlights of the ASCO annual meeting 2018 for head and neck cancers]. AB - BACKGROUND: Immunotherapeutic strategies are becoming increasingly more important for head and neck cancer and numerous clinical trials were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) 2018. OBJECTIVE: In this review the most interesting clinical trials and trial results for immunotherapy of head and neck cancer are summarized. MATERIAL AND METHODS: All abstracts and presentations on immunotherapy of head and neck cancer at the annual meeting of the ASCO 2018 were screened to select the most interesting trials for a more detailed analysis. RESULTS: For head and neck cancer, practice changing phase III trial results were missing, but several noteworthy new strategies and trial results for immunotherapy were presented. Neoadjuvant immunotherapy trials, results concerning immunotherapy in old age, prognostic implications of immune-mediated adverse events and new immunotherapy combinations are summarized in this article. CONCLUSION: The role of immunotherapy for the treatment of head and neck cancer is markedly increasing. Many pioneering trials are currently ongoing, in the phase of data analysis or in planning. PMID- 30402816 TI - Development of Aggression Subtypes from Childhood to Adolescence: a Group-Based Multi-Trajectory Modelling Perspective. AB - The persistence of elevated subtypes of aggression beginning in childhood have been associated with long-term maladaptive outcomes. Yet it remains unclear to what extent there are clusters of individuals following similar developmental trajectories across forms (i.e., physical and indirect) and functions (i.e., proactive and reactive) of aggression. We aimed to identify groups of children with distinct profiles of the joint development of forms and functions of aggression and to identify risk factors for group membership. A sample of 787 children was followed from birth to adolescence. Parent and teacher reports, and standardised assessments were used to measure two forms and two functions of aggressive behaviour, between six and 13 years of age along with preceding child, maternal, and family-level risk-factors. Analyses were conducted using a group based multi-trajectory modelling approach. Five trajectory groups emerged: non aggressors, low-stable, moderate-engagers, high-desisting, and high-chronic. Coercive parenting increased membership risk in the moderate-engagers and high chronic groups. Lower maternal IQ increased membership risk in both high desisting and high-chronic groups, whereas maternal depression increased membership risk in the high-desisting group only. Never being breastfed increased membership risk in the moderate-engagers group. Boys were at greater risk for belonging to groups displaying elevated aggression. Individuals with chronic aggression problems use all subtypes of aggression. Risk factors suggest that prevention programs should start early in life and target mothers with lower IQ. Strategies to deal with maternal depression and enhance positive parenting while replacing coercive parenting tactics should be highlighted in programming efforts. PMID- 30402817 TI - Time to Listen More and Talk Less. PMID- 30402818 TI - Concentration of Opioid-Related Industry Payments in Opioid Crisis Areas. PMID- 30402819 TI - Apple Watch Steps. PMID- 30402820 TI - Trends, Management Patterns, and Predictors of Leaving Against Medical Advice among Patients with Documented Noncompliance Admitted for Acute Myocardial Infarction. PMID- 30402821 TI - Older Adults' Perceptions of Healthcare Overuse. PMID- 30402822 TI - Influence of Age, Health, and Function on Cancer Screening in Older Adults with Limited Life Expectancy. AB - BACKGROUND/OBJECTIVES: We examined the relationship between cancer screening and life expectancy predictors, focusing on the influence of age versus health and function, in older adults with limited life expectancy. DESIGN: Longitudinal cohort study SETTING: National Health and Aging Trends Study (NHATS) with linked Medicare claims. PARTICIPANTS: Three cohorts of adults 65+ enrolled in fee-for service Medicare were constructed: women eligible for breast cancer screening (n = 2043); men eligible for prostate cancer screening (n = 1287); men and women eligible for colorectal cancer screening (n = 3759). MEASUREMENTS: We assessed 10 year mortality risk using 2011 NHATS data, then used claims data to assess 2-year prostate and breast cancer screening rates and 3-year colorectal cancer screening rates. Among those with limited life expectancy (10-year mortality risk > 50%), we stratified participants at each level of predicted mortality risk and split participants in each risk stratum by the median age. We assembled two sub-groups from these strata that were matched on predicted life expectancy: a "younger sub group" with relatively poorer health/functional status and an "older sub-group" with relatively better health/functional status. We compared screening rates between sub-groups. RESULTS: For all three cancer screenings, the younger sub groups (average ages 73.4-76.1) had higher screening rates than the older sub groups (average ages 83.6-86.9); screening rates were 42.9% versus 34.2% for prostate cancer screening (p = 0.02), 33.6% versus 20.6% for breast cancer screening (p < 0.001), 13.1% versus 6.7% for colorectal cancer screening in women (p = 0.006), and 20.5% versus 12.1% for colorectal cancer screening in men (p = 0.002). CONCLUSION: Among older adults with limited life expectancy, those who are relatively younger with poorer health and functional status are over-screened for cancer at higher rates than those who are older with the same predicted life expectancy. PMID- 30402823 TI - The bovine herpesvirus 1 regulatory proteins, bICP4 and bICP22, are expressed during the escape from latency. AB - Following acute infection of mucosal surfaces by bovine herpesvirus 1 (BoHV-1), sensory neurons are a primary site for lifelong latency. Stress, as mimicked by the synthetic corticosteroid dexamethasone, consistently induces reactivation from latency. Two viral regulatory proteins (VP16 and bICP0) are expressed within 1 h after calves latently infected with BoHV-1 are treated with dexamethasone. Since the immediate early transcription unit 1 (IEtu1) promoter regulates both BoHV-1 infected cell protein 0 (bICP0) and bICP4 expressions, we hypothesized that the bICP4 protein is also expressed during early stages of reactivation from latency. In this study, we tested whether bICP4 and bICP22, the only other BoHV-1 protein known to be encoded by an immediate early gene, were expressed during reactivation from latency by generating peptide-specific antiserum to each protein. bICP4 and bICP22 protein expression were detected in trigeminal ganglionic (TG) neurons during early phases of dexamethasone-induced reactivation from latency, operationally defined as the escape from latency. Conversely, bICP4 and bICP22 were not readily detected in TG neurons of latently infected calves. In summary, it seems clear that all proteins encoded by known BoHV-1 IE genes (bICP4, bICP22, and bICP0) were expressed during early stages of dexamethasone induced reactivation from latency. PMID- 30402824 TI - HIV-1 infection renders brain vascular pericytes susceptible to the extracellular glutamate. AB - Reduced pericytes' coverage of endothelium in the brain is one of the structural changes leading to breach of the blood-brain barrier during HIV infection. We previously showed in central memory T (TCM) cells that HIV latency increases cellular susceptibility to DNA damage. In this study, we investigated susceptibility of primary brain pericytes infected with HIV-1 to DNA damage in response to glutamate and TNF-alpha, both known to induce neuronal death during chronic inflammatory conditions. To infect pericytes, we used a single-cycle HIV 1 pseudotyped with VSV-G envelope glycoprotein and maintained the cultures until latency was established. Our data indicate that pericytes silence HIV-1 expression at similar rate compared to primary TCM cells. TNF-alpha and IL-1beta caused partial reactivation of the virus suggesting that progression of disease and neuroinflammation might facilitate virus reactivation from latency. Significant increases in the level of gammaH2AX, which reflect DNA damage, were observed in infected cultures exposed to TNF-alpha and glutamate at day 2 post infection. Glutamate, an excitatory neurologic stimuli, also caused increases in the gammaH2AX level in latently infected pericytes, whereas PARP and DNA-PK inhibitors caused reductions in cell population suggesting that HIV-1 latency affects repairs of single- and double-strand DNA breaks. For comparison, we also analyzed latently infected astrocytes and determined that DNA damage response in astrocytes is less affected by HIV-1. In conclusion, our results indicate that productive infection and HIV-1 latency in pericytes interfere with DNA damage response, rendering them vulnerable to the agents that are characteristic of chronic neuroinflammatory disease conditions. PMID- 30402825 TI - Approaches to Resolve False Reporting in Neutralizing Antibody Assays Caused by Reagent Leaching from Affinity Capture Elution Solid Phase. AB - Insufficient drug tolerance presents a major challenge in the development of neutralizing antibody (NAb) assays for biotherapeutics. Sample pre-treatment using solid-phase extraction with acid dissociation (SPEAD) is widely reported to improve drug tolerance. In this paper, a case study is presented in which SPEAD was used in conjunction with a competitive ligand binding NAb assay format. A significant degree of biotin-drug conjugate leaching was observed resulting in the reporting of both false positive and false negative results in NAb assay. Mitigation steps have been evaluated to address drug/biotin-drug conjugate leaching. These steps included assessment of the streptavidin-coated plate in conjunction with biotin-drug conjugates at various biotin molar challenge ratios (MCR). In addition, an alternative method based on covalent capture of the drug on an aldehyde-activated plate was assessed. Both approaches were compared for the degree of drug/biotin-drug conjugate leaching during the second elution step of the SPEAD procedure. Moreover, the impact of various conditions on the assay performance was assessed, including elution pH, sample incubation time, and biotin MCR. For the covalent drug capture method, capture conditions were evaluated. Optimized conditions in both streptavidin capture and covalent capture methods enabled a significant reduction of drug/biotin-drug conjugate leaching. A streptavidin high binding capacity approach using biotin-drug conjugate with a MCR of 50:1 was chosen as the optimal method yielding a NAb assay with a fit for purpose sensitivity (153 ng/mL) and a drug tolerance of up to 50 MUg/mL with 500 ng/mL PC. PMID- 30402827 TI - Comment on "Neuronal nitric oxide synthase inhibition reduces brain damage by promoting collateral recruitment" in a cerebral hypoxia-ischemia mice model. PMID- 30402826 TI - Outcomes of Neoadjuvant Chemoradiation in Patients with Gastro-esophageal Junction Adenocarcinoma: a Retrospective Cohort Study in Iran. AB - PURPOSE: The optimal treatment for locally advanced GEJ and cardia adenocarcinoma is controversial. Several studies have shown that treating these patients with neoadjuvant chemoradiotherapy followed by surgery leads to survival benefits, and there are also studies that have declared conflicting results. It seems that there is still room for discussion. We calculated the survival rates and pathologic responses in our patients with characteristics which we mentioned above. METHODS: Patients with locally advanced, non-metastatic GEJ and cardia adenocarcinomas (only patients with Siewert's type I and II), who were referred to Imam Khomeini hospital (Institute of cancer) between 2005 and 2014 and received neoadjuvant chemoradiation and underwent surgery were enrolled in this retrospective cohort study. Evaluations were done every 3 months. RESULTS: Thirty two patients enrolled in this study. Median follow up time was 23 months (Reverse Kaplan-Meier method). The rates of 1-year survival, 2-year survival, 3-year survival, 4-year survival, and 5-year survival were 75%, 52%, 52%, 37%, and 37%, respectively. No local recurrences occurred among patients; however, four patients experienced distal recurrence in the following locations: two cases (6.3%) in the liver, one case (3.1%) in the lung, and one case (3.1%) in the peritoneum. The rate of complete pathologic response (T0N0) was 21.9%. CONCLUSIONS: Neoadjuvant chemoradiation in patients with locally advanced GEJ and cardia adenocarcinoma will lead to a survival benefit. PMID- 30402828 TI - The function of hyperpolarization-activated cyclic nucleotide-gated channel in diabetic cystopathy. AB - OBJECTIVE: We aimed at investigating changes in the expression and physiological function of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in interstitial cells of Cajal (ICC) in diabetic state. MATERIALS AND METHODS: Twenty adult female Sprague-Dawley (SD) rats were randomly assigned to control and Zucker diabetic fatty (ZDF) group. The protein and mRNA expression of HCN isoforms and C-kit in the rat bladders were detected using Western blotting and reverse transcription-polymerase chain reaction (RT-PCR). The bladder contraction was evaluated using a bladder smooth muscle strip test. Whole cell patch-clamp techniques were used to detect the activity of HCN channels. Immunofluorescent staining was used to the positive expression of HCN and C-kit in ICC. RESULTS: cAMP, as HCN channel-specific stimulant, could increase the frequency and amplitude of spontaneous contractions in both group, while cAMP inducing contraction of ZDF rats, was still significantly lower compared with the control group. Acute bladder ICCs were isolated by collagenase digestion. Classic Ih current pattern was recorded on ICCs while Ih current amplitude of ICCs from ZDF diabetic rats was significantly lower than the control group. The expression and mRNA of HCN1-4 isoforms in ZDF diabetic rats were both significantly lower compared with the control group. Meanwhile, the number of c-kit positive cells in ZDF diabetic rats showed no significant differences compared with controls. The morphological structure of ICC in the bladder of ZDF rats was relatively loose and the number of their cell process was apparently decreased. CONCLUSIONS: The structure of ICCs in ZDF rats was relatively loose, their connection to each other was also diminished. The expression of HCN was down-regulated and its response to cAMP was also decreased. HCN channels in bladder ICCs might regulate detrusor contraction. Changes in HCN expression and activity in bladder ICCs might be one of the most important mechanisms of diabetic cystopathy. PMID- 30402829 TI - Highly expressed miR-182-5p can promote preeclampsia progression by degrading RND3 and inhibiting HTR-8/SVneo cell invasion. AB - OBJECTIVE: The role of miR-182-5p in preeclampsia was studied, and its mechanism was also explored. PATIENTS AND METHODS: Fifty patients with preeclampsia were assigned to the study group and 50 normal pregnant women to the control group. The age, weight, blood pressure, urinary protein, and weight of newborns were compared between the two groups. The placental tissues of the above-mentioned subjects were collected, and quantitative Reverse Transcriptase-Polymerase Chain Reaction (qRT-PCR) assay was used to detect the expression of miR-182-5p. MiR-182 5p was overexpressed or knocked down using a cell transfection assay in HTR 8/SVneov cell, which is a kind of human chorionic trophoblast cell. Changes in cell migration and invasiveness before and after transfection were determined by wound healing test and transwell assay, respectively. Western blot was performed to analyze the change of RND3 protein level before and after transfection. The biological prediction of the relationship between miR-182-5p and RND3 was performed and a dual luciferase reporter gene experiment was designed to verify the results. Finally, a rescue experiment was conducted to investigate whether RND3 could affect the role of miRNA-182-5p in the capacity of cell migration and invasion. RESULTS: Preeclampsia patients had higher systolic blood pressure, diastolic blood pressure, and urinary protein than normal pregnant women, while neonatal weight decreased compared with normal pregnant women. MiRNA-182-5p was highly expressed in placental tissues of patients with preeclampsia. After miRNA 182-5p was overexpressed, the migration and invasion of HTR-8/SVneo cells were significantly attenuated, and the mRNA and protein levels of RND3 were markedly downregulated, and vice versa. The dual luciferase reporting assay confirmed that miRNA-182-5p could bind to 3'UTR of RND3. In addition, the results of rescue experiment showed that overexpressing miRNA-182-5p could markedly inhibit the migration and invasion of HTR-8/SVneo cells; however, when RND3 was simultaneously overexpressed, the inhibitory effect of miRNA-182-5p was partially reversed. CONCLUSIONS: The highly expressed miRNA-182-5p in patients with preeclampsia promoted the development of preeclampsia, the possible mechanism of which might be that the increased miRNA-182-5p expression could inhibit the migratory and invasive ability of trophoblast cells through targeted degrading RND3 protein. PMID- 30402830 TI - The involvement of miR-155 in blood pressure regulation in pregnant hypertension rat via targeting FOXO3a. AB - OBJECTIVE: Pathogenesis factor of pregnant hypertension is still unclear and lacks of effective treatment. MiR-155 is a recently discovered miRNA molecule with differential expression in pregnant hypertension, which participates in the disease regulation. As a downstream target gene of miR-155, FOXO3a is correlated with blood pressure regulation. We investigated the regulatory role and mechanism of miR-155 in pregnant hypertension. MATERIALS AND METHODS: We established a pregnant hypertension rat model, on which miR-155 inhibitor or FOXO3a siRNA was applied, followed by HE staining, 24 h urea protein, blood pressure and serum creatine assay to evaluate disease severity. RESULTS: MiR-155 expression was significantly elevated in model rats, accompanied by a reduction of the FOXO3a level. MiR-155 inhibitor suppressed miR-155 expression, increased FOXO3a level and placental tissue morphology by HE staining, and depressed blood pressure as well as serum creatine level. Downregulation of FOXO3a by specific siRNA resulted in opposite effects. These results illustrated the miR-155 mediated FOXO3a expression in pregnant hypertension. CONCLUSIONS: The inhibition of miR-155 improves the damage of pregnant hypertension via the upregulation of FOXO3a, which provides academic leads for the future therapy of pregnant hypertension. PMID- 30402831 TI - Up-regulation of miR-517-5p inhibits ERK/MMP-2 pathway: potential role in preeclampsia. AB - OBJECTIVE: To investigate the potential role of miRNA-517-5p in preeclampsia and its underlying mechanism. MATERIALS AND METHODS: Placenta samples were obtained from 20 women with preeclampsia and 20 women with normal pregnancies. Expression level of miR-517-5p in placenta samples and JAR cells was detected. MiRNA-517-5p mimics or inhibitor was transfected in JAR cells, followed by detection of proliferative and invasive abilities of JAR cells. In addition, the expressions of extracellular regulated protein kinases (ERK), phospho-extracellular regulated protein kinases (p-ERK) and matrix metalloproteinase-2 (MMP-2) in JAR cells were evaluated by Western blot. Meanwhile, the mRNA level of MMP-2 was evaluated by Real-time polymerase chain reaction (PCR). The luciferase assay was applied to identify the target gene of miRNA-517-5p. RESULTS: Increased level of miR-517-5p was detected in placenta samples of preeclampsia patients compared with normal pregnancies. MiRNA-517-5p could regulate proliferative and invasive abilities of JAR cells. Furthermore, miRNA-517-5p could regulate ERK/MMP-2 pathway in JAR cells, which would contribute to the pathophysiology of preeclampsia. The luciferase assay showed MMP-2 was the target gene of miR-517-5p. Further studies showed that MMP-2 was dysregulated in preeclampsia. CONCLUSIONS: MiR-517-5p is highly expressed in placenta samples of preeclampsia pregnancies, which could promote proliferative and invasive abilities of JAR cells by inhibiting ERK/MMP-2 pathway. PMID- 30402832 TI - MicroRNA-210 promotes spinal cord injury recovery by inhibiting inflammation via the JAK-STAT pathway. AB - OBJECTIVE: To investigate the effect of microRNA-210 on the spinal cord injury (SCI) and its underlying mechanism. MATERIALS AND METHODS: The mouse SCI model was established. Mice were randomly assigned into 4 groups, namely the sham operation group (sham group), surgery group (SCI group), surgery+NC group (SCI+NC group) and surgery+microRNA-210 overexpression group (SCI+microRNA-210 mimics group). The mRNA levels of microRNA-210 and the key genes in the JAK-STAT pathway of the four groups were detected by Real-Time Polymerase Chain Reaction (RT-PCR) at different time points. Protein levels of JAK2 and STAT3 in mice of the four groups were detected by Western blot. To investigate the role of microRNA-210 in SCI recovery, changes in the motor function of mice were detected. RESULTS: Grip strengths of right and left forelimbs in mice from the sham group were temporarily decreased at the early stage after surgery, which were gradually recovered to the preoperative levels on the 3rd postoperative day. However, mice in SCI group were unable to complete the grip strength determination at the early stage after surgery. Mice in SCI group were capable of grasping on the 7th postoperative day. Besides, grip strengths of mice in SCI group were remarkably lower than those of sham group until the end-point (on the 50th day). Furthermore, mRNA levels of microRNA-210 in mice of SCI group were decreased in a time-dependent manner (p<0.05). Higher grip strengths were observed in mice of SCI+microRNA-210 mimics group in comparison with those of SCI group and SCI+NC group (p<0.05). In addition, Western blot showed that protein levels of JAK2 and STAT3 in mice of SCI group were increased in a time-dependent manner (p<0.05). Moreover, protein levels of JAK2, STAT3, and MCP-1 in mice of SCI+NC group were remarkably higher than those in the sham group and SCI+microRNA-210 mimics group (p<0.05). CONCLUSIONS: MicroRNA-210 is down-regulated in SCI mice. Grip strengths of SCI mice can be recovered after microRNA-210 overexpression via inhibiting inflammatory response by the JAK-STAT pathway. PMID- 30402833 TI - MiR-124 regulates osteoblast differentiation through GSK-3beta in ankylosing spondylitis. AB - OBJECTIVE: Ankylosing spondylitis (AS) is a spastic and spinal joint disease with the characteristic of pathological ossification. Bioinformatics analysis demonstrated that there is a complementary binding site between microRNA-124 (miR 124) and the 3'-UTR of glycogen synthase kinase-3beta (GSK-3beta) mRNA. We aimed to investigate the role of miR-124 in regulating GSK-3beta expression, Wnt/beta catenin pathway activity, and osteoblast differentiation of spinal ligament fibroblasts. PATIENTS AND METHODS: The ligament tissues of AS and the femoral neck fracture patients were collected. MiR-124 and GSK-3beta mRNA expressions were detected by using quantitative Real-time PCR (qRT-PCR). GSK-3beta and beta catenin protein expressions were detected by using Western blot. Ligament fibroblasts were isolated and induced to differentiate into osteoblasts. Alizarin red S staining (ARS) was used to identify osteoblast differentiation. Expressions of miR-124, GSK-3beta, beta-catenin, Osterix, and runt-related transcription factor 2 (RUNX2) were detected during differentiation. The cells were divided into two groups as agomiR-normal control (NC) transfection group and agomir miR 124 transfection group. Alkaline phosphatase (ALP) activity and Alizarin Red S staining were detected. RESULTS: MiR-124 and beta-catenin expressions in the ligament of AS patients increased, while GSK-3beta level reduced compared with control. MiR-124, beta-catenin, Osterix, and RUNX2 expressions gradually elevated, whereas GSK-3beta level gradually declined following increased osteoblasts differentiation. Antagomir miR-124 transfection significantly up regulated the expression of GSK-3beta in osteoblast differentiation, significantly decreased the expression of beta-catenin, Osterix, and RUNX2, and significantly inhibited osteoblast differentiation. CONCLUSIONS: MiR-124 decreased and GSK-3beta elevated in AS ligament tissue. Down-regulation of miR 124 expression enhanced GSK-3beta expression, weakened Wnt/beta-catenin pathway activity, and inhibited the differentiation of ligament fibroblasts into osteoblasts. PMID- 30402834 TI - CCL3 participates in the development of rheumatoid arthritis by activating AKT. AB - OBJECTIVE: To investigate whether CC chemokine 3 (CCL3) could exert a certain effect on rheumatoid arthritis (RA) by regulating inflammatory responses and provide a new direction for the treatment of RA. PATIENTS AND METHODS: Totally 47 RA patients (10 males and 37 females) with complete clinical data were included. Meanwhile, 27 healthy volunteers with same age and gender were recruited as healthy controls. The mRNA and protein level of CCL3 in the peripheral blood mononuclear cells (PBMCs) of RA patients and normal controls were detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and Western blot, respectively. The inflammatory infiltration of synovial tissue was observed by hematoxylin and eosin (HE) staining. Immune fluorescence was used to further analyze the level of CCL3 in T and B cells of synovial tissue in RA patients. Simultaneously, real-time flow cytometry was applied to detect the level of CCL3 in T and B cells of PBMCs in the normal control group and the RA group. Western blot was used to detect the level of pAKT in RA-FLS treated with different concentrations of recombinant human CCL3. Besides, enzyme-linked immunosorbent assay (ELISA) was applied to detect the levels of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and receptor activator of nuclear factor kappa-B ligand (RANKL) in the culture supernatant of RA-FLS stimulated by different doses of recombinant human CCL3. RESULTS: The level of CCL3 in peripheral blood and synovial fluid of RA patients was markedly higher than that of normal controls. Inflammatory cells were infiltrated in synovial tissue of RA patients. Meanwhile, CCL3 was mainly expressed in CD4+ T cells. CCL3 treatment in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) could activate the PI3K/AKT signaling pathway to different degrees and increase the expression of cytokines including interleukin-6 (IL-6), IL-1beta, TNF-alpha, and RANKL. These results indicated that CCL3 might participate in the progression of RA by activating AKT. CONCLUSIONS: We showed that CCL3 enhanced the expression level of pro-inflammatory cytokines such as IL-6, IL-1beta, TNF-alpha, and RANKL by activating the PI3K/AKT signaling pathway. Besides, CCL3 could up-regulate CD4+T cells to mediate the inflammatory response of RA. These findings might provide new directions for the prevention of RA. PMID- 30402835 TI - Effect of hypoxia on the Twist1 in EMT of cervical cancer cells. AB - OBJECTIVE: To explore the effect of hypoxia on the Twist1 expression in epithelial-mesenchymal transition of the cervical cancer cells. MATERIALS AND METHODS: In this study, we simulated the normoxia and hypoxia environment, where HeLa cells were cultured, respectively. Cell invasion ability was measured by the transwell assay, while the GLI-1 protein and mRNA expressions were measured by Real-time polymerase chain reaction (RT-PCR) and Western blot assays. After that, HeLa cells were transfected with the GLI-1-specific siRNA, followed by the measurement of mRNA and protein expressions using RT-PCR and Western blot assays, as well as the cell invasion ability by the transwell assay. RESULTS: We found that in hypoxic environment, GLI-1 was up-regulated in HeLa cells, with enhanced invasion ability. However, silencing the expression of GLI-1 could reverse the up regulation of GLI-1 compromising the invasion ability of HeLa cells. CONCLUSIONS: Hypoxia may account for the increased invasion of HeLa cells, which is realized by the up-regulated GLI-1. PMID- 30402836 TI - LncRNA HOTAIR participates in the development and progression of adrenocortical carcinoma via regulating cell cycle. AB - OBJECTIVE: To explore the role of HOTAIR in the pathogenesis of adrenocortical carcinoma (ACC) and its underlying mechanism. PATIENTS AND METHODS: Differentially expressed lncRNA (HOTAIR) in ACC was screened out from the GEO database. The survival analysis and ROC curve were performed according to HOTAIR expressions in ACC patients. The correlation between HOTAIR expression and clinical information of ACC patients was analyzed by chi-square test. The univariate and multivariate COX regression analysis was carried out to analyze the relationship between HOTAIR expression, disease-free survival (DFS) and overall survival (OS) of ACC patients. We then detected HOTAIR expression in 77 ACC tissues and 30 normal tissues by qRT-PCR (quantitative Real-time polymerase chain reaction). ACC cell lines were further screened out for the following in vitro experiments. After altering HOTAIR expression in ACC cells by plasmid transfection, proliferation and cell cycle were detected by Cell Counting Kit-8 (CCK-8) and colony formation assay, respectively. Finally, Western blot was utilized to detect expressions of cell cycle-related genes in ACC cells. RESULTS: HOTAIR was overexpressed in ACC tissues than that of normal tissues. HOTAIR expression was remarkably increased in ACC with T3 and T4 stage than that of T1 and T2 stage. Moreover, HOTAIR expression was remarkably increased in ACC with stage III and IV than that of stage I and II. HOTAIR was an independent prognostic factor for DFS and OS of ACC patients. For in vitro experiments, inhibited proliferation and arrested cell cycle were observed in H295R cells transfected with si-HOTAIR. Opposite results were obtained after SW-13 cells were transfected with HOTAIR overexpression plasmid. Furthermore, expressions of cell cycle-related genes, including Cyclin D1, p-Rb and p-GSK3beta were remarkably decreased after HOTAIR knockdown. CONCLUSIONS: We demonstrated for the first time that HOTAIR is overexpressed in ACC and is a prognostic risk factor in ACC patients. HOTAIR participates in the development and progression of ACC via shortening cell cycle and promoting proliferation of ACC cells. PMID- 30402837 TI - MiR-218 promotes apoptosis of U2OS osteosarcoma cells through targeting BIRC5. AB - OBJECTIVE: Baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) is a member of apoptosis inhibition family which suppresses caspase activity. Osteosarcoma tissues have significantly higher BIRC5 and lower microRNA-218 (miR 218) level than adjacent tissues, indicating tumor suppressor role of miR-218 in osteosarcoma. Bioinformatics analysis showed satisfactory targeting correlation between miR-218 and 3'-UTR of BIRC5 mRNA. This study, thus, investigated if dysregulation of miR-218 and BIRC5 affected apoptosis of osteosarcoma cells U2OS. PATIENTS AND METHODS: A total of 42 osteosarcoma patients were collected for tumor and adjacent tissues to compare miR-218 and BIRC5 expressions. Dual luciferase reporter gene assay examined targeted regulation between miR-218 and BIRC5. In vitro cultured U2OS cells were treated with miR-218 mimic and/or si BIRC5. Caspase-3 activity was measured by spectrometry while flow cytometry was used to test cell apoptosis, plus protein expression assay by Western blot assay. RESULTS: Compared to adjacent tissues, osteosarcoma tissues had significantly depressed miR-218 expression and elevated BIRC5 expression (p<0.05). miR-21 targeted 3'-UTR of BIRC5 to suppress its expression. The elevation of miR-218 and/or silencing BIRC5 significantly depressed BRIC5-induced inhibition on caspase-5, and facilitated U2OS cell apoptosis (p<0.05). CONCLUSIONS: We observed that miR-218 was significantly down-regulated in osteosarcoma tissues, which had elevated BIRC5 expression. MiR-218 targeted and inhibited BIRC5 expression, weakened caspase-5 inhibition by BIRC5, and facilitated U2OS osteosarcoma cell apoptosis. PMID- 30402838 TI - ERCC polymorphisms and risk of osteosarcoma: a meta-analysis. AB - OBJECTIVE: The association between excision repair cross-complementation (ERCC) gene family (ERCC1 and ERCC2) and osteosarcoma risk was controversial. The aim of this study was to evaluate the association between ERCC1 or ERCC2 and osteosarcoma risk by systematic meta-analysis. MATERIALS AND METHODS: Relative studies were retrieved from electronic databases without language restriction. The last search was updated on March 2017. Quality assessment was analyzed by the Newcastle-Ottawa Scale (NOS) score, which was recommended by the Agency for Healthcare Research and Quality (AHRQ). Meta-analysis was conducted by R language package (R 3.12). RESULTS: This meta-analysis was performed based on 4 case control studies that included 1208 cases and 2448 controls. The ERCC2-rs1799793 AA+AC > CC (OR=1.3428, 95% CI=1.0201; 1.7674) had an effect on the risk of osteosarcoma development, whereas, there were no significant associations among the other ERCC SNPs (ERCC1 rs3212986, ERCC1 rs11615, and ERCC2 rs13181) and osteosarcoma. CONCLUSIONS: The ERCC2 rs1799793 polymorphism is related to the high risk of osteosarcoma development. PMID- 30402839 TI - MiR-128-3p overexpression sensitizes hepatocellular carcinoma cells to sorafenib induced apoptosis through regulating DJ-1. AB - OBJECTIVE: DJ-1 expression is elevated in a variety of tumors and is related to the survival of tumor cells under adverse stimuli. DJ-1 3'-untranslated region (3'-UTR) contains the target of miR-128-3p, and the expression of miR-128-3p is decreased in hepatoma cells. Therefore, we speculate and address in this study, that miR-128-3p can regulate DJ-1 expression in hepatocellular carcinoma (HCC) and play an important role in HCC cells survival. MATERIALS AND METHODS: MiR-128 3p and DJ-1 expression in HCC cell lines were measured using quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and Western blot analysis. Dual luciferase reporter assay was adopted to confirm the miR-128-3p binding sequences in the 3'-UTR of DJ-1. Sorafenib-induced apoptosis was evaluated by flow cytometry, and the apoptosis-associated proteins were detected by Western blot analysis. Overexpression of miR-128-3p and DJ-1 were achieved via transfection with miR-128-3p mimic and DJ-1 plasmid, respectively. RESULTS: We revealed that miR-128-3p expression was downregulated, while DJ-1 expression was upregulated in HCC cell lines, and DJ-1 expression can be regulated by miR-128-3p via directly binding to it. Moreover, functional assays showed that overexpression of miR-128 3p sensitized HCC cells to sorafenib-induced apoptosis, and this phenomenon was partly abolished by DJ-1. Mechanistically, PTEN/PI3K/Akt signaling pathway was found to participate in the miR-128-3p induced sensitivity to sorafenib via DJ-1. CONCLUSIONS: We conclude that miR-128-3p overexpression sensitized HCC to sorafenib-induced apoptosis via PTEN/PI3K/Akt signaling pathway by regulating DJ 1 expression. PMID- 30402840 TI - The effects of interventional therapy on serum HTATIP2/TIP30, B7-H4 and short term curative effect in primary hepatocellular carcinoma. AB - OBJECTIVE: To explore the effects of interventional therapy on human immunodeficiency virus (HIV)-1 Tat interactive protein 2/Tat interactive protein 30 (HTATIP2/TIP30), B7-H4 and short-term curative effect in primary hepatocellular carcinoma. PATIENTS AND METHODS: 62 patients with primary hepatocellular carcinoma admitted in our hospital from June 2015 to June 2016 were enrolled in this study and divided into observation group (n = 31) and control group (n = 31) according to the random number table. The patients in the control group were treated with radiofrequency ablation, and the patients in the observation group were treated with transcatheter arterial chemoembolization (TACE). The patients in both groups received liver protection therapy, hydration, antiemetic and stomach protection. The curative effects, the serum HTATIP2/TIP30, B7-H4, alanine aminotransferase (ALT) and total bilirubin in serum (TBIL), life quality before and after treatment, and survival during the 1-year follow-up, were compared. RESULTS: The total short-term effective rate (70.97%) was higher than the control group (38.71%) (p < 0.05). The serum levels of HTATIP2/TIP30 and B7-H4 were decreased after treatment in both groups (observation group: t = 17.1838, 18.9795, control group: t = 8.3787, 10.6393, p < 0.05). The serum levels of HTATIP2/TIP30 and B7-H4 after treatment in the observation group were lower than the control group (t = 12.2975, 10.5361, p < 0.05). The levels of ALT and TBIL were decreased after treatment (observation group: t = 15.1716, 34.5771, control group: t = 8.3374, 17.3015, p < 0.05). The levels of ALT and TBIL were lower in the observation groups than the control group (t = 15.2697, 16.8592, p < 0.05). The improvement rate of life quality in the observation group (80.65%) was higher than the control group (54.84%) (p < 0.05). The survival rates of the two groups after 1-year follow-up were not statistically different (p > 0.05). CONCLUSIONS: The short-term curative effect of interventional therapy of primary hepatocellular carcinoma is good. It can decrease serum HTATIP2/TIP30 and B7-H4, improves the liver function and the life quality of patients, prolonging the survival time. It has a high research value and it is worthy of further application. PMID- 30402841 TI - lncRNA HOXB-AS3 promotes hepatoma by inhibiting p53 expression. AB - OBJECTIVE: We investigate the mechanism of HOXB-AS3 in promoting the development of hepatocellular carcinoma. PATIENTS AND METHODS: The expression of HOXB-AS3 in tumor tissues and adjacent tissues of hepatocellular carcinoma was detected by quantitative real time-polymerase chain reaction (qRT-PCR), and the relationship between the expression of HOXB-AS3 and tumor tissues was analyzed. The effects of HOXB-AS3 and p53 on cell proliferation, cell cycle and apoptosis were detected by plate cloning experiment and flow cytometry. The binding relationship between HOXB-AS3 and DNMT1 and the regulation mechanism of DNMT1 on p53 were tested by RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) experiments, respectively. Western blot was used to detect the expression of p53 after knockdown of HOXB-AS3. The torsion experiment was performed to assess whether HOXB-AS3 regulated the proliferation and apoptosis of hepatoma cells by inhibiting p53 expression. RESULTS: The results of qRT-PCR showed that the expression of HOXB-AS3 was significantly higher in cancerous tissues of patients with hepatocellular carcinoma than in adjacent tissues. The expression of HOXB AS3 in patients in stage III and IV was significantly higher than that in stage I and II. Inhibition of HOXB-AS3 expression in liver cancer cells including Hep3B and LM3 could promote cell proliferation, inhibit cell apoptosis and induce cell cycle arrest in the G0/G1 phase. The results of RIP and ChIP experiments showed that HOXB-AS3 inhibited the expression of p53 by binding to DNMT1, and overexpression of p53 in Hep3B cells could partially reverse the changes in cell proliferation and apoptosis induced by HOXB-AS3. CONCLUSIONS: Highly expressed HOXB-AS3 was confirmed to promote the proliferation of hepatocellular carcinoma cells and inhibit apoptosis, and the mechanism was related to the regulation role of HOXB-AS3 in p53 expression by binding to DNMT1. PMID- 30402842 TI - Increasing miR-150 and lowering HMGA2 inhibit proliferation and cycle progression of colon cancer in SW480 cells. AB - OBJECTIVE: High mobility group protein A2 (HMGA2) is a kind of oncogene that regulates cell proliferation and cycle. HMGA2 up-regulation is related to the occurrence of multiple tumors including colorectal cancer. MiR-150 is found down regulated in colorectal cancer tissue. Bioinformatics analysis shows the complementary targeted relationship between miR-150 and the 3'-UTR of HMGA2. This study explores the role of microRNA-150 (miR-150) in regulating HMGA2 expression, colorectal cancer cell proliferation, and cycle. PATIENTS AND METHODS: Colorectal cancer patients were enrolled to collect cancer and para-carcinoma tissues. MiR 150 and HMGA2 expressions were tested in tissue. MiR-150, HMGA2, and Cyclin A levels in colorectal cancer cell line SW480, and normal colorectal epithelial cell line FHC were compared. The targeted relationship between miR-150 and the 3' UTR of HMGA2 was evaluated by dual luciferase reporter gene assay. SW480 cells were divided into five groups, including miR-control, miR-150 mimic, small interfere normal control (si-NC), si-HMGA2, and miR-150 mimic + si-HMGA2. Cell cycle was determined by using flow cytometry. The cell proliferation was detected by using the cell counting kit 8 (CCK-8) test. RESULTS: HMGA2 expression was significantly increased, while miR-150 levels were significantly declined in colorectal cancer tissue compared with that in para-carcinoma tissue (p<0.05). HMGA2 and Cyclin A levels were higher significantly, whereas miR-150 expression was lower significantly in SW480 cells compared to that in FHC cells (p<0.05). MiR-150 targeted band to the 3'-UTR of HMGA. MiR-150 mimic and/or si-HMGA2 significantly reduced HMGA2 and Cyclin A expressions, blocked cell cycle in the G0/G1 phase, and attenuated cell proliferation. CONCLUSIONS: We observed that miR 150 down-regulated Cyclin A expression to block colorectal cancer cell cycle and inhibit proliferation through targeted inhibiting HMGA2. PMID- 30402843 TI - Increased EWSAT1 expression promotes cell proliferation, invasion and epithelial mesenchymal transition in colorectal cancer. AB - OBJECTIVE: Long non-coding RNAs (lncRNAs) have recently been identified as crucial regulators in colorectal cancer (CRC) progression. The aim of the study is to investigate the clinical role and biological effects of long non-coding RNA EWSAT1 in CRC. PATIENTS AND METHODS: The expression of lncRNA EWSAT1 was detected in 106 cases of fresh CRC tissues and matched adjacent normal tissues by qRT-PCR analyses. The Kaplan-Meier analysis and log-rank test were used to assess the association between lncRNA EWSAT1 expression and overall survival (OS) rate of CRC patients. Cell proliferation and invasion capacity were evaluated by CCK8 assay, colony formation, and transwell invasion assays. The protein expression was detected using western blot analysis. RESULTS: LncRNA EWSAT1 expression was abnormally higher in CRC tissues compared to matched adjacent normal tissues. Higher lncRNA EWSAT1 expression significantly associated with depth of invasion, lymph node metastasis, and advanced tumor-node-metastasis (TNM) stage in CRC patients. Patients with higher EWSAT1 expression exhibited shorter OS compared with patients with lower EWSAT1 expression. Furthermore, lncRNA EWSAT1 knockdown significantly suppressed cell proliferation and invasion in CRC. In addition, lncRNA EWSAT1 knockdown suppressed cell epithelial-mesenchymal transition (EMT) through reducing Snail1, Snail2, and N-cadherin expression, but increasing E cadherin expression in CRC cells. CONCLUSIONS: Downregulation of lncRNA EWSAT1 suppressed cell proliferation and invasion of CRC, which indicated that EWSAT1 may be a potential target of CRC treatment. PMID- 30402844 TI - GLI-1 facilitates the EMT induced by TGF-beta1 in gastric cancer. AB - OBJECTIVE: To explore how GLI-1 affects the EMT induced by TGF-beta1 in gastric cancer. MATERIALS AND METHODS: Following 24 hours of culture of SGC-7901 cells in presence of TGF-beta1, we observed the changes in morphology as well as mRNA and protein expressions of GLI-1, E-cadherin and Vimentin by RT-PCR and Western blot. Transwell assay was conducted to evaluate the changes in invasion ability of SGC 7901 cells. Then, SGC-7901 cells were co-treated with TGF-beta1 and GANT 61, and changes of the above indexes were also detected using the corresponding methods. RESULTS: In presence of TGF-beta1, EMT was initiated in SGC-7901 cells EMT with increased cell invasion ability, and the mRNA and protein expressions of E cadherin were downregulated, while those of the GLI-1 and Vimentin were upregulated. Conversely, the co-treatment of TGF-beta1 and GANT 61 suppressed the increased cell invasion ability induced only by TGF-beta1, and the changes in mRNA and protein expressions of these factors were abolished. CONCLUSIONS: We found that GLI-1 facilitates the EMT induced by TGF-beta1 in SGC-7901 cells, which may serve as a potential target in developing the clinical treatment of gastric cancer. PMID- 30402845 TI - MicroRNA-556-3p promotes the progression of esophageal cancer via targeting DAB2IP. AB - OBJECTIVE: To detect the expression of microRNA-556-3p in esophageal cancer (EC) tissues and to elucidate the mechanisms underlying microRNA-556-3p in promoting EC progression. PATIENTS AND METHODS: QRT-PCR (quantitative Real-Time Polymerase Chain Reaction) was performed to detect microRNA-556-3p expression in 65 cases of EC tissues, 30 cases of normal esophageal tissues and EC cell lines. The overall survival (OS) of EC patients was calculated based on the 10-year follow-up data. For in vitro experiments, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) and transwell assay were performed to evaluate the effect of microRNA-556-3p on the proliferative and invasive abilities of EC cells. The effect of microRNA-556-3p on DAB2IP and MAPK pathway was determined by Western blot and qRT-PCR. The binding condition between microRNA-556-3p and DAB2IP was further confirmed by Luciferase reporter gene assay. RESULTS: MicroRNA-556-3p expression was upregulated in EC tissues than that of paracancerous tissues. EC patients with higher expression of microRNA-556-3p presented a shorter OS than those with lower expression. Moreover, microRNA-556-3p overexpression in EC cells remarkably promoted cell viability. Upregulated microRNA-556-3p in Eca109 and Eca7906 cell lines markedly increased cell proliferation and invasion. The expression level of DAB2IP was negatively regulated by microRNA-556-3p verified by the Luciferase reporter gene assay. CONCLUSIONS: MicroRNA-556-3p blocked the translation of DAB2IP at mRNA level by directly binding to 3'UTR of DAB2IP, thereafter enhancing the proliferation of Eca109 and Eca7906 cells. MicroRNA-556 3p promoted the occurrence and development of EC. Our study provided a new theoretical basis and therapeutic target for EC treatment. PMID- 30402846 TI - LncRNA-NEF inhibits proliferation, migration and invasion of esophageal squamous cell carcinoma cells by inactivating wnt/beta-catenin pathway. AB - OBJECTIVE: Our study aimed to investigate the role of lncRNA-Neighboring Enhancer of FOXA2 (NEF) in esophageal squamous-cell carcinoma. PATIENTS AND METHODS: Tumor tissues and adjacent tissues were obtained from esophageal squamous-cell carcinoma patients, and blood samples were extracted from both patients with esophageal squamous-cell carcinoma and healthy volunteers. The expression of NEF was detected by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). All patients were followed-up for 5 years and ROC curve analysis and survival analysis were performed to evaluate the diagnostic and prognostic values of serum NEF for esophageal squamous-cell carcinoma. NEF expression vector was transfected into cells of esophageal squamous-cell carcinoma cell lines. Cell proliferation, migration and invasion were detected by CCK-8 assay, transwell migration assay, and transwell invasion assay, respectively. The interaction between NEF and wnt/beta-catenin pathway were explored by Western blot and qRT-PCR. RESULTS: Expression of NEF was significantly downregulated in tumor tissues than in adjacent tissues in most patients. Serum level of NEF was higher in esophageal squamous-cell carcinoma patients than in healthy controls, and was significantly correlated with tumor size and tumor distant tumor metastasis. Serum NEF is a promising diagnostic and prognostic marker for esophageal squamous-cell carcinoma. NEF overexpression inhibited cancer cell proliferation, migration and invasion. NEF overexpression decreased the expression levels of wnt/beta-catenin pathway-related proteins, while Wnt activator showed no significant effects on NEF. However, Wnt inhibitor reduced the effects of NEF overexpression on cell proliferation, migration and invasion. CONCLUSIONS: LncRNA NEF may inhibit the proliferation, migration and invasion of esophageal squamous-cell carcinoma cells by inactivating with wnt/beta-catenin pathway. PMID- 30402847 TI - HIF-1alpha restricts proliferation and apoptosis of Tca8113 cells through up regulation of Hippo signaling pathway under hypoxic conditions. AB - OBJECTIVE: The hypoxia-inducible factor-1alpha (HIF-1alpha) is a key factor for tumor cells adaptation to hypoxia. Studies have shown that under hypoxic conditions, HIF-1alpha expression was significantly increased in human tongue squamous cell carcinoma cells (Tca8113). This research aims to determine the exact mechanism of HIF-1alpha on the proliferation and apoptosis of Tca8113 cells. MATERIALS AND METHODS: Tca8113 cells were cultured under normoxia and hypoxia. Real Time-PCR and Western blot were used to measure the expression levels of HIF-1alpha and TAZ. Under hypoxic condition, HIF-1alpha siRNA was transfected into Tca8113 cells. CCK8 was used to measure the proliferation of Tca8113 cells. Flow cytometry was used to detect apoptosis of Tca8113 cells. RESULTS: Under hypoxic condition, the expression levels of HIF-1alpha and TAZ at both mRNA and protein levels were significantly increased (p <0.05). The downregulation of HIF-1alpha by siRNA significantly inhibited Tca8113 cells proliferation, increased their apoptosis, and reduced the expression level of TAZ. CONCLUSIONS: Under hypoxic conditions, HIF-1alpha inhibits the proliferation and apoptosis of Tca8113 cells via the elevation of the Hippo signaling pathway. PMID- 30402848 TI - LncRNA SNHG15 promotes proliferation and migration of lung cancer via targeting microRNA-211-3p. AB - OBJECTIVE: To investigate whether lncRNA (long non-coding RNA) SNHG15 could regulate the proliferation and migration of lung cancer via microRNA-211-3p and its underlying mechanism. PATIENTS AND METHODS: SNHG15 expression in 55 LC (lung cancer) tissues and 30 normal lung tissues was detected by qRT-PCR (quantitative Real Time-Polymerase Chain Reaction). The relationship between SNHG15 expression and pathological characteristics of LC patients was analyzed the by Kaplan-Meier method. The target microRNA of SNHG15 was predicted by bioinformatics and verified by dual-luciferase reporter gene assay. Viability, cell cycle and migration of LC cells after altering expressions of SNHG15 or microRNA-211-3p were detected by cell counting kit-8 (CCK-8), flow cytometry and transwell assay, respectively. RESULTS: SNHG15 was highly expressed in LC tissues than that of normal lung tissues. Besides, LC patients with stage I-II presented lower expression of SNHG15 than those with stage III-IV. SNHG15 expression was correlated to tumor size, TNM stage, and lymph node metastasis, whereas not correlated to age and sex of LC patients. For in vitro studies, SNHG15 knockdown resulted in viability reduction, cell cycle arrest and reduced migration of LC cells, which were reversed by the microRNA-211-3p knockdown. CONCLUSIONS: SNHG15 is highly expressed in LC tissues, which promotes the occurrence and progression of LC via regulating proliferation and migration of LC cells by targeting microRNA-211-3p. PMID- 30402849 TI - MiR-24 promotes the proliferation and apoptosis of lung carcinoma via targeting MAPK7. AB - OBJECTIVE: To explore the role of microRNA-24 (miR-24) in the proliferation and apoptosis of lung carcinoma, and to investigate its underlying mechanism. PATIENTS AND METHODS: The expression level of miR-24 in 50 pairs of lung carcinoma tissues and para-cancerous tissues was detected by quantitative Real time polymerase chain reaction (qRT-PCR). The relationship between miR-24 expression and pathological indicators of lung carcinoma was analyzed. Meanwhile, the corresponding plasmids of miR-24 were constructed. The viability, proliferation, apoptosis and cell cycle of lung carcinoma cells after transfection with miR-24 plasmids were detected by cell counting kit-8 (CCK-8), colony formation assay, and flow cytometry, respectively. The binding condition of miR-24 and MAPK7 was predicted by bioinformatics and verified by Luciferase reporter gene assay. The regulatory effect of miR-24 on MAPK7 in lung carcinoma cells was further detected. RESULTS: MiR-24 was significantly overexpressed in lung carcinoma tissues than that of para-cancerous tissues. Compared with lung carcinoma patients with Grade I-II and tumor size smaller than 3 cm, upregulated miR-24 expression was observed in those with Grade III-IV and tumor size larger than 3 cm. The overall survival (OS) of patients with higher miR-24 expression was remarkably shorter than those with lower expression. Results of clinical data analysis suggested that miR-24 expression was correlated with tumor size and tumor node metastasis (TNM), whereas not correlated with age, gender and lymph node metastasis. In vitro experiments demonstrated that miR-24 overexpression promoted the viability, proliferation and cell cycle of lung carcinoma cells, whereas inhibited cell apoptosis. Furthermore, luciferase reporter gene assay indicated that miR-24 could bind to MAPK7. Meanwhile, overexpressed miR-24 resulted in decreased mRNA and protein levels of MAPK7. In addition, decreased apoptosis and increased cell cycle induced by miR-24 overexpression could be partially reversed by MAPK7 overexpression. CONCLUSIONS: We found that miR-24 promoted lung carcinoma development by increasing cell proliferation and inhibiting cell apoptosis via targeting MAPK7. PMID- 30402850 TI - Increased HSPG2 expression independently predicts poor survival in patients with oligoastrocytoma and oligodendroglioma. AB - OBJECTIVE: Perlecan, which is also called heparan sulfate proteoglycan 2 (HSPG2), is a protein encoded by the HSPG2 gene that maps to 1p36.12 in the human genome. In this study, we assessed the independent prognostic value of HSPG2 in terms of overall survival (OS) and recurrence-free survival (RFS) in patients with LGG. PATIENTS AND METHODS: A retrospective study was conducted by using data in the Cancer Genome Atlas-Low Grade Glioma (TCGA-LGG). RESULTS: Increased HSPG2 expression was an independent prognostic indicator of poor OS in oligoastrocytoma (HR: 1.644, 95% CI: 1.116-2.423, p = 0.012) and in oligodendroglioma (HR: 1.459, 95% CI: 1.138-1.871, p = 0.003). In addition, increased HSPG2 expression independently predicted poor RFS in oligodendroglioma (HR: 1.402, 95% CI: 1.110 1.770, p = 0.005). Furthermore, we observed that high HSPG2 expression was associated with significantly shorter OS and RFS in oligodendroglioma, no matter the patients received radiotherapy or not. Using copy number alterations (CNAs) and DNA methylation data in TCGA-LGG, we found that DNA copy deletion was generally associated with decreased HSPG2 expression. Regression analysis suggested a weak negative correlation between HSPG2 expression and HSPG2 DNA methylation (Pearson's r = -0.388). CONCLUSIONS: Increased HSPG2 expression could independently predict poor OS in oligoastrocytoma and oligodendroglioma and also independently predicted poor RFS in oligodendroglioma. Its expression is modulated by both DNA copy number and DNA methylation in oligodendroglioma. PMID- 30402851 TI - Regulation of mTOR by miR-107 to facilitate glioma cell apoptosis and to enhance cisplatin sensitivity. AB - OBJECTIVE: The aberrant increasing expression of mammalian target of rapamycin (mTOR) participates in tumor occurrence and drug resistance. It has been found elevation of mTOR expression but reducing miR-107 expression in glioma tissues. Thus, we investigated the regulatory role of miR-107 on mTOR expression as well as glioma cell proliferation, apoptosis and cisplatin (DDP) resistance. PATIENTS AND METHODS: Dual luciferase reporter gene assay was applied to confirm targeted regulation between miR-107 and mTOR. Tumor tissues were collected from glioma patients, in parallel with normal tissues after brain contusion surgery. Expressions of miR-107, mTOR and p-mTOR were compared. DDP-resistant cell line U251/DPP was generated. U251/DPP cells were further treated with miR-107 mimic or si-mTOR to examine the change of miR-107, mTOR, p-mTOR and survivin levels. Flow cytometry was used to quantify the effect of DDP treatment on cell proliferation or apoptosis. RESULTS: Bioinformatics analysis revealed complementary binding sites between miR-107 and 3'-UTR of mTOR mRNA. Dual luciferase assay confirmed targeted regulation between miR-107 and mTOR. Compared to control group, in glioma tissues, mTOR and p-mTOR expressions were significantly elevated, while the level of miR-107 expression was markedly decreased. Of note, U251/DDP cells presented weakened apoptosis compared to U251 cells, with high levels of mTOR, p mTOR and survivin and reduction of miR-107 expression. However, the transfection of miR-107 mimic and/or si-mTOR remarkably suppressed expressions of mTOR, p-mTOR and survivin in U251/DPP cells, weakened cell proliferation and enhanced apoptosis. CONCLUSIONS: We demonstrated that the level of miR-107 was correlated with DDP resistance in glioma cells. Over-expression of miR-107 decreased DPP resistance of glioma cells via inhibition of mTOR, which provides academic basis for the future anti-glioma therapy. PMID- 30402852 TI - MiR-126 induces myeloma cell line Karpas707 apoptosis by downregulating anti apoptotic protein MCL. AB - OBJECTIVE: Myeloma seriously threats human life and health and needs more efficacy treatment method in the clinic. MiR-126 regulates cell proliferation and apoptosis. This study explores the regulatory role of miR-126 in myeloma and related molecular mechanism. MATERIALS AND METHODS: MiR-126 and control were synthesized and transfected to myeloma cell line Karpas707 using Lipofectamine. Cell apoptosis was evaluated by MTT assay, caspase-3 activity detection, and flow cytometry. Myeloid cell leukemin (MCL) siRNA and plasmid were transfected to Karpas707 cells to test its impact on cell apoptosis. RESULTS: MTT assay revealed that miR-126 significantly restrained Karpas707 cell growth (p=0.0017). Cell apoptosis detection showed that miR-126 significantly promoted phosphatidylserine eversion and caspase-3 activation (p=0.031), and downregulated MCL level (p=0.017). MCL siRNA markedly enhanced Karpas707 cell apoptosis induced by miR 126 (p=0.024), while the MCL overexpression apparently inhibited Karpas707 cell apoptosis induced by miR-126 (p=0.0073). CONCLUSIONS: MiR-126 induces Karpas707 cell apoptosis by downregulating anti-apoptotic protein MCL, which provides a theoretical basis for the target selection of myeloma. PMID- 30402853 TI - Sirtuin 6 promotes cell aging of myeloma cell line KM-HM_(31) by via Hippo signal pathway. AB - OBJECTIVE: Myeloma poses a serious risk for people's health and life quality. Molecular targeted treatment of myeloma emerges as a promising therapy. This study aimed to determine the effect of Sirtuin 6 on myeloma KM-HM_(31) cell aging and provide evidence for clinical treatment. MATERIALS AND METHODS: Myeloma KM HM_(31) cell aging model induced by Carbamide peroxide (CP) was generated. Cells were transfected with Sirtuin 6 over-expression plasmid and specific siRNA. Western blot was used to study Sirtuin 6 expression, P53, P16, and Hippo in KM HM_(31) cells. beta-galactosidase assay was applied to measure cell aging. Verteporfin inhibited Hippo signal pathway and measured aging of KM-HM_(31) cells. RESULTS: The levels of Sirtuin 6, aging protein P53, and P16 were remarkably elevated while Hippo expression was significantly inhibited in CP induced KM-HM_(31) cells. Transfection of Sirtuin 6 over-expression plasmid enhanced Sirtuin 6 expression in KM-HM_(31) cells and potentiated cell aging with downregulation of Hippo protein. In contrast, a block of Sirtuin 6 resulted in the opposite effect. Moreover, Verteporfin inhibited Hippo signal pathway and enhanced CP-induced KM-HM_(31) cell aging, which contributed similar effect as Sirtuin 6 did. CONCLUSIONS: We showed that sirtuin 6 facilitates CP-induced myeloma cell KM-HM_(31) aging via suppressing Hippo. PMID- 30402854 TI - Application of minimal residual disease monitoring in pediatric patients with acute lymphoblastic leukemia. AB - Acute lymphoblastic leukemia (ALL) is a malignant neoplastic disease characterized by abnormal hyperplasia of immature lymphatic cells and has become the most common tumor in children. Although the efficacy of acute lymphoblastic leukemia in children was significantly increased with the adjustment of chemotherapy regimen, there were still a few patients who failed in treatment. The main reasons were relapse and drug resistance. Minimal residual disease (MRD) refers to a state in which there remain traces of leukemia cells that could not be detected using morphological methods in leukemia patients who are in complete remission after receiving the induction chemotherapy or bone marrow transplantation, which is considered to be the main cause of recurrence. The most commonly used methods for detection of MRD include flow cytometry (FCM), real time quantitative polymerase chain reaction (RQ-PCR) and next-generation sequencing (NGS). MRD evaluation plays an important role in evaluating prognosis, predicting recurrence, guiding risk stratify and individualized therapy for children with ALL. In this paper, we reviewed the progresses in major detection methods for MRD that have been made in the clinical application of pediatric ALL. PMID- 30402855 TI - Nrf2-ARE signaling pathway regulates the expressions of A1R and ENT1 in the brain of epileptic rats. AB - OBJECTIVE: To explore the behavioral changes and the expressions of the A1 receptor (A1R) and balanced nucleoside transporter-1 (ENT1) in the brain of epileptic rats after activating the NF-E2-related factor 2 (Nrf2)-ARE signaling pathway. MATERIALS AND METHODS: Adult male Sprague-Dawley (SD) rats were randomly divided into normal control group, epilepsy group, and t-butylhydroquinone (tBHQ) group, with 10 rats in each group. Lithium-pilocarpine induced epilepsy model in rats was established. The first epileptic latency and seizure frequency within 1 hour were observed in each group using the Racine scoring system. HE (Hematoxylin and Eosin) staining was used to observe the pathological lesions in the brain tissue of each group. The expressions of A1R, ENT1, and relative genes in Nrf2 ARE pathway in rat hippocampus was detected by immunohistochemistry and Western blot. RESULTS: Compared with rats in epileptic group, the first seizure latency was prolonged and the seizure frequency decreased in tBHQ group (p<0.05). The degree of brain lesions in tHBQ group was lighter than that of epilepsy group. ENT1 expression in rat hippocampus of epileptic group was significantly upregulated than that of normal control group and tBHQ group. Besides, the protein levels of A1R, Nrf2, HO-1, and ARE in rat hippocampus of epilepsy group markedly decreased compared with those of normal control group. However, protein expressions of A1R, Nrf2, HO-1, and ARE proteins in rat hippocampus of tBHQ group were markedly upregulated. CONCLUSIONS: Activation of the Nrf2-ARE signaling pathway can reduce the pathological damage of rat hippocampal neurons, prolong the latency of seizures, and reduce the degree of epileptic seizure in rats. PMID- 30402856 TI - PVT1 protects diabetic peripheral neuropathy via PI3K/AKT pathway. AB - OBJECTIVE: To investigate whether Plasmacytoma Variant Translocation 1 (PVT1) could regulate the occurrence and progression of diabetic peripheral neuropathy (DPN) via activating the PI3K/AKT pathway. MATERIALS AND METHODS: Diabetes model in rats was constructed by streptozotocin (STZ) injection. PVT1 expression in diabetic rats and control rats was detected by quantitative real time-polymerase chain reaction (qRT-PCR). Rats were injected with PVT1 overexpression lentivirus or vector, respectively, followed by determination of mechanical withdrawal threshold (MWT), thermal withdrawal latency (TWL) and sensory nerve conduction velocity (SNCV). Cell apoptosis of dorsal root ganglia (DRG) was accessed by TUNEL. Western blot was performed to detect the expressions of neurodegeneration related genes and neurogenesis-related genes. The regulatory effect of PVT1 on the PI3K/AKT pathway was detected by Western blot. RESULTS: PVT1 was downregulated in diabetic rats compared with that of controls. Diabetic rats presented higher MWT, TWL and SNCV. Cell apoptosis of DRG was pronounced in diabetic rats. The amount of inflammation-related glial cells increased in diabetic rats. PVT1 overexpression remarkably decreased MWT and TWL. PVT1 downregulated expressions of neurodegeneration-related genes and upregulated neurogenesis-related genes. Western blot results suggested that PI3K/AKT pathway in diabetic rats was blocked, which was reversed by PVT1 overexpression. CONCLUSIONS: PVT1 is lowly expressed in diabetic rats, leading to decreased mechanical withdrawal threshold, thermal withdrawal latency and sensory nerve conduction velocity. PVT1 protects diabetic peripheral neuropathy via PI3K/AKT pathway. PMID- 30402857 TI - HOXA11-AS regulates diabetic arteriosclerosis-related inflammation via PI3K/AKT pathway. AB - OBJECTIVE: This study aims to explore whether homeobox A11 antisense RNA (HOXA11 AS) could regulate inflammation induced by diabetic arteriosclerosis (DAA) via PI3K/AKT pathway. PATIENTS AND METHODS: Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was used to detect expressions of HOXA11-AS and proinflammatory genes in carotid endarterectomy samples of symptomatic and asymptomatic atherosclerosis (AS) patients, diabetes mellitus (DM), and non-DM patients. The above-mentioned genes in DM animal model and non-DM animal model were also detected. We detected the expression of HOXA11-AS in vascular smooth muscle cells (VSMCs) treated with platelet-derived growth factor (PDGF) or PDGF inhibitor imatinib, respectively. Subsequently, we applied cell transfection technology to interfere with the expression of HOXA11-AS in VSMCs. In vascular endothelial cells (VECs) and VSMCs, we detected the effect of HOXA11-AS on the expressions of genes related to the proliferation, migration, and cell cycle. Then, VSMCs were treated with tumor necrosis factor-alpha (TNF-alpha), and the expression of HOXA11-AS was examined in VSMCs. The effect of HOXA11-AS on TNF alpha-induced inflammation in VSMCs was detected as well. Finally, we analyzed the effect of HOXA11-AS on PDGF-induced activation of PI3K/AKT pathway in VSMCs and VECs. RESULTS: HOXA11-AS expression was markedly increased in carotid endarterectomy specimens of symptomatic AS patients compared to that of asymptomatic AS patients. Expression levels of HOXA11-AS and pro-inflammatory genes were significantly elevated in carotid endarterectomy specimens of DM patients. Similarly, HOXA11-AS expression was also significantly increased in carotid arteries of DM mice compared with that of non-DM mice. PDGF could upregulate HOXA11-AS expression in VSMCs, which was reversed by PDGF inhibitor imatinib. HOXA11-AS knockdown could reduce the expressions of the proliferation associated gene (PCNA) and the cycle-related genes (p21, p53), and also inhibited the proliferation and migration of VSMCs induced by PDGF. HOXA11-AS was upregulated by TNF-alpha. HOXA11-AS knockdown remarkably downregulated expressions of inflammation-related genes in VSMCs induced by TNF-alpha. In VECs, low expression of HOXA11-AS can inhibit the expression of TNF-alpha-induced pro inflammatory genes and PDGF-induced vascular inflammation-related genes. Low expression of HOXA11-AS inhibited PDGF-induced activation of PI3K/AKT pathway in VSMCs and VECs. CONCLUSIONS: HOXA11-AS may participate in DAA by activating the PI3K/AKT pathway to regulate inflammation in VSMCs and VECs. PMID- 30402858 TI - TUG1 promotes diabetic atherosclerosis by regulating proliferation of endothelial cells via Wnt pathway. AB - OBJECTIVE: To explore the specific role of TUG1 in regulating the occurrence and progression of diabetic atherosclerosis and its underlying mechanism. PATIENTS AND METHODS: TUG1 expressions in coronary artery disease (CAD) tissues, normal arterial tissues, endothelial cells induced by high-dose glucose and tumor necrosis factor-alpha (TNF-alpha) were detected by quantitative Real-time polymerase chain reaction (qRT-PCR). The effects of TUG1 on proliferation, migration and cell cycle of human umbilical vein endothelial cells (HUVECs) were detected by cell counting kit-8 (CCK-8), transwell assay and flow cytometry, respectively. Subsequently, protein expressions of proliferation-related genes, cell cycle-related genes and Wnt pathway-related genes were detected by Western blot after altering TUG1 expression in HUVECs. Further rescue experiments were carried out to explore whether TUG1 could regulate diabetic atherosclerosis via Wnt pathway. RESULTS: Overexpressed TUG1 was found in CAD tissues and endothelial cells induced by high-dose glucose and TNF-alpha compared with those of controls. TUG1 overexpression remarkably promoted proliferation, migration and cell cycle of HUVECs. Protein expressions of beta-catenin and c-Myc were upregulated by overexpression of TUG1. Rescue experiments indicated that XAV-939, the inhibitor of Wnt pathway, could partially reverse the increased proliferative and migratory changes in HUVECs induced by TUG1 overexpression. CONCLUSIONS: We found that overexpressed TUG1 stimulates proliferation and migration of endothelial cells via Wnt pathway, thereby promoting the occurrence and progression of diabetic atherosclerosis. PMID- 30402859 TI - Obesity in the European region: social aspects, epidemiology and preventive strategies. AB - Obesity related to metabolic syndrome is gaining an increasing importance as the main risk factor for diseases and disability in the European region. We herein review the increasing trend of obesity and overweight in males and females from Europe, preventive programs addressed to children, youngsters, adult population and subjects with particular diseases which can profit from healthy nutrition. The main feature is that some European countries have implemented programs on World Health Organization (WHO) proposals, while some others have focused attention only on some aspects. Based on the reported obesity increase over the last twenty years, prevention programs seem to have been ineffective. Most likely, the effects will be observed later on. In this concern, it will be fundamental to continue and finance the countries of the European region, where those programs have been extensively applied, to obtain even better results in terms of obesity prevention. PMID- 30402860 TI - Long non-coding RNA expression profile in permanent atrial fibrillation patients with rheumatic heart disease. AB - OBJECTIVE: Atrial fibrillation (AF) is the most common type of arrhythmia, especially in rheumatic heart disease (RHD) patients. The differences in structural remodeling and electrical remodeling between the left and right atrium associated with AF in RHD patients are well known, and alterations in the expression profiles of long noncoding RNAs (lncRNAs) in the left atrium have also been investigated. However, the role of lncRNAs in the right atrium (RA) remains largely unknown. PATIENTS AND METHODS: We identified differentially expressed lncRNAs in RA tissues of RHD patients with AF or a normal sinus rhythm (NSR) using microarray analysis. Then, we performed gene ontology (GO) and KEGG pathway analyses for functional annotation of the deregulated lncRNAs. Finally, we constructed a lncRNA-mRNA co-expression network. RESULTS: Of the 22,829 human non coding RNAs analyzed, a total of 1,909 long non-coding RNAs were detected. A total of 182 lncRNAs (117 downregulated and 65 upregulated) were shown to be differentially expressed (fold-change > 1.5) in AF patients compared with NSR patients. Many lncRNAs might be partially involved in an AF-related pathway. CONCLUSIONS: AF dysregulates the expression of lncRNAs in the RA of RHD patients. These findings may be useful for exploring potential therapeutic treatments for AF in RHD patients. PMID- 30402861 TI - Homocysteine induced oxidative stress in human umbilical vein endothelial cells via regulating methylation of SORBS1. AB - OBJECTIVE: The aim of the present study was to investigate the mechanism of homocysteine (Hcy) induced oxidative stress in the human umbilical vein endothelial cells (HUVECs). PATIENTS AND METHODS: The HUVECs were isolated from umbilical vein vascular wall of 12 patients and treated with Hcy. The malondialdehyde (MDA) level was measured using the thiobarbituric acid (TBA) method. The expressions of superoxide dismutase 2 (SOD2), endothelial nitric oxide synthase (eNOS), and intercellular adhesion molecule 1 (ICAM-1) were detected by Western blot and RT-PCR. The genome-wide DNA methylation assay was performed using the Infinium Human Methylation 450 BeadChip. The specific DNA methylation was determined using bisulfite sequencing analysis. To evaluate the role of sorbin and SH3 domain-containing protein 1 (SORBS1), the HUVECs were transfected with small interfere RNA (siRNA) targeting SORBS1 (SORBS1-siRNA). RESULTS: Hcy induced MDA level in HUVECs, and increased ICAM-1 expression both in protein and mRNA levels. The protein and mRNA levels of SOD2 and eNOS were inhibited by Hcy induction. However, the effects of Hcy on MDA level and expressions of SOD2, eNOS, and ICAM-1 were attenuated by folic acid (Fc) and vitamin B12 (B12) treatment. DNA total methylation level in Hcy treated cells was significantly decreased compared to the control group, while the DNA total methylation levels were increased after treatment with Fc and B12. The methylation level of SORBS1 in Hcy treatment group was higher than that of control group. And the methylation level of SORBS1 induced by Hcy was attenuated by Fc and B12 treatment. SORBS1-siRNA transfection induced the MDA levels and reduced the expressions of SOD2 in HUVECs. CONCLUSIONS: We indicated that Hcy induced oxidative stress in HUVECs via regulating methylation of SORBS1. We also found that Fc and B12 treatment attenuated the oxidative stress and inflammation induced by Hcy in HUVECs. The findings indicated that Fc and B12 might be effective agents for the treatment of Hcy induced AS. PMID- 30402862 TI - GPIIb/IIIa expression changes in atrial fibrillation post radiofrequency ablation. AB - OBJECTIVE: Atrial fibrillation (AF) is one of the most common arrhythmias affecting the patient's quality of life, and its complications of thromboembolism can lead to serious consequences. AF patients are often in hypercoagulation status that can affect the prognosis. GPIIb/IIIa is a fibrinogen receptor that can bind to the ligands of platelet and cause aggregation. Therefore, GPIIb/IIIa can be treated as a marker of hemagglutination. This work aims to analyze the changes of GPIIb/IIIa after radiofrequency ablation of atrial fibrillation, and to investigate its relationship with recurrence. PATIENTS AND METHODS: A total of AF 80 patients in our hospital received radiofrequency ablation from January 2017 to August 2017. Peripheral blood was collected 1 week after surgery. A total of 40 healthy volunteers were enrolled as control group. GPIIb/IIIa was analyzed by enzyme-linked immunosorbent assay (ELISA). High-sensitivity troponin (hs-cTnT), fasting plasma glucose (FPG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (TC), and triglyceride levels (TG) were analyzed by using electrochemical luminescence assay. Body mass index (BMI), smoking index, and age were recorded. RESULTS: Compared with the non-recurrence group, GPIIb/IIIa, hs-cTnT, FPG, LDL, TC, and TG levels increased, whereas HDL level declined in the recurrence group (p < 0.05). There was a positive correlation between GPIIb/IIIa and hs-cTnT, FPG, LDL, TC, TG, BMI, and smoking index, and a negative correlation with HDL (p < 0.05). GPIIb/IIIa was positively correlated with postoperative recurrence (p < 0.05). CONCLUSIONS: Increased GPIIb/IIIa expression after radiofrequency ablation of AF is associated with myocardial injury, suggesting a risk of postoperative recurrence. PMID- 30402863 TI - Suppression of microRNA-101 attenuates hypoxia-induced myocardial H9c2 cell injury by targeting DIMT1-Sp1/survivin pathway. AB - OBJECTIVE: MicroRNAs (miRNAs) are small single-stranded RNAs in eukaryotic cells, which play important regulatory roles in the pathogenesis of various diseases. We aimed to investigate the effects of miRNA-101 (miR-101) on hypoxia-induced myocardial infarction (MI) cell injury model (myocardial H9c2 cell injury model). The possible target gene of miR-101 was also analyzed. MATERIALS AND METHODS: H9c2 cells were exposed to hypoxia treatment. Cell viability, migration, invasion, apoptosis and the expression of miR-101 were detected using CCK-8 assay, transwell assay, flow cytometer analysis, Western blotting and qRT-PCR, respectively. Then, the effects of miR-101 overexpression or suppression on the cell injury induced by hypoxia were assessed. Dual luciferase reporter assay was used to analyze the possible target gene of miR-101. Finally, the effects of dimethyladenosine transferase 1 homolog (DIMT1), the possible target gene of miR 101, on H9c2 cell injury were investigated. RESULTS: Hypoxia significantly induced H9c2 cell injury. miR-101 was up-regulated after hypoxia induction. Hypoxia-induced cell injury was significantly reversed by miR-101 suppression and exacerbated by miR-101 overexpression. DIMT1 was a direct target gene of miR-101. Knockdown of DIMT1 markedly inhibited the protective effects of miR-101 suppression on hypoxia-induced cell injury by suppressing specific protein 1 (Sp1)/Survivin pathway. CONCLUSIONS: We verified the critical roles of miR-101 in regulating myocardial cell injury induced by hypoxia. DIMT1-mediated the Sp1/Survivin pathway was also involved in this process. Our findings replenished the understanding of the regulatory roles of miRNAs in hypoxia-induced MI cell injury and provided new molecular target for therapy and diagnosis of MI. PMID- 30402864 TI - Clinical efficacy of different side branch protection techniques on patients receiving coronary intervention and prognostic analysis. AB - OBJECTIVE: To investigate and analyze the clinical efficacy of different side branch protection techniques on patients receiving coronary intervention and the patient's prognosis. PATIENTS AND METHODS: A total of 80 patients with coronary heart disease treated in Jiangmen Central Hospital from January 2014 to January 2017 were collected. According to different side branch protection strategies selected during operation, they were divided into jailed wire technique (JWT) group (n=20), jailed balloon technique (JBT) group (n=20), balloon-stent kissing technique (BSKT) group (n=20), and BSKT+RW group (n=20). The relevant operation parameters and the prevalence of adverse reactions at 1 month and 6 months after operation were compared among the four groups. RESULTS: The success rate of operation and relevant operation parameters in BSKT+RW group were slightly superior to those in the other three groups, but there were no significant differences among the four groups (p>0.05). Besides, the prevalence rates of adverse reactions at 1 month and 6 months after the operation had no significant differences among the four groups, but they were slightly lower in BSKT+RW group than those in the other three groups. CONCLUSIONS: There are no significant differences in the clinical efficacy and postoperative recovery of patients receiving coronary intervention among the four kinds of different side branch protection techniques. However, BSKT+RW is slightly superior to the other three treatment methods, which, therefore, is a preferred choice if the patient's economic conditions permit. PMID- 30402865 TI - HOTAIR promotes myocardial fibrosis through regulating URI1 expression via Wnt pathway. AB - OBJECTIVE: To investigate whether HOX transcript antisense RNA (HOTAIR) regulates myocardial fibrosis via promoting proliferation of cardiac fibroblasts (CFs) and upregulating the expression levels of fibrotic proteins through activating Wnt signaling pathway. MATERIALS AND METHODS: The expression level of HOTAIR in Ang II-induced cardiac fibroblasts was detected by quantitative Real-time-polymerase chain reaction (qRT-PCR). Overexpression or knockdown of HOTAIR expression was achieved by lentivirus transfection. The effects of HOTAIR on regulating cell proliferation, migration and apoptosis were measured by cell counting kit-8 (CCK 8) test, transwell assay and flow cytometry, respectively. Western blot and qRT PCR experiments were performed to detect expressions of fibrosis-related genes and Wnt pathway-related genes. Target gene of HOTAIR was predicted by bioinformatics analysis. Rescue assays were conducted to assess whether HOTAIR could regulate cell proliferation and fibrosis by activating Wnt signaling pathway via URI1. RESULTS: QRT-PCR results showed that HOTAIR expression in Ang II-induced CF cells was significantly higher than that in control. HOTAIR overexpression in CF cells can promote cell proliferation and migration, inhibit apoptosis, and promote the expressions of fibrosis-related genes. Western blot results indicated that HOTAIR could upregulate URI1 expression and activate Wnt signaling pathway. In addition, rescue assay demonstrated that overexpression of URI1 reversed the inhibitory effect of HOTAIR knockdown on Wnt pathway. CONCLUSIONS: Highly expressed HOTAIR promoted proliferation and migration of cardiac fibroblasts. HOTAIR remarkably upregulated fibrosis-related genes in CF cells. The mechanism of HOTAIR in regulating myocardial fibrosis might be related to the activation of Wnt signaling pathway through targeting URI1 expression. PMID- 30402866 TI - HOTAIR alleviates ox-LDL-induced inflammatory response in Raw264.7 cells via inhibiting NF-kappaB pathway. AB - OBJECTIVE: To investigate the possible role of hox transcript antisense intergenic RNA (HOTAIR) in the pathogenesis of atherosclerosis and its underlying mechanism. PATIENTS AND METHODS: The expression of HOTAIR in peripheral blood lymphocytes of atherosclerosis (AS) and healthy controls was detected by quantitative Real-time-polymerase chain reaction (qRT-PCR). In vitro AS model was established by ox-LDL induction in Raw264.7 cells. Viability of Raw264.7 cells after ox-LDL induction was detected by cell counting kit-8 (CCK-8) assay. Levels of TC (total cholesterol), TG (triglyceride), LDL-C (low density lipoprotein cholesterol) and HDL-C (high density lipoprotein cholesterol) in Raw264.7 cells were detected by enzyme-linked immunosorbent assay (ELISA). Overexpression plasmid of HOTAIR was constructed. Levels of TG, TC, LDL-C, and HDL were detected again after HOTAIR overexpression by ELISA. CD68+ cells and CD168+ cells in Raw264.7 cells were detected by flow cytometry. Protein expressions of pro inflammatory and anti-inflammatory genes were detected by Western blot. Lipid metabolism in Raw264.7 cells was evaluated by oil red O staining and Western blot, respectively. Finally, rescue experiments were conducted to explore the specific mechanism of HOTAIR in regulating AS development. RESULTS: HOTAIR was lowly expressed in peripheral blood lymphocytes of AS patients and Raw264.7 cells induced by ox-LDL. Overexpression of HOTAIR upregulated adipose genes (PPARalpha and CPT-1) and downregulated lipogenesis genes (SREBP-1c and ACS). Besides, overexpression of HOTAIR decreased expressions of pro-inflammatory cytokines (TNF alpha and IL-1beta), but increased expressions of anti-inflammatory cytokines (IL 4 and IL-10). In the in vitro AS model, FXR1 was remarkably downregulated in Raw264.7 cells. HOTAIR reduced inflammatory response via promoting FXR1 expression in Raw264.7 cells. Rescue experiments showed that the effect of HOTAIR on nuclear factor-kappa B (NF-kappaB) pathway was reversed by FXR1 knockdown. CONCLUSIONS: We found that TAIR was lowly expressed in AS patients. Overexpression of HOTAIR can reduce the lipid accumulation and inhibit inflammatory response by suppressing FXR1 via NF-kappaB pathway. PMID- 30402867 TI - Role of GSPE in improving early cerebral vascular damage by inhibition of Profilin-1 expression in a ouabain-induced hypertension model. AB - OBJECTIVE: Grape seed proanthocyanidin extract (GSPE), as one of the most popular natural drug extracted from the grape, has been reported to improve endothelial function and arteriosclerosis. However, little is known about the influence of GSPE on hypertension and vascular remodeling. Profilin-1, an Actin-binding protein, is closely involved in the remodeling of large vessels in ouabain induced hypertension. To date, there is no effective prevention or treatment in place for the high incidence of ischemic stroke associated with hypertension. In this study, we aimed to determine the role of GSPE via inhibition Profilin-1 in ischemic cerebral cortices of ouabain-hypertension rats and potentially provide a new target to prevent stroke associated with hypertension. MATERIALS AND METHODS: The blood pressure of male Sprague-Dawley (SD) rats was measured during a period of ouabain-induced hypertension. The expression of Profilin-1, vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) in the cerebral cortex were determined by quantitative Real Time-PCR (qRT-PCR) and Western blot. Histopathological and behavioral tests were also conducted. RESULTS: Blood pressure elevation started at week 5 and reached clinical standards for hypertension at week 8. GSPE was proved to suppress Profilin-1 and VEGF levels through inhibition of Profilin-1-protein kinase B (AKT)-hypoxia inducible factor-1alpha (HIF-1alpha) signal pathway and promote eNOS expression. Moreover, the histopathological and ethiological improvement was observed in GSPE over-expression and Profilin-1 inhibition groups. CONCLUSIONS: We detected that GSPE could improve cerebral vascular damage through inhibiting Profilin-1 in an ouabain-induced hypertension model. PMID- 30402868 TI - Endogenous nerve growth factor stimulation: effects on auditory pathway neural cells in a mouse model. AB - OBJECTIVE: In the present study, we investigated whether high-pressure hypotonic saline solution (Hphss) affects the basal level of Nerve Growth Factor (NGF) and expression of receptors in the cochlea, bark earing, retina, and visual cortex. MATERIALS AND METHODS: For this study, we used three weeks old female Sprague Dawley (SD) rats (n = 12). Rats were housed in polypropylene cages and were kept under standard conditions (12 h light:12 h dark cycle) with free access to water and food (Purina chow food). A specific dispenser was employed to deliver sterile hypotonic saline at high pressure (pressing emission level (PEL): 7 g/s; emission time (ET): 0.5 s). Rats were divided into two groups: untreated (n = 6) and treated with Hphss (n = 6), three times per day, for 10 consecutive days. Treatment was performed in both nostrils with 50 ul of Hphss using a microsyringe equipped with a plastic tip. RESULTS: We observed a significant enhancement in the level of NGF in the cochlea and bark earing, but not in the retina and visual cortex. This is likely because the nasolacrimal duct pathway does not appear to have an effect on the retina, and the visual cortex appears to be too far from the cribriform plate to be reached by nasal NGF. CONCLUSIONS: This treatment can significantly protect and/or delay degeneration of cochlear auditory NGF-target cells. It is free from side effects and can be used in chronic diseases for as long as needed. It remains to be investigated whether the effects of short-term therapy are long-lasting, or if the treatment must be repeated. PMID- 30402869 TI - Oral ulcer healing and anti-Candida efficacy of an alcohol-free chitosan-curcumin mouthwash. AB - OBJECTIVE: The purpose of this study was to investigate oral ulcer healing and anti-Candida efficacy of an alcohol-free 0.1% chitosan-curcumin mouthwash. MATERIALS AND METHODS: A buccal mucosal ulcer was induced in hamster by topical application of acetic acid. The test mouthwash was applied to the ulcer twice a day for 7 consecutive days beginning on the fourth day after the ulcer induction. The anti-Candida efficacy of the mouthwash was determined against both free floating and biofilm forms of Candida albicans. RESULTS: The mouthwash significantly decreased the ulcer severity with a better ulcer healing efficacy than that of a standard benzydamine mouthwash. The mouthwash also exerted a comparable anti-Candida efficacy to a standard chlorhexidine mouthwash. CONCLUSIONS: An alcohol-free 0.1% chitosan-curcumin mouthwash may serve as a safe and potential topical alternative agent in the management of oral inflammatory ulcer and of candidiasis. PMID- 30402870 TI - Optimising management of patients with hepatitis C virus in the age of direct acting antivirals: results of a Delphi consensus. AB - OBJECTIVE: To optimize the management of patients with chronic hepatitis C virus (HCV). MATERIALS AND METHODS: We developed two questionnaires to determine Italian healthcare professionals' opinions on the overall management of HCV chronic liver disease and the use of direct-acting antivirals (DAAs) in the treatment of HCV. A Delphi consensus method using the RAND/UCLA appropriateness method was used to determine opinions of an expert panel (EP) of specialists. RESULTS: Overall 443 physicians from 167 Italian centres completed the two questionnaires. The EP confirmed the importance of collaboration with general practitioners (GPs) and HCV testing in high-risk groups, but did not agree on treating patients over 80 years of age with DAAs. Over 90% agreed that it was important to quantify HCV-RNA, determine genotype, and test for anti-HIV and HBsAg before starting DAAs. Transient elastography (FibroScan(r)) was used by >90% to evaluate the stage of liver fibrosis while serum biomarkers were used by <20%. Adherence to therapy, drug-drug interactions and the possibility of treating advanced liver disease were decisive factors in therapy choice. Monthly monitoring during therapy was considered appropriate and 80% were in favor of HCV RNA testing 24 weeks after the end of the therapy to confirm sustained virological response (SVR). Over 80% agreed that it was necessary to continue follow-up of patients with advanced fibrosis/cirrhosis. CONCLUSIONS: Scientific organizations should review their guideline recommendations to facilitate access to DAAs. PMID- 30402871 TI - Paraquat poisoning in Western French Guyana: a public health problem persisting ten years after its withdrawal from the French market. AB - OBJECTIVE: Paraquat poisoning has almost disappeared from metropolitan France following its ban from the European market ten years ago. However, due to neighboring countries still authorizing paraquat use, French Guyana seems in a different situation. Here we aimed to report a series of paraquat-poisoned patients admitted to the emergency department of the Western French Guyana Hospital in Saint-Laurent du Maroni, to raise awareness of national health authorities on this persistent major issue. PATIENTS AND METHODS: We conducted a retrospective observational study describing the clinical features, the prognostic factors and the final outcome of paraquat-poisoned patients admitted to the emergency department between January 2008 and August 2014. RESULTS: Twenty six paraquat-poisoned patients were included in the study. The median estimated paraquat dose intentionally ingested was 105 mg/kg (interquartile range, IQR: 359). Eighteen patients were treated with the cyclophosphamide/dexamethasone combination and seventeen with N-acetylcysteine in addition to the usual supportive care. Six patients survived and twenty died within a median 36h delay after admission (IQR: 130). Death was associated with cardiovascular (65%) and respiratory (35%) failure. Based on a bivariate analysis, predictive factors of death included (p<=0.05): advanced age, higher ingested paraquat dose, altered renal function, hypokalemia, acidosis, and dark blue dithionite test, observed on hospital admission. CONCLUSIONS: Paraquat poisoning still persists in French Guyana despite its withdrawal from the market. It is possible to determine the probability of death on patient admission based on routine clinical and biological parameters. There is an urgent need to request neighboring countries to ban paraquat with the aim of eradicating this dramatically life-threatening poisoning. PMID- 30402872 TI - Preterm birth after loop electrosurgical excision procedure (LEEP): how cone features and microbiota could influence the pregnancy outcome. AB - OBJECTIVE: In the last years, the mean age of women who underwent cervical treatment for high-grade cervical intraepithelial neoplasia (CIN 2-3) is similar to the age of women having their first pregnancy. The aim of this study was to evaluate the risk of preterm birth in subsequent pregnancies after loop electrosurgical excision procedure (LEEP). PATIENTS AND METHODS: From January 2013 to January 2016 the study identified a total of 1435 women, nulliparous, who underwent LEEP for CIN 2-3, and who wished to have their first pregnancy. Before surgery, the lengths of the cervix were calculated by transvaginal sonography. After the treatment, the dimension of the removed tissue was evaluated. During the pregnancy, all women carried out periodic transvaginal sonography and vaginal cervical swabs. RESULTS: The average age of patients was 31.96+/-5.24 years; the interval between the surgical procedure and pregnancy was 12.04+/-4.67 months; the gestational age at births was 37.53+/-2.91 weeks. The first vaginal and cervical swab performed during pregnancy was negative in 81.8% of patients. The most prevalent infections were related to C. Albicans, G. Vaginalis, and Group B Streptococcus (GBS). The rate of preterm delivery was significantly higher in women with a minor cervical length. CONCLUSIONS: The length and the volume of cervical tissue excised have been shown to be directly related to the risk for preterm birth. Furthermore, vaginal infections and their persistence during pregnancy in women with a history of LEEP may be associated with an increased risk for preterm birth, compared with women with no history of LEEP. PMID- 30402873 TI - Targeting patients' microbiota with probiotics and natural fibers in adults and children with constipation. AB - OBJECTIVE: Functional constipation (FC) is a common condition in which the gut microbiota composition plays a fundamental role. The increasing knowledge on the role of gut microbes in the regulation of gut motility and stool consistency has allowed reconsidering, with a new scientific-based approach, the possibility to target the composition of intestinal bacterial populations for FC treatment. In this review, we evaluate recent attempts that used prebiotics, natural fibers or probiotics to treat FC, with a deep microbiome-based focus. MATERIALS AND METHODS: This is a literature review of articles published in Medline, Web of Science, and the Cochrane Library. Studies on FC in adults and children were identified using the following terms: constipation AND probiotics OR prebiotics OR synbiotics PR fibers OR microbiome OR microbiota. Selected animal studies were also considered if showing mechanistic observations. RESULTS: FC is associated with alteration in microbiome composition. Motility and fecal consistency are affected with different efficacy by the type of fiber, prebiotic or probiotic strain used in patients. CONCLUSIONS: Selected bacterial strains, mainly belonging to the Bifidobacterium genus, and some poorly or non-fermented natural fibers, such as Psyllium, may significantly improve FC and may represent the basis for an effective supplementation. PMID- 30402875 TI - Vitamin D3 promotes cerebral angiogenesis after cerebral infarction in rats by activating Shh signaling pathway. AB - OBJECTIVE: This study aims at investigating the neuroprotective role of Vitamin D3 (VitD3) in rats with cerebral infarction and its molecular mechanisms. MATERIALS AND METHODS: Male Sprague- Dawley (SD) rats were selected and randomly divided into sham operation group, middle cerebral artery occlusion (MCAO) model group, and VitD3 treatment group. The therapeutic effect of VitD3 was evaluated via neurobehavioral scoring and triphenyltetrazolium chloride (TTC) staining. For the evaluation of VitD3 influence on cerebral blood perfusion, Micro-PET imaging technique was applied. The mRNA levels of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1) gene were detected via Real-Time Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Immunofluorescence staining assay was employed to determine the changes in micro-vessel density. Bromodeoxyuridine (Brdu) assay was used to count the number of new vascular endothelial cells. Protein expressions of key genes in the Shh signaling pathway were detected by Western blotting. RESULTS: Our results showed that VitD3 improved the score of neurological function and decreased the size of cerebral infarction in MCAO rats. VitD3 improved cerebral perfusion in the ischemic area after MCAO. VitD3 up-regulated levels of vascular growth-related factors. VitD3 elevated micro-vessel density after cerebral infarction and promoted the proliferation of vascular endothelial cells in the ischemic cortex. The sonic hedgehog (Shh) signaling pathway in the ischemic cortex of MCAO rats was activated after VitD3 treatment. CONCLUSIONS: We showed that VitD3 improves cerebral perfusion and reduces neurological impairment in MCAO rats via activating the Shh signaling pathway. PMID- 30402874 TI - Charged molecular silica trigger in vitro NETosis in human granulocytes via both oxidative and autophagic pathways. AB - OBJECTIVE: Neutrophils play a key role in immunity and are known to respond to exogenous threats by releasing neutrophil extracellular traps (NETs) through NETosis, a process involving the release of neutrophils nuclear DNA decorated with proteins into the extracellular space. In this study, attention has been focused on the ability of differently charged molecular systems polyhedral oligomeric silsesquioxanes (POSS) to induce NETosis. MATERIALS AND METHODS: NETs formation was induced by phorbol myristate acetate (PMA) (positive control) and POSS treatment and visualized by confocal microscopy. Moreover, NETs production was quantified by Sytox green staining. Oxidative stress, autophagy as well as endocytosis involvement in the observed phenomena was evaluated by a specific inhibitory approach. RESULTS: Results obtained in this study demonstrate a POSS time and dose-dependent ability in inducing NETs release irrespectively to their charge. POSS induced NETosis is a consequence of their internalization, as demonstrated by the strong reduction in NETs formation after endocytosis inhibition. Moreover, POSS induced NETosis involves both an increase in superoxide anion generation and autophagy pathway activation as demonstrated by the protective effect displayed by sodium azide and wortmannin. CONCLUSIONS: Data presented in this study indicate that nanomaterials and molecular systems could have a role in the onset of inflammatory phenomena. PMID- 30402876 TI - Combined treatment with myo-inositol, alpha-lipoic acid, folic acid and vitamins significantly improves sperm parameters of sub-fertile men: a multi-centric study. AB - OBJECTIVE: Reduction in motility and number of spermatozoa and change in their morphology are some of the most relevant causes of male infertility. Production of reactive oxygen species may affect motility, morphology and DNA stability of spermatozoa. This study aimed at evaluating the effect of combined treatment with myo-inositol, alpha-lipoic acid, folic acid, betaine and vitamins (namely, Sinopol(r)) on semen parameters of sub-fertile men. PATIENTS AND METHODS: We recruited 143 sub-fertile men, 26-53 years aged, no-smokers, without any testicular pathologies, with a normal endocrinological/metabolic profile, and no concomitant consumption of drugs. Out of them, 25 patients did not meet study inclusion criteria mainly due to the history of genital diseases that came to light after Sinopol(r) prescription. Among the 118 men that fulfilled inclusion criteria, 10 (8.4%) patients were lost at follow-up and in 8 (6.8%) cases the partner got pregnant spontaneously. Thus, 100 patients completed the study and semen analysis was performed before and after 90 days of treatment. RESULTS: Semen quality improved after 90 days of treatments, with a statistically significant increase of sperm concentration (p=0.0009), of number of spermatozoa (p=0.0017), of progressive motility (p=0.0047), of total motile sperm count (p=0.0010), and of normal sperm morphology (p<0.0001). CONCLUSIONS: For the first time we reported that a combination of nutraceuticals composed of myo-inositol, alpha-lipoic acid, folic acid, betaine and vitamins improves sperm parameters in sub-fertile men. We are aware that to clarify the clinical relevance of the data studies with larger sample sizes and longer durations are needed, as well as evaluation of myo-inositol and alpha-lipoic acid co-treatment effectiveness in improving the chances to obtain a pregnancy spontaneously or following assisted reproduction. PMID- 30402878 TI - Evaluation of condylar structures on panoramic radiographs in adolescent patients with celiac disease. AB - BACKGROUND: Celiac disease (CD) is a common disorder that usually originates from calcium malabsorption. Thus, it is accepted that patients with CD have lower bone mineral density than that of healthy individuals. The aim of this study was to assess condylar height, width, area, and perimeter on digital panoramic radiographs in patients with CD. MATERIALS AND METHODS: Panoramic radiographs obtained from 44 patients with CD were age- and sex-matched with 44 Class 1 (ANB: 2 +/- 2 degrees ) patients, and outcomes were analyzed. Radiographs were digitized using Image J software, and condylar height, width, area, and perimeter were compared. RESULTS: Condylar area (cm2) (3.66+/-1.02), perimeter (cm) (9.29 +/- 1.38), and height (cm) (2.69 +/- 0.46) values were significantly higher (P < 0.05) in the control group than those in the patient group (area (cm2): 2.52 +/- 0.63, perimeter (cm): 8.47 +/- 1.42, height (cm): 2.51 +/- 0.37), whereas width (cm) (celiac: 2.83 +/- 0.63, control: 3.00 +/- 0.59) did not differ between the groups (P > 0.05). CONCLUSIONS: These outcomes may be due to the low bone density of patients with CD. A controlled trial conducted using a larger sample is needed to support and extend these data. PMID- 30402877 TI - Neuroprotective effects of Potentilla fulgens on spinal cord injury in rats: an immunohistochemical analysis. AB - This examination was performed to research the advantage of the antioxidant impact of Potentilla fulgens on spinal cord injury (SCI) in rats. In the SCI model of this examination, the tolerably serious lesion was performed at the L1 L2 spinal segmental level. Spinal cord injury animals were given P. fulgens 400 mg/kg/day, intraperitoneally. At seven days post-lesion, exploratory rats were executed after intraperitoneal administration of ketamine HCL (0.15 ml/100 g body weight). Spinal cord specimens were taken for histological examination or assurance of malondialdehyde (MDA) and glutathione (GSH) levels and myeloperoxidase (MPO) action. SCI caused a remarkable decline in spinal cord GSH content, trailed by noteworthy increments in MDA levels and MPO action. Degenerative changes in some multipolar and bipolar nerve cells and picnotic changes in the nuclei of glial cells were likewise noticed. Remarkable development was seen in cells and vascular structures of P. fulgens treated groups when contrasted with untreated groups. P. fulgens application may influence angiogenetic improvement in vein endothelial cells, reduce inflammatory cell aggregation by influencing cytokine system and may make apoptotic nerve cells and neuroprotective component in glial cells. PMID- 30402879 TI - Acrylamide adverse cerebellar changes in rats: possible oligodendrogenic role of omega 3 and green tea. AB - BACKGROUND: Humans are widely exposed to Acrylamide (ACR) and its neurotoxicity is a significant public health issue attracting wide attention. AIM OF WORK: Investigating ACR-induced adverse cerebellar changes in rats and studying the possible Oligodendrogenic role of Omega 3 and Green Tea. MATERIAL AND METHODS: Twenty four adult albino rats weighing 150 -200gm were randomly divided into four equal groups (6 rats each) as follows; Group I: (control), Group II: The rats received ACR 45mg/kg/day, Group III: The rats received ACR concomitant with Omega3 at a dosage of 200mg/kg/day, Group IV: The rats received ACR concomitant with Green Tea dissolved in drinking water at a dosage of 5gm/litre. The rats were euthanized 8 weeks from the experiment. Malondialdehyde (MDA) and Glutathione (GSH) were measured in cerebellar homogenates. Sections of 5 um thickness from specimens from the cerebellum were stained with Hx & E, Silver stain and immunohistochemical stains; PDGFalpha (for Oligodendrocytes), GFAP (for Astrocytes) and BCL2 (Antiapoptotic). RESULTS: Omega3 and Green Tea had improved MDA & GSH as compared to ACR group. Histologically, ACR group showed variable degrees of cellular degeneration. Omega3 had induced Oligodendrogenesis in group III. The optical density of silver stain was significantly p<0.05 increased in group III & IV as compared to ACR group. Area % of positive PDGFalpha was significantly increased in ACR+omega3 group as compared to ACR group. Area % of positive GFAP was significantly decreased in group III & IV as compared to ACR group. Area % of positive BCL2 was significantly increased in omega3 received groups as compared to ACR group. CONCLUSIONS: Concomitant administration of Omega 3 or green Tea with ACR might mitigate its adverse cerebellar changes with an Oligodendrogenic role of Omega 3. PMID- 30402880 TI - M281, an Anti-FcRn Antibody: Pharmacodynamics, Pharmacokinetics, and Safety Across the Full Range of IgG Reduction in a First-in-Human Study. AB - M281 is a fully human, anti-neonatal Fc receptor (FcRn) antibody that inhibits FcRn-mediated immunoglobulin G (IgG) recycling to decrease pathogenic IgG while preserving IgG production. A randomized, double-blind, placebo-controlled, first in-human study with 50 normal healthy volunteers was designed to probe safety and the physiological maximum for reduction of IgG. Intravenous infusion of single ascending doses up to 60 mg/kg induced dose-dependent serum IgG reductions, which were similar across all IgG subclasses. Multiple weekly doses of 15 or 30 mg/kg achieved mean IgG reductions of ~85% from baseline and maintained IgG reductions >=75% from baseline for up to 24 days. M281 was well tolerated, with no serious or severe adverse events (AEs), few moderate AEs, and a low incidence of infection-related AEs similar to placebo treatment. The tolerability and consistency of M281 pharmacokinetics and pharmacodynamics support further evaluation of M281 in diseases mediated by pathogenic IgG. PMID- 30402883 TI - Hepcidin mediated iron homoeostasis as immune regulator in visceral leishmaniasis patients. AB - AIM: Iron is key ingredient for immunosurveillance and host-pathogen interaction. Intracellular pathogen steals the iron from the host, but how parasite orchestrates iron acquisition and affects immune responses remains controversial. We aimed to study the iron homoeostasis in visceral leishmaniasis (VL) and its influence on immune machinery. METHODS AND RESULTS: This study was performed on purified monocytes and T cells, peripheral blood mononuclear cells and splenic aspirates for transcriptional analyses of iron homoeostasis (hepcidin, DMT1, transferrin receptor, ferroportin) and immune modulations (IFN-gamma, HLA-DR, IL 10, iNOS, IL-6). Serum/plasma was used for determination of iron, total/transferrin iron-binding capacity and anti-leishmania antibody titres in cases. We report that VL-induced perturbation in iron homoeostasis may cause immune dysfunctions. VL cases had decreased iron uptake by transferrin-dependent and transferrin-independent routes while elevated hepcidin, degraded sole iron exporter ferroportin. Therefore, it appears that perturbation in iron homoeostasis has essential role in HLA-DR mediated antigen presentation and innate armoury by downregulating iNOS as well as altering IFN-gamma, IL-6 and IL 10 profiles. CONCLUSION: The iron homoeostasis by hepcidin can serve as one of the crucial determinants for regulating immune cell signalling; therefore, targeting iron metabolism, specifically hepcidin alone or in combination with agonists, can serve to clear infection. PMID- 30402882 TI - Diagnostic approach with genetic tests for global developmental delay and/or intellectual disability: Single tertiary center experience. AB - The child with global developmental delay (GDD)/intellectual disability (ID) is deserving of the appropriate evaluation available for improving the health and well-being of patients and their families. To better elucidate the diagnostic approach of genetic tests for patients with GDD and/or ID, we evaluated the results in a cohort of 75 patients with clinical features of GDD and/or ID who were referred for diagnostic workup. A total of 75 children were investigated for GDD or ID in the pediatric neurology department. Ten patients (13%, 10/75) with a clinically recognizable syndrome were diagnosed by single-gene analysis. Next, chromosomal microarray was performed as a first-tier test, and 25 patients (33%, 25/75) showed structural abnormalities. Then, two fragile X syndrome (3%, 2/75) were confirmed by FMR1 gene fragment analysis. Thirty-eight remaining patients received a gene panel by next-generation sequencing. Eight patients were found to have an underlying genetic etiology: CHD8, ZDHHC9, MBD5, CACNA1H, SMARCB1, FOXP1, NSD1, and PAX6. As a result, 45 patients (60%, 45/75) had been diagnosed by genetic tests. Among 30 undiagnosed patients, brain structural abnormalities related to GDD/ID were observed in eight patients (11%, 8/75). However, in 22 patients (29%, 22/75), the causes of GDD/ID remained uncertain. A genetic diagnostic approach of GDD/ID by sequential molecular analysis can help in the planning of treatment, assigning the risk of occurrence in siblings, and providing emotional relief for the family. PMID- 30402884 TI - Adolescent social stress and social context influence the intake of ethanol and sucrose in male rats soon and long after the stress exposures. AB - Social instability stress in adolescent rats (SS; postnatal day 30-45, daily 1 hr isolation +new cage partner) alters behavioural responses to psychostimulants, but differences in voluntary consumption of natural and drug rewards are unknown. SS also is associated with an atypical behavioural repertoire, for example reduced social interactions. Here, we investigated whether SS rats differ from control (CTL) rats in ethanol (EtOH) or sucrose intake in experiments involving different social contexts: alone, in the presence of an unfamiliar peer, in the presence of its cage partner, or in competition against its cage partner. SS rats drank more EtOH than CTL rats irrespective of social context, although the effects were driven primarily by those tested soon after the test procedure rather than weeks later in adulthood. SS and CTL rats did not differ in sucrose intake, except in adulthood under conditions of competition for limited access (SS>CTL). Adolescent rats drank more sucrose than adults, in keeping with evidence that adolescents are more sensitive to natural rewards than adult animals. Overall, adolescent SS modified the reward value of EtOH and sucrose, perhaps through stress/glucocorticoids modifying the development of the mesocorticolimbic system. PMID- 30402885 TI - Pathological complete response after neoadjuvant pembrolizumab and radiation. PMID- 30402886 TI - Expression of T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain on CD4+ T cells in patients with atopic dermatitis. AB - The T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is a co-inhibitory receptor mainly expressed on T cells. Although TIGIT plays an important role in various autoimmune diseases, its role in atopic dermatitis (AD) remains unclear. In this study, we examined the expression levels of TIGIT and their association with clinical features in patients with AD. TIGIT expression on CD4+ T cells, central memory T cells, effector memory T cells and regulatory T cells was determined by flow cytometry. CD4+ T cells exhibited enhanced TIGIT expression in patients with AD compared with healthy individuals. In particular, effector memory T cells and regulatory T cells, but not central memory T cells, exhibited higher TIGIT expression in patients with AD than in healthy individuals. The frequency of TIGIT+ cells among CD4+ T cells was significantly increased in patients with mild AD compared with healthy individuals, while decreased in patients with severe AD. Consistently, the frequency of TIGIT+ cells among CD4+ T cells was negatively correlated with both serum thymus and activation-regulated chemokine levels and immunoglobulin E levels in patients with AD. Furthermore, TIGIT expression on CD4+ T cells inhibited cell proliferation in patients with AD. These results suggest that TIGIT expression on CD4+ T cells in patients with AD may be increased to suppress chronic cutaneous inflammation. Moreover, TIGIT expression may be impaired in a subset of patients with AD, leading to a deterioration of skin inflammation. Our study may provide new insight into a TIGIT pathway-based therapeutic approach for AD. PMID- 30402887 TI - VA-ECMO Support in Nonsurgical Patients With Refractory Cardiogenic Shock: Pre Implant Outcome Predictors. AB - Refractory cardiogenic shock (RCS) is associated with a high mortality. Veno arterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used as acute cardiopulmonary support but selection of VA-ECMO candidates remains challenging. There are limited data on which pre-VA-ECMO variables that predict outcome. The aim of this study was to identify pre-VA-ECMO predictors of 90-day mortality. We retrospectively analyzed 76 consecutive patients (median age 52; interquartile range [IQR]: 37-60) supported with VA-ECMO due to RCS. The association between pre-implant variables and all-cause mortality at 90 days was analyzed with multivariable logistic regression. Main etiologies of RCS were acute myocardial infarction 51% and other AHF etiologies 49%. Cardiopulmonary resuscitation was performed in 54% of patients before initiation of VA-ECMO. Median duration of VA-ECMO was 5 days (IQR: 2-11). The 90-day overall mortality was 49% and in-hospital mortality was 50%; 46% died on VA-ECMO, 37% were successfully weaned, 13% were bridged to heart transplantation, and 4% to left ventricular assist device. Multivariable logistic regression analysis identified arterial lactate (odds ratio [OR] per mmol/L: 1.15; 95% confidence interval [CI]: 1.06-1.24; P = 0.001) and number of inotropes and vasopressors (OR per agent: 2.14; 95% CI: 1.26-3.63; P = 0.005) as independent predictors of 90-day mortality. In RCS patients arterial lactate level and number of inotropes and vasopressors were identified as independent pre-VA-ECMO predictors of 90-day mortality. Thus, the severity of cardiogenic shock expressed as levels of lactate and vasoactive agents just before start of VA-ECMO may be more predictive of outcome than the specific etiology of cardiogenic shock. PMID- 30402889 TI - Sociology of Health and Illness - Mildred Blaxter New Writer Prize. PMID- 30402888 TI - Supplementation of L-glycine and L-glutamate to Japanese quails from 01 to 36 days of age using the ideal protein concept. AB - Experiment I: T1-1 = basal diet with 25% crude protein (CP) + limiting amino acids (LA); T1-2 = 20% CP + LA; T1-3 = 20% CP + LA + L-glycine; T1-4 = 20% CP + LA + L-glutamate; T1-5 = 20% CP + LA + L-glycine + L-glutamate. Experiment II: T2-1 = basal diet with 22% CP + LA; T2-2 = 20% CP + LA; T2-3 = 17.6% CP + LA + L-glycine; T2-4 = 17.6% CP + LA + L-glutamate; T2-5 = 17.6% CP + LA + L-glycine + L-glutamate. The reduction of dietary protein based on the concept of ideal protein decreases nitrogen excretion in quails when L-glycine is added to the diets. Quails fed diets supplemented with L-glutamate as the non-specific nitrogen source equivalent to the nitrogen level of the control diet had increased nitrogen excretion. However, quails had reduced nitrogen excretion in both experiments when L-glycine was added to diets with L-glutamate. Carcass fat was increased by reducing dietary protein, but fat deposition was reduced by adding L-glutamate and L-glycine, or both. The dietary addition of L-glutamate and L-glycine in quails based on the ideal protein concept is not necessary (Exp. I). Although the total nitrogen, electrolytic balance and glycine level were adjusted in diets, quails had decreased performance. Therefore, other hypotheses besides protein reduction need to be studied (Exp. II). Protein reduction with supplementation of only limiting essential amino acids does not affect quail performance. Dietary addition of L-glycine reduces nitrogen excretion. PMID- 30402891 TI - Enantioselective C2-alkylation of indoles via a redox-relay Heck reaction of 2 indole triflates. AB - A palladium-catalyzed enantioselective redox-relay Heck reaction of 2-indole triflates and disubstituted alkenes is reported. This process combines readily available indole triflates with a variety of alkenes to afford a range of indole derivatives bearing a stereocenter adjacent to C2. Enantioselectivity is achieved through use of a simple pyridine-oxazoline ligand. Tuning the electronics of the indole, through judicious choice of N-protecting group, is required to ensure selective beta hydride elimination away from the indole core. Utility of this method is highlighted in a modular formal synthesis of an S1P1 agonist precursor developed by Merck. PMID- 30402892 TI - Health and the Sustainable Development Goals: Challenges for four Pacific countries. AB - Sustainable Development Goal 3 (SDG 3) focuses on health and well-being. To understand the in-country monitoring challenges for developing countries of reporting against SDG 3, this research sought published data for the four Pacific countries of Fiji, Papua New Guinea (PNG), the Solomon Islands, and Vanuatu within a region with well-documented and significant health challenges. This research found that there are limited recent, comprehensive, and comparable data with identified sources against the SDG 3 outcome indicators at an in-country level. Without such data, there is a risk of relying on data that may be inaccurate because of aggregation, estimation, and modelling. The results from these data can influence the funding and other resources that could be made available to the Melanesian countries to address health inequities. PMID- 30402893 TI - Serving a community sentence with a mental health treatment requirement: Offenders' perspectives. AB - BACKGROUND: Safe alternatives to custody for offenders with mental disorder are vital, not least as self-harm, and violence rates are rising among them in prisons. In England and Wales, the Criminal Justice Act 2003 allows a mental health treatment requirement (MHTR) to supplement a community or suspended prison sentence, but this combination is poorly understood and rarely sought. AIM: To explore offenders' perspectives on the MHTR. METHODS: We interviewed all 25 consenting offenders under an MHTR in two probation areas. Verbatim transcripts of their audio-taped narratives were analysed using grounded theory methods. RESULTS: Their core concern was "instability," characterised by many health and social difficulties and resolved by achieving stability, which included not reoffending as well as becoming healthy, substance free, and "having a life." Most considered that the MHTR helped their motivation and service provision, but some cited poor supervisor accessibility, supervisor role confusion, and sense of stigma under the order as stressful and threatening good outcomes. CONCLUSIONS: This first account of offenders' perspectives on the MHTR suggests a model in which, under it, offenders see themselves making progress as courts require. They understand the risk of return to court and imprisonment if in breach. This model of understanding how MHTRs work could provide for professional guidance and evaluation of their effectiveness. PMID- 30402894 TI - Transport of salvianolic acid B via the human organic anion transporter 1B1 in the liver. AB - Salvianolic acid B (SAB) has a high concentration in the liver, but the mechanism of its distribution in the liver is unclear. The aim of this study was to investigate the mechanisms of hepatic uptake of SAB. In this study, we first explored the uptake features of SAB in HepG2 cells and the effect of rifampicin on uptake. Then, we explored the effects of SAB on the uptake of pitavastatin in HepG2 cells. Finally, we established an HEK239T-OATP1B1 cell model to confirm whether OATP1B1 mediated the transport of SAB. Results showed that the uptake kinetic parameters Vmax and Km for SAB in HepG2 cells were 21.28 +/- 2.06 pmol mg 1 per protein min-1 and 28.47 +/- 7.36 MUM, respectively. Rifampicin inhibited the uptake of SAB in HepG2 cells (IC50 was 5.85 +/- 1.70 MUM), and SAB affected the uptake of pitavastatin in HepG2 cells (IC50 was 27.67 +/- 1.90 MUM). The uptake kinetic parameters Vmax and Km for SAB in HEK239T-OATP1B1 were 60.03 +/- 6.16 pmol mg-1 per protein min-1 and 87.24 +/- 15.28 MUM, respectively, whereas in EGFP-HEK293 cells were 14.04 +/- 2.53 pmol mg-1 per protein min-1 and 56.53 +/ 15.50 MUM. The SAB had no effect of on the expression of OATP1B1 in HEK239T OATP1B1 cells. In conclusion, this study demonstrated that OATP1B1 contributes to the transport and accumulation of SAB in the liver. PMID- 30402895 TI - Porphyrin-Stabilized Nitrenium Dication. AB - Nitrenium dications are isoelectronic to neutral trivalent boron compounds and tertiary carbocations, and are usually very electron-deficient and difficult to isolate. Azepine-fused NiII-porphyrin dimer was synthesized by oxidative amination of beta-beta linked NiII-porphyrin dimer and its N-aryl congener was synthesized by two-fold Buchwald-Hartwig amination of beta-to-beta linked and dichlorinated NiII-porphyrin dimer. Oxidation of the NH congener gave a neutral aminyl radical and a nitrenium ion successively similarly to the previously reported NH-bridged NiII-porphyrin dimer. On the other hand, oxidation of the N aryl congener afforded formal nitrenium dication in a single-step two-electron oxidation, which was isolated as a stable molecule. The chemical stability of the nitrenium dication has been improved by chlorine substitution at the most reactive beta-position. The structural, optical, magnetic, electrochemical properties of these compounds mentioned above have been fully characterized. PMID- 30402896 TI - Patterns of weight loss and their determinants in a sample of adults with overweight and obesity intending to lose weight. AB - AIM: Weight loss success is highly variable among individuals. Cluster analysis contributes to future intervention development by recognising this individual variability and identifying different weight loss patterns. Identifying determinants that differentiate between these patterns would explain the source of variability. Thus, we aimed to identify weight loss patterns and their determinants in adults with overweight and obesity. METHODS: The present study is a secondary analysis of data from the PortionControl@HOME study. The weight of 175 adults was measured at 0, 3 and 12 months and potential determinants were self-reported using validated questionnaires at 0 and 3 months. Weight loss patterns were identified based on percent weight change during Phase 1 (0-3 months) and Phase 2 (3-12 months) using cluster analysis. Determinants were assessed using multinomial logistic regression. RESULTS: We identified three weight loss patterns: (i) low success, demonstrating low weight loss achievement, (ii) moderate success, demonstrating successful weight loss in Phase 1 followed by partial regain in Phase 2 and (iii) high success, demonstrating weight loss in Phase 1 followed by continued weight loss in Phase 2. Compared to the moderate success pattern, the low success pattern was negatively associated with power of food at baseline (i.e. the appetitive drive to consume highly palatable food) (odds ratio, OR = 0.42, 95% CI = 0.21-0.86) and change in portion control behaviour (i.e. the use of behavioural strategies to control the amount of food consumed) (OR = 0.28, 95% CI = 0.10-0.78). CONCLUSIONS: Three weight loss patterns were identified in adults with overweight and obesity. Adults with greater power of food and increased portion control behaviour were less likely to exhibit an unsuccessful weight loss pattern. PMID- 30402897 TI - A data mining and item response mixture modeling method to retrospectively measure Diagnostic and Statistical Manual of Mental Disorders-5 attention deficit hyperactivity disorder in the 1970 British Cohort Study. AB - OBJECTIVE: To facilitate future outcome studies, we aimed to develop a robust and replicable method for estimating a categorical and dimensional measure of Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) attention deficit hyperactivity disorder (ADHD) in the 1970 British Cohort Study (BCS70). METHOD: Following a data mining framework, we mapped DSM-5 ADHD symptoms to age 10 BCS70 data (N = 11,426) and derived a 16-item scale (alpha = 0.85). Mapping was validated by an expert panel. A categorical subgroup was derived (n = 594, 5.2%), and a zero-inflated item response theory (IRT) mixture model fitted to estimate a dimensional measure. RESULTS: Subgroup composition was comparable with other ADHD samples. Relative risk ratios (ADHD/not ADHD) included boys = 1.38, unemployed fathers = 2.07, below average reading = 2.58, and depressed parent = 3.73. Our estimated measures correlated with two derived reference scales: Strengths and Difficulties Questionnaire hyperactivity (r = 0.74) and a Rutter/Conners-based scale (r = 0.81), supporting construct validity. IRT model items (symptoms) had moderate to high discrimination (0.90-2.81) and provided maximum information at average to moderate theta levels of ADHD (0.5-1.75). CONCLUSION: We extended previous work to identify ADHD in BCS70, derived scales from existing data, modeled ADHD items with IRT, and adjusted for a zero-inflated distribution. Psychometric properties were promising, and this work will enable future studies of causal mechanisms in ADHD. PMID- 30402898 TI - The psychological and genetic factors of the addictive behaviors (PGA) study. AB - OBJECTIVES: Most of the addiction studies focus on very specific aspects of addictions, often with contradictory results, and integrated studies are quite rare. Experimental studies comparing underlying mechanisms of addictions and analyzing data from an integrative psychological and genetic perspective are almost nonexistent. The aim of the present paper is to describe the research protocol of the Psychological and Genetic Factors of Addictive Behaviors (PGA) study, which applies an integrative approach to understanding the acquisition, development, and maintenance of addictive behaviors. METHODS: A wide-spectrum national study was carried out. Data were collected from 3,003 adolescents. Addictions to both psychoactive substances and behaviors were thoroughly assessed via psychometrically robust scales, which also included assessment related to a wide range of related psychological dimensions. Additionally, a DNA sample was also collected from participants. RESULTS: The paper presents the detailed methodology of the PGA study. Data collection procedures, instrumentation, and the analytical approach used to attain the research objectives are described. CONCLUSIONS: Future plans, along with potential contributions of the PGA study, are also discussed. It is envisaged that the study will provide a unique opportunity to test possible mechanisms and causal pathways mediating the associations of genetic factors, psychological characteristics, and addictions. PMID- 30402899 TI - Radical Addition/Cyclization Reaction of 2-Vinylanilines with Alkynes: Synthesis of Naphthalenes via Electron Catalysis. AB - A cascade radical addition/cyclization reaction of 2-vinylanilines with alkynes for the synthesis of biologically important naphthalene derivatives is reported. In this transformation, the in-situ-formed diazonium salts from 2-vinylanilines served as efficient aryl radical precursors and the reaction was run under metal free conditions. PMID- 30402900 TI - Tunable luminescent properties of BaGd2 O4 :Eu3+ scintillating phosphors by Pr3+ codoping. AB - BaGd2 O4 :Eu3+ scintillating phosphors by Pr3+ -codoping were synthesized at 1300 degrees C in air using a solid-state reaction method. The as-synthesized phosphors were characterized by X-ray diffraction (XRD), photoluminescence (PL) including excitation and emission spectra, radioluminescence (RL) spectra excited by X-ray and thermoluminescence (TL) spectra. Both the PL and RL spectra are composed of the featured trivalent europium (Eu3+ ) without any praseodymium (Pr3+ ) ions, and the PL and RL intensities as well as the lifetimes of BaGd2 O4 :Eu3+ scintillating phosphors decrease dramatically with an increasing concentration of Pr3+ ions. Finally, the TL spectra reveal the trap concentration of the existing defects decrease with an increasing concentration of Pr3+ ions, while the relative TL intensity ratio of the high temperature band to the low temperature one increases with an increasing concentration of Pr3+ ions, which results in the afterglow suppression of BaGd2 O4 :Eu3+ scintillating phosphors. PMID- 30402901 TI - Application of modified mesoporous boehmite (gamma-AlOOH) with green synthesis carbon quantum dots for a fabrication biosensor to determine trace amounts of doxorubicin. AB - An important form of carbon nanoparticles that are used for a wide range of applications, are carbon dots (CDs). In this study, a very easy, in expensive and green process was described for the preparation of CDs by using hydrothermal treatment of Tragacanth Gum (TG). A rapid assay for the determination of trace amounts of an anticancer medication doxorubicin (DOX) was developed, based on the quenching of the CDs derived from their aggregation. Electrostatic interaction between CDs and DOX could lead to fluorescence quenching. The optimized biosensor showed a detection range from 1 to 400 ng mL-1 and a limit of detection of 0.4 ng mL-1 . In the following, the synthesized CDs modified the Boehmite (Boh) mesoporous surface based on hydrogen bonding. The Boh has been used as supports and ideal hosts in this method, in which the particle size distribution of CDs in the pores of Boh is limited and they have controlled pore sizes. Accordingly, the surface-to-volume ratio and the presence of high-volume pores increased the longevity and sustainability of CDs; also prevented the aggregation of the CDs and improved their photo stability. The advantages of Boh are large pore volume, high surface area, and narrow size distribution. Variable factors influencing optical sensor response in DOX measurement were evaluated and optimized. In optimal conditions, the linear range was calculated from 1 to 500 ngmL-1 and the detection limit was 0.2 ng mL-1 . The sensors were used for measuring DOX in human blood plasma. PMID- 30402902 TI - Development and Implementation of the Inaugural Anatomy Education Research Institute (AERI 2017). AB - Education research is increasingly being recognized as a legitimate route for faculty development in universities. However, many anatomy faculty lack the appropriate training and access to experienced mentors who can help them develop their own education research projects. Inspired by the American Physiological Society's Institute for Teaching and Learning, the coauthors proposed and developed the inaugural Anatomy Education Research Institute (AERI 2017). Funded by an American Association of Anatomists Innovations grant, the five-day institute was held in Bloomington, Indiana in July 2017. The coauthors spent two years preparing the conference schedule, inviting speakers who could discuss education research topics and mentor applicants, reviewing applications, developing assessment instruments for the institute, and hosting the institute. A total of 62 registered participants (applicants and invited speakers) attended AERI 2017. Through a series of presentations and workshops, participants were introduced to many aspects of education research and the Scholarship of Teaching and Learning, including developing rigorous education research questions, determining appropriate methods to assess these questions, and searching the education research literature. Each day also included regular time devoted to work on their own education research project with help from more experienced mentors. Throughout the conference, participants were encouraged to post information on Twitter, using the hashtag #AERI2017. Participants had strong positive impressions of the conference and strongly requested future AERI conferences be held. Follow-up analyses will assess the institute in alignment with Kirkpatrick's Four Levels of Evaluation Model, though preliminary evaluation indicates AERI 2017 met the original aims of the proposal. PMID- 30402903 TI - PTPN22 1858C>T polymorphism is associated with increased CD154 expression and higher CD4+ T cells percentage in rheumatoid arthritis patients. AB - BACKGROUND: CD40 is a costimulatory molecule for B cells, and CD154 is a marker of CD4+ T cells activation. CD40-CD154 interaction promotes pro-inflammatory cytokines secretion and autoantibodies production. PTPN22 gene encodes LYP protein, an inhibitor of T- and B-cell activation. PTPN22 1858C>T polymorphism confers rheumatoid arthritis (RA) susceptibility. Hence, we evaluate the relationship between 1858C>T polymorphism with CD40 and CD154 expression and IFN gamma secretion in RA patients. METHODS: PTPN22 1858C>T polymorphism was genotyped in 315 RA patients and 315 control subjects (CS) using PCR-RFLP method. Later, we selected only ten anti-CCP-positive RA patients, naive to disease modifying antirheumatic drugs and ten CS, all with known 1858C>T PTPN22 genotype. The CD40 and CD154 membrane expressions were determined by flow cytometry in peripheral B and T cells, correspondingly. RESULTS: The B cells percentage and mCD40 expression were similar between RA and CS (P > 0.05) and we did not find an association between these variables and the 1858C>T polymorphism. The CD4+ T cells percentage was higher in RA patients than CS (P = 0.003), and in the RA group, the CD4+ T cells percentage and mCD154 expression were higher in the 1858 T allele carriers (P = 0.008 and P = 0.032, respectively). The IFN-gamma levels were lower in RA patients carrying the PTPN22 risk allele (P = 0.032). CONCLUSION: The PTPN22 1858 T risk allele is associated with increased CD4+ T cells percentage and high mCD154 expression in RA patients, which could favor the pro-inflammatory cytokine release and the establishment of the inflammatory response at the seropositive RA. PMID- 30402904 TI - Circadian disruption: What do we actually mean? AB - The circadian system regulates physiology and behavior. Acute challenges to the system, such as those experienced when traveling across time zones, will eventually result in re-synchronization to local environmental time cues, but this re-synchronization is oftentimes accompanied by adverse short-term consequences. When such challenges are experienced chronically, adaptation may not be achieved, as for example in the case of rotating night shift workers. The transient and chronic disturbance of the circadian system is most frequently referred to as "circadian disruption", but many other terms have been proposed and used to refer to similar situations. It is now beyond doubt that the circadian system contributes to health and disease, emphasizing the need for clear terminology when describing challenges to the circadian system and their consequences. The goal of this review is to provide an overview of the terms used to describe disruption of the circadian system, discuss proposed quantifications of disruption in experimental and observational settings with a focus on human research, and highlight limitations and challenges of currently available tools. For circadian research to advance as a translational science, clear, operationalizable, and scalable quantifications of circadian disruption are key, as they will enable improved assessment and reproducibility of results, ideally ranging from mechanistic settings, including animal research, to large-scale randomized clinical trials. PMID- 30402905 TI - Androgen Deprivation Therapy Use Increases the Risk of Heart Failure in Patients With Prostate Cancer: A Population-Based Cohort Study. AB - The aim of this study was to investigate the relationship between androgen deprivation therapy and heart failure among prostate cancer patients. This cohort study used the data from the Taiwan Longitudinal Health Insurance Database 2005. In the full cohort study, we identified 1244 prostate cancer patients who had received androgen deprivation therapy as the study cohort and 1806 prostate cancer patients who did not receive androgen deprivation therapy as the comparison cohort. To eliminate potential bias, we performed a propensity score matched cohort study. Each prostate cancer patient was tracked for 1 year from the index date to ascertain whether they were subsequently diagnosed with heart failure. In the full cohort study, incidence rates of heart failure per 100 person-years within the 1-year follow-up period were 4.00 (95%CI, 2.95-5.30) and 1.89 (95%CI, 1.30-2.66) for androgen deprivation therapy users and nonusers, respectively. In addition, the multivariable Cox regression indicated that the hazard ratio (HR) of heart failure among androgen deprivation therapy users was 1.72 (95%CI, 1.08-2.73) compared with those androgen deprivation therapy nonusers. In the propensity score-matched cohort study, the adjusted HR for heart failure among androgen deprivation therapy users was 1.92 (95%CI, 1.15-3.18) compared with propensity score-matched nonusers. In conclusion, this study found that androgen deprivation therapy users had a higher risk of heart failure than nonusers among prostate cancer patients in both the full cohort study and the propensity score-matched study. PMID- 30402906 TI - Mandibular first premolar apical morphology: A stereomicroscopic study. AB - The aim of this study was to investigate the size, shape and position of the physiological foramen and the relationship between the age and gender to the location and size of the apical foramen of mandibular first premolars. One hundred and one extracted human mandibular first premolar teeth were examined; age and gender of the patients were recorded. Apices of teeth were examined stereomicroscopically for number, size and shape of apical foramina; frequency and deviation of accessory foramina from the apex and the relation with age and gender. Sixty-four of the premolars had one foramen and 23% had two. The distances from the foramina openings to the apices ranged from 0.07 to 2.18 mm. In younger range irregular shape was dominant (41%), whilst in older range, round shape was dominant (45%). The shape of the apical foramen changed with age and the distance from the foramen to the anatomical apex increased with age. PMID- 30402907 TI - Maternity care hospital trends in providing postdischarge breastfeeding supports to new mothers-United States, 2007-2015. AB - BACKGROUND: Hospitals that provide maternity care can play an important role in providing or directing mothers to postdischarge breastfeeding support, which improves breastfeeding duration especially when providing multiple support modes. This study described 2007-2015 national trends in postdischarge breastfeeding supports among United States maternity care hospitals. METHODS: Data were from the Maternity Practices in Infant Nutrition and Care survey, a biennial census of maternity care hospitals in the United States and territories. Hospitals reported whether they provided nine support types, which we categorized into three support modes: physical contact (eg, return visits), active reaching out (eg, telephone calls), and referrals (eg, to lactation consultants). We calculated prevalence of each support type, each support mode, and providing all three support modes for each survey year and examined trends over 2007-2015. For 2015, we assessed differences by hospital- and area-level characteristics. RESULTS: Prevalence of providing all three support modes increased from 24% (2007) to 31% (2015). Nearly all (99%) hospitals provided referrals in each survey year. Fewer offered physical contact and active reaching out. However, from 2007 to 2015, the prevalence of physical contact increased from 39% to 46%; active reaching out increased from 54% to 64%. In 2015, smaller and rural hospitals were more likely to provide all three discharge supports. CONCLUSIONS: Prevalence of offering referrals was high, but there is room for improvement in providing physical contact and active reaching out to ensure multiple modes of support are available to help mothers reach their breastfeeding goals. PMID- 30402908 TI - The relationship between phospholipids and insulin resistance: From clinical to experimental studies. AB - Insulin resistance induced by high-fat diet and impropriate life style is a major contributor to the pathogenesis of metabolic disease. However, the underlying molecular mechanisms remain unclear. Recent studies in metabolic dysfunction have extended this beyond simply elevated cholesterol and triglycerides levels and have identified a key role for lipid metabolism. For example, altered phospholipid metabolism has now become central in the pathogenesis of metabolic disease. In this review, we discuss the association between insulin sensitivity and phospholipid metabolism and highlight the most significant discoveries generated over the last several decades. Finally, we summarize the current knowledge surrounding the molecular mechanisms related to phospholipids and insulin resistance and provide new insight for future research into their relationship. PMID- 30402909 TI - How chromosomal rearrangements shape adaptation and speciation: Case studies in Drosophila pseudoobscura and its sibling species D. persimilis. AB - The gene arrangements of Drosophila have played a prominent role in the history of evolutionary biology from the original quantification of genetic diversity to current studies of the mechanisms for the origin and establishment of new inversion mutations within populations and their subsequent fixation between species supporting reproductive barriers. This review examines the genetic causes and consequences of inversions as recombination suppressors and the role that recombination suppression plays in establishing inversions in populations as they are involved in adaptation within heterogeneous environments. This often results in the formation of clines of gene arrangement frequencies among populations. Recombination suppression leads to the differentiation of the gene arrangements which may accelerate the accumulation of fixed genetic differences among populations. If these fixed mutations cause incompatibilities, then inversions pose important reproductive barriers between species. This review uses the evolution of inversions in Drosophila pseudoobscura and D. persimilis as a case study for how inversions originate, establish, and contribute to the evolution of reproductive isolation. This article is protected by copyright. All rights reserved. PMID- 30402910 TI - Ultrasound imaging of the fetal secondary palate: methodological description of a two dimensional approach, and a case series. AB - OBJECTIVE: to describe our two dimensional (2D) ultrasound approach to visualize the fetal secondary palate, and plot its growth curve, and to describe demonstrate its clinical implementation. METHODS: this is a two parts retrospective study. First, we measured the antero-posterior length of the bony secondary palate, from the soft to hard palate interface (SHPI) line to the alveolar ridge, blindly by two operators during routine scans of low risk fetuses, and plot a longitudinal growth curve. In the second part, we describe four cases of prenatal diagnosis of secondary palate cleft. RESULTS: sixty eight fetuses were included. 14-15 weeks (n=20), 21-24 weeks (n=32) and 29-35 weeks (n=16). The bony secondary palate elongates along gestation from a mean of 5.3 mm (+/- 0.46 mm) at 14-15 weeks to 15.9 mm (+/- 1.7 mm) at 29-35 mm. we found high intra and inter-observer correlation between measurements. All four cases diagnosed by this approach where confirmed postnatally. CONCLUSIONS: the SHPI, representing the normally developed secondary bony palate, can be imaged in the fetus by direct 2D ultrasound as early as 14 weeks. A gap within, or non visualization of the SHPI is highly suggestive for a secondary palate cleft. PMID- 30402911 TI - Development of new 3D human ex vivo models to study sebaceous gland lipid metabolism and modulations. AB - OBJECTIVES: Sebaceous glands maintain skin homeostasis by producing sebum. Low production can induce hair loss and fragile skin. Overproduction provokes seborrhoea and may lead to acne and inflammatory events. To better study sebaceous gland maintenance, sebocyte maturation, lipid production and ageing or inflammatory processes, we developed innovative 3D ex vivo models for human sebaceous glands. MATERIALS AND METHODS: Culture conditions and analytical methods optimized on sebocyte monolayers were validated on extracted sebaceous glands and allowed the development of two 3D models: (a) "air-liquid" interface and (b) human fibronectin-coated "sandwich" method. Lipid production was assessed with microscopy, fluorometry or flow cytometry analysis after Nile Red staining. Specific lipids (particularly squalene and peroxidized squalene) were measured by Gas or liquid Chromatography and Mass spectrometry. RESULTS: This study allowed us to select appropriate conditions and design Seb4Gln culture medium inducing sebocyte proliferation and neutral lipid production. The "air-liquid" model was appropriate to induce sebocyte isolation. The "sandwich" model enabled sebaceous gland maintenance up to 42 days. A treatment with Insulin Growth Factor-1 allowed validation of the model as we succeeded in mimicking dynamic lipid overproduction. CONCLUSION: Functional sebocyte maturation and physiological maintenance were preserved up to 6 weeks in our models. Associated with functional assays, they provide a powerful platform to mimic physiological skin lipid metabolism and to screen for active ingredients modulating sebum production. PMID- 30402915 TI - Diagnostic Biomarkers for Predicting Adverse Early Pregnancy Outcomes: Scientific Impact Paper No. 58. PMID- 30402914 TI - Admissible multiarm stepped-wedge cluster randomized trial designs. AB - Numerous publications have now addressed the principles of designing, analyzing, and reporting the results of stepped-wedge cluster randomized trials. In contrast, there is little research available pertaining to the design and analysis of multiarm stepped-wedge cluster randomized trials, utilized to evaluate the effectiveness of multiple experimental interventions. In this paper, we address this by explaining how the required sample size in these multiarm trials can be ascertained when data are to be analyzed using a linear mixed model. We then go on to describe how the design of such trials can be optimized to balance between minimizing the cost of the trial and minimizing some function of the covariance matrix of the treatment effect estimates. Using a recently commenced trial that will evaluate the effectiveness of sensor monitoring in an occupational therapy rehabilitation program for older persons after hip fracture as an example, we demonstrate that our designs could reduce the number of observations required for a fixed power level by up to 58%. Consequently, when logistical constraints permit the utilization of any one of a range of possible multiarm stepped-wedge cluster randomized trial designs, researchers should consider employing our approach to optimize their trials efficiency. PMID- 30402913 TI - Effects of In-Hospital Exercise on Sarcopenia in Hepatoma Patients Who Underwent Transcatheter Arterial Chemoembolization. AB - BACKGROUND AND AIMS: Sarcopenia is a prognostic factor in hepatocellular carcinoma (HCC) patients. HCC patients who underwent transcatheter arterial chemoembolization (TACE) are at a risk of muscle atrophy. We aimed to investigate the effects of in-hospital exercise on muscle mass and factors associated with muscle hypertrophy in HCC patients who underwent TACE. METHODS: We enrolled 209 HCC patients who underwent TACE. Patients were classified into either an Exercise (n=102) or Control (n=107) group. In the Exercise group, patients were treated with in-hospital exercise (median 2.5 metabolic equivalents/20-40 min/day). The effects of exercise on muscle mass were evaluated by changes in skeletal muscle index (DeltaSMI) between before and after TACE. Factors associated with an increase in SMI were analyzed by logistic regression and decision-tree analyses. RESULTS: There was no significant difference in serum albumin and bilirubin levels between the two groups. DeltaSMI was significantly higher in the Exercise group than in the Control group (0.28 cm2 /m2 vs. -1.11 cm2 /m2 , P=0.0029). In the logistic regression analysis, exercise was an independent factor for an increase in SMI (HR 2.13; 95% CI 1.215-3.846; P=0.0085). Moreover, the decision tree analysis showed that exercise was the initial divergence variable for an increase in SMI (the ratio of increased SMI: 53% in the exercise group vs. 36% in the Control group). CONCLUSIONS: In-hospital exercises increased muscle mass in HCC patients who underwent TACE. In addition, exercise was an independent factor for muscle hypertrophy. Thus, in-hospital exercise may prevent sarcopenia in HCC patients who underwent TACE. PMID- 30402916 TI - Predictors of first-year nonadherence and discontinuation of statins among older adults: a retrospective cohort study. AB - AIMS: The aim of this study was to examine the level of and predictors of statin nonadherence and discontinuation among older adults. METHODS: Among 22 340 Australians aged >=65 years who initiated statin therapy from January 2014 to December 2015, we estimated the first-year nonadherence (proportion of days covered [PDC] <0.80) and discontinuation (>=90 days without statin coverage) rates. Predictors of nonadherence and discontinuation were examined via multivariable logistic regression. Analyses were performed separately for general beneficiaries (with a higher co-payment; n = 4841) and concessional beneficiaries (with a lower co-payment; n = 17 499). RESULTS: During the one-year follow-up, 55.1% were nonadherent (concessional 52.6%; general beneficiaries 64.2%) and 44.7% discontinued statins (concessional 43.1%; general beneficiaries 50.4%). Among concessional beneficiaries, those aged 75-84 years and >=85 years were more likely to discontinue than people aged 65-74 years (odds ratio 1.11, 95% confidence interval 1.04-1.19 and 1.38, 1.23-1.54, respectively). Diabetes was associated with an increased likelihood of nonadherence and discontinuation, while hypertension, angina and congestive heart failure were associated with a lower likelihood of nonadherence and discontinuation. Anxiety was associated with an increased likelihood of discontinuation, but polypharmacy (concurrent use of five or more drugs) was associated with a lower likelihood of nonadherence and discontinuation. Statin initiation by a general medical practitioner was associated with both increased likelihood of nonadherence and discontinuation. Similar predictors of nonadherence and discontinuation were identified for the general beneficiaries. CONCLUSIONS: Among older adults prescribed statins, first year nonadherence and discontinuation are high. Specific population subgroups such as people aged >=85 years, those with diabetes or anxiety may require additional attention to improve statin adherence. PMID- 30402917 TI - Effects of ketamine/xylazine and isoflurane on rat brain glucose metabolism measured by 18 F-fluorodeoxyglucose-positron emission tomography. AB - The aim of the present study was to investigate changes in glucose metabolism in male Wistar rats induced by the anesthetics isoflurane and ketamine combined with xylazine via 18 F-fluorodeoxyglucose-positron emission tomography. We analyzed the differential effects of the anesthetics on 18 F-fluorodeoxyglucose uptake and pharmacokinetics in 33 rats using quantification methods: 1) the standardized uptake value, 2) voxel-based analyses, and 3) kinetic analysis. Both anesthetics reduced glucose uptake in the entire brain. The voxel-based analyses detected smaller uptake reductions in the bilateral primary somatosensory system cortex and part of the limbic system in the ketamine-xylazine (KX) group and in the vestibular nucleus in the isoflurane group. Through kinetic analysis, we found that the volume of distribution and the membrane transport rate K1 were reduced in the KX group. Through various methods of 18 F-fluorodeoxyglucose-positron emission tomography quantification, the present study found that anesthesia with the ketamine-xylazine combination induced a global reduction of glucose metabolism compared with isoflurane; this reduction of metabolism was relatively lower in the primary somatosensory cortex and part of the limbic system. The volume of distribution of 18 F-fluorodeoxyglucose and its Glut1-mediated transport across the brain membranes (K1 ) were decreased in the KX group. This article is protected by copyright. All rights reserved. PMID- 30402918 TI - Risk of neurosyphilis in HIV-infected persons with syphilis lacking signs or symptoms of central nervous system infection. AB - OBJECTIVES: People living with HIV (PLWH) are at increased risk of asymptomatic neurosyphilis; thus, it has been common practice to perform a lumbar puncture (LP) in all PLWH presenting with syphilis regardless of stage, signs or symptoms. However, this practice varies widely among clinicians. Our objective was to elucidate the number of LPs required to diagnose a single case of asymptomatic neurosyphilis. METHODS: We performed an electronic health record (EHR) review of PLWH who were diagnosed with syphilis of any stage over a 10-year period. EHRs were reviewed to determine the number of subjects who had an LP performed, what proportion had neurological signs or symptoms, and whether a diagnosis of neurosyphilis was made at presentation or follow-up. RESULTS: In 261 separate episodes of syphilis in 230 subjects, we found the major risk factors for asymptomatic neurosyphilis to be low CD4 T-cell count (P = 0.0007), high rapid plasma reagin (RPR) titre (P = 0.019) and lack of HIV virological suppression (P = 0.003). The majority of our subjects (78%) with neurosyphilis presented with central nervous system (CNS) symptoms. We estimate, if standard practice is to perform LP in all patients, that the number needed to test (NNTT) = 38. CONCLUSIONS: This large number of potentially unnecessary LPs, along with heterogeneity of presentation, and the never-nil risk of asymptomatic neurosyphilis should be incorporated into clinical decision-making. The majority of PLWH presenting with a serological diagnosis of syphilis, but no neurological signs or symptoms, do not necessarily require an LP for an evaluation of asymptomatic neurosyphilis. PMID- 30402920 TI - A systematic knowledge synthesis on the spatial dimensions of Q fever epidemics. AB - From 2007 through 2010, the Netherlands experienced the largest Q fever epidemic ever reported. This study integrates the outcomes of a multidisciplinary research programme on spatial airborne transmission of Coxiella burnetii and reflects these outcomes in relation to other scientific Q fever studies worldwide. We have identified lessons learned and remaining knowledge gaps. This synthesis was structured according to the four steps of quantitative microbial risk assessment (QMRA): (a) Rapid source identification was improved by newly developed techniques using mathematical disease modelling; (b) source characterization efforts improved knowledge but did not provide accurate C. burnetii emission patterns; (c) ambient air sampling, dispersion and spatial modelling promoted exposure assessment; and (d) risk characterization was enabled by applying refined dose-response analyses. The results may support proper and timely risk assessment and risk management during future outbreaks, provided that accurate and structured data are available and exchanged readily between responsible actors. PMID- 30402919 TI - Raman characterization of human skin aging. AB - BACKGROUND: Skin aging is a complex biological process mixing intrinsic and extrinsic factors, such as sun exposure. At the molecular level, skin aging affects in particular the extracellular matrix proteins. MATERIALS AND METHODS: Using Raman imaging, which is a nondestructive approach appropriate for studying biological samples, we analyzed how aging modifies the matrix proteins of the papillary and reticular dermis. Biopsies from the buttock and dorsal forearm of volunteers younger than 30 and older than 60 were analyzed in order to identify chronological and photoaging processes. Analyses were performed on skin section, and Raman spectra were acquired separately on the different dermal layers. RESULTS: We observed differences in dermal matrix structure and hydration state with skin aging. Chronological aging alters in particular the collagen of the papillary dermis, while photoaging causes a decrease in collagen stability by altering proline and hydroxyproline residues in the reticular dermis. Moreover, chronological aging alters glycosaminoglycan content in both dermal compartments. CONCLUSION: Alterations of the papillary and reticular dermal matrix structures during photo- and chronological aging were clearly depicted by Raman spectroscopy. PMID- 30402921 TI - Gestational Weight Gain and Offspring Bone Mass: Different Associations in Healthy Weight Versus Overweight Women. AB - Weight management strategies during pregnancy reduce child cardiometabolic risk. However, because maternal weight has an overall positive correlation with offspring bone mass, pregnancy weight management could adversely affect child bone health. We aimed to estimate associations between gestational weight gain (GWG) and bone mineralization in the offspring at 7 years of age, and test early pregnancy body mass index (BMI) as an effect modifier. We analyzed prospective data from 2167 mother-child pairs from the Generation XXI birth cohort who underwent whole-body dual-energy X-ray absorptiometry at 7 years of age. GWG was analyzed as a continuous measure and using the Institute of Medicine categories. In the whole sample and for each early pregnancy BMI category (under/normal weight and overweight/obese), relationships between GWG and offspring bone measures (bone mineral content [BMC], bone areal density [aBMD], size-corrected BMC [scBMC], and height) at 7 years were fitted through local polynomial regression and smoothing splines. The magnitude of associations was estimated through linear regression coefficients (95% CIs), crude and adjusted for maternal age, height, educational level, and child gestational age. In under/normal weight mothers, GWG was associated with slightly increased bone measures at 7 years (per 5 kg of GWG, BMC: 0.07 SD [95% CI, 0.01 to 0.12]; aBMD: 0.10 SD [95% CI, 0.05 to 0.15], scBMC: 0.11SD [95% CI, 0.06 to 0.16], and height: 0.05 SD [95% CI, 0.00 to 0.10]), while in overweight/obese mothers no effect of GWG on bone was observed (BMC: 0.02 SD [95% CI, -0.04 to 0.09]; aBMD: 0.02 SD [95% CI, -0.04 to 0.08], scBMC: 0.01 SD [95% CI, -0.06 to 0.08], and height: 0.02 SD [95% CI, -0.04 to 0.08]). Also, no advantageous effect of gaining weight above the Institute of Medicine recommendations was observed in either early pregnancy BMI group. Our results suggest that adherence to Institute of Medicine recommendations for pregnancy weight gain is unlikely to have a negative repercussion on offspring bone health, particularly in women with excess weight in early pregnancy. (c) 2018 American Society for Bone and Mineral Research. PMID- 30402922 TI - Development of an 18-item abbreviated Chinese version of Berger's HIV Stigma Scale. AB - AIM: Human immunodeficiency virus (HIV) stigma in people living with HIV is associated with depression and poor treatment adherence. The current literature lacks a Chinese instrument to measure HIV stigma in Taiwan. Thus, the purpose of this study was to develop an abbreviated Chinese translation version of Berger's HIV Stigma Scale. METHODS: The instrument development process was guided by Brislin's Translation Model of establishment of construct validity and convergent validity and verification of reliability. RESULTS: This study recruited 540 HIV infected adults (January-November 2015). Data analysis using confirmatory factor analysis resulted in an 18-item abbreviated Chinese version of Berger's HIV Stigma Scale, consisting with four factors: personalized stigma (seven items), disclosure concerns (three items), negative self-image (four items), and concerns with public attitudes toward people with HIV (four items). The final model demonstrated a good fit. A positive correlation between HIV stigma and depression was found. The Cronbach alpha for internal consistency was 0.92. CONCLUSION: The 18-item abbreviated Chinese version of Berger's HIV Stigma Scale demonstrated adequate reliability and validity to assess HIV stigma among Chinese people living with HIV. It is a feasible tool that allows for rapid assessment of HIV related stigma. PMID- 30402923 TI - Circuit development in the master clock network of mammals. AB - Daily rhythms are generated by the circadian timekeeping system, which is orchestrated by the master circadian clock in the suprachiasmatic nucleus (SCN) of mammals. Circadian timekeeping is endogenous and does not require exposure to external cues during development. Nevertheless, the circadian system is not fully formed at birth in many mammalian species and it is important to understand how SCN development can affect the function of the circadian system in adulthood. The purpose of the current review is to discuss the ontogeny of cellular and circuit function in the SCN, with a focus on work performed in model rodent species (i.e., mouse, rat, and hamster). Particular emphasis is placed on the spatial and temporal patterns of SCN development that may contribute to the function of the master clock during adulthood. Additional work aimed at decoding the mechanisms that guide circadian development is expected to provide a solid foundation upon which to better understand the sources and factors contributing to aberrant maturation of clock function. PMID- 30402924 TI - Mood-related central and peripheral clocks. AB - Mood disorders, including major depression, bipolar disorder, and seasonal affective disorder, are debilitating disorders that affect a significant portion of the global population. Individuals suffering from mood disorders often show significant disturbances in circadian rhythms and sleep. Moreover, environmental disruptions to circadian rhythms can precipitate or exacerbate mood symptoms in vulnerable individuals. Circadian clocks exist throughout the central nervous system and periphery, where they regulate a wide variety of physiological processes implicated in mood regulation. These processes include monoaminergic and glutamatergic transmission, hypothalamic-pituitary-adrenal axis function, metabolism, and immune function. While there seems to be a clear link between circadian rhythm disruption and mood regulation, the mechanisms that underlie this association remain unclear. This review will touch on the interactions between the circadian system and each of these processes and discuss their potential role in the development of mood disorders. While clinical studies are presented, much of the review will focus on studies in animal models, which are attempting to elucidate the molecular and cellular mechanisms in which circadian genes regulate mood. PMID- 30402925 TI - Nickel Metal-Organic Frameworks Monolayers for Photoreduction of Diluted CO2 : Metal-Node-Dependent Activity and Selectivity. AB - Photocatalytic conversion of diluted CO2 into solar fuel is highly appealing yet still in its infancy. Herein, we demonstrate the metal-node-dependent performance for photoreduction of diluted CO2 by constructing Ni metal-organic framework (MOF) monolayers (Ni MOLs). In diluted CO2 (10 %), Ni MOLs exhibit a highest apparent quantum yield of 1.96 % with a CO selectivity of 96.8 %, which not only exceeds reported systems in diluted CO2 but also is superior to most catalysts in pure CO2 . Whereas isostructural Co MOLs is almost inactive in diluted CO2 , indicating the performance is dependent on the metal nodes. Experimental and theoretical investigations show that strong CO2 binding affinity of Ni MOLs is the crucial factor, which stabilizes the Ni-CO2 adducts and facilitates CO2 -to CO conversion. PMID- 30402926 TI - Neuronal phase consistency tracks dynamic changes in acoustic spectral regularity. AB - The brain parses the auditory environment into distinct sounds by identifying those acoustic features in the environment that have common relationships (e.g., spectral regularities) with one another and then grouping together the neuronal representations of these features. Although there is a large literature that tests how the brain tracks spectral regularities that are predictable, it is not known how the auditory system tracks spectral regularities that are not predictable and that change dynamically over time. Furthermore, the contribution of brain regions downstream of the auditory cortex to the coding of spectral regularity is unknown. Here, we addressed these two issues by recording electrocorticographic activity, while human patients listened to tone-burst sequences with dynamically varying spectral regularities, and identified potential neuronal mechanisms of the analysis of spectral regularities throughout the brain. We found that the degree of oscillatory stimulus phase consistency (PC) in multiple neuronal-frequency bands tracked spectral regularity. In particular, PC in the delta-frequency band seemed to be the best indicator of spectral regularity. We also found that these regularity representations existed in multiple regions throughout cortex. This widespread reliable modulation in PC both in neuronal-frequency space and in cortical space - suggests that phase based modulations may be a general mechanism for tracking regularity in the auditory system specifically and other sensory systems more generally. Our findings also support a general role for the delta-frequency band in processing the regularity of auditory stimuli. PMID- 30402927 TI - Value-based assessment of hysterectomy approaches. AB - AIM: By evaluating operative outcomes relative to cost, we compared the value of minimally invasive hysterectomy approaches, including a technique discussed less often in the literature, laparoscopic retroperitoneal hysterectomy (LRH), which incorporates retroperitoneal dissection and ligation of the uterine arteries at their vascular origin. METHODS: Retrospective chart review of all women (N = 2689) aged greater than or equal to 18 years who underwent hysterectomy for benign conditions from 2011 to 2013 at a high-volume hospital in Maryland, USA. Procedures included: laparoscopic supracervical hysterectomy, robotic-assisted laparoscopic hysterectomy (RALH), total laparoscopic hysterectomy, laparoscopic assisted vaginal hysterectomy, total vaginal hysterectomy (TVH), and LRH. RESULTS: Total vaginal hysterectomy had the highest intraoperative complication rate (9.6%; P < 0.0001) but the lowest postoperative complication rate (1.8%; P < 0.0001). Robotics had the highest postoperative complication rate (11.4%; P < 0.0001). LRH had the shortest operative time (71.2 min; P < 0.0001) and the lowest intraoperative complication rates (2.1%; P < 0.0001). LRH and TVH were the least costly (averaging $4061 and $6416, respectively), while RALH was the most costly ($9354). Taking both operative outcomes and cost into account, LRH, TVH and laparoscopic-assisted vaginal hysterectomy yielded the highest value scores; total laparoscopic hysterectomy, RALH, and laparoscopic supracervical hysterectomy yielded the lowest. CONCLUSION: Understanding the value of surgical interventions requires an evaluation of both operative outcomes and direct hospital costs. Using a quality-cost framework, the LRH approach as performed by high-volume laparoscopic specialists emerged as having the highest calculated value. PMID- 30402928 TI - Monitoring serum proangiogenic cytokines from hepatocellular carcinoma patients treated with sorafenib. AB - BACKGROUND: Several factors, including proangiogenic cytokines, have been reported as predictive markers for the treatment effect of sorafenib in patients with hepatocellular carcinoma (HCC); however, most of them were determined based on one-time measurements prior to treatment. METHODS: We consecutively recruited 80 advanced HCC patients who were treated with sorafenib prospectively. Serum levels of eight proangiogenic cytokines and the appearance of adverse events were monitored periodically, and their correlations with the prognoses of the patients were evaluated. RESULTS: Among six significant risk factors for overall survival in univariate analyses, high angiopoietin-2 (hazard ratio, 2.06), high hepatocyte growth factor (hazard ratio, 2.08), and poor performance status before the treatment (hazard ratio, 2.48) were determined as independent risk factors. In addition, high angiopoietin-2 at the time of progressive disease was a marker of short post-progression survival (hazard ratio, 4.27). However, there was no significant variable that predicted short progression-free survival except the presence of hepatitis B virus surface antigen. CONCLUSIONS: Predictions of overall survival and post-progression survival were possible by periodically measuring serum proangiogenic cytokines, especially angiopoietin-2, in patients with HCC treated with sorafenib. PMID- 30402929 TI - Neutrophilia and hyperamylasemia in patients with immediate food allergy. AB - BACKGROUND: Presently, little is known about laboratory findings several hours after oral food challenge (OFC) in patients with IgE-mediated immediate food allergy (FA). METHODS: One hundred and twelve subjects who underwent OFC at our institute between June 1, 2016, and March 31, 2018, were enrolled in this study. Changes in laboratory data several hours after OFC were examined. RESULTS: OFC was positive in 76 patients and negative in 36. Increases in absolute neutrophil count (ANC) were significantly higher in the OFC-positive than in the OFC negative subjects (median, 2306 vs. 637; p<0.00001). Multivariate regression analysis revealed a significant correlation between neutrophilia and the development of gastrointestinal symptoms (t=3.63; p<0.001). Serum interleukin-6 levels increased in 43.8% of the patients with marked neutrophilia and showed a significant positive correlation with ANC (r=0.64; p<0.001). Serum amylase level increased in 33.3% of the OFC-positive patients and was higher than 100 U/L (median, 642 U/L) in five patients in whom serum lipase levels also increased markedly (1197 U/L). There was a significant negative correlation between an increase in the serum amylase level and a decrease in absolute eosinophil count (r=-0.36, p<0.01). CONCLUSIONS: This study first revealed marked neutrophilia after OFC in patients with immediate FA showing gastrointestinal symptoms, which may provide a new insight into the relationship between symptoms and laboratory data. A considerable increase in the serum amylase level after OFC was also shown here in patients with immediate FA, suggesting that the pancreas is a target organ for immediate FA. This article is protected by copyright. All rights reserved. PMID- 30402930 TI - Active vaccination against interleukin-5 as long-term treatment for insect-bite hypersensitivity in horses. AB - BACKGROUND: Insect-bite hypersensitivity (IBH) in horses is a chronic allergic dermatitis caused by insect bites. Horses suffer from pruritic skin lesions, caused by type-I/type-IV allergic reactions accompanied by prominent eosinophil infiltration into the skin. Interleukin-5 (IL-5) is the key cytokine for eosinophils and we have previously shown that targeting IL-5 by vaccination reduces disease symptoms in horses. OBJECTIVE: Here, we analyzed the potential for long-term therapy by assessing a second follow-up year of the previously published study. METHODS: The vaccine consisted of equine IL-5 (eIL-5) covalently linked to a cucumber mosaic virus-like particle (VLP) containing a universal T cell epitope (CuMVTT ) using a semi-crossover design to follow vaccinated horses during a second treatment season. Thirty Icelandic horses were immunized with 300 MUg of eIL-5-CuMVTT without adjuvant. RESULTS: The vaccine was well tolerated and did not reveal any safety concerns throughout the study. Upon vaccination, all horses developed reversible anti-eIL-5 auto-antibody titers. The mean course of eosinophil levels was reduced compared to placebo treatment leading to significant reduction of clinical lesion scores. Horses in their second vaccination year showed a more pronounced improvement of disease symptoms when compared to first treatment year, most likely due to more stable antibody titers induced by a single booster injection. Hence, responses could be maintained over two seasons and the horses remained protected against disease symptoms. CONCLUSION: Yearly vaccination against IL-5 may be a long-term solution for the treatment of IBH and other eosinophil-mediated diseases in horses and other species including humans. PMID- 30402931 TI - Chemo-preventive and therapeutic effect of the dietary flavonoid kaempferol: A comprehensive review. AB - Kaempferol, a natural flavonoid present in several plants, possesses a wide range of therapeutic properties such as antioxidant, anticancer, and anti-inflammatory. It has a significant role in reducing cancer and can act as a therapeutic agent in the treatment of diseases and ailments such as diabetes, obesity, cardiovascular diseases, oxidative stress, asthma, and microbial contamination disorders. Kaempferol acts through different mechanisms: It induces apoptosis (HeLa cervical cancer cells), decreases cell viability (G2/M phase), downregulates phosphoinositide 3-kinase (PI3K)/AKT (protein kinase B) and human T cell leukemia/lymphoma virus-I (HTLV-I) signaling pathways, suppresses protein expression of epithelial-mesenchymal transition (EMT)-related markers including N cadherin, E-cadherin, Slug, and Snail, and metastasis-related markers such as matrix metallopeptidase 2 (MMP-2). Accordingly, the aim of the present review is to collect information pertaining to the effective role of kaempferol against various degenerative disorders, summarize the antioxidant, anti-inflammatory, anticancer, antidiabetic, and antiaging effects of kaempferol and to review the progress of recent research and available data on kaempferol as a protective and chemotherapeutic agent against several ailments. PMID- 30402932 TI - Efficacy of cannabinoids in paediatric epilepsy. AB - There are hundreds of compounds found in the marijuana plant, each contributing differently to the antiepileptic and psychiatric effects. Cannabidiol (CBD) has the most evidence of antiepileptic efficacy and does not have the psychoactive effects of ?9 -tetrahydrocannabinol. CBD does not act via cannabinoid receptors and its antiepileptic mechanism of action is unknown. Despite considerable community interest in the use of CBD for paediatric epilepsy, there has been little evidence for its use apart from anecdotal reports, until the last year. Three randomized, placebo-controlled, double-blind trials in Dravet syndrome and Lennox-Gastaut syndrome found that CBD produced a 38% to 41% median reduction in all seizures compared to 13% to 19% on placebo. Similarly, CBD resulted in a 39% to 46% responder rate (50% convulsive or drop-seizure reduction) compared to 14% to 27% on placebo. CBD was well tolerated; however, sedation, diarrhoea, and decreased appetite were frequent. CBD shows similar efficacy to established antiepileptic drugs. WHAT THIS PAPER ADDS: Cannabidiol (CBD) shows similar efficacy in the severe paediatric epilepsies to other antiepileptic drugs. Careful down-titration of benzodiazepines is essential to minimize sedation with adjunctive CBD. PMID- 30402934 TI - Performance of routine assessment of patient index data 3 (RAPID3) in monitoring disease activity of Chinese rheumatoid arthritis patients. AB - AIM: To explore the performance of routine assessment of patient index data 3 (RAPID3) in reflecting disease activity in Chinese rheumatoid arthritis (RA) patients. METHOD: The clinical data of 189 consecutive RA patients, including RAPID3 questionnaire, Disease Activity Score based on 28-joint count (DAS28), clinical disease activity index (CDAI) and simplified disease activity index (SDAI), and ultrasonography of hand and wrist joints were collected. The consistency between RAPID3 and DAS28, CDAI, SDAI in RA patients with different disease activities was performed by Spearman's correlations, kappa and/or weighted kappa coefficients. RESULT: RAPID3 score was significantly associated with DAS28 and erythrocyte sedimentation rate (ESR), DAS28 with C-reactive protein (CRP), CDAI, SDAI (r = 0.797, 0.786, 0.784, and 0.760 respectively, P < 0.001 for all). RAPID3 was also significantly correlated with tender joint count, swollen joint count, ESR and CRP. The agreement of RAPID3 with DAS28 scoring systems was better in patients with moderate/high disease activity than those in remission/low disease activity. Ultrasonographic subclinical synovitis was presented in 42.3%-48.6% of patients in remission/low disease activity defined by various scoring criteria including RAPID3 with no significant difference observed (P = 0.22, >0.05). CONCLUSION: RAPID3 showed good correlation with DAS28 scoring systems, especially in patients with moderate/high disease activity. RAPID3 is a reliable and convenient tool to monitor disease activity. PMID- 30402935 TI - A dosimetric study on the use of 3D-printed customized boluses in photon therapy: A hydrogel and silica gel study. AB - PURPOSE: The aim of the study was to compare the dose differences between two kinds of materials (silica gel and hydrogel) used to prepare boluses based on three-dimensional (3D) printing technologies and commercial bolus in head phantoms simulating nose, ear, and parotid gland radiotherapy. METHODS AND MATERIALS: We used 3D printing technology to make silica gel and hydrogel boluses. To evaluate the clinical feasibility, intensity modulated radiation therapy (IMRT) plans were created for head phantoms that were bolus-free or had a commercial bolus, a silica gel bolus, or a hydrogel bolus. Dosimetry differences were compared in simulating nose, ear, and parotid gland radiotherapy separately. RESULTS: The air gaps were smaller in the silica gel and hydrogel bolus than the commercial one. In nose plans, it was shown that the V95% (relative volume that is covered by at least 95% of the prescription dose) of the silica gel (99.86%) and hydrogel (99.95%) bolus were better than the commercial one (98.39%) and bolus-free (87.52%). Similarly, the homogeneity index (HI) and conformity index (CI) of the silica gel (0.06; 0.79) and hydrogel (0.058; 0.80) bolus were better than the commercial one (0.094; 0.72) and bolus-free (0.59; 0.53). The parameters of results (HI, CI, V95% ) were also better in 3D printing boluses than in the commercial bolus or without bolus in ear and parotid plans. CONCLUSIONS: Silica gel and hydrogel boluses were not only good for fit and a high level of comfort and repeatability, but also had better parameters in IMRT plans. They could replace the commercial bolus for clinical use. PMID- 30402933 TI - Prevalence and predictors of gestational diabetes mellitus: a nationwide multicentre prospective study. AB - AIM: Prevalence rates of gestational diabetes mellitus (GDM) show considerable variation among different countries and regions of the world. The primary aim of this study was to determine the nationwide prevalence and predictors of GDM in Turkey. METHODS: We conducted prospective nationwide screening among pregnant women. Between August 2016 and November 2017, a total of 2643 pregnant women from 51 centres in 12 different regions were enrolled. A two-step screening method and Carpenter and Coustan criteria were used in the diagnosis of GDM. Clinical and biochemical data were obtained using electronic database software. RESULTS: The national prevalence of GDM was found to be 16.2% [95% confidence intervals (CI) 15.0% to 17.4%] without a significant difference between urban and rural regions. Women with GDM were older (mean age: 32 +/- 5 vs. 28 +/- 5 years, P < 0.001) and heavier (mean BMI: 27.2 +/- 5.1 vs. 24.7 +/- 4.7 kg/m2 , P < 0.001) than their counterparts without GDM. The prevalence of GDM tended to increase with age (< 25 years, 6.9%; 26-35 years, 15.6%; and 36-45 years, 32.7%; P < 0.001). Maternal age, maternal BMI, history of previous GDM and family history of diabetes mellitus were independent predictors of developing GDM (P < 0.05 for all). Low risk women (age < 25 years, BMI < 25 kg/m2 , no family history of diabetes) comprised 10.7% of the total population and the prevalence of GDM in these women was 4.5% (95% CI 2.4% to 7.8%). CONCLUSION: The results of this nationwide study indicate that GDM is very common, affecting one in seven pregnancies in Turkey. Implementation of international guidelines on screening and management of this public health problem is required. PMID- 30402936 TI - Finding events in a continuous world: A developmental account. AB - Event segmentation is a fundamental process of human cognition that organizes the continuous flux of activity into discrete, hierarchical units. The mechanism of event segmentation in infants seems to parallel the mechanism studied in adults, which centers on action predictability. Statistical learning appears to bootstrap infants' event segmentation by generating action predictions without relying on prior knowledge. Infants' first-hand experiences with goal-directed actions further enhance their prediction of others' actions. Scaffolds for event segmentation are available in the input, with caregivers providing redundant cues to event boundaries through the use of motionese and acoustic packaging. Research points to the importance of developing event segmentation skills for development in other areas of cognition, including memory, social competence, and language, though more work is needed to capture the directionality of effects. Although event segmentation is a relatively new area of focus in cognition, this process illuminates how children make sense of an ever-changing world. PMID- 30402938 TI - A lump on the palate. PMID- 30402937 TI - Understanding the participation of GREM1 polymorphisms in nonsyndromic cleft lip with or without cleft palate in the Brazilian population. AB - BACKGROUND: GREM1, which encodes Gremlin 1, an antagonist of bone morphogenic proteins with effects on proliferation and apoptosis, has been considered a candidate gene for nonsyndromic cleft lip with or without cleft palate (NSCL+/ P). In this study, we investigated potential associations of single nucleotide polymorphisms (SNP) in GREM1 and NSCL+/-P risk in the Brazilian population. Additionally, SNP-SNP interactions of GREM1 with previously reported rs1880646 variant in NTN1 (netrin 1), a gene also responsible for apoptotic phenotypes were verified. METHODS: Applying Taqman allelic discrimination assays, we evaluated the variants rs16969681, rs16969816, rs16969862, and rs1258763 in 325 case-parent trios and in 1,588 isolated samples in a case-control study. Allelic and genotypic analyses, as well as interaction tests assessing gene-environmental factor (GxE) and SNP-SNP interaction with rs1880646 variant in NTN1, were performed based on logistic regression analysis adjusted for the effects of gender and genomic ancestry proportions. RESULTS: The risk alleles of all SNP were undertransmitted in NSCL+/-P trios, though the case-control analysis confirmed only the association with rs16969862 alleles (OR: 0.78, 95% CI: 0.63 0.96, p = .02). The GxE interaction analysis revealed a significant interaction between maternal environmental contact with agrotoxics and rs16969816 (OR: 0.25, 95% CI: 0.08-0.74, p = .01), and pairwise interaction test with NTN1 rs1880646 yielded significant p values in the 1,000 permutation test for rs16969681, rs16969816, and rs16969862. CONCLUSION: The GREM1 is involved in the etiology of NSCL+/-P in the Brazilian population and reveal that the interaction between GREM1 and NTN1 may be related with the pathogenesis of this common craniofacial malformation. PMID- 30402940 TI - Improvement of nail lesions in a patient with psoriatic arthritis by switching the treatment from an anti-interleukin-17A antibody to an anti-tumor necrosis factor-alpha antibody. PMID- 30402941 TI - Human BDNF rs6265 polymorphism as a mediator for the generalization of contextual anxiety. AB - The Met allele of the human brain-derived neurotrophic factor (BDNF) gene might be a risk factor for anxiety disorders and is associated with reduced hippocampal volume. Notably, hippocampus plays a crucial role in contextual learning and generalization. The role of the BDNF gene variation in human context-conditioning and generalization is still unknown. We investigated 33 carriers of the Met allele (18 females) and 32 homozygous carriers of the Val allele (15 females) with a virtual-reality context-conditioning paradigm. Electric stimulations (unconditioned stimulus, US) were unpredictably delivered in one virtual office (CTX+), but never in another virtual office (CTX-). During generalization, participants revisited CTX+ and CTX- and a generalization office (G-CTX), which was a mix of the other two. Rating data indicated successful conditioning (more negative valence, higher arousal, anxiety and contingency ratings for CTX+ than CTX-), and generalization of conditioned anxiety by comparable ratings for G-CTX and CTX+. The startle data indicated discriminative learning for Met allele carriers, but not for Val homozygotes. Moreover, a trend effect suggests that startle responses of only the Met carriers were slightly potentiated in G-CTX versus CTX-. In sum, the BDNF polymorphism did not affect contextual learning and its generalization on a verbal level. However, the physiological data suggest that Met carriers are characterized by fast discriminative contextual learning and a tendency to generalize anxiety responses to ambiguous contexts. We propose that such learning may be related to reduced hippocampal functionality and the basis for the risk of Met carriers to develop anxiety disorders. PMID- 30402942 TI - Nuclear abnormalities in vascular myocytes in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). AB - Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a stroke and dementia syndrome with degeneration and loss of vascular smooth muscle cells (VSMCs). The disease is due to mutations in NOTCH3 playing an important role in VSMC differentiation, proliferation and apoptosis. Searching for a possible cause of VSMC dysfunction in CADASIL, we investigated morphology and proliferative activity the affected myocytes. In material from autopsy brains and skin-muscle biopsies of patients with CADASIL diagnosis, assessment of VSMCs in arterial vessels at the level of light and electron microscopy was performed. Proliferative activity of VSMCs was evaluated in immune reactions to proliferative markers: proliferating cell nuclear antigen, and cyclins B1 and D. In CADASIL, abnormal morphology of VSMC nuclei was observed in 18.1%, 11.5%, and 6.9% of the cerebral, skin, and skeletal muscle vessels, respectively. The affected myocytes showed variability in nuclear size, irregularity in nuclear shape, and abnormal chromatin appearance. Frequently, double nuclei of equal size or micronuclei were observed. Sometimes, even multinuclear myocytes were found. In some of the nuclei immune reactions to the examined proliferative markers were positive. Aberrant structure and number of VSCM nuclei, and their immunoreactivity to proliferative markers suggest mitotic instability of vascular myocytes in CADASIL. We speculate that mutant NOTCH3 which is unable to control properly VSMC proliferation, and may be responsible for their premature or inappropriate entry into mitosis, irreversible arrest of the cell cycle, senescence or degeneration and loss. PMID- 30402943 TI - Office blood pressure measurement types: Different methodology-Different clinical conclusions. AB - The measurement of blood pressure in the office (OBP) remains the basis for hypertension diagnosis and management for more than half a century. Despite the increasing use of out-of-office blood pressure measurement using home and less so ambulatory monitoring and their endorsement by hypertension societies, at present and for some time to come it is likely that in many people the diagnosis and management of hypertension will be based on OBP measurement alone. OBP measurement is a very variable method affected by multiple factors, which have major impact on the OBP level, reproducibility and prognostic ability. Thus, there are several types of OBP measurement, depending on the device type, conditions, observer's presence and the number of readings. The 4 main OBP types are: Type I: Auscultatory OBP in clinical practice; Type II: Automated attended OBP in clinical practice; Type III: Research setting OBP; Type IV: Unattended automated OBP. These OBP types have different standardization level, different reproducibility, different clinical relevance and different thresholds for hypertension diagnosis. Unless the methodological details of OBP measurement are reported, any conclusions based on such measurements in clinical research and in practice are questionable. PMID- 30402944 TI - Upper molar morphology, homologies and evolutionary patterns of chinchilloid rodents (Mammalia, Caviomorpha). AB - Chinchilloidea are a clade of caviomorph rodents that includes seven living species, the Dinomyidae Dinomys branickii, the Chinchillidae Lagostomus maximus, two species of Chinchilla and three species of Lagidium. In addition, two extinct families are traditionally considered chinchilloids - Neoepiblemidae and Cephalomyidae. The phylogeny of the Chinchilloidea has so far not been well established and is based on partial analyses. Studying the anatomy and ontogeny of extinct and extant taxa, we propose homologies for the upper molars of Chinchilloidea for which these homologies have not been previously proposed: that is the Chinchillidae Prolagostomus, Lagostomus, Lagidium and Chinchilla, and the Neoepiblemidae Neoepiblema and Phoberomys. We identify patterns of occlusal simplification within Chinchilloidea and evaluate its importance in an evolutionary context. A phylogenetic analysis recovered Dinomyidae, Chinchillidae and Neoepiblemidae as clades. 'Cephalomyidae' have not been not recovered as a monophyletic group and 'cephalomyids' are closely related to Neoepiblemidae. Branisamys is not included within the Dinomyidae and appears to be a basal chinchilloid. PMID- 30402945 TI - The bowel movement characteristics of exclusively breastfed and exclusively formula fed infants differ during the first three months of life. AB - AIM: Breastfed infants pass more stools and more liquid stools than formula fed infants and some have no bowel movements or infrequent stools for several days or weeks. We compared exclusively breastfed and exclusively formula fed infants for the first three months. METHODS: This study of 118 infants was carried out in the maternity ward of the Lille University Jeanne de Flandre Hospital, France, in 2015. The outcomes were the number and consistency of stools and the prevalence of infrequent stools. RESULTS: At three months, 84 infants remained and we compared 40 who were exclusively breastfed and 13 who were exclusively formula fed. Daily stool frequency was significantly higher in the breastfed than formula fed infants during the first (4.9 +/- 1.7 vs. 2.3 +/- 1.6, p < 0.001) and second (3.2 +/- 1.6 vs. 1.6 +/- 1.5, p = 0.003) months. Stools were more liquid in the breastfed infants during the first three months. Infrequent stools occurred in 28% of breastfed and 8% of formula fed infants at least once. (p = 0.25). CONCLUSION: Exclusively breastfed infants produced more stools than exclusively formula fed infants during the first two months and more liquid stools during the first three. Infrequent stools were 3.5 times more likely in the breastfed infants. PMID- 30402946 TI - Nitric Oxide Synthase Enzymology in the Twenty Years After the Nobel Prize. AB - This review briefly summarizes what was known about NO synthase (NOS) enzymology at the time of the Nobel prize award in 1998, and then discusses from the Author's perspective some of the advances in NOS enzymologic research over the subsequent twenty years, focused on five aspects: The maturation process of NOS enzymes and its regulation; the mechanism of NO synthesis; the redox roles played by the 6R-tetrahydrobiopterin cofactor; the role of protein conformational behavior in enabling NOS electron transfer and its regulation by NOS structural elements and calmodulin; and the catalytic cycling pathways of NOS enzymes, their regulation, and their influence on NOS activity. PMID- 30402947 TI - The COMT Val158 Met polymorphism does not modulate the after-effect of tDCS on working memory. AB - Transcranial direct current stimulation (tDCS) can alter cortical excitability, neural plasticity and cognitive-behavioral performance, however its effects are known to vary across studies. A partial account of this variability relates to individual differences in dopamine function. Indeed, dopaminergic manipulations alter the physiological and cognitive-behavioral effects of tDCS, and gene polymorphisms related to dopamine have predicted individual response to online tDCS (i.e., stimulation overlapping with the critical task). Notably, the role of individual differences in dopamine has not yet been properly assessed in the effect of offline tDCS (i.e., stimulation prior to the critical task). We investigated if and how the COMT Val158 Met polymorphism (rs4680) modulates the after-effect of prefrontal tDCS on verbal working memory (WM). 139 participants were genotyped for the COMT Val158 Met polymorphism and received anodal-over left, cathodal-over-right (AL-CR), cathodal-over-left, anodal-over-right (CL-AR), or sham stimulation over the dorsolateral prefrontal cortex in a between subjects, pretest-posttest study design. WM was assessed using the N-back task. The results provide no evidence that the COMT polymorphism impacts the after effect of prefrontal tDCS on WM. Taken together with previous findings on dopamine and tDCS interactions, the results of the present study suggest that (i) indirect markers of dopamine (such as COMT) are differently related to online and offline effects of tDCS, and (ii) findings from studies involving pharmacological manipulation should be generalized with caution to findings of inter-individual differences. In sum, we argue that state (i.e., a manipulation of) and trait (i.e., baseline) differences in dopamine may exert different effects on online and offline tDCS. This article is protected by copyright. All rights reserved. PMID- 30402948 TI - Purified vitexin compound 1, a new neolignan isolated compound, promotes PUMA dependent apoptosis in colorectal cancer. AB - Purified vitexin compound 1 (VB1, a neolignan isolated and extracted from the seed of Chinese herb Vitex negundo) is an effective antitumor agent and exhibits promising clinical activity against various cancers including colorectal cancer. However, it remains unknown about the precise underlying mechanism associated with the antitumor effect of VB1 and how it triggers apoptosis in cancer cells. Here, we demonstrated that VB1 promoted apoptosis via p53-dependent induction of p53 upregulated modulator of apoptosis (PUMA) and further to induce Bax (Bcl-2 associated X protein) activation and mitochondrial dysfunction in colon cancer HCT-116 and LoVo cells. Deficiency in p53, PUMA, or Bax abrogated VB1-induced apoptosis and promoted cell survival in HCT-116 cells. Furthermore, the combination of VB1 with chemotherapeutic drugs 5-fluorouracil (5-FU) or NVP BZE235 resulted in a synergistic antitumor effect via PUMA induction in HCT-116 cells. VB1 significantly suppressed the cell proliferation of wild-type (WT) HCT 116 and LoVo cells in vitro and tumor growth in vivo. The results indicate that p53/PUMA/Bax axis plays a critical role in VB1-induced apoptosis and VB1 may have valuable clinical applications in cancer therapy as a novel anticancer agent used alone or in combination with other chemotherapeutic drugs. PMID- 30402949 TI - Low prioritization of latent tuberculosis infection-A systemic barrier to tuberculosis control: A qualitative study in Ontario, Canada. AB - BACKGROUND: Eliminating tuberculosis (TB) in low-incidence countries is an important global health priority, and Canada has committed to achieve this goal. The elimination of TB in low-incidence countries requires effective management and treatment of latent tuberculosis infection (LTBI). This study aimed to understand and describe the system-level barriers to LTBI treatment for immigrant populations in the Greater Toronto and Hamilton Area, Ontario, Canada. METHODS: A qualitative study that used purposive sampling to recruit and interview health system advisors and planners (n = 10), providers (n = 13), and clients of LTBI health services (n = 9). Data were recorded, transcribed verbatim, and analyzed using content analysis. RESULTS: Low prioritization of LTBI was an overarching theme that impacted four dimensions of LTBI care: management, service delivery, health literacy, and health care access. These factors explained, in part, inequities in the system that were linked to variations in health care quality and health care access. While some planners and providers at the local level were attempting to prioritize LTBI care, there was no clear pathway for information sharing. CONCLUSIONS: This multiperspective study identified barriers beyond the typical socioeconomic determinants and highlighted important upstream factors that hinder treatment initiation and adherence. Addressing these factors is critical if Canada is to meet the WHO's global call to eradicate TB in all low incidence settings. PMID- 30402950 TI - Recovery of regional systolic and diastolic myocardial function after acute myocardial infarction evaluated by two-dimensional speckle tracking echocardiography. AB - PURPOSE: The assessment of temporal changes in systolic and diastolic regional left ventricle function by two-dimensional speckle tracking echocardiography (STE) after successful reperfusion therapy of acute myocardial infarction (AMI). METHODS: A total of 97 consecutive patients admitted with AMI and treated with successful percutaneous coronary intervention were included in this study. On days 1, 2, 3, 7, 30 and 180 following admission patients underwent transthoracic echocardiography with subsequent measurement of systolic longitudinal strain (SLS), systolic longitudinal strain rate (SRS) and early diastolic longitudinal strain rate (SRe) in left ventricular segments by speckle tracking technique. RESULTS: The largest increase in regional SLS and SRS was observed between day 1 and 2. On days 3, 7, 30 and 180 further improvement was noticeable, but the changes were less significant. The highest prognostic value among STE parameters for predicting systolic function recovery after 6-month-long follow-up was achieved by measuring SLS on day 3 (area under the curve = 0.878). CONCLUSIONS: The most of regional systolic function recovery occurs within the first 2 days. The recovery of regional diastolic function takes longer - the most significant part of improvement occurs within the first 7 days. STE parameters have prognostic value for predicting the improvement of systolic function after 180 days. PMID- 30402951 TI - Berberine alleviates oxidized low-density lipoprotein-induced macrophage activation by downregulating galectin-3 via the NF-kappaB and AMPK signaling pathways. AB - Macrophage activation plays a central role in neoatherosclerosis and in-stent restenosis after percutaneous coronary intervention (PCI). Galectin-3, mainly expressed on macrophages, is an important regulator of inflammation. This study aimed to investigate the effects of berberine (BBR) on oxidized low-density lipoprotein (ox-LDL)-induced macrophage activation and galectin-3 expression and their underlying mechanisms. THP-1-derived macrophages were pretreated with BBR prior to stimulation with ox-LDL. Galectin-3 expression was measured by real-time PCR, Western blotting, and confocal microscopy. Macrophage activation was assessed by lipid accumulation, expression of inflammatory cytokines, and CD11b and CD86. Plasma galectin-3 levels were measured in patients undergoing PCI at baseline and after BBR treatment for 3 months. BBR suppressed ox-LDL-induced upregulation of galectin-3 and macrophage activation. Overexpression of galectin 3 intervened the inhibitory effect of BBR on macrophage activation. BBR activated phospho-AMPK and inhibited phospho-NF-kappaB p65 nuclear translocation. AMPK inhibition and NF-kappaB activation abolished the inhibitory effects of BBR on galectin-3 expression and macrophage activation. Combination of BBR and rosuvastatin exerted greater effects than BBR or rosuvastatin alone. However, BBR treatment did not further reduce plasma galectin-3 after PCI in patients receiving standard therapy. In conclusion, BBR alleviates ox-LDL-induced macrophage activation by downregulating galectin-3 via the NF-kappaB and AMPK signaling pathways. PMID- 30402952 TI - UPLC-QTOF-MS analysis of a carbonic anhydrase-inhibiting extract and fractions of Luffa acutangula (L.) Roxb (ridge gourd). AB - INTRODUCTION: Luffa acutangula (L.) Roxb, commonly known as ridge gourd (cucurbitaceae), is a common vegetable cultivated in India. It is also a well used medicinal plant in Indian traditional medicine. OBJECTIVES: To analyse the phenolics content of the most potent carbonic anhydrase-inhibiting fraction from an extract of L. acutangula. MATERIALS AND METHODS: An aqueous ethanol extract of dried fruits of L. acutangula was successively fractionated into petroleum ether, dichloromethane and ethyl acetate. The extract and subsequent fractions were assessed for carbonic anhydrase-inhibitory activity and the enzyme inhibition kinetics were determined for the most active fraction. Total phenolic and flavonoid content of the extract and subsequent fractions were determined spectrophotometrically. Ultra-performance liquid chromatography-quadrupole/time of-flight mass spectrometry (UPLC-QTOF-MS) analysis was used to tentatively identify the major phenolics in the most active fraction. RESULTS: The concentration of total phenolics and total flavonoids in the extract and each fraction thereof correlated with the level of carbonic anhydrase inhibition activity. The ethyl acetate fraction of the aqueous ethanol extract of L. acutangula had the highest carbonic anhydrase inhibition activity. The enzyme kinetics analysis indicated a mixed mode of inhibition. UPLC-QTOF-MS analysis of the ethyl acetate fraction indicated a number of phenolic acids, hydroxycoumarins, flavones, flavanones, and flavonoids. CONCLUSION: The correlation of total phenolic content with carbonic anhydrase inhibition suggested further research that might confirm that phenolic compounds of L. acutangula offer potential therapeutic benefits against carbonic anhydrase related disorders. PMID- 30402954 TI - Reduction in butyrate-producing Lachnospiraceae contributes to stress-induced visceral hypersensitivity in rats. AB - BACKGROUND AND AIM: Emerging evidence indicates that psychological stress is involved in the pathogenesis of irritable bowel syndrome (IBS), which is characterized by visceral hypersensitivity and may be accompanied by gut dysbiosis. However, how such stress contributes to the development of visceral hypersensitivity is incompletely understood. Here, we aimed to investigate the influence that stress-induced microbial changes exert on visceral sensitivity, as well as the possible underlying mechanisms associated with this effect. METHODS: Male Sprague-Dawley rats underwent chronic water avoidance stress (WAS) to induce visceral hypersensitivity. Visceral sensitivity, colonic tight junction protein (TJP) expression, and short chain fatty acids of cecal contents were measured. Fecal samples were collected to characterize microbiota profiles. In a separate study, oral gavage of Roseburia in WAS rats was conducted to verify its potential role in the effectiveness on visceral hypersensitivity. RESULTS: Repeated WAS caused visceral hypersensitivity, altered fecal microbiota composition and function, and decreased occludin expression in the colon. Stressed rats exhibited reduced representation of pathways involved in the metabolism of butyrate and reduced abundance of several operational taxonomic units (OTUs) associated with butyrate-producing bacteria, such as Lachnospiraceae. Consistently, supplementation with Roseburia hominis, a species belonging to Lachnospiraceae, significantly increased cecal butyrate content. Moreover, Roseburia supplementation alleviated visceral hypersensitivity and prevented the decreased expression of occludin. CONCLUSIONS: Reduction in the abundance of butyrate producing Lachnospiraceae, which is beneficial for the intestinal barrier, was involved in the formation of visceral hypersensitivity. R. hominis is a potential probiotic for treating stress-induced visceral hypersensitivity. PMID- 30402955 TI - Chitinase 3-like 1 protein plays a critical role in respiratory syncytial virus induced airway inflammation. AB - BACKGROUND: Chitinase 3-like 1 protein (CHI3L1) (YKL-40 in humans and breast regression protein [BRP]-39 in mice) is required for optimal allergen sensitization and Th2 inflammation in various chronic inflammatory diseases including asthma. However, the role of CHI3L1 in airway inflammation induced by respiratory viruses has not been investigated. The aim of this study was to investigate the relationship between CHI3L1 and airway inflammation caused by respiratory syncytial virus (RSV) infection. METHODS: We measured YKL-40 levels in human nasopharyngeal aspirate (NPA) from hospitalized children presenting with acute respiratory symptoms. Wild-type (WT) and BRP-39 knockout (KO) C57BL/6 mice were inoculated with live RSV (A2 strain). Bronchoalveolar lavage fluid and lung tissue samples were obtained on day 7 after inoculation to assess lung inflammation, airway reactivity, and expression of cytokines and BRP-39. RESULTS: In human subjects, YKL-40 and IL-13 levels in NPA were higher in children with RSV infection than in control subjects. Expression of BRP-39 and Th2 cytokines, IL-13 in particular, was increased following RSV infection in mice. Airway inflammation caused by RSV infection was reduced in BRP-39 KO mice as compared to WT mice. Th2 cytokine levels were not increased in the lungs of RSV-infected BRP 39 KO mice. BRP-39 regulated M2 macrophage activation in RSV-infected mice. Additionally, treatment with anti-CHI3L1 antibody attenuated airway inflammation and Th2 cytokine production in RSV-infected WT mice. CONCLUSION: These findings suggest that CHI3L1 could contribute to airway inflammation induced by RSV infection. CHI3L1 could be a potential therapeutic candidate for attenuating Th2 associated immunopathology during RSV infection. PMID- 30402957 TI - Antioxidant and reactive oxygen species scavenging properties of cellular albumin in HepG2 cells is mediated by the glutathione redox system. AB - This study was carried out to examine the role of intracellular albumin in the modulation of oxidative damage induced by glutathione modifiers in HepG2 cells. Also, the relationship of albumin synthesis with oxidative stress factors including antioxidants was studied. HepG2 cell culture was supplemented with glutathione modifiers; L-Buthionine-sulfoximine (BSO; 0.1 and 1.0 mM) or N-acetyl cysteine (NAC; 1 and 10 mM) and the cell viability and changes in reduced glutathione (GSH), oxidized glutathione (GSSG), reactive oxygen species (ROS), catalase, and superoxide dismutase were measured. Besides, albumin expression at protein and mRNA levels was determined in cells pretreated with BSO or NAC. Kinetic studies showed that albumin expression in HepG2 cells is correlated with GSH and GSSG levels. Changes in albumin expression at protein and mRNA levels reached their maximum (19% and 55%, respectively) in the cells 6 H after NAC treatments. A substantial decrease in intracellular albumin due to BSO (27%) was associated with a significant increase in the generation of cellular ROS (17%). In contrast, increased albumin synthesis (intracellular and secretory) was associated with inhibition in cellular ROS. Overall data may suggest that albumin expression in coordination with the glutathione redox system is part of the antioxidant defense mechanism in liver cells. PMID- 30402956 TI - Alterations of colonic sensitivity and gastric dysmotility after acute cisplatin and granisetron. AB - BACKGROUND: Cisplatin is a highly emetogenic antineoplastic drug and induces peripheral neuropathy when given in cycles. Granisetron, a 5-HT3 antagonist, is clinically used to prevent chemotherapy-induced nausea/emesis and abdominal pain in irritable bowel syndrome. The effects of cisplatin on visceral sensitivity and those of granisetron in the context of cancer chemotherapy are not well known. METHODS: Adult male Wistar rats received two intraperitoneal injections 30 minutes apart: granisetron (1 mg kg-1 )/vehicle and cisplatin (6 mg kg-1 )/vehicle. Thereafter, nausea-like behavior was measured as bedding intake for 4 hours, and gastric dysmotility was measured radiographically for 8 hours. Gastric weight and size were determined ex vivo and samples of the forestomach, corpus, ileum, and colon were obtained for histological analysis at 4 and 30 hours after cisplatin/vehicle. Visceral sensitivity was measured as abdominal contractions in response to mechanical intracolonic stimulation 2 hours after cisplatin/vehicle. KEY RESULTS: Cisplatin-induced bedding intake and gastric dysmotility, and granisetron blocked these effects, which occurred in the absence of frank mucositis. Visceral sensitivity was reduced to a similar extent by both drugs alone or in combination. CONCLUSIONS AND INFERENCES: Cisplatin-induced bedding intake and gastric dysmotility were blocked by granisetron, confirming the involvement of serotonin acting on 5-HT3 receptors. Unexpectedly, visceral sensitivity to colonic distension was reduced, to the same extent, by cisplatin, granisetron, and their combination, suggesting important mechanistic differences with nausea and gastric dysmotility that warrant further investigation. PMID- 30402958 TI - Characterisation of the Toxoplasma gondii tyrosine transporter and its phosphorylation by the calcium-dependent protein kinase 3. AB - Toxoplasma gondii parasites rapidly exit their host cell when exposed to calcium ionophores. Calcium-dependent protein kinase 3 (TgCDPK3) was previously identified as a key mediator in this process, as TgCDPK3 knockout (?cdpk3) parasites fail to egress in a timely manner. Phosphoproteomic analysis comparing WT with ?cdpk3 parasites revealed changes in the TgCDPK3-dependent phosphoproteome that included proteins important for regulating motility, but also metabolic enzymes, indicating that TgCDPK3 controls processes beyond egress. Here we have investigated a predicted direct target of TgCDPK3, ApiAT5-3, a putative transporter of the major facilitator superfamily, and show that it is rapidly phosphorylated at serine 56 after induction of calcium signalling. Conditional knockout of apiAT5-3 results in transcriptional upregulation of most ribosomal subunits, but no alternative transporters, and subsequent parasite death. Mutating the S56 to a non-phosphorylatable alanine leads to a fitness cost, suggesting that phosphorylation of this residue is beneficial, albeit not essential, for tyrosine import. Using a combination of metabolomics and heterologous expression, we confirmed a primary role in tyrosine import for ApiAT5-3. However, no significant differences in tyrosine import could be detected in phosphorylation site mutants showing that if tyrosine transport is affected by S56 phosphorylation, its regulatory role is subtle. PMID- 30402959 TI - Association of dietary inflammatory index with metabolic profile in metabolically healthy and unhealthy obese people. AB - AIM: Obesity is an emerging public health problem, with its incidence on the rise. An abnormal metabolic profile is a risk factor for developing obesity. Dietary factors play a central role in the regulation of inflammation and obesity. The aim of the present study was to determine the prevalence of metabolically healthy obese and metabolically unhealthy obese (MUO) phenotypes, and their association with dietary inflammatory index (DII) among obese Iranian people. METHODS: A cross-sectional study was conducted from July to October 2017 among 300 obese participants in southern Tehran. DII scores were computed based on the overall inflammatory properties of 32 dietary components using dietary intake assessed by food frequency questionnaire. MUO phenotype was defined as having three or more of these metabolic abnormalities: high blood glucose, high triglycerides, low high-density lipoprotein cholesterol, elevated blood pressure or abdominal obesity. The association was determined using logistic regression analysis. RESULTS: The MUO phenotype (n = 176) was found in 63.5% of obese participants. Compared with participants in the first quartile, those in the fourth quartile of DII score (more pro-inflammatory diet) had higher odds of MUO phenotype (odds ratio, OR: 2.58 (95% CI: 1.19-5.59), P = 0.04), and there was a significant association between the continuous form of DII score and the odds of MUO phenotype (OR: 1.18 (95% CI: 1.01-1.37)) after adjusting for potential confounders. CONCLUSIONS: Higher DII scores were positively associated with the MUO phenotype. A more pro-inflammatory diet is a potential risk factor for MUO phenotype. PMID- 30402960 TI - Periodicity, repression, and the molecular architecture of the mammalian circadian clock. AB - Large molecular machines regulate daily cycles of transcriptional activity and help generate rhythmic behavior. In recent years, structural and biochemical analyses have elucidated a number of principles guiding the interactions of proteins that form the basis of circadian timing. In its simplest form, the circadian clock is composed of a transcription/translation feedback loop. However, this description elides a complicated process of activator recruitment, chromatin decompaction, recruitment of coactivators, expression of repressors, formation of a repressive complex, repression of the activators, and ultimately degradation of the repressors and reinitiation of the cycle. Understanding the core principles underlying the clock requires careful examination of molecular and even atomic level details of these processes. Here we review major structural and biochemical findings in circadian biology and make the argument that shared protein interfaces within the clockwork are critical for both the generation of rhythmicity and timing of the clock. This article is protected by copyright. All rights reserved. PMID- 30402961 TI - Cardiovascular disease management in people with diabetes outside North America and Western Europe in 2006 and 2015. AB - AIM: Optimal treatment of cardiovascular disease is essential to decrease mortality among people with diabetes, but information is limited on how actual treatment relates to guidelines. We analysed changes in therapeutic approaches to anti-hypertensive and lipid-lowering medications in people with Type 2 diabetes from 2006 and 2015. METHODS: Summary data from clinical services in seven countries outside North America and Western Europe were collected for 39 684 people. Each site summarized individual-level data from outpatient medical records for 2006 and 2015. Data included: demographic information, blood pressure (BP), total cholesterol levels and percentage of people taking statins, anti hypertensive medication (angiotensin-converting enzyme inhibitors, calcium channel blockers, angiotensin II receptor blockers, thiazide diuretics) and antiplatelet drugs. RESULTS: From 2006 to 2015, mean cholesterol levels decreased in six of eight sites (range: -0.5 to -0.2), whereas the proportion with BP levels > 140/90 mmHg increased in seven of eight sites. Decreases in cholesterol paralleled increases in statin use (range: 3.1 to 47.0 percentage points). Overall, utilization of anti-hypertensive medication did not change. However, there was an increase in the use of angiotensin II receptor blockers and a decrease in angiotensin-converting enzyme inhibitors. The percentage of individuals receiving calcium channel blockers and aspirin remained unchanged. CONCLUSIONS: Our findings indicate that control of cholesterol levels improved and coincided with increased use of statins. The percentage of people with BP > 140/90 mmHg was higher in 2015 than in 2006. Hypertension treatment shifted from using angiotensin-converting enzyme inhibitors to angiotensin II receptor blockers. Despite the potentially greater tolerability of angiotensin II receptor blockers, there was no associated improvement in BP levels. PMID- 30402962 TI - Expression patterns common and unique to ulcerative colitis and celiac disease. AB - Autoimmune diseases like celiac disease (CeD) and ulcerative colitis (UC) show a common genetic background defined by the existence of shared susceptibility loci. We aimed to go deeper into this common genetic background through performing a cross-disease study based on gene expression. We measured the expression of 21 genes located in 13 CeD-UC susceptibility regions, and 10 genes in five CeD risk regions. Determinations were carried out in colon/rectum samples from 13 UC patients (inflamed and uninflamed tissue) and four colon samples from controls. Duodenal samples from 19 CeD patients and 12 controls were used for comparisons. Differences were analyzed using the Bayesian method. The shared chromosomal regions containing TNFAIP3, PTPN2, ICOSLG, C1orf106, and IL21 showed similar results in both diseases. FASLG, PLEK, CCR4, and TAGAP, all located in CeD risk loci, were up-regulated in both CeD and UC patients. Finally, ZFP36L1, ZMIZ1, PUS10, UBE2L3, and BACH2 showed opposite results in CeD and UC. A high complexity underlies autoimmune common susceptibility loci, as the expression pattern of the studied genes does not always correlate with the one expected attending to the apparent genetic background. Differentially expressed genes such as ZFP36L1, ZMIZ1, PUS10, and BACH2 deserve further research in autoimmune diseases. PMID- 30402963 TI - Prospective Study of Long-term Effect between Multifidus Muscle Bundle and Conventional Open Approach in One-level Posterior Lumbar Interbody Fusion. AB - OBJECTIVE: To compare postoperative imaging results, clinical outcomes and complications between the multifidus muscle bundle (MMB) approach and the conventional open (CO) approach in one-level posterior lumbar interbody fusion (PLIF). METHODS: Based on the inclusion and exclusion criteria, 201 of 351 patients in our hospital were enrolled in this prospective study and underwent MMB-PLIF or CO-PLIF randomly: 111 patients in the MMB-PLIF group and 90 patients in the CO-PLIF group. A total of 100 patients failed to be followed up in the following 7-9 years. Therefore, in this study, 52 patients of the MMB group and 49 patients of the CO group were included. We evaluated the differences in terms of multifidus atrophy rate, intervertebral disc height and segmental lordosis restoration of the operation segment, lumbar lordosis restoration, fusion rate, visual analogue scale (VAS) for back and leg pain, Oswestry disability index (ODI), complication rates, and patient satisfaction rates between the two groups. Correlation between multifidus muscle degeneration and the incidence of complications was investigated, and we compared the multifidus muscle degeneration rate between patients with or without intractable back pain or adjacent segment degeneration. RESULTS: There were no significant differences in age, sex, body mass index (BMI), diagnosis, segments distribution, and mean follow-up time between the MMB-PLIF group and the CO-PLIF group. In addition, no differences regarding sex, age, or BMI were found between the lost follow-up group and the successful follow-up group. In regard to imaging and clinical evaluation, at the final follow-up, there were significant differences in multifidus atrophy rates (27.0% +/- 6.8% vs 38.7% +/- 10.9%), lumbar lordosis restoration (4.6 degrees +/- 2.5 degrees vs 3.0 degrees +/- 1.9 degrees ), postoperative VAS for back pain (1.1 +/- 0.9 vs 1.8 +/- 1.2), ODI (7.7 +/- 5.0 vs 12.4 +/- 6.7), and patient satisfaction rates (86.5% vs 61.2%) between MMB-PLIF and CO-PLIF groups. However, there were no significant differences in segmental lordosis, intervertebral height restoration, postoperative VAS for leg pain or fusion rate between the two groups. In regards to complications, there were significant differences in the incidence of adjacent segment degeneration (3.8% vs 14.3%), intractable back pain (3.8% vs 22.4%), and residual neurological symptoms (5.8% vs 20.4%) between the two groups (P < 0.05) at the final follow up. In addition, patients with adjacent segment degeneration and intractable back pain were observed with more significant multifidus muscle atrophy than those without these two complications (31.9% +/- 1.1% vs 39.6% +/- 2.1% and 30.9% +/- 1.1% vs 42.8% +/- 2.1%). CONCLUSION: Compared with CO-PLIF, MMB-PLIF had advantages in relation to protection of the multifidus muscle, better maintenance of lumbar lordosis, reduced lower back pain and ODI score, fewer complications, and a higher patient satisfaction rate. Protection of the multifidus muscle in lumbar surgery is an important aspect of minimally invasive surgery. PMID- 30402964 TI - Predicting shifts in the functional composition of tropical forests under increased drought and CO2 from trade-offs among plant hydraulic traits. AB - Tropical forest responses are an important feedback on global change, but changes in forest composition with projected increases in CO2 and drought are highly uncertain. Here we determine shifts in the most competitive plant hydraulic strategy (the evolutionary stable strategy or ESS) from changes in CO2 and drought frequency and intensity. Hydraulic strategies were defined along a spectrum from drought avoidance to tolerance by physiology traits. Drought impacted competition more than CO2 , with elevated CO2 reducing but not reversing drought-induced shifts in the ESS towards more tolerant strategies. Trait plasticity and/or adaptation intensified these shifts by increasing the competitive ability of the drought tolerant relative to the avoidant strategies. These findings predict losses of drought avoidant evergreens from tropical forests under global change, and point to the importance of changes in precipitation during the dry season and constraints on plasticity and adaptation in xylem traits to forest responses. PMID- 30402965 TI - A comparison of childhood dietary intake between anorexia nervosa and healthy leanness. AB - BACKGROUND: The number of adolescent patients with anorexia nervosa is increasing. In addition, an increase of preadolescent patients with premenarchal onset has also been recognized. However, detection of the disease in childhood and adolescence is not always easy because the symptoms are not characteristic during this period. This study was performed to investigate detection of anorexia nervosa in children/adolescents by comparing energy and nutrient intakes between patients with anorexia nervosa and healthy thin persons. METHODS: The subjects were 13 girls aged 14.4+/-3.5 years with anorexia nervosa and 320 healthy girls aged 12.4+/-1.3 years. Dietary intake was evaluated by using a validated diet history questionnaire designed for children/adolescents. Daily energy and nutrient intakes were expressed as a percentage of the age and sex matched reference amount. RESULTS: Healthy lean (BMI < 50th percentile) girls with an above average score for desiring thinness showed higher fat and lower cereal intake, and a trend of lower carbohydrate intake. In contrast, patients with anorexia nervosa, compared with thin (BMI < 5th percentile) girls, characteristically showed significantly lower energy, fat, zinc, vitamin C, and confectionery intake. CONCLUSIONS: Lean girls with an above average desire for thinness appear to restrict their energy intake by reducing their intake of carbohydrates such as cereals while maintaining a relatively high fat intake. On the other hand, girls with anorexia nervosa showed the avoidance of fat and preference of vegetables. This characteristic eating pattern could be a useful clue for detection of anorexia nervosa among thin children and adolescents. This article is protected by copyright. All rights reserved. PMID- 30402966 TI - Maternal smoking during pregnancy and the risk of strabismus in offspring: a meta analysis. AB - The effect of maternal smoking during pregnancy on strabismus in offspring remains unclear. We conducted a meta-analysis to summarize epidemiological evidences on the association between maternal smoking during pregnancy and the risk of offspring strabismus. Eligible studies were searched from the PubMed, Ovid, Embase and CNKI databases up to May 2018. The qualities of included articles were assessed with the Newcastle-Ottawa Scale and the assessment scale recommended by the Agency for Healthcare Research and Quality. Odds ratios (ORs) corresponding with its 95% confidence intervals (CIs) were pooled to estimate the effects of maternal cigarette smoking on the risk of offspring strabismus. Subgroup analyses and meta-regression were performed to explore the potential sources of heterogeneity. The Begg's test and Egger's test were used to assess the publication bias. Eleven articles involving 4,833 patients with strabismus were included. The pooled OR showed that maternal smoking during pregnancy was significantly associated with strabismus in offspring (OR = 1.46, 95% CI = 1.32 1.60). Compared with less than 10 cigarettes per day (OR = 1.17, 95% CI = 1.06 1.29), maternal smoking 10 cigarettes or more per day during pregnancy significantly increased the risk of offspring strabismus (OR = 1.79, 95% CI = 1.39-2.31). The risk of developing esotropia and exotropia for smoking pregnant women, respectively, increased by 65% (OR = 1.65, 95% CI = 1.31-2.09 and OR = 1.65, 95% CI = 1.24-2.19) than those who did not smoke during pregnancy. Additionally, the increased risk of maternity smoking associated with offspring strabismus was stable across all subgroup analyses. Overall, maternal smoking during pregnancy was associated with a significantly increased risk of offspring strabismus and the result was persistent in subgroup analyses, suggesting the importance in changing smoking habit or smoking cessation for women who are pregnant or preparing to. PMID- 30402967 TI - Single C-F Bond Activation of the CF3 Group with a Lewis Acid: CF3 -Cyclopropanes as Versatile 4,4-Difluorohomoallylating Agents. AB - The selective activation of one C-F bond (single activation) of the CF3 group on cyclopropanes was achieved for the first time. When (trifluoromethyl)cyclopropanes were treated with arenes, allylsilanes, silyl enol ethers, or hydrosilanes in the presence of Me2 AlCl, fluoride elimination and the subsequent ring opening proceeded to afford 4,4-difluorohomoallylated products. In the absence of external nucleophiles, an alkyl group of AlR3 was effectively introduced to provide the corresponding 1,1-difluoroalkenes. PMID- 30402968 TI - Thrombocytopenia: A prognostic factor for hepatocellular carcinoma patients with portal vein tumor thrombus after hepatectomy. AB - BACKGROUND AND AIM: Portal vein tumor thrombus (PVTT) predicts a poor prognosis in hepatocellular carcinoma (HCC) patients. Platelets (PLTs) play an important role in HCC progression and metastasis. However, the relationship between PLTs and PVTT remains unclear. This study aimed to evaluate the value of PLT counts in the prognosis of HCC patients with PVTT after hepatectomy. METHODS: From January 2002 to December 2012, 694 HCC patients with PVTT after hepatectomy were evaluated. The patients were divided into the thrombocytopenia group (PLT < 100 * 109 /L), the normal group, and the thrombocytosis group (PLT > 300 * 109 /L) based on the preoperative PLT level. A propensity score matching (PSM) analysis was used. RESULTS: Before the PSM, PVTT patients with thrombocytopenia exhibited longer recurrence-free survival (RFS) and overall survival (OS) compared with those with normal PLT counts (both P < 0.001) or thrombocytosis (P = 0.008 and P = 0.046). For the thrombocytopenia group and the normal group, the 1-, 2-, and 3 year RFS values were 30.0%, 17.6%, and 15.7% and were 10.8%, 6.6%, and 5.8% (P < 0.001), respectively; the 1-, 2-, and 3-year OS values were 61.9%, 37.9%, and 31.2% and were 38.3%, 23.3%, and 16.0% (P < 0.001), respectively. After the PSM, the median survival time was 16.6 versus 8.6 months (P < 0.002) in the two groups. A subgroup analysis revealed that thrombocytopenia is associated with improved OS in those with type I PVTT (P = 0.021) or type II PVTT (P = 0.029). CONCLUSION: According to the PSM, preoperative thrombocytopenia predicts an increased RFS and OS in HCC patients with PVTT after hepatectomy. PMID- 30402969 TI - West Nile virus infection in horses in Saudi Arabia (in 2013-2015). AB - West Nile virus (WNV) is an important emerging zoonotic arbovirus giving rise to clinical syndromes of varying severity in humans and horses. Culex mosquitoes are the main vector. Although WNV has been reported in many countries in the Middle East and Asia, little is known about its prevalence in equine populations in the Arabian Peninsula. We have carried out a serological study on 200 horses to assess WNV infection in the Eastern and Central regions of Saudi Arabia in 2013 2015. Sera were tested for the presence of WNV antibodies in parallel using a commercial enzyme-linked immunosorbent assay (ELISA) kit and microneutralization (MN) tests. In comparison with the MN assay used as "gold standard," we find the ELISA had a sensitivity of 94.7% and specificity of 80.1%. The prevalence of WNV neutralizing antibody ranged from 5 (17.3%) of 29 sera collected in Riyadh up to 15 (55.6%) of 27 sera collected from Al-Qateef. These findings highlight the need to be aware of the possibility of WNV disease in humans and horses presenting with central nervous system disease in the Kingdom of Saudi Arabia. PMID- 30402971 TI - Resveratrol reverses the negative effect of smoking on peri-implant repair in the tibia of rats. AB - OBJECTIVES: Innovative approaches capable to improve peri-implant bone repair are relevant in the presence of smoking, a risk factor for healing around implants. This study investigated the effect of resveratrol (RESV) on peri-implant repair and its influence on bone-related markers in rats submitted to cigarette smoking inhalation (CSI). MATERIALS AND METHODS: One titanium implant was inserted in each tibiae of rats assigned to: CSI+RESV(n:18); CSI+ placebo(n:18); Non CSI(n:18). One implant was removed for counter-torque and the peri-implant tissue was collected for mRNA quantification of BMP-2, OPN, Runx2, Lrp-5, Osx, beta catenin, Dkk1, OPG, and RANKL. The other tibia was submitted to MicroCT to measure: bone volume, bone porosity, trabecular spacing, trabecular thickness and bone-implant contact (BIC). RESULTS: No differences were detected between counter torque in CSI+RESV and Non-CSI group (p>0.05), whereas CSI+placebo group presented lower values when compared to the others (p<0.05). RESV improved the BIC in CSI rats without differences when compared to non-CSI group (p>0.05), whereas CSI+placebo showed reduced BIC when compared to the other groups (p<0.05). RESV reduced RANKL/OPG and Lrp-5 levels and increased beta-catenin in CSI rats when compared to CSI+placebo (p<0.05). CONCLUSION: Although further investigations should be considered using oral models of dental implants, within the limits of the present study, it was concluded that RESV reverses the negative effects of smoking in the peri-implant repair, benefiting the modulation of bone related markers. This article is protected by copyright. All rights reserved. PMID- 30402970 TI - High sodium intake increases blood pressure and risk of kidney disease. From the Science of Salt: A regularly updated systematic review of salt and health outcomes (August 2016 to March 2017). AB - The purpose of this review was to identify, summarize, and critically appraise studies on dietary salt and health outcomes that were published from August 2016 to March 2017. The search strategy was adapted from a previous systematic review on dietary salt and health. Studies that meet standards for methodological quality criteria and eligible health outcomes are reported in detailed critical appraisals. Overall, 47 studies were identified and are summarized in this review. Two studies assessed all-cause or disease-specific mortality outcomes, eight studies assessed morbidity reduction-related outcomes, three studies assessed outcomes related to symptoms/quality of life/functional status, 25 studies assessed blood pressure (BP) outcomes and other clinically relevant surrogate outcomes, and nine studies assessed physiologic surrogate outcomes. Eight of these studies met the criteria for outcomes and methodological quality and underwent detailed critical appraisals and commentary. Five of these studies found adverse effects of salt intake on health outcomes (BP; death due to kidney disease and initiation of dialysis; total kidney volume and composite of kidney function; composite of cardiovascular disease (CVD) events including, and risk of mortality); one study reported the benefits of salt restriction in chronic BP and two studies reported neutral results (BP and risk of CKD). Overall, these articles confirm the negative effects of excessive sodium intake on health outcomes. PMID- 30402972 TI - Distinct effects of (R)-modafinil and its (R)- and (S)-fluoro-analogs on mesolimbic extracellular dopamine assessed by voltammetry and microdialysis in rats. AB - Psychostimulant use disorders remain an unabated public health concern worldwide, but no FDA approved medications are currently available for treatment. Modafinil (MOD), like cocaine, is a dopamine reuptake inhibitor and one of the few drugs evaluated in clinical trials that has shown promise for the treatment of cocaine or methamphetamine use disorders in some patient subpopulations. Recent structure activity relationship and preclinical studies on a series of MOD analogs have provided insight into modifications of its chemical structure that may lead to advancements in clinical efficacy. Here, we have tested the effects of the clinically available (R)-enantiomer of MOD on extracellular dopamine levels in the nucleus accumbens shell, a mesolimbic dopaminergic projection field that plays significant roles in various aspects of psychostimulant use disorders, measured in vivo by fast-scan cyclic voltammetry and by microdialysis in Sprague Dawley rats. We have compared these results with those obtained under identical experimental conditions with two novel and enantiopure bis(F) analogs of MOD, JBG1-048 and JBG1-049. The results show that (R)-modafinil (R-MOD), JBG1-048, and JBG1-049, when administered intravenously with cumulative drug-doses, will block the dopamine transporter and reduce the clearance rate of dopamine, increasing its extracellular levels. Differences among the compounds in their maximum stimulation of dopamine levels, and in their time course of effects were also observed. These data highlight the mechanistic underpinnings of R-MOD and its bis(F) analogs as pharmacological tools to guide the discovery of novel medications to treat psychostimulant use disorders. PMID- 30402973 TI - Carotid Intima-Media Roughness and Elasticity in Hypertensive Patients With Normal Carotid Intima-Media Thickness. AB - OBJECTIVES: To investigate carotid intima-media roughness (IMR) in hypertensive patients with normal carotid intima-media thickness (IMT) using automatic identification software and the correlation between carotid IMR and risk factors. METHODS: This case-control study comprised 61 hypertensive patients with normal carotid IMT and 51 control participants. Carotid IMR, carotid IMT, pulsed wave velocity (PWV), stiffness (beta), and arterial compliance were determined by carotid ultrasound and image postprocessing using an automatic identification program and echo-tracking analysis software. RESULTS: Carotid IMR, mean carotid IMT, maximum carotid IMT, beta, and PWV in the hypertension group were higher than those in the control group (58.24 versus 34.61 MUm, 641.17 versus 576.48 MUm, 746.82 versus 640.55 MUm, 9.42 versus 7.35, and 7.10 versus 5.86 m/s, respectively; P < .05), and arterial compliance was lower than that in the control group (0.70 versus 0.95 mm2 /kPa; P < .05). Intima-media roughness was correlated with maximum IMT, mean IMT, PWV, beta, age, diagnosis of hypertension for greater than 1 year, and pulse pressure. Multivariate logistic regression showed that age, diagnosis of hypertension for greater than 1 year, and pulse pressure were influential factors for IMR in hypertensive patients, with odds ratios of 6.719 (95% confidence interval, 1.658-27.221; P = .008), 4.726 (95% confidence interval, 1.174-19.022; P = .029), and 3.998 (95% confidence interval, 1.033-15.466; P = .045), respectively. CONCLUSIONS: Carotid IMR and the elasticity index have important clinical importance in evaluating the risk of early atherosclerosis in hypertensive populations. PMID- 30402974 TI - Origin of Photoinduced Geometrical Change of Copper (I) Complexes from the Quantum Chemical Topology View. AB - Copper (I) complexes (CIC) have been of great interest due to their applications as redox mediators, hole-transport materials and molecular switches. CIC present drastic geometrical change at excited states that interfere with their luminescence properties. The photophysical process has been explained in terms of a Jahn-Teller effect. Here we propose an alternative explanation for the photoinduced structural change of CIC. A photoexcitation of a CIC (S0->S1), a metal-to-ligand charge transfer produces a stabilization of the ligand and destabilization of the metal. A subsequent electron transfer, through an intersystem crossing process (T2->T1), intensifies the metal ligand energetic differences within the complex. The energy profile of each state results from the balance between the metal and the ligand energy changes. The electrons losses originate an increase of the attractive potential energy within the copper basin, which is not compensated by the associated reduction of the repulsive atomic potential. To counterbalance the atomic destabilization, the copper center polarizes its valence shell (defined by ?2rho(r) and ?2Vne(r)) during the deactivation path. This polarization increases the magnitude of the intra-atomic nuclear-electron interactions within the copper atom and provokes the flattering of the structure to obtain the geometry with the maximum interaction between the charge depletions of the metal with the charge concentrations of the ligand. PMID- 30402975 TI - Maternal genitourinary infections and risk of birth defects in the National Birth Defects Prevention Study. AB - BACKGROUND: Genitourinary infections (GUIs) are common among sexually active women. Yet, little is known about the risk of birth defects associated with GUIs. METHODS: Using data from the National Birth Defects Prevention Study, a multisite, population-based, case-control study, we assessed self-reported maternal GUIs in the month before through the third month of pregnancy (periconception) from 29,316 birth defect cases and 11,545 unaffected controls. We calculated odds ratios (ORs) and 95% confidence intervals to estimate the risk of 52 major structural birth defects associated with GUIs. We also calculated risk of birth defects associated with each type of GUI: urinary tract infection (UTI) and sexually transmitted infection (STI). RESULTS: In our analysis, 10% (n = 2,972) of case and 9% (n = 1,014) of control mothers reported a periconceptional GUI. A GUI was significantly associated with 11 of the 52 birth defects examined (ORs ranging from 1.19 to 2.26): encephalocele, cataracts, cleft lip, esophageal atresia, duodenal atresia/stenosis, small intestinal atresia/stenosis, colonic atresia/stenosis, transverse limb deficiency, conoventricular septal defect, atrioventricular septal defect, and secundum atrial septal defect. A periconceptional UTI was significantly associated with nine birth defects (ORs from 1.21 to 2.48), and periconceptional STI was significantly associated with four birth defects (ORs ranging from 1.63 to 3.72). CONCLUSIONS: While misclassification of GUIs in our analysis is likely, our findings suggest GUIs during the periconceptional period may increase the risk for specific birth defects. PMID- 30402977 TI - Collision-induced mass spectrometric fragmentation of protonated dimethoate and omethoate generated by electrospray ionization. AB - RATIONALE: Dimethoate (DIM, S=P (OMe)2 -S-CH2 -C(O)-NH-CH3 ) is a dimethyl phosphorodithioate pesticide widely used in agri- and horticulture that undergoes biotransformation in vivo by desulfuration into its more toxic oxono-derivative omethoate (OM, O=P (OMe)2 -S-CH2 -C(O)-NH-CH3 ). OM inhibits acetylcholinesterase thus provoking cholinergic crisis in vivo, ultimately leading to death. Quantitative approaches for the determination of DIM and OM in environmental and toxicological samples make use of tandem mass spectrometry (MS2 ). Nevertheless, so far interpretation of resulting product ions is incomplete and sometimes contradictory. METHODS: DIM and OM as well as their deuterated analogues (fully deuterated at both methoxy groups bound to the phosphorus atom) were analysed by MS2 and MS3 after positive electrospray ionization and collision-induced dissociation (CID) in a linear ion trap to characterize fragmentations. The accurate mass of product ions was determined in a time-of-flight mass analyser. H/D-exchange experiments were carried out for further support of product ion identification. In addition, density functional theory (DFT) computations were used to calculate both the most stable protonation sites of DIM and OM and the changes in the diverse bond lengths after protonation. RESULTS: Some identical and some related product ions of DIM and OM were found but also striking individual differences. Fragmentation pathways were proposed and product ions identified. Most fragmentations followed the common rules of charge migration fragmentation. DFT calculations supported experimental findings. CONCLUSIONS: Discrepancies present in the literature so far are clarified and a deeper insight is provided into the fragmentation processes of organophosphorus pesticides. The combination of diverse experimental and theoretical approaches yielded consistent results, thus demonstrating continuous progress in understanding gas-phase reactions in MS experiments. PMID- 30402978 TI - Instrumental evaluation sensitively detects subclinical skin changes by the epidermal growth factor receptor inhibitors and risk factors for severe acneiform eruption. AB - Epidermal growth factor receptor inhibitors (EGFRI), EGFR tyrosine kinase inhibitors (TKI) and anti-EGFR antibodies commonly develop skin toxicities including acneiform eruption (AfE). However, precise skin changes and risk factors for severe AfE are still unclear. The objective of the current study was elucidation of the useful parameters for early and sensitive detection of the skin changes by EGFRI. Transepidermal water loss (TEWL), skin surface hydration, skin surface lipid levels and erythema/melanin index were serially measured for 2 weeks in 19 EGFR-TKI afatinib/erlotinib-treated patients and for 8 weeks in 20 anti-EGFR antibody cetuximab-treated patients. The TEWL levels of the cheek in the patients who developed AfE of grade 2 and more (AfE >= Gr2) were already elevated at 7 days after the initiation of afatinib/erlotinib therapy compared with those before therapy as well as in patients with grade 1 or less (AfE <= Gr1). In patients treated with cetuximab, the skin surface hydration on the cheek in AfE >= Gr2 patients significantly decreased compared with that of AfE <= Gr1 patients at the 2nd and 6th week. Baseline skin surface lipid levels and erythema index on the cheek of patients with AfE >= Gr2 were significantly higher than those with AfE <= Gr1. The small sample size of the present study, especially for logistic regression analysis, is a limitation. In conclusion, instrumental evaluation declared rapid inflammatory changes of the skin by EGFRI and elucidated oily skin as a risk for severe AfE. PMID- 30402979 TI - Parallel learning processes of a visuomotor adaptation task in a changing environment. AB - During the control of reaching movements, a key contribution of the visual system is the localization of relevant environmental targets. In motor adaptation processes, the visual evaluation of effector motor behavior enables learning from errors, which demands continuous visual attentional focus. However, most current adaptation paradigms include static targets; therefore, when a learning situation develops in a highly variable environment and there is a double demand for visual resources (environment and motor performance), the evolution of learning processes is unknown. In order to understand how learning processes evolve in a variable environment, a video game task was designed in which subjects were asked to manage a 60 degrees counterclockwise-rotated cursor to capture descending targets with initially unpredictable trajectories. During the task, the cursor and eye movements were recorded to dissect visuomotor coordination. We observed that the pursuit of the targets conditioned a predominant and continuous visual inspection of the environment instead of the rotated cursor. As learning progressed, subjects exhibited a linear reduction in directional error and selected a motor strategy based on the degree of reward, which improved the performance. These results suggest that when the environment demands high visual attention, error-based and reinforced motor learning processes are implemented simultaneously, thus enabling efficient predictive behavior. PMID- 30402980 TI - Dysregulated circular RNAs in medulloblastoma regulate proliferation and growth of tumor cells via host genes. AB - Circular RNAs (circRNAs) have been demonstrated to be involved in various biological processes. Nevertheless, the function of circRNAs in medulloblastoma (MB) is still unknown. The present study aimed to investigate the expression profiles of circRNAs and related mechanisms for regulating the proliferation and growth of tumor cells in MB. The expression profiles of circRNAs were screened from four normal cerebellum and four MB samples using a HiSeq Sequencer. Bioinformatic analysis was employed to predict the interaction between circRNAs and mRNAs in MB. Subsequently, the expression levels of eight differential circRNAs [circ-SKA3 (hsa_circ_0029696), circ-DTL (hsa_circ_0000179), circ-CRTAM, circ-MAP3K5 (hsa_circ_0006856), circ-RIMS1-1 (hsa_circ_0132250), circ-RIMS1-2 (hsa_circ_0076967), circ-FLT3-1 (hsa_circ_0100165), and circ-FLT3-2 (hsa_circ_0100168)] were validated using quantitative reverse transcription polymerase chain reaction. Moreover, circ-SKA3 and circ-DTL were silenced using small interfering RNAs and their host genes were overexpressed to investigate their role in the pathogenesis of MB. A total of 33 circRNAs were found to be differentially expressed in MB tissues (fold change >= 2.0, FDR <0.05), of which three were upregulated and 30 were downregulated; six circRNAs were experimentally validated successfully. Upregulated circ-SKA3 and circ-DTL promoted the proliferation migration and invasion in vitro by regulating the expression of host genes. This novel study exploited the profiling of circRNAs in MB and demonstrated that circ-SKA3 and circ-DTL were crucial in the tumorigenesis and development of MB and might be considered as novel and potential biomarkers for the diagnosis and new targets for the intervention of MB. PMID- 30402981 TI - Okuda lecture: Challenges of hepatitis B in the era of antiviral therapy. AB - Nucleos(t)ide analogs (NAs) are effective, safe, and convenient antiviral therapy to suppress replication of hepatitis B virus, which can be translated into improved long-term outcome of chronic hepatitis B patients. The current recommended first-line NAs, namely, entecavir and tenofovir, are largely free from problems of drug resistance. Nonetheless, there are still a few challenges in the era of NA. First, the risk of hepatocellular carcinoma can only be reduced but not eliminated, particularly among cirrhotic patients. For cirrhotic patients who have persistent low-level viremia on NA, that is, partial responders, the risk of hepatocellular carcinoma is higher than those with complete viral suppression. The best strategy to manage partial responders to entecavir or tenofovir is uncertain. Second, immune-tolerant patients are very difficult to treat with NA. A significant proportion of immune-tolerant patients will have detectable viremia despite a few years of continuous NA treatment, and the rate of hepatitis B e-antigen seroconversion is very low. Third, most patients need long-term treatment as NA cannot eliminate covalently closed circular DNA in the hepatocytes. Some patients can consider stop NA according to treatment guidelines, but viral and clinical relapses often occur after treatment cessation. There is no concrete consensus on when one should stop NA in a hepatitis B e-antigen-negative patient among different treatment guidelines. New biomarkers such as hepatitis B surface antigen level can be used to select patients to stop NA, but the data are still preliminary. PMID- 30402982 TI - Effect of spraying of fine water particles on facial skin moisture and viscoelasticity in adult women. AB - BACKGROUND/PURPOSE: It is known that the elderly and adult women with reduction in sebum secretion have reduced skin barrier function, drying of the skin in a low humidity environment is accompanied by physiological distress. As our hypothesis, when fine water particles are sprayed on the skin, the water content of the corneal layer is significantly increased. In the present study, we examined the ability of fine water particles to improve facial skin moisture levels in adult women. METHODS: We examined skin conductance, transepidermal water loss (TEWL), and skin elasticity as an index of skin barrier function at the cheek in 17 healthy adult women in the spraying of fine water particles, in the environment temperature at 24 degrees C and 34.5% relative humidity. RESULTS: The skin conductance of stratum corneum after 120 minute of spraying, A condition (peak particle size below 0.5 MUm) was 119.7 +/- 25.1%, B condition (peak particle size 1.8 MUm) was 100.4 +/- 31.7%, C condition (peak particle size 5.4 MUm) was 110.1 +/- 25.0%, and the A condition was significantly higher than the B condition. Also, skin elasticity in the A condition tended to be higher value than in the other conditions. Transepidermal water loss (TEWL) after 120 minute of spraying showed a lower value in the A condition than in the other conditions. In the A condition, the skin conductance steadily maintained their initial levels up to 360 minute after spraying. CONCLUSION: Especially, by spraying smallest fine water particles, skin barrier function at the cheek was improved. These data indicated that non-charged fine water particles played an important role on moisten skin in a low humidity environment. PMID- 30402983 TI - Assessment of beam-matched linacs quality/accuracy for interchanging SBRT or SRT patient using VMAT without replanning. AB - PURPOSE: Dosimetric accuracy is critical when switching a patient treated with stereotactic body radiation therapy (SBRT) or stereotactic fractionated radiotherapy (SRT) among beam-matched linacs. In this study, the dose delivery accuracy of volumetric modulated arc therapy (VMAT) plans for SBRT/SRT patients were evaluated on three beam-matched linacs. METHOD: Beam data measurements such as percentage depth dose (PDD10 ), beam profiles, output factors, and multi-leaf collimator (MLC) leaf transmission factor for 6 MV photon beam were performed on three beam-matched linacs. The EdgeTM diode detector was used for measurements of beams of field size less than 5 * 5 cm2 . Ten lung and 15 brain plans were generated using VMAT with the same beam model. Modulation complexity score of the VMAT plan (MCSv) was used as a plan complexity indicator. Doses were measured using ArcCHECKTM and GafChromicTM EBT3 films. The measurements were compared with calculated doses through absolute dose gamma comparison using 3%/2 mm and 2%/2 mm criteria. Correlation between difference in passing rates among beam-matched linacs and MCSv was evaluated using the Pearson coefficient. Point doses were measured with the A1SL micro ion chamber. RESULTS: Difference in beam outputs, beam profiles, and MLC leaf transmission factors of beam-matched linacs were all within +/-1%, except the difference in output factor for 1 * 1 cm2 field between linac 1 and 3 (1.3%). For all 25 cases, passing rates of measured doses on three linacs were all higher than 90% when using 2%/2 mm gamma criteria. The average difference in point dose measurements among three beam-matched linacs was 0.1 +/- 0.2% (P > 0.05, one-way ANOVA). CONCLUSION: Minimal differences in beam parameters, point doses, and passing rates among three linacs proved the viability of swapping SBRT/SRT using VMAT among beam-matched linacs. The effect of plan complexity on passing rate difference among beam-matched linacs is not statistically significant. PMID- 30402984 TI - Effect of phytic acid on the setting times and tensile strengths of calcium silicate-based cements. AB - This study aimed to evaluate and compare the effect of 1% phytic acid as a mixing medium on the setting times and diametral tensile strengths of different calcium silicate-based cements. Specimens for four experimental groups (n = 20/each) were fabricated by mixing ProRoot MTA(r) (Dentsply) and Biodentine(r) (Septodont) powders with their original liquids or with 1% phytic acid. Half of the samples in each group were immediately subjected to setting time tests, whereas the remaining half was subjected to the diametral tensile strength test after 3 weeks. When mixed with their original liquids, the setting time of MTA was significantly longer than that of Biodentine(r) (P < 0.05). When mixed with phytic acid, the initial and final setting times of both test materials significantly decreased (P < 0.05). The diametral tensile strength of Biodentine(r) was significantly greater than that of MTA (P < 0.05). However, phytic acid had no effect on this outcome (P > 0.05). PMID- 30402986 TI - The relationship between frailty, functional dependence, and healthcare needs among community-dwelling people with moderate to severe dementia. AB - This paper examines the healthcare needs of community-dwelling older people living in Porto, Portugal, diagnosed with moderate or severe dementia, linked to functional dependency, cognitive decline, limitations in the activities of daily life, and frailty levels. A sample of 83 participants was recruited. Data were collected between 2013 and 2017. A sociodemographic questionnaire, the Clinical Dementia Rating (CDR), the Barthel Index (BI), the Lawton and Brody Instrumental Activities of Daily Living (IADL) Scale, and the Edmonton Frail Scale (EFS) were used. A set of 26 healthcare needs was defined to support the assessment. The Pearson chi-square or Fisher's exact test (as appropriate) was used to examine the association of the needs (unmet and met) with the levels of dementia and frailty. Participants were diagnosed previously with moderate or severe dementia and benefited from a structured home-care program. There was a high number rated as "severe dementia," "fully dependent," "severely or fully dependent in the activities of daily living (ADL)," and "severe frailty." There were statistically significant differences among needs identified in people with moderate or severe dementia and moderate or severe frailty. The most prevalent healthcare needs in the sample were food preparation, medication/taking pills, looking after their home, toilet use, sensory problems, communication/interaction, bladder, bowels, eating and drinking, memory, sleeping, and falls prevention. In particular, the study identifies a set of needs that are present simultaneously in both frailty and dementia stages. This study underlines that despite well-structured home-care programs for people with dementia, unmet health needs remain. Timely healthcare needs assessment may help professionals to avoid fragmented care and to tailor quality-integrated interventions, including the emotional and psychological balance of the caregiver. PMID- 30402985 TI - The role impairment associated with mental disorder risk profiles in the WHO World Mental Health International College Student Initiative. AB - OBJECTIVE: The objective of this study is to assess the contribution of mental comorbidity to role impairment among college students. METHODS: Web-based self report surveys from 14,348 first-year college students (Response Rate [RR] = 45.5%): 19 universities, eight countries of the World Mental Health International College Student Initiative. We assessed impairment (Sheehan Disability Scales and number of days out of role [DOR] in the past 30 days) and seven 12-month DSM-IV disorders. We defined six multivariate mental disorder classes using latent class analysis (LCA). We simulated population attributable risk proportions (PARPs) of impairment. RESULTS: Highest prevalence of role impairment was highest among the 1.9% of students in the LCA class with very high comorbidity and bipolar disorder (C1): 78.3% of them had severe role impairment (vs. 20.8%, total sample). Impairment was lower in two other comorbid classes (C2 and C3) and successively lower in the rest. A similar monotonic pattern was found for DOR. Both LCA classes and some mental disorders (major depression and panic, in particular) were significant predictors of role impairment. PARP analyses suggest that eliminating all mental disorders might reduce severe role impairment by 64.6% and DOR by 44.3%. CONCLUSIONS: Comorbid mental disorders account for a substantial part of role impairment in college students. PMID- 30402988 TI - Recurrent monomorphic epitheliotropic intestinal T-cell lymphoma with aberrant CD20 expression: An implication for anti-CD20 (rituximab) antibody therapy? PMID- 30402989 TI - Histopathological findings of an exposed human pulp carbonised by CO2 laser irradiation: A case report. AB - This report shows the healing process of an exposed pulp carbonised by CO2 laser irradiation prior to the application of a capping material. Six intact teeth from four volunteers were irradiated by CO2 laser and randomly capped with either an adhesive resin (SE bond) (n = 3) or calcium hydroxide-based cement (Dycal) (n = 3). The laser was operated in super-pulsed mode (power output, 0.5 W) for an irradiation time of 30 s. All cavities were restored with composite resin. Each tooth was extracted at approximately 30, 50 or 260 days post treatment and prepared for histological evaluation. CO2 laser irradiation controlled exudate and bleeding from each exposed pulp. Histological images revealed Dycal promoted complete dentine bridge formation at the carbonised pulp surface, and laser energy affected not only the pulp surface but also the deeper part of the pulp chamber. PMID- 30402987 TI - Naltrexone differentially modulates the neural correlates of motor impulse control in abstinent alcohol-dependent and polysubstance-dependent individuals. AB - Identifying key neural substrates in addiction disorders for targeted drug development remains a major challenge for clinical neuroscience. One emerging target is the opioid system, where substance-dependent populations demonstrate prefrontal opioid dysregulation that predicts impulsivity and relapse. This may suggest that disturbances to the prefrontal opioid system could confer a risk for relapse in addiction due to weakened 'top-down' control over impulsive behaviour. Naltrexone is currently licensed for alcohol dependence and is also used clinically for impulse control disorders. Using a go/no-go (GNG) task, we examined the effects of acute naltrexone on the neural correlates of successful motor impulse control in abstinent alcoholics (AUD), abstinent polysubstance dependent (poly-SUD) individuals and controls during a randomised double blind placebo controlled fMRI study. In the absence of any differences on GNG task performance, the AUD group showed a significantly greater BOLD response compared to the control group in lateral and medial prefrontal regions during both placebo and naltrexone treatments; effects that were positively correlated with alcohol abstinence. There was also a dissociation in the positive modulating effects of naltrexone in the orbitofrontal cortex (OFC) and anterior insula cortex (AIC) of the AUD and poly-SUD groups respectively. Self-reported trait impulsivity in the poly-SUD group also predicted the effect of naltrexone in the AIC. These results suggest that acute naltrexone differentially amplifies neural responses within two distinct regions of a salience network during successful motor impulse control in abstinent AUD and poly-SUD groups, which are predicted by trait impulsivity in the poly-SUD group. PMID- 30402990 TI - The effects of curcumin-containing supplements on biomarkers of inflammation and oxidative stress: A systematic review and meta-analysis of randomized controlled trials. AB - Besides other benefits, curcumin is getting more recognized for its antioxidant and anti-inflammatory properties, highlighting the importance of curcumin application for chronic disease prevention. This systematic review and meta analysis of randomized controlled trials (RCTs) was conducted to assess the influence of curcumin-containing supplements on biomarkers of inflammation and oxidative stress. MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials were searched till January 2018 for eligible studies. The selected studies were evaluated for their quality using the Cochrane risk of bias tool and relevant data were extracted from included studies. Data were pooled using the inverse variance method and expressed as standardized mean difference (SMD) with 95% confidence intervals (95% CI). Fifteen RCTs were included in the final analysis. The meta-analysis indicated that curcumin supplementation significantly decreased interleukin 6 (IL-6) (SMD -2.08; 95% CI [-3.90, -0.25]; p = 0.02), high-sensitivity C-reactive protein (hs-CRP) (SMD -0.65; 95% CI [-1.20, 0.10], p = 0.02), and malondialdehyde (MDA) concentrations (SMD -3.14; 95% CI [ 4.76, -1.53], p < 0.001). Though, curcumin supplementation had no significant effect on tumor necrosis factor-alpha (SMD -1.62; 95% CI [-3.60, 0.36]; p = 0.10) and superoxide dismutase levels (SMD 0.34; 95% CI [-1.06, 1.74], p = 0.63). Overall, this meta-analysis suggests that taking curcumin-containing supplements may exert anti-inflammatory and antioxidant properties through a significant reduction in IL-6, hs-CRP, and MDA levels. PMID- 30402991 TI - Adaptive neurogenesis in the cerebral cortex and contralateral subventricular zone induced by unilateral cortical devascularization: Possible modulation by dopamine neurotransmission. AB - Understanding endogenous neurogenesis and neuronal replacement to mature circuits is a topic of discussion as a therapeutic alternative under acute and chronic neurodegenerative disorders. Adaptive neurogenic response may result as a result of ischemia which could support long-term recovery of behavioral functions. Endogenous sources of neural progenitors may be stimulated by changes in blood flow or neuromodulation. Using a mouse model of unilateral cortical devascularization, we have observed reactive neurogenesis in the perilesional cortex and subventricular zone neurogenic niche. C57BL/6L 4 weeks old male mice were craneotomized at 1 mm caudal from frontal suture and 1 mm lateral from midline to generate a window of 3 mm side. Brain injury was produced by removal of the meninges and superficial vasculature of dorsal parietal cortex. BrdU agent (50 mg/kg, ip) was injected to lesioned and sham animals, during days 0 and 1 after surgery. Sagittal sections were analyzed at 1, 4, 7, and 10 days post injury. A time-dependent increase in BrdU+ cells in the perilesional parietal cortex was accompanied by augmented BrdU+ cells in the sub ventricular and rostral migratory stream of ipsilateral and contralateral hemispheres. Neural progenitors and neuroblasts proliferated in the lesioned and non-lesioned subventricular zone and rostral migratory stream on day 4 after injury. Augmented contralateral neurogenesis was associated with an increase in vesicular monoamine transporter 2 protein in the striosomal sub ventricular neurogenic niche of non lesioned hemisphere. PMID- 30402992 TI - A qualitative study of the experiences and perceptions of adults with chronic musculoskeletal conditions following a 12-week Pilates exercise programme. AB - INTRODUCTION: The aim of the present study was to explore the experiences and perceptions of adult patients with chronic musculoskeletal conditions following a Pilates exercise programme. A qualitative approach was taken to both data collection and analysis, with alignment to the philosophy of interpretive phenomenology. Participants included 15 women and seven men with a range of chronic musculoskeletal conditions, including nonspecific low back pain, peripheral joint osteoarthritis and a range of postsurgical conditions. The age range was from 36 years to 83 years, and the mean age was 57 years (standard deviation 14.1 years). METHODS: Data were collected via digital recordings of four focus groups in three North-West of England physiotherapy clinics. The data were transcribed verbatim and then analysed using a thematic framework. Data were verified by a researcher and randomly selected participants, and agreement was achieved between all parties. RESULTS: The results were organized into five main themes: physical improvements; Pilates promotes an active lifestyle: improved performance at work and hobbies; psychosocial benefits and improved confidence; increased autonomy in managing their own condition; and motivation to continue with exercise. CONCLUSION: The study was the first to investigate individual perceptions of the impact of Pilates on the daily lives of people with chronic conditions. The Pilates-based exercise programme enabled the participants to function better and manage their condition more effectively and independently. Further to previous work, the study revealed psychological and social benefits which increase motivation to adhere to the programme and promote a healthier lifestyle. PMID- 30402993 TI - Use of solitary confinement in children and young people. PMID- 30402994 TI - Long-term safety and efficacy of turoctocog alfa in prophylaxis and treatment of bleeding episodes in severe haemophilia A: Final results from the guardian 2 extension trial. AB - INTRODUCTION: Turoctocog alfa is a recombinant factor VIII (FVIII) molecule, approved for treatment and prophylaxis of bleeding in patients with haemophilia A. In the guardian 1 (adolescents/adults) and guardian 3 (children) phase 3 trials, turoctocog alfa demonstrated a favourable efficacy and safety profile. Guardian 1 or 3 completers could enrol in the guardian 2 extension. Final guardian 2 results are reported here. AIM: Investigate long-term safety and efficacy of turoctocog alfa administered for prophylaxis and treatment of bleeds. METHODS: In this phase 3b open-label trial, previously treated males of all ages with severe haemophilia A received prophylaxis regimens of turoctocog alfa or on demand treatment of bleeds. The primary safety endpoint was frequency of FVIII inhibitor development. Efficacy endpoints included annualized bleeding rate (ABR) during prophylaxis, haemostatic response in treatment of bleeds and number of injections required to treat bleeds. RESULTS: Overall, 213 patients were dosed with turoctocog alfa; 207 patients received prophylaxis; 19 received on-demand treatment. No FVIII inhibitors (>=0.6 BU) were reported. For all patients on prophylaxis, overall median ABR was 1.37 bleeds/y; success rate for treatment of bleeds was 90.2%; and 88.2% of bleeds were controlled with 1-2 injections of turoctocog alfa. For the on-demand regimen, overall median ABR was 30.44 bleeds/y; success rate for treatment of bleeds was 96.7%; and 94.9% of bleeds were controlled with 1-2 injections of turoctocog alfa. CONCLUSION: Extended use of turoctocog alfa is safe and effective for prevention and treatment of bleeding episodes in previously treated patients with haemophilia A across all ages. PMID- 30402995 TI - Enantioselective Electrophilic Aromatic Nitration - A Chiral Auxiliary Approach. AB - Enantioselective electrophilic aromatic nitration methodology is needed to advance chirality-assisted synthesis (CAS). We now report an enantioselective aromatic nitration strategy operating with chiral diester auxiliaries, which provides an enantioselective synthesis of a C3v-symmetric tribenzotriquinacene (TBTQ). These axially-chiral structures are much sough-after building blocks for CAS, but they were not accessible prior to this work in enantioenriched form without resolution of enantiomers. Our nitration strategy controls the stereochemistry of threefold nitration reactions from above the aromatic rings with chiral diester arms. Dicarbonyl-to-arenenium chelation rigidifies the reaction systems, so that remote stereocenters are able to position the ester directing groups selectively over specific atoms of the TBTQ frameworks. Closely guided by computational design, a more selective through-space directing arm was first predicted with density-functional theory (DFT) and then confirmed in the laboratory to outperform the initial structural design. Our enantio- and regioselective TBTQ synthesis opens a new pathway to access building blocks for CAS. PMID- 30402996 TI - Synthesis and in vitro characterization of trehalose-based inhibitors of mycobacterial trehalose 6-phosphate phosphatases. AB - alpha,alpha'-Trehalose plays roles in the synthesis of several cell wall components involved in pathogenic mycobacteria virulence. Its absence in mammalian biochemistry makes trehalose-related biochemical processes potential targets for chemotherapy. The trehalose-6-phosphate synthase (TPS)/trehalose-6 phosphate phosphatase (TPP) pathway, also referred to as the OtsA/OtsB2 pathway, is the major pathway involved in the production of trehalose in Mycobacterium tuberculosis (Mtb). In addition, TPP is essential for Mtb survival. We describe the synthesis of 6-phosphonic acid 4 (TMP), 6-(methylene)phosphonic acid 5 (TEP) , and 6-N-phosphonamide 6 (TNP) derivatives of alpha,alpha'-trehalose. These non hydrolyzable substrate analogs of TPP were examined as inhibitors of Mtb, M. lentiflavum (Mlt), and M. triplex (Mtx) TPP. In all cases the compounds inhibited Mtx TPP most strongly, with TMP (IC50 = 288 +/- 32 MUM) inhibiting most strongly, followed by TNP (IC50 = 421 +/- 24 MUM) and TEP (IC50 = 1959 +/- 261 MUM). The results also indicate significant differences in the analog binding profile when comparing Mtb TPP, Mlx TPP, and Mtx TPP homologs. PMID- 30402997 TI - Trajectories of health behaviors across early childhood cancer survivorship. AB - OBJECTIVE: The majority of childhood cancer survivors develop at least one late effect subsequent to treatment (eg, cardiovascular disease and obesity). Consistent engagement in recommended health behaviors may mitigate some of these conditions. Researchers have identified early survivorship as a teachable moment, yet few studies have examined positive health behaviors during this period. METHODS: Families of children with cancer (ages 5-17) were initially recruited following a diagnosis or relapse of cancer. Three years post diagnosis, survivors (n = 82, Mage = 13.3, SD = 3.7) and their mothers (n = 103, Mage = 41.1, SD = 7.6) completed a questionnaire assessing exercise, dietary, and sleep patterns among survivors. A follow-up assessment was conducted 2 years later. Mixed models tested change in health behavior over time. RESULTS: At 3- and 5-year post diagnosis, mother and self-report indicated that few survivors engaged in appropriate levels of low-intensity exercise, fruit/vegetable intake, and dairy consumption. However, most survivors engaged in recommended levels of high intensity exercise, fast food restriction, and sleep. Health behaviors remained stable over time, except for mother report of sleep duration, which decreased (b = -0.6, P < 0.001). Brain tumor diagnosis predicted a larger decrease in self report of sleep duration compared with other diagnoses (P = 0.04). Income predicted fast food intake such that higher income was associated with decreased intake over time, whereas lower income was associated with increased intake (P = 0.04). CONCLUSIONS: During early survivorship, several health behaviors fell short of expectations for exercise and diet and did not improve upon reaching 5 year post diagnosis. Providers should evaluate survivors' health behaviors, including sleep, early and often, intervening when necessary. PMID- 30402998 TI - Effects of loss of consciousness on maxillofacial fractures in simple falls. AB - BACKGROUND/AIMS: Loss of consciousness while falling is reported to increase the risk of more severe injury. However, few studies of maxillofacial injuries have been reported. The aim of this study was to investigate the effects of loss of consciousness on maxillofacial fractures in falls on a level surface (simple falls). MATERIAL AND METHODS: Patients with maxillofacial fractures caused by simple falls were subdivided into two categories: patients who fell without loss of consciousness and patients who fell with loss of consciousness, according to the Guidelines for the Diagnosis and Management of Syncope (version 2009). The severity of the injuries was compared between these two groups. RESULTS: In 413 patients with maxillofacial fractures, 58 cases were falls without loss of consciousness, and 44 cases were falls with loss of consciousness. In falls with loss of consciousness, 54.5% were reflex syncope, followed by syncope due to orthostatic hypotension (15.9%), epilepsy (15.9%), and cardiac syncope (9.1%). The average number of fracture lines in the mandible was significantly lower in falls without loss of consciousness (1.53 +/- 0.7) than in falls with loss of consciousness (2.00 +/- 1.00) (P = 0.045). The average Facial Injury Severity Scale score was lower in falls without loss of consciousness (2.24 +/- 1.20) than in falls with loss of consciousness (2.68 +/- 1.39). Fractures of other parts of the body were significantly more common in falls without loss of consciousness (22.2%) than in falls with loss of consciousness (9.1%) (P = 0.0135). CONCLUSIONS: Patients with loss of consciousness and maxillofacial fractures due to simple falls showed a tendency to sustain more severe maxillofacial injuries than those without loss of consciousness. PMID- 30402999 TI - Response to Letter to 'Removal of retained products of conception showing marked vascularity without uterine artery embolization: Two case reports'. PMID- 30403000 TI - Photophysics and photodynamics of Pyronin Y in n-alcohols. AB - The photophysical properties and photodynamics of Pyronin Y (PyY) dye compound in seven polar protic solvents (n-alcohols) were examined as a function of temperature by using UV-visible, steady-state and time-resolved fluorescence spectroscopy techniques. To understand dye-solvent interactions, photophysical parameters including Stokes' shifts, fluorescence quantum yields and fluorescence lifetimes were determined. To examine the effect of solvent polarity, the difference between the ground state dipole moment and the excited state dipole moment was determined. For this purpose, the multiple regression analysis and the Kamlet-Taft technique were used. Moreover, photodynamic parameters, rotational relaxation times and steady-state anisotropy were calculated. The result showed that the specific interactions of PyY with the solvent molecules take place through hydrogen bonding. As the hydrocarbon chain of the alcohols gets longer, photophysical parameters diminish, probably because of weaker hydrogen bonding. Furthermore, it was found out that the dipole moment of excited states (MUe ) is higher than that of the ground state (MUg ). In addition, Brownian motions increased with the increasing temperature that weakened the fluorescence character of PyY. It was also revealed that the rotation of PyY increased with a prolonged hydrocarbon chain of alcohol series, due to the lesser extent of hydrogen bonding. PMID- 30403001 TI - Four years after stroke, two-thirds of working aged survivors have returned to work. PMID- 30403003 TI - Response to the Letter to the Editor on "Antecedent rest may not be necessary for automated office blood pressure at lower treatment targets". PMID- 30403002 TI - Being acknowledged by others and bracketing negative thoughts and feelings: Frail older people's narrations of how existential loneliness is eased. AB - AIMS AND OBJECTIVES: The aim of this study was to describe how EL was eased, as narrated by frail older people. BACKGROUND: Existential loneliness (EL) is an unavoidable part of the human condition. It is a complex phenomenon that has been described as disconnection from life. If EL is acknowledged in the care of older people, the experience of EL can be reduced. DESIGN: In this qualitative study, we used an exploratory and descriptive design. METHODS: The study was based on 22 narrative interviews with frail older people, 76 to 101 years old, who were receiving long-term care and services. We analysed the data using conventional content analysis. RESULTS: Being acknowledged by others, that is, being the focus of others' concern, eased the experience of EL, as did encountering intimacy and having meaningful exchanges of thoughts and feelings. Further, EL was pushed into the background and eased when participants could bracket negative thoughts and feelings, that is, when they could adjust and accept the present situation, view life in the rear-view mirror, be in contact with spiritual dimensions and withdraw and distract themselves. CONCLUSION: Existential loneliness can be eased by experiencing meaningful togetherness with others and oneself when something else comes to the forefront, pushing EL to the background. Frail older peoples' opportunities to ease EL may be facilitated by health care staff (HCS) providing person-centred care and create possibilities for solitary time and meaningful togetherness. IMPLICATIONS FOR PRACTICE: If frail older people's ongoing processes of adjusting and accepting their situation are understood and confirmed by people in their environment, for example, by nurses, family and friends, the experience of living a meaningful life can be supported, which, in turn, can ease EL. PMID- 30403004 TI - Amyloid beta soluble forms and plasminogen activation system in Alzheimer's disease: Consequences on extracellular maturation of brain-derived neurotrophic factor and therapeutic implications. AB - Soluble oligomeric forms of amyloid beta (Abeta) play an important role in causing the cognitive deficits in Alzheimer's disease (AD) by targeting and disrupting synaptic pathways. Thus, the present research is directed toward identifying the neuronal pathways targeted by soluble forms and, accordingly, develops alternative therapeutic strategies. The neurotrophin brain-derived neurotrophic factor (BDNF) is synthesized as a precursor (pro-BDNF) which is cleaved extracellularly by plasmin to release the mature form. The conversion from pro-BDNF to BDNF is an important process that regulates neuronal activity and memory processes. Plasmin-dependent maturation of BDNF in the brain is regulated by plasminogen activator inhibitor-1 (PAI-1), the natural inhibitor of tissue-type plasminogen activator (tPA). Therefore, tPA/PAI-1 system represents an important regulator of extracellular BDNF/pro-BDNF ratio. In this review, we summarize the data on the components of the plasminogen activation system and on BDNF in AD. Moreover, we will hypothesize a possible pathogenic mechanism caused by soluble Abeta forms based on the effects on tPA/PAI-1 system and on the consequence of an altered conversion from pro-BDNF to the mature BDNF in the brain of AD patients. Translation into clinic may include a better characterization of the disease stage and future direction on therapeutic targets. PMID- 30403005 TI - Past is prologue: host community assembly and the risk of infectious disease over time. AB - Infectious disease risk is often influenced by host diversity, but the causes are unresolved. Changes in diversity are associated with changes in community structure, particularly during community assembly; therefore, by incorporating change over time, host community assembly may provide a framework to resolve causation. In turn, community assembly can be driven by many processes, including resource enrichment. To test the hypothesis that community assembly causally links host diversity to future disease, we experimentally manipulated host diversity and resource supply to hosts, then allowed communities to assemble for 2 years (surveyed 2012-2014). Initially, host diversity increased disease. Subsequently, host diversity did not directly alter disease. However, host diversity determined the trajectory of host community assembly, altering colonisation by exotic host species and richness-independent host phylogenetic diversity, which together reversed the initial increase in disease. Ultimately, incorporating the temporal dimension of community assembly revealed novel mechanisms linking host diversity to future disease. PMID- 30403007 TI - Study of selected birth defects among American Indian/Alaska Native population: A multi-state population-based retrospective study, 1999-2007. AB - BACKGROUND: Higher prevalence of selected birth defects has been reported among American Indian/Alaska Native (AI/AN) newborns. We examine whether known risk factors for birth defects explain the higher prevalence observed for selected birth defects among this population. METHODS: Data from 12 population-based birth defects surveillance systems, covering a birth population of 11 million from 1999 to 2007, were used to examine prevalence of birth defects that have previously been reported to have elevated prevalence among AI/ANs. Prevalence ratios (PRs) were calculated for non-Hispanic AI/ANs and any AI/ANs (regardless of Hispanic ethnicity), adjusting for maternal age, education, diabetes, and smoking, as well as type of case-finding ascertainment surveillance system. RESULTS: After adjustment, the birth prevalence of two of seven birth defects remained significantly elevated among AI/ANs compared to non-Hispanic whites (NHWs): anotia/microtia was almost threefold higher, and cleft lip +/- cleft palate was almost 70% higher compared to NHWs. Excluding AI/AN subjects who were also Hispanic had only a negligible impact on adjusted PRs. CONCLUSIONS: Additional covariates accounted for some of the elevated birth defect prevalences among AI/ANs compared to NHWs. Exclusion of Hispanic ethnicity from the AI/AN category had little impact on birth defects prevalences in AI/ANs. NHWs serve as a viable comparison group for analysis. Birth defects among AI/ANs require additional scrutiny to identify modifiable risk and protective factors. PMID- 30403006 TI - Comparison of automated clinical and research blood pressure measurements: Implications for clinical practice and trial design. AB - Discrepancies between clinic and research blood pressure (BP) measurements lead to uncertainties in translating hypertension management guidelines into practice. We assessed the concordance between standardized automated clinic BP, from a primary care clinic, and research BP, from a randomized trial conducted at the same site. Mean single-visit clinic BP was higher by 4.4/3.8 mm Hg (P = 0.007/<0.001). Concordance in systolic BP (SBP) improved with closer proximity of measurements (difference = 2.5 mm Hg, P = 0.21 for visits within 7 days), but not averaging across multiple visits (difference =5.1(9.2) mm Hg; P < 0.001). This discrepancy was greater among female participants. Clinic-based difference in SBP between two visits was more variable than research-based change (SD = 19.6 vs 14.0; P = 0.002); a 2-arm trial using clinic measurements would need 95% more participants to achieve comparable power. Implementation of a bundled standardization intervention decreased discrepancies between clinic and research BP, compared to prior reports. However, clinic measurements remained higher and more variable, suggesting treatment to research-based targets may lead to overtreatment and using clinic BP approximately halves power in trials. PMID- 30403008 TI - Lactate dehydrogenase A: A key player in carcinogenesis and potential target in cancer therapy. AB - Elevated glycolysis remains a universal and primary character of cancer metabolism, which deeply depends on dysregulated metabolic enzymes. Lactate dehydrogenase A (LDHA) facilitates glycolytic process by converting pyruvate to lactate. Numerous researches demonstrate LDHA has an aberrantly high expression in multiple cancers, which is associated with malignant progression. In this review, we summarized LDHA function in cancer research. First, we gave an introduction of structure, location, and basic function of LDHA. Following, we discussed the transcription and activation mode of LDHA. Further, we focused on the function of LDHA in cancer bio-characteristics. Later, we discussed the clinical practice of LDHA in cancer prevention and treatment. What we discussed gives a precise insight into LDHA especially in cancer research, which will contribute to exploring cancer pathogenesis and its handling measures. PMID- 30403010 TI - Population-based birth defects surveillance, epidemiology, and public health practice. PMID- 30403009 TI - Biomimetic Synthesis of Ag2 Se Quantum Dots with Enhanced Photothermal Properties and as "Gatekeepers" to Cap Mesoporous Silica Nanoparticles for Chemo Photothermal Therapy. AB - Ag2 Se quantum dots (QDs) with near-infrared (NIR) fluorescence have been widely utilized in NIR fluorescence imaging in vivo because of their narrow bulk band gap and excellent biocompatibility. However, most of synthesis methods for Ag2 Se QDs are expensive and the reactants are toxic. Herein, a new protein-templated biomimetic synthesis approach is proposed for the preparation of Ag2 Se QDs by employing bovine serum albumin (BSA) as a template and dispersant. The BSA templated Ag2 Se QDs (Ag2 Se@BSA QDs) showed NIR fluorescence with high fluorescence quantum yield (~21.2 %), excellent biocompatibility and good dispersibility in different media. Moreover, the obtained Ag2 Se@BSA QDs exhibited remarkable photothermal conversion (~27.8 %), which could be used in photothermal therapy. As a model application in biomedicine, the Ag2 Se@BSA QDs were used as "gatekeepers" to cap mesoporous silica nanoparticles (MSNs) by means of electrostatic interaction. By taking the advantages of NIR fluorescence and photothermal property of Ag2 Se@BSA QDs, the obtained MSN-DOX-Ag2 Se nanoparticles (MDA NPs) were employed as a nanoplatform for combined chemo photothermal therapy. Compared with free DOX and MDA NPs without NIR laser, the laser-treated MDA NPs exhibited lower cell viability in vitro, implying that Ag2 Se@BSA QDs are highly promising photothermal agents and the MDA NPs are potential carriers for chemo-photothermal therapy. PMID- 30403011 TI - The National Spina Bifida Patient Registry: A Decade's journey. AB - BACKGROUND: The National Spina Bifida Patient Registry (NSBPR) was established in 2008, as a partnership between the CDC and spina bifida (SB) clinics throughout the United States. The purpose of this study is to explore the initial work of this project through a literature review of published studies from the NSBPR and provide a description of how this body of literature has developed overtime. METHODS: We included studies indexed in MEDLINE by means of PubMed from January 2009 through April 2018. Included articles were appraised to identify key themes relevant to SB demographics, interventions, and outcomes. Additionally, information regarding objectives, hypotheses, and results of each study was summarized. RESULTS: We identified 13 articles meeting inclusion criteria. These publications described findings or explored associations using NSBPR variables. They were grouped into four categories: general characteristics (4 studies), mobility and skin injury (2 studies), bowel continence (3 studies), and bladder continence (5 studies). CONCLUSIONS: The NSBPR represents one of the largest described clinical samples of individuals living with SB. The first decade of studies have focused primarily on descriptive analyses and on identifying predictors of clinical outcomes. These initial results may help develop interventions (including culturally appropriate initiatives), be a resource for developing international evidence-based standards of care and best-practices, and lead to improved outcomes for individuals living with SB globally. Additionally, the results underscore the strengths of the NSBPR's design and highlight the potential breadth of research topics that could be addressed in the future. PMID- 30403012 TI - National Cancer Database report of nonmetastatic esophageal small cell carcinoma. AB - BACKGROUND: Esophageal small cell carcinoma (ESCC) is a rare malignancy for which there is no consensus management approach. This is the largest known analysis of nonmetastatic ESCC patients to date, evaluating national practice patterns and outcomes of surgical-based therapy vs chemoradiotherapy (CRT) vs chemotherapy alone. METHODS: The National Cancer Data Base was queried for esophageal cancer patients with histologically confirmed nonmetastatic ESCC. Univariable and multivariable logistic regression ascertained factors associated with receipt of surgical-based management. Kaplan-Meier analysis evaluated overall survival (OS) and the log-rank test is used to compare OS between groups; Cox univariate and multivariate analyses determined variables associated with OS. RESULTS: Altogether, 323 patients were analyzed; 64 (20%) patients underwent surgical based therapy, 211 (65%) CRT, and 48 (15%) chemotherapy alone. On multivariable analysis, no single factor significantly predicted for administration of surgery. Despite no OS differences between the surgery-based (median OS 21 months) and CRT arms (18 months), both were superior to CT alone (10 months) (P < 0.001). Among other factors, receiving any local therapy independently predicted for higher OS over chemotherapy alone on Cox multivariate analysis (P < 0.001). CONCLUSIONS: This study of a large, contemporary national database demonstrates that most ESCC is treated with CRT in the United States; adding local therapy to systemic therapy may be beneficial to these patients, although individualized multidisciplinary management is still recommended. PMID- 30403014 TI - Unsolved Questions on the Anatomy of the Ventricular Conduction System. AB - We reviewed the anatomical characteristics of the conduction system in the ventricles of human and ungulate hearts and then raised some questions to be answered by clinical and anatomical studies in the future. The ventricular conduction system is a 3-dimensional structure as compared to the 2-dimensional character of the atrial conduction system. The proximal part consisting of the atrioventricular node, the bundle of His and fascicles are groups of conducting cells surrounded by fibrous connective tissue so as to insulate from the underlying myocardium. Their location and morphological characters are well established. The bundle of His is a cord like structure but the left and right fascicles are broad at the proximal and branching at the distal part. The more distal part of fascicles and Purkinje system are linear networks of conducting cells at the immediate subendocardium but the intra-mural network is detected at the inner half of the ventricular wall. The papillary muscle also harbors Purkinje system not in the deeper part. It is hard to recognize histologically in human hearts but conducting cells as well as Purkinje cells are easily recognized in ungulate hearts. Further observation on human and ungulate hearts with myocardial infarct, we could find preserved Purkinje system at the subendocardium in contrast to the damaged system at the deeper myocardium. Further studies are necessary on the anatomical characteristics of this peripheral conduction system so as to correlate the clinical data on hearts with ventricular arrhythmias. PMID- 30403016 TI - Distal Radial Approach through the Anatomical Snuff Box for Coronary Angiography and Percutaneous Coronary Intervention. PMID- 30403017 TI - Protective Effect of Right Ventricular Mitochondrial Damage by Cyclosporine A in Monocrotaline-induced Pulmonary Hypertension. AB - BACKGROUND AND OBJECTIVES: Mitochondria play a key role in the pathophysiology of heart failure and mitochondrial permeability transition pore (MPTP) play a critical role in cell death and a critical target for cardioprotection. The aim of this study was to evaluate the protective effects of cyclosporine A (CsA), one of MPTP blockers, and morphological changes of mitochondria and MPTP related proteins in monocrotaline (MCT) induced pulmonary arterial hypertension (PAH). METHODS: Eight weeks old Sprague-Dawley rats were randomized to control, MCT (60 mg/kg) and MCT plus CsA (10 mg/kg/day) treatment groups. Four weeks later, right ventricular hypertrophy (RVH) and morphological changes of right ventricle (RV) were done. Western blot and reverse transcription polymerase chain reaction (RT PCR) for MPTP related protein were performed. RESULTS: In electron microscopy, CsA treatment prevented MCT-induced mitochondrial disruption of RV. RVH was significantly increased in MCT group compared to that of the controls but RVH was more increased with CsA treatment. Thickened medial wall thickness of pulmonary arteriole in PAH was not changed after CsA treatment. In western blot, caspase-3 was significantly increased in MCT group, and was attenuated in CsA treatment. There were no significant differences in voltage-dependent anion channel, adenine nucleotide translocator 1 and cyclophilin D expression in western blot and RT-PCR between the 3 groups. CONCLUSIONS: CsA reduces MCT induced RV mitochondrial damage. Although, MPTP blocking does not reverse pulmonary pathology, it may reduce RV dysfunction in PAH. The results suggest that it could serve as an adjunctive therapy to PAH treatment. PMID- 30403018 TI - New Therapeutic Target for Pulmonary Arterial Hypertension. PMID- 30403015 TI - Triglyceride-Rich Lipoproteins and Novel Targets for Anti-atherosclerotic Therapy. AB - Although elevated serum low-density lipoprotein-cholesterol (LDL-C) is without any doubts accepted as an important risk factor for cardiovascular disease (CVD), the role of elevated triglycerides (TGs)-rich lipoproteins as an independent risk factor has until recently been quite controversial. Recent data strongly suggest that elevated TG-rich lipoproteins are an independent risk factor for CVD and that therapeutic targeting of them could possibly provide further benefit in reducing CVD morbidity, events and mortality, apart from LDL-C lowering. Today elevated TGs are treated with lifestyle interventions, and with fibrates which could be combined with omega-3 fatty acids. There are also some new drugs. Volanesorsen, is an antisense oligonucleotid that inhibits the production of the Apo C-III which is crucial in regulating TGs metabolism because it inhibits lipoprotein lipase (LPL) and hepatic lipase activity but also hepatic uptake of TGs-rich particles. Evinacumab is a monoclonal antibody against angiopoietin-like protein 3 (ANGPTL3) and it seems that it can substantially lower elevated TGs levels because ANGPTL3 also regulates TGs metabolism. Pemafibrate is a selective peroxisome proliferator-activated receptor alpha modulator which also decreases TGs, and improves other lipid parameters. It seems that it also has some other possible antiatherogenic effects. Alipogene tiparvovec is a nonreplicating adeno associated viral vector that delivers copies of the LPL gene to muscle tissue which accelerates the clearance of TG-rich lipoproteins thus decreasing extremely high TGs levels. Pradigastat is a novel diacylglycerol acyltransferase 1 inhibitor which substantially reduces extremely high TGs levels and appears to be promising in treatment of the rare familial chylomicronemia syndrome. PMID- 30403020 TI - The Role of Transthoracic Echocardiography in Patients with Acute Ischemic Stroke: We Should Pay More Attention to Left Ventricular Ejection Fraction. PMID- 30403019 TI - Left Ventricular Ejection Fraction Predicts Poststroke Cardiovascular Events and Mortality in Patients without Atrial Fibrillation and Coronary Heart Disease. AB - BACKGROUND AND OBJECTIVES: It is controversial that decreased left ventricular function could predict poststroke outcomes. The purpose of this study is to elucidate whether left ventricular ejection fraction (LVEF) can predict cardiovascular events and mortality in acute ischemic stroke (AIS) without atrial fibrillation (AF) and coronary heart disease (CHD). METHODS: Transthoracic echocardiography was conducted consecutively in patients with AIS or transient ischemic attack at Soonchunhyang University Hospital between January 2008 and July 2016. The clinical data and echocardiographic LVEF of 1,465 patients were reviewed after excluding AF and CHD. Poststroke disability, major adverse cardiac events (MACE; nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death) and all-cause mortality during 1 year after index stroke were prospectively captured. Cox proportional hazards regressions analysis were applied adjusting traditional risk factors and potential determinants. RESULTS: The mean follow-up time was 259.9+/-148.8 days with a total of 29 non-fatal strokes, 3 myocardial infarctions, 33 cardiovascular deaths, and 53 all-cause mortality. The cumulative incidence of MACE and all-cause mortality were significantly higher in the lowest LVEF (<55) group compared with the others (p=0.022 and 0.009). In prediction models, LVEF (per 10%) had hazards ratios of 0.54 (95% confidence interval [CI], 0.36-0.80, p=0.002) for MACE and 0.61 (95% CI, 0.39-0.97, p=0.037) for all-cause mortality. CONCLUSIONS: LVEF could be an independent predictor of cardiovascular events and mortality after AIS in the absence of AF and CHD. PMID- 30403022 TI - Adrenal Insufficiency in a Patient with Acute Myocardial Infarction Plus Shock. PMID- 30403021 TI - Pivotal Role of Intraoperative Transesophageal Echocardiography for Detecting Iatrogenic Aortic Regurgitation due to Cardiac Catheterization. PMID- 30403023 TI - Metal Oxide Interlayer for Long-Lived Lithium-Selenium Batteries. AB - A lithium-selenium (Li-Se)-alkali activated carbon hybrid cell with a tungsten oxide interlayer is implemented for the first time. The Se hybrid at a Se loading of 70 % in the full Li-Se cell delivers a large reversible capacity of 625 mA h gSe -1 , in comparison with 505.8 mA h gSe -1 achieved for the pristine Se cell. This clearly shows the advantage of the carbon in improving the capacity of the Li-Se cell. A tungsten oxide interlayer is drop-cast over the battery separator to further circumvent the issues of polyselenide dissolution and shuttle, which cause severe capacity fading. The oxide layer conducts Li ions, as evidenced from the Li-ion diffusion coefficient of 4.2*10-9 cm2 s-1 , and simultaneously blocks the polyselenide crossover, as it is impermeable to polyselenides, thereby reducing the capacity fading with cycling. The outcome of this unique approach is reflected in the reversible capacities of 808 and 510 mA h gSe -1 achieved for the Li-oxide@separator/Se-alkali activated carbon cell before and after 100 cycles, respectively, thus demonstrating that carbon and oxide can efficiently restrict the capacity fading and improve the performances of Li-Se cells. PMID- 30403024 TI - Maternal immunization downregulates offspring TCD4 regulatory cells (Tregs) thymic maturation without implications for allergy inhibition. AB - The regulation of offspring allergy development mediated by maternal immunization was evidenced by several groups, and this mechanism seems to involve the induction of regulatory T cells (Tregs) on offspring. Here, we aimed to evaluate whether the effect of maternal immunization on offspring Tregs occurs as a result of peripheral or central modulation. Briefly, C57BL/6 female mice were immunized with OVA in Alum or Alum alone and boosted with OVA in saline or saline only after 10 and 20 days. Non-immunized offspring serum, thymus and spleen were evaluated at 3 or 20 days old, and some groups of pups were submitted to neonatal OVA-immunization protocol for the subsequent evaluation of antibody production and allergic response. Our experimental protocol could be validated because maternal OVA-immunization inhibited offspring allergic response as evidenced by the suppression of offspring IgE production and allergic lung inflammation. Interestingly, maternal immunization reduced the frequency of offspring thymic Tregs with an opposite effect on spleen Tregs. Furthermore, after neonatal immunization, the frequency of lung-infiltrated Tregs was also augmented on offspring from immunized mothers. In conclusion, maternal OVA-immunization can inhibit the thymic maturation of offspring Tregs without implications on peripheral Tregs induction and allergy inhibition. PMID- 30403013 TI - 2018 Korean Guideline of Atrial Fibrillation Management. AB - Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in the general population. The Korean Heart Rhythm Society organized a Korean AF Management Guideline Committee and analyzed all available studies regarding the management of AF, including studies on Korean patients. This guideline is based on recent data of the Korean population and the recent guidelines of the European Society of Cardiology, European Association for Cardio-Thoracic Surgery, American Heart Association, and Asia Pacific Heart Rhythm Society. Expert consensus or guidelines for the optimal management of Korean patients with AF were achieved after a systematic review with intensive discussion. This article provides general principles for appropriate risk stratification and selection of anticoagulation therapy in Korean patients with AF. This guideline deals with optimal stroke prevention, screening, rate and rhythm control, risk factor management, and integrated management of AF. PMID- 30403025 TI - CCR2 upregulated on peripheral T cells in osteoarthritis but not in bone marrow. AB - Osteoarthritis (OA) is a condition affecting millions of patients around the world, causing pain and disability and often resulting in joint replacement surgery. The aetiology of OA has long been attributed to mechanical wear mainly due to the increased prevalence of OA in load bearing joints among older patients. However, recent studies reveal a complex molecular disease causality in which inflammation, nutritional deficit and angiogenesis lead to the destruction of the joint structure. The aim of this study was to examine chemokine receptor expression in peripheral blood and bone marrow in OA patients. We devised a protocol for extracting healthy bone marrow from patients undergoing hip arthroplasty due to coxarthrosis. Flow cytometry was used to determine the expression of 18 chemokine receptors on CD4 and CD8 T cells from bone marrow and blood from 7 osteoarthritis patients and peripheral blood from 9 healthy controls. We found a significantly increased fraction of CCR2 expressing CD4 and CD8 T cell in peripheral blood compared to healthy controls. Also, there was a significant decrease in CXCR3 (Th1) (P < 0.01) expressing T cells in peripheral blood from OA patients. Finally, multivariate analysis was used to separate T cell profiles from healthy controls and OA patients and demonstrate that the divergence of chemokine receptor expression occurs in the mature T cell subsets. In conclusion, we find increased CCR2 expression in peripheral blood from OA patients that possibly may be targeted in future clinical studies. PMID- 30403026 TI - Lateral orbitofrontal dysfunction in the Sapap3 knockout mouse model of obsessive compulsive disorder AB - Background: Obsessive-compulsive disorder (OCD) is a common psychiatric disorder that affects about 2% of the population, but the underlying neuropathophysiology of OCD is not well understood. Although increasing lines of evidence implicate dysfunction of the orbitofrontal cortex (OFC) in OCD, a detailed understanding of the functional alterations in different neuronal types in the OFC is still elusive. Methods: We investigated detailed activity pattern changes in putative pyramidal neurons and interneurons, as well as local field potential oscillations, in the lateral OFC underlying OCD-relevant phenotypes. We applied in vivo multichannel recording in an awake OCD mouse model that carried a deletion of the Sapap3 gene, and in wildtype littermates. Results: Compared with wildtype mice, the lateral OFC of Sapap3 knockout mice exhibited network dysfunction, demonstrated by decreased power of local field potential oscillations. The activity of inhibitory and excitatory neurons in the lateral OFC showed distinct perturbations in Sapap3 knockout mice: putative interneurons exhibited increased activity; putative pyramidal neurons exhibited enhanced bursting activity; and both putative pyramidal neurons and interneurons exhibited enhanced discharge variability and altered synchronization. Limitations: To exclude motor activity confounders, this study examined functional alterations in lateral OFC neurons only when the mice were stationary. Conclusion: We provide, to our knowledge, the first direct in vivo electrophysiological evidence of detailed functional alterations in different neuronal types in the lateral OFC of an OCD mouse model. These findings may help in understanding the underlying neuropathophysiology and circuitry mechanisms for phenotypes relevant to OCD, and may help generate and refine hypotheses about potential biomarkers for further investigation. PMID- 30403028 TI - Oxford Medical Degrees. PMID- 30403027 TI - Statutes of the University of Edinburgh, Relative to the Degree of M.D. 1833. PMID- 30403029 TI - Collectanea: Miscellaneous. PMID- 30403030 TI - British Association for the Advancement of Science. PMID- 30403031 TI - Account of a Case of Pulmonary Consumption, in Which Nearly the Whole of the Right Lung Was Converted into an Immense Vomica, Attended with Universal Adhesion, and Partial Absorption of the Pleural Sac. PMID- 30403032 TI - Medical Reform. PMID- 30403033 TI - On the Use of Colchicum in Erysipelas. PMID- 30403034 TI - List of Questions to Be Answered by the Governors of Hospitals, &c. PMID- 30403035 TI - On the Classification, Administration, Modus Operandi, and Combination of Medicines. PMID- 30403037 TI - Collectanea: Pathology and Practice. PMID- 30403036 TI - Meteorological Register: From December 1 to February 28. PMID- 30403038 TI - Errata. AB - [This corrects the article on p. 297 in vol. 1.]. PMID- 30403039 TI - Cases Extracted from the Obstetric Note-Book of the Welbeck-Street Dispensary, by Permission of Henry Davies, M.D. PMID- 30403041 TI - Mr. Mayo on Sir Charles Bell's Discoveries. PMID- 30403040 TI - College of Physicians. PMID- 30403042 TI - Cases Extracted from the Note-Book of Henry Davies, M.D., Physician to the British Lying-In Hospital, &c. PMID- 30403043 TI - What Can the Legisiature Do for Us? PMID- 30403044 TI - Comparison of the Circular and Flap Operations in Amputating the Thigh. PMID- 30403045 TI - Self-Supporting Dispensaries. PMID- 30403046 TI - Collectanea: Pathology and Practice. PMID- 30403047 TI - Observations on the Treatment of Bronchocele. PMID- 30403048 TI - On the Sense of Equilibrium, and on Its Disturbance. PMID- 30403049 TI - Case of Strangulated Hernia, with Adhesions to the Sac. PMID- 30403050 TI - A Case, in Which a Collection of Fluid and Coagulable Matter, to the Amount of Several Pints, Took Place between the Membranes of the Brain. PMID- 30403051 TI - Collectanea: Miscellaneous. PMID- 30403052 TI - Meteorological Register: From March 1 to May 31. PMID- 30403054 TI - A Case of Lithotomy by the High Operation; with Remarks. PMID- 30403053 TI - Observations on Catarrhal and Catarrho-Rheumatic Ophthalmia. PMID- 30403055 TI - On the Removal of Morbid Enlargements of the Integuments of the Nose. PMID- 30403057 TI - Collectanea: Miscellaneous. PMID- 30403056 TI - Heads of Clinical Observations on Mistakes and Oversights in the Treatment of Strangulated Hernia. PMID- 30403058 TI - Medical Society of London. PMID- 30403059 TI - Meteorological Register: From September 1 to November 30. PMID- 30403060 TI - Cases of Ligature of the Common Carotid Artery. PMID- 30403061 TI - On Inflammatory and Spasmodic Strictures of the Urethra. PMID- 30403062 TI - Dispensaries. PMID- 30403063 TI - A Case of Peritonitis, with Foecal Abscess, in Which the Patient Recovered; with Remarks. PMID- 30403064 TI - The Proposed Scotch Ascendancy in the College of Physicians. PMID- 30403065 TI - Cases Extracted, by Permission, from the Note-Books of Henry Davies, M.D.: No. II. PMID- 30403066 TI - The Examination at Apothecaries' Hall. PMID- 30403067 TI - Case of Recovery from an Abdominal Abscess. PMID- 30403068 TI - Account of Two Cases of Phthisis, Attended with Peculiar Circumstances. PMID- 30403069 TI - Collectanea: Pathology and Practice. PMID- 30403070 TI - Case of Empyema. PMID- 30403072 TI - A Case of Softening of the Brain, with Strumous Tubercles, Causing Apoplexy and Palsy. PMID- 30403071 TI - Case of Empyema: With Remarks. PMID- 30403073 TI - Collectanea: Miscellaneous. PMID- 30403074 TI - Cases Extracted, by Permission, from the Note-Books of Henry Davies, M.D. PMID- 30403075 TI - The College of Physicians. PMID- 30403076 TI - Case of Amputation of the Shoulder-Joint. PMID- 30403077 TI - Collectanea: Pathology and Practice. PMID- 30403079 TI - Royal College of Surgeons in London. PMID- 30403078 TI - Meteorological Register: From June 1 to August 31. PMID- 30403080 TI - Observations on Permanent Strictures of the Urethra. PMID- 30403081 TI - The Aldersgate-Street Dispensary. PMID- 30403082 TI - Collectanea: Miscellaneous. PMID- 30403083 TI - Case of Traumatic Tetanus, Occurring in the Norfolk and Norwich Hospital. PMID- 30403084 TI - Account of Several Cases of Carditis: With Remarks. PMID- 30403085 TI - Meteorological Register. PMID- 30403087 TI - Society of Apothecaries: Regulations to Be Observed by Students Intending to Qualify Themselves to Practise as Apothecaries in England and Wales. PMID- 30403086 TI - Cases Extracted from the Note-Book of Henry Davies, M.D.: Cases of Erysipelas Treated with the Nitrate of Silver. PMID- 30403088 TI - Case of Intus-Susception, Successfully Treated. PMID- 30403090 TI - Case of Morbid Adhesion of the Placenta. PMID- 30403089 TI - Biography of Dr. Maton. PMID- 30403091 TI - Collectanea: Pathology and Practice. PMID- 30403092 TI - Some Account of a Tumour, Induced by Haemorrhage, from Rupture of the Nutritious Artery, within the Femur; with Comments on the Treatment. PMID- 30403093 TI - On the Thymus Gland. PMID- 30403094 TI - On the Causes of Some of the Symptoms Which Attend Diseases and Injuries of the Brain. PMID- 30403095 TI - Collectanea: Pathology and Practice. PMID- 30403096 TI - Mr. Key's Cases of Femoral Hernia and Impenetrable Stricture. PMID- 30403097 TI - Meteorological Register. PMID- 30403098 TI - Two Cases of Bronchocele. PMID- 30403099 TI - Mr. Key's Case of Ulceration of the Cartilages of the Larynx. PMID- 30403100 TI - Structure of the Placenta. Examination of the Hunterian Preparations at the College of Surgeons. PMID- 30403102 TI - Collectanea: Miscellaneous. PMID- 30403101 TI - Mr. Shepherd's New Forceps, for the Extraction of Stumps of Teeth, and His Safety Forceps for Whole Teeth. PMID- 30403103 TI - Evidence on the State of the Medical Profession. PMID- 30403104 TI - Collectanea: Miscellaneous. PMID- 30403106 TI - Account of a Case of Choleroid Affection, Produced by the Poison of Muscles. PMID- 30403105 TI - Cases Extracted from the Note-Book of Henry Davies, M.D. PMID- 30403107 TI - Collectanea: Pathology and Practice. PMID- 30403108 TI - Address. PMID- 30403109 TI - An Account of the Examination of Two Bodies, Found in the Vaults of the Ruins of Wymondham Abbey, in Norfolk. PMID- 30403110 TI - Some Account of Two Cases of Inflammatory Tumour, Produced by the Deposit of the Larva of a Large Fly (OEstrus Humanus) beneath the Cutis, in the Human Subject: Accompanied with Drawings of the Larva. PMID- 30403112 TI - Meteorological Register: From June 1 to August 31. PMID- 30403111 TI - Account of Three Cases of Carditis: With Remarks. PMID- 30403113 TI - A Case of Delirium Tremens Successfully Treated by Large Doses of Opium. PMID- 30403114 TI - The Royal Medical and Chirurgical Society. PMID- 30403116 TI - Retrospect of the Late Improvements in Medicine, Surgery, &c. PMID- 30403115 TI - Account of Several Cases of Carditis: With Remarks. PMID- 30403117 TI - Meteorological Register: From September 1 to November 30. PMID- 30403118 TI - Cases Extracted from the Note-Book of Henry Davies, M.D.: Cases of Retained Placenta. PMID- 30403119 TI - Case of Ulcerated Caecum. PMID- 30403120 TI - Collectanea: Miscellaneous. PMID- 30403121 TI - On the Formation of Artificial Pupil, without Injury to the Crystalline Lens or Its Capsule. PMID- 30403122 TI - A Case of Loss of Nose from Syphilis, and Restoration by the Taliacotian Operation; with Remarks. PMID- 30403123 TI - Collectanea: Pathology and Practice. PMID- 30403124 TI - Remarks on Aneurisms of the Cerebral Arteries: With Cases. PMID- 30403125 TI - Intrinsically Safe Gel Polymer Electrolyte Comprising Flame-Retarding Polymer Matrix for Lithium Ion Battery Application. AB - State-of-the-art (SOTA) liquid electrolyte/polyolefin separator setups used in lithium ion batteries (LIBs) suffer from the hazard of leakage and high flammability. To address these issues, phosphonate, a flame-retarding moiety, is chemically bonded to a polymer matrix to fabricate a nonflammable gel polymer electrolyte (GPE). The obtained phosphonate-based polymer matrix as well as its corresponding GPE (gelled with flammable SOTA nonaqueous liquid electrolyte) shows remarkable flame resistivity. Unlike poly(vinylidene fluoride- co hexafluoropropylene)-based GPEs, the phosphonate-based GPE does not react with lithiated graphite at high temperatures. Both features indicate that the phosphonate-based GPE is superior to SOTA GPEs in the aspect of safety performance. As the flame-retarding moiety is chemically bonding to the polymer, the parasitic reactions between the flame-retarding moiety and the electrodes are avoided. Consequently, LIB cells comprising phosphonate-based GPE show good capacity retention comparable to cells comprising SOTA GPEs. Compared with SOTA GPEs, phosphonate-based polymer-based GPEs show improved intrinsic safety performance and comparable cycle life. Therefore, phosphonate-based polymers exhibit high potential to be used as a new class of polymer matrix for GPE used in LIBs. PMID- 30403126 TI - Rosuvastatin- and Heparin-Loaded Poly(l-lactide- co-caprolactone) Nanofiber Aneurysm Stent Promotes Endothelialization via Vascular Endothelial Growth Factor Type A Modulation. AB - This study explored a new rosuvastatin calcium- and heparin-loaded poly(l-lactide co-caprolactone) (PLCL) scaffold for covered stents for treating aneurysms. The mechanism of rosuvastatin-induced endothelialization via vascular endothelial growth factor (VEGF)-A elevation was further explored. Rosu50, Rosu75, Rosu100, and phosphate-buffered saline (PBS) nanofibrous scaffolds were fabricated by coaxial electrospinning and observed by electron microscopy. Anticoagulation and pro-endothelialization properties were tested. Sixteen rabbits were selected for an in vivo assay and underwent microsurgery to establish a carotid aneurysm model. The animals were treated with covered stents and followed for 4 months using digital subtraction angiography (DSA), electron microscopy, and histology. Rosuvastatin-treated human umbilical vein endothelial cell (HUVEC) viability, function, and VEGF-A modulation were further studied to elucidate the pro endothelialization mechanism of rosuvastatin. Our study demonstrates that rosuvastatin and heparin can be incorporated into PLCL nanofibers via electrospinning. Rosu100 nanofiber scaffolds exhibited significant anticoagulation properties. The viability of HUVECs transferred to Rosu100 nanofiber scaffolds was increased significantly. In vivo, DSA revealed that the Rosu100 group had better outcomes than the PBS group. In addition, the Rosu100 stents induced more integrated endothelialization. Further study demonstrated that rosuvastatin promoted HUVEC viability and function in vitro. The effects of rosuvastatin may be attributed to an elevation in VEGF-A. We demonstrated that rosuvastatin- and heparin-loaded PLCL-covered stents show favorable anticoagulation and pro-endothelialization properties in vitro and in vivo in a rabbit aneurysm model. VEGF-A elevation played a crucial role in rosuvastatin promoted endothelialization. This work provides an additional option for treating cerebral aneurysms with covered stents. PMID- 30403127 TI - ARB-1740, a RNA Interference Therapeutic for Chronic Hepatitis B Infection. AB - Current approved nucleoside analogue treatments for chronic hepatitis B virus (HBV) infection are effective at controlling viral titer but are not curative and have minimal impact on the production of viral proteins such as surface antigen (HBsAg), the HBV envelope protein believed to play a role in maintaining the immune tolerant state required for viral persistence. Novel agents are needed to effect HBV cure, and reduction of HBV antigenemia may potentiate activation of effective and long-lasting host immune control. ARB-1740 is a clinical stage RNA interference agent composed of three siRNAs delivered using lipid nanoparticle technology. In a number of cell and animal models of HBV, ARB-1740 caused HBV RNA reduction, leading to inhibition of multiple elements of the viral life cycle including HBsAg, HBeAg, and HBcAg viral proteins as well as replication marker HBV DNA. ARB-1740 demonstrated pan-genotypic activity in vitro and in vivo, targeting three distinct highly conserved regions of the HBV genome, and effectively inhibited replication of nucleoside analogue-resistant HBV variants. Combination of ARB-1740 with a capsid inhibitor and pegylated interferon-alpha led to greater liver HBsAg reduction which correlated with more robust induction of innate immune responses in a human chimeric mouse model of HBV. The preclinical profile of ARB-1740 demonstrates the promise of RNA interference and HBV antigen reduction in treatment strategies driving toward a cure for HBV. PMID- 30403128 TI - Design of a De Novo Aggregating Antimicrobial Peptide and a Bacterial Conjugation Based Delivery System. AB - Antibacterial resistance necessitates the development of novel treatment methods for infections. Protein aggregates have recently been applied as antimicrobials to disrupt bacterial homeostasis. Past work on protein aggregates has focused on genome mining for aggregation-prone sequences in bacterial genomes rather than on rational design of aggregating antimicrobial peptides. Here, we use a synthetic biology approach to design an artificial gene encoding a de novo aggregating antimicrobial peptide. This artificial gene, opaL (overexpressed protein aggregator lipophilic), disrupts bacterial homeostasis by expressing extremely hydrophobic peptides. When this hydrophobic sequence is disrupted by acidic residues, consequent aggregation and antimicrobial effect decrease. Further, we developed a probiotic delivery system using the broad-host range conjugative plasmid RK2 to transfer the gene from donor to recipient bacteria. We utilize RK2 to mobilize a shuttle plasmid carrying opaL by adding the RK2 origin of transfer. We show that opaL is nontoxic to the donor, allowing for maintenance and transfer since its expression is under control of a promoter with a recipient-specific T7 RNA polymerase. Upon mating of donor and recipient Escherichia coli, we observe selective growth repression in T7 polymerase-expressing recipients. This technique could be used to target desired pathogens by selecting pathogen specific promoters to control T7 RNA polymerase expression and provides a basis for the design and delivery of aggregating antimicrobial peptides. PMID- 30403129 TI - Integrated Surface Functionalization of Li-Rich Cathode Materials for Li-Ion Batteries. AB - As candidates for high-energy density cathodes, lithium-rich (Li-rich) layered materials have attracted wide interest for next-generation Li-ion batteries. In this work, surface functionalization of a typical Li-rich material Li1.2Mn0.56Ni0.17Co0.07O2 is optimized by fluorine (F)-doped Li2SnO3 coating layer and electrochemical performances are also enhanced accordingly. The results demonstrate that F-doped Li2SnO3-modified material exhibits the highest capacity retention (73% after 200 cycles), with approximately 1.2, 1.4, and 1.5 times of discharge capacity for Li2SnO3 surface-modified, F-doped, and pristine electrodes, respectively. To reveal the fundamental enhancement mechanism, intensive surface Li+ diffusion kinetics, postmortem structural characteristics, and aging tests are performed for four sample systems. The results show that the integrated coating layer plays an important role in addressing interface compatibility, not only limited in stabilizing the bulk structure and suppressing side reactions, synergistically contributing to the performance enhancement for the active electrodes. These findings not only pave the way to commercial application of the Li-rich material but also shed new light on surface modification in batteries and other energy storage fields. PMID- 30403130 TI - Two Mutations Commonly Associated with Daptomycin Resistance in Enterococcus faecium LiaST120A and LiaRW73C Appear To Function Epistatically in LiaFSR Signaling. AB - The cyclic antimicrobial lipopeptide daptomycin is now frequently used as a first line therapy in serious infections caused by multidrug-resistant Enterococcus faecium. Resistance to daptomycin in E. faecium is mediated by activation of the LiaFSR membrane stress response pathway. Deletion of liaR, encoding the response regulator of the system, restores susceptibility to daptomycin, suggesting that the LiaFSR pathway is a potential target for the development of drugs that would induce hypersusceptibility to daptomycin and make it more difficult for enterococci to become daptomycin-resistant. In clinical isolates of E. faecium, substitutions in the membrane-bound histidine kinase LiaS (T120A) and its response regulator LiaR (W73C) are found together, suggesting a potential epistatic relationship in daptomycin resistance. Using in vitro phosphorylation studies, we show that while the phosphotransfer rate of wild-type LiaS and LiaST120A to either wild-type LiaR or LiaRW73C remains rapid and comparable, the LiaS-dependent dephosphorylation rate of phosphorylated LiaRW73C is markedly higher. When the two adaptive mutants LiaRW73C and LiaST210A are paired, however, LiaS-mediated LiaR dephosphorylation is restored back to wild-type levels. Taken together with earlier work showing that LiaRW73C leads to an increased level of oligomerization and subsequently favors an increased level of transcription of the LiaFSR regulon, the net effect of the two commonly found LiaST120A and LiaRW73C alleles would be to coordinately increase the strength and persistence of LiaFSR signaling and decrease daptomycin susceptibility. The in vitro approaches developed in this work also provide the basis for screens for identifying drug candidates that inhibit the LiaFSR pathway. PMID- 30403131 TI - Sequential Engineering of Ternary CuFeNi with a Vertically Layered Structure for Efficient and Bifunctional Catalysis of the Oxygen and Hydrogen Evolution Reactions. AB - Developing efficient and earth-abundant electrocatalysts for electrochemical water splitting is greatly desired due to growing energy demands. Herein, we develop a promising hierarchical nickel-iron-copper nitride electrode that is fabricated via a three-step process, starting with a hydrothermal synthesis of nickel-iron hydroxide on nickel foam and followed by the direct growth of copper metal-organic frameworks and, finally, low temperature ammonization. This approach yields a material that is an efficient catalyst for both the oxygen evolution reaction and the hydrogen evolution reaction. The as-fabricated heterostructured nickel-iron-copper nitride electrode exhibits an excellent activity with an overpotential of only 121 mV for the oxygen evolution reaction and an even a lower overpotential of 33 mV for the hydrogen evolution reaction. Additionally, this structure displays strong long-term stability with only a negligible increase in potential after 500 cycles of uninterrupted cyclic voltammetry testing. To the best of our knowledge, this as-prepared hierarchical nickel-iron-copper nitride is one of the most promising alternatives for the electrochemical oxygen and hydrogen evolution reactions. PMID- 30403132 TI - Effective Interactions between Chemically Active Colloids and Interfaces. AB - Chemically active colloids can achieve force- and torque-free motility ("self propulsion") via the promotion, on their surface, of catalytic chemical reactions involving the surrounding solution. Such systems are valuable both from a theoretical perspective, serving as paradigms for nonequilibrium processes, as well as from an application viewpoint, according to which active colloids are envisioned to play the role of carriers ("engines") in novel lab-on-a-chip devices. The motion of such colloids is intrinsically connected with a "chemical field", i.e., the distribution near the colloid of the number densities of the various chemical species present in the solution, and with the hydrodynamic flow of the solution around the particle. In most of the envisioned applications, and in virtually all reported experimental studies, the active colloids operate under spatial confinement (e.g., within a microfluidic channel, a drop, a free-standing liquid film, etc.). In such cases, the chemical field and the hydrodynamic flow associated with an active colloid are influenced by any nearby confining surfaces, and these disturbances couple back to the particle. Thus, an effective interaction with the spatial confinement arises. Consequently, the particle is endowed with means to perceive and to respond to its environment. Understanding these effective interactions, finding the key parameters which control them, and designing particles with desired, preconfigured responses to given environments, require interdisciplinary approaches which synergistically integrate methods and knowledge from physics, chemistry, engineering, and materials science. Here we review how, via simple models of chemical activity and self-phoretic motion, progress has recently been made in understanding the basic physical principles behind the complex behaviors exhibited by active particles near interfaces. First, we consider the occurrence of "interface-bounded" steady states of chemically active colloids near simple, nonresponsive interfaces. Examples include particles "sliding" along, or "hovering" above, a hard planar wall while inducing hydrodynamic flow of the solution. These states lay the foundations for concepts like the guidance of particles by the topography of the wall. We continue to discuss responsive interfaces: a suitable chemical patterning of a planar wall allows one to bring the particles into states of motion which are spatially localized (e.g., within chemical stripes or along chemical steps). These occur due to the wall responding to the activity-induced chemical gradients by generating osmotic flows, which encode the surface-chemistry of the wall. Finally, we discuss how, via activity-induced Marangoni stresses, long-ranged effective interactions emerge from the strong hydrodynamic response of fluid interfaces. These examples highlight how in this context a desired behavior can be potentially selected by tuning suitable parameters (e.g., the phoretic mobility of the particle, or the strength of the Marangoni stress at an interface). This can be accomplished via a judicious design of the surface chemistry of the particle and of the boundary, or by the choice of the chemical reaction in solution. PMID- 30403133 TI - A Screen for Membrane Fission Catalysts Identifies the ATPase EHD1. AB - Membrane fission manifests during cell division, synaptic transmission, vesicular transport, and organelle biogenesis, yet identifying proteins that catalyze fission remains a challenge. Using a facile and robust assay system of supported membrane tubes in a microscopic screen that directly monitors membrane tube scission, we detect robust GTP- and ATP-dependent as well as nucleotide independent fission activity in the brain cytosol. Using previously established interacting partner proteins as bait for pulldowns, we attribute the GTP dependent fission activity to dynamin. Biochemical fractionation followed by mass spectrometric analyses identifies the Eps15-homology domain-containing protein1 (EHD1) as a novel ATP-dependent membrane fission catalyst. Together, our approach establishes an experimental workflow for the discovery of novel membrane fission catalysts. PMID- 30403134 TI - Laser-Cut Polymer Tape Templates for Scalable Filtration Fabrication of User Designed and Carbon-Nanomaterial-Based Electrochemical Sensors. AB - We report here a simple filtration method for the scalable fabrication of user designed and carbon-nanomaterial-based electrode arrays using laser-cut poly(vinyl chloride) (PVC) tape templates. This method can produce electrode arrays with high uniformity and low resistance from the dilute dispersions of single-walled carbon nanotubes (SWNTs) and graphene nanoplatelets (GNPs). For these two carbon arrays, the SWNT array is demonstrated to possess several interesting properties, e.g., good mechanical properties, excellent flexibility, and favorable electrochemical behavior. Moreover, its porous structure enables the construction of a paperlike solid-state electrochemical sensor using Nafion electrolytes, which is suitable for the on-site monitoring of trace phenol pollutants in electrolyte-free water. Besides, an electrochemically addressable 36-zone sensor was constructed by this method. With the aid of an inexpensive 3D printer, the addressable sensor can achieve the semiautomatic and high-throughput evaluation of antioxidant capacity on a series of vegetables and fruits using a single-channel electrochemical analyzer. PMID- 30403135 TI - Ligand-Capped Ultrapure Metal Nanoparticle Sensors for the Detection of Cutaneous Leishmaniasis Disease in Exhaled Breath. AB - Human cutaneous leishmaniasis, although designated as one of the most neglected tropical diseases, remains underestimated due to its misdiagnosis. The diagnosis is mainly based on the microscopic detection of amastigote forms, isolation of the parasite, or the detection of Leishmania DNA, in addition to its differential clinical characterization; these tools are not always available in routine daily practice, and they are expensive and time-consuming. Here, we present a simple-to use, noninvasive approach for human cutaneous leishmaniasis diagnosis, which is based on the analysis of volatile organic compounds in exhaled breath with an array of specifically designed chemical gas sensors. The study was realized on a group of n = 28 volunteers diagnosed with human cutaneous leishmaniasis and a group of n = 32 healthy controls, recruited in various sites from Tunisia, an endemic country of the disease. The classification success rate of human cutaneous leishmaniasis patients achieved by our sensors test was 98.2% accuracy, 96.4% sensitivity, and 100% specificity. Remarkably, one of the sensors, based on CuNPs functionalized with 2-mercaptobenzoxazole, yielded 100% accuracy, 100% sensitivity, and 100% specificity for human cutaneous leishmaniasis discrimination. While AuNPs have been the most extensively used in metal nanoparticle-ligand sensing films for breath sensing, our results demonstrate that chemical sensors based on ligand-capped CuNPs also hold great potential for breath volatile organic compounds detection. Additionally, the chemical analysis of the breath samples with gas chromatography coupled to mass spectrometry identified nine putative breath biomarkers for human cutaneous leishmaniasis. PMID- 30403136 TI - Hydrolysis and Transport Characteristics of Tyrosol Acyl Esters in Rat Intestine. AB - Lipophenols such as palmitoyl esters of green-tea polyphenols (GTP) have been allowed for use as food additives for oxidation control. However, their digestive absorption remains unexplored. In this paper, the hydrolysis and transport characteristics of tyrosol acyl esters (TYr-Es) with various fatty acids (C12:0, C14:0, C16:0, C18:0, C18:1, and C18:2) were evaluated using the everted-rat-gut sac model for the first time. HPLC-UV measurements demonstrated that TYr-Es were hydrolyzed to TYr, which contributed significantly to TYr transport across the sacs. The hydrolysis and transport rates correlated negatively with the chain lengths of their lipid moieties but showed a positive correlation with the degree of unsaturation. In general, all TYr-Es exhibited sustained-release behavior; therefore, the production of TYr-Es may serve as a useful way to prolong the duration of action and further improve the bioactivities of TYr. PMID- 30403137 TI - Targeted Inhibition of Enzymatic Browning in Wheat Pastry Dough. AB - Enzymatic browning primarily affects fruits and vegetables but also occurs in wheat-based food. Herein, the browning behavior in wheat pastry dough was investigated aiming toward a targeted inhibitory treatment without influencing the pastry dough properties such as workability or taste. Dough discoloration is attributed to several subsequent enzyme-substrate reactions, which can selectively be inhibited by food additives. In most cases, an effective and lasting inhibition is only guaranteed by compounds acting upon multiple inhibition pathways. Despite their effectiveness, the unlimited use of commercial inhibitors is nondesirable due to necessary labeling, thus sustainable and natural inhibitors usually occurring as conventional food ingredients are of interest. It is shown that white wine combined with lemon juice revealed itself as an ideal combination for prevention of enzymatic browning in pastry dough. PMID- 30403138 TI - Impact of Six Typical Processing Methods on the Chemical Composition of Tea Leaves Using a Single Camellia sinensis Cultivar, Longjing 43. AB - While the Camellia sinensis cultivar and processing method are key factors that affect tea flavor and aroma, the chemical changes in nonvolatile components associated with the tea processing method using a single cultivar of C. sinensis have not been reported. Fresh leaves from C. sinensis Longjing 43 were subjected to six tea processing methods and evaluated by targeted and untargeted chromatographic procedures. On the basis of targeted assessment of the total catechin content, three clusters were identified: yellow-green, oolong-white dark, and black. However, principal component analysis of the total tea metabolome identified four chemical phenotypes: green-yellow, oolong, black white, and dark. Differences in the non-catechin components included amino acids and gamma-aminobutyric acid, which increased in white tea, and dihydroxyphenylalanine, valine, betaine, and theophylline, which increased in dark tea. Overall, this study identified a wide range of chemicals that are affected by commonly used tea processing methods and potentially affect the bioactivity of various tea types. PMID- 30403139 TI - Quantitative Sensitization Efficiencies in NIR-Emissive Homoleptic Ln(III) Complexes Using 2-(5-Methylpyridin-2-yl)-8-hydroxyquinoline. AB - A series of isostructural lanthanide complexes [Ln(MPQ)3] (Ln = Nd, Gd, Er, Yb, Lu) using a monoanionic tridentate methylpyridyl-substituted 8-hydroxyquinoline ligand (MPHQ = 2-(5-methylpyridin-2-yl)-8-hydroxyquinoline) have been prepared and characterized using elemental analysis (CHN), single-crystal X-ray diffraction (XRD), and 1H NMR spectroscopy. This ligand forms homoleptic charge neutral lanthanide complexes with three coordinated ligands arranged in an "up-up down" fashion around the metal center. The photophysical properties of the Nd, Er, and Yb complexes were investigated using absorption and emission spectroscopy, with the latter species displaying efficient sensitization in the Near Infra-Red (NIR) region and a photoluminescence quantum yield (PLQY) as high as 1.0% in CH2Cl2 solution. The intersystem crossing and energy-transfer processes involved in the antenna effect were further investigated using transient absorption techniques, which revealed essentially quantitative sensitization efficiencies for the NIR-emitting cations. PMID- 30403140 TI - Three-Component Ring-Opening Reactions of Cyclic Ethers, alpha-Diazo Esters, and Weak Nucleophiles under Metal-Free Conditions. AB - A protocol for three-component reactions of cyclic ethers, alpha-diazo esters, and weak nitrogen, oxygen, carbon, and sulfur nucleophiles (p Ka = 2.2-14.8) to afford a variety of structurally complex alpha-oxyalkylated esters is reported. These reactions involve intermolecular activation of the cyclic ether (present in excess) by the alpha-diazo ester to form an oxonium ylide under metal-free conditions, followed by ring opening by the nucleophile. PMID- 30403141 TI - Bacterial Nanobionics via 3D Printing. AB - Investigating the multidimensional integration between different microbiological kingdoms possesses potential toward engineering next-generation bionic architectures. Bacterial and fungal kingdom exhibits mutual symbiosis that can offer advanced functionalities to these bionic architectures. Moreover, functional nanomaterials can serve as probing agents for accessing newer information from microbial organisms due to their dimensional similarities. In this article, a bionic mushroom was created by intertwining cyanobacterial cells with graphene nanoribbons (GNRs) onto the umbrella-shaped pileus of mushroom for photosynthetic bioelectricity generation. These seamlessly merged GNRs function as agents for mediating extracellular electron transport from cyanobacteria resulting in photocurrent generation. Additionally, three-dimensional (3D) printing technique was used to assemble cyanobacterial cells in anisotropic, densely packed geometry resulting in adequate cell-population density for efficient collective behavior. These 3D printed cyanobacterial colonies resulted in comparatively higher photocurrent (almost 8-fold increase) than isotropically casted cyanobacteria of similar seeding density. An insight of the proposed integration between cyanobacteria and mushroom derives remarkable advantage that arises from symbiotic relationship, termed here as engineered bionic symbiosis. Existence of this engineered bionic symbiosis was confirmed by UV-visible spectroscopy and standard plate counting method. Taken together, the present study augments scientific understanding of multidimensional integration between the living biological microworld and functional abiotic nanomaterials to establish newer dimensionalities toward advancement of bacterial nanobionics. PMID- 30403142 TI - Structural and Chemical Approach toward Understanding the Aqueous Corrosion of Sodium Aluminoborate Glasses. AB - Despite an ongoing strenuous effort to understand the compositional and structural drivers controlling the chemical durability of oxide glasses, there is still no complete consensus on the basic mechanism of glass dissolution that applies to a wide composition space. One major reason for this problem is the structural complexity contained within the multicomponent silicate glasses chosen for glass corrosion studies. The nonsilicate network polyhedra present in these glasses interact with one another, often in unpredictable ways, by forming a variety of structural associations, for example, Al[IV]-B[III] and B[III]-B[IV], resulting in significant influence on both the structure of the glass network and related macroscopic properties. Likewise, the formation of a variety of next neighbor linkages, as well as increasingly complex interactions involving Si and differently coordinated next-nearest neighbor cations, is very difficult to decipher experimentally. Consideration of these factors motivates instead a different strategy: that is, the study of a sequence of SiO2-free ternary or quaternary glass compositions, whose structures can be unambiguously determined and robustly linked to their corrosion properties. With this aim, the present study is focused on understanding the structural drivers governing the kinetics and mechanism of corrosion of ternary Na2O-Al2O3-B2O3 glasses (in water) over a broad composition space comprising compositions with distinct structural features. It has been shown that the addition of Al2O3 to binary sodium borate glasses decreases their corrosion rate in water and converts their dissolution behavior from congruent to incongruent leading to the formation of six coordinated alumina, and higher concentration of four-coordinated boron (in comparison to pre-dissolution glasses) in post-dissolution glass samples. The drivers controlling the corrosion kinetics and mechanism in these glasses based on their underlying structure have been elucidated. Some open questions have been proposed which require an extensive analysis of surface chemistry of pre- and post-dissolution samples and will be investigated in our future work. PMID- 30403143 TI - Landau Quantization in Coupled Weyl Points: A Case Study of Semimetal NbP. AB - Weyl semimetal (WSM) is a newly discovered quantum phase of matter that exhibits topologically protected states characterized by two separated Weyl points with linear dispersion in all directions. Here, via combining theoretical analysis and magneto-infrared spectroscopy of an archetypal Weyl semimetal, niobium phosphide, we demonstrate that the coupling between Weyl points can significantly modify the electronic structure of a WSM and provide a new twist to the protected states. These findings suggest that the coupled Weyl points should be considered as the basis for analysis of realistic WSMs. PMID- 30403144 TI - Zonal cortical scarring and tubular thyroidization in kidney biopsies of patients with SLE-histologic indicator for antiphospholipid antibodies. AB - Antiphospholipid antibody syndrome (APS) is an acquired prothrombotic autoimmune disease caused by the presence of antibodies against anionic phospholipids or plasma proteins bound to phospholipids on cell membranes. It can be a primary disease or secondary to other autoimmune diseases, most commonly systemic lupus erythematosus (SLE). Laboratory testing for antiphospholipid antibodies (aPL) may be only transiently positive, so APS could be missed until a catastrophic thrombotic episode or pregnancy morbidity occurs. In the kidneys, this manifests as thrombotic microangiopathy (TMA), and patients present with hypertensive urgency and acute kidney injury. However, APS may not always have a catastrophic presentation but instead a more smoldering course. Kidney biopsy may not show obvious active TMA lesions but rather only chronic injury in the form of zonal cortical scarring and tubular thyroidization. Still, it may warrant anticoagulation therapy. So it is important to recognize this pattern of injury in the biopsy. Herein, we retrospectively study the correlation between presence of this histologic feature in kidney biopsies of SLE patients and positive aPL testing results (anticardiolipin antibodies and/or lupus anticoagulant). Kidney biopsies of SLE patients from 2004 to 2015 ( n = 186) were screened for presence or absence of zonal cortical scarring. Their electronic medical records were reviewed for aPL results. Our study showed low sensitivity (33%) but higher positive predictive value (62%), specificity (89%) and negative predictive value (71%). This histologic finding is therefore not a sensitive screening tool, but if present, greatly increases the likelihood of underlying aPL. We want to emphasize that recognition of this histologic feature in the biopsies of SLE patients is important so as not to miss the opportunity to treat with anticoagulation therapy and possibly slow down the chronic renal damage. PMID- 30403145 TI - Reviewing the clinical significance of 'fear of abandonment' in borderline personality disorder. AB - OBJECTIVES:: To review and highlight the clinical significance of the symptom 'fear of abandonment' in borderline personality disorder (BPD). METHODS:: A systematic search of the literature was conducted using MEDLINE and PubMed, employing search terms including 'fear of abandonment', 'borderline personality disorder' and 'rejection'. The most relevant English-language articles and books were selected for this review. RESULTS:: Fear of abandonment is widely recognised as a core symptom in BPD; a biopsychosocial explanation for the occurrence of the symptom is presented. While fear of abandonment may differ in its clinical presentation, it has a significant impact on therapeutic engagement, suicidal behaviour and non-suicidal self-injury, clinical management and prognosis. Most evidence based psychotherapies for BPD address the phenomenon of fear of abandonment; however, the lack of specifically targeted treatment interventions is disproportionate to its prominence and clinical significance. CONCLUSIONS:: Given its defining role in BPD, we recommend fear of abandonment as an important subject of future research and a specific therapy target. PMID- 30403146 TI - Shar Pei Larynx: Supraglottic and Postcricoid Mucosal Redundancy and Its Association With Medical Comorbidities. AB - OBJECTIVES:: The aim of this study is to describe a clinical entity the authors term "Shar Pei larynx," characterized by redundant supraglottic and postcricoid mucosa that the authors hypothesize coexists in patients with obstructive sleep apnea, laryngopharyngeal reflux, and obesity. By exploring this hypothesis, the authors hope to set the foundation for future research with the goal of identifying whether Shar Pei larynx is a marker for untreated sleep apnea or other diseases. STUDY DESIGN:: Retrospective chart review. SETTING:: Two tertiary care academic institutions. METHODS:: Data were collected from a 5-year period by querying for patients described to have "Shar Pei larynx" or "posterior supraglottic and/or postcricoid mucosal redundancy" on laryngoscopic findings. Relevant demographic and clinical characteristics were analyzed, with a focus on associations with obesity, sleep apnea, and laryngopharyngeal reflux. RESULTS:: Thirty-two patients were identified with physical findings consistent with Shar Pei larynx. Twenty-six patients (81.3%) were obese; 16 (50%) were morbidly obese. Twenty-two patients (68.8%) either had an existing diagnosis of obstructive sleep apnea or were diagnosed on polysomnography performed after initial evaluation. Sixteen patients (50%) had type 2 diabetes mellitus, and 87.5% of these patients were obese. Twenty-eight patients (87.5%) noted histories of reflux, with a median reflux symptom index of 27 of 45. Five patients underwent procedures to reduce mucosal redundancy related to Shar Pei larynx. CONCLUSIONS:: This pilot study confirms that the majority of patients diagnosed with Shar Pei larynx also had diagnoses of obesity, obstructive sleep apnea, and reflux disease. The demonstrated association is strong enough to warrant further study. PMID- 30403147 TI - Metabolism and Redox in Pulmonary Vascular Physiology and Pathophysiology. AB - This review considers how some systems controlling pulmonary vascular function are potentially regulated by redox processes to examine how and why conditions such as prolonged hypoxia, pathological mediators and other factors promoting vascular remodeling contribute to the development of pulmonary hypertension (PH). Aspects of vascular remodeling induction mechanisms are described associated with shifts in glucose metabolism through the pentose phosphate pathway and increased cytosolic NADPH generation by glucose-6-phosphate dehydrogenase, increased glycolysis generation of cytosolic NADH and lactate, mitochondrial dysfunction associated with superoxide dismutase-2 depletion, changes in reactive oxygen species and iron metabolism, and redox signaling. The regulation and impact of hypoxia-inducible factor and the function of cGMP-dependent and redox regulation of protein kinase G are considered for their potential roles as key sensors and coordinators of redox and metabolic processes controlling the progression of vascular pathophysiology in PH, and how modulating aspects of metabolic and redox regulatory systems potentially function in beneficial therapeutic approaches. PMID- 30403148 TI - Nrf2 Regulates the Hepatoprotective Effects of Remote Ischemic Conditioning in Hemorrhagic Shock. AB - AIMS: Remote ischemic conditioning (RIC) protects against organ ischemia/reperfusion injury in experimental and clinical settings. We have demonstrated that RIC prevents liver and lung inflammation/injury following hemorrhagic shock/resuscitation (S/R). In the current study, we used a murine model of S/R to investigate the role of Nrf2 in mediating hepatoprotection. RESULTS: The combination of RIC with S/R caused a synergistic rise in Nrf2 and its translocation to the nucleus in the liver. Increased activation of Nrf2 by RIC augmented HO-1 and autophagy and exerted hepatoprotection, concurrent with reductions in S/R-induced TNF-alpha and IL-6. In Nrf2 KO animals, RIC did not exert hepatoprotection, and failed to upregulate HO-1 and autophagy. Furthermore, resuscitating wildtype animals with blood from donor wildtype animals undergoing RIC was hepatoprotective, but not in Nrf2 KO recipient animals. Interestingly, RIC blood from Nrf2 KO donor animals was also not protective when used to resuscitate wildtype animals, suggesting a role for Nrf2 both in the afferent arm of RIC where protective factors are generated and also in the efferent arm where organ protection is exerted. Finally, RIC plasma prevented oxidant-induced zebrafish mortality, but not in Nrf2a morpholino knockdown fish. INNOVATION: Activation of Nrf2 is an essential mechanism underlying the hepatoprotective effects of RIC. Nrf2 appears to play a role in the afferent limb of RIC protection, as its absence precludes the generation of the protective humoral factors induced by RIC. CONCLUSION: Our studies demonstrate the critical role of Nrf2 in the ability of RIC to prevent organ injury following S/R. PMID- 30403149 TI - The crucible of early career psychiatry. AB - OBJECTIVE:: To capture the voices of psychiatrists as they reflect on challenges at the early stages of the career trajectory. METHOD:: Early career psychiatrists contributed reflections that identified various challenges in the transition from trainee to consultant psychiatrist. RESULTS:: Common difficulties included negotiating role transition and conflict. Specific events had deep impact such as involvement with a patient who had committed suicide. CONCLUSIONS:: Challenges in the early career stage as a consultant psychiatrist may have lasting or career defining impact. Written reflection is a valuable tool that can impart collective learning, provide validation and engender support among peers. PMID- 30403150 TI - Characterizing a Sample of Chinese Patients With Type 2 Diabetes and Selected Health Outcomes. AB - PURPOSE: The purpose of the study is to describe the characteristics and selected health outcomes of a sample of Chinese patients with type 2 diabetes (T2DM) and to examine gender differences based on social cognitive theory. There is limited study in theory-driven research conducted in China and a lack of evidence in collectively examining the associated factors among Chinese patients with T2DM based on a theory, especially among those living in a suburban area. METHODS: Following a cross-sectional design, data were collected from 207 patients (50.2% women; mean age, 56.1 years) with T2DM from an outpatient clinic in a suburban area of Beijing, China. Participants completed a survey, and clinical values were retrieved from the patients' medical records. RESULTS: Of the participants, more than half had suboptimal glycemic control; only a small proportion had recommended levels in performing self-management behaviors. A large proportion had metabolic syndrome and were overweight or obese. Compared with men, women demonstrated poorer health literacy and problem solving, received less social support, and presented with more depressive symptoms. CONCLUSION: Glycemic control and self-management were suboptimal in this sample, and a large proportion of the sample was at risk of developing cardiovascular disease. Gender differences exist regarding health literacy, depressive symptoms, problem solving, and social support. Social cognitive theory may provide a lens for addressing factors that are important in improving health outcomes among Chinese patients with T2DM. This evidence will help health care providers to identify pertinent factors through a multifactorial approach, therefore providing tailored care for Chinese patients with T2DM. PMID- 30403152 TI - Impact of Health Plan Deductibles and Health Insurance Marketplace Enrollment on Health Care Experiences. AB - High-deductible health plans (HDHPs) have become increasingly prevalent among employer-sponsored health plans and plans offered through the Health Insurance Marketplace in the United States. This study examined the impact of deductible levels on health care experiences in terms of care access, affordability, routine checkup, out-of-pocket cost, and satisfaction using data from the Health Reform Monitoring Survey. The study also tested whether the experiences of Marketplace enrollees differed from off-Marketplace individuals, controlling for deductible levels. Results from multivariable and propensity score weighted regression models showed that many of the outcomes were adversely affected by deductible levels and Marketplace enrollment. These results highlight the importance of efforts to help individuals choose the plan that fits both their medical needs and their budgets. The study also calls for more attention to improving provider acceptance of HDHPs and Marketplace plans as these plans become increasingly common over time. PMID- 30403151 TI - Exploring the Factors Associated With Rejection From a Closed Cybercrime Community. AB - Research examining the illicit online market for cybercrime services operating via web forums, such as malicious software, personal information, and hacking tools, has greatly improved our understanding of the practices of buyers and sellers, and the social forces that structure actor behavior. The majority of these studies are based on open markets, which can be accessed by anyone with minimal barriers to entry. There are, however, closed communities operating online that are thought to operate with greater trust and reliability between participants, as they must be vetted and approved by existing community members. The decision to allow individuals to join a forum may reflect restrictive deterrence practices on the part of existing members, as those applicants may threaten the security or operations of the group. This study utilized a quantitative analysis to understand the factors associated with rejection for individuals who sought membership in the organized and sophisticated closed forum run by and for cybercriminals called Darkode. The findings demonstrated that individuals whose perceived engagement with the hacker community and cybercrime marketplace were considered too risky for membership. The implications of this study for our understanding of restrictive deterrence theory, as well as criminal market operations on and offline were explored in depth. PMID- 30403153 TI - Response to the letter to the editor: "New data for venous thromboembolism in patients with small cell lung cancer: A review". PMID- 30403154 TI - Comparison of cyanoacrylate closure and radiofrequency ablation for the treatment of incompetent great saphenous veins: 36-Month outcomes of the VeClose randomized controlled trial. AB - OBJECTIVE: To evaluate the 36-month efficacy and safety of cyanoacrylate closure for the treatment of incompetent great saphenous veins in comparison with radiofrequency ablation. METHODS: In this multicenter, prospective, randomized controlled trial, 222 symptomatic subjects with incompetent great saphenous veins were assigned to either cyanoacrylate closure or radiofrequency ablation. The primary endpoint, complete closure of the target great saphenous vein, was determined using duplex ultrasound examination starting from three-month visit. RESULTS: At month 36, the great saphenous vein closure rates were 94.4% for the cyanoacrylate closure group and 91.9% for the radiofrequency ablation group. Stable improvement in symptoms and quality of life was observed in both groups. Adverse event rates between the 24- and 36-month visits were similar between the groups as were serious adverse events which were infrequent and judged unrelated to either the device or the procedure in both groups. CONCLUSIONS: This trial continues to demonstrate the safety and efficacy of cyanoacrylate closure for the treatment of great saphenous vein incompetence with great saphenous vein closure rate at 36 months similar to that of radiofrequency ablation, indicating non inferiority of cyanoacrylate closure to radiofrequency ablation. The improvement in quality of life outcomes were also sustained and similar between the two treatment groups. PMID- 30403155 TI - Doppler Illusion Prevails Over Pratt Effect in Risset Tones. AB - Changes in frequency such as those found in Risset tones have been associated with moving sound sources in the vertical plane (Pratt effect) and the horizontal plane (Doppler illusion). We investigated the reported origin and motion of unspatialized Risset tones presented monotically and diotically, and Risset tones simulated to be in the sagittal or coronal plane, approaching or receding, from above or horizontally. Independent of the artificial spatialization used (none, spatializing frequency components collectively or individually, elevated or not), upward glissandi were more likely to be judged as approaching than receding, and downward glissandi as receding than approaching, in most cases from the horizon. Glissandi associations with horizontal movements were more common in stimuli simulated on the sagittal plane than in stimuli simulated on the coronal plane. These findings suggest that the Doppler illusion is stronger than the Pratt effect, at least for Risset tones presented over headphones and simulated to be in the sagittal plane. These findings may contribute to better understanding of the association between auditory motion perception and changes in frequency. PMID- 30403156 TI - Initial Studies of Validity of the Children's Occupational Performance Questionnaire. AB - Studies of validity of a new caregiver report measure, the Children's Occupational Performance Questionnaire (COPQ) designed to address children's performance in the domains of personal and instrumental activities of daily living (IADLs), social participation, play/leisure, and education/work are presented. I examined criterion-related and discriminant validity of the COPQ. Criterion-related validity was addressed by correlating children's COPQ scores with those from the Vineland Adaptive Behavior Scale (VABS-II). Quasi experimental methods were used to compare COPQ scores from a heterogeneous group of children with disabilities with those from neurotypical children matched by age. COPQ scores correlated highly with scores from the VABS-II including social interaction, communication, daily living skills, and motor skills. Capacity of the COPQ to discriminate between children with and without disabilities varied dependent on age, and the occupational domain being considered. Preliminary support for the validity of COPQ as a measure of occupational performance for children was provided. Further study of the tool's psychometrics and with larger samples is needed. PMID- 30403160 TI - Perspectives on Neuroscience and Behavior. PMID- 30403157 TI - Estimating effects of HIV sequencing data completeness on transmission network patterns and detection of growing HIV transmission clusters. AB - OBJECTIVES: HIV nucleotide sequence data can identify clusters of persons with genetically similar strains suggesting transmission. We simulated the effect of lowered data completeness, defined by the percent of persons with diagnosed HIV with a reported sequence, on transmission patterns and detection of growing HIV transmission clusters. METHODS: We analyzed HIV surveillance data for persons with HIV diagnosed during 2008-2014 who resided in Michigan or Washington. We calculated genetic distances, constructed the inferred transmission network for each jurisdiction, and compared transmission network characteristics and detection of growing transmission clusters in the full dataset with artificially reduced datasets. RESULTS: Simulating lower levels of completeness resulted in decreased percentages of persons linked to a cluster from high completeness (full dataset) to low completeness (5%) (Michigan: 54% to 18%; Washington, 46% to 16%). Patterns of transmission between certain populations remained robust as data completeness level was reduced. As data completeness was artificially decreased, sensitivity of cluster detection substantially diminished in both states. In Michigan, sensitivity decreased from 100% with the full dataset, to 62% at 50% completeness and 21% at 25% completeness. In Washington, sensitivity decreased from 100% with the full dataset, to 71% at 50% completeness and 29% at 25% completeness. CONCLUSIONS: Lower sequence data completeness limits the ability to detect clusters that may benefit from investigation; however, inferences can be made about transmission patterns even with low data completeness, given sufficient numbers. Data completeness should be prioritized, as lack of or delays in detection of transmission clusters could result in additional infections. PMID- 30403161 TI - Metabolic resuscitation strategies to prevent organ dysfunction in sepsis. AB - Sepsis is the main cause of death among patients admitted to the intensive care unit (ICU). As current treatment is limited to antimicrobial therapy and supportive care, mortality remains high, which warrants efforts to find novel therapies. Mitochondrial dysfunction is emerging as a key process in the induction of organ dysfunction during sepsis and metabolic resuscitation might reveal to be a novel cornerstone in the treatment of sepsis. Here, we review novel strategies to maintain organ function in sepsis by precluding mitochondrial dysfunction by lowering energetic demand to allow preservation of ATP-levels, while reducing free radical generation. As the most common strategy to suppress metabolism, i.e. cooling, does not reveal unequivocal beneficial effects and may even increase mortality, caloric restriction or modulation of energy sensing pathways (i.e. Sirtuins, AMPK) may offer safe alternatives. Similar effects may be offered when mimicking hibernation by hydrogen sulphide (H2S). In addition H2S may also confer beneficial effects through upregulation of anti-oxidant mechanisms, similar to the other gasotransmitters nitric oxide (NO) and carbon monoxide (CO), which display anti-oxidant and anti-inflammatory effects in sepsis. Additionally, oxidative stress may be averted by systemic or mitochondria targeted anti-oxidants of which a wide range are able to lower inflammation, and reduce organ dysfunction and mortality from sepsis. Together, mitochondrial dysfunction plays a key role in the pathophysiology of sepsis. As a consequence, metabolic resuscitation might reveal to be a novel cornerstone in the treatment of sepsis. PMID- 30403162 TI - Identifying Cystogenic Paracrine Signaling Molecules in Cyst Fluid of Patients with Polycystic Kidney Disease. AB - In autosomal dominant polycystic kidney disease (ADPKD) paracrine signaling molecules in cyst fluid can induce proliferation and cystogenesis of neighboring renal epithelial cells. However, the identity of this "cyst inducing factor" is still unknown. The aim of this study was to identify paracrine signaling proteins in cyst fluid using an 3D in vitro cystogenesis assay. We collected cyst fluid from 15 ADPKD patients who underwent kidney or liver resection (55 cysts from 13 nephrectomies, 5 cysts from 2 liver resections). For each sample, the ability to induce proliferation and cyst formation was tested using the cystogenesis assay (RPTEC/TERT1 cells in Matrigel with cyst fluid added for 14 days). Kidney cyst fluid induced proliferation and cyst growth of renal epithelial cells in a dose dependent fashion. Liver cyst fluid also induced cystogenesis. Using size exclusion chromatography, 56 cyst fluid fractions were obtained of which only the fractions between 30-100 kDa showed cystogenic potential. Mass spectrometry analysis of samples that tested positive or negative in the assay identified 43 candidate cystogenic proteins. GO analysis showed an enrichment for proteins classified as enzymes, immunity proteins, receptors and signaling proteins. A number of these proteins have previously been implicated in ADPKD, including Secreted Frizzeld-Related Protein 4, S100A8, osteopontin, and CRELD1. In conclusion, both kidney and liver cyst fluids contain paracrine signaling molecules that drive cyst formation. Using size exclusion chromatography and mass spectrometry, we procured a candidate list for future studies. Ultimately, cystogenic paracrine signaling molecules may be targeted to abrogate cystogenesis in ADPKD. PMID- 30403163 TI - Renal release of Ac-SDKP is part of an antifibrotic peptidergic system in the kidney. AB - The anti-fibrotic peptide Ac-SDKP is released from Thymosin beta4 (Tbeta4) by meprin-alpha and prolyl oligopeptidase (POP) enzymes and is hydrolyzed by angiotensin-converting enzyme (ACE). Ac-SDKP is present in urine however it is not clear if de novo tubular release exists or the glomerular filtration is the main source. We hypothesized that Ac-SDKP is released in the lumen of the nephron and that it has an anti-fibrotic effect. We determined the presence of Tbeta4, meprin-alpha, and POP in the kidneys of Sprague-Dawley rats. The stop-flow technique was used to evaluate Ac-SDKP formation in different nephron segments. Finally, we decreased Ac-SDKP formation by inhibiting the POP enzyme and evaluated the long-term effect in renal fibrosis. The precursor Tbeta4, and the releasing enzymes meprin-alpha and POP were expressed in kidney. POP enzyme activity was almost double in the renal medulla compared to the renal cortex. Using the stop-flow technique, we detected the highest Ac-SDKP concentrations in the distal nephron. The infusion of a POP inhibitor into the kidney decreased the amount of Ac-SDKP in distal nephron segments and in the proximal nephron to a minor extent. An ACE inhibitor increased the Ac-SDKP content in all nephron segments, but the increase was highest in the distal portion. The chronic infusion of a POP inhibitor increased kidney medullary fibrosis, which was prevented by Ac-SDKP. We conclude that Ac-SDKP is released by the nephron and is part of an important antifibrotic system in the kidney. PMID- 30403164 TI - STAT1 regulates macrophage number and phenotype and prevents renal fibrosis after ischemia/reperfusion injury. AB - Renal ischemia/reperfusion injury (IRI) leads to acute kidney injury or delayed allograft function which predisposes to fibrosis in the native kidney or kidney transplant. Here we investigated the role of the signal transducer and activator of transcription 1 (STAT1) in inflammatory responses following renal IRI. Our study showed that a subsequent stimulation of Janus Kinase 2/STAT1 and toll-like receptor 4 pathways led to greater STAT1 activation followed by increased cytokine transcription compared to single-pathway stimulation in murine renal tubular cells. Moreover, we observed increased activation of STAT1 under hypoxic conditions. In vivo, STAT1-/- mice displayed less acute tubular necrosis and decreased macrophage infiltration 24 hours upon renal ischemia. However, investigation of the healing phase (30 days upon IRI) revealed significantly more fibrosis in STAT1-/- than in wildtype kidneys. In addition, we demonstrated increased macrophage infiltration in STAT1-/- kidneys. Flow cytometry analysis revealed that STAT1 deficiency drives an alternatively activated macrophage phenotype, which is associated with down-regulated CD80 expression, decreased intracellular reactive oxygen species production and enhanced ability for phagocytosis. Further, we detected immunohistochemically enhanced STAT1 expression in human renal allograft biopsies with no interstitial fibrosis/tubular atrophy (IF/TA) compared to specimens with severe IF/TA without specific etiology. Thus, STAT1-activation drives macrophages towards an alternatively activated phenotype and enhances fibrogenesis indicating a potential STAT1-driven protective mechanism in tissue repair after ischemic injury. PMID- 30403165 TI - Radiographic Analysis of National Football League Players' Fifth Metatarsal Morphology Relationship to Proximal Fifth Metatarsal Fracture Risk. AB - BACKGROUND:: Fractures of the proximal fifth metatarsal are one of the most common foot injuries in athletes. Repetitive stresses endured by the fifth metatarsal can lead to stress fracture, delayed union, and refracture, making optimal treatment challenging. A radiographic analysis of fifth metatarsal morphology and foot type in National Football League (NFL) players was performed to investigate morphologic risk factors for these injuries. METHODS:: This was a case-control study that looked at NFL players treated between 1992 and 2012, as well as participants at the NFL Combine. Ninety-six feet (51 athletes) were included. Fractures were present in 15 feet. Two reviewers assessed fifth metatarsal morphology and foot type on anteroposterior, lateral, and oblique radiographs. Differences in foot type and metatarsal morphology between athletes with and without fractures were determined. RESULTS:: On anteroposterior radiographs, significant differences in apex medullary canal width, 4-5 intermetatarsal angle, fifth metatarsal angle, and talar head uncovering were observed between fractured and non-fractured feet ( P = .001, .003, .004, .008, respectively). On lateral radiographs, significant differences in the fifth metatarsal length, distance to apex, apex height, fifth metatarsal angle, and talocalcaneal angle were observed between fractured and nonfractured feet ( P = .04, .01, .02, .01, .01, respectively). On oblique radiographs, a significant difference was observed in apex height between fractured and nonfractured feet ( P = .002). CONCLUSION:: Individuals with long, narrow, and straight fifth metatarsals with an adducted forefoot were most at risk for fifth metatarsal fractures. With this insight, attempts at fracture prevention can be implemented via footwear modifications, orthoses, and off-loading braces that account for those aforementioned morphologic attributes that place athletes at risk. LEVEL OF EVIDENCE:: Level III, retrospective comparative study. PMID- 30403166 TI - Measles and Rubella Seroprevalence in Mother-Infant Pairs in Rural Nepal and the United States: Pre- and Post-Elimination Populations. AB - We sought to compare seroprevalence of protective measles and rubella-specific antibody in mother-infant pairs across two populations: a pre-disease elimination Nepal population with recently introduced rubella vaccine and post-disease elimination U.S. population. Qualitative measles and rubella immunoglobulin G was assessed in maternal serum and cord blood from 258 pairs in Nepal, 2012-2013 and 49 pairs in Seattle, WA, 2014-2015. High rates of protective antibody were observed in both populations. Two hundred and forty-four (95%) pregnant women in Nepal had protective measles antibody versus 44 (92%) in Seattle (P = 0.42). Ninety-six percent of infants in Nepal (N = 246) and Seattle (N = 43) had protective measles antibody (P = 0.75). Ninety-four percentage of pregnant women in Nepal (N = 242) and Seattle (N = 45) had protective rubella antibody (P = 0.23). Two hundred and thirty-eight (93%) infants in Nepal had protective rubella antibody versus 44 (98%) in Seattle (P = 0.12). Continued surveillance will be necessary to ensure protective immunity, inform progress toward disease elimination in Nepal and avoid reemergence in the United States. PMID- 30403167 TI - Liuwei Dihuang exhibits antidiabetic effects through inhibiting alpha-amylase and alpha-glucosidase. AB - OBJECTIVE: Liuwei Dihuang (LWDH) is a famous traditional herbal medicine formula in China that may regulate the balance of kidney yin yang and has been used to restore functional insufficiency of the kidney for a long time in China. METHODS: In this study, the water extract of LWDH was tested for its alpha-Amylase and alpha-Glucosidase inhibitory activities, and its anti-diabetic property in streptozotocin (STZ)-induced diabetic mice was also analyzed. RESULTS: LWDH extract inhibited alpha-Glucosidase and alpha-Amylase activities in a dose- dependent manner. Treatment of streptozotocin-induced diabetic mice with LWDH extract decreased camp, fasting blood glucose, TC, TG, LDL-c, HbA1C, Urine volume levels and Urine sugar, increased HDL-c level when compared to STZ induced diabetic mice. CONCLUSION: This study demonstrates that extract of LWDH can inhibit alpha-amylase and alpha-glucosidase activities and shows anti-diabetic effect in a mice preclinical model. PMID- 30403168 TI - JTC-801 Suppresses Melanoma Cells Growth through the PI3K-Akt-mTOR Signaling Pathways. AB - Melanoma is considered as one of the most potentially fatal and aggressive malignancies. Due to the limited efficacy or drug resistance of the current targeted therapies of melanoma, developing new therapeutic drugs against new targets to effectively control tumor growth is greatly needed. In this study, the effect of JTC-801, a selective small-molecule antagonist of nociceptin receptor and analgesic agent, on a melanoma cell line, M14, has been studied. We demonstrate herein that JTC-801 could efficiently suppress the proliferation, migration and invasion capacity of the M14 melanoma cells, and induced a strong apoptosis. Importantly, our results provide the underlying molecular mechanism of these effects. JTC-801 cells regulate M14 cells by inhibiting the PI3K-Akt-mTOR pathway. These results suggest that JTC-801 should be further studied in preclinical modes to establish whether it represents a potential small anticancer candidate drug against melanoma. PMID- 30403169 TI - Gastric carcinoma with a gastrointestinal stromal tumor - A case report and literature review. AB - Gastric carcinoma (GC) with gastrointestinal stromal tumor (GIST) is encountered very rarely in the clinic, and few cases have been reported in the literature. Here, we present a case involving a 72-year-old man who was diagnosed with gastric antrum adenocarcinoma accompanied by neuroendocrine differentiation and a GIST in the fundus, according to a preoperative examination and postoperative pathology. The patient then underwent a distal radical gastrectomy and GIST resection. After the operation, the patient was administered combined chemo radiotherapy and subsequently underwent a 9-month follow-up examination. The gene mutations involved in this case were explored via high-throughput sequencing. The high-throughput gene mutation analysis indicated an exon5 mutation in the TP53 gene and copy number amplification of FGF19, CCND1, and FGFR2 in the gastric antrum adenocarcinoma. A gene sequencing analysis of the gastric fundus stromal tumor demonstrated an exon11 non-frame shift deletion mutation in the KIT gene. These findings suggested that this patient's cancer might be sensitive to AZD1775 (a TP53-targeted drug) or targeted drugs such as FGF19, CCND1 and FGFR2, and should be sensitive to imatinib. PMID- 30403170 TI - Bone and dental abnormalities as first signs of familial Gardner's syndrome in a Chinese family: a literature review and a case report. AB - Gardner's syndrome (GS) is an autosomal dominant disease characterized by the presence of familial adenomatous polyposis (FAP) as well as extraintestinal manifestations such as osteomas, dental anomalies, epidermoid cysts and ocular abnormalities. These intestinal polyps carry a 100% risk of malignant change, so early diagnosis is crucial. As craniofacial osteomas and dental anomalies of GS usually precede gastrointestinal symptoms, otolaryngologists, oral surgeons and dentists play an important role in the diagnosis of GS. GS is extensively reported in literature in the Caucasian race but not in the Mongoloid race. We report a case of a 22-year-old patient with a manifestation of three features of GS - multiple osteomas, soft tissue tumors and dental anomalies in the craniofacial region, with no intestinal polyps at the time of reporting. A family pedigree with our patient as the proband was constructed and revealed 3 consecutive generations in his lineage with GS. PMID- 30403171 TI - Diagnostic efficacy of serum procalcitonin, C-reactive protein concentration and clinical pulmonary infection score in Ventilator-Associated Pneumonia. AB - OBJECTIVE: The aim of this study was to evaluate the diagnostic efficacy of serum procalcitonin (PCT), c-reactive protein (CRP) concentration and clinical pulmonary infection score(CPIS) in ventilator-associated pneumonia(VAP). METHODS: Forty-nine patients who were admitted to the intensive care unit (ICU) of Zhejiang Hospital with suspected VAP were recruited in this study. The serum level of PCT and CRP of all patients were measured and CPIS was calculated at the time of VAP suspected diagnosis. Of the included 49 patients, 24 were finally confirmed of VAP by microbiology assay. And the other 25 patients were considered as clinical suspected VAP without microbiology confirmation. The diagnostic sensitivity, specificity and area under the receiver operating characteristic (ROC) curve (AUC) were calculated using the serum PCT, CRP concentration and CPIS. The correlation among serum PCT, CRP concentration and CPIS were also evaluated by Spearson correlation test. RESULTS: A total of 100 bronchoscopic aspiration sputum specimen were examined in bacterial culture. 30 samples were found with suspected pathogenic bacteria. Six samples were found with 2 types of suspected pathogenic bacteria. PCT serum concentration and CPIS score were significantly different (P<0.05) between the patient group [1.4 (0.68 ~ 2.24), 6.0 (4.25 ~ 8.00)] and the control group [0.4 (0.17 ~ 1.39), 3.0 (1.00 ~ 5.00)] ; However, the serum CRP [102.8(66.75 ~ 130.90) vs 86.1(66.95 ~ 110.10)] was not statistically different between the two groups (P>0.05). A significant correlation was found between serum PCT and CRP concentrations (r=0.55, P<0.01), but not between PCT vs CPIS and CRP vs CPIS (p>0.05). The diagnostic sensitivity, specificity and AUC were 72.0%, 75.0%, 0.81 (0.69 ~ 0.93) for CPIS; 60.0%, 87.5%, 0.76 (0.62 ~ 0.90) for PCT and 68.0%, 58.3%, 0.59 (0.43 ~ 0.76) for CRP. CONCLUSION: PCT serum level and CPIS score are elevated in VAP patients and could therefore represent potential biomarkers for VAP early diagnosis. PMID- 30403172 TI - Lycorine inhibits melanoma A375 cell growth and metastasis through the inactivation of the PI3K/AKT signaling pathway. AB - Malignant melanoma, one of the most aggressive skin cancers, has a very high mortality rate. Currently, the number of drugs to treat melanoma is low. Although new immunotherapeutic approaches based on the use of antibodies against immune checkpoints have shown long term responses, it is urgent to develop novel anti melanoma drugs with a high efficiency and a low toxicity in a large number of patients. Lycorine, a natural product, has been reported to exert antitumor effects on some cancers. However, the impact of lycorine on melanoma cells is still unknown. Using the CCK8 assay, we found that lycorine can suppress the proliferation of melanoma A375 cells in a dose-time-dependent manner. Moreover, a transwell assay showed that lycorine inhibited the migration and invasion of A375 cells significantly. Further, lycorine treatment could induce the apoptosis of the A375 cells. Biochemical analyses showed that the expression level of the anti apoptosis Bcl-2 protein decreased, while the expression of the pro-apoptosis protein Bax and active caspase-3 increased after lycorine treatment. Finally, using western blot assay, we found that the antitumor effects of lycorine on A375 cells might be through the inactivation of the PI3K/Akt signaling pathway. Based on these observations, we suggest that lycorine may be an interesting candidate for further studies on its ability to represent a novel antitumor drug for human melanoma treatment in the future. PMID- 30403173 TI - Incidence and risk factors of the temporomandibular joint disorders in the patients without condylar fractures. AB - OBJECTIVE: To evaluate the incidence and risk factors of the temporomandibular joint disorders (TMD) in the patients suffering from maxillo-facial injury without condylar fractures. METHODS: sixty patients without condylar fractures were recruited from Feb 2014 to Nov 2015 in the department of stomatology, Lishui people's hospital. The incidence of TMD was recorded at 1, 3, 6, 9 and 12 months after injury through MRI examination. The risk factors for TMD were evaluated by logistic regression analysis. RESULTS: the TMD incidence rates were 25.0%, 30.0%, 35.0%, 41.7% and 48.3% at 1, 3, 6, 9 and 12 months after injury with no statistical difference between male and female (P>0.05). Logistic regression indicated that disorder of occlusal relationship (OR=1.84,95%CI:1.36-2.78) and hemi-mastication (OR=1.56, 95% CI:1.23- 2.24) were independent risk factors for the development of TMD. CONCLUSION: there was a high incidence of temporomandibular joint disorders in the patients suffering from maxillo-facial injury without condylar fractures. The disorder of occlusal relationship and hemi mastication were independent risk factors for the development of post-injury TMD. PMID- 30403174 TI - Analysis of the long-term efficacy of core decompression with synthetic calcium sulfate bone grafting on non-traumatic osteonecrosis of the femoral head. AB - OBJECTIVE: to investigate the safety and long-term efficacy of core decompression with synthetic calcium-sulfate bone grafting on non-traumatic osteonecrosis of the femoral head. METHOD: a total of 76 patients with non-traumatic osteonecrosis of the femoral head were admitted to our hospital from February 2012 to November 2014 and included in the study. All the patients were treated by core decompression with synthetic calcium-sulfate bone grafting. After treatment, the patients were followed-up for 12 months. The operation time, intraoperative blood loss, and perioperative complications were also recorded intraoperatively to evaluate the clinical efficacy and safety. The preoperative and postoperative pain scores measured by visual analogy score (VAS) were also recorded and compared. RESULTS: all of the 76 patients were successfully operated and included in the study. The mean operation time was 34.6+/-14.2 min, and the intraoperative blood loss was 23.6+/-8.9 mL. The patients hip functions were assessed on the basis of the Harris hip score, 3 and 12 months after operation. The excellent rates 3 and 12 months after operation were significantly higher than those before operation (P<0.05). The imaging stabilities of the hip joints 3 and 12 months after operation were significantly higher than those before operation (P<0.05). The patient postoperative pain scores (VAS score) gradually decreased. The VAS scores 12 months after operation were significantly lower than those before operation (P<0.05). CONCLUSION: the long-term efficacy of core decompression with synthetic calcium-sulfate bone grafting on non-traumatic osteonecrosis of the femoral head is good and accompanied with significantly improved postoperative joint functions. PMID- 30403175 TI - Laparoscopic combined with hysteroscopic repair or operative hysteroscopy in the treatment of symptomatic cesarean-induced diverticulum. AB - OBJECTIVE: The postmenstrual bleeding with cesarean-induced diverticulum is a bothersome symptom and can be confused with other abnormal-uterine bleeding disease. The aim of the present study was to evaluate the efficacy and safety of laparoscopic combined with hysteroscopic repair vs operative hysteroscopy in treatment of symptomatic cesarean-induced diverticulum. METHODS: Eighty-two women with cesarean-induced diverticulum who underwent either laparoscopic combined with hysteroscopic repair or operative hysteroscopy between January 2012 and September 2015 were retrospectively included in the study. We evaluated the menstrual duration before and after the surgery, the width, length and depth of the niche, operating time, blood loss, complications, and postoperative pregnancy status. RESULTS: 62.2% (51/82) patients started to have postmenstrual bleeding immediately when they gained regular menstruation after their cesarean section. The laparoscopic group has longer operative time and greater blood loss (p<0.001). Both groups have a significant improvement in their menstruation duration ( p< 0.001). The patients in the laparoscopic repair group had a greater improvement in bringing the uterine bleeding into normal menstruation duration (P=0.046) and the same in pregnancy rate (P=0.505). The interval between operation and pregnancy in laparoscopic combined with hysteroscopic group was much longer than the hysteroscopic group (27 vs 10 months, p<0.001). CONCLUSION: the laparoscopic repair exhibited a better efficiency in bringing the uterine bleeding into normal menstruation duration and in improving the pregnancy rate However, there was not a clear absolute advantage for one of the two type of surgeries. Thus, patients with post-cesarean section diverticulum (PCSD) should choose with caution the type of surgery, considering the residual myometrial thickness (RMT), the age, the desire for further fertility and ovarian reserve capacity. PMID- 30403176 TI - Computational QSAR model combined molecular descriptors and fingerprints to predict HDAC1 inhibitors. AB - The dynamic balance between acetylation and deacetylation of histones plays a crucial role in the epigenetic regulation of gene expression. It is equilibrated by two families of enzymes: histone acetyltransferases and histone deacetylases (HDACs). HDACs repress transcription by regulating the conformation of the higher order chromatin structure. HDAC inhibitors have recently become a class of chemical agents for potential treatment of the abnormal chromatin remodeling process involved in certain cancers. In this study, we constructed a large dataset to predict the activity value of HDAC1 inhibitors. Each compound was represented with seven fingerprints, and computational models were subsequently developed to predict HDAC1 inhibitors via five machine learning methods. These methods include naive Bayes, kappa-nearest neighbor, C4.5 decision tree, random forest, and support vector machine (SVM) algorithms. The best predicting model was CDK fingerprint with SVM, which exhibited an accuracy of 0.89. This model also performed best in five-fold cross-validation. Some representative substructure alerts responsible for HDAC1 inhibitors were identified by using MoSS in KNIME, which could facilitate the identification of HDAC1 inhibitors. PMID- 30403177 TI - miR-25 Promotes Melanoma Progression by regulating RNA binding motif protein 47. AB - Melanoma is the most aggressive skin cancer, and accounts for the major part of skin cancer-related deaths in the world. In addition, the underlying mechanism of tumor progression in melanoma remains far from being elucidated. In this study, we have evaluated the function of miR-25 in melanoma. First, we examined the expression of miR-25 in four melanoma cell lines (A875, MV3, M14 and uacc-257) and in a normal melanocyte cell line (HEM-a). Then, we overexpressed miR-25 in M14 cells. Our results show that miR-25 promotes M14 cell proliferation and migration. We found that miR-25 up-regulates the PI3K/Akt/mTOR signaling pathway in these tumor cells. Furthermore, a luciferase-based reporter gene assay showed that miR-25 could directly target the RNA-binding motif protein 47 (RBM47). Taken together, our findings suggest that RBM47 is a promising target for the treatment of melanoma. PMID- 30403178 TI - Effects of continuous positive airway pressure on elderly patients with obstructive sleep apnea: a meta-analysis. AB - OBJECTIVE: the aim of the study was to evaluate the efficacy of continuous positive airway pressure (CPAP) for the treatment of obstructive sleep apnea in the elderly. METHOD: a comprehensive search for qualified clinical trials was performed on April, 2016. Basic demographic information of enrolled subjects, study design, survival rate, cardiovascular events, quality of life scores, and neurocognitive data were extracted for analysis. RESULTS: A total of seven clinical trials were included in this meta-analysis, in which untreated elderly patients exhibited worse survival rate than those with CPAP (OR=2.22, 95% CI=1.64 to 3.01, P< 0.00001). Treated elderly patients exhibited less cardiovascular risk than those without CPAP (RR=0.49, 95% CI=0.36 to 0.66, P<0.00001) and a statistically significant improvement on all the domains of Quebec Sleepiness Questionnaire, supported by pooled weighted mean difference. Furthermore, CPAP treatment partially improved the cognitive functions. CONCLUSION: CPAP treatment achieves improvements in decreasing mortality and controlling cardiovascular events and exhibits few effects on neurocognitive function. Further large-scale, well-designed interventional investigation is needed. PMID- 30403179 TI - Overexpression of SLC25A15 is involved in the proliferation of cutaneous melanoma and leads to poor prognosis. AB - Melanoma is a skin tumor with a high degree of malignancy, poor prognosis and few effective therapies. Deprivation of the arginine from cancer cells through transport inhibition and arginine depletion is a novel strategy for cancer therapy. In this study, we have investigated the effect of SLC25A15, which encodes the mitochondrial ornithine carrier 1, on melanoma progression. Using bioinformatics methods to screen the data from TCGA and GEO, we found that SLC25A15 is overexpressed in patients with melanoma and negatively related with the overall and disease-free survival rates. Knockdown the expression of SLC25A15 by siRNA could effectively inhibit the proliferation of A375 melanoma cells, as detected by CCK8 and colony formation. Furthermore, SLC25A15 siRNA was able to promote apoptosis of A375 cells, which exhibited decreased expression levels of the anti-apoptotic protein Bcl-2 while showing increased pro-apoptotic protein Bax and cleaved caspase-3. All these results suggest that the overexpression of SLC25A15 is involved in the progression of melanoma and may predict the prognosis of melanoma. This may shed new lights on the diagnosis and therapy of melanoma in the future. PMID- 30403180 TI - Overexpression of RBM10 induces osteosarcoma cell apoptosis and inhibits cell proliferation and migration. AB - Osteosarcoma is the most common malignant bone tumor with high incidence in adolescence and poor prognosis. RBM10, a member of RBPs, was reported to be a tumor suppressor in many kinds of cancers. However, the roles of RBM10 in osteosarcoma remain unknown. In this study, we found that overexpression of RBM10 decreased osteosarcoma cell proliferation and colony formation in soft agar, and inhibited osteosarcoma cell migration and invasion. Our results also revealed that RBM10 overexpression induced osteosarcoma cell apoptosis via the inhibition of Bcl-2, the activation of caspase-3, and the transcription and production of TNF-alpha. Our results indicated that RBM10 acts as a tumor suppressor in osteosarcoma. This could enable to define a new strategy for diagnosis and treatment of patients with osteosarcoma. PMID- 30403181 TI - NPS - 2143 (hydrochloride) inhibits melanoma cancer cell proliferation and induces autophagy and apoptosis. AB - Melanoma is a common and aggressive skin cancer caused by the oncogenic transformation of melanocytes. NPS-2143 (hydrochloride) is a calcification drug that acts as an antagonist of the calcium-sensing receptor (CaSR) and consequently stimulates the release of parathyroid hormone. In the present work, we treated cells from the human melanoma cell line M14 to investigate the effects of NPS-2143 on melanoma cells and elucidate their underlying mechanisms. We observed that NPS-2143 inhibits the survival and proliferation of M14 cells and suppresses the migration and proliferation of M14 cells by inducing apoptosis. The Bax/Bcl-2 ratio in M14 cells was enhanced by the NPS-2143 treatment, suggesting that the mitochondrial apoptotic pathway was activated. The expression and phosphorylation of proteins involved in the PI3K signaling pathway were altered by NPS-2143 treatment. Our data show that NPS-2143 impacts the viability and induces the apoptosis of melanoma M14 cells through its impact on the PI3K signaling pathway. It suggests that NPS-2143 could represent a promising candidate for melanoma treatment. PMID- 30403182 TI - Knock-down of filaggrin influences the mitogen-activated protein kinases signaling pathway in normal human epidermal keratinocytes. AB - BACKGROUND: Filaggrin is an essential structural protein of the stratum corneum binding to the keratin intermediate filaments to form a dense protein-lipid matrix. However, the function of filaggrin in epidermal terminal differentiation is not completely understood. AIM: To evaluate the effects of filaggrin on normal human epidermal keratinocytes (NHEKs) and to investigate the relevant mechanisms. METHODS: Short hairpin RNA (shRNA) technology was used to knock-down filaggrin in normal human epidermal keratinocytes (NHEKs). Western blot and real-time quantitative PCR (qRT-PCR) were performed to detect expression of filaggrin, differentiation-related proteins and MAPK-related proteins. RESULTS: Filaggrin was successfully knocked down in NHEKs (99% efficiency). We found that the lack of filaggrin significantly decreased the expression of some differentiation related proteins, including Cytokeratin 5 protein, Cytokeratin 14 protein, ST14 protein and SPRR3 protein (P<0.05). In addition, filaggrin knock-down significantly decreased expression of p-p38, p-ERK1/2, p-JNK, p-Akt, and p-NF kappaB in NHEKs. CONCLUSION: Our study shows that filaggrin regulates epidermal terminal differentiation and impairs MAPK signaling pathway in normal human epidermal keratinocytes. PMID- 30403183 TI - UNBS5162 inhibits colon cancer growth via suppression of PI3K/Akt signaling pathway. AB - Colon cancer is a common cause of cancer-related death worldwide. However, the underlying mechanism of tumor progression of colon cancer remains far from being elucidated. In the present study, we report the role of UNBS5162 in colon cancer. UNBS5162 is a naphthalimide that can intercalate into DNA and suppress the expression level of CXCL chemokines. Here, we investigated its effect on cell proliferation, mobility and apoptosis in HCT116 cells, and explored the underlying mechanism. A CCK8 assay revealed that UNBS5162 can block the proliferation of colon cancer cells. Base on a Transwell assay, we showed that cell migration and invasion ability of HCT116 cells are inhibited by UNBS5162. In addition, Annexin V-FITC/PI assay and Western blot analysis were performed to detect whether UNBS5162 could induce cell apoptosis. The results indicated that UNBS5162 increases the number of apoptotic cells remarkably. Furthermore, Western blot analysis demonstrated that UNBS5162 down-regulates the expression level of Bcl2, and up-regulates that of Bax as well as the level of activated Caspase-3. Moreover, we examined the impact of UNBS5162 on PI3K/Akt signaling pathway. UNBS5162 substantially inhibited the phosphorylation of Akt and its downstream effector mTOR, and reduced the expression of p-70. Taken together, these results suggest that UNBS5162 should be considered as a potent therapeutic anticancer agent that targets the PI3K/AKT signaling pathway. PMID- 30403184 TI - Analysis of the association between CDH2 gene polymorphism and osteoarthritis risk. AB - OBJECTIVE: to define the cadherin 2 (CDH2) gene polymorphism in Chinese osteoarthritis and control populations and to explore the correlation between CDH2 gene polymorphism and the risk of osteoarthritis. METHOD: a total of 476 patients with osteoarthritis were collected and 380 control subjects were included in the study. Clinical data such as gender, age and functional score were collected. The blood and tissue samples were collected and genotyped by PCR. Data analysis was performed using SPSS 19.0, Hapioview 4.2 and SNPstats softwares. RESULTS: the association of rs11083271 and osteoarthritis was initially validated in this study population (P = 0.016, OR = 1.43 (1.07- 1.93)]. The risk of OA was significantly higher in heterozygous T/C than in homozygous T/T and C/C in rs11083271. By adjusting the age, according to gender stratification analysis, the heterozygous T/C genotype in rs11083271 significantly increased the risk of OA incidence in males [p = 0.011, 3.40 (1.55 7.43)]. The remaining rs sites were not significantly associated with OA. Notably, the association of rs11564299 with OA, regardless of genotyping, gene frequency and RNA expression levels in the study population, was not confirmed. CONCLUSION: in this study, we have analyzed the association between CDH2 gene polymorphism and OA in Chinese population. We found that rs11083271 heterozygous T/C genotype significantly increases the risk of OA and the severity of the disease. By contrast, the rs11564299 locus and OA have no significant correlation in the Chinese population. The role of rs11083271 in the regulation of CDH2 expression levels and the mechanisms by which it impacts OA remain to be further studied. PMID- 30403185 TI - Relationship between depression and blood cytokine levels in lung cancer patients. AB - OBJECTIVE: To study the correlation between depression and blood cytokine levels in lung cancer patients. METHODS: 92 patients with advanced lung cancer were evaluated for depression using the scoring index of depression self-rating scale. Lack of depression (n=24), mild depression (n=45), and moderate depression (n=23) were found in the cohort. Meanwhile, 40 healthy subjects were selected as the control group. The levels of IL-10, IL-6, IL-8, and TNF-alpha in each group were detected by sandwich enzyme-linked immunosorbent assays, and their correlation with the degree of depression was analyzed. RESULTS: The levels of IL-10, IL-6, IL-8, and TNF-alpha were all higher than those in the control group (P<0.05). Moreover, the depression statuses of patients with lung cancer were positively correlated with IL-10, IL-6, and TNF-alpha levels (r = 0.705, 0.301, and 0.446, P<0.01); however, the level of IL-8 was not relevant (r=0.136, p>0.05). CONCLUSION: Serum levels of IL-10, IL-6, and TNF-alpha are associated with depression scoring in patients with lung cancer. PMID- 30403187 TI - Exploring the dynamic changes between pulmonary and cutaneous sarcoidosis based on gene expression. AB - Sarcoidosis is a disease involving the growth of abnormal inflammatory granulomas and affecting multisystems. It has an unknown etiology. The lung and the skin are the most commonly involved organs. Although large amounts of research have focused on the pathogenesis of sarcoidosis, little is known about the link between cutaneous sarcoidosis and pulmonary sarcoidosis. Moreover, the gene expression profiles provide a novel way to find diagnostic or prognostic biomarkers. Therefore, the aim of this study was to analyze the differentially expressed genes (DEGs) in pulmonary sarcoidosis and cutaneous sarcoidosis patients and to compare them to healthy individuals. DEGs and their biological functions are dynamically dysregulated, and several common disease-related genes and mutual disease progression-related genes were identified which linked pulmonary sarcoidosis and cutaneous sarcoidosis together. The biological functional pathways regulated by these DEGs may allow to define the common mechanism shared by different type of sarcoidosis, providing novel insight into the common pathogenesis of sarcoidosis and opening the way to the development of new therapeutic strategies. PMID- 30403186 TI - Complement protein C5a enhances the beta-amyloid-induced neuro-inflammatory response in microglia in Alzheimer's disease. AB - OBJECTIVE: The dysregulation of neuro-inflammation is one of the attributes of the pathogenesis of Alzheimer's disease (AD). Over-expression of complement proteins co-localizes with neurofibrillary tangles, thereby indicating that a complement system may be involved in neuro-inflammation. Here, we report the influence of complement activation on the neuro-inflammation using a microglial cell line. METHODS: first, we performed a cytotoxic assay using the microglial cells BV-2. Second, after treatment of BV-2 cells with Abeta42 and/ or C5a, the anaphylatoxin derived from C5, we determined the expression levels of the pro inflammatory factors TNF-alpha, IL-1beta, and IL-6. Finally, we explored whether this neuroinflammatory response was mediated by JAK/ STAT3 signaling. RESULTS: C5a had an enhanced effect on the neural cell viability of BV-2 cells treated with Abeta42. In addition, C5a also increased the Abeta-induced neuro inflammatory response, and these effects were blocked by the C5aR antagonist, PMX205. Finally, we demonstrated that the neuro-inflammatory responses induced by Abeta and C5a were mediated through JAK/STAT3 signaling. By blocking this pathway with an antagonist, AG490, the expression of TNF-alpha, IL-1beta, and IL-6 was alleviated. CONCLUSION: The complement protein C5a could exaggerate the Abeta induced neuroinflammatory response in microglia, and C5aR may be a potential therapeutic tool for AD treatment. PMID- 30403188 TI - Auto-delineation of oropharyngeal clinical target volumes using 3D convolutional neural networks. AB - Accurate clinical target volume (CTV) delineation is essential to ensure proper tumor coverage in radiation therapy. This is a particularly difficult task for head-and-neck cancer patients where detailed knowledge of the pathways of microscopic tumor spread is necessary. This paper proposes a solution to auto segment these volumes in oropharyngeal cancer patients using a two-channel 3D U Net architecture. The first channel feeds the network with the patient's CT image providing anatomical context, whereas the second channel provides the network with tumor location and morphological information. Radiation therapy simulation computer tomography scans and their corresponding manually delineated CTV and gross tumor volume (GTV) delineations from 285 oropharyngeal patients previously treated at MD Anderson Cancer Center were used in this study. CTV and GTV delineations underwent rigorous group peer-review prior to the start of treatment delivery. The convolutional network's parameters were fine-tuned using a training set of 210 patients using 3-fold cross-validation. During hyper-parameter selection, we use a score based on the overlap (dice similarity coefficient (DSC)) and missed volumes (false negative dice (FND)) to minimize any possible under-treatment. Three auto-delineated models were created to estimate tight, moderate, and wide CTV margin delineations. Predictions on our test set (75 patients) resulted in auto-delineations with high overlap and close surface distance agreement (DSC > 0.75 on 96% of cases for tight and moderate auto delineation models and 97% of cases having mean surface distance ? 5.0 mm) to the ground-truth. We found that applying a 5 mm uniform margin expansion to the auto-delineated CTVs would cover at least 90% of the physician CTV volumes for a large majority of patients; however, determination of appropriate margin expansions for auto-delineated CTVs merits further investigation. PMID- 30403189 TI - The impact of keels and tails on turtle swimming performance and their potential as models for biomimetic design. AB - Stability and turning performance are two key metrics of locomotor performance in animals, and performance in both of these metrics can be improved through a variety of morphological structures. Aquatic vehicles are often designed with keels and rudders to improve their stability and turning performance, but how keels and rudders function in rigid-bodied animals is less understood. Aquatic turtles are a lineage of rigid-bodied animals that have the potential to function similarly to engineered vehicles, and also might make use of keels and rudders to improve their stability and turning performance. To test these possibilities, we trained turtles to follow a mechanically controlled prey stimulus under three sets of conditions: with no structural modifications, with different sized and shaped keels, and with restricted tail use. We predicted that keels in turtles would function similarly to those in aquatic vehicles to reduce oscillations, and that turtles would use the tail like a rudder to reduce oscillations and improve turning performance. We found that the keel designs we tested did not reduce oscillations in turtles, but that the tail was used similarly to a rudder, with benefits to both the magnitude of oscillations they experienced and turning performance. These data show how variation in the accessory structures of rigid bodied animals can impact swimming performance, and suggest that such variation among turtles could serve as a biomimetic model in designing aquatic vehicles that are stable as well as maneuverable and agile. PMID- 30403190 TI - First-principles calculations and Raman scattering evidence for local symmetry lowering in rhombohedral ilmenite: temperature- and pressure-dependent studies. AB - ATiO3-type materials may exist in two different crystalline forms: the perovskite and ilmenite. While many papers have devoted their attention to evaluating the structural properties of the perovskite phase, the structural stability of the ilmenite one still remains unsolved. Here, we present our results based on the lattice dynamics and first-principles calculations (density functional theory) of the CdTiO3 ilmenite phase, which are confronted with experimental data obtained through micro Raman spectroscopy that is a very good tool to probe the local crystal structure. Additional Raman bands, which are not foreseen from group theory for the ilmenite rhombohedral structure, appeared in both low temperature (under vacuum condition) and high-pressure (at room temperature) spectra. The behavior can be explained by considering the local loss of inversion symmetry operation which reduces the overall space group from [Formula: see text] ([Formula: see text]) to [Formula: see text] ([Formula: see text]). Our results can also be extended to other ilmenite-type compositions. PMID- 30403191 TI - Quantitative cone-beam CT reconstruction with polyenergetic scatter model fusion. AB - Scatter can account for large errors in cone-beam CT (CBCT) due to its wide field of view, and its complicated nature makes its compensation difficult. Iterative polyenergetic reconstruction algorithms offer the potential to provide quantitative imaging in CT, but they are usually incompatible with scatter contaminated measurements. In this work, we introduce a polyenergetic convolutional scatter model that is directly fused into the reconstruction process, and exploits information readily available at each iteration for a fraction of additional computational cost. We evaluate this method with numerical and real CBCT measurements, and show significantly enhanced electron density estimation and artifact mitigation over pre-calculated fast adaptive scatter kernel superposition (fASKS). We demonstrate our approach has two levels of benefit: reducing the bias introduced by estimating scatter prior to reconstruction; and adapting to the spectral and spatial properties of the specimen. PMID- 30403192 TI - Structures and magnetic properties of small [Formula: see text] and Co n-1Cr+ (n = 3-5) clusters. AB - Small cobalt clusters [Formula: see text] and their single chromium atom doped counterparts Co n-1Cr+ (n = 3-5) were studied mass spectrometrically by measuring the infrared multiple photon dissociation (IRMPD) spectra of the corresponding argon tagged complexes. The geometric and electronic structures of the [Formula: see text] and Co n-1Cr+ (n = 3-5) clusters as well as their Ar complexes were optimized by density functional theory (DFT) calculations. The obtained lowest energy structures were confirmed by comparing the IRMPD spectra of [Formula: see text] and [Formula: see text] (n = 3-5, m = 3 and 4) with the corresponding calculated IR spectra. The calculations reveal that the doped Co n-1Cr+ clusters retain the geometric structures of the most stable [Formula: see text] clusters. However, the coupling of the local magnetic moments within the clusters is altered in a size-dependent way: the Cr atom is ferromagnetically coupled in Co2Cr+ and Co3Cr+, while it is antiferromagnetically coupled in Co4Cr+. PMID- 30403193 TI - Stray light in cone beam optical computed tomography: III. Evaluation of a redesigned large-volume commercial scanner based on a convergent light source. AB - Optical cone beam computed tomography (CT), using a digital camera to acquire 2D projection images, provides a fast, mechanically simple method for 3D radiation dosimetry. However, original cone beam designs had poor accuracy as a result of considerable scatter/stray light reaching the camera. Previously, our group presented a redesigned convergent light source for optical cone beam CT that considerably reduced stray light contribution and improved accuracy (Dekker et al 2016 Phys. Med. Biol. 61 2910). Here, we performed an evaluation of a newly updated commercial optical cone beam CT scanner (VistaTM, ModusQA, London, Canada) based on that design. Two different light source configurations were examined: the manufacturer's default configuration which uses a 10 cm wide, 5 cm high diffuser light source, and a smaller, 1.5 cm diameter diffuser light source that more closely aligns with our previously described design. We imaged large volume (15 cm diameter cylinders) absorbing and scattering solution phantoms as well as a 1.25 cm diameter absorber placed within 15 cm diameter gel-like scattering phantom. Optical CT reconstructions were compared against narrow-beam measurements of attenuation made by placing an aperture in the optical CT system. Our results show that considerable stray light is present when using the manufacturer's default configuration, as cupping artifacts and large (?10%) discrepancies between optical CT and narrow-beam attenuation measurements occur when imaging scattering phantoms. However, when imaging is performed using the 1.5 cm diameter source, optical CT measurements agree with narrow-beam measurements within ~3% for both absorbing and scattering objects, as well as the small absorber in a scattering medium. Using this light source will require higher optical quality vessels than are currently provided by the manufacturer. PMID- 30403194 TI - Physico-chemical properties and optimization of the deformable FlexyDos3D radiation dosimeter. AB - Deformable 3D radiation dosimetry is receiving growing interest for the validation of image-guided radiotherapy treatments (IGRT) of moving and deformable targets. Previously, a proof-of-concept of a flexible anthropomorphic 3D dosimeter called 'FlexyDos3D' has been demonstrated. One of the concerns with respect to the FlexyDos3D dosimeter is its dose-response instability. The effect of different formulations of the dosimeter on its stability were investigated. A stable formulation for the dosimeter was found by optimising the ratios of curing agent and base of the silicone matrix between 3% and 4.5% [w/w] curing agent. The effects of elevated curing temperatures and times upon the dosimetric properties were also investigated and the dose-response was found to be independent of curing times for curing times over an hour at 120 degrees C. 1H NMR spectra of the dosimeter chemical constituents and the effect of radiation dose were determined. The evaporation and diffusion rates of chloroform in the dosimeter were determined and are the likely cause of the dosimeters depth-dose profile uncertainties. A composition for a stable silicone dosimeter which can be cured quickly at elevated temperatures was found, demonstrating the potential for 3D printing of patient-specific dosimeters. However, it is suggested that another radical initiator be used in future formulations of the dosimeter. PMID- 30403195 TI - Exogenous imaging contrast and therapeutic agents for intravascular photoacoustic imaging and image-guided therapy. AB - Intravascular photoacoustic (IVPA) imaging has been developed in recent years as a viable imaging modality for the assessment of atherosclerotic plaques. Exogenous imaging contrast and therapeutic agents further enhance this imaging modality and provide significant benefits. Imaging contrast agents can significantly increase photoacoustic signal, resulting in enhanced plaque detection and characterization. The ability to use these particles to molecularly target markers of disease progression makes it possible to determine patient specific levels of risk and plan treatments accordingly. With improved diagnosis, clinicians will be able to use therapeutic agents that are synergistic with IVPA imaging to treat atherosclerotic patients. Pre-clinical and clinical studies with relevance to IVPA imaging have shown promise in the area of diagnosis and therapeutics. In this review, we present a variety of imaging contrast agents that are either designed for or are compatible with IVPA imaging, cover uses of therapeutic agents that compliment this imaging modality, and discuss future directions of research in the field. PMID- 30403196 TI - Discriminating lung adenocarcinoma from lung squamous cell carcinoma using respiration-induced tumor shape changes. AB - Based on 4D-CT, we aimed to characterize the pattern of morphological changes in lung tumors during respiration, and investigated its potential in non-invasively differentiating lung adenocarcinoma (AC) and squamous cell carcinoma (SCC). We applied a 3D surface analysis on 22 tumors (13 AC, 9 SCC) to investigate the tumor regional morphological fluctuations in response to respiration phases. Tumor surface vertices among ten respiratory phases were matched using surface based registration, and the shape descriptors (rho and detJ) were calculated and tracked across respiration stages in a regionally aligned scenario. Pair-wise group comparisons were performed between lung AC and SCC subtypes, in terms of ratios of maximal shape changes as well as correlation coefficients between tumor shape and respiratory stage indicators from the lung. AC type tumors had averaged larger surface measurements at exhale than at inhale, and these surface measurements were negatively correlated with lung volumes across respiratory stages. In contrast, SCC type tumors had averaged smaller surface measurements at exhale than at inhale, and the correlations with lung volumes were positive. The group differences in maximal shape changes as well as correlations were both statistically significant (p < 0.05). We developed a non-invasive lung tumor sub-type detection pipeline based on respiration-induced tumor surface deformation. Significant differences in deformation patterns were detected between lung AC and SCC. The derived surface measurements may potentially serve as a new non-invasive imaging biomarker of lung cancer subtypes. PMID- 30403197 TI - Optimized image acquisition for dopamine transporter imaging with ultra-high resolution clinical pinhole SPECT. AB - SPECT can be used to image dopamine transporter (DaT) availability in the human striatum, e.g. for diagnosis of Parkinson's disease (PD). As traditional SPECT provides limited resolution and sensitivity, we proposed a full ring focusing multi-pinhole SPECT system (G-SPECT-I (Beekman 2015 Eur. J. Nucl. Med. Mol. Imaging 42 S209)) which demonstrated a 2.5 mm reconstructed resolution in phantom scans. G-SPECT-I achieves data completeness in the scan region of interest by translating the patient bed with an xyz-stage and combining projections from all bed positions into image reconstruction using a scanning focus method (SFM). This paper aims to develop dedicated SFM parameters for performing a DaTscan with high effective sensitivity and appropriate sampling. To this end, the axial scanning length was restricted and transaxial bed trajectories with a reduced number of positions based on a convex hull data-completeness model were tested. Quantitative accuracy was assessed using full G-SPECT-I simulations of an Alderson phantom based on measured system matrices. For each sampling strategy, the specific binding ratio (SBR) and asymmetry index (AI) in the left and right striatum, as well as the Localized SBR (L-SBR) and the Localized AI (L-AI) in eight striatal sub-regions were calculated and compared to those of the reference scan which performs full brain oversampling using 112 bed positions. Results show that structures essential for PD diagnosis were visually and quantitatively barely affected even when using the lowest number of bed translations (i.e. 4). The maximum deviation from the reference was only 1.5%, 1.5%, 5.5% and 7.0% for the SBR, AI, L-SBR and L-AI, respectively, when 4 positions were used. Thus, it is possible to perform an accurate DaTscan with a confined axial scan region and a limited number of focused bed positions. This enables protocols for extremely fast dynamic SPECT scans with less than half-minute time frames, which can be useful for motion correction. PMID- 30403198 TI - Direct contacts of microglia on myelin sheath and Ranvier's node in the corpus callosum in rats. AB - Over the recent years, it has been found that microglia pseudopodia contact synapses, detect sick ones and prune them, even in adult animals. Myelinated nerves also carry out plasticity in which microglia remove myelin debris by phagocytosis. However, it remains unknown whether microglia explore structures on nerve fibers, such as Ranvier's node (RN) or myelin sheath, before they become debris. By double or triple staining RNs or myelin sheathes and microglia in healthy rat corpus callosum, this study unveiled direct contacts of microglia pseudopodia with RNs and with para- and inter-nodal myelin sheathes, which was then verified by electron microscopic observations. Our data indicated that microglia also explore unmyelinated nerve fibers. Furthermore, we used the animals with matured white matter; therefore, microglia may be actively involved in plasticity of matured white matter tracts as it does for synapse pruning, instead of only passively phagocytize myelin debris. PMID- 30403199 TI - Protective Effect of Anthocyanin on Paraquat-Induced Apoptosis and Epithelial Mesenchymal Transition in Alveolar Type II Cells. AB - BACKGROUND Paraquat (PQ) can over-accumulate in alveolar epithelial cells. Anthocyanin (An) can exert anti-oxidative properties. The role of An in PQ induced toxicity is unclear, so we aimed to explore whether An could inhibit epithelial mesenchymal transition (EMT) induced by PQ in alveolar cells. MATERIAL AND METHODS lveolar epithelial cells were treated with PQ and An with concentration gradient for 12, 24, and 48 h. The cell viability, ROS level, and apoptosis rate were determined using the Cell Counting Kit-8 (CCK-8) and flow cytometry, respectively. The lactate dehydrogenase (LDH) leakage, methane dicarboxylic aldehyde (MDA) level, glutathione peroxidase (GPx), and superoxide dismutase (SOD) activities were determined by spectrophotometric method. The mRNA and protein expressions were detected using quantitative real-time PCR (qPCR) and Western blot, respectively. RESULTS An reduced the PQ-induced apoptosis in a dose dependent manner. Moreover, An reduced the ratio of Bax/Bcl-2 to ROS level. We found that An suppressed the activity of LDH and MDA and improved SOD and GPX levels. Additionally, the level of PQ-induced E-cadherin was decreased by An while the expressions of vimentin, alpha-smooth muscle actin (alpha-SMA), and collagens type I (col-I) were increased. Furthermore, An inhibited the levels of transforming growth factor beta1 (TGF-beta1) and activin receptor-like kinase 5 (ALK5) and reduced the phosphorylation of smad2. CONCLUSIONS Our study shows newly discovered effects of anthocyanidins on EMT and supports their chemopreventive effects in paraquat-induced apoptosis in alveolar type II cells. PMID- 30403201 TI - Wolf predation on wild ungulates: how slope and habitat cover influence the localization of kill sites. AB - Based on data collected along the Ligurian Apennines and Alps (N-W Italy), we analysed the main environmental and human-related factors influencing the distribution of kill sites of the wolf Canis lupus. We mapped and digitized 62 kill sites collected during 2007-2016. Around each kill site, we defined a buffer corresponding to the potential hunting area of wolves. We compared kill site plots and an equal number of random plots. We formulated a model of kill site distribution following an approach presence versus availability by binary logistic regression analysis; we tested the hypothesis that wolf choice of kill sites is influenced by the physiography and the land use of the area. Among the preyed wild ungulates, we identified 23 roe deer Capreolus capreolus, 18 fallow deer Dama dama, 16 wild boars Sus scrofa, and 5 chamois Rupicapra rupicapra. Binary logistic regression analysis showed a negative effect of the road density, the urban areas, the mixed forests, and a positive effect of steep slopes and open habitats. Prey are more vulnerable to predators under certain conditions and predators are capable of selecting for these conditions. Wolves achieved this by selecting particular habitats in which to kill their prey: they preferred steep, open habitats far from human presence, where wild ungulates are more easily detectable and chasable. PMID- 30403200 TI - Erratum: Exposure to cuticular bacteria can alter host behavior in a funnel weaving spider. AB - [This corrects the article DOI: 10.1093/cz/zox064.][This corrects the article DOI: 10.1093/cz/zox064.]. PMID- 30403202 TI - Whole-cell circular dichroism difference spectroscopy reveals an in vivo-specific deca-heme conformation in bacterial surface cytochromes. AB - We established whole-cell circular dichroism difference spectroscopy to identify the inter-heme interaction in deca-heme cytochrome protein MtrC in whole cell. Our data showed that the heme alignment of reduced MtrC in whole cell is distinct from that in purified one, suggesting the in vivo specific electron transport kinetics. PMID- 30403203 TI - ZIF-8@polyoxometalate derived Si-doped ZnWO4@ZnO nanocapsules with open-shaped structures for efficient visible light photocatalysis. AB - In this work, we report silicon doped ZnWO4@ZnO nanocapsules with open-shaped structures obtained by a facile encapsulation-calcination strategy derived from ZIF-8 and polyoxometalates. Owing to the unique structure and elemental composition, the as-prepared samples respond well to visible light irradiation for degradating Rhodamine B. The possible photocatalytic reaction mechanisms are presented based on density functional theory (DFT) calculations. PMID- 30403204 TI - Advancements in fractal plasmonics: structures, optical properties, and applications. AB - The structural characteristics of plasmonic nanostructures directly influence their plasmonic properties, and therefore, their potential role in applications ranging from sensing and catalysis to light- and energy-harvesting. For a structure to be compatible with a selected application, it is critical to accurately tune the plasmonic properties over a specific spectral range. Fabricating structures that meet these stringent requirements remains a significant challenge as plasmon resonances are generally narrow with respect to the considered selected spectral range. Adapted from their well-established role in GHz applications, plasmonic fractal structures have emerged as architectures of interest due to their ability to support multiple tunable resonances over broad spectral domains. Here, we review the advancements that have been made in the growing field of fractal plasmonics. Iterative and space-filling geometries that can be prepared by advanced nanofabrication techniques, notably electron beam lithography, are presented along with the optical properties of such structures and metasurfaces. The distributions of electromagnetic enhancement for some of these fractals is shown, along with how the resonances can be mapped experimentally. This review also explores how fractal structures can be used for applications in solar cell and plasmon-based sensing applications. Finally, the future areas of physical and analytical science that could benefit from fractal plasmonics are discussed. PMID- 30403205 TI - Potential of ultramicroporous metal-organic frameworks in CO2 clean-up. AB - This article explains the need for energy-efficient large-scale CO2 capture and briefly mentions the requirements for optimal solid sorbents for this application. It illustrates the potential of ultra-microporous metal-organic frameworks (MOFs, pore size: <7.0 A) for the separation of CO2 from industrially abundant greenhouse gas mixtures. Some high-performing and well-studied MOFs are discussed to communicate the present status of the field. From their structural features, some successful design principles for creating such ultra-microporous MOFs are derived. Towards the close, favorable CO2 diffusion in many of these small pore MOFs is highlighted. PMID- 30403206 TI - Synergistic effect of bimetallic PdAu nanocrystals on oxidative alkyne homocoupling. AB - Bimetallic PdAu nanocrystals with different component ratios were obtained to investigate alkyne homocoupling. We found that the synergistic effect of Pd and Au plays an important role in the reaction. Alkynes with a variety of substituent groups could efficiently be converted into the corresponding 1,3-diynes through oxidative coupling. PMID- 30403207 TI - Towards a quantum cascade laser-based implant for the continuous monitoring of glucose. AB - Continuous glucose monitoring enables an improved disease management for people with diabetes. However, state-of-the-art, enzyme-based, minimally invasive sensors lose their sensitivity over time and have to be replaced periodically. Here, we present the in vitro investigation of a quantum cascade laser-based measurement scheme that conceptually should be applicable over elongated periods of time due to its reagent-free nature and may therefore be considered as an approach towards long-term implantation. The method uses a miniaturized optofluidic interface in transflection geometry to measure the characteristic mid infrared absorption properties of glucose. A glucose sensitivity of 3.2 mg dL-1 is achieved in aqueous glucose solutions. While this sensitivity drops to 12 mg dL-1 in the presence of biologically plausible, maximum concentrations of other monosaccharides, it is still well within the medically acceptable range according to Parkes error grid analysis. With a response time of less than five minutes, our sensor should be able to react adequately fast to physiological changes in glucose concentration. Finally, no drift or deterioration was found during an extended, 42 days in vitro experiment. These results underline the potential of this technique for its conceivable applicability in vivo as a long-term glucose monitoring implant. PMID- 30403208 TI - Development of a method for multiple vitamin D metabolite measurements by liquid chromatography coupled with tandem mass spectrometry in dried blood spots. AB - There are two forms of vitamin D which are essential to the human body, i.e. vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). The inactive metabolites of vitamin D are commonly used for quantitative analysis because of their longer half-life, stability, and relatively high blood concentrations. This paper presents the development of a high-throughput and sensitive method for determining four vitamin D metabolites in dried blood spots using liquid chromatography coupled with tandem mass spectrometry. This method allows for the determination of 25(OH)D2 and 25(OH)D3 concentrations, as well as the epimeric form 3-epi-25(OH)D3 and 24,25(OH)2D3. The analyzed material is capillary blood taken from the fingertip, deposited on filter paper. Four different chromatographic columns were tested to separate all compounds, in particular, the epimeric form. The column of choice was F5 (Phenomenex, Torrance, CA, USA). In order to prove the consistency between the results for DBS, used as an alternative biological matrix, and serum, comparative studies of these two materials were carried out in nearly 100 individuals. The results indicated their positive correlation. The evaluation of short-term stability of metabolites in DBS within the month showed no change in metabolite concentration. During the validation, the impact of the matrix on the ionization of the tested compounds was evaluated. Capillary blood and venous blood collected for different anticoagulants were also compared. The smallest differences in the results were obtained for citrate. In order to achieve a limit of quantitation of 0.2 ng ml-1, sample preparation involved derivatization using a Cookson-type reagent, 4-(4' dimethylaminophenyl)-1,2,4-triazoline-3,5-dione (DAPTAD). PMID- 30403209 TI - New insights of Raman spectroscopy for oral clinical applications. AB - Oral injuries are currently diagnosed by histopathological analysis of biopsy, which is an invasive procedure and does not give immediate results. On the other hand, the Raman spectroscopy technique is a real-time and minimally invasive analytical tool with a notable diagnostic capability. At the current stage, researchers are widely aware of the diagnostic potential of the technique and how it is considered promising for providing biochemical information in real time and without damaging the tissue. The problem originates from a lack of relevant studies and clinical trials that could show the actual use of Raman spectroscopy to help patients. Our goal here is to narrow the relationship between physicists, chemists, engineers, computer scientists, and the medical community, and in fact discuss the potential of Raman spectroscopy as a novel clinical analysis method. In the present study, we focused on the use of Raman spectroscopy as a daily clinical practice. In this context, additional studies and in vivo tests should be performed with the same approach as a real application. We want to show the scientific and industrial community what is really necessary for this, starting from a clinical point of view. Using our previous experience publishing different oral pathologies and types of samples, we also aim to discuss the current state and potential of Raman spectroscopy and what is required to implement Raman spectroscopy for oral clinical applications. PMID- 30403210 TI - Live single cell analysis using synchrotron FTIR microspectroscopy: development of a simple dynamic flow system for prolonged sample viability. AB - Synchrotron radiation Fourier transform infrared microspectroscopy (SR-microFTIR) of live biological cells has the potential to provide far greater biochemical and morphological detail than equivalent studies using dehydrated, chemically-fixed single cells. Attempts to measure live cells using microFTIR are complicated by the aqueous environment required and corresponding strong infrared absorbance by water. There is also the additional problem of the limited lifetime of the cells outside of their preferred culture environment. In this work, we outline simple, cost-effective modifications to a commercially available liquid sample holder to perform single live cell analysis under an IR microscope and demonstrate cell viability up to at least 24 hours. A study using this system in which live cells have been measured at increasing temperature has shown spectral changes in protein bands attributed to alpha-beta transition, consistent with other published work, and proves the ability to simultaneously induce and measure biochemical changes. An additional study of deuterated palmitic acid (D31-PA) uptake at different timepoints has made use of over 200 individual IR spectra collected over ~4 hours, taking advantage of the ability to maintain viable cell samples for longer periods of time in the measurement environment, and therefore acquire greatly increased numbers of spectra without compromising on spectral quality. Further developments of this system are planned to widen the range of possible experiments, and incorporate more complex studies, including drug-cell interaction. PMID- 30403212 TI - Acidic pH-responsive polymer nanoparticles as a TLR7/8 agonist delivery platform for cancer immunotherapy. AB - Synthetic imidazoquinoline-based toll-like receptor (TLR) 7/8 bi-specific agonists are promising vaccine adjuvants that can induce maturation of dendritic cells (DCs) and activate them to secrete pro-inflammatory cytokines. However, in vivo efficacy of these small molecule agonists is often hampered by their fast clearance from the injection site, limiting their use to topical treatments. In this study, we investigated the use of acidic pH-responsive poly(lactide-co glycolide) (PLGA) nanoparticles for endo-lysosome specific release of 522, a novel TLR7/8 agonist. Bicarbonate salt was incorporated into the new formulation to generate carbon dioxide (CO2) gas at acidic pH, which can disrupt the polymer shell to rapidly release the payload. Compared to conventional PLGA nanoparticles, the pH responsive formulation resulted in 33-fold higher loading of 522. The new formulation demonstrated acid-responsive CO2 gas generation and drug release. The acid-responsive formulation increased the in vitro expression of co-stimulatory molecules on DCs and improved antigen-presentation via MHC I, both of which are essential for CD8 T cell priming. In vivo studies showed that the pH-responsive formulation elicited stronger antigen-specific CD8 T cell and natural killer (NK) cell responses than conventional PLGA nanoparticles, resulting in enhanced anticancer efficacy in a murine melanoma tumor model. Our results suggest that acidic-pH responsive, gas-generating nanoparticles are an efficient TLR7/8 agonist delivery platform for cancer immunotherapy. PMID- 30403211 TI - Lab-simulated downhole leaching of formaldehyde from proppants by high performance liquid chromatography (HPLC), headspace gas chromatography-vacuum ultraviolet (HS-GC-VUV) spectroscopy, and headspace gas chromatography-mass spectrometry (HS-GC-MS). AB - The ability of different methods to analyze formaldehyde and other leachates from proppants was investigated under lab-simulated downhole conditions. These methods include high performance liquid chromatography (HPLC), headspace gas chromatography-vacuum ultraviolet spectroscopy (HS-GC-VUV), and headspace gas chromatography-mass spectrometry (HS-GC-MS). Two different types of resin-coated proppants, phenol-formaldehyde- and polyurethane-based, were examined. Each proppant was tested at different time intervals (1, 4, 15, 20, or 25 hours) to determine the timeframe for chemical dissolution. Analyses were performed at room temperature and heated (93 degrees C) to examine how temperature affected the concentration of leachates. Multiple matrices were examined to mimic conditions in subsurface environment including deionized water, a solution surrogate to mimic the ionic concentration of produced water, and recovered produced water. The complexity of these samples was further enhanced to simulate downhole conditions by the addition of shale core. The influence of matrix components on the analysis of formaldehyde was greatly correlated to the quantity of formaldehyde measured. Of the three techniques surveyed, HS-GC-MS was found to be better suited for the analysis of formaldehyde leachates in complex samples. It was found that phenol-formaldehyde resin coated proppants leached higher concentrations of formaldehyde than the polyurethane resin coated proppants. PMID- 30403213 TI - Improved photovoltaic performance of perovskite solar cells based on three dimensional rutile TiO2 nanodendrite array film. AB - In order to explore high performance and stable perovskite solar cells (PSCs), the design and optimization of electron transport layer (ETL) have been paid more and more attention. Vertically oriented, one-dimensional (1D) TiO2 nanostructured array films are considered superior ETLs because of their rapid electron transporting property and open pore architectures. In this study, a three dimensional (3D) rutile TiO2 nanodendrite array (RTNDA) film containing 1D trunks and branches was fabricated through second hydrothermal treatment of 1D rutile TiO2 nanorod array (RTNRA) film hydrothermally grown on a fluorine tin oxide (FTO) conductive glass. The resulting 3D-RTNDA film not only facilitates close contact with mixed-ion perovskite (Cs0.05(FA0.83MA0.17)0.95Pb(I0.9Br0.1)3) film, but also promotes the formation of a perovskite layer with larger crystal grain sizes. Both can efficiently retard the interface charge recombination, and thus result in a significantly improved power conversion efficiency (PCE) of 18.0%, improved by 20% as compared to that (15.0%) of the device fabricated with the 1D RTNRA film. Spectroscopic, electrochemical and photoelectrochemical measurements indicate that the improved photovolatic performance can be mainly ascribed to the largely suppressed hysteresis effect, the increased open-circuit voltage and fill factor stemming from the more effective hole blocking and electron transport. The results presented here demonstrate that 3D-RTNDA film with 3D rutile TiO2 hierarchical nanoarchitecture is a promising ETL selection in designing high performance PSCs. PMID- 30403214 TI - Optical properties of size selected neutral Ag clusters: electronic shell structures and the surface plasmon resonance. AB - We present optical absorption spectra from the ultraviolet to the visible for size selected neutral Agn clusters (n = 5-120) embedded in solid Ne. We compare the spectra to time-dependent density functional calculations (TDDFT) that address the influence of the Ne matrix. With increasing size, several highly correlated electron excitations gradually develop into a single surface plasmon. Its energy is situated between 3.9 and 4.1 eV and varies with size according to the spherical electronic shell model. The plasmon energy is highest for clusters with atom numbers fully filling states with the lowest radial quantum number (e.g. 1s, 1p, 1d,...). TDDFT calculations for clusters with several candidate geometrical structures embedded in Ne show excellent agreement with the experimental data, demonstrating that the absorption bands depend only weakly on the exact structure of the cluster. PMID- 30403215 TI - Correction: Liposomes loading sodium chloride as effective thermo-seeds for microwave ablation of hepatocellular carcinoma. AB - Correction for 'Liposomes loading sodium chloride as effective thermo-seeds for microwave ablation of hepatocellular carcinoma' by Jie Yu, Ping Liang et al., Nanoscale, 2017, 9, 11068-11076. PMID- 30403216 TI - 3D Ti3C2Tx aerogels with enhanced surface area for high performance supercapacitors. AB - Two-dimensional titanium carbide as a novel electrode material has been widely researched in the field of energy storage in recent years. However, the restacking of Ti3C2Tx nanosheets is still a challenge, which largely restricts their development. Here, we employ the 3D architecture of a Ti3C2Tx aerogel to restrict the restacking of 2D Ti3C2Tx nanosheets. This special structure can not only effectively reduce the restacking of 2D materials, but also accelerate the transport of electrolyte ions in the electrode. The as-prepared Ti3C2Tx aerogel possessed a large special surface area of 108 m2 g-1 and achieved a special capacitance of 349 F g-1 which is retained even at a high scan rate of 2000 mV s 1 in the 3 M H2SO4 electrolyte, indicating an ultrahigh rate capability. Moreover, at a higher current density of 20 A g-1, 90% of the initial capacitance is also retained after 20 000 charging-discharging cycles, revealing an excellent cycling stability. Furthermore, the mechanism of charge storage was investigated. PMID- 30403217 TI - Railing cells along 3D microelectrode tracks for continuous-flow dielectrophoretic sorting. AB - We demonstrate a unique microfluidic device for continuous-flow cell sorting by railing target cells along physical tracks (electrode sidewalls) based on the combined effect of dielectrophoresis and hydrodynamic drag. The tracks are the raised digits of comb-like structures made of conducting bulk silicon as the electrodes. Unlike other volumetric electrodes, the structures feature a segmented sidewall profile with linear and concave segments forming the tracks and supporting columns, respectively. The interdigitated bulk electrodes lead to a built-in flow chamber in which the digits (tracks) extend downstream at a characteristic angle with respect to the flow, which runs through the passages between the columns. Target cells leaving the passages are levitated and docked against the tracks under positive dielectrophoresis and railed under hydrodynamic drag. Railing efficiency, as high as >95%, is reported against the activation voltage and flow rate for the designs 7 degrees , 16 degrees , and 26 degrees as the track angles. A collection efficiency of about 86% is noted for both target (HCT116) and non-target cells (K562) in the 16 degrees design at a sample flow rate of 8.3 MUL min-1 and an activation voltage of 12.5 Vp at 200 kHz. This performance is comparable if not better than those obtained with thin-film surface microelectrodes and yet achieved here at an order of magnitude higher sample flow rate. This enhancement mainly arises from a considerably low drag along the tracks in relation to the chamber top or bottom surface where the thin film electrodes would be typically placed. PMID- 30403218 TI - Synthesis and mass spectrometric analysis of disaccharides from methanolysis of heparan sulfate. AB - The quantification of heparan sulfate (HS) in biological matrices, e.g., urine, cerebrospinal fluid, tissue samples etc., is of great importance for the diagnosis and prognosis of several of the mucopolysaccharidosis (MPS) disorders, which are lysosomal storage diseases of impaired glycosaminoglycan metabolism. The development of suitable assays for this purpose is challenging due to the high molecular weight and complexity of HS. Recent efforts towards this goal include the acid catalysed methanolysis of HS, which desulfates the polymer and results in the formation of disaccharide cleavage products which can be detected and quantified by LC-MS/MS. We have synthesized a library of 12 HS-derived disaccharides as methanolysis standards via the stereoselective 1,2-cis glycosylation of suitably protected GlcA and IdoA acceptors with a 2-deoxy-2 azido thioglucoside donor. This facilitated identification of the major peaks in the LC-MS/MS chromatograms, and potentially will allow the monitoring of specific metabolites as surrogate markers for genotype. This work also paves the way towards a fully quantitative LC-MS/MS assay for HS via the preparation of a suitably labelled derivative. PMID- 30403220 TI - Preventive mechanism of bioactive dietary foods on obesity-related inflammation and diseases. AB - Obesity is associated with low-grade chronic inflammation of adipose tissue, which leads to the development of metabolic disorders such as insulin resistance, type 2 diabetes, cardiovascular disease (CVD), and cancer. Obesity and a high calorie diet are associated with altered endocrine and metabolic functions of adipose tissue, contributing to systemic inflammation as a result of the release of pro-inflammatory cytokines/adipokines into the circulation and metabolic endotoxemia. Furthermore, the accumulation of proinflammatory macrophages within the visceral adipose tissue may also be a major cause of chronic inflammation of adipocytes. Thus, it is important to understand the factors that regulate the function of both adipocytes and macrophages to find attractive strategies against the burden of obesity-induced health problems. Although the vast range of activities of dietary bioactive compounds on obesity and inflammation have been widely investigated, the mechanisms underlying their beneficial effects on obesity-associated inflammatory response are still poorly understood. This review focuses on the molecular biology mechanism of obesity-induced inflammation and the reciprocal interactions between the major molecular mechanisms and a range of dietary bioactive compounds. PMID- 30403219 TI - Effect of Grifola frondosa 95% ethanol extract on lipid metabolism and gut microbiota composition in high-fat diet-fed rats. AB - This study aimed to investigate the effects of 95% ethanol extract of G. frondosa (GF95) on lipid metabolism and gut microbiota composition in high-fat diet (HFD) fed rats. UPLC/Q-TOF MS indicated that GF95 was enriched with flavones, fatty acids and so on. Meanwhile, we found that body weight, serum lipid or liver index (total cholesterol, triglyceride, and low density lipoprotein cholesterol) levels were significantly decreased in GF95-treated HFD-fed rats. Furthermore, GF95 treatment regulated mRNA expression levels involved in lipid metabolism. GF95 consumption significantly enhanced the excretion of bile acids in the cecum. Besides, in this study, a higher abundance of Butyricimonas genus was revealed in the GF95 group, which is highly related to the highest production of short-chain fatty acids in the caecum contents among the experimental groups. Interestingly, results from network analysis showed that Butyricimonas were negatively correlated with serum and liver lipid profiles. PMID- 30403221 TI - Identification of four single-stranded DNA homopolymers with a solid-state nanopore in alkaline CsCl solution. AB - DNA sequencing via solid-state nanopores is a promising technique with the potential to surpass the performance of conventional sequencers. However, the identification of all four nucleotide homopolymers with a typical SiN nanopore is yet to be clearly demonstrated because a guanine homopolymer rapidly forms a G quadruplex in a typical KCl aqueous solution. To address this issue, we introduced an alkaline CsCl aqueous solution, which denatures the G-quadruplex into a single-stranded structure by disrupting the hydrogen-bonding network between the guanines and preventing the binding of the K+ ion to G-quartets. Using this alkaline CsCl solution, we provided a proof-of-principle that single stranded DNA homopolymers of all four nucleotides could be statistically identified according to their blockade currents with the same single nanopore. We also confirmed that a triblock DNA copolymer of three nucleotides exhibited a trimodal Gaussian distribution whose peaks correspond to those of the DNA homopolymers. Our findings contribute to the development of practical DNA sequencing with a solid-state nanopore. PMID- 30403222 TI - Selective alkyl ether cleavage by cationic bis(phosphine)iridium complexes. AB - Catalysts capable of heterolytic silane activation have been successfully applied to the conversion of alkyl ethers to silyl ethers via C-O bond cleavage. The previously-reported cationic pincer-supported iridium complex for this transformation suffers from poor selectivity with regard to monodealkylation of substrate ethers. We demonstrate that a simple non-pincer iridium complex offers improved selectivity and is capable of benzylic ether cleavage in the presence of reductively-labile alkyl and aryl halide functionality. Preliminary mechanistic experiments suggest a neutral tetrahydridosilyliridium resting state which is consistent with previous mechanistic hypotheses. These experiments suggest that a pincer ligand framework is not required for activity in ether cleavage reactions and that simple cationic bis(phosphine)iridium complexes may offer improved selectivity profiles for applications to more-complex substrate molecules. PMID- 30403223 TI - Donor- and acceptor-enynals/enynones. AB - Enynals and enynones have emerged as focal substrates in organic synthesis in view of their structure diversity, high reactivity and intermediate variety. Transition metal- or Lewis acid-promoted protocols starting from enynals/enynones could provide efficient and direct access to functionalized homo- or heterocyclic compounds. In consideration of the different electronic properties of substituents on the alkyne group of enynals/enynones, they are classified into two kinds in this review, namely donor-enynals/enynones with non-electron withdrawing substituents and acceptor-enynals/enynones with electron-withdrawing moieties. Herein we mainly introduced three kinds of transformations based on benzo-fused donor- and acceptor-enynals/enynones, including their reactions with alkenes, alkynes, and H2O, respectively. PMID- 30403224 TI - Nickel-catalyzed regioselective arylation of aromatic amides with aryl iodides enabled by an N,O-bidentate directing group. AB - A bidentate directing group enabled regioselective arylation of C(sp2)-H bonds in aromatic carboxamides with aryl iodides under nickel-catalysis is reported, which provides the corresponding products in moderate to good yields. This protocol using the inexpensive and low-toxic Ni catalyst can tolerate a wide range of functional groups. PMID- 30403225 TI - A synthetic study toward the core structure of (-)-apicularen A. AB - A concise synthetic strategy towards the core structure of (-)-apicularen A has been described in an 11-step synthetic sequence from a known intermediate. The key steps include tandem isomerization followed by C-O and C-C bond-forming reactions and iodocyclization strategies for the synthesis of a bicyclic ether embedded in the macrolactone ring. The applied reagent-controlled Keck-Maruoka allylation, Lin Pu alkynylation and Ricket-Diels-Alder reactions were used to simplify the synthetic sequence of related natural products. An intramolecular Yamaguchi lactonization constructed the macrolactone core, while the attempt to install the C11 hydroxyl chiral centre either under catalytic hydrogenation conditions or oxidative conditions was not successful. PMID- 30403226 TI - Isolation and characterization of a high-spin mixed-valent iron dinitrogen complex. AB - We report a rare example of a mixed-valence iron compound with an FeNNFe core, which gives insight into the structural, spectroscopic, and magnetic influences of single-electron reductions and oxidations. In the new compound, the odd electron is localized as judged from Mossbauer spectra at 80 K and infrared spectra at room temperature, and the backbonding into the N2 unit is intermediate between diiron(i) and diiron(0) congeners. Magnetic susceptibility and relaxation studies on the series of FeNNFe compounds show significant magnetic anisotropy, but through-barrier pathways enable fairly rapid magnetic relaxation. PMID- 30403227 TI - Metal-assisted selective recognition of biothiols by a synthetic receptor array. AB - A synergistic combination of a deep cavitand host, fluorophore guests and transition metal ions can be used to sense small molecule thiols of biological interest with good efficiency and selectivity in complex aqueous media. PMID- 30403228 TI - An electro-elastic theory for the mechanically-assisted photo-induced spin transition in core-shell spin-crossover nanoparticles. AB - The development of heterostructure materials may lead to new features that cannot be obtained with natural materials. Here we simulate a model structurally hybrid core-shell nanoparticle with different lattice parameters between an electronically inert shell and an active spin crossover core. The nanoparticle consists of a 2D core with 20 * 20 size with square symmetry, surrounded by a shell made of 10 atomic layers. The low temperature photoexcitation of the core shows a significant environment-dependent behavior. In particular, we demonstrate that a shell with a large lattice parameter accelerates the low-spin to high-spin photoexcitation process of the core through the single domain nucleation mechanism while a moderate shell lattice parameter leads to spatially-homogeneous growth of the high-spin fraction. We found that the mechanical retro-action of the shell may cause elastic instability of the core leading to efficient control and manipulation of its photo-conversion. PMID- 30403229 TI - A comparative study of NiCo2O4 catalyst supported on Ni foam and from solution residuals fabricated by a hydrothermal approach for electrochemical oxygen evolution reaction. AB - Residuals have rarely been granted attention when employing a hydrothermal approach to prepare binder-free supported catalysts. Using Ni foam supported NiCo2O4 catalyst for oxygen evolution reaction as an example, it was found that the catalytic activity of NiCo2O4 from the residuals loaded on glass carbon is comparable to Ni foam supported NiCo2O4, while the specific activity and turnover frequency value of the former catalyst are many times higher than that of the supported catalyst. In view of sustainability and green development, residuals should be given more attention when catalyst is prepared using the hydrothermal fabrication approach. PMID- 30403230 TI - Pyridinium lead tribromide and pyridinium lead triiodide: quasi-one-dimensional perovskites with an optically active aromatic pi-system. AB - Two novel hybrid organic-inorganic perovskites, pyridinium lead tribromide and pyridinium lead triiodide, are prepared. Based on the XRD data, we find that the compounds are quasi-one-dimensional crystals of Pna21 symmetry. DFT calculations demonstrate that the valence band of the new compounds is comprised of the occupied p-orbitals of the halogen anions, while their conduction bands CB and CB + 1 are composed mainly of the unoccupied pi-orbitals of the aromatic pyridinium rings. The computed DOS matches well with the recorded XPS spectra. The pyridinium lead tribromide and pyridinium lead triiodide absorption peaks derived from the experimental DRS are located at ~3.1 eV and ~2.4 eV, respectively. An agreement between the experimentally and theoretically predicted absorption spectra is found. The synthesized compounds extend the range of quasi-one dimensional organometallic perovskites suitable for optical and possibly electronic applications. PMID- 30403231 TI - Mechanochemical carbon-carbon bond formation that proceeds via a cocrystal intermediate. AB - We report the first cocrystal as an intermediate in a solid-state organic reaction wherein molecules of barbituric acid and vanillin assume a favorable orientation for the subsequent Knoevenagel condensation. PMID- 30403232 TI - Nitrosonium ion catalysis: aerobic, metal-free cross-dehydrogenative carbon heteroatom bond formation. AB - Catalytic cross-dehydrogenative coupling of heteroarenes with thiophenols and phenothiazines has been developed under mild and environmentally benign reaction conditions. For the first time, NOx+ was applied for catalytic C-S and C-N bond formation. A comprehensive scope for the C-H/S-H and C-H/N-H cross dehydrogenative coupling was demonstrated with >60 examples. The sustainable cross-coupling conditions utilize ambient oxygen as the terminal oxidant, while water is the sole by-product. PMID- 30403233 TI - Reactivity of rhodium and iridium peroxido complexes towards hydrogen in the presence of B(C6F5)3 or [H(OEt2)2][B{3,5-(CF3)2C6H3}4]. AB - The peroxido complexes trans-[M(4-C5F4N)(O2)(CNtBu)(PR3)2] (1: M = Rh, R = Et; 2a: M = Ir, R = iPr) can be used in the metal-mediated hydrogenation of O2. The reaction of trans-[Rh(4-C5F4N)(O2)(CNtBu)(PEt3)2] (1) with B(C6F5)3 and H2 gave trans-[Rh(4-C5F4N)(CNtBu)(PEt3)2] (3), OPEt3 and (H2O).B(C6F5)3, whereas treatment of [H(OEt2)2][B{3,5-(CF3)2C6H3}4] with 1 in the presence of H2 yielded trans-[Rh(4-C5F4N)(CNtBu)(PEt3)2] (3) and H2O2. The reactivity of 2a towards B(C6F5)3 and BClCy2 was also studied and an intermediate was detected which is assigned to be trans-[Ir(4-C5F4N)(Cl)(OOBCy2)(CNtBu)(PiPr3)2] (4a). PMID- 30403234 TI - 3D hierarchical Co3O4@Co3S4 nanoarrays as anode and cathode materials for oxygen evolution reaction and hydrogen evolution reaction. AB - With the increasing energy demand and environmental pollution, hydrogen production by water splitting is one of the best ways to solve the energy shortage. Three-dimensional (3D) hierarchical Co3O4@Co3S4/NF was first synthesized directly in situ, grown on the nickel foam through a simple hydrothermal process, and the anion-exchange reaction and the Ostwald ripening mechanism were investigated by adjusting the reaction time. The oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) activities of Co3O4@Co3S4/NF 24 h were investigated, and the required overpotentials were 270 mV and 143 mV, when the current density was 100 mA cm-2 and 20 mA cm-2, respectively. Subsequently, the overall water splitting activity of Co3O4@Co3S4/NF-24 h was investigated; when the current density was 10 mA cm-2, the low cell voltage was 1.53 V, which, to our knowledge, was among the smallest values reported for electro-driven water splitting so far. This high catalytic activity is attributed to the construction of the O-S interface and the increased electron transfer rate at the beginning of the reaction. Through XRD, SEM and XPS characterization, it is proven that Co3O4@Co3S4/NF-24 h is relatively stable and is expected to be an efficient and stable water splitting catalyst. PMID- 30403235 TI - Mn(ii)-catalysed alkylation of methylene ketones with alcohols: direct access to functionalised branched products. AB - Herein an operationally simple alkylation of methylene ketones with primary alcohols is reported. Use of an inexpensive and earth abundant Mn/1,10 phenanthroline system enables direct access to a series of functionalised branched ketones including one-pot sequential double alkylation and Alzheimer's drug donepezil. Preliminary mechanistic investigation, determination of the rate and order of reactions and deuterium labeling experiments support the participation of the hydrogen-borrowing strategy for the ketone alkylation. PMID- 30403237 TI - Multifunctional Zn-Al layered double hydroxides for surface-enhanced Raman scattering and surface-enhanced infrared absorption. AB - Surface-enhanced Raman scattering (SERS) and surface-enhanced infrared absorption (SEIRA) are complementary techniques, and both provide fingerprint structural information on various materials with a high sensitivity. Herein, Zn-Al layered double hydroxides (LDHs) are proposed for the first time as highly sensitive and uniform substrates for both SERS and SEIRA. Zn-Al LDHs show a remarkable SERS effect with an enhancement factor (EF) as high as 1.637 * 104 by using 4 mercaptobenzoic acid (4-MBA) as the probe molecule, where the charge transfer and hydrogen bonds are believed to result in the SERS effect. Interestingly, Zn-Al LDHs also exhibit SEIRA by using 4-methoxybenzenethiol (4-MTP), where the resultant substrates possess excellent long-term stability. This study not only presents a facile route to fabricate LDH materials, but also provides a novel substrate that can be used in both SERS and SEIRA. PMID- 30403236 TI - Element selective oxidation on Rh-Pd bimetallic alloy surfaces. AB - The interactions between oxygen and Rh-Pd bimetallic alloy surfaces were investigated using surface sensitive experimental techniques and density functional theory calculations. The alloy surfaces were oxidized under 10-5 Torr and 100 mTorr oxygen upon heating above 250 degrees C. A thin Rh oxide layer was preferentially formed on a Rh1Pd9(100) surface, while a thin Pd oxide layer was formed on a Rh1Pd9(111) surface, though the Rh oxide is thermodynamically more stable irrespective of the surface orientation. Chemical analyses revealed that the initial Rh fraction for the (111) surface was significantly lower than that for the (100) surface, which suggests that the oxidized element on the surface is kinetically selected depending on the near surface initial composition. PMID- 30403238 TI - Manipulating triplet states: tuning energies, absorption, lifetimes, and annihilation rates in anthanthrene derivatives. AB - The photophysical properties of anthanthrene, four anthanthrene derivatives containing varying phenyl and p-tBu-phenyl substituents, and two anthanthrones with phenyl and p-tBu-phenyl substituents are examined. In general, as the anthanthrenes and anthanthrones become more substituted, red-shifts are observed in the peak maxima of the ground- and excited-state absorption and fluorescence spectra. The anthanthrones have large (>0.8) intersystem crossing (ISC) quantum yields (PhiT) likely caused by npi* character in the ground or excited states. A bromo-substituted anthanthrene has a unity ISC yield due to an ISC rate constant of 2.5 * 1010 s-1 caused by heavy-atom induced, spin-orbit coupling. This leads to low fluorescence quantum yields (PhiF) in these three derivatives. The parent anthanthrene and remaining derivatives behave much differently. All have PhiF values from 0.58-0.84 with lower PhiT values as radiative decay outcompetes ISC. The anthanthrones have remarkable excited-state absorption with strong, broad transitions across the visible region with weaker transitions extending to nearly two MUm. The anthanthrenes have very similar-shaped, broad transitions in the visible which can be shifted ~60 nm by controlling the substituents. The triplet lifetimes range from 31-1200 MUs and increase as the ISC yields decrease; the bromo-substituted anthanthrene is the shortest, followed by the anthanthrones then the other anthanthrenes. The rate of triplet-triplet annihilation is also affected by the presence of substituents; as the amount of steric bulk is increased, the rate of annihilation decreases. PMID- 30403239 TI - Interfacially synthesized Fe-soc-MOF nanoparticles combined with ICG for photothermal/photodynamic therapy. AB - Recently, fabrication of nanoscale MOFs (NMOFs) has attracted great attention for biomedical applications. NMOFs not only maintain the structural diversity and physicochemical properties of bulk MOFs, but also possess suitable dimensions, making them potential nanocarriers for imaging agents and drug molecules. In this work, highly monodispersed Fe-soc-MOF nanoparticles (about 100 nm) were fabricated through the liquid-solid-solution (LSS) method. Indocyanine green (ICG) was conjugated to the surface-modified Fe-soc-MOF to construct a multifunctional theranostic platform. The Fe-soc-MOF@PEG-NH2-ICG nanoparticles (FPINs) were tested for photothermal therapy (PTT)/photodynamic therapy (PDT) both in vitro and in vivo. Due to their low toxicity, good biocompatibility and excellent photothermal/photodynamic effect, the as-synthesized FPINs could be used to inhibit and kill cancer cells efficiently under the 808 nm laser irradiation. PMID- 30403240 TI - NiCo2O4/NiCoP nanoflake-nanowire arrays: a homogeneous hetero-structure for high performance asymmetric hybrid supercapacitors. AB - Transition metal phosphides (TMPs) represent an important class of compounds with metalloid characteristics and good electrical conductivity, which are of great benefit to enhance electrochemical performances. Thus it is important to clarify the correlation between the electrochemical properties and the phosphating degree of the precursor. Herein, we report a superior electrode for battery-like capacitors based on NiCo2O4/NiCoP hetero-structure nanoflake-nanowire arrays grown on nickel foams using a one-pot facile hydrothermal approach and a controllable phosphorization treatment method. The Ni-Co precursor nanoflake nanowire array based electrode treated with 500 mg NaH2PO2 shows significantly improved electrochemical performances with an ultrahigh specific capacitance of 2288.8 F g-1 and 1644 F g-1 at a current density of 1 A g-1 and 20 A g-1, respectively. The electrode also shows superior cycling stability. In addition, the NiCo2O4/NiCoP//AC device exhibits a relatively high energy density of 35.5 W h kg-1 at 750.4 W kg-1. The results suggest that this NiCo2O4/NiCoP nanoflake nanowire array is a promising electrode material for high performance hybrid supercapacitor applications. PMID- 30403241 TI - Experimental and theoretical study of dimer-of-dimers-type tetrarhodium(ii) complexes bridged by 1,4-benzenedicarboxylate linkers. AB - Two dimer-of-dimers-type tetrarhodium complexes, [Rh4(piv)6(BDC)] ([1]; piv = pivalate) and [Rh4(piv)6(F4BDC)] ([2]), in which two paddlewheel-type dirhodium units are linked by 1,4-benzenedicarboxylate (BDC) and 1,4 tetrafluorobenzenedicarboxylate (F4BDC), respectively, have been synthesized and characterized via single-crystal X-ray diffraction analyses, ESI-MS, 1H NMR, infrared spectroscopy, Raman spectroscopy, and elemental analyses. Crystal structure analyses of [1(THF)4] and [2(THF)4], which are crystallized from THF solutions of [1] and [2], respectively, revealed that dihedral angles (phi) between two -CO2 units and phenyl rings of the BDC linker in [1(THF)4] are almost co-planar (phi = 2.8 degrees ), whereas those of the F4BDC linker in [2(THF)4] are largely inclined (phi = 78.3 degrees ). Density functional theory calculations clarified that (i) their dihedral angles of optimized geometries of [1(THF)4] and [2(THF)4] are almost the same as their experimental geometries, and (ii) the rotation energy barriers of phenyl moieties in [1(THF)4] and [2(THF)4] estimated by potential energy surface analyses are 12.0 and 8.4 kcal mol-1, respectively, indicating that hydrogen bondings are formed between two -CO2 units and four hydrogen atoms of phenyl rings of the BDC linker in [1(THF)4], whereas two -CO2 units and four fluorine groups on the phenyl ring of the F4BDC linker in [2(THF)4] are electrostatically and sterically repulsed. Electrochemical properties and electronic structures of [1(THF)4] and [2(THF)4] are strongly influenced by the electronic states of dicarboxylate linkers, whereas absorption spectra are strongly influenced by the dihedral angles between two -CO2 units and phenyl rings of dicarboxylate linkers. PMID- 30403242 TI - Tetraphenylethylene-based glycoclusters with aggregation-induced emission (AIE) properties as high-affinity ligands of bacterial lectins. AB - Tetraphenylethylene (TPE) is fluorescent through aggregation induced emission (AIE) in water. Herein, TPE was used as the core of glycoclusters that target the bacterial lectins LecA and LecB of Pseudomonas aeruginosa. Synthesis of these TPE based glycoclusters was accomplished by using azide-alkyne "click" chemistry. The AIE properties of the resulting glycoclusters could be readily verified, but imaging could not be pursued due to the overlap of the fluorescence signals from cells and bacteria. Nonetheless, the glycoclusters displayed nanomolar affinities toward LecA and LecB. Further evaluation in a cell-based anti-adhesive assay highlighted a limited decrease in adhesion (20%) for the fucosylated glycocluster. This confirmed that these TPE-based glycoclusters are indeed LecA and LecB high-affinity ligands. Nevertheless, the hypotheses involving their application in imaging or anti-adhesive therapy could not be verified. PMID- 30403243 TI - Potent anti-proliferative activities of organochalcogenocyanates towards breast cancer. AB - The pharmacological importance, particularly the anti-cancer and chemopreventive potentials, of organochalcogen compounds has attracted wide research attention recently. Herein we describe the synthesis of a series of organochalcogenocyanates that have one or more selenocyanate or thiocyanate units in a single molecule. The anti-proliferative activity of these organochalcogenocyanates in different breast cancer cells shows that selenocyanates exhibit much higher anti-proliferative activities than thiocyanates in general. Our study reveals that the activity of benzyl selenocyanate (1, BSC) could be significantly enhanced by 4-nitro substitution (12), which was more selective towards triple-negative breast cancer cells (MDA MB-231) over other ER+ breast cancer cells (MCF-7 and T-47D). Furthermore, to the best of our knowledge, this is the first report on the synthesis of compounds having more than two selenocyanate units with promising anti-proliferative activities. Our studies further indicate that the apoptotic activities of selenocyanates are associated with modulation of cellular morphology and cell cycle arrest at S-phase. Selenocyanates also inhibited cellular migration and exhibited weak antioxidant activities. An effective binding interaction of compound 12 with serum albumin indicates its feasible transport in the bloodstream for its enhanced anti-cancer properties. Mechanistic studies by western blot analysis demonstrate that benzylic selenocyanates exhibit anti proliferative activities by modulating key cellular proteins such as Survivin, Bcl-2 and COX-2; this was further supported by molecular docking studies. The results of this study would be helpful in designing suitable chemotherapeutic and chemopreventive drugs in the future. PMID- 30403244 TI - Studying polymer solutions with particle-based models linked to classical density functionals: co-non-solvency. AB - We demonstrate the potential of hybrid particle-based models, where interactions are introduced through functionals of local order parameters, in describing multicomponent polymer solutions. The link to a free-energy-like functional is advantageous for controlling the thermodynamics of the model. We focus on co-non solvency - the collapse of polymer chains in dilute mixtures with two miscible good solvents, having different affinities towards the polymer. We employ a simple model where polymers and solvents are represented, respectively, by worm like chains and single particles. Non-bonded interactions are captured by a polynomial which is third order in local densities and can, therefore, describe liquid-vapour coexistence. The parameterisation of the functional benefits from an elementary mean-field approximation to the statistical mechanics of the model. The model provides a framework for Monte Carlo simulations using a particle-to mesh algorithm. Studies with conventional generic bead-spring and all-atom models have demonstrated that co-non-solvency is caused by preferential binding of the better solvent (termed cosolvent) with polymer. Hence, segmental loops bridged by cosolvent molecules are formed, initiating polymer collapse. The mesoscopic hybrid model differs conceptually from the conventional microscopic descriptions. Yet, it reproduces the same co-non-solvency mechanism supporting its universality. Films of adsorbed ternary solutions, showing co-non-solvency in the dilute regime, are considered at high concentrations. In this case, chains do not collapse. The properties of loops and tails of the adsorbed polymer agree with early theoretical predictions obtained for concentrated binary solutions. PMID- 30403245 TI - Trisubstituted alkenes with a single activator as dipolarophiles in a highly diastereo- and enantioselective [3+2] cycloaddition with vinyl epoxides under Pd catalysis. AB - 1,1,2-Trisubstituted alkenes with a single strongly electronic withdrawing activator, which are unreactive electron-deficient alkenes in transition metal catalyzed [3+2] cycloaddition with vinyl three-membered heterocycles, were used in the Pd-catalyzed asymmetric cycloaddition of vinyl epoxides, affording multifunctionalized tetrahydrofurans in high yields with high diastereo- and enantioselectivities. PMID- 30403246 TI - Hybrid functional calculations of electronic and thermoelectric properties of GaS, GaSe, and GaTe monolayers. AB - Motivated by the recent success in the experimental synthesis of two-dimensional group-III monochalcogenides, we investigate the structural, electronic and thermoelectric properties of GaS, GaSe and GaTe monolayers based on the first principles approach by using density functional theory and the semi-classical Boltzmann transport equation. The electronic band structures demonstrate that the GaS, GaSe, and GaTe monolayers are wide bandgap semiconductors having an indirect bandgap of 3.73 eV, 3.27 eV, and 2.46 eV respectively. We have evaluated the thermoelectric properties comprising the Seebeck coefficient, electrical conductivity per relaxation time, electronic thermal conductivity per relaxation time, electronic specific heat, thermoelectric figure of merit and power factor at various temperatures from 50 K to 800 K. It is found that GaS, GaSe and GaTe monolayers could be suitable candidates for low temperature efficient thermoelectric materials because of the high value of the thermoelectric figure of merit below room temperature. PMID- 30403247 TI - Size effects in plasma-enhanced nano-transfer adhesion. AB - Plasma bonding and layer-by-layer transfer molding have co-existed for decades, and here we offer a combination of the two that drives both techniques to the nanoscale. Using fluorinated elastomeric stamps, lines of plasma-treated poly(dimethylsiloxane) (PDMS) were stacked into multi-layer woodpile structures via transfer molding, and we observe a pronounced size effect wherein nanoscale lines (<=280 nm period) require ultra-low plasma dose (<20 J) and fail to bond at the much higher range of plasma dose (600 J to 900 J) recommended in the PDMS plasma bonding literature. The size effect appears to be related to the thickness of the oxide film that develops on the PDMS surface during treatment, and we employ an empirical relationship, , to estimate the thickness of this film in the low plasma dose (<100 J) regime. The empirical relationship shows good agreement with existing studies on plasma-treated PDMS oxide film thickness, and the transition between successful transfer and delamination coincides well with a critical value of the oxide thickness relative to the thickness of the transferred layer. Through peel testing, we identified a transition in failure mode of flat plasma-bonded PDMS consistent with the optimal plasma dose in previous literature but otherwise observed strong, irreversible adhesion even at ultra-low plasma dose. By demonstrating the importance of low plasma dose for plasma-enhanced nano-transfer adhesion, these results advance our understanding of irreversible adhesion of soft materials at the nanoscale and open up new opportunities within the relatively unstudied ultra-low dose plasma treatment regime. PMID- 30403248 TI - Restricting shuttling in bis(imidazolium)...pillar[5]arene rotaxanes using metal coordination. AB - Metal coordination to a series of bis (imidazolium)...pillar[5]arene [2]rotaxanes through the formation of metal-carbene bonds facilitates a new strategy to restrict the shuttling motion in [2]rotaxanes. Whereas the pillar[5]arene macrocycle rapidly shuttles along the full length of the bis (imidazolium) rod for the parent [2]rotaxane, Ag(i) coordination to the imidazolium groups through the formation of N-heterocyclic carbenes leads to restricted motion, effectively confining the shuttling motion of the [2]rotaxane. The Ag(i) coordinated [2]rotaxanes can be reacted further, either removing the Ag-carbene species to recreate the parent [2]rotaxane, or reaction with more bulky Pd(ii) species to further restrict the shuttling motion through steric inhibition. PMID- 30403250 TI - Cage dynamics leads to double relaxation of the intermediate scattering function in a binary colloidal system. AB - A system of binary colloids where one fraction of particles is aggregating by forming irreversible bonds and the other fraction of particles only interacts as hard spheres, is simulated using Brownian cluster dynamics. These aggregating species always formed percolating clusters for the case of diffusing hard spheres while for the static case, formation of percolating clusters depended on the fraction of static hard spheres in the system. The dynamics of the hard spheres inside the percolating clusters was studied by restarting the simulation after the kinetics of aggregation was arrested. Two cases were studied, one where the percolated particles moved within the bonds or cage dynamics was allowed and another where the movement within the bonds was not allowed or the cages were static. The hard spheres showed anomalous diffusion in both cases. The mean square displacement showed that for the case of dynamic cages we always had diffusive hard spheres irrespective of the fraction of hard spheres for volume fractions below 0.49. Static cages, depending on the fraction of hard spheres, showed either diffusive or arrested behavior of hard spheres. The intermediate scattering function of only the hard sphere particles showed double relaxation similar to the colloidal glass system for low volume fraction, where the fraction of hard sphere particles was small. For higher fractions we observed only a single stretched exponential. We could differentiate between slow and fast particles for both static and dynamic cages. For the case of static cages the hard spheres were permanently stuck inside the cages while for the case of dynamic cages almost all the hard spheres were moving in and out of the cages. PMID- 30403254 TI - Synthesis and potassium KV7 channel opening activity of thioether analogues of the analgesic flupirtine. AB - Flupirtine, an opener of neuronal voltage gated potassium channels (KV7.2/3), has been used as a therapeutic alternative for pain treatment in patients refractory to NSAIDs and opioids. Because flupirtine is associated with rare but fatal drug induced liver injury that may result from the formation of toxic metabolites upon metabolic oxidation, we synthesized novel derivatives with the goal of identifying equally active and ultimately safer KV7.2/3 channel openers. Four thioether analogues were designed to lack a nitrogen atom that would be a prerequisite for the formation of toxic para-quinone diimines, and form sulfoxide and sulfone metabolites instead. KV7.2/3 channel opening activity and hepatotoxicity data of twelve novel flupirtine analogues, four thioethers and their respective sulfoxide and sulfone metabolites are reported. PMID- 30403253 TI - Tuneable shape-memory properties of composites based on nanoparticulated plant biomass, lignin, and poly(ethylene carbonate). AB - In this article, we propose a thermally responsive shape-memory polymer (SMP) consisting of poly(ethylene carbonate) and non-deteriorated lignin nanoparticles. This SMP was obtained readily by thermal kneading and melt molding without requiring any chemical reaction. The shape-recovering properties of the SMP can be tuned by changing the feed ratio of the components. The estimation of viscoelastic, thermal and mechanical properties of the SMP reveals that the stepwise structural transitions in the SMP rendered a dynamic shape-recovering behavior. PMID- 30403255 TI - Polymer margination in uniform shear flows. AB - We address the issue of polymer margination (migration towards surfaces) in uniform shear flows through extensive LBMD (lattice-Boltzmann molecular dynamics) simulations. In particular we consider the effect of monomer size, a on the chain's overall margination tendency for chains of length N = 16, 32 monomers in flows at multiple shear rates [small gamma, Greek, dot above]. We observed higher margination of chains with larger radii monomers in comparison to smaller radii monomer chains of the same length N. We quantify this effect by considering various measures such as the distribution of the maximum extent of the chain into the channel bulk, zm, distribution of its center of mass in the direction normal to the surface, zc and the distributions of the chain's radius of gyration in directions parallel and perpendicular to the surface i.e. Rx, Ry and Rz respectively. PMID- 30403257 TI - Aerobic oxidation of 5-hydroxymethylfurfural to 5-hydroxymethyl-2-furancarboxylic acid and its derivatives by heterogeneous NHC-catalysis. AB - The application of the oxidative system composed of a heterogeneous triazolium pre-catalyst, iron(ii) phthalocyanine and air is described for the selective conversion of 5-hydroxymethylfurfural (HMF) into the added-value 5-hydroxymethyl 2-furancarboxylic acid (HMFCA). The disclosed one-pot two-step procedure involved sequential oxidative esterifications of HMF to afford a polyester oligomer having hydroxyl and carboxyl terminal groups (Mw = 389-1258), which in turn was hydrolyzed by a supported base (Ambersep 900 OH) to yield HMFCA in 87% overall yield. The same strategy was adopted for the effective synthesis of ester and amide derivatives of HMFCA by nucleophilic depolymerization of the oligomeric intermediate with methanol and butylamine, respectively. The utilization of the disclosed oxidative system for the direct conversion of HMF and furfural into their corresponding ester, amide, and thioester derivatives is also reported. PMID- 30403258 TI - Novel flavin-based fluorescent proteins with red-shifted emission bands: a computational study. AB - The iLOV protein is a promising member of the class of flavin mononucleotide (FMN) based fluorescent proteins (FbFPs). It is becoming a popular tool for bioanalytical applications and bioimaging as a competitor of the well-known green fluorescent protein and its analogues. The main limitation of FbFPs is that all the members have close values of their absorption and emission band maxima. Therefore the upcoming challenge is to introduce novel variants of FbFPs to extend their color palette. We report the results of computational studies of iLOV variants, introducing point mutations and chromophore analogues. We found that point mutations of the apoprotein and substitution of FMN with either 8 amino-FMN or 8-methylamino-FMN lead to the red shift of emission bands up to 100 nm. Substitution with 1-deaza-FMN and the point mutations of the apoprotein result in a set of novel fluorescent proteins with emission bands in the "transparent" window where light readily penetrates through mammalian tissues. Newly suggested FbFPs can be used for multicolor imaging and also as components of FRET pairs. PMID- 30403259 TI - Circular RNA hsa_circ_0000523 regulates the proliferation and apoptosis of colorectal cancer cells as miRNA sponge. AB - Among the novel class of endogenous long non-coding RNAs, circular RNA (circRNA) is known as a key regulator in the development and progression of different cancers. Its function and mechanism in the tumorigenesis of colorectal cancer, however, has not been well studied. This study thus aimed to investigate potential regulation of colorectal cancer by circRNAs and the corresponding regulatory mechanism. We demonstrated that the expression of circRNA hsa_circ_0000523 (also known as circ_006229) was down-regulated in different colorectal cancer cell lines. It was also found that interference of hsa_circ_0000523 induced proliferation and suppressed apoptosis of colorectal cancer cells, the proliferation rate of which was reduced by the overexpression of hsa_circ_0000523. In addition, we found that miR-31 could recognize hsa_circ_0000523 sequence and that it acted as a "sponge" of miR-31, indirectly regulating Wnt/beta-catenin signaling pathway, which was involved in the progression of colorectal cancer. The results suggested that the expression of hsa_circ_0000523 correlated to the tumorigenesis of colorectal cancer cells. In addition, as a sponge of miR-31, the low level of hsa_circ_0000523 led to activation of Wnt/beta-catenin signaling pathway, inducing the subsequent progress of colorectal cancer. PMID- 30403261 TI - Correlation between pathogenic species and clinical findings, disease severity, and visual outcome in patients with fungal keratitis. AB - PURPOSE: To determine whether a correlation exists between pathogenic species and clinical findings, disease severity, and visual outcome in patients with keratitis and fungal growth in microbiological culture. METHODS: A retrospective study of patients with fungal growth in the microbiological culture of corneal scrapings. Patients were treated at an ophthalmologic reference center in Southeastern Brazil from January 1992 to October 2015. RESULTS: Medical records of 181 patients (131 males and 50 females) with a mean age of 47 +/- 18 years were analyzed. The three most common etiologies were Fusarium sp. (38.7%), Aspergillus sp. (15%), and Candida sp. (13.2%). Among these, Fusarium sp. was the most frequent in patients aged L50 years (p=0.002) and in those with a recent history of a foreign body and/or ocular trauma (p=0.01). Candida sp. was the most frequent etiology in patients aged >50 years (p=0.002), in those with postoperative ocular surgery (p=0.002); in those with a previous ocular pathology (p=0.0007); and in immunodepressed patients (p=0.0004). CONCLUSION: Fusarium sp. was predominant in patients aged L50 years and those with a recent history of foreign body and/or ocular trauma, whereas Candida sp. was predominant in older adults, in those with a postoperative ocular surgery, in those with a previous ocular pathology, and in immunodepressed patients. PMID- 30403260 TI - The rs878081 polymorphism of AIRE gene increases the risk of rheumatoid arthritis in a Chinese Han population: a case-control study. AB - The autoimmune regulator (AIRE), a transcriptional regulator expressed in medullary thymic epithelial cells, plays an important role in thymocyte education and negative selection. Several citations studying the association between the rs878081 exon polymorphism of the AIRE gene and the risk of rheumatoid arthritis (RA) in different populations have yielded conflicting findings. Thus, this case control study involving 300 RA cases and 300 controls was aimed to identify whether such association existed in a Chinese Han population from East China. The rs878081 polymorphism of the AIRE gene was genotyped. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using the chi-squared test, genetic model analysis, and stratification analysis. Genetic model analysis showed significant correlations between the TT genotype and the risk of RA (OR: 1.89, 95%CI: 1.03-3.47 in TT vs CC; OR: 1.84, 95%CI: 1.02-3.31 in TT vs CC+TC). Stratification analyses of sex, age, smoking, and alcoholism suggested that the rs878081 polymorphism of the AIRE gene increased RA risk among non-smokers. In conclusion, rs878081 polymorphism of AIRE gene increases the risk of RA in a Chinese Han population. PMID- 30403262 TI - Evaluation of toxic retinopathy caused by antimalarial medications with spectral domain optical coherence tomography. AB - PURPOSE: To investigate the frequency of toxic retinopathy in patients with lupus erythematosus and rheumatoid arthritis with long-term use of chloroquine diphosphate or hydroxychloroquine through spectral domain optical coherence tomography and the outcomes of ophthalmological exams (visual acuity - Snellen's table, color vision test - Ishihara's table, fundoscopy, and retinography - red free). METHODS: A cross-sectional study was carried out involving the ophthalmologic evaluation of patients using regular chloroquine diphosphate or hydroxychloroquine for a period of 1 year or longer. The patients completed a questionnaire on their opinions and treatment regularity. The same patients underwent ophthalmologic examination and spectral domain optical coherence tomography. RESULTS: The prevalence of toxic retinopathy caused by antimalarials was 4.15% (9 of 217 patients), 7.4% (4 of 54 patients) following chloroquine diphosphate usage, and 0.82% (1 of 121 patients) following hydroxychloroquine usage. Only patients with advanced stage maculopathy presented abnormalities during the ophthalmologic exam: the color vision test was altered in 11.1%, and visual acuity and fundoscopy were altered in 33.3%. Identification of early toxic retinopathy, detected in six patients, was possible using spectral domain optical coherence tomography. The mean duration of antimalarial drug usage among patients with toxic retinopathy was 10.4 years. Only 31% of the patients reported some symptoms during treatment, and although 24% were afraid to use the medication, they did so as prescribed. CONCLUSION: Use of spectral domain optical coherence tomography was essential for the diagnosis of early-stage antimalarial toxic retinopathy in patients with the following characteristics: asymptomatic, antimalarial use 7 days a week for a period of more than 5 years, and normal clinical ophthalmologic examination. PMID- 30403263 TI - Effect of accelerated corneal crosslinking on ocular response analyzer waveform derived parameters in progressive keratoconus. AB - PURPOSE: To evaluate the effect of accelerated corneal crosslinking on corneal biomechanics with an ocular response analyzer in patients with progressive keratoconus. METHODS: In this retrospective study, 50 eyes of 45 patients with progressive keratoconus who underwent accelerated corneal crosslinking were evaluated with ocular response analyzer waveform parameters before and one year after corneal crosslinking. Paired two-tailed Student's t-test was performed to compare the parameters before vs. after corneal crosslinking. RESULTS: Mean patient age was 17.6 +/- 3.6 (range 9-25) years. A significant increase was observed in p1 area, p2 area, h2, and dive2 values. No significant difference in corneal hysteresis, corneal resistance factor, or other waveform-derived parameters was observed at one year postoperatively. CONCLUSION: For estimating the effect of accelerated corneal crosslinking on corneal biomechanics, parameters such as p1 area, p2 area, h2, and dive2 are more sensitive than corneal hysteresis and corneal resistance factor. These results may help us to find out which corneal crosslinking method is most effective for stiffening the cornea. PMID- 30403264 TI - Effects of ranibizumab and amfenac on the functional abilities and radiosensitivity of uveal melanoma cells. AB - PURPOSE: To evaluate the effects of ranibizumab and amfenac in human uveal melanoma cell lines and to explore the ability of these compounds to sensitize uveal melanoma cells to radiation therapy. METHODS: The 92.1 human uveal melanoma cell line was cultured and subjected to the proposed treatment (ranibizumab, amfenac, and a combination of both). Proliferation, migration, and invasion assays of the 92.1 uveal melanoma cell line were assessed after pretreatment with ranibizumab (125 mg/mL), amfenac (150 nM), or a combination of both. In addition, proliferation rates were assessed after treatment with ranibizumab and amfenac, and the cells were subsequently exposed to various radiation doses (0, 4, and 8 Gy). RESULTS: Proliferation assay: cells treated with a combination of ranibizumab and amfenac had lower proliferation rates than controls (p=0.016) and than those treated with only ranibizumab (p=0.033). Migration assay: a significantly lower migration rate was observed in cells treated with amfenac than the control (p=0.014) and than those treated with ranibizumab (p=0.044). Invasion assay: there were no significant differences among the studied groups. Irradiation exposure: in the 4 Gy dose group, there were no significant differences among any groups. In the 8 Gy dose group, treatment with ranibizumab, amfenac, and their combination prior to application of the 8 Gy radiation led to a marked reduction in proliferation rates (p=0.009, p=0.01, and p=0.034, respectively) compared with controls. CONCLUSION: Combination of ranibizumab and amfenac reduced the proliferation rate of uveal melanoma cells; however, only amfenac monotherapy significantly decreased cell migration. The radiosensitivity of the 92.1 uveal melanoma cell line increased following the administration of ranibizumab, amfenac, and their combination. Further investigation is warranted to determine if this is a viable pretreatment strategy to render large tumors amenable to radiotherapy. PMID- 30403265 TI - Association between systemic activity index and dry eye severity in patients with primary Sjogren syndrome. AB - PURPOSE: The aim of the present study was to compare the severity of ocular and systemic findings among patients with primary Sjogren syndrome. METHODS: The study followed a prospective controlled design and comprised two groups; the test group included 58 eyes of 58 patients newly diagnosed with primary Sjogren syndrome with poor dry eye test findings and the control group included 45 right eyes of 45 healthy age- and sex-matched individuals. The ocular surface disease index score, tear osmolarity, Schirmer I test without anesthesia, fluorescein tear breakup time, and cornea-conjunctiva staining with lissamine green (van Bijsterveld scoring) were used to examine tear function in the patients via a complete ophthalmological examination. The results were graded and classified on the basis of a Dry Eye WorkShop report and results of the corneal and conjunctival staining test, Schirmer's test, and fluorescein tear breakup time test. Discomfort, severity and frequency of symptoms, visual symptoms, conjunctival injection, eyelid-meibomian gland findings, and corneal-tear signs were interpreted. Disease activity was scored per the EULAR Sjogren's syndrome disease activity index (ESSDAI) via systemic examination and laboratory evaluations, and the EULAR Sjogren's syndrome patient-reported index (ESSPRI) assessed via a survey of patient responses. RESULTS: Mean patient age was 48.15 +/- 16.34 years in the primary Sjogren syndrome group and 44.06 +/- 9.15 years in the control group. Mean fluorescein tear breakup time was 4.51 +/- 2.89s in the primary Sjogren syndrome group and 10.20 +/- 2.39 s in the control group. Mean Schirmer I test result was 3.51 +/- 3.18 mm/5 min in the primary Sjogren syndrome group and 9.77+/-2.30 mm/5 min in the control group. Mean ocular surface disease index score was 18.56 +/- 16.09 in the primary Sjogren syndrome group, and 19.92 +/- 7.16 in the control group. Mean osmolarity was 306.48 +/- 19.35 in the primary Sjogren syndrome group, and 292.54 +/- 10.67 in the control group. Mean lissamine green staining score was 2.17 +/- 2.76 in the primary Sjogren syndrome group, and 0.00 in the control group. Statistically significant differences were found berween the primary Sjogren syndrome group and control group in terms of fluorescein tear breakup time, Schirmer's test, lissamine green staining, and osmolarity tests (p=0.036, p=0.041, p=0.001, and p=0.001 respectively). The Dry Eye WorkShop score was 2.15 +/- 0.98, the EULAR Sjogren's syndrome disease activity index score was 11.18 +/- 4.05, and the EULAR Sjogren's syndrome patient reported index score was 5.20+/-2.63. When potential associations of the Dry Eye Workshop Study scores and osmolarity scores with the Eular Sjogren's syndrome disease activity index scores were evaluated, the results were found to be statistically significant (p=0.001, p=0.001 respectively). CONCLUSION: The results showed an association between dry eye severity and systemic activity index in primary Sjogren syndrome patients. PMID- 30403266 TI - The experience of the partners of women with breast cancer. AB - OBJECTIVE: To understand the experience of partners of women with breast cancer. METHOD: This was a qualitative study, based on the theoretical-methodological framework of existential and phenomenological psychology, and carried out with the partners of women with breast cancer who attended a center for rehabilitation after mastectomy. The data were collected in interviews between June and November 2014, based on a guiding question. RESULTS: Ten partners participated in the study. On discovering the disease, the partners experienced emotional distress caused by the fear of losing their partners. Before this suffering, they demonstrated the ability to react: willingness to provide care, to comfort and to support the women in search of treatment, and together, seek to reverse adverse situations. They also showed sensitivity and recognized the intense emotional suffering of the women caused by the challenges faced throughout the course of treatment. CONCLUSION: The present study showed the intense suffering of the partners of women with breast cancer and their difficulty to ask for help. Thus, health professionals must be alert, addressing their needs throughout the treatment process to mitigate suffering. PMID- 30403267 TI - Care and management actions developed in the Supervised Curricular Internship: perceptions by involved actors. AB - OBJECTIVE: To assess the Supervised Curricular Internship of the Nursing undergraduate course of two higher education institutions in the state of Sao Paulo based on specific skills described in the Brazilian National Curriculum Guidelines regarding preparation to the development of nursing care and management actions from the perceptions of professors, undergraduate students, and alumni. METHOD: Descriptive study in which a questionnaire was applied to 59 undergraduate students, 111 alumni, and 27 professors of a Nursing undergraduate course involved in the Supervised Curricular Internship in the analyzed institutions. RESULTS: The perceptions of the actors involved in the development of management and care actions were positive, although part of the alumni pointed out that the Supervised Curricular Internship does not allow the students to: develop all the activities performed by the nursing team; work towards comprehensive health care; professional technical confidence; and interfere with the work dynamics. CONCLUSION: In the perception of those involved, the Supervised Curricular Internship is seen as positive and important in the training of students, as it introduces students into the professional reality of nurses. However, this discipline still needs structural changes, particularly in the perception of the alumni. PMID- 30403268 TI - Evaluation of patient safety culture: comparative study in university hospitals. AB - OBJECTIVE: To conduct a benchmarking comparison of the composites of patient safety culture based on the evaluation of Brazilian and Portuguese nurses working in university hospitals. METHOD: Quantitative, cross-sectional, comparative survey. Data collected between April and December 2014, in two teaching hospitals, applying the instrument Hospital Survey on Patient Safety Culture, in the versions translated and adapted to the countries. RESULTS: 762 nurses distributed in four services participated in the study, 195 Brazilians and 567 Portuguese. Seven of the 12 composites of safety culture showed significant differences between hospitals. The highlights were those related to: "management support for patient safety" (+/-17); "handoffs and transitions" (+/-15); "teamwork across units" (+/-14); and "overall perceptions of patient safety" (+/ 10). CONCLUSION: The dimension that had the highest significant difference between the studied institutions was "management support for patient safety". These data may support the managers of the study hospitals, enabling continuous improvements and advancements. PMID- 30403270 TI - Effect of lifestyle interventions on diabetic peripheral neuropathy in patients with type 2 diabetes, result of a randomized clinical trial. AB - OBJECTIVES: Diabetic peripheral neuropathy (DPN) is the most common and troublesome complication of diabetes leading to great morbidity and resulting in a huge economic burden for diabetes care. Over half of people with diabetes develop neuropathy. Also, DPN is a major cause of reduced quality of life due to pain, sensory loss, gait instability, fall-related injury, and foot ulceration and amputation. The aim of this study was evaluating the effects of lifestyle interventions on diabetic neuropathy severity in diabetes type 2 outpatients. METHODS: This clinical trial conducted on 74 patients with DPN that divided with random allocation into intervention or control group. The lifestyle interventions applied in the intervention group beginning four educational sessions on lifestyle that emphasize strategies for lowering blood sugar, increasing physical activity, promoting weight loss, prudent diet, and foot caring. Each session was lasted for1.5 hour. Then patients followed for 12 weeks. During this period, they received counseling on mentioned lifestyle interventions. DPN severity in both groups measured using modified Toronto Clinical Neuropathy Score (mTCNS) at the beginning of study and at the end of counseling for 12 weeks. RESULTS: Comparing differences of mean of DNP severity before and after lifestyle intervention between two groups of study, there was a significant difference (p<0.001). DNP severity in control group had not any change or it increased in some participants, but DNP decreased in intervention group, after applying lifestyle intervention. CONCLUSION: Lifestyle interventions can contribute to reducing DPN severity, and consequently decreasing neuropathic pain. PMID- 30403269 TI - Development of a virtual simulation game on basic life support. AB - OBJECTIVE: To validate the content of a virtual learning object in the format of a Role Playing Game - educational simulation game about basic life support, aimed at academics and health professionals. METHOD: Methodological, construction and validation study with qualitative data approach on the content of a virtual learning object, conducted between August and September 2016. RESULTS: The game was developed in 13 screens, of which nine presented contents of basic life support, and the others presented general guidelines for progress in the game. The five suggestions of the experts were accepted by the researchers, and were mostly related to organization, clarity and vocabulary. No item was considered inappropriate by the judges, and the game had a mean content validity index of 0.96 and a Kappa value of 0.92. In the Likert scale evaluation, the game was considered in all analyzes as an excellent content for a virtual learning object. CONCLUSION: This learning technology is expected to support teaching of basic life support techniques for academics and health professionals, and to stimulate the development of similar teaching strategies in other scenarios, in order to bring advancements to the design of health training processes. PMID- 30403271 TI - Ultrasound guided superficial cervical plexus block versus greater auricular nerve block for postoperative tympanomastoid surgery pain: A prospective, randomized, single blind study. AB - OBJECTIVES: The aim of the study was to investigate the effect of ultrasound guided superficial cervical plexus (SCP) block versus greater auricular nerve (GAN) block for on postoperative tympanomastoid surgery analgesia. METHODS: In this prospective, randomized, single-blind study, a total of 50 patients aged between 25 and 70 years, those who were in the American Society of Anesthesiologists I-II class and underwent tympanomastoid surgery were included in the study. Patients were randomized to either Group Y: intravenous patient controlled analgesia tramadol (IV PCA) + SCP block; n=25 and Group G: IV PCA + GAN block; n=25. Postoperative pain was evaluated at the 2nd, 6th, 12nd, and 24th hours using the Visual Analogue Scale (VAS) and postoperative 6th, 12nd, and 24th hour follow-up results were evaluated to identify the quantity of tramadol use. RESULTS: The VAS scores at all measures time were found to be no statistically significant difference between groups (p>0.05). The amounts of PCA tramadol consumption at all measures time were significantly lower in Group Y than in Group G (p<0.05). CONCLUSION: The results of this study have indicated that SCP and GAN blocks can be used for pain control after tympanomastoid surgery. We believe that the only disadvantage of SCP block application with lower amounts of tramadol use is that the complications that can occur are more serious than those that can occur in GAN application. PMID- 30403272 TI - Radiofrequency thermocoagulation combined with pulsed radiofrequency for gasserian ganglion blockage. AB - OBJECTIVES: Trigeminal neuralgia (TN) has been effectively treated by radiofrequency thermocoagulation (RFT) of the gasserian ganglion. Recently, pulsed radiofrequency (PRF) is becoming an alternative therapy for patients with trigeminal neuralgia. It is unclear whether the combination of RFT with PRF may decrease post-operative complications while maintaining longterm pain relief. METHODS: Twelve patients with idiopathic TN who had undergone combined RFT and PRF of the gasserian ganglion were evaluated. PRF (42 degrees C, 45V, 20 ms, 120 seconds) was administered, and then RFT (65 degrees C, 90 seconds) was performed to the gasserian ganglion. The post-operative pain relief and complications were evaluated at 1, 6, 12 and, 24 months after treatment. RESULTS: 10 patients (83.3%) reported significant pain relief (VAS 3) at 1 month following the treatment, while 8 patients (66.6%) at 6 months, 5 patients (41.6) at 12 months, and 2 patients (16.6%) at 24 months were pain-free. Two of the patients did not have pain relief (VAS >=3), and 2 patients were still pain-free by the 24th month. The mean time of pain relief was 14 months. One patient had numbness in the tongue for about a year, while in the other patients, no serious complications were reported. CONCLUSION: A combination of RFT with PRF could help eliminate postoperative complications of trigeminal neuralgia. We sugesst that combining RFT and PRF therapy may serve to decrease the side effects but not increase the pain relief. PMID- 30403273 TI - Research on the efficacy of the rectus sheath block method. AB - OBJECTIVES: We aimed to retrospectively investigate the efficacy of ultrasound guided rectus sheath block (RSB) method in our study. METHODS: We scanned 235 patient files operated for abdominal pathology. Patients meeting the criteria were evaluated for intra-operative rectus sheath block and two different groups were formed. In these two groups of patients visual analogue scale (VAS) values recorded from the postoperative pain follow-up form and analgesic delivery (DEL) and analgesic demand (DEM) values recorded from patient controlled analgesia (PCA) device were compared. In addition, complaints of nausea, vomiting and constipation were evaluated. RESULTS: Postoperative VAS values (Postoperative 1, 12 and 24 hours p<0.001), DEM values (Postoperative 1, 12 and 24 hours p<0.001) and total amount of morphine consumed (Postoperative 1, 12 and 24 hours p<0.001) were lower in patients with RSB. Also, in patients with RSB nausea (p=0.014) and vomiting was less seen postoperatively (p=0.007). In the first 24 hours after surgery, constipation was seen in 8 patients with RSB and constipation was seen in 30 patients without RSB (p=0.00). CONCLUSION: Ultrasound guided rectus sheath block is an effective method for postoperative pain control. PMID- 30403274 TI - [Prevalence of bipolar spectrum disorders in migraine patients]. AB - OBJECTIVES: Comorbidity of migraine and mood disorders has long been recognized. Most of the studies have focused on the relationship between migraine and major depression with only few studies suggesting a special association between migraine and bipolar spectrum disorders. We aimed to evaluate the prevalence of bipolar disorder in migraine patients in a specialized headache outpatient clinic. METHODS: The sample consisted of 78 consecutive patients with migraine headache presenting to the specialized headache outpatient clinic in a Medical Faculty. Migraine diagnosis was established with the International Headache Society's criteria for migraine. Patients were evaluated with Structured Clinical Interview for DSM-IV for mood disorders. Bipolar spectrum definition was broadened with the presence of Akiskal's criteria for affective temperaments (cyclothymic, hyperthymic, irritable, and depressive). RESULTS: Patients in the bipolar spectrum comprised 10.3% (n=8) of the sample. 11 patients (14.1%) had a diagnosis of unipolar depression and 7 patients (9%) had a diagnosis of dysthymic disorder. 41% of the patients (n=32) had an affective temperament. Bipolar disorder was observed with increased frequency in this migraine sufferer population, supporting previous findings of increased prevalence of bipolar disorders in patients with migraine. CONCLUSION: Increased frequency of affective temperaments might be considered in the context of a common pathophysiological background for migraine and bipolar disorders where these temperaments are sub threshold presentations of mood disorders. Therefore, the definition of patients with comorbid migraine and bipolar disorder may serve as a more homogenic subgroup of mood disorders for further studies. PMID- 30403275 TI - A probable case of movement disorder (Tardive dyskinesia) due to duloxetine treatment. AB - Tardive dyskinesia and tardive dystonia are caused by dopamine receptor blocking agents, mostly antipsychotics and sometimes antidepressants or calcium channel blockers. Duloxetine is a serotonin-noradrenaline reuptake inhibitor used in the treatment of diabetic neuropathic pain and fibromyalgia, as well as major depression. In this case, we aimed to discuss the tardive dyskinesia-like appearance of a patient using duloxetine due to fibromyalgia. PMID- 30403276 TI - Migraine-like visual aura: Can it be an early-onset symptom of astrocytoma? AB - Photopsia, fortification spectra, and the slow propagation of a scintillating scotoma across the visual field are typical diagnostic features of the visual aura of migraine. In the vast majority of cases, the diagnosis can be made without the need for further investigations. Herein, we report three consecutive cases with an astrocytoma and discuss clinical features of migraine-like visual aura. PMID- 30403277 TI - [Late diagnosed cervical myelomalesia in a case of Fahr disease experiencing a neuropathic pain]. AB - Fahr disease is an idiopathic disorder characterized with deposition of calcium and a few other minerals in basal ganglia, cerebellum and subcortical brain area. A 51 years old female with the complaints of pain, numbness, tingling and weakness in both upper extremities for six months was referred to our electromyography laboratory with a suspicion of carpal tunnel syndrome. She got the diagnosis of Fahr disease upon the investigations for the convulsions that she experienced ten years ago. Beside, she had a generalized anxiety disoder. Neurological examination revealed mild to moderate weakness in flexion and extension of forearm, and extension of hand on both sides. She described dysesthesia on C6 & C7 dermatomes, bilaterally. Symmetric calsifications on both cerebellar hemispheres and basala ganglia were present on cranial CT. Median and ulnar nerve conduction studies were normal on both sides. Concentric needle electromyography revealed chronic neurogenic changes on the morphology of motor unit potentials recorded from the muscles of C6 & C7, bilaterally. Cervical magnetic resonance imaging revealed discopathies on C4-5, C5-6 and C6-7 levels causing myelomalacia. Neuropathic pain, paresthesia or muscle weakness on upper extremities are rare in Fahr disease. Presented case got the diagnosis of cervical discopathies in late as those findings were supposed to be related with Fahr disease. Therefore, clinicians should be aware of common findings occured during the course of this disease, and consider the possible coincidental pathologies when the atypical neurological deficits are observed in these patients. PMID- 30403278 TI - Headache in challenging and special circumstances: Pregnancy and lactation. AB - Headache has special importance during pregnancy and postpartum period. The health-care professionals and patients report headache management as challenging during pregnancy and lactation period. Cautions are recommended in preganancy and lactation due to maternal and fetal/newborn risks. Most headaches in the first trimester are due primary headaches. Nevertheless, the incidence of secondary headaches increase in the last trimester and post-partum period. Red flags prompt early evaluation in a patient with headache. Assessment of headache patient requires a detailed history of the headache characteristics and performing appropriate examinations. Approach to headache and strategies to promote best practice in preganancy and lactation will be reviewed. PMID- 30403279 TI - Impaired spermatogenesis, tubular wall disruption, altered blood-testis barrier composition and intratubular lymphocytes in an infertile Beagle dog - a putative case of autoimmune orchitis. AB - Impairment of blood-testis barrier integrity can be observed during inflammation, infection, trauma and experimental autoimmune orchitis, which is inducible in rodents. In the present study, an initially fertile two-year-old Beagle dog was presented with a decline in total sperm number resulting in azoospermia within five months, verified by twice-monthly semen analyses. The dog was clinically healthy with bilateral small testes and showed normal thyroid function. Bacterial cultures of semen were negative and serum biochemical analyses showed no abnormal findings. To determine causes of azoospermia, the dog was castrated. Histological examinations of hematoxylin-eosin stained testicular sections revealed impaired spermatogenesis, seminiferous tubules with spermatogenic arrest or Sertoli-cell only syndrome as well as focal interstitial and even intratubular lymphocytic infiltrations. Germ cell sloughing, apoptosis and giant cells were also observed in some tubules. Subsequent immunostainings of smooth-muscle-actin, claudin3, claudin11 and connexin43 demonstrated, for the first time, a mechanical and functional disruption of the tubular wall and alterations of blood-testis barrier proteins in these tubules. Presence of claudin3 and claudin11 in canine testis was confirmed using RT-PCR and sequencing and/ or Western-blot analyses. All findings suggested a possible spontaneous autoimmune orchitis to be the underlying cause for the observed azoospermia. PMID- 30403280 TI - [Transcultural adaptation to the Spanish language of the Balance Evaluation Systems Test (BESTest) in older adults]. AB - INTRODUCTION: The risk of falls in older adults increases because of the decrease in strength, flexibility, balance and sensory changes affecting functionality and quality of life. For this reason, an integral system of evaluation of equilibrium is necessary, for preventive purposes or for early therapeutic interventions. AIM: To present the results of the transcultural translation and adaptation process of the Balance Evaluation Systems Test (BESTest) to Spanish language. SUBJECTS AND METHODS: The original version of the BESTest was translated into Spanish, following the process of retro-traduction and cultural adaptation considering the semantic, idiomatic, conceptual and experiential equivalences. Subsequently the version was reviewed by a panel of experts qualifying clarity, coherence, relevance and sufficiency. The pilot test included 32 adults between 50 and 80 years old. RESULTS: It was possible to carry out the complete translation of the instrument, the instructions for the subject and for the evaluator. Most items of the test reached the maximum score of 4.0 (100%), nine items achieved an average score of 3.9 (99%), one item got an average score of 3.8 (95%) and two items achieved an average score of 3.7 (92.5%). CONCLUSIONS: With this study the Spanish speakers community has a pertinent sufficient, coherent and clear instrument in order to identify the control postural system altered to focus treatment and to get better functional outcomes from balance evaluation in older adults. PMID- 30403281 TI - [Ten years' experience with vagus nerve stimulation in a paediatric population]. AB - INTRODUCTION: Fifty million people are affected by epilepsy. Up to 30% are not controlled with the aid of antiepileptic drugs. The vagus nerve stimulator (VNS) is a therapeutic alternative that must be taken into account. AIMS: To determine the effect of the VNS in a cohort of paediatric patients with refractory epilepsy. PATIENTS AND METHODS: A retrospective study of children with a VNS implanted between 2008 and 2017 in a tertiary hospital. Epidemiological, aetiological, clinical and electrophysiological data, along with VNS parameters were analysed. RESULTS: The study included 35 patients, with a mean age when the VNS was implanted of 12.84 years (range: 3.1-18.7 years) and a mean time between onset of epilepsy and implantation of 7.2 years (range: 1.3-17.7 years). The causation was structural in 62.9% of cases. The most frequent epileptic conditions were: Lennox-Gastaut syndrome and focal epilepsy, with a predominance of tonic seizures (57.1%). The video electroencephalogram showed multifocal anomalies (54%) and a pattern of epileptic encephalopathies (34.3%). Intellectual disability was associated in 94% of the cases. The mean of previous antiepileptic drugs was 9.6 +/- 3 (range: 4-16). 43% responded to treatment (>= 50% reduction in number of seizures), with a mean reduction of 67.3%, which improved with higher ages of onset of epilepsy. Three patients were seizure-free (8.5%). The number of seizures decreased by 33% at six months and by 47.4% at 24 months. There was also a notable degree of cognitive (57%) and behavioural improvement (53%). In 28% of cases there were some side effects, but in general they were mild. CONCLUSIONS: The VNS is a valid option in refractory epilepsy, with improvements not only in terms of seizures but also regarding cognitive behavioural aspects, this being very important for the paediatric population. PMID- 30403282 TI - The importance of glutamate in the neuro-endocrinological functions in multiple sclerosis, related to fatigue. AB - Multiple sclerosis is an inflammatory disease, which still today affects the Northern-hemisphere population, generating a socioeconomically burden. One of the most unfavorable symptoms in this chronic disorder is fatigue. In this review, we favor and sustain a main alteration of the hypothalamus-pituitary-axis complex and its physiopathologic consequences, mostly related to glutamate and corticoid levels. We try to sustain our hypothesis in what is already reported, corroborating that the inflammatory cells release mainly glutamate, a neuro-toxic substance which leads to a demyelinating effect and as a main result fatigue as a symptom. When this hypothesis is demonstrated, we could trace therapeutic targets to stop the release of glutamate of these immunologic cells, in order to avoid fatigue in multiple sclerosis patients. PMID- 30403284 TI - [XXXII Reunion da Sociedade Galega de Neuroloxia. Communications]. PMID- 30403283 TI - [Neuroimaging in fibromyalgia]. AB - INTRODUCTION: Most current research suggests that fibromyalgia is a disease produced by an alteration in the processing of pain signals in the central nervous system. In recent years, advances in non- or minimally-invasive brain imaging techniques have made it possible to discover how different areas of the nervous system are involved in the aetiopathogenesis of diseases that up until now have been considered as having a functional profile. AIM: To describe the objectified functional and the structural changes that take place in the brains of patients with fibro-myalgia by means of the currently available neuroimaging techniques. DEVELOPMENT: This work reviews the clinical studies, both anatomical and molecular, that have been conducted to date in the field of fibromyalgia using different brain imaging techniques. CONCLUSIONS: Different, but related, areas of the central nervous system have been described as altering not only the functional but also the structural form, in patients with fibromyalgia. These involved areas extend beyond the pain circuits, which would explain the variety of symptoms in patients, in addition to the characteristic pain reported by them. PMID- 30403285 TI - [A new mutation in the ALDH3A2 gene in a boy with Sjogren-Larsson syndrome]. PMID- 30403286 TI - Ketogenic diets for drug-resistant epilepsy. AB - BACKGROUND: Ketogenic diets (KDs), being high in fat and low in carbohydrates, have been suggested to reduce seizure frequency in people with epilepsy. At present, such diets are mainly recommended for children who continue to have seizures despite treatment with antiepileptic drugs (AEDs) (drug-resistant epilepsy). Recently, there has been interest in less restrictive KDs, including the modified Atkins diet (MAD), and the use of these diets has extended into adult practice. This is an update of a review first published in 2003 and last updated in 2016. OBJECTIVES: To assess the effects of KDs for drug-resistant epilepsy by reviewing the evidence from randomised controlled trials. SEARCH METHODS: For the latest update we searched the Cochrane Epilepsy Group's Specialized Register (11 April 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 11 April 2017), MEDLINE (Ovid, 11 April 2017), ClinicalTrials.gov (11 April 2017) and the WHO International Clinical Trials Registry Platform (ICTRP, 11 April 2017). We imposed no language restrictions. We checked the reference lists of retrieved studies for additional reports of relevant studies. SELECTION CRITERIA: Randomised controlled trials or quasi-randomised controlled trials of ketogenic diets for people with drug-resistant epilepsy. DATA COLLECTION AND ANALYSIS: Two review authors independently applied predefined criteria to extract data and assessed study quality. MAIN RESULTS: We identified 11 randomised controlled trials (RCTs) that generated 15 publications.All trials applied an intention-to treat analysis with varied randomisation methods. The 11 studies recruited 778 patients; 712 children and adolescents and 66 adults. We assessed all 11 studies to be at low to unclear risk of bias for the following domains: random sequence generation, allocation concealment and selective reporting. For the other domains (blinding, incomplete outcome data, other bias) assessments were varied (low, unclear and high risk of bias). We could not conduct a meta-analysis due to the heterogeneity of the studies and the quality of the evidence was low to very low (GRADE ratings).Reported rates of seizure freedom reached as high as 55% in a classical 4:1 KD group after three months and reported rates of seizure reduction reached as high as 85% in a classical 4:1 KD group after three months (GRADE rating low).One trial found no significant difference between the fasting-onset and gradual-onset KD for rates of seizure freedom, and reported a greater rate of seizure reduction in the gradual-onset KD group.Studies assessing the efficacy of the MAD reported seizure freedom rates of up to 25% and seizure reduction rates of up to 60% in children. One study used a simplified MAD (sMAD) and reported seizure freedom rates of 15% and seizure reduction rates of 56% in children. One study utilised a MAD in adults and reported seizure reduction rates of 35%, but no patients became seizure free (GRADE rating low).Adverse effects of the dietary interventions were experienced in all studies. The most commonly reported adverse effects were gastrointestinal syndromes. It was common that adverse effects were the reason for participants dropping out of trials (GRADE rating low). Other reasons for dropout included lack of efficacy and non-acceptance of the diet (GRADE rating low).Although there was some evidence for greater antiepileptic efficacy for a classical 4:1 KD over lower ratios, the classical 4:1 KD was consistently associated with more adverse effects.One study assessed the effect of dietary interventions on quality of life, cognition and behavioural functioning, reporting participants in the KD group to be more active, more productive and less anxious after four months, compared to the control group. However, no significant difference was found in quality-adjusted life years (QALYs) between the KD group and control group at four or 16 months (GRADE rating very low). AUTHORS' CONCLUSIONS: The RCTs discussed in this review show promising results for the use of KDs in epilepsy. However, the limited number of studies, small sample sizes and the limited studies in adults, resulted in a low to very low overall quality of evidence.There were adverse effects within all of the studies and for all KD variations, such as short-term gastrointestinal-related disturbances and increased cholesterol. However, study periods were short, therefore the long-term risks associated with these adverse effects is unknown. Attrition rates remained a problem with all KDs and across all studies; reasons for this being lack of observed efficacy and dietary tolerance.Only one study reported the use of KDs in adults with epilepsy; therefore further research would be of benefit.Other more palatable but related diets, such as the MAD, may have a similar effect on seizure control as the classical KD, but this assumption requires more investigation. For people who have medically intractable epilepsy or people who are not suitable for surgical intervention, KDs remain a valid option; however, further research is required. PMID- 30403287 TI - CCR6 defines a subset of activated memory T cells of Th17 potential in immune thrombocytopenia. AB - Current researches have determined the significance of C-C chemokine receptor (CCR)6 expression as either a marker of T helper cells (Th) or an effector and regulator of T cell function. However, the roles of CCR6 in the pathogenesis of immune thrombocytopenia (ITP) are unclear. In this study, we aimed to investigate the phenotype and functional characteristics of circulating CCR6+ T cells in blood from chronic ITP patients and healthy controls. We found that the frequency of CCR6+ CD4+ cells was higher in ITP patients than in healthy controls. Anti CD3/anti-CD28 stimulation induced rapid expansion of CCR6+ CD4+ cells in ITP patients. CCR6+ CD4+ cells had a phenotype of activated cells and predominantly expressed CD45RO. Forkhead box protein P3 (FoxP3) and CD25-positive cells were exclusively detected within the CCR6+ CD4+ cells. In ITP patients, CCR6+ regulatory T cells (Treg ) were decreased and positively correlated with platelet counts and transforming growth factor (TGF)-beta plasma levels. In contrast to CCR6- counterparts, CCR6+ CD4+ cells produced higher levels of interleukin (IL) 17A. The frequency of CCR6+ Th17 was higher in ITP patients and positively correlated with IL-17A levels in supernatant. Most importantly, CCR6+ CD4+ cell subpopulations, but not CCR6- CD4+ , were closely correlated to treatment response of ITP patients. These findings suggest that circulating CCR6+ CD4+ cells in ITP patients have characteristics of activated memory Th17 phenotype and could be used to monitor disease activity and treatment response. PMID- 30403289 TI - Function of a laminin_G_3 module as a carbohydrate-binding module in an arabinofuranosidase from Ruminiclostridium josui. AB - Laminin_G_3 modules can exist together with family-43 catalytic modules of glycoside hydrolase (GH43), but their functions are unknown. Here, a laminin_G_3 module and a GH43 module derived from a Ruminiclostridium josui modular arabinofuranosidase Abf43A-Abf43B-Abf43C were produced individually as RjLG3 and RjGH43_22, respectively, or combined as RjGH43-1 to gain insights into their activities. Isothermal calorimetry analysis showed that RjLG3 has high affinity toward 32 -alpha-l-arabinofuranosyl-(1,5)-alpha-l-arabinotriose but not for alpha 1,5-linked arabinooligosaccharides, which suggests that RjLG3 interacts specifically with a branched arabinofuranosyl residue of an arabinooligosaccharide but not an arabinofuranosyl residue at the end of alpha 1,5-linked arabinooligosaccharides. RjGH43-1 (with CBM) shows higher activity toward sugar beet arabinan than RjGH43_22 (without CBM), which suggests that the LG3 module in RjGH43-1 plays an important role in substrate hydrolysis as a carbohydrate-binding module. PMID- 30403288 TI - Alzheimer's Abeta1-40 peptide degradation by thermolysin: evidence of inhibition by a C-terminal Abeta product. AB - The interaction of the amyloid-beta peptide (Abeta) with thermolysin (TLN) was investigated by X-ray crystallography. Structural models of the complexes of TLN with several Abeta fragments show that, despite the numerous possible cleavage sites of the Abeta sequence, the C-terminal product of Ala30-Ile31 cleavage does not dissociate, thus inhibiting the enzyme. The high similarity between the TLN structural motif and neprilysin (NEP), the most extensively studied peptidase associated with Abeta clearance, suggests that NEP should be more efficient against Abeta polymorphs where Ala30-Ile31 is inaccessible, which is in agreement with studies in living mice that point to the limited role of NEP in degrading soluble Abeta and its higher ability to degrade insoluble and/or oligomeric Abeta forms, producing only the Abeta10-37 intermediate. PMID- 30403290 TI - Different mechanisms involved in liraglutide and glucagon-like peptide-1 vasodilatation in rat mesenteric small arteries. AB - BACKGROUND AND PURPOSE: Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates insulin biosynthesis and secretion in a glucose-dependent manner, and has been reported to induce vasodilatation. Here, the aim was to examine the possible vasorelaxant effect of GLP-1 and the underlying mechanisms. EXPERIMENTAL APPROACH: Rat mesenteric arteries (diameter ~ 200-400 MUm) and human subcutaneous arteries were mounted in microvascular myographs for isometric tension recordings. The effect of GLP-1 on vascular responses was examined at normoglycemic conditions and at high glucose. KEY RESULTS: In rat mesenteric arteries and human subcutaneous arteries without branches, physiological concentrations (1-100 nM) of GLP-1(7-36) and liraglutide failed to cause relaxation, or affect contractions evoked by electrical field stimulation. In contrast to GLP-1(7-36), liraglutide induced relaxations antagonized by the GLP-1 receptor antagonist, exendin-(9-39) in branched mesenteric arteries. In contrast to liraglutide, GLP-1 leftward shifted concentration relaxation curves for bradykinin in subcutaneous arteries from patients with peripheral arterial disesase, an effect insensitive to exendin-(9-39). In normoglycemic conditions neither GLP-1 nor liraglutide changed acetylcholine relaxation in rat mesenteric arteries. In arteries exposed to 40 mM glucose, GLP-1, in contrast to liraglutide, potentiated acetylcholine-induced relaxation by a mechanism that was not antagonized by exendin-(9-39). GLP-1 decreased superoxide levels measured with dihydroethidium in rat mesenteric arteries exposed to 40 mM glucose. CONCLUSION AND IMPLICATIONS: Our findings suggest that a GLP-1 receptor-dependent mechanism is involved in liraglutide relaxation in branched arteries in normoglycemic conditions, while GLP-1 inhibition of vascular superoxide levels contributes to GLP-1 receptor-independent potentiation of endothelium-dependent vasodilatation in hyperglycemia. PMID- 30403292 TI - Introduction to the special issue on NEUTROPHILS of the European Journal of Clinical Investigation. PMID- 30403291 TI - Effects of stably incorporated iron on protein phosphatase-1 structure and activity. AB - Protein phosphatase-1 (PP1) drives a large amount of phosphoSer/Thr protein dephosphorylations in eukaryotes to counteract multiple kinases in signaling pathways. The phosphatase requires divalent metal cations for catalytic activity and contains iron naturally. Iron has been suggested to have an influence on PP1 activity through Fe2+ and Fe3+ oxidation states. However, much biochemical and all structural data have been obtained with recombinant PP1 containing Mn2+ ions. Purifying iron-containing PP1 from Escherichia coli has thus far not been possible. Here, we present the preparation, characterization, and structure of iron-bound PP1alpha in inactive and active states. We establish a key role for the electronic/redox properties of iron in PP1 activity and shed light on the difference in substrate specificity between iron- and manganese-containing PP1. PMID- 30403293 TI - Spectroscopic Determination of the Electronic Structure of a Uranium Single-Ion Magnet. AB - Early actinide ions have large spin-orbit couplings and crystal field interactions, leading to large anisotropies. The success in using actinides as single-molecule magnets has so far been modest, underlining the need for rational strategies. Indeed, the electronic structure of actinide single-molecule magnets and its relation to their magnetic properties remains largely unexplored. Here we investigate a uranium(III) single molecule magnet, [UIII{SiMe2NPh}3-tacn)(OPPh3)] (2), by means of a combination of magnetic, spectroscopic and theoretical methods, elucidating the origin of its static and dynamic magnetic properties. PMID- 30403294 TI - Protective effects of diphenyleneiodonium, an NADPH oxidase inhibitor, on lipopolysaccharide-induced acute lung injury. AB - NADPH oxidase (NOX) plays an important role in inflammatory response by producing reactive oxygen species (ROS). The inhibition of NOX has been shown to induce anti-inflammatory effects in a few experimental models. The aim of this study was to investigate the effects of diphenyleneiodonium (DPI), a NOX inhibitor, on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in a rat model. Sprague Dawley rats were intraperitoneally administered by DPI (5 mg/kg) 30 minutes after intratracheal instillation of LPS (3 mg/kg). After 6 hours, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. The NOX activity in lung tissue was significantly increased in LPS-treated rats. It was significantly attenuated by DPI. DPI-treated rats showed significant reduction in the intracellular ROS, the number of inflammatory cells, and cytokines (TNF-alpha and IL-6) in BALF compared with LPS-treated rats. In lung tissue, DPI-treated rats showed significantly decreased malondialdehyde content and increased activity of glutathione peroxidase and superoxide dismutase compared with LPS-treated rats. Lung injury score, myeloperoxidase activity, and inducible nitric oxide synthase expression were significantly decreased in DPI-treated rats compared with LPS treated animals. Western blotting analysis demonstrated that DPI significantly suppressed LPS-induced activation of NF-kappaB and ERK1/2 and SAPK/JNK in MAPK pathway. Our results suggest that DPI may have protective effects on LPS-induced ALI thorough anti-oxidative and anti-inflammatory effects which may be due to inactivation of the NF-kappaB, ERK1/2, and SAPK/JNK pathway. These results suggest the therapeutic potential of DPI as an anti-inflammatory agent in ALI. PMID- 30403295 TI - The C-terminal region of tumor necrosis factor-like weak inducer of apoptosis is required for interaction with advanced glycation end products. AB - Previously, we found that endogenously produced pro-inflammatory molecules, advanced glycation end products (AGEs), interact with tumor necrosis factor-like weak inducer of apoptosis (TWEAK), and attenuate its immunomodulatory function. In the present study, to elucidate the mechanism by which AGEs attenuate TWEAK function, we searched for regions responsible for TWEAK-AGE interaction using TWEAK deletion mutants. Pull-down assays with the TWEAK mutants and AGEs revealed that the C-terminal half of TWEAK, which is the region essential for receptor stimulation, was required for this interaction. On the other hand, the N-terminal deletion mutants did not exhibit a significant decrease in AGE binding. Moreover, a moderate decrease in the AGE binding by double-deletion in quartered C-terminal half regions and a substantial decrease by triple-deletion in this region were observed. In addition, full-length TWEAK stimulated IL-8 gene expression in endothelial EA.hy.926 cells, whereas the triple-deletion mutant lost much of this activity, suggesting that the TWEAK-AGE interaction sites overlap with the region needed to exert normal function of TWEAK. Our present findings may help to elucidate the pathophysiological roles of the TWEAK-AGE interaction for prevention and treatment of AGE-related inflammatory diseases. This article is protected by copyright. All rights reserved. PMID- 30403296 TI - Photo-Fenton and Riboflavin-photosensitized Processes of the Isoxaflutole Herbicide. AB - The proherbicide Isoxaflutole (IXF) hydrolyzes spontaneously to diketonitrile (DKN) a phytotoxic compound with herbicidal activity. In this work, the sensitized degradation of IXF using Riboflavin (Rf), a typical environmentally friendly sensitizer, Fenton and photo-Fenton processes has been studied. The results indicate that only the photo-Fenton process produces a significant degradation of the IXF. Photolysis experiments of IXF sensitized by Riboflavin is not a meaningful process, IXF quenches the Rf excited triplet (3 Rf*) state with a quenching rate constant of 1.5 . 107 m-1 s-1 and no reaction is observed with the species O2 (1 Deltag ) or O2.- generated from 3 Rf*. The Fenton reaction produces no changes in the IXF concentration. While the photo-Fenton process of the IXF, under typical conditions, it produces a degradation of 99% and a mineralization to CO2 and H2 O of 88%. A rate constant value of 1.0 * 109 m-1 s 1 was determined for the reaction between IXF and HO. The photo-Fenton process degradation products were identified by UHPLC-MS/MS analysis. PMID- 30403297 TI - Quenching of the Singlet and Triplet Excited States of Pterin by Amino Acids. AB - Unconjugated oxidized pterins accumulate in the skin of patients suffering from vitiligo and, under UVA irradiation, photosensitize the oxidation of amino acids. In this work, we study the interaction of the singlet and triplet excited states of pterin (Ptr), the parent compound of oxidized pterins, with four oxidizable amino acids: tryptophan (Trp), tyrosine (Tyr), histidine (His) and methionine (Met). Steady-state and time-resolved fluorescence measurements and laser flash photolysis experiments were performed to investigate the quenching of the Ptr excited states by the amino acids in aqueous solution. The singlet excited states of Ptr are quenched by Met mainly via a dynamic process and by Trp via a combination of dynamic and static processes. His does not quench singlet excited states of Ptr, and quenching by Tyr could not be investigated due to the low solubility of this amino acid. The triplet excited states of Ptr are quenched by the four studied amino acids, and the corresponding bimolecular quenching rate constants are in the range of diffusion controlled limit. The assessment of the results in the context of the Ptr-photosensitization of amino acids suggests that triplet excited state of Ptr is the species that initiates the photochemical processes. PMID- 30403298 TI - Prognostic value of progesterone receptor expression in tubo-ovarian high-grade serous carcinoma of the coeur cohort. AB - The association between progesterone receptor (PR) expression and improved outcome of ovarian cancer patients has been reported with conflicting results (1). To clarify the prognostic role of PR expression patients, Luo et al. (1) performed a meta-analysis of 28 published studies. The authors found that PR expression detected by immunohistochemistry (IHC) was associated with favorable overall survival (hazard ratio [HR] = 0.86) combining studies not stratified by histotypes. This article is protected by copyright. All rights reserved. PMID- 30403299 TI - Cohort Study of Albumin versus Lactated Ringer's for Postoperative Cardiac Surgery Fluid Resuscitation in the Intensive Care Unit. AB - PURPOSE: A new postcardiac surgery fluid resuscitation strategy was implemented in our Cardiovascular Intensive Care Unit (CVICU) to implement evidence-based practice. We transitioned from a primarily albumin fluid-based strategy to a lactated Ringer's fluid-based strategy. We sought to determine whether a new postoperative fluid resuscitation strategy significantly altered the fluid composition for postcardiac surgery patients and what effect that would have on fluid resuscitation costs. Secondary outcomes included various clinical parameters. METHODS: This was a retrospective, before-and-after cohort study of postcardiac surgery patients in an academic quaternary care intensive care unit (ICU) during two different 3-month time intervals. A total of 192 patients were studied; 108 pre-intervention and 84 post-intervention. The intervention consisted of surveying stakeholders regarding potential concerns of reducing albumin use, an educational intervention addressing those concerns, and removing albumin from the routine postcardiac surgery ICU admission order set. RESULTS: In the post-intervention time period, albumin use decreased significantly compared to pre-invention (p<0.01), and lactated Ringer's volume increased significantly (p<0.01). However, total volume administered for resuscitation was not significantly different pre- and post-intervention (1129 ml vs. 1369 ml, p=0.136). There was a net-cost savings between the pre-intervention and post intervention period (3 months) of $30,549.20, with the albumin reduction accounting for most of those savings. Secondary outcomes were not significantly different between groups. CONCLUSIONS: An albumin fluid reduction strategy was successful in reducing the amount of albumin fluid used for postcardiac surgery patients and resulted in substantial cost savings. This article is protected by copyright. All rights reserved. PMID- 30403300 TI - Adjunctive Use of Cidofovir and Intravenous Immunoglobulin to Treat Invasive Adenoviral Disease in Solid Organ Transplant Recipients. AB - BACKGROUND: Infections with adenoviruses (ADVs) can result in considerable mortality and morbidity in solid organ transplant (SOT) recipients. Standard therapy for ADV infections in transplant recipients is not established. At our institution, intravenous cidofovir and immunoglobulin have been used to treat disseminated or invasive ADV in SOT and hematopoietic stem cell transplant recipients. METHODS: A retrospective case series of SOT recipients treated with cidofovir and intravenous immunoglobulin was performed. RESULTS: Five SOT recipients (four renal and one heart transplant) with adenovirus infection were treated successfully with cidofovir and immunoglobulin. Cidofovir was discontinued after the first negative ADV viral load and resolution of clinical symptoms, given the concern for nephrotoxicity in renal transplant recipients. Renal tubular acidosis type 2 and iritis were observed in two patients receiving therapy. CONCLUSION: Symptom resolution and a single negative ADV viral load may be indicators for cidofovir discontinuation. PMID- 30403301 TI - Non-IgE-mediated gastrointestinal allergies - do they have a place in a New Model of the Allergic March. AB - The rise in food allergy has been described as the "second wave" of the allergy epidemic, with some developed countries reporting a prevalence of 10% of challenge proven food allergies. Recognition of the Allergic March has played a crucial role in identifying causality in allergic conditions, linking atopic dermatitis to food allergy and food allergy to other atopic disorders, thereby highlighting opportunities in prevention and the importance of early intervention. This publication will establish the value of weaving the less well understood, non-IgE mediated, food allergy into the Allergic March and mapping its progression through childhood and its associated co-morbidities. The proposed non-IgE mediated Allergic March highlights the concomitant presentation of gastrointestinal symptoms and atopic dermatitis as early presenting symptoms in confirmed non-IgE mediated allergies and the later development of atopic co morbidities including asthma and allergic rhinitis, similar to the IgE-mediated Allergic March. This publication highlights recent observations of a link between non-IgE mediated food allergy in early childhood and functional gastrointestinal disorders in later life and also the reported occurrence of extra-intestinal manifestations at later ages. Although significant limitations exist in regards to the proposed evolution of the Allergic March model, the authors hope that this publication will influence the management of non-IgE mediated gastrointestinal allergies and inform future research and interventions. This article is protected by copyright. All rights reserved. PMID- 30403303 TI - Melatonin-deficient rice plants show a common semidwarf phenotype either dependent or independent of brassinosteroid biosynthesis. AB - Melatonin-deficient rice with a semidwarf erect-leaf phenotype was created by suppressing serotonin N-acetyltransferase 2 (SNAT2). We generated an RNAi transgenic rice that suppressed tryptophan decarboxylase (TDC), which encodes the first TDC enzyme committed step for melatonin biosynthesis in plants catalyzing the conversion of tryptophan into tryptamine, to determine whether other transgenic rice with downregulated melatonin biosynthetic genes exhibited the same erect-leaf phenotype as the snat2 RNAi rice. The TDC RNAi rice produced significantly less melatonin than the wild type and exhibited a semidwarf phenotype, but no erect-leaf phenotype was observed. In contrast, tryptamine 5 hydroxylase (T5H) knockout Sekiguchi rice and caffeic acid O-methyltransferase (COMT) RNAi rice seedlings were semidwarf phenotypes with erect leaves, as was the snat2 RNAi rice due to a melatonin deficiency. All RNAi rice plants showing erect-leaf phenotypes had lower expression levels of the DWARF4 gene, which is a key enzyme for brassinosteroid (BR) biosynthesis, leading to lower BR levels than their respective wild types. Suppressing melatonin synthesis did not alter the contents of indole 3-acetic acid (IAA), suggesting the irrelevance of melatonin deficiency to IAA biosynthesis. These data indicate that a semidwarf seedling is a common rice phenotype by the lack of melatonin synthesis with or without BR suppression in a melatonin biosynthetic gene-specific manner. PMID- 30403302 TI - Geraniin Differentially Modulates Chromosome Stability of Colon Cancer and Noncancerous Cells by Oppositely Regulating Their Spindle Assembly Checkpoint. AB - Geraniin has been reported to specifically induce apoptosis in multiple human cancers, but the underlying mechanism is poorly defined. The spindle assembly checkpoint (SAC) is a surveillance system to ensure high-fidelity chromosome segregation during mitosis. Weakening of SAC to enhance chromosome instability (CIN) can be therapeutic because very high levels of CIN are lethal. In this study, we have investigated the effects of geraniin on the SAC of colorectal cancer HCT116 cells and noncancerous colon epithelial CCD841 cells. We find that treatment of HCT116 cells with geraniin leads to dose-dependent decrease of cell proliferation, colony formation and anchorage-independent growth. Geraniin is found to induce apoptosis in mitotic and post-mitotic HCT116 cells. Furthermore, geraniin weakens the SAC function of HCT116 cells by decreasing the transcriptional expression of several SAC kinases (particularly Mad2 and Bub1), which in turn leads to premature anaphase entry, mitotic aberrations and CIN in HCT116 cells. In contrast, the proliferation of CCD841 cells is slightly inhibited by geraniin. Even more interestingly, geraniin increases the transcriptional expression of several SAC kinases (e.g., Mad1 and BubR1) to strengthen SAC efficiency, which contributes to the reduction of mitotic aberrations and CIN in CCD841 cells. Altogether, our findings reveal that the SAC pathway in human colon cancer and noncancerous cell lineages responses oppositely to geraniin treatment, resulting CIN promotion and suppression, respectively. Specific abrogation of SAC to induce catastrophic CIN in HCT116 cells may account for the selective anticancer action of geraniin. This article is protected by copyright. All rights reserved. PMID- 30403304 TI - Paediatric Extrapolation: A Necessary Paradigm Shift. AB - Legislative initiatives have been successful in increasing the availability of approved therapies for paediatric patients. However, additional measures to ensure the timely completion of paediatric studies are necessary to further increase the number of medicines available to children. Over the last three years, international experts convened to revise the ICH E11 guideline on clinical investigations of medicinal products in paediatric populations to harmonise approaches to paediatric extrapolation, striving to reduce substantial differences between regions in the acceptance of data for global paediatric medicine development programmes. Several areas of therapeutics development in children, such as HIV and partial-onset seizures, have been streamlined and require fewer numbers of children enrolled in clinical trials because of the appropriate application of paediatric extrapolation. Based on this experience, it is clear that for paediatric extrapolation strategies to reach their full potential there is the need to understand the quality and quantity of data, often collected in adult patients, that will inform the appropriateness of the use of paediatric extrapolation, as well as to identify gaps in knowledge with respect to disease pathophysiology, organ maturation, or drug target ontogeny. The generation of information that enhances our current understanding of these gaps in knowledge can further decrease the need for larger, paediatric clinical trials, and can increase the efficiency of paediatric therapeutics development as well as protect children from participation in unnecessary studies. We hope that this publication will increase awareness, input, and support from all the stakeholders involved in paediatric therapeutics development. PMID- 30403305 TI - Reappraisal of Contemporary Pharmacokinetic and Pharmacodynamic Principles for Informing Aminoglycoside Dosing. AB - Therapeutic drug management is regularly performed for aminoglycosides in an effort to maximize their effectiveness and safety. The ratio of maximum plasma drug concentration to minimum inhibitory concentration (Cmax /MIC) has long been regarded as the primary pharmacokinetic/pharmacodynamic (PK/PD) index of clinical efficacy for aminoglycosides due to their concentration-dependent killing. In this review, however, we discuss why the area under the plasma concentration-time curve (AUC)/MIC ratio may be a more reliable indicator of bacterial killing and clinical efficacy for these agents. The definitive AUC/MIC efficacy targets for aminoglycosides are less clear, unlike those that exist for fluoroquinolones. Evaluation of available literature suggests that an AUC/MIC ratio of 30-50 for aminoglycoside therapy may provide optimal outcomes when targeting non-critically ill immunocompetent patients with low-bacterial burden gram-negative infections such as urinary tract infections, or in patients receiving additional gram negative therapy with good source control. However, an AUC/MIC target of 80-100 may be more prudent when treating patients with aminoglycoside monotherapy or in critically ill patients with high-bacterial burden infections, such as nosocomial pneumonia. Reappraisal of current antimicrobial susceptibility breakpoints for aminoglycosides against gram-negative bacteria may also be necessary to achieve these AUC/MIC targets and ensure that current empiric doses are not grossly suboptimal in critically ill patients. Although it has been historically difficult to calculate AUCs in clinical practice, equation-based and Bayesian approaches now can be used to estimate the AUC in clinical practice, with limited PK sampling. Additional research is needed to better define optimal AUC/MIC targets for efficacy, especially when drugs are used in combination, as well as PK/PD targets associated with suppression of resistance. It is also important to determine if AUC can predict nephrotoxicity of these agents or whether trough concentrations should be used instead. This article is protected by copyright. All rights reserved. PMID- 30403306 TI - "Normal-appearing" scalp areas are also affected in lichen planopilaris and frontal fibrosing alopecia: an observational histopathologic study of 40 patients. AB - Lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) are lymphocyte mediated scarring alopecias which clinically affect primarily the anterior and mid scalp. However, unaffected scalp areas have not yet been investigated in a systemic manner. In this study we assessed histopathologic changes in affected and unaffected scalp in both diseases and healthy control subjects and compared these findings with clinical signs and scalp symptoms. We have demonstrated that "normal-appearing" scalp that is devoid of clinical lesions of LPP and FFA showed lymphocytic perifollicular inflammation around the isthmus/infundibulum areas in 65% of biopsy specimens, perifollicular fibrosis in 15% and mucin deposits in 7.5% of the cases. None of these findings were found in control samples. No direct correlation was found between the degree of histopathological inflammation, scalp symptoms and clinical lesions in the corresponding affected scalp areas. This preliminary study suggests that both diseases may be more generalized processes which affect the scalp and therefore, need systemic or total scalp therapy. This article is protected by copyright. All rights reserved. PMID- 30403307 TI - Prominent physical inactivity in acute dementia care: Psychopathology seems to be more important than the dose of sedative medication. AB - INTRODUCTION: To objectively quantify patients' physical activity and analyze the relationships between physical activity levels, psychopathology, and sedative medication in acute hospital dementia care. MATERIALS AND METHODS: In this cross sectional study, we assessed the patients' physical activity based on data collection by hybrid motion sensors attached on their lower back. Daily doses of antipsychotics have been converted to olanzapine-equivalents and daily benzodiazepine medication is reported as diazepam-equivalents. We assessed patients' neuropsychiatric symptoms with the Neuropsychiatric Inventory and the Cohen-Mansfield Agitation Inventory. RESULTS: We analyzed motion sensor data from 64 patients (MMSE M = 18.6). On average, patients were lying for 11.5 hours, sitting/standing sedentary for 10.3 hours, sitting/standing active for 1.0 hours, and walking for 1.2 hours per day. The analysis revealed no correlations between patients' physical activity and antipsychotic or benzodiazepine medication. More severe neuropsychiatric symptoms were associated with a decrease in the patients' physical activity (r = .32, P = .01). In particular, patients with apathy symptoms were less physically active than patients without apathy symptoms. DISCUSSION: The results reveal that most of the patients in acute dementia care had very low levels of physical activity. Their physical inactivity may be due to the severity of their neuropsychiatric symptoms, especially apathy. Antipsychotic and benzodiazepine medication appeared to have less impact on patients' physical activity. Dementia care should pay more attention to prevent physical inactivity in patients. PMID- 30403308 TI - Wetland compensation and its impacts on beta-diversity. AB - The anthropogenic degradation of natural ecological communities can cause biodiversity loss in the form of biotic homogenization (i.e., reduced beta diversity). Biodiversity offsetting practices, such as compensatory wetland mitigation, may inadvertently cause biotic homogenization if they produce locally homogenous or regionally recurring communities. The fact that compensation wetlands often resemble degraded wetlands suggests that potential impacts to beta diversity are likely. Yet, it is unknown how high-quality, low-quality (degraded), and compensation wetlands compare in terms of beta-diversity. We compared the beta-diversity of high-quality, low-quality, and compensation wetlands at local and regional scales. beta-diversity was quantified as the average distance to group centroids in multivariate space based on pairwise comparisons of community composition. The local spatial structure of beta diversity was assessed using species turnover across plots. Indicator species analysis was used to describe compositional differences potentially contributing to differences in beta-diversity. Overall, the beta-diversity of compensation sites did not differ from high-quality or low-quality natural wetlands. However, compensation wetlands had a high degree of internal turnover along the hydrological gradient, which culminated in homogenous zones in the wettest areas. Compared to high-quality wetlands, low-quality wetlands had significantly lower beta-diversity at local scales, but significantly greater beta-diversity at regional scales. Indicator species results showed that compensation wetlands were distinguished by low conservation value species typically found in old fields and waste areas. This analysis also indicated that the invasive grass Phalaris arundinacea was indicative of low-quality and compensation wetlands. This species is likely contributing to differing patterns of beta-diversity between high quality and low-quality wetlands. These results indicate that conclusions regarding beta-diversity depend on scale and scope of analysis. Particularly, the unique architecture of compensation wetlands makes conclusions regarding within site beta-diversity dependent on the observer's position along the hydrological gradient. Additionally, while we conclude that compensation wetlands are not contributing to biotic homogenization at the regional scale, these wetlands are distinct from both high-quality and low-quality wetlands in their composition and structure. Therefore, assessments of the overall success of wetland mitigation programs should acknowledge the reality of these differences. PMID- 30403310 TI - Preventing anabolic steroid abuse; a long way to go. AB - In 2017 Rich Piana, an American body builder and internet celebrity, suddenly died at the age of 46. Piana was not particularly successful as a competitive body builder, however, he became an internet sensation due to his massive body size and controversial videos about his long term anabolic steroid- and growth hormone abuse. Shortly after his death many speculated that his demise must have been related to his steroid addiction. The autopsy, however, was inconclusive about the cause of death [1]. This article is protected by copyright. All rights reserved. PMID- 30403309 TI - Evaluation of different cerebrospinal fluid and white matter fMRI filtering strategies-Quantifying noise removal and neural signal preservation. AB - This study examines the impact of using different cerebrospinal fluid (CSF) and white matter (WM) nuisance signals for data-driven filtering of functional magnetic resonance imaging (fMRI) data as a cleanup method before analyzing intrinsic brain fluctuations. The routinely used temporal signal-to-noise ratio metric is inappropriate for assessing fMRI filtering suitability, as it evaluates only the reduction of data variability and does not assess the preservation of signals of interest. We defined a new metric that evaluates the preservation of selected neural signal correlates, and we compared its performance with a recently published signal-noise separation metric. These two methods provided converging evidence of the unfavorable impact of commonly used filtering approaches that exploit higher numbers of principal components from CSF and WM compartments (typically 5 + 5 for CSF and WM, respectively). When using only the principal components as nuisance signals, using a lower number of signals results in a better performance (i.e., 1 + 1 performed best). However, there was evidence that this routinely used approach consisting of 1 + 1 principal components may not be optimal for filtering resting-state (RS) fMRI data, especially when RETROICOR filtering is applied during the data preprocessing. The evaluation of task data indicated the appropriateness of 1 + 1 principal components, but when RETROICOR was applied, there was a change in the optimal filtering strategy. The suggested change for extracting WM (and also CSF in RETROICOR-corrected RS data) is using local signals instead of extracting signals from a large mask using principal component analysis. PMID- 30403311 TI - Regulation of glioma cell invasion by 3q26 gene products PIK3CA, SOX2 and OPA1. AB - Diffuse gliomas progress by invading neighboring brain tissue to promote post operative relapse. Transcription factor SOX2 is highly expressed in invasive gliomas and maps to chromosome region 3q26 together with the genes for PI3K/AKT signaling activator PIK3CA and effector molecules of mitochondria fusion and cell invasion, MFN1 and OPA1. Gene copy number analysis at 3q26 from 129 glioma patient biopsies revealed mutually exclusive SOX2 amplifications (26%) and OPA1 losses (19%). Both forced SOX2 expression and OPA1 inactivation increased LN319 glioma cell invasion in vitro and promoted cell dispersion in vivo in xenotransplanted D. rerio embryos. While PI3 kinase activity sustained SOX2 expression, pharmacological PI3K/AKT pathway inhibition decreased invasion and resulted in SOX2 nucleus-to-cytoplasm translocation in a mTORC1-independent manner. Chromatin immuno-precipitation and luciferase reporter gene assays together demonstrated that SOX2 trans-activates PIK3CA and OPA1. Thus, SOX2 activates PI3K/AKT signaling in a positive feedback loop, while OPA1 deletion is interpreted to counter-act OPA1 trans-activation. Remarkably, neuro-imaging of human gliomas with high SOX2 or low OPA1 genomic imbalances revealed significantly larger necrotic tumor zone volumes, corresponding to higher invasive capacities of tumors, while autologous necrotic cells are capable of inducing higher invasion in SOX2 overexpressing or OPA1 knocked-down relative to parental LN319. We thus propose necrosis volume as a surrogate marker for the assessment of glioma invasive potential. Whereas glioma invasion is activated by a PI3K/AKT-SOX2 loop, it is reduced by a cryptic invasion suppressor SOX2-OPA1 pathway. Thus, PI3K/AKT-SOX2 and mitochondria fission represent connected signaling networks regulating glioma invasion. This article is protected by copyright. All rights reserved. PMID- 30403312 TI - Gagging prevalence and its association with dental fear in 4-12-year-old children in a dental setting. AB - AIM: The aims were to determine the prevalence of gagging in children in the dental setting, detect any association between gagging and dental fear in that setting, and determine if the association varied by type of setting. DESIGN: A total of 734 children (4-12 years old), seeking dental care either at a University paediatric dental clinic (UC) or at a private paediatric practice (PP), filled out the Greek version of the Gagging Assessment Scale (GAS, subjective assessment) and the Greek version of the Children's Fear Survey Schedule-Dental Subscale (CFSS-DS). The shorter form of the Gagging Problem Assessment-dentist part for children (GPA-de-c/SF, dentist's objective measurement) was used to assess their gag reflex. RESULTS: A total of 209 children (28.47%) gagged according to the GPA-de-c/SF. There was no significant difference in gagging between UC and PP children. Children rated as gaggers on the GPA-de-c/SF reported significantly higher GAS and CFSS-DS scores (U = 33 629.000; P < 0.001, U = 31 955.500, P < 0.001, respectively). Also, there was a significant association between GAS and CFSS-DS (rho = 0.307, P < 0.001). CONCLUSIONS: In the dental setting, there were significant relationships between dental fear, the dentist's objective measurement of gagging severity, and the child's subjective gagging assessment. PMID- 30403313 TI - Quantitative characterization of single-cell adhesion properties by atomic force microscopy using protein-functionalized microbeads. AB - A method was developed to characterize the adhesion properties of single cells by using protein-functionalized atomic force microscopy (AFM) probes. The quantification by force spectroscopy of the mean detachment force between cells and a gelatin-functionalized colloidal tip reveals differences in cell adhesion properties that are not within reach of a traditional bulk technique, the washing assay. In this latter method, experiments yield semiquantitative and average adhesion properties of a large population of cells. They are also limited to stringent conditions and cannot highlight disparities in adhesion in the subset of adherent cells. In contrast, this AFM-based method allows for a reproducible and quantitative investigation of the adhesive properties of individual cells in common cell culture conditions and allows for the detection of adhesive subpopulations of cells. These characteristics meet the critical requirements of many fields, such as the study of cancer cell migratory abilities. PMID- 30403314 TI - Multistate occupancy modeling improves understanding of amphibian breeding dynamics in the Greater Yellowstone Area. AB - Discerning the determinants of species occurrence across landscapes is fundamental to their conservation and management. In spatially and climatologically complex landscapes, explaining the dynamics of occurrence can lead to improved understanding of short versus long-term trends and offer novel insight on local versus regional change. We examined the changes in occupancy for two species of anurans with different life histories over a decade using hundreds of wetland sites in Yellowstone and Grand Teton national parks. To account for the joint dynamics of wetland drying and amphibian breeding, we adopted a multistate occupancy model as a means to investigate mechanistic relationship of observed occurrence patterns with climatological drivers of wetland hydrologic variability. This approach allowed us to decompose occupancy dynamics into habitat changes caused by wetland drying and amphibian breeding activity, conditional on available water and previous breeding state. Over our 10-year time series, we observed considerable variability in climate drivers and the proportion of dry wetlands. Boreal Chorus Frogs (Pseudacris maculata) were more responsive to changes in wetland inundation status than Columbia Spotted Frogs (Rana luteiventris) as indicated by higher breeding colonization probabilities under favorable (wet) conditions. Both species had high probabilities of breeding persistence in permanently inundated wetlands with prior breeding. Despite the absence of multi-year drought in our time series, mechanistic relationships described here offer insights on how future climate variation may result in reduced and/or shifted occurrence patterns for pond-breeding anurans in the Greater Yellowstone Area. Further, our modeling approach may prove valuable in evaluating determinants of occurrence for other species that are dependent on wetlands or other dynamic habitats. This article is protected by copyright. All rights reserved. PMID- 30403315 TI - Inhibition, shifting and updating in relation to psychometric intelligence across ability groups in the psychiatric population. AB - BACKGROUND: Assessment of intelligence and executive function (EF) is common in complex neuropsychiatric practice. Although previous studies have shown that EF and intelligence are related, it is unknown whether these constructs relate to one another in a similar manner across different ability groups (mild intellectual disability, borderline intellectual disability and normal/high intelligence). This study therefore examines the relation between three EFs (inhibition, shifting and updating) and intelligence in a heterogeneous psychiatric sample. It is hypothesised that the strength of the relation between intelligence and the three EFs decreases when the level of intelligence increases, in accordance with Spearman's Law of Diminishing Returns. METHODS: In a cross-sectional, between and within subject design, one of the three intelligence tests (Kaufman Adolescent and Adult Intelligence Test and Wechsler Adult Intelligence Scale - third and fourth editions) and several EF tests (Stroop Colour-Word Test, Trail Making Test and Spatial Working Memory task) were administered to 250 neuropsychiatric inpatients and outpatients (Mage = 39.8, standard deviation = 14.3, 52.8% male). Based upon their full-scale IQ score, patients were divided into three ability groups (mild intellectual disability, borderline intellectual disability or normal/high intelligence). The relation between EF and intelligence was assessed through analyses of the correlation pattern; groups were compared using analysis of covariance. RESULTS: Analyses showed significant correlations between the constructs of EF and intelligence. A significant interaction effect was found for shifting, with highest correlations in the normal to high intelligence group, but not for inhibition and updating. CONCLUSIONS: Results support a specific role for shifting in this EF-intelligence relation. The correlational pattern of updating and intelligence, as well as the differential relation of shifting and intelligence across ability groups, suggests that EF tasks may not measure distinct EFs in lower intellectual ability but rely on cognitive primitives such as processing speed. EF tasks can be considered less valid indicators of EF ability. Implications in terms of the need for development of specific tasks to measure cognition in low intellectual ability are discussed. PMID- 30403316 TI - Precision medicine in type 2 diabetes. AB - The Precision Medicine Initiative defines precision medicine as 'an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment and lifestyle for each person'. This approach will facilitate more accurate treatment and prevention strategies in contrast to a one-size-fits-all approach, in which disease treatment and prevention strategies are developed for generalized usage. Diabetes is clearly more heterogeneous than the conventional subclassification into type 1 and type 2 diabetes. Monogenic forms of diabetes like MODY and neonatal diabetes have paved the way for precision medicine in diabetes, as carriers of unique mutations require unique treatment. Diagnosis of diabetes in the past has been dependent upon measuring one metabolite, glucose. By instead including six variables in a clustering analysis, we could break down diabetes into five distinct subgroups, with better prediction of disease progression and outcome. The severe insulin resistant diabetes (SIRD) cluster showed the highest risk of kidney disease and highest prevalence of nonalcoholic fatty liver disease, whereas patients in the insulin-deficient cluster 2 (SIDD) had the highest risk of retinopathy. In the future, this will certainly be improved and expanded by including genetic, epigenetic and other biomarker to allow better prediction of outcome and choice of more precise treatment. PMID- 30403317 TI - CYP2C19 pharmacogenetics versus standard of care dosing for selecting antiplatelet therapy in patients with coronary artery disease: A meta-analysis of randomized clinical trials. AB - OBJECTIVES: This study aimed to evaluate the efficacy and safety of personalized genotype-guided selection of antiplatelet therapy versus standard of care in patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: Clopidogrel is the most frequently used P2Y12 receptor antagonist in patients with coronary artery disease. However, genetic variations of clopidogrel are associated with inter-individual response variability which could limit its efficacy. METHODS: Electronic databases were searched for all randomized clinical trials (RCTs) evaluating genotype-guided therapy versus standard of care in patients undergoing stent implantation. Aggregated risk ratios (RRs) and 95% CIs were calculated using a random-effects model. RESULTS: We included 6 RCTs with a total of 2,371 patients. When compared with standard of care, the use of genotype guided therapy did not significantly reduce major adverse cardiovascular events (MACE) (RR 0.67; 95% CI: 0.35-1.27; P = 0.22). However, MACE was significantly reduced in the subset of trials which enrolled only acute coronary syndromes (ACS) (P < 0.01). In addition, there was a significant reduction in myocardial infarction in the genotype-guided group (RR 0.44; 95% CI: 0.28-0.70; P < 0.01; I2 = 0%). Other clinical outcomes were not significantly different: cardiovascular mortality (RR 0.68; 95% CI: 0.27-1.74; P = 0.42), stroke (RR 0.62; 95% CI: 0.23 1.65; P = 0.34), stent thrombosis (RR 0.37; 95% CI: 0.13-1.06; P = 0.06), and bleeding (RR 0.68; 95% CI: 0.43-1.06; P = 0.09). CONCLUSION: In patients undergoing stent implantation, MACE with genotype-guided therapy was not significantly reduced; however, there was a signal towards reduction of MACE in ACS patients, as well as a lower rate of MI, though this will require further confirmation in adequately powered trials. PMID- 30403318 TI - In situ Second-Harmonic Generation Circular Dichroism with Submonolayer Sensitivity. AB - In this work, we present an experimental setup for the in situ and ex situ study of the optical activity of samples, which can be prepared under ultra-high vacuum (UHV) conditions by second-harmonic generation circular dichroism (SHG-CD) over a broad spectral range. The use of a racemic mixture as a qualified reference for the anisotropy factor is described and, as an example, the chiroptical properties of 1.5 MUm thick (multilayers) as well as sub-monolayer thin films of the R- and S-enantiomer of 1,1'-Bi-2-naphthol (BINOL) evaporated onto BK7 substrates were investigated. PMID- 30403319 TI - Ynamide-Mediated Thiopeptide Synthesis. AB - Thioamide substitution has evolved into an important tool for the chemical biology of peptides and proteins. However, exploration of its full potential has been hampered by insufficient synthetic strategies for site-specific introduction of a thioamide bond to a peptide backbone. A novel ynamide-mediated two-step thiopeptide bond formation strategy with easily available monothiocarboxylic acids as the thioacyl donors is described. The alpha-thioacyloxyenamide intermediates formed from the addition reactions of ynamides and monothiocarboxylic acids are stable and can be purified, characterized and stored. Their appropriate balance between activity and stability enables them to act as effective thioacylating reagents to afford thiopeptide bonds under mild reaction conditions. Notorious issues such as racemization/epimerization and the use of toxic and noxious thionating reagents, which have long plagued thiopeptide synthesis, have been addressed. Some side chain functional groups of amino acids such as -OH, -CONH2, and the NH of indole are tolerated, rendering their protection during thiopeptide synthesis unnecessary. Importantly, the modular nature of this strategy guarantees the site-specific incorporation of a thioamide bond to peptide backbone in both the solution and solid phase. PMID- 30403320 TI - Facilitators and barriers to using neurological outcome measures in developed and developing countries. AB - OBJECTIVE: To identify and compare factors influencing the use of standardized outcome measures by neurological physical therapists working in representative developed (Canada) and developing (India) countries. METHODS: A self-administered web-based questionnaire on facilitators and barriers to using neurological outcome measures was sent by email to neurological physical therapists in Canada and India. Frequencies of responses to each question were computed. Differences between countries were assessed using two-proportion z test. RESULTS: Of 317 respondents, the use of standardized outcome measures was higher for Indian (96.7%) compared with Canadian physical therapists (89.2%). Among the most highly reported facilitators, three were common for both countries (known validity and reliability, outcome measures learned in professional training, and recommended in clinical practice guidelines). Three highly reported barriers were also common for India and Canada (lack of time, relying on judgement for clinical decisions, and unavailability of the assessment tools). Nevertheless, there were differences in the percentages of barriers and facilitators between countries. CONCLUSION: Understanding the factors influencing the uptake of outcome measures among neurological physical therapists working in a developed (Canada) and a developing country (India) can help identify whether strategies should or should not be modified to facilitate knowledge translation in different geographical, professional, or social contexts. PMID- 30403322 TI - Successful treatment of Ureaplasma-induced hyperammonemia syndrome post-lung transplant. AB - Hyperammonemia, in the absence of significant liver dysfunction, is an uncommon but often fatal occurrence following orthotopic lung transplant. Prior reports have provided evidence to support Ureaplasma species as an etiology for this syndrome. This case report describes an individual post-lung transplant, treated emperically with doxycycline along with other measures to lower ammonia levels, at the time hyperammonemia with encephalopathy was recognized. The patient clinically improved. Ureaplasma species were subsequently identified using 16S ribosomal RNA gene PCR/sequencing of pleural fluid, and by culture of bronchoalveolar (BAL) fluid. This case provides further support for empiric treatment of Ureaplasma species upon recognition of hyperammonemia syndrome post lung transplant. PMID- 30403321 TI - Relationship between subjective visual vertical and balance in individuals with multiple sclerosis. AB - BACKGROUND: Subjective visual vertical (SVV) deviations have been correlated to abnormal cerebellar function in individuals diagnosed with multiple sclerosis (MS). It has been shown that individuals with MS have increased incidence of SVV abnormalities, yet this is not routinely tested in this population during physical therapy evaluation. OBJECTIVE: This study aims to determine if there is a relationship between SVV and balance performance in people with MS who have cerebellar involvement. We hypothesize that individuals with greater SVV deviations will have worse balance performance. METHODS: Fifteen females and five males (mean age 54.5 years [+/-7.03 SD]) with the diagnosis of MS and cerebellar involvement participated. Computerized SVV testing included rod and rod-and-frame conditions. None of the balance outcomes were correlated with the rod-only condition. Because there was a difference in magnitude of results within the rod and-frame condition, based on whether the frame was rotated clockwise (CW) or counterclockwise (CCW), they were analysed independently. RESULTS: For all six of the balance outcomes, there was a statistically significant moderate correlation with SVV deviations when the frame was tilted CCW: Barthel Index (r = -0.47, p = 0.018), Berg Balance Score (r = -0.59, p = 0.003), gait velocity (r = -0.52, p = 0.010), International Cooperative Ataxia Rating Scale (r = 0.56, p = 0.006), Scale for the Assessment and Rating of Ataxia (r = 0.62, p = 0.002), and Timed Up and Go (r = 0.58, p = 0.003). Interestingly, the Barthel Index was the only outcome that had statistical significance with a moderate correlation (r = -0.66, p = 0.001) when the frame was rotated CW. In this cohort, greater deviations during the rod-and-frame condition of SVV testing correlated with worse functional outcomes, especially when the frame was tilted CCW. CONCLUSION: Individuals with MS who demonstrate decreased balance performance may rely more heavily on visual backgrounds. Implementation of SVV assessment for individuals with MS may provide clinicians with valuable information to identify clinical interventions. PMID- 30403323 TI - MYOD1 involvement in myopathy. PMID- 30403324 TI - Longitudinal brain magnetic resonance imaging and real-time quaking induced conversion analysis in presymptomatic Creutzfeldt-Jakob disease. PMID- 30403325 TI - Adult-onset Rasmussen encephalitis treated with mitoxantrone. PMID- 30403326 TI - Periodontal ligament on pulp-free root slices - an in vitro model for early tooth (re)integration. An exploratory study AB - Reintegration of freshly extracted healthy teeth is very successful, most likely due to the regenerative capacity of their roots' residual periodontal ligament (PDL). We hypothesised that in vitro cultures of the consecutive slices of a sectioned root will represent the entity of PDL cell types engaged in tooth-sided reintegration. For confirmation, apex and pulp from human premolars were removed and roots cut into 6 to 9 about 1 mm thick slices. These were immobilised to separate wells and cultured for 20 days, under daily inspection for the initiation of cell outgrowth (ICO). ICO and the distribution of vital slices along, the cell growth around as well as the expansion of outgrown cells off the root axes after 20 days were displayed for each tooth as 3D-like profiles. Of the 81 slices from 11 teeth, 55 showed ICO; 64% within one week and 96% within two weeks. Such dynamics compare to the early (day 2-5) and the intermediate (day 9 14) integration phase reported for PDL cells in vivo. Experimental phase contrast images of a single slice showed at ICO few fibroblast- and stem/progenitor- like cells. Four and five days later at the same site cells had grown in number and changed in shape and space over time. This exploratory study indicates that in root slice cultures PDL cells behave similarly to those during reintegration in vivo. It favours our hypothesis, which is now to be adequately verified. Eventually, the model may facilitate the identification of outgrowing cells and cellular changes over time, as triggered by tissue rupture. It may further allow for emulating cellular interactions between the root surface and alveolar bone or engineered constructs, natural or engineered scaffolds, or other tissue, in an in vivo-like situation. PMID- 30403327 TI - Sex differences in social attention in autism spectrum disorder. AB - Although reduced social attention and increased nonsocial attention have been reported in individuals with autism spectrum disorder (ASD), the studies have relied on predominantly male samples and have been underpowered to examine sex differences. These processes may differ for females with ASD, who have been shown to be dissimilar to males in social motivation and nonsocial features, including circumscribed interests (CI). The goal of this study was to compare social and nonsocial visual attention between males and females with ASD on a validated eye tracking paradigm. Eighty-five school-aged (6-10 years) males and females with and without ASD completed a paired preference task of face and object stimuli (half of which related to common CI). After covarying for chronological and mental age, the presence of concurrently presented CI images reduced prioritization and attention to faces for males more than females, replicating previous findings. ASD females maintained comparable attention patterns to typically developing females, suggesting that previous findings of reduced social attention and increased attention to CI-related objects in autism may be specific to males. These findings are also inconsistent with the "extreme male brain" theory of autism. The more normative orienting and attention to social stimuli for females with ASD may indicate distinct phenotypic characteristics relative to males and possibly serve as a protective effect. Autism Res 2018, 11: 1264-1275. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: As autism is more commonly diagnosed in males, less is known about females with autism. Two areas of interest include the interests held by individuals with autism and how socially motivated they are. We used eye tracking as a way to understand these two areas. Our data reveal that elementary school aged females (6-10 years) with autism attended to faces comparatively to females without autism, suggesting that (1) they were more socially motivated than males with autism and (2) the images of common interests were less motivating to them. PMID- 30403328 TI - Reduced distractor interference in neurotypical adults with high expression of autistic traits irrespective of stimulus type. AB - Attention atypicality is evident in autism spectrum disorder (ASD) and its broader phenotype with previous studies suggesting that in some cases participants can be more efficient at ignoring distracting irrelevant information. However, it is not clear to what extent this improved filtering capacity is driven by perceptual atypicality, such as local bias or atypical face processing, which is also sometimes reported in these populations. For instance, better ability to ignore the global aspect of a display could stem from a local perceptual bias rather than from improved distractor inhibition. To test whether distractor suppression per se, is associated with high expression of autistic traits, in the present study a large cohort of neurotypical participants (n = 218), in whom expression of autistic traits was assessed, performed two nonspatial attention selection tasks with different categories of stimuli (global/local and face/scene). Importantly, both tasks involved a conflict with one aspect of the stimuli designated as the target and the other designated as the distractor. Across the two experiments adults with high autistic traits were overall, better able to ignore distractors than adults with low autistic traits, irrespective of the type of perceptual processing involved. These results support the notion that autistic tendencies are associated with increased attention filtering (at least when target and distractor remain constant) which is not dependent on perceptual biases. Thus, future work in the broader autism phenotype should explicitly consider the effect played by attention mechanisms in this population. Autism Res 2018, 11: 1345-1355. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: In the present study, we show that neurotypical adults with high autistic traits are better able to avoid distraction from conspicuous (but completely irrelevant) distractors when told in advance to do so. This ability is not affected by the type of visual input (for instance, whether the distractor is a face or whether small rather than large letters should be reported). This finding could be important in better understanding the way attention is utilized in Autism. PMID- 30403330 TI - Cancer Theranostic Applications of Albumin-Coated Tobacco Mosaic Virus Nanoparticles. AB - Nanotechnology holds great promise in cancer drug delivery, and of particular interest are theranostic approaches in which drug delivery and imaging are integrated. In this work, we studied and developed the plant virus tobacco mosaic virus (TMV) as a platform nanotechnology for drug delivery and imaging. Specifically, a serum albumin (SA)-coated TMV formulation was produced. The SA coating fulfils two functions: SA provides a stealth coating for enhanced biocompatibility; it also acts as a targeting ligand enabling efficient tumor accumulation of SA-TMV versus TMV in mouse models of breast and prostate cancer. We demonstrate drug delivery of the chemotherapy doxorubicin (DOX); TMV-delivered DOX outperformed free DOX, resulting in significant delayed tumor growth and increased survival. Furthermore, we demonstrated the ability of SA-coated TMV loaded with chelated Gd(DOTA) for magnetic resonance imaging detection of tumors. In the future, we envision the application of such probes as theranostic, where first imaging is performed to assess whether the nanoparticles are effective at targeting a particular patient tumor. If targeting is confirmed, the therapeutic would be added and treatment can begin. The combination of imaging and therapy would allow to monitor disease progression and therefore inform about the effectiveness of the drug delivery approach. PMID- 30403331 TI - A Targeted and pH-Responsive Bortezomib Nanomedicine in the Treatment of Metastatic Bone Tumors. AB - Bortezomib is a boronate proteasome inhibitor widely used as an efficient anticancer drug; however, the clinical use of bortezomib is hampered by its adverse effects such as hematotoxicity and peripheral neuropathy, and low efficacy on solid tumors due to unfavorable pharmacokinetics and poor penetration in the solid tumors. In this study, we developed a tripeptide Arg-Gly-Asp (RGD) targeted dendrimer conjugated with catechol and poly(ethylene glycol) groups for the targeted delivery of bortezomib to metastatic bone tumors. Bortezomib was loaded on the dendrimer via a boronate-catechol linkage with pH-responsive property, which plays an essential role in the control of bortezomib loading and release. The nontargeted bortezomib nanomedicine showed minimal cytotoxicity at pH 7.4, but significantly increased anticancer activity when cyclic RGD (cRGD) moieties were anchored on the dendrimer surface. The ligand cRGD enabled efficient internalization of the bortezomib complex by breast cancer cells such as MDA-MB-231 cells. The targeted nanomedicine efficiently depressed the progression of metastatic bone tumors and significantly inhibited the tumor associated osteolysis in a model of bone tumors. This study provided an insight into the development of nanomedicine for metastatic bone tumors. PMID- 30403332 TI - Bioinspired Dual-Enzyme Colloidosome Reactors for High-Performance Biphasic Catalysis. AB - In this paper, a novel method for the construction of colloidosomes as a microreactor for dual-enzyme cascade biphasic reaction has been reported. A lipase-glucose oxidase (GOx) enzyme pair is employed in this system. A water soluble enzyme GOx is compartmentalized inside the colloidosomes. A hydrophobic environment-favored enzyme Candida Antarctica lipase B (CalB) is adsorbed on the outer surfaces of the colloidosomes. The catalysis system is set up by introducing these dual-enzyme-immobilized microcapsules into acetic ether. H2O2 is produced in the aqueous phase by the doped GOx, and then H2O2 diffused out of the microcapsules is utilized by CalB to catalyze the oxidation of ethyl acetate. Finally, the formed peracids oxidized N-heteroaromatic in situ. Furthermore, no obvious yield decline is observed in four reaction cycles. Thus, our work provides a new strategy for the design of high-performance biomimicking reactors for multiple enzyme cascade reactions and further expands the potential application area of colloidosomes. PMID- 30403333 TI - Photothermal-Assisted Optical Stretching of Gold Nanoparticles. AB - The synergy of photothermal energy and optical forces generated by tightly focused laser beams can be used to transform the shape of gold nanoparticles. Here, the combination of these two effects is demonstrated to be an effective way of elongating gold nanoparticles (Au NPs), massively tuning their plasmonic properties. The photothermal effect of the laser increases the temperature of Au NPs above the melting point, and optical forces deform the molten Au NPs. As a result, the shape of Au NPs transforms from nanospheres into nanorods or dimers, depending on the power and time of irradiation as well as the surface energy of the substrate. This process is reversible by using high laser power to transform nanorods back to nanospheres due to capillary dewetting. Such light-induced transformations of nanostructures not only provide a facile way to tune plasmon resonances but also shed light on how the synergistic effect of photothermal energy and optical forces works on plasmonic nanoparticles. PMID- 30403334 TI - Rapid and On-Site Detection of Uranyl Ions via Ratiometric Fluorescence Signals Based on a Smartphone Platform. AB - Fluorescent quantum dots (QDs) of carbon and semiconductors have superior optical properties and show great potential in sensing applications. This paper reports a novel method for rapid detection of uranyl ions via ratiometric fluorescence signals by employing two types of QDs as the key materials. As the most soluble and stable toxic uranium species, uranyl has been recognized as an important index for nuclear industrial wastewater. However, its on-site, rapid, and sensitive determination remains challenging. This work uses the ratiometric fluorescent signal of QDs and combines a smartphone-based handheld device for on site and rapid detection of uranyl. The ratiometric fluorescent probe is achieved by integrating carbon dots (C-dots) and CdTe QDs (MPA@CdTe QDs) through chemical hybridization. The presence of uranyl ions greatly quenches the red fluorescence of the CdTe QDs, whereas the green fluorescence keeps constant, leading to an obvious color change. An app and a 3D-printed accessory have been developed on a smartphone to analyze and calculate the content of uranyl on the basis of captured fluorescence signals from a test strip with an immobilized probe. This new designed mobile detection system displays good analytical performance for uranyl ions in a wide concentration range of 1 to 150 MUM, which shows a great potential application in controlling the nuclear industrial pollution. PMID- 30403335 TI - Metal Catalysts for Layer-Exchange Growth of Multilayer Graphene. AB - Metal-induced layer-exchange growth of amorphous carbon (a-C) is a unique technique for fabricating high-quality, uniform multilayer graphene (MLG) directly on an insulating material. Here, we investigated the effect of transition-metal species on the interaction between metals and a-C in the temperature range of 600-1000 degrees C. As a result, metals were classified into four groups: (1) layer exchange (Co, Ni, Cr, Mn, Fe, Ru, Ir, and Pt), (2) carbonization (Ti, Mo, and W), (3) local MLG formation (Pd), and (4) no graphitization (Cu, Ag, and Au). Some layer-exchange metals allowed for low temperature MLG synthesis at 600 degrees C, whereas others allowed for high quality MLG with a Raman G/D peak ratio of up to 8.3. Based on the periodic table, we constructed metal selection guidelines for growing MLG on an insulator, opening the door for applications that combine advanced electronic devices with carbon materials. PMID- 30403337 TI - Organic Transistor-Based Chemical Sensors for Wearable Bioelectronics. AB - Bioelectronics for healthcare that monitor the health information on users in real time have stepped into the limelight as crucial electronic devices for the future due to the increased demand for "point-of-care" testing, which is defined as medical diagnostic testing at the time and place of patient care. In contrast to traditional diagnostic testing, which is generally conducted at medical institutions with diagnostic instruments and requires a long time for specimen analysis, point-of-care testing can be accomplished personally at the bedside, and health information on users can be monitored in real time. Advances in materials science and device technology have enabled next-generation electronics, including flexible, stretchable, and biocompatible electronic devices, bringing the commercialization of personalized healthcare devices increasingly within reach, e.g., wearable bioelectronics attached to the body that monitor the health information on users in real time. Additionally, the monitoring of harmful factors in the environment surrounding the user, such as air pollutants, chemicals, and ultraviolet light, is also important for health maintenance because such factors can have short- and long-term detrimental effects on the human body. The precise detection of chemical species from both the human body and the surrounding environment is crucial for personal health care because of the abundant information that such factors can provide when determining a person's health condition. In this respect, sensor applications based on an organic-transistor platform have various advantages, including signal amplification, molecular design capability, low cost, and mechanical robustness (e.g., flexibility and stretchability). This Account covers recent progress in organic transistor-based chemical sensors that detect various chemical species in the human body or the surrounding environment, which will be the core elements of wearable electronic devices. There has been considerable effort to develop high performance chemical sensors based on organic-transistor platforms through material design and device engineering. Various experimental approaches have been adopted to develop chemical sensors with high sensitivity, selectivity, and stability, including the synthesis of new materials, structural engineering, surface functionalization, and device engineering. In this Account, we first provide a brief introduction to the operating principles of transistor-based chemical sensors. Then we summarize the progress in the fabrication of transistor based chemical sensors that detect chemical species from the human body (e.g., molecules in sweat, saliva, urine, tears, etc.). We then highlight examples of chemical sensors for detecting harmful chemicals in the environment surrounding the user (e.g., nitrogen oxides, sulfur dioxide, volatile organic compounds, liquid-phase organic solvents, and heavy metal ions). Finally, we conclude this Account with a perspective on the wearable bioelectronics, especially focusing on organic electronic materials and devices. PMID- 30403336 TI - Electrochemical Corrosion Engineering for Ni-Fe Oxides with Superior Activity toward Water Oxidation. AB - The traditional synthesis for bimetallic-based electrocatalysts is challengeable for fine composition and elemental distribution because of the uncontrollable growth speed of nanostructures utilizing metal salt precursors. Herein, a unique electrochemical corrosion engineering strategy is developed via electrochemically transforming metal solid substrates (iron foil and nickel foam) into a highly active Ni-Fe oxide film for oxygen evolution, rather than directly utilizing metal ion precursors. This synthesis involves electrochemical corrosion of a Fe foil in an aqueous electrolyte along with electrochemical passivation of Ni foam (NF). The released trace Fe ions gradually incorporate into passivated NF surfaces to construct Ni-Fe oxide film and crucially improve composition distribution in the catalyst film. As a result, the resulted film with an ultralow mass loading (0.22 mg cm-2) delivers large current densities of 500 mA cm-2 at overpotential of only 270 mV in 6.0 M KOH at 60 degrees C, outperforming many reported NiFe catalysts requiring much higher mass loadings. More interestingly, the as-prepared catalyst almost reaches the standard (500 mA cm-2 within the overpotential of 300 mV) in commercial water electrolysis with long term stability for at least 10 h. This work may provide a unique synthesis strategy for nonprecious transition-metal catalysts for desirable water splitting and can be expanded to many other electrocatalysis systems. PMID- 30403338 TI - Marriage of an Ether-Based Electrolyte with Hard Carbon Anodes Creates Superior Sodium-Ion Batteries with High Mass Loading. AB - Inferior rate performance, insufficient cycle life, and low mass loading have restricted the practical application of hard carbon (HC) anodes in sodium-ion batteries (NIBs). Here, a compatible strategy is developed by matching HC anodes with an ether-based electrolyte. Systematical investigation reveals that good compatibility of the electrode-electrolyte systems forms thinner but a more sustainable solid-electrolyte interphase and delivers a higher ionic conductivity and Na+ ion diffusion coefficient than the commonly used ester-based electrolytes. Therefore, an excellent electrochemical performance is demonstrated with a long cycle life (~196 mA h/g and 90% capacity retention after 2000 cycles at 1 A/g), a super rate capability (~51% capacity retention at 10 A/g) at a mass loading of 1.5 mg/cm2, and a high initial Coulombic efficiency of 85.9%. More importantly, a high reversible areal capacity of 4.3 mA h/cm2 can be achieved at an ultrahigh mass loading of 17 mg/cm2, superior to all reported HC anodes. Our findings not only shed light on the design of high-performance battery systems but also promise a commercial transformation from the lab test to mass production of NIBs. PMID- 30403339 TI - Assembly of Metal-Phenolic/Catecholamine Networks for Synergistically Anti Inflammatory, Antimicrobial, and Anticoagulant Coatings. AB - The development of a facile and versatile strategy to endow surfaces with synergistically anti-inflammatory, antimicrobial, and anticoagulant functions is of particular significance for blood-contacting biomaterials and medical devices. In this work, we report a simple and environmentally friendly "one-pot" method inspired by byssal cuticle chemistry, namely, [Fe(dopa)3] coordination chemistry for assembly of copper ions (Cu2+) and plant polyphenol (tannic acid)/catecholamine (dopamine or norepinephrine) to form metal phenolic/catecholamine network-based coatings. This one-pot method enabled us to easily develop a multifunctional surface based on the combination of the characteristic functions of metal ions and plant polyphenol or catecholamine. The residual phenolic hydroxyl groups on the coatings imparted the modified surface with excellent antioxidant and anti-inflammatory functions. The robust chelation of copper ions to the metal-phenolic/catecholamine networks provided not only durable antibacterial property but also glutathione peroxidase like catalytic capability to continuously and controllably produce antithrombotic nitric oxide by catalyzing endogenous S-nitrothiol. The biological functions of such coatings could be well regulated by adjusting the ratios of the feed concentration of Cu2+ ions to plant polyphenol or catecholamine. We envision that our simple, multifunctional, and bioinspired coating strategy can hold great application promise for bioengineering blood-contacting devices. PMID- 30403340 TI - Engineering of High-Density Thin-Layer Graphite Foam-Based Composite Architectures with Superior Compressibility and Excellent Electromagnetic Interference Shielding Performance. AB - Three-dimensional (3D) graphene architectures with well-controlled structure and excellent physiochemical properties have attracted considerable interest due to their potential applications in flexible electronic devices. However, the majority of the existing 3D graphene still encounters several drawbacks such as brittleness, non-uniform building units, and limited scale (millimeter or even micrometer), which severely limits its practical applications. Herein, we demonstrate a new scalable technique for the preparation of thin-layer graphite foam (GF) with controllable densities (27.2-69.2 mg cm-3) by carbonization of polyacrylonitrile using a template-directed thermal annealing approach. By integrating the GF with poly(dimethylsiloxane) (PDMS), macroscopic porous GF@PDMS with variable thin-layer GF contents ranging from 15.9 to 31.7% was further fabricated. Owing to the robust interconnected porous network of the GF and the synergistic effect between GF and PDMS, GF@PDMS with a 15.9% thin-layer GF content exhibited an impressive 254% increase in compressive strength over the bare GF. In addition, such 15.9% GF@PDMS can totally recover after the first compression cycle at a 95% strain and maintain ~88% recovery even after 1000 compression cycles at an 80% strain, demonstrating its superior compressibility. Moreover, all of the as-prepared GF@PDMS samples possessed high electrical conductivity (up to 34.3 S m-1), relatively low thermal conductivity (0.062-0.076 W m-1 K-1), and excellent electromagnetic interference shielding effectiveness (up to 36.1 dB) over a broad frequency range of 8.2-18 GHz, indicating their great potential as promising candidates for high-performance electromagnetic wave absorption in flexible electronic devices. PMID- 30403341 TI - High-Pressure Synthesis of Manganese Monocarbide: A Potential Superhard Material. AB - In this paper, we report for the first time formation of novel manganese monocarbide (MnC) using laser-heated diamond anvil cell (LHDAC). The synthesis was carried out at high pressure-high temperature (HPHT) and subsequently quenched to ambient condition. The formation and reproducibility have been confirmed in the pressure range of 4.7 to 9.2 GPa. Employing contribution of different probes viz.X-ray diffraction (XRD), selected area electron diffraction (SAED), and ab initio electronic structure calculation, the structure of MnC was found to be ZnS type i.e. a cubic lattice with a = 4.4294(2) A. The bulk modulus has been determined to be 170(5) GPa from in situ high-pressure X-ray diffraction (HPXRD). Hardness of ZnS type MnC is estimated from an empirical relation to be about 40 GPa, making it a potential superhard material. PMID- 30403342 TI - Investigating the Effect of Two-Point Surface Attachment on Enzyme Stability and Activity. AB - Immobilization on solid supports provides an effective way to improve enzyme stability and simplify downstream processing for biotechnological applications, which has been widely used in research and in applications. However, surface immobilization may disrupt enzyme structure due to interactions between the enzyme and the supporting substrate, leading to a loss of the enzyme catalytic efficiency and stability. Here, we use a model enzyme, nitroreductase (NfsB), to demonstrate that engineered variants with two strategically positioned surface tethering sites exhibit improved enzyme stability when covalently immobilized onto a surface. Tethering sites were designed based on molecular dynamics (MD) simulations, and enzyme variants containing cysteinyl residues at these positions were expressed, purified, and immobilized on maleimide-terminated self-assembled monolayer (SAM) surfaces. Sum frequency generation (SFG) vibrational spectroscopy and attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy were used to deduce the NfsB enzyme orientations, which were found to be consistent with those predicted from the MD simulations. Thermal stability analyses demonstrated that NfsB variants immobilized through two tethering sites exhibited generally improved thermal stability compared with enzymes tethered at only one position. For example, NfsB enzyme chemically immobilized via positions 423 and 111 exhibits at least 60% stability increase compared to chemically immobilized NfsB mutant via a single site. This research develops a generally applicable and systematic approach using a combination of simulation and experimental methods to rationally select protein immobilization sites for the optimization of surface-immobilized enzyme activity and stability. PMID- 30403343 TI - Polymer-Assisted In Situ Growth of All-Inorganic Perovskite Nanocrystal Film for Efficient and Stable Pure-Red Light-Emitting Devices. AB - In the past few years, substantial progress has been made in perovskite light emitting devices. Both pure green and infrared thin-film perovskite light emitting devices with external quantum efficiency over 20% have been successfully achieved. However, pure-red and blue thin-film perovskite light-emitting diodes still suffer from inferior efficiency. Therefore, the development of efficient and stable thin-film perovskite light-emitting diodes with pure-red and blue emissions is urgently needed for possible applications as a new display technology and solid-state lighting. Here, we demonstrate an efficient light emitting diode with pure-red emission based on polymer-assisted in situ growth of high-quality all-inorganic CsPbBr0.6I2.4 perovskite nanocrystal films with homogenous distribution of nanocrystals with size 20-30 nm. With this method, we can dramatically reduce the formation temperature of CsPbBr0.6I2.4 and stabilize its perovskite phase. Eventually, we successfully demonstrate a pure-red-emission perovskite light-emitting diode with a high external quantum efficiency of 6.55% and luminance of 338 cd/m2. Furthermore, the device obtains an ultralow turn-on voltage of 1.5 V and a half-lifetime of over 0.5 h at a high initial luminance of 300 cd/m2. PMID- 30403344 TI - Measurement and Manipulation of the Charge State of an Adsorbed Oxygen Adatom on the Rutile TiO2(110)-1*1 Surface by nc-AFM and KPFM. AB - For the first time, the charge states of adsorbed oxygen adatoms on the rutile TiO2(110)-1*1 surface are successfully measured and deliberately manipulated by a combination of noncontact atomic force microscopy and Kelvin probe force microscopy at 78 K under ultrahigh vacuum and interpreted by extensive density functional theory modeling. Several kinds of single and double oxygen adatom species are clearly distinguished and assigned to three different charge states: Oad-/2Oad-, Oad2-/2Oad2-, and Oad--Oad2-, i.e., formal charges of either one or two electrons per atom. Because of the strong atomic-scale image contrast, these states are clearly resolved. The observations are supported by measurements of the short-range force and local contact potential difference as a function of the tip-sample distance as well as simulations. Comparison with the simulations suggests subatomic resolution by allowing us to resolve the rotated oxygen p orbitals. In addition, we manage to reversibly switch the charge states of the oxygen adatoms between the Oad- and Oad2- states, both individually and next to another oxygen, by modulating the frequency shift at constant positive voltage during both charging and discharging processes, i.e., by the tip-induced electric field of one orientation. This work provides a novel route for the investigation of the charge state of the adsorbates and opens up novel prospects for studying transition-metal-oxide-based catalytic reactions. PMID- 30403345 TI - New Strategy toward a Dual Functional Nanocatalyst at Ambient Conditions: Influence of the Pd-Co Interface in the Catalytic Activity of Pd@Co Core-Shell Nanoparticles. AB - Bimetallic nanostructures with a combination of noble and nonnoble metals hold promise for improving catalyst activity and selectivity. Here, we report the synthesis of Pd@Co (PC) core-shell morphology nanoparticles with three different ratios of palladium (Pd) and cobalt (Co), and a possibility to fine tune the ratio of core and shell thickness. PC exhibits superior and selective hydrogenation as well as oxidation catalytic activity at ambient or near-ambient conditions. Various characterization techniques have been employed to confirm the core-shell morphology. Without any pre-treatment or activation, fresh catalysts with different Pd to Co ratios, that is, 2:1, 1:1, and 1:2, were subjected to olefin (phenylacetylene) hydrogenation and oxidation (styrene to styrene oxide) reaction. The catalytic activity results demonstrate that the 1:1 ratio of Pd/Co is the most active composition for controlled and stepwise reduction of phenyl acetylene to styrene and then to ethyl benzene; 1:1 Pd/Co shows 100% styrene conversion in 30 min. with an order of magnitude higher turnover frequency than other catalysts. The 1:1 PC ratio is also the most active composition for selective oxidation of styrene to styrene oxide. NAPXPS (near-ambient pressure XPS) results show that the active sites for catalytic C?C hydrogenation and oxidation reaction are Co0 and Co3+, respectively. However, the superior catalytic performance can be attributed to Co0 (for reduction) or Co3+ (for oxidation), and the Pd-Co interface plays a critical role in stabilizing the required functional character. NAPXPS results confirm that the superior catalytic performance can be attributed not only to Co0 or Co3+, but also to the Pd-Co interface. The electronic effect and synergism between Co and Pd helps Co to stabilize in different oxidation states depending on the reaction conditions, and making it a dual functional catalyst. PMID- 30403346 TI - Nanocellulose, a Versatile Green Platform: From Biosources to Materials and Their Applications. AB - With increasing environmental and ecological concerns due to the use of petroleum based chemicals and products, the synthesis of fine chemicals and functional materials from natural resources is of great public value. Nanocellulose may prove to be one of the most promising green materials of modern times due to its intrinsic properties, renewability, and abundance. In this review, we present nanocellulose-based materials from sourcing, synthesis, and surface modification of nanocellulose, to materials formation and applications. Nanocellulose can be sourced from biomass, plants, or bacteria, relying on fairly simple, scalable, and efficient isolation techniques. Mechanical, chemical, and enzymatic treatments, or a combination of these, can be used to extract nanocellulose from natural sources. The properties of nanocellulose are dependent on the source, the isolation technique, and potential subsequent surface transformations. Nanocellulose surface modification techniques are typically used to introduce either charged or hydrophobic moieties, and include amidation, esterification, etherification, silylation, polymerization, urethanization, sulfonation, and phosphorylation. Nanocellulose has excellent strength, high Young's modulus, biocompatibility, and tunable self-assembly, thixotropic, and photonic properties, which are essential for the applications of this material. Nanocellulose participates in the fabrication of a large range of nanomaterials and nanocomposites, including those based on polymers, metals, metal oxides, and carbon. In particular, nanocellulose complements organic-based materials, where it imparts its mechanical properties to the composite. Nanocellulose is a promising material whenever material strength, flexibility, and/or specific nanostructuration are required. Applications include functional paper, optoelectronics, and antibacterial coatings, packaging, mechanically reinforced polymer composites, tissue scaffolds, drug delivery, biosensors, energy storage, catalysis, environmental remediation, and electrochemically controlled separation. Phosphorylated nanocellulose is a particularly interesting material, spanning a surprising set of applications in various dimensions including bone scaffolds, adsorbents, and flame retardants and as a support for the heterogenization of homogeneous catalysts. PMID- 30403347 TI - n? pi* Interactions Modulate the Properties of Cysteine Residues and Disulfide Bonds in Proteins. AB - Noncovalent interactions are ubiquitous in biology, taking on roles that include stabilizing the conformation and assembly of biomolecules and providing an optimal environment for enzymatic catalysis. Here, we describe a noncovalent interaction that engages the sulfur atoms of cysteine residues and disulfide bonds in proteins-their donation of electron density into an antibonding orbital of proximal amide carbonyl groups. This n->pi* interaction tunes the reactivity of the CXXC motif, which is the critical feature of thioredoxin and other enzymes involved in redox homeostasis. In particular, an n->pi* interaction lowers the pKa value of the N-terminal cysteine residue of the motif, which is the nucleophile that initiates catalysis. In addition, the interplay between disulfide n->pi* interactions and C5 hydrogen bonds leads to hyperstable b sheets. Finally, n->pi* interactions stabilize vicinal disulfide bonds, which are naturally diverse in function. These previously unappreciated n->pi* interactions are strong and underlie the ability of cysteine residues and disulfide bonds to engage in the structure and function of proteins. PMID- 30403348 TI - Control on Dimensions and Supramolecular Chirality of Self-Assemblies through Light and Metal Ions. AB - Precise control over helical chirality and dimensions of molecular self assemblies, a remaining challenge for both chemists and materials scientists, is the key to manipulate the property and performance of supramolecular materials. Herein, we report that a cholesterol-azopyridine conjugate could self-assemble into organogels with photocontrollable dimensional transition from 2D microbelts to 1D nanotubes and finally to 0D nanoparticles. The E/ Z-Photoisomerization of the 4-azopyridine unit is the major driving force for the dimensional transformation. Furthermore, the self-assembled structures were observed to exhibit metal ion-mediated helicity inversion through the metal coordination. These observations were collectively confirmed by several techniques including scanning electron microscopy, atomic force microscopy, circular dichroism, and X ray crystallography. The rational design of building blocks for the construction of dimension and chirality controllable self-assembly systems may lead to versatile applications in smart display, advanced optoelectronic device, and supramolecular asymmetric catalysis. PMID- 30403349 TI - Optimization of Novel 1-Methyl-1 H-Pyrazole-5-carboxamides Leads to High Potency Larval Development Inhibitors of the Barber's Pole Worm. AB - A phenotypic screen of a diverse library of small molecules for inhibition of the development of larvae of the parasitic nematode Haemonchus contortus led to the identification of a 1-methyl-1 H-pyrazole-5-carboxamide derivative with an IC50 of 0.29 MUM. Medicinal chemistry optimization targeted modifications on the left hand side (LHS), middle section, and right-hand side (RHS) of the scaffold in order to elucidate the structure-activity relationship (SAR). Strong SAR allowed for the iterative and directed assembly of a focus set of 64 analogues, from which compound 60 was identified as the most potent compound, inhibiting the development of the fourth larval (L4) stage with an IC50 of 0.01 MUM. In contrast, only 18% inhibition of the mammary epithelial cell line MCF10A viability was observed, even at concentrations as high as 50 MUM. PMID- 30403350 TI - Disentangling Coupling Effects in the Infrared Spectra of Liquid Water. AB - A quantitative characterization of intermolecular and intramolecular couplings that modulate the OH-stretch vibrational band in liquid water has so far remained elusive. Here, we take up this challenge by combining the centroid molecular dynamics formalism, which accounts for nuclear quantum effects, with the MB-pol potential energy function, which accurately reproduces the properties of water across all phases, to model the infrared (IR) spectra of various isotopic water solutions with different levels of vibrational couplings, including those that cannot be probed experimentally. Analysis of the different IR OH-stretch line shapes provides direct evidence for the partially quantum-mechanical nature of hydrogen bonds in liquid water, which is emphasized by synergistic effects associated with intermolecular coupling and many-body electrostatic interactions. Furthermore, we quantitatively demonstrate that intramolecular coupling, which results in Fermi resonances due to the mixing between HOH-bend overtones and OH stretch fundamentals, is responsible for the shoulder located at ~3250 cm-1 of the IR OH-stretch band of liquid water. PMID- 30403351 TI - Experimental Study of the Motion of Patchy Particle Swimmers Near a Wall. AB - In this work, we demonstrate our ability to precisely tailor the surface activity of self-propelled active colloids by varying the size of the active area. The quasi two-dimensional autonomous motion of spherical patchy particle swimmers is studied in a chemical environment in the vicinity of a solid boundary. Oxidative decomposition of hydrogen peroxide into oxygen and water occurs only on a well defined Pt-coated section of the polystyrene particle surface. The asymmetric distribution of product molecules interacting with the particle leads to the autonomous motion, which is characterized as the patch size varies from 11 to 25 to 50% of the particle surface area. The phoretic motion of patchy particle swimmers is analytically predicted by a model developed by Popescu et al. and shows good agreement with the experimentally observed velocities when the influence of the wall on the preferential rotational motion of the particles near the solid boundary is considered. The study illustrates the potential to precisely engineer the motion of particles by controlling their properties rather than depending on changes in the environment. PMID- 30403353 TI - Template-Driven Dense Packing of Pentagonal Molecules in Monolayer Films. AB - The integration of molecules with irregular shape into a long-range, dense and periodic lattice represents a unique challenge for the fabrication of engineered molecular scale architectures. The tiling of pentagonal molecules on a two dimensional (2D) plane can be used as a proof-of-principle investigation to overcome this problem because basic geometry dictates that a 2D surface cannot be filled with a periodic arrangement of pentagons, a fundamental limitation that suggests that pentagonal molecules may not be suitable as building blocks for dense films. However, here we show that the 2D covalent organic framework (COF) known as COF-1 can direct the growth of pentagonal guest molecules as dense crystalline films at the solution/solid interface. We find that the pentagonal molecule corannulene adsorbs at two different sites on the COF-1 lattice, and that multiple molecules can adsorb into well-defined clusters patterned by the COF. Two types of these dense periodic packing motifs lead to a five-fold symmetry reduction compatible with translational symmetry, one of which gives an unprecedented high molecular density of 2.12 molecules/nm2. PMID- 30403352 TI - Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. AB - DNA damage repair enzymes are promising targets in the development of new therapeutic agents for a wide range of cancers and potentially other diseases. The enzyme poly(ADP-ribose) glycohydrolase (PARG) plays a pivotal role in the regulation of DNA repair mechanisms; however, the lack of potent drug-like inhibitors for use in cellular and in vivo models has limited the investigation of its potential as a novel therapeutic target. Using the crystal structure of human PARG in complex with the weakly active and cytotoxic anthraquinone 8a, novel quinazolinedione sulfonamides PARG inhibitors have been identified by means of structure-based virtual screening and library design. 1-Oxetan-3-ylmethyl derivatives 33d and 35d were selected for preliminary investigations in vivo. X ray crystal structures help rationalize the observed structure-activity relationships of these novel inhibitors. PMID- 30403354 TI - Palladium-Catalyzed Arylation/Heteroarylation of Indoles: Access to 2,3 Functionalized Indolines. AB - A palladium-catalyzed diastereoselective dearomatization of N-(2 bromobenzoyl)indoles by an arylation/heteroarylation sequence is reported. Diverse functionalized indolines are accessed in good to excellent yields and selectivity. Studies conducted on the effects of copper in the reaction revealed that, along with improving conversions, the additive inhibits epimerization of the product. PMID- 30403356 TI - Two-Dimensional Radial or Ring-Banded Nonbirefringent Spherulites of Semifluorinated Alkanes Coexistent with Close-Packed Self-Assembled Surface Nanodomains. AB - A series of semifluorinated alkanes (C nF2 n+1C mH2 m+1 diblocks, F n H m, n = 6, 8, 10; m = 16, 18, 20), when cast as films onto solid substrates, were found to form ring-banded or radial spherulites when heated above their isotropic temperature and subsequently cooled down to room temperature, demonstrating that the formation of two-dimensional (2D) spherulites is a general feature of molecular fluorocarbon-hydrocarbon diblocks. These spherulites are not birefringent, a seldom encountered feature for such structures (never, so far, for spherulites made of small molecules). They also provide examples of fluorinated 2D spherulites. Film morphology was analyzed by optical microscopy, interferometric profilometry, atomic force microscopy (AFM), and scanning electron microscopy. Increasing the length of the Fn segment favors the formation of ring-banded spherulites, whereas short Fn segments tend to favor extended radial stripes. Variation of the cooling rate provides control over the size and morphology of the spherulites: slow cooling promotes fibers and radial spherulites, whereas fast cooling fosters ring-banded spherulites. The AFM studies of F10 H16 films revealed that the latter consist of stacks of regularly spaced lamellae. We also observed that, remarkably, stacked lamellae (repeating distance ~6 nm) can coexist with a layer of close-packed monodisperse circular self-assembled surface nanodomains of Fn Hm diblocks (~30 nm in diameter); the latter are known to form from such diblocks at interfaces at room temperature. Substrates partially covered with F10 H16 contain incomplete ring-banded spherulites and smaller objects in which the lamellae and circular nanodomains coexist. PMID- 30403355 TI - Proximity-Induced Superconductivity with Subgap Anomaly in Type II Weyl Semi Metal WTe2. AB - Due to the nontrivial topological band structure in type II Weyl semi-metal tungsten ditelluride (WTe2), unconventional properties may emerge in its superconducting phase. While realizing intrinsic superconductivity has been challenging in the type II Weyl semi-metal WTe2, the proximity effect may open an avenue for the realization of superconductivity. Here, we report the observation of proximity-induced superconductivity with a long coherence length along the c axis in WTe2 thin flakes based on a WTe2/NbSe2 van der Waals heterostructure. Interestingly, we also observe anomalous oscillations of the differential resistance during the transition from the superconducting to the normal state. Theoretical calculations show excellent agreement with experimental results, revealing that such a subgap anomaly is the intrinsic property of WTe2 in superconducting state induced by the proximity effect. Our findings enrich the understanding of the superconducting phase of type II Weyl semi-metals and pave the way for their future applications in topological quantum computing. PMID- 30403357 TI - H-Bonding Mediated Asymmetric Intramolecular Diels-Alder Reaction in the Formal Synthesis of (+)-Aplykurodinone-1. AB - An asymmetric formal total synthesis of (+)-aplykurodinone-1 was achieved using a route, in which hydrogen bonding serves as a stereochemical control element governing the pi-facial selectivity of intramolecular Diels-Alder (IMDA) reaction of an enone tethered 2-pyrone. In the IMDA process, the configuration at a stereogenic, hydroxyl bearing an alpha-carbon in the enone dienophile is conveyed in a highly effective manner through intramolecular hydrogen bonding with the enone carbonyl oxygen. The tricyclic lactone, generated in this process, was successfully converted to a late stage intermediate in Danishefsky's synthesis of aplykurodinone-1. PMID- 30403358 TI - Cu-Catalyzed Enantioselective Reductive Coupling of 1,3-Dienes and Aldimines. AB - Catalytic chemo- and enantioselective generation of 1,3-disubstituted allyl-Cu complexes from a Cu-H addition to 1,3-dienes followed by in situ reactions with aldimines to construct homoallylic amines is presented. The method is distinguished by an unprecedented pathway to generate enantiomerically enriched allyl-Cu species, allowing reactions with a wide range of aldimines in high chemo , site-, diastereo-, and enantioselectivity. Functionalization provides useful building blocks that are otherwise difficult to access. PMID- 30403359 TI - Synthesis of Polyaromatic Rings: Rh(III)-Catalyzed [5 + 1] Annulation of Enaminones with Vinyl Esters through C-H Bond Functionalization. AB - An expedient [5 + 1] annulation method via Rh(III)-catalyzed C-H bond functionalization of enaminones to synthesize polyaromatic rings is described. The reaction tolerates a broad range of functional groups and offers a new entry to construct polycyclic aromatic compounds with amino and formyl substituents. A possible reaction mechanism was proposed based on the results obtained from isotope labeling experiments. PMID- 30403360 TI - Emergence of blaVEB and blaGES among VIM-producing Pseudomonas aeruginosa clinical isolates in Alexandria, Egypt. AB - Thirty-three Pseudomonas aeruginosa isolates, resistant to one or more beta lactams, were included in this study. Identification of tested strains was confirmed using MALDI-TOF/MS. Phenotypic and genotypic beta-lactamase patterns were investigated. Most of the isolates were resistant to carbapenems (32 out of 33) and to the extended-spectrum cephalosporins (ESC) (30 out of 33). Phenotypically, the production of extended-spectrum beta-lactamase (ESBL), metallo-beta-lactamases (MBL), and carbapenemases was detected in 10, 23, and 9 isolates, respectively. However, AmpC hyperproduction was not phenotypically detected among all isolates. Genotypically, ESBL and MBL encoding genes were detected in 23 and 27 isolates, respectively. Altogether 27 strains were detected as blaVIM positive and 16 strains carried blaOXA-10 gene. To the best of our knowledge, this is the first report of P. aeruginosa clinical isolates harboring blaVEB together with blaGES in Egypt, where 5 of our 30 ESC-resistant isolates showed this genotype. Our results confirmed that resistance of P. aeruginosa isolates to beta-lactam antibiotics is mediated via multiple beta-lactamases belonging to different molecular classes. To the best of our knowledge, this is the first report of blaVEB among P. aeruginosa clinical isolates from Egypt. Ten isolates harbored blaVEB and five of them co-harbored blaVEB together with blaGES, blaVIM, and blaOXA-10. PMID- 30403361 TI - High rate of colistin and fosfomycin resistance among carbapenemase-producing Enterobacteriaceae in Turkey. AB - When the problem with carbapenem-resistant Enterobacteriaceae (CRE) increases, the older antimicrobial agents such as colistin and fosfomycin are used for the treatment of these infections. In this study, the broth microdilution method for colistin and the agar dilution method for fosfomycin were used for a total of 147 multidrug-resistant (MDR) or extensively drug-resistant (XDR) strains of CRE. The study included Klebsiella pneumoniae (91.16%), Escherichia coli (7.48%), Enterobacter cloacae (0.68%), and Serratia marcescens (0.68%). All these strains produce various types of carbapenemase, including OXA-48, NDM, and KPC. Some of these strains also have three different carbapenemase mechanisms, including OXA 48 (78.23%), NDM (2.04%), and KPC (0.68%) or OXA-48 and NDM (10.88%), or OXA-48 and KPC (0.68%). About 76.19% of the strains and 67.35% of the strains were resistant for colistin and fosfomycin, respectively. A total of 21 out of 35 colistin-susceptible strains were found to be susceptible to fosfomycin. This study showed that the resistance rates of colistin and fosfomycin are high. The MDR and XDR strains of CRE are spreading in our region and thus a monitoring system for CRE should be followed. Moreover, the applicability of antimicrobial stewardship programs should be increased in all inpatient and outpatient settings. PMID- 30403362 TI - Carbapenem resistance in Acinetobacter baumannii is associated with enhanced survival on hospital fabrics. AB - The success of Acinetobacter baumannii as an emerging organism is probably linked to its high resistance to adverse environmental conditions. This study was conducted to analyze the association between some factors that may favor the dissemination of A. baumannii clinical isolates. A total of 47 clinical strains of A. baumannii were evaluated to carbapenem, the ability to produce biofilm, the susceptibility to some antiseptics, and the survival time on cotton fabrics. Most of the isolates were resistant to carbapenem (72.3%), produced biofilm (83%), and survived more than 7 (51%) days on fabrics. A significant association between decreased susceptibility to antiseptics containing chlorhexidine or triclosan and carbapenem resistance and survival on fabrics could be observed. The resistance to carbapenem was significantly associated with survival on fabric, but not with the ability to form biofilm. The survival of the isolates on fabric was not associated with the ability to produce biofilms. Characteristics, such as resistance to antibiotics, ability to form biofilm, and survival on dry surfaces, probably contribute to the proliferation of this organism when selected in the hospital environment and can partly explain its success as responsible for nosocomial infection. PMID- 30403363 TI - The Influence of Athletic Trainers on the Incidence and Management of Concussions in High School Athletes. AB - CONTEXT: In many US high schools, the athletic trainer (AT) has the responsibility to identify and manage athletes with concussions. Although the availability of ATs varies a great deal among schools, how the level of AT availability in high schools affects the reported incidence and management of sport-related concussions (SRCs) is unknown. OBJECTIVE: To determine how the presence of an AT affects the reporting and management of SRCs. DESIGN: Prospective cohort study. PATIENTS OR OTHER PARTICIPANTS: A total of 2459 (female = 37.5%, age = 16.1 +/- 1.2 years) athletes from 31 Wisconsin high schools were categorized as having low availability (LoAT), mid availability (MidAT), or high availability (HiAT) of ATs. Athletic trainers recorded the incidence, days lost from sport, and postconcussion management through return to sport. The incidence of SRC reporting among categories was examined using a multivariate Cox proportional hazards model. Fisher exact tests were used to determine if postconcussion management differed based on AT availability. RESULTS: The incidence of reported SRCs was lower for the LoAT schools (2.4%) compared with the MidAT (5.6%, hazard ratio = 2.59, P = .043) and HiAT (7.0%, hazard ratio = 3.33, P = .002) schools. The median time before the first AT interaction was longer for LoAT schools (24.0 hours) than for MidAT (0.5 hours, post hoc P = .012) and HiAT (0.2 hours, post hoc P = .023) schools. The number of post-SRC interactions was different in all groups (LoAT = 2 interactions, MidAT = 3, and HiAT = 4; all post hoc P values < .05). Days lost were greater for MidAT and HiAT (both 14 days lost) schools compared with LoAT schools (11.5 days lost, post hoc P = .231 and P = .029, respectively). Athletes at LoAT schools were less likely to undergo a return-to-play protocol (9/18 SRCs, 50.0%) than athletes at MidAT (44/47 SRCs, 93.6%; post hoc P = .001) or HiAT (64/64 SRCs, 100%; post hoc P < .001) schools. CONCLUSIONS: The level of AT availability positively influenced the reported incidence of SRCs as well as postconcussion management activities in this sample of high schools. PMID- 30403364 TI - Atrial fibrillation detected initially during acute medical illness: A systematic review. AB - OBJECTIVE:: There is uncertainty about the incidence of and prognosis associated with atrial fibrillation that is documented for the first time in the setting of an acute stressor, such as surgery or medical illness. Our objective was to perform a systematic review of the incidence and long-term recurrence rates for atrial fibrillation occurring transiently with stress in the setting of acute medical illness. DATA SOURCES:: Medline, Embase and Cochrane Central to September 2017. STUDY SELECTION:: We included retrospective and prospective observational studies, and randomised controlled trials. The population of interest included patients hospitalised for medical (i.e. non-surgical) illness who developed newly diagnosed atrial fibrillation. Studies were included if they included data on either the incidence of atrial fibrillation or the rate of atrial fibrillation recurrence in atrial fibrillation occurring transiently with stress patients following hospital discharge. DATA EXTRACTION:: Two reviewers collected data independently and in duplicate. We characterised each study's methodology for ascertainment of prior atrial fibrillation history, atrial fibrillation during hospitalisation and atrial fibrillation recurrence after hospital discharge. DATA SYNTHESIS:: Thirty-six studies reported the incidence of atrial fibrillation. Ten used a prospective design and included a period of continuous electrocardiographic (ECG) monitoring. Atrial fibrillation incidence ranged from 1% to 44%, which was too heterogeneous to justify meta-analysis ( I2=99%). In post-hoc meta-regression models, the use of continuous ECG monitoring explained 13% of the variance in atrial fibrillation incidence, while care in an intensive care unit explained none. Two studies reported the long-term rate of atrial fibrillation recurrence following atrial fibrillation occurring transiently with stress. Neither of these studies used prospective, systematic monitoring. Recurrence rates at 5 years ranged from 42% to 68%. CONCLUSIONS:: The incidence of atrial fibrillation with medical illness may be as high as 44%, with higher estimates in reports using continuous ECG monitoring. Within 5 years following hospital discharge, atrial fibrillation recurrence is documented in approximately half of patients; however, the true rate may be higher. PROTOCOL REGISTRATION: PROSPERO CRD42016043240. PMID- 30403365 TI - Severe B cell-mediated disease activation despite two cycles of alemtuzumab in a patient with multiple sclerosis. AB - Alemtuzumab is a potent monoclonal CD52 antibody used to treat patients with multiple sclerosis (MS). However, recent literature reports have described paradoxical activation of B cell-mediated disease within 1 year of the first cycle of alemtuzumab. We raise awareness that severe B cell-mediated disease activation could develop, even after two cycles of alemtuzumab, in some vulnerable MS patients; therefore, individualized therapeutic strategies should be considered in clinical practice. We also propose that a novel regulatory B cell subset may be a candidate for a predictive biomarker of disease activation in MS patients treated with alemtuzumab. PMID- 30403366 TI - Real-life use of left ventricular circulatory support with Impella in cardiogenic shock after acute myocardial infarction: 12 years AMC experience. AB - AIMS:: Mortality in cardiogenic shock patients remains high. Short-term mechanical circulatory support with Impella can be used to support the circulation in these patients, but data from randomised controlled studies and 'real-world' data are sparse. The aim is to describe real-life data on outcomes and complications of our 12 years of clinical experience with Impella in patients with cardiogenic shock after acute myocardial infarction and to identify predictors of 6-month mortality. METHODS:: We describe a single-centre registry from October 2004 to December 2016 including all patients treated with Impella for cardiogenic shock after acute myocardial infarction. We report outcomes and complications and identify predictors of 6-month mortality. RESULTS:: Our overall clinical experience consists of 250 patients treated with Impella 2.5, Impella CP or Impella 5.0. A total of 172 patients received Impella therapy for cardiogenic shock, of which 112 patients had cardiogenic shock after acute myocardial infarction. The mean age was 60.1+/-10.6 years, mean arterial pressure was 67 (56 77) mmHg, lactate was 6.2 (3.6-9.7) mmol/L, 87.5% were mechanically ventilated and 59.6% had a cardiac arrest before Impella placement. Overall 30-day mortality was 56.2% and 6-month mortality was 60.7%. Complications consisted of device related vascular complications (17.0%), non-device-related bleeding (12.5%), haemolysis (7.1%) and stroke (3.6%). In a multivariate analysis, pH before Impella placement is a predictor of 6-month mortality. CONCLUSIONS:: Our registry shows that Impella treatment in cardiogenic shock after acute myocardial infarction is feasible, although mortality rates remain high and complications occur. PMID- 30403367 TI - Ultrasound and contrast enhanced ultrasound imaging in the diagnosis of acute aortic pathologies. AB - Conventional ultrasound is worldwide the first-line imaging modality for the prompt diagnosis in the daily practice because it is a cost-effective and easy to perform technique. The additional application of contrast media has been used to enhance the intravascular contrast and to improve the imaging diagnostic accuracy in the detection, classification and follow-up of vascular pathologies. Contrast enhanced ultrasound has the advantage of being a safe, fast and dynamic non invasive imaging tool with excellent results in the diagnosis of acute aortic pathologies, especially the detection of endoleaks after endovascular aneurysm repair. This review describes the diagnostic and therapeutic roles of ultrasound and contrast-enhanced ultrasound imaging in the most common vascular pathologies such as aortic dissections, aneurysms and endoleaks. Keywords: Endoleak, contrast media, ultrasonography, aorta. PMID- 30403368 TI - Attentional Selection Mediates Framing and Risk-Bias Effects. AB - Humans display a number of puzzling choice patterns that contradict basic principles of rationality. For example, they show preferences that change as a result of task framing or of adding irrelevant alternatives into the choice set. A recent theory has proposed that such choice and risk biases arise from an attentional mechanism that increases the relative weighting of goal-consistent information and protects the decision from noise after the sensory stage. Here, using a divided-attention method based on the dot-probe technique, we showed that attentional selection toward values congruent with the task goal takes place while participants make choices between alternatives that consist of payoff sequences. Moreover, we demonstrated that the magnitude of this attentional selection predicts risk attitudes, indicating a common underlying cognitive process. The results highlight the dynamic interplay between attention and choice mechanisms in producing framing effects and risk biases. PMID- 30403370 TI - Evaluation of the Sofia Streptococcus pneumoniae FIA test for the detection of S. pneumoniae antigen in urine. AB - In this study, we evaluated the Sofia Streptococcus pneumoniae FIA test (Quidel Corporation, San Diego, CA, USA), a new immunofluorescence-based lateral flow test for the qualitative detection of S. pneumoniae antigen in urine or cerebrospinal fluid specimens. The analyses of 100 non-concentrated urine samples (including 50 samples from S. pneumoniae cases) showed a sensitivity and specificity (95 % CI) of, respectively, 66.0 % (52.2-77.6) and 100.0 % (92.9 100.0) for the Sofia test, and 62.0 % (48.2-74.1) and 98.0 % (89.5-99.7) for the BinaxNOW SPN Antigen Card. There were no significant differences in sensitivity and specificity between the tests (McNemar's tests, P=0.625 and P=1.000). In conclusion, this study indicates that the Streptococcus pneumoniae FIA test shows similar sensitivity and specificity rates compared to the BinaxNOW SPN Antigen Card. PMID- 30403369 TI - Biomechanical Comparison of Ulnar Collateral Ligament Reconstruction With the Docking Technique Versus Repair With Internal Bracing. AB - BACKGROUND:: The modified Jobe technique of ulnar collateral ligament (UCL) reconstruction has previously been biomechanically compared with primary repair augmented with internal bracing. However, the docking technique has not been compared with repair with internal bracing. HYPOTHESIS:: Load to failure, gapping, and valgus opening angle are similar under valgus loading at 90 degrees of flexion between repair with internal bracing and the docking technique for the UCL. STUDY DESIGN:: Controlled laboratory study. METHODS:: Nine matched pairs of fresh-frozen cadaveric elbows were potted with the forearm in neutral rotation. The palmaris longus tendon graft was harvested, and the bone was sectioned 14 cm proximal and distal to the elbow joint. First, native UCL testing was performed at 90 degrees of flexion with 0.5 N.m preload, followed by a 5 N.m valgus moment to the elbow in cycles of 1, 10, 100, and 1000 at 1 Hz. The specimens were then loaded to failure at a rate of 0.2 mm/s. Next, the elbows were randomly divided into matched pairs to undergo either UCL reconstruction with docking technique or UCL repair augmented with internal bracing. Last, these specimens underwent testing as aforementioned. RESULTS:: Load to failure, gapping, and valgus opening angle did not differ significantly between native ligaments that underwent reconstruction or repair with internal bracing, paired native ligaments and reconstructions, paired native ligaments and repairs augmented with internal bracing, or reconstructions and repairs augmented with internal bracing. CONCLUSION:: UCL reconstruction with docking technique and repair augmented with internal bracing provides valgus stability to the medial elbow comparable to the native ligament at 90 degrees . No significant differences were noted between docking reconstruction and repair techniques for load to failure, gapping, or valgus opening angle during cyclic loading at time zero. CLINICAL RELEVANCE:: Our results suggest that UCL repair with internal bracing has a similar biomechanical profile at the time of initial fixation compared with the docking technique of UCL reconstruction. PMID- 30403371 TI - Evaluation of fast-acting bactericidal activity and substantivity of an antiseptic agent, olanexidine gluconate, using an ex vivo skin model. AB - PURPOSE: We assessed the fast-acting bactericidal activity and substantivity of olanexidine gluconate (OLG) to investigate its remaining bactericidal activity on the skin after rinsing and drying by using an ex vivo Yucatan micropig (YMP) skin model. METHODOLOGY: The fast-acting bactericidal activity was evaluated in pigskin models inoculated with methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, vancomycin-resistant Enterococcus faecalis (VRE), Acinetobacter baumannii, Corynebacterium minutissimum and Cutibacterium acnes. To evaluate substantivity, the YMP skin piece first had 1.5 % OLG, chlorhexidine gluconate (CHG) formulations or 10 % povidone-iodine (PVP-I) applied to it, and was then rinsed with distilled water, incubated for 4, 6, 8 or 12 h and inoculated with the test bacteria (MRSA, S. epidermidis and VRE). The viable bacteria remaining at 1 min of exposure of bacteria were counted to measure the quantity of antiseptic molecules retaining bactericidal activity. To determine the factors contributing to the substantivity, the stratum corneum (SC) of the YMP skin that had had OLG or CHG applied to it was exfoliated using a tape stripping method and the amount of antiseptic was quantitated. RESULTS: OLG showed a fast-acting bactericidal activity that was similar to or stronger than that of CHG formulations up to a concentration of 1 % and PVP-I with a short exposure time of 30 s, and substantivity until 12 h after rinsing, whereas the other antiseptics hardly showed any substantivity. There was 2.8 times or more OLG in the SC than CHG. CONCLUSION: OLG has fast-acting activity and substantivity, which are required properties for an antiseptic, and is useful for preventing infections. PMID- 30403373 TI - Light-dependent pathways for dopaminergic amacrine cell development and function. AB - Retinal dopamine is a critical modulator of high acuity, light-adapted vision and photoreceptor coupling in the retina. Dopaminergic amacrine cells (DACs) serve as the sole source of retinal dopamine, and dopamine release in the retina follows a circadian rhythm and is modulated by light exposure. However, the retinal circuits through which light influences the development and function of DACs are still unknown. Intrinsically photosensitive retinal ganglion cells (ipRGCs) have emerged as a prime target for influencing retinal dopamine levels because they costratify with DACs in the inner plexiform layer and signal to them in a retrograde manner. Surprisingly, using genetic mouse models lacking specific phototransduction pathways, we find that while light influences the total number of DACs and retinal dopamine levels, this effect does not require ipRGCs. Instead, we find that the rod pathway is a critical modulator of both DAC number and retinal dopamine levels. PMID- 30403376 TI - [Urinary lithiasis, a disease followed through its historical footprints.] AB - OBJETIVE: Through two historic episodes we find that they are closely related with urinary lithiasis. METHODS: The cases are described and documented in the same historical account. RESULTS: The lithiasic disease of two historical known characters. Both in a different cultural environment looked for a miraculous healing. CONCLUSIONS: Cure was not achieved in the first case but in the second. Both happened in the Middle Age within a period of 100 years and more than 5,000 kilometers away from each other. PMID- 30403375 TI - [A child's memory.] AB - OBJECTIVES: It is exceptional that the data of a disease are taken from a historical account in which the author, King Alfonso X the Wise himself, in one of the songs (Cantigas) to Mary, the Virgin (monument of universal literature), recites the facts from his childhood in the city of Cuenca, in the middle of August of 1226. These Facts had a great resonance. METHODS: The medical studies were in full decay that did not improve until the creation of the Universities (Paris, Naples, Padua, Bologna and Montpellier). In this Cantiga some good physicals, doctors, are mentioned. There does Peter of Montpellier come from, the Court miniadoctor for King Fernando III that took care of his wife Beatriz of Swabia (daughter of Felipe, Roman King, and Irene Angelo). She was baptized like Isabel but adopted the name in memory of her older sister, empress of the Holy Roman Empire that died in 1212 in a battle. RESULTS: Beatriz, with a very advanced pregnancy, "had such a great fever" and dismay due to a probable urinary cause: "but Pero de Monpisler and other good physicals, they said: -she will not live". Her husband, Fernando III, had marched twelve weeks before, in campaign, to the lands of his ally the King of Baeza. Their children Fadrique and Alfonso, the elder one, were with Queen Beatriz. Condemned by doctors, the patient implored her healing to a miraculous image of Mary, the Virgin, which devotees brought over her in the days when the Assumption festivity was coming. The healing became effective and coincided with the return of Fernando III after the capture of the fortified town of Capela. CONCLUSIONS: Alfonso, in thanksgiving for the healing of his mother, Queen Beatriz, would dedicate this Cantiga to Mary, the Virgin. PMID- 30403374 TI - The insulin/IGF signaling cascade modulates SUMOylation to regulate aging and proteostasis in Caenorhabditis elegans. AB - Although aging-regulating pathways were discovered a few decades ago, it is not entirely clear how their activities are orchestrated, to govern lifespan and proteostasis at the organismal level. Here, we utilized the nematode Caenorhabditis elegans to examine whether the alteration of aging, by reducing the activity of the Insulin/IGF signaling (IIS) cascade, affects protein SUMOylation. We found that IIS activity promotes the SUMOylation of the germline protein, CAR-1, thereby shortening lifespan and impairing proteostasis. In contrast, the expression of mutated CAR-1, that cannot be SUMOylated at residue 185, extends lifespan and enhances proteostasis. A mechanistic analysis indicated that CAR-1 mediates its aging-altering functions, at least partially, through the notch-like receptor glp-1. Our findings unveil a novel regulatory axis in which SUMOylation is utilized to integrate the aging-controlling functions of the IIS and of the germline and provide new insights into the roles of SUMOylation in the regulation of organismal aging. PMID- 30403377 TI - [Is there a correlation between abdominal leak pressure point, incontinence severity and quality of life in patients with stress urinary incontinence?] AB - OBJECTIVES: To evaluate if there is a correlation between the abdominal leak pressure point (ALPP) of the urodynamic study and several tools to evaluate severity and quality of life associated to stress urine incontinence (SUI). METHODS: Prospective correlation study of women referred to urodynamic study for stress urinary incontinence in Centro Urologico Profesor Bengio between September 2014 and October 2015. Anamnesis, physical examination (where the SUI was demonstrated), ICIQSF urine incontinence questionnaire and incontinence impact questionnaire (IIQ-7) were performed to every patient. Uroflowmetry and complete urodynamic study were performed in all cases. Intrinsic sphincter deficiency (ISD) was defined as ALPP value <= 60 cm H2O. The relation between abdominal leak pressure point (ALPP) and incontinence severity measurements and quality of life (daily protectors, Sandvik score, ISIQ-SF score and short IIQ7 score) was evaluated with the Spearman coefficient correlation. RESULTS: 105 females were studied. Mean ALPP was 84 H2O cm (30-170). 21 and 84 patients had ALPP values lower and higher than 60 H2O cm respectively. There were no differences between the groups when general and demographic characteristics were evaluated. No correlation between ALPP and incontinence severity measurements was demonstrated: daily protectors (rho 0.10; p NS), Sandvik severity score (rho 0.05; p NS), ISIQ SF score (rho 0.0004; p NS) and IIQ7 Score (rho 0.06; p NS). When patients with IED (ALPP <= 60 cm H2O) and those without IED DEI (ALPP > 60 cm H2O) were analyzed, there was no statistically significant difference between the groups in the comparison according to severity and quality of life questionnaires. CONCLUSIONS: In this series, there is not a significant correlation between abdominal leak pressure point and severity and quality of life measurements in patients with stress urinary incontinence. PMID- 30403372 TI - Germline VRC01 antibody recognition of a modified clade C HIV-1 envelope trimer and a glycosylated HIV-1 gp120 core. AB - VRC01 broadly neutralizing antibodies (bnAbs) target the CD4-binding site (CD4BS) of the human immunodeficiency virus-1 (HIV-1) envelope glycoprotein (Env). Unlike mature antibodies, corresponding VRC01 germline precursors poorly bind to Env. Immunogen design has mostly relied on glycan removal from trimeric Env constructs and has had limited success in eliciting mature VRC01 bnAbs. To better understand elicitation of such bnAbs, we characterized the inferred germline precursor of VRC01 in complex with a modified trimeric 426c Env by cryo-electron microscopy and a 426c gp120 core by X-ray crystallography, biolayer interferometry, immunoprecipitation, and glycoproteomics. Our results show VRC01 germline antibodies interacted with a wild-type 426c core lacking variable loops 1-3 in the presence and absence of a glycan at position Asn276, with the latter form binding with higher affinity than the former. Interactions in the presence of an Asn276 oligosaccharide could be enhanced upon carbohydrate shortening, which should be considered for immunogen design. PMID- 30403378 TI - [Renal cell carcinoma in von Hippel-Lindau disease. Nephron sparing surgery.] AB - OBJECTIVES: We reviewed the feasibility and safety of nephron sparing surgery for renal cell carcinoma in patients with von Hippel Lindau (VHL) disease. METHODS: We selected 22 patients with (VHL) disease with a mean age of 43 (range 30-56), from whom 16 underwent radical nephrectomy or nephron sparing surgery at our department between 2000 and 2015. RESULTS: A total of 33 tumors were treated, by either tumorectomy (n=20), partial nephrectomy (n=5), percutaneous renal radiofrequency ablation (n=3) edaor radical nephrectomy (n=5). All procedures were successfully completed without intraoperative and postoperative complications. The diameter of the tumor ranged from 2.8 to 4.8 cm. The interval between treatments in patients operated more than once was 40 months. Renal function stayed stable with basal creatinine and current creatinine 0.74 +/- 0.21 mg/dl and 0.93 +/- 0.22 mg/dl respectively. Median follow-up was 72.3 months. Cancer-specific survival was 97%. CONCLUSIONS: nephron sparing surgery in renal tumors >3 cm is an effective and safe treatment for VHL patients. PMID- 30403379 TI - [Therapeutic compliance in patients with renal lithiasis and biochemical risk factors.] AB - OBJECTIVE: To evaluate patient compliance with treatment for urinary lithiasis and to detect differences in adherence, causes of this behavior and associated factors. METHODS: We performed a retrospective study of 93 patients with positive urinary metabolic study (UMS) for lithogenic pathology, diagnosed between 2013 and 2015, gathering data from the digital medical records and a structured telephonic questionnaire in 75 of them. Results were analyzed using the X2 test. RESULTS: 68% of the patients were males. Median age 42.92 (12.17) years. Mean follow up was 2.65 years. Most frequent metabolic alterations were: Hyperoxaluria (42.7%), Hypercalciuria (33.3%) and hipocitraturia (30.7%). Most frequently prescribed drugs: Potassium citrate (70.7%), Thiazide diuretics (26.7%) and calcium supplements (15.1). 84.2% of the patients did not know their UMS and 29.8% did not know the treatment prescribed. 41.9% followed the doses prescribed less than 50% of the times. Dietetic treatment was abandoned by 65% of the patients and pharmacological treatment by 43.5%, mainly due to laziness (62.9% vs 46.2%). 72.6% of the compliant patients experienced improvement. We find a significant relationship between academic level and diagnosis knowledge (p=0.022) and treatment (p=0.036). There were no differences in compliance depending on the number of drugs taken. CONCLUSIONS: Despite urine metabolic study being well valued and treatment well tolerated therapeutic compliance is very low. Most patients would repeat or restart the treatment prescribed in case of recurrence. Diagnostic and therapeutic information provided was not understood. PMID- 30403380 TI - Does the use of fluoroscopy really affect the success rate of retrograde intrarenal surgery? AB - INTRODUCTION: Fluoroscopy is used for access sheath insertion and postoperative control during retrograde intrarenal surgery (RIRS) operation but with this technique both patient and operation team are exposed to radiation. The use of fluoroscopy is disadvantage for both patient and surgeon. Considering results of recent studies, it is clearly seen that fluoroscopy doesn't affect the success and complication rates of RIRS. In this study, we aimed to compare the results of both fluoroscopy and fluoroscopy-free groups, to show if there is a significant difference. METHODS: 385 patients were included in the study and they were divided into two groups. 284 patients were in Group I where fluoroscopy was used. 101 patients were in Group II and fluoroscopy was not used The success rates of primary operation and final success rates were compared. Data from both groups were evaluated objectively using classification systems and imaging methods. RESULTS: Success rates (primary and final) were higher in Group II, and that can be attributed to experience gained over time. Complication rate was lower and success rate was higher in fluoroscopy-free group. According to multivariate analysis, It is clear that the stone dimension is the foreground of the factors that influence the success, and the effect of the stone location is also observed. CONCLUSION: When considering the comparison of success and complication rates between two groups, it is clearly understood that the use of fluoroscopy has not a positive effect on results. According to the outcomes of our study, fluoroscopy-free RIRS can be performed with safe and high success rates. This outcome also leads an important point for avoiding unnecessary radiation exposure. PMID- 30403381 TI - Drug resistance restricts the efficacy of short term low dose Mitomycin-C treatment in UMUC-3 bladder cancer cells. AB - OBJECTIVE: Mitomycin-c (MMC) is the most used intravesical adjuvant agent in non muscle invasive bladder cancer to prevent recurrence. However, a consensus on about appropriate dosage and treatment schedule of MMC is lacking. We, therefore, aimed to evaluate the most appropriate MMC dosage using an in vitro model of high grade human bladder cancer. METHODS: UMUC-3 cells, a model for high-grade bladder cancer, were exposed to MMC in different time courses to assess its toxicological effects. XTT cell proliferation kit was used to evaluate the effect of MMC on the proliferation of UMUC-3 cell line. Gene expression analysis for the MDR1, BCL2 and ANXA5 genes was performed by Real-time PCR and flow cytometry analysis were conducted to evaluate the cell death mechanism and acquired resistance after MMC exposure. An ANXA5 kit was used to detect apoptotic cells, and 7-AAD was used to detect necrotic cells. RESULTS: Cell proliferation was prevented to a large extent (IC50, 0.17-0.081 mg/mL) and cytotoxic effects were observed after 5 MUg/mL and 10 MUg/mL MMC administrations for 1 and 2-h, after the 4th and 2nd dose cycles, respectively. Moreover, cell death was observed at 5 MUg/mL and 10 MUg/mL MMC applications for 1-h and 2-h by the sixth and second week, respectively. Flow cytometry exhibits increased subpopulation of drugextruding UMUC-3 cells after a single dose of MMC for 1-h. MMC did not increase the number of apoptotic or necrotic cells; yet, MDR1 (multiple drug resistance) and ANXA5 (apoptotic) expression levels were increased and BCL2 (anti-apoptotic) expression was decreased. LIMITATIONS: In-vitro nature of the study and working with only one cell culture are inherit limitations of this project. CONCLUSION: A single dose of MMC administration for 1 or 2-h results in drug-resistance. If maintenance treatment is administered for one hour, it should be continued throughout a 6-week period. PMID- 30403382 TI - [Nested variant Transitional Cell Carcinoma. Report of two cases and bibliographic review.] AB - OBJECTIVE: Nested type transitional cell carcinoma of the bladder is a rare histological variant among bladder tumors. Although clinical presentation is similar to the other bladder tumors, its macroscopic appearance may be equivocally benign, with submucosal growing which is difficult to detect on cystoscopy, so that diagnosis may be delayed. METHODS: We present the characteristics of nested type transitional cell carcinoma and review the differential diagnosis for this entity with possible counterfeiters. RESULTS: In this article, we report two cases of nested type transitional cell carcinoma that presents, in one of them, all three growing patterns. CONCLUSIONS: Microscopically nested transitional cell carcinoma is characterized by a cell distribution forming nests and tubules. They generally present low cytologic atypia simulating a low grade urothelial carcinoma, or benign bladder lesions such as von Brunn nests or nefrogenic adenoma. PMID- 30403384 TI - [Inguinoscrotal hematoma after radical orchiectomy.] PMID- 30403383 TI - [Hyponatremia as a presenting sign of metastatic disease in muscle invasive bladder cancer.] AB - OBJECTIVE: Bladder cancer is a commonly diagnosed malignancy in Europe, being 30% muscle-invasive at diagnosis. In these patients, metastases can develop both at diagnosis and after progression. Metastatic disease can manifest in a number of different ways, even as hydroelectrolytic alterations. In this work, we go through the causes of hyponatremia in patients suffering from bladder cancer and its relationship with disseminated disease. METHOD: We present two cases of patients with muscleinvasive bladder cancer with a common electrolytic misbalance, hyponatremia. RESULTS: As a result of the study, bone and cerebral metastases were revealed. CONCLUSIONS: The electrolytic alterations in the oncologic patient can have several causes: chemotherapy, urinary diversion, pain, or even to the tumor itself or its metastases. It is necessary to conduct an exhaustive study in order to discard the most important causes of hyponatremia and be able to decide an appropriate treatment. PMID- 30403385 TI - [Urinoma secondary to ureteral fistula.] PMID- 30403386 TI - Enoxaparin-Induced Massive Abdominal Wall Hematoma Presenting in Hypovolemic Shock. PMID- 30403387 TI - Dabigatran-Associated Thrombocytopenia. PMID- 30403388 TI - Protective Action of Diazoxide on Isoproterenol-Induced Hypertrophy Is Mediated by Reduction in MicroRNA-132 Expression. AB - INTRODUCTION AND METHODS: The effects of diazoxide on cardiac hypertrophy and miR 132 expression were characterized in adult rats and in cardiomyocytes. Diazoxide effects on reactive oxygen species (ROS) production and on the cAMP-response element binding (CREB) transcription factor's abundance in cardiomyocytes were also analyzed. ROS measurements used a fluorescent dye. Western blot analysis and quantitative Reverse Transcription Polymerase Chain Reaction were used to measure phosphorylated form of CREB (pCREB) abundance and miR-132 expression, respectively. RESULTS: Isoproterenol (ISO) induced cardiac hypertrophy, an effect that was mitigated by diazoxide. The rate of ROS production, CREB phosphorylation, and miR-132 expression increased after the addition of ISO. H2O2 increased pCREB abundance and miR-132 expression; upregulation of miR-132 was blocked by the specific inhibitor of CREB transcription, 666-15. Consistent with a role of ROS on miR-132 expression, diazoxide prevented the increase in ROS production, miR-132 expression, and pCREB abundance produced by ISO. Phosphorylation of CREB by ISO was prevented by U0126, an inhibitor of mitogen activated protein kinase. CONCLUSIONS: Our data first demonstrate that diazoxide mitigates hypertrophy by preventing an increase in miR-132 expression. The mechanism likely involves less ROS production leading to less phosphorylation of CREB. Our data further show that ROS enhance miR-132 transcription, and that ISO effects are probably mediated by the mitogen-activated protein kinase pathway. PMID- 30403389 TI - Limited Impact of beta-Adrenergic Receptor Activation on Left Ventricular Diastolic Function in Rat Models of Hypertensive Heart Disease. AB - BACKGROUND: Hypertension is a major cause of left ventricular (LV) diastolic dysfunction. Although beta-adrenergic receptor (beta-AR) blockers are often used to manage hypertension, the impact of beta-AR activation on LV lusitropic effects and hence filling pressures in the hypertensive heart with LV diastolic dysfunction is uncertain. METHODS: Using tissue Doppler imaging and Speckle tracking software, we assessed LV function in isoflurane anesthetised spontaneously hypertensive (SHR) and Dahl salt-sensitive (DSS) rats before and after beta-AR activation [isoproterenol (ISO) administration]. RESULTS: As compared to normotensive Wistar Kyoto control rats, or DSS rats not receiving NaCl in the drinking water, SHR and DSS rats receiving NaCl in the drinking water had a reduced myocardial relaxation as indexed by lateral wall e' (early diastolic tissue velocity at the level of the mitral annulus) and an increased LV filling pressure as indexed by E/e'. However, LV ejection fraction and deformation and motion were preserved in both SHR and DSS rats. The administration of ISO resulted in a marked increase in ejection fraction and decrease in LV filling volumes in all groups, and an increase in e' in SHR, but not DSS rats. However, after ISO administration, although E/e' decreased in DSS rats in association with a reduced filling volume, E/e' in SHR remained unchanged and SHR retained greater values than Wistar Kyoto control. CONCLUSIONS: The hypertensive heart is characterized by reductions in myocardial relaxation and increases in filling pressures, but beta-AR activation may fail to improve myocardial relaxation and when this occurs, it does not reduce LV filling pressures. PMID- 30403390 TI - Cytomegalovirus gastroenteritis with pyloric stenosis and persistent malabsorption in a patient with common variable immunodeficiency. PMID- 30403391 TI - Sudden cardiac arrest in patients without overt heart disease: limited value of next generation sequencing. AB - Introduction Unexplained Sudden Cardiac Arrest (USCA), unrelated to coronary or structural heart disease, occurs in up to 10% of the patients and is often attributed to an inherited arrhythmia syndrome. Family screening and genetic testing may be helpful in clarifying the cause of the USCA. Objectives To assess usefulness of clinical evaluation and genetic testing in patients after USCA and in their families. Patients and methods In the years 2014-2017, we studied 44 unrelated patients after USCA and 96 of their relatives. All patients and relatives underwent comprehensive cardiac evaluation. In 31 USCA patients, a genetic study by next-generation sequencing (NGS) was performed. The Kaplan-Meier survival curve was constructed in order to compare the event-free survival depending on clinical diagnosis//genotype. The adverse event was defined as adequate implantable cardioverter-defibrillator discharge. Results Based on the clinical evaluation, the diagnosis was established in 39% probands (long QT syndrome 21%; short QT syndrome 7%; Brugada syndrome 7%; catecholaminergic polymorphic ventricular tachycardia and early repolarization syndrome, 2% each). Ventricular arrhythmia was identified in relatives of 19% probands. In 18/ 31 (54.8%) probands, 23 rare gene variants were identified, of these only 2 were classified as pathogenic. Event-free survival over median 4.5 years was similar in patients with or without clinical diagnosis, with or without an identified rare genetic variant. Conclusions This study shows the significance of extensive clinical assessment in unexplained sudden cardiac arrest victims and their relatives. Routine genetic testing by NGS in the patients is of little diagnostic and prognostic value. PMID- 30403392 TI - Antimicrobial consumption and influenza incidence monthly trends in 2014 at the community level in Poland. AB - Introduction Antibiotic resistance is nowadays one of the most important public health threats. It is mainly caused by inappropriate antibiotic usage. Objectives We aimed to characterize the seasonal trends of antimicrobial consumption (AC) and to assess the possible relation between the influenza incidence and AC in 2014 at the community level in Poland. Patients and methods Antimicrobial consumption, influenza incidence, and the number of inhabitants vaccinated against influenza were examined at the community level. The AC data were based on the sale and then converted to defined daily doses (DDD) per 1000 inhabitants per day according to the Anatomical Therapeutic Chemical Classification System and the DDD methodology. The data on incidence of influenza and influenza-like cases were based on notifications from primary care doctors. Results The majority of antimicrobials were consumed at the community level. The mean community consumption of antimicrobials for systemic use in Poland in 2014 was 22.50 DDD per 1000 inhabitants per day . The most frequently consumed substances were oral amoxicillin, amoxicillin with enzyme inhibitor and cefuroxime. Two seasonal peaks of antibiotic consumption were observed. Seasonal trends of antibiotic consumption were similar to influenza incidence trends during the studied period. The highest AC was observed in the voivodeship with the highest influenza incidence. Conclusions The extent of outpatient AC and the seasonal coincidence of influenza occurrence and AC pose an important risk for antibiotic overuse and misuse, which are the main causes of antibiotic resistance occurrence and spread. PMID- 30403393 TI - Atmospheric surfaces. PMID- 30403394 TI - Tuning the reactivity of copper complexes supported by tridentate ligands leading to two-electron reduction of dioxygen. AB - A series of copper complexes bearing polypyridyl tridentate ligands have been prepared to fine tune their reactivity toward the oxygen reduction reaction (ORR). During the process of preparation of our copper complexes, we successfully obtained two new crystal structures which are [Cu2(MU-Cl)2(adpa)2](ClO4)2 (2b) and [Cu2(addpa)(CH3CN)2(ClO4)2](ClO4)2 (3a) and a new structure [Cu2(addpa)(CH3CN)2(H2O)2](ClO4)4 (3b) captured after the catalytic ORR. Electrochemical studies and stoichiometric chemical reduction of copper(ii) complexes by ascorbic acid indicated that the presence of an anthracene unit helps to facilitate the reduction of Cu(ii) as well as the stabilisation of Cu(i) species. Regarding oxygen activation, the dinuclear Cu(i) complex 3a showed significantly higher ORR activity than its analogous mononuclear complex 2a. Complex 3a was also found to be relatively robust and competent in catalytic O2 reduction. The observed H2O2 product after this catalysis, together with the data obtained from DFT calculations supported that 3a exhibited a 2H+, 2e- catalytic activity towards the ORR as opposed to the expected 4H+, 4e- process usually found in copper complexes with tridentate ligands. The proton (H+) source for this process was expected from ascorbic acid which also serves as a reducing agent in this reaction. This work highlighted an approach for tuning the ORR activity of the copper complexes by the introduction of a conjugated-pi moiety to the supporting ligand. PMID- 30403400 TI - Migraine Treatment in Pregnant Women Presenting to Acute Care: A Retrospective Observational Study. AB - OBJECTIVE: To assess the acute treatment of pregnant women presenting to a hospital with migraine. BACKGROUND: Migraine is a common problem in pregnancy; however, migraine treatment is challenging in pregnant women for fears of medication teratogenicity and lack of data in this population. To date, no study has directly explored physician practices for treatment of acute migraine in pregnant women. METHODS: We conducted a retrospective chart review of medication administration for pregnant women who presented to an acute care setting with a migraine attack and received neurology consultation between 2009 and 2014. RESULTS: We identified 72 pregnant women with migraine who were treated with pain medications. Fifty-one percent (37/72) were in the third trimester of pregnancy, 39% (28/72) in the second trimester, and 10% (7/72) in the first trimester. Thirty-two percent (23/72) had not tried any acute medications at home before coming to the hospital, and 47% (34/72) presented in status migrainosus. Patients received treatment in the hospital for a median of 23 hours (interquartile range = 5-45 hours). The most common medications prescribed were metoclopramide in 74% (53/72) of patients (95% confidence interval [CI] 62-82%) and acetaminophen in 69% (50/72) of patients (95% CI 58-79%). Metoclopramide was administered along with diphenhydramine in 81% (44/53) of patients (95% CI 71-91%). Acetaminophen was the most frequent medicine administered first (53%, 38/72). Patients were often treated with butalbital (35%, 25/72) or opioids (30%, 22/72), which were used as second- or third-line treatments in 29% of patients (20/72). Thirty-eight percent (27/72) received an intravenous (IV) fluid bolus, 24% received IV magnesium (17/72), and 6% (4/72) had peripheral nerve blocks performed. CONCLUSIONS: While the majority of pregnant women with acute migraine received medications considered relatively safe in pregnancy, there was variation in treatment choice and sequence. Some acute medications considered potentially hazardous for fetal health and less effective for migraine (opioids and butalbital) were used frequently, whereas other treatments that may have low teratogenic risk (nerve blocks, IV fluid boluses, and triptans) were used less or not at all. These results indicate a need for developing guidelines and protocols to standardize acute treatment of migraine in pregnancy. PMID- 30403401 TI - HLA-DR Class II expression on myeloid and lymphoid cells in relation to HLA-DRB1 as a genetic risk factor for visceral leishmaniasis. AB - Genetic variation at HLA-DRB1 is a risk factor for visceral leishmaniasis (VL) caused by Leishmania donovani. The single nucleotide polymorphism rs9271252 upstream of the DRB1 gene provides a perfect tag for protective versus risk HLA DRB1 four-digit alleles. In addition to the traditional role of the membrane distal region of HLA class II molecules in antigen presentation and CD4 T-cell activation, the membrane-proximal region mediates 'non-traditional' multi functional activation, differentiation, or death signals, including in DR expressing T cells. To understand how HLA-DR contributes to disease pathogenesis, we examined expression at the protein level in circulating myeloid (CD14+ , CD16+ ) and lymphoid (CD4+ , CD8+ , CD19+ ) cells of VL patients (pre- and post treatment) compared with endemic healthy controls (EHC). Although DR expression is reduced in circulating myeloid cells in active disease relative to EHC and post-treatment groups, expression is enhanced on CD4+ DR+ and CD8+ DR+ T cells consistent with T-cell activation. Cells of all myeloid and lymphoid populations from active cases were refractory to stimulation of DR expression with interferon gamma (IFN-gamma). In contrast, all populations except CD19+ B cells from healthy blood bank controls showed enhanced DR expression following IFN-gamma stimulation. The rs9271252 genotype did not impact significantly on IFN-gamma activated DR expression in myeloid, B or CD8+ T cells, but CD4+ T cells from healthy individuals homozygous for the risk allele were particularly refractory to activated DR expression. Further analysis of DR expression on subsets of CD4+ T cells regulating VL disease could uncover additional ways in which pleiotropy at HLA DRB1 contributes to disease pathogenesis. PMID- 30403403 TI - Flip-flop organization in the chloroplast genome of Capsosiphon fulvescens (Ulvophyceae, Chlorophyta. AB - To better understand organelle genome evolution of the ulvophycean green alga Capsosiphon fulvescens, we sequenced and characterized its complete chloroplast genome. The circular chloroplast genome was 111,561 bp in length with 31.3% GC content that contained 108 genes including 77 protein-coding genes, two copies of rRNA operons, and 27 tRNAs. In this analysis, we found the two types of isoform, called heteroplasmy, were likely caused by a flip-flop organization. The flip flop mechanism may have caused structural variation and gene conversion in the chloroplast genome of C. fulvescens. In a phylogenetic analysis based on all available ulvophycean chloroplast genome data, including a new C. fulvescens genome, we found three major conflicting signals for C. fulvescens and its sister taxon Pseudoneochloris marina within 70 individual genes: i) monophyly with Ulotrichales, ii) monophyly with Ulvales, and iii) monophyly with the clade of Ulotrichales and Ulvales. Although the 70-gene concatenated phylogeny supported monophyly with Ulvales for both species, these complex phylogenetic signals of individual genes need further investigations using a data-rich approach (i.e., organelle genome data) from broader taxon sampling. This article is protected by copyright. All rights reserved. PMID- 30403402 TI - Gabapentin Enacarbil Extended-Release for Alcohol Use Disorder: A Randomized, Double-Blind, Placebo-Controlled, Multisite Trial assessing Efficacy and Safety. AB - BACKGROUND: Several single-site alcohol treatment clinical trials have demonstrated efficacy for immediate-release (IR) gabapentin in reducing drinking outcomes among individuals with alcohol dependence. The purpose of this study was to conduct a large, multisite clinical trial of gabapentin enacarbil extended release (GE-XR) (HORIZANT(r) ), a gabapentin prodrug formulation, to determine its safety and efficacy in treating alcohol use disorder (AUD). METHODS: Men and women (n= 346) who met DSM-5 criteria for at least moderate AUD were recruited across 10 US clinical sites. Participants received double-blind GE-XR (600 mg twice a day [BID]) or placebo and a computerized behavioral intervention (Take Control) for 6 months. Efficacy analyses were pre-specified for the last 4 weeks of the treatment period. RESULTS: The GE-XR and placebo groups did not differ significantly on the primary outcome measure, percentage of subjects with no heavy drinking days (28.3 vs 21.5, respectively, p=0.157). Similarly, no clinical benefit was found for other drinking measures (percent subjects abstinent, percent days abstinent, percent heavy drinking days, drinks per week, drinks per drinking day), alcohol craving, alcohol-related consequences, sleep problems, smoking, and depression/anxiety symptoms. Common side-effects were fatigue, dizziness, and somnolence. A population pharmacokinetics analysis revealed that patients had lower gabapentin exposure levels compared with those in other studies using a similar dose but for other indications. CONCLUSION: Overall, GE XR at 600 mg BID did not reduce alcohol consumption or craving in individuals with AUD. It is possible that, unlike the IR formulation of gabapentin, which showed efficacy in smaller Phase 2 trials at a higher dose, GE-XR is not effective in treating AUD, at least not at doses approved by the FDA for treating other medical conditions. This article is protected by copyright. All rights reserved. PMID- 30403404 TI - Perceived Collective Efficacy and Parenting Competence: The Roles of Quality of Life and Hope. AB - Parents' perceptions of their parenting competence predict successful implementation of parenting tasks and contribute to their interest and involvement in parenting and to their children's development. Thus, identifying factors that contribute to parents' perceptions of parenting competence can help inform efforts to promote children's safety and well-being. The present study employs social disorganization theory to examine the relationship between collective efficacy and parents' sense of competence, measured along two dimensions: parental efficacy and parental satisfaction. It examines the direct association between the two constructs and whether the association is mediated by parent perceptions of their quality of life (QOL) and sense of hope. Data were collected from 198 parents residing in a neighborhood in southern Tel Aviv, Israel. The analyses indicated that high collective efficacy was directly associated with high parental efficacy, but not with high parental satisfaction. Using structural equation modeling, a mediation model was found whereby higher collective efficacy was associated with (a) higher QOL, which in turn was related to a greater sense of hope, which was linked with higher parental efficacy; and (b) higher QOL, which was directly associated with higher parental satisfaction. The findings provide further support to the idea that neighborhood characteristics play an important role in parents' ability to care for their children. PMID- 30403405 TI - Anti-Calcitonin Gene-Related Peptide (CGRP) Therapies: Update on a Previous Review After the American Headache Society 60th Scientific Meeting, San Francisco, June 2018. AB - OBJECTIVE: To briefly update and correct the available data on anti-calcitonin gene-related peptide (CGRP) therapies for headache since the American Headache Society 60th Scientific Meeting, San Francisco, June 2018. BACKGROUND: CGRP is a target for primary headache therapies. METHODS: The author briefly reviews the new data and publications on gepants and anti-CGRP and anti-CGRP receptor monoclonal antibodies since the writing of his previous review in May 2018, with an emphasis on data provided at the American Headache Society 60th Scientific Meeting, San Francisco, June 2018. RESULTS: The US Food and Drug Administration (FDA) approved erenumab-aooe, an anti-CGRP receptor monoclonal antibody, for the prevention of migraine on May 17, 2018. On September 14, 2018, the FDA approved fremanezumab-vfrm and on September 26, 2018, the FDA approved galcanezumab-gnlm, both anti-CGRP ligand monoclonal antibodies for the prevention of migraine. Galcanezumab showed effectiveness in preventing episodic cluster headache as well, although has not yet been submitted to the FDA for this indication. Both galcanezumab and fremanezumab failed to prevent chronic cluster headache. Eptinezumab will likely be submitted to the FDA for prevention of migraine later in 2018. Two gepants, ubrogepant and rimegepant, have completed positive pivotal trials for the acute treatment of migraine, but have not yet been submitted to the FDA for this indication. A press release with data on the effectiveness of daily atogepant in migraine prevention provides some details. An announcement at the meeting suggests daily rimegepant will be tested for prevention as well. CONCLUSIONS: The development of anti-CGRP therapies opens a new era in the acute and preventive treatment of primary headache disorders. PMID- 30403406 TI - The Headache Cooperative of New England (HCNE) Symposium on Calcitonin Gene Related Peptide. PMID- 30403408 TI - The Toll-like receptor 3 agonist poly(I:C) induces rapid and lasting changes in gene expression related to glutamatergic function and increases ethanol self administration in rats. AB - BACKGROUND: Growing evidence suggests that neuroimmune signaling via Toll-like receptors (TLRs) alters brain circuitry related to alcohol use disorders. Both ethanol exposure and the TLR3 agonist, poly(I:C), increase brain TLR3 expression in neurons and glia. Furthermore, previous studies have shown that cortical TLR3 expression is correlated with lifetime ethanol intake in humans. METHODS: The current experiments investigated the consequences of poly(I:C) treatment on gene expression in two brain regions contributing to alcohol reinforcement, the insular cortex (IC) and nucleus accumbens (Acb) and on operant ethanol self administration, in Long Evans rats. RESULTS: TLR3 activation increased mRNA levels of neuroimmune genes (TLR3, COX2), glutamatergic genes (mGluR2, mGluR3, GLT1), and the trophic factor BDNF in Acb and IC. Furthermore, increases in each of these genes were correlated with increases in TLR3 mRNA, suggesting that TLR3 induction of these genes may impact excitatory transmission in IC and Acb. TLR3 activation also increased ethanol self-administration 18 days post-injection, and enhanced the effects of the mGluR2/3 agonist LY379268 to reduce ethanol self administration following poly(I:C). CONCLUSIONS: Together, these findings suggest lasting consequences of TLR3 activation on gene expression including increases in Group II mGluRs in the Acb. Furthermore, we show an important role for TLR3 signaling in ethanol intake, and a functional involvement of Group II mGluRs. This article is protected by copyright. All rights reserved. PMID- 30403407 TI - In vitro comparison of linear vs triangular screw configuration to stabilize complete uniarticular parasagittal fractures of the proximal phalanx in horses. AB - OBJECTIVE: To assess fracture gap reduction and stability of linear vs triangular 4.5-mm lag screw repair of experimental, uniarticular, and complete forelimb proximal phalanx (P1) fractures. STUDY DESIGN: Experimental. SAMPLE POPULATION: Fourteen equine cadaver limbs/horses. METHODS: Simulated fractures were repaired with 2 lag screws under 4-Nm insertion torque (linear repair). Computed tomography (CT) imaging was performed with the leg unloaded and loaded to forces generated while walking. The fracture repair was revised to include 3 lag screws placed with the same insertion torque (triangular repair) prior to CT. The width of the fracture gap was assessed qualitatively by 2 observers and graded on the basis of gap measurements relative to the average voxel size at dorsal, mid, and palmar P1 sites. Interobserver agreement was assessed with Cohen's kappa. The effect of repair type, loading condition, and measurement site on fracture gap grades was evaluated by using Kendall's tau-b correlation coefficients and paired nonparametric tests. Significance was set at P <= .05. RESULTS: Agreement between loading and fracture gap widening was fair in triangular (kappa = 0.53) and excellent in linear (kappa = 0.81) repairs. Loading resulted in fracture gap distraction in linear repairs (Plinear = .008). Triangular repairs reduced fractures better irrespective of loading (Punloaded = .003; Ploaded < .001). The type of repair was not correlated with fracture gap grades at unloaded mid and loaded dorsal P1 sites. CONCLUSION: Repair of uniarticular complete parasagittal fractures with a triangular screw configuration improved in vitro fracture gap reduction and stability. CLINICAL SIGNIFICANCE: Triangular lag screw repair likely improves biomechanical conditions during postoperative weight bearing. PMID- 30403410 TI - Dissipation behavior of chlorpyrifos residues and risk assessment in sugarcane fields. AB - As chlorpyrifos is used globally to control pests in sugarcane fields, analysis of its residues on food crops is essential to assess products safety for human being. In this study, chlorpyrifos content in sugarcane plants, soil and juice were determined using a gas chromatography with an electron capture detector. The limit of quantification was 0.01 mg/kg for plant and soil, 0.01 mg/L for juice. The degradation and residual risk in sugarcane fields after applying chlorpyrifos to two sample sites (Changsha and Danzhou, China) were assessed. Chlorpyrifos concentrations in plants and soil decreased rapidly over time, reaching a degradation rate ranging from 98.82% to 99.25% on day 35. The half-life of chlorpyrifos in both plants and soil was only 5.97-6.12 days. Regardless of application dosage (standard or high) at pre-harvest interval of 60 days, chlorpyrifos was undetectable in the harvested sugarcane. Risk assessment indicated that chlorpyrifos residue in sugarcane did not pose a health risk to human beings. PMID- 30403409 TI - 4-Phenylbutyric Acid Protects Ethanol-induced Damage in the Developing Mouse Brain. AB - BACKGROUND: Ethanol exposure during pregnancy may result in fetal alcohol spectrum disorders (FASD). One of the most deleterious consequences of ethanol exposure is neuronal loss in the developing brain. Previously we have shown ethanol exposure induced neuroapoptosis in the brain of postnatal day 4 (PD4) mice but not PD12 mice. This differential susceptibility may result from insufficient cellular stress response system such as unfolded protein response (UPR, also known as ER stress) in PD4 mice. In this study, we compared the effect of ethanol on endoplasmic reticulum (ER) stress in PD4 and PD12 mice and determined whether the inhibition of ER stress could protect the developing brain from ethanol-damage. METHODS: We used a third trimester equivalent mouse model of FASD. PD4 and PD12 C57BL/6 mice were subcutaneously injected with saline (control), ethanol, ethanol plus 4-phenylbutyric acid (4-PBA), a chemical chaperone known as ER stress inhibitor, and 4-PBA alone. The expression of apoptosis marker, ER stress markers, and markers for glial cell activation were examined in the cerebral cortex. RESULTS: Ethanol induced neuroapotosis and increased the expression ER stress markers, such as ATF6, GRP78, IRE1alpha, MANF and caspase-12 in PD4 but not PD12 mice. Ethanol exposure also activated microglia and astrocytes. Interestingly, treatment of 4-PBA attenuated ethanol induced neuroapoptosis. Moreover, 4-PBA inhibited the expression of aforementioned ER stress markers and ethanol-induced glial activation in PD4 mice. CONCLUSIONS: ER stress plays an important role in ethanol-induced damage to the developing brain. Inhibition of ER stress is neuroprotective and may provide a new therapeutic strategy to treat FASD. This article is protected by copyright. All rights reserved. PMID- 30403411 TI - Pregnancy after cancer: Timing is everything. PMID- 30403412 TI - Transfusion medicine history illustrated: evacuation, resuscitation and transfusion near "The The Front," First World War. PMID- 30403413 TI - Synthetic cannabinoid: an unexpected cause of coagulopathy. PMID- 30403414 TI - How we evaluate red blood cell compatibility and transfusion support for patients with sickle cell disease undergoing hematopoietic progenitor cell transplantation. AB - Multiple hematopoietic progenitor cell (HPC) transplantation options for patients with sickle cell disease (SCD) are currently under investigation. Patients with SCD have a high rate of alloimmunization to red blood cell antigens, often complicating transfusion support. Transfusion reactions, including acute and delayed hemolytic reactions, have been observed despite immunosuppressive regimens. Allogeneic donor transplants have been shown to carry a risk of prolonged reticulocytopenia and acute hemolysis with severe anemia in nonmyeloablative regimens. We discuss our experience providing transfusion support to patients with SCD undergoing HPC transplantation, propose an outline for a complete pretransplantation evaluation, and discuss donor/recipient compatibility issues and their implications. PMID- 30403415 TI - Psychosocial characteristics of blood donors influence their voluntary nonmedical lapse. AB - BACKGROUND: Approximately 10% of Dutch donors lapse yearly. Common reasons are nonvoluntary medical issues (e.g., low hemoglobin), reaching the upper age limit, and voluntary (e.g., own request, nonresponse). Little is known about predictors of voluntary noncompliance (lapses). Psychosocial characteristics have been linked to various health behaviors, including voluntary noncompliance. Hence, we investigated whether psychosocial characteristics, measured before the first donation, similarly predict subsequent voluntary nonmedical lapse. STUDY DESIGN AND METHODS: New donors (n = 4861) randomly received a blood donation survey between July 2008 and March 2009, before their first appointment at the blood bank. Voluntary lapses included personal reasons, nonresponse to invitations, donor who could not be reached, and no show. Univariate and multivariate Cox regression models of lapse on psychosocial characteristics and confounders (e.g., demographics) were estimated. RESULTS: Of 2964 donors who took the questionnaire, more than one-third (36.5%) had voluntarily lapsed due to nonmedical reasons by 2016. Univariate regression showed that lapse negatively associated with norms, attitudes, and intentions toward blood donation; self-efficacy; and more donation experience. Lapse positively associated with anxiety. Multivariate Cox models showed that lapse was primarily driven by anxiety and need for information. CONCLUSION: Certain psychosocial characteristics increase risks of voluntary lapse. Especially donors with higher donation anxiety had increased lapsing risks. They might benefit from extra attention during donation. Donors with more information need or wish about procedure and patients were less likely to lapse, indicating that binding with the blood bank might prevent lapse. Generally, this study showed that donor lapse and donor return are determined by different psychosocial factors not just the reverse of each other. PMID- 30403416 TI - High-colored plasma: a red signal for transfusion. PMID- 30403418 TI - Genome-wide SNP markers breathe new life into phylogeography and species delimitation for the problematic short-necked turtles (Chelidae: Emydura) of eastern Australia. AB - Understanding the evolutionary history of diversifying lineages and the delineation of evolutionarily significant units and species remain major challenges for evolutionary biology. Low cost representational sampling of the genome for single nucleotide polymorphisms (SNPs) shows great potential at the temporal scales that are typically the focus of species delimitation and phylogeography. We apply these markers to a case study of a freshwater turtle, Emydura macquarii, whose systematics has so far defied resolution, to bring to light a dynamic system of substantive allopatric lineages diverging on independent evolutionary trajectories, but held back in the process of speciation by low level and episodic exchange of alleles across drainage divides on various timescales. In the context of low-level episodic gene flow, speciation is often reticulate, rather than a bifurcating process. We argue that species delimitation needs to take into account the pattern of ancestry and descent of diverging lineages in allopatry together with the recent and contemporary processes of dispersal and gene flow that retard and obscure that divergence. Underpinned by a strong focus on lineage diagnosabilty, this combined approach provides a means for addressing the challenges of incompletely isolated populations with uncommon, but recurrent gene flow in studies of species delimitation, a situation likely to be frequently encountered. Taxonomic decisions in cases of allopatry often require subjective judgements. Our strategy, which adds an additional level of objectivity before that subjectivity is applied, reduces the risk of taxonomic inflation that can accompany lineage approaches to species delimitation. This article is protected by copyright. All rights reserved. PMID- 30403419 TI - Back to the future: Treatment-free remission and pregnancy in chronic myeloid leukemia. PMID- 30403420 TI - Validation of an ELISA for detection of neutrophil gelatinase-associated lipocalin (NGAL) in equine serum. AB - BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) has been shown to be a useful marker of kidney injury in people and dogs, but has not been described in horses. OBJECTIVES: The aim of the study was to validate a commercially available porcine-specific ELISA to measure serum concentrations of equine NGAL. METHODS: Intra- and interassay imprecisions were evaluated by multiple measurements on equine serum pools. Assay inaccuracy was determined by the linearity under dilution. Overlapping performance was assessed by measuring NGAL concentrations in horses with normal and elevated serum creatinine levels. RESULTS: Intra- and interassay imprecision (coefficient of variation) ranged from 5.35% to 28.39%. The ELISA showed no signs of inaccuracy. Overlapping performance was acceptable, as the assay was able to detect the expected differences of NGAL levels in horses with normal and elevated serum creatinine concentrations. CONCLUSIONS: Equine serum NGAL concentrations could be quantified reliably using the porcine-specific ELISA. PMID- 30403421 TI - Diet and trophic interactions of a circumglobally significant gelatinous marine zooplankter, Dolioletta gegenbauri (Uljanin, 1884). AB - Gelatinous zooplankton play a crucial role in marine planktonic food webs. However, primarily due to methodological challenges, the in situ diet of zooplankton remains poorly investigated and little is known about their trophic interactions including feeding behavior, prey selection, and in situ feeding rates. This is particularly true for gelatinous zooplankton including the marine pelagic tunicate, Dolioletta gegenbauri. In this study, we applied an 18S rRNA amplicon metabarcoding approach to identify the diet of captive-fed and wild caught D. gegenbauri on the mid-continental shelf of the South Atlantic Bight (SAB), USA. Sequencing-based approaches were complimented with targeted quantitative real time PCR (Polymerase Chain Reaction) analyses. Captive-fed D. gegenbauri gut content was dominated by pico-, nano- and microplankton including picodinoflagellates (picozoa) and diatoms. These results suggested that diatoms were concentrated by D. gegenbauri relative to their concentration in the water column. Analysis of wild-caught doliolids by quantitative real time PCR utilizing a group-specific diatom primer set confirmed that diatoms were concentrated by D. gegenbauri, particularly by the gonozooid life stage associated with actively developing blooms. Sequences derived from larger metazoans were frequently observed in wild-caught animals but not in captive-fed animals suggesting experimental bias' associated with captive feeding. These studies revealed that the diet of D. gegenbauri is considerably more diverse than previously described, that parasites are common in wild populations, and that prey quality, quantity and parasites are likely all important factors in regulating doliolid population dynamics in continental shelf environments. This article is protected by copyright. All rights reserved. PMID- 30403422 TI - Transition-Metal-Free Three-Component Radical 1,2-Amidoalkynylation of Unactivated Alkenes. AB - A transition-metal-free radical 1,2-amidoalkynylation of unactivated alkenes is presented. alpha-Amido-oxy acids are used as amidyl radical precursors that are oxidized by an organic photoredox catalyst (4CzlPN). The electrophilic N-radicals chemoselectively react with various aliphatic alkenes and the adduct radicals are then trapped by ethynylbenziodoxolones (EBX) reagents to eventually provide the amidoalkynylation products. These transformations, which are conducted under practical and mild conditions, possess high functional group tolerance and show broad substrate scope. Mechanistic studies support the radical nature of these cascades. PMID- 30403423 TI - Non-random association patterns in a plant-mycorrhizal fungal network reveal host symbiont specificity. AB - Arbuscular mycorrhizal (AM) fungi are obligate plant symbionts that have important functions in most terrestrial ecosystems, but there remains an incomplete understanding of host-fungus specificity and the relationships between species or functional groups of plants and AM fungi. Here, we aimed to provide a comprehensive description of plant-AM fungal interactions in a biodiverse semi natural grassland. We sampled all plant species in a 1000 m2 homogeneous plot of dry calcareous grassland in two seasons (summer and autumn) and identified root colonizing AM fungi by SSU rDNA sequencing. In the network of 33 plant and 100 AM fungal species, we found a significant effect of both host plant species and host plant functional group on AM fungal richness and community composition. Comparison with network null models revealed a larger-than-random degree of partner selectivity among plants. Grasses harbored a larger number of AM fungal partners and were more generalist in partner selection, compared with forbs. More generalist partner association and lower specialization were apparent among obligately, compared with facultatively, mycorrhizal plant species and among locally more abundant plant species. This study provides the most complete dataset of co-occurring plant and AM fungal taxa to date, showing that at this particular site, the interaction network is assembled non-randomly, with moderate selectivity in associations between plant species and functional groups and their fungal symbionts. This article is protected by copyright. All rights reserved. PMID- 30403424 TI - Pregnancy after cancer: Does timing of conception affect infant health? AB - BACKGROUND: The objective of this retrospective cohort study was to determine whether women who conceive soon after treatment for cancer have higher risks of adverse pregnancy outcomes. METHODS: Vital records data were linked to cancer registry diagnosis and treatment information in 3 US states. Women who conceived their first pregnancy after diagnosis between ages 20 and 45 years with any invasive cancer or ductal carcinoma in situ were eligible. Log-binomial models were used to compare risks in cancer survivors who conceived in each interval to the risks in matched comparison births to women without cancer. RESULTS: Women who conceived <=1 year after starting chemotherapy for any cancer had higher risks of preterm birth than comparison women (chemotherapy alone: relative risk [RR], 1.9; 95% confidence interval [CI], 1.3-2.7; chemotherapy with radiation: RR, 2.4; 95% CI, 1.6-3.6); women who conceived >=1 year after starting chemotherapy without radiation or >=2 years after chemotherapy with radiation did not. In analyses imputing the treatment end date for breast cancer survivors, those who conceived >=1 year after finishing chemotherapy with or without radiation had no higher risks than women without cancer. The risk of preterm birth in cervical cancer survivors largely persisted but was somewhat lower in pregnancies conceived after the first year (for pregnancies conceived <=1 year after diagnosis: RR, 3.5; 95% CI, 2.2-5.4; for pregnancies conceived >1 year after diagnosis: RR, 2.4; 95% CI, 1.6-3.5). CONCLUSIONS: In women who received chemotherapy, the higher risk of preterm birth was limited to those survivors who had short intervals between treatment and conception.Cancer 2018;124:000-000. PMID- 30403425 TI - Effect of the diets with pumpkin silage and synthetic beta-carotene on the carotenoid, immunoglobulin and bioactive protein content and fatty acid composition of colostrum. AB - Forty Simmental cows were divided into four groups with 10 per group to investigate the effect of a transition diet supplemented with synthetic beta carotene and natural carotenoid-rich feed (pumpkin silage) on chemical composition of the colostrum. The control group (I) was fed grass and maize silage and supplemental concentrates, group II additionally received 400 mg/day/cow of synthetic beta-carotene, in group, III 40% DM of maize silage was replaced with pumpkin silage to increase beta-carotene intake by 400 mg in relation to group I, and in group IV 60% DM of maize silage was replaced with pumpkin silage without adjusting for beta-carotene. Colostrum was collected from the cows within 5 hr of calving to determine colostrum composition, the content of immunoglobulins and carotenoids, total antioxidant status (TAS), the content of some bioactive proteins and the composition of fatty acids. The study showed that the experimental diets had no effect on the gross composition of colostrum. The content of alpha-carotene, beta-carotene and violaxanthin was significantly higher in group IV than in group I and that of lutein higher in group IV than in groups I and II. Total antioxidant status of colostrum in group IV was significantly higher than in group I. Groups III and IV were characterized by a higher concentration of immunoglobulin IgG in relation to group I. IgM level in groups II, III and IV was significantly higher than in group I and that in groups III and IV was also higher than in group II. The highest IgA concentration was observed in group IV and the lowest in group I. Lysozyme concentration was higher in group IV compared to groups I and II. The diets had no effect on the total content of SFA, MUFA and PUFA in colostrum. PMID- 30403427 TI - The effect of caffeine loading on cerebral autoregulation in preterm infants. AB - AIM: To evaluate cerebral autoregulation changes in preterm infants receiving a loading dose of caffeine base. METHODS: In a cohort of 30 preterm infants, we extracted measures of cerebral autoregulation using time and frequency domain techniques to determine the correlation between mean arterial pressure (MAP) and tissue oxygenation index (TOI) signals. These measures included the cerebral oximetry index (COx), cross-correlation and coherence measures, and were extracted prior to caffeine loading and in the 2 hours following administration of 10 mg/kg caffeine base. RESULTS: We observed acute reductions in time domain correlation measures, including the cerebral oximetry index (linear mixed-model coefficient -0.093, standard error 0.04; p = 0.028) and the detrended cross correlation coefficient (rho5 coefficient -0.13, standard error 0.055; p = 0.025). These reductions suggested an acute improvement in cerebral autoregulation. Features from detrended cross-correlation analysis also showed greater discriminative value than other methods in identifying changes prior to and following caffeine administration. CONCLUSION: We observed a reduced correlation between MAP and TOI from near-infrared spectroscopy following caffeine administration. These findings suggest an acute enhanced capacity for cerebral autoregulation following a loading dose of caffeine in preterm infants, contributing to our understanding of the physiological impact of caffeine therapy. This article is protected by copyright. All rights reserved. PMID- 30403426 TI - Left ventricular blood flow patterns at rest and under dobutamine stress in healthy pigs. AB - Intracardiac blood flow patterns are affected by the morphology of cardiac structures and are set up to support the heart's pump function. Exercise affects contractility and chamber size as well as pre- and afterload. The aim of this study was to test the feasibility of four-dimensional phase contrast cardiovascular MRI under pharmacological stress and to study left ventricular blood flow under stress. 4D flow data were successfully acquired and analysed in 12 animals. During dobutamine infusion, heart rate and ejection fraction increased (82 +/- 5 bpm versus 124 +/- 3 bpm/46 +/- 9% versus 65 +/- 7%; both p < 0.05). A decrease in left ventricular end-diastolic volume (72 +/- 14 mL versus 55 +/- 8 mL; p < 0.05) and end-systolic volume (40 +/- 15 mL versus 19 +/- 6 mL; p < 0.05) but no change in stroke volume were observed. Trans-mitral diastolic inflow velocity increased under dobutamine and the trajectory of inflowing blood was directed towards the anterior septum with increased inflow angle (26 +/- 5 degrees ) when compared with controls (15 +/- 2 degrees ). In 5/6 animals undergoing stress diastolic vortices developed later, and in 3/6 animals vortices collapsed earlier with significantly smaller cross-sectional area during diastole. The vorticity index was not affected. Under the stress condition direct flow (% ejection within the next heart beat) increased from 43 +/- 6% to 53 +/- 8%. 4D MRI blood flow acquisition and analysis are feasible in pig hearts under dobutamine-induced stress. Flow patterns characterized by high blood velocity and antero-septally oriented diastolic inflow as well as decreased ventricular volumes are unfavourable conditions for diastolic vortex development under pharmacological stress, and cardiac output is increased by a rise in heart rate and directly ejected left ventricular blood volume. PMID- 30403429 TI - Recurrence of adenomatoid odontogenic tumor. PMID- 30403428 TI - Effects of eccentric versus concentric contractions of the biceps brachii on intracortical inhibition and facilitation. AB - Differences in the neural mechanisms underpinning eccentric (ECC) and concentric (CON) contractions exist; however, the acute effects of fatiguing muscle contractions on intracortical and corticospinal excitability are not well understood. Therefore, we compared maximal ECC and CON contractions of the right biceps brachii (BB) muscle for changes in corticospinal excitability, short- (SICI) and long-interval intracortical inhibition (LICI) and intracortical facilitation (ICF) up to 1 hour post-exercise. Fourteen right-handed adults (11 M/3F; 26.8 +/- 2.9 year) undertook a single session of 3 sets of 10 maximal ECC or CON contractions (180-second rest between sets) on an isokinetic dynamometer (40 degrees /s) separated by 1 week, in a randomized crossover study. Maximum voluntary isometric contraction torque (MVIC), maximal muscle compound waves (MMAX ), and motor-evoked potentials elicited through transcranial magnetic stimulation (TMS) were recorded via surface electromyography from the right BB. MVIC decreased (P < 0.001) immediately after ECC and CON contractions similarly, but the decrease was sustained at 1 hour post-ECC contractions only. MMAX was reduced immediately (P = 0.014) and 1 hour post-exercise (P = 0.019) only for ECC contractions. SICI and ICF increased immediately after ECC and CON contractions (P < 0.001), but LICI increased only after ECC contractions (P < 0.001), and these increases remained at 1 hour post-ECC contractions only. These findings suggest that ECC contractions induced a longer-lasting neuromodulatory effect on intracortical inhibition and facilitation, which could indicate a central compensatory response to peripheral fatigue. PMID- 30403430 TI - INQ-15 cut-off scores for suicidal ideation screening of women with chronic, invisible illnesses. AB - In the interpersonal theory of suicide, perceived burdensomeness (PB) and thwarted belongingness (TB) are proximal triggers of suicidal ideation. Using the 15-item version of the Interpersonal Needs Questionnaire (INQ-15), suicidal ideation in psychiatric inpatients was predicted by the PB and TB scales, and cut off scores were recommended. In this study, women (N = 942) who reported one or more chronic, invisible illnesses completed an online survey including the INQ-15 and the Suicide Behaviours Questionnaire-Revised (SBQ-R). PB and TB correlated significantly with SBQ-R total scores (r = 0.575 and 0.437, respectively; p < 0.01). In a Receiver Operating Characteristic analysis, scores of 17 for PB and 37 for TB maximized the correct classification of high-risk and low-risk participants, with slightly higher classification accuracy for PB than TB (AUCs = 0.781 and 0.701, respectively). These results support the INQ-15 scales in screening for suicidal ideation among chronically ill women. PMID- 30403431 TI - Serosal invasion is a strong prognostic factor for hepatocellular carcinoma after hepatectomy. AB - AIM: The clinical impact of serosal invasion by hepatocellular carcinoma (HCC) remains unclear. This study aimed to clarify the significance of serosal invasion as a prognostic factor for patients who underwent hepatectomy for HCC. METHODS: This retrospective study investigated patients who underwent hepatectomy for HCC between 2003 October and 2016 September in Ehime University Hospital. A total of 161 cases were enrolled after excluding cases of concomitant distant metastasis, macroscopic tumor remnant, mixed HCC, and re-hepatectomy. We classified these 161 patients into groups with serosal invasion detected (S[+]) and serosal invasion undetected (S[-]). We compared patient characteristics, perioperative data, pathological findings, and prognosis between S(+) and S(-) groups. RESULTS: Serosal invasion was observed in 19 of the 161 patients (12%). The 5-year recurrence-free survival rate was lower for S(+) (13.0%) than for S(-) (28.7%, P = 0.006). The 5-year overall survival (OS) rate was lower for S(+) (24.7%) than for S(-) (63.9%, P < 0.001). Regarding OS, serosal invasion, preoperative alpha fetoprotein value, presence of invasion to hepatic veins, and liver cirrhosis were independent predictors in multivariate analyses. The 3-year OS rate after recurrence was poorer in the S(+) group (22.9%) than in the S(-) group (49.7%, P = 0.001). CONCLUSIONS: Serosal invasion was a strong predictor of worse outcomes after hepatectomy for HCC. Patients showing serosal invasion need close postoperative follow-up or consideration of adjuvant treatment. PMID- 30403432 TI - Clinical Pharmacy Services in a Multidisciplinary Specialty Pain Clinic. AB - PURPOSE: To describe a model of clinical pharmacy services as part of a multidisciplinary specialty pain clinic by discussing 1) the role of a clinical pharmacist in a specialty setting, including clinical interventions implemented, and 2) how integration of a clinical pharmacist may translate into an improved patient care model for the management of chronic pain. METHODS: A retrospective chart review was conducted of pharmacist visits from October 1, 2013 to September 30, 2015 in a specialty pain clinic at an academic medical center in Los Angeles, CA. Data were collected regarding medication-related problems (MRPs) identified by the pharmacist, interventions implemented to resolve the MRPs, and types of medication care coordination activities (MCCAs) performed by the pharmacist, such as responding to medication refill requests and insurance issues. Descriptive statistics were used. IRB approval was obtained prior to initiating the study. RESULTS: At least 1 MRP was identified in 98.7% of the 380 visits. Problems identified by the clinical pharmacist were divided into 5 categories: medication refills needed (43%), medication appropriateness/effectiveness (18%), miscellaneous (17%), safety (16%), and nonadherence/patient variables (6%). Interventions focused on referral to appropriate providers, medication counseling, medication initiation, dose adjustment, and medication discontinuation. The most common MCCA was responding to refill requests. CONCLUSION: A clinical pharmacist can identify many MRPs and implement interventions in chronic pain management. Integration of clinical pharmacy services may improve practice management by facilitating the completion of MCCAs and increase access to patients' needs outside the clinic. This article is protected by copyright. All rights reserved. PMID- 30403433 TI - Guillain-Barre syndrome post renal transplant: A systematic review. AB - BACKGROUND: Guillain-Barre syndrome (GBS) is a common ascending polyneuropathy in adults. It is often associated with preceding viral or diarrhoeal illness with cytomegalovirus (CMV), Epstein-Barr virus (EBV), or Campylobacter jejuni. Solid organ transplant recipients are more susceptible to opportunistic infections with CMV than the general population as a result of immunosuppressive therapies to prevent graft rejection. However, reports of GBS are rare in this population. OBJECTIVE: To systematically review cases of GBS in renal transplant patients to evaluate causative pathogens or triggers, management and associated morbidity and mortality. METHODS AND RESULTS: We conducted a systematic search of the MEDLINE database uncovering 17 cases of GBS in renal transplant patients in the literature. The majority of cases were in males (81%) and patients who received deceased donor renal transplants (87%). The mean age was 44.7 years (SD 13). The time between transplant and onset of symptoms ranged from 2 days to 10 years (Mean = 720 days). GBS was commonly associated with antecedent viral (CMV 12; EBV 1) or diarrhoeal (2) illness while two cases were attributed to calcineurin inhibitor use. All patients recovered fully or partially after treatment with anti-viral or anti-bacterial agents, immunoglobulins, and/or plasma exchange. CONCLUSION: Cytomegalovirus is the most common trigger for GBS in the post-renal transplant setting. Other triggers include campylobacter jejuni and calcineurin inhibitors. GBS should be considered in transplant patients presenting with weakness or paralysis in order to institute timely management. PMID- 30403434 TI - Specific Ion Effects on an Oligopeptide: Bidentate Binding Matters for the Guanidinium Cation. AB - Ion-protein interactions are important for protein function, yet challenging to rationalize owing to the multitude of possible ion-protein interactions. To explore specific ion effects on protein binding sites, we investigate the interaction of different salts with the zwitterionic peptide triglycine in solution. Dielectric spectroscopy shows that salts affect the peptide's reorientational dynamics, with a more pronounced effect for denaturing cations (Li+ , guanidinium (Gdm+ )) and anions (I- , SCN- ) than for weakly denaturing ones (K+ , Cl- ). The effects of Gdm+ and Li+ were found to be comparable. Molecular dynamics simulations confirm the enhanced binding of Gdm+ and Li+ to triglycine, yet with a different binding geometry: While Li+ predominantly binds to the C-terminal carboxylate group, bidentate binding to the terminus and the nearest amide is particularly important for Gdm+ . This bidentate binding markedly affects peptide conformation, and may help to explain the high denaturation activity of Gdm+ salts. PMID- 30403435 TI - Hydrogenation of CO2 to Formate with H2 : Transition Metal Free Catalyst Based on a Lewis Pair. AB - Hydrogenation of CO2 to formate with H2 in the absence of transition metal is a long-standing challenge in catalysis. The reactions between tris(pentafluorophenyl)borane (BCF) and K2 CO3 (or KHCO3 ) are found to form a Lewis pair (K2 [(BCF)2 -CO3 ]) which can react with both H2 and CO2 to produce formate. Based on these stoichiometric reactions, the first catalytic hydrogenation process of CO2 to formate using transition metal free catalyst (BCF/M2 CO3 , M=Na, K, and Cs) is reported. The highest TON value of this catalytic process is up to 3941. Further research revealed the reaction mechanism in which the Lewis pair enables the splitting of H2 and the insertion of CO2 into the B-H bond. PMID- 30403436 TI - Diurnal variation of frequency domain T-wave alternans on 24-hour ambulatory electrocardiogram in subjects without heart disease: Significant effect of autonomic nervous activity of the heart. AB - BACKGROUND: T-wave alternans (TWA) is a risk stratification predictor for sudden cardiac death. However, little is known about the diurnal variation of TWA. Whether TWA are affected by heart rate (HR) or cardiac autonomic nervous activity in the subjects without significant structural heart disease in daily life is not fully understood. Thus, this study was aimed to clarify these issues. METHODS: Frequency domain (FD)-TWA analysis was conducted in 47 subjects without significant structural heart disease using 24-hr ambulatory electrocardiogram (AECG). Measurement of heart rate variability (HRV) was performed in order to evaluate the autonomic activity of the heart. The maximum FD-TWA value in each period was measured four times per day (A, 00:00-6:00 hr; B, 06:00-12:00 hr; C, 12:00-18:00 hr; D, 18:00-24:00 hr). Correlations between FD-TWA and either HR or HRV parameters (LF/HF, LFnu, HFnu, SDNN, CVNN, pNN50) were analyzed in each period (A-D). RESULTS: There was diurnal variation of FD-TWA (median, inter quartile range [IQR]: A, 8.2 [6.5, 10.6] MUV; B, 10.1 [8.4, 15.0] MUV; C, 17.6 [12.3, 25.0] MUV: D, 11.9 [9.1, 19.9] MUV; p < 0.0001). Maximum FD-TWA had positive correlations with HR and LF/HF (HR, r = 0.496, p < 0.0001; LF/HF, r = 0.414, p = 0.004), while FD-TWA had a negative correlation with HFnu (r = -0.291, p = 0.048). On multiple linear regression analysis, HR had an independent effect on log FD-TWA amplitude (beta = 0.461, p = 0.001). CONCLUSIONS: FD-TWA has marked diurnal variation in the daily life of the subjects without significant structural heart disease. This variation could be more strongly affected by HR than the HRV indices. PMID- 30403437 TI - Could fragmented QRS predict mortality in aortic stenosis patients after transcatheter aortic valve replacement? AB - BACKGROUND: Fragmented QRS evaluated in 12-derivation electrocardiography has widely been accepted as a sign of myocardial fibrosis. The prognostic value of that marker has been demonstrated, particularly, in cardiac diseases that accompany myocardial scar and fibrosis. Myocardial fibrosis is also an issue in patients with aortic stenosis. In this study, we wanted to determine whether fragmented QRS could predict all-cause mortality in aortic stenosis patients after transcatheter aortic valve replacement (TAVR). METHOD: In this study, we evaluated a total of 116 eligible patients on whom we performed TAVR between 2014 and 2018. Patients' demographic and clinical findings, echocardiography results, in-hospital and 30-day mortality, long-term survival statuses were noted. Patient's ECGs before the procedure were evaluated in regard to the occurrence of fragmented QRS. Predictors of mortality were evaluated using univariable and multivariable Cox regression analysis. RESULTS: The study population consisted of 116 patients of median age 79 (IQR 75-83), 64 females (55.2%). Mortality occurred in 27 (23%) patients; median follow-up time was 319 (IQR 122-719) days. Fragmented QRS was observed in 44 out of 116 (37.9%) patients. The presence of a fragmented QRS (HR = 2.178, 95% CI 0.999-4.847, p = 0.050), a history of stroke (HR = 3.463, 95% CI 1.276-9.398, p = 0.015), and the creatinine levels at admission (HR = 2.198, 95% CI 1.068-4.520, p = 0.030) were associated with the long-term mortality in multivariable Cox regression analysis. CONCLUSION: Like in the case of the other diseases associated with myocardial fibrosis, fragmented QRS could also predict mortality in aortic stenosis patients after TAVR procedure. PMID- 30403438 TI - Development of a reverse transcription recombinase polymerase amplification combined with lateral-flow dipstick assay for avian influenza H9N2 HA gene detection. AB - H9N2 avian influenza viruses (AIVs) have been detected from wild birds and domestic poultry worldwide. Serious diseases combined with secondary infection have caused high mortality and great economic losses to poultry industry. Therefore, simple, rapid, sensitive and accurate methods suitable for field detection of H9N2 AIVs are crucial to efficiently control virus infection and spread in time. In this study, an isothermal reverse transcription recombinase polymerase amplification with lateral-flow dipstick (RT-RPA-LFD) assay for detection of hemagglutinin (HA) gene of H9 subtype influenza viruses was developed. The optimal forward and reverse primers targeting HA gene of H9 subtype influenza viruses were labeled with fluorescein isothiocyanate (FITC) and biotin at the 5'-end, respectively. The amplification reaction could be finished in 20 min at a wide temperature range of 30-42 degrees C, and then the products could be visualized with naked eyes. The developed H9 RT-RPA-LFD was able to detect 0.15 pg of H9N2 AIV RNA, which was 10 times more sensitive than that of conventional RT-PCR. The H9 RT-RPA-LFD assay did not detect nucleic acids extracted from H9 negative samples or from other poultry respiratory pathogens. The clinical performance of H9 RT-RPA-LFD was determined by testing 120 cloacal samples collected from chickens with respiratory syndromes. The coincidence rate of the detection results between RT-RPA-LFD and conventional RT-PCR was 95.8%. Therefore, the developed RT-RPA-LFD assay provides a rapid, reliable and sensitive method for field diagnosis of H9 subtype AIVs. PMID- 30403439 TI - Alcohol Amination Catalyzed by Copper Powder as a Self-Supported Catalyst. AB - Catalytic alcohol amination is a sustainable reaction for N-alkyl amine synthesis. Homogeneous and supported copper catalysts have long been studied for this reaction and have given some impressive results. In this study, copper powder is found to behave as an active catalyst for alcohol amination, giving better catalytic performance than metal-oxide-supported nanocopper catalysts. Catalyst characterization suggests that the copper powder can be considered as a self-supported nanocopper catalyst (i.e., nanocopper supported on copper particles). These results might promote the study of unsupported transition metal powders in sustainable catalytic reactions. PMID- 30403440 TI - Natural Compounds with xanthine oxidase inhibitory activity: A review. AB - Hyperuricemia (HUA), a disease due to an elevation of BUA (body uric acid) level and responsible for various diseases like gout, cardiovascular disorders, and renal failure, is a major ground debate for the medical science these days. Considering the risk factors linked with allopathic drugs for the treatment of this disease, the debate has now become a special issue. Previously, we critically discussed the role of dietary polyphenols in the treatment of HUA. Besides dietary food plants, many researchers figure out the tremendous effects of medicinal plants derived phytochemicals against HUA. Keeping in mind all these aspects, we reviewed all possible managerial studies related to HUA through medicinal plants (isolated compounds). In the current review article, we comprehensively discussed various bioactive compounds, chemical structures and structure-activity relationship with responsible key enzyme xanthine oxidase. This article is protected by copyright. All rights reserved. PMID- 30403441 TI - Electrocardiographic predictors of myocardial fibrosis and apical hypertrophic cardiomyopathy. AB - BACKGROUND: Electrocardiography (ECG) may be an efficacious diagnostic and prognostic tool in hypertrophic cardiomyopathy (HCM). This study aimed to investigate association between deep T-wave inversion (TWI) and apical HCM, and between fragmented QRS (fQRS) complex and myocardial fibrosis in patients with HCM. METHODS: Patients with documented HCM by cardiac magnetic resonance imaging (CMR) during 2005-2015 were studied. The 12-lead ECG and CMR were performed on the same day. All patients underwent CMR for the assessment of cardiac structure, function, and late gadolinium enhancement (LGE). LGE was used to detect myocardial fibrosis. RESULTS: One hundred forty-four HCM (mean age 66 +/- 15.8 years, 60.4% male) were included. Twenty-nine (20.14%) subjects had deep TWI, and apical HCM was found in 76 (52.78%). Deep TWI was associated with apical HCM with the Odds ratio (95%CI) of 5.82 (2.07, 16.04) and p < 0.001 in univariate analysis model. The association was still significant in multivariate analysis with adjusted Odds ratio (95%CI) of 9.86 (3.17, 30.66), p < 0.001. Forty-seven (32.64%) subjects had fQRS complex, and myocardial fibrosis was detected in 101 (70.14%). fQRS complex was found to be associated with myocardial fibrosis in univariate analysis with the Odds ratio (95%CI) = 2.75 (1.16, 6.54), p = 0.019. However, the association cannot be demonstrated in the multivariate analysis. CONCLUSION: Deep TWI is independently associated with apical HCM, but the relationship between fQRS complex and myocardial fibrosis did not survive multivariate analysis. PMID- 30403442 TI - Vectorcardiogram in athletes: The Sun Valley Ski Study. AB - BACKGROUND: Global electrical heterogeneity (GEH) is associated with sudden cardiac death (SCD) in adults of 45 years and above. However, GEH has not been previously measured in young athletes. The goal of this study was to establish a reference for vectorcardiograpic (VCG) metrics in male and female athletes. METHODS: Skiers (n = 140; mean age 19.2 +/- 3.5 years; 66% male, 94% white; 53% professional athletes) were enrolled in a prospective cohort. Resting 12-lead ECGs were interpreted per the International ECG criteria. Associations of age, sex, and athletic performance with GEH were studied. RESULTS: In age and training level-adjusted analyses, male sex was associated with a larger T vector [T peak magnitude +186 (95% CI 106-266) uV] and a wider spatial QRS-T angle [+28.2 (17.3 39.2) degrees ] as compared to women. Spatial QRS-T angle in the ECG left ventricular hypertrophy (LVH) voltage group (n = 21; 15%) and normal ECG group did not differ (67.7 +/- 25.0 vs. 66.8 +/- 28.2; p = 0.914), suggesting that ECG LVH voltage in athletes reflects physiological remodeling. In contrast, skiers with right ventricular hypertrophy (RVH) voltage (n = 26, 18.6%) had wider QRS-T angle (92.7 +/- 29.6 vs. 66.8 +/- 28.2 degrees ; p = 0.001), larger SAI QRST (194.9 +/- 30.2 vs. 157.8 +/- 42.6 mV * ms; p < 0.0001), but similar peak SVG vector magnitude (1976 +/- 548 vs. 1939 +/- 395 uV; p = 0.775) as compared to the normal ECG group. Better athletic performance was associated with the narrower QRS-T angle. Each 10% worsening in an athlete's Federation Internationale de' Ski downhill ranking percentile was associated with an increase in spatial QRS-T angle by 2.1 (95% CI 0.3-3.9) degrees (p = 0.013). CONCLUSION: Vectorcardiograpic adds nuances to ECG phenomena in athletes. PMID- 30403443 TI - Stem Cells Translational Medicine. PMID- 30403444 TI - Regenerative Medicine in the State of Florida: Letter Outlining the Florida Organization for Regenerative Medicine. PMID- 30403445 TI - Traumatic Brain Injury in Early Childhood and Risk of Attention Deficit/Hyperactivity Disorder and Autism Spectrum Disorder: A Nationwide Longitudinal Study. AB - OBJECTIVE: Early childhood (< 3 years of age) is a critical period for neurodevelopment. This study investigated the correlation between early childhood traumatic brain injury (TBI) and subsequent risk of attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and developmental delay (DD) by analyzing a national-scale cohort. METHODS: Data from the National Health Insurance Research Database, which comprises health care information from > 99% of the Taiwanese population, were analyzed. Children with TBI in their early childhood were enrolled from 1998-2008, and the incidence of subsequent ADHD, ASD, or DD (according to ICD-9 criteria) was assessed and compared with controls without TBI. Patients' age, number of TBI events, and TBI severity were investigated for the risk of ADHD, ASD, or DD. RESULTS: A total of 7,801 and 31,204 children were enrolled in the TBI and control cohorts, respectively. The TBI cohort exhibited a higher incidence of subsequent ADHD, ASD, or DD than the controls (all P < .001). Diagnoses of ADHD, ASD, or DD in the TBI cohort were made at a younger age compared with the controls. Cox regression demonstrated the highest hazard ratios (HRs) of ADHD, ASD, or DD with repeated TBI events, severe TBI, and TBI events before 1 year of age, with the exception that the HR of ASD did not significantly increase after repeated TBI (P = .335). In addition, cumulative HRs (> 10 years) of ADHD, ASD, or DD were increased after TBI (all P < .001). CONCLUSIONS: Data from this study suggest that the incidence of ADHD, ASD, and DD significantly increased after TBI events in early childhood (< 3 years of age). The risk factors include severe TBI, repeated TBI events, and TBI at a younger age. The long-term follow-up demonstrated an increased cumulative risk of ADHD, ASD, and DD after TBI. PMID- 30403447 TI - Hospitals in systems fare better in value-based climate versus their independent peers. PMID- 30403446 TI - Prevalence and Correlates of Benzodiazepine Use, Misuse, and Use Disorders Among Adults in the United States. AB - OBJECTIVE: Although benzodiazepine misuse and use disorders are associated with adverse health effects, it is unknown what proportion of benzodiazepine users misuse them or meet criteria for benzodiazepine use disorders. The goal of this study was to examine the prevalence and correlates of benzodiazepine use, misuse, and use disorders among US adults. METHODS: Data from 102,000 adults 18 years and older who participated in the 2015-2016 National Surveys on Drug Use and Health were used. IMS Health Total Patient Tracker data were also examined. Descriptive analyses and multinomial logistic regressions were applied. RESULTS: Among US adults in 2015-2016, 12.5% (annual average, 95% CI, 12.19%-12.81%) used benzodiazepines, 2.1% (95% CI, 2.03%-2.25%) misused benzodiazepines at least once, and 0.2% (95% CI, 0.15%-0.22%) had benzodiazepine use disorders. Among benzodiazepine users, 17.1% (95% CI, 16.30%-17.93%) misused benzodiazepines, and 1.5% (95% CI, 1.26%-1.72%) had benzodiazepine use disorders. Benzodiazepine use was associated with emergency room visits, suicidal ideation, use of most substances, and mental disorders. Benzodiazepine misuse without use disorders was associated with younger age, male sex, being black, poor educational attainment, being uninsured and unemployed, being single, having family income below $50,000, and having suicidal ideation and other specific substance use problems. Correlates of benzodiazepine use disorders were similar, but most correlates were associated with benzodiazepine use disorders more strongly than with misuse without use disorders. CONCLUSIONS: While benzodiazepine use is highly prevalent among US adults, benzodiazepine use disorders are relatively rare among benzodiazepine users. Our results help characterize benzodiazepine users and identify adults at risk for misuse and use disorders. PMID- 30403448 TI - Physician Assistants Help Drive Quality Improvement. PMID- 30403449 TI - Case Study 1: PAs Central to Reducing Hospital Readmissions. PMID- 30403450 TI - Case Study 2: LWBS Rates Drop. PMID- 30403451 TI - PA Home Visits Sharply Reduce Hospital Readmissions After Heart Surgery. PMID- 30403452 TI - Copy-and-Paste Should Be Used Carefully. PMID- 30403453 TI - Assess Anesthesia Patient Satisfaction Correctly. PMID- 30403454 TI - Recommended Questions from the American Society of Anesthesiologists. PMID- 30403455 TI - CANDOR Toolkit Helps After Adverse Events. PMID- 30403466 TI - Life Cycle Impact and Benefit Trade-Offs of a Produced Water and Abandoned Mine Drainage Cotreatment Process. AB - A cotreatment process for produced water and abandoned mine drainage (AMD) has been established and demonstrated at the pilot-scale. The present study evaluates the potential of the proposed process to aid in management of two high volume wastewater resources in Pennsylvania. A systems-level approach is established to evaluate the primary trade-offs, including cotreatment process environmental impacts, transportation impacts, and environmental benefits realized from precluding direct AMD release to the environment. Life cycle impact assessment was used to quantify the environmental and human health impacts as well as to identify "hot spots" of the cotreatment process. Electricity use was found to be the dominant contributor to all impact categories. Extending the system boundary to include transportation of the two wastewaters to a to-be-determined cotreatment site revealed the important impact of transportation. An optimization approach was employed (using the region of Southwest Pennsylvania) to evaluate minimization of transportation distance considering the location and number of treatment sites. Finally, a quantitative analysis of environmental benefits realized by precluding direct AMD release to the environment was performed. The results suggest that the magnitude of benefit realized in treating a highly polluted AMD is greater than the magnitude of impacts from the cotreatment process. PMID- 30403467 TI - Gd3+:DOTA-Modified 2-Hydroxypropyl-beta-Cyclodextrin/4-Sulfobutyl Ether-beta Cyclodextrin-Based Polyrotaxanes as Long Circulating High Relaxivity MRI Contrast Agents. AB - A family of five water-soluble Gd3+:1,4,7,10-tetraazacyclododecane-1,4,7 tetraacetic acid-modified polyrotaxane (PR) magnetic resonance contrast agents bearing mixtures of 2-hydroxypropyl-beta-cyclodextrin and 4-sulfobutylether-beta cyclodextrin macrocycles threaded onto Pluronic cores were developed as long circulating magnetic resonance contrast agents. Short diethylene glycol diamine spacers were utilized for linking the macrocyclic chelator to the PR scaffold prior to Gd3+ chelation. The PR products were characterized by 1H NMR, gel permeation chromatography/multiangle light scattering, dynamic light scattering, and analytical ultracentrifugation. Nuclear magnetic relaxation dispersion and molar relaxivity measurements at 23 degrees C revealed that all the PR contrast agents displayed high spin-spin T1 relaxation and spin-lattice T2 relaxation rates relative to a DOTAREM control. When injected at 0.05 mmol Gd/kg body weight in BALB/c mice, the PR contrast agents increased the T1-weighted MR image intensities with longer circulation times in the blood pool than DOTAREM. Excretion of the agents occurred predominantly via the renal or biliary routes depending on the polyrotaxane structure, with the longest circulating L81 Pluronic-based agent showing the highest liver uptake. Proteomic analysis of PR bearing different beta-cyclodextrin moieties indicated that lipoproteins were the predominant component associated with these materials after serum exposure, comprising as much as 40% of the total protein corona. We infer from these findings that Gd(III)-modified PR contrast agents are promising long-circulating candidates for blood pool analysis by MRI. PMID- 30403468 TI - Controllable Negative Thermal Expansion by Mechanical Pulverizing in Hexagonal Mn0.965Co1.035Ge Compounds. AB - Negative thermal expansion (NTE) material as a compensator is very important for accurately controlling the thermal expansion of materials. Along with the magnitude of the coefficient of thermal expansion, the operating temperature window of the NTE materials is also a major concern. However, only a few of the NTE materials possess both a large operating temperature range and a large thermal expansion coefficient. To explore this type of new NTE material, the Mn0.965Co1.035Ge fine powders were prepared by mechanical ball milling (BM). These fine powders show a largely extended NTE operation temperature window simultaneously possessing a giant thermal expansion coefficient. For samples treated with different BM times, such as the BM-0.5h, BM-4h, and BM-12 h samples, the operating temperature window (Delta T) and linear thermal expansion coefficient (alphaL) are 167 K (222-389 K) and ~ -63 ppm/K, 221 K (140-360 K) and ~ -41.3 ppm/K, and 208 K (234-442 K) and ~ -40 ppm/K, respectively, which are larger than most well-known NTE materials. More strikingly, all BM samples have a large constant linear NTE coefficient with an ultrawide temperature window covering room temperature. For these three samples, these values are ~ -52 ppm/K (140 K), ~ -58.3 ppm/K (110 K), and ~ -65 ppm/K (80 K), respectively. The origin of the excellent NTE properties is discussed based on the thermomagnetic measurements and X-ray absorption spectroscopic results. PMID- 30403469 TI - alpha-Amine Desaturation of d-Arginine by the Iron(II)- and 2-(Oxo)glutarate Dependent l-Arginine 3-Hydroxylase, VioC. AB - When challenged with substrate analogues, iron(II)- and 2-(oxo)glutarate dependent (Fe/2OG) oxygenases can promote transformations different from those they enact upon their native substrates. We show here that the Fe/2OG enzyme, VioC, which is natively an l-arginine 3-hydroxylase, catalyzes an efficient oxidative deamination of its substrate enantiomer, d-Arg. The reactant complex with d-Arg retains all interactions between enzyme and substrate functional groups, but the required structural adjustments and opposite configuration of C2 position this carbon more optimally than C3 to donate hydrogen (H*) to the ferryl intermediate. The simplest possible mechanism, C2 hydroxylation followed by elimination of ammonia, is inconsistent with the demonstrated solvent origin of the ketone oxygen in the product. Rather, the reaction proceeds via a hydrolytically labile C2-iminium intermediate, demonstrated by its reductive trapping in solution with NaB2H4 to produce racemic [2H]Arg. Of two alternative pathways to the iminium species, C2 hydroxylation followed by dehydration versus direct desaturation, the latter possibility appears to be more likely, because the former mechanism would be expected to result in detectable incorporation of 18O from 18O2. The direct desaturation of a C-N bond implied by this analysis is analogous to that recently posited for the reaction of the l-Arg 4,5-desaturase, NapI, thus lending credence to the prior mechanistic proposal. Such a pathway could also potentially be operant in a subset of reactions catalyzed by Fe/2OG N demethylases, which have instead been purported to enact C-N bond cleavage by methyl hydroxylation and elimination of formaldehyde. PMID- 30403470 TI - Rapid and Sensitive Detection of Aspergillus niger Using a Single-Mediator System Combined with Redox Cycling. AB - Rapid and sensitive mold detection is becoming increasingly important, especially in indoor environments. Common mold detection methods based on double-mediated electron transfer between an electrode and molds are not highly sensitive and reproducible, although they are rapid and simple. Here, we report a sensitive and reproducible detection method specific to Aspergillus niger ( A. niger), based on a single-mediator system combined with electrochemical-chemical (EC) redox cycling. Intracellular NAD(P)H-oxidizing enzymes in molds can convert electro inactive hydroxy-nitro(so)arenes into electro-active hydroxy-aminoarenes. Since the membrane and wall of A. niger is well permeable to both a substrate (4-nitro 1-naphthol) and a reduced product (4-amino-1-naphthol) in tris buffer (pH 7.5) solution, the electrochemical signal is increased in the presence of A. niger due to two reactions: (i) enzymatic reduction of the substrate to the reduced product and (ii) electrochemical oxidation of the reduced product to an oxidized product. When a reducing agent (NADH) is present in the solution, the oxidized product is reduced back to the reduced product and then electrochemically reoxidized. This EC redox cycling significantly amplifies the electrochemical signal. Moreover, the background level is low and highly reproducible because the substrate and the reducing agent are electro-inactive at an applied potential of 0.20 V. The calculated detection limit for A. niger in a common double-mediator system consisting of Fe(CN)63- and menadione is ~2 * 104 colony-forming unit (CFU)/mL, but the detection limit in the single-mediator system combined with EC redox cycling is ~2 * 103 CFU/mL, indicating that the newly developed single-mediator system is more sensitive. Importantly, the detection method requires only an incubation period of 10 min and does not require a washing step, an electrode modification step, or a specific probe. PMID- 30403471 TI - Engineering Metal-Organic Frameworks for Photoacoustic Imaging-Guided Chemo /Photothermal Combinational Tumor Therapy. AB - Imaging-guided therapy has considerable potential in tumor treatment. Different treatments have been integrated to realize combinational tumor therapy with improved therapeutic efficiency. Herein, the conventional metal-organic framework (MOF) MIL-100 is utilized to load curcumin with excellent encapsulation capacity. Polydopamine-modified hyaluronic acid (HA-PDA) is coated on the MIL-100 surface to construct engineering MOF nanoparticles (MCH NPs). The HA-PDA coating not only improves the dispersibility and stability of NPs but also introduces a tumor targeting ability to this nanosystem. A two-stage augmented photothermal conversion capability is introduced to this nanosystem by encapsulating curcumin in MIL-100 pores and then coating HA-PDA on the surface, which confer the MCH NPs with strong photothermal conversional efficiency. After being intravenously injected into xenograft HeLa tumor-bearing mice, MCH NPs prefer to accumulate at the tumor site and achieve photoacoustic imaging-guided chemo-/photothermal combinational tumor therapy, generating nearly complete tumor ablation. Engineering MOFs is an efficient platform for imaging-guided combinational tumor therapy, as confirmed by in vitro and in vivo evaluations. PMID- 30403472 TI - Ultrasmall All-In-One Nanodots Formed via Carbon Dot-Mediated and Albumin-Based Synthesis: Multimodal Imaging-Guided and Mild Laser-Enhanced Cancer Therapy. AB - Integration of multiple diagnostic/therapeutic modalities into a single system with ultrasmall size, excellent photothermal/photodynamic properties, high cellular uptake efficiency, nuclear delivery capacity, rapid renal clearance, and good biosafety is highly desirable for cancer theranostics, but still remains challenging. Here, a novel type of multifunctional nanodots (denoted as BCCGH) was synthesized by mixing bovine serum albumin, carbon dots, and metal ions (Cu2+ and Gd3+), followed by the conjugation with a photosensitizer (HPPH). The nanodots hold great promise for fluorescence/photoacoustic/magnetic resonance/photothermal imaging-guided synergistic photothermal/photodynamic therapy (PDT) because of their appealing properties such as high photothermal conversion efficiency (68.4%), high longitudinal relaxivity (11.84 mM-1 s-1, 7 T), and superior colloidal stability with negligible Gd3+ release. Benefiting from the massive cellular uptake, endoplasmic reticulum/mitochondrion-targeting ability, and mild near-infrared laser irradiation-promoted nuclear delivery of BCCGH, a high anticancer therapeutic efficiency is achieved in the subsequent in vitro PDT. Besides, as revealed by the in vivo/ex vivo results, the nanodots also exhibit excellent tumor accumulation, efficient renal clearance, complete tumor ablation, and exceptional biosafety. To summarize, this work develops a carbon dot-mediated and albumin-based synthetic approach for constructing ultrasmall and multifunctional nanodots, which may hold great potential for cancer theranostics and beyond. PMID- 30403473 TI - DARK Classics in Chemical Neuroscience: Opium, a Friend or Foe. AB - Opium has found great use medicinally for its analgesic properties and has been witnessed as one of the most popular medications used in psychiatry. Opium derivatives have been shown as efficacious for relieving pain and the treatment of epileptic seizures, but progressive research toward their use in the treatment of neurodegenerative diseases remain elusive. To gain more insight into the other properties of opium such as anti-inflammatory properties, herein we discuss basic information regarding opium, opium content and mechanism of action, pharmacology of opium derivatives, the role of opium in the prevention of neurodegeneration, and adverse effects of opium derivatives on neuronal health. PMID- 30403474 TI - Chemical and Biomolecule Sensing with Organic Field-Effect Transistors. AB - The strong and controllable chemical sensitivity of organic semiconductors (OSCs) and the amplification capability of transistors in circuits make use of OSC-based field-effect transistors compelling for chemical sensors. Analytes detected and assayed range from few-atom gas-phase molecules that may have adverse health and security implications to biomacromolecules (proteins, nucleic acids) that may be markers for physiological processes and medical conditions. This review highlights recent progress in organic field-effect transistor (OFET) chemical sensors, emphasizing advances from the past 5 years and including aspects of OSC morphology and the role of adjacent dielectrics. Design elements of the OSCs and various formats for the devices are illustrated and evaluated. Challenges associated with the present state of the art and future opportunities are also discussed. PMID- 30403475 TI - Actively Targeted Magnetothermally Responsive Nanocarriers/Doxorubicin for Thermochemotherapy of Hepatoma. AB - Nanodrug-delivery systems modified with targeting molecules allow antitumor drugs to localize to tumor sites efficiently. CD147 protein is expressed highly on hepatoma cells. Firstly, we synthesized magnetothermally responsive nanocarriers/doxorubicin (MTRN/DOX) which was composed of manganese zinc (Mn-Zn) ferrite magnetic nanoparticles, amphiphilic and thermosensitivity copolymer drug carriers together with DOX. Then CD147-MTRN/DOX was formed with MTRN/DOX and monoclonal antibody that specifically binds to CD147 protein. It could target hepatoma cells actively and improve the DOX concentration in the tumor sites. Subsequently, an external alternating magnetic field elevated the temperature of the thermomagnetic particles, resulting in structural changes in the thermosensitive copolymer drug carriers, thereby releasing DOX. Hence, CD147 MTRN/DOX could enhance the responsiveness of hepatoma cells to the pre-existing chemotherapy drugs owing to active targeting combined synergistically with thermotherapy and chemotherapy, which has more significant anticancer effects than MTRN/DOX. PMID- 30403476 TI - Dynamic Nuclear Polarization of Metal-Organic Frameworks Using Photoexcited Triplet Electrons. AB - While dynamic nuclear polarization based on photoexcited triplet electrons (triplet-DNP) has the potential to hyperpolarize nuclear spins of target substrates in the low magnetic field at room temperature, there has been no triplet-DNP system offering structural rigidity and substrate accessibility. Here, we report the first example of triplet-DNP of nanoporous metal-organic frameworks. Accommodation of a carboxylate-modified pentacene derivative in a partially deuterated ZIF-8 (D-ZIF-8) results in a clear 1H NMR signal enhancement over thermal equilibrium. PMID- 30403477 TI - Morphology-Controlled Discharge Profile and Reversible Cu Extrusion and Dissolution in Biomimetic CuS. AB - Metal sulfide materials such as CuS, SnS2, Co9S8, and MoS2 are high-capacity anode materials for Li-ion batteries with high capacity. However, these materials go through a conversion reaction with Li+, which is accompanied by inevitably huge volume expansions, thereby causing performance degradation. Here, we report a nanoscale engineering route to efficiently control the overall volume expansion for enhanced performance. We engineered CuS with nanoplate assembly on a nanostring, leading to a nanostructure mimicking the crassula baby necklace (CBN) in the natural plant. Using in situ transmission electron microscopy, we probed the lithiation kinetics and dynamic structural transformations. Due to the linkage of the central nanostring, the CuS CBN exhibited a fast Li+ diffusion along the axial direction and high mechanical stability during lithiation. The volume expansion was minimal for our CuS CBN due to the pre-engineered gap and pores between these plates. The CuS followed a two-step lithiation process, with Cu2S and Li2S formation as the first step and Cu extrusion in the later stage. Interestingly, during the Cu2S-to-Cu conversion, we observed an incubation period before the metallic Cu extrusion, which is featured by the formation of an amorphous structure due to the large lattice strain and distortion associated with the displacement of Cu by Li ions. In the final stage, the lithiated amorphous phase recrystallized to a composite of Cu nanocrystals in a polycrystalline Li2S matrix. Associated with the nanoscale size, the Cu nanocrystals can reversibly dissolve into the matrix upon delithiation. The present work demonstrates tailoring of desired functionality in electrodes using bionic engineering methods. PMID- 30403478 TI - Microscale Objects via Restructuring of Large, Double-Stranded DNA Molecules. AB - As the interest in DNA nanotechnology increases, so does the need for larger and more complex DNA structures. In this work, we describe two methods of using large, double-stranded (ds) DNA to self-assemble sequence-specific, nonrepetitive microscale structures. A model system restructures T7 DNA (40 kb) through sequence-specific biotinylation followed by intramolecular binding to a 40 nm diameter neutravidin bead to create T7 "rosettes". This model system informed the creation of "nodal DNA" where "nodes" with single-stranded DNA flaps are attached to a large dsDNA insert so that a complementary oligonucleotide "strap" bridges the two nodes for restructuring to form a DNA "bolo". To do this in high yield, several methodologies were developed, including a protection/deprotection scheme using RNA/RNase H and dialysis chambers, which remove excess straps while retaining large DNA molecules. To assess these restructuring processes, the DNA was adsorbed onto supported lipid bilayers, allowing for a visual assay of their structure using single-molecule fluorescence microscopy. Good agreement between the expected and observed fluorescence intensity measurements of the individual features of restructured DNA for both the DNA rosettes and bolos gives us a high degree of confidence that both processes give sequence-specific restructuring of large, dsDNA molecules to create microscale objects. PMID- 30403479 TI - Factors Affecting Hydrogen Atom Transfer Reactivity of Metal-Oxo Porphyrinoid Complexes. AB - There has been considerable interest in hydrogen atom transfer (HAT) reactions mediated by metal/oxygen species because of their central role in metalloenzyme function as well as synthetic catalysts. This Account focuses on our progress in synthesizing high-valent metal-oxo and metal-hydroxo porphyrinoid complexes and determining their reactivities in a range of HAT processes. For these studies we have utilized corrolazine and corrole ligands, which are a ring-contracted subclass of porphyrinoid compounds designed to stabilize high-valent metal complexes. The high-valent manganese complex MnV(O)(TBP8Cz) (TBP8Cz = octakis(4- tert-butylphenyl)corrolazine3-) provided an early example of a well-characterized low-potential oxidant that can still be effective at abstracting H atoms from certain C-H/O-H bonds. Approximating the thermodynamics of the HAT reactivity of the MnV(O) complex and related species with the help of a square scheme approach, in which HAT can be formally separated into proton (p Ka) and electron transfers ( E degrees ), indicates that affinity for the proton (i.e., the basicity) is a key factor in promoting HAT. Anionic axial ligands have a profound influence on the HAT reactivity of MnV(O)(TBP8Cz), supporting the conclusion that basicity is a critical parameter in determining the reactivity. The influence of Lewis acids on MnV(O)(TBP8Cz) was examined, and it was shown that both the electronic structure and reactivity toward HAT were significantly altered. High-valent Cr(O), Re(O), and Fe(O) corrolazines were prepared, and a range of HAT reactions were studied with these complexes. The chromium and manganese complexes form a rare pair of structurally characterized CrV(O) and MnV(O) species in identical ligand environments, allowing for a direct comparison of their HAT reactivities. Although the CrV(O) species was the better oxidant as measured by redox potentials, the MnV(O) species was significantly more reactive in HAT oxidations, pointing again to basicity as a key determinant of HAT reactivity. The iron complex, FeIV(O)(TBP8Cz+*), is an analogue of the heme enzyme Compound I intermediate, and was found to be mildly reactive toward H atom abstraction from C-H bonds. In contrast, ReV(O)(TBP8Cz) was inert toward HAT, although one electron oxidation to ReV(O)(TBP8Cz+*) led to some interesting reactivity mediated by the pi-radical-cation ligand alone. Other ligand modifications, including peripheral substitution as well as novel alkylation of the meso position on the Cz core, were examined for their influence on HAT. A highly sterically encumbered corrole, tris(2,4,6-triphenylphenyl)corrole (ttppc), was employed for the isolation and structural characterization of the first MnIV(OH) complex in a porphyrinoid environment, MnIV(OH)(ttppc). This complex was highly reactive in HAT with O-H substrates and was found to be much more reactive than its higher-oxidation-state counterpart MnV(O)(ttppc), providing important mechanistic insights. These studies provided fundamental knowledge on the relationship between structure and function in high-valent M(O) and M(OH) models of heme enzyme reactivity. PMID- 30403480 TI - Influence of Metal Substitution on the Pressure-Induced Phase Change in Flexible Zeolitic Imidazolate Frameworks. AB - Metal-organic frameworks that display step-shaped adsorption profiles arising from discrete pressure-induced phase changes are promising materials for applications in both high-capacity gas storage and energy-efficient gas separations. The thorough investigation of such materials through chemical diversification, gas adsorption measurements, and in situ structural characterization is therefore crucial for broadening their utility. We examine a series of isoreticular, flexible zeolitic imidazolate frameworks (ZIFs) of the type M(bim)2 (SOD; M = Zn (ZIF-7), Co (ZIF-9), Cd (CdIF-13); bim- = benzimidazolate), and elucidate the effects of metal substitution on the pressure responsive phase changes and the resulting CO2 and CH4 step positions, pre-step uptakes, and step capacities. Using ZIF-7 as a benchmark, we reexamine the poorly understood structural transition responsible for its adsorption steps and, through high-pressure adsorption measurements, verify that it displays a step in its CH4 adsorption isotherms. The ZIF-9 material is shown to undergo an analogous phase change, yielding adsorption steps for CO2 and CH4 with similar profiles and capacities to ZIF-7, but with shifted threshold pressures. Further, the Cd2+ analogue CdIF-13 is reported here for the first time, and shown to display adsorption behavior distinct from both ZIF-7 and ZIF-9, with negligible pre-step adsorption, a ~50% increase in CO2 and CH4 capacity, and dramatically higher threshold adsorption pressures. Remarkably, a single-crystal-to-single-crystal phase change to a pore-gated phase is also achieved with CdIF-13, providing insight into the phase change that yields step-shaped adsorption in these flexible ZIFs. Finally, we show that the endothermic phase change of these frameworks provides intrinsic heat management during gas adsorption. PMID- 30403481 TI - Crystal and Magnetic Structures and Properties of (Lu1- xMn x)MnO3 Solid Solutions. AB - (Lu1- xMn x)MnO3 solid solutions, having the perovskite-type structure and Pnma space group, with 0 <= x <= 0.4 were synthesized by a high-pressure, high temperature method at 6 GPa and about 1670 K from Lu2O3 and Mn2O3. Their crystal and magnetic structures were studied by neutron powder diffraction. The degree of octahedral MnO6 tilting decreases in (Lu1- xMn x)MnO3 with increasing x. Only the incommensurate (IC) spin structure with a propagation vector of k = ( k0, 0, 0) and k0 ~ 0.44 remains in (Lu0.9Mn0.1)MnO3 in the whole temperature range below the Neel temperature TN = 36 K, and the commensurate noncollinear E-type structure that has been reported in the literature for undoped o-LuMnO3 is not observed. (Lu1- xMn x)MnO3 samples with 0.2 <= x <= 0.4 have a ferrimagnetic structure with a propagation vector of k = (0, 0, 0) and ferromagnetic (FM) ordering of Mn3+ and Mn4+ cations at the B site, which are antiferromagnetically coupled to a noncollinear predominantly FM arrangement of Mn2+ at the A site. The ferrimagnetic Curie temperature, TC, increases monotonically from 67 K for x = 0.2 to 118 K for x = 0.4. Magnetic and dielectric properties of (Lu1- xMn x)MnO3 and a composition-temperature phase diagram are also reported. PMID- 30403482 TI - A Stable Zr(IV)-Based Metal-Organic Framework Constructed from C?C Bridged Di isophthalate Ligand for Sensitive Detection of Cr2O72- in Water. AB - As the Cr2O72- anion is highly toxic, new sensors have been developing for its effective detection from water, among which metal-organic frameworks (MOFs) show distinct superiority over many other materials. Herein, a new fluorescent Zr(IV) based MOF, [Zr6O4(OH)8(H2O)4(sbtc)2] (referred to as BUT-28), based on the di isophthalate ligand with a central CH?CH moiety, trans-stilbene-3,3',5,5' tetracarboxylate (sbtc4-), has been prepared and structurally determined. The MOF shows excellent stability in neutral, highly acidic, and weakly basic aqueous solutions. Moreover, no essential uptake loss in three cycles of water vapor adsorption-desorption measurements was observed for BUT-28, suggesting the robustness of the porous framework and its great potential for long-term use. Fluorescent measurements were carried out for BUT-28 and an isostructural MOF, Zr abtc, which is constructed from the di-isophthalate ligand with a central N?N moiety, azobenzene-3,3',5,5'-tetracarboxylate (abtc4-). Interestingly, Zr-abtc shows very weak fluorescent emission. In contrast, BUT-28 exhibits relatively strong fluorescence and serves as a promising sensory material for the detection of trace Cr2O72- (limit of detection: 36 ppb) in aqueous solutions by selective and sensitive fluorescence quenching effect. PMID- 30403483 TI - Regiochemical Effects on Mechanophore Activation in Bulk Materials. AB - Mechanochromic force probes, including spiropyran derivatives, have proven to be useful in visualizing the stress/strain distribution and fracture behavior in polymeric materials. Here, we report the macroscopic response of silicone elastomers including cross-links made up of three spiropyran (SP) regioisomers. The SP derivatives SP( o), SP( m), and SP( p) are connected to the network through an identical attachment point on the indoline fragment and regioisomeric attachments ortho, meta, and para to the spirocyclic C-O bond on the benzaldehyde fragment, respectively. The relative colorimetric response of these regioisomers under quasi-static uniaxial tensile load is SP( o) > SP( m) > SP( p), consistent with the expected mechanical sensitivity of the regioisomers obtained from molecular modeling. The extrapolated strain onset for detectable activation of all three regioisomers, however, is indistinguishable and occurs at ~90% uniaxial strain. Finally, the ratiometric response of the three isomers is constant across the strains investigated (90-135% uniaxial strain), in contrast to expectations based on simulations of strained intact polymer networks. PMID- 30403484 TI - Iodine-Catalyzed Iso-Nazarov Cyclization of Conjugated Dienals for the Synthesis of 2-Cyclopentenones. AB - Molecular iodine was identified as an efficient catalyst for the cycloisomerization of conjugated dienals to substituted 2-cyclopentenones. DFT calculations suggested an unexpected concerted character for this cyclization. PMID- 30403485 TI - Eosin Y- and Copper-Catalyzed Dark Reaction To Construct Ene-gamma-Lactams. AB - Eosin Y, a common organo-photocatalyst in visible-light photoredox processes, was found to show excellent catalytic activities for thermal redox reactions under a catalytic amount of Cu(OAc)2. With this catalytic system, vinyl azides and ketene silyl acetals combine to form formal [3 + 2] cycloadducts by alpha-ester radical addition without light irradiation. This method provides a mild and straightforward paradigm to prepare important synthons of five-membered ene-gamma lactams and bridge ring lactams. It is the first example of an eosin Y-catalyzed redox reaction in the dark. PMID- 30403486 TI - Potent Antiglioblastoma Agents by Hybridizing the Onium-Alkyloxy-Stilbene Based Structures of an alpha7-nAChR, alpha9-nAChR Antagonist and of a Pro-Oxidant Mitocan. AB - Adenocarcinoma and glioblastoma cell lines express alpha7- and alpha9alpha10 containing nicotinic acetylcholine receptors (nAChRs), whose activation promotes tumor cell growth. On these cells, the triethylammoniumethyl ether of 4-stilbenol MG624, a known selective antagonist of alpha7 and alpha9alpha10 nAChRs, has antiproliferative activity. The structural analogy of MG624 with the mitocan RDM 4'BTPI, triphenylphosphoniumbutyl ether of pterostilbene, suggested us that molecular hybridization among their three substructures (stilbenoxy residue, alkylene linker, and terminal onium) and elongation of the alkylene linker might result in novel antitumor agents with higher potency and selectivity. We found that lengthening the ethylene bridge in the triethylammonium derivatives results in more potent and selective toxicity toward adenocarcinoma and glioblastoma cells, which was paralleled by increased alpha7 and alpha9alpha10 nAChR antagonism and improved ability of reducing mitochondrial ATP production. Elongation of the alkylene linker was advantageous also for the triphenylphosphonium derivatives resulting in a generalized enhancement of antitumor activity, associated with increased mitotoxicity. PMID- 30403487 TI - Fibroblast Growth Factor Receptor 4 (FGFR4) Selective Inhibitors as Hepatocellular Carcinoma Therapy: Advances and Prospects. AB - Hepatocellular carcinoma (HCC) is a lethal disease with limited therapeutic options and a particularly poor prognosis. Aberrant fibroblast growth factor 19 (FGF19) signaling through fibroblast growth factor receptor 4 (FGFR4) has been identified as an oncogenic driver for a subset of patients with HCC. FGFR4 is therefore a promising target for the treatment of HCC harboring aberrant FGF19 FGFR4 signaling, and several FGFR4 inhibitors have advanced to clinical trial. In this review, we summarize the latest developments in FGFR4 inhibitors, including the known pharmacophores, their binding mode, selectivity, and clinical implications, as well as the optimization strategy of introducing an acrylamide into a known pan-FGFR inhibitor targeting Cys552 of FGFR4 to provide selective covalent FGFR4 inhibitors. PMID- 30403488 TI - Visible Light-Induced Radical Cyclization of Tertiary Bromides with Isonitriles To Construct Trifluoromethylated Quaternary Carbon Center. AB - The reaction of trifluoromethylated tertiary bromides with isonitriles induced by visible light is reported. Defluorination was avoided in a radical process. This method provides an efficient approach to compounds containing a trifluoromethylated quaternary carbon center, most of which show excellent potential to be agrochemicals. In addition, the bromides were prepared from perfluoroisobutylene, which is a waste from industry, after several steps. This reaction shows a feasible transfer of harmful waste into useful compounds. PMID- 30403489 TI - Correction to "Pharmacokinetics and Bioavailability of the Isoflavones Formononetin and Ononin and Their in Vitro Absorption in Ussing Chamber and Caco 2 Cell Models". PMID- 30403490 TI - Expectations of rural community-based medical education: a case study from Thailand. AB - INTRODUCTION: Thailand has recognised and sought to remedy rural medical workforce shortages. The Collaborative Project to Increase Production of Rural Doctors (CPIRD) has improved rural workforce recruitment through publicly funding medical school places for students with rural backgrounds. However, challenges in rural retention continue. CPIRD is seeking to develop a Thai rural community based medical education (RCBME) program in the southern region of Thailand to improve preparation for rural practice and rural medical retention rates. Prospective stakeholder consultations will allow the understanding of expectations and concerns of stakeholders required for successful RCBME implementation. This study aims to explore stakeholders' expectations of the Southern Thai RCBME initiative. METHODS: A qualitative case study comprised a purposive sample of students, clinical educators, policymakers, rural health professionals and local community stakeholders, all likely to be involved in a new RCBME program in Songkhla Province, Thailand. Individual semi-structured interviews were audiotaped, transcribed in Thai and coded using Worley's symbiosis framework. Following this, text and quotes used in the initial analysis were translated into English, discussed and reanalysed for emergent themes across the framework. RESULTS: A total of 21 participants contributed RCBME stakeholder perspectives. They demonstrated expectations and concerns in each of the relationship axes of the symbiosis model including the clinical, institutional, social and personal axes. Three major themes emerged from the data that integrated stakeholder perspectives on the implication of RCBME in Thailand. These themes were a dramatic shift in Thai medical education paradigm, seeing rural practice as a future career, and collaboration to improve education and health in rural services. CONCLUSION: This study comprehensively describes Thai stakeholder expectations of RCBME and demonstrates that, although some principles of RCBME are universal, context does influence the expectations and capacity of stakeholders to contribute to RCBME. Prospective formal stakeholder engagement is recommended to ensure successful implementation of new educational innovations. PMID- 30403491 TI - Cardiac rehabilitation services for people in rural and remote areas: an integrative literature review. AB - INTRODUCTION: Morbidity and mortality from heart disease continues to be high in Australia with cardiac rehabilitation (CR) recognised as best practice for people with heart disease. CR is known to reduce mortality, reoccurrence of heart disease, hospital readmissions and costs, and to improve quality of life. Australian Aboriginal and Torres Strait Islanders (Australian First Peoples or Indigenous peoples) have a greater need for CR due to their higher burden of disease. However, CR referral, access and attendance remain low for all people who live in rural and remote areas. The aim of this integrative review was to identify barriers, enablers and pathways to CR for adults living independently in rural and remote areas of high-income countries, including Australia. METHODS: Studies were identified through five online data bases, plus reference lists of the selected studies. The studies focused on barriers and enablers of CR for adults in rural and remote areas of Australia and other high-income countries, in English peer-reviewed journals (2007-2016). A mix of qualitative, quantitative and mixed method studies were reviewed through a modified Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), followed by a critical review and thematic analysis. RESULTS: Sixteen studies were selected: seven qualitative, four quantitative and five mixed method. Five themes that influence CR attendance were identified: referral, health services pathways and planning; cultural and geographic factors necessitating alternative and flexible programs; professional roles and influence; knowing, valuing, and psychosocial factors; and financial costs - personal and health services. Factors identified that impact on referral and access to CR were hospital inpatient education programs on heart disease and risk factors; discharge processes including CR eligibility criteria and referral to ensure continuum and transition of care; need for improved accessibility of services, both geographically and through alternative programs, including home based with IT and/or telephone support. Also, the need to ensure that health professionals understand, value and support CR; the impact of mental health, coping with change and competing priorities; costs including travel, medications and health professional consultations; as well as low levels of involvement of Australian First Peoples in their own care and poor cultural understanding by non-Australian First Peoples staff all negatively impact on CR access and attendance. CONCLUSION: This study found weak systems with low referral rates and poor access to CR in rural and remote areas. Underlying factors include lack of health professional and public support, often based on poor perception of benefits of CR, compounded by scarce and inflexible services. Low levels of involvement of Australian First Peoples, as well as a lack of cultural understanding by non-Australian First Peoples staff, is evident. Overall, the findings demonstrate the need for improved models of referral and access, greater flexibility of programs and professional roles, with management support. Further, increased education and involvement of Australian First Peoples, including Indigenous health workers taking a lead in their own people's care, supported by improved education and greater cultural awareness of non Australian First Peoples staff, is required. PMID- 30403492 TI - The Role and Influence of Traditional and Scientific Knowledge in Naturopathic Education: A Qualitative Study. AB - OBJECTIVES: To explore the perceptions, experiences, and attitudes toward scientific and traditional knowledge within contemporary naturopathic education. DESIGN: A qualitative focus group and semistructured individual interview study. SETTINGS/LOCATION: Naturopathic educational organizations and institutions in North America (United States/Canada) and Australia. SUBJECTS: Seven focus groups (three in Australia and four in the United States/Canada) involving a total of 29 students, and one-on-one interviews with 28 faculty and professional leaders of the naturopathic profession from Australia, Canada, and the United States. RESULTS: Four themes have been identified in this study, including finding the balance between traditional and scientific knowledge; supporting the balance through critical appraisal in the curriculum; the exception of traditional knowledge in the critical gaze; and focusing on critical thinking in the naturopathic curriculum. Both naturopathic students and leaders highlight the significance of balancing tradition and science in the naturopathic educational context, although they hold diverse differing viewpoints. The importance of critical appraisal skills as well as the differentiation between critical thinking and critical appraisal have also been emphasized by participants with regard to the future development of naturopathic curriculum. CONCLUSIONS: This is the first study focusing on the interface between traditional and scientific knowledge within the naturopathic education setting. The development of a framework for the critical appraisal of traditional naturopathic knowledge is required to help navigate the variety of knowledge sources available to naturopathic students and to help deliver the best outcomes for their future clinical practice. PMID- 30403493 TI - Accuracy of Dioscorides', De materia medica (First Century C.E.), Regarding Diuretic Activity of Plants. AB - OBJECTIVES: Assess whether an ancient text on herbal medicine accurately characterizes a class of herbal diuretics. DESIGN: The Greek text of Dioscorides De materia medica was assessed for herbs stated to have diuretic activity, and then modern research was sought to determine how accurate the ancient assessment of these herbs was. RESULTS: Of the 105 plants cited as having diuretic activity by Dioscorides, 56 (53.3%) genuses are confirmed as being diuretic in animal or human research. For another 38 (36.2%) genuses, no research related to diuresis could be identified. Six (5.7%) genuses had mixed results in modern research, whereas a mere 5 (4.8%) genuses were shown to not have diuretic activity. Considering the 67 genuses that were investigated, 56 (83.6%) were confirmed. CONCLUSION: This analysis confirms that Dioscorides was accurate in determining the diuretic nature of herbs, raising the possibility that he was right about other therapeutic suggestions concerning herbs he made. For the remaining herbs that have not been assessed for diuretic effect, it is not yet known if Dioscorides was accurate. Our findings suggest that the 38 herbs Dioscorides categorized as diuretics that have not been studied for diuretic function are candidates for research in this regard. PMID- 30403494 TI - Lysophosphatidic acid represses autophagy in prostate carcinoma cells. AB - Lysophosphatidic acid (LPA) is a small signaling phospholipid that mediates diverse functions including cell proliferation, migration and survival by engaging LPA-agonized G-protein coupled receptors. Autophagy is a survival mechanism in response to nutrient depletion or organellar damage that encloses idle or damaged organelles within autophagosomes that are then delivered to lysosomes for degradation. However, the relationship between LPA and autophagy is largely unknown. The purpose of this study is to elucidate whether LPA affects autophagy through the ERK1/2 and/or the Akt/mTOR signaling pathways. In this study, we investigated the effect of LPA on autophagy-regulating pathways in various prostate-derived cancer cells including PC3, LNCaP and Du145 cells grown in complete medium and exposed to serum-free medium. Using Western blotting and ELISA, we determined that LPA stimulates the ERK and mTOR pathways in complete and serum-free medium. The mTOR pathway led to phosphorylation of S6K and ULK, which respectively stimulates protein synthesis and arrests autophagy. Consistent with this, LPA exposure suppressed autophagy as measured by LC3 maturation and formation of GFP-LC3 puncta. Altogether, these results suggest that LPA suffices to activate mTORC1 and suppress autophagy in prostate cancer cells. PMID- 30403495 TI - An Intervention by a Patient-Designed Do-It-Yourself Mobile Device App Reduces HbA1c in Children and Adolescents with Type 1 Diabetes: A Randomized Double Crossover Study. AB - BACKGROUND: Prevention of type 1 diabetes mellitus (T1DM)-related complications is dependent on metabolic control. The recommended glycated hemoglobin (HbA1c) values <7.5% (58.5 mmol/mol) are met only by a minority of diabetic children and especially adolescents. The aim of this study was to evaluate the impact of an intervention comprising the use of Webdia, a patient-designed app for smartphones, on metabolic control of T1DM in children. METHODS: Fifty-five patients with T1DM, 10-18 years of age, were included in this single-center, randomized double-crossover study. We tested an intervention consisting of using Webdia for 3 months with monthly feedback and adaptation of the treatment. Main outcome was modification of HbA1c. Secondary outcomes were the prevalence of hypoglycemia and quality of life (QoL). RESULTS: Of the 55 included patients, 33 completed the study, 9 dropped out, and 13 were excluded due to insufficient use of the app. The app was well accepted by the users who completed the study (46.4% rated the program as good and 39.3% as excellent). The intervention led to a reduction of HbA1c by 0.33%, compared to the control group in which HbA1c rose by 0.21% (P = 0.048) in patients with HbA1c values >8.0% (63.9 mmol/mol) at inclusion, without increasing the prevalence of hypoglycemia (8.52 +/- 9.45 hypoglycemic events during last 2 weeks of intervention vs. 7.62 +/- 6.37 observation, P = 0.680). QoL scores were not modified. CONCLUSIONS: The intervention resulted in a significant decrease in HbA1c, without increasing the prevalence of hypoglycemia in patients with initial HbA1c >8.0% (63.9 mmol/mol). PMID- 30403496 TI - The temperature of water ingested before exercise alters the onset of physiological heat loss responses. AB - This study sought to determine whether the ingested water temperature prior to exercise alters the onset threshold and subsequent thermosensitivity of local vasomotor and sudomotor responses after exercise begins. Twenty males (age: 24+/ 4 y, weight: 75.8+/-8.1 kg, VO2peak: 52.3+/-7.7 mL.kg-1.min-1) ingested 3.2 ml.kg 1 of 1.5 degrees C, 37 degrees C, or 50oC water, rested 5 min, then cycled at 50% VO2peak for 15 min at 23.0+/-0.9 degrees C and 32+/-10%RH. Mean body temperature (Tb), local sweat rate (LSR) and skin blood flow (SBF) were measured. In a subset of 8 people (age: 25+/-5 y, weight: 78.6+/-8.3 kg, VO2peak: 48.9+/-11.1 mL.kg 1.min-1), blood pressure was measured and cutaneous vascular conductance (CVC) was determined. The change in Tbwas greater at the onset of LSR with 1.5oC (0.19+/-0.15oC) compared to 50oC (LSR: 0.11+/-0.12oC; P=0.04) but not 37oC (0.14+/-0.14oC, P=0.23) water ingestion, but did not differ between trials for SBF (1.5oC: 0.18+/-0.15oC, 37oC: 0.11+/-0.13oC, 50oC: 0.09+/-0.09oC; P=0.07). Conversely, the thermosensitivity of LSR and SBF were not different (LSR: 1.5oC: 1.11+/-0.75 mgzmin-1zcm-2z degrees C-1, 37 oC: 1.11+/-0.75 mgzmin-1zcm-2z degrees C-1, 50oC: 1.34+/-1.11 mgzmin-1zcm-2z degrees C-1; P=0.46; SBF: 1.5oC: 717+/ 882%baselineAUz degrees C-1, 37oC: 517+/-606%baselineAUz degrees C-1, 50oC: 857+/ 904%baselineAUz degrees C-1; P=0.95). After 15 min of exercise, LSR and SBF were greater with 50oC (LSR: 0.40+/-0.17 mgzmin-1zcm-2, SBF: 407+/-149%baselineAU,) compared to 1.5 degrees C water ingestion (LSR: 0.31+/-0.19 mgzmin-1zcm-2; P=0.02; SBF: 279+/-117%baselineAU; P<0.001), but not 37oC (LSR: 0.50+/-0.22 mgzmin-1zcm-2, SBF: 324+/-169%baselineAU). CVC was statistically unaffected (1.5 degrees C:275+/-81%baselineCVC, 37 degrees C:340+/-114%baselineCVC, 50 degrees C:384+/-160%baselineCVC; P=0.30). Collectively these results support the concept of visceral thermoreceptors modifying the central drive for thermoeffector responses. PMID- 30403497 TI - Maternal Personality and Psychosocial Variables Associated with Initiation Compared to Maintenance of Breastfeeding: A Study in Low Obstetric Risk Women. AB - INTRODUCTION: The benefits of breastfeeding are well known for mother and child. Research about the predictive factors related to the initiation and maintenance of breastfeeding is of great interest to public health. AIM: To analyze the factors associated with the timely initiation of breastfeeding at immediate postpartum and the variables that facilitate their maintenance 4 months after birth. MATERIALS AND METHODS: A longitudinal prospective design was used, including four stages: first trimester of pregnancy (personality), third trimester (childbirth expectations, breastfeeding intention, pregnancy worries, and coping strategies), immediately after childbirth (initiation of breastfeeding and childbirth satisfaction), and 4 months after birth (continuation of breastfeeding). RESULTS: A sample of 116 women took part in the study from the first trimester to 4 months after birth. Timely initiation of breastfeeding is associated with vaginal birth (p < 0.000) and with variables related to the absence of stress factors: fewer worries regarding childbirth (p = 0.009), higher satisfaction during birth in relation to holding the baby (p > 0.000), and the meeting of expectations (p = 0.017). These associations disappear when the type of birth is introduced. Maintenance of breastfeeding is associated with maternal personality and psychosocial variables: openness to experience (p = 0.007), increased worries about coping with the baby (p = 0.046), relationship with partner (p = 0.047), and overt emotional expression (p = 0.040). CONCLUSION: Different factors are associated with initiation and maintenance of breastfeeding. Specific prevention strategies are needed, aimed toward health care staff for improving breastfeeding initiation and to empower women during the entire pregnancy for breastfeeding maintenance. PMID- 30403498 TI - Obstructive Apnea Causes Microvascular Perfusion Mal-Distribution in the Lungs of Rats. AB - Obstructive sleep apnea (OSA) is associated with significant cardiovascular consequences, including pulmonary hypertension. Yet, little is known about its effects on pulmonary microvascular perfusion. To investigate this, we clamped the tracheal cannulas of anesthetized, spontaneously breathing rats to simulate obstructive apnea. The clamp remained in place for 10 breaths before it was released to allow the animals to again breathe spontaneously. We repeated this every 20 seconds until the rat experienced a total of 5 apneic episodes of 10 breaths each. We then infused into a femoral vein 108 4 um diameter fluorescent latex particles which became trapped within the pulmonary microcirculation. We removed the lungs, allowed them to air-dry, and quantified the particle distributions in sections of the lungs using Dispersion Index analysis, which is a method we developed previously. The log of the Dispersion Index (logDI) is a measure of perfusion mal-distribution. Greater values correspond to greater maldistribution. Apneic lungs had average logDI values of 1.28+/-0.24. Rats not subjected to apnea had average logDI values of 0.85+/-0.08 (p<=0.05). Rats that received latex particles 10 minutes or 24 hours after apnea had average logDI values of 0.97+/-0.31, and 0.84+/-0.38, respectively (n.s.). Our results demonstrate for the first time, that few apneic events produced significant but temporary perfusion mal-distribution within the pulmonary microcirculation. Repeated nightly episodes of this phenomenon over months and years may explain why human patients with OSA suffer from significantly greater cardiovascular disease than those who do not. PMID- 30403499 TI - Sex and individual differences in meal patterns mediate the persistency of running-associated high fat diet avoidance in rats. AB - The modern environment is characterized by convenient access to a variety of high fat (HF) foods and encourages excess energy intake, which leads to weight gain. While healthier diets and exercise are common interventions that facilitate energy balance, meal patterns also influence body weight and energy metabolism. The current study characterized the association between exercise, diet choice, and meal patterns in rats. Unlike sedentary rats that prefer a HF to a chow diet, wheel running rats initially avoid the HF diet. Subsequently, the running-induced HF diet avoidance persists longer in males than females. We hypothesized that differences in meal patterns contribute to sex differences in the prevalence and persistency of HF diet avoidance. During two-diet choice, rats did not mix chow and HF diet within a meal and consumed discrete meals of each diet. Exercise decreased chow meal size in both sexes (4.5 vs. 5.7 kcal) but decreased total meal frequency only in male rats. Analyses of individual differences revealed WR rats that maintained HF diet avoidance (HF avoiders) had larger chow than HF meals (5.2 vs. 1.3 kcal) upon initial three days of diet choice. Compared with rats that reversed HF avoidance (HF eaters), HF avoiders had shorter latency to consume their first meal of HF diet (2.6 vs. 98.9 min) upon initial running and diet choice. Taken together, these results suggest that both sex and individual differences in meal patterns contribute to differences in the persistency of exercise-associated HF diet avoidance. PMID- 30403500 TI - Resistance to Data Loss of Glycemic Variability Measurements in Long-Term Continuous Glucose Monitoring. AB - BACKGROUND: Continuous glucose monitoring (CGM) is a method of estimating blood glucose values from those recorded in the interstitial fluid. Because increasingly longer CGM measurements are possible, errors and data loss become more and more likely and potentially more damaging to accurate calculations of glycemic variability (GV) indices. Our research investigates the resistance of the CGM recording to data loss. METHODS: We collected 71 CGM recordings (duration of min: 2, max: 265, median: 42 days) from patients with type 1 diabetes and used three algorithms to introduce missing data. We calculated mean and standard deviation (SD) of absolute percentage error of 12 variability indices and correlated those with the percentage of missing data and duration of the measurements. RESULTS: Mean absolute percentage error of variability indices increased linearly with the percentage of missing data along with SD of absolute percentage error. Except for mean amplitude of glycemic excursions and time spent in hypoglycemia, all absolute errors never exceeded 25%, while mean absolute errors stayed below 5%. The gradient removal algorithm introduced errors larger than the single datapoint and block removal algorithms. The absolute percentage error of variability indices correlated negatively with the duration of the CGM measurements. CONCLUSIONS: Standard GV measurements in long-term glucose monitoring are robustly resistant to data loss. PMID- 30403502 TI - The Public Conversation and the Public's Health: A Public Health of Consequence, December 2018. PMID- 30403503 TI - Identifying Opioid Overdose Deaths Using Vital Statistics Data. PMID- 30403501 TI - Consistency Between Opioid-Related Mortality Trends Derived From Poison Center and National Vital Statistics System, United States, 2006-2016. AB - OBJECTIVES: To determine the association between poison center opioid exposure calls and National Vital Statistics System (NVSS) deaths. METHODS: We categorized Centers for Disease Control and Prevention NVSS mortality and the Researched Abuse, Diversion and Addiction-Related Surveillance System poison center program cases from 2006 to 2016 by International Classification of Diseases, Tenth Revision, codes (heroin [T40.1]; natural or semisynthetic opioids [T40.2]; methadone [T40.3]; synthetic opioids, other than methadone [T40.4]). We scaled rates by 100 000 population and calculated Pearson correlation coefficients. Sensitivity analysis excluded polysubstance cases involving either heroin or synthetic opioids as well as natural and semisynthetic opioids. RESULTS: The NVSS mortality and poison center program exposure rates showed similar trends from 2006 to 2012, and diverged after 2012 for all opioids combined, natural and semisynthetic opioids, and synthetic opioids (r = -0.37, -0.12, and 0.30, respectively). Sensitivity analysis with removal of heroin or synthetic opioid polysubstance deaths markedly improved correlations for all opioids combined and natural and semisynthetic opioids (r = 0.87 and 0.36, respectively). CONCLUSIONS: The NVSS mortality and poison center exposure rates showed similar trends from 2006 to 2012 then diverged, with sensitivity analysis suggesting polysubstance cases also involving heroin or illicit fentanyl as the cause. Public Health Implications. The NVSS and poison center program may provide complementary data when trends diverge. Public health interventions must include both licit and illicit opioids for maximal impact. PMID- 30403504 TI - Interpersonal Violence in Afghanistan-Beyond a Strictly Public Health Approach. PMID- 30403505 TI - Fighting the Health Challenges of Diabetes in Hong Kong: A Window Into Mainland China. PMID- 30403506 TI - Skills and Tools for Public Health Professionals to Address Corporate Power to Protect Human and Planetary Health. PMID- 30403507 TI - How Massachusetts, Vermont, and New York Are Taking Action to Address the Opioid Epidemic. PMID- 30403508 TI - McKee and Stuckler Respond. PMID- 30403510 TI - On Health Priorities, BRICS Countries, and Equity. PMID- 30403511 TI - Public Health Voices From China. PMID- 30403512 TI - Prevention of Obesity in Early Childhood: What Are the Next Steps? PMID- 30403513 TI - The NaloxBox Program in Rhode Island: A Model for Community-Access Naloxone. PMID- 30403514 TI - HIV Preexposure Prophylaxis. PMID- 30403515 TI - Marcus et al. Respond. PMID- 30403517 TI - News From The Nation's Health. PMID- 30403518 TI - AJPH Global News. PMID- 30403516 TI - Older Persons in The Netherlands and the United States: Similar in Trends in Life in Good Cognitive Health and Different in Trends in Life Without Disability/Poor Health. PMID- 30403519 TI - American Funding Cutback to East Jerusalem Hospitals: A Blow to the Health of the City. PMID- 30403522 TI - Prioritizing Top Health Issues in China Beyond 2018: A Health Equity Perspective. PMID- 30403521 TI - Multicomponent Obesity Prevention Intervention in Low-Income Preschoolers: Primary and Subgroup Analyses of the NET-Works Randomized Clinical Trial, 2012 2017. AB - OBJECTIVES: To evaluate a multicomponent obesity prevention intervention among diverse, low-income preschoolers. METHODS: Parent-child dyads (n = 534) were randomized to the Now Everybody Together for Amazing and Healthful Kids (NET Works) intervention or usual care in Minneapolis, MN (2012-2017). The intervention consisted of home visits, parenting classes, and telephone check ins. The primary outcomes were adjusted 24- and 36-month body mass index (BMI). RESULTS: Compared with usual care, the NET-Works intervention showed no significant difference in BMI change at 24 (-0.12 kg/m2; 95% confidence interval [CI] = -0.44, 0.19) or 36 months (-0.19 kg/m2; 95% CI = -0.64, 0.26). Energy intake was significantly lower in the NET-Works group at 24 (-90 kcal/day; 95% CI = -164, -16) and 36 months (-101 kcal/day; 95% CI = -164, -37). Television viewing was significantly lower in the NET-Works group at 24 (rate ratio = 0.84; 95% CI = 0.75, 0.93) and 36 months (rate ratio = 0.88; 95% CI = 0.78, 0.99). Children with baseline overweight or obesity had lower BMI in the NET-Works group than those in usual care at 36 months (-0.71 kg/m2; 95% CI = -1.30, -0.12). Hispanic children had lower BMI in the NET-Works group than those in usual care at 36 months (-0.59 kg/m2; 95% CI = -1.14, -0.04). CONCLUSIONS: In secondary analyses, NET-Works significantly reduced BMI over 3 years among Hispanic children and children with baseline overweight or obesity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01606891. PMID- 30403523 TI - Machine Learning in Neurooncology Imaging: From Study Request to Diagnosis and Treatment. AB - OBJECTIVE: Machine learning has potential to play a key role across a variety of medical imaging applications. This review seeks to elucidate the ways in which machine learning can aid and enhance diagnosis, treatment, and follow-up in neurooncology. CONCLUSION: Given the rapid pace of development in machine learning over the past several years, a basic proficiency of the key tenets and use cases in the field is critical to assessing potential opportunities and challenges of this exciting new technology. PMID- 30403524 TI - CT of Gastric Volvulus: Interobserver Reliability, Radiologists' Accuracy, and Imaging Findings. AB - OBJECTIVE: The objective of this study was to identify CT findings and determine interobserver reliability of surgically proven gastric volvulus. MATERIALS AND METHODS: This single-center retrospective study included 30 patients (21 women, nine men; mean age, 73 years old) with surgically proven gastric volvulus who underwent preoperative CT and 31 age- and sex-matched control subjects (21 women, nine men; mean age, 74 years old) with large hiatal hernias who were imaged for reasons other than abdominal pain. Two blinded radiologists reviewed the CT images and recorded findings of organoaxial and mesenteroaxial gastric volvulus and ischemia. Interobserver reliability, reader accuracy, sensitivity, specificity, and likelihood ratios of each CT finding were calculated. RESULTS: The radiologists were overall 90% accurate (55/61; six false-negatives per reader) in identifying gastric volvulus. Interobserver agreement was substantial (kappa = 0.71) for identifying the presence or absence of gastric volvulus. Agreement for most CT findings of gastric volvulus (11/14, 79%) was excellent (5/14, 36%) or substantial (6/14, 43%); the remaining findings showed moderate agreement (3/14, 21%). The most frequent and sensitive CT findings of volvulus with high positive likelihood ratios were stenosis at the hernia neck (reader 1, sensitivity = 80%, positive likelihood ratio = 26.66; reader 2, sensitivity = 77%, positive likelihood ratio = 12.83) and transition point at the pylorus (reader 1, sensitivity = 80%, positive likelihood ratio = 17; reader 2, sensitivity = 70%, positive likelihood ratio = 15). The presence of perigastric fluid or a pleural effusion were significantly more frequent in patients with ischemia at surgical pathology (p < 0.05 in all comparisons, both radiologists). CONCLUSION: In our series, CT showed substantial interobserver agreement and fair accuracy in identifying the presence of gastric volvulus. PMID- 30403525 TI - Assessment of the American College of Radiology Thyroid Imaging Reporting and Data System for Thyroid Nodule Malignancy Risk Stratification in a Pediatric Population. AB - OBJECTIVE: The purpose of this study is to assess the diagnostic performance of the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TIRADS) for malignancy risk in pediatric thyroid nodules. MATERIALS AND METHODS: Two radiologists reviewed ultrasound images of 74 tissue-proven thyroid nodules in 62 children. Points were given for individual features and then added to determine the ACR TI-RADS category, ranging from 1 (benign) to 5 (high suspicion). Kappa coefficients were generated to assess intra- and interobserver agreement. Generalized linear mixed-effects models were used to estimate the odds of malignancy with construction of a supplementary ROC curve. RESULTS: Fifty-four nodules were benign and 20 were malignant, with a median ACR TI-RADS category of 4 (interquartile range, 4-5). Nineteen of 20 (95.0%) malignant nodules were rated as TI-RADS category 4 or 5. There was substantial intraobserver agreement (kappa = 0.69-0.77; p < 0.001) and moderate interobserver agreement (kappa = 0.37; p = 0.002) for TIRADS category. Univariable analysis showed that, with every 1-unit increase of TI-RADS category, the likelihood of malignancy increased 2.63 times (95% CI, 1.08-6.41; p = 0.03). After adjusting for nodule size, TI-RADS category remained marginally associated with malignancy (adjusted odds ratio, 2.27; 95% CI, 0.93-5.54; p = 0.07). The AUC was 0.75 (95% CI, 0.64-0.86). An optimal cut point of TI-RADS category 5 was selected, with TI-RADS category 5 nodules 10.44 times (95% CI, 2.71-40.21; p < 0.0001) more likely than categories 1-4 nodules to be malignant. CONCLUSION: ACR TI-RADS discriminates well between malignant and benign nodules in a pediatric population, particularly at TI-RADS category 5. PMID- 30403526 TI - Incidental Renal Lesions on Lumbar Spine MRI: Who Needs Follow-Up? AB - OBJECTIVE: Incidentally discovered renal lesions on lumbar spine MRI are a common occurrence. Many follow-up recommendations are generated by radiologists encountering renal lesions to help characterize the finding as a benign cyst or a more complex, potentially malignant lesion. We hypothesized that analysis of T2 weighted imaging features of incidentally discovered renal lesions could reliably distinguish complex renal lesions from simple cysts. MATERIALS AND METHODS: Two independent readers retrospectively evaluated 149 renal lesions identified on lumbar spine MRI examinations. Presence or absence of a complex renal lesion was determined using T2-weighted imaging only. Using dedicated renal cross-sectional imaging examinations as the reference standard, statistical analysis was performed to determine the accuracy of lumbar spine MRI in predicting a complex and potentially neoplastic renal lesion. RESULTS: Of 149 renal lesions, 115 were simple cysts, and 34 were complex renal lesions (20 Bosniak II cysts, nine renal cell carcinomas, three Bosniak IIF cysts, and two angiomyolipomas). Lumbar spine MRI readers identified 72 lesions as simple cysts and 77 lesions as complex renal lesions. Reader sensitivity for detection of a complex renal lesion on lumbar spine MRI was 94% (95% CI, 80-99%); specificity, 63% (95% CI, 53-72%); positive predictive value, 43% (95% CI, 37-49%); and negative predictive value, 97% (95% CI, 90-99%). Readers correctly identified all neoplastic and potentially neoplastic lesions (>= Bosniak IIF). Interreader agreement was excellent (kappa = 0.84). CONCLUSION: Follow-up imaging may not be required in all cases of incidentally discovered renal lesions on lumbar spine MRI. Analysis of T2 weighted imaging alone appears to reliably rule out neoplastic and potentially neoplastic complex renal lesions. PMID- 30403527 TI - What Does Deep Learning See? Insights From a Classifier Trained to Predict Contrast Enhancement Phase From CT Images. AB - OBJECTIVE: Deep learning has shown great promise for improving medical image classification tasks. However, knowing what aspects of an image the deep learning system uses or, in a manner of speaking, sees to make its prediction is difficult. MATERIALS AND METHODS: Within a radiologic imaging context, we investigated the utility of methods designed to identify features within images on which deep learning activates. In this study, we developed a classifier to identify contrast enhancement phase from whole-slice CT data. We then used this classifier as an easily interpretable system to explore the utility of class activation map (CAMs), gradient-weighted class activation maps (Grad-CAMs), saliency maps, guided backpropagation maps, and the saliency activation map, a novel map reported here, to identify image features the model used when performing prediction. RESULTS: All techniques identified voxels within imaging that the classifier used. SAMs had greater specificity than did guided backpropagation maps, CAMs, and Grad-CAMs at identifying voxels within imaging that the model used to perform prediction. At shallow network layers, SAMs had greater specificity than Grad-CAMs at identifying input voxels that the layers within the model used to perform prediction. CONCLUSION: As a whole, voxel-level visualizations and visualizations of the imaging features that activate shallow network layers are powerful techniques to identify features that deep learning models use when performing prediction. PMID- 30403528 TI - Spectrum of Voriconazole-Induced Periostitis With Review of the Differential Diagnosis. AB - OBJECTIVE: Voriconazole is an antifungal medication used primarily for the treatment of Candida and Aspergillus infections. A fairly newly described side effect of long-term voriconazole use is periostitis. The purpose of this article is to describe the main differential consideration-hypertrophic osteoarthropathy and other differential diagnoses, including venous stasis, thyroid acropachy, and hypervitaminosis A. CONCLUSION: With knowledge of imaging appearance, clinical manifestations, and outcomes, radiologists can make an accurate diagnosis of voriconazole-induced periostitis, and clinical teams can initiate appropriate management. PMID- 30403529 TI - High-Fidelity Simulation Training for the Diagnosis and Management of Adverse Contrast Media Reactions. AB - OBJECTIVE: Adverse reactions to contrast media are potentially life-threatening events that require prompt recognition and management by radiologists who may have little experience with them. The objectives of this project were to develop and assess a simulation-based program that would equip radiology trainees with appropriate knowledge and skills to recognize and manage adverse contrast media reactions. MATERIALS AND METHODS: Fifteen adverse contrast media reaction scenarios were developed to run on high-fidelity adult and pediatric mannequins in a simulation center. Ninety-six radiology trainees (postgraduate year 2-6) participated in the program, which consisted of two didactic lectures and a simulation session. For each simulation session, seven scenarios were chosen. Objective quizzes assessing knowledge and subjective questionnaires assessing comfort were completed both before and after the simulation. A survey assessing the overall program was also completed. RESULTS: All 96 radiology trainees viewed the didactic lectures, attended a simulation session, and completed the pre- and postsimulation quizzes and questionnaires. Mean scores increased from 69% to 82% (p < 0.001) and from 3.1 to 4.5 out of 5 (p < 0.001) on the objective and subjective tests, respectively. Statistically significant improvement was also seen when participants were separated according to level of training. On the final program evaluation survey, scores ranged from 4.5 to 4.7 out of 5. CONCLUSION: We describe the development of a high-fidelity simulation program with a larger variety of scenarios than in prior studies that can provide radiologists the knowledge and skills needed to recognize and manage adverse contrast media reactions. We saw a statistically significant improvement in knowledge and comfort levels across all levels of training. PMID- 30403530 TI - Anterior Inferior Iliac Spine Morphology: Comparison of Symptomatic Hips With Femoroacetabular Impingement and Asymptomatic Hips. AB - OBJECTIVE: The objective of our study was to compare anterior inferior iliac spine (AIIS) morphology in symptomatic hips with femoroacetabular impingement (FAI) and in asymptomatic hips, determine the prevalence of impingement morphology in patients with a radiographic "crossover" sign, and identify potential risk factors for having impingement morphology. MATERIALS AND METHODS: For this retrospective study, we identified consecutive symptomatic hips with FAI (n = 54) and asymptomatic hips (n = 35) in patients who underwent CT from 2015 to 2017. Two radiologists blindly and independently evaluated 3D CT images of each hip and graded the AIIS morphology according to the Hetsroni classification scheme. The prevalence of AIIS morphology types was calculated. Associations of AIIS morphology types with symptoms and the crossover sign were evaluated with a chi-square test. A multivariable logistic regression determined risk factors for abnormal AIIS morphology (i.e., type 2 or 3). RESULTS: There was no difference in the prevalence of AIIS morphology types for symptomatic hips with FAI versus asymptomatic hips (p = 0.44) or for hips with a positive versus those with a negative crossover sign (p = 0.21). There was moderate interobserver agreement (kappa = 0.44) and good-to-excellent intraobserver agreement (kappa = 0.67 and 0.90) for grading AIIS morphology. Age, sex, femoral version, acetabular version, alpha angle, lateral center edge angle, and the crossover sign were not significant risk factors for abnormal AIIS morphology in patients with FAI (p = 0.11-0.79). CONCLUSION: There is no difference in AIIS morphology between symptomatic hips with FAI versus asymptomatic hips or between hips with and those without the radiographic crossover sign. Age, sex, and other FAI parameters are not risk factors for developing AIIS impingement morphology. PMID- 30403531 TI - Supraspinatus Myotendinous Junction Injuries: MRI Findings and Prevalence. AB - OBJECTIVE: The purpose of this study is to describe the MRI findings and evaluate the prevalence of supraspinatus myotendinous injuries. MATERIALS AND METHODS: Among 1001 consecutive shoulders that underwent either conventional MRI or MR arthrography between January and December 2016, 843 shoulders were included. All MR images were retrospectively analyzed for identification and classification into the appropriate grade of acute or chronic rotator cuff myotendinous injuries. Other MRI findings, such as the presence of rotator cuff tendon insertional tears, and clinical information were also evaluated. RESULTS: At MRI, 0.47% (4/843) of shoulders had supraspinatus myotendinous injuries involving the anterior muscular bundle exclusively. Chronic grade III (n = 2), acute grade III (n = 1), and acute grade II (n = 1) injuries were identified in three men and one woman (mean age, 44 years) with a clinical history of trauma (n = 2) or of progressive shoulder pain (n = 2). A concurrent supraspinatus insertional tendon tear with either partial (n = 1) or full (n = 1) thickness was present in half the cases. Loss of tension of the myotendinous junction in grade III myotendinous junction injuries led to severe atrophy and fatty infiltration of the anterior supraspinatus. CONCLUSION: Supraspinatus myotendinous junction injuries are uncommon at MRI. These lesions invariably involve the anterior bundle of the supraspinatus muscle and may occur with a concomitant insertional tendon tear. High-grade chronic injuries lead to selective atrophy and fatty infiltration of the anterior supraspinatus muscle. PMID- 30403532 TI - Multiparametric MRI Features and Pathologic Outcome of Wedge-Shaped Lesions in the Peripheral Zone on T2-Weighted Images of the Prostate. AB - OBJECTIVE: This study investigates the multiparametric MRI (mpMRI) characteristics and pathologic outcome of wedge-shaped lesions observed on T2 weighted images. MATERIALS AND METHODS: Seventy-six patients with histologically confirmed prostate cancer underwent preoperative 3-T MRI before undergoing radical prostatectomy. Two radiologists worked in consensus to mark wedge-shaped regions of hypointensity on T2-weighted images and assess their appearance on apparent diffusion coefficient (ADC) maps (to determine the degree of hypointensity) and dynamic contrast-enhanced (DCE) MRI (DCE-MRI) (to assess whether they showed early enhancement). The pathologic outcome of wedge-shaped lesions was assessed by matching MR images with whole-mount histologic specimens retrospectively. The difference in quantitative ADC values between malignant and benign wedge-shaped lesions was assessed using a t test. RESULTS: Thirty-five wedge-shaped regions were identified, 12 (34%) of which were found be malignant. Most malignant wedge-shaped regions were highly hypointense (10/12; 83%) on ADC maps and showed early enhancement on DCE-MRI (7/12; 58%). However, benign wedge shaped lesions were predominantly mildly hypointense (13/23; 57%) on ADC maps and showed no early enhancement (15/23; 65%). Histologic correlates of the benign wedge-shaped regions showed prostatitis (acute inflammation [7/23; 30%] or chronic inflammation [9/23; 39%]), hemosiderin-laden macrophages (6/23; 26%), prominent blood vessels (7/23; 30%), intraluminal blood (6/23; 26%), and nonspecific atrophy (6/23; 26%). The mean (+/- SD) quantitative ADC value of malignant wedge-shaped regions (1.13 +/- 0.11 MUm2/ms) was significantly lower (p = 0.0001) than that of benign wedge-shaped regions (1.52 +/- 0.27 MUm2/ms). CONCLUSION: This study shows that a greater percentage of wedge-shaped features are malignant than was previously thought. Of importance, mpMRI (specifically, ADC maps) can distinguish between malignant and benign wedge-shaped features. PMID- 30403533 TI - Improving Radiology Peer Learning: Comparing a Novel Electronic Peer Learning Tool and a Traditional Score-Based Peer Review System. AB - OBJECTIVE: The purpose of this study was to compare the yields of peer learning between a radiology electronic peer learning tool (PLT) and a score-based peer review (SBPR) system. MATERIALS AND METHODS: This retrospective study was performed from May 1, 2017, through October 31, 2017, at a 776-bed academic hospital performing more than 620,000 radiology examinations annually. Use of a PLT that generates alerts facilitating closed-loop feedback was initiated on March 1, 2017. Functions included providing peers with the following: clinical follow-up after review of prior reports, positive feedback, and consultation to solicit second opinions. In the same period, an SBPR system yielded the following scores: 1, agree with original interpretation; 2, minor discrepancy; 3, moderate discrepancy; and 4, major discrepancy. Potential learning opportunities were defined as cases receiving a clinical follow-up alert (PLT system) and reports scored 3 or 4 (SBPR system). Primary outcome was clinically significant feedback per total reports reviewed, measured as radiology report addendum rate (number with addenda divided by number of reports reviewed monthly for each system). The secondary outcome was potential learning opportunity rate (number of clinical follow-up alerts or reports scored 3 or 4 divided by the total number of radiology reports reviewed monthly). A paired t test was used for statistical analysis. RESULTS: The overall PLT report addendum rate was 11.2% (23 addenda/206 reports) versus 0.27% (13 addenda/4861 reports) for SBPR (p = 0.03), a 41-fold difference (11.2/0.27). The potential learning opportunity rate for PLT was 50.0% (206 clinical follow-up alerts among 412 total alerts) versus 0.53% (26 scored 3 or 4 among 4861 reports reviewed) for SBPR (p = 0.00003), a 94-fold difference (50/0.53). CONCLUSION: A PLT improves radiology peer learning with a significantly higher yield of clinically significant feedback and potential learning opportunities compared with a traditional SBPR system. PMID- 30403534 TI - Impact of a Health Information Technology-Enabled Appropriate Use Criterion on Utilization of Emergency Department CT for Renal Colic. AB - OBJECTIVE: The purpose of this study was to evaluate the impact of an appropriate use criterion (AUC) for renal colic based on local best practice, implemented as electronic clinical decision support (CDS), on the emergency department (ED) use of CT for patients with suspected nephrolithiasis. MATERIALS AND METHODS: This retrospective cohort study was performed in the EDs of a level I trauma center (study site) and local comparable hospital (control site). An AUC for patients younger than 50 years with a history of uncomplicated nephrolithiasis presenting with renal colic was developed by an interdisciplinary emergency medicine, emergency radiology, and urology team and embedded as CDS. AUC-consistent CT of ureter requests received no CDS alert. Otherwise, the orderer was alerted to consider a trial of symptomatic control or discharge without CT. A natural language processing tool mined ED notes for visits in September 2010-February 2012 (before AUC implementation) and April 2013-September 2014 (1 year after implementation) for concept unique identifiers of flank tenderness or renal or ureteral pain. Manual review excluded noneligible cases; the others were reviewed by a multidisciplinary team. Chi-square tests were used to assess for CT rate differences, the primary outcome. RESULTS: The final sample included 467 patients (194 study site) before and 306 (88 study site) after AUC implementation. The study site's CT of ureter rate decreased from 23.7% (46/194) to 14.8% (13/88) (p = 0.03) after implementation of the AUC. The rate at the control site remained unchanged, 49.8% (136/273) versus 48.2% (105/218) (p = 0.3). CONCLUSION: Implementing an AUC based on local best practice as CDS may effectively curb potential imaging overuse in a subset of ED patients with renal colic unlikely to have a complicated course or alternative dangerous diagnosis. PMID- 30403535 TI - Prevalence and Antimicrobial Resistance of Escherichia coli, Enterococcus spp. and the Major Foodborne Pathogens in Calves in Latvia. AB - The aim of the present study was to detect the prevalence and antimicrobial resistance of fecal indicators and major foodborne pathogens in feces of calves and to identify the factors associated with increased prevalence of resistant bacteria on farms. Altogether, 180 rectal swabs were collected from 18 farms in Latvia. Samples were investigated to detect the prevalence and antimicrobial resistance of Escherichia coli, Enterococcus spp., Listeria monocytogenes, Yersinia enterocolitica, Salmonella spp., Staphylococcus aureus, and Campylobacter spp. Among all, 64% (74/110) of commensal E. coli, 100% (78/78) Enterococcus faecalis and 96% (22/23) Enterococcus faecium isolates were resistant at least to one antibiotic. The prevalence of extended-spectrum beta lactamase (ESBL)/AmpC-producing E. coli were 11.1% (20/180) with blaCTX-M, blaTEM, and blaCMY genes identified. Campylobacter jejuni (12.8%, 23/180) and Campylobacter coli (2.8%, 5/180) were the most resistant to tetracycline (61%, 14/23; 100%, 5/5) and fluoroquinolones (61%, 14/23; 100%, 5/5). Prevalence of L. monocytogenes was 0.6% (1/180) and S. aureus 1.7% (3/180). All samples were Salmonella and Y. enterocolitica negative. Farm size, bought calves, contact with other calves, and antimicrobial treatment of cows were associated with increased prevalence of resistant E. coli and Enterococcus spp. Despite the low overall usage of antimicrobials in Latvia, the high rates of antimicrobial resistance in fecal indicators and Campylobacter, in addition to the high prevalence of ESBL producing E. coli, highlights the necessity for the prudent use of antimicrobials in dairy farms in Latvia. PMID- 30403536 TI - Biology of Tumor Associated Macrophages in Diffuse Large B Cell Lymphoma. AB - The tumor associated microenvironment is known to play a vital role during the development and progression of different malignant tumors. As a part of tumor microenvironment, tumor associated macrophages (TAMs) are crucial for the genesis, proliferation, metastasis, and survival of tumor cells. Recently, more and more studies showed that TAMs were related with poor clinical status and survival in patients with diffuse large B cell lymphoma (DLBCL). Considering the complex roles which TAMs play in the tumor microenvironment of DLBCL, the aim of this study was to review the biological mechanisms between TAMs and DLBCL cells, including extracellular matrix remodeling and angiogenesis promotion, tumor promotion, immune suppression, and phagocytosis inhibition. This review will help us to further understand the comprehensive impact of TAMs on DLBCL and explore possible prognostic markers and therapeutic targets. PMID- 30403537 TI - 3D human bone marrow stromal and endothelial cell spheres promote bone healing in an osteogenic niche. AB - The current study used an ex vivo [embryonic day (E)18] chick femur defect model to examine the bone regenerative capacity of implanted 3-dimensional (3D) skeletal-endothelial cell constructs. Human bone marrow stromal cell (HBMSC) and HUVEC spheroids were implanted within a bone defect site to determine the osteogenic potential of the skeletal-endothelial cell unit. Cells were pelleted as co- or monocell spheroids and placed within 1-mm-drill defects in the mid diaphysis of E18 chick femurs and cultured organotypically for 10 d. Micro computed tomography analysis revealed significantly ( P = 0.0001) increased levels of bone volume (BV) and BV/tissue volume ratio in all cell-pellet groups compared with the sham defect group. The highest increase was seen in BV in femurs containing the HUVEC and HBMSC monocell constructs. Type II collagen expression was particularly pronounced within the cell spheres containing HBMSCs and HUVECs, and CD31-positive cell clusters were prominent within HUVEC-implanted defects. These studies demonstrate the importance of the 3D osteogenic endothelial niche interaction in bone regeneration. Elucidating the component cell interactions in the osteogenic-vascular niche and the role of exogenous factors in driving these osteogenic processes will aid the development of better bone reparative strategies.-Inglis, S., Kanczler, J. M., Oreffo, R. O. C. 3D human bone marrow stromal and endothelial cell spheres promote bone healing in an osteogenic niche. PMID- 30403538 TI - Comorbid TBI-depression costs in veterans: a chronic effect of neurotrauma consortium (CENC) study. AB - BACKGROUND: The U.S. Veterans Health Administration (VHA) provides depression treatment to veterans with Traumatic Brain Injury (TBI). VHA costs of comorbid TBI-depression were estimated by Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) status over 14 years. METHODS: VHA-USING veterans with TBI DIAGNOSED IN 2000-2010 were followed through FY2014. TBI severity was determined using the Department of Defense criteria. Depression was identified by the Elixhauser algorithm. Generalized linear and seemingly unrelated regression models were used to estimate the impact of depression on annual per veteran and total VHA inpatient, outpatient, and pharmaceutical costs, by OEF/OIF status. RESULTS: A total of 66.57% of pre-OEF/OIF and 87.46% of OEF/OIF veterans had depression. Depression was estimated to increase annual total ($1,847), outpatient ($1,558), and pharmaceutical ($287) costs for pre-OEF/OIF, and $1,228, $1,685, and $191 for OEF/OIF veterans. However, depression was estimated to lower annual inpatient costs by $648 per OEF/OIF veteran. The annual VHA cost for all veterans with comorbid TBI-depression was estimated at $1,101,329,953. CONCLUSIONS: The estimated annual cost for Veterans with comorbid TBI-depression was more than $1 billion. TBI and depression screening/treatment may result in reduced inpatient VHA costs in OEF/OIF veterans exposed to TBI. VHA policymakers should consider screening for TBI and depression in pre-OEF/OIF veterans. PMID- 30403539 TI - Impact of Event Severity on Hospital Rankings Based on Heart Failure Readmission Rates. AB - The Medicare Readmissions Reduction Program penalizes hospitals with higher than expected readmission rates after discharge for congestive heart failure (CHF). This exploratory study analyzed whether categorizing readmissions by event severity might have implications for the program. The authors used the 5% MedPAR (Medicare Provider and Analysis Review) data for 2008 to 2014 and ranked 1820 hospitals based on all readmissions, readmissions for CHF, short-stay CHF readmissions, and readmissions for severe CHF with evidence of cardiogenic shock. Ranking hospitals based on severe CHF readmissions changes their relative rank order significantly compared to counting all readmissions. If confirmed in the full Medicare data, the finding could inform the design of the Readmission Reduction Program. PMID- 30403540 TI - Liraglutide Promotes the Osteogenic Differentiation in MC3T3-E1 Cells Via Regulating the Expression of Smad2/3 Through PI3K/Akt and Wnt/beta-Catenin Pathways. AB - Diabetes is a worldwide health problem with increasing prevalence. Some reports indicate the interplay between bone and glucose metabolism. The imbalance between bone resorption and formation resulted in the structural integrity and strength of bone. Glucagon-like peptide-1 (GLP-1) and its agonists (Liraglutide) have an anabolic action on bone remodeling by stimulating osteoblast differentiation as well as increasing osteoblast longevity. However, the underlying mechanisms remain elusive. We detected the presence of GLP-1 receptor (GLP-1R) in MC3T3-E1 cells via immunocytochemistry assay. Alkaline phosphatase activity assay, alizarin red stain, quantitative real-time polymerase chain reaction, and western blot were employed to detect the effect of Liraglutide on osteogenic differentiation. Liraglutide promoted the expression of GLP-1R in a dosage- and time-dependent manner, and it enhanced the osteogenic differentiation in MC3T3-E1 cells. Liraglutide application improved the levels of Smad2/3 and p-Smad2/3; however, the silencing of Smad2/3 blocked the osteogenic differentiation induced by Liraglutide. What is more, the application of PI3K and Wnt inhibitors inhibited the upregulation of Akt, p-Akt, beta-catenin, Smad2/3, and p-Smad2/3 induced by Liraglutide. Liraglutide facilitated the osteogenic differentiation via the regulation of Smad2/3 via PI3K/AKT and Wnt/beta-catenin pathways. These data revealed a new mechanism of Liraglutide inducing osteogenic differentiation and provided theory evidence to maintain normal bone metabolism during diabetes therapy. PMID- 30403541 TI - Politics and Pandemics. PMID- 30403542 TI - The Impact of Loneliness on Outcomes of Pulmonary Rehabilitation in Patients with COPD. AB - Psychological factors such as negative affect have been demonstrated to impact course and treatment of chronic obstructive pulmonary disease (COPD). However, little is known about the respective impact of social factors. In several other chronic diseases, loneliness has been shown to predict morbidity, but little is known about its impact on COPD. Therefore, this study examined the associations between loneliness and outcome measures of a pulmonary rehabilitation program (PR). Before and after a 3-week inpatient PR program, patients with COPD (N = 104) underwent a 6-min walking test to measure functional exercise capacity. Loneliness was assessed with the Loneliness Scale. The Medical Outcomes Study 36 item short form, 9-item Patient Health Questionnaire, and 7-item General Anxiety Disorder questionnaire were administered as measures of health-related quality of life (HQoL), depression, and anxiety, respectively. Multiple regression analyses showed that at the start of PR, more loneliness was associated with worse levels of functional exercise capacity, HQoL, depression, and anxiety, but with greater improvements in functional exercise capacity and HQoL over the course of PR, even after controlling for age, sex, lung function, and smoking status. Patients with stronger decreases in loneliness from start to end of PR showed stronger improvements in functional exercise capacity and HQoL over the course of PR. The present study shows that subjective loneliness is associated with relevant treatment outcomes in patients with COPD undergoing pulmonary rehabilitation. Therefore, loneliness should be addressed in patients with COPD as it could play a significant role in their disease progression. PMID- 30403543 TI - Steps in Mechanotransduction Pathways that Control Cell Morphology. AB - It is increasingly clear that mechanotransduction pathways play important roles in regulating fundamental cellular functions. Of the basic mechanical functions, the determination of cellular morphology is critical. Cells typically use many mechanosensitive steps and different cell states to achieve a polarized shape through repeated testing of the microenvironment. Indeed, morphology is determined by the microenvironment through periodic activation of motility, mechanotesting, and mechanoresponse functions by hormones, internal clocks, and receptor tyrosine kinases. Patterned substrates and controlled environments with defined rigidities limit the range of cell behavior and influence cell state decisions and are thus very useful for studying these steps. The recently defined rigidity sensing process provides a good example of how cells repeatedly test their microenvironment and is also linked to cancer. In general, aberrant extracellular matrix mechanosensing is associated with numerous conditions, including cardiovascular disease, aging, and fibrosis, that correlate with changes in tissue morphology and matrix composition. Hence, detailed descriptions of the steps involved in sensing and responding to the microenvironment are needed to better understand both the mechanisms of tissue homeostasis and the pathomechanisms of human disease. Expected final online publication date for the Annual Review of Physiology Volume 81 is February 10, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30403544 TI - Rethinking assumptions about how trial and nuisance variability impact neural task performance in a fast processing regime. AB - Task performance is determined not only by the amount of task-relevant signal present in our brains, but also by the presence of noise, which can arise from multiple sources. Internal noise, or "trial variability", manifests as trial-by trial variations in neural responses under seemingly identical conditions. External factors can also translate into noise, particularly when a task requires extracting a particular type of information from our environment amid changes in other task-irrelevant, "nuisance" parameters. To better understand how signal, trial variability and nuisance variability combine to determine neural task performance, we explored their interactions, both in simulation and when applied to recorded neural data. This exploration revealed that trial variability is typically larger than a neuron's task-relevant signal for tasks with fast reaction times, where spike count integration windows are short. In this low signal-to-trial variability regime, nuisance variability has the counterintuitive property of having a negligible impact on single-neuron task performance, even when it dominates the task-relevant signal. The inconsequential impact of nuisance variability on individual neurons also extends to descriptions of population performance, under the assumption that both trial and nuisance variability are uncorrelated between neurons. These results demonstrate that some basic intuitions about neural coding are misguided in the context of a fast processing, low spike count regime. PMID- 30403545 TI - In vitro reconstitution of DNA replication initiated by genetic recombination: A T4 bacteriophage model for a type of DNA synthesis important for all cells. AB - Using a mixture of ten purified DNA replication and DNA recombination proteins encoded by the bacteriophage T4 genome, plus two homologous DNA molecules, we have reconstituted the genetic recombination-initiated pathway that initiates DNA replication forks at late times of T4 bacteriophage infection. Inside the cell, this recombination-dependent replication (RDR) is required to produce the long concatemeric T4 DNA molecules that serve as substrates for packaging the shorter, genome-sized viral DNA into phage heads. The five T4 proteins that catalyze DNA synthesis on the leading strand plus the proteins required for lagging strand DNA synthesis are essential for the reaction, as are a special mediator protein (gp59) and a Rad51/RecA analog (the T4 UvsX strand-exchange protein). Related forms of RDR are widespread in living organisms - for example, they play critical roles in the homologous recombination events that can restore broken ends of the DNA double helix, restart broken DNA replication forks, and cross-over chromatids during meiosis in eukaryotes. Those processes are considerably more complex, and the results presented here should be informative for dissecting their detailed mechanisms. PMID- 30403547 TI - Vancomycin-Resistant Enterococcus faecium in Tunisia: Emergence of Novel Clones. AB - Vancomycin-resistant Enterococci (VRE) are a major public health problem worldwide, since they are commonly implicated in nosocomial infections in various regions in the world. The aim of our study was to investigate genetic features and clonal relationship of VRE in the Military hospital of Tunisia. A total of 10 VRE strains were initially detected and identified by the Viteck II compact(r) (BioMerieux(r)) automated system, then confirmed by PCR using specific primers. These VRE strains were isolated during the period extended between September 2015 and January 2017 from anal and blood samples from patients hospitalized mainly in the neonatology service and intensive care unit. All these strains were identified as Enterococcus faecium and carried the vanA gene. Other acquired resistance genes were also detected by PCR: [ermB (n = 6); tetL (n = 6); tetM (n = 2); aac(6')-Ie-aph(2'')-Ia (n = 10); aph(3')-III-a (n = 9); ant(6)-Ia (n = 8)]. The insertion sequence IS16 was detected in all our tested strains. Esp virulence gene was detected in only one strain. The clonal relatedness of VRE strains screened by pulse-field gel electrophoresis and multi-locus sequence typing showed four clones: two related clones A1 (one strain) and A2 (one strain) ascribed to ST80 belonged to CC17, the other remaining two clones, named B (one strain) and C (seven strains), revealed two new sequences types assigned to ST1463 and ST1464 respectively. The emergence of novel clones of VRE in this hospital could be a warning of rapid evolution of these resistant bacteria, which calls for new surveillance strategies, strict hygiene and practices. PMID- 30403546 TI - MLSB-Resistant Staphylococcus aureus in Central Greece: Rate of Resistance and Molecular Characterization. AB - The aim of the present study was to determine the rate and mechanisms of resistance to macrolides, lincosamides, and streptogramin B (MLSB) antibiotics of Staphylococcus aureus collected in Central Greece. Of the 2,893 S. aureus collected during 2012-2017, 1,161 isolates (40.2%) exhibited resistance to at least one of the MLSB agents. The rate of erythromycin resistance was statistically significantly higher in methicillin-resistant S. aureus (MRSA) (58.6%) than in methicillin-sensitive S. aureus (MSSA) isolates (20.7%) (p = 0.002). Two hundred seventy-five representative MLSB-resistant S. aureus, including 81 MSSA and 194 MRSA isolates, were further studied. Thirty-eight MSSA isolates carried ermC, 26 MSSA were positive for ermA, whereas 17 isolates carried msrA gene. Among MRSA, the ermA gene was identified in the majority of the isolates (n = 153). Thirty-seven MRSA isolates carried ermC; three isolates carried msrA, whereas the remaining MRSA was positive for two genes (ermA and ermC). Phylogenetic analysis showed that ST225, which belongs to CC5, was the most prevalent, accounting for 137 MRSA isolates. Higher genetic diversity was found in the group of MSSA isolates, which comprised of 13 sequence types. Whole genome sequencing data showed that all ermA-positive S. aureus, with the exception of one ST398 isolate, harbored the ermA-carrying Tn554 transposon integrated into their chromosomes. Furthermore, Illumina sequencing followed by polymerase chain reaction screening identified that ermC, which was identified in a polyclonal population of MSSA and MRSA isolates, was carried by small plasmids, like pNE131. These findings highlighted the important role of high-risk clones and of mobile elements carrying resistance genes in the successful dissemination of MLSB-resistant staphylococci. PMID- 30403548 TI - Kinematic analysis of bimanual movements during food handling by head-fixed rats. AB - Bimanual coordination - in which both hands work together to achieve a goal - is crucial for the basic needs of life, such as gathering and feeding. Such coordinated motor skill is highly developed in primates, where it has been most extensively studied. Rodents also exhibit remarkable dexterity and coordination of forelimbs during food handling and consumption. However, rodents have been less commonly used in the study of bimanual coordination because of limited quantitative measuring techniques. Here we describe a high-resolution tracking system that enables kinematic analysis of rat forelimb movement. The system is used to quantify forelimb movements bilaterally in head-fixed rats during food handling and consumption. Forelimb movements occurring naturally during feeding were encoded as continuous 3-D trajectories. The trajectories were then automatically segmented and analyzed, using a novel algorithm, according to the laterality of movement speed or the asymmetry of movement direction across the forelimbs. Bilateral forelimb movements were frequently observed during spontaneous food handling. Both symmetry and asymmetry in movement direction were frequently observed, with symmetric bilateral movements quantitatively more common. The proposed method overcomes a limitation in the precise quantification of bimanual coordination in rodents. This enables the use of powerful rodent based research tools such as optogenetics and chemogeneticsin the further investigation of neural mechanisms of bimanual coordination. PMID- 30403549 TI - Different SUMO paralogs determine the fate of WT and mutant CFTRs: biogenesis vs. degradation. AB - A pathway for CFTR degradation is initiated by Hsp27 which cooperates with Ubc9 and binds to the common F508del mutant to modify it with SUMO-2/3. These SUMO paralogs form poly-chains, which are recognized by the ubiquitin ligase, RNF4, for proteosomal degradation. Here, protein array analysis identified the SUMO E3, PIAS4, which increased WT and F508del CFTR biogenesis in CFBE airway cells. PIAS4 increased immature CFTR three-fold and doubled expression of mature CFTR, detected by biochemical and functional assays. In cycloheximide chase assays, PIAS4 slowed immature F508del degradation 3-fold and stabilized mature WT CFTR at the PM. PIAS4 knockdown reduced WT and F508del CFTR expression by 40-50%, suggesting a physiological role in CFTR biogenesis. PIAS4 modified F508del CFTR with SUMO-1 in vivo and reduced its conjugation to SUMO-2/3. These SUMO paralog specific effects of PIAS4 were reproduced in vitro using purified F508del NBD1 and SUMOylation reaction components. PIAS4 reduced endogenous ubiquitin conjugation to F508del CFTR by ~50% and blocked the impact of RNF4 on mutant CFTR disposal. These findings indicate that different SUMO paralogs determine the fates of WT and mutant CFTRs, and they suggest that a paralog switch during biogenesis can direct these proteins to different outcomes: biogenesis vs. degradation. PMID- 30403550 TI - Clinical Application and Potential of Fecal Microbiota Transplantation. AB - Fecal microbiota transplantation (FMT) is a well-established treatment for recurrent Clostridioides difficile infection. FMT has become a more readily available and useful new treatment option as a result of stool banks. The current state of knowledge indicates that dysbiosis of the gut microbiota is implicated in several disorders in addition to C. difficile. Randomized controlled studies have shown FMT to be somewhat effective in treating ulcerative colitis, irritable bowel syndrome, and hepatic encephalopathy. In addition, FMT has been beneficial in treating several other conditions, such as the eradication of multidrug resistant organisms and graft-versus-host disease. We expect that FMT will soon be implemented as a treatment strategy for several new indications, although further studies are needed. Expected final online publication date for the Annual Review of Medicine Volume 70 is January 27, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30403551 TI - The Global Landscape of Tuberculosis Therapeutics. AB - Tuberculosis (TB) is one of the oldest infections afflicting humans yet remains the number one infectious disease killer worldwide. Despite decades of experience treating this disease, TB regimens require months of multidrug therapy, even for latent infections. There have been important recent advances in treatment options across the spectrum of TB, from latent infection to extensively drug-resistant (XDR) TB disease. In addition, new, potent drugs are emerging out of the development pipeline and are being tested in novel regimens in multiple currently enrolling trials. Shorter, safer regimens for many forms of TB are now available or are in our near-term vision. We review recent advances in TB therapeutics and provide an overview of the upcoming clinical trials landscape that will help define the future of worldwide TB treatment. Expected final online publication date for the Annual Review of Medicine Volume 70 is January 27, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30403552 TI - The ARP2/3 complex prevents excessive formin activity during cytokinesis. AB - Cytokinesis completes cell division by constriction of an acto-myosin contractile ring that separates the two daughter cells. Here, we use the early C. elegans embryo to explore how the actin filament network in the ring and the surrounding cortex is regulated by the single cytokinesis formin CYK-1 and the ARP2/3 complex, which nucleate non-branched and branched filaments, respectively. We show that CYK-1 and the ARP2/3 complex are the predominant F-actin nucleators responsible for generating distinct cortical F-actin architectures, and that depletion of either nucleator affects the kinetics of cytokinesis. CYK-1 is critical for normal F-actin levels in the contractile ring, and acute inhibition of CYK-1 after furrow ingression slows ring constriction rate, suggesting that CYK-1 activity is required throughout ring constriction. Surprisingly, although the ARP2/3 complex does not localize in the contractile ring, depletion of the ARP2 subunit or treatment with ARP2/3 complex inhibitor delays contractile ring formation and constriction. We present evidence that the delays are due to an excess in formin-nucleated cortical F-actin, suggesting that the ARP2/3 complex negatively regulates CYK-1 activity. We conclude that the kinetics of cytokinesis are modulated by interplay between the two major actin filament nucleators. [Media: see text] [Media: see text] [Media: see text] [Media: see text]. PMID- 30403553 TI - Characterization of Acquired Antimicrobial Resistance Genes in Environmental Stenotrophomonas maltophilia Isolates from Brazil. AB - Stenotrophomonas maltophilia is an opportunist pathogen that has intrinsic resistance to the majority of antibiotics and has a high ability to adapt in different environments; however, there are few reports of acquired resistance genes in S. maltophilia. The aim of this study was to investigate the antimicrobial resistance profile, the presence of mutations in the quinolone resistance determining region, the presence of acquired resistance genes, and the different plasmid families in S. maltophilia isolated from Brazilian soils. A total of 16 isolates were obtained from a variety of agricultural soils with different cultures of Brazil and they were nonsusceptible to most of the antibiotics tested. No mutations were detected in the gyrA gene and only one (Ser 80-Ile) was detected in the parC gene. A diversity of acquired resistance genes was found, including the qnrA, qnrB, qnrS, oqxA, oqxB, blaSHV, blaCTX-M-Gp1, blaPER, blaOXA-1-like, blaOXA-48-like, and sul1. All isolates presented ColE-like plasmids and only one presented IncL/M. These results show, for the first time, the presence of qnrA and oqxAB genes and the presence of qnrB and qnrS genes for the second time in the world in S. maltophilia. PMID- 30403554 TI - Cohabitation Status Influenced Admittance to Specialized Palliative Care for Cancer Patients: A Nationwide Study from the Danish Palliative Care Database. AB - BACKGROUND: The utilization of the health care system varies in relation to cohabitation status, but conflicting results have been found in studies investigating the association in relation to specialized palliative care (SPC). OBJECTIVE: To investigate the association between cohabitation status and admittance to SPC; to establish whether this association differed between hospital-based palliative care team/units (mainly outpatient/home care) and hospice (mainly inpatient care). DESIGN: A nationwide study based on the Danish Palliative Care Database, which is linked with additional registers. MEASUREMENTS: The study population included all patients dying from cancer in Denmark between 2010 and 2012 (n = 44,480). The associations were investigated using logistic regression analysis adjusted for sex, age, diagnosis, and geography and standardized absolute prevalences. RESULTS: Comparison with cohabiting patients showed that overall admittance to SPC was lowest among patients who were widows/widowers (odds ratio [OR] = 0.86; 95% confidence interval [CI]: 0.81-0.91) and those who had never married (OR = 0.74; 95% CI: 0.68-0.80). Patients living alone were more likely to be admitted to a hospice [e.g., divorced OR = 1.41 (95% CI: 1.31-1.52)] than to a hospital-based palliative care team/unit [e.g., never married OR = 0.64 (95% CI: 0.59-0.70)] compared with cohabiting patients. Standardized prevalences of overall admittance to SPC showed a similar pattern, for example, admittance was highest (41%) for patients cohabiting and lowest (30%) for patients who had never married. CONCLUSION: Cohabiting individuals were favored in admittance to SPC. Compared with cohabiting patients it is unlikely that patients living alone have lower needs for SPC: results point toward inequity in admittance to specialist health care, a problem that should be addressed. PMID- 30403555 TI - Primary Care Providers' Attitudes and Practices Regarding Cancer Screening in Older Adults. AB - Cancer screening decisions for older adults should be individualized. However, conducting such complex shared decisions may be challenging for primary care providers (PCPs). Additionally, there is little information about how PCPs make these decisions. This study consisted of a provider survey and chart review to assess current PCP approaches to breast and colorectal cancer (CRC) screening for patients ages >=75 years. PCP survey questions: panel age, comfort with discussion of screening harms and benefits, screening decision-making process, and discussion style. One hundred charts were chosen from a random sample of male and female patients ages >=75 with a recent office visit. Chart reviews assessed whether providers recommended screening for breast and/or CRC in patients ages >=75, if there was a documented screening discussion, and if screening was completed. Fifty-one PCPs completed the survey. PCPs varied in the proportions of older adults they recommended for breast and CRC screening; 90.2% reported feeling very (43.1%) or somewhat (47.1%) comfortable discussing reasons for/against screening with older patients. Top screening considerations: life expectancy (84.3%), patient preference (82.4%), and severity of medical conditions (70.6%). Three-quarters (74.55%) reported a shared decision-making approach with discussion of harms/benefits. Of 61 eligible patients, 8 (13.1%) had a documented discussion regarding mammography; of 58 patients eligible for CRC screening, 7 (12.1%) had a documented discussion. Findings showed inconsistency in PCP approaches to cancer screening in older adults and in documentation of discussion. There is ample room for improvement in standardizing approaches and documentation of cancer screening discussions with older patients. PMID- 30403556 TI - Providers' Perspectives on Palliative Care in a Neuromedicine-Intensive Care Unit: End-of-Life Expertise and Barriers to Referral. AB - OBJECTIVE: This study identifies health care providers' perspectives on palliative care at end of life (EOL) in a neuromedicine-intensive care unit (Neuro-ICU) and barriers to providing palliative care. BACKGROUND: Provider's EOL expertise is crucial in making timely referrals to palliative care as expectation of patient death can be high. Barriers to referral need to be clearly identified so as to engage quality initiatives that improve EOL care delivery. DESIGN AND PARTICIPANTS: The study is a survey design using a mixed-methods approach. Providers at a large academic medical center, including doctors, nurses, and social workers, completed a quality improvement survey. MEASUREMENTS: Forty-one providers responded to Likert-type scales assessing their perspectives on palliative care. Their EOL expertise was independently assessed. In addition, barriers to palliative care referral were collected using a checklist and open ended responses. The latter were reliably content analyzed through a card-sort technique. RESULTS: Three palliative care perspectives were identified: foundational perspective, comfort-care perspective, and holistic perspective. Regression analysis shows that providers' perspectives are differentially related to their EOL expertise. Frequencies of provider-reported barriers to referring patients to palliative care (e.g., lack of care coordination) were determined. CONCLUSIONS: Health care providers hold multiple perspectives on what they consider palliative care. Their perspectives are related systematically to different aspects of their EOL expertise. In-house training and quality initiatives could focus on unifying providers' perspectives to create a common language for understanding palliative care. Eliminating individual, intergroup, and organizational barriers is necessary for creating an optimal environment for patients and their families who find themselves, often suddenly, in a Neuro-ICU. PMID- 30403557 TI - Efficacy of Multiple Dexamethasone Intravitreal Implants for Refractory Retinal Vein Occlusion-Related Macular Edema and Effect of Prior Vitrectomy. AB - PURPOSE: To evaluate the efficacy of dexamethasone intravitreal implants (DEX implant) in patients with treatment-resistant macular edema (ME) owing to branch and central retinal vein occlusion (BRVO/CRVO), and the influence of prior vitrectomy on this treatment. METHODS: Multicenter retrospective chart review was performed on 40 CRVO and 32 BRVO eyes with persistent ME despite intravitreal anti-vascular endothelial growth factor agents and/or intravitreal triamcinolone, and/or laser therapy. Each patient received >=1 dexamethasone 700 MUg implant between March 2011 and December 2015. Thirteen patients underwent prior vitrectomy. Data were collected on best-corrected visual acuity (BCVA), central macular thickness (CMT), time to relapse, and adverse events. RESULTS: At the end of follow-up, BRVO eyes had a lesser CMT reduction from baseline compared to CRVO eyes (-122.50 +/- 152.47 MUm and -202.26 +/- 194.09 MUm, respectively). Neither BRVO nor CRVO eyes had a sustained BCVA benefit (P = 0.7041 and P = 0.7027, respectively). Vitrectomized and nonvitrectomized eyes overall had a sustained significant CMT reduction throughout the study with -192.46 +/- 172.62 MUm and 164.02 +/- 180.36 MUm, respectively, at final follow-up. Similar time to relapse of 24.4 +/- 6.5 and 23.3 +/- 13.5 weeks, respectively, was observed. By the end of follow-up, BCVA had only improved in vitrectomized eyes. However, multivariable regression analyses showed no significant association between vitrectomy status and CMT or BCVA change after the first and last injection. Cataract formation and ocular hypertension occurred in 25% and 17%, respectively. CONCLUSIONS: Multiple DEX implant are effective in reducing CMT in patients resistant to previous treatments and appear to be similarly effective in vitrectomized and nonvitrectomized eyes. PMID- 30403558 TI - High-Deductible Health Plans and Prevention. AB - High-deductible health plans (HDHPs) are becoming more popular owing to their potential to curb rising health care costs. Relative to traditional health insurance plans, HDHPs involve higher out-of-pocket costs for consumers, which have been associated with lower utilization of health services. We focus specifically on the impact that HDHPs have on the use of preventive services. We critique the current evidence by discussing the benefits and drawbacks of the research designs used to examine this relationship. We also summarize the findings from the most methodologically sophisticated studies. We conclude that the balance of the evidence shows that HDHPs are reducing the use of some preventive service, especially screenings. However, it is not clear if HDHPs affect all preventive services. Additional research is needed to determine why variability in conclusions exists among studies. We describe an agenda for future research that can further inform public health decision makers on the impact of HDHPs on prevention. Expected final online publication date for the Annual Review of Public Health Volume 40 is April 1, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30403559 TI - An adaptive multi-stage phase I dose-finding design incorporating continuous efficacy and toxicity data from multiple treatment cycles. AB - Phase I designs traditionally use the dose-limiting toxicity (DLT), a binary endpoint from the first treatment cycle, to identify the maximum-tolerated dose (MTD) assuming a monotonically increasing relationship between dose and efficacy. In this article, we establish a general framework for a multi-stage adaptive design where we jointly model a continuous efficacy outcome and continuous/quasi continuous toxicity endpoints from multiple treatment cycles. The normalized Total Toxicity Profile (nTTP) is used as an illustration for quasi-continuous toxicity endpoints, and we replace DLT with nTTP to take into account multiple grades and types of toxicities. In addition, the proposed design accommodates non monotone dose-efficacy relationships, and longitudinal toxicity data in effort to capture the adverse events from multiple cycles. Stage 1 of our design uses toxicity data to perform dose-escalation and identify a set of initially allowable (safe) doses; stage 2 of our design incorporates an efficacy outcome to update the set of allowable doses for each new cohort and randomizes the new cohort of patients to the allowable doses with emphasis towards those with higher predicted efficacy. Stage 3 uses all data from all treated patients at the end of the trial to make final recommendations. Simulations showed that the design had a high probability of making the correct dose selection and good overdose control across various dose-efficacy and dose-toxicity scenarios. In addition, the proposed design allows for early termination when all doses are too toxic. To our best knowledge, the proposed dual-endpoint dose-finding design is the first such study to incorporate multiple cycles of toxicities and a continuous efficacy outcome. PMID- 30403560 TI - Brush border protocadherin CDHR2 promotes the elongation and maximized packing of microvilli in vivo. AB - Transporting epithelial cells optimize their morphology for solute uptake by building an apical specialization: a dense array of microvilli that serves to increase membrane surface area. In the intestinal tract, individual cells build thousands of microvilli, which pack tightly to form the brush border. Recent studies implicate adhesion molecule CDHR2 in the regulation of microvillar packing via the formation of adhesion complexes between the tips of adjacent protrusions. To gain insight on how CDHR2 contributes to brush border morphogenesis and enterocyte function under native in vivo conditions, we generated mice lacking CDHR2 expression in the intestinal tract. Although CDHR2 KO mice are viable, body weight trends lower and careful examination of tissue, cell, and brush border morphology revealed several perturbations that likely contribute to reduced functional capacity of KO intestine. In the absence of CDHR2, microvilli are significantly shorter, and exhibit disordered packing and a 30% decrease in packing density. These structural perturbations are linked to decreased levels of key solute processing and transporting factors in the brush border. Thus, CDHR2 functions to elongate microvilli and maximize their numbers on the apical surface, which together serve to increase the functional capacity of enterocyte. PMID- 30403561 TI - Learning to shape virtual patient locomotor patterns: Internal representations adapt to exploit interactive dynamics. AB - This work aims to understand the sensorimotor processes used by humans when learning how to manipulate a virtual model of locomotor dynamics. Prior research shows that when interacting with novel dynamics, humans develop internal models that map neural commands to limb motion, and vice-versa. Whether this can be extrapolated to locomotor rehabilitation, a continuous and rhythmic activity that involves dynamically complex interactions is unknown. In this case, humans could default to model-free strategies. These competing hypotheses were tested with a novel interactive locomotor simulator that reproduced the dynamics of hemiparetic gait. A group of 16 healthy subjects practiced using a small robotic manipulandum to alter the gait of a virtual patient (VP) that had an asymmetrical locomotor pattern modeled after stroke survivors. The point of interaction was the ankle of the VP's affected leg, and the goal was to make the VP's gait symmetrical. Internal model formation was probed with unexpected force channels and null force fields. Generalization was assessed by changing the target locomotor pattern and comparing outcomes with a second group of 10 naive subjects who did not practice the initial symmetrical target pattern. Results supported the internal model hypothesis with aftereffects and generalization of manipulation skill. Internal models demonstrated refinements that capitalized on the natural pendular dynamics of human locomotion. This work shows that despite the complex interactive dynamics involved in shaping locomotor patterns, humans nevertheless develop and use internal models that are refined with experience. PMID- 30403563 TI - Una Mujer Fantastica. PMID- 30403562 TI - Factors Affecting Mortality in Fournier Gangrene: A Single Center Experience. AB - BACKGROUND: The objective of this study was to determine the clinical and laboratory features affecting mortality in Fournier gangrene. PATIENTS AND METHODS: This retrospective case control study was designed to evaluate patients treated for Fournier gangrene in our center between 2010 and 2018. Those patients were divided into two groups: discharged patients (group 1) and deceased patients (group 2). Comparisons were made regarding clinical and demographic features; leukocyte, neutrophil and lymphocyte count results; neutrophil to lymphocyte ratio (NLR); Fournier's Gangrene Severity Index (FGSI) scores; number of debridements; complications; and mortality rates. RESULTS: Twenty-three patients (19 males, 4 females) were evaluated; mean age was 65.91 +/- 16.34 years. The most common cause of the disease and comorbidity were perianal abscess (n = 14; 60.9%) and type 1 diabetes mellitus (n = 11; 47.8%), respectively. Escherichia coli was the pathogen identified most often (n = 17; 73.9%). The total mortality rate was 21.7% (n = 5). Neutrophil to lymphocyte ratio, FGSI, number of debridements, and complication rates were higher in group 2 (p < 0.05). There was a substantial difference between the groups regarding perianal abscess in group 1 and rectum cancer in group 2 (p < 0.05). CONCLUSION: In conclusion, it was believed that the mortality rate could be predicted by combining the NLR value with the FGSI score. PMID- 30403564 TI - Parent-Initiated Sexual Orientation Change Efforts With LGBT Adolescents: Implications for Young Adult Mental Health and Adjustment. AB - Studies of adults who experienced sexual orientation change efforts (SOCE) have documented a range of health risks. To date, there is little research on SOCE among adolescents and no known studies of parents' role related to SOCE with adolescents. In a cross-sectional study of 245 LGBT White and Latino young adults (ages 21-25), we measured parent-initiated SOCE during adolescence and its relationship to mental health and adjustment in young adulthood. Measures include being sent to therapists and religious leaders for conversion interventions as well as parental/caregiver efforts to change their child's sexual orientation during adolescence. Attempts by parents/caregivers and being sent to therapists and religious leaders for conversion interventions were associated with depression, suicidal thoughts, suicidal attempts, less educational attainment, and less weekly income. Associations between SOCE, health, and adjustment were much stronger and more frequent for those reporting both attempts by parents and being sent to therapists and religious leaders, underscoring the need for parental education and guidance. PMID- 30403565 TI - Poor Queer Studies: Class, Race, and the Field. AB - This study asks, What are the material conditions under which queer studies is done in the academy? It finds a longstanding association of queer studies with the well-resourced, selective colleges and flagship campuses that are the drivers of class and race stratification in higher education in the U.S. That is, the field of queer studies, as a recognizable academic formation, has been structured by the material and intellectual resources of precisely those institutions that most steadfastly refuse to adequately serve poor and minority students, including poor and minority queer students. In response, "poor queer studies" calls for a critical reorientation of queer studies toward working-poor schools, students, theories, and pedagogies. Taking the College of Staten Island, CUNY as a case study, it argues for structural crossing over or "queer-class ferrying" between high-status institutions that have so brilliantly dominated queer studies' history and low-status worksites of poor queer studies. PMID- 30403566 TI - A Critical and Intersectional Model of LGBTQ Microaggressions: Toward a More Comprehensive Understanding. AB - This article summarizes a proposed critical and intersectional model of LGBTQ microaggressions that can be used by scholars and practitioners from multiple disciplines. Drawing on critical and intersectional paradigms and decades of research from multiple fields, we constructed a model that acknowledges the breadth, depth, scope, and complexity of LGBTQ microaggressions. This proposed model includes the following elements: hegemonic influences, intersectional complexities, perpetration, interpersonal and environmental contexts, and responses. PMID- 30403567 TI - Before AIDS: Gay Health Politics in the 1970s. PMID- 30403568 TI - Quantifying Sexual Orientation Among Homeless and Unstably Housed Women in a Longitudinal Study: Identity, Behavior, and Fluctuations Over a Three-Year Period. AB - Sexual orientation has been linked to certain health conditions, and yet quantifying sexual orientation in longitudinal studies is challenging. This study examined different methods of accounting for sexual orientation in a cohort study of 300 homeless and unstably housed women followed every 6 months over 3 years. Altogether, 39.7% (n = 119) could be considered sexual minority at one or more time points based on identity and/or behavior; 16.3% (n = 49) reported shifts in sexual identity. Only 24.0% (n = 72) were identified as sexual minority through a single measure of sexual identity, 27.0% (n = 81) were identified with a single measure of identity and behavior, 33.0% (n = 99) were identified through annual measures of identity and behavior, and 22.0%-22.3% (n = 66-67) were identified through latent class analysis including all identity/behavior measures. This study found that sexual fluidity is common in unstably housed women, and many sexual minority women would be missed in longitudinal studies with different methods of accounting for sexual orientation. PMID- 30403569 TI - A Decade of Microaggression Research and LGBTQ Communities: An Introduction to the Special Issue. AB - Though the Supreme Court of the U.S. legalized same-sex marriage in 2015, heterosexism and transphobia has continued to manifest through many systems in the US - from lack of federal protection in employment non-discrimination laws to polices that prohibit transgender people from using bathroom and public facilities that match their gender identities. Heterosexist and transphobic discrimination have also persisted through interpersonal interactions - ranging from more overt forms (e.g., hate crimes, bullying) to more subtle forms of discrimination, otherwise known as microaggressions. Since 2008, there have been hundreds of articles written on microaggressions, with dozens focusing specifically on experiences of lesbian, gay, bisexual, transgender, and queer (LGBTQ) people. Qualitative and quantitative studies have revealed that LGBTQ people who experience microaggressions have reported negative outcomes like depression, low self-esteem, and trauma. This special issue aims to further Microaggression Theory by providing theoretical and empirical papers that focus on the manifestation and impact of microaggressions on LGBTQ people. Using an interdisciplinary approach, articles range in topic from intersectional identities, to health and psychological outcomes, to advancing research methods. Future studies regarding microaggressions and LGBTQ people are discussed- highlighting the influence of the changing landscape of heterosexism and transphobia within general society, as well as new dynamics that have formed and developed within LGBTQ communities. PMID- 30403570 TI - Complex Intimacy: Theorizing Older Gay Men's Social Lives. AB - This qualitative study explores the social lives of older gay men. In-depth interviews were conducted with 10 gay men over the age of 65 to elicit details about their relationships with other people. Findings paint a complex picture of older gay social life that is compounded by significant events affecting gay men from a particular socio-historical period. Three overarching themes emerged that capture the social lives of the participants: (1) coming of age as a gay man in the 20th century; (2) dealing with the aging body; and (3) enduring loss and the consequent impact on social life. The participants reported that being in a gay environment and closing the gay generational divide helped them adjust to their changing social lives in later life. This study adds to the ongoing discussion about the experiences of older gay men and makes suggestions for future research and practice considerations. PMID- 30403571 TI - Managing Clonal Hematopoiesis in Patients With Solid Tumors. PMID- 30403572 TI - Neoadjuvant (Chemo)radiotherapy With Total Mesorectal Excision Only Is Not Sufficient to Prevent Lateral Local Recurrence in Enlarged Nodes: Results of the Multicenter Lateral Node Study of Patients With Low cT3/4 Rectal Cancer. AB - PURPOSE: Improvements in magnetic resonance imaging (MRI), total mesorectal excision (TME) surgery, and the use of (chemo)radiotherapy ([C]RT) have improved local control of rectal cancer; however, we have been unable to eradicate local recurrence (LR). Even in the face of TME and negative resection margins (R0), a significant proportion of patients with enlarged lateral lymph nodes (LLNs) suffer from lateral LR (LLR). Japanese studies suggest that the addition of an LLN dissection (LLND) could reduce LLR. This multicenter pooled analysis aims to ascertain whether LLNs actually pose a problem and whether LLND results in fewer LLRs. PATIENTS AND METHODS: Data from 1,216 consecutive patients with cT3/T4 rectal cancers up to 8 cm from the anal verge who underwent surgery in a 5-year period were collected. LLND was performed in 142 patients (12%). MRIs were re evaluated with a standardized protocol to assess LLN features. RESULTS: On pretreatment MRI, 703 patients (58%) had visible LLN, and 192 (16%) had a short axis of at least 7 mm. One hundred eight patients developed LR (5-year LR rate, 10.0%), of which 59 (54%) were LLRs (5-year LLR rate, 5.5%). After multivariable analyses, LLNs with a short axis of at least 7 mm resulted in a significantly higher risk of LLR (hazard ratio, 2.060; P = .045) compared with LLNs of less than 7 mm. In patients with LLNs at least 7 mm, (C)RT plus TME plus LLND resulted in a 5-year LLR of 5.7%, which was significantly lower than that in patients who underwent (C)RT plus TME (5-year LLR, 19.5%; P = .042). CONCLUSION: LLR is still a significant problem after (C)RT plus TME in LLNs with a short axis at least 7 mm on pretreatment MRI. The addition of LLND results in a significantly lower LLR rate. PMID- 30403573 TI - Role of Donor Clonal Hematopoiesis in Allogeneic Hematopoietic Stem-Cell Transplantation. AB - PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) occurs in the blood of approximately 20% of older persons. CHIP is linked to an increased risk of hematologic malignancies and of all-cause mortality; thus, the eligibility of stem-cell donors with CHIP is questionable. We comprehensively investigated how donor CHIP affects outcome of allogeneic hematopoietic stem-cell transplantation (HSCT). METHODS: We collected blood samples from 500 healthy, related HSCT donors (age >= 55 years) at the time of stem-cell donation for targeted sequencing with a 66-gene panel. The effect of donor CHIP was assessed on recipient outcomes, including graft-versus-host disease (GVHD), cumulative incidence of relapse/progression (CIR/P), and overall survival (OS). RESULTS: A total of 92 clonal mutations with a median variant allele frequency of 5.9% were identified in 80 (16.0%) of 500 donors. CHIP prevalence was higher in donors related to patients with myeloid compared with lymphoid malignancies (19.2% v 6.3%; P <= .001). In recipients allografted with donor CHIP, we found a high cumulative incidence of chronic GVHD (cGVHD; hazard ratio [HR], 1.73; 95% CI, 1.21 to 2.49; P = .003) and lower CIR/P (univariate: HR, 0.62; 95% CI, 0.40 to 0.97; P = .027; multivariate: HR, 0.63; 95% CI, 0.41 to 0.98; P = .042) but no effect on nonrelapse mortality. Serial quantification of 25 mutations showed engraftment of 24 of 25 clones and disproportionate expansion in half of them. Donor-cell leukemia was observed in two recipients. OS was not affected by donor CHIP status (HR, 0.88; 95% CI, 0.65 to 1.321; P = .434). CONCLUSION: Allogeneic HSCT from donors with CHIP seems safe and results in similar survival in the setting of older, related donors. Future studies in younger and unrelated donors are warranted to extend these results. Confirmatory studies and mechanistic experiments are warranted to challenge the hypothesis that donor CHIP might foster cGVHD development and reduce relapse/progression risk. PMID- 30403575 TI - Informed, Patient-Centered Decisions Associated with Better Health Outcomes in Orthopedics: Prospective Cohort Study. AB - BACKGROUND: A goal of shared decision making (SDM) is to ensure patients are well informed and receive preferred treatments. However, the relationship between SDM and health outcomes is not clear. OBJECTIVE: The purpose was to examine whether patients who are well informed and receive their preferred treatment have better health outcomes. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study at an academic medical center surveyed new patients with knee or hip osteoarthritis, herniated disc, or spinal stenosis 1 week after seeing a specialist and again 6 months later. Main Outcomes and Measures. The survey assessed knowledge, preferred treatment, and quality of life (QoL). The percentage of patients who were well informed and received preferred treatment was calculated (informed, patient centered [IPC]). A follow-up survey assessed QoL, decision regret, and satisfaction. Regression analyses with generalized estimating equations to account for clustering tested a priori hypotheses that patients who made IPC decisions would have higher QoL. RESULTS: Response rate was 70.3% (652/926) for initial and 85% (551/648) for follow-up. The sample was 63.9 years old, 52.8% were female, 62.6% were college educated, and 49% had surgery. One-third (37.4%) made IPC decisions. Participants who made IPC decisions had significantly better overall (0.05 points (SE 0.02) for EQ-5D, P = 0.004) and disease-specific quality of life (4.22 points [SE 1.82] for knee, P = 0.02; 4.46 points [SE 1.54] for hip, P = 0.004; and 6.01 points [SE 1.51] for back, P < 0.0001), higher satisfaction and less regret. LIMITATIONS: Observational study at a single academic center with limited diversity. CONCLUSIONS: Well-informed patients who receive their preferred treatment also had better health outcomes and higher satisfaction. PMID- 30403577 TI - Parallel Valuation: A Direct Comparison of EQ-5D-3L and EQ-5D-5L Societal Value Sets. AB - OBJECTIVE: To compare and contrast EQ-5D-5L (5L) and EQ-5D-3L (3L) health state values derived from a common sample. METHODS: Data from the 2017 US EQ-5D valuation study were analyzed. Value sets were estimated with random-effects linear regression based on composite time trade-off (cTTO) valuations for 3L and 5L health states with 2 approaches to model specification: main effects only and additional N3/N45 terms. Properties of the descriptive system and value set characteristics were compared by examining distributions of predicted index scores, ceiling effects, and single-level transition values from adjacent corner health states. Mean transition values were calculated for all predicted 3L and 5L health states and plotted against baseline index scores. RESULTS: A total of 1062 respondents were included in the analysis. The observed mean cTTO values for the worst possible 3L and 5L health states were -0.423 and -0.343, respectively. The range of scale was larger with the 3L, compared to the 5L, for both main effects and N term models. Values for the mildest 5L health states (range, 0.857-0.924) were similar to 11111 for the 3L. Parameter estimates for matched dimension levels differed by <|0.07| except for the most severe level of Mobility. For the main effects model, 3L mean transition values were greater for more severe baseline 3L index scores, whereas 5L mean transition values remained constant irrespective of the baseline index score. CONCLUSIONS: Compared to the 3L, the 5L exhibited a lower ceiling effect and improved measurement properties. There was a larger range of scale for the 3L compared to 5L; however, this difference was driven by differences in preference for the most severe level of problems in Mobility. PMID- 30403578 TI - Simple Inclusion of Complex Diagnostic Algorithms in Infectious Disease Models for Economic Evaluation. AB - INTRODUCTION: Cost-effectiveness models for infectious disease interventions often require transmission models that capture the indirect benefits from averted subsequent infections. Compartmental models based on ordinary differential equations are commonly used in this context. Decision trees are frequently used in cost-effectiveness modeling and are well suited to describing diagnostic algorithms. However, complex decision trees are laborious to specify as compartmental models and cumbersome to adapt, limiting the detail of algorithms typically included in transmission models. METHODS: We consider an approximation replacing a decision tree with a single holding state for systems where the time scale of the diagnostic algorithm is shorter than time scales associated with disease progression or transmission. We describe recursive algorithms for calculating the outcomes and mean costs and delays associated with decision trees, as well as design strategies for computational implementation. We assess the performance of the approximation in a simple model of transmission/diagnosis and its role in simplifying a model of tuberculosis diagnostics. RESULTS: When diagnostic delays were short relative to recovery rates, our approximation provided a good account of infection dynamics and the cumulative costs of diagnosis and treatment. Proportional errors were below 5% so long as the longest delay in our 2-step algorithm was under 20% of the recovery time scale. Specifying new diagnostic algorithms in our tuberculosis model was reduced from several tens to just a few lines of code. DISCUSSION: For conditions characterized by a diagnostic process that is neither instantaneous nor protracted (relative to transmission dynamics), this novel approach retains the advantages of decision trees while embedding them in more complex models of disease transmission. Concise specification and code reuse increase transparency and reduce potential for error. PMID- 30403576 TI - Cost-effectiveness of Initiating an Insulin Pump in T1D Adults Using Continuous Glucose Monitoring Compared with Multiple Daily Insulin Injections: The DIAMOND Randomized Trial. AB - BACKGROUND: The economic impact of both continuous glucose monitoring (CGM) and insulin pumps (continuous subcutaneous insulin infusion [CSII]) in type 1 diabetes (T1D) have been evaluated separately. However, the cost-effectiveness of adding CSII to existing CGM users has not yet been assessed. OBJECTIVE: The aim of this study was to evaluate the societal cost-effectiveness of CSII versus continuing multiple daily injections (MDI) in adults with T1D already using CGM. METHODS: In the second phase of the DIAMOND trial, 75 adults using CGM were randomized to either CGM+CSII or CGM+MDI (control) and surveyed at baseline and 28 weeks. We performed within-trial and lifetime cost-effectiveness analyses (CEAs) and estimated lifetime costs and quality-adjusted life-years (QALYs) via a modified Sheffield T1D model. RESULTS: Within the trial, the CGM+CSII group had a significant reduction in quality of life from baseline (-0.02 +/- 0.05 difference in difference [DiD]) compared with controls. Total per-person 28-week costs were $8,272 (CGM+CSII) versus $5,623 (CGM+MDI); the difference in costs was primarily attributable to pump use ($2,644). Pump users reduced insulin intake (-12.8 units DiD) but increased the use of daily number of test strips (+1.2 DiD). Pump users also increased time with glucose in range of 70 to 180 mg/dL but had a higher HbA1c (+0.13 DiD) and more nonsevere hypoglycemic events. In the lifetime CEA, CGM+CSII would increase total costs by $112,045 DiD, decrease QALYs by 0.71, and decrease life expectancy by 0.48 years. CONCLUSIONS: Based on this single trial, initiating an insulin pump in adults with T1D already using CGM was associated with higher costs and reduced quality of life. Additional evidence regarding the clinical effects of adopting combinations of new technologies from trials and real-world populations is needed to confirm these findings. PMID- 30403581 TI - Early Development of Value of Information Methods. PMID- 30403579 TI - Low Health Literacy and Health Information Avoidance but Not Satisficing Help Explain "Don't Know" Responses to Questions Assessing Perceived Risk. AB - BACKGROUND: People who say they don't know (DK) their disease risk are less likely to engage in protective behavior. PURPOSE: This study examined possible mechanisms underlying not knowing one's risk for common diseases. METHODS: Participants were a nationally representative sample of 1005 members of a standing probability-based survey panel who answered questions about their comparative and absolute perceived risk for diabetes and colon cancer, health literacy, risk factor knowledge and health information avoidance, and beliefs about illness unpredictability. Survey satisficing was a composite assessment of not following survey instructions, nondifferentiation of responses, haphazard responding, and speeding. The primary outcomes were whether a person selected DK when asked absolute and comparative risk perception questions about diabetes or colon cancer. Base structural equation modeling path models with pathways from information avoidance and health literacy/knowledge to DK responding for each DK outcome were compared to models that also included pathways from satisficing or unpredictability beliefs. RESULTS: Base models contained significant indirect effects of health literacy (odds ratios [ORs] = 0.94 to 0.97, all P < 0.02) and avoidance (ORs = 1.05 to 1.15, all P < 0.01) on DK responding through risk factor knowledge and a direct effect of avoidance (ORs = 1.21 to 1.28, all P < 0.02). Adding the direct effect for satisficing to models resulted in poor fit (for all outcomes, residual mean square error estimates >0.17, all weighted root mean square residuals >3.2, all Comparative Fit Index <0.47, all Tucker-Lewis Index <0.49), indicating that satisficing was not associated with DK responding. Unpredictability was associated with not knowing one's diabetes risk (OR = 1.01, P < 0.01). LIMITATIONS: The data were cross-sectional; therefore, directionality of the pathways cannot be assumed. CONCLUSIONS: DK responders may need more health information, but it needs to be delivered differently. Interventions might include targeting messages for lower health literacy audiences and disrupting defensive avoidance of threatening health information. PMID- 30403580 TI - Comparing the Performance of 2 Health Utility Measures in the Medicare Health Outcome Survey (HOS). AB - BACKGROUND: The Medicare Health Outcomes Survey (HOS), a nationwide annual survey of Medicare beneficiaries, includes the Centers for Disease Control and Prevention's HRQOL-4 questionnaire and Veterans RAND 12-item Health Survey (VR 12). This study compared EQ-5D scores derived from the HRQOL-4 (dEQ-5D) to SF-6D scores derived from VR-12. METHODS: Data were from Medicare HOS Cohort 15 (2012 baseline; 2014 follow-up). We included participants aged 65+ ( n = 105,473). We compared score distributions, evaluated known-groups validity, assessed each index as a predictor for mortality, and estimated quality-adjusted life years (QALYs) using the dEQ-5D and SF-6D. RESULTS: Compared to the SF-6D, the dEQ-5D had a higher mean score (0.787 v. 0.691) and larger standard deviation (0.310 v. 0.101). The decreases in estimated scores associated with chronic conditions were greater for the dEQ-5D than for the SF-6D. For example, dEQ-5D scores for persons with depression decreased 0.456 points compared to 0.141 points for the SF-6D. The dEQ-5D strongly predicted mortality, as adjusted hazard ratios for the first to fourth quintiles, relative to the fifth quintile, were 2.2, 1.7, 1.8, and 1.5, respectively, while the association between SF-6D and mortality was weaker or nonexistent (adjusted hazard ratios were 1.3, 1.1, 1.0, and 0.6, respectively). Compared to the SF-6D, QALYs estimated using the dEQ-5D were higher overall (5.6 v. 4.9 years), higher for persons with less debilitating conditions (e.g., hypertension, 5.0 v. 4.4 years), and lower for more debilitating conditions (e.g. depression, 2.5 v. 2.8 years). CONCLUSIONS: Compared to the SF-6D, the dEQ-5D was better able to measure individuals' overall health; detect the differential impact of chronic conditions, particularly among persons in poorer health; and predict mortality. The HRQOL-4 questionnaire may be valuable for monitoring and improving health outcomes for the Medical HOS data set. PMID- 30403582 TI - Prostaglandin D2 Levels Regulate CD103+ Conventional Dendritic Cell Activation in Neonates During Respiratory Viral Infection. AB - During respiratory viral infection, conventional dendritic cells (cDCs) take up antigen and migrate to the draining lymph nodes to present viral antigen and activate cytotoxic T lymphocytes; however, regulation of cDC activation and migration may be age dependent. In this study, we used a mouse model of paramyxoviral infection (Sendai virus) and demonstrated that cDCs, which have migrated from lungs to the draining lymph nodes, are delayed in expressing activation markers in neonatal mice compared with adults. Neonatal lung cDCs expressed reduced levels of MHC Class II (major histocompatibility complex II) and CCR7 (chemokine receptor type 7) on postinfection days 3 and 5, respectively. The level of the CCR7 ligand CCL19 was significantly reduced in neonatal lungs during the course of viral infection. Interestingly, the arachidonic acid metabolite prostaglandin D2 (PGD2) was present at significantly higher levels in neonatal bronchoalveolar lavage fluid compared with adults. This was associated with increased expression of lipocalin PGD2 synthase mRNA levels in neonatal lungs and in isolated neonatal tracheal epithelial cells. Although thymic stromal lymphopoietin (TSLP) expression has been associated with increased PGD2 production, we found that TSLP levels were reduced in neonatal lungs. Importantly, blocking PGD2 function using a prostaglandin D2 receptor 1 (DP1) antagonist restored cDC activation in neonates. Together, these data suggest that cDC activation in neonates is delayed by a PGD2 mechanism and associated decreased chemokine signals. PMID- 30403583 TI - Brenneria corticis sp. nov., isolated from symptomatic bark of Populus*euramericana canker. AB - A Gram-stain-negative, facultatively anaerobic, motile bacterial strain, designated gBX10-1-2T, was isolated from symptomatic bark of Populus*euramericana canker in China. Phylogenetic analysis based on its 16S rRNA gene sequence showed that the novel isolate belonged to the genus Brenneria, and shared the highest sequence similarity to Brenneria nigrifluens LMG 2694T (98.3 %). In the phylogenetic trees based on the four housekeeping genes sequences, the novel strain formed a separate branch different from B. nigrifluens LMG 2694T, indicating that the novel strain should be classified as a novel species. The genome sequence-derived average nucleotide identity (ANI) values between the novel isolate and B. nigrifluens LMG 2694T, Brenneria roseaesubsp. roseae FRB 222T and Brenneria roseaesubsp. americana FRB 223T were less than 85 %, lower than the proposed species boundary ANI cut-off value (95-96 %). The DNA G+C content was 56.2 mol%, and the main fatty acids were C16 : 0, C16 : 1omega7c, C18 : 1omega7c and C17 : 0cyclo. Based on the phenotypic and genotypic characteristics, strain gBX10-1-2T represents a novel species of genus Brenneria, for which the name Brenneria corticis sp. nov. is proposed. The type strain is gBX10-1-2T (=CFCC 11842T=KCTC 42840T). PMID- 30403584 TI - Nocardioides silvaticus sp. nov., isolated from forest soil. AB - A Gram-stain-positive, non-motile, rod-shaped bacterial strain S-34T was isolated from forest soil. According to 16S rRNA gene sequence analysis, strain S-34T was related to Nocardioides members and showed the highest similarities to Nocardioides thalensis NCCP-696T (97.3 %) and Nocardioides panacisoliGsoil 346T (97.0 %), Nocardioides litorisoli X-2T (96.5 %) and Nocardioides immobilis FLL521T (96.4 %). Phylogenetic trees showed that strain S-34T fell within the cluster containing strain S-34T and N. immobilis FLL521T. The levels of DNA-DNA relatedness between strain S-34T and N. thalensis CCTCC AB 2016296T and between strain S-34T and N. panacisoli KCTC 19470T were 50.6 and 58.8 %, respectively. The genome orthoANI value between strain S-34T and N. immobilis CCTCC AB 2017083T was 82.4 %. Strain S-34T had ll-diaminopimelic acid in the cell-wall peptidoglycan, diphosphatidylglycerol, phosphatidylglycerol, four unknown phospholipids and one unknown lipid as the polar lipids, meanquinone-8(H4) as the only respiratory quinone and iso-C16 : 0, C17:1omega8c, C17:1omega6c, C17 : 0 and C17 : 0 10-methyl (tbsa) as the major fatty acids. The genome length of strain S 34T was 4.53 Mb containing 52 contigs and with a DNA G+C content of 71.2 mol%. Strain S-34T could be distinguished from the other Nocardioides members mainly based on the data of phylogenetic analyses, DNA-DNA hybridization, polar lipids and some biochemical differences. Therefore, strain S-34T represents a novel species of the genus Nocardioides, for which the name Nocardioidessilvaticus sp. nov. is proposed. The type strain is S-34T (=KCTC 49137T=CCTCC AB 2018079T). PMID- 30403585 TI - Aquabacterium tepidiphilum sp. nov., a moderately thermophilic bacterium isolated from a hot spring. AB - A Gram-stain-negative, aerobic, non-spore-forming and rod-shaped bacterium, designated YIM 730274T, was isolated from a sediment sample collected from a hot spring located in Tibet, PR China, and was characterized by using a polyphasic taxonomy approach. Cells were motile by means of a polar flagellum. The strain was oxidase- and catalase-positive, and contained polyalkanoates and polyphosphate as storage polymers. Growth occurred at 25-50 degrees C, at pH 6.0 8.5 and with 0.5-1.0 % NaCl. The major fatty acids (>10 %) were summed feature 3 (C16 : 1omega6c and/or C16 : 1omega7c), summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c) and C16 : 0. The known polar lipids comprised of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol and phosphatidylserine. The isoprenoid quinone was Q-8. The G+C content of genomic DNA was 70.7 mol%. The results of phylogenetic analyses based on 16S rRNA gene sequences indicated that the strain forms a monophyletic branch at the periphery of the evolutionary radiation occupied by the genus Aquabacterium in the class Betaproteobacteria. The most closely related phylogenetic neighbours were Aquabacterium limnoticumABP-4T (97.8 % 16S rRNA gene sequence identity) and Aquabacterium communeB8T (97.2 % 16SrRNA gene sequence identity). DNA-DNA relatedness values between YIM 730274T and A. limnoticum KCTC 23306T (46.4+/-0.4 %) and A. commune DSM 11901T (42.2+/-1.2 %) were well below the 70 % limit for species identification. YIM 730274T was distinguishable from other members of the genus Aquabacterium by the differences in phenotypic, chemotaxonomic and genotypic characteristics. YIM 730274T merits recognition as a representative of a novel species of the genus Aquabacterium. It is proposed that the isolate should be classified in the genus Aquabacterium as representing a novel species, Aquabacteriumtepidiphilum sp. nov. The type strain is YIM 730274T (=KCTC 52716T=CCTCC AB 2016295T). PMID- 30403586 TI - Klebsiella huaxiensis sp. nov., recovered from human urine. AB - A strain of a member of the genus Klebsiella, WCHKl090001, was recovered from a human urine sample in PR China in 2017. Phylogenetic analysis based on gyrA and rpoB housekeeping genes revealed that the strain was distinct from any previously described species of the genus Klebsiella though it was clustered with the Klebsiella oxytoca phylogroup, including Klebsiella grimontii, Klebsiella michiganensis and Klebsiella oxytoca. The whole-genome sequence of strain WCHKl090001 has an up to 87.18 % average nucleotide identity with those of type strains of all known species of the genus Klebsiella. In silico DNA-DNA hybridization (isDDH) values between strain WCHKl090001 and type strains of all known species of the genus Klebsiella ranged from 22.3 to 35.2 %. Strain WCHKl090001 could be distinguished from species of the Klebsiella oxytocaphylogroup by its negative Voges-Proskauer reaction. Genotypic and phenotypic characteristics from this study indicate that strain WCHKl090001 should be considered to represent a novel species of the genus Klebsiella, for which the name Klebsiellahuaxiensis sp. nov. is proposed. The type strain is WCHKl090001T (=GDMCC 1.1379T=CNCTC 7650T). PMID- 30403587 TI - Effect of acidic and alkali shocks on expression of efaA gene in Enterococcus faecalis, isolated from root canal infection. AB - Enterococcus faecalis is an important opportunistic infectious agent involving the oral cavity and endodontics. The aim of this study was to evaluate the expression ratio of efaA gene in biofilm producer E. faecalis before and after receiving acidic and alkali shocks. One hundred E. faecalis isolates were gathered from 170 infectious root canals. After analysis of biofilm formation by the Microtiterplate method, the presence of efaA gene was examined by PCR and its expression was evaluated by Real-time PCR, one before applying any stressed to isolates and another by applying acidic and alkali shock. Chi-square method was used for statistical analysis. Eighty-two percent of samples had efaA gene. Evaluation of biofilm formation, 49% of the isolates were strong biofilm producer, 42% moderate and 10 % of them had no biofilm. 59% overexpression of efaA gene was observed in biofilm producer isolates, while there were no significant changes in samples with acidic stress and decreased expression after alkali shock. Findings of the present study, indicates importance of efaA gene in biofilm formation and pathogenesis of E. faecalis. Acid had no effect of expression of this gene but alkali reduced expression of this gene in a significant level. These results indicate the importance of efaA and acidic conditions in biofilm production by E. faecalis. PMID- 30403589 TI - Comparison the biodegradation of herbicide pyroxasulfone by some soil bacteria. AB - The biodegradation of pyroxasulfone (C12H14F5N3O4S), which is the selective herbicide in wheat farming in Turkey is compared with some soil bacteria. These microorganisms were isolated in collected soil samples in Thrace region of Turkey from an agricultural area previously unexposed to pyroxasulfone. The microbial biodegradation of pyroxasulfone was investigated using liquid experiments with identified cultures to determine which of the microorganisms shows best removal performance under agitated culture conditions. The experiments continued about two weeks. Five different apparatuses, were set up and pyroxasulfone in 750 ppm concentration (advised concentration of wheat farmers) was added to each Erlenmayer flasks. Approximately 107CFU/ml of each bacteria added to these flasks. These flasks were shaken at 130rpm at 27 0C in sterile conditions for 8 days. Every day, each sample was collected by filtering from flasks and Chemical Oxygen Demand (COD), biochemical oxygen demand (BOD5), total organic carbon (TOC) was determined. As a result of the study, best removal performance observed in Bacillus thuringiensis and Fusarium fujikuroi as 91 and 93% at 7 days in COD, 88 and 83% in BOD5, 90 and 86% in TOC parameters. The lowest performance was seen on Clostridium tetani species for COD, BOD5 and TOC as 55%, 61% and 60% respectively on 7 days. The performance for Bacillus simplex and Bacillus megaterium species occurred between 70% and 80% for these three parameters. PMID- 30403588 TI - Gene expression of ING4 gene in pancreatic cancers and splice forms of ING4 gene. AB - Pancreatic cancer is characterized by rapid metastasis and resistant to medical treatments. As the other cancers, mutations of tumor suppressor genes that involved in suppression of cell growth are observed in pancreatic cancers. ING4 protein is one of the proteins involved in the regulation of p53 tumor suppressor gene functions. ING4 involved in suppression of cell proliferation, chromosome rearrangement, cell migration, and angiogenesis. In this study, gene expressions and splicing variants of ING4 gene were investigated. Fresh tumor and normal specimens of the same pancreatic cancer patients were used. Gene expression study carried out by calculating the brightness of the bands on agarose gel and splicing variants were detected by direct sequencing. According to the results, three splice forms of ING4 and a decrease in gene expression of ING4 were determined. Splicing type of ING4 affects the translocation of ING4 proteins into the nucleus. To determine the gene expression of each splicing variant, will further clarify the role of ING4 in pancreatic cancers. PMID- 30403590 TI - Expression of toll-like receptor 4 and its connection with type 2 diabetes mellitus. AB - Toll-like receptor 4 (TLR4) plays an important role in modulating innate immunity. Type 2 diabetes mellitus (T2DM) is a chronic disease that is characterized by impaired insulin resistance and abnormal immune response. Genetic background and consequently genetic factors might have a key role in both onset and progression of T2DM-related complications. The aim of this work was to study the role of toll-like receptor 4 (TLR4) in the development of type 2 diabetes mellitus (T2DM). This study was carried out on 90 subjects, 30 type 2 diabetic patients, 30 patients with impaired glucose tolerance and 30 age and gender matched healthy controls. mRNA expression of (TLR4) was assessed by reverse transcriptase PCR (RT-PCR) using real time PCR.. Results showed significant statistical difference between the three studied groups regarding BMI, serum FBG, HDL, TGs, TC, LDL, HOMA -IR and mRNA expression of TLR4 with highest level of TLR4 mRNA expression in T2DM patients. From this study, it might be concluded that high expression of (TLR4) is associated with T2DM. PMID- 30403591 TI - MiR-122 exerts anti-proliferative and apoptotic effects on nasopharyngeal carcinoma cells via the PI3K/AKT signaling pathway. AB - To investigate the effects of microRNA-122 (miR-122) on the proliferation and apoptosis of nasopharyngeal carcinoma (NPC) HONE-1 cells, and its correlation with the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Human NPC cell line (HONE-1) was transfected with miR-122 inhibitor (anti-miR-122 group), negative controls (vector control group) via lipofectamines, and HONE-1 cell lines undergoing no transfection were selected (non-transfection group). The expression of miR-122, cell proliferation, apoptosis, and expressions of PI3K/AKT pathway and downstream target proteins in the three groups were determined using fluorescence quantitative polymerase chain reaction (qPCR), cell counting kit-8 (CCK8), immunofluorescence (IF) and Western blotting, respectively. The expression of miR-122 in the anti-miR-122 group was significantly lower than corresponding expressions in the non-transfection and vector control groups after 48h of transfection (p <0.05). The proliferation of cells in the anti-miR-122 group was significantly reduced with time after transfection (p <0.05). After 48h of transfection, the extent of apoptosis in the anti-miR-122 group (47.11 +/- 1.95%) was significantly higher than that in normal control (7.37 +/- 0.82%) and vector control group (8.54 +/- 0.96%; p <0.05). There were no significant differences in the expressions of PI3K, AKT, mTOR protein, and the downstream signal proteins (p70S6K and 4E-BP1) in the three groups (p >0.05). However, the expressions of phosphorylated forms of these proteins were significantly lower in the anti-miR-122 group than in the non transfection and vector control groups (p <0.05). IF results revealed that there were no significant differences in the fluorescence intensity value of PI3K and Akt among the three groups of patients (p>0.05). Inhibition of the expression of miR-122 in NPC suppresses the proliferation, and promotes their apoptosis through the PI3K/AKT signal transduction pathway. PMID- 30403592 TI - The role of PLC-IP3 cascade on 4-aminopyridine (4-AP) contracture in electrically driven rat atrial and diaphragmatic strips: new evidence by neomycin and heparin. AB - Induction of cardiac contractures by 4-AP in Ca2+-free medium implied the involvement of SR and PLC-IP3 cascade. Thus, the role of PLC-IP3 cascade against contractile actions of 4-AP in electrically-driven rat atrial and diaphragmatic strips were studied both in the presence, and absence of Ca2+ using neomycin, a PLC inhibitor, and heparin, an IP3-R antagonist. 4-AP was applied cumulatively in logarithmically increasing concentrations in the range of 1-16ug/ml, and the preparations were treated with neomycin (400uM) or heparin (400ug/ml) for 3min prior to 4-AP injection. Post-rest potentiation in atrial strips was obtained by interruption of stimulation for 30min. 4-AP caused biphasic alteration in twitch amplitudes, as initially increased up to 16mM and then depressed due to contracture development, which were not affected significantly by neomycin and heparin. Both atrial and denervated diaphragmatic strips challenged to 4-AP in the presence and absence of Ca2+ developed dose dependent contractures which were significantly antagonized both by neomycin and heparin (p<0.05). Post-rest first contractions in controls were found to be reduced by 2min exposure to 4mM 4-AP and augmented by 3min exposure to heparin alone. 4-AP responses in the presence of neomycin and heparin were significantly higher than with those only treated with 4-AP alone and lesser than controls. Because of the fact that 4-AP inducing contracture in Ca2+-free medium, Ca2+ causing contracture should be of SR in origin. Depending on these results, it was concluded that activation of PLC-IP3 cascade by 4-AP is involved in the mediation of contracture and contractile actions of this molecule. PMID- 30403593 TI - Optimization of DNA isolation method from Formalin-Fixed-Paraffin-Embedded tissues (FFPE) and comparative performance of four different Polymerase Chain Reaction (PCR) kits. AB - The tissue sample may have important genetic information in diagnostic, prognostic and counselling issues. Formalin-Fixed-Paraffin-Embedded (FFPE) is a routine method for preserving tissues. However, DNA isolated from FFPE tissue is often difficult to be amplified in PCR due to fragmentation and DNA-protein crosslinks. This study aimed to optimize the DNA isolation method from FFPE tissue and compare the performance of four different PCR ready-to-use kits. Genomic DNA was isolated from FFPE tissue colon of Short-segment Hirschsprung (S HSCR) patients and prostate cancer tissue using Quick-DNATM FFPE Kit (Zymo Research) with and without pre-heating treatment in KOH/NOH solution. Primers for Androgen Receptor (AR) gene and four different PCR kits: MyTaq HS Red Mix 2X (BioLine), FastStart Taq DNA Polymerase (Roche), KAPA2G fast PCR Kit 2X (KAPA Biosystem) and KOD FX Neo (Toyobo) were used for amplification. DNA electrophoresis was performed to compare the PCR results. BioLine and Toyobo kits gave better PCR results than those of Roche and KAPA Biosystem. Increasing amount of Taq polymerase and dNTPs of Roche kit by two-fold could increase the quality of PCR results. Toyobo could amplify DNA up to 417 bp, however, none of these PCR kits could amplify DNA above 450 bp. Pre-heated treatment of FFPE tissue in NaOH/KOH did not improve the DNA quality and PCR results. Toyobo PCR ready-to-use kit gave the best result among the other three PCR kits used in this study in amplifying DNA isolated from FFPE tissue. Designing the primers producing amplicon not more than 450 bp is suggested. PMID- 30403594 TI - Biosynthesis of silver nanoparticles from leaf extract of Litchi chinensis and its dynamic biological impact on microbial cells and human cancer cell lines. AB - Green synthesis of metallic nanoparticles has attracted a great deal of attention from scientific community due to its biocompatibility and environment friendly nature. In the present study, silver nanoparticles were biologically synthesized using leave extracts of Litchi chinensis. Biosynthesized silver nanoparticles were characterized and their applications were observed by different methodologies. Bio-reduction reaction was confirmed by the surface plasmon resonance of silver nanoparticles at 417 nm through UV-VIS spectrophotometer. FTIR analysis revealed that the amine groups present in the leaf extracts were responsible for the reduction of silver ions to silver nanoparticles. X-ray diffraction analysis was used to determine the crystalline nature of silver nanoparticles and their diameter was noted in the range of 41-55 nm by scanning electron microscopy. Antibacterial activity was observed against gram positive and gram negative strains of bacteria. Furthermore, human epithelial type 2 cancer cells (HEp-2) and Human breast adenocarcinoma cells lines (MCF-7) were treated with the biosynthesized silver nanoparticles using MTT assay. The resulting cell death rate was noted up to 40.91+1.99%. This study concludes that plant mediated biosynthesis of nanoparticles is the superior alternative compared to chemical and physical approaches, to utilize them as drug delivery tool and need to conjugate apoptosis inducing biological agents with silver nanoparticles to suppress the uncontrolled division of cancer cells. PMID- 30403595 TI - Combination of anti-early apoptotic cell autoantibodies and anti-SSA autoantibodies in lupus nephritis. AB - The aim of this study was to investigate the association of anti-early apoptotic cell autoantibodies, anti-SSA, and anti-SSB with clinical features of lupus nephritis (LN). Multiparameter flow cytometry was used to determine early apoptotic cells and for measuring the simultaneous binding of annexin V, 7-AAD, and IgG from LN patients (n = 39). The association between clinical features of LN and autoantibodies against early apoptotic cells, and between the autoantibodies and anti-SSA and anti-SSB, were further investigated. Thirteen LN patients (33.3 %) were positive for autoantibodies against early apoptotic cells. The prevalence of anti-SSA and anti-SSB were similar in patients with anti-early apoptotic cell autoantibodies and those without (anti-SSA: 9/13 versus 15/26; anti-SSB: 3/13 versus 4/26). Anti-early apoptotic cell antibody-positive patients had lower C3 levels (0.34 +/- 0.22) than the antibody-negative patients (0.47 +/- 0.17, p = 0.059); and significantly higher anti-dsDNA levels (502.99 +/- 275.48 versus 214.13 +/- 229.29, p = 0.001). In univariate logistic regression analysis, the presence of anti-early apoptotic cell antibody could predict poor short-term prognosis (HR 7.500, 95 % CI: 1.210 - 46.504, p = 0.030), while patients who were double positive for anti-SSA and anti-early apoptotic cell antibody had significantly increased risk of poor short-term outcome (HR 17.500, 95 % CI: 2.500 - 122.500, p = 0.004). The combination of anti-early apoptotic cell autoantibodies and anti-SSA might be of predictive value in LN. PMID- 30403596 TI - Inhibitory effects of various solvent extracts from Rhamnus frangula leaves on some inflammatory and metabolic enzymes. AB - Many enzymes are involved in numerous pathologies which are related to metabolic reactions and inflammatory diseases such as pancreatic lipase, alpha-amylase, alpha-glucosidase and xanthine oxidase and secreted phospholipases A2 (Group IIA, V and X), respectively. Therefore, inhibiting these enzymes offer the potential to block production of more inflammatory substances and decrease the risk factors for cardiovascular diseases. The purpose of this study was to investigate some potent, bioavailable and selective inhibitors of some catalytic proteins implicated to metabolic syndrome and their antioxidant effects from various solvent extracts of R. frangula leaves. The anti-inflammatory, obesity, diabete and XO potentials were evaluated through analyses of inhibition activities of corresponding metabolites.The water extract exhibited an important inhibitory effect on human, dromedary and stingray sPLA2-G IIA achieved an IC50 of 0.16+/ 0.06, 0.19+/-0.05 and 0.07+/-0.01 mg/mL, respectively. Likewise, the same fraction demonstrated the highest pancreatic lipase inhibitory activity using two different substrates. Indeed, 50% of dromedary pancreatic lipase inhibition was demonstrated for 5 min and 15 min using olive oil and TC4 substrates, respectively. Besides, it was established that methanolic extract had more effective inhibitory lipase activity than ORLISTAT used as a specific inhibitor of gastric, pancreatic and carboxyl ester lipase for treating obesity, with an IC50 of 5.51+/-0.27 and 91.46+/-2.3 ug/mL, respectively. In the case of alpha amylase, alpha-glucosidase and xanthine oxidase, the crude methanolic extract showed a potential inhibitory effect with an IC50 of 45+/-3.45, 3+/-0.15 and 27+/ 1.71 ug/mL, respectively. Conclusively, R. frangula leaves extracts showed a potential value of some sPLA2, some metabolic enzymes and XO inhibitors as anti inflammatory and metabolic syndrome drugs. PMID- 30403597 TI - Preventive effect of Juniperus procera extract on liver injury induced by lithocholic acid. AB - Bile acids are strong cytotoxic endogenous compounds implicated in several diseases in various organs, such as the liver, gallbladder and small and large intestines. Lithocholic acid is one such acid, produced by flora, and causes liver injury, cholestasis, and colon cancer. The present study aimed to examine the preventive effects of Juniperus procera extract on lithocholic acid-induced liver injury in experimental mice. Forty adult male mice were divided equally into four groups. The negative control group gained free access to food and water. The second group was orally treated with 150 mg/kg of Juniperus procera extract alone, the third group was treated with 1% lithocholic acid alone and the fourth group was co-treated with 150 mg/kg of Juniperus procera extract and 1% lithocholic acid. Blood and hepatic tissues were collected and assayed for biochemical, molecular and histopathological changes. Lithocholic acid toxicity shows a significant increase in the serum levels of the liver function parameters, which were prevented via the Juniperus procera co-administration. Furthermore, lithocholic acid significantly downregulates the mRNA expression of ABCG8, OATP2, SULT2A, CAR, FXR, CYP2B10, MRP2 and UGT1A, and Juniperus procera prevented this effect. Histopathological investigations of the hepatic tissues showed that lithocholic acid exhibited severe hepatotoxicity, with areas of irregularly distributed necrosis with inflammatory infiltration. Juniperus procera co-treated group showed a slight change in the hepatic tissue, diminished necrotic areas, and inflammatory infiltration. In conclusion, this study clarified the preventive effect of Juniperus procera extract administration on hepatotoxicity induced by lithocholic acid exposure in experimental mice. PMID- 30403598 TI - Virtual screening of natural anti-filarial compounds against glutathione-S transferase of Brugia malayi and Wuchereria bancrofti. AB - Glutathione-S-transferase also referred as GST is one of the major detoxification enzymes in parasitic helminths. The crucial role played by GST in various chronic infections has been well reported. The dependence of nematodes on detoxification enzymes to maintain their survival within the host established the crucial role of GST in filariasis and other related diseases. Hence, this well-established role of GST in filariasis along with its greater nonhomology with its human counterpart makes it an important therapeutic drug target. Here in this study, we have tried to explore the inhibitory potential of some of the well-reported natural ant-filarial compounds against the GST from Wuchereria bancrofti (W.bancrofti) and Brugia malayi (B.malayi). In silico virtual screening, approach was used to screen the selected natural compounds against GST from W.bancrofti and B.malayi. On the basis of our results, here we are reporting some of the natural compounds which were found to be very effective against GSTs. Along with we have also revealed the characteristic of the active site of BmGST and WbGST and the role of important active site residues involve in the binding of natural compounds within the active site of GSTs. This information will oped doors for using natural compounds as anti-filarial therapy and will also be helpful for future drug discovery. PMID- 30403599 TI - Comparison of the cytotoxic, genotoxic and apoptotic effects of Sugammadex and Neostigmine on human embryonic renal cell (HEK-293). AB - Acetylcholinesterase inhibitors, including Neostigmine, have been used to reverse neuromuscular blockage for many years. Sugammadex reverses this blockage using its gamma cyclodextrin ring, a mechanism that differs from that of cholinesterases and so circumvents the side effects of Neostigmine. Although the superiority of Sugammadex to Neostigmine has been outlined in several clinical studies, to our knowledge, there is not any research into cell culture that compares the cytotoxic, genotoxic and apoptotic effects of the two drugs. Hence, this is the first study to compare the cytotoxic, genotoxic and apoptotic effects of different dosages of both drugs on human embryonic renal (HEK-293) cells. In this study, the cytotoxicity, genotoxicity and apoptotic effects of Sugammadex and Neostigmine on HEK-293 cells were analyzed with using the MTT, Comet Assay and Flow Cytometric Annexin-V methods, respectively. The results demonstrate that Neostigmine at 50, 100, 250, and 500 ug/mL is more cytotoxic than equivalent dosages of Sugammadex. Neostigmine at 500 and 1000 ug/mL was found to be more genotoxic, and Neostigmine at 500 ug/mL had a statistically higher risk of causing apoptosis and necrosis than Sugammadex (p<0.05). Neostigmine administered in-vitro in the same doses as Sugammadex had greater cytotoxic, genotoxic and apoptotic effects on HEK-293 cells. PMID- 30403600 TI - The highly conserved domain of RND multidrug efflux pumps in pathogenic Gram negative bacteria. AB - RND (Resistance-Nodulation-Division) family transporters have a vital role in both intrinsic and acquired multi-drug resistance in Gram-negative bacteria. It is important to find a conserved domain in the RND family between different pathogenic bacteria for diagnostic and therapeutic purpose. Total sequences of three-component system RND efflux pumps were retrieved from NCBI nucleotide and protein database and were subjected to conservation and variation analysis using the multiple sequence alignment feature of the CLC workbench. The phylogenetic tree for main transporters was drawn and the three-dimensional structure was also evaluated. From the sequence conservation analysis, highly conserved residues with 282 base pair (94 amino acid) long were identified. The location of the highly conserved domain is positioned in the domain 1 crystallographic structure of AcrB Escherichia coli and MexB Pseudomonas aeruginosa. The main transporter component phylogenetic tree shows the clusters of different genotypes and their evolutionary association. Each of three components of RND proteins is crucial for drug efflux, and the absence of even one component makes the entire complex totally nonfunctional. Therefore, this highly conserved region can be used to disable the RND multidrug efflux pumps. In addition, this highly conserved can also be used for diagnostic aspects. PMID- 30403601 TI - Effect of boric acid on some elemental levels on rat's liver and kidney tissues during mercury chloride exposure. AB - In this study, the effect of boric acid on the important trace elements copper (Cu), iron (Fe), zinc (Zn), manganese (Mn) and nickel (Ni) in liver and kidney tissue of rats treated with mercury chloride was investigated. Twenty-four male Wistar albino rats (weighing 200 +/- 300 g) were divided into 3 groups: Control (C), Mercury chloride (HgCl2), Mercury chloride (HgCl2) + boric acid (BA). Iron and copper were decreased whereas Mn, Zn and Ni levels were increased in liver tissue in Hg administered group compared to control. Cu (p<0.01) and Mn (p<0.001) levels were increased in Hg + BA administered group compared to Hg group. Renal tissue Cu (p<0.01), Mn and Zn levels were increased whereas Ni (p<0.05) and Fe levels were decreased in Hg administered group compared to control group. Cu (p<0.001) and Zn (p<0.05) content increased in Hg + BA group compared to control group. As a result, it is thought that boric acid may have an effect on important trace element levels such as copper (Cu), iron (Fe), zinc (Zn), manganese (Mn), nickel (Ni) in case of oxidative stress caused by mercury chloride. PMID- 30403602 TI - 5-HT promotes pulmonary arterial smooth muscle cell proliferation through the TRPC channel. AB - Pulmonary arterial hypertension is caused by an imbalance of pulmonary vasoconstriction and vasodilation. Pulmonary arteriolar remodeling is a primary pathological change and proliferation of pulmonary arterial smooth muscle cells (PASMC) is an important pathological basis for pulmonary arteriolar remodeling. Vasoactive substances, such as 5-HT, may play a role in proliferation of PASMC via unknown mechanisms. In vitro experiments with PASMC showed that the TRPC channel inhibitor SKF96365 inhibited the effects 5-HT and DOI on PASMC proliferation and G2M percentage increase, and decreased expression of TRPC1, TRPC6 and calcineurin A/NFATc3 induced by 5-HT and DOI. SKF96365 inhibited binding of NFATc3 and DNA promoted by 5-HT and DOI. Therefore, 5-HT may affect the TRPC channel to promote proliferation of PASMC; upregulate expression of TRPC1, TRPC6, and calcineurin A/NFATc3; and therefore promote NFATc3 nuclear translocation. There may be crosstalk between 5-HT and TRPC, which may contribute to the pathogeneis of pulmonary arterial hypertension and this may be a novel therapeutic target for treating pulmonary arterial hypertension. PMID- 30403603 TI - Can Panax Ginseng protect against fertility disorders in hypothyroid female albino rats? AB - Hypothyroidism is an endocrine disorder due to decreased thyroid hormone production. This endocrine disorder significantly affects the menstrual cycle and fertility. The aim of this present study was to assess the efficacy of Panax ginseng, one of traditional Chinese medicine, in ameliorating the gonadal hormonal dysfunction and lowering oxidative stress accompanied with hypothyroidism in adult female albino rats. After confirming regularity of the oestrus cycle in the female rats in this study, hypothyroidism was induced by using daily 5.0 mg kg-1 oral dose of Neo-mercazole. The hypothyroid rats were randomly grouped into two groups; hypothyroid group (H): did not received any treatment, group II (H+G) was treated with Panax ginseng extract for one months after hypothyroidism induction. Another two groups were included in the study, a negative control group (Euthyroid group) and a positive control group; received Panax ginseng extract only. Hypothyroidism resulted in irregularity of oestrus cycle accompanied with decrease in luteinizing hormone (LH), follicular stimulating hormone (FSH) and estradiol (E2), while prolactin (PRL), progesterone (P) and testosterone (T) hormone were significantly elevated. Hypothyroidism elevated capsae-3 and 8OH-deoxy guanosine expression and increased secretion of corticosterone and ERK1/2. This study showed that Panax ginseng improved hypothyroid-induced deterioration in trophic and gonadal hormones through free radicals' scavenger. PMID- 30403604 TI - Predicting some quality factors of annual ryegrass (Lolium multiflorum lam.) by means of spectral reflectance values. AB - This study was conducted to predict some quality factors of the annual ryegrass (Lolium multiflorum Lam.) with spectral reflectance values in the Forage Crops Laboratory in the Department of Field Crops at the Agriculture Faculty, Akdeniz University, Turkey. In the study, variations resulting from different implementations (moisture level, bale density, propionic acid application and storage period) made during haymaking were determined with reflectance values. For reflectance measurements, a portable spectroradiometer and a contact probe (plant probe) were used and predicting models were created. Results of this study showed that quality factors of dried Annual ryegrass could be predicted with reflectance values, and that reflectances had higher efficacy in the red region for, the red and green, and the NIR region for crude protein, crude ash and crude cellulose, respectively. The results reveal that in dried annual ryegrass, there are significant relationships between feed quality factors such as crude protein, crude ash and crude cellulose, and reflectance values, and that especially crude protein levels can be rapidly and cheaply predicted by using reflectance values. PMID- 30403605 TI - Effect of medicated thread moxibustion on apoptosis of hippocampal neurons in rat models of chronic cerebral ischemic vascular dementia. AB - To investigate the effect of medicated thread moxibustion onapoptosis in hippocampal neuronsin a rat model of chronic cerebral ischemic vascular dementia. A total of 40 male Wistar rats were randomly divided into normal group and sham operated group (7 rats each), and rat model of chronic cerebral ischemic vascular dementia (14 rats). The model group rats were treated with medicated thread moxibustion two weeks after surgery, once a day, with one day break every six days, (24 times in all)and an observation period of 4 weeks. At the end of therapy, H&E staining was used to monitor changes in the neurons in CA1 area of the rat hippocampus. Changes in related indexes such as Bax, Bc1-2 and C-fos of neuron apoptosis in hippocampus CA1 area were determined by immunohistochemistry, while protein expression was semi-quantitatively assayed using imaging analysis technique. There was significant hippocampal neuronal necrosis six weeks after model establishment, but the necrosis was milder in rats in the medicated thread moxibustion group. Bax and C-fos were positively expressed and significantly higher in the hippocampus of chronic cerebral ischemic vascular dementia rats (model group) than in the medicated thread moxibustion group after treatment (p <0.01). The expression of Bcl-2 was increased in the medicated thread group after treatment, and was higher in the model group, but comparable to that in the sham operated group (p=0.975>0.05). Medicated thread moxibustion alleviates hippocampal neuronal necrosis, inhibits neuron apoptosis in hippocampus CA1 area, protects nerves, and maintains relative equilibrium inBax/Bcl-2 through down regulation of C-fos and Bax and up-regulation of Bcl-2. Thus, cell apoptosis related pathway may be one of its mechanisms of action. PMID- 30403606 TI - Association analysis of tolerance to dieback phenomena and trunk form using ISSR markers in Quercus brantii. AB - Oak decline is a complex syndrome in which several damaging agents interact and bring about a serious dieback in tree condition. Genetic diversity is a key factor for better adoption of natural populations to environmental stresses. The objective of this research was to identify the association of polymorphism patterns of different reproducible genomic Inter simple sequence repeats (ISSR markers) to level of dieback phenomena and also growth type in 18 different stands of Persian oak in central Zagros region. Totally, 180 trees were sampled and evaluated for growth type, tree diameter at breast height (DBH) and level of tree dieback. Genomic DNAs extracted of fresh leaves amplified using 15 multi locus ISSR primers. The population structure determined using the Bayesian model based clustering method implemented in STRUCTURE software by Monte Carlo Markov Chain (MCMC) method. Five distinct sub-populations (K=5) determined by the log likelihood of the data. Genome wide association study (GWAS) performed using the generalized linear model (GLM) and the mixed linear model (MLM) with Kinship matrix. Informative alleles recognized for level of tolerance to dieback and tree growth type traits. It was observed a significant co-segregation for phenotypic data and some of amplified fragments. Identification of these informative DNA markers can be utilized for pre-screening of high quality oak seedlings in early growth stages and better management in restoration of damaged stands. PMID- 30403607 TI - A meta-analysis of association between serum iron levels and lung cancer risk. AB - Many studies conducted on the relationship between serum iron levels and lung cancer risk had produced inconsistent results. We therefore conducted a meta analysis to determine whether serum iron levels were lower in lung cancer patients compared to those in controls.A literature survey was conducted by searching the PubMed, WanFang, CNKI, and SinoMed databases for articles published as of Mar 1, 2018. Standard mean differences (SMD) with the corresponding 95% confidence intervals (CI) were executed by Stata 12.0 software. A total of 13 publications involving 1118 lung cancer patients and 832 controls were included in our study. The combined results showed that serum iron levels in lung cancer cases had no significantly lower when compared to those in controls [summary SMD = -0.125, 95%CI= -0.439, 0.189, Z = 0.78, p for Z test= 0.435], with high heterogeneity (I2= 89.9%, P< 0.001) found. In the stratified analysis by geographic locations, consistent results were found for serum iron levels between lung cancer patients and controls both in Asian populations [summary SMD = 0.113, 95%CI= -0.471, 0.245] and European populations [summary SMD = -0.215, 95%CI= -0.835, 0.404]. Publication bias was not found when evaluated by Begg's funnel plot and Egger's regression asymmetry test.In summary, the current study showed that serum iron levels had no significant association on lung cancer risk. PMID- 30403608 TI - Ectopic spleen mimicking hepatocellular carcinoma in the late post-operative period of bariatric surgery. AB - An ectopic spleen occurs with less than 600 cases reported and has a large series of splenectomies less than 0.3%. Its highest prevalence occurs between 20 and 40 years of age, being more frequent in female patients. To present an original case report on the occurrence of ectopic spleen, mimicking hepatocellular carcinoma (HCC) after bariatric surgery. Occurrence of migratory spleen after late bariatric surgery, mimicking an HCC discovered in a routine evaluation. JCA patient, male, 66 years old, previously with sleep apnea, hypertensive and diabetic patients on medication regularly, who weighed 112.8 kg, with a BMI of 43.4 kg / m2. After 2 years of by-pass, a routine evaluation identified hepatobiliary surface on hepatic ultrasound performing MRI imaging suggestive of HCC. The team opted for a new laparoscopy with the possibility of cavity inventory beyond the biopsy of the tumor lesion already identified, to track intra-abdominal metastases and to review anatomy. The operation revealed that the suggestive lesion was subcapsular implanted only in the falciform and hepatic surface in segment amenable to total resection. The anatomopathological results of the lesions were described as congenital splenic cells compatible with ectopic spleen. The emergence of the ectopic spleen after laparoscopic bypass has not been reported so far because it is a non-traumatic surgery. The lesion in question had a benign behavior, with hepatic subcapsular implantation restricted to the falciform ligament, capable of total resection. Patient evolved well following follow up with gastroenterologist. PMID- 30403609 TI - Assessing the Learning Curve of Holmium Laser Enucleation of Prostate (HoLEP). A Systematic Review. AB - We systematically assessed the learning curve of Holmium laser enucleation of the prostate using the available literature to identify, as our primary outcome, the average number of cases required to reach competency. A computerized search of PubMed and Scopus for articles published from inception through to January 2018 was performed including 24 studies with a total of 5173 patients. Even though different outcome measures require varying case-loads to reach a plateau, Holmium laser enucleation of prostate has an acceptable learning curve with a proposed figure approximating 25-50 cases, with a structured mentorship programme aiding for faster progress. PMID- 30403612 TI - Aims and Scope. PMID- 30403611 TI - REPLY. PMID- 30403615 TI - Multi-Source Ensemble Learning for the Remote Prediction of Parkinson's Disease in the Presence of Source-wise Missing Data. AB - As the collection of mobile health data becomes pervasive, missing data can make large portions of datasets inaccessible for analysis. Missing data has shown particularly problematic for remotely diagnosing and monitoring Parkinson's disease (PD) using smart-phones. This contribution presents multi-source ensemble learning, a methodology which combines dataset deconstruction with ensemble learning and enables participants with incomplete data (i.e. where not all sensor data is available) to be included in the training of machine learning models and achieves a 100% participant retention rate. We demonstrate the proposed method on a cohort of 1,513 participants, 91.2% of which contributed incomplete data in tapping, gait, voice and/or memory tests. The use of multi-source ensemble learning, alongside convolutional neural networks (CNNs) capitalizing on the amount of available data, increases PD classification accuracy from 73.1% to 82.0% as compared to traditional techniques. The increase in accuracy is found to be partly caused by the use of multi-channel CNNs and partly caused by developing models using the large cohort of participants. Furthermore, through bootstrap sampling we reveal that feature selection is better performed on a large cohort of participants with incomplete data than on a small number of participants with complete data. The proposed method is applicable to a wide range of wearable/remote monitoring datasets that suffer from missing data and contributes to improving the ability to remotely monitor PD via revealing novel methods of accounting for symptom heterogeneity. PMID- 30403616 TI - Heart Rate Variability-based Driver Drowsiness Detection and its Validation with EEG. AB - OBJECTIVE: Driver drowsiness detection is a key technology that can prevent fatal car accidents caused by drowsy driving. The present work proposes a driver drowsiness detection algorithm based on heart rate variability (HRV) analysis and validates the proposed method by comparing with electroencephalography (EEG) based sleep scoring. METHODS: Changes in sleep condition affect the autonomic nervous system (ANS) and then HRV, which is defined as an RR interval (RRI) fluctuation on an electrocardiogram (ECG) trace. Eight HRV features are monitored for detecting changes in HRV by using multivariate statistical process control (MSPC) which is a well-known anomaly detection method. RESULT: The performance of the proposed algorithm was evaluated through an experiment using a driving simulator. In this experiment, RRI data were measured from 34 participants during driving, and their sleep onsets were determined based on the EEG data by a sleep specialist. The validation result of the experimental data with the EEG data showed that drowsiness was detected in 12 out of 13 drowsy episodes prior to the sleep onsets, and the false positive rate was 1.7 times per hour. CONCLUSION: The present work also demonstrates the usefulness of the framework of HRV-based anomaly detection that was originally proposed for epileptic seizure prediction. SIGNIFICANCE: The proposed method can contribute to prevent accidents caused by drowsy driving. PMID- 30403618 TI - BioPhysical Modeling, Characterization and Optimization of Electro-Quasistatic Human Body Communication. AB - Human Body Communication (HBC) has emerged as an alternative to radio wave communication for connecting low power, miniaturized wearable and implantable devices in, on and around the human body. HBC uses the human body as the communication channel between on-body devices. Previous studies characterizing the human body channel has reported widely varying channel response much of which has been attributed to the variation in measurement setup. This calls for the development of a unifying bio-physical model of HBC supported by in-depth analysis and an understanding of the effect of excitation, termination modality on HBC measurements. This paper characterizes the human body channel up to 1MHz frequency to evaluate it as a medium for broadband communication. The communication occurs primarily in the electro-quasistatic (EQS) regime at these frequencies through the subcutaneous tissues. A lumped bio-physical model of HBC is developed, supported by experimental validations that provides insight into some of the key discrepancies found in previous studies. Voltage loss measurements are carried out both with an oscilloscope and a miniaturized wearable prototype to capture the effects of non-common ground. Results show that the channel loss is strongly dependent on the termination impedance at the receiver end, with up to 4dB variation in average loss for different termination in an oscilloscope and an additional 9 dB channel loss with wearable prototype compared to an oscilloscope measurement. The measured channel response with capacitive termination reduces low-frequency loss and allows flat-band transfer function down to 13 KHz, establishing the human body as a broadband communication channel. Analysis of the measured results and the simulation model shows that instruments with input impedance (Vector Network Analyzer, Spectrum Analyzer) provides pessimistic estimation of channel loss at low frequencies. Instead (1) high impedance (2) capacitive termination should be used at the receiver end for accurate voltage mode loss measurements of the HBC channel at low frequencies. The experimentally validated bio-physical model shows that capacitive voltage mode termination can improve the low frequency loss by up to 50dB, which helps broadband communication significantly. PMID- 30403617 TI - In vivo detection of chronic kidney disease using tissue deformation fields from dynamic MR imaging. AB - OBJECTIVE: Chronic kidney disease (CKD) is a serious medical condition characterized by gradual loss of kidney function. Early detection and diagnosis is mandatory for adequate therapy and prognostic improvement. Hence, in the current pilot study we explore the use of image registration methods for detecting renal morphologic changes in patients with CKD. METHODS: Ten healthy volunteers and nine patients with presumed CKD underwent dynamic T1 weighted imaging without contrast agent. From real and simulated dynamic time series, kidney deformation fields were estimated using a poroelastic deformation model. From the deformation fields several quantitative parameters reflecting pressure gradients, and volumetric and shear deformations were computed. Eight of the patients also underwent a kidney biopsy as a gold standard. RESULTS: We found that the absolute deformation, normalized volume changes, as well as pressure gradients correlated significantly with arteriosclerosis from biopsy assessments. Furthermore, our results indicate that current image registration methodologies are lacking sensitivity to recover mild changes in tissue stiffness. CONCLUSION: Image registration applied to dynamic time series correlated with structural renal changes and should be further explored as a tool for invasive measurements of arteriosclerosis. SIGNIFICANCE: Under the assumption that the proposed framework can be further developed in terms of sensitivity and specificity, it can provide clinicians with a non-invasive tool of high spatial coverage available for characterization of arteriosclerosis and potentially other pathological changes observed in chronic kidney disease. PMID- 30403619 TI - Reference-Based Integral MR-EPT:Simulation and Experiment Studies on the 9.4T MRI. AB - Current integral-equation (IE) based MR electrical properties tomography (EPT) methods utilize simulated incident radio-frequency (RF) fields, which are inaccurate and lead to reconstruction errors. To improve the accuracy and practicability of IE-based MR-EPT methods, a new approach is presented that obtains the incident fields using reference subjects and RF field mapping techniques. The Incident field approximation (IFA) is first demonstrated in this paper. This approximation assumes that two imaged subjects with similar coil/subject interactions will have similar incident RF fields, thus one can feed the estimation of the incident fields within the imaged subject into the calculation of those within a homogeneous subject (reference subject). This is done by measuring the total RF fields ( field) of the reference using field mapping techniques, using the known EPs of the reference subject and by rearranging Ampere's Law and the integral equations. The calculated incident RF fields are then used to reconstruct the EPs' distribution with a three dimensional (3D) integral-based MR-EPT method. Numerical simulation results indicated that the incident RF fields obtained from the reference subject provide accurate 3D reconstruction of EPs with less than 16% root mean square error (RMSE) in noise-free scenario while the conventional IE method had more than 28% RMSE. The phantom-based experiments at 9.4T MRI system have also been conducted to evaluate the performance of the proposed method and the results indicated that the proposed method achieved desirable robustness against the noise in practical scenario with less than 21% RMSE while the conventional differential equation based method showed worse than 37% RMSE. PMID- 30403620 TI - iDeLog: Iterative Dual Spatial and Kinematic Extraction of Sigma-Lognormal Parameters. AB - The Kinematic Theory of rapid movements and its associated Sigma-Lognormal model have been extensively used in a large variety of applications. While the physical and biological meaning of the model have been widely tested and validated for rapid movements, some shortcomings have been detected when it is used with continuous long and complex movements. To alleviate such drawbacks, and inspired by the motor equivalence theory and a conceivable visual feedback, this paper proposes a novel framework to extract the Sigma-Lognormal parameters, namely iDeLog. Specifically, iDeLog consists of two steps. The first one, influenced by the motor equivalence model, separately derives an initial action plan defined by a set of virtual points and angles from the trajectory and a sequence of lognormals from the velocity. In the second step, based on a hypothetical visual feedback compatible with an open-loop motor control, the virtual target points of the action plan are iteratively moved to improve the matching between the observed and reconstructed trajectory and velocity. During experiments conducted with handwritten signatures, iDeLog obtained promising results as compared to the previous development of the Sigma-Lognormal. PMID- 30403621 TI - Numerical Quadrature for Probabilistic Policy Search. AB - Learning control policies has become an appealing alternative to the derivation of control laws based on classic control theory. Model-based approaches have proven an outstanding data efficiency, especially when combined with probabilistic models to eliminate model bias. However, a major difficulty for these methods is that multi-step-ahead predictions typically become intractable for larger planning horizons and can only poorly be approximated. In this paper, we propose the use of numerical quadrature to overcome this drawback and provide significantly more accurate multi-step-ahead predictions. As a result, our approach increases data efficiency and enhances the quality of learned policies. Furthermore, policy learning is not restricted to optimizing locally around one trajectory, as numerical quadrature provides a principled approach to extend optimization to all trajectories starting in a specified starting state region. Thus, manual effort, such as choosing informative starting points for simultaneous policy optimization, is significantly decreased. Furthermore, learning is highly robust to the choice of initial policy and, thus, interaction time with the system is minimized. Empirical evaluations on simulated benchmark problems show the efficiency of the proposed approach and support our theoretical results. PMID- 30403622 TI - Phase Linearity Measurement: a novel index for brain functional connectivity. AB - The problem of describing how different brain areas interact between each other has been granted a great deal of attention in the last years. The idea that neuronal ensembles behave as oscillators and that they communicate through synchronization is now widely accepted. To this regard, EEG and MEG provide the signals that allow the estimation of such communication in vivo. Hence, phase based metrics are essential. However, the application of phased-based metrics for measuring brain connectivity has proved problematic so far, since they appear to be less resilient to noise as compared to amplitude-based ones. In this paper, we address the problem of designing a purely phase-based brain connectivity metric, insensitive to volume conduction and resilient to noise. The proposed metric, named Phase Linearity Measurement (PLM), is based on the analysis of similar behaviors in the phases of the recorded signals. The PLM is tested in two simulated datasets as well as in real MEG data acquired at the Naples MEG center. Due to its intrinsic characteristics, the PLM shows considerable noise rejection properties as compared to other widely adopted connectivity metrics. We conclude that the PLM might be valuable in order to allow better estimation of phasebased brain connectivity. PMID- 30403623 TI - Learning-Based Quality Control for Cardiac MR Images. AB - The effectiveness of a cardiovascular magnetic resonance (CMR) scan depends on the ability of the operator to correctly tune the acquisition parameters to the subject being scanned and on the potential occurrence of imaging artefacts such as cardiac and respiratory motion. In the clinical practice, a quality control step is performed by visual assessment of the acquired images: however, this procedure is strongly operatordependent, cumbersome and sometimes incompatible with the time constraints in clinical settings and large-scale studies. We propose a fast, fully-automated, learning-based quality control pipeline for CMR images, specifically for short-axis image stacks. Our pipeline performs three important quality checks: 1) heart coverage estimation, 2) inter-slice motion detection, 3) image contrast estimation in the cardiac region. The pipeline uses a hybrid decision forest method - integrating both regression and structured classification models - to extract landmarks as well as probabilistic segmentation maps from both long- and short-axis images as a basis to perform the quality checks. The technique was tested on up to 3000 cases from the UK Biobank as well as on 100 cases from the UK Digital Heart Project, and validated against manual annotations and visual inspections performed by expert interpreters. The results show the capability of the proposed pipeline to correctly detect incomplete or corrupted scans (e.g. on UK Biobank, sensitivity and specificity respectively 88% and 99% for heart coverage estimation, 85% and 95% for motion detection), allowing their exclusion from the analysed dataset or the triggering of a new acquisition. PMID- 30403624 TI - Unsupervised Feature Extraction via Deep Learning for Histopathological Classification of Colon Tissue Images. AB - Histopathological examination is today's gold standard for cancer diagnosis. However, this task is time consuming and prone to errors as it requires a detailed visual inspection and interpretation of a pathologist. Digital pathology aims at alleviating these problems by providing computerized methods that quantitatively analyze digitized histopathological tissue images. The performance of these methods mainly rely on features that they use, and thus, their success strictly depends on the ability of these features successfully quantifying the histopathology domain. With this motivation, this paper presents a new unsupervised feature extractor for effective representation and classification of histopathological tissue images. This feature extractor has three main contributions: First, it proposes to identify salient subregions in an image, based on domain-specific prior knowledge, and to quantify the image by employing only the characteristics of these subregions instead of considering the characteristics of all image locations. Second, it introduces a new deep learning based technique that quantizes the salient subregions by extracting a set of features directly learned on image data and uses the distribution of these quantizations for image representation and classification. To this end, the proposed deep learning based technique constructs a deep belief network of restricted Boltzmann machines (RBMs), defines the activation values of the hidden unit nodes in the final RBM as the features, and learns the quantizations by clustering these features in an unsupervised way. Third, this extractor is the first example of successfully using restricted Boltzmann machines in the domain of histopathological image analysis. Our experiments on microscopic colon tissue images reveal that the proposed feature extractor is effective to obtain more accurate classification results compared to its counterparts. PMID- 30403625 TI - Data-driven Elasticity Imaging Using Cartesian Neural Network Constitutive Models and the Autoprogressive Method. AB - Quasi-static elasticity imaging techniques rely on model-based mathematical inverse methods to estimate mechanical parameters from force-displacement measurements. These techniques introduce simplifying assumptions that preclude exploration of unknown mechanical properties with potential diagnostic value. We previously reported a data-driven approach to elasticity imaging using artificial neural networks (NNs) that circumvents limitations associated with model-based inverse methods. NN constitutive models can learn stress-strain behavior from forcedisplacement measurements using the Autoprogressive method (AutoP) without prior assumptions of the underlying constitutive model. However, information about internal structure was required. We invented Cartesian neural network constitutive models (CaNNCMs) that learn the spatial variations of material properties. We are presenting the first implementation of CaNNCMs trained with AutoP to develop data-driven models of 2-D linear-elastic materials. Both simulated and experimental force-displacement data were used as input to AutoP to show that CaNNCMs are able to model both continuous and discrete material property distributions with no prior information of internal object structure. Furthermore, we demonstrate that CaNNCMs are robust to measurement noise and can reconstruct reasonably accurate Young's modulus images from a sparse sampling of measurement data. CaNNCMs are an important step toward clinical use of data driven elasticity imaging using AutoP. PMID- 30403626 TI - 2.44 GHz Surface Acoustic Wave Resonator Phase Noise Measured by Carrier Suppression Technique. AB - The phase noise of surface acoustic wave resonators is explored by a passive measurement system based on the carrier suppression technique. The measurements are focused on 2.44 GHz quartz crystal resonators. These resonators are characterized in term of motional parameters. The power dissipated through the resonators is around 500 MUW. The second order frequency-temperature coefficient of the resonators has been measured to be around -0.038 ppm/ degrees C2 that corresponds to a classical ST-cut. The resonator conditioning is presented. The measured noise exhibits a 1/f frequency fluctuation behavior. The short term stability (flicker floor) is given in term of Allan standard deviation. The order of magnitude is around 2.10-10. Additional measurements are given for resonators at 433 MHz and 915 MHz in order to compare them. The results are presented according the intrinsic quality factor of the resonators and compared to previous works done in the past by T. Parker. These additional data provide valuable information on the dependence of the flicker noise levels on resonator frequency. PMID- 30403627 TI - Characteristics of SH0-wave Converted to T(0, 1)-wave Based on a T-shaped Plate Wrapped Around a Pipe. AB - Ultrasonic guided waves are widely used in industrial NDT for pipes and plates, where pipe-waves and plate-waves exhibit similar behaviors for some specific modes. This paper investigates the characteristics of an SH0 mode plate-wave converted to a T(0, 1) mode pipe-wave based on their similar dispersion and wave structure properties. First, the analytical solution is initially proposed to analyze the characteristics of the SH0-wave propagation in a model of arrayed plates coupled to a pipe. The dispersion curves of the SH-waves are established in a bounded double layer plate in which the effect of the material and the effect of the thickness ratio of the layers are both considered. An equivalent model of a T-shaped plate wrapped around a pipe is then presented and the numerical simulation of the SH0-wave propagation in the T-shaped plate is studied. Finally, the validity of the model is verified by experiments in which the PPM EMAT to generate the SH0-wave and the arrayed PPM EMAT to detect the T(0, 1)-wave are designed and built. PMID- 30403628 TI - High-Order Hadamard-Encoded Transmission For Tissue Background Suppression In Ultrasound Contrast Imaging: Memory Effect And Decoding Schemes. AB - Hadamard-encoded multi-pulses (HEM) transmit has recently been utilized for tissue background suppression in ultrasound contrast imaging to enhance contrast to4 tissue ratio (CTR). Nonetheless, second harmonic component in HEM transmit results in residual tissue background after decoding and thus compromises detection of contrast microbubbles. Theoretically, high-order HEM transmit can produce harmonic-free background but the memory effect which considers the nonlinear contribution of previous bit waveform into next one in the progress of harmonic generation may limit the achievable tissue suppression. In this study, three possible harmonic-free pairs using time-shifted subtraction (SH1, SH2 and SH3) in the fourth-order Hadamard decoding are analyzed and experimentally compared using hydrophone measurement and B12 mode imaging. Moreover, orthogonal decoding of HEM transmit is also proposed with pulse-inversion harmonic suppression (PIHS) to remedy memory effect on tissue background. Results shows that SH3, which utilizes the third and the fourth rows for decoding, provides the lowest magnitude of tissue background among all possible decoding pairs and performs comparably to the reference pulse inversion and amplitude modulation (PIAM) sequence in terms of CTR. For PIHS orthogonal decoding, the pulse subtraction effectively removes the harmonic interferences from memory effect and thus further improves the CTR by 5.4 dB compared to SH3. For high-order HEM transmit, PIHS orthogonal decoding can help to eliminate residual tissue background due to memory effect and is comparable to Hadamard decoding in temporal resolution and possible motion artifacts. PMID- 30403629 TI - Three-dimensional flow studies in cylindrical magnetohydrodynamic experiments using ultrasound array velocimetry. AB - Crystal growth processes can profit from an electromagnetically driven melt flow, since controlling them allows to optimize the mass and heat transfer in the melt and thereby improves the structural and electrical properties of the grown crystals. This process optimization requires a precise understanding of magnetohydrodynamic (MHD) phenomena in crystal growth. Studying time-dependent MHD demands for a high temporal resolution combined with a long measurement duration to analyze transitional flow behavior. Furthermore, a spatially resolved measurement of the global flow structure is desired to capture complex 3-D flow structures. We present an Ultrasound Array Doppler Velocimeter (UADV) for time resolved flow imaging in MHD model experiments with low-melting metals. Flow imaging at frame rates of several Hertz is achieved by using a combined spatial and temporal multiplexing scheme. Long-running measurements are enabled by an FPGA-based signal processing which reduces the measurement data rate by a factor of 5. A reconstruction of the 3-D flow structure in cylindrical containers with a rotation-symmetric flow is proposed. The UADV is demonstrated at an MHD experiment with a melt flow in a cylindrical container driven by a traveling magnetic field. The transition from a laminar to a time-dependent flow is studied revealing an oscillating flow. The demonstration of the 3-D reconstruction gives a comprehensive insight into the global flow structure. Hence, the UADV method is shown to be a valuable tool for measuring complex, time-dependent melt flows, which can contribute to a better understanding of the flow phenomena during crystal growth. PMID- 30403630 TI - Synthetic data generation for end-to-end thermal infrared tracking. AB - The usage of both off-the-shelf and end-to-end trained deep networks have significantly improved performance of visual tracking on RGB videos. However, the lack of large labeled datasets hampers the usage of convolutional neural networks for tracking in thermal infrared (TIR) images. Therefore, most state of the art methods on tracking for TIR data are still based on hand-crafted features. To address this problem, we propose to use image-to-image translation models. These models allow us to translate the abundantly available labeled RGB data to synthetic TIR data. We explore both the usage of paired and unpaired image translation models for this purpose. These methods provide us with a large labeled dataset of synthetic TIR sequences, on which we can train end-to-end optimal features for tracking. To the best of our knowledge we are the first to train end-to-end features for TIR tracking. We perform extensive experiments on VOT-TIR2017 dataset. We show that a network trained on a large dataset of synthetic TIR data obtains better performance than one trained on the available real TIR data. Combining both data sources leads to further improvement. In addition, when we combine the network with motion features we outperform the state of the art with a relative gain of over 10%, clearly showing the efficiency of using synthetic data to train end-to-end TIR trackers. PMID- 30403631 TI - Deep Visual Saliency on Stereoscopic Images. AB - Visual saliency on stereoscopic 3D (S3D) images has been shown to be heavily influenced by image quality. Hence, this dependency is an important factor in image quality prediction, image restoration and discomfort reduction, but it is still very difficult to predict such a nonlinear relation in images. In addition, most algorithms specialized in detecting visual saliency on pristine images may unsurprisingly fail when facing distorted images. In this paper, we investigate a deep learning scheme named Deep Visual Saliency (DeepVS) to achieve a more accurate and reliable saliency predictor even in the presence of distortions. Since visual saliency is influenced by low-level features (contrast, luminance and depth information) from a psychophysical point of view, we propose seven low level features derived from S3D image pairs and utilize them in the context of deep learning to detect visual attention adaptively to human perception. During analysis, it turns out that the low-level features play a role to extract distortion and saliency information. To construct saliency predictors, we weight and model the human visual saliency through two different network architectures, a regression and a fully convolutional neural networks (CNNs). Our results from thorough experiments confirm that the predicted saliency maps are up to 70 % correlated with human gaze patterns, which emphasize the need for the hand crafted features as input to deep neural networks in S3D saliency detection. PMID- 30403632 TI - Scientific Visualization as a Microservice. AB - In this paper, we propose using a decoupled architecture to create a microservice that can deliver scientific visualization remotely with efficiency, scalability, and superior availability, affordability and accessibility. Through our effort, we have created an open source platform, Tapestry, which can be deployed on Amazon AWS as a production use microservice. The applications we use to demonstrate the efficacy of the Tapestry microservice in this work are: (1) embedding interactive visualizations into lightweight web pages, (2) creating scientific visualization movies that are fully controllable by the viewers, (3) serving as a rendering engine for high-end displays such as power-walls, and (4) embedding data-intensive visualizations into augmented reality devices efficiently. In addition, we show results of an extensive performance study, and suggest how applications can make optimal use of microservices such as Tapestry. PMID- 30403633 TI - Modeling the Kinematics of Human Locomotion over Continuously Varying Speeds and Inclines. AB - Powered knee and ankle prostheses can perform a limited number of discrete ambulation tasks. This is largely due to their control architecture, which uses a finite-state machine to select among a set of task-specific controllers. A non switching controller that supports a continuum of tasks is expected to better facilitate normative biomechanics. This paper introduces a predictive model that represents gait kinematics as a continuous function of gait cycle percentage, speed, and incline. The basis model consists of two parts: basis functions that produce kinematic trajectories over the gait cycle, and task functions that smoothly alter the weight of basis functions in response to task. Kinematic data from ten able-bodied subjects walking at twenty-seven combinations of speed and incline generate training and validation data for this data-driven model. Convex optimization accurately fits the model to experimental data. Automated model order reduction improves predictive abilities by capturing only the most important kinematic changes due to walking tasks. Constraints on range of motion and jerk ensure the safety and comfort of the user. This model produces a smooth continuum of trajectories over task, an impossibility for finite-state control algorithms. Random sub-sampling validation indicates basis modeling predicts untrained kinematics more accurately than linear interpolation. PMID- 30403634 TI - On String Languages Generated by Spiking Neural P Systems With Structural Plasticity. AB - Spiking neural P systems (SNP systems) are parallel and non-deterministic models of computation, inspired by the neural system of the brain. A variant of SNP systems known as SNP systems with structural plasticity (SNPSP systems) includes the feature of adding or removing synapses among neurons. This feature is inspired by plasticity from neuroscience during cognition and learning. Despite the reductionist framework of SNP and SNPSP systems, such as brain-like systems are capable of computational universality. In particular, we use SNPSP systems in this paper to compute some classes of languages from the Chomsky hierarchy: FIN, REG, and RE. The computations of such classes continue a research direction established in the previous paper. We also emphasize the (dis)advantages of synapse plasticity in the neural system, compared with existing features of SNP systems, when generating languages. PMID- 30403635 TI - Improving the Inference of Co-occurrence Networks in the Bovine Rumen Microbiome. AB - The importance of the composition and signature of rumen microbial communities has gained increasing attention. One of the key techniques was to infer co abundance networks through correlation analysis based on relative abundances. In this study, we proposed the use of a framework including a compendium of two correlation measures and three dissimilarity metrics to mitigate the compositional effect in the inference of significant associations in the bovine rumen microbiome. We tested the framework on rumen microbiome data including both 16S rRNA and KEGG genes associated with methane production in cattle. Based on the identification of significant positive and negative associations supported by multiple metrics, two co-occurrence networks, e.g. co-presence and mutual exclusion networks, were constructed. Significant modules associated with methane emissions were identified. In comparison to previous studies, our analysis demonstrates that deriving microbial associations based on the correlations between relative abundances may not only lead to missing information but also produce spurious associations. To bridge together different co-presence and mutual-exclusion relations, a multiplex network model has been proposed for integrative analysis of co-occurrence networks which has great potential to support the prediction of animal phytotypes and to provide additional insights into biological mechanisms of the microbiome associated with the traits. PMID- 30403636 TI - Using Unlabeled Data to Discover Bivariate Causality with Deep Restricted Boltzmann Machines. AB - An important question in microbiology is whether treatment causes changes in gut flora, and whether it also affects metabolism. The reconstruction of causal relations purely from non-temporal observational data is challenging. We address the problem of causal inference in a bivariate case, where the joint distribution of two variables is observed. In this contribution, we introduce a novel method of causality discovering which is based on the widely used assumption that if X causes Y, then P(X) and P(Y|X) are independent. We propose to explore a semi supervised approach where P(Y|X) and P(X) are estimated from labeled and unlabeled data respectively, whereas the marginal probability is estimated potentially from much more unlabeled data than the conditional distribution. We illustrate by experiments on several benchmarks of biological network reconstruction that the proposed approach is very competitive in terms of computational time and accuracy compared to the state-of-the-art methods. Finally, we apply the proposed method to an original medical task where we study whether drugs confound human metagenome. PMID- 30403637 TI - Introducing Heuristic Information into Ant Colony Optimization Algorithm for Identifying Epistasis. AB - Epistasis learning, which is aimed at detecting associations between multiple Single Nucleotide Polymorphisms (SNPs) and complex diseases, has gained increasing attention in genome wide association studies. Although much work has been done on mapping the SNPs underlying complex diseases, there is still difficulty in detecting epistatic interactions due to the lack of heuristic information to expedite the search process. In this study, a method EACO is proposed to detect epistatic interactions based on ant colony optimization (ACO) algorithm, the highlights of which are the introduced heuristic information, fitness function, and a candidate solutions filtration strategy. The heuristic information multi-SURF* is introduced into EACO method for identifying epistasis, and it is incorporated into ant-decision rules to guide the search with linear time. Two functionally complementary fitness functions, mutual information and the Gini index, are combined to effectively evaluate the associations between SNP combinations and the phenotype. Furthermore, a strategy for candidate solutions filtration is provided to adaptively retain all optimal solutions which yields a more accurate way for epistasis searching. Experiments of EACO with seven methods are performed on both simulation data sets and a real data set of age-related macular degeneration. Results indicate that EACO is promising in identifying epistasis. PMID- 30403638 TI - Deep FisherNet for Image Classification. AB - Despite the great success of convolutional neural networks (CNNs) for the image classification task on data sets such as Cifar and ImageNet, CNN's representation power is still somewhat limited in dealing with images that have a large variation in size and clutter, where Fisher vector (FV) has shown to be an effective encoding strategy. FV encodes an image by aggregating local descriptors with a universal generative Gaussian mixture model (GMM). FV, however, has limited learning capability and its parameters are mostly fixed after constructing the codebook. To combine together the best of the two worlds, we propose in this brief a neural network structure with FV layer being part of an end-to-end trainable system that is differentiable; we name our network FisherNet that is learnable using back propagation. Our proposed FisherNet combines CNN training and FV encoding in a single end-to-end structure. We observe a clear advantage of FisherNet over plain CNN and standard FV in terms of both classification accuracy and computational efficiency on the challenging PASCAL visual object classes object classification and emotion image classification tasks. PMID- 30403639 TI - Convergence Conditions for Solving Robust Iterative Learning Control Problems Under Nonrepetitive Model Uncertainties. AB - Learning from saved measurement and control data to refine the performance of output tracking is the core feature of iterative learning control (ILC). Even though this implementation process of ILC does not need any model knowledge, ILC typically requires the strict repetitiveness of the control systems, especially on the plant models of them. The questions of interest in this paper are: 1) whether and how can robust ILC problems be solved with respect to the nonrepetitive (or iteration-dependent) model uncertainties and 2) can convergence conditions be developed with the effective contraction mapping (CM)-based approach to ILC? The answers to these questions are affirmative, and the CM-based approach is applicable to robust ILC that accommodates certain nonrepetitive uncertainties, especially in the plant models. In particular, an Hinfinity-norm condition is proposed to ensure the robust ILC convergence, which can be solved to determine learning gain matrices. Simulation tests are performed to illustrate the validity of our presented Hinfinity-based analysis results. PMID- 30403640 TI - Inverting the Generator of a Generative Adversarial Network. AB - Generative adversarial networks (GANs) learn a deep generative model that is able to synthesize novel, high-dimensional data samples. New data samples are synthesized by passing latent samples, drawn from a chosen prior distribution, through the generative model. Once trained, the latent space exhibits interesting properties that may be useful for downstream tasks such as classification or retrieval. Unfortunately, GANs do not offer an ''inverse model,'' a mapping from data space back to latent space, making it difficult to infer a latent representation for a given data sample. In this paper, we introduce a technique, inversion, to project data samples, specifically images, to the latent space using a pretrained GAN. Using our proposed inversion technique, we are able to identify which attributes of a data set a trained GAN is able to model and quantify GAN performance, based on a reconstruction loss. We demonstrate how our proposed inversion technique may be used to quantitatively compare the performance of various GAN models trained on three image data sets. We provide codes for all of our experiments in the website (https://github.com/ToniCreswell/InvertingGAN). PMID- 30403574 TI - Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. AB - BACKGROUND: Patients who have had an acute coronary syndrome are at high risk for recurrent ischemic cardiovascular events. We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving 18,924 patients who had an acute coronary syndrome 1 to 12 months earlier, had a low-density lipoprotein (LDL) cholesterol level of at least 70 mg per deciliter (1.8 mmol per liter), a non-high-density lipoprotein cholesterol level of at least 100 mg per deciliter (2.6 mmol per liter), or an apolipoprotein B level of at least 80 mg per deciliter, and were receiving statin therapy at a high-intensity dose or at the maximum tolerated dose. Patients were randomly assigned to receive alirocumab subcutaneously at a dose of 75 mg (9462 patients) or matching placebo (9462 patients) every 2 weeks. The dose of alirocumab was adjusted under blinded conditions to target an LDL cholesterol level of 25 to 50 mg per deciliter (0.6 to 1.3 mmol per liter). The primary end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. RESULTS: The median duration of follow-up was 2.8 years. A composite primary end point event occurred in 903 patients (9.5%) in the alirocumab group and in 1052 patients (11.1%) in the placebo group (hazard ratio, 0.85; 95% confidence interval [CI], 0.78 to 0.93; P<0.001). A total of 334 patients (3.5%) in the alirocumab group and 392 patients (4.1%) in the placebo group died (hazard ratio, 0.85; 95% CI, 0.73 to 0.98). The absolute benefit of alirocumab with respect to the composite primary end point was greater among patients who had a baseline LDL cholesterol level of 100 mg or more per deciliter than among patients who had a lower baseline level. The incidence of adverse events was similar in the two groups, with the exception of local injection-site reactions (3.8% in the alirocumab group vs. 2.1% in the placebo group). CONCLUSIONS: Among patients who had a previous acute coronary syndrome and who were receiving high-intensity statin therapy, the risk of recurrent ischemic cardiovascular events was lower among those who received alirocumab than among those who received placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY OUTCOMES ClinicalTrials.gov number, NCT01663402 .). PMID- 30403641 TI - Seeing All From a Few: l1-Norm-Induced Discriminative Prototype Selection. AB - Prototype selection aims to remove redundancy and irrelevance from large-scale data by selecting an informative subset, which makes it possible to see all data from a few prototypes. However, due to the outliers and uncertain distribution of the data, the selected prototypes are generally less representative and diversified. To alleviate this issue, we develop, in this paper, a l1-norm induced discriminative prototype selection model (l1-ProSe). Inspired by the good performance of sparse representation, the sparsity property of data is rationally exploited in the formulated model. Meanwhile, to characterize the pairwise similarity in the learned sparse representation space, a more promising l1-norm metric is applied for robust selection instead of the popularly used Euclidean metric in previous works. Considering the convexity of the model to be solved, a composite block coordinate descent solver is presented with rigorous theoretical analysis on its convergence. Furthermore, we extend our model to support online prototype selection by using already obtained prototypes and newly arrived data. Experimental results on synthetic data sets and some applications such as video summarization, motion segmentation, and scene categorization demonstrate that the proposed method is considerably superior to the state-of-the-art methods in the prototype selection. PMID- 30403642 TI - Toward Resolution-Invariant Person Reidentification via Projective Dictionary Learning. AB - Person reidentification (ReID) has recently been widely investigated for its vital role in surveillance and forensics applications. This paper addresses the low-resolution (LR) person ReID problem, which is of great practical meaning because pedestrians are often captured in LRs by surveillance cameras. Existing methods cope with this problem via some complicated and time-consuming strategies, making them less favorable, in practice, and meanwhile, their performances are far from satisfactory. Instead, we solve this problem by developing a discriminative semicoupled projective dictionary learning (DSPDL) model, which adopts the efficient projective dictionary learning strategy, and jointly learns a pair of dictionaries and a mapping function to model the correspondence of the cross-view data. A parameterless cross-view graph regularizer incorporating both positive and negative pair information is designed to enhance the discriminability of the dictionaries. Another weakness of existing approaches to this problem is that they are only applicable for the scenario where the cross-camera image sets have a globally uniform resolution gap. This fact undermines their practicality because the resolution gaps between cross camera images often vary person by person in practice. To overcome this hurdle, we extend the proposed DSPDL model to the variational resolution gap scenario, basically by learning multiple pairs of dictionaries and multiple mapping functions. A novel technique is proposed to rerank and fuse the results obtained from all dictionary pairs. Experiments on five public data sets show the proposed method achieves superior performances to the state-of-the-art ones. PMID- 30403644 TI - Exploring Joint AB-LSTM with embedded lemmas for Adverse Drug Reaction discovery. AB - This work focuses on the detection of Adverse Drug Reactions (ADRs) in Electronic Health Records (EHRs) written in Spanish. The World Health Organization underlines the importance of reporting ADRs for patients' safety. The fact is that ADRs tend to be under-reported in daily hospital praxis. In this context, automatic solutions based on text mining can help to alleviate the workload of experts. Nevertheless, these solutions pose two challenges: 1) EHRs show high lexical variability, the characterization of the events must be able to deal with unseen words or contexts and 2) ADRs are rare events, hence, the system should be robust against skewed class distribution. To tackle these challenges deep neural networks seem appropriate because they allow a high-level representation. Specifically, we opted for a Joint AB-LSTM network, a sub-class of the Bidirectional Long Short-Term Memory network. Besides, in an attempt to reinforce lexical variability we proposed the use of embeddings created using lemmas. We compared this approach with supervised event extraction approaches based on either symbolic or dense representations. Experimental results showed that the Joint AB-LSTM approach outperformed previous approaches, achieving an f-measure of 73.3. PMID- 30403643 TI - Neuroadaptive Fault-Tolerant Control of Quadrotor UAVs: A More Affordable Solution. AB - This paper investigates the position and attitude tracking control problem of a quadrotor unmanned aerial vehicle subject to modeling uncertainties and actuator failures. A comprehensive mathematical model reflecting the nonlinearity and state-space coupling of the dynamics as well as actuation faults and external disturbances is derived. By combining the radial basis function neural networks (NNs) with virtual parameter estimating algorithms, an indirect NN-based adaptive fault-tolerant control scheme is developed, which exhibits several attractive features as compared with most existing methods: 1) it is not only robust and adaptive to nonparametric uncertainties but also tolerant to unexpected actuation faults; 2) it ensures stable tracking without the need for precise information on system model; and 3) it only involves one lumped parameter adaptation, thus is structurally simpler and computationally less expensive, rendering the resultant scheme less demanding in programming and more affordable for onboard implementation. The effectiveness and benefits of the proposed method are confirmed via computer simulation. PMID- 30403645 TI - Outdoor Shadow Estimating Using Multiclass Geometric Decomposition Based on BLS. AB - Illumination is a significant component of an image, and illumination estimation of an outdoor scene from given images is still challenging yet it has wide applications. Most of the traditional illumination estimating methods require prior knowledge or fixed objects within the scene, which makes them often limited by the scene of a given image. We propose an optimization approach that integrates the multiclass cues of the image(s) [a main input image and optional auxiliary input image(s)]. First, Sun visibility is estimated by the efficient broad learning system. And then for the scene with visible Sun, we classify the information in the image by the proposed classification algorithm, which combines the geometric information and shadow information to make the most of the information. And we apply a respective algorithm for every class to estimate the illumination parameters. Finally, our approach integrates all of the estimating results by the Markov random field. We make full use of the cues in the given image instead of an extra requirement for the scene, and the qualitative results are presented and show that our approach outperformed other methods with similar conditions. PMID- 30403646 TI - Dual Encoding for Abstractive Text Summarization. AB - Recurrent neural network-based sequence-to-sequence attentional models have proven effective in abstractive text summarization. In this paper, we model abstractive text summarization using a dual encoding model. Different from the previous works only using a single encoder, the proposed method employs a dual encoder including the primary and the secondary encoders. Specifically, the primary encoder conducts coarse encoding in a regular way, while the secondary encoder models the importance of words and generates more fine encoding based on the input raw text and the previously generated output text summarization. The two level encodings are combined and fed into the decoder to generate more diverse summary that can decrease repetition phenomenon for long sequence generation. The experimental results on two challenging datasets (i.e., CNN/DailyMail and DUC 2004) demonstrate that our dual encoding model performs against existing methods. PMID- 30403647 TI - Text Image Deblurring Using Kernel Sparsity Prior. AB - Previous methods on text image motion deblurring seldom consider the sparse characteristics of the blur kernel. This paper proposes a new text image motion deblurring method by exploiting the sparse properties of both text image itself and kernel. It incorporates the L0-norm for regularizing the blur kernel in the deblurring model, besides the L0 sparse priors for the text image and its gradient. Such a L0-norm-based model is efficiently optimized by half-quadratic splitting coupled with the fast conjugate descent method. To further improve the quality of the recovered kernel, a structure-preserving kernel denoising method is also developed to filter out the noisy pixels, yielding a clean kernel curve. Experimental results show the superiority of the proposed method. The source code and results are available at: https://github.com/shenjianbing/text-image-deblur. PMID- 30403648 TI - hPSD: A Hybrid PU-Learning-Based Spammer Detection Model for Product Reviews. AB - Spammers, who manipulate online reviews to promote or suppress products, are flooding in online commerce. To combat this trend, there has been a great deal of research focused on detecting review spammers, most of which design diversified features and thus develop various classifiers. The widespread growth of crowdsourcing platforms has created large-scale deceptive review writers who behave more like normal users, that the way they can more easily evade detection by the classifiers that are purely based on fixed characteristics. In this paper, we propose a hybrid semisupervised learning model titled hybrid PU-learning-based spammer detection (hPSD) for spammer detection to leverage both the users' characteristics and the user-product relations. Specifically, the hPSD model can iteratively detect multitype spammers by injecting different positive samples, and allows the construction of classifiers in a semisupervised hybrid learning framework. Comprehensive experiments on movie dataset with shilling injection confirm the superior performance of hPSD over existing baseline methods. The hPSD is then utilized to detect the hidden spammers from real-life Amazon data. A set of spammers and their underlying employers (e.g., book publishers) are successfully discovered and validated. These demonstrate that hPSD meets the real world application scenarios and can thus effectively detect the potentially deceptive review writers. PMID- 30403649 TI - Stimulation of melanin synthesis in melanoma cells by cold plasma. AB - Skin color is derived from epidermal melanocytes that contain specialized organelles in which melanin is formed. The formation of melanin is a well orchestrated process, and reactive oxygen species (ROS) play a role in numerous enzymatic conversions, such as the reactions catalyzed by tyrosinase and tyrosine hydroxylase. Currently, there is ample evidence that cold plasma exerts biological effects on cells through the impact of ROS and reactive nitrogen species (RNS). Modulation of melanin biosynthesis by cold plasma has not yet been investigated. This study investigated melanin biosynthesis of human melanoma cell lines with different endogenous melanin contents (SK-Mel 28, G-361, FM-55-P and MNT-1) in response to cold plasma-derived reactive species. Initially, the distribution of melanosomes, via immunofluorescence, and the influence of microphthalmia-associated transcription factor (MiTF), as a key transcription factor, was investigated. In our experimental setup, all of the tested cell lines had an elevated melanin content after exposure to cold plasma. These promising results suggest a novel potential application of cold plasma for the regulation of melanogenesis and may be a useful tool for influencing skin color in the future. PMID- 30403651 TI - Rational design of an improved photo-activatable intein for the production of head-to-tail cyclized peptides. AB - Head-to-tail cyclization of genetically encoded peptides and proteins can be achieved with the split intein circular ligation of peptides and proteins (SICLOPPS) method by inserting the desired polypeptide between the C- and N terminal fragments of a split intein. To prevent the intramolecular protein splicing reaction from spontaneously occurring upon folding of the intein domain, we have previously rendered this process light-dependent in a photo-controllable variant of the M86 intein, using genetically encoded ortho-nitrobenzyltyrosine at a structurally important position. Here, we report improvements on this photo intein with regard to expression yields and rate of cyclic peptide formation. The temporally defined photo-activation of the purified stable intein precursor enabled a kinetic analysis that identified the final resolution of the branched intermediate as the rate-determining individual reaction of the three steps catalyzed by the intein. With this knowledge, we prepared an R143H mutant with a block F histidine residue. This histidine is conserved in most inteins and helps catalyze the third step of succinimide formation. The engineered intein formed the cyclic peptide product up to 3-fold faster within the first 15 min after irradiation, underlining the potential of protein splicing pathway engineering. The broader utility of the intein was also shown by formation of the 14-mer sunflower trypsin inhibitor 1. PMID- 30403652 TI - Highlight Issue: Plasma Medicine. PMID- 30403650 TI - Chemistry and biochemistry of cold physical plasma derived reactive species in liquids. AB - Reactive oxygen and nitrogen species deposited by cold physical plasma are proposed as predominant effectors in the interaction between discharge and biomedical application. Most reactive species found in plasma sources are known in biology for inter- and intracellular communication (redox signaling) and mammalian cells are equipped to interpret the plasma derived redox signal. As such, considerable effort has been put into the investigation of potential clinical applications and the underlying mechanism, with a special emphasis on conditions orchestrated significantly via redox signaling. Among these, immune system control in wound healing and cancer control stands out with promising in vitro and in vivo effects. From the fundamental point of view, further insight in the interaction of the plasma-derived species with biological systems is desired to (a) optimize treatment conditions, (b) identify new fields of application, (c) to improve plasma source design, and (d) to identify the trajectories of reactive species. Knowledge on the biochemical reactivity of non-thermal plasmas is compiled and discussed. While there is considerable knowledge on proteins, lipids and carbohydrates have not received the attention deserved. Nucleic acids have been profoundly investigated yet focusing on molecule functionality rather than chemistry. The data collected underline the efforts taken to understand the fundamentals of plasma medicine but also indicate 'no man's lands' waiting to be discovered. PMID- 30403653 TI - Clinical Reasoning: A State of the Science Report. AB - Clinical reasoning is the cognitive process that nurses use to gather and incorporate information into a larger bank of personal knowledge. This incorporated information guides therapeutic actions, and helps determine client care. Since the process guides therapeutic actions regarding client care, failure to use the process effectively leads to poor clinical decision-making, inappropriate actions, or inaction. Because of the criticality of this process, this paper presents an analysis of the literature that reveals the current state of the science of clinical reasoning, identifies gaps in knowledge, and elucidates areas for future research. A systematic review of the databases the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Educational Resources Information Center (ERIC), PsychInfo, the Education Full Text (H.W. Wilson), and PubMed revealed 873 articles on the topic of clinical reasoning. Quality appraisal narrowed the field to 27 pieces of literature. Appendix A gives the State of the Science Coding Sheet used to identify the selections used in this research. Appendix B contains a summary of this literature. Although analysis of this literature shows that three theories exist on how to utilize most effectively the clinical reasoning process presently; a clear consistent definition is lacking. Additional research should focus on closing gaps that exist in defining the process, understanding the process, establishing linkages to non-clinical reasoning processes, and developing measures to both develop and accurately measure clinical reasoning. PMID- 30403654 TI - Is Rajyoga helpful in maintaining patient's biochemical and hematological profile during breast cancer treatment? AB - The present study is the case of a breast cancer patient who visited the local unit of the Brahma Kumaris (BK). Conversations with the patient revealed that the patient was being treated in the Post Graduate Institute of Medical Education and Research, Chandigarh, India. The treatment of the patient included the surgery, radiotherapy, and chemotherapy. The patient narrated her ability to manage the psychological stress associated with the cancer treatment. She ascribed it to the positive attitude developed by her practice of the Rajyoga meditation from last 15 years. Rajyoga involved the daily meditation and regular listening to the specified commentary recommended by BK. Patient's health remains stable during the whole treatment process as analyzed by the mammography, histopathology and PET scan. The patient was also able to maintain the total body weight, biochemical and hematological profile within normal physiological range. The present case study is an attempt to provide Rajyoga as supportive means to the maintenance of patient's biochemical and hematological profile, and overall general health during breast cancer treatment. PMID- 30403655 TI - FSH inhibits AMH to support ovarian estradiol synthesis in infantile mice. AB - Anti-Mullerian hormone (AMH) regulates ovarian function in cyclic females, notably by preventing premature FSH-mediated follicular growth and steroidogenesis. Its expression in growing follicles is controlled by FSH and by estradiol (E2). In infantile females, there is a transient increase in the activity of the gonadotrope axis, as reflected by elevated levels of both gonadotropins and E2. We previously demonstrated in mice that elevated FSH concentrations are necessary to induce E2 production by preantral/early antral follicles through the stimulation of aromatase expression without supporting their growth. However, whether this action of FSH could involve AMH is unknown. Here, we show that Amh mRNA and protein abundance and serum AMH levels are elevated in infantile mouse females, as compared with those in adults. By experimentally manipulating FSH and E2 levels in infantile mice, we demonstrate that high FSH concentrations lower Amh expression specifically in preantral/early antral follicles, whereas E2 has no effect. Importantly, treatment of infantile ovaries in organotypic cultures with AMH decreases FSH-mediated expression of Cyp19a1 aromatase but it does not alter the expression of cyclin D2 mediating granulosa cell proliferation. Overall, our data indicate that the infantile elevation in FSH levels suppresses Amh expression in preantral/early antral follicles, thereby favoring Cyp19a1 aromatase expression and E2 production. Together with recent discoveries that AMH can act on both the hypothalamus and the pituitary to increase gonadotropin levels, this work suggests that AMH is a critical regulator of the gonadotrope axis during the infantile period, thereby contributing to adult reproductive function programming. PMID- 30403656 TI - Androgen excess in breast cancer development: implications for prevention and treatment. AB - The aim of this review is to highlight the pivotal role of androgen excess in the development of breast cancer. Available evidence suggests that testosterone controls breast epithelial growth through a balanced interaction between its two active metabolites: cell proliferation is promoted by estradiol while it is inhibited by dihydrotestosterone. A chronic overproduction of testosterone (e.g. ovarian stromal hyperplasia) results in an increased estrogen production and cell proliferation that are no longer counterbalanced by dihydrotestosterone. This shift in the androgen/estrogen balance partakes in the genesis of ER-positive tumors. The mammary gland is a modified apocrine gland, a fact rarely considered in breast cancerogenesis. When stimulated by androgens, apocrine cells synthesize Epidermal Growth Factor (EGF) and EGF-related peptides that trigger the ErbB family receptors. These include the EGF receptor and the Human Epithelial Growth Factor 2, both well known for stimulating cellular proliferation. As a result, an excessive production of androgens is capable of directly stimulating growth in apocrine and apocrine-like tumors, a subset of ER-negative/AR-positive tumors. The key role of androgen excess in the genesis of different subtypes of breast cancer has significant clinical implications for both treatment and prevention. Our belief stems from a thorough analysis of the literature, where an abundance of evidence is present to justify a clinical trial that would investigate the effectiveness of treating the underlying excessive androgen production. PMID- 30403657 TI - Profiling analysis of long non-coding RNA and mRNA in parathyroid carcinoma. AB - Parathyroid carcinoma (PCa) is a rare endocrine neoplasia that typically has unfavourable outcomes. The contribution of long non-coding RNAs (lncRNAs) to the development of malignant and benign parathyroid tumours remains largely unknown. In this study, we explored transcriptomic profiling of lncRNA and mRNA expression in 6 PCa, 6 parathyroid adenoma (PAd) and 4 normal parathyroid (PaN) tissues. In total, 2641 lncRNA transcripts and 2165 mRNA transcripts were differentially expressed between PCa and PAd. Enrichment analysis demonstrated that dysregulated transcripts were involved mainly in the extracellular matrix (ECM)-receptor interaction and energy metabolism pathways. Bioinformatics analysis suggested that ATF3, ID1, FOXM1, EZH2 and MITF may be crucial to parathyroid carcinogenesis. Series test of cluster analysis segregated differentially expressed lncRNAs and mRNAs into several expression profile models, among which the "plateau" profile representing components specific to parathyroid carcinogenesis was selected to build a co-expression network. Seven lncRNAs and three mRNAs were selected for quantitative RT-PCR validation in 16 PCa, 41 PAd and 4 PaN samples. Receiver operator characteristic curves analysis showed that lncRNA PVT1 and GLIS2-AS1 yielded the area under the curve values of 0.871 and 0.860, respectively. Higher hybridization signals were observed in PCa for PVT1 and PAd for GLIS2-AS1. In conclusion, the current evidence indicates that PAd and PCa partially share common signalling molecules and pathways, but have independent transcriptional events. Differentially expressed lncRNAs and mRNAs have intricate interactions and are involved in parathyroid tumourigenesis. The lncRNA PVT1 and GLIS2-AS1 may be new potential markers for the diagnosis of PCa. PMID- 30403658 TI - Correlation of Expression Levels of Micro Ribonucleic Ccid-10b (miR-10b) and Micro Ribonucleic Acid-181b (miR-181b) with Gastric Cancer and Its Diagnostic Significance. AB - BACKGROUND The aim of this study was to explore the expression levels of micro ribonucleic acid-10b (miR-10b) and micro ribonucleic acid-181b (miR-181b) in gastric cancer tissues, as well as their application value in clinical diagnosis and treatment. MATERIAL AND METHODS A total of 120 patients with gastric cancer who were diagnosed and treated in the Department of Gastroenterology of our hospital were enrolled in this study. The gastric cancer tissues and paracancerous tissues were collected for measuring the expression of miR-10b and miR-181b by in situ hybridization and reverse transcription-polymerase chain reaction (RT-PCR). The 5-year survival rate was also analyzed. RESULTS The expressions of miR-10b and miR-181b in gastric cancer tissues were both upregulated and were significantly higher than those in the paracancerous tissues (p<0.05). In addition, the expressions of miR-10b and miR-181b in gastric cancer tissues were correlated with tumor size, degree of pathological differentiation, depth of infiltration, tumor node metastasis (TNM) staging, and lymph node metastasis, as well as local lymph node and distant metastasis (p<0.05). For patients in stage II and III, the expressions of miR-10b and miR-181b were significantly correlated with the 5-year survival rate. CONCLUSIONS The high expressions of miR-10b and miR-181b are significantly correlated with poor prognosis in stage II and III patients with gastric cancer, suggesting that their expressions might be criteria for evaluating the prognosis of gastric cancer. PMID- 30403659 TI - EBP1: A crucial growth regulator downstream of receptor kinases across kingdoms. AB - Controlling organ growth and development is crucial for all multicellular organisms and is controlled by plasma membrane localized receptor kinases (RKs) across kingdoms, including animals and plants. A central RK in plants is FERONIA (FER), which perceives endogenous rapid alkalinization factor (RALF) peptides to regulate a plethora of biological responses, including growth and development. However, it remained largely unknown how RALF sensing by FER at the plasma membrane is translated into a nuclear response. A key step forward is presented by Li and colleagues, who show that FER increases ERBB3 binding protein 1 (EBP1) mRNA translation and directly phosphorylates EBP1 to shift its subcellular localization from the cytoplasm to the nucleus where it controls growth and development through its regulation of transcription. Importantly, EBP1 is described as a transcriptional and translational regulator in mammals by acting downstream of epidermal growth factor receptor (EGFR) signaling, suggesting that animals and plants use similar conserved pathways to fine-tune growth and development. Furthermore, this work highlights the importance of protein translation as a direct output of RK signaling, a mechanism that is largely unknown in plants. PMID- 30403661 TI - Ecological patterns in anchialine caves. AB - Anchialine caves are characterized by high levels of endemism and extreme conditions. However, few ecological studies have been conducted in these ecosystems. This study integrates biotic and abiotic parameters of two sets of cave systems with contrasting high and low species richness. Seven ecological patterns are used to explain the expected species richness and density in an anchialine cave. In addition, the population size for conspicuous macrofauna was estimated. The high impact that single-events have on anchialine fauna are also reported. These findings reinforce the conclusions of previous studies of the high extinction risk of anchialine cave fauna, and substantiate the necessity of ad hoc conservation strategies for anchialine caves. PMID- 30403662 TI - From incubation to release: Hand-rearing as a tool for the conservation of the endangered African penguin. AB - The African penguin (Spheniscus demersus) population is estimated at 25,000 breeding pairs, approximately 5% of that at the start of the 20th century, and the species is currently classified as Endangered. In the last two decades, the hand-rearing of penguin chicks that were abandoned by their parents due to oil spills or other circumstances has become a valuable conservation tool to limit mortality and to bolster the population at specific colonies. We summarize and evaluate the techniques employed by the Southern African Foundation for the Conservation of Coastal Birds (SANCCOB) to incubate and hand-rear African penguin eggs and chicks. From 2012 to 2016, a total of 694 eggs and 2819 chicks were received by SANCCOB's Chick Rearing Unit. It was estimated that 13% of the eggs were infertile, and 81% of the fertile eggs hatched successfully. The overall release rate for chicks was 77%, with a higher release rate for chicks that were pre-emptively removed (93%) followed by chicks that had been abandoned by their parents (78%), chicks admitted due to avian pox lesions (61%), chicks that hatched from artificially-incubated eggs (57%), and chicks admitted due to injuries or deformities (25%). Rescuing and hand-rearing eggs and chicks has been a successful strategy for African penguins, and might be also applicable for the conservation of other threatened seabird species whose population are critically low or during natural or anthropogenic events that could have disastrous population impacts (e.g. oil spills, disease outbreaks, catastrophic weather events, strong El Nino years, etc.). PMID- 30403660 TI - Genome-wide CRISPR-dCas9 screens in E. coli identify essential genes and phage host factors. AB - High-throughput genetic screens are powerful methods to identify genes linked to a given phenotype. The catalytic null mutant of the Cas9 RNA-guided nuclease (dCas9) can be conveniently used to silence genes of interest in a method also known as CRISPRi. Here, we report a genome-wide CRISPR-dCas9 screen using a starting pool of ~ 92,000 sgRNAs which target random positions in the chromosome of E. coli. To benchmark our method, we first investigate its utility to predict gene essentiality in the genome of E. coli during growth in rich medium. We could identify 79% of the genes previously reported as essential and demonstrate the non-essentiality of some genes annotated as essential. In addition, we took advantage of the intermediate repression levels obtained when targeting the template strand of genes to show that cells are very sensitive to the expression level of a limited set of essential genes. Our data can be visualized on CRISPRbrowser, a custom web interface available at crispr.pasteur.fr. We then apply the screen to discover E. coli genes required by phages lambda, T4 and 186 to kill their host, highlighting the involvement of diverse host pathways in the infection process of the three tested phages. We also identify colanic acid capsule synthesis as a shared resistance mechanism to all three phages. Finally, using a plasmid packaging system and a transduction assay, we identify genes required for the formation of functional lambda capsids, thus covering the entire phage cycle. This study demonstrates the usefulness and convenience of pooled genome-wide CRISPR-dCas9 screens in bacteria and paves the way for their broader use as a powerful tool in bacterial genomics. PMID- 30403663 TI - Evidence that regulation of intramembrane proteolysis is mediated by substrate gating during sporulation in Bacillus subtilis. AB - During the morphological process of sporulation in Bacillus subtilis two adjacent daughter cells (called the mother cell and forespore) follow different programs of gene expression that are linked to each other by signal transduction pathways. At a late stage in development, a signaling pathway emanating from the forespore triggers the proteolytic activation of the mother cell transcription factor sigmaK. Cleavage of pro-sigmaK to its mature and active form is catalyzed by the intramembrane cleaving metalloprotease SpoIVFB (B), a Site-2 Protease (S2P) family member. B is held inactive by two mother-cell membrane proteins SpoIVFA (A) and BofA. Activation of pro-sigmaK processing requires a site-1 signaling protease SpoIVB (IVB) that is secreted from the forespore into the space between the two cells. IVB cleaves the extracellular domain of A but how this cleavage activates intramembrane proteolysis has remained unclear. Structural studies of the Methanocaldococcus jannaschii S2P homolog identified closed (substrate occluded) and open (substrate-accessible) conformations of the protease, but the biological relevance of these conformations has not been established. Here, using co-immunoprecipitation and fluorescence microscopy, we show that stable association between the membrane-embedded protease and its substrate requires IVB signaling. We further show that the cytoplasmic cystathionine-beta-synthase (CBS) domain of the B protease is not critical for this interaction or for pro-sigmaK processing, suggesting the IVB-dependent interaction site is in the membrane protease domain. Finally, we provide evidence that the B protease domain adopts both open and closed conformations in vivo. Collectively, our data support a substrate-gating model in which IVB-dependent cleavage of A on one side of the membrane triggers a conformational change in the membrane-embedded protease from a closed to an open state allowing pro-sigmaK access to the caged interior of the protease. PMID- 30403665 TI - Anopheles mosquitoes may drive invasion and transmission of Mayaro virus across geographically diverse regions. AB - The Togavirus (Alphavirus) Mayaro virus (MAYV) was initially described in 1954 from Mayaro County (Trinidad) and has been responsible for outbreaks in South America and the Caribbean. Imported MAYV cases are on the rise, leading to invasion concerns similar to Chikungunya and Zika viruses. Little is known about the range of mosquito species that are competent MAYV vectors. We tested vector competence of 2 MAYV genotypes in laboratory strains of six mosquito species (Aedes aegypti, Anopheles freeborni, An. gambiae, An. quadrimaculatus, An. stephensi, Culex quinquefasciatus). Ae. aegypti and Cx. quinquefasciatus were poor MAYV vectors, and had either poor or null infection and transmission rates at the tested viral challenge titers. In contrast, all Anopheles species were able to transmit MAYV, and 3 of the 4 species transmitted both genotypes. The Anopheles species tested are divergent and native to widely separated geographic regions (Africa, Asia, North America), suggesting that Anopheles may be important in the invasion and spread of MAYV across diverse regions of the world. PMID- 30403666 TI - Psychometric validation of the Young Parenting Inventory - Revised (YPI-R2): Replication and Extension of a commonly used parenting scale in Schema Therapy (ST) research and practice. AB - This study aimed at developing a revised validated version of the Young Parenting Inventory (YPI) known as YPI-R2 that had 17 theoretical subscales. Using separate ratings for fathers and mothers samples from Singapore (n = 582, 617), Manila (n = 520, 538), Jakarta (n = 366, 383), and the USA (n = 204, 214), exploratory and confirmatory factor analysis (CFA) were conducted. This resulted in five subscales for fathers and six for mothers. The 17 theoretical subscales were not supported. Construct, convergent, and divergent validity of this new revised alternative YPI-R2 were also demonstrated. The stringent incremental validity test showed that the YPI-R2 accounted for additional statistically significant variance over and above that contributed by gender and three other established parenting instruments in predicting clinically relevant outcomes. Partial invariance of its factor structure was demonstrated through multigroup CFA using Eastern and Western samples. Finally, significant correlations with the 18 Early Maladaptive Schemas (EMSs) supported a central tenet of schema therapy that these are associated with early negative parenting patterns. Parenting norms in both Eastern and Western cultures that were associated with ill-being were also discussed thus showing the cross-cultural relevance of the YPI-R2. PMID- 30403664 TI - Comparison of clinical symptoms, gastric motility and fat intake in the early chronic pancreatitis patients with anti-acid therapy-resistant functional dyspepsia patients. AB - BACKGROUND: There was no available data concerning the clinical differentiation between the updated definition of early chronic pancreatitis (ECP) and anti-acid therapy-resistant functional dyspepsia (RFD). AIMS: We aimed to determine whether clinical symptoms, gastric motility, psychogenic factors and fat intake can help distinguish early chronic pancreatitis (ECP) from anti-acid therapy-resistant functional dyspepsia patients with pancreatic enzyme abnormalities (RFD-P) and anti-acid therapy-resistant functional dyspepsia (RFD) patients using endosonography. METHODS: We enrolled 102 consecutive patients presenting with typical symptoms of RFD patients (n = 52), ECP patients (n = 25) and RFD-P patients (n = 25). ECP patients were diagnosed based on the criteria recommended by the Japan Pancreatic Association. Gastric motility was evaluated by 13C acetate breath tests. Severity of duodenal inflammation was examined. RESULTS: 24.5% of RFD patients were determined as ECP using endosonography. Abdominal pain score in Gastrointestinal Symptom Rating Scale (GSRS) in the patients with ECP was significantly lower compared to that in the patients with RFD-P. There were no significant differences in State-Trait Inventory (STAI)-state/-trait scores, Self-Rating Questionnaire for Depression (SRQ-D) scores and clinical symptoms for fat intake among three groups. The early phase of gastric emptying (AUC5; AUC15) in ECP and RFD-P patients were significantly disturbed compared to those in RFD patients. CONCLUSIONS: Evaluation of severity of abdominal pain and measurement of the early phase of gastric emptying will be useful tools to distinguish ECP patients from RFD patients. Accurate diagnosis of ECP patients may contribute to the prevention from advancing of chronic pancreatitis. PMID- 30403667 TI - Pink shrimp Farfantepenaeus duorarum spatiotemporal abundance trends along an urban, subtropical shoreline slated for restoration. AB - The Biscayne Bay Coastal Wetlands (BBCW) project of the Comprehensive Everglades Restoration Plan (CERP) aims to reduce point-source freshwater discharges and spread freshwater flow along the mainland shoreline of southern Biscayne Bay. These actions will be taken to approximate conditions in the coastal wetlands and bay that existed prior to construction of canals and water control structures. An increase in pink shrimp (Farfantepenaeus duorarum) density to >= 2 individuals m 2 during the wet season (i.e., August-October) along the mainland shoreline was previously proposed as an indication of BBCW success. This study examined pre BBCW baseline densities and compared them with the proposed target. Densities were monitored by seasonal (wet, dry) throw-trapping (1 m2 replicated in triplicate) at 47 sites along ~22 km of the southwestern Biscayne Bay coastline over 10 years (2007-2016). Densities varied across years and were most often higher in dry seasons. Quantile regression revealed density limitation by four habitat attributes: water temperature ( degrees C), depth (m), salinity (ppt), and submerged aquatic vegetation (SAV: % cover). Procrustean analyses that tested for concordance between the spatial and temporal distributions of shrimp densities and habitat metrics found that water temperature, water depth, and salinity explained ~ 28%, 28%, and 22% of density variability, respectively. No significant relationship with SAV was observed. Hierarchical clustering was used to identify spatially and temporally similar groupings of pink shrimp densities by sites or season-years. Significant groupings were then investigated with respect to potentially limiting habitat attributes. Six site and four year-season clusters were identified. Although habitat attributes significantly differed among spatial clusters, within-cluster median pink shrimp densities did not correlate with within-cluster minima, maxima, medians, or standard deviations of habitat attributes. Overall, pink shrimp density ([Formula: see text] = 0.86, SD = 1.32 shrimp m-2) was significantly lower (t(alpha = 0.10,2),939 = -26.53, P <0.0001) than the 2 shrimp m-2 CERP Interim Goal target. Pink shrimp density corresponded significantly with salinity and appeared limited to density < 2 shrimp m-2 by salinity < ~18 ppt. Salinity is an environmental attribute that will be directly influenced by CERP implementation. PMID- 30403668 TI - Evaluating patients', physicians' and pharmacy professionals' perception and concern regarding generic medicines in Gondar town, northwest Ethiopia: A multi stakeholder, cross-sectional survey. AB - BACKGROUND: Generic medicine prescribing has become common practice in many countries. However, data regarding the perceptions of stakeholders (patients, prescribers and dispensers) regarding generic medicines in Ethiopia is scarce. The present survey aimed to investigate the perception of patients, physicians and pharmacy professionals regarding generic medicines in Ethiopia. METHODS: A quantitative cross-sectional survey was conducted in Gondar town, Northwest Ethiopia between January 1 and February 1, 2017. The questionnaire, comprised of 5-point Likert scale items on perception and concerns regarding generic medicine, was administered to patients, physicians and pharmacy professionals working in the community drug retail outlets. Frequencies, percentages, and median were calculated using Statistical Package for the Social Sciences (SPSS) software version 21.0 for Windows to describe different variables. RESULTS: The survey was completed by 612 participants. More than half of patients, 56% (n = 219) knew about the term brand and generic medicines and 38.7% (n = 151) of patients agreed/strongly agreed that brand medicines are more effective. Nearly half, 47% (n = 184) of patients agreed that they should have the option of choosing between generic and brand medicines and 61.4% (n = 240) of patients believed that cost should be considered before a medicineis prescribed. The majority of physicians 70.6% (n = 101) indicated a very low generic medicine prescription rate. 56% (n = 130) of physicians and 87.2% (n = 68) of pharmacy professionals agreed that they need a standard guideline to both prescribers and pharmacists on brand substitution process. Furthermore, 39.9% (n = 57) of the physicians and 87.2% (n = 68) of pharmacy professionals agreed that drug advertisements by the manufacturers would influence their prescribing/dispensing practice. CONCLUSIONS: Overall, our findings demonstrate a knowledge gap among patients towards the perception of generics, perceiving generics are less effective and inferior in quality compared to their branded equivalents. The majority of physicians reported a very low generic medicine prescribing rate and the majority pharmacy professionals' dispensing practice was influenced by drug advertisements. Hence, a customized educational program should be developed and implemented to patients, prescribers and dispensers so as to boost the acceptability of generic medicines and increase generic prescribing and/or substitution. PMID- 30403669 TI - Menopausal Hormone Therapy use and breast cancer risk by receptor subtypes: Results from the New South Wales Cancer Lifestyle and EvaluAtion of Risk (CLEAR) study. AB - Breast cancer risk is increased with current Menopausal Hormone Therapy (MHT) use, with higher risks reported for ER+ (Estrogen Receptor positive), and ER+/PR+ (Estrogen and Progesterone Receptor positive) breast cancers than those of ER- and ER-/PR- status, respectively. There is limited evidence to suggest MHT use is associated with the specific subtype characterised as ER+/PR+/HER2- (Estrogen and Progesterone Receptor positive and Human Epidermal growth factor Receptor2 negative) status. This study aims to investigate the MHT-breast cancer relationship for breast cancer tumor receptor subtypes defined by ER expression alone, by ER and PR expression only and by joint expression of ER, PR, and HER2. Analyses compared 399 cancer registry-verified breast cancer cases with receptor status information and 324 cancer-free controls. We used multinomial logistic regression to estimate adjusted odds ratios (aORs) and 95% Confidence Intervals (CI) for current and past versus never MHT use, for subgroups defined by tumor receptor expression. Current, but not past, use of MHT was associated with an elevated risk of ER+ breast cancer (aOR = 2.04, 95%CI: 1.28-3.24) and ER+/PR+ breast cancer (aOR = 2.29, 1.41-3.72). Current MHT use was also associated with an elevated risk of the ER+/PR+/HER2- subtype (aOR = 2.30, 1.42-3.73). None of the other subtypes based on ER, ER/PR or ER/PR/HER2 expression were significantly associated with current MHT use in this analysis. Current, but not past, use of MHT increases the risk of breast cancer, with consistently higher risks reported for ER+ and ER+/PR+ subtypes and mounting evidence regarding the specific ER+/PR+/HER2- subtype. Our findings contribute to quantification of the effects of MHT, and support efforts to articulate the receptor-mediated mechanisms by which MHT increases the risk of breast cancer. PMID- 30403670 TI - Role of L-carnitine in protection against the cardiac oxidative stress induced by aspartame in Wistar albino rats. AB - Aspartame (ASP) has been used as an alternative to sucrose for diabetics and obese people worldwide. Co-administration of L-carnitine (LC) with ASP has a protective effect against the liver and kidney toxicity induced of ASP. The goal of the investigation was to assess the enhancement of LC effect on the cardiac toxicity caused of ASP. The rats were divided into 6 groups: control with saline, LC (10 mg/kg), ASP (75 mg/kg), ASP (150 mg/kg), LC with 75 mg/kg of ASP, and LC with 150 mg/kg ASP. The antioxidants were determined by measuring the activities of myeloperoxidase, xanthine oxidase, superoxide dismutase, catalase, and glutathione peroxidase, and by assessing the levels of lipid peroxidation, total thiols, and glutathione. There was a significant elevation in LPO, in conjunction with a significant decline in the enzymatic antioxidants superoxide dismutase, catalase, and glutathione peroxidase and the non-enzymatic antioxidants glutathione and thiols. The cardiac myofibrils were found in a disarrayed pattern in ASP treated-animals as compared to the control rats. The animals treated with ASP-HD showed more than one apoptotic cell with a large tail and a small head, and the relaxed loops of the damaged DNA were extended to form a comet-shaped structure. These effects may be due to the excessive generation of reactive oxygen species by ASP, which reduces cardiac function. Co-administration of LC with ASP improved all of the above-mentioned parameters that were disrupted of ASP alone. This study evidences a sufficient originality in showing how LC plays a positive role against cardiac toxicity of ASP. PMID- 30403671 TI - Bleeding, cramping, and satisfaction among new copper IUD users: A prospective study. AB - OBJECTIVE: We assess change in bleeding, cramping, and IUD satisfaction among new copper (Cu) IUD users during the first six months of use, and evaluate the impact of bleeding and cramping on method satisfaction. METHODS: We recruited 77 women ages 18-45 for this prospective longitudinal observational cohort study. Eligible women reported regular menses, had no exposure to hormonal contraception in the last three months, and desired a Cu IUD for contraception. We collected data prospectively for 180 days following IUD insertion. Monthly, participants reported bleeding scores using the validated pictorial blood loss assessment chart (PBAC), IUD satisfaction using a five-point Likert scale, and cramping using a six-level ordinal scale. We used multiple imputation to address nonrandom attrition. Structural equation models for count and ordered outcomes were used to model bleeding, cramping, and IUD satisfaction growth curves over the six monthly repeated assessments. RESULTS: Bleeding significantly decreased (approximately 23%) over the course of the study from an estimated PBAC = 195 at one month post insertion to PBAC = 151 at six months (t = -2.38, p<0.05). Additionally, IUD satisfaction improved over time (t = 2.65, p<0.01), increasing from between "Neutral" and "Satisfied" to "Satisfied" over the six month study. Cramping decreased notably over the six month study from between biweekly and weekly, to once or twice a month (t = -4.38, p<0.001). Finally, bleeding, but not cramping, was associated with IUD satisfaction across the study (t = -2.31, p<0.05) and at study end (t = -2.81, p<0.01). CONCLUSIONS: New Cu IUD users reported decreasing bleeding and cramping, and increasing IUD satisfaction, over the first six months. Method satisfaction was negatively associated with bleeding. PMID- 30403672 TI - Elucidating the active interaction mechanism of phytochemicals withanolide and withanoside derivatives with human serum albumin. AB - Withania somnifera (Ashwagandha) is an efficient medicinal plant known in Ayurveda and Chinese medicine since ancient times, whose extracts are consumed orally as food supplement or as a health tonic owing to its several restorative properties for various CNS disorders, inflammation, tumour, stress, rheumatism etc. In this study, we have analyzed the binding interaction of four derivatives of Withania somnifera (Withanolide A, Withanolide B, Withanoside IV and Withanoside V) with HSA because of their important pharmacological properties. To unravel the binding between derivatives of Withania somnifera and HSA, fluorescence spectroscopy was used. Binding studies were further studied by molecular docking and dynamics and results confirmed greater stability upon binding of derivatives with HSA. Circular dichroism data illustrated change in the secondary structure of protein upon interaction with these derivatives, particularly the helical structure was increased and beta-sheets and random coils were decreased. Furthermore, morphological and topological changes were observed using AFM and TEM upon binding of ligands with HSA indicating that HSA withnoside/withanolide complexes were formed. All the results cumulatively demonstrate strong binding of withanosides and withanolides derivatives with serum albumin, which should further be explored to study the pharmacokinetics and pharmacodynamics of these derivatives. PMID- 30403673 TI - Tool making cockatoos adjust the lengths but not the widths of their tools to function. AB - The ability to innovatively use or even manufacture different tools depending on a current situation can be silhouetted against examples of stereotyped, inborn tool use/manufacture and is thus often associated to advanced cognitive processing. In this study we confronted non-specialized, yet innovative tool making birds, Goffin's cockatoos (Cacatua goffiniana), with an apparatus featuring an out-of-reach food reward that could be placed at different distances from a tool opening. Alternatively, the food stayed at a constant distance but the tool opening in the front of the apparatus had different diameters. We used a novel material for tool manufacture (cardboard) that demanded an incrementally increased manufacturing effort from the actor, depending on the length of the tool required. We found that our subjects used two strategies to succeed in this tasks: either by making carboard-stripe tools using the full length of the material sheets originally offered or by adjusting the lengths of their tools to different goal distances. Subjects also discarded cardboard stripes that were too short to reach the goal prior to use and discarded longer pieces when the goal was further away than when it was close. Nevertheless, likely due to morphological constraints, the birds failed to adjust the widths of their tools depending on the diameter of the tool opening. PMID- 30403674 TI - Magnitude and correlates of intimate partner violence against female garment workers from selected factories in Bangladesh. AB - Intimate partner violence (IPV) is a huge public health, development and human rights issue worldwide. Despite the fact that working women in patriarchal contexts commonly report higher level of IPV, literature on this subject is still scanty. This paper assessed the magnitude of different types of IPV against female garment workers and identified its correlates using cross-sectional survey data collected during September-December, 2016 from 800 female garment workers randomly selected from lists provided by eight garment factories in and around Dhaka, Bangladesh. The results reveal high levels of IPV experienced by the workers (physical = 34%; sexual = 43%; economic = 35%, last 12 months). Logistic regression results were nuanced. While the worker's ability to mobilize resources in crises reduced IPV, her savings beyond a threshold increased its likelihood. Moreover, her ownership of jewellery/ large household assets increased the likelihood of IPV. Having moderately or highly controlling husband, substance abuse by husband and his involvement in extramarital sex predicted IPV. Although the worker's education up to 6 years or more was protective, education more than the husband increased the likelihood of IPV. Young age, having two or more children, experience of non-partner sexual violence and high acceptance of IPV increased the likelihood of IPV. Middle income group protected against IPV, while household food insecurity increased its likelihood. Work at a factory in the Export Processing Zone protected against IPV. The findings indicate that financial empowerment alone is not sufficient to protect the workers from IPV; interventions that combine gender empowerment training for workers in the context of better factory working conditions may be useful in reducing IPV; working with men is essential in this endeavour. PMID- 30403676 TI - Deep language space neural network for classifying mild cognitive impairment and Alzheimer-type dementia. AB - It has been quite a challenge to diagnose Mild Cognitive Impairment due to Alzheimer's disease (MCI) and Alzheimer-type dementia (AD-type dementia) using the currently available clinical diagnostic criteria and neuropsychological examinations. As such we propose an automated diagnostic technique using a variant of deep neural networks language models (DNNLM) on the verbal utterances of affected individuals. Motivated by the success of DNNLM on natural language tasks, we propose a combination of deep neural network and deep language models (D2NNLM) for classifying the disease. Results on the DementiaBank language transcript clinical dataset show that D2NNLM sufficiently learned several linguistic biomarkers in the form of higher order n-grams to distinguish the affected group from the healthy group with reasonable accuracy on very sparse clinical datasets. PMID- 30403675 TI - Association between leisure-time activities and school failure in adolescents: The 1993 Birth Cohort. AB - AIM: To evaluate the relationship between leisure-time activities at 11 years old and the incidence of school failures from 11 to 15 years in adolescents. METHODS: The sample comprised 4,090 adolescents from the 1993 Pelotas Birth Cohort, Brazil. The outcome was measured as the number of school failures from 11 to 15 years, based on reported information from cohort participants and their parents. The exposures were collected at 11 years old, as follows: reading; meeting friends; talking to parents; and dating. RESULTS: In the group from 11 to 15 years old, 53.3% failed at school at least once. Meeting friends 4-7 times/week (RR = 1.15) and dating 1-3 times/week (RR = 1.22) were associated with high risk for school failure. Reading showed an inverse relationship with school failures (1-3 times/week RR = 0.83; 4-7 times/week RR = 0.71). Reading at least once a week could prevent around 16% of school failures. CONCLUSION: The context in which adolescents are inserted plays a relevant role in school performance. Understanding these factors may help to propose actions to reduce school failure rates even further. PMID- 30403677 TI - Poetic speech melody: A crucial link between music and language. AB - Research on the music-language interface has extensively investigated similarities and differences of poetic and musical meter, but largely disregarded melody. Using a measure of melodic structure in music--autocorrelations of sound sequences consisting of discrete pitch and duration values--, we show that individual poems feature distinct and text-driven pitch and duration contours, just like songs and other pieces of music. We conceptualize these recurrent melodic contours as an additional, hitherto unnoticed dimension of parallelistic patterning. Poetic speech melodies are higher order units beyond the level of individual syntactic phrases, and also beyond the levels of individual sentences and verse lines. Importantly, auto-correlation scores for pitch and duration recurrences across stanzas are predictive of how melodious naive listeners perceive the respective poems to be, and how likely these poems were to be set to music by professional composers. Experimentally removing classical parallelistic features characteristic of prototypical poems (rhyme, meter, and others) led to decreased autocorrelation scores of pitches, independent of spoken renditions, along with reduced ratings for perceived melodiousness. This suggests that the higher order parallelistic feature of poetic melody strongly interacts with the other parallelistic patterns of poems. Our discovery of a genuine poetic speech melody has great potential for deepening the understanding of the music-language interface. PMID- 30403678 TI - Diversity of Ooencyrtus spp. (Hymenoptera: Encyrtidae) parasitizing the eggs of Stenozygum coloratum (Klug) (Hemiptera: Pentatomidae) with description of two new species. AB - Ooencyrtus spp. (Hymenoptera, Chalcidoidea, Encyrtidae) are important natural enemies of agricultural and forest insect pests, and are distributed worldwide. Their reduced dimensions, highly variable morphological characters and possible effect of wide host range and abiotic factors, make correct identification at the species level particularly difficult. This paper combined molecular, morphological, and biological data to characterize a group of Ooencyrtus spp. emerging from the eggs of the variegated caper bug, Stenozygum coloratum in the east Mediterranean area. COI and ITS2 sequencing revealed the presence of six and five divergent clades, respectively. Three clades were identified as Ooencyrtus telenomicida, Ooencyrtus pityocampae and O. pistaciae. Two clades represent new species which are here described and named Ooencyrtus zoeae and Ooencyrtus mevalbelus. These features were combined with reliable morphological characters to facilitate the separation of these species. A dichotomous key and a new synonymy are proposed. Ooencyrtus pistaciae had two distinct COI clades but only one ITS2 clade. Crossbreeding trials that included Ooencyrtus telenomicida, Ooencyrtus melvabelus sp. nov. and Ooencyrtus zoeae sp. nov. confirmed their reproductive isolation. COI sequences showed 0-0.8% and 4-9% within and between species genetic differences, respectively. ITS2 showed 0.4-5.9% genetic differences between species, with no genetic differences within species. Haplotype diversity of Israeli and Turkish populations of the various species was 0-0.98 and was particularly low in Ooencyrtus pityocampae, whose Israeli population showed no diversity. The discovery of the Ooencyrtus spp. on the eggs of the caper bug, and their abundance support the idea that the bug can be used as an alternative host for augmentation of populations of these parasitoids in agricultural and forestry systems. PMID- 30403680 TI - Cell colony counter called CoCoNut. AB - Clonogenic assays are powerful tools for testing cell reproductive death after biological damage caused by, for example, ionizing radiation. Traditionally, the methods require a cumbersome, slow and eye-straining manual counting of viable colonies under a microscope. To speed up the counting process and minimize those issues related to the subjective decisions of the scoring personnel, we developed a semi-automated, image-based cell colony counting setup, named CoCoNut (Colony Counter developed by the Nutech department at the Technical University of Denmark). It consists in an ImageJ macro and a photographic 3D-printed light-box, conceived and demonstrated to work together for Crystal Violet-stained colonies. Careful attention was given to the image acquisition process, which allows background removal (i.e. any unwanted element in the picture) in a minimally invasive manner. This is mainly achieved by optimal lighting conditions in the light-box and dividing the image of a flask that contains viable colonies by the picture of an empty flask. In this way, CoCoNut avoids using aggressive background removal filters that usually lead to suboptimal colony count recovery. The full method was tested with V79 and HeLa cell survival samples. Results were compared to other freely available tools. CoCoNut proved able to successfully distinguish between single and merged colonies and to identify colonies bordering on flask edges. CoCoNut software calibration is fast; it requires the adjustment of a single parameter that is the smallest colony area to be counted. The employment of a single parameter reduces the risk of subjectivity, providing a robust and user-friendly tool, whose results can be easily compared over time and among different bio-laboratories. The method is inexpensive and easy to obtain. Among its advantages, we highlight the possibility of combining the macro with a perfectly reproducible 3D-printed light-box. The CoCoNut software and the 3D printer files are provided as supporting information (S1 CoCoNut Files). PMID- 30403679 TI - Characterization of the endocannabinoid system in subcutaneous adipose tissue in periparturient dairy cows and its association to metabolic profiles. AB - Adipose tissue (AT) plays a major role in metabolic adaptations in postpartum (PP) dairy cows. The endocannabinoid (eCB) system is a key regulator of metabolism and energy homeostasis; however, information about this system in ruminants is scarce. Therefore, this work aimed to assess the eCB system in subcutaneous AT, and to determine its relation to the metabolic profile in peripartum cows. Biopsies of AT were performed at 14 d prepartum, and 4 and 30 d PP from 18 multiparous peripartum cows. Cows were categorized retrospectively according to those with high body weight (BW) loss (HWL, 8.5 +/- 1.7% BW loss) or low body weight loss (LWL, 2.9 +/- 2.5% BW loss) during the first month PP. The HWL had higher plasma non-esterified fatty acids and a lower insulin/glucagon ratio PP than did LWL. Two-fold elevated AT levels of the main eCBs, N arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), were found 4 d PP compared with prepartum in HWL, but not in LWL cows. AT levels of the eCB-like molecules oleoylethanolamide, palmitoylethanolamide, and of arachidonic acid were elevated PP compared with prepartum in all cows. The abundance of monoglyceride lipase (MGLL), the 2-AG degrading enzyme, was lower in HWL vs. LWL AT PP. The relative gene expression of the cannabinoid receptors CNR1 and CNR2 in AT tended to be higher in HWL vs. LWL PP. Proteomic analysis of AT showed an enrichment of the inflammatory pathways' acute phase signaling and complement system in HWL vs. LWL cows PP. In summary, eCB levels in AT were elevated at the onset of lactation as part of the metabolic adaptations in PP dairy cows. Furthermore, activating the eCB system in AT is most likely associated with a metabolic response of greater BW loss, lipolysis, and AT inflammation in PP dairy cows. PMID- 30403681 TI - An improved geomechanical model for the prediction of fracture generation and distribution in brittle reservoirs. AB - It is generally difficult to predict fractures of low-permeability reservoirs under high confining pressures by data statistical method and simplified strain energy density method. In order to establish a series of geomechanical models for the prediction of multi-scale fractures in brittle tight sandstones, firstly, through a series of rock mechanics experiments and CT scanning, we determined 0.85 sigmac as the key thresholds for mass release of elastic strain energy and bursting of micro-fractures. A correlation between fracture volume density and strain energy density under uniaxial stress state was developed based on the Theory of Geomechanics. Then using the combined Mohr-Coulomb criterion and Griffith's criterion and considering the effect of filling degree in fractures, we continued to modify and deduce the mechanical models of fracture parameters under complex stress states. Finally, all the geomechanical equations were loaded into the finite element (FE) platform to quantitatively simulate the present-day 3-D distributions of fracture density, aperture, porosity, permeability and occurrence based on paleostructure restoration of the Keshen anticline. Its predictions agreed well with in-situ core observations and formation micro imaging (FMI) interpretations. The prediction results of permeability were basically consistent with the unobstructed flow distributions before and after the reservoir reformation. PMID- 30403682 TI - Development of epithelial tissues: How are cleavage planes chosen? AB - The cross-section of a cell in a monolayer epithelial tissue can be modeled mathematically as a k-sided polygon. Empirically studied distributions of the proportions of k-sided cells in epithelia show remarkable similarities in a wide range of evolutionarily distant organisms. A variety of mathematical models have been proposed for explaining this phenomenon. The highly parsimonious simulation model of (Patel et al., PLoS Comput. Biol., 2009) that takes into account only the number of sides of a given cell and cell division already achieves a remarkably good fit with empirical distributions from Drosophila, Hydra, Xenopus, Cucumber, and Anagallis. Within the same modeling framework as in that paper, we introduce additional options for the choice of the endpoints of the cleavage plane that appear to be biologically more realistic. By taking the same data sets as our benchmarks, we found that combinations of some of our new options consistently gave better fits with each of these data sets than previously studied ones. Both our algorithm and simulation data are made available as research tools for future investigations. PMID- 30403683 TI - Nutritional resilience in Nepal following the earthquake of 2015. AB - BACKGROUND: The 2015 earthquake in Nepal caused massive damages and triggered relief activities to minimize human suffering. The post-earthquake nutrition and food security situation in the hardest hit areas remains uncertain. METHODS: Two national cross-sectional surveys were conducted in 2014 and 2016 among households (HH) with pre-school aged children or newly married women. Of the 21 village development committees (VDCs) included in this sample, 7 fell within "earthquake affected" areas. This paper presents data from 982 HH, 1015 women, and 883 children from 2014 and 1056 HH, 1083 women, and 998 children from 2016 living in these areas, with longitudinal overlap of about 55%. Prevalence estimates and 95% confidence intervals were calculated, and logistic regression was used to calculate p-values, both using robust estimates of standard errors to account for clustering. RESULTS: From 2014 to 2016, child wasting (weight-for-height z score <-2) fell from 4.5% (95% CI 3.3%- 6.1%) to 2.1% (1.4%- 3.1%) and food insecurity (assessed using the household food insecurity access scale) dropped from 17.6% (11.7%- 25.6%) to 12.4% (6.9%- 21.2%). Child stunting prevalence remained similar at both time-points. Improvements were also evident in dietary diversity and breastfeeding indicators. CONCLUSIONS: Nutrition and food security conditions remained comparable or improved one year after the earthquake despite evidence of structural and other damage. Livelihood resilience to shocks and/or effective nutrition, food or health interventions may have helped buffer the impact on nutrition, although this hypothesis requires further exploration. PMID- 30403684 TI - USA300 methicillin-resistant Staphylococcus aureus in Stockholm, Sweden, from 2008 to 2016. AB - Methicillin-resistant Staphylococcus aureus (MRSA) USA300 isolates have been recognized globally, not only in community but also in healthcare settings. USA300 isolates were initially resistant only to methicillin, but resistance to non-beta-lactams has emerged with time. To evaluate the prevalence and antimicrobial susceptibility of USA300 isolates in Stockholm, we conducted a nine year retrospective study. Of 5359 consecutive MRSA cases in Stockholm, isolates from 285 cases were USA300 strains according to the pulsed-field gel electrophoresis pattern. Of these cases, repeated isolates with altered antibiotic resistance patterns were observed in six individuals. Therefore, antimicrobial susceptibility testing was performed on totally 291 isolates. To study the phylogenetic relatedness of isolates in transmission events and genomic resistance traits, 35 isolates were further studied by whole genome sequencing (WGS). The incidence of MRSA was increased from 17.6 per 100,000 inhabitants in 2008 to 37.3 per 100,000 inhabitants in 2016, while the proportion of USA300 cases declined from 6.6% in 2008 to 2.6% in 2016. Among the USA300 isolates, 73.5% were community-associated, 21.3% healthcare-associated, and 5.2% had unknown acquisition. The highest resistance rate among non-beta-lactams was found in erythromycin (86%), followed by fluoroquinolones (68-69%). 57% of the isolates were resistant to both erythromycin and fluoroquinolone. Simultaneous resistance to four non-beta-lactam antibiotic classes was found in six isolates. Four isolates were susceptible to all non-beta-lactam antibiotics. Ceftaroline, daptomycin, linezolid, mupirocin, rifampicin, teicoplanin, telavancin, trimethoprim-sulfamethoxazole and vancomycin retained full activity in the study. WGS analysis indicated that isolates from an outbreak were phylogenetically closely related. In conclusion, USA300 MRSA isolates in Stockholm have neither been limited to the community setting, nor remained susceptible to non-beta lactam agents. WGS is becoming a useful tool in tracing transmission events. The results herein provide the most up-to-date and comprehensive information regarding status of USA300 strains in this geographic area. PMID- 30403685 TI - A longitudinal study of attitudes toward evolution among undergraduates who are members of the Church of Jesus Christ of Latter-day Saints. AB - Polling data reveal a decades-long residual rejection of evolution in the United States, based on perceived religious conflict. Similarly, a strong creationist movement has been documented internationally, including in the Muslim world. Members of the Church of Jesus Christ of Latter-day Saints (LDS, Mormon), a generally conservative denomination, have historically harbored strong anti evolution sentiments. We report here a significant shift toward acceptance, compared to attitudes 30 years earlier, by students at Brigham Young University, which is owned and operated by the LDS church. This change appears to have multiple explanations. Students currently entering the university have been exposed to a much-improved introduction to evolution during high school. More importantly, there has been a significant decrease in negative messaging from Church authorities and in its religious education system. There is also evidence that current students have been positively influenced toward evolution by their parents, a large percentage of whom were BYU students, who earlier were given a strong science education deemed compatible with the maintenance of religious belief. A pre-post comparison demonstrates that a majority of current students become knowledgeable and accepting following a course experience focused on evolutionary principles delivered in a faith-friendly atmosphere. Elements of that classroom pedagogy, intended to promote reconciliation, are presented. Our experience may serve as a case-study for prompting changes in acceptance of evolution in other conservative religious groups. PMID- 30403686 TI - Hypertension prevalence, awareness, treatment and control in Ghanaian population: Evidence from the Ghana demographic and health survey. AB - Hypertension is a major cause of cardiovascular disease morbidity and mortality in Ghana. This study examines the prevalence, awareness, treatment and control of hypertension among Ghanaian aged 15-49 years. This cross-sectional study retrieved data from the 2014 Ghana Demographic and Health Survey (GDHS). The sample, comprising of 13,247 respondents aged 15-49 years, was analysed using descriptive statistics, Chi-Square tests, independent sample t-tests and binary logistic regressions. The overall prevalence of hypertension was 13.0% (12.1% for males and 13.4% for females). Among respondents who had hypertension, 45.6% were aware of their hypertension status; 40.5% were treating the condition while 23.8% had their blood pressure controlled (BP <140/90 mmHg). Socio-economic and demographic factors, health insurance coverage and recent visit to health facilities played significant roles in hypertension prevalence and awareness. While region of residence and health facility visits were predictors of hypertension treatment, age and region of residence predicted hypertension control in this population. This study suggests that in order to address the increasing burden of hypertension in Ghana, there should be an expansion of the National Health Insurance Scheme and development of measures to reduce health inequities. Also, some of the determining factors such as age, gender, marital status are similar to other cultures; therefore, existing interventions from those cultures could be adapted in addressing hypertension prevalence, awareness, treatment and control in Ghana. PMID- 30403687 TI - Association between mitochondrial DNA copy number and cardiovascular disease: Current evidence based on a systematic review and meta-analysis. AB - BACKGROUND: Mitochondria are energy-producing structure of the cell and help to maintain redox environment. In cardiovascular disease, the number of mitochondrial DNA (mtDNA) will changes accordingly compare to normal condition. Some investigators ask whether it has a clear association between mtDNA and cardiovascular disease with its adverse events. Thus, we conduct the meta analysis to assess the role of circulating mtDNA in evaluating cardiovascular disease. METHODS: The meta-analysis was conducted in accordance with a predetermined protocol following the recommendations of Cochrane Handbook of Systematic Reviews. We searched the Pubmed, Embase, the Cochrane Central Register of Controlled Trials and World Health Organization clinical trials registry center to identify relevant studies up to the end of October 2017. Data were analyzed using STATA. Besides, publication bias and meta-regression analysis were also conducted. RESULTS: We collected results from 5 articles for further analyses with 8,252 cases and 20,904 control. The normalized mtDNA copy number level is lower in cardiovascular disease (CVD) than the control groups with a pooled standard mean difference (SMD) of -0.36(95%CI,-0.65 to -0.08); The pooled odds ratio (OR) for CVD proportion associated with a 1-SD (standard deviation) decrease in mtDNA copy number level is 1.23 (95% CI,1.06-1.42); The OR for CVD patients with mtDNA copy number lower than median level is 1.88(95% CI,1.65 2.13); The OR for CVD patients with mtDNA copy number located in the lowest quartile part is 2.15(95% CI, 1.46-3.18); the OR between mtDNA copy number and the risk of sudden cardiac death (SCD) is 1.83(95% CI, 1.22-2.74). CONCLUSION: Although inter-study variability, the overall performance test of mtDNA for evaluating CVD and SCD revealed that the mtDNA copy number presented the potential to be a biomarker for CVD and SCD prediction. Given that, the fewer copies of mtDNA, the higher the risk of CVD. PMID- 30403688 TI - The effect of neonatal hypothyroidism and low family income on intellectual disability: A population-based cohort study. AB - BACKGROUND: To investigate relationships among neonatal hypothyroidism, family income, and intellectual disability, as well as the combined effects of neonatal hypothyroidism and low family income on intellectual disability. METHODS: Data were extracted from the National Health Insurance Service-National Sample Cohort from 2002 to 2011. This retrospective study included 91,247 infants. The presence of intellectual disability was based on the disability evaluation system in Korea. Newborn hypothyroidism was identified from diagnosis and prescription codes. Family income was determined from average monthly insurance premiums. Cox proportional hazards models were used to calculate adjusted hazard ratios. RESULTS: Of the 91,247 infants, 208 were considered to have intellectual disability (29.18 cases per 100,000 person-year). The risk of intellectual disability was higher in infants with hypothyroidism than in those without hypothyroidism (hazard ratio = 5.28, P: < .0001). The risk of intellectual disability was higher in infants with low family income than in those with high family income (hazard ratio = 2.32, P: < .0001). The risk of intellectual disability was higher in infants with hypothyroidism and low family income than in those without hypothyroidism and with high family income (hazard ratio = 36.05, P: < .0001). CONCLUSIONS: Neonatal hypothyroidism and low family income were associated with the risk of intellectual disability in Korea. Additionally, neonatal hypothyroidism and low family income significantly increased the risk of intellectual disability. Public health policymakers should consider providing additional resources for alleviating neonatal hypothyroidism among low-income families. PMID- 30403689 TI - Tooth development, histology, and enamel microstructure in Changchunsaurus parvus: Implications for dental evolution in ornithopod dinosaurs. AB - The great diversity of dinosaurian tooth shapes and sizes, and in particular, the amazing dental complexity in derived ornithischians has attracted a lot of attention. However, the evolution of dental batteries in hadrosaurids and ceratopsids is difficult to understand without a broader comparative framework. Here we describe tooth histology and development in the "middle" Cretaceous ornithischian dinosaur Changchunsaurus parvus, a small herbivore that has been characterized as an early ornithopod, or even as a more basal ornithischian. We use this taxon to show how a "typical" ornithischian dentition develops, copes with wear, and undergoes tooth replacement. Although in most respects the histological properties of their teeth are similar to those of other dinosaurs, we show that, as in other more derived ornithischians, in C. parvus the pulp chamber is not invaded fully by the newly developing replacement tooth until eruption is nearly complete. This allowed C. parvus to maintain an uninterrupted shearing surface along a single tooth row, while undergoing continuous tooth replacement. Our histological sections also show that the replacement foramina on the lingual surfaces of the jaws are likely the entry points for an externally placed dental lamina, a feature found in many other ornithischian dinosaurs. Surprisingly, our histological analysis also revealed the presence of wavy enamel, the phylogenetically earliest occurrence of this type of tissue. This contradicts previous interpretations that this peculiar type of enamel arose in association with more complex hadrosauroid dentitions. In view of its early appearance, we suggest that wavy enamel may have evolved in association with a shearing-type dentition in a roughly symmetrically-enameled crown, although its precise function still remains somewhat of a mystery. PMID- 30403690 TI - Field evaluation of low-dose warfarin baits to control wild pigs (Sus scrofa) in North Texas. AB - Wild pigs (Sus scrofa) are a highly detrimental invasive species that occupy a rapidly expanding range within the United States. In Australia, field trials evaluating baits containing 0.09% warfarin resulted in wild pig population reduction >95%. The objective of this study was to conduct an EPA-approved field trial to evaluate the use of bait containing low-dose warfarin (0.01% and 0.005%) in reducing wild pig numbers in Texas. An 8-week field test was conducted in the panhandle ~100 km southeast of Amarillo. Two ~8 km2 treatment plots were selected and each presented with either 0.01% or 0.005% warfarin baits. One control plot (~8 km2) was presented placebo. The baits were delivered using 30 species specific feeders per plot (n = 90) that kept wildlife from accessing the toxicant. Pig movements and feed consumption were monitored during pre-treatment, treatment, and post-treatment periods. All pigs with VHF transmitters within the 0.005% warfarin-treated plot (n = 14) succumbed to the warfarin (100% mortality). Overall, 35 wild pigs were found dead from warfarin toxicosis, within both treatment plots. Total feed consumption by wild pigs was reduced by ~97.8% and ~96.2% for the 0.005% and 0.01% warfarin baited plots, respectively, indicating the absence of pigs was a result of toxic bait consumption. Results of 97 systematic searches of the treatment plots indicated no warfarin-induced non target wildlife fatalities. Warfarin residues in wild pig livers averaged 3.69 mg/kg (n = 13) and 2.89 mg/kg (n = 9) for pigs recovered within the 0.005% plot and 0.01% warfarin plot, respectively. This study is the first efficacy field evaluation of a wild pig toxicant conducted in the US. The results suggest low dose warfarin bait, presented in species-specific feeders, can effectively reduce wild pig numbers and pose minimal risk to non-target wildlife and domestic animals. A product containing warfarin may provide another management tool in reducing wild pig problems. PMID- 30403692 TI - Psychometric properties of the Danish Parental Stress Scale: Rasch analysis in a sample of mothers with infants. AB - The Parental Stress Scale (PSS) was developed as a short measure of perceived stress resulting from being a parent. The current study examined the psychometric properties of the Danish version in a sample of 1110 mothers of children aged 0 to 12 months using Rasch models. Emphasis was placed on the issues of uni dimensionality and absence of differential item functioning relative to the age and educational level of the mothers. Results showed that no adequate fit could be established for the full PSS scale with 18 dichotomized items. Further analyses showed that items 2 and 11 had to be eliminated from the scale, and that the remaining items did not make up a unidimensional PSS scale, but two subscales measuring different aspect of parental stress: a 9-item scale measuring parental stress and a 7-item scale measuring lack of parental satisfaction. Fit to the Rasch model could not be established for any of the two subscales. For the parental stress subscale, we found evidence of local dependence for four item pairs (3 and 4, 9 and 10, 10 and 16, 12 and 16), as well as evidence of two items functioning differentially: item 16 relative to level of education, and item 3 relative to both age and educational level. For the lack of parental satisfaction subscale, we found evidence of local dependence between some two pairs (1 and 17, 17 and 18), but no evidence of differential item functioning. Both subscales fit graphical loglinear Rasch models adjusting for local dependence and differential item functioning. Plotting the adjusted subscale scores against one another showed that the two-scale solution provides additional information, as some mothers are stressed but not lacking in parental satisfaction. PMID- 30403691 TI - DNMTs and SETDB1 function as co-repressors in MAX-mediated repression of germ cell-related genes in mouse embryonic stem cells. AB - In embryonic stem cells (ESCs), the expression of development-related genes, including germ cell-related genes, is globally repressed. The transcription factor MAX represses germ cell-related gene expression in ESCs via PCGF6-polycomb repressive complex 1 (PRC1), which consists of several epigenetic factors. However, we predicted that MAX represses germ cell-related gene expression through several additional mechanisms because PCGF6-PRC1 regulates the expression of only a subset of genes repressed by MAX. Here, we report that MAX associated with DNA methyltransferases (DNMTs) and the histone methyltransferase SETDB1 cooperatively control germ cell-related gene expression in ESCs. Both DNA methylation and histone H3 lysine 9 tri-methylation of the promoter regions of several germ cell-related genes were not affected by knockout of the PRC1 components, indicating that the MAX-DNMT and MAX-SETDB1 pathways are independent of the PCGF6-PRC1 pathway. Our findings provide insights into our understanding of MAX-based repressive mechanisms of germ cell-related genes in ESCs. PMID- 30403694 TI - Diversity and effect of Trichoderma isolated from the roots of Pinus densiflora within the fairy ring of pine mushroom (Tricholoma matsutake). AB - Pine mushroom (PM, Tricholoma matsutake) is an important ectomycorrhizal fungus in Asia primarily due to its value as a food delicacy. Recent studies have shown that fairy rings of PM have distinctive fungal communities, which suggests that other fungi influence the growth of PM. Trichoderma is a well-known saprotrophic fungus commonly found in pine roots within PM fairy rings; however, little is known about the diversity of Trichoderma associated with PM and how these species influence PM growth. This study focused on diversity of Trichoderma isolated from pine roots within PM fairy rings and how these species affect the growth of PM isolate. Based on tef1a phylogenetic analyses, nine Trichoderma species (261 isolates) were identified. Trichoderma songyi and T. spirale were the dominant species, and Trichoderma community varied geographically. Growth experiments indicated that metabolites from five Trichoderma species had a significant influence on the growth of PM isolates. Metabolites of two Trichoderma species increased PM growth, while those of three Trichoderma species suppressed the growth. Within the fairy rings, Trichoderma that had a positive or neutral effect comprised the majority of Trichoderma communities. The results of this study suggest that various Trichoderma species co-exist within PM fairy rings and that these species influence PM growth. PMID- 30403695 TI - The effect evaluation of advanced penlight. AB - Pupil diameter measurement is crucial for physical assessment and disease monitoring in a health and nursing care situation. A general penlights (GPLs) is frequently used and allow for an approximate and indirect measurement of the pupil diameter. Health caregivers or nurses generally have less confidence in the value of the pupil diameter measured using the GPL. The Advanced Penlight (APL) is a new device designed for accurate measurement of the pupil diameter. The purpose of the presented research was to compare the accuracies and operational times of the pupil diameter measurements by means of the GPL and APL. One-group post-test and single-blind study designed was used in this study. The innovation of the APL is the addition of a perspective measurement ruler (PMR) attached to one side of the penlight that allows precise measurement of the pupil diameter before and after pupillary contraction. The PMR can be rotated by any angle for adaptation to the measurement conditions. After standard pupil diameter measurements by a refractometer (RM) were performed on a subjects, ninety study participants measured the pupil diameters of the same subject separately by the GPL and APL. A self-administered questionnaire was used to assess the opinions of the participants after using the GPL compare to the APL. The mean age of the participants was 20.01 (SD = 0.47) years and 83% of them were female senior nursing students. There were no statistically significant differences between the average values of pupil diameters measured by the APL and the RM. Compared to the GPL, the pupil diameter measured by APL was much similar to the RM measurement. The average operational time was 8.72 seconds shorter (t = -3.81, p = 0.001) for the APL measurement compared to the GPL measurement. The average scores of convenience and confidence on pupil diameter measurements of questionnaire were higher for the APL compared to the GPL. The APL can increase the accuracy and save operating time of pupil diameter measurement and thereby promote the quality of health assessment and nursing care practice. PMID- 30403693 TI - Future directions in meditation research: Recommendations for expanding the field of contemplative science. AB - The science of meditation has grown tremendously in the last two decades. Most studies have focused on evaluating the clinical effectiveness of mindfulness based interventions, neural and other physiological correlates of meditation, and individual cognitive and emotional aspects of meditation. Far less research has been conducted on more challenging domains to measure, such as group and relational, transpersonal and mystical, and difficult aspects of meditation; anomalous or extraordinary phenomena related to meditation; and post-conventional stages of development associated with meditation. However, these components of meditation may be crucial to people's psychological and spiritual development, could represent important mediators and/or mechanisms by which meditation confers benefits, and could themselves be important outcomes of meditation practices. In addition, since large numbers of novices are being introduced to meditation, it is helpful to investigate experiences they may encounter that are not well understood. Over the last four years, a task force of meditation researchers and teachers met regularly to develop recommendations for expanding the current meditation research field to include these important yet often neglected topics. These meetings led to a cross-sectional online survey to investigate the prevalence of a wide range of experiences in 1120 meditators. Results show that the majority of respondents report having had many of these anomalous and extraordinary experiences. While some of the topics are potentially controversial, they can be subjected to rigorous scientific investigation. These arenas represent largely uncharted scientific terrain and provide excellent opportunities for both new and experienced researchers. We provide suggestions for future directions, with accompanying online materials to encourage such research. PMID- 30403696 TI - Species- and developmental stage-specific effects of allelopathy and competition of invasive Impatiens glandulifera on co-occurring plants. AB - BACKGROUND: Impacts of invasive species on native communities are often difficult to assess, because they depend on a range of factors, such as species identity and traits. Such context-dependencies are poorly understood yet, but knowledge is required to predict the impact of invasions. MATERIALS AND METHODS: We assessed species- and developmental stage-specificity of competitive and allelopathic effects of the invasive plant Impatiens glandulifera on different developmental stages of four native plant species. While some studies have shown a reduction in plant growth caused by I. glandulifera, the magnitude of its impact is ambiguous. For our study we used seedlings and juveniles of I. glandulifera and the native target species Geum urbanum, Filipendula ulmaria, Urtica dioica, and Salix fragilis (seedlings only of the latter), which often co-occur with I. glandulifera in different habitats. Plants were grown in competition with I. glandulifera or treated with I. glandulifera leaf material, or 2-metoxy-1,4 naphtoquinone (2-MNQ), its supposedly main allelochemical. RESULTS AND CONCLUSIONS: Overall I. glandulifera had a negative effect on the growth of all target species depending on the species and on the plant's developmental stage. F. ulmaria was the least affected and U. dioica the most, and seedlings were less affected than juveniles. The species-specific response to I. glandulifera may lead to an altered community composition in the field, while growth reduction of seedlings and juveniles should give I. glandulifera an advantage in cases where plant recruitment is crucial. 2-MNQ led to minor reductions in plant growth, suggesting that it may not be the only allelopathic substance of I. glandulifera. Surprisingly, I. glandulifera was not fully tolerant to 2-MNQ. This autotoxicity could contribute to I. glandulifera population dynamics. We conclude that I. glandulifera reduces the growth of native vegetation and alters early successional stages without fully hindering it. PMID- 30403697 TI - Catecholaminergic polymorphic ventricular tachycardia patients with multiple genetic variants in the PACES CPVT Registry. AB - BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is often a life-threatening arrhythmia disorder with variable penetrance and expressivity. Little is known about the incidence or outcomes of CPVT patients with >=2 variants. METHODS: The phenotypes, genotypes and outcomes of patients in the Pediatric and Congenital Electrophysiology Society CPVT Registry with >=2 variants in genes linked to CPVT were ascertained. The American College of Medical Genetics & Genomics (ACMG) criteria and structural mapping were used to predict the pathogenicity of variants (3D model of pig RyR2 in open-state). RESULTS: Among 237 CPVT subjects, 193 (81%) had genetic testing. Fifteen patients (8%) with a median age of 9 years (IQR 5-12) had >=2 variants. Sudden cardiac arrest occurred in 11 children (73%), although none died during a median follow up of 4.3 years (IQR 2.5-6.1). Thirteen patients (80%) had at least two RYR2 variants, while the remaining two patients had RYR2 variants plus variants in other CPVT-linked genes. Among all variants identified, re-classification of the commercial laboratory interpretation using ACMG criteria led to the upgrade from variant of unknown significance (VUS) to pathogenic/likely pathogenic (P/LP) for 5 variants, and downgrade from P/LP to VUS for 6 variants. For RYR2 variants, 3D mapping using the RyR2 model suggested that 2 VUS by ACMG criteria were P/LP, while 2 variants were downgraded to likely benign. CONCLUSIONS: This severely affected cohort demonstrates that a minority of CPVT cases are related to >=2 variants, which may have implications on family-based genetic counselling. While multi-variant CPVT patients were at high-risk for sudden cardiac arrest, there are insufficient data to conclude that this genetic phenomenon has prognostic implications at present. Further research is needed to determine the significance and generalizability of this observation. This study also shows that a rigorous approach to variant re-classification using the ACMG criteria and 3D mapping is important in reaching an accurate diagnosis, especially in the multi-variant population. PMID- 30403699 TI - Do honeybees (Apis mellifera) differentiate between different pollen types? AB - Bees receive nectar and pollen as reward for pollinating plants. Pollen of different plant species varies widely in nutritional composition. In order to select pollen of appropriate nutritional quality, bees would benefit if they could distinguish different pollen types. Whether they rely on visual, olfactory and/or chemotactile cues to distinguish between different pollen types, has however been little studied. In this study, we examined whether and how Apis mellifera workers differentiate between almond and apple pollen. We used differential proboscis extension response conditioning with olfactory and chemotactile stimulation, in light and darkness, and in summer and winter bees. We found that honeybees were only able to differentiate between different pollen types, when they could use both chemotactile and olfactory cues. Visual cues further improved learning performance. Summer bees learned faster than winter bees. Our results thus highlight the importance of multisensory information for pollen discrimination. PMID- 30403698 TI - Phylogeny, biogeography and taxonomic re-assessment of Multifurca (Russulaceae, Russulales) using three-locus data. AB - Multifurca is a small genus newly established to accommodate lactarioid and russuloid species with some characters reminiscent of corticoid members of Russulaceae. It shows an amphi-pacific distribution with strong preference for the tropical zone of the Northern Hemisphere and thus has particular significance for biogeographical study. Using worldwide samples and three loci (ITS, 28S rDNA and rpb2), we demonstrated that Multifurca is split into two highly supported major clades that are here recognized at the subgeneric level: subg. Furcata subg. nov. exclusively includes lactarioid species, while subg. Multifurca includes species with a russuloid habit. Using phylogenetic species recognition and comparison of genetic distances we recognize five new and six previously described species, almost double the known number of species before this study. Molecular dating using a Bayesian method suggested that Multifurca originated in early Paleocene and diversified in the Eocene. The most recent interspecific divergences occurred both in Asia and America, roughly at the same time around the Pliocene. Ancestral area reconstruction and comparisons of genetic distances and morphology suggested an early divergence within Australasia or tropical Asia. From the early Miocene to Pliocene, multiple dispersals/migrations to Australasia and North America by island hopping or land bridge likely happened. Vicariance at the late Tertiary might be the most likely mechanism accounting for the eastern Asia-southeastern North America and Australasia-tropical Asia disjunct distributions. The shared polymorphisms in the ITS alignment, numerous degenerated base pairs in the rpb2 sequences and weak conflict between the ITS and LSU genealogies of M. subg. Furcata suggest recent speciation. Host specificity of Multifurca species or species pairs is relatively low. Host shifts are believed to have aided establishment in new territories during the dispersals and migrations. PMID- 30403700 TI - The lead ores circulation in Central China during the early Western Han Dynasty: A case study with bronze vessels from the Gejiagou site. AB - This study first publishes lead isotope data of bronze vessels from Central China in Western Han Dynasty and attempts to find out the lead ores circulation of this time by taking bronzes from the Gejiagou site (Nanyang City, Henan Province) as an example. The elemental concentrations suggest the lead should be introduced on purpose and indicate the provenance information of lead ores. All the lead isotope ratios conform to the characteristics of common lead and most of them are similar to Nanyang local lead ores. The lead of another two bronzes, NY9 and NY13, should be imported from southern China. Combined with the historical background of early Western Han Dynasty, the wider range of the lead ore circulation may be an indicator for, as the loose policy, economic prosperity and transportation improvement. PMID- 30403701 TI - Biomass recalcitrance in barley, wheat and triticale straw: Correlation of biomass quality with classic agronomical traits. AB - The global production of cereal straw as an agricultural by-product presents a significant source of biomass, which could be used as feedstock for the production of second generation biofuels by fermentation. The production of sugars for fermentation is an important measure of straw quality and in its suitability for biofuel production. In this paper, we present a characterization of straw digestibility from a wide range of cereal. Our main objective is to evaluate the variability of fermentable sugars released from different species including wheat (Triticum durum L., Triticum aestivum L.), barley (Hordeum vulgare L.) and triticale (X Triticosecale Wittmack). To this end, we adapted a saccharification method (IAS Method) capable of detecting significant differences of released sugars between cultivars and species, while using separately another method that would serve as a control and with which we could contrast our results (CNAP method). ANOVA analyses revealed that barley has a higher saccharification potential than wheat and triticale and shows more variation between genotypes. Thus, populations derived from crosses among them such as Steptoe * Morex and OWB Dominant * OWB Recessive hold potential for the identification of genetic basis for saccharification-related traits. The correlation of glucose released between the two methods was moderate (R2 = 0.57). An evaluation of the inter- and intra- specific correlation between a number of chemical and agronomical parameters and saccharification suggests that the cell wall thickness and lignin content in straw could be used in breeding programs for the improvement of the saccharification potential. Finally, the lack of correlation between grain yield and saccharification suggests that it would be possible to make a selection of genotypes for dual purpose, low recalcitrance and grain yield. PMID- 30403702 TI - Primary structures of different isoforms of buffalo pregnancy-associated glycoproteins (BuPAGs) during early pregnancy and elucidation of the 3 dimensional structure of the most abundant isoform BuPAG 7. AB - Pregnancy-associated glycoproteins (PAGs) are expressed during pregnancy by the trophoectodermal cells of fetus. Presence of PAGs in dam's circulation has been widely used in pregnancy diagnosis. The present study reports the identification and characterization of different PAG isoforms in buffalo during early stages of pregnancy. The PAG mRNAs isolated from fetal cotyledons (Pregnancy stages: 45, 75 and 90 days) were successfully cloned in pJET1.2 vector and transformed in E. coli. A total of 360 random clones were sequenced and correlated with their stages of expression. A total of 12 isoforms namely, BuPAG 1, 2, 4, 6, 7, 8, 9, 13, 15, 16, 18 and one new isoform were identified. BuPAG 7 was found as the most abundant isoform in all three stages followed by BuPAG 18. Further, a large number of variants were found for most of these isoforms. Phylogenetic relationship of identified BuPAGs showed that BuPAG 2 belonged to an ancient group while other members clustered with modern group. Three-dimensional (3D) structure of BuPAG 7 was determined by homology modeling and molecular dynamic (MD) simulations which displayed a typical fold represented by other aspartic proteinase (AP) family members. Molecular docking of Pepstatin inhibitor with BuPAG 7 revealed to interact through various hydrogen bonding and hydrophobic interactions. Various amino acid substitutions were observed in peptide-binding cleft of BuPAG 7. Superimposition of BuPAG 7 with homologous structures revealed the presence of a 35-41 amino acid long insertion (alpha helix connected by two loops) near the N- terminus which seems to be a unique feature of BuPAG 7 in AP family. This is the first report on identification and sequence characterization of PAG isoforms in buffalo with unique finding that these isoforms represent many transcript variants. We also report 3D structure of the most abundant isoform BuPAG 7 for the first time. PMID- 30403703 TI - Habitat preference and den characterization of Indian Pangolin (Manis crassicaudata) in a tropical lowland forested landscape of southwest Sri Lanka. AB - The Indian pangolin (Manis crassicaudata) is under threat due to hunting for local consumption and illegal trafficking of scales and meat. The dearth of scientific studies on the ecology of the M. crassicaudata has impaired accurate assessments of its conservation needs. This study investigated the habitat preference and burrow characteristics of M. crassicaudata in a tropical lowland rainforest in southwest Sri Lanka. A total of 75 burrows (54 feeding burrows and 21 resting burrows) of M. crassicaudata in four different habitat types i.e. secondary forest, Pine-dominated forest, rubber cultivations and tea-dominated home gardens bordering forest were observed using fixed-width transects in order to characterize resting and feeding burrows of this species. The highest density of resting burrows was recorded from the secondary forest (4ha-1), followed by rubber cultivations (2.5ha-1) while no resting burrows were recorded in the Pine dominated forest and the tea-dominated home gardens bordering forest. Feeding burrows were more abundant in the Pine-dominated forest (5.7ha-1). The burrow depth, burrow opening height, and width were significantly larger in resting burrows compared to feeding burrows. Resting burrows were located at higher elevations (75-100m) with moderately high slopes (450-600), dense canopy cover (>75%) and away from human habitation. Feeding burrows showed a greater variability in terms of associated environmental features. The study further revealed that Indian pangolins exclusively prefer habitats with rocks and boulders under which they dig resting burrows while the location of feeding burrows largely overlaps with the distribution of prey species. The resting burrow design consisted of a bending tunnel that initially slopes downward and then gradually inclines at an angle between 20 and 300, leading to the resting chamber. Our study highlights the importance of conserving fragmented secondary natural forests in changing landscapes of the southwest lowlands of Sri Lanka as these habitats appear to be critical to sustaining populations of M. crassicaudata. PMID- 30403704 TI - A genome-wide data assessment of the African lion (Panthera leo) population genetic structure and diversity in Tanzania. AB - The African lion (Panthera leo), listed as a vulnerable species on the IUCN Red List of Threatened Species (Appendix II of CITES), is mainly impacted by indiscriminate killing and prey base depletion. Additionally, habitat loss by land degradation and conversion has led to the isolation of some subpopulations, potentially decreasing gene flow and increasing inbreeding depression risks. Genetic drift resulting from weakened connectivity between strongholds can affect the genetic health of the species. In the present study, we investigated the evolutionary history of the species at different spatiotemporal scales. Therefore, the mitochondrial cytochrome b gene (N = 128), 11 microsatellites (N = 103) and 9,103 SNPs (N = 66) were investigated in the present study, including a large sampling from Tanzania, which hosts the largest lion population among all African lion range countries. Our results add support that the species is structured into two lineages at the continental scale (West-Central vs East Southern), underlining the importance of reviewing the taxonomic status of the African lion. Moreover, SNPs led to the identification of three lion clusters in Tanzania, whose geographical distributions are in the northern, southern and western regions. Furthermore, Tanzanian lion populations were shown to display good levels of genetic diversity with limited signs of inbreeding. However, their population sizes seem to have gradually decreased in recent decades. The highlighted Tanzanian African lion population genetic differentiation appears to have resulted from the combined effects of anthropogenic pressure and environmental/climatic factors, as further discussed. PMID- 30403705 TI - Serum sclerostin and irisin as predictive markers for atherosclerosis in Egyptian type II diabetic female patients: A case control study. AB - Diabetes mellitus represents a major independent risk factor for developing fatal cardiovascular diseases (CVDs) presumably through accelerating atherosclerosis; the underlying cause of most CVDs. Notably, this relative risk is reported to be higher in women than men. Endeavors directed towards identifying novel reliable predictive biomarkers are immensely thereby urged to improve the long-term outcome in these diabetic female patients. Sclerostin (SOST) is a Wnt signaling antagonist whereas irisin is a muscle-derived factor released after exercising which enhances browning of white adipose tissue. Emerging lines of evidence hint at potential crosstalk between them and CVDs. The present study aimed to assess the serum levels of SOST and irisin in Egyptian type 2 diabetic (T2DM) female patients with and without atherosclerosis and explore the possible relationship between both markers and other studied parameters among the studied cohorts. In this case-control study, 69 female subjects were enrolled; 39 type 2 diabetes patients with atherosclerosis (T2DM+ATHR), 22 type 2 diabetes patients without atherosclerosis (T2DM-ATHR) and 8 healthy controls. Their serum levels of SOST and irisin were assessed using ELISA. Significant increase in SOST levels were found in T2DM+ATHR compared to T2DM-ATHR and control (259.9 +/-17.98 vs. 165.8+/ 13.12 and 142.0+/-13.31 pg/mL respectively, P<0.001). Conversely, irisin levels were significantly lower in T2DM+ATHR (P<0.001) and T2DM-ATHR (P<0.01) compared to the control group (32.91+/-2.545 and 58.55+/-13.19 vs. 473.6+/-112.7 pg/mL). Interestingly, significant correlations between the levels of SOST and both irisin and fasting blood glucose were noticed in T2DM+ATHR group (r = 0.3754 and 0.3381 respectively, P<0.05). In conclusion, to the best of our knowledge, this study is the first to demonstrate the correlation between SOST and irisin levels in atherosclerotic T2DM female patients implying their potential implication in diabetic cardiovascular pathophysiology and supporting their use as reliable diagnostic/prognostic biomarkers for monitoring and preventing CVDs progression of T2DM female patients. PMID- 30403706 TI - Time wears on: Assessing how bone wears using 3D surface texture analysis. AB - Use-wear analysis provides a means of studying traces produced on animal bone during manufacture and use in an effort to reconstruct these processes. Often, these analyses are qualitative and based on experience and expertise. Previous studies have focused on interpreting final traces, but little is known about how these traces develop and change over time. We propose the use of an innovative quantitative method for studying bone surface traces that aims to reduce any unreliable or non-replicable results that can confound more traditional qualitative analyses. We seek to understand the basics of use-wear formation over Time by taking incremental molds of bone specimens subjected to a controlled, mechanical experiment. This study assesses how bone wears during extended use on three Material types (fresh skin, processed leather, or dry bark), from three initial Manufacturing states (unworked, ground with sandstone, or scraped with flint). With data obtained from a confocal disc-scanning microscope, we then apply 3D surface texture analysis using ISO 25178 parameters: surface roughness [Sa], autocorrelation length [Sal], peak curvature [Spc], and upper material ratio [Smr1]. We employ a multilevel multivariate Bayesian model to explain parameter variation under experimental conditions. Our findings show how duration of use strongly affects the transformation of the bone's surface. Unworked bone is completely distinguishable from bone used for long time intervals and those modified by scraping. Interestingly, material wear does not often produce type specific traces, but does affect the rate of bone alteration and how it is transformed. Specifically, fresh skin transforms bone at a faster rate than other materials. This novel quantitative and experimental approach enhances our understanding of the use of bone as a raw material for making and using tools and provides a foundation for future exploration of archaeological materials and questions. PMID- 30403707 TI - Value of information analysis of an early intervention for subthreshold panic disorder: Healthcare versus societal perspective. AB - BACKGROUND: Panic disorder is associated with high productivity costs. These costs, which should be included in cost-effectiveness analyses (CEA) from a societal perspective, have a considerable impact on cost-effectiveness estimates. However, they are often omitted in published CEAs. It is therefore uncertain whether choosing a societal perspective changes priority setting in future research as compared to a healthcare perspective. OBJECTIVES: To identify research priorities regarding the cost-effectiveness of an early intervention for subthreshold panic disorder using value of information (VOI) analysis and to investigate to what extent priority setting depends on the perspective. METHODS: We calculated the cost-effectiveness of an early intervention for panic disorder from a healthcare perspective and a societal perspective. We performed a VOI analysis, which estimates the expected value of eliminating the uncertainty surrounding cost-effectiveness estimates, for both perspectives. RESULTS: From a healthcare perspective the early intervention was more effective at higher costs compared to usual care (?17,144 per QALY), whereas it was cost-saving from a societal perspective. Additional research to eliminate parameter uncertainty was valued at ?129.7 million from a healthcare perspective and ?29.5 million from a societal perspective. Additional research on the early intervention utility gain was most valuable from a healthcare perspective, whereas from a societal perspective additional research would generate little added value. CONCLUSIONS: Priority setting for future research differed substantially according to the perspective. Our study underlines that the health-economic perspective of CEAs on interventions for panic disorder must be chosen carefully in order to avoid inappropriate choices in research priorities. PMID- 30403708 TI - The roles of preventive and curative health care in economic development. AB - INTRODUCTION: Both the preventive and curative healthcare provisions accumulate agents' health stock and stimulate economies' productivities. However, with limited medical resources, increases in preventive health expenditure crowd out curative expenditure, and vice versa, which in turn impairs the population's health and deters economic growth. This research aims to provide a empirically rigorous test on the hypothesis that optimally allocating health expenditure between prevention and cures stimulates economic growth within different countries, especially developed countries, and investigates whether health services are luxury goods on the path of economic development. METHODS: Based on OECD country experiences, this present study uses the system generalized method of moments (GMM) estimation method to examine the roles of preventive and curative healthcare services over the path of economic development and proves that preventive and curative health spending have non-linear effects on economic performance. RESULTS: For growth maximization, the optimal share of preventive health expenditure to GDP is 0.44% with per capita GDP at US$40,465; the real share is 0.25% with per capita GDP at US$35,230. The optimal share of curative health expenditure to GDP is 10.96% with per capita GDP at US$41,816; the real share is 8.26% with per capita GDP at US$35,230. Accordingly, the estimated optimal provision of health services are currently underprovided. This research further estimates the effects of income on demand for care and shows that the income elasticities of preventive and curative health care are greater than unity. Health services are luxury goods. CONCLUSIONS: Economies with higher incomes demand such services more than those with lower incomes. The large positive effects of income on preventive care use exist. PMID- 30403709 TI - Sympatric and allopatric niche shift of endemic Gypsophila (Caryophyllaceae) taxa in the Iberian Peninsula. AB - Several species of the Gypsophila genus are endemic to the Iberian Peninsula, including gypsophytes of particular ecological, evolutionary and biochemical interest, and taxa that have undergone both sympatric and allopatric genetic differentiation. The niche shift among these taxa has been assessed using ecological niche modelling and ordination techniques, adopting a niche overlap approach to compare the similarity and equivalency of the ecological niches. We used the Maximum Entropy method to study the potential distribution of these taxa in different eras: the Last Glacial Maximum (LGM), the Mid Holocene and the current conditions. We present evidence of niche shift during the speciation of G. bermejoi, with a strong niche overlap between the parental taxa (G. struthium subsp. struthium and G. tomentosa), yet both overlap much more weakly with the hybrid species. This phenomenon may be explained by genetic and epigenetic interactions, and it has been described in other species. We also studied the sister subspecies G. struthium subsp. struthium and G. struthium subsp. hispanica, with mostly allopatric distributions and with the Iberian System mountain range acting as a geographical barrier. The Iberian System and other mountain ranges may have favored differences in the climatic conditions on either side of the mountain range, which is consistent with an incipient process of bioclimatic ecological speciation. These results seem to indicate that niche shift can occur over very different timespans. In the case of G. bermejoi, speciation may have produced significant niche shifting in one or two generations due to its alloploid nature. By contrast, G. struthium subsp. struthium and G. struthium subsp. hispanica seem to have undergone a more gradual process of allopatric genetic differentiation driven by bioclimatic factors. Both these processes are relatively recent and they will have been strongly influenced by the climate change at the end of LGM. PMID- 30403710 TI - Effect of diet protein restriction on progression of chronic kidney disease: A systematic review and meta-analysis. AB - BACKGROUND: Dietary protein restriction has long been thought to play an important role in the progression of chronic kidney disease (CKD); however, the effect of dietary protein on the rate of decline in kidney function remains controversial. OBJECTIVE: We undertook a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the influence of protein restriction on chronic kidney disease. METHOD: Ovid MEDLINE (from 1946 to March 5, 2016), EMBASE (from 1966 to March 5, 2016), and the Cochrane Library (Inception to March 5, 2016) were searched to identify RCTs comparing different levels of protein intake for at least 24 weeks in adult patients with CKD. The outcomes included kidney failure events, the rate of change in estimated glomerular filtration rate (eGFR) per year, all cause death events, and changes in proteinuria, serum phosphorus concentration, serum albumin, and body mass index (BMI). RESULTS: Nineteen trials with 2492 subjects were analyzed. A low protein diet reduced the risk of kidney failure (odds ratio (OR) = 0.59, 95% CI: 0.41 to 0.85) and end-stage renal disease (ESRD) (OR = 0.64, 95% CI: 0.43 to 0.96), but did not produce a clear beneficial effect for all cause death events (OR = 1.17, 95% CI: 0.67 to 2.06). The change in the mean difference (MD) for the rate of decline in the eGFR was significant (MD: -1.85, P = 0.001), and for proteinuria (MD: -0.44, P = 0.02). A low protein diet also reduced the serum phosphorus concentration (MD: -0.37, 95% CI: -0.5 to -0.24) and BMI (MD: -0.61, 95% CI: -1.05 to -0.17). However the change in albumin presented no significant difference between two groups (MD: 0.23, 95% CI: -0.51 to 0.97). CONCLUSIONS: Based on the findings of our meta-analysis, protein-restricted diet may reduce the rate of decline in renal function and the risk of kidney failure for CKD populations, but did not produce a clear beneficial effect for all cause death events. Besides However, the optimal level of protein intake in different participants is left unanswered, and the nutritional status should be regarded with caution. PMID- 30403711 TI - Higher-level cognitive functions in Dutch elite and sub-elite table tennis players. AB - This study aimed to investigate the higher-level cognitive functions (i.e. metacognition and executive functions) of Dutch competitive table tennis players to better understand its relevance for performance in this fast and complex sport. Thirty elite (age 16 +/- 4) and thirty age and sex-matched sub-elite peers (age 16 +/- 5) were assessed on metacognition and executive functions (working memory, inhibitory control, cognitive flexibility) using D-KEFS tests. Compared to norm scores, both the Dutch competitive elite and sub-elite table tennis players scored above average on all tests (p < 0.05). MANOVA showed a main effect for performance level (elites outscored sub-elites; p < 0.05). T-tests revealed that elite players make less mistakes on tests for inhibitory control (CWI-3: 0.9 +/- 0.9; CWI-4: 1.1 +/- 1.2) than sub-elite players (CWI-3: 1.8 +/- 1.1; CWI-4: 2.6 +/- 1.5) (p < 0.05). When controlling for training hours in a MANCOVA, no significant main effect of performance level remained (p > 0.05). In conclusion, Dutch elite and sub-elite table tennis players are characterized by above-average scores on higher-level cognitive functions compared to norm scores. A relation with performance level has been shown, which may be explained by the greater exposure to table tennis for elite compared to sub-elite players. However, longitudinal research is needed to indicate the direction of this association. PMID- 30403712 TI - Land Use, anthropogenic disturbance, and riverine features drive patterns of habitat selection by a wintering waterbird in a semi-arid environment. AB - River ecosystems in semi-arid environments provide an array of resources that concentrate biodiversity, but also attract human settlement and support economic development. In the southwestern United States, land-use change, drought, and anthropogenic disturbance are compounding factors which have led to departures from historical conditions of river ecosystems, consequently affecting wildlife habitat, including important wintering areas for migratory birds. The Rio Grande (River) in central New Mexico is the lifeblood of the Middle Rio Grande Valley (MRGV), maintaining large urban and agricultural centers and riparian and wetland resources, which disproportionately support a diversity of wildlife. The MRGV has been identified as the most important wintering area for the Rocky Mountain Population of greater sandhill cranes (Antigone canadensis tabida). Presently, however, changes in the hydrogeomorphology of the Rio Grande and landscape modification by humans have reshaped the MRGV and winter habitat for sandhill cranes. To evaluate these impacts, we investigated how land-use practices, anthropogenic disturbance, and river morphology influenced patterns of diurnal and roosting habitat selection by sandhill cranes. During the diurnal period, sandhill cranes relied heavily on managed public lands selecting agriculture crops, such as corn fields, and wetlands for foraging and loafing while avoiding areas with increasing densities of human structures. Sandhill cranes selected areas for roosting in the Rio Grande characterized by shallower water interspersed with sandbars, wide channel width, low bank vegetation, and farther away from disturbances associated with bridges. Our results establish and identify the central processes driving patterns of diel habitat selection by wintering sandhill cranes. Land use and riverine trends have likely gradually reduced winter habitat to managed public lands and limited reaches of the Rio Grande, underscoring the importance of natural resources agencies in supporting migratory birds and challenges involved when managing for wildlife in highly pressured semi-arid environments. PMID- 30403713 TI - Identifying wildlife corridors for the restoration of regional habitat connectivity: A multispecies approach and comparison of resistance surfaces. AB - Many large-scale connectivity initiatives have been proposed around the world with the aim of maintaining or restoring connectivity to offset the impacts on biodiversity of habitat loss and fragmentation. Frequently, these are based on the requirements of a single focal species of concern, but there is growing attention to identifying connectivity requirements for multi-species assemblages. A number of methods for modelling connectivity have been developed; likewise, different approaches have been used to construct resistance surfaces, the basic input data for connectivity analyses. In this study we modelled connectivity for a multi-species group of vertebrates representative of heavily fragmented forests in north-central Victoria, Australia. For each species, we used least-cost modelling and compared two alternate resistance surfaces, based on species distribution models and on expert opinion, respectively. We integrated the connectivity results across individual species to obtain a multi-species connectivity map for the region. A resistance surface based on expert assessment of the relative use of land-cover classes by the target species was more informative than one based on species distribution models. The former resulted in pathways more strongly aligned with existing patches and strips of native vegetation. In this region, pathways aligned with streams and their associated riparian vegetation have relatively high ecological potential and feasibility to contribute to regional connectivity for the assemblage of forest vertebrates. PMID- 30403714 TI - Oral and anal sexual practice and associated factors among preparatory school youths in Dire Dawa city administration, Eastern Ethiopia. AB - BACKGROUND: Human Immunodeficiency Virus greatly affects young peoples in developing countries, of which sexual transmission is the major route including vaginal, oral and anal sex. Understanding the full range of sexual behavior among young people, especially oral and anal sexual experience is very crucial to design appropriate intervention strategies. This study was to assess oral and anal sexual experience and associated factors among preparatory school youths in Dire Dawa city, Eastern Ethiopia. METHODS: School based cross sectional study was conducted among 1067 school youths attending preparatory school. Systematic random sampling method was used to select study participants. Data were collected using self-administered questionnaire and entered in to Epi-data version 3.3.1 and exported to SPSS 20 for analysis. Descriptive and bivariate logistic regression was done. Variables in bivariate analysis with P< 0.25 were entered to multiple bivariate logistic regression analysis to determine predictor variables. P < 0.05 was declared as statistically significance and AOR with 95% CI used to assess strength of association. RESULTS: The proportion of youths who reported having oral sex was 9% (88) and that of anal sex was 6.7% (66). Having multiple sexual partners was reported by 65.8% and 56.5% of youths who ever engaged in oral and anal sex respectively. From those who ever engaged to oral sex and anal sex 15.9% and 34.8% consistently used condom respectively. Oral sex practice was significantly associated with intimate partner ever engaged to oral sex practice (AOR = 4.53, 95% CI: 2.26-9.05), ever engaged to vaginal sex (AOR = 16.38, 95% CI: 7.22-37.19), older age (20-24years) (AOR = 2.45, 95% CI: 1.24-4.86), ever drinking alcohol (AOR = 2.11,95% CI:1.02-4.34), and ever smoke shisha (AOR = 2.85,95% CI:1.4-5.83). Similarly anal sex experience was significantly associated with intimate partner ever engaged to anal sex (AOR = 5.34, 95% CI: 4.2-26.98), ever engaged to vaginal sex (AOR = 10.64, 95% CI: 2.39-11.9), ever watching pornographic movies (AOR = 3.86, 95% CI: 1.45-10.29) and parental monitoring of youth's sexual behavior (AOR = 2.63, 95% CI: 1.12-6.19). CONCLUSIONS: Significant proportion of youths had engaged in oral and anal sexual practice and multiple sexual partners were common among youths for oral and anal sex. In the contrary consistent condom use was very poor. A combination of sexual health education intervention strategies should be implemented at family, school and community level. PMID- 30403715 TI - Children's syntactic representation of the transitive constructions in Mandarin Chinese. AB - Two studies are presented that investigate the effect of linguistic cues on Mandarin speakers' comprehension of transitive constructions. Study 1 investigated Mandarin-speaking 2- to 4-year-olds' and adults' comprehension of the SVO (Subject-verb-object) construction, ba-construction (SbaOV), and subjectless ba-construction ((S)baOV) with novel verbs using the forced choice pointing paradigm (FCPP). Study 2 investigated another group of participants with similar ages' comprehension of the SVO construction, the ba-construction, the long and short passive constructions with novel verbs and FCPP. Although these constructions have differing cue strengths, participants in the same age groups comprehended these construction types equally well. The results suggest that children as young as two attended to the case markers of ba and bei, allowing them to employ abstract syntactic representations in comprehending Mandarin transitive constructions. The findings demonstrate that children are sensitive early on to the structural information encoded in the constructions. PMID- 30403716 TI - Use of healthcare services and expenditure in the US in 2025: The effect of obesity and morbid obesity. AB - OBJECTIVE: This paper explores the contribution of body-mass index (BMI) categories in shaping past trends of use of healthcare services and associated expenditure in the US and projects results to 2025. METHODS: The study uses Medical Expenditure Panel Survey (MEPS) data for 2000-2012, reweighted on National Health and Nutrition Survey (NHANES) data for 1972-2012 and US Census Bureau data, to carry out projections for up to 2025. A combination of logistic regressions and generalized linear models was used to model use and associated expenditure for the following healthcare services: inpatient care (with/without surgery), office-based care, outpatient-care, drug prescription and home health care. Quantile regressions were used to analyse and project BMI levels. RESULTS: 20.5 million individuals will be severely obese in 2025. Normal-weight and overweight individuals have stable trends in use for many healthcare services. Conversely, use of healthcare services in patients in class II and class III obesity will increase substantially. Total healthcare expenditure increases more quickly in the obese population than in normal-weight individuals. CONCLUSIONS: Class III obesity (BMI>=40 kg/m2) significantly affects demand and expenditure for all healthcare services. Careful healthcare service planning and implementing effective policy actions to counteract such trends is crucial to meet future demand. PMID- 30403717 TI - Mastectomized women's perception of breast cancer early detection. AB - BACKGROUND: A third of new cases of breast cancer could be detected early, which would prevent more serious consequences, such as mastectomy and death. Access to the subjectivity of mastectomized patients becomes relevant to elucidate failures in early detection of breast cancer and thus improve the cancer care network. Given that, the present study aimed to identify mastectomized women's perception of the quality of care provided by the cancer care network for the early detection and diagnosis of breast cancer. METHODS: Qualitative study carried out at a public outpatient cancer center in the city of Fortaleza, Ceara, Northeastern Brazil, to analyze the perceptions of 26 women who had undergone mastectomy after breast cancer based on Symbolic Interactionism. RESULTS: The thematic analysis showed how women (re)structure their lives in the face of the structural and social aspects of coping with breast. Two essential themes emerged: "Contradictions regarding access to primary health care services and obstacles to the organization of SUS formal care network services" and "The informal and private health care network increase quality care coverage". CONCLUSIONS: The absence of effective measures in Primary Health Care and patients' 'pilgrimage' in the formal health care network have delayed early detection breast cancer. PMID- 30403719 TI - Sialic acid facilitates binding and cytotoxic activity of the pore-forming Clostridium perfringens NetF toxin to host cells. AB - NetF-producing type A Clostridium perfringens is an important cause of canine and foal necrotizing enteritis. NetF, related to the beta-sheet pore-forming Leukocidin/Hemolysin superfamily, is considered a major virulence factor for this disease. The main purpose of this work is to demonstrate the pore-forming activity of NetF and characterize the chemical nature of its binding site. Electron microscopy using recombinant NetF (rNetF) confirmed that NetF is able to oligomerize and form large pores in equine ovarian (EO) cell membranes and sheep red blood cells. These oligomeric pores appear to be about 4-6 nm in diameter, and the number of oligomer subunits to vary from 6 to 9. Sodium periodate treatment rendered EO cells non-susceptible to NetF, suggesting that NetF binding requires cell surface carbohydrates. NetF cytotoxicity was also inhibited by a lectin that binds sialic acid, by sialidase, and by free sialic acid in excess, all of which clearly implicate sialic acid-containing membrane carbohydrates in NetF binding and/or toxicity for EO cells. Binding of NetF to sheep red blood cells was not inhibited by the gangliosides GM1, GM2 and GM3, nor did the latter promote membrane permeabilization in liposomes, suggesting that they do not constitute the cellular receptors. In contrast, treatment of EO cells with different proteases reduced their susceptibility to NetF, suggesting that the NetF receptor is a sialic acid-containing glycoprotein. PMID- 30403718 TI - Transcriptome profile analysis of leg muscle tissues between slow- and fast growing chickens. AB - Chicken is widely favored by consumers because of some unique features. The leg muscles occupy an important position in the market. However, the specific mechanism for regulating muscle growth speed is not clear. In this experiment, we used Jinghai yellow chickens with different body weights at 300 days as research subjects. The chickens were divided into fast- and slow-growing groups, and we collected leg muscles after slaughtering for use in RNA-seq. After comparing the two groups, 87 differentially expressed genes (DEGs) were identified (fold change >= 2 and FDR < 0.05). The fast-growing group had 42 up-regulated genes and 45 down-regulated genes among these DEGs compared to the slow-growing group. Six items were significantly enriched in the biological process: embryo development ending in birth or egg hatching, chordate embryonic development, embryonic skeletal system development, and embryo development as well as responses to ketones and the sulfur compound biosynthetic process. Two significantly enriched pathways were found in the KEGG pathway analysis (P-value < 0.05): the insulin signaling pathway and the adipocytokine signaling pathway. This study provides a theoretical basis for the molecular mechanism of chicken growth and for improving the production of Jinghai yellow chicken. PMID- 30403720 TI - PRY-1/Axin signaling regulates lipid metabolism in Caenorhabditis elegans. AB - The nematode Caenorhabditis elegans constitutes a leading animal model to study how signaling pathway components function in conserved biological processes. Here, we describe the role of an Axin family member, PRY-1, in lipid metabolism. Axins are scaffolding proteins that play crucial roles in signal transduction pathways by physically interacting with multiple factors and coordinating the assembly of protein complexes. Genome-wide transcriptome profiling of a pry-1 mutant revealed differentially regulated genes that are associated with lipid metabolism such as vitellogenins (yolk lipoproteins), fatty acid desaturases, lipases, and fatty acid transporters. Consistent with these categorizations, we found that pry-1 is crucial for the maintenance of lipid levels. Knockdowns of vit genes in a pry-1 mutant background restored lipid levels, suggesting that vitellogenins contribute to PRY-1 function in lipid metabolic processes. Additionally, lowered expression of desaturases and lipidomic analysis provided evidence that fatty acid synthesis is reduced in pry-1 mutants. Accordingly, an exogenous supply of oleic acid restored depleted lipids in somatic tissues of worms. Overall, our findings demonstrate that PRY-1/Axin signaling is essential for lipid metabolism and involves the regulation of yolk proteins. PMID- 30403721 TI - Concentrations of pharmaceuticals and other micropollutants in groundwater downgradient from large on-site wastewater discharges. AB - Large subsurface treatment systems (LSTS) and rapid infiltration basins (RIB) are preferred onsite wastewater treatments compared to direct discharge of treated wastewater to streams and adjacent facilities. Discharge of these wastewater treatments may result in contaminant loading to aquifers that also serve as drinking water sources downgradient from the discharge site. Until recently, few studies have characterized the contribution of micropollutants (e.g. pharmaceuticals, fragrances, flame retardants, etc.) to receiving aquifers. We conducted a pilot project to characterize the occurrence of micropollutants in groundwater downgradient from 7 on-site treatment systems in Minnesota, USA: 5 community LSTS and 2 municipal RIB. One downgradient monitoring well was sampled three times at each facility over one year. Of 223 micropollutants analyzed, 35 were detected. Total sample concentrations ranged from 90 to 4,039 ng/L. Sulfamethoxazole (antibiotic) was detected in all samples at concentrations from 7 to 965 ng/L. Other pharmaceuticals (0.12-1,000 ng/L), organophosphorus flame retardants (10-500 ng/L), and other anthropogenic chemicals (4-775 ng/L) were also detected. The numbers and concentrations of micropollutants detected were inversely related to dissolved oxygen and depth to water. Ratios of pharmaceutical concentrations to human-health screening values were <0.10 for most samples. However, concentrations of carbamazepine and sulfamethoxazole exceeded screening values at two sites. Study results illustrate that large on site wastewater systems designed to discharge to permeable soil or shallow groundwater effectively deliver pharmaceuticals and other micropollutants to groundwater aquifers and could contribute micropollutants to drinking water via water supply wells. PMID- 30403722 TI - The Howiesons Poort lithic sequence of Klipdrift Shelter, southern Cape, South Africa. AB - Howiesons Poort (HP) sites, over the past decades, have provided exceptional access to anthropogenic remains that are enhancing our understanding of early modern human behaviour during the Middle Stone Age in southern Africa. Here, we analyse the technological and typological trends in the lithic record that form part of these behaviours, based on the HP sequence recently excavated at Klipdrift Shelter, located on the southern Cape coast of South Africa. This study contributes to enhance knowledge on the mechanisms of changes that occurred during the transition to the post-HP. Despite patterns of continuity observed, notably for core reduction methods, the seven successive lithic assemblages show significant changes in the typological characteristics and raw material selection but also in the relative importance of blade production over time. However, these changes are not necessarily synchronic and occur either as gradual processes or as abrupt technological shifts. Consequently, we cross-examine the association between the lithic phasing and other anthropogenic remains within the HP sequence at Klipdrift Shelter. We explore the implications of these patterns of changes in terms of cultural behaviours and population dynamics during the HP and we highlight the relationship between the different phases of the HP sequence at Klipdrift Shelter and those from other South African HP sites. PMID- 30403724 TI - Reducing levels of medical device contamination through package redesign and opening technique. AB - OBJECTIVES: The goal of this research was to evaluate how material curl, package structure and handling of pouches containing medical devices affect rates of contact between non-sterile surfaces and sterile devices during aseptic transfer. METHODS: One hundred and thirty-six individuals with practical experience in aseptic technique were recruited. Participants were asked to present the contents of four different pouch designs (a standard, one designed to curl in, another to curl out and one that incorporated a tab) using two transfer techniques. During the first block of trials "standard technique" was used; participants presented using their typical methods to the sterile field. Trials in the second block employed "modified technique"; participants were instructed to grab the package at the top center and present package contents using a single, fluid motion. The outside of the pouch and the backs of the participants' hands were coated using a simulated contaminant before each trial. The simulant was undetectable in the visible spectrum, but fluoresced under a black light. The dependent variable was recorded in a binary fashion and analyzed using a generalized linear mixed model. RESULTS: Participants were between 20-57 and the averaged year 5.1 years of experience in aseptic technique. The data analysis was based on generalized linear mixed effects (GLMM) model, which accommodates the repeated measurements within the same participant. The effect of the pouch design was significant (P<0.001), but the effect of aseptic technique did not suggest significance (P = 0.088). Specifically, pouches designed with the material curled outward resulted in significantly fewer contacts with non-sterile surfaces than the other styles, including the inward, tab, and standard styles; this was true regardless of the used aseptic technique, standard (P = 0.0171, P = 0.0466, P = 0.0061, respectively) or modified (P<0.0001 for all comparisons)). CONCLUSION: Results presented here contribute to a growing body of knowledge that investigates packaging as a potential route of contamination for sterile devices during aseptic presentation. Specifically, we provide insights regarding how both package design and opening technique can be informed in ways that build safety into the healthcare system. PMID- 30403725 TI - Socio-economic factors associated with periodontal conditions among Brazilian elderly people - Multilevel analysis of the SBSP-15 study. AB - : The objective of the present study was to analyze individual, contextual and social support factors associated with periodontal condition among 2332 dentate elderly Brazilian participants from the Sao Paulo State Oral Health Survey 2015 (SBSP-15). METHODS: This study used the database compiled by the SBSP-15, conducted from January to December in 2015. The associations were made by relative risk (RR), with Multilevel Poisson Regressions, among individual, contextual and social support variables, and had periodontal diseases as outcomes. RESULTS: The mean age of elders was 70.13 years (SD 5.67). The risk factors for all outcomes of periodontal diseases were male gender and self perceived color of non-white skin. Regarding social support, feeling unhappy was a risk factor for the presence of shallow periodontal pockets (3-5mm) RR 1.43(CI 95% 1.10-1.86). The coverage of the Family Health Strategy (FHS) was a protective factor for gingival bleeding RR = 0.7(CI 95% 0.44-0.99) and calculus RR = 0.75(CI 95% 0.60-0.95), and a risk factor for the number of lost sextants (sextants with only one tooth or without any teeth) RR = 1.12(CI 95% 1.00-1.28). Living in municipalities with more than 90% fluoridation coverage was a protective factor for the number of lost sextants RR = 0.89(CI 95% 0.78-0.99). CONCLUSIONS: The study showed evidence that individual (gender and self-perceived skin color), contextual (coverage of the family health strategy and water fluoridation) and social support factors (feeling unhappy) are associated with the clinical outcomes of periodontal diseases in Brazilian elders. This reinforces the need for transdisciplinary actions in the FHS, stimulating work together and intersectoral collaboration between FHS and NASF (Family Health Support Center). PMID- 30403723 TI - Structure of the Golgi apparatus is not influenced by a GAG deletion mutation in the dystonia-associated gene Tor1a. AB - Autosomal-dominant, early-onset DYT1 dystonia is associated with an in-frame deletion of a glutamic acid codon (DeltaE) in the TOR1A gene. The gene product, torsinA, is an evolutionarily conserved AAA+ ATPase. The fact that constitutive secretion from patient fibroblasts is suppressed indicates that the DeltaE torsinA protein influences the cellular secretory machinery. However, which component is affected remains unclear. Prompted by recent reports that abnormal protein trafficking through the Golgi apparatus, the major protein-sorting center of the secretory pathway, is sometimes associated with a morphological change in the Golgi, we evaluated the influence of DeltaE-torsinA on this organelle. Specifically, we examined its structure by confocal microscopy, in cultures of striatal, cerebral cortical and hippocampal neurons obtained from wild-type, heterozygous and homozygous DeltaE-torsinA knock-in mice. In live neurons, the Golgi was assessed following uptake of a fluorescent ceramide analog, and in fixed neurons it was analyzed by immuno-fluorescence staining for the Golgi marker GM130. Neither staining method indicated genotype-specific differences in the size, staining intensity, shape or localization of the Golgi. Moreover, no genotype-specific difference was observed as the neurons matured in vitro. These results were supported by a lack of genotype-specific differences in GM130 expression levels, as assessed by Western blotting. The Golgi was also disrupted by treatment with brefeldin A, but no genotype-specific differences were found in the immuno-fluorescence staining intensity of GM130. Overall, our results demonstrate that the DeltaE-torsinA protein does not drastically influence Golgi morphology in neurons, irrespective of genotype, brain region (among those tested), or maturation stage in culture. While it remains possible that functional changes in the Golgi exist, our findings imply that any such changes are not severe enough to influence its morphology to a degree detectable by light microscopy. PMID- 30403726 TI - Tarin stimulates granulocyte growth in bone marrow cell cultures and minimizes immunosuppression by cyclo-phosphamide in mice. AB - Chemotherapeutic drugs, such as cyclophosphamide, cause severe immunosuppression and patients become susceptible to infections. Based on this, the immunomodulatory potential of tarin, a lectin from Colocasia esculenta, was evaluated in bone marrow cell cultures and in cyclophosphamide-immunosuppressed mice. Tarin promoted maintenance of hematopoietic progenitors and repopulation of Gr1 cells in vitro which was supported by in vivo results. In immunosuppressed mice, tarin increased bone marrow cell numbers and altered cell profile distribution by enhancing the frequency of Gr1+ progenitors, including Ly6 CintLy6-Glo, and anticipating their proliferation/differentiation in mature cells, especially Ly6-CloLy6-Ghi. Bone marrow cells harvested from tarin-treated immunosuppressed mice proliferated in response to GM-CSF or G-CSF in vitro and, the low numbers of bone marrow cells in the G0 phase, combined with a high number cells undergoing apoptosis confirmed that tarin promoted a faster and intense proliferation/differentiation, even in the presence of CY-induced toxicity. As a result, tarin minimized leukopenia in immunosuppressed mice promoting a faster recovery of peripheral leucocytes and protected erythroid bone marrow cells from CY-cytotoxicity in a dose-dependent manner. Data suggest that tarin could be considered a potential adjuvant to decrease leukopenia and possibly ameliorate anemia, if carefully evaluated in human cancer cell lineages and in clinical trials. PMID- 30403727 TI - MIRAGE syndrome is a rare cause of 46,XY DSD born SGA without adrenal insufficiency. AB - BACKGROUND: MIRAGE syndrome, a congenital multisystem disorder due to pathogenic SAMD9 variants, describes a constellation of clinical features including 46,XY disorders of sex development (DSD), small for gestational age (SGA) and adrenal insufficiency (AI). It is poorly understood whether SAMD9 variants underlie 46,XY DSD patients born SGA (46,XY DSD SGA) without AI. This study aimed to define the frequency and phenotype of SAMD9 variants in 46,XY DSD SGA without AI. METHODS: Forty-nine Japanese patients with 46,XY DSD SGA (Quigley scale, 2 to 6; gestational age-matched birth weight percentile, <10) without history of AI were enrolled. The single coding exon of SAMD9 was PCR-amplified and sequenced for each patient. Pathogenicity of an identified variant was verified in vitro. Placenta tissues were obtained from the variant-carrying patient, as well as from another previously described patient, and were analyzed histologically. RESULTS: In one 46,XY DSD SGA patient, a novel heterozygous SAMD9 variant, p.Phe1017Val, was identified. Pathogenicity of the mutant was experimentally confirmed. In addition to DSD and SGA, the patient had neonatal thrombocytopenia, severe postnatal grow restriction, chronic diarrhea and susceptibility to infection, all features consistent with MIRAGE, leading to premature death at age 14 months. The patient did not have any manifestations or laboratory findings suggesting AI. Placenta tissues of the two variant-carrying patients were characterized by maldevelopment of distal villi without other findings of maternal underperfusion. CONCLUSIONS: MIRAGE syndrome is a rare cause of 46,XY DSD SGA without AI. This study exemplifies that AI is a common feature of MIRAGE syndrome but that the absence of AI should not rule out a diagnosis of the syndrome. PMID- 30403728 TI - Is acne in adolescence associated with prostate cancer risk? Evidence from a meta analysis. AB - INTRODUCTION: Previous studies regarding the relationship between acne and prostate cancer risk have reported inconsistent results. We performed the present meta-analysis of observational studies to summarize the evidence on this association. METHODS: A comprehensive literature search up to March 2018 was performed in PubMed, Scopus, Web of Science, and Chinese National Knowledge Infrastructure (CNKI) databases. Summary odds ratios (ORs) with 95% confidence intervals (CIs) were estimated with a random effects model. The Q statistic and the I2 index were used to evaluate the heterogeneity across the studies. RESULTS: Eight studies were ultimately included in this meta-analysis. In the overall analysis, no significant association was found between acne and prostate cancer risk (OR = 1.08, 95% CI 0.93-1.25). A significant heterogeneity was observed across studies (P = 0.006, I2 = 64.5%). In the subgroup analysis by study design, a significant association was observed in the cohort studies (OR = 1.51, 95% CI 1.19-1.93) but not in the case-control studies (OR = 0.98, 95% CI 0.86-1.12). CONCLUSIONS: In summary, this meta-analysis did not find an association between acne in adolescence and prostate cancer risk. However, because there was some heterogeneity in the overall analysis and a significant association was observed in the meta-analysis of the cohort studies, further well-designed large prospective studies are warranted to confirm our results. PMID- 30403729 TI - Modeling household transmission dynamics: Application to waterborne diarrheal disease in Central Africa. AB - INTRODUCTION: We describe a method for analyzing the within-household network dynamics of a disease transmission. We apply it to analyze the occurrences of endemic diarrheal disease in Cameroon, Central Africa based on observational, cross-sectional data available from household health surveys. METHODS: To analyze the data, we apply formalism of the dynamic SID (susceptible-infected-diseased) process that describes the disease steady-state while adjusting for the household age-structure and environment contamination, such as water contamination. The SID transmission rates are estimated via MCMC method with the help of the so-called synthetic likelihood approach. RESULTS: The SID model is fitted to a dataset on diarrhea occurrence from 63 households in Cameroon. We show that the model allows for quantification of the effects of drinking water contamination on both transmission and recovery rates for household diarrheal disease occurrence as well as for estimation of the rate of silent (unobserved) infections. CONCLUSIONS: The new estimation method appears capable of genuinely capturing the complex dynamics of disease transmission across various human, animal and environmental compartments at the household level. Our approach is quite general and can be used in other epidemiological settings where it is desirable to fit transmission rates using cross-sectional data. SOFTWARE SHARING: The R-scripts for carrying out the computational analysis described in the paper are available at https://github.com/cbskust/SID. PMID- 30403730 TI - Antibiotics for amniotic-fluid colonization by Ureaplasma and/or Mycoplasma spp. to prevent preterm birth: A randomized trial. AB - OBJECTIVE: To assess whether antibiotics used for treatment in asymptomatic second-trimester women positive for Mycoplasma or Ureaplasma spp. detected by amniotic-fluid PCR prevents preterm delivery. DESIGN: A randomized, double-blind, placebo-controlled trial. SETTING: 10 maternal fetal medicine centers in France. POPULATION: Women with a singleton pregnancy who underwent amniocentesis between 16 and 20 weeks' gestation (weeks) for Down syndrome screening. A sample of 238 women with PCR-positive findings per treatment group was needed to show a 50% reduction in the preterm delivery rate. METHODS: Amniotic fluid was tested. Women with positive findings on real-time PCR of amniotic fluid for Mycoplasma hominis, Mycoplasma genitalium, Ureaplasma urealyticum and Ureaplasma parvum were randomized to receive josamycin or placebo. Amniotic fluid was also tested for 16S PCR. MAIN OUTCOME MEASURES: The primary outcome was delivery before 37 weeks. RESULTS: In total, 1043 women underwent amniotic-fluid screening with specific PCR detection between July 2008 and July 2011: PCR detection failed in 27 (2.6%), and 20 (1.9%) underwent termination of pregnancy. Among the 1016 women with PCR results, 980 had available data for the primary outcome (delivery before 37 weeks) and 29 (3.0%) were positive for Ureaplasma and/or Mycoplasma spp. Because of the low rate of women with PCR-positive findings, the trial was stopped prematurely. In total, 19 women were randomized to receive placebo (n = 8) or josamycin (n = 11) and their characteristics were comparable, as was the rate of preterm delivery and secondary outcomes. In comparing all PCR-positive and negative women regardless of treatment, PCR positivity for Ureaplasma and/or Mycoplasma spp. was not associated with any adverse pregnancy or neonatal outcome. Amniotic-fluid screening by 16S PCR showed no other bacterial colonization associated with preterm birth. CONCLUSIONS: Because of a low amniotic fluid colonization rate, the trial was interrupted. Maternal amniotic fluid colonization by Mycoplasma and/or Ureaplasma spp. at 16-20 weeks in asymptomatic women is rare and not associated with adverse pregnancy outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00718705. PMID- 30403731 TI - Adolescents have unfavorable opinions of adolescents who use e-cigarettes. AB - INTRODUCTION: While evidence suggests positive opinions of smokers are associated with tobacco use, research exploring adolescents' opinions of e-cigarette users is nascent. We hypothesized that adolescents harbor positive opinions of e cigarette users, and that these opinions will be more positive among adolescents willing to try or who have used e-cigarettes. METHODS: Participants were 578 U.S. adolescents (ages 14 to 20) recruited from ten California schools. An online survey assessed their attitudes toward and opinions of adolescents who use e cigarettes in 2015-2016. Analyses examined whether these variables were associated with willingness to try and use (ever vs. never) of e-cigarettes. RESULTS: The majority (61%) of participants had negative overall opinions toward adolescent e-cigarette users. Few participants ascribed positive traits (i.e., sexy, cool, clean, smart, and healthy) to e-cigarette users. Participants who were willing to try or had used e-cigarettes endorsed positive traits more than those unwilling to try and never-users (all p < .01). Participants sometimes endorsed negative traits (i.e., unattractive, trashy, immature, disgusting, and inconsiderate) to describe e-cigarette users. Unwilling and never-users viewed negative traits as more descriptive of e-cigarette users than willing or ever users (all p < .01). CONCLUSIONS: Adolescents generally had somewhat negative opinions of other adolescents who use e-cigarettes. Building on adolescents' negativity toward adolescent e-cigarette users may be a productive direction for prevention efforts, and clinicians can play an important role by keeping apprised of the products their adolescent patients are using and providing information on health effects to support negative opinions or dissuade formation of more positive ones. PMID- 30403732 TI - Torsional shear strength of steel joined with high performance aerospace adhesives at cryogenic and elevated temperatures. AB - Pure torsional shear tests of joints glued with two different aerospace grade adhesives were performed using a specifically designed and constructed torsional shear test equipment. The developed test equipment allows for measuring of pure torsional shear strength under cryogenic and at elevated temperature conditions. The adhesives Hysol EA 9321 and 3M Scotch-Weld EC-9323-2 B/A were used to join steel torsional shear test specimens. Torsional shear tests were performed from 180 degrees C to 150 degrees C. In addition torsional shear fatigue tests were also performed at various loads and the effect of cryogenic aging (cyclic cooling and warming) on the torsional strength of the joints was investigated. The results showed that both sets of adhesive joints achieved three times higher torsional shear strength at -180 degrees C compared to room temperature. PMID- 30403733 TI - Transmissibility of emerging viral zoonoses. AB - Effective public health research and preparedness requires an accurate understanding of which virus species possess or are at risk of developing human transmissibility. Unfortunately, our ability to identify these viruses is limited by gaps in disease surveillance and an incomplete understanding of the process of viral adaptation. By fitting boosted regression trees to data on 224 human viruses and their associated traits, we developed a model that predicts the human transmission ability of zoonotic viruses with over 84% accuracy. This model identifies several viruses that may have an undocumented capacity for transmission between humans. Viral traits that predicted human transmissibility included infection of nonhuman primates, the absence of a lipid envelope, and detection in the human nervous system and respiratory tract. This predictive model can be used to prioritize high-risk viruses for future research and surveillance, and could inform an integrated early warning system for emerging infectious diseases. PMID- 30403734 TI - Quantity processing of Chinese numeral classifiers: Distance and congruity effects. AB - A numeral classifier is required between a numeral and a noun in Chinese, which comes in two varieties, sortal classifier (C) and mensural classifier (M). A recent linguistic theory suggests that C/Ms carry quantity information, where C and M converge as the multiplicand, with numeral as the multiplier, but C and M diverge in the mathematical values they denote. However, previous empirical studies were sparse and presented inconsistent results. This study aimed to investigate the mathematical function of C/Ms using the number-size task in which participants had to choose from two C/M phrases the one that represents a larger quantity or in a larger font size. If C/M phrases engage quantity processing like numbers, distance and congruity effects should emerge. As expected, participants performed more accurately and faster at comparing two distant stimuli than two proximate ones, indicating that the mathematical values of C/M were represented like a mental number line. Moreover, participants' performance was partially influenced by the irrelevant information from the other dimension, suggesting that the mathematical values of C/Ms and the physical font size interfere with each other. These results corroborated that C/Ms play a role in magnitude cognition. PMID- 30403736 TI - Improved model adaptation approach for recognition of reduced-frame-rate continuous speech. AB - In distributed speech recognition applications, the front-end device that stands for any handheld electronic device like smartphones and personal digital assistants (PDAs) captures the speech signal, extracts the speech features, and then sends the speech-feature vector sequence to the back-end server for decoding. Since the front-end mobile device has limited computation capacity, battery power and bandwidth, there exists a feasible strategy of reducing the frame rate of the speech-feature vector sequence to alleviate the drawback. Previously, we proposed a method for adjusting the transition probabilities of the hidden Markov model to enable it to address the degradation of recognition accuracy caused by the frame-rate mismatch between the input and the original model. The previous model adaptation method is referred to as the adapting-then connecting approach that adapts each model individually and then connects the adapted models to form a word network for speech recognition. We have found that this model adaption approach introduces transitions that skip too many states and increase the number of insertion errors. In this study, we propose an improved model adaptation approach denoted as the connecting-then-adapting approach that first connects the individual models to form a word network and then adapts the connected network for speech recognition. This new approach calculates the transition matrix of a connected model, adapts the transition matrix of the connected model according to the frame rate, and then creates a transition arc for each transition probability. The new approach can better align the speech feature sequence with the states in the word network and therefore reduce the number of insertion errors. We conducted experiments to investigate the effectiveness of our new approach and analyzed the results with respect to insertion, deletion, and substitution errors. The experimental results indicate that the proposed new method obtains a better recognition rate than the old method. PMID- 30403735 TI - The relationship between serum hepatitis B virus DNA level and liver histology in patients with chronic HBV infection. AB - BACKGROUND: There is no consensus regarding the relationship between HBV DNA and liver fibrosis, and the relationship between HBV DNA and the degree of liver cirrhosis has not been reported in patients with chronic HBV infection. METHODS: From January 2011 to December 2016, liver biopsies were performed on 396 patients with chronic hepatitis B and cirrhosis. Assessments of liver fibrosis and cirrhosis were based on the Laennec staging system. RESULTS: Serum levels of HBV DNA were correlated with fibrosis and cirrhosis (KW = 73.946, P<0.001). Serum HBV DNA level was correlated with mild fibrosis, moderate to severe fibrosis and cirrhosis (P = 0.009, P<0.001, and P<0.001, respectively). The HBeAg-positive group and HBeAg-negative group showed significant differences in HBV DNA levels, and the rates of mild fibrosis, severe fibrosis and cirrhosis were significantly different between these two groups (F = 17.585, P<0.001 and F = 6.017, P = 0.003, respectively). The replication status of the serum HBV DNA affected fibrosis formation as well as cirrhosis (chi2 = 53.76, P<0.001). In the HBeAg-positive group, the sensitivity, specificity and AUC values of HBV DNA as a predictor for mild fibrosis and cirrhosis were 64.3%, 78.94% and 0.818, respectively, and 81.0%, 69.2%, and 0.871, respectively. In the HBeAg-negative group, the sensitivity, specificity and AUC values of HBV DNA for liver sclerosis prediction were 48%, 76.8% and 0.697, respectively. CONCLUSIONS: Different HBV DNA levels had different effects on the formation of fibrosis and sclerosis in liver tissues. HBV DNA levels can predict mild fibrosis and cirrhosis in liver tissue, which is enhanced in HBeAg-positive patients. PMID- 30403737 TI - Integrated transcriptome and hormone profiling highlight the role of multiple phytohormone pathways in wheat resistance against fusarium head blight. AB - Fusarium head blight (FHB or scab) caused by Fusarium spp. is a destructive disease of wheat. Since the most effective sources of FHB resistance are typically associated with unfavorable agronomic traits, breeding commercial cultivars that combine desired agronomic traits and a high level of FHB resistance remains a considerable challenge. A better understanding of the molecular mechanisms governing FHB resistance will help to design more efficient and precise breeding strategies. Here, multiple molecular tools and assays were deployed to compare the resistant variety Sumai3 with three regionally adapted Canadian cultivars. Macroscopic and microscopic disease evaluation established the relative level of Type II FHB resistance of the four varieties and revealed that the F. graminearum infection process displayed substantial temporal differences among organs. The rachis was found to play a critical role in preventing F. graminearum spread within spikes. Large-scale, organ-specific RNA seq at different times after F. graminearum infection demonstrated that diverse defense mechanisms were expressed faster and more intensely in the spikelet of resistant varieties. The roles of plant hormones during the interaction of wheat with F. graminearum was inferred based on the transcriptomic data obtained and the quantification of the major plant hormones. Salicylic acid and jasmonic acid were found to play predominantly positive roles in FHB resistance, whereas auxin and ABA were associated with susceptibility, and ethylene appeared to play a dual role during the interaction with F graminearum. PMID- 30403738 TI - Elderly patients' (>=65 years) experiences associated with discharge; Development, validity and reliability of the Discharge Care Experiences Survey. AB - BACKGROUND: A review of the literature reveals a lack of validated instruments that particularly measure quality in the hospital discharge process. This study aims to develop and validate a survey instrument feasible for measuring quality (>=65 years) related to the discharge process based on elderly patients' experiences. METHODS: Construction of the Discharge Care Patient Experience Survey (DICARES) was based on 16 items identified by literature reviews. Intraclass correlation for test-retest was applied to assess consistency of the survey. Explorative factors analysis was applied to identify and validate the factor structures of the DICARES. Cronbach's alpha was used to assess internal reliability. To evaluate the external validity of the final DICARES questionnaire the patients' scores were correlated with scores obtained from the three other questionnaires; the Nordic Patient Experiences Questionnaire, the 12-Item Short Form Health Survey and Subjective Health Complaints. The DICARES association with readmissions was examined. RESULTS: A total of 270 patients responded (64.4%). The mean age of participants was 77.1 years and 57.8% were men. The exploratory factor analysis resulted in a 10-item instrument consisting of three factors explaining 63.5% of the total variance. The Cronbach's alpha were satisfactory (>=70). Overall intraclass correlation was 0.76. A moderate Spearman correlation (rho = 0.54, p <0.01) was found between the total mean DICARES score and total mean score of the Nordic Patient Experiences Questionnaire. The total mean DICARES score was inversely associated with the quality indicator based on readmissions (OR 0.62, CI 95: 0.41-0.95, p = 0.028). CONCLUSION: We have developed a 10-item questionnaire consisting of three factors which may be a feasible instrument for measuring quality of the discharge process in elderly patients. Further testing in a wider population should be carried out before implementation in health care settings. PMID- 30403739 TI - Inferring information flow in spike-train data sets using a trial-shuffle method. AB - Understanding information processing in the brain requires the ability to determine the functional connectivity between the different regions of the brain. We present a method using transfer entropy to extract this flow of information between brain regions from spike-train data commonly obtained in neurological experiments. Transfer entropy is a statistical measure based in information theory that attempts to quantify the information flow from one process to another, and has been applied to find connectivity in simulated spike-train data. Due to statistical error in the estimator, inferring functional connectivity requires a method for determining significance in the transfer entropy values. We discuss the issues with numerical estimation of transfer entropy and resulting challenges in determining significance before presenting the trial-shuffle method as a viable option. The trial-shuffle method, for spike-train data that is split into multiple trials, determines significant transfer entropy values independently for each individual pair of neurons by comparing to a created baseline distribution using a rigorous statistical test. This is in contrast to either globally comparing all neuron transfer entropy values or comparing pairwise values to a single baseline value. In establishing the viability of this method by comparison to several alternative approaches in the literature, we find evidence that preserving the inter-spike-interval timing is important. We then use the trial-shuffle method to investigate information flow within a model network as we vary model parameters. This includes investigating the global flow of information within a connectivity network divided into two well-connected subnetworks, going beyond local transfer of information between pairs of neurons. PMID- 30403740 TI - A retrospective seroepidemiologic survey of Chlamydia pneumoniae infection in patients in Beijing between 2008 and 2017. AB - BACKGROUND: Chlamydia pneumoniae (C. pneumoniae) is an obligate intracellular bacterium and a human pathogen that causes respiratory infectious diseases. More than 50% of the adult population worldwide was once infected with C. pneumoniae, but investigations into this topic are insufficient in mainland China. METHODS: Anti-C. pneumoniae IgG and IgM antibodies were detected using micro immunofluorescence test in serum samples of patients visiting Peking Union Medical College Hospital between 2008 and 2017 for routine medical purposes, and the aim of this retrospective study was to analyze the test results. RESULTS: Among 12,050 serum specimens tested for anti-C. pneumoniae IgG and IgM antibodies, the overall prevalence of anti-C. pneumoniae IgG antibodies was 86.6%, 87.2% for men and 86.0% for women. Adult men (>20 years) were found to have a significantly higher prevalence of anti-C. pneumoniae IgG than women (chi2 = 30.32, P = 0.000). 3 to 5 years old patients were observed to have the lowest prevalence of anti-C. pneumoniae IgG, 42.8%, then increased with age, reaching the highest level of 98.6% in patients over 70 years of age. In the 10,434 specimens with C. pneumoniae IgG antibodies, the total geometric mean titer (GMT) for C. pneumoniae IgG was 45.71. Although GMTs were found to be significantly higher among all men than among all women (t = 5.916, P = 0.000), sex difference actually began in patients over 40 years of age and increased in the elderly. In the total 12,050 specimens, 1.2% had anti-C. pneumoniae IgM, 3.3% had anti-C. pneumoniae IgG with titers equal to or greater than 1:512; 0.39% had >=4-fold increasing titers of antibodies in acute and convalescent phase paired samples, and 4.4% were finally confirmed to have acute antibodies against C. pneumoniae. 6 to 10 years old patients were found to have the highest rate of both IgM antibodies (3.9%) and acute antibodies (6.2%) against C. pneumoniae. Acute antibodies against C. pneumoniae were found to be more frequent in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD, 14.0%, chi2 = 20.43, P = 0.000), patients with pneumonia (7.8%, chi2 = 51.87, P = 0.000) and patients with acute respiratory tract infection (12.3%, chi2 = 60.91, P = 0.000) than among all patients (4.4%). Both anti-C. pneumoniae IgG and IgM antibodies should be tested for acute antibodies against C. pneumoniae as testing for either alone will underestimate by a maximum of two-thirds the incidence of acute antibodies against C. pneumoniae. CONCLUSIONS: More than 86% of Chinese patients on an average were once infected with C. pneumoniae. Adult men had both a higher prevalence and higher levels of antibodies than women. 6 to10 year old patients were found to have the most frequent acute infection of C. pneumoniae. C. pneumoniae is associated with AECOPD, pneumonia and acute respiratory tract infection. Anti-C. pneumoniae IgG and IgM should be tested simultaneously to avoid underestimation of acute antibodies against C. pneumoniae. PMID- 30403741 TI - Annotation and analysis of the mitochondrial genome of Coniothyrium glycines, causal agent of red leaf blotch of soybean, reveals an abundance of homing endonucleases. AB - Coniothyrium glycines, the causal agent of soybean red leaf blotch, is a USDA APHIS-listed Plant Pathogen Select Agent and potential threat to US agriculture. Sequencing of the C. glycines mt genome revealed a circular 98,533-bp molecule with a mean GC content of 29.01%. It contains twelve of the mitochondrial genes typically involved in oxidative phosphorylation (atp6, cob, cox1-3, nad1-6, and nad4L), one for a ribosomal protein (rps3), four for hypothetical proteins, one for each of the small and large subunit ribosomal RNAs (rns and rnl) and a set of 30 tRNAs. Genes were encoded on both DNA strands with cox1 and cox2 occurring as adjacent genes having no intergenic spacers. Likewise, nad2 and nad3 are adjacent with no intergenic spacers and nad5 is immediately followed by nad4L with an overlap of one base. Thirty-two introns, comprising 54.1% of the total mt genome, were identified within eight protein-coding genes and the rnl. Eighteen of the introns contained putative intronic ORFs with either LAGLIDADG or GIY-YIG homing endonuclease motifs, and an additional eleven introns showed evidence of truncated or degenerate endonuclease motifs. One intron possessed a degenerate N acetyl-transferase domain. C. glycines shares some conservation of gene order with other members of the Pleosporales, most notably nad6-rnl-atp6 and associated conserved tRNA clusters. Phylogenetic analysis of the twelve shared protein coding genes agrees with commonly accepted fungal taxonomy. C. glycines represents the second largest mt genome from a member of the Pleosporales sequenced to date. This research provides the first genomic information on C. glycines, which may provide targets for rapid diagnostic assays and population studies. PMID- 30403742 TI - An ELISA-based method for detection of rabies virus nucleoprotein-specific antibodies in human antemortem samples. AB - Rabies is a fatal encephalitic disease in humans and animals caused by lyssaviruses, most commonly rabies virus (RABV). Human antemortem diagnosis of rabies is a complex process involving multiple sample types and tests for the detection of antibodies, antigen (protein), and nucleic acids (genomic RNA). Serological diagnosis of human rabies includes the detection of either neutralizing or binding antibodies in the cerebrospinal fluid (CSF) or serum samples from unimmunized individuals without prior rabies vaccination or passive immunization with purified immunoglobulins. While neutralizing antibodies are targeted against the surface-expressed glycoprotein (G protein), binding antibodies to viral antigens are predominantly against the nucleoprotein (N protein), although there can be antibodies against all RABV-expressed proteins. To determine N protein-specific antibody responses in the CSF and serum during RABV infection, we developed an enzyme-linked immunosorbent assay (ELISA) with purified recombinant N protein expressed in E. coli. N protein-specific immunoglobulin (Ig) subtypes IgG and IgM were detected in the CSF or serum of previously diagnosed human rabies cases. In addition, anti-N protein seroconversion was demonstrated over the course of illness in individual rabies cases. We compared the N protein ELISA results to those of an indirect fluorescent antibody (IFA) test, the current binding antibody assay used in diagnosis, and show that our ELISA is consistent with the IFA test. Sensitivity and specificity of the N protein ELISA ranged from 78.38-100% and 75.76-96.77% with respect to the IFA results. Our data provide evidence for the use of an N protein ELISA as an additional option for the detection of RABV-specific IgG or IgM antibodies in human CSF or serum specimens. PMID- 30403743 TI - Defining heatwave thresholds using an inductive machine learning approach. AB - Establishing appropriate heatwave thresholds is important in reducing adverse human health consequences as it enables a more effective heatwave warning system and response plan. This paper defined such thresholds by focusing on the non linear relationship between heatwave outcomes and meteorological variables as part of an inductive approach. Daily data on emergency department visitors who were diagnosed with heat illnesses and information on 19 meteorological variables were obtained for the years 2011 to 2016 from relevant government agencies. A Multivariate Adaptive Regression Splines (MARS) analysis was performed to explore points (referred to as "knots") where the behaviour of the variables rapidly changed. For all emergency department visitors, two thresholds (a maximum daily temperature >= 32.58 degrees C for 2 consecutive days and a heat index >= 79.64) were selected based on the dramatic rise of morbidity at these points. Nonetheless, visitors, who included children and outside workers diagnosed in the early summer season, were reported as being sensitive to heatwaves at lower thresholds. The average daytime temperature (from noon to 6 PM) was determined to represent an alternative threshold for heatwaves. The findings have implications for exploring complex heatwave-morbidity relationships and for developing appropriate intervention strategies to prevent and mitigate the health impact of heatwaves. PMID- 30403744 TI - Comparison of FIB-4 and transient elastography in evaluating liver fibrosis of chronic hepatitis C subjects in community. AB - BACKGROUND AND AIM: The role of non-invasive methods to evaluate fibrosis severity of chronic hepatitis C (CHC) subjects in community needs to be explored. This study investigated FIB-4 and transient elastography (TE) in staging liver fibrosis of CHC subjects in community. METHODS: A total of 905 subjects who were positive for anti-HCV antibody from five districts of Tainan City of Taiwan were invited to participate in surveillance activities for CHC. FIB-4 and TE were measured for each participant. RESULTS: A total of 502 subjects with detectable HCV RNA and valid TE were enrolled. The distribution of FIB-4 and TE values differed markedly. Both methods exhibited a strongest correlation in subjects with at age 50~60 years (r = 0.655, p <0.001). FIB-4 score increased proportionally with age (p <0.001), but TE did not (p = 0.142). The intraclass correlation efficient of both methods was 0.255 (p <0.001). Subjects with TE defined advanced fibrosis exhibited younger age, higher BMI, higher platelet count, lower FIB-4 score, higher incidence of fatty liver and splenomegaly, and higher controlled attenuation parameter value than those defined by FIB-4. By multivariate logistic regression analysis, higher ALT levels, higher incidence of fatty liver, and presence of splenomegaly were the independent factors associated with advanced fibrosis defined by TE rather than defined by FIB-4. CONCLUSIONS: FIB-4 and TE defined different distribution of fibrosis stages in same HCV population. FIB-4 was deeply influenced by age whereas TE was not. TE had the advantages over than FIB-4 in strong association with splenomegaly and in detecting the role of non-alcoholic fatty liver disease in advanced fibrosis. PMID- 30403745 TI - Water-soluble cranberry extract inhibits Vibrio cholerae biofilm formation possibly through modulating the second messenger 3', 5' - Cyclic diguanylate level. AB - Quorum sensing (QS) and nucleotide-based second messengers are vital signaling systems that regulate bacterial physiology in response to changing environments. Disrupting bacterial signal transduction is a promising direction to combat infectious diseases, and QS and the second messengers are undoubtedly potential targets. In Vibrio cholerae, both QS and the second messenger 3', 5'-cyclic diguanylate (c-di-GMP) play a central role in controlling motility, motile-to sessile life transition, and virulence. In this study, we found that water soluble extract from the North American cranberry could significantly inhibit V. cholerae biofilm formation during the development/maturation stage by reducing the biofilm matrix production and secretion. The anti-biofilm effect by water soluble cranberry extract was possibly through modulating the intracellular c-di GMP level and was independent of QS and the QS master regulator HapR. Our results suggest an opportunity to explore more functional foods to fight stubborn infections through interference with the bacterial signaling systems. PMID- 30403746 TI - Using linked electronic health records to report healthcare-associated infections. AB - BACKGROUND: Reporting of strategic healthcare-associated infections (HCAIs) to Public Health England is mandatory for all acute hospital trusts in England, via a web-based HCAI Data Capture System (HCAI-DCS). AIM: Investigate the feasibility of automating the current, manual, HCAI reporting using linked electronic health records (linked-EHR), and assess its level of accuracy. METHODS: All data previously submitted through the HCAI-DCS by the Oxford University Hospitals infection control (IC) team for methicillin-resistant and methicillin-susceptible Staphylococcus aureus (MRSA, MSSA), Clostridium difficile, and Escherichia coli, through March 2017 were downloaded and compared to outputs created from linked EHR, with detailed comparisons between 2013-2017. FINDINGS: Total MRSA, MSSA, E. coli and C. difficile cases entered by the IC team vs linked-EHR were 428 vs 432, 795 vs 816, 2454 vs 2450 and 3365 vs 3393 respectively. From 2013-2017, most discrepancies (32/37 (86%)) were likely due to IC recording errors. Patient and specimen identifiers were completed for >98% of cases by both methods, with very high agreement (>97%). Fields relating to the patient at the time the specimen was taken were complete to a similarly high level (>99% IC, >97% linked-EHR), and agreement was fairly good (>80%) except for the main and treatment specialties (57% and 54% respectively) and the patient category (55%). Optional, organism specific data-fields were less complete, by both methods. Where comparisons were possible, agreement was reasonably high (mostly 70-90%). CONCLUSION: Basic factual information, such as demographic data, is almost-certainly better automated, and many other data fields can potentially be populated successfully from linked-EHR. Manual data collection is time-consuming and inefficient; automated electronic data collection would leave healthcare professionals free to focus on clinical rather than administrative work. PMID- 30403747 TI - Smaller volumes in the lateral and basal nuclei of the amygdala in patients with panic disorder. AB - The amygdala plays an important functional role in fear and anxiety. Abnormalities in the amygdala are believed to be involved in the neurobiological basis of panic disorder (PD). Previous structural neuroimaging studies have found global volumetric and morphological abnormalities in the amygdala in patients with PD. Very few studies, however, have explored for structural abnormalities in various amygdala sub-regions, which consist of various sub-nuclei, each with different functions. This study aimed to evaluate for volumetric abnormalities in the amygdala sub-nuclei, in order to provide a better understanding neurobiological basis of PD. Thirty-eight patients with PD and 38 matched healthy control (HC) participants underwent structural MRI scanning. The volume of the whole amygdala, as well as its consistent sub-nuclei, were calculated using FreeSurfer software. Relative volumes of these amygdala sub-regions were compared between the two groups. Results showed significantly smaller volumes in the right lateral and basal nuclei in the patients with PD compared with the HC. Lateral and basal nuclei are thought to play crucial role for processing sensory information related with anxiety and fear. Our results suggest that these particular amygdala sub-regions play a role in the development of PD symptoms. PMID- 30403748 TI - Investigation of Ldb19/Art1 localization and function at the late Golgi. AB - The arrestin-related family of proteins (ARTs) are potent regulators of membrane traffic at multiple cellular locations in the yeast Saccharomyces cerevisiae. Several ARTs act at multiple locations, suggesting that ARTs with well established functions at one location may have additional, as of yet, uncharacterized roles at other locations in the cell. To more fully understand the spectrum of cellular functions regulated by ART proteins, we explored the localization and function of Ldb19/Art1, which has previously been shown to function at the plasma membrane, yet is reported to localize to the trans-Golgi network (TGN). We report that the C-terminal fusion of Ldb19 with GFP is functional and, as previously reported, localizes to the TGN. We further establish that Ldb19 associates with late stages of TGN maturation that are enriched in the clathrin adaptor protein complex-1 (AP-1). Additionally, we present genetic interaction assays that suggest Ldb19 acts at the late TGN in a mechanism related to that of AP-1. However, Ldb19 and AP-1 have dissimilar phenotypes in a subset of assays of membrane traffic, suggesting Ldb19 functions at the TGN are distinct from those of AP-1. Together these results indicate Ldb19 functions at the TGN, in addition to its well-established role in endocytosis. PMID- 30403750 TI - Correction: Biologically anchored knowledge expansion approach uncovers KLF4 as a novel insulin signaling regulator. AB - [This corrects the article DOI: 10.1371/journal.pone.0204100.]. PMID- 30403749 TI - Lack of serological and molecular evidence of arbovirus infections in bats from Brazil. AB - Viruses are important agents of emerging zoonoses and are a substantial public health issue. Among emerging viruses, an important group are arboviruses, which are characterized by being maintained in nature in cycles involving hematophagous arthropod vectors and a wide range of vertebrate hosts. Recently, bats have received increasing attention as an important source for the emergence of zoonoses and as possible viral reservoirs. Among the arboviruses, there are many representatives of the genera Flavivirus and Alphavirus, which are responsible for important epidemics such as Dengue virus, Zika virus and Chikungunya virus. Due to the importance of analyzing potential viral reservoirs for zoonosis control and expanding our knowledge of bat viruses, this study aimed to investigate the presence of viruses of the Alphavirus and Flavivirus genera in bats. We analyzed serum, liver, lungs and intestine from 103 bats sampled in northeast and southern Brazil via Nested-PCR and the hemagglutination inhibition test. All samples tested in this study were negative for arboviruses, suggesting that no active or past infection was present in the captured bats. These data indicate that the bats examined herein probably do not constitute a reservoir for these viruses in the studied areas. Further studies are needed to clarify the role of bats as reservoirs and sources of infection of these viral zoonoses. PMID- 30403751 TI - The sex specific effect of alcohol consumption on circulating levels of CTRP3. AB - The goal of this project was to establish the effect of alcohol consumption on the circulating levels of the adipose tissue derived protein C1q TNF Related Protein 3 (CTRP3). Adipose tissue secretes several adipokines, such as adiponectin and leptin, which exert a multitude of biological effects important for human health. However, adipose tissue is extremely sensitive to alcohol consumption, leading not only to disrupted fat storage, but also to disruptions in adipokine production. Changes to adipokine secretion could have widespread biological effects and potentially contribute to alcohol-induced ailments, such as alcoholic fatty liver disease (ALD). CTRP3 has been previously demonstrated to attenuate fatty liver disease, and suppression of CTRP3 with alcohol consumption could contribute to development of and progression to alcoholic fatty liver disease. To examine the effect of ethanol consumption on circulating adipokine levels, male and female mice were fed an ethanol containing diet (Lieber-DeCarli 5% (v/v) ethanol diet) for 10-days followed by a single gavage of 5 g/kg ethanol (the NIAAA model), or for 6-weeks with no binge added (chronic model). In female mice, adiponectin levels increased ~2-fold in both models of ethanol feeding, but in male mice increased adiponectin levels were only observed after chronic ethanol feeding. On the other hand, in female mice, circulating CTRP3 levels decreased by ~75% and ~50% in the NIAAA and chronic model, respectively, with no changes observed in the male mice in either feeding model. Leptin levels were unchanged with ethanol feeding regardless of model or sex of mice. Lastly, chronic ethanol feeding led to a significant increase in mortality (~50%) in female mice, with no difference in relative ethanol consumption. These findings indicate that ethanol consumption can dysregulate adipokine secretion, but that the effects vary by sex of animal, method of ethanol consumption, and adipokine examined. These findings also indicate that female mice are more sensitive to the chronic effects of ethanol than male mice. Notably, this is the first study to document the effects of ethanol consumption on the circulating levels of CTRP3. Understanding the impact of excessive alcohol consumption on adipokine production and secretion could identify novel mechanisms of alcohol-induced human disease. However, the mechanism responsible for the increased sensitivity remains elusive. PMID- 30403752 TI - Overcoming mechanical adversity in extreme hindleg weapons. AB - The size of sexually selected weapons and their performance in battle are both critical to reproductive success, yet these traits are often in opposition. Bigger weapons make better signals. However, due to the mechanical properties of weapons as lever systems, increases in size may inhibit other metrics of performance as different components of the weapon grow out of proportion with one another. Here, using direct force measurements, we investigated the relationship between weapon size and weapon force production in two hindleg weapon systems, frog-legged beetles (Sagra femorata) and leaf-footed cactus bugs (Narnia femorata), to test for performance tradeoffs associated with increased weapon size. In male frog-legged beetles, relative force production decreased as weapon size increased. Yet, absolute force production was maintained across weapon sizes. Surprisingly, mechanical advantage was constant across weapon sizes and large weaponed males had disproportionately large leg muscles. In male leaf footed cactus bugs, on the other hand, there was no relationship between weapon size and force production, likely reflecting the importance of their hindlegs as signals rather than force-producing structures of male-male competition. Overall, our results suggest that when weapon force production is important for reproductive success, large weaponed animals may overcome mechanical challenges by maintaining proportional lever components and investing in (potentially costly) compensatory mechanisms. PMID- 30403753 TI - A computational strategy for finding novel targets and therapeutic compounds for opioid dependence. AB - Opioids are widely used for treating different types of pains, but overuse and abuse of prescription opioids have led to opioid epidemic in the United States. Besides analgesic effects, chronic use of opioid can also cause tolerance, dependence, and even addiction. Effective treatment of opioid addiction remains a big challenge today. Studies on addictive effects of opioids focus on striatum, a main component in the brain responsible for drug dependence and addiction. Some transcription regulators have been associated with opioid addiction, but relationship between analgesic effects of opioids and dependence behaviors mediated by them at the molecular level has not been thoroughly investigated. In this paper, we developed a new computational strategy that identifies novel targets and potential therapeutic molecular compounds for opioid dependence and addiction. We employed several statistical and machine learning techniques and identified differentially expressed genes over time which were associated with dependence-related behaviors after exposure to either morphine or heroin, as well as potential transcription regulators that regulate these genes, using time course gene expression data from mouse striatum. Moreover, our findings revealed that some of these dependence-associated genes and transcription regulators are known to play key roles in opioid-mediated analgesia and tolerance, suggesting that an intricate relationship between opioid-induce pain-related pathways and dependence may develop at an early stage during opioid exposure. Finally, we determined small compounds that can potentially target the dependence-associated genes and transcription regulators. These compounds may facilitate development of effective therapy for opioid dependence and addiction. We also built a database (http://daportals.org) for all opioid-induced dependence-associated genes and transcription regulators that we discovered, as well as the small compounds that target those genes and transcription regulators. PMID- 30403755 TI - Impacts of soil salinity on Bt protein concentration in square of transgenic Bt cotton. AB - Insect-resistance of transgenic Bacillus thuringiensis (Bt) cotton varies among plants organs and with different environmental conditions. The objective of this study was to examine the influence of soil salinity on Bt protein concentration in cotton squares and to elucidate the potential mechanism of Bt efficacy reduction. Two cotton cultivars (NuCOTN 33B and CCRI 07, salt-sensitive and salt tolerant) were subjected to salinity stress under four natural saline levels in field conditions in 2015 and 2016 and seven regimes of soil salinity ranged from 0.5 to 18.8 dS m-1 in greenhouse conditions in 2017. Results of field studies revealed that Bt protein content was not significantly changed at 7.13 dS m-1 salinity, but exhibited a significant drop at the 10.41 and 14.16 dS m-1 salinity. The greenhouse experiments further showed similar trends that significant declines of the insecticidal protein contents in squares were detected when soil salinity exceeded 9.1 dS m-1. Meanwhile, high salinity resulted in significant reduction in contents of soluble protein and total nitrogen, activities of nitrate reductase (NR), glutamine synthetase (GS) and glutamic-pyruvic transaminase (GPT), but increased amino acid content, activities of protease and peptidase in cotton squares. High salinity also decreased root vigor (RV), root total absorption area (RTA) and root active absorption area (RAA). The extent of decrease of Bt protein content was more pronounced in NuCOTN 33B than CCRI 07, and CCRI07 exhibited stronger enzymes activities involved in square protein synthesis and higher levels of RV, RTA and RAA. Therefore, the results of our present study indicated that insecticidal protein expression in cotton squares were significantly affected by higher salinity (equal to or higher than 9.1 dS m-1), reduced protein synthesis and increased protein degradation in squares and reduced metabolic activities in roots might lead to the decrease of Bt protein content in squares. PMID- 30403754 TI - Metabolomic insights of macrophage responses to graphene nanoplatelets: Role of scavenger receptor CD36. AB - Graphene nanoplatelets (GNPs) are novel two-dimensional engineered nanomaterials consisting of planar stacks of graphene. Although human exposures are increasing, our knowledge is lacking regarding immune-specific responses to GNPs and mechanisms of interactions. Our current study utilizes a metabolite profiling approach to evaluate macrophage responses to GNPs. Furthermore, we assessed the role of the scavenger receptor CD36 in mediating these GNP-induced responses. GNPs were purchased with dimensions of 2 MUm * 2 MUm * 12 nm. Macrophages were exposed to GNPs at different concentrations of 0, 25, 50, or 100 MUg/ml for 1, 3, or 6 h. Following exposure, no cytotoxicity was observed, while GNPs readily associated with macrophages in a concentration-dependent manner. After the 1h pretreatment of either a CD36 competitive ligand sulfo-N-succinimidyl oleate (SSO) or a CD36 specific antibody, the cellular association of GNPs by macrophages was significantly reduced. GNP exposure was determined to alter mitochondrial membrane potential while the pretreatment with a CD36 antibody inhibited these changes. In a separate exposure, macrophages were exposed to GNPs at concentrations of 0, 50, or 100 MUg/mL for 1 or 3h or 100 MUM SSO (a CD36 specific ligand) for 1h and collected for metabolite profiling. Principal component analysis of identified compounds determined differential grouping based on exposure conditions. The number of compounds changed following exposure was determined to be both concentration- and time-dependent. Identified metabolites were determined to relate to several metabolism pathways such as glutathione metabolism, Pantothenate and CoA biosynthesis, Sphingolipid metabolism, Purine metabolism, arachidonic acid metabolism and others. Lastly, a number of metabolites were found in common between cells exposed to the CD36 receptor ligand, SSO, and GNPs suggesting both CD36-dependent and independent responses to GNP exposure. Together our data demonstrates GNP-macrophage interactions, the role of CD36 in the cellular response, and metabolic pathways disrupted due to exposure. PMID- 30403757 TI - Reduction of Acquisition time using Partition of the sIgnal Decay in Spectroscopic Imaging technique (RAPID-SI). AB - To overcome long acquisition times of Chemical Shift Imaging (CSI), a new Magnetic Resonance Spectroscopic Imaging (MRSI) technique called Reduction of Acquisition time by Partition of the sIgnal Decay in Spectroscopic Imaging (RAPID SI) using blipped phase encoding gradients inserted during signal acquisition was developed. To validate the results using RAPID-SI and to demonstrate its usefulness in terms of acquisition time and data quantification; simulations, phantom and in vivo studies were conducted, and the results were compared to standard CSI. The method was based upon the partition of a magnetic resonance spectroscopy (MRS) signal into sequential sub-signals encoded using blipped phase encoding gradients inserted during signal acquisition at a constant time interval. The RAPID-SI technique was implemented on a clinical 3 T Siemens scanner to demonstrate its clinical utility. Acceleration of data collection was performed by inserting R (R = acceleration factor) blipped gradients along a given spatial direction during data acquisition. Compared to CSI, RAPID-SI reduced acquisition time by the acceleration factor R. For example, a 2D 16x16 data set acquired in about 17 min with CSI, was reduced to approximately 2 min with the RAPID-SI (R = 8). While the SNR of the acquired RAPID-SI signal was lower compared to CSI by approximately the factor ?R, it can be improved after data pre-processing and reconstruction. Compared to CSI, RAPID-SI reduces acquisition time, while preserving metabolites information. Furthermore, the method is flexible and could be combined with other acceleration methods such as Parallel Imaging. PMID- 30403756 TI - Effects of a preconception lifestyle intervention in obese infertile women on diet and physical activity; A secondary analysis of a randomized controlled trial. AB - BACKGROUND: Lifestyle changes are notoriously difficult. Since women who intend to become pregnant are more susceptible to lifestyle advice, interventions during this time window might be more effective than interventions during any other period in life. We here report the effects of the first large preconception lifestyle intervention RCT on diet and physical activity in obese infertile women. METHODS: In total, 577 women were randomized between a six-month lifestyle intervention program (intervention group; N = 290) or prompt infertility treatment (control group; N = 287). Self-reported dietary behaviors and physical activity were assessed at baseline, three, six and twelve months after randomization. Mixed models were used to analyze differences between groups. RESULTS: Compared to the control group, the intervention group reduced their intake of sugary drinks at three months (-0.5 glasses/day [95% C.I. = -0.9; 0.2]), of savory snacks at three (-2.4 handful/week [-3.4;-1.4]) and at six months (-1.4 handful/week [-2.6;-0.2]), and of sweet snacks at three (-2.2 portion/week [-3.3;-1.0]) and twelve months after randomization (-1.9 portion/week [-3.5;-0.4]). Also, the intervention group was more moderate to vigorous physically active at three months after randomization compared to the control group (169.0 minutes/week [6.0; 332.1]). CONCLUSION: Our study showed that obese infertile women who followed a six-month preconception lifestyle intervention program decreased their intake of high caloric snacks and beverages, and increased their physical activity. These changes in lifestyle may not only improve women's health but their offspring's health too. PMID- 30403758 TI - Accuracy of health administrative data to identify cases of reportable travel or migration-related infectious diseases in Ontario, Canada. AB - An ongoing challenge of estimating the burden of infectious diseases known to disproportionately affect migrants (e.g. malaria, enteric fever) is that many health information systems, including reportable disease surveillance systems, do not systematically collect data on migrant status and related factors. We explored whether health administrative data linked to immigration records offered a viable alternative for accurately identifying cases of hepatitis A, malaria and enteric fever in Ontario, Canada. Using linked health care databases generated by Ontario's universal health care program, we constructed a cohort of medically attended individuals with presumed hepatitis A, malaria or enteric fever in Peel region using diagnostic codes. Immigrant status was ascertained using linked immigration data. The sensitivity and positive predictive value (PPV) of diagnostic codes was evaluated through probabilistic linkage of the cohort to Ontario's reportable disease surveillance system (iPHIS) as the reference standard. Linkage was successful in 90.0% (289/321) of iPHIS cases. While sensitivity was high for hepatitis A and enteric fever (85.8% and 83.7%) and moderate for malaria (69.0%), PPV was poor for all diseases (0.3-41.3%). The accuracy of diagnostic codes did not vary by immigrant status. A dated coding system for outpatient physician claims and exclusion of new immigrants not yet eligible for health care were key challenges to using health administrative data to identify cases. Despite this, we show that linkages of health administrative and immigration records with reportable disease surveillance data are feasible and have the potential to bridge important gaps in estimating burden using either data source independently. . PMID- 30403760 TI - Correction: Evaluation of a novel biodegradable thermosensitive keto-hydrogel for improving postoperative pain in a rat model. AB - [This corrects the article DOI: 10.1371/journal.pone.0186784.]. PMID- 30403759 TI - A simple saccadic reading test to assess ocular motor function in cerebellar ataxia. AB - Cerebellar ataxia is a neurological disorder due to dysfunction of the cerebellum that affects coordination of fine movement, gait, and balance. Although ataxic patients commonly exhibit abnormal eye movement and have difficulties with saccadic reading, quantification of ocular motor abilities during reading in the clinical setting is rarely done. In this study, we assess visual performance with simple reading tests that can be used in the clinical setting and performed video infrared oculography in 11 patients with hereditary or acquired cerebellar ataxia and 11 age-matched controls. We found that compared with controls, ataxic patients read significantly slower on regularly and irregularly spaced 120 single digit number reading tasks (read aloud) (p = 0.02 for both) but not on a word reading task (read silently), although there was large variability on the word reading task. Among the 3 reading tasks, the regularly spaced number reading task had the greatest difference (44%) between ataxic patients and controls. Analysis of oculography revealed that ataxic patients had slower reading speeds on the regularly spaced number reading task because of significantly higher saccade and fixation counts, impairment of small amplitude progressive saccades as well as large amplitude, line-changing saccades, greater fixation dispersion, and irregularity of scan paths and staircase gaze patterns. Our findings show that infrared oculography remains the gold standard in assessment of ocular motor difficulties during reading in ataxic patients. In the absence of this capability in the clinical setting, a simple 120 regularly spaced single-digit saccadic number reading test, which most patients can perform in less than 2 minutes, can be a possible biomarker for ocular motor abilities necessary for reading. PMID- 30403761 TI - Single unit activities recorded in the thalamus and the overlying parietal cortex of subjects affected by disorders of consciousness. AB - The lack of direct neurophysiological recordings from the thalamus and the cortex hampers our understanding of vegetative state/unresponsive wakefulness syndrome and minimally conscious state in humans. We obtained microelectrode recordings from the thalami and the homolateral parietal cortex of two vegetative state/unresponsive wakefulness syndrome and one minimally conscious state patients during surgery for implantation of electrodes in both thalami for chronic deep brain stimulation. We found that activity of the thalamo-cortical networks differed among the two conditions. There were half the number of active neurons in the thalami of patients in vegetative state/unresponsive wakefulness syndrome than in minimally conscious state. Coupling of thalamic neuron discharge with EEG phases also differed in the two conditions and thalamo-cortical cross frequency coupling was limited to the minimally conscious state patient. When consciousness is physiologically or pharmacologically reversibly suspended there is a significant increase in bursting activity of the thalamic neurons. By contrast, in the thalami of our patients in both conditions fewer than 17% of the recorded neurons showed bursting activity. This indicates that these conditions differ from physiological suspension of consciousness and that increased thalamic inhibition is not prominent. Our findings, albeit obtained in a limited number of patients, unveil the neurophysiology of these conditions at single unit resolution and might be relevant for inspiring novel therapeutic options. PMID- 30403762 TI - Ecology of reproduction of Anopheles arabiensis in an urban area of Bobo Dioulasso, Burkina Faso (West Africa): Monthly swarming and mating frequency and their relation to environmental factors. AB - Swarming is a key part of the natural system of reproduction of anopheline mosquito populations, and a better understanding of swarming and mating systems in a targeted species in its natural habitat would contribute to better design control strategies with a greater chance of success. Our study investigated the monthly occurrence of swarming and the mating frequency (within swarms) of Anopheles arabiensis in Dioulassoba, Burkina Faso and their relationship with local environmental factors. Mosquitoes collected from swarms were described in terms of body size, recent sugar meal intake, and female repletion, insemination, and Plasmodium falciparum infection status. Swarms of An. arabiensis were found in each month of the year. Both start and end times of swarming varied significantly between months, correlating with the time of sunset. Swarming mostly started after or coincided with sunset from late July to early October but occurred before sunset from late October to early July. Swarming duration, the number of mosquitoes and mating pairs per swarm, and time to first mating were significantly different between months in an inverse relationship with the monthly rainfall. The number of mating pairs was strongly and positively correlated with swarm size. Almost all the females caught in copula were inseminated but a very few were blood fed; no P. falciparum infection was observed. Males caught in copula and in solo were similar in body size and in the proportion which had taken a recent sugar meal. Our investigations showed that An. arabiensis reproductive activities are most frequent during the dry season, suggesting either the species' preference for dry climatic conditions or a lack of available breeding sites during the rainy season due to the seasonal flooding in this area. Targeting interventions to kill mosquitoes in swarms or to achieve an over-flooding ratio of sterile males during the rainy season would increase their efficiency in reducing the population density of this vector. PMID- 30403763 TI - A survey on adolescent health information seeking behavior related to high-risk behaviors in a selected educational district in Isfahan. AB - BACKGROUNDS: The characteristics and conditions of growth and development have made adolescence one of the most vital and influential ages for prevention and health promotion, especially in the area of high-risk behaviors. Accordingly, the aim of this study was to determine adolescent health information seeking behavior related to high-risk behaviors in a selected educational district in Isfahan (Iran). METHODOLOGY: The present study was of an applied type, which was conducted using the survey research method. The statistical population consisted of adolescent students at public schools in Isfahan (6519 subjects), and the sample size was determined to be 364 based on Cochran's formula. The sampling method was of a cluster sampling type, and the data collection tool was a researcher-made questionnaire. The validity of the questionnaire was approved by medical librarians, and using the Cronbach's alpha method, the reliability was obtained to be 0.85. SPSS 16 software was used for data analysis at two statistical levels: descriptive and inferential (independent t-test, one-sample t test, chi-square, Pearson correlation coefficient and Mann-Whitney). FINDINGS: "Lack of mobility" was the most important health information need related to adolescent high-risk behaviors. The most important sources to obtain health information related to high-risk behaviors were "the Internet" with a mean score of 3.69 and "virtual social media" with a mean score of 3.49 out of 5. Adolescents had a positive attitude towards health information. The most important barriers to seeking health information were mentioned as follows: "difficulty in determining the quality of information found", "absence of appropriate information", and "concerns about the disclosure of their problems or illness to others". From the perspective of adolescents, the most important criterion for the evaluation of information quality was "the trueness and correctness of the information" and the need for health information related to high-risk behaviors was higher in girls than in boys. CONCLUSIONS/SIGNIFICANCE: Considering adolescents' positive attitude towards use of health information, it is necessary to put valid information at their disposal through different information resources, taking into account their level of information literacy. Accordingly, medical librarians' abilities are suggested to be used for the production, evaluation, and introduction of health-related reading materials in the field of high-risk behaviors in easy language and suitable for adolescents. PMID- 30403764 TI - Semantic analysis and the evolution towards participative branding: Do locals communicate the same destination brand values as DMOs? AB - Participative branding is a process by which DMOs, locals and visitors contribute, through their activity in social media, to the definition of the emotional values associated to a destination. From the communicative point of view it is particularly important that DMOs and local citizens work together in the transmission of a set of coherent values that compose a personalised identity. This paper presents a novel methodology, based on semantic similarity measures, that permits to make an automated analysis of the emotional values transmitted by official tourist offices and by local citizens through social media. A study of 54,000 tweets from 9 main European tourist destinations highlights the lack of a strategy towards the communication of a distinctive brand and a strong gap between the official view transmitted by the DMOs of the destinations and the one communicated by their residents. PMID- 30403765 TI - Simple but robust improvement in multivoxel pattern classification. AB - Multivoxel pattern analysis (MVPA) typically begins with the estimation of single trial activation levels, and several studies have examined how different procedures for estimating single trial activity affect the ultimate classification accuracy of MVPA. Here we show that the currently preferred estimation procedures impart spurious positive correlations between the means of different category activity estimates within the same scanner run. In other words, if the mean of the estimates for one type of trials is high (low) in a given scanner run, then the mean of the other type of trials is also high (low) for that same scanner run, and the run-level mean across all trials therefore shifts from run to run. Simulations show that these correlations occur whenever there is a need to deconvolve overlapping trial activities in the presence of noise. We show that subtracting each voxel's run-level mean across all trials from all the estimates within that run (i.e., run-level mean centering of estimates), by cancelling out these mean shifts, leads to robust and significant improvements in MVPA classification accuracy. These improvements are seen in both simulated and real data across a wide variety of situations. However, we also point out that there could be cases when mean activations are expected to shift across runs and that run-level mean centering could be detrimental in some of these cases (e.g., different proportion of trial types between different runs). PMID- 30403767 TI - In vitro axenic germination and cultivation of mixotrophic Pyroloideae (Ericaceae) and their post-germination ontogenetic development. AB - Background and Aims: Pyroloids, forest sub-shrubs of the Ericaceae family, are an important model for their mixotrophic nutrition, which mixes carbon from photosynthesis and from their mycorrhizal fungi. They have medical uses but are difficult to cultivate ex situ; in particular, their dust seeds contain undifferentiated, few-celled embryos, whose germination is normally fully supported by fungal partners. Their germination and early ontogenesis thus remain elusive. Methods: An optimized in vitro cultivation system of five representatives from the subfamily Pyroloideae was developed to study the strength of seed dormancy and the effect of different media and conditions (including light, gibberellins and soluble saccharides) on germination. The obtained plants were analysed for morphological, anatomical and histochemical development. Key Results: Thanks to this novel cultivation method, which breaks dormancy and achieved up to 100 % germination, leafy shoots were obtained in vitro for representatives of all pyroloid genera (Moneses, Orthilia, Pyrola and Chimaphila). In all cases, the first post-germination stage is an undifferentiated structure, from which a root meristem later emerges, well before formation of an adventive shoot. Conclusions: This cultivation method can be used for further research or for ex situ conservation of pyroloid species. After strong seed dormancy is broken, the tiny globular embryo of pyroloids germinates into an intermediary zone, which is functionally convergent with the protocorm of other plants with dust seeds such as orchids. Like the orchid protocorm, this intermediary zone produces a single meristem: however, unlike orchids, which produce a shoot meristem, pyroloids first generate a root meristem. PMID- 30403766 TI - GnRH agonist long protocol versus GnRH antagonist protocol for various aged patients with diminished ovarian reserve: A retrospective study. AB - This retrospective analysis compared the efficiency of the gonadotropin- releasing hormone (GnRH) antagonist (GnRH-ant) protocol and the GnRH agonist long (GnRH-a) protocol for patients with diminished ovarian reserve (DOR). A total of 1,233 patients with DOR (anti-Mullerian hormone <1.1 ng/mL) were recruited for this retrospective case-control study. They were divided into two groups according to female age. Younger patients were assigned to POSEIDON group3 (PG3: age <=35 years); older patients were assigned to POSEIDON group 4 (PG4: age >35 years). All patients with DOR underwent controlled ovarian stimulation and fresh embryo transfer (ET) on day 3. We recruited 283 GnRH-a and 54 GnRH-ant cycles for PG3, and 663 GnRH-a and 233 GnRH-ant cycles for PG4. In PG3, the GnRH-a protocol was associated with a lower ET cancellation rate (30/283 = 10.2% vs. 12/54 = 22.2%, p = 0.018) and a higher live birth rate (7/54 = 13.0% vs. 78/283 = 27.6%, p = 0.024) than the GnRH-ant protocol for the initiated cycles. Furthermore, the GnRH-a protocol was correlated with a higher implantation rate than the GnRH-ant protocol for ET cycles (146/577 = 25.3% vs. 11/103 = 10.7%, P = 0.027). No differences in the ET cancellation rate, live birth rate and implantation rate between GnRH-a and GnRH-ant groups were observed among PG4 patients. In conclusion, the GnRH-a protocol was more effective than the GnRH-ant protocol for young patients with DOR. The low ET cancellation rate and high implantation rate may be related to embryo quality or endometrial receptivity, which warrant further investigation. PMID- 30403768 TI - Next Generation Diagnostics for Melioidosis: Evaluation of a Prototype i-STAT Cartridge to Detect Burkholderia pseudomallei Biomarkers. AB - Background: Infection with the gram-negative bacterium Burkholderia pseudomallei can result in melioidosis, a life-threatening disease that can be difficult to diagnose. Culture remains the gold standard for diagnosis but requires laboratory resources not available in many endemic regions. A lateral flow immunoassay has shown promise for POC diagnostics but suffers from low sensitivity when used on blood samples. PCR also has low sensitivity on blood, attributed to the low bacterial numbers in blood observed in melioidosis patients, even when bacteraemic. Methods: A prototype i-STAT cartridge was developed to utilize the monoclonal antibody specific for the capsule of pathogenic Burkholderia species employed on the LFI. The resulting POC assay was evaluated on 414 clinical specimens from Darwin, Australia and Cambodia. Results: The i-STAT assay accurately distinguished Australian blood culture positive melioidosis patients from Australian patients hospitalized with other infections (AUC = 0.91, 95% CI 0.817 - 1.0). We derived an assay cutoff with 76% sensitivity and 94% specificity that correctly classified 88% (n=74) of the Australian patients. Interestingly, only 46% (6/13) of the culture-positive melioidosis patients in Cambodia were classified correctly. Of great importance however, the assay detected capsule from blood samples for 32% of blood culture negative melioidosis patients in both cohorts and previously undiagnosed melioidosis patients in Cambodia. In addition the assay showed high sensitivity and specificity for urine, pus and sputum. Conclusions: Diagnostic tools that are not dependent upon the growth kinetics or the levels of bacteremia of B. pseudomallei represent the next-generation of diagnostics and must be pursued further. PMID- 30403769 TI - circCTIC1 promotes the self-renewal of colon TICs through BPTF-dependent c-Myc expression. AB - Colon tumor is a conman tumor in the world. There are kinds of cells in colon tumor bulk, and only a small population can initiate tumor efficiently and termed as tumor initiating cells (TICs). With self-renewal and differentiation capacities, colon TICs drive colon tumorigenesis, metastasis and relapse. However, the molecular mechanisms of colon TICs self-renewal are elusive. Here, we found a circular RNA (circCTIC1) was highly expressed in colon tumor and colon TICs. circCTIC1 knockdown impaired the self-renewal of colon TICs, and its overexpression played an opposite role. circCTIC1 promoted the expression of c Myc, and drove the self-renewal of colon TIC through c-Myc dependent manner. circCTIC1 interacted with NURF complex, and recruited NURF complex onto c-Myc promoter, and finally drove the transcriptional initiation of c-Myc. Altogether, circCTIC1 drove the self-renewal of colon TICs through BPTF-mediated c-Myc expression. PMID- 30403770 TI - HITS-PR-HHblits: protein remote homology detection by combining PageRank and Hyperlink-Induced Topic Search. AB - As one of the most important fundamental problems in protein sequence analysis, protein remote homology detection is critical for both theoretical research (protein structure and function studies) and real world applications (drug design). Although several computational predictors have been proposed, their detection performance is still limited. In this study, we treat protein remote homology detection as a document retrieval task, where the proteins are considered as documents and its aim is to find the highly related documents with the query documents in a database. A protein similarity network was constructed based on the true labels of proteins in the database, and the query proteins were then connected into the network based on the similarity scores calculated by three ranking methods, including PSI-BLAST, Hmmer and HHblits. The PageRank algorithm and Hyperlink-Induced Topic Search (HITS) algorithm were respectively performed on this network to move the homologous proteins of query proteins to the neighbors of the query proteins in the network. Finally, PageRank and HITS algorithms were combined, and a predictor called HITS-PR-HHblits was proposed to further improve the predictive performance. Tested on the SCOP and SCOPe benchmark datasets, the experimental results showed that the proposed protocols outperformed other state-of-the-art methods. For the convenience of the most experimental scientists, a web server for HITS-PR-HHblits was established at http://bioinformatics.hitsz.edu.cn/HITS-PR-HHblits, by which the users can easily get the results without the need to go through the mathematical details. The HITS PR-HHblits predictor is a protocol for protein remote homology detection using different sets of programs, which will become a very useful computational tool for proteome analysis. PMID- 30403771 TI - The impact of comorbidity on the quality of life of people with dementia: findings from the IDEAL study. AB - Background: The aim was to investigate the comorbidity profile of people with dementia and examine the associations between severity of comorbidity, health related quality of life (HRQoL) and quality of life (QoL). Methods: The improving the experience of Dementia and Enhancing Active Life (IDEAL) cohort consisted of 1,547 people diagnosed with dementia who provided information on the number and type of comorbid conditions. Participants also provided ratings of their health related and dementia-specific QoL. Results: The majority of the sample were living with more than one chronic condition. Hypertension was commonly reported and frequently combined with connective tissue disease, diabetes and depression. The number of comorbid conditions was associated with low QoL scores, and those with severe comorbidity (>=5 conditions) showed the greatest impact on their well being. Conclusions: Comorbidity is an important risk factor for poor QoL and health status in people with dementia. Greater recognition of the nature and impact of comorbidity is needed to inform support and interventions for people with dementia and a multidisciplinary approach to care provision is recommended. PMID- 30403772 TI - Metabolic effects of breaking prolonged sitting with standing or light walking in older South Asians and White Europeans: a randomized acute study. AB - Background: Prolonged sitting is common in older adults and associated with insulin resistance and poor cardiometabolic health. We investigate whether breaking prolonged sitting with regular short bouts of standing or light walking improves postprandial metabolism in older white European and South Asian adults and whether effects are modified by ethnic group. Methods: Thirty South Asian (15 women) and 30 white European (14 women) older adults (65-79 years) undertook three experimental conditions in random order. 1) Prolonged sitting: continuous sitting during a 7.5 h observation period consuming two standardised mixed meals. 2) Standing breaks: sitting interrupted with 5 mins of standing every 30 mins (accumulating 60 mins of standing over the observation period). 3) Walking Breaks: sitting interrupted with 5 mins of self-paced light walking every 30 mins (accumulating 60 mins of walking). Blood samples (glucose, insulin, triglycerides) and blood pressure were sampled regularly throughout each condition. Results: Compared with prolonged sitting, walking breaks lowered postprandial insulin by 16.3 mU/l, (95% CI 19.7, 22.0) with greater reductions (p = 0.029) seen in South Asians (22.4 mU/l; 12.4, 32.4) than White Europeans (10.3 mU/l; 5.9, 14.7). Glucose (0.3 mmol/l; 0.1, 0.5) and blood pressure (4 mmHg; 2, 6), but not triglycerides, were lower with walking breaks, with no ethnic differences. Standing breaks did not improve any outcome. Conclusions: Breaking prolonged sitting with short bouts of light walking, but not standing, resulted in clinically meaningful improvements in markers of metabolic health in older adults, with South Asians gaining a greater reduction in postprandial insulin. PMID- 30403773 TI - Appropriate dosing regimen of temocillin in patients with underlying kidney diseases: a retrospective study at a large District Hospital in the UK. PMID- 30403774 TI - Cardiac resynchronization therapy-induced acute shortening of QRS duration predicts long-term mortality only in patients with left bundle branch block. AB - Aims: QRS narrowing with initiation of biventricular pacing might be an acute electrocardiographic indicator of correction of left bundle branch block (LBBB) induced depolarization delay and asynchrony. However, its impact on prognosis remains controversial, especially in non-LBBB patients. Our goal was to evaluate the impact of QRS narrowing on long-term mortality and morbidity in a large cohort of patients undergoing cardiac resynchronization therapy (CRT) with different pre-implantation QRS types: LBBB, non-LBBB, and permanent right ventricular pacing. Methods and results: This study included consecutive patients who underwent CRT device implantation. Study endpoints: death from any cause or urgent heart transplantation and death from any cause/urgent heart transplantation or hospital admission for heart failure. All pre- and post implantation electrocardiograms were analysed using digital callipers, high amplitude augmentation, 100 mm/s paper speed, and global QRS duration measurement method. A total of 552 CRT patients entered the survival analysis. During the 9 years observation period, 232 (42.0%) and 292 (52.9%) patients met primary and secondary endpoints, respectively. QRS narrowing predicted survival in the Kaplan Meier analysis only in patients with LBBB. Multivariate Cox regression model showed that QRS narrowing was the major determinant of both study endpoints, with hazard ratios of 0.46 and 0.43, respectively. There was a strong relationship between mortality risk and shortening/widening of the QRS, albeit only in the LBBB group. Patients with non-LBBB morphologies had unfavourable prognosis similar to that in LBBB patients without QRS narrowing. Conclusion: Acute QRS narrowing in patients with LBBB might be a desirable endpoint of CRT device implantation. PMID- 30403775 TI - Combined Non-Ablative Laser and Microfat Grafting for Burn Scar Treatment. AB - Background: Burn scar treatment persists as an unsolved problem, with thousands of affected patients disfigured for life. Objectives: We present our experience with the use of combined treatments for patients with burn scars. Methods: This is a case series report of the senior author's experience over the course of 8 years using the combined treatments of Fraxel Restore (fractional laser) and microfat graft injection for 288 patients with burn scars. Results: Laser treatment reduced scar intensity and attenuated skin irregularities and hyperpigmentation. All patients demonstrated marked improvement of skin texture and an increase in scar softness after 3 sessions of microfat grafting. However, the degree of improvement varied between patients and was related to the severity of the scar and the type of tissue. Overall, a 40-80% improvement was noted in our patients. All patients and their families expressed satisfaction with the results. Conclusions: The combined treatment of Fraxel and microfat grafting is an effective technique for improving the appearance of a hypertrophic scar or keloid on burn patients. Fat tissue stem cells may have helped to repair the damaged skin. PMID- 30403776 TI - Identification of the novel Ido1 imprinted locus and its potential epigenetic role in pregnancy loss. AB - Previous studies show that aberrant tryptophan catabolism reduces maternal immune tolerance and adversely impacts pregnancy outcomes. Tryptophan depletion in pregnancy is facilitated by increased activity of tryptophan-depleting enzymes (i.e., the IDO1 and IDO2) in the placenta. In mice, inhibition of IDO1 activity during pregnancy results in fetal loss, however, despite its important role, regulation of Ido1 gene transcription is unknown. The current study shows that the Ido1 and Ido2 genes are imprinted and maternally expressed in mouse placentas. DNA methylation analysis demonstrates that 9 CpG sites at the Ido1 promoter constitute a differentially methylated region that is highly methylated in sperm but unmethylated in oocytes. Bisulfite cloning sequencing analysis shows that the paternal allele is hypermethylated while the maternal allele shows low levels of methylation in E9.5 placenta. Further study in E9.5 placentas from the CBA/J X DBA/2 spontaneous abortion mouse model reveals that aberrant methylation of Ido1 is linked to pregnancy loss. DNA methylation analysis in humans shows that IDO1 is hypermethylated in human sperm but partially methylated in placentas, suggesting similar methylation patterns to mouse. Importantly, analysis in euploid placentas from first trimester pregnancy loss reveals that IDO1 methylation significantly differs between the two placenta cohorts, with most CpG sites showing increased percent of methylation in miscarriage placentas. Our study suggests that DNA methylation is linked to regulation of Ido1/IDO1 expression and altered Ido1/IDO1 DNA methylation can adversely influence pregnancy outcomes. PMID- 30403777 TI - Elucidating the role of Agl in bladder carcinogenesis by generation and characterization of genetically engineered mice. AB - Amylo-alpha-1,6-glucosidase,4-alpha-glucanotransferase (AGL) is an enzyme primarily responsible for glycogen debranching. Germline mutations lead to glycogen storage disease type III (GSDIII). We recently found AGL to be a tumor suppressor in xenograft models of human bladder cancer (BC) and low levels of AGL expression in BC are associated with poor patient prognosis. However, the impact of low AGL expression on the susceptibility of normal bladder to carcinogenesis is unknown. We address this gap by developing a germline Agl knockout (Agl-/-) mouse that recapitulates biochemical and histological features of GSDIII. Agl-/- mice exposed to N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) had a higher BC incidence compared with wild-type mice (Agl+/+). To determine if the increased BC incidence observed was due to decreased Agl expression in the urothelium specifically, we developed a urothelium-specific conditional Agl knockout (Aglcko) mouse using a Uroplakin II-Cre allele. BBN-induced carcinogenesis experiments repeated in Aglcko mice revealed that Aglcko mice had a higher BC incidence than control (Aglfl/fl) mice. RNA sequencing revealed that tumors from Agl-/- mice had 19 differentially expressed genes compared with control mice. An 'Agl Loss' gene signature was developed and found to successfully stratify normal and tumor samples in two BC patient datasets. These results support the role of AGL loss in promoting carcinogenesis and provide a rationale for evaluating Agl expression levels, or Agl Loss gene signature scores, in normal urothelium of populations at risk of BC development such as older male smokers. PMID- 30403778 TI - A novel IncQ plasmid carrying gene blaCTX-M-3 in Pseudomonas aeruginosa. PMID- 30403779 TI - Risk factors for unnecessary antibiotic therapy: a major role for clinical management. AB - Introduction: Assessment of antimicrobial use places an emphasis on therapeutic aspects of infected patients. Our aim was to determine the risk factors for unnecessary antibiotic therapy (UAT). Methods: This was a prospective, multicentre study evaluating all curative antibiotic therapies prescribed over two consecutive days through the same electronic medical records. Each item that could participate in the antibiotic prescriptions was collected from the computerized file: the reason for hospitalization, comorbid conditions, suspected or definitive diagnosis of infection, microbial analyses. UAT was defined as the recognition of non-infectious syndromes, non-bacterial infections, use of redundant antimicrobials, and continuation of empirical broad-spectrum antimicrobials. Results: Four hundred fifty-three antibiotic therapies were analysed at 17 institutions. An infectious disease was the reason for hospitalization in 201 cases (44%). An unspecified diagnosis of infection was observed in 104 cases (23%). Microbial samples were taken in 296 cases (65%), allowing isolation of a pathogen in 156 cases (53%). Unspecified diagnosis was associated with the absence of a microbial sample: 56/104 (54%) versus 240/349 (69%), p = 0.005. A total of 158 non-infectious syndromes were observed (35%). UAT was observed in 169 cases (37%), due to non-infectious syndromes in 106 cases. In multivariate analysis, the modifiable risk factors for UAT were unspecified diagnosis: AOR = 1.83 [1.04-3.20], and absence of a blood culture: AOR = 5.26 [2.56-10.00]. Conclusion: Unnecessary antibiotic therapy is associated with an unspecified diagnosis and the absence of microbial testing. Antimicrobial stewardship programmes should focus on diagnostic difficulties and microbial testing, with the latter facilitating antibiotic reassessment and therapeutic interruption. PMID- 30403780 TI - A 30-day drastic thinning of the basal interventricular septum in isolated cardiac sarcoidosis masquerading as a hypertrophic cardiomyopathy. PMID- 30403781 TI - The cost of providing and scaling up surgery: a comparison of a district hospital and a referral hospital in Zambia. AB - The lack of access to quality-assured surgery in rural parts of sub-Saharan Africa, where the numbers of trained health workers are often insufficient, presents challenges for national governments. The case for investing in scaling up surgical systems in low-resource settings is 3-fold: the potential beneficial impact on a large proportion of the global burden of disease; better access for rural populations who have the greatest unmet need; and the economic case. The economic losses from untreated surgical conditions far exceed any expenditure that would be required to scale up surgical care. We identified the resources used in delivering surgery at a rural district-level hospital and an urban based referral hospital in Zambia and calculated their cost through a combination of bottom-up costing and step-down accounting. Surgery performed at the referral hospital is ~50% more expensive compared with the district hospital, mostly because of the higher cost of hospital stay. The low bed occupancy rates at the two hospitals suggest underutilization of the capacity, and/or missing elements of needed capacity, to conduct surgery. Nevertheless, our study confirms that scaling up district-level surgery makes sense, through bringing economies of scale, while acknowledging the need for more comprehensive assessments and costing of capacity constraints. We quantified the economies of scale under different scaling scenarios. If surgery at the district hospital was scaled up by 10, 20 or 50%, the total cost of surgery would increase proportionately less than that, i.e. by 6, 12 and 30%, respectively. If this were to lead to less demand for surgery at the referral hospital, say 10% less surgery, it would result in a reduction of 2.7% in the total cost. Although the health system as a whole would benefit, the referring hospitals would not derive the full economic benefit, unless Government increased resources for district-level surgery. PMID- 30403782 TI - Fat-1 Transgene Is Associated With Improved Reproductive Outcomes. AB - High intake of omega-3 polyunsaturated fatty acids (PUFAs) has been associated with a variety of health benefits. However, the role of omega-3 PUFAs in female reproductive function is unclear, with studies showing both positive and negative effects. The type of diet that omega-3 fatty acids are consumed with, for example, a balanced diet vs a high-fat diet (HFD), may influence how omega-3 fatty acids affect female reproductive function. To address the role of omega-3 PUFAs in female reproduction, we used the fat-1 mouse both with and without HFD exposure. Fat-1 mice constitutively express the fat-1 transgene, allowing the conversion of omega-6 to omega-3 fatty acids to yield an optimal tissue ratio of omega-6 to omega-3 fatty acids (~1:1). In our study, at 15 weeks of age, fat-1 mice had elevated primordial follicles compared with wild-type controls with both standard chow and HFD feeding. Higher serum levels of the omega-3 docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and eicosapentaenoic acid (EPA) were positively associated with primordial follicle numbers, whereas the ratio of the omega-6 arachidonic acid to EPA + DPA + DHA had the opposite effect. Furthermore, fat-1 mice had increased pregnancy rates and shorter time to pregnancy when fed an HFD compared with wild-type mice. In conclusion, our novel preclinical model suggests that high tissue levels of long-chain omega-3 PUFAs are associated with an improved ovarian reserve and improved reproductive outcomes. Further studies are needed to evaluate omega-3 PUFAs as a potential intervention strategy in women with diminished ovarian reserve. PMID- 30403783 TI - Adverse employment histories and health functioning: the CONSTANCES study. AB - Background: With changing employment histories in European labour markets, occupational health research needs to be supplemented by an approach that integrates adverse characteristics of entire employment histories, in terms of precarious, discontinued and disadvantaged employment careers. We analyse associations of adverse employment histories and six measures of health functioning, including affective, physical and cognitive functioning. Methods: We use baseline data from the CONSTANCES study with detailed retrospective data on previous employment histories that are linked to current health functioning among people aged 45-60 years (men = 15 134; women = 16 584). The following career characteristics are assessed (all referring to careers between ages 25 and 45 years): number of jobs with temporary contracts, number of job changes, number of unemployment periods, years out of work, mode occupational position and lack of job promotion. The measures of health functioning range from depressive symptoms, standing balance, walking speed, lung function, to verbal memory and semantic fluency. Results: For both men and women, multilevel regressions (participant nested in health-examination centre) revealed that adverse employment histories are associated with poor health functioning later on, in particular persistent disadvantage in terms of low occupational position, repeated periods of unemployment and weak labour-market ties (years out of work). Findings remain consistent after excluding respondents who had a health-related career interruption or already retired before age 45 years and, additionally, after adjusting for age, partnership and education. Conclusion: Findings call for increased intervention efforts among more disadvantaged groups of the labour market at early-career stages. PMID- 30403784 TI - Polymorphisms in the host CYP2C19 gene and antibiotic-resistance attributes of Helicobacter pylori isolates influence the outcome of triple therapy. AB - Objectives: Eradication of Helicobacter pylori is influenced by susceptibility to antimicrobial agents, elevated bacterial load and degree of acid inhibition, which can be affected by genotypes of drug-metabolizing enzymes [cytochrome P450 (CYP) 2C19 polymorphism]. Theoretically, the choice and dose of proton pump inhibitor may also influence the suppression of H. pylori infection. The CYP2C19 genotype has recently been found to have an impact on peptic ulcer healing, H. pylori eradication and therapeutic efficacy of proton pump inhibitors. Methods: Here, we investigated the impact of the CYP2C19 genotype polymorphism and the success of triple therapy (fluoroquinolones/metronidazole/clarithromycin) on antibiotic-resistant strains in eradicating H. pylori in human subjects with non ulcer dyspepsia (NUD), in human subjects with peptic ulcer disease (PUD) and in asymptomatic human subjects (positive and negative for H. pylori infection). Results: Based on the CYP2C19 genotypes, determined by Droplet Digital PCR (ddPCR) analysis, we found 11.2%, 62.5% and 26.3% corresponding to rapid metabolizers, intermediate metabolizers and poor metabolizers, respectively. However, we did not find any significant effect for homozygous ABCB1 or CYP2C19*2 and CYP2C19*3 alleles. We detected several participants heterozygous for both ABCB1 and CYP2C19*2, CYP2C19*3 and CYP2C19*17 loci. The participants heterozygous for both ABCB1 and CYP2C19*2 and *3 loci should be defined as intermediate and poor metabolizers according to the haplotype analysis in the NUD, PUD and asymptomatic subjects. Conclusions: Consequently, fluoroquinolones/metronidazole/clarithromycin-based triple therapies can be used to eradicate H. pylori infection, if one does not know the CYP2C19 genotype of the patient. PMID- 30403786 TI - Endocrine disruption of androgenic activity by perfluoroalkyl substances: clinical and experimental evidence. AB - Background: Considerable attention has been paid to perfluoroalkyl compounds (PFCs) because of their worldwide presence in humans, wildlife, and environment. A wide variety of toxicological effects is well supported in animals, including testicular toxicity and male infertility. For these reasons, the understanding of epidemiological associations and of the molecular mechanisms involved in the endocrine-disrupting properties of PFCs on human reproductive health is a major concern. Objective: To investigate the relationship between PFCs exposure and male reproductive health. Design: This study was performed within a screening protocol to evaluate male reproductive health in high schools. Patients: this is a cross-sectional study on 212 exposed males from the Veneto region, one of the four areas worldwide heavily polluted with PFCs, and 171 non-exposed controls. Main outcome measures: Anthropometrics, seminal parameters and sex hormones were measured in young males from exposed areas, compared with age-matched controls. We also performed biochemical studies in established experimental models. Results: We found that increased levels of PFCs in plasma and seminal fluid positively correlate with circulating T and with a reduction of semen quality, testicular volume, penile length and AGD. Experimental evidence points towards an antagonistic action of PFOA on the binding of T to AR in gene reporter assay, competition assay on AR-coated SPR chip and AR nuclear translocation assay. Discussion: This study documents that PFCs have a substantial impact on human health as they interfere with hormonal pathways, potentially leading to male infertility. PMID- 30403788 TI - The MIPEX Health strand: a longitudinal, mixed-methods survey of policies on migrant health in 38 countries. AB - Background: Within health systems, equity between migrants and native-born citizens is still a long way from being achieved. Benchmarking the equitability of policies on migrant health is essential for monitoring progress and identifying positive and negative aspects of national policies. For this purpose, the 2015 round of the Migrant Integration Policy Index (MIPEX) was expanded to include a strand on health, in a collaborative project carried out between 2013 and 2017 in 38 countries. Methods: Indicators of policies to promote equity were derived from the 2011 Recommendations of the Council of Europe on 'mobility, migration and access to health care' and used to construct a questionnaire compatible with MIPEX methodology. This yielded scores for Entitlement, Accessibility, Responsiveness and Measures to achieve change. Results: As a measuring instrument, the questionnaire has a high degree of internal consistency, while exploratory factor analysis showed a coherent relationship between its statistical structure and the four scales it comprises. Measures to achieve change were strongly associated with Responsiveness, but not at all with Entitlements and only slightly with Accessibility. Examining the results from the sub-sample of 34 'European' countries, wide variations in the equitability of policies were found: these were mainly associated with a country's wealth (GDP), but differences between EU13 and EU15 countries were too extreme to explain completely in such terms. Conclusions: The MIPEX Health strand is a robust measurement tool that has already yielded a number of important results and is providing a valuable resource for both researchers and policy-makers. PMID- 30403789 TI - 'Cardiac rehabilitation works': but it should be tailored individually, started early, and followed for a lifetime. PMID- 30403787 TI - In vivo evaluation of the antifungal activity of sertraline against Aspergillus fumigatus. AB - Background: Invasive pulmonary aspergillosis is a life-threatening fungal disease principally caused by the ubiquitous mould Aspergillus fumigatus. This clinical entity is a major cause of morbidity and mortality (principally, but not restricted to, immunocompromised individuals). A few recent reports suggest in vitro fungicidal activity of sertraline against Aspergillus spp., but this activity has not yet been investigated in vivo. Objectives: To evaluate the antifungal activity of sertraline in two in vivo models of aspergillosis. Methods: The antifungal activity of sertraline as monotherapy at three different doses (3, 10 and 15 mg/kg) was evaluated in Galleria mellonella and in a murine model of invasive pulmonary aspergillosis. Therapeutic efficacy parameters determined were larval survival and health index score for G. mellonella, whereas pulmonary fungal burden, galactomannan and lung histopathology were assessed in the murine model. Results: Sertraline treatments improved larval survival and health index score, especially at doses of 10 and 15 mg/kg. Moreover, 10 mg/kg sertraline was able to reduce pulmonary fungal burden with an efficacy comparable with that of 3 mg/kg amphotericin B and 10 mg/kg voriconazole. Conclusions: To the best of our knowledge, this is the first in vivo study that evaluates the antifungal activity of sertraline against A. fumigatus, showing a possible promising option for the adjuvant treatment of pulmonary aspergillosis. PMID- 30403785 TI - Early microglial activation and peripheral inflammation in dementia with Lewy bodies. AB - Inflammation is increasingly recognized as part of the pathology of neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease, but its role in dementia with Lewy bodies remains unclear. Using multimodal imaging and peripheral cytokine analysis, we therefore investigated central and peripheral inflammation in this common form of dementia. Nineteen participants with probable dementia with Lewy bodies and 16 similarly aged controls underwent 3 T MRI and PET imaging with 11C-PK11195, a marker of microglial activation in vivo. Peripheral blood inflammatory cytokines were also measured in all subjects, as well as in an additional 10 controls, using the Mesoscale Human Cytokine 36 plex panel and additional assays for high sensitivity c-reactive protein, tumour necrosis factor receptor 1, IL-34, YKL-40 (chitinase-3-like protein 1) and colony stimulating factor 1. To test for the presence of in vivo amyloid, 11C-Pittsburgh compound B PET imaging was also performed in 16 of the dementia with Lewy body participants. Microglial activation was elevated in dementia with Lewy bodies subjects with mild disease when compared to those with moderate/severe impairment, where disease severity was indexed by cognitive performance on the revised Addenbrooke's Cognitive Examination. In patients, strong correlations were found between cognitive performance and 11C-PK11195 non-displaceable binding potential in several regions including the caudate nucleus (R = 0.83, P = 0.00008) and cuneus (R = 0.77, P = 0.0005). Several inflammatory cytokines were altered in the patients compared to controls, with elevated macrophage inflammatory protein-3 (P = 0.001), IL-17A (P = 0.008) and IL-2 (P = 0.046) and reduced IL-8 (P = 0.024). There was no correlation between cortical 11C Pittsburgh compound B standardized uptake value ratio and clinical features, regional 11C-PK11195 binding or peripheral cytokine levels. Nor was there any regional correlation between 11C-PK11195 non-displaceable binding potentials and 11C-Pittsburgh compound B standardized uptake value ratios. Our findings provide evidence for both central and peripheral inflammatory changes in dementia with Lewy bodies, with microglial activation occurring early in the disease in key regions known to be associated with pathology, before declining as cognition declines. Raised peripheral cytokines associated with T cell function further suggest a role for the adaptive immune system in the pathogenesis of the disease. PMID- 30403790 TI - A changing landscape. PMID- 30403791 TI - Eye Clinic as a Potential Site to Measure Blood Pressure. PMID- 30403792 TI - The cause of shortness of breath and fever. PMID- 30403793 TI - Is steroid therapy really banned for lymphocytic myocarditis before excluding viral infection? PMID- 30403794 TI - TISSUES 2.0: an integrative web resource on mammalian tissue expression. PMID- 30403796 TI - Corrigendum to "Sublethal and Hormesis Effects of Clothianidin on the Black Cutworm (Lepidoptera: Noctuidae)". PMID- 30403795 TI - ANCO-GeneDB: annotations and comprehensive analysis of candidate genes for alcohol, nicotine, cocaine and opioid dependence. AB - Studies have shown that genetic factors play an important role in the risk to substance addiction and abuse. So far, various genetic and genomic studies have reported the related evidence. These rich, but highly heterogeneous, data provide us an unprecedented opportunity to systematically collect, curate and assess the genetic and genomic signals from published studies and to perform a comprehensive analysis of their features, functional roles and druggability. Such genetic data resources have been made available for other disease or phenotypes but not for major substance dependence yet. Here, we report comprehensive data collection and secondary analyses of four phenotypes of dependence: alcohol dependence, nicotine dependence, cocaine dependence and opioid dependence, collectively named as Alcohol, Nicotine, Cocaine and Opioid (ANCO) dependence. We built the ANCO GeneDB, an ANCO-dependence-associated gene resource database. ANCO-GeneDB includes resources from genome-wide association studies and candidate gene-based studies, transcriptomic studies, methylation studies, literature mining and drug target data, as well as the derived data such as spatial-temporal gene expression, promoters, enhancers and expression quantitative trait loci. All associated genes and genetic variants are well annotated by using the collected evidence. Based on the collected data, we performed integrative, secondary analyses to prioritize genes, pathways, eQTLs and tissues that are significantly enriched in ANCO-related phenotypes. PMID- 30403797 TI - Adrenal venous sampling with or without adrenocorticotropic hormone stimulation: A meta-analysis. AB - Context: Adrenal venous sampling (AVS) with or without adrenocorticotropic hormone (ACTH) stimulation is the test of choice to identify patients with a surgically curable subtype of primary aldosteronism (PA). Whether AVS with ACTH stimulation is more effective than AVS without ACTH stimulation remains controversial. Objective: To compare the effectiveness of AVS with ACTH stimulation and AVS without ACTH stimulation in patients with PA. Methods: The Cochrane Library, PubMed, Embase, and Web of Science databases were searched to identify relevant articles. All cohort studies comparing the 2 techniques (AVS with ACTH stimulation and AVS without ACTH stimulation in patient with PA) were included in the analysis. Results: A total of 14 studies met the inclusion criteria, and they were analyzed. AVS with ACTH stimulation did not significantly reduce the number of incorrect lateralization more than AVS without ACTH stimulation in patients with PA [OR: 0.76, 95% confidence interval (CI): 0.36, 1.59; P=0.47]. AVS with ACTH stimulation significantly reduced the number of unsuccessful cannulations of both adrenal veins more than AVS without ACTH stimulation in patients with PA (OR: 0.26, 95% CI: 0.17, 0.40; P<0.00001). For subgroup analyses, it also significantly reduced the number of unsuccessful cannulations of left adrenal vein and right adrenal vein (OR: 0.14, 95% CI: 0.06, 0.33; P<0.00001 and OR: 0.30, 95% CI: 0.12, 0.71; P=0.007, respectively). Conclusion: AVS with ACTH stimulation can significantly reduce the number of unsuccessful cannulations, without significantly reducing the number of incorrect lateralization. Further studies are still needed to verify these findings. PMID- 30403798 TI - Effects of elevated atmospheric [CO2] on nitrogen (N) assimilavntion and growth of C3 vascular plants will be similar regardless of N-form assimilated. AB - Atmospheric carbon dioxide concentration ([CO2]) increased from around 280 ppm in 1750 to 400 ppm in 2016 and is likely to continue to increase throughout this century. Bloom (2015 a,b) and Rubio-Asensio and Bloom (2017) argued that wheat, Arabidopsis and C3 plants in general respond more positively to elevated atmospheric [CO2] under ammonium (NH4+) nutrition than under nitrate (NO3-) nutrition because elevated CO2 inhibits their photoreduction of NO3- and hence reduces their total plant nitrogen (N) assimilation and ultimately growth. Here, it is argued that the weight of evidence in the literature indicates that elevated atmospheric [CO2] does not inhibit NO3- assimilation and growth of C3 vascular plants. New data for common bean and wheat support this view and indicate that the effects of elevated atmospheric [CO2] on N assimilation and growth of C3 vascular plants will be similar regardless of the form of N assimilated. PMID- 30403799 TI - Associations Between Breast Cancer Survivorship and Adverse Mental Health Outcomes: A Systematic Review. AB - Background: We aimed to systematically review the evidence on adverse mental health outcomes in breast cancer survivors (>=1 year) compared with women with no history of cancer. Methods: Studies were identified by searching MEDLINE, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature, and the Social Sciences Citation Index, and through backward citation tracking. Two researchers selected the studies, extracted data, and assessed the risk of bias. Results: Sixty studies were included. Of 38 studies of depression, 33 observed more depression in breast cancer survivors; this was statistically significant in 19 studies overall, including six of seven where depression was ascertained clinically, three of four studies of antidepressants, and 13 of 31 that quantified depressive symptoms. Of 21 studies of anxiety, 17 observed more anxiety in breast cancer survivors, statistically significant in 11 studies overall, including two of four with clinical/prescription-based outcomes, and in eight of 17 of anxiety symptoms. Breast cancer survivors also had statistically significantly increased symptoms/frequency of neurocognitive dysfunction (18 of 24 studies), sexual dysfunctions (5 of 6 studies), sleep disturbance (5 of 5 studies), stress-related disorders/PTSD (2 of 3 studies), suicide (2 of 2 studies), somatisation (2 of 2 studies), and bipolar and obsessive-compulsive disorders (1 of 1 study each). Studies were heterogeneous in terms of participants' characteristics, time since diagnosis, ascertainment of outcomes, and measures reported. Approximately one-half of the studies were at high risk of selection bias and confounding by socio-economic status. Conclusions: There is compelling evidence of an increased risk of anxiety, depression and suicide, and neurocognitive and sexual dysfunctions in breast cancer survivors compared with women with no prior cancer. This information can be used to support evidence based prevention and management strategies. Further population-based and longitudinal research would help to better characterize these associations. PMID- 30403800 TI - Temperature response of Rubisco kinetics in Arabidopsis thaliana: thermal breakpoints and implications for reaction mechanisms. AB - Enhancement of Rubisco kinetics could improve photosynthetic efficiency, ultimately resulting in increased crop yield. However, imprecise knowledge of the reaction mechanism and the individual rate constants limits our ability to optimize the enzyme. Membrane inlet mass spectrometry (MIMS) may offer benefits over traditional methods for determining individual rate constants of the Rubisco reaction mechanism, as it can directly monitor concentration changes in CO2, O2, and their isotopologs during assays. However, a direct comparison of MIMS with the traditional radiolabel method of determining Rubisco kinetic parameters has not been made. Here, the temperature responses of Rubisco kinetic parameters from Arabidopsis thaliana were measured using radiolabel and MIMS methods. The two methods provided comparable parameters above 25 degrees C, but temperature responses deviated at low temperature as MIMS-derived catalytic rates of carboxylation, oxygenation, and CO2/O2 specificity showed thermal breakpoints. Here, we discuss the variability and uncertainty surrounding breakpoints in the Rubisco temperature response and the relevance of individual rate constants of the reaction mechanisms to potential breakpoints. PMID- 30403801 TI - 'Ten Commandments' for the 2018 ESC/EACTS Guidelines on Myocardial Revascularization. PMID- 30403803 TI - Takotsubo: the myth of rapid and complete recovery. PMID- 30403802 TI - Acute coronary sydromes: the impressive impact of guideline-based management in NSTEMI. PMID- 30403804 TI - Regenerating the heart. PMID- 30403806 TI - New EHJ International Editorial Board Member. PMID- 30403805 TI - What's new in the Fourth Universal Definition of Myocardial infarction? PMID- 30403807 TI - Simon Ray MD. PMID- 30403808 TI - Recombination and large structural variations shape interspecific edible bananas genomes. AB - Admixture and polyploidization are major recognized eukaryotic genome evolutionary processes. Their impacts on genome dynamics vary among systems and are still partially deciphered. Many banana cultivars are triploid (sometimes diploid) interspecific hybrids between Musa acuminata (A genome) and M. balbisiana (B genome). They have no or very low fertility, are vegetatively propagated and have been classified as 'AB', 'AAB' or 'ABB' based on morphological characters. We used NGS sequence data to characterize the A vs. B chromosome composition of nine diploid and triploid interspecific cultivars, to compare the chromosome structures of A and B genomes and analyze A/B chromosome segregations in a polyploid context. We showed that interspecific recombination occurred frequently between A and B chromosomes. We identified two large structural variations between A and B genomes, a reciprocal translocation and an inversion that locally affected recombination and led to segregation distortion and aneuploidy in a triploid progeny. Interspecific recombination and large structural variations explained the mosaic genomes observed in edible bananas. The unprecedented resolution in deciphering their genome structure allowed us to start revisiting the origins of banana cultivars and provided new information to gain insight into the impact of interspecificity on genome evolution. It will also facilitate much more effective assessment of breeding strategies. PMID- 30403809 TI - Not all hyperphosphataemias should be treated. PMID- 30403810 TI - Comparison of high glomerular filtration rate thresholds for identifying hyperfiltration. AB - Background: High glomerular filtration rate (GFR) is often used as a surrogate for single-nephron hyperfiltration. Our objective was to determine the definition for high GFR that best reflects clinical and structural characteristics of hyperfiltration. Methods: We studied living kidney donors at the Mayo Clinic and Cleveland Clinic. Potential donors underwent evaluations that included measured GFR (mGFR) by iothalamate clearance and estimated GFR (eGFR) by the serum creatinine-based Chronic Kidney Disease-Epidemiology collaboration (CKD-EPI) equation. High GFR was defined by the 95th percentile for each method (mGFR or eGFR) using either overall or age-specific thresholds. High mGFR was defined as both corrected and uncorrected for body surface area. The association of high GFR by each definition with clinical characteristics and radiologic findings (kidney volume) was assessed. In the subset that donated, the association of high GFR with kidney biopsy findings (nephron number and glomerular volume) and single nephron GFR was assessed. Results: We studied 3317 potential donors, including 2125 actual donors. The overall 95th percentile for corrected mGFR was 134 mL/min/1.73 m2 and for eGFR was 118 mL/min/1.73 m2. The age-based threshold for uncorrected mGFR was 198 mL/min - 0.943*Age, for corrected mGFR it was 164 mL/min/1.73 m2 - 0.730*Age and for eGFR it was 146 mL/min/1.73 m2 - 0.813*Age. High age-based uncorrected mGFR had the strongest associations with higher single nephron GFR, larger glomerular volume, larger kidney volume, male gender, higher body mass index and higher 24-h urine albumin, but also had the strongest association with high nephron number. A high age-height-gender-based uncorrected mGFR definition performed almost as well but had a weaker association with nephron number and did not associate with male gender. Conclusions: High age based uncorrected mGFR showed the most consistent associations reflective of hyperfiltration. However, high age-based uncorrected mGFR has limited clinical utility because it does not distinguish between hyperfiltration and high nephron number. PMID- 30403811 TI - Sildenafil for the treatment of preeclampsia, an update: should we still be enthusiastic? AB - Preeclampsia is a hypertensive disorder of pregnancy and the clinical manifestation of severe endothelial dysfunction associated with maternal and foetal morbidity and mortality. The primum movens of the disease is the defect of invasion of the uterine arteries by foetal syncytiotrophoblasts, which causes a maladaptive placental response to chronic hypoxia and the secretion of the soluble form of type 1 vascular growth endothelial factor receptor, also called soluble fms-like tyrosine kinase 1 (sFlt-1), the major player in the pathophysiology of the disease. Among its different effects, sFlt-1 induces abnormal sensitivity of the maternal vessels to the vasoconstrictor angiotensin II. This leads to the hypertensive phenotype, recently shown to be abrogated by the administration of sildenafil citrate, which can potentiate the vasodilatory mediator nitrite oxide. This review focuses on the mechanisms of maternal endothelial dysfunction in preeclampsia and discusses the therapeutic window of sildenafil use in the context of preeclampsia, based on the results from preclinical studies and clinical trials. Safety issues recently reported in neonates have considerably narrowed this window. PMID- 30403812 TI - MicroR408 regulates defense response in sweet potato upon wounding. AB - MicroRNAs play diverse roles in plant development and defense responses by binding to their mRNA targets based on sequence complementarity. In this study, a wound-related miR408 and its target genes in sweet potato (Ipomoea batatas) are proposed by small RNA deep sequencing and transcriptome analysis. The expression patterns of miR408 and the miR408 precursor were significantly repressed by wounding and jasmonate (JA). In contrast, expression of the putative target genes IbKCS (3-ketoacyl-CoA synthase 4),IbPCL (Plantacyanins), and IbGAUT (galacturonosyltransferase 7-like) of miR408 was increased following wounding, whereas only IbKCS was increased after JA treatment. The target cleavage site mapping and Agrobacterium-mediated transient assay demonstrated that IbKCS,IbPCL, and IbGAUT were the targets of miR408. The expression of miR408-targeting genes was repressed in transgenic sweet potatoes overexpressing miR408. This result further indicated a relationship between miR408 and its target genes. Notably, miR408-overexpressing plants showed a semi-dwarf phenotype and attenuated resistance to insect feeding, while transgenic plants overexpressing IbKCS exhibited more insect resistance than plants overexpressing only the empty vector. Collectively, sweet potato reduces the abundance of miR408 upon wounding to elevate the expression of IbKCS, IbPCL, and IbGAUT. The expression of IbKCS enhances the defense system to against herbivore wounding. PMID- 30403814 TI - Attributes, Attitudes, and Practices of Clinicians Concerned with Opioid Prescribing. AB - Background: Many clinicians who prescribe opioids for chronic noncancer pain (CNCP) express concerns about opioid misuse, addiction, and physiological dependence. We evaluated the association between the degree of clinician concerns (highly vs less concerned), clinician attributes, other attitudes and beliefs, and opioid prescribing practices. Methods: A web-based survey of clinicians at a multispecialty medical practice. Results: Compared with less concerned clinicians, clinicians highly concerned with opioid misuse, addiction, and physiological dependence were more confident prescribing opioids (risk ratio [RR] = 1.34, 95% confidence interval [CI] = 1.08-1.67) but were more reluctant to do so (RR = 1.13, 95% CI = 1.03-1.25). They were more likely to report screening patients for substance use disorder (RR = 1.18, 95% CI = 1.01-1.37) and to discontinue prescribing opioids to a patient due to aberrant opioid use behaviors (RR = 1.30, 95% CI = 1.13-1.50). They were also less likely to prescribe benzodiazepines and opioids concurrently (RR = 0.40, 95% CI = 0.25-0.65). Highly concerned clinicians were more likely to work in clinics which engage in "best practices" for opioid prescribing requiring urine drug screening (RR = 4.65, 95% CI = 2.51-8.61), prescription monitoring program review (RR = 2.90, 95% CI = 1.84 4.56), controlled substance agreements (RR = 4.88, 95% CI = 2.64-9.03), and other practices. Controlling for clinician concern, prescribing practices were also associated with clinician confidence, reluctance, and satisfaction. Conclusions: Highly concerned clinicians are more confident but more reluctant to prescribe opioids. Controlling for clinician concern, confidence in care and reluctance to prescribe opioids were associated with more conservative prescribing practices. PMID- 30403813 TI - Impaired urinary concentration ability is a sensitive predictor of renal disease progression in Joubert syndrome. AB - Background: Joubert syndrome (JS) is an inherited ciliopathy characterized by a complex midbrain-hindbrain malformation and multiorgan involvement. Renal disease, mainly juvenile nephronophthisis (NPH), was reported in 25-30% patients although only ~18% had a confirmed diagnosis of chronic kidney disease (CKD). NPH often remains asymptomatic for many years, resulting in delayed diagnosis. The aim of the study was to identify a biomarker able to quantify the risk of progressive CKD in young children with JS. Methods: Renal features were investigated in 93 Italian patients, including biochemical tests, ultrasound and 1-deamino-8D-arginine vasopressin test in children with reduced basal urine osmolality. A subset of patients was followed-up over time. Results: At last examination, 27 of 93 subjects (29%) presented with CKD, ranging from isolated urinary concentration defect (UCD) to end-stage renal disease. Both normal and pathological urine osmolality levels remained stable over time, even when obtained at very early ages. Follow-up data showed that the probability of developing CKD can be modelled as a function of the urine osmolality value, exceeding 75% for levels <600 mOsm/kg H2O, and significantly increased in patients with an early diagnosis of isolated UCD. Conclusions: We conclude that the frequency of CKD in JS increases with age and is higher than previously reported. Urine osmolality represents an early sensitive quantitative biomarker of the risk of CKD progression. PMID- 30403816 TI - Erratum. PMID- 30403815 TI - Organizational uptake of NICE guidance in promoting employees' psychological health. AB - Background: Annual costs to organizations of poor mental health are estimated to be between L33 billion and L42 billion. The UK's National Institute for Clinical Excellence (NICE) has produced evidence-based guidance on improving employees' psychological health, designed to encourage organizations to take preventative steps in tackling this high toll. However, the extent of implementation is not known outside the National Health Service. Aims: To assess the awareness and implementation of NICE guidance on workplace psychological health. Methods: A total of 163 organizations participated in a survey of UK-based private, public and third sector organizations employing an accumulated minimum of 322 033 workers. Results: Seventy-seven per cent of organizations were aware of the NICE guidance for improving mental well-being in the workplace, but only 37% were familiar with its recommendations. Less than half were aware of systems in place for monitoring employees' mental well-being and only 12% confirmed that this NICE guidance had been implemented in their workplace. Where employee health and well being featured as a regular board agenda item, awareness and implementation of NICE guidance were more likely. Significant associations were found between organizational sector and size and uptake of many specific features of NICE guidance. Conclusions: The majority of organizations are aware of NICE guidance in general, but there is a wide gap between this and possession of detailed knowledge and implementation. The role of sector and size of organization is relevant to uptake of some features of NICE guidance, although organizational leadership is important where raised awareness and implementation are concerned. PMID- 30403817 TI - Effects of Moderate Cycling Exercise on Blood Glucose Regulation Following Successful Clinical Islet Transplantation. AB - Context: Islet transplantation is effective in preventing hypoglycemia in individuals with type 1 diabetes (T1D). However, it is currently unknown whether transplanted islets regulate plasma glucose concentrations appropriately during and after exercise in human islet transplant recipients (ITx). Objective: To determine the effect of exercise on plasma glucose, insulin, and glucagon concentrations in ITx compared to individuals without diabetes (CON). Intervention: Participants completed two conditions in random order, 1) 45 minutes of aerobic exercise (60% VO2peak), and 2) 45 minutes of seated rest. Blood samples were drawn at baseline, immediately post-exercise/rest, and every 15 minutes throughout a 60-minute recovery period. Post-exercise (24 hours) interstitial glucose was monitored using continuous glucose monitors. Results: Twenty-four participants (12 ITx, 12 CON) completed the protocol. Plasma glucose decreased more over time with exercise in ITx compared to CON [main effects of treatment (p=0.019), time (p=0.001) and group (p=0.012)]. Plasma glucose was lower during exercise versus rest in ITx, but not CON [treatment by group interaction (p=0.028)]. Plasma glucose decreased more during exercise versus the rest session [treatment by time interaction (p=0.001)]. One ITx and one CON experienced plasma glucose concentrations <3.5 mmol/L at the end of exercise, both of whom returned above that threshold within 15 minutes. Nocturnal CGM glucose below 3.5 mmol/L was detected in two CON, but no ITx. Conclusion: Despite a greater plasma glucose decline during exercise in ITx, hypoglycemia risk was similar during and following exercise in ITx compared to CON. PMID- 30403818 TI - Alterations of peritoneal transport characteristics in dialysis patients with ultrafiltration failure: tissue and capillary components. AB - Background: Ultrafiltration failure (UFF) in peritoneal dialysis (PD) patients is due to altered peritoneal transport properties leading to reduced capacity to remove excess water. Here, with the aim to establish the role of local alterations of the two major transport barriers, peritoneal tissue and capillary wall, we investigate changes in overall peritoneal transport characteristics in UFF patients in relation to corresponding local alterations of peritoneal tissue and capillary wall transport properties. Methods: Six-hour dwell studies using 3.86% glucose solutions and radioisotopically labelled serum albumin added to dialysate as a volume marker were analysed in 31 continuous ambulatory PD patients, 20 with normal ultrafiltration (NUF) and 11 with UFF. For each patient, the physiologically based parameters were evaluated for both transport barriers using the spatially distributed approach based on the individual intraperitoneal profiles of volume and concentrations of glucose, sodium, urea and creatinine. Results: UFF patients as compared with NUF patients had increased solute diffusivity in both barriers, peritoneal tissue and capillary wall, decreased tissue hydraulic conductivity and increased local lymphatic absorption and functional decrease in the fraction of the ultra-small pores. This resulted in altered distribution of fluid and solutes in the peritoneal tissue, and decreased penetration depths of fluid and solutes into the tissue in UFF patients. Conclusions: Mathematical modelling using a spatially distributed approach for the description of clinical data suggests that alterations both in the capillary wall and in the tissue barrier contribute to UFF through their effect on transport and distribution of solutes and fluid within the tissue. PMID- 30403819 TI - A test case for Mars: human sleep and performance during a 13 month stay in Antarctica. AB - Study Objectives: Manned spaceflights from Earth to Mars will likely become reality within the next decades. Humans will be exposed to prolonged isolation, confinement, and altered photoperiods in artificial atmospheric conditions, with potential adverse effects on sleep and performance. On Earth, polar environments serve as space-analogues to study human adaptation, yet few studies include polysomnography due to operational constraints. Methods: Polysomnography, subjective sleepiness and fatigue and psychomotor performance were measured every six weeks in 13 males ("Hivernauts") during a 13-month winter-over campaign at Concordia (Antarctica). Stability and robustness of inter-individual differences were examined by means of intra-class correlations. Results: Hivernauts present with high-altitude periodic breathing, increased sleep onset latencies and reduced psychomotor speed. Except for obstructive apneas, all sleep, sleepiness and psychomotor performance variables remain stable over time. Individual differences in respiratory variables show the highest degree of stability and robustness, followed by fatigue and situational sleepiness, sleep fragmentation and psychomotor speed, suggesting moderate to substantial trait-like characteristics for these variables. Phase-delays are suspected in Hivernauts, both in individuals with imposed and self-selected bedtimes. A significant decline in psychomotor speed over time is observed in the latter group. Conclusions: Space-analog conditions such as isolated confinement, extreme photoperiods and altered atmospheric conditions affect human sleep and performance. However, individual responses to these extreme environmental challenges show large differences and remain relatively stable under prolonged exposure. Ad hoc polysomnographic, including respiratory function monitoring is therefore recommended for selecting eligible candidates for extra-terrestrial sojourns. PMID- 30403820 TI - Corrigendum. PMID- 30403822 TI - Does paid vacation leave protect against depression among working Americans? A national longitudinal fixed effects analysis. AB - Objectives The United States is the only advanced economy globally that does not guarantee its workers paid vacation leave. Although empirical studies have linked paid vacation leave to happiness and stress, no study has investigated the association between paid vacation leave and depression. Using a nationally representative longitudinal sample of 3380 working men and women aged 45-52 years from the National Longitudinal Survey of Youth 1979, this study explored whether paid vacation leave may protect against depression. Methods Multivariate linear and logistic regression models were employed to estimate the impacts of the number of annual paid vacation days of leave measured at age 40 on depression measured using the 7-item Center for Epidemiologic Studies Depression Scale (CES D) short form (CES-D-SF) scale at age 50. Models were adjusted for demographic and socioeconomic factors, physical health, weekly hours, and individual fixed effects. Results For every ten additional days of paid vacation leave, the odds of depression in women was 29% lower [odds ratio (OR) 0.71, 95% confidence interval (CI) 0.55-0.92, P=0.01); there was no association in men. Linear regression models showed no association in either men or women. For every 10 days of paid leave, the odds of depression were 36% lower in White women and 38% lower in women with >=2 children. Conclusions This study provides the first evidence on the linkage between paid vacation leave and depression, and supports a protective effect in White women with >=2 children. Should this association be truly causal, and assuming a uniform effect across all ages in working adult women, the results from this study would suggest that a hypothetical increase in the average number of days of paid vacation leave of 10 days could avoid an estimated 568 442 cases of depression in women each year and lead to a cost savings of US$2.94 billion annually. Policies that mandate paid vacation leave may have marked positive impacts on the population health and economic burden of depression among working women in the USA. PMID- 30403823 TI - Evaluation, Management, and Outcomes of Lunate and Perilunate Dislocations. AB - Lunate and perilunate dislocations are potentially devastating injuries that are often unrecognized at initial evaluation. Prompt recognition and treatment is necessary to prevent adverse sequelae, including median nerve dysfunction, carpal instability, posttraumatic arthritis, reduced functionality, and avascular necrosis. In patients who are surgical candidates, operative intervention is warranted to restore carpal kinematics and provide optimal outcomes. [Orthopedics. 201x; xx(x):xx-xx.]. PMID- 30403821 TI - Admixture mapping identifies novel loci for obstructive sleep apnea in hispanic/latino americans. AB - Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Its prevalence and severity vary across ancestral background. Although OSA traits are heritable, few genetic associations have been identified. To identify genetic regions associated with OSA and improve statistical power, we applied admixture mapping on three primary OSA traits (the apnea hypopnea index [AHI], overnight average oxyhemoglobin saturation [SaO2] and percentage time SaO2<90%) and a secondary trait (respiratory event duration) in a Hispanic/Latino American population study of 11,575 individuals with significant variation in ancestral background. Linear mixed models were performed using previously inferred African, European and Amerindian local genetic ancestry markers. Global African ancestry was associated with a lower AHI, higher oxyhemoglobin saturation and shorter event duration. Admixture mapping analysis of the primary OSA traits identified local African ancestry at the chromosomal region 2q37 as genome-wide significantly associated with AHI (P<5.7*10-5), and European and Amerindian ancestries at 18q21 suggestively associated with both AHI and percentage time SaO2<90% (P<10-3). Follow-up joint ancestry-SNP association analyses identified novel variants in ferrochelatase (FECH), significantly associated with AHI and percentage time SaO2<90% after adjusting for multiple tests (P<8*10-6). These signals contributed to the admixture mapping associations and were replicated in independent cohorts. In this first admixture mapping study of OSA, novel associations with variants in the iron/heme metabolism pathway suggest a role for iron in influencing respiratory traits underlying OSA. PMID- 30403824 TI - Complications Following Internal Fixator in the Treatment of Pelvic Fracture. AB - The aim of this systematic review was to investigate the incidence of complications of the internal fixator in the treatment of anterior pelvic ring injury. The literature was comprehensively searched from 1980 to January 2017 to identify potential studies. Six studies involving 272 cases of anterior pelvic ring injury treated with the internal fixator were included in this meta analysis. The rates of wound infection, heterotopic ossification, nerve paresthesia, pain, and fracture dislocation were 5.7%, 35.1%, 28.2%, 3.7%, and 3.0%, respectively. This new technique should be prudently used to treat pelvic fractures. [Orthopedics. 201x; xx(x):xx-xx.]. PMID- 30403825 TI - Use of Magnetic Growing Intramedullary Nails in Compression During Intercalary Allograft Reconstruction. AB - Traditionally, intercalary allograft reconstruction after tumor resection has had a high rate of complications, particularly nonunion. Plate and intramedullary nail fixation have been used alone and in combination to improve union rates. This study sought to evaluate a new technique that uses a magnetic growing intramedullary nail to compress the osteotomy sites to aid in healing and to answer 2 questions: (1) What is the union rate and the time to union when using magnetic growing intramedullary nails? (2) What complications occur with this technique? Eight patients with 15 osteotomy sites with a minimum follow-up of 14 months were retrospectively reviewed. Seven of the 8 patients underwent initial reconstruction with the magnetic nail, whereas 1 patient underwent treatment of a nonunion that occurred with prior carbon fiber nail fixation. Twelve of the 15 osteotomy sites had healed by an average of 9 months. Nonunions occurred in 2 patients with an associated failure of the hardware. One of these patients healed after revision surgery. Of the patients who healed at both sites, 1 had a fracture through the allograft, 1 had backing out of a locking screw that required removal, and 1 required a manipulation under anesthesia of the knee. Two patients underwent successful limb lengthening needed because of an expected limb length discrepancy after healing occurred. Use of growing intramedullary nails in compression mode led to an 87% union rate at final follow-up with acceptable complications. This technique provides a viable alternative to standard nail and plate fixation when intercalary allografts are used. [Orthopedics. 2018; 41(6):330-335.]. PMID- 30403826 TI - Effect of Anterior Anchor on Clinical Outcomes of Type II SLAP Repairs in an Active Population. AB - This study evaluated the role of anchor position in persistence of pain and/or revision biceps tenodesis after arthroscopic repair of type II superior labrum anterior and posterior (SLAP) lesions and assessed for patient- and injury specific variables influencing clinical outcomes. Active-duty service members who underwent arthroscopic repair of type II SLAP lesions between March 1, 2007, and January 23, 2012, were identified. Patients with less than 2-year clinical follow up; type I, III, and IV SLAP lesions; and primary treatment with biceps tenodesis and/or rotator cuff repair at the time of index surgery were excluded. Demographic, preoperative, and operative variables, including anchor positions, were reviewed and evaluated for association with outcomes. Total failure rate (defined as either surgical and/or clinical failure), anchor position, and return to military function were the primary outcomes of interest. Forty-nine patients underwent type II SLAP repairs with a mean follow-up of 52.3 months. Forty-eight (97.9%) were men, and mean age was 35.2 years. Eleven patients (22%) underwent subsequent subpectoral biceps tenodesis. Forty patients (82%) returned to military function, whereas 9 patients (18%) had medical discharge for significant, rate-limiting, shoulder pain. Age was a significant predictor of surgical failure. Patients with anchor position anterior to the biceps attachment had no increased risk of clinical or surgical failure compared with patients with only posterior-based anchors. Anchor placement anterior to the biceps tendon was not associated with inferior outcomes. Younger age was shown to be a poor prognostic factor in patients' ability to return to active duty. Revision with biceps tenodesis showed significant utility in achieving good clinical outcomes and return to duty in more than 90% of patients. Patient-, injury-, and surgery specific variables need to be identified as prognostic indicators so that clinical outcomes can continue to be improved. [Orthopedics. 201x; xx(x):xx-xx.]. PMID- 30403827 TI - Drains Are Not Beneficial in Primary Shoulder Arthroplasty. AB - The purpose of this study was to determine if clinical differences exist between closed drainage use in primary shoulder arthroplasty and postoperative complications. A retrospective review was performed of all primary total shoulder and reverse total shoulder arthroplasty procedures at the authors' institution during a 2-year period. A total of 378 of 636 shoulder arthroplasty patients met inclusion criteria. Drains were used in 111 patients. The authors did not identify a significant relationship between drain use and postoperative complications. When complications were stratified just by the presence or absence of risk factors, irrespective of whether a drain was used, no significant relationship was identified. This study does not support the routine use of closed drainage systems in primary shoulder arthroplasty, including for patients with risk factors for potentially developing postoperative complications. [Orthopedics. 201x; xx(x):xx-xx.]. PMID- 30403828 TI - Dipole-Switchable Poly(para-phenyleneethynylene)s: Ferroelectric Conjugated Polymers. AB - Dipolar 2,3-difluorobenzene units are introduced into the backbone of a poly(para phenyleneethynylene) (PPE) to generate a ferroelectric conjugated polymer. The structural features of the partially fluorinated PPE allow for the generation of a remanent polarization in the solid state; the difluorinated benzene rings behave as molecular rotors at high temperature, while at room temperature, stacking of such rings clamps down the ring orientation. The molecular dipoles can still be oriented by moderate external electrical fields at room temperature, and this PPE is then ferroelectric. The concept should be transferable to other poly(aryleneethynylene)s, and novel conjugated ferroelectric conjugated polymers will be accessible using this concept. PMID- 30403829 TI - Automated methods to test connectedness and quantify indirectness of evidence in network meta-analysis. AB - Network meta-analysis compares multiple treatments from studies that form a connected network of evidence. However, for complex networks, it is not easy to see if the network is connected. We use simple techniques from graph theory to test the connectedness of evidence networks in network meta-analysis. The method is to build the adjacency matrix for a network, with rows and columns corresponding to the treatments in the network and entries being one or zero depending on whether the treatments have been compared or not, and with zeros along the diagonal. Manipulation of this matrix gives the indirect connection matrix. The entries of this matrix determine whether two treatments can be compared, directly or indirectly. We also describe the distance matrix, which gives the minimum number of steps in the network required to compare a pair of treatments. This is a useful assessment of an indirect comparison as each additional step requires further assumptions of homogeneity in, for example, design and target populations of included trials. If there are no loops in the network, the distance is a measure of the degree of assumptions needed; it is approximately this with loops. We illustrate our methods using several constructed examples and giving R code for computation. We have also implemented the techniques in the Stata package "network." The methods provide a fast way to ensure comparisons are only made between connected treatments and to assess the degree of indirectness of a comparison. PMID- 30403830 TI - Kinetic Traps to Activate Stereomutation in Supramolecular Polymers. AB - The helical stereomutation in the kinetically controlled coassembly of the reported carbonyl-bridged triarylamines (CBTs) is described. The copolymerization of chiral CBTs (S)-1 or (R)-1 with achiral 2 in sergeants-and-soldiers (SaS) experiments results in a tunable helicity conditioned by the percentage of the chiral sergeant and by the cooling rate. The dissimilar inherent chirality of the extended monomeric (M) and intramolecularly H-bonded metastable (M*) species, as well as the different stability of the kinetic trap of the chiral CBTs (S)-1/(R) 1 and the achiral CBT 2, condition the chirality transfer and afford J-aggregates of inverse handedness. PMID- 30403831 TI - Discovery of New CDK8/CycC ligands with a Novel Virtual Screening Tool. AB - Selective inhibition of Cyclin-dependent kinase 8 and cyclin C (CDK8/CycC) has been suggested as a promising strategy for reducing mitogenic signals in cancer cells with reduced toxic effects on normal cells. We developed a novel virtual screening protocol for drug development and applied it to discovering new CDK8/CycC type II ligands, which is likely to achieve long residence time and specificity. We first analyzed binding thermodynamics of 11 published pyrazolourea ligands using molecular dynamics simulations and a free energy calculation method, VM2, and extracted the key binding information to assist virtual screening. The urea moiety was found to be the critical structural contributor of the reference ligands. Starting with the urea moiety we conducted substructure-based searches with our newly developed Superposition and Single Point Energy Evaluation method, followed by free energy calculations, and singled out three purchasable compounds for bio-assay testing. The ranking from the experimental result is completely consistent with the predicted rankings. A potent drug-like compound has a Kd value of 42.5 nM, which is comparable to the most potent reference ligands and provided a good starting point for further improvement. This study shows that our novel virtual screening protocol is an accurate and efficient tool for drug development. PMID- 30403832 TI - Temporal effects of cytokine treatment on lubricant synthesis and matrix metalloproteinase activity of fibroblast-like synoviocytes. AB - Fibroblast-like synoviocytes (FLS) are major contributors to the composition and function of synovial fluid (SF). In disease, changes to important SF molecules such as hyaluronic acid (HA), lubricin, and numerous inflammatory markers contribute to a loss of SF functional properties. Previous studies characterized the ability of FLS to produce SF molecules in short-term cultures using continuous cytokine supplementation. This study assessed the HA, lubricin, and matrix metalloproteinase-2 (MMP-2) secretion profile of FLS over 12 days of culture. FLS were subjected to continuous, intermittent, and sequential cytokine treatments of interleukin-1 beta (IL-1beta), tumour necrosis factor-alpha (TNF alpha), and transforming growth factor-beta 1 (TGF-beta1). HA was assessed by an enzyme-linked immunosorbent assay (ELISA) for content and agarose gel electrophoresis for molecular weight distribution. Relative lubricin content was determined by western blot. Pro MMP-2 and active MMP-2 were quantified by gelatin zymography. All intermittent and sequential treatments significantly increased secretion of high-molecular-weight (>3 MDa) HA for the duration of the culture. Sequentially treated groups elevated lubricin synthesis, whereas only groups receiving IL-1beta and TNF-alpha for 2 days followed by TGF-beta1 for 1 day reduced active MMP-2 to unstimulated control levels. These data provide important information on the long-term functional potential of cytokine-stimulated FLS and suggest that temporal regulation of cytokine exposure can be a powerful tool to guide healthy synovial secretions. PMID- 30403833 TI - Design, Synthesis, and Biological Evaluation of Polyaminocarboxylate Ligand-Based Theranostic Conjugates for Antibody-Targeted Cancer Therapy and Near-Infrared Optical Imaging. AB - We report the design, synthesis, and evaluation of polyaminocarboxylate ligand based antibody conjugates for potential application in targeted cancer therapy and near-infrared (NIR) fluorescence imaging. We synthesized a new polyaminocarboxylate chelate (CAB-NE3TA) as a potential anticancer agent. CAB NE3TA displayed potent inhibitory activities against various cancer cell lines. We then designed a multifunctional theranostic platform (CAB-NE3TA-PAN-IR800) constructed on an epidermal growth factor receptor (EGFR)-targeted antibody (panitumumab, PAN) labeled with a NIR fluorescent dye. We also built the first atomistic model of the EGFR-PAN complex and loaded it with the cytotoxic CAB NE3TA and the NIR dye. The therapeutic (CAB-NE3TA-PAN) and theranostic (CAB-NE3TA PAN-IR800) conjugates were evaluated using an EGFR-positive A431 (human skin cancer) cell xenograft mouse model. Biodistribution studies using NIR fluorescence imaging demonstrated that the CAB-NE3TA-PAN labeled with the IR800 dye selectively targeted the A431 tumors in mice and resulted in prolonged retention in the tumor tissue and displayed excellent clearance in blood and normal organs. The therapeutic conjugate was capable of significantly inhibiting tumor growth, leading to nearly complete disappearance of tumors in the mice. The results of our pilot in vivo studies support further evaluation of the novel ligand-based therapeutic and theranostic conjugates for targeted iron chelation cancer therapy and imaging applications. PMID- 30403836 TI - From the Editors. PMID- 30403835 TI - Abnormal sensory gating in patients with different types of focal dystonias. AB - BACKGROUND: Movement execution in healthy individuals increases the somatosensory temporal discrimination threshold. These changes are a result of mechanisms of sensory gating at the subcortical level. Although the somatosensory temporal discrimination threshold is abnormally increased in patients with focal dystonias, the effect of movement execution on somatosensory temporal discrimination in dystonic patients is unknown. OBJECTIVES: The objective of this study was to determine whether somatosensory temporal discrimination threshold modulation induced by voluntary movement is normal in different forms of focal dystonia. METHODS: We enrolled 71 dystonic patients (24 with blepharospasm, 31 with cervical dystonia, and 16 with focal hand dystonia) and 39 age-matched healthy participants. Paired stimuli for the somatosensory temporal discrimination threshold were triggered by movement execution at movement onset and at various time intervals thereafter. We analyzed the kinematic features of the motor task to ascertain whether tactile input induces changes in movement parameters. RESULTS: Movement execution led to greater and longer lasting increases in somatosensory temporal discrimination threshold values, both upon movement onset and at various time intervals thereafter, in patients with cervical dystonia and focal hand dystonia than in those with blepharospasm or the healthy participants. Somatosensory temporal discrimination testing did not induce any changes in the mean velocity of index finger movements in either patients or healthy participants. CONCLUSIONS: Somatosensory temporal discrimination threshold changes induced by movement execution are abnormal in focal dystonias. This abnormality is related to the type of dystonia. Abnormal gating of sensory information is likely involved in movement-induced triggering or worsening of different forms focal dystonia. PMID- 30403837 TI - Analysis of Inner Ear Anomalies in Unilateral Congenital Aural Atresia Combined With Microtia. AB - Objectives: The aim of this study was to analyze the incidence of inner ear anomalies in patients with unilateral congenital aural atresia (CAA) combined with microtia. Methods: We retrospectively reviewed 61 patients with unilateral CAA combined with microtia who underwent high-resolution temporal bone computed tomography (TBCT) and hearing examination. Inner ear anomalies were analyzed using TBCT and evaluated according to the Jahrsdoerfer grading system, Marx classification, and extent of inferior displacement of the mastoid tegmen. Results: Inner ear anomalies were observed in 14 patients (23.0%). Lateral semicircular canal (LSCC) dysplasia was the most common inner ear anomaly, with an incidence of 16.4%. The incidence was significantly higher on the pathologic side than on the unaffected side (P=0.002). All vascular anomalies were observed in the high-riding jugular bulb, with an incidence of 24.6%. The incidence was significantly higher on the pathologic side than on the unaffected side (P<0.001). LSCC dysplasia was significantly more common in patients with a lower Jahrsdoerfer score (odds ratio, 0.66; P=0.004). Conclusion: The incidence of inner ear anomalies was relatively high in patients with unilateral CAA combined with microtia; LSCC dysplasia was the most common anomaly and the probability of coexistence was higher in patients with a lower Jahrsdoerfer score. PMID- 30403838 TI - Clinical Characteristics and Management of Saccular Cysts: A Single Institute Experience. AB - Objectives: A saccular cyst is defined as a dilated saccule of the larynx, filled with mucus, and is located between the false vocal cords and the thyroid cartilage. Although this uncommon laryngeal condition is benign in nature, it could lead to dyspnea, stridor, and airway obstruction, depending on its size and location. Furthermore, some saccular cysts have been associated with laryngeal carcinoma. This study aimed to characterize this rather uncommon laryngeal condition to aid in determining the proper management of this pathology. Methods: Medical records were retrospectively reviewed of all patients with saccular cysts diagnosed and treated between 2006 and 2017 at a tertiary otolaryngologic care center. Results: Seven patients with saccular cysts were identified (male:female=2:5; mean age, 34.1 years); two were pediatric patients. Surgical intervention was performed in all patients by laryngo-microsurgery using CO2 laser. There was no recurrence after the initial surgical treatment. Conclusion: Saccular cysts can be managed endoscopically using CO2 laser, without requiring an external approach. Therefore, an endoscopic approach should be actively considered for an optimal treatment outcome. PMID- 30403839 TI - Exploiting Evanescent Field Polarization for Giant Chiroptical Modulation from Achiral Gold Half-Rings. AB - For applications seeking to realize on-chip polarization-discriminating nanoantennas, efficient energy conversion from surface waves to far-field radiation is desirable. However, the response of individual nanoantennas to the particular polarization states achievable in surface waves, such as evanescent fields, has not yet been thoroughly investigated. Here, we report the giant modulation of visible light scattering from achiral gold half-rings when switching between evanescent surface wave excitation produced from the total internal reflection of left-handed and right-handed circularly polarized light. The effect is driven by a differing relative phase between the in-plane transverse and longitudinal field oscillations of the evanescent wave depending on the incident light handedness. Because longitudinal field oscillations are not found in free-space excitation, this presents a fundamentally different mechanism for chiroptical responses as traditional mechanisms for circular dichroism only account for purely transversal field oscillations. Although the half-ring scattering modulation is dependent on the wave-vector orientation, an orientation invariant response is also realized in planar chiral nanoantennas composed of 8 half-rings in a rotationally symmetric arrangement, with up to 50% scattering modulation observed at 725 nm. Although both structures are found to produce scattering modulation when switching the handedness of free-space light, the distinct polarization properties of evanescent fields are shown to be strictly required to observe giant scattering modulation. These results ultimately deepen our understanding of the range of possible chiroptical effects in light-matter interactions. PMID- 30403840 TI - Surface-Limited Superconducting Phase Transition on 1 T-TaS2. AB - Controlling superconducting phase transition on a two-dimensional (2D) material is of great fundamental and technological interest from the viewpoint of making 2D resistance-free electronic circuits. Here, we demonstrate that a 1 T-to-2 H phase transition can be induced on the topmost monolayer of bulk (<100 nm thick) 1 T-TaS2 by thermal annealing. The monolayer 2 H-TaS2 on bulk 1 T-TaS2 exhibits a superconducting transition temperature ( Tc) of 2.1 K, which is significantly enhanced compared to that of bulk 2 H-TaS2. Scanning tunneling microscopy measurements reveal a 3 * 3 charge density wave (CDW) in the phase-switched monolayer at 4.5 K. The enhanced Tc is explained by the suppressed 3 * 3 CDW and a charge-transfer doping from the 1 T substrate. We further show that the monolayer 2 H-TaS2 could be switched back to 1 T phase by applying a voltage pulse. The observed surface-limited superconducting phase transition offers a convenient way to prepare robust 2D superconductivity on bulk 1 T-TaS2 crystal, thereby bypassing the need to exfoliate monolayer samples. PMID- 30403841 TI - Computing the 3D Radial Distribution Function from Particle Positions: An Advanced Analytic Approach. AB - The radial distribution function, g( r), is ubiquitously used to analyze the internal structure of particulate systems. However, experimentally derived particle coordinates are always confined to a finite sample volume. This poses a particular challenge on computing g( r): Once the radial distance, r, extends beyond the sample boundaries in at least one dimension, substantial deviations from the true g( r) function can occur. State of the art algorithms for g( r) mitigate this issue for instance by using artificial periodic boundary conditions. However, ignoring the finite nature of the sample volume distorts g( r) significantly. Here, we present a simple, analytic algorithm for the computation of g( r) in finite samples. No additional assumptions about the sample are required. The key idea is to use an analytic solution for the intersection volume between a spherical shell and the sample volume. In addition, we discovered a natural upper bound for the radial distance that only depends on sample size and shape. This analytic approach will prove to be invaluable for the quantitative analysis of the increasing amount of experimentally derived tomography data. PMID- 30403842 TI - Chemo-Selection Strategy for Limited Proteolysis Experiments on the Proteomic Scale. AB - Described here is a chemo-selective enrichment strategy, termed the semitryptic peptide enrichment strategy for proteolysis procedures (STEPP), to isolate the semitryptic peptides generated in mass spectrometry-based proteome-wide applications of limited proteolysis methods. The strategy involves reacting the epsilon-amino groups of lysine side chains and any N-termini created in the limited proteolysis reaction with isobaric mass tags. A subsequent digestion of the sample with trypsin and the chemo-selective reaction of the newly exposed N termini of the tryptic peptides with N-hydroxysuccinimide (NHS)-activated agarose resin removes the tryptic peptides from solution, leaving only the semitryptic peptides with one nontryptic cleavage site generated in the limited proteolysis reaction for subsequent LC-MS/MS analysis. As part of this work, the STEPP technique is interfaced with two different proteolysis methods, including the pulse proteolysis (PP) and limited proteolysis (LiP) methods. The STEPP-PP workflow is evaluated in two proof-of-principle experiments involving the proteins in a yeast cell lysate and two well-studied drugs, cyclosporin A and geldanamycin. The STEPP-LiP workflow is evaluated in a proof-of-principle experiment involving the proteins in two cell culture models of human breast cancer, MCF-7 and MCF-10A cell lines. The STEPP protocol increased the number of semitryptic peptides detected in the LiP and PP experiments by 5- to 10-fold. The STEPP protocol not only increases the proteomic coverage, but also increases the amount of structural information that can be gleaned from limited proteolysis experiments. Moreover, the protocol also enables the quantitative determination of ligand binding affinities. PMID- 30403843 TI - TC4/Ag Metal Matrix Nanocomposites Modified by Friction Stir Processing: Surface Characterization, Antibacterial Property, and Cytotoxicity in Vitro. AB - Numerous antibacterial biomaterials have been developed, but a majority of them suffer from poor biocompatibility. With the purpose of reducing biomaterial related infection and cytotoxicity, friction stir processing (FSP) was employed to embed silver nanoparticles (Ag NPs) in a Ti-6Al-4V (TC4) substrate. Characterization using scanning electron microscopy, transmission electron microscopy, and three-dimensional atom probe tomography illustrates that NPs are distributed more homogeneously on the surface of TC4 as the groove depth increases, and silver-rich NPs with a size from 10 to 20 nm exist as metallic silver diffused into the substrate, where the silver content is 4.3-5.6%. Electrochemical impedance spectroscopy shows that both FSP and the addition of silver have positive effects on corrosion resistance. The modified samples effectively inhibit both Staphylococcus aureus and Escherichia coli strains and slightly reduce their adhesion while not displaying any cytotoxicity to bone mesenchymal stem cells in vitro. The antibacterial effect is independent of Ag ion release and is likely due to the number of embedded silver NPs on the surface, which directly contact and subsequently destroy the cell membrane. Our study shows that the TC4/Ag metal matrix nanocomposite is a potential infection related biomaterial and that embedding Ag NPs tightly on a biomaterial surface is an effective strategy for striking a balance between the antibacterial effect and biocompatibility, providing an innovative approach for accurately controlling the cytotoxicity of infection-related biomaterials. PMID- 30403844 TI - Role of Surface Morphology on Exciton Recombination in Single Quantum Dot-in-Rods Revealed by Optical and Atomic Structure Correlation. AB - The physical structure of colloidal quantum dot (QD) nanostructures strongly influences their optical and electronic behavior. A fundamental understanding of this interplay between structure and function is crucial to fully tailor the performance of QDs and their assemblies. Here, by directly correlating the atomic and chemical structure of single CdSe-CdS quantum dot-in-rods with time-resolved fluorescence measurements on the same structures, we identify morphological irregularities at their surfaces that moderate photoluminescence efficiencies. We find that two nonradiative exciton recombination mechanisms are triggered by these imperfections: charging and trap-assisted nonradiative processes. Furthermore, we show that the proximity of the surface defects to the CdSe core of the core-shell structures influences whether the charging or trap-assisted nonradiative channel dominates exciton recombination. Our results extend to other QD nanostructures and emphasize surface roughness as a crucial parameter when designing colloidal QDs with specific excitonic fates. PMID- 30403845 TI - Thermally Persistent High-Spin Ground States in Octahedral Iron Clusters. AB - Chemical oxidation and reduction of the all-ferrous (HL)2Fe6 in THF affords isostructural, coordinatively unsaturated clusters of the type [(HL)2Fe6] n: [(HL)2Fe6][BArF24] (1, n = +1; where [BArF24]- = tetrakis[(3,5 trifluoromethyl)phenyl]borate), [Bu4N][(HL)2Fe6] (2a, n = -1), [P][(HL)2Fe6] (2b, n = -1; where [P]+ = tributyl(1,3-dioxolan-2-ylmethyl)phosphonium), and [Bu4N]2[(HL)2Fe6] (3, n = -2). Each member of the redox-transfer series was characterized by zero-field 57Fe Mossbauer spectroscopy, near-infrared spectroscopy, single-crystal X-ray crystallography, and magnetometry. Redox directed trends are observed when comparing the structural metrics within the [Fe6] core. The metal octahedron [Fe6] decreases marginally in volume as the molecular reduction state increases as gauged by the Fe-Feavg distance varying from 2.608(11) A ( n = +1) to 2.573(3) ( n = -2). In contrast, the mean Fe-N distances and ?Fe-N-Fe angles correlate linearly with the [Fe6] oxidation level, or alternatively, the changes observed within the local Fe-N4 coordination planes vary linearly with the aggregate spin ground state. In general, as the spin ground state ( S) increases, the Fe-N(H)avg distances also increase. The structural metric perturbations within the [Fe6] core and measured spin ground states were rationalized extending the previously proposed molecular orbital diagram derived for (HL)2Fe6. Chemical reduction of the (HL)2Fe6 cluster results in an abrupt increase in spin ground state from S = 6 for the all-ferrous cluster, to S = 19/2 in the monoanionic 2b and S = 11 for the dianionic 3. The observation of asymmetric intervalence charge transfer bands in 3 provides further evidence of the fully delocalized ground state observed by 57Fe Mossbauer spectroscopy for all species examined (1-3). For each of the clusters examined within the electron-transfer series, the observed spin ground states thermally persist to 300 K. In particular, the S = 11 in dianionic 3 and S = 19/2 in the monoanionic 2b represent the highest spin ground states isolated up to room temperature known to date. The increase in spin ground state results from population of the antibonding orbital band comprised of the Fe-N sigma* interactions. As such, the thermally persistent ground states arise from population of the resultant single spin manifolds in accordance with Hund's rules. The large spin ground states, indicative of strong ferromagnetic electronic alignment of the valence electrons, result from strong direct exchange electronic coupling mediated by Fe-Fe orbital overlap within the [Fe6] cores, equivalent to a strong double exchange magnetic coupling B for 3 that was calculated to be 309 cm-1. PMID- 30403846 TI - Heterostructure-Promoted Oxygen Electrocatalysis Enables Rechargeable Zinc-Air Battery with Neutral Aqueous Electrolyte. AB - Neutral aqueous zinc-air batteries (ZABs) are an emerging type of energy devices with substantially elongated lifetime and improved recyclability compared to conventional alkaline ZABs. However, their development is impeded by the lack of robust bifunctional catalyst at the air-electrode for the oxygen evolution reaction (OER) and the oxygen reduction reaction (ORR). Here, we report the controlled synthesis of NiFe2O4/FeNi2S4 heterostructured nanosheets (HNSs) that are highly efficient in catalyzing OER and ORR, therefore enabling neutral rechargeable ZABs. Associated with the formation of abundant oxide/sulfide interfaces over NiFe2O4/FeNi2S4 HNSs' surfaces, the catalyst's oxygen binding energy can be effectively tuned to enhance the OER and ORR activities, as revealed by the density functional theory calculations. In 0.2 M phosphate buffer solution, the optimized NiFe2O4/FeNi2S4 HNSs present an excellent oxygen electrocatalytic activity and stability, with much lower OER and ORR overpotentials than single-component FeNi2S4 or NiFe2O4 and with negligible performance decay in accelerated durability testing. When used as an air electrode, the NiFe2O4/FeNi2S4 HNSs can deliver a power density of 44.4 mW cm-2 and a superior cycling stability (only 0.6% decay after 900 cycles at 0.5 mA cm 2), making the resultant ZAB the most efficient and robust one with a neutral aqueous electrolyte reported to date. This work highlights the essential function of the heterostructure interface in oxygen electrocatalysis, opening a new avenue to advanced neutral metal-air batteries. PMID- 30403847 TI - Gold(I)-Catalyzed Enantioselective Annulations between Allenes and Alkene Tethered Oxime Ethers: A Straight Entry to Highly Substituted Piperidines and aza Bridged Medium-Sized Carbocycles. AB - Piperidine scaffolds are present in a wide range of bioactive natural products and are therefore considered as highly valuable, privileged synthetic targets. In this manuscript, we describe a gold-catalyzed annulation strategy that allows a straightforward assembly of piperidines and piperidine-containing aza-bridged products from readily available alkene-tethered oxime ethers (or esters) and N allenamides. Importantly, we demonstrate the advantages of using oxime derivatives over imines, something pertinent to the whole area of gold catalysis, and provide relevant mechanistic experiments that shed light into the factors affecting the annulation processes. Moreover, we also describe preliminary experiments demonstrating the viability of enantioselective versions of the above reactions. PMID- 30403848 TI - Model Colibactins Exhibit Human Cell Genotoxicity in the Absence of Host Bacteria. AB - Colibactins are genotoxic secondary metabolites produced in select Enterobacteriaceae, which induce downstream DNA double-strand breaks (DSBs) in human cell lines and are thought to promote the formation of colorectal tumors. Although key structural and functional features of colibactins have been elucidated, the full molecular mechanisms regulating these phenotypes remain unknown. Here, we demonstrate that free model colibactins induce DSBs in human cell cultures and do not require delivery by host bacteria. Through domain targeted editing, we demonstrate that a subset of native colibactins generated from observed module skipping in the nonribosomal peptide synthetase-polyketide synthase (NRPS-PKS) biosynthetic assembly line share DNA alkylation phenotypes with the model colibactins in vitro. However, module skipping eliminates the strong DNA interstrand cross-links formed by the wild-type pathway in cell culture. This product diversification during the modular NRPS-PKS biosynthesis produces a family of metabolites with varying observed mechanisms of action (DNA alkylation versus cross-linking) in cell culture. The presence of membranes separating human cells from model colibactins attenuated genotoxicity, suggesting that membrane diffusion limits colibactin activity and could account for the reported bacterium-human cell-to-cell contact phenotype. Additionally, extracellular supplementation of the colibactin resistance protein ClbS was able to intercept colibactins in an Escherichia coli-human cell transient infection model. Our studies demonstrate that free model colibactins recapitulate cellular phenotypes associated with module-skipped products in the native colibactin pathway and define specific protein domains that are required for efficient DNA interstrand cross-linking in the native pathway. PMID- 30403849 TI - Biosynthesis of Novel Statins by Combining Heterologous Genes from Xylaria and Aspergillus. AB - For many secondary metabolites, heterologous synthesis is the definitive step to determine their required biosynthetic genes. Using a multivector expression system in Saccharomyces cerevisiae, we reconstituted not only two natural statins from two fungal species, i.e., lovastatin from Aspergillus terreus and FR901512 from Xylaria grammica, but also new statin structures by mixing their genes. Combinatorial gene exchange experiments revealed the functional promiscuity of two polyketide synthases in A. terreus, lovB, and lovF; they could synthesize FR901512 with Xylaria genes. Key structure determinants of statins are essential accessory genes that are irreplaceable across species. PMID- 30403850 TI - Seed Storage Proteins of Faba Bean ( Vicia faba L): Current Status and Prospects for Genetic Improvement. AB - Faba bean ( Vicia faba L.) is one of the foremost candidate crops for simultaneously increasing both sustainability and global supply of plant protein. On a dry matter basis, its seeds contain about 29% protein of which more than 80% consists of globulin storage proteins (vicilin and legumin). However, to achieve optimum utilization of this crop for human and animal nutrition, both protein content and quality have to be improved. Though initial investigations on the heritability of these traits indicated the possibility for genetic improvement, little has been achieved so far, partly due to the lack of genetic information coupled with the complex relationship between protein content and grain yield. This review reports on the current knowledge on Vicia faba seed storage proteins, their structure, composition, and genetic control, and highlights key areas for further improvement of the content and composition of Vicia faba seed storage proteins on the basis of recent advances in Vicia faba genome knowledge and genetic tools. PMID- 30403851 TI - The Changes in Metabolisms of Membrane Lipids and Phenolics Induced by Phomopsis longanae Chi Infection in Association with Pericarp Browning and Disease Occurrence of Postharvest Longan Fruit. AB - This study investigated the changes in metabolisms of membrane lipids and phenolics caused by Phomopsis longanae Chi infection in association with pericarp browning and fruit disease occurrence of postharvest longans. Compared with the uninoculated-longans, the longans inoculated by P. longanae exhibited higher cellular membrane permeability; higher PLD, lipase, and LOX activities; and higher levels of saturated fatty acids (SFAs) and phosphatidic acid but lower levels of phosphatidylinositol, phosphatidylcholine, and unsaturated fatty acids (USFAs). Additionally, the longans inoculated by P. longanae showed higher activities of POD and PPO but a lower amount of total phenolics. These findings suggested that infection of P. longanae enhanced activities of PLD-, lipase-, and LOX- stimulated degradations of membrane lipids and USFAs, which destroyed the integrity of the cell membrane structure, resulting in enzymatic browning by contact of phenolics with POD and PPO, and resulting in reduction of resistance to pathogen infection and accordingly accelerated disease occurrence of postharvest longan fruit. PMID- 30403852 TI - Catalytic Regio- and Enantioselective Haloazidation of Allylic Alcohols. AB - Herein we report a highly regio- and stereoselective haloazidation of allylic alcohols. This enantioselective reaction uses readily available materials and can be performed on a variety of alkyl-substituted alkenes and can incorporate either bromine or chlorine as the electrophilic halogen component. Both halide and azido groups of the resulting products can be transformed into valuable building blocks with complete stereospecificity. The first example of an enantioselective 1,4 haloazidation of a conjugated diene is reported as well as its application to a concise synthesis of an aza-sugar. PMID- 30403853 TI - Physiological Effects of Copper Oxide Nanoparticles and Arsenic on the Growth and Life Cycle of Rice ( Oryza sativa japonica 'Koshihikari'). AB - A factorial study was conducted to evaluate the phytotoxicity of copper oxide nanoparticles (nCuO, 0.1-100 mg/L), arsenic (As, 0 and 10 mg/kg), and their interaction to rice plants ( Oryza sativa japonica 'Koshihikari') during the life cycle. No significant effect was observed on seed germination. The main effects of nCuO and As were observed on lengths and biomasses of seedling shoots and roots and on root branching. The interaction between nCuO and As also significantly influenced these parameters. nCuO addition increased Cu uptake in seedlings and generally improved seedling growth. With As addition, As was highly concentrated in roots and increased in shoots, and seedling growth was also inhibited. Additionally, nCuO and As had significant main and interaction effects on mature plant dry biomass, panicle number, total grain weight, average grain weight, and several other panicle parameters. Moreover, nCuO and As interacted to affect panicle emergence. nCuO also decreased As accumulation in dehusked grains. The accelerated heading stage by nCuO may help shorten the life cycle of rice plants, thereby reducing As accumulation in grains. This study is the first to examine the influence of nCuO in combination with As on the life cycle of rice plants. PMID- 30403854 TI - Computational Exploration of a Pd(II)-Catalyzed gamma-C-H Arylation Where Stereoselectivity Arises from Attractive Aryl-Aryl Interactions. AB - The enantioselective Pd(II)-catalyzed gamma-C-H arylation of picolinamides with a chiral BINOL phosphate ligand was explored using density functional theory (DFT). Enantioselectivity arises from attractive aryl-aryl interactions between the pseudoequatorial phenyl substituent of the substrate and the chiral BINOL phosphate ligand. PMID- 30403855 TI - ezCADD: A Rapid 2D/3D Visualization-Enabled Web Modeling Environment for Democratizing Computer-Aided Drug Design. AB - As abundant and user-friendly as computer-aided drug design (CADD) software may seem, there is still a large underserved population of biomedical researchers around the world, particularly those with no computational training and limited research funding. To address this important need and help scientists overcome barriers that impede them from leveraging CADD in their drug discovery work, we have developed ezCADD, a web-based CADD modeling environment that manifests four simple design concepts: easy, quick, user-friendly, and 2D/3D visualization enabled. In this paper, we describe the features of three fundamental applications that have been implemented in ezCADD: small-molecule docking, protein-protein docking, and binding pocket detection, and their applications in drug design against a pathogenic microbial enzyme as an example. To assess user experience and the effectiveness of our implementation, we introduced ezCADD to first-year pharmacy students as an active learning exercise in the Principles of Drug Action course. The web service robustly handled 95 simultaneous molecular docking jobs. Our survey data showed that among the 95 participating students, 97% completed the molecular docking experiment on their own at least partially without extensive training; 88% considered ezCADD easy and user-friendly; 99-100% agreed that ezCADD enhanced the understanding of drug-receptor structures and recognition; and the student experience in molecular modeling and visualization was significantly improved from zero to a higher level. The student feedback represents the baseline data of user experience from noncomputational researchers. It is demonstrated that in addition to supporting drug discovery research, ezCADD is also an effective tool for promoting science, technology, engineering, and mathematics (STEM) education. More advanced CADD applications are being developed and added to ezCADD, available at http://dxulab.org/software . PMID- 30403856 TI - Salivary and gut microbiomes play a significant role in in vitro oral bioaccessibility, biotransformation and intestinal absorption of arsenic from food. AB - The release of a toxicant from a food matrix during the gastrointestinal digestion is a crucial determinant of the toxicant's oral bioavailability. We present a modified setup of the human simulator of the gut microbial ecosystem (SHIME), with four sequential gastrointestinal reactors (oral, stomach, small intestine, and colon), including the salivary and colonic microbiomes. Naturally arsenic-containing rice, mussels and nori seaweed were digested in the presence of microorganisms, and in vitro oral bioaccessibility, bioavailability and metabolism of arsenic species were evaluated. When food matrices were digested with salivary bacteria, the soluble arsenic in the gastric digestion stage increased for mussel and nori samples, but no coincidence impact was found in the small intestinal and colonic digestion stages. However, the simulated small intestinal absorption of arsenic was increased in all food matrices (1.2-2.7 fold higher) following digestion with salivary microorganisms. No significant transformation of the arsenic species occurred except for the arsenosugars present in mussels and nori. In those samples, conversions between the oxo arsenosugars were observed in the small intestinal digestion stage whereupon the thioxo analogs became major metabolites. These results expand our knowledge on the likely metabolism and oral bioavailability of arsenic during the human digestion and provide information valuable for future risk assessments of dietary arsenic. PMID- 30403857 TI - Correspondence between Spectral-Derived and Viscosity-Derived Local Composition in Binary Liquid Mixtures Having Specific Interactions with Preferential Solvation Theory. AB - Local interactions between unlike molecules (1-2) in solution are commonly measured with spectroscopy and used to estimate local composition. Herein, a viscosity model based on preferential solvation (PS) theory is developed for aqueous and nonaqueous binary liquid mixtures containing a dipolar aprotic solvent that provides local composition considering the hydration or solvation shell around complex (1-2) molecules. Spectral-derived and viscosity-derived local composition distributions showed similar trends with bulk composition, and their correspondence is attributed to characteristics of the hydration or solvation shell. Viscosity-derived local compositions were consistent with literature molecular simulations, whereas spectral-derived local composition distributions contained artifacts. The PS viscosity model is also applicable to nonpolar-polar mixtures for which self-association occurs, and it can be used to estimate solvent mixture dipolarity/polarizability. Since the PS viscosity model only requires bulk viscosity, it may provide a means to estimate microviscosity or the solvent environment around biomolecules. PMID- 30403858 TI - Direct Evidence for Li Ion Hopping Conduction in Highly Concentrated Sulfolane Based Liquid Electrolytes. AB - We demonstrate that Li+ hopping conduction, which cannot be explained by conventional models i.e., Onsager's theory and Stokes' law, emerges in highly concentrated liquid electrolytes composed of LiBF4 and sulfolane (SL). Self diffusion coefficients of Li+ ( DLi), BF4- ( DBF4), and SL ( DSL) were measured with pulsed-field gradient NMR. In the concentrated electrolytes with molar ratios of SL/LiBF4 <= 3, the ratios DSL/ DLi and DBF4/ DLi become lower than 1, suggesting faster diffusion of Li+ than SL and BF4-, and thus the evolution of Li+ hopping conduction. X-ray crystallographic analysis of the LiBF4/SL (1:1) solvate revealed that the two oxygen atoms of the sulfone group are involved in the bridging coordination of two different Li+ ions. In addition, the BF4- anion also participates in the bridging coordination of Li+. The Raman spectra of the highly concentrated LiBF4-SL solution suggested that Li+ ions are bridged by SL and BF4- even in the liquid state. Moreover, detailed investigation along with molecular dynamics simulations suggests that Li+ exchanges ligands (SL and BF4-) dynamically in the highly concentrated electrolytes, and Li+ hops from one coordination site to another. The spatial proximity of coordination sites, along with the possible domain structure, is assumed to enable Li+ hopping conduction. Finally, we demonstrate that Li+ hopping suppresses concentration polarization in Li batteries, leading to increased limiting current density and improved rate capability compared to the conventional concentration electrolyte. Identification and rationalization of Li+ ion hopping in concentrated SL electrolytes is expected to trigger a new paradigm of understanding for such unconventional electrolyte systems. PMID- 30403859 TI - AtLHT1 Transporter Can Facilitate the Uptake and Translocation of a Glycinergic Chlorantraniliprole Conjugate in Arabidopsis thaliana. AB - Understanding of the transporters involved in the uptake and translocation of agrochemicals in plants could provide an opportunity to guide pesticide to the site of insect feeding. The product of Arabidopsis thaliana gene AtLHT1 makes a major contribution to the uptake into the roots of free amino acids and some of their derivatives. Here, a chlorantraniliprole-glycine conjugate (CAP-Gly-1) was tested for its affinity to AtLHT1 both in planta and in vitro. Seedlings deficient in AtLHT1 exhibited a reduction with respect to both the uptake and root-to-shoot transfer of CAP-Gly-1; plants in which AtLHT1 was constitutively expressed were more effective than wild type in term of their root uptake of CAP Gly-1. Protoplast patch clamping showed that the presence in the external medium of CAP-Gly-1 was able to induce AtLHT1 genotype-dependent inward currents. An electrophysiology-based experiment carried out in Xenopus laevis oocytes expressing AtLHT1 showed that AtLHT1 had a high in vitro affinity for CAP-Gly-1. The observations supported the possibility of exploiting AtLHT1 as a critical component of a novel delivery system for amino acid-based pesticide conjugates. PMID- 30403860 TI - Adsorption and Desorption Behaviors of Spirotetramat in Various Soils and Its Interaction Mechanism. AB - Spirotetramat is a pesticide with bidirectional systemicity and can effectively control pests by inhibiting the biosynthesis of fatty acids. In this study, adsorption and desorption behaviors of spirotetramat in six soils and its interaction mechanism were studied using the batch equilibrium method and infrared radiation. The results showed that the adsorption and desorption behaviors of spirotetramat conformed to the Freundlich isotherm model. The values of adsorption capacities KF-ads ranged from 2.11 to 12.40, and the values of desorption capacities KF-des varied from 2.97 to 32.90. From the hysteresis coefficient, spirotetramat was easily desorbed from the test soils. The adsorption capacity of the soil to spirotetramat enhanced with an increasing temperature. Moreover, the changes in pH values and exogenous addition of humic acid and surfactant could also affect soil adsorption capacity, but for desorption, there was no correlation. PMID- 30403861 TI - Role of Conformational Fluctuations of Protein toward Methylation in DNA by Cytosine-5-methyltransferase. AB - Methylation of cytosine is the common epigenetic modification in genomes ranging from bacteria to mammals, and aberrant methylation leads to human diseases including cancer. Recognition of a cognate DNA sequence by DNA methyltransferases and flipping of a target base into the enzyme active site pocket are the key steps in DNA methylation. Using molecular dynamics simulations and enhanced sampling techniques here we elucidate the role of conformational fluctuations of protein and active or passive involvement of protein elements that mediate base flipping and formation of the closed catalytic complex. The free energy profiles for the flipping of target cytosine into the enzyme active site support the major groove base eversion pathway; and the results show that the closed state of enzyme increases the free energy barrier, whereas the open state reduces it. We found that the interactions of the key loop residues of protein with cognate DNA altered the protein motions, and modulation of protein fluctuations relates to the closed catalytic complex formation. Methylation of cytosine in the active site of the closed complex destabilizes the interactions of catalytic loop residues with cognate DNA and reduces the stability of the closed state. Our study provides microscopic insights on the base flipping mechanism coupled with enzyme's loop motions and provides evidence for the role of conformational fluctuations of protein in the enzyme-catalyzed DNA processing mechanism. PMID- 30403862 TI - The Molecular Dance of Fibronectin: Conformational Flexibility Leads to Functional Versatility. AB - Fibronectin, a large multimodular protein and one of the major fibrillar components of the extracellular matrix, has been the subject of study for many decades and plays critical roles in embryonic development and tissue homeostasis. Moreover, fibronectin has been implicated in the pathology of many diseases, including cancer, and abnormal depositions of fibronectin have been identified in a number of amyloid and nonamyloid lesions. The ability of fibronectin to carry all these diverse functionalities depends on interactions with a large number of molecules, including adhesive and signaling cell surface receptors, other components of the extracellular matrix, and growth factors and cytokines. The regulation and integration of such large number of interactions depends on the modular architecture of fibronectin, which allows a large number of conformations, exposing or destroying different binding sites. In this Review, we summarize the current knowledge regarding the conformational flexibility of fibronectin, with an emphasis on how it regulates the ability of fibronectin to interact with various signaling molecules and cell-surface receptors and to form supramolecular assemblies and fibrillar structures. PMID- 30403863 TI - Oxygenophilic Lewis Acid Promoted Synthesis of 2-Arylindoles from Anilines and Cyanoepoxides in Alcohol. AB - A convenient synthetic method to indoles from anilines and cyanoepoxides was developed under the catalysis of BF3.OEt2 or AlCl3 in alcohols. The reaction involves a tandem reaction of the regiospecific ring-opening of cyanoepoxides with anilines, elimination of cyanide, intramolecular aromatic electrophilic substitution, and water elimination. The Lewis acid generated protic acid is an efficient catalyst. The method features readily accessible starting materials, wide substrate scope, transition-metal-free environment, and regiospecificity in the ring-opening of cyanoepoxides. PMID- 30403864 TI - Isoproturon-induced salicylic acid confers Arabidopsis resistance to isoproturon phytotoxicity and degradation in plants. AB - This study identified the effect of salicylic acid on degradation of isoproturon in Arabidopsis. Three T-DNA insertion mutant lines pal1-1, pal1-2 and eps1-1 defective in salicylic acid synthesis were tested, which showed higher isoproturon accumulation and toxic symptom in the mutants. When treated with 5 mg/L salicylic acid, these lines displayed a lower level of isoproturon and showed attenuated toxic symptom. RNA-sequencing study identified 2651 (1421 up and 1230 down) differentially expressed genes (DEGs) in eps1-1 and 2211 (1556 up and 655 down) in pal1-2 mutant plants (> 2.0 fold change, p< 0.05). Some of the DEGs covered Phase I?III reaction components like glycosyltransferases (GTs) and ATP-binding cassette transporters (ABCs). Using ultra performance liquid chromatography-time of fight tandem-mass spectrometer/mass spectrometer (UPLC-TOF MS/MS), thirteen Phase I and four Phase II metabolites were characterized. Of these, two metabolites 1-OH-isopropyl-benzene-O-glucoside and 4-isopropylphenol-S 2-methylbutanoyl-serine have been identified and reported for the first time. PMID- 30403865 TI - Reply to "Comment on 'Negative Deviations from the Debye-Huckel Limiting Law for High-Charge Polyvalent Electrolytes: Are They Real?' ". AB - In their "Comment on 'Negative Deviations from the Debye-Huckel Limiting Law for High-Charge Polyvalent Electrolytes: Are They Real?' " Biver and Malatesta, citing my respective paper, argue that my analysis of experimental data of their group is wrong and so is my conclusion that negative deviations observed by them are not physically real. Here I rebut their arguments and explain why their rejection of my work is unjustified, and why those authors do not in any way prove me wrong. The core of my study and conclusion remains intact: Negative deviations in the case of high-charge electrolytes with | z+ z-| > 3 do not always happen, and so far, such observed deviations are not convincingly supported by theory. PMID- 30403866 TI - Optimized Continuous Application of Hyperpolarized Xenon to Liquids. AB - In recent years, NMR with hyperpolarized (HP) xenon inside functionalized host structures (e.g., cryptophanes) have become a potential candidate for the direct observation of metabolic processes (i.e., molecular imaging). A critical issue for real applications is the dissolution of the HP-gas in the liquid which contains the host. In this work, we present recent developments for an improved and controlled dissolution of HP-Xe in liquids using hollow fiber membranes and different compressor systems. The designed apparatus consists of a compressor and a membrane unit. The compressor provides HP-129Xe continuously at small adjustable pressures and in a polarization-preserving way. The membrane unit enables a molecular solution of the HP-gas in aqueous liquids, avoiding the formation of bubbles or even foams. Two different types of compressors were tested in terms of function and useful materials. Special emphasis was put on a systematic reduction of transfer losses in the gas and liquid phase. In order to optimize the system parameters, several physical models were developed to describe the transport and the losses of nuclear polarization. Finally, the successful implementation was demonstrated in several experiments. HP-Xe was dissolved in an aqueous cryptophane-A-(OCH2COOH)6 solution, and stable Xe signals could be measured over 35 min, only limited by the size of the gas reservoir. Such long and stable experimental conditions enabled the study of chemical exchange of xenon between cryptophane and water environments even for a time consuming 2D NMR experiment. The good signal stability over the measurement time allowed an exact determination of the residence time of the Xe atom inside the cryptophane, resulting in an average residence time of 44.5 +/- 2.7 ms. PMID- 30403867 TI - Characteristics of Time-Dependent Selenium Biofortification of Rice ( Oryza sativa L.). AB - The application of selenite to soil has increasingly been used to produce Se enriched food. This study investigated the biofortification characteristics of Se in rice after application of selenite to soil at different growth stages. The results showed that the application of Se during booting stage resulted in the highest concentration of Se in brown rice due to the highest upward translocation of Se. More than 90% of Se in the brown rice was organic species, with selenomethionine predominated. The proportion of selenomethionine in the brown rice decreased with the delay in application time. The rice grown in the acidic soil had higher Se concentrations than in the neutral soil. With increasing soil Cd level, Se accumulation and the proportion of Se-methylselenocysteine in the brown rice were reduced. This study provides a theoretical basis for the production of Se-enriched rice in clean soil or slightly to moderately Cd contaminated soil. PMID- 30403868 TI - DBU-Promoted Cascade Annulation of Nitroarylcyclopropane-1,1-dicarbonitriles and 3-Aryl-2-cyanoacrylates: An Access to Highly Functionalized Cyclopenta[ b]furan Derivatives. AB - A DBU-promoted cascade annulation of nitroarylcyclopropane-1,1-dicarbonitriles and 3-aryl-2-cyanoacrylates for the synthesis of highly functionalized cyclopenta[ b]furan derivatives is described. High stereoselectivity, fused cyclopentane and furan can be established in a single reaction, highlighting the high efficiency and step-economy of this protocol. This reaction offers a novel and straightforward protocol to the synthesis of cyclopenta[ b]furans featuring the [3 + 2] cycloadditions of nitroarylcyclopropane-1,1-dicarbonitriles with 3 aryl-2-cyanoacrylates. PMID- 30403869 TI - SBOL on the Web: Bringing the Synthetic Biology Open Language to the Web browser. AB - The Synthetic Biology Open Language (SBOL) is a data standard for the in silico representation of biological designs, such as engineered genetic circuits and their constituent DNA and protein components. The SBOL specification is implemented in the form of software libraries, which can then be used to add SBOL support to both new and existing software tools. Examples of existing SBOL libraries include libSBOLj for Java, libSBOL for C, and pySBOL for Python. These libraries can be used to develop software that runs on a server or is installed locally on a computer. However, currently there are no libraries that can be used to develop SBOL software that runs directly in a Web browser. This omission is notable considering the increasing dominance of JavaScript and the Web as a platform for modern applications. This paper presents sboljs, a JavaScript software library for SBOL that is capable of being used both on the server and in the Web browser. PMID- 30403870 TI - Deep Learning for Nonadiabatic Excited-State Dynamics. AB - In this work we show that deep learning (DL) can be used for exploring complex and highly nonlinear multistate potential energy surfaces of polyatomic molecules and related nonadiabatic dynamics. Our DL is based on deep neural networks (DNNs), which are used as accurate representations of the CASSCF ground- and excited-state potential energy surfaces (PESs) of CH2NH. After geometries near conical intersection are included in the training set, the DNN models accurately reproduce excited-state topological structures; photoisomerization paths; and, importantly, conical intersections. We have also demonstrated that the results from nonadiabatic dynamics run with the DNN models are very close to those from the dynamics run with the pure ab initio method. The present work should encourage further studies of using machine learning methods to explore excited state potential energy surfaces and nonadiabatic dynamics of polyatomic molecules. PMID- 30403871 TI - Femtosecond Vibrational Sum-Frequency Generation Spectroscopy of Chiral Molecules in Isotropic Liquid. AB - Vibrationally resonant optically active (VOA) sum-frequency generation (SFG) is a second-order nonlinear process sensitive to the stereospecific vibrational structure of chiral molecules. We demonstrate that a femtosecond VOA SFG signal can be measured in the isotropic bulk of a chiral liquid. The chiral, achiral, and VOA SFG spectra of R- and S-limonene and their racemic mixture in the C-H stretching frequency region are characterized. In particular, it is shown that the observed circular intensity difference (CID) signal, which can provide distinguishable stereochemical vibrational information between enantiomers, arises from interference of the electric-dipole allowed antisymmetric Raman tensor-induced and Raman optical activity (ROA) tensor-induced SFG fields. Furthermore, we show that the CID and linear polarization intensity difference (LID) SFG spectra are connected to the real and imaginary parts of the effective chiral VOA SFG susceptibility, respectively. We anticipate that the present technique will be of use in transient chiroptical spectroscopy and stereochemical vibrational imaging studies. PMID- 30403872 TI - Enhanced Separation of Butane Isomers via Defect Control in a Fumarate/Zirconium Based Metal Organic Framework. AB - The discovery of appropriate synthetic reaction conditions for fabricating a stable zirconium-based molecular sieve (Zr-fum-fcu-MOF) with minimal defects and its utilization in the challenging separation of linear paraffins from branched paraffins is reported. The crystallinity and structural defects were modulated and adjusted at the molecular level by controlling the synthetic reaction conditions (i.e., amounts of modulators and ligands). The impact of molecular defects on the separation of n-butane from iso-butane was studied through the preparation, fine characterization, and performance evaluation of Zr-fum-fcu-MOFs with varying degrees of defects. Defect-rich Zr-fum-fcu-MOFs were found to have poor n-butane/iso-butane separation, mainly driven by thermodynamics, while Zr fum-fcu-MOFs with fewer or minimal defects showed efficient separation, driven mainly by kinetics and full molecular exclusion mechanisms. The impact of intrinsic defects (i.e., missing organic or inorganic blocks) on the associated mechanisms involved in the separation of n-butane/iso-butane was evidenced through single-gas adsorption, mixed-gas column breakthrough experiments, and calorimetric studies. This investigation demonstrates, for the first time, the importance of controlling intrinsic defects to maintain the selective exclusion behavior of hydrocarbon isomers when using molecular sieves. PMID- 30403873 TI - Screening Magnetic Two-Dimensional Atomic Crystals with Nontrivial Electronic Topology. AB - To date, only a few two-dimensional (2D) magnetic crystals have been experimentally confirmed, such as CrI3 and CrGeTe3, all with very low Curie temperatures ( TC). High-throughput first-principles screening over a large set of materials yields 89 magnetic monolayers including 56 ferromagnetic (FM) and 33 antiferromagnetic compounds. Among them, 24 FM monolayers are promising candidates possessing TC higher than that of CrI3. High TC monolayers with fascinating electronic phases are identified: (i) quantum anomalous Hall and valley Hall effects coexist in a single material RuCl3 or VCl3, leading to a valley-polarized quantum anomalous Hall state; (ii) TiBr3, Co2NiO6, and V2H3O5 are revealed to be half-metals. More importantly, a new type of fermion dubbed type-II Weyl ring is discovered in ScCl. Our work provides a database of 2D magnetic materials, which could guide experimental realization of high temperature magnetic monolayers with exotic electronic states for future spintronics and quantum computing applications. PMID- 30403874 TI - Transport of Spin-Entangled Triplet Excitons Generated by Singlet Fission. AB - Singlet fission provides a promising route for overcoming the Shockley-Queisser limit in solar cells using organic materials. Despite singlet fission dynamics having been extensively investigated, the transport of the various intermediates in relation to the singlet and triplet states is largely unknown. Here we employ temperature-dependent ultrafast transient absorption microscopy to image the transport of singlet fission intermediates in single crystals of tetracene. These measurements suggest a mobile singlet fission intermediate state at low temperatures, with a diffusion constant of 36 cm2s-1 at 5 K, approaching that for the free singlet excitons, which we attribute to the spin-entangled correlated triplet pair state 1[TT]. These results indicate that 1[TT] could transport with a similar mechanism as the bright singlet excitons, which has important implications in designing materials for singlet fission and spintronic applications. PMID- 30403875 TI - Electron-Hole Correlations Govern Auger Recombination in Nanostructures. AB - The fast nonradiative decay of multiexcitonic states via Auger recombination is a fundamental process affecting a variety of applications based on semiconductor nanostructures. From a theoretical perspective, the description of Auger recombination in confined semiconductor nanostructures is a challenging task due to the large number of valence electrons and exponentially growing number of excited excitonic and biexcitonic states that are coupled by the Coulomb interaction. These challenges have restricted the treatment of Auger recombination to simple, noninteracting electron-hole models. Herein we present a novel approach for calculating Auger recombination lifetimes in confined nanostructures having thousands to tens of thousands of electrons, explicitly including electron-hole interactions. We demonstrate that the inclusion of electron-hole correlations are imperative to capture the correct scaling of the Auger recombination lifetime with the size and shape of the nanostructure. In addition, correlation effects are required to obtain quantitatively accurate lifetimes even for systems smaller than the exciton Bohr radius. Neglecting such correlations can result in lifetimes that are two orders of magnitude too long. We establish the utility of the new approach for CdSe quantum dots of varying sizes and for CdSe nanorods of varying diameters and lengths. Our new approach is the first theoretical method to postdict the experimentally known "universal volume scaling law" for quantum dots and makes novel predictions for the scaling of the Auger recombination lifetimes in nanorods. PMID- 30403876 TI - Moire Intralayer Excitons in a MoSe2/MoS2 Heterostructure. AB - Spatially periodic structures with a long-range period, referred to as a moire pattern, can be obtained in van der Waals bilayers in the presence of a small stacking angle or of lattice mismatch between the monolayers. Theoretical predictions suggest that the resulting spatially periodic variation of the band structure modifies the optical properties of both intra- and interlayer excitons of transition metal dichalcogenide heterostructures. Here, we report on the impact of the moire pattern formed in a MoSe2/MoS2 heterobilayer encapsulated in hexagonal boron nitride. The periodic in-plane potential results in a splitting of the MoSe2 exciton and trion in emission and (for the exciton) absorption spectra. The observed energy difference between the split peaks is fully consistent with theoretical predictions. PMID- 30403877 TI - Theory-driven formative research on on-site, shared sanitation quality improvement among landlords and tenants in peri-urban Lusaka, Zambia. AB - Rapid, unplanned urbanization in low-income countries is leading to increasing problems of dealing with human waste. On-site sanitation systems are often rudimentary, unhygienic, and poorly maintained. In-depth, on-site interactive interviews were conducted with 33 landlords and 33 tenants in a neighborhood in peri-urban Lusaka to understand on-site, shared sanitation quality improvement behaviors and preferences. Respondents were asked about housing characteristics, toilet histories, and financial decision-making. Improved, shared toilets were common (79%), but many were of low quality and poorly cleaned. Poor coordination among tenants, barriers to communication between landlords and tenants, and landlords viewing sanitation as a required basic service to provide instead of something for which tenants will pay more rent all limit the quality of sanitation in this setting. Landlord-directed interventions targeting non-health motivations for sanitation improvement and introducing effective cleaning systems may increase peri-urban sanitation quality. PMID- 30403878 TI - The Validity of Optical Coherence Tomography Angiography as a Screening Test for the Early Detection of Retinal Changes in Patients with Hydroxychloroquine Therapy. AB - PURPOSE: The aim of this study was to quantitatively compare both the vessel density of macular capillary plexuses and the foveal avascular zone (FAZ) areas of patients receiving hydroxychloroquine (HCQ) therapy for more than 5 years while using age- and sex-matched controls. METHODS: The patients undergoing HCQ who were screened for toxic effects were evaluated. The FAZ parameters included the area, perimeter, and the acircularity index. The foveal density and vessel density values of both the superficial capillary plexus (SCP) and deep capillary plexus (DCP) were measured using optical coherence tomography angiography (OCTA). RESULTS: This study included 80 eyes of 40 subjects: 20 subjects in the HCQ group and 20 subjects in the control group. The FAZ perimeter and the FAZ area in the SCP and full retinal vasculature were significantly larger in the HCQ group than in the control group (p < 0.05 for all). Additionally, the vessel density of fovea in the SCP and DCP was significantly lower in the HCQ group than in the control group (p < 0.05 for all). CONCLUSIONS: OCTA provides objective documentation about FAZ and vessel density features in patients using long-term HCQ therapy before toxicity begins, and it can be used as a screening tool for detecting early changes in the macula. PMID- 30403879 TI - The impact of support programmes for survivors of sexual violence: micro-level evidence from eastern Democratic Republic of the Congo. AB - In the eastern Democratic Republic of the Congo there are several support programmes for sexual violence survivors, but their impacts are rarely systematically assessed. We investigated the effects for women from two support programmes that include both survivors of sexual and gender-based violence (SGBV) and others. Specifically, we estimated (1) the effect of SGBV on social exclusion and economic well-being, and (2) the effects of support programmes on social exclusion and economic well-being, as well as differential effects for SGBV survivors and others. Based on an original survey of 1,203 women, we found that survivors felt less included across various social settings, but their economic well-being was no different than that of other women. We also found that support programmes significantly improve both perceived social inclusion and economic well-being for survivors and non-survivors. The effects on economic well-being were larger for survivors. In conclusion, these support programmes brought important benefits to survivors and non-survivors alike, although there is potential for improvement, particularly on social inclusion for SGBV survivors. PMID- 30403880 TI - Senior fitness test; a useful tool to measure physical fitness in persons with acquired brain injury. AB - OBJECTIVES: To evaluate the feasibility and usability of the senior fitness test (SFT) in persons with acquired brain injury (ABI). METHODS: A pilot cohort design with a convenience sample of persons with ABI was used. RESULTS: Persons with ABIs (n = 47) were younger than their healthy counterparts (n = 172) were but performed significantly worse on sit to stand, 6-min walk test (6MWT) and 2.45-m up and go. This difference was accentuated in the age groups >60 years of age. Persons with ABIs, divided into subgroups traumatic brain injury (TBI; n = 12) and cerebral insult (CI; n = 35), showed significant differences in leg strength, upper extremity flexibility and walking capacity. Persons with CI were weaker, less flexible in upper and lower extremities, walked shorter distance and were less mobile. CI but not TBI performed significantly worse when compared to healthy elderly persons. CONCLUSION: This study indicates that SFT is feasible, safe and useful tool for persons with ABI, to evaluate physical capacity, endurance, strength and flexibility. The submaximal test was well tolerated and could be performed by all participants irrespective of age or diagnosis. The distribution of test scores indicates responsiveness to change and no ceiling or floor effects. PMID- 30403881 TI - Altered expression of the core circadian clock component PERIOD2 contributes to osteoarthritis-like changes in chondrocyte activity. AB - In osteoarthritis, chondrocytes undergo a phenotype shift characterised by reduced expression of SOX9 (sry-box 9) and increased production of cartilage degrading enzymes, e.g. MMP13 (matrix metalloproteinase 13) and ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5). The chondrocyte clock is also altered. Specifically, the peak level of PER2 is elevated, but peak level of BMAL1 reduced in osteoarthritic chondrocytes. The purpose of this study was to determine whether increased PER2 expression causes disease-associated changes in chondrocyte activity and to identify whether known risk factors for osteoarthritis induce changes in PER2 and BMAL1 expression. Primary human chondrocytes isolated from macroscopically normal cartilage were serum-starved overnight then re-fed with serum-replete media with/without interleukin 1beta (IL 1beta) (10 ng/mL), hydrogen peroxide (100 uM) or basic calcium phosphate (BCP) crystals (50 ug/mL). Peak level of BMAL1 was lower, whereas PER2 levels remained elevated for longer, in chondrocytes treated with IL-1beta, hydrogen peroxide or BCP crystals compared to untreated cells. Levels of SOX9 were lower, whereas levels of ADAMTS5 and MMP13 were higher, in chondrocytes exposed to any of the three treatments compared to untreated cells. Knockdown of PER2 using siRNA partially abrogated the effects of each treatment on chondrocyte phenotype marker expression. Similarly, in chondrocytes isolated from osteoarthritic cartilage PER2 knockdown was associated with increased SOX9, reduced ADAMTS5 and reduced RNA and protein levels of MMP13 indicating partial mitigation of the osteoarthritic phenotype. Conversely, further ablation of BMAL1 expression in osteoarthritic chondrocytes resulted in a further reduction in SOX9 and increase in MMP13 expression. Overexpression of PER2 in the H5 chondrocyte cell line led to increased ADAMTS5 and MMP13 and decreased SOX9 expression. Localised inflammation, oxidative stress and BCP crystal deposition in osteoarthritic joints may contribute to disease pathology by inducing changes in the chondrocyte circadian clock. PMID- 30403883 TI - An improved method for studying whole sections of late developing wheat grain. AB - Whole sections are important for investigation in situ of the development of cell morphology and accumulation of storage substance in cereal kernels. We developed an improved, simple method to obtain good quality whole histological sections of wheat grains during mid- and late-stage (28 and 35 days post anthesis) grain filling. The wheat grains were fixed and dehydrated, cleared in chloroform for 3 days and infiltrated in paraffin at 55 degrees C for 3 - 5 days. The infiltrated grains then were embedded in paraffin wax, softened using diethyl pyrocarbonate (DEPC) water before sectioning. After these treatments, the wheat grains can be sectioned easily at 10 - 25 MUm while retaining the cellular structure and antigenicity. The cell structure, cell distribution, autofluorescence, starch accumulation and localization in situ of bam1, one of the genes encoding beta amylase transcripts in the sections of the late developing wheat grain were observed readily. PMID- 30403882 TI - Probabilistic Disjoint Principal Component Analysis. AB - One of the most relevant problems in principal component analysis and factor analysis is the interpretation of the components/factors. In this paper, disjoint principal component analysis model is extended in a maximum-likelihood framework to allow for inference on the model parameters. A coordinate ascent algorithm is proposed to estimate the model parameters. The performance of the methodology is evaluated on simulated and real data sets. PMID- 30403884 TI - Sex differences in concussion: a review of brain anatomy, function, and biomechanical response to impact. AB - OBJECTIVE: Provide a potential explanation for sex differences associated with concussions. RESEARCH DESIGN: Review of current literature from complementary disciplines to synthesize a theory to explains sex differences in individuals with concussion. METHODS: Systematic review focusing on sex-related differences in individuals with concussion. Articles published in peer-reviewed journals after 2000 were reviewed and discussed among the authors to determine common themes across the different disciplines represented in the literature review. RESULTS: There are differences in brain structure between sexes. The male corpus callosum has larger fibers and cross-sectional area compared to females. Females tend to utilize both hemispheres of the brain for most tasks, while males are more lateralized. Computation models of concussive impacts indicate that the greater strains occur at the corpus callosum. The corpus callosum is the conduit for interhemispheric connections within the brain; therefore, it stands to reason that increased strain in this area may affect interhemispheric communications resulting in a difference in perceived symptoms between males and females. CONCLUSIONS: Strain injury of the corpus callosum may affect females to a greater extent since their ability to process information may become more disrupted than males. PMID- 30403885 TI - Award Winners for 2018 AJPH Paper and Reviewer of the Year. PMID- 30403886 TI - Survey data in neurousrgery. PMID- 30403887 TI - Simple Structure Detection Through Bayesian Exploratory Multidimensional IRT Models. AB - In modern validity theory, a major concern is the construct validity of a test, which is commonly assessed through confirmatory or exploratory factor analysis. In the framework of Bayesian exploratory Multidimensional Item Response Theory (MIRT) models, we discuss two methods aimed at investigating the underlying structure of a test, in order to verify if the latent model adheres to a chosen simple factorial structure. This purpose is achieved without imposing hard constraints on the discrimination parameter matrix to address the rotational indeterminacy. The first approach prescribes a 2-step procedure. The parameter estimates are obtained through an unconstrained MCMC sampler. The simple structure is, then, inspected with a post-processing step based on the Consensus Simple Target Rotation technique. In the second approach, both rotational invariance and simple structure retrieval are addressed within the MCMC sampling scheme, by introducing a sparsity-inducing prior on the discrimination parameters. Through simulation as well as real-world studies, we demonstrate that the proposed methods are able to correctly infer the underlying sparse structure and to retrieve interpretable solutions. PMID- 30403888 TI - Shift work and sex are variants across Karolinska Sleep Questionnaire and the application of linking analysis as a step forward using Item Response Theory. AB - The frequency of sleep disturbances is considerably higher in the night and shift workers and in females than in day workers and males, respectively. However, a subjective sleep scale must be invariant across these groups, independently of the level of their members on the scale. This study is aimed to test the invariance of the Karolinska Sleep Questionnaire's (KSQ) items by shift work and sex. We used the data from a census that covered more than 90% (N = 1648) of the nurses from the main institute of the largest public hospital complex of Brazil. Firstly, we intend to find the KSQ's dimensionality using factorial analysis and Item Response Theory (IRT) performed by Graded Response Model. Differential Item Functioning (DIF) was the technique used to test the invariance of each KSQ's dimensions. In case of variance detection, we applied the linking analysis. Intending to test the KSQ's consistency with external variables, we assessed correlations between KSQ's dimensions with health variables, i.e., self-reported health status and musculoskeletal pain. We have found one scale and two subscales from one general and another bidimensional factor structure of the KSQ, respectively. In these dimensions, the KSQ's items fitted well to the IRT and we have identified DIF by shift work. However, we have found DIF by sex just in one item on the general factor. Linking analysis showed as a possible step forward in the variance issue placing on to the same scale the shift work groups in the items with DIF. All correlations between KSQ's dimensions with health variables were significant. Our findings allow us to argue that KQS's items were variant by shift work and sex in a nursing staff census from the largest public hospital complex of Brazil, but we can go on using linking analysis. This could be used as an evidence for the construct validity should go beyond the traditional dimensionality assessment. The dimensionalities of KSQ fit well for other population but individuals living in Scandinavian countries. PMID- 30403889 TI - How do you choose the appropriate migraine pharmacotherapy for an elderly person? PMID- 30403890 TI - Biometric Alterations of Mouse Embryonic Eye Structures Due to Short-Term Folic Acid Deficiency. AB - PURPOSE: Folic acid (FA) is an essential nutrient for normal embryonic development. FA deficiency (FAD) in maternal diet increases the risk of several defects among the progeny, especially, neural tube defects. The eye begins its development from the neural tube; however, the relationship between FAD and ocular development in the offspring has been little explored and it isn't known how the FAD affects the formation of the eye. Our objective was to analyze the effect of maternal FAD on mouse embryos ocular biometry. METHODS: Female mice C57/BL/6J were distributed into three different groups, according to the assigned diet: control group fed a standard FA diet (2 mg FA/kg), FAD group for short term fed (0 mg FA/kg + 1% succinylsulfathiazole) from the day after mating until day 14.5 of gestation, and FAD group for long term fed the same FA-deficient diet for 6 weeks prior mating and continued with this diet during gestation. A total of 57 embryos (19 embryos of each dietary group) at 14.5 gestational days were evaluated. As indicators of changes in ocular biometry, we analyze two parameters: area and circularity of the lens and whole eye, and the area of the retina. The program used in the treatment and selection of the areas of interest was ImageJ. The statistical analysis was performed by IBM SPSS Statistics 19. RESULTS: Regarding the measures of the area, FA-deficient lenses and eyes were smaller than that of controls. We have also observed increase in the size of the neural retina, spatially, in embryos from females fed FAD diet during long term. On the other hand, as regard to circularity measures, we have seen that eyes and lenses were more circular than control. CONCLUSION: Maternal FAD diet for a very short term generates morphological changes in ocular structures to the offspring. PMID- 30403891 TI - Advances and challenges in understanding the role of the lipid raft proteome in human health. AB - INTRODUCTION: Phase separation as a biophysical principle drives the formation of liquid-ordered 'lipid raft' membrane microdomains in cellular membranes, including organelles. Given the critical role of cellular membranes in both compartmentalization and signaling, clarifying the roles of membrane microdomains and their mutual regulation of/by membrane proteins is important in understanding the fundamentals of biology, and has implications for health. Areas covered: This article will consider the evidence for lateral membrane phase separation in model membranes and organellar membranes, critically evaluate the current methods for lipid raft proteomics and discuss the biomedical implications of lipid rafts. Expert commentary: Lipid raft homeostasis is perturbed in numerous chronic conditions; hence, understanding the precise roles and regulation of the lipid raft proteome is important for health and medicine. The current technical challenges in performing lipid raft proteomics can be overcome through well controlled experimental design and careful interpretation. Together with technical developments in mass spectrometry and microscopy, our understanding of lipid raft biology and function will improve through recognition of the similarity between organelle and plasma membrane lipid rafts and considered integration of published lipid raft proteomics data. PMID- 30403892 TI - Pharmacology of new and developing intravenous therapies for the management of seizures and epilepsy. AB - INTRODUCTION: Antiepileptic drugs (AEDs) are administered orally for chronic use. Parenteral formulations might be necessary when the oral route is not feasible (e.g. an impairment of consciousness, trauma, dysphagia, gastrointestinal illness) or for treatment of seizure emergencies. At present, few intravenous (IV) formulations are available on the market. Areas covered: The purpose of this review is to summarize the pharmacological characteristics and clinical applications of IV medications that have been recently introduced to the armamentarium of epilepsy therapy or are currently being developed. Apart from AEDs, other compounds belonging to different pharmacological classes (e.g. diuretics, anesthetics), which have shown potential effectiveness in seizure control, are taken into consideration, and the pathophysiological premises supporting their use for epilepsy treatment are illustrated. The authors give particular focus to immunomodulatory and immunosuppressive agents, which have become the therapeutic cornerstones for immune-mediated epilepsies, despite regulatory obstacles. Expert opinion: In several circumstances, especially in the case of seizure-related emergencies, clinical practice seems not match literature based evidence, and several IV AEDs are still used off-label. Strong evidence derived from randomized clinical trials (RCTs) is needed to support the effectiveness and tolerability of any therapeutic approach, however common and "accepted' it may be, in order to guarantee patient safety and well-being. PMID- 30403893 TI - Amyloid from a histochemical perspective. A review of the structure, properties and types of amyloid, and a proposed staining mechanism for Congo red staining. AB - Amyloid is a diverse group of unrelated peptides or proteins that have positive functionality or are associated with various pathologies. Despite vast differences, all amyloids share several features that together uniquely define the group. 1) All amyloids possess a characteristic cross-beta pattern with X-ray diffraction typical of beta-sheet secondary protein structures. 2) All amyloids are birefringent and dichroic under polarizing microscopy after staining with Congo red, which indicates a crystalline-like (ordered) structure. 3) All amyloids cause a spectral shift in the peak wavelength of Congo red with conventional light microscopy due to perturbation of pi electrons of the dye. 4) All amyloids show heightened intensity of fluorescence with Congo red, which suggests an unusual degree of packing of the dye onto the substrate. The beta portion of amyloid molecules, the only logical substrate for specific Congo red staining under histochemical conditions, consists of a stack of beta-sheets laminated by hydrophilic and hydrophobic interactions between adjacent pairs. Only the first and last beta-sheets are accessible to dyes. Each sheet is composed of numerous identical peptides running across the width of the sheet and arranged in parallel with side chains in register over the length of the fibril. Two sets of grooves are bordered by side chains. X grooves run perpendicular to the long axis of the fibril; these grooves are short (the width of the sheet) and number in the hundreds or thousands. Y grooves are parallel with the long axis. Each groove runs the entire length of the fibril, but there are very few of them. While Congo red is capable of ionic bonding with proteins via two sulfonic acid groups, physical constraints on the staining solution preclude ionic interactions. Hydrogen bonding between dye amine groups and peptide carbonyls is the most likely primary bonding mechanism, because all beta-sheets possess backbone carbonyls. Various amino acid residues may form secondary bonds to the dye via any of three van der Waals forces. It is possible that Congo red binds within the Y grooves, but that would not produce the characteristic staining features that are the diagnostic hallmarks of amyloid. Binding in the X grooves would produce a tightly packed series of dye molecules over the entire length of the fibril. This would account for the signature staining of amyloid by Congo red: dichroic birefringence, enhanced intensity of fluorescence and a shift in visible absorption wavelength. PMID- 30403894 TI - Growth failure in Crohn's disease children: may the first treatment have a role? AB - INTRODUCTION: Growth failure in children is a frequent feature of childhood-onset Crohn's disease (CD), and stunting can persist into adulthood. Growth is an important outcome by which to judge the effectiveness of therapies in children; currently available studies in CD children have focused on the short-term impact of treatments on growth, and there are limited data regarding the long-term effects of treatments upon growth. Areas covered: We designed the present article to review whether the first treatment performed in newly diagnosed CD children may have a role on the future growth course. We conducted a systematic literature search to identify relevant studies published on the PubMed database from January 2002 up to now. We found only six surveys that documented mid-term growth course in newly diagnosed CD patients. Expert commentary: In the last years there have been relevant advances in the clinical management of CD children; however, there is a lack of knowledge about the best strategy to reverse growth failure. Children treated with enteral nutrition have appropriate height and weight gain but do not reverse the growth course. Further surveys are required to better explore not only clinical outcomes but also long-term growth course following each therapeutic strategy. PMID- 30403895 TI - Role of calcium in reactive oxygen species-induced apoptosis in Candida albicans: An antifungal mechanism of antimicrobial peptide, PMAP-23. AB - PMAP-23 ( RIIDLLWRVRRPQKPKFVTVWVR -NH2) is an antimicrobial peptide (AMP) derived from porcine myeloid. Membrane disruption is thought to underpin the anticandidal activity of PMAP-23. However, many AMPs act via mechanisms other than simple membrane permeabilization. Here, we investigated the anticandidal mechanism of PMAP-23 at low concentrations. Membrane disruption and depolarization and rapid K+ efflux were observed in Candida albicans cells treated with 5 uM PMAP-23. In contrast, 2.5 uM PMAP-23 caused membrane depolarization and K+ efflux without membrane disruption. The lower PMAP-23 concentration increased cytosolic and mitochondrial Ca2+ levels. Disruption of Ca2+ homeostasis altered the NAD+/NADH ratio and resulted in reactive oxygen species (ROS) accumulation and glutathione oxidation. PMAP-23 treatment also stimulated apoptosis, as evidenced by metacaspase activation, DNA fragmentation, and phosphatidylserine externalization. Pretreatment with the mitochondrial Ca2+ uptake inhibitor (ruthenium red) or ROS scavenger (N-acetylcysteine) attenuated these apoptotic events. Our results suggest that PMAP-23 induces apoptosis as antifungal mechanism, and mitochondrial Ca2+-induced ROS is major factor to trigger the apoptosis. Thus, the anticandidal activity of PMAP-23 is not based solely on disruption of biological membranes but also involves induction of apoptosis via mitochondrial Ca2+-dependent ROS. PMAP-23 mode of action sheds new light on the antifungal mechanism of antimicrobial peptides, supporting the role of Ca2+ and ROS in apoptosis regulation. PMID- 30403896 TI - Morphine sulfate abuse-deterrent formulations for the treatment of chronic pain. AB - INTRODUCTION: Abuse-deterrent formulations have been developed to reduce inappropriate opioid use. The aim of this paper is to review existing literature about currently available morphine abuse-deterrent formulations. Areas covered: The US FDA has currently attributed an 'abuse-deterrent formulation' label to two different morphine compounds: an agonist/antagonist combination, and a morphine formulation with physical barrier. The combination of morphine sulfate and naltrexone showed bioequivalence with extended release morphine. Naltrexone was found in low levels or non-detectable in most of the patients. If the capsules are tampered, the orally available naltrexone would be released, causing a decreased euphoria expected by the use of morphine. The application of physical and chemical barriers to the active compound aims at preventing manipulation of the opioid tablet. This abuse-deterrent formulation obtained with a physical barrier did not reduce drug liking compared to ER morphine. Expert commentary: Available data from literature suggest that both formulations may offer an alternative with lower abuse potential in the treatment of chronic pain. Nevertheless, current evidence suggests that only a little percentage of abusers may stop abusing drugs as result of reformulation. More post-marketing studies are advocated to evaluate the real impact of abuse-deterrent formulations. PMID- 30403897 TI - Treatment with secukinumab in multi-comorbid patients with psoriatic arthritis. AB - No evidence-based approaches exist to guide the choice of specific biological agent in patients with psoriatic arthritis (PsA). Case reports may provide useful information to help treatment choice in clinical practice. We report two cases of patients with PsA, one of them with a 14-year-long medical history, and the other with lung involvement. Several different DMARDs with overall modest efficacy and lack of tolerability were used in both cases before switching the patients to secukinumab. Secukinumab allowed for a rapid improvement of the patients' symptoms without any safety concern. Our experience may be useful to the current knowledge on 'real world' use of secukinumab, which appears to effective and safe in challenging patients with comorbidities and poor tolerability to previous used biological agents. PMID- 30403898 TI - Successful therapy of plaque-type psoriasis with secukinumab in patients with multiple comorbidities treated with previous biologic therapies. AB - PURPOSE: Biologic therapy in psoriatic patients with multiple comorbidities is challenging due to worsening of associated diseases and possible side effects of concomitant medications. MATERIALS AND METHODS: We describe three patients with multiple comorbidities documenting successful treatment of psoriasis with secukinumab following failure of multiple conventional and biologic DMARDs. RESULTS: The first case is an obese 59-year-old woman (HBV + with latent tuberculosis) with arterial hypertension and 12-year history of breast cancer. The second is a 45-year-old obese man (HCV + with occult HBV infection on therapy with multiple antipsychotics and taking methadone for opioid dependence), while the last is a 39-year-old man with severe obesity, non-alcoholic hepatosteatosis, and NYHA class II heart failure. All three patients had undergone previous conventional (methotrexate, cyclosporine, retinoids and phototherapy) and multiple biologic treatments (one or more of the following: adalimumab, ustekinumab, etanercept, infliximab originator and biosimilar) that were discontinued for inefficacy and/or adverse effects. All patients underwent therapy with secukinumab, which was associated with sustained clinical benefits and no clinically relevant safety findings. CONCLUSIONS: The present three cases add further evidence that secukinumab is effective and well tolerated in difficult to treat psoriatic patients with multiple comorbidities, namely HBV, latent TBC infection, and hepatic impairment. PMID- 30403899 TI - Research progress of circular RNAs in lung cancer. AB - Lung cancer is one of the most common cancers and the leading cause of cancer related death worldwide. Despite encouraging results achieved with targeted therapy in recent years, the early diagnosis and treatment of lung cancer remains a major problem. Circular RNA (circRNA), a type of RNA with covalently closed continuous loop structures, has structural stability and certain tissue specificity. Recent studies have found that circRNAs have an important role in tumor development and are expected to be revealed as new targets for tumor prediction and treatment. Research on the biological functions and regulation mechanisms of circRNAs in lung cancer is in its infancy but is gathering momentum. In this review, we discuss the properties, biogenesis, biological function, and research progress of circRNAs in lung cancer to provide a theoretical foundation and new directions for studies on circRNAs in lung cancer. PMID- 30403900 TI - FGFR genes mutation is an independent prognostic factor and associated with lymph node metastasis in squamous non-small cell lung cancer. AB - Targeting FGFRs is one of the most promising therapeutic strategies in squamous non-small cell lung cancer (SQCC). However, different FGFR genomic aberrations can be associated with distinct biological characteristics that result in different clinical outcomes or therapeutic consequences. Currently, the full spectrum of FGFR gene aberrations and their clinical significance in SQCC have not been comprehensively studied. Here, we used Next-generation sequencing to investigate the presence of FGFR gene mutations in 143 tumors from patients with stage I, II or III SQCC and who had not been treated with chemotherapy or radiotherapy prior to surgery. FGFR gene mutations were identified in 24 cases, resulting in an overall frequency of 16.9%. Among the mutations, 7% (10/143) were somatic mutations, and 9.8% (14/143) germline mutations. FGFR mutations were significantly associated with an increased risk of lymph node metastasis. SQCC patients with a FGFR somatic mutation had shorter OS (overall survival, log rank P = 0.005) and DFS (disease-free survival,log rank P = 0.004) compared with those without an FGFR mutation. The multivariate analysis confirmed that a somatic mutation was an independent poor prognostic factor for OS (HR: 4.26, 95% CI: 1.49 12.16, P = 0.007) and DFS (HR: 3.16, 95% CI: 1.20-8.35, P = 0.020). Our data indicate that FGFR genes mutation is an independent prognostic factor and associated with lymph node metastasis in stage I to III Chinese SQCC patients. PMID- 30403901 TI - Maternal demographic and intrapartum antecedents of severe neonatal outcomes at term. AB - OBJECTIVE: To determine key demographic and intrapartum antecedents predisposing to severe adverse neonatal outcome at term. METHODS: This was a retrospective cohort study of severe adverse neonatal outcomes of nonanomalous singleton term births at an Australian tertiary maternity unit between January 2007 and April 2017. Serious neonatal outcome (SNO) was defined as any of the following: Apgar score <=3 at 5 min, severe respiratory distress syndrome, severe acidosis, admission into neonatal intensive care unit (NICU), stillbirth, or neonatal death. Multivariable generalized estimating equations were used to identify key demographic and intrapartum risk factors predisposing to poor neonatal outcomes. RESULTS: There were 77 888 births with SNO occurring in 7247 (9.3%) cases. Young maternal age, raised BMI, indigenous ethnicity, nulliparity, smoking, illicit drug use, and diabetes mellitus were more common in the SANO cohort. Instrumental birth (aOR 3.24, 95%CI 3.02-3.47, p < .001), emergency cesarean section (aOR 1.61, 95%CI 1.49-1.73, p < .001), emergency cesarean for nonreassuring fetal status (aOR 3.45, 95%CI 3.04-3.92, p < .001), cord accidents (aOR 4.98, 95%CI 2.81-8.83, p < .001) and intrapartum hemorrhage (aOR 1.42, 95%CI 1.08-1.87, p = .01) were major antecedents. Induction of labor (aOR 1.08, 95%CI 1.01-1.15, p = .03), prolonged second stage (aOR 1.76, 95%CI 1.55-2.00, p < .001) and use of intramuscular opioids/narcotics (aOR 1.41, 95%CI 1.30-1.52, p < .001) were also associated with adverse neonatal outcome. Low birth weight (< 5th and <10th centiles) and macrosomia (> 90th and >95th centiles) and delivery at 37 weeks and >41 weeks were additional risk factors. CONCLUSION: There are multiple maternal and intrapartum risk factors which can predispose to severe outcomes in the neonate. PMID- 30403902 TI - A literature review of immersion pulmonary edema. AB - IMPORTANCE: Immersion pulmonary edema (IPE) is a rare but important complication associated with surface swimming and underwater diving. It tends to reoccur and can be fatal. It is not very well-known to clinicians involved in the care of individuals participating in aquatic activities. We performed a systematic review of immersion pulmonary edema to describe the condition and provide guidelines for its management. EVIDENCE REVIEW: We searched PubMed to identify case reports and studies using the MeSH terms "immersion," "pulmonary edema," "cold-induced," "exercise," "hemodynamics," "water immersion,'' "cardiovascular response," alone and in combinations. We identified 121 relevant articles including 54 case reports. We reviewed in detail 24 studies and all 54 case reports. FINDINGS: The incidence of IPE is estimated to be around 1.1- 1.8%. The risk factors for IPE include age >50 years, female sex, overhydration before exercise, tight wetsuits, cold water exposure and physically trained individuals such as endurance athletes. Individuals with pre-existing heart disease are at increased risk, however, IPE is seen even in healthy individuals. Symptoms such as cough, sputum production, hemoptysis and shortness of breath can occur immediately after immersion. Combination of water immersion, cold exposure, and exercise lead to an increase in pulmonary capillary pressures and eventual pulmonary capillary stress failure that leads to the flooding of alveolar spaces and edema. Conclusion and relevance: Clinicians should be aware of IPE to avoid overestimating the severity of coronary or valvular conditions sometimes coincidentally present in IPE victims. Management is usually supportive. Functional and clinical recovery usually happens spontaneously within 24 h to 2 days, with or without diuretic therapy and a beta-adrenergic agonist. IPE can be recurrent and fatal, hence subjects with a history of IPE should undergo extensive cardiopulmonary investigation and should avoid cold water and physically demanding swimming events or avoid immersion activities. PMID- 30403903 TI - Interprofessional pharmacotherapy workshop: intervention to improve health professionals' and students' attitudes towards collaboration between physicians and pharmacists. AB - Collaboration between physicians and pharmacists is recognized as an important factor for reducing medication errors and improving patient outcomes. Therefore, two pharmacotherapy workshops were delivered in Croatia - one for pre registration medical (n=42, 4th-6th year) and pharmacy (n=38, 4th-5th year) students, and the other one for physicians (n=18) and pharmacists (n=23). The purpose of this study was to determine whether participation in common pharmacotherapy workshop could improve attitudes among participants towards interprofessional collaboration between pharmacists and physicians. Attitudes were measured by validated questionnaire "Scale of Attitudes Towards Collaboration Between Pharmacists and Physicians" at the beginning and at the end of the workshops. Three complex clinical scenarios were presented during the workshops. Participants were given general information about cases (all participants) and 2 groups of specific information (only for medical students/physicians and only for pharmacy students/pharmacists). For the first scenario, medical and pharmacy students/professionals were not allowed to exchange their specific information. However, participants collaborated for the 2nd and 3rd scenarios in order to achieve the hypothesized therapeutic goals. Before the workshops, pharmacists and pharmacy students showed more positive attitudes than physicians and medical students. However, the workshop contributed in closing the gap by equating health care professionals' attitudes. Additionally, students' attitudes were more positive after the workshop with an increase of 10% for medical and 2.2% for pharmacy students. This study indicates that interprofessional pharmacotherapy workshops could significantly improve attitudes toward collaboration between physicians and pharmacists for both students and practicing professionals. PMID- 30403904 TI - A Novel Thermoresponsive Gel as a Potential Delivery System for Lipoxin. AB - The objective of this study was to evaluate a novel thermoresponsive polyisocyanopeptide (PIC)-based hydrogel as an injectable carrier for local drug delivery for periodontal applications. Three formulations of PIC gels, 0.2%, 0.5%, and 1% w/w, were prepared. As controls, commercially available poloxamer 407 (P407) gels of 20% and 26% w/w were used. Lipoxin A4 (LXA4), a proresolving drug, was suspended into the gel solutions. The systems were evaluated regarding dynamic mechanical properties, injectability and stability, release and bioactivity of LXA4, and cytocompatibility. Results showed that the gelation temperatures of PIC and P407 gels were around 13 degrees C to 23 degrees C. PIC gels were less viscous and mechanically weaker than P407 gels due to the low polymer concentrations. However, PIC gels kept gel integrity for at least 2 wk when incubated with phosphate-buffered saline, whereas P407 gels were disintegrated totally within 1 wk. LXA4 was chemically stable in both neutral and alkaline medium for over 1 mo. The release of LXA4 from either 1% PIC or 26% P407 gels depicted an initial burst release followed by a sustained release for around 4 d. The extent of burst release was negatively correlated to the polymer concentration. LXA4 remained bioactive after release from PIC gels. No cytotoxicity was observed for 1% PIC gel. However, 26% P407 inhibited periodontal ligament cell and gingival epithelial cell growth. In conclusion, the thermoresponsive PIC gel is a potential candidate for periodontal drug delivery. PMID- 30403905 TI - Informing CONOPS and medical countermeasure deployment strategies after an improvised nuclear device detonation: the importance of delayed treatment efficacy data. AB - PURPOSE: In the wake of a nuclear detonation, individuals with acute radiation syndrome will be a significant source of morbidity and mortality. Mathematical modeling can compare response strategies developed for real-world chaotic conditions after a nuclear blast in order to identify optimal strategies for administering effective treatment to these individuals. To maximize responders' abilities to save lives it is critical to understand how treatment efficacy is impacted by real-world conditions and levels of supportive care. To illustrate the importance of these factors, we developed a mathematical model of cytokine administration 24 h after the blast with varying levels of supportive care described in the primary literature. CONCLUSION: The results highlight the proportionally higher life-saving benefit of administering cytokines to individuals with a moderate to high dose of radiation exposure, compared to those with a lower dose. However, the fidelity of mathematical models is dependent on the primary data informing them. We describe the data needed to fully explore the impact of timing, dosage, and fractional benefit of cytokines and supportive care treatment in non-optimal situations that could be seen after a nuclear detonation. Studies addressing these types of knowledge gaps are essential to evaluating the relative efficacy of countermeasures to refine existing plans and help develop new strategies and priorities. PMID- 30403906 TI - Fertility preservation with random-start controlled ovarian stimulation and embryo cryopreservation for early pregnancy-associated breast cancer. AB - We report a case of fertility preservation using random-start controlled ovarian stimulation (COS), intracytoplasmic sperm injection (ICSI) and embryo cryopreservation in a patient with early pregnancy-associated breast cancer. A 34 year-old nulliparous woman at 5 weeks of gestation was diagnosed with estrogen receptor (ER) positive, progesterone receptor (PR) positive and human epidermal growth factor receptor-2 (HER-2) negative infiltrating intraductal carcinoma. Urgent neoadjuvant chemotherapy was deemed necessary and the patient decided to terminate the pregnancy. Random-start COS was initiated 5 days after pregnancy termination using a letrozole-based protocol. The beta human chorionic gonadotropin level on the day of COS start was 119.8 mIU/mL. Twenty-nine oocytes were retrieved after 11 days of COS. Seventeen oocytes underwent successful fertilization and 10 blastocysts were cryopreserved. The patient subsequently initiated neoadjuvant chemotherapy with her oncologist. The current case highlights the feasibility of random-start COS and embryo cryopreservation for fertility preservation immediately after the termination of an early pregnancy in a patient with pregnancy-associated breast cancer. PMID- 30403907 TI - Serine protease modulation of Dependence Receptors and EMT protein expression. AB - Expression of the tumour suppressor Deleted in Colorectal Cancer (DCC) and the related protein neogenin is reduced by the mammalian serine protease chymotrypsin or the bacterial serine protease subtilisin, with increased cell migration. The present work examines whether these actions are associated with changes in the expression of cadherins, beta-catenin and vimentin, established markers of the Epithelial-Mesenchymal Transition (EMT) which has been linked with cell migration and tumour metastasis. The results confirm the depletion of DCC and neogenin and show that chymotrypsin and subtilisin also reduce expression of beta-catenin in acutely prepared tissue sections but not in human mammary adenocarcinoma MCF-7 or MDA-MB-231 cells cultured in normal media, or primary normal human breast cells. A loss of beta-catenin was also seen in low serum media but transfecting cells with a dcc-containing plasmid induced resistance. E-cadherin was not consistently affected but vimentin was induced by low serum-containing media and was increased by serine proteases in MCF-7 and MDA-MB-231 cells in parallel with increased wound closure. Vimentin might contribute to the promotion of cell migration. The results suggest that changes in EMT proteins depend on the cells or tissues concerned and do not parallel the expression of DCC and neogenin. The increased cell migration induced by serine proteases is not consistently associated with the expression of the EMT proteins implying either that the increased migration may be independent of EMT or supporting the view that EMT is not itself consistently related to migration. (241). PMID- 30403908 TI - Inhibitors of the renin-angiotensin system ameliorates clinical and pathological aspects of experimentally induced nephrotoxic serum nephritis. AB - INTRODUCTION: Chronic kidney disease (CKD) is a global health concern, but the current treatments only slow down the progression. Thus an improved understanding of the pathogenesis and novel treatments of CKD are needed. The nephrotoxic nephritis (NTN) model has the potential to study the pathogenesis of CKD as it resembles human CKD. The classical treatments with angiotensin II receptor blocker (ARB) or the angiotensin-converting enzyme inhibitor (ACE I) have shown a clinical effect in CKD. METHODS: We characterized the disease development in the NTN model over 11 weeks by investigating functional and histopathological changes. We tested doses of 15 and 30 mg/kg/day enalapril and losartan in the NTN model in order to investigate the effect of inhibiting the renin-angiotensin system (RAS). RESULTS: The NTN model displayed albuminuria peaking on days 6-7, mesangial expansion (ME), renal fibrosis, inflammation and iron accumulation peaking on day 42. However, albuminuria, ME, renal fibrosis and inflammation were still significantly present on day 77, suggesting that the NTN model is useful for studying both the acute and chronic disease phases. Enalapril and losartan significantly enhanced the glomerular filtration rate (GFR) and decreased albuminuria, ME, renal fibrosis and inflammation of NTN-induced kidney disease in mice. CONCLUSIONS: This is the first study showing a comprehensive pathological description of the chronic features of the murine NTN model and that inhibiting the RAS pathway show a significant effect on functional and morphological parameters. PMID- 30403910 TI - Safety of two doses of an inactivated hepatitis a vaccine given 6 months apart in healthy toddlers, children, and adolescents aged 12 months to 15 years in China: a phase IV study. AB - Hepatitis A is a vaccine-preventable infection caused by the HA virus (HAV) with transitional to intermediate endemicity in China. An inactivated vaccine first licensed in China in 2010 (Avaxim(r) 80U Pediatric) is indicated for primary and booster vaccination in children from 12 months to 15 years of age. This Phase IV, open-label, single-arm trial supported licensure in pediatric age groups in China. A total of 355 healthy infants and toddlers (< 2 years of age), children (2 to 11 years of age), and adolescents (>= 12 years of age) were enrolled to receive two doses of intramuscular HA vaccine, separated by 6 months. Participants were split into Group 1 (infants and toddlers: N = 270) and Group 2 (children and adolescents: N = 85). Safety was assessed by solicited injection site and systemic adverse events (AEs) for 7 days and unsolicited AEs for 30 days after each vaccination. Serious AEs (SAEs) were collected throughout. Immunogenicity was not assessed. Analyses were descriptive. Both vaccinations were very well tolerated in each group. The incidence of solicited injection site reactions was lower in Group 1 (17.9%) than Group 2 (33.3%) and for solicited systemic reactions was similar for each group. The incidence of unsolicited AEs in Group 1 was 6.3% and none in Group 2. For solicited and unsolicited AEs the incidence was slightly higher after the first vaccination. There were no SAEs. Overall, the good safety profile of this pediatric HA vaccine was confirmed in infants, toddlers, children, and adolescents aged 12 months to 15 years in China. PMID- 30403911 TI - Association between training volume and lower extremity overuse injuries in young female athletes: implications for early sports specialization. AB - BACKGROUND: Recent studies indicated greater risk of overuse injuries among young female athletes than their male counterparts. However, few studies have focused on female athletes and the effect of single-sport participation on lower extremity overuse injuries. OBJECTIVE: The objective of this study is to identify an independent risk variable for lower extremity overuse injuries based on status of sport participations (single- and multisports) in young female athletes. METHODS: In this cross-sectional study, 12-18-year-old female athletes were asked to complete electronic questionnaires describing their current sport participation and previous injury history. Range of motion (ROM), muscular strength, and performance parameters were measured at the time of completion of electronic questionnaires. Potential risk variables were compared between single- and multisport athletes and entered into a logistic regression model. Adjusted odds ratio (aOR), 95% confidence intervals (95% CIs), and p values were recorded to find an association with increased likelihood of lower extremity overuse injuries. RESULTS: The study cohort comprised 236 female young athletes (single sport athletes: N = 60, multisport athletes: N = 176). A few variables including age, BMI, weekly hours of training for a sport, knee ROM, ankle ROM, and knee extensor strength were identified as potential risk variables. A logistic regression analysis showed an independent association between increased weekly hours of training for a sport and greater likelihood of histories of lower extremity overuse injuries (aOR = 1.091, 95% CIs: 1.007-1.183, p = .034). CONCLUSION: Although status of single- or multisports participation was not a significant risk variable, increased training volume was found to be an independent contributing factor for greater likelihood of lower extremity overuse injury histories in 12-18 years female athletes. The current study identified that single-sport athletes trained nearly twice as many hours per week when compared to multisport athletes, which may explain an underlying mechanism of sports specialization. PMID- 30403909 TI - A multicenter REtrospective observational study of first-line treatment with PERtuzumab, trastuzumab and taxanes for advanced HER2 positive breast cancer patients. RePer Study. AB - We carried out a retrospective observational study of 264 HER2-positive advanced breast cancer (ABC) patients to explore the efficacy of first-line treatment with pertuzumab/trastuzumab/taxane in real-world setting. Survival data were analyzed by Kaplan Meier curves and log rank test. Median follow-up, length of pertuzumab/trastuzumab/taxane treatment and of pertuzumab, trastuzumab maintenance were 21, 4 and 15 months, respectively. The response rate was 77.3%, and the clinical benefit rate 93.6%. Median progression-free survival (mPFS) was 21 months, and median overall survival (mOS) was not reached. When comparing patients by trastuzumab-pretreatment, similar PFS were observed, although a longer OS was reached in trastuzumab-naive patients (p = 0.02). Brain metastases at baseline and their development in course of therapy were associated with significantly shorter PFS (p = 0.0006) and shorter OS, although at a not fully statistically relevant extent (p = 0.06). The addition of maintenance endocrine therapy (ET) to pertuzumab/trastuzumab maintenance was associated with longer PFS (p = 0.0001), although no significant differences were detected in OS (p = 0.31). Results were confirmed by propensity score analysis (p = 0.003 and p = 0.46, respectively). In multivariate models, longer PFS was related to lower Performance Status (PS) (p = 0.07), metastatic stage at diagnosis (p = 0.006) and single metastatic site (p < 0.0001). An OS advantage was observed with lower PS (p < 0.0001), single metastatic site (p = 0.004), no prior exposure to trastuzumab (p = 0.004) and response to pertuzumab-based treatment (p = 0.003). Our results confirm that trastuzumab/pertuzumab/taxane is the standard of care as first-line treatment of patients with HER2-positive ABC even in the real-world setting. Moreover, the double-maintenance therapy (HER2 block and ET) is strongly recommended when feasible. PMID- 30403912 TI - Role of individual S4 segments in gating of Cav3.1 T-type calcium channel by voltage. AB - Contributions of voltage sensing S4 segments in domains I - IV of CaV3.1 channel to channel activation were analyzed. Neutralization of the uppermost charge in individual S4 segments by exchange of arginine for cysteine was employed. Mutant channels with single exchange in domains I - IV, in two adjacent domains, and in all four domains were constructed and expressed in HEK 293 cells. Changes in maximal gating charge Qmax and the relation between Qmax and maximal conductance Gmax were evaluated. Qmax was the most affected by single mutation in domain I and by double mutations in domains I + II and I + IV. The ratio Gmax/Qmax proportional to opening probability of the channel was significantly decreased by the mutation in domain III and increased by mutations in domains I and II. In channels containing double mutations Gmax/Qmax ratio increased significantly when the mutation in domain I was included. Mutations in domains II and III zeroed each other. Mutation in domain IV prevented the decrease caused by the mutation in domain III. Neither ion current nor gating current was observed when channels with quadruple mutations were expressed. Immunocytochemistry analysis did not reveal the presence of channel protein in the cell membrane. Likely, quadruple mutation results in a structural change that affects the channel's trafficking mechanism. Altogether, S4 segments in domains I-IV of the CaV3.1 channel unequally contribute to channel gating by voltage. We suggest the most important role of the voltage sensor in the domain I and lesser roles of voltage sensors in domains II and III. PMID- 30403913 TI - Human monocyte-derived macrophages inhibit HCMV spread independent of classical antiviral cytokines. AB - Infection of healthy individuals with human cytomegalovirus (HCMV) is usually unnoticed and results in life-long latency, whereas HCMV reactivation as well as infection of newborns or immunocompromised patients can cause life-threatening disease. To better understand HCMV pathogenesis we studied mechanisms that restrict HCMV spread. We discovered that HCMV-infected cells can directly trigger plasmacytoid dendritic cells (pDC) to mount antiviral type I interferon (IFN-I) responses, even in the absence of cell-free virus. In contrast, monocyte-derived cells only expressed IFN-I when stimulated by cell-free HCMV, or upon encounter of HCMV-infected cells that already produced cell-free virus. Nevertheless, also in the absence of cell-free virus, i.e., upon co-culture of infected epithelial/endothelial cells and monocyte-derived macrophages (moMPhi) or dendritic cells (moDC), antiviral responses were induced that limited HCMV spread. The induction of this antiviral effect was dependent on cell-cell contact, whereas cell-free supernatants from co-culture experiments also inhibited virus spread, implying that soluble factors were critically needed. Interestingly, the antiviral effect was independent of IFN-gamma, TNF-alpha, and IFN-I as indicated by cytokine inhibition experiments using neutralizing antibodies or the vaccinia virus-derived soluble IFN-I binding protein B18R, which traps human IFN-alpha and IFN-beta. In conclusion, our results indicate that human macrophages and dendritic cells can limit HCMV spread by IFN-I dependent as well as independent mechanisms, whereas the latter ones might be particularly relevant for the restriction of HCMV transmission via cell-to-cell spread. PMID- 30403914 TI - The ATG5-binding and coiled coil domains of ATG16L1 maintain autophagy and tissue homeostasis in mice independently of the WD domain required for LC3-associated phagocytosis. AB - Macroautophagy/autophagy delivers damaged proteins and organelles to lysosomes for degradation, and plays important roles in maintaining tissue homeostasis by reducing tissue damage. The translocation of LC3 to the limiting membrane of the phagophore, the precursor to the autophagosome, during autophagy provides a binding site for autophagy cargoes, and facilitates fusion with lysosomes. An autophagy-related pathway called LC3-associated phagocytosis (LAP) targets LC3 to phagosome and endosome membranes during uptake of bacterial and fungal pathogens, and targets LC3 to swollen endosomes containing particulate material or apoptotic cells. We have investigated the roles played by autophagy and LAP in vivo by exploiting the observation that the WD domain of ATG16L1 is required for LAP, but not autophagy. Mice lacking the linker and WD domains, activate autophagy, but are deficient in LAP. The LAP-/- mice survive postnatal starvation, grow at the same rate as littermate controls, and are fertile. The liver, kidney, brain and muscle of these mice maintain levels of autophagy cargoes such as LC3 and SQSTM1/p62 similar to littermate controls, and prevent accumulation of SQSTM1 inclusions and tissue damage associated with loss of autophagy. The results suggest that autophagy maintains tissue homeostasis in mice independently of LC3 associated phagocytosis. Further deletion of glutamate E230 in the coiled-coil domain required for WIPI2 binding produced mice with defective autophagy that survived neonatal starvation. Analysis of brain lysates suggested that interactions between WIPI2 and ATG16L1 were less critical for autophagy in the brain, which may allow a low level of autophagy to overcome neonatal lethality. Abbreviations: CCD: coiled-coil domain; CYBB/NOX2: cytochrome b-245: beta polypeptide; GPT/ALT: glutamic pyruvic transaminase: soluble; LAP: LC3-associated phagocytosis; LC3: microtubule-associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; NOD: nucleotide-binding oligomerization domain; NADPH: nicotinamide adenine dinucleotide phosphate; RUBCN/Rubicon: RUN domain and cysteine-rich domain containing Beclin 1-interacting protein; SLE: systemic lupus erythematosus; SQSTM1/p62: sequestosome 1; TLR: toll-like receptor; TMEM: transmembrane protein; TRIM: tripartite motif-containing protein; UVRAG: UV radiation resistance associated gene; WD: tryptophan-aspartic acid; WIPI: WD 40 repeat domain: phosphoinositide interacting. PMID- 30403915 TI - Interrelations among Multiple Metrics of Immune and Physiological Function in a Squamate, the Common Gartersnake (Thamnophis sirtalis). AB - The field of ecoimmunology has made it clear that individual and ecological contexts are critical for interpreting an animal's immune response. In an effort to better understand the relevance of commonly used immunological assays, we tested how different metrics of immunity and physiological function were interrelated in naturally parasitized individuals of a well-studied reptile, the common gartersnake (Thamnophis sirtalis). Overall, we found that bactericidal ability, an integrative measure of innate immunity, was often correlated with more specific immunological and physiological tests (lysis and oxidative stress) but was not related to tissue-level inflammation that was determined by histopathology. The only hematological metric that correlated with tissue-level inflammation was the prevalence of monocytes in blood smears. Finally, using histological techniques, we describe natural parasitism throughout the organ systems in these individuals, finding that neither the presence nor the burden of parasite load affected the physiological and immune metrics that we measured. By performing comprehensive assessments of physiological and immune processes, we are better able to draw conclusions about how to interpret findings from specific assays in wild organisms. PMID- 30403916 TI - Heightened Immune System Function in Polar Bears Using Terrestrial Habitats. AB - Climate change is altering the distribution of some wildlife species while warming temperatures are facilitating the northward expansion of pathogens, potentially increasing disease risk. Melting of Arctic sea ice is increasingly causing polar bears (Ursus maritimus) of the southern Beaufort Sea (SBS) to spend summer on land, where they may encounter novel pathogens. Here, we tested whether SBS polar bears on shore during summer exhibited greater immune system activity than bears remaining on the sea ice. In addition, we tested whether the type of immune response correlated with body condition, because adaptive responses (slowly developing defenses against specific pathogens) often require less energy than innate responses (rapid defenses not based on pathogen identity). After accounting for body condition, we found that polar bears on shore exhibited higher total white blood cell counts, neutrophils, and monocytes than bears on the ice, suggesting more infections. Lymphocytes, eosinophils, basophils, and globulins did not differ. C-reactive protein, an indicator of inflammation, also did not differ between habitats. Body condition was associated with variables indicative of both innate and adaptive immunity, suggesting that neither response was uniquely limited by energy resources. Our data indicate that as more polar bears spend longer periods of time on shore, they may experience more infections. We encourage continued health monitoring of this species and studies of the long term fitness consequences from disease. PMID- 30403917 TI - Deja vu and the entorhinal cortex: dissociating recollective from familiarity disruptions in a single case patient. AB - Past research has demonstrated a relationship between deja vu and the entorhinal cortex in patients with wider medial temporal lobe damage. The aim of the present research was to investigate this crucial link in a patient (MR) with a selective lesion to the left lateral entorhinal cortex to provide a more direct exploration of this relationship. Two experiments investigated the experiences of deja vecu (using the IDEA questionnaire) and deja vu (using an adapted DRM paradigm) in MR and a set of matched controls. The results demonstrated that MR had quantitatively more and qualitatively richer recollective experiences of deja vecu. In addition, under laboratory-based deja vu conditions designed to elicit both false recollection (critical lures) and false familiarity (weakly-associated lures), MR only revealed greater memory impairments for the latter. The present results are therefore the first to demonstrate a direct relationship between the entorhinal cortex and the experience of both deja vu and deja vecu. They furthermore suggest that the entorhinal cortex is involved in both weakly associative false memory as well as strongly-associative memory under conditions that promote familiarity-based processing. PMID- 30403918 TI - Providing early detection and early intervention for autism spectrum disorder in South Africa: stakeholder perspectives from the Western Cape province. AB - We set out to examine key stakeholder perspectives on early detection and intervention for autism spectrum disorder (ASD) in South Africa. Early detection and intervention improves child and family outcomes and lessens long-term costs. We focused on stakeholders in the Western Cape province, one of the better resourced in terms of healthcare. Eight senior management level stakeholders, two each from government's Health, Education, and Social Development, and the non profit sector were identified using purposive sampling. In-depth interviews focused on key implementation- related themes. The National Integrated Early Childhood Development Policy was the most relevant to early detection and intervention. This policy, however, is not ASD specific. This lack of specificity is in keeping with an emerging theme: ASD was only seen within the context of other developmental disabilities, particularly by Health and Social Development. Specific ASD early detection and intervention may not currently align with Health and Social Development departmental goals. These departments are primarily responsible for identifying and providing services and financial support to young children with ASD. Increased ASD knowledge and local South African statistics on prevalence, burden and associated costs may alter this approach. At this time, ASD early intervention may be more closely aligned with Education department goals. PMID- 30403919 TI - When motion improves working memory. AB - In the present study, we used a complex span task to explore how memory traces resulting from Self-Performed Task (SPT) and Verbal Task (VT) are maintained in working memory. Participants memorised series of five sentences describing an action either through SPT or VT. Between pairs of sentences, participants performed a concurrent task that varied according to its nature and its cognitive load. The concurrent task was either a verbal task, a low cognitive load motor task or a high cognitive load motor task. A control condition served as a baseline. First, we observed that performance in SPT and VT did not decrease with verbal or motor suppression, but was lower with an increase of the cognitive load. This suggests that memory traces are maintained through attentional refreshing whatever the encoding (SPT or VT). Second, while the enactment effect was replicated in the control condition, it tended to vanish with a verbal concurrent task; moreover, it was reversed with motor concurrent tasks. Surprisingly, the latter effect resulted from an increase of VT memory performance when participants repeated the same gesture between sentences. Finally, our results provide additional evidence that the enactment effect does not rely on attention. PMID- 30403920 TI - Removal of Dimethyl Sulfide via a Bio-Scrubber under Anoxic Conditions. AB - The anoxic lab-scale bio-scrubber was studied to investigate the dimethyl sulfide (DMS) removal performance under different operation conditions for 315 days. DMS removal in bio-scrubber system was performed by controlling and changing the operation parameters, including inlet concentration, empty bed residence time (EBRT) and spraying density (SD) of irrigation. Best conditions in the system were achieved for SD of 0.18 m3/m2 h within EBRT of 40 s at an inlet gas concentration of 150 mg/m3 which resulted a removal of 93% for the waste gas stream in the bio-scrubber column and bio-degradation in bio-reactor tank was led to 89% of DMS removal that transferred bio-reactor, while 91.5% of input chemical oxygen demand (COD) removed successfully was obtained. The use of the closer values of the average experimental yield to the theoretical value (YDMS/NO3-) of 0.74 led to elemental sulfur (So) and other sulfur forms production rather than sulfate (SO42-) as an end product, that also was recognized as the pale-yellow colored substances of So appeared within the biomass. PMID- 30403921 TI - Bilingualism leads to greater auditory capacity. AB - The objective of this article is to investigate the effects of bilingualism on auditory capacity of young adults using a dichotic consonant-vowel (CV) test. Listeners were asked to identify distinct CVs dichotically presented to each ear through headphones. CV identification accuracy in both ears served as a measure of auditory capacity of listeners. Eighty normal hearing participants including 40 bilinguals (23 males and 17 females) and 40 monolinguals (11 males and 29 females) were used as study sample. Members of the bilingual group acquired their second language before entering elementary school. The bilingual listeners had higher mean both-ear-correct scores than did monolingual listeners, indicating a greater auditory capacity in the bilingual group than in the monolingual group. The finding of greater auditory capacity in bilinguals using a task requiring divided attention reflects greater ability to store and recall auditory information in bilinguals. However, the inconsistency of results across studies of bilingual advantages indicates that there is a need for further research in this area using both linguistic and non-linguistic tasks and considering age of acquisition as a possible moderating variable. PMID- 30403922 TI - Validation of a Florida Strawberry Anthracnose Fruit Rot (AFR) Warning System in Iowa. AB - Field validation of a disease-warning system for strawberry anthracnose fruit rot (AFR), caused by Colletotrichum acutatum sensu lato, that was originally developed for use in Florida was conducted in Iowa from 2012 to 2014. Day-neutral strawberry (cv. Tristar) was artificially inoculated with the pathogen at the start of the fruit maturation period. A factorial combination in replicated trials of two spray timing methods (the Florida warning system and prescheduled, calendar-based timing) and two fungicides (captan and pyraclostrobin) was compared, along with a nonsprayed control. The calendar-based and warning system based treatments provided statistically equivalent control of AFR incidence compared with the nonsprayed control, and the warning system treatments required an average of 1.7 fewer fungicide sprays annually than the calendar-based treatments. Further analysis of the field data suggested that the warning system might underestimate AFR risk under high disease pressure; in these circumstances, a lower action threshold value may need to be adopted. Overall, these results indicated that the Florida warning system can be valuable for helping Midwest strawberry growers control AFR with less reliance on fungicide sprays, but it may require modification to account for periods of high inoculum pressure, subject to results of further field trials. PMID- 30403923 TI - Anaerobic biological treatment of industrial saline wastewater: Fixed bed Reactor performance and analysis of the microbial community structure and abundance. AB - The purpose of the present work is to treat saline Tuna fish wastewater, with salt concentration of 43 g L-1 and total organic carbon (TOC) of 8.3 g L-1, using an anaerobic fixed bed reactor involving salt-tolerant bacteria from natural hypersaline environment during 150 days. The highest volatile solids (VS) removal efficiency of 84.1% was recorded for the organic loading rate (OLR) of 1.04 g TOC L-1.d-1 and the lowest salinity of 14.6 g NaCl L-1. In addition, the maximum biogas production of 0.8 L-1.d-1 for a working volume of 4L and an organic loading rate of 2.07 g TOC L-1.d-1 correlated with the decrease of Volatile fatty acids (VFA) content. The Polymerase Chain Reaction-Denaturing Gradient Gel Electrophoresis (PCR-DGGE) and the phylogenetic analysis of the bacterial community showed the action of hydrolytic, acidogenic, halotolerant sulfate reducing and halophilic fermentative bacterium during the processing time. A stable archaeal and methanogenic community's diversity including hydrogenotrophic methanogens was demonstrated with Quantitative-PCR (Q-PCR). The highest bacterial population abundance was detected for 1.45 g TOC L-1.d-1 and the important methanogenic community abundance for 2.07 g TOC L-1.d-1 may be related to the highest biogas production in this charge for an effluent salinity of 27.7 g NaCl L-1. PMID- 30403924 TI - Synthesis of urchin-like and yolk-shell TiO2 microspheres with enhanced photocatalytic properties. AB - The novel urchin-like and yolk-shell titania microspheres (henceforth called UYTMs) with nanowires/microspheres hierarchical structures were successfully synthesized by a synthetic sol-gel and hydrothermal method without using any template. Uniform TiO2 microspheres were firstly prepared by the sol-gel method, and the great monodispersed properties was delicately regulated by using the surfactant of KCl, aniline and a proper amount of water. The urchin-like yolk shell morphology was further achieved by a NaOH-assisted hydrothermal process, and the diameter and shell thickness of the UYTMs were highly controlled by the concentration of NaOH. The detailed morphology, chemical composition and crystallinity of the UYTMs were systematically characterized by several techniques, and the underlying formation mechanisms was attentively discussed as well. The photodegradation of methylthionine chloride experiments indicated the UYTMs showed much better photocatalytic activity than that of commercial P25. This is mainly because the UYTMs exhibited much more reactive sites, higher adsorption ability and tuned optical absorption behaviour owing to their large specific surface area, hierarchical structures and the special hollow yolk-shell structure. PMID- 30403925 TI - High Betrayal Adolescent Sexual Abuse and Nonsuicidal Self-Injury: The Role of Depersonalization in Emerging Adults. AB - Adolescent sexual abuse can interfere with healthy development. Sexual abuse that is perpetrated by close other(s)-high betrayal-can be additionally harmful, with sexual abuse being linked with dissociation and nonsuicidal self-injury (NSSI). Depersonalization, a dissociative subtype characterized by disconnection between oneself and one's body and/or thoughts, may further explain the role of dissociation in NSSI. The purpose of the current study was to: 1) isolate the impact of adolescent sexual abuse on NSSI; and 2) examine depersonalization as a pathway between high betrayal adolescent sexual abuse and NSSI. Participants (N = 192) were college students who completed online measures assessing sexual abuse, dissociation, and NSSI. While controlling for child sexual abuse and adult sexual abuse, adolescent sexual abuse predicted NSSI. Moreover, there was an indirect effect of high betrayal adolescent sexual abuse on NSSI through depersonalization, while controlling for child sexual abuse, adult sexual abuse, and medium betrayal (perpetrator: unclose other) adolescent sexual abuse. Findings from the current study have implications for relational cultural therapy as an evidence-informed treatment that highlights the relational harm of interpersonal trauma, while incorporating contextual elements, such as development of maladaptive coping strategies, into therapy. PMID- 30403926 TI - Students' self-reported fears and the perceived origins thereof. AB - The objective of this study was to explore the five most frequently reported fears in a sample of university students, and investigate the origins of these fears. The study employed a cross-sectional design with convenience sampling. Data were collected using a self-report questionnaire and analysed using a combination of descriptive statistics and content analysis. Participants consisted of 544 first-year psychology students. This study identified academic failure, animals, general failure, losing loved ones to death, and violence/crime as the top five fears among a sample of university students. 'Conditioning experiences' was one of the most prominent pathways in the acquisition of all these fears. Negative information transmission was also a dominant pathway relating to the origin of fear such as academic failure and violence/crime. However, 'modelling experiences' was not identified as a prominent pathway in the present study. These findings contribute to identifying the origins of first-year students' self-reported fears by using the three pathways theory. These findings may contribute meaningfully to the development and implementation of prevention and intervention programmes at higher education institutions. PMID- 30403927 TI - Virtual-reality exergaming improves performance during high-intensity interval training. AB - PURPOSE: To determine if: (i) mean power output and enjoyment of high-intensity interval training (HIIT) are enhanced by virtual-reality (VR)-exergaming (track mode) compared to standard ergometry (blank mode), (ii) if mean power output of HIIT can be increased by allowing participants to race against their own performance (ghost mode) or by increasing the resistance (hard mode), without compromising exercise enjoyment. METHODS: Sixteen participants (8 males, 8 females, VO2max: 41.2 +/- 10.8 ml-1.kg-1.min-1) completed four VR-HIIT conditions in a partially-randomised cross-over study; (1a) blank, (1b) track, (2a) ghost, and (2b) hard. VR-HIIT sessions consisted of eight 60 s high-intensity intervals at a resistance equivalent to 70% (77% for hard) maximum power output (PMAX), interspersed by 60 s recovery intervals at 12.5% PMAX, at a self-selected cadence. Expired gases were collected and VO2 measured continuously. Post exercise questionnaires were administered to identify differences in indices related to intrinsic motivation, subjective vitality, and future exercise intentions. RESULTS: Enjoyment was higher for track vs. blank (difference: 0.9; 95% CI: 0.6, 1.3) with no other differences between conditions. There was no difference in mean power output for track vs. blank, however it was higher for track vs. ghost (difference: 5 Watts; CI: 3, 7), and hard vs. ghost (difference: 19 Watts; 95% CI: 15, 23). CONCLUSIONS: These findings demonstrate that VR exergaming is an effective intervention to increase enjoyment during a single bout of HIIT in untrained individuals. The presence of a ghost may be an effective method to increase exercise intensity of VR-HIIT. PMID- 30403928 TI - Geopolymerization enhanced hydrothermal synthesis of analcime from steel slag and CFBC fly ash and heavy metal adsorption on analcime. AB - This work is focused on crystal phase transition of solid wastes and functional application of crystal analcime in waste water purification, which provide a new environment-friendly route. In this paper, analcime was synthesized from steel slag and Circulating fluidized bed combustion (CFBC) fly ash (CFA) by hydrothermal method enhanced via geopolymerization (non-crystallized process). Then the analcimes were used for the removal of heavy metal ions (Pb2+, Cu2+) in aqueous solutions. Both the raw materials and products were characterized by XRF, XRD, FT-IR, SEM-EDS, and TEM. The results showed that non-crystallized process reduced the time of hydrothermal reaction and promoted the purity of analcime. The adsorption kinetics of analcime were all well fitted the pseudo-second-order model, and adsorption isotherms were well described by the Langmuir model. The maximum adsorption capacity of analcime for Pb2+ and Cu2+ were around 75.76, and 21.83 mg/g, respectively. The preference order observed for adsorption is Pb2+ > Cu2+. PMID- 30403929 TI - Social Connectedness Moderates the Relationship Between Warfare Exposure, PTSD Symptoms, and Health Among Older Adults. AB - OBJECTIVE: The goal of the current study is to examine whether social connectedness among older adults mitigates the risk of poor health due to exposure to warfare and related symptoms of posttraumatic stress disorder (PTSD). Prior research has indicated a protective role for social connectedness in the face of trauma in general. However, this same association has not been examined among older adults exposed to warfare, even though they are potentially a more vulnerable population with unique social needs. METHOD: The study used cross sectional data from the Israeli component of the Survey of Health, Ageing, and Retirement in Europe (SHARE-Israel; N = 1,557, mean age = 69.03, age range = 50 to 105). It employed a composite scale of social connectedness, data on exposure to war-related events during the 2014 Israel-Gaza conflict, and ensuing symptoms of PTSD. Social connectedness, warfare exposure, and PTSD symptoms were used to predict physical and mental health, as well as engagement in health behaviors. RESULTS: Warfare exposure and PTSD symptoms were related to worse health. Moreover, social connectedness moderated this association, such that persons suffering from PTSD symptoms suffered less from worse health when they were highly connected. This trend was found for physical and mental health and in relation to health behaviors. CONCLUSIONS: While war-related PTSD is indeed related to poorer health, social connectedness moderates the strength of the association. Practitioners should be aware of the protective role of social connectedness in the context of warfare exposure in old age, and intervention programs with this population should strive toward bolstering social connections. PMID- 30403930 TI - Adaptation and Psychometric Evaluation of the Children's Knowledge of Abuse Questionnaire (CKAQ-RIII) in Greek Elementary School Children. AB - The purpose of the present study was to culturally adapt and validate the Children's Knowledge of Abuse Questionnaire-RIII (CKAQ-RIII), a tool that examines children's understanding of sexual abuse concepts, for use in Greek elementary schools. A sample of 467 Greek school children between the ages of 6-9 was recruited from a private school. The CKAQ-RIII was administrated three times, before and immediately after a Child Sexual Abuse (CSA) prevention intervention program, as well as during a one-year follow-up evaluation. A subsample of the original population (N = 113) completed the one year follow up administration of CKAQ-RIII, along with the Body Awareness (BA) and the Emotional Differentiation (ED) subscales of the Emotion Awareness Questionnaire (EAQ). Internal consistency was high for the inappropriate touch scale (ITS) of the CKAQ-RIII and moderate for the appropriate touch subscale (ATS). Inter-item analysis showed that the majority of items were in an acceptable range. Pearson correlation coefficients analyses revealed strong associations between the two subscales of ITS and ATS, and the overall scores of the questionnaire. A mixed-subjects analysis of variance on the ITS showed an increase in knowledge post intervention, with third graders (8-9 year olds) generally scoring higher at baseline and demonstrating greater knowledge gains post intervention. A mixed-subjects analysis of variance was also conducted for the ATS where no significant increase in knowledge was found. Furthermore, analysis revealed a good concurrent criterion validity with good levels of agreement between CKAQ-RIII and ED, whereas no relationship was established between CKAQ-RIII and BA. PMID- 30403931 TI - How Future Orientation is Associated with Depressive Symptoms in Multiethnoracial Adults: Basic Psychological Needs as a Mediator. AB - We examined the role of basic psychological needs as a mediator of the association between future orientation and depressive symptoms in a sample of 202 (159 female and 43 male) multiethnoracial adults. Multiple mediation analysis with 10,000 bootstraps was conducted to test for mediation. The association between future orientation and depressive symptoms was found to be accounted for by dimensions of basic psychological needs. Specifically, future orientation was negatively related to depressive symptoms through positive associations involving autonomy and competence, but not relatedness. The present findings are the first to not only point to the importance of examining future orientation in understanding depressive symptoms in multiethnoracial adults, but they are also the first to suggest possible mechanisms by which believing in a changeable future might foster stronger satisfaction of basic psychological needs, especially autonomy and competence, that might help multiethnoracials garner greater protection when encountering stressful situations in their lives. PMID- 30403932 TI - Social determinants of health affecting utilisation of routine maternity services in Nepal: a narrative review of the evidence. AB - Nepal has one of the highest maternal and neonatal mortality rates among low- and middle-income countries. Nepal's health system focuses on life-saving interventions provided during the antenatal to postpartum period. However, the inequality in the uptake of maternity services is of major concern. This study aimed to synthesise evidence from the literature regarding the social determinants of health on the use of maternity services in Nepal. We conducted a structured narrative review of studies published from 1994 to 2016. We searched five databases: PubMed; CINAHL; EMBASE; ProQuest and Global Index Medicus using search terms covering four domains: access and use; equity determinants; routine maternity services and Nepal. The findings of the studies were summarised using the World Health Organization's Social Determinants of Health framework. A total of 59 studies were reviewed. A range of socio-structural and intermediary-level determinants was identified, either as facilitating factors, or as barriers, to the uptake of maternity services. These determinants were higher socioeconomic status; education; privileged ethnicities such as Brahmins/Chhetris, people following the Hindu religion; accessible geography; access to transportation; family support; women's autonomy and empowerment; and a birth preparedness plan. Findings indicate the need for health and non-health sector interventions, including education linked to job opportunities; mainstreaming of marginalised communities in economic activities and provision of skilled providers, equipment and medicines. Interventions to improve maternal health should be viewed using a broad 'social determinants of health' framework. PMID- 30403933 TI - The perceptions, health-seeking behaviours and access of Scheduled Caste women to maternal health services in Bihar, India. AB - The caste system is a complex social stratification system which has been abolished, but remains deeply ingrained in India. Scheduled Caste (SC) women are one of the historically deprived groups, as reflected in poor maternal health outcomes and low utilisation of maternal healthcare services. Key government schemes introduced in 2005 mean healthcare-associated costs should now be far less of a deterrent. This paper examines the factors contributing to this low use of maternal health services by investigating the perceptions, health-seeking behaviours and access of SC women to maternal healthcare services in Bihar, India. Eighteen in-depth, semi-structured interviews were conducted with SC women in Bihar. Data were analysed using Framework Analysis and presented using the AAAQ Toolbox. Main facilitating factors included the introduction of accredited social health activists (ASHAs), free maternal health services, the Janani Shishu Suraksha Karyakram (JSSK), and changes in the cultural acceptability of institutional delivery. Main barriers included inadequate ASHA coverage, poor information access, transport costs and unauthorised charges to SC women from healthcare staff. SC women in Bihar may be inequitably served by maternal health services, and in some cases may face specific discrimination. Recommendations to improve SC service utilisation include research into the improvement of postnatal care, reducing unauthorised payments to healthcare staff and improvements to the ASHA programme. PMID- 30403935 TI - Immunotherapy Combinations in Multiple Myeloma - Known Unknowns. PMID- 30403936 TI - Ethical Problems in Decision Making in the Neonatal ICU. PMID- 30403937 TI - A Trial of a Triple-Drug Treatment for Lymphatic Filariasis. AB - BACKGROUND: The World Health Organization has targeted lymphatic filariasis for global elimination by 2020 with a strategy of mass drug administration. This trial tested whether a single dose of a three-drug regimen of ivermectin plus diethylcarbamazine plus albendazole results in a greater sustained clearance of microfilariae than a single dose of a two-drug regimen of diethylcarbamazine plus albendazole and is noninferior to the two-drug regimen administered once a year for 3 years. METHODS: In a randomized, controlled trial involving adults from Papua New Guinea with Wuchereria bancrofti microfilaremia, we assigned 182 participants to receive a single dose of the three-drug regimen (60 participants), a single dose of the two-drug regimen (61 participants), or the two-drug regimen once a year for 3 years (61 participants). Clearance of microfilariae from the blood was measured at 12, 24, and 36 months after trial initiation. RESULTS: The three-drug regimen cleared microfilaremia in 55 of 57 participants (96%) at 12 months, in 52 of 54 participants (96%) at 24 months, and in 55 of 57 participants (96%) at 36 months. A single dose of the two-drug regimen cleared microfilaremia in 18 of 56 participants (32%) at 12 months, in 31 of 55 participants (56%) at 24 months, and in 43 of 52 participants (83%) at 36 months (P=0.02 for the three-drug regimen vs. a single dose of the two-drug regimen at 36 months). The two-drug regimen administered once a year for 3 years cleared microfilaremia in 20 of 59 participants (34%) at 12 months, in 42 of 56 participants (75%) at 24 months, and in 51 of 52 participants (98%) at 36 months (P=0.004 for noninferiority of the three-drug regimen vs. the two-drug regimen administered once a year for 3 years at 36 months). Moderate adverse events were more common in the group that received the three-drug regimen than in the combined two-drug-regimen groups (27% vs. 5%, P<0.001). There were no serious adverse events. CONCLUSIONS: The three-drug regimen induced clearance of microfilariae from the blood for 3 years in almost all participants who received the treatment and was superior to the two-drug regimen administered once and noninferior to the two-drug regimen administered once a year for 3 years. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT01975441 .). PMID- 30403939 TI - Burton's Line from Chronic Lead Intoxication. PMID- 30403938 TI - Elotuzumab plus Pomalidomide and Dexamethasone for Multiple Myeloma. AB - BACKGROUND: The immunostimulatory monoclonal antibody elotuzumab plus lenalidomide and dexamethasone has been shown to be effective in patients with relapsed or refractory multiple myeloma. The immunomodulatory agent pomalidomide plus dexamethasone has been shown to be effective in patients with multiple myeloma that is refractory to lenalidomide and a proteasome inhibitor. METHODS: Patients with multiple myeloma that was refractory or relapsed and refractory to lenalidomide and a proteasome inhibitor were randomly assigned to receive elotuzumab plus pomalidomide and dexamethasone (elotuzumab group) or pomalidomide and dexamethasone alone (control group). The primary end point was investigator assessed progression-free survival. RESULTS: A total of 117 patients were randomly assigned to the elotuzumab group (60 patients) or the control group (57 patients). After a minimum follow-up period of 9.1 months, the median progression free survival was 10.3 months in the elotuzumab group and 4.7 months in the control group. The hazard ratio for disease progression or death in the elotuzumab group as compared with the control group was 0.54 (95% confidence interval [CI], 0.34 to 0.86; P=0.008). The overall response rate was 53% in the elotuzumab group as compared with 26% in the control group (odds ratio, 3.25; 95% CI, 1.49 to 7.11). The most common grade 3 or 4 adverse events were neutropenia (13% in the elotuzumab group vs. 27% in the control group), anemia (10% vs. 20%), and hyperglycemia (8% vs. 7%). A total of 65% of the patients in each group had infections. Infusion reactions occurred in 3 patients (5%) in the elotuzumab group. CONCLUSIONS: Among patients with multiple myeloma in whom treatment with lenalidomide and a proteasome inhibitor had failed, the risk of progression or death was significantly lower among those who received elotuzumab plus pomalidomide and dexamethasone than among those who received pomalidomide plus dexamethasone alone. (Funded by Bristol-Myers Squibb and AbbVie Biotherapeutics; ELOQUENT-3 ClinicalTrials.gov number, NCT02654132 .). PMID- 30403940 TI - Terra Nova. PMID- 30403941 TI - HSD17B13 and Chronic Liver Disease in Blacks and Hispanics. PMID- 30403942 TI - Daratumumab for Delayed Red-Cell Engraftment after Allogeneic Transplantation. AB - Daratumumab, a human IgG1kappa monoclonal antibody targeting CD38, is used to treat multiple myeloma. We describe successful treatment with daratumumab in a case of treatment-refractory pure red-cell aplasia after ABO-mismatched allogeneic stem-cell transplantation. The patient was a 72-year-old man with the myelodysplastic syndrome who received a transplant from an HLA-matched, unrelated donor with a major ABO incompatibility (blood group A in the donor and blood group O in the recipient). The patient had persistent circulating anti-A antibodies and no red-cell recovery 200 days after transplantation. Standard treatments had no effect. Within 1 week after the initiation of treatment with daratumumab, he no longer required transfusions. PMID- 30403943 TI - A Phase 3 Trial of l-Glutamine in Sickle Cell Disease. PMID- 30403944 TI - HCV-Associated Liver Fibrosis and HSD17B13. PMID- 30403945 TI - Inhibition of Casein Kinase 1 Alpha in Acute Myeloid Leukemia. PMID- 30403946 TI - Neisseria gonorrhoeae - Rising Infection Rates, Dwindling Treatment Options. PMID- 30403947 TI - Sunitinib Alone or after Nephrectomy in Renal Cancer. PMID- 30403948 TI - Getting Rid of Stupid Stuff. PMID- 30403949 TI - Ingestion of Lead-Contaminated Packs of Opium. PMID- 30403950 TI - Vitamin D Supplementation in Pregnancy and Lactation and Infant Growth. PMID- 30403951 TI - Case 23-2018: A Man with Episodes of Confusion and Hypoglycemia. PMID- 30403952 TI - Case 34-2018: A 58-Year-Old Woman with Paresthesia and Weakness of the Left Foot and Abdominal Wall. PMID- 30403953 TI - Advancing toward the Elimination of Lymphatic Filariasis. PMID- 30403955 TI - The Relationship between Severity of Hearing Loss and Subjective Tinnitus Loudness among Patients Seen in a Specialist Tinnitus and Hyperacusis Therapy Clinic in UK. AB - BACKGROUND: Hearing loss is often associated with the phantom sound of tinnitus. However, the degree of the association between severity of hearing loss and tinnitus loudness taking into account the impact of other variables (e.g., emotional disturbances) is not fully understood. This is an important question for audiologists who are specialized in tinnitus rehabilitation as patients often ask whether the loudness of their tinnitus will increase if their hearing gets worse. PURPOSE: To explore the relationship between tinnitus loudness and pure tone hearing thresholds. RESEARCH DESIGN: This was a retrospective cross sectional study. STUDY SAMPLE: 445 consecutive patients who attended a Tinnitus and Hyperacusis Therapy Specialist Clinic in UK were included. DATA COLLECTION AND ANALYSIS: The results of audiological tests and self-report questionnaires were gathered retrospectively from the records of the patients. Multiple regression analysis was used to assess the relationship between tinnitus loudness, hearing loss and other variables. RESULTS: The regression model showed a significant relationship between the pure tone average (PTA) at the frequencies 0.25, 0.5, 1, 2, and 4 kHz of the better ear and the tinnitus loudness as measured via visual analogue scale (VAS), r (regression coefficient) = 0.022 (p < 0.001). Other variables significantly associated with tinnitus loudness were tinnitus annoyance (r = 0.49, p < 0.001) and the effect of tinnitus on life (r = 0.09, p = 0.006). The regression model explained 52% of the variance of tinnitus loudness. CONCLUSIONS: Although increased tinnitus loudness was associated with worse PTA, the relationship was very weak. Tinnitus annoyance and impact of tinnitus on life were more strongly correlated with tinnitus loudness than PTA. PMID- 30403954 TI - Single-Dose Zoliflodacin (ETX0914) for Treatment of Urogenital Gonorrhea. AB - BACKGROUND: Antibiotic-resistant Neisseria gonorrhoeae has prompted the development of new therapies. Zoliflodacin is a new antibiotic that inhibits DNA biosynthesis. In this multicenter, phase 2 trial, zoliflodacin was evaluated for the treatment of uncomplicated gonorrhea. METHODS: We randomly assigned eligible men and women who had signs or symptoms of uncomplicated urogenital gonorrhea or untreated urogenital gonorrhea or who had had sexual contact in the preceding 14 days with a person who had gonorrhea to receive a single oral dose of zoliflodacin (2 g or 3 g) or a single 500-mg intramuscular dose of ceftriaxone in a ratio of approximately 70:70:40. A test of cure occurred within 6+/-2 days after treatment, followed by a safety visit 31+/-2 days after treatment. The primary efficacy outcome measure was the proportion of urogenital microbiologic cure in the microbiologic intention-to-treat (micro-ITT) population. RESULTS: From November 2014 through December 2015, a total of 179 participants (167 men and 12 women) were enrolled. Among the 141 participants in the micro-ITT population who could be evaluated, microbiologic cure at urogenital sites was documented in 55 of 57 (96%) who received 2 g of zoliflodacin, 54 of 56 (96%) who received 3 g of zoliflodacin, and 28 of 28 (100%) who received ceftriaxone. All rectal infections were cured in all 5 participants who received 2 g of zoliflodacin and all 7 who received 3 g, and in all 3 participants in the group that received ceftriaxone. Pharyngeal infections were cured in 4 of 8 participants (50%), 9 of 11 participants (82%), and 4 of 4 participants (100%) in the groups that received 2 g of zoliflodacin, 3 g of zoliflodacin, and ceftriaxone, respectively. A total of 84 adverse events were reported: 24 in the group that received 2 g of zoliflodacin, 37 in the group that received 3 g of zoliflodacin, and 23 in the group that received ceftriaxone. According to investigators, a total of 21 adverse events were thought to be related to zoliflodacin, and most such events were gastrointestinal. CONCLUSIONS: The majority of uncomplicated urogenital and rectal gonococcal infections were successfully treated with oral zoliflodacin, but this agent was less efficacious in the treatment of pharyngeal infections. (Funded by the National Institutes of Health and Entasis Therapeutics; ClinicalTrials.gov number, NCT02257918 .). PMID- 30403956 TI - The Effects of Extended Input Dynamic Range on Laboratory and Field-Trial Evaluations in Adult Hearing Aid Users. AB - BACKGROUND: Digital hearing aids using a 16-bit analog-to-digital converter (ADC) provide a 96-dB input dynamic range. The level at which the ADC peak clips and distorts input signals ranges between 95 and 105 dB SPL. Recent research evaluated the effect of extending the input dynamic range in a commercially available hearing aid. Although the results were promising, several limitations were noted by the authors. Laboratory testing was conducted using recordings from hearing aids set for a flat 50-dB loss; however, field testing was conducted with hearing aids fitted for their hearing loss. In addition, participants rarely encountered input levels of sufficient intensity to adequately test the feature and were unable to directly compare aids with and without extended input dynamic range (EIDR) under identical conditions. PURPOSE: The effects of EIDR under realistic and repeatable test conditions both within and outside the laboratory setting were evaluated. RESEARCH DESIGN: A repeated measures design was used. The experiment was single-blinded. STUDY SAMPLE: Twenty adults (14 males and six females) between the ages of 30 and 71 years (average age 62 years) who were experienced hearing aid users participated. DATA COLLECTION AND ANALYSIS: Each participant was fit with Oticon Opn hearing instruments binaurally using the National Acoustics Laboratory-Nonlinear 1 fitting strategy. Participants completed a two-week trial period using hearing aids with EIDR and a two-week trial period without EIDR. The initial EIDR condition trial period was counterbalanced. After each trial, laboratory evaluations were obtained at 85 dBC using the Connected Speech Test, the Hearing in Noise Test, and the acceptable noise level (ANL). Satisfaction ratings were conducted at 85 dBC using speech in quiet and in noise as well as music. Field-trial evaluations were obtained using the abbreviated profile of hearing aid benefit (APHAB). Satisfaction ratings were also conducted in the field at 85 dBC using speech and music. After the study, each participant indicated which trial period they preferred overall. Repeated measures analysis of variances were conducted to assess listener performance. Pairwise comparisons were then completed for significant main effects. RESULTS: In the laboratory, results did not reveal significant differences between EIDR conditions on any speech perception in noise test or any satisfaction rating measurement. In the field, results did not reveal significant differences between the EIDR conditions on the APHAB or on any of the satisfaction rating measurements. Nine participants (45%) preferred the EIDR condition. Fifteen participants (75%) indicated that speech clarity was the most important factor in determining the overall preference. Sixteen participants (80%) preferred the EIDR condition that resulted in the lower ANL. CONCLUSIONS: The use of EIDR in hearing aids within and outside the laboratory under realistic and repeatable test conditions did not positively or negatively impact performance or preference. Results disagreed with previous findings obtained in the laboratory that suggested EIDR improved performance; however, results agreed with previous findings obtained in the field. Future research may consider the effect of hearing aid experience, input level, and noise acceptance on potential benefit with EIDR. PMID- 30403957 TI - Measurement of Thresholds Using Auditory Steady-State Response and Cochlear Microphonics in Children with Auditory Neuropathy. AB - BACKGROUND: The detection of precise hearing thresholds in infants and children with auditory neuropathy (AN) is challenging with current objective methods, especially in those younger than six months of age. PURPOSE: The aim of this study was to compare the thresholds using auditory steady-state response (ASSR) and cochlear microphonics (CM) in children with AN and children with normal hearing. RESEARCH DESIGN: The thresholds of CM, ASSR, and visual reinforcement audiometry (VRA) tests were recorded; the ASSR and VRA frequencies used were 250, 500, 1000, 2000, and 4000 Hz. STUDY SAMPLE: The participants in this study were 15 children with AN (27 ears) (1-7.6 years, median age 4.1 years) and ten children with normal hearing (20 ears) (1-8 years, median age four years). DATA COLLECTION AND ANALYSIS: The thresholds of the three methods were compared, and histograms were used to represent frequency distributions of threshold differences obtained from the three methods. RESULTS: In children with normal hearing, the average CM thresholds (84.5 dB) were significantly higher than the VRA thresholds (10.0-10.8 dB); in children with AN, both CM and VRA responses were seen at high signal levels (88.9 dB and 70.6-103.4 dB, respectively). In normal children, the difference between mean VRA and ASSR thresholds ranged from 17.5 to 30.3 dB, which was significantly smaller than the difference seen between the mean CM and VRA thresholds (71.5-72.3 dB). The correlation between VRA and ASSR in children with normal hearing ranged from 0.38 to 0.48, whereas no such correlation was seen in children with AN at any frequency (0.03-0.19). CONCLUSIONS: Our results indicated that ASSR and CM were poor predictors of the conventional behavioral threshold in children with AN. PMID- 30403958 TI - Factors that impact on the burden of Escherichia coli bacteraemia: multivariable regression analysis of 2011-2015 data from West London. AB - BACKGROUND: The incidence of Escherichia coli bacteraemia in England is increasing amid concern regarding the roles of antimicrobial resistance and nosocomial acquisition on burden of disease. AIM: To determine the relative contributions of hospital-onset E. coli blood stream infection and specific E. coli antimicrobial resistance patterns to the burden and severity of E. coli bacteremia in West London. METHODS: Patient and antimicrobial susceptibility data were collected for all cases of E. coli bacteraemia between 2011 and 2015. Multivariable logistic regression was used to determine the association between the category of infection (hospital or community-onset) and length of stay, intensive care unit admission, and 30-day all-cause mortality. FINDINGS: E. coli bacteraemia incidence increased by 76% during the study period, predominantly due to community-onset cases. Resistance to quinolones, third-generation cephalosporins, and aminoglycosides also increased over the study period, occurring in both community- and hospital-onset cases. Hospital-onset and non susceptibility to either quinolones or third-generation cephalosporins were significant risk factors for prolonged length of stay, as was older age. Rates of mortality were 7% and 12% at 7 and 30 days, respectively. Older age, a higher comorbidity score, and bacteraemia caused by strains resistant to three antibiotic classes were all significant risk factors for mortality at 30 days. CONCLUSION: Multidrug resistance, increased age, and comorbidities were the main drivers of adverse outcome. The rise in E. coli bacteraemia was predominantly driven by community-onset infections, and initiatives to prevent community-onset cases should be a major focus to reduce the quantitative burden of E. coli infection. PMID- 30403959 TI - Abnormal Erythrocyte Morphology in Drug Reaction with Eosinophilia and Systemic Symptoms. PMID- 30403960 TI - 'Sutureless Nasal Alar Repair with Trichloroacetic acid and Surgical Glue'. PMID- 30403961 TI - The effect of antimicrobial washes on antibacterial resistance in hidradenitis suppurativa lesions. PMID- 30403962 TI - Bronchiectasis. AB - Bronchiectasis is an important clinical syndrome because of its increasing prevalence, significant economic burden on health care, and associated morbidity. Until recently, the disease was considered an orphan and essentially neglected from a therapeutic standpoint, but many recent advances have been made in the field. Several national registries have formed to provide databases from which to study patients with bronchiectasis. Experts published a consensus definition of a bronchiectasis-specific exacerbation that will serve as a unified definition for future clinical trials. Several inhaled antibiotic trials aimed at reducing exacerbation frequency have been completed. Researchers have investigated nonculture techniques, such as 16S ribosomal RNA (rRNA) and whole genome sequencing, to characterize the microbiological characteristics. Studies of anti Pseudomonas antibodies are providing interesting insight into varying host responses to chronic Pseudomonas infection. After three successful trials demonstrating that macrolides reduce exacerbations in bronchiectasis, other antiinflammatory agents have been investigated, and a trial of a novel antiinflammatory drug is ongoing. A relatively robust study has been published in airway clearance, a therapy that is accepted universally as beneficial but that has never been accompanied by strong evidence. To build on the successes with bronchiectasis thus far, investigators must develop better definitions of phenotypes of bronchiectasis. In this regard, clinical tools have been developed to quantify disease severity and predict prognosis. Studies of different clinical phenotypes of bronchiectasis in patients with bronchiectasis have been published. With continued advances in the field of bronchiectasis, there is hope that evidenced-based therapies will become available. PMID- 30403963 TI - Distribution of three isoforms of antimicrobial peptide, chrysophsin-1, -2 and 3, in the red sea bream, Pagrus (Chrysophrys) major. AB - We report here a liquid chromatography/electrospray ionization-tandem mass spectrometry assay for the quantification of three isoforms of antimicrobial peptide (AMP), chrysophsin-1, -2 and -3, in the red sea bream, Pagrus (Chrysophrys) major. Chrysophsin-1 was mainly distributed in the pyloric caeca and gills, followed by intestine and stomach. Chrysophsin-2 was detected in the gills and stomach, but chrysophsin-3 was only in the gills. The present procedure is valuable as a general method for simultaneous determination of the level of multiple AMP isoforms in fish tissues, and the data give important information for understanding the significance of each AMP isoform in host defense. PMID- 30403964 TI - Association between rs738409 polymorphism in patatin-like phospholipase domain containing protein 3 (PNPLA3) gene and hepatocellular carcinoma susceptibility: Evidence from case-control studies. AB - OBJECTIVES: Numerous studies have investigated the association between patatin like phospholipase domain-containing protein-3 (PNPLA3) rs738409 C > G polymorphism and the risk of hepatocellular carcinoma (HCC). However, the results are conflicting and inconclusive among different populations. Thus, a meta analysis was performed to resolve this inconsistency. METHODS: Potentially related studies were investigated in PubMed, Cochrane Library, EMBASE, and Chinese Biomedical Database (CBM) up to June 12, 2018. The odds ratio (OR) with a 95% confidence interval (CI) was used to explore the strength of the associations. Subgroup analysis was performed according to ethnicity and etiology of cases. Publication bias detection was conducted using Egger's test. RESULTS: Fourteen case-control studies were included in this meta-analysis, reporting a total of 3527 HCC patients and 7184 controls. Overall results revealed that PNPLA3 rs738409 C > G polymorphism was associated with an increased risk of HCC in the populations studied with various types of etiology under allelic model (OR = 1.59, 95%CI: 1.20-2.10, P = 0.001), dominant model (OR = 1.55, 95%CI: 1.13 2.13, P = 0.007), homozygous model (OR = 2.76, 95%CI: 1.52-5.01, P = 0.001), heterozygous model (OR = 1.31, 95%CI: 1.01-1.69, P = 0.039), and recessive model (OR = 2.42, 95%CI: 1.51-3.87, P < 0.001). A significant increased risk was observed in patients with HCC related to alcoholic cirrhosis under all genetic models (C vs. G: OR = 3.35, 95%CI: 2.14-5.24, P < 0.001; CC vs.GG: OR = 11.02, 95%CI: 4.35-27.88, P < 0.001; CC vs. GC: OR = 2.75, 95%CI: 1.72-4.39, P < 0.001; GG vs. CC + CG: OR = 5.82, 95%CI: 2.93-11.57, P < 0.001; CG + GG vs. CC: OR = 4.08, 95%CI: 2.33-7.13, P < 0.001), with respect to specific etiology of HCC. A significant increased risk was also revealed in patients with HCC due to virus related cirrhosis under allelic model (OR = 1.19, 95%CI: 1.07-1.32, P = 0.001), dominant model (OR = 1.17, 95%CI: 1.02-1.35, P = 0.03), homozygous model (OR = 1.47, 95%CI: 1.17-1.85, P = 0.001), and recessive model (OR = 1.43, 95%CI: 1.15 1.76, P = 0.001). Subgroup analysis on ethnicity revealed that the polymorphism was associated with increased risk of HCC in Caucasians under allelic model (OR = 1.65, 95%CI: 1.12-2.45, P = 0.012), dominant model (OR = 1.63, 95%CI: 1.04-4.25, P = 0.035), homozygous model (OR = 2.88, 95%CI: 1.27-6.55, P = 0.012), and recessive model (OR = 2.48, 95%CI: 1.32-4.65, P = 0.005). CONCLUSIONS: Our study suggests a significant increased association between PNPLA3 rs738409 C > G polymorphism and HCC risk in the entire populations studied, especially in Caucasians. Therefore, PNPLA3 rs738409 C > G polymorphism may be a risk factor for virus and alcoholic-related HCC. PMID- 30403965 TI - Application of deep learning to predict advanced neoplasia using big clinical data in colorectal cancer screening of asymptomatic adults. AB - BACKGROUND AND AIMS: We aimed to develop deep learning models for the prediction of the risk of advanced colorectal neoplasia (ACRN) in asymptomatic adults based on which colorectal cancer screening could be customized. METHODS: We collected data on 26 clinical and laboratory parameters including age, sex, smoking status, body mass index, complete blood count, blood chemistry, and tumor marker from 70,336 first-time screening colonoscopy recipients. For reference, we used a logistic regression (LR) model with nine variables. Two deep neural network (DNN) models were developed: Model 1 used the same nine variables and Model 2 included all 26 variables. The area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were compared for the models in a randomly split test set. RESULTS: Compared with the LR model (AUC, 0.721; 95% confidence interval [CI], 0.680-0.762), the DNN Model 1 (AUC, 0.817; 95% CI, 0.789-0.847) and Model 2 (AUC, 0.860; 95% CI, 0.837-0.883) showed significantly improved performance with respect to the prediction of ACRN (both P<.001). For a sensitivity of 80%, the specificity of the LR, and DNN Models 1 and 2 were 50.5%, 65.8%, and 78.8%, respectively (both P vs LR model < .001), indicating that the colonoscopy workload required to detect a similar number of ACRNs could be reduced by 58.4% and 73.7% using the DNNs. CONCLUSIONS: The application of DNNs to big clinical data could significantly improve the prediction of ACRNs compared with the LR model, implying the potential for realizing further improvements using large quantities and various types of biomedical information. PMID- 30403966 TI - Efficacy of 3 fine-needle biopsy techniques for suspected pancreatic malignancies in the absence of an on-site cytopathologist. AB - BACKGROUND AND AIMS: EUS-guided fine-needle aspiration/biopsy (EUS-FNA/B) has a high diagnostic accuracy for pancreatic tumors. Most reports have focused on the diagnostic yield of cytology or histology; the ability of various FNA/B techniques to obtain an adequate mass of cells or tissue has rarely been investigated. METHODS: Patients with suspected pancreatic malignancy were sampled by EUS-FNB using a 22-gauge ProCore needle by either the stylet slow-pull-back technique (group A), conventional negative-suction after stylet removal (group B) or non-suction after stylet removal (group C) in the absence of on-site cytopathologist. The adequacy of 3 techniques based on the diagnostic yield, cellularity, blood contamination, and core-tissue acquisition was evaluated. RESULTS: A total of 50 patients (27 males) were analyzed. The mean tumor size was 21 to 40 mm in 54%. The rate of a good or excellent proportion of cellularity was highest in group A compared with groups B and C (72% vs 60% vs 50%, p = 0.049). A >25% rate of blood contamination was more prevalent in group B (30% vs 42% vs 10%, p = 0.009). The rate of adequate core-tissue acquisition was not different (52% vs 34% vs 50%, p = 0.140). Based on the multivariate generalized estimation equation, stylet slow-pull-back technique and a tumor size of >40 mm were a favorable factor for diagnostic adequacy. CONCLUSIONS: The stylet slow-pull-back technique might enable acquisition of tissue and assessment of cellularity for the diagnosis of pancreatic tumors suspected to be malignant. PMID- 30403967 TI - Baseline serum/cerebrospinal fluid ratio of carcinoembryonic antigen and carbohydrate antigen series biomarkers in non-neoplastic diseases: a cross sectional study on 224 patients. AB - BACKGROUND: The measurement of carcinoembryonic antigen, carbohydrate antigen series biomarkers in cerebrospinal fluid (CSF), is useful for the diagnosis of brain metastasis and leptomeningeal metastases to a certain extent. Their serum/CSF ratios may be of benefit to earlier diagnosis and treatment. However, the normal reference values of the ratios were not available. Accordingly, in this study we analyzed the serum/CSF ratios of tumor markers levels in non neoplastic diseases patients for possible normal values. MATERIAL AND METHODS: We screened our database for paired CSF and serum samples which have been collected by lumbar puncture. 224 pairs of CSF and serum samples were obtained and compared. The 97.5th percentile, maximum value, and their serum/CSF ratios were obtained. RESULTS: The 97.5th percentile and maximum value of CSF CEA, CA125, CA19-9, CA15-3, CA724, and CYFRA21-1 concentration for overall participants were 0.572 MU/mL, 4.343 MU/mL, 2.872 MU/mL, 2.108 MU/mL, 1.62 MU/mL, and 1.997 MU/mL, respectively. Gender had no significant difference in these CSF biomarkers except CA15-3. The 97.5th percentile serum/CSF ratio of CEA, CA125, CA19-9, CA15-3, CA724, and CYFRA21-1 level were 34.554, 44.772, 51.232, 20.941, 20.737, and 5.389 respectively. The serum/CSF ratios in different age groups were also described. CONCLUSIONS: Here, serum/CSF ratios of six tumor markers were determined in non neoplastic diseases. The usefulness of this index for diagnosis, management, and prognostic utility of leptomeningeal metastases must be validated in larger cohort studies over the long term. PMID- 30403968 TI - Molecular analysis of virulence genes of Salmonella Infantis isolated from chickens and turkeys. AB - In this study, virulence genes of S. Infantis strains, which are commonly isolated from chickens and turkeys in Turkey, were analyzed, and the virulence genes of S. Infantis and other common serovars aside from S. Infantis were compared. In this study, 200 S. Infantis strains isolated from litter, powder, environmental sources, rodent samples and broiler chicken carcasses from a chicken slaughterhouse obtained from chickens (broiler chickens, breeders, laying hens) and 24 S. Infantis strains isolated and identified from litter, powder, environmental and rodent samples obtained from turkeys were analyzed. A total of 40 strains, comprising 10 strains from each Salmonella serovar (S. Typhimurium, S. Enteritidis, S. Kentucky and S. Hadar) (chicken-origin) were also selected from the collection of strains for comparison with S. Infantis strains. The virulence genes of 264, comprising 224 S. Infantis strains and 40 strains from common serovars other than S. Infantis were analyzed. A conventional polymerase chain reaction (PCR) was used to analyze the 11 genes associated with the virulence (sipA, sipD, sopD, sopB, sopE, sopE2, sitC, ssaR, sifA, spvC and pefA) in these strains. SipA, ssaR and sopE genes were found in the 209 S. Infantis strains (93.3%), sipD in 208 (92.85%), sopB in 207 (92.41%), sitC in 206 (91.96%), sifA in 203 (90.62%), sopD in 198 (88.39%), sopE2 in 166 (74.1%), spvC in 20 (8.92%) and the pefA virulence gene in one strain (0.44%). It was found that 74.55% of S. Infantis strains were distributed in gene patterns 1 and 2. In this study, the sopE2 virulence gene in S. Infantis strains was analyzed for the first time. The involvement of the dominant gene patterns of the S. Infantis strains isolated from broiler chicken and broiler chicken carcasses, and the fact that none of S. Infantis strains belonging to the breeders and laying hens were included in these patterns, indicated that S. Infantis entered the broilers not through the breeders, but through environmental factors. The presence of sipA, sipD, sopD, ssaR, sopB, sopE, sifA and sitC virulence genes in S. Infantis strains were found to be similar, but remarkable differences were found compared to the S. Typhimurium and S. Enteritidis strains in the presence of sopE2, spvC and pefA virulence genes. This study examining the virulence genes of S. Infantis strains provides detailed information aimed at providing an understanding of the pathogenesis and epidemiology of Salmonella in poultry. PMID- 30403969 TI - Assessing the relevance of exposure time in differentiated Caco-2/HT29 cocultures. Effects of silver nanoparticles. AB - In vitro models of the intestinal barrier are being increasingly used to evaluate nanoparticles (NPs) exposure risk. Nevertheless, most of these studies have focused on short-term exposures lasting no more than 24 h of duration, which could underestimate the toxic effects of a given compound under a more realistic setting. Since the assessment of longer exposure time-points is crucial to evaluate the risk of cumulative exposure to NPs, we have analyzed the effects of AgNPs at different exposure time-points between 6 h and 4 days on the barrier model system constituted by Caco-2/HT29 cells. Our results indicate that i) the system is stable during this time frame; ii) AgNPs affect the barrier's integrity only at the highest concentration tested (100 MUg/mL), and only after 96 h of exposure; iii) cellular uptake of AgNPs showed a time-dependent and concentration dependent increase; iv) translocation through the barrier was only observed at the highest concentration and only after 96 h of exposure; v) the expression of genes involved in the barrier's structure differs depending on the exposure time analyzed. All these results reinforce our proposal of expanding exposure times beyond 24 h when performing assays for hazard assessment of NPs using in vitro models of the intestinal barrier. PMID- 30403970 TI - Unity and diversity in working memory load: Evidence for the separability of the executive functions updating and inhibition using machine learning. AB - OBJECTIVE: According to current theoretical models of working memory (WM), executive functions (EFs) like updating, inhibition and shifting play an important role in WM functioning. The models state that EFs highly correlate with each other but also have some individual variance which makes them separable processes. Since this theory has mostly been substantiated with behavioral data like reaction time and the ability to execute a task correctly, the aim of this paper is to find evidence for diversity (unique properties) of the EFs updating and inhibition in neural correlates of EEG data by means of using brain-computer interface (BCI) methods as a research tool. To highlight the benefit of this approach we compare this new methodology to classical analysis approaches. METHODS: An existing study has been reinvestigated by applying neurophysiological analysis in combination with support vector machine (SVM) classification on recorded electroencephalography (EEG) data to determine the separability and variety of the two EFs updating and inhibition on a single trial basis. RESULTS: The SVM weights reveal a set of distinct features as well as a set of shared features for the two EFs updating and inhibition in the theta and the alpha band power. SIGNIFICANCE: In this paper we find evidence that correlates for unity and diversity of EFs can be found in neurophysiological data. Machine learning approaches reveal shared but also distinct properties for the EFs. This study shows that using methods from brain-computer interface (BCI) research, like machine learning, as a tool for the validation of psychological models and theoretical constructs is a new approach that is highly versatile and could lead to many new insights. PMID- 30403971 TI - Coarse-to-fine information integration in human vision. AB - Coarse-to-fine theories of vision propose that the coarse information carried by the low spatial frequencies (LSF) of visual input guides the integration of finer, high spatial frequency (HSF) detail. Whether and how LSF modulates HSF processing in naturalistic broad-band stimuli is still unclear. Here we used multivariate decoding of EEG signals to separate the respective contribution of LSF and HSF to the neural response evoked by broad-band images. Participants viewed images of human faces, monkey faces and phase-scrambled versions that were either broad-band or filtered to contain LSF or HSF. We trained classifiers on EEG scalp-patterns evoked by filtered scrambled stimuli and evaluated the derived models on broad-band scrambled and intact trials. We found reduced HSF contribution when LSF was informative towards image content, indicating that coarse information does guide the processing of fine detail, in line with coarse to-fine theories. We discuss the potential cortical mechanisms underlying such coarse-to-fine feedback. PMID- 30403972 TI - Replacement of fish meal with Bacillus pumillus SE5 and Pseudozyma aphidis ZR1 fermented soybean meal in diets for Japanese seabass (Lateolabrax japonicus). AB - This study examined the effects of replacing fish meal (FM) with three different types of soybean meal (SM) including untreated SM, Bacillus pumillus SE5 (BP) fermented SM (BPFSM) and Pseudozyma aphidis ZR1 (PA) fermented SM (PAFSM) in diets for Japanese seabass (Lateolabrax japonicus). A basal diet was formulated using FM (FM diet), and six other diets were produced by substituting 40 or 80% of FM with SM, BPFSM or PAFSM (SM40, SM80, BPFSM40, BPFSM80, PAFSM40 and PAFSM80 diets). Each diet was fed to triplicate groups of fish (7.14 +/- 0.05 g) twice daily for eight weeks. Replacing 40% of FM with SM sources did not significantly influence growth (P > 0.05), while increasing the substitution level to 80% led to reduced growth rates (P < 0.05). The groups received SM80 and PAFSM80 diets showed significantly higher feed conversion ratio and lower protein digestibility than FM group. Furthermore, notably lower dry matter digestibility was detected in SM80 group. Remarkably lower serum total antioxidant capacity was found in the SM80 group, and catalase activity did not significantly differ between FM and BPFSM40 groups. Serum malondialdehyde concentration was enhanced by increasing FM replacement level and the highest value was observed in the SM80 fed fish. FM and PAFSM40 groups showed significantly higher lysozyme activity than the SM80 group. Fish fed the BPFSM40 diet exhibited the highest complement C3 activity and the lowest value was observed in the SM80 group. Expression of lysozyme gene in spleen was down-regulated in the SM80 group, and no significant difference in expression of C3 gene was found among FM, BPFSM40 and PAFSM40 groups. Digestive enzymes activity and gut morphology were significantly influenced by FM replacement. Expression of HSP70 and pro-inflammatory genes including TNF-alpha and IL-1beta were up-regulated by FM replacement and relatively lower expression levels were found by using fermented SM. An opposite trend was observed for the anti-inflammatory TGF-beta gene expression. Serum d-lactate concentration was significantly increased by replacing 80% of FM with any of the SM sources. These findings indicated that using fermented SM, particularly BPFSM, beneficially influences feed utilization, antioxidant capacity, innate immunity and gut health in juvenile Japanese seabass. PMID- 30403973 TI - The use of "QUAD Shot" in Anal Canal Squamous Cell Carcinoma: A Case Study with Review of the Literature. AB - CONTEXT: Patients with locoregional anal carcinoma who don't qualify for standard definitive chemoradiation are candidates for a short course of palliative hypofractionated radiotherapy such as QUAD Shot. METHODS: A 57-year-old man with massive locoregional squamous cell carcinoma of the anal canal was treated with QUAD Shot (14.8 Gy in 4 fractions over 2 consecutive days) repeated every 4 weeks for a total of 2 courses. RESULTS: He reported symptomatic relief following each course of radiation. In regard to his first QUAD Shot, his pain was 10/10 in severity at the time of admission and 4/10 at the time of discharge. In regard to his second QUAD Shot, his pain was 8/10 at the time of admission and 0/10 at the time of discharge. He did not experience any treatment related toxicity. He passed away 15 weeks after the first course. CONCLUSION: QUAD Shot is both efficacious and safe for palliation in patients with anal carcinoma. PMID- 30403974 TI - A case for not adjusting birth weight customized standards for ethnicity: Observations from a unique Australian cohort. AB - BACKGROUND: Low birth weight is more common in infants of Indigenous (Aboriginal and/or Torres Strait Islander) than of Caucasian Australian mothers. Controversy exists on whether fetal growth is normally different in different populations. OBJECTIVE: We sought to determine the relationships of birth weight, birth weight centiles and smoking with perinatal outcomes in Indigenous versus non-Indigenous infants to determine if Caucasian growth charts could be applied to Indigenous infants. STUDY DESIGN: Data were analysed for Indigenous status, maternal age and smoking, and perinatal outcomes in 45,754 singleton live born infants of at least 20 weeks gestation or 400 g birth weight delivered in New South Wales, Australia between June 2010 and July 2015. RESULTS: Indigenous infants (N=6372, 14%) had a mean birth weight 67 grams lower than non-Indigenous infants (p <0.0001) (adjusting for infant sex and maternal BMI). Indigenous mean birth weight centile was 4.2 units lower (p<0.0001). Adjusting for maternal age, smoking, BMI and infant sex reduced the difference in birthweight/centiles to non-significance (12 grams; p=0.07). CONCLUSIONS: Disparities exist between Indigenous and non Indigenous Australian infants for birth weight, birth weight centile and adverse outcome rates. Adjusting for smoking and maternal age removed any significant difference in birth weights and birthweight centiles for Indigenous infants. Our data indicate that birth weight centiles should not be adjusted for Indigenous ethnicity as this normalises disadvantage; as Caucasian and Indigenous Australians have diverged for approximately 50,000 years it is likely that the same conclusions apply to other ethnic groups. The disparities in birth weight centiles associated with smoking will likely perpetuate Indigenous disadvantage into the future as low birth weight is linked to the development of chronic non communicable disease and poorer educational attainment; similar problems may affect other indigenous populations. PMID- 30403975 TI - Childbirth-Specific Patient-Reported Outcomes as Predictors of Hospital Satisfaction. AB - BACKGROUND: Under value-based payment programs, patient-reported experiences and outcomes (PROs) can impact hospital and physician revenue. To enable obstetrical providers to improve the childbirth experience, a framework for understanding what women expect and desire during childbirth is needed. OBJECTIVE: To identify key predictors of childbirth hospital satisfaction using the Childbirth Experiences Survey (CBEX). STUDY DESIGN: This study builds on a larger effort that used Patient-Reported Outcomes Management Information System (PROMIS(r)) methodology to develop a childbirth-specific preliminary PRO item bank. These efforts led to the development of an antepartum and postpartum survey (CBEX Parts 1 and 2). All phases of the study were conducted with the participation of a community-based research team. We conducted a prospective observational study using national survey response panels organized through Nielsen to identify women's antepartum values and preferences (V&P) for childbirth (CBEX Part 1). Eligible participants were US pregnant women (English or Spanish speaking) >18 years old, and > 20 weeks pregnant. Women were re-contacted and invited to participate in a postpartum follow-up survey to collect information about their childbirth PROs, including childbirth satisfaction (CBEX Part 2). In bivariate analyses, we tested whether predisposing conditions (e.g., patient characteristics or previous experiences), V&P, PROs, and the "gaps" between V&P and PROs were predictors of women's satisfaction with hospital childbirth services. Multivariable logistic regression models were fitted to examine the simultaneous effect of predictors on hospital satisfaction, adjusted for key predisposing conditions. RESULTS: Of 500 women who anticipated a vaginal delivery at the time of the antepartum survey, who labored prior to delivery, and who answered the postpartum survey, key findings included: 1) the strongest predictors of women's satisfaction with hospital childbirth services were items in the domains of staff communication, compassion, empathy, and respect; and 2) 23 childbirth-specific PROs were identified. Examples of these PROs, such as being told about progress in labor and being involved in decisions regarding labor pain management, appeared especially relevant to women experiencing childbirth. A final model predicting women's satisfaction with hospital childbirth services included a total of eight items that could be optimized by doctors, midwives, and hospitals. These included the patient's report of how well she coped with labor pain, whether the hospital provided adequate space and food for their support person, and whether she received practical support for feeding the newborn. CONCLUSIONS: This study identified 23 childbirth-specific PROs that were predictors of childbirth hospital satisfaction. The implementation of CBEX Parts 1 and 2 in a multi-hospital setting may lead to the development of childbirth hospital performance measures and strategies for improvement of the childbirth experience. PMID- 30403976 TI - The Impact of An Early Oral Feeding Protocol on Inflammatory Cytokine Changes after Esophagectomy. AB - BACKGROUND: The aim of the current study was to investigate the impact of early oral feeding (EOF) on inflammatory cytokine levels after McKeown minimally invasive esophagectomy (MIE) for cancer. METHODS: This study was based on a randomized controlled trial (NCT01998230). Patients with esophageal cancer who received McKeown MIE were randomly allocated into a group that started oral feeding on postoperative day (POD) 1 (EOF group) or a second group that received nil by mouth until 7 days after surgery (late oral feeding, LOF group). We chose 86 patients, including 46 patients in the EOF group and 40 patients in the LOF group, in which to analyze inflammatory cytokine levels (interleukin-6, IL-6; interleukin-8, IL-8; tumor necrosis factor-a, TNF-alpha; and monocyte chemotactic protein-1, MCP-1). RESULTS: The EOF and LOF groups exhibited similar preoperative IL-6, IL-8 TNF-alpha and MCP-1 levels. The levels of the four inflammatory cytokines at POD 1 and POD 3 were significantly higher than the preoperative levels (all P < 0.001). At POD 5, the levels of all four inflammatory cytokines were decreased compared with those at POD 1 and POD 3. At POD 3 and POD 5, the levels of IL-6, IL-8 and TNF-alpha were significantly lower in the EOF group than in the LOF group (all P < 0.05). At POD 3, the MCP-1 levels in the EOF group were significantly lower than those in the LOF group (all P < 0.05). CONCLUSIONS: Compared with conventional rehabilitation programs, the EOF protocol may decrease stress response after McKeown MIE. PMID- 30403977 TI - Management of bilateral partial anomalous pulmonary venous connection. AB - Bilateral partial anomalous venous connections are rare. Here, we present a patient who underwent the modified Warden procedure to re-route the superior vena cava with the partial anomalous veins to the left atrium and to reconstruct the innominate vein and superior vena cava with a polytetrafluoroethylene conduit to the right atrial appendage. The procedure was successfully performed without using foreign materials in the pulmonary venous route. Furthermore, it prevented the obstruction of blood flow. PMID- 30403978 TI - Anomalous superior caval drainage of the great cardiac vein. PMID- 30403979 TI - Three-dimensional printing PEEK implant: a novel choice for the reconstruction of chest wall defect. AB - BACKGROUND: The purpose of this study is to use three-dimensional printing (3DP) polyether-ether-ketone (PEEK) implants for skeletal reconstructions after wide excision of chest wall. 3DP PEEK implants were expected to provide a better physiological simulation than traditional ones due to a closer elastic modulus to cortical bone and similar biomechanical properties. METHODS: 18 patients (mean age, 44.5 years), comprising 6 males and 12 females, underwent adequate radical wide excision for tumors and chest wall reconstruction using 3DP PEEK implants. Surgical data, which includes patient demographic characteristics, implant preparation parameters, and preoperative and postoperative pulmonary function test results was collected and analyzed. RESULTS: 10 patients with rib tumors and 8 patients with sternum tumors were selected for the study. The mean chest wall defect size was 173.6 +/- 151.5 cm2 (range 55 to 625 cm2). The mean weight of a single 3DP PEEK rib and sternum was 28g and 104g respectively. The flexural and tensile strength of PEEK implants were 141 +/- 7 MPa and 89 +/- 3 MPa respectively. Preoperative and postoperative pulmonary function tests revealed that mean forced vital capacity was from 2.79 +/- 0.68 L to 2.40 +/- 0.70 L with a reduction of 14.0%(P<0.001).No side effects were observed 6-12 months post surgery. CONCLUSIONS: These findings suggest that 3DP PEEK implant is a safe and effective alternative in the reconstruction of chest wall defects. The pulmonary function of the patient may be preserved effectively after surgery. PMID- 30403980 TI - Participating in a TweetChat: Practical Tips from The Thoracic Surgery Social Media Network (#TSSMN). AB - The Thoracic Surgery Social Media Network (TSSMN) was formed as a collaborative effort by leading journals in the field of cardiothoracic surgery, The Annals of Thoracic Surgery and The Journal of Thoracic and Cardiovascular Surgery. The primary goals of the initiative are to bring social media attention to key publications from both journals and to highlight major accomplishments in the specialty. The aim of this article is to describe in a step-by-step fashion how to effectively participate in a TSSMN TweetChat, provide an overview of the various tweeting platforms available and best practices on the use of social media. PMID- 30403981 TI - Modified Infarct Exclusion Technique for Repair of Post Infarction Ventricular Septal Rupture. AB - Repair of ventricular septal rupture post acute myocardial infarction remains a surgical challenge. Several techniques for the closure of these defects have been described. We modified the infarct exclusion technique as described by Tirone David. In this technique two separate pericardial patches are used. The first patch excludes the rupture. The second patch is sutured to the margins of the first patch which provides strength to the margins of the first patch. It is simple, durable and has reduced incidence of residual ventricular septal defects and patch dehiscence. PMID- 30403982 TI - Pediatric biventricular assist device for myocarditis and complicated left ventricular thrombus. AB - An eight-year-old girl presenting with fulminant myocarditis and cardiogenic shock was placed on peripheral extracorporeal membrane oxygenation (ECMO). Patient was switched to central ECMO due to inadequate venous drainage and echocardiogram showed left ventricular (LV) thrombus. She underwent removal of LV thrombus with LV venting. Echocardiogram showed LV thrombus again two day later. The LV thrombus was again removed and biventricular ventricular assist device was initiated to avoid further thrombus formation. Mechanical circulatory support was completely weaned off after 7 days. She recovered fully without any neurological deficit. PMID- 30403983 TI - Distal Stent Graft-Induced New Entry after Endovascular Repair of Type B Aortic Dissection. AB - BACKGROUND: Experience is limited with distal stent graft-induced new entry (SINE) after endovascular thoracic aortic repair (TEVAR) of type B dissection (TBAD). We report the management strategy and outcomes in such patients. METHODS: Clinical data were analyzed for 95 patients (age 53.2+/-10.9 years; 82 males) developing distal SINE after TEVAR for TBAD. RESULTS: Follow-up was 100% (95/95) for 7.2+/-3 years after primary TEVAR. Distal SINE occurred at mean 2.7+/-2.4 years. Re-TEVAR was performed for 78, with routine stent grafts in 64 and a more tapered graft in 14. Three patients were managed surgically and 14 medically. Two patients died after re-TEVAR. During follow-up at 5.8+/-2.9 years, late death occurred in 19 patients, 7 with medical therapy and 12 with re-TEVAR. Distal SINE recurred in 11 at 3.5+/-1.7 years after re-TEVAR. Re-intervention significantly improved survival up to 8 years (88.3% vs 63.5%, P=0.001) versus medical therapy. In 64 patients with routine stent grafts, mortality was 24%, distal SINE recurred in 20%, and recurrence-free survival was 56% at 6 years. No death and recurrence of SINE occurred in 14 patients with the more tapered stent graft. Predictors for distal SINE after primary TEVAR were stent graft length (mm) (hazard ratio, HR, 0.984, P=0.037) and chronic phase (HR 1.725, P=0.049). CONCLUSIONS: In TBAD patients with distal SINE after TEVAR, reintervention with re-TEVAR could improve long-term survival significantly. Recurrence of distal SINE was high after re TEVAR using routine stent grafts. More tapered stent grafts may be helpful in preventing the recurrence of distal SINE. PMID- 30403984 TI - Revisiting the Warburg Effect: Some Tumors Hold Their Breath. AB - Studies have shown that tumors commonly exhibit normal or enhanced respiration in addition to glycolytic metabolism. In this issue, Courtney et al. (2018) report a reduction in mitochondrial function in kidney cancer patients and thus a classic "Warburg Effect" that further illustrates the heterogeneity of human cancer metabolism. PMID- 30403985 TI - Carbohydrates: Not All that Bad? AB - Dietary carbohydrates have been demonized for presumed negative effects on health. However, Liu et al. (2018) identify new pathways for conversion of glucose into acetate that consume reactive oxygen species. A study relating human carbohydrate consumption to all-cause mortality also suggests that moderately high-carbohydrate diets can be beneficial. PMID- 30403986 TI - When Soluble Fibers Meet Hepatocellular Carcinoma: The Dark Side of Fermentation. AB - Fermentation of dietary soluble fibers by our gut microbiota generates short chain fatty acids (SCFAs) and metabolites, upholding health and being a valuable food supplement. Recently, in Cell, Singh et al. (2018) discovered that fermentable, dietary soluble fibers (e.g., inulin) induced cholestasis and hepatocellular carcinoma (HCC) while improving metabolic dysfunction. PMID- 30403987 TI - A Microbiota Assimilation. AB - While the gut microbiota's malleability makes it highly responsive to our environment, it also renders it susceptible to rapid selection by factors associated with an industrialized lifestyle. Recently, in Cell, Vangay et al. (2018) have tracked and revealed rapid and profound changes in the gut community of immigrants to one that resembles long-term residents of the U.S. PMID- 30403988 TI - 24-Hour Intraocular Pressure Control with Fixed-dose Combination Brinzolamide 1%/Brimonidine 0.2%: A Multicenter, Randomized Trial. AB - PURPOSE: To determine the intraocular pressure (IOP)-lowering effect of fixed combination brinzolamide 1%/brimonidine 0.2% (BBFC) over a 24-hour period. DESIGN: Prospective, multicenter, double-masked, parallel-group clinical trial conducted at 16 academic and non-academic sites in the USA. PARTICIPANTS: Subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT) aged >=18 years, with mean baseline IOP measurements in at least one eye of >=21 and <28 mmHg. METHODS: Duplicate, mean pneumatonometer IOP measurements were collected every 2 hours over a 24-hour period in controlled light conditions in overnight facilities. Daytime (8 AM-8 PM) and nocturnal (10 PM-6 AM) IOP measurements were collected in a sitting or supine position, respectively. Baseline 24-hour IOP was measured in untreated subjects after a washout phase (up to 4 weeks) and eligibility phase. Following the baseline visit, subjects were randomized 1:1 to receive masked BBFC or Vehicle, one drop three times daily (8 AM, 3 PM, 10 PM) for 4 weeks. At Week 4, IOP measurements were repeated in both groups under the same conditions. MAIN OUTCOME MEASURE: Mean change from Baseline in 24-hour IOP at Week 4. RESULTS: Of 125 subjects randomized, 123 (98%; BBFC, n=62; Vehicle, n=61) completed the study. No subjects randomized to BBFC discontinued from the study. At Week 4, BBFC-treated eyes had significantly reduced mean 24-hour IOP vs Vehicle (least squares mean difference [95% confidence interval]: -2.5 [-3.3, 1.7]; P < 0.001); daytime (-3.4 [ 4.3, -2.6]; P < 0.001) and nocturnal (-1.2 [ 2.3, 0.0]; P = 0.053) reductions were observed. Mean change from Baseline was significantly different between BBFC- and Vehicle-treated eyes at all day-time points and three of five nocturnal time points (10 PM, 12 AM, 6 AM; secondary endpoint). The frequency of adverse events was similar between treatment groups; in the BBFC arm, ocular hyperemia, corneal abrasion, and dysgeusia were the most frequently reported, consistent with events described in the drug label. CONCLUSIONS: This first large, multicenter study of 24-hour IOP control with BBFC met its primary endpoint; BBFC demonstrated significantly superior 24-hour IOP lowering efficacy vs Vehicle following 4 weeks of three-times-daily treatment in subjects with OAG or OHT. PMID- 30403989 TI - Acyclovir induces cell cycle perturbation and apoptosis in Jurkat leukemia cells, and enhances chemotherapeutic drug cytotoxicity. AB - AIMS AND METHODS: Many antiviral agents have been reported to present direct cytotoxic activity in cancer, showing antiproliferative and proapoptotic effects through different mechanisms. In the present study, we took into account the cytotoxic action of the antiviral drug acyclovir (ACV) on leukemia cells, by investigating cell cycle perturbations and apoptosis induction upon drug administration to three still unexplored cell lines, namely Jurkat, U937, and K562. At the same time, the cytotoxicity of cisplatin (CDDP) and 5-fluorouracil (5-FU) in combination with ACV was assessed, thus to evaluate if the antiviral agent could enhance cancer cell sensitivity to these chemotherapeutic drugs. FINDINGS AND SIGNIFICANCE: Our results showed that ACV cytotoxic action was maximum in Jurkat cells (acute T cell leukemia), which showed a dose- and time dependent reduction of cell viability after drug exposure. The flow cytometric analysis of cell cycle revealed a delay/block in S phase and an increase of the sub-G1 peak upon ACV administration, thereby indicating apoptotic cell death. The activation of caspase-3 and the presence of nuclear DNA fragmentation confirmed the induction of apoptosis in ACV-treated cells. Interestingly, the pre-treatment of Jurkat cells with ACV for 72 h or 7 days increased CDDP and 5-FU cytotoxicity, suggesting enhanced leukemia cell sensitivity to these anticancer drugs. PMID- 30403990 TI - CB2-deficiency is associated with a stronger hypertrophy and remodeling of the right ventricle in a murine model of left pulmonary artery occlusion. AB - AIMS: Pulmonary hypertension (PH) leads to right ventricular (RV) adaptation and remodeling and has deleterious long-term effects on RV function. The endocannabinoid receptor CB2 has been associated with protective effects in adaptation and remodeling of the left ventricle after ischemia. Therefore, we investigated the role of CB2 receptor in RV adaptation after occlusion of the left pulmonary artery (LPA) in a murine model. MAIN METHODS: C57/Bl6 (WT)- and CB2 receptor-deficient (Cnr2-/-)-mice underwent paramedian sternotomy and LPA was occluded using a metal clip. Right heart hemodynamic study (Millar(r)) preceded organ harvesting for immunohistochemistry and mRNA analysis 7 and 21 days (d) post-occlusion. KEY FINDINGS: LPA occlusion led to higher RV systolic pressure in Cnr2-/--hearts, while hemodynamics were comparable with WT-hearts after 21d. Cnr2 /--hearts showed higher macrophage infiltration and lower interleukin-10 expression after 7 d, but otherwise a comparable inflammatory mediator expression profile. Cardiomyocyte-hypertrophy was stronger in Cnr2-/--mice, presenting with higher tenascin-C expression than WT-hearts. Planimetry revealed higher collagen area in Cnr2-/--hearts and small areas of cardiomyocyte-loss. Surrounding cardiomyocytes were cleaved caspase-3- and TUNEL positive in Cnr2-/--hearts. This was associated by maladaptation of myosin heavy-chain isoforms and lower reactive oxygen scavenger enzymes induction in Cnr2-/--hearts. We found comparable morphological changes in both lungs between the two genotypes. SIGNIFICANCE: LPA occlusion led to increased systolic pressure and adaptation of RV in CB2 deficient mice. CB2 receptor seems to modulate RV adaptation through expression of contractile elements, reactive oxygen scavenger enzymes, and inflammatory response in order to prevent cardiomyocyte apoptosis. PMID- 30403991 TI - Elusive Conformational Dynamics of PPARgamma Inactivation Tied Down by Chemical Cross-Linking. AB - In this issue of Structure, Zheng et al. (2018) have described the dynamics of PPARgamma in complex with a non-agonist by exploring its solution-phase conformational landscape through chemical cross-linking in combination with a multitude of different treatment conditions, including their new synthetic anti diabetic non-agonist, revealing the physical mechanism of PPARgamma inactivation. PMID- 30403992 TI - Unique Characteristics of the Parasite Polyamine Pathway. AB - A critical function of spermidine is in the formation of hypusine, an essential post-translational modification of eukaryotic initiation factor eIF5A. In this issue of Structure, Afandor et al. (2018) determine the crystal structure of trypanosomal deoxyhypusine synthase, which shows that gene duplication and subsequent mutations provide significant differences from the mammalian equivalent exploitable for drug design. PMID- 30403993 TI - Dimerization of the Pragmin Pseudo-Kinase Regulates Protein Tyrosine Phosphorylation. PMID- 30403994 TI - A Pseudo-Kinase Double Act. PMID- 30403996 TI - B Cell Receptor Crosslinking Augments Germinal Center B Cell Selection when T Cell Help Is Limiting. AB - Antigen-dependent engagement of germinal center (GC) B cell receptors (BCRs) promotes antigen internalization and presentation for follicular helper T cells. However, whether BCR signaling is critical or synergistic with T cell help for GC B cell selection or differentiation is unclear. Here, by adapting an experimental approach that enables independent delivery of BCR-crosslinking antigen or T cell help to GC B cells in vivo, we showed that T cell help was sufficient to induce GC B cell expansion and plasmablast formation. However, although BCR crosslinking could not by itself promote GC B cell selection or differentiation, it could synergize with T cell help to enhance the GC and plasmablast responses when T cell help was limiting. These findings indicate that GC B cells can integrate variable inputs from T cell help and BCR signaling in vivo for an optimal process of selection and differentiation, critical for potent long-term humoral immunity. PMID- 30403997 TI - Characterization of a Mouse Model of Borjeson-Forssman-Lehmann Syndrome. AB - Mutations of the transcriptional regulator PHF6 cause the X-linked intellectual disability disorder Borjeson-Forssman-Lehmann syndrome (BFLS), but the pathogenesis of BFLS remains poorly understood. Here, we report a mouse model of BFLS, generated using a CRISPR-Cas9 approach, in which cysteine 99 within the PHD domain of PHF6 is replaced with phenylalanine (C99F). Mice harboring the patient specific C99F mutation display deficits in cognitive functions, emotionality, and social behavior, as well as reduced threshold to seizures. Electrophysiological studies reveal that the intrinsic excitability of entorhinal cortical stellate neurons is increased in PHF6 C99F mice. Transcriptomic analysis of the cerebral cortex in C99F knockin mice and PHF6 knockout mice show that PHF6 promotes the expression of neurogenic genes and represses synaptic genes. PHF6-regulated genes are also overrepresented in gene signatures and modules that are deregulated in neurodevelopmental disorders of cognition. Our findings advance our understanding of the mechanisms underlying BFLS pathogenesis. PMID- 30403995 TI - A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates. AB - Zika virus (ZIKV) causes severe neurologic complications and fetal aberrations. Vaccine development is hindered by potential safety concerns due to antibody cross-reactivity with dengue virus and the possibility of disease enhancement. In contrast, passive administration of anti-ZIKV antibodies engineered to prevent enhancement may be safe and effective. Here, we report on human monoclonal antibody Z021, a potent neutralizer that recognizes an epitope on the lateral ridge of the envelope domain III (EDIII) of ZIKV and is protective against ZIKV in mice. When administered to macaques undergoing a high-dose ZIKV challenge, a single anti-EDIII antibody selected for resistant variants. Co-administration of two antibodies, Z004 and Z021, which target distinct sites on EDIII, was associated with a delay and a 3- to 4-log decrease in peak viremia. Moreover, the combination of these antibodies engineered to avoid enhancement prevented viral escape due to mutation in macaques, a natural host for ZIKV. PMID- 30403998 TI - Rapid Disruption of Dishevelled Activity Uncovers an Intercellular Role in Maintenance of Prickle in Core Planar Polarity Protein Complexes. AB - Planar polarity, the coordinated polarization of cells in the plane of a tissue, is important for normal tissue development and function. Proteins of the core planar polarity pathway become asymmetrically localized at the junctions between cells to form intercellular complexes that coordinate planar polarity between cell neighbors. Here, we combine tools to rapidly disrupt the activity of the core planar polarity protein Dishevelled, with quantitative measurements of protein dynamics and levels, and mosaic analysis, to investigate Dishevelled function in maintenance of planar polarity. We provide mechanistic insight into the hierarchical relationship of Dishevelled with other members of the core planar polarity complex. Notably, we show that removal of Dishevelled in one cell causes rapid release of Prickle into the cytoplasm in the neighboring cell. This release of Prickle generates a self-propagating wave of planar polarity complex destabilization across the tissue. Thus, Dishevelled actively maintains complex integrity across intercellular junctions. PMID- 30403999 TI - MICU1 Confers Protection from MCU-Dependent Manganese Toxicity. AB - The mitochondrial calcium uniporter is a highly selective ion channel composed of species- and tissue-specific subunits. However, the functional role of each component still remains unclear. Here, we establish a synthetic biology approach to dissect the interdependence between the pore-forming subunit MCU and the calcium-sensing regulator MICU1. Correlated evolutionary patterns across 247 eukaryotes indicate that their co-occurrence may have conferred a positive fitness advantage. We find that, while the heterologous reconstitution of MCU and EMRE in vivo in yeast enhances manganese stress, this is prevented by co expression of MICU1. Accordingly, MICU1 deletion sensitizes human cells to manganese-dependent cell death by disinhibiting MCU-mediated manganese uptake. As a result, manganese overload increases oxidative stress, which can be effectively prevented by NAC treatment. Our study identifies a critical contribution of MICU1 to the uniporter selectivity, with important implications for patients with MICU1 deficiency, as well as neurological disorders arising upon chronic manganese exposure. PMID- 30404002 TI - Analysis of Single-Cell RNA-Seq Identifies Cell-Cell Communication Associated with Tumor Characteristics. AB - Tumor ecosystems are composed of multiple cell types that communicate by ligand receptor interactions. Targeting ligand-receptor interactions (for instance, with immune checkpoint inhibitors) can provide significant benefits for patients. However, our knowledge of which interactions occur in a tumor and how these interactions affect outcome is still limited. We present an approach to characterize communication by ligand-receptor interactions across all cell types in a microenvironment using single-cell RNA sequencing. We apply this approach to identify and compare the ligand-receptor interactions present in six syngeneic mouse tumor models. To identify interactions potentially associated with outcome, we regress interactions against phenotypic measurements of tumor growth rate. In addition, we quantify ligand-receptor interactions between T cell subsets and their relation to immune infiltration using a publicly available human melanoma dataset. Overall, this approach provides a tool for studying cell-cell interactions, their variability across tumors, and their relationship to outcome. PMID- 30404001 TI - Reliability of Whole-Exome Sequencing for Assessing Intratumor Genetic Heterogeneity. AB - Multi-region sequencing is used to detect intratumor genetic heterogeneity (ITGH) in tumors. To assess whether genuine ITGH can be distinguished from sequencing artifacts, we performed whole-exome sequencing (WES) on three anatomically distinct regions of the same tumor with technical replicates to estimate technical noise. Somatic variants were detected with three different WES pipelines and subsequently validated by high-depth amplicon sequencing. The cancer-only pipeline was unreliable, with about 69% of the identified somatic variants being false positive. Even with matched normal DNA for which 82% of the somatic variants were detected reliably, only 36%-78% were found consistently in technical replicate pairs. Overall, 34%-80% of the discordant somatic variants, which could be interpreted as ITGH, were found to constitute technical noise. Excluding mutations affecting low-mappability regions or occurring in certain mutational contexts was found to reduce artifacts, yet detection of subclonal mutations by WES in the absence of orthogonal validation remains unreliable. PMID- 30404000 TI - Revealing the Critical Regulators of Cell Identity in the Mouse Cell Atlas. AB - Recent progress in single-cell technologies has enabled the identification of all major cell types in mouse. However, for most cell types, the regulatory mechanism underlying their identity remains poorly understood. By computational analysis of the recently published mouse cell atlas data, we have identified 202 regulons whose activities are highly variable across different cell types, and more importantly, predicted a small set of essential regulators for each major cell type in mouse. Systematic validation by automated literature and data mining provides strong additional support for our predictions. Thus, these predictions serve as a valuable resource that would be useful for the broad biological community. Finally, we have built a user-friendly, interactive web portal to enable users to navigate this mouse cell network atlas. PMID- 30404003 TI - A Screen Using iPSC-Derived Hepatocytes Reveals NAD+ as a Potential Treatment for mtDNA Depletion Syndrome. AB - Patients with mtDNA depletion syndrome 3 (MTDPS3) often die as children from liver failure caused by severe reduction in mtDNA content. The identification of treatments has been impeded by an inability to culture and manipulate MTDPS3 primary hepatocytes. Here we generated DGUOK-deficient hepatocyte-like cells using induced pluripotent stem cells (iPSCs) and used them to identify drugs that could improve mitochondrial ATP production and mitochondrial function. Nicotinamide adenine dinucleotide (NAD) was found to improve mitochondrial function in DGUOK-deficient hepatocyte-like cells by activating the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1alpha). NAD treatment also improved ATP production in MTDPS3-null rats and in hepatocyte-like cells that were deficient in ribonucleoside-diphosphate reductase subunit M2B (RRM2B), suggesting that it could be broadly effective. Our studies reveal that DGUOK-deficient iPSC-derived hepatocytes recapitulate the pathophysiology of MTDPS3 in culture and can be used to identify therapeutics for mtDNA depletion syndromes. PMID- 30404004 TI - SNIP1 Recruits TET2 to Regulate c-MYC Target Genes and Cellular DNA Damage Response. AB - The TET2 DNA dioxygenase regulates gene expression by catalyzing demethylation of 5-methylcytosine, thus epigenetically modulating the genome. TET2 does not contain a sequence-specific DNA-binding domain, and how it is recruited to specific genomic sites is not fully understood. Here we carried out a mammalian two-hybrid screen and identified multiple transcriptional regulators potentially interacting with TET2. The SMAD nuclear interacting protein 1 (SNIP1) physically interacts with TET2 and bridges TET2 to bind several transcription factors, including c-MYC. SNIP1 recruits TET2 to the promoters of c-MYC target genes, including those involved in DNA damage response and cell viability. TET2 protects cells from DNA damage-induced apoptosis dependending on SNIP1. Our observations uncover a mechanism for targeting TET2 to specific promoters through a ternary interaction with a co-activator and many sequence-specific DNA-binding factors. This study also reveals a TET2-SNIP1-c-MYC pathway in mediating DNA damage response, thereby connecting epigenetic control to maintenance of genome stability. PMID- 30404005 TI - BRAF Splice Variant Resistance to RAF Inhibitor Requires Enhanced MEK Association. AB - Expression of aberrantly spliced BRAF V600E isoforms (BRAF V600E DeltaEx) mediates resistance in 13%-30% of melanoma patients progressing on RAF inhibitors. BRAF V600E DeltaEx confers resistance, in part, through enhanced dimerization. Here, we uncoupled BRAF V600E DeltaEx dimerization from maintenance of MEK-ERK1/2 signaling. Furthermore, we show BRAF V600E DeltaEx association with its substrate, MEK, is enhanced and required for RAF inhibitor resistance. RAF inhibitor treatment increased phosphorylation at serine 729 (S729) in BRAF V600E DeltaEx. Mutation of S729 to a non-phosphorylatable residue reduced BRAF V600E DeltaEx-MEK interaction, reduced dimerization or oligomerization, and increased RAF inhibitor sensitivity. Conversely, mutation of the BRAF dimerization domain elicited partial effects on MEK association and RAF inhibitor sensitivity. Our data implicate BRAF S729 in resistance to RAF inhibitor and underscore the importance of substrate association with BRAF V600E DeltaEx. These findings may provide opportunities to target resistance driven by aberrantly spliced forms of BRAF V600E. PMID- 30404006 TI - Genetic Models Reveal cis and trans Immune-Regulatory Activities for lincRNA Cox2. AB - An inducible gene expression program is a hallmark of the host inflammatory response. Recently, long intergenic non-coding RNAs (lincRNAs) have been shown to regulate the magnitude, duration, and resolution of these responses. Among these is lincRNA-Cox2, a dynamically regulated gene that broadly controls immune gene expression. To evaluate the in vivo functions of this lincRNA, we characterized multiple models of lincRNA-Cox2-deficient mice. LincRNA-Cox2-deficient macrophages and murine tissues had altered expression of inflammatory genes. Transcriptomic studies from various tissues revealed that deletion of the lincRNA Cox2 locus also strongly impaired the basal and inducible expression of the neighboring gene prostaglandin-endoperoxide synthase (Ptgs2), encoding cyclooxygenase-2, a key enzyme in the prostaglandin biosynthesis pathway. By utilizing different genetic manipulations in vitro and in vivo, we found that lincRNA-Cox2 functions through an enhancer RNA mechanism to regulate Ptgs2. More importantly, lincRNA-Cox2 also functions in trans, independently of Ptgs2, to regulate critical innate immune genes in vivo. PMID- 30404007 TI - Shiga Toxin/Lipopolysaccharide Activates Caspase-4 and Gasdermin D to Trigger Mitochondrial Reactive Oxygen Species Upstream of the NLRP3 Inflammasome. AB - The non-canonical caspase-4 and canonical NLRP3 inflammasomes are both activated by intracellular lipopolysaccharide (LPS), but the crosstalk between these two pathways remains unclear. Shiga toxin 2 (Stx2)/LPS complex, from pathogenic enterohemorrhagic Escherichia coli, activates caspase-4, gasdermin D (GSDMD), and the NLRP3 inflammasome in human THP-1 macrophages, but not mouse macrophages that lack the Stx receptor CD77. Stx2/LPS-mediated IL-1beta secretion and pyroptosis are dependent on mitochondrial reactive oxygen species (ROS) downstream of the non-canonical caspase-4 inflammasome and cleaved GSDMD, which is enriched at the mitochondria. Blockade of caspase-4 activation and ROS generation as well as GSDMD deficiency significantly reduces Stx2/LPS-induced IL-1beta production and pyroptosis. The NLRP3 inflammasome plays a significant role in amplifying Stx2/LPS-induced GSDMD cleavage and pyroptosis, with significant reduction of these responses in NLRP3-deficient THP-1 cells. Together, these data show that Stx2/LPS complex activates the non-canonical inflammasome and mitochondrial ROS upstream of the NLRP3 inflammasome to promote cytokine maturation and pyroptosis. PMID- 30404008 TI - Zika Virus Infection in Hypothalamus Causes Hormone Deficiencies and Leads to Irreversible Growth Delay and Memory Impairment in Mice. AB - Zika virus (ZIKV) can cause microcephaly in the fetus. However, its effects on body growth and the development of children with postnatal ZIKV infection are largely unknown. To examine this, we intraperitoneally challenged mouse pups with ZIKV. Infection causes an irreversible growth delay and deficits in spatial learning and memory, with growth-relevant hormones significantly reduced during infection. These effects are associated with ZIKV RNA expression in the hypothalamus, blood, and brain but not in the pituitary and thyroid. Infection is also associated with hypothalamic inflammation, and ZIKV antigen is detectable in neuroendocrine cells producing thyrotropin-releasing hormone. Moreover, early administration of growth hormone could significantly improve growth delay. Our results demonstrate that ZIKV can infect the hypothalamus, causing multi-hormone deficiencies and delayed growth and development in a mouse model. Therefore, prospective multidisciplinary follow-up of ZIKV-infected children may be necessary to understand potential effects of this virus on childhood development. PMID- 30404009 TI - Combined Positive and Negative Feedback Allows Modulation of Neuronal Oscillation Frequency during Sensory Processing. AB - A key step in sensory information processing involves modulation and integration of neuronal oscillations in disparate frequency bands, a poorly understood process. Here, we investigate how top-down input causes frequency changes in slow oscillations during sensory processing and, in turn, how the slow oscillations are combined with fast oscillations (which encode sensory input). Using experimental connectivity patterns and strengths of interneurons, we develop a system-level model of a neuronal circuit controlling these oscillatory behaviors, allowing us to understand the mechanisms responsible for the observed oscillatory behaviors. Our analysis discovers a circuit capable of producing the observed oscillatory behaviors and finds that a detailed balance in the strength of synaptic connections is the critical determinant to produce such oscillatory behaviors. We not only uncover how disparate frequency bands are modulated and combined but also give insights into the causes of abnormal neuronal activities present in brain disorders. PMID- 30404010 TI - The Scalloped and Nerfin-1 Transcription Factors Cooperate to Maintain Neuronal Cell Fate. AB - The ability of cells to stably maintain their fate is governed by specific transcription regulators. Here, we show that the Scalloped (Sd) and Nervous fingers-1 (Nerfin-1) transcription factors physically and functionally interact to maintain medulla neuron fate in the Drosophila melanogaster CNS. Using Targeted DamID, we find that Sd and Nerfin-1 occupy a highly overlapping set of target genes, including regulators of neural stem cell and neuron fate, and signaling pathways that regulate CNS development such as Notch and Hippo. Modulation of either Sd or Nerfin-1 activity causes medulla neurons to dedifferentiate to a stem cell-like state, and this is mediated at least in part by Notch pathway deregulation. Intriguingly, orthologs of Sd and Nerfin-1 have also been implicated in control of neuronal cell fate decisions in both worms and mammals. Our data indicate that this transcription factor pair exhibits remarkable biochemical and functional conservation across metazoans. PMID- 30404011 TI - PPARgammaDelta5, a Naturally Occurring Dominant-Negative Splice Isoform, Impairs PPARgamma Function and Adipocyte Differentiation. AB - Peroxisome-proliferator-activated receptor gamma (PPARgamma) regulates glucose and lipid homeostasis, insulin signaling, and adipocyte differentiation. Here, we report the skipping of exon 5 as a legitimate splicing event generating PPARgammaDelta5, a previously unidentified naturally occurring truncated isoform of PPARgamma, which lacks the entire ligand-binding domain. PPARgammaDelta5 is endogenously expressed in human adipose tissue and, during adipocyte differentiation, lacks ligand-dependent transactivation ability and acts as a dominant-negative isoform reducing PPARgamma activity. Ligand-mediated PPARgamma activation induces exon 5 skipping in a negative feedback loop, suggesting alternative splicing as a mechanism regulating PPARgamma activity. PPARgammaDelta5 overexpression modifies the PPARgamma-induced transcriptional network, significantly impairing the differentiation ability of adipocyte precursor cells. Additionally, PPARgammaDelta5 expression in subcutaneous adipose tissue positively correlates with BMI in two independent cohorts of overweight or obese and type 2 diabetic patients. From a functional perspective, PPARgammaDelta5 mimics PPARG dominant-negative mutated receptors, possibly contributing to adipose tissue dysfunction. These findings open an unexplored scenario in PPARG regulation and PPARgamma-related diseases. PMID- 30404012 TI - Brief Local Application of Progesterone via a Wearable Bioreactor Induces Long Term Regenerative Response in Adult Xenopus Hindlimb. AB - The induction of limb repair in adult vertebrates is a pressing, unsolved problem. Here, we characterize the effects of an integrated device that delivers drugs to severed hindlimbs of adult Xenopus laevis, which normally regenerate cartilaginous spikes after amputation. A wearable bioreactor containing a silk protein-based hydrogel that delivered progesterone to the wound site immediately after hindlimb amputation for only 24 hr induced the regeneration of paddle-like structures in adult frogs. Molecular markers, morphometric analysis, X-ray imaging, immunofluorescence, and behavioral assays were used to characterize the differences between the paddle-like structures of successful regenerates and hypomorphic spikes that grew in untreated animals. Our experiments establish a model for testing therapeutic cocktails in vertebrate hindlimb regeneration, identify pro-regenerative activities of progesterone-containing bioreactors, and provide proof of principle of brief use of integrated device-based delivery of small-molecule drugs as a viable strategy to induce and maintain a long-term regenerative response. PMID- 30404013 TI - The alpha2delta-like Protein Cachd1 Increases N-type Calcium Currents and Cell Surface Expression and Competes with alpha2delta-1. AB - Voltage-gated calcium channel auxiliary alpha2delta subunits are important for channel trafficking and function. Here, we compare the effects of alpha2delta-1 and an alpha2delta-like protein called Cachd1 on neuronal N-type (CaV2.2) channels, which are important in neurotransmission. Previous structural studies show the alpha2delta-1 VWA domain interacting with the first loop in CaV1.1 domain-I via its metal ion-dependent adhesion site (MIDAS) motif and additional Cache domain interactions. Cachd1 has a disrupted MIDAS motif. However, Cachd1 increases CaV2.2 currents substantially (although less than alpha2delta-1) and increases CaV2.2 cell surface expression by reducing endocytosis. Although the effects of alpha2delta-1 are abolished by mutation of Asp122 in CaV2.2 domain-I, which mediates interaction with its VWA domain, the Cachd1 responses are unaffected. Furthermore, Cachd1 co-immunoprecipitates with CaV2.2 and inhibits co immunoprecipitation of alpha2delta-1 by CaV2.2. Cachd1 also competes with alpha2delta-1 for effects on trafficking. Thus, Cachd1 influences both CaV2.2 trafficking and function and can inhibit responses to alpha2delta-1. PMID- 30404015 TI - Tools for Rapid High-Resolution Behavioral Phenotyping of Automatically Isolated Drosophila. AB - Sparse manipulation of neuron excitability during free behavior is critical for identifying neural substrates of behavior. Genetic tools for precise neuronal manipulation exist in the fruit fly, Drosophila melanogaster, but behavioral tools are still lacking to identify potentially subtle phenotypes only detectible using high-throughput and high spatiotemporal resolution. We developed three assay components that can be used modularly to study natural and optogenetically induced behaviors. FlyGate automatically releases flies one at a time into an assay. FlyDetect tracks flies in real time, is robust to severe occlusions, and can be used to track appendages, such as the head. GlobeDisplay is a spherical projection system covering the fly's visual receptive field with a single projector. We demonstrate the utility of these components in an integrated system, FlyPEZ, by comprehensively modeling the input-output function for directional looming-evoked escape takeoffs and describing a millisecond-timescale phenotype from genetic silencing of a single visual projection neuron type. PMID- 30404014 TI - Caveolin-1 Modulates Mechanotransduction Responses to Substrate Stiffness through Actin-Dependent Control of YAP. AB - The transcriptional regulator YAP orchestrates many cellular functions, including tissue homeostasis, organ growth control, and tumorigenesis. Mechanical stimuli are a key input to YAP activity, but the mechanisms controlling this regulation remain largely uncharacterized. We show that CAV1 positively modulates the YAP mechanoresponse to substrate stiffness through actin-cytoskeleton-dependent and Hippo-kinase-independent mechanisms. RHO activity is necessary, but not sufficient, for CAV1-dependent mechanoregulation of YAP activity. Systematic quantitative interactomic studies and image-based small interfering RNA (siRNA) screens provide evidence that this actin-dependent regulation is determined by YAP interaction with the 14-3-3 protein YWHAH. Constitutive YAP activation rescued phenotypes associated with CAV1 loss, including defective extracellular matrix (ECM) remodeling. CAV1-mediated control of YAP activity was validated in vivo in a model of pancreatitis-driven acinar-to-ductal metaplasia. We propose that this CAV1-YAP mechanotransduction system controls a significant share of cell programs linked to these two pivotal regulators, with potentially broad physiological and pathological implications. PMID- 30404016 TI - The Mammalian Spermatogenesis Single-Cell Transcriptome, from Spermatogonial Stem Cells to Spermatids. AB - Spermatogenesis is a complex and dynamic cellular differentiation process critical to male reproduction and sustained by spermatogonial stem cells (SSCs). Although patterns of gene expression have been described for aggregates of certain spermatogenic cell types, the full continuum of gene expression patterns underlying ongoing spermatogenesis in steady state was previously unclear. Here, we catalog single-cell transcriptomes for >62,000 individual spermatogenic cells from immature (postnatal day 6) and adult male mice and adult men. This allowed us to resolve SSC and progenitor spermatogonia, elucidate the full range of gene expression changes during male meiosis and spermiogenesis, and derive unique gene expression signatures for multiple mouse and human spermatogenic cell types and/or subtypes. These transcriptome datasets provide an information-rich resource for studies of SSCs, male meiosis, testicular cancer, male infertility, or contraceptive development, as well as a gene expression roadmap to be emulated in efforts to achieve spermatogenesis in vitro. PMID- 30404017 TI - Selective Laminin-Directed Differentiation of Human Induced Pluripotent Stem Cells into Distinct Ocular Lineages. AB - The extracellular matrix plays a key role in stem cell maintenance, expansion, and differentiation. Laminin, a basement membrane protein, is a widely used substrate for cell culture including the growth of human induced pluripotent stem cells (hiPSCs). Here, we show that different isoforms of laminin lead to the selective differentiation of hiPSCs into different eye-like tissues. Specifically, the 211 isoform of the E8 fragment of laminin (LN211E8) promotes differentiation into neural crest cells via Wnt activation, whereas LN332E8 promotes differentiation into corneal epithelial cells. The immunohistochemical distributions of these laminin isoforms in the developing mouse eye mirrors the hiPSC type that was induced in vitro. Moreover, LN511E8 enables generation of dense hiPSC colonies due to actomyosin contraction, which in turn led to cell density-dependent YAP inactivation and subsequent retinal differentiation in colony centers. Thus, distinct laminin isoforms determine the fate of expanded hiPSCs into eye-like tissues. PMID- 30404018 TI - Oncogenic R132 IDH1 Mutations Limit NADPH for De Novo Lipogenesis through (D)2 Hydroxyglutarate Production in Fibrosarcoma Cells. PMID- 30404019 TI - The regulation of skin fibrosis in systemic sclerosis by extracellular ATP via P2Y2 purinergic receptor. AB - Tissue injury/hypoxia and oxidative stress induced-extracellular ATP can act as a damage-associated molecular pattern molecules (DAMPs), which initiates inflammatory response. Objective was to elucidate the role of extracellular ATP in skin fibrosis in systemic sclerosis (SSc). We identified that hypoxia enhanced ATP release, and extracellular ATP enhanced IL-6 production more significantly in SSc fibroblasts than in normal fibroblasts. There were no significant differences of P2X and P2Y receptors expressions between normal and SSc fibroblasts. Non selective P2 receptor antagonist and selective-P2Y2 receptor antagonists, kaempferol and AR-C118925XX, significantly inhibited ATP-induced IL-6 production and phosphorylation of p38 in SSc fibroblasts. ATP-induced IL-6 production was significantly inhibited by p38 inhibitors, SB203580 and doramapimod. Collagen type I production in SSc fibroblasts by ATP-induced IL-6/IL-6 receptor trans signaling was inhibited by kaempferol and SB203580. Amount of ATP in bleomycin treated skin was increased, and administration of AR-C118925XX significantly inhibited bleomycin-induced dermal fibrosis in mice. These results suggest that vasculopathy-induced hypoxia and oxidative stress might enhance ATP release in the dermis in SSc, and extracellular ATP-induced phosphorylation of p38 via P2Y2 receptor might enhance IL-6 and collagen type I production in SSc fibroblasts. P2Y2 receptor antagonists therapy could be a treatment for skin sclerosis in patients with SSc. PMID- 30404020 TI - The calcium-sensing receptor regulates epidermal intracellular Ca2+ signaling and re-epithelialization after wounding. AB - Extracellular Ca2+ (Ca2+o) is a crucial regulator of epidermal homeostasis and its receptor, the Ca2+-sensing receptor (CaSR), conveys the Ca2+o signals to promote keratinocyte adhesion, differentiation, and survival via activation of intracellular Ca2+ (Ca2+i) and E-cadherin-mediated signaling. Here, we took genetic loss-of-function approaches to delineate the functions of CaSR in wound re-epithelialization. Cutaneous injury triggered a robust CaSR expression and a surge of Ca2+i in epidermis. CaSR and E-cadherin were co-expressed at the cell cell membrane between migratory keratinocytes in the nascent epithelial tongues. Blocking the expression of CaSR or E-cadherin in cultured keratinocytes markedly inhibited the wound-induced Ca2+i propagation and their ability to migrate collectively. Depleting CaSR also suppressed keratinocyte proliferation by down regulating the E-cadherin/epidermal growth factor receptor (EGFR)/mitogen activated protein kinase (MAPK) signaling axis. Blunted epidermal Ca2+i response to wounding and retarded wound healing were observed in the keratinocyte-specific CaSR knockout (EpidCasr-/-) mice, whose shortened neo-epithelia exhibited declined E-cadherin expression and diminished keratinocyte proliferation and differentiation. Conversely, stimulating endogenous CaSR with calcimimetic NPS R568 accelerated wound re-epithelialization through enhancing the epidermal Ca2+i signals and E-cadherin membrane expression. These findings demonstrated a critical role for the CaSR in epidermal regeneration and its therapeutic potential for improving skin wound repair. PMID- 30404021 TI - Aging in skin of color: Disruption to elastic fiber organization is detrimental to skin's biomechanical function. AB - Skin aging is a complex process involving the additive effects of time-dependent intrinsic aging and changes elicited via skin's interaction with the environment. Maintaining optimal skin function is essential for healthy aging across global populations; yet most research focuses on lightly-pigmented skin (Fitzpatrick phototypes I-III), with little emphasis on skin of color (Fitzpatrick phototypes V-VI). Here, we explore the biomechanical and histologic consequences of aging in black African-American volunteers. We found that healthy young buttock and dorsal forearm skin was biomechanically resilient, highly elastic and characterized histologically by strong interdigitation of rete ridges, abundant organized fibrillar collagen and plentiful arrays of elastic fibers. In contrast, intrinsically aged buttock skin was significantly less resilient, less elastic and was accompanied by effacement of rete ridges with reduced deposition of both elastic fibers and fibrillar collagens. In chronically photoexposed dorsal forearm, significant impairment of all biomechanical functions was identified, with complete flattening of rete ridges and marked depletion of elastic fibers and fibrillar collagens. We conclude that in skin of color, both intrinsic aging and photoaging significantly impact skin function and composition, despite the additional photoprotective properties of increased melanin. Improved public health advice regarding the consequences of chronic photoexposure and the importance of multimodal photoprotection use for all is of global significance. PMID- 30404022 TI - Lentigines Formation in Caucasian Women - Interaction Between Particulate Matter and Solar Ultraviolet Radiation. PMID- 30404023 TI - Comparison between common performance-based tests and self-reports of physical function in People with Multiple Sclerosis: Does Sex or Gender Matter? AB - OBJECTIVE: To estimate the extent to which sex/gender differences affect the relationships between tests of physical performance and self-reports about function in everyday life activities. Ecological validity is an important psychometric property when choosing tests of physical function, as they need to relate to everyday function. In Multiple Sclerosis (MS), the EQUI scale, modified Canadian Aerobic Fitness Test, grip strength, vertical jump, push-up, partial curl-up, gait speed (comfortable/fast), six-minute walk test, and nine-hole peg test are commonly used but the extent to which they relate to everyday function is understudied and the extent to which ecological validity of these tests differ between women and men is unknown. DESIGN: A cross-sectional analysis was conducted on a random sample of men and women recruited for a study on the life impact of MS. Correlations between pairs of performance tests of physical function (PerfO) and self-report items (SRO) pairs of variables with theoretical coherence were calculated and gender effects identified using linear regression. SETTING: Participants were recruited from MS clinic at Montreal Neurological Hospital. PARTICIPANTS: The sample comprised of140 women and 48 men with MS INTERVENTIONS: Not applicable Main Outcomes Measures RESULTS: The mean age of the participants was 43 (SD:10). Sixty PerfO and SRO items yielded 165 theoretically linked pairs separately for women and men. Of these 330 possible pairs, 77 pairs (23%) had correlations >=0.8, showing strong support for the link between performance tests and everyday function; 203 pairs provided moderate support (r>=0.5). Thirty-one pairs had a statistically significant interaction with gender with men having higher correlations than women (n=27/31). CONCLUSION: The results support the ecological validity for physical performance tests, particularly balance tests and particularly for men. The observation that many indicators of everyday function derived from SROs were related to physical performance supports the routine use of SROs in clinical practice to guide therapy to meet the needs of clients with MS. PMID- 30404024 TI - Strain differences in hippocampal synaptic dysfunction in the TgCRND8 mouse model of Alzheimer's disease: Implications for improving translational capacity. AB - In Alzheimer's disease (AD), characterized by cognitive deterioration, synaptic alterations are frequently reported. The TgCRND8 model, in which mice develop AD like amyloid beta plaque formation, has been used to investigate the effects of amyloidosis on synaptic function. Background strain impacts the behavioral and neuropathological phenotype of mice in this model, but whether this extends to synaptic function is unknown. We investigated the influence of background strain on basal synaptic transmission and long-term potentiation (LTP) in the hippocampus of TgCRND8 mice (13-16 months) on hybrid backgrounds of (129SvEv/Tac) x (C3H/C57/129SvEv/Tac) (aka "129") or (C57) x (C3H/C57) (aka "C3H"). In littermate controls, basal synaptic transmission was significantly reduced, whereas the amplitude of excitatory postsynaptic potentials was significantly higher after LTP induction in 129 vs. C3H mice. In 129 TgCRND8 mice, deficits in hippocampal LTP were more severe than in C3H TgCRND8 relative to controls. Compared to controls, network excitability was decreased in transgenics from both strains. These data suggest that 129 TgCRND8 mice are the more appropriate model to evaluate the efficacy of potential AD treatments on synaptic function, owing to their significant deficit in LTP. Such studies are critical in order to improve the translational capacity of basic science research. PMID- 30404025 TI - Rates of Detection of Adenoma, Sessile Serrated Adenoma, and Advanced Adenoma are Stable over Time and Modifiable. PMID- 30404026 TI - Genomic Medicine and Implications for Hepatocellular Carcinoma Prevention and Therapy. AB - The pathogenesis of hepatocellular carcinoma (HCC) is poorly understood, but recent advances in genomics have increased our understanding of the mechanisms by which HBV, HCV, alcohol, fatty liver disease, and other environmental factors, such as aflatoxin, cause liver cancer. Genetic analyses of liver tissues from patients have provided important information about tumor initiation and progression. Findings from these studies can potentially be used to individualize the management of HCC. In addition to sorafenib, other multi-kinase inhibitors have recently been approved for treatment of HCC and the preliminary success of immunotherapy has raised hopes. Continued progress in genomic medicine could improve classification of HCCs based on their molecular features and lead to new treatments for patients with liver cancer. PMID- 30404027 TI - Immobilization of beta-galactosidase by complexation: Effect of interaction on the properties of the enzyme. AB - In the present work, we aimed to explore the molecular binding between alginate and beta-galactosidase, as well as the effect of this interaction on the activity retention, thermal stability, and kinetic properties of the enzyme. The impact of pH and enzyme/alginate ratio on physicochemical properties (turbidity, morphology, particle size distribution, zeta-potential, FTIR, and isothermal titration calorimetry) was also evaluated. The ratio of biopolymers and pH of the system directly affected the critical pH of complex formation; however, a low alginate concentration (0.1 wt%) could achieve an electrical charge equivalence at pH 3.4 with 93.72% of yield. The binding between beta-galactosidase and alginate was an equilibrium between enthalpic and entropic contributions, which promoted changes in the structure of the enzyme. Nevertheless, this conformational modification was reversible after the dissociation of the complex, which allowed the enzyme to regain its activity. These findings will likely broaden functional applications of enzyme immobilization. PMID- 30404028 TI - Possible use of corn starch as tanning agent in leather industry: Controlled (gradual) degradation by H2O2. AB - High molecular weight/size and poor solubility of native starch seems to be preliminary drawbacks in its possible use in leather processing as a tanning/retanning agent. For this purpose, firstly the native starch which has too large molecular size to penetrate between skin fiber matrix was oxidized with H2O2 in different molar ratios for disintegrating into appropriate molecular size that can be used in tanning process. Then, the product yields, water solubilities and degree of substitutions of oxidized starches were determined. Also, the oxidized starch samples were characterized by Fourier Transforms Infrared (FT-IR) Spectroscopy, Gel Permeation Chromatography (GPC) and Proton Nuclear Magnetic Resonance (1H NMR) Spectroscopy. According to the GPC results, the oxidized starch samples which their molecular weights were reduced for penetrating into skin fibers were selected and they were used in tanning process of goat skins. The tanning effects of selected oxidized starches were evaluated according to shrinkage temperatures, filling coefficients and Scanning Electron Microscopy (SEM) analysis. From the results, it was revealed that the native corn starch can be oxidized with H2O2 in a controlled manner and oxidized starch can be utilized as a tanning/retanning agent in leather making. PMID- 30404029 TI - Fabrication of porous starch microspheres by electrostatic spray and supercritical CO2 and its hemostatic performance. AB - Effective control of bleeding is critical to saving lives whether on the battle field or in civilian life. Microporous starch (MS) is a promising hemostat for its extensive sources, huge surface area and good biocompatibility. However, the hemostatic performance of MS is limited because of its complex preparation process and lack of effective component to activate coagulation factors. Herein, porous starch microspheres modified by calcium (Ca-PSM) with dense shell and honeycomb micro-porous core were prepared by electrostatic spray and supercritical CO2 for the first time. The topological morphology of Ca-PSM changed with the increase of Tween-80 content within 0.5%. Ca-PSM possessed excellent water absorbability due to high specific surface area, and what's more, it showed good hemostatic performance because of the synergistic effects of physical adsorption and chemical activation mechanisms. The results of thrombelastograph (TEG) showed that the initial clotting time (R) and coagulation time (R + K) of Ca-PSM-1 were shortened by 47.1%, 53.3% than that of control group. The maximum blood clot strength (MA) of Ca-PSM-1 was also significantly raised. Furthermore, it was noteworthy that Ca-PSM could activate clotting cascade and induce erythrocyte adsorption. In summary, Ca-PSM as a hemostat will be a promising and alternative candidate for clinical application. PMID- 30404030 TI - Synthesis, characterization and biomedical applications of a novel Schiff base on methyl acrylate-functionalized chitosan bearing p-nitrobenzaldehyde groups. AB - Amino-functionalization has gained significant attention in the chemical modification of carbohydrate polymers due to their potential biomedical applications. Here, the preparation of innovative functionalized chitosan bearing amino-containing groups and equipped with p-nitrobenzaldehyde groups, resulting in an aminated chitosan bearing p-nitrobenzaldehyde (AmCs-pNBA) was described for the first time. The most important advantage of the chitosan functionalization was the success of its preparation at room temperature, avoiding the polymerization of methyl acrylate and instead it reacted entirely with chitosan. The resulting methyl acrylate chitosan was subsequently improved by the synthesized AmCs-pNBA Schiff base via the condensation of aldehyde groups with aminated chitosan. The structural characteristics of AmCs-pNBA were examined by FT-IR, XRD, TGA, SEM, and elemental analysis techniques. The antimicrobial, antioxidant, and anti-biofilm activities of AmCs-pNBA were assessed in vitro. The results revealed that this newly synthesized chitosan derivative displayed significant superior antibacterial, antioxidant, and anti-biofilm activities over the original chitosan. Besides, cytotoxicity and hemolytic analysis of the AmCs pNBA were also evaluated. Results indicated that AmCs-pNBA support cell viability and proliferation without obvious hemolysis. These results show the potential of synthesizing the novel biomaterial candidate, AmCs-pNBA, with improved antibacterial, anti-biofilm, and antioxidant properties that may open a new perspective in biomedical applications. PMID- 30404031 TI - Molecular recognition of double-stranded DNA by a synthetic, homoaromatic tripeptide (YYY): The spectroscopic and calorimetric study. AB - The intermolecular interactions of a homoaromatic tripeptide, H-Tyr-Tyr-Tyr-OH (YYY) with model double-stranded (ds) DNA (ct-DNA) have been investigated by isothermal titration calorimetric (ITC) method along with various biophysical techniques such as fluorescence, time correlated single photon counting (TCSPC) and circular dichroism (CD) spectroscopy. The binding affinity [log (K) at 25 degrees C] of the YYY to ct-DNA is calculated as ~4.3. The binding mode of the YYY to ds-DNA is elucidated by fluorescence intercalator displacement (FID) assay, melting temperature analysis, viscosity measurement and salt-induced fluorescence quenching study. The studies establish that the YYY recognizes the groove of the ct-DNA. The temperature dependent ITC studies show that the binding interaction is thermodynamically favourable. The compensation between enthalpy and entropy leads to the overall Gibbs free energy change almost invariant. Finally, the generality of the YYY to recognize ds-DNA has been analyzed with other model ds-DNA, ds26, which reveals almost similar binding affinity of the YYY as ct-DNA. The studies elucidate both the spectroscopic and calorimetric insight of the interactions of a homoaromatic tripeptide with ds-DNA and hold the promise of future applications as DNA targeting drug. PMID- 30404032 TI - IL6 receptor blockade preserves articular cartilage and increases bone volume following ischemic osteonecrosis in immature mice. AB - OBJECTIVE: Juvenile ischemic osteonecrosis (JIO) of the femoral head is one of the most serious hip disorders causing a permanent deformity of the femoral head in childhood. We recently reported that interleukin 6 (IL6) is predominantly increased in the hip synovial fluid of patients with JIO and that articular chondrocytes are primary source of IL6. This study investigated whether an inhibition of IL6 receptor improves cartilage preservation and bone healing in JIO. METHOD: A small animal model (i.e., 6-week-old mouse) of JIO was treated with either saline or tocilizumab, an IL6 receptor blocker, for 6 weeks. RESULTS: TUNEL-positive chondrocytes in the articular cartilage were reduced by the tocilizumab treatment, concomitant with the increase in cartilage matrix. The levels of a cartilage anabolic marker Sox9 was significantly increased in the articular cartilage of mice treated with tocilizumab. Micro-CT assessment showed tocilizumab treatment significantly increased trabecular epiphyseal bone volume (P = 0.001, n = 10), thickness (P = 0.007) and number (P = 0.014) and decreased bone separation (P = 0.002) and its deformity (P = 0.003). A bone formation marker, BMP2, and an angiogenic marker, vascular endothelial growth factor (VEGF), were both significantly increased by tocilizumab treatment under hypoxia using human chondrocytes while the bone resorption marker, RANKL/OPG ratio, was reduced. CONCLUSION: Tocilizumab treatment following ischemic osteonecrosis has cartilage anabolic effect and increases bone volume in JIO mouse model. The findings lead to a possible application of tocilizumab for preclinical study using a large animal model of JIO and a clinical trial to validate this treatment. PMID- 30404034 TI - Submission title: An unusual cause of hematochezia. PMID- 30404033 TI - Immunoglobulin E blockade during food allergen ingestion enhances the induction of inhibitory immunoglobulin G antibodies. PMID- 30404036 TI - Tofacitinib for the Treatment of Pyoderma Gangrenosum. PMID- 30404035 TI - Ethnic, Racial, and Sex Differences in Etiology, Symptoms, Treatment, and Symptom Outcomes of Patients With Gastroparesis. AB - BACKGROUND & AIMS: Gastroparesis is a chronic disorder of the stomach characterized by nausea, vomiting, early satiety, postprandial fullness, and abdominal pain. There is limited information on gastroparesis in minority populations. We assessed ethnic, racial, and sex variations in the etiology, symptoms, quality of life, gastric emptying, treatments, and symptom outcomes of patients with gastroparesis. METHODS: We collected information from the National Institutes of Health Gastroparesis Consortium on 718 adult patients, from September 2007 through December 2017. Patients were followed every 4 or 6 months, when data were collected on medical histories, symptoms (based on answers to the PAGI-SYM questionnaires), and quality of life (based on SF-36). Follow-up information collected at 1 year (48 week) was used in this analysis. Comparisons were made between patients of self-reported non-Hispanic white, non-Hispanic black, and Hispanic ethnicities, as well as and between male and female patients. RESULTS: Our final analysis included 552 non-Hispanic whites (77%), 83 persons of Hispanic ethnicity (12%), 62 non-Hispanic blacks (9%), 603 women (84%), and 115 men (16%). A significantly higher proportion of non-Hispanic blacks (60%) had gastroparesis of diabetic etiology than of non-Hispanic whites (28%); non Hispanic blacks also had more severe retching (2.5 vs 1.7 score) and vomiting (2.9 vs 1.8 score) and a higher percentage were hospitalized in the past year (66% vs 38%). A significantly higher proportion of Hispanics had gastroparesis of diabetic etiology (59%) than non-Hispanic whites (28%), but Hispanics had less severe nausea (2.7 vs 3.3 score), less early satiety (3.0 vs 3.5 score), and a lower proportion used domperidone (8% vs 21%) or had a peripherally inserted central catheter (1% vs 7%). A higher proportion of women had gastroparesis of idiopathic etiology (69%) than men (46%); women had more severe symptoms of stomach fullness (3.6 vs 3.1 score), early satiety (3.5 vs 2.9 score), postprandial fullness (3.7 vs 3.1 score), bloating (3.3 vs 2.6 score), stomach visibly larger (3.0 vs 2.1 score), and upper abdominal pain (2.9 vs 2.4 score). A lower proportion of women were hospitalized in past year (39% vs 53% of men). CONCLUSIONS: In patients with gastroparesis, etiologies, symptom severity, and treatments vary among races and ethnicities and between sexes. ClinicalTrials.gov Identifier: NCT01696747. PMID- 30404037 TI - Obliterative Portal Venopathy without Cirrhosis is Prevalent in Pediatric Cystic Fibrosis Liver Disease with Portal Hypertension. PMID- 30404038 TI - Cardiogenic Dysphagia by Dysphagia Megalatriensis & Aortica. PMID- 30404039 TI - KIF14 promotes tumor progression and metastasis and is an independent predictor of poor prognosis in human gastric cancer. AB - The kinesin family member 14 (KIF14) is a potential oncogene and is involved in the metastasis of various cancers. Nevertheless, its function in gastric cancer (GC) remains poorly defined. The expression of KIF14 was examined in GC cell lines and a clinical cohort of GC specimens by qPCR, western blotting and immunohistochemistry (IHC) staining. The relationship between KIF14 expression and the clinicopathological features was analyzed. The effect of KIF14 on cell proliferation, colony formation, invasion and migration were investigated in vitro and in vivo. The expression of KIF14 was significantly increased in the GC tissues and cell lines. High KIF14 expression was associated with tumor stage, tumor-node-metastasis (TNM) stage and metastasis. KIF14 was an independent prognostic factor for the overall survival of GC, and a higher expression of KIF14 predicted a poorer survival. KIF14 silencing resulted in attenuated proliferation, invasion and migration in human gastric cancer cells, whereas KIF14 ectopic expression facilitated these biological abilities. Notably, the depressed expression of KIF14 inhibited Akt phosphorylation, while overexpressed KIF14 augmented Akt phosphorylation. Additionally, there was a significant correlation between the expression of KIF14 and p-Akt in GC tissues. Importantly, the proliferation, invasion and migration of the GC cells, which was promoted by KIF14 overexpression, was abolished by the Akt inhibitor MK-2206, while Akt overexpression greatly rescued the effects induced by KIF14 knockdown. Our findings are the first to demonstrate that KIF14 is overexpressed in GC, is correlated with poor prognosis and plays a crucial role in the progression and metastasis of GC. PMID- 30404041 TI - The betaC1 Protein of Geminivirus-Betasatellite Complexes: A Target and Repressor of Host Defenses. PMID- 30404040 TI - Paternal hyperglycemia induces transgenerational inheritance of susceptibility to hepatic steatosis in rats involving altered methylation on Pparalpha promoter. AB - OBJECTIVE: Diabetes exerts adverse effects on the initiation or progression of diabetes and metabolic syndrome in the next generation. In past studies, limited attention has been given to the fathers' role in shaping the metabolic landscape of offspring. Our study was designed to investigate how paternal hyperglycemia exerts an intergenerational effect in mammals as well as the underlying mechanisms. METHODS: Hyperglycemia was introduced in male rats by intraperitoneally injected streptozotocin and these males were bred with healthy females to generate offspring. The metabolic profiles of the progeny were assessed; DNA methylation profiles and gene expression were investigated. Mutagenesis constructs of the Ppara promoter region, and a luciferase reporter assay were used to determine transcription factor binding sites (TFBSs) and the effects of hypermethylation on Ppara transcription. RESULTS: Paternal hyperglycemia induced increased liver weight, and plasma TC, TG, LDL, accumulation of triglycerides in the liver. We discovered that CpG 13 in the amplified promoter region (-852 to -601) of Ppara was hypermethylated in adult offspring liver and expression of Ppara, Acox1, Cpt-1alpha, and Cd36 was down regulated. Hypermethylation of CpG site 13 in the Ppara promoter inhibited the gene transcription, probably through abrogation of SP1 binding. The same epigenetic alteration was discovered in the fetus (E16.5) liver of hyperglycemic father's progeny. CONCLUSIONS: Paternal hyperglycemia may induce epigenetic modification of Ppara in offspring's liver, probably through interaction with SP1 binding, causing impaired lipid metabolism. Our investigation may have implications for the understanding of father-offspring interactions with the potential to account for metabolic syndromes. PMID- 30404042 TI - Systemic sclerosis and exposure to heavy metals. AB - As a mirror image of the Roman god Janus Bifrons, the environment has a hidden face. To highlight this hidden face of the environment in the field of systemic sclerosis (SSc) will allow to identify responsible agents emerging in the future. To date, there is, in fact, a growing scientific evidence that environmental factors have a crucial impact on both alterations and modulation of epigenetic determinants, resulting in SSc onset and progression. It has been well established that there is a marked correlation between SSc onset and occupational exposure to crystalline silica and organic solvents. More recently, an association between SSc and exposure to heavy metals has further been found, including: antimony, cadmium, lead, mercury. These latter findings interestingly underscore that occupational exposure to heavy metals should be systematically checked in all SSc patients at diagnosis, as the identification of the occupational toxic agent will allow its interruption, which may result in potential improvement of SSc outcome. PMID- 30404043 TI - A tissue-specific enhancer of the C. elegans nhr-67/tailless gene drives coordinated expression in uterine stem cells and the differentiated anchor cell. AB - The nhr-67 nuclear receptor gene of Caenorhabditis elegans encodes the ortholog of the Drosophila tailless and vertebrate Tlx genes. In C. elegans, nhr-67 plays multiple roles in the development of the uterus during L2 and L3 larval stages. Four pre-VU cells are born in the L2 stage and form the precursor complement for the ventral surface of the mature uterus. One of the four pre-VU cells becomes the anchor cell (AC), which exits the cell cycle and differentiates, while the remaining three VU cells serve as stem cells that populate the ventral uterus. The nhr-67 gene functions in the development of both VU cell lineages and AC differentiation. Hypomorphic mutations in nhr-67 identify a 276bp region of the distal promoter that is sufficient to activate nhr-67 expression in pre-VU cells and the AC. The 276bp region includes 8 conserved potential cis-acting sites, including two E boxes and a nuclear receptor binding site. Mutational analysis demonstrates that the two E boxes are required for expression of nhr-67 in uterine precursor cells. The E/daughterless ortholog HLH-2 binds these sites as a homodimer, thus playing a central role in activating nhr-67 expression in the uterine precursors. At least two other binding activities, one of which may be the nhr-25/Ftz-F1 nuclear receptor transcription factor, also contribute to uterine precursor cell expression. The organization of the nhr-67 uterine precursor enhancer is compared to similar conserved enhancers in the egl-43, lag 2, and lin-3 genes, which contain the same HLH-2-binding E boxes and are similarly expressed in both pre-VU cells and the AC. This basic regulatory module allows the coordinated expression of at least four genes. Expression of genes in different cells that must coordinate to form a mature organ is driven by a shared set of promoter elements, which integrate multiple transcription factor inputs. PMID- 30404044 TI - Genomic analysis of MCR-1 and CTX-M-8 co-producing Escherichia coli ST58 isolated from a polluted mangrove ecosystem in Brazil. AB - OBJECTIVES: Genomic surveillance studies monitoring the dissemination of multidrug-resistant Enterobacteriaceae in polluted aquatic ecosystems are urgently required. The aim of this study was to report the draft genome sequence of an MCR-1 and CTX-M-8 co-producing Escherichia coli isolated from a polluted mangrove ecosystem in Northeast Brazil. METHODS: Total genomic DNA was sequenced on an Illumina NextSeq platform and was assembled using CLC Genomics Workbench. The whole-genome sequence was evaluated through bioinformatics tools available from the Center of Genomic Epidemiology as well as additional in silico analysis. RESULTS: The genome size was calculated at 5089467bp, comprising a total of 5068 protein-coding sequences. The strain was assigned to sequence type 58 (ST58) and revealed the presence of mcr-1, blaCTX-M-8 and other clinically significant genes responsible for conferring resistance to colistin, beta-lactams, trimethoprim and quinolones. In addition, genes conferring resistance to silver (silR) and quaternary ammonium compounds (sugE) were identified. CONCLUSION: These data provide valuable information for comparative genomic analysis regarding the dissemination of MCR-1-producing E. coli at the human-animal-environment interface. PMID- 30404045 TI - Genomic features of a highly virulent, ceftiofur-resistant, CTX-M-8-producing Escherichia coli ST224 causing fatal infection in a domestic cat. AB - OBJECTIVES: Escherichia coli strains producing extended-spectrum beta-lactamases (ESBLs), especially CTX-M-type, have been largely described in companion animals; however, genomic data are lacking to clarify the clinical impact of ESBL producing isolates in these hosts. The aim of this study was to present the genomic features of a highly virulent, ceftiofur-resistant, CTX-M-8-producing E. coli isolate from a case of pneumonia in a domestic cat with fatal outcome. METHODS: Genomic DNA was sequenced using an Illumina NextSeq 500 platform and was assembled using CLC Genomic Workbench. Genomic data were analysed using online bioinformatics tools. RESULTS: The genome size was evaluated at 5.1Mb, with 5334 protein-coding sequences. The strain was assigned to sequence type 224 (ST224) and presented genes conferring resistance to beta-lactams (blaCTX-M-8), sulphonamides (sul2), tetracycline (tetA) and trimethoprim (dfrA14) as well as chromosomal point mutations in ParC (S80I), GyrA (S83L) and GyrB (D87N). In addition, the presence of the virulence genes cba, gad, ipfA, iroN, iss, mchF and tsh was detected. CONCLUSION: This draft genome sequence might provide important data for a better understanding of genomic aspects regarding the dissemination of CTX-M-8-producing E. coli in the human-animal-environment interface. PMID- 30404046 TI - Temporal trends, determinants, and impact of high-intensity statin prescriptions after percutaneous coronary intervention: Results from a large single-center prospective registry. AB - BACKGROUND: High-intensity statins (HIS) are recommended for secondary prevention following percutaneous coronary intervention (PCI). We aimed to describe temporal trends and determinants of HIS prescriptions after PCI in a usual-care setting. METHODS: All patients with age <=75 years undergoing PCI between January 2011 and May 2016 at an urban, tertiary care center and discharged with available statin dosage data were included. HIS were defined as atorvastatin 40 or 80 mg, rosuvastatin 20 or 40 mg, and simvastatin 80 mg. RESULTS: A total of 10,495 consecutive patients were included. Prevalence of HIS prescriptions nearly doubled from 36.6% in 2011 to 60.9% in 2016 (P < .001), with a stepwise increase each year after 2013. Predictors of HIS prescriptions included ST-segment elevation myocardial infarction/non-ST-segment elevation myocardial infarction (odds ratio [OR] 4.60, 95% CI 3.98-5.32, P < .001) and unstable angina (OR 1.31, 95% CI 1.19-1.45, P < .001) as index event, prior myocardial infarction (OR 1.48, 95% CI 1.34-1.65, P < .001), and co-prescription of beta-blocker (OR 1.26, 95% CI 1.12-1.43, P < .001). Conversely, statin treatment at baseline (OR 0.86, 95% CI 0.77-0.96, P = .006), Asian races (OR 0.73, 95% CI 0.65-0.83, P< .001), and older age (OR 0.90, 95% CI 0.88-0.92, P < .001) were associated with reduced HIS prescriptions. There was no significant association between HIS prescriptions and 1-year rates of death, myocardial infarction, or target-vessel revascularization (adjusted hazard ratio 0.98, 95% CI 0.84-1.15, P = .84), although there was a trend toward reduced mortality (adjusted hazard ratio 0.71, 95% CI 0.50-1.00, P = .05). CONCLUSION: Although the rate of HIS prescriptions after PCI has increased in recent years, important heterogeneity remains and should be addressed to improve practices in patients undergoing PCI. PMID- 30404047 TI - Admission diagnoses among patients with heart failure: Variation by ACO performance on a measure of risk-standardized acute admission rates. AB - BACKGROUND: A key quality metric for Accountable Care Organizations (ACOs) is the rate of hospitalization among patients with heart failure (HF). Among this patient population, non-HF-related hospitalizations account for a substantial proportion of admissions. Understanding the types of admissions and the distribution of admission types across ACOs of varying performance may provide important insights for lowering admission rates. METHODS: We examined admission diagnoses among 220 Medicare Shared Savings Program ACOs in 2013. ACOs were stratified into quartiles by their performance on a measure of unplanned risk standardized acute admission rates (RSAARs) among patients with HF. Using a previously validated algorithm, we categorized admissions by principal discharge diagnosis into: HF, cardiovascular/non-HF, and noncardiovascular. We compared the mean admission rates by admission type as well as the proportion of admission types across RSAAR quartiles (Q1-Q4). RESULTS: Among 220 ACOs caring for 227,356 patients with HF, the median (IQR) RSAARs per 100 person-years ranged from 64.5 (61.7-67.7) in Q1 (best performers) to 94.0 (90.1-99.9) in Q4 (worst performers). The mean admission rates by admission types for ACOs in Q1 compared with Q4 were as follows: HF admissions: 9.8 (2.2) vs 14.6 (2.8) per 100 person years (P < .0001); cardiovascular/non-HF admissions: 11.1 (1.6) vs 15.9 (2.6) per 100 person years (P < .0001); and noncardiovascular admissions: 42.7 (5.4) vs 69.6 (11.3) per 100 person-years (P < .0001). The proportion of admission due to HF, cardiovascular/non-HF, and noncardiovascular conditions was 15.4%, 17.5%, and 67.1% in Q1 compared with 14.6%, 15.9%, and 69.4% in Q4 (P < .007). CONCLUSIONS: Although ACOs with the best performance on a measure of all-cause admission rates among people with HF tended to have fewer admissions for HF, cardiovascular/non HF, and noncardiovascular conditions compared with ACOs with the worst performance (highest admission rates), the largest difference in admission rates were for noncardiovascular admission types. Across all ACOs, two-thirds of admissions of patients with HF were for noncardiovascular causes. These findings suggest that comprehensive approaches are needed to reduce the diverse admission types for which HF patients are at risk. PMID- 30404048 TI - Removal of fluoride and natural organic matter from natural tropical brackish waters by nanofiltration/reverse osmosis with varying water chemistry. AB - In the context of decentralised brackish water treatment in development applications, the influence of water quality on membrane separation was investigated with real waters. High ionic strength (low net driving pressure) on fluoride (F) retention by nanofiltration (NF) and reverse osmosis (RO) was investigated over a wide pH range (2-12). Further, the influence of pH on the permeation of natural organic matter (NOM) fractions, in particular low molecular weight (LMW) neutrals, was elucidated. Natural and semi-natural waters from Tanzania with similar F concentrations of about 50 mg L-1 but varying NOM and inorganic carbon (IC) concentration were filtered with an NF and RO, namely NF270 and BW30. F retention by NF270 for the feed water with highest ionic strength and IC concentration was lower and attributed to charge screening. This parameter further reduced at high pH due to co-ions (F- and CO32-) interactions and combined (synergistic) effect of high salt concentration and pH on F. High NOM resulted in higher membrane zeta potential in comparison with low NOM natural water. However, there was no significant difference in F retention due to the fact that F retention enhancement was annulled by deposit formation on the membrane. The fraction of NOM found in NF/RO permeates was dominated by LMW neutrals. This was attributed to their size and uncharged nature, while their higher concentration at low pH remains unexplained. More humic substances (HS) of higher molecularity and aromaticity permeated the NF270 when compared with BW30, which can be explained with the different membrane molecular weight cut off (MWCO). The study highlights the complexity of treating tropical natural waters with elevated F and NOM concentrations. In order to develop appropriate membrane systems that will achieve optimal F and NOM removal, the influence of water quality parameters such as pH, NOM content, ionic strength and IC concentration requires understanding. Seasonal variation of water quality as well as operational fluctuations, which occur in particular when such treatment processes are operated with renewable energy, will require such challenges to be addressed. Further, given the high permeability of low molecular weight (LMW) organics significant permeate side fouling may be expected. PMID- 30404049 TI - Amelanotic Meningeal Melanoma with Leptomeningeal Dissemination: A Case Report and Systematic Literature Review. AB - BACKGROUND: Meningeal melanoma is a rare tumor of the central nervous system, whose amelanotic variant is the so-called 'amelanotic meningeal melanoma (AMM)'. AMM does not produce melanin and therefore does not exhibit typical short-T1 and short-T2 signal on MRI, and thus can be easily misdiagnosed and be inappropriately managed. To date, only four AMM cases were reported in English literature, here we reported the fifth case. CASE DESCRIPTION: A 26-year-old female presented with a 4-month history of progressive headache and nausea, the conventional MRI demonstrated a posterior fossa mass accompanied by diffuse leptomeningeal dissemination. Repeated cerebrospinal fluid cytology screening showed negative results. The functional MR examinations including diffusion weighted imaging (DWI), proton MR spectroscopy (1H-MRS) and dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI) provided complementary information. The final diagnosis of amelanotic meningeal melanoma was made by immunohistochemistry. Despite gross total excision of the tumor, the disease progressed, and the patient died 10 months after diagnosis. CONCLUSIONS: Our experience with this case demonstrated that meningeal melanoma should be included in the differential diagnosis when an intracranial mass is accompanied by leptomeningeal dissemination, and especially when 1H-MRS and DSC-PWI indicate a malignant tumor whereas DWI does not. And the loss of a typical melanin signal should not server as an excluding criterion for meningeal melanoma. PMID- 30404050 TI - Ankylosing Spondylitis Manifested by Extensive Cervical Erosions with Spontaneous Anterior Atlantoaxial Subluxation. AB - PURPOSE: We present a rare case of atlantoaxial instability as a result of bone erosions in a patient with ankylosing spondylitis and review the literature. We describe the radiographic characters, pathology and treatment of the case, hoping to shed light on the rare clinical manifestation. METHODS: We present a case of a 36-year-old male with an 8-year history of ankylosing spondylitis with a progressive neck pain, low back pain, hand numbness and motion limitation of neck. Cervical radiography showed anterior atlantoaxial subluxation with bone erosions at the odontoid process, mass lateral of atlas and edge of vertebrae. The patient was diagnosed as ankylosing spondylitis according to the modified New York criteria and underwent a posterior C0 to C6 occipitocervical arthrodesis surgery and C3 to C6 laminectomy to reconstruct atlantoaxial stability and relieve cervical compression. RESULTS: The symptoms of neck pain and hand numbness improved at the 1-year follow-up, and the patient completely resumed normal activities. Imaging examinations showed the realignment of C1-2 with complete decompression of spinal cord and fusion of atlantooccipital joint. The internal fixation has remained stable and progressive bone erosions changes were not found after the surgery. CONCLUSIONS: Extensive cervical erosions with spontaneous atlantoaxial subluxation in ankylosing spondylitis is extremely rare. The erosive change of atlantoaxial bone may be an early feature of ankylosing spondylitis. Cervical spine radiographic examination are essential for ankylosing spondylitis patients with neck pain. Complete decompression and internal fixation are necessary to prevent serious neurological morbidity from spinal cord injury for such patients. PMID- 30404051 TI - Surgical Management of Moderate Basal Ganglia Intracerebral Hemorrhage: Comparison of Safety and Efficacy of Endoscopic Surgery, Minimally Invasive Puncture and Drainage, and Craniotomy. AB - OBJECTIVE: To date, no standard surgical procedure has been proven effective for intracerebral hemorrhage (ICH), particularly deep hematomas. This retrospective study evaluated the effectiveness and safety of endoscopic surgery, minimally invasive puncture and drainage, and craniotomy for treating moderate basal ganglia ICH. METHODS: Patients with basal ganglia ICH (N = 177) were divided into 3 groups based on therapeutic intervention as follows: endoscopic surgery group (n = 61), minimally invasive puncture and drainage group (n = 60), and craniotomy group (n = 56). Patient characteristics at admission were recorded. Operative time; blood loss during operation; evacuation rate; postoperative complications secondary to perihematomal edema, including rebleeding, infectious meningitis, pulmonary infection, gastrointestinal bleeding, and epilepsy; mortality; and Glasgow Outcome Scale scores were compared among the 3 groups. RESULTS: Minimally invasive puncture and drainage was the least traumatic procedure and had the shortest operative time, but it could not remove the hematoma quickly; moreover, it had the highest rebleeding rate. Craniotomy was effective in removing the hematoma but resulted in marked trauma and had the highest incidence of pulmonary infection. Endoscopic surgery was safer and more effective than the other 2 surgical methods, with greater improvement in neurologic outcomes and no change in mortality. CONCLUSIONS: Minimally invasive neuroendoscopic management has the advantages of direct vision, efficient hematoma evacuation, and relatively good results. Endoscopic surgery may be a more promising approach for the treatment of moderate basal ganglia ICH. PMID- 30404052 TI - Stereotactic Aspiration of Necrotic Brain Tissue for treating Malignant Middle Cerebral Artery Infarction: A Report of 13 consecutive Cases. AB - OBJECTIVE: This study aimed to evaluate the efficacy and safety of stereotactic aspiration of necrotic brain tissue for treating malignant middle cerebral artery infarction (MMI) in patients older than 60 years of age. METHODS: A total of 13 consecutive patients with MMI, with the mean age of 67+/-6.62 years, were enrolled in the study. These patients were treated with stereotactic aspiration of necrotic brain tissue within 72h from stroke onset between January 2016 and June 2017. The surgical results and clinical outcomes were evaluated in response to stereotactic aspiration of necrotic brain tissue. RESULTS: The mean pre operative infarction volume in the patients was found to be 153.46+/-9.39ml according to the latest computed tomography(CT). The 30-day mortality was 2 out of 13 patients (15.4%). Patients were followed up for 6 months to evaluate the efficacy of stereotactic aspiration of necrotic brain tissue using modified Rankin Scale (mRS). Among the 11 surviving surgical patients, 6 (54.5%)had mRS of 3 (defined as moderate disability) , 4 (36.4%) had mRS of 4(defined as moderately severe disability) , and 1 (9.1%) had mRS of 5 (defined as severe disability) . The probability of 6-month unfavorable outcome, defined as mRS 5 or 6 (death), was 3 out of 13(23.1%). CONCLUSIONS: Our results suggest the stereotactic aspiration of necrotic brain tissue is an effective and safe method in MMI patients over 60 years of age. PMID- 30404053 TI - Learning Curve for Lumbar Decompressive Laminectomy in Biportal Endoscopic Spinal Surgery Using the Cumulative Summation Test for Learning Curve. AB - OBJECTIVE: The purpose of the present study was to determine the learning curve for biportal endoscopic spinal surgery (BESS) for decompressive laminectomy in lumbar spinal stenosis using a learning curve cumulative summation test (LC CUSUM). METHODS: The surgeon was proficient in open and microscopic decompressive laminectomy in lumbar spinal stenosis but did not have any experience with BESS or other endoscopic surgery techniques. The learning curve of BESS was investigated using LC-CUSUM analysis. Procedure success was defined as an operative time <75 minutes, the mean operative time with microscopic decompression laminectomy. RESULTS: The present study included the first 60 patients who had undergone single-level decompressive laminectomy using BESS by a single orthopedic surgeon. The mean operative time for decompressive laminectomy by BESS was 83.8 +/- 37.9 minutes. The mean operative time in the early learning period (<=30 cases) and late learning period (second 30 cases) was 105.3 +/- 39.7 minutes and 62.4 +/- 19.9 minutes, respectively. The overall complication rate was ~10%. The LC-CUSUM signaled competency for surgery at the 58th operation, indicating that sufficient evidence had accumulated to prove that the surgeon was competent. Thus, a trainee with no experience with BESS had reached adequate performance at 58 cases. CONCLUSIONS: The results of the present study have demonstrated that a substantial learning period could be needed before adequate performance can be achieved with lumbar decompressive laminectomy using BESS. PMID- 30404054 TI - Placement of Ommaya Reservoirs using Electromagnetic Neuronavigation and Neuroendoscopy: A retrospective study with cost-benefit analysis. AB - OBJECTIVE: Placement of intraventricular catheters in oncology patients is associated with high complication rates. Placing Ommaya reservoirs with the Zero Error Precision Protocol (ZEPP), a combination of neuronavigation (AxiEM stealth frameless neuronavigation system) and direct verification of catheter tip placement with a flexible neuroendoscope is associated with decreased complication rates as a result of increased catheter placement accuracy. However, ZEPP costs more than traditional methods of catheter placement and the question of whether this increased accuracy with ZEPP is cost-effective is unknown METHODS: We performed a single-center retrospective chart review of 50 consecutive Ommaya reservoir patient placements between 2010 and 2017. Twenty five ventricular catheters were placed using the ZEPP protocol and 25 ventricular catheters were placed using only AxiEM stealth navigation. Postoperative catheter accuracy and complication rates were assessed. A cost-benefit analysis was then conducted to determine if the overall cost for placing ommayas with ZEPP was effective compared to the alternative method of using neuronavigation alone. RESULTS: In the non-ZEPP cohort, 10/25 catheters were placed within the optimal location compared to 25/25 catheters placed in with the ZEPP cohort. Three complications occurred in the non-ZEPP cohort: two malpositioned catheters requiring surgical revision and one catheter related hemorrhage resulting in a prolonged stay in the intensive care unit. No complications occurred in the ZEPP cohort. A Cost-benefit analysis showed $4,784 savings (US dollars) per patient with ZEPP utilization due to the high complication-associated costs. CONCLUSIONS: Implementation of a combined neuronavigation and neuroendoscopic protocol (ZEPP) for verifying ventricular catheter placement in Ommaya reservoirs improved catheter tip accuracy, resulted in lower complication rates, and was more cost effective when compared to the non-ZEPP cohort who used only neuronavigation. ZEPP can be used for ventricular shunt catheter placement in order to decrease complications and verify catheter tip accuracy in Ommaya or standard ventriculoperitoneal shunts. PMID- 30404055 TI - Pulsed Radiofrequency Versus Continuous Radiofrequency for Facet Joint Low Back Pain: A Systematic Review. AB - OBJECTIVE: Compare pulsed radiofrequency treatment (PRF) with continuous radiofrequency treatment (CRF) to improve pain, functionality, and safety profile in patients with facet joint CLBP. METHODS: A systematic and critical review of recent literature was conducted in accordance with the PRISMA guidelines. The sources of the data were PubMed, Embase, Cochrane, Clinical Trials, and Lilacs. The MeSH terms were: "low back pain," "zygapophyseal joint" and "pulsed radiofrequency treatment." Papers included in the review were original research articles in peer-reviewed journals. The articles were thoroughly examined and compared on the basis of study design and outcomes. Only studies that met the eligibility criteria were included. OUTCOMES: Three randomized clinical trials (RCTs), with a total of 103 patients (39 in the PRF group, 44 in the CRF group, and 20 in the control group were included in the final analysis. Among the three trials, two compared PRF with CRF, and one trial compared three groups: PRF, CRF, and Control with intervention as conventional treatment. The studies reported greater pain control and better functionality with CRF compared to PRF. PRF showed a decrease in Visual Analogue Scale (VAS) and Oswestry disability index (ODI) in two studies, and one study reported increased pain and disability after the intervention. No side effects were reported. CONCLUSION: The PRF treatment is less effective than CRF regarding pain control and the return of functionality in patients with facet joint CLBP. We recommend the CRF after conventional treatment with a large safety profile. PMID- 30404056 TI - Description of a Modified Technique (mini craniotomy-basal membranotomy) for Chronic Subdural Hematoma Surgery and Evaluation of the Contribution of Basal Membranotomy Performed as Part of This Technique to Cerebral Expansion. AB - OBJECTIVE: To determine the effectiveness of basal membranotomy performed to ensure cerebral expansion in patients operated for chronic subdural hematoma. METHODS: Patients who were operated for unilateral chronic subdural hematoma and underwent basal membranotomy in addition to hematoma drainage were included in the first phase of the study. After the superficial membranous structures were excised, the maximum perpendicular distance between the internal tabula and the cerebral surface was measured after subdural hematoma evacuation. Subsequently, basal membranotomy was performed, the maximum perpendicular distance between the internal tabula and the cerebral surface was measured again, and the improvement in cerebral expansion was statistically calculated. The improvement of cerebral expansion in the patients who had undergone double burr hole drainage was statistically calculated in the second stage of the study. RESULTS: The cerebral expansion after the basal membrane excision was 41.1% in those with a 1.5- to 2 cm hematoma, 43.1% in those with a 2.1- to 3-cm hematoma, 43.5% in those with a 3.1- to 4-cm hematoma, and 45.4% in those with a hematoma thicker than 4 cm on average. No recurrence was seen during the 6-month follow-up in any patient. Double burr hole drainage revealed similar values for cerebral expansion increase with a mean value of 10%. The burr hole drainage was repeated because of recurrence in 5 patients during the 2-month follow-up. CONCLUSIONS: The mini craniotomy-basal membranotomy technique provided statistically significantly better cerebral expansion in patients with chronic subdural hematoma when compared with the double burr hole drainage technique. PMID- 30404057 TI - Sellar Atypical Teratoid/Rhabdoid Tumor Presenting with Subarachnoid and Intraventricular Hemorrhage. AB - BACKGROUND: Atypical teratoid/rhabdoid tumors (ATRT) are uncommon malignancies of the central nervous system and often difficult to distinguish radiographically and pathologically from other common tumors. In this report, we present the first case of sellar ATRT presenting with subarachnoid (SAH) and intraventricular (IVH) hemorrhage. CASE DESCRIPTION: A 62 year-old female presented with symptoms of headache, diabetes insipidus, hypothyroidism, and seizures was found to have a sellar tumor with hemorrhagic transformation. Surgical resection was undertaken with pathology consistent with ATRT. Despite early surgical intervention, she later expired before being able to start craniospinal radiation and chemotherapy. CONCLUSION: Although known to present with intratumoral hemorrhage, to date no cases of ATRT presenting with SAH or IVH have been reported in the literature. Considering our report that ATRT can present with SAH and IVH, establishing the correct diagnosis via radiographic imaging, gender, pathology and molecular markers is paramount for speedy treatment and management. PMID- 30404058 TI - Reporting Interim Results Can Show the Feasibility of Practicing Outcome-Based Neurovascular Care Within Randomized Trials: An Opinion. AB - BACKGROUND: Randomized trials of commonly performed surgical interventions are notoriously difficult to conduct. The trial methodology may nevertheless be the best way to offer outcome-based neurovascular care in the presence of uncertainty. One obstacle to promoting such trials is the conventional prohibition of publication and dissemination of interim results as the trial progresses. METHODS: We review the scientific and statistical reasons against the publication of interim analyses as well as exceptions that can occur when 1 treatment is unexpectedly shown to be harmful or when the results of other trials have convincingly shown the comparative benefits of a new intervention. We also discuss the promotion of difficult surgical trials. RESULTS: Reasons to support the conventional ban on publication of interim results include control of statistical errors, prevention of invalid conclusions, and dissemination of false claims of equivalence of rival interventions. In the early phases of a trial, usually 1 treatment cannot be shown superior to the other. We believe, contrary to the received view, that a transparent report of the early progress of certain trials can be justified, even when interim results are inconclusive, to promote the recruitment of participating centers and the practice of a novel way to offer neurovascular care in the presence of uncertainty in the best medical interest of patients. CONCLUSIONS: In our opinion, the early publication of inconclusive interim results may increase awareness of the feasibility of surgical care trials. PMID- 30404059 TI - Epidemiology of Moyamoya Disease in China: Single-Center, Population-Based Study. AB - BACKGROUND: To our knowledge, no previous study has described the nationwide epidemiologic features of moyamoya disease (MMD) in China. We describe the epidemiologic features including the relative prevalence, age distribution, gender distribution, and initial clinical manifestations of patients with MMD treated at a single institution in China. METHODS: Our cohort included 4128 patients with MMD. Their demographic and clinical characteristics were obtained by retrospective chart review. RESULTS: The median age for the onset of symptoms was 30.36 years. The age distribution of patients with MMD was bimodal, with the highest peak detection rate at 35-45 years of age and a smaller peak at 5-9 years of age. The ratio of female-to-male patients was 1:1. The disease occurred mainly in the Han people and was rarely seen in minority nationalities. In our cohort, transient ischemic attack was the most common initial clinical manifestation (48.13%). The other initial manifestations included infarction (22.62%), hemorrhage (16.45%), and headache 230/4128 (5.57%). In north and northeast China, the ischemic type was more predominate while the hemorrhagic type was relatively rare. However, the percentage of hemorrhagic type in East China was higher than anywhere else in China. CONCLUSIONS: This study confirmed some unique epidemiologic features as the studies previously reported in China, but it also revealed some new sight and tendency about moyamoya in China. As a lack of national epidemiologic studies, this study indicated the outline of moyamoya in China. PMID- 30404060 TI - Muscle Forehead Flap: a salvage surgery for closure of cutaneous fistula after cranioplasty exposure. PMID- 30404061 TI - Cage Subsidence and Fusion Rate in Extreme Lateral Interbody Fusion with and without Fixation. AB - OBJECTIVE: To examine the subsidence rate in patients undergoing extreme lateral interbody fusion (XLIF) using data from a 2-year retrospective study to assess the effect of supplemental fixation on the stand-alone procedure. METHODS: Demographic and perioperative data for all patients who underwent XLIF for degenerative lumbar disorders between June 2012 and January 2016 were collected and divided into 4 groups: the stand-alone (SA), lateral fixation, unilateral pedicle screw, and bilateral pedicle screw (BPS) groups. The disk height (DH), lumbar lordotic (LL) angle, and segmental lordotic (SL) angle were measured preoperatively and 3 days, 3 months, 1 year, and 2 years postoperatively. Clinical outcomes were evaluated using Japanese Orthopaedic Association (JOA) and visual analog scale (VAS) scores. Fusion was defined according to computed tomography scan. RESULTS: There were 126 vertebrae in 107 patients treated. SL angle, LL angle, and DH significantly increased postoperatively in all groups. Although the preoperative and 2-year postoperative DHs in the SA group were similar, the other measures showed significant differences from baseline at each follow-up visit. No significant effects on SL angle or DH were found in any of the groups. A significant difference in the LL angle was found in the BPS group compared with the other groups. At the last follow-up, high-grade subsidence was found in 26.89% of all cases, the fusion rate was 85.71%, and the VAS and JOA scores were significantly improved in all groups. CONCLUSIONS: Supplemental fixation did not significantly influence cage subsidence or SL angle. Only BPS fixation significantly improved the LL angle. The 2-year fusion rate was satisfactory. PMID- 30404062 TI - Retromedullary Hemangioblastoma Mimicking a PICA Aneurysm: Case Report & Literature Review. AB - BACKGROUND: Hemangioblastomas (HBMs) are benign vascular neoplasms that most commonly arise within the cerebellum. While other vascular lesions should be considered in the differential diagnosis, HBMs rarely resemble aneurysms on neuroimaging and only one case of a cerebellar HBM mimicking a posterior fossa aneurysm has been reported. Here we describe a retromedullary HBM that masqueraded as a distal posterior inferior cerebellar artery (PICA) medullary branch aneurysm. CASE DESCRIPTION: A 63-year-old asymptomatic male was incidentally diagnosed with an unruptured 3-mm left PICA aneurysm via CT angiography (CTA) during a workup for carotid stenosis. Two years later, the presumed aneurysm enlarged to 6.5-mm and prompted elective treatment. Endovascular treatment was unsuccessful, and the patient was immediately transitioned to a craniotomy for aneurysm clipping. After microsurgical dissection, the lesion was visualized on the posterior medullary surface with several small arterial feeders extending from the brainstem into the aneurysm dome, but no major parent vessel was observed. Since a clip could not be safely applied to these small vessels, they were instead coagulated and the lesion was completely resected. Final pathology revealed hemangioblastoma (WHO Grade I). CONCLUSIONS: To our knowledge, this is the second case of HBM mimicking a PICA aneurysm. Given the rarity of PICA medullary branch aneurysms and their highly symptomatic nature, other etiologies, especially HBM, should be strongly considered when an apparent distal PICA aneurysm is diagnosed in an asymptomatic patient. If the lesion is unamenable to endovascular treatment, there should be high suspicion for HBM and subsequent craniotomy should be pursued. PMID- 30404063 TI - Successful emergent endovascular mechanical thrombectomy for pediatric and young adult cerebral venous sinus thrombosis in coma. AB - BACKGROUND: Cerebral venous sinus thrombosis (CVST) is a relatively uncommon cause of stroke in pediatric and young adult. The clinical course of CVST is also highly variable. In particular, coma has been noted as a predictor of poor outcome. The standard treatment for CVST in adults is systemic anticoagulation, which can lead to recanalization. Endovascular mechanical thrombectomy (EMT) is considered as possibly indicated in the event of failure to respond to anticoagulation or a comatose state. However, the role of endovascular therapy in the management of pediatric and young CVST is unclear. Here, we describe three cases of successful emergent EMT for pediatric and young CVST presenting in a comatose state. CASE DESCRIPTION: A 17-year-old boy presented with rapid deterioration and comatose state despite anticoagulation using heparin. Emergent EMT was performed for CVST. Balloon percutaneous transmural angioplasty (PTA) and catheter aspiration were repeatedly performed and partial recanalization of the superior sagittal sinus (SSS) was achieved by the end of the procedure. The child was discharged without neurological deficits. Another 2 comatose cases with CVST underwent emergent EMT with balloon PTA and catheter aspiration and partial recanalization was again achieved. These patients finally showed complete SSS recanalization and were discharged without neurological deficits. CONCLUSION: Pediatric and young comatose CVST warrants endovascular mechanical thrombectomy as soon as possible. PMID- 30404064 TI - Variability in Clinical Presentation and Pathologic Implications of Ectopic Pituitary Tumors: Critical Review of the Literature. AB - PURPOSE: Pituitary tumors are common, well-described skull base tumors of sellar origin. However, there are reports of rare ectopic pituitary tumors that are found exclusively outside of the sella turcica. Ectopic pituitary tumors have not been holistically analyzed. This study describes presentation and clinical patterns found among patients with ectopic pituitary tumors. METHODS: A comprehensive review of the literature was performed for clinical descriptions of ectopic pituitary tumors. Reports of 85 applicable cases were evaluated. RESULTS: The most common locations of ectopic pituitary tumors were the sphenoid sinus, clivus, suprasellar space, nasopharynx, and cavernous sinus. The majority of ectopic pituitary tumors were reported as being functional secretory tumors; they were statistically significantly more likely to be functional tumors than sellar pituitary tumors. ACTH, PRL, GH, and TSH-secreting tumors were most commonly found. Bone invasion was reported in more than one third of the cases, and malignant transformations were reported in six cases. A large majority of patients presented with hormonal, neurological, or physiologic symptoms. CONCLUSIONS: Ectopic pituitary tumors are a rare entity of pituitary tumors with a presentation that can mimic those of other skull base tumors. Clinical presentation often correlates to location of the tumor. Ectopic pituitary tumors were significantly more likely to be functional secretory tumors. They may also exhibit more aggressive behavior than sellar-located tumors. Ectopic pituitary tumors may be part of a spectrum of presenting pathologies. Further genetic or genomic analysis is needed to better understand their pathogenesis and clinical presentations. PMID- 30404065 TI - Dengue Fever Presenting With Cervicodorsal Acute Spinal Spontaneous Subdural Hematoma-Case Report And Review Of Literature. AB - BACKGROUND: Neurological complications are increasingly being reported in dengue epidemics. Intra-spinal hematomas are rare and those associated with dengue fever are still rarer with only one being reported in literature. CASE DESCRIPTION: We report a case of dengue fever presenting with acute onset quadriparesis (upper limbs MRC 4/5 and lower limbs 0/5) and urinary incontinence. Patient was radiologically diagnosed with cervicodorsal acute to subacute anterior epidural hematoma. Based on clinical and radiological evaluations patient underwent an anterior cervical approach with manubriotomy, C6-D4 right anterolateral partial oblique corpectomies for evacuation of hematoma. Intraoperatively however there was no evidence of anterior epidural collection and the dura revealed a bluish hue. A durotomy revealed subdural hematoma. After evacuation of the hematoma patient remained paraplegic and her upper limb power worsened by MRC one grade. Postoperative MRI revealed good evacuation and no new bleed, however the intramedullary T2W signal hyperintensities extending up to C2 persisted. She was on ventilatory support for almost 5 months. For diaphragmatic incapacity she underwent bilateral cervical phrenic nerve stimulation (Diaphragmatic pacing). Inspite of initial improvement she succumbed to multiple underlying comorbidities. CONCLUSIONS: Acute spontaneous SSDH's are extremely rare but should be kept in mind in patients with dengue haemorrhagic fever. The radiological findings could be deceptive and plain CT and MR should be used as complementary studies to establish the diagnosis of Acute spontaneous SSDH. The outcomes of SSDH are guarded and elaborate patient counselling preoperatively should be done keeping these in perspective. PMID- 30404066 TI - Proximal Middle Cerebral Artery Aneurysms: Microsurgical Management and Therapeutic Results. AB - BACKGROUND: Management of proximal (M1) middle cerebral artery (MCA) aneurysms can be challenging. Because of the diversity of aneurysm morphology and location of M1 aneurysms, the surgical strategy should be tailored to each individual case, especially for complex cases. We assessed the safety and efficacy of an algorithmic strategy for the management of M1 aneurysms. METHODS: A prospective single-center study of M1 aneurysms treated with microsurgery was performed. Our algorithmic strategy was determined by the location and complexity (e.g., size, shape) of the aneurysms. The surgical modalities included neck clipping, aneurysm resection and/or trapping, and proximal occlusion with revascularization. The clinical and radiographic data were analyzed. RESULTS: From January 2007 to March 2017, 92 proximal MCA aneurysms in 92 patients were treated microsurgically. Aneurysm treatment techniques included clipping in 55, proximal occlusion in 21, aneurysm resection in 11, and trapping in 4. Bypass techniques included 2 anterior temporal artery reconstructions, 5 middle cerebral bifurcation reconstructions, 4 parent artery reanastomoses, 2 interpositional bypasses, 25 high-flow bypasses, and 7 medium-flow bypasses. Overall, good outcomes (modified Rankin scale score, 0-2) were seen in 49 of 92 patients (53.3%) at discharge and in 79 of 91 (86.8%) at the last follow-up visit. On the latest angiogram, 78 of 90 aneurysms (86.7%) had been completely occluded without a remnant. Bypass patency was confirmed in 38 of 43 bypass procedures. CONCLUSIONS: Our present treating strategy might provide a benefit for patients with proximal MCA aneurysms. PMID- 30404067 TI - Anterior Communicating Artery Complex Aneurysms: Anatomic Characteristics as Predictors of Surgical Outcome in 300 Cases. AB - OBJECTIVE: Anterior communicating artery (ACoA) complex aneurysms are challenging to treat microsurgically. The authors report their experience with microsurgical treatment of ACoA aneurysms and examine the anatomic characteristics of these aneurysms as predictors of outcome. METHODS: The authors queried their institution's aneurysm database for records of consecutive patients treated for ACoA aneurysms via microsurgical clip ligation. Data included patient demographics and clinical/radiographic presentation characteristics as well as operative techniques. Glasgow Outcome Scale (GOS) scores at hospital discharge and 6-month as well as 1-year follow-up were analyzed. RESULTS: Of 319 ACoA aneurysms that underwent treatment, 259 were ruptured and 60 were unruptured. Average GOS at 1-year follow-up for all patients was 4.6. Average GOS for patients with ruptured aneurysms correlated with Hunt and Hess grade at presentation, presence of frontal hemorrhages, and need for multiple clips during surgery. Notably, 142 (44.5%) of aneurysms originated mainly from the ACoA artery; 12 (3.8%) primarily from the A1 branch; 3 (0.9%) from the A2 branch; and 162 (50.8%) from the A1/A2 junction. Aneurysm projection was superior in 118 (37%), inferior in 106 (33.2%), anterior in 88 (27.6%), and posterior in 7 (2.2%). Patients with aneurysms originating from the A1 segment had worse outcomes. Posteriorly projecting aneurysms were more likely to be unruptured and larger than other aneurysm configurations. CONCLUSIONS: The aneurysm's exact location in relation to the adjacent neurovascular structures is potentially predictive of outcomes in the microsurgical treatment of ACoA aneurysms. PMID- 30404069 TI - Taguchi design-based enhancement of heavy metals bioremoval by agroindustrial waste biomass from artichoke. AB - The Taguchi method of designing experiments is based on a system of tabulated designs (arrays) that enables the maximum number of variables to be estimated in a neutral (orthogonal) balanced manner with a minimum number of experimental sets. Heavy metals remediation of aqueous streams is of special concern due to its highly toxic and persistent nature. Taguchi approach was used for enhanced bioadsorptive removal of Pb(II), Cu(II) and Cd(II) from aqueous solutions using agroindustrial waste biomass from globe artichoke as inexpensive sorbent. Sorbent biomass was characterized as to its chemical composition by infrared spectroscopy (FTIR), revealing the presence of hydroxyl, carboxyl, sulphonic and amine functional groups. Ranks of four factors (pH, temperature, sorbent dosage and initial metal concentration) at three levels each, in a L9 array were conducted, in batch sorption tests, for the individual metal ions of concern. The sorption capacity (qe) values were transformed into an accurate signal-to-noise (S/N) ratio for a "higher is better" response. The best conditions for individual heavy metal sorption were determined reaching up to 86.2 mg.g-1 for Pb, 35.8 mg.g-1 for Cd and 24.4 mg.g-1 for Cu. This paper also discusses the equilibria and kinetic aspects of the sorption process. Sorption isotherms were successfully described by the Sips model. In addition, the experimental data showed that the uptake kinetic profiles of the three metal ions closely fitted the pseudo-second order model. Conclusively, the agroindustrial waste biomass from globe artichoke represents a potentially viable sorbent for the bioremoval of Pb(II), Cu(II) and Cd(II) ions from aqueous systems. PMID- 30404068 TI - Inhibition of mTORC2/RICTOR Impairs Melanoma Hepatic Metastasis. AB - Mammalian target of rapamycin complex 2 (mTORC2) with its pivotal component rapamycin-insensitive companion of mTOR (RICTOR) is the major regulator of AKT phosphorylation and is increasingly implicated in tumor growth and progression. In cutaneous melanoma, an extremely aggressive and highly metastatic disease, RICTOR overexpression is involved in tumor development and invasiveness. Therefore, we investigated the impact of RICTOR inhibition in melanoma cells in vitro and in vivo with special emphasis on hepatic metastasis. Moreover, our study focused on the interaction of tumor cells and hepatic stellate cells (HSC) which play a crucial role in the hepatic microenvironment. In silico analysis revealed increased RICTOR expression in melanoma cells and tissues and indicated higher expression in advanced melanoma stages and metastases. In vitro, transient RICTOR knock-down via siRNA caused a significant reduction of tumor cell motility. Using a syngeneic murine splenic injection model, a significant decrease in liver metastasis burden was detected in vivo. Moreover, stimulation of melanoma cells with conditioned medium (CM) from activated HSC or hepatocyte growth factor (HGF) led to a significant induction of AKT phosphorylation and tumor cell motility. Blocking of RICTOR expression in cancer cells diminished constitutive and HGF-induced AKT phosphorylation as well as cell motility. Interestingly, RICTOR blockade also led to an abrogation of CM-induced effects on AKT phosphorylation and motility in melanoma cells. In conclusion, these results provide first evidence for a critical role of mTORC2/RICTOR in melanoma liver metastasis via cancer cell/HSC interactions. PMID- 30404070 TI - Selective adsorption and bioavailability relevance of the cyclic organics in anaerobic pretreated coal pyrolysis wastewater by lignite activated coke. AB - This study originally investigated the selective adsorption of cyclic organics in APCPW by LAC, corresponding to the change of the bioavailability. As a product from low rank coal, LAC showed more oxygen (O)-containing groups and mesoporous structure than PAC. Adsorption mechanisms were analyzed by equilibrium isotherms and kinetics models combined with physicochemical properties of adsorbent and adsorbates. The results indicated that selectivity of LAC was dominated by chemical interaction and its mesoporous, and was enhanced by hydrophobicity of adsorbates. In addition, PAC and LAC were applied for the treatment of APCPW. Compared with PAC, LAC adsorption exhibited superior removal efficiency of Tph, TOC and TN at 85.90%, 91.15% and 51.64%, respectively. Furthermore, preferential adsorption of biotoxic and bioresistant cyclic organics by LAC was further proved by GC-MS analysis, resulting in increased bioavailability of APCPW. Specifically, LAC exerted sustained detoxication capacity until 86.50% reduction of TU by D. magna evaluation, and lowered toxicity rank (TU = 4.51, classIII) to T. pyriformis than that after PAC adsorption (TU > 10, ClassIV). Meanwhile, biodegradability was also improved by 9.17% after LAC adsorption. Lastly, LAC would exhibit great economic benefits as an alternative for PAC in subsequent process after anaerobic pretreatment. PMID- 30404071 TI - The renin-angiotensin system as a target to solve the riddle of endocrine pancreas homeostasis. AB - Local renin-angiotensin system (RAS) in the pancreas is linked to the modulation of glucose-stimulated insulin secretion (GSIS) in beta cells and insulin sensitivity in target tissues, emerging as a promising tool in the prevention and/or treatment of obesity, diabetes, and systemic arterial hypertension. Insulin resistance alters pancreatic islet cell distribution and morphology and hypertrophied islets exhibit upregulated angiotensin II type 1 receptor, which drives oxidative stress, apoptosis, and fibrosis, configuring beta cell dysfunction and diminishing islet lifespan. Pharmacological modulation of RAS has shown beneficial effects in diet-induced obesity model, mainly related to the translational potential that angiotensin receptor blockers and ECA2/ANG (1-7)/MAS receptor axis modulation have when it comes to islet preservation and type 2 diabetes prevention and/or treatment. This review describes the existing evidence for different approaches to blocking RAS elements in the management of insulin resistance and diabetes and focuses on islet remodeling and GSIS in rodents and humans. PMID- 30404072 TI - Tabernaemontana catharinensis leaves effectively reduce the irritant contact dermatitis by glucocorticoid receptor-dependent pathway in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Tabernaemontana catharinensis, popularly known as snakeskin, is used in traditional medicine to treat skin inflammatory disorders. To confirm the topical anti-inflammatory effect of T. catharinensis leaves, we evaluated the therapeutic effect of crude extract (TcE) and its different fractions on irritant contact dermatitis model in mice and verified its anti inflammatory action mechanism. MATERIALS AND METHODS: The qualitative phytochemical analysis of TcE and its dichloromethane, n-butanol and ethyl acetate fractions was performed by UHPLC-ESI-HRMS. The gel accelerated stability was performed to ensure the effectiveness formulation. We investigated the TcE' inhibitory effect, its fractions and a gel formulation containing TcE in irritant contact dermatitis models induced by unique (1000 MUg/ear) and multiple (400 MUg/ear) croton oil application, evaluated by the ear edema formation, inflammatory cell infiltration (MPO activity measurement and histological procedure) and pro-inflammatory cytokines levels. The action glucocorticoid-like of TcE was investigated using a glucocorticoid receptor antagonist (mifepristone; 50 mg/kg, s.c.). RESULTS: The treatments (10 MUg/ear) reduced the ear edema and MPO activity by 100% and 94 +/- 3% (TcE) 85 +/- 4% and 88 +/- 3% (dichloromethane fraction), 83 +/- 6% and 73 +/- 11% (n-butanol fraction) and 86 +/- 6% and 93 +/- 4% (ethyl acetate fraction) and 100% (dexamethasone solution), respectively to the acute ICD model. The TcE and dexamethasone gel (15 mg/ear) also reduced by 66 +/- 6% and 70 +/- 5% the ear edema and by 58 +/- 14% and 84 +/- 4% the MPO activity, respectively. To the chronic ICD model, the TcE and dexamethasone (10 MUg/ear) also reduced the ear edema (66 +/- 6% and 70 +/- 5%) and the MPO activity (58 +/- 14% and 84 +/- 4%); on the 9th day of the experiment. TcE and dexamethasone also reduced the pro-inflammatory cytokines (MIP-2, IL-1beta and TNF-alpha) levels in acute ICD model induced by croton oil. Besides, mifepristone prevented the topical anti-edematogenic effect of TcE' and dexamethasone' solutions by 97 +/- 9% to TcE and 75 +/- 15% to dexamethasone. The accelerated stability study of T.catharinensis gels showed no relevant changes at low temperatures. The dereplication of the TcE and fractions revealed the presence of indole alkaloids, triterpenes, and flavonoids by UHPLC-ESI-HRMS. These classes of compounds are known in the literature for present potential anti-inflammatory action, supporting the results obtained. CONCLUSION: The results confirm the topical popular use ofT.catharinensis leaves in the treatment of skin inflammation and demonstrate the TcE' potential for the development of a promising topical anti-inflammatory agent to treat inflammatory disorders. PMID- 30404073 TI - Early administration of empagliflozin preserved heart function in cardiorenal syndrome in rat. AB - This study tested the hypothesis that early administration of empagliflozin (Empa), an inhibitor of glucose recycling in renal tubules, could preserve heart function in cardiorenal syndrome (CRS) in rat. Chronic kidney disease (CKD) was caused by 5/6 subtotal nephrectomy and dilated cardiomyopathy (DCM) by doxorubicin (DOX) treatment. In vitro results showed that protein expressions of cleaved-caspase3 and autophagy activity at 24 h/48 h in NRK-52P cells were significantly upregulated by para-Creso treatment; these were significantly downregulated by Empa treatment. Flow cytometric analysis showed that annexin-V (i.e., early/late apoptosis) in NRK-52P cells expressed an identical pattern to cleaved-caspase3 between the two groups (all p < 0.001). Adult-male-SD rats (n = 18) were equally categorized into group 1 (sham-control), group 2 (CRS) and group 3 [CRS + Empa; 20 mg/kg/day]. By day-42 after CRS induction, left-ventricular ejection fraction (LVEF) level exhibited an opposite pattern, whereas LV end diastolic dimension and creatinine level displayed the same pattern, to cleaved caspase3 among the three groups (all p < 0.0001). In LV tissues, protein expressions of inflammatory (tumor-necrosis factor-alpha/nuclear-factor kappaB/interleukin-1beta/matrix-metalloprotianse-9), oxidative stress (NOX-1/NOX 2/oxidized protein), apoptotic (mitochondrial-Bax/cleaved-caspase-3/cleaved PARP), fibrotic (transforming-growth factor-beta/Smad3), DNA/mitochondrial-damage (gamma-H2AX/cytosolic-cytochrome-C) and heart failure (brain natriuretic peptide (BNP) levels displayed an opposite pattern to LVEF among the three groups (all p < 0.0001). Additionally, cellular expressions of DNA-damage/heart-failure (gamma H2AX+//XRCC1+CD90+//BNP+) biomarkers and histopathological findings of fibrotic/condensed collagen-deposition areas and apoptotic nuclei showed an identical pattern, whereas connexin43 and small-vessel number exhibited an opposite pattern, to inflammation among the three groups (all p < 0.0001). In conclusion, Empa therapy protected heart and kidney against CRS injury. PMID- 30404074 TI - Electrochemical degradation of insecticide hexazinone with Bi-doped PbO2 electrode: Influencing factors, intermediates and degradation mechanism. AB - Electrochemical degradation of hexazinone in aqueous solution using Bi-doped PbO2 electrodes as anodes was investigated. The main influencing parameters on the electrocatalytic degradation of hexazinone were analyzed as function of initial hexazinone concentration, current density, initial pH value and Na2SO4 concentration. The experiment results showed that the electrochemical oxidization reaction of hexazinone fitted pseudo-first-order kinetics model. 99.9% of hexazinone can be decontaminated using Bi-doped PbO2 electrode as anode for 120 min. Comparing with pure PbO2 electrode, the Bi-doped PbO2 electrodes possess higher hexazinone and COD removal ratio, higher ICE and lower energy consumption in the electrocatalytic degradation process. The results revealed that electrochemical oxidation using Bi-doped PbO2 anodes was an efficient method for the elimination of hexazinone in aqueous solution. The electrocatalytic oxidization mechanism of hexazinone with Bi-doped PbO2 anode was discussed, then the possible degradation pathway of hexazinone with two parallel sub-routes was elucidated according to 15 intermediates identified using HPLC-MS. PMID- 30404075 TI - Bioaccumulation and trophic transfer of total mercury in the subtropical Olifants River Basin, South Africa. AB - The present study describes total mercury (THg) levels in surface water, sediment and biota from the Olifants River Basin (ORB) (South Africa) and investigates the trophic transfer of THg by means of trophic magnification factors (TMFs) in the subtropical ORB food web. Although levels in surface water, sediment and invertebrates were low, elevated levels of THg were measured in fish species of higher trophic levels (0.10-6.1 MUg/g dw). This finding supports the biomagnificative character of mercury. THg concentrations in fish from the present study were find to be higher than most values reported in fish from other African aquatic ecosystems and comparable or lower compared to more industrialized regions. Fish length, trophic level, sediment THg levels and TOC in sediment were determining factors for THg levels in fish tissue. Concentrations were found to be higher in larger (and older) fish. Mercury has a high affinity for organic matter and will bind with the TOC in sediment, thus reducing the bioavailability of THg for aquatic biota which is reflected in the significant negative correlation between THg and TOC in sediment. A significant positive relationship between relative trophic level and THg concentrations was observed and also TMFs indicate biomagnification in the ORB food web. However, the trend of lower TMFs in tropical areas compared to temperate and arctic regions was not supported by the results. The consumption of fish from higher trophic levels at the average South African consumption rate is expected to pose a significant health risk. PMID- 30404077 TI - Carbon Monoxide Releasing Molecule 3 Inhibits Osteoclastogenic Differentiation of RAW264.7 Cells by Heme Oxygenase-1. AB - BACKGROUND/AIMS: Increased osteoclastogenic differentiation may disrupt the balance of bone resorption and formation, giving rise to bone defective disease. The study aimed to investigate the influence of carbon monoxide releasing molecule 3 on osteoclastogenic differentiation of RAW264.7 cells, and explore the possible mechanism underlying the regulatory effect. METHODS: Influence of CORM-3 on the proliferation of RAW264.7 cells was determined by CCK-8 assay. RAW264.7 cells were divided into four groups: Control group; Osteoclastogenic differentiation group, in which cells were induced osteoclastogenic differentiation in medium supplemented with 100MUg/L RANKL and 50MUg/L M-CSF; Degassed CORM-3-osteoclastogenic differentiation group, in which cells were pretreated with 200MUmol/L degassed CORM-3 for 6hrs, and then induced osteoclastogenic differentiation; CORM-3-osteoclastogenic differentiation group, in which cells were pretreated with 200MUmol/L CORM-3, and then induced osteoclastogenic differentiation. The mRNA and protein expression of RANK, TRAP, MMP-9, Cts-K and HO-1 of the cells during the osteoclastogenic differentiation was checked by RT-qPCR and Western blot. The induced osteoclasts were identified by TRAP staining. The HO-1 expression of the RAW264.7 cells was silenced by lentivirus transfection, and the expression of RANK, TRAP, MMP-9 and Cts-K was examined by RT-qPCR and Western blot. RESULTS: CORM-3 promoted the proliferation of RAW264.7 cells at the concentration of 200MUmol/L. Pretreatment with CORM-3, but not degassed CORM-3, significantly decreased the mRNA and protein expression of osteoclast-specific marker TRAP, RANK, MMP-9 and Cts-K induced by RANKL and M CSF on day 5, 7 and 9 during the osteoclastogenic differentiation (P< 0.05). After HO-1 was silenced by lentivirus transfection, the mRNA and protein expression of TRAP, RANK, MMP-9 and Cts-K in group with CORM-3 pretreatment maintained the same level as in osteoclastogenic differentiation group. CONCLUSION: CORM-3 inhibits osteoclastogenic differentiation of RAW264.7 cells via releasing CO. The inhibitory effect is mediated partially by HO-1 pathway. The results suggest the potential application of CORM-3 on some bone defective diseases. PMID- 30404076 TI - TPPP3 Promotes Cell Proliferation, Invasion and Tumor Metastasis via STAT3/ Twist1 Pathway in Non-Small-Cell Lung Carcinoma. AB - BACKGROUND/AIMS: Non-small-cell lung carcinoma (NSCLC) is the leading cause of cancer death, with tumor metastasis being mainly responsible for lung cancer associated mortality. Our previous studies have found that tubulin polymerization promoting protein family member 3 (TPPP3) acted as a potential oncogene in NSCLC. Little is known about the function of TPPP3 in tumor metastasis. METHODS: RT-qPCR and IHC were used to investigate the expression of TPPP3 in NSCLC tissues. CCK8 assay and transwell assay were used to measure proliferation and migration of NSCLC cells in vitro and xenograft model was performed to assess the tumor growth and metastasis in vivo. RESULTS: In the present study, upregulation of TPPP3 was found to correlate with an increased metastasis capability of NSCLC. Ectopic expression of TPPP3 significantly enhanced cell proliferation in vitro and promoted tumor growth in vivo. Furthermore, overexpression of TPPP3 remarkably promoted NSCLC cell migration and invasion along with the upregulation of Twist1 both in vitro and in vivo. Further investigations showed that activation of STAT3 was required for TPPP3-mediated upregulation of Twist1, cell migration and invasion. A strong positive correlation between TPPP3 and Twist1 expression was identified in NSCLC tissues. Patients with low TPPP3 or low Twist1 in NSCLC tissues had a better prognosis with longer overall survival (OS) and disease-free survival (DFS). CONCLUSION: Overall, this study demonstrates that TPPP3 promotes the metastasis of NSCLC through the STAT3/Twist1 pathway. PMID- 30404078 TI - Lesions Mimicking Melanoma at Dermoscopy Confirmed Basal Cell Carcinoma: Evaluation with Reflectance Confocal Microscopy. AB - BACKGROUND: Atypical basal cell carcinoma (BCC), characterized by equivocal dermoscopic features typical of malignant melanoma (MM), can be difficult to diagnose. Reflectance confocal microscopy (RCM) enables in vivo imaging at nearly histological resolution. OBJECTIVES: To evaluate with RCM atypical melanocytic lesions identified in dermoscopy, according to common RCM criteria for the differential diagnosis of BCC, and to identify representative RCM parameters for superficial (sBCCs) and nonsuperficial (nsBCCs) basal cell carcinomas (BCCs). METHODS: A retrospective analysis of consecutive patients evaluated with RCM, selecting excised lesions classified at dermoscopy with >=1 score from the re visited 7-point checklist, mimicking melanoma, registered between 2010 and 2016. Cluster analysis identified BCC subclassifications. RESULTS: Of 178 atypical lesions, 34 lesions were diagnosed as BCCs with RCM. Lesions were confirmed BCCs with histopathology. Dermoscopic features included atypical network (55.9%) and regression structures (35.5%) associated with sBCCs, and an atypical vascular pattern (58.8%) and irregular blotches (58.8%) with nsBCCs. Hierarchical cluster analysis identified 2 clusters: cluster 1 (100% sBCCs) was characterized by the presence of cords connected to the epidermis (90%, p < 0.001), tumor islands located in the epidermis (100%, p < 0.001), smaller vascular diameter (100%, p < 0.001) and solar elastosis (90%, p = 0.017), and cluster 2 (nsBCCs 85%) was defined by the dermic location of tumor islands (87.5%, p < 0.001) with branch like structures (70.8%, p = 0.007) and surrounding collagen (83.3%, p = 0.012), peripheral palisading (83.3%, p = 0.012) and coiled vascular morphology (79.2%, p < 0.001) with a larger vascular diameter (50%, p < 0.001). CONCLUSIONS: RCM is able to diagnose BCCs mimicking melanoma at dermoscopy and seems able to identify sBCCs and nsBCCs. PMID- 30404079 TI - EEG and Clinical Factors Associated with Mild Cognitive Impairment in Coronary Artery Disease Patients. AB - BACKGROUND: Although an impaired cognitive status in patients with coronary artery disease (CAD) is not rare, the neurophysiological and clinical indicators of mild cognitive impairment (MCI) have been insufficiently investigated so far. METHODS: EEG and neuropsychological testing as well as clinical examination were performed on 122 patients with CAD, who were divided into two groups, those with MCI (n = 60; mean age 57.4 +/- 5.81 years) and those without MCI (n = 62; mean age 57.0 +/- 5.04 years). Binary logistic regression was used to identify the relationship between EEG and clinical variables and the probability of MCI. RESULTS: Higher theta/alpha ratios, theta1 rhythm power with closed eyes in the frontal and occipital areas of the left hemisphere, and alpha2 rhythm power with eyes open in the frontal areas of the right hemisphere were associated with an increased risk for MCI in CAD patients. A low educational level, type 2 diabetes mellitus, and severe coronary lesions according to the SYNTAX Score (>=23 points) increased the risk for MCI as well. CONCLUSIONS: The findings of our study show that a theta activity increase in frontal and occipital sites, as well as high theta/alpha ratios, may be considered as the earliest EEG markers of vascular cognitive disorders. PMID- 30404080 TI - Enteral Baicalin, a Flavone Glycoside, Reduces Indicators of Cardiac Surgery Associated Acute Kidney Injury in Rats. AB - BACKGROUND/AIMS: Cardiac surgery-associated acute kidney injury (CSA-AKI) is one of the most common postoperative complications in intensive care medicine. Baicalin has been shown to have anti-inflammatory and antioxidant roles in various disorders. We aimed to test the protective effects of baicalin on CSA-AKI using a rat model. METHODS: Sprague-Dawley rats underwent 75 min of cardiopulmonary bypass (CPB) with 45 min of cardioplegic arrest (CA) to establish the AKI model. Baicalin was administered at different doses intragastrically 1 h before CPB. The control and treated rats were subjected to the evaluation of different kidney injury index and inflammation biomarkers. RESULTS: Baicalin significantly attenuated CPB/CA-induced AKI in rats, as evidenced by the lower levels of serum creatinine, serum NGAL, and Kim1. Baicalin remarkably inhibited oxidative stress, reflected in the decreased malondialdehyde and myeloperoxidase activity, and enhanced superoxide dismutase activity and glutathione in renal tissue. Baicalin suppressed the expression of IL-18 and iNOS, and activated the Nrf2/HO-1 pathway. CONCLUSION: Our data indicated that baicalin mediated CPB/CA induced AKI by decreasing the oxidative stress and inflammation in the renal tissues, and that baicalin possesses the potential to be developed as a therapeutic tool in clinical use for CSA-AKI. PMID- 30404081 TI - Consumer Acceptance and Expectations of a Mobile Health Application to Photograph Skin Lesions for Early Detection of Melanoma. AB - BACKGROUND: Mobile teledermoscopy may facilitate skin self-examinations (SSEs) and further improve monitoring and detection of melanoma. OBJECTIVE: To assess consumer acceptability and expectations of a mobile health app used to: (i) instruct SSE and (ii) conduct consumer-performed mobile teledermoscopy. METHODS: People aged 18 years and above were invited to participate in either (i) an online survey or (ii) focus group in Brisbane, Australia. Participants were asked about their SSE practices, mobile teledermoscopy acceptance, and app design and functionality. The online survey responses and focus group discussions were coded by two researchers who conducted thematic analysis. RESULTS: Four focus groups were held with a total of 28 participants; 88 participants completed the online survey. The mean ages of participants in the focus group and online survey were 46 and 38 years, respectively. There were more males in the focus groups (61%, 17/28) compared to the online survey (19%, 17/88). Regular SSEs were conducted by 56 (64%) of the online survey participants. Barriers to SSE were forgetfulness (44%), low self-perceived risk of melanoma (25%) and low confidence in conducting SSEs (25%). The large majority of online survey participants (95%) would consider sending photos of their skin lesions to a medical practitioner via an app. Focus group participants reported that they would accept using mobile teledermoscopy; however, they would prefer to use it to monitor lesions between face-to-face consultations. CONCLUSIONS: Overall, participants had positive views on using mobile teledermoscopy to send images of skin lesions to a dermatologist or other medical practitioner. PMID- 30404082 TI - Within-Population Variations in Home Range Use and Food Patch Use of Japanese Macaques: A Perspective of Intergroup Hostility. AB - Behavioral mechanisms of intergroup feeding competition remain unclear, despite its importance as a benefit of group living. Japanese macaques in the coastal and highland forests of Yakushima, Japan, are ideal study subjects because the intensity of intergroup feeding competition differs without phylogenetic effects. We aimed to test whether macaques modify home range use and food patch use in response to the location-specific risk of intergroup encounters. Using behavioral data from 3 groups, we examined the border avoidance and the effects of food patch location on food patch use. All 3 groups used the border less frequently than expected from its area. In the coastal forest characterized by frequent intergroup aggression, the smaller subordinate group, not the larger dominant group, increased the number of co-feeding individuals along the border. This response might reduce the potential costs of intergroup aggression. Feeding duration in one patch, visual scanning, and co-feeding with adult males did not depend on food patch location for the 2 groups. In contrast, the highland group did not modify food patch use along the border owing to the low risk of intergroup encounters. Our results highlight the importance of intergroup hostility as a social factor affecting animal behavior. PMID- 30404083 TI - Validation of a Noninvasive Hair Trapping Method for Extractive-Foraging Primates. AB - Hair is a useful source of biological information. For example, the bulb can be a source of high-quality genetic material, whereas the shaft can be useful for measuring heavy metals and some hormones, such as cortisol. The stable isotope composition of hair is another valuable source of biological information. Consequently, noninvasive methods of hair sampling have become important research tools. Several hair-trapping methods have been developed for use on mammals, but these are rarely deployed on primates in part because their travel patterns can be difficult to predict and because many species are averse to novel objects in their environments. Yet if a species has a natural propensity to envision, manipulate, and withdraw extractable food resources, then a baited receptacle lined with double-sided tape may prove successful as a hair trap. Recently, researchers demonstrated the success of such a contraption with tufted capuchins, a Neotropical monkey species with a high degree of somatosensory intelligence and a proclivity for extractive foraging. Here, we replicate this method in a population of tool-using long-tailed macaques (Macaca fascicularis). Our trials validate the effectiveness of the method, suggesting that it is suitable for long tailed macaques and other extractive-foraging primates. PMID- 30404084 TI - A Molecular Epidemiological Investigation of Carriage of the Adeno-Associated Virus in Murine Rodents and House Shrews in China. AB - OBJECTIVE: To investigate the prevalence of the adeno-associated virus (AAV) in murine rodents and house shrews in 4 provinces of China. METHODS: A total of 469 murine rodents and 19 house shrews were captured between May 2015 and May 2017. Cap gene of AAV sequences was obtained to evaluate the genetic characteristics of rat AAV. RESULTS: Rat AAVs were found in 54.7% (267/488) of throat swabs, 14.3% (70/488) of fecal samples, and 18.4% (41/223) of serum samples. Rat AAVs were detected in 3 species of murine rodents including Rattus norvegicus (34.8%), R. tanezumi (43.0%), and R. losea (2.3%), and house shrews (Suncus murinus) (26.1%) from the selected sampling sites. Fourteen near-full-length Cap gene sequences, ranging in length from 2,156 to 2,169 nt, were isolated from the fecal samples of R. norvegicus and R. tanezumi. These 14 sequences shared a high identity of 97.4% at the nucleotide level and 99.1% at the amino acid level. Phylogenetic analysis showed that the rat AAV formed a distinct clade, distinguishable from the AAV discovered in humans and in other animals. CONCLUSIONS: A high prevalence of rat AAV that was highly conserved within the Cap gene was found in 3 common murine rodents and house shrews in China. PMID- 30404085 TI - Redesigning Skin Cancer Early Detection and Care Using a New Mobile Health Application: Protocol of the SKIN Research Project, a Randomised Controlled Trial. AB - Patients often detect melanoma themselves; therefore, regular skin self examinations (SSEs) play an important role in the early detection and prompt treatment of melanoma. Mobile teledermoscopy is a technology that may facilitate consumer SSEs and rapid communication with a dermatologist. This paper describes the planned randomised controlled trial of an intervention to determine whether mobile technologies can help improve the precision of SSE in consumers. A randomised controlled trial will be conducted to evaluate mobile teledermoscopy enhanced SSE versus naked-eye SSE. Participants in each group will conduct three home whole-body SSEs at baseline, 1 and 2 months, then present for a clinical skin examination (CSE) by a doctor after the 2-month SSE. Specifically, participants will identify skin lesions that meet the AC (asymmetry and colour) rule for detecting a suspicious skin spot. The primary outcomes are sensitivity and specificity of the skin lesions selected by the participants as needing attention by a doctor, compared to the clinical diagnosis by the dermatologist that will serve as the reference standard for this analysis. For the mobile teledermoscopy-enhanced SSE group, researchers will assess the number, location and type of lesions (1) sent by the participant via mobile teledermoscopy, (2) found at CSE or (3) missed by the participant. For the naked-eye SSE group, researchers will assess the number, location and type of lesions (1) recorded on their body chart by the participant, (2) found at CSE or (3) missed by the participant. Secondary outcomes are based on participants' self-reported data via online questionnaires. PMID- 30404086 TI - JAK2V617F, CALR, and MPL Mutations and Bone Marrow Histology in Patients with Essential Thrombocythaemia. AB - INTRODUCTION: Mutations in the JAK2, CALR, and MPL genes have been shown to have prognostic value in essential thrombocythaemia (ET), but no clear association with morphological changes has been reported so far. We investigated the possible correlation between gene mutations and histopathological features in bone marrow (BM) biopsies of patients with ET. METHODS: Marrow cellularity, fibrosis, and the number of total and dysmorphic megakaryocytes and clusters of megakaryocytes were compared to gene mutations in 90 cases of ET at diagnosis. RESULTS: The JAK2V617F mutation was found in 58.9%, CALR in 28.9%, and MPL in 4.4% of the cases, and 7.8% were triple-negative. JAK2V617F-mutated ET showed a high BM cellularity, the lowest number of clusters of megakaryocytes and the highest number of dysmorphic megakaryocytes; CALR-mutated ET showed a reduced BM cellularity, many clusters of large megakaryocytes, and very few dysmorphic megakaryocytes; MPL-mutated ET showed the lowest BM cellularity, the highest number of clustered and large megakaryocytes, and the lowest number of dysmorphic megakaryocytes. Triple negative ET cases had the highest BM cellularity. CONCLUSIONS: Distinct morphological patterns were associated with gene mutations in ET, supporting the classification of ET into different subtypes. PMID- 30404087 TI - Cervical Measurement and Pessary Application in Relation to Gestational Age at Delivery in Patients Treated with Fetoscopic Endotracheal Occlusion. AB - OBJECTIVE: To evaluate the impact of cervical length and cervical pessary application in congenital diaphragmatic hernia (CDH) treated by the fetoscopic endotracheal occlusion (FETO) procedure. METHODS: The study group consisted of 80 patients with severe CDH treated by FETO. Cervical length measurement was performed by transvaginal ultrasound in all patients within the 24 h prior to the FETO procedure. The study group (n = 44) had cervical pessaries applied routinely within the 24 h following the FETO procedure, whereas the control group (n = 36) were not offered pessaries and only had cervical length measurement performed. RESULTS: The median cervical length was 31 (range 22-45) mm. The median gestational age at delivery was 34.7 (range 27.8-39.2) weeks. Gestational age at delivery correlated significantly with gestational age at balloon removal (r = 0.768; p < 0.0001) and premature rupture of membranes (r = 0.501; p = 0.003). There was no significant correlation between gestational age at delivery and cervical length before the procedure (r = 0.141; p = 0.26) or pessary application (r = 0.081; p = 0.51). In the multivariate linear regression model, the only factor independently associated with gestational age at delivery was gestational age at fetoscopic balloon removal (beta = 0.713; p < 0.0001). CONCLUSION: In cases of severe CDH treated by the FETO procedure, neither cervical length before the procedure nor cervical pessary application was associated with gestational age at delivery. PMID- 30404088 TI - Evaluation of a Standardized Bakery Product (SUTMEK) as a Potential Tool for Baked-Milk Tolerance and Immunotherapy Research Studies. AB - BACKGROUND AND OBJECTIVES: About 65-80% of children with IgE-mediated cow's milk allergy (CMA) can tolerate extensively heated milk. We have invested in the mass fabrication of a test product containing milk protein baked at 180 degrees C for 30 min (SUTMEK-milk) and a milk-free placebo (SUTMEK-placebo) to carry out a standardised double-blind placebo-controlled food challenge (DBPCFC) test in patients with CMA. METHODS: We studied children with IgE-mediated CMA between 13 and 48 months of age. Specific IgEs (spIgE) to milk proteins were quantified. A DBPCFC with our bakery products was performed, and factors determining reactivity to extensively heated milk were evaluated. We also tested the applicability of SUTMEK products in baked-milk oral immunotherapy in a pilot assessment. RESULTS: We studied 15 children (8 girls, 7 boys) with a median age of 26 months (range: 13-48 months). Nine (60%) patients tolerated a challenge with extensively heated milk, while 6 (40%) were found reactive (anaphylaxis: 2, wheezing: 2, urticaria: 2). spIgE to milk, alpha-lactalbumin, and casein, and the wheal diameter on skin prick testing were higher in the reactive group than the tolerant groups (p = 0.001, p = 0.001, p = 0.002, and p = 0.048, respectively). Receiver-operating characteristic curve analyses yielded the following cut-off values for spIgEs that would predict a reactivity to extensively heated milk; milk: 25 kU/L (area under curve, AUC: 0.981), casein: 32 kU/L (AUC: 0.983), and alpha-lactalbumin: 17 kU/L (AUC: 0.981). Nine patients have tolerated well a continued daily consumption of SUTMEK-milk or -placebo for 6 months at the desired doses. CONCLUSIONS: Our bakery products were successfully used in DBPCFC studies and qualified as an acceptable tool for use in the research of interventional tolerance induction. Although spIgE appears useful in determining children at high risk of reacting to extensively heated milk, the predictive cut-off values are still far from being perfect. PMID- 30404089 TI - High-Throughput Sequencing of Putative Novel microRNAs in Rhesus Monkey Peripheral Blood Mononuclear Cells following EV71 and CA16 Infection. AB - OBJECTIVES: Enterovirus 71 (EV71) and Coxsackievirus A16 (CA16) remain the major pathogens in hand, foot, and mouth disease (HFMD) cases, but the mechanisms of the different pathogeneses that follow EV71 and CA16 infection remain largely unknown. METHODS: Herein, we utilized microRNA (miRNA) deep sequencing to investigate the roles of novel differentially expressed miRNAs in peripheral blood mononuclear cells (PBMCs) infected with EV71 and CA16. RESULTS: The results identified 13 novel differentially expressed miRNAs in each group. Additionally, the target genes were predicted by the miRanda and RNAhybrid programs, and a total of 2,501 targets were found in the two databases. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that these targets were mainly involved in cell development and were associated with nervous system development, system development, multicellular organism development, the Wnt signaling pathway, the PDGF signaling pathway, and the EGF receptor signaling pathway. Finally, a coexpression regulatory network was built with the key targets to further extrapolate the functional interactions of the targets and their coexpressed genes. CONCLUSION: Our results not only revealed potential biomarkers or targets for the diagnosis and treatment of HFMD, but also provided new insights to explore the mechanisms of EV71 and CA16 pathogenesis. PMID- 30404090 TI - Body Piercing: A National Survey in France. AB - BACKGROUND: There are no recent data available in France regarding body piercing (BP). OBJECTIVE: We examined the demographics, motivations, quality of life, cutaneous conditions, and cutaneous side effects after BP within the French population. METHODS: A representative sample of 5,000 individuals (aged 15 and over) from the general population responded to a survey online between April and August 2017. Data regarding demographics, BP characteristics (location, age at first piercing, hesitation, regrets, motivations, cutaneous side effects), tobacco, skin conditions (acne, contact eczema, atopic eczema, rosacea, psoriasis, vitiligo), and tattoos were collected. Respondents also filled an SF 12 quality of life questionnaire. RESULTS: Overall, 12% of the respondents reported at least one BP (women: 19.4%, men: 8.4%, p < 0.01). The prevalence was highest among those aged between 25 and 34 years (25.8%). Individuals with BP were more likely to smoke (p < 0.01). The most common body parts for piercings were the external part of the ear (42%), the navel (24%), the tongue (15%), and the nose (11%). Gender differences included localization (belly button and nose for women, eyebrows for men) and motivations (embellishment of the body for women, individuality and sexuality for men). A total of 33.6% of the study participants reported having skin problems after BP, primarily infection (44%). Individuals with BPs were more likely to report having contact eczema, atopic dermatitis, and acne. BP was associated with a lower mental quality of life score. CONCLUSION: This is the largest epidemiological study on BP in France to date. It allows us to draw a precise current snapshot of French indi viduals with BP. PMID- 30404091 TI - Childhood Cancer Treatments and Associated Endocrine Late Effects: A Concise Guide for the Pediatric Endocrinologist. AB - Endocrine complications are frequently observed in childhood cancer survivors (CCS); in many instances, these complications develop months to years after the completion of cancer therapy. The estimated prevalence of endocrine late effects is 50% among CCS; the main risk factors are external beam radiation that includes key endocrine organs (the hypothalamus/pituitary, thyroid and gonads) and/or alkylating agents. Novel agents targeting tumor growth have increased the options available to a small number of patients albeit with the need for treatment over long periods of time. Some of these agents, such as certain tyrosine kinase inhibitors and immune system modulators have been shown to cause permanent endocrine deficits. This chapter offers a brief summary of the conventional treatment strategies for the most common cancers of childhood and a brief overview of the endocrine late effects most commonly associated with these exposures. The impact of targeted therapies on the endocrine system will also be discussed. The aim of this chapter is to provide basic guidance to the consulting pediatric endocrinologist in preparation for the clinical encounter with a CCS. A more detailed discussion of the management of specific endocrine late effects can be found in the other chapters in this series. PMID- 30404092 TI - Extracellular RNA Sensing by Pattern Recognition Receptors. AB - RNA works as a genome and messenger in RNA viruses, and it sends messages in most of the creatures of the Earth, including viruses, bacteria, fungi, plants, and animals. The human innate immune system has evolved to detect single- and double stranded RNA molecules from microbes by pattern recognition receptors and induce defense reactions against infections such as the production of type I interferons and inflammatory cytokines. To avoid cytokine toxicity causing chronic inflammation or autoimmunity by sensing self-RNA, the activation of RNA sensors is strictly regulated. All of the Toll-like receptors that recognize RNA are localized to endosomes/lysosomes, which require internalization of RNA for sensing through an endocytic pathway. RIG-I-like receptors sense RNA in cytosol. These receptors are expressed in a cell type-specific fashion, enabling sensing of RNA for a wide range of microbial invasions. At the same time, both endosomal and cytoplasmic receptors have strategies to respond only to RNA of pathogenic microorganisms or dying cells. RNA are potential vaccine adjuvants for immune enhancement against cancer and provide a benefit for vaccinations. Understanding the detailed molecular mechanisms of the RNA-sensing system will help us to broaden the clinical utility of RNA adjuvants for patients with incurable diseases. PMID- 30404093 TI - Effect of Hawthorn Leaf Flavonoids in Dehydroepiandrosterone-Induced Polycystic Ovary Syndrome in Rats. AB - OBJECTIVE: To evaluate the potential beneficial effects of hawthorn leaf flavonoids (HLF) against polycystic ovary syndrome (PCOS) in a rat model of disease and elucidate the underlying molecular mechanism. METHODS: The PCOS model was established by subcutaneous injection of dehydroepiandrosterone (DHEA, 60 mg/kg/day) for 21 consecutive days. HLF (200 mg/kg/day) were orally administered simultaneously or after the injection. The body weight was regularly monitored and recorded. The ovaries were weighed and histologically examined via hematoxylin and eosin staining. The number of follicular cysts was counted under a light microscope. The serous hormones were measured using enzyme-linked immunosorbent assay kits. Insulin resistance (IR) was calculated as HOMA-IR = fasting insulin (uU/L) * fasting glucose (mM)/22.5. The estrous cycle was determined by vaginal smear. The relative expression of tumor necrosis factor alpha and interleukin-6 was measured by real-time polymerase chain reaction. The superoxide dismutase activity and malondialdehyde content was determined using commercially available kits. RESULTS: DHEA induced a significant increase of body weight, ovary weight, number of follicular cysts, serous hormones, IR, inflammatory cytokines, and oxidative stress, and it also impaired the estrous cycle. Oral administration of HLF greatly alleviated these complications. Little toxicity of HLF was observed in our rat model. CONCLUSION: HLF manifest protective effects against PCOS progression in the animal model, which may hold great promise for future clinical applications. PMID- 30404094 TI - Perceptual Inhibition Associated with Sensory Integration for Balance in Older Adults. AB - AIMS: Inhibition associated with perception has been implicated in sensory integration processes for balance when sensory conflict occurs. The current study examines the associations of three measures of inhibition (perceptual inhibition, motor inhibition, and Stroop interference) with standing balance under sensory conflict conditions in younger and older adults. METHODS: Perceptual inhibition, motor inhibition, and Stroop interference were measured in younger and older subjects. Standing balance under conditions of sensory conflict was evaluated using a modified dynamic posturography protocol. Correlative analysis was performed to examine the associations between the inhibition measures and sway. RESULTS: In older adults only, perceptual inhibition was correlated with sway when sensory conflict was present. Stroop interference and motor inhibition were not significantly correlated with sway under any posturography conditions. CONCLUSION: Measures of perceptual inhibition are associated with reduced sensory integration capability for balance during sensory conflict conditions in older adults. PMID- 30404095 TI - Next-Generation Robotic Head and Neck Surgery. AB - Following the inception of transoral robotic surgery (TORS) in 2005, the field of robotic head and neck surgery has undergone refinement and innovation. Optimizing patient outcome, preserving function, and limiting morbidity are the key drivers. The next leap forward is another generation of flexible robotic surgical systems. Several such systems are under clinical and preclinical evaluation. A new single port (Sp) robotic surgical architecture is now available integrating three fully articulating instruments and a flexible three-dimensional high-definition camera delivered through a 25-mm cannula. Preclinical feasibility studies of the Sp in human cadaver and porcine models suggest improved application compared to existing platforms for oropharyngeal and nasopharyngeal resection. With 3-handed manipulation of tissue, traction and countertraction may be used to deliver a more precise surgical dissection of head and neck anatomy than is currently possible. The single-port design permits greater access and maneuverability for the bedside surgical assistant. An alternative currently available in clinical use includes the Flex(r) system using a robotic camera and manually controlled endoscopic instruments. The Cambridge Medical Robotics Versius system is undergoing preclinical evaluation for TORS and may offer a novel modular approach. All of these systems allow the head and neck surgeon to reach further beyond the upper aerodigestive tract with greater agility and precision, expanding the boundaries of minimal access head and neck surgery. PMID- 30404096 TI - Impact of the Timing of Placement of an Intracranial Pressure Monitor on Outcomes in Children with Severe Traumatic Brain Injury. AB - BACKGROUND: Severe traumatic brain injury (sTBI) is the leading cause of morbidity and mortality from trauma. Brain Trauma Foundation guidelines recommend intracranial pressure (ICP) monitoring in sTBI. We hypothesized that early ICP monitor placement was associated with better outcomes in children. METHODS: This was a retrospective study of children with sTBI admitted to the participating pediatric intensive care units (PICUs) and entered into the Virtual Pediatric Systems (VPS), LLC, database between 1 January 2010 and 31 December 2015. We compared outcomes of patients who had an ICP monitor placed early (<=6 h from PICU admission) to those with later placement (> 6 to < 72 h). We collected demographics, diagnoses, procedure data, illness severity scores, outcomes, and site data. Multivariable regression analysis was used to identify variables independently associated with outcomes. RESULTS: Twenty-seven percent of 3,608 patients with sTBI underwent ICP monitoring, 355 in the early and 156 in the later ICP monitoring groups, respectively. A higher proportion of patients in the early ICP monitoring group had worse markers of illness/injury severity; unadjusted analysis showed higher mortality in this group (31.3 vs. 21.8%, p = 0.029). Multivariable regression analysis showed that ICP monitoring was not independently associated with any of the outcomes. CONCLUSION: Time to ICP monitoring was not associated with outcomes after pediatric sTBI. PMID- 30404097 TI - Doc, I Have COPD: Will I Tolerate Moderate-High Altitude? PMID- 30404098 TI - Giant Prolactinomas. AB -

Prolactin-secreting adenomas (prolactinomas) are the most common secreting adenomas of the pituitary. Microprolactinomas (diameter <10 mm) are frequently diagnosed in women whereas macroprolactinomas (maximum diameter >10 mm) are generally seen in men. Most macroprolactinomas measure between 10 and 40 mm. Giant prolactinomas, measuring >40 mm, are rare, accounting for only 1-5% of all prolactinomas. Although generally benign, giant prolactinomas are aggressive and invasive, extending into the suprasellar region and also involve the cavernous sinuses. The optic chiasm is frequently involved which leads to visual damage and patients occasionally suffer from ophthalmoplegia. Long-term (usually lifetime) therapy with high-dose dopamine agonists (cabergoline or bromocriptine), together with pituitary surgery in some cases and radiotherapy if required, can achieve biochemical remission, tumor control, and clinical improvement in most patients. . PMID- 30404099 TI - Contents Vol. 114, 2018. PMID- 30404100 TI - Outcome of Internal Neurolysis for Trigeminal Neuralgia without Neurovascular Compression and Its Relationship with Intraoperative Trigeminocardiac Reflex. AB - BACKGROUND: Internal neurolysis (IN) is an effective surgical treatment for trigeminal neuralgia (TN) without neurovascular compression (NVC) or postoperative recurrence. However, the trigeminal nerve is directly manipulated during the procedure, and there is a high incidence of trigeminocardiac reflex (TCR). The aim of this study was to retrospectively analyze the outcome of IN and to explore its relationship with the occurrence of intraoperative TCR. METHODS: Surgical and anesthesia records of 27 TN patients who underwent surgical treatment with IN at our department between March 2010 and September 2016 were retrospectively analyzed. Patients were divided into 2 groups on the basis of the occurrence of TCR during surgery, and clinical characteristics were compared. Pain intensity was assessed by the Barrow Neurological Institute (BNI) pain intensity score and BNI facial numbness score. RESULTS: TCR was observed in 23 of 27 patients (85.2%); it manifested as obvious changes in mean arterial pressure and heart rate by at least 20% of the baseline values. Trigeminal nerve atrophy was found in 9 patients (33.3%). The immediate pain-free rate was 96.3%, and the "excellent" rate was 72.1% for follow-up, with a rate of numbness or hypesthesia of 97.1%. These outcomes were retrospectively compared between the TCR and non TCR groups, and there was a nonsignificantly higher "excellent" rate in the TCR group than in the non-TCR group. CONCLUSIONS: This study demonstrated that IN is an effective treatment for TN without NVC and has a close relationship with intraoperative TCR. To our knowledge, this is the first research describing TCR during IN. PMID- 30404101 TI - Developing and Gathering Validity Evidence for a Simulation-Based Test of Competencies in Lung Ultrasound. AB - BACKGROUND: Clinical lung ultrasound (LUS) is a fast bedside diagnostic tool which can assist clinicians in decisions regarding the treatment and monitoring of patients with respiratory symptoms. LUS training and education differ widely, and is often done in a clinical setting, with potential risks for patients if decisions are made based on the wrong interpretations. No clear guidelines or recommendations for objective and standardized assessment of LUS skills exist, and those that do are often based on a fixed time-frame or an arbitrary number of examinations performed; this does not ensure adequate competencies. OBJECTIVES: The study aimed to develop and gather validity evidence for a practical, simulation-based test in LUS. METHODS: Nine cases were developed in collaboration with 3D Systems Healthcare, Littleton, CO, USA, representing the most common diagnosis and sonographic findings in patients with respiratory symptoms. Thirty six participants with different levels of competence in LUS, completed the test. The participants were divided into groups, i.e., novices, intermediates, and experienced, according to their experience with LUS, the number of examinations they had performed, and any research they had conducted. Their answers were used for item analyses. RESULTS: The intraclass correlation coefficient, Cronbachs' alpha, was 0.69 summarized, and there was a statistically significant difference (p < 0.001) between the novices and the trained participants (intermediates and experienced). A pass/fail score of 16 points was calculated according to the contrasting-groups method. CONCLUSION: We developed a test for the assessment of clinical competencies in LUS. The test proved solid validity evidence, and a pass/fail standard without any false-negatives, and only 2 explained false positives. PMID- 30404102 TI - Re-Irradiation with Stereotactic Radiosurgery/Radiotherapy for Recurrent High Grade Gliomas: Improved Survival in the Modern Era. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy of stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (fSRT) as salvage therapy for recurrent high-grade glioma and to look at the overall efficacy of treatment with linear accelerator (LINAC)-based radiosurgery and fractionated radiotherapy. METHODS: From 2010 to 2017, a total of 25 patients aged 23-74 years were re-irradiated with LINAC-based SRS and fSRT. Patients were treated to a median dose of 25 Gy in 5 fractions. RESULTS: The median overall survival (OS) after (initial) diagnosis was 39 months with an actuarial 1-, 3-, and 5-year OS rate of 88, 56, and 30%, respectively. After treatment with SRS or fSRT, the median OS was 9 months with an actuarial 1-year OS rate of 29%. Local control, assessed for 28 tumors, after 6 months was 57%, while local control after 1 year was 39%. Three patients experienced local failure. There was no evidence of toxicity noted after SRS or fSRT throughout the follow-up period. CONCLUSION: SRS and fSRT remain a safe, reasonable, effective treatment option for re-irradiation following recurrent glioblastoma. Additionally, treatment volume may predict local control in the salvage setting. PMID- 30404108 TI - Pulmonary Vasculitis and Alveolar Hemorrhage. PMID- 30404109 TI - Pathogenesis of ANCA-Associated Pulmonary Vasculitis. AB - Antineutrophil cytoplasmic antibodies (ANCAs) are autoantibodies specific for antigens located in the cytoplasmic granules of neutrophils and lysosomes of monocytes. ANCAs are associated with a spectrum of necrotizing vasculitis that includes granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis. Pulmonary vasculitis and related extravascular inflammation and fibrosis are frequent components of ANCA vasculitis. In this review, we detail the factors that have been associated with the origin of the ANCA autoimmune response and summarize the most relevant clinical observations, in vitro evidence, and animal studies strongly indicating the pathogenic potential of ANCA. In addition, we describe the putative sequence of pathogenic mechanisms driven by ANCA-induced activation of neutrophils that result in small vessel necrotizing vasculitis and extravascular granulomatous necrotizing inflammation. PMID- 30404110 TI - Diffuse Alveolar Hemorrhage and Pulmonary Vasculitides: Histopathologic Findings. AB - Vasculitides are a heterogeneous group of disorders in which inflammation of blood vessel walls is present at least some time during the course of the disease. Vasculitides can affect any caliber or type of vessel in many anatomic sites; however, the disease can alter more than just vasculature. Given the diversity of vasculitides, in 2012, a revised classification system was proposed to categorize vasculitides by the type of vessel involved including size, function, and structural attributes. In the lung, vasculitis impacts both the pulmonary vessels and parenchyma. Extrapulmonary involvement, particularly with concomitant kidney involvement, is a frequent occurrence. Pulmonary vasculitides often present with hemoptysis, pathologically manifested as diffuse alveolar hemorrhage (DAH) with or without capillaritis and can be life threatening when diffuse throughout the lungs. Etiologies for DAH include both primary and secondary vasculitides, along with collagen-vascular diseases, infection, and drug toxicity. Therefore, diagnosing the specific vasculitic etiology often relies on comprehensive assessment of all clinical, laboratory/serological, imaging, and histopathologic features that may be present. The most common primary pulmonary vasculitides often affect small vessels and are associated with circulating antineutrophilic cytoplasmic antibodies (ANCAs). In the 2012 classification, these include granulomatosis with polyangiitis (formerly Wegener granulomatosis), eosinophilic granulomatosis with polyangiitis (formerly Churg Strauss' syndrome), and microscopic polyangiitis. Other less frequent vasculitides that are non-ANCA associated or affect medium- to large-sized vessels can have pulmonary involvement. These entities are usually associated with extrapulmonary disease and include polyarteritis nodosa, Takayasu's arteritis, Behcet's disease, and antibasement membrane antibody disease (formerly Goodpasture's syndrome). Although all vasculitides have vessel wall inflammation at some phase in the disease process, their histopathologic findings are as diverse as the group of diseases themselves. The characteristic histologic findings of the pulmonary vasculitides will be reviewed here. PMID- 30404111 TI - Granulomatosis with Polyangiitis (Wegener's Granulomatosis): Evolving Concepts in Treatment. AB - Granulomatosis with polyangiitis (GPA), formerly termed Wegener's granulomatosis, is the most common of the pulmonary vasculitides. GPA typically involves the upper respiratory tract, lower respiratory tract (bronchi and lung), and kidney, with varying degrees of disseminated vasculitis. Cardinal histologic features include a necrotizing vasculitis involving small vessels, extensive "geographic" necrosis, and granulomatous inflammation. The spectrum and severity of the disease is heterogeneous, ranging from indolent disease involving only one site to fulminant, multiorgan vasculitis. Circulating antibodies against cytoplasmic components of neutrophils (ANCAs) play a role in the pathogenesis, and often correlate with activity of the disease. Treatment strategies are evolving. Cyclophosphamide (CYC) plus corticosteroids was the mainstay of therapy for generalized, multisystemic GPA since the 1970s. However, within the past decade, rituximab (RTX), a monoclonal antibody directed against B cells, has been shown to be at least as effective (and possibly more effective) as CYC. Furthermore, the use of RTX may reduce the need for maintenance immunosuppression. Optimal therapy for GPA remains controversial, and additional studies are required to determine the role and duration of maintenance therapy following successful induction therapy. PMID- 30404112 TI - Microscopic Polyangiitis: New Insights into Pathogenesis, Clinical Features and Therapy. AB - Microscopic polyangiitis (MPA) is one of the main clinical presentations of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Although the disease is defined by clinical and pathological criteria, the anti myeloperoxidase (MPO) specificity of ANCAs is observed in almost 80% of MPA patients. The direct pathogenic role of anti-MPO antibodies has been proven in animal models, in which the disease was transmitted by transfer of anti-MPO antibodies or anti-MPO-specific splenocytes. The most frequently affected organs in this disease are the kidneys and the lungs. Necrotizing and crescentic glomerulonephritis can be revealed by rapidly progressive renal failure, but kidney injury can be more slowly progressive and lead to end-stage renal disease without major extrarenal manifestations. The most frequent pulmonary manifestation is diffuse alveolar hemorrhage, but some patients may present with chronic interstitial fibrosis leading to respiratory failure. General signs such as fever and weight loss, muscular and articular symptoms, peripheral neuropathy, and cutaneous involvement may also reveal the disease. Although the relapse rate is quite low after induction of remission, 5-year mortality is 25%, with even higher mortality rates in older patients (> 65 years old), or those with significant kidney dysfunction. Iatrogenic causes (particularly infections) are an important cause of deaths in these vulnerable patients. Future studies are warranted to determine the optimal maintenance immunosuppressive regimen to minimize side effects of immunosuppression. PMID- 30404113 TI - Antineutrophil Cytoplasmic Antibody-Associated Lung Fibrosis. AB - Pulmonary fibrosis is observed in a substantial number of patients with ANCA associated vasculitis (AAV), 15% in a recent German series, and may be more frequent in Asian populations. ANCA are usually of anti-MPO specificity and microscopic polyangiitis is the most frequent vasculitis. Pulmonary fibrosis may increase the risk of death in patients with AAV. Treatment for AAV in patients with lung fibrosis should follow the international guidelines for vasculitis. The role of anti-fibrotic drugs (pirfenidone, nintedanib) in this condition is still unknown. Pulmonary fibrosis precedes the diagnosis of AAV or is diagnosed concomitantly in most of the cases. Interestingly, 4% to 35% of patients with pulmonary fibrosis are ANCA-positive, but only 7% to 23% of the patients with pulmonary fibrosis and anti-MPO will develop AAV during follow-up. ANCA positivity may be detected in idiopathic or non idiopathic pulmonary fibrosis. In the absence of vasculitis, the detection of ANCA does not influence the diagnostic work-up of patients with lung fibrosis. If an Idiopathic Pulmonary Fibrosis diagnosis is considered, an anti-fibrotic therapy should be considered, according to local and international guidelines. PMID- 30404114 TI - Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss). AB - Eosinophilic granulomatosis with polyangiitis (EGPA), formerly called Churg Strauss syndrome, is a systemic necrotizing vasculitis of small- and medium-size vessels, characterized by asthma and blood eosinophilia. EGPA typically occurs in patients with preexisting asthma, and involves the skin, lungs, and peripheral nerves. Poor-prognosis factors (i.e., involvement(s) of the gastrointestinal tract, heart, and/or kidney) have been assessed with the Five-Factor Score (FFS). One-third of the patients have anti-myeloperoxidase antineutrophil cytoplasm antibodies, and their presence seems to differentiate between two phenotypes, with different clinical characteristics and prognoses. Overall survival has improved markedly since the use of glucocorticoids and immunosuppressants, but relapse rates remain high. All patients require glucocorticoids, and for those with severe/refractory disease and FFS-defined poor prognoses, immunosuppressants should be used (cyclophosphamide for induction and azathioprine for maintenance therapy). Recent advances in EGPA management, including several novel immunomodulatory drugs and targeted biotherapies, were or are being evaluated to improve EGPA patients' prognoses. PMID- 30404115 TI - Alveolar Hemorrhage in Vasculitis (Primary and Secondary). AB - Defined by the accumulation of red blood cells into the alveolar space, diffuse alveolar hemorrhage (DAH) is a severe and potentially fatal medical condition requiring careful attention. In contrast to simple extravasation of erythrocytes facilitated by impaired hemostasis or hemodynamic causes, DAH in vasculitis is due to capillaritis, that is, inflammation of capillaries. Dyspnea, hemoptysis, chest infiltrates, and abrupt fall of blood hemoglobin level represent the cardinal features of DAH; yet, hemoptysis is lacking in one-third of cases. Bronchoalveolar lavage, retrieving bright red fluid, is the best diagnostic clue, also excluding infection and other causes of hemoptysis. Although not recommended, lung biopsy is the gold standard for the diagnosis of DAH and pulmonary capillaritis. Pulmonary capillaritis may be primary as in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis or secondary to drugs (especially antithyroid drugs such as propylthiouracil), infections, connective tissue diseases especially systemic lupus erythematosus, or other small vessel vasculitides. Newer toxic causes of drugs of abuse may be difficult to diagnose. Granulomatosis with polyangiitis and microscopic polyangiitis are the most common causes of capillaritis and DAH, whereas DAH is extremely rare in eosinophilic granulomatosis with polyangiitis. When pulmonary capillaritis is not secondary to underlying systemic vasculitis, idiopathic pauci-immune pulmonary capillaritis may be considered, with or without ANCA. Supportive treatment strategy is mandatory in all cases of DAH. Mechanical ventilation and extracorporeal membrane oxygenation may be used in severe cases. Early identification and removal of the putative drug is crucial in drug-induced vasculitis/DAH and may obviate the need for immunosuppressive therapy. High-dose corticosteroids, intravenous cyclophosphamide, and recently rituximab are the mainstay of treatment in vasculitis. Plasma exchange is recommended in anti glomerular basement membrane disease and in severe DAH associated with systemic lupus erythematosus and is used in selected cases in ANCA-associated vasculitis. PMID- 30404116 TI - Antiglomerular Basement Membrane Disease. AB - Antiglomerular basement membrane (anti-GBM) disease is a rare but life threatening autoimmune vasculitis that is characterized by the development of pathogenic autoantibodies to type IV collagen antigens expressed in the glomerular and alveolar basement membranes. Once deposited in tissue, these autoantibodies incite a local capillaritis which manifests as rapidly progressive glomerulonephritis (GN) in 80 to 90% of patients, and with concurrent alveolar hemorrhage in ~50%. A small proportion of cases may present with pulmonary disease in isolation. Serological testing for anti-GBM antibodies may facilitate rapid diagnosis, though renal biopsy is often required to confirm the presence of necrotizing or crescentic GN and linear deposition of autoantibody on the glomerular basement membrane. Alveolar hemorrhage may be evident clinically, or detected on imaging, pulmonary function testing, or bronchoscopy. Prompt treatment with plasmapheresis, cyclophosphamide, and steroids is usually indicated to remove pathogenic autoantibodies, to prevent their ongoing production, and to ameliorate end-organ inflammation. Alveolar hemorrhage is usually responsive to this treatment, and long-term respiratory sequelae are uncommon. Renal prognosis is more variable, though with aggressive treatment, independent renal function is maintained at 1 year in more than 80% of patients not requiring renal replacement therapy at presentation. Relapse in uncommon in anti-GBM disease, unless there is a concomitant antineutrophil cytoplasm antibody (present in 30-40%), in which case maintenance immunosuppression is recommended. PMID- 30404117 TI - Treatment of Pulmonary Vasculitis. AB - Pulmonary vasculitis can be heterogeneous and have some pathophysiological, clinical, and biological specificities that might influence treatment choices. Main vasculitides associated with pulmonary vasculitis include antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, immune complex small vessel vasculitis, and antiglomerular basement membrane disease. Patient characteristics and association of lung involvement with other manifestations affecting disease severity may also influence treatment strategy. Alveolar hemorrhage frequently requires urgent treatment to control the underlying disease and provide supportive care such as mechanical ventilation. The level of evidence of each treatment strategy varies according to the underlying disease, but treatment is usually based on a combination of glucocorticoids and immunosuppressive agents, especially cyclophosphamide and rituximab. The role of plasma exchanges, widely used in patients with severe vasculitis, is controversial, based on results from recent prospective randomized controlled trials. PMID- 30404118 TI - [Correction of Intraarticular Malunion of the Distal Radius Based on a Computer Assisted Virtual Planning]. AB - BACKGROUND: Computer-assisted 3D-virtual planning of extraarticular corrective procedures at the distal radius and transfer of the virtually planned procedure to the radius in vivo has been recently described. In contrast to this analogue studies on intraarticular corrective procedures are still lacking. With regard to the difficulties of the technique and the potential risks a similar technique would be valuable, that overcomes the problems of the limited access and the difficulties of reposition and fixation. This study presents a technique for intraarticular corrective procedures at the distal radius based on computer assisted 3D- virtual planning and custom made patient specific instruments. PATIENTS AND METHODS: Between 2013 and 2016, 6 patients (1 female and 5 male) underwent intraarticular corrective osteotomy of the distal radius. The average age was 48 (38-60) years, the interval between injury and correction 10 (4-13) months. All patients had been previously operated externally. The computer assisted planning was performed in cooperation with an external industrial partner ((Materialise NV, 15 Technologielaan, 3001 Leuven, Belgium). Therefore CT scans of both wrists and forearms were performed at our institution following a special protocol from which both distal radii were virtually reconstructed. The mirror-image of the 3-D-model of the uninjured radius was superposed over the 3-D image of the malunited radius so that the malunion was exactly visualized. The correction as well as the desired position of the implants was planned step by step via an online-conference. The stabilisation of the fragments was simulated by introducing plates and screws into the 3-D-images. Based on this plan for every step of the procedure patient-specific drilling and sawing guides were produced (Fa. Materialise) and supplied to our institution. The operative strategy and technique is demonstrated by a typical example and will vary with the individual situation of the patient. RESULTS: No complications occurred. All patients gained bony union. No additional procedures were required. Postoperative CT-scans confirmed that step offs were regularly well corrected but gaps often persisted. PMID- 30404119 TI - Percutaneous K-wires vs palmar locking plate fixation for different types of distal radial fractures: a comparison of the outcomes of two methods to controll our guidelines. AB - : The objective of the study was a comparison of the outcomes of K-wire vs plate fixation for distal radial fractures used according to the proposed institutional algorithm. Fracture configurations A2, A3, B1, B2, C1 and some C2 were operated on with K-wire pinning, whereas B3 and some B2, C3 and some C2 were with locking palmar-plate fixation. PATIENTS AND METHODS: Four hundred and sixty-seven patients were non-randomly allocated for either K-wire (n = 363) or palmarplate (n = 104) fixation. The results were assessed at 3 and 12 months by the same outcome measures. RESULTS: At the 3-month assessment, statistically significant differences in grip strength and the DASH scores were noted in favour of the plate-fixation group. At the 12-month assessment, statistically significant differences were observed in the wrist palmar and dorsal flexion, favouring the plate-fixation group. Statistically significant differences were noted in radiological measures of the palmar tilt and the ulnar variance, both favouring the plate-fixation method. Meaningful secondary dislocations were noted in ten patients, all in the K-wire-fixation group. CONCLUSION: We conclude that palmar locking plate fixation in even more severe fractures leads to better radiological and clinical outcomes than K-wire fixation in less severe fractures. PMID- 30404120 TI - [Carpal tunnel syndrome and ATTR-amyloidosis]. AB - BACKGROUND: Carpal tunnel syndrome is the most common compression syndrome of a peripheral nerve. It mostly affects patients older than 50 years. One cause for a carpal tunnel syndrome is transthyretin (ATTR) amyloid, which deposits in the carpal tunnel tissue. Carpal tunnel syndrome can be the first symptom of ATTR amyloidosis, which in the worst case leads to amyloid cardiomyopathy with the symptoms of heart failure with reduction in quality and time of life. For this article, all histological tissue samples of carpal tunnel tissue, collected from 2010 to 2018, were evaluated according to age and gender of each patient. Evaluation of the ATTR amyloid content in different regions of the carpal tunnel has enabled a recommendation for resection for optimal histological diagnosis. MATERIAL AND METHODS: In the Amyloid Registry Kiel, all cases are archived according to type of amyloid and available tissue. We evaluated 582 resected tissue samples of patients with ATTR amyloid in the carpal tunnel, collected from 2010 to the beginning of 2018. In addition, amyloid load of two different regions of the carpal tunnel (synovial tissue and tissue of the flexor retinaculum) were compared. RESULTS: The majority of resections came from women (53 %). The median age was 78 years for the entire collective, 77 years for men and 79 years for women. Specimens of the flexor retinaculum contained significantly more amyloid (9.66 % amyloid) than specimens of the synovial tissue (2.10 % amyloid). The prevalence of ATTR amyloid in carpal tunnel syndrome is 11.66 %. CONCLUSIONS: Both men and women develop a carpal tunnel syndrome caused by ATTR amyloid. In particular, at the age of over 50 years, amyloid deposits should be considered in the context of the etiological clarification of the carpal tunnel syndrome. Early histological diagnosis is highly relevant to identify the risk of cardiac amyloidosis. For an early and correct diagnosis of ATTR amyloidosis, histological examination of the flexor retinaculum is particularly necessary, and a sample excision should always be obtained and examined histologically. PMID- 30404121 TI - Risk Factors of Carpal Tunnel Syndrome for Male Patient Undergoing Carpal Tunnel Release. AB - INTRODUCTION: Although the major cause of carpal tunnel syndrome (CTS) remains idiopathic, many male CTS patients are clinically different from female patients and often have specific risk factors associated with their conditions. An accurate analysis of such propensity has yet to be established. The purpose of this study is to compare male and female patients by analyzing the risk factors associated with CTS patients who underwent surgical treatment, with focus on their occupation. PATIENTS/MATERIAL AND METHODS: retrospective chart review of 818 patients with CTS was performed to identify the associated risk factors. Patients were stratified by gender: female (n = 707, 86.4 %) and male (n = 111, 13.6 %). The mean patient age was 54.5 (range: 16-85 yr.) for all groups. The medical history and risk factors of each patient was thoroughly reviewed by medical charts and telephone survey. We categorized the risk factors of CTS into 7 categories: anatomic, neuropathic, inflammatory, alteration of fluid balance, distal radius fracture associated, occupational risk factor related, and idiopathic. Occupations of CTS patients were divided into high risk occupations (vibratory tools, assembly jobs, and food processing and packaging jobs, and other occupations of repetitive wrist motion and forceful gripping) and nonrisk occupations. All variables were analyzed with chi-square or Fisher's exact test for differences between men and women. RESULTS: The number of individuals with known risk factors of CTS was greater in male, compared to that of female patients; 97 (87.4 %) male patients had the risk factors of CTS, while 361 (51.1 %) female patients (p < 0.001) did. In subgroup analysis of risk factors, male patients had frequent risk factors in neuropathic, inflammatory, and alteration of fluid balance (p < 0.001). Occupational risk was strongly associated with male gender (p < 0.001). CONCLUSION: Male CTS patients who underwent surgery are more likely to have a reason and have many occupational risk factors than women. PMID- 30404122 TI - ["Pathway protection" - enhanced motoneuron regeneration by end-to-side coaptation of sensory axons]. AB - Proximal nerve injuries and delayed nerve repair lead to reduced peripheral nerve regeneration. Poor functional results after nerve injury are clinically a very challenging problem. Experimental studies defined "chronic axotomy" of the neuron and the proximal part of a dissected nerve that are separated from their distal target, as well as "chronic denervation" of the distal nerve stump as an independent factors that reduce regenerative capacity of injured nerves. The denervated distal nerve undergoes changes associated with Wallerian degeneration. Denervated Schwann cells change their phenotype to interact with in-growing axons and increase the expression of growth factors. These changes lead to a pro regenerative environment in the distal nerve stump. This growth-permissive environment deteriorates with time leading to significantly reduced nerve regeneration. Clinically, delayed nerve repair and long regeneration distances often result in inadequate functional outcomes. Different "pathway protection" techniques were developed to improve nerve regeneration and reduce the chronic denervation of the distal nerve. Most of these "babysitter" procedures used a motor donor nerve which was coapted usually end-to-side to the denervated distal nerve stump. Experimental studies showed that in-growing donor axons increase neurotrophic factor levels and improved reinnervation of distal targets. Motor "babysitter" procedures are, however, associated with a motor donor nerve deficit. In recent years, sensory "pathway protection" was investigated to avoid such motor deficit. Motoneuron regeneration of its axons can, in experimental animal models, be improved by end-to-side coaptation of sensory donor axons to either a denervated distal nerve stump or to a long autologous nerve graft, both of which undergo changes associated with chronic denervation. Sensory "pathway protection" has already been successfully clinically applied, however long-term functional analysis awaits. PMID- 30404123 TI - Image-guided versus palpation-guided injections for the treatment of chronic lateral epicondylopathy: a randomized controlled clinical trial. AB - BACKGROUND: There have been several studies published comparing the ultrasound guided with the "blind" infiltrations in the shoulder's area. On the contrary, there is only very limited data regarding the necessity of ultrasound guidance in lateral epicondylitis. MATERIALS AND METHODS: A prospective, randomized, blinded at initial and follow-up evaluation, comparative clinical trial was conducted, involving 44 patients with a history of chronic persistent epicondylopathy. The patients were randomly divided into 2 groups of 22 people each. Group A patients underwent three ultrasound-guided betamethazone injections, while group B included those who underwent three "blind" injections, centered at the palpable point of maximum pain. The evaluation was done before and after (4 and 12 weeks) the injections using the Visual Analogue Scale for pain (VAS, 0-10) and the Roles & Maudsley score. RESULTS: There was not any significant statistical difference between the two groups as for mean VAS at 4 weeks (p = 0.150, t-test) and mean VAS at 12 weeks (p = 0.286, t-test). Furthermore, the final success rate, as measured by the Roles & Maudsley score, was slightly superior in group B (67 % of the patients with excellent or good results) when compared with group A (46 % of the patients), but without any statistical difference (p = 0.161, chi-square). CONCLUSION: Our trial proved that an ultrasound-guided injection is not superior than a palpation-guided injection of corticosteroids in the treatment of lateral epicondylopathy. PMID- 30404124 TI - [The revenue from finger replantation and revision amputation: Is it cost covering?] AB - BACKGROUND: Finger amputation injuries are frequently treated conditions in occupational accident hospitals. They are either treated by replantation or revision amputation. The costs of these two treatment options differ significantly. This study aims to determine if the revenue generated from the treatment of finger amputation injuries in the German DRG system is cost-covering and if there are differences depending on the type of health insurance. METHODS: Based on our hospital's cost data from the years 2014 and 2015, we performed an analysis of the revenue generated from finger replantation and finger revision amputation and compared it with the cost data of the nationwide calculation hospitals in Germany. In addition, we compared the revenue generated from patients with statutory health insurance with the revenue from patients with workers' compensation insurance. RESULTS: During the study period, a total of 90 patients were treated for finger amputation. For primary finger revision amputation, the actual costs were lower compared to the cost data of the nationwide calculation hospitals (? 3551 vs. ? 3809, p = 0.442). After deduction of all costs, the revenue was 1,008 Euros for patients with statutory health insurance and 688 Euros for patients with workers' compensation insurance (p = 0.578). In contrast, the costs of complex finger reconstruction procedures were considerably underestimated. In cases of primary finger replantation or secondary finger revision amputation, losses of 260 Euros were recorded for patients with statutory health insurance. In patients with workers' compensation insurance, the revenue of complex finger reconstruction procedures after deduction of all costs was cost-covering (? 900, p = 0.403). CONCLUSIONS: In the German DRG system, the reimbursement for the treatment of finger amputation depends on the type of health insurance. In patients with workers' compensation insurance, cost-covering revenue is generated from both finger revision amputation and finger replantation, whereas in patients with statutory health insurance, only the revenue of primary finger revision amputation appears to be cost-covering. Hence for finger amputation injuries with subsequent complex reconstruction procedures, a revision of the cost calculation is required to avoid inappropriate incentives in patient care. PMID- 30404125 TI - Treatment of neglected, severely displaced, open malunion of the distal radius and ulna in an elderly person with Alzheimer's disease - a case report. AB - The case of a patient suffering from Alzheimer's disease who sustained epiphyseal, severely dislocated fractures of the distal radius and ulna is reported. As the patient was incapacitated and attempts to contact her curator failed, the decision was made on a conservative treatment of the fractures. This treatment eventually failed and resulted in malunion with exposure of bone fragments above the skin. After obtaining informed consent from her curator, a corrective osteotomy was performed using an original method, followed by fixation of bone fragments in almost anatomical position by intramedullary K wires. At a 6 month follow-up, the patient was using her hand in daily life and did not complain of any pain. An X-ray showed consolidation of the bones in the distal forearm in an acceptable position. PMID- 30404126 TI - Successful treatment of paediatric lower limb CRPS by continuous epidural anaesthesia: a report of 2 cases. AB - CRPS occurs in children less frequently than in adults, but in the last two decades it has become a well-established entity in children and adolescents. The symptomatology, course, responsiveness to treatment and prognosis of the paediatric disease is also different from the "adult" form. The paper presents the successful treatment of two cases of paediatric CRPS involving the lower limb, by continuous epidural anaesthesia with bupivacaine. Both patients developed the condition after minor trauma or overuse. CRPS diagnosis was based on clinical grounds. Both patients presented a history of psychological distress, due to familial problems. In one patient, the initial treatment was lumbar sympathetic block, resulting in immediate and complete recovery. After relapse of the disease at four months, the next intervention included continuous epidural infusion of bupivacaine, with an excellent and rapid response. In the 2nd case, continuous epidural infusion was used primarily with the same, excellent and fast result. The article discusses clinical peculiarities, treatment modalities and other aspects of paediatric CRPS. Poor awareness of the condition in the paediatric community is also emphasized. PMID- 30404127 TI - ? PMID- 30404128 TI - [Travel report CK Spies - ASSH International Traveling Fellowship 2018]. PMID- 30404129 TI - Anti-neuroinflammatory Effects of 12-Dehydrogingerdione in LPS-Activated Microglia through Inhibiting Akt/IKK/NF-kappaB Pathway and Activating Nrf-2/HO-1 Pathway. AB - Ginger, one of worldwide consumed dietary spice, in fact, it is not only famous as food supplements, and also believed to exert a variety of remarkable pharmacological activity as herbal remedies. In this study, a ginger constituent, 12-dehydrogingerdione (DHGD) was proven that has comparable anti-inflammatory activity with positive control 6-shogaol in inhibiting LPS-induce dinterleukin (IL)-6, tumor necrosis factor (TNF)-alpha, prostaglandin (PG) E2, nitric oxide (NO), inducible NO synthase (iNOS) and cyclooxygenase (COX)-2, without interfering with COX-1 in cultured microglial cells. Subsequent mechanistic studies indicate that 12-DHGD may inhibit neuro-inflammation through suppressing the LPS-activated Akt/IKK/NF-kappaB pathway. Furthermore, 12-DHGD markedly promoted the activation of NF-E2-related factor (Nrf)-2 and heme oxygenase (HO) 1, and we demonstrated that the involvement of HO-1 on the production of pro inflammatory mediators such as NO and TNF-alpha by using a HO-1 inhibitor, Zinc protoporphyrin (Znpp). These results indicate that 12-DHGD may protect against neuro-inflammation by inhibiting Akt/IKK/IkappaB/NF-kappaB pathway and promoting Nrf-2/HO-1 pathway. PMID- 30404130 TI - Antioxidants and Second Messengers of Free Radicals. AB - In the recent years, numerous research on the pathology of oxidative stress has been completed by intense studies on redox signaling implementing various experimental models and clinical trials. [...]. PMID- 30404131 TI - Effect of Ratio in Ammonium Nitrate on the Structural, Microstructural, Magnetic, and AC Conductivity Properties of BaFe12O19. AB - This paper investigates the effect of the ratio of ammonium nitrate (AN) on the structural, microstructural, magnetic, and alternating current (AC) conductivity properties of barium hexaferrite (BaFe12O19). The BaFe12O19 were prepared by using the salt melt method. The samples were synthesized using different powder to-salt weight ratio variations (1:3, 1:4, 1:5, 1:6 and 1:7) of BaCO3 + Fe2O3 and ammonium nitrate salt. The NH4NO3 was melted on a hot plate at 170 degrees C. A mixture of BaCO3 and Fe2O3 were added into the NH4NO3 melt solution and stirred for several hours using a magnetic stirrer under a controlled temperature of 170 degrees C. The heating temperature was then increased up to 260 degrees C for 24 hr to produce an ash powder. The x-ray diffraction (XRD) results show the intense peak of BaFe12O19 for all the samples and the presence of a small amount of the impurity Fe2O3 in the samples, at a ratio of 1:5 and 1:6. From the Fourier transform infra-red (FTIR) spectra, the band appears at 542.71 cm - 1 and 432.48 cm - 1 , which corresponding to metal-oxygen bending and the vibration of the octahedral sites of BaFe12O19. The field emission scanning electron microscope (FESEM) images show that the grains of the samples appear to stick each other and agglomerate at different masses throughout the image with the grain size 5.26, 5.88, 6.14, 6.22, and 6.18 um for the ratios 1:3, 1:4, 1:5, 1:6, and 1:7 respectively. From the vibrating sample magnetometer (VSM) analysis, the magnetic properties of the sample ratio at 1:3 show the highest value of coercivity Hc of 1317 Oe, a saturation magnetization Ms of 91 emu/g, and a remnant Mr of 44 emu/g, respectively. As the temperature rises, the AC conductivity is increases with an increase in frequency. PMID- 30404133 TI - Exploring the Emergence of RNA Nucleosides and Nucleotides on the Early Earth. AB - Understanding how life began is one of the most fascinating problems to solve. By approaching this enigma from a chemistry perspective, the goal is to define what series of chemical reactions could lead to the synthesis of nucleotides, amino acids, lipids, and other cellular components from simple feedstocks under prebiotically plausible conditions. It is well established that evolution of life involved RNA which plays central roles in both inheritance and catalysis. In this review, we present historically important and recently published articles aimed at understanding the emergence of RNA nucleosides and nucleotides on the early Earth. PMID- 30404132 TI - Apoprotein E and Reverse Cholesterol Transport. AB - Apoprotein E (apoE) is a multifunctional protein. Its best-characterized function is as a ligand for low-density lipoprotein (LDL) receptor family members to mediate the clearance of apoB-containing atherogenic lipoproteins. Among its other functions, apoE is involved in cholesterol efflux, especially from cholesterol-loaded macrophage foam cells and other atherosclerosis-relevant cells, and in reverse cholesterol transport. Reverse cholesterol transport is a mechanism by which excess cellular cholesterol is transported via lipoproteins in the plasma to the liver where it can be excreted from the body in the feces. This process is thought to have a role in the attenuation of atherosclerosis. This review summarizes studies on the role of apoE in cellular cholesterol efflux and reverse cholesterol transport and discusses the identification of apoE mimetic peptides that may promote these pathways. PMID- 30404134 TI - Optimization of the Synthesis of Glycerol Derived Monoethers from Glycidol by Means of Heterogeneous Acid Catalysis. AB - We present an efficient and green methodology for the synthesis of glycerol monoethers, starting from glycidol and different alcohols, by means of heterogeneous acid catalysis. A scope of Bronsted and Lewis acid catalysts were applied to the benchmark reaction of glycidol and methanol. The selected catalysts were cationic exchangers, such as Nafion NR50, Dowex 50WX2, Amberlyst 15 and K10-Montmorillonite, both in their protonic form and exchanged with Al(III), Zn(II) and Fe(III). Thus, total conversions were reached in short times by using 1 and 5% mol catalyst loading and room temperature, without the need for excess glycidol or the presence of a solvent. Finally, these conditions and the best catalysts were successfully applied to the reaction of glycidol with several alcohols such as butanol or isopropanol. PMID- 30404135 TI - Immobilized Cells of Bacillus circulans ATCC 21783 on Palm Curtain for Fermentation in 5 L Fermentation Tanks. AB - Palm curtain was selected as carrier to immobilize Bacillus circulans ATCC 21783 to produce beta-cyclodextrin (beta-CD). The influence for immobilization to CGTase activity was analyzed to determine the operation stability. 83.5% cyclodextrin glycosyltransferases (CGTase) of the 1st cycle could be produced in the 7th cycle for immobilized cells, while only 28.90% CGTase was produced with free cells. When palm curtain immobilized cells were reused at the 2th cycle, enzyme activities were increased from 5003 to 5132 U/mL, which was mainly due to physical adsorption of cells on palm curtain with special concave surface structure. Furthermore, conditions for expanded culture of immobilized cells in a 5 L fermentation tank were optimized through specific rotation speed procedure (from 350 r/min to 450 r/min with step size of 50 r/min) and fixed ventilation capacity (4.5 L/min), relations between biomass, enzyme activity, pH, and oxygen dissolution was investigated, and the fermentation periods under the two conditions were both 4 h shorter. Compared with free cell, immobilized cell was more stable, effective, and had better application potential in industries. PMID- 30404136 TI - Prevailing Clusters of Canine Behavioural Traits in Historical US Demand for Dog Breeds (1926-2005). AB - Drawing on American Kennel Club (AKC) puppy registration numbers for approximately 82 varieties of pedigree dogs between 1926 and 2005, the current article analyses behavioural reports on 32,005 dogs of these varieties reported through the Canine Behavioural Assessment and Research Questionnaire (C-BARQ). Cluster analysis of C-BARQ scores indicates that the 82 breeds fell into six clusters. Average scores for each of the 14 behavioural subscales and 22 miscellaneous traits in C-BARQ were calculated for each cluster, and the breeds in each cluster with average scores most similar to the cluster averages were selected as titular breeds. Titular breeds for each cluster were the Maltese terrier, the Great Dane, the Akita, the Australian shepherd, the American Staffordshire terrier, and the Weimaraner. Using the AKC data, we tracked longitudinal trends in annual registration numbers of breeds of each cluster over the period from 1926 to 2005. This period was subdivided into periods with differing overall trends by fitting natural cubic splines to the overall raw trend and considering both the spline and its derivative curves. Differences in the absolute numbers of dogs and trends in registrations over nearly 80 years were identified: an Early period (1926-1944, during which total registration numbers were very low); a Mid-Century Period (1945-1971, during which total registration numbers were tending to rise from year to year); a First Decline (1972-1979, a brief period during which registration numbers experienced a trend of more gradual decline); a Recovery (1980-1992, where registration numbers began to gradually rise again); and a Second Decline (1993-2005, a second sustained period of falling registration numbers, more dramatic than the first decline). The current article describes the ways in which the clustered behaviour of dogs associate with these trends. That said, there is no compelling evidence that shifts in the popularity within or between the clusters reflect consumer canine behavioural preferences. Understanding historic trends in the demand for certain canine behavioural traits could help veterinary and urban animal management stakeholders to anticipate future needs for education and infrastructure. PMID- 30404138 TI - Preparation and Characterization of Expanded Clay-Paraffin Wax-Geo-Polymer Composite Material. AB - Paraffin-based phase change material (PCM) is impregnated into the pores of lightweight expanded clay aggregate (LECA) through vacuum impregnation to develop PCM containing macro-capsules of LECA. Three different grades of LECA varying in size and morphology are investigated to host the PCM to determine the impregnation effectiveness, viability for coating, and its stability. The produced LECA-PCM is coated with geopolymer paste (GP) to provide leak proofing during the phase change. The PCM is thermophysically characterized by employing differential scanning calorimetry (DSC) and the temperature history method (THM) to determine the phase transition and the latent heat. The stability of the macro capsules is determined by weight loss through rapid thermal cycling (RTC) at elevated temperatures. Leakage of the PCM is tested using the diffusion-oozing circle test (DOCT). The results show that the GP coated LECA-PCM macro-capsules achieved 87 wt % impregnation efficiencies and no noticeable loss of PCM, which indicates leak proofing of the developed capsules up to 1000 RTC. PMID- 30404137 TI - Long Low-Loss-Litium Niobate on Insulator Waveguides with Sub-Nanometer Surface Roughness. AB - In this paper, we develop a technique for realizing multi-centimeter-long lithium niobate on insulator (LNOI) waveguides with a propagation loss as low as 0.027 dB/cm. Our technique relies on patterning a chromium thin film coated on the top surface of LNOI into a hard mask with a femtosecond laser followed by chemo mechanical polishing for structuring the LNOI into the waveguides. The surface roughness on the waveguides was determined with an atomic force microscope to be 0.452 nm. The approach is compatible with other surface patterning technologies, such as optical and electron beam lithographies or laser direct writing, enabling high-throughput manufacturing of large-scale LNOI-based photonic integrated circuits. PMID- 30404139 TI - Multi-Year Mapping of Major Crop Yields in an Irrigation District from High Spatial and Temporal Resolution Vegetation Index. AB - Crop yield estimation is important for formulating informed regional and national food trade policies. The introduction of remote sensing in agricultural monitoring makes accurate estimation of regional crop yields possible. However, remote sensing images and crop distribution maps with coarse spatial resolution usually cause inaccuracy in yield estimation due to the existence of mixed pixels. This study aimed to estimate the annual yields of maize and sunflower in Hetao Irrigation District in North China using 30 m spatial resolution HJ-1A/1B CCD images and high accuracy multi-year crop distribution maps. The Normalized Difference Vegetation Index (NDVI) time series obtained from HJ-1A/1B CCD images was fitted with an asymmetric logistic curve to calculate daily NDVI and phenological characteristics. Eight random forest (RF) models using different predictors were developed for maize and sunflower yield estimation, respectively, where predictors of each model were a combination of NDVI series and/or phenological characteristics. We calibrated all RF models with measured crop yields at sampling points in two years (2014 and 2015), and validated the RF models with statistical yields of four counties in six years. Results showed that the optimal model for maize yield estimation was the model using NDVI series from the 120th to the 210th day in a year with 10 days' interval as predictors, while that for sunflower was the model using the combination of three NDVI characteristics, three phenological characteristics, and two curve parameters as predictors. The selected RF models could estimate multi-year regional crop yields accurately, with the average values of root-mean-square error and the relative error of 0.75 t/ha and 6.1% for maize, and 0.40 t/ha and 10.1% for sunflower, respectively. Moreover, the yields of maize and sunflower can be estimated fairly well with NDVI series 50 days before crop harvest, which implicated the possibility of crop yield forecast before harvest. PMID- 30404140 TI - Health Literacy but Not Frailty Predict Self-Care Behaviors in Patients with Heart Failure. AB - Heart failure (HF) is a chronic condition requiring continuous self-care. Health literacy is increasingly recognized as a key factor of self-care behaviors in patients with chronic diseases. Recently, frailty in chronic diseases has also been associated with self-care behaviors. However, relationships among health literacy, frailty, and self-care in the HF population are not well understood. Therefore, this cross-sectional study aimed to identify the impact of health literacy and frailty on self-care behaviors in patients with HF. Data were collected from 281 adults attending a cardiovascular outpatient clinic in Korea. Health literacy, frailty, and self-care behaviors were measured using Korean validated instruments. The mean scores of health literacy and self-care behaviors were 8.89 (+/-3.44) and 31.49 (+/-5.38), respectively. The prevalence of frailty was around 26.3%. Health literacy was significantly associated with frailty and self-care behaviors. In a hierarchical linear regression analysis, health literacy was a significant determinant of self-care behaviors after adjusting for confounding variables, but frailty was not. Educational level was also a significant predictor of self-care behaviors. Our main findings showed that health literacy can facilitate improvements in HF self-care behaviors. Healthcare professionals should assess patients' health literacy and educational backgrounds when designing self-management programs. PMID- 30404141 TI - A Turn-On Detection of DNA Sequences by Means of Fluorescence of DNA-Templated Silver Nanoclusters via Unique Interactions of a Hydrated Ionic Liquid. AB - Nucleic acid stability and structure, which are crucial to the properties of fluorescent DNA-templated silver nanoclusters (DNA-Ag NCs), significantly change in ionic liquids. In this work, our purpose was to study DNA-Ag NCs in a buffer containing the hydrated ionic liquid of choline dihydrogen phosphate (choline dhp) to improve fluorescence for application in DNA detection. Due to the stabilisation of an i-motif structure by the choline cation, a unique fluorescence emission-that was not seen in an aqueous buffer-was observed in choline dhp and remained stable for more than 30 days. A DNA-Ag NCs probe was designed to have greater fluorescence intensity in choline dhp in the presence of a target DNA. A turn-on sensing platform in choline dhp was built for the detection of the BRCA1 gene, which is related to familial breast and ovarian cancers. This platform showed better sensitivity and selectivity in distinguishing a target sequence from a mutant sequence in choline dhp than in the aqueous buffer. Our study provides new evidence regarding the effects of structure on properties of fluorescent DNA-Ag NCs and expands the applications of fluorescent DNA-Ag NCs in an ionic liquid because of improved sensitivity and selectivity. PMID- 30404142 TI - Effects of the Environmental Temperature on Aedes aegypti and Aedes albopictus Mosquitoes: A Review. AB - The temperature of the environment is one of the most important abiotic factors affecting the life of insects. As poikilotherms, their body temperature is not constant, and they rely on various strategies to minimize the risk of thermal stress. They have been thus able to colonize a large spectrum of habitats. Mosquitoes, such as Ae. aegypti and Ae. albopictus, vector many pathogens, including dengue, chikungunya, and Zika viruses. The spread of these diseases has become a major global health concern, and it is predicted that climate change will affect the mosquitoes' distribution, which will allow these insects to bring new pathogens to naive populations. We synthesize here the current knowledge on the impact of temperature on the mosquito flight activity and host-seeking behavior (1); ecology and dispersion (2); as well as its potential effect on the pathogens themselves and how climate can affect the transmission of some of these pathogens (3). PMID- 30404144 TI - Development of Nanocomposite-Based Strain Sensor with Piezoelectric and Piezoresistive Properties. AB - Sensors provide aninterface between mechanical systems and the physical world. With the move towardsIndustry 4.0 and cyber-physical systems, demands for cost effective sensors are rapidly increasing. Conventional sensors used for monitoring manufacturing processes are often bulky and need complex processes. In this study, a novel high-sensitive nanocomposite-based sensor is developed for measuring strain. The developed sensor is comprised of polyvinylidene fluoride (PVDF) as a piezoelectric polymer matrix, and embedded carbon nanotube (CNT) nanoparticles creating a conductive network. Exhibiting both piezoelectric and piezoresistive properties, the developed sensors are capable of strain measurement over a wide frequency band, including static and dynamic measurements. The piezoresistive and piezoelectric properties are fused to improve the overall sensitivity and frequency bandwidth of the sensor. To simulate the sensor, a 3D random walk model and a 2D finite element (FE) model are used to predict the electrical resistivity and the piezoelectric characteristics of the sensor, respectively. The developed models are verified with the experimental results. The developed nanocomposite sensors were employed for strain measurement of a cantilever beam under static load, impulse excitation, free and forced vibrations, collecting both piezoelectric and piezoresistive properties measurements. The obtained signals were fused and compared with those of a reference sensor. The results show that the sensor is capable of strain measurement in the range of 0-10 kHz, indicating its effectiveness at measuring both static and high frequency signals which is an important feature of the sensor. PMID- 30404143 TI - Rapid Separation of Enantiomeric Impurities in Chiral Molecules by a Self Referential Weak Measurement System. AB - We propose a self-referential fast detection scheme for a frequency domain weak measurement system for the detection of enantiomeric impurities in chiral molecules. In a transmissive weak measurement system, the optical rotation (OR) is used to modify the pre-selected polarization state and the post-selection polarization state. We obtained the sum and difference of the optical rotations produced by the sample and the standard by rotating the quarter wave plate in the system. Then, we estimate the ratio of chiral molecules to enantiomeric impurities using the ratio of the central wavelength shifts caused by the addition and subtraction states described above. In this paper, our system has an optical resolution of 1.88 * 10-5 degrees . At the same time, we completed the detection of the ratio of the two substances in the mixture of L-proline and D proline in different proportions, which proved that our system can quickly detect the content of enantiomeric impurities in chiral molecules. PMID- 30404145 TI - Phytochemical Molluscicides and Schistosomiasis: What We Know and What We Still Need to Learn. AB - Worldwide schistosomiasis remains a serious public health problem with approximately 67 million people infected and 200 million at risk of infection from inhabiting or transiting endemically active regions. Africa, South America, the Caribbean, and the Middle East are the main transmission regions of Schistosoma mansoni. The fight against transmission through the use of molluscicides is not recent and has been advocated as the only activity with the possibility of interruption of transmission in small, epidemiologically active outbreaks. Euphorbia milii var. hislopii (syn. splendens) (Des Moulins, 1826) is the most promising for use in official schistosomiasis control programs according to the WHO. In this review, we show that an understanding of some how E. milii latex affects the snail vector and their parasites from a molecular level to field conditions is lacking. On the other hand, this type of treatment could also provide a rationale for the control of schistosomiasis and other parasitosis. Several publications contribute to enforcing the use of E. milii latex in endemic countries as a cheap alternative or complement to mass drug treatment with praziquantel, the only available drug to cure the patients (without preventing re infection). PMID- 30404146 TI - Real-Space Probing of the Local Magnetic Response of Thin-Film Superconductors Using Single Spin Magnetometry. AB - We report on direct, real-space imaging of the stray magnetic field above a micro scale disc of a thin film of the high-temperature superconductor YBa2Cu3O7-delta (YBCO) using scanning single spin magnetometry. Our experiments yield a direct measurement of the sample's London penetration depth and allow for a quantitative reconstruction of the supercurrents flowing in the sample as a result of Meissner screening. These results show the potential of scanning single spin magnetometry for studies of the nanoscale magnetic properties of thin-film superconductors, which could be readily extended to elevated temperatures or magnetic fields. PMID- 30404147 TI - Bereaved Family Members' Satisfaction with Care during the Last Three Months of Life for People with Advanced Illness. AB - BACKGROUND: Studies evaluating the end-of-life care for longer periods of illness trajectories and in several care places are currently lacking. This study explored bereaved family members' satisfaction with care during the last three months of life for people with advanced illness, and associations between satisfaction with care and characteristics of the deceased individuals and their family members. METHODS: A cross-sectional survey design was used. The sample was 485 family members of individuals who died at four different hospitals in Sweden. RESULTS: Of the participants, 78.7% rated the overall care as high. For hospice care, 87.1% reported being satisfied, 87% with the hospital care, 72.3% with district/county nurses, 65.4% with nursing homes, 62.1% with specialized home care, and 59.6% with general practitioners (GPs). Family members of deceased persons with cancer were more likely to have a higher satisfaction with the care. A lower satisfaction was more likely if the deceased person had a higher educational attainment and a length of illness before death of one year or longer. CONCLUSION: The type of care, diagnoses, length of illness, educational attainment, and the relationship between the deceased person and the family member influences the satisfaction with care. PMID- 30404148 TI - Anthracyclines as Topoisomerase II Poisons: From Early Studies to New Perspectives. AB - Mammalian DNA topoisomerases II are targets of anticancer anthracyclines that act by stabilizing enzyme-DNA complexes wherein DNA strands are cut and covalently linked to the protein. This molecular mechanism is the molecular basis of anthracycline anticancer activity as well as the toxic effects such as cardiomyopathy and induction of secondary cancers. Even though anthracyclines have been used in the clinic for more than 50 years for solid and blood cancers, the search of breakthrough analogs has substantially failed. The recent developments of personalized medicine, availability of individual genomic information, and immune therapy are expected to change significantly human cancer therapy. Here, we discuss the knowledge of anthracyclines as Topoisomerase II poisons, their molecular and cellular effects and toxicity along with current efforts to improve the therapeutic index. Then, we discuss the contribution of the immune system in the anticancer activity of anthracyclines, and the need to increase our knowledge of molecular mechanisms connecting the drug targets to the immune stimulatory pathways in cancer cells. We propose that the complete definition of the molecular interaction of anthracyclines with the immune system may open up more effective and safer ways to treat patients with these drugs. PMID- 30404149 TI - Extraction and Analysis of Phenolic Compounds in Rice: A Review. AB - Rice represents the main source of calorie intake in many world countries and about 60% of the world population include rice in their staple diet. Whole grain rice, also called brown rice, represent the unpolished version of the more common white rice including bran, germ, and endosperm. Many health-promoting properties have been associated to the consumption of whole grain rice and, for this reason, great attention has been paid by the scientific community towards the identification and the quantification of bioactive compounds in this food item. In this contribution, the last five years progresses in the quali-quantitative determination of phenolic compounds in rice have been highlighted. Special attention has been devoted to the most recent strategies for the extraction of the target compounds from rice along with the analytical approaches adopted for the separation, identification and quantification of phenolic acids, flavonoids, anthocyanins, and proanthocyanidins. More specifically, the main features of the "traditional" extraction methods (i.e., maceration, ultrasound-assisted extraction) have been described, as well as the more innovative protocols involving advanced extraction techniques, such as MAE (microwave-assisted extraction). The predominant role of HPLC in the definition of the phenolic profile has been examined also presenting the most recent results obtained by using mass spectrometry-based detection systems. In addition, the most common procedures aimed to the quantification of the total amount of the cited classes of phenolic compounds have been described together with the spectrophotometric protocols aimed to the evaluation of the antioxidant properties of rice phenolic extracts (i.e., FRAP, DPPH, ABTS and ORAC). PMID- 30404151 TI - AMP-Activated Protein Kinase (AMPK)-Dependent Regulation of Renal Transport. AB - AMP-activated kinase (AMPK) is a serine/threonine kinase that is expressed in most cells and activated by a high cellular AMP/ATP ratio (indicating energy deficiency) or by Ca2+. In general, AMPK turns on energy-generating pathways (e.g., glucose uptake, glycolysis, fatty acid oxidation) and stops energy consuming processes (e.g., lipogenesis, glycogenesis), thereby helping cells survive low energy states. The functional element of the kidney, the nephron, consists of the glomerulus, where the primary urine is filtered, and the proximal tubule, Henle's loop, the distal tubule, and the collecting duct. In the tubular system of the kidney, the composition of primary urine is modified by the reabsorption and secretion of ions and molecules to yield final excreted urine. The underlying membrane transport processes are mainly energy-consuming (active transport) and in some cases passive. Since active transport accounts for a large part of the cell's ATP demands, it is an important target for AMPK. Here, we review the AMPK-dependent regulation of membrane transport along nephron segments and discuss physiological and pathophysiological implications. PMID- 30404150 TI - Associations among Bruxism, Gastroesophageal Reflux Disease, and Tooth Wear. AB - The relationship between bruxism and tooth wear is contentious in the literature. The pathophysiological processes of tooth wear may be complicated by the relationship between bruxism and gastroesophageal reflux disease (GERD). The objective of this study was to evaluate the associations among bruxism, GERD, and tooth wear. Two complementary studies were performed: a case-control study to verify the linkage between GERD and bruxism and a cross-sectional study on the same cohort to establish the connection between GERD and tooth wear in bruxism patients. A cohort of 363 consecutive bruxism patients and 363 matched control participants were recruited. Gastroesophageal reflux disease was diagnosed in accordance with the Montreal criteria. Tooth wear was scored based on the index recommended by Smith and Knight. Logistic regression analyses were performed. After adjustment, GERD was identified as a risk factor of bruxism. Bruxism with reflux symptoms for extensive time-periods was associated with severe tooth wear for the whole dentition (odds ratio, 4.70, 95% confidence interval, 2.04-10.83). Increased odds ratios for severe tooth wear were also found in all tooth locations and palatal/lingual and occlusal/incisal surfaces of bruxism patients with GERD for extensive time-periods. In conclusion, strong associations were identified among bruxism, GERD, and tooth wear. PMID- 30404152 TI - First Description of Colistin and Tigecycline-Resistant Acinetobacter baumannii Producing KPC-3 Carbapenemase in Portugal. AB - Herein, we describe a case report of carbapenem-resistant Acinetobacter baumannii and Klebsiella pneumoniae isolates that were identified from the same patient at a Tertiary University Hospital Centre in Portugal. Antimicrobial susceptibility and the molecular characterization of resistance and virulence determinants were performed. PCR screening identified the presence of the resistance genes blaKPC 3, blaTEM-1 and blaSHV-1 in both isolates. The KPC-3 K. pneumoniae isolate belonged to the ST-14 high risk clone and accumulated an uncommon resistance and virulence profile additional to a horizontal dissemination capacity. In conclusion, the molecular screening led to the first identification of the A. baumannii KPC-3 producer in Portugal with a full antimicrobial resistance profile including tigecycline and colistin. PMID- 30404153 TI - Pinpointed Stimulation of EphA2 Receptors via DNA-Templated Oligovalence. AB - DNA nanostructures enable the attachment of functional molecules to nearly any unique location on their underlying structure. Due to their single-base-pair structural resolution, several ligands can be spatially arranged and closely controlled according to the geometry of their desired target, resulting in optimized binding and/or signaling interactions. Here, the efficacy of SWL, an ephrin-mimicking peptide that binds specifically to EphrinA2 (EphA2) receptors, increased by presenting up to three of these peptides on small DNA nanostructures in an oligovalent manner. Ephrin signaling pathways play crucial roles in tumor development and progression. Moreover, Eph receptors are potential targets in cancer diagnosis and treatment. Here, the quantitative impact of SWL valency on binding, phosphorylation (key player for activation) and phenotype regulation in EphA2-expressing prostate cancer cells was demonstrated. EphA2 phosphorylation was significantly increased by DNA trimers carrying three SWL peptides compared to monovalent SWL. In comparison to one of EphA2's natural ligands ephrin-A1, which is known to bind promiscuously to multiple receptors, pinpointed targeting of EphA2 by oligovalent DNA-SWL constructs showed enhanced cell retraction. Overall, we show that DNA scaffolds can increase the potency of weak signaling peptides through oligovalent presentation and serve as potential tools for examination of complex signaling pathways. PMID- 30404154 TI - Analytical Profiling of Proanthocyanidins from Acacia mearnsii Bark and In Vitro Assessment of Antioxidant and Antidiabetic Potential. AB - The proanthocyanidins from ethanol extracts (80%, v/v) of Acacia mearnsii (A. mearnsii) bark on chemical-based and cellular antioxidant activity assays as well as carbolytic enzyme inhibitory activities were studied. About 77% of oligomeric proanthocyanidins in ethanol extracts of A. mearnsii bark were found by using normal-phase HPLC. In addition, HPLC-ESI-TOF/MS and MALDI-TOF/TOF MS analyses indicated that proanthocyanidins from A. mearnsii bark exhibited with a degree of polymerization ranging from 1 to 11. These results of combined antioxidant activity assays, as well as carbolytic enzyme inhibitory activities of proanthocyanidins from A. mearnsii bark, indicated an encouraging antioxidant capacity for the high polyphenol content and a potential for use as alternative drugs for lowering the glycemic response. PMID- 30404155 TI - Multitarget Tracking Algorithm Based on Adaptive Network Graph Segmentation in the Presence of Measurement Origin Uncertainty. AB - To deal with the problem of multitarget tracking with measurement origin uncertainty, the paper presents a multitarget tracking algorithm based on Adaptive Network Graph Segmentation (ANGS). The multitarget tracking is firstly formulated as an Integer Programming problem for finding the maximum a posterior probability in a cost flow network. Then, a network structure is partitioned using an Adaptive Spectral Clustering algorithm based on the Nystrom Method. In order to obtain the global optimal solution, the parallel A* search algorithm is used to process each sub-network. Moreover, the trajectory set is extracted by the Track Mosaic technique and Rauch-Tung-Striebel (RTS) smoother. Finally, the simulation results achieved for different clutter intensity indicate that the proposed algorithm has better tracking accuracy and robustness compared with the A* search algorithm, the successive shortest-path (SSP) algorithm and the shortest path faster (SPFA) algorithm. PMID- 30404156 TI - Temperature Measurement Method for Blast Furnace Molten Iron Based on Infrared Thermography and Temperature Reduction Model. AB - The temperature measurement of blast furnace (BF) molten iron is a mandatory requirement in the ironmaking process, and the molten iron temperature is significant in estimating the molten iron quality and control blast furnace condition. However, it is not easy to realize real-time measurement of molten iron temperature because of the harsh environment in the blast furnace casthouse and the high-temperature characteristics of molten iron. To achieve continuous detection of the molten iron temperature of the blast furnace, this paper proposes a temperature measurement method based on infrared thermography and a temperature reduction model. Firstly, an infrared thermal imager is applied to capture the infrared thermal image of the molten iron flow after the skimmer. Then, based on the temperature distribution of the molten iron flow region, a temperature mapping model is established to measure the molten iron temperature after the skimmer. Finally, a temperature reduction model is developed to describe the relationship between the molten iron temperature at the taphole and skimmer, and the molten iron temperature at the taphole is calculated according to the temperature reduction model and the molten iron temperature after the skimmer. Industrial experiment results illustrate that the proposed method can achieve simultaneous measurement of molten iron temperature at the skimmer and taphole and provide reliable temperature data for regulating the blast furnace. PMID- 30404157 TI - The Mitochondrial Genes BAK1, FIS1 and SFN are Linked with Alterations in Mitochondrial Membrane Potential in Barrett's Esophagus. AB - Barrett's esophagus and esophageal cancer lack prognostic markers that allow the tailoring of personalized medicine and biomarkers with potential to provide insight into treatment response. This study aims to characterize mitochondrial function across the metaplasia-dysplasia-adenocarcinoma disease sequence in Barrett's esophagus and examines the functional effect of manipulating mitochondrial genes. Mitochondrial genes of interest were validated in in vitro cell lines across the metaplasia (QH), dysplasia (GO) and adenocarcinoma (OE33) sequence and in in vivo patient tissue samples. These genes were subsequently knocked down in QH and OE33 cells and the functional effect of siRNA-induced knockdown on reactive oxygen species production, mitochondrial mass, mitochondrial membrane potential and cellular metabolism was investigated. Three global mitochondrial genes (BAK1, FIS1 and SFN) were differentially altered across the in vivo Barrett's disease sequence. We also demonstrate that knockdown of BAK1, FIS1 and SFN in vitro resulted in significant alterations in mitochondrial membrane potential; however, no differences in reactive oxygen species or mitochondrial mass were observed. Furthermore, knockdown of these genes in esophageal adenocarcinoma cells significantly altered cellular metabolism. In conclusion, we found that differential expression of BAK1, FIS1, and SFN were altered across the Barrett's disease sequence and manipulation of these genes elicited significant effects on mitochondrial membrane potential. PMID- 30404158 TI - Toxin Profiles of Okadaic Acid Analogues and Other Lipophilic Toxins in Dinophysis from Japanese Coastal Waters. AB - The identification and quantification of okadaic acid (OA)/dinophysistoxin (DTX) analogues and pectenotoxins (PTXs) in Dinophysis samples collected from coastal locations around Japan were evaluated by liquid chromatography mass spectrometry. The species identified and analyzed included Dinophysis fortii, D. acuminata, D. mitra (Phalacroma mitra), D. norvegica, D. infundibulus, D. tripos, D. caudata, D. rotundata (Phalacroma rotundatum), and D. rudgei. The dominant toxin found in D. acuminata was PTX2 although some samples contained DTX1 as a minor toxin. D. acuminata specimens isolated from the southwestern regions (Takada and Hiroshima) showed characteristic toxin profiles, with only OA detected in samples collected from Takada. In contrast, both OA and DTX1, in addition to a larger proportion of PTX2, were detected in D. acuminata from Hiroshima. D. fortii showed a toxin profile dominated by PTX2 although this species had higher levels of DTX1 than D. acuminata. OA was detected as a minor toxin in some D. fortii samples collected from Yakumo, Noheji, and Hakata. PTX2 was also the dominant toxin found among other Dinophysis species analyzed, such as D. norvegica, D. tripos, and D. caudata, although some pooled picked cells of these species contained trace levels of OA or DTX1. The results obtained in this study re-confirm that cellular toxin content and profiles are different even among strains of the same species. PMID- 30404159 TI - Functional Insights into the Roles of Hormones in the Dendrobium officinale Tulasnella sp. Germinated Seed Symbiotic Association. AB - Dendrobium is one of the largest genera in the Orchidaceae, and D. officinale is used in traditional medicine, particularly in China. D. officinale seeds are minute and contain limited energy reserves, and colonization by a compatible fungus is essential for germination under natural conditions. When the orchid mycorrhizal fungi (OMF) initiates symbiotic interactions with germination-driven orchid seeds, phytohormones from the orchid or the fungus play key roles, but the details of the possible biochemical pathways are still poorly understood. In the present study, we established a symbiotic system between D. officinale and Tulasnella sp. for seed germination. RNA-Seq was used to construct libraries of symbiotic-germinated seeds (DoTc), asymbiotic-germinated seeds (Do), and free living OMF (Tc) to investigate the expression profiles of biosynthesis and metabolism pathway genes for three classes of endogenous hormones: JA (jasmonic acid), ABA (abscisic acid) and SLs (strigolactones), in D. officinale seeds and OMF under symbiotic and asymbiotic conditions. Low concentrations of endogenous JA, ABA, or SLs were detected in the D. officinale-Tulasnella symbiont compared with the asymbiotic tissues. Gene annotation results suggest that the expression of DEGs (differentially expressed genes) related to JA and ABA biosynthesis from D. officinale were down-regulated, while most of the key DEGs related to SL biosynthesis from D. officinale were up-regulated in the symbiotic germinated seeds compared with the asymbiotic germinated seeds. Moreover, in the OMF, we found a significantly up-regulated differential expression of the JA and ABA biosynthesis-related genes in the symbiotic interaction, with the opposite expression trends to those found in Dendrobium. This indicates that Dendrobium seed symbiotic germination may be stimulated by the apparent involvement of the OMF in the production of hormones, and relatively low concentrations of endogenous JA, ABA, or SLs might be maintained to promote the growth of the D. officinale-Tulasnella symbiotic protocorm-like body. These results will increase our understanding of the possible roles played by endogenous hormones in the regulation of the orchid-fungus symbiosis. PMID- 30404160 TI - Antibiotic Use on Goat Farms: An Investigation of Knowledge, Attitudes, and Behaviors of Missouri Goat Farmers. AB - Use of low dose, prophylactic antibiotics contributes to the emergence of antibiotic resistant bacteria. In one study, goat meat in Missouri was found to have a higher percentage of antibiotic residues at slaughter than the national average, so we attempted to identify factors related to goat production that may contribute to this issue. Using the knowledge, attitude, and behavior (KAB) model, we interviewed 11 Missouri goat farmers about factors affecting antibiotic use. Most of the farmers did not have specific protocols for managing illnesses and only relied on veterinarians for major health issues. Many felt veterinarians lacked knowledge about goat medicine so instead relied on other farmers' or their own experiences for treatment modalities. While most agreed that antibiotic resistance was a concern, only 4 of the 11 indicated that they only used antibiotics when prescribed by the veterinarian. Veterinarians should be relied on and valued for their medical expertise, but they are not always being utilized in this manner. Therefore, veterinary education should emphasize goat health management to a greater extent than it currently does, and soft skills to build collaborative relationships with farmers should be taught to promote preventative health measures and more judicious use of antibiotics. PMID- 30404161 TI - In Silico Prediction of O6-Methylguanine-DNA Methyltransferase Inhibitory Potency of Base Analogs with QSAR and Machine Learning Methods. AB - O6-methylguanine-DNA methyltransferase (MGMT), a unique DNA repair enzyme, can confer resistance to DNA anticancer alkylating agents that modify the O6-position of guanine. Thus, inhibition of MGMT activity in tumors has a great interest for cancer researchers because it can significantly improve the anticancer efficacy of such alkylating agents. In this study, we performed a quantitative structure activity relationship (QSAR) and classification study based on a total of 134 base analogs related to their ED50 values (50% inhibitory concentration) against MGMT. Molecular information of all compounds were described by quantum chemical descriptors and Dragon descriptors. Genetic algorithm (GA) and multiple linear regression (MLR) analysis were combined to develop QSAR models. Classification models were generated by seven machine-learning methods based on six types of molecular fingerprints. Performances of all developed models were assessed by internal and external validation techniques. The best QSAR model was obtained with Q2Loo = 0.83, R2 = 0.87, Q2ext = 0.67, and R2ext = 0.69 based on 84 compounds. The results from QSAR studies indicated topological charge indices, polarizability, ionization potential (IP), and number of primary aromatic amines are main contributors for MGMT inhibition of base analogs. For classification studies, the accuracies of 10-fold cross-validation ranged from 0.750 to 0.885 for top ten models. The range of accuracy for the external test set ranged from 0.800 to 0.880 except for PubChem-Tree model, suggesting a satisfactory predictive ability. Three models (Ext-SVM, Ext-Tree and Graph-RF) showed high and reliable predictive accuracy for both training and external test sets. In addition, several representative substructures for characterizing MGMT inhibitors were identified by information gain and substructure frequency analysis method. Our studies might be useful for further study to design and rapidly identify potential MGMT inhibitors. PMID- 30404162 TI - Regulating the Optoelectronic Properties of Nickel Dithiolene by the Substituents: A Theoretical Study. AB - Dithiolene-based complexes show great potential to be applied as materials for organic optoelectronic devices. In this study, we theoretically designed a series of complexes based on nickel dithiolene and its substituted derivatives, the optoelectronic properties of which were comparatively studied by density functional theory (DFT)/time-dependent density functional theory (TD-DFT). The results show that the charge injection property of nickel dithiolene complexes can be significantly improved with introduction of electron-withdrawing groups. The charge transportation property of nickel dithiolene depends on the conjugation degree of the system. The energy gaps between highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) are determined by the substituents, which makes the maximum absorption wavelength red shift from the visible to the near-infrared (NIR) region. The electron density difference graph shows that the electron transition from the ground state to the first excited state is assigned to pi-pi* transition mainly from HOMO to LUMO. The regularity of substituent effect revealed by us in this study will shed light on the application of nickel dithiolenes as potential optoelectronic materials. PMID- 30404163 TI - A Comparative Quantitative LC-MS/MS Profiling Analysis of Human Pancreatic Adenocarcinoma, Adjacent-Normal Tissue, and Patient-Derived Tumour Xenografts. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide; it develops in a relatively symptom-free manner, leading to rapid disease progression and metastasis, leading to a 5-year survival rate of less than 5%. A lack of dependable diagnostic markers and rapid development of resistance to conventional therapies are among the problems associated with management of the disease. A better understanding of pancreatic tumour biology and discovery of new potential therapeutic targets are important goals in pancreatic cancer research. This study describes the comparative quantitative LC MS/MS proteomic analysis of the membrane-enriched proteome of 10 human pancreatic ductal adenocarcinomas, 9 matched adjacent-normal pancreas and patient-derived xenografts (PDXs) in mice (10 at F1 generation and 10 F2). Quantitative label free LC-MS/MS data analysis identified 129 proteins upregulated, and 109 downregulated, in PDAC, compared to adjacent-normal tissue. In this study, analysing peptide MS/MS data from the xenografts, great care was taken to distinguish species-specific peptides definitively derived from human sequences, or from mice, which could not be distinguished. The human-only peptides from the PDXs are of particular value, since only human tumour cells survive, and stromal cells are replaced during engraftment in the mouse; this list is, therefore, enriched in tumour-associated proteins, some of which might be potential therapeutic or diagnostic targets. Using human-specific sequences, 32 proteins were found to be upregulated, and 113 downregulated in PDX F1 tumours, compared to primary PDAC. Differential expression of CD55 between PDAC and normal pancreas, and expression across PDX generations, was confirmed by Western blotting. These data indicate the value of using PDX models in PDAC research. This study is the first comparative proteomic analysis of PDAC which employs PDX models to identify patient tumour cell-associated proteins, in an effort to find robust targets for therapeutic treatment of PDAC. PMID- 30404164 TI - Systemic Capillary Leak Syndrome (Clarkson Syndrome) in Cancer Patients: A Systematic Review. AB - Systemic capillary leak syndrome (SCLS) is a rare disease characterized by shock caused by capillary hyperpermeability. The disease can occur in cancer patients and effective therapeutic strategies have not been established yet. The aim of the study was to analyze the clinical and laboratory data, treatment modalities, and mortality rate of patients and to identify contributing factors leading to mortality of SCLS in cancer. We searched MEDLINE (inception to July 2018) and of 4612 articles, we identified 62 case reports on SCLS associated with cancer or cancer-related drugs in a total of 53 articles. SCLS was associated with cancer itself in 43.6%, with anti-cancer agents in 51.6% and bone marrow transplantation (BMT) in 4.8%. Among anti-cancer agents, granulocyte-colony stimulating factor (G CSF) was the most frequently associated drug (14.6%), followed by interleukin (IL)-2 (11.4%). The most common associated malignancies were hematologic (61.3%) with non-Hodgkin lymphoma (22.7%) and multiple myeloma (12.9%) being the leading causes. Common symptoms and signs included dyspnea (27.4%), edema (67.7%), hypotension (32.2%), pleural effusion (29.0%), ascites (22.7%), oliguria (22.7%), and weight gain (21.0%). Patients with SCLS were treated with steroids (59.7%), volume replacement (33.8%), diuretics (24.2%), inotropes (9.6%), methylxanthines (12.8%), beta2 agonists (4.8%), while intravenous immunoglobulins (IVIG) were administered in 2 patients (3.2%) only. Among sixteen deaths during follow-up, four were directly attributed to SCLS. Hematologic malignancies were associated with an increased risk for mortality (hazard ratio (HR) 8.820, 95% confidence interval (CI) 1.126-69.063, p = 0.038). Taken together, SCLS can be one important adverse event in cancer patients and careful monitoring of fluid volume is required in the management of SCLS. PMID- 30404165 TI - Off-Training Levels of Physical Activity and Sedentary Behavior in Young Athletes: Preliminary Results during a Typical Week. AB - The level of physical activity (PA) and sedentary behavior (SED) off-training of young athletes may reveal the quality of recovery from training and highlight health related issues. Thus, the aim was to identify and describe young athletes' PA and SED off-training, according to daily life activities. Eight athletes (15.7 +/- 2 years, 1.72 +/- 0.6 m height, 62.9 +/- 10.2 kg) of a sport talent program wore on their waist a tri-axial accelerometer (ActiGraph(r) wGT9X-link, Shalimar, FL, USA) at 30 Hz for 15 consecutive days, and reported their schedule. A two step cluster analysis classified three groups according to sedentary PA and MVPA. The Sedentary (56.9%), presented the highest sedentary PA (mean [CI], 37.37 [36.45-38.29] min/hour); The Hazardous (19.4%) had the lowest values of sedentary and MVPA (10.07 [9.41-10.36] min/hour and 8.67 [7.64-9.70] min/hour, respectively). Balanced (23.7%) had the highest MVPA (28.61 [27.16-30.07] min/hour). Sedentary had the lowest count of home time associated (20%) and higher school (26%) time when compared to the Hazardous (13%). The Balanced showed the highest count of school (61%) and home time (47%). Different profiles for young athletes revealed alarming behavior in the associations with sedentary PA, sitting and SED breaks, which may influence performance and health. PMID- 30404166 TI - Electron-Transfer Properties of Phenyleneethynylene Linkers Bound to Gold via a Self-Assembled Monolayer of Molecular Tripod. AB - The three-point adsorption of tripod-shaped molecules enables the formation of robust self-assembled monolayers (SAMs) on solid surfaces, where the component molecules are fixed in a strictly upright orientation. In the present study, SAMs of a rigid molecular tripod consisting of an adamantane core and three CH2SH groups were employed to arrange ferrocene on a gold surface through oligo(p phenyleneethynylene) linkers. Cyclic voltammetry of the monolayers demonstrated high surface coverage of ferrocene, yet the molecular interaction among adjacent ferrocene units was negligible. This was because of the extended intermolecular distance caused by the bulky tripod framework. The rates of electron transfer from the ferrocene to the gold surface through different linker lengths were determined by electrochemical measurements, from which the decay factor for oligo(p-phenyleneethynylene) wire was evaluated. PMID- 30404167 TI - A Novel High Sensitivity Type II Collagen Blood-Based Biomarker, PRO-C2, for Assessment of Cartilage Formation. AB - N-terminal propeptide of type II collagen (PIINP) is a biomarker reflecting cartilage formation. PIINP exists in two main splice variants termed as type IIA and type IIB collagen NH2-propeptide (PIIANP, PIIBNP). PIIANP has been widely recognized as a cartilage formation biomarker. However, the utility of PIIBNP as a marker in preclinical and clinical settings has not been fully investigated yet. In this study, we aimed to characterize an antibody targeting human PIIBNP and to develop an immunoassay assessing type II collagen synthesis in human blood samples. A high sensitivity electrochemiluminescence immunoassay, hsPRO-C2, was developed using a well-characterized antibody against human PIIBNP. Human cartilage explants from replaced osteoarthritis knees were cultured for ten weeks in the presence of growth factors, insulin-like growth factor 1 (IGF-1) or recombinant human fibroblast growth factor 18 (rhFGF-18). The culture medium was changed every seven days, and levels of PIIBNP, PIIANP, and matrix metalloproteinase 9-mediated degradation of type II collagen (C2M) were analyzed herein. Serum samples from a cross-sectional knee osteoarthritis cohort, as well as pediatric and rheumatoid arthritis samples, were assayed for PIIBNP and PIIANP. Western blot showed that the antibody recognized PIIBNP either as a free fragment or attached to the main molecule. Immunohistochemistry demonstrated that PIIBNP was predominately located in the extracellular matrix of the superficial and deep zones and chondrocytes in both normal and osteoarthritic articular cartilage. In addition, the hsPRO-C2 immunoassay exhibits acceptable technical performances. In the human cartilage explants model, levels of PIIBNP, but not PIIANP and C2M, were increased (2 to 7-fold) time-dependently in response to IGF 1. Moreover, there was no significant correlation between PIIBNP and PIIANP levels when measured in knee osteoarthritis, rheumatoid arthritis, and pediatric serum samples. Serum PIIBNP was significantly higher in controls (KL0/1) compared to OA groups (KL2/3/4, p = 0.012). The hsPRO-C2 assay shows completely different biological and clinical patterns than PIIANP ELISA, suggesting that it may be a promising biomarker of cartilage formation. PMID- 30404168 TI - A THz Receiver with Novel Features and Functionality. AB - The presented THz receiver is based on an antenna coupled titanium micro bolometer. A new geometrical design improves the robustness and extends the lifetime of the sensor. A study of sensor lifetime using different biasing currents is presented. The lifetime was verified by several tests and over 1000 operating hours. A new micro-bolometer sensitivity measurement algorithm is presented in the paper and measurement results using the proposed algorithm are shown. The new algorithm was developed to be suitable for ATM production testing. In the paper, a novel feature called "sensitivity boosting" is described, together with its influence on sensitivity and lifetime. PMID- 30404169 TI - Label-Free Monitoring of Uptake and Toxicity of Endoprosthetic Wear Particles in Human Cell Cultures. AB - The evaluation of the biological effects of endoprosthetic wear particles on cells in vitro relies on a variety of test assays. However, most of these methods are susceptible to particle-induced interferences; therefore, label-free testing approaches emerge as more reliable alternatives. In this study, impedance-based real-time monitoring of cellular viability and metabolic activity were performed following exposure to metallic and ceramic wear particles. Moreover, label-free imaging of particle-exposed cells was done by high-resolution darkfield microscopy (HR-ODM) and field emission scanning electron microscopy (FESEM). The isolated human fibroblasts were exposed to CoCr28Mo6 and alumina matrix composite (AMC) ceramic particles. HR-ODM and FESEM revealed ingested particles. For impedance measurements, cells were seeded on gold-plated microelectrodes. Cellular behavior was monitored over a period of 48 h. CoCr28Mo6 and AMC particle exposure affected cell viability in a concentration-dependent manner, i.e., 0.01 mg/mL particle solutions led to small changes in cell viability, while 0.05 mg/mL resulted in a significant reduction of viability. The effects were more pronounced after exposure to CoCr28Mo6 particles. The results were in line with light and darkfield microcopy observations indicating that the chosen methods are valuable tools to assess cytotoxicity and cellular behavior following exposure to endoprosthetic wear particles. PMID- 30404170 TI - Field Testing of the Use of Intake24-An Online 24-Hour Dietary Recall System. AB - Dietary assessment is important for monitoring and evaluating population intakes. Online tools can reduce the level of participant burden and the time taken to complete records, compared with other methods. The study aimed to field test an online dietary recall tool (Intake24) to test the suitability for collecting dietary information in Scottish national surveys and to develop the system based on feedback and emerging issues. Previous Scottish Health Survey participants, aged 11+ years, were invited to complete Intake24 and provide feedback about it. Of those who agreed to take part, 60% completed at least one recall. Intake24 was found to be user-friendly, enjoyable to use, and easy to follow and understand. Users agreed they would like to use Intake24 often, (44% compared with 15% who disagreed) and >75% felt the system accurately captured their dietary intakes. The main challenge reported was finding foods within the database. Of those completing fewer recalls than requested, the majority reported that they believed they had completed the required number or reported not receiving emails requesting they complete a further recall. Intake24 was found to be a user friendly tool allowing dietary assessment without interviewer presence. Feedback indicated the method for recall reminders needs to be refined and tailored. PMID- 30404171 TI - Enhancement of Image Quality in LCD by Doping gamma-Fe2O3 Nanoparticles and Reducing Friction Torque Difference. AB - Improving image sticking in liquid crystal display (LCD) has attracted tremendous interest because of its potential to enhance the quality of the display image. Here, we proposed a method to evaluate the residual direct current (DC) voltage by varying liquid crystal (LC) cell capacitance under the combined action of alternating current (AC) and DC signals. This method was then used to study the improvement of image sticking by doping gamma-Fe2O3 nanoparticles into LC materials and adjusting the friction torque difference of the upper and lower substrates. Detailed analysis and comparison of residual characteristics for LC materials with different doping concentrations revealed that the LC material, added with 0.02 wt% gamma-Fe2O3 nanoparticles, can absorb the majority of free ions stably, thereby reducing the residual DC voltage and extending the time to reach the saturated state. The physical properties of the LC materials were enhanced by the addition of a small amount of nanoparticles and the response time of doping 0.02 wt% gamma-Fe2O3 nanoparticles was about 10% faster than that of pure LC. Furthermore, the lower absolute value of the friction torque difference between the upper and lower substrates contributed to the reduction of the residual DC voltage induced by ion adsorption in the LC cell under the same conditions. To promote the image quality of different display frames in the switching process, we added small amounts of the nanoparticles to the LC materials and controlled friction technology accurately to ensure the same torque. Both approaches were proven to be highly feasible. PMID- 30404173 TI - Development of an Immunoassay for Detection of Staphylococcal Enterotoxin-Like J, A Non-Characterized Toxin. AB - Staphylococcal enterotoxins (SEs) are the cause of staphylococcal food poisoning (SFP) outbreaks. Recently, many new types of SEs and SE-like toxins have been reported, but it has not been proved whether these new toxins cause food poisoning. To develop an immunoassay for detection of SE-like J (SElJ), a non characterized toxin in SFP, a mutant SElJ with C-terminus deletion (SElJ?C) was expressed and purified in an E. coli expression system. Anti-SElJ antibody was produced in rabbits immunized with the SElJ?C. Western blotting and sandwich enzyme-linked immunosorbent assay (ELISA) detection systems were established and showed that the antibody specifically recognizes SElJ without cross reaction to other SEs tested. The limit of detection for the sandwich ELISA was 0.078 ng/mL, showing high sensitivity. SElJ production in S. aureus was detected by using the sandwich ELISA and showed that selj-horboring isolates produced a large amount of SElJ in the culture supernatants, especially in that of the strain isolated from a food poisoning outbreak in Japan. These results demonstrate that the immunoassay for detection of SElJ is specific and sensitive and is useful for determining the native SElJ production in S. aureus isolated from food poisoning cases. PMID- 30404172 TI - A Distinct Pattern of Circulating Amino Acids Characterizes Older Persons with Physical Frailty and Sarcopenia: Results from the BIOSPHERE Study. AB - Physical frailty and sarcopenia (PF&S) are hallmarks of aging that share a common pathogenic background. Perturbations in protein/amino acid metabolism may play a role in the development of PF&S. In this initial report, 68 community-dwellers aged 70 years and older, 38 with PF&S and 30 non-sarcopenic, non-frail controls (nonPF&S), were enrolled as part as the "BIOmarkers associated with Sarcopenia and Physical frailty in EldeRly pErsons" (BIOSPHERE) study. A panel of 37 serum amino acids and derivatives was assayed by UPLC-MS. Partial Least Squares Discriminant Analysis (PLS-DA) was used to characterize the amino acid profile of PF&S. The optimal complexity of the PLS-DA model was found to be three latent variables. The proportion of correct classification was 76.6 +/- 3.9% (75.1 +/- 4.6% for enrollees with PF&S; 78.5 +/- 6.0% for nonPF&S). Older adults with PF&S were characterized by higher levels of asparagine, aspartic acid, citrulline, ethanolamine, glutamic acid, sarcosine, and taurine. The profile of nonPF&S participants was defined by higher concentrations of alpha-aminobutyric acid and methionine. Distinct profiles of circulating amino acids and derivatives characterize older people with PF&S. The dissection of these patterns may provide novel insights into the role played by protein/amino acid perturbations in the disabling cascade and possible new targets for interventions. PMID- 30404174 TI - Dual-Band Perfect Metamaterial Absorber Based on an Asymmetric H-Shaped Structure for Terahertz Waves. AB - We designed an ultra-thin dual-band metamaterial absorber by adjusting the side strips' length of an H-shaped unit cell in the opposite direction to break the structural symmetry. The dual absorption peaks approximately 99.95% and 99.91% near the central resonance frequency of 4.72 THz and 5.0 THz were obtained, respectively. Meanwhile, a plasmon-induced transmission (PIT) like reflection window appears between the two absorption frequencies. In addition to theoretical explanations qualitatively, a multi-reflection interference theory is also investigated to prove the simulation results quantitatively. This work provides a way to obtain perfect dual-band absorption through an asymmetric metamaterial structure, and it may achieve potential applications in a variety of fields including filters, sensors, and some other functional metamaterial devices. PMID- 30404175 TI - A System for Generating Customized Pleasant Pedestrian Routes Based on OpenStreetMap Data. AB - In this work, we present a system that generates customized pedestrian routes entirely based on data from OpenStreetMap (OSM). The system enables users to define to what extent they would like the route to have green areas (e.g., parks, squares, trees), social places (e.g., cafes, restaurants, shops) and quieter streets (i.e., with less road traffic). We present how the greenness, sociability, and quietness factors are defined and extracted from OSM as well as how they are integrated into a routing cost function. We intrinsically evaluate customized routes from one-thousand trips, i.e., origin-destination pairs, and observe that these are, in general, as we intended-slightly longer but significantly more social, greener, and quieter than the respective shortest routes. Based on a survey taken by 156 individuals, we also evaluate the system's usefulness, usability, controlability, and transparency. The majority of the survey participants agree that the system is useful and easy to use and that it gives them the feeling of being in control regarding the extraction of routes in accordance with their greenness, sociability, and quietness preferences. The survey also provides valuable insights into users requirements and wishes regarding a tool for interactively generating customized pedestrian routes. PMID- 30404176 TI - The Relationship between Running Power and Running Economy in Well-Trained Distance Runners. AB - A novel running wearable called the Stryd Summit footpod fastens to a runner's shoe and estimates running power. The footpod separates power output into two components, Stryd power and form power. The purpose of this study was to measure the correlations between running economy and power and form power at lactate threshold pace. Seventeen well-trained distance runners, 9 male and 8 female, completed a running protocol. Participants ran two four-minute trials: one with a self-selected cadence, and one with a target cadence lowered by 10%. The mean running economy expressed in terms of oxygen cost at self-selected cadence was 201.6 +/- 12.8 mL.kg-1.km-1, and at lowered cadence was 204.5 +/- 11.5 mL.kg-1.km 1. Ventilation rate and rating of perceived exertion (RPE) were not significantly different between cadence conditions with one-tailed paired t-test analysis (ventilation, p = 0.77, RPE, p = 0.07). Respiratory exchange ratio and caloric unit cost were significantly greater with lower cadence condition (respiratory exchange ratio, p = 0.03, caloric unit cost, p = 0.03). Mean power at self selected cadence was 4.4 +/- 0.5 W.kg-1, and at lowered cadence was 4.4 +/- 0.5 W.kg-1. Mean form power at self-selected cadence was 1.1 +/- 0.1 W.kg-1, and at lowered cadence was 1.1 +/- 0.1 W.kg-1. There were positive, linear correlations between running economy and power (self-selected cadence and lower cadence, r = 0.6; the 90% confidence interval was 0.2 to 0.8); running economy and form power (self-selected cadence and lower cadence r = 0.5; the 90% confidence interval was 0.1 to 0.8). The findings suggest running economy is positively correlated with Stryd's power and form power measures yet the footpod may not be sufficiently accurate to estimate differences in the running economy of competitive runners. PMID- 30404177 TI - Mitigation of CSI Temporal Phase Rotation with B2B Calibration Method for Fine Grained Motion Detection Analysis on Commodity Wi-Fi Devices. AB - Limitations of optical devices for motion sensing such as small coverage, sensitivity to obstacles, and privacy exposure result in the need for improvement. As motion sensing based on radio frequency signals is not constrained by the limitation above, channel state information (CSI) from Wi-Fi devices could be used to improve sensing performance under the above circumstances. Unfortunately, CSI phase cannot be practically obtained due to the temporal phase rotation generated from Wi-Fi chips. Therefore, it would be rather complicated to realize motion analysis, especially the direction of motion. To mitigate the issue, this paper proposes a CSI calibration method that employs a back-to-back channel between Wi-Fi transceivers for phase rotation removal while preserving the original CSI phase. Through experiment, calibrated CSI showed a high similarity to the channel without phase rotation measured using a Vector Network Analyzer (VNA). Another experiment was conducted to observe Doppler frequency due to simple hand gestures using the Wavelet transform. A visual analysis revealed that the Doppler frequency of calibrated CSI could correctly capture the motion pattern. To the best of the authors' knowledge, this is the first calibration method that maintains the original CSI and is applicable for in depth motion analysis. PMID- 30404178 TI - Exploring Interactions between the Gut Microbiota and Social Behavior through Nutrition. AB - Microbes influence a wide range of host social behaviors and vice versa. So far, however, the mechanisms underpinning these complex interactions remain poorly understood. In social animals, where individuals share microbes and interact around foods, the gut microbiota may have considerable consequences on host social interactions by acting upon the nutritional behavior of individual animals. Here we illustrate how conceptual advances in nutritional ecology can help the study of these processes and allow the formulation of new empirically testable predictions. First, we review key evidence showing that gut microbes influence the nutrition of individual animals, through modifications of their nutritional state and feeding decisions. Next, we describe how these microbial influences and their social consequences can be studied by modelling populations of hosts and their gut microbiota into a single conceptual framework derived from nutritional geometry. Our approach raises new perspectives for the study of holobiont nutrition and will facilitate theoretical and experimental research on the role of the gut microbiota in the mechanisms and evolution of social behavior. PMID- 30404179 TI - Distribution and Phytoavailability of Potentially Toxic Metals in Different Fe/Mg Mine Tailings. AB - The environmental risk of potentially toxic metals in tailing soils is of universal concern. We conducted a 3-month pot experiment to research the distribution and variations of potentially toxic metals (PTMs), and the translocation and accumulation capability of these metals (Cr, Ni, Mn, Cu, Zu) in natural plants for three Fe/Mg tailing soils (serpentine-type, olivine-type and magnetite-type) with growth of a grass plant-Imperata cylindrica. We used comparative analysis, regression analysis and correlation analysis to process relevant experimental data. Results showed the rhizosphere tailing soils decreased from 3.70% to 16.8%, compared to the bulk soils, after growth of Imperata cylindrica, and the acid soluble fraction of Mn, Cu and Zn increased significantly. Cu and Zn were more bioavailable than other PTMs, especially for serpentine-type tailing soils. Linear regression analysis indicated that non residual fractions showed different effects on metal concentrations of Imperata cylindrica. The non-residual metal fractions of serpentine-type and olivine-type tailing soils showed better correlations with metal concentrations in grass plants than those of magnetite-type tailing soils. We found that the chemical compositions of tailing soils showed remarkable effects on Ni and Mn compared with other elements, especially Mg and Al. Overall, the grass plant can alter the metal distribution, enhance metal bioavailability and promote land use of Fe/Mg tailing soils. PMID- 30404181 TI - Metformin Hydrochloride-Loaded PLGA Nanoparticle in Periodontal Disease Experimental Model Using Diabetic Rats. AB - Evidence shows that metformin is an antidiabetic drug, which can exert favorable anti-inflammatory effects and decreased bone loss. The development of nanoparticles for metformin might be useful for increased therapeutic efficacy. The aim of this study was to evaluate the effect of metformin hydrochloride loaded Poly (d,l-Lactide-co-glycolide) (PLGA)/(MET-loaded PLGA) on a ligature induced periodontitis model in diabetic rats. MET-loaded PLGA were characterized by mean diameter, particle size, polydispensity index, and entrapment efficiency. Maxillae were scanned using Microcomputed Tomography (uCT) and histopathological and immunohistochemical analysis. IL-1beta and TNF-alpha levels were analyzed by ELISA immunoassay. Quantitative RT-PCR was used (AMPK, NF-kappaB p65, HMGB1, and TAK-1). The mean diameter of MET-loaded PLGA nanoparticles was in a range of 457.1 +/- 48.9 nm (p < 0.05) with a polydispersity index of 0.285 (p < 0.05), Z potential of 8.16 +/- 1.1 mV (p < 0.01), and entrapment efficiency (EE) of 66.7 +/- 3.73. Treatment with MET-loaded PLGA 10 mg/kg showed low inflammatory cells, weak staining by RANKL, cathepsin K, OPG, and osteocalcin, and levels of IL-1beta and TNF-alpha (p < 0.05), increased AMPK expression gene (p < 0.05) and decreased NF-kappaB p65, HMGB1, and TAK-1 (p < 0.05). It is concluded that MET-loaded PLGA decreased inflammation and bone loss in periodontitis in diabetic rats. PMID- 30404182 TI - An Accurate and Effective Method for Measuring Osimertinib by UPLC-TOF-MS and Its Pharmacokinetic Study in Rats. AB - Osimertinib, a new-generation inhibitor of the epidermal growth factor, has been used for the clinical treatment of advanced T790M mutation-positive tumors. In this research, an original analysis method was established for the quantification of osimertinib by ultra-performance liquid chromatography with time of flight mass spectrometry (UPLC-TOF-MS) in rat plasma. After protein precipitation with acetonitrile and sorafinib (internal standard, IS), they were chromatographed through a Waters XTerra MS C18 column. The mobile phase was acetonitrile and water (including 0.1% ammonia). The relative standard deviation (RSD) of the intra- and inter-day results ranged from 5.38 to 9.76% and from 6.02 to 9.46%, respectively, and the extraction recovery and matrix effects were calculated to range from 84.31 to 96.14% and from 91.46 to 97.18%, respectively. The results illustrated that the analysis method had sufficient specificity, accuracy and precision. Meanwhile, the UPLC-TOF-MS method for osimertinib was successfully applied into the pharmacokinetics of SD rats. PMID- 30404183 TI - Expression of the Biofilm-Associated Genes in Methicillin-Resistant Staphylococcus aureus in Biofilm and Planktonic Conditions. AB - The role of genes that are essential for development of Staphylococcus aureus biofilm during infection is not fully known. mRNA from two methicillin-resistant S. aureus strains that formed weak and strong biofilm on polystyrene plates were isolated at five time points from cells grown in biofilm and planktonic culture. Quantitative real-time PCR analysis showed that the expression levels of investigated genes under biofilm conditions were significantly higher than under planktonic conditions. The expression levels of the gene encoding elastin binding protein (ebps) and laminin binding protein (eno) were significantly increased in biofilm at 3 h, both in strongly and weakly adhering strain. The peak expression of fib gene encoding fibrinogen binding protein was found at 6 and 8 h in the case of strongly and weakly adhering strain, respectively. The expression of icaA and icaD genes in both strains was significantly higher under biofilm conditions when comparing to planktonic cells during 12 h. The expression level of the genes encoding binding proteins and the glucosamine polymer polysaccharide intercellular adhesin (PIA) slowly decreased after 24 h. Finally, we found that the expression levels of genes encoding binding factors in weakly adhering strain were significantly lower than in strongly adhering strain. PMID- 30404184 TI - Acid Free Oxidation and Simple Dispersion Method of MWCNT for High-Performance CFRP. AB - Carbon nanotubes (CNT) provide an outstanding property spectrum which can be used to improve a wide range of materials. However, the transfer of properties from the nanoscale to a macroscopic material is a limiting factor. Different approaches of functionalizing the surface of a CNT can improve the interaction with the surrounding matrix but is connected to difficult and expensive treatments, which are usually inconvenient for industrial applications. Here, a simple and eco-friendly method is presented for the oxidation of CNT, where hydrogen peroxide (H2O2) is the only chemical needed and no toxic emissions are released. Also, the extensive step of the incorporation of CNT to an epoxy matrix is simplified to an ultrasonic dispersion in the liquid hardener component. The effectiveness is proven by mechanical tests of produced CNT/CFRP and compared to a conventional processing route. The combination of those simple and cost efficient strategies can be utilized to produce multiscale composites with improved mechanical performance in an ecological and economical way. PMID- 30404185 TI - Novel Rhodanine Derivative, 5-[4-(4-Fluorophenoxy) phenyl]methylene-3-{4-[3-(4 methylpiperazin-1-yl) propoxy]phenyl}-2-thioxo-4-thiazolidinone dihydrochloride, Induces Apoptosis via Mitochondria Dysfunction and Endoplasmic Reticulum Stress in Human Colon Cancer Cells. AB - We previously reported that 5-[4-(4-fluorophenoxy) phenyl] methylene-3-{4-[3-(4 methylpiperazin-1-yl)propoxy]phenyl}-2-thioxo-4-thiazolidinone dihydrochloride (KSK05104) has potent, selective and metabolically stable IKKbeta inhibitory activities. However, the apoptosis-inducing of KSK05104 and its underlying mechanism have not yet been elucidated in human colon cancer cells. We show that KSK05104 triggered apoptosis, as indicated by externalization of Annexin V targeted phosphatidylserine residues in HT-29 and HCT-116 cells. KSK05104 induced the activation of caspase-8, -9, and -3, and the cleavage of poly (ADP ribose) polymerase-1 (PARP-1). KSK05104-induced apoptosis was significantly suppressed by pretreatment with z-VAD-fmk (a broad caspase inhibitor). KSK05104 also induced release of cytochrome c (Cyt c), apoptosis inducing factor (AIF), and endonuclease G (Endo G) by damaging mitochondria, resulting in caspase-dependent and -independent apoptotic cell death. KSK05104 triggered endoplasmic reticulum (ER) stress and changed the intracellular calcium level ([Ca2+]i). Interestingly, treatment with KSK05104 activated not only ER stress marker proteins including inositol-requiring enzyme 1-alpha (IRE-1alpha) and protein kinase RNA-like endoplasmic reticulum kinase (PERK), but also MU-calpain, and caspase-12 in a time-dependent manner. KSK05104-induced apoptosis substantially decreased in the presence of BAPTA/AM (an intracellular calcium chelator). Taken together, these results suggest that mitochondrial dysfunction and ER stress contribute to KSK05104-induced apoptosis in human colon cancer cells. PMID- 30404186 TI - Bacterial Superantigen Toxins, CD28, and Drug Development. AB - During severe bacterial infections, death and disease are often caused by an overly strong immune response of the human host. Acute toxic shock is induced by superantigen toxins, a diverse set of proteins secreted by Gram-positive staphylococcal and streptococcal bacterial strains that overstimulate the inflammatory response by orders of magnitude. The need to protect from superantigen toxins led to our discovery that in addition to the well-known MHC class II and T cell receptors, the principal costimulatory receptor, CD28, and its constitutively expressed coligand, B7-2 (CD86), previously thought to have only costimulatory function, are actually critical superantigen receptors. Binding of the superantigen into the homodimer interfaces of these costimulatory receptors greatly enhances B7-2/CD28 engagement, leading to excessive pro inflammatory signaling. This finding led to the design of short receptor dimer interface mimetic peptides that block the binding of superantigen and thus protect from death. It then turned out that such a peptide will protect also from Gram-negative bacterial infection and from polymicrobial sepsis. One such CD28 mimetic peptide is advancing in a Phase 3 clinical trial to protect from lethal wound infections by flesh-eating bacteria. These host-oriented therapeutics target the human immune system itself, rendering pathogens less likely to become resistant. PMID- 30404180 TI - Hydrogen Peroxide and Redox Regulation of Developments. AB - Reactive oxygen species (ROS), which were originally classified as exclusively deleterious compounds, have gained increasing interest in the recent years given their action as bona fide signalling molecules. The main target of ROS action is the reversible oxidation of cysteines, leading to the formation of disulfide bonds, which modulate protein conformation and activity. ROS, endowed with signalling properties, are mainly produced by NADPH oxidases (NOXs) at the plasma membrane, but their action also involves a complex machinery of multiple redox sensitive protein families that differ in their subcellular localization and their activity. Given that the levels and distribution of ROS are highly dynamic, in part due to their limited stability, the development of various fluorescent ROS sensors, some of which are quantitative (ratiometric), represents a clear breakthrough in the field and have been adapted to both ex vivo and in vivo applications. The physiological implication of ROS signalling will be presented mainly in the frame of morphogenetic processes, embryogenesis, regeneration, and stem cell differentiation. Gain and loss of function, as well as pharmacological strategies, have demonstrated the wide but specific requirement of ROS signalling at multiple stages of these processes and its intricate relationship with other well-known signalling pathways. PMID- 30404187 TI - Characterization and Analysis of Strain Heterogeneity at Grain-Scale of Titanium Alloy with Tri-Modal Microstructure during Tensile Deformation. AB - Grain-scale strain heterogeneity characteristics play a critical role in the ductile damage behavior and mechanical properties of two-phase titanium alloys. In this work, the grain-scale strain distribution, strain heterogeneity, and strain localization of titanium alloy with tri-modal microstructure (consisting of equiaxed alpha (alphap), lamellar alpha (alphal), and beta transformed matrix (betat)) during tensile deformation were experimentally investigated. The results show that the strain probability distribution of the whole microstructure obeys normal distribution during deformation. Significant strain heterogeneities exist in each constituent (alphap, alphal, and betat) and the whole microstructure. At lower macro-strain, alphap and alphal exhibit higher average strain than those of betat and the whole of the microstructure. Meanwhile, strain heterogeneity of each constituent is small and has a negligible change. The strain heterogeneity of the whole microstructure is mainly determined by alphap. At larger macro strain, some highly deformed regions produce and their positions do not change during further deformation. As a result, the strain heterogeneity of each constituent increases fast, and the strain heterogeneity of whole microstructure is mainly related to alphal in this deformation stage. On the other hand, two types of strain localization may be generated within alphap and alphal and at the alphap/betat and alphal/betat boundaries, respectively. The former type is caused by transgranular intense slip deformation and presents crystal orientation dependence. The latter type is related to the boundary sliding and presents spatial distribution dependence for alphal. These strain localizations greatly determine the micro-damages, thus forming the corresponding micro-voids within alphap and alphal and the micro-cracks at alphap/betat and alphal/betat boundaries in tri-modal microstructure at larger deformation. PMID- 30404188 TI - Exosomes and Exosome-Inspired Vesicles for Targeted Drug Delivery. AB - The similarities between exosomes and liposomes, together with the high organotropism of several types of exosomes, have recently prompted the development of engineered-exosomes or exosome-mimetics, which may be artificial (liposomal) or cell-derived vesicles, as advanced platforms for targeted drug delivery. Here, we provide the current state-of-the-art of using exosome or exosome-inspired systems for drug delivery. We review the various approaches investigated and the shortcomings of each approach. Finally the challenges which have been identified to date in this field are summarized. PMID- 30404189 TI - Screening Method to Evaluate Amino Acid-Decarboxylase Activity of Bacteria Present in Spanish Artisanal Ripened Cheeses. AB - A qualitative microplate screening method, using both low nitrogen (LND) and low glucose (LGD) decarboxylase broths, was used to evaluate the biogenic amine (BA) forming capacity of bacteria present in two types of Spanish ripened cheeses, some of them treated by high hydrostatic pressure. BA formation in decarboxylase broths was later confirmed by High Performance Liquid Chromatography (HPLC). An optimal cut off between 10-25 mg/L with a sensitivity of 84% and a specificity of 92% was obtained when detecting putrescine (PU), tyramine (TY) and cadaverine (CA) formation capability, although these broths showed less capacity detecting histamine forming bacteria. TY forming bacteria were the most frequent among the isolated BA forming strains showing a strong production capability (exceeding 100 mg/L), followed by CA and PU formers. Lactococcus, Lactobacillus, Enterococcus and Leuconostoc groups were found as the main TY producers, and some strains were also able to produce diamines at a level above 100 mg/L, and probably ruled the BA formation during ripening. Enterobacteriaceae and Staphylococcus spp., as well as some Bacillus spp. were also identified among the BA forming bacteria isolated. PMID- 30404190 TI - Rapid Weight Loss and Dietary Inadequacies among Martial Arts Practitioners from Poland. AB - Healthy nutrition and maintaining a normal body weight are very important for reducing the risk of various diseases not only among the general population, but also among athletes, especially combat sport athletes. The aim of the study was to evaluate the prevalence of rapid weight loss (RWL) and to indicate eventual dietary inadequacies among professional martial arts practitioners. Sixty-two male athletes (aged: 23 +/- 4) completed a questionnaire (i.e., frequency of food group consumption, questions about training and RWL) and single 24-h dietary recall. This study confirmed the high prevalence of RWL in athletes (58%) for two to three days before the competition, which allowed for reduction of 3.4 +/- 1.0 kg (4.3 +/- 1.5%) of their body weight. Many dietary inaccuracies were found such as: lower than recommended by nutrition experts, level of consumption of dairy products, grain products, fruit, and vegetables, and insufficient intake of energy, carbohydrates, minerals (especially iodine, potassium, calcium) and vitamins (especially D, folate, C, E) during the training day. Adequate nutrition is a natural support for the whole training process, and may allow for regulation of body weight in a longer period and in a safer manner; thus, there is a need for nutrition education dedicated to athletes and their trainers. PMID- 30404191 TI - Bilateral Optic Neuritis Secondary to Nivolumab Therapy: A Case Report. AB - Pediatric glioblastoma multiforme is an uncommon and highly mortal brain cancer. New therapeutic treatments are being intensively investigated by researchers in order to extend the survival of patients. The immune checkpoint inhibitor nivolumab in the treatment of pediatric glioblastoma multiforme is currently under review; it is a human immunoglobulin G4 monoclonal antibody that works against the programmed cell death protein 1 receptor, designed to enhance an immunologic reaction against cancer cells. Herein, we describe the first report of a bilateral optic neuritis induced by nivolumab in a grade 4 glioblastoma multiforme patient. PMID- 30404192 TI - Induction of Expandable Adipose-Derived Mesenchymal Stem Cells from Aged Mesenchymal Stem Cells by a Synthetic Self-Replicating RNA. AB - Adipose-derived mesenchymal stem cells (ADSCs) have attracted attention due to their potential for use in the treatment of various diseases. However, the self renewal capacity of ADSCs is restricted and their function diminishes during passage. We previously generated induced tissue-specific stem cells from mouse pancreatic cells using a single synthetic self-replicating Venezuelan Equine Encephalitis (VEE)-reprogramming factor (RF) RNA replicon (SR-RNA) expressing the reprogramming factors POU class 5 homeobox 1 (OCT4), Krueppel-like factor 4 (KLF4), Sex determining region Y-box 2 (SOX2), and Glis Family Zinc Finger 1 (GLIS1). This vector was used to generate induced pluripotent stem (iPS) cells. Here, we applied this SR-RNA vector to generate human iTS cells from aged mesenchymal stem cells (hiTS-M cells) deficient in self-renewal that were derived from adipose tissue. These hiTS-M cells transfected with the SR-RNA vector survived for 15 passages. The hiTS-M cells expressed cell surface markers similar to those of human adipose-derived mesenchymal stem cells (hADSCs) and differentiated into fat cells and osteoblasts. Global gene expression profiling showed that hiTS-M cells were transcriptionally similar to hADSCs. These data suggest that the generation of iTS cells has important implications for the clinical application of autologous stem cell transplantation. PMID- 30404193 TI - Material Characterization of a Magnetorheological Fluid Subjected to Long-Term Operation in Damper. AB - This paper investigates the field-dependent rheological properties of magnetorheological (MR) fluid used to fill in MR dampers after long-term cyclic operation. For testing purposes, a meandering MR valve was customized to create a double-ended MR damper in which MR fluid flowed inside the valve due to the magnetic flux density. The test was conducted for 170,000 cycles using a fatigue dynamic testing machine which has 20 mm of stroke length and 0.4 Hz of frequency. Firstly, the damping force was investigated as the number of operating cycles increased. Secondly, the change in viscosity of the MR fluid was identified as in use thickening (IUT). Finally, the morphological observation of MR particles was undertaken before and after the long-term operation. From these tests, it was demonstrated that the damping force increased as the number of operating cycles increases, both when the damper is turn on (on-state) and off (off-state). It is also observed that the particle size and shape changed due to the long operation, showing irregular particles. PMID- 30404195 TI - Physical Fitness Characteristics That Relate to Work Sample Test Battery Performance in Law Enforcement Recruits. AB - This study determined relationships between an agency-specific fitness test battery (PT500), and a work sample test battery (WSTB) in law enforcement recruits. Retrospective analysis on 219 males and 34 females from one agency was conducted. The PT500 comprised: push-ups, sit-ups, and mountain climbers in 120 s; pull-ups; and 201 m and 2.4 km runs. The WSTB comprised: 99 yard (90.53 m) obstacle course (99OC); body drag (BD) with a 165 pound (75 kg) dummy; 6 foot (1.83 m) chain link fence (CLF) and solid wall (SW) climb; and 500 yard (457.2 m) run (500R). Partial correlations, controlling for sex, calculated PT500 and WSTB relationships (p < 0.05). Stepwise regression determined whether fitness predicted WSTB performance. The 500R related to all PT500 assessments (r range = 0.127-0.574), 99OC related to all bar push-ups and mountain climbers, and BD related to none. The CLF related to sit-ups, pull-ups, and 2.4 km run; SW related to mountain climbers, pull-ups, and 2.4 km run (r range = -0.127--0.315). Push ups, pull-ups, and 2.4 km run were involved in predictive relationships for 99OC, CLF, SW, and 500R (r2 range = 0.217-0.500). To perform better in the WSTB and job specific tasks, developing upper-body strength and aerobic fitness may be beneficial. PMID- 30404194 TI - Unique MicroRNA and mRNA Interactions in EGFR-Mutated Lung Adenocarcinoma. AB - The EGFR gene was one of the first molecules to be selected for targeted gene therapy. EGFR-mutated lung adenocarcinoma, which is responsive to EGFR inhibitors, is characterized by a distinct oncogenic pathway in which unique microRNA (miRNA)-mRNA interactions have been observed. However, little information is available about the miRNA-mRNA regulatory network involved. Both miRNA and mRNA expression profiles were investigated using microarrays in 155 surgically resected specimens of lung adenocarcinoma with a known EGFR mutation status (52 mutated and 103 wild-type cases). An integrative analysis of the data was performed to identify the unique miRNA-mRNA regulatory network in EGFR mutated lung adenocarcinoma. Expression profiling of miRNAs and mRNAs yielded characteristic miRNA/mRNA signatures (19 miRNAs/431 mRNAs) in EGFR-mutated lung adenocarcinoma. Five of the 19 miRNAs were previously listed as EGFR-mutation specific miRNAs (i.e., miR-532-3p, miR-500a-3p, miR-224-5p, miR-502-3p, and miR 532-5p). An integrative analysis of miRNA and mRNA expression revealed a refined list of putative miRNA-mRNA interactions, of which 63 were potentially involved in EGFR-mutated tumors. Network structural analysis provided a comprehensive view of the complex miRNA-mRNA interactions in EGFR-mutated lung adenocarcinoma, including DUSP4 and MUC4 axes. Overall, this observational study provides insight into the unique miRNA-mRNA regulatory network present in EGFR-mutated tumors. Our findings, if validated, would inform future research examining the interplay of miRNAs and mRNAs in EGFR-mutated lung adenocarcinoma. PMID- 30404196 TI - Defined Small Molecules Produced by Himalayan Medicinal Plants Display Immunomodulatory Properties. AB - Plant-derived compounds that modulate the immune responses are emerging as frontline treatment agents for cancer, infectious diseases and autoimmunity. Herein we have isolated 40 phytochemicals from five Bhutanese Sowa Rigpa medicinal plants-Aconitum laciniatum, Ajania nubegina, Corydalis crispa, Corydalis dubia and Pleurospermum amabile-and tested 14 purified compounds for their immunomodulatory properties using a murine dendritic cell (DC) line, and cytotoxicity against a human cholangiocyte cell line using xCELLigence real time cell monitoring. These compounds were: pseudaconitine, 14 veratryolpseudaconitine, 14-O-acetylneoline, linalool oxide acetate, (E) spiroether, luteolin, luteolin-7-O-beta-d-glucopyranoside, protopine, ochrobirine, scoulerine, capnoidine, isomyristicin, bergapten, and isoimperatorin. Of the 14 compounds tested here, scoulerine had adjuvant-like properties and strongly upregulated MHC-I gene and protein expression whereas bergapten displayed immunosuppressive properties and strongly down-regulated gene and protein expression of MHC-I and other co-stimulatory molecules. Both scoulerine and bergapten showed low cytotoxicity against normal healthy cells that were consistent with their immunoregulatory properties. These findings highlight the breadth of immunomodulatory properties of defined compounds from Bhutanese medicinal plants and show that some of these compounds exert their mechanisms of action by modulating DC activity. PMID- 30404197 TI - Applications of Metal-Organic Frameworks in Food Sample Preparation. AB - Food samples such as milk, beverages, meat and chicken products, fish, etc. are complex and demanding matrices. Various novel materials such as molecular imprinted polymers (MIPs), carbon-based nanomaterials carbon nanotubes, graphene oxide and metal-organic frameworks (MOFs) have been recently introduced in sample preparation to improve clean up as well as to achieve better recoveries, all complying with green analytical chemistry demands. Metal-organic frameworks are hybrid organic inorganic materials, which have been used for gas storage, separation, catalysis and drug delivery. The last few years MOFs have been used for sample preparation of pharmaceutical, environmental samples and food matrices. Due to their high surface area MOFs can be used as adsorbents for the development of sample preparation techniques of food matrices prior to their analysis with chromatographic and spectrometric techniques with great performance characteristics. PMID- 30404198 TI - Receptor Tyrosine Kinase-Targeted Cancer Therapy. AB - In the past two decades, several molecular targeted inhibitors have been developed and evaluated clinically to improve the survival of patients with cancer. Molecular targeted inhibitors inhibit the activities of pathogenic tyrosine kinases. Particularly, aberrant receptor tyrosine kinase (RTK) activation is a potential therapeutic target. An increased understanding of genetics, cellular biology and structural biology has led to the development of numerous important therapeutics. Pathogenic RTK mutations, deletions, translocations and amplification/over-expressions have been identified and are currently being examined for their roles in cancers. Therapies targeting RTKs are categorized as small-molecule inhibitors and monoclonal antibodies. Studies are underway to explore abnormalities in 20 types of RTK subfamilies in patients with cancer or other diseases. In this review, we describe representative RTKs important for developing cancer therapeutics and predicting or evaluated resistance mechanisms. PMID- 30404199 TI - Minimal/Measurable Residual Disease Monitoring in NPM1-Mutated Acute Myeloid Leukemia: A Clinical Viewpoint and Perspectives. AB - Acute myeloid leukemia (AML) with NPM1 gene mutations is currently recognized as a distinct entity, due to its unique biological and clinical features. We summarize here the results of published studies investigating the clinical application of minimal/measurable residual disease (MRD) in patients with NPM1 mutated AML, receiving either intensive chemotherapy or hematopoietic stem cell transplantation. Several clinical trials have so far demonstrated a significant independent prognostic impact of molecular MRD monitoring in NPM1-mutated AML and, accordingly, the Consensus Document from the European Leukemia Net MRD Working Party has recently recommended that NPM1-mutated AML patients have MRD assessment at informative clinical timepoints during treatment and follow-up. However, several controversies remain, mainly with regard to the most clinically significant timepoints and the MRD thresholds to be considered, but also with respect to the optimal source to be analyzed, namely bone marrow or peripheral blood samples, and the correlation of MRD with other known prognostic indicators. Moreover, we discuss potential advantages, as well as drawbacks, of newer molecular technologies such as digital droplet PCR and next-generation sequencing in comparison to conventional RQ-PCR to quantify NPM1-mutated MRD. In conclusion, further prospective clinical trials are warranted to standardize MRD monitoring strategies and to optimize MRD-guided therapeutic interventions in NPM1-mutated AML patients. PMID- 30404200 TI - Hypertension Status and Associations with Self-Rated Health and General Practitioner Health Seeking in a Rural Australian Cohort. AB - Hypertension is the most frequently managed condition by Australian general practitioners (GP). Knowledge of hypertension and blood pressure (BP) values may motivate individuals to seek GP management. Our study aims to determine the associations of knowledge of BP values, BP perception, GP health seeking, and self-rated health (SRH) in a rural population. Two-hundred and seventy-eight (278) residents responded to the health survey on socio-demographic profile, medical history, BP knowledge and perception, SRH, and GP visit frequency. Associations were evaluated using Chi-squared test and multivariate logistic regression. Cohort mean age was 63.6 (12.4) years with 63.3% females. Hypertension (37.8%) was the most common condition. GP visits were made at least once every month (19.1%), every 2-6 months (35.6%), >6 months (11.5%), or only when needed (29.5%). Univariate analyses showed age, education, alcohol consumption, comorbidities, hypertension status, and SRH were significantly associated with visit frequency. After adjustments, hypertension status (OR = 3.6, 95% CI [1.7, 7.9]) and poor SRH (OR = 3.1, 95% CI [1.4, 7.0]) were significantly associated with frequent monthly visits. Our cohort demonstrated that having hypertension and poor self-rated health were associated with frequent monthly GP visits. The perception of high blood pressure does not drive seeking additional GP input. PMID- 30404201 TI - The Status of Pet Rabbit Breeding and Online Sales in the UK: A Glimpse into an Otherwise Elusive Industry. AB - Conditions of pet rabbit breeding colonies and breeder practices are undocumented and very little is known about the pet rabbit sales market. Here, multiple methods were employed to investigate this sector of the UK pet industry. A freedom of information request sent to 10% of councils revealed confusion and inconsistency in licensing conditions. Data from 1-month of online sale adverts (3446) identified 646 self-declared breeders, of which 1.08% were licensed. Further, despite veterinary advice to vaccinate rabbits from five weeks, only 16.7% rabbits were vaccinated and 9.2% of adult rabbits were neutered. Thirty three breeders completed a questionnaire of which 51.5% provided smaller housing than recommended, the majority housed rabbits singly and bucks were identified as most at risk of compromised welfare. However, most breeders provided enrichment and gave a diet compliant with recommended guidelines. Mini-lops and Netherland dwarfs were the most commonly sold breeds, both of which are brachycephalic, which can compromise their health and wellbeing. From sales data extrapolation, we estimate that 254,804 rabbits are purposefully bred for the UK online pet sales market each year. This data is the first of its kind and highlights welfare concerns within the pet rabbit breeding sector, which is unregulated and difficult to access. PMID- 30404203 TI - Preparation of Polymer Electrolyte Membranes via Radiation-Induced Graft Copolymerization on Poly(ethylene-alt-tetrafluoroethylene) (ETFE) Using the Crosslinker N,N'-Methylenebis(acrylamide). AB - Polymer electrolyte membranes (PEM) prepared by radiation-induced graft copolymerization are investigated. For this purpose, commercial poly(ethylene-alt tetrafluoroethylene) (ETFE) films were activated by electron beam treatment and subsequently grafted with the monomers glycidyl methacrylate (GMA), hydroxyethyl methacrylate (HEMA) and N,N'-methylenebis(acrylamide) (MBAA) as crosslinker. The target is to achieve a high degree of grafting (DG) and high proton conductivity. To evaluate the electrochemical performance, the PEMs were tested in a fuel cell and in a vanadium redox-flow battery (VRFB). High power densities of 134 mW?cm-2 and 474 mW?cm-2 were observed, respectively. PMID- 30404202 TI - A Broadband Phototransistor Based on Three-Dimensional Reduced Graphene Oxide Foam. AB - Three-dimensional (3D) cross-linked polymer-like reduced graphene oxide foams (rGOFs) with a seamlessly continuous graphene network, exhibit high photoresponsive and conductivity and have received much attention regarding solar cells and supercapacitors. However, little attention has been paid to photodetection applications of 3D rGOFs. Here we report a novel broadband phototransistor based on metal-3D GFs-metal, which exhibits a high light absorption and a wide spectra response ranging at least from 400 to 1600 nm wavelength with a maximum photoresponsivity of 10 mA/W at 400 nm. In particular, stable and reproducible photocurrent cycles are achieved under different light blue light (405 nm), green light (532 nm), and NIR (808 nm) irradiations. Moreover, the device displays a typical transistor characteristic with a rapid response time of 18 ms at under 532 nm irradiation. The excellent performances indicate 3D rGOF as a promising candidate for future photodetection application. PMID- 30404204 TI - Enhanced Sensitivity of a Hydrogen Sulfide Sensor Based on Surface Acoustic Waves at Room Temperature. AB - In this contribution, a new surface acoustic wave (SAW)-based sensor was proposed for sensing hydrogen sulfide (H2S) at room temperature (30 degrees C), which was composed of a phase discrimination circuit, a SAW-sensing device patterned with delay line, and a triethanolamine (TEA) coating along the SAW propagation path of the sensing device. The TEA was chosen as the sensitive interface for H2S sensing, owing to the high adsorption efficiency by van der Waals' interactions and hydrogen bonds with H2S molecules at room temperature. The adsorption in TEA towards H2S modulates the SAW propagation, and the change in the corresponding phase was converted into voltage signal proportional to H2S concentration was collected as the sensor signal. A SAW delay line patterned on Y-cut quartz substrate with Al metallization was developed photographically, and lower insertion and excellent temperature stability were achieved thanks to the single phase unidirectional transducers (SPUDTs) and lower cross-sensitivity of the piezoelectric substrate. The synthesized TEA by the reaction of ethylene oxide and ammonia was dropped into the SAW propagation path of the developed SAW device to build the H2S sensor. The developed SAW sensor was characterized by being collecting into the phase discrimination circuit. The gas experimental results appear that fast response (7 s at 4 ppm H2S), high sensitivity (0.152 mV/ppm) and lower detection limit (0.15 ppm) were achieved at room temperature. It means the proposed SAW sensor will be promising for H2S sensing. PMID- 30404205 TI - Substrate Temperature Dependent Properties of Sputtered AlN:Er Thin Film for In Situ Luminescence Sensing of Al/AlN Multilayer Coating Health. AB - The integrity and reliability of surface protective coatings deposited on metal surface could be in-situ monitored via the attractive luminescence sensing technique. In this paper, we report the influence of substrate temperature on the properties of erbium (Er) doped aluminum nitride (AlN) film, which could be applied as a luminescent layer for monitoring the health of multilayered Al/AlN coating. The AlN:Er films were deposited via reactive radio-frequency magnetron sputtering, and the silicon substrate temperature was varied from non-intentional heating up to 400 degrees C. The composition, morphology, crystalline structure, and dielectric function of the AlN:Er films deposited under these different substrate temperature conditions were studied. These properties of the AlN:Er films show strong correlation with the substrate temperature maintained during film fabrication. The obtained AlN:Er films, without further annealing, exhibited photoluminescence peaks of the Er3+ ions in the visible wavelength range and the strongest photoluminescence intensity was observed for the AlN:Er film deposited with the temperature of substrate kept at 300 degrees C. The results demonstrated in this work offer guidance to optimize the substrate temperature for the deposition of AlN:Er film for future application of this sensing technique to thin metal components. PMID- 30404206 TI - Signaling Pathways Induced by Leptin during Epithelial-Mesenchymal Transition in Breast Cancer. AB - Leptin is an adipokine that is overexpressed in obese and overweight people. Interestingly, women with breast cancer present high levels of leptin and of its receptor ObR. Leptin plays an important role in breast cancer progression due to the biological processes it participates in, such as epithelial-mesenchymal transition (EMT). EMT consists of a series of orchestrated events in which cell cell and cell-extracellular matrix interactions are altered and lead to the release of epithelial cells from the surrounding tissue. The cytoskeleton is also re-arranged, allowing the three-dimensional movement of epithelial cells into the extracellular matrix. This transition provides cells with the ability to migrate and invade adjacent or distal tissues, which is a classic feature of invasive or metastatic carcinoma cells. In recent years, the number of cases of breast cancer has increased, making this disease a public health problem worldwide and the leading cause of death due to cancer in women. In this review, we focus on recent advances that establish: (1) leptin as a risk factor for the development of breast cancer, and (2) leptin as an inducer of EMT, an event that promotes tumor progression. PMID- 30404207 TI - Use of a Smartphone Application Can Improve Assessment of High-Fat Food Consumption in Overweight Individuals. AB - BACKGROUND: We evaluated the feasibility of an application for measuring the frequency of consumption of high-fat foods and compared this application with standard methods. METHODS: Twenty-six females and thirty six males aged 20-40 were enrolled in Poland. Participants completed the Block Screening Questionnaire for Fat Intake (BSQF; Q1) and a second questionnaire (Q2) with additional high fat foods. The participants were then monitored for ten days in a real-time manner using a smartphone application that employed the same lists of food as Q2. RESULTS: Most subjects (84%) gave replies to at least three prompts on at least 5 days. The results from Q1 and the application were correlated (r = 0.42, p < 0.001). Energy intake and the frequency of consumption of high-fat foods were correlated in the overweight/obese group (r = 0.83, p < 0.001). The mean differences between Q2 and the app were similar in both groups but the agreement limits were wider in the overweight/obese group than in the normal weight group. CONCLUSIONS: An application for mobile devices is a feasible tool for capturing the frequency of high-fat food consumption and it seems to improve the measured variable, especially in overweight or obese people. PMID- 30404208 TI - Phosphorus Solubilization by Bacillus Species. AB - Microbial solubilization applies the natural ability of a microorganism to liberate phosphorus from unavailable structures. The main mechanism recognized to be responsible for the solubilization of phosphorus is the production of different types of organic acids. Three kinds of Bacillus species and three types of raw materials (poultry bones, fish bones, and ash) were tested for solubilization. The following parameters were compared for all discussed cases: pH, specific growth rate, solubilization factor, released phosphorus concentration, and total and individual concentration of organic acids. Utilization of ash brought about the highest specific and maximum specific growth rates. A decrease in pH was observed in most of the discussed cases with the exception of fish bones. At the same time, fish bones had the highest concentration of released P2O5 and the highest total concentration of produced organic acids (gluconic, lactic, acetic, succinic, and propionic) in all discussed cases. The tested Bacillus species produced the mentioned acids with the exception of B. megaterium, where propionic acid was not present. The lactic and acetic acids were those produced in the highest amount. The kind of raw materials and type of Bacillus species used in solubilization had a strong influence on the kind of organic acids that were detected in the broth culture and its total concentration, which had a direct influence on the amount of released phosphorus. The combination of Bacillus megaterium with the fish bones at 5 g/L is proposed as the pair that gives the highest concentration of released phosphorus (483 +/- 5 mg/L). PMID- 30404209 TI - Thermodynamic Study of the Corrosion of Refractories by Sodium Carbonate. AB - The corrosion of refractories by sodium salts in waste liquid at high temperature has become a serious problem. This paper focuses on the thermodynamic characterization of sodium carbonate (Na2CO3) corrosion of six refractories by FactSage modelling in combination with X-ray diffraction (XRD). Three of the refractories are oxides (Fe2O3, Al2O3, and Cr2O3), and the other three are synthetics spinels (magnesium chromium, MgO.Cr2O3; magnesioferrite, MgO.Fe2O3; and, magnesium aluminium, MgO.Al2O3). First, thermodynamic simulations were carried out with the FactSage thermodynamics model using the reaction package to predict the direction of the Na2CO3 corrosion reaction in terms of the Gibbs free energy. Then, the reactions between the six refractories and Na2CO3 were conducted through a series of refractories/Na2CO3 reaction tests. The XRD analytical method was used to describe and understand the chemistry and interpret mineral matter transformation. The products of the tests were also determined by X-ray diffraction and the experimental observations were compared with the results of the thermodynamic simulations. Furthermore, the strength of sodium corrosion of the refractory materials was comprehensively discussed. The results show that MgO.Al2O3 has the best thermal stability and it is hard to corrode by Na2CO3, while the chrome-containing refractory reacts easily with Na2CO3 with a considerably high amount of corrosion product at a temperature of 600 degrees C. These experimental results are in agreement with the thermodynamic calculations. PMID- 30404210 TI - The Dimensions of Pet-Owner Loyalty and the Relationship with Communication, Trust, Commitment and Perceived Value. AB - Loyalty is one of the greatest intangible assets that any organization can possess and improving client loyalty is a primary marketing goal that can have a significant financial impact on any business. This quantitative study examined the mediating role of communication on the relationship between satisfaction and loyalty (attitudinal and behavioral) in veterinary clinics, along with the moderating roles of trust, commitment, perceived value, and relational characteristics. Responses collected from 351 pet-owners through social media were analyzed using descriptive and inferential statistics. The results show that attitudinal loyalty (AL) has a strong positive relationship with communication at multiple points in a veterinary clinic, whereas the relationship with behavioral loyalty (BL) was not as clear. Additional findings suggest that AL, which is influenced by trust in the veterinarian, communication from staff members and commitment, has a strong positive relationship with behavioral intentions, increases the number of products and services that a pet-owner consumes at his or her primary veterinary clinic, and attenuates the role of cost in receiving veterinary care. These findings can help veterinary clinic owners and managers in developing and implementing relationship strategies that improve pet-owner loyalty. PMID- 30404211 TI - Pathotypes of Xanthomonas axonopodis pv. dieffenbachiae Isolated from Anthurium andraeanum in China. AB - Anthurium blight, caused by Xanthomonas axonopodis pv. dieffenbachiae (Xad), is one of the most serious diseases of Anthurium andraeanum. However, little is known about variations in virulence between Xad pathotypes. Here, we examined the virulence of 68 Xad strains isolated from 30 anthurium plants from five regions of China against five different anthurium cultivars. Seven bacterial pathotypes were identified based on disease index and incidence analyses following foliar spray or leaf-clip inoculation. The resulting disease susceptibility patterns for pathotypes I-VII were RRRSS, RRSRS, RSRSR, RRSSS, RSSRS, RSSSS, and SSSSS, respectively. Overall, 72% of tested strains belonged to pathotypes VI or VII and were highly virulent. A further 22.1% of strains showed medium-level virulence and were classed as pathotype III, IV, or V, while the remaining 5.9% of strains were pathotype I or II, showing low virulence. Further analysis revealed differences in the virulence of Xad strains from the same anthurium cultivar, with variation also observed in pathovars associated with the same cultivar from different areas. Our results reveal the diversity and complexity of the Xad population structure in China and suggest that investigation of Xad pathotypes provides useful information to guide the identification and use of resistant varieties of A. andraeanum. PMID- 30404212 TI - Speciation of Selenium in Brown Rice Fertilized with Selenite and Effects of Selenium Fertilization on Rice Proteins. AB - Foliar Selenium (Se) fertilizer has been widely used to accumulate Se in rice to a level that meets the adequate intake level. The Se content in brown rice (Oryza sativa L.) was increased in a dose-dependent manner by the foliar application of sodium selenite as a fertilizer at concentrations of 25, 50, 75, and 100 g Se/ha. Selenite was mainly transformed to organic Se, that is, selenomethionine in rice. Beyond the metabolic capacity of Se in rice, inorganic Se also appeared. In addition, four extractable protein fractions in brown rice were analyzed for Se concentration. The Se concentrations in the glutelin and albumin fractions saturated with increasing Se concentration in the fertilizer compared with those in the globulin and prolamin fractions. The structural analyses by fluorescence spectroscopy, Fourier transform infrared spectrometry, and differential scanning calorimetry suggest that the secondary structure and thermostability of glutelin were altered by the Se treatments. These alterations could be due to the replacements of cysteine and methionine to selenocysteine and selenomethionine, respectively. These findings indicate that foliar fertilization of Se was effective in not only transforming inorganic Se to low-molecular-weight selenometabolites such as selenoamino acids, but also incorporating Se into general rice proteins, such as albumin, globulin glutelin, and prolamin, as selenocysteine and selenomethionine in place of cysteine and methionine, respectively. PMID- 30404213 TI - Purification, Preliminary Structure and Antitumor Activity of Exopolysaccharide Produced by Streptococcus thermophilus CH9. AB - In the present study, the preliminary structure and in vitro antitumor activity of three exopolysaccharides (EPSs) from Streptococcus thermophilus CH9 were investigated. Then, three purified fractions of EPS-1a, EPS-2a, and EPS-3a were obtained by chromatography using DEAE-52 cellulose and Sephadex G-100, respectively. The average molecular weight of EPS-1a, EPS-2a, and EPS-3a, were 1.80 * 106, 1.06 * 106 and 1.05 * 106. The monosaccharide composition of EPS-3a was dramatically different from the others. The EPS-1a and EPS-2a were mainly composed of mannose, in a ratio of 69.82% and 57.09%, respectively, while EPS-3a was mainly composed of glucose (63.93%), without mannose. In addition, the surface morphology observed suggested that there were protein particles on the sugar chain of EPS-3a and EPS-3a was a protein-containing polysaccharide. Furthermore, EPS-3a exhibited higher antitumor activity against human liver cancer HepG2 cells in vitro. The antitumor activity of EPS-3a in HepG2 cells was associated with cell apoptosis. HE staining and Hoechst 33342 staining showed that with the treatment of EPS-3a, HepG2 cells had typical morphological changes. Flow cytometry analysis showed that the cell cycle was arrested at G0/G1 phase. PMID- 30404214 TI - Hemodynamics in Cardiac Development. AB - The beating heart is subject to intrinsic mechanical factors, exerted by contraction of the myocardium (stretch and strain) and fluid forces of the enclosed blood (wall shear stress). The earliest contractions of the heart occur already in the 10-somite stage in the tubular as yet unsegmented heart. With development, the looping heart becomes asymmetric providing varying diameters and curvatures resulting in unequal flow profiles. These flow profiles exert various wall shear stresses and as a consequence different expression patterns of shear responsive genes. In this paper we investigate the morphological alterations of the heart after changing the blood flow by ligation of the right vitelline vein in a model chicken embryo and analyze the extended expression in the endocardial cushions of the shear responsive gene Tgfbeta receptor III. A major phenomenon is the diminished endocardial-mesenchymal transition resulting in hypoplastic (even absence of) atrioventricular and outflow tract endocardial cushions, which might be lethal in early phases. The surviving embryos exhibit several cardiac malformations including ventricular septal defects and malformed semilunar valves related to abnormal development of the aortopulmonary septal complex and the enclosed neural crest cells. We discuss the results in the light of the interactions between several shear stress responsive signaling pathways including an extended review of the involved Vegf, Notch, Pdgf, Klf2, eNos, Endothelin and Tgfbeta/Bmp/Smad networks. PMID- 30404215 TI - Isolation of A Novel Bacillus thuringiensis Phage Representing A New Phage Lineage and Characterization of Its Endolysin. AB - Phages, the parasites of bacteria, are considered as a new kind of antimicrobial agent due to their ability to lyse pathogenic bacteria. Due to the increase of available phage isolates, the newly isolated phage showed increasing genomic similarities with previously isolated phages. In this study, the novel phage vB_BthS_BMBphi, infecting the Bacillus thuringiensis strain BMB171, is isolated and characterized together with its endolysin. This phage is the first tadpole like phage infecting the Bacillus strains. Genomic analysis shows that the phage genome is dissimilar to all those of previously characterized phages, only exhibiting low similarities with partial regions of the B. thuringiensis prophages. Phylogenetic analysis revealed that the phage was distant from the other Bacillus phages in terms of evolution. The novel genome sequence, the distant evolutionary relationship, and the special virion morphology together suggest that the phage vB_BthS_BMBphi could be classified as a new phage lineage. The genome of the phage is found to contain a restriction modification system, which might endow the phage with immunity to the restriction modification system of the host bacterium. The function of the endolysin PlyBMB encoded by the phage vB_BthS_BMBphi was analyzed, and the endolysin could lyse all the tested Bacillus cereus group strains, suggesting that the endolysin might be used in controlling pathogenic B. cereus group strains. The findings of this study enrich the understanding of phage diversity and provide a resource for controlling the B. cereus group pathogenic bacteria. PMID- 30404216 TI - Benzylisoquinoline Alkaloids Biosynthesis in Sacred Lotus. AB - Sacred lotus (Nelumbo nucifera Gaertn.) is an ancient aquatic plant used throughout Asia for its nutritional and medicinal properties. Benzylisoquinoline alkaloids (BIAs), mostly within the aporphine and bisbenzylisoquinoline structural categories, are among the main bioactive constituents in the plant. The alkaloids of sacred lotus exhibit promising anti-cancer, anti-arrhythmic, anti-HIV, and anti-malarial properties. Despite their pharmacological significance, BIA metabolism in this non-model plant has not been extensively investigated. In this review, we examine the diversity of BIAs in sacred lotus, with an emphasis on the distinctive stereochemistry of alkaloids found in this species. Additionally, we discuss our current understanding of the biosynthetic genes and enzymes involved in the formation of 1-benzylisoquinoline, aporphine, and bisbenzylisoquinoline alkaloids in the plant. We conclude that a comprehensive functional characterization of alkaloid biosynthetic enzymes using both in vitro and in vivo methods is required to advance our limited knowledge of BIA metabolism in the sacred lotus. PMID- 30404217 TI - TD-LSTM: Temporal Dependence-Based LSTM Networks for Marine Temperature Prediction. AB - Changes in ocean temperature over time have important implications for marine ecosystems and global climate change. Marine temperature changes with time and has the features of closeness, period, and trend. This paper analyzes the temporal dependence of marine temperature variation at multiple depths and proposes a new ocean-temperature time-series prediction method based on the temporal dependence parameter matrix fusion of historical observation data. The Temporal Dependence-Based Long Short-Term Memory (LSTM) Networks for Marine Temperature Prediction (TD-LSTM) proves better than other methods while predicting sea-surface temperature (SST) by using Argo data. The performances were good at various depths and different regions. PMID- 30404218 TI - Synthesis of a Novel and Salt Sensitive Superabsorbent Hydrogel Using Soybean Dregs by UV-Irradiation. AB - A biomass based hydrogel soybean dregs-Poly(acrylic acid) (SD-PAA) was synthesized under UV radiation while using agricultural waste soybean dregs. Maximum absorption of SD-PAA is 3587 g.g-1 in distilled water and 302.0 g.g-1 in 150 mM NaCl aqueous solution. Moreover, the influence of granularity, salt solution, and ions in the solutions on water absorption is systematically studied. Sensitivity sequence of the hydrogel to cations was K+ < Na+ < NH4+ < Al3+ < Fe3+ < Mg2+ < Ca2+, and that to anions was PO43- > SO42- > Cl-. Moreover, the experimental results showed that SD-PAA water retention capability remained 37% after centrifugating for 60 min and 0.2% being dried at 60 degrees C for 70 h. Meanwhile, the swelling data agree well with the pseudo-second-order kinetic model and Fickian diffusion mechanism. PMID- 30404219 TI - Genome Editing in Model Strain Myxococcus xanthus DK1622 by a Site-Specific Cre/loxP Recombination System. AB - Myxococcus xanthus DK1622 is a rich source of novel secondary metabolites, and it is often used as an expression host of exogenous biosynthetic gene clusters. However, the frequency of obtaining large genome-deletion variants by using traditional strategies is low, and progenies generated by homologous recombination contain irregular deletions. The present study aims to develop an efficient genome-engineering system for this bacterium based on the Cre/loxP system. We first verified the functionality of the native cre system that was integrated into the chromosome with an inducible promoter PcuoA. Then we assayed the deletion frequency of 8-bp-spacer-sequence mutants in loxP by Cre recombinase which was expressed by suicide vector pBJ113 or self-replicative vector pZJY41. It was found that higher guanine content in a spacer sequence had higher deletion frequency, and the self-replicative vector was more suitable for the Cre/loxP system, probably due to the leaky expression of inducible promoter PcuoA. We also inspected the effects of different antibiotics and the native or synthetic cre gene. Polymerase chain reaction (PCR) and sequencing of new genome joints confirmed that the Cre/loxP system was able to delete a 466 kb fragment in M. xanthus. This Cre/loxP-mediated recombination could serve as an alternative genetic manipulation method. PMID- 30404221 TI - AMP-Activated Protein Kinase and Host Defense against Infection. AB - 5'-AMP-activated protein kinase (AMPK) plays diverse roles in various physiological and pathological conditions. AMPK is involved in energy metabolism, which is perturbed by infectious stimuli. Indeed, various pathogens modulate AMPK activity, which affects host defenses against infection. In some viral infections, including hepatitis B and C viral infections, AMPK activation is beneficial, but in others such as dengue virus, Ebola virus, and human cytomegaloviral infections, AMPK plays a detrimental role. AMPK-targeting agents or small molecules enhance the antiviral response and contribute to the control of microbial and parasitic infections. In addition, this review focuses on the double-edged role of AMPK in innate and adaptive immune responses to infection. Understanding how AMPK regulates host defenses will enable development of more effective host-directed therapeutic strategies against infectious diseases. PMID- 30404220 TI - A Novel Circular RNA Generated by FGFR2 Gene Promotes Myoblast Proliferation and Differentiation by Sponging miR-133a-5p and miR-29b-1-5p. AB - It is well known that fibroblast growth factor receptor 2 (FGFR2) interacts with its ligand of fibroblast growth factor (FGF) therefore exerting biological functions on cell proliferation and differentiation. In this study, we first reported that the FGFR2 gene could generate a circular RNA of circFGFR2, which regulates skeletal muscle development by sponging miRNA. In our previous study of circular RNA sequencing, we found that circFGFR2, generated by exon 3-6 of FGFR2 gene, differentially expressed during chicken embryo skeletal muscle development. The purpose of this study was to reveal the real mechanism of how circFGFR2 affects skeletal muscle development in chicken. In this study, cell proliferation was analyzed by both flow cytometry analysis of the cell cycle and 5-ethynyl-2' deoxyuridine (EdU) assays. Cell differentiation was determined by analysis of the expression of the differentiation marker gene and Myosin heavy chain (MyHC) immunofluorescence. The results of flow cytometry analysis of the cell cycle and EdU assays showed that, overexpression of circFGFR2 accelerated the proliferation of myoblast and QM-7 cells, whereas knockdown of circFGFR2 with siRNA reduced the proliferation of both cells. Meanwhile, overexpression of circFGFR2 accelerated the expression of myogenic differentiation 1 (MYOD), myogenin (MYOG) and the formation of myotubes, and knockdown of circFGFR2 showed contrary effects in myoblasts. Results of luciferase reporter assay and biotin-coupled miRNA pull down assay further showed that circFGFR2 could directly target two binding sites of miR-133a-5p and one binding site of miR-29b-1-5p, and further inhibited the expression and activity of these two miRNAs. In addition, we demonstrated that both miR-133a-5p and miR-29b-1-5p inhibited myoblast proliferation and differentiation, while circFGFR2 could eliminate the inhibition effects of the two miRNAs as indicated by rescue experiments. Altogether, our data revealed that a novel circular RNA of circFGFR2 could promote skeletal muscle proliferation and differentiation by sponging miR-133a-5p and miR-29b-1-5p. PMID- 30404222 TI - An Introduction to 3D Bioprinting: Possibilities, Challenges and Future Aspects. AB - Bioprinting is an emerging field in regenerative medicine. Producing cell-laden, three-dimensional structures to mimic bodily tissues has an important role not only in tissue engineering, but also in drug delivery and cancer studies. Bioprinting can provide patient-specific spatial geometry, controlled microstructures and the positioning of different cell types for the fabrication of tissue engineering scaffolds. In this brief review, the different fabrication techniques: laser-based, extrusion-based and inkjet-based bioprinting, are defined, elaborated and compared. Advantages and challenges of each technique are addressed as well as the current research status of each technique towards various tissue types. Nozzle-based techniques, like inkjet and extrusion printing, and laser-based techniques, like stereolithography and laser-assisted bioprinting, are all capable of producing successful bioprinted scaffolds. These four techniques were found to have diverse effects on cell viability, resolution and print fidelity. Additionally, the choice of materials and their concentrations were also found to impact the printing characteristics. Each technique has demonstrated individual advantages and disadvantages with more recent research conduct involving multiple techniques to combine the advantages of each technique. PMID- 30404223 TI - Molecular Evidence for Two Domestication Events in the Pea Crop. AB - Pea, one of the founder crops from the Near East, has two wild species: Pisum sativum subsp. elatius, with a wide distribution centered in the Mediterranean, and P. fulvum, which is restricted to Syria, Lebanon, Israel, Palestine and Jordan. Using genome wide analysis of 11,343 polymorphic single nucleotide polymorphisms (SNPs) on a set of wild P. elatius (134) and P. fulvum (20) and 74 domesticated accessions (64 P. sativum landraces and 10 P. abyssinicum), we demonstrated that domesticated P. sativum and the Ethiopian pea (P. abyssinicum) were derived from different P. elatius genepools. Therefore, pea has at least two domestication events. The analysis does not support a hybrid origin of P. abyssinicum, which was likely introduced into Ethiopia and Yemen followed by eco geographic adaptation. Both P. sativum and P. abyssinicum share traits that are typical of domestication, such as non-dormant seeds. Non-dormant seeds were also found in several wild P. elatius accessions which could be the result of crop to wild introgression or natural variation that may have been present during pea domestication. A sub-group of P. elatius overlaps with P. sativum landraces. This may be a consequence of bidirectional gene-flow or may suggest that this group of P. elatius is the closest extant wild relative of P. sativum. PMID- 30404225 TI - Indoor Air Quality Real-Time Monitoring in Airport Terminal Areas: An Opportunity for Sustainable Management of Micro-Climatic Parameters. AB - Indoor air quality (IAQ) management in public spaces is assuming a remarkable importance. Busy environments, like airport terminals, are currently regarded as possible hotspots and IAQ is a crucial element for passengers and staff protection, as well as a key aspect of airport passenger experience. A one-month monitoring period has been performed on IAQ in the airport of Bologna (Italy), as prototypal example of large regional airport. Four strategic areas within the airport have been equipped with electronic monitoring platforms, including different contaminants and two microclimatic sensors. Data suggest that daily variation in IAQ parameters typically follow the activity pattern of the different environments under study (i.e., passengers' flows) for gaseous contaminants, where particulate matter counts oscillate in a definite range, with a significant role played by ventilation system. Gaseous contaminants show a correlation between indoor and outdoor concentrations, mainly due to airside activities. Micro-climatic comfort parameters have been tested to match with standards for commercial environments. As results appears in line with typical households IAQ values, the current air ventilation system appears to be adequate. Nevertheless, an integrated air management system, based on real-time monitoring, would lead to optimization and improvement in environmental and economical sustainability. PMID- 30404224 TI - Locally Oriented Scene Complexity Analysis Real-Time Ocean Ship Detection from Optical Remote Sensing Images. AB - Due to strong ocean waves, broken clouds, and extensive cloud cover interferences, ocean ship detection performs poorly when using optical remote sensing images. In addition, it is a challenge to detect small ships on medium resolution optical remote sensing that cover a large area. In this paper, in order to balance the requirements of real-time processing and high accuracy detection, we proposed a novel ship detection framework based on locally oriented scene complexity analysis. First, the proposed method can separate a full image into two types of local scenes (i.e., simple or complex local scenes). Next, simple local scenes would utilize the fast saliency model (FSM) to rapidly complete candidate extraction, and for complex local scenes, the ship feature clustering model (SFCM) will be applied to achieve refined detection against severe background interferences. The FSM considers a fusion enhancement image as an input of the pulse response analysis in the frequency domain to achieve rapid ship detection in simple local scenes. Next, the SFCM builds the descriptive model of the ship feature clustering algorithm to ensure the detection performance on complex local scenes. Extensive experiments on SPOT-5 and GF-2 ocean optical remote sensing images show that the proposed ship detection framework has better performance than the state-of-the-art methods, and it addresses the tricky problem of real-time ocean ship detection under strong waves, broken clouds, extensive cloud cover, and ship fleet interferences. Finally, the proposed ocean ship detection framework is demonstrated on an onboard processing hardware. PMID- 30404226 TI - Improvement of Anomalous Behavior Detection of GNSS Signal Based on TDNN for Augmentation Systems. AB - The reliability of a navigation system is crucial for navigation purposes, especially in areas where stringent performance is required, such as civil aviation or intelligent transportation systems (ITSs). Therefore, integrity monitoring is an inseparable part of safety-critical navigation applications. The receiver autonomous integrity monitor (RAIM) has been used with the global navigation satellite system (GNSS) to provide integrity monitoring within avionics itself, such as in civil aviation for lateral navigation (LNAV) or the non-precision approach (NPA). However, standard RAIM may not meet the stricter aviation availability and integrity requirements for certain operations, e.g., precision approach flight phases, and also is not sufficient for on-ground vehicle integrity monitoring of several specific ITS applications. One possible way to more clearly distinguish anomalies in observed GNSS signals is to take advantage of time-delayed neural networks (TDNNs) to estimate useful information about the faulty characteristics, rather than simply using RAIM alone. Based on the performance evaluation, it was determined that this method can reliably detect flaws in navigation satellites significantly faster than RAIM alone, and it was confirmed that TDNN-based integrity monitoring using RAIM is an encouraging alternative to improve the integrity assurance level of RAIM in terms of GNSS anomaly detection. PMID- 30404228 TI - A New Dataset for Source Identification of High Dynamic Range Images. AB - Digital source identification is one of the most important problems in the field of multimedia forensics. While Standard Dynamic Range (SDR) images are commonly analyzed, High Dynamic Range (HDR) images are a less common research subject, which leaves space for further analysis. In this paper, we present a novel database of HDR and SDR images captured in different conditions, including various capturing motions, scenes and devices. As a possible application of this dataset, the performance of the well-known reference pattern noise-based source identification algorithm was tested on both kinds of images. Results have shown difficulties in source identification conducted on HDR images, due to their complexity and wider dynamic range. It is concluded that capturing conditions and devices themselves can have an impact on source identification, thus leaving space for more research in this field. PMID- 30404229 TI - Modeling of Protein Structural Flexibility and Large-Scale Dynamics: Coarse Grained Simulations and Elastic Network Models. AB - Fluctuations of protein three-dimensional structures and large-scale conformational transitions are crucial for the biological function of proteins and their complexes. Experimental studies of such phenomena remain very challenging and therefore molecular modeling can be a good alternative or a valuable supporting tool for the investigation of large molecular systems and long-time events. In this minireview, we present two alternative approaches to the coarse-grained (CG) modeling of dynamic properties of protein systems. We discuss two CG representations of polypeptide chains used for Monte Carlo dynamics simulations of protein local dynamics and conformational transitions, and highly simplified structure-based elastic network models of protein flexibility. In contrast to classical all-atom molecular dynamics, the modeling strategies discussed here allow the quite accurate modeling of much larger systems and longer-time dynamic phenomena. We briefly describe the main features of these models and outline some of their applications, including modeling of near-native structure fluctuations, sampling of large regions of the protein conformational space, or possible support for the structure prediction of large proteins and their complexes. PMID- 30404230 TI - Research on a 3-DOF Motion Device Based on the Flexible Mechanism Driven by the Piezoelectric Actuators. AB - This paper describes the innovative design of a three-dimensional (3D) motion device based on a flexible mechanism, which is used primarily to produce accurate and fast micro-displacement. For example, the rapid contact and separation of the tool and the workpiece are realized by the operation of the 3D motion device in the machining process. This paper mainly concerns the device performance. A theoretical model for the static performance of the device was established using the matrix-based compliance modeling (MCM) method, and the static characteristics of the device were numerically simulated by finite element analysis (FEA). The Lagrangian principle and the finite element analysis method for device dynamics are used for prediction to obtain the natural frequency of the device. Under no load conditions, the dynamic response performance and linear motion performance of the three directions were tested and analyzed with different input signals, and three sets of vibration trajectories were obtained. Finally, the scratching experiment was carried out. The detection of the workpiece reveals a pronounced periodic texture on the surface, which verifies that the vibration device can generate an ideal 3D vibration trajectory. PMID- 30404227 TI - Rationale of Probiotic Supplementation during Pregnancy and Neonatal Period. AB - Probiotics are living microorganisms that confer a health benefit when administered in adequate amounts. It has been speculated that probiotics supplementation during pregnancy and in the neonatal period might reduce some maternal and neonatal adverse outcomes. In this narrative review, we describe the rationale behind probiotic supplementation and its possible role in preventing preterm delivery, perinatal infections, functional gastrointestinal diseases, and atopic disorders during early life. PMID- 30404232 TI - A Comparison of Proteins Expressed between Human and Mouse Adipose-Derived Mesenchymal Stem Cells by a Proteome Analysis through Liquid Chromatography with Tandem Mass Spectrometry. AB - Adipose-derived mesenchymal stem cells (ADSCs) have become a common cell source for cell transplantation therapy. Clinical studies have used ADSCs to develop treatments for tissue fibrosis, such as liver cirrhosis and pulmonary fibroma. The need to examine and compare basic research data using clinical research data derived from mice and humans is expected to increase in the future. Here, to better characterize the cells, the protein components expressed by human ADSCs used for treatment, and mouse ADSCs used for research, were comprehensively analyzed by liquid chromatography with tandem mass spectrometry. We found that 92% (401 type proteins) of the proteins expressed by ADSCs in humans and mice were consistent. When classified by the protein functions in a gene ontology analysis, the items that differed by >5% between human and mouse ADSCs were "biological adhesion, locomotion" in biological processes, "plasma membrane" in cellular components, and "antioxidant activity, molecular transducer activity" in molecular functions. Most of the listed proteins were sensitive to cell isolation processes. These results show that the proteins expressed by human and murine ADSCs showed a high degree of correlation. PMID- 30404231 TI - Exploring the Perceived Barriers to Following a Mediterranean Style Diet in Childbearing Age: A Qualitative Study. AB - A considerable amount of research has focused on interventions in pregnancy to promote health in current and future generations. This has yielded inconsistent results and focus has turned towards improving health in the preconception period. Promotion of healthy dietary patterns similar to a Mediterranean diet in the preconception years has been suggested as a dietary strategy to prevent maternal obesity and optimize offspring health. However, it is uncertain whether adoption is acceptable in women of childbearing age. This qualitative study aims to investigate the perceived barriers to following a Mediterranean diet in women of childbearing age. Semi-structured focus groups were used to generate deep insights to be used to guide the development of a future intervention. Nulliparous women aged between 20 and 47 years were recruited (n = 20). Six focus groups were digitally audio recorded and transcribed verbatim by the researcher. Thematic analysis was used to analyze data, which occurred in parallel with data collection to ascertain when data saturation was reached. Five core themes were identified: Mediterranean diet features, perceived benefits, existing dietary behavior and knowledge, practical factors, and information source. The present study highlights that a Mediterranean diet is acceptable to childbearing-aged women, and the insights generated will be helpful in developing an intervention to promote Mediterranean diet adoption. PMID- 30404234 TI - Poly(N-isopropylacrylamide-co-2-((diethylamino)methyl)-4-formyl-6-methoxyphenyl acrylate) Environmental Functional Copolymers: Synthesis, Characterizations, and Grafting with Amino Acids. AB - Vanillin was used to synthesize a new derivative with an active aldehyde group and response to pH. It is named 2-((diethylamino) methyl)-4-formyl-6 methoxyphenyl acrylate, abbreviated to DEAMVA. The chemical structures were evaluated by 1H, 13C nuclear magnetic resonance (NMR), infrared (IR), and UV-Vis spectroscopy, and all results demonstrated good statement. In order to achieve the dual responsive behavior thermo-pH with functionality, free radical polymerization of N-isopropylacrylamide with DEAMVA in different molar ratios (5, 10, 15 mol%) has been used, with azobisisobutyronitrile (AIBN) as the initiator. The chemical structure of the polymers was investigated by 1H NMR and IR. The dual responsive functional copolymer was exposed to a grafted process with tryptophan and tyrosine, both of which were also evaluated by 1HNMR and IR. Copolymers before and after grafting were physically investigated by size exclusion chromatography (SEC) for estimation of the molecular weight, the glass transition temperature by differential scanning calorimeter (DSC) and scanning electron microscope (SEM) for the surface morphology. The phase separation or lower critical solution temperature (LCST) (Tc) of the polymer solution was determined not only by a turbidity method using the change in the transmittance with temperature, but also by micro-DSC. The conversion to an amino acid-grafted polymer was detected through Beer's law for the absorption of the -CH=N- imine group by UV-Vis-Spectroscopy. PMID- 30404233 TI - Motion Periods of Planet Gear Fault Meshing Behavior. AB - Vibration sensors are, generally, fixed on the housing of planetary gearboxes for vibration monitoring. When a local fault occurred on the tooth of a planet gear, along with the system operating, the faulty tooth will mesh with the ring gear or sun gear at different positions referring to the fixed sensor. With consideration of the attenuation effect, the amplitudes of the fault-induced vibrations will be time-varying due to the time-varying transfer paths. These variations in signals are valuable information to identify the fault existence as well as the severity and types. However, the fault-meshing positions are time-varying and elusive due to the complicated kinematics or the compound motion behaviors of the internal rotating components. It is tough to accurately determine every fault meshing position though acquiring information from multi-sensors. However, there should exist some specific patterns of the fault meshing positions referring to the single sensor. To thoroughly investigate these motion patterns make effective fault diagnosis feasible merely by a single sensor. Unfortunately, so far few pieces of literature explicitly demonstrate these motion patterns in this regard. This article proposes a method to derive the motion periods of the fault-meshing positions with a faulty planet gear tooth, in which two conditions are considered: 1. The fault-meshing position initially occurs at the ring gear; 2. The fault-meshing position initially occurs at the sun gear. For each scenario, we derive the mathematical expression of the motion period in terms of rotational angles. These motion periods are, in essence, based on the teeth number of gears of a given planetary gearbox. Finally, the application of these motion periods for fault diagnosis is explored with experimental studies. The minimal required data length of a single sensor for effective fault diagnosis is revealed based on the motion periods. PMID- 30404235 TI - Polarized Light Field Imaging for Single-Shot Reflectance Separation. AB - We present a novel computational photography technique for single-shot separation of diffuse/specular reflectance, as well as novel angular domain separation of layered reflectance. We present two imaging solutions for this purpose: two-way polarized light-field (TPLF) imaging and four-way polarized light-field (FPLF) imaging. TPLF imaging consists of a polarized light-field camera, which simultaneously captures two orthogonal states of polarization. A single photograph of a subject acquired with the TPLF camera under polarized illumination then enables standard separation of diffuse (depolarizing) and polarization preserving specular reflectance using light-field sampling. We further demonstrate that the acquired data also enable novel angular separation of layered reflectance including separation of specular reflectance and single scattering in the polarization preserving component, as well as separation of shallow scattering from deep scattering in the depolarizing component. FPLF imaging further generalized the functionality of TPLF imaging under uncontrolled unpolarized or partially polarized illumination such as outdoors. We apply our approach for efficient acquisition of facial reflectance including diffuse and specular normal maps and novel separation of photometric normals into layered reflectance normals for layered facial renderings. We validate our proposed single-shot layered reflectance separation under various imaging conditions and demonstrate it to be comparable to an existing multi-shot technique that relies on structured lighting while achieving separation results under a variety of illumination conditions. PMID- 30404236 TI - Application of Improved Singular Spectrum Decomposition Method for Composite Fault Diagnosis of Gear Boxes. AB - Aiming at the problem that the composite fault signal of the gearbox is weak and the fault characteristics are difficult to extract under strong noise environment, an improved singular spectrum decomposition (ISSD) method is proposed to extract the composite fault characteristics of the gearbox. Singular spectrum decomposition (SSD) has been proved to have higher decomposition accuracy and can better suppress modal mixing and pseudo component. However, noise has a great influence on it, and it is difficult to extract weak impact components. In order to improve the limitations of SSD, we chose the minimum entropy deconvolution adjustment (MEDA) as the pre-filter of the SSD to preprocess the signal. The main function of the minimum entropy deconvolution adjustment is to reduce noise and enhance the impact component, which can make up for the limitations of SSD. However, the ability of MEDA to reduce noise and enhance the impact signal is greatly affected by its parameter, the filter length. Therefore, to improve the shortcomings of MEDA, a parameter adaptive method based on Cuckoo Search (CS) is proposed. First, construct the objective function as the adaptive function of CS to optimize the MEDA algorithm. Then, the pre-processed signal is decomposed into singular spectral components (SSC) by SSD, and the meaningful components are selected by Correlation coefficient. For the existing modal mixing phenomenon, the SSC component is reconstructed to eliminate the misjudgment of the result. Then, the frequency spectrum analysis is performed to obtain the frequency information for fault diagnosis. Finally, the effectiveness and superiority of ISSD are validated by simulation signals and applying to compound faults of a Gear box test rig. PMID- 30404237 TI - Nonlinear Stability Analysis of Eccentrically Stiffened Functionally Graded Truncated Conical Sandwich Shells with Porosity. AB - : This paper analyzes the nonlinear buckling and post-buckling characteristics of the porous eccentrically stiffened functionally graded sandwich truncated conical shells resting on the Pasternak elastic foundation subjected to axial compressive loads. The core layer is made of a porous material (metal foam) characterized by a porosity coefficient which influences the physical properties of the shells in the form of a harmonic function in the shell's thickness direction. The physical properties of the functionally graded (FG) coatings and stiffeners depend on the volume fractions of the constituents which play the role of the exponent in the exponential function of the thickness direction coordinate axis. The classical shell theory and the smeared stiffeners technique are applied to derive the governing equations taking the von Karman geometrical nonlinearity into account. Based on the displacement approach, the explicit expressions of the critical buckling load and the post-buckling load-deflection curves for the sandwich truncated conical shells with simply supported edge conditions are obtained by applying the Galerkin method. The effects of material properties, core layer thickness, number of stiffeners, dimensional parameters, semi vertex angle and elastic foundation on buckling and post-buckling behaviors of the shell are investigated. The obtained results are validated by comparing with those in the literature. PMID- 30404238 TI - Income Changes Due to Disability Ratings and Participation in Economic Activities Caused by Industrial Accidents: A Population-Based Study of Data from the Fourth Panel Study of Workers' Compensation Insurance (PSWCI). AB - Industrial accidents cost a huge amount of money, but they also have negative consequences in many respects. We analyzed the data of the first to fourth panel study of workers' compensation insurance (PSWCI). Repeated measures ANOVA was used to compare the annual income before and after the industrial accident, and a general linear model was used to identify changes in income due to disability ratings and participation in economic activities. The wages before the industrial accident and the annual income varied among the disabilities ratings. In addition, for affected workers, the average income during four years post accident was lower than the average income before the accident. Regression analysis to see changes in income after the industrial accident showed that the group with a disability rating of 11-14 and no injuries had a suffered a greater income decrease than those with a disability rating of 1-3, and the unemployment group saw a greater decrease in income than the employment group. Workers who were affected by industrial accidents received lower incomes than before the accident, and even considering different disability ratings, there was a greater decrease in income among the unemployed group than in the working group. PMID- 30404239 TI - Opinion on the Hurdles and Potential Health Benefits in Value-Added Use of Plant Food Processing By-Products as Sources of Phenolic Compounds. AB - Plant foods, their products and processing by-products are well recognized as important sources of phenolic compounds. Recent studies in this field have demonstrated that food processing by-products are often richer sources of bioactive compounds as compared with their original feedstock. However, their final application as a source of nutraceuticals and bioactives requires addressing certain hurdles and challenges. This review discusses recent knowledge advances in the use of plant food processing by-products as sources of phenolic compounds with special attention to the role of genetics on the distribution and biosynthesis of plant phenolics, as well as their profiling and screening, potential health benefits, and safety issues. The potentialities in health improvement from food phenolics in animal models and in humans is well substantiated, however, considering the emerging market of plant food by-products as potential sources of phenolic bioactives, more research in humans is deemed necessary. PMID- 30404240 TI - D2R-TED: Data-Domain Reduction Model for Threshold-Based Event Detection in Sensor Networks. AB - The reduction of sensor network traffic has become a scientific challenge. Different compression techniques are applied for this purpose, offering general solutions which try to minimize the loss of information. Here, a new proposal for traffic reduction by redefining the domains of the sensor data is presented. A configurable data reduction model is proposed focused on periodic duty-cycled sensor networks with events triggered by threshold. The loss of information produced by the model is analyzed in this paper in the context of event detection, an unusual approach leading to a set of specific metrics that enable the evaluation of the model in terms of traffic savings, precision, and recall. Different model configurations are tested with two experimental cases, whose input data are extracted from an extensive set of real data. In particular, two new versions of Send-on-Delta (SoD) and Predictive Sampling (PS) have been designed and implemented in the proposed data-domain reduction for threshold based event detection (D2R-TED) model. The obtained results illustrate the potential usefulness of analyzing different model configurations to obtain a cost benefit curve, in terms of traffic savings and quality of the response. Experiments show an average reduction of 76 % of network packages with an error of less than 1%. In addition, experiments show that the methods designed under the proposed D2R-TED model outperform the original event-triggered SoD and PS methods by 10 % and 16 % of the traffic savings, respectively. This model is useful to avoid network bottlenecks by applying the optimal configuration in each situation. PMID- 30404241 TI - Occupational Risk Prevention through Smartwatches: Precision and Uncertainty Effects of the Built-In Accelerometer. AB - Wearable technology has had a significant growth in the last years; this is particularly true of smartwatches, due to their potential advantages and ease of use. These smart devices integrate sensors that can be potentially used within industrial settings and for several applications, such as safety, monitoring, and the identification of occupational risks. The accelerometer is one of the main sensors integrated into these devices. However, several studies have identified that sensors integrated into smart devices may present inaccuracies during data acquisition, which may influence the performance of their potential applications. This article presents an analysis from the metrological point of view to characterize the amplitude and frequency response of the integrated accelerometers in three currently available commercial smartwatches, and it also includes an analysis of the uncertainties associated with these measurements by adapting the procedures described in several International Organization for Standardization (ISO) standards. The results show that despite the technical limitations produced by the factory configuration, these devices can be used in various applications related to occupational risk assessment. Opportunities for improvement have also been identified, which will allow us to take advantage of this technology in several innovative applications within industrial settings and, in particular, for occupational health purposes. PMID- 30404242 TI - eTPM: A Trusted Cloud Platform Enclave TPM Scheme Based on Intel SGX Technology. AB - Today cloud computing is widely used in various industries. While benefiting from the services provided by the cloud, users are also faced with some security issues, such as information leakage and data tampering. Utilizing trusted computing technology to enhance the security mechanism, defined as trusted cloud, has become a hot research topic in cloud security. Currently, virtual TPM (vTPM) is commonly used in a trusted cloud to protect the integrity of the cloud environment. However, the existing vTPM scheme lacks protections of vTPM itself at a runtime environment. This paper proposed a novel scheme, which designed a new trusted cloud platform security component, 'enclave TPM (eTPM)' to protect cloud and employed Intel SGX to enhance the security of eTPM. The eTPM is a software component that emulates TPM functions which build trust and security in cloud and runs in 'enclave', an isolation memory zone introduced by SGX. eTPM can ensure its security at runtime, and protect the integrity of Virtual Machines (VM) according to user-specific policies. Finally, a prototype for the eTPM scheme was implemented, and experiment manifested its effectiveness, security, and availability. PMID- 30404243 TI - Pressure Monitoring Cell for Constrained Battery Electrodes. AB - Testing of improved battery components and new electrochemical energy storage materials in a coin cell format as a test cell is becoming the state of the art. The pressure on the electrode surfaces inside an electrochemical cell is one of the important parameters for high ionic/electronic conductivity and the cyclic lifetime. A self-designed pressure monitoring cell allows both applying an adjustable pressure and monitoring the state of charge-dependent cell pressure during cycling. The load cell shows a reciprocal behavior of the temperature sensitivity dependent on the ambient temperature and requires constant temperature conditions while monitoring the cell pressure. Further, dependent on the initial cell pressure, the relaxation time of the assembled pressure monitoring cell must be considered. The present paper describes the setup, the influence of the environment temperature and the mechanical relaxation of the pressure monitoring cell. The first cycling results, using an NCM/graphite coin cell, demonstrate the functionality of the pressure monitoring cell measuring the cell's pressure as a function of the C-rate. PMID- 30404244 TI - A Modified Extended Kalman Filter for a Two-Antenna GPS/INS Vehicular Navigation System. AB - Recently, the integration of an inertial navigation system (INS) and the Global Positioning System (GPS) with a two-antenna GPS receiver has been suggested to improve the stability and accuracy in harsh environments. As is well known, the statistics of state process noise and measurement noise are critical factors to avoid numerical problems and obtain stable and accurate estimates. In this paper, a modified extended Kalman filter (EKF) is proposed by properly adapting the statistics of state process and observation noises through the innovation-based adaptive estimation (IAE) method. The impact of innovation perturbation produced by measurement outliers is found to account for positive feedback and numerical issues. Measurement noise covariance is updated based on a remodification algorithm according to measurement reliability specifications. An experimental field test was performed to demonstrate the robustness of the proposed state estimation method against dynamic model errors and measurement outliers. PMID- 30404245 TI - WebCircRNA: Classifying the Circular RNA Potential of Coding and Noncoding RNA. AB - Circular RNAs (circRNAs) are increasingly recognized to play crucial roles in post-transcriptional gene regulation including functioning as microRNA (miRNA) sponges or as wide-spread regulators, for example in stem cell differentiation. It is therefore highly relevant to identify if a transcript of interest can also function as a circRNA. Here, we present a user-friendly web server that predicts if coding and noncoding RNAs have circRNA isoforms and whether circRNAs are expressed in stem cells. The predictions are made by random forest models using sequence-derived features as input. The output scores are converted to fractiles, which are used to assess the circRNA and stem cell potential. The performances of the three models are reported as the area under the receiver operating characteristic (ROC) curve and are 0.82 for coding genes, 0.89 for long noncoding RNAs (lncRNAs) and 0.72 for stem cell expression. We present WebCircRNA for quick evaluation of human genes and transcripts for their circRNA potential, which can be essential in several contexts. PMID- 30404247 TI - Detoxification and Immune Transcriptomic Response of the Gill Tissue of Bay Scallop (Argopecten irradians) Following Exposure to the Algicide Palmitoleic Acid. AB - Palmitoleic acid (PA) is an effective algicide against Alexandrium tamarense. However, the toxicological mechanism of PA exposure is unclear. The transcript abundance and differentially expressed genes (DEGs) in gills of bay scallop were investigated following 80 mg/L PA exposure up to 48 h using the Illumina HiSeq 4000 deep-sequencing platform with the recommended read length of 100 bp. De novo assembly of paired-end reads yielded 62,099 unigenes; 5414 genes were identified as being significantly increased, and 4452 were decreased. Based on gene ontology classification and enrichment analysis, the 'cellular process', 'metabolic process', 'response to stimulus', and 'catalytic process' with particularly high functional enrichment were revealed. The DEGs, which are related to detoxification and immune responses, revealed that acid phosphatase, fibrinogen C domain-containing protein, cyclic AMP-responsive element-binding protein, glutathione reductase, ATP-binding cassette, nuclear factor erythroid 2-related factor, NADPH2:quinone reductase, and cytochrome P450 4F22, 4B1, and 2C8-related gene expression decreased. In contrast, some genes related to glutathione S transferase, C-type lectin, superoxide dismutase, toll-like receptors, and cytochrome P450 2C14, 2U1, 3A24 and 4A2 increased. The results of current research will be a valuable resource for the investigation of gene expression stimulated by PA, and will help understanding of the molecular mechanisms underlying the scallops' response to PA exposure. PMID- 30404246 TI - Depressive Symptoms and Vegetarian Diets: Results from the Constances Cohort. AB - The association between depressive symptoms and vegetarian diets is controversial. This study examines the cross-sectional association between depressive symptoms and vegetarian diets while controlling for potential confounders. Among 90,380 subjects from the population-based Constances cohort, depressive symptoms were defined by a score >=19 on the Centre of Epidemiologic Studies-Depression (CES-D) scale and diet types (omnivorous, pesco-vegetarian, lacto-ovo-vegetarian and vegan) were determined with a food frequency questionnaire. Associations between depressive symptoms and diet were estimated through logistic regressions adjusting for socio-demographics, other foods, alcohol and tobacco consumption, physical activity and health-related concerns; specificity analyses considered the exclusion of any other food group. Depressive symptoms were associated with pesco-vegetarian and lacto-ovo-vegetarian diets in multivariable analyses (Odds-Ratio [95% confidence interval]: 1.43 [1.19-1.72] and 1.36 [1.09-1.70], respectively), especially in case of low legumes intake (p for interaction < 0.0001), as well as with the exclusion of any food group (e.g., 1.37 [1.24-1.52], 1.40 [1.31-1.50], 1.71 [1.49-1.97] for meat, fish and vegetables exclusion, respectively). Regardless of food type, the Odds-Ratio of depressive symptoms gradually increased with the number of excluded food groups (p for trend < 0.0001). Depressive symptoms are associated with the exclusion of any food group from the diet, including but not restricted to animal products. PMID- 30404248 TI - Influence of Geometry and Surrounding Conditions on Fluid Flow in Paper-Based Devices. AB - Fluid flow behaviour in paper is of increasing interest due to the advantages and expanding use of microfluidic paper-based analytical devices (known as uPADs). Applications are expanding from those which often have low sample fluid volumes, such as diagnostic testing, to those with an abundance of sample fluid, such as water quality testing. The rapid development of enhanced features in MUPADs, along with a need for increased sensitivity and specificity in the embedded chemistry requires understanding the passively-driven fluid motion in paper to enable precise control and consistency of the devices. It is particularly important to understand the influence of parameters associated with larger fluid volumes and to quantify their impact. Here, we experimentally investigate the impacts of several properties during imbibition in paper, including geometry (larger width and length) and the surrounding conditions (humidity and temperature) using abundant fluid reservoirs. Fluid flow velocity in paper was found to vary with temperature and width, but not with length of the paper strip and humidity for the conditions we tested. We observed substantial post-wetting flow for paper strips in contact with a large fluid reservoir. PMID- 30404250 TI - Fabrication of Vacuum-Sealed Capacitive Micromachined Ultrasonic Transducer Arrays Using Glass Reflow Process. AB - This paper presents a process for the fabrication of vacuum-sealed capacitive micromachined ultrasonic transducer (CMUT) arrays using glass reflow and anodic bonding techniques. Silicon through-wafer interconnects have been investigated by the glass reflow process. Then, the patterned silicon-glass reflow wafer is anodically bonded to an SOI (silicon-on-insulator) wafer for the fabrication of CMUT devices. The CMUT 5 * 5 array has been successfully fabricated. The resonant frequency of the CMUT array with a one-cell radius of 100 um and sensing gap of 3.2 um (distance between top and bottom electrodes) is observed at 2.84 MHz. The Q factor is approximately 1300 at pressure of 0.01 Pa. PMID- 30404249 TI - Quasi-Optical Terahertz Microfluidic Devices for Chemical Sensing and Imaging. AB - We first review the development of a frequency domain quasi-optical terahertz (THz) chemical sensing and imaging platform consisting of a quartz-based microfluidic subsystem in our previous work. We then report the application of this platform to sensing and characterizing of several selected liquid chemical samples from 570-630 GHz. THz sensing of chemical mixtures including isopropylalcohol-water (IPA-H2O) mixtures and acetonitrile-water (ACN-H2O) mixtures have been successfully demonstrated and the results have shown completely different hydrogen bond dynamics detected in different mixture systems. In addition, the developed platform has been applied to study molecule diffusion at the interface between adjacent liquids in the multi-stream laminar flow inside the microfluidic subsystem. The reported THz microfluidic platform promises real-time and label-free chemical/biological sensing and imaging with extremely broad bandwidth, high spectral resolution, and high spatial resolution. PMID- 30404251 TI - A CMOS MEMS Humidity Sensor Enhanced by a Capacitive Coupling Structure. AB - A capacitive coupling structure is developed to improve the performances of a capacitive complementary metal oxide semiconductor (CMOS) microelectromechanical system (MEMS) humidity sensor. The humidity sensor was fabricated by a post-CMOS process. Silver nanowires were dispersed onto the top of a conventional interdigitated capacitive structure to form a coupling electrode. Unlike a conventional structure, a thinner sensitive layer was employed to increase the coupling capacitance which dominated the sensitive capacitance of the humidity sensor. Not only static properties but also dynamic properties were found to be better with the aid of coupling capacitance. At 25 degrees C, the sensitive capacitance was 11.3 pF, the sensitivity of the sensor was measured to be 32.8 fF/%RH and the hysteresis was measured to be 1.0 %RH. Both a low temperature coefficient and a fast response (10 s)/recovery time (17 s) were obtained. PMID- 30404253 TI - Assembly of a 3D Cellular Computer Using Folded E-Blocks. AB - The assembly of integrated circuits in three dimensions (3D) provides a possible solution to address the ever-increasing demands of modern day electronic devices. It has been suggested that by using the third dimension, devices with high density, defect tolerance, short interconnects and small overall form factors could be created. However, apart from pseudo 3D architecture, such as monolithic integration, die, or wafer stacking, the creation of paradigms to integrate electronic low-complexity cellular building blocks in architecture that has tile space in all three dimensions has remained elusive. Here, we present software and hardware foundations for a truly 3D cellular computational devices that could be realized in practice. The computing architecture relies on the scalable, self configurable and defect-tolerant cell matrix. The hardware is based on a scalable and manufacturable approach for 3D assembly using folded polyhedral electronic blocks (E-blocks). We created monomers, dimers and 2 * 2 * 2 assemblies of polyhedral E-blocks and verified the computational capabilities by implementing simple logic functions. We further show that 63.2% more compact 3D circuits can be obtained with our design automation tools compared to a 2D architecture. Our results provide a proof-of-concept for a scalable and manufacture-ready process for constructing massive-scale 3D computational devices. PMID- 30404252 TI - Magnetic Particle Plug-Based Assays for Biomarker Analysis. AB - Conventional immunoassays offer selective and quantitative detection of a number of biomarkers, but are laborious and time-consuming. Magnetic particle-based assays allow easy and rapid selection of analytes, but still suffer from the requirement of tedious multiple reaction and washing steps. Here, we demonstrate the trapping of functionalised magnetic particles within a microchannel for performing rapid immunoassays by flushing consecutive reagent and washing solutions over the trapped particle plug. Three main studies were performed to investigate the potential of the platform for quantitative analysis of biomarkers: (i) a streptavidin-biotin binding assay; (ii) a sandwich assay of the inflammation biomarker, C-reactive protein (CRP); and (iii) detection of the steroid hormone, progesterone (P4), towards a competitive assay. Quantitative analysis with low limits of detection was demonstrated with streptavidin-biotin, while the CRP and P4 assays exhibited the ability to detect clinically relevant analytes, and all assays were completed in only 15 min. These preliminary results show the great potential of the platform for performing rapid, low volume magnetic particle plug-based assays of a range of clinical biomarkers via an exceedingly simple technique. PMID- 30404254 TI - Delay Kalman Filter to Estimate the Attitude of a Mobile Object with Indoor Magnetic Field Gradients. AB - More and more services are based on knowing the location of pedestrians equipped with connected objects (smartphones, smartwatches, etc.). One part of the location estimation process is attitude estimation. Many algorithms have been proposed but they principally target open space areas where the local magnetic field equals the Earth's field. Unfortunately, this approach is impossible indoors, where the use of magnetometer arrays or magnetic field gradients has been proposed. However, current approaches omit the impact of past state estimates on the current orientation estimate, especially when a reference field is computed over a sliding window. A novel Delay Kalman filter is proposed in this paper to integrate this time correlation: the Delay MAGYQ. Experimental assessment, conducted in a motion lab with a handheld inertial and magnetic mobile unit, shows that the novel filter better estimates the Euler angles of the handheld device with an 11.7 degrees mean error on the yaw angle as compared to 16.4 degrees with a common Additive Extended Kalman filter. PMID- 30404255 TI - High-Resolution Microfluidic Paper-Based Analytical Devices for Sub-Microliter Sample Analysis. AB - This work demonstrates the fabrication of microfluidic paper-based analytical devices (uPADs) suitable for the analysis of sub-microliter sample volumes. The wax-printing approach widely used for the patterning of paper substrates has been adapted to obtain high-resolution microfluidic structures patterned in filter paper. This has been achieved by replacing the hot plate heating method conventionally used to melt printed wax features into paper by simple hot lamination. This patterning technique, in combination with the consideration of device geometry and the influence of cellulose fiber direction in filter paper, led to a model uPAD design with four microfluidic channels that can be filled with as low as 0.5 uL of liquid. Finally, the application to a colorimetric model assay targeting total protein concentrations is shown. Calibration curves for human serum albumin (HSA) were recorded from sub-microliter samples (0.8 uL), with tolerance against +/-0.1 uL variations in the applied liquid volume. PMID- 30404256 TI - Unconventional Electrochemistry in Micro-/Nanofluidic Systems. AB - Electrochemistry is ideally suited to serve as a detection mechanism in miniaturized analysis systems. A significant hurdle can, however, be the implementation of reliable micrometer-scale reference electrodes. In this tutorial review, we introduce the principal challenges and discuss the approaches that have been employed to build suitable references. We then discuss several alternative strategies aimed at eliminating the reference electrode altogether, in particular two-electrode electrochemical cells, bipolar electrodes and chronopotentiometry. PMID- 30404257 TI - Three-Dimensional Fabrication for Microfluidics by Conventional Techniques and Equipment Used in Mass Production. AB - This paper presents a simple three-dimensional (3D) fabrication method based on soft lithography techniques and laminated object manufacturing. The method can create 3D structures that have undercuts with general machines for mass production and laboratory scale prototyping. The minimum layer thickness of the method is at least 4 um and bonding strength between layers is over 330 kPa. The performance reaches conventional fabrication techniques used for two dimensionally (2D)-designed microfluidic devices. We fabricated some 3D structures, i.e., fractal structures, spiral structures, and a channel-in-channel structure, in microfluidic channels and demonstrated 3D microfluidics. The fabrication method can be achieved with a simple black light for bio-molecule detection; thus, it is useful for not only lab-scale rapid prototyping, but also for commercial manufacturing. PMID- 30404258 TI - High Throughput Studies of Cell Migration in 3D Microtissues Fabricated by a Droplet Microfluidic Chip. AB - Arrayed three-dimensional (3D) micro-sized tissues with encapsulated cells (microtissues) have been fabricated by a droplet microfluidic chip. The extracellular matrix (ECM) is a polymerized collagen network. One or multiple breast cancer cells were embedded within the microtissues, which were stored in arrayed microchambers on the same chip without ECM droplet shrinkage over 48 h. The migration trajectory of the cells was recorded by optical microscopy. The migration speed was calculated in the range of 3-6 um/h. Interestingly, cells in devices filled with a continuous collagen network migrated faster than those where only droplets were arrayed in the chambers. This is likely due to differences in the length scales of the ECM network, as cells embedded in thin collagen slabs also migrate slower than those in thick collagen slabs. In addition to migration, this technical platform can be potentially used to study cancer cell-stromal cell interactions and ECM remodeling in 3D tumor-mimicking environments. PMID- 30404259 TI - Large-Scale Integration of All-Glass Valves on a Microfluidic Device. AB - In this study, we developed a method for fabricating a microfluidic device with integrated large-scale all-glass valves and constructed an actuator system to control each of the valves on the device. Such a microfluidic device has advantages that allow its use in various fields, including physical, chemical, and biochemical analyses and syntheses. However, it is inefficient and difficult to integrate the large-scale all-glass valves in a microfluidic device using conventional glass fabrication methods, especially for the through-hole fabrication step. Therefore, we have developed a fabrication method for the large scale integration of all-glass valves in a microfluidic device that contains 110 individually controllable diaphragm valve units on a 30 mm * 70 mm glass slide. This prototype device was fabricated by first sandwiching a 0.4-mm-thick glass slide that contained 110 1.5-mm-diameter shallow chambers, each with two 50-MUm diameter through-holes, between an ultra-thin glass sheet (4 MUm thick) and another 0.7-mm-thick glass slide that contained etched channels. After the fusion bonding of these three layers, the large-scale microfluidic device was obtained with integrated all-glass valves consisting of 110 individual diaphragm valve units. We demonstrated its use as a pump capable of generating a flow rate of approximately 0.06-5.33 MUL/min. The maximum frequency of flow switching was approximately 12 Hz. PMID- 30404260 TI - Robust Design of an Optical Micromachine for an Ophthalmic Application. AB - This article describes an approach to the robust design of an optical micromachine consisting of a freeform optics, an amplification linkage, and an actuator. The robust design approach consists of monolithic integration principles to minimize assembly efforts and of an optimization of the functional components with respect to robustness against remaining assembly and manufacturing tolerances. The design approach presented involves the determination of the relevant tolerances arising from the domains manufacturing, assembly, and operation of the micromachine followed by a sensitivity analysis with the objective of identifying the worst offender. Subsequent to the above described steps, an optimization of the functional design of the freeform optics with respect to a compensation of the effects of the tolerances is performed. The result leads to a robust design of the freeform optics and hence ensures a defined and optimal minimum performance of the micromachine in the presence of tolerances caused by the manufacturing processes and the operation of the micromachine. The micromachine under discussion is the tunable optics of an ophthalmic implant, an artificial accommodation system recently realized as a demonstration model at a scale of 2:1. The artificial accommodation system will be developed to replace the human crystalline lens in the case of a cataract. PMID- 30404262 TI - Design and Manufacturing of a Passive Pressure Sensor Based on LC Resonance. AB - The LC resonator-based passive pressure sensor attracts much attention because it does not need a power source or lead wires between the sensing element and the readout system. This paper presents the design and manufacturing of a passive pressure sensor that contains a variable capacitor and a copper-electroplated planar inductor. The sensor is fabricated using silicon bulk micro-machining, electroplating, and anodic bonding technology. The finite element method is used to model the deflection of the silicon diaphragm and extract the capacitance change corresponding to the applied pressure. Within the measurement range from 5 to 100 kPa, the sensitivity of the sensor is 0.052 MHz/kPa, the linearity is 2.79%, and the hysteresis error is 0.2%. Compared with the sensitivity at 27 degrees C, the drop of output performance is 3.53% at 140 degrees C. PMID- 30404261 TI - Advances in Microfluidic Paper-Based Analytical Devices for Food and Water Analysis. AB - Food and water contamination cause safety and health concerns to both animals and humans. Conventional methods for monitoring food and water contamination are often laborious and require highly skilled technicians to perform the measurements, making the quest for developing simpler and cost-effective techniques for rapid monitoring incessant. Since the pioneering works of Whitesides' group from 2007, interest has been strong in the development and application of microfluidic paper-based analytical devices (MUPADs) for food and water analysis, which allow easy, rapid and cost-effective point-of-need screening of the targets. This paper reviews recently reported MUPADs that incorporate different detection methods such as colorimetric, electrochemical, fluorescence, chemiluminescence, and electrochemiluminescence techniques for food and water analysis. PMID- 30404263 TI - A Rapid Micromixer for Centrifugal Microfluidic Platforms. AB - This paper presents an innovative mixing technology for centrifugal microfluidic platforms actuated using a specially designed flyball governor. The multilayer microfluidic disc was fabricated using a polydimethylsiloxane (PDMS) replica molding process with a soft lithography technique. The operational principle is based on the interaction between the elastic covering membrane and an actuator pin installed on the flyball governor system. The flyball governor was used as the transducer to convert the rotary motion into a reciprocating linear motion of the pin pressing against the covering membrane of the mixer chamber. When the rotation speed of the microfluidic disc was periodically altered, the mixing chamber was compressed and released accordingly. In this way, enhanced active mixing can be achieved with much better efficiency in comparison with diffusive mixing. PMID- 30404264 TI - Hybrid Integration of Magnetoresistive Sensors with MEMS as a Strategy to Detect Ultra-Low Magnetic Fields. AB - In this paper, we describe how magnetoresistive sensors can be integrated with microelectromechanical systems (MEMS) devices enabling the mechanical modulation of DC or low frequency external magnetic fields to high frequencies using MEMS structures incorporating magnetic flux guides. In such a hybrid architecture, lower detectivities are expected when compared with those obtained for individual sensors. This particularity results from the change of sensor's operating point to frequencies above the 1/f noise knee. PMID- 30404266 TI - Characterizing the Deformation of the Polydimethylsiloxane (PDMS) Membrane for Microfluidic System through Image Processing. AB - Polydimethylsiloxane (PDMS) membranes have been widely used in the microfluidic community to achieve various functions such as control, sensing, filter, etc. In this paper, an experimental process was proposed to directly characterize the deformation of the on-chip PDMS membrane at large deformation based on the image processing method. High precision pressures were applied on the surface of the PDMS membrane with fixed edges and a series deformation of the PDMS membrane were captured by the imaging system. The Chan and Vese (CV) level set method was applied to segment the images of the deformed membrane. The volumes wrapped by the deformed membranes were obtained, and pressure-volumes relationships of the PDMS membranes with different geometry parameters were also calculated. Then the membrane capacitance can be derived by differentiating the curve of pressure volumes. In addition, the theoretical estimation of the capacitance of the PDMS membrane at large deformation was also obtained through finite element simulation (FEM), which was in good agreement with the experimental results. These results are expected to be significant for designing and on-chip measuring of such PDMS membrane based microfluidic components in our future work. PMID- 30404265 TI - A Comprehensive Review of Optical Stretcher for Cell Mechanical Characterization at Single-Cell Level. AB - This paper presents a comprehensive review of the development of the optical stretcher, a powerful optofluidic device for single cell mechanical study by using optical force induced cell stretching. The different techniques and the different materials for the fabrication of the optical stretcher are first summarized. A short description of the optical-stretching mechanism is then given, highlighting the optical force calculation and the cell optical deformability characterization. Subsequently, the implementations of the optical stretcher in various cell-mechanics studies are shown on different types of cells. Afterwards, two new advancements on optical stretcher applications are also introduced: the active cell sorting based on cell mechanical characterization and the temperature effect on cell stretching measurement from laser-induced heating. Two examples of new functionalities developed with the optical stretcher are also included. Finally, the current major limitation and the future development possibilities are discussed. PMID- 30404267 TI - Low-Cost BD/MEMS Tightly-Coupled Pedestrian Navigation Algorithm. AB - Pedestrian Dead Reckoning (PDR) by combining the Inertial Measurement Unit (IMU) and magnetometer is an independent navigation approach based on multiple sensors. Since the inertial component error is significantly determined by the parameters of navigation equations, the navigation precision may deteriorate with time, which is inappropriate for long-time navigation. Although the BeiDou (BD) navigation system can provide high navigation precision in most scenarios, the signal from satellites is easily degraded because of buildings or thick foliage. To solve this problem, a tightly-coupled BD/MEMS (Micro-Electro-Mechanical Systems) integration algorithm is proposed in this paper, and a prototype was built for implementing the integrated system. The extensive experiments prove that the BD/MEMS system performs well in different environments, such as an open sky environment and a playground surrounded by trees and thick foliage. The proposed algorithm is able to provide continuous and reliable positioning service for pedestrian outdoors and thereby has wide practical application. PMID- 30404268 TI - Multiparameter Microwave Characterization and Probing of Ultralow Glucose Concentration Using a Microfabricated Biochip. AB - This paper presents a planar biochip consisting of electromagnetically coupled, symmetric, square open loops for the multiparameter microwave characterization of deionized water, a phosphate-buffered saline solution, and a fructose-deionized water solution. The characterization additionally includes the probing of an ultralow glucose concentration in a very small volume of human sera and in solutions of d-glucose powder and deionized water. The interaction between the coupled electromagnetic field and the aqueous solution sample translates into a predictable relationship between the electrical characteristics of the biochip (magnitude and phase of S-parameters, attenuation, phase constant, group delay, characteristic impedance, and effective complex permittivity) and the physical properties of the solution. Owing to the microfabrication technology used for fabricating the proposed microbiochip, it is possible to develop robust, compact square open loops with a microsized coupling gap that characterizes a very small volume (1 MUL) of the sample. Additionally, the biochip's impedance peaks at its resonances were modeled using glucose-level-dependent coupling capacitance between folded square open loops and mutual inductance between center-loaded T shaped stubs. These peaks linearly shifted in frequencies and markedly varied in impedance. Consequently, a physiologically relevant amount of glucose (50-400 mg/dL) with a high sensitivity (up to 2.036 Omega/(mg.dL-1)) and an ultralow detection limit (up to 4.8 nmol/L) was linearly detected. PMID- 30404269 TI - Compensation Method for Die Shift Caused by Flow Drag Force in Wafer-Level Molding Process. AB - Wafer-level packaging (WLP) is a next-generation semiconductor packaging technology that is important for realizing high-performance and ultra-thin semiconductor devices. However, the molding process, which is a part of the WLP process, has various problems such as a high defect rate and low predictability. Among the various defect factors, the die shift primarily determines the quality of the final product; therefore, predicting the die shift is necessary to achieve high-yield production in WLP. In this study, the die shift caused by the flow drag force of the epoxy molding compound (EMC) is evaluated from the die shift of a debonded molding wafer. Experimental and analytical methods were employed to evaluate the die shift occurring during each stage of the molding process and that resulting from the geometrical changes after the debonding process. The die shift caused by the EMC flow drag force is evaluated from the data on die movements due to thermal contraction/expansion and warpage. The relationship between the die shift and variation in the die gap is determined through regression analysis in order to predict the die shift due to the flow drag force. The results can be used for die realignment by predicting and compensating for the die shift. PMID- 30404270 TI - The GenePOC Platform, a Rational Solution for Extreme Point-of-Care Testing. AB - Extreme point-of-care (POC) testing for infections, as performed (endured) in low resource settings, developing countries, tropical areas, or in conditions following emergency crises or natural disasters, must be undertaken under environmental, logistic, and societal conditions which impose a significant deal of stress on local human populations and healthcare providers. For disease diagnostics or management, simple and robust biomedical equipment and reagents are required and needed. This chapter aims to overview some of these stresses (requirements) and intends to describe some of the solutions already engineered at the heart of centripetal (centrifugal) microfluidic platforms such as that of GenePOC Inc. to enable rapid, robust, and reproducible nucleic acid-based diagnostics of infectious diseases, to better control the morbidity and mortality of infections and the expanding threat posed by antimicrobial resistance. PMID- 30404271 TI - Application of Vertical Electrodes in Microfluidic Channels for Impedance Analysis. AB - This paper presents a microfluidic device with electroplated vertical electrodes in the side walls for impedance measurement. Based on the proposed device, the impedance of NaCl solutions with different concentrations and polystyrene microspheres with different sizes was measured and analyzed. The electroplating and SU-8-PDMS (SU-8-poly(dimethylsiloxane)) bonding technologies were firstly integrated for the fabrication of the proposed microfluidic device, resulting in a tightly three-dimensional structure for practical application. The magnitude of impedance of the tested solutions in the frequency range of 1 Hz to 100 kHz was analyzed by the Zennium electrochemical workstation. The results show that the newly designed microfluidic device has potential for impedance analysis with the advantages of ease of fabrication and the integration of 3D electrodes in the side walls. The newly designed impedance sensor can distinguish different concentrations of polystyrene microspheres and may have potential for cell counting in biological areas. By integrating with other techniques such as dielectrophoresis (DEP) and biological recognition technology, the proposed device may have potential for the assay to identify foodborne pathogen bacteria. PMID- 30404272 TI - Switching between Magnetotactic and Aerotactic Displacement Controls to Enhance the Efficacy of MC-1 Magneto-Aerotactic Bacteria as Cancer-Fighting Nanorobots. AB - The delivery of drug molecules to tumor hypoxic areas could yield optimal therapeutic outcomes. This suggests that effective cancer-fighting micro- or nanorobots would require more integrated functionalities than just the development of directional propelling constructs which have so far been the main general emphasis in medical micro- and nanorobotic research. Development of artificial agents that would be most effective in targeting hypoxic regions may prove to be a very challenging task considering present technological constraints. Self-propelled, sensory-based and directionally-controlled agents in the form of Magnetotactic Bacteria (MTB) of the MC-1 strain have been investigated as effective therapeutic nanorobots in cancer therapy. Following computer-based magnetotactic guidance to reach the tumor area, the microaerophilic response of drug-loaded MC-1 cells could be exploited in the tumoral interstitial fluid microenvironments. Accordingly, their swimming paths would be guided by a decreasing oxygen concentration towards the hypoxic regions. However, the implementation of such a targeting strategy calls for a method to switch from a computer-assisted magnetotactic displacement control to an autonomous aerotactic displacement control. In this way, the MC-1 cells will navigate to tumoral regions and, once there, target hypoxic areas through their microaerophilic behavior. Here we show not only how the magnitude of the magnetic field can be used for this purpose but how the findings could help determine the specifications of a future compatible interventional platform within known technological and medical constraints. PMID- 30404273 TI - Ionoprinted Multi-Responsive Hydrogel Actuators. AB - We report multi-responsive and double-folding bilayer hydrogel sheet actuators, whose directional bending response is tuned by modulating the solvent quality and temperature and where locally crosslinked regions, induced by ionoprinting, enable the actuators to invert their bending axis. The sheets are made multi responsive by combining two stimuli responsive gels that incur opposing and complementary swelling and shrinking responses to the same stimulus. The lower critical solution temperature (LCST) can be tuned to specific temperatures depending on the EtOH concentration, enabling the actuators to change direction isothermally. Higher EtOH concentrations cause upper critical solution temperature (UCST) behavior in the poly(N-isopropylacrylamide) (pNIPAAm) gel networks, which can induce an amplifying effect during bilayer bending. External ionoprints reliably and repeatedly invert the gel bilayer bending axis between water and EtOH. Placing the ionoprint at the gel/gel interface can lead to opposite shape conformations, but with no clear trend in the bending behavior. We hypothesize that this is due to the ionoprint passing through the neutral axis of the bilayer during shrinking in hot water. Finally, we demonstrate the ability of the actuators to achieve shapes unique to the specific external conditions towards developing more responsive and adaptive soft actuator devices. PMID- 30404274 TI - Towards an Implantable, Low Flow Micropump That Uses No Power in the Blocked-Flow State. AB - Low flow rate micropumps play an increasingly important role in drug therapy research. Infusions to small biological structures and lab-on-a-chip applications require ultra-low flow rates and will benefit from the ability to expend no power in the blocked-flow state. Here we present a planar micropump based on gallium phase-change actuation that leverages expansion during solidification to occlude the flow channel in the off-power state. The presented four chamber peristaltic micropump was fabricated with a combination of Micro Electro Mechanical System (MEMS) techniques and additive manufacturing direct write technologies. The device is 7 mm * 13 mm * 1 mm (<100 mm3) with the flow channel and exterior coated with biocompatible Parylene-C, critical for implantable applications. Controllable pump rates from 18 to 104 nL/min were demonstrated, with 11.1 +/- 0.35 nL pumped per actuation at an efficiency of 11 mJ/nL. The normally-closed state of the gallium actuator prevents flow and diffusion between the pump and the biological system or lab-on-a-chip, without consuming power. This is especially important for implanted applications with periodic drug delivery regimens. PMID- 30404275 TI - Affinity-Bead-Mediated Enrichment of CD8+ Lymphocytes from Peripheral Blood Progenitor Cell Products Using Acoustophoresis. AB - Acoustophoresis is a technique that applies ultrasonic standing wave forces in a microchannel to sort cells depending on their physical properties in relation to the surrounding media. Cell handling and separation for research and clinical applications aims to efficiently separate specific cell populations. Here, we investigated the sorting of CD8 lymphocytes from peripheral blood progenitor cell (PBPC) products by affinity-bead-mediated acoustophoresis. PBPC samples were obtained from healthy donors (n = 4) and patients (n = 18). Mononuclear cells were labeled with anti-CD8-coated magnetic beads and sorted on an acoustophoretic microfluidic device and by standard magnetic cell sorting as a reference method. CD8 lymphocytes were acoustically sorted with a mean purity of 91% +/- 8% and a median separation efficiency of 63% (range 15.1%-90.5%) as compared to magnetic sorting (purity 91% +/- 14%, recovery 29% (range 5.1%-47.3%)). The viability as well as the proliferation capacity of sorted lymphocytes in the target fraction were unimpaired and, furthermore, hematopoietic progenitor cell assay revealed a preserved clonogenic capacity post-sorting. Bead-mediated acoustophoresis can, therefore, be utilized to efficiently sort less frequent CD8+ lymphocytes from PBPC products in a continuous flow mode while maintaining cell viability and functional capacity of both target and non-target fractions. PMID- 30404276 TI - Recent Developments in Optofluidic Lens Technology. AB - Optofluidics is a rapidly growing versatile branch of adaptive optics including a wide variety of applications such as tunable beam shaping tools, mirrors, apertures, and lenses. In this review, we focus on recent developments in optofluidic lenses, which arguably forms the most important part of optofluidics devices. We report first on a number of general characteristics and characterization methods for optofluidics lenses and their optical performance, including aberrations and their description in terms of Zernike polynomials. Subsequently, we discuss examples of actuation methods separately for spherical optofluidic lenses and for more recent tunable aspherical lenses. Advantages and disadvantages of various actuation schemes are presented, focusing in particular on electrowetting-driven lenses and pressure-driven liquid lenses that are covered by elastomeric sheets. We discuss in particular the opportunities for detailed aberration control by using either finely controlled electric fields or specifically designed elastomeric lenses. PMID- 30404277 TI - The Graphene/l-Cysteine/Gold-Modified Electrode for the Differential Pulse Stripping Voltammetry Detection of Trace Levels of Cadmium. AB - Cadmium(II) is a common water pollutant with high toxicity. It is of significant importance for detecting aqueous contaminants accurately, as these contaminants are harmful to human health and environment. This paper describes the fabrication, characterization, and application of an environment-friendly graphene (Gr)/l-cysteine/gold electrode to detect trace levels of cadmium (Cd) by differential pulse stripping voltammetry (DPSV). The influence of hydrogen overflow was decreased and the current response was enhanced because the modified graphene extended the potential range of the electrode. The Gr/l-cysteine/gold electrode showed high electrochemical conductivity, producing a marked increase in anodic peak currents (vs. the glass carbon electrode (GCE) and boron-doped diamond (BDD) electrode). The calculated detection limits are 1.15, 0.30, and 1.42 ug/L, and the sensitivities go up to 0.18, 21.69, and 152.0 nA.mm-2.ug-1.L for, respectively, the BDD electrode, the GCE, and the Gr/l-cysteine/gold electrode. It was shown that the Gr/l-cysteine/gold-modified electrode is an effective means for obtaining highly selective and sensitive electrodes to detect trace levels of cadmium. PMID- 30404278 TI - Fabrication of Dish-Shaped Micro Parts by Laser Indirect Shocking Compound Process. AB - Compound process technology has been investigated for many years on a macro scale, but only a few studies can be found on a micro scale due to the difficulties in tool manufacturing, parts transporting and punch-die alignment. In this paper, a novel technology of combining the laser shock wave and soft punch was introduced to fabricate the dish-shaped micro-parts on copper to solve these difficulties. This compound process includes deep drawing, punching and blanking and these processes can be completed almost at the same time because the duration time of laser is quite short, so the precision of the micro-parts can be ensured. A reasonable laser energy of 1550 mJ made the morphology, depth of deformation, dimensional accuracy and surface roughness achieve their best results when the thickness of the soft punches was 200 MUm. In addition, thicker soft punches may hinder the compound process due to the action of unloading waves based on the elastic wave theory. So, the greatest thickness of the soft punches was 200 MUm. PMID- 30404279 TI - A Robot-Assisted Cell Manipulation System with an Adaptive Visual Servoing Method. AB - Robot-assisted cell manipulation is gaining attention for its ability in providing high throughput and high precision cell manipulation for the biological industry. This paper presents a visual servo microrobotic system for cell microinjection. We investigated the automatic cell autofocus method that reduced the complexity of the system. Then, we produced an adaptive visual processing algorithm to detect the location of the cell and micropipette toward the uneven illumination problem. Fourteen microinjection experiments were conducted with zebrafish embryos. A 100% success rate was achieved either in autofocus or embryo detection, which verified the robustness of the proposed automatic cell manipulation system. PMID- 30404280 TI - Cell Monitoring and Manipulation Systems (CMMSs) based on Glass Cell-Culture Chips (GC3s). AB - We developed different types of glass cell-culture chips (GC3s) for culturing cells for microscopic observation in open media-containing troughs or in microfluidic structures. Platinum sensor and manipulation structures were used to monitor physiological parameters and to allocate and permeabilize cells. Electro thermal micro pumps distributed chemical compounds in the microfluidic systems. The integrated temperature sensors showed a linear, Pt1000-like behavior. Cell adhesion and proliferation were monitored using interdigitated electrode structures (IDESs). The cell-doubling times of primary murine embryonic neuronal cells (PNCs) were determined based on the IDES capacitance-peak shifts. The electrical activity of PNC networks was detected using multi-electrode arrays (MEAs). During seeding, the cells were dielectrophoretically allocated to individual MEAs to improve network structures. MEA pads with diameters of 15, 20, 25, and 35 um were tested. After 3 weeks, the magnitudes of the determined action potentials were highest for pads of 25 um in diameter and did not differ when the inter-pad distances were 100 or 170 um. Using 25-um diameter circular oxygen electrodes, the signal currents in the cell-culture media were found to range from approximately -0.08 nA (0% O2) to -2.35 nA (21% O2). It was observed that 60 nm thick silicon nitride-sensor layers were stable potentiometric pH sensors under cell-culture conditions for periods of days. Their sensitivity between pH 5 and 9 was as high as 45 mV per pH step. We concluded that sensorized GC3s are potential animal replacement systems for purposes such as toxicity pre-screening. For example, the effect of mefloquine, a medication used to treat malaria, on the electrical activity of neuronal cells was determined in this study using a GC3 system. PMID- 30404281 TI - Farewell to Animal Testing: Innovations on Human Intestinal Microphysiological Systems. AB - The human intestine is a dynamic organ where the complex host-microbe interactions that orchestrate intestinal homeostasis occur. Major contributing factors associated with intestinal health and diseases include metabolically active gut microbiota, intestinal epithelium, immune components, and rhythmical bowel movement known as peristalsis. Human intestinal disease models have been developed; however, a considerable number of existing models often fail to reproducibly predict human intestinal pathophysiology in response to biological and chemical perturbations or clinical interventions. Intestinal organoid models have provided promising cytodifferentiation and regeneration, but the lack of luminal flow and physical bowel movements seriously hamper mimicking complex host microbe crosstalk. Here, we discuss recent advances of human intestinal microphysiological systems, such as the biomimetic human "Gut-on-a-Chip" that can employ key intestinal components, such as villus epithelium, gut microbiota, and immune components under peristalsis-like motions and flow, to reconstitute the transmural 3D lumen-capillary tissue interface. By encompassing cutting-edge tools in microfluidics, tissue engineering, and clinical microbiology, gut-on-a chip has been leveraged not only to recapitulate organ-level intestinal functions, but also emulate the pathophysiology of intestinal disorders, such as chronic inflammation. Finally, we provide potential perspectives of the next generation microphysiological systems as a personalized platform to validate the efficacy, safety, metabolism, and therapeutic responses of new drug compounds in the preclinical stage. PMID- 30404282 TI - 3D Printed Paper-Based Microfluidic Analytical Devices. AB - As a pump-free and lightweight analytical tool, paper-based microfluidic analytical devices (MUPADs) attract more and more interest. If the flow speed of MUPAD can be programmed, the analytical sequences could be designed and they will be more popular. This reports presents a novel MUPAD, driven by the capillary force of cellulose powder, printed by a desktop three-dimensional (3D) printer, which has some promising features, such as easy fabrication and programmable flow speed. First, a suitable size-scale substrate with open microchannels on its surface is printed. Next, the surface of the substrate is covered with a thin layer of polydimethylsiloxane (PDMS) to seal the micro gap caused by 3D printing. Then, the microchannels are filled with a mixture of cellulose powder and deionized water in an appropriate proportion. After drying in an oven at 60 degrees C for 30 min, it is ready for use. As the different channel depths can be easily printed, which can be used to achieve the programmable capillary flow speed of cellulose powder in the microchannels. A series of microfluidic analytical experiments, including quantitative analysis of nitrite ion and fabrication of T-sensor were used to demonstrate its capability. As the desktop 3D printer (D3DP) is very cheap and accessible, this device can be rapidly printed at the test field with a low cost and has a promising potential in the point-of-care (POC) system or as a lightweight platform for analytical chemistry. PMID- 30404283 TI - Quantification of Vortex Generation Due to Non-Equilibrium Electrokinetics at the Micro/Nanochannel Interface: Spectral Analysis. AB - We report on our investigation of a low Reynolds number non-equilibrium electrokinetic flow in a micro/nanochannel platform. Non-equilibrium electrokinetic phenomena include so-called concentration polarization in a moderate electric field and vortex formation in a high electric field. We conducted a spectral analysis of non-equilibrium electrokinetic vortices at a micro/nanochannel interface. We found that periodic vortices are formed while the frequency varies with the applied voltages and solution concentrations. At a frequency as high as 60 Hz, vortex generation was obtained with the strongest electric field and the lowest concentration. The power spectra show increasing frequency with increasing voltage or decreasing concentration. We expect that our spectral analysis results will be useful for micromixer developers in the micromachine research field. PMID- 30404284 TI - Design and Experiment of a Solder Paste Jetting System Driven by a Piezoelectric Stack. AB - To compensate for the insufficiency and instability of solder paste dispensing and printing that are used in the SMT (Surface Mount Technology) production process, a noncontact solder paste jetting system driven by a piezoelectric stack based on the principle of the nozzle-needle-system is introduced in this paper, in which a miniscule gap exists between the nozzle and needle during the jetting process. Here, the critical jet ejection velocity is discussed through theoretical analysis. The relations between ejection velocity and needle structure, needle velocity, and nozzle diameter were obtained by FLUENT software. Then, the prototype of the solder paste jetting system was fabricated, and the performance was verified by experiments. The effects of the gap between nozzle and needle, the driving voltage, and the nozzle diameter on the jetting performance and droplet diameter were obtained. Solder paste droplets 0.85 mm in diameter were produced when the gap between the nozzle and needle was adjusted to 10 MUm, the driving voltage to 80 V, the nozzle diameter to 0.1 mm, and the variation of the droplet diameter was within +/-3%. PMID- 30404285 TI - A Multithread Nested Neural Network Architecture to Model Surface Plasmon Polaritons Propagation. AB - Surface Plasmon Polaritons are collective oscillations of electrons occurring at the interface between a metal and a dielectric. The propagation phenomena in plasmonic nanostructures is not fully understood and the interdependence between propagation and metal thickness requires further investigation. We propose an ad hoc neural network topology assisting the study of the said propagation when several parameters, such as wavelengths, propagation length and metal thickness are considered. This approach is novel and can be considered a first attempt at fully automating such a numerical computation. For the proposed neural network topology, an advanced training procedure has been devised in order to shun the possibility of accumulating errors. The provided results can be useful, e.g., to improve the efficiency of photocells, for photon harvesting, and for improving the accuracy of models for solid state devices. PMID- 30404286 TI - Light-Addressable Potentiometric Sensor as a Sensing Element in Plug-Based Microfluidic Devices. AB - A plug-based microfluidic system based on the principle of the light-addressable potentiometric sensor (LAPS) is proposed. The LAPS is a semiconductor-based chemical sensor, which has a free addressability of the measurement point on the sensing surface. By combining a microfluidic device and LAPS, ion sensing can be performed anywhere inside the microfluidic channel. In this study, the sample solution to be measured was introduced into the channel in a form of a plug with a volume in the range of microliters. Taking advantage of the light addressability, the position of the plug could be monitored and pneumatically controlled. With the developed system, the pH value of a plug with a volume down to 400 nL could be measured. As an example of plug-based operation, two plugs were merged in the channel, and the pH change was detected by differential measurement. PMID- 30404288 TI - A New Method of Fixing High-Aspect-Ratio Microstructures by Gel. AB - In the microfabrication processes, it is necessary to examine the quality of the structures to ensure the whole process runs smoothly. However, the examination process of pattern defects is interrupted during the fabrication of high-aspect ratio microstructures. The inevitable pattern defects arise from capillary forces which occur during the liquid drying process. In this paper, a new method that enables us to fix the microstructures with gel to restrict deformations before the rinsed liquid drying process has been proposed. It is effective to avoid the capillary forces by preventing the formation of the liquid level. The process parameters, types of gel, gel time and observation time were discussed and the flatness and thickness of the gel layer could be controlled. A series of high aspect-ratio microstructures were fixed in good condition by gel. PMID- 30404287 TI - Microfluidic Autologous Serum Eye-Drops Preparation as a Potential Dry Eye Treatment. AB - Dry eye is a problem in tearing quality and/or quantity and it afflicts millions of persons worldwide. An autologous serum eye-drop is a good candidate for dry eye treatment; however, the eye-drop preparation procedures take a long time and are relatively troublesome. Here we use spiral microchannels to demonstrate a strategy for the preparation of autologous serum eye-drops, which provide benefits for all dry eye patients; 100% and 90% removal efficiencies are achieved for 10 MUm microbeads and whole human blood cells, respectively. Since our strategy allows researchers to integrate other functional microchannels into one device, such a microfluidic device will be able to offer a new one-step preparation system for autologous serum eye-drops. PMID- 30404289 TI - Gravity-Based Precise Cell Manipulation System Enhanced by In-Phase Mechanism. AB - This paper proposes a gravity-based system capable of generating high-resolution pressure for precise cell manipulation or evaluation in a microfluidic channel. While the pressure resolution of conventional pumps for microfluidic applications is usually about hundreds of pascals as the resolution of their feedback sensors, precise cell manipulation at the pascal level cannot be done. The proposed system successfully achieves a resolution of 100 millipascals using water head pressure with an in-phase noise cancelation mechanism. The in-phase mechanism aims to suppress the noises from ambient vibrations to the system. The proposed pressure system is tested with a microfluidic platform for pressure validation. The experimental results show that the in-phase mechanism effectively reduces the pressure turbulence, and the pressure-driven cell movement matches the theoretical simulations. Preliminary experiments on deformability evaluation with red blood cells under incremental pressures of one pascal are successfully performed. Different deformation patterns are observed from cell to cell under precise pressure control. PMID- 30404290 TI - Synthesis and Electro-Magneto-Mechanical Properties of Graphene Aerogels Functionalized with Co-Fe-P Amorphous Alloys. AB - Graphene aerogels (GAs) are functionalized with Fe-Co-P alloy using an electro deposition method. The Fe-Co-P alloy coated on the graphene nanosheets is found to possess an amorphous structure and a nanoporous architecture of GAs. The electro-mechanical properties of GAs are significantly affected by the Fe-Co-P nanoparticles embedded inside GAs. The electro-mechanical responses of GA/Fe-Co-P nanoporous hybrid structures are sensitive to an applied magnetic field, demonstrating that they are promising for electro-magneto-mechanical applications. The light-weight, high-strength and nanoporous GAs functionalized with Fe-Co-P amorphous alloys are desirable sensors, actuators, and nano-electro mechanical systems that could be controlled or manipulated by mechanical, electric and magnetic fields. PMID- 30404292 TI - Combining Electro-Osmotic Flow and FTA(r) Paper for DNA Analysis on Microfluidic Devices. AB - FTA(r) paper can be used to protect a variety of biological samples prior to analysis, facilitating ease-of-transport to laboratories or long-term archive storage. The use of FTA(r) paper as a solid phase eradicates the need to elute the nucleic acids from the matrix prior to DNA amplification, enabling both DNA purification and polymerase chain reaction (PCR)-based DNA amplification to be performed in a single chamber on the microfluidic device. A disc of FTA(r) paper, containing a biological sample, was placed within the microfluidic device on top of wax-encapsulated DNA amplification reagents. The disc containing the biological sample was then cleaned up using Tris-EDTA (TE) buffer, which was passed over the disc, via electro-osmotic flow, in order to remove any potential inhibitors of downstream processes. DNA amplification was successfully performed (from buccal cells, whole blood and semen) using a Peltier thermal cycling system, whereupon the stored PCR reagents were released during the initial denaturing step due to the wax barrier melting between the FTA(r) disc and PCR reagents. Such a system offers advantages in terms of a simple sample introduction interface and the ability to process archived samples in an integrated microfluidic environment with minimal risk of contamination. PMID- 30404291 TI - Plasmonic Structures, Materials and Lenses for Optical Lithography beyond the Diffraction Limit: A Review. AB - The rapid development of nanotechnologies and sciences has led to the great demand for novel lithography methods allowing large area, low cost and high resolution nano fabrications. Characterized by unique sub-diffraction optical features like propagation with an ultra-short wavelength and great field enhancement in subwavelength regions, surface plasmon polaritons (SPPs), including surface plasmon waves, bulk plasmon polaritons (BPPs) and localized surface plasmons (LSPs), have become potentially promising candidates for nano lithography. In this paper, investigations into plasmonic lithography in the manner of point-to-point writing, interference and imaging were reviewed in detail. Theoretical simulations and experiments have demonstrated plasmonic lithography resolution far beyond the conventional diffraction limit, even with ultraviolet light sources and single exposure performances. Half-pitch resolution as high as 22 nm (~1/17 light wavelength) was observed in plasmonic lens imaging lithography. Moreover, not only the overview of state-of-the-art results, but also the physics behind them and future research suggestions are discussed as well. PMID- 30404294 TI - Locally-Actuated Graphene-Based Nano-Electro-Mechanical Switch. AB - The graphene nano-electro-mechanical switches are promising components due to their outstanding switching performance. However, most of the reported devices suffered from a large actuation voltages, hindering them from the integration in the conventional complementary metal-oxide-semiconductor (CMOS) circuit. In this work, we demonstrated the graphene nano-electro-mechanical switches with the local actuation electrode via conventional nanofabrication techniques. Both cantilever-type and double-clamped beam switches were fabricated. These devices exhibited the sharp switching, reversible operation cycles, high on/off ratio, and a low actuation voltage of below 5 V, which were compatible with the CMOS circuit requirements. PMID- 30404293 TI - Cytostretch, an Organ-on-Chip Platform. AB - Organ-on-Chips (OOCs) are micro-fabricated devices which are used to culture cells in order to mimic functional units of human organs. The devices are designed to simulate the physiological environment of tissues in vivo. Cells in some types of OOCs can be stimulated in situ by electrical and/or mechanical actuators. These actuations can mimic physiological conditions in real tissue and may include fluid or air flow, or cyclic stretch and strain as they occur in the lung and heart. These conditions similarly affect cultured cells and may influence their ability to respond appropriately to physiological or pathological stimuli. To date, most focus has been on devices specifically designed to culture just one functional unit of a specific organ: lung alveoli, kidney nephrons or blood vessels, for example. In contrast, the modular Cytostretch membrane platform described here allows OOCs to be customized to different OOC applications. The platform utilizes silicon-based micro-fabrication techniques that allow low-cost, high-volume manufacturing. We describe the platform concept and its modules developed to date. Membrane variants include membranes with (i) through-membrane pores that allow biological signaling molecules to pass between two different tissue compartments; (ii) a stretchable micro-electrode array for electrical monitoring and stimulation; (iii) micro-patterning to promote cell alignment; and (iv) strain gauges to measure changes in substrate stress. This paper presents the fabrication and the proof of functionality for each module of the Cytostretch membrane. The assessment of each additional module demonstrate that a wide range of OOCs can be achieved. PMID- 30404295 TI - High-Throughput Assessment of Drug Cardiac Safety Using a High-Speed Impedance Detection Technology-Based Heart-on-a-Chip. AB - Drug cardiac safety assessments play a significant role in drug discovery. Drug induced cardiotoxicity is one of the main reasons for drug attrition, even when antiarrhythmic drugs can otherwise effectively treat the arrhythmias. Consequently, efficient drug preclinical assessments are needed in the drug industry. However, most drug efficacy assessments are performed based on electrophysiological tests of cardiomyocytes in vitro and cannot effectively provide information on drug-induced dysfunction of cardiomyocyte beating. Here we present a heart-on-a-chip device for evaluating the drug cardiac efficacy using a high-speed impedance detection technology. Verapamil and doxorubicin were utilized to test this heart-on-a-chip, and multiple parameters of cardiomyocyte beating status are used to reveal the effects of drugs. The results show that drug efficacy or cardiotoxicity can be determined by this heart-on-a-chip. We believe this heart-on-a-chip will be a promising tool for the preclinical assessment of drug cardiac efficacy. PMID- 30404297 TI - Wide Field-of-View Fluorescence Imaging with Optical-Quality Curved Microfluidic Chamber for Absolute Cell Counting. AB - Field curvature and other aberrations are encountered inevitably when designing a compact fluorescence imaging system with a simple lens. Although multiple lens elements can be used to correct most such aberrations, doing so increases system cost and complexity. Herein, we propose a wide field-of-view (FOV) fluorescence imaging method with an unconventional optical-quality curved sample chamber that corrects the field curvature caused by a simple lens. Our optics simulations and proof-of-concept experiments demonstrate that a curved substrate with lens dependent curvature can reduce greatly the distortion in an image taken with a conventional planar detector. Following the validation study, we designed a curved sample chamber that can contain a known amount of sample volume and fabricated it at reasonable cost using plastic injection molding. At a magnification factor of approximately 0.6, the curved chamber provides a clear view of approximately 119 mm2, which is approximately two times larger than the aberration-free area of a planar chamber. Remarkably, a fluorescence image of microbeads in the curved chamber exhibits almost uniform intensity over the entire field even with a simple lens imaging system, whereas the distorted boundary region has much lower brightness than the central area in the planar chamber. The absolute count of white blood cells stained with a fluorescence dye was in good agreement with that obtained by a commercially available conventional microscopy system. Hence, a wide FOV imaging system with the proposed curved sample chamber would enable us to acquire an undistorted image of a large sample volume without requiring a time-consuming scanning process in point-of-care diagnostic applications. PMID- 30404296 TI - Microfluidic Approaches for Manipulating, Imaging, and Screening C. elegans. AB - The nematode C. elegans (worm) is a small invertebrate animal widely used in studies related to fundamental biological processes, disease modelling, and drug discovery. Due to their small size and transparent body, these worms are highly suitable for experimental manipulations. In recent years several microfluidic devices and platforms have been developed to accelerate worm handling, phenotypic studies and screens. Here we review major tools and briefly discuss their usage in C. elegans research. PMID- 30404298 TI - Mimicking the Kidney: A Key Role in Organ-on-Chip Development. AB - Pharmaceutical drug screening and research into diseases call for significant improvement in the effectiveness of current in vitro models. Better models would reduce the likelihood of costly failures at later drug development stages, while limiting or possibly even avoiding the use of animal models. In this regard, promising advances have recently been made by the so-called "organ-on-chip" (OOC) technology. By combining cell culture with microfluidics, biomedical researchers have started to develop microengineered models of the functional units of human organs. With the capacity to mimic physiological microenvironments and vascular perfusion, OOC devices allow the reproduction of tissue- and organ-level functions. When considering drug testing, nephrotoxicity is a major cause of attrition during pre-clinical, clinical, and post-approval stages. Renal toxicity accounts for 19% of total dropouts during phase III drug evaluation-more than half the drugs abandoned because of safety concerns. Mimicking the functional unit of the kidney, namely the nephron, is therefore a crucial objective. Here we provide an extensive review of the studies focused on the development of a nephron-on-chip device. PMID- 30404299 TI - Quantification of Vortex Generation Due to Non-Equilibrium Electrokinetics at the Micro/Nanochannel Interface: Particle Tracking Velocimetry. AB - We describe a quantitative study of vortex generation due to non-equilibrium electrokinetics near a micro/nanochannel interface. The microfluidic device is comprised of a microchannel with a set of nanochannels. These perm-selective nanochannels induce flow instability and thereby produce strong vortex generation. We performed tracking visualization of fluorescent microparticles to obtain velocity fields. Particle tracking enables the calculation of an averaged velocity field and the velocity fluctuations. We characterized the effect of applied voltages and electrolyte concentrations on vortex formation. The experimental results show that an increasing voltage or decreasing concentration results in a larger vortex region and a strong velocity fluctuation. We calculate the normalized velocity fluctuation-whose meaning is comparable to turbulent intensity-and we found that it is as high as 0.12. This value is indicative of very efficient mixing, albeit with a small Reynolds number. PMID- 30404300 TI - Flexible Holographic Fabrication of 3D Photonic Crystal Templates with Polarization Control through a 3D Printed Reflective Optical Element. AB - In this paper, we have systematically studied the holographic fabrication of three-dimensional (3D) structures using a single 3D printed reflective optical element (ROE), taking advantage of the ease of design and 3D printing of the ROE. The reflective surface was setup at non-Brewster angles to reflect both s- and p polarized beams for the interference. The wide selection of reflective surface materials and interference angles allow control of the ratio of s- and p polarizations, and intensity ratio of side-beam to central beam for interference lithography. Photonic bandgap simulations have also indicated that both s and p polarized waves are sometimes needed in the reflected side beams for maximum photonic bandgap size and certain filling fractions of dielectric inside the photonic crystals. The flexibility of single ROE and single exposure based holographic fabrication of 3D structures was demonstrated with reflective surfaces of ROEs at non-Brewster angles, highlighting the capability of the ROE technique of producing umbrella configurations of side beams with arbitrary angles and polarizations and paving the way for the rapid throughput of various photonic crystal templates. PMID- 30404301 TI - Application of Robust, Packaged Long-Period Fiber Grating for Strain Measurement. AB - This paper proposes an optical fiber strain sensor based on packaged long-period fiber gratings (PLPFG) which is fabricated by the micro-electromechanical systems (MEMS) process and packaged with poly-dimethylsiloxane (PDMS) polymer materials. The optical fiber sensor packaged with PDMS improves robustness effectively. The proposed PLPFG sensors have periods of 610, 650, 660 MUm and fiber diameter of 48, 60, 72 MUm, respectively. The resonance dip of the PLPFG grows when a strain loaded onto the sensor. The results show that the largest strain sensitivity of the PLPFG strain sensor was -0.0652 dB/MUepsilon from 0-1200 MUepsilon and the linearity (R2) was 0.9812. Accordingly, the proposed PLPFG sensor has good potential for high-sensitivity strain sensing applications. PMID- 30404303 TI - Characterization of a Laterally Oscillating Microresonator Operating in the Nonlinear Region. AB - Microresonators are popular structures used in a variety of applications. They generally operate in the linear region where the vibration amplitude is limited, thereby limiting the signal-to-noise ratio. The nonlinear vibration region, where amplitudes and, consequently, the signal-to-noise ratio are relatively large, is generally avoided owing to instabilities and complexities in analysing the vibrations. In this work, a nonlinear dynamic model with a damping constant obtained from Monte Carlo simulation was derived to describe the vibration responses of microresonators operating in the nonlinear region. A laterally oscillating comb-drive driven resonator was designed, fabricated and characterized at various pressures and driving signals to validate the model. A simple method to extract the quality factor of the resonator in the nonlinear region was also proposed. The measured quality factors were compared with those obtained from the nonlinear model and a good agreement was obtained. PMID- 30404304 TI - Fabrication of a Cell Fixation Device for Robotic Cell Microinjection. AB - Automation of cell microinjection greatly reduces operational difficulty, but cell fixation remains a challenge. Here, we describe an innovative device that solves the fixation problem without single-cell operation. The microarray cylinder is designed with a polydimethylsiloxane (PDMS) material surface to control the contact force between cells and the material. Data show that when the injection velocity exceeds 1.5 mm/s, microinjection success rate is over 80%. The maximum value of the adhesion force between the PDMS plate and the cell is 0.0138 N, and the need can be met in practical use of the robotic microinjection. PMID- 30404305 TI - A Modified Lattice Configuration Design for Compact Wideband Bulk Acoustic Wave Filter Applications. AB - High-performance bulk acoustic wave (BAW) filters have been widely applied in the advanced radio frequency (RF) wireless communication systems in the past decade. However, the demand for filters with large bandwidth, up to 10%, still puts a significant stress on the typical aluminum nitride (AlN)-based BAW filters. In this work, a modified lattice configuration is proposed to achieve a wideband filter response using AlN-based BAW resonators. The single stage of this novel topology comprises two auxiliary inductors paralleled in the balanced input and output of the conventional lattice topology. In multi-stage configuration, adjacent two auxiliary inductors can be combined into one; thus, the number of auxiliary inductors decreases exponentially, enabling the compact integration of filter chips. The circuit analysis is performed to reveal the working principle of this configuration. The systematic design methodology is developed ranging from the schematic design to the electromagnetic (EM) simulation. For proof-of concept validation purposes, a prototype film bulk acoustic wave filter in this configuration is designed and fabricated. The measured 3-dB bandwidth is 400 MHz at the central frequency of 3.25 GHz (12.3% relative bandwidth), which demonstrates a huge superiority in contrast with the conventional ladder and lattice topologies. PMID- 30404302 TI - Organ-Tumor-on-a-Chip for Chemosensitivity Assay: A Critical Review. AB - With a mortality rate over 580,000 per year, cancer is still one of the leading causes of death worldwide. However, the emerging field of microfluidics can potentially shed light on this puzzling disease. Unique characteristics of microfluidic chips (also known as micro-total analysis system) make them excellent candidates for biological applications. The ex vivo approach of tumor on-a-chip is becoming an indispensable part of personalized medicine and can replace in vivo animal testing as well as conventional in vitro methods. In tumor on-a-chip, the complex three-dimensional (3D) nature of malignant tumor is co cultured on a microfluidic chip and high throughput screening tools to evaluate the efficacy of anticancer drugs are integrated on the same chip. In this article, we critically review the cutting edge advances in this field and mainly categorize each tumor-on-a-chip work based on its primary organ. Specifically, design, fabrication and characterization of tumor microenvironment; cell culture technique; transferring mechanism of cultured cells into the microchip; concentration gradient generators for drug delivery; in vitro screening assays of drug efficacy; and pros and cons of each microfluidic platform used in the recent literature will be discussed separately for the tumor of following organs: (1) Lung; (2) Bone marrow; (3) Brain; (4) Breast; (5) Urinary system (kidney, bladder and prostate); (6) Intestine; and (7) Liver. By comparing these microchips, we intend to demonstrate the unique design considerations of each tumor-on-a-chip based on primary organ, e.g., how microfluidic platform of lung-tumor-on-a-chip may differ from liver-tumor-on-a-chip. In addition, the importance of heart-liver intestine co-culture with microvasculature in tumor-on-a-chip devices for in vitro chemosensitivity assay will be discussed. Such system would be able to completely evaluate the absorption, distribution, metabolism, excretion and toxicity (ADMET) of anticancer drugs and more realistically recapitulate tumor in vivo-like microenvironment. PMID- 30404306 TI - Integration of a Droplet-Based Microfluidic System and Silicon Nanoribbon FET Sensor. AB - We present a novel microfluidic system that integrates droplet microfluidics with a silicon nanoribbon field-effect transistor (SiNR FET), and utilize this integrated system to sense differences in pH. The device allows for selective droplet transfer to a continuous water phase, actuated by dielectrophoresis, and subsequent detection of the pH level in the retrieved droplets by SiNR FETs on an electrical sensor chip. The integrated microfluidic system demonstrates a label free detection method for droplet microfluidics, presenting an alternative to optical fluorescence detection. In this work, we were able to differentiate between droplet trains of one pH-unit difference. The pH-based detection method in our integrated system has the potential to be utilized in the detection of biochemical reactions that induce a pH-shift in the droplets. PMID- 30404307 TI - A Reduced Graphene Oxide Based Radio Frequency Glucose Sensing Device Using Multi Dimensional Parameters. AB - A reduced graphene oxide (RGO) based glucose sensor using a radio frequency (RF) signal is demonstrated. An RGO with outstanding electrical property was employed as the interconnector material between signal electrodes in an RF electric circuit, and it was functionalized with phenylbutyric acid (PBA) as a linker molecule to bind glucoses. By adding glucose solution, the fabricated sensor with RGO and PBA showed detecting characteristics in RF signal transmission and reflection. Frequency dependent electrical parameters such as resistance, inductance, shunt conductance and shunt capacitance were extracted from the RF results under the equivalent circuit model. These parameters also provided sensing characteristics of glucose with different concentrations. Using these multi-dimensional parameters, the RF sensor device detected glucose levels in the range of 1-4 mM, which ordinarily covers the testing range for diabetes or medical examination. The RGO based RF sensor, which fits well to a linear curve with fine stability, holds considerable promise for biomaterials detection, including glucose. PMID- 30404308 TI - Stacked Integration of MEMS on LSI. AB - Two stacked integration methods have been developed to enable advanced microsystems of microelectromechanical systems (MEMS) on large scale integration (LSI). One is a wafer level transfer of MEMS fabricated on a carrier wafer to a LSI wafer. The other is the use of electrical interconnections using through-Si vias from the structure of a MEMS wafer on a LSI wafer. The wafer level transfer methods are categorized to film transfer, device transfer connectivity last, and immediate connectivity at device transfer. Applications of these transfer methods are film bulk acoustic resonator (FBAR) on LSI, lead zirconate titanate (Pb(Zr,Ti)O3) (PZT) MEMS switch on LSI, and surface acoustic wave (SAW) resonators on LSI using respective methods. A selective transfer process was developed for multiple SAW filters on LSI. Tactile sensors and active matrix electron emitters for massive parallel electron beam lithography were developed using the through-Si vias. PMID- 30404309 TI - Fluid-Mediated Stochastic Self-Assembly at Centimetric and Sub-Millimetric Scales: Design, Modeling, and Control. AB - Stochastic self-assembly provides promising means for building micro-/nano structures with a variety of properties and functionalities. Numerous studies have been conducted on the control and modeling of the process in engineered self assembling systems constituted of modules with varied capabilities ranging from completely reactive nano-/micro-particles to intelligent miniaturized robots. Depending on the capabilities of the constituting modules, different approaches have been utilized for controlling and modeling these systems. In the quest of a unifying control and modeling framework and within the broader perspective of investigating how stochastic control strategies can be adapted from the centimeter-scale down to the (sub-)millimeter-scale, as well as from mechatronic to MEMS-based technology, this work presents the outcomes of our research on self assembly during the past few years. As the first step, we leverage an experimental platform to study self-assembly of water-floating passive modules at the centimeter scale. A dedicated computational framework is developed for real time tracking, modeling and control of the formation of specific structures. Using a similar approach, we then demonstrate controlled self-assembly of microparticles into clusters of a preset dimension in a microfluidic chamber, where the control loop is closed again through real-time tracking customized for a much faster system dynamics. Finally, with the aim of distributing the intelligence and realizing programmable self-assembly, we present a novel experimental system for fluid-mediated programmable stochastic self-assembly of active modules at the centimeter scale. The system is built around the water floating 3-cm-sized Lily robots specifically designed to be operative in large swarms and allows for exploring the whole range of fully-centralized to fully distributed control strategies. The outcomes of our research efforts extend the state-of-the-art methodologies for designing, modeling and controlling massively distributed, stochastic self-assembling systems at different length scales, constituted of modules from centimetric down to sub-millimetric size. As a result, our work provides a solid milestone in structure formation through controlled self-assembly. PMID- 30404310 TI - A Reconfigurable Microfluidics Platform for Microparticle Separation and Fluid Mixing. AB - Microfluidics is an engineering tool used to control and manipulate fluid flows, with practical applications for lab-on-a-chip, point-of-care testing, and biological/medical research. However, microfluidic platforms typically lack the ability to create a fluidic duct, having an arbitrary flow path, and to change the path as needed without additional design and fabrication processes. To address this challenge, we present a simple yet effective approach for facile, on demand reconfiguration of microfluidic channels using flexible polymer tubing. The tubing provides both a well-defined, cross-sectional geometry to allow reliable fluidic operation and excellent flexibility to achieve a high degree of freedom for reconfiguration of flow pathways. We demonstrate that microparticle separation and fluid mixing can be successfully implemented by reconfiguring the shape of the tubing. The tubing is coiled around a 3D-printed barrel to make a spiral microchannel with a constant curvature for inertial separation of microparticles. Multiple knots are also made in the tubing to create a highly tortuous flow path, which induces transverse secondary flows, Dean flows, and, thus, enhances the mixing of fluids. The reconfigurable microfluidics approach, with advantages including low-cost, simplicity, and ease of use, can serve as a promising complement to conventional microfabrication methods, which require complex fabrication processes with expensive equipment and lack a degree of freedom for reconfiguration. PMID- 30404311 TI - An Implantable Intravascular Pressure Sensor for a Ventricular Assist Device. AB - The aim of this study is to investigate the intravascular application of a micro electro-mechanical system (MEMS) pressure sensor to directly measure the hemodynamic characteristics of a ventricular assist device (VAD). A bio- and hemo compatible packaging strategy is implemented, based on a ceramic thick film process. A commercial sub-millimeter piezoresistive sensor is attached to an alumina substrate, and a double coating of polydimethylsiloxane (PDMS) and parylene-C is applied. The final size of the packaged device is 2.6 mm by 3.6 mm by 1.8 mm. A prototype electronic circuit for conditioning and read-out of the pressure signal is developed, satisfying the VAD-specific requirements of low power consumption (less than 14.5 mW in continuous mode) and small form factor. The packaged sensor has been submitted to extensive in vitro tests. The device displayed a temperature-independent sensitivity (12 MU V/V/mmHg) and good in vitro stability when exposed to the continuous flow of saline solution (less than 0.05 mmHg/day drift after 50 h). During in vivo validation, the transducer has been successfully used to record the arterial pressure waveform of a female sheep. A small, intravascular sensor to continuously register the blood pressure at the inflow and the outflow of a VAD is developed and successfully validated in vivo. PMID- 30404312 TI - A Method of Three-Dimensional Micro-Rotational Flow Generation for Biological Applications. AB - We report a convenient method to create a three-dimensional micro-rotational fluidic platform for biological applications in the direction of a vertical plane (out-of-plane) without contact in an open space. Unlike our previous complex fluidic manipulation system, this method uses a micro-rotational flow generated near a single orifice when the solution is pushed from the orifice by using a single pump. The three-dimensional fluidic platform shows good potential for fluidic biological applications such as culturing, stimulating, sorting, and manipulating cells. The pattern and velocity of the micro-rotational flow can be controlled by tuning the parameters such as the flow rate and the liquid-air interface height. We found that bio-objects captured by the micro-rotational flow showed self-rotational motion and orbital motion. Furthermore, the path length and position, velocity, and pattern of the orbital motion of the bio-object could be controlled. To demonstrate our method, we used embryoid body cells. As a result, the orbital motion had a maximum length of 2.4 mm, a maximum acceleration of 0.63 m/s2, a frequency of approximately 0.45 Hz, a maximum velocity of 15.4 mm/s, and a maximum rotation speed of 600 rpm. The capability to have bio-objects rotate or move orbitally in three dimensions without contact opens up new research opportunities in three-dimensional microfluidic technology. PMID- 30404313 TI - Study of a Microfluidic Chip Integrating Single Cell Trap and 3D Stable Rotation Manipulation. AB - Single cell manipulation technology has been widely applied in biological fields, such as cell injection/enucleation, cell physiological measurement, and cell imaging. Recently, a biochip platform with a novel configuration of electrodes for cell 3D rotation has been successfully developed by generating rotating electric fields. However, the rotation platform still has two major shortcomings that need to be improved. The primary problem is that there is no on-chip module to facilitate the placement of a single cell into the rotation chamber, which causes very low efficiency in experiment to manually pipette single 10-micron scale cells into rotation position. Secondly, the cell in the chamber may suffer from unstable rotation, which includes gravity-induced sinking down to the chamber bottom or electric-force-induced on-plane movement. To solve the two problems, in this paper we propose a new microfluidic chip with manipulation capabilities of single cell trap and single cell 3D stable rotation, both on one chip. The new microfluidic chip consists of two parts. The top capture part is based on the least flow resistance principle and is used to capture a single cell and to transport it to the rotation chamber. The bottom rotation part is based on dielectrophoresis (DEP) and is used to 3D rotate the single cell in the rotation chamber with enhanced stability. The two parts are aligned and bonded together to form closed channels for microfluidic handling. Using COMSOL simulation and preliminary experiments, we have verified, in principle, the concept of on-chip single cell traps and 3D stable rotation, and identified key parameters for chip structures, microfluidic handling, and electrode configurations. The work has laid a solid foundation for on-going chip fabrication and experiment validation. PMID- 30404314 TI - High-Pressure Acceleration of Nanoliter Droplets in the Gas Phase in a Microchannel. AB - Microfluidics has been used to perform various chemical operations for pL-nL volumes of samples, such as mixing, reaction and separation, by exploiting diffusion, viscous forces, and surface tension, which are dominant in spaces with dimensions on the micrometer scale. To further develop this field, we previously developed a novel microfluidic device, termed a microdroplet collider, which exploits spatially and temporally localized kinetic energy. This device accelerates a microdroplet in the gas phase along a microchannel until it collides with a target. We demonstrated 6000-fold faster mixing compared to mixing by diffusion; however, the droplet acceleration was not optimized, because the experiments were conducted for only one droplet size and at pressures in the 10-100 kPa range. In this study, we investigated the acceleration of a microdroplet using a high-pressure (MPa) control system, in order to achieve higher acceleration and kinetic energy. The motion of the nL droplet was observed using a high-speed complementary metal oxide semiconductor (CMOS) camera. A maximum droplet velocity of ~5 m/s was achieved at a pressure of 1-2 MPa. Despite the higher fluid resistance, longer droplets yielded higher acceleration and kinetic energy, because droplet splitting was a determining factor in the acceleration and using a longer droplet helped prevent it. The results provide design guidelines for achieving higher kinetic energies in the microdroplet collider for various microfluidic applications. PMID- 30404315 TI - 3D Finite Element Simulation of Graphene Nano-Electro-Mechanical Switches. AB - In this paper, we report the finite element method (FEM) simulation of double clamped graphene nanoelectromechanical (NEM) switches. Pull-in and pull-out characteristics are analyzed for graphene NEM switches with different dimensions and these are consistent with the experimental results. This numerical model is used to study the scaling nature of the graphene NEM switches. We show the possibility of achieving a pull-in voltage as low as 2 V for a 1.5-MUm-long and 3 nm-thick nanocrystalline graphene beam NEM switch. In order to study the mechanical reliability of the graphene NEM switches, von Mises stress analysis is carried out. This analysis shows that a thinner graphene beam results in a lower von Mises stress. Moreover, a strong electrostatic force at the beam edges leads to a mechanical deflection at the edges larger than that around the center of the beam, which is consistent with the von Mises stress analysis. PMID- 30404316 TI - Design, Analysis, and Verification of Ka-Band Pattern Reconfigurable Patch Antenna Using RF MEMS Switches. AB - This paper proposes a radiating pattern reconfigurable antenna by employing RF Micro-electromechanical Systems (RF MEMS) switches. The antenna has a low profile and small size of 4 mm * 5 mm * 0.4 mm, and mainly consists of one main patch, two assistant patches, and two RF MEMS switches. By changing the RF MEMS switches operating modes, the proposed antenna can switch among three radiating patterns (with main lobe directions of approximately -17.0 degrees , 0 degrees and +17.0 degrees ) at 35 GHz. The far-field vector addition model is applied to analyse the pattern. Comparing the measured results with analytical and simulated results, good agreements are obtained. PMID- 30404317 TI - Microfluidic Neurons, a New Way in Neuromorphic Engineering? AB - This article describes a new way to explore neuromorphic engineering, the biomimetic artificial neuron using microfluidic techniques. This new device could replace silicon neurons and solve the issues of biocompatibility and power consumption. The biological neuron transmits electrical signals based on ion flow through their plasma membrane. Action potentials are propagated along axons and represent the fundamental electrical signals by which information are transmitted from one place to another in the nervous system. Based on this physiological behavior, we propose a microfluidic structure composed of chambers representing the intra and extracellular environments, connected by channels actuated by Quake valves. These channels are equipped with selective ion permeable membranes to mimic the exchange of chemical species found in the biological neuron. A thick polydimethylsiloxane (PDMS) membrane is used to create the Quake valve membrane. Integrated electrodes are used to measure the potential difference between the intracellular and extracellular environments: the membrane potential. PMID- 30404318 TI - Thermoelectric Responsive Shape Memory Graphene/Hydro-Epoxy Composites for Actuators. AB - A series of thermoelectric responsive shape memory hydro-epoxy (H-EP) composites filled with different contents of graphene were developed and characterized. Compared with traditional actuation materials, these novel shape memory composites exhibit attractive properties, such as light weight, large deformation, good processability and high response speed, making them good candidates for actuator materials. The effect of graphene content on the shape memory composites was studied in terms of mechanical, dynamic mechanical analysis (DMA), electrical properties, and thermoelectric responsive shape memory test. The results show that when graphene content was 2 wt %, the bend strength of the composite improved by about 47% with a storage modulus larger than other composites. The shape recovery ratio of the composites was about 100%, and the shape recovery speed increased with the increment of graphene content, applied voltage, and temperature. Due to the excellent actuation performance, the graphene/hydro-epoxy composite has potential applications in the actuator in the future. PMID- 30404319 TI - Free-Standing Self-Assemblies of Gallium Nitride Nanoparticles: A Review. AB - Gallium nitride (GaN) is an III-V semiconductor with a direct band-gap of 3 . 4 e V . GaN has important potentials in white light-emitting diodes, blue lasers, and field effect transistors because of its super thermal stability and excellent optical properties, playing main roles in future lighting to reduce energy cost and sensors to resist radiations. GaN nanomaterials inherit bulk properties of the compound while possess novel photoelectric properties of nanomaterials. The review focuses on self-assemblies of GaN nanoparticles without templates, growth mechanisms of self-assemblies, and potential applications of the assembled nanostructures on renewable energy. PMID- 30404320 TI - A Novel Classification Technique of Arteriovenous Fistula Stenosis Evaluation Using Bilateral PPG Analysis. AB - The most common treatment for end-stage renal disease (ESRD) patients is the hemodialysis (HD). For this kind of treatment, the functional vascular access that called arteriovenous fistula (AVF) is done by surgery to connect the vein and artery. Stenosis is considered the major cause of dysfunction of AVF. In this study, a noninvasive approach based on asynchronous analysis of bilateral photoplethysmography (PPG) with error correcting output coding support vector machine one versus rest (ESVM-OVR) for the degree of stenosis (DOS) evaluation is proposed. An artificial neural network (ANN) classifier is also applied to compare the performance with the proposed system. The testing data has been collected from 22 patients at the right and left thumb of the hand. The experimental results indicated that the proposed system could provide positive predictive value (PPV) reaching 91.67% and had higher noise tolerance. The system has the potential for providing diagnostic assistance in a wearable device for evaluation of AVF stenosis. PMID- 30404321 TI - 21.69-24.36 GHz MEMS Tunable Band-Pass Filter. AB - The K-band microelectromechanical systems (MEMS) tunable band-pass filter, with a wide-frequency tunable range and miniature size, is able to fulfill the requirements of the multiband satellite communication systems. A novel 21.69 24.36 GHz MEMS tunable band-pass filter is designed, analyzed, fabricated and measured. This paper also designs and analyzes an inductively tuned slow-wave resonator, which consists of the MEMS capacitive switch, the MEMS capacitor and the short metal line. The proposed filter has four different work states by changing the capacitance values of the MEMS switches. Measured results demonstrate that, for all four states, the insertion loss is 2.81, 3.27, 3.65 and 4.03 dB at 24.36, 23.2, 22.24 and 21.69 GHz, respectively. The actuation voltage is 0, 20, 16 and 26 V, respectively. The 3 dB bandwidth of the tunable filter is 5.4%, 6.2%, 5.7% and 5.9%, respectively. This study contributes to the design of miniature millimeter tunable filters with a wide-frequency tunable range. PMID- 30404322 TI - Design and Analysis of a New Tuning Fork Structure for Resonant Pressure Sensor. AB - This paper presents a micromachined resonant pressure sensor. The sensor is designed to optimize the sensitivity and reduce the cross-talk between the driving electrodes and sensing electrodes. The relationship between the sensitivity of the sensor and the main design parameters is analyzed both theoretically and numerically. The sensing and driving electrodes are optimized to get both high sensing capacitance and low cross-talk. This sensor is fabricated using a micromachining process based on a silicon-on-insulator (SOI) wafer. An open-loop measurement system and a closed-loop self-oscillation system is employed to measure the characteristics of the sensor. The experiment result shows that the sensor has a pressure sensitivity of about 29 Hz/kPa, a nonlinearity of 0.02%FS, a hysteresis error of 0.05%FS, and a repeatability error of 0.01%FS. The temperature coefficient is less than 2 Hz/ degrees C in the range of -40 to 80 degrees C and the short-term stability of the sensor is better than 0.005%FS. PMID- 30404323 TI - Antireflective SiC Surface Fabricated by Scalable Self-Assembled Nanopatterning. AB - An approach for fabricating sub-wavelength antireflective structures on SiC material is demonstrated. A time-efficient scalable nanopatterning method by rapid thermal annealing of thin metal film is applied followed by a dry etching process. Size-dependent optical properties of the antireflective SiC structures have been investigated. It is found that the surface reflection of SiC in the visible spectral range is significantly suppressed by applying the antireflective structures. Meanwhile, optical transmission and absorption could be tuned by modifying the feature size of the structure. It is believed that this effective fabrication method of antireflective structures could also be realized on other semiconductor materials or devices. PMID- 30404324 TI - Investigation of the Influence of Glucose Concentration on Cancer Cells by Using a Microfluidic Gradient Generator without the Induction of Large Shear Stress. AB - A microfluidic device capable of precise chemical control is helpful to mimic tumor microenvironments in vitro, which are closely associated with malignant progression, including metastasis. Cancer cells under a concentration gradient of oxygen and other sustenance materials inside a tumor in vivo have recently been reported to increase the probability of metastasis. The influence of glucose concentration on cancer cells has not been measured well, whereas that of oxygen concentration has been thoroughly examined using microfluidic devices. This is because glucose concentrations can be controlled using microfluidic concentration gradient generators, which trade off temporal stability of the glucose concentration and shear stress on the cells; by contrast, oxygen concentration can be easily controlled without microfluidic device-induced shear stresses. To study cell division and migration responses as a function of glucose concentration, we developed a microfluidic device to observe cell behaviors under various chemical conditions. The device has small-cross-section microchannels for generating a concentration gradient and a large-cross-section chamber for cell culture. With this design, the device can achieve both a cell culture with sufficiently low shear stress on cell activity and a stable glucose concentration gradient. Experiments revealed that a low glucose concentration increased the total migration length of HeLa cells and that HeLa cells under a glucose concentration gradient exhibit random motion rather than chemotaxis. PMID- 30404325 TI - Enhanced Throughput for Electrokinetic Manipulation of Particles and Cells in a Stacked Microfluidic Device. AB - Electrokinetic manipulation refers to the control of particle and cell motions using an electric field. It is an efficient technique for microfluidic applications with the ease of operation and integration. It, however, suffers from an intrinsic drawback of low throughput due to the linear dependence of the typically very low fluid permittivity. We demonstrate in this work a significantly enhanced throughput for electrokinetic manipulation of particles and cells by the use of multiple parallel microchannels in a two-layer stacked microfluidic device. The fabrication of this device is simple without the need of a precise alignment of the two layers. The number of layers and the number of microchannels in each layer can thus be further increased for a potentially high throughput electrokinetic particle and cell manipulations. PMID- 30404326 TI - Investigation of Antireflection Nb2O5 Thin Films by the Sputtering Method under Different Deposition Parameters. AB - In this study, Nb2O5 ceramic was used as the target to deposit the Nb2O5 thin films on glass substrates with the radio frequency (RF) magnetron sputtering method. Different deposition temperatures and O2 ratios were used as parameters to investigate the optical properties of Nb2O5 thin films. The deposition parameters were a pressure of 5 * 10-3 Torr, a deposition power of 100 W, a deposition time of 30 min, an O2 ratio (O2/(O2 + Ar), in sccm) of 10% and 20%, and deposition temperatures of room temperature (RT), 200, 300 and 400 degrees C, respectively. We found that even if the deposition temperature was 400 degrees C, the deposited Nb2O5 thin films revealed an amorphous phase and no crystallization phase was observed. The optical properties of transmittance of Nb2O5 thin films deposited on glass substrates were determined by using a ultraviolet-visible (UV-vis) spectrophotometer (transmittance) and reflectance spectra transmittance (reflectance, refractive index, and extinction coefficient) in the light wavelength range of 250-1000 nm. When the O2 ratio was 10% and the deposition temperature increased from RT to 200 degrees C, the red-shift was clearly observed in the transmittance curve and the transmission ratio had no apparent change with the increasing deposition temperature. When the O2 ratio was 20%, the red-shift was not observed in the transmittance curve and the transmission ratio apparently decreased with the increasing deposition temperature. The variations in the optical band gap (Eg) values of Nb2O5 thin films were evaluated from the Tauc plot by using the quantity hnu (the photon energy) on the abscissa and the quantity (alphahnu)r on the ordinate, where alpha is the optical absorption coefficient, c is the constant for direct transition, h is Planck's constant, nu is the frequency of the incident photon, and the exponent r denotes the nature of the transition. As the O2 ratio of 10% or 20% was used as the deposition atmosphere, the measured Eg values decreased with the increase of the deposition temperature. The reflectance ratio, extinction coefficient, and refractive index curves of Nb2O5 thin films were also investigated in this study. We would show that those results were influenced by the deposition temperature and O2 ratio. PMID- 30404327 TI - Fabrication and Microassembly of a mm-Sized Floating Probe for a Distributed Wireless Neural Interface. AB - A new class of wireless neural interfaces is under development in the form of tens to hundreds of mm-sized untethered implants, distributed across the target brain region(s). Unlike traditional interfaces that are tethered to a centralized control unit and suffer from micromotions that may damage the surrounding neural tissue, the new free-floating wireless implantable neural recording (FF-WINeR) probes will be stand-alone, directly communicating with an external interrogator. Towards development of the FF-WINeR, in this paper we describe the micromachining, microassembly, and hermetic packaging of 1-mm3 passive probes, each of which consists of a thinned micromachined silicon die with a centered O(diameter) 130 MUm through-hole, an O81 MUm sharpened tungsten electrode, a 7 turn gold wire-wound coil wrapped around the die, two 0201 surface mount capacitors on the die, and parylene-C/Polydimethylsiloxane (PDMS) coating. The fabricated passive probe is tested under a 3-coil inductive link to evaluate power transfer efficiency (PTE) and power delivered to a load (PDL) for feasibility assessment. The minimum PTE/PDL at 137 MHz were 0.76%/240 MUW and 0.6%/191 MUW in the air and lamb head medium, respectively, with coil separation of 2.8 cm and 9 kOmega receiver (Rx) loading. Six hermetically sealed probes went through wireless hermeticity testing, using a 2-coil inductive link under accelerated lifetime testing condition of 85 degrees C, 1 atm, and 100%RH. The mean-time-to-failure (MTTF) of the probes at 37 degrees C is extrapolated to be 28.7 years, which is over their lifetime. PMID- 30404328 TI - Controllable Acoustic Mixing of Fluids in Microchannels for the Fabrication of Therapeutic Nanoparticles. AB - Fifteen years ago, surface acoustic waves (SAW) were found to be able to drive fluids and numerous applications in microfluidics have been developed since. Here, we review the progress made and report on new approaches in setting-up microfluidic, continuous flow acoustic mixing. In a microchannel, chaotic advection is achieved by generation of a SAW driven fluid jet perpendicular to the mean flow direction. Using a high speed video camera and particle image velocimetry, we measure the flow velocities and show that mixing is achieved in a particularly controllable and fast way. The mixing quality is determined as a function of system parameters: SAW power, volume flux and fluid viscosity. Exploring the parameter space of mixing provides a practical guide for acoustic mixing in microchannels and allows for adopting conditions to different solvents, as e.g., required for the generation of nanoscale particles from alcoholic phases. We exemplarily demonstrate the potential of SAW based continuous flow mixing for the production of therapeutic nucleic acid nanoparticles assembled from polymer and lipid solutions. PMID- 30404329 TI - Energy Dissipation in Graphene Mechanical Resonators with and without Free Edges. AB - Graphene-based nanoelectromechanical systems (NEMS) have high future potential to realize sensitive mass and force sensors owing to graphene's low mass density and exceptional mechanical properties. One of the important remaining issues in this field is how to achieve mechanical resonators with a high quality factor (Q). Energy dissipation in resonators decreases Q, and suppressing it is the key to realizing sensitive sensors. In this article, we review our recent work on energy dissipation in doubly-clamped and circular drumhead graphene resonators. We examined the temperature (T) dependence of the inverse of a quality factor ( Q - 1 ) to reveal what the dominant dissipation mechanism is. Our doubly-clamped trilayer resonators show a characteristic Q - 1 -T curve similar to that observed in monolayer resonators: Q - 1 ? T 2 above ~100 K and ? T 0.3 below ~100 K. By comparing our results with previous experimental and theoretical results, we determine that the T 2 and T 0.3 dependences can be attributed to tensile strain induced by clamping metals and vibrations at the free edges in doubly-clamped resonators, respectively. The Q - 1 -T curve in our circular drumhead resonators indicates that removing free edges and clamping metal suppresses energy dissipation in the resonators, resulting in a linear T dependence of Q - 1 in a wide temperature range. PMID- 30404331 TI - Operation of Droplet-Microfluidic Devices with a Lab Centrifuge. AB - Microfluidic devices are valuable for a variety of biotechnology applications, such as synthesizing biochemical libraries, screening enzymes, and analyzing single cells. However, normally, the devices are controlled using specialized pumps, which require expert knowledge to operate. Here, we demonstrate operation of poly(dimethylsiloxane) devices without pumps. We build a scaffold that holds the device and reagents to be infused in a format that can be inserted into a 50 mL falcon tube and spun in a common lab centrifuge. By controlling the device design and centrifuge spin speed, we infuse the reagents at controlled flow rates. We demonstrate the encapsulation and culture of clonal colonies of red and green Escherichia coli in droplets seeded from single cells. PMID- 30404332 TI - Resonance Spectrum Characteristics of Effective Electromechanical Coupling Coefficient of High-Overtone Bulk Acoustic Resonator. AB - A high-overtone bulk acoustic resonator (HBAR) consisting of a piezoelectric film with two electrodes on a substrate exhibits a high quality factor (Q) and multi mode resonance spectrum. By analyzing the influences of each layer's material and structure (thickness) parameters on the effective electromechanical coupling coefficient (Keff2), the resonance spectrum characteristics of Keff2 have been investigated systematically, and the optimal design of HBAR has been provided. Besides, a device, corresponding to one of the theoretical cases studied, is fabricated and evaluated. The experimental results are basically consistent with the theoretical results. Finally, the effects of Keff2 on the function of the crystal oscillators constructed with HBARs are proposed. The crystal oscillators can operate in more modes and have a larger frequency hopping bandwidth by using the HBARs with a larger Keff2.Q. PMID- 30404330 TI - Neural Circuits on a Chip. AB - Neural circuits are responsible for the brain's ability to process and store information. Reductionist approaches to understanding the brain include isolation of individual neurons for detailed characterization. When maintained in vitro for several days or weeks, dissociated neurons self-assemble into randomly connected networks that produce synchronized activity and are capable of learning. This review focuses on efforts to control neuronal connectivity in vitro and construct living neural circuits of increasing complexity and precision. Microfabrication based methods have been developed to guide network self-assembly, accomplishing control over in vitro circuit size and connectivity. The ability to control neural connectivity and synchronized activity led to the implementation of logic functions using living neurons. Techniques to construct and control three dimensional circuits have also been established. Advances in multiple electrode arrays as well as genetically encoded, optical activity sensors and transducers enabled highly specific interfaces to circuits composed of thousands of neurons. Further advances in on-chip neural circuits may lead to better understanding of the brain. PMID- 30404333 TI - Micromachined Resonators: A Review. AB - This paper is a review of the remarkable progress that has been made during the past few decades in design, modeling, and fabrication of micromachined resonators. Although micro-resonators have come a long way since their early days of development, they are yet to fulfill the rightful vision of their pervasive use across a wide variety of applications. This is partially due to the complexities associated with the physics that limit their performance, the intricacies involved in the processes that are used in their manufacturing, and the trade-offs in using different transduction mechanisms for their implementation. This work is intended to offer a brief introduction to all such details with references to the most influential contributions in the field for those interested in a deeper understanding of the material. PMID- 30404336 TI - Micro/Nano Devices for Chemical Analysis. AB - Since the concept of micro total analysis systems (u-TAS) has been advocated, various kinds of micro/nano devices have been developed by researchers in many fields, such as in chemistry, chemical engineering, mechanical engineering, electric engineering, biology, and medicine, among others.[...]. PMID- 30404335 TI - Direct Growth of Carbon Nanotubes on New High-Density 3D Pyramid-Shaped Microelectrode Arrays for Brain-Machine Interfaces. AB - Silicon micromachined, high-density, pyramid-shaped neural microelectrode arrays (MEAs) have been designed and fabricated for intracortical 3D recording and stimulation. The novel architecture of this MEA has made it unique among the currently available micromachined electrode arrays, as it has provided higher density contacts between the electrodes and targeted neural tissue facilitating recording from different depths of the brain. Our novel masking technique enhances uniform tip-exposure for variable-height electrodes and improves process time and cost significantly. The tips of the electrodes have been coated with platinum (Pt). We have reported for the first time a selective direct growth of carbon nanotubes (CNTs) on the tips of 3D MEAs using the Pt coating as a catalyzer. The average impedance of the CNT-coated electrodes at 1 kHz is 14 kOmega. The CNT coating led to a 5-fold decrease of the impedance and a 600-fold increase in charge transfer compared with the Pt electrode. PMID- 30404337 TI - Integration of an Optical Ring Resonator Biosensor into a Self-Contained Microfluidic Cartridge with Active, Single-Shot Micropumps. AB - While there have been huge advances in the field of biosensors during the last decade, their integration into a microfluidic environment avoiding external tubing and pumping is still neglected. Herein, we show a new microfluidic design that integrates multiple reservoirs for reagent storage and single-use electrochemical pumps for time-controlled delivery of the liquids. The cartridge has been tested and validated with a silicon nitride-based photonic biosensor incorporating multiple optical ring resonators as sensing elements and an immunoassay as a potential target application. Based on experimental results obtained with a demonstration model, subcomponents were designed and existing protocols were adapted. The newly-designed microfluidic cartridges and photonic sensors were separately characterized on a technical basis and performed well. Afterwards, the sensor was functionalized for a protein detection. The microfluidic cartridge was loaded with the necessary assay reagents. The integrated pumps were programmed to drive the single process steps of an immunoassay. The prototype worked selectively, but only with a low sensitivity. Further work must be carried out to optimize biofunctionalization of the optical ring resonators and to have a more suitable flow velocity progression to enhance the system's reproducibility. PMID- 30404338 TI - Reliability Design and Electro-Thermal-Optical Simulation of Bridge-Style Infrared Thermal Emitters. AB - Designs and simulations of silicon-based micro-electromechanical systems (MEMS) infrared (IR) thermal emitters for gas sensing application are presented. The IR thermal emitter is designed as a bridge-style hotplate (BSH) structure suspended on a silicon frame for realizing a good thermal isolation between hotplate and frame. For investigating the reliability of BSH structure, three kinds of fillet structures were designed in the contact corner between hotplate and frame. A 3 dimensional finite element method (3D-FEM) is used to investigate the electro thermal, thermal-mechanical, and thermal-optical properties of BSH IR emitter using software COMSOLTM (COMSOL 4.3b, COMSOL Inc., Stockholm, Sweden). The simulation results show that the BSH with oval fillet has the lowest stress distribution and smoothest flows of stress streamlines, while the BSH with square fillet has the highest temperature and stress distribution. The thermal-optical and thermal-response simulations further indicate that the BSH with oval fillet is the optimal design for a reliable IR thermal emitter in spite of having slight inadequacies in emission intensity and modulation bandwidth in comparison with other two structures. PMID- 30404339 TI - Development of a Multi-Stage Electroosmotic Flow Pump Using Liquid Metal Electrodes. AB - Injection of liquid metal into a polydimethylsiloxane (PDMS) channel can provide a simple, cheap, and fast method to fabricate a noncontact electrode for micro electroosmotic flow (EOF) pumps. In this study, a multi-stage EOF pump using liquid metal noncontact electrodes was proposed and demonstrated for high-flow velocity applications. To test the pumping performance of this EOF pump and measure the flow velocity, fluorescent particles were added into deionized (DI) water to trace the flow. According to the experimental results, the pump with a five-stage design can drive a water flow of 5.57 MUm/s at 10 V, while the PDMS gap between the electrode and the pumping channel is 20 MUm. To provide the guidance for the pump design, parametric studies were performed and fully discussed, such as the PDMS gap, pumping channel dimension, and stage number. This multi-stage EOF pump shows potential for many high-flow-velocity microfluidic applications. PMID- 30404340 TI - Novel Capacitive Sensing System Design of a Microelectromechanical Systems Accelerometer for Gravity Measurement Applications. AB - This paper presents an in-plane sandwich nano-g microelectromechanical systems (MEMS) accelerometer. The proof-mass fabrication is based on silicon etching through technology using inductive coupled plasma (ICP) etching. The capacitive detection system, which employs the area-changing sensing method, combines elementary capacitive pickup electrodes with periodic-sensing-array transducers. In order to achieve a large dynamic range with an ultrahigh resolution, the capacitive detection system employs two periodic-sensing-array transducers. Each of them can provide numbers for the signal period in the entire operating range. The suspended proof-mass is encapsulated between two glass caps, which results in a three dimensional structure. The measured resonant frequency and quality factor (Q) are 13.2 Hz and 47, respectively. The calibration response of a +/-0.7 g input acceleration is presented, and the accelerometer system presents a sensitivity of 122 V/g and a noise floor of 30 ng/?Hz (at 1 Hz, and 1 atm). The bias stability for a period of 10 h is 30 MUg. The device has endured a shock up to +/-2.6 g, and the full scale output appears to be approximately +/-1.4 g presently. This work presents a new opportunity for highly sensitive MEMS fabrication to enable future high-precision measurement applications, such as for gravity measurements. PMID- 30404342 TI - PSO-Based Algorithm Applied to Quadcopter Micro Air Vehicle Controller Design. AB - Due to the rapid development of science and technology in recent times, many effective controllers are designed and applied successfully to complicated systems. The significant task of controller design is to determine optimized control gains in a short period of time. With this purpose in mind, a combination of the particle swarm optimization (PSO)-based algorithm and the evolutionary programming (EP) algorithm is introduced in this article. The benefit of this integration algorithm is the creation of new best-parameters for control design schemes. The proposed controller designs are then demonstrated to have the best performance for nonlinear micro air vehicle models. PMID- 30404334 TI - Microfluidic-Based Multi-Organ Platforms for Drug Discovery. AB - Development of predictive multi-organ models before implementing costly clinical trials is central for screening the toxicity, efficacy, and side effects of new therapeutic agents. Despite significant efforts that have been recently made to develop biomimetic in vitro tissue models, the clinical application of such platforms is still far from reality. Recent advances in physiologically-based pharmacokinetic and pharmacodynamic (PBPK-PD) modeling, micro- and nanotechnology, and in silico modeling have enabled single- and multi-organ platforms for investigation of new chemical agents and tissue-tissue interactions. This review provides an overview of the principles of designing microfluidic-based organ-on-chip models for drug testing and highlights current state-of-the-art in developing predictive multi-organ models for studying the cross-talk of interconnected organs. We further discuss the challenges associated with establishing a predictive body-on-chip (BOC) model such as the scaling, cell types, the common medium, and principles of the study design for characterizing the interaction of drugs with multiple targets. PMID- 30404341 TI - Rapid Capture and Analysis of Airborne Staphylococcus aureus in the Hospital Using a Microfluidic Chip. AB - In this study we developed a microfluidic chip for the rapid capture, enrichment and detection of airborne Staphylococcus (S.) aureus. The whole analysis took about 4 h and 40 min from airborne sample collection to loop-mediated isothermal amplification (LAMP), with a detection limit down to about 27 cells. The process did not require DNA purification. The chip was validated using standard bacteria bioaerosol and was directly used for clinical airborne pathogen sampling in hospital settings. This is the first report on the capture and analysis of airborne S. aureus using a novel microfluidic technique, a process that could have a very promising platform for hospital airborne infection prevention (HAIP). PMID- 30404343 TI - Deformability-Based Electrokinetic Particle Separation. AB - Deformability is an effective property that can be used in the separation of colloidal particles and cells. In this study, a microfluidic device is proposed and tested numerically for the sorting of deformable particles of various degrees. The separation process is numerically investigated by a direct numerical simulation of the fluid-particle-electric field interactions with an arbitrary Lagrangian-Eulerian finite-element method. The separation performance is investigated with the shear modulus of particles, the strength of the applied electric field, and the design of the contracted microfluidic devices as the main parameters. The results show that the particles with different shear moduli take different shapes and trajectories when passing through a microchannel contraction, enabling the separation of particles based on their difference in deformability. PMID- 30404344 TI - A New Method for a Piezoelectric Energy Harvesting System Using a Backtracking Search Algorithm-Based PI Voltage Controller. AB - This paper presents a new method for a vibration-based piezoelectric energy harvesting system using a backtracking search algorithm (BSA)-based proportional integral (PI) voltage controller. This technique eliminates the exhaustive conventional trial-and-error procedure for obtaining optimized parameter values of proportional gain (Kp), and integral gain (Ki) for PI voltage controllers. The generated estimate values of Kp and Ki are executed in the PI voltage controller that is developed through the BSA optimization technique. In this study, mean absolute error (MAE) is used as an objective function to minimize output error for a piezoelectric energy harvesting system (PEHS). The model for the PEHS is designed and analyzed using the BSA optimization technique. The BSA-based PI voltage controller of the PEHS produces a significant improvement in minimizing the output error of the converter and a robust, regulated pulse-width modulation (PWM) signal to convert a MOSFET switch, with the best response in terms of rise time and settling time under various load conditions. PMID- 30404346 TI - Multiscale and Multimaterial Fabrication: The Challenge Ahead. AB - In the editorial published in March 2016, I mentioned that one of the aims of Micromachines is to cover topics and technologies beyond silicon-based microsystems and microdevices [1].[...]. PMID- 30404345 TI - Full Polymer Dielectric Elastomeric Actuators (DEA) Functionalised with Carbon Nanotubes and High-K Ceramics. AB - Dielectric elastomer actuators (DEA) are special devices which have a simple working and construction principle and outstanding actuation properties. The DEAs consist of a combination of different materials for the dielectric and electrode layers. The combination of these layers causes incompatibilities in their interconnections. Dramatic differences in the mechanical properties and bad adhesion of the layers are the principal causes for the reduction of the actuation displacement and strong reduction of lifetime. Common DEAs achieve actuation displacements of 2% and a durability of some million cycles. The following investigations represent a new approach to solving the problems of common systems. The investigated DEA consists of only one basic raw polymer, which was modified according to the required demands of each layer. The basic raw polymer was modified with single-walled carbon nanotubes or high-k ceramics, for example, lead magnesium niobate-lead titanate. The development of the full polymer DEA comprised the development of materials and technologies to realise a reproducible layer composition. It was proven that the full polymer actuator worked according to the theoretical rules. The investigated system achieved actuation displacements above 20% regarding thickness, outstanding interconnections at each layer without any failures, and durability above 3 million cycles without any indication of an impending malfunction. PMID- 30404347 TI - A Simple Method for Fabrication of Microstructures Using a PDMS Stamp. AB - We report a simple method to fabricate PDMS (polydimethylsiloxane) microwell arrays on glass by using a PDMS stamp to study cell-to-cell adhesion. In the cell to-cell study, a glass substrate is required since glass has better cell attachment. The microwell arrays are replicated from an SU-8 master mold, and then are transferred to a glass substrate by lifting the PDMS stamp, followed by oxygen plasma bonding of the PDMS stamp on the glass substrate. For the cell-to cell adhesion, four different types of PDMS arrays (e.g., rectangle, bowtie, wide rhombus, and rhombus) were designed to vary the cell-to-cell contact length. The transfer success rates of the microwell arrays were measured as a function of both the contact area of the PDMS and the glass substrate and the different ratios between the base polymers and the curing agent. This method of generating the microwell arrays will enable a simple and robust construction of PDMS-based devices for various biological applications. PMID- 30404348 TI - In-Situ Testing of the Thermal Diffusivity of Polysilicon Thin Films. AB - This paper presents an intuitive yet effective in-situ thermal diffusivity testing structure and testing method. The structure consists of two doubly clamped beams with the same width and thickness but different lengths. When the electric current is applied through two terminals of one beam, the beam serves as thermal resistor and the resistance R(t) varies as temperature rises. A delicate thermodynamic model considering thermal convection, thermal radiation, and film to-substrate heat conduction was established for the testing structure. The presented in-situ thermal diffusivity testing structure can be fabricated by various commonly used micro electro mechanical systems (MEMS) fabrication methods, i.e., it requires no extra customized processes yet provides electrical input and output interfaces for in-situ testing. Meanwhile, the testing environment and equipment had no stringent restriction, measurements were carried out at normal temperatures and pressures, and the results are relatively accurate. PMID- 30404349 TI - Baking Powder Actuated Centrifugo-Pneumatic Valving for Automation of Multi-Step Bioassays. AB - We report a new flow control method for centrifugal microfluidic systems; CO2 is released from on-board stored baking powder upon contact with an ancillary liquid. The elevated pressure generated drives the sample into a dead-end pneumatic chamber sealed by a dissolvable film (DF). This liquid incursion wets and dissolves the DF, thus opening the valve. The activation pressure of the DF valve can be tuned by the geometry of the channel upstream of the DF membrane. Through pneumatic coupling with properly dimensioned disc architecture, we established serial cascading of valves, even at a constant spin rate. Similarly, we demonstrate sequential actuation of valves by dividing the disc into a number of distinct pneumatic chambers (separated by DF membranes). Opening these DFs, typically through arrival of a liquid to that location on a disc, permits pressurization of these chambers. This barrier-based scheme provides robust and strictly ordered valve actuation, which is demonstrated by the automation of a multi-step/multi-reagent DNA-based hybridization assay. PMID- 30404350 TI - Bifurcation Control of an Electrostatically-Actuated MEMS Actuator with Time Delay Feedback. AB - The parametric excitation system consisting of a flexible beam and shuttle mass widely exists in microelectromechanical systems (MEMS), which can exhibit rich nonlinear dynamic behaviors. This article aims to theoretically investigate the nonlinear jumping phenomena and bifurcation conditions of a class of electrostatically-driven MEMS actuators with a time-delay feedback controller. Considering the comb structure consisting of a flexible beam and shuttle mass, the partial differential governing equation is obtained with both the linear and cubic nonlinear parametric excitation. Then, the method of multiple scales is introduced to obtain a slow flow that is analyzed for stability and bifurcation. Results show that time-delay feedback can improve resonance frequency and stability of the system. What is more, through a detailed mathematical analysis, the discriminant of Hopf bifurcation is theoretically derived, and appropriate time-delay feedback force can make the branch from the Hopf bifurcation point stable under any driving voltage value. Meanwhile, through global bifurcation analysis and saddle node bifurcation analysis, theoretical expressions about the system parameter space and maximum amplitude of monostable vibration are deduced. It is found that the disappearance of the global bifurcation point means the emergence of monostable vibration. Finally, detailed numerical results confirm the analytical prediction. PMID- 30404351 TI - An On-Chip RBC Deformability Checker Significantly Improves Velocity-Deformation Correlation. AB - An on-chip deformability checker is proposed to improve the velocity-deformation correlation for red blood cell (RBC) evaluation. RBC deformability has been found related to human diseases, and can be evaluated based on RBC velocity through a microfluidic constriction as in conventional approaches. The correlation between transit velocity and amount of deformation provides statistical information of RBC deformability. However, such correlations are usually only moderate, or even weak, in practical evaluations due to limited range of RBC deformation. To solve this issue, we implemented three constrictions of different width in the proposed checker, so that three different deformation regions can be applied to RBCs. By considering cell responses from the three regions as a whole, we practically extend the range of cell deformation in the evaluation, and could resolve the issue about the limited range of RBC deformation. RBCs from five volunteer subjects were tested using the proposed checker. The results show that the correlation between cell deformation and transit velocity is significantly improved by the proposed deformability checker. The absolute values of the correlation coefficients are increased from an average of 0.54 to 0.92. The effects of cell size, shape and orientation to the evaluation are discussed according to the experimental results. The proposed checker is expected to be useful for RBC evaluation in medical practices. PMID- 30404353 TI - Flexible, Penetrating Brain Probes Enabled by Advances in Polymer Microfabrication. AB - The acquisition of high-fidelity, long-term neural recordings in vivo is critically important to advance neuroscience and brain-machine interfaces. For decades, rigid materials such as metal microwires and micromachined silicon shanks were used as invasive electrophysiological interfaces to neurons, providing either single or multiple electrode recording sites. Extensive research has revealed that such rigid interfaces suffer from gradual recording quality degradation, in part stemming from tissue damage and the ensuing immune response arising from mechanical mismatch between the probe and brain. The development of "soft" neural probes constructed from polymer shanks has been enabled by advancements in microfabrication; this alternative has the potential to mitigate mismatch-related side effects and thus improve the quality of recordings. This review examines soft neural probe materials and their associated microfabrication techniques, the resulting soft neural probes, and their implementation including custom implantation and electrical packaging strategies. The use of soft materials necessitates careful consideration of surgical placement, often requiring the use of additional surgical shuttles or biodegradable coatings that impart temporary stiffness. Investigation of surgical implantation mechanics and histological evidence to support the use of soft probes will be presented. The review concludes with a critical discussion of the remaining technical challenges and future outlook. PMID- 30404352 TI - Neural Probes for Chronic Applications. AB - Developed over approximately half a century, neural probe technology is now a mature technology in terms of its fabrication technology and serves as a practical alternative to the traditional microwires for extracellular recording. Through extensive exploration of fabrication methods, structural shapes, materials, and stimulation functionalities, neural probes are now denser, more functional and reliable. Thus, applications of neural probes are not limited to extracellular recording, brain-machine interface, and deep brain stimulation, but also include a wide range of new applications such as brain mapping, restoration of neuronal functions, and investigation of brain disorders. However, the biggest limitation of the current neural probe technology is chronic reliability; neural probes that record with high fidelity in acute settings often fail to function reliably in chronic settings. While chronic viability is imperative for both clinical uses and animal experiments, achieving one is a major technological challenge due to the chronic foreign body response to the implant. Thus, this review aims to outline the factors that potentially affect chronic recording in chronological order of implantation, summarize the methods proposed to minimize each factor, and provide a performance comparison of the neural probes developed for chronic applications. PMID- 30404355 TI - Hybrid Microfluidic Platform for Multifactorial Analysis Based on Electrical Impedance, Refractometry, Optical Absorption and Fluorescence. AB - This paper describes the development of a novel microfluidic platform for multifactorial analysis integrating four label-free detection methods: electrical impedance, refractometry, optical absorption and fluorescence. We present the rationale for the design and the details of the microfabrication of this multifactorial hybrid microfluidic chip. The structure of the platform consists of a three-dimensionally patterned polydimethylsiloxane top part attached to a bottom SU-8 epoxy-based negative photoresist part, where microelectrodes and optical fibers are incorporated to enable impedance and optical analysis. As a proof of concept, the chip functions have been tested and explored, enabling a diversity of applications: (i) impedance-based identification of the size of micro beads, as well as counting and distinguishing of erythrocytes by their volume or membrane properties; (ii) simultaneous determination of the refractive index and optical absorption properties of solutions; and (iii) fluorescence based bead counting. PMID- 30404354 TI - Modeling of Microdevices for SAW-Based Acoustophoresis - A Study of Boundary Conditions. AB - We present a finite-element method modeling of acoustophoretic devices consisting of a single, long, straight, water-filled microchannel surrounded by an elastic wall of either borosilicate glass (pyrex) or the elastomer polydimethylsiloxane (PDMS) and placed on top of a piezoelectric transducer that actuates the device by surface acoustic waves (SAW). We compare the resulting acoustic fields in these full solid-fluid models with those obtained in reduced fluid models comprising of only a water domain with simplified, approximate boundary conditions representing the surrounding solids. The reduced models are found to only approximate the acoustically hard pyrex systems to a limited degree for large wall thicknesses and but not very well for acoustically soft PDMS systems shorter than the PDMS damping length of 3 mm. PMID- 30404356 TI - Continuously Operating Biosensor and Its Integration into a Hermetically Sealed Medical Implant. AB - An integration concept for an implantable biosensor for the continuous monitoring of blood sugar levels is presented. The system architecture is based on technical modules used in cardiovascular implants in order to minimize legal certification efforts for its perspective usage in medical applications. The sensor chip operates via the principle of affinity viscometry, which is realized by a fully embedded biomedical microelectromechanical systems (BioMEMS) prepared in 0.25-um complementary metal-oxide-semiconductor (CMOS)/BiCMOS technology. Communication with a base station is established in the 402-405 MHz band used for medical implant communication services (MICS). The implant shall operate within the interstitial tissue, and the hermetical sealing of the electronic system against interaction with the body fluid is established using titanium housing. Only the sensor chip and the antenna are encapsulated in an epoxy header closely connected to the metallic housing. The study demonstrates that biosensor implants for the sensing of low-molecular-weight metabolites in the interstitial may successfully rely on components already established in cardiovascular implantology. PMID- 30404357 TI - Oxide-Oxide Thermocompression Direct Bonding Technologies with Capillary Self Assembly for Multichip-to-Wafer Heterogeneous 3D System Integration. AB - Plasma- and water-assisted oxide-oxide thermocompression direct bonding for a self-assembly based multichip-to-wafer (MCtW) 3D integration approach was demonstrated. The bonding yields and bonding strengths of the self-assembled chips obtained by the MCtW direct bonding technology were evaluated. In this study, chemical mechanical polish (CMP)-treated oxide formed by plasma-enhanced chemical vapor deposition (PE-CVD) as a MCtW bonding interface was mainly employed, and in addition, wafer-to-wafer thermocompression direct bonding was also used for comparison. N2 or Ar plasmas were utilized for the surface activation. After plasma activation and the subsequent supplying of water as a self-assembly mediate, the chips with the PE-CVD oxide layer were driven by the liquid surface tension and precisely aligned on the host wafers, and subsequently, they were tightly bonded to the wafers through the MCtW oxide-oxide direct bonding technology. Finally, a mechanism of oxide-oxide direct bonding to support the previous models was discussed using an atmospheric pressure ionization mass spectrometer (APIMS). PMID- 30404359 TI - Cell Migration According to Shape of Graphene Oxide Micropatterns. AB - Photolithography is a unique process that can effectively manufacture micro/nano sized patterns on various substrates. On the other hand, the meniscus-dragging deposition (MDD) process can produce a uniform surface of the substrate. Graphene oxide (GO) is the oxidized form of graphene that has high hydrophilicity and protein absorption. It is widely used in biomedical fields such as drug delivery, regenerative medicine, and tissue engineering. Herein, we fabricated uniform GO micropatterns via MDD and photolithography. The physicochemical properties of the GO micropatterns were characterized by atomic force microscopy (AFM), scanning electron microscopy (SEM), and Raman spectroscopy. Furthermore, cell migration on the GO micropatterns was investigated, and the difference in cell migration on triangle and square GO micropatterns was examined for their effects on cell migration. Our results demonstrated that the GO micropatterns with a desired shape can be finely fabricated via MDD and photolithography. Moreover, it was revealed that the shape of GO micropatterns plays a crucial role in cell migration distance, speed, and directionality. Therefore, our findings suggest that the GO micropatterns can serve as a promising biofunctional platform and cell-guiding substrate for applications to bioelectric devices, cell-on-a-chip, and tissue engineering scaffolds. PMID- 30404358 TI - Review of Microfluidic Photobioreactor Technology for Metabolic Engineering and Synthetic Biology of Cyanobacteria and Microalgae. AB - One goal of metabolic engineering and synthetic biology for cyanobacteria and microalgae is to engineer strains that can optimally produce biofuels and commodity chemicals. However, the current workflow is slow and labor intensive with respect to assembly of genetic parts and characterization of production yields because of the slow growth rates of these organisms. Here, we review recent progress in the microfluidic photobioreactors and identify opportunities and unmet needs in metabolic engineering and synthetic biology. Because of the unprecedented experimental resolution down to the single cell level, long-term real-time monitoring capability, and high throughput with low cost, microfluidic photobioreactor technology will be an indispensible tool to speed up the development process, advance fundamental knowledge, and realize the full potential of metabolic engineering and synthetic biology for cyanobacteria and microalgae. PMID- 30404360 TI - Design Optimization and Fabrication of High-Sensitivity SOI Pressure Sensors with High Signal-to-Noise Ratios Based on Silicon Nanowire Piezoresistors. AB - In order to meet the requirement of high sensitivity and signal-to-noise ratios (SNR), this study develops and optimizes a piezoresistive pressure sensor by using double silicon nanowire (SiNW) as the piezoresistive sensing element. First of all, ANSYS finite element method and voltage noise models are adopted to optimize the sensor size and the sensor output (such as sensitivity, voltage noise and SNR). As a result, the sensor of the released double SiNW has 1.2 times more sensitivity than that of single SiNW sensor, which is consistent with the experimental result. Our result also displays that both the sensitivity and SNR are closely related to the geometry parameters of SiNW and its doping concentration. To achieve high performance, a p-type implantation of 5 * 1018 cm 3 and geometry of 10 um long SiNW piezoresistor of 1400 nm * 100 nm cross area and 6 um thick diaphragm of 200 um * 200 um are required. Then, the proposed SiNW pressure sensor is fabricated by using the standard complementary metal-oxide semiconductor (CMOS) lithography process as well as wet-etch release process. This SiNW pressure sensor produces a change in the voltage output when the external pressure is applied. The involved experimental results show that the pressure sensor has a high sensitivity of 495 mV/V.MPa in the range of 0-100 kPa. Nevertheless, the performance of the pressure sensor is influenced by the temperature drift. Finally, for the sake of obtaining accurate and complete information over wide temperature and pressure ranges, the data fusion technique is proposed based on the back-propagation (BP) neural network, which is improved by the particle swarm optimization (PSO) algorithm. The particle swarm optimization-back-propagation (PSO-BP) model is implemented in hardware using a 32-bit STMicroelectronics (STM32) microcontroller. The results of calibration and test experiments clearly prove that the PSO-BP neural network can be effectively applied to minimize sensor errors derived from temperature drift. PMID- 30404361 TI - Microfluidic 3D Helix Mixers. AB - Polymeric microfluidic systems are well suited for miniaturized devices with complex functionality, and rapid prototyping methods for 3D microfluidic structures are increasingly used. Mixing at the microscale and performing chemical reactions at the microscale are important applications of such systems and we therefore explored feasibility, mixing characteristics and the ability to control a chemical reaction in helical 3D channels produced by the emerging thread template method. Mixing at the microscale is challenging because channel size reduction for improving solute diffusion comes at the price of a reduced Reynolds number that induces a strictly laminar flow regime and abolishes turbulence that would be desired for improved mixing. Microfluidic 3D helix mixers were rapidly prototyped in polydimethylsiloxane (PDMS) using low-surface energy polymeric threads, twisted to form 2-channel and 3-channel helices. Structure and flow characteristics were assessed experimentally by microscopy, hydraulic measurements and chromogenic reaction, and were modeled by computational fluid dynamics. We found that helical 3D microfluidic systems produced by thread templating allow rapid prototyping, can be used for mixing and for controlled chemical reaction with two or three reaction partners at the microscale. Compared to the conventional T-shaped microfluidic system used as a control device, enhanced mixing and faster chemical reaction was found to occur due to the combination of diffusive mixing in small channels and flow folding due to the 3D helix shape. Thus, microfluidic 3D helix mixers can be rapidly prototyped using the thread template method and are an attractive and competitive method for fluid mixing and chemical reactions at the microscale. PMID- 30404362 TI - Variable-Focus Liquid Lens Integrated with a Planar Electromagnetic Actuator. AB - In this paper, we design, fabricate and characterize a new electromagnetically actuated variable-focus liquid lens which consists of two polymethyl methacrylate (PMMA) substrates, a SU-8 substrate, a polydimethylsiloxane (PDMS) membrane, a permanent magnet and a planar electromagnetic actuator. The performance of this liquid lens is tested from four aspects including surface profiling, optical observation, variation of focal length and dynamic response speed. The results shows that with increasing current, the optical chamber PDMS membrane bulges up into a shape with a smaller radius of curvature, and the picture recorded by a charge-coupled device (CCD) camera through the liquid lens also gradually becomes blurred. As the current changes from -1 to 1.2 A, the whole measured focal length of the proposed liquid lens ranges from -133 to -390 mm and from 389 to 61 mm. Then a 0.8 A square-wave current is applied to the electrode, and the actuation time and relaxation time are 340 and 460 ms, respectively. The liquid lens proposed in the paper is easily integrated with microfluidic chips and medical detecting instruments due to its planar structure. PMID- 30404363 TI - Electrostatic Comb-Drive Actuator with High In-Plane Translational Velocity. AB - This work reports the design and opto-mechanical characterization of high velocity comb-drive actuators producing in-plane motion and fabricated using the technology of deep reactive ion etching (DRIE) of silicon-on-insulator (SOI) substrate. The actuators drive vertical mirrors acting on optical beams propagating in-plane with respect to the substrate. The actuator-mirror device is a fabrication on an SOI wafer with 80 MUm etching depth, surface roughness of about 15 nm peak to valley and etching verticality that is better than 0.1 degree. The travel range of the actuators is extracted using an optical method based on optical cavity response and accounting for the diffraction effect. One design achieves a travel range of approximately 9.1 um at a resonance frequency of approximately 26.1 kHz, while the second design achieves about 2 um at 93.5 kHz. The two specific designs reported achieve peak velocities of about 1.48 and 1.18 m/s, respectively, which is the highest product of the travel range and frequency for an in-plane microelectromechanical system (MEMS) motion under atmospheric pressure, to the best of the authors' knowledge. The first design possesses high spring linearity over its travel range with about 350 ppm change in the resonance frequency, while the second design achieves higher resonance frequency on the expense of linearity. The theoretical predications and the experimental results show good agreement. PMID- 30404364 TI - In-Plane MEMS Shallow Arch Beam for Mechanical Memory. AB - We demonstrate a memory device based on the nonlinear dynamics of an in-plane microelectromechanical systems (MEMS) clamped-clamped beam resonator, which is deliberately fabricated as a shallow arch. The arch beam is made of silicon, and is electrostatically actuated. The concept relies on the inherent quadratic nonlinearity originating from the arch curvature, which results in a softening behavior that creates hysteresis and co-existing states of motion. Since it is independent of the electrostatic force, this nonlinearity gives more flexibility in the operating conditions and allows for lower actuation voltages. Experimental results are generated through electrical characterization setup. Results are shown demonstrating the switching between the two vibrational states with the change of the direct current (DC) bias voltage, thereby proving the memory concept. PMID- 30404365 TI - Cost-Efficient Wafer-Level Capping for MEMS and Imaging Sensors by Adhesive Wafer Bonding. AB - Device encapsulation and packaging often constitutes a substantial part of the fabrication cost of micro electro-mechanical systems (MEMS) transducers and imaging sensor devices. In this paper, we propose a simple and cost-effective wafer-level capping method that utilizes a limited number of highly standardized process steps as well as low-cost materials. The proposed capping process is based on low-temperature adhesive wafer bonding, which ensures full complementary metal-oxide-semiconductor (CMOS) compatibility. All necessary fabrication steps for the wafer bonding, such as cavity formation and deposition of the adhesive, are performed on the capping substrate. The polymer adhesive is deposited by spray-coating on the capping wafer containing the cavities. Thus, no lithographic patterning of the polymer adhesive is needed, and material waste is minimized. Furthermore, this process does not require any additional fabrication steps on the device wafer, which lowers the process complexity and fabrication costs. We demonstrate the proposed capping method by packaging two different MEMS devices. The two MEMS devices include a vibration sensor and an acceleration switch, which employ two different electrical interconnection schemes. The experimental results show wafer-level capping with excellent bond quality due to the re-flow behavior of the polymer adhesive. No impediment to the functionality of the MEMS devices was observed, which indicates that the encapsulation does not introduce significant tensile nor compressive stresses. Thus, we present a highly versatile, robust, and cost-efficient capping method for components such as MEMS and imaging sensors. PMID- 30404366 TI - A WSi-WSiN-Pt Metallization Scheme for Silicon Carbide-Based High Temperature Microsystems. AB - In this paper, we present and discuss our new WSi-WSiN-Pt metallization scheme for SiC-based microsystems for applications in harsh environments. Stoichiometric material WSi was selected as contact material for SiC. The diffusion barrier material WSiN was deposited from the same target as the contact material in order to limit the number of different chemical elements in the scheme. Our scheme was kept as simple as possible regarding the number of layers and chemical elements. Our scheme shows very good long-term stability and suitability for SiC-based microsystems. The experimental evaluation concept used here includes a combination of physical, electrical, and mechanical analysis techniques. This combined advance is necessary since modern physical analysis techniques still offer only limited sensitivity for detecting minimal changes in the metallization scheme. PMID- 30404367 TI - Acoustically Triggered Disassembly of Multilayered Polyelectrolyte Thin Films through Gigahertz Resonators for Controlled Drug Release Applications. AB - Controlled drug release has a high priority for the development of modern medicine and biochemistry. To develop a versatile method for controlled release, a miniaturized acoustic gigahertz (GHz) resonator is designed and fabricated which can transfer electric supply to mechanical vibrations. By contacting with liquid, the GHz resonator directly excites streaming flows and induces physical shear stress to tear the multilayered polyelectrolyte (PET) thin films. Due to the ultra-high working frequency, the shear stress is greatly intensified, which results in a controlled disassembling of the PET thin films. This technique is demonstrated as an effective method to trigger and control the drug release. Both theory analysis and controlled release experiments prove the thin film destruction and the drug release. PMID- 30404368 TI - Tunable Particle Focusing in a Straight Channel with Symmetric Semicircle Obstacle Arrays Using Electrophoresis-Modified Inertial Effects. AB - In this work, a novel microfluidic platform for tunable particle focusing in a straight channel with symmetric semicircle obstacle arrays using electrophoresis (EP)-modified inertial effects was presented. By exerting an EP force on the charged microparticles, a relative velocity gap between microspheres and fluid in a straight channel with symmetric semicircle obstacle arrays was implemented. The relative velocity and fluid shear will induce shear-slip lift force (Saffman lift force) perpendicular to the mainstream direction. Therefore, the focusing pattern can be altered using the electrophoresis-induced Saffman force. The effects of electric field direction, flow rate, electric field magnitude, and particle size were also studied. This demonstrates the possibility of adjusting the particle inertial focusing pattern in a straight channel with with symmetric semicircle obstacle arrays using electrophoresis. Manipulation of the lateral migration of focusing streaks increases controllability in applications such as blood cell filtration and the separation of cells by size. PMID- 30404369 TI - A Dewetting Model for Double-Emulsion Droplets. AB - The evolution of double-emulsion droplets is of great importance for the application of microdroplets and microparticles. We study the driving force of the dewetting process, the equilibrium configuration and the dewetting time of double-emulsion droplets. Through energy analysis, we find that the equilibrium configuration of a partial engulfed droplet depends on a dimensionless interfacial tension determined by the three relevant interfacial tensions, and the engulfing part of the inner phase becomes larger as the volume of the outer phase increases. By introducing a dewetting boundary, the dewetting time can be calculated by balancing the driving force, caused by interfacial tensions, and the viscous force. Without considering the momentum change of the continuous phase, the dewetting time is an increasing function against the viscosity of the outer phase and the volume ratio between the outer phase and inner phase. PMID- 30404370 TI - A New Microfluidic Device for Classification of Microalgae Cells Based on Simultaneous Analysis of Chlorophyll Fluorescence, Side Light Scattering, Resistance Pulse Sensing. AB - Fast on-site monitoring of foreign microalgae species carried by ship ballast water has drawn more and more attention. In this paper, we presented a new method and a compact device of classification of microalgae cells by simultaneous detection of three kinds of signals of single microalgae cells in a disposable microfluidic chip. The microfluidic classification device has advantages of fast detection, low cost, and portability. The species of a single microalgae cell can be identified by simultaneous detection of three signals of chlorophyll fluorescence (CF), side light scattering (SLS), and resistance pulse sensing (RPS) of the microalgae cell. These three signals represent the different characteristics of a microalgae cell. A compact device was designed to detect these three signals of a microalgae cell simultaneously. In order to demonstrate the performance of the developed system, the comparison experiments of the mixed samples of three different species of microalgae cells between the developed system and a commercial flow cytometer were conducted. The results show that three kinds of microalgae cells can be distinguished clearly by our developed system and the commercial flow cytometer and both results have good agreement. PMID- 30404371 TI - A Fuzzy Adaptive Tightly-Coupled Integration Method for Mobile Target Localization Using SINS/WSN. AB - In recent years, mobile target localization for enclosed environments has been a growing interest. In this paper, we have proposed a fuzzy adaptive tightly coupled integration (FATCI) method for positioning and tracking applications using strapdown inertial navigation system (SINS) and wireless sensor network (WSN). The wireless signal outage and severe multipath propagation of WSN often influence the accuracy of measured distance and lead to difficulties with the WSN positioning. Note also that the SINS are known for their drifted error over time. Using as a base the well-known loosely-coupled integration method, we have built a tightly-coupled integrated positioning system for SINS/WSN based on the measured distances between anchor nodes and mobile node. The measured distance value of WSN is corrected with a least squares regression (LSR) algorithm, with the aim of decreasing the systematic error for measured distance. Additionally, the statistical covariance of measured distance value is used to adjust the observation covariance matrix of a Kalman filter using a fuzzy inference system (FIS), based on the statistical characteristics. Then the tightly-coupled integration model can adaptively adjust the confidence level for measurement according to the different measured accuracies of distance measurements. Hence the FATCI system is achieved using SINS/WSN. This innovative approach is verified in real scenarios. Experimental results show that the proposed positioning system has better accuracy and stability compared with the loosely-coupled and traditional tightly-coupled integration model for WSN short-term failure or normal conditions. PMID- 30404372 TI - Microfluidic Paper-Based Sample Concentration Using Ion Concentration Polarization with Smartphone Detection. AB - A simple method for microfluidic paper-based sample concentration using ion concentration polarization (ICP) with smartphone detection is developed. The concise and low-cost microfluidic paper-based ICP analytical device, which consists of a black backing layer, a nitrocellulose membrane, and two absorbent pads, is fabricated with the simple lamination method which is widely used for lateral flow strips. Sample concentration on the nitrocellulose membrane is monitored in real time by a smartphone whose camera is used to collect the fluorescence images from the ICP device. A custom image processing algorithm running on the smartphone is used to track the concentrated sample and obtain its fluorescence signal intensity for quantitative analysis. Two different methods for Nafion coating are evaluated and their performances are compared. The characteristics of the ICP analytical device especially with intentionally adjusted physical properties are fully evaluated to optimize its performance as well as to extend its potential applications. Experimental results show that significant concentration enhancement with fluorescence dye sample is obtained with the developed ICP device when a fast depletion of fluorescent dye is observed. The platform based on the simply laminated ICP device with smartphone detection is desired for point-of-care testing in settings with poor resources. PMID- 30404373 TI - Electrothermal Actuators for SiO2 Photonic MEMS. AB - This paper describes the design, fabrication and characterization of electrothermal bimorph actuators consisting of polysilicon on top of thick (>10 MU m ) silicon dioxide beams. This material platform enables the integration of actuators with photonic waveguides, producing mechanically-flexible photonic waveguide structures that are positionable. These structures are explored as part of a novel concept for highly automated, sub-micrometer precision chip-to-chip alignment. In order to prevent residual stress-induced fracturing that is associated with the release of thick oxide structures from a silicon substrate, a special reinforcement method is applied to create suspended silicon dioxide beam structures. The characterization includes measurements of the post-release deformation (i.e., without actuation), as well as the deflection resulting from quasi-static and dynamic actuation. The post-release deformation reveals a curvature, resulting in the free ends of 800 MU m long silicon dioxide beams with 5 MU m-thick polysilicon to be situated approximately 80 MU m above the chip surface. Bimorph actuators that are 800 MU m in length produce an out-of-plane deflection of approximately 11 MU m at 60 mW dissipated power, corresponding to an estimated 240 ? C actuator temperature. The delivered actuation force of the 800 MU m-long bimorph actuators having 5 MU m-thick polysilicon is calculated to be approximately 750 MUN at 120 mW . PMID- 30404374 TI - Fluid Micro-Reservoirs Array Design with Auto-Pressure Regulation for High-Speed 3D Printers. AB - Three dimensional (3D) printing technology is rapidly evolving such that printing speed is now a crucial factor in technological developments and future applications. For printing heads based on the inkjet concept, the number of nozzles on the print head is a limiting factor of printing speed. This paper offers a method to practically increase the number of nozzles unlimitedly, and thus to dramatically ramp up printing speed. Fluid reservoirs are used in inkjet print heads to supply fluid through a manifold to the jetting chambers. The pressure in the reservoir's outlet is important and influences device performance. Many efforts have been made to regulate pressure inside the fluid reservoirs so as to obtain a constant pressure in the chambers. When the number of nozzles is increased too much, the regulation of uniform pressure among all the nozzles becomes too complicated. In this paper, a different approach is taken. The reservoir is divided into an array of many micro-reservoirs. Each micro-reservoir supports one or a few chambers, and has a unique structure with auto-pressure regulation, where the outlet pressure is independent of the fluid level. The regulation is based on auto-compensation of the gravity force and a capillary force having the same dependence on the fluid level; this feature is obtained by adding a wedge in the reservoir with a unique shape. When the fluid level drops, the gravitational force and the capillary force decrease with it, but at similar rates. Terms for the force balance are derived and, consequently, a constant pressure in the fluid micro-reservoir segment is obtained automatically, with each segment being autonomous. This micro reservoir array is suggested for the enlargement of an inkjet print head and the achievement of high speed 3D printing. PMID- 30404375 TI - A Rapid Prototyping Technique for Microfluidics with High Robustness and Flexibility. AB - In microfluidic device prototyping, master fabrication by traditional photolithography is expensive and time-consuming, especially when the design requires being repeatedly modified to achieve a satisfactory performance. By introducing a high-performance/cost-ratio laser to the traditional soft lithography, this paper describes a flexible and rapid prototyping technique for microfluidics. An ultraviolet (UV) laser directly writes on the photoresist without a photomask, which is suitable for master fabrication. By eliminating the constraints of fixed patterns in the traditional photomask when the masters are made, this prototyping technique gives designers/researchers the convenience to revise or modify their designs iteratively. A device fabricated by this method is tested for particle separation and demonstrates good properties. This technique provides a flexible and rapid solution to fabricating microfluidic devices for non-professionals at relatively low cost. PMID- 30404376 TI - UV Light-Induced Aggregation of Titania Submicron Particles. AB - In this study, aggregation of TiO2 (rutile and anatase) submicron particles in deionized (DI) water under ultra-violet (UV) light irradiation was investigated. While no aggregation was observed in the dark, rutile and anatase submicron particles started aggregating upon application of UV light and ceased aggregation in about 2 and 8.4 h, respectively. It has been demonstrated that UV light directly mitigated the particle mobility of TiO2, resulting in a neutralization effect of the Zeta potential. It was also observed that rutile particles aggregated much faster than anatase particles under UV radiation, indicating that the Zeta potential of as-prepared rutile is less than that of anatase in deionized (DI) water. In addition, the interaction energy of rutile and anatase particles was simulated using the Derjaguin-Landau-Verwey-Overbeek (DLVO) model. The results showed a significant reduction of barrier energy from 118.2 kBT to 33.6 kBT for rutile and from 333.5 kBT to 46.1 kBT for anatase, respectively, which further validated the remarkable influence of UV irradiation on the aggregation kinetics of rutile and anatase submicron particles. This work presents a further understanding of the aggregation mechanism of light-controlled submicron particles and has a promising potential application in environmental remediation. PMID- 30404378 TI - Power Generation by Reverse Electrodialysis in a Microfluidic Device with a Nafion Ion-Selective Membrane. AB - An energy conversion microchip consisting of two circular microchambers and a Nafion-filled microchannel is fabricated using standard micro-electro-mechanical systems (MEMS) techniques. When the chambers are filled with KCl solutions with different concentrations, the Nafion microchannel acts as a cation-selective membrane and results in the generation of electrical power through a reverse electrodialysis (RED) process. The current-potential characteristics of the Nafion membrane are investigated for devices with various microchannel lengths and electrolyte concentration ratios. It is shown that for a given voltage, the current and generated power increase with a reducing channel length due to a lower resistance. In addition, a maximum power density of 755 mW/m2 is obtained given an electrolyte concentration ratio of 2000:1 (unit is mM). The optimal device efficiency is found to be 36% given a channel length of 1 mm and a concentration ratio of 1000:1 (mM). Finally, no enhancement of the short circuit current is observed at higher concentration ratios. PMID- 30404377 TI - Electro-Deformation of Fused Cells in a Microfluidic Array Device. AB - We present a new method of analyzing the deformability of fused cells in a microfluidic array device. Electrical stresses-generated by applying voltages (4 20 V) across discrete co-planar microelectrodes along the side walls of a microfluidic channel-have been used to electro-deform fused and unfused stem cells. Under an electro-deformation force induced by applying an alternating current (AC) signal, we observed significant electro-deformation phenomena. The experimental results show that the fused stem cells were stiffer than the unfused stem cells at a relatively low voltage (<16 V). However, at a relatively high voltage, the fused stem cells were more easily deformed than were the unfused stem cells. In addition, the electro-deformation process is modeled based on the Maxwell stress tensor and structural mechanics of cells. The theoretical results show that a positive correlation is found between the deformation of the cell and the applied voltage, which is consistent with the experimental results. Combined with a numerical analysis and experimental study, the results showed that the significant difference of the deformation ratio of the fused and unfused cells is not due to their size difference. This demonstrates that some other properties of cell membranes (such as the membrane structure) were also changed in the electrofusion process, in addition to the size modification of that process. PMID- 30404379 TI - Precision Position Control of a Voice Coil Motor Using Self-Tuning Fractional Order Proportional-Integral-Derivative Control. AB - The object of this study is to develop a self-tuning fractional order proportional-integral-derivative (SFOPID) controller for controlling the mover position of a direct drive linear voice coil motor (VCM) accurately under different operational conditions. The fractional order proportional-integral derivative (FOPID) controller can improve the control performances of the conventional integer order PID controller with respect to the additional fractional differential and integral orders; however, choosing five interdependent control parameters including proportional, integral, and derivative gains, as well as fractional differential and integral orders appropriately is arduous in practical applications. In this regard, the SFOPID controller is proposed in which the five control parameters are optimized dynamically and concurrently according to an adaptive differential evolution algorithm with a high efficiency adaptive selection mechanism. Experimental results reveal that the SFOPID controller outperforms PID and FOPID controllers with regard to the nonlinear VCM control system under both nominal and payload conditions. PMID- 30404380 TI - 3C-Silicon Carbide Microresonators for Timing and Frequency Reference. AB - In the drive to miniaturise and integrate reference oscillator components, microelectromechanical systems (MEMS) resonators are excellent candidates to replace quartz crystals. Silicon is the most utilised resonator structural material due to its associated well-established fabrication processes. However, when operation in harsh environments is required, cubic silicon carbide (3C-SiC) is an excellent candidate for use as a structural material, due to its robustness, chemical inertness and high temperature stability. In order to actuate 3C-SiC resonators, electrostatic, electrothermal and piezoelectric methods have been explored. Both electrothermal and piezoelectric actuation can be accomplished with simpler fabrication and lower driving voltages, down to 0.5 V, compared to electrostatic actuation. The vibration amplitude at resonance can be maximised by optimising the design and location of the electrodes. Electrical read out of the resonator can be performed with electrostatic or piezoelectric transduction. Finally, a great deal of research has focused on tuning the resonant frequency of a 3C-SiC resonator by adjusting the DC bias applied to the electrodes, with a higher (up to 160-times) tuning range for electrothermal tuning compared to piezoelectric tuning. Electrothermal tuning lowers the frequency, while piezoelectric tuning can be used to raise the frequency. PMID- 30404381 TI - One-Dimensional Thermal Analysis of the Flexible Electronic Devices Integrated with Human Skin. AB - A one-dimensional analytic thermal model for the flexible electronic devices integrated with human skin under a constant and pulsed power is developed. The Fourier heat conduction equation is adopted for the flexible electronics devices while the Pennes bio-heat transfer equation is adopted for the skin tissue. Finite element analysis is performed to validate the analytic model through the comparison of temperature distributions in the system. The influences of geometric and loading parameters on the temperature increase under a pulsed power are investigated. It is shown that a small duty cycle can reduce the temperature increase of the system effectively. A thin substrate can reduce the device temperature but increase the skin surface temperature. The results presented may be helpful to optimize the design of flexible electronic devices to reduce the adverse thermal influences in bio-integrated applications. PMID- 30404382 TI - An Interference-Assisted Thermal Bonding Method for the Fabrication of Thermoplastic Microfluidic Devices. AB - Solutions for the bonding and sealing of micro-channels in the manufacturing process of microfluidic devices are limited; therefore, further technical developments are required to determine these solutions. In this study, a new bonding method for thermoplastic microfluidic devices was developed by combining an interference fit with a thermal treatment at low pressure. This involved a process of first injection molding thermoplastic substrates with a microchannel structure, and then performing bonding experiments at different bonding conditions. The results indicated the successful bonding of microchannels over a wide range of bonding pressures with the help of the interference fit. The study also determined additional advantages of the proposed bonding method by comparing the method with the conventional thermal bonding method. PMID- 30404383 TI - Automatic Path Tracking and Target Manipulation of a Magnetic Microrobot. AB - Recently, wireless controlled microrobots have been studied because of their great development prospects in the biomedical field. Electromagnetic microrobots have the advantages of control agility and good precision, and thus, have received much attention. Most of the control methods for controlling a magnetic microrobot use manual operation. Compared to the manual method, the automatic method will increase the accuracy and stability of locomotion and manipulation of microrobots. In this paper, we propose an electromagnetic manipulation system for automatically controlling the locomotion and manipulation of microrobots. The microrobot can be automatically controlled to track various paths by using visual feedback with an expert control algorithm. A positioning accuracy test determined that the position error ranges from 92 to 293 MUm, which is less than the body size (600 MUm) of the microrobot. The velocity of the microrobot is nearly proportional to the applied current in the coils, and can reach 5 mm/s. As a micromanipulation tool, the microrobot is used to manipulate microspheres and microgears with the automatic control method. The results verify that the microrobot can drag, place, and drive the microstructures automatically with high precision. The microrobot is expected to be a delicate micromachine that could play its role in microfluidics and blood vessels, where conventional instruments are hard to reach. PMID- 30404384 TI - A Y-Shaped Microfluidic Device to Study the Combined Effect of Wall Shear Stress and ATP Signals on Intracellular Calcium Dynamics in Vascular Endothelial Cells. AB - The intracellular calcium dynamics in vascular endothelial cells (VECs) in response to wall shear stress (WSS) and/or adenosine triphosphate (ATP) have been commonly regarded as an important factor in regulating VEC function and behavior including proliferation, migration and apoptosis. However, the effects of time varying ATP signals have been usually neglected in the past investigations in the field of VEC mechanobiology. In order to investigate the combined effects of WSS and dynamic ATP signals on the intracellular calcium dynamic in VECs, a Y-shaped microfluidic device, which can provide the cultured cells on the bottom of its mixing micro-channel with stimuli of WSS signal alone and different combinations of WSS and ATP signals in one single micro-channel, is proposed. Both numerical simulation and experimental studies verify the feasibility of its application. Cellular experimental results also suggest that a combination of WSS and ATP signals rather than a WSS signal alone might play a more significant role in VEC Ca2+ signal transduction induced by blood flow. PMID- 30404385 TI - Microfluidic Mixing and Analog On-Chip Concentration Control Using Fluidic Dielectrophoresis. AB - Microfluidic platforms capable of complex on-chip processing and liquid handling enable a wide variety of sensing, cellular, and material-related applications across a spectrum of disciplines in engineering and biology. However, there is a general lack of available active microscale mixing methods capable of dynamically controlling on-chip solute concentrations in real-time. Hence, multiple microfluidic fluid handling steps are often needed for applications that require buffers at varying on-chip concentrations. Here, we present a novel electrokinetic method for actively mixing laminar fluids and controlling on-chip concentrations in microfluidic channels using fluidic dielectrophoresis. Using a microfluidic channel junction, we co-flow three electrolyte streams side-by-side so that two outer conductive streams enclose a low conductive central stream. The tri-laminar flow is driven through an array of electrodes where the outer streams are electrokinetically deflected and forced to mix with the central flow field. This newly mixed central flow is then sent continuously downstream to serve as a concentration boundary condition for a microfluidic gradient chamber. We demonstrate that by actively mixing the upstream fluids, a variable concentration gradient can be formed dynamically downstream with single a fixed inlet concentration. This novel mixing approach offers a useful method for producing variable on-chip concentrations from a single inlet source. PMID- 30404386 TI - Self-Aligned Interdigitated Transducers for Acoustofluidics. AB - The surface acoustic wave (SAW) is effective for the manipulation of fluids and particles at microscale. The current approach of integrating interdigitated transducers (IDTs) for SAW generation into microfluidic channels involves complex and laborious microfabrication steps. These steps often require full access to clean room facilities and hours to align the transducers to the precise location. This work presents an affordable and innovative method for fabricating SAW-based microfluidic devices without the need for clean room facilities and alignment. The IDTs and microfluidic channels are fabricated using the same process and thus are precisely self-aligned in accordance with the device design. With the use of the developed fabrication approach, a few types of different SAW-based microfluidic devices have been fabricated and demonstrated for particle separation and active droplet generation. PMID- 30404387 TI - Recent Advancements in Liquid Metal Flexible Printed Electronics: Properties, Technologies, and Applications. AB - This article presents an overview on typical properties, technologies, and applications of liquid metal based flexible printed electronics. The core manufacturing material-room-temperature liquid metal, currently mainly represented by gallium and its alloys with the properties of excellent resistivity, enormous bendability, low adhesion, and large surface tension, was focused on in particular. In addition, a series of recently developed printing technologies spanning from personal electronic circuit printing (direct painting or writing, mechanical system printing, mask layer based printing, high resolution nanoimprinting, etc.) to 3D room temperature liquid metal printing is comprehensively reviewed. Applications of these planar or three-dimensional printing technologies and the related liquid metal alloy inks in making flexible electronics, such as electronical components, health care sensors, and other functional devices were discussed. The significantly different adhesions of liquid metal inks on various substrates under different oxidation degrees, weakness of circuits, difficulty of fabricating high-accuracy devices, and low rate of good product-all of which are challenges faced by current liquid metal flexible printed electronics-are discussed. Prospects for liquid metal flexible printed electronics to develop ending user electronics and more extensive applications in the future are given. PMID- 30404388 TI - Numerical Model of Streaming DEP for Stem Cell Sorting. AB - Neural stem cells are of special interest due to their potential in neurogenesis to treat spinal cord injuries and other nervous disorders. Flow cytometry, a common technique used for cell sorting, is limited due to the lack of antigens and labels that are specific enough to stem cells of interest. Dielectrophoresis (DEP) is a label-free separation technique that has been recently demonstrated for the enrichment of neural stem/progenitor cells. Here we use numerical simulation to investigate the use of streaming DEP for the continuous sorting of neural stem/progenitor cells. Streaming DEP refers to the focusing of cells into streams by equilibrating the dielectrophoresis and drag forces acting on them. The width of the stream should be maximized to increase throughput while the separation between streams must be widened to increase efficiency during retrieval. The aim is to understand how device geometry and experimental variables affect the throughput and efficiency of continuous sorting of SC27 stem cells, a neurogenic progenitor, from SC23 cells, an astrogenic progenitor. We define efficiency as the ratio between the number of SC27 cells over total number of cells retrieved in the streams, and throughput as the number of SC27 cells retrieved in the streams compared to their total number introduced to the device. The use of cylindrical electrodes as tall as the channel yields streams featuring >98% of SC27 cells and width up to 80 um when using a flow rate of 10 uL/min and sample cell concentration up to 105 cells/mL. PMID- 30404389 TI - An Enhanced Electroosmotic Micromixer with an Efficient Asymmetric Lateral Structure. AB - Homogeneous and rapid mixing in microfluidic devices is difficult to accomplish, owing to the low Reynolds number associated with most flows in microfluidic channels. Here, an efficient electroosmotic micromixer based on a carefully designed lateral structure is demonstrated. The electroosmotic flow in this mixer with an asymmetrical structure induces enhanced disturbance in the micro channel, helping the fluid streams' folding and stretching, thereby enabling appreciable mixing. Quantitative analysis of the mixing efficiency with respect to the potential applied and the flow rate suggests that the electroosmotic microfluidic mixer developed in the present work can achieve efficient mixing with low applied potential. PMID- 30404390 TI - A Resonant Piezoelectric Diaphragm Pump Transferring Gas with Compact Structure. AB - In order to improve the output capacity of a piezoelectric pump when transferring gas, this paper presents a compact resonant piezoelectric diaphragm pump (hereinafter referred to as the piezoelectric diaphragm pump), which is driven by a rectangular piezoelectric vibrator. The compact structure can effectively release the vibrating constraints of the vibrator, and enlarge its center output displacement, so as to increase the volume change rate of the pump chamber. Based on the structure and the working principle of this piezoelectric diaphragm pump, a dynamic model for the diaphragm system is established in this paper, and an analysis on factors affecting the resonant frequency of the system is then conducted. We tested on the prototype under the driving voltage of 260 Vpp. The results show that the diaphragm system reaches resonance under the driving frequency of 265 Hz, which is very close to the fundamental frequency of check valve. Compared with the rectangular piezoelectric vibrator's amplitude, the diaphragm's amplitude is double amplified. At this time, the piezoelectric diaphragm pump achieves the maximum gas flow rate as 186.8 mL/min and the maximum output pressure as 56.7 kPa. PMID- 30404391 TI - The Effect of Moment of Inertia on the Liquids in Centrifugal Microfluidics. AB - The flow of liquids in centrifugal microfluidics is unidirectional and dominated by centrifugal and Coriolis forces (i.e., effective only at T-junctions). Developing mechanisms and discovering efficient techniques to propel liquids in any direction other than the direction of the centrifugal force has been the subject of a large number of studies. The capillary force attained by specific surface treatments, pneumatic energy, active and passive flow reciprocation and Euler force have been previously introduced in order to manipulate the liquid flow and push it against the centrifugal force. Here, as a new method, the moment of inertia of the liquid inside a chamber in a centrifugal microfluidic platform is employed to manipulate the flow and propel the liquid passively towards the disc center. Furthermore, the effect of the moment of inertia on the liquid in a rectangular chamber is evaluated, both in theory and experiments, and the optimum geometry is defined. As an application of the introduced method, the moment of inertia of the liquid is used in order to mix two different dyed deionized (DI) waters; the mixing efficiency is evaluated and compared to similar mixing techniques. The results show the potential of the presented method for pumping liquids radially inward with relatively high flow rates (up to 23 mm3/s) and also efficient mixing in centrifugal microfluidic platforms. PMID- 30404393 TI - A Study on the Influence of the Nozzle Lead Angle on the Performance of Liquid Metal Electromagnetic Micro-Jetting. AB - To improve the jetting performance of liquid metals, an electromagnetic micro jetting (EMJ) valve that realizes drop-on-demand (DOD) jetting while not involving any valve core or moving parts was designed. The influence of the lead angle of the nozzle on the jetting of liquid metal gallium (Ga) was investigated. It was found that the Lorentz force component parallel to the nozzle that jets the electrified liquid Ga is always larger than its internal friction; thus, jet can be generated with any lead angle but with different kinetic energies. Experimental results show that the mass of the jetting liquid, the jetting distance, the initial velocity of the jet, and the resulting kinetic energy of the jet increase first and then decrease. When the lead angle is 90 degrees , the mass of the jetting liquid and the kinetic energy are at their maximum. When the angle is 80 degrees , the initial velocity achieves its maximum, with a calculated value of 0.042 m/s. Moreover, very close and comparatively high kinetic energies are obtained at 80 degrees and 90 degrees , indicating that angles in between this range can produce a preferable performance. This work provides an important theoretical basis for the design of the EMJ valve, and may promote the development and application of micro electromagnetic jetting technology. PMID- 30404392 TI - Temporal Transition of Mechanical Characteristics of HUVEC/MSC Spheroids Using a Microfluidic Chip with Force Sensor Probes. AB - In this paper, we focus on the mechanical characterization of co-cultured spheroids of human umbilical vein endothelial cells (HUVECs) and mesenchymal stem cells (MSC) (HUVEC/MSC spheroids). HUVEC/MSC spheroids aggregate during culture, thereby decreasing in size. Since this size decrease can be caused by the contractility generated by the actomyosin of MSCs, which are intracellular frames, we can expect that there is a temporal transition for the mechanical characteristics, such as stiffness, during culture. To measure the mechanical characteristics, we use a microfluidic chip that is integrated with force sensor probes. We show the details of the measurement configuration and the results of mechanical characterization of the HUVEC/MSC spheroids. To evaluate the stiffness of the spheroids, we introduce the stiffness index, which essentially shows a spring constant per unit size of the spheroid at a certain time during measurement. From the measurement results, we confirmed that the stiffness index firstly increased during the days of culture, although after four days of culture, the stiffness index decreased. We confirmed that the proposed system can measure the stiffness of HUVEC/MSC spheroids. PMID- 30404394 TI - Non-Lithographic Silicon Micromachining Using Inkjet and Chemical Etching. AB - We introduce a non-lithographical and vacuum-free method to pattern silicon. The method combines inkjet printing and metal assisted chemical etching (MaCE); we call this method "INKMAC". A commercial silver ink is printed on top of a silicon surface to create the catalytic patterns for MaCE. The MaCE process leaves behind a set of silicon nanowires in the shape of the inkjet printed micrometer scale pattern. We further show how a potassium hydroxide (KOH) wet etching process can be used to rapidly etch away the nanowires, producing fully opened cavities and channels in the shape of the original printed pattern. We show how the printed lines (width 50-100 um) can be etched into functional silicon microfluidic channels with different depths (10-40 um) with aspect ratios close to one. We also used individual droplets (minimum diameter 30 um) to produce cavities with a depth of 60 um and an aspect ratio of two. Further, we discuss using the structured silicon substrate as a template for polymer replication to produce superhydrophobic surfaces. PMID- 30404395 TI - Free-Standing GaMnAs Nanomachined Sheets for van der Pauw Magnetotransport Measurements. AB - We report on the realization of free-standing GaMnAs epilayer sheets using nanomachining techniques. By optimizing the growth conditions of the sacrificial Al0.75Ga0.25As layer, free-standing metallic GaMnAs (with ~6% Mn) microsheets (with TC ~85 K) with integrated electrical probes are realized for magnetotransport measurements in the van der Pauw geometry. GaMnAs epilayer needs to be physically isolated to avoid buckling effects stemming from the release of lattice mismatch strain during the removal of the AlGaAs sacrificial layer. From finite element analysis, symmetrically placed and serpentine-shaped electrical leads induce minimal thermal stress at low temperatures. From magnetotransport measurements, changes in magnetic anisotropy are readily observed. PMID- 30404396 TI - Fabrication of Pneumatic Microvalve for Tall Microchannel Using Inclined Lithography. AB - We used inclined lithography to fabricate a pneumatic microvalve for tall microchannels such as those used to convey large cells. The pneumatic microvalve consists of three layers. The upper layer is the actual liquid microchannel, which has a parallelogram-shaped cross section of width 500 MUm, height 100 MUm, and an acute angle of 53.6 degrees . The lower layer is a pneumatic microchannel that functions as an actuator, and the middle layer is a thin polydimethylsiloxane membrane between the upper and lower layers. The operation of the pneumatic microchannel actuator causes the thin membrane to bend, resulting in the bending of the liquid microchannel and its closure. It was confirmed that the closure of the liquid microchannel completely stopped the flow of the HeLa cell suspension that was used to demonstrate the operation of the microvalve. The HeLa cells that passed through the microchannel were also observed to retain their proliferation and morphological properties. PMID- 30404399 TI - Analysis and Optimization of Thermodiffusion of an FBG Sensor in the Gas Nitriding Process. AB - In this paper, we report the numerical calculations for a thermo-optical model and the temperature sensitivity of a fiber Bragg grating (FBG) sensor. The thermally-induced behaviors of a FBG sensor in the gas nitriding process were analyzed for temperatures ranging from 100-650 degrees C. The FBG consisted of properly chosen photosensitive fiber materials with an optimized thermo-optic coefficient. The experimental and optimized thermo-optic coefficient results were consistent in terms of temperature sensitivity. In these experiments, the temperature sensitivity of the FBG was found to be 11.9 pm/ degrees C. PMID- 30404398 TI - Fabrication and Characterization of Capacitive Micromachined Ultrasonic Transducers with Low-Temperature Wafer Direct Bonding. AB - This paper presents a fabrication method of capacitive micromachined ultrasonic transducers (CMUTs) by wafer direct bonding, which utilizes both the wet chemical and O2plasma activation processes to decrease the bonding temperature to 400 degrees C. Two key surface properties, the contact angle and surface roughness, are studied in relation to the activation processes, respectively. By optimizing the surface activation parameters, a surface roughness of 0.274 nm and a contact angle of 0 degrees are achieved. The infrared images and static deflection of devices are assessed to prove the good bonding effect. CMUTs having silicon membranes with a radius of 60 MUm and a thickness of 2 MUm are fabricated. Device properties have been characterized by electrical and acoustic measurements to verify their functionality and thus to validate this low-temperature process. A resonant frequency of 2.06 MHz is obtained by the frequency response measurements. The electrical insertion loss and acoustic signal have been evaluated. This study demonstrates that the CMUT devices can be fabricated by low temperature wafer direct bonding, which makes it possible to integrate them directly on top of integrated circuit (IC) substrates. PMID- 30404397 TI - Polymer Microfluidics: Simple, Low-Cost Fabrication Process Bridging Academic Lab Research to Commercialized Production. AB - Using polymer materials to fabricate microfluidic devices provides simple, cost effective, and disposal advantages for both lab-on-a-chip (LOC) devices and micro total analysis systems (MUTAS). Polydimethylsiloxane (PDMS) elastomer and thermoplastics are the two major polymer materials used in microfluidics. The fabrication of PDMS and thermoplastic microfluidic device can be categorized as front-end polymer microchannel fabrication and post-end microfluidic bonding procedures, respectively. PDMS and thermoplastic materials each have unique advantages and their use is indispensable in polymer microfluidics. Therefore, the proper selection of polymer microfabrication is necessary for the successful application of microfluidics. In this paper, we give a short overview of polymer microfabrication methods for microfluidics and discuss current challenges and future opportunities for research in polymer microfluidics fabrication. We summarize standard approaches, as well as state-of-art polymer microfluidic fabrication methods. Currently, the polymer microfluidic device is at the stage of technology transition from research labs to commercial production. Thus, critical consideration is also required with respect to the commercialization aspects of fabricating polymer microfluidics. This article provides easy-to understand illustrations and targets to assist the research community in selecting proper polymer microfabrication strategies in microfluidics. PMID- 30404400 TI - Optimization Design and Simulation of a Multi-Source Energy Harvester Based on Solar and Radioisotope Energy Sources. AB - A novel multi-source energy harvester based on solar and radioisotope energy sources is designed and simulated in this work. We established the calculation formulas for the short-circuit current and open-circuit voltage, and then studied and analyzed the optimization thickness of the semiconductor, doping concentration, and junction depth with simulation of the transport process of beta particles in a semiconductor material using the Monte Carlo simulation program MCNP (version 5, Radiation Safety Information Computational Center, Oak Ridge, TN, USA). In order to improve the efficiency of converting solar light energy into electric power, we adopted PC1D (version 5.9, University of New South Wales, Sydney, Australia) to optimize the parameters, and selected the best parameters for converting both the radioisotope energy and solar energy into electricity. The results concluded that the best parameters for the multi-source energy harvester are as follows: Na is 1 * 1019 cm-3, Nd is 3.8 * 1016 cm-3, a PN junction depth of 0.5 MUm (using the 147Pm radioisotope source), and so on. Under these parameters, the proposed harvester can achieve a conversion efficiency of 5.05% for the 147Pm radioisotope source (with the activity of 9.25 * 108 Bq) and 20.8% for solar light radiation (AM1.5). Such a design and parameters are valuable for some unique micro-power fields, such as applications in space, isolated terrestrial applications, and smart dust in battlefields. PMID- 30404401 TI - A Versatile Bonding Method for PDMS and SU-8 and Its Application towards a Multifunctional Microfluidic Device. AB - This paper reports a versatile and irreversible bonding method for poly(dimethylsiloxane) (PDMS) and SU-8. The method is based on epoxide opening and dehydration reactions between surface-modified PDMS and SU-8. A PDMS replica is first activated via the low-cost lab equipment, i.e., the oxygen plasma cleaner or the corona treater. Then both SU-8 and plasma-treated PDMS samples are functionalized using hydrolyzed (3-aminopropyl)triethoxysilane (APTES). Ultimately, the samples are simply brought into contact and heated to enable covalent bonding. The molecular coupling and chemical reactions behind the bonding occurring at the surfaces were characterized by water contact angle measurement and X-ray photoelectron spectroscopy (XPS) analysis. The reliability of bonded PDMS-SU-8 samples was examined by using tensile strength and leakage tests, which revealed a bonding strength of over 1.4 MPa. The presented bonding method was also applied to create a metal-SU-8-PDMS hybrid device, which integrated SU-8 microfluidic structures and microelectrodes. This hybrid system was used for the effective trapping of microparticles on-chip, and the selective releasing and identification of predefined trapped microparticles. The hybrid fabrication approach presented here, based on the PDMS-SU-8 bonding, enables multifunctional integration in complex microfluidic devices. PMID- 30404402 TI - Influence of Asymmetry and Driving Forces on the Propulsion of Bubble-Propelled Catalytic Micromotors. AB - Bubble-propelled catalytic micromotors have recently been attracting much attention. A bubble-propulsion mechanism has the advantage of producing a stronger force and higher speed than other mechanisms for catalytic micromotors, but the nature of the fluctuated bubble generation process affects the motions of the micromotors, making it difficult to control their motions. Thus, understanding of the influence of fluctuating bubble propulsion on the motions of catalytic micromotors is important in exploiting the advantages of bubble propelled micromotors. Here, we report experimental demonstrations of the bubble propelled motions of propeller-shaped micromotors and numerical analyses of the influence of fluctuating bubble propulsion on the motions of propeller-shaped micromotors. We found that motions such as trochoid-like motion and circular motion emerged depending on the magnitude or symmetricity of fluctuations in the bubble-propulsion process. We hope that those results will help in the construction and application of sophisticated bubble-propelled micromotors in the future. PMID- 30404403 TI - Fabrication of SiNx Thin Film of Micro Dielectric Barrier Discharge Reactor for Maskless Nanoscale Etching. AB - The prevention of glow-to-arc transition exhibited by micro dielectric barrier discharge (MDBD), as well as its long lifetime, has generated much excitement across a variety of applications. Silicon nitride (SiNx) is often used as a dielectric barrier layer in DBD due to its excellent chemical inertness and high electrical permittivity. However, during fabrication of the MDBD devices with multilayer films for maskless nano etching, the residual stress-induced deformation may bring cracks or wrinkles of the devices after depositing SiNx by plasma enhanced chemical vapor deposition (PECVD). Considering that the residual stress of SiNx can be tailored from compressive stress to tensile stress under different PECVD deposition parameters, in order to minimize the stress-induced deformation and avoid cracks or wrinkles of the MDBD device, we experimentally measured stress in each thin film of a MDBD device, then used numerical simulation to analyze and obtain the minimum deformation of multilayer films when the intrinsic stress of SiNx is -200 MPa compressive stress. The stress of SiNx can be tailored to the desired value by tuning the deposition parameters of the SiNx film, such as the silane (SiH4)-ammonia (NH3) flow ratio, radio frequency (RF) power, chamber pressure, and deposition temperature. Finally, we used the optimum PECVD process parameters to successfully fabricate a MDBD device with good quality. PMID- 30404404 TI - The High Q Factor Lateral Field-Excited Thickness Shear Mode Film Bulk Acoustic Resonator Working in Liquid. AB - A high Q factor film bulk acoustic resonator operating in thickness shear mode excited by a lateral field is described in this paper. The influence of electrode parameters on the resonator performance is studied by the finite element method. The results showed that three key electrode parameters, including the gap, length and width, played important roles in the optimization of the resonator performance. The highest Q factor of up to 643 was obtained when the parallel electrodes were designed to be 100 um * 10 um with the electrode gap of 10 um. Based on the simulation results, the AlN-based film bulk acoustic resonator with a solidly mounted structure was fabricated. The testing results showed that the real device operated at the resonance frequency of 1.94 GHz with the Q factor of 405 in air, 216 in water and 102 in phosphate buffered saline solution. PMID- 30404406 TI - Investigation of Surface Pre-Treatment Methods for Wafer-Level Cu-Cu Thermo Compression Bonding. AB - To increase the yield of the wafer-level Cu-Cu thermo-compression bonding method, certain surface pre-treatment methods for Cu are studied which can be exposed to the atmosphere before bonding. To inhibit re-oxidation under atmospheric conditions, the reduced pure Cu surface is treated by H2/Ar plasma, NH3 plasma and thiol solution, respectively, and is covered by Cu hydride, Cu nitride and a self-assembled monolayer (SAM) accordingly. A pair of the treated wafers is then bonded by the thermo-compression bonding method, and evaluated by the tensile test. Results show that the bond strengths of the wafers treated by NH3 plasma and SAM are not sufficient due to the remaining surface protection layers such as Cu nitride and SAMs resulting from the pre-treatment. In contrast, the H2/Ar plasma-treated wafer showed the same strength as the one with formic acid vapor treatment, even when exposed to the atmosphere for 30 min. In the thermal desorption spectroscopy (TDS) measurement of the H2/Ar plasma-treated Cu sample, the total number of the detected H2 was 3.1 times more than the citric acid treated one. Results of the TDS measurement indicate that the modified Cu surface is terminated by chemisorbed hydrogen atoms, which leads to high bonding strength. PMID- 30404407 TI - Electrokinetic Phenomena in Pencil Lead-Based Microfluidics. AB - Fabrication of microchannels and associated electrodes to generate electrokinetic phenomena often involves costly materials and considerable effort. In this study, we used graphite pencil-leads as low cost, disposable 3D electrodes to investigate various electrokinetic phenomena in straight cylindrical microchannels, which were themselves fabricated by using a graphite rod as the microchannel mold. Individual pencil-leads were employed as the micro-electrodes arranged along the side walls of the microchannel. Efficient electrokinetic phenomena provided by the 3D electrodes, including alternating current electroosmosis (ACEO), induced-charge electroosmosis (ICEO), and dielectrophoresis (DEP), were demonstrated by the introduced pencil-lead based microfluidic devices. The electrokinetic phenomena were characterized by micro particle image velocimetry (micro-PIV) measurements and microscopy imaging. Highly efficient electrokinetic phenomena using 3D pencil-lead electrodes showed the affordability and ease of this technique to fabricate microfluidic devices embedded with electrodes for electrokinetic fluid and particle manipulations. PMID- 30404409 TI - Simulation Study of Inertial Micro-Switch as Influenced by Squeeze-Film Damping and Applied Acceleration Load. AB - Squeeze-film damping and acceleration load are two major issues in the design of inertial micro-switches. In order to deeply and systematically study these two issues, this paper proposes a typical vertically-driven inertial micro-switch, wherein the air and electrode gaps were chosen to design the required damping ratio and threshold value, respectively. The switch was modeled by ANSYS Workbench, and the simulation program was optimized for computational accuracy and speed. Transient analysis was employed to investigate the relationship between the damping ratio, acceleration load, and the natural frequency, and the dynamic properties (including contact bounce, contact time, response time, and threshold acceleration) of the switch. The results can be used as a guide in the design of inertial micro-switches to meet various application requirements. For example, increasing the damping ratio can prolong the contact time of the switch activated by short acceleration duration or reduce the contact bounce of the switch activated by long acceleration duration; the threshold value is immune to variations in the damping effect and acceleration duration when the switch is quasi-statically operated; the anti-jamming capability of the switch can be improved by designing the sensing frequency of the switch to be higher than the acceleration duration but much lower than the other order frequencies of the switch. PMID- 30404405 TI - Microfabricated Physiological Models for In Vitro Drug Screening Applications. AB - Microfluidics and microfabrication have recently been established as promising tools for developing a new generation of in vitro cell culture microdevices. The reduced amounts of reagents employed within cell culture microdevices make them particularly appealing to drug screening processes. In addition, latest advancements in recreating physiologically relevant cell culture conditions within microfabricated devices encourage the idea of using such advanced biological models in improving the screening of drug candidates prior to in vivo testing. In this review, we discuss microfluidics-based models employed for chemical/drug screening and the strategies to mimic various physiological conditions: fine control of 3D extra-cellular matrix environment, physical and chemical cues provided to cells and organization of co-cultures. We also envision future directions for achieving multi-organ microfluidic devices. PMID- 30404408 TI - Microfluidic Fabrication of Hydrocortisone Nanocrystals Coated with Polymeric Stabilisers. AB - Hydrocortisone (HC) nanocrystals intended for parenteral administration of HC were produced by anti-solvent crystallisation within coaxial assemblies of pulled borosilicate glass capillaries using either co-current flow of aqueous and organic phases or counter-current flow focusing. The organic phase was composed of 7 mg/mL of HC in a 60:40 (v/v) mixture of ethanol and water and the anti solvent was milli-Q water. The microfluidic mixers were fabricated with an orifice diameter of the inner capillary ranging from 50 um to 400 um and operated at the aqueous to organic phase flow rate ratio ranging from 5 to 25. The size of the nanocrystals decreased with increasing aqueous to organic flow rate ratio. The counter-current flow microfluidic mixers provided smaller nanocrystals than the co-current flow devices under the same conditions and for the same geometry, due to smaller diameter of the organic phase stream in the mixing zone. The Z average particle size of the drug nanocrystals increased from 210-280 nm to 320 400 nm after coating the nanocrystals with 0.2 wt % aqueous solution of hydroxypropyl methylcellulose (HPMC) in a stirred vial. The differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) analyses carried out on the dried nanocrystals stabilized with HPMC, polyvinyl pyrrolidone (PVP), and sodium lauryl sulfate (SLS) were investigated and reported. The degree of crystallinity for the processed sample was lowest for the sample stabilised with HPMC and the highest for the raw HC powder. PMID- 30404410 TI - Novel Compound-Forming Technology Using Bioprinting and Electrospinning for Patterning a 3D Scaffold Construct with Multiscale Channels. AB - One of the biggest challenges for tissue engineering is to efficiently provide oxygen and nutrients to cells on a three-dimensional (3D) engineered scaffold structure. Thus, achieving sufficient vascularization of the structure is a critical problem in tissue engineering. This facilitates the need to develop novel methods to enhance vascularization. Use of patterned hydrogel structures with multiscale channels can be used to achieve the required vascularization. Patterned structures need to be biocompatible and biodegradable. In this study, gelatin was used as the main part of a hydrogel to prepare a biological structure with 3D multiscale channels using bioprinting combined with selection of suitable materials and electrostatic spinning. Human umbilical vein endothelial cells (HUVECs) were then used to confirm efficacy of the structure, inferred from cell viability on different engineered construct designs. HUVECs were seeded on the surface of channels and cultured in vitro. HUVECs showed high viability and diffusion within the construct. This method can be used as a practical platform for the fabrication of engineered construct for vascularization. PMID- 30404411 TI - The Prevalence of Osteoarthritis and Risk Factors in the Korean Population: The Sixth Korea National Health and Nutrition Examination Survey (VI-1, 2013). AB - Background: Knee osteoarthritis is highly prevalent, especially among the elderly. However, its risk factors have not been well identified, especially in the Korean population. This study aimed to assess the epidemiologic characteristics and risk factors of knee osteoarthritis in the Korean population. Methods: Data of 2,280 (1,295 women) participants of the 2013 Korea National Health and Nutrition Examination Survey aged >=50 years who underwent knee radiography were analyzed. According to the American College of Rheumatology clinical/radiographic classification criteria, knee osteoarthritis was defined as knee pain and radiographic knee osteoarthritis. The association between risk factors and knee osteoarthritis was analyzed using the chi-square test and binominal logistic regression. Results: The participants had an average age of 62.6 years; 56.8% of them were women. The average body mass index was 24.2 kg/m2 , and 296 (13%) participants were diagnosed with knee osteoarthritis. After adjustment for multiple risk factors, age of >=65 years (adjusted odds ratio [OR], 2.552; 95% confidence interval [CI], 1.868-3.486), female sex (OR, 2.050; 95% CI, 1.275-3.295), obesity (body mass index, >=25.0 kg/m2 ; OR, 1.563; 95% CI, 1.191-2.051), hypertension (OR, 1.394; 95% CI, 1.052-1.846), low educational level (lower than or equal to elementary school: OR, 4.761; 95% CI, 2.131-10.635; middle school: OR, 3.184; 95% CI, 1.375-7.369), and low strength exercise frequency (<2 times/wk; OR, 1.829; 95% CI, 1.202-2.784) increased the risk of knee osteoarthritis. Conclusion: Old age, sex, obesity, hypertension, low educational level, and low strength exercise frequency were found to be risk factors for knee osteoarthritis. PMID- 30404412 TI - Hyperbilirubinemia and Follow-up Auditory Brainstem Responses in Preterm Infants. AB - Objectives: Neonatal hyperbilirubinemia is considered one of the most common causative factors of hearing loss. Preterm infants are more vulnerable to neuronal damage caused by hyperbilirubinemia. This study aimed to evaluate the effect of hyperbilirubinemia on hearing threshold and auditory pathway in preterm infants by serial auditory brainstem response (ABR). In addition, we evaluate the usefulness of the unconjugated bilirubin (UCB) level compared with total serum bilirubin (TSB) on bilirubin-induced hearing loss. Methods: This study was conducted on 70 preterm infants with hyperbilirubinemia who failed universal newborn hearing screening by automated ABR. The diagnostic ABR was performed within 3 months after birth. Follow-up ABR was conducted in patients with abnormal results (30 cases). TSB and UCB concentration were compared according to hearing threshold by ABR. Results: The initial and maximal measured UCB concentration for the preterm infants of diagnostic ABR >=40 dB nHL group (n=30) were statistically higher compared with ABR <=35 dB nHL group (n=40) (P=0.031 and P=0.003, respectively). In follow-up ABR examination, 13 of the ABR >=40 dB nHL group showed complete recovery, but 17 had no change or worsened. There was no difference in bilirubin level between the recovery group and non-recovery group. Conclusion: UCB is a better predictor of bilirubin-induced hearing loss than TSB in preterm infants as evaluated by serial ABR. Serial ABR testing can be a useful, noninvasive methods to evaluate early reversible bilirubin-induced hearing loss in preterm infants. PMID- 30404413 TI - Immediate Effects of a Single Exercise on Behavior and Memory in the Early Period of Traumatic Brain Injury in Rats. AB - OBJECTIVE: To evaluate the immediate effect of single exercise on physical performance and memory in the early stage of traumatic brain injury (TBI) in rats. METHODS: Ninety TBI rats were randomly assigned to T0 (sedentary), T10 (treadmill 10 m/min for 30 minutes), or T20 (treadmill 20 m/min for 30 minutes) groups, on day 3 (D3), D7, and D14 after TBI, respectively. Rotarod (RR), Barnes maze (BM), brain magnetic resonance imaging (MRI) and MR spectroscopy were performed immediately before and 6 hours after exercise. Rats were sacrificed for immunohistochemistry with heat shock protein 70 (Hsp70) and glial fibrillary acidic protein (GFAP). RESULTS: On D3, the T10 and T20 groups demonstrated significant improvement in RR (p<0.05). On D7, only the T20 group showed significantly enhanced RR (p<0.05). In BM on D3, the T20 group showed significant deterioration compared with the other groups (p<0.05). Lesion volume did not significantly differ among the groups. MR spectroscopy on D3 showed that only the T20 group had significantly increased choline/creatine and 0.9/creatine (p<0.05). In the perilesional area on D3, only T20 had a significantly higher Hsp70 and GFAP than the T0 group. On D7, Hsp70 was significantly higher in the T20 group than in the T0 group (p<0.05). In the ipsilesional hippocampus on D3, the T20 group showed a significantly higher Hsp70 and GFAP than the T0 group (p<0.05). CONCLUSION: A single session of low-intensity exercise in the early period of TBI improves behavioral performance without inducing cognitive deficits. However, high-intensity exercise can exacerbate cognitive function in the early period after TBI. Therefore, the optimal timing of rehabilitation and exercise intensity are crucial in behavior and memory recovery after TBI. PMID- 30404414 TI - Comparison Between Neuromuscular Electrical Stimulation to Abdominal and Back Muscles on Postural Balance in Post-stroke Hemiplegic Patients. AB - OBJECTIVE: To compare the effects of neuromuscular electrical stimulation (NMES) to abdominal muscles and back muscles on postural balance in post-stroke hemiplegic patients. METHODS: Thirty post-stroke hemiplegic patients were prospectively enrolled and randomly assigned to one of the three groups: core muscle-strengthening exercise (CME) with NMES to abdominal muscles (group A), CME with NMES to back muscles (group B), and CME alone (group C). All subjects underwent their targeted interventions for 30 minutes each day, 5 days per week for 3 weeks under a conventional stroke rehabilitation program. Subjects were evaluated using Korean version of Berg Balance Scale (K-BBS), Trunk Impairment Scale (TIS), Korean version of Modified Barthel Index (K-MBI), Weight Distribution Index (WDI), and Stability Index (SI) just before and 3 weeks after intervention. RESULTS: Changes in K-BBS (p<0.05) and TIS (p<0.05) were significantly higher in group A (18.5+/-8.10, 6.6+/-1.90) and group B (19.9+/ 5.44, 7.0+/-2.26) than in group C (8.4+/-4.14, 3.1+/-0.99). However, K-MBI, WDI, and SI failed to show any significant difference. No significant difference in all outcomes was observed between groups A and B. CONCLUSION: The effect of NMES to the abdominal muscles was similar to the effect on back muscles in terms of postural balance. This finding indicated that the NMES to the abdominal muscles may be an alternative for post-stroke hemiplegic patients contraindicated for NMES to the back muscles. Additional studies investigating the effects of NMES on abdominal and back muscles are needed. PMID- 30404415 TI - Predictors of Community Participation Among Individuals With First Stroke: A Thailand Study. AB - OBJECTIVE: To describe perceived participation among persons with first stroke and to identify the predictors based on the International Classification of Functioning, Disability and Health (ICF) concept of participation after stroke. METHODS: A total of 121 participants completed 4 questionnaires: the Impact on Participation and Autonomy (IPA), Personal Resource Questionnaire (PRQ2000), Hospital Anxiety and Depression Scale (HADS), and personal history. They were evaluated for their balance, motor function, functional and walking ability. RESULTS: The majority of participants perceived participation restriction in family role as poor to very poor. The best predictors of participation included social support, walking and balance, functional ability, number of secondary health problems and affected side, account for 66.6% of the variances in participation. CONCLUSION: The study highlights the importance of social support, walking and balance performance, functional ability in daily living, and number of secondary health problems after stroke. These factors that facilitate participation after stroke should be addressed by health personnel during rehabilitation. PMID- 30404416 TI - Long-Term Outcomes of FIM Motor Items Predicted From Acute Stage NIHSS of Patients With Middle Cerebral Artery Infarct. AB - OBJECTIVE: To outline the association between the National Institutes of Health Stroke Scale (NIHSS) in the acute stage and the Functional Independence Measure (FIM) of motor items several months later. METHODS: Seventy-nine infarct cases with middle-cerebral-artery region transferred to long-term rehabilitation facilities were analyzed. Patients were allocated to either the model-development group or the confirmatory group at a 2:1 ratio. Independent variables were based on the NIHSS during the acute care and on demographic factors such as age and modified Rankin Scale (mRS) before onset. Multivariate logistic analyses were performed to predict the independence of each FIM motor item. These models were evaluated in the confirmatory group. RESULTS: Multivariate logistic analyses in the model-development group (n=53) indicated that at least one NIHSS item was statistically significantly associated with the functional independence of a single FIM motor item. Of the NIHSS items, the affected lower extremity item was the most widely associated with 11 of the FIM motor items, except for eating and shower transfer. The affected upper extremity function was the second widely involved factor associated with 7 of the FIM motor items including eating, grooming, bathing, toileting, bed transfer, toilet transfer, and shower transfer. Age and mRS were also statistically significant contributing factors. The obtained predictive models were assessed in the confirmatory group (n=26); these were successful except for the stairs climb item. CONCLUSION: In combination with age and pre-stroke status, the NIHSS items (especially the affected extremity items) may be useful for the prediction of long-term outcome in terms of activities in daily living. PMID- 30404417 TI - Influence of Hip Fracture on Knee Pain During Postoperative Rehabilitation. AB - OBJECTIVE: To investigate whether fracture type, surgical procedure, or fracture grade affect knee pain during postoperative rehabilitation after a hip fracture. METHODS: We conducted a retrospective case-controlled study of 139 patients during postoperative rehabilitation after surgery for hip fractures. Patients were divided into two groups: patients experiencing knee pain during the first week of postoperative rehabilitation, and patients without knee pain. We compared the types of fracture, surgical procedure, and fracture grade between the two groups. RESULTS: We enrolled 52 patients (37.4%) with knee pain during the first weeks of postoperative rehabilitation. For type of fracture, knee pain was more common with intertrochanteric fracture than with femur neck fracture (48.8% vs. 21.1%, respectively; p=0.001). For the surgical procedure, there was no significant difference between the groups. For the fracture grade, the grades classified as unstable fractures were more common in the group of intertrochanteric fracture patients with knee pain than in those without knee pain (74.1% vs. 36.4%, respectively; p=0.002). CONCLUSION: Intertrochanteric fracture affected knee pain after hip fracture surgery more than did femur neck fracture, particularly in unstable fractures. Furthermore, there was no difference in each fracture type according to the surgical procedure. Careful examination and management for knee pain is needed in patients with hip fracture surgery. PMID- 30404418 TI - A New Functional Scale and Ambulatory Functional Classification of Duchenne Muscular Dystrophy: Scale Development and Preliminary Analyses of Reliability and Validity. AB - OBJECTIVE: To develop a simplified functional scale and classification system to evaluate the functional abilities of patients with Duchenne muscular dystrophy (DMD). METHODS: A Comprehensive Functional Scale for DMD (CFSD) was developed using the modified Delphi method. The accompanying Ambulatory Functional Classification System for DMD (AFCSD) was developed based on previously published classification systems. RESULTS: The CFSD consists of 21 items and 78 sub-items, assessing body structure and function, activities, and participation. Inter-rater intraclass correlation coefficient values were above 0.7 for 17 items. The overall limits of agreement between the two examiners ranged from -6.21 to 3.11. The Spearman correlation coefficient between the total score on the AFCSD and the Vignos Functional Scale was 0.833, and 0.714 between the total score of the AFCSD and the Brooke scale. Significant negative correlations existed between the total score for each functional level of the AFCSD and each functional grade of the Vignos and Brooke scales. The total scores of the CFSD varied significantly between the functional grades of the Vignos scale, and specific grades of the Brooke scale. For the AFCSD, total scores of the CFSD varied significantly between the functional levels. CONCLUSION: We have developed a new scale and the associated classification system, to assess the functional ability of children diagnosed with DMD. Preliminary evaluation of the psychometric properties of the functional scale and classification systems indicate sufficient reliability and concurrent validity. PMID- 30404419 TI - Psychometric Properties of Three Fatigue Rating Scales in Individuals With Late Effects of Polio. AB - OBJECTIVE: To evaluate the psychometric properties of the Fatigue Severity Scale (FSS), the Fatigue Impact Scale (FIS), and the Multidimensional Fatigue Inventory (MFI-20) in persons with late effects of polio (LEoP). More specifically, we explored the data completeness, scaling assumptions, targeting, reliability, and convergent validity. METHODS: A postal survey including FSS, FIS, and MFI-20 was administered to 77 persons with LEoP. Responders received a second survey after 3 weeks to enable test-retest reliability analyses. RESULTS: Sixty-one persons (mean age, 68 years; 54% women) responded to the survey (response rate 79%). Data quality of the rating scales was high (with 0%-0.5% missing item responses), the corrected item-total correlations exceeded 0.4 and the scales showed very little floor or ceiling effects (0%-6.6%). All scales had an acceptable reliability (Cronbach's ? >=0.95) and test-retest reliability (intraclass correlation coefficient, >=0.80). The standard error of measurement and the smallest detectable difference were 7%-10% and 20%-28% of the possible scoring range. All three scales were highly correlated (Spearman's correlation coefficient rs=0.79 0.80; p<0.001). CONCLUSION: The FSS, FIS, and MFI-20 exhibit sound psychometric properties in terms of data completeness, scaling assumptions, targeting, reliability, and convergent validity, suggesting that these three rating scales can be used to assess fatigue in persons with LEoP. As FSS has fewer items and therefore is less time consuming it may be the preferred scale. However, the choice of scale depends on the research question and the study design. PMID- 30404420 TI - Golf Swing Rotational Velocity: The Essential Follow-Through. AB - OBJECTIVE: To evaluate if shoulder and pelvic angular velocities differ at impact or peak magnitude between professional and amateur golfers. Golf swing rotational biomechanics are a key determinant of power generation, driving distance, and injury prevention. We hypothesize that shoulder and pelvic angular velocities would be highly consistent in professionals. METHODS: Rotational velocities of the upper-torso and pelvis throughout the golf swing and in relation to phases of the golf swing were examined in 11 professionals and compared to 5 amateurs using three-dimensional motion analysis. RESULTS: Peak rotational velocities of professionals were highly consistent, demonstrating low variability (coefficient of variation [COV]), particularly upper-torso rotational velocity (COV=0.086) and pelvic rotational velocity (COV=0.079) during down swing. Peak upper-torso rotational velocity and peak X-prime, the relative rotational velocity of uppertorso versus pelvis, occurred after impact in follow-through, were reduced in amateurs compared to professionals (p=0.005 and p=0.005, respectively) and differentiated professionals from most (4/5) amateurs. In contrast, peak pelvic rotational velocity occurred in down swing. Pelvic velocity at impact was reduced in amateurs compared to professionals (p=0.019) and differentiated professionals from most (4/5) amateurs. CONCLUSION: Golf swing rotational velocity of professionals was consistent in pattern and magnitude, offering benchmarks for amateurs. Understanding golf swing rotational biomechanics can guide swing modifications to help optimize performance and prevent injury. PMID- 30404421 TI - Cost of Rehabilitation Treatment of Patients With Cerebral Palsy in Korea. AB - OBJECTIVE: To investigate rehabilitation treatment cost of patients with cerebral palsy (CP) according to age. METHODS: We analyzed the cost of rehabilitation treatment from 2007 to 2013 for patients diagnosed with CP by sourcing data from the National Health Information Database. RESULTS: While the number of recently born children requiring rehabilitation treatment has decreased, the number of patients requiring this treatment in other age groups has gradually increased. In addition, annual physical therapy, occupational therapy, hydrotherapy, and botulinum toxin injection treatment costs per person have increased. On the other hand, the number of orthopedic surgeries and selective dorsal rhizotomy performed has decreased. CONCLUSION: This study investigated trends in the cost of treatment for patients with CP. This study can be used as a basis to provide treatment support for patients with CP. PMID- 30404422 TI - Disability Registration State of Children With Cerebral Palsy in Korea. AB - OBJECTIVE: To investigate the disability registration state of children with cerebral palsy (CP) in Korea. METHODS: Based on the National Health Information Database, the disability registration state was examined for brain lesion disability and other possible complicated disabilities accompanying brain disorder in children diagnosed with CP aged up to 5 years old who were born between 2002 and 2008. RESULTS: Of children diagnosed with CP, 73.1% were registered as having brain lesion disability for the first time before they turned 2 years old. The younger the children, the more likely they will have 1st and 2nd degree disability. However, when the age of children is increased, such likelihood is decreased. The percentage of children registered as having overlapping disabilities was 7%-20%. CONCLUSION: It is important to establish a more accurate standard to rate disability and provide national support systems for children with CP with various severities and multiple disabilities. By reorganizing the current disability registration system for pediatric brain lesions, the system could serve as a classification standard to provide medical and social welfare services. PMID- 30404423 TI - Parents' Perspectives and Clinical Effectiveness of Cranial-Molding Orthoses in Infants With Plagiocephaly. AB - OBJECTIVE: To investigate the clinical effectiveness of and parents' perspectives on cranial-molding orthotic treatment. METHODS: Medical charts were reviewed for 82 infants treated for plagiocephaly with cranial-molding orthoses in our clinic from April 2012 to July 2016 retrospectively. Infants who were clinically diagnosed with positional plagiocephaly and had a Cranial Vault Asymmetry Index (CVAI) of more than 3.5% were included. Pre- and post-treatment CVAI was obtained by three-dimensional head-surface laser scan. Parents' perceptions of good outcome (satisfaction) were evaluated with the Goal Attainment Scale (GAS). The GAS score assessed how much the parent felt that his or her initial goal for correcting the skull asymmetry was achieved after the treatment. RESULTS: The compliance with cranial-molding orthoses was 90.2% (74 of 82 infants). There were 53 infants (65% of the 82 infants) who had adverse events with the cranial molding orthoses during the study. Heat rash was found in 29 cases (35.4%) and was the most common adverse event. The mean GAS T-score was 51.9+/-10.2. A GAS T score of 0 or more was identified for 71.6% of parents. The GAS T-score was significantly related to the age (p<0.001), the initial CVAI, and the difference of CVAI during the treatment (p<0.001). CONCLUSION: Parents' perception of good outcome was correlated with the anthropometric improvement in cranialmolding orthotic treatment in infants with plagiocephaly. A high percentage of parents felt that the treatment met their initial goals in spite of a high occurrence of adverse events. PMID- 30404424 TI - Effect of Type D Personality on Short-Term Cardiac Rehabilitation in Patients With Coronary Artery Disease. AB - OBJECTIVE: To investigate the effect of type D personality on cardiac rehabilitation (CR) participation rates and the effect of a short-term CR program. METHODS: Study participants included patients diagnosed with acute coronary syndrome who underwent percutaneous coronary intervention. Patients completed the Type D personality Scale (DS-14) and the Hospital Anxiety and Depression Scale (HADS) at program entry. Subjects were recommended participation in 6 weeks of CR exercise training. Cardiopulmonary exercise test (CPET) was conducted before and after completion of the training. CR participation refers to completion of the 6-week CR exercise program and performance of the secondary CPET. Drop-out refers to the subjects who were unable to participate in the 6 week CR exercise program or to perform the secondary CPET. RESULTS: At baseline, type D personality was evident in 21 of 63 patients (33.3%). Type D patients were more often depressed (57.1%) and anxious (38.1%) than non-type D patients (31.0% and 9.5%, respectively). At baseline, participants with type D personality showed a decreased body mass index (24.6 vs. 26.1 kg/m2, p=0.025). The type D group displayed a lower CR participation rate (5/21, 23.8%) compared with the non-type D group of (22/42, 52.4%). Logistic regression analysis revealed the association of type D personality with CR drop-out rate (odds ratio=3.87; 95% confidence interval, 1.2-12.5; p<0.05). CONCLUSION: Type D personality was independently associated with drop-out from CR program and with significantly higher levels of anxiety and depressive mood. PMID- 30404426 TI - Limitation of Intraoperative Transcranial Electrical Stimulation-Motor Evoked Potential Monitoring During Brain Tumor Resection Adjacent to the Primary Motor Cortex. AB - Transcranial electrical stimulation-motor evoked potential (TES-MEP) is a valuable intraoperative monitoring technique during brain tumor surgery. However, TES can stimulate deep subcortical areas located far from the motor cortex. There is a concern about false-negative results from the use of TES-MEP during resection of those tumors adjacent to the primary motor cortex. Our study reports three cases of TES-MEP monitoring with false-negative results due to deep axonal stimulation during brain tumor resection. Although no significant change in TES MEP was observed during surgery, study subjects experienced muscle weakness after surgery. Deep axonal stimulation of TES could give false-negative results. Therefore, a combined method of TES-MEP and direct cortical stimulation-motor evoked potential (DCS-MEP) or direct subcortical stimulation should be considered to overcome the limitation of TES-MEP. PMID- 30404425 TI - Evaluating Korean Personal Assistance Services Classification System. AB - OBJECTIVE: To evaluate the utility of using the Personal Assistance Services classification system (PAS-CS) that examines individuals with disabilities for services and government funding. To this end, this study also tests for significant differences in PAS-CS scores across disability grades and disability types. METHODS: A retrospective analysis was conducted using the 2014 National Survey on People with Disabilities (NSPD) data set. We selected patients with three types of disabilities (physical disabilities, brain lesions, and visual impairments). We compared the average PAS-CS scores of patients with different disability types and grades using general linear models with multiple comparisons. RESULTS: A total of 4,810 patients were included in the analysis. Patients with brain lesions had the highest average PAS-CS scores in activities of daily living (ADL) and instrumental activities of daily living (IADL) domains. Patients with visual impairments had the highest average scores in 'Disease specific disability' and 'Social-environment' domains. For patients with physical disabilities and visual impairments, no PAS-CS domains were significantly different between patients with disability grade III and those with disability grade IV (p>0.05). CONCLUSION: The PAS-CS scores of disability grades were not equivalent among individuals with different disability types. The Korean Ministry of Health and Welfare currently only considers certain disability grades for PAS preeligibility, as a result disregarding the characteristics of different disability types. Thus, the current PAS-CS requires modifications. PMID- 30404427 TI - Spinal Accessory Nerve Injury Induced by Manipulation Therapy: A Case Report. AB - Spinal accessory nerve (SAN) injury mostly occurs during surgical procedures. SAN injury caused by manipulation therapy has been rarely reported. We present a rare case of SAN injury associated with manipulation therapy showing scapular winging and droopy shoulder. A 42-year-old woman visited our outpatient clinic complaining of pain and limited active range of motion (ROM) in right shoulder and scapular winging after manipulation therapy. Needle electromyography and nerve conduction study suggested SAN injury. Physical therapy (PT) three times a week for 2 weeks were prescribed. After a total of 6 sessions of PT and modality, the patient reported that the pain was gradually relieved during shoulder flexion and abduction with improved active ROM of shoulder. Over the course of 2 months follow-up, the patient reported almost recovered shoulder ROM and strength as before. She did not complain of shoulder pain any more. PMID- 30404428 TI - Renal replacement therapy in neonates with an inborn error of metabolism. AB - Hyperammonemia can caused by several different genetic inborn errors of metabolism including urea cycle defects, organic acidemias, fatty acid oxidation defects, and certain disorders of amino acid metabolism. High levels of ammonia are extremely neurotoxic, leading to astrocyte swelling, brain edema, coma, severe disability, and even death. Thus, emergency treatment for hyperammonemia must begin before a precise diagnosis is established. In neonates with hyperammonemia caused by an inborn error of metabolism, a few studies have suggested that peritoneal dialysis, intermittent hemodialysis, and continuous renal replacement therapy are effective modalities for decreasing plasma level of ammonia. In this review, we discuss the current literature related to the use of renal replacement therapy for treating neonates with hyperammonemia caused by an inborn error of metabolism, including optimal prescriptions, prognosis, and outcomes. We also review the literature on new technologies and instrumentation for renal replacement therapy in small babies. PMID- 30404429 TI - High antistreptolysin O titer is associated with coronary artery lesions in patients with Kawasaki disease. AB - Purpose: In Kawasaki disease(KD) patients, coronary artery complications, incomplete and refractory types occur more frequently in patients with streptococcal or other bacterial/viral infections. Recently, we observed a higher incidence of coronary lesions in KD patients with high anti-streptolysin O(ASO) titer. Therefore, we hypothesized that KD patients diagnosed with concurrent streptococcal infection have poor prognosis, with respect to treatment response and development of coronary artery lesions. Methods: A retrospective review was performed in 723 patients with KD who were admitted to two major hospitals between June 2010 and September 2017. Results: Among 723 patients with KD, 11 initially showed an elevated ASO titer (> 320 IU/mL) or elevated follow-up ASO titer after treatment. Of these patients, 5 showed no response to the first IVIG treatment, 3 had abnormalities of the coronary arteries. This is a significantly higher proportion of patients with a high ASO titer (n = 3; 27.3%) than those with a normal ASO titer (n = 53; 7.4%, P = 0.047). A severe clinical course was seen in 81.8% of patients in the high ASO group versus 14.5% of patients in the normal ASO group. Conclusion: It is not certain whether acute streptococcal infection may cause KD, but this study revealed that KD with high ASO titers showed higher rates of severe clinical course. It may be helpful to analyze concurrent streptococcal infection in patients with a severe clinical course. PMID- 30404430 TI - Particulate matter and childhood allergic diseases. AB - Particulate matter (PM) is a ubiquitous air pollutant that is a growing public health concern. Previous studies have suggested that PM is associated with asthma development and exacerbation of asthma symptoms. Although several studies have suggested increased risks of atopic dermatitis, allergic rhinitis, and allergic sensitization in relation to PM exposure, the evidence remains inconsistent. The plausible mechanisms underlying these effects are related to oxidative stress, enhancement of sensitization to allergens, inflammatory and immunological responses, and epigenetics. This review discusses the effect of PM on childhood allergic diseases, along with plausible mechanisms. Further studies are required to understand the role of PM exposure on childhood allergic diseases to reduce childhood allergic diseases. PMID- 30404431 TI - Remote ischemic preconditioning: the hunt is still open. PMID- 30404432 TI - Molecular Similarity-Based Domain Applicability Metric Efficiently Identifies Out of-Domain Compounds. AB - Domain applicability (DA) is a concept introduced to gauge the reliability of quantitative structure-activity relationship (QSAR) predictions. A leading DA metric is ensemble variance, which is defined as the variance of predictions by an ensemble of QSAR models. However, this metric fails to identify large prediction errors in melting point (MP) data, despite the availability of large training data sets. In this study, we examined the performance of this metric on MP data and found that, for most molecules, ensemble variance increased as their structural similarity to the training molecules decreased. However, the metric decreased for "out-of-domain" molecules, i.e., molecules with little to no structural similarity to the training compounds. This explains why ensemble variance fails to identify large prediction errors. In contrast, a new molecular similarity-based DA metric that considers the contributions of all training molecules in gauging the reliability of a prediction successfully identified predictions of MP data for which the errors were large. To validate our results, we used four additional data sets of diverse molecular properties. We divided each data set into a training set and a test set at a ratio of approximately 2:1, ensuring a small fraction of the test compounds are out of the training domain. We then trained random forest (RF) models on the training data and made RF predictions for the test set molecules. Results from these data sets confirm that the new DA metric significantly outperformed ensemble variance in identifying predictions for out-of-domain compounds. For within-domain compounds, the two metrics performed similarly, with ensemble variance marginally but consistently outperforming the new DA metric. The new DA metric, which does not rely on an ensemble of QSAR models, can be deployed with any machine-learning method, including deep neural networks. PMID- 30404433 TI - Tightly Sealed 3D Lipid Structure Monolithically Generated on Transparent SU-8 Microwell Arrays for Biosensor Applications. AB - Artificial lipid membranes are excellent candidates for new biosensing platforms because their structures are similar to cell membranes and it is relatively easy to modify the composition of the membrane. The freestanding structure is preferable for this purpose because of the more manageable reconstitution of the membrane protein. Therefore, most of the lipid membranes for biosensing are based on two-dimensional structures that are fixed on a solid substrate (unlike floating liposomes) even though they have some disadvantages, such as low stability, small surface area, and potential retention of solvent in the membrane. In this paper, three-dimensional freestanding lipid bilayer (3D FLB) arrays were fabricated uniformly on SU-8 microwells without any toxic solvent. The 3D FLBs have better stability and larger surface area due to their cell-like structure. In order to improve the sealing characteristics of the 3D FLBs, the applied frequency of the ac field was controlled during the electroformation. The 3D FLBs were observed through transparent SU-8 microwell arrays using confocal microscopy and demonstrated perfect sealing until 5.5 days after the electroformation at more than 1 kHz. Also, the details of the sealing of a fixed 3D freestanding lipid structure were discussed for the first time. The unilamellarity and biofunctionality of the 3D FLBs were verified by a transport protein (alpha-hemolysin) assay. PMID- 30404435 TI - Recent Advances in Microfluidic Techniques for Systems Biology. PMID- 30404434 TI - Wearable, Luminescent Oxygen Sensor for Transcutaneous Oxygen Monitoring. AB - We present a new concept for a wearable oxygen (O2) sensor for transcutaneous O2 pressure (tcpO2) monitoring by combining the technologies of luminescent gas sensing and wearable devices. O2 monitoring has been exhaustively studied given its central role in diagnosing various diseases. The ability to quantify the physiological distribution and real-time dynamics of O2 from the subcellular to the macroscopic level is required to fully understand mechanisms associated with both normal physiological and pathological conditions. Despite its profound biological and clinical importance, few effective methods exist for noninvasively quantifying O2 in a physiological setting. The wearable sensor developed here consists of three components: a luminescent sensing film attached onto skin by a carbon tape, an organic light-emitting diode (OLED) as a light source, and an organic photodiode (OPD) as a light detector. All the components are solution processable and integrated on a plane in a bandage-like configuration. To verify the performance, tcpO2 variations by pressure-induced occlusion were measured in the lower arm and a thumb by the wearable sensor, and the results were comparable to those measured by a commercial instrument. In addition to its flexibility, other features of this sensor render it a potential low-cost solution for the simultaneous monitoring of tcpO2 in any part of a body. PMID- 30404436 TI - Dual-Responsive Doxorubicin-Conjugated Polymeric Micelles with Aggregation Induced Emission Active Bioimaging and Charge Conversion for Cancer Therapy. AB - In recent years, intelligent polymeric micelles with multifunctions are in urgent demand for cancer diagnosis and therapy. Herein, pH and redox dual-responsive prodrug micelles with aggregation-induced emission (AIE) active cellular imaging and charge conversion have been prepared for combined chemotherapy and bioimaging based on a novel doxorubicin-conjugated amphiphilic PMPC-PAEMA-P (TPE- co-HD)-ss P (TPE- co-HD)-PAEMA-PMPC copolymer. The doxorubicin is conjugated via a pH cleavable imine linkage and can be packed in the hydrophobic core along with the glutathione (GSH)-sensitive disulfide bond. The DOX-conjugated inner core is sealed with a pH-responsive PAEMA as the "gate", which would rapidly open in the acidic condition, following the drug release and charge conversion-mediated acceleration of endocytosis. After an efficient internalization, the disulfide bond can be cleaved by the high concentration of GSH causing the further accelerated drug release. Meanwhile, intracellular drug delivery can be traced due to the AIE behavior of micelles. Moreover, great tumor inhibition in vitro and in vivo has been demonstrated for these DOX-conjugated micelles. This smart prodrug micelle system would be a desirable drug carrier for cancer therapy and bioimaging. PMID- 30404437 TI - Single-Molecule Tracking Approaches to Protein Synthesis Kinetics in Living Cells. AB - Decades of traditional biochemistry, structural approaches, and, more recently, single-molecule-based in vitro techniques have provided us with an astonishingly detailed understanding of the molecular mechanism of ribosome-catalyzed protein synthesis. However, in order to understand these details in the context of cell physiology and population biology, new techniques to probe the dynamics of molecular processes inside the cell are needed. Recent years' development in super-resolved fluorescence microscopy has revolutionized imaging of intracellular processes, and we now have the possibility to directly peek into the microcosm of biomolecules in their native environment. In this Perspective, we discuss how these methods are currently being applied and further developed to study the kinetics of protein synthesis directly inside living cells. PMID- 30404438 TI - Integrin alphavbeta3-Targeted [64Cu]CuS Nanoparticles for PET/CT Imaging and Photothermal Ablation Therapy. AB - Copper sulfide (CuS) nanoparticles have been considered one of the most clinical relevant nanosystems because of their straightforward chemistry, small particle size, low toxicity, and intrinsic theranostic characteristics. In our previous studies, radioactive [64Cu]CuS nanoparticles were successfully developed to be used as efficient radiotracers for positron emission tomography and for photothermal ablation therapy of cancer cells using near-infrared laser irradiation. However, the major challenge of CuS nanoparticles as a theranostic platform is the lack of a means for effective targeted delivery to the tumor site. To overcome this challenge, we designed and synthesized angiogenesis targeting [64Cu]CuS nanoparticles, which are coupled with cyclic RGDfK peptide [c(RGDfK)] through polyethylene glycol (PEG) linkers using click chemistry. In assessing their tumor-targeting efficacy, we found that the tumor uptakes of [64Cu]CuS-PEG-c(RGDfK) nanoparticles at 24 h after intravenous injection were significantly greater (8.6% +/- 1.4% injected dose/gram of tissue) than those of nontargeted [64Cu]CuS-PEG nanoparticles (4.3% +/- 1.2% injected dose/gram of tissue, p < 0.05). Irradiation of tumors in mice administered [64Cu]CuS-PEG c(RGDfK) nanoparticles induced 98.7% necrotic areas. In contrast, irradiation of tumors in mice administered nontargeted CuS-PEG nanoparticles induced 59% necrotic areas ( p < 0.05). The angiogenesis-targeting [64Cu]CuS nanoparticles may serve as a promising platform for image-guided ablation therapy with high efficacy and minimal side effects in future clinical translation of this novel class of multifunctional nanomaterials. PMID- 30404439 TI - Chiral Supramolecular U-Shaped Catalysts Induce the Multiselective Diels-Alder Reaction of Propargyl Aldehyde. AB - The Diels-Alder reaction, which is a traditional [4 + 2] cycloaddition with two carbon-carbon bond formations, is one of the most powerful tools to synthesize versatile and unique six-membered rings. We show that chiral supramolecular U shaped boron Lewis acid catalysts promote the unprecedented multiselective Diels Alder reaction of propargyl aldehyde with cyclic dienes. Independent from the substrate control, enantio-, endo/exo-, pi-facial-, regio-, site-, and substrate selectivities could be controlled by the present U-shaped catalysts. The obtained reaction products could access the concise synthesis of chiral diene ligands and a key intermediate of (+)-sarkomycin. The results presented here might partially contribute to the development of artificial enzyme-like supramolecular catalysts for multiselective reactions, which will be able to target organic compounds that have thus far eluded synthesis. PMID- 30404440 TI - Antagonists for Constitutively Active Mutant Estrogen Receptors: Insights into the Roles of Antiestrogen-Core and Side-Chain. AB - A major risk for patients having estrogen receptor alpha (ERalpha)-positive breast cancer is the recurrence of drug-resistant metastases after initial successful treatment with endocrine therapies. Recent studies have implicated a number of activating mutations in the ligand-binding domain of ERalpha that stabilize the agonist conformation as a prominent mechanism for this acquired resistance. There are several critical gaps in our knowledge regarding the specific pharmacophore requirements of an antagonist that could effectively inhibit all or most of the different mutant ERs. To address this, we screened various chemotypes for blocking mutant ER-mediated transcriptional signaling and identified RU58668 as a model compound that contains structural elements that support potent ligand-induced inhibition of mutant ERs. We designed and synthesized a focused library of novel antagonists and probed how small and large perturbations in different ligand structural regions influenced inhibitory activity on individual mutant ERs in breast cancer cells. Effective inhibition derives from both nonpolar and moderately polar motifs in a multifunctional side chain of the antagonists, with the nature of the ligand core making important contributions by increasing the potency of ligands possessing similar types of side chains. Some of our new antagonists potently blocked the transcriptional activity of the three most common mutant ERs (L536R, Y537S, D538G) and inhibited mutant ER-mediated cell proliferation. Supported by our molecular modeling, these studies provide new insights into the role of specific components, involving both the ligand core and multifunctional side chain, in suppressing wild-type and mutant ER-mediated transcription and breast cancer cell proliferation. PMID- 30404441 TI - Toward Locard's Exchange Principle: Recent Developments in Forensic Trace Evidence Analysis. PMID- 30404442 TI - ChiE1 from Coprinopsis cinerea is Characterized as a Processive Exochitinase and Revealed to Have a Significant Synergistic Action with Endochitinase ChiIII on Chitin Degradation. AB - Fruiting bodies that exhibit strong autolysis of Coprinopsis cinerea are a good resource for the chitinolytic system. In this study, a new Chitinase ChiE1 from C. cinerea was cloned, heterologously expressed, and characterized. Biochemical analysis demonstrated that ChiE1 is an exochitinase with a processive mode of action. Although ChiE1 contains only a single catalytic domain without a binding domain, it can bind to and degrade insoluble chitin powder and colloidal chitin. The combination of ChiE1 and C. cinerea endochitinase ChiIII could increase the amount of reducing sugar released from chitin powder by approximately 120% compared to using ChiE1 and ChiIII alone. The synergistic action of ChiE1 and ChiIII on degradation of chitin powder is higher than all previously reported synergism of chitinases. The recombinant Chitinase ChiE1 expressed in Pichia pastoris may be used as a synergistic chitinase for a reconstituted chitinolytic system for agricultural, biological, and environmental applications. PMID- 30404443 TI - Citrate-Coated, Size-Tunable Octahedral Platinum Nanocrystals: A Novel Route for Advanced Electrocatalysts. AB - The development of green and scalable syntheses for the preparation of size- and shape-controlled metal nanocrystals is of high interest in many areas, including catalysis, electrocatalysis, nanomedicine, and electronics. In this work, a new synthetic approach based on the synergistic action of physical parameters and reagents produces size-tunable octahedral Pt nanocrystals, without the use of catalyst-poisoning reagents and/or difficult-to-remove coatings. The synthesis requires sodium citrate, ascorbic acid, and fine control of the reduction rate in aqueous environment. Pt octahedral nanocrystals with particle size as low as 7 nm and highly developed {111} facets have been achieved, as demonstrated by transmission electron microscopy, X-ray diffraction, and electrochemical methods. The absence of sticky molecules together with the high quality of the surface makes these nanocrystals ideal candidates in electrocatalysis. Notably, 7 nm bismuth-decorated octahedral nanocrystals exhibit superior performance for the electrooxidation of formic acid in terms of both specific and mass activities. PMID- 30404444 TI - Enhanced Plasmonic Particle Trapping Using a Hybrid Structure of Nanoparticles and Nanorods. AB - Plasmon-enhanced particle trapping was demonstrated using a hybrid structure of nanoparticles and nanorods. In order to intensify localized surface plasmon resonance (LSPR), gold nanoparticles (AuNPs) were deposited on zinc oxide nanorods (ZnONRs). The synergistic effect caused by the hybrid structure was identified experimentally. Numerical analysis revealed that the LSPR-induced photophysical processes such as plasmonic heating and near-field enhancement were improved by the existence of ZnONRs. The role of the ZnONR in enhancing the particle-trapping velocity was explored by examining the scattered electric field, Poynting vector, and temperature gradient over the nanostructures calculated from the simulation. It was found that polystyrene microparticles and Escherichia coli cells were successfully trapped by using the ZnONR/AuNP plasmonic structure. A relatively high dielectric constant and nanorod geometry of ZnO enabled the hybrid substrate to enhance trapping performance, compared with a control case fabricated using only gold nanoislands. PMID- 30404445 TI - Coupled Multimodal Dynamics of Hydrogen-Containing Ion Networks in Water Deficient, Sodium Hydroxide-Aluminate Solutions. AB - The (meta)stability of low water activity sodium hydroxide/aluminate (Na+OH /Al(OH)4-) electrolytes dictates kinetics in the Bayer process for aluminum refining and high-level nuclear waste processing. We utilized quasi-elastic neutron scattering (QENS) and proton nuclear magnetic resonance spectroscopy (1H NMR) in extremely concentrated sodium aluminate solutions to investigate the picosecond (ps) to microsecond (ms) timescale motions of H-bearing species (Al(OH)4- monomers/clusters, OH- and H2O). In the QENS data, in contrast to typical liquids, no short-time translational diffusion was observed at 293 K, but two types of localized motions were found: (i) local backbone tumbling or a formation of large hydrated ion clusters on the order of 40-60 ps; and (ii) much slower, complex, and collective dynamics of the ensemble of H-bearing species on the order of 350-750 ps. Variable temperature, pulsed field gradient, diffusion ordered 1H NMR was used to determine the ensemble translational motion along with relaxometry to calculate rotational correlation coefficients. The ensemble rotational correlation times were on the order of 184-300 ps from 1H NMR, which is consistent with the timescale of the QENS components. Complementary molecular dynamics simulation of NaOH solutions exhibit extensive ion networks potentially responsible for the observed dynamical coupling of water with the motion of large hydrated ion clusters. Understanding these collective motions will aid in predicting the behavior of complex solutions during aluminum production and during nuclear waste processing. PMID- 30404446 TI - Spectroscopy and Stability of AlOP: A Possible Progenitor of Interstellar Metal. AB - Standard and explicitly correlated coupled cluster theory computations in conjunction with large basis sets are performed to characterize the [Al,P,O] isomers. Three isomers, namely linear-AlOP, bent-AlOP and linear-OAlP, are found as stable species. Their optimized equilibrium geometries, harmonic vibrational frequencies, rotational constants and relative energies are deduced. In addition, a set of spectroscopic parameters is generated from the three-dimensional potential energy surfaces (3D-PESs) of each isomer at the (R)CCSD(T)/aug-cc-pV5Z level. Linear isomers have X3?- electronic ground state and are characterized as weakly bound systems or floppy molecules, due to their low frequency bending modes (< 150 cm-1). The dipole moment of linear-AlOP is evaluated 1.48 Debye. A much larger dipole moment is computed for linear-OAlP (5.01 Debye), indicating less ionic character in AlOP. OAlP isomer is thus a good candidate to be detected in interstellar media by radioastronomy. PMID- 30404447 TI - Understanding the Alkylation of a Phenol by 1-(3-Chloropropyl)pyrrolidine: Evidence for the Intermediacy of an Azetidinium Ion. AB - The final synthetic step in the synthesis of cediranib, AZD2171, 1, is the alkylation of a phenol with an alkyl halide to generate an ether. Our need to understand and control the formation of synthetic impurities generated in this step of the synthesis led us to investigate the kinetics and mechanism of the alkylation of indolphenol, 2, 4-[(4-fluoro-2-methyl-1 H-indol-5-yl)oxy]-6 methoxyquinazolin-7-ol, by chloropyrrolidine, 3, 1-(3-chloropropyl)pyrrolidine. Studies in 1-methyl-2-pyrrolidinone (NMP) established that the active alkylating agent is the azetidinium ion, 4, 4-azoniaspiro[3.4]octane, formed via a slow intramolecular cyclization reaction of chloropyrrolidine, 3. The azetidinium ion was isolated as its tetraphenylborate salt from water by heating 3 in the presence of aqueous potassium tetraphenyl borate, and its competence as an intermediate was demonstrated by its fast reaction with 2 to yield cediranib, 1. PMID- 30404448 TI - Single Amino Acid Variant Discovery in Small Numbers of Cells. AB - We have performed deep proteomic profiling down to as few as 9 Panc-1 cells using sample fractionation, TMT multiplexing, and a carrier/reference strategy. Off line fractionation of the TMT-labeled sample pooled with TMT-labeled carrier Panc 1 whole cell proteome was achieved using alkaline reversed phase spin columns. The fractionation in conjunction with the carrier/reference (C/R) proteome allowed us to detect 47 414 unique peptides derived from 6261 proteins, which provided a sufficient coverage to search for single amino acid variants (SAAVs) related to cancer. This high sample coverage is essential in order to detect a significant number of SAAVs. In order to verify genuine SAAVs versus false SAAVs, we used the SAVControl pipeline and found a total of 79 SAAVs from the 9-cell Panc-1 sample and 174 SAAVs from the 5000-cell Panc-1 C/R proteome. The SAAVs as sorted into high confidence and low confidence SAAVs were checked manually. All the high confidence SAAVs were found to be genuine SAAVs, while half of the low confidence SAAVs were found to be false SAAVs mainly related to PTMs. We identified several cancer-related SAAVs including KRAS, which is an important oncoprotein in pancreatic cancer. In addition, we were able to detect sites involved in loss or gain of glycosylation due to the enhanced coverage available in these experiments where we can detect both sites of loss and gain of glycosylation. PMID- 30404449 TI - Electronic Excitations in Complex Molecular Environments: Many-Body Green's Functions Theory in VOTCA-XTP. AB - Many-body Green's functions theory within the GW approximation and the Bethe Salpeter Equation (BSE) is implemented in the open-source VOTCA-XTP software, aiming at the calculation of electronically excited states in complex molecular environments. Based on Gaussian-type atomic orbitals and making use of resolution of identity techniques, the code is designed specifically for nonperiodic systems. Application to a small molecule reference set successfully validates the methodology and its implementation for a variety of excitation types covering an energy range from 2 to 8 eV in single molecules. Further, embedding each GW-BSE calculation into an atomistically resolved surrounding, typically obtained from Molecular Dynamics, accounts for effects originating from local fields and polarization. Using aqueous DNA as a prototypical system, different levels of electrostatic coupling between the regions in this GW-BSE/MM setup are demonstrated. Particular attention is paid to charge-transfer (CT) excitations in adenine base pairs. It is found that their energy is extremely sensitive to the specific environment and to polarization effects. The calculated redshift of the CT excitation energy compared to a nucelobase dimer treated in vacuum is of the order of 1 eV, which matches expectations from experimental data. Predicted lowest CT energies are below that of a single nucleobase excitation, indicating the possibility of an initial (fast) decay of such an UV excited state into a binucleobase CT exciton. The results show that VOTCA-XTP's GW-BSE/MM is a powerful tool to study a wide range of types of electronic excitations in complex molecular environments. PMID- 30404450 TI - Elimination of Finite-Size Effects on Binding Free Energies via the Warp-Drive Method. AB - The accurate calculation of protein-ligand binding free energies is necessary for computer-aided drug design. The alchemical perturbation method frequently used for binding free energy calculations under periodic boundary conditions suffers from finite-size effects related to the cell-size dependence of the charging free energy at different cell sizes. The finite-size effect on the binding free energy of charged ligands is not negligible in comparison to the binding free energy itself. In this study, we propose an effective perturbation protocol for calculating the binding free energy termed the "warp-drive" method for eliminating the finite-size effect. When the warp-drive method is applied, a solution system consisting of a protein-ligand complex and an unbound ligand located at a distant position is used. Diminished partial charges of the bound ligand simultaneously emerge in the other unbound ligand, and in turn, the total charge of the system does not change at all intermediate states. To assess the performance of the warp-drive method, charging free energies for systematically varied cell sizes are examined and compared to those calculated via alchemical perturbation. In contrast to that of alchemical perturbation, the charging free energy obtained via the warp-drive method does not exhibit finite-size effects, even for typical cell sizes without any corrections, and this result is in good agreement with that calculated on the basis of alchemical perturbation levels measured from large cells with full corrections of the finite-size effect. This finding reveals an advantage of the warp-drive method, as alchemical perturbation is computationally costly due to the large cell sizes and specificities involved in correction schemes depending on the total charge of proteins and components of solvent molecules. PMID- 30404451 TI - Battle against Vancomycin-Resistant Bacteria: Recent Developments in Chemical Strategies. AB - Vancomycin, a natural glycopeptide antibiotic, was used as the antibiotic of last resort for the treatment of multidrug-resistant Gram-positive bacterial infections. However, almost 30 years after its use, resistance to vancomycin was first reported in 1986 in France. This became a major health concern, and alternative treatment strategies were urgently needed. New classes of molecules, including semisynthetic antibacterial compounds and newer generations of the previously used antibiotics, were developed. Semisynthetic derivatives of vancomycin with enhanced binding affinity, membrane disruption ability, and lipid binding properties have exhibited promising results against both Gram-positive and Gram-negative bacteria. Various successful approaches developed to overcome the acquired resistance in Gram-positive bacteria, intrinsic resistance in Gram negative bacteria, and other forms of noninherited resistance to vancomycin have been discussed in this Perspective. PMID- 30404452 TI - Adsorption of Pluronic Surfactants in Alkylene Carbonates on Silica. AB - Adsorption of triblock Pluronic surfactants bearing poly(ethylene oxide) (PEO) chains of different lengths, L-62 (5 EO groups on each end), L-64 (13 EO groups on each end), and F-68 (79 EO groups on each end), on silica has been characterized using atomic force microscopy (AFM). The solvent used herein was a mixture of ethylene carbonate (EC) and propylene carbonate (PC). The three Pluronic surfactants were dissolved in the mixed solvent, with the PEO chain acting as a solvophilic group and the poly(propylene oxide) (PPO) chain acting as a solvophobic group. The approaching force curve measurements for the three Pluronics (at 10 mmol dm-3) revealed repulsive forces from an apparent separation of 20-30 nm. The most solvophilic Pluronic surfactant with the longest PEO chain (F-68) showed continuously increasing repulsive interaction with decreasing separation. The Milner-Witten-Cates (MWC) theory described the repulsive force curve data of F-68, suggesting that F-68 forms a polymer brush on the silica surface. The retracting force curve measurements detected stretching forces for the three Pluronic systems. These stretching forces were observed more frequently for the L-62 system than for the F-68 system, but the pull-off distance was shorter for L-62 than for F-68. PMID- 30404453 TI - Identifying Electronic Modes by Fourier Transform from delta-Kick Time-Evolution TDDFT Calculations. AB - Time-dependent density-functional theory (TDDFT) is widely used for calculating electron excitations in clusters and large molecules. For optical excitations, TDDFT is customarily applied in two distinct approaches: transition-based linear response TDDFT (LR-TDDFT) and the real-time formalism (RT-TDDFT). The former directly provides the energies and transition densities of the excitations, but it requires the calculation of a large number of empty electron states, which makes it cumbersome for large systems. By contrast, RT-TDDFT circumvents the evaluation of empty orbitals, which is especially advantageous when dealing with large systems. A drawback of the procedure is that information about the nature of individual spectral features is not automatically obtained, although it is of course contained in the time-dependent induced density. Fourier transform of the induced density has been used in some simple cases, but the method is, surprisingly, not widely used to complement the RT-TDDFT calculations; although the reliability of RT-TDDFT spectra is now widely accepted, a critical assessment for the corresponding transition densities and a demonstration of the technical feasibility of the Fourier-transform evaluation for general cases is still lacking. In the present work, we show that the transition densities of the optically allowed excitations can be efficiently extracted from a single delta kick time-evolution calculation even in complex systems like noble metals. We assess the results by comparison with the corresponding LR-TDDFT ones and also with the induced densities arising from RT-TDDFT simulations of the excitation process. PMID- 30404454 TI - Spectral directional cues captured by hearing device microphones in individual human ears. AB - Spatial hearing abilities with hearing devices ultimately depend on how well acoustic directional cues are captured by the microphone(s) of the device. A comprehensive objective evaluation of monaural spectral directional cues captured at 9 microphone locations integrated in 5 hearing device styles is presented, utilizing a recent database of head-related transfer functions (HRTFs) that includes data from 16 human and 3 artificial ear pairs. Differences between HRTFs to the eardrum and hearing device microphones were assessed by descriptive analyses and quantitative metrics, and compared to differences between individual ears. Directional information exploited for vertical sound localization was evaluated by means of computational models. Directional information at microphone locations inside the pinna is significantly biased and qualitatively poorer compared to locations in the ear canal; behind-the-ear microphones capture almost no directional cues. These errors are expected to impair vertical sound localization, even if the new cues would be optimally mapped to locations. Differences between HRTFs to the eardrum and hearing device microphones are qualitatively different from between-subject differences and can be described as a partial destruction rather than an alteration of relevant cues, although spectral difference metrics produce similar results. Dummy heads do not fully reflect the results with individual subjects. PMID- 30404455 TI - Integral identities for reflection, transmission, and scattering coefficients. AB - Several integral identities related to acoustic scattering are presented. In each case the identity involves the integral over frequency of a physical quantity. For instance, the integrated transmission loss, a measure of the transmitted acoustic energy through an inhomogeneous layer, is shown to have a simple expression in terms of spatially averaged physical quantities. Known identities for the extinction cross section and for the acoustic energy loss in a slab with a rigid backing, are shown to be special cases of a general procedure for finding such integral identities. PMID- 30404456 TI - Highly directional pressure sensing using the phase gradient. AB - Many methods of two-microphone directional sensing have limited bandwidth. For active intensity, finite-difference error can be removed by using the phase and amplitude gradient estimator method. Using similar principles, a directional pressure sensor based on the phase gradient is developed that is accurate up to the spatial Nyquist frequency, and beyond if phase unwrapping is applied. A highly directional frequency-independent array response of arbitrary order can be achieved with two microphones. The method is compared against beamforming and traditional gradient sensing for single and multiple sources and is found to have improved localization capabilities and increased bandwidth. PMID- 30404457 TI - Measurements of ultrasonic deterrents and an acoustically branded hairdryer: Ambiguities in guideline compliance. AB - Acoustic radiation from three commercial pest deterrents and two hair dryers were measured in an anechoic chamber. The deterrents were chosen because the frequency range at which they emit the most energy is either in the very high-frequency sound band (11.2-17.8 kHz) or the ultrasound band (greater than 17.8 kHz). These are sources that may be heard by a subset of the general population, with the young typically having better high frequency sensitivity. A hairdryer reported to increase the frequency of the motor noise above the audible hearing range was compared with a standard hairdryer. The outputs of the deterrents are compared against six international regulations and guidelines for audible and ultrasound exposure. Multiple ambiguities in the application of these guidelines are discussed. These ambiguities could lead to a device being considered as in compliance despite unconventionally high levels. Even if a device measured here meets a guideline, actual exposures can exceed those taken here and may therefore breach guidelines if the listener is closer to the device or reflections increase the exposure level. PMID- 30404458 TI - Measurements of two-dimensional spatial coherence of normal-incidence seafloor scattering. AB - Measurements have been made near normal incidence of the two-dimensional spatial coherence of the acoustic field scattered from the lakebed in Seneca Lake, New York. In the test region, the lakebed consists of a series of sediment layers created by a sequence of distinct depositional processes. The spatial coherence length of the scattered field is shown to be dependent on the structure of the underlying sediment sequences. Significant ping-to-ping variability in the spatial coherence surface was also observed for each sediment sequence. This variability is quantified by a two-dimensional spatial coherence metric that measures the coherence lengths and asymmetric coherence surface orientation. The ping-to-ping variation of the surface asymmetry appears to be linked to the spatial isotropy of the sediment scattering strength. The scattering strength of the deepest observed sequence in the sub-bottom is the most spatially isotropic and the ping-to-ping variability of the coherence lengths and surface orientations are random. The scattering strength of the shallower sequences is spatially anisotropic and the coherence lengths and surface orientations show intervals of non-random ping-to-ping behavior. PMID- 30404460 TI - Public exposure to ultrasound and very high-frequency sound in air. AB - Recent work showing the presence of a new generation of ultrasound (US) sources in public places has reopened the debate about whether there are adverse effects of US on humans, and has identified weaknesses in standards and exposure guidelines. Systems that rely on very high-frequency sound (VHFS) and US include public-address voice-alarm (PAVA) systems (whose operational status is often monitored using tones at ~20 kHz) and pest deterrents. In this study, sound pressure levels (SPLs) produced by 16 sources that were either publically available or installed in busy public spaces were measured. These sources were identified through a citizen science project, wherein members of the public were asked to provide smartphone recordings of VHFS/US sources. With measurements made in realistic listening positions, pest deterrents were found that produced levels of up to 100 dB SPL at ~20 kHz, and a hand dryer was found to produce 84 dB SPL at 40 kHz. PAVA systems were found to emit lower levels of up to 76 dB SPL at ~20 kHz. Pest deterrents measured breach recommended safe listening limits for public exposure for people who are nearby even for relatively short periods. PMID- 30404461 TI - Statistical characterization and modeling of noise effects in near-ultrasound aerial acoustic communications. AB - In this paper, the statistical properties of near-ultrasound acoustic noise in typical indoor environments are investigated. The results indicate that near ultrasound noise exhibits impulsive behavior and that its first-order probability density functions can be accurately modeled by using a Gaussian mixture or symmetric alpha-stable (SalphaS) distributions. Furthermore, a practical approach for estimating the parameters of the SalphaS noise in near-ultrasound aerial acoustic communication receivers is proposed. The problem of modeling memory effects in near-ultrasound acoustic noise is also considered and a simple noise model with memory is proposed based on multiple linear stable processes. The proposed statistical noise models can be used to analyze, simulate, and optimize the performance of various near-ultrasound aerial acoustic communication systems. It is believed that the analysis may contribute to the development of more efficient near-ultrasound aerial communication systems for a range of practical applications. PMID- 30404459 TI - Multidimensional stimulus encoding in the auditory nerve of the barn owl. AB - Auditory perception depends on multi-dimensional information in acoustic signals that must be encoded by auditory nerve fibers (ANF). These dimensions are represented by filters with different frequency selectivities. Multiple models have been suggested; however, the identification of relevant filters and type of interactions has been elusive, limiting progress in modeling the cochlear output. Spike-triggered covariance analysis of barn owl ANF responses was used to determine the number of relevant stimulus filters and estimate the nonlinearity that produces responses from filter outputs. This confirmed that ANF responses depend on multiple filters. The first, most dominant filter was the spike triggered average, which was excitatory for all neurons. The second and third filters could be either suppressive or excitatory with center frequencies above or below that of the first filter. The nonlinear function mapping the first two filter outputs to the spiking probability ranged from restricted to nearly circular-symmetric, reflecting different modes of interaction between stimulus dimensions across the sample. This shows that stimulus encoding in ANFs of the barn owl is multidimensional and exhibits diversity over the population, suggesting that models must allow for variable numbers of filters and types of interactions between filters to describe how sound is encoded in ANFs. PMID- 30404462 TI - Echo integration using non-vertical sonar beams: The bias caused by non-uniform distribution of fish within the echo beam. AB - The equivalent beam angle is a key parameter in echo integration, where it is assumed that targets are uniformly distributed within the sampling volume of the transducer beam. For a horizontally oriented sonar, this assumption is violated if the vertical distribution of fish is non-uniform throughout a sample, potentially causing a substantial bias in estimates of fish abundance or biomass. This paper investigates the magnitude of this bias using observations and simulated data, where in each case the vertical distribution of fish within a limited geographical area is estimated. PMID- 30404463 TI - The challenge of distinguishing mechanical, electrical and piezoelectric losses. AB - Understanding the energy loss in piezoelectric materials is of significant importance for manufacturers of acoustic transducers. The contributions to the power dissipation due to nonzero phase angles of the mechanical, electrical, and piezoelectric constants can be separated in the expression for power dissipation density. However, this division into separate contributions depends on the piezoelectric constitutive equation form used. Thus, it is problematic to identify any of the three terms with a specific physical domain, electric or mechanical, or to a coupling as is common in the discussion of loss in piezoelectric materials. Therefore, assumptions on the phase of the material constants based on this distinction could be erroneous and lead to incorrect piezoelectric models. This study demonstrates the challenge of distinguishing mechanical, electrical, and piezoelectric losses by investigating the power dissipation density and its contributions in a piezoelectric rod for all four piezoelectric constitutive equation forms. PMID- 30404464 TI - Southbound migration corridor of pygmy blue whales off the northwest coast of Australia based on data from ocean bottom seismographs. AB - A line array of 14 ocean bottom seismographs was deployed on the Exmouth Plateau northwest of the North West Cape in Western Australia in December 2014-January 2015. Acoustic data collected with this array were used to evaluate the corridor of the southbound migration of pygmy blue whales of the eastern Indian Ocean population. It is found that pygmy blue whales tended to travel southward much further away from the Western Australian coast, at distances of up to 400 km from shore, than that expected from data on their northbound migration. This is an important observation providing additional information on the migration pattern of pygmy blue whales, which is crucial for assessing their population and migration by passive acoustic means. PMID- 30404465 TI - Tracking the dynamic representation of consonants from auditory periphery to cortex. AB - In order to perceive meaningful speech, the auditory system must recognize different phonemes amidst a noisy and variable acoustic signal. To better understand the processing mechanisms underlying this ability, evoked cortical responses to different spoken consonants were measured with electroencephalography (EEG). Using multivariate pattern analysis (MVPA), binary classifiers attempted to discriminate between the EEG activity evoked by two given consonants at each peri-stimulus time sample, providing a dynamic measure of their cortical dissimilarity. To examine the relationship between representations at the auditory periphery and cortex, MVPA was also applied to modelled auditory-nerve (AN) responses of consonants, and time-evolving AN-based and EEG-based dissimilarities were compared with one another. Cortical dissimilarities between consonants were commensurate with their articulatory distinctions, particularly their manner of articulation, and to a lesser extent, their voicing. Furthermore, cortical distinctions between consonants in two periods of activity, centered at 130 and 400 ms after onset, aligned with their peripheral dissimilarities in distinct onset and post-onset periods, respectively. In relating speech representations across articulatory, peripheral, and cortical domains, the understanding of crucial transformations in the auditory pathway underlying the ability to perceive speech is advanced. PMID- 30404466 TI - Localization of broadband sounds carrying interaural time differences: Effects of frequency, reference location, and interaural coherence. AB - The auditory processes involved in the localization of sounds in rooms are still poorly understood. The present study investigated the auditory system's across frequency processing of interaural time differences (ITDs) and the impact of the interaural coherence (IC) of the stimuli in ITD discrimination and localization. First, ITD discrimination thresholds were measured as a function of signal frequency, reference ITD, and IC using critical-band wide noises. The resulting data were fitted with a set of analytical functions and ITD weights were derived using concepts from signal detection theory. Inspired by the weighted-image model [Stern, Zeiberg, and Trahiotis. (1988). J. Acoust. Soc. Am. 84, 156-165], the derived ITD weights were then integrated in a simplified localization model using an optimal combination of ITD information across frequency. To verify this model, a series of localization experiments were conducted using broadband noise in which ITD and IC were varied across frequency. The model predictions were in good agreement with the experimental data, supporting the assumption that the auditory system performs a weighted integration of ITD information across frequency to localize a sound source. The results could be valuable for the design of new paradigms to measure localization in more complex acoustic conditions and may provide constraints for future localization models. PMID- 30404467 TI - Generalization of the primary tone phase variation method: An exclusive way of isolating the frequency-following response components. AB - The primary tone phase variation (PTPV) technique combines selective sub averaging with systematic variation of the phases of multitone stimuli. Each response component having a known phase relationship with the stimulus components phases can be isolated in the time domain. The method was generalized to the frequency-following response (FFR) evoked by a two-tone (f 1 and f 2) stimulus comprising both linear and non-linear, as well as transient components. The generalized PTPV technique isolated each spectral component present in the FFR, including those sharing the same frequency, allowing comparison of their latencies. After isolation of the envelope component f 2 - f 1 from its harmonic distortion 2f 2 - 2f 1 and from the transient auditory brainstem response, a computerized analysis of instantaneous amplitudes and phases was applied in order to objectively determine the onset and offset latencies of the response components. The successive activation of two generators separated by 3.7 ms could be detected in all (N = 12) awake adult normal subjects, but in none (N = 10) of the sleeping/sedated children with normal hearing thresholds. The method offers an unprecedented way of disentangling the various FFR subcomponents. These results open the way for renewed investigations of the FFR components in both human and animal research as well as for clinical applications. PMID- 30404468 TI - Finite element modeling of ultrasound measurement systems for gas. Comparison with experiments in air. AB - Quantitative modeling of ultrasound measurement systems is of considerable value for design, analysis, and interpretation of measurements, methods, and systems. In this work, a model is developed for description of transmit-receive measurement systems based on radial-mode transducer operation in a homogeneous fluid medium. Axisymmetric finite element (FE) modeling is used for the transmitting and receiving piezoelectric transducers and sound propagation in the medium. Transmission-line modeling is used for transmitting and receiving cabling and electronics. The model potentially accounts for the full frequency response of the transducers, including radial and thickness modes, mode coupling, and interaction with the medium. Reciprocal transducers are assumed in the model, and linearity in all parts of the system. Near field effects are accounted for using diffraction correction. Simulations are compared with measurements for the transmit-receive voltage-to-voltage transfer function of two piezoelectric ceramic disk transducers vibrating in air at 1 atm, over the frequency range of the first two radial modes of the disks, and the time domain voltage waveforms at the electric terminals of the transmitting and receiving transducers. The results demonstrate that quantitative simulations of the measurement system can be done with reasonable accuracy. Potentials of improvement are identified and discussed. PMID- 30404469 TI - Efficient prediction of acoustic pulses accounting for fractional travel time. AB - Predicting a full waveform of an acoustic broadband signal propagating over different impedance surfaces is a stringent test of both the method used in the modeling of propagation and the surface impedance models. It has been shown that predicted waveforms might be sensitive to the fractional travel time, when the propagation time of the pulse does not equal an integer number of computational time steps. A method overcoming this issue is developed and demonstrated for different propagation conditions: a pulse propagating over a snow layer, frozen ground, and their combinations along the propagating path with homogeneous and vertically stratified atmosphere for a range of 60 m. For the numerical simulations, a conventional one-way parabolic equation with the Crank-Nicholson numerical algorithm is modified to improve computational efficiency and insure that the experimental time of arrival and spatial location of the receiver are matched exactly to the digital grids used in the simulations. The results are in a good agreement with experimental measurements and prior knowledge, and confirm that physical properties of a snow layer, sublayer ground, atmospheric conditions, and the order of range dependent ground properties affect the pulse waveforms. PMID- 30404470 TI - Self-translation induced minimum audible angle. AB - The minimum audible angle has been studied with a stationary listener and a stationary or a moving sound source. The study at hand focuses on a scenario where the angle is induced by listener self-translation in relation to a stationary sound source. First, the classic stationary listener minimum audible angle experiment is replicated using a headphone-based reproduction system. This experiment confirms that the reproduction system is able to produce a localization cue resolution comparable to loudspeaker reproduction. Next, the self-translation minimum audible angle is shown to be 3.3 degrees in the horizontal plane in front of the listener. PMID- 30404471 TI - Voice Onset Time in English voiceless stops is affected by following postvocalic liquids and voiceless onsets. AB - Voice Onset Time is an important characteristic of stop consonants that plays a large role in perceptual discrimination in many languages, and is widely used in phonetic research. The current paper aims to account for Voice Onset Time variation in English that has defied previously understood phonetic and lexical factors, particularly involving stops that are followed in the word by liquids and voiceless obstruents. 122 Canadian English speakers produced 120 /p/- and /k/ initial words (n = 17 533), and word-initial Voice Onset Time was analyzed. It was found that Voice Onset Time is shorter when the following syllable starts with a voiceless obstruent, and that this effect is mediated by speech rate. Voice Onset Time is also longer before postvocalic liquids, even when they are intervocalic. Voice Onset Time generally decreases through the course of the task, and speakers tend to drift during the course of a word reading task, and this is best accounted for by the residual Voice Onset Time of recently spoken words. PMID- 30404472 TI - Evaluation of a near-end listening enhancement algorithm by combined speech intelligibility and listening effort measurements. AB - Previous studies showed that near-end listening enhancement (NELE) algorithms can significantly improve speech intelligibility in noisy environments. This study investigates the benefit of the NELE algorithm AdaptDRC in normal-hearing listeners at signal-to-noise ratios (SNRs) for which speech intelligibility is at ceiling, by evaluating listening effort for processed and unprocessed speech in the presence of speech-shaped and cafeteria noise. The results suggest that the NELE algorithm is able to reduce listening effort over a wide range of SNRs. Hence, listening effort seems to be applicable for evaluating NELE algorithms over a much wider SNR range than speech intelligibility. PMID- 30404473 TI - Intelligibility assessment of cleft lip and palate speech using Gaussian posteriograms based on joint spectro-temporal features. AB - Intelligibility is considered as one of the primary measures for speech rehabilitation of individuals with a cleft lip and palate (CLP). Currently, speech processing and machine-learning-based objective methods are gaining more research interest as a way to quantify speech intelligibility. In this work, joint spectro-temporal features computed from a time-frequency representation of speech are explored to derive speech representations based on Gaussian posteriograms. A comparative framework using dynamic time warping (DTW) is used to quantify the intelligibility of child CLP speech. The DTW distance is used to score sentence-level intelligibility and tested for correlation with perceptual intelligibility ratings obtained from expert speech-language pathologists. A baseline DTW system using the conventional Mel-frequency cepstral coefficients (MFCCs) is also developed to compare the performance of the proposed system. Spearman's rank correlation coefficient between the objective intelligibility scores and the perceptual intelligibility rating is studied. A Williams significance test is conducted to assess the statistical significance of the correlation difference between the methods. The results show that the system based on joint spectro-temporal features significantly outperforms the MFCC-based system. PMID- 30404474 TI - Potential audibility of ultrasonic signal monitoring of Public Address and Life Safety Sound Systems. AB - Ultrasonic surveillance monitoring, to check the operational integrity of Public Address (PA) and Emergency Communication Systems, has been in existence for over 40 years-particularly in Europe. Since its inception, there has been debate as to the potential audibility that these systems may have. As the vast majority of sound systems engineers and designers have not heard or experienced any effects, it has generally been assumed that the general public do not either. Recently, however, concern has been raised and claims of ill effects have been reported with respect to ultrasonic emissions. There is, however, little or no data as to the ultrasonic sound levels that sound systems actually emit. This paper discusses the results of an initial survey of ultrasound radiated by a sample of some 50 sound systems and compares the results with a number of international standards-there currently being little or no specific guidance. This paper reviews the technology involved, typical emission levels, and concludes by making a number of recommendations to assist with the control of ultrasonic emissions to help mitigate unintended side effects. It is shown that most PA systems generate ultrasonic levels of under 70 dB at normal listener locations. PMID- 30404475 TI - Context integration deficit in tone perception in Cantonese speakers with congenital amusia. AB - Congenital amusia is a neuro-developmental disorder of pitch processing. This study investigated how this deficit affects lexical tone perception with and without context. Twenty-three Cantonese-speaking amusics and 23 controls were tested on the identification of high-variation tone stimuli in isolation vs in a carrier sentence. The controls generally achieved a higher accuracy with context than in isolation, suggesting that speech context facilitated tone identification. In contrast, amusics generally failed to benefit from the context, despite some variation among different tones. These findings provide insights into the underlying deficits of amusia, revealing a context integration deficit of tone perception in amusia. PMID- 30404477 TI - Diagnosis of bearing defects under variable speed conditions using energy distribution maps of acoustic emission spectra and convolutional neural networks. AB - This letter proposes an efficient scheme for the early diagnosis of bearing defects using a convolutional neural network (CNN) and energy distribution maps (EDMs) of acoustic emission spectra. The CNN automates the process of feature extraction from the EDM. The features learned by the CNN are used by an ensemble classifier, that is, a combination of a multilayer perceptron that is integral to typical CNN architectures and a support vector machine to diagnose bearing defects. The experimental results confirm that the proposed scheme diagnoses bearing defects more effectively than existing methods under variable speed conditions. PMID- 30404476 TI - Benefit of binaural listening as revealed by speech intelligibility and listening effort. AB - In contrast to the well-known benefits for speech intelligibility, the advantage afforded by binaural stimulus presentation for reducing listening effort has not been thoroughly examined. This study investigated spatial release of listening effort and its relation to binaural speech intelligibility in listeners with normal hearing. Psychometric functions for speech intelligibility of a frontal target talker masked by a stationary speech-shaped noise were estimated for several different noise azimuths, different degrees of reverberation, and by maintaining only interaural level or time differences. For each of these conditions, listening effort was measured using a categorical scaling procedure. The results revealed that listening effort was significantly reduced when target and masker were spatially separated in anechoic conditions. This effect extended well into the range of signal-to-noise ratios (SNRs) in which speech intelligibility was at ceiling, and disappeared only at the highest SNRs. In reverberant conditions, spatial release from listening effort was observed for high, but not low, direct-to-reverberant ratios. The findings suggest that listening effort assessment can be a useful method for revealing the benefits of spatial separation of sources under realistic listening conditions comprising favorable SNRs and low reverberation, which typically are not apparent by other means. PMID- 30404478 TI - Data clustering analysis of early reflections in small room. AB - It is common to increase the number of measurement points to improve the robustness of multipoint room equalization. However, the measurement of numerous points is extremely time-consuming and laborious. This letter analyzes the early reflections extracted from a large amount of room impulse responses using a K means clustering algorithm, revealing that the spatial distribution of early reflections in the same cluster is not disorganized but regular and predictable. Furthermore, the results of the Monte Carlo simulation suggest that the appropriate selection of measurement positions can reduce the number of measurement points without compromising the robustness of multipoint room equalization. PMID- 30404479 TI - Measurements of ultrasound from public address and voice alarm systems in public places. AB - Concerns have been raised about potential health effects of public exposure to ultrasound; however, there are few published surveys of measurements taken in public places. Results are presented of measurements taken in a selection of public places including train stations, shopping centres, galleries and museums, and the difficulties of taking measurements with conventional equipment are highlighted. Tones were identified in the 20 kHz third-octave band at 8 of the 14 locations tested; the characteristics of the tones are consistent with their source being Public Address or Voice Alarm systems. The measured results do not exceed existing interim guidelines for public exposure to ultrasound, and existing research suggests that no significant undesirable effects would be anticipated following exposure to ultrasound of this nature for short periods. The measured data may be reviewed against future public exposure guidelines which consider the variation in response across the population and between continuous and pulsed sources. PMID- 30404480 TI - A hybrid method to simulate elastic wave scattering of three-dimensional objects. AB - A hybrid method based on the finite-difference method and equivalence principle to simulate elastic wave scattering of three-dimensional objects is proposed. In this method, the near fields are first calculated in a rectangular volume containing the object by the finite-difference method. Then the displacements and tractions on a virtual surface are transformed to the far field by the application of the equivalence principle in elastodynamics. The feasibility is verified by comparing modeling results with the analytical solution for the canonical point force source radiation problem. Modeling for complex scatterer structures shows the advantage of this method in handling multi-scale scattering problems. PMID- 30404481 TI - Mechanical and acoustic performance prediction model for elastomers in different environmental conditions. AB - This study focuses on the constitutive model, including temperature and pressure effects, to investigate the dynamic, mechanical, and acoustic properties of elastomers in the frequency domain under different underwater conditions. The developed constitutive relation is based on the Havriliak-Negami (H-N) model by implementing experimental Young's modulus data and using the Williams-Landel Ferry (WLF) shift function for relaxation time calculation. The H-N model accurately captures the dynamic mechanical modulus for a wide range of frequencies for constant temperature and pressure based on measured dynamic mechanical thermal analysis data. Since the WLF shift function is related with the relaxation time for different temperatures and pressures, the proposed model represents a simple and accurate prediction of the dynamic modulus for varying external conditions. The relationship between Young's modulus and the acoustic properties of the rubber structure can be established by investigating the hydro wave propagation process. The predictions from the proposed model are verified by comparing with mechanical and acoustic experimental data at different temperatures and pressures. Additionally, the parametric study is conducted to investigate the effect of H-N parameters on mechanical and acoustic properties of elastomer materials. The proposed model can be used to predict the mechanical and acoustic properties in different environmental conditions accurately. PMID- 30404482 TI - Frequency bands for ultrasound, suitable for the consideration of its health effects. AB - It is proposed that the ultrasound frequency spectrum should be divided into three bands in order to facilitate a more rational assessment of its health effects. Whilst statement of the frequencies at the borders of these bands facilitates their definition, it is recognized that these observables vary continuously with frequency and consequently these border frequencies should not be used to rule out the possibility of a given effect occurring. The lowest band, US(A), lies between 17.8 and 500 kHz. In this band acoustic cavitation and its associated forces form the dominant process resulting in biological effects in liquids and soft tissues, whereas health effects from airborne ultrasound have been reported but are far less researched. In the middle band, US(B), between 500 kHz and 100 MHz, temperature rise in tissues becomes the most important biological effect of exposure. The highest band, US(C), covers frequencies above 100 MHz, for which the radiation force becomes an increasingly important biophysical mechanism. A justification for the selection of 17.8 kHz in preference to any other threshold for the lower frequency limit for ultrasound is given. PMID- 30404483 TI - Diving behavior of Cuvier's beaked whales inferred from three-dimensional acoustic localization and tracking using a nested array of drifting hydrophone recorders. AB - Echolocation pulses from Cuvier's beaked whales are used to track the whales' three-dimensional diving behavior in the Catalina Basin, California. In 2016, five 2-element vertical hydrophone arrays were suspended from the surface and drifted at ~100-m depth. Cuvier's beaked whale pulses were identified, and vertical detection angles were estimated from time-differences-of-arrival of either direct-path signals received on two hydrophones or direct-path and surface reflected signals received on the same hydrophone. A Bayesian state-space model is developed to track the diving behavior. The model is fit to these detection angle estimates from at least four of the drifting vertical arrays. Results show that the beaked whales were producing echolocation pulses and are presumed to be foraging at a mean depth of 967 m (standard deviation = 112 m), approximately 300 m above the bottom in this basin. Some whales spent at least some time at or near the bottom. Average swim speed was 1.2 m s-1, but swim direction varied during a dive. The average net horizontal speed was 0.6 m s-1. Results are similar to those obtained from previous tagging studies of this species. These methods may allow expansion of dive studies to other whale species that are difficult to tag. PMID- 30404484 TI - Sustained underwater acoustic communications with environmental-based time reversal. AB - The usage of time-reversal in underwater communications relies on array channel matched-filtering, coherent channel replica alignment and summation. Traditionally, replicas are channel responses to probe signals received at a previous time. These are noisy and subject to distortion due to channel variability. This paper offers an alternative where noisy and potentially distorted channel replicas are replaced by noise-free and time-updated replicas generated by a numerical model constrained on previously data-identified environmental parameters. The method is applied on real data, where a quadrature phase shift key modulated signal on a 25.6 kHz carrier at 4 kbit/s was transmitted in a shallow water area over a distance of approximately 900 m. Sustained analysis without supervision shows that the proposed method may attain a mean square error gain up to 5.4 dB when compared to traditional time-reversal. PMID- 30404485 TI - Perceptual grouping in the cocktail party: Contributions of voice-feature continuity. AB - Cocktail parties pose a difficult yet solvable problem for the auditory system. Previous work has shown that the cocktail-party problem is considerably easier when all sounds in the target stream are spoken by the same talker (the voice continuity benefit). The present study investigated the contributions of two of the most salient voice features-glottal-pulse rate (GPR) and vocal-tract length (VTL)-to the voice-continuity benefit. Twenty young, normal-hearing listeners participated in two experiments. On each trial, listeners heard concurrent sequences of spoken digits from three different spatial locations and reported the digits coming from a target location. Critically, across conditions, GPR and VTL either remained constant or varied across target digits. Additionally, across experiments, the target location either remained constant (Experiment 1) or varied (Experiment 2) within a trial. In Experiment 1, listeners benefited from continuity in either voice feature, but VTL continuity was more helpful than GPR continuity. In Experiment 2, spatial discontinuity greatly hindered listeners' abilities to exploit continuity in GPR and VTL. The present results suggest that selective attention benefits from continuity in target voice features and that VTL and GPR play different roles for perceptual grouping and stream segregation in the cocktail party. PMID- 30404486 TI - Real-time tracking of a surface ship using a bottom-mounted horizontal array. AB - The cascade of blind deconvolution and array invariant has been successful to localize and track a surface ship radiating random waveforms, using a 56-m long vertical array in 100-m deep shallow water. In this paper, it is shown that a 60 m long, bottom-mounted horizontal array can be utilized for blind deconvolution to extract the Green's functions from the same ship (100-800 Hz), in conjunction with the array invariant for source-range estimation. The additional information obtained with a horizontal array is the source bearing (azimuth angle, phi) from the well-resolved ray angle identified for blind deconvolution to extract the phase component of the unknown source waveforms. The overall tracking performance shows good agreement with global positioning system (GPS) measurements to less than 11% in terms of standard deviation of relative range error at ranges of 0.3 1.5 km, except when the ship is around the broadside (e.g., |phi|<25 degrees ) of the horizontal array. On the other hand, the source bearings are in excellent agreement with the GPS data except near the endfire due to the lower angular resolution. The potential for simultaneous localization of multiple ships is also discussed. PMID- 30404487 TI - Dynamic stabilization of the Rayleigh-Benard instability by acceleration modulation. AB - This paper presents the results of an experimental investigation of the parametric stabilization of Rayleigh-Benard convection through the imposition of sinusoidal vibration. The ability to dynamically stabilize Rayleigh-Benard convection using acceleration modulation is of interest to groups who design and study thermoacoustic machines as the introduction of parasitic convection can have deleterious effects on the desired operation and thermodynamic efficiency of the device. These performance issues caused by suspected convective instability have been seen both in traveling wave thermoacoustic refrigerators and cryogenic pulse tube chillers. This paper reports the results of an experiment intended to determine the vibratory, fluidic, and geometric conditions under which a small, rectangular container of statically unstable fluid may be stabilized by vertical vibration with comparison to the computational methods of R. M. Carbo [J. Acoust. Soc. Am. 135, 654-668 (2014)]. Measurements are obtained using a large displacement kinematic shaker of an original design with the convecting gas characterized using both thermal transport measurements and flow visualization employing tracer particles illuminated by a diode laser light sheet phase-locked to the shaker. These experiments are believed to be the first demonstrating the suppression of convection through vibration in rectangular containers. PMID- 30404489 TI - Axial stress determination using highly nonlinear solitary waves. AB - This article presents a nondestructive evaluation (NDE) method to infer the neutral temperature and the axial stress in thick beams. The method relies on the propagation of highly nonlinear solitary waves generated at one end of a chain of spherical particles in a dry point contact with the beam to be evaluated. The waves are reflected back to the chain and the research hypothesis is that the axial stress, which influences the beam's stiffness, affects the amplitude and speed of the reflected waves. To verify this hypothesis a general finite element model of thermally stressed beams was developed and coupled to a discrete particle model able to predict the propagation of the waves along an L-shaped granular medium. The models were validated experimentally to quantify the repeatability of the setup, the sensitivity of the wave features on the thermal stress, and the independence of the wave features on the neutral temperature of the beam. The hypothesis was proven valid by both the numerical and the experimental results. In the future, these findings may be used to refine a NDE method to assess stress in columns, to infer the neutral temperature of continuous welded rails, and to prevent thermal buckling of critical structures. PMID- 30404488 TI - Green's function extraction by crosscorrelation and multidimensional deconvolution for outdoor sound propagation. AB - In this work, the Green's function is estimated from outdoor measurements of controlled-sources. Crosscorrelation and multidimensional deconvolution have successfully been employed for Green's function retrieval. Crosscorrelation assumes a lossless medium and equipartitioned wavefield; when these assumptions are not satisfied it may result in a Green's function smeared with the source point-spread function. Multidimensional deconvolution removes the point-spread function from the retrieved Green's function. Both methods are employed to estimate the Green's function between two array stations for a single and multiple controlled-sources. The results demonstrate that the source-to-center radius has a negligible effect on the retrieved Green's function, if the source to-center radius is larger than the distance between the two array stations. PMID- 30404490 TI - Three dimensional photoacoustic tomography in Bayesian framework. AB - The image reconstruction problem (or inverse problem) in photoacoustic tomography is to resolve the initial pressure distribution from detected ultrasound waves generated within an object due to an illumination by a short light pulse. Recently, a Bayesian approach to photoacoustic image reconstruction with uncertainty quantification was proposed and studied with two dimensional numerical simulations. In this paper, the approach is extended to three spatial dimensions and, in addition to numerical simulations, experimental data are considered. The solution of the inverse problem is obtained by computing point estimates, i.e., maximum a posteriori estimate and posterior covariance. These are computed iteratively in a matrix-free form using a biconjugate gradient stabilized method utilizing the adjoint of the acoustic forward operator. The results show that the Bayesian approach can produce accurate estimates of the initial pressure distribution in realistic measurement geometries and that the reliability of these estimates can be assessed. PMID- 30404491 TI - Many listeners cannot discriminate major vs minor tone-scrambles regardless of presentation rate. AB - A tone-scramble is a random sequence of pure tones. Previous studies have found that most listeners (~ 70%) perform near chance in classifying rapid tone scrambles composed of multiple copies of notes in G-major vs G-minor triads; the remaining listeners perform nearly perfectly [Chubb, Dickson, Dean, Fagan, Mann, Wright, Guan, Silva, Gregersen, and Kowalski (2013). J. Acoust. Soc. Am. 134(4), 3067-3078; Dean and Chubb (2017). J. Acoust. Soc. Am. 142(3), 1432-1440]. This study tested whether low-performing listeners might improve with slower stimuli. In separate tasks, stimuli were tone-scrambles presented at 115, 231, 462, and 923 notes per min. In each task, the listener classified (with feedback) stimuli as major vs minor. Listeners who performed poorly in any of these tasks performed poorly in all of them. Strikingly, performance was worst in the task with the slowest stimuli. In all tasks, most listeners were biased to respond "major" ("minor") if the stimulus ended on a note high (low) in pitch. Dean and Chubb introduced the name "scale-sensitivity" for the cognitive resource that separates high- from low-performing listeners in tone-scramble classification tasks, suggesting that this resource confers sensitivity to the full gamut of qualities that music can attain by being in a scale. In ruling out the possibility that performance in these tasks depends on speed of presentation, the current results bolster this interpretation. PMID- 30404492 TI - Normal incidence sound transmission loss evaluation with a general upstream tube wave decomposition formula. AB - This study presents a method for measuring the normal incidence sound transmission loss of acoustical materials used in classical piping systems from upstream surface complex reflection coefficient measurements only. Based on the standard transfer function method, the wave field of the upstream tube is further decomposed, and the relationship between the complex reflection coefficient and the twice-transmitted wave is deduced. Similar to the so-called upstream surface impedance (USI) method, two microphone locations and air cavities with several depths are required. As a validation of the proposed method, both symmetrical and non-symmetrical materials are investigated. The influence of the air cavity on the experiment result is also discussed. A comparison of the results between the proposed method and existing methods reveals a perfect agreement with the verified USI method. PMID- 30404493 TI - Pressure calibration of a digital microelectromechanical system microphone by comparison. AB - In the field of noise control and monitoring, a new generation of small and low cost microelectro-mechanical system (MEMS) microphones is nowadays widely adopted. MEMS microphones, after recognition as traceable measurement instruments, could open up promising measurements based on wireless sensor networks. Current standards do not apply specifically to digital microphones. In this work, a pressure calibration procedure by comparison is carried out for a digital MEMS microphone and a sensitivity parameter suitable for metrological purposes is proposed. Measurement procedure and results between 20 Hz and 20 kHz are presented along with uncertainty contributions. PMID- 30404495 TI - Composite honeycomb metasurface panel for broadband sound absorption. AB - Composite honeycomb sandwich panels have been adopted in a wide range of applications owing to their excellent mechanical properties. This paper demonstrates a design of a composite honeycomb metasurface panel that can achieve 90% sound absorption from 600 to 1000 Hz with a thickness less than 30 mm. The panel is comprised of periodically and horizontally arranged honeycomb "supercells" which consist of unit cells of different geometric parameters (pore size). Two different analytical models (Helmholtz resonator model and micro perforated panel model) are used to calculate the sound absorption of the panel, and they are further validated by a numerical model. The relatively broadband sound absorption is found to be attributed to the coupling between unit cells, which is illustrated by both the complex frequency plane theory and the calculated sound intensity field. PMID- 30404494 TI - The possible role of brain rhythms in perceiving fast speech: Evidence from adult aging. AB - The rhythms of speech and the time scales of linguistic units (e.g., syllables) correspond remarkably to cortical oscillations. Previous research has demonstrated that in young adults, the intelligibility of time-compressed speech can be rescued by "repackaging" the speech signal through the regular insertion of silent gaps to restore correspondence to the theta oscillator. This experiment tested whether this same phenomenon can be demonstrated in older adults, who show age-related changes in cortical oscillations. The results demonstrated a similar phenomenon for older adults, but that the "rescue point" of repackaging is shifted, consistent with a slowing of theta oscillations. PMID- 30404497 TI - Wireless communication between personal electronic devices and hearing aids using high frequency audio and ultrasound. AB - Hearing aids continue to be the main intervention for hearing loss but ease of use and control is of concern due to the small size of these aids. While technological advances in Bluetooth Low Energy have allowed for improved wireless control, in particular between personal electronic devices, its use for communication with hearing aids is problematic due to limited battery life. This paper outlines the implementation of acoustic wireless communication between personal electronic devices and hearing aids using On-Off Keying (OOK) and Frequency Shift Keying (FSK) between the frequencies of 16 and 20 kHz. Reliable communication with bit error rates less than 10-3 were achieved for OOK with maximum data signalling rates of 50, 35.7, and 27.8 bits per second (bps) obtained over 1, 2, and 3 metres respectively, while FSK provided maximum data signalling rates of 83.3, 50, and 27.8 bps over the same distances. PMID- 30404496 TI - Infants use onset asynchrony cues in auditory scene analysis. AB - This experiment investigated the effect of onset asynchrony on the segregation of concurrent vowels in infants and adults. Two vowels, randomly chosen from seven American-English vowels, were superimposed. Each vowel pair contained one vowel by a male and one by a female talker. A train of such vowel pairs was presented to listeners, who were trained to respond to the male target vowel /i:/ or /u:/. The ability to identify the target vowel was compared among three conditions: synchronous onset, 100-, and 200-ms onset asynchrony. Experiment 1 measured performance, in d', in 7-month-old infants and adults. Infants and adults performed better with asynchronous than synchronous vowel onset, regardless of asynchrony duration. Experiment 2 compared the proportion of 3-month-old infants achieving an 80% correct criterion with and without onset asynchrony. Significantly more infants reached criterion with asynchronous than with synchronous vowel onset. Asynchrony duration did not influence performance. These experiments show that infants, as young as 3 months old, benefit from onset asynchrony. PMID- 30404499 TI - Direct simulation of acoustic scattering problems involving fluid-structure interaction using an efficient immersed boundary-lattice Boltzmann method. AB - An efficient immersed boundary-lattice Boltzmann method (IB-LBM) is applied to carry out the direct simulation of acoustic scattering problems involving fluid structure interaction. In the simulation, the lattice Boltzmann method is adopted for the fluid domain, the immersed boundary method is used to handle the fluid structure interaction and the instantaneous fluid pressure perturbation is computed to obtain the acoustic field. Compared with the conventional IB-LBMs, a force correction technique is introduced in this method to enforce the non-slip boundary conditions at the immersed boundaries and the acoustic scattering field thus can be obtained more accurately. The study of the numerical result comparison with the conventional IB-LBMs or analytical solutions is conducted on four acoustic problems, such as acoustic radiation from a pulsing cylinder, acoustic scattering from a static cylinder with pulse, or harmonic Gaussian sources and a moving two-dimensional sedimentating particle. The better efficiency of the present method is validated. PMID- 30404498 TI - Leveraging audiovisual speech perception to measure anticipatory coarticulation. AB - A noninvasive method for accurately measuring anticipatory coarticulation at experimentally defined temporal locations is introduced. The method leverages work in audiovisual (AV) speech perception to provide a synthetic and robust measure that can be used to inform psycholinguistic theory. In this validation study, speakers were audio-video recorded while producing simple subject-verb object sentences with contrasting object noun rhymes. Coarticulatory resistance of target noun onsets was manipulated as was metrical context for the determiner that modified the noun. Individual sentences were then gated from the verb to sentence end at segmental landmarks. These stimuli were presented to perceivers who were tasked with guessing the sentence-final rhyme. An audio-only condition was included to estimate the contribution of visual information to perceivers' performance. Findings were that perceivers accurately identified rhymes earlier in the AV condition than in the audio-only condition (i.e., at determiner onset vs determiner vowel). Effects of coarticulatory resistance and metrical context were similar across conditions and consistent with previous work on coarticulation. These findings were further validated with acoustic measurement of the determiner vowel and a cumulative video-based measure of perioral movement. Overall, gated AV speech perception can be used to test specific hypotheses regarding coarticulatory scope and strength in running speech. PMID- 30404500 TI - A perceptual dissimilarities based nonlinear sound quality model for range hood noise. AB - The application of sound quality in household appliances has gradually increased in recent years. In addition to modeling algorithms, appropriate acoustic metrics that characterize product sounds also play an important role in developing models. In this study, an artificial neural network based sound quality model for range hood noise was established with the combination of prior metric selection by multidimensional scaling (MDS) analysis of perceptual dissimilarities. First, sounds in different environments, speeds, and positions were recorded, and their annoyance was evaluated by grouped anchor semantic differential subjective jury testing. Then, the timbre space underlying dissimilarity judgments were analyzed by CLASCAL, an accurate MDS algorithm. Each dimension of the space was well explained by some metrics through stepwise regression. Finally, a sound quality model was established based on a back propagation neural network (BPNN). Results show that the combination of BPNN and CLASCAL can address the interpretation of the sound quality model and the ability to model nonlinearity for high accuracy. In addition, the application of noise control on range hoods showed that passive and active noise control (ANC) measures improve sound quality, especially ANC systems. PMID- 30404501 TI - The ventriloquist paradigm: Studying speech processing in conversation with experimental control over phonetic input. AB - This article presents the ventriloquist paradigm, an innovative method for studying speech processing in dialogue whereby participants interact face-to-face with a confederate who, unbeknownst to them, communicates by playing pre-recorded speech. Results show that the paradigm convinces more participants that the speech is live than a setup without the face-to-face element, and it elicits more interactive conversation than a setup in which participants believe their partner is a computer. By reconciling the ecological validity of a conversational context with full experimental control over phonetic exposure, the paradigm offers a wealth of new possibilities for studying speech processing in interaction. PMID- 30404502 TI - Ultrasound in air-Guidelines, applications, public exposures, and claims of attacks in Cuba and China. AB - This editorial introduces a Special Issue of the Journal of the Acoustical Society of America, on "Ultrasound in Air." In this Special Issue, one paper covers ways of categorizing the ultrasonic regimes, and three papers cover human effects. One of those three, plus five others, constitute the six papers that report on the measured outputs of commercial devices. Two cover calibration, and the final three papers cover novel applications. This editorial outlines the context in which these papers provide individual studies, including the development of technology and guidelines for safe exposure, and ending with an analysis of what is currently known about claims of sonic attacks on embassy staff in Cuba and China. PMID- 30404503 TI - Estimation and experiment for sound absorption coefficient of three clearance types using a bundle of nested tubes. AB - Closely packed nested structure circular tubes form three types of clearances: circular clearances, concentric clearances, and longitudinal clearances. The cross-sectional shape of rice straw, including the above-mentioned three types of clearances, is similar to that of the samples of the present study. Herein, the propagation constant and characteristic impedance of the circular, concentric, and longitudinal clearances surrounded by three cylindrical surfaces are treated as a transfer matrix. Then, by connecting these transfer matrices in parallel, a transfer matrix integrating these clearances is determined, and the sound absorption coefficient is calculated. Test samples that have three types of clearances are also created, and measure their sound absorption coefficients. The contributions of the concentric and circular clearances are significant because of the dimensions of the used tubes. The results of the calculations that took eccentricity into account revealed no significant impact on the sound absorption coefficient in wide-frequency range. The results of the calculations that took flexure into account revealed that the theoretical value was close to the measured value in the low-frequency range. PMID- 30404504 TI - Effects of very high-frequency sound and ultrasound on humans. Part II: A double blind randomized provocation study of inaudible 20-kHz ultrasound. AB - Some people have reported symptoms such as nausea, dizziness, and headaches that they attribute to ultrasound (US) emitted by devices in public places. The primary aim of the present study was to investigate whether inaudible US can provoke adverse symptoms compared to a sham presentation, under double-blind conditions. A second aim was to investigate whether the expectation of US being present could provoke adverse symptoms (a nocebo response). The US stimulus was a 20 kHz tone presented continuously for 20 min set to at least 15 dB below the participants' detection threshold, giving a typical sound pressure level (SPL) of 84 dB. No evidence that US provoked symptoms was found, but there was evidence of small nocebo effects. A case study on an individual with high self-reported sensitivity to US gave similar results. The present study did not reproduce the severe symptoms reported previously by some members of the public; this may be due to the SPL or duration of the stimulus, or strength of the nocebo stimulus. These findings cannot be used to predict outcomes from exposures to sounds that are audible to the individual in question, or to sounds with higher SPLs, longer durations, or different frequency content. PMID- 30404505 TI - Encoding speech in cochlear implants using simultaneous amplitude and rate modulation. AB - To improve speech perception for cochlear implant (CI) users, it is essential to improve the transmission of temporal envelopes. The most common speech processors deliver temporal envelopes via the CI using fixed-rate amplitude modulated (AM) pulse trains. Psychophysical studies suggest that rate modulation (RM) and AM are perceived by a shared temporal integration mechanism, but the potential for them to constructively combine to encode temporal envelopes has yet to be explored. In this experiment, a speech processing strategy called amplitude and rate temporal modulation was developed to encode speech temporal envelopes with simultaneous AM and RM. The strategy was tested for perception of clean speech at 60 and 40 dBA, and 60 dBA speech in noise (+10 dB SNR). The amount of RM was varied and the amount of AM was held constant to determine whether the addition of RM could enhance the perception of temporal envelopes and improve speech understanding. At the lowest RM amount, speech scores were poorest for all speech conditions. For 60 dBA clean speech and speech in noise, speech scores were significantly better at the highest RM amounts, suggesting that RM combined with AM can be used to enhance perception of temporal envelopes. PMID- 30404506 TI - Optimized decentralized adaptive control of noise and vibration for periodic disturbances. AB - Decentralized control has great potential to facilitate the implementations of multichannel active noise/vibration control systems. The main drawback, however, is its inherent risk of system instability. In this letter an optimized decentralized adaptive control algorithm subject to periodic disturbances is reported. The algorithm employs the scheme of a decentralized filtered-x least mean square algorithm and utilizes optimized reference filters so that the stability of the control system can be ensured. Simulation results based on a realistic vibration isolation system demonstrate that both the stability and the convergent speed could be significantly improved. PMID- 30404508 TI - Ultrasonic noise measurements in the work environment. AB - In many countries, ultrasonic noise is included in the list of factors harmful to health in the work environment. For the frequency range above 20 kHz, there is no clear and complete information on the factors influencing the result of a measurement of sound pressure level. Moreover, there are no current international standards for performing measurements of ultrasonic noise at work stations. This article presents a possibility for the adaptation of the existing measurement methods [e.g., ISO 9612:2009 (2009)] to the ultrasonic range. In particular, it discusses the requirements for measuring instruments, procedures to be followed while performing measurements, the application of a correction to measurement results, and the determination of measurement uncertainty. The development of a consistent method of ultrasonic noise measurement is of utmost importance in carrying out an assessment and reducing the risk of exposure to this physical factor in the work environment. PMID- 30404507 TI - Analytical solution for converging elliptic shear wave in a bounded transverse isotropic viscoelastic material with nonhomogeneous outer boundary. AB - Dynamic elastography methods-based on optical, ultrasonic, or magnetic resonance imaging-are being developed for quantitatively mapping the shear viscoelastic properties of biological tissues, which are often altered by disease and injury. These diagnostic imaging methods involve analysis of shear wave motion in order to estimate or reconstruct the tissue's shear viscoelastic properties. Most reconstruction methods to date have assumed isotropic tissue properties. However, application to tissues like skeletal muscle and brain white matter with aligned fibrous structure resulting in local transverse isotropic mechanical properties would benefit from analysis that takes into consideration anisotropy. A theoretical approach is developed for the elliptic shear wave pattern observed in transverse isotropic materials subjected to axisymmetric excitation creating radially converging shear waves normal to the fiber axis. This approach, utilizing Mathieu functions, is enabled via a transformation to an elliptic coordinate system with isotropic properties and a ratio of minor and major axes matching the ratio of shear wavelengths perpendicular and parallel to the plane of isotropy in the transverse isotropic material. The approach is validated via numerical finite element analysis case studies. This strategy of coordinate transformation to equivalent isotropic systems could aid in analysis of other anisotropic tissue structures. PMID- 30404509 TI - Iterative solutions of the array equations for rapid design and analysis of large projector arrays. AB - A fast computational method for modeling and simulation of large projector arrays is presented. The method is based on the array equations that account for the acoustic interaction among the projector elements as well as the individual characteristics of each projector. Unlike the existing solution method in which the acoustic interaction must be known a priori in the form of interaction impedance matrix Z, the present method seeks the solution of modified array equations through iterations without explicitly evaluating the Z matrix. This significantly speeds up the analysis of complex arrays with surrounding structures, where the evaluation of the Z matrix may require a large number of time-consuming finite element computations. The method is compared with the traditional Z-matrix method for the case of a cylindrical array of 72 * 8 Tonpilz transducers. For the same level of accuracy, the iterative method is shown to be up to 2 orders-of-magnitude faster than the Z-matrix method. The method can be used for rapid design and analysis of active sonar arrays and medical ultrasonic transducers, often made of hundreds and even thousands of elements. PMID- 30404510 TI - Feasibility of interleaved Bayesian adaptive procedures in estimating the equal loudness contour. AB - A Bayesian adaptive procedure, the interleaved-equal-loudness contour (IELC) procedure, was developed to improve the efficiency in estimating the equal loudness contour. Experiment 1 evaluated the test-retest reliability of the IELC procedure using six naive normal-hearing listeners. Two IELC runs of 200 trials were conducted and excellent test-retest reliability was found at both the group and individual levels. Using the same group of listeners, Experiment 2 compared the IELC procedure to two other procedures that required frequency-by-frequency testing. One of these procedures was the commonly adopted interleaved staircase (ISC) procedure from Jesteadt [(1980). Atten. Percept. Psychophys. 28, 85-88]. The other procedure, the interleaved maximum-likelihood (IML) procedure, was a modification of the updated maximum-likelihood procedure [Shen and Richards (2012). J. Acoust. Soc. Am. 132, 957-967]. For each of the ISC and IML procedures, two runs of approximately 500 trials were conducted, followed by one additional IELC run. The test-retest reliability of the IELC procedure was comparable to that of the ISC and IML procedure. The accuracies of all three procedures measured in Experiment 2 were similar, which was superior to the accuracies of the IELC runs from Experiment 1, indicating a potential training effect. PMID- 30404511 TI - Bone-conducted sound in a dolphin's mandible: Experimental investigation of elastic waves mediating information on sound source position. AB - Mammals use binaural or monaural (spectral) cues to localize acoustic sources. While the sensitivity of terrestrial mammals to changes in source elevation is relatively poor, the accuracy achieved by the odontocete cetaceans' biosonar is high, independently of where the source is. Binaural/spectral cues are unlikely to account for this remarkable skill. In this paper, bone-conducted sound in a dolphin's mandible is studied, investigating its possible contribution to sound localization. Experiments are conducted in a water tank by deploying, on the horizontal and median planes of the skull, ultrasound sources that emit synthetic clicks between 45 and 55 kHz. Elastic waves propagating through the mandible are measured at the pan bones and used to localize source positions via either binaural cues or a correlation-based full-waveform algorithm. Exploiting the full waveforms and, most importantly, reverberated coda, it is possible to enhance the accuracy of source localization in the vertical plane and achieve similar resolution of horizontal- vs vertical-plane sources. The results noted in this paper need to be substantiated by further experimental work, accounting for soft tissues and making sure that the data are correctly mediated to the internal ear. If confirmed, the results would favor the idea that dolphin's echolocation skills rely on the capability to analyze the coda of biosonar echoes. PMID- 30404512 TI - Effects of very high-frequency sound and ultrasound on humans. Part I: Adverse symptoms after exposure to audible very-high frequency sound. AB - Various adverse symptoms resulting from exposure to very high-frequency sound (VHFS) and ultrasound (US) have previously been reported. This study aimed to establish whether these symptoms are experienced under controlled laboratory conditions and are specific to VHFS/US. To do this, participants were exposed to VHFS/US (at frequencies between 13.5 and 20 kHz and sound pressure levels between 82 and 92 dB) and to a 1 kHz reference stimulus, both at 25 dB above their hearing threshold. The VHFS/US and reference stimuli were presented 4 times, each time for 3 min, during which participants performed a sustained attention task, rated their symptom severity, and had their galvanic skin response (GSR) measured to assess their level of anxiety. Prior to exposure, participants were assigned either to a symptomatic or an asymptomatic group, based on their prior history of symptoms that they attributed to VHFS/US. In both groups, overall discomfort ratings were higher in the VHFS/US condition than the reference condition. In the symptomatic group only, difficulty concentrating and annoyance were also rated higher in the VHFS/US than the reference condition. No difference between the two stimulus conditions was seen in performance on the attention task or on average GSRs for either group. PMID- 30404513 TI - ACT: An Automatic Centroid Tracking tool for analyzing vocal tract actions in real-time magnetic resonance imaging speech production data. AB - Real-time magnetic resonance imaging (MRI) speech production data have expanded the understanding of vocal tract actions. This letter presents an Automatic Centroid Tracking tool, ACT, which obtains both spatial and temporal information characterizing multi-directional articulatory movement. ACT auto-segments an articulatory object composed of connected pixels in a real-time MRI video, by finding its intensity centroids over time and returns kinematic profiles including direction and magnitude information of the object. This letter discusses the utility of ACT, which outperforms other similar object tracking techniques, by demonstrating its successful online tracking of vertical larynx movement. ACT can be deployed generally for dynamic image processing and analysis. PMID- 30404514 TI - Cortical markers of auditory stream segregation revealed for streaming based on tonotopy but not pitch. AB - The brain decomposes mixtures of sounds, such as competing talkers, into perceptual streams that can be attended to individually. Attention can enhance the cortical representation of streams, but it is unknown what acoustic features the enhancement reflects, or where in the auditory pathways attentional enhancement is first observed. Here, behavioral measures of streaming were combined with simultaneous low- and high-frequency envelope-following responses (EFR) that are thought to originate primarily from cortical and subcortical regions, respectively. Repeating triplets of harmonic complex tones were presented with alternating fundamental frequencies. The tones were filtered to contain either low-numbered spectrally resolved harmonics, or only high-numbered unresolved harmonics. The behavioral results confirmed that segregation can be based on either tonotopic or pitch cues. The EFR results revealed no effects of streaming or attention on subcortical responses. Cortical responses revealed attentional enhancement under conditions of streaming, but only when tonotopic cues were available, not when streaming was based only on pitch cues. The results suggest that the attentional modulation of phase-locked responses is dominated by tonotopically tuned cortical neurons that are insensitive to pitch or periodicity cues. PMID- 30404516 TI - On modified wavenumber filters for rail contribution estimations. AB - This brief communication exposes an overview of various wavenumber filters to separate the rail contribution to pass-by noise via the wave signature extraction method [Zea, Manzari, Squicciarini, Feng, Thompson, and Lopez Arteaga, J. Sound Vib. 409, 24-42 (2017)]. It has been found that the originally proposed filters underestimate the rail noise at frequencies above 1.6 kHz due to the presence of higher-order wave families that is unaccounted for. The goal of this letter is thus to propose and examine different filter functions that can capture such waves, and to assess whether the rail contribution estimations can be improved. PMID- 30404517 TI - Assessment of short-term exposure to an ultrasonic rodent repellent device. AB - The objectives of the present study were to investigate the acoustical properties of the very high frequencies and/or ultrasound signals produced by a repellent device and to investigate potential adverse factors as a result of short-term exposure to these signals. Potential adverse effects were evaluated perceptually with 25 young and 25 middle-aged persons, all with normal hearing thresholds, in a quiet room using different outcome measures, including a 15-item survey presented before and immediately after each condition. Spectral analyses showed that, besides emitting frequency modulated sounds in the expected frequency ranges, a faint but audible sound in the 4-5 kHz range was present. On average, a relatively short exposure to the sound produced by a repellent device did not lead to significant adverse effects. Yet, when the signal was perceived, as it was frequently for the younger population at the two lower frequencies settings (12-14 kHz, 25-25 kHz) and with 2 sources emitting, it was considered to be disturbing by several participants. Given the increasing usage of ultrasonic devices as well as the much longer exposure of high frequency and ultrasound in domestic usage, careful consideration and better guidelines are required, especially for those who are most sensitive to sound. PMID- 30404518 TI - Simultaneous localization of a surface ship and a submerged towed source (L). AB - The cascade of blind deconvolution and array invariant has been successful for localizing a single source, either a surface ship or a submerged source, using a vertical array without knowledge of the environment or source waveform in shallow water. In this letter, the blind deconvolution is extended to a two-source case where individual Green's functions are separately extracted by exploiting a distinct group of modes strongly excited at different source depths. The subsequent array invariant confirms that a surface ship and a towed source at 50 m depth can be simultaneously localized using a 56-m long vertical array in 100-m deep shallow water. PMID- 30404519 TI - A coupler-based calibration method for ear-probe microphones. AB - The calibration of ear-probe microphones can increase the precision of calibrating stimulus levels in situ and of measuring acoustic responses from the ear. This paper proposes a methodology to measure the sensitivity of an ear-probe microphone, requiring only an acoustic coupler and a calibrated reference microphone. The input impedance of the coupler is measured, enabled by a preliminary acoustic Thevenin calibration of the ear probe, and the plane-wave transfer impedance of the coupler is calculated analytically. Using these two quantities, the pressure transfer function between the reference microphone and the ear-probe microphone is estimated. This enables estimating the sensitivity of the ear-probe microphone. The proposed and an existing method were compared, resulting in substantially similar ear-probe microphone sensitivities. The proposed method is practically feasible in producing reliable measurements of sound pressure in the ear canal and calibrating stimulus levels in a clinical setting. PMID- 30404520 TI - Shape oscillation and stability of an encapsulated microbubble translating in an acoustic wave. AB - Encapsulated microbubbles (EMBs) are associated with a wide variety of important medical applications, including sonography, drug delivery, and sonoporation. The nonspherical oscillations, or shape modes, of EMBs strongly affect their stability and acoustic signature, and thus are an important factor to consider in the design and utilization of EMBs. Under acoustic forcing, EMBs often translate with significant velocity, which can excite shape modes, yet few studies have addressed the effect of translation on the shape stability of EMBs. In this work, the shape stability of an EMB subject to translation is investigated through development of an axisymmetric model for the case of small deformations. The potential flow in the bulk volume of the external flow is modeled using an asymptotic analysis. Viscous effects within the thin boundary layer at the interface are included, owing to the no-slip boundary condition, using Prosperetti's theory [Q. Appl. Math. 34, 339 (1977)]. In-plane stress and bending moment due to the encapsulation are incorporated into the model through the dynamic boundary condition at the interface. The evolution equations for radial oscillation, translation, and shape oscillation of an EMB are derived, which can be reduced to model an uncoated gas bubble by neglecting the encapsulation properties. These equations are solved numerically to analyze the shape mode stability of an EMB and a gas bubble subject to an acoustic, traveling plane wave. The findings demonstrate the counterintuitive result that translation has a more destabilizing effect on an EMB than on a gas bubble. The no-slip condition at the encapsulating membrane is the main factor responsible for mediating this interfacial instability due to translation. PMID- 30404521 TI - Uncertainty analysis on free-field reciprocity calibration of measurement microphones for airborne ultrasound. AB - Airborne ultrasound has been used for various purposes, including object detection and pest repellent systems. Recently, it has been used in haptic technology for virtual reality. The safety of exposure to airborne ultrasound has been studied as its use has increased. Although airborne ultrasound cannot be directly perceived by humans, some research has found that exposure to very high sound pressure levels can harm the human body. Thus, quantitative characterization of airborne ultrasound is essential. To contribute to the safe use of airborne ultrasound, this paper established the acoustic standards in Japan in terms of sound pressure from 20 to 100 kHz. This paper evaluates the measurement uncertainty in the free-field reciprocity calibration of quarter-inch condenser microphones, following the document "Guide to the Expression of Uncertainty in Measurement," and describes a few significant uncertainty components, such as deviation from the plane sound field. As a result, it is realized that the expanded uncertainty of 0.3-0.7 dB in a frequency range from 20 to 100 kHz. PMID- 30404522 TI - Piecewise assembled acoustic arrays based on reconfigurable tessellated structures. AB - Physically reconfigurable, tessellated acoustic arrays inspired by origami structures have recently been leveraged to adaptively guide acoustic energy. Yet, the prior work only examined tessellated arrays composed from uniform folding patterns, so that the limited folding-induced shape change prohibits broad acoustic field tailoring. To explore a wider range of opportunities by origami inspired acoustic arrays, here, piecewise geometries are assembled from multiple folding patterns so that acoustic transducer elements are reconfigured in more intricate ways upon array folding. An analytical model of assembled geometries and resulting acoustic wave radiation from the oscillating facets is formulated. Using the theoretical tool, parametric investigations are undertaken to study the adaptation of acoustic energy transmission caused by folding and modularity of the array assembly. A proof-of-concept specimen is fabricated and experiments are conducted to validate the theoretical model and to investigate the efficacy of the piecewise acoustic array concept. The total findings reveal that the assembly of tessellated acoustic arrays may emulate the wave radiation emitted by ideal acoustic sources of intricate shapes. Moreover, by exploitation of origami folding actions, the shape adaptations of the proposed arrays permit straightforward wave guiding opportunities for diverse application needs. PMID- 30404523 TI - Evanescent waves in simulated ear canals: Experimental demonstration and method for compensation. AB - Evanescent waves emerge from a small sound source that radiates into a waveguide with a larger cross-sectional area, but unlike planar waves, do not propagate far from the source. Evanescent waves thus contaminate in-ear calibration of acoustic stimuli. Measurements with an otoacoustic-emission (OAE) probe inserted at the entrance of long tubes of various diameters show a decline in the evanescent wave with distance from the source when advancing a probe tube through the OAE probe and into the long tube. The amplitude of the evanescent pressure increases with frequency and depends strongly on the diameter of the long tube. Modifying the shape of the aperture of the probe's sound source, thus effectively enlarging its diameter and redirecting acoustic flow, greatly reduced evanescent waves. The reduction in evanescent-wave pressure was observed in calibration cavities used to determine the Thevenin-equivalent source pressure and impedance of the probe. Errors in source calibrations were considerably larger in the unmodified configuration. An alternative method is proposed for calculation of acoustic source parameters that models the evanescent-wave pressure and reduces its influence on the calculation. This reduction greatly improves the quality of source calibrations, which should improve the accuracy of ear-canal impedance measurements and related quantities. PMID- 30404524 TI - Optimized reactive silencers with narrow side-branch tubes. AB - This paper presents a theoretical study of the sound propagation in a waveguide loaded by an array of flush-mounted narrow side-branch tubes, forming a simple low-frequency reactive silencer. The individual tube-lengths and the distances between the adjacent tubes are optimized in order to maximize the minimum transmission loss over a given frequency range. The transmission properties of the silencer are calculated using the transfer matrix method, heuristic evolutionary approach is employed for the determination of the optimal parameters. The numerical results are validated against the finite element method simulation. A comprehensive parametric study is performed to demonstrate the optimized silencer performance as a function of the number of side-branch tubes, and the frequency range. It is shown that for the given frequency range, the minimum transmission loss of the optimized silencer increases linearly with the number of the side-branch tubes. PMID- 30404525 TI - Using Schlieren imaging to estimate the geometry of a shock wave radiated by a trumpet bell. AB - The Schlieren method has been used before to visualize weak shock waves radiated from the open ends of brass instruments, but no attempt has previously been undertaken, however, to measure the geometry of the radiated wavefronts using the Schlieren images. In this paper Schlieren visualization is used to estimate the geometry of the two-dimensional shock wavefronts radiated from the bell of a trumpet at different frequencies. It is observed that the geometry of the shocks does change with frequency, in the expected manner. The propagation speeds of these shocks are also calculated, and they too exhibit the anticipated behavior. PMID- 30404526 TI - Masking release in temporally fluctuating noise depends on comodulation and overall level in Cope's gray treefrog. AB - Many animals communicate acoustically in large social aggregations. Among the best studied are frogs, in which males form large breeding choruses where they produce loud vocalizations to attract mates. Although chorus noise poses significant challenges to communication, it also possesses features, such as comodulation in amplitude fluctuations, that listeners may be evolutionarily adapted to exploit in order to achieve release from masking. This study investigated the extent to which the benefits of comodulation masking release (CMR) depend on overall noise level in Cope's gray treefrog (Hyla chrysoscelis). Masked signal recognition thresholds were measured in response to vocalizations in the presence of chorus-shaped noise presented at two levels. The noises were either unmodulated or modulated with an envelope that was correlated (comodulated) or uncorrelated (deviant) across the frequency spectrum. Signal-to noise ratios (SNRs) were lower at the higher noise level, and this effect was driven by relatively lower SNRs in modulated conditions, especially the comodulated condition. These results, which confirm that frogs benefit from CMR in a level-dependent manner, are discussed in relation to previous studies of CMR in humans and animals and in light of implications of the unique amphibian inner ear for considerations of within-channel versus across-channel mechanisms. PMID- 30404527 TI - Free-field reciprocity calibration of measurement microphones at frequencies up to 150 kHz. AB - Microphones are typically calibrated in a free field at frequencies up to 40 kHz using primary and secondary methods. This upper frequency is sufficiently high as to cover most sound measurement applications related with airborne noise assessment. However, other applications such as measurement of noise emitted by ultrasound cleaning machines, failure detection in aeronautic structures, and the investigation of the perception mechanisms of ultrasound may require that the sensitivity of the microphone is known at frequencies up to 150 kHz. In any of these applications, it is critical to establish a well-defined traceability chain to SI units to support any measurement result. In order to extend the frequency range of absolute free-field calibration, typical reciprocity measurement systems and measurement methods must undergo a series of changes and adaptations which may include using other types of microphones rather than laboratory standard microphones, changing the type of measurement signal, improving the methods for eliminating unwanted reflections from walls, cross-talk, distortion, etc. Herein, a strategy for the changes and adaptations to the existing measurement methodologies, and the determination of the microphone parameters is outlined, the results of its implementation are discussed, and calibrations results are presented and discussed. PMID- 30404528 TI - Clinicopathologic factors associated with recurrence and long-term survival in node-negative advanced gastric cancer patients. AB - BACKGROUND: despite a better prognosis in node-negative advanced gastric cancer (GC), a proportion of patients have a tumor recurrence within five years and eventually die due to cancer-related causes. The present study aimed to evaluate the predictive factors of tumor recurrence and long-term survival in node negative advanced GC. METHODS: a total of 646 node-negative advanced GC patients who underwent a curative gastrectomy in our institution were included in the study. The impact of different clinicopathologic factors on tumor recurrence and overall survival were analyzed. RESULTS: tumor recurrences were observed in 181 patients and the cumulative recurrence rate at two-years and five-years were 50.8% and 86.2%, respectively. Lymphovascular invasion, advanced T stage (T3-T4) and an inadequate number of retrieved lymph nodes (LNs) were independent predictive factors of tumor recurrence in node-negative advanced GC. Older age, an upper 1/3 tumor, lymphovascular invasion, infiltration growth pattern (INFgamma) and the depth of tumor invasion (T4 stage) were independently associated with long-term survival. With regard to node-negative patients with >= 15 retrieved LNs, infiltration growth pattern (INFgamma) and advanced T stage (T3 T4) were independent risk factors for both tumor recurrence and long-term survival. CONCLUSION: in addition to lymphovascular invasion, inadequate RLNs and advanced T stage, the prognostic significance of infiltration growth pattern in node-negative advanced GC was especially emphasized. These risk factors should be considered when selecting candidates for adjuvant chemotherapy and postoperative surveillance. PMID- 30404529 TI - Cystic tumors of the pancreas. An update of the surgical experience in a single institution. AB - BACKGROUND: the aim of the present study was to analyze the clinicopathological features of patients undergoing pancreatic surgical resections due to cystic neoplasms of the pancreas. MATERIAL AND METHODS: demographic data, form of presentation, radiologic images and location of the tumors within the pancreas were analyzed. Data was also collected on the type of surgery (open/laparoscopic), postoperative complications and their severity and oncologic outcomes. RESULTS: eighty-two pancreatic resections were performed. The mean age of patients was 57 years and 49 (59%) were female. Forty-one tumors (50%) were incidental and the most frequent symptoms in the group of symptomatic patients were abdominal pain (63.4%) and weight loss (36.5%). Thirty-two tumors (39%) were located in the tail of the pancreas, 25 (30.5%) in the head and 20 (24.4%) in the body. Thirty-nine (47.5%) distal pancreatectomies, 16 central, ten duodenal pancreatectomies and one enucleation were performed; 40 (48.5%) were carried out laparoscopically. Mean hospital stay was ten days and eight patients (7%) experienced severe complications, one was a pancreatic fistula. Sixty-six tumors (80.5%) were recorded as non-invasive and 16 (19.5%) as invasive: seven intraductal mucinous papillary tumors, one cystic mucinous tumor, four solid pseudopapillary tumors and four cystic neuroendocrine tumors. There was a median follow-up of 64 months; disease-free survival at five and ten years was 97.4% in the patients with non-invasive tumors and 84.6% and 70.5% in the invasive tumors group (p < 0.01). CONCLUSIONS: fifty percent of cystic neoplasms of the pancreas are incidental. Two phenotypes exist, invasive and non-invasive. PMID- 30404530 TI - Bidirectional Associations Between Adiposity, Sedentary Behavior, and Physical Activity: A Longitudinal Study in Children. AB - BACKGROUND: Previous studies have reported on the associations between obesity and sedentary behavior (SB) or physical activity (PA) in children. This study examined longitudinal and bidirectional associations between adiposity and SB and PA in children. METHODS: Participants were 356 children in England. PA was measured at 7 and 9 years of age using accelerometry. Outcome and exposures were time in SB and PAs and concurrent body mass index z score and fat index (FI). RESULTS: Adiposity at baseline was positively associated with changes in SB (beta = 0.975 for FI) and negatively associated with changes in moderate to vigorous PA (beta = -0.285 for body mass index z score, beta = -0.607 for FI), vigorous PA (beta = -0.095 for FI), and total PA (beta = -48.675 for FI), but not vice versa. The changes in SB, moderate to vigorous PA, and total PA for children with overweight/obesity were significantly more adverse than those for children with healthy weight. CONCLUSIONS: A high body mass index z score or high body fatness at baseline was associated with lower moderate to vigorous PA and vigorous PA after 2 years, but not vice versa, which suggests that in this cohort adiposity influenced PA and SB, but the associations between adiposity and SB or PA were not bidirectional. PMID- 30404531 TI - Poststroke Delirium Clinical Motor Subtypes: The PRospective Observational POLIsh Study (PROPOLIS). AB - Although delirium is the most common neurobehavioral complication after stroke, its motor subtypes-hypoactive, hyperactive, mixed, and none-as well as their risk factors are not well characterized. Motor subtypes influence recognition and prognosis of delirium in hospitalized patients. The aim of this prospective study was to assess the frequency of poststroke delirium subtypes and to describe their predictive models. Consecutive patients with stroke were screened for delirium with the Confusion Assessment Method for the Intensive Care Unit. Delirium was diagnosed according to DSM-5 criteria, and subtypes were classified with the Delirium Motor Subtype Scale-4. Baseline demographic characteristics, biochemistry, stroke-related data, medications, neurological deficits, and premorbid cognitive and functional impairments were assessed. Out of 750 patients (mean age, 71.75 years [SD=13.13]), 203 (27.07%) had delirium: 85 (11.34%) were hypoactive, 77 (10.27%) were mixed hypoactive-hyperactive, 31 (4.13%) were hyperactive, and 10 (1.33%) had an unspecified type. Cognitive impairment at the time of hospital admission and spatial neglect, among other factors, were identified as the best predictors for all motor delirium subtypes. Screening for poststroke delirium is important because the hypoactive subtype bears the worst prognosis and is misdiagnosed the most compared with other subtypes. All identified factors for the predictive models of delirium subtypes are routinely assessed during hospital admission. Their occurrence in patients with stroke should alert the treating physician to the high risk for a particular delirium subtype. PMID- 30404532 TI - Utility of the Clock Drawing Test in the Assessment of Catatonia. PMID- 30404533 TI - Bifrontal Hypermetabolism on Brain FDG-PET in a Case of C9orf72-Related Behavioral Variant of Frontotemporal Dementia. PMID- 30404534 TI - Retrograde Autobiographical Memory From PTA Emergence to Six-Month Follow-Up in Moderate to Severe Traumatic Brain Injury. AB - The overwhelming focus of research on memory following traumatic brain injury (TBI) has been on anterograde amnesia, and very little attention has been paid to retrograde amnesia. There is evidence to suggest that retrograde autobiographical memory deficits exist after severe TBI, although there have been no prospective studies of autobiographical memory in a representative sample of moderate to severe cases recruited from hospital admissions. The purpose of the present study was to report changes in autobiographical memory performance among a group of patients soon after emergence from posttraumatic amnesia (PTA) and at the 6-month follow-up compared with a healthy control (HC) group. The authors also examined associations with anterograde memory function and community integration to assist in understanding the functional impact of autobiographical memory deficits and potential underlying mechanisms. The Autobiographical Memory Interview and the Rey Auditory Verbal Learning Test were used as measures of retrograde and anterograde memory, respectively, and the Community Integration Questionnaire was used as a measure of functional outcome in the TBI group. The results demonstrated that both personal semantic and episodic autobiographical memory scores were impaired following emergence from PTA and at the 6-month follow-up. Only subtle differences emerged in change over time in different injury severity groups. Recent retrograde memory function was associated with anterograde memory performance, which supports some degree of overlap in underlying mechanisms. The findings suggest that autobiographical memory deficits are prevalent following moderate to severe TBI and warrant consideration in rehabilitation. PMID- 30404535 TI - Is there a role for lithium orotate in psychiatry? PMID- 30404536 TI - Mental health disorder, pain, and pain treatment among long-term care residents: Evidence from the Minimum Data Set 3.0. AB - OBJECTIVE: This study evaluated: (a) associations between long-term care residents' mental health disorder diagnoses and their pain self-reports and pain treatments, and (b) the extent to which communication, cognitive, and physical functioning problems help explain disparities in the pain and pain treatments of long-term care residents with and without mental health disorders. METHOD: Minimum Data Set 3.0 records of 8,300 residents of Department of Veterans Affairs Community Living Centers were used to determine statistically unadjusted and adjusted cross-sectional associations between residents' mental health diagnoses and their pain and pain treatments. RESULTS: Residents diagnosed with dementia and serious mental illness (SMI) were less likely, and those diagnosed with depressive disorder, post-traumatic stress disorder (PTSD), and substance use disorder (SUD) were more likely, to report recent, severe, and debilitating pain. Among residents affirming recent pain, those with dementia or SMI diagnoses were twice as likely to obtain no treatment for their pain and significantly less likely to receive as-needed pain medication and non-pharmacological pain treatments than were other residents. Those with either depressive disorder or PTSD were more likely, and those with SUD less likely, to obtain scheduled pain medication. In general, these associations remained even after statistically adjusting for residents' demographic characteristics, other mental health disorder diagnoses, and functioning. CONCLUSION: Long-term care residents with mental health disorders experience disparities in pain and pain treatment that are not well-explained by their functioning deficits. They may benefit from more frequent, thorough pain assessments and from more varied and closely tailored pain treatment approaches. PMID- 30404537 TI - Engineering a Brighter Future: The Evolving Role of the Pharmacist in the Era of the HeartMate 3. AB - Continuous-flow left-ventricular assist devices (CF-LVADs) are an option for patients with end-stage heart failure requiring durable mechanical circulatory support. Two of the older-generation CF-LVADs have been associated with multiple device-related complications, including bleeding and thrombosis. The newest generation CF-LVAD, the HeartMate 3, was engineered specifically to prevent device-related thrombosis. As more data enhance our understanding of the burden of bleeding and thrombotic adverse events, patients with durable mechanical circulatory support may require less-aggressive antithrombotic therapy. PMID- 30404538 TI - Biological characteristics and immunological properties in Muscovy ducks of H5N6 virus-like particles composed of HA-TM/HA-TMH3 and M1. AB - Highly pathogenic avian influenza viruses (HPAIVs), including H5N6 strains, pose threats to the health of humans and poultry. Waterfowl play a crucial role as a reservoir of HPAIVs. Since current influenza vaccines induce poor antibody titres in waterfowl, there is an urgent need to develop an efficient vaccine against H5N6 infection. In this study, we constructed two H5N6 virus-like particles (VLPs) composed of matrix-1 (M1) and haemagglutinin of wildtype (HA-TM) or haemagglutinin with transmembrane domain replacement (HA-TMH3) (designated as H5N6 VLPs-TM and H5N6 VLPs-TMH3). Biological characteristics of the composed H5N6 VLPs were compared including localization, expression, contents of HA trimers, thermal stability, morphology and immunogenicity in Muscovy ducks. Our results indicate that the H5N6 VLPs-TMH3 contained more HA trimers and presented better thermal stability. Moreover, Muscovy ducks immunized with H5N6 VLPs-TMH3 produced higher titres of HI antibody and IFN-gamma compared with those immunized with the same dose of H5N6 VLP-TM, thus providing a promising approach for the development of influenza virus vaccines for waterfowl. RESEARCH HIGHLIGHTS H5N6 VLPs-TMH3 had more HA trimers and resisted higher temperature than H5N6 VLPs-TM H5N6 VLPs-TMH3 induced higher titre of HI than H5N6 VLPs-TM in Muscovy ducks. PMID- 30404539 TI - Recent Updates in the Pharmacological Management of Sepsis and Septic Shock: A Systematic Review Focused on Fluid Resuscitation, Vasopressors, and Corticosteroids. AB - OBJECTIVE: Describe recent developments in the pharmacological management of sepsis and septic shock, focusing on fluid resuscitation, vasopressors, and corticosteroids. DATA SOURCES: A literature search limited to randomized controlled trials written in the English language reporting mortality and other clinically relevant outcomes that were published from July 1, 2016, to August 31, 2018, in patients aged >= 18 years. Titles and abstracts were reviewed for relevance. References for pertinent review articles were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Relevant randomized controlled trials conducted in patients meeting the pre-defined inclusion criteria were considered for inclusion. DATA SYNTHESIS: From an initial search that identified 147 studies, 14 original research studies met inclusion criteria and were included in this review. Risk of bias (ROB) was assessed using the Revised Cochrane ROB assessment tool, with most included studies having a low ROB. Relevance to Patient Care and Clinical Practice: Sepsis and septic shock pose a significant burden on public health. Despite advances in our understanding of sepsis, mortality remains unacceptably high. Recent developments in the pharmacological management of septic shock have focused on determining optimal composition and dosage of fluid resuscitation, enhanced use of vasopressor therapy, and clarifying the role of corticosteroids. This systematic review will provide recommendations for application to practice focusing on recent research on these topics. CONCLUSIONS: Although recent developments in the pharmacological management of sepsis are encouraging, clinicians must be keen to utilize patient-specific factors to guide therapy and continue to strive to address the remaining unanswered questions. PMID- 30404540 TI - A double recombinant herpes virus of turkeys for the protection of chickens against Newcastle, infectious laryngotracheitis and Marek's diseases. AB - A double recombinant strain of herpes virus of turkeys (HVT) was constructed that contains the fusion (F) gene from Newcastle disease virus (NDV) and the gD plus gI genes from infectious laryngotracheitis virus (ILTV) inserted into a non essential region of the HVT genome. Expression of the F protein was controlled by a human cytomegalovirus promoter, whereas expression of gD plus gI was driven by an ILTV promoter. The double recombinant vaccine virus (HVT-NDV-ILT) was fully stable genetically and phenotypically following extended passage in cell culture and infection of chickens. Safety of the vaccine virus was confirmed by overdose and backpassage studies in specific-pathogen-free chickens. Chickens vaccinated with a single dose of HVT-NDV-ILT administered by the in ovo route were highly protected from challenge with the velogenic NDV (GB Texas), ILTV (LT 96-3) and Marek's disease virus (GA 5) strains (97%, 94% and 97%, respectively). Similarly, chickens vaccinated with a single dose by subcutaneous (SC) route at 1 day of age were highly protected from challenge with the same three viruses (100%, 100%, and 88%, respectively). The protection level of a single dose given by in ovo or SC route against challenge with a virulent Marek's disease virus strain demonstrates that insertion of multiple genes from two different pathogens within the HVT genome had no adverse effect on the capacity of HVT to protect against Marek's disease. These results demonstrate that HVT-NDV-ILT is a safe and efficacious vaccine for simultaneous control of NDV, ILTV and Marek's diseases. PMID- 30404542 TI - Vaccination of chickens with the 34 kDa carboxy-terminus of Bpmp72 reduces colonization with Brachyspira pilosicoli following experimental infection. AB - The anaerobic intestinal spirochaete Brachyspira pilosicoli colonizes the large intestine of a variety of species of mammals and birds, and may result in colitis, diarrhoea and reductions in growth rate. Naturally occurring infections in chickens are largely confined to adult laying and breeding birds. In this study, the 34 kD carboxy-terminus of the prominent outer membrane protein Bmp72 of B. pilosicoli was expressed as a histidine-tagged recombinant protein and used to immunize two groups (B and C) of 15 individually housed layer chickens. Vaccination was with either 100 MUg (B) or 1 mg (C) protein emulsified with Freund's incomplete adjuvant delivered into the pectoral muscles, followed three weeks later by 1 mg of protein in phosphate buffered saline delivered via crop tube. Two weeks later these and 15 non-vaccinated positive control birds (group A) housed in the same room were challenged via crop tube with B. pilosicoli avian strain CPS1. B. pilosicoli was detected in the faeces of all control birds and in 14 of the vaccinated birds in each vaccinated group at some point over the 30-day period following challenge. Colonization was delayed and the duration of excretion was significantly reduced (P = 0.0001) in both groups of vaccinated birds compared to the non-vaccinated control birds. Fewer immunized birds had abnormal caecal contents at post mortem examination compared to non-vaccinated birds, but the difference was not statistically significant. This study indicates that recombinant Bmp72 C-terminus has potential to be developed for use as a vaccine component to provide protection against B. pilosicoli infections. RESEARCH HIGHLIGHTS Laying chickens were immunized with recombinant Brachyspira pilosicoli membrane protein Bpmp72. Immunized birds had a highly significant reduction in the duration of colonization. Fewer immunized than control birds had abnormal caecal contents after infection. Bpmp72 showed potential for use as a novel vaccine component for B. pilosicoli. PMID- 30404541 TI - Brain-targeted delivery of PEGylated nano-bacitracin A against Penicillin sensitive and -resistant Pneumococcal meningitis: formulated with RVG29 and Pluronic(r) P85 unimers. AB - Pneumococcal meningitis (PM), caused by Streptococcus pneumonia, remains a high burden disease in developing countries. Antibiotic therapy has been limited due to the inefficiency of drug transport across the blood-brain barrier (BBB) and the emergence of drug-resistant strains. In our preliminary study, PEGylated nano self-assemblies of bacitracin A (PEGylated Nano-BA12K) demonstrated a strong antibacterial potency against S. pneumonia. In this study, the potential application of this micelle for the treatment of both Penicillin-sensitive and resistant PM was studied. To address BBB-targeting and -crossing issues, PEGylated Nano-BA12K was formulated with a specific brain-targeting peptide (rabies virus glycopeptide-29, RVG29) and a P-glycoprotein inhibitor (Pluronic(r) P85 unimers) to construct a mixed micellar system (RVG29-Nano-BAP85). RVG29-Nano BAP85 demonstrated a strong antibacterial potency against 13 clinical isolates of S. pneumonia, even higher than that of Penicillin G, a conventional anti-PM agent. RVG29-Nano-BAP85 had more cellular uptake in brain capillary endothelial cells (BCECs) and higher BBB-crossing efficiency than single formulated Nano-BAs as shown in an in vitro BBB model. The enhanced BBB-permeability was attributed to the synergetic effect of RVG29 and P85 unimers through receptor-mediated transcytosis, exhaustion of ATP, and reduction in membrane microviscosity. In vivo results further demonstrated that RVG29-Nano-BAP85 was able to accumulate in brain parenchyma as confirmed by in vivo optical imaging. In addition, RVG29-Nano BAP85 exhibited high therapeutic efficiencies in both Penicillin-sensitive and resistant PM mouse models with negligible systemic toxicity. Collectively, RVG29 Nano-BAP85 could effectively overcome BBB barriers and suppressed the growth of both drug-sensitive and -resistant S. pneumonia in the brain tissues, which demonstrated its potential for the treatment of PM. PMID- 30404543 TI - Fully tuned RBF neural network controller for ultrasound hyperthermia cancer tumour therapy. AB - Thermal dose is an important clinical efficacy index for hyperthermia cancer treatment. This paper presents a new direct radial basis function (RBF) neural network controller for high-temperature hyperthermia thermal dose during the therapeutic procedure of cancer tumours by short-time pulses of high-intensity focused ultrasound (HIFU). The developed controller is stabilized and automatically tuned based on Lyapunov functions and ant colony optimization (ACO) algorithm, respectively. In addition, this thermal dose control system has been validated using one-dimensional (1-D) biothermal tissue model. Simulation results showed that the fully tuned RBF neural network controller outperforms other controllers in the previous studies by achieving targeted thermal dose with shortest treatment times less than 13.5 min, avoiding the tissue cavitation during the thermal therapy. Moreover, the maximum value of its mean integral time absolute error (MTAE) is 98.64, which is significantly less than the resulted errors for the manual-tuned controller under the same treatment conditions of all tested cases. In this study, integrated ACO method with robust RBF neural network controller provides a successful and improved performance to deliver accurate thermal dose of hyperthermia cancer tumour treatment using the focused ultrasound transducer without external cooling effect. PMID- 30404544 TI - Efficacy of different photoprotection strategies in preventing actinic keratosis new lesions after photodynamic therapy. The ATHENA study: a two-center, randomized, prospective, assessor-blinded pragmatic trial. AB - BACKGROUND: Treatment of actinic keratosis (AK) and field cancerization with photodynamic therapy (PDT) is an effective therapeutic approach with a significant reduction in the number of AK lesions (-75% or more) associated with a significant cosmetic improvement of the photodamaged skin. Recently, also, the daylight PDT (DL-PDT) has proven to be as effective as the conventional PDT (C PDT), but with a better tolerability. After C-PDT and DL-PDT it is advised to use photoprotection strategies to improve the clinical evolution and prevent the appearance of new AK lesions that usually appear 3-6 months after the last phototherapy session. However, there are no robust clinical data regarding the type of photoprotection to be used (SPF level, duration of treatment, etc.) after successful PDT. STUDY AIM: The present study (ATHENA trial) evaluated the efficacy and tolerability of a topical product based on 0.8% piroxicam and 50+ solar filters (ACTX), applied twice a day as sequential therapy after C-PDT or DL PDT on the evolution of AK lesions number compared to the use of very high photoprotection products commonly used in this clinical setting (SPF50+ or SPF100+ associated with photolyase) (Standard Sunscreens: SS group). SUBJECTS AND METHODS: This was a multicenter, randomized, two-arm, prospective controlled, assessor-masked outcome evaluation, parallel group (1:1), pragmatic study of 6 months duration in patients with multiple AK lesions suitable for photodynamic therapy. The objectives of the study were the evaluation of the evolution of the number of AK lesions during the period of treatment/application of the study products, and the Investigator global clinical assessment score (IGA score; 4: marked improvement, 3: good, 2: moderate; 1 no improvement; 0: worsening) 2, 3, and 6 months after the last PDT session. A total of 68 subjects (50 men, 18 women; mean age 70 years), 34 assigned to treatment with ACTX and 34 to treatment with SS (17 treated with a SPF50+ and 17 with a photolyase-containing SPF100+ products), were enrolled in the study. RESULTS: The number of AK lesions present before C-PDT/DL-PDT was 11.8 +/- 5.8 in the ACTX group and 12.4 +/- 6.9 in the SS group. In both groups, there was a progressive reduction of AK lesions observed at baseline (-86% and -87% after 2 months and -88% and -83% at month 3 in ACTX and in the SS group, respectively). At month 6, AK mean lesion number was 1.8 +/- 1.6 in the ACTX and 3.2 +/- 2.3 in the SS group; this difference was statistically significant (p = 0.03). The IGA score at the end of the study was 3.2 in the ACTX and 2.7 in the SS group (p = 0.05). The percentage of subjects with an IGA score of 4/3 (very good or good) was 81% in the ACTX and 55% in the SS group (p = 0.06). CONCLUSION: In subjects with AK treated with C-PDT or DL PDT, a "medicalized" photoprotection treatment is associated with a favorable clinical outcome with progressive reduction of lesions. In contrast to a very high photoprotection (SPF50+ or SPF100+/photolyase), the use of piroxicam 0.8%/SPF 50+ is associated with a significantly greater improvement in clinical evolution of AK lesions. PMID- 30404545 TI - Safety of Sodium Hyaluronate Eye Drop with C12-Benzailonium Chloride. AB - PURPOSE: In this study, we investigated the effects of commercially available multi-dose Sodium Hyaluronate 0.1% (Hyalein(r); Santen, Osaka, Japan) containing 0.003% C12 benzalkonium chloride (BAC) on the corneal epithelial and its degree of safety. METHODS: Japanese white male rabbits were divided into 4 groups. The corneas of each group exposed to one of the following solutions, Sodium Hyaluronate 0.1%, C12- benzalkomium chloride (BAC), C12, 14, 16-BAC Mixture, and Hank's Balanced Salt Solution (HBSS)(as control) respectively. Corneal transepithelial electrical resistance (TER) changes after 60 seconds of exposure to the above solutions were measured in living rabbits. TER reflects the barrier function of the epithelium. In addition, scanning electron microscopy (SEM) was used to examine the acute effects of the above solutions on the integrity of the corneal epithelium of four groups. RESULTS: There was no significant decrease in the corneal TER after exposure of the cornea to Hyalein(r) eye drops as compared to HBSS control eyes. Also, BAC mixture solution and C12-BAC did not produce any significant decrease in the corneal TER as compared to HBSS control eyes. All the corneal epithelium exposed to Hyalein(r), 0.003% C12-BAC and 0.003% BAC mixture exhibited a regular appearance of the superficial cells with a high density of microvilli. CONCLUSION: This study confirms that Hyalein(r) has no acute hazardous effect on corneal epithelium. PMID- 30404546 TI - Viewpoint: A hypothesis arising from the epidemiology of schizophrenia in Maori. PMID- 30404547 TI - Pregnane glycoside from Huernia saudi-arabica as latent schistosomicidal mediator. AB - Development of a novel agent for control of schistosomiasis is a mandate. In vitro anti-schistosomal activity of the aerial parts of Huernia saudi-arabica were examined. Chromatographic investigations of the ethanol extract (EE) were afforded three compounds. Pregnane glycoside (CI) 12-beta-p-hydroxy-benzoyl-20-O acetyl-boucerin-3-O-beta-D-glucopyranosyl-(1->4)-beta-D-cymaropyranosyl-(1->4) beta-D-cymaropyranoside, in addition to two flavonoids (CII) luteolin-4'-O-beta-D neohesperidoside and (CIII)quercetin-3-rutinoside were recognized via spectral analysis. The schistosomicidal effects were evaluated using scanning electron microscope (SEM). In-vitro bioassays on the viability (mobility, morphological changes and mortality) of Schistosoma mansoni adults, cercariae, miracidia and eggs at different concentrations 2.5, 5, 12.5, 25 and 50 MUg/ml of EE and 2.6, 5.2, 13, 26 and 52 MUM of CI in incubation times 1,2,4,6,12hrs were carried out. EE and CI evidenced in-vitro anti-schistosomal activity with a dose and incubation time-dependent fashion. The effect of EE and CI was evident by the topography damage showed by SEM. EE proved moderate in-vitro cytotoxicity with IC50 of 8.48 ug/ml. PMID- 30404548 TI - A mixed-methods process evaluation of Family Navigation implementation for autism spectrum disorder. AB - There is growing interest in Family Navigation as an approach to improving access to care for children with autism spectrum disorder, yet little data exist on the implementation of Family Navigation. The aim of this study was to identify potential failures in implementing Family Navigation for children with autism spectrum disorder, using a failure modes and effects analysis. This mixed-methods study was set within a randomized controlled trial testing the effectiveness of Family Navigation in reducing the time from screening to diagnosis and treatment for autism spectrum disorder across three states. Using standard failure modes and effects analysis methodology, experts in Family Navigation for autism spectrum disorder (n = 9) rated potential failures in implementation on a 10 point scale in three categories: likelihood of the failure occurring, likelihood of not detecting the failure, and severity of failure. Ratings were then used to create a risk priority number for each failure. The failure modes and effects analysis detected five areas for potential "high priority" failures in implementation: (1) setting up community-based services, (2) initial family meeting, (3) training, (4) fidelity monitoring, and (5) attending testing appointments. Reasons for failure included families not receptive, scheduling, and insufficient training time. The process with the highest risk profile was "setting up community-based services." Failure in "attending testing appointment" was rated as the most severe potential failure. A number of potential failures in Family Navigation implementation-along with strategies for mitigation-were identified. These data can guide those working to implement Family Navigation for children with autism spectrum disorder. PMID- 30404549 TI - QuilliChew extended-release chewable tablets for the treatment of ADHD in patients ages 6 years old and above. AB - INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder affecting as many as 6.4 million children and adolescents in the United States. Since amphetamine (AMPH) and methylphenidate (MPH) were found to be effective more than 60 years ago, numerous formulations of these compounds have been developed. New preparations have focused on convenience, with extended-release (ER) drugs allowing once-daily dosing. Multiple ER formulations do not require patients to swallow a tablet or capsule. Recent ER preparations include liquids, oral disintegrating tablets, and chewable tablets. Several new formulations use ion exchange technology containing both immediate-release and ER components. Areas covered: Quillichew ERTM (MPH-ERCT) is an ER methylphenidate designed to be chewed before swallowing. The technology and pharmacokinetics, along with efficacy and safety data, are presented. Expert opinion: Extensive safety and efficacy data exist for MPH. ER formulations can be distinguished by preparation (tablet, capsule, liquid) and onset and duration of effect, but efficacy is similar for all ER MPH products. Each formulation has attributes, such as ease of titration, portability, and taste, that make it more acceptable for certain patients. Because AMPH and MPH are so effective, current technology research is focused on improving safety, convenience, and onset and duration of effect. PMID- 30404551 TI - Human rights framework: An ethical imperative for psychiatry. PMID- 30404550 TI - Characteristics and Diversity Of ACGME Accredited EMS Fellowship Programs. AB - INTRODUCTION: There is little published data in regards to Emergency Medical Services (EMS) fellowship programs. The purpose of this study was to obtain program characteristics and diversity data regarding EMS fellowship programs. METHODS: A survey was sent to program directors at all EMS fellowship programs accredited by the Accreditation Council of Graduate Medical Education (ACGME). Data collected included: year program started, year program accredited, unfilled fellow positions, number of EMS faculty, gender, and race/ethnicity. Gender and race/ethnicity data from EMS fellowships were compared to emergency medicine (EM) residencies using data from the American Association of Medical Colleges. Data were analyzed using IBM SPSS with descriptive statistics, and Chi-square tests. RESULTS: The response rate for the survey was 88% (45/51) of all EMS fellowship programs that were accredited at the time of this survey. Most programs (71%) offer a one-year EMS fellowship, with the remaining offering an optional second year. The median number of physician response vehicles per program was 1.0 (IQR 0.0-2.0), with 24% (11/45) not having a dedicated physician response vehicle. This survey identified that 118 EMS fellows have graduated since inception of the accreditation process, while 34 positions went unfilled. The median number of EMS fellow positions per program was 2.0 (IQR 1.0-2.0), with a range of 1-4. It was noted that 31% of programs had no female EMS faculty, and 48% of programs had no under-represented minority EMS faculty. There was a significantly larger proportion of female faculty in EM residency programs (30.5%;949/3,107) compared to EMS fellowships (19%; 53/274), OR =1.8, 95% CI:1.3-2.5, p < 0.0001. There was a significantly larger proportion of female fellows in EMS (56%; 66/118) vs. female residents in EM (38%; 2,193/5,777), OR =2.1, 95% CI:1.4-3.0, p < 0.0001. There was a significantly larger proportion of under-represented minority faculty in EM residency programs (19.7%;786/3,978) vs. EMS fellowships (12.0%, 33/274), OR =1.8, 95% CI:1.2-2.6, p < 0.002. CONCLUSION: A significant number of EMS fellowship positions have remained unfilled since implementation of an accreditation process for EMS fellowships. The percentage of females and under represented minority faculty in EMS programs was much lower than for EM residency programs. PMID- 30404552 TI - Ameloblastoma: a retrospective single institute study of 34 subjects. AB - OBJECTIVE: This study aims to clarify demographic and clinical aspects of patients with ameloblastoma treated at a single Finnish institute during 1985 2016. Associations between predictor variables (gender and age) and outcome variables (location, tumour type, growth patterns and average tumour size) were sought. MATERIALS AND METHODS: A retrospective cohort study was designed and implemented including 34 patients diagnosed with primary ameloblastoma and treated at the Helsinki University Central Hospital. Patient records were investigated, and tissue samples re-evaluated. The chi-square test was used on all categorized variables and t-test for continuous ones. A p value equal to or under .05 was considered significant. RESULTS: Males were slightly more predominant among the Finnish patients with ameloblastoma. Maxillary tumours were seen exclusively in male patients (p = .034). Additionally, these patients were older than patients with mandibular tumours (p = .007). A mixture in histological growth patterns was more common than originally anticipated. The study revealed a wide range of clinical signs and subjective symptoms, of which pain or other sensations were experienced most often. CONCLUSIONS: This study of 34 subjects shows that southern Finnish patients with ameloblastoma do not substantially differ from patients in similar study designs. PMID- 30404553 TI - Mimengosides J and K: two new neuroprotective triterpenoids from the fruits of Buddleja lindleyana. AB - Two new 11-methoxyl substituted triterpenoids, named as mimengosides J (1) and K (2), along with seven known compounds, were isolated from the fruits of Buddleja lindleyana. Their structures were elucidated on the basis of spectroscopic analysis. In addition, the new ones were evaluated for protective effects against damage of SH-SY5Y cells induced by 1-methyl-4-phenylpyridinium ion (MPP+) and the results indicated that those may be one of the candidate compositions of Buddleja lindleyana for the treatment of neurodegenerative disease. [Formula: see text]. PMID- 30404554 TI - Nanoencapsulation of betamethasone valerate using high pressure homogenization solvent evaporation technique: optimization of formulation and process parameters for efficient dermal targeting. AB - Betamethsone valerate (BMV), a medium potency topical corticosteroid, is one of the most commonly employed pharmacological agents for the management of atopic dermatitis in both adults and children. Despite having remarkable pharmacological efficacy, these agents have limited clinical implication due to poor penetration across the startum cornum (SC). To mitigate issues related to targeted delivery, stability, and solubility as well as to potentiate therapeutic and clinical implication, the nanodelivery systems have gained remarkable recognition. Therefore, this study was aimed to encapsulate BMV into the chitosan nanoparticles (CS-NPs) for optimum dermal targeting and improved penetration across the SC. The prepared NPs were characterized for particle size, zeta potential, polydispersity index, entrapment efficiency, loading capacity, crystallinity, thermal behavior, morphology, in vitro release kinetics, drug permeation across the SC, and percentage of drug retained into various skin layers. Results showed that optimized BMV-CS-NPs exhibited optimum physicochemical characteristics including small particle size (< 250 +/- 28 nm), higher zeta potential (+58 +/- 8 mV), and high entrapment efficiency (86 +/- 5.6%) and loading capacity (34 +/- 7.2%). The in vitro release study revealed that BMV-CS-NPs displayed Fickian-diffusion type mechanism of release in simulated skin surface (pH 5.5). Drug permeation efficiency and the amount of BMV retained into the epidermis and the dermis were comparatively higher in case of BMV-CS-NPs compared to BMV solution. Conclusively, we anticipated that BMV-CS-NPs could be a promising nanodelivery system for efficient dermal targeting of BMV and improved anti-AD efficacy. PMID- 30404555 TI - Tumor clonality and resistance mechanisms in EGFR mutation-positive non-small cell lung cancer: implications for therapeutic sequencing. AB - While the development of EGFR-targeted tyrosine kinase inhibitors (TKIs) has revolutionized treatment of EGFR mutation-positive non-small-cell lung cancer, acquired resistance to therapy is inevitable, reflecting tumor evolution. Recent studies show that EGFR mutation-positive non-small-cell lung cancer is highly heterogeneous at the cellular level, facilitating clonal expansion of resistant tumors via multiple molecular mechanisms. Here, we review the mechanistic differences between first-, second- and third-generation EGFR-targeted TKIs and speculate how these features could explain differences in clinical activity between these agents from a clonal evolution perspective. We hypothesize that the molecular dissection of tumor resistance mechanisms will facilitate optimal sequential use of EGFR TKIs in individual patients, thus maximizing the duration of chemotherapy-free treatment and survival benefit. PMID- 30404556 TI - Anagrelide is an anti-megakaryocytic and not an anti-platelet agent. PMID- 30404557 TI - Multivalent activation of GLP-1 and Sulfonylurea receptors modulates beta-cell Second Messenger Signaling and Insulin Secretion. AB - Linking two pharmacophores that bind different cell surface receptors into a single molecule can enhance cell-targeting specificity to cells that express the complementary receptor pair. In this report, we developed and tested a synthetic multivalent ligand consisting of glucagon-like peptide-1 (GLP-1) linked to glibenclamide (Glb) for signaling efficacy in beta-cells. Expression of receptors for these ligands, as a combination, are relatively specific to the beta-cell in the pancreas. The multivalent GLP-1/Glb increased both intracellular cAMP and Ca2+, although Ca2+ responses were significantly depressed compared to the monomeric Glb. Moreover, GLP-1/Glb increased glucose-stimulated insulin secretion in a dose-dependent manner. However, unlike the combined monomers, GLP-1/Glb did not augment insulin secretion at non-stimulatory glucose concentrations in INS 832/13 beta-cells or human islets of Langerhans. These data suggest that linking two binding elements into a single bivalent ligand, such as GLP-1 and Glb, can provide a unique functional agent targeted to beta-cells. PMID- 30404558 TI - RNA interference may suppresses stress granule formation by preventing Argonaute 2 recruitment. AB - RNA-induced silencing complex (RISC) is formed during RNA interference (RNAi), while stress granules (SG) are assembled in response to cellular stress. Here, we demonstrate an interesting connection between RISC and SG that may involve Argonaute 2 (Ago2), a core component of RISC. We analyzed SG induction by arsenite, the commonly used SG inducer. SG formation was suppressed in Hsf1 or Hif1alpha shRNA -transfected cells, but not in Hsf1 or Hif1alpha -knockout cells, suggesting that RNAi per se (rather than gene deficiency) may account for the suppressive effect on SG. In support, the suppressive effect of RNAi on SG formation was reversed by the RISC-loading inhibitor aurintricarboxylic acid (ATA). In non-RNAi cells, arsenite induced the accumulation of Ago2 in SGs as shown by its co-localization and co-immunoprecipitation with SG proteins; but Ago2 was not recruited to SG in the cells with RNAi. Consistently, arsenite induced the dissociation of Ago2 from RISC proteins in non-RNAi cells, but not in RNAi cells. CRISPR-cas9-medicated ablation of Ago2 attenuated SG formation during arsenite treatment, suggesting a critical role of Ago2 in SG assembly. Together, these results indicate that RISC and SG may compete for some key components, such as Ago2. In response to cellular stress, Ago2 is recruited for SG assembly; however, during RNAi, Ago2 is held in RISC becoming unavailable for SG formation. PMID- 30404560 TI - MicroRNA-143 inhibits proliferation and promotes apoptosis of thymocyte by targeting CXCL13 in myasthenia gravis mice models. AB - Myasthenia gravis (MG) is an autoimmune neuromuscular disorder, affecting the quality of life of millions of people worldwide. The current study aims to determine the relationship between microRNA-143 (miR-143) and CXCL13, and whether it influences the pathogenesis of myasthenia gravis (MG). Thymus specimens were resected from patients with thymic hyperplasia combined MG, and then infused into normal mouse cavities to establish MG mice models. Immunohistochemistry, RT-qPCR, in situ hybridization detection, and Western blot analysis were employed to identify the expression of miR-143 and CXCL13 in MG and normal mice. The obtained thymocytes were cultured in vitro and transfected with a series of miR-143 mimic, miR-143 inhibitor, oe-CXCL13 or siRNA against CXCL13. MTT and flow cytometry assays were employed to assess cell viability, cycle entry, and apoptosis of the thymocytes. Dual luciferase reporter assay provided verification, confirming CXCL13 was the target gene of miR-143. Low miR-143 expression in the thymus tissues of the MG mice was detected, which presented with a reciprocal relationship with the expression rate of CLCX13. Observations in relation to the interactions between miR-143 mimic or siRNA CXCL13 exposure resulted in reduced cell viability, with a greater number of cells arrested at the G0/G1 phase, and a greater rate of induced apoptosis. Furthermore, overexpression of CXCL13 rescued miR-143 mimic-induced apoptosis. The findings have identified the potential role of miR-143 as a MG development mediator by targeting CXCL13. The key results obtained provide a promising experimental basis for the targeted intervention treatment of miR-143. PMID- 30404561 TI - Resuming Publication of an Established Journal, Part 3. PMID- 30404559 TI - Adipose-derived mesenchymal stem cells accelerate diabetic wound healing in a similar fashion as bone marrow-derived cells. AB - We have previously shown that bone marrow-derived mesenchymal stem cells (BMSC) accelerate wound healing in a diabetic mouse model. We hypothesized that adipose tissue-derived stem cells (ADSC), of greater translational potential to human therapy, similarly improve diabetic wound healing. In this study, in vitro, the characterization and function of murine ADSC and BMSC, or human diabetic and non diabetic ADSC were evaluated by flow cytometry, cell viability, and VEGF expression. In vivo, biomimetic collagen scaffolds containing murine ADSC or BMSC were used to treat diabetic wounds on mice, and human diabetic ADSC or non diabetic ADSC were used to treat back wounds on nude mice; wound healing was evaluated by area, local VEGF expression, and angiogenesis. The results showed that delivery of murine ADSC or BMSC increased diabetic healing similarly, compared with acellular controls (p < 0.0001). Histology showed similarly increased cellular proliferation, VEGF expression, capillary density, numbers of macrophages and smooth muscle cells with ADSC or BMSC treatment. Cell survival and migration of ADSC or BMSC within the scaffolds were similar (p = 0.781). Notch signaling was activated similarly with ADSC or BMSC. Delivery of human diabetic ADSC enhanced wound healing similar to non-diabetic ADSC in a nude mouse wound model. In conclusion, murine ADSC delivered in a biomimetic-collagen scaffold enhanced diabetic wound healing with similar therapeutic effect as murine BMSC. Human non-diabetic or diabetic ADSC similarly promote wound healing. These data suggest that ADSC are a reasonable choice for translational therapy for human diabetic wounds. PMID- 30404562 TI - Risk Management with Clients Who Stalk, Threaten, and Harass Mental Health Professionals. AB - Although most psychologists will at some point be confronted with a client who engages in stalking, threatening, or harassing behavior (STHB), few feel prepared to manage these situations. In this article, the results of a survey of 112 psychologists who endorsed experiencing STHB are reported. Psychologists were asked about their perceptions of client motivations and personality pathology, frequency of use of 18 risk management responses, and perceived effectiveness of these responses. The effectiveness of risk management strategies differed by client level of personality organization and motivation for STHB. Some of the most commonly used risk management responses were among those most likely to result in adverse outcomes, particularly with certain types of clients. Efforts to develop empirically derived risk management strategies for clinicians confronted with STHB should integrate contextual variables, such as client personality and motivation. PMID- 30404563 TI - Coenzyme Q10 supplementation in acute ischemic stroke: Is it beneficial in short term administration? AB - BACKGROUNDS AND AIMS: Clinical studies demonstrated that the efficacy of Coenzyme Q10 (CoQ10) as an adjuvant therapeutic agent in several neurological diseases such as Parkinson disease (PD), Huntington disease (HD), and migraine. The purpose of this study is to investigate oxidative stress effects, antioxidant enzymes activity, neuroinflammatory markers levels, and neurological outcome in acute ischemic stroke (AIS) patients following administration of CoQ10 (300 mg/day). METHODS: Patients with AIS (n = 60) were randomly assigned to a placebo group (wheat starch, n = 30) or CoQ10-supplemented group (300 mg/day, n = 30). The intervention was administered for 4 weeks. Serum CoQ10 concentration, malondialdehyde (MDA), superoxide dismutase (SOD) activity, glial fibrillary acidic protein (GFAP) levels as primary outcomes and National Institute of Health Stroke Scale (NIHSS), Modified Ranking Scale (MRS), and Mini-Mental State Examination (MMSE) as secondary outcome were measured at the both beginning and end of the study. RESULTS: Forty-four subjects with AIS completed the intervention study. A significant increase in CoQ10 level was observed in the supplement-treated group compared with placebo group (mean difference = 26.05 +/- 26.63 ng/ml, 14.12 +/- 14.69 ng/ml, respectively; P = 0.01), moreover CoQ10 supplementation improved NIHSS and MMSE scores significantly (P = 0.05, P = 0.03 respectively). but there were no statistically significant differences in MRS score, MDA, SOD, and GFAP levels between the two groups. CONCLUSIONS: CoQ10 probably due to low dose and short duration of supplementation, no favorable effects on MDA level, SOD activity and GFAP level. PMID- 30404564 TI - To Retweet or Not to Retweet: Understanding What Features of Cardiovascular Tweets Influence Their Retransmission. AB - Twitter is one of the largest social networking sites (SNSs) in the world, yet little is known about what cardiovascular health related tweets go viral and what characteristics are associated with retransmission. The current study aims to identify a function of the observable characteristics of cardiovascular tweets, including characteristics of the source, content, and style that predict the retransmission of these tweets. We identified a random sample of 1,251 tweets associated with CVD originating from the United States between 2009 and 2015. Automated coding was conducted on the affect values of the tweets as well as the presence/absence of any URL, mention of another user, question mark, exclamation mark, and hashtag. We hand-coded the tweets' novelty, utility, theme, and source. The count of retweets was positively predicted by message utility, health organization source, and mention of user handle, but negatively predicted by the presence of URL and nonhealth organization source. Regarding theme, compared to the tweets focusing on risk factor, tweets on treatment and management predicted fewer retweets while supportive tweets predicted more retweets. These findings suggest opportunities for harnessing Twitter to better disseminate cardiovascular educational and supportive information on SNSs. PMID- 30404565 TI - Association Between Sitting, Screen Time, Fitness Domains, and Fundamental Motor Skills in Children Aged 5-16 Years: Cross-Sectional Population Study. AB - BACKGROUND: To examine the associations between school-age children's sedentary behavior, screen time, and 3 physical activity attributes: muscular strength, cardiorespiratory endurance (CRE), and fundamental movement skills. METHODS: Cross-sectional survey of 2734 children in years 2 and 4 and 3671 adolescents in years 6, 8, and 10. Total sitting time, 6 screen time behaviors, and physical activity were measured by self-report. Muscular strength was assessed by standing broad jump; CRE by 20-m shuttle run test; and fundamental movement skills by process-oriented checklists. Associations between incremental sitting and screen time (in hours) and meeting the healthy zone of physical activity attributes were examined using logistic regression. RESULTS: After adjusting for covariates and physical activity, children had lower odds of achieving the healthy zone for muscular strength and CRE for each hour of week (but not weekend) screen time. For adolescents, each hour of screen time per day was associated with lower odds of achieving the healthy fitness zone for CRE, locomotor skills, and overall healthy zone, and each hour of weekend screen time was associated with lower odds of achieving the healthy zone for most attributes and overall healthy zone. The associations were slightly stronger among adolescent girls than boys. The findings were similar for total sitting time. CONCLUSIONS: Screen time was associated with a lower likelihood to achieve healthy zones of physical activity attributes, and the effect was more consistent and slightly stronger among adolescents than children. This may suggest that the negative effects of screen time are incremental, emerging during adolescence. PMID- 30404566 TI - STAT3-induced upregulation of long noncoding RNA HNF1A-AS1 promotes the progression of oral squamous cell carcinoma via activating Notch signaling pathway. AB - Long non-coding RNAs (lncRNAs) are a group of biomarkers which can regulate the biological processes of various human cancers. LncRNA HNF1A-AS1 has been reported in human cancers for its oncogenic role. This study focused on the biological function and molecular mechanism of HNF1A-AS1 in oral squamous cell carcinoma (OSCC). The high expression of HNF1A-AS1 was examined in OSCC tissues and cell lines. Kaplan Meier method revealed that high expression of HNF1A-AS1 predicted poor prognosis for patients with OSCC. Results of loss-of-function assays demonstrated that silenced HNF1A-AS1 inhibited the proliferation, migration and epithelial-mesenchymal transition (EMT) of OSCC cells. Mechanically, HNF1A-AS1 was positively regulated by the transcription factor STAT3. Recently, Notch signaling pathway has been reported in human malignancies. In this study, we analyzed the correlation between HNF1A-AS1 and Notch signaling pathway. It was uncovered that the expression of Notch1 and Hes1 (the core factors of Notch signaling pathway) was negatively regulated by HNF1A-AS1 knockdown. Rescue assays further demonstrated the positive regulatory effects of HNF1A-AS1 on Notch signaling pathway in OSCC. In conclusion, upregulation of HNF1A-SA1 induced by transcription factor STAT3 promotes OSCC progression by activating Notch signaling pathway. PMID- 30404567 TI - Activation of CXCL5-CXCR2 axis promotes proliferation and accelerates G1 to S phase transition of papillary thyroid carcinoma cells and activates JNK and p38 pathways. AB - C-X-C motif chemokine ligand 5 (CXCL5) is initially identified to recruit neutrophils by interacting with its receptor, C-X-C motif chemokine receptor 2 (CXCR2). Our prior work demonstrated that the expression levels of CXCL5 and CXCR2 were higher in the papillary thyroid carcinoma (PTC) tumors than that in the non-tumors. This study was performed to further investigate how this axis regulates the growth of PTC cells. B-CPAP cells (BRAFV600E) and TPC-1 cells (RET/PTC rearrangement) expressing CXCR-2 were used as in vitro cell models. Our results showed that the recombinant human CXCL5 (rhCXCL5) promoted the proliferation of PTC cells. rhCXCL5 accelerated the G1/S transition, upregulated the expression of a group of S (DNA synthesis) or M (mitosis)-promoting cyclins and cyclin-dependent kinases (CDKs), and downregulated CDK inhibitors in PTC cells. The CDS region of homo sapiens CXCL5 gene was inserted into an eukaryotic expression vector to mediate the overexpression of CXCL5 in PTC cells. The phosphorylation of c-Jun N-terminal kinases (JNK) and p38, and the nuclear translocation of c-Jun were enhanced by CXCL5 overexpression, whereas attenuated by CXCR2 antagonist SB225002. Additionally, CXCL5/CXCR2 axis, JNK and p38 pathway inhibitors, SB225002, SP600125 and SB203580, suppressed the growth of PTC cells overexpressing CXCL5 in nude mice, respectively. Collectively, our study demonstrates a growth-promoting effect of CXCL5-CXCR2 axis in PTC cells in vitro and in vivo. PMID- 30404568 TI - Initial microbial community of the neonatal stomach immediately after birth. AB - The purpose of this prospective cross-sectional cohort pilot study is to explore the initial microbial community of gastric aspirate fluid as collected immediately after birth and its relationships with mode of delivery and preterm birth. Twenty-nine gastric aspirate samples collected immediately after birth from infants born between 24-40 weeks gestation were analyzed for microbial composition. Total microbial content was low in many samples, with a substantial number sharing taxonomic composition with negative controls. qPCR targeting the 16S rRNA gene showed that infants delivered vaginally had a higher microbial load than infants delivered by C-section. Some pre-term samples showed high relative abundance of genus Ureaplasma, consistent with previous literature that has implicated infections with this taxon as a potential cause of pre-term birth. Vaginally born term infant samples, by contrast, had significantly higher levels of genus Lactobacillus with Lactobacillus crispatus the most dominant species. Microbial evaluation showed that vaginally born term infant gastric aspirate samples had higher levels of lactobacilli than pre-terms. Samples from many infants had low microbial load near the edge of the detection limit. PMID- 30404569 TI - Empowerment Through Difference: An Online Difference-Education Intervention Closes the Social Class Achievement Gap. AB - A growing body of work suggests that teaching college students a contextual understanding of difference-that students' different experiences in college are the result of participating in different contexts before college-can improve the academic performance of first-generation students (i.e., students whose parents do not have 4-year college degrees). However, only one empirical study, using an in-person panel format, has demonstrated the benefits of this intervention approach. In the present research, we conduct two studies to test the effectiveness of a new difference-education intervention administered online to individual students. In both studies, first-year students read senior students' and recent graduates' stories about how they adjusted to college. In the difference-education condition, stories conveyed a contextual understanding of difference. We found that the online intervention effectively taught students a contextual understanding of difference and closed the social class achievement gap by increasing first-generation students' psychological empowerment and, thereby, end-of-second-year grades. PMID- 30404570 TI - Role of gut microbiota in intestinal wound healing and barrier function. AB - The mammalian intestine harbors a highly complex and abundant ensemble of bacteria that flourish in a nutrient-rich environment while profoundly influencing many aspects of host biology. The intestine coevolved with its resident microbes in a manner where the mucosa developed a barrier function to segregate the resident microbes from the rest of the body, and yet paradoxically, allowing integration of microbial signals for the host benefit. In this review, we provided a comprehensive overview of why the gut microbiota is key to the efficient development and maintenance of the intestinal barrier. We also highlighted how a destabilized equilibrium between gut microbiota and the host may eventuate in a wide range of intestinal diseases characterized by the disrupted intestinal barrier. Finally, the review delineated how microenvironmental changes in the injured mucosa result in an enrichment of a pro regenerating consortium of bacteria, which augments mucosal wound repair and restoration of barrier functions. PMID- 30404571 TI - Medical Family Therapy: Advanced Applications. PMID- 30404572 TI - Predictors and trajectory of performance status in patients with advanced cancer: A secondary data analysis of the international European Palliative Care Cancer Symptom study. AB - BACKGROUND:: Performance status, a predictor of cancer survival, and ability to maintain independent living deteriorate in advanced disease. Understanding predictors of performance status trajectory could help identify those at risk of functional deterioration, target support for independent living and reduce service costs. The relationship between symptoms, analgesics and performance status is poorly delineated. AIM:: The aim of this study is to determine whether demographics, analgesics, disease characteristics, quality-of-life domains and C reactive protein predict the trajectory of Karnofsky Performance Status (KPS) in patients with advanced cancer. DESIGN:: The study design is the secondary data analysis of the international prospective, longitudinal European Palliative Care Cancer Symptom study (ClinicalTrials.gov: NCT01362816). A multivariable regression model was built for KPS area under the curve per day (AUC). SETTING AND PARTICIPANTS:: This included adults with advanced, incurable cancer receiving palliative care, without severe cognitive impairment and who were not imminently dying ( n = 1739). RESULTS:: The mean daily KPS AUC ( n = 1052) was 41.1 (standard deviation = 14.1). Opioids ( p < 0.001), co-analgesics ( p = 0.023), poorer physical functioning ( p < 0.001) and appetite loss ( p = 0.009) at baseline were explanatory factors for lower KPS AUC. A subgroup analysis of participants with C-reactive protein data ( n = 240) showed that only C-reactive protein ( p = 0.040) and physical function ( p < 0.001) were associated with lower KPS AUC. CONCLUSION:: This study is novel in determining explanatory factors for subsequent functional trajectories in an international dataset and identifying systemic inflammation as a candidate therapeutic target to improve functional performance. The effect of interventions targeting physical function, appetite and inflammation, such as those used for cachexia management, on maintaining functional status in patients with advanced cancer needs to be investigated. PMID- 30404573 TI - The Need-Relevant Instructor Behaviors Scale: Development and Initial Validation. AB - PURPOSE: This article outlines the development and validation of the Need Relevant Instructor Behaviors Scale (NIBS). Drawing from self-determination theory, the NIBS is the first observation tool designed to code the frequency and the intensity of autonomy-, competence-, and relatedness-relevant behaviors of exercise instructors. The scale also captures the frequency of need-indifferent behaviors. METHODS: The behaviors of 27 exercise instructors were coded by trained raters on two occasions, before and after they received training in adaptive motivational communication. RESULTS: Findings supported the structural validity and reliability of the scale. The scale's sensitivity to detect changes in frequency and intensity of need-relevant behaviors was also evidenced. CONCLUSIONS: The NIBS is a new tool that offers a unique, tripartite assessment of need-relevant behaviors of leaders in the physical activity domain. PMID- 30404574 TI - Expectations for tonal cadences: Sensory and cognitive priming effects. AB - Studies examining the formation of melodic and harmonic expectations during music listening have repeatedly demonstrated that a tonal context primes listeners to expect certain (tonally related) continuations over others. However, few such studies have (1) selected stimuli using ready examples of expectancy violation derived from real-world instances of tonal music, (2) provided a consistent account for the influence of sensory and cognitive mechanisms on tonal expectancies by comparing different computational simulations, or (3) combined melodic and harmonic representations in modelling cognitive processes of expectation. To resolve these issues, this study measures expectations for the most recurrent cadence patterns associated with tonal music and then simulates the reported findings using three sensory-cognitive models of auditory expectation. In Experiment 1, participants provided explicit retrospective expectancy ratings both before and after hearing the target melodic tone and chord of the cadential formula. In Experiment 2, participants indicated as quickly as possible whether those target events were in or out of tune relative to the preceding context. Across both experiments, cadences terminating with stable melodic tones and chords elicited the highest expectancy ratings and the fastest and most accurate responses. Moreover, the model simulations supported a cognitive interpretation of tonal processing, in which listeners with exposure to tonal music generate expectations as a consequence of the frequent (co )occurrence of events on the musical surface. PMID- 30404575 TI - Development and assessment of the Korean Author Recognition Test. AB - This research reports the development and evaluation of a Korean Author Recognition Test (KART), designed as a measure of print exposure among young adults. Based on the original, English-language version of the Author Recognition Test (ART), the KART demonstrates significant relationships with offline measures of language ability, as well as online measures of word recognition. In particular, KART scores were related to participants' responses on the Comparative Reading Habits (CRH) checklist, suggesting that KART is a valid measure of print exposure. In addition, KART scores showed reliable correlations with offline measures of vocabulary knowledge and language comprehension. Finally, results from a lexical decision task showed that KART scores modulated the magnitude of the word familiarity effect, such that the effect was smaller for participants with higher KART scores The results suggest that the ART is a language-universal task that measures print exposure, which is useful for explaining individual differences in language comprehension abilities and word recognition processes. PMID- 30404576 TI - Perspectives of people with dementia and carers on advance care planning and end of-life care: A systematic review and thematic synthesis of qualitative studies. AB - BACKGROUND:: Advance care planning aims to ensure that care received during serious and chronic illness is consistent with the person's values, preferences and goals. However, less than 40% of people with dementia undertake advance care planning internationally. AIM:: This study aims to describe the perspectives of people with dementia and their carers on advance care planning and end-of-life care. DESIGN:: Systematic review and thematic synthesis of qualitative studies. DATA SOURCES:: Electronic databases were searched from inception to July 2018. RESULTS:: From 84 studies involving 389 people with dementia and 1864 carers, five themes were identified: avoiding dehumanising treatment and care (remaining connected, delaying institutionalisation, rejecting the burdens of futile treatment); confronting emotionally difficult conversations (signifying death, unpreparedness to face impending cognitive decline, locked into a pathway); navigating existential tensions (accepting inevitable incapacity and death, fear of being responsible for cause of death, alleviating decisional responsibility); defining personal autonomy (struggling with unknown preferences, depending on carer advocacy, justifying treatments for health deteriorations); and lacking confidence in healthcare settings (distrusting clinicians' mastery and knowledge, making uninformed choices, deprived of hospice access and support at end of life). CONCLUSION:: People with dementia and their carers felt uncertain in making treatment decisions in the context of advance care planning and end-of life care. Advance care planning strategies that attend to people's uncertainty in decision-making may help to empower people with dementia and carers and strengthen person-centred care in this context. PMID- 30404577 TI - Promoting academic general practice: perspectives from early career clinical academics. PMID- 30404578 TI - Long non-coding RNA ARAP1-AS1 promotes the progression of bladder cancer by regulating miR-4735-3p/NOTCH2 axis. AB - Accumulative reports have documented the critical functions of long non-coding RNAs (lncRNAs) in the progression of malignant tumors, including bladder cancer (BCa). LncRNA ARAP1-AS1 was chosen to be the object of this study due to it was significantly upregulated in the BCa samples of TCGA database. qRT-PCR further validated the dysregulation of ARAP1-AS1 in 88 pairs of BCa tissues and six BCa cells. Kaplan Meier analysis was utilized to analyze the prognostic value of ARAP1-AS1 for patients with BCa. To evaluate the oncogenic property of ARAP1-AS1 in bladder cancer, loss-of-function assays were conducted in two BCa cells in which ARAP1-AS1 was expressed highest. Mechanically, ARAP1-AS1 was enriched in the cytoplasm of BCa cells, suggesting that ARAP1-AS1 might act as a ceRNA to regulate gene expression and biological processes in bladder cancer. It was certified that ARAP1-AS1 can bind with miR-4735-3p in BCa cells. Moreover, functional assays supported the hypothesis that miR-4735-3p is a tumor suppressor in BCa. Additionally, NOTCH2 mRNA could be targeted by miR-4735-3p in BCa cells. The results of all mechanism experiments indicated that ARAP1-AS1 regulated miR 4735-3p/NOTCH2 axis in BCa by acting as a ceRNA. All our research findings may bring novel insights into the treatment of bladder cancer. PMID- 30404579 TI - Salt and cardiovascular disease in PURE: A large sample size cannot make up for erroneous estimations. AB - The latest Prospective Urban Rural Epidemiology (PURE) study claims that salt reduction should be confined to settings where its intake exceeds 12.7 g/day and that eating less than 11.1 g/day of salt could increase cardiovascular risk. More specifically, Mente et al. suggested that (a) salt intake was positively associated with stroke only when it exceeded 12.7 g/day, (b) salt intake was inversely associated with myocardial infarction and total mortality, and (c) these associations were largely independent of blood pressure. These provocative findings challenge the robust evidence on the role of salt reduction in the prevention of cardiovascular disease and call into question the World Health Organization's global recommendation to reduce salt intake to less than 5 g/day. However, Mente et al.'s re-analysis of the PURE data has several severe methodological problems, including erroneous estimations of salt intake from a single spot urine using the problematic Kawasaki formula. As such, these implausible results cannot be used to refute the strong evidence supporting the benefits of salt reduction for the general population worldwide. PMID- 30404580 TI - Advances in immunosensors for clinical applications. AB - Immunoassay technique performs a fast, simple, reliable, and sensitive analysis of different compounds, being applied in several areas of interest such as clinical analysis for medical diagnosis, as well as in environmental analysis, and food quality control. The latest research activities in this field are represented by the attempts to achieve a low limit of detection by developing of new signal amplification strategies, eliminate the interferences, and decrease the cost of analysis. PMID- 30404581 TI - The combination of levomepromazine (methotrimeprazine) and rotigotine enables the safe and effective management of refractory nausea and vomiting in a patient with idiopathic Parkinson's disease. AB - BACKGROUND:: This case report describes a patient with known idiopathic Parkinson's disease, being managed with transdermal rotigotine, whose refractory nausea and vomiting was successfully controlled with subcutaneous levomepromazine. No drug-induced extrapyramidal side effects emerged. CASE PRESENTATION:: A patient was found to have a locally advanced serous carcinoma, causing secondary bowel obstruction. Furthermore, due to compromised oral access, the patient's oral antiparkinsonian medications for motor control were converted to transdermal rotigotine. Unfortunately, the patient's nausea and vomiting was refractory to a number of recommended antiemetic options. CASE MANAGEMENT:: Low dose levomepromazine was administered on a, 'when required' basis, via subcutaneous injection. CASE OUTCOME:: After the first dose of levomepromazine, the patient's nausea and vomiting completely subsided and no extrapyramidal side effects were observed. This was confirmed by daily assessments, revealing no worsening of the motor symptoms associated with idiopathic Parkinson's disease. CONCLUSIONS:: The pharmacology of rotigotine and levomepromazine appear complementary and may allow for the simultaneous use of both drugs, with favourable outcomes. This case report highlights that rotigotine may afford protection against antipsychotic induced extrapyramidal side effects, while preserving antiemetic effects. Such combinations may have a role in the end-of life management of idiopathic Parkinson's disease. PMID- 30404582 TI - Percutaneous Intervention After Previous Mitral Valve Surgery: Implications for the Perioperative Anesthesiology Proceduralist. AB - The advent of percutaneous therapies has significantly altered therapeutic options for patients with valvular heart disease. Building on the success of transcatheter aortic valve replacement, both expanded indications and purpose built devices are now being used to address percutaneous approaches for mitral valve pathology. While surgical mitral valve repair remains the gold standard for addressing significant mitral valve pathology, there has been a progressive increase in the utilization of bioprosthetic valves despite their limited lifespan. The risks of reoperation to address mitral valve repair failure or bioprosthetic valve dysfunction is not insignificant. In light of the aging population and the potential for significant associated comorbidities, less invasive alternative techniques hold particular appeal. Utilization of commercially available transcatheter aortic valve replacement valves for failed surgical valves has been shown to have better short-term mortality than would be predicted for open reoperation. As a result, the US Food and Drug Administration approved the utilization of transcatheter mitral valve-in-valve replacement for the failed bioprosthetic valve in high surgical risk patients. Despite the favorable outcomes, transcatheter mitral valve-in-valve is not without procedural challenges and potential complications including malpositioning, embolization, paravalvular leak, and outflow tract obstruction. Awareness of these challenges, mitigation strategies, and therapeutic options is imperative to optimizing outcomes in this high-risk patient population. PMID- 30404583 TI - Participation in competitive employment after severe traumatic brain injury: New employment versus return to previous (pre-injury) employment. AB - There is limited literature comparing the clinical and employment characteristics of clients accessing new employment with those resuming previous employment. To address this gap, a multi-centre observational study was conducted of all active clients with severe TBI from the 11 community rehabilitation services (n = 588) of the New South Wales Brain Injury Rehabilitation Program. Demographic, injury, clinical and vocational data were collected by treating clinicians employing a purpose-designed protocol. New employment constituted almost 40% of competitive employment outcomes. Clients accessing new employment were significantly more likely to be younger, single, less educated, with more severe injuries and more likely to be displaying challenging behaviours than those resuming pre-injury work. Kaplan-Meier analyses found time to RTW was significantly longer for new employment. Stability of new employment was significantly poorer with jobs twice as likely to break down compared to previous employment. New employment positions were also more likely to be part-time and unskilled compared to previous employment. The results found that placement into new employment made a substantial contribution to employment outcomes after TBI but requires more intensive and tailored programmes to meet the multiple clinical and workplace challenges. PMID- 30404584 TI - The role of the King's College London General Practitioner's Society and the effect on students' perceptions of general practice. PMID- 30404586 TI - Moderating Effects of Depression, Food Cravings, and Weight-Related Quality-of Life on Associations of Treatment-Targeted Psychosocial Changes and Physical Activity in Adolescent Candidates for Bariatric Surgery. AB - BACKGROUND: Physical activity is a strong predictor of sustaining weight loss. Yet physical activity has been challenging to maintain. Adolescent bariatric surgery is increasing, and there is typically an initial 6-month period when improving health behaviors such as physical activity are addressed by a clinic based team. However, there is minimal understanding of how to target psychosocial factors relevant for behavioral changes. METHODS: A group of 15 adolescent candidates for bariatric surgery (mean age = 15.1 y; mean body mass index = 55.9 kg/m2) were assessed on changes in 3 theory-based predictors of physical activity from baseline-month 3 and baseline-month 6. RESULTS: Changes in physical activity related self-regulation and self-efficacy over 3 months significantly predicted change in physical activity over 6 months. Reciprocal relationships were also significant, including the prediction of physical activity change by change in negative mood. The clinical psychology-based factor of weight-related quality-of life significantly moderated the prediction of self-regulation via physical activity, and degree of depressive symptoms significantly moderated the prediction of changes in physical activity through self-efficacy changes. CONCLUSIONS: Because improvements in several theory-based psychosocial variables related to physical activity have demonstrated a carry-over to controlling eating, the improved understanding of those variables for treating adolescents with severe obesity was useful. PMID- 30404587 TI - Knockdown of linc00152 inhibits the progression of gastric cancer by regulating microRNA-193b-3p/ETS1 axis. AB - BACKGROUND: Gastric cancer (GC) is a serious threat for public health worldwide. Long non-coding RNA (lncRNA) linc00152 has been well reported to be an oncogene and a potential biomarker in multiple cancers including GC. However, the molecular mechanisms of linc00152 in GC development need to be further investigated. METHODS: RT-qPCR assay was employed to detect the levels of linc00152, microRNA-193b-3p (miR-193b-3p) and ETS1 mRNA. ETS1 protein level was measured by western blot assay. Cell proliferative, migratory and invasive capacities were assessed by colony formation together with CCK-8 assays, transwell migration and invasion assays, respectively. Bioinformatics analyses and luciferase reporter assay were used to explore whether miR-193b-3p could interact with linc00152 or ETS1 3'UTR. The roles and molecular basis of linc00152 silence on the growth of GC xenograft tumors were tested in vivo. RESULTS: Linc00152 expression was notably upregulated in GC tissues and cells. The proliferative, migratory and invasive abilities of GC cells were weakened by linc00152 depletion, miR-193b-3p overexpression or ETS1 knockdown. Linc00152 upregulation inhibited miR-193b-3p expression by direct interaction and abolished miR-193b-3p-mediated anti-proliferation, anti-migration and anti-invasion effects in GC cells. ETS1 was a target of miR-193b-3p and linc00152 could promote ETS1 expression by downregulating miR-193b-3p. In vivo experiments further validated that linc00152 knockdown inhibited the growth of GC xenograft tumors by upregulating miR-193b-3p and downregulating ETS1. CONCLUSION: Knockdown of linc00152 inhibited GC progression by sequestering miR-193b-3p from ETS1 in vitro and in vivo, elucidating a novel molecular mechanism of linc00152 in promoting GC carcinogenesis. PMID- 30404585 TI - The relationship between plasma renin activity and serum lipid profiles in patients with primary arterial hypertension. AB - INTRODUCTION:: The aim of the study was to evaluate clinical and biochemical differences between patients with low-renin and high-renin primary arterial hypertension (AH), mainly in reference to serum lipids, and to identify factors determining lipid concentrations. MATERIALS AND METHODS:: In untreated patients with AH stage 1 we measured plasma renin activity (PRA) and subdivided the group into low-renin (PRA < 0.65 ng/mL/h) and high-renin (PRA ? 0.65 ng/mL/h) AH. We compared office and 24-h ambulatory blood pressure, serum aldosterone, lipids and selected biochemical parameters between subgroups. Factors determining lipid concentration in both subgroups were assessed in regression analysis. RESULTS:: Patients with high-renin hypertension ( N = 58) were characterized by higher heart rate ( p = 0.04), lower serum sodium ( p < 0.01) and aldosterone-to-renin ratio ( p < 0.01), and significantly higher serum aldosterone ( p = 0.03), albumin ( p < 0.01), total protein ( p < 0.01), total cholesterol ( p = 0.01) and low-density lipoprotein cholesterol (LDL-C) ( p = 0.04) than low-renin subjects ( N = 39). In univariate linear regression, only PRA in the low-renin group was in a positive relationship with LDL-C ( R2 = 0.15, beta = 1.53 and p = 0.013); this association remained significant after adjustment for age, sex, and serum albumin and aldosterone concentrations. CONCLUSIONS:: Higher serum levels of total and LDL-C characterized high-renin subjects, but the association between LDL-C level and PRA existed only in low-renin primary AH. PMID- 30404588 TI - Research prioritisation exercises related to the care of children and young people with life-limiting conditions, their parents and all those who care for them: A systematic scoping review. AB - BACKGROUND:: In planning high-quality research in any aspect of care for children and young people with life-limiting conditions, it is important to prioritise resources in the most appropriate areas. AIM:: To map research priorities identified from existing research prioritisation exercises relevant to infants, children and young people with life-limiting conditions, in order to inform future research. DESIGN:: We undertook a systematic scoping review to identify existing research prioritisation exercises; the protocol is publicly available on the project website. DATA SOURCES:: The bibliographic databases ASSIA, CINAHL, MEDLINE/MEDLINE In Process and Embase were searched from 2000. Relevant reference lists and websites were hand searched. Included were any consultations aimed at identifying research for the benefit of neonates, infants, children and/or young people (birth to age 25 years) with life-limiting, life-threatening or life shortening conditions; their family, parents, carers; and/or the professional staff caring for them. RESULTS:: A total of 24 research prioritisation exercises met the inclusion criteria, from which 279 research questions or priority areas for health research were identified. The priorities were iteratively mapped onto an evolving framework, informed by World Health Organization classifications. This resulted in identification of 16 topic areas, 55 sub-topics and 12 sub-sub topics. CONCLUSION:: There are numerous similar and overlapping research prioritisation exercises related to children and young people with life-limiting conditions. By mapping existing research priorities in the context in which they were set, we highlight areas to focus research efforts on. Further priority setting is not required at this time unless devoted to ascertaining families' perspectives. PMID- 30404589 TI - Editorial. PMID- 30404590 TI - Medicinal cannabis for chemotherapy-induced nausea and vomiting: prescribing with limited evidence. PMID- 30404591 TI - Gluten in "gluten-free" manufactured foods in Australia: a cross-sectional study. PMID- 30404592 TI - Deprescribing proton pump inhibitors: why, when and how. PMID- 30404593 TI - Prevalence and correlates of exposure to second hand smoke (SHS) among 14 to 15 year old schoolchildren in a medical officer of health area in Sri Lanka. AB - BACKGROUND: Despite reports that Southeast Asia has one of the highest prevalence for childhood exposure to second hand smoke (SHS), there are limited data on SHS exposure among schoolchildren in individual countries in the region, including Sri Lanka. This study aimed to determine the prevalence and correlates of SHS among schoolchildren in a Medical Officer of Health (MOH) region in the country. METHODS: We conducted a cross-sectional study, sampling from nice schools in one MOH region following a two-stage cluster sample design and probability proportionate to size sampling techniques. Data were obtained through a self completed anonymous questionnaire on socio-demographic and health behaviour risk factors. We achieved an 89.5% response rate, corresponding to a total of 311 students in the final sample. RESULTS: The prevalence of exposure to SHS during the previous week was 17.6% at home and 25.7% in enclosed public places. There were no significant differences in exposure to SHS between sexes. Univariable analysis found that the presence of smokers at home and mother's unemployment status were significantly associated with a higher risk of exposure to SHS at home. These variables remained significant in multivariable analysis. Non Sinhalese ethnicity and presence of smokers at home were significantly associated with exposure to SHS in public places, in both uni- and multivariable analysis. Unemployment status of mother was also found to be a significant determinant of exposure to SHS in public places in multivariable analysis. CONCLUSION: Despite numerous antismoking activities and strong antismoking legislation, the prevalence of SHS exposure among schoolchildren is higher in enclosed public places than homes. The implementation and enforcement of antismoking legislation is imperative to tackle this and should be supported by the provision of education for schoolchildren and their families on the health risks of SHS. The high-risk groups identified here could be prioritised for preventive programmes. PMID- 30404594 TI - Pilot field testing of the chronic pain classification for ICD-11: the results of ecological coding. AB - BACKGROUND: A task force of the International Association for the Study of Pain (IASP) has developed a classification of chronic pain for the ICD-11 consisting of seven major categories. The objective was to test whether the proposed categories were exhaustive and mutually exclusive. In addition, the perceived utility of the diagnoses and the raters' subjective diagnostic certainty were to be assessed. METHODS: Five independent pain centers in three continents coded 507 consecutive patients. The raters received the definitions for the main diagnostic categories of the proposed classification and were asked to allocate diagnostic categories to each patient. In addition, they were asked to indicate how useful they judged the diagnosis to be from 0 (not at all) to 3 (completely) and how confident they were in their category allocation. RESULTS: The two largest groups of patients were coded as either chronic primary pain or chronic secondary musculoskeletal pain. Of the 507 patients coded, 3.0% had chronic pain not fitting any of the proposed categories (97% exhaustiveness), 20.1% received more than one diagnosis. After adjusting for double coding due to technical reasons, 2.0% of cases remained (98% uniqueness). The mean perceived utility was 1.9 +/- 1.0, the mean diagnostic confidence was 2.0 +/- 1.0. CONCLUSIONS: The categories proved exhaustive with few cases being classified as unspecified chronic pain, and they showed themselves to be mutually exclusive. The categories were regarded as useful with particularly high ratings for the newly introduced categories (chronic cancer-related pain among others). The confidence in allocating the diagnoses was good although no training regarding the ICD-11 categories had been possible at this stage of the development. PMID- 30404595 TI - Socioeconomic, demographic and lifestyle-related factors associated with unhealthy diet: a cross-sectional study of university students. AB - BACKGROUND: Food habits are important to promote and maintain good health throughout life, and unhealthy diet is a modifiable and preventable risk factor. University students are a key group of adults among whom to promote healthy lifestyles. The aim of this study is to determine the factors associated with unhealthy diet in a sample of university students. METHODS: An electronic cross sectional survey was conducted with university students (n=593) from inland Spain, during the 2016-2017 academic year. The survey collected information on the participants' food habits using an annual food frequency questionnaire. We also collected socioeconomic and demographic data and lifestyle-related information. A multivariate logistic regression was used for analysis. RESULTS: The multivariate logistic regression revealed that the factors associated with an unhealthy diet were: being male, being underweight compared to the reference category (normal weight), having a mother of low socioeconomic status, the family home not being in the university city and, finally, studying a non health-related course CONCLUSION: Among students of the University of Castilla-La Mancha, being male, being underweight, the family home not being in the university city, having a mother of low socioeconomic status, and, finally, not studying a health-related course are the factors associated with a lower quality diet. Following a healthy diet is key in reducing the health costs of non-communicable diseases, and ensuring an acceptable long-term quality of life in populations. PMID- 30404597 TI - Factors associated with social support in child-rearing among mothers in post disaster communities. AB - BACKGROUND: Natural disasters have long-term negative impacts on the health and socioenvironmental conditions of a population, affecting the physical environment as well as the relationships within the community, including social networks. Mothers in post-disaster communities may have difficulty receiving social support not only from family members and relatives but also from members of their community, such as people in their neighborhoods. This study focused on mothers with infants and preschool-aged children in post-disaster communities. The associations of social support with sociodemographic characteristics and socioenvironmental conditions related to child-rearing among mothers in post disaster communities were assessed. METHODS: An anonymous self-administered questionnaire survey was conducted in October 2015 in 988 households in areas affected by the Great East Japan Earthquake and Tsunami. The data collected on sociodemographic and socioenvironmental characteristics included the presence of pre-disaster acquaintances in the neighborhood and social support for child rearing. The associations of sociodemographic and socioenvironmental characteristics with social support were examined. RESULTS: We analyzed 215 completed questionnaires from mothers living in different houses from those they lived in before the disaster to reflect continuous relationships with people from the pre-disaster communities. Social support was significantly associated with infant sex, extended family, support obtained from relatives not living together, pre-disaster acquaintances, use of child support resources, and no perceived difficulties in child-rearing. In addition, the presence of pre-disaster acquaintances was associated with categories of mental/physical place of comfort and child-rearing support, with adjusted odds ratios of 1.88 (95% CI 1.03-3.44) and 2.84 (95% CI 1.46-5.52) compared with mothers who did not have any pre disaster acquaintances. CONCLUSIONS: Factors associated with the obtainment of social support in child-rearing among mothers in post-disaster communities were attributed not only to mothers themselves and family members but also to socioenvironmental factors such as the presence of pre-disaster acquaintances. The presence of pre-disaster acquaintances promoted rich social support in child rearing in post-disaster communities. When reconstructing a community following changes in residence location after a disaster, the pre-disaster relationships among the community dwellers should be considered from the viewpoint of child rearing support. PMID- 30404596 TI - Evolution and functional characterization of pectate lyase PEL12, a member of a highly expanded Clonostachys rosea polysaccharide lyase 1 family. AB - BACKGROUND: Pectin is one of the major and most complex plant cell wall components that needs to be overcome by microorganisms as part of their strategies for plant invasion or nutrition. Microbial pectinolytic enzymes therefore play a significant role for plant-associated microorganisms and for the decomposition and recycling of plant organic matter. Recently, comparative studies revealed significant gene copy number expansion of the polysaccharide lyase 1 (PL1) pectin/pectate lyase gene family in the Clonostachys rosea genome, while only low numbers were found in Trichoderma species. Both of these fungal genera are widely known for their ability to parasitize and kill other fungi (mycoparasitism) and certain species are thus used for biocontrol of plant pathogenic fungi. RESULTS: In order to understand the role of the high number of pectin degrading enzymes in Clonostachys, we studied diversity and evolution of the PL1 gene family in C. rosea compared with other Sordariomycetes with varying nutritional life styles. Out of 17 members of C. rosea PL1, we could only detect two to be secreted at acidic pH. One of them, the pectate lyase pel12 gene was found to be strongly induced by pectin and, to a lower degree, by polygalacturonic acid. Heterologous expression of the PEL12 in a PL1-free background of T. reesei revealed direct enzymatic involvement of this protein in utilization of pectin at pH 5 without a requirement for Ca2+. The mutants showed increased utilization of pectin compounds, but did not increase biocontrol ability in detached leaf assay against the plant pathogen Botrytis cinerea compared to the wild type. CONCLUSIONS: In this study, we aimed to gain insight into diversity and evolution of the PL1 gene family in C. rosea and other Sordariomycete species in relation to their nutritional modes. We show that C. rosea PL1 expansion does not correlate with its mycoparasitic nutritional mode and resembles those of strong plant pathogenic fungi. We further investigated regulation, specificity and function of the C. rosea PEL12 and show that this enzyme is directly involved in degradation of pectin and pectin-related compounds, but not in C. rosea biocontrol. PMID- 30404598 TI - One-day oral polyethylene glycol based cleanout is effective for pre-colonoscopy preparation in children. AB - BACKGROUND: The adequacy of pre-procedure preparation is the principal determinant of the quality of colonoscopy in pediatric as in adult patients. There is a lack of consensus, among providers on a standard pre-procedure regimen. Professional society guidelines include the use of Polyethylene glycol (PEG). Herein we report on the provider-assessed adequacy of a one day, age categorized dosing, PEG based cleanout regimen in children undergoing colonoscopy in a tertiary institution. METHODS: The standard bowel preparation regime at our institution includes an age dependent minimum PEG dosing regimen in addition to clear liquids the day prior to the procedure. We retrospectively abstracted relevant indices including patient demographics, prep quality, procedure impairment, duration and completion from an institutional quality monitoring survey tool between 2015 and 2016 and similarly abstracted prospectively recorded indices that included the dataset above as well as additional fields for procedure deviations and additional laxative use. RESULTS: A total of 642 procedures (mean age 12.2 years; F: 380) were accrued, nonadherence to the cleanout regimen (7.3%) and additional laxative use (3.1%) were observed in a small proportion of the prospective dataset subjects, adequate cleanout defined as thin or thick liquid but no solids present was reported in 79.5% and 15.8% of cases and impaired study from inadequate cleanout was reported in 11.8% of studies albeit the cecum was reached and the terminal ileum was intubated in 97.8 and 93.6% of studies. The duration of the study was significantly longer with the presence of a fellow trainee assisting in the procedure. Patient age and gender did not correlate with prep adequacy or cecal and ileal intubation rates, inadequate cleanout was significantly associated with impairment and incomplete studies. CONCLUSION: A one day, single agent, osmotic laxative (Polyethylene glycol) based cleanout regimen is effective in routine pre-procedure cleanout for standard colonoscopy in pediatric age range patients. PMID- 30404599 TI - Ultrasound-guided versus low dose computed tomography scanning guidance for lumbar facet joint injections: same accuracy and efficiency. AB - BACKGROUND: The purpose of this study was to investigate the feasibility, accuracy and efficiency of the facet joint injections in the lumbar spine by ultrasound guided versus lose dose computed tomography (CT) guidance. METHODS: First the examination on the joint space of the facet joints of the lumbar spine was obtained by the ultrasound in 10 patients. Second forty patients were randomized assigned into two groups: ultrasound group and low dose CT group. Comparison was made in the clinical efficiency between the ultrasound-guided group and CT group. The feasibility, accuracy and efficiency of the ultrasound guided lumbar facet joint injections were also evaluated. RESULTS: A total of 88 lumbar facet joints from L1 to S1 were clearly visualized in the 10 patients. Both the ultrasound and the CT measurements showed the same average depth and lateral distance to the reference point (P > 0.05). And 86.5% of the facet joint injections (64/74) were correctly performed under the ultrasound guidance in the first time. The exact placement of the needle tips was evaluated by CT. After the lumbar facet joint injections, the clinical efficiency was almost the same in the ultrasound-guided group as in the CT group. CONCLUSIONS: The lumbar facet joint space can be accurately demonstrated by ultrasound. The ultrasound-guided facet joint injection in the lumbar spine obtained almost the same satisfactory feasibility, accuracy and clinical efficiency compared with low dose CT. Ultrasound technique could provide the real-time monitoring. TRIAL REGISTRATION: This study was registered on Chinese Clinical Trial Registry ( ChiCTR1800018819 , retrospective registered on 11/10/2018). PMID- 30404600 TI - Retinal-image quality and contrast sensitivity function in eyes with epiretinal membrane: a cross-sectional observational clinical study. AB - BACKGROUND: To investigate the effect of idiopathic epiretinal membrane (ERM) on the retinal-image quality and psychophysical contrast sensitivity function (CSF). METHODS: Forty-four subjects with diagnosis of idiopathic unilateral ERM were enrolled in this cross-sectional observational clinical study. The fellow unaffected eyes were set as the control group. For retinal-image quality assessment, an Optical Quality Analysis System (OQAS) based on double-pass technique was used to evaluate objective scatter index (OSI) and Strehl ratio. For visual performance, the CSF under photopic condition was measured. RESULTS: For retinal-image quality, the result of double-pass device revealed a significant lower Strehl ratio and larger OSI in the ERM eyes compared to the fellow eyes (all P < 0.05). For visual performance, the CSF at all spatial frequencies under photopic condition were also significantly degraded in the ERM eyes compared to the fellow eyes (all P < 0.05). For the ERM eyes, the reduction of Strehl ratio and CSF was 29.41 and 54.39%, respectively, and the increase of OSI was 164.10% compared to the fellow eyes. Besides, BCVA significantly correlated to the total CSF (ERM eyes, r = - 0.53, P < 0.001; the fellow eyes, r = - 0.467, P = 0.002) and Strehl ratio (ERM eyes, r = - 0.485, P = 0.001; the fellow eyes, r = - 0.311, P = 0.043) in both of the ERM and the fellow eyes. CONCLUSION: Eyes affected with ERM showed poorer retinal-image quality and visual performance than the normal eyes. Retinal-image quality measured by OQAS based on double-pass technique could be useful for assessing the retinal-image quality for ERM-affected eyes, in which retinal scattering was significantly increased. PMID- 30404602 TI - Study on differentially expressed genes related to defoliation traits in two alfalfa varieties based on RNA-Seq. AB - BACKGROUND: Alfalfa (Medicago sativa) is a widely cultivated, essential commercial forage crop. The protein content in its leaves is the critical factor in determining the quality of alfalfa. Thus far, the understanding of the molecular mechanism of alfalfa defoliation traits remains unclear. The transcriptome database created by RNA-Seq is used to identify critical genes related to defoliation traits. RESULTS: In this study, we sequenced the transcriptomes of the Zhungeer variety (with easy leaf abscission) and WL319HQ variety (without easy leaf abscission). Among the identified 66,734 unigenes, 706 differentially expressed genes (DEGs) upregulated, and 392 unigenes downregulated in the Zhungeer vs WL319HQ leaf. KEGG pathway annotations showed that 8,414 unigenes were annotated to 87 pathways and contained 281 DEGs. Six DEGs belonging to the "Carotenoid biosynthesis", "Plant hormone signal transduction" and "Circadian rhythm-plant" pathways involved in defoliation traits were identified and validated by RT-qPCR analyses. CONCLUSIONS: This study used RNA-Seq to discover genes associated with defoliation traits between two alfalfa varieties. Our transcriptome data dramatically enriches alfalfa functional genomic studies. In addition, these data provide theoretical guidance for field production practice and genetic breeding, as well as references for future study of defoliation traits in alfalfa. PMID- 30404601 TI - New insights into the evolution and functional divergence of the SWEET family in Saccharum based on comparative genomics. AB - BACKGROUND: The SWEET (Sugars Will Eventually be Exported Transporters) gene family is a recently identified group of sugar transporters that play an indispensable role in sugar efflux, phloem loading, plant-pathogen interaction, nectar secretion, and reproductive tissue development. However, little information on Saccharum SWEET is available for this crop with a complex genetic background. RESULTS: In this study, 22 SWEET genes were identified from Saccharum spontaneum Bacterial Artificial Chromosome libraries sequences. Phylogenetic analyses of SWEETs from 11 representative plant species showed that gene expansions of the SWEET family were mainly caused by the recent gene duplication in dicot plants, while these gene expansions were attributed to the ancient whole genome duplication (WGD) in monocot plant species. Gene expression profiles were obtained from RNA-seq analysis. SWEET1a and SWEET2s had higher expression levels in the transitional zone and maturing zone than in the other analyzed zones. SWEET1b was mainly expressed in the leaf tissues and the mature zone of the leaf of both S. spontaneum and S. officinarum, and displayed a peak in the morning and was undetectable in both sclerenchyma and parenchyma cells from the mature stalks of S. officinarum. SsSWEET4a?4b had higher expression levels than SWEET4c and were mainly expressed in the stems of seedlings and mature plants. SWEET13s are recently duplicated genes, and the expression of SWEET13s dramatically increased from the maturing to mature zones. SWEET16b's expression was not detected in S. officinarum, but displayed a rhythmic diurnal expression pattern. CONCLUSIONS: Our study revealed the gene evolutionary history of SWEETs in Saccharum and SWEET1b was found to be a sucrose starvation-induced gene involved in the sugar transportation in the high photosynthetic zones. SWEET13c was identified as the key player in the efflux of sugar transportation in mature photosynthetic tissues. SWEET4a?4b were found to be mainly involved in sugar transportation in the stalk. SWEET1a?2a?4a?4b?13a?16b were suggested to be the genes contributing to the differences in sugar contents between S. spontaneum and S. officinarum. Our results are valuable for further functional analysis of SWEET genes and utilization of the SWEET genes for genetic improvement of Saccharum for biofuel production. PMID- 30404603 TI - Resource use and clinical outcomes in patients with atrial fibrillation with ablation versus antiarrhythmic drug treatment. AB - BACKGROUND: The objective of our study was to compare resource use and clinical outcomes among atrial fibrillation (AF) patients who underwent catheter ablation versus antiarrhythmic drug (AAD) treatment. METHODS: A retrospective cohort design using the Clinical Practice Research Data-Hospital Episode Statistics linkage data from England (2008-2013) was used. Patients undergoing catheter ablation treatment for AF were indexed to the date of first procedure. AAD patients with at least two different AAD drugs were indexed to the first fill of the second AAD. Patients were matched using 1:1 propensity matching. Primary endpoints including inpatient and outpatient visits were compared between ablation and AAD cohorts in the 4 months-1 year period after index. Secondary endpoints including heart failure, stroke, cardioversion, mortality, and a composite outcome were compared for the 4 months-3 years post-index period in the two groups. Cox-proportional hazards models were estimated for clinical outcomes comparison. RESULTS: A total of 558 patients were matched in the two groups for resource utilization comparison. The average number of cardiovascular (CV) related outpatient visits in the 4-12 months post-index period were significantly lower in the ablation group versus the AAD group (1.76 vs 3.57, p < .0001). There was no significant difference in all-cause and CV-related inpatient visits and all-cause outpatient visits among the two groups. For secondary endpoints comparison, 615 matched patients in each group emerged. Ablation patients had 38% lower risk of heart failure (hazard ratio [HR] 0.62, p = 0.0318), 50% lower risk of mortality (HR 0.50, p = 0.0082), and 43% lower risk of experiencing a composite outcome (HR 0.57, p = 0.0009) as compared to AAD treatment cohort. CONCLUSION: AF ablation was associated with significantly lower CV-related outpatient visits, and lower risk of heart failure and mortality versus AAD therapy. PMID- 30404604 TI - Hypertriglyceridaemia in extremely preterm infants receiving parenteral lipid emulsions. AB - BACKGROUND: Lipid emulsions (LE) are routinely administered as part of parenteral nutrition in neonates. There is a wide variation in clinical practice of plasma triglyceride monitoring during LE therapy. Our aim was to evaluate the incidence of hypertriglyceridaemia (Plasma triglyceride > 2.8 mmol/L) and its association with mortality and major morbidities in extremely preterm infants on parenteral nutrition. METHODS: A retrospective review of 195 infants < 29 weeks gestation. Lipid emulsion was commenced at 1 g/kg/day soon after birth and increased by 1 g/kg daily up to 3 g/kg/day and continued until the infant was on at least 120 ml/kg/day of enteral feeds. Plasma triglyceride concentrations were measured at each increment and the lipid emulsion dosage was adjusted to keep plasma triglyceride concentrations <=2.8 mmol/L. RESULTS: Hypertriglyceridemia was noted in 38 neonates (32.5% in 23-25 weeks and 16.1% in 26-28 weeks). Severe hypertriglyceridemia (> 4.5 mmol/L) was noted in 11 infants (10.0% in 23-25 weeks and 4.5% in 26-28 weeks). Hypertriglyceridemia was associated with an increase in mortality (unadjusted OR 3.5; 95% CI 1.13-10.76; 0.033) and severe retinopathy of prematurity (unadjusted OR 4.06; 95% CI 1.73-9.59; 0.002) on univariate analysis. However, this association became non-significant in multivariate analysis with adjustment for gestation and birthweight. CONCLUSIONS: Hypertriglyceridemia is common in extremely preterm infants receiving parenteral lipid emulsions. Regular monitoring and prompt adjustment of lipid intake in the presence of hypertriglyceridemia, minimising the length of exposure to hypertriglyceridemia, may mitigate potential consequences. PMID- 30404606 TI - Trends in cervical cancer incidence and survival in Estonia from 1995 to 2014. AB - BACKGROUND: Cervical cancer (CC) incidence in Estonia is the third highest in Europe, even though an organised nation-wide screening program has been in place since 2006. The aim of the study was to analyse the incidence and survival of CC in Estonia, focusing on age, morphology and stage at diagnosis. METHODS: Data from Estonian Cancer Registry were used to analyse age-standardized (world) and age-specific incidence for 1968-2014 rates. Joinpoint regression was used to estimate the annual percentage change (APC) for incidence trends. Age-period cohort model was used to summarise time trends in terms of cohort and period effects. Relative survival ratios (RSR) were calculated for cases diagnosed in 1995-2014. Union for International Cancer Control version 7 of the TNM classification for malignant tumours was used to categorise stage. RESULTS: The age-standardized incidence of CC increased since 1980s at a rate of 0.8% per year. A significant increase was seen for all age groups except for 70+. The incidence of squamous cell carcinoma mimicked the overall trend, while adenocarcinoma showed increase since mid-1990s (APC 6.7). Age-period-cohort modelling showed strong cohort effects with the lowest risk for birth-cohorts born around 1940 and significantly increasing risks for successive cohorts born thereafter. No period effects were seen. The proportion of stage IV cases increased from 13% in 2005-2009 to 18% in 2010-2014. A significant increase was seen in the overall 5-year RSR from 1995 to 1999 to 2010-2014 (58% vs 66%). In 2010-2014, the 5-year RSRs ranged from 89% in women aged 15-39 to 41% in age group 70+. For stages I to IV, the respective RSRs were 98, 74, 57 and 22%. CONCLUSIONS: The inadequate uptake and insufficient quality of the Pap-smear based screening program has not brought along a decline in the incidence of CC in Estonia. Stage distribution has shifted towards later stages. New approaches are needed to prevent CC in Estonia. PMID- 30404605 TI - Quantitative proteomic analysis of aqueous humor from patients with drusen and reticular pseudodrusen in age-related macular degeneration. AB - BACKGROUND: To identify novel biomarkers related to the pathogenesis of dry age related macular degeneration (AMD), we adopted a human retinal pigment epithelial (RPE) cell culture model that mimics some features of dry AMD including the accumulation of intra- and sub-RPE deposits. Then, we investigated the aqueous humor (AH) proteome using a data-independent acquisition method (sequential window acquisition of all theoretical fragment ion mass spectrometry) for dry AMD patients and controls. METHODS: After uniformly pigmented polarized monolayers of human fetal primary RPE (hfRPE) cells were established, the cells were exposed to 4-hydroxy-2-nonenal (4-HNE), followed by Western blotting, immunofluorescence analysis and ELISA of cells or conditioned media for several proteins of interest. Data-dependent acquisition for identification of the AH proteome and SWATH-based mass spectrometry were performed for 11 dry AMD patients according to their phenotypes (including soft drusen and reticular pseudodrusen [RPD]) and 2 controls (3 groups). RESULTS: Increased intra- and sub-RPE deposits were observed in 4-HNE-treated hfRPE cells compared with control cultures based on APOA1, cathepsin D, and clusterin immunoreactivity. Additionally, the differential abundance of proteins in apical and basal chambers with or without 4-HNE treatment confirmed the polarized secretion of proteins from hfRPE cells. A total of 119 proteins were quantified in dry AMD patients and controls by SWATH-MS. Sixty-five proteins exhibited significantly altered abundance among the three groups. A two-dimensional principal component analysis plot was generated to identify typical proteins related to the pathogenesis of dry AMD. Among the identified proteins, eight proteins, including APOA1, CFHR2, and CLUS, were previously considered major components or regulators of drusen. Three proteins (SERPINA4, LUM, and KERA proteins) have not been previously described as components of drusen or as being related to dry AMD. Interestingly, the LUM and KERA proteins, which are related to extracellular matrix organization, were upregulated in both RPD and soft drusen. CONCLUSIONS: Differential protein expression in the AH between patients with drusen and RPD was quantified using SWATH-MS in the present study. Detailed proteomic analyses of dry AMD patients might provide insights into the in vivo biology of drusen and RPD. PMID- 30404607 TI - Lamellar rotation surgery: a new procedure for repairing upper eyelid defects. AB - BACKGROUND: To report "Lamellar Rotation Surgery",a new technique for repairing large and moderate full-thickness upper eyelid defects. METHODS: A two-stage technique is described in which a vertical incision is made in the tarsus of the lower eyelid with elevation of the lateral posterior lamella while sparing the lower eyelid orbicularis and skin to be rotated superiorly to form the reconstructed posterior lamella of the upper eyelid. Additionally, a lateral periosteal flap is used to reconstruct the lateral canthal tendon, and a McGregor procedure is used to reconstruct the anterior lamella of the upper eyelid. The flap is divided during a second-stage surgery at 3 months. Three cases are described to showcase this technique. RESULTS: Good functional and aesthetic results were achieved for the eyelids. CONCLUSIONS: This new procedure may help to address the challenge of repairing full-thickness defects of the upper eyelid. TRIAL REGISTRATION: Registration number: ChiCTR1800018990 , 20 Oct 2018, retrospectively registered. PMID- 30404608 TI - A mouthful - airway matters in intraoperative neuromonitoring in auditory brainstem implant surgery for the pediatric patient: a case series. AB - BACKGROUND: The Auditory brainstem implant (ABI) is a new surgical option for hearing impaired children. Intraoperative neurophysiology monitoring includes brainstem mapping of cranial nerve (CN) IX, X, XI, XII and their motor nuclei, and corticobulbar tract motor-evoked potential. These require laryngeal electrodes and intra-oral pins, posing a challenge to airway management especially in the pediatric airway, where specialized electromyogram (EMG) tracheal tubes are not available. Challenges include determining the optimum position on the endotracheal tube (ETT) in which to place laryngeal electrode, and the increase in external diameter of ETT contributed by the wrapping the electrode around the shaft of ETT; this may necessitate downsizing of the tracheal tube. An appropriate size ETT minimizes displacement, which in turn can affect electrode contact with the vocal cords. Finally, a small thus crowded pediatric airway makes for difficult visualization during placement of intraoral neuromonitoring electrodes. The use of a videolaryngoscope helps determine optimum electrode placement. CASE PRESENTATION: We describe intraoperative neurophysiology monitoring and airway management for the first two ABI procedures in Singapore, conducted for children with congenitally absent cochlear nerves. CONCLUSION: Neurophysiology cranial nerve IX, X, XII monitoring in the ABI procedure requires intraoral placement of electrodes. Care should be exercised during placement and removal. Vagus nerve monitoring in children requires attention to tube preparation, and consideration should be given to avoidance of airway topicalization. PMID- 30404609 TI - An unusual presentation of prominent crista terminalis mimicking a right atrial mass: a case report. AB - BACKGROUND: The crista terminalis is a variation of normal anatomical structure within the right atrium which may be misdiagnosed with an abnormal atrial mass normally visualized in the standard views on the transthoracic echocardiogram. CASE PRESENTATION: In this case presentation, we demonstrated a rare case report describing the accidental discovery of a right atrial mass-like structure in a 54 year old Asian man without physical discomfort during an echocardiographic examination. These findings naturally caused some concern as the differential diagnosis such as right atrial myxoma or thrombus and further examination were organized. The subsequent positron emission tomography/magnetic resonance imaging (PET/MRI) differentiated a true right atrial mass from a strip extending into the atrium in accordance with prominent crista terminalis. CONCLUSION: A preferable understanding of the complex anatomy and PET/MRI appearance of a prominent crista terminalis will minimize the misdiagnosis of this structure and avoiding unnecessary anxiety and more invasive examinations. PMID- 30404611 TI - Deblender: a semi-/unsupervised multi-operational computational method for complete deconvolution of expression data from heterogeneous samples. AB - BACKGROUND: Towards discovering robust cancer biomarkers, it is imperative to unravel the cellular heterogeneity of patient samples and comprehend the interactions between cancer cells and the various cell types in the tumor microenvironment. The first generation of 'partial' computational deconvolution methods required prior information either on the cell/tissue type proportions or the cell/tissue type-specific expression signatures and the number of involved cell/tissue types. The second generation of 'complete' approaches allowed estimating both of the cell/tissue type proportions and cell/tissue type-specific expression profiles directly from the mixed gene expression data, based on known (or automatically identified) cell/tissue type-specific marker genes. RESULTS: We present Deblender, a flexible complete deconvolution tool operating in semi /unsupervised mode based on the user's access to known marker gene lists and information about cell/tissue composition. In case of no prior knowledge, global gene expression variability is used in clustering the mixed data to substitute marker sets with cluster sets. In addition, we integrate a model selection criterion to predict the number of constituent cell/tissue types. Moreover, we provide a tailored algorithmic scheme to estimate mixture proportions for realistic experimental cases where the number of involved cell/tissue types exceeds the number of mixed samples. We assess the performance of Deblender and a set of state-of-the-art existing tools on a comprehensive set of benchmark and patient cancer mixture expression datasets (including TCGA). CONCLUSION: Our results corroborate that Deblender can be a valuable tool to improve understanding of gene expression datasets with implications for prediction and clinical utilization. Deblender is implemented in MATLAB and is available from ( https://github.com/kondim1983/Deblender/ ). PMID- 30404610 TI - The initial deficiency of protein processing and flavonoids biosynthesis were the main mechanisms for the male sterility induced by SX-1 in Brassica napus. AB - BACKGROUND: Rapeseed (Brassica napus) is an important oil seed crop in the Brassicaceae family. Chemical induced male sterility (CIMS) is one of the widely used method to produce the hybrids in B. napus. Identification of the key genes and pathways that involved in CIMS were important to understand the underlying molecular mechanism. In the present report, a multi-omics integrative analysis, including of the proteomic, transcriptomic and miRNAs, combined with morphological and physiological analysis were conducted. RESULTS: Earlier degeneration of the tapetosomes and elaioplasts, aberrantly stacking in tapetal cells and incompletely deposition in tryphine of pollen wall were observed in chemical hybridization agent (CHA) of SX-1 treated B. napus through SEM and TEM analysis. It was revealed that the deficiencies in protein processing in endoplasmic reticulum (ER) and flavonoids biosynthesis were occurred at early stage in the SX-1 treated materials. Subsequently, plant hormone signal transduction, biosynthesis of amino acids, fatty acids and steroid in anther at later stages were identified down-regulated after SX-1 treatment. 144 transcript factors (TFs) were also indentified to down-regulated at early stage, which suggested the early regulation in anther and pollen wall development were disordered in CHA treated B. napus. In addition, 7 important miRNAs were identified and 2 of the predicted target genes of miRNAs were Rf-like genes. CONCLUSIONS: Taken together, an interaction network of candidate genes and the putative metabolism pathways were constructed based on the multi-omics integrative analysis, it provided a new insight into the male sterility induced by CHA of SX-1 in B. napus. PMID- 30404612 TI - The dynamic monitoring of CEA in response to chemotherapy and prognosis of mCRC patients. AB - BACKGROUND: The role of carcinoembryonic antigen (CEA) change patterns in tumor response and long-term outcome is unclear. This study aimed to investigate the correlation between changes in CEA levels and tumor response as a potential prognostic model. METHODS: CEA levels were determined from baseline to progression. A chi2 test was used to assess the correlation between CEA changes and tumor response. Univariate and multivariate COX models were used to explore the correlation of CEA changes to progression-free survival (PFS) and overall survival (OS). RESULTS: All 114 patients were divided into five groups according to CEA change pattern (A: patients had an initial fast CEA decrease that then turned into a slow increase; B: patients had an initial slow CEA decrease that then turned to a slow increase; C: patients had a continually slow CEA increase; D: patients had a continually fast CEA increase; E: patients had an initial fast CEA decrease that then turned into a fast increase). Patients in Group A had the longest OS and PFS while Group E patients had the shortest OS. Baseline to week 12 and week 12 to week 18 change rates were consistent with tumor response and progression, respectively. An increase in CEA level by >=2.7% from week 12 to 18 was an independent negative prognostic factor of OS. CONCLUSIONS: CEA changes mirror the tumor response to first-line chemotherapy and are associated with prognosis. CEA monitoring may be a substitute for computed tomography during the CEA stable period of treatment. PMID- 30404613 TI - Differential effects of coconut versus soy oil on gut microbiota composition and predicted metabolic function in adult mice. AB - BACKGROUND: Animal studies show that high fat (HF) diet-induced gut microbiota contributes to the development of obesity. Oil composition of high-fat diet affects metabolic inflammation differently with deleterious effects by saturated fat. The aim of the present study was to examine the diversity and metabolic capacity of the cecal bacterial community in C57BL/6 N mice administered two different diets, enriched respectively with coconut oil (HFC, high in saturated fat) or soy oil (HFS, high in polyunsaturated fat). The relative impact of each hypercaloric diet was evaluated after 2 and 8 weeks of feeding, and compared with that of a low-fat, control diet (LF). RESULTS: The HFC diet induced the same body weight gain and fat storage as the HFS diet, but produced higher plasma cholesterol levels after 8 weeks of treatment. At the same time point, the cecal microbiota of HFC diet-fed mice was characterized by an increased relative abundance of Allobaculum, Anaerofustis, F16, Lactobacillus reuteri and Deltaproteobacteria, and a decreased relative abundance of Akkermansia muciniphila compared to HFS mice. Comparison of cecal microbiota of high-fat fed mice versus control mice indicated major changes that were shared between the HFC and the HFS diet, including the increase in Lactobacillus plantarum, Lutispora, and Syntrophomonas, while some other shifts were specifically associated to either coconut or soy oil. Prediction of bacterial gene functions showed that the cecal microbiota of HFC mice was depleted of pathways involved in fatty acid metabolism, amino acid metabolism, xenobiotic degradation and metabolism of terpenoids and polyketides compared to mice on HFS diet. Correlation analysis revealed remarkable relationships between compositional changes in the cecal microbiota and alterations in the metabolic and transcriptomic phenotypes of high fat fed mice. CONCLUSIONS: The study highlights significant differences in cecal microbiota composition and predictive functions of mice consuming a diet enriched in coconut vs soy oil. The correlations established between specific bacterial taxa and various traits linked to host lipid metabolism and energy storage give insights into the role and functioning of the gut microbiota that may contribute to diet-induced metabolic disorders. PMID- 30404614 TI - Overall survival and time trends in breast and cervical cancer incidence and mortality in the Regional Health District (RHD) of Barretos, Sao Paulo, Brazil. AB - BACKGROUND: Breast and cervical cancers represent a significant cause of morbidity and mortality among women. The purpose of this study was to analyse the survival and time trends in two of the most common female cancers in the Regional Health District (RHD) of Barretos, Sao Paulo, Brazil. METHODS: From 2000 through 2015, we calculated the breast and cervical cancer incidence and mortality rates per 100,000 women who were age-standardized to the world population. We obtained the time trends using the Joinpoint Regression software. We estimated the overall survival rates using the Kaplan-Meier methods. RESULTS: The age-standardized rates (ASR) for incidence of breast cancer increased annually, with an average annual percentage change (AAPC) of 4.3 (95% Confidence Interval (CI): 2.4 to 6.3) for invasive breast cancer and 10.2 (95% CI: 6.1 to 14.5) for in situ breast cancer. The mortality rates for invasive breast cancer decreased with an AAPC of 0.2 (95% CI: -1.9 to 2.4). The ASR incidence of invasive cervical cancer showed an AAPC of - 1.9 (95% CI: -4.7 to 0.9). For in situ cases, the ASR showed an AAPC of 9.3 (95% CI: 3.3 to 15.7). The ASR mortality for cervical cancer showed an AAPC of - 5.3 (95% CI: -9.5 to - 0.8). The Kaplan-Meier analysis indicated 5-year overall survival rates of 74.3% for breast cancer and 70.7% for cervical cancer. CONCLUSIONS: The incidence of in situ and invasive breast cancer is increasing, while the mortality rates remain stable. We observed an increase in the incidence of in situ cervical cancer and a decrease in invasive incidence rates during the study period, and we noted that the cervical cancer mortality significantly declined during the study period. PMID- 30404615 TI - Correction to: Factors associated with late presentation of cervical cancer cases at a district hospital: a retrospective study. AB - It has been highlighted, that the original article [1] contained errors in Fig. 1. On the 3rd level, the first box should read "Records with any required information = 157" and the second box should read "Records without any required information = 0". Those were incorrectly captured as "Records with complete information = 157" and "Records without any required information = 157" respectively in the original article. This Correction article shows the correct Fig. 1. PMID- 30404616 TI - Screening of differentially expressed proteins from syncytiotrophoblast for severe early-onset preeclampsia in women with gestational diabetes mellitus using tandem mass tag quantitative proteomics. AB - BACKGROUND: Previous studies have revealed that women with gestational diabetes mellitus (GDM) have an increased risk of developing preeclampsia (PE). The possible reason is the abnormal lipid metabolism caused by GDM that leads to dysfunction of vascular endothelial cells and atherosclerosis, resulting in the onset of PE. However, studies focusing on the pathogenesis of PE in syncytiotrophoblast of GDM patients are lacking. This study aimed to compare differentially expressed proteins from syncytiotrophoblast between women with GDM and women with GDM with subsequently developed PE. METHODS: Syncytiotrophoblast samples were obtained from pregnant women immediately after delivery. To explore the protein expression changes of syncytiotrophoblast that might explain the pathogenesis of PE in women with GDM, quantitative proteomics was performed using tandem mass tag (TMT) isobaric tags and liquid chromatography-tandem mass spectrometry. Bioinformatics analysis was performed to enrich the biological processes that these differentially expressed proteins were involved in. RESULTS: A total of 28,234 unique peptides and 4140 proteins were identified in all samples. Among them, 23 differentially expressed proteins were identified between patients with GDM and patients with GDM with subsequently developed PE. Therein, 11 proteins were upregulated and 12 proteins were downregulated. Two relative proteins (FLT1 and PABPC4) were independently verified using immunoblotting analysis. Bioinformatic results indicated that the onset of PE in patients with GDM is a multifactorial disorder, involving factors such as apoptosis, transcriptional misregulation, oxidative stress, lipid metabolism, cell infiltration and migration, and angiogenesis. CONCLUSION: These results indicated that the inadequacy of endometrium infiltration, angiogenic disorder, and oxidative stress in syncytiotrophoblast are more likely to occur in patients with GDM and may be the potential mechanisms leading to such patients secondarily developing severe early-onset PE. PMID- 30404617 TI - Unexpected patterns of segregation distortion at a selfish supergene in the fire ant Solenopsis invicta. AB - BACKGROUND: The Sb supergene in the fire ant Solenopsis invicta determines the form of colony social organization, with colonies whose inhabitants bear the element containing multiple reproductive queens and colonies lacking it containing only a single queen. Several features of this supergene - including suppressed recombination, presence of deleterious mutations, association with a large centromere, and "green-beard" behavior - suggest that it may be a selfish genetic element that engages in transmission ratio distortion (TRD), defined as significant departures in progeny allele frequencies from Mendelian inheritance ratios. We tested this possibility by surveying segregation ratios in embryo progenies of 101 queens of the "polygyne" social form (3512 embryos) using three supergene-linked markers and twelve markers outside the supergene. RESULTS: Significant departures from Mendelian ratios were observed at the supergene loci in 3-5 times more progenies than expected in the absence of TRD and than found, on average, among non-supergene loci. Also, supergene loci displayed the greatest mean deviations from Mendelian ratios among all study loci, although these typically were modest. A surprising feature of the observed inter-progeny variation in TRD was that significant deviations involved not only excesses of supergene alleles but also similarly frequent excesses of the alternate alleles on the homologous chromosome. As expected given the common occurrence of such "drive reversal" in this system, alleles associated with the supergene gain no consistent transmission advantage over their alternate alleles at the population level. Finally, we observed low levels of recombination and incomplete gametic disequilibrium across the supergene, including between adjacent markers within a single inversion. CONCLUSIONS: Our data confirm the prediction that the Sb supergene is a selfish genetic element capable of biasing its own transmission during reproduction, yet counterselection for suppressor loci evidently has produced an evolutionary stalemate in TRD between the variant homologous haplotypes on the "social chromosome". Evidence implicates prezygotic segregation distortion as responsible for the TRD we document, with "true" meiotic drive the most likely mechanism. Low levels of recombination and incomplete gametic disequilibrium across the supergene suggest that selection does not preserve a single uniform supergene haplotype responsible for inducing polygyny. PMID- 30404618 TI - Trends in the ease of cigarette purchase among Korean adolescents: evidence from the Korea youth risk behavior web-based survey 2005-2016. AB - BACKGROUND: According to the Juvenile Protection Act in Korea, no one is allowed to sell, rent, or distribute tobacco products to adolescents. Furthermore, the Framework Convention on Tobacco Control Article 16 prohibits the sale of tobacco products to minors. In this study, we investigated the trends in and associated factors of the ease of cigarette purchase among Korean adolescents from 2005 to 2016. METHODS: The analyses were based on the data of the Korea Youth Risk Behavior Web-based Survey. We estimated the trends in the ease of cigarette purchase from 2005 to 2016 and evaluated associated factors. Ease of cigarette purchase was defined as the proportion of adolescents who were able to purchase cigarettes from among those who had tried to purchase cigarettes in the past 30 days. RESULTS: The ease of cigarette purchase began decreasing since 2008 (81.3%) compared to 2005 (83.9%). It decreased to 76.5% in 2013 and further decreased to 71.4% in 2016. The ease of cigarette purchase increased for adolescents who were in higher grades, smoked larger amounts of cigarettes per day, lived in metropolitan cities, had problematic drinking in the past year, and had close friends who smoked. It decreased in adolescents who had current smokers among their family members. CONCLUSIONS: Although the proportion of adolescents who were able to purchase cigarettes significantly decreased starting in 2008, more than 70% of Korean adolescents can still purchase cigarettes. Enforcement of the Juvenile Protection Act must be strengthened in order to prevent cigarette use among adolescents. PMID- 30404620 TI - A case report of scrub typhus complicated with myocarditis and rhabdomyolysis. AB - BACKGROUND: Scrub typhus is a zoonotic disease caused by Orientia tsutsugamushi, a gram-negative intracellular bacterium. Myocarditis and rhabdomyolysis are rare complications of scrub typhus. CASE PRESENTATION: We report a case of scrub typhus, which was simultaneously complicated with myocarditis and rhabdomyolysis. A 54-year-old woman presented to our hospital with myalgia in the upper and lower limbs, oedema and a fever of 7 days' duration. We confirmed the diagnosis of scrub typhus complicated with myocarditis by pericardial fluid analysis and cardiac magnetic resonance imaging results. The pericardial fluid showed characteristics of an exudate, an elevated immunofluorescence assay (IFA) IgG titer of 1:2048 and a positive 16S rRNA qPCR result. We also diagnosed rhabdomyolysis by the patient's presenting symptoms, elevated muscle enzyme levels and bone scan results. CONCLUSION: We report for the first time a case of scrub typhus complicated with both myocarditis and rhabdomyolysis, the causative agent of which was the Boryong genotype of O. tsutsugamushi. PMID- 30404619 TI - Comparison of implementation strategies to influence adherence to the clinical pathway for screening, assessment and management of anxiety and depression in adult cancer patients (ADAPT CP): study protocol of a cluster randomised controlled trial. AB - BACKGROUND: Health service change is difficult to achieve. One strategy to facilitate such change is the clinical pathway, a guide for clinicians containing a defined set of evidence-based interventions for a specific condition. However, optimal strategies for implementing clinical pathways are not well understood. Building on a strong evidence-base, the Psycho-Oncology Co-operative Research Group (PoCoG) in Australia developed an evidence and consensus-based clinical pathway for screening, assessing and managing cancer-related anxiety and depression (ADAPT CP) and web-based resources to support it - staff training, patient education, cognitive-behavioural therapy and a management system (ADAPT Portal). The ADAPT Portal manages patient screening and prompts staff to follow the recommendations of the ADAPT CP. This study compares the clinical and cost effectiveness of two implementation strategies (varying in resource intensiveness), designed to encourage adherence to the ADAPT CP over a 12-month period. METHODS: This cluster randomised controlled trial will recruit 12 cancer service sites, stratified by size (large versus small), and randomised at site level to a standard (Core) versus supported (Enhanced) implementation strategy. After a 3-month period of site engagement, staff training and site tailoring of the ADAPT CP and Portal, each site will "Go-live", implementing the ADAPT CP for 12 months. During the implementation phase, all eligible patients will be introduced to the ADAPT CP as routine care. Patient participants will be registered on the ADAPT Portal to complete screening for anxiety and depression. Staff will be responsible for responding to prompts to follow the ADAPT CP. The primary outcome will be adherence to the ADAPT CP. Secondary outcomes include staff attitudes to and experiences of following the ADAPT CP, using the ADAPT Portal and being exposed to ADAPT implementation strategies, collected using quantitative and qualitative methods. Data will be collected at T0 (baseline, after site engagement), T1 (6 months post Go-live) and T2 (12 months post Go live). DISCUSSION: This will be the first cluster randomised trial to establish optimal levels of implementation effort and associated costs to achieve successful uptake of a clinical pathway within cancer care. TRIAL REGISTRATION: The study was registered prospectively with the ANZCTR on 22/3/2017. Trial ID ACTRN12617000411347. PMID- 30404621 TI - The impact of adjuvant therapies on patient survival and the recurrence patterns for resected stage IIa-IVa lower thoracic oesophageal squamous cell carcinoma. AB - BACKGROUND: This study evaluated the impact of adjuvant therapies on patient survival and disease recurrence patterns to identify an effective adjuvant therapy for resected lower thoracic oesophageal squamous cell carcinoma (LTESCC). METHODS: Clinical data of 127 patients with stage IIa-IVa LTESCC with a minimum 2 year follow-up after oesophagectomy were analysed. The survival and recurrence patterns were compared among patients who received adjuvant radiotherapy, adjuvant chemotherapy, adjuvant chemoradiotherapy, or surgery alone. RESULTS: Eighty-eight patients (69.3%) were identified as having disease recurrence. The regional lymph node recurrence rate was 57.5%, and the recurrence rates were high in the lower neck, upper mediastinum, and upper abdomen. Compared to surgery alone, adjuvant radiotherapy or chemoradiotherapy significantly decreased the recurrence rate (p < 0.05). Adjuvant chemoradiotherapy significantly improved overall survival, disease-free survival, and locoregional recurrence-free survival compared to surgery alone (p = 0.01, 0.01, and 0.00, respectively). Pathologically positive lymph nodes (PPLNs) in the lower mediastinum represented a potential risk factor for cervical recurrence (HR 2.97, 95%CI 1.19-7.39). Multivariable analysis showed that postoperative radiotherapy (HR 0.30, 95%CI 0.13-0.68) and PPLNs in the upper mediastinum (HR 3.72, 95%CI 1.30-10.67) were independent risk factors for upper mediastinal recurrence, while postoperative radiotherapy (HR 0.37, 95%CI 0.16-0.85) and PPLNs in the abdomen (HR 2.57, 95%CI 1.12-5.92) were independent risk factors for abdominal recurrence. CONCLUSION: Adjuvant chemoradiotherapy was the most effective adjuvant therapy for resected stage IIa-IVa LTESCC. The lower neck, upper mediastinum, and upper abdomen were high-risk regions for postoperative radiotherapy. The regions of PPLNs may be important factors for individual targets. PMID- 30404623 TI - Incidence and predictors of left ventricular thrombus by cardiovascular magnetic resonance in acute ST-segment elevation myocardial infarction treated by primary percutaneous coronary intervention: a meta-analysis. AB - INTRODUCTION: The incidence of left ventricular (LV) thrombus formation in ST segment elevation myocardial infarction (STEMI) patients in the current era of primary percutaneous coronary intervention (PCI) is not well established. We performed a meta-analysis to assess the actual incidence and predictors of LV thrombus by cardiovascular magnetic resonance (CMR) in STEMI treated by primary PCI. METHODS: We searched MEDLINE and EMBASE databases up to February 2018. We included all studies published as a full-text article, reporting the incidence of LV thrombus by CMR within 1 month following acute STEMI in patients treated by primary PCI. A binary random-effects model was used to estimate the pooled incidence of LV thrombus. The diagnostic performance of transthoracic echocardiography (TTE) as compared with CMR was pooled to obtain the sensitivity and specificity of TTE with CMR as the gold standard. Embolic and bleeding complications of LV thrombus were also evaluated. RESULTS: Ten studies were included in the meta-analysis. The incidence of LV thrombus by CMR in all-comer STEMI patients (n = 2072) was 6.3% with 96% of LV thrombus occurring in those with anterior STEMI (12.2% incidence). When only anterior STEMI with LVEF< 50% were considered (n = 447), the incidence of LV thrombus was 19.2%. Compared with CMR, the sensitivity of TTE to detect LV thrombus was 29% with a specificity of 98%. The sensitivity of TTE increased to 70% in those with anterior STEMI and reduced LVEF. LV thrombus resolved in 88% of cases by 3 to 6 months. After 1-2 years follow-up, the embolic complication rate was similar at 1.5% (P = 0.25) but the bleeding complication rate was significantly higher (8.8% versus 0.5%, P < 0.001) in the LV thrombus group on triple therapy when compared to the no LV thrombus group on dual antiplatelet therapy. CONCLUSION: In the primary PCI era, CMR detection of an LV thrombus post-STEMI remains high with incidence of nearly 20% in anterior STEMI with depressed LVEF. Patients with LV thrombus treated by triple therapy had similar embolic complications but higher bleeding complications than those with no LV thrombus treated with dual antiplatelet therapy. A 3 month follow-up CMR scan to guide anticoagulation duration might help mitigate bleeding risk. PMID- 30404622 TI - Effects of oral contraceptives and natural menstrual cycling on environmental learning. AB - BACKGROUND: Endogenous ovarian hormones as well as exogenous oestradiol and progesterone play an important role in cognitive processing. Specifically, these hormones play a role in different aspects of memory, both in terms of storage capacity and temporal duration of the mnemonic track. These hormones also have various effects on different types of memory (i.e., verbal, visuo-spatial, prospective). This study investigated the effects of hormones on topographic memory, a type of memory specifically needed to recall a pathway and to acquire spatial information about locations, distances, and directions. METHODS: We compared 25 naturally cycling women (NCW) in two different cycling phases, the early follicular phase (4th - 5th days) and the mid-luteal phase (20th-21st days), with 26 women taking oral contraceptives (OC) tested in the active pill phase (20th to 21st day of OC cycle) and the inactive pill phase (2nd to 4th day of OC cycle). Both groups performed the Walking Corsi Test to assess topographic memory in their respective cycling phases. Women were instructed to learn an eight-step sequence path and recall the path five minutes later. RESULTS: We found that the two groups differed in terms of learning the 8-step sequence path; OC users were always better (4-5 days vs. 20-21 days) than NCW. No differences emerged in the delayed recall of the same path. CONCLUSIONS: As already observed in other memory domains (i.e., verbal memory, emotional memory), OC users showed an advantage in terms of topographic learning. Our results might be explained by hormonal mechanisms and may suggest the future application of OC in women with topographic disorders or visuo-spatial difficulties. PMID- 30404624 TI - Analysis of MCQ and distractor use in a large first year Health Faculty Foundation Program: assessing the effects of changing from five to four options. AB - BACKGROUND: Multiple choice questions are commonly used in summative assessment. It is still common practice for tertiary institutions and accrediting bodies to use five-option single best answer multiple choice questions, despite a substantial body of evidence showing that multiple choice questions with only three or four options provide effective and discriminatory assessment. METHODS: In this study we investigated the distribution of distractor efficacy in exams from four large first-year undergraduate courses in chemistry and in anatomy and physiology in a Health Faculty; assessed the impact on overall student score after changing from five-option to four-option single best answer multiple choice questions; and assessed the impact of changing from five options to four options on item difficulty and discrimination. RESULTS: For the five-option questions analysed, 19% had four effective distractors, which is higher than previous studies, but still a minority of questions. After changing from five to four options, the overall student performance on all multiple choice questions was slightly lower in the second offering of one course, slightly higher in the second offering of another course, and similar in the second offering for two courses. For a subset of questions that were used in both offerings, there were negligible differences in item difficulty and item discrimination between offerings. CONCLUSIONS: These results provide further evidence that five-option questions are not superior to four-option questions, with reduction to four options making little if any difference to overall performance, particularly when MCQ is used in conjunction with other assessment types (including short answer questions, and practical or laboratory assessment). Further areas of study that arise from these findings are: to investigate the reasons for resistance to changing established assessment practice within institutions and by accrediting bodies; and to analyse student perceptions of the impact of a reduced number of options in MCQ-based assessment. PMID- 30404625 TI - Reconstruction of composite defects of the scalp and neurocranium-a treatment algorithm from local flaps to combined AV loop free flap reconstruction. AB - BACKGROUND: Reconstruction of cranial composite defects, including all layers of the scalp and the neurocranium, poses an interdisciplinary challenge. Especially after multiple previous operations and/or radiation therapy, sufficient reconstruction is often only possible using microsurgical free flap transplantation. The aim of this study was to analyze the therapy of interdisciplinary cases with composite defects including the scalp and neurocranium. METHODS: From 2009 to 2017, 23 patients with 18 free flaps and 10 pedicled/local flaps were analyzed. First choices for free flaps were muscle flaps followed by fasciocutaneous flaps. RESULTS: Except for four patients, a stable coverage could be reached in the first operation. Three of these patients received a local scalp rotation flap in the first operation and needed an additional free flap because the local flap was no longer sufficient for coverage after wound healing deficiency or tumor relapse. The superficial temporal artery or external carotid artery served as recipient vessels. In special cases, venous grafts or an arteriovenous loop (AV loop) were used as extensions for the recipient vessels. CONCLUSIONS: In summary, an interdisciplinary approach with radical debridement of infected or necrotic tissue and the reconstruction of the dura mater are essential to reach a stable, long-lasting reconstructive result. Based on our experience, free flaps seem to be the first choice for patients after multiple previous operations and/or radiation therapy. PMID- 30404626 TI - SRC inhibition prevents P-cadherin mediated signaling and function in basal-like breast cancer cells. AB - BACKGROUND: Basal-like breast cancer (BLBC) is a poor prognosis subgroup of triple-negative carcinomas that still lack specific target therapies and accurate biomarkers for treatment selection. P-cadherin is frequently overexpressed in these tumors, promoting cell invasion, stem cell activity and tumorigenesis by the activation of Src-Family kinase (SRC) signaling. Therefore, our aim was to evaluate if the treatment of BLBC cells with dasatinib, the FDA approved SRC inhibitor, would impact on P-cadherin induced tumor aggressive behavior. METHODS: P-cadherin and SRC expression was evaluated in a series of invasive Breast Cancer and contingency tables and chi-square tests were performed. Cell-cell adhesion measurements were performed by Atomic Force Microscopy, where frequency histograms and Gaussian curves were applied. 2D and 3D cell migration and invasion, proteases secretion and self-renew potential were evaluated in vitro. Student's t-tests were used to determine statistically significant differences. The cadherin/catenin complex interactions were evaluated by in situ proximity ligation assay, and statistically significant results were determined by using Mann-Whitney test with a Bonferroni correction. In vivo xenograft mouse models were used to evaluate the impact of dasatinib on tumor growth and survival. ANOVA test was used to evaluate the differences in tumor size, considering a confidence interval of 95%. Survival curves were estimated by the Kaplan-Meier's method, using the log-rank test to assess significant differences for mice overall survival. RESULTS: Our data demonstrated that P-cadherin overexpression is significantly associated with SRC activation in breast cancer cells, which was also validated in a large series of primary tumor samples. SRC activity suppression with dasatinib significantly prevented the in vitro functional effects of P-cadherin overexpressing cells, as well as their in vivo tumorigenic and metastatic ability, by increasing mice overall survival. Mechanistically, SRC inhibition affects P-cadherin downstream signaling, rescues the E-cadherin/p120 catenin complex to the cell membrane, recovering cell-cell adhesion function. CONCLUSIONS: In conclusion our findings show that targeting P-cadherin/SRC signaling and functional activity may open novel therapeutic opportunities for highly aggressive and poor prognostic basal-like breast cancer. PMID- 30404628 TI - Patients' perspectives of acceptability of ART, TB and maternal health services in a subdistrict of Johannesburg, South Africa. AB - BACKGROUND: The field of acceptability of health services is emerging and growing in coherence. But there are gaps, including relatively little integration of elements of acceptability. This study attempted to analyse collectively three elements of acceptability namely: patient-provider, patient-service organisation and patient-community interactions. METHODS: Mixed methods were used to analyse secondary data collected as part of the Researching Equity in Access to Health Care (REACH) study of access to tuberculosis (TB) treatment, antiretroviral therapy (ART) and maternal health (MH) services in South Africa's public health sector. RESULTS: Provider acceptability was consistently high across all the three tracer services at 97.6% (ART), 96.6% (TB) and 96.4% (MH). Service acceptability was high only for TB tracer (70.1%). Community acceptability was high for both TB (83.6%) and MH (96.8%) tracers. CONCLUSION: Through mixed methods, this paper provides a nuanced view of acceptability of health services. PMID- 30404629 TI - Is it possible to overcome issues of external validity in preclinical animal research? Why most animal models are bound to fail. AB - BACKGROUND: The pharmaceutical industry is in the midst of a productivity crisis and rates of translation from bench to bedside are dismal. Patients are being let down by the current system of drug discovery; of the several 1000 diseases that affect humans, only a minority have any approved treatments and many of these cause adverse reactions in humans. A predominant reason for the poor rate of translation from bench to bedside is generally held to be the failure of preclinical animal models to predict clinical efficacy and safety. Attempts to explain this failure have focused on problems of internal validity in preclinical animal studies (e.g. poor study design, lack of measures to control bias). However there has been less discussion of another key factor that influences translation, namely the external validity of preclinical animal models. REVIEW OF PROBLEMS OF EXTERNAL VALIDITY: External validity is the extent to which research findings derived in one setting, population or species can be reliably applied to other settings, populations and species. This paper argues that the reliable translation of findings from animals to humans will only occur if preclinical animal studies are both internally and externally valid. We review several key aspects that impact external validity in preclinical animal research, including unrepresentative animal samples, the inability of animal models to mimic the complexity of human conditions, the poor applicability of animal models to clinical settings and animal-human species differences. We suggest that while some problems of external validity can be overcome by improving animal models, the problem of species differences can never be overcome and will always undermine external validity and the reliable translation of preclinical findings to humans. CONCLUSION: We conclude that preclinical animal models can never be fully valid due to the uncertainties introduced by species differences. We suggest that even if the next several decades were spent improving the internal and external validity of animal models, the clinical relevance of those models would, in the end, only improve to some extent. This is because species differences would continue to make extrapolation from animals to humans unreliable. We suggest that to improve clinical translation and ultimately benefit patients, research should focus instead on human-relevant research methods and technologies. PMID- 30404630 TI - Barriers to exchanging healthcare information in inter-municipal healthcare services: a qualitative case study. AB - BACKGROUND: In recent years, inter-municipal cooperation in healthcare services has been an important measure implemented to meet future demographic changes in western countries. This entails an increased focus on communication and information sharing across organisational borders. Technology enables efficient and effective solutions to enhance such cooperation. However, the systems in the healthcare sector tend not to communicate with one another. There is a lack of literature focusing on communication and information sharing in inter-municipal healthcare services. The aim of this article is to investigate both the characteristics of communication and information sharing, and the factors that serve as barriers to communication and information sharing for employees in inter municipal healthcare services. METHODS: In this study, a qualitative case study approach is used to investigate both characteristics of communication and information sharing, and factors enabling barriers to communication and information sharing for employees in newly established inter-municipal healthcare services. Data collection methods were individual interviews, focus group interviews, observation studies and a workshop. A total of 18 persons participated in the study. The interviews, observations and workshop were conducted over a period of ten months. RESULTS: Communication and information sharing practices were found to be complex and characterised by multiple actors, information types and a combination of multiple actions. Findings indicate that 1. IT capability and usability 2. Differences 3. Privacy, confidentiality and security and 4. Awareness are all factors enabling barriers to communication and information sharing in inter-municipal healthcare services. Specifically, these barriers were related to lack of EHR usability, inadequate workflow processes, digital systems incompatibility, the understanding of needs in different systems and knowledge and practices regarding privacy and confidentiality. CONCLUSION: By focusing on the context of inter-municipal cooperation when assessing communication and information sharing in healthcare services, this article contributes to close a gap in existing knowledge. The perspective of the employees provides useful insight, and findings can be relevant for future theory development and for managers and policymakers in inter-municipal services. PMID- 30404627 TI - Determinants of the urinary and serum metabolome in children from six European populations. AB - BACKGROUND: Environment and diet in early life can affect development and health throughout the life course. Metabolic phenotyping of urine and serum represents a complementary systems-wide approach to elucidate environment-health interactions. However, large-scale metabolome studies in children combining analyses of these biological fluids are lacking. Here, we sought to characterise the major determinants of the child metabolome and to define metabolite associations with age, sex, BMI and dietary habits in European children, by exploiting a unique biobank established as part of the Human Early-Life Exposome project ( http://www.projecthelix.eu ). METHODS: Metabolic phenotypes of matched urine and serum samples from 1192 children (aged 6-11) recruited from birth cohorts in six European countries were measured using high-throughput 1H nuclear magnetic resonance (NMR) spectroscopy and a targeted LC-MS/MS metabolomic assay (Biocrates AbsoluteIDQ p180 kit). RESULTS: We identified both urinary and serum creatinine to be positively associated with age. Metabolic associations to BMI z-score included a novel association with urinary 4-deoxyerythreonic acid in addition to valine, serum carnitine, short-chain acylcarnitines (C3, C5), glutamate, BCAAs, lysophosphatidylcholines (lysoPC a C14:0, lysoPC a C16:1, lysoPC a C18:1, lysoPC a C18:2) and sphingolipids (SM C16:0, SM C16:1, SM C18:1). Dietary-metabolite associations included urinary creatine and serum phosphatidylcholines (4) with meat intake, serum phosphatidylcholines (12) with fish, urinary hippurate with vegetables, and urinary proline betaine and hippurate with fruit intake. Population-specific variance (age, sex, BMI, ethnicity, dietary and country of origin) was better captured in the serum than in the urine profile; these factors explained a median of 9.0% variance amongst serum metabolites versus a median of 5.1% amongst urinary metabolites. Metabolic pathway correlations were identified, and concentrations of corresponding metabolites were significantly correlated (r > 0.18) between urine and serum. CONCLUSIONS: We have established a pan-European reference metabolome for urine and serum of healthy children and gathered critical resources not previously available for future investigations into the influence of the metabolome on child health. The six European cohort populations studied share common metabolic associations with age, sex, BMI z-score and main dietary habits. Furthermore, we have identified a novel metabolic association between threonine catabolism and BMI of children. PMID- 30404631 TI - Bereaved parents' experiences of research participation. AB - BACKGROUND: As understandings of the impacts of end-of-life experiences on parents' grief and bereavement increase, so too does the inclusion of bereaved parents into research studies exploring these experiences. However, designing and obtaining approval for these studies can be difficult, as guidance derived from bereaved parents' experiences of the research process are limited within the current literature. METHODS: We aimed to explore bereaved parents' experiences of research participation in a larger grounded theory study exploring experiences of the death of a child in the paediatric intensive care unit. Data were obtained during follow-up phone calls made to 19 bereaved parents, five of whom provided data from their spouse, 1 week after their participation in the study. Participants were asked to reflect on their experiences of research participation, with a focus on recruitment methods, timing of research contact, and the location of their interview. Parents' responses were analysed using descriptive content analysis. RESULTS: Our findings demonstrate that despite being emotionally difficult, parents' overall experiences of research participation were positive. Parents preferred to be contacted initially via a letter, with an opt in approach viewed most favourably. Most commonly, participants preferred that research contact occurred within 12-24 months after their child's death, with some suggesting contact after 6 months was also appropriate. Parents also preferred research interviews conducted in their own homes, though flexibility and parental choice was crucial. CONCLUSIONS: Findings from this study offer further insight to researchers and research review committees, to help ensure that future studies are conducted in a way that best meets the unique needs of bereaved parents participating in research. PMID- 30404632 TI - Self-reported walking and associated factors in the Spanish population with chronic obstructive pulmonary disease. AB - BACKGROUND: The level of physical activity among individuals with chronic obstructive pulmonary disease (COPD) is associated with the disease severity and prognosis. The aim of this study was to describe the prevalence of self-reported walking at least 150 min per week and the associated factors among the Spanish population with COPD. METHODS: Analyses were based on data drawn from the 2009 European Health Interview Survey in Spain (2009 EHIS). Twenty-two thousand one hundred eighty-eight subjects participated in the survey (response rate of 96.5%). Participants were classified according to international physical activity recommendations. The prevalence of walking among participants with and without COPD (>=40 years old) was described. Univariate and multivariate logistic regression models were used to study the association of walking with socio demographic and health outcome variables. RESULTS: Of the participants with COPD, 55.0% reached the minimum walking recommendations compared to 59.9% of the general population. The level of walking physical activity of the participants with COPD differed according to sex, age, educational level, area of residence, living as a couple, self-rated health status, mental health, body mass index and hospital admissions. In the multivariate analysis, being male, < 65 years old, living in an area with >=50,000 inhabitants, no diagnosed depression or anxiety and self-reported good to very good health were factors significantly associated with walking >=150 min per week. CONCLUSIONS: Sex, age, area of residence, mental disorders and self-rated health are associated with weekly walking time in the Spanish population with COPD. PMID- 30404633 TI - A quest for sphincter-saving surgery in ultralow rectal tumours-a single-centre cohort study. AB - INTRODUCTION: Despite the progress in the treatment of colorectal cancer, there is still no optimal strategy for tumours located adjacent to the anal sphincter. This study aims to evaluate oncological and functional results of surgery for rectal cancer in unfavourable locations in proximity to anal sphincters. MATERIALS AND METHODS: Patients with rectal cancer, which was either initially infiltrating the anal sphincter or located in the close proximity of the sphincter, were included in the study. Patients were submitted to extralevator abdominoperineal resection (APR), intersphincteric resection, or transanal total mesorectal excision (TaTME). Primary outcomes were perioperative data: operative time, blood loss, complications, length of stay (LOS), and 30-day mortality. Secondary outcomes were pathological quality of the specimens and functional outcome 6 months after defunctioning ileostomy closure. RESULTS: Among patients with cancer adjacent to the anal sphincter, 13 (25%) underwent APR, 14 (27%) patients were submitted to intersphincteric resection, and 25 (48%) patients were treated with the TaTME approach. Operative time was 240 (210-270 IQR) for APR, 212.5 (170-260 IQR) for intersphincteric resection, and 270 (240-330 IQR) for TaTME (p = 0.018). Perioperative morbidity was 31% for APR, 36% for intersphincteric resections, and 12% for the TaTME group (p = 0.181). Complete mesorectal excision was achieved in 92% of specimens in the TaTME group, 93% in intersphincteric resections, and 78% in the APR group (p = 0.72). Median circumferential resection margin in APR was 6 mm (4-7 IQR), in intersphincteric resections 7.5 mm (2.5-10 IQR), and in the TaTME group 4 mm (2.8-8 IQR). All patients after intersphincteric resections developed major low anterior resection syndrome (LARS). Four patients in the TaTME group developed minor LARS, and 21 had major LARS. CONCLUSION: Sphincter-saving rectal resections are a feasible alternative to APR with good clinical, pathological, and oncological outcomes. Intersphincteric resections and TaTME seem to be equal in terms of clinicopathological results. The functional outcome is yet to be investigated. TRIAL REGISTRATION: The study was retrospectively registered in Thai Clinical Trials Registry (23-07-2018, ID TCTR20180724001 ). PMID- 30404634 TI - Spatial cognition in minimally invasive surgery: a systematic review. AB - BACKGROUND: Spatial cognition is known to play an important role in minimally invasive surgery (MIS), as it was found to enable faster surgical skill acquisition, reduce surgical time and errors made and significantly improve surgical performance. No prior research attempted to summarize the available literature, to indicate the level of importance of the individual spatial abilities and how they impact surgical performance and skill acquisition in MIS. METHODS: Psychological and medical databases were systematically searched to identify studies directly exploring spatial cognition in MIS learning and performance outcomes. Articles written in the English language articles, published between 2006 and 2016, investigating any and all aspect of spatial cognition in direct relation to influence over performance or learning of MIS, were deemed eligible. RESULTS: A total of 26 studies satisfied this criterion and were included in the review. The studies were very heterogeneous and the vast majority of the participants were novice trainees but with variable degree of skills. There were no clinical studies as almost all studies were conducted on either box trainers or virtual reality simulators. Mental rotation ability was found to have a clear impact on operative performance and mental practice was identified as an effective tool to enhance performance, pre-operatively. Ergonomic set-up of the MIS equipment has a marked influence on MIS performance and learning outcomes. CONCLUSIONS: Spatial cognition was found to play an important role in MIS, with mental rotation showing a specific significance. Future research is required to further confirm and quantify these findings in the clinical settings. PMID- 30404635 TI - Primary care clinicians' perspectives about quality measurements in safety-net clinics and non-safety-net clinics. AB - BACKGROUND: Quality metrics, pay for performance (P4P), and value-based payments are prominent aspects of the current and future American healthcare system. However, linking clinic payment to clinic quality measures may financially disadvantage safety-net clinics and their patient population because safety-net clinics often have worse quality metric scores than non-safety net clinics. The Minnesota Safety Net Coalition's Quality Measurement Enhancement Project sought to collect data from primary care providers' (PCPs) experiences, which could assist Minnesota policymakers and state agencies as they create a new P4P system. Our research study aims are to identify PCPs' perspectives about 1) quality metrics at safety net clinics and non-safety net clinics, 2) how clinic quality measures affect patients and patient care, and 3) how payment for quality measures may influence healthcare. METHODS: Qualitative interviews with 14 PCPs (4 individual interviews and 3 focus groups) who had worked at both safety net and non-safety net primary care clinics in Minneapolis-St Paul Minnesota USA metropolitan area. Qualitative analyses identified major themes. RESULTS: Three themes with sub-themes emerged. Theme #1: Minnesota's current clinic quality scores are influenced more by patients and clinic systems than by clinicians. Theme #2: Collecting data for a set of specific quality measures is not the same as measuring quality healthcare. Subtheme #2.1: Current quality measures are not aligned with how patients and clinicians define quality healthcare. Theme #3: Current quality measures are a product of and embedded in social and structural inequities in the American health care system. Subtheme #3.1: The current inequitable healthcare system should not be reinforced with financial payments. Subtheme #3.2: Health equity requires new metrics and a new healthcare system. Overall, PCPs felt that the current inequitable quality metrics should be replaced by different metrics along with major changes to the healthcare system that could produce greater health equity. CONCLUSION: Aligning payment with the current quality metrics could perpetuate and exacerbate social inequities and health disparities. Policymakers should consider PCPs' perspectives and create a quality-payment framework that does not disadvantage patients who are affected by social and structural inequities as well as the clinics and providers who serve them. PMID- 30404636 TI - Hormonal and metabolic indicators before and after farrowing in sows affected with postpartum dysgalactia syndrome. AB - BACKGROUND: Postpartum dysgalactia syndrome (PDS) in sows is difficult to diagnose and the pathogenesis is obscure. Hormonal changes related to the disease are often difficult to distinguish from those found in the normal transition period from gestation to lactation. The study aimed to investigate metabolic and hormonal changes related to PDS with the goal of identifying potential biomarkers in sows suffering from PDS (PDS+). Selected biomarkers were examined by comparing 38 PDS+ sows with 38 PDS negative (PDS-) sows. The sows were sampled every 24 h from 60 h ante partum (a.p.) to 36 h post partum (p.p.). RESULTS: Compared to the baseline (60 to 36 h a.p.), cortisol in serum and saliva and fasting blood glucose concentrations increased in PDS+ as well as PDS- sows. C-peptide decreased relative to the baseline in PDS+ sows, and prolactin and 8-epi prostaglandin F2 alpha (8-epi-PGF2alpha) decreased in PDS- sows. Concentrations of cortisol in serum and saliva, salivary chromogranin A (CgA), fasting blood glucose, C-peptide, and 8-epi-PGF2alpha differed significantly between PDS+ and PDS- sows, with levels of cortisol in serum and saliva, salivary CgA, and 8-epi PGF2alpha in serum being different in the two groups already before parturition. Concentrations of salivary CgA were significantly lower in PDS- sows than in PDS+ sows during the entire study period. CONCLUSIONS: The results suggest that salivary CgA, cortisol and serum 8-epi-PGF2alpha may potentially serve as early diagnostic indicators for PDS. The consistently higher salivary CgA concentration in PDS+ sows compared to PDS- sows may indicate that homeostatic disturbances are present between 36 to 60 h before parturition in sows developing PDS. The higher serum and saliva cortisol concentration in PDS+ sows compared to PDS- sows could reflect an early sign of inflammation or stress. The significantly lower C peptide in PDS+ sows compared to PDS- sows may reflect a lower food intake. Our results contribute to the understanding of the pathogenesis of PDS, and the homeostatic disturbances detected before parturition warrants further investigation. The diagnostic potential of the markers identified in this study should be investigated further in a larger population of sows. PMID- 30404637 TI - Aloe-emodin induces apoptosis in human oral squamous cell carcinoma SCC15 cells. AB - BACKGROUND: Oral and pharyngeal cancer is the most common malignant human cancers. Chemotherapy is an effective approach for anti-oral cancer therapy, while the drug tolerance and resistance remain a problem for oral cancer patients. Aloe-emodin, rhein and physcion are classified as anthraquinones, which are the main pharmacodynamic ingredients of Rheum undulatum L.. This study was undertaken to investigate whether aloe-emodin, rhein and physcion show inhibiting growth and inducing apoptosis in oral squamous cell carcinoma SCC15 cells. We found that aloe-emodin show inhibiting growth and inducing apoptosis in oral squamous cell carcinoma SCC15 cells, we also investigated the underlying mechanisms of apoptosis induced by aloe-emodin. METHODS: Thiazolyl blue tetrazolium bromide (MTT) test was used to detect cell proliferation. Cell apoptosis was detected by flow cytometry. We also used western blot analysis to detect the potential mechanisms of apoptosis. RESULTS: Aloe-emodin, rhein and physcion inhibit the proliferation of SCC15 cells and the order of inhibition level are aloe-emodin > Rhein > Physcion, the half maximal inhibitory concentrations (IC50) value of aloe-emodin was 60.90 MUM at 48 h of treatment. Aloe-emodin treatment resulted in a time- and dose-dependent decrease in cell viability and increased the apoptotic cell ratio. The results of western blotting showed the expression levels of caspase-9 and caspase-3 proteins increased following aloe-emodin treatment. CONCLUSIONS: Our results revealed that aloe emodin treatment could inhibit cell viability of SCC15 cells and the potential mechanism of inhibition might be through the induction of apoptosis by regulation of the expression levels of caspase-9 and caspase-3. This indicates that aloe emodin may be a good agent for anti-oral cancer drug exploring. PMID- 30404639 TI - Evaluating health research priority-setting in low-income countries: a case study of health research priority-setting in Zambia. AB - : Priority-setting (PS) for health research presents an opportunity for the relevant stakeholders to identify and create a list of priorities that reflects the country's knowledge needs. Zambia has conducted several health research prioritisation exercises that have never been evaluated. Evaluation would facilitate gleaning of lessons of good practices that can be shared as well as the identification of areas of improvement. This paper describes and evaluates health research PS in Zambia from the perspectives of key stakeholders using an internationally validated evaluation framework. METHODS: This was a qualitative study based on 28 in-depth interviews with stakeholders who had participated in the PS exercises. An interview guide was employed. Data were analysed using NVIVO 10. Emerging themes were, in turn, compared to the framework parameters. RESULTS: Respondents reported that, while the Zambian political, economic, social and cultural context was conducive, there was a lack of co-ordination of funding sources, partners and research priorities. Although participatory, the process lacked community involvement, dissemination strategies and appeals mechanisms. Limited funding hampered implementation, monitoring and evaluation. Research was largely driven by the research funders. CONCLUSIONS: Although there is apparent commitment to health research in Zambia, health research PS is limited by lack of funding, and consistently used explicit and fair processes. The designated national research organisation and the availability of tools that have been validated and pilot tested within Zambia provide an opportunity for focused capacity strengthening for systematic prioritisation, monitoring and evaluation. The utility of the evaluation framework in Zambia could indicate potential usefulness in similar low-income countries. PMID- 30404638 TI - What maximizes the effectiveness and implementation of technology-based interventions to support healthcare professional practice? A systematic literature review. AB - BACKGROUND: Technological support may be crucial in optimizing healthcare professional practice and improving patient outcomes. A focus on electronic health records has left other technological supports relatively neglected. Additionally, there has been no comparison between different types of technology based interventions, and the importance of delivery setting on the implementation of technology-based interventions to change professional practice. Consequently, there is a need to synthesise and examine intervention characteristics using a methodology suited to identifying important features of effective interventions, and the barriers and facilitators to implementation. Three aims were addressed: to identify interventions with a technological component that are successful at changing professional practice, to determine if and how such interventions are theory-based, and to examine barriers and facilitators to successful implementation. METHODS: A literature review informed by realist review methods was conducted involving a systematic search of studies reporting either: (1) behavior change interventions that included technology to support professional practice change; or (2) barriers and facilitators to implementation of technological interventions. Extracted data was quantitative and qualitative, and included setting, target professionals, and use of Behaviour Change Techniques (BCTs). The primary outcome was a change in professional practice. A thematic analysis was conducted on studies reporting barriers and facilitators of implementation. RESULTS: Sixty-nine studies met the inclusion criteria; 48 (27 randomized controlled trials) reported behavior change interventions and 21 reported practicalities of implementation. The most successful technological intervention was decision support providing healthcare professionals with knowledge and/or person-specific information to assist with patient management. Successful technologies were more likely to operationalise BCTs, particularly "instruction on how to perform the behavior". Facilitators of implementation included aligning studies with organisational initiatives, ensuring senior peer endorsement, and integration into clinical workload. Barriers included organisational challenges, and design, content and technical issues of technology based interventions. CONCLUSIONS: Technological interventions must focus on providing decision support for clinical practice using recognized behavior change techniques. Interventions must consider organizational context, clinical workload, and have clearly defined benefits for improving practice and patient outcomes. PMID- 30404640 TI - Towards a re-emergence of chloroquine sensitivity in Cote d'Ivoire? AB - BACKGROUND: Resistance of Plasmodium falciparum to anti-malarial drugs has hampered efforts to eradicate malaria. Recent reports of a decline in the prevalence of chloroquine-resistant P. falciparum in several countries, including Malawi and Zambia, is raising the hope of reintroducing chloroquine in the near future, ideally in combination with another anti-malarial drug for the treatment of uncomplicated malaria. In Cote d'Ivoire, the decrease in the clinical efficacy of chloroquine, in addition to a high proportion of clinical isolates carrying the Thr-76 mutant allele of the pfcrt gene, had led to the discontinuation of the use of chloroquine in 2004. Previous studies have indicated the persistence of a high prevalence of the Thr-76 mutant allele despite the withdrawal of chloroquine as first-line anti-malarial drug. This present study is conducted to determine the prevalence of the Thr-76T mutant allele of the Pfcrt gene after a decade of the ban on the sale and use of chloroquine in Cote d'Ivoire. RESULTS: Analysis of the 64 sequences from all three study sites indicated a prevalence of 15% (10/64) of the Thr-76 mutant allele against 62% (40/64) of the Lys-76 wild-type allele. No mutation of the allele Thr-76 was observed at Anonkoua Koute while this mutant allele was in 31% (5/16) and 25% (5/20) of isolate sequences from Port-Bouet and Ayame respectively. CONCLUSION: More than a decade after the discontinuation of the use of chloroquine in Cote d'Ivoire, the proportion of parasites sensitive to this anti-malarial seems to increase in Anonkoua-koute, Port-bouet and Ayame. PMID- 30404641 TI - Znf179 E3 ligase-mediated TDP-43 polyubiquitination is involved in TDP-43- ubiquitinated inclusions (UBI) (+)-related neurodegenerative pathology. AB - BACKGROUND: The brain predominantly expressed RING finger protein, Znf179, is known to be important for embryonic neuronal differentiation during brain development. Downregulation of Znf179 has been observed in motor neurons of adult mouse models for amyotrophic lateral sclerosis (ALS), yet the molecular function of Znf179 in neurodegeneration has never been previously described. Znf179 contains the classical C3HC4 RING finger domain, and numerous proteins containing C3HC4 RING finger domain act as E3 ubiquitin ligases. Hence, we are interested to identify whether Znf179 possesses E3 ligase activity and its role in ALS neuropathy. METHODS: We used in vivo and in vitro ubiquitination assay to examine the E3 ligase autoubiquitination activity of Znf179 and its effect on 26S proteasome activity. To search for the candidate substrates of Znf179, we immunoprecipitated Znf179 and subjected to mass spectrometry (MS) analysis to identify its interacting proteins. We found that ALS/ FTLD-U (frontotemporal lobar degeneration (FTLD) with ubiquitin inclusions)-related neurodegenerative TDP-43 protein is the E3 ligase substrate of Znf179. To further clarify the role of E3 ubiquitin ligase Znf179 in neurodegenerative TDP-43-UBI (ubiquitinated inclusions) (+) proteinopathy, the effect of Znf179-mediated TDP-43 polyubiquitination on TDP-43 protein stability, aggregate formation and nucleus/cytoplasm mislocalization were evaluated in vitro cell culture system and in vivo animal model. RESULTS: Here we report that Znf179 is a RING E3 ubiquitin ligase which possesses autoubiquitination feature and regulates 26S proteasome activity through modulating the protein expression levels of 19S/20S proteasome subunits. Our immunoprecipitation assay and MS analysis results revealed that the neuropathological TDP-43 protein is one of its E3 ligase substrate. Znf179 interactes with TDP-43 protein and mediates polyubiquitination of TDP-43 in vitro and in vivo. In neurodegenerative TDP-43 proteinopathy, we found that Znf179 mediated polyubiquitination of TDP-43 accelerates its protein turnover rate and attenuates insoluble pathologic TDP-43 aggregates, while knockout of Znf179 in mouse brain results in accumulation of insoluble TDP-43 and cytosolic TDP-43 inclusions in cortex, hippocampus and midbrain regions. CONCLUSIONS: Here we unveil the important role for the novel E3 ligase Znf179 in TDP-43-mediated neuropathy, and provide a potential therapeutic strategy for combating ALS/ FTLD U neurodegenerative pathologies. PMID- 30404642 TI - Challenges arising when seeking broad consent for health research data sharing: a qualitative study of perspectives in Thailand. AB - BACKGROUND: Research funders, regulatory agencies, and journals are increasingly expecting that individual-level data from health research will be shared. Broad consent to such sharing is considered appropriate, feasible and acceptable in low and middle-income settings, but to date limited empirical research has been conducted to inform the design of such processes. We examined stakeholder perspectives about how best to seek broad consent to sharing data from the Mahidol Oxford Tropical Medicine Research Unit, which implemented a data sharing policy and broad consent to data sharing in January 2016. METHODS: Between February and August 2017 qualitative data were collected at two sites, Bangkok and the Thai-Myanmar border town of Mae Sot. We conducted eighteen semi structured interviews. We also conducted four focus group discussions with a total of nineteen people. Descriptive and thematic coding informed analysis of aspects of data sharing that are considered most important to inform participants about, and the best ways to explain complex and abstract topics relating to data sharing. RESULTS: The findings demonstrated that clinical trial participants prioritise information about the potential benefits and harms of data sharing. Stakeholders made multiple suggestions for clarifying information provided about data sharing on such topics. There was significant variation amongst stakeholders' perspectives about how much information should be provided about data sharing, and it was clear that effective information provision should be responsive to the study, the study population, the individual research participant and the research context. CONCLUSIONS: Effectively communicating about data sharing with research participants is challenging in practice, highlighting the importance of robust and effective data sharing governance in this context. Broad consent should incorporate effective and efficient explanations of data sharing to promote informed decision-making, without impeding research participants' understandings of key aspects of the research from which data will be shared. Further work is required to refine both the development of core information about data sharing to be provided to all research participants, and appropriate solutions for context specific-challenges arising when explaining data sharing. PMID- 30404644 TI - Key nodes affecting patient satisfaction in a cross-regional referral service process: an empirical analysis study in Sichuan. AB - BACKGROUND: The referral service is a significant component of healthcare reform in China, and the measurement of patient satisfaction with the referral service process will help to improve the quality of referral medical delivery. Furthermore, the referral service in China includes inter-institutional collaborations between hospitals at different levels and multi-nodes throughout the referral process. It is therefore necessary to identify the key nodes that affect patient satisfaction during the referral service process. METHODS: This study conducted a questionnaire survey of 110 patients to collect data regarding patient satisfaction at the following healthcare nodes: primary-level hospital, referral appointment registration, claim of appointment number in the outpatient department, examination service, admission service, and overall satisfaction during the referral service process. Correlation analysis and logistic regression methods were used to establish a mathematical model of patient satisfaction between five nodes and overall satisfaction. Additionally, a peak-end model was formed to identify the peak node impacting overall patient satisfaction during the referral service based on the sample data. RESULTS: Over 80% of referral patients rated the overall referral service as 'good'. The correlation analysis revealed that there was a significant correlation between the satisfaction of each node and the overall satisfaction (P < 0.05). The results of the regression model showed that the satisfaction of five nodes determined the overall satisfaction and that "admission service at the higher-level hospital" exerted the greatest impact on overall satisfaction (beta = 0.312), while "referral appointment registration" had the lowest influence on overall satisfaction (beta = 0.177). The peak-end model also revealed that "admission service at the higher level hospital" had a greater effect on overall satisfaction. CONCLUSION: Our study showed that the key nodes affecting patient satisfaction were "transferring service at the primary-level hospital" and "admission service at the higher-level hospital". Furthermore, the efficacy of the referral services is determined by the gatekeepers' management of the referral system at the primary-level hospital and the allocation and management of bed resources at the higher-level hospital. These findings can serve as a science-based guidance for them to improve their performance in inter-regional healthcare collaborations in the referral service process. PMID- 30404643 TI - Isolation and characterization of GFAP-positive porcine neural stem/progenitor cells derived from a GFAP-CreERT2 transgenic piglet. AB - BACKGROUND: The porcine brain is gyrencephalic with similar gray and white matter composition and size more comparable to the human rather than the rodent brain; however, there is lack of information about neural progenitor cells derived from this model. RESULTS: Here, we isolated GFAP-positive porcine neural stem cells (NSCs) from the brain explant of a transgenic piglet, with expression of CreERT2 under the control of the GFAP promoter (pGFAP-CreERT2). The isolated pGFAP CreERT2 NSCs showed self-renewal and expression of representative NSC markers such as Nestin and Sox2. Pharmacological inhibition studies revealed that Notch1 signaling is necessary to maintain NSC identity, whereas serum treatment induced cell differentiation into reactive astrocytes and neurons. CONCLUSIONS: Collectively, these results indicate that GFAP promoter-driven porcine CreERT2 NSCs would be a useful tool to study neurogenesis of the porcine adult central nervous system and furthers our understanding of its potential clinical application in the future. ?. PMID- 30404646 TI - Effects of a multifaceted intervention QI program to improve ICU performance. AB - BACKGROUND: To benefit from the increasing clinical evidence, organisational changes have been among the main drivers behind the reduction of ICU mortality during the last decade. Increasing demand, costs and complexity, amplifies the need for optimisation of clinical processes and resource utilisation. Thus, multidisciplinary teamwork and critical care processes needs to be adapted to profit from increased availability of human skill and technical resources in a cost-effective manner. Inadequate clinical performance and outcome data compelled us to design a quality improvement project to address current work processes and competence utilisation. METHODS: During revision period, clinical processes, professional performance and clinical competence were targeted using "scientific production management methodology" approach. As part of the project, an intensivist training program was instituted, and full time intensivist coverage was obtained in the process of creating multi-professional teams, composed of certified intensivists, critical care nurses, assistant nurses, physiotherapists and social counsellors. The use of staff resources and clinical work-processes were optimised in accordance with the outcome of a "value stream mapping". In this process, efforts to enhance the personal dynamics and performance within the teams were paramount. Clinical and economic outcome data were analysed during a seven year follow up period. RESULTS: * Consecutive reduced overall ICU (24%) and long-term (600 days) mortality. The effect on ICU mortality was especially pronounced in the subgroup of patients > 65 years (30%) * Consecutive reduced length of stay (43%, septic patients) and time on ventilator (for septic patients and patients > 65 years of age (23 resp.52%). * Substantial increase in life years gained (13,140 life years) as well as quality-adjusted life-years (9593 QALY: s) over the study period. * High cost-effectiveness as ICU costs were reduced while patient outcomes were improved. Disregarding the cost reduction in ICU, the intervention is highly cost effective with cost- effectiveness ratios of (75?/QALY) and (55? / life year) CONCLUSIONS: We have shown favourable results of a QI project aiming to improve the clinical performance and quality through the development of multi-professional interaction, teamwork and systematic revisions of work processes. The economic evaluation shows that the intervention is highly cost-effective and potentially dominating. PMID- 30404645 TI - Tonicity inversely modulates lipocalin-2 (Lcn2/24p3/NGAL) receptor (SLC22A17) and Lcn2 expression via Wnt/beta-catenin signaling in renal inner medullary collecting duct cells: implications for cell fate and bacterial infection. AB - BACKGROUND: We have previously evidenced apical expression of the 24p3/NGAL/lipocalin-2 receptor (Lcn2-R; SLC22A17) in inner medullary collecting duct (IMCD) cells, which are present in vivo in a hyperosmotic/-tonic environment that activates canonical Wnt/beta-catenin signaling. The localization of Lcn2-R in the inner medulla is intriguing considering local bacterial infections trigger toll-like receptor-4 (TLR-4)-mediated secretion of the bacteriostatic Fe3+-free (apo-)Lcn2. AIM: To determine the effects of osmolarity/tonicity changes, Wnt/beta-catenin and TLR-4 activation on Lcn2-R and Lcn2 expression and cell viability in rat primary IMCD and mouse (m)IMCD3 cells. METHODS: Normosmolarity/ tonicity was 300 mosmol/l whereas hyperosmolarity/-tonicity was induced by adding 100 mmol/l NaCl + 100 mmol/l urea (600 mosmol/l, 1-7 days). Lcn2-R and Lcn2 expression were determined by qPCR, immunoblotting, flow cytometry and immunofluorescence microscopy. beta-catenin was silenced by RNAi. Cell viability/death was determined with MTT and LDH release assays. TLR-4 was activated by bacterial lipopolysaccharides (LPS). RESULTS: Hyperosmotic/-tonic media upregulated Lcn2-R by ~4-fold and decreased Lcn2 expression/secretion, along with Wnt/beta-catenin activation, in IMCD cells. These effects of hyperosmotic/-tonic media on Lcn2-R/Lcn2 expression were reverted by normosmolarity/-tonicity, beta-catenin silencing and/or LPS. Exposure of cells with endogenous or stably overexpressing Lcn2-R to apo-Lcn2 or LPS decreased cell viability. CONCLUSIONS: Lcn2-R upregulation and Lcn2 downregulation via Wnt/beta catenin may promote adaptive osmotolerant survival of IMCD cells in response to hyperosmolarity/-tonicity whereas Lcn2 upregulation and Lcn2-R downregulation via TLR-4 and/or normosmolarity/-tonicity may protect IMCD cells against bacterial infections and prevent autocrine death induction by Lcn2. PMID- 30404647 TI - Porcine epidemic diarrhea virus S1 protein is the critical inducer of apoptosis. AB - BACKGROUND: Porcine Epidemic Diarrhea (PED) is an acute and highly contagious enteric disease caused by PED virus (PEDV), characterized by vomitting, watery diarrhea and fatal dehydration with high mortality in sucking piglets of one week of age. Although PEDV induced cell apoptosis has been established in vitro and in vivo, the functional protein that contributes to this event remains unclear. METHODS: The activation or cleavage of main apoptosis-associated molecular such as AIFM1, caspase-3, caspase-8, caspase-9 and PARP in PEDV infected host cells were analyzed by western blotting. The nuclear change of infected cell was monitored by confocal immunofluorescence assay. The overexpressing plasmids of 16 non-structural proteins (Nsp1-16) and 6 structural proteins (M, N, E, ORF3, S1 and S2) were constructed by cloning. Cell apoptosis induced by PEDV or overexpression non-structural or structural proteins was measured by the flow cytometry assay. RESULTS: PEDV could infect various host cells including Vero, Vero-E6 and Marc-145 and cause obvious cytopathic effects, including roundup, cell fusion, cell membrane vacuolation, syncytium formation and cause apparent apoptosis. In infected cells, PEDV-induced apoptosis is accompanied by nuclear concentration and fragmentation as a result of caspase-3 and caspase-8 activation and AIFM1 and PARP cleavage. Overexpression of S1 Spike protein of PEDV SM98 strain effectively induced host cell apoptosis, while the expression of the other non-structure proteins (Nsp1-16) and structural proteins (M, N, E, S2 and ORF3) has no or less effect on cell apoptosis. Similarly, expression of S1 protein from wild-type strain BJ2011 or cell-adapted strain CV777, also induce apoptosis in transfected cells. Finally, we demonstrated that the S1 proteins from various coronavirus family members such as TGEV, IBV, CCoV, SARS and MERS could also induce Vero-E6 cells apoptosis. CONCLUSION: S1 Spike protein is one of the most critical functional proteins that contribute to cell apoptosis. Expression of S1 proteins of the coronavirus tested in this study could all induce cell apoptosis suggesting S1 maybe is an effective inducer in Coronavirus-induced cell apoptosis and targeting S1 protein expression probably is a promising strategy to inhibit coronavirus infection and thus mediated apoptosis on host cells. PMID- 30404648 TI - A laparoscopic approach for removal of ovarian remnant tissue in 32 dogs. AB - BACKGROUND: Surgical treatment of ovarian remnant syndrome (ORS) in dogs usually necessitates large celiotomies and considerable manipulation of organs because of the relatively deep position of ovarian remnant tissue, large patient size, and often encountered adhesions. In women, laparoscopic treatment of ORS is successful and has significant advantages over laparotomy. Since laparoscopic ovariectomy has significant advantages over open ovariectomy in dogs, including reduced surgical stress and postoperative pain and shorter convalescence period, the rationale for a laparoscopic approach of canine ORS is evident. Feasibility and efficacy of a laparoscopic approach for treatment of ORS in dogs was prospectively evaluated using a standardized protocol for diagnosis, treatment, and follow-up. Treatment success was evaluated by histology of removed tissues, postoperative hormone testing, and long-term clinical follow-up. RESULTS: Thirty two client-owned predominantly medium and large breed dogs diagnosed with ORS underwent abdominal ultrasound for ovarian remnant localization prior to laparoscopic surgery for removal of ovarian remnants. Tissue dissection and excision was performed using a vessel sealing forceps. Laparoscopy subjectively enabled detailed visibility and facilitated detection and removal of suspected ovarian tissue in all cases. Histology confirmed ovarian origin of removed tissue in all dogs. Additionally, a GnRH stimulation test was performed in fourteen dogs after a median follow-up of 10.5 months, which verified absence of residual functional ovarian remnant tissue in all dogs. Median surgery duration was 97.5 min and mean total convalescence duration, subjectively scored by owners, was 1.5 +/- 0.7 days. No major complications occurred. Adhesions were observed in 79% of the dogs, complicated the surgical approach, and significantly affected surgery duration (85 versus 109 min; p = 0.03). Minor hemorrhage occurred in 12% and significantly increased surgery duration (95.5 versus 128 min; p = 0.02). Trendelenburg position and lateral tilting of the patient were essential for proper access to ovarian remnants. GnRH stimulation test results and/or absence of clinical signs indicative of ORS after a median follow-up period of 22.5 months confirmed treatment efficacy in all dogs. CONCLUSION: Laparoscopic surgery for ORS in dogs is effective with minimal complications and short convalescence and can successfully replace the conventional, more invasive open surgical procedure. PMID- 30404649 TI - Exploring the behavioural drivers of veterinary surgeon antibiotic prescribing: a qualitative study of companion animal veterinary surgeons in the UK. AB - BACKGROUND: Multi-drug resistant bacteria are an increasing concern in both human and veterinary medicine. Inappropriate prescribing and use of antibiotics within veterinary medicine may be a contributory factor to antimicrobial resistance (AMR). The 'One Health' Initiative aims to work across species and environments to reduce AMR, however; little is currently known about the factors which influence antibiotic prescribing among veterinary surgeons in companion animal practice. This paper reports on qualitative data analysis of interviews with veterinary surgeons whose practice partially or wholly focuses on companion animals (N = 16). The objective of the research was to explore the drivers of companion animal veterinary surgeons' antibiotic prescribing behaviours. The veterinary surgeons interviewed were all practising within the UK (England (n = 4), Scotland (n = 11), Northern Ireland (n = 1)). A behavioural thematic analysis of the data was undertaken, which identified barriers and facilitators to specific prescribing-related behaviours. RESULTS: Five components of prescribing behaviours were identified: 1) confirming clinical need for antibiotics; 2) responding to clients; 3) confirming diagnosis; 4) determining dose, duration and type of antibiotic; and 5) preventing infection around surgery (with attendant appropriate and inappropriate antibiotic prescribing behaviours). Barriers to appropriate prescribing identified include: business, diagnostic, fear, habitual practice and pharmaceutical factors. Facilitators include: AMR awareness, infection prevention, professional learning and regulation and government factors. CONCLUSION: This paper uses a behavioural lens to examine drivers which are an influence on veterinary surgeons' prescribing behaviours. The paper contributes new understandings about factors which influence antibiotic prescribing behaviours among companion animal veterinary surgeons. This analysis provides evidence to inform future interventions, which are focused on changing prescribing behaviours, in order to address the pressing public health concern of AMR. PMID- 30404650 TI - Correction to: The all age asthma cohort (ALLIANCE) - from early beginnings to chronic disease: a longitudinal cohort study. AB - Following publication of the original article [1], the author flagged aspects of the article that affected readability of some of the article's scientific content. PMID- 30404652 TI - Reversible dilative cardiomyopathy after electrical injury: a case report. AB - BACKGROUND: Dilative cardiomyopathy is an uncommon cardiac complication of electric shock. CASE PRESENTATION: We report a case of a 12-year-old German boy with a high voltage injury who developed a four-chamber dilative cardiomyopathy, which was diagnosed on the 13th week postburn. One year after the accident, echocardiography showed a normal function of his heart with 64% ejection fraction and normal cavities' dimensions. CONCLUSIONS: Despite the fact that dilative cardiomyopathy is not very common in electrical injuries but can be fatal, a prolonged echocardiography follow-up for patients with electrical injury could be recommended. Until now this case is the first child with severe burns after electrocution, who developed a reversible dilative cardiomyopathy. PMID- 30404651 TI - GABA, glutamine, glutamate oxidation and succinic semialdehyde dehydrogenase expression in human gliomas. AB - BACKGROUND: Bioenergetic characterisation of malignant tissues revealed that different tumour cells can catabolise multiple substrates as salvage pathways, in response to metabolic stress. Altered metabolism in gliomas has received a lot of attention, especially in relation to IDH mutations, and the associated oncometabolite D-2-hydroxyglutarate (2-HG) that impact on metabolism, epigenetics and redox status. Astrocytomas and oligodendrogliomas, collectively called diffuse gliomas, are derived from astrocytes and oligodendrocytes that are in metabolic symbiosis with neurons; astrocytes can catabolise neuron-derived glutamate and gamma-aminobutyric acid (GABA) for supporting and regulating neuronal functions. METHODS: Metabolic characteristics of human glioma cell models - including mitochondrial function, glycolytic pathway and energy substrate oxidation - in relation to IDH mutation status and after 2-HG incubation were studied to understand the Janus-faced role of IDH1 mutations in the progression of gliomas/astrocytomas. The metabolic and bioenergetic features were identified in glioma cells using wild-type and genetically engineered IDH1 mutant glioblastoma cell lines by metabolic analyses with Seahorse, protein expression studies and liquid chromatography-mass spectrometry. RESULTS: U251 glioma cells were characterised by high levels of glutamine, glutamate and GABA oxidation. Succinic semialdehyde dehydrogenase (SSADH) expression was correlated to GABA oxidation. GABA addition to glioma cells increased proliferation rates. Expression of mutated IDH1 and treatment with 2-HG reduced glutamine and GABA oxidation, diminished the pro-proliferative effect of GABA in SSADH expressing cells. SSADH protein overexpression was found in almost all studied human cases with no significant association between SSADH expression and clinicopathological parameters (e.g. IDH mutation). CONCLUSIONS: Our findings demonstrate that SSADH expression may participate in the oxidation and/or consumption of GABA in gliomas, furthermore, GABA oxidation capacity may contribute to proliferation and worse prognosis of gliomas. Moreover, IDH mutation and 2-HG production inhibit GABA oxidation in glioma cells. Based on these data, GABA oxidation and SSADH activity could be additional therapeutic targets in gliomas/glioblastomas. PMID- 30404653 TI - Satellite cells maintain regenerative capacity but fail to repair disease associated muscle damage in mice with Pompe disease. AB - Pompe disease is a metabolic myopathy that is caused by glycogen accumulation as a result of deficiency of the lysosomal enzyme acid alpha glucosidase (GAA). Previously, we showed that adult muscle stem cells termed satellite cells are present at normal levels in muscle from patients with Pompe disease, but that these are insufficiently activated to repair the severe muscle pathology. Here we characterized the muscle regenerative response during disease progression in a mouse model of Pompe disease and investigated the intrinsic capacity of Gaa-/- satellite cells to regenerate muscle damage. Gaa-/- mice showed progressive muscle pathology from 15 weeks of age as reflected by increased lysosomal size, decreased fiber diameter and reduced muscle wet weight. Only during the first 15 weeks of life but not thereafter, we detected a gradual increase in centrally nucleated fibers and proliferating satellite cells in Gaa-/- muscle, indicating a mild regenerative response. The levels of Pax7-positive satellite cells were increased in Gaa-/- mice at all ages, most likely as result of enhanced satellite cell activation in young Gaa-/- animals. Surprisingly, both young and old Gaa-/- mice regenerated experimentally-induced muscle injury efficiently as judged by rapid satellite cell activation and complete restoration of muscle histology. In response to serial injury, Gaa-/- mice also regenerated muscle efficiently and maintained the satellite cell pool. These findings suggest that, similar to human patients, Gaa-/- mice have insufficient satellite cell activation and muscle regeneration during disease progression. The initial endogenous satellite cell response in Gaa-/- mice may contribute to the delayed onset of muscle wasting compared to human patients. The rapid and efficient regeneration after experimental muscle injury suggest that Gaa-/- satellite cells are functional stem cells, opening avenues for developing muscle regenerative therapies for Pompe disease. PMID- 30404654 TI - A brain-penetrant triazolopyrimidine enhances microtubule-stability, reduces axonal dysfunction and decreases tau pathology in a mouse tauopathy model. AB - BACKGROUND: Alzheimer's disease (AD) and related tauopathies are neurodegenerative diseases that are characterized by the presence of insoluble inclusions of the protein tau within brain neurons and often glia. Tau is normally found associated with axonal microtubules (MTs) in the brain, and in tauopathies this MT binding is diminished due to tau hyperphosphorylation. As MTs play a critical role in the movement of cellular constituents within neurons via axonal transport, it is likely that the dissociation of tau from MTs alters MT structure and axonal transport, and there is evidence of this in tauopathy mouse models as well as in AD brain. We previously demonstrated that different natural products which stabilize MTs by interacting with beta-tubulin at the taxane binding site provide significant benefit in transgenic mouse models of tauopathy. More recently, we have reported on a series of MT-stabilizing triazolopyrimidines (TPDs), which interact with beta-tubulin at the vinblastine binding site, that exhibit favorable properties including brain penetration and oral bioavailability. Here, we have examined a prototype TPD example, CNDR-51657, in a secondary prevention study utilizing aged tau transgenic mice. METHODS: 9-Month old female PS19 mice with a low amount of existing tau pathology received twice weekly administration of vehicle, or 3 or 10 mg/kg of CNDR-51657, for 3 months. Mice were examined in the Barnes maze at the end of the dosing period, and brain tissue and optic nerves were examined immunohistochemically or biochemically for changes in MT density, axonal dystrophy, and tau pathology. Mice were also assessed for changes in organ weights and blood cell numbers. RESULTS: CNDR-51657 caused a significant amelioration of the MT deficit and axonal dystrophy observed in vehicle-treated aged PS19 mice. Moreover, PS19 mice receiving CNDR-51657 had significantly lower tau pathology, with a trend toward improved Barnes maze performance. Importantly, no adverse effects were observed in the compound treated mice, including no change in white blood cell counts as is often observed in cancer patients receiving high doses of MT-stabilizing drugs. CONCLUSIONS: A brain-penetrant MT-stabilizing TPD can safely correct MT and axonal deficits in an established mouse model of tauopathy, resulting in reduced tau pathology. PMID- 30404655 TI - Correction to: PHF8 upregulation contributes to autophagic degradation of E cadherin, epithelial-mesenchymal transition and metastasis in hepatocellular carcinoma. AB - In the publication of this article [1], there are two inadvertent errors. PMID- 30404656 TI - Tissue-enhanced plasma proteomic analysis for disease stratification in amyotrophic lateral sclerosis. AB - BACKGROUND: It is unclear to what extent pre-clinical studies in genetically homogeneous animal models of amyotrophic lateral sclerosis (ALS), an invariably fatal neurodegenerative disorder, can be informative of human pathology. The disease modifying effects in animal models of most therapeutic compounds have not been reproduced in patients. To advance therapeutics in ALS, we need easily accessible disease biomarkers which can discriminate across the phenotypic variants observed in ALS patients and can bridge animal and human pathology. Peripheral blood mononuclear cells alterations reflect the rate of progression of the disease representing an ideal biological substrate for biomarkers discovery. METHODS: We have applied TMTcalibratorTM, a novel tissue-enhanced bio fluid mass spectrometry technique, to study the plasma proteome in ALS, using peripheral blood mononuclear cells as tissue calibrator. We have tested slow and fast progressing SOD1G93A mouse models of ALS at a pre-symptomatic and symptomatic stage in parallel with fast and slow progressing ALS patients at an early and late stage of the disease. Immunoassays were used to retest the expression of relevant protein candidates. RESULTS: The biological features differentiating fast from slow progressing mouse model plasma proteomes were different from those identified in human pathology, with only processes encompassing membrane trafficking with translocation of GLUT4, innate immunity, acute phase response and cytoskeleton organization showing enrichment in both species. Biological processes associated with senescence, RNA processing, cell stress and metabolism, major histocompatibility complex-II linked immune-reactivity and apoptosis (early stage) were enriched specifically in fast progressing ALS patients. Immunodetection confirmed regulation of the immunosenescence markers Galectin-3, Integrin beta 3 and Transforming growth factor beta-1 in plasma from pre symptomatic and symptomatic transgenic animals while Apolipoprotein E differential plasma expression provided a good separation between fast and slow progressing ALS patients. CONCLUSIONS: These findings implicate immunosenescence and metabolism as novel targets for biomarkers and therapeutic discovery and suggest immunomodulation as an early intervention. The variance observed in the plasma proteomes may depend on different biological patterns of disease progression in human and animal model. PMID- 30404657 TI - Assessing the impact of choosing different deformable registration algorithms on cone-beam CT enhancement by histogram matching. AB - BACKGROUND: The aim of this work is to assess the impact of using different deformable registration (DR) algorithms on the quality of cone-beam CT (CBCT) correction with histogram matching (HM). METHODS AND MATERIALS: Data sets containing planning CT (pCT) and CBCT images for ten patients with prostate cancer were used. Each pCT image was registered to its corresponding CBCT image using one rigid registration algorithm with mutual information similarity metric (RR-MI) and three DR algorithms with normalized correlation coefficient, mutual information and normalized mutual information (DR-NCC, DR-MI and DR-NMI, respectively). Then, the HM was performed between deformed pCT and CBCT in order to correct the distribution of the Hounsfield Units (HU) in CBCT images. RESULTS: The visual assessment showed that the absolute difference between corrected CBCT and deformed pCT was reduced after correction with HM except for soft tissue-air and soft-tissue-bone interfaces due to the improper registration. Furthermore, volumes comparison in terms of average HU error showed that using DR-NCC algorithm with HM yielded the lowest error values of about 55.95 +/- 10.43 HU compared to DR-MI and DR-NMI for which the errors were 58.60 +/- 10.35 and 56.58 +/- 10.51 HU, respectively. Tissue class's comparison by the mean absolute error (MAE) plots confirmed the performance of DR-NCC algorithm to produce corrected CBCT images with lowest values of MAE even in regions where the misalignment is more pronounced. It was also found that the used method had successfully improved the spatial uniformity in the CBCT images by reducing the root mean squared difference (RMSD) between the pCT and CBCT in fat and muscle from 57 and 25 HU to 8HU, respectively. CONCLUSION: The choice of an accurate DR algorithm before performing the HM leads to an accurate correction of CBCT images. The results suggest that applying DR process based on NCC similarity metric reduces significantly the uncertainties in CBCT images and generates images in good agreement with pCT. PMID- 30404659 TI - Interprofessional palliative care education for pediatric oncology clinicians: an evidence-based practice review. AB - OBJECTIVE: Clinician education and expertise in palliative care varies widely across pediatric oncology programs. The purpose of this evidence-based practice review was to identify interprofessional palliative care education models applicable to pediatric oncology settings as well as methods for evaluating their impact on clinical practice. RESULTS: Based on a literature search in PubMed, CINAHL and Embase, which identified 13 articles meeting inclusion/exclusion criteria, the following three themes emerged: (1) establishment of effective modalities and teaching strategies, (2) development of an interprofessional palliative care curriculum, and (3) program evaluation to assess impact on providers' self-perceived comfort in delivering palliative care and patient/family perceptions of care received. Remarkably, health professionals reported receiving limited palliative care training, with little evidence of systematic evaluation of practice changes following training completion. Improving palliative care delivery was linked to the development and integration of an interprofessional palliative care curriculum. Suggested evaluation strategies included: (1) eliciting patient and family feedback, (2) standardizing care delivery measures, and (3) evaluating outcomes of care. PMID- 30404658 TI - Recurrent mutations at estrogen receptor binding sites alter chromatin topology and distal gene expression in breast cancer. AB - BACKGROUND: The mutational processes underlying non-coding cancer mutations and their biological significance in tumor evolution are poorly understood. To get better insights into the biological mechanisms of mutational processes in breast cancer, we integrate whole-genome level somatic mutations from breast cancer patients with chromatin states and transcription factor binding events. RESULTS: We discover that a large fraction of non-coding somatic mutations in estrogen receptor (ER)-positive breast cancers are confined to ER binding sites. Notably, the highly mutated estrogen receptor binding sites are associated with more frequent chromatin loop contacts and the associated distal genes are expressed at higher level. To elucidate the functional significance of these non-coding mutations, we focus on two of the recurrently mutated estrogen receptor binding sites. Our bioinformatics and biochemical analysis suggest loss of DNA-protein interactions due to the recurrent mutations. Through CRISPR interference, we find that the recurrently mutated regulatory element at the LRRC3C-GSDMA locus impacts the expression of multiple distal genes. Using a CRISPR base editor, we show that the recurrent C->T conversion at the ZNF143 locus results in decreased TF binding, increased chromatin loop formation, and increased expression of multiple distal genes. This single point mutation mediates reduced response to estradiol induced cell proliferation but increased resistance to tamoxifen-induced growth inhibition. CONCLUSIONS: Our data suggest that ER binding is associated with localized accumulation of somatic mutations, some of which affect chromatin architecture, distal gene expression, and cellular phenotypes in ER-positive breast cancer. PMID- 30404660 TI - Outcomes and factors of elbow arthroscopy upon returning to sports for throwing athletes with osteoarthritis. AB - BACKGROUND: Elbow arthroscopy had good functional outcome for throwing athletes. Returning to sports is a major concern for all athletes, but only a few reports have investigated the clinical factors related to the duration of returning to sports. The present study evaluates the efficacy of elbow arthroscopic surgery on throwing elbows with osteoarthritis and defines the clinical factors related to the duration of the returning to sports. METHODS: This was a retrospective study with fifteen active baseball throwing athletes with elbow osteoarthritis who were treated with elbow arthroscopy. Perioperative clinical factors were analyzed for functional outcomes. A multiple linear regression analysis was used to analyze the clinical factors associated with the duration of returning to training and sports. RESULTS: The 15 patients' mean age was 27 years. The mean follow-up time was 2.6 years. The mean procedural complexity was 3.1 +/- 1.6 (range 1-6). The elbow total range of motion (ROM) improved significantly from 100.7 +/- 28.7 degrees to 125.7 +/- 18.5 degrees (p = 0.001). The terminal flexion range of the elbow increased significantly from 116.0 +/- 22.6 degrees to 130.0 +/- 13.2 degrees (p = 0.001), and the terminal extension range improved from 15.3 +/- 11.1 degrees to 4.3 +/- 5.9 degrees (p = 0.001). Before the operation, the average subjective patient outcome for return to sports (SPORTS) score was 3.4 +/ 1.5, which increased significantly to 9.67 +/- 0.45 (p = 0.003) at the last follow-up. The multiple linear regression analysis revealed that higher procedural complexity hinders the athletes from returning to competition. CONCLUSIONS: Elbow arthroscopy offered highly satisfactory results in the throwing elbows of elite athletes and significantly improved the range of motion and SPORTS score. The procedural complexity was significantly related to the duration of returning to competition. Early and aggressive arthroscopic intervention is recommended for elite throwing athletes with elbow osteoarthritis who fail to respond to conservative treatment. PMID- 30404661 TI - Death of preceding child and maternal healthcare services utilisation in Nigeria: investigation using lagged logit models. AB - BACKGROUND: One of the factors responsible for high level of childhood mortality in Nigeria is poor utilization of maternal healthcare (MHC) services. Another important perspective which has been rarely explored is the influence of childhood death on MHC service utilization. In this study, we examined the relationship between death of preceding child and MHC services utilization [antenatal care (ANC), skilled attendant at birth (SAB), and postnatal care (PNC)] among Nigerian women and across the six geo-political zones of the country. METHODOLOGY: We analyzed reproductive history dataset for 16,747 index births extracted from the 2013 Nigeria Demographic and Health Survey. The main explanatory variable was survival status of preceding child; therefore, only second or higher order births were considered. Analysis involved the use of descriptive statistics and lagged logit models fitted for each measure of MHC utilization. Association and statistical significance were expressed as adjusted odds ratio (AOR) with 95% confidence interval. RESULTS: The use of MCH services for most recent births in the 2013 Nigeria DHS were ANC (56.0%), SAB (34.7%), and PNC (27.3%). Univariate models revealed that the death of preceding child was associated with lesser likelihood of ANC (OR = 0.64, CI 0.57-0.71), SAB (OR = 0.56, CI 0.50-0.63), and PNC (OR = 0.65, CI 0.55-0.69). Following adjustment for maternal socio-economic and bio-demographic variables, statistical significance in the relationship disappeared for the three MHC indicators: ANC (AOR = 1.00, CI 0.88-1.14), SAB (AOR = 0.97, CI 0.81-1.15), and PNC (AOR = 0.95, CI 0.83-1.11). There were no significant variations across the six geo-political regions in Nigeria. The likelihood of ANC utilization was higher when the preceding child died in Northcentral (AOR = 1.19, CI 0.84-1.70), Northeast (AOR = 1.26, CI 0.99 1.59), and South-south (AOR = 1.19, CI 0.72-1.99) regions while the reverse is the case in Southeast (AOR = 0.39, CI 0.23-0.60). For the Southeast, similar result was obtained for ANC, SAB, and PNC. CONCLUSION: Death of a preceding child does not predict MHC services use in Nigeria especially when maternal socio economic characteristics are controlled. Variations across the Northern and Southern regions did not attain statistical significance. Interventions are needed to reverse the pattern such that greater MHC utilization is recorded among women who have experienced child death. PMID- 30404663 TI - Simulation-based benchmarking of isoform quantification in single-cell RNA-seq. AB - Single-cell RNA-seq has the potential to facilitate isoform quantification as the confounding factor of a mixed population of cells is eliminated. However, best practice for using existing quantification methods has not been established. We carry out a benchmark for five popular isoform quantification tools. Performance is generally good for simulated data based on SMARTer and SMART-seq2 data. The reduction in performance compared with bulk RNA-seq is small. An important biological insight comes from our analysis of real data which shows that genes that express two isoforms in bulk RNA-seq predominantly express one or neither isoform in individual cells. PMID- 30404662 TI - LaminA/C regulates epigenetic and chromatin architecture changes upon aging of hematopoietic stem cells. AB - BACKGROUND: The decline of hematopoietic stem cell (HSC) function upon aging contributes to aging-associated immune remodeling and leukemia pathogenesis. Aged HSCs show changes to their epigenome, such as alterations in DNA methylation and histone methylation and acetylation landscapes. We previously showed a correlation between high Cdc42 activity in aged HSCs and the loss of intranuclear epigenetic polarity, or epipolarity, as indicated by the specific distribution of H4K16ac. RESULTS: Here, we show that not all histone modifications display a polar localization and that a reduction in H4K16ac amount and loss of epipolarity are specific to aged HSCs. Increasing the levels of H4K16ac is not sufficient to restore polarity in aged HSCs and the restoration of HSC function. The changes in H4K16ac upon aging and rejuvenation of HSCs are correlated with a change in chromosome 11 architecture and alterations in nuclear volume and shape. Surprisingly, by taking advantage of knockout mouse models, we demonstrate that increased Cdc42 activity levels correlate with the repression of the nuclear envelope protein LaminA/C, which controls chromosome 11 distribution, H4K16ac polarity, and nuclear volume and shape in aged HSCs. CONCLUSIONS: Collectively, our data show that chromatin architecture changes in aged stem cells are reversible by decreasing the levels of Cdc42 activity, revealing an unanticipated way to pharmacologically target LaminA/C expression and revert alterations of the epigenetic architecture in aged HSCs. PMID- 30404664 TI - Acute radiodermatitis in modern adjuvant 3D conformal radiotherapy for breast cancer - the impact of dose distribution and patient related factors. AB - PURPOSE: This study was performed to evaluate skin toxicity during modern three dimensional conformal radiotherapy (3D-CRT) and to evaluate the importance of dose distribution and patient related factors. MATERIAL AND METHODS: This study comprises 255 patients with breast cancer treated with tangential three dimensional conformal radiotherapy (3D-CRT) after breast conserving surgery between 03/2012 and 05/2017. The median prescribed dose was 50.4 Gy (range 50 50.4) and 92.2% of the patients received a sequential boost of 10-16 Gy. Adverse skin toxicities (according to CTCAE v. 4.03 and the occurrence of moist desquamations) were assessed at the end of treatment. The dose distribution in the skin (5 mm strip from the patient outline) and in the CTV was evaluated and correlated to the CTCAE scores and the occurrence of moist desquamation. RESULTS: 42.4% of the patients developed grade I, 55.7% grade II and 2% grade III skin toxicities. Moist desquamation was observed in 59 cases (23.1%). Dose distribution within the CTV and skin was homogenous with only small areas receiving 107% of the prescribed dose (median: 0.7 cm3) in the CTV and 105% (median 0.5 cm3) in the skin. On univariate analysis breast size as well as V107%(CTV), V105%(skin) and V80%(skin) correlated significantly (p < 0.05) with the incidence of skin toxicity. On multivariate analysis only V80%(skin) was confirmed as independent risk factor. CONCLUSION: Modern tangential multi-field 3D-CRT allows a homogeneous dose distribution with similar skin toxicity as compared to studies performing IMRT. Dose distribution within the skin (V80%) might have a relevant impact on the severity of skin toxicity and the occurrence of moist desquamation. PMID- 30404666 TI - High-risk environments for eating foods surplus to requirements: a multilevel analysis of adolescents' non-core food intake in the National Diet and Nutrition Survey (NDNS). AB - OBJECTIVE: Interventions to reduce adolescents' non-core food intake (i.e. foods high in fat and sugar) could target specific people or specific environments, but the relative importance of environmental contexts v. individual characteristics is unknown. DESIGN: Cross-sectional. SETTING: Data from 4d food diaries in the UK National Diet and Nutrition Survey (NDNS) 2008-2012 were analysed. NDNS food items were classified as 'non-core' based on fat and sugar cut-off points per 100g of food. Linear multilevel models investigated associations between 'where' (home, school, etc.) and 'with whom' (parents, friends, etc.) eating contexts and non-core food energy (kcal) per eating occasion (EO), adjusting for variables at the EO (e.g. time of day) and adolescent level (e.g. gender).ParticipantsAdolescents (n 884) aged 11-18 years. RESULTS: Only 11 % of variation in non-core energy intake was attributed to differences between adolescents. In adjusted models, non-core food intake was 151 % higher (ratio; 95 % CI) in EO at 'Eateries' (2.51; 2.14, 2.95) and 88 % higher at 'School' (1.88; 1.65, 2.13) compared with 'Home'. EO with 'Friends' (1.16; CI 1.03, 1.31) and 'Family & friends' (1.21; 1.07, 1.37) contained 16-21 % more non-core food compared with eating 'Alone'. At the individual level, total energy intake and BMI, but not social class, gender or age, were weakly associated with more non core energy intake. CONCLUSIONS: Regardless of individual characteristics, adolescents' non-core food consumption was higher outside the home, especially at eateries. Targeting specific eating contexts, not individuals, may contribute to more effective public health interventions. PMID- 30404665 TI - Systematic review and meta-analysis of diagnostic accuracy of detection of any level of diabetic retinopathy using digital retinal imaging. AB - BACKGROUND: Visual impairment from diabetic retinopathy (DR) is an increasing global public health concern, which is preventable with screening and early treatment. Digital retinal imaging has become a preferred choice as it enables higher coverage of screening. The aim of this review is to evaluate how different characteristics of the DR screening (DRS) test impact on diagnostic test accuracy (DTA) and its relevance to a low-income setting. METHODS: We conducted a systematic literature search to identify clinic-based studies on DRS using digital retinal imaging of people with DM (PwDM). Summary estimates of different sub-groups were calculated using DTA values weighted according to the sample size. The DTA of each screening method was derived after exclusion of ungradable images and considering the eye as the unit of analysis. The meta-analysis included studies which measured DTA of detecting any level of DR. We also examined the effect on detection from using different combinations of retinal fields, pupil status, index test graders and setting. RESULTS: Six thousand six hundred forty-six titles and abstracts were retrieved, and data were extracted from 122 potentially eligible full reports. Twenty-six studies were included in the review, and 21 studies, mostly from high-income settings (18/21, 85.7%), were included in the meta-analysis. The highest sensitivity was observed in the mydriatic greater than two field strategy (92%, 95% CI 90-94%). The highest specificity was observed in greater than two field methods (94%, 95% CI 93-96%) where mydriasis did not affect specificity. Overall, there was no difference in sensitivity between non-mydriatic and mydriatic methods (86%, 95% CI 85-87) after exclusion of ungradable images. The highest DTA (sensitivity 90%, 95% CI 88-91%; specificity 95%, 95% CI 94-96%) was observed when screening was delivered at secondary/tertiary level clinics. CONCLUSIONS: Non-mydriatic two-field strategy could be a more pragmatic approach in starting DRS programmes for facility-based PwDM in low-income settings, with dilatation of the pupils of those who have ungradable images. There was insufficient evidence in primary studies to draw firm conclusions on how graders' background influences DTA. Conducting more context-specific DRS validation studies in low-income and non-ophthalmic settings can be recommended. PMID- 30404667 TI - Blood on board: The development of a prehospital blood transfusion program in a Canadian helicopter emergency medical service. AB - CLINICIAN'S CAPSULE What is known about the topic? Emerging evidence regarding prehospital blood transfusions for patients in hemorrhagic shock is positive. What did this study ask? Describe the implementation and stewardship of a prehospital blood transfusion program, as well as basic demographics and blood traceability. What did this study find? We provided blood transfusion to 274 mainly male trauma patients, and just 1.2% of units were wasted. Why does this study matter to clinicians? Implementation of a similar program at other prehospital organizations can be sustainably achieved. PMID- 30404668 TI - The factors associated with food fussiness in Irish school-aged children. AB - OBJECTIVE: To establish the factors that determine food fussiness, to explore if child age determines the extent to which these factors influence food fussiness and to identify whether parental neophobia is an independent determinant of food fussiness. DESIGN: Cross-sectional data from the National Children's Food Survey (2003-2004). The Children's Eating Behaviour Questionnaire (CEBQ) assessed eating behaviours in children. The Food Neophobia Scale (FNS) assessed parental food neophobia. Young children were classified as 5-8 years old with older children classified as 9-12 years old. SETTING: Republic of Ireland.ParticipantsNationally representative sample of Irish children aged 5-12 years (n 594). RESULTS: Parents identifying child's food preferences as a barrier to providing their child with a healthy diet was significantly associated with increased food fussiness in younger (P<0.001) and older children (P<0.001). Higher levels of parental neophobia were significantly associated with an increase in food fussiness in younger (P<0.05) and older (P<0.001) children. Food advertising as a barrier to providing a healthy diet was inversely associated with food fussiness in younger children (P<0.05). In older children, there was a significant inverse association between child's BMI and food fussiness (P<0.05), but not to the extent that a difference in weight status was noted. Family mealtimes in older children were associated with significantly lower levels of food fussiness (P<0.05). CONCLUSIONS: Findings from the present study identify that a child's age does determine the extent to which certain factors influence food fussiness and that parental neophobia is an independent determinant of food fussiness. PMID- 30404669 TI - Managing the opioid epidemic: back to the basics with resuscitation. PMID- 30404670 TI - Cognitive load theory as a framework for simulation-based, ultrasound-guided internal jugular catheterization training: Once is not enough. AB - CLINICIAN'S CAPSULE What is known about the topic? Cognitive load theory can be used to guide simulation-based training for procedural skills. What did this study ask? How can cognitive load theory be used to overcome the challenges of learning ultrasound-guided internal jugular catheterization? What did this study find? All trainees approached or exceeded expert benchmarks, with evidence of retention over time. Why does this study matter to clinicians? This curriculum may better prepare trainees for performing this important procedure in the clinical setting. PMID- 30404671 TI - Selective serotonin reuptake inhibition increases noise burst-induced unconditioned and context-conditioned freezing. AB - OBJECTIVE: Whereas long-term administration of selective serotonin reuptake inhibitors (SSRIs) is effective for the treatment of anxiety disorders, acute administration of these drugs may exert a paradoxical anxiogenic effect. The aim of the present study was to explore the possible effect of an SSRI in situations of unconditioned or limited conditioned fear. METHODS: Male Sprague Dawley rats were administered a single dose of an SSRI, escitalopram, before acquisition or expression of context conditioned fear, where noise bursts were used as the unconditioned stimulus. Freezing was assessed as a measure of unconditioned fear (=the acute response to noise bursts) or conditioned fear (=the response to the context), respectively. RESULTS: Noise bursts elicited an acute increase in freezing but no robust conditioned response 7 days after exposure. Administration of escitalopram before testing exacerbated the freezing response during presentation of the unconditioned stimulus and also unmasked a conditioned response; in contrast, administration of escitalopram prior to acquisition did not influence the conditioned response. CONCLUSION: The data suggest that freezing in rats exposed to a stimulus inducing relatively mild fear may be enhanced by acute pretreatment with an SSRI regardless of whether the freezing displayed by the animals is an acute unconditioned response to the stimulus in question or a conditioned response to the same stimulus. PMID- 30404672 TI - Profiles of primary and secondary callous-unemotional features in youth: The role of emotion regulation. AB - There is increasing evidence for multiple pathways in the development of callous unemotional (CU) features, including primary and secondary profiles. Understanding affect regulation strategies among variants may provide further insight to the development and treatment of CU features. This study evaluated whether profiles of CU features could be identified within a clinical sample of youth using measures of affect dysregulation, affect suppression, anxiety, and maltreatment. We also examined whether these profiles were consistent across gender. Participants (N = 418; 56.7% female) ranged in age from 12 to 19 years (M = 15.04, SD = 1.85) and were drawn from a clinical sample. Latent profile analysis (LPA) was conducted using five indicators, including affect regulation, suppression, anxiety, CU features, and maltreatment. The best fitting model, a four-profile solution, included a low (low CU/dysregulation), anxious (low CU/high dysregulation), primary CU (high CU/low dysregulation), and secondary CU profile (high CU/dysregulation/maltreatment). LPAs found the same four-profile model when conducted separately for males and females. This is the first study to examine gender and include affect regulation strategies in the examination of primary and secondary profiles of CU. PMID- 30404673 TI - Individual-, maternal- and household-level factors associated with stunting among children aged 0-23 months in Bangladesh. AB - OBJECTIVE: Childhood stunting remains a major public health concern in Bangladesh. To accelerate the reduction rate of stunting, special focus is required during the first 23 months of a child's life when the bulk of growth takes place. Therefore the present study explored individual-, maternal- and household-level factors associated with stunting among children under 2 years of age in Bangladesh. DESIGN: Data were collected through a nationwide cross sectional survey conducted between October 2015 and January 2016. A two-stage cluster random sampling procedure was applied to select 11 428 households. In the first stage, 210 enumerations areas (EA) were selected with probability proportional to EA size (180 EA from rural areas, thirty EA from urban slums). In the second stage, an average of fifty-four households were selected from each EA through systematic random sampling. SETTING: Rural areas and urban slums of Bangladesh.ParticipantsA total of 6539 children aged 0-23 months. RESULTS: Overall, 29.9 % of the children were stunted. After adjusting for all potential confounders in the modified Poisson regression model, child's gender, birth weight (individual level), maternal education, age at first pregnancy, nutrition (maternal level), administrative division, place of residence, socio-economic status, food security status, access to sanitary latrine and toilet hygiene condition (household level) were significantly associated with stunting. CONCLUSIONS: The study identified a number of potentially addressable multilevel risk factors for stunting among young children in Bangladesh that should be addressed through comprehensive multicomponent interventions. PMID- 30404674 TI - We Are Caregivers: Social Identity Is Associated with Lower Perceived Stress among Rural Informal Caregivers. AB - ABSTRACTInformal caregivers often experience high stress levels with little support, especially in rural settings. With a mixed-methods approach, this research explored experiences of rural informal caregivers, including how social identification as a caregiver, social interactions, and formal and informal coping support related to perceived stress. Major focus group themes (n = 8) included lacking available services, balancing challenges, unmet practical needs, and strong community identity. Survey data (n = 22) revealed that perceived coping support (e.g., having someone to turn to), social interactions, and caregiver identity (e.g., perceiving the role as important to one's self-concept) were associated with lower life upset stress, but only caregiver identity was associated with managing the personal distress and negative feelings associated with caregiving stress. Results suggest that, although available rural services may fall short, other options might alleviate caregiver stress, including facilitating access to coping support, encouraging social interactions, and enhancing caregiver social identity. PMID- 30404675 TI - Operational and Financial Considerations of Using Drones for Medical Support of Mass Events in Poland. AB - OBJECTIVE: The implementation of drones in the medical security system requires a proper planning of the cooperation of different services, dividing the area into sectors, assessing potential risks, and other factors. This study refers to the cost analysis of using drones in the medical support of mass events. The aim of this research is to analyze the costs of unmanned aerial vehicle (UAV) implementation in the mass event medical support system. METHODS: The description includes purchase and maintenance costs of UAVs. The analysis also involves ways of raising funds for projects related to the UAV sector. Apart from the financial aspect, staff and drone operator training issues are the subjects of this analysis as well. RESULTS: This study is based on a specialist research involving drones and referring to reports on the current situation in Poland and in the world. CONCLUSIONS: The presented funds required for such projects and the way of raising these funds illustrate the range of the project and its requirements. (Disaster Med Public Health Preparedness. 2018;page 1 of 6). PMID- 30404676 TI - Innovative Exercise as an Intervention for Older Adults with Knee Osteoarthritis: A Pilot Feasibility Study. AB - ABSTRACTExercise has potential to mitigate morbidity in knee osteoarthritis (OA). Participants with knee OA were randomized to a Square-stepping Exercise (SSE) group (2x/week for 24 weeks) or a control group. We assessed the feasibility of SSE and its effectiveness on symptoms (WOMAC), balance (Fullerton), mobility, and walking speed at 12 and 24 weeks. The SSE group had a 49.3% attendance rate and trended toward improvement in the 30-second chair stand at 12 (F = 1.8, p = .12, etap2 = 0.16), and 24 weeks, (F = 3.4, p = .09, etap2 = 0.18), and walking speed at 24 weeks, compared to controls. There were no differences in symptoms or balance. The low attendance and recruitment demonstrated limited feasibility of SSE in adults with knee OA. Trends suggest the potential for SSE to improve lower extremity functional fitness and walking speed. SSE should be further studied for effectiveness on symptoms and balance, in addition to improving feasibility. PMID- 30404677 TI - Changing Beliefs About Emotions in IBS: A Single Case Design. AB - BACKGROUND: Previous research suggests benefits of targeting beliefs about the unacceptability of emotions in treatment for irritable bowel syndrome (IBS). AIMS: The current study developed and tested an intervention focusing on beliefs and behaviours around emotional expression. METHOD: Four participants with IBS attended five group sessions using cognitive behavioural techniques focusing on beliefs about the unacceptability of expressing emotions. Bi-weekly questionnaires were completed and a group interview was conducted. This study used an AB design with four participants. RESULTS: Averages indicate that participants showed decreases in beliefs about unacceptability of emotions and emotional suppression during the intervention, although this was not reflected in any of the individual trends in Beliefs about Emotions Scale scores and was significant in only one individual case for Courtauld Emotional Control Scale scores. Affective distress and quality of life improved during follow-up, with only one participant not improving with regard to distress. Qualitative data suggest that participants felt that the intervention was beneficial, referencing the value in sharing their emotions. CONCLUSIONS: This study suggests the potential for beliefs about emotions and emotional suppression to be addressed in cognitive behavioural interventions in IBS. That beliefs and behaviours improved before outcomes suggests they may be important processes to investigate in treatment for IBS. PMID- 30404678 TI - The prognostic significance of repeated prehospital shocks for out-of-hospital cardiac arrest survival. AB - For a French translation of the original research, please see the Supplementary Material at DOI: 10.1017/cem.2018.437 CLINICIAN'S CAPSULE What is known about the topic? The prognostic implications of repeated shocks for out-of-hospital cardiac arrest are uncertain. What did this study ask? What is the association between the number of prehospital shocks and survival in patients suffering from an out of-hospital cardiac arrest? What did this study find? Survival remains possible even after a high number of shocks for patients suffering from an OHCA. Why does this study matter to clinicians? The probabilities presented may prove useful in decision modelling to guide resuscitation efforts for these patients. PMID- 30404679 TI - Childhood infections and common carotid intima media thickness in adolescence. AB - Atherosclerotic changes can be measured as changes in common carotid intima media thickness (CIMT). It is hypothesised that repeated infection-associated inflammatory responses in childhood contribute to the atherosclerotic process. We set out to determine whether the frequency of infectious diseases in childhood is associated with CIMT in adolescence. The study is part of the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) population-based birth cohort. At age 16 years, common CIMT was measured. We collected general practitioner (GP) diagnosed infections and prescribed antibiotics. Parent-reported infections were retrieved from annual questionnaires. Linear regression analysis assessed the association between number of infections during the first 4 years of life and common CIMT. Common CIMT measurement, GP and questionnaire data were available for 221 participants. No association was observed between the infection measures and CIMT. In a subgroup analysis, significant positive associations with CIMT were observed in participants with low parental education for 2-3 or ?7 GP diagnosed infections (+26.4 um, 95% CI 0.4-52.4 and +26.8 um, 95% CI 3.6-49.9, respectively) and ?3 antibiotic prescriptions (+35.5 um, 95%CI 15.8-55.3). Overall, early childhood infections were not associated with common CIMT in adolescence. However, a higher number of childhood infections might contribute to the inflammatory process of atherosclerosis in subgroups with low education, this needs to be confirmed in future studies. PMID- 30404680 TI - Emergency overcrowding and access block: A smaller problem than we think. AB - CLINICIAN'S CAPSULE What is known about the topic? Emergency access block is the number one emergency department (ED) safety concern; many believe it cannot be solved without increased hospital capacity. What did this study ask? The objective was to measure emergency access blocks (problem) as a fraction of inpatient capacity (potential solution). What did this study find? Delays to care space averaged 46,000 hours per ED per year - large, but only 1% of inpatient capacity. Why does this study matter to clinicians? Emergency access gaps are small relative to hospital capacity; if viewed as a hospital problem, small improvements could eliminate them. PMID- 30404681 TI - Hospital Discharge Decisions Concerning Older Patients: Understanding the Underlying Process. AB - ABSTRACTWe aimed to understand clinical decision-making processes that influence the orientation of older patients after hospital discharge. We compared discharge decisions (i.e., discharge home, or nursing home stay) of the hospital team with those of an expert panel. Both panel and hospital team made their decisions independently. The blind study included 102 patients (mean age: 83.13 +/- 6.74). There is a statistically significant difference between expert and hospital team decisions (p < .001; kappa coefficient: 0.468). Panel decisions were more closely associated with isolation (p = .018), reliable caregivers (p = .004), social problems (p = .001), and behavioural symptoms perceived as aggressive (p = .001). Both decision processes considered refusal of care (p = 0,025 and 0.016 respectively) and social problems (p = .001 and < 0.001 respectively). Discharge planning models differ depending on the country, team and patient's condition. Our study suggests more precise evaluation of patients' needs. PMID- 30404682 TI - Severe Heart Dysfunction Caused by Leptospiral Myocarditis. PMID- 30404683 TI - Learning in the Lassa Belt. PMID- 30404684 TI - Multiple Hepatic Hydatid Cysts in an Iraqi Refugee. PMID- 30404685 TI - Typhoid in a Kenyan Village: Its Impact, Its Prevention. PMID- 30404686 TI - [Multidisciplinary Team and Nutrition Management for Bariatric Surgery]. AB - Bariatric surgery remains the most successful treatment for morbid obesity. Multiple departments may be involved due to the presence of various co morbidities and the complex procedure. Thus,the establishment of a multidisciplinary team based on endocrinology,gastrointestinal surgery,nutrition,and psychology is important to ensure a successful bariatric surgery. Although the bariatric surgery has definite effectiveness in decreasing body weight and improving comorbidities,patients may still face the risks including protein and/or micronutrient malnutrition and other complications after the bariatric surgery. The medium-and long-term follow-up and nutrition management after bariatric surgery mainly focus on the following two aspects: weight loss and improvement of obesity-related complications; and assessment and treatment of possible nutritional deficiencies and eating disorders. PMID- 30404687 TI - [History, Recent Advancements, and Prospects in Bariatric/Metabolic Surgery]. AB - Bariatric/metabolic surgery is the most effective method to treat morbid obesity and its complications. Tracing its origin back to jejunoileal bypass in 1950s, bariatric/metabolic surgery has been continuously improved after more than 60 years of development. At present, the mainstream surgical procedures include sleeve gastrectomy, Roux-en-Y gastric bypass, biliopancreatic diversion/duodenal switch, and mini gastric bypass. In addition, new procedures such as single anastomosis duodenal switch, duodenal-jejunal bypass with sleeve gastrectomy, laparoscopic greater curvature plication and endoscopic surgeries have been developed. This article reviews the history, status quo, and prospects of bariatric/metabolic surgery. PMID- 30404688 TI - [Body Contouring After Bariatric Surgery]. AB - While overweight and obesity have gradually became global concerns. Bariatric surgery is an effective and safe option for improving quality of life and alleviating psychosocial distress in obese individuals. However,body contouring is required to solve skin problems associated with massive weight loss after bariatric surgery. This article reviews the indications,importance,and postoperative complications of body contouring after bariatric surgery. PMID- 30404689 TI - [Nonalcoholic Fatty Liver Disease and Weight Loss]. AB - Nonalcoholic fatty liver disease(NAFLD)refers to hepatic steatosis without other known causes such as alcohol abuse or hepatic virus infection. NAFLD has become a chronic disease worldwide,and its prevalence is constantly growing. Hepatic insulin resistance caused by obesity results in the deposition of triglycerides in the liver,promoting the occurrence and development of NAFLD. Weight loss is the only safe and effective method for NAFLD. Lifestyle intervention plays a cornerstone role in treating NAFLD;however,most patients can not achieve and maintain the ideal body weight by lifestyle intervention alone. Glucagon-like peptide-1 receptor agonist and metabolic surgery are promising treatments for NAFLD. PMID- 30404690 TI - [Human Body Water Composition Measurement:Methods and Clinical Application]. AB - Being the largest single component of the human body,water is essential for life. Disease can lead to salt and water imbalance, and it is particularly important to measure the content and distribution of water in body. The current body water measurement methods are still not mature,and it's even hard to measure extracellular and intracellular water. Isotope dilution method(ID),bioelectrical impedance analysis(BIA),skinfold thickness measurement,and resonant cavity perturbation(RCP)are the commonly used methods for measuring human body water composition. This paper analyzes the advantages and disadvantages of these methods and concludes that all these four methods can be used to measure total body water;more specifically,ID and BIA can measure extracellular water and intracellular water,whereas BIA is more suitable for clinical applications such as monitoring of fluid balance,guiding of fluid management,assessment of lymphedema and nutritional risk,and management of obesity. Body water measurement will play more important roles in diagnosis,prevention,treatment,and prognosis of diseases. PMID- 30404691 TI - [Effectiveness of Laparoscopic Sleeve Gastrectomy in Treating Obesity and Its Co morbidities]. AB - Objective To analyze the effectiveness and safety of laparoscopic sleeve gastrectomy (LSG) in treating obesity and its co-morbidities.Methods The clinical data of obese patients undergoing LSG in Peking Union Medical College Hospital from August 2012 to August 2017 were retrospectively analyzed. Medium-term outcome measures included excess weight loss (%EWL),co-morbidity improvement,and complications.Results Seventy-five obese patients comprising 28 men[ body mass index(BMI):(47.3+/-7.5)kg/m 2) ] and 47 women [BMI (41.1+/-7.0) kg/m 2] were enrolled in this analysis. The common co-morbidities were liver dysfunction (53.3%),dyslipidemia (52.0%),obstructive sleep apnea (45.3%),type 2 diabetes mellitus (38.7%),and arterial hypertension (37.3%),which were improved by 75.0%,58.3%,83.3%,75.0% and 58.3% three years after surgery. The mean %EWL at 1,2,and 3 years after surgery was 81.6+/-34.7,80.9+/-30.2 and 79.7+/ 30.8,respectively. The proportions of patients achieving successful weight loss were 81.7% (n=49),81.0% (n=34),and 79.3% (n=23) at 1,2,and 3 years (%EWL>50%). Early severe complications (Clavien-Dindo classification>2) occurred in 2.6% of patients,and the most common late complications was gastroesophageal reflux disease,which could be relieved by acid suppressants.Conclusion LSG is effective and safe in treating obesity and its co-morbidities. PMID- 30404692 TI - [Perioperative Evaluation of Obstructive Sleep Apnea in Bariatric Surgery Population]. AB - Objective To evaluate the prevalence and clinical characteristics of obstructive sleep apnea (OSA) in bariatric surgery population.Methods Consecutive patients undergoing preoperative evaluation for bariatric surgery and referred for sleep monitoring in Peking Union Medical College Hospital from January 2009 to December 2015 were retrospectively analyzed. Age,gender,symptoms of snoring,fatigue,apnea and somnolence,apnea hyponea index (AHI),arterial blood gas,pulmonary function,sleep respiratory monitoring,positive airway therapy of OSA,and postoperative complications were recorded. The clinical characteristics of OSA groups at different severity were compared using AHI>=5 events/hour and AHI>=15 events/hour as cut-off values. Correlation analysis was applied to identify the clinical factors associated with AHI.Results Of 42 patients with complete sleeping monitoring data before bariatric surgery,30(71.4%) were diagnosed as OSA,14 (33.3%) were moderate or severe and 11 (26.2%) were severe. Also,OSA was not detected before the bariatric surgery in 25 cases (83.3%). Compared with patients with AHI<5 events/hour,patients with AHI>=5 events/hour had significantly older age (t=2.869,P=0.007),higher proportion of observed apnea (P=0.035),higher AHI (z=-4.592,P=0.000),higher proportion of night pulse oxygen saturation(SpO2) below 90% (z=-2.746,P=0.006),lower mean SpO2 (t=-2.071,P=0.046) and lower lowest SpO2 (t=-3.914,P=0.000). Compared with AHI<15 events/hour group,the AHI>=15 events/hour group had significantly higher BMI (t=2.281,P=0.043),male ratio (P=0.005),incidence of hypertension (P=0.011),proportion of observed apnea (P=0.001),percentage of smoking history (P=0.017),partial pressure of carbon dioxide(PaCO2)(t=3.478,P=0.002),AHI (z= 4.592,P=0.000),and proportion of night SpO2 below 90% (z=-4.530,P=0.000); in addition,the forced expiratory volume in one second(FEV1)% predicted (t= 3.377,P=0.002),forced vital capacity(FVC)% predicted (t=-2.342,P=0.026),night time mean SpO2 (t=-3.392,P=0.007),lowest SpO2 (t=-5.535,P=0.000) were significantly decreased. Correlation analysis showed that,in populations with normal PaCO2 (n=36),AHI was positively correlated with age (r=0.450,P=0.006) and BMI (r=0.384,P=0.021) and negatively correlated with FEV1% predicted (r= 0.457,P=0.008) and FVC% predicted (r=-0.432,P=0.013). Partial correlation analysis showed that,after age and BMI were adjusted,AHI was not correlated with FEV1% predicted(r=-0.287,P=0.125)and FVC%predicted(r=-0.241,P=0.200).Conclusion The incidence and underdiagnosis rate of OSA are high in bariatric surgery population. OSA should be routinely screened in bariatric population to reduce the postoperative complication. PMID- 30404693 TI - [Relationship between Depression and Quality of Life in Patients with Severe Obesity]. AB - Objective To investigate the depression status and quality of life (QoL) of patients with severe obesity who have undergone bariatric surgery and to evaluate their potential correlation.Methods A total of 50 patients with severe obesity who had undergone elective bariatric surgery in the general surgical ward of Peking Union Medical College from January 2013 to December 2017 were enrolled in this study. The general data were collected. The patient's depression status and QoL were assessed by the Zung's Depression Self-Assessment Scale and the SF-36 Quality of Life Scale,respectively.Results The depression score was (44.85+/ 9.07) scores in these 50 patients,including 38 patients (76%) without depression and 12 (24%) with mild depression. The scores of the mental emotional,physical,psychomotor,and psychological barrier dimensions of patients with severe obesity were (3.70+/-1.25),(18.65+/-4.10),(4.25+/-1.35),and (18.75+/ 5.46)scores,respectively. The physiological function score of patients with mild depression was (95.83+/-10.21)scores,which was significantly higher than those without depression (68.42+/-38.95) scores(F=6.209,P=0.011). The vitality and mental health scores were (46.67+/-14.72) and (57.33+/-14.68) scores in patients with mild depression,which were significantly lower than those [(65.79+/-21.94) (F=4.867,P=0.030) and (75.16+/-17.21) scores (F=0.212,P=0.032)] in patients without depression. Correlation analysis showed that the mental-emotional score was positively correlated with physical score in patients with severe obesity (r=0.503,P=0.015),whereas the depression score was negatively correlated with the general health status (r=-0.430,P=0.032),vitality (r=-0.594,P=0.002),social functioning (r=-0.455,P=0.022),mental health (r=-0.562,P=0.003),and QoL score (r= 0.439,P=0.028).Conclusions The QoL is remarkably affected by depression in patients with severe obesity before surgery. Assessment of the mental status of patients with severe obesity may help to identify this problem and thus improve the QoL. PMID- 30404694 TI - [Associations of Socioeconomic Factors,Nutrients Intake,and Gut Microbiota of Healthy Pregnant Women in the Third Trimester with Gestational Weight Gain]. AB - Objective To investigate the associations of socioeconomic factors,nutrients intake,and gut microbiota of healthy pregnant women in the third trimester with gestational weight gain (GWG).Methods We recruited 98 pregnant women in the third trimester who had received antenatal care in the Department of Obstetrics Gynecology,Peking Union Medical College Hospital from October,2015 to May,2016. We collected socioeconomic information through a structured questionnaire covering age,ethnicity,height,pre-pregnancy weight,and education. Nutritional status of these pregnant women was assessed by a 24-hour dietary intake recall. The participants were provided with collective tubes for faecal sample collection at home;their weight before the delivery was recorded. The pre-pregnancy weight and GWG were classified according to World Health Organization body mass index (BMI) standard for adults and the Institute of Medicine GWG guidelines (2009),respectively. The gut microbiota of the participants were analyzed using a whole-metagenome shotgun sequencing method.Results Insufficient and excessive GWG accounted for 15.3% and 50.0% of the cohort,respectively. Appropriate GWG level was associated with intakes of fat (F=3.113,P=0.049),carbohydrates (F=3.750,P=0.027),and dietary fiber (F=4.499,P=0.014) but not with age (F=2.495,P=0.088),ethnicity (Chi 2=0.065,P=0.968),education (Chi 2=0.827,P=0.661),or pre-pregnancy BMI (F=0.121,P=0.887). Compared with the participants with appropriate GWG,those with excessive GWG had significantly higher abundance of Akkermansia muciniphila,Atopobium parvulum,and Alistipes indistinctus as well as lower abundance of Lactobacillus rhamnosus,Weissella unclassified,Eubacterium ventriosum,Ruminococcus torques,and Bacteroides uniformis. Compared with the participants with appropriate GWG,those with insufficient GWG had significantly higher abundance of Dialister invisus,Alistipes unclassified,Peptoniphilus harei,Escherichia unclassified,Parvimonas unclassified,Campylobacter ureolyticus,Lactobacillus crispatus,and Fusobacterium nucleatum and lower abundance of Eubacterium ventriosum.Conclusions Abnormal GWG is common in pregnant women. GWG is significantly associated with gut microbiota as well as with nutritional factors including fat,carbohydrate,and dietary fiber intake. PMID- 30404695 TI - [Multicenter Cross-sectional Community-based Nutrition Risk Screening in 3885 Chinese Elderly Adults]. AB - Objective To evaluate the nutrition risks in Chinese elderly adults in community and provide the basis for malnutrition prevention.Methods The study population comprised of adults aged 60 years or older selected from communities. A stratified multi-stage cluster sampling method was used to investigate older adults in rural and urban areas with structured questionnaire. Nutrition Screening Initiative (NSI) checklist was used to screen nutritional status. Analyses were stratified according to age,gender,different regions,rural and urban areas,and income.Results A total of 3885 older adults with complete information were enrolled for final analyses,among whom 1894 (48.8%) were males and 1991 (51.2%) were females; 56.2% aged 60-69 years,28.8% aged 70-79 years,and 15% aged over 80 years; 1665(42.9%) were urban residents; 1592(41.0%) were in the eastern region,1211(31.2%) in the central region,and 1082(27.8%) in the western region. Up to 48.4% of the elderly adults were at high nutritional risk,and the nutritional risk was significantly higher in females (50.7%) than in males (46.0%),in individuals aged over 80 years (53.0%) than in other age groups,in urban area (41.7%) than in rural area (53.9%),and in eastern region (52.9%) than in other regions. Significant differences were found between nutritional status and the following variables: age (Chi 2=33.7,P=0.000),gender (Chi 2=15.7,P=0.000),different regions (Chi 2=72.0,P=0.000),rural and urban areas (Chi 2=69.4,P=0.000),income (Chi 2=304.9,P=0.000),and living arrangement (Chi 2=128.1,P=0.000).Conclusion Elder adults in community are at high nutritional risk. PMID- 30404696 TI - [Effects of Endothelial Progenitor Cells on Vascularization and Osteogenesis of Tissue-engineered Bones in Beagle Dogs]. AB - Objective The explore the effects of endothelial progenitor cells(EPCs)on vascularization and osteogenesis of tissue-engineered bones in Beagle dogs.Methods Bone marrow mesenchymal stem cells(BMSCs)and EPCs from bone marrow of Beagle dogs were isolated,cultured,and expanded and then seeded in beta tricalcium phosphate(TCP)scaffolds. The cell scaffold complexes(EPCs/ BMSCs/TCP group and BMSCs/TCP group)and the blank TCP scaffold were transplanted into the limb muscles of Beagle dogs,respectively. The relative CT values were calculated in the 3rd and 6th month through CT scan after operation. The vascularization and the osteogenesis were detected 6 months after operation by histological examination.Results Three months after the surgery,the relative CT value in the EPCs/BMSCs/TCP group was(366.67+/-19.51)HU,significantly higher than that[(163.00+/-30.81)HU] in the BMSCs/TCP group(t=2.10,P=0.0006);6 months after surgery,the relative CT value in the EPCs/BMSCs/TCP group was(553.34+/ 26.86)HU,which was also significantly higher than that[(241.34+/-21.57)HU] in the BMSCs/TCP group(t=2.11,P=0.0006). The relative CT values at 6 months after operation were significantly higher than those at 3 months after operation in both BMSCs/TCP group(t=2.10,P=0.0255)and EPCs/BMSCs/TCP group(t=2.10,P=0.0006). Six months after the operation,HE staining showed no bone formation or calcium deposition in the blank TCP group,and osteoblasts,mature bone trabeculae,and calcium deposition were observed in EPCs/BMSCs/TCP group and BMSCs/TCP group. Immunohistochemical staining showed that the number of peripheral,central,and whole vessels in the EPCs/BMSCs/TCP group was 21.67+/-1.45,23.33+/-2.60,and 45.00+/-1.16,which were significantly higher than those in the BMSCs/TCP group[8.67+/-0.88(t=2.07,P=0.0016),9.33+/-0.67(t=2.07,P=0.0065),and 18.00+/ 1.00(t=2.07,P=0.001),respectively]. The number of vessels was not significantly different between the BMSCs/TCP group and the blank TCP group(18.00+/-1.00 vs. 16.67+/-2.40;t=2.07,P=0.636). The osteogenic area of the EPCs/BMSCs/TCP group was(1 322 000+/-141 300)pixel,significantly higher than that of the BMSCs/TCP group[(874 900+/-49 430)pixel;t=2.10,P=0.04]. BMSCs/TCP group showed significantly higher bone area in the peripheral area than in the central region[(170 000+/-42 320)pixel vs.(613 900+/-90 290)pixel;t=2.10,P=0.02];in contrast,there was no statistically significant difference in bone area between the peripheral region and the central region in the EPCs/BMSCs/TCP group[(376 400+/-20 160)pixel vs.(310 400+/-6917)pixel;t=2.10,P=0.07].Conclusion EPCs as seed cells combined with BMSCs can promote vascularization and osteogenesis of tissue-engineered bone in Beagle dogs. PMID- 30404697 TI - [Monoenergetic Reconstructions Using Detector-based Spectral CT for Imaging of Small Lesions in the Rabbit VX2 Liver Cancer Models]. AB - Objective To evaluate the value of virtual monoenergetic(monoE)using dual-layer detector spectrum CT in detecting small lesions in rabbit VX2 liver cancer models.Methods Hepatic VX2 double tumor models were established in 24 New Zealand white rabbits by CT-guided puncture. All the rabbits underwent CT scans by using dual-layer detector CT to generate conventional 120-keV polychromatic images and monoE images with energy levels ranging from 40 to 100 keV during the arterial phase. The quantity of the lesion and measurement of the lesion length as well as the objective evaluations[signal noise ratio(SNR)and contrast noise ratio(CNR)] and the subjective evaluations(overall image quality score)of the image quality were independently measured by two radiologists. The results were compared with pathological findings.Results Pathology confirmed that 30 lesions were successfully established,with an average size of(3.99+/-0.91)mm. Eighteen(47.40%)and 30(100%)lesions were detected by conventional images and monoE images with energy levels from 40 to 65 keV,respectively. The correlation between the length diameter of fresh pathological specimens and the measurements of lesion length diameter on 40(r=0.948,P=0.000),45(r=0.958,P=0.000),50(r=0.972,P=0.000),55(r=0.952,P=0.000),6 (r=0.921,P=0.000),65 keV(r=0.917,P=0.000)monoE images was better than that on conventional images(r=0.206,P=0.270). The subjective evaluation scores of the quality of the 40,45,50,and 55 keV monoE images were 4.50(4.00,4.50)(P=0.000),5.00(5.00,5.00)(P=0.000),5.00(4.50,5.00)(P=0.000),and 4.00(4.00,4.50)(P=0.002),respectively,which were significantly higher than the conventional mixed energy images[3.00(2.50,3.00)]. The objective evaluation of image quality showed that the SNR and CNR of monoE images decreased with the increase of the energy level of the monoE image. The CNR of monoE images with 40(P=0.000),45(P=0.002),and 50 keV(P=0.011)were higher than that of the conventional image. The CNR of monoE images with 40(P=0.000),45(P=0.000),50(P=0.000),and 55 keV(P=0.002)were higher than that of the conventional images.Conclusion Dual-layer detector spectrum CT monoE image in the low-energy state of 45-50 keV can improve the detection rate of small lesions in rabbit hepatic VX2 tumor models with better noise control and provide better image quality compared with conventional polychromatic images. PMID- 30404698 TI - [Induction of Epileptic Seizures in Mouse Models of Chronic Restraint Stress]. AB - Objective To investigate the sensitivity of mouse models of chronic restraint stress to conditions that induce epileptic seizures.Methods Male C57BL/6J mice were randomized into chronic restraint stress(CRS)group and normal control(NC)group. The modeling results were evaluated by sucrose preference test and forced swimming test. Kainic aicd(KA)was intraperitoneally injected to induce acute seizures. Seizure onset time,duration,and scores were recorded and compared.Results During the forced swimming test,the immobility time was(120.9+/ 13.5)s in CRS group and only(59.1+/-9.8)s in NC group(t=3.700,P=0.0019). During the sucrose preference test,the water consumption proportion at 0-24 h and 0-48 h were(64.7+/-4.7)% and(73.3+/-3.0)%,respectively,in CRS group,significantly lower than those[(77.2+/-2.5)%(t=2.672,P=0.0167)and(83.0+/-2.8)%(t=2.386,P=0.0297)] in NC group. Although there was no significant difference in the total number of acute seizures[(11.5+/-1.1)times vs.(13.7+/-2.1)times;t=0.9767,P=0.3465],mice in CRS group had significantly higher severe seizure score than in control group[(66+/-10)scores vs.(37+/-5)scores;t=2.777,P=0.0157]. The seizure onset time was(138+/-26)s in CRS group,which was significantly shorter than that in NC group[(234+/-28)s;t=2.485,P=0.0274]. The seizure duration of the CRS group was(61+/-16)min,which was significantly longer than that of the NC group[(37+/ 5)min;t=3.342,P=0.0053].Conclusion CRS mice are more susceptible to KA-induced acute epileptic seizures. PMID- 30404699 TI - [Efficacy and Prognostic Factors of Cetuximab Therapy in Treating KRAS or All RAS Wild-type Metastatic Colorectal Cancer]. AB - Objective To explore the efficacy and prognostic factors of cetuximab therapy for KRAS or all RAS wild-type(WT)metastatic colorectal cancer(mCRC).Methods We screened mCRC patients receiving at least two cycles of cetuximb and chemotherapy from those with KRAS WT(before November 2013)or all-RAS-WT(after November 2013)in the Department of Medical Oncology,Peking Union Medical College Hospital from November 2007 to December 2016. The relationship between the clinicopathological characteristics and the efficacy was retrospectively analyzed.Results A total of 60 patients were included. For the 34 patients receiving cetuximab as first-line treatment,the objective response rate(ORR)was 55.9%,and the progression-free survival and overall survival(OS)was 10 and 24 months,respectively. All-RAS-WT mCRC had significantly lower risk of progression than those with KRAS-only WT(P=0.012),and left-sided colorectal cancer had higher ORR than right-sided colon cancer(62.1% vs. 0,P=0.033)during the first-line treatment. The median OS of the eight patients continuing cetuximab beyond first-line progression was 35.0(95%CI:23.6-46.4)months.Conclusions The efficacy of cetuximab for left-sided colorectal cancer was better than for right-sided colon cancer,and patients with all-RAS-WT have lower risk of progression than those with KRAS-only-WT. Patients benefiting from first-line cetuximab and continuing cetuximab beyond progression survive longer. PMID- 30404700 TI - [Diagnosis and Treatment of Epithelioid Hemangioendothelioma]. AB - Objective To evaluate the clinical feature,diagnosis,and treatment of epithelioid hemangioendothelioma(EHE).Methods Data of 30 EHE patients admitted from January 2001 to December 2017 were retrospectively analyzed. The auxiliary examinations,treatment method,pathological findings,and prognoses were analyzed.Results There were 10 male patients and 20 females aged(47.9+/ 16.1)years. The lesions sized(5.8+/-2.8)cm. Seventeen cases(56.7%)were asymptomatic and 17(56.7%)had no positive sign. The most common locations of EHE were scalp and spine,followed by liver. Nineteen patients underwent surgical operation(surgery group)and 11 only accepted needle biopsy(biopsy group). EHE was pathologically confirmed in all cases. CD34 and CD31 showed the highest positive rates in immunohistochemical stains. Twenty-three cases were followed up by(74.1+/-56.8)months. Seventeen cases survived and 6 died. The 1-,3-,and 5-year cumulative survival rates were 95.7%,86.3%,and 73.6%,respectively. The metastasis(14.3% vs. 77.8%,P=0.007)and mortality(7.1% vs. 55.6%,P=0.018)rates were significantly lower in surgery group than in biopsy group.Conclusions EHE is a rare tumor without specific symptom or sign. It can occur in any system of the body. Diagnosis depends mainly on pathology. The prognosis is acceptable. Complete surgical resection reduces distant metastases and mortality. PMID- 30404701 TI - [Predictive Value of Texture Analysis in the Treatment of Magnetic Resonance guided Focused Ultrasound Surgery for Symptomatic Uterine Fibroids]. AB - Objective To evaluate the predictive value of texture analysis in the treatment of magnetic resonance-guided focused ultrasound surgery(MRgFUS)for symptomatic uterine fibroids.Methods Totally 16 patients with symptomatic uterine fibroids who accepted MRgFUS in Peking Union Medical College Hospital from April 2010 to January 2013 were included. Enhanced magnetic resonance imaging(MRI)was performed before treatment,immediately after treatment,and during the 12-month follow-up. The TexRAD software was used to measure the texture parameters of the fibroids in T2WI sagittal images,and the texture indicators including means and standard deviations(SD),entropy,mean of positive pixels(MPP),skewness,and kurtosis were collected. The fibroid's volume and their change rates were calculated by measuring the relevant diameter of the target fibroid. The Uterine Fibroid Symptoms and Quality of Life(UFS-QOL)was used to calculate the symptom severity scores(SSS)and its change rate. The statistical difference of parameters among the groups was analyzed. The correlations between each texture parameter and the therapeutic outcome of the fibroids were analyzed respectively.Results The average volume for fibroids before treatment was(96.5+/-84.9)cm 3,which was reduced to(55.1+/-71.0)cm 3 after treatment for 12 months,and the volume change rate(epsilonV%)was(49+/-20)%. The standardized SSS score before treatment was(34.18+/-15.29)scores,decreased to(17.78+/-11.84)scores 12 months after treatment,with a change rate of(45+/-32)%,and the non-perfused volume ratio(NPV%)was(62+/-20)%. There were significant differences among the parameters mean,SD,entropy,and MPP among three groups(all P<0.05),and the changes of them were regular,all of which showed a significant decrease immediately after treatment and a significant increase 12 months after treatment,and the increase degree was higher than the preoperative level. SD(SSF2:r=0.503,P=0.047;SSF4:r=0.529,P=0.035;SSF6:r=0.519,P=0.039)and entropy(SSF2:r=0.527,P=0.036;SSF4:r=0.517,P=0.040;SSF6:r=0.495,P=0.050)of the after-treatment group moderately associated with the epsilonV%. Entropy of the before-treatment group was moderately associated with NPV%(SSF2:r=0.507,P=0.045;SSF4:r=0.543,P=0.030;SSF6:r=0.548,P=0.028).Conclusion There is a certain correlation between the changes of MRI texture parameters before and after treatment and the effect of MRgFUS in the treatment of uterine fibroids,and texture analysis may have certain value in the predicting the effect of MRgFUS on uterine fibroids. PMID- 30404703 TI - [Research Advances in Autophagy and Diabetic Neuropathy]. AB - Recent studies have found that autophagy is involved in the development of many chronic complications of diabetes. However,the specific mechanism between autophagy and diabetic neuropathy(DN)remains unclear. This article reviews the latest research on the pathogenesis of autophagy and DN,with an attempt to find new targets and ideas for the treatment of DN. PMID- 30404702 TI - [Value of Elasticity Contrast Index of Ultrasonography in Differentiating Benign and Malignant Cervical Lymph Nodes]. AB - Objective To investigate the diagnostic value of elasticity contrast index(ECI)in the differential diagnosis between benign and malignant cervical lymph nodes.Methods Cervical lymph nodes of 48 patients were examined by traditional ultrasound and ECI in Peking University Third Hospital between December 2016 and April 2017. Patients were further divided into free-hand group and non-free-hand group according to the use of manual compression or not. With pathological or clinical follow-up results as the gold standard,we compared the diagnostic values of traditional ultrasound,ECI,and their combination in the differential diagnosis between benign and malignant lymph nodes.Results Totally 138 lymph nodes were collected from 46 patients,among which 76 were benign and 62 were malignant. The ECI value of malignant lymph nodes(1.69+/-0.89)were significantly higher than that of benign lymph nodes(1.32+/-0.87)(t=-2.46,P=0.015).The area under receiver operating characteristic(ROC)curve for traditional ultrasound in discrimination of malignant cervical lymph nodes with benign ones was 0.899,with an optimal cut off value of 7,which had a sensitivity of 93.5% and a specificity of 84.2%. The area under ROC curve for ECI was 0.649,with an optimal cut-off value of 1.25,which had a sensitivity of 59.7% and a specificity of 60.5%. For their combination,the area under ROC curve was 0.724,with a sensitivity of 93.5% and a specificity of 51.3%. In the group without using free-hand technique,the mean ECI value was 1.77+/-0.94 for malignant nodes,which was significantly higher than that(1.26+/-0.81)for benign nodes(t=-3.09,P=0.003). In the group requiring free hand technique,the ECI value for malignant nodes was 1.33(1.01,1.44),showing no significant difference with benign ones[1.32(0.78,2.18);z= 0.20,P=0.843].Conclusions Conventional ultrasound has higher diagnostic value than ECI and their combination in differentiating benign and malignant lymph nodes. The role of ECI in evaluating other organs requires further investigations. PMID- 30404704 TI - [TWIK-related Acid Sensitive K + Channels in the Regulation of Respiration and Sleep]. AB - TWIK-related acid-sensitive K + channel(TASK)is an important member of the two pore-domain potassium channels family. It is widely expressed in the central nervous system and peripheral tissues and is extremely sensitive to hypoxia and pH changes in extracellular fluid. TASK participates in regulating the expression of respiratory center and the respiratory movement and also plays certain role in sleep regulation. This article reviews the recent advances in the roles of TASK in the regulation of respiration and sleep. PMID- 30404705 TI - [Research Advances in Hypothalamic-pituitary Dysfunction Related to Traumatic Brain Injury]. AB - Traumatic brain injury(TBI)is a major cause of hypothalamopituitary dysfunction. TBI-related hypothalamopituitary dysfunction is more common in the acute phase. Disturbance of pituitary/gonadal axis and growth hormone axis,as well as posterior pituitary dysfunction including central diabetes insipidus and syndrome of inappropriate antidiuretic hormone secretion,are the most frequently seen. During the chronic phase of TBI,anterior hypopituitarism is the major concern,which affects the quality of life. Risk factors for hypothalamopituitary dysfunction following TBI include low Glasgow score,high body mass index,hypoxia,older age,longer intensive care unit stay and longer coma status,radiological evidence of acute brain injury,and increased intracranial pressure. Children and adolescents are in a crucial period of growth and development,and therefore TBI-related pituitary dysfunction during this period can substantially affect the cognition and behaviors. There is currently no reliable biochemical marker predicting hypothalamopituitary dysfunctions. Therefore,it is of great importance to evaluate the pituitary function and take appropriate hormone replacement for moderate-severe TBI patients or mild TBI patients with apparent symptoms,especially for patients with water-electrolyte disturbance and adrenal deficiency. Growth hormone and gonadal hormone replacement therapies are crucial for children and adolescents. PMID- 30404706 TI - [Evaluation of Uterine Tumor Angiogenesis with Quantitative Magnetic Resonance Imaging Perfusion Parameters]. AB - The development and metastasis of uterine tumors depend highly on tumor angiogenesis. Multiphase dynamic contrast-enhanced magnetic resonance imaging can quantitatively describe the hemodynamic changes of uterine tumors based on a variety of tracer kinetic models and time-signal curves and by simulating the distribution of contrast inside and outside the blood vessels. Functional parameters can accurately and noninvasively assess tumor angiogenesis. It provides a non-invasive functional evaluation method for the differential diagnosis,staging,response evaluation,and prognostic prediction of uterine tumors. PMID- 30404707 TI - [Pulmonary Bulla and Bilateral Diffusely-distributed Nodules: Report of One Case and Literature Review]. AB - Lung cancer is mostly characterized by a pulmonary solid mass on CT. In rare cases,patients do not have these typical manifestation but present with diffusely distributed small nodules and pulmonary bullae,which can easily be misdiagnosed. A special case of lung adenocarcinoma was managed in our hospital from September 24th to December 19th in 2016. Under high-resolution CT,multiple nodules were seen in both lungs,mostly in the upper lungs,involving the pleura and interlobular fissures. Some nodules had cystic changes. A large bulla was seen in the left upper lung. Its wall was thickened with multiple nodules. Lung adenocarcinoma was pathologically confirmed. PMID- 30404708 TI - [Visually Isoattenuating Pancreatic Acinar Cell Carcinoma:Report of One Case]. AB - Acinar cell carcinoma of pancreas(ACCP)is a rare pancreatic exocrine tumor that accounts for about 1% of pancreatic tumors. The typical imaging manifestations of ACCP are as follows:(1)the tumor is large in volume,partially or completely exophytic;(2)complete or incomplete capsule is visible with thin linear enhancement;(3)CT density and MRI signal:plain CT images reveals that the tumors have similar or slightly hypodense densities relative to the adjacent normal pancreas,the solid part of ACCP has low to intermediate signal intensity on T1WI and intermediate to high signal intensity on T2WI compared with the surrounding normal pancreas;(4)pattern of enhancement:tumors exhibit heterogeneous enhancement and it is less than that in the surrounding normal pancreas;(5)fissure-like,swirling necrosis that may be a characteristic change of tumor;(6)pancreatic and biliary duct dilatation is rare;(7)adjacent organs and blood vessels around the pancreas may be invaded;(8)distant metastasis of liver and other parts may be observed;(9)PET-CT shows high FDG uptake. An ACCP patient with atypical imaging manifestations was treated in Peking Union Medical College Hospital from November 2015 to August 2017. The lesion manifested iso-enhancement and many imaging examinations failed to find the tumor. The patient ultimately underwent surgery and diagnosed as ACCP by pathology. PMID- 30404709 TI - [Contrast Enhanced T2 Fluid-attenuated Inversion Recovery Imaging in Diagnosing Macular Edema Caused by Retinal Vein Occlusion:Report of One Case]. AB - Conventional contrast-enhanced T1WI is a useful tool for evaluating the choroid but can not be used to evaluate the retina due to its small blood supply. Contrast-enhanced T2 fluid-attenuated inversion recovery imaging(CE-T2FLAIR)is sensitive to low-concentration MRI contrast;however,its role in the diagnosis of macular edema has not been described. A patient with macular edema caused by retinal vein occlusion was diagnosed by CE-T2FLAIR in the Hainan Branch of Chinese PLA General Hospital from July 20,2017 to August 4,2017,and our findings confirmed that CE-T2FLAIR could provide valuable imaging evidence for the diagnosis and evaluation of macular edema. PMID- 30404710 TI - ? PMID- 30404711 TI - [Multiple personalities in a 15-year-old girl]. AB - This case report is about a 15-year-old girl, who had multiple personalities. Dissociative identity disorder (DID) is a complex disorder characterised by two or more distinct identities or dissociated personalities. These states or identities alternately control the person's behaviour, accompanied by memory impairment of important information. The diagnosis is relatively uncommon in clinical practice in Denmark and is associated with controversy regarding its validity. The growing empirical research on DID supports its validity as a psychiatric disorder, but the disorder may however suffer from under- or misdiagnosis. PMID- 30404712 TI - [Complex intervention research for families with prior gestational diabetes mellitus]. AB - Women with prior gestational diabetes mellitus (GDM) have a seven-fold increased risk of developing Type 2 diabetes. There are currently no systematic initiatives in Denmark to ensure prevention of Type 2 diabetes in this target group. To address the missed opportunity, we suggest applying complex intervention research and participatory methods to develop a coherent healthcare pathway during pregnancy and post-partum, which systematically supports women with prior GDM and their families as well as strengthens their capacity to make healthy choices in everyday life. PMID- 30404713 TI - [Interaction between microbiota and immune system in colorectal cancer]. AB - In vivo- and in vitro research accumulate mounting evidence, that the interaction between the colorectal microbiota and the immune system plays an important role in the development and progression of colorectal cancer and for the treatment outcomes. In future, modulation of the microbiota and immune system will, by all accounts, become important targets for prevention and treatment of colorectal cancer. In this review, we summarise current knowledge on bacterial drivers, biofilm formation, colon cancer sidedness and oncological treatment of colorectal cancer including the use of checkpoint inhibitors. PMID- 30404714 TI - [The challenges faced by researchers involving patients as partners in research]. AB - This review presents recent findings from the literature on the challenges that researchers may face, when patients get involved as partners in research: which patients to recruit, how to clarify and set boundaries to the roles of the patient and the researcher, and how to evaluate the outcome of involvement. Patient involvement may challenge the professional identity of a researcher. Researchers are often uncertain about how to establish a meaningful collaboration with partners whose knowledge comes from the lived experience of being a patient. PMID- 30404715 TI - [A woman with hidrosadenitis suppurativa underwent multiple operations for abscesses]. AB - In this case report a 42-year-old woman presented with a long history of hidrosadenitis suppurativa (HS). Due to recurrent abscesses and post-operative complications, she underwent 69 operations in general anaesthesia as well as numerous incisions in local anaesthesia in 2013-2017. The abscesses were repeatedly treated with simple incisions, although a Danish guideline from 2016 does not recommend this procedure as treatment of patients with HS, since there is a high rate of recurrence. This illustrates the necessity of increasing knowledge of the treatment of HS. We recommend an interdisciplinary cooperation in a dermatological setting to avoid acute surgery. PMID- 30404716 TI - [Multiple vertebral fractures after denosumab discontinuation]. AB - Recent reports imply, that denosumab discontinuation may lead to an increased risk of multiple vertebral fractures. This is a case report about two postmenopausal women, both with previous fragility fractures, who presented multiple vertebral fractures after denosumab discontinuation. One of the women also had symptomatic hypoparathyroid hypercalcaemia, six months after denosumab was discontinued. We recommend, that denosumab treatment should not be stopped without considering an alternative treatment. PMID- 30404717 TI - Predicting outstanding results after anatomic total shoulder arthroplasty using percentage of maximal outcome improvement. AB - BACKGROUND: The purpose of this study was to determine whether thresholds in the percentage of maximal improvement in the Simple Shoulder Test (SST) or American Shoulder and Elbow Surgeons (ASES) score exist for predicting "excellent" patient satisfaction after total shoulder arthroplasty (TSA). METHODS: A retrospective query identified patients who underwent TSA with a minimum of 2 years' follow-up. Preoperative and postoperative SST and ASES scores and postoperative patient satisfaction were recorded. Receiver operating characteristic curve analyses were performed to determine thresholds in the percentage of maximal improvement in the SST and ASES scores that predict excellent satisfaction. Univariate and multivariate analyses determined preoperative factors that predicted achievement of these thresholds. RESULTS: A total of 301 and 319 patients had at least 2 years' follow-up for the SST score and ASES score, respectively. We determined 72.1% of maximal improvement in the SST score to be the threshold for excellent satisfaction (area under the curve, 0.777; 95% confidence interval, 0.712-0.841; P < .001). We determined 75.6% of maximal improvement in the ASES score to be the threshold for excellent satisfaction (area under the curve, 0.799; 95% confidence interval, 0.743-0.856; P < .001). Both groups showed significant positive correlations between percentage of maximal score achieved and excellent satisfaction (r = 0.396 for SST score [P < .001] and r = 0.325 for ASES score [P < .001]). Younger age was the only independent predictor for achieving the SST score threshold. No independent predictors existed for the ASES score threshold. CONCLUSION: Achievement of 72.1% of maximal SST score improvement and achievement of 75.6% of maximal ASES score improvement represent thresholds for achievement of excellent satisfaction after TSA. Most preoperative factors did not have an impact on the likelihood of achieving these thresholds. PMID- 30404718 TI - High-Flow Nasal Cannula Oxygen Supported-Transesophageal Echocardiography Under Sedation in a Respiratory Compromised Patient. PMID- 30404719 TI - 4-tert-Pentylphenoxyalkyl derivatives - Histamine H3 receptor ligands and monoamine oxidase B inhibitors. AB - The synthesis and biological activity of 4-tert-pentylphenoxypropyl derivatives are described in this manuscript. All compounds (except one) showed human histamine H3 receptor affinity with Ki values below 760 nM. The inhibitory activity toward human monoamine oxidase B (hMAO B) was evaluated using a fluorometric Amplex-Red assay, and most of the compounds were effective in the submicromolar range. Among them, 1-(3-(4-tert-pPentylphenoxy)propyl)pyrrolidine (5) exhibited hMAO B inhibitory activity with an IC50 value of 4.5 nM. In addition, hMAO B inhibition by 5 was shown to be non-competitive and reversible. Further, recently described potent histamine H3 receptor ligands - 4-tert pentylphenoxyalkyl derivatives (with a 4-8 carbon spacer) - were evaluated for hMAO B inhibitory activity, and some of them displayed activity in the submicromolar range. Selected compounds were also tested for human MAO A (hMAO A) inhibitory potencies and exhibited no activity. Moreover, molecular modeling studies were carried out for tested compounds to explain their molecular mechanism of hMAO B inhibition and the selectivity of compounds for hMAO B over hMAO A. PMID- 30404720 TI - To save a child's spleen: 50 years from Toronto to ATOMAC. AB - Pediatric surgeons brought forth non-operative treatment for children with blunt spleen injury more than 50 years ago. At the time, this proposal was deemed reckless by many adult surgeons, and debate ensued for decades. Despite criticisms, pediatric surgeons refined the clinical pathways for children with spleen injury leading to current safe and efficient outcomes. These outcomes are defined by rare splenectomies, few blood transfusions, and short length of hospital stay. This review will address the role of the spleen through historical perceptions and scientific evidence. In addition, evolution of contemporary clinical pathways will be outlined. PMID- 30404721 TI - Disparities in the allocation of research funding to gynecologic cancers by Funding to Lethality scores. AB - PURPOSE: To analyze National Cancer Institute (NCI) funding distributions to gynecologic cancers compared to other cancers from 2007 to 2014. METHODS: The NCI's Surveillance, Epidemiology and End Results (SEER), Cancer Trends Progress Report, and Funding Statistics were used to analyze 18 cancer sites. Site specific mortality to incidence ratios (MIR) were normalized per 100 cases and multiplied by person-years of life lost to derive cancer-specific lethality. NCI funding was divided by its lethality to calculate Funding to Lethality scores for gynecologic malignancies and compared to 15 other cancer sites. RESULTS: Ovarian, cervical, and uterine cancers ranked 10th (score 0.097, SD 0.008), 12th (0.087, SD 0.009), and 14th (0.057, SD 0.006) for average Funding to Lethality scores. The highest average score was for prostate cancer (score 1.182, SD 0.364). In U.S. dollars per 100 incident cases, prostate cancer received an average of $1,821,000 per person-years of life lost, while ovarian cancer received $97,000, cervical cancer $87,000, and uterine cancer $57,000. Ovarian and cervical cancers had lower average Funding to Lethality scores compared to nine other cancers, while uterine cancer was lower than 13 other cancers (p < 0.01 for all comparisons). Analyses of eight-, five-, and three-year trends for gynecologic cancers showed nearly universal decreasing Funding to Lethality scores. CONCLUSION: Funding to Lethality scores for gynecologic cancers are significantly lower than other cancer sites, indicating a disparity in funding allocation that persists over the most recent eight years of available data. Prompt correction is required to ensure critical discoveries for women with gynecologic cancers. PMID- 30404722 TI - Mid-term Results of a Novel Dedicated Venous Stent for the Treatment of Chronic Thoracic Central Vein Obstruction of Benign Aetiology. AB - OBJECTIVES: Endovascular treatment is indicated for the treatment of symptomatic thoracic central vein obstruction (TCVO) but is limited by high rates of restenosis and the need for re-intervention. The aim was to assess the safety and mid-term patency of a novel dedicated venous stent for the treatment of TCVO of benign aetiology. METHODS: This was a prospective single centre observational study of 20 patients (median age 65 years, 50% male) referred for the treatment of symptomatic chronic (>three months duration) TCVO between May 2016 and January 2018. Balloon angioplasty with implantation of a self expanding nitinol stent (Vici, Boston Scientific, Marlborough, MA, USA) was performed in all patients. Clinical records including demographics, aetiologies and types of TCVO, and procedural details were recorded. Patients were followed up clinically at one, six, and 12 months. Primary and assisted primary patency were reported. RESULTS: All 20 lesions were total occlusions, of which 55% (n = 11) were de novo, 10% (n = 2) peri-stent restenosis, and 35% (n = 7) in-stent re-occlusion. The aetiology of TCVO was predominantly (95%) because of multiple or prolonged central venous line insertion. The procedural success rate was 90% (18/20) with no procedural complications. The median follow up was 13.5 months. Primary patency was 100% at 6 months. One patient required re-intervention for stent in segment restenosis at 7 months. The assisted primary patency rate was 100% at 12 months. CONCLUSION: Endovascular treatment of benign TCVO with the novel dedicated venous stent was safe and effective in relieving obstructive symptoms with excellent one year patency rates. PMID- 30404724 TI - Fire. PMID- 30404723 TI - A systematic review and meta-analysis revealing realistic outcomes following paediatric torsion of testes. AB - INTRODUCTION: Reported testicular loss rates following paediatric testicular torsion often reflect the surgical decision-making process, rather than long-term survival of the testes. OBJECTIVES: We aim to perform systematic analysis and meta-analysis to investigate testicular salvage rates and to assess predictors of long-term viability. STUDY DESIGN: Systematic review according to PRISMA guidelines was performed to investigate immediate and long-term (>12 months) testicular loss rates following torsion in the paediatric population. Literature search and study inclusion were performed by two investigators. A study quality score was derived and attributed to each study. Predictors of testicular loss were described. Proportions meta-analysis was performed with random effects modelling, and testing for heterogeneity. RESULTS: Twelve studies were includedm, 6 reporting early orchidectomy rates, and 6 reporting long-term outcomes. Study quality was generally low. DISCUSSION: The mean early testicular loss rate was 39%, whereas meta-analysis revealed late loss to approach 50%. Predictors of outcomes include prehospital symptom duration, location of presentation, transfer to a tertiary centre, social affluence and use of ultrasound prior to diagnosis or transfer. CONCLUSIONS: This study has shown a considerable late testicular loss rate, which must be relayed to families even after testicular salvage. Delay in time to presentation is consistently found to predict poor outcomes. PMID- 30404725 TI - Cardiovascular magnetic resonance imaging pattern in patients with autoimmune rheumatic diseases and ventricular tachycardia with preserved ejection fraction. AB - BACKGROUND: Ventricular tachycardia/fibrillation (VT/VF) may occur in autoimmune rheumatic diseases (ARDs). We hypothesized that cardiovascular magnetic resonance (CMR) can identify arrhythmogenic substrates in ARD patients. PATIENTS - METHODS: Using a 1.5 T system, we evaluated 61 consecutive patients with various types of ARDs and normal left ventricular ejection fraction (LVEF) on echocardiography. A comparison of patients with recent VT/VF and those that never experienced VT/VF was performed. CMR parameters included left and right ventricular (LV and RV) end systolic and end-diastolic volumes (ESV and EDV), T2 signal ratio of myocardium over skeletal muscle, early/late gadolinium enhancement (EGE and LGE), T1/T2 mapping and extracellular volume fraction (ECV). RESULTS: 21 (34%) patients had a history of recent, electrocardiographically identified, VT/VF. No demographic or functional CMR variables differed significantly between groups. The same was the case for T2 signal ratio and EGE/LGE. Median native T1 mapping values were significantly higher in patients with VT/VF compared to those without [1135.0 (1076.0, 1201.0) vs. 1050.0 (1025.0, 1078.0), p < 0.001], as was the case for mean T2 mapping [60.4 (6.6) vs. 55.0 (7.9), p = 0.009] and median ECV values [32.0 (30.0, 32.0) vs. 29.0 (28.0, 31.5), p = 0.001]. After multivariate corrections for age, LVEDV, LVEF, RVEDV, RVEF, T2 signal ratio, EGE and LGE, these remained significant predictors of having experienced VT/VF in the past. CONCLUSIONS: T1/T2-mapping and ECV offer incremental value as identifiers of arrhythmogenic substrates in ARD patients, beyond traditionally used indices. They can thus guide implantable cardiac defibrillator (ICD) implantation in ARD patients presenting with VT/VF and normal LVEF. PMID- 30404727 TI - Sleep and the human impacts of climate change. PMID- 30404726 TI - Combined testing of copeptin and high-sensitivity cardiac troponin T at presentation in comparison to other algorithms for rapid rule-out of acute myocardial infarction. AB - BACKGROUND: We aimed to directly compare the diagnostic and prognostic performance of a dual maker strategy (DMS) with combined testing of copeptin and high-sensitivity (hs) cardiac troponin T (cTnT) at time of presentation with other algorithms for rapid rule-out of acute myocardial infarction (AMI). METHODS: 922 patients presenting to the emergency department with suspected AMI and available baseline copeptin measurements qualified for the present TRAPID-AMI substudy. Diagnostic measures using the DMS (copeptin <10, <14 or < 20 pmol/L and hs-cTnT<=14 ng/L), the 1 h-algorithm (hs-cTnT<12 ng/L and change <3 ng/L at 1 h), as well as the hs-cTnT limit-of-blank (LoB, <3 ng/L) and -detection (LoD, <5 ng/L) were compared. Outcomes were assessed as combined end-points of death and myocardial re-infarction. RESULTS: True-negative rule-out using the DMS could be achieved in 50.9%-62.3% of all patients compared to 35.0%, 45.3% and 64.5% using LoB, LoD or the 1 h-algorithm, respectively. The DMS showed NPVs of 98.1%-98.3% compared to 99.2% for the 1 h-algorithm, 99.4% for the LoB and 99.3% for the LoD. Sensitivities were 93.5%-94.8%, as well as 96.8%, 98.7% and 98.1%, respectively. Addition of clinical low-risk criteria such as a HEART-score <= 3 to the DMS resulted in NPVs and sensitivities of 100% with a true-negative rule-out to 33.8% 41.6%. Rates of the combined end-point of death/MI within 30 days ranged between 0.2% and 0.3% for all fast-rule-out protocols. CONCLUSION: Depending on the applied copeptin cut-off and addition of clinical low-risk criteria, the DMS might be an alternative to the hs-cTn-only-based algorithms for rapid AMI rule out with comparable diagnostic measures and outcomes. PMID- 30404729 TI - GLP-1RA promotes brown adipogenesis of C3H10T1/2 mesenchymal stem cells via the PI3K-AKT-mTOR signaling pathway. AB - OBJECTIVE: In this study, we investigated whether the GLP-1RA, liraglutide, affected differentiation of C3H10T1/2 mesenchymal stem cells (MSCs) to mature brown adipocytes and involvement of PI3K/AKT/mTOR signaling pathway in this process. METHODS: C3H10T1/2 MSCs were induced to differentiate into brown adipocytes and treated with liraglutide (10 nM and 100 nM) for 0, 2, 4, 6 and 8 days with or without PI3K inhibitor LY294002. Oil red O staining was used for lipid droplet staining and cell proliferation was determined by cell counts. Quantitative realtime PCR was employed to determine the expression of adipogenic and mitochondrial genes, mitochondrial DNA (mtDNA). Western blot analyses were used for quantification of protein levels in PI3K/AKT/mTOR signaling pathway. RESULTS: Liraglutide increased proliferation of C3H10T1/2 MSCs and formation of multilocular lipid droplets during differentiation. Adipogenic and mitochondrial genes, mtDNA were promoted by liraglutide. Moreover, liraglutide treatment increased the levels of phosphorylated AKT and mTOR. LY294002 not only attenuated differentiation of C3H10T1/2 MSCs into brown adipocytes, but also reduced phosphorylated AKT and mTOR levels. However, co-treatment with liraglutide and LY294002 decreased the expression of adipogenic and mitochondrial genes, mtDNA, and phosphorylated AKT and mTOR levels compared to C3H10T1/2 MSCs treated with liraglutide 100 nM. CONCLUSION: GLP-1RA promotes brown adipogenesis of C3H10T1/2 mesenchymal stem cells, and PI3K/AKT/mTOR signaling pathway is involved in GLP 1RA-mediated promotion of differentiation. PMID- 30404728 TI - Reciprocal relationships between daily sleep and mood: A systematic review of naturalistic prospective studies. AB - An intimate relationship exists between sleep and affective states. Disturbances in sleep are common across a spectrum of psychopathologies, and are recognised as precipitating or prodromal factors for mood disorders. Conversely, affective states can impact sleep quality and ability to fall asleep. However, one of the main limitations of this literature is that studies have typically assessed sleep and mood at one time point and studies are often laboratory-based, where measurement of both sleep and mood has dubious ecological validity. The aim of the current review was to systematically examine the evidence for associations between day-to-day fluctuations in sleep and mood in naturalistic studies using ambulatory diary techniques. Electronic databases (EMBASE, PsycINFO, PubMed, and SCOPUS) were searched for studies using experience sampling methodology to investigate daily associations between sleep and mood in naturalistic environments in healthy and clinical samples. Findings of the included studies supported the notion of a reciprocal relationship between subjective sleep variables (sleep quality, sleep duration and sleep latency) and daytime affective states over the short term, and highlight the potential clinical importance of daily sleep disturbance in the prediction and prevention of the development of psychopathology in the future. PMID- 30404730 TI - A strategy of targeting B10 cell by CD19scFv-IL10R for tumor therapy. AB - IL-10 producing B (B10) cells, a subset of regulatory B (Breg) cells, produce IL 10 and play immunosuppressive roles in antitumor immunity. B10 cells are associated with enhanced tumor-aggressiveness and a poorer prognosis. To specifically inhibit the IL-10 secreted by B cells, we constructed the recombinant plasmid pcCD19scFv-IL10R, which contained the gene of anti-CD19 single-chain variable fragment (CD19scFv) and the extracellular domain of IL 10R1. Soluble CD19scFv-IL10R protein was identified in vitro and in vivo after the cells were transfected with pcCD19scFv-IL10R plasmid or the mice were injected with the plasmid. The fusion protein had the bispecific ability to target both IL-10 and CD19 molecules in vitro. Intramuscularly (i.m.) injecting mice with pcCD19scFv-IL-10R plasmid inhibited hepatocellular carcinoma growth in vivo. Mice treated with pcCD19scFv-IL-10R showed a significant reduction in B10 cells and regulatory T (Treg) cells, but an increase in the anti-tumor Th1 immune response and the cytotoxic CD8+ T cell response. Thus, targeting B10 cells by CD19scFv-IL10R molecule may offer a new avenue for tumor therapy. PMID- 30404731 TI - MicroRNA-503 regulates hypoxia-induced cardiomyocytes apoptosis through PI3K/Akt pathway by targeting IGF-1R. AB - Coronary heart disease is the second highest specific cause of death. H9c2 cardiomyocytes were subjected to hypoxia (1% O2) for 0, 6, 12, 24 and 48 h. Cell apoptosis and the activity of caspase3/7 was detected using ELISA; western blot was applied to determine the cleaved-caspase3 (c-caspase3), cleaved-PARP (c-PARP) and cytochrome C (Cyto C) expression after the inhibitor negative control (in NC), miR-503 inhibitor, mimic negative control (mi-NC) and miR-503 mimic were transfected into cells for 48 h. Moreover, flow cytometry was applied to evaluate mitochondrial membrane potential. In addition, luciferase reporter gene assay was used for detection the relationship between miR-503 and insulin-like growth factor-1 receptor (IGF-1R). Real-time PCR showed microRNA-503 (miR-503) was elevated in a time-dependent manner under hypoxia. MiR-503 inhibition prevented cell apoptosis and reduced caspase3/7 activity and the expression of c-caspase3 and c-PARP, prevented mitochondrial membrane potential collapse and reduced the cyto C level in cytosol. While, miR-503 overexpression showed a pro-apoptotic role and resulted in mitochondrial membrane potential loss. MiR-503 directly targets IGF-1R in H9c2 cardiomyocytes. The depletion of IGF-1R using a specific IGF-1R siRNA (siIGF-1R) abolished anti-apoptotic function of miR-503 inhibitor, and LY294002 showed a similar trend. In summary, miR-503 promoted cell apoptosis, caused mitochondrial membrane potential collapse and the emancipation of cyto C from mitochondrial through PI3K/Akt pathway via targeting IGF-1R in H9c2 cardiomyocytes. PMID- 30404732 TI - Planar compression of extracellular substrates induces S phase arrest via ATM independent CHK2 activation. AB - Cell proliferation is regulated not only by soluble chemical factors but also by mechanical cues surrounding cells. Mechanical stretch of extracellular substrates is known to promote cell proliferation by driving exit from the G0 phase and entry into the S phase. Here, we report that planer compression of extracellular substrates induces cell cycle arrest in the S phase. The compression-induced S phase arrest is mediated by the checkpoint kinase 2 (CHK2)-p53 pathway. In contrast to the canonical S phase checkpoint pathway activated by DNA damage, CHK2 activation by the substrate compression is independent of ataxia telangiectasia mutated (ATM). We further find that disassembly of the actin cytoskeleton is required for the compression-induced S phase arrest. Notably, cancer cells do not exhibit S phase arrest upon the substrate compression. Our results suggest a novel mechanism for homeostatic control of cell growth under mechanical perturbations. PMID- 30404733 TI - Vaccine adjuvant ARNAX promotes mucosal IgA production in influenza HA vaccination. AB - Adjuvant stimulates pattern-recognition receptors (PRRs) expressed by dendritic cells, which causes immune-enhancing of T lymphocytes. Adjuvant also induces innate immune response in whole-body cells via PRRs to evoke cytokinemia. A cytokine-mediated immune response is important for the systemic protection of a host from microbial infections. Using an influenza subcomponent vaccine in a mouse model, we intranasally administered a TLR3-specific adjuvant ARNAX + HA split vaccine to mice. ARNAX efficiently induced mucosal IgA and systemic IgG production by nasal drop. Moreover, ARNAX + HA simultaneously induced CD8 and CD4 T cell activation. We have previously shown that ARNAX does not induce harmful systemic cytokine production. Thus, our findings indicate that the ARNAX + HA vaccine is a harmless prophylactic vaccine for flu that induces HA-specific T cell activation and IgA/IgG production. These results suggested that ARNAX + antigen enhanced the immune response without inducing inflammatory toxicity for vaccination against infectious diseases. PMID- 30404734 TI - Structural analysis of activating mutants of YfiB from Pseudomonas aeruginosa PAO1. AB - Bacterial cyclic-di-GMP (c-di-GMP) is an important messenger molecule that influences diverse cellular processes including motility, virulence and cytotoxicity systems, polysaccharide synthesis and biofilm formation. The YfiBNR tripartite signalling system in P. aeruginosa modulates the cellular c-di-GMP levels in response to signals received from the periplasm. In this study, we analyse the structures of activating mutants of the outer membrane protein YfiB that give rise to increased surface attachment and biofilm formation. The F48S and W55L mutants of YfiB(27-168) crystallize in the same dimeric arrangement as our previously reported YfiB structures that preclude complex formation with YfiR. The L43P mutant of YfiB(27-168) is monomeric and forms a stable complex with YfiR. The YfiB(L43P)-YfiR crystal structure reveals a dramatic rearrangement of the N-terminal fragment, which is implicated in increased YfiB activation and membrane attachment, upon YfiR binding. Comparison with our previous complex structure between YfiB(59-168) and YfiR reveals extensive interactions between the N-terminal fragment of YfiB (residues 35-55) and YfiR. PMID- 30404736 TI - Enhanced calcium entry via activation of NOX/PKC underlies increased vasoconstriction induced by methylglyoxal. AB - Advanced glycation end-products (AGEs) play a pivotal role in macro- and micro vascular diabetic complications. We investigated the mechanism by which methylglyoxal (an endogenous generator of AGEs) affects vascular contractility using the isolated artery technique. Contractile responses to vasoconstrictors phenylephrine (PE), angiotensin II (Ang II), vasopressin (VP) and KCl were measured in the isolated rat aorta following one-our exposure to methylglyoxal (50-200 MUM). The perfused rat kidney was employed to confirm the effect of methylglyoxal on microvessels. Methylglyoxal-induced changes in cytosolic calcium were measured in the smooth muscle layer of the aorta with the calcium-sensing fluorophore Fluo-4 AM. Methylglyoxal significantly increased maximal contraction of the rat aorta to PE, Ang II and VP. Similar results were seen in response to the depolarizing vasoconstrictor KCl in macro and micro vessels. The methylglyoxal-induced increases in aortic contraction mediated by the agonist and KCl were endothelium independent. Methylglyoxal-induced increases in KCl dependent aortic contraction were abolished after the removal of extracellular calcium or in the presence of the calcium channel blocker nifedipine. Incubation with the antioxidant N-acetyl-l-cysteine (NAC), apocynin (a nonselective NADPH oxidase (NOX) inhibitor) or chelerythrine (a protein kinase C (PKC) inhibitor) prior to methylglyoxal pre-treatment reversed the methylglyoxal-induced increases in the rat aortic contractility. In conclusion, the formation of AGEs increases vasoconstriction of both macro- and micro-vessels by increasing the voltage activated calcium entry in vascular smooth muscles in a NOX and PKC dependent manner. PMID- 30404735 TI - Comprehensive analysis of long noncoding RNA-associated competing endogenous RNA network in cholangiocarcinoma. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) can interact with microRNAs (miRNAs) as a competing endogenous RNA (ceRNA) to regulate the expression of target genes, which can largely influence on tumorigenesis and tumor progression. However, the role of lncRNA-mediated ceRNAs in cholangiocarcinoma (CCA) remains unknown. This study aimed to develop novel lncRNAs as well as their action mechanisms in CCA. METHODS: The expression profiles of lncRNAs, miRNAs, and mRNAs of 36 CCA tissues and 9 non-tumor bile duct tissues were obtained from The Cancer Genome Atlas (TCGA) database. The differentially expressed RNAs werre identified using the DESeq package in R. The ceRNA network was constructed in CCA based on bioinformatics generated from miRcode, miRTarBase, miRDB, and TargetScan. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using "DAVID 6.8" and R packages "Clusterprofile". Survival analysis was performed based on Kaplan-Meier curve analysis. RESULTS: We identified a total of 1411 differentially expressed lncRNAs, 3494 mRNAs, and 64 miRNAs between CCA and matched normal tissues. By combining the data predicted by databases with intersection RNAs, a lncRNA-miRNA-mRNA ceRNA network consisting of 116 lncRNAs, 14 miRNAs and 59 mRNAs was established. According to the survival analysis, we detected 11 DElncRNA to have a significant impact on the overall survival in patients with CCA (P < 0.05). CONCLUSIONS: Our study identified novel lncRNAs associated with CCA progression and prognosis and provided data to further understand lncRNA-mediated ceRNA regulatory mechanisms in the pathogenesis of CCA. PMID- 30404737 TI - Living with Severe Bronchopulmonary Dysplasia-Parental Views of Their Child's Quality of Life. AB - OBJECTIVE: To assess parents' views of their children's health-related quality of life (HRQoL) and the association between neonatal morbidities and HRQoL in children with severe bronchopulmonary dysplasia (BPD) who survived to 18-36 months of corrected age. STUDY DESIGN: Study population included infants born <32 weeks of gestational age with severe BPD. At 18-36 months of corrected age, parents of children with severe BPD completed age appropriate validated Pediatric Quality of Life Inventory assessing parental views of their child's physical (PHY QoL) and psychosocial HRQoL (PS-QoL). Ten neonatal morbidities provided a composite morbidity score between 0 and 10. Linear regression evaluated associations between PHY-QoL and PS-QoL with composite morbidity score, adjusting for gestational age, sex, corrected age at assessment. RESULTS: Seventy children (67% male, gestational age 26.1 +/- 2.0 weeks, and birth weight 797 +/- 318g) were enrolled at 27.1 +/- 5.8 months of corrected age. Mean PHY-QoL and PS-QoL were 78.0 +/- 21.9 and 75.3 +/- 17.9, respectively, both significantly lower than reported means for term and preterm cohorts, with the exception of emotional QoL. Adjusted postnatal composite morbidity score was cumulatively associated with poorer PHY-QoL (P = .002) and poorer PS-QoL (P = .015). Presence of each additional neonatal morbidity was associated with a 4.4-point decrease in PHY-QoL and 2.8-point decrease in PS-QoL. CONCLUSIONS: In this cohort, parental perceived HRQoL for their child with severe BPD was lower than expected for term and preterm populations. Neonatal morbidities had an additive association with poorer parental assessment of PHY-QoL and PS-QoL. These findings may aid in care of children with severe BPD and their families, both in the intensive care nursery and postdischarge. PMID- 30404738 TI - Obesity is Associated with Higher Blood Pressure and Higher Levels of Angiotensin II but Lower Angiotensin-(1-7) in Adolescents Born Preterm. AB - OBJECTIVES: To evaluate if obesity is associated with increased angiotensin II (Ang II) and decreased angiotensin-(1-7) or Ang-(1-7) in the circulation and urine among adolescents born prematurely. STUDY DESIGN: In a cross-sectional analysis of 175 14-year-olds born preterm with very low birth weight, we quantified plasma and urinary Ang II and Ang-(1-7) and compared their levels between subjects with overweight/obesity (body mass index >=85th percentile, n = 61) and those with body mass index <85th percentile (n = 114) using generalized linear models, adjusted for race and antenatal corticosteroid exposure. RESULTS: Overweight/obesity was associated with higher systolic blood pressure and a greater proportion with high blood pressure. After adjustment for confounders, overweight/obesity was associated with an elevated ratio of plasma Ang II to Ang (1-7) (beta: 0.57, 95% CI 0.23-0.91) and higher Ang II (beta: 0.21 pmol/L, 95% CI 0.03-0.39) but lower Ang-(1-7) (beta: -0.37 pmol/L, 95% CI -0.7 to -0.04). Overweight/obesity was associated with a higher ratio of urinary Ang II to Ang-(1 7) (beta: 0.21, 95% CI -0.02 to 0.44), an effect that approached statistical significance. CONCLUSIONS: Among preterm-born adolescents, overweight/obesity was associated with increased Ang II but reduced Ang-(1-7) in the circulation and the kidney as well as higher blood pressure. Obesity may compound the increased risk of hypertension and cardiovascular disease in individuals born prematurely by further augmenting the prematurity-associated imbalance in the renin-angiotensin system. PMID- 30404739 TI - The Impact of Time Interval between Extubation and Reintubation on Death or Bronchopulmonary Dysplasia in Extremely Preterm Infants. AB - OBJECTIVE: To explore the relation between time to reintubation and death or bronchopulmonary dysplasia (BPD) in extremely preterm infants. STUDY DESIGN: This was a subanalysis from an ongoing multicenter observational study. Infants with birth weight <=1250 g, requiring mechanical ventilation, and undergoing their first elective extubation were prospectively followed throughout hospitalization. Time to reintubation was defined as the time interval between first elective extubation and reintubation. Univariate and multivariate logistic regression analyses were performed to evaluate associations between time to reintubation, using different observation windows after extubation (24-hour intervals), and death/BPD (primary outcome) or BPD among survivors (secondary outcome). aORs were computed with and without the confounding effects of cumulative mechanical ventilation duration. RESULTS: Of 216 infants included for analysis, 103 (48%) were reintubated at least once after their first elective extubation. Reintubation was associated with lower gestational age/weight and greater morbidities compared with infants never reintubated. After adjusting for confounders, reintubation within observation windows ranging between 24 hours and 3 weeks postextubation was associated with increased odds of death/BPD (but not BPD among survivors), independent of the cumulative mechanical ventilation duration. Reintubation within 48 hours from extubation conferred higher risk adjusted odds of death/BPD vs other observation windows. CONCLUSIONS: Although reintubation after elective extubation was independently associated with increased likelihood of death/BPD in extremely preterm infants, the greatest risk was attributable to reintubation within the first 48 hours postextubation. Prediction models capable of identifying the highest-risk infants may further improve outcomes. PMID- 30404740 TI - Galectin-9-like from Angiostrongylus cantonensis young adult worms modulates eosinophil chemotaxis in vitro. AB - BACKGROUND/PURPOSE: Eosinophils are recruited to the brain of mice after infection with Angiostrongylus canonensis. Several factors produced by infected mice are well known playing the role to chemoattract eosinophils from the blood into the brain. The purpose of this study is to investigate whether Angiostronylus cantonensis young-adult worms (AcYA) have components which have eosinophilic chemotactic activity. METHODS: Eosinophil chemotactic activity of AcYA was tested by Boyden blind-well chamber technique. The components of AcYA were analysed by SDS-PAGE and Mass spectrometry. Furthermore, galectin-9 in the cerebrospinal fluid (CSF) of infected mice and galectin-9-like in AcYA were measured by ELISA technic and also were recognized by western blot analysis respectively. RESULTS: Excretory-secretory products of AcYA did not show eosinophil chemotactic activity. However, the extracts of AcYA showed protein concentration-dependent eosinophil chemotactic activity and reached the peak at the 24 MUg/ml. The eosinophil chemotactic activity was significantly reduced by lactose. The components of AcYA at molecular weights of approximatively 15 kDa and 35 kDa showed several galectins component in Mass spectrometric analysis. Furthermore, galectin-9-like in AcYA was recognized by ELISA and western blot analysis. In parallel with increase of galectin-9 in the CSF, eosinophils were also significantly increased in mouse after infected with A. cantonensis. CONCLUSION: Galectin-9-like in AcYA and galectin-9 in mouse CSF were confirmed demonstrating eosinophil chemotactic activity both in vitro study and in the infection of mouse in this study. PMID- 30404741 TI - Age-related effects in compound production: Intact lexical representations but more effortful encoding. AB - The production of nominal compounds in the presence of morphological, semantic, and unrelated distractor words (picture-word interference paradigm) was investigated in young (M = 27 years) and older (M = 70.5 years) German speakers to test models of speech production and lexical representation. Constituent distractors of compound targets (lip or stick for the target LIPSTICK) speeded compound naming, while naming was slowed by distractors that were categorically related to the compound as a whole (powder -> LIPSTICK). Furthermore, no effects were obtained for distractors from the same category as the first constituent of compound targets in picture-naming latencies (toe -> LIPSTICK). These effects were present in both age groups and indicate that compounds are stored holistically at the lemma level, and as morphemes at the word-form level, unaffected by age. Main effects of age revealed overall slower picture naming and less accurate responses in the elderly. Furthermore, older speakers showed stronger morphological facilitation, while semantic distractor effects were unaffected by age. In a non-verbal attentional control task (Simon task), older speakers were slower overall and showed larger processing costs than young speakers in the conflict (incongruent) condition. Our data replicate a decline in non-verbal attentional control with age and also reveal slower and more error prone picture-naming in the elderly. These language-specific changes, however, seem to be independent from attentional control and are likely to result from less fluent morpho-phonological encoding in the elderly. PMID- 30404742 TI - Immunohematologic issues in ABO-incompatible allogeneic hematopoietic stem cell transplantation. AB - It is a conceptual paradox to perform allogeneic hematopoietic stem cell transplantations across the ABO blood group border, when we, on the other hand, put so much effort into preventing ABO-incompatible transfusions. In clinical practice though it is still controversial whether ABO-incompatible allogeneic hematopoietic stem cell transplant have detrimental effects on patient outcomes in view of overall survival, non-relapse mortality, and graft-versus-host disease. However, the number of ABO-incompatible transplantations will probably continue to increase, unless solid evidence about contraindications can be presented. In the meantime, all necessary measures to reduce the acute hemolysis risk have to be taken regarding graft manipulation and correct selection of ABO group blood components for transfusion. In addition the immunohematologic challenges dealing with gradual ABO group shift have to be handled. These puzzling but exciting issues are addressed briefly in this What's Happening manuscript. PMID- 30404743 TI - 2018 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation. AB - The Canadian Cardiovascular Society (CCS) Atrial Fibrillation Guidelines Committee provides periodic reviews of new data to produce focused updates that address clinically important advances in atrial fibrillation (AF) management. This 2018 Focused Update addresses: (1) anticoagulation in the context of cardioversion of AF; (2) the management of antithrombotic therapy for patients with AF in the context of coronary artery disease; (3) investigation and management of subclinical AF; (4) the use of antidotes for the reversal of non vitamin K antagonist oral anticoagulants; (5) acute pharmacological cardioversion of AF; (6) catheter ablation for AF, including patients with concomitant AF and heart failure; and (7) an integrated approach to the patient with AF and modifiable cardiovascular risk factors. The recommendations were developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) standards. Individual studies and literature were reviewed for quality and bias; the literature review process and evidence tables are included as Supplementary Material and are available on the CCS Web site. Details of the updated recommendations are presented, along with their background and rationale. This document is linked to an updated summary of all CCS AF guidelines recommendations, from 2010 to the present 2018 Focused Update, which is provided in the Supplementary Material. PMID- 30404744 TI - Targeted Therapeutic Drug Monitoring for Direct Oral Anticoagulants: What Is Its Potential Place and Can It Limit Black Swan Events? PMID- 30404745 TI - Age as a Critical Determinant of Atrial Fibrillation: A Two-sided Relationship. AB - The incidence of atrial fibrillation (AF), the most common sustained arrhythmia and a major public health burden, increases exponentially with age. However, mechanisms underlying this long-recognized association remain incompletely understood. Experimental and human studies have demonstrated the involvement of aging in several arrhythmogenic processes, including atrial electrical and structural remodelling, disturbed calcium homeostasis, and enhanced atrial ectopic activity/increased vulnerability to re-entry induction. Given this wide range of putative mechanisms, the task of delineating the specific effects of aging responsible for AF promotion is not simple, as aging is itself associated with increasing prevalence of a host of AF-predisposing conditions, including heart failure, coronary artery disease, and hypertension. Although we usually think of old age promoting AF, there is also evidence that young age may actually have a protective effect against AF occurrence. For example, the low AF incidence among populations of young patients with significant structural congenital heart disease and substantial atrial enlargement/remodelling suggests that younger age might protect against fibrillation in the diseased atrium; efforts at understating how younger age may prevent AF might be helpful in elucidating missing mechanistic links between AF and age. The goal of this paper is to review the epidemiologic and pathophysiologic evidence regarding mechanisms underlying age-related AF. Although the therapeutic options for AF have recently improved, major gaps still remain and a better understanding of the special relationship between age and AF may be important for the identification of new targets for therapeutic innovation. PMID- 30404746 TI - The Importance and Future of Population Screening for Atrial Fibrillation. AB - Atrial fibrillation (AF) is a common and progressive heart rhythm disorder that causes structural, functional, and electrical remodelling of the heart. Although we do not fully understand AF yet, this arrhythmia is one clinical feature of a syndrome that is represented by irregularly irregular atrial rhythm accompanied by progressive atrial structural and functional remodelling. Although ischemic stroke, the most feared complication of AF, can be prevented by anticoagulation, the asymptomatic or paroxysmal nature of AF makes timely diagnosis of AF difficult. Thus, appropriate screening method for AF is necessary. In this review, we will discuss the importance and future perspectives of population screening for AF. PMID- 30404747 TI - The Guideline-Policy Gap in Direct-Acting Oral Anticoagulants Usage in Atrial Fibrillation: Evidence, Practice, and Public Policy Considerations. AB - Atrial fibrillation has a high disease burden-both in prevalence and associated consequences. Despite anticoagulation being an effective treatment in atrial fibrillation, stroke prevention is slow to reflect evidence-based practice. Real world data reveal a substantial portion of patients who would benefit from anticoagulation, yet do not receive it adequately or at all. A large part of this suboptimal treatment is due to the underutilization of direct oral anticoagulants (DOACs). In response to abundant evidence published over a short timeframe, international guidelines have adopted DOAC usage ahead of policy and fund holders. This paper reviews the evidence and values that influence published guidelines, patient-physician decision making, and policy framework on DOAC usage. An important factor is the access gap between patients who qualify for DOAC according to evidence-based guidelines and the subset of this cohort who are eligible for DOAC based on government funded policy. We analyse the Canadian health system in detail-including drug approval and funding process. Health care systems in other countries are explored, with emphasis on similar universal health care systems that may help overcome barriers common to Canada. We will discuss strategies to: (1) improve awareness of the risk and preventability of stroke; (2) enable physicians to provide evidence-based DOAC usage; (3) empower patients to improve adherence and persistence; (4) collect real-life data that encourages patient self-monitoring, physician outcomes auditing, and building evidence that is useful for policy makers; and (5) use postmarketing data in negotiating shared risk management between pharmaceuticals and government to improve access to DOACs. PMID- 30404748 TI - Antithrombotic Therapy for Atrial Fibrillation and Coronary Disease Demystified. AB - Atrial fibrillation (AF) is a progressive chronic disease characterized by exacerbations and periods of remission. It is estimated that up to 20% to 30% of those with AF also have coronary artery disease (CAD), and 5% to 15% will require percutaneous coronary intervention (PCI). In patients with concomitant AF and CAD, management remains challenging and requires a careful and balanced assessment of the risk of bleeding against the anticipated impact on ischemic outcomes (AF-related stroke and systemic embolism, as well as ischemic coronary events). Oral anticoagulation (OAC) is indicated for the prevention of AF-related stroke and systemic embolism, whereas antiplatelet therapy is indicated for the prevention of coronary events. Each offers a relative efficacy benefit (dual antiplatelet therapy [DAPT] is more effective than OAC alone in reducing cardiovascular death, myocardial infarction, stent thrombosis, and ischemic coronary events in a population with acute coronary syndromes [ACS]), but with a relative compromise (DAPT is significantly inferior to OAC for the prevention of stroke/systemic embolism in an AF population at increased risk of stroke). The purpose of this review is to explore the current evidence and rationale for antithrombotic treatment strategies in patients with both AF and CAD. Specifically, there is a focus on how to best tailor the therapeutic choices (OAC and antiplatelet therapy) to individual patients based on their underlying coronary presentation. PMID- 30404749 TI - Atrial Fibrillation and Heart Failure: Untangling a Modern Gordian Knot. AB - Heart failure (HF) and atrial fibrillation (AF) share common risk factors and frequently coexist. Both are highly prevalent in our aging population, and mortality associated with the combination is significantly higher than for each alone. An intricate link exists between AF and HF, including interrelated mechanisms and pathophysiology. Asymptomatic left ventricular systolic or diastolic dysfunction can exacerbate or be exacerbated by AF, resulting in HF with reduced ejection fraction or preserved ejection fraction. A number of treatment strategies have improved symptoms, exercise tolerance, and quality of life for patients with HF, but few have resulted in alteration in prognosis. Sinus rhythm, achieved pharmacologically, has not altered important outcomes, including cardiovascular or total mortality in patients with HF. In recent studies, catheter ablation to achieve sinus rhythm seems to have a significant impact on symptoms, heart function, and possibly mortality. Until future studies can confirm or clarify the impact of catheter ablation on outcomes, the field remains cautious but optimistic that better treatment strategies for patients with HF with reduced ejection fraction or preserved ejection fraction are within reach. PMID- 30404750 TI - Mechanisms and Clinical Significance of Arrhythmia-Induced Cardiomyopathy. AB - Arrhythmia-induced cardiomyopathy (AIC) is characterized by left ventricular systolic dysfunction for which the primary cause is arrhythmia. The hallmark of AIC is its reversibility once the arrhythmia is properly controlled. Any tachyarrhythmia can potentially cause AIC (often called "tachycardiomyopathy"), with atrial fibrillation (AF) being by far the most common in clinical practice. The pathophysiological mechanisms underlying AIC need further clarification, but the available evidence, principally from animal models, implicates metabolic dysfunction due to increased oxygen requirements, neurohormonal adaptive mechanisms, and cellular Ca2+ mishandling as important contributors. Tachycardia is a common denominator of most cases of AIC, but other components specific to the patient and the arrhythmia have been implicated. The diagnosis of AIC requires the exclusion of a primary causative role of other conditions such as hypertension, primary cardiomyopathies, and valve disease, which may require specific pharmacological and invasive therapies. Catheter ablation is emerging as a safe and effective alternative to antiarrhythmic medication and has an established role in the management of AIC. Recent studies showing improved cardiac function and mortality rates in patients with heart failure and concomitant AF dramatically illustrate the often-unrecognized scope of AIC and the potential benefits of interventional therapy. Major AF trials do not otherwise focus specifically on AIC, and careful analysis of the literature is necessary to appreciate the clinical characteristics and therapeutic implications. This contemporary review summarizes the current understanding of pathophysiological mechanisms underlying AIC, discusses the clinical implications, and offers a general approach to management, with a particular focus on AF-induced cardiomyopathy. PMID- 30404751 TI - Persistent Atrial Fibrillation Ablation: Where Do We Go From Here? AB - Catheter ablation is being used increasingly for the treatment of atrial fibrillation (AF). Pulmonary vein antral isolation is considered the "cornerstone" for the ablation of AF. This approach has demonstrated consistent rates of success for paroxysmal AF, but the rates of success for persistent AF are lower. There has long been a hypothesis that additional ablation beyond pulmonary vein isolation is required to achieve better outcomes in the population with persistent AF. However, large clinical trials have demonstrated recently that such approaches as empiric linear ablation and/or ablation of complex fractionated electrograms may add no benefit over pulmonary vein isolation alone in persistent AF. Furthermore, new technologies are improving the durability and outcome of pulmonary vein isolation alone. These observations have endorsed a search for new potential targets for adjuvant ablation, which currently include ablation of dynamic phenomena during AF such as rotational and focal activations, ablation of scar regions in the atria, isolation of the left atrial posterior wall, and ablation of nonpulmonary vein triggers. Whether any of these additional approaches will add to the success of ablation for persistent AF is unknown. Smaller study results are mixed. Only the performance of large-scale randomized trials will definitively answer whether additional ablation over pulmonary vein isolation alone with improve outcomes for persistent AF. PMID- 30404752 TI - Data Linking Diabetes Mellitus and Atrial Fibrillation-How Strong Is the Evidence? From Epidemiology and Pathophysiology to Therapeutic Implications. AB - According to estimates, around 5% of the world population has hazel eyes. And there are about as many people with diabetes mellitus (DM). Red hair occurs naturally in up to 2% of the human population. And about as many people are estimated to have atrial fibrillation (AF). If a hazel eyed person with red hair does not surprise us, should a diabetic patient with AF? Accumulating epidemiologic data suggest, however, that the DM-AF association may be more than a simple coincidence. But, how strong is this evidence? Experimental studies bring evidence for a DM-induced atrial proarrhythmic remodelling. But how relevant are these data for the clinical setting? In this review, we aim to provide a critical analysis of the existing clinical and experimental, epidemiologic, and mechanistic data that bridge DM and AF, we emphasize a number of questions that remain to be answered, and we identify hotspots for future research. The therapeutic implications of the DM-AF coexistence are also discussed, with a focus on rhythm control and on conventional and DM-specific upstream therapies for AF management. PMID- 30404753 TI - The Multiple Causes of Stroke in Atrial Fibrillation: Thinking Broadly. AB - Atrial fibrillation (AF) is numerically the most important risk factor for stroke. It is well established that patients with AF have a 5-fold increased risk of stroke relative to those without and that anticoagulation reduces the risk of stroke by approximately two-thirds. Definitively attributing the mechanism of an individual stroke to AF is more problematic, however. In fact, there is no way to reliably establish the etiology of any ischemic infarction. This necessitates screening for all potential stroke risk factors and treating accordingly. The pattern of infarction is often used to classify the presumed mechanism of infarction as thrombotic or embolic, although even this is approach is based on association and increasingly is recognized as not completely reliable. Furthermore, it should not dictate management-patients with perforating arterial territory infarcts with AF also require and benefit from anticoagulation. Likewise, if other potential embolic sources beyond AF are identified, anticoagulation remains the standard of care. The traditional conceptual model of the mechanistic link between AF and cardioembolic infarction is likely oversimplified. Long-term cardiac rhythm recording studies indicate an inconsistent temporal relationship between AF and infarction. This suggests that cardioembolic stroke in patients with AF may result from the underlying atrial cardiopathy, rather than the rhythm disturbance leading to atrial stasis and thromboembolism. We reviewed traditional and current concepts, as well as evidence for the role of AF in ischemic stroke. PMID- 30404754 TI - The Impact of Cardiac Rehabilitation on Mental and Physical Health in Patients With Atrial Fibrillation: A Matched Case-Control Study. AB - BACKGROUND: Patients with atrial fibrillation (AF) experience symptom burden, exercise intolerance, weight gain, poor mental health, and diminished quality of life (QoL). Cardiac rehabilitation (CR) is recommended for patients with heart disease, and its benefits are well established, yet clinical guidelines for patients with AF do not include the referral to CR. METHODS: In this matched retrospective, case-control study, we examined the impact of CR on changes in QoL, mental health, and cardiometabolic health indicators in patients with or without persistent or permanent AF. Patients attended CR that addressed risk factor management and provided support services and exercise training twice weekly for 3 months. Height, body mass, waist circumference, blood pressure, and heart rate were measured, and the Short Form-36 and Hospital Anxiety and Depression Scale were administered at baseline and 3 months follow-up. RESULTS: A total of 94 patients (AF, n = 47; no AF, n = 47) (aged 70 +/- 8 years) participated. Significant improvements in 2 of the 8 subscales and the Physical Component Summary of the Short Form-36 were observed across groups after CR (P < 0.05). Significant interactions revealed that the effect of CR was greater for energy, emotional well-being, social functioning, pain, and the Physical Component Summary in patients without AF (P < 0.05 for each). No significant improvements in anxiety (AF: -1.3 +/- 3.4; no AF: -1.3 +/- 4.3), depression (AF: 1.1 +/- 2.9; no AF: -0.4 +/- 2.7), body mass index (AF: -0.5 +/- 1.2; no AF: -0.8 +/- 1.5, kg/m2), waist circumference (AF: -1.7 +/- 4.6; no AF: 0.4 +/- 8.1, cm), or blood pressure (AF: -2.3 +/- 17.1/-3.9 +/- /9.3; no AF: 1.8 +/- 16.4/-0.8 +/- /9.3 mm Hg) were observed across groups after CR. CONCLUSIONS: CR improved QoL to a greater extent in patients with heart disease without than with persistent or permanent AF. PMID- 30404755 TI - Taking the Pulse of Atrial Fibrillation: A Practical Approach to Rate Control. AB - Despite major advances in atrial fibrillation (AF) catheter ablation, rate control remains the most widely used management strategy for AF in the general population. In addition to its use as a primary approach to control symptoms and prevent complications of AF, rate control is often a necessary complement to rhythm-control strategies, especially with antiarrhythmic drugs. The value of rate-control therapy is supported by several large randomized clinical trials showing no difference in major cardiovascular outcomes between rate-control and rhythm-control strategies with currently available therapeutic approaches (antiarrhythmic drugs and/or catheter ablation). Despite its extensive use, the rational basis for rate-control therapy is underemphasized in clinical teaching and practice. In this article, we aim to provide evidence-based thoughts on important practical aspects of rate-control therapy in AF by reviewing 5 clinically relevant issues. We (1) highlight the pharmacological differences between the mechanisms of action of beta-blockers and Ca2+-channel blockers for AF rate control and the practical implications for therapeutic decision making; (2) review the controversies surrounding the use of digoxin for AF rate control in the light of recently published work; (3) discuss the evidence for rate control heart rate targets in patients with AF and preserved left-ventricular function; (4) examine how heart rate targets may differ in patients with heart failure and reduced vs preserved left-ventricular ejection fraction and the importance of heart-rate lowering for the effectiveness of cardiac resynchronization therapy in patients with heart failure and AF; (5) discuss the relationship between AF, exercise capacity, and rate-controlling drug class. PMID- 30404756 TI - Insights on Atrial Fibrillation in Congenital Heart Disease. AB - Patients with congenital heart disease (CHD) have been surviving late into adulthood, with atrial arrhythmias being the most common long-term complication. In recent reports, atrial fibrillation (AF) tended to be the most common form of arrhythmias among groups of patients with adult CHD (ACHD) older than 50 years of age. When compared with their adult counterparts without CHD, AF in patients with ACHD has been characterized by a higher incidence and prevalence, younger age of onset, and a greater risk of progression to persistent AF. Risk factors for the development of AF are not well known but include older age, left atrial dilation, systemic hypertension, and multiple cardiac surgeries. Data on management options such as optimal antiarrhythmic drug therapy, indications for anticoagulation, and efficacy and safety of catheter ablation are limited. There is a crucial need for further research exploring management, prevention, and monitoring strategies for the growing ACHD patient population with AF. This report will provide a contemporary review of the epidemiology, pathophysiology, and management options for AF in this complex patient population. PMID- 30404757 TI - Managing Direct Oral Anticoagulants in Patients With Antiepileptic Medication. AB - Current guidance recommends avoiding concomitant use of direct-acting oral anticoagulants and enzyme-inducing antiepileptic drugs because of theoretical drug interactions potentially leading to subtherapeutic drug concentrations and treatment failure. We describe a case documenting a significant interaction between phenobarbital and rivaroxaban, and then apixaban. This case illustrates and supports the concerns regarding concomitant use of these medications. Additionally, in this case the interaction was managed with concentration-guided dosing of apixaban, suggesting this approach may represent a feasible strategy for managing patients requiring treatment with direct-acting oral anticoagulants and enzyme-inducing antiepileptic drugs. PMID- 30404758 TI - Even judges are CSI fans. PMID- 30404760 TI - Effectiveness and Complications of the AMS AdVanceTM Male Sling System for the Treatment of Stress Urinary Incontinence: A Prospective Multicenter Study. AB - OBJECTIVE: To evaluate the effectiveness and tolerance of the AdVance Male Sling System for the treatment of male stress urinary incontinence in patients after prostatic surgery. METHODS: An international, observational, prospective, multicenter study was conducted on male patients with urinary incontinence after prostatic surgery. Patients underwent a 24-hour pad test with a threshold at 250 g. All patients were operated with the same AdVance implant procedure. They were seen 6 weeks later, and examined again at 3, 6, 12, and 24 months. Incontinence was measured using 1-hour and 24-hour pad tests, the number of protective pads used, ICIQ-SF and IQoL questionnaires. Success was defined as no urinary leakage and no pad use. Patient improvement was defined as a reduction of more than 50% in leakage and no more than one pad used per day. Any perioperative and late complications were documented. RESULTS: From January 2007 to November 2012, 113 patients were successfully operated on. At 24 months after surgery, the mean weight of the 1-hour pad test had decreased from 48.7 g to 6.6 g (P < 0.001) while that of the 24-hour pad test decreased to 45.0 g from 113.9 g (P < 0.001). Success and improvement occurred in 22.6% and 58.0% of the patients, respectively. Seventy-five patients (80.6%) used none or one protective pad daily, and the IQoL and ICIQ-SF scores were both significantly improved. Fourteen patients (12.4%) required a second intervention. Three patients (2.7%) had a Clavien IIIb complication. CONCLUSION: The AdVance Male Sling System is an effective treatment for mild to moderate male stress urinary incontinence. Complications from its use are rare and 24-month results are satisfactory. PMID- 30404762 TI - More unaffected first-degree relatives of essential tremor cases have mild cognitive deficits than age-matched controls. AB - BACKGROUND: In numerous case-control studies, essential tremor (ET) has been associated with cognitive impairment. ET is often familial. However, cognitive impairment has not been studied in family members of ET cases. Endophenotypes are measurable clinical characteristics that may be present in individuals with increased risk for disease; as such, they may be present before disease onset. We administered a global cognitive screen to first-degree relatives of ET cases (FD ET) and age-matched controls (Co). METHODS: We administered the Montreal Cognitive Assessment (MoCA) to 156 FD-ET and 73 Co, none of whom were diagnosed with ET or reported tremor. MoCA <26 was considered suggestive of cognitive impairment. RESULTS: FD-ET and Co were similar with respect to age (60.1 +/- 8.3 vs. 60.9 +/- 7.4 years) and numerous demographic factors. FD-ET and Co also had similar MoCA scores; however, 34 of 156 (21.8%) FD-ET had a MoCA score <26 vs only 5 (6.9%) of 73 Co (p = 0.004). In a univariate logistic regression model, FD ET were 3.79 times more likely to have a low (<26) MoCA than were Co (odds ratio = 3.79, p = 0.008). In a multivariate logistic regression model, adjusting for age and other covariates, FD-ET were 4.83 times more likely to have a low MoCA than were Co (odds ratio = 4.83, p = 0.003). CONCLUSION: More FD-ET had low MoCA scores when compared with Co. These data provide additional support for the scientific notions that (1) cognitive difficulties are a disease-associated feature of ET and (2) there may be a pre-tremor phase of illness in ET. PMID- 30404763 TI - The key role of T cells in Parkinson's disease pathogenesis and therapy. AB - This review focuses on the role of T lymphocytes in the pathogenesis of Parkinson's disease and highlights evidence for modulation of the T cell response as an effective neuroprotective strategy. In preclinical models of Parkinson's disease, modulation of the T cell response results in neuroprotection. Peripheral markers of T cell response show changes in Parkinson's patients relative to controls that have potential application as diagnostic and therapeutic biomarkers. The article also discusses the important immunomodulatory effects of dopamine which may confound study of T cells in patients on dopaminergic therapies, and highlights glatiramer acetate, an FDA-approved therapy for multiple sclerosis that works through modulating the T cell response, as a promising target for translation. PMID- 30404764 TI - Efficacy and Cardiotoxic Safety Profile of Raltitrexed in Fluoropyrimidines Pretreated or High-Risk Cardiac Patients With GI Malignancies: Large Single Center Experience. AB - BACKGROUND: Gastrointestinal (GI) cancer patients may not be considered for therapy with fluoropyrimidines (FPs) because of previous cardiovascular (CV) toxicity or preexisting risk factors; such patients may benefit from raltitrexed based therapy. PATIENTS AND METHODS: Patient, tumor, and treatment characteristics, as well as clinical outcomes of all consecutively treated patients with raltitrexed at the Royal Marsden Hospital between October 1998 and July 2011 were examined. GI cancer patients who developed CV toxicity as a result of FPs and those with significant CV risk factors receiving raltitrexed were included in this analysis. RESULTS: A total of 247 patients (155 and 92 with CV FP-related CV toxicities and significant CV risk factors, respectively) treated with raltitrexed alone or in combination were examined after a median follow-up of 47.1 months. CV toxicity profiles of patients receiving capecitabine (n = 110) and 5-fluorouracil (n = 45) were largely similar. Of raltitrexed-treated patients, 13 (5%) experienced CV toxicities and 1 (< 0.1%) died as a result of myocardial infarction. The median progression-free survival (PFS) and overall survival (OS) were 36.0 months (95% confidence interval [CI], 26.5-48.6) and 44.3 months (95% CI, 33.1-56.8), respectively. The 5-year survival for early stage GI malignancies (n = 140) was 62.0% (95% CI, 50.1-71.9). Median PFS and OS were not reached in this group (interquartile range = 38.4 months to NR); median PFS and OS for advanced GI malignancies (n = 107) were 18.8 (95% CI, 11.9-25.7) and 23.7 months (95% CI, 17.0-26.9), respectively. CONCLUSION: A raltitrexed-based regimen is well-tolerated therapy with comparable efficacy to FPs in patients with GI malignancies with significant CV toxicities or risk factors. PMID- 30404765 TI - A multiscale kinetics model for the analysis of starch amylolysis. AB - Simple exponential decaying functions are commonly used for fitting the kinetics of starch digested by amylolytic enzymes. A common assumption is that a sole exponential function can account for the kinetics of the whole digestible starch. Recent studies using logarithm-of-slope (LOS) plots showed that digestion kinetics can exhibit multi-scale behavior, an effect reflecting starch fractions with different digestion characteristics. This work proposed an extension of the widely used Goni et al.'s model to account for two starch fractions; one fraction linked with fast digestion rate and other with slow digestion rates. The fitting of experimental data was carried out by solving numerically a nonlinear least squares problem. The estimated parameters have a straightforward interpretation in terms of reaction rates and digestible/resistant starch fractions. Two experimental examples were used for illustrating the performance of the multi exponential function. PMID- 30404766 TI - Relations Between the Use of Electronic Health and the Use of General Practitioner and Somatic Specialist Visits in Patients With Type 1 Diabetes: Cross-Sectional Study. AB - BACKGROUND: The prevalence of diabetes and the use of electronic health (eHealth) are increasing. People with diabetes need frequent monitoring and follow-up of health parameters, and eHealth services can be of great value. However, little is known about the association between the use of eHealth and provider-based health care services among people with diabetes. OBJECTIVE: The objective of this study was to investigate the use of 4 different eHealth platforms (apps, search engines, video services, and social media sites) and associations with the use of provider-based health care visits among people diagnosed with type 1 diabetes mellitus (T1DM). METHODS: We used email survey data collected from 1250 members of the Norwegian Diabetes Association (aged 18 to 89 years) in 2018. Eligible for analyses were the 523 respondents with T1DM. Using descriptive statistics, we estimated the use of eHealth and the use of general practitioners (GPs) and somatic specialist outpatient services. By logistic regressions, we studied the associations between the use of these provider-based health services and the use of eHealth, adjusted for gender, age, education, and self-rated health. RESULTS: Of the sample of 523 people with T1DM, 90.7% (441/486) had visited a GP once or more, and 61.0% (289/474) had visited specialist services during the previous year. Internet search engines (such as Google) were used for health purposes sometimes or often by 84.0% (431/513), apps by 55.4% (285/514), social media (such as Facebook) by 45.2% (232/513), and video services (such as YouTube) by 23.3% (118/506). Participants aged from 18 to 39 years used all forms of eHealth more than people aged 40 years and older, with the exception of social media. The use of search engines was positively associated with the use of somatic specialist services (odds ratio 2.43, 95% CI 1.33-4.45). GP visits were not associated with any kind of eHealth use. CONCLUSIONS: eHealth services are now widely used for health support and health information by people with T1DM, primarily in the form of search engines but often in the form of apps and social media as well. We found a positive association between the use of search engines and specialist visits and that people with T1DM are frequent users of eHealth, GPs, and specialist services. We found no evidence that eHealth reduces the use of provider-based health care; these services seem to be additional rather than alternative. Future research should focus on how health care services can meet and adapt to the high prevalence of eHealth use. Our results also indicate that many patients with T1DM do not visit specialist clinics once a year as recommended. This raises questions about collaboration in health care services and needs to be followed up in future research. PMID- 30404767 TI - Automated Extraction of Diagnostic Criteria From Electronic Health Records for Autism Spectrum Disorders: Development, Evaluation, and Application. AB - BACKGROUND: Electronic health records (EHRs) bring many opportunities for information utilization. One such use is the surveillance conducted by the Centers for Disease Control and Prevention to track cases of autism spectrum disorder (ASD). This process currently comprises manual collection and review of EHRs of 4- and 8-year old children in 11 US states for the presence of ASD criteria. The work is time-consuming and expensive. OBJECTIVE: Our objective was to automatically extract from EHRs the description of behaviors noted by the clinicians in evidence of the diagnostic criteria in the Diagnostic and Statistical Manual of Mental Disorders (DSM). Previously, we reported on the classification of entire EHRs as ASD or not. In this work, we focus on the extraction of individual expressions of the different ASD criteria in the text. We intend to facilitate large-scale surveillance efforts for ASD and support analysis of changes over time as well as enable integration with other relevant data. METHODS: We developed a natural language processing (NLP) parser to extract expressions of 12 DSM criteria using 104 patterns and 92 lexicons (1787 terms). The parser is rule-based to enable precise extraction of the entities from the text. The entities themselves are encompassed in the EHRs as very diverse expressions of the diagnostic criteria written by different people at different times (clinicians, speech pathologists, among others). Due to the sparsity of the data, a rule-based approach is best suited until larger datasets can be generated for machine learning algorithms. RESULTS: We evaluated our rule-based parser and compared it with a machine learning baseline (decision tree). Using a test set of 6636 sentences (50 EHRs), we found that our parser achieved 76% precision, 43% recall (ie, sensitivity), and >99% specificity for criterion extraction. The performance was better for the rule-based approach than for the machine learning baseline (60% precision and 30% recall). For some individual criteria, precision was as high as 97% and recall 57%. Since precision was very high, we were assured that criteria were rarely assigned incorrectly, and our numbers presented a lower bound of their presence in EHRs. We then conducted a case study and parsed 4480 new EHRs covering 10 years of surveillance records from the Arizona Developmental Disabilities Surveillance Program. The social criteria (A1 criteria) showed the biggest change over the years. The communication criteria (A2 criteria) did not distinguish the ASD from the non-ASD records. Among behaviors and interests criteria (A3 criteria), 1 (A3b) was present with much greater frequency in the ASD than in the non-ASD EHRs. CONCLUSIONS: Our results demonstrate that NLP can support large-scale analysis useful for ASD surveillance and research. In the future, we intend to facilitate detailed analysis and integration of national datasets. PMID- 30404768 TI - A Tool to Measure Young Adults' Food Intake: Design and Development of an Australian Database of Foods for the Eat and Track Smartphone App. AB - BACKGROUND: Dietary assessment is reliant on the collection of accurate food and beverage consumption data. Technology has been harnessed to standardize recording and provide automatic nutritional analysis to reduce cost and researcher burden. OBJECTIVE: To better assess the diet of young adults, especially relating to the contribution of foods prepared outside the home, a database was needed to support a mobile phone data collection app. The app also required usability testing to assure ease of entry of foods and beverages. This paper describes the development of the Eat and Track app (EaT app) and the database underpinning it. METHODS: The Australian Food and Nutrient Database 2011-13, consisting of 5740 food items was modified. Four steps were undertaken: (1) foods not consumed by young adults were removed, (2) nutritionally similar foods were merged, (3) foods available from the 30 largest ready-to-eat food chains in Australia were added, and (4) long generic food names were shortened and simplified. This database was used to underpin the EaT app. Qualitative, iterative usability testing of the EaT app was conducted in three phases using the "Think Aloud" method. Responses were sorted and coded using content analysis. The System Usability Scale (SUS) was administered to measure the EaT app's perceived usability. RESULTS: In total, 1694 (29.51%) foods were removed from the Australian Food and Nutrient Database, including 608 (35.89%) ingredients, 81 (4.78%) foods already captured in the fast food chain information, 52 (3.07%) indigenous foods, 25 (1.48%) nutrients/dietary supplements, and 16 (0.94%) child-specific foods. The remaining 912 (53.84%) foods removed were not consumed by young adults in previous surveys or were "not defined" in the Australian Food and Nutrient Database. Another 220 (3.83%) nutritionally similar foods were combined. The final database consisted of 6274 foods. Fifteen participants completed usability testing. Issues identified by participants fell under six themes: keywords for searching, history list of entered foods, amounts and units, the keypad, food names, and search function. Suggestions for improvement were collected, incorporated, and tested in each iteration of the app. The SUS of the final version of the EaT app was rated 69. CONCLUSIONS: A food and beverage database has been developed to underpin the EaT app, enabling data collection on the eating-out habits of 18- to 30-year-old Australians. The development process has resulted in a database with commonly used food names, extensive coverage of foods from ready-to-eat chains, and commonly eaten portion sizes. Feedback from app usability testing led to enhanced keyword searching and the addition of functions to enhance usability such as adding brief instructional screens. There is potential for the features of the EaT app to facilitate the collection of more accurate dietary intake data. The database and the app will be valuable dietary assessment resources for researchers. PMID- 30404769 TI - Patterns of Patients' Interactions With a Health Care Organization and Their Impacts on Health Quality Measurements: Protocol for a Retrospective Cohort Study. AB - BACKGROUND: Data collected by health care organizations consist of medical information and documentation of interactions with patients through different communication channels. This enables the health care organization to measure various features of its performance such as activity, efficiency, adherence to a treatment, and different quality indicators. This information can be linked to sociodemographic, clinical, and communication data with the health care providers and administrative teams. Analyzing all these measurements together may provide insights into the different types of patient behaviors or more accurately to the different types of interactions patients have with the health care organizations. OBJECTIVE: The primary aim of this study is to characterize usage profiles of the available communication channels with the health care organization. The main objective is to suggest new ways to encourage the usage of the most appropriate communication channel based on the patient's profile. The first hypothesis is that the patient's follow-up and clinical outcomes are influenced by the patient's preferred communication channels with the health care organization. The second hypothesis is that the adoption of newly introduced communication channels between the patient and the health care organization is influenced by the patient's sociodemographic or clinical profile. The third hypothesis is that the introduction of a new communication channel influences the usage of existing communication channels. METHODS: All relevant data will be extracted from the Clalit Health Services data warehouse, the largest health care management organization in Israel. Data analysis process will use data mining approach as a process of discovering new knowledge and dealing with processing data extracted with statistical methods, machine learning algorithms, and information visualization tools. More specifically, we will mainly use the k-means clustering algorithm for discretization purposes and patients' profile building, a hierarchical clustering algorithm, and heat maps for generating a visualization of the different communication profiles. In addition, patients' interviews will be conducted to complement the information drawn from the data analysis phase with the aim of suggesting ways to optimize existing communication flows. RESULTS: The project was funded in 2016. Data analysis is currently under way and the results are expected to be submitted for publication in 2019. Identification of patient profiles will allow the health care organization to improve its accessibility to patients and their engagement, which in turn will achieve a better treatment adherence, quality of care, and patient experience. CONCLUSIONS: Defining solutions to increase patient accessibility to health care organization by matching the communication channels to the patient's profile and to change the health care organization's communication with the patient to a highly proactive one will increase the patient's engagement according to his or her profile. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/10734. PMID- 30404770 TI - Implementations of Virtual Reality for Anxiety-Related Disorders: Systematic Review. AB - BACKGROUND: Although traditional forms of therapy for anxiety-related disorders (eg, cognitive behavioral therapy, CBT) have been effective, there have been long standing issues with these therapies that largely center around the costs and risks associated with the components comprising the therapeutic process. To treat certain types of specific phobias, sessions may need to be held in public, therefore risking patient confidentiality and the occurrence of uncontrollable circumstances (eg, weather and bystander behavior) or additional expenses such as travel to reach a destination. To address these issues, past studies have implemented virtual reality (VR) technologies for virtual reality exposure therapy (VRET) to provide an immersive, interactive experience that can be conducted privately and inexpensively. The versatility of VR allows various environments and scenarios to be generated while giving therapists control over variables that would otherwise be impossible in a natural setting. Although the outcomes from these studies have been generally positive despite the limitations of legacy VR systems, it is necessary to review these studies to identify how modern VR systems can and should improve to treat disorders in which anxiety is a key symptom, including specific phobias, posttraumatic stress disorder and acute stress disorder, generalized anxiety disorder, and paranoid ideations. OBJECTIVE: The aim of this review was to establish the efficacy of VR-based treatment for anxiety-related disorders as well as to outline how modern VR systems need to address the shortcomings of legacy VR systems. METHODS: A systematic search was conducted for any VR-related, peer-reviewed articles focused on the treatment or assessment of anxiety-based disorders published before August 31, 2017, within the ProQuest Central, PsycINFO, and PsycARTICLES databases. References from these articles were also evaluated. RESULTS: A total of 49 studies met the inclusion criteria from an initial pool of 2419 studies. These studies were a mix of case studies focused solely on VRET, experimental studies comparing the efficacy of VRET with various forms of CBT (eg, in vivo exposure, imaginal exposure, and exposure group therapy), and studies evaluating the usefulness of VR technology as a diagnostic tool for paranoid ideations. The majority of studies reported positive findings in favor of VRET despite the VR technology's limitations. CONCLUSIONS: Although past studies have demonstrated promising and emerging efficacy for the use of VR as a treatment and diagnostic tool for anxiety-related disorders, it is clear that VR technology as a whole needs to improve to provide a completely immersive and interactive experience that is capable of blurring the lines between the real and virtual world. PMID- 30404772 TI - Use of Grading of Recommendations, Assessment, Development, and Evaluation to Combat Fake News: A Case Study of Influenza Vaccination in Pregnancy. AB - BACKGROUND: The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework is a validated evaluation tool used to assess the quality of scientific publications. It helps in enhancing clinicians' decision making process and supports production of informed healthy policy. OBJECTIVE: The purpose of this report was two-fold. First, we reviewed the interpretation of observational studies. The second purpose was to share or provide an example using the GRADE criteria. METHODS: To illustrate the use of the GRADE framework to assess publications, we selected a study evaluating the risk of spontaneous abortion (SAB) after influenza vaccine administration. RESULTS: Since 2004, the Centers for Disease Control and Prevention and the Advisory Committee on Immunization Practice have recommended influenza vaccination of pregnant women. Previous studies have not found an association between influenza vaccination and SAB. However, in a recent case-control study by Donahue et al, a correlation with SAB in women who received the H1N1 influenza vaccine was identified. For women who received H1N1-containing vaccine in the previous and current influenza season, the adjusted odds ratio (aOR) for SAB was 7.7 (95% CI, 2.2-27.3), while the aOR for women not vaccinated in the previous season but vaccinated in the current season was 1.3 (95% CI, 0.7-2.7). CONCLUSIONS: Our goal is to enable the readers to critique published literature using appropriate evaluation tools such as GRADE. PMID- 30404773 TI - Health Care Professionals' Social Media Behavior and the Underlying Factors of Social Media Adoption and Use: Quantitative Study. AB - BACKGROUND: In the last decade, social media has emerged as a newer platform for knowledge dissemination, information exchange, and interpersonal communication for health care professionals (HCPs). However, the underlying behaviors of HCPs and the ethical use of social media for productivity enhancement and a sustainable health care system remain ambiguous. OBJECTIVE: This study seeks to understand the factors that relate to the frequency use of social media in the health care discipline. It also aims to explore the underlying online behaviors of HCPs, which include the exchange of medical information with peers, interpersonal communication, and productivity enhancement in their daily practice. METHODS: This study adopted the quantitative method in collecting and analyzing data. A survey instrument based on the behavioral and technology acceptance theories was developed for this purpose. The survey was distributed via social media platforms to 973 participants that included physicians, pharmacists, and allied HCPs working in the United Arab Emirates. The responses from 203 completed questionnaires (response rate 20.3%) were analyzed. RESULTS: Of 203 respondents, 133 HCPs used WhatsApp (65.5%); therefore, WhatsApp had the highest number of users compared to Facebook and YouTube, with 101 users out of 203 (49.7%). Overall, 109 of 203 (53.6%) HCPs used social media platforms for the exchange of peer medical information and 108 of 203 (53.2%) used social media several times during the day to improve their interpersonal communication with colleagues. However, only 71 of 203 (34.9%) utilized social media to enhance their productivity in general. The structural model equation showed that behavioral intention (beta=.47; P<.001), habit (beta=.26; P=.001), attitude (beta=.20; P=.002), and perceived usefulness (beta=.12; P=.09) were positively and significantly related to frequency of use. The model explained a rate of 45% variance in the frequency of use and a rate of 17% variance in the social media intention of use. CONCLUSIONS: The research highlights the significant factors that relate to the adoption of social media platforms in health care practice. Based on the findings of this study, the use of online platforms facilitates the exchange of medical information among peers and enhances the share of experiences that support HCP's learning and development. Moreover, social media platforms foster a higher level of communication among practitioners and might improve daily productivity. Future researchers might explore other variables such as training and external factors. For instance, they may draw on areas related to guidelines and policies. From this standpoint, the health care discipline can benefit from highly interactive platforms and adopt them for development, collaboration, and better health outcomes. PMID- 30404771 TI - Dual Use of a Patient Portal and Clinical Video Telehealth by Veterans with Mental Health Diagnoses: Retrospective, Cross-Sectional Analysis. AB - BACKGROUND: Access to mental health care is challenging. The Veterans Health Administration (VHA) has been addressing these challenges through technological innovations including the implementation of Clinical Video Telehealth, two-way interactive and synchronous videoconferencing between a provider and a patient, and an electronic patient portal and personal health record, My HealtheVet. OBJECTIVE: This study aimed to describe early adoption and use of My HealtheVet and Clinical Video Telehealth among VHA users with mental health diagnoses. METHODS: We conducted a retrospective, cross-sectional analysis of early My HealtheVet adoption and Clinical Video Telehealth engagement among veterans with one or more mental health diagnoses who were VHA users from 2007 to 2012. We categorized veterans into four electronic health (eHealth) technology use groups: My HealtheVet only, Clinical Video Telehealth only, dual users who used both, and nonusers of either. We examined demographic characteristics and mental health diagnoses by group. We explored My HealtheVet feature use among My HealtheVet adopters. We then explored predictors of My HealtheVet adoption, Clinical Video Telehealth engagement, and dual use using multivariate logistic regression. RESULTS: Among 2.17 million veterans with one or more mental health diagnoses, 1.51% (32,723/2,171,325) were dual users, and 71.72% (1,557,218/2,171,325) were nonusers of both My HealtheVet and Clinical Video Telehealth. African American and Latino patients were significantly less likely to engage in Clinical Video Telehealth or use My HealtheVet compared with white patients. Low-income patients who met the criteria for free care were significantly less likely to be My HealtheVet or dual users than those who did not. The odds of Clinical Video Telehealth engagement and dual use decreased with increasing age. Women were more likely than men to be My HealtheVet or dual users but less likely than men to be Clinical Video Telehealth users. Patients with schizophrenia or schizoaffective disorder were significantly less likely to be My HealtheVet or dual users than those with other mental health diagnoses (odds ratio, OR 0.50, CI 0.47-0.53 and OR 0.75, CI 0.69-0.80, respectively). Dual users were younger (53.08 years, SD 13.7, vs 60.11 years, SD 15.83), more likely to be white, and less likely to be low-income than the overall cohort. Although rural patients had 17% lower odds of My HealtheVet adoption compared with urban patients (OR 0.83, 95% CI 0.80-0.87), they were substantially more likely than their urban counterparts to engage in Clinical Video Telehealth and dual use (OR 2.45, 95% CI 1.95-3.09 for Clinical Video Telehealth and OR 2.11, 95% CI 1.81-2.47 for dual use). CONCLUSIONS: During this study (2007-2012), use of these technologies was low, leaving much potential for growth. There were sociodemographic disparities in access to My HealtheVet and Clinical Video Telehealth and in dual use of these technologies. There was also variation based on types of mental health diagnosis. More research is needed to ensure that these and other patient-facing eHealth technologies are accessible and effectively used by all vulnerable patients. PMID- 30404774 TI - Functional Analysis of a Putative Target of Spatially Varying Selection in the Menin1 Gene of Drosophila melanogaster. AB - While significant effort has been devoted to investigating the potential influence of spatially varying selection on genomic variation, relatively little effort has been devoted to experimental analysis of putative variants or genes experiencing such selection. Previous population genetic work identified an amino acid polymorphism in the Mnn1 gene as one of the most strongly latitudinally differentiated SNPs in the genome of Drosophila melanogaster in the United States and Australia. Here we report the results of our transgenic analysis of this amino acid polymorphism. Genotypes carrying alternative Mnn1 alleles differed in multiple phenotypes in a direction generally consistent with phenotypic differences previously observed along latitudinal clines. These results support inferences from earlier population genomic work that this variant influences fitness, and support the idea that the alleles exhibiting clines may be likely to have pleiotropic effects that are correlated along the axes favored by natural selection. PMID- 30404776 TI - Jen Gunter: Poking the snake oil. PMID- 30404775 TI - A novel FAS mutation with variable expressivity in a family with unicentric and idiopathic multicentric Castleman disease. PMID- 30404777 TI - Independent yet overlapping pathways ensure the robustness and responsiveness of trans-Golgi network functions in Arabidopsis. AB - The trans-Golgi-network (TGN) has essential housekeeping functions in secretion, endocytosis and protein sorting, but also more specialized functions in plant development. How the robustness of basal TGN function is ensured while specialized functions are differentially regulated is poorly understood. Here, we investigate two key regulators of TGN structure and function, ECHIDNA and the Transport Protein Particle II (TRAPPII) tethering complex. An analysis of physical, network and genetic interactions suggests that two network communities are implicated in TGN function and that ECHIDNA and TRAPPII belong to distinct yet overlapping pathways. Whereas ECHIDNA and TRAPPII colocalized at the TGN in interphase cells, their localization diverged in dividing cells. Moreover, ECHIDNA and TRAPPII localization patterns were mutually independent. TGN structure, endocytosis and sorting decisions were differentially impacted in echidna and trappii mutants. Our analyses point to a partitioning of specialized TGN functions, with ECHIDNA being required for cell elongation and TRAPPII for cytokinesis. Two independent pathways able to compensate for each other might contribute to the robustness of TGN housekeeping functions and to the responsiveness and fine tuning of its specialized functions. PMID- 30404779 TI - Accreditation-a verification ritual lacking verification. PMID- 30404778 TI - SLIC-CAGE: high-resolution transcription start site mapping using nanogram-levels of total RNA. AB - Cap analysis of gene expression (CAGE) is a methodology for genome-wide quantitative mapping of mRNA 5' ends to precisely capture transcription start sites at a single nucleotide resolution. In combination with high-throughput sequencing, CAGE has revolutionized our understanding of the rules of transcription initiation, led to discovery of new core promoter sequence features, and discovered transcription initiation at enhancers genome-wide. The biggest limitation of CAGE is that even the most recently improved version (nAnT iCAGE) still requires large amounts of total cellular RNA (5 ug), preventing its application to scarce biological samples such as those from early embryonic development or rare cell types. Here, we present SLIC-CAGE, a Super-Low Input Carrier-CAGE approach to capture 5' ends of RNA polymerase II transcripts from as little as 5-10 ng of total RNA. This dramatic increase in sensitivity is achieved by specially designed, selectively degradable carrier RNA. We demonstrate the ability of SLIC-CAGE to generate data for genome-wide promoterome with 1000-fold less material than required by existing CAGE methods, by generating a complex, high-quality library from mouse embryonic day 11.5 primordial germ cells. PMID- 30404780 TI - Levodopa-induced dyskinesia in Parkinson disease: A population-based cohort study. AB - OBJECTIVE: To assess dyskinesia frequency in a population-based cohort of patients with Parkinson disease (PD). Dyskinesia complicates levodopa treatment and affects quality of life. METHODS: Utilizing the 1991-2010 population-based, parkinsonism-incident cohort of Olmsted County, MN (n = 669), accessed via the Rochester Epidemiology Project, we identified patients with PD and abstracted levodopa-related dyskinesia information. RESULTS: Of 309 patients with PD (46.2% with parkinsonisms), 279 (90.3%) received levodopa. Most (230/279; 82.4%) had been treated by a Mayo Clinic neurologist. Median age of the 309 patients with PD at the time of diagnosis was 74.1 years (range 33.1-97.8 years). Median-age levodopa initiation in this cohort was 75 years (range 37-98 years), and median duration levodopa treatment was 6 years (range 2 months to 19.8 years). Dyskinesia was documented in 84 of 279 patients (30.1%). Median time from levodopa initiation to dyskinesia onset was 4 years (range 2 months to 20 years); those with dyskinesia (65.5%; 55/84) developed it within 5 years of levodopa initiation (9 within the first year). Dyskinesia was mild in 57/84 (67.9%), moderate in 16/84 (19.1%), and severe in 9/84 (10.7%); severity was not reported in 2 cases. Dyskinesia severity led to levodopa adjustments or amantadine initiation in 60.7% (51/84 of those with dyskinesia), with improvement in 23/51 (45.1%). Thirteen patients with dyskinesia underwent deep brain stimulation, reporting marked improvement. Postmortem examination confirmed Lewy body disease in 7 autopsied cases. CONCLUSIONS: Levodopa-induced dyskinesia affected 30% of the patients with PD in our cohort. Mayo neurologists favoring levodopa dosage optimization treated most patients. Dyskinesia was severe in 3.2% of all levodopa treated patients with PD (10.7% of all patients with dyskinesia) with marked improvement among those treated with deep brain stimulation. PMID- 30404781 TI - Nomograms to predict naming decline after temporal lobe surgery in adults with epilepsy. AB - OBJECTIVE: To develop and externally validate models to predict the probability of postoperative naming decline in adults following temporal lobe epilepsy surgery using easily accessible preoperative clinical predictors. METHODS: In this retrospective, prediction model development study, multivariable models were developed in a cohort of 719 patients who underwent temporal lobe epilepsy surgery at Cleveland Clinic and externally validated in a cohort of 138 patients who underwent temporal lobe surgery at one of 3 epilepsy surgery centers in the United States (Columbia University Medical Center, Emory University School of Medicine, University of Washington School of Medicine). RESULTS: The development cohort was 54% female with an average age at surgery of 36 years (SD 12). Twenty six percent of this cohort experienced clinically relevant postoperative naming decline. The model included 5 variables: side of surgery, age at epilepsy onset, age at surgery, sex, and education. When applied to the external validation cohort, the model performed very well, with excellent calibration and a c statistic (reflecting discriminatory ability) of 0.81. A second model predicting moderate to severe postoperative naming decline included 3 variables: side of surgery, age at epilepsy onset, and preoperative naming score. This model generated a c statistic of 0.84 in the external validation cohort and showed good calibration. CONCLUSION: Externally validated nomograms are provided in 2 easy-to use formats (paper version and online calculator) clinicians can use to estimate the probability of naming decline in patients considering epilepsy surgery for treatment of pharmacoresistant temporal lobe epilepsy. PMID- 30404784 TI - Concussion serum biomarkers: A quest for the Holy Grail? PMID- 30404783 TI - Vitiligo after alemtuzumab treatment: Secondary autoimmunity is not all about B cells. AB - OBJECTIVE: To report 3 patients with relapsing-remitting multiple sclerosis (RRMS) showing vitiligo after treatment with alemtuzumab. METHODS: Retrospective case series including flow cytometric analyses and T-cell receptor (TCR) sequencing of peripheral blood mononuclear cells. RESULTS: We describe 3 cases of alemtuzumab-treated patients with RRMS developing vitiligo 52, 18, and 14 months after alemtuzumab initiation. Histopathology shows loss of epidermal pigmentation with absence of melanocytes and interface dermatitis with CD8+ T-cell infiltration. Also compatible with pathophysiologic concepts of vitiligo, peripheral blood mononuclear cells of one patient showed high proportions of CD8+ T cells with an activated (human leukocyte antigen-DR+), memory (CD45RO+), and type 1 cytokine (interferon-gamma + tumor necrosis factor-alpha) phenotype at vitiligo onset compared to a control cohort of alemtuzumab-treated patients with RRMS (n = 30). Of note, analysis of CD8 TCR repertoire in this patient revealed a highly increased clonality and reduced repertoire diversity compared to healthy controls and treatment-naive patients with RRMS. We observed a predominance of single clones at baseline in this patient and alemtuzumab treatment did not substantially affect the proportions of most abundant clones over time. CONCLUSION: The 3 cases represent a detailed description of vitiligo as a T-cell mediated secondary autoimmune disease following alemtuzumab treatment. The prevailing concept of unleashed B-cell responses might therefore not cover all facets of alemtuzumab-related secondary autoimmunity. Mechanistic studies, especially on TCR repertoire, might help clarify the underlying mechanisms. PMID- 30404782 TI - Concussion BASICS II: Baseline serum biomarkers, head impact exposure, and clinical measures. AB - OBJECTIVE: To examine the effect of concussion history and cumulative exposure to collision sports on baseline serum biomarker concentrations, as well as associations between biomarker concentrations and clinical assessments. METHODS: In this observational cohort study, beta-amyloid peptide 42 (Abeta42), total tau, S100 calcium binding protein B (S100B), ubiquitin carboxy-terminal hydrolyzing enzyme L1 (UCH-L1), glial fibrillary acidic protein, microtubule associated protein 2, and 2',3'-cyclic-nucleotide 3'-phosphodiesterase serum concentrations were measured in 415 (61% male, 40% white, aged 19.0 +/- 1.2 years) nonconcussed collegiate athletes without recent exposure to head impacts. Regression analyses were used to evaluate the relationship between self-reported history of concussion(s), cumulative years playing collision sports, clinical assessments, and baseline biomarker concentrations. Football-specific analyses were performed using a modified Cumulative Head Impact Index. Clinical assessments included symptom, cognitive, balance, and oculomotor tests. RESULTS: Athletes with a greater number of concussions had a higher baseline Abeta42 concentration only (rho = 0.140, p = 0.005, small effect size). No biomarker concentrations correlated with cumulative exposure to collision sports. Race status fully mediated the correlations of S100B, UCH-L1, and Abeta42 with cognitive scores. Football exposure, specifically, was not associated with serum biomarker concentrations or clinical assessment scores based on the modified Cumulative Head Impact Index. CONCLUSION: Concussion-related serum biomarkers showed no consistent association with concussion history, cumulative exposure to collision sports, or clinical assessments in a sample of healthy collegiate athletes. Serum Abeta42 concentrations could increase following multiple previous concussions. Considering race status is essential when investigating links between biomarkers and cognition. The biomarkers studied may not detect residual effects of concussion or repetitive head impact exposure in otherwise asymptomatic collegiate athletes without recent exposure to head impacts. Much more research is needed for identifying reliable and valid blood biomarkers of brain trauma history. PMID- 30404785 TI - Concussion Biomarkers Assessed in Collegiate Student-Athletes (BASICS) I: Normative study. AB - OBJECTIVE: To describe variability in concussion biomarker concentrations collected from serum in a sample of healthy collegiate athletes, as well as report reliability metrics in a subsample of female athletes. METHODS: In this observational cohort study, beta-amyloid peptide 42 (Abeta42), total tau, S100 calcium binding protein B (S100B), ubiquitin carboxy-terminal hydrolyzing enzyme L1 (UCH-L1), glial fibrillary acidic protein, microtubule associated protein 2, and 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase) serum concentrations were measured in 415 (61% male, 40% white, aged 19.0 +/- 1.2 years) nonconcussed collegiate athletes without recent exposure to head impacts. Standardized normative distributions are reported for each biomarker. We evaluated main effects (analyses of variance) of sex and race, reporting demographic-specific normative metrics when appropriate. In a subset of 31 female participants, test retest reliability (Pearson r) and reliable change indices (80%, 90%, and 95% confidence intervals) across a 6- to 12-month interval are reported for Abeta42, total tau, S100B, and UCH-L1. RESULTS: Males exhibited higher UCH-L1 (p < 0.001, Cohen d = 0.75) and S100B (p < 0.001, d = 0.56) than females, while females had higher CNPase (p < 0.001, d = 0.43). Regarding race, black participants had higher baseline levels of UCH-L1 (p < 0.001, d = 0.61) and S100B (p < 0.001, d = 1.1) than white participants. Conversely, white participants had higher baseline levels of Abeta42 (p = 0.005, d = 0.28) and CNPase (p < 0.001, d = 0.46). Test retest reliability was generally poor, ranging from -0.02 to 0.40, and Abeta42 significantly increased from time 1 to time 2. CONCLUSION: Healthy collegiate athletes express concussion-related serum biomarkers in variable concentrations. Accounting for demographic factors such as sex and race is essential. Evidence suggested poor reliability for serum biomarkers; however, understanding how other factors influence biomarker expression, as well as knowledge of reliable change metrics, may improve clinical interpretation and future study designs. PMID- 30404786 TI - Concussion BASICS III: Serum biomarker changes following sport-related concussion. AB - OBJECTIVE: To evaluate changes in serum biomarker concentrations (beta-amyloid peptide 42 [Abeta42], total tau, ubiquitin carboxy-terminal hydrolyzing enzyme L1, S100 calcium binding protein B [S100B], glial fibrillary acidic protein [GFAP], microtubule associated protein 2 [MAP2], and 2',3'-cyclic-nucleotide 3' phosphodiesterase [CNPase]) after sport-related concussion (SRC) in a sample of collegiate athletes. Associations with clinical outcomes were also investigated. METHODS: Participants in this case-control study included 36 athletes (50% male, 61% white, aged 19.7 +/- 1.0 years) with SRC. Twenty-nine also had baseline blood drawn, allowing for within-patient analyses of concentration changes. Between group analyses incorporated 86 demographically matched controls (51% male, 63% white, aged 19.6 +/- 1.1 years). Biomarker sensitivity/specificity for SRC vs controls and relative to standardized normative cutoffs was evaluated (receiver operating characteristics). We also analyzed associations between post-SRC clinical outcomes and both biomarker change from baseline and post-SRC concentrations. RESULTS: The majority of blood samples had concentrations of GFAP, MAP2, and CNPase below limits of quantification. Within-patient analyses indicated elevated S100B after SRC (p = 0.003, 67% of patients elevated), especially for blood samples collected <4 hours post-SRC (88% of patients). Significant between-group differences were limited to blood draws <4 hours post SRC: Abeta42 (81% of SRC > control median, area under the curve [AUC] = 0.75 [95% confidence interval 0.59-0.91]), total tau (75% SRC > control, AUC = 0.74 [0.56 0.79]), and S100B (88% SRC > control; AUC [specific to white race] = 0.82 [0.72 0.93]). Using standardized normative cutoffs (z > 1.0), specificity ranged from 79.1% to 89.3% while sensitivity was <70%. Biomarkers were not associated with clinical outcomes. CONCLUSION: For SRC, diagnostic accuracy of serum biomarkers appears best if blood is collected within a few hours. Accurate blood marker identification of SRC appears somewhat dependent on the "healthy" comparison. Additional research must evaluate whether physiologic changes in the absence of clinical changes, or vice versa, are relevant for concurrent or future neurologic health. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that certain serum biomarkers are elevated from baseline and higher than demographically matched controls after sport-related concussion. PMID- 30404787 TI - Correction: Setting an implementation research agenda for Canadian investments in global maternal, newborn, child and adolescent health: a research prioritization exercise. PMID- 30404789 TI - Neonatal Abstinence Syndrome Due to Maternal Kratom Use. AB - Neonatal abstinence syndrome (NAS) is increasing in incidence and most commonly associated with maternal opioid use during pregnancy. Nonopioid alternatives to treat opioid dependence are highly sought after in the country's current opioid epidemic. Whether Kratom, a legal, widely available herbal supplement, should be classified as an opioid is contentious. Although the US Food and Drug Administration has recently addressed this controversy, Kratom continues to be marketed as a nonopioid remedy for opioid withdrawal. Its use is increasing in the United States. We describe an infant with NAS born to a mother with daily Kratom tea ingestion to self-treat opioid dependence. Pediatricians and parents should be aware of the risk of NAS due to Kratom use during pregnancy. PMID- 30404788 TI - Screening for a new primary cancer in patients with existing metastatic cancer: a retrospective cohort study. AB - BACKGROUND: Cancer screening aims to detect malignant disease early in its natural history when interventions might improve patient outcomes. Such benefits are unclear when screening occurs for patients with an existing high risk of death. Our aim was to study the extent of routine cancer screening for a new primary cancer in patients with existing metastatic cancer. METHODS: We used administrative databases from Ontario to identify a retrospective cohort of adults of eligible screening age (>= 50 yr) who had a diagnosis of stage IV (metastatic) colorectal, lung, breast or prostate cancer between 2007 and 2012. We calculated the cumulative incidence of cancer screening over time for colorectal and breast cancer. RESULTS: Among the 20 992 patients with metastatic lung, breast or prostate cancer, 2.9%, 6.3% and 13.3% of patients, respectively, underwent testing for colorectal cancer within 1 year of cancer diagnosis. Within 3 years of diagnosis, rates reached 4.1%, 12.3% and 27.5%, respectively (8.5% of all patients). Incidence of colorectal cancer testing was higher among patients who received their diagnoses more recently compared with patients with diagnoses from earlier time periods (p = 0.0143). Among the 10 034 women with metastatic lung or colorectal cancer, 8.7% and 8.0% of patients, respectively, underwent breast cancer screening within 1 year of cancer diagnosis. Within 3 years of diagnosis, screening rates reached 10.2% and 13.1%, respectively. INTERPRETATION: Our findings indicate excessive rates of cancer screening among patients with metastatic cancer who are unlikely to benefit. Further studies are warranted to identify predictors for screening, resource implications, potential and real harms borne by patients, and the impact of a recent Choosing Wisely statement recommending against the practice. PMID- 30404790 TI - The World Was Not Built for Us: Improving Access to Care for Transgender Youth. PMID- 30404792 TI - FMDV leader protease cleaves G3BP1 and G3BP2 and inhibits stress granule formation. AB - Like other viruses, the picornavirus foot-and-mouth disease virus (FMDV, genus aphthovirus), one of the most notorious pathogens in global livestock industry, needs to navigate antivirals host responses to establish an infection. There is substantial insight into how FMDV suppresses the type I IFN response, but it is largely unknown whether and how FMDV modulates the integrated stress response. Here, we show that the stress response is suppressed during FMDV infection. Using a chimeric recombinant encephalomyocarditis virus (EMCV), in which we functionally replaced the endogenous stress response antagonist by FMDV Lpro or 3Cpro, we demonstrate an essential role for Lpro in suppressing stress granule (SG) formation. Consistently, infection with a recombinant FMDV lacking Lpro resulted in SG formation. Additionally, we show that Lpro cleaves the known SG scaffold proteins G3BP1 and G3BP2, but not TIA-1. We demonstrate that the closely related equine rhinitis A virus (ERAV) Lpro also cleaves G3BP1 and G3BP2 and also suppresses SG formation, indicating that these abilities are conserved amongst aphthoviruses. Neither FMDV or ERAV Lpro interfered with phosphorylation of PKR or eIF2alpha, indicating that Lpro does not affect SG formation by inhibiting the PKR-triggered signaling cascade. Taken together, our data suggest that aphthoviruses actively target scaffolding proteins G3BP1 and G3BP2 and antagonize SG formation to modulate the integrated stress response.IMPORTANCE The picornavirus foot and mouth disease virus (FMDV) is a notorious animal pathogen that puts a major economic burden on global life stock industry. Outbreaks have significant consequences for animal health and product safety. Like many other viruses, FMDV must manipulate antiviral host responses to establish infection. Upon infection, viral dsRNA is detected which results in activation of the PKR mediated stress response, leading to a stop in cellular and viral translation and the formation of stress granules (SG), which are thought to have antiviral properties. Here we show that FMDV can suppress SG formation via its leader protease (Lpro). Simultaneously we observed that Lpro can cleave the SG scaffolding proteins G3BP1 and G3BP2. Understanding the molecular mechanisms of FMDV's antiviral host response evasion strategies may help to develop countermeasures to control FMDV infections in the future. PMID- 30404793 TI - Infection and functional modulation of human monocytes and macrophages by varicella zoster virus. AB - Varicella zoster virus (VZV) is associated with viraemia during primary infection that is presumed to stem from infection of circulating immune cells. Whilst VZV has been shown to be capable of infecting a number of different subsets of circulating immune cells such as T cells, dendritic cells and NK cells, less is known about the interaction between VZV and monocytes. Here, we demonstrate that blood derived human monocytes are permissive VZV replication in vitro VZV infected monocytes exhibited each temporal class of VZV gene expression as evidenced by immunofluorescent staining. VZV virions were observed on the cell surface and viral nucleocapsids were observed in the nucleus of VZV infected monocytes by scanning electron microscopy. In addition, VZV infected monocytes were able to transfer infectious virus to human fibroblasts. Infected monocytes displayed impaired dextran-mediated endocytosis and cell surface immunophenotyping revealed downregulation of CD14, HLA-DR, CD11b and the M-CSF receptor. Analysis of the impact of VZV infection on M-CSF stimulated monocyte to macrophage differentiation demonstrated loss of cell viability, indicating that VZV infected monocytes were unable to differentiate into viable macrophages. In contrast, macrophages differentiated from monocytes prior to exposure to VZV were highly permissive to infection. This study defines the permissiveness of these myeloid cell types to productive VZV infection and identifies functional impairment of VZV infected monocytes.IMPORTANCE Primary varicella infection results in widespread dissemination of the virus throughout the host. Viral transportation is known to be directly influenced by susceptible immune cells in the circulation. Moreover, infection of immune cells by VZV results in attenuation of the anti-viral mechanisms used to control infection and limit spread. Here, we provide evidence that human monocytes, which are highly abundant in the circulation, are permissive to productive VZV infection. Furthermore, monocyte derived macrophages were also highly permissive to VZV infection, although VZV infected monocytes are unable to differentiate into macrophages. Exploring the relationships between VZV and permissive immune cells such as human monocytes and macrophages elucidates novel immune evasion strategies and provides further insight into the control VZV has over the immune system. PMID- 30404794 TI - FoxO1 Suppresses Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication and Controls Viral Latency. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) has latent and lytic replication phases, both of which contribute to the development of KSHV-induced malignancies. Among numerous factors identified to regulate KSHV life cycle, oxidative stress, caused by imbalanced clearing and production of reactive oxygen species (ROS), has been shown to robustly disrupt KSHV latency and induce viral lytic replication. In this study, we identify an important role of antioxidant defense factor forkhead box protein O1 (FoxO1) in KSHV lifecycle. Either chemical inhibition of the FoxO1 function or knockdown of FoxO1 expression led to the increase of intracellular ROS level that was subsequently sufficient to disrupt KSHV latency and induce viral lytic reactivation. On the other hand, treatment with N-acetyl-L-cysteine (NAC), an oxygen free radical scavenger, led to the reduction of FoxO1 inhibition-induced ROS level and ultimately the attenuation of KSHV lytic reactivation. These findings reveal that FoxO1 plays a critical role in keeping KSHV latency in check by maintaining intracellular redox balance.IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with several cancers including Kaposi's sarcoma (KS). Both KSHV latent and lytic replication phases are important for the development of KS. Identification of factors regulating KSHV latent to lytic switch can provide insights into the pathogenesis of KSHV-induced malignancies. In this study, we have shown that antioxidant defense factor forkhead box protein O1 (FoxO1) maintains KSHV latency by suppressing viral lytic replication. Inhibition of FoxO1 disrupts KSHV latency and induces viral lytic replication by increasing intracellular ROS level. Significantly, treatment with an oxygen free radical scavenger N-acetyl-L cysteine (NAC) attenuates FoxO1 inhibition-induced intracellular ROS level and KSHV lytic replication. Our works reveal a critical role of FoxO1 in suppressing KSHV lytic replication, which could be targeted for antiviral therapy. PMID- 30404795 TI - HIV-1 antisense protein of different clades induces autophagy and associates to the autophagy factor p62. AB - The existence of the antisense transcript-encoded HIV-1 Antisense Protein (ASP) was recently reinforced by in silico analyses providing evidence for recent appearance of this gene in the viral genome. Our previous studies led to the detection of ASP in various cell lines by Western blot, flow cytometry and confocal microscopy analyses and reported that it induced autophagy, potentially through multimer formation. Herein, our goals were to assess autophagy induction by ASP from different clades, and to identify the implicated autophagy factors. We first demonstrated that ASP formed multimers, partly through its amino region and cysteine residues. Removal of this region was further associated with lower induction of autophagy, as assessed by autophagosome formation. ASP from different clades (A, B, C, D, and G) were next tested and were detected in monomeric and multimeric forms at various levels and all induced autophagy (clade A ASP being less efficient), as determined by LC3-II and p62 (SQSTM1) levels. Furthermore, CRISPR-based knock-out of ATG5, ATG7 and p62 genes led to increased ASP levels. Confocal microscopy analyses showed that ASP co-localized with p62 and LC3-II in autophagosome-like structures. Co-immunoprecipitation experiments further demonstrated that p62 associated with ASP through its PB1 domain. Interestingly, immunoprecipitation experiments supported that ASP is ubiquitinated and that ubiquitination was modulating its stability. We are thus suggesting that ASP induces autophagy through p62 interaction and that its abundance is controlled by autophagy, in which ubiquitin plays an important role. Understanding the mechanisms underlying ASP degradation is essential to better assess its function.IMPORTANCE In the present study, we provide the first evidence that a new HIV-1 protein termed ASP derived from different clades acts similarly in inducing autophagy, an important cellular process implicated in the degradation of excess or defective cellular material. We have gained further knowledge on the mechanism mediating the activation of autophagy. Our studies have important ramification in the understanding of viral replication and the pathogenesis associated with HIV-1 in infected individuals. Indeed, autophagy is implicated in antigen presentation during immune response and could thus be rendered inefficient in infected cells, such as dendritic cells. Furthermore, a possible link with HIV-1-associated Neurological Disorder (HAND) might also be a possible association with the capacity of ASP to induce autophagy. Our studies hence demonstrate the importance in conducting further studies on this protein, as it could represent a new interesting target for antiretroviral therapies and vaccine design. PMID- 30404796 TI - Hepatitis B e antigen inhibits NF-kappaB activity by interrupting K63-linked ubiquitination of NEMO. AB - Viruses have adopted diverse strategies to suppress antiviral responses. Hepatitis B virus (HBV), a virus that is prevalent world-wide, manipulates the host's innate immune system to evade scavenging. It is reported that the hepatitis B e antigen (HBeAg) can interfere with NF-kappaB activity, which then leads to high viral loads, while HBV with the G1896A mutation remains infectious without the production of HBeAg but can induce more severe proinflammatory response and liver damage. The aim of current work was to study the molecular mechanism by which HBeAg suppresses IL-1beta-stimulated NF-kappaB activity, which leads to the suppression of the innate immune responses to HBV infection. Our study revealed that HBeAg could interact with NEMO, a regulatory subunit associated with IkappaB kinase, which regulates the activation of NF-kappaB. HBeAg suppressed the IL-1beta-induced TRAF6-dependent K63-linked ubiquitination of NEMO, thereby downregulating NF-kappaB activity and promoting virus replication. We further demonstrated the inhibitory effect of HBeAg on the NF kappaB signaling pathway using primary human hepatocytes, HBV-infected HepG2-NTCP cells and clinical liver samples. Our study reveals a molecular mechanism where HBeAg suppresses IL-1beta-induced NF-kappaB activation by decreasing the TRAF6 dependent K63-ubiquitination of NEMO, which may thereby enhance HBV replication and promote a persistent infection.IMPORTANCE The role of HBeAg in inflammatory responses during the infection of hepatitis B virus (HBV) is not fully understood, and several previous reports with regard to the NF-kappaB pathway are controversial. In this report, we showed that HBeAg could suppress both TLR2 and IL-1beta-induced activation of NF-kappaB in cells and clinical samples and we further revealed novel molecular mechanisms. We found that HBeAg can associate with NEMO, the regulatory subunit for IkappaB kinase (IKK) that controls the NF kappaB signaling pathway, and thereby inhibits TRAF6-mediated K63-linked ubiquitination of NEMO, resulting in down-regulation of NF-kappaB activity and promotion of virus replication. In contrast, the HBeAg-negative HBV mutant can induce higher level of NF-kappaB activity. These results are important for understanding the HBV-induced pathogenesis of chronic hepatitis and indicate that different clinical measures should be considered to treat HBeAg-positive and HBeAg-negative infections, our findings represent a conceptual advance in HBV related suppression of NF-kappaB signaling. PMID- 30404791 TI - PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia. AB - The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. Fully exploiting this finding will require unraveling the molecular genetics underlying phenotypic variability in mitochondrial priming. Here, we report that mitochondrial apoptosis resistance in T cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2). In T-ALL clinical specimens, loss-of-function mutations of PRC2 core components (EZH2, EED, or SUZ12) were associated with mitochondrial apoptosis resistance. In T-ALL cells, PRC2 depletion induced resistance to apoptosis induction by multiple chemotherapeutics with distinct mechanisms of action. PRC2 loss induced apoptosis resistance via transcriptional up-regulation of the LIM domain transcription factor CRIP2 and downstream up-regulation of the mitochondrial chaperone TRAP1 These findings demonstrate the importance of mitochondrial apoptotic priming as a prognostic factor in T-ALL and implicate mitochondrial chaperone function as a molecular determinant of chemotherapy response. PMID- 30404797 TI - The Deletion of Both Tyrosine-Based Endocytosis Signal and Endoplasmic Reticulum Retrieval Signal in the Cytoplasmic Tail of Spike Protein Attenuates PEDV in Pigs. AB - Porcine epidemic diarrhea virus (PEDV) causes high mortality in neonatal piglets. The PEDV spike (S) protein contains two intracellular sorting motifs YxxPhi (tyrosine-based motif YEVF or YEAF) and KVHVQ at the cytoplasmic tail, yet their functions have not been fully elucidated. Some Vero cell-adapted and/or attenuated PEDV variants contain ablations in these two motifs. We hypothesized that these motifs contribute to viral pathogenicity. By transiently expressing PEDV S proteins with mutations in the motifs, we confirmed that the motif KVHVQ is involved in retention of the S proteins in the endoplasmic reticulum-Golgi intermediate compartment (ERGIC). In addition, we identified that the YxxPhi motif triggers endocytosis of S proteins. These two motifs synergistically regulate the level of S expressed on the cell surface. To investigate their role in viral pathogenicity, we generated three recombinant PEDVs by introducing deletions or a mutation in the two motifs of the infectious clone of PEDV PC22A strain (icPC22A): 1) icDelta10aa (DeltaYxxPhiEKVHVQ); 2) icDelta5aa (DeltaKVHVQ); and 3) icYA (Y1378A, to an inactivated motif AEVF). Infection of Vero cells with icDelta10aa resulted in larger syncytia and more virions with reduced number of S protein projections on the surface compared with icPC22A. Furthermore, we orally inoculated five groups of 5-day-old gnotobiotic piglets with the three mutants, icPC22A, or mock. The mutant icDelta10aa caused less severe diarrhea rate and significantly milder intestinal lesions than icPC22A, icDelta5aa and icYA. These data suggest that the deletion of both motifs can reduce the virulence of PEDV in piglets.IMPORTANCE Many coronaviruses (CoVs) possess conserved motifs YxxPhi and/or KxHxx/KKxx in the cytoplasmic tail of the S protein. The KxHxx/KKxx motif has been identified as the ER-retrieval signal, but the function of the YxxPhi motif in the intracellular sorting of CoV S proteins remains controversial. In this study, we showed that the YxxPhi of PEDV S protein is an endocytosis signal. Furthermore, using reverse genetics technology, we evaluated its role in PEDV pathogenicity in neonatal piglets. Our results explain one attenuation mechanism of Vero cell-adapted PEDV variants lacking functional YxxPhi and KVHVQ motifs. Knowledge from this study may aid in the design of efficacious live attenuated vaccines against PEDV, as well as other CoVs bearing the same motif in their S protein. PMID- 30404798 TI - Reactivation of Simian Varicella Virus (SVV) in Rhesus Macaques After CD4 T Cell Depletion. AB - Rhesus macaques intrabronchially inoculated with simian varicella virus (SVV), the counterpart of human varicella zoster virus (VZV), developed primary infection with viremia and rash, which resolved upon clearance of viremia followed by establishment of latency. To assess the role of CD4 T cell immunity in reactivation, monkeys were treated with a single 50 mg/kg dose of a humanized monoclonal anti-CD4 antibody; within 1 week, circulating CD4 T cells were reduced from 40-60% to 5-30% of the total T cell population and remained low for 2 months. Very low viremia was seen only in some of the treated monkeys. Zoster rash developed after 7 days in the monkey with the most extensive CD4 T cell depletion (5%) and in all other monkeys at 10-49 days post-treatment, with recurrent zoster in one treated monkey. SVV DNA was detected in the lung from 2 of 5 monkeys, in bronchial lymph nodes from 1 of the 5 monkeys, and in ganglia from at least two dermatomes in 3 of 5 monkeys. Immunofluorescence analysis of skin rash, lung, lymph node and ganglia revealed SVV ORF 63 protein in: sweat glands in skin; type II cells in lung alveoli, macrophages and dendritic cells in lymph nodes, and the neuronal cytoplasm of ganglia. Detection of SVV antigen in multiple tissues upon CD4 T cell depletion and virus reactivation suggests a critical role for CD4 T cell immunity in controlling varicella virus latency.IMPORTANCE Reactivation of latent VZV in humans can result in serious neurological complications. VZV-specific cell-mediated immunity is critical for the maintenance of latency. Similar to VZV in humans, SVV causes varicella in monkeys, establishes latency in ganglia, and reactivates to produce shingles. Herein, we show that depletion of CD4 T cells in rhesus macaques results in SVV reactivation, with virus antigens found in zoster rash and SVV DNA and antigens found in lungs, lymph nodes and ganglia. These results suggest the critical role of CD4 T cell immunity in controlling varicella virus latency. PMID- 30404799 TI - Interferon-alpha Enhances NK Cell Function and the Suppressive Capacity of HIV specific CD8+ T Cells. AB - Current shock-and-kill strategies for the eradication of the HIV-1 reservoir have resulted in blips of viremia but not in a decrease in the size of the latent reservoir in patients on suppressive antiretroviral therapy (ART). This discrepancy could potentially be explained by an inability of the immune system to kill HIV-1-infected cells following the reversal of latency. Furthermore, some studies have suggested that certain latency-reversing agents (LRAs) may inhibit CD8+ T cell and NK cell responses. In this study, we tested the hypothesis that IFN-alpha could improve the function of NK cells from chronic progressors (CP) on ART. We show here that IFN-alpha treatment enhanced cytokine secretion, polyfunctionality, degranulation, and the cytotoxic potential of NK cells from healthy donors (HD) and CP. We also show that this cytokine enhanced the viral suppressive capacity of NK cells from HD and elite controllers or suppressors (ES). Furthermore, IFN-alpha enhanced global CP CD8+ T cell cytokine responses and the suppressive capacity of ES CD8+ T cells. Our data suggest that IFN-alpha treatment may potentially be used as an immunomodulatory agent in HIV-1 cure strategies.Importance: Data suggests that HIV+ individuals unable to control infection fail to do so due to impaired cytokine production and/cytotoxic effector cell function. Consequently, the success of cure agendas such as the shock-and-kill strategy will probably depend on enhancing patient effector cell function. In this regard, NK cells are of particular interest as they complement the function of CD8+ T cells. Here, we demonstrate the ability of short course IFN-alpha treatments to effectively enhance such effector functions in chronic progressor NK cells without inhibiting their general CD8+ T cell function. These results point to the possibility of exploring such short course IFN-alpha treatments for the enhancement of effector cell function in HIV+ patients in future cure strategies. PMID- 30404800 TI - Crustacean Genome Exploration Reveals the Evolutionary Origin of White Spot Syndrome Virus. AB - White spot syndrome virus (WSSV) is a crustacean-infecting, double-stranded DNA virus and is the most serious viral pathogen in the global shrimp industry. WSSV is the sole recognized member of the family Nimaviridae, and the lack of genomic data on other nimaviruses has obscured the evolutionary history of WSSV. Here, we investigated the evolutionary history of WSSV by characterizing WSSV relatives hidden in host genomic data. We surveyed 14 host crustacean genomes and identified five novel nimaviral genomes. Comparative genomic analysis of Nimaviridae identified 28 "core genes" that are ubiquitously conserved in Nimaviridae; unexpected conservation of 13 uncharacterized proteins highlighted yet unknown essential functions underlying the nimavirus replication cycle. The ancestral Nimaviridae gene set contained five baculoviral per os infectivity factor homologs and a sulfhydryl oxidase homolog, suggesting a shared phylogenetic origin of Nimaviridae and insect-associated double-stranded DNA viruses. Moreover, we show that novel gene acquisition and subsequent amplification reinforced the unique accessory gene repertoire of WSSV. Expansion of unique envelope protein and nonstructural virulence-associated genes may have been the key genomic event that made WSSV such a deadly pathogen.IMPORTANCE White spot syndrome virus (WSSV) is the deadliest viral pathogen threatening the global shrimp aquaculture. The evolutionary history of WSSV has remained a mystery, because few WSSV relatives, or nimaviruses, had been reported. Our aim was to trace the history of WSSV using the genomes of novel nimaviruses hidden in host genome data. We demonstrate that WSSV emerged from a diverse family of crustacean infecting large DNA viruses. By comparing the genomes of WSSV and its relatives, we show that WSSV possesses an expanded set of unique host-viral interaction related genes. This extensive gene gain may have been the key genomic event that made WSSV such a deadly pathogen. Moreover, conservation of insect-infecting virus protein homologs suggests a common phylogenetic origin of crustacean infecting Nimaviridae and other insect-infecting DNA viruses. Our work redefines the previously poorly-characterized crustacean virus family and reveal the ancient genomic events that preordained the emergence of a devastating shrimp pathogen. PMID- 30404801 TI - Mutations in the spike protein of MERS-CoV transmitted in Korea increase resistance towards antibody-mediated neutralization. AB - The Middle East respiratory syndrome coronavirus (MERS-CoV) poses a threat to public health. The virus is endemic in the Middle East but can be transmitted to other countries by travel activity. The introduction of MERS-CoV into the Republic of Korea by an infected traveler resulted in a hospital outbreak of MERS that entailed 186 cases and 38 deaths. The MERS-CoV spike (S) protein binds to the cellular protein DPP4 via its receptor binding domain (RBD) and mediates viral entry into target cells. During the MERS outbreak in Korea emergence and spread of viral variants was observed that harbored mutations in the RBD, D510G and I529T. Counterintuitively, these mutations were found to reduce DPP4 binding and viral entry into target cells. Here, we investigated whether they also exerted pro-viral effects. We confirm that changes D510G and I529T reduce S protein binding to DPP4 but show that this reduction only translates into diminished viral entry when expression of DPP4 on target cells is low. Both mutations did not modulate S protein binding to sialic acids, S protein activation by host cell proteases and inhibition of S protein-driven entry by interferon-induced transmembrane proteins. In contrast, changes D510G and I529T increased resistance of S protein-driven entry to neutralization by monoclonal antibodies and serum from a convalescent MERS patient. These findings indicate that MERS-CoV variants with reduced neutralization sensitivity were transmitted during the Korean outbreak and that the responsible mutations were compatible with robust infection of cells expressing high levels of DPP4.IMPORTANCE MERS-CoV has pandemic potential and it is important to identify mutations in viral proteins that might augment viral spread. In the course of a large hospital outbreak of MERS in the Republic of Korea in 2015 the spread of a viral variant was observed that contained mutations in the viral spike protein. These mutations were found to reduce receptor binding and viral infectivity. However, it remained unclear whether they also exerted pro-viral effects. We demonstrate that these mutations reduce sensitivity to antibody-mediated neutralization and are compatible with robust infection of target cells expressing high amounts of the viral receptor DPP4. PMID- 30404802 TI - Cell-to-cell transmission is the main mechanism supporting bovine viral diarrhea virus spread in cell culture. AB - After initiation of an infective cycle, spread of virus infection can occur fundamentally in two different ways: (i) viral particles can be released into the external environment and diffuse through the extracellular space until they interact with a new host cell, or (ii) virions can remain associated with infected cells promoting the direct passage between infected and uninfected cells that is referred to as direct cell-to-cell transmission. Although evidence for cell-associated transmission has accumulated for many different viruses, the ability of members of the genus pestivirus to use this mode of transmission has not been reported. Here we used a novel recombinant virus expressing the envelope glycoprotein E2 fused to mCherry fluorescent protein to monitor the spreading of bovine viral diarrhea virus (BVDV, the type member of pestiviuses) infection. To demonstrate direct cell-to-cell transmission of BVDV we developed a cell co culture system that allowed us to prove the direct transmission from infected to uninfected cells in the presence of neutralizing antibodies. This mode of transmission requires cell-cell contacts and clathrin-mediated receptor-dependent endocytosis. Notably, it overcomes antibody blocking of the BVDV receptor CD46 indicating that cell-to-cell transmission of the virus involves the engagement of co-receptors on the target cell.Importance. BVDV causes one of the economically most important viral infections for the cattle industry. The virus is able to cross the placenta and infect the fetus leading to the birth of persistently infected animals, which are reservoirs for the spread of BVDV. The occurrence of persistent infection has hampered the efficacy of vaccination because it requires eliciting levels of protection close to sterilizing immunity to prevent fetal infections. While vaccination prevents disease, BVDV can be detected when animals with neutralizing antibodies are challenged with the virus. Virus cell-to-cell transmission allows overcoming barriers imposed to free virus dissemination such as antibodies or epithelial barriers. Here, we show for the first time that BVDV exploits cell-cell contacts to propagate infection in a process that is resistant to antibody neutralization. Our results provide new insights into the mechanisms underlying the pathogenesis of BVDV infection and can aid the design of effective control strategies. PMID- 30404803 TI - HSV-1 ICP22 suppresses CD80 expression by murine dendritic cells. AB - Herpes simplex virus type-1 (HSV-1) has the ability to delay its clearance from the eye during ocular infection. Here we show that ocular infection of mice with HSV-1 suppresses expression of the costimulatory molecule CD80, but not CD86, in the cornea. The presence of neutralizing anti-HSV-1 antibodies did not alleviate this suppression. At the cellular level, HSV-1 consistently downregulated the expression of CD80 by dendritic cells but not other antigen-presenting cells. Furthermore, flow cytometric analysis of HSV-1 infected corneal cells during a 7 day period reduced CD80 expression in dendritic cells (DCs) but not B cell, macrophages or monocytes. This suppression was associated with the presence of virus. Similar results were obtained using infected or transfected spleen cells or bone-marrow derive DCs. A combination of roscovitine treatment, transfection with immediate early genes (IE) and infection with a recombinant HSV-1 lacking ICP22 gene shown the importance of ICP22 in down-regulation of CD80 promoter but not CD86 promoter in vitro and in vivo At the mechanistic level, we show that the HSV-1 immediate-early gene, ICP22 binds the CD80 promoter and that this interaction is required for HSV-1-mediated suppression of CD80 expression. Conversely, forced expression of CD80 by ocular infection of mice with a recombinant HSV-1 exacerbated corneal scarring in infected mice. Taken together these studies identify ICP22 mediated suppression of CD80 expression in dendritic cells as central to delayed clearance of the virus and limitation of the cytopathological response to primary infection in the eye.IMPORTANCE HSV-1 induced eye disease is a major public health problem. Eye disease is associated closely with immune responses to the virus and is exacerbated by delayed clearance of the primary infection. The immune system relies on antigen presenting cells of the innate immune system to activate T cell response. We found that HSV-1 utilizes a robust and finely targeted mechanism of local immune evasion. It downregulates the expression of the costimulatory molecule CD80 but not CD86, on resident dendritic cells irrespective of the presence of anti-HSV-1 antibodies. The effect is mediated by direct binding of HSV-1 ICP22, the product of an immediate early gene of HSV-1, to the promoter of CD80. This immune evasion mechanism dampens the host immune response and thus reduces eye disease in ocularly infected mice. Therefore, ICP22 may be a novel inhibitor of CD80 that could be used to modulate immune response. PMID- 30404804 TI - Sensitivity to Broadly Neutralizing Antibodies of Recently Transmitted HIV-1 Clade CRF02_AG Viruses with a Focus on Evolution over Time. AB - Broadly neutralizing antibodies (bnAbs) are promising agents for prevention and/or treatment of HIV-1 infection. However, the diversity among HIV-1 envelope (Env) glycoproteins impacts bnAbs potency and breadth. Neutralization data on CRF02_AG clade are scarce although it is highly prevalent in West Africa and Europe. We assessed the sensitivity to bnAbs of a panel of 33 early-transmitted CRF02_AG viruses over a 15-year period of the French epidemic (1997-2012). Env pseudotyped CRF02_AG viruses were best neutralized by the CD4 binding site (CD4bs)-directed bnAbs (VRC01, 3BNC117, NIH45-46G54W and N6) and the gp41 membrane proximal external region (MPER)-directed bnAb 10E8, in terms of both potency and breadth. We observed a higher resistance to bnAbs targeting the V1/V2 glycan region (PG9, PGT145) and the V3-glycan region (PGT121, 10-1074). Combinations were required to achieve a full coverage across this subtype. We observed an increased resistance to bnAbs targeting the CD4bs linked to the diversification of CRF02_AG Env over the course of the epidemic, a phenomenon which was previously described for subtypes B and C. These data on the sensitivity to bnAbs of CRF02_AG viruses, including only recently transmitted viruses, will inform future passive immunization studies. Considering the drift of the HIV-1 species towards higher resistance to neutralizing antibodies, it appears necessary to keep updating existing panels for evaluation of future vaccine and passive immunization studies.IMPORTANCE Major progress occurred during the last decade leading to isolation of human monoclonal antibodies, termed broadly neutralizing antibodies (bnAbs) due to their capacity to neutralize various strains of HIV-1. Several clinical trials are on the move in order to evaluate their efficacy in preventive or therapeutic strategies. However, no single bnAb is active against 100% of strains. It is important to gather data on the sensitivity to neutralizing antibodies of all genotypes, especially those more widespread in regions where the prevalence of HIV-1 infection is high. Here we assembled a large panel of clade CRF02_AG viruses, the most frequent genotype circulating in West Africa and the second most frequent in several European countries. We evaluated their sensitivity to bnAbs, including those the most advanced in clinical trials, and looked for the best combinations. In addition, we observed a trend toward increased resistance to bnAbs over the course of the epidemic. PMID- 30404805 TI - Murine Cytomegalovirus glycoprotein O promotes epithelial cell infection in vivo. AB - Cytomegaloviruses (CMVs) establish systemic infections across diverse cell types. Glycoproteins that alter tropism can potentially guide their spread. Glycoprotein O (gO) is a non-essential fusion complex component of both human (HCMV) and murine CMV (MCMV). We tested its contribution to MCMV spread from the respiratory tract. In vitro, MCMV lacking gO poorly infected fibroblasts and epithelial cells. Cell binding was intact but penetration was delayed. By contrast myeloid infection was preserved, and in the lungs, where myeloid and type 2 alveolar epithelial cells are the main viral targets, MCMV lacking gO showed a marked preference for myeloid infection. Its poor epithelial cell infection was associated with poor primary virus production and reduced virulence. Systemic spread, which proceeds via infected CD11c+ myeloid cells, was initially intact but then diminished, because less epithelial infection led ultimately to less myeloid infection. Thus, tight linkage between peripheral and systemic MCMV infections gave gO-dependent infection a central role in host colonization.IMPORTANCE Human cytomegalovirus is a leading cause of congenital disease. This reflects its capacity for systemic spread. A vaccine is needed, but the best viral targets are unclear. Attention has focussed on the virion membrane fusion complex. It has 2 forms, so we need to know what each contributes to host colonization. One includes the virion glycoprotein O. We used murine cytomegalovirus, which has equivalent fusion complexes, to determine the importance of glycoprotein O after mucosal infection. We show that it drives local virus replication in epithelial cells. It was not required to infect myeloid cells, which establish systemic infection, but poor local replication reduced systemic spread as a secondary effect. Therefore targeting glycoprotein O of human cytomegalovirus has the potential to reduce both local and systemic infections. PMID- 30404806 TI - Development of a primary human cell model for the study of human cytomegalovirus replication and spread within salivary epithelium. AB - Various aspects of human cytomegalovirus (HCMV) pathogenesis including its ability to replicate in specific cells and tissues and the mechanism(s) of horizontal transmission are not well understood, predominantly because of the strict species specificity exhibited by HCMV. Murine CMV (MCMV), which contains numerous gene segments highly similar to that of HCMV, has been useful for modeling some aspects of CMV pathogenesis, however, it remains essential to build relevant human cell-based systems to investigate how the HCMV counterparts function. The salivary gland epithelium is a site of persistence for both human and murine cytomegaloviruses and salivary secretions appear to play an important role in horizontal transmission. Therefore, it is important to understand how HCMV is replicating within the glandular epithelial cells so that it might be possible to therapeutically prevent transmission. In the current study, we describe the development of a salivary epithelial model derived from primary human "salispheres". Initial infection of these primary salivary cells with HCMV occurs in a manner similar to that reported for established epithelial lines, in that gH/gL/UL128/UL130/UL131A (Pentamer) positive strains can infect and replicate, while lab adapted Pentamer null strains do not. However, while HCMV does enter the lytic phase and produce virus in the salivary epithelial cells, it fails to exhibit robust spread throughout the culture and persists in a low percentage of salivary cells. The current study demonstrates the utility of these primary tissue derived cells for studying HCMV replication in salivary epithelial cells in vitro IMPORTANCE Human cytomegalovirus (HCMV) infects the majority of the world's population and although it typically establishes a quiescent infection with little to no disease in most individuals, the virus is responsible for a variety of devastating sequelae in immunocompromised adults and in developing fetuses. Therefore, identifying the viral properties essential for replication, spread and horizontal transmission are important areas of medical science. Our studies use novel human salivary gland-derived cellular models to investigate the molecular details by which HCMV replicates in salivary epithelial cells and provide insight into the mechanisms by which the virus persists in the salivary epithelium where it gains access to fluids centrally important for horizontal transmission. PMID- 30404807 TI - Induction and suppression of NF-kappaB signalling by a DNA virus of Drosophila. AB - Interactions between the insect immune system and RNA viruses have been extensively studied in Drosophila, where RNA interference, NF-kappaB and JAK-STAT pathways underlie antiviral immunity. In response to RNA interference, insect viruses have convergently evolved suppressors of this pathway that act by diverse mechanisms to permit viral replication. However, interactions between the insect immune system and DNA viruses have received less attention, primarily because few Drosophila-infecting DNA virus isolates are available. Here, we use a recently isolated DNA virus of Drosophila melanogaster, Kallithea virus (family Nudiviridae), to probe known antiviral immune responses and virus evasion tactics in the context of DNA virus infection. We find that fly mutants for RNA interference and Immune deficiency (Imd), but not Toll, pathways are more susceptible to Kallithea virus infection. We identify the Kallithea virus-encoded protein gp83 as a potent inhibitor of Toll signalling, suggesting that Toll mediates antiviral defense against Kallithea virus infection, but that it is suppressed by the virus. We find that Kallithea virus gp83 inhibits Toll signalling through the regulation of NF-kappaB transcription factors. Furthermore, we find that gp83 of the closely related Drosophila innubila nudivirus (DiNV) suppresses D. melanogaster Toll signalling, suggesting an evolutionary conserved function of Toll in defense against DNA viruses. Together, these results provide a broad description of known antiviral pathways in the context of DNA virus infection and identify the first Toll pathway inhibitor in a Drosophila virus, extending the known diversity of insect virus-encoded immune inhibitors.IMPORTANCE Co-evolution of multicellular organisms and their natural viruses may lead to an intricate relationship in which host survival requires effective immunity, and virus survival depends on evasion of such responses. Insect antiviral immunity, and reciprocal virus immune suppression tactics, have been well-studied in Drosophila melanogaster, primarily during RNA, but not DNA, virus infection. Therefore, we describe interactions between a recently-isolated Drosophila DNA virus (Kallithea virus - KV) and immune processes known to control RNA viruses, such as RNAi and Imd pathways. We find that KV suppresses the Toll pathway, and identify gp83 as a KV-encoded protein that underlies this suppression. This immunosuppressive ability is conserved in another nudivirus, suggesting the Toll pathway has conserved antiviral activity against DNA nudiviruses, which have evolved suppressors in response. Together, these results indicate that DNA viruses induce and suppress NF-kappaB responses, and advance the application of KV as a model to study insect immunity. PMID- 30404808 TI - Fatty acid synthase promotes the palmitoylation of Chikungunya virus nsP1. AB - Chikungunya virus (CHIKV) is transmitted to people by mosquitoes, and CHIKV infection causes fever and joint pain. Fatty acid synthase (FASN) has been identified as a proviral factor for CHIKV. How FASN participates in CHIKV replication remains to be elucidated. In this study, we demonstrated that palmitic acid (PA) can restore the suppression of CHIKV replication by FASN inhibitors. The palmitoylation and plasma membrane localization of CHIKV nsP1 were reduced by FASN inhibitors. Triple mutation of Cys417, Cys418, and Cys419 in nsP1 blocked its palmitoylation and severely disrupted CHIKV replication. Furthermore, two zinc-finger D-H-H-C domain-containing palmitoyltransferases (ZDHHCs) including ZDHHC2 and ZDHHC19 promoted nsP1 palmitoylation and CHIKV replication. Our results not only identified the key enzymes for the palmitoylation of nsP1 but also provided mechanistic insights into the roles of FASN in CHIKV replication.Importance S-Palmitoylation is an important form of lipid posttranslational modification, which affects the function of proteins by regulating their transport, stability and localization. Previous studies have shown that FASN is critical for CHIKV replication; however, the mechanism for this function of FASN remains unknown. The key zinc-finger D-H-H-C domain containing palmitoyltransferases involved in the palmitoylation of nsP1 are not clear. We demonstrated that FASN promoted CHIKV replication through nsP1 palmitoylation. ZDHHC2 and ZDHHC19 were identified as the major enzymes for nsP1 palmitoylation. Since nsP1 proteins are conserved in alphaviruses, our results highlight the mechanisms by which alphavirus nsP1 is palmitoylated. PMID- 30404809 TI - Selective Editing of HSV-1 Enables IFN Induction and Viral Replication That Destruct Malignant Cells. AB - Oncolytic herpes simplex virus 1 (HSV-1), devoid of the gamma134.5 gene, exerts antitumor activities. However, the oncolytic effect differs, ranging from pronounced to little responses. Although viral and host factors are involved, much remains to be deciphered. Here we report that engineered HSV-1 (DeltaN146), bearing amino acids 147-263 of gamma134.5, replicates competently in and lyses malignant cells refractory to the gamma134.5 null mutant. Upon infection, DeltaN146 precludes phosphorylation of translation initiation factor eIF2alpha, ensuring viral protein synthesis. On the other hand, DeltaN146 activates interferon regulatory factor 3 and IFN expression, known to prime immunity against virus and tumor. Nevertheless, DeltaN146 exhibits sustained replication even exposed to exogenous IFN-alpha. In a 4T1 tumor model, DeltaN146 markedly reduces tumor growth and metastasis formation. This coincides with viral replication or T cell infiltration in primary tumors. DeltaN146 is undetectable in normal tissues in vivo. Herein, targeted HSV-1 editing results in a unique anti-neoplastic agent that enables inflammation without major interference of viral growth within tumor cells.IMPORTANCE Oncolytic herpes simplex virus 1 is a promising agent for cancer immunotherapy. Due to a complex virus-host interaction, less is clear about what viral signature(s) constitutes a potent oncolytic backbone. Through molecular or genetic dissection, we show that selective editing of the gamma134.5 gene enables viral replication in malignant cells, activation of transcription factor IRF3 and subsequent induction of type I IFN. This translates into profoundly reduced primary tumor growth and metastasis burden in an aggressive breast carcinoma model in vivo. Our work reveals a distinct oncolytic platform that is amendable for further development. PMID- 30404810 TI - Extensive Diversity of RNA Viruses in Australian Ticks. AB - Understanding the microbiome of ticks in Australia is of considerable interest given the ongoing debate over whether Lyme disease, and its causative agent the bacterium Borrelia burgdorferi sensu lato, are present in Australia. The diversity of bacteria infecting Australian ticks has been studied using both culture and metagenomics based techniques. However, little is known about the virome of Australian ticks, including whether this includes viruses with the potential to infect mammals. We used a meta-transcriptomics approach to reveal the diversity and evolution of viruses from Australian ticks collected from two locations on the central-east coast of Australia, including metropolitan Sydney. From this we identified 19 novel RNA viruses belonging to 12 families, as well as one previously described RNA virus. The majority of these viruses were related to arthropod-associated viruses suggesting that they do not utilize mammalian hosts. However, two novel viruses discovered in ticks feeding on bandicoot marsupials clustered closely within the mammalian-associated hepacivirus and pestivirus groups (family Flaviviridae). Another bandicoot tick yielded a novel coltivirus (family Reoviridae) - a group of largely tick-associated viruses containing the known human pathogen Colorado tick fever virus and its relative Eyach virus. Importantly, our transcriptomic data provided no evidence for the presence of B. burgdorferi s.l. in any tick sample, providing further evidence against the presence of Lyme Disease in Australia. In sum, this study reveals that Australian ticks harbor a diverse virome, including some viruses that merit additional screening in the context of emerging infectious disease.IMPORTANCE Each year a growing number of individuals along the east coast of Australia experience debilitating disease following tick bites. As there is no evidence for the presence of the causative agent of Lyme disease, Borrelia Burgdorferi sensu lato, in Australian ticks, the etiological basis of this disease syndrome remains controversial. To characterize the viruses associated with Australian ticks, particularly those that might be associated with mammalian infection, we performed unbiased RNA sequencing on 146 ticks collected across two locations along the coast of New South Wales, Australia. This revealed 19 novel RNA viruses from a diverse set of families. Notably, three of these viruses clustered with known mammalian viruses, including a novel coltivirus that was related to the human pathogen Colorado tick fever virus. PMID- 30404811 TI - Proposals for revised IWG 2018 hematological response criteria in patients with MDS included in clinical trials. AB - The heterogeneity of myelodysplastic syndromes (MDS) has made evaluating patient response to treatment challenging. In 2006, an International Working Group (IWG) proposed a revision to previously published standardized response criteria (IWG 2000) for uniformly evaluating clinical responses in MDS. These IWG 2006 criteria have been used prospectively in many clinical trials in MDS, but proved challenging in several of them, especially for the evaluation of erythroid response. In this report, we provide rationale for modifications (IWG 2018) of these recommendations, mainly for "hematological improvement" criteria used for lower risk MDS, based on recent practical and reported experience in clinical trials. Most suggestions relate to erythroid response assessment, which are refined in an overall more stringent manner. Two major proposed changes are the differentiation between "procedures" and "criteria" for hematologic improvement erythroid (HI-E) assessment and a new categorization of transfusion burden subgroups. PMID- 30404812 TI - Resolution of sickle cell disease associated inflammation and tissue damage with 17R-Resolvin D1. AB - The endogenous lipid mediators Resolvins (Rv) play a key role in the resolution of inflammation. Sickle cell disease (SCD), a genetic disorder of hemoglobin, is characterized by inflammatory and vaso-occlusive pathologies. We document in humanized SCD mice altered pro-resolving events following hypoxia/reperfusion. We demonstrate novel protective actions of 17R-RvD1 (7S, 8R, 17R-trihydroxy-4Z, 9E, 11E, 13Z, 15E, 19Z-docosahexaenoic acid), in reducing ex vivo human SCD blood leukocyte recruitment by microvascular endothelial cells and in vivo neutrophil adhesion and transmigration. In SCD mice exposed to hypoxia/reoxygenation, oral administration of 17R-RvD1 reduces systemic/ local inflammation and vascular dysfunction in lung and kidney. The mechanism of action of 17R-RvD1 involves: (i) enhancement of SCD erythrocytes and polymorphonuclear-leukocyte efferocytosis; (ii) blunting of NF-kappaB activation and (iii) reduction in inflammatory cytokines, vascular activation markers and E-selectin expression. Thus, 17R-RvD1 could represent a possible new therapeutic strategy for the inflammatory vasculopathy of SCD. PMID- 30404814 TI - Placenta Specific 8 Suppresses IL-18 Production through Regulation of Autophagy and Is Associated with Adult Still Disease. AB - Adult Still disease (ASD) is a systemic disorder of unknown etiology characterized by high spiking fever, rash, and arthritis. The purpose of this study was to identify genes specifically associated with the active phase of the disease. In this study, we have reported that placenta specific 8 (PLAC8) was a newly specific gene involved in ASD. DNA microarray and validation analysis using human monocytes revealed that the expression of PLAC8 was significantly higher in active-ASD patients than in inactive-ASD patients and healthy controls. In ASD, PLAC8 expression level correlated with serum levels of CRP, ferritin, IL-1beta, and IL-18. Stimulation of monocytes with LPS results in PLAC8 upregulation. LPS or nigericin stimulation of PLAC8-overexpressing human monocytic cell line (THP 1), but not mock THP-1 cells, was associated with a significant decrease in IL 1beta and IL-18 production. PLAC8 overexpression in THP-1 cells was associated with enhanced autophagy and suppression of IL-1beta and IL-18 production. Therefore, we found that PLAC8 was upregulated in activated monocytes, as was IL 1beta and IL-18. The upregulated PLAC8 acts on the synthesis of inactive precursors of IL-1beta and IL-18 and seemed to suppress the production of IL 1beta and IL-18 by negative feedback through enhanced autophagy, resulting in the suppression of ASD. The results highlight the role of PLAC8 in the pathogenesis of ASD and suggest its potential suitability as an activity marker and therapeutic target in ASD. PMID- 30404813 TI - Gasdermin D Promotes AIM2 Inflammasome Activation and Is Required for Host Protection against Francisella novicida. AB - The DNA sensor absent in melanoma 2 (AIM2) forms an inflammasome complex with ASC and caspase-1 in response to Francisella tularensis subspecies novicida infection, leading to maturation of IL-1beta and IL-18 and pyroptosis. AIM2 is critical for host protection against F. novicida infection in vivo; however, the role of pyroptosis downstream of the AIM2 inflammasome is unknown. Recent studies have identified gasdermin D (GSDMD) as the molecule executing pyroptosis by forming pores on the plasma membrane following activation by inflammatory caspase 1 and -11. In this study, we report that GSDMD-deficient mice were susceptible to F. novicida infection compared with wild type mice. Interestingly, we observed that GSDMD is required for optimal caspase-1 activation and pyroptotic cell death in F. novicida-infected bone marrow-derived macrophages. Furthermore, caspase-1 activation was compromised in bone marrow-derived macrophages lacking GSDMD stimulated with other AIM2 inflammasome triggers, including poly(dA:dT) transfection and mouse CMV infection. Overall, our study highlights a function, to our knowledge previously unknown, for GSDMD in promoting caspase-1 activation by AIM2 inflammasome. PMID- 30404815 TI - Sublytic C5b-9 Induces IL-23 and IL-36a Production by Glomerular Mesangial Cells via PCAF-Mediated KLF4 Acetylation in Rat Thy-1 Nephritis. AB - Sublytic C5b-9 formation on glomerular mesangial cells in rat Thy-1 nephritis (Thy-1N), a model of human mesangioproliferative glomerulonephritis, is accompanied by the production of proinflammatory cytokines, but the relationship between sublytic C5b-9 and cytokine synthesis and the underlying mechanism remains unclear. To explore the problems mentioned above, in this study, we first examined the levels of proinflammatory ILs (e.g., IL-23 and IL-36a) as well as transcription factor (KLF4) and coactivator (PCAF) in the renal tissues of Thy-1N rats and in the glomerular mesangial cell line (HBZY-1) stimulated by sublytic C5b-9. Then, we further determined the role of KLF4 and PCAF in sublytic C5b-9 induced IL-23 and IL-36a production as well as the related mechanism. Our results showed that the levels of KLF4, PCAF, IL-23, and IL-36a were obviously elevated. Mechanistic investigation revealed that sublytic C5b-9 stimulation could increase IL-23 and IL-36a synthesis through KLF4 and PCAF upregulation, and KLF4 and PCAF could form a complex, binding to the IL-23 or IL-36a promoter in a KLF4-dependent manner, causing gene transcription. Importantly, KLF4 acetylation by PCAF contributed to sublytic C5b-9-induced IL-23 and IL-36a transcription. Besides, the KLF4 binding regions on IL-23 or IL-36a promoters and the KLF4 lysine site acetylated by PCAF were identified. Furthermore, silencing renal KLF4 or PCAF gene could significantly inhibit IL-23 or IL-36a secretion and tissue damage of Thy-1N rats. Collectively, these findings implicate that the KLF4/PCAF interaction and KLF4 acetylation by PCAF play a pivotal role in the sublytic C5b 9-mediated IL-23 and IL-36a production of Thy-1N rats. PMID- 30404816 TI - Internet of instruments: Connectivity of research instruments and artificial intelligence could drastically advance experimental science. PMID- 30404817 TI - Rab22A recruits BLOC-1 and BLOC-2 to promote the biogenesis of recycling endosomes. AB - Recycling endosomes (REs) are transient endosomal tubular intermediates of early/sorting endosomes (E/SEs) that function in cargo recycling to the cell surface and deliver the cell type-specific cargo to lysosome-related organelles such as melanosomes in melanocytes. However, the mechanism of RE biogenesis is largely unknown. In this study, by using an endosomal Rab-specific RNAi screen, we identified Rab22A as a critical player during RE biogenesis. Rab22A-knockdown results in reduced RE dynamics and concurrent cargo accumulation in the E/SEs or lysosomes. Rab22A forms a complex with BLOC-1, BLOC-2 and the kinesin-3 family motor KIF13A on endosomes. Consistently, the RE-dependent transport defects observed in Rab22A-depleted cells phenocopy those in BLOC-1-/BLOC-2-deficient cells. Further, Rab22A depletion reduced the membrane association of BLOC-1/BLOC 2. Taken together, these findings suggest that Rab22A promotes the assembly of a BLOC-1-BLOC-2-KIF13A complex on E/SEs to generate REs that maintain cellular and organelle homeostasis. PMID- 30404818 TI - Low and middle income countries look to CQC for guidance. PMID- 30404820 TI - Initial bud outgrowth occurs independent of auxin flow out of buds. AB - Apical dominance is the process whereby the shoot tip inhibits the growth of axillary buds along the stem. It has been proposed that the shoot tip, which is the predominant source of the plant hormone auxin, prevents bud outgrowth by suppressing auxin canalization and export from axillary buds into the main stem. In this theory, auxin flow out of axillary buds is a prerequisite for bud outgrowth and buds are triggered to grow by an enhanced proportional flow of auxin from the buds. A major challenge of directly testing this model is in being able to create a bud- or stem-specific change in auxin transport. Here we evaluate the relationship between specific changes in auxin efflux from axillary buds and bud outgrowth after shoot tip removal (decapitation) in pea (Pisum sativum L.). The auxin transport inhibitor 1-N-Naphthylphthalamic acid (NPA) and to a lesser extent, the auxin perception inhibitor p-chlorophenoxyisobutyric acid (PCIB), effectively blocked auxin efflux from axillary buds of intact and decapitated plants without affecting auxin flow in the main stem. Gene expression analyses indicate that NPA and PCIB regulate auxin-inducible, and biosynthesis and transport genes in axillary buds within 3 hours after application. These inhibitors had no effect on initial bud outgrowth after decapitation or cytokinin (benzyladenine; BA) treatment. Inhibitory effects of PCIB and NPA on axillary bud outgrowth only became apparent from 48 hours after treatment. These findings demonstrate that the initiation of decapitation- and cytokinin-induced axillary bud outgrowth is independent of auxin canalization and export from the bud. PMID- 30404819 TI - Phosphorylation of Parkin at serine 65 is essential for its activation in vivo. AB - Mutations in PINK1 and Parkin result in autosomal recessive Parkinson's disease (PD). Cell culture and in vitro studies have elaborated the PINK1-dependent regulation of Parkin and defined how this dyad orchestrates the elimination of damaged mitochondria via mitophagy. PINK1 phosphorylates ubiquitin at serine 65 (Ser65) and Parkin at an equivalent Ser65 residue located within its N-terminal ubiquitin-like domain, resulting in activation; however, the physiological significance of Parkin Ser65 phosphorylation in vivo in mammals remains unknown. To address this, we generated a Parkin Ser65Ala (S65A) knock-in mouse model. We observe endogenous Parkin Ser65 phosphorylation and activation in mature primary neurons following mitochondrial depolarization and reveal this is disrupted in Parkin S65A/S65A neurons. Phenotypically, Parkin S65A/S65A mice exhibit selective motor dysfunction in the absence of any overt neurodegeneration or alterations in nigrostriatal mitophagy. The clinical relevance of our findings is substantiated by the discovery of homozygous PARKIN (PARK2) p.S65N mutations in two unrelated patients with PD. Moreover, biochemical and structural analysis demonstrates that the ParkinS65N/S65N mutant is pathogenic and cannot be activated by PINK1. Our findings highlight the central role of Parkin Ser65 phosphorylation in health and disease. PMID- 30404822 TI - Emergency care in England faces "year round crisis," BMA warns. PMID- 30404821 TI - ANGUSTIFOLIA Regulates Actin Filament Alignment for Nuclear Positioning in Leaves. AB - During dark adaptation, plant nuclei move centripetally toward the mid-plane of the leaf blade; thus the nuclei in both the adaxial and abaxial sides become positioned at the inner periclinal walls of cells. This centripetal nuclear positioning implies that a characteristic cell polarity exists within a leaf, but little is known about the mechanism underlying this process. Here we show that ANGUSTIFOLIA (AN) and ACTIN7 regulate centripetal nuclear positioning in Arabidopsis (Arabidopsis thaliana) leaves. Two mutants defective in the positioning of nuclei in the dark were isolated and designated as unusual nuclear positioning 1 (unp1) and unp2. In the dark, nuclei of unp1 were positioned at the anticlinal walls of adaxial and abaxial mesophyll cells and abaxial pavement cells, whereas the nuclei of unp2 were positioned at the anticlinal walls of mesophyll and pavement cells in both the adaxial and abaxial sides. unp1 was caused by a dominant-negative mutation in ACTIN7, and unp2 resulted from a recessive mutation in AN. Actin filaments in unp1 were fragmented and reduced in number, which led to pleiotropic defects in nuclear morphology, cytoplasmic streaming, and plant growth. The mutation in AN caused aberrant positioning of nuclei-associated actin filaments at the anticlinal walls. AN was detected in the cytosol, where it physically interacted with plant-specific dual-specificity tyrosine phosphorylation-regulated kinases (DYRKPs) and itself. The DYRK inhibitor (1Z)-1-(3-ethyl-5-hydroxy-2(3H)-benzothiazolylidene)-2-propanone (INDY) significantly inhibited dark-induced nuclear positioning. Collectively, these results suggest that the AN-DYRKP complex regulates the alignment of actin filaments during centripetal nuclear positioning in leaf cells. PMID- 30404823 TI - Role of G-proteins and phosphorylation in the distribution of AGS3 to cell puncta. AB - Activator of G-protein signaling 3 (AGS3, also known as GPSM1) exhibits broad functional diversity and oscillates among different subcellular compartments in a regulated manner. AGS3 consists of a tetratricopeptide repeat (TPR) domain and a G-protein regulatory (GPR) domain. Here, we tested the hypothesis that phosphorylation of the AGS3 GPR domain regulates its subcellular distribution and functionality. In contrast to the cortical and/or diffuse non-homogeneous distribution of wild-type (WT) AGS3, an AGS3 construct lacking all 24 potential phosphorylation sites in the GPR domain localized to cytosolic puncta. This change in localization was revealed to be dependent upon phosphorylation of a single threonine amino acid (T602). The punctate distribution of AGS3-T602A was rescued by co-expression of Galphai and Galphao but not Galphas or Galphaq Following treatment with alkaline phosphatase, both AGS3-T602A and WT AGS3 exhibited a gel shift in SDS-PAGE as compared to untreated WT AGS3, consistent with a loss of protein phosphorylation. The punctate distribution of AGS3-T602A was lost in an AGS3-A602T conversion mutant, but was still present upon T602 mutation to glutamate or aspartate. These results implicate dynamic phosphorylation as a discrete mechanism to regulate the subcellular distribution of AGS3 and associated functionality. PMID- 30404824 TI - Polarity sorting drives remodeling of actin-myosin networks. AB - Cytoskeletal networks of actin filaments and myosin motors drive many dynamic cell processes. A key characteristic of these networks is their contractility. Despite intense experimental and theoretical efforts, it is not clear what mechanism favors network contraction over expansion. Recent work points to a dominant role for the nonlinear mechanical response of actin filaments, which can withstand stretching but buckle upon compression. Here we present an alternative mechanism. We study how interactions between actin and myosin-2 at the single filament level translate into contraction at the network scale by performing time lapse imaging on reconstituted quasi-2D-networks mimicking the cell cortex. We observe myosin end-dwelling after it runs processively along actin filaments. This leads to transport and clustering of actin filament ends and the formation of transiently stable bipolar structures. Further we show that myosin-driven polarity sorting produces polar actin asters, which act as contractile nodes that drive contraction in crosslinked networks. Computer simulations comparing the roles of the end-dwelling mechanism and a buckling-dependent mechanism show that the relative contribution of end-dwelling contraction increases as the network mesh-size decreases. PMID- 30404827 TI - Localization of all four ZnT zinc transporters in Dictyostelium and impact of ZntA and ZntB knockout on bacteria killing. AB - Professional phagocytes have developed an extensive repertoire of autonomous immunity strategies to ensure killing of bacteria. Besides phagosome acidification and the generation of reactive oxygen species, deprivation of nutrients and the lumenal accumulation of toxic metals are essential to kill ingested bacteria or inhibit the growth of intracellular pathogens. Here, we used the soil amoeba Dictyostelium discoideum, a professional phagocyte that digests bacteria for nutritional purposes, to decipher the role of zinc poisoning during phagocytosis of nonpathogenic bacteria and visualize the temporal and spatial dynamics of compartmentalized, free zinc using fluorescent probes. Immediately after particle uptake, zinc is delivered to phagosomes by fusion with 'zincosomes' of endosomal origin, and also by the action of one or more zinc transporters. We localized the four Dictyostelium ZnT transporters to endosomes, the contractile vacuole and the Golgi complex, and studied the impact of znt knockouts on zinc homeostasis. We show that zinc is delivered into the lumen of Mycobacterium smegmatis-containing vacuoles, and that Escherichia coli deficient in the zinc efflux P1B-type ATPase ZntA are killed faster than wild-type bacteria. PMID- 30404828 TI - Soluble alpha-synuclein facilitates priming and fusion by releasing Ca2+ from the thapsigargin-sensitive Ca2+ pool in PC12 cells. AB - alpha-Synuclein is associated with Parkinson's disease, and is mainly localized in presynaptic terminals and regulates exocytosis, but its physiological roles remain controversial. Here, we studied the effects of soluble and aggregated alpha-synuclein on exocytosis, and explored the molecular mechanism by which alpha-synuclein interacts with regulatory proteins, including Rab3A, Munc13-1 (also known as Unc13a) and Munc18-1 (also known as STXBP1), in order to regulate exocytosis. Through fluorescence recovery after photobleaching experiments, overexpressed alpha-synuclein in PC12 cells was found to be in a monomeric form, which promotes exocytosis. In contrast, aggregated alpha-synuclein induced by lactacystin treatment inhibits exocytosis. Our results show that alpha-synuclein is involved in vesicle priming and fusion. alpha-Synuclein and phorbol 12 myristate 13-acetate (PMA), which is known to enhance vesicle priming mediated by Rab3A, Munc13-1 and Munc18-1, act on the same population of vesicles, but regulate priming independently. Furthermore, the results show a novel effects of alpha-synuclein on mobilizing Ca2+ release from thapsigargin-sensitive Ca2+ pools to enhance the ATP-induced [Ca2+]i increase, which enhances vesicle fusion. Our results provide a detailed understanding of the action of alpha-synuclein during the final steps of exocytosis. PMID- 30404829 TI - The use of decellularised animal tissue to study disseminating cancer cells. AB - Since the establishment of cell culture, common practice has been to grow adherent cells in 2D monolayers. Although cells behave completely differently when grown in these artificial conditions, the ease of 2D culturing has meant that this practice still prevails today, and adopting conditions that more closely reflect the natural microenvironment has been met with substantial inertia. The alternative, animal models that mimic natural human physiology, are less accessible, strictly regulated and require licences and expensive facilities. Although transition from 2D to 3D cell culturing is gathering momentum, there is a clear need for alternative culturing methods that more closely resemble in vivo conditions. Here we show that decellularised organs gleaned from discarded animal carcasses are ideal biomimetic scaffolds to support secondary tumour initiation in vitro. This article describes how to decellularise tissue, perform basic histochemistry and immunofluorescence procedures for cell and matrix detection; and follows cancer cell behaviour on this matrix by way of an example. As integration into the traditional work flow is easy and inexpensive we hope this article will encourage other researchers to adopt this approach. PMID- 30404830 TI - Cytokine exocytosis and JAK/STAT activation in the Drosophila ovary requires the vesicle trafficking regulator alpha-Snap. AB - How vesicle trafficking components actively contribute to regulation of paracrine signaling is unclear. We genetically uncovered a requirement for alpha-soluble NSF attachment protein (alpha-Snap) in the activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway during Drosophila egg development. alpha-Snap, a well-conserved vesicle trafficking regulator, mediates association of N-ethylmaleimide-sensitive factor (NSF) and SNAREs to promote vesicle fusion. Depletion of alpha-Snap or the SNARE family member Syntaxin1A in epithelia blocks polar cells maintenance and prevents specification of motile border cells. Blocking apoptosis rescues polar cell maintenance in alpha-Snap-depleted egg chambers, indicating that the lack of border cells in mutants is due to impaired signaling. Genetic experiments implicate alpha-Snap and NSF in secretion of a STAT-activating cytokine. Live imaging suggests that changes in intracellular Ca2+ are linked to this event. Our data suggest a cell type specific requirement for particular vesicle trafficking components in regulated exocytosis during development. Given the central role for STAT signaling in immunity, this work may shed light on regulation of cytokine release in humans. PMID- 30404826 TI - Enigma proteins regulate YAP mechanotransduction. AB - Human cells can sense mechanical stress acting upon integrin adhesions and respond by sending the YAP (also known as YAP1) and TAZ (also known as WWTR1) transcriptional co-activators to the nucleus to drive TEAD-dependent transcription of target genes. How integrin signaling activates YAP remains unclear. Here, we show that integrin-mediated mechanotransduction requires the Enigma and Enigma-like proteins (PDLIM7 and PDLIM5, respectively; denoted for the family of PDZ and LIM domain-containing proteins). YAP binds to PDLIM5 and PDLIM7 (hereafter PDLIM5/7) via its C-terminal PDZ-binding motif (PBM), which is essential for full nuclear localization and activity of YAP. Accordingly, silencing of PDLIM5/7 expression reduces YAP nuclear localization, tyrosine phosphorylation and transcriptional activity. The PDLIM5/7 proteins are recruited from the cytoplasm to integrin adhesions and F-actin stress fibers in response to force by binding directly to the key stress fiber component alpha-actinin. Thus, forces acting on integrins recruit Enigma family proteins to trigger YAP activation during mechanotransduction.This article has an associated First Person interview with the first author of the paper. PMID- 30404825 TI - Fibronectin regulates growth factor signaling and cell differentiation in primary lens cells. AB - Lens epithelial cells are bound to the lens extracellular matrix capsule, of which laminin is a major component. After cataract surgery, surviving lens epithelial cells are exposed to increased levels of fibronectin, and so we addressed whether fibronectin influences lens cell fate, using DCDML cells as a serum-free primary lens epithelial cell culture system. We found that culturing DCDMLs with plasma-derived fibronectin upregulated canonical TGFbeta signaling relative to cells plated on laminin. Fibronectin-exposed cultures also showed increased TGFbeta signaling-dependent differentiation into the two cell types responsible for posterior capsule opacification after cataract surgery, namely myofibroblasts and lens fiber cells. Increased TGFbeta activity could be identified in the conditioned medium recovered from cells grown on fibronectin. Other experiments showed that plating DCDMLs on fibronectin overcomes the need for BMP in fibroblast growth factor (FGF)-induced lens fiber cell differentiation, a requirement that is restored when endogenous TGFbeta signaling is inhibited. These results demonstrate how the TGFbeta-fibronectin axis can profoundly affect lens cell fate. This axis represents a novel target for prevention of late-onset posterior capsule opacification, a common but currently intractable complication of cataract surgery. PMID- 30404831 TI - Alpha-synuclein fibrils recruit TBK1 and OPTN to lysosomal damage sites and induce autophagy in microglial cells. AB - Autophagic dysfunction and protein aggregation have been linked to several neurodegenerative disorders, but the exact mechanisms and causal connections are not clear and most previous work was done in neurons and not in microglial cells. Here, we report that exogenous fibrillary, but not monomeric, alpha-synuclein (AS, also known as SNCA) induces autophagy in microglial cells. We extensively studied the dynamics of this response using both live-cell imaging and correlative light-electron microscopy (CLEM), and found that it correlates with lysosomal damage and is characterised by the recruitment of the selective autophagy-associated proteins TANK-binding kinase 1 (TBK1) and optineurin (OPTN) to ubiquitylated lysosomes. In addition, we observed that LC3 (MAP1LC3B) recruitment to damaged lysosomes was dependent on TBK1 activity. In these fibrillar AS-treated cells, autophagy inhibition impairs mitochondrial function and leads to microglial cell death. Our results suggest that microglial autophagy is induced in response to lysosomal damage caused by persistent accumulation of AS fibrils. Importantly, triggering of the autophagic response appears to be an attempt at lysosomal quality control and not for engulfment of fibrillar AS.This article has an associated First Person interview with the first author of the paper. PMID- 30404832 TI - CAP1-mediated actin cycling via ADF/cofilin proteins is essential for asymmetric division in mouse oocytes. AB - Dynamic reorganization of the actin cytoskeleton is fundamental to a number of cellular events, and various actin-regulatory proteins modulate actin polymerization and depolymerization. Adenylyl cyclase-associated proteins (CAPs), highly conserved actin monomer-binding proteins, have been known to promote actin disassembly by enhancing the actin-severing activity of the ADF/cofilin protein family. In this study, we found that CAP1 regulated actin remodeling during mouse oocyte maturation. Efficient actin disassembly during oocyte maturation is essential for asymmetric division and cytokinesis. CAP1 knockdown impaired meiotic spindle migration and asymmetric division, and resulted in an accumulation of excessive actin filaments near the spindles. In contrast, CAP1 overexpression reduced actin mesh levels. CAP1 knockdown also rescued a decrease in cofilin family protein overexpression-mediated actin levels, and simultaneous expression of human CAP1 (hCAP1) and cofilin synergistically decreased cytoplasmic actin levels. Overexpression of hCAP1 decreased the amount of phosphorylated cofilin, indicating that CAP1 facilitated actin depolymerization via interaction with ADF/cofilin during mouse oocyte maturation. Taken together, our results provide evidence for the importance of dynamic actin recycling by CAP1 and cofilin in the asymmetric division of mouse female gametes.This article has an associated First Person interview with the first author of the paper. PMID- 30404833 TI - Biphasic recruitment of TRF2 to DNA damage sites promotes non-sister chromatid homologous recombination repair. AB - TRF2 (TERF2) binds to telomeric repeats and is critical for telomere integrity. Evidence suggests that it also localizes to non-telomeric DNA damage sites. However, this recruitment appears to be precarious and functionally controversial. We find that TRF2 recruitment to damage sites occurs by a two-step mechanism: the initial rapid recruitment (phase I), and stable and prolonged association with damage sites (phase II). Phase I is poly(ADP-ribose) polymerase (PARP)-dependent and requires the N-terminal basic domain. The phase II recruitment requires the C-terminal MYB/SANT domain and the iDDR region in the hinge domain, which is mediated by the MRE11 complex and is stimulated by TERT. PARP-dependent recruitment of intrinsically disordered proteins contributes to transient displacement of TRF2 that separates two phases. TRF2 binds to I-PpoI induced DNA double-strand break sites, which is enhanced by the presence of complex damage and is dependent on PARP and the MRE11 complex. TRF2 depletion affects non-sister chromatid homologous recombination repair, but not homologous recombination between sister chromatids or non-homologous end-joining pathways. Our results demonstrate a unique recruitment mechanism and function of TRF2 at non-telomeric DNA damage sites. PMID- 30404834 TI - Elongated mitochondrial constrictions and fission in muscle fatigue. AB - Mitochondria respond to stress and undergo fusion and fission at variable rates, depending on cell status. To understand mitochondrial behavior during muscle fatigue, we investigated mitochondrial ultrastructure and expression levels of a fission- and stress-related protein in fast-twitch muscle fibers of mice subjected to fatigue testing. Mice were subjected to running at increasing speed until exhaustion at 45 min-1 h. In further experiments, high-intensity muscle stimulation through the sciatic nerve simulated the forced treadmill exercise. We detected a rare phenotype characterized by elongated mitochondrial constrictions (EMCs) connecting two separate segments of the original organelles. EMCs are rare in resting muscles and their frequency increases, albeit still at low levels, in stimulated muscles. The constrictions are accompanied by elevated phosphorylation of Drp1 (Dnm1l) at Ser 616, indicating an increased translocation of Drp1 to the mitochondrial membrane. This is indicative of a mitochondrial stress response, perhaps leading to or facilitating a long-lasting fission event. A close apposition of sarcoplasmic reticulum (SR) to the constricted areas, detected using both transmission and scanning electron microscopy, is highly suggestive of SR involvement in inducing mitochondrial constrictions. PMID- 30404835 TI - CCDC102B functions in centrosome linker assembly and centrosome cohesion. AB - The proteinaceous centrosome linker is an important structure that allows the centrosome to function as a single microtubule-organizing center (MTOC) in interphase cells. However, the assembly mechanism of the centrosome linker components remains largely unknown. In this study, we identify CCDC102B as a new centrosome linker protein that is required for maintaining centrosome cohesion. CCDC102B is recruited to the centrosome by C-Nap1 (also known as CEP250) and interacts with the centrosome linker components rootletin and LRRC45. CCDC102B decorates and facilitates the formation of rootletin filaments. Furthermore, CCDC102B is phosphorylated by Nek2A (an isoform encoded by NEK2) and is disassociated from the centrosome at the onset of mitosis. Together, our findings reveal a molecular role for CCDC102B in centrosome cohesion and centrosome linker assembly.This article has an associated First Person interview with the first authors of the paper. PMID- 30404836 TI - Parallel signaling pathways regulate excitable dynamics differently to mediate pseudopod formation during eukaryotic chemotaxis. AB - In eukaryotic chemotaxis, parallel signaling pathways regulate the spatiotemporal pseudopod dynamics at the leading edge of a motile cell through the characteristic dynamics of an excitable system; however, differences in the excitability and the physiological roles of individual pathways remain to be elucidated. Here, we found that two different pathways, mediated by soluble guanylyl cyclase (sGC) and phosphoinositide 3-kinase (PI3K), caused similar all or-none responses for sGC localization and phosphatidylinositol 3,4,5 trisphosphate production but with different refractory periods, by undertaking simultaneous observations of the excitable properties of the two pathways in Dictyostelium cells. Owing to the shorter refractory period, sGC signaling responded more frequently to chemoattractants, leading to pseudopod formation with higher frequency. sGC excitability was regulated negatively by its product cGMP and by cGMP-binding protein C (GbpC) through the suppression of F-actin polymerization, providing the underlying delayed negative-feedback mechanism for the cyclical pseudopod formation. These results suggest that parallel pathways respond to environmental cues on different timescales in order to mediate chemotactic motility in a manner based on their intrinsic excitability. PMID- 30404837 TI - Cullin-3-KCTD10-mediated CEP97 degradation promotes primary cilium formation. AB - Primary cilia are antenna-like sensory organelles that transmit various extracellular signals. Ciliogenesis requires the removal of CP110 and its interactor CEP97 from the mother centriole for initiating ciliary axoneme extension, but the underlying mechanism remains unknown. Here we show that CEP97 is partially degraded upon serum starvation by the ubiquitin-proteasome system. CEP97 was polyubiquitinated in serum-starved cells, and overexpression of a non ubiquitinatable CEP97 mutant effectively blocked CP110 removal and ciliogenesis induced by serum-starvation. Through several screening steps, we identified the Cullin-3-RBX1-KCTD10 complex as the E3 ligase that mediates CEP97 degradation and removal from the mother centriole. Depletion of each component of this E3 complex caused aberrant accumulation of CEP97 on the centrosome, suppressed the removal of CEP97 and CP110 from the mother centriole, and impaired ciliogenesis. Moreover, KCTD10 was specifically localized on the mother centriole. These results suggest that CEP97 degradation by the Cullin-3-RBX1-KCTD10 complex play a crucial role in serum-starvation-induced CP110 removal and ciliogenesis. PMID- 30404838 TI - TI-VAMP/VAMP7-SNARE-Rab-GTPase interaction network within a ciliary membrane targeting complex. AB - The rhodopsin-VxPx-Arf4 complex initiates expansion of vertebrate rod photoreceptor cilia-derived light-sensing organelles through stepwise assembly of the conserved trafficking network. Here, we examine its role in the sorting of VAMP7/TI-VAMP-an R-SNARE possessing a regulatory longin domain (LD)-into rhodopsin transport carriers (RTCs). During RTC formation and trafficking, VAMP7 co-localizes with the ciliary cargo rhodopsin and interacts with the Rab11-Rabin8 Rab8 trafficking module. Rab11 and Rab8 bind VAMP7 LD, whereas Rabin8 interacts with the SNARE domain. The Arf/Rab11 effector FIP3 regulates VAMP7 access to Rab11. At the ciliary base, VAMP7 forms a complex with the cognate SNAREs syntaxin 3 and SNAP-25. When expressed in transgenic animals, GFP-VAMP7DeltaLD fusion protein, and a Y45E phosphomimetic mutant, colocalize with endogenous VAMP7. GFP-VAMP7-R150E mutant displays considerable localization defects that imply an important role of the R-SNARE motif in intracellular trafficking, rather than cognate SNARE pairing. Our study defines the link between VAMP7 and the ciliary targeting nexus that is conserved across diverse cell types, and contributes to general understanding of how functional Arf and Rab networks assemble SNAREs in membrane trafficking. PMID- 30404839 TI - Engaging with patients on research to inform better care. PMID- 30404840 TI - Youth engagement in the YouthCan IMPACT trial. PMID- 30404841 TI - Involving people with lived experience in research on suicide prevention. PMID- 30404842 TI - Beyond the patient: lessons from community engagement in a rural First Nation. PMID- 30404843 TI - Describing the process of ethical conduct of research in an Ontario-wide First Nations diabetes research project. PMID- 30404844 TI - Engaging parents to research childhood interventions aimed at preventing common health problems. PMID- 30404845 TI - Partnering with families of children with medical complexity to evaluate interventions. PMID- 30404846 TI - Effectiveness of parents and clinicians working together to improve pain management in newborns. PMID- 30404847 TI - Patient engagement in pediatric concussion research. PMID- 30404848 TI - Patient and caregiver involvement in a multicentre clustered hemodialysis trial. PMID- 30404849 TI - Patient engagement in a trial testing a new strategy of care for acute heart failure. PMID- 30404850 TI - Patient engagement in research related to accelerated surgical care and treatment for hip fracture. PMID- 30404851 TI - Engaging older adults as partners in transitional care research. PMID- 30404852 TI - Engaging patients to select measures for a primary care audit and feedback initiative. PMID- 30404853 TI - Community members co-designing a trial of medication access. PMID- 30404854 TI - Engaging patients to improve equitable access to community resources. PMID- 30404855 TI - Patient and paramedic engagement in prehospital emergency medicine research. PMID- 30404856 TI - Engaging patients to develop a patient-reported outcome measure for the emergency department. PMID- 30404857 TI - Demonstrating the value of patient-oriented research in Ontario. PMID- 30404858 TI - Assembly of the beta4-integrin interactome based on proximal biotinylation in the presence and absence of heterodimerization. AB - Integrin-mediated laminin adhesions mediate epithelial cell anchorage to basement membranes and are critical regulators of epithelial cell polarity. Integrins assemble large multiprotein complexes that link to the cytoskeleton and convey signals into the cells. Comprehensive proteomic analyses of actin network-linked focal adhesions (FA) have been performed, but the molecular composition of intermediate filament-linked hemidesmosomes (HD) remains incompletely characterized. Here we have utilized proximity-dependent biotin identification (BioID) technology to label and characterize the interactome of epithelia specific beta4-integrin that, as alpha6beta4-heterodimer, forms the core of HDs. The analysis identified ~150 proteins that were specifically labeled by BirA tagged integrin-beta4. In addition to known HDs proteins, the interactome revealed proteins that may indirectly link integrin-beta4 to actin-connected protein complexes, such as FAs and dystrophin/dystroglycan complexes. The specificity of the screening approach was validated by confirming the HD localization of two candidate beta4-interacting proteins, utrophin (UTRN) and ELKS/Rab6-interacting/CAST family member 1 (ERC1). Interestingly, while establishment of functional HDs depends on the formation of alpha6beta4 heterodimers, the assembly of beta4-interactome was not strictly dependent on alpha6-integrin expression. Our survey to the HD interactome sets a precedent for future studies and provides novel insight into the mechanisms of HD assembly and function of the beta4-integrin. PMID- 30404859 TI - Patient commentary: Stop hyping artificial intelligence-patients will always need human doctors. PMID- 30404860 TI - One size does not fit all: Size-based plasma DNA diagnostics. AB - Understanding the biological properties of plasma cell-free DNA may expand its applications in oncology (Mouliere et al, this issue). PMID- 30404861 TI - 68Ga-DOTA-GGNle-CycMSHhex targets the melanocortin-1 receptor for melanoma imaging. AB - Melanocortin-1 receptor (MC1R) is a molecular target for melanoma imaging and therapy because of its overexpression on rodent and human melanoma cells. Here, we evaluated the MC1R targeting and specificity of 68Ga-DOTA-GGNle-CycMSHhex and Cy5.5-GGNle-CycMSHhex using murine and human melanoma cells, and murine and xenografted tumors. 68Ga-DOTA-GGNle-CycMSHhex was used first in human as an imaging probe to evaluate the possibility of radionuclide therapy in patients with advanced-stage melanoma. 68Ga-DOTA-GGNle-CycMSHhex and Cy5.5-GGNle-CycMSHhex displayed MC1R-specific targeting properties in murine and human melanoma cells, as well as in murine melanoma and human melanoma-xenografted tumors. Both B16/F10 and M21 melanoma lesions could be easily imaged by positron emission tomography using 68Ga-DOTA-GGNle-CycMSHhex The first-in-human images of melanoma brain metastases in patients demonstrated the clinical relevance of MC1R as a molecular target for melanoma imaging, highlighting the potential of 68Ga-DOTA-GGNle CycMSHhex as an MC1R-targeting melanoma imaging probe and underscoring the need to develop MC1R-targeting therapeutic agents for treating patients with metastatic melanoma. PMID- 30404862 TI - Calcified nodules in retinal drusen are associated with disease progression in age-related macular degeneration. AB - Drusen are lipid-, mineral-, and protein-containing extracellular deposits that accumulate between the basal lamina of the retinal pigment epithelium (RPE) and Bruch's membrane (BrM) of the human eye. They are a defining feature of age related macular degeneration (AMD), a common sight-threatening disease of older adults. The appearance of heterogeneous internal reflectivity within drusen (HIRD) on optical coherence tomography (OCT) images has been suggested to indicate an increased risk of progression to advanced AMD. Here, in a cohort of patients with AMD and drusen, we show that HIRD indicated an increased risk of developing advanced AMD within 1 year. Using multimodal imaging in an independent cohort, we demonstrate that progression to AMD was associated with increasing degeneration of the RPE overlying HIRD. Morphological analysis of clinically imaged cadaveric human eye samples revealed that HIRD was formed by multilobular nodules. Nanoanalytical methods showed that nodules were composed of hydroxyapatite and that they differed from spherules and BrM plaques, other refractile features also found in the retinas of patients with AMD. These findings suggest that hydroxyapatite nodules may be indicators of progression to advanced AMD and that using multimodal clinical imaging to determine the composition of macular calcifications may help to direct therapeutic strategies and outcome measures in AMD. PMID- 30404864 TI - Wnt1 is an Lrp5-independent bone-anabolic Wnt ligand. AB - WNT1 mutations in humans are associated with a new form of osteogenesis imperfecta and with early-onset osteoporosis, suggesting a key role of WNT1 in bone mass regulation. However, the general mode of action and the therapeutic potential of Wnt1 in clinically relevant situations such as aging remain to be established. Here, we report the high prevalence of heterozygous WNT1 mutations in patients with early-onset osteoporosis. We show that inactivation of Wnt1 in osteoblasts causes severe osteoporosis and spontaneous bone fractures in mice. In contrast, conditional Wnt1 expression in osteoblasts promoted rapid bone mass increase in developing young, adult, and aged mice by rapidly increasing osteoblast numbers and function. Contrary to current mechanistic models, loss of Lrp5, the co-receptor thought to transmit extracellular WNT signals during bone mass regulation, did not reduce the bone-anabolic effect of Wnt1, providing direct evidence that Wnt1 function does not require the LRP5 co-receptor. The identification of Wnt1 as a regulator of bone formation and remodeling provides the basis for development of Wnt1-targeting drugs for the treatment of osteoporosis. PMID- 30404865 TI - A well-preserved respiratory system in a Silurian ostracod. AB - Ostracod crustaceans are diverse and ubiquitous in aqueous environments today but relatively few known species have gills. Ostracods are the most abundant fossil arthropods but examples of soft-part preservation, especially of gills, are exceptionally rare. A new ostracod, Spiricopia aurita (Myodocopa), from the marine Silurian Herefordshire Lagerstatte (430 Mya), UK, preserves appendages, lateral eyes and gills. The respiratory system includes five pairs of gill lamellae with hypobranchial and epibranchial canals that conveyed haemolymph. A heart and associated vessels had likely evolved in ostracods by the Mid-Silurian. PMID- 30404863 TI - Enhanced detection of circulating tumor DNA by fragment size analysis. AB - Existing methods to improve detection of circulating tumor DNA (ctDNA) have focused on genomic alterations but have rarely considered the biological properties of plasma cell-free DNA (cfDNA). We hypothesized that differences in fragment lengths of circulating DNA could be exploited to enhance sensitivity for detecting the presence of ctDNA and for noninvasive genomic analysis of cancer. We surveyed ctDNA fragment sizes in 344 plasma samples from 200 patients with cancer using low-pass whole-genome sequencing (0.4*). To establish the size distribution of mutant ctDNA, tumor-guided personalized deep sequencing was performed in 19 patients. We detected enrichment of ctDNA in fragment sizes between 90 and 150 bp and developed methods for in vitro and in silico size selection of these fragments. Selecting fragments between 90 and 150 bp improved detection of tumor DNA, with more than twofold median enrichment in >95% of cases and more than fourfold enrichment in >10% of cases. Analysis of size-selected cfDNA identified clinically actionable mutations and copy number alterations that were otherwise not detected. Identification of plasma samples from patients with advanced cancer was improved by predictive models integrating fragment length and copy number analysis of cfDNA, with area under the curve (AUC) >0.99 compared to AUC <0.80 without fragmentation features. Increased identification of cfDNA from patients with glioma, renal, and pancreatic cancer was achieved with AUC > 0.91 compared to AUC < 0.5 without fragmentation features. Fragment size analysis and selective sequencing of specific fragment sizes can boost ctDNA detection and could complement or provide an alternative to deeper sequencing of cfDNA. PMID- 30404866 TI - Colour pattern predicts outcome of female contest competition in a sexually monomorphic fish. AB - Selection arising from social competition over non-mating resources, i.e. resources that do not directly and immediately affect mating success, offers a powerful alternative to sexual selection to explain the evolution of conspicuous ornaments, particularly in females. Here, we address the hypothesis that competition associated with the territoriality exhibited by both males and females in the cichlid fish Tropheus selects for the display of a conspicuous colour pattern in both sexes. The investigated pattern consists of a vertical carotenoid-coloured bar on a black body. Bar width affected the probability of winning in size-matched female-female, but not male-male, contests for territory possession. Our results support the idea that the emergence of female territoriality contributed to the evolution of sexual monomorphism from a dimorphic ancestor, in that females acquired the same conspicuous coloration as males to communicate in contest competition. PMID- 30404867 TI - Reproductive resilience of an estuarine fish in the eye of a hurricane. AB - Spatial and temporal patterns of spawning activity are important measures of resilience in fishes that directly link environmental disturbances with reproductive success. We acoustically monitored spawning in spotted seatrout (Cynoscion nebulosus) from April through September 2017 at 15 sites near Port Aransas, Texas, which coincided with the landfall of a category 4 hurricane (Harvey) on 25 August. Spawning sounds were recorded every day of the study across all sites and were also confirmed during the hurricane at two sites located within the eye of the storm. Daily spawning continued after the hurricane, but the onset of spawning shifted 2.12 h earlier for 5 days, after which it returned to the pre-storm schedule. These results illustrate the resilience of seatrout to intense, episodic disturbances and offer insights on the phenotypic plasticity of estuarine fishes to cope with projected increases in environmental variability. PMID- 30404868 TI - A wood-warbler produced through both interspecific and intergeneric hybridization. AB - Hybridization between divergent taxa can provide insight into the breakdown of characters used in mate choice, as well as reproductive compatibility across deep evolutionary timescales. Hybridization can also occur more frequently in declining populations, as there is a smaller pool of conspecific mates from which to choose. Here, we report an unusual combination of factors that has resulted in a rare, three-species hybridization event among two genera of warblers, one of which is experiencing significant population declines. We use bioacoustic, morphometric and genetic data, to demonstrate that an early generation female hybrid between a golden-winged warbler (Vermivora chrysoptera) and a blue-winged warbler (V. cyanoptera) went on to mate and successfully reproduce with a chestnut-sided warbler (Setophaga pensylvanica). We studied the product of this event-a putative chrysoptera * cyanoptera * pensylvanica hybrid-and show that this male offspring sang songs like S. pensylvanica, but had morphometric traits similar to Vermivora warblers. The hybrid's maternal parent had V. chrysoptera mitochondrial DNA and, with six plumage-associated loci, we predicted the maternal parent's phenotype to show that it was likely an early generation Vermivora hybrid. That this hybridization event occurred within a population of Vermivora warblers in significant decline suggests that females may be making the best of a bad situation, and that wood-warblers in general have remained genetically compatible long after they evolved major phenotypic differences. PMID- 30404869 TI - Risk factors for MI are more potent in women, finds study. PMID- 30404870 TI - Obesity-associated breast inflammation among Hispanic/Latina breast cancer patients. AB - Breast white adipose tissue inflammation (BWATi) is associated with obesity and higher breast cancer (BC) risk among non-Hispanic white women. Obesity is prevalent in Hispanic/Latina BC patients, and the occurrence of BWATi in this population is not well-characterized. The association between BWATi and body mass index (BMI) was evaluated in Hispanic/Latina BC patients who underwent mastectomy. BWATi was defined as the presence of crown-like structures of the breast (CLS-B), detected by CD68 immunohistochemistry in non-tumor breast tissue. BWATi severity was quantified as number of CLS-B/cm2. Adipocyte diameter was measured using hematoxylin and eosin (H&E) stained breast tissue sections. Preoperative BMI (within 1 week prior to mastectomy) was categorized as normal (18.5 to <25.0 kg/m2), overweight (25.0 to <30.0 kg/m2), class I obesity (30.0 to <35.0 kg/m2), and class II-III obesity (35.0 kg/m2 or above). Patient charts were abstracted to record clinicopathologic features and liver function tests <90 days before mastectomy. The study included 91 women (mean age 69 years; range 36-96 years). Prevalence of BWATi increased with BMI (24% in normal weight, 34% in overweight, 57% in class I obesity, and 65% in class II-III obesity; P for trend <0.01). Severe BWATi (>0.27 CLS-B/cm2) was associated with higher BMI (P for trend=0.046) and greater adipocyte diameter (P=0.04). Adjusting for BMI, neoadjuvant chemotherapy and elevated alanine aminotransferase were associated with severe BWATi, and current smoking was associated with mild BWATi (all P<0.05). BWATi was associated with higher BMI in Hispanic/Latina BC patients, consistent with previously described associations in other populations. PMID- 30404871 TI - Locomotor constraints favour the evolution of the human pygmy phenotype in tropical rainforests. AB - The convergent evolution of the human pygmy phenotype in tropical rainforests is widely assumed to reflect adaptation in response to the distinct ecological challenges of this habitat (e.g. high levels of heat and humidity, high pathogen load, low food availability, and dense forest structure), yet few precise adaptive benefits of this phenotype have been proposed. Here, we describe and test a biomechanical model of how the rainforest environment can alter gait kinematics such that short stature is advantageous in dense habitats. We hypothesized that environmental constraints on step length in rainforests alter walking mechanics such that taller individuals are expected to walk more slowly due to their inability to achieve preferred step lengths in the rainforest. We tested predictions from this model with experimental field data from two short statured populations that regularly forage in the rainforest: the Batek of Peninsular Malaysia and the Tsimane of the Bolivian Amazon. In accordance with model expectations, we found stature-dependent constraints on step length in the rainforest and concomitant reductions in walking speed that are expected to compromise foraging efficiency. These results provide the first evidence that the human pygmy phenotype is beneficial in terms of locomotor performance and highlight the value of applying laboratory-derived biomechanical models to field settings for testing evolutionary hypotheses. PMID- 30404872 TI - Marginal sinks or potential refuges? Costs and benefits for coral-obligate reef fishes at deep range margins. AB - Escalating climate-related disturbances and asymmetric habitat losses will increasingly result in species living in more marginal habitats. Marginal habitats may represent important refuges if individuals can acquire adequate resources to survive and reproduce. However, resources at range margins are often distributed more sparsely; therefore, increased effort to acquire resources can result in suboptimal performance and lead to marginal populations becoming non self-sustaining sink-populations. Shifting resource availability is likely to be particularly problematic for dietary specialists. Here, we use extensive in situ behavioural observations and physiological condition measurements to examine the costs and benefits of resource-acquisition along a depth gradient in two obligate corallivore reef fishes with contrasting levels of dietary specialization. As expected, the space used to secure coral resources increased towards the lower depth margin. However, increased territory sizes resulted in equal or greater availability of resources within deeper territories. In addition, we observed decreased competition and no differences in foraging distance, pairing behaviour, body condition or fecundity at greater depths. Contrary to expectation, our results demonstrate that coral-obligate fishes can select high-quality coral patches on the deeper-reef to access equal or greater resources than their shallow-water counterparts, with no extra costs. This suggests depth offers a viable potential refuge for some at-risk coral-specialist fishes. PMID- 30404873 TI - Contrasting evolutionary history, anthropogenic declines and genetic contact in the northern and southern white rhinoceros (Ceratotherium simum). AB - The white rhinoceros (Ceratotherium simum) has a discontinuous African distribution, which is limited by the extent of sub-Saharan grasslands. The southern population (SWR) declined to its lowest number around the turn of the nineteenth century, but recovered to become the world's most numerous rhinoceros. In contrast, the northern population (NWR) was common during much of the twentieth century, declining rapidly since the 1970s, and now only two post reproductive individuals remain. Despite this species's conservation status, it lacks a genetic assessment of its demographic history. We therefore sampled 232 individuals from extant and museum sources and analysed ten microsatellite loci and the mtDNA control region. Both marker types reliably partitioned the species into SWR and NWR, with moderate nuclear genetic diversity and only three mtDNA haplotypes for the species, including historical samples. We detected ancient interglacial demographic declines in both populations. Both populations may also have been affected by recent declines associated with the colonial expansion for the SWR, and with the much earlier Bantu migrations for the NWR. Finally, we detected post-divergence secondary contact between NWR and SWR, possibly occurring as recently as the last glacial maximum. These results suggest the species was subjected to regular periods of fragmentation and low genetic diversity, which may have been replenished upon secondary contact during glacial periods. The species's current situation thus reflects prehistoric declines that were exacerbated by anthropogenic pressure associated with the rise of late Holocene technological advancement in Africa. Importantly, secondary contact suggests a potentially positive outcome for a hybrid rescue conservation strategy, although further genome-wide data are desirable to corroborate these results. PMID- 30404874 TI - Sexual dimorphism in a top predator (Notophthalmus viridescens) drives aquatic prey community assembly. AB - Intraspecific variation can have important consequences for the structure and function of ecological communities, and serves to link community ecology to evolutionary processes. Differences between the sexes are an overwhelmingly common form of intraspecific variation, but its community-level consequences have never been experimentally investigated. Here, we manipulate the sex ratio of a sexually dimorphic predacious newt in aquatic mesocosms, then track their impact on prey communities. Female and male newts preferentially forage in the benthic and pelagic zones, respectively, causing corresponding reductions in prey abundances in those habitats. Sex ratio differences also explained a large proportion (33%) of differences in the composition of entire pond communities. Ultimately, we demonstrate the impact of known patterns of sexual dimorphism in a predator on its prey, uncovering overlooked links between evolutionary adaptation and the structure of contemporary communities. Given the extreme prevalence of sexual dimorphism, we argue that the independent evolution of the sexes will often have important consequences for ecological communities. PMID- 30404875 TI - Building the differences: a case for the ground tissue patterning in plants. AB - A key question in biology is to understand how interspecies morphological diversities originate. Plant roots present a huge interspecific phenotypical variability, mostly because roots largely contribute to adaptation to different kinds of soils. One example is the interspecific cortex layer number variability, spanning from one to several. Here, we review the latest advances in the understanding of the mechanisms expanding and/or restricting cortical layer number in Arabidopsis thaliana and their involvement in cortex pattern variability among multi-cortical layered species such as Cardamine hirsuta or Oryza sativa. PMID- 30404876 TI - Local meteorological conditions reroute a migration. AB - For migrating animals, realized migration routes and timing emerge from hundreds or thousands of movement decisions made along migration routes. Local weather conditions along migration routes continually influence these decisions, and even relatively small changes in en route weather may cumulatively result in major shifts in migration patterns. Here, we analysed satellite tracking data to score a discrete navigation decision by a large migratory bird as it navigated a high latitude, 5000 m elevation mountain range to understand how those navigational decisions changed under different weather conditions. We showed that wind conditions in particular areas along the migration pathway drove a navigational decision to reroute a migration; conditions encountered predictably resulted in migrants routing either north or south of the mountain range. With abiotic conditions continuing to change globally, simple decisions, such as the one described here, might additively emerge into new, very different migration routes. PMID- 30404877 TI - Dental ontogeny in extinct synapsids reveals a complex evolutionary history of the mammalian tooth attachment system. AB - The mammalian dentition is uniquely characterized by a combination of precise occlusion, permanent adult teeth and a unique tooth attachment system. Unlike the ankylosed teeth in most reptiles, mammal teeth are supported by a ligamentous tissue that suspends each tooth in its socket, providing flexible and compliant tooth attachment that prolongs the life of each tooth and maintains occlusal relationships. Here we investigate dental ontogeny through histological examination of a wide range of extinct synapsid lineages to assess whether the ligamentous tooth attachment system is unique to mammals and to determine how it evolved. This study shows for the first time that the ligamentous tooth attachment system is not unique to crown mammals within Synapsida, having arisen in several non-mammalian therapsid clades as a result of neoteny and progenesis in dental ontogeny. Mammalian tooth attachment is here re-interpreted as a paedomorphic condition relative to the ancestral synapsid form of tooth attachment. PMID- 30404878 TI - Elements of time and place: manganese and barium in shark vertebrae reflect age and upwelling histories. AB - As upper-level predators, sharks are important for maintaining marine food web structure, but populations are threatened by fishery exploitation. Sustainable management of shark populations requires improved understanding of migration patterns and population demographics, which has traditionally been sought through physical and/or electronic tagging studies. The application of natural tags such as elemental variations in mineralized band pairs of elasmobranch vertebrae cartilage could also reveal endogenous and exogenous processes experienced by sharks throughout their life histories. Here, elemental profiles were characterized in vertebrae encompassing complete life histories (birth-to-death) of shortfin mako (Isurus oxyrinchus), common thresher (Alopias vulpinus) and blue shark (Prionace glauca) of known tag and recapture locations in the eastern North Pacific Ocean. All sharks were injected with oxytetracycline at initial capture, released and subsequently recaptured, with individual liberty times ranging from 215 days to 6 years. Vertebral band pairs forming over the liberty intervals were verified by counting the number of band pairs deposited since the oxytetracycline band. Regular oscillations in vertebrae manganese (Mn) content corresponded well with the number of validated band pairs, suggesting that Mn variation could be used to age sharks. Increases in vertebrae barium concentration were correlated with times when individuals occupied areas with high coastal upwelling indices, the timing and spatial intensity of which varied from year to year. Interspecific relationships were probably influenced by behavioural differences in horizontal and vertical habitat use, feeding habits and thermoregulatory physiology. These results indicate that vertebral sclerochronology has the potential to advance our knowledge of elasmobranch life history including age and growth estimation and environmental reconstruction. PMID- 30404879 TI - Non-stationary climate-salmon relationships in the Gulf of Alaska. AB - Studies of climate effects on ecology often account for non-stationarity in individual physical and biological variables, but rarely allow for non-stationary relationships among variables. Here, we show that non-stationary relationships among physical and biological variables are central to understanding climate effects on salmon (Onchorynchus spp.) in the Gulf of Alaska during 1965-2012. The relative importance of two leading patterns in North Pacific climate, the Pacific Decadal Oscillation (PDO) and North Pacific Gyre Oscillation (NPGO), changed around 1988/1989 as reflected by changing correlations with leading axes of sea surface temperature variability. Simultaneously, relationships between the PDO and Gulf of Alaska environmental variables weakened, and long-standing temperature-salmon and PDO-salmon covariance declined to zero. We propose a mechanistic explanation for changing climate-salmon relationships in terms of non stationary atmosphere-ocean interactions coinciding with changing PDO-NPGO relative importance. We also show that regression models assuming stationary climate-salmon relationships are inappropriate over the multidecadal time scale we consider. Relaxing assumptions of stationary relationships markedly improved modelling of climate effects on salmon catches and productivity. Attempts to understand the implications of changing climate patterns in other ecosystems might also be aided by the application of models that allow associations among environmental and biological variables to change over time. PMID- 30404880 TI - An experimental test of the mutation-selection balance model for the maintenance of genetic variance in fitness components. AB - Despite decades of research, the factors that maintain genetic variation for fitness are poorly understood. It is unclear what fraction of the variance in a typical fitness component can be explained by mutation-selection balance (MSB) and whether fitness components differ in this respect. In theory, the level of standing variance in fitness due to MSB can be predicted using the rate of fitness decline under mutation accumulation, and this prediction can be directly compared to the standing variance observed. This approach allows for controlled statistical tests of the sufficiency of the MSB model, and could be used to identify traits or populations where genetic variance is maintained by other factors. For example, some traits may be influenced by sexually antagonistic balancing selection, resulting in an excess of standing variance beyond that generated by deleterious mutations. We describe the underlying theory and use it to test the MSB model for three traits in Drosophila melanogaster We find evidence for differences among traits, with MSB being sufficient to explain genetic variance in larval viability but not male mating success or female fecundity. Our results are consistent with balancing selection on sexual fitness components, and demonstrate the feasibility of rigorous statistical tests of the MSB model. PMID- 30404881 TI - Tropical tree diversity mediates foraging and predatory effects of insectivorous birds. AB - Biodiversity affects the structure of ecological communities, but little is known about the interactive effects of diversity across multiple trophic levels. We used a large-scale forest diversity experiment to investigate the effects of tropical tree species richness on insectivorous birds, and the subsequent indirect effect on predation rates by birds. Diverse plots (four tree species) had higher bird abundance (61%), phylogenetic diversity (61%), and functional diversity (55%) than predicted based on single-species monocultures, which corresponded to higher attack rates on artificial caterpillars (65%). Tree diversity effects on attack rate were driven by complementarity among tree species, with increases in attack rate observed on all tree species in polycultures. Attack rates on artificial caterpillars were higher in plots with higher bird abundance and diversity, but the indirect effect of tree species richness was mediated by bird diversity, providing evidence that diversity can interact across trophic levels with consequences tied to ecosystem services and function. PMID- 30404882 TI - Isogamy in large and complex volvocine algae is consistent with the gamete competition theory of the evolution of anisogamy. AB - Although the gamete competition theory remains the dominant explanation for the evolution of anisogamy, well-known exceptions to its predictions have raised doubts about the completeness of the theory. One of these exceptions is isogamy in large or complex species of green algae. Here, we show that this exception may be explained in a manner consistent with a game-theoretic extension of the original theory: a constraint on the minimum size of a gamete may prevent the evolution of continuously stable anisogamy. We show that in the volvocine algae, both gametes of isogamous species retain an intact chloroplast, whereas the chloroplast of the microgamete in anisogamous species is invariably degenerate. The chloroplast, which functions in photosynthesis and starch storage, may be necessary to provision a gamete for an extended period when gamete encounter rates are low. The single chloroplast accounts for most of the volume of a typical gamete, and thus may constrain the minimum size of a gamete, preventing the evolution of anisogamy. A prediction from this hypothesis, that isogametes should be larger than the microgametes of similar-size species, is confirmed for the volvocine algae. Our results support the gamete competition theory. PMID- 30404883 TI - Intraspecific brain size variation between coexisting sunfish ecotypes. AB - Variation in spatial complexity and foraging requirements between habitats can impose different cognitive demands on animals that may influence brain size. However, the relationship between ecologically related cognitive performance and brain size is not well established. We test whether variation in relative brain size and brain region size is associated with habitat use within a population of pumpkinseed sunfish composed of different ecotypes that inhabit either the structurally complex shoreline littoral habitat or simpler open-water pelagic habitat. Sunfish using the littoral habitat have on average 8.3% larger brains than those using the pelagic habitat. We found little difference in the proportional sizes of five brain regions between ecotypes. The results suggest that cognitive demands on sunfish may be reduced in the pelagic habitat given no habitat-specific differences in body condition. They also suggest that either a short divergence time or physiological processes may constrain changes to concerted, global modifications of brain size between sunfish ecotypes. PMID- 30404884 TI - Acute drivers influence recent inshore Great Barrier Reef dynamics. AB - Understanding the dynamics of habitat-forming organisms is fundamental to managing natural ecosystems. Most studies of coral reef dynamics have focused on clear-water systems though corals inhabit many turbid regions. Here, we illustrate the key drivers of an inshore coral reef ecosystem using 10 years of biological, environmental, and disturbance data. Tropical cyclones, crown-of thorns starfish, and coral bleaching are recognized as the major drivers of coral loss at mid- and offshore reefs along the Great Barrier Reef (GBR). In comparison, little is known about what drives temporal trends at inshore reefs closer to major anthropogenic stress. We assessed coral cover dynamics using state-space models within six major inshore GBR catchments. An overall decline was detected in nearly half (46%) of the 15 reefs at two depths (30 sites), while the rest exhibited fluctuating (23%), static (17%), or positive (13%) trends. Inshore reefs responded similarly to their offshore counterparts, where contemporary trends were predominantly influenced by acute disturbance events. Storms emerged as the major driver affecting the inshore GBR, with the effects of other drivers such as disease, juvenile coral density, and macroalgal and turf per cent cover varying from one catchment to another. Flooding was also associated with negative trends in live coral cover in two southern catchments, but the mechanism remains unclear as it is not reflected in available metrics of water quality and may act through indirect pathways. PMID- 30404886 TI - Prey abundance and urbanization influence the establishment of avian predators in a metropolitan landscape. AB - Urbanization causes the simplification of natural habitats, resulting in animal communities dominated by exotic species with few top predators. In recent years, however, many predators such as hawks, and in the US coyotes and cougars, have become increasingly common in urban environments. Hawks in the Accipiter genus, especially, are recovering from widespread population declines and are increasingly common in urbanizing landscapes. Our goal was to identify factors that determine the occupancy, colonization and persistence of Accipiter hawks in a major metropolitan area. Through a novel combination of citizen science and advanced remote sensing, we quantified how urban features facilitate the dynamics and long-term establishment of Accipiter hawks. Based on data from Project FeederWatch, we quantified 21 years (1996-2016) of changes in the spatio-temporal dynamics of Accipiter hawks in Chicago, IL, USA. Using a multi-season occupancy model, we estimated Cooper's (Accipiter cooperii) and sharp-shinned (A. striatus) hawk occupancy dynamics as a function of tree canopy cover, impervious surface cover and prey availability. In the late 1990s, hawks occupied 26% of sites around Chicago, but after two decades, their occupancy fluctuated close to 67% of sites and they colonized increasingly urbanized areas. Once established, hawks persisted in areas with high levels of impervious surfaces as long as those areas supported high abundances of prey birds. Urban areas represent increasingly habitable environments for recovering predators, and understanding the precise urban features that drive colonization and persistence is important for wildlife conservation in an urbanizing world. PMID- 30404887 TI - Facebook ad claiming that vaccines can kill is banned by UK regulator. PMID- 30404888 TI - Under 16s are at highest risk of being stabbed going home from school, UK study finds. PMID- 30404885 TI - A host immune hormone modifies parasite species interactions and epidemics: insights from a field manipulation. AB - Parasite epidemics can depend on priority effects, and parasite priority effects can result from the host immune response to prior infection. Yet we lack experimental evidence that such immune-mediated priority effects influence epidemics. To address this research gap, we manipulated key host immune hormones, then measured the consequences for within-host parasite interactions, and ultimately parasite epidemics in the field. Specifically, we applied plant immune signalling hormones to sentinel plants, embedded into a wild host population, and tracked foliar infections caused by two common fungal parasites. Within-host individuals, priority effects were altered by the immune-signalling hormone, salicylic acid (SA). Scaling up from within-host interactions, hosts treated with SA experienced a lower prevalence of a less aggressive parasite, increased burden of infection by a more aggressive parasite, and experienced fewer co-infections. Together, these results indicate that by altering within-host priority effects, host immune hormones can drive parasite epidemics. This study therefore experimentally links host immune hormones to within-host priority effects and parasite epidemics, advancing a more mechanistic understanding of how interactions among parasites alter their epidemics. PMID- 30404889 TI - Those who also served: medics in the first world war. PMID- 30404892 TI - Hurricane Florence tests team at Brunswick Medical Center. PMID- 30404890 TI - Identification of Peracetylated Quercetin as a Selective 12-Lipoxygenase Pathway Inhibitor in Human Platelets. AB - The inflammatory response is necessary for the host's defense against pathogens; however, uncontrolled or unregulated production of eicosanoids has been associated with several types of chronic inflammatory diseases. Thus, it is not surprising that enzymes implicated in the production of eicosanoids have been strategically targeted for potential therapeutic approaches. The 12(S) hydroxyeicosatetraenoic acid [12(S)-HETE] lipid mediator is among inflammatory molecules that are abundantly produced in various diseases and is primarily biosynthesized via the 12(S)-lipoxygenase pathway. The effects of the abundance of 12(S)-HETE and its contribution to several chronic inflammatory diseases have been well studied over the last few years. While most developed compounds primarily target the 5-lipoxygenase (5-LO) or the cyclooxygenase (COX) pathways, very few compounds selectively inhibiting the 12-lipoxygenase (12-LO) pathway are known. In this study, we examined whether the distribution of hydroxyl groups among flavones could influence their potency as 12-LO inhibitors. Using human platelets, the human embryonic kidney 293 (HEK293) cell line expressing 5-LO, and human polymorphonuclear leukocytes (PMNLs) we investigated the effects of these compounds on several inflammatory pathways, namely, 12-LO, 5-LO, and COX. Using high-resolution respirometry and flow cytometry, we also evaluated some normal cell functions that could be modulated by our compounds. We identified a peracetylated quercetin (compound 6) that exerts potent inhibitory activity toward the platelet 12-LO pathway (IC50 = 1.53 MUM) while having a lesser affinity toward the COX pathway. This study characterizes the peracetylated quercetin (compound 6) as a more selective platelet-type 12-LO inhibitor than baicalein, with no measurable nontargeted effects on the platelet's activation or overall cell's oxygen consumption. PMID- 30404893 TI - Schweitzer retires from Public Health Service. PMID- 30404891 TI - Subcellular Localization and Activity of the Mitogen-Activated Protein Kinase Kinase 7 (MKK7) gamma Isoform are Regulated through Binding to the Phosphatase Calcineurin. AB - Calcineurin (CaN) phosphatase signaling is regulated by targeting CaN to substrates, inhibitors, and scaffold proteins containing docking motifs with the consensus sequence of PxIxIT. Here, we identify the docking of CaN to the gamma isoform of MKK7, a component of the c-Jun N-terminal kinase (JNK) pathway. Because of alternative splicing of a single exon within the N-terminal domain, MKK7gamma encodes a unique PxIxIT motif (PIIVIT) that is not present in MKK7alpha or beta We found that MKK7gamma bound directly to CaN through this PIIVIT motif in vitro, immunoprecipitated with CaN from cell extracts, and exhibited fluorescence resonance energy transfer (FRET) with CaN in the cytoplasm but not in the nucleus of living cells. In contrast, MKK7alpha and beta exhibited no direct binding or FRET with CaN and were localized more in the nucleus than the cytoplasm. Furthermore, the inhibition of CaN phosphatase activity increased the basal phosphorylation of MKK7gamma but not MKK7beta Deletion of the MKK7gamma PIIVIT motif eliminated FRET with CaN and promoted MKK7gamma redistribution to the nucleus; however, the inhibition of CaN activity did not alter MKK7gamma localization, indicating that MKK7gamma cytoplasmic retention by CaN is phosphatase activity independent. Finally, the inhibition of CaN phosphatase activity in vascular smooth muscle cells, which express MKK7gamma mRNA, enhances JNK activation. Overall, we conclude that the MKK7gamma-specific PxIxIT motif promotes high-affinity CaN binding that could promote novel cross talk between CaN and JNK signaling by limiting MKK7gamma phosphorylation and restricting its localization to the cytoplasm. PMID- 30404894 TI - Treatment considerations for potential uropathogens detected by precision microbiological testing. AB - PURPOSE: The clinical and microbiological data for urinary tract infections (UTIs) for 6 organisms detected by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) at community health systems were examined. SUMMARY: The use of precision microbiological diagnostic testing such as MALDI-TOF and real-time quantitative polymerase chain reaction has increased the ability to detect a wider spectrum of organisms. This has raised questions of the clinical relevance of infrequently encountered organisms, especially when cultured from urine. This article reviews clinical and microbiological data for UTIs for 6 organisms detected by MALDI-TOF at community health systems (Actinotignum schaalii, Chryseobacterium indologenes, Aerococcus urinae, Aerococcus sanguinicola, Corynebacterium riegelii, and Corynebacterium urealyticum). Since little information currently exists, most of the data associating the aforementioned organisms with UTIs were derived from case reports. Although these organisms are more readily identified using precision microbiological diagnostic testing methods, infection should not be assumed based on culture results alone since asymptomatic bacteriuria has been reported. Similar to more common urinary pathogens, clinical correlation is essential. To facilitate treatment, we provide a table of empirical options likely to achieve clinical success based on in vivo and in vitro data. If available, pathogen-specific susceptibility data should be used to direct therapy. CONCLUSION: Clinical and microbiological data and potential treatment options were presented for 6 traditionally underrecognized organisms that are increasingly being found from urinary specimens. The treatment recommendations should be interpreted cautiously as they were devised through the use of very limited data. PMID- 30404895 TI - Qualitative study of patient experiences of responsibility in warfarin therapy. AB - PURPOSE: Results of a study to characterize the experiences of warfarin-treated patients, including their experiences in taking medication, communicating with clinical pharmacists, and International Normalized Ratio (INR) monitoring, are reported. METHODS: A qualitative analysis of data obtained during interviews with 40 patients at a Veterans Affairs medical center warfarin clinic was conducted. In semistructured interviews, the patients were asked to describe the process whereby their INR values were monitored by pharmacists and their understanding of self-management responsibilities, including medication adherence and implementation of lifestyle modifications that might influence the effectiveness of anticoagulation therapy. RESULTS: Analysis of interview results indicated that patients' experience in the event of variation in INR levels is characterized by misperceptions of the instructions regarding appropriate dietary and lifestyle behaviors, misattribution of responsibility for abnormal readings, and provider uncertainty in ascertaining causation for out-of-range INR values. Patients frequently reported that they interpret pharmacist questions to imply that they are responsible for variable INR values. This perception may indirectly lead to adverse consequences such as withholding of information from anticoagulation care providers and skipping clinic appointments, which could in turn result in suboptimal clinical outcomes. CONCLUSION: Analysis of results of qualitative interviews of patients receiving warfarin indicated that patients may interpret routine questioning about INR variation as implying that they are to blame for poor anticoagulation control. PMID- 30404896 TI - Sex differences in risk factors for myocardial infarction: cohort study of UK Biobank participants. AB - OBJECTIVES: To investigate sex differences in risk factors for incident myocardial infarction (MI) and whether they vary with age. DESIGN: Prospective population based study. SETTING: UK Biobank. PARTICIPANTS: 471 998 participants (56% women; mean age 56.2) with no history of cardiovascular disease. MAIN OUTCOME MEASURE: Incident (fatal and non-fatal) MI. RESULTS: 5081 participants (1463 (28.8%) of whom were women) had MI over seven years' mean follow-up, resulting in an incidence per 10 000 person years of 7.76 (95% confidence interval 7.37 to 8.16) for women and 24.35 (23.57 to 25.16) for men. Higher blood pressure indices, smoking intensity, body mass index, and the presence of diabetes were associated with an increased risk of MI in men and women, but associations were attenuated with age. In women, systolic blood pressure and hypertension, smoking status and intensity, and diabetes were associated with higher hazard ratios for MI compared with men: ratio of hazard ratios 1.09 (95% confidence interval 1.02 to 1.16) for systolic blood pressure, 1.55 (1.32 to 1.83) for current smoking, 2.91 (1.56 to 5.45) for type 1 diabetes, and 1.47 (1.16 to 1.87) for type 2 diabetes. There was no evidence that any of these ratios of hazard ratios decreased with age (P>0.2). With the exception of type 1 diabetes, the incidence of MI was higher in men than in women for all risk factors. CONCLUSIONS: Although the incidence of MI was higher in men than in women, several risk factors were more strongly associated with MI in women compared with men. Sex specific associations between risk factors and MI declined with age, but, where it occurred, the higher relative risk in women remained. As the population ages and the prevalence of lifestyle associated risk factors increase, the incidence of MI in women will likely become more similar to that in men. PMID- 30404897 TI - Could artificial intelligence make doctors obsolete? PMID- 30404898 TI - An in vivo translation-reporter system for the study of protein synthesis in zebrafish embryos. AB - Control of gene expression at the translation level is increasingly regarded as a key feature in many biological processes. Simple, inexpensive, and reliable procedures to visualise sites of protein production are required to allow observation of the spatiotemporal patterns of mRNA translation at subcellular resolution. We present a method, named SPoT (for Subcellular Patterns of Translation), developed upon the original TimeStamp technique (Lin et al., 2008), consisting in the expression of a fluorescent protein fused to a tagged, self cleavable protease domain. Addition of a cell-permeable protease inhibitor instantly stabilizes newly produced, tagged protein allowing to distinguish recently synthesized protein from preexisting one. After a brief protease inhibitor treatment, the ratio of tagged vs non-tagged forms is highest at sites where proteins are the most recent, i.e. sites of synthesis. Therefore, by comparing tagged and non-tagged protein it is possible to spotlight sites of translation. By specifically expressing the SPoT cassette in neurons of transgenic zebrafish embryos, we reveal sites of neuronal protein synthesis in diverse cellular compartments during early development. PMID- 30404899 TI - Seasonal variations in cellular and humoral immunity in male striped hamsters (Cricetulus barabensis). AB - Animals in the non-tropical zone usually demonstrate seasonal variations in immune function, which is important for their survival. In the present study, seasonal changes in immunity in striped hamsters (Cricetulus barabensis) were investigated to test the winter immunoenhancement hypothesis. Male hamsters were wild captured in the fall and winter in 2014 and in the spring and summer in 2015. Body mass, body fat mass and blood glucose levels were all the highest in the summer in hamsters, whereas body fatness and thymus mass had no seasonal changes. Spleen mass was the highest in the fall and white blood cells and phytohaemagglutinin (PHA) response indicative of cellular immunity were the lowest in the summer among the four seasons, which supported the winter immunoenhancement hypothesis. IgG and IgM titres were the lowest in the fall, which was against this hypothesis. Body fat mass had no correlations with cellular and humoral immunity, suggesting it was not the reason of seasonal changes in cellular and humoral immunity in males. Leptin titres were higher in the spring and summer than in the fall and winter. No correlation between leptin and cellular and humoral immunity suggested that leptin did not mediate their seasonal changes. Similarly corticosterone levels were also higher in the spring and summer than in the fall and winter, which were correlated negatively with cellular immunity but positively with Ig G levels. This result implied that corticosterone has a suppressive effect on cellular immunity and enhancing effect on humoral immunity. In summary, distinct components of immune systems exhibited different seasonal patterns. PMID- 30404900 TI - Neural activation following offensive aggression in Japanese quail. AB - Aggression is a fundamental part of animal social behaviour. In avian species, little is known about its neural representation. In particular, neural activity following offensive aggression has not been studied in detail. Here, we investigated the patterns of brain activation using immediate-early gene (IEG) expression in male Japanese quail that showed pronounced aggressive behaviours during a 30 min male-male interaction and compared them to those of males that did not interact with a conspecific. In aggressive males, we found a massive induction of the IEG zenk in pallial brain structures such as the intermediate medial mesopallium, the caudomedial mesopallium and the intermediate medial nidopallium. To a lesser extent, activation was observed in subpallial areas such as the nucleus taeniae of the amygdala and in the medial portion of the bed nucleus of the stria terminalis. Our data suggest that the modulation of aggressive behaviour involves the integration of multisensory information. PMID- 30404901 TI - Promoter-enhancer looping and shadow enhancers of the mouse alphaA-crystallin locus. AB - Gene regulation by enhancers is important for precise temporal and spatial gene expression. Enhancers can drive gene expression regardless of their location, orientation, or distance from the promoter. Changes in chromatin conformation and chromatin looping occur to bring the promoter and enhancers into close proximity. alphaA-crystallin ranks among one of the most abundantly expressed genes and proteins in the mammalian lens. The alphaA-crystallin locus is characterized by a 16 kb chromatin domain marked by two distal enhancers, 5' DCR1 and 3' DCR3. Here we used chromatin conformation capture (3C) analysis and transgenic approaches to analyze temporal control of the mouse alphaA-crystallin gene. We find that DCR1 is necessary, but not sufficient alone to drive expression at E10.5 in the mouse lens pit. Chromatin looping revealed interaction between the promoter and the region 3' to DCR1, identifying a novel enhancer region in the alphaA-crystallin locus. We determined that this novel enhancer region, DCR1S, recapitulates the temporal control by DCR1. Acting as shadow enhancers, DCR1 and DCR1S are able to control expression in the lens vesicle at E11.5. It remains to be elucidated however, which region of the alphaA-crystallin locus is responsible for expression in the lens pit at E10.5. PMID- 30404902 TI - Monitoring and evaluation of immune status of female Kunming mice maintained in different biosafety level laboratories. AB - High-level biosafety laboratories (BSL), such as BSL-3 and BSL-4, which deal with high infectivity and virulence pathogens, have become indispensable. Mice are frequently used in animal BSL (ABSL) to establish animal models for infection and to evaluate in vivo immune responses. A project of monitoring and evaluation on physiology and immune status of mice housed in different ABSL labs was performed in the ABSL-2/3/4 labs of Kunming National High-level Biosafety Research Center, China. Female Kunming mice were housed in the ABSL-2/3/4 labs for one month, and mouse behaviors, body physiology/immune status, pulmonary immune status and respiratory bacteria composition were evaluated and compared among mice from the different labs. Mice settled in their new housing environment of the different labs after transfer and gained weight steadily. Blood hematology testing, serum cytokine/chemokine profiles, and blood/spleen lymphocyte constitutions were comparable between the ABSL-2/3/4 labs. The numbers of different pulmonary leukocytes in the bronchoalveolar lavage fluid were at baseline levels in mice from the ABSL-2/3/4 labs. Diversity and dominance of mice respiratory bacteria were semblable among the ABSL-2/3/4 labs. Our results confirm the stability of physiology and immune status of Kunming mice maintained in different ABSL-2/3/4 labs for at least one month. PMID- 30404903 TI - Potassium fertilization arrests malate accumulation and alters soluble sugar metabolism in apple fruit. AB - Effects of different potassium (K) levels, which were K0 (no fertilizer), K1 (71.5g KCl Plant-1 yr-1), K2 (286.7g KCl Plant-1 yr-1), and K3 (434g KCl Plant-1 yr-1), were evaluated based on sugar and organic acid metabolism levels from 70 to 126 days after bloom (DAB) in the developing fruit of potted five-year old apple (Malus domestica, Borkh.) trees. The results indicate that K fertilization promoted greater fruit mass, higher Ca2+ and soluble solid content, and lower titratable acid content, as well as increased pH values at harvest. With the application of different levels of K fertilizer, fructose, sorbitol, glucose, and sucrose accumulation rates significantly change during fruit development. Fruit in the K2 group had higher fructose, sucrose, and glucose content than those in other treatment groups at 126 DAB. These changes in soluble sugar are related to the activity of metabolic enzymes. Sucrose synthase (SS) and Sorbitol dehydrogenase (SDH) activity in the K2 treated fruit were significantly higher than those in other treatment groups from 70-126 DAB. Malate content in K supplemented fruit was notably lower than that in non K-supplemented fruit, and K3 treated fruit had the lowest malate content during fruit development. Cytosolic malic enzyme (ME) and phosphoenolpyruvate carboxykinase (PEPCK) activity significantly increased in fruit under the K2 treatment during 112-126 DAB and 98-126 DAB, respectively. In addition, the Ca2+ concentration increased with increasing K fertilization levels, which promoted a maximum of 11.72 mg g-1 dry weight in apple fruit. These results show that K levels can alter soluble sugar and malate levels due to the interaction between sugars and acid-metabolic enzymes in fruit. PMID- 30404904 TI - Effect of temperature change on synaptic transmission at crayfish neuromuscular junctions. AB - Ectothermic animals in areas characterised by seasonal changes are susceptible to extreme fluctuations in temperature. To survive through varied temperatures, ectotherms have developed unique strategies. This study focuses on synaptic transmission function at cold temperatures, as it is a vital component of ectothermic animals' survival. For determining how synaptic transmission is influenced by an acute change in temperature (20 degrees C to 10 degrees C within a minute) and chronic cold (10 degrees C), the crayfish (Procambarus clarkii) neuromuscular junction (NMJ) was used as a model. To simulate chronic cold conditions, crayfish were acclimated to 15 degrees C for 1 week and then to 10 degrees C for 1 week. They were then used to examine the synaptic properties associated with the low output nerve terminals on the opener muscle in the walking legs and high output innervation on the abdominal deep extensor muscle. The excitatory postsynaptic potentials (EPSPs) of the opener NMJs increased in amplitude with acute warming (20 degrees C) after being acclimated to cold; however, the deep extensor muscles showed varied changes in EPSP amplitude. Synaptic transmission at both NMJs was enhanced with exposure to the modulators serotonin or octopamine. The membrane resistance of the muscles decreased 33% and the resting membrane potential hyperpolarised upon warm exposure. Analysis of haemolymph indicated that octopamine increases during cold exposure. These results suggest bioamine modulation as a possible mechanism for ensuring that synaptic transmission remains functional at low temperatures. PMID- 30404905 TI - Influence of correlated antigen presentation on T-cell negative selection in the thymus. AB - The thymus is the primary organ for the generation of naive T cells, a key component of the immune system. Tolerance of T cells to self is achieved primarily in the thymic medulla, where immature T cells (thymocytes) sample self peptides presented by medullary thymic epithelial cells (mTECs). A sufficiently strong interaction activates the thymocytes leading to negative selection. A key question of current interest is whether there is any structure in the manner in which mTECs present peptides: can any mTEC present any peptide at any time, or are there particular patterns of correlated peptide presentation? We investigate this question using a mathematical model of negative selection. We find that correlated patterns of peptide presentation may be advantageous in negatively selecting low-degeneracy thymocytes (that is, those thymocytes which respond to relatively few peptides). We also quantify the probability that an auto-reactive thymocyte exits the thymus before it encounters a cognate antigen. The results suggest that heterogeneity of gene co-expression in mTECs has an effect on the probability of escape of autoreactive thymocytes. PMID- 30404906 TI - Aerodynamics of manoeuvring flight in brown long-eared bats (Plecotus auritus). AB - In this study, we explicitly examine the aerodynamics of manoeuvring flight in animals. We studied brown long-eared bats flying in a wind tunnel while performing basic sideways manoeuvres. We used particle image velocimetry in combination with high-speed filming to link aerodynamics and kinematics to understand the mechanistic basis of manoeuvres. We predicted that the bats would primarily use the downstroke to generate the asymmetries for the manoeuvre since it has been shown previously that the majority of forces are generated during this phase of the wingbeat. We found instead that the bats more often used the upstroke than they used the downstroke for this. We also found that the bats used both drag/thrust-based and lift-based asymmetries to perform the manoeuvre and that they even frequently switch between these within the course of a manoeuvre. We conclude that the bats used three main modes: lift asymmetries during downstroke, thrust/drag asymmetries during downstroke and thrust/drag asymmetries during upstroke. For future studies, we hypothesize that lift asymmetries are used for fast turns and thrust/drag for slow turns and that the choice between up and downstroke depends on the timing of when the bat needs to generate asymmetries. PMID- 30404907 TI - Social eavesdropping allows for a more risky gliding strategy by thermal-soaring birds. AB - Vultures are thought to form networks in the sky, with individuals monitoring the movements of others to gain up-to-date information on resource availability. While it is recognized that social information facilitates the search for carrion, how this facilitates the search for updrafts, another critical resource, remains unknown. In theory, birds could use information on updraft availability to modulate their flight speed, increasing their airspeed when informed on updraft location. In addition, the stylized circling behaviour associated with thermal soaring is likely to provide social cues on updraft availability for any bird operating in the surrounding area. We equipped five Gyps vultures with GPS and airspeed loggers to quantify the movements of birds flying in the same airspace. Birds that were socially informed on updraft availability immediately adopted higher airspeeds on entering the inter-thermal glide; a strategy that would be risky if birds were relying on personal information alone. This was embedded within a broader pattern of a reduction in airspeed (approx. 3 m s-1) through the glide, likely reflecting the need for low speed to sense and turn into the next thermal. Overall, this demonstrates (i) the complexity of factors affecting speed selection over fine temporal scales and (ii) that Gyps vultures respond to social information on the occurrence of energy in the aerial environment, which may reduce uncertainty in their movement decisions. PMID- 30404909 TI - Patients with type 1 diabetes are missing out on flash glucose devices, finds BMJ investigation. PMID- 30404908 TI - Financial Costs Incurred by Living Kidney Donors: A Prospective Cohort Study. AB - BACKGROUND: Approximately 40% of the kidneys for transplant worldwide come from living donors. Despite advantages of living donor transplants, rates have stagnated in recent years. One possible barrier may be costs related to the transplant process that potential willing donors may incur for travel, parking, accommodation, and lost productivity. METHODS: To better understand and quantify the financial costs incurred by living kidney donors, we conducted a prospective cohort study, recruiting 912 living kidney donors from 12 transplant centers across Canada between 2009 and 2014; 821 of them completed all or a portion of the costing survey. We report microcosted total, out-of-pocket, and lost productivity costs (in 2016 Canadian dollars) for living kidney donors from donor evaluation start to 3 months after donation. We examined costs according to (1) the donor's relationship with their recipient, including spousal (donation to a partner), emotionally related nonspousal (friend, step-parent, in law), or genetically related; and (2) donation type (directed, paired kidney, or nondirected). RESULTS: Living kidney donors incurred a median (75th percentile) of $1254 ($2589) in out-of-pocket costs and $0 ($1908) in lost productivity costs. On average, total costs were $2226 higher in spousal compared with emotionally related nonspousal donors (P=0.02) and $1664 higher in directed donors compared with nondirected donors (P<0.001). Total costs (out-of-pocket and lost productivity) exceeded $5500 for 205 (25%) donors. CONCLUSIONS: Our results can be used to inform strategies to minimize the financial burden of living donation, which may help improve the donation experience and increase the number of living donor kidney transplants. PMID- 30404910 TI - The geographic mosaic of coevolution in mutualistic networks. AB - Ecological interactions shape adaptations through coevolution not only between pairs of species but also through entire multispecies assemblages. Local coevolution can then be further altered through spatial processes that have been formally partitioned in the geographic mosaic theory of coevolution. A major current challenge is to understand the spatial patterns of coadaptation that emerge across ecosystems through the interplay between gene flow and selection in networks of interacting species. Here, we combine a coevolutionary model, network theory, and empirical information on species interactions to investigate how gene flow and geographical variation in selection affect trait patterns in mutualistic networks. We show that gene flow has the surprising effect of favoring trait matching, especially among generalist species in species-rich networks typical of pollination and seed dispersal interactions. Using an analytical approximation of our model, we demonstrate that gene flow promotes trait matching by making the adaptive landscapes of different species more similar to each other. We use this result to show that the progressive loss of gene flow associated with habitat fragmentation may undermine coadaptation in mutualisms. Our results therefore provide predictions of how spatial processes shape the evolution of species-rich interactions and how the widespread fragmentation of natural landscapes may modify the coevolutionary process. PMID- 30404911 TI - A flexible organic reflectance oximeter array. AB - Transmission-mode pulse oximetry, the optical method for determining oxygen saturation in blood, is limited to only tissues that can be transilluminated, such as the earlobes and the fingers. The existing sensor configuration provides only single-point measurements, lacking 2D oxygenation mapping capability. Here, we demonstrate a flexible and printed sensor array composed of organic light emitting diodes and organic photodiodes, which senses reflected light from tissue to determine the oxygen saturation. We use the reflectance oximeter array beyond the conventional sensing locations. The sensor is implemented to measure oxygen saturation on the forehead with 1.1% mean error and to create 2D oxygenation maps of adult forearms under pressure-cuff-induced ischemia. In addition, we present mathematical models to determine oxygenation in the presence and absence of a pulsatile arterial blood signal. The mechanical flexibility, 2D oxygenation mapping capability, and the ability to place the sensor in various locations make the reflectance oximeter array promising for medical sensing applications such as monitoring of real-time chronic medical conditions as well as postsurgery recovery management of tissues, organs, and wounds. PMID- 30404912 TI - Inhibition of tumor growth by agonists of growth hormone-releasing hormone. PMID- 30404913 TI - Criticality in tumor evolution and clinical outcome. AB - How mutation and selection determine the fitness landscape of tumors and hence clinical outcome is an open fundamental question in cancer biology, crucial for the assessment of therapeutic strategies and resistance to treatment. Here we explore the mutation-selection phase diagram of 6,721 tumors representing 23 cancer types by quantifying the overall somatic point mutation load (ML) and selection (dN/dS) in the entire proteome of each tumor. We show that ML strongly correlates with patient survival, revealing two opposing regimes around a critical point. In low-ML cancers, a high number of mutations indicates poor prognosis, whereas high-ML cancers show the opposite trend, presumably due to mutational meltdown. Although the majority of cancers evolve near neutrality, deviations are observed at extreme MLs. Melanoma, with the highest ML, evolves under purifying selection, whereas in low-ML cancers, signatures of positive selection are observed, demonstrating how selection affects tumor fitness. Moreover, different cancers occupy specific positions on the ML-dN/dS plane, revealing a diversity of evolutionary trajectories. These results support and expand the theory of tumor evolution and its nonlinear effects on survival. PMID- 30404914 TI - Structure-guided development of selective M3 muscarinic acetylcholine receptor antagonists. AB - Drugs that treat chronic obstructive pulmonary disease by antagonizing the M3 muscarinic acetylcholine receptor (M3R) have had a significant effect on health, but can suffer from their lack of selectivity against the M2R subtype, which modulates heart rate. Beginning with the crystal structures of M2R and M3R, we exploited a single amino acid difference in their orthosteric binding pockets using molecular docking and structure-based design. The resulting M3R antagonists had up to 100-fold selectivity over M2R in affinity and over 1,000-fold selectivity in vivo. The crystal structure of the M3R-selective antagonist in complex with M3R corresponded closely to the docking-predicted geometry, providing a template for further optimization. PMID- 30404915 TI - Evolution of weak cooperative interactions for biological specificity. AB - A hallmark of biological systems is that particular functions and outcomes are realized in specific contexts, such as when particular signals are received. One mechanism for mediating specificity is described by Fisher's "lock and key" metaphor, exemplified by enzymes that bind selectively to a particular substrate via specific finely tuned interactions. Another mechanism, more prevalent in multicellular organisms, relies on multivalent weak cooperative interactions. Its importance has recently been illustrated by the recognition that liquid-liquid phase transitions underlie the formation of membraneless condensates that perform specific cellular functions. Based on computer simulations of an evolutionary model, we report that the latter mechanism likely became evolutionarily prominent when a large number of tasks had to be performed specifically for organisms to function properly. We find that the emergence of weak cooperative interactions for mediating specificity results in organisms that can evolve to accomplish new tasks with fewer, and likely less lethal, mutations. We argue that this makes the system more capable of undergoing evolutionary changes robustly, and thus this mechanism has been repeatedly positively selected in increasingly complex organisms. Specificity mediated by weak cooperative interactions results in some useful cross-reactivity for related tasks, but at the same time increases susceptibility to misregulation that might lead to pathologies. PMID- 30404916 TI - Coupled molecular dynamics mediate long- and short-range epistasis between mutations that affect stability and aggregation kinetics. AB - Multiple mutations are typically required to significantly improve protein stability or aggregation kinetics. However, when several substitutions are made in a single protein, the mutations can potentially interact in a nonadditive manner, resulting in epistatic effects, which can hamper protein-engineering strategies to improve thermostability or aggregation kinetics. Here, we have examined the role of protein dynamics in mediating epistasis between pairs of mutations. With Escherichia coli transketolase (TK) as a model, we explored the epistatic interactions between two single variants H192P and A282P, and also between the double-mutant H192P/A282P and two single variants, I365L or G506A. Epistasis was determined for several measures of protein stability, including the following: the free-energy barrier to kinetic inactivation, ??G ?; thermal transition midpoint temperatures, T m; and aggregation onset temperatures, T agg Nonadditive epistasis was observed between neighboring mutations as expected, but also for distant mutations located in the surface and core regions of different domains. Surprisingly, the epistatic behaviors for each measure of stability were often different for any given pairwise recombination, highlighting that kinetic and thermodynamic stabilities do not always depend on the same structural features. Molecular-dynamics simulations and a pairwise cross-correlation analysis revealed that mutations influence the dynamics of their local environment, but also in some cases the dynamics of regions distant in the structure. This effect was found to mediate epistatic interactions between distant mutations and could therefore be exploited in future protein-engineering strategies. PMID- 30404917 TI - Drosophila intestinal stem and progenitor cells are major sources and regulators of homeostatic niche signals. AB - Epithelial homeostasis requires the precise balance of epithelial stem/progenitor proliferation and differentiation. While many signaling pathways that regulate epithelial stem cells have been identified, it is probable that other regulators remain unidentified. Here, we use gene-expression profiling by targeted DamID to identify the stem/progenitor-specific transcription and signaling factors in the Drosophila midgut. Many signaling pathway components, including ligands of most major pathways, exhibit stem/progenitor-specific expression and have regulatory regions bound by both intrinsic and extrinsic transcription factors. In addition to previously identified stem/progenitor-derived ligands, we show that both the insulin-like factor Ilp6 and TNF ligand eiger are specifically expressed in the stem/progenitors and regulate normal tissue homeostasis. We propose that intestinal stem cells not only integrate multiple signals but also contribute to and regulate the homeostatic signaling microenvironmental niche through the expression of autocrine and paracrine factors. PMID- 30404918 TI - NOXA genetic amplification or pharmacologic induction primes lymphoma cells to BCL2 inhibitor-induced cell death. AB - Although diffuse large B cell lymphoma (DLBCL) cells widely express the BCL2 protein, they rarely respond to treatment with BCL2-selective inhibitors. Here we show that DLBCL cells harboring PMAIP1/NOXA gene amplification were highly sensitive to BCL2 small-molecule inhibitors. In these cells, BCL2 inhibition induced cell death by activating caspase 9, which was further amplified by caspase-dependent cleavage and depletion of MCL1. In DLBCL cells lacking NOXA amplification, BCL2 inhibition was associated with an increase in MCL1 protein abundance in a BIM-dependent manner, causing a decreased antilymphoma efficacy. In these cells, dual inhibition of MCL1 and BCL2 was required for enhanced killing. Pharmacologic induction of NOXA, using the histone deacetylase inhibitor panobinostat, decreased MCL1 protein abundance and increased lymphoma cell vulnerability to BCL2 inhibitors in vitro and in vivo. Our data provide a mechanistic rationale for combination strategies to disrupt lymphoma cell codependency on BCL2 and MCL1 proteins in DLBCL. PMID- 30404919 TI - A scorpion venom peptide Ev37 restricts viral late entry by alkalizing acidic organelles. AB - Viral infection still threatens human health all over the world, and many people die from viral diseases every year. However, there are no effective vaccines or drugs for preventing or managing most viral diseases. Thus, the discovery and development of broad-spectrum antiviral agents remain urgent. Here, we expressed and purified a scorpion venom peptide, Ev37, from the scorpion Euscorpiops validus in a prokaryotic system. We found that rEv37 can inhibit dengue virus type 2 (DENV-2), hepatitis C virus (HCV), Zika virus (ZIKV) and herpes simplex virus type 1 (HSV-1) infections in a dose-dependent manner at noncytotoxic concentrations, but that it has no effect on Sendai virus (SeV) and Adenovirus (AdV) infections in vitro. Furthermore, rEv37 alkalized acidic organelles to prevent low pH-dependent fusion of the viral membrane-endosomal membrane, which mainly blocks the release of the viral genome from the endosome to the cytoplasm and then restricts viral late entry. Taken together, our results indicate that the scorpion venom peptide Ev37 is a broad-spectrum antiviral agent with a specific molecular mechanism against viruses undergoing low pH-dependent fusion activation during entry into host cells. We conclude that Ev37 is a potential candidate for development as an antiviral drug. PMID- 30404920 TI - Polyamine synthesis as a target of MYC oncogenes. AB - This paper is in recognition of the 100th birthday of Dr. Herbert Tabor, a true pioneer in the polyamine field for over 70 years, who served as the editor-in chief of the Journal of Biological Chemistry from 1971 to 2010. We review current knowledge of MYC proteins (c-MYC, MYCN, and MYCL) and focus on ornithine decarboxylase 1 (ODC1), an important bona fide gene target of MYC, which encodes the sentinel, rate-limiting enzyme in polyamine biosynthesis. Although notable advances have been made in designing inhibitors against the "undruggable" MYCs, their downstream targets and pathways are currently the main avenue for therapeutic anticancer interventions. To this end, the MYC-ODC axis presents an attractive target for managing cancers such as neuroblastoma, a pediatric malignancy in which MYCN gene amplification correlates with poor prognosis and high-risk disease. ODC and polyamine levels are often up-regulated and contribute to tumor hyperproliferation, especially of MYC-driven cancers. We therefore had proposed to repurpose alpha-difluoromethylornithine (DFMO), an FDA-approved, orally available ODC inhibitor, for management of neuroblastoma, and this intervention is now being pursued in several clinical trials. We discuss the regulation of ODC and polyamines, which besides their well-known interactions with DNA and tRNA/rRNA, are involved in regulating RNA transcription and translation, ribosome function, proteasomal degradation, the circadian clock, and immunity, events that are also controlled by MYC proteins. PMID- 30404921 TI - Single-cell RNA-Seq analysis identifies a noncoding interleukin 4 (IL-4) RNA that post-transcriptionally up-regulates IL-4 production in T helper cells. AB - High-throughput sequencing has revealed a tremendous complexity of cellular transcriptomes, which is partly due to the generation of multiple alternative transcripts from a single gene locus. Because alternative transcripts often have low abundance in bulk cells, the functions of most of these transcripts and their relationship to their canonical counterparts remain unclear. Here, we applied single-cell RNA-Seq to analyze the transcriptome complexity of in vitro differentiated, murine type 2 T helper (Th2) cells. We found that cytokine gene transcripts contribute most of the intercellular heterogeneity, with a group of universal cytokines, including interleukins 1a, 2, 3, and 16, being bimodally expressed. At the single-cell level, usage of alternative promoters prevalently generated alternative transcripts. For instance, although undetectable in bulk cells, a noncoding RNA isoform of IL-4 (IL4nc), which was driven by an intronic promoter in the IL-4 locus, was predominantly expressed in a subset of the Th2 cells. IL4nc displayed distinct temporal expression patterns compared with the canonical IL-4 mRNA and post-transcriptionally promoted the production of IL-4 protein in the Th2 cells. In conclusion, our findings reveal a mechanism whereby minor noncanonical transcripts post-transcriptionally regulate expression of their cognate canonical genes. PMID- 30404923 TI - Specificity and mechanism of carbohydrate demethylation by cytochrome P450 monooxygenases. AB - Degradation of carbohydrates by bacteria represents a key step in energy metabolism that can be inhibited by methylated sugars. Removal of methyl groups, which is critical for further processing, poses a biocatalytic challenge because enzymes need to overcome a high energy barrier. Our structural and computational analysis revealed how a member of the cytochrome P450 family, evolved to oxidize a carbohydrate ligand. Using structural biology, we ascertained the molecular determinants of substrate specificity and revealed a highly specialized active site complementary to the substrate chemistry. Invariance of the residues involved in substrate recognition across the subfamily suggests that they are critical for enzyme function and when mutated, the enzyme lost substrate recognition. The structure of a carbohydrate active P450 adds mechanistic insight into monooxygenase action on a methylated monosaccharide and reveals the broad conservation of the active site machinery across the subfamily. PMID- 30404922 TI - DNA-linked inhibitor antibody assay (DIANA) as a new method for screening influenza neuraminidase inhibitors. AB - Influenza neuraminidase is responsible for the escape of new viral particles from the infected cell surface. Several neuraminidase inhibitors are used clinically to treat patients or stockpiled for emergencies. However, the increasing development of viral resistance against approved inhibitors has underscored the need for development of new antivirals effective against resistant influenza strains. A facile, sensitive, and inexpensive screening method would help achieve this goal. Recently, we described a multiwell plate-based DNA-linked inhibitor antibody assay (DIANA). This highly sensitive method can quantify femtomolar concentrations of enzymes. DIANA also has been applied to high-throughput enzyme inhibitor screening, allowing evaluation of inhibition constants from a single inhibitor concentration. Here, we report the design, synthesis, and structural characterization of a tamiphosphor derivative linked to a reporter DNA oligonucleotide for the development of a DIANA-type assay to screen potential influenza neuraminidase inhibitors. The neuraminidase is first captured by an immobilized antibody, and the test compound competes for binding to the enzyme with the oligo-linked detection probe, which is then quantified by qPCR. We validated this novel assay by comparing it with the standard fluorometric assay and demonstrated its usefulness for sensitive neuraminidase detection as well as high-throughput screening of potential new neuraminidase inhibitors. PMID- 30404925 TI - 'End-to-End' stacking of small dsRNA. AB - PELDOR (pulse electron-electron double resonance) is an established method to study intramolecular distances and can give evidence for conformational changes and flexibilities. However, it can also be used to study intermolecular interactions as for example oligerimization. Here, we used PELDOR to study the 'end-to-end' stacking of small double stranded (ds)RNAs. For this study, the dsRNA molecules were only singly labelled with the spin label TPA to avoid multi spin effects and to measure only the intermolecular stacking interactions. It can be shown that small dsRNAs tend to assemble to rod-like structures due to pi-pi interactions between the base pairs at the end of the strands. On the one hand, these interactions can influence or complicate measurements aimed at the determining of the structure and dynamics of the dsRNA molecule itself. On the other hand, it can be interesting to study such intermolecular stacking interactions in more detail, as for example their dependence on ion concentration. We quantitatively determined the stacking probability as a function of the monovalent NaCl salt and the dsRNA concentration. From this data the dissociation constant Kd was deduced and found to depend on the ratio between the NaCl salt and dsRNA concentrations. Additionally, the distances and distance distributions obtained predict a model for the stacking geometry of dsRNAs. Introducing a nucleotide overhangs at one end of the dsRNA molecule restricts the stacking to the other end, leading only to dimer formations. Introducing such an overhang at both ends of the dsRNA molecule fully suppresses stacking, as we could demonstrate by PELDOR experiments quantitatively. PMID- 30404924 TI - The kinetic characteristics of human and trypanosomatid phosphofructokinases for the reverse reaction. AB - Eukaryotic ATP-dependent phosphofructokinases (PFKs) are often considered unidirectional enzymes catalysing the transfer of a phospho moiety from ATP to fructose 6-phosphate (F6P) to produce ADP and fructose 1,6-bisphosphate (F16BP). The reverse reaction is not generally considered to occur under normal conditions and has never been demonstrated for any eukaryotic ATP-dependent PFKs, though it does occur in PPi-dependent PFKs and has been experimentally shown for bacterial ATP-dependent PFKs. Evidence is provided via two orthogonal assays that all three human PFK isoforms can catalyse the reverse reaction in vitro , allowing determination of kinetic properties. Additionally, the reverse reaction was shown possible for PFKs from three clinically important trypanosomatids; these enzymes are contained within glycosomes in vivo This compartmentalisation may facilitate reversal, given the potential for trypanosomatids to have an altered ATP/ADP ratio in glycosomes compared to the cytosol. The kinetic properties of each trypanosomatid PFK were determined, including the response to natural and artificial modulators of enzyme activity. The possible physiological relevance of the reverse reaction in trypanosomatid and human PFKs is discussed. PMID- 30404926 TI - Novel Factor XIII variant identified through whole genome sequencing in a child with intracranial hemorrhage. AB - Pediatric stroke can be either hemorrhagic or ischemic, with about 5% of hemorrhagic strokes being caused by genetic coagulopathies. We report an 8 month old presenting with a hemorrhagic stroke caused by severe Factor XIII deficiency (OMIM # 613225) in whom rapid whole genome sequencing identified a novel variant in the F13A1 gene c.1352_1353delAT (p.His451ArgfsTer29). PMID- 30404927 TI - Urolithin A, a novel natural compound to target PI3K/AKT/mTOR pathway in pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy and is highly resistant to standard treatment regimens. Targeted therapies against KRAS, a mutation present in an overwhelming majority of PDAC cases, have been largely ineffective. However, inhibition of downstream components in the KRAS signaling cascade provide promising therapeutic targets in the management of PDAC and warrant further exploration. Here, we investigated Urolithin A (Uro A), a novel natural compound derived from pomegranates, which targets numerous kinases downstream of KRAS, in particular the PI3K/AKT/mTOR signaling pathways. We showed that treatment of PDAC cells with Uro A blocked the phosphorylation of AKT and p70S6K in vitro, successfully inhibited the growth of tumor xenografts, and increased overall survival (OS) of Ptf1aCre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mice compared to vehicle or gemcitabine therapy alone. Histological evaluation of these Uro A-treated tumor samples confirmed mechanistic actions of Uro A via decreased phosphorylation of AKT and p70S6K, reduced proliferation, and increased cellular apoptosis in both xenograft and PKT mouse models. Additionally, Uro A treatment reprogrammed the tumor microenvironment, as evidenced by reduced levels of infiltrating immunosuppressive cell populations such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and regulatory T-cells (Tregs). Overall, this work provides convincing preclinical evidence for the utility of Uro A as a therapeutic agent in PDAC through suppression of the PI3K/AKT/mTOR pathway. PMID- 30404928 TI - The Buoyancy of Cryptococcus neoformans Is Affected by Capsule Size. AB - Cryptococcus neoformans is an environmental pathogenic fungus with a worldwide geographical distribution that is responsible for hundreds of thousands of human cryptococcosis cases each year. During infection, the yeast undergoes a morphological transformation involving capsular enlargement that increases microbial volume. To understand the factors that play a role in environmental dispersal of C. neoformans and C. gattii, we evaluated the cell density of Cryptococcus using Percoll isopycnic gradients. We found differences in the cell densities of strains belonging to C. neoformans and C. gattii species complexes. The buoyancy of C. neoformans strains varied depending on growth medium. In minimal medium, the cryptococcal capsule made a major contribution to the cell density such that cells with larger capsules had lower density than those with smaller capsules. Removing the capsule, by chemical or mechanical methods, increased the C. neoformans cell density and reduced buoyancy. Melanization of the C. neoformans cell wall, which also contributes to virulence, produced a small but consistent increase in cell density. Encapsulated C. neoformans sedimented much more slowly in seawater as its density approached the density of water. Our results suggest a new function for the capsule whereby it can function as a flotation device to facilitate transport and dispersion in aqueous fluids.IMPORTANCE The buoyancy of a microbial cell is an important physical characteristic that may affect its transportability in fluids and interactions with tissues during infection. The polysaccharide capsule surrounding C. neoformans is required for infection and dissemination in the host. Our results indicate that the capsule has a significant effect on reducing cryptococcal cell density, altering its sedimentation in seawater. Modulation of microbial cell density via encapsulation may facilitate dispersal for other important encapsulated pathogens. PMID- 30404929 TI - Complement Susceptibility in Relation to Genome Sequence of Recent Klebsiella pneumoniae Isolates from Thai Hospitals. AB - The capacity to resist the bactericidal action of complement (C') is a strong but poorly understood virulence trait in Klebsiella spp. Killing requires activation of one or more C' pathways, assembly of C5b-9 membrane attack complexes (MACs) on the surface of the outer membrane (OM), and penetration of MACs into the target bilayer. We interrogated whole-genome sequences of 164 Klebsiella isolates from three tertiary hospitals in Thailand for genes encoding surface-located macromolecules considered to play a role in determination of C' resistance. Most isolates (154/164) were identified as Klebsiella pneumoniae, and the collection conformed to previously established population structures and antibiotic resistance patterns. The distribution of sequence types (STs) and capsular (K) types were also typical of global populations. The majority (64%) of isolates were resistant to C', and the remainder were either rapidly or slowly killed. All isolates carried genes encoding capsular polysaccharides (K antigens), which have been strongly linked to C' resistance. In contrast to previous reports, there were no differences in the amount of capsule produced by C'-resistant isolates compared to C'-susceptible isolates, nor was there any correlation between serum reactivity and the presence of hypermucoviscous capsules. Similarly, there were no correlations between the presence of genes specifying lipopolysaccharide O side chains or major OM proteins. Some virulence factors were found more frequently in C'-resistant isolates but were considered to reflect clonal ST expansion. Thus, no single gene accounts for the C' resistance of the isolates sequenced in this study.IMPORTANCE Multidrug-resistant Klebsiella pneumoniae is responsible for an increasing proportion of nosocomial infections, and emerging hypervirulent K. pneumoniae clones now cause severe community-acquired infections in otherwise healthy individuals. These bacteria are adept at circumventing immune defenses, and most survive and grow in serum; their capacity to avoid C' mediated destruction is correlated with their invasive potential. Killing of Gram negative bacteria occurs following activation of the C' cascades and stable deposition of C5b-9 MACs onto the OM. For Klebsiella, studies with mutants and conjugants have invoked capsules, lipopolysaccharide O-side chains, and OM proteins as determinants of C' resistance, although the precise roles of the macromolecules are unclear. In this study, we sequenced 164 Klebsiella isolates with different C' susceptibilities to identify genes involved in resistance. We conclude that no single OM constituent can account for resistance, which is likely to depend on biophysical properties of the target bilayer. PMID- 30404930 TI - Temporal Variability of Escherichia coli Diversity in the Gastrointestinal Tracts of Tanzanian Children with and without Exposure to Antibiotics. AB - The stability of the Escherichia coli populations in the human gastrointestinal tract is not fully appreciated, and represents a significant knowledge gap regarding gastrointestinal community structure, as well as resistance to incoming pathogenic bacterial species and antibiotic treatment. The current study examines the genomic content of 240 Escherichia coli isolates from 30 children, aged 2 to 35 months old, in Tanzania. The E. coli strains were isolated from three time points spanning a six-month time period, with and without antibiotic treatment. The resulting isolates were sequenced, and the genomes compared. The findings in this study highlight the transient nature of E. coli strains in the gastrointestinal tract of these children, as during a six-month interval, no one individual contained phylogenomically related isolates at all three time points. While the majority of the isolates at any one time point were phylogenomically similar, most individuals did not contain phylogenomically similar isolates at more than two time points. Examination of global genome content, canonical E. coli virulence factors, multilocus sequence type, serotype, and antimicrobial resistance genes identified diversity even among phylogenomically similar strains. There was no apparent increase in the antimicrobial resistance gene content after antibiotic treatment. The examination of the E. coli from longitudinal samples from multiple children in Tanzania provides insight into the genomic diversity and population variability of resident E. coli within the rapidly changing environment of the gastrointestinal tract of these children.IMPORTANCE This study increases the number of resident Escherichia coli genome sequences, and explores E. coli diversity through longitudinal sampling. We investigate the genomes of E. coli isolated from human gastrointestinal tracts as part of an antibiotic treatment program among rural Tanzanian children. Phylogenomics demonstrates that resident E. coli are diverse, even within a single host. Though the E. coli isolates of the gastrointestinal community tend to be phylogenomically similar at a given time, they differed across the interrogated time points, demonstrating the variability of the members of the E. coli community in these subjects. Exposure to antibiotic treatment did not have an apparent impact on the E. coli community or the presence of resistance and virulence genes within E. coli genomes. The findings of this study highlight the variable nature of specific bacterial members of the human gastrointestinal tract. PMID- 30404931 TI - Surface Exposure and Packing of Lipoproteins into Outer Membrane Vesicles Are Coupled Processes in Bacteroides. AB - Outer membrane vesicles (OMVs) are spherical structures derived from the outer membranes (OMs) of Gram-negative bacteria. Bacteroides spp. are prominent components of the human gut microbiota, and OMVs produced by these species are proposed to play key roles in gut homeostasis. OMV biogenesis in Bacteroides is a poorly understood process. Here, we revisited the protein composition of Bacteroides thetaiotaomicron OMVs by mass spectrometry. We confirmed that OMVs produced by this organism contain large quantities of glycosidases and proteases, with most of them being lipoproteins. We found that most of these OMV-enriched lipoproteins are encoded by polysaccharide utilization loci (PULs), such as the sus operon. We examined the subcellular locations of the components of the Sus system and found a split localization; the alpha-amylase SusG is highly enriched in OMVs, while the oligosaccharide importer SusC remains mostly in the OM. We found that all OMV-enriched lipoproteins possess a lipoprotein export sequence (LES), and we show that this signal mediates translocation of SusG from the periplasmic face of the OM toward the extracellular milieu. Mutations in the LES motif caused defects in surface exposure and recruitment of SusG into OMVs. These experiments link, for the first time, surface exposure to recruitment of proteins into OMVs. We also show that surface-exposed SusG in OMVs is active and rescues the growth of bacterial cells incapable of growing on starch as the only carbon source. Our results support the role of OMVs as "public goods" that can be utilized by other organisms with different metabolic capabilities.IMPORTANCE Species from the Bacteroides genus are predominant members of the human gut microbiota. OMVs in Bacteroides have been shown to be important for the homeostasis of complex host-commensal relationships, mainly involving immune tolerance and protection from disease. OMVs carry many enzymatic activities involved in the cleavage of complex polysaccharides and have been proposed as public goods that can provide growth to other bacterial species by release of polysaccharide breakdown products into the gut lumen. This work shows that the presence of a negatively charged rich amino acid motif (LES) is required for efficient packing of the surface-exposed alpha-amylase SusG into OMVs. Our findings strongly suggest that surface exposure is coupled to packing of Bacteroides lipoproteins into OMVs. This is the first step in the generation of tailor-made probiotic interventions that can exploit LES-related sequences to generate Bacteroides strains displaying proteins of interest in OMVs. PMID- 30404932 TI - Sinorhizobium meliloti, a Slow-Growing Bacterium, Exhibits Growth Rate Dependence of Cell Size under Nutrient Limitation. AB - Bacterial cells need to coordinate the cell cycle with biomass growth to maintain cell size homeostasis. For fast-growing bacterial species like Escherichia coli and Bacillus s ubtilis, it is well-known that cell size exhibits a strong dependence on the growth rate under different nutrient conditions (known as the nutrient growth law). However, cell size changes little with slow growth (doubling time of >90 min) for E. coli, posing the interesting question of whether slow-growing bacteria species also observe the nutrient growth law. Here, we quantitatively characterize the cell size and cell cycle parameter of a slow growing bacterium, Sinorhizobium meliloti, at different nutrient conditions. We find that S. meliloti exhibits a threefold change in its cell size when its doubling time varies from 2 h to 6 h. Moreover, the progression rate of its cell cycle is much longer than that of E. coli, suggesting a delicate coordination between the cell cycle progression rate and the biomass growth rate. Our study shows that the nutrient growth law holds robustly regardless of the growth capacity of the bacterial species, generalizing its applicability among the bacterial kingdom.IMPORTANCE The dependence of cell size on growth rate is a fundamental principle in the field of bacterial cell size regulation. Previous studies of cell size regulation mainly focus on fast-growing bacterial species such as Escherichia coli and Bacillus subtilis We find here that Sinorhizobium meliloti, a slow-growing bacterium, exhibits a remarkable growth rate-dependent cell size pattern under nutrient limitation, generalizing the applicability of the empirical nutrient growth law of cell size. Moreover, S. meliloti exhibits a much slower speed of cell cycle progression than E. coli does, suggesting a delicate coordination between the cell cycle progression rate and the biomass growth rate. PMID- 30404933 TI - The Fourth International Neonatal and Maternal Immunization Symposium (INMIS 2017): Toward Integrating Maternal and Infant Immunization Programs. AB - Prevention of serious infections in pregnant mothers, newborns, and young infants through immunization during pregnancy and in early life has the potential to further reduce maternal and neonatal morbidity and mortality worldwide. In the past decade, research in this field has advanced substantially, from the understanding of the biology and immunology of pregnancy and early life, to the active development of several candidate vaccines, for which challenges and opportunities for global implementation are under consideration. Experts from academia, industry, regulatory and funding agencies, public health, and international organizations met in Brussels (Belgium) from 10 to 12 September 2017, at the 4th International Neonatal and Maternal Immunization Symposium (INMIS), to review the most relevant advances in maternal and neonatal immunization. The overarching focus of the conference was to identify the path forward to achieve integration of maternal and early life immunization strategies for the successful implementation of vaccines in antenatal care and pediatric programs for reduction of maternal and infant mortality worldwide.IMPORTANCE This report provides an overview of the proceedings of the 4th International Maternal and Neonatal Immunization Symposium, where presentations focused on the state-of the-art research on the development and implementation of vaccines given during pregnancy for the protection of mothers and infants. PMID- 30404934 TI - Establishment and Application of Rapid Diagnosis for Reverse Transcription Quantitative PCR of Newly Emerging Goose-Origin Nephrotic Astrovirus in China. AB - In 2017, a new type of goose-origin astrovirus (GoAstV) that is completely different from previously identified avian astroviruses (which have only 30.0% to 50.5% homology with GoAstV) has been isolated from diseased geese in China. This disease can cause joint swelling in sick geese, and the anatomy shows a clear precipitation of urate in the kidney. The rate of death and culling can reach more than 30%, revealing the disease's severe pathogenicity. To quickly and accurately diagnose the newly emerging disease, we established a highly specific reverse transcription-quantitative PCR (RT-qPCR) method of detecting GoAstV. Sensitivity testing showed that the minimum amount of test sample for this method is 52.5 copies/MUl. Clinical application confirmed that this method can quickly and effectively detect GoAstV, providing a diagnostic platform for the prevention and control of goose disease.IMPORTANCE Goose-origin astrovirus (GoAstV), as a newly emerging virus in 2017, is different from previously known astroviruses in the genus Avastrovirus So far, few studies have focused on the novel virus. Considering the infectious development of astrovirus (AstV), we established a reverse transcription-quantitative PCR (RT-qPCR) assay with a strong specificity to quickly and accurately diagnose GoAstV. Confirmed by clinical application, this method can quickly and accurately detect prevalent GoAstV. The assay is thus convenient for clinical operation and is applicable to the monitoring of GoAstV disease. PMID- 30404935 TI - The Enterococcus Cassette Chromosome, a Genomic Variation Enabler in Enterococci. AB - Enterococcus faecium has a highly variable genome prone to recombination and horizontal gene transfer. Here, we have identified a novel genetic island with an insertion locus and mobilization genes similar to those of staphylococcus cassette chromosome elements SCCmec This novel element termed the enterococcus cassette chromosome (ECC) element was located in the 3' region of rlmH and encoded large serine recombinases ccrAB similar to SCCmec Horizontal transfer of an ECC element termed ECC::cat containing a knock-in cat chloramphenicol resistance determinant occurred in the presence of a conjugative rep pLG1 plasmid. We determined the ECC::cat insertion site in the 3' region of rlmH in the E. faecium recipient by long-read sequencing. ECC::cat also mobilized by homologous recombination through sequence identity between flanking insertion sequence (IS) elements in ECC::cat and the conjugative plasmid. The ccrABEnt genes were found in 69 of 516 E. faecium genomes in GenBank. Full-length ECC elements were retrieved from 32 of these genomes. ECCs were flanked by attR and attL sites of approximately 50 bp. The attECC sequences were found by PCR and sequencing of circularized ECCs in three strains. The genes in ECCs contained an amalgam of common and rare E. faecium genes. Taken together, our data imply that ECC elements act as hot spots for genetic exchange and contribute to the large variation of accessory genes found in E. faecium IMPORTANCE Enterococcus faecium is a bacterium found in a great variety of environments, ranging from the clinic as a nosocomial pathogen to natural habitats such as mammalian intestines, water, and soil. They are known to exchange genetic material through horizontal gene transfer and recombination, leading to great variability of accessory genes and aiding environmental adaptation. Identifying mobile genetic elements causing sequence variation is important to understand how genetic content variation occurs. Here, a novel genetic island, the enterococcus cassette chromosome, is shown to contain a wealth of genes, which may aid E. faecium in adapting to new environments. The transmission mechanism involves the only two conserved genes within ECC, ccrAB Ent, large serine recombinases that insert ECC into the host genome similarly to SCC elements found in staphylococci. PMID- 30404936 TI - Mixed Chlamydia trachomatis Peptide Antigens Provide a Specific and Sensitive Single-Well Colorimetric Enzyme-Linked Immunosorbent Assay for Detection of Human Anti-C. trachomatis Antibodies. AB - Sensitive and specific detection of anti-Chlamydia trachomatis antibodies in standard enzyme-linked immunosorbent assays (ELISAs) is compromised by cross reactivity and poor sensitivity of classical C. trachomatis antigens. Previously, we discovered 48 strongly reactive peptide antigens of C. trachomatis-specific B cell epitopes from 21 immunodominant proteins. By comprehensive individual testing of 11 top-ranked peptide antigens, we found very high sensitivity and specificity for detection of anti-C. trachomatis antibodies in chemiluminescent ELISAs. The current study established a labor-saving colorimetric ELISA by using a mixture of 12 strongly reactive C. trachomatis peptide antigens (Ctr Mix1) in a single well/serum rather than assaying reactivity to each individual peptide. For performance evaluation, we used a simulated population of 212 anti-C. trachomatis antibody-positive and -negative sera from 125 women with NAAT-confirmed active C. trachomatis infection and from 87 healthy women at low risk for C. trachomatis infection. In comparison to a composite reference standard (CRS) for anti-C. trachomatis antibody status, the Ctr Mix1 IgG ELISA achieved 93.9% sensitivity, significantly superior to the 49% to 79% sensitivities of four commercial anti-C. trachomatis IgG ELISAs, and 98% specificity of all tested assays. Compared to the labor-intensive individual peptide testing, this mixed peptide ELISA retained high specificity with only marginal, ~5% sensitivity loss. By ROC-AUC, likelihood ratio, and predictive value analyses, the Ctr Mix1 ELISA performed satisfactorily at 10% to 75% prevalence range of anti-C. trachomatis antibodies but significantly better than commercial ELISAs. Thus, the labor-saving mixed peptide colorimetric ELISA format provides simultaneously high specificity and sensitivity for detection of anti-C. trachomatis antibodies.IMPORTANCE For detection of anti-C. trachomatis antibodies by serological assays, use of classical chlamydial antigens results in high cross-reactivity and poor sensitivity. Previously, we discovered 48 strongly reactive peptide antigens of C. trachomatis-specific B-cell epitopes from 21 immunodominant proteins, and individual testing and combined scoring of 5 to 11 peptide antigens provided highly sensitive and specific detection of anti-C. trachomatis antibodies in chemiluminescent ELISAs. To simplify this method, this study established a single well labor-saving colorimetric ELISA using a mixture of 12 strongly reactive C. trachomatis peptide antigens (Ctr Mix1) for detection of anti-C. trachomatis antibodies. This Ctr Mix1 ELISA (94% sensitivity and 98% specificity) outperformed 4 commercial ELISAs (49% to 79% sensitivity and 98% specificity). This ELISA can be easily implemented and commercialized, with convenient setup for use in nonspecialized laboratories. Thus, this mixed peptide assay with superior specificity and sensitivity will improve serodiagnosis of C. trachomatis infections. PMID- 30404937 TI - Characterization of Staphylococcal Cassette Chromosome mec Elements from Methicillin-Resistant Staphylococcus pseudintermedius Infections in Australian Animals. AB - We examined the oxacillin resistance phenotype and genomic structure of staphylococcal cassette chromosome mec (SCCmec) elements from 77 veterinary methicillin-resistant Staphylococcus pseudintermedius (MRSP) isolates. Isolates were characterized by oxacillin broth microdilution, whole-genome sequencing, and bioformatics analysis. Five previously described SCCmec elements, and a sixth novel element, were identified: SCCmec III (also known as II-III), PsiSCCmec 57395, and SCCmec NA45 (a SCCmec VII variant), all previously described in MRSP, and SCCmec IVg and SCCmec VT, previously described in both methicillin-resistant Staphylococcus aureus (MRSA) and MRSP. The sixth element was novel and found among nine geographically clustered isolates. This novel pseudostaphylococcal cassette chromosome (PsiSCCmec KW21) contained a class A mec gene complex but lacked ccr genes. It also harbored heavy metal (cadmium) resistance determinants. The median oxacillin MIC values among PsiSCCmec KW21, SCCmec III, and SCCmec VT isolates were significantly higher than those determined for the SCCmec NA45 VII variant isolates and PsiSCCmec 57395 and SCCmec IVg isolates. PsiSCCmec KW21 was found exclusively in sequence type 497 (ST497), an MRSP clone that is locally successful in Victoria, Australia. Future studies are necessary to determine if this clone has disseminated further afield and if PsiSCCmec KW21 has moved into other MRSP lineages or staphylococcal species.IMPORTANCE Staphylococcus pseudintermedius is a significant veterinary pathogen and occasional cause of infections in humans. beta-Lactams are an important group of antimicrobials used to treat staphylococcal infections in humans and animals. However, when staphylococci become methicillin resistant via the acquisition of a mobile genetic element called staphylococcal cassette chromosome mec (SCCmec), they become resistant to all beta-lactams. This study detected a novel SCCmec element among a cluster of methicillin-resistant S. pseudintermedius isolates from animals in Australia. It also detected SCCmec elements in S. pseudintermedius that had high similarity to those identified in methicillin-resistant Staphylococcus aureus, demonstrating how human and animal pathogens can share the same resistance determinants. PMID- 30404938 TI - Hydroxypropyl-Beta-Cyclodextrin Reduces Inflammatory Signaling from Monocytes: Possible Implications for Suppression of HIV Chronic Immune Activation. AB - Monocytes from HIV-infected patients produce increased levels of inflammatory cytokines, which are associated with chronic immune activation and AIDS progression. Chronic immune activation is often not restored even in patients showing viral suppression under ART. Therefore, new therapeutic strategies to control inflammation and modulate immune activation are required. Hydroxypropyl beta-cyclodextrin (HP-BCD) is a cholesterol-sequestering agent that has been reported to be safe for human use in numerous pharmaceutical applications and that has been shown to inactivate HIV in vitro and to control SIV infection in vivo Since cellular cholesterol content or metabolism has been related to altered cellular activation, we evaluated whether HP-BCD treatment could modulate monocyte response to inflammatory stimuli. Treatment of monocytes isolated from HIV-positive and HIV-negative donors with HP-BCD inhibited the expression of CD36 and TNF-alpha after LPS stimulation, independent of raft disruption. Accordingly, HP-BCD-treated cells showed significant reduction of TNF-alpha and IL-10 secretion, which was associated with lower mRNA expression. LPS-induced p38MAPK phosphorylation was dampened by HP-BCD treatment, indicating this pathway as a target for HP-BCD-mediated anti-inflammatory response. The expression of HLA-DR was also reduced in monocytes and dendritic cells treated with HP-BCD, which could hinder T cell activation by these cells. Our data suggest that, besides its well-known antiviral activity, HP-BCD could have an immunomodulatory effect, leading to decreased inflammatory responses mediated by antigen-presenting cells, which may impact HIV pathogenesis and AIDS progression.IMPORTANCE Chronic immune activation is a hallmark of HIV infection and is often not controlled even in patients under antiretroviral therapy. Indeed, chronic diseases with inflammatory pathogenesis are being reported as major causes of death for HIV-infected persons. Hydroxypropyl-beta cyclodextrin (HP-BCD) is a cholesterol-sequestering drug that inhibits HIV replication and infectivity in vitro and in vivo Recent studies have demonstrated the importance of cholesterol metabolism and content in different inflammatory conditions; therefore, we investigated the potential of HP BCD as an immunomodulatory drug, regulating the activation of cells from HIV infected patients. Treatment of monocytes with HP-BCD inhibited the expression and secretion of receptors and mediators that are usually enhanced in HIV patients. Furthermore, we investigated the molecular mechanisms associated with the immunomodulatory effect of HP-BCD. Our results indicate that, besides reducing viral replication, HP-BCD treatment may contribute to modulation of chronic immune activation associated with AIDS. PMID- 30404940 TI - Persistent "Sag" in Prefrontal Cortex Function following Adolescent Binge Drinking. PMID- 30404939 TI - Identification of an Exceptionally Long Intron in the HAC1 Gene of Candida parapsilosis. AB - The unfolded protein response (UPR) in the endoplasmic reticulum (ER) is well conserved in eukaryotes from metazoa to yeast. The transcription factor HAC1 is a major regulator of the UPR in many eukaryotes. Deleting HAC1 in the yeast Candida parapsilosis rendered cells more sensitive to DTT, a known inducer of the UPR. The deletion strain was also sensitive to Congo red, calcofluor white, and the antifungal drug ketoconazole, indicating that HAC1 has a role in cell wall maintenance. Transcriptomic analysis revealed that treatment of the wild type with DTT resulted in the increased expression of 368 genes. Comparison with mutant cells treated with DTT reveals that expression of 137 of these genes requires HAC1 Enriched GO term analysis includes response to ER stress, cell wall biogenesis and glycosylation. Orthologs of many of these are associated with UPR in Saccharomyces cerevisiae and Candida albicans Unconventional splicing of an intron from HAC1 mRNA is required to produce a functional transcription factor. The spliced intron varies in length from 19 bases in C. albicans to 379 bases in Candida glabrata, but has not been previously identified in Candida parapsilosis and related species. We used RNA-seq data and in silico analysis to identify the HAC1 intron in 12 species in the CTG-Ser1 clade. We show that the intron has undergone major contractions and expansions in this clade, reaching up to 848 bases. Exposure to DTT induced splicing of the long intron in C. parapsilosis HAC1, inducing the UPR.IMPORTANCE The unfolded protein response (UPR) responds to the build-up of misfolded proteins in the endoplasmic reticulum. The UPR has wide ranging functions from fungal pathogenesis to applications in biotechnology. The UPR is regulated through the splicing of an unconventional intron in the HAC1 gene. This intron has been described in many fungal species and is of variable length. Until now it was believed that some members of the CTG-Ser1 clade such as C. parapsilosis did not contain an intron in HAC1, suggesting that the UPR was regulated in a different manner. Here we demonstrate that HAC1 plays an important role in regulating the UPR in C. parapsilosis We also identified an unusually long intron (626 bp) in C. parapsilosis HAC1 Further analysis showed that HAC1 orthologs in several species in the CTG-Ser1 clade contain long introns. PMID- 30404941 TI - Human bacterial repertoire of the urinary tract: a potential paradigm shift. AB - The aim of this article is to review the human repertoire of bacteria already described by culture and metagenomic techniques in urine, and published in the literature. Our study led us to compare this repertoire with other human repertoires available.We followed automatic and manual bibliographical methods and found 562 bacterial species reported in the literature as part of the human urinary microbiota. Of the 562 species, 322 were described only by culture, 101 by both culture and metagenomics, and 139 only by metagenomic. Three hundred and fifty-two species (62.6%) have been associated with at least one case report of human infection, of which 225 (40.0%) have been described as causative agents of urinary tract infection. The urinary tract bacterial repertoire contains 21.4% of the known prokaryotic diversity associated with human beings (464 in common) and share 23.6% species with the human gut microbiota (350 in common, 62.3% of the urine species). Urinary repertoire shares a significant difference in aero intolerant species compared with gut microbiota (100/562; 17.8% and 505/1484; 34.0% respectively; p<0.001; OR=9.0 [7.0-11.4]). Studies using high-throughput sequencing show a higher proportion of aero-intolerant bacteria in urine (74/240, 30.8%).Most pathogenic bacteria are part of the commensal human urinary tract bacteria and their pathogenicity may occur following any imbalance of this microbiota. The restoration of urinary tract health can occur following a fecal transplantation. The potential gut origin of the human bacterial microbiota has to be explored. PMID- 30404942 TI - Towards the development of a cfDNA-based in-vitro diagnostic test for infectious diseases: A review of evidence for tuberculosis. AB - Detection of circulating free DNA (cfDNA) has transformed the field of oncology and prenatal diagnostics. Clinical application of cfDNA for disease diagnosis and monitoring, however, is relatively recent in the field of infectious disease. The potential of cfDNA as a non-invasive diagnostic and monitoring tool is especially promising for tuberculosis (TB) as it enables detection of both pulmonary and extrapulmonary TB from easily accessible urine and/or blood samples from any age group. However, despite the potential of cfDNA detection to identify TB, very few studies are described in the literature to date. A comprehensive search of the literature identified 15 studies that report detecting M. tuberculosis DNA in the blood and urine of TB patients with non-genitourinary disease, but in only six of them were the methodological steps considered suitable for cfDNA isolation and detection. The sensitivities and specificities for diagnosis of pulmonary and extrapulmonary TB cases reported in these six studies are highly variable, falling in the range of 29-79% and 67-100%, respectively. While most studies could not meet the performance requirements of the high-priority target product profiles (TPP) published by the World Health Organization (WHO), the study results nonetheless show promise for a point-of-care detection assay. Better designed prospective studies, using appropriate samples, will be required to validate cfDNA as a TB biomarker. PMID- 30404943 TI - The genetic diversity of multi and extensively drug resistant Mycobacterium tuberculosis in the capital of Iran revealed by whole genome sequencing. AB - The emergence and spread of multidrug resistant (MDR) Mycobacterium tuberculosis complex (MTBC) strains is a critical global health problem. Between 2014 and 2018, 606 MTBC strains were isolated from 13,892 suspected pulmonary tuberculosis (TB) patients in Tehran, Iran, including 16 MDR-TB (2.6%) cases. A combination of phenotypic and genotypic methods (whole genome sequencing), was employed for the identification of additional drug resistances and strain-to-strain genetic distances as a marker for recent transmission events. MDR and extensively drug resistant (XDR) TB cases were almost exclusively infected by lineage 2/Beijing strains (14/16, p <0.001). We further showed that recent transmission and/or recent introduction of lineage 2/Beijing strains contribute to high XDR-TB rates among all MDR-TB cases and should be considered an emerging threat for TB control in Tehran. In addition, the extensive pre-existing drug resistance profiles of M/XDR strains will further challenge TB diagnostics in the region. PMID- 30404945 TI - Streptococcus pneumoniae serotype 3 in Mexico (1994-2017): decrease of the unusual CC4909 lineage post-PCV13 introduction. AB - Streptococcus pneumoniae expressing serotype 3 have high virulence and case fatality ratio. Most studies of serotype 3 pneumococci have focused on a single lineage, the widespread ST180. To evaluate the serotype 3 lineages causing infections in Mexico we characterized 196 isolates recovered in 1994-2017. The isolates were mostly susceptible to all antimicrobials tested. A single meningitis isolate was resistant to penicillin and resistance to erythromycin was 5.2%. The isolates represented the widely disseminated clonal complex CC180 (n=140), the unusual CC4909 (n=42), CC260 (n=11), and a few singletons (n=3). CC260 was less frequent among pneumococcal invasive disease isolates than CC180 and CC4909 (p=0.015). There was a decrease of CC4909 (p<0.001) in the post-PCV13 period (2012-2017). The CC4909 isolates were represented mostly by ST1119 (n=40), seemingly having a restricted geographic origin, with isolates in the pubmlst database having been recovered only in Mexico, USA and Germany. Genomic analysis of publicly available genomes showed that ST1119 isolates have less than 32% similarity with ST180 isolates, indicating that these lineages are more separated than revealed by traditional multilocus sequence typing. Considering the suggestions of a lower efficacy of the 13-valent pneumococcal conjugate vaccine against serotype 3, the different dynamics of the two major serotype 3 lineages in Mexico following the introduction of PCV13 should be closely monitored. PMID- 30404946 TI - Validation and implementation of a diagnostic algorithm for DNA detection of Bordetella pertussis, B. parapertussis and B. holmesii in a pediatric referral hospital in Barcelona, Spain. AB - Objectives: This study aimed to validate a comprehensive diagnostic protocol based on real-time PCR for the rapid detection and identification of B. pertussis, B. parapertussis and B. holmesii, as well as its implementation in the diagnostic routine of a reference children's hospital.Methods: The new algorithm included a triplex qPCR targeting IS481 gene (in B. pertussis, B. holmesii and some B. bronchiseptica strains), pIS1001 (B. parapertussis-specific) and rnase P as human internal control. Two confirmatory singleplex for B. pertussis (ptxA-Pr) and B. holmesii (hIS1001) were performed if IS481 was positive. Analytical validation included determination of linear range, linearity, efficiency, precision, sensitivity and a reference panel with clinical samples. Once validated, the new algorithm was prospectively implemented in children with clinical suspicion of whooping cough presenting to Hospital Sant Joan de Deu (Barcelona, Spain), during 12 months.Results: Lower limits of detection obtained were 4.4, 13.9 and 27.3 genomic equivalents/mL of sample for IS481 (on B. pertussis), pIS1001 and hIS1001, and 777.9 for ptxA-Pr. qPCR efficiencies ranged from 86.0% to 96.9%. Intra and inter-assay variabilities were <3% and <5%. Among 566 samples analyzed, B. pertussis, B. holmesii and B. parapertussis were detected in 11.1%, 0.9% (only in >4 years females) and 0.2% of samples, respectively.Conclusions: The new algorithm proved to be a useful microbiological diagnostic tool for whooping cough, demonstrating a low rate of other Bordetella non-pertussis in our surveilled area. PMID- 30404944 TI - Simultaneous Quantification of Plasmodium Antigens and Host Factor CRP in Asymptomatic Individuals with Confirmed Malaria Using a Novel Multiplex Immunoassay. AB - INTRODUCTION: Malaria rapid diagnostic tests (RDTs) detect primarily Plasmodium (P.) falciparum antigen histidine-rich protein 2 (HRP2) and the malaria-conserved antigen lactate dehydrogenase (LDH) for P. vivax and other malaria species. The performance of RDTs and their utility is dependent on circulating antigen concentration distributions in infected individuals in a malaria endemic population and the limit-of-detection of the RDT for the antigens. A multiplexed immunoassay for the quantification of HRP2, P. vivax LDH and all malaria LDH (Pan LDH) was developed to measure accurately circulating antigen concentration and their distribution in an endemic population. The assay also measures C -reactive protein (CRP) as an indicator of inflammation. METHODS: Validation was conducted with clinical specimens from 397 asymptomatic donors from Myanmar and Uganda confirmed by PCR for infection and from participants in induced blood-stage malaria challenge studies. RESULTS: The assay has lower limit-of-detection for HRP2, Pan LDH, P. vivax LDH and CRP were 0.2 pg/mL, 9.3 pg/mL, 1.5 pg/mL and 26.6 ng/mL, respectively. At thresholds for HRP2, Pan LDH, and P. vivax LDH of 2.3 pg/mL, 47.8 pg/mL, and 75.1 pg/mL, respectively, and specificity >= 98.5%, sensitivities for ultrasensitive PCR confirmed infections were 93.4, 84.9 and 48.9% respectively. Plasmodium LDH (pLDH) concentration correlated closely with parasite density, in contrast to HRP2. CRP levels were moderately higher in P. falciparum infections with confirmed antigenemia versus clinical specimens with no antigen. CONCLUSIONS: The 4-plex array is a sensitive tool for quantifying diagnostic antigens in malaria infections and supporting the evaluation of new ultrasensitive RDTs. PMID- 30404947 TI - Can microtubule motors use every available track? AB - Flagellar assembly and function depend on cargo traveling via motors on microtubule doublets. Bertiaux, Mallet et al. (2018. J. Cell Biol https://doi.org/10.1083/jcb.201805030) find that only a subset of available doublets are used for this transport in trypanosomes, leading to questions about how and why this is achieved. PMID- 30404948 TI - FAM92A1 is a BAR domain protein required for mitochondrial ultrastructure and function. AB - Mitochondrial function is closely linked to its dynamic membrane ultrastructure. The mitochondrial inner membrane (MIM) can form extensive membrane invaginations known as cristae, which contain the respiratory chain and ATP synthase for oxidative phosphorylation. The molecular mechanisms regulating mitochondrial ultrastructure remain poorly understood. The Bin-Amphiphysin-Rvs (BAR) domain proteins are central regulators of diverse cellular processes related to membrane remodeling and dynamics. Whether BAR domain proteins are involved in sculpting membranes in specific submitochondrial compartments is largely unknown. In this study, we report FAM92A1 as a novel BAR domain protein localizes to the matrix side of the MIM. Loss of FAM92A1 caused a severe disruption to mitochondrial morphology and ultrastructure, impairing organelle bioenergetics. Furthermore, FAM92A1 displayed a membrane-remodeling activity in vitro, inducing a high degree of membrane curvature. Collectively, our findings uncover a role for a BAR domain protein as a critical organizer of the mitochondrial ultrastructure that is indispensable for mitochondrial function. PMID- 30404950 TI - Blood pressure lowering in acute intracerebral hemorrhage. PMID- 30404949 TI - HGF-induced migration depends on the PI(3,4,5)P3-binding microexon-spliced variant of the Arf6 exchange factor cytohesin-1. AB - Differential inclusion or skipping of microexons is an increasingly recognized class of alternative splicing events. However, the functional significance of microexons and their contribution to signaling diversity is poorly understood. The Met receptor tyrosine kinase (RTK) modulates invasive growth and migration in development and cancer. Here, we show that microexon switching in the Arf6 guanine nucleotide exchange factor cytohesin-1 controls Met-dependent cell migration. Cytohesin-1 isoforms, differing by the inclusion of an evolutionarily conserved three-nucleotide microexon in the pleckstrin homology domain, display differential affinity for PI(4,5)P2 (triglycine) and PI(3,4,5)P3 (diglycine). We show that selective phosphoinositide recognition by cytohesin-1 isoforms promotes distinct subcellular localizations, whereby the triglycine isoform localizes to the plasma membrane and the diglycine to the leading edge. These data highlight microexon skipping as a mechanism to spatially restrict signaling and provide a mechanistic link between RTK-initiated phosphoinositide microdomains and Arf6 during signal transduction and cancer cell migration. PMID- 30404951 TI - Safety and effectiveness of transcatheter closure of atrial septal defects: Initial results in Fukushima Prefecture. AB - BACKGROUND: Atrial septal defect is the third most common type of congenital heart disease. Surgical closure was the standard treatment for atrial septal defects before transcatheter closure was approved as minimally invasive treatment in Japan in 2006. In our hospital, this procedure has been performed since 2015. OBJECTIVE: To evaluate the safety and effectiveness of transcatheter closure of atrial septal defects in our hospital. METHODS: Thirty patients (mean age 57.0 +/ 19.7 years, 11 males), who underwent transcatheter closure of atrial septal defect between September 2015 and February 2018 at the Fukushima Medical University Hospital, were enrolled. All procedures were performed under general anesthesia with angiographic and transesophageal echocardiographic guidance. Safety and effectiveness were evaluated by the procedural results and complications. RESULTS: All 30 patients successfully underwent transcatheter closure of atrial septal defects and no patient developed complications. New York Heart Association functional class was improved, and the right ventricular area and right atrium area were decreased, postoperatively. CONCLUSION: Transcatheter closure is a safe and effective treatment for atrial septal defects, and thus could be an alternative option to open heart surgery. PMID- 30404952 TI - Inotropic effects of a single intravenous recommended dose of pimobendan in healthy dogs. AB - We investigated the effects of an injectable pimobendan solution (0.15 mg/kg) on cardiac function in healthy dogs. Fifteen dogs were divided into placebo, intravenous pimobendan injection, and subcutaneous pimobendan injection groups. In the placebo, the heart rate, systolic and end-diastolic left ventricular pressure (LVPs and LVEDP), and peak positive (max dP/dt) and negative (min dP/dt) first derivatives of the left ventricular pressure did not change for 60 min. After the intravenous pimobendan injection, LVEDP decreased significantly within 5 min, while the max dP/dt increased, and the effects continued until 60 min. In comparison, there were no hemodynamic changes after the subcutaneous pimobendan injection. This study demonstrates that injectable pimobendan induced a rapid inotropic effect and decreased the LVEDP in dogs. PMID- 30404953 TI - Infiltrative lipoma causing vertebral deformation and spinal cord compression in a dog. AB - A 4-year-old, male Bernese mountain dog was evaluated for a 1-year history of right hemiparesis. Computed tomography revealed a large hypoattenuating mass severely deforming the C5 vertebral arch, invading the C6 spinal canal, and causing spinal cord compression. The signal characteristics of magnetic resonance imaging indicated a lesion composed of adipose tissue. The mass was removed via right hemilaminectomy, and histopathological examination confirmed it was an infiltrative lipoma. The compressive lesion remained unresolved, so the dog underwent a second operation, after which he regained some ambulatory function. Although postoperative adjunctive radiation therapy was performed, the dog died 201 days after the first operation. PMID- 30404954 TI - A case of pulmonary toxoplasmosis resembling multiple lung metastases of nasal lymphoma in a cat receiving chemotherapy. AB - An 11-year-old cat presented with nasal discharge and lacrimation and was diagnosed with nasal lymphoma. Although the cat showed favorable progression after undergoing chemotherapy, CT imaging demonstrated enlarged pulmonary nodules caused by Toxoplasma gondii. Following the cessation of chemotherapy, the cat was prescribed clindamycin hydrochloride for toxoplasmosis treatment; however, the cat developed kidney lymphoma and died. No T. gondii organisms were observed in the whole body necropsy specimens. It is known that immunocompromised human patients, including those who undergo chemotherapy, are considered at risk for toxoplasmosis. However, the risk of developing toxoplasmosis in cats undergoing chemotherapy is currently unknown. Findings from this case report suggest that cats with chemotherapy-resistant pulmonary masses might have a T. gondii infection rather than metastatic disease. PMID- 30404955 TI - Effect of fisetin and probiotic supplementation on erythrocyte osmotic fragility, malondialdehyde concentration and superoxide dismutase activity in broiler chickens exposed to heat stress. AB - The aim of the study was to evaluate effects of fisetin and probiotic on erythrocyte osmotic fragility (EOF), malondialdehyde (MDA) and superoxide dismutase (SOD) in broiler chickens exposed to heat stress. Sixty day-old broilers were divided into: Group I (control) given distilled water; Group II, fisetin (5 mg/kg); Group III, probiotic Saccharomyces cerevisiae (4.125 * 106 cfu/100 ml); and Group IV, fisetin (5 mg/kg) + probiotic (4.125 * 106 cfu/100 ml) orally for 7 days. Blood samples collected from 42-day-old birds were evaluated for EOF, serum MDA concentration and SOD activity. Percentage EOF at 0.5% NaCl was lower (P<0.05) in fisetin, probiotic and fisetin + probiotic groups (34.26 +/ 0.98%, 35.65 +/- 0.81% and 34.25 +/- 1.98%, respectively) than in controls (48.42 +/- 0.40%). The MDA concentrations in broiler chickens administered with fisetin (14.37 +/- 1.15 nmol/l), probiotic (5.66 +/- 1.06 nmol/l) and fisetin + probiotic (4.136 +/- 0.58 nmol/l) were lower (P<0.05) than in controls (22.64 +/- 2.95 nmol/l). Activities of SOD were higher (P<0.05) in fisetin, probiotic and fisetin + probiotic broiler chickens (6.34 +/- 0.24 IU/l, 5.67 +/- 0.09 IU/l and 5.93 +/- 0.13 IU/l, respectively) than in controls (5.37 +/- 0.09 IU/l). Fisetin + probiotic ameliorated oxidative stress changes in broiler chickens better than fisetin or probiotic alone. In conclusion, administration of fisetin or probiotic and, especially their combination, decreased EOF, lipoperoxidation and increased superoxide dismutase activity in broiler chickens exposed to heat stress. PMID- 30404956 TI - Revisiting the Interaction Force Measurement between Lipid Bilayers Using a Surface Forces Apparatus (SFA). AB - In this review, previous researches that measured intermembrane forces using the Surface Forces Apparatus are recapitulated. Different types of interaction forces are reported between two lipid bilayers including non-specific interactions (e.g., van der Waals, electrostatic, steric hydration, thermal undulation, and hydrophobic) and specific interactions (e.g., ligand-receptor). By measuring absolute distance and interaction forces at the sub-angstrom level and at a few nano-Newtons resolution, respectively, magnitudes, working ranges, and decay lengths of interaction between lipid bilayers are investigated. Utilizing recently developed fluorescence microscopy attachments, simultaneous fluorescence imaging of membrane proteins and lipid phases can be performed during approach/separation cycles of two lipid bilayer deposited surfaces, which can reveal cooperative effects between lipid phases and various types of membrane proteins. PMID- 30404957 TI - Preparation of Pinolenic Acid Concentrates from Pine Nut Oil Fatty Acids by Solvent Fractionation. AB - Pinolenic acid (PLA), which is a fatty acid (FA) exclusively found in the oils of edible pine nuts, has an appetite-suppression effect, thereby being effective to reduce body weight in humans. PLA concentrates would be suitable for use in functional foods and nutraceuticals due to the health benefits of PLA. PLA concentrates were prepared from free FA (FFA) obtained from pine nut oil using solvent fractionation. Siberian pine nut oil containing 18.3 wt% PLA was used as the starting material for the fractionation. The fractionation was performed in n hexane at ultra-low temperatures down to -85 degrees C. The PLA concentrates produced under the optimal conditions established in this study (temperature, -85 degrees C; n-hexane-to-FFA ratio (v/w), 30:1; fractionation time, 36 h) contained 69.8 wt% PLA. The yield of PLA was 77.4 wt% of the initial PLA weight in the FFA. These results suggest that solvent fractionation is a more effective approach to prepare PLA concentrates with higher PLA contents at a particular yield of PLA than published methods using urea crystallization (e.g., PLA content = ~47 wt%, yield of PLA = ~77 wt%, Woo et al. (2016)) or lipase-catalyzed reactions (e.g., PLA content = ~30 wt%, yield of PLA = ~61 wt%, Lee et al. (2011)). The resulting PLA concentrates contained 11 of the 12 different species of FA present in the FFA, thereby indicating that the PLA concentrates prepared by solvent fractionation have more diverse FA profiles than those prepared by urea crystallization (e.g., 7 species of FA, Woo et al. (2016)). PMID- 30404958 TI - Stability Evaluations of Different Types of Vegetable Oil-based Emulsions. AB - The study was aimed at evaluating the effects of vegetable oils on emulsion stability. Palm olein (POo), olive oil (OO), safflower oil (SAF), grape seed oil (GSO), soybean oil (SBO) and sunflower oil (SFO) with different degree of saturation levels were chosen as major ingredient of oil phases. All the emulsions were stored at 4C, 27C and 40C for 35 days and subjected to all the stability tests, including temperature variation, centrifuge test, cycle test, pH and slip melting point. The results indicated that POo exhibited the highest stability, followed by SAF, OO, GSO, SFO and SBO. In addition, the results implied that the degree of saturation levels of vegetable oils does give significant effect on emulsion stability based on the centrifuge testing for an approximate 30% usage level of oil. The POo-based emulsion exhibited good emulsion stability throughout the experimental period indicated that POo could be a good carrier oil for various applications in cosmetic industry. PMID- 30404959 TI - Polydimethylsiloxane Shows Strong Protective Effects in Continuous Deep-Frying Operations. AB - Polydimethylsiloxane (PDMS) was previously reported to show no protective effect in continuous deep-frying. In this study, we used canola oil with/without added PDMS to deep-fry shredded potato at 180 degrees C either continuously or with 10 , 20-, or 30-min intervals between frying sessions for 6 h. In continuous deep frying in canola oil not containing PDMS, far more oil vapor was generated from the oil and the water in the potato compared to frying with 20- and 30-min intervals between sessions and the oil in the fryer accordingly had a lower polar compound content (PC). The longer the oil was used to deep-fry potato, the more steam was generated from potato. Thus, polar compounds evaporated into the air in the steam, resulting in a low PC value of oil in the fryer. In contrast, both thermal deterioration and oil vaporization were remarkably inhibited in canola oil containing PDMS regardless of the frying pattern, and the PC value of the oil in the fryer increased in proportion to the amount of potato deep-fried. Canola oil with/without added PDMS was heated at 180 degrees C for 6 h to confirm the effect of water released from potato on the oxidation of oil. A large increase in PC was observed in canola oil not containing PDMS when heated without water but this increase was inhibited to some extent when water was supplied continuously. On the other hand, the PC of canola oil containing PDMS was far lower than that of oil not containing PDMS, but the addition of water promoted an increase in PC. In conclusion, we observed superior protective effects of PDMS regardless of the deep-frying pattern employed, but the PC value nonetheless increased as the amount of food deep-fried increased. In addition, we confirmed that water in potato strongly correlates to PC increase of oil in the fryer. PMID- 30404960 TI - A Specific Thin Layer Chromatography Method for the Identification and Separation of Medium Chain Acylglycerols. AB - Medium chain fatty acids (MCFAs), have gained nutritional relevance in the past few years. They are continuously used in obtaining structured lipids like medium chain acylglycerols (MCAs) for various purposes. However, because of their chemical structure pertaining carbon chain length and the presence of saturated and unsaturated fatty acids, sensitive detection techniques are required for their correct identification and separation. In the present work, a specific thin layer chromatography (TLC) method for MCAs was developed. The proposed method consisted of the use of a mixture of hexane: acetone (70:30 v/v) as mobile phase, since it proved effectiveness for the separation of compounds of interest (MCAs) as well as having the necessary sensitivity to separate different species of monoacylglycerols (MAGs), diacylglycerols (DAGs) and triacylglycerols (TAGs) of MCFAs. For observation of the compounds, a single oxidizing agent was not sufficient, thus a combination of visualization reagents was used (first a 10 % solution of sulphuric acid in methanol followed by a 10 % solution of phosphomolybdic acid in methanol) achieving the correct visualization of the desired compounds. PMID- 30404961 TI - Recovery of gamma-Oryzanol from Rice Bran Acid Oil by an Acid-base Extraction Method with the Assistance of Response Surface Methodology. AB - A rapid and low energy consumption method for the recovery of gamma-oryzanol from rice bran acid oil (RBAO), a byproduct of rice bran oil (RBO) refining, is presented. The RBAO was converted to the fatty acid ethyl ester (FAEE) and was used as the starting material. The dissolved gamma-oryzanol was separated from the FAEE using an acid-base extraction method with alkaline aqueous ethanol and hexane as extraction media. A systematic investigation of the extraction yield was carried out by applying response surface methodology (RSM) based on central composite design (CCD) and Derringer's desirability function. The concentration of NaOH, the percentage of ethanol in water, the hexane content and their interactions showed significant effects on the yield of gamma-oryzanol and FAEE. The optimal extraction conditions were as follows: extraction time of 1 min at room temperature (28-32 degrees C); extraction medium: 1.855 M NaOH; 75.91% ethanol in water and 20.59% hexane in the total volume of the extractant; and FAEE to extractant ratio of 1:10 corresponding to a maximum gamma-oryzanol yield of 75.82+/-3.44% and the desired FAEE yield of 54.42+/-7.80%. The gamma-oryzanol rich fraction was further purified by washing with a 2% Na2CO3 solution, obtaining 69.94% recovery yield with 89.90% purity of gamma-oryzanol. The purified gamma-oryzanol showed good scavenging activity on the 1,1-diphenyl-2 picrylhydrazyl (DPPH) radical and the ABTS radical and was comparable to the commercial product, clearly suggesting that the presented process was efficient and feasible. PMID- 30404962 TI - Calorimetric Study of Micelle Formation of Alkylammonium Chlorides in Water. AB - Calorimetric measurements were conducted on aqueous solutions of n-alkylammonium chlorides (CnAC; H(CH2)nNH3Cl, n = 1 - 12) at 298.15 K. The solute partial molar enthalpy, Hs, was evaluated with reference to the infinitely diluted state. At low concentrations, the Hs increased with the molality, mt, until the critical micelle concentration (CMC) was reached. In the concentration range between the CMC and about three times the CMC, the Hs decreased linearly with increasing log mt. The Hs observed at the CMC was taken as the enthalpy of micelle formation, DeltaHm, which was expressed as DeltaHm / kJ mol-1 = 20.1 - 1.4n for CnAC with n from 7 to 12. The Gibbs energy of micelle formation, DeltaGm, was estimated from the CMC values: DeltaGm / kJ mol-1 = 4.1 - 3.3 n with n from 5 to 12. The entropy of micelle formation, DeltaSm, was calculated as TDeltaSm / kJ mol-1 = 16.4 + 1.9 n with n from 7 to 12. The large positive entropy term was determined to be the driving force for micelle formation. It was inferred that the difference of the CMC of CnAC and sodium n-alkyl sulfate (SCnS;H(CH2)nOSO3Na, n = 5 - 13) homologs seemed to be caused by the difference in the number of possible hydrogen bonds to the head group of the micelle state. Based on an attempt to calculate the Hs for C12AC from the partial molar enthalpy and the concentrations of the constituent individual ions above the CMC, the increase in concentration of the micellar ions seemed to be the largest contribution to the concentration dependence of the Hs. PMID- 30404963 TI - Structures of Yellow Xanthophylls and Metabolism of Astaxanthin in the Prawn Penaeus japonicus. AB - The dried powder of Paracoccus carotinifaciens (PANAFERD-AX(r)) contains (3S,3'S) astaxanthin as a major carotenoid. Administration of PANAFERD-AX(r) for pigmentation of the prawn Penaeus japonicus was examined. Total carotenoid contents in the carapace, muscle, and head of the prawn were dose-dependently increased depending on the amount of PANAFERD-AX(r) administered. Furthermore, not only the amounts of astaxanthins (astaxanthin diester, astaxanthin monoester, and free astaxanthin) but also the amounts of yellow xanthophylls, isoastaxanthin (1), 5,6-dihydropenaeusxanthin (2), penaeusxanthin (3), tetrahydroxypirardixanthin (4), and curstaxanthin (5), were dose-dependently increased with the administration of PANAFERD-AX(r). 5,6-Dihydropenaeusxanthin (2) and penaeusxanthin (3) are new carotenoids isolated from the prawn P. japonicus. These structures were determined to be (3R,4S,5R,6R,6'S)-5,6-dihydro 3,4,4'- trihydroxy-beta,epsilon-caroten-3'-one (2) and (3R,4S,6'S)-3,4,4' trihydroxy-beta,epsilon-caroten-3'-one (3) by UV/vis, ESI TOF MS, 1H NMR, and CD spectral data. The metabolism of astaxanthin to these yellow xanthophylls in the prawn was discussed. PMID- 30404964 TI - Preparation of High Purity Delta5-Olefinic Acids from Pine Nut Oil via Repeated Lipase-Catalyzed Esterification. AB - Delta5-Olefinic acids have been characterized in gymnosperm plants and have been reported to have several biological health benefits. Delta5-Olefinic acids from pine nut oil were effectively concentrated by repeated lipase-catalyzed esterification. The pine nut oil contained three major Delta5-olefinic acids, namely taxoleic acid (C18:2 Delta5,9), pinolenic acid (C18:3 Delta5,9,12), and sciadonic acid (C20:3 Delta5,11,14). The fatty acids present in pine nut oil were selectively esterified with ethanol using Lipozyme RM IM from Rhizomucor miehei as a biocatalyst. The Delta5-olefinic acids were concentrated in the unesterified fatty acid fraction. The optimum molar ratio of the substrates (fatty acid:ethanol), temperature, the enzyme loading, and the reaction time were 1:7, 25 degrees C, 5% of total substrate weight, and 6 h, respectively. There was no significant effect in the concentration of Delta5-olefinic acids when water was added in the reaction mixture. The same protocol and optimum conditions were employed for two times repeated lipase-catalyzed esterifications. In first lipase catalyzed esterification, the Delta5-olefinic acids content in the pine nut oil increased from 17 mol% to 51 mol% with a yield of 40 mol%. In a second lipase catalyzed esterification, with the Delta5-olefinic acids-concentrated fatty acids obtained from the first reaction as the substrate, the Delta5-olefinic acids content increased to 86 mol% with a yield of 15 mol%. Finally, a maximum Delta5 olefinic acids content of ca. 96 mol% with a yield of 6 mol% was obtained via a third lipase-catalyzed esterification. PMID- 30404965 TI - Protective Effect of Hyperforin on beta Amyloid Protein Induced Apoptosis in PC12 Cells and Colchicine Induced Alzheimer's Disease: An Anti-oxidant and Anti inflammatory Therapy. AB - The current investigation aimed to scrutinize the neuro-protective effect of hyperforin on beta-amyloid peptide (Abeta)1-42 and H2O2 induced injury in PC12 cells and colchicine induced Alzheimer's disease (AD). PC12 cells were treated with H2O2 and (Abeta)1-42 in the presence of hyperforin. The cell viability was determined via suing the MTT assay; malondialdehyde (MDA) and lactate dehydrogenase (LDH) levels were also scrutinized. Colchicine induced the destruction of memory and learning which was exhibited in neurobehavioral theory (passive avoidance and Morris water maze) connected with reduced activity of acetylcholinesterase (AChE). Anti-oxidant and inflammatory parameters also estimated. Hyperforin dose dependently increased the cell viability and reduced the MDA and LDH release via PC12 cell injured with H2O2 and (Abeta)1-42. Hyperforin treatment lead to a considerable enhance in TLT in the retention trials as comparisian to acquisition trial suggesting as boosting memory and learning in rats. Hyperforin treatments significantly increase the AChE and reduced the superoxide dismutase, glutathione, MDA, protein carbonyl, glutathione peroxdiase, catalase, NF-kB and IL-1beta at dose dependent manner. In summary, the model of H2O2 and (Abeta)1-42 induced PC12 cell injury was successfully developed and dose dependently treatment of hypoforin showed the neuroprotective effect against the H2O2 and (Abeta)1-42 induced cell damage. These finding clearly exhibited that hyperforin reverted the colchicine induced neuro-chemical and behavioural alteration via potent anti-inflammatory and anti-oxidant activity. PMID- 30404966 TI - Medium-chain Triglycerides with Maltodextrin Increase Fat Oxidation during Moderate-intensity Exercise and Extend the Duration of Subsequent High-intensity Exercise. AB - Medium-chain triglycerides (MCT) are useful for increasing fat utilization during exercise. The highest rate of fat oxidation during submaximal exercise tends to precede the lactate threshold in untrained adults. In our previous study, blood lactate concentration was more than 4 mmol/L (onset of blood lactate) in recreational athletes during exercise at a workload corresponding to 60% peak O2 uptake (V?o2), which was below ventilation threshold. In the present study, we investigated the effect of 2 week of ingestion of food containing 6 g MCT on substrate oxidation during moderate-intensity (50% peak V?o2) exercise and high intensity (70% peak V?o2) exercise in recreational athletes. For comparison, two experimental trials were conducted after participants had been administered isoenergic test foods (MCT-supplemented food with mainly maltodextrin-containing carbohydrate (MCT + CHO) or CHO) for 2 weeks, with a washout period between trials. Participants were instructed to perform cycle ergometer exercise at a workload corresponding to 50% peak V?o2 for 40 min followed by a workload corresponding to 70% peak V?o2 until exhaustion. Fat oxidation was significantly increased in the MCT + CHO trial (13.3 +/- 2.7 g/40 min, mean +/- SD, p < 0.05) during moderate-intensity exercise and the duration was extended significantly (23.5 +/- 19.4 min, p < 0.05) during subsequent high-intensity exercise, compared with that observed in the CHO trial (fat oxidation; 11.7 +/- 2.8 g/40 min, duration; 17.6 +/- 16.1 min). In conclusion, continuous ingestion of 6 g MCT with maltodextrin could increase fat oxidation during moderate-intensity exercise and extend the duration of subsequent high-intensity exercise in recreational athletes, compared with the ingestion of isoenergic maltodextrin alone. PMID- 30404967 TI - Two Types of Volatile Polyenes in the Brown Alga Sargassum thunbergii. AB - An essential oil from the brown alga Sargassum thunbergii, prepared by a simultaneous distillation extraction method, contained in two types of volatile polyenes with a terminal double bond such as (6Z,9Z,12Z,15Z,18Z)-1,6,9,12,15,18 henicosahexaene and (6Z,9Z,12Z,15Z)-1,6,9,12,15-henicosapentaene and with their saturated terminal structures such as (3Z,6Z,9Z,12Z,15Z,18Z)-3,6,9,12,15,18 henicosahexaene and (3Z,6Z,9Z,12Z,15Z)-3,6,9,12,15-henicosapentaene. These volatile polyenes were identified by comparison with the GC-MS and NMR spectra of synthetics. The polyenes with the saturated terminal structures were found in the brown algae for the first time. PMID- 30404968 TI - A Scandium Arylsulfonate-based Coordination Polymer as a Heterogeneous Catalyst for the Friedel-Crafts Reaction of Indoles with Aldehydes. AB - The scandium sulfonate-based coordination polymer Sc2(BPDS)3, which is easily prepared by mixing scandium triisopropoxides and biphenyl-4,4'-disulfonic acid (BPDSA), is an air-stable and storable solid that effectively catalyzes the Friedel-Crafts reaction of indoles with aromatic aldehydes under heterogeneous conditions to afford various aryl(diindolyl)methanes. The catalyst can be reused without significant loss of activity after separation from the reaction mixture by simple centrifugation followed by drying. PMID- 30404969 TI - Tunisian Clematis flammula Essential Oil Enhances Wound Healing: GC-MS Analysis, Biochemical and Histological Assessment. AB - The aerial part of Clematis flammula (Ranunculaceae) has been traditionally used in the treatment of skin diseases including mycotic infection in the Tunisian traditional medicine. The study was undertaken to extract and determine the essential oil chemical composition of Clematis flammula aerial parts and to assess the potential of anemonin in wound healing on mechanically wounded wistar rats. The essential oil was obtained by hydrodistillation and analyzed by GC-MS. Anemonin was isolated and then incorporated as active in a cream for which the cytotoxicity was evaluated by methyl thiazolyl tetrazolium (MTT)-based colorimetric assay. Then, its potential in wound healing on mechanically wounded wistar rats was assessed. The GC-MS analysis showed that the major compound was protoanemonin (86.74%) which spontaneously dimerised in part to form the anemonin. The wound healing activity of anemonin cream exhibited a non toxic potential of anemonin at a concentration of 25 ug/mL with a cell migration efficiency that reaches more than 80% after 48 hours of treatment. Wound healing efficiency was evaluated by monitoring morphological and skin histological analyses. Comparable wound surface reduction of the group treated by anemonin cream (p >= 0.05) when compared to the reference treated group. The skin histological analysis showed the completely wound closure. Antioxidant activity was assessed by the malondialdehyde (MDA) rates and antioxidant enzymes (glutathione peroxidase (GPx) and catalase) determination. The results provided strong support for the effective wound healing activity of anemonin cream, making it a promising candidate as a therapeutic agent in tissue repairing processes. PMID- 30404970 TI - Phylogenetic Diversity of Nitrogenase Reductase Genes and Possible Nitrogen Fixing Bacteria in Thermophilic Chemosynthetic Microbial Communities in Nakabusa Hot Springs. AB - Chemosynthetic microbial communities develop and form dense cell aggregates in slightly alkaline sulfidic hot springs in the temperature range of 70-86 degrees C at Nakabusa, Japan. Nitrogenase activity has recently been detected in the microbial communities collected. To identify possible members capable of nitrogen fixation, we examined the diversities of 16S rRNA and nitrogenase reductase (NifH) gene sequences in four types of chemosynthetic communities with visually different colors and thicknesses. The results of a 16S rRNA gene analysis indicated that all four microbial communities had similar bacterial constituents; the phylum Aquificae was the dominant member, followed in abundance by Thermodesulfobacteria, Firmicutes, and Thermotogae. Most of the NifH sequences were related to sequences reported in hydrothermal vents and terrestrial hot springs. The results of a phylogenetic analysis of NifH sequences revealed diversity in this gene among the communities collected, distributed within 7 phylogenetic groups. NifH sequences affiliated with Aquificae (Hydrogenobacter/Thermocrinis) and Firmicutes (Caldicellulosiruptor) were abundant. At least two different energy metabolic pathways appeared to be related to nitrogen fixation in the communities analyzed; aerobic sulfur/hydrogen oxidizing bacteria in Aquificae and fermentative bacteria in Firmicutes. The metabolic characteristics of these two dominant phyla differed from those previously inferred from nitrogenase activity assays on chemosynthetic communities, which were associated with hydrogen-dependent autotrophic sulfate reduction. These assays may correspond to the observed NifH sequences that are distantly related to the known species of Thermodesulfovibrio sp. (Nitrospirae) detected in the present study. The activities of nitrogen-fixing organisms in communities may depend on redox states as well as the availability of electron donors, acceptors, and carbon sources. PMID- 30404971 TI - Intracellular Polyphosphate Levels in Gluconacetobacter diazotrophicus Affect Tolerance to Abiotic Stressors and Biofilm Formation. AB - Gluconacetobacter diazotrophicus is a plant growth-promoting bacterium that is used as a bioinoculant. Phosphate (Pi) modulates intracellular polyphosphate (polyP) levels in Escherichia coli, affecting cellular fitness and biofilm formation capacity. It currently remains unclear whether environmental Pi modulates polyP levels in G. diazotrophicus to enhance fitness in view of its technological applications. In high Pi media, cells accumulated polyP and degraded it, thereby improving survival, tolerance to environmental stressors, biofilm formation capacity on abiotic and biotic surfaces, and competence as a growth promoter of strawberry plants. The present results support the importance of Pi and intracellular polyP as signals involved in the survival of G. diazotrophicus. PMID- 30404972 TI - "Duckweed-Microbe Co-Cultivation Method" for Isolating a Wide Variety of Microbes Including Taxonomically Novel Microbes. AB - We herein described a new microbial isolation method using the interaction between the floating aquatic plant, duckweed, and microbes. We harvested microbial cells from Japanese loosestrife roots and co-cultivated these cells with aseptic duckweed using artificial inorganic medium for the plant for four weeks. During the co-cultivation, some duckweeds were collected every week, and the roots were used for microbial isolation using a low-nutrient plate medium. As a result, diverse microbial isolates, the compositions of which differed from those of the original source (Japanese loosestrife root), were obtained when the roots of duckweed were collected after 2 weeks of cultivation. We also successfully isolated a wide variety of novel microbes, including two strains within the rarely cultivated phylum, Armatimonadetes. The present study shows that a duckweed-microbe co-cultivation approach together with a conventional technique (direct isolation from a microbial source) effectively obtains more diverse microbes from a sole environmental sample. PMID- 30404973 TI - Impact of Physical Activity on Coronary Plaque Volume and Components in Acute Coronary Syndrome Patients After Early Phase II Cardiac Rehabilitation. AB - BACKGROUND: Cardiac rehabilitation (CR) is an established multidisciplinary secondary preventive program. We investigated the effects of CR involving intensive physical activity (PA) on coronary plaque volume and components in patients with acute coronary syndrome (ACS).Methods and Results:We enrolled 32 consecutive patients with ACS in early phase II CR and randomly assigned them to an intensive CR group (n=18; CR participation >=twice/week, daily PA >=9,000 steps) or a standard CR group (n=14; CR participation >=once/2weeks, daily PA >=6,000 steps). Serial integrated backscatter intravascular ultrasound was performed for non-culprit lesions at baseline and after 8 months. Baseline clinical data were identical between the 2 groups. Unexpectedly, CR participation and PA did not differ significantly between the 2 groups, and there was no significant difference in plaque volume (PV) or components between the 2 groups. Subsequently, we classified the patients into 2 groups according to median PA (7,000 steps). There were significant differences in percent change of PV and of lipid volume between these 2 groups. In addition, these changes were negatively and independently correlated with PA. CONCLUSIONS: No significant difference was observed in PV or components between the intensive CR and the standard CR groups. Intensive PA, however, may retard coronary PV and ameliorate lipid component in patients with ACS participating in late phase II CR. PMID- 30404974 TI - Glycosphingolipid GM2 Induces Invasiveness in Irradiation-tolerant Lung Cancer Cells. AB - Glycans, including glycosphingolipids, are broadly expressed in plasma membranes and play important roles in cell-cell interactions. Recently, it has been revealed that glycans participate in the regulation of malignant phenotypes of cancer cells, e.g. growth and invasion. However, their roles in irradiation tolerant cancer cells have not yet been elucidated. In this study, we show that specific glycosphingolipids are highly expressed in invasive, irradiation tolerant lung cancer cells. Particularly, the glycosphingolipid GM2 contributes to the development of an invasive phenotype in these lung cancer cells. Our results suggest that glycosphingolipids, including GM2, are implicated in the regulation of invasiveness in irradiation-tolerant lung cancer cells and may therefore serve as potential therapeutic targets for lung cancers following radiotherapy.Key words: glycosphingolipids, GM2, invasion, lung cancer cells, radiotherapy. PMID- 30404975 TI - The effect of colostrum intake on osteoprotegerin and bone metabolic markers in the blood of newborn calves during the first week of life. AB - The aim of this study was to elucidate the bone metabolic status after taking colostrum in newborn calves. Fourteen neonatal calves were randomly allocated to two groups fed either unheated or heated (60 degrees C, 30 min) colostrum three times on the first day (2 l every 10 hr; 6 l in total). Heat treatment on colostrum was to reduce the bone metabolic markers assumed as heat-sensitive. The concentrations of four bone metabolic markers (the enzymes from bone cells or the bone collagen fragments) and a bone protective protein, osteoprotegerin (OPG), were measured in the blood of calves during a week after the birth and in the colostrum. The colostral concentrations of four bone metabolic markers were reduced by heating. Then those circulatory markers peaked after colostrum intake in the calves fed unheated colostrum; whereas those fed heated colostrum did not show such changes. However, the plasma tartrate resistant acid phosphatase 5b (TRAP5b) activity was transiently increased after taking colostrum in both groups. Meanwhile, heating did not decrease colostral OPG and there was no significant rise in the serum OPG concentrations after the first colostrum intake in both groups. The study revealed that the blood concentrations of studied bone metabolic markers depended on those colostral values except for TRAP5b. Based on the plasma TRAP5b changes, accelerated formation of premature osteoclast cells may be induced by colostrum intake. Meanwhile, colostral OPG absorption is less likely to impact on its circulating levels. PMID- 30404976 TI - Comparison of Characteristics and 3-Year Outcomes in Patients With Acute Heart Failure With Preserved, Mid-Range, and Reduced Ejection Fraction. AB - BACKGROUND: The clinical characteristics and outcomes of acute heart failure (AHF) according to left ventricular ejection fraction (LVEF) have not been fully elucidated, especially for patients with mid-range LVEF. We performed a comprehensive comparison of the epidemiology, patterns of in-hospital management, and clinical outcomes in AHF patients with different LVEF categories.Methods and Results:The Korean Acute Heart Failure (KorAHF) registry is a prospective multicenter cohort of hospitalized AHF patients in Korea. A total of 5,374 patients enrolled in the KorAHF registry were classified according to LVEF based on the 2016 ESC guidelines. More than half of the HF patients (58%) had reduced EF (HFrEF), 16% had mid-range EF (HFmrEF), and 25% had preserved EF (HFpEF). The HFmrEF patients showed intermediate epidemiological profiles between HFrEF and HFpEF and had a propensity to present as de-novo HF with ischemic etiology. Patients with lower LVEF had worse short-term outcomes, and the all-cause in hospital mortality, including urgent heart transplantation, of HFrEF, HFmrEF, and HFpEF was 7.1%, 3.6%, and 3.0%, respectively. Overall, discharged AHF patients showed poor 3-year all-cause death up to 38%, which was comparable between LVEF subgroups (P=0.623). CONCLUSIONS: Each LVEF subgroup of AHF patients was a heterogeneous population with diverse characteristics, which have a significant effect on the clinical outcomes. This finding suggested that focused phenotyping of AHF patients could help identify the optimal management strategy and develop novel effective therapies. PMID- 30404977 TI - Successful Bipolar Radiofrequency Catheter Ablation of Premature Ventricular Contractions Originating From the Left Ventricular Posterior Papillary Muscle. PMID- 30404978 TI - Cardiac Allograft Vasculopathy - Heart Transplantation Provides Insights Into Pathogenesis and Treatment of Arteriosclerosis. PMID- 30404979 TI - Mesenteroaxial Gastric Volvulus Diagnosed with MR Imaging during the Early Stages of Pregnancy. PMID- 30404980 TI - Effective Combination of Different Surgical Strategies for Deep Sternal Wound Infection and Mediastinitis. AB - PURPOSE: Timing and ideal reconstructive approach in deep sternal wound infection (DSWI) and mediastinitis still remain controversially debated. We present our own combined surgical strategy of bilateral pectoralis major muscle flap (BPMMF) or omental flap (OF) transposition. METHODS: Between July 2010 and July 2016, poststernotomy patients with DSWI and mediastinitis underwent a secondary wound closure with modified BPMMF (Group A, center for disease control class (CDC)-II, n = 21; Group B, CDC-III, n = 20) or with OF (Group C, CDC-III, n = 19) following vacuum-assisted closure (VAC). RESULTS: Significant risk factors for mediastinitis (CDC-III) were chronic obstructive pulmonary disease (COPD; p = 0.001), peripheral arterial disease (PAD; p = 0.012), cardiopulmonary bypass (CPB) time (p = 0.027), total operation time (p = 0.039), total intensive care unit (ICU) stay (p = 0.011), and blood transfusion (p = 0.049). Mean antibiotic therapy (18.4 +/- 8.8[B] vs. 36.2 +/- 24.4[C] days, p = 0.026) and length of hospitalization (25.2 +/- 12.1[B] vs 53.8 +/- 18.5 days[C], p = 0.053) were significantly longer in group C. In-hospital death was 3/19 (15.8%) in group C versus 0 in group B (p = 0.026). Frequency of recurrent mediastinitis was equal (p = 0.92); however, complications occurred more often in group C (31.6% vs. 0%, p = 0.031). The mean follow-up time was 111 +/- 62 days. CONCLUSION: In younger (<70 years) patients without sternal bone necrosis, the BPMMF is superior to the OF technique with relatively low recurrence and mortality risks. PMID- 30404981 TI - Repurposing of approved cardiovascular drugs against ischemic cerebrovascular disease by disease-disease associated network-assisted prediction. AB - Stroke is one of the leading causes of death and disability globally, while intravenous thrombolysis with recombinant tissue plasminogen activator remains the only FDA-approved therapy for ischemic stroke. The attempts to develop new treatments for acute ischemic stroke meet costly and spectacularly disappointing results, which requires both long time and high costs, whereas repurposing of safe existing drugs to new indications provides a cost-effective and not time consuming alternative. Vascular protection is a promising strategy for improving stroke outcome, as vascular function is critical to both cardiovascular diseases (CVD) and ischemic cerebrovascular disease (ICD). Vascular function related biological processes and pathways maybe the critical associations between CVD and ICD. In this study, a multi-database, in silico target identification, gene function enrichment, and network pharmacology analysis integration approach was proposed and applied to investigate the FDA-approved CVD drugs repurposing for ICD. A list of 119 candidate drugs can be obtained for further investigation of their potential in ICD treatment. As a pleiotropic drug with multi-target, carvedilol was set an example to investigate its promising potential for ICD therapy. Our results indicated that the mode of action of carvedilol for ICD treatment may tightly associated with vascular function regulation and the mechanism is multi-target and multi-signaling pathway related. The disease disease association network-assisted prediction needs further investigations. In summary, the proposed methods herein may provide a promising alternative to inferring novel disease indications for known drugs. PMID- 30404982 TI - Premature ovarian insufficiency may be associated with the mutations in mitochondrial tRNA genes. AB - Premature ovarian insufficiency (POI) is a common endocrine disorder featured by the triad constituting of amenorrhea for at least four months, to date, the molecular pathogenesis of POI is largely undetermined. Despite several investigations have reported an increase in reactive oxygen species (ROS) content in idiopathic POI, the role of mitochondrial DNA (mtDNA) mutations/variants in the progression of POI has not been widely investigated. The current study aimed to explore the association between mt-tRNA mutations/variants and POI; we first used the PCR-Sanger sequencing to detect the mutations/variants in mt-tRNA genes from 50 POI patients and 30 healthy subjects. In addition, we evaluated the mitochondrial functions by using trans-mitochondrial cybrid cells containing these potential pathogenic mt-tRNA mutations. Consequently, five mutations: tRNALeu(UUR) C3303T, tRNAMet A4435G, tRNAGln T4363C, tRNACys G5821A and tRNAThr A15951G were identified. Notably, these mutations occurred at the extremely conserved nucleotides of the corresponding mt-tRNAs and may result the failure in mt-tRNA metabolism and subsequently lead to the impairment in mitochondrial protein synthesis. Furthermore, biochemical and molecular analyses of the cybrid cells containing these mutations showed a significantly lower level of ATP production when compared with the controls, whereas the ROS levels were much higher in POI patients carrying these mt-tRNA mutations, strongly indicated that these mt-tRNA mutations may cause the mitochondrial dysfunction, and play active roles in the progression and pathogensis of POI. Together, this study shaded additional light on the molecular mechanism of POI that was manifestated by mt tRNA mutations. PMID- 30404983 TI - ? PMID- 30404984 TI - ? PMID- 30404985 TI - ? PMID- 30404986 TI - ? PMID- 30404987 TI - ? PMID- 30404988 TI - ? PMID- 30404989 TI - ? PMID- 30404990 TI - ? PMID- 30404991 TI - ? PMID- 30404992 TI - ? PMID- 30404993 TI - ? PMID- 30404994 TI - Basal cell adenocarcinoma on bulbar conjunctiva of third eyelid in a dog. AB - An 8-year-old castrated Toy poodle presented with swelling and proptosis of the right third eyelid caused by an exophytic mass on the bulbar surface. Histologically, the mass was composed of stratified neoplastic basaloid cells, arranged in nests and interconnecting islands, which were mixed with tubular structures. Immunohistochemically, the basaloid cells were positive for p63 and cytokeratin (CK) 14, and the inner epithelial cells of the tubular structures were positive for CK7, CK8, and CK19. According to these findings, the mass was diagnosed as a basal cell adenocarcinoma. Although basal cell adenocarcinoma is rare in animals, it should be included in the list of differential diagnoses for superficial tumors of bulbar conjunctiva of third eyelid in dogs. PMID- 30404995 TI - The factors influencing the eating behaviour of shiftworkers: what, when, where and why. AB - Shiftwork leads to altered eating patterns, with workers often eating foods at all times across the 24h period. Strategies to reduce the burden of shiftwork on the workers should be prioritised and altering these eating patterns is an important area for change. This narrative review examines the current evidence on the individual and environmental factors influencing the eating behaviours of shiftworkers. A systematic search was conducted and yielded 62 articles. These were split into four themes that influence eating patterns; When shiftworkers eat, What type of foods shiftworkers eat, Where the food is sourced from, and Why shiftworkers choose to eat on shift. Irregular working hours was the biggest influence on when workers ate on shift, shift-type was the biggest influence on what workers ate, the majority of food was sourced from canteens and cafeterias, and socialising with colleagues was the biggest reason why workers chose to eat. While more research is needed to explore multiple industries and shift-types, and to investigate the ideal size, type and timing of food on shift, this review has highlighted that future research into shiftworker eating needs to adopt an integrative approach and consider the different individual and social contexts that influence eating patterns. PMID- 30404996 TI - Low-level lead exposure and cardiovascular disease: the roles of telomere shortening and lipid disturbance. AB - Lead exposure contributing to cardiovascular diseases is known and recognized widely. As the deleterious effects of low lead exposure attained increasing attention over the last decades, there have been numerous studies exploring the association of low levels of lead exposure and cardiovascular diseases. Moreover, it has been observed that lead exposure could cause telomere shortening and lipid disturbance, and that telomere shortening and lipid disturbance are closely related with cardiovascular diseases. Hence, telomere shortening and lipid disturbance might play an important role in the pathophysiological process of chronic low levels of lead exposure contributing to cardiovascular diseases. This review is intended to explore views of the rarely mentioned mechanism, telomere shortening and lipid disturbance, and the cardiovascular effects of low levels of lead exposure. PMID- 30404997 TI - Social behavior, neuroimmune markers and glutamic acid decarboxylase levels in a rat model of valproic acid-induced autism. AB - Autism is a complex neurodevelopmental disorder characterized by impaired social communication and social interactions, and repetitive behaviors. The etiology of autism remains unknown and its molecular basis is not yet well understood. Pregnant Sprague-Dawley (SD) rats were administered 600 mg/kg of valproic acid (VPA) by intraperitoneal injection on day 12.5 of gestation. Both 11- to 13-week old male and female rat models of VPA-induced autism showed impaired sociability and impaired preference for social novelty as compared to the corresponding control SD rats. Significantly reduced mRNA expressions of social behavior related genes, such as those encoding the serotonin receptor, brain-derived neurotrophic factor and neuroligin3, and significantly increased expression levels of proinflammatory cytokines, such as interleukin-1 beta and tumor necrosis factor-alpha, were noted in the hippocampi of both male and female rats exposed to VPA in utero. The hippocampal expression level of gamma amino butyric acid (GABA) enzyme glutamic acid decarboxylase (GAD) 67 protein was reduced in both male and female VPA-exposed rats as compared to the corresponding control animals. Our results indicate that developmental exposure to VPA affects the social behavior in rats by modulating the expression levels of social behavior related genes and inflammatory mediators accompanied with changes in GABA enzyme in the hippocampus. PMID- 30404998 TI - Effect of decabrominated diphenyl ether exposure on spatial learning and memory, the expression and phosphorylation of hippocampal glutamate receptor subunits in adult Sprague-Dawley rats. AB - Previous studies have reported the potential developmental neurobehavioral effects of decabrominated diphenyl ethers (BDE 209) on developing animals, but the effects on adult animals are rare or controversial and the mechanism is not fully understood. In the present study, male adult Sprague-Dawley rats performed poor spatial learning and memory in Morris water maze after exposure to BDE 209 by gavage for 30 days. The expression of hippocampal glutamate receptor subunits NR1, NR2B and GluR1, the phosphorylation of NR2B subunit at Ser1301 (p-NR2B Ser1303) and GluR1 subunit at Ser831 (p-GluR1 Ser831) were all decreased, and the phosphorylation ratio of NR2B revealed an increasing trend after BDE 209 exposure. The present study provided evidence that BDE 209 could induce spatial learning and memory deficits in adult rats, and further explored the potential mechanism. PMID- 30404999 TI - Melatonin antagonizes oxidative stress-induced mitochondrial dysfunction in retinal pigmented epithelium cells via melatonin receptor 1 (MT1). AB - High energy-consumption in retinal pigmented epithelium (RPE) cells poses oxidative stress (OS) and contributes to mitochondrial dysfunction (MD) for retinal degeneration-associated diseases. In the present study, we evaluated the protective role of Melatonin, a natural antioxidant, against the hydrogen peroxide (H2O2)-induced damage to RPE cells. The cellular viability, apoptosis, the expression of apoptosis-associated proteins and mitochondrial function were examined in the retinal ARPE-19 cells, post the treatment with H2O2 or (and) with Melatonin. The regulation by Melatonin receptor 1 (MT1) on the Melatonin-mediated protection was also examined via MT1 knockdown with siRNA. Results demonstrated that Melatonin significantly ameliorated cell viability reduction, reduced apoptosis and downregulated the apoptosis-associated proteins in H2O2-treated ARPE-19 cells. The H2O2-induced mitochondrial dysfunction was also significantly blocked by the Melatonin treatment, presenting as a reduced accumulation of reactive oxygen species (ROS) and mitochondrial superoxide and an ameliorated reduction of mitochondrial membrane potential (MMP). In addition, the knockdown of MT1 with MT1-specific siRNA inhibited the Melatonin-mediated protection against OS damage in ARPE-19 cells. In summary, we confirmed the protective role of Melatonin against H2O2-induced mitochondrial dysfunction in RPE cells. MT1 knockdown blocked such protective role of Melatonin. It is implied that Melatonin exerts a protective role against oxidative stress via Melatonin-MT1 signaling in RPE cells. PMID- 30405000 TI - Thalidomide protects against acute pentylenetetrazol and pilocarpine-induced seizures in mice. AB - Thalidomide was originally developed to treat primary neurological and psychiatric diseases. There are reports of anticonvulsant effects of thalidomide in rats and antiepileptic effects in patients. Hence, thalidomide (100, 200 and 400 mg/kg) was herein administered to mice to evaluate possible protection against seizures induced by the systemic administration of neurotoxins: 10 mg/kg of 4-aminopyridine (4-AP), 90 mg/kg of pentylenetetrazol (PTZ), or 380 mg/kg of pilocarpine. The effect of an NO and COX inhibitor (7-NI and ibuprofen, respectively) was also examined. The results show that thalidomide (1) induces the typical sedative effects, (2) has no anticonvulsant effect in mice treated with 4-AP, and (3) has anticonvulsant effect (400 mg/kg) in mice treated with PTZ and pilocarpine. It was found that 7-NI has an anticonvulsant effect in the pilocarpine model and that thalidomide's effect is not enhanced by its presence. However, thalidomide (200 mg/kg) plus 7-NI or ibuprofen tend to have a toxic effect in PTZ model. On the other hand, the combination of thalidomide and 7-NI or ibuprofen protects against pilocarpine-induced seizures. In conclusion, thalidomide did not exert an anticonvulsant effect for clonic-tonic type convulsions (4-AP), but it did so for seizures induced by PTZ and pilocarpine (representing absence seizures and status epilepticus, respectively). NO and prostaglandins were involved in the convulsive process elicited by pilocarpine. PMID- 30405001 TI - Approaches of validation of a 2-week combined repeated oral dose toxicity study with plasma micro sampling toxicokinetics (PMS-TK) in common marmosets. AB - We investigated the viability of a combined repeated dose toxicity study, including toxicokinetics (TK), in common marmosets according to the ICH-S4, ICH S3A and ICH-S7A Guidelines using valsartan as test article whose non-clinical repeated dose toxicity studies had been conducted using this species for regulatory purpose. Valsartan was administered orally to 3 animals/sex at 200 mg/kg/day for 2 weeks. In addition to the routine parameters in repeated dose toxicity studies, safety pharmacology parameters (examinations of the central nervous, respiratory and cardiovascular systems) were also evaluated. The Plasma Micro Sampling Toxicokinetics (PMS-TK) method required ultrasensitive quantitation, was employed to evaluate the relationship between toxic changes and plasma concentrations as well as the effects of frequent blood sampling in individual animals. In valsartan, toxic findings (a deteriorated physical condition; moribundity of one male and one female on Day 14; sporadic vomitus; decreases in body weights and food consumption; decreases in erythrocytic parameters; and renal changes such as an increase in urea nitrogen, dilation of the tubules and hypertrophy of the tubular epithelium) were similar and plasma concentrations comparable to the results in the approval information. Furthermore, no side effects caused by frequent blood sampling were confirmed in the negative control group. Consequently, a combined repeated dose toxicity study including TK analysis using the PMS-TK method is viable in common marmosets and contributes to animal welfare. PMID- 30405002 TI - Association between Pepsin in Bronchoalveolar Lavage Fluid and Prognosis of Chronic Fibrosing Interstitial Lung Disease. AB - Chronic fibrosing interstitial lung disease (ILD)s are characterized by chronic progressive fibrosis of lung which include idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia (NSIP), and connective tissue disease associated interstitial lung disease (CTD-ILD). IPF is an irreversible fibrotic lung disease which results in respiratory failure. Although NSIP and CTD-ILD can be improved or stable by treatment with corticosteroid or immunosuppressant, some of them progress to fibrotic lung diseases. Aspiration of gastric contents is suggested as an aggravating factor of ILDs. We measured pepsin, a marker of gastric aspiration, in bronchoalveolar lavage (BAL) fluid of chronic fibrosing ILD patients to evaluate the association between BAL fluid pepsin and prognosis of chronic fibrosing ILDs. Patients with chronic fibrosing ILDs, who underwent bronchoscopy between December 2010 and April 2015 were prospectively enrolled. Pepsin levels were measured using a commercial ELISA kit. Clinical characteristics, lung function data, and mortality were analyzed. Fifty-one patients with chronic fibrosing ILDs were enrolled (26 with IPF, 15 with NSIP, and 10 with CTD-ILD). Pepsin levels in BAL fluid were 69.87 +/- 74.16 ng/mL in IPF, 110.68 +/- 94.93 ng/mL in NSIP, and 101.87 +/- 88.44 ng/mL in CTD-ILDs. There were no statistically significant differences in BAL fluid pepsin levels among patients with the different chronic fibrosing ILDs. In multivariate regression analysis, higher BAL pepsin levels were associated with higher mortality (adjusted odds ratio [aOR] = 1.021, p = 0.025). BAL fluid pepsin may be used as a prognostic marker for predicting mortality in chronic fibrosing ILD patients. PMID- 30405003 TI - Maternal Separation as Early-Life Stress Causes Enhanced Allergic Airway Responses by Inhibiting Respiratory Tolerance in Mice. AB - Epidemiologic studies indicate that exposure to psychosocial stress in early childhood is a risk factor of adult-onset asthma, but the mechanisms of this relationship are poorly understood. Therefore, we examined whether early-life stress increases susceptibility to adult-onset asthma by inhibiting the development of respiratory tolerance. Neonatal BALB/c female mice were aerosolized with ovalbumin (OVA) to induce immune tolerance prior to immune sensitization with an intraperitoneal injection of OVA and the adjuvant aluminum hydroxide. Maternal separation (MS) was applied as an early-life stressor during the induction phase of immune tolerance. The mice were challenged with OVA aerosol in adulthood, and allergic airway responses were evaluated, including airway hyper-responsiveness to inhaled methacholine, inflammatory cell infiltration, bronchoalveolar lavage fluid levels of interleukin (IL)-4, IL-5, and IL-13, and serum OVA-specific IgE. We then evaluated the effects of MS on the development of regulatory T (Treg) cells in bronchial lymph nodes (BLN) and on splenocyte proliferation and cytokine expression. In mice that underwent MS and OVA tolerization, the allergic airway responses and OVA-induced proliferation and IL-4 expression of splenocytes were significantly enhanced. Furthermore, exposure to MS was associated with a lower number of Treg cells in the BLN. These findings suggest that exposure to early-life stress prevents the acquisition of respiratory tolerance to inhaled antigen due to insufficient Treg cell development, resulting in Th2-biased sensitization and asthma onset. We provide the evidence for inhibitory effects of early-life stress on immune tolerance. The present findings may help to clarify the pathogenesis of adult-onset asthma. PMID- 30405004 TI - Antimicrobial Stewardship Programmes in Community Healthcare Organisations in England: A Cross-Sectional Survey to Assess Implementation of Programmes and National Toolkits. AB - OBJECTIVE: The aim of this study was to assess antimicrobial stewardship activities in Community Healthcare Organisations (CHOs) with focus on the implementation of the two national antimicrobial stewardship toolkits, TARGET (Treat Antibiotics Responsibly, Guidance, Education, Tools) and SSTF (Start Smart, then Focus). The study utilised a web-based survey comprising 34 questions concerning antimicrobial policies and awareness and implementation of antimicrobial stewardship toolkits. This was distributed to pharmacy teams in all 26 CHOs in England. Twenty CHOs (77%) responded. An antimicrobial stewardship (AMS) committee was active in 50% of CHOs; 25% employed a substantive pharmacist post and 70% had a local antibiotic policy. Fourteen of the responding CHOs were aware of both AMS toolkits, five organisations were aware of either SSTF or TARGET, and one organisation was not aware of either toolkit. Of the organisations aware of SSTF and TARGET, eight had formally reviewed both toolkits, though three had not reviewed either. Less than half of the respondents had developed local action plans for either toolkit. National guidance in England has focused attention on initiatives to improve AMS implementation in primary and secondary care; more work is required to embed AMS activities and the implementation of national AMS toolkit recommendations within CHOs. PMID- 30405005 TI - SseL Deubiquitinates RPS3 to Inhibit Its Nuclear Translocation. AB - Many Gram-negative bacterial pathogens use type III secretion systems to deliver virulence proteins (effectors) into host cells to counteract innate immunity. The ribosomal protein S3 (RPS3) guides NF-kappaB subunits to specific kappaB sites and plays an important role in the innate response to bacterial infection. Two E. coli effectors inhibit RPS3 nuclear translocation. NleH1 inhibits RPS3 phosphorylation by IKK-beta, an essential aspect of the RPS3 nuclear translocation process. NleC proteolysis of p65 generates an N-terminal p65 fragment that competes for full-length p65 binding to RPS3, thus also inhibiting RPS3 nuclear translocation. Thus, E. coli has multiple mechanisms by which to block RPS3-mediated transcriptional activation. With this in mind, we considered whether other enteric pathogens also encode T3SS effectors that impact this important host regulatory pathway. Here we report that the Salmonella Secreted Effector L (SseL), which was previously shown to function as a deubiquitinase and inhibit NF-kappaB signaling, also inhibits RPS3 nuclear translocation by deubiquitinating this important host transcriptional co-factor. RPS3 deubiquitination by SseL was restricted to K63-linkages and mutating the active site cysteine of SseL abolished its ability to deubiquitinate and subsequently inhibit RPS3 nuclear translocation. Thus, Salmonella also encodes at least one T3SS effector that alters RPS3 activities in the host nucleus. PMID- 30405006 TI - High Performance Seesaw Torsional CMOS-MEMS Relay Using Tungsten VIA Layer. AB - In this paper, a seesaw torsional relay monolithically integrated in a standard 0.35 MUm complementary metal oxide semiconductor (CMOS) technology is presented. The seesaw relay is fabricated using the Back-End-Of-Line (BEOL) layers available, specifically using the tungsten VIA3 layer of a 0.35 MUm CMOS technology. Three different contact materials are studied to discriminate which is the most adequate as a mechanical relay. The robustness of the relay is proved, and its main characteristics as a relay for the three different contact interfaces are provided. The seesaw relay is capable of a double hysteretic switching cycle, providing compactness for mechanical logic processing. The low contact resistance achieved with the TiN/W mechanical contact with high cycling life time is competitive in comparison with the state-of-the art. PMID- 30405008 TI - Viroid Diseases in Pome and Stone Fruit Trees and Koch's Postulates: A Critical Assessment. AB - Composed of a naked circular non-protein-coding genomic RNA, counting only a few hundred nucleotides, viroids-the smallest infectious agents known so far-are able to replicate and move systemically in herbaceous and woody host plants, which concomitantly may develop specific diseases or remain symptomless. Several viroids have been reported to naturally infect pome and stone fruit trees, showing symptoms on leaves, fruits and/or bark. However, Koch's postulates required for establishing on firm grounds the viroid etiology of these diseases, have not been met in all instances. Here, pome and stone fruit tree diseases, conclusively proven to be caused by viroids, are reviewed, and the need to pay closer attention to fulfilling Koch's postulates is emphasized. PMID- 30405007 TI - A 5-Methylcytosine Site of Growth Differentiation Factor 9 (GDF9) Gene Affects Its Tissue-Specific Expression in Sheep. AB - Growth differentiation factor 9 (GDF9) plays an important role in the early folliculogenesis of sheep. This study investigated the mRNA expression of ovine GDF9 in different tissues by real-time PCR. GDF9 exhibits significantly higher levels of expression (p < 0.01) in the ovary, relative to other tissues, indicating that its expression is tissue specific. To explore the regulatory mechanism of this tissue-specific expression, the methylation level of one CpG island (-1453 to -1854) of GDF9 promoter in ovary and heart was determined. In this region (-1987 to -1750), only the mC-4 site was present in the Sp4 binding site showed differential methylation between the heart and ovary; with increased (p < 0.01) methylation being observed in the heart. Additionally, the methylation level was negatively correlated with GDF9 mRNA expression (R = -0.75, p = 0.012), indicating that the methylation of this site plays an important role in transcriptional regulation of GDF9. The methylation effect of the mC-4 site was confirmed by using dual-luciferase. Site-directed mutation (methylation) of mC-4 site significantly reduced (p < 0.05) basal transcriptional activity of GDF9 promoter in oocytes. These results imply that methylation of GDF9 promoter CpG island mC-4 site may affect the binding of the Sp4 transcription factor to the GDF9 promoter region in sheep, thereby regulating GDF9 expression and resulting in a tissue-specific expression. PMID- 30405009 TI - Meeting Review: 2018 International Workshop on Structure and Function of the Lentiviral gp41 Cytoplasmic Tail. AB - Recent developments in defining the role of the lentiviral envelope glycoprotein (Env) cytoplasmic tail (CT) in Env trafficking and incorporation into virus particles have advanced our understanding of viral replication and transmission. To stimulate additional progress in this field, the two-day International Workshop on Structure and Function of the Lentiviral gp41 Cytoplasmic Tail, co organized by Eric Freed and James Hoxie, was held at the National Cancer Institute in Frederick, MD (26-27 April 2018). The meeting served to bring together experts focused on the role of gp41 in HIV replication and to discuss the emerging mechanisms of CT-dependent trafficking, Env conformation and structure, host protein interaction, incorporation, and viral transmission. The conference was organized around the following three main hot topics in gp41 research: the role of host factors in CT-dependent Env incorporation, Env structure, and CT-mediated trafficking and transmission. This review highlights important topics and the advances in gp41 research that were discussed during the conference. PMID- 30405010 TI - Cigarette Smoking Modulation of Saliva Microbial Composition and Cytokine Levels. AB - Tobacco use has been implicated as an immunomodulator in the oral cavity and contributes to the development of oral cancer. In the present study, we investigated the effects of cigarette smoking on bacterial diversity and host responses compared to healthy nonsmoking controls. Saliva samples were collected from eighteen smokers and sixteen nonsmoking individuals by passive drool. The 16S rRNA gene was used to characterize the salivary microbiome by using the Illumina MiSeq platform. Cytokine and chemokine expression analyses were performed to evaluate the host response. Significant differences in cytokine and chemokine expression levels of MDC, IL-10, IL-5, IL-2, IL-4, IL-7, adrenocorticotropic hormone (ACTH), insulin, and leptin were observed between smokers and nonsmokers. Taxonomic analyses revealed differences between the two groups, and some bacterial genera associated with the smokers group had correlations with hormones and cytokines identified as statistically different between smokers and nonsmokers. These factors have been associated with inflammation and carcinogenesis in the oral cavity. The data obtained may aid in the identification of the interactions between the salivary microbiome, host inflammatory responses, and metabolism in smokers. PMID- 30405011 TI - Effects of CTCP Modification on Microstructure and Wear Behavior of CTCP NiCrBSi/Heat Resistant Steel Composite Layer. AB - A CTCP-NiCrBSi/heat resistant steel composite layer was designed and fabricated by vacuum fusion sintering. The structure of the composite layer was similar to reinforced concrete. Numerous reinforced regions with a cylindrical shape were evenly distributed in the heat resistant steel. Modified cast tungsten carbide particles (CTCP) reinforced NiCrBSi matrix composite constituted the reinforced region (CTCP-NiCrBSi). The microstructure of the composite layers was investigated by scanning electron microscope (SEM), energy dispersive x-ray spectrometer (EDS), and image analysis. The wear behavior of the composite layer was estimated on the ring-on-disc rig at a temperature range of room temperature (RT) to 800 degrees C in air. The microstructure and wear behavior of the composite layer with modified CTCP were compared with those with primary CTCP. The results showed that the poor chemical resistance of W2C and the interdiffusion of elements were responsible for the dissolution of unmodified CTCP in the molten NiCrBSi alloy. A WC outer shell formed on the surface of the CTCP after surface carburizing modification. The WC outer shell could effectively resist the dissolution of CTCP in NiCrBSi during the sintering process. The content of WC/W2C in modified CTCP-NiCrBSi increased by about 12.0 vol. % when compared with that in the primary CTCP-NiCrBSi. The wear rate of the composite layer with modified CTCP was lower than that with primary CTCP between RT and 700 degrees C. The wear rates of the composite layer decreased with increasing temperature from RT to 700 degrees C and increased above 700 degrees C. PMID- 30405012 TI - Ag2CO3 Decorating BiOCOOH Microspheres with Enhanced Full-Spectrum Photocatalytic Activity for the Degradation of Toxic Pollutants. AB - The development of excellent full-spectrum photocatalysts is of vital significance to its practical application in environmental remediation. Herein, flower-like Ag2CO3/BiOCOOH type I heterostructures were prepared via a facile method and exhibited powerful photocatalytic activity by removing various toxic pollutants (rhodamine B, methyl blue, and tetracycline hydrochloride) under simulated sunlight irradiation. The boosted photocatalytic performance is attributed to the expanded range of the absorption spectrum and alleviated separation rate of the photo-induced electrons and holes. The photoluminescence spectra and trapping experiment were applied to clarify the photocatalytic reaction mechanism of Ag2CO3/BiOCOOH. The holes and *O2- were detected as the dominant reactive species involved in pollutant degradation. This work provides a novel full-spectrum-driven photocatalyst of Ag2CO3/BiOCOOH, which could effectively degrade toxic pollutants under simulated sunlight. PMID- 30405013 TI - On the High Formability of AZ31-0.5Ca Magnesium Alloy. AB - In this work, we investigated the effect of Ca on the formability of the AZ31 Mg alloy. For this purpose, the microstructure, texture, mechanical properties and formability of AZ31 Mg alloy samples containing 0.5 wt. % Ca (AZ31-0.5Ca) were studied. For comparison, the performance of Ca-Free AZ31 alloy samples with similar grain size was also investigated. In addition, formability of this alloy was reached at a high punch speed. The results of this work showed that the addition of 0.5 wt. % Ca can enhance the formability of the AZ31 alloy, which was three times greater than that of the Ca-Free AZ31 alloy. The improved formability was attributed to the formation of (Mg,Al)2Ca particles (~1 MUm), which, in turn, contribute to reducing the intensity of the strong basal texture during the primary processing of the alloy. The in-grain misorientation axis analysis determined by electron back-scattered diffraction and critical resolved shear stress calculations carried out by the viscoplastic self-consistent model showed that the non-basal slip systems could be activated in the AZ31-0.5Ca alloy. PMID- 30405014 TI - Possible Involvement of 2',3'-Cyclic Nucleotide-3'-Phosphodiesterase in the Protein Phosphorylation-Mediated Regulation of the Permeability Transition Pore. AB - Calcium as a secondary messenger regulates the phosphorylation of several membrane-bound proteins in brain and liver mitochondria. Regulation of the activity of different protein kinases and phosphatases by Ca2+ occurs through its binding with calmodulin. The protein phosphorylation is strongly dependent on the Ca2+-induced mitochondrial permeability transition pore (mPTP) opening. 2',3' Cyclic nucleotide-3'-phosphodiesterase (CNPase) was phosphorylated by protein kinases A and C. CNPase and melatonin (MEL) might interact with calmodulin. The effects of the calmodulin antagonist calmidazolium and the inhibitor of protein kinase A H89 on mPTP opening in rat brain mitochondria of male Wistar rats were investigated. In addition, the role of CNPase, serine/threonine kinases, and MEL in the mPTP opening was examined. The anti-CNPase antibody added to rat brain mitochondria (RBM) reduced the content of CNPase in mitochondria. The threshold [Ca2+] decreased, and mitochondrial swelling was accelerated in the presence of the anti-CNPase antibody. H89 enhanced the effect of anti-CNPase antibody and accelerated the swelling of mitochondria, while CmZ abolished the effect of anti CNPase antibody under mPTP opening. The levels of phospho-Akt and phospho GSK3beta increased, while the MEL content did not change. It can be assumed that CNPase may be involved in the regulation of these kinases, which in turn plays an important role in mPTP functioning. PMID- 30405015 TI - A Mobile Cough Strength Evaluation Device Using Cough Sounds. AB - Although cough peak flow (CPF) is an important measurement for evaluating the risk of cough dysfunction, some patients cannot use conventional measurement instruments, such as spirometers, because of the configurational burden of the instruments. Therefore, we previously developed a cough strength estimation method using cough sounds based on a simple acoustic and aerodynamic model. However, the previous model did not consider age or have a user interface for practical application. This study clarifies the cough strength prediction accuracy using an improved model in young and elderly participants. Additionally, a user interface for mobile devices was developed to record cough sounds and estimate cough strength using the proposed method. We then performed experiments on 33 young participants (21.3 +/- 0.4 years) and 25 elderly participants (80.4 +/- 6.1 years) to test the effect of age on the CPF estimation accuracy. The percentage error between the measured and estimated CPFs was approximately 6.19%. In addition, among the elderly participants, the current model improved the estimation accuracy of the previous model by a percentage error of approximately 6.5% (p < 0.001). Furthermore, Bland-Altman analysis demonstrated no systematic error between the measured and estimated CPFs. These results suggest that the developed device can be applied for daily CPF measurements in clinical practice. PMID- 30405016 TI - Site-Specific Labeling of Proteins with Near-IR Heptamethine Cyanine Dyes. AB - Convenient labeling of proteins is important for observing its function under physiological conditions. In tissues particularly, heptamethine cyanine dyes (Cy 7) are valuable because they absorb in the near-infrared (NIR) region (750-900 nm) where light penetration is maximal. In this work, we found Cy-7 dyes with a meso-Cl functionality covalently binding to proteins with free Cys residues under physiological conditions (aqueous environments, at near neutral pH, and 37 degrees C). It transpired that the meso-Cl of the dye was displaced by free thiols in protein, while nucleophilic side-chains from amino acids like Tyr, Lys, and Ser did not react. This finding shows a new possibility for convenient and selective labeling of proteins with NIR fluorescent probes. PMID- 30405017 TI - Light-Tuned DC Conductance of Anatase TiO2 Nanotubular Arrays: Features of Long Range Charge Transport. AB - Experimental results related to the photoactivated dc conductance of anatase TiO2 nanotubular arrays (aTNTAs) under pulsed irradiation by a laser light inside and outside the fundamental absorption band are presented. It is found that the mobility and diffusion coefficients of charge carriers in the examined aTNTA are extremely low due to a strong charge-phonon coupling, abundance of shallow traps, and hopping conductivity between adjacent nanotubes. We consider that the confining electric field appeared within the array structure due to the difference in the local concentrations of excess electrons and holes at large values of the dc conductance suppresses the drift current. In this case, the dc conductance of such aTNTAs is mainly matured by the diffusion of mobile carriers. A recurrent kinetic model for evolution of the dc conductance of aTNTAs under laser irradiation has been proposed to interpret the experimental results. PMID- 30405019 TI - Endogenous Ovarian Angiogenesis in Polycystic Ovary Syndrome-Like Rats Induced by Low-Frequency Electro-Acupuncture: The CLARITY Three-Dimensional Approach. AB - We sought to determine the role of ovarian vascularity and neo-angiogenesis in the development of mature follicles in polycystic ovary syndrome (PCOS) and to identify any changes induced by low-frequency electro-acupuncture (EA). Twenty eight 21-day-old female Wistar rats were randomly divided into four groups Control, Obesity, PCOS-like, and PCOS-like-EA (n = 7/group). Rats in the Obesity group were fed a high-fat diet throughout the experiment. Rats in the PCOS-like and PCOS-like-EA groups were implanted with a sustained-release tube containing 5alpha-dihydrotestosterone (DHT) beneath the skin of the neck. Rats in the PCOS like-EA group received low-frequency EA treatment starting at 70 days for 30 min five times a week for four weeks. At the end of the experiment, all rats were euthanized and perfused with hydrogel. The ovaries were collected for clarification and imaging, and ovarian vascularity and neo-angiogenesis were analyzed. Compared with Control and Obesity rats, the ovaries in DHT-induced PCOS like rats were smaller in size and had fewer mature follicles and corpora lutea. EA increased angiogenesis in the antral follicles of PCOS-like rats, which in turn promoted follicle maturation, ovulation, and CL formation. Therefore, endogenous ovarian angiogenesis plays a very important role in follicular maturation and might be one of the peripheral and direct mechanisms of EA on PCOS. PMID- 30405020 TI - Smart Shoe-Assisted Evaluation of Using a Single Trunk/Pocket-Worn Accelerometer to Detect Gait Phases. AB - Wearable sensors may enable the continuous monitoring of gait out of the clinic without requiring supervised tests and costly equipment. This paper investigates the use of a single wearable accelerometer to detect foot contact times and estimate temporal gait parameters (stride time, swing and stance duration). The experiments considered two possible body positions for the accelerometer: over the lower trunk and inside a trouser pocket. The latter approach could be implemented using a common smartphone. Notably, during the experiments, the ground truth was obtained by using a pair of sensorized shoes. Unlike ambient sensors and camera-based systems, sensorized shoes enable the evaluation of body worn sensors even during longer walks. Experiments showed that both trunk and pocket positions achieved promising results in estimating gait parameters, with a mean absolute error below 50 ms. PMID- 30405018 TI - Recent Trends in Covalent and Metal Organic Frameworks for Biomedical Applications. AB - Materials science has seen a great deal of advancement and development. The discovery of new types of materials sparked the study of their properties followed by applications ranging from separation, catalysis, optoelectronics, sensing, drug delivery and biomedicine, and many other uses in different fields of science. Metal organic frameworks (MOFs) and covalent organic frameworks (COFs) are a relatively new type of materials with high surface areas and permanent porosity that show great promise for such applications. The current study aims at presenting the recent work achieved in COFs and MOFs for biomedical applications, and to examine some challenges and future directions which the field may take. The paper herein surveys their synthesis, and their use as Drug Delivery Systems (DDS), in non-drug delivery therapeutics and for biosensing and diagnostics. PMID- 30405021 TI - An 8-Week Ketogenic Diet Alternated Interleukin-6, Ketolytic and Lipolytic Gene Expression, and Enhanced Exercise Capacity in Mice. AB - Adjusting dietary fat intake is reported to affect mitochondrial biogenesis and fatty acid oxidation (FAO), and thus may enhance exercise capacity. However, a high-fat diet where carbohydrate intake is not limited enough also makes it difficult for athletes to maintain weight, and may fail to force the body to utilize fat. As such, a low-carbohydrate, high-fat, ketogenic diet (KD) may be viable. We have previously reported that an eight-week KD enhances exercise capacity, and suggested the mechanism to be enhanced lipolysis and ketolysis. In the present study, we investigated how an eight-week KD alters mRNA expression during fatty acid mobilization, FAO and ketolysis. We found that an eight-week KD may remodel the lipid metabolism profile, thus contributing to influence exercise capacity. We also found that ketolysis, lipolysis and FAO adaptations may contribute to enhanced exhaustive exercise performance. Along with enhanced FAO capacity during exhaustive exercise, a KD may also alter IL-6 synthesis and secretion profile, thus contribute to fatty acid mobilization, ketolysis, lipolysis and preventing muscle damage. Both the lipid metabolism response and IL 6 secretion appeared to be muscle fiber specific. Taken together, the previous and present results reveal that an eight-week KD may enhance exercise performance by up-regulating ketolysis and FAO ability. Therefore, a KD may have the potential to prevent muscle damage by altering IL-6 secretion profile, indicating that a KD may be a promising dietary approach in endurance athletes, sports, and for injury prevention. PMID- 30405022 TI - A Pilot Clinical Study of Liquid Ubiquinol Supplementation on Cardiac Function in Pediatric Dilated Cardiomyopathy. AB - BACKGROUND: Pediatric dilated cardiomyopathy (PDCM) is a life-threatening type of cardiac muscle dysfunction in children. Ubiquinone is a lipid-soluble nutrient that participates in energy synthesis. Recently, a novel hydrophilic ubiquinol supplement was developed. The purpose of this study was to assess the effect of liquid ubiquinol supplementation (10 mg/kg body weight/day) on cardiac function in children with PDCM. METHODS: Ten children diagnosed with PDCM were recruited to this study and administered with liquid ubiquinol for 24 weeks. The cardiac function was measured by echocardiography. The New York Heart Association (NYHA) functional classification was used to assess symptoms of heart failure. Plasma coenzyme Q10 levels were measured during the study. RESULTS: Ejection fraction (EF) and fractional shortening (FS) were significantly higher than the baseline values until week 16 of supplementation. Subjects who had higher plasma coenzyme Q10 concentration had significantly better EF and FS values. In addition, 30% of the subjects showed improvement in the NYHA classification after 24 weeks of supplementation. CONCLUSION: Liquid ubiquinol supplementation is associated with an increase the level of coenzyme Q10 to complementary improve cardiac function (particularly EF and FS) and ameliorate the symptoms of heart failure in children with PDCM. PMID- 30405023 TI - DNA Modified with Boron-Metal Cluster Complexes [M(C2B9H11)2]-Synthesis, Properties, and Applications. AB - Together with tremendous progress in biotechnology, nucleic acids, while retaining their status as "molecules of life", are becoming "molecular wires", materials for the construction of molecular structures at the junction between the biological and abiotic worlds. Herein, we present an overview of the approaches for incorporating metal centers into nucleic acids based on metal boron cluster complexes (metallacarboranes) as the metal carriers. The methods are modular and versatile, allowing practical access to innovative metal containing DNA for various applications, such as nucleic acid therapeutics, electrochemical biosensors, infrared-sensitive probes, and building blocks for nanoconstruction. PMID- 30405024 TI - Lung Function Assessment as an Early Biomonitor of Mercury-Induced Health Disorders in Artisanal and Small-Scale Gold Mining Areas in Indonesia. AB - The evaluation of mercury impact on humans is currently nonspecific because the body characteristics (homeostasis) of each human being varies. Therefore, in the early diagnosis of mercury toxicity, one of the most important monitoring parameters is the respiratory function examination. In this study, respiratory function was examined with a portable spirometer and correlated with the mercury levels in hair from the noses and heads of subjects. Samples were taken from artisanal and small-scale gold mining (ASGM) areas (villages of East Tulabolo and Dunggilata) and control areas (villages of Bongo and Longalo) in Gorontalo Province, Indonesia. A statistical analysis with the Mann-Whitney test (alternative) showed significant differences in lung function between the polluted and control areas (alpha = 0.03). The analysis of nasal and head hair samples with particle-induced X-ray emissions (PIXE) showed that the mercury levels in the ASGM area were considerably higher than in the more homogeneous control areas. This study confirms that a pulmonary function test is a quick and precise alternative way to monitor the impact of mercury on humans, especially atmospheric mercury, because we detected a negative correlation between pulmonary function and the level of mercury in hair. PMID- 30405025 TI - Impact of Pulsed Electric Fields on the Volatile Compounds Produced in Whole Onions (Allium cepa and Allium fistulosum). AB - The objective of this research was to investigate the effect of pulsed electric field (PEF) processing on the volatile compounds produced in onion cultivars. The changes in the volatile compounds of onions were assessed comparing results observed while measured immediately and 24 h after PEF treatment using headspace solid-phase microextraction gas chromatography-mass spectrometry (HS-SPME-GC-MS). Significant increases in the concentrations of propanethial S-oxide, propenyl propyl thiosulfinate, 2-methyl-2-pentenal, dipropyl disulfide, propenyl propyl disulfide, methyl propyl disulfide, and methyl propenyl disulfide were observed immediately after PEF treatment. The concentrations of propenyl propyl thiosulfinate, dipropyl disulfide, methyl propyl disulfide, dipropyl trisulfide, methyl propyl trisulfide, and propenyl propyl trisulfide increased after 24 h compared to initial concentrations. It is postulated that these changes are due to PEF-induced cell permeabilisation that facilitates enzyme-substrate reactions after the PEF treatment. PMID- 30405026 TI - Wearable Hardware Design for the Internet of Medical Things (IoMT). AB - As the life expectancy of individuals increases with recent advancements in medicine and quality of living, it is important to monitor the health of patients and healthy individuals on a daily basis. This is not possible with the current health care system in North America, and thus there is a need for wireless devices that can be used from home. These devices are called biomedical wearables, and they have become popular in the last decade. There are several reasons for that, but the main ones are: expensive health care, longer wait times, and an increase in public awareness about improving quality of life. With this, it is vital for anyone working on wearables to have an overall understanding of how they function, how they were designed, their significance, and what factors were considered when the hardware was designed. Therefore, this study attempts to investigate the hardware components that are required to design wearable devices that are used in the emerging context of the Internet of Medical Things (IoMT). This means that they can be used, to an extent, for disease monitoring through biosignal capture. In particular, this review study covers the basic components that are required for the front-end of any biomedical wearable, and the limitations that these wearable devices have. Furthermore, there is a discussion of the opportunities that they create, and the direction that the wearable industry is heading in. PMID- 30405028 TI - Improving the Water Resistance and Mechanical Properties of Feather Keratin/Polyvinyl Alcohol/Tris(Hydroxymethyl)Aminomethane Blend Films by Cross Linking with Transglutaminase, CaCl2, and Genipin. AB - The high moisture sensitivity of feather keratin/polyvinyl alcohol/tris(hydroxymethyl)aminomethane (FK/PVA/Tris) blend films hinders their application in the packaging field. Thus, in order to improve the water resistance and mechanical properties of such blend films, we attempted cross linking the blend film with cross-linking agents such as transglutaminase (TG), CaCl2, and genipin. Obvious differences in the morphology of the blended films were observed by scanning electron microscopy before and after cross-linking, indicating that cross-linking can inhibit the phase separation of the blend film. Conformational changes in the blend films after cross-linking were detected by Fourier transform infrared spectroscopy. Importantly, from examination of the total soluble mass, contact angle measurements, and water vapor permeability tests, it was apparent that cross-linking greatly improved the water resistance of the blend films, in addition to enhancing the mechanical properties (i.e., tensile strength and elongation at break). However, cross-linking was also found to reduce the oxygen barrier properties of the blend films. Therefore, cross linking appears to be an effective method for promoting the application of FK/PVA/Tris blend films in the packaging field. PMID- 30405027 TI - Recent Developments for Flexible Pressure Sensors: A Review. AB - Flexible pressure sensors are attracting great interest from researchers and are widely applied in various new electronic equipment because of their distinct characteristics with high flexibility, high sensitivity, and light weight; examples include electronic skin (E-skin) and wearable flexible sensing devices. This review summarizes the research progress of flexible pressure sensors, including three kinds of transduction mechanisms and their respective research developments, and applications in the fields of E-skin and wearable devices. Furthermore, the challenges and development trends of E-skin and wearable flexible sensors are also briefly discussed. Challenges of developing high extensibility, high sensitivity, and flexible multi-function equipment still exist at present. Exploring new sensing mechanisms, seeking new functional materials, and developing novel integration technology of flexible devices will be the key directions in the sensors field in future. PMID- 30405029 TI - A Novel One-Transistor Dynamic Random-Access Memory (1T DRAM) Featuring Partially Inserted Wide-Bandgap Double Barriers for High-Temperature Applications. AB - These days, the demand on electronic systems operating at high temperature is increasing owing to bursting interest in applications adaptable to harsh environments on earth, as well as in the unpaved spaces in the universe. However, research on memory technologies suitable to high-temperature conditions have been seldom reported yet. In this work, a novel one-transistor dynamic random-access memory (1T DRAM) featuring the device channel with partially inserted wide bandgap semiconductor material toward the high-temperature application is proposed and designed, and its device performances are investigated with an emphasis at 500 K. The possibilities of the program operation by impact ionization and the erase operation via drift conduction by a properly high drain voltage have been verified through a series of technology computer-aided design (TCAD) device simulations at 500 K. Analyses of the energy-band structures in the hold state reveals that the electrons stored in the channel can be effectively confined and retained by the surrounding thin wide-bandgap semiconductor barriers. Additionally, for more realistic and practical claims, transient characteristics of the proposed volatile memory device have been closely investigated quantifying the programming window and retention time. Although there is an inevitable degradation in state-1/state-0 current ratio compared with the case of room-temperature operation, the high-temperature operation capabilities of the proposed memory device at 500 K have been confirmed to fall into the regime permissible for practical use. PMID- 30405030 TI - Examining Canadian Equine Industry Participants' Perceptions of Horses and Their Welfare. AB - The diversity of the Canadian equine industry makes determining baseline attitudes and beliefs a challenge. Adult members of the Canadian equine industry (n = 901) participated in an online survey to report demographic information and views on the role of horses and their ability to experience affective states. Questions regarding the welfare state of all horses in the industry, potential ways to address welfare issues, and eight short scenarios were presented. Qualitative analysis, descriptive statistics, and a Chi-squared test for independence examined survey results and potential relationships. Participants strongly believed horses were capable of feeling positive and negative emotions, particularly pain and fear, but rarely were these beliefs reflected in their answers regarding aspects of equine welfare, which may be due to the large bias in these beliefs. Lack of knowledge and financial difficulties were noted as the biggest threats to equine welfare. Overall, there was widespread agreement regarding the presence of welfare issues within the equine industry, but opinions were more divided regarding how to best address them and which horses were most at risk. Understanding these perceptions may be useful to direct educational programs and industry-wide initiatives to address equine welfare through human behaviour change. PMID- 30405031 TI - Insights into Tear Film Stability from Babies and Young Adults: A Study of Human Meibum Lipid Conformation and Rheology. AB - Babies have the most stable tears and people with dry eye have the least stable tears. Meibum may contribute to tear film stability, so in this study, the hydrocarbon chain conformation and rheology of meibum from babies was studied for the first time. Infrared spectroscopy was used to measure lipid phase transitions. Rheology was measured using Langmuir film technology. Meibum from 25 donors 1 to 13 years old was compared with meibum from 18 donors 13 to 25 years old. The phase transition temperature and lipid order (stiffness) increased with increasing age from 1 to 25 years. The increase in meibum lipid order from 1 to 25 years of age may contribute to the instability of the tear film with age and contribute to films with a higher reciprocal compressibility modulus that are not as compressible and not as viscoelastic. Changes in the lipid phase transition parameters of meibum lipid with dry eye are an exacerbation of the changes observed with age. The lower reciprocal compressibility moduli of meibum films from children and babies compared with meibum from adults reiterates higher stability in their films which spread better, resist deformation, and facilitates their ability to be quickly restored after blinking. PMID- 30405032 TI - Influence of Mono- and Bimetallic PtOx, PdOx, PtPdOx Clusters on CO Sensing by SnO2 Based Gas Sensors. AB - To obtain a nanocrystalline SnO2 matrix and mono- and bimetallic nanocomposites SnO2/Pd, SnO2/Pt, and SnO2/PtPd, a flame spray pyrolysis with subsequent impregnation was used. The materials were characterized using X-ray diffraction (XRD), a single-point BET method, transmission electron microscopy (TEM), and high angle annular dark field scanning transmission electron microscopy (HAADF STEM) with energy dispersive X-ray (EDX) mapping. The electronic state of the metals in mono- and bimetallic clusters was determined using X-ray photoelectron spectroscopy (XPS). The active surface sites were investigated using the Fourier Transform infrared spectroscopy (FTIR) and thermo-programmed reduction with hydrogen (TPR-H2) methods. The sensor response of blank SnO2 and nanocomposites had a carbon monoxide (CO) level of 6.7 ppm and was determined in the temperature range 60-300 degrees C in dry (Relative Humidity (RH) = 0%) and humid (RH = 20%) air. The sensor properties of the mono- and bimetallic nanocomposites were analyzed on the basis of information on the electronic state, the distribution of modifiers in SnO2 matrix, and active surface centers. For SnO2/PtPd, the combined effect of the modifiers on the electrophysical properties of SnO2 explained the inversion of sensor response from n- to p-types observed in dry conditions. PMID- 30405033 TI - Adsorption of Pb (II) Ions onto Hydroxyapatite Nanopowders in Aqueous Solutions. AB - Contamination of water with heavy metals such as lead is a major worldwide problem because they affect the physiological functions of living organisms, cause cancer, and damage the immune system. Hydroxyapatite, (Ca5(PO4)3OH) is considered one of the most effective materials for removing heavy metals from contaminated water. The hydroxyapatite nanopowders (N-HAp) obtained by a co precipitation method were used in this research to determine the effectiveness in removing lead ions from contaminated solutions. In this study, we have investigated the structure and morphology of N-HAp nanopowders using X-ray diffraction (XRD), electronic transmission microscopy (TEM), and scanning electron microscopy (SEM). The structure information was also obtained by spectroscopy measurements. The Fourier transform infrared spectroscopy (FTIR) and Raman spectroscopy measurements revealed the presence of peaks corresponding to the phosphate and hydroxyl groups. The ability of N-HAp nanopowders to adsorb lead ions from aqueous solutions were established. The results of the kinetic and equilibrium studies on the removal of Pb (II) from aqueous solution revealed that the adsorption of lead (II) cations is due to the surface reaction with the hydroxyl terminal groups on the adsorbent and the combination of the positive charges of the metal cations with the negative charges on the adsorbent surfaces. These observations could validate the use of these ceramic nanopowders in ecological remediation strategies. PMID- 30405034 TI - NRF2 Is One of the Players Involved in Bone Marrow Mediated Drug Resistance in Multiple Myeloma. AB - Multiple myeloma with clonal plasma expansion in bone marrow is the second most common hematologic malignancy in the world. Though the improvement of outcomes from the achievement of novel agents in recent decades, the disease progresses and leads to death eventually due to the elusive nature of myeloma cells and resistance mechanisms to therapeutic agents. In addition to the molecular and genetic basis of resistance pathomechanisms, the bone marrow microenvironment also contributes to disease progression and confers drug resistance in myeloma cells. In this review, we focus on the current state of the literature in terms of critical bone marrow microenvironment components, including soluble factors, cell adhesion mechanisms, and other cellular components. Transcriptional factor nuclear factor erythroid-derived-2-like 2 (NRF2), a central regulator for anti oxidative stresses and detoxification, is implicated in chemoresistance in several cancers. The functional roles of NRF2 in myeloid-derived suppressor cells and multiple myeloma cells, and the potential of targeting NRF2 for overcoming microenvironment-mediated drug resistance in multiple myeloma are also discussed. PMID- 30405035 TI - Electronic Cigarettes and Smoking Cessation in the Perioperative Period of Cardiothoracic Surgery: Views of Australian Clinicians. AB - For patients who smoke, electronic cigarettes may offer a pathway to achieve tobacco abstinence and reduce the risk of postoperative complications. Clinicians have a pivotal role in supporting smoking cessation by patients with lung cancer and coronary artery disease throughout the perioperative period of cardiothoracic surgery. However, the views of Australian cardiothoracic clinicians on electronic cigarettes and smoking cessation are unknown. Semi-structured interviews were conducted with 52 cardiothoracic surgeons, anaesthetists, nurses and physiotherapists in six hospitals in Sydney and thematically analysed. Clinicians' knowledge about electronic cigarettes and the regulatory environment surrounding them was limited. Clinicians believed that: electronic cigarettes, though unlikely to be safe, were safer than tobacco cigarettes; electronic cigarettes may have a harm reduction role in public health; and electronic cigarettes were a potential smoking cessation tool for the extraordinary circumstances of surgery. The professional role of a clinician and their views about electronic cigarettes as a perioperative smoking cessation aid had an influence on future clinician-patient interactions. Electronic cigarette use is increasing in Australia and clinicians are likely to receive more frequent questions about electronic cigarettes as a cessation aid. Stronger guidance for clinicians is needed on the topic of electronic cigarettes and cardiothoracic surgery. PMID- 30405036 TI - A Smartphone-Based System for Automated Bedside Detection of Crackle Sounds in Diffuse Interstitial Pneumonia Patients. AB - In this work, we present a mobile health system for the automated detection of crackle sounds comprised by an acoustical sensor, a smartphone device, and a mobile application (app) implemented in Android. Although pulmonary auscultation with traditional stethoscopes had been used for decades, it has limitations for detecting discontinuous adventitious respiratory sounds (crackles) that commonly occur in respiratory diseases. The proposed app allows the physician to record, store, reproduce, and analyze respiratory sounds directly on the smartphone. Furthermore, the algorithm for crackle detection was based on a time-varying autoregressive modeling. The performance of the automated detector was analyzed using: (1) synthetic fine and coarse crackle sounds randomly inserted to the basal respiratory sounds acquired from healthy subjects with different signal to noise ratios, and (2) real bedside acquired respiratory sounds from patients with interstitial diffuse pneumonia. In simulated scenarios, for fine crackles, an accuracy ranging from 84.86% to 89.16%, a sensitivity ranging from 93.45% to 97.65%, and a specificity ranging from 99.82% to 99.84% were found. The detection of coarse crackles was found to be a more challenging task in the simulated scenarios. In the case of real data, the results show the feasibility of using the developed mobile health system in clinical no controlled environment to help the expert in evaluating the pulmonary state of a subject. PMID- 30405037 TI - Looking at Flavonoid Biodiversity in Horticultural Crops: A Colored Mine with Nutritional Benefits. AB - Flavonoids represent a wide group of plant secondary metabolites implicated in many physiological roles, from the attraction of pollinators to the protection against biotic or abiotic stresses. Flavonoids are synthetized in a number of horticultural crops that are important components of our daily diet. In the last decades, the consumption of vegetables rich in antioxidants has been strongly promoted from the perspective of prevention/protection against chronic diseases. Therefore, due to their nutritional importance, several attempts have been made to enhance flavonoid levels in species of agronomic interest. In this review, we focus on the flavonoid biodiversity among the major horticultural species, which is responsible of differences among closely related species and influences the qualitative/quantitative composition. We also review the role of flavonoids in the nutritional quality of plant products, contributing to their organoleptic and nutritional properties, and the main strategies of biofortification to increase their content. PMID- 30405038 TI - Thermal and Mechanical Properties of Expanded Graphite/Paraffin Gypsum-Based Composite Material Reinforced by Carbon Fiber. AB - Phase change material (PCM) is a kind of thermal energy storage material. Solid liquid PCM composite materials must overcome the issues of material leakage and low thermal conductivity before they are suitable for widespread use in the fields of building and industry. In this study, porous expanded graphite (EG) is used as a carrier, which absorbs the PCM to fabricate EG/paraffin composites (EG/P) containing 90.6% paraffin, and a latent heat of up to 105.3 J/g was measured. Because gypsum board is widely used in buildings, therefore, EG/P composites are suitable to be integrated into gypsum to develop expanded graphite/paraffin gypsum-based composite material (EGPG) for thermal energy storage. In order to optimize the performance of EGPG, carbon fiber (CF) is used to reinforce their thermal and mechanical properties. The test results show that when 1 wt % CF is incorporated into the EGPG, the thermal conductivity increased 36.0%, and thus EGPG shows superior thermal control through the significantly increased efficiency of heat transfer. After 1 wt % CF was added, the flexural and compressive strength of EGPG were increased by 65.6% and 6.4%, respectively. The improved thermal and mechanical performance of EGPG modified by CF demonstrates that it is a structural-functional integrated building material suitable for building envelope system. PMID- 30405040 TI - Effects of F-Doping on the Electrochemical Performance of Na2Ti3O7 as an Anode for Sodium-Ion Batteries. AB - The effects of fluorine (F) doping on the phase, crystal structure, and electrochemical performance of Na2Ti3O7 are studied by X-ray diffraction (XRD), scanning electron microscopy (SEM), and electrochemical measurements. F-doping does not change the crystal structure of NTO, although it has an effect on the morphology of the resultant product. As an anode material for sodium-ion batteries, the specific capacity of Na2Ti3O7 exhibits a 30% increase with F doping owing to the improved sodium ion diffusion coefficient. F-doped Na2Ti3O7 also displays an enhanced rate capability and favourable cycling performance for more than 800 cycles. PMID- 30405041 TI - Macromolecule Orientation in Nanofibers. AB - Electrospinning is now commercially used for the fabrication of nano/micro fibers. Compared with spider dragline silk, artificial fibers have poor mechanical properties. Unlike natural silk, which has a hierarchical structure with an approximate 3-fold symmetry, the molecular structure of spun fiber has neither folding nor orientation. To date, it is almost impossible to control molecule orientation during the spinning process. Here, we show that macromolecule orientation can be easily controlled using the laminar flow of fluid mechanics. A lasting laminar flow in a long needle can order macromolecules. We find that the orientation of macromolecules can greatly affect the morphology and mechanical properties of fibers. We expect our technology to be helpful for more sophisticated fabrication of fibers with ordered macromolecules and DNA-like twists. PMID- 30405042 TI - Chiral Separation of the Phenylglycinol Enantiomers by Stripping Crystallization. AB - Stripping crystallization (SC) is introduced in this work for chiral purification of R-phenylglycinol from the enantiomer mixture with an initial concentration ranging from 0.90 to 0.97. As opposed to the solid-liquid transformation in melt crystallization, the three-phase transformation occurs in SC at low pressures during the cooling process. SC combines melt crystallization and vaporization to produce a crystalline product and mixture vapor from a mixture melt due to the three-phase transformation. Thermodynamic calculations were applied to determine the operating pressure for the three-phase transformation during the cooling process in the SC experiments. To consider the possible deviations between the calculated and the actual three-phase transformation conditions, the product purity and the recovery ratio of R-phenylglycinol were investigated within a range of operating pressures during the cooling process. PMID- 30405043 TI - Caenorhabditis elegans as a Model Host to Monitor the Candida Infection Processes. AB - C. elegans has several advantages as an experimental host for the study of infectious diseases. Worms are easily maintained and propagated on bacterial lawns. The worms can be frozen for long term storage and still maintain viability years later. Their short generation time and large brood size of thousands of worms grown on a single petri dish, makes it relatively easy to maintain at a low cost. The typical wild type adult worm grows to approximately 1.5 mm in length and are transparent, allowing for the identification of several internal organs using an affordable dissecting microscope. A large collection of loss of function mutant strains are readily available from the C. elegans genetic stock center, making targeted genetic studies in the nematode possible. Here we describe ways in which this facile model host has been used to study Candida albicans, an opportunistic fungal pathogen that poses a serious public health threat. PMID- 30405039 TI - The Role of Co-Stimulatory Molecules in Chagas Disease. AB - Chagas disease, caused by Trypanosoma cruzi, is a potentially life-threatening tropical disease endemic to Latin American countries that affects approximately 8 million people. In the chronic phase of the disease, individuals are classified as belonging to the indeterminate clinical form or to the cardiac and/or digestive forms when clinical symptoms are apparent. The relationship between monocytes and lymphocytes may be an important point to help clarify the complexity that surrounds the clinical symptoms of the chronic phase of Chagas disease. The co-stimulatory signals are essential to determining the magnitude of T cell response to the antigen. The signals are known to determine the regulation of subsequent adaptive immune response. However, little is known about the expression and function of these molecules in Chagas disease. Therefore, this review aims to discuss the possible role of main pathways of co-stimulatory molecule-receptor interactions in this pathology that could be crucial to understand the disease dynamics. PMID- 30405044 TI - Interrelationships between Multiple Climatic Factors and Incidence of Foodborne Diseases. AB - Climatic factors can affect the incidence of foodborne diseases (FBDs). Moreover, microbial network inference is useful for predicting the interrelationships between the incidence of FBDs and climatic factors. However, the interrelationships between FBD pathogens and most climatic factors are unknown. Using principal component analysis (PCA) and partial correlation coefficient matrices (PCCMs), we determined the intra-ecosystem interrelationship network of the multiple combined effects of 5 climatic factors (temperature, relative humidity, rainfall, insolation, and cloudiness) and the monthly incidences of 12 bacterial FBDs. Many FBD pathogens are interrelated with multiple combined factors. Salmonellosis has strong positive interrelationships with Vibrio parahaemolyticus and enterohemorrhagic Escherichia coli, and the interrelationships between Staphylococcus aureus/enteropathogenic E. coli/enterotoxigenic E. coli exhibits a typical triangular pattern with the combined effects of all 5 climatic factors. Meanwhile, campylobacteriosis and Clostridium perfringens infections are negatively interrelated with insolation and cloudiness. Enteroinvasive E. coli, Bacillus cereus, Listeria spp., and Yersinia enterocolitica are significantly interrelated with any climatic factor combination. The interrelationships or higher-order interrelationships among these climatic factors play an important role in the incidence of FBDs, although the underlying mechanisms remain unclear. Our results will serve as a foundation for more sophisticated models of future FBD patterns with regard to climate change. PMID- 30405045 TI - Synthesis of Jacaranone-Derived Nitrogenous Cyclohexadienones and Their Antiproliferative and Antiprotozoal Activities. AB - The cytotoxic and antiprotozoal activities of the phytoquinoide, jacaranone, and related compounds have been an ongoing topic in recent drug discovery. Starting from the natural product-derived cyclohexadienone scaffold, a series of nitrogen containing derivatives were synthesized and subsequently evaluated for their antiproliferative and antiprotozoal activity. Anticancer potency was analyzed using different types of cancer cell lines: MDA-MB-231 breast cancer, CCRF-CEM leukemia, HCT-116 colon cancer, U251 glioblastoma, and, in addition, non tumorigenic MRC-5 lung fibroblasts. Antiproliferative activities at micromolar concentrations could be shown. Antiprotozoal activity was assessed against Plasmodium falciparum NF54 and Trypanosoma brucei rhodesiense STIB900. For all compounds, selectivity indices (SI) were calculated based on assessed cytotoxicity towards L6 cells. In addition, the structure-activity-relationships and physicochemical parameters of these compounds are discussed. PMID- 30405046 TI - From the Eye of the Storm: An IoT Ecosystem Made of Sensors, Smartphones and UAVs. AB - The development of Unmanned Aerial Vehicles (UAV) along with the ubiquity of Internet of Things (IoT) enables the creation of systems that, leveraging 5G enhancements, can provide real-time multimedia communications and data streaming. However, the usage of the UAVs introduces new constraints, such as unstable network communications and security pitfalls. In this work, the experience of implementing a system architecture for data and multimedia transmission using a multi-UAV system is presented. The system aims at creating an IoT ecosystem to bridge UAVs and other types of devices, such as smartphones and sensors, while coping with the fallback in an unstable communication environment. Furthermore, this work proposes a detailed description of a system architecture designed for remote drone fleet control. The proposed system provides an efficient, reliable and secure system for multi-UAV remote control that will offer the on-demand usage of available sensors, smartphones and unmanned vehicle infrastructure. PMID- 30405047 TI - Dielectric, Ferroelectric, and Magnetic Properties of Sm-Doped BiFeO3 Ceramics Prepared by a Modified Solid-State-Reaction Method. AB - Sm-doped BiFeO3 (BFO) material was prepared using a modified solid-state-reaction method, which used fast heating and cooling during the sintering process. The Sm doping level varied between 1 mol % to 8 mol %. Processing parameters, such as sintering temperature and annealing temperature, were optimized to obtain high quality samples. Based on their dielectric properties, the optimum sintering and annealing temperatures were found to be 300 degrees C and 825 degrees C, respectively. Leakage-free square-shaped ferroelectric hysteresis loops were observed in all samples. The remnant polarization was maximized in the 5 mol % doped sample (~35 MUC/cm2). Furthermore, remnant magnetization was increased after the Sm doping and the 8 mol%-doped sample possessed the largest remnant magnetization of 0.007 emu/g. Our results demonstrated how the modified solid state-reaction method proved to be an effective method for preparing high-quality BiFeO3 ceramics, as well as how the Sm dopant can efficiently improve ferroelectric and magnetic properties. PMID- 30405048 TI - The Natural Flavonoid Compound Deguelin Inhibits HCMV Lytic Replication within Fibroblasts. AB - Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus for which there is no vaccine or cure. This viral infection, once acquired, is life-long, residing latently in hematopoietic cells. However, latently infected individuals with weakened immune systems often undergo HCMV reactivation, which can cause serious complications in immunosuppressed and immunocompromised patients. Current anti viral therapies target late stages of viral replication, and are often met with therapeutic resistance, necessitating the development of novel therapeutics. In this current study, we identified a naturally-occurring flavonoid compound, deguelin, which inhibits HCMV lytic replication. Our findings reveal that nanomolar concentrations of deguelin significantly suppress the production of the infectious virus. Further, we show that deguelin inhibits the lytic cycle during the phase of the replication cycle consistent with early (E) gene and protein expression. Importantly, our data reveal that deguelin inhibits replication of a ganciclovir-resistant strain of HCMV. Together, our findings identify a novel, naturally occurring compound that may prove useful in the treatment of HCMV replication. PMID- 30405049 TI - Pediococcus pentosaceus-Fermented Cordyceps militaris Inhibits Inflammatory Reactions and Alleviates Contact Dermatitis. AB - Cordyceps militaris is a medicinal mushroom used to treat immune-related diseases in East Asia. We investigated the anti-inflammatory effect of the extract of C. militaris grown on germinated Rhynchosia nulubilis (GRC) fermented with Pediococcus pentosaceus ON89A isolated from onion (GRC-ON89A) in vivo as well as in vitro. The anti-inflammatory effect of GRC-ON89A was investigated in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. The total polyphenol content (TPC) and total flavonoid content (TFC) in the GRC-ON89A ethanol extract were significantly increased compared to that in GRC. GRC-ON89A hexane fraction (GRC-ON89A-Hex) inhibited the release of nitric oxide (NO) compared to that of the LPS-treated control without cytotoxicity in LPS-stimulated RAW 264.7 macrophages. GRC-ON89A-Hex decreased the inducible NO synthase (iNOS), cyclooxygenase 2 (COX2), and tumor necrosis factor (TNF)-alpha mRNA expression in LPS-stimulated RAW 264.7 macrophages. In addition, pre-treatment with GRC-ON89A Hex significantly inhibited LPS-stimulated phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-kappaB. To induce allergic contact dermatitis (ACD), 1-fluoro-2, 4-dinitrofluorobenzene (DNFB) was applied to the surface of the right ears of C57BL/6N mice. GRC-ON89A reduced the ear swelling and thickness in DNFB-induced ACD mice. This study demonstrates the potential usefulness of GRC-ON89A as an anti-inflammatory dietary supplement or drug. PMID- 30405051 TI - Anti-Cancer Drug Sensitivity Assay with Quantitative Heterogeneity Testing Using Single-Cell Raman Spectroscopy. AB - A novel anti-cancer drug sensitivity testing (DST) approach was developed based on in vitro single-cell Raman spectrum intensity (RSI). Generally, the intensity of Raman spectra (RS) for a single living cell treated with drugs positively relates to the sensitivity of the cells to the drugs. In this study, five cancer cell lines (BGC 823, SGC 7901, MGC 803, AGS, and NCI-N87) were exposed to three cytotoxic compounds or to combinations of these compounds, and then they were evaluated for their responses with RSI. The results of RSI were consistent with conventional DST methods. The parametric correlation coefficient for the RSI and Methylthiazolyl tetrazolium assay (MTT) was 0.8558 +/- 0.0850, and the coefficient of determination was calculated as R2 = 0.9529 +/- 0.0355 for fitting the dose-response curve. Moreover, RSI data for NCI-N87 cells treated by trastuzumab, everolimus (cytostatic), and these drugs in combination demonstrated that the RSI method was suitable for testing the sensitivity of cytostatic drugs. Furthermore, a heterogeneity coefficient H was introduced for quantitative characterization of the heterogeneity of cancer cells treated by drugs. The largest possible variance between RSs of cancer cells were quantitatively obtained using eigenvalues of principal component analysis (PCA). The ratio of H between resistant cells and sensitive cells was greater than 1.5, which suggested the H-value was effective to describe the heterogeneity of cancer cells. Briefly, the RSI method might be a powerful tool for simple and rapid detection of the sensitivity of tumor cells to anti-cancer drugs and the heterogeneity of their responses to these drugs. PMID- 30405050 TI - Lactobacillus rhamnosus GG Protects the Epithelial Barrier of Wistar Rats from the Pepsin-Trypsin-Digested Gliadin (PTG)-Induced Enteropathy. AB - Celiac disease (CD) is a chronic immune-mediated disorder, characterized by enhanced paracellular permeability across the intestinal epithelium. The complex system of intercellular junctions, including tight junctions (TJs) and adherens junctions (AJs), seals together the epithelial cells to form a continuous layer. The improvements in barrier integrity have been related to modifications in intercellular junction protein expression. Polyamines (spermidine, spermine, and putrescine) actively participate in the modulation of the AJ expression. Both in vitro and in vivo studies have demonstrated that also probiotics can promote the integrity and the function of the intestinal barrier. On these bases, the present work investigated the protective effects exerted by Lactobacillus rhamnosus GG (L.GG) against the pepsin-trypsin-digested gliadin (PTG)-induced enteropathy in jejunal tissue samples of Wistar rats. In particular, the probiotic effects have been evaluated on the intestinal mucosal architecture, polyamine metabolism and intercellular junction protein expression (ZO-1, Occludin, Claudin-1, beta catenin and E-cadherin). The results from this study indicate that L.GG protects the intestinal mucosa of rats from PTG-induced damage, by preventing the reduction of the expression of the intercellular junction proteins. Consequently, a role for L.GG in the therapeutic management of the gluten-related disorders in humans could be hypothesized. PMID- 30405053 TI - Emerging Role of Immune Checkpoint Blockade in Pancreatic Cancer. AB - Immune checkpoint blockade (ICB) with programmed cell death protein-1(PD 1)/programmed death ligand -1(PD-L1) antibodies has revolutionized the management of several cancers, especially non-small cell lung cancer, melanoma, urothelial, and renal cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers associated with high morbidity and mortality. Based on available data, it's obvious that ICB has limited success in PDACs, which can be explained by the low immunogenicity and immunosuppressive tumor microenvironment of these tumors. In this review article, we focus on PD-L1 expression and microsatellite instability (MSI) in PDAC, and their roles as prognostic and predictive markers. We also discuss data supporting combination therapies to augment cancer immunity cycle. Combining anti-PD-1/PD-L1 agents with other modalities such as vaccines, chemotherapy, and radiation could potentially overcome resistance patterns and increase immune responsiveness in PDAC. PMID- 30405054 TI - Complex Effect of Concrete Composition on the Thermo-Mechanical Behaviour of Mass Concrete. AB - The current work presents the complex investigation of the influence of cement and aggregate type on the thermo-mechanical behavior of mass concrete. Six types of cement with different amounts of non-clinker constituents and four types of aggregates are used in experimental tests. Particular attention was given to the low clinker cements with high amounts of siliceous fly ash and ground blast furnace slag. The experimental research covered the determination of thermal, mechanical, and rheological properties of early age concrete with different constituents. Experimental results have been used both to validate the numerical model and analysis of exemplary foundation slab. The results confirm the importance of the concrete mix composition and it has been shown that the early age volume deformation and possible cracking is the result of the concerted action of thermal and mechanical properties of concrete. The obtained results indicate granite as the best aggregate for mass concrete. Considering the type of cement, much better behaviour of mass concrete has been noted for cements with fly ash and composite cements containing both fly ash and slags than cements only with slag. PMID- 30405052 TI - A DNA Methylation-Based Test for Breast Cancer Detection in Circulating Cell-Free DNA. AB - BACKGROUND: Breast cancer (BrC) is the most frequent neoplasm in women. New biomarkers, including aberrant DNA methylation, may improve BrC management. Herein, we evaluated the detection and prognostic performance of seven genes' promoter methylation (APC, BRCA1, CCND2, FOXA1, PSAT1, RASSF1A and SCGB3A1). METHODS: Methylation levels were assessed in primary BrC tissues by quantitative methylation-specific polymerase chain reaction (QMSP) and in circulating cell free DNA (ccfDNA) by multiplex QMSP from two independent cohorts of patients (Cohort #1, n = 137; and Cohort #2, n = 44). Receiver operating characteristic (ROC) curves were constructed, and log-rank test and Cox regression were performed to assess the prognostic value of genes' methylation levels. RESULTS: The gene-panel APC, FOXA1, RASSF1A, SCGB3A1 discriminated normal from cancerous tissue with high accuracy (95.55%). In multivariable analysis, high PSAT1 methylation levels [>percentile 75 (P75)] associated with longer disease-free survival, whereas higher FOXA1-methylation levels (>P75) associated with shorter disease-specific survival. The best performing panel in ccfDNA (APC, FOXA1 and RASSF1A) disclosed a sensitivity, specificity and accuracy over 70%. CONCLUSIONS: This approach enables BrC accurate diagnosis and prognostic stratification in tissue samples, and allows for early detection in liquid biopsies, thus suggesting a putative value for patient management. PMID- 30405056 TI - ChREBP Reciprocally Regulates Liver and Plasma Triacylglycerol Levels in Different Manners. AB - Carbohydrate response element-binding protein (ChREBP) has an important role in the carbohydrate-mediated regulation of hepatic de novo lipogenesis, but the mechanism for how it regulates plasma triacylglycerol (TAG) levels has not been established. This study aimed to clarify the role of ChREBP in regulation of plasma TAG levels. We analyzed the metabolic changes in mice infected with an adenovirus expressing ChREBP Delta196 (Ad-ChREBP). Compared with adenovirus harboring green fluorescent protein infected mice, Ad-ChREBP-infected mice had higher plasma free fatty acid levels and paradoxically lower plasma 3 hydroxybutyrate levels through decreased fatty acid oxidation, rather than ketogenesis. Consistent with their hepatomegaly and increased lipogenic gene expression, the liver TAG contents were much higher. Regarding lipid composition, C16:0 was much lower and C18:1n-9 was much higher, compatible with increased stearoyl CoA desaturase-1 and ELOVL fatty acid elongase 6 expression. Furthermore, Ad-ChREBP-infected mice had decreased plasma TAG and very low density lipoprotein (VLDL)-TAG levels, consistent with decreased Angiopoietin like protein 3 (Angptl3) and increased fibroblast growth factor (Fgf21) mRNA and protein levels. Finally, Ad-ChREBP infection increased white adipose tissue Ucp1 mRNA levels with increased plasma Fgf21 levels. Because Fgf21 and Angptl3 are known to activate and suppress lipolysis in adipose tissues and oxidative tissues, ChREBP appears to regulate plasma TAG levels by modulating Fgf21 and Angptl3 levels. Thus, ChREBP overexpression led to dissociation of hepatic steatosis from hyperlipidemia. PMID- 30405057 TI - Characterization of the Escherichia coli Virulent Myophage ST32. AB - The virulent phage ST32 that infects the Escherichia coli strain ST130 was isolated from a wastewater sample in China and analyzed. Morphological observations showed that phage ST32 belongs to the Myoviridae family, as it has an icosahedral capsid and long contractile tail. Host range analysis showed that it exhibits a broad range of hosts including non-pathogenic and pathogenic E. coli strains. Interestingly, phage ST32 had a much larger burst size when amplified at 20 degrees C as compared to 30 degrees C or 37 degrees C. Its double-stranded DNA genome was sequenced and found to contain 53,092 bp with a GC content of 44.14%. Seventy-nine open reading frames (ORFs) were identified and annotated as well as a tRNA-Arg. Only nineteen ORFs were assigned putative functions. A phylogenetic tree using the large terminase subunit revealed a close relatedness with four unclassified Myoviridae phages. A comparative genomic analysis of these phages showed that the Enterobacteria phage phiEcoM-GJ1 is the closest relative to ST32 and shares the same new branch in the phylogenetic tree. Still, these two phages share only 47 of 79 ORFs with more than 90% identity. Phage ST32 has unique characteristics that make it a potential biological control agent under specific conditions. PMID- 30405058 TI - Organic Waste Buyback as a Viable Method to Enhance Sustainable Municipal Solid Waste Management in Developing Countries. AB - Many developing countries have inadequate Municipal Solid Waste (MSW) management systems due to lack of not only the awareness, technologies, finances, but also a proper governance that is able to enforce and monitor the regulations. Not all the solutions practiced by and in developed countries fit to the developing country contexts. The local conditions and limitations must always be taken into account when proposing waste management options for developing countries. The excessively high organic waste fraction in MSW and relatively inexpensive labor markets available in developing countries are two of the strengths that have not yet been utilized fully. This manuscript is an attempt to point out the benefits we receive from the above two strengths if we establish organic waste buyback programs. This can only become successful if we find solutions to: (1) collect source-separated organic waste, and then (2) find stable markets for the products made from organic waste. Compost or biogas could be the best bet developing countries can consider as products. However, there must be some policy interventions to support buyback programs at the waste collection stage as well as at the product marketing stage. Implementation of such organic waste buyback centers that can offer some incentives can indirectly motivate residents to do source separation. This will in turn also help promote more recycling, as any waste bin that has no organics in it is much easier for anyone (e.g., waste pickers) to look for other recyclables. Developing country settings such as the Green Container composting program in Cajica, Colombia, and buyback centers in South Africa that are presented later in the manuscript are thought to be the places where the concept can be implemented with little effort. The environment, economy, and society are considered to be the three dimensions (or pillars) of sustainability. Interestingly, the organic waste buyback centers solution has positive implications on all three aspects of sustainability. Thus, it also supports the 2030 Agenda of the United Nations (UN), by making specific contributions to the Sustainable Development Goals (SDGs) such as zero hunger (SDG 2), affordable and clean energy (SDG 7), climate action (SDG 13), clean water and sanitation (SDG 6), and sustainable cities and communities (SDG 11). PMID- 30405055 TI - Persistence and Intra-Host Genetic Evolution of Zika Virus Infection in Symptomatic Adults: A Special View in the Male Reproductive System. AB - We followed the presence of Zika virus (ZIKV) in four healthy adults (two men and two women), for periods ranging from 78 to 298 days post symptom onset. The patients were evaluated regarding the presence of the virus in different body fluids (blood, saliva, urine and semen), development of immune responses (including antibodies, cytokines and chemokines), and virus genetic variation within samples collected from semen and urine during the infection course. The analysis was focused primarily on the two male patients who shed the virus for up to 158 days after the initial symptoms. ZIKV particles were detected in the spermatozoa cytoplasm and flagella, in immature sperm cells and could also be isolated from semen in cell culture, confirming that the virus is able to preserve integrity and infectivity during replication in the male reproductive system (MRS). Despite the damage caused by ZIKV infection within the MRS, our data showed that ZIKV infection did not result in infertility at least in one of the male patients. This patient was able to conceive a child after the infection. We also detected alterations in the male genital cytokine milieu, which could play an important role in the replication and transmission of the virus which could considerably increase the risk of ZIKV sexual spread. In addition, full genome ZIKV sequences were obtained from several samples (mainly semen), which allowed us to monitor the evolution of the virus within a patient during the infection course. We observed genetic changes over time in consensus sequences and lower frequency intra-host single nucleotide variants (iSNV), that suggested independent compartmentalization of ZIKV populations in the reproductive and urinary systems. Altogether, the present observations confirm the risks associated with the long-term replication and shedding of ZIKV in the MRS and help to elucidate patterns of intra-host genetic evolution during long term replication of the virus. PMID- 30405061 TI - Generalized Self-Efficacy, Dispositional Optimism, and Illness Acceptance in Women with Polycystic Ovary Syndrome. AB - Polycystic ovary syndrome (PCOS) is one of the most common chronic endocrinopathies affecting between 5 and 10% of reproductive age women. A diagnosis of PCOS very often causes a deterioration in the woman's self-esteem and self-image, and consequently her quality of life (QoL). The purpose of the study was to investigate generalized self-efficacy, dispositional optimism and acceptance of illness in women with PCOS and to explore factors that affect these variables. The study was performed between January and November 2016 among women with PCOS using health care services. The study used a diagnostic survey with questionnaires. The research instruments included the Generalized Self-Efficacy Scale (GSES), the Life Orientation Test-Revised (LOT-R), the Acceptance of Illness Scale (AIS), and a standardized interview questionnaire. Among the PCOS patients studied, the mean score for generalized self-efficacy was 28.74 (+/ 5.16), dispositional optimism-13.56 (+/-4.28), and acceptance of illness-27.90 (+/-7.74). The respondents' generalized self-efficacy was determined by their residence, education, socio-economic standing, BMI, and time from diagnosis (p < 0.05), while socio-economic standing was a determinant of dispositional optimism (p < 0.05). Determinants of illness acceptance in women with PCOS included their residence, socio-economic standing, and time from diagnosis (p < 0.05). Increased generalized self-efficacy and dispositional optimism contributed to more illness acceptance in PCOS patients. The present study, compared with others on the subject, will enable specialists providing care to women with PCOS to gain a deeper and more comprehensive understanding of the situation and condition of their patients. It will also allow for a better response to the needs of PCOS patients, and provide them with individualized, holistic specialist care, diagnostics, and treatment. PMID- 30405060 TI - Versatility of Synthetic tRNAs in Genetic Code Expansion. AB - Transfer RNA (tRNA) is a dynamic molecule used by all forms of life as a key component of the translation apparatus. Each tRNA is highly processed, structured, and modified, to accurately deliver amino acids to the ribosome for protein synthesis. The tRNA molecule is a critical component in synthetic biology methods for the synthesis of proteins designed to contain non-canonical amino acids (ncAAs). The multiple interactions and maturation requirements of a tRNA pose engineering challenges, but also offer tunable features. Major advances in the field of genetic code expansion have repeatedly demonstrated the central importance of suppressor tRNAs for efficient incorporation of ncAAs. Here we review the current status of two fundamentally different translation systems (TSs), selenocysteine (Sec)- and pyrrolysine (Pyl)-TSs. Idiosyncratic requirements of each of these TSs mandate how their tRNAs are adapted and dictate the techniques used to select or identify the best synthetic variants. PMID- 30405059 TI - Insights on Allergic Rhinitis Management from a Northern Cyprus Perspective and Evaluation of the Impact of Pharmacist-Led Educational Intervention on Patients' Outcomes. AB - BACKGROUND AND OBJECTIVE: the global prevalence of allergic rhinitis (AR) is rising and yet there is scarce information concerning the diagnosis, management and treatment patterns of AR in Northern Cyprus (NC). This study aims to provide a unique perspective on AR management as well as assessing the effectiveness of the pharmacist-led educational intervention for improving care of AR patients. METHODS: across-sectional survey was carried out with community pharmacists (n = 70), patients (n = 138) and ear, nose and throat (ENT) specialists (n = 12) in NC. For a controlled interventional trial, trained pharmacists provided a brief education on management of AR and nasal spray technique for patients while other pharmacists provided the usual care. Quality of life (QoL) and other outcome measures on the perceived symptom severity of the two groups were compared after a 6-week period. RESULTS: only 33.3% of the ear, nose and throat (ENT) specialists and 15.7% of the community pharmacists are aware of the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines. The majority of patients (63%) self-managed with over-the-counter medications. Nasal congestion (96.4%) is the most bothersome symptom and oral antihistamines are the most commonly purchased medications (51.4%), indicating a pattern of suboptimal management. The pharmacists-led educational intervention has resulted in statistically more significant improvement in regards to nasal congestion and QoL for the intervention group patients (p < 0.05). CONCLUSION: the current management of AR has not been in accordance with the ARIA guidelines in NC. An educational intervention of the pharmacists can enhance the symptom management and improve the QoL in patients with AR. PMID- 30405062 TI - Combining the Photocatalysis and Absorption Properties of Core-Shell Cu-BTC@TiO2 Microspheres: Highly Efficient Desulfurization of Thiophenic Compounds from Fuel. AB - A core-shell Cu-benzene-1,3,5-tricarboxylic acid (Cu-BTC)@TiO2 was successfully synthesized for photocatalysis-assisted adsorptive desulfurization to improve adsorptive desulfurization (ADS) performance. Under ultraviolet (UV) light irradiation, the TiO2 shell on the surface of Cu-BTC achieved photocatalytic oxidation of thiophenic S-compounds, and the Cu-BTC core adsorbed the oxidation products (sulfoxides and sulfones). The photocatalyst and adsorbent were combined using a distinct core-shell structure. The morphology and structure of the fabricated Cu-BTC@TiO2 microspheres were verified by scanning electron microscopy, high-resolution transmission electron microscopy, energy-dispersive x ray spectroscopy, X-ray powder diffraction, nitrogen adsorption-desorption and X ray photoelectron spectroscopy analyses. A potential formation mechanism of Cu BTC@TiO2 is proposed based on complementary experiments. The sulfur removal efficiency of the microspheres was evaluated by selective adsorption of benzothiophene (BT) and dibenzothiophene (DBT) from a model fuel with a sulfur concentration of 1000 ppmw. Within a reaction time of 20 min, the BT and DBT conversion reached 86% and 95%, respectively, and achieved ADS capacities of 63.76 and 59.39 mg/g, respectively. The BT conversion and DBT conversion obtained using Cu-BTC@TiO2 was 6.5 and 4.6 times higher, respectively, than that obtained using Cu-BTC. A desulfurization mechanism was proposed, the interaction between thiophenic sulfur compounds and Cu-BTC@TiO2 microspheres was discussed, and the kinetic behavior was analyzed. PMID- 30405063 TI - Influence of Mediterranean Diet on Blood Pressure. AB - Hypertension is the main risk factor for cardiovascular disease (CVD) and all cause mortality. Some studies have reported that food typical of the Mediterranean diet (MedDiet), such as whole grains, vegetables, fruits, nuts, and extra virgin olive oil, have a favorable effect on the risk of hypertension, whereas food not typical of this dietary pattern such as red meat, processed meat, and poultry has an unfavorable effect. In this review, we have summarized observational and intervention studies, meta-analyses, and systematic reviews that have evaluated the effects of the MedDiet as a pattern towards blood pressure (BP). However, the number of such studies is small. In general terms, the MedDiet has a favorable effect in reducing BP in hypertensive or healthy people but we do not have enough data to declare how strong this effect is. Many more studies are required to fully understand the BP changes induced by the MedDiet. PMID- 30405064 TI - Active Food Packaging Coatings Based on Hybrid Electrospun Gliadin Nanofibers Containing Ferulic Acid/Hydroxypropyl-Beta-Cyclodextrin Inclusion Complexes. AB - In this work, hybrid gliadin electrospun fibers containing inclusion complexes of ferulic acid (FA) with hydroxypropyl-beta-cyclodextrins (FA/HP-beta-CD-IC) were prepared as a strategy to increase the stability and solubility of the antioxidant FA. Inclusion complex formation between FA and HP-beta-CD was confirmed by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimeter (DSC), and X-ray diffraction (XRD). After adjusting the electrospinning conditions, beaded-free fibers of gliadin incorporating FA/HP beta-CD-IC with average fiber diameters ranging from 269.91 +/- 73.53 to 271.68 +/- 72.76 nm were obtained. Control gliadin fibers containing free FA were also produced for comparison purposes. The incorporation of FA within the cyclodextrin molecules resulted in increased thermal stability of the antioxidant compound. Moreover, formation of the inclusion complexes also enhanced the FA photostability, as after exposing the electrospun fibers to UV light during 60 min, photodegradation of the compound was reduced in more than 30%. Moreover, a slower degradation rate was also observed when compared to the fibers containing the free FA. Results from the release into two food simulants (ethanol 10% and acetic acid 3%) and PBS also demonstrated that the formation of the inclusion complexes successfully resulted in improved solubility, as reflected from the faster and greater release of the compounds in the three assayed media. Moreover, in both types of hybrid fibers, the antioxidant capacity of FA was kept, thus confirming the suitability of electrospinning for the encapsulation of sensitive compounds, giving raise to nanostructures with potential as active packaging structures or delivery systems of use in pharmaceutical or biomedical applications. PMID- 30405065 TI - Identification of a 2'-O-Methyluridine Nucleoside Hydrolase Using the Metagenomic Libraries. AB - Ribose methylation is among the most ubiquitous modifications found in RNA. 2'-O methyluridine is found in rRNA, snRNA, snoRNA and tRNA of Archaea, Bacteria, and Eukaryota. Moreover, 2'-O-methylribonucleosides are promising starting materials for the production of nucleic acid-based drugs. Despite the countless possibilities of practical use for the metabolic enzymes associated with methylated nucleosides, there are very few reports regarding the metabolic fate and enzymes involved in the metabolism of 2'-O-alkyl nucleosides. The presented work focuses on the cellular degradation of 2'-O-methyluridine. A novel enzyme was found using a screening strategy that employs Escherichia coli uracil auxotroph and the metagenomic libraries. A 2'-O-methyluridine hydrolase (RK9NH) has been identified together with an aldolase (RK9DPA)-forming a part of a probable gene cluster that is involved in the degradation of 2'-O-methylated nucleosides. The RK9NH is functional in E. coli uracil auxotroph and in vitro. The RK9NH nucleoside hydrolase could be engineered to enzymatically produce 2'-O methylated nucleosides that are of great demand as raw materials for production of nucleic acid-based drugs. Moreover, RK9NH nucleoside hydrolase converts 5 fluorouridine, 5-fluoro-2'-deoxyuridine and 5-fluoro-2'-O-methyluridine into 5 fluorouracil, which suggests it could be employed in cancer therapy. PMID- 30405067 TI - Orthogonal Chirp Division Multiplexing for Underwater Acoustic Communication. AB - The objective of this study is to investigate a novel Underwater Acoustic Communication (UWAC) system based on a modulated chirp signal termed as Orthogonal Chirp Division Multiplexing (OCDM). Originating from the Fresnel transform, OCDM uses chirp signals to exploit the multipath diversity of the channel, achieving a good robustness against frequency fading, especially in the underloaded scenario where only a subset of the available waveforms is modulated. The implementation of the OCDM system for the UWAC scenario is described, and the performance results over an experimental water tank and realistic replayed underwater channel are compared against the traditional Orthogonal Frequency Division Multiplexing (OFDM) transmission scheme. PMID- 30405066 TI - Phloridzin, an Apple Polyphenol, Exerted Unfavorable Effects on Bone and Muscle in an Experimental Model of Type 2 Diabetes in Rats. AB - It is believed that apple fruits contain components with health-promoting effects, including some antidiabetic activity. One of the most known apple compounds is phloridzin, a glucoside of phloretin. Phloridzin and phloretin were reported to exert some favorable skeletal effects in estrogen-deficient rats and mice. The aim of the study was to investigate the effects of phloridzin on musculoskeletal system in rats with type 2 diabetes induced by a high-fat diet (HFD) and streptozotocin (STZ). The experiments were performed on mature female Wistar rats, divided into control rats (fed a standard laboratory diet), HFD/STZ control rats, and HFD/STZ rats receiving phloridzin (20 or 50 mg/kg/day per os) for four weeks. Serum biochemical parameters, muscle mass and strength, bone mass, density, histomorphometric parameters and mechanical properties were determined. The HFD/STZ rats developed hyperglycemia, with decreases in the muscle mass and strength and profound osteoporotic changes. Phloridzin at 20 mg/kg markedly augmented the unfavorable effects of diabetes on the muscle mass and strength and decreased growth of bones, whereas, at 50 mg/kg, it did not affect most of the investigated musculoskeletal parameters. Results of the study indicate the possibility of unfavorable effects of phloridzin on the musculoskeletal system in conditions of hyperglycemia. PMID- 30405068 TI - Cystic Fibrosis Gene Therapy: Looking Back, Looking Forward. AB - Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes a cAMP-regulated anion channel. Although CF is a multi-organ system disease, most people with CF die of progressive lung disease that begins early in childhood and is characterized by chronic bacterial infection and inflammation. Nearly 90% of people with CF have at least one copy of the DeltaF508 mutation, but there are hundreds of CFTR mutations that result in a range of disease severities. A CFTR gene replacement approach would be efficacious regardless of the disease-causing mutation. After the discovery of the CFTR gene in 1989, the in vitro proof-of concept for gene therapy for CF was quickly established in 1990. In 1993, the first of many gene therapy clinical trials attempted to rescue the CF defect in airway epithelia. Despite the initial enthusiasm, there is still no FDA-approved gene therapy for CF. Here we discuss the history of CF gene therapy, from the discovery of the CFTR gene to current state-of-the-art gene delivery vector designs. While implementation of CF gene therapy has proven more challenging than initially envisioned; thanks to continued innovation, it may yet become a reality. PMID- 30405069 TI - A Portable Phase-Domain Magnetic Induction Tomography Transceiver with Phase-Band Auto-Tracking and Frequency-Sweep Capabilities. AB - This paper presents a portable magnetic induction tomography (MIT) transceiver integrated circuit to miniaturize conventional equipment-based MIT systems. The miniaturized MIT function is enabled through single-chip transceiver implementation. The proposed MIT transceiver utilizes a phase-locked loop (PLL) for frequency sweeping and a phase-domain sigma-delta modulator with phase-band auto-tracking for a full-range fine-phase resolution. The designed transceiver is fabricated and verified to achieve the measured signal to noise and distortion ratio (SNDR) of 101.7 dB. Its system-level prototype including in-house magnetic sensor coils is manufactured and functionally verified for four different material types. PMID- 30405070 TI - Carcinogenic Potency of Airborne Polycyclic Aromatic Hydrocarbons in Relation to the Particle Fraction Size. AB - Polycyclic aromatic hydrocarbons (PAHs) that are bound to particulate matter can have adverse effects on human health. Particle size plays an important role in assessing health risks. The aim of this study was to compare concentrations of PAHs bound to particle fractions PM10, PM2.5, and PM1, as well as to estimate their carcinogenic potency and relative contributions of the individual PAHs to the carcinogenic potency in relation to the size of the particle. Measurements of ten PAHs were carried out in 2014 at an urban location in the northern part of Zagreb, Croatia. 24-h samples of the PM10, PM2.5, and PM1 particle fraction were collected over forty days per season. Carcinogenic potency of PAHs was estimated by calculating benzo(a)pyrene equivalent concentrations while using three different toxic equivalence factor (TEF) schemes. The total carcinogenic potency (TCP) and percentage contributions differed significantly depending on the TEF scheme used. The lowest PAH mass concentrations and TCPs were in summer and the highest in winter. The contributions of individual PAHs to the sum of PAH mass concentrations remained similar in all fractions and seasons, while in fractions PM10-2.5 and PM2.5-1 they varied significantly. Road traffic represented the important source of PAHs in all fractions and throughout all seasons. Other sources (wood and biomass burning, petroleum combustion) were also present, especially during winter as a consequence of household heating. The highest contribution to the TCP came from benzo(a)pyrene, dibenzo(ah)antrachene, indeno(1,2,3,cd)pyrene, and benzo(b)fluoranthene (together between 87% and 96%) in all fractions and seasons. In all cases, BaP showed the highest contribution to the TCP regardless relatively low contributions to the mass of total PAHs and it can be considered as a good representative for assessing the carcinogenicity of the PAH mixture. When comparing the TCP of PAHs in PM10 and PM2.5 fractions, it was found that about 21-26% of carcinogenic potency of the PAH mixture belonged to the PM2.5 fraction. Comparison of TCP in PM2.5 and PM1 showed that about 86% of carcinogenic potency belonged to the PM1 fraction, regardless of the TEF scheme used. PMID- 30405071 TI - Study on Cardiotoxicity and Mechanism of "Fuzi" Extracts Based on Metabonomics. AB - To investigate the toxicity of water and ethanol "Fuzi" (FZ) extracts and to explore the toxicity mechanism in rats. Water and ethanol extracts were prepared. Three groups of rats received the water extract, ethanol extract, or water by oral gavage for seven days. Pathological section staining of heart tissue. Colorimetric analysis was used to determine serum lactate dehydrogenase. The metabolic expression of small molecules in rats was measured by a metabolomics method. Western blotting was used to detect the expression of phosphoinositide 3 kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR), transforming growth factor-beta1 (TGF-beta1), and caspase-3. Immunohistochemistry was used to detect the expression of CTnI, mTOR, and TGF-beta1. The water and ethanol FZ extracts exert cardiotoxic effects via activating the PI3K/Akt/mTOR signaling pathway to induce cardiomyocyte apoptosis. PMID- 30405073 TI - Gas Phase Hydrogenation of Furaldehydes via Coupling with Alcohol Dehydrogenation over Ceria Supported Au-Cu. AB - We have investigated the synthesis and application of Au-Cu/CeO2 (Cu: Au = 2) in the continuous gas phase (P = 1 atm; T = 498 K) coupled hydrogenation of 5 hydroxymethyl-2-furaldehyde (HMF) with 2-butanol dehydrogenation. STEM-EDX analysis revealed a close surface proximity of both metals in Au-Cu/CeO2 post TPR. XPS measurements suggest (support -> metal) charge transfer to form Audelta- and strong metal-support interactions to generate Cu0 and Cu+. Au-Cu/CeO2 promoted the sole formation of 2,5-dihydroxymethylfuran (DHMF) and 2-butanone in the HMF/2-butanol coupling with full hydrogen utilisation. Under the same reaction conditions, Au/CeO2 was fully selective to DHMF in standard HMF hydrogenation (using an external hydrogen supply), but delivered a lower production rate and utilised less than 0.2% of the hydrogen supplied. Exclusive C=O hydrogenation and -OH dehydrogenation is also demonstrated for the coupling of a series of m-substituted (-CH3, -CH2CH3, -CH2OH, -CF3, -N(CH3)2, -H) furaldehydes with alcohol (1-propanol, 1-butanol, 2-propanol, 2-butanol, cyclohexanol) dehydrogenation over Au-Cu/CeO2, consistent with a nucleophilic mechanism. In each case, we observed a greater hydrogenation rate and hydrogen utilisation efficiency with a 3-15 times lower E-factor in the coupling process relative to standard hydrogenation. Our results demonstrate the feasibility of using hydrogen generated in situ through alcohol dehydrogenation for the selective hydrogenation of m-furaldehydes with important industrial applications. PMID- 30405072 TI - Physical Exercise Improves Glycemic and Inflammatory Profile and Attenuates Progression of Periodontitis in Diabetic Rats (HFD/STZ). AB - The authors aimed to evaluate the effects of physical exercise on the metabolism and progression of periodontal disease (PD), induced by ligature in diabetic rats induced by high fat diet and streptozotocin (HFD/STZ). Diabetes Mellitus (DM) was induced by four weeks of a hyperlipidic diet associated with a single low-dose of streptozotocin (35 mg/kg/animal). The exercise groups swam for 60 min/day for eight weeks (five times/week). In the last two weeks of exercise, a ligature was placed around the right and left mandibular first molars. The authors determined alveolar bone loss by morphometry. Blood biochemical profile and serum levels of IL-10 and TNF-alpha were evaluated by colorimetric and enzyme-linked immunosorbent assays (ELISA), respectively. The diabetic animals subjected to exercise showed decreased alveolar bone loss, lower glycemia, triacylglycerols and glycosylated hemoglobin levels than the controls. Total cholesterol and its fractions (High density lipoprotein-HDL-c, Low density lipoprotein-LDL-c and Very low density lipoprotein-VLDL-c) remained similar among the groups. Animals with PD showed higher levels of TNF-alpha and lower levels of IL-10, when compared to animals without PD. In diabetic animals with PD, physical exercise decreased TNF alpha levels and increased IL-10 levels as well as the IL10/TNF-alpha ratio. In conclusion, eight weeks of physical exercise improved glycemic control and systemic inflammatory profile, and attenuated alveolar bone loss in rats with DM and PD. PMID- 30405074 TI - Synthesis and Optimization of Chitosan Nanoparticles Loaded with L-Ascorbic Acid and Thymoquinone. AB - The combination of compounds with different classes (hydrophobic and hydrophilic characters) in single chitosan carrier is a challenge due to the hydrophilicity of chitosan. Utilization of l-ascorbic acid (LAA) and thymoquinone (TQ) compounds as effective antioxidants is marred by poor bioavailability and uptake. Nanoparticles (NPs) solved the problem by functioning as a carrier for them because they have high surface areas for more efficient delivery and uptake by cells. This research, therefore, synthesized chitosan NPs (CNPs) containing LAA and TQ, CNP-LAA-TQ via ionic gelation routes as the preparation is non-toxic. They were characterized using electron microscopy, zetasizer, UV-VIS spectrophotometry, and infrared spectroscopy. The optimum CNP-LAA-TQ size produced was 141.5 +/- 7.8 nm, with a polydispersity index (PDI) of 0.207 +/- 0.013. The encapsulation efficiency of CNP-LAA-TQ was 22.8 +/- 3.2% for LAA and 35.6 +/- 3.6% for TQ. Combined hydrophilic LAA and hydrophobic TQ proved that a myriad of highly efficacious compounds with poor systemic uptake could be encapsulated together in NP systems to increase their pharmaceutical efficiency, indirectly contributing to the advancement of medical and pharmaceutical sectors. PMID- 30405075 TI - Superhydrophobic Surface Preparation and Wettability Transition of Titanium Alloy with Micro/Nano Hierarchical Texture. AB - Microstructures are applied to various hydrophobic/hydrophilic surfaces due to the role of adjusting the surface wettability. In this paper, a 1064 nm pulsed picosecond laser was applied to prepare a micro/nano hierarchical structure on the surface of the titanium alloy (Ti-6Al-4V). The microstructures consist of dimple arrays with various diameters, depths, and areal densities. They are obtained by controlling the pulse energy and the number of pulses. The nanostructures are periodic ripples, which are defined as laser-induced periodic surface structure (LIPSS), and the dimensional parameter of LIPSS can be adjusted by changing the laser energy density and scanning speed. The contact angles of various laser textured surfaces were measured. It is found that the contact angle increases with the density of micro-textured surface increases, and the wetting state of textured surfaces conforms to the Cassie model. Some laser processed samples were subjected to low-temperature annealing treatment. It is observed that the low-temperature annealing process can accelerate the surface wettability transition significantly, which is attributed to the change of the hydroxyl groups on the surface. Finally, a superhydrophobic surface with the maximum contact angle of 144.58 degrees is obtained. PMID- 30405077 TI - The Balancing Act in Ferroelectric Transistors: How Hard Can It Be? AB - For some years now, the ever continuing dimensional scaling has no longer been considered to be sufficient for the realization of advanced CMOS devices. Alternative approaches, such as employing new materials and introducing new device architectures, appear to be the way to go forward. A currently hot approach is to employ ferroelectric materials for obtaining a positive feedback in the gate control of a switch. This work elaborates on two device architectures based on this approach: the negative-capacitance and the piezoelectric field effect transistor, i.e., the NC-FET (negative-capacitance field-effect transistor), respectively pi -FET. It briefly describes their operation principle and compares those based on earlier reports. For optimal performance, the adopted ferroelectric material in the NC-FET should have a relatively wide polarization field loop (i.e., "hard" ferroelectric material). Its optimal remnant polarization depends on the NC-FET architecture, although there is some consensus in having a low value for that (e.g., HZO (Hafnium-Zirconate)). pi -FET is the piezoelectric coefficient, hence its polarization-field loop should be as high as possible (e.g., PZT (lead-zirconate-titanate)). In summary, literature reports indicate that the NC-FET shows better performance in terms of subthreshold swing and on-current. However, since its operation principle is based on a relatively large change in polarization the maximum speed, unlike in a pi -FET, forms a big issue. Therefore, for future low-power CMOS, a hybrid solution is proposed comprising both device architectures on a chip where hard ferroelectric materials with a high piezocoefficient are used. PMID- 30405076 TI - Supplementation of Abelmoschus manihot Ameliorates Diabetic Nephropathy and Hepatic Steatosis by Activating Autophagy in Mice. AB - Diabetic nephropathy (DN) is a diabetic complication marked by albuminuria and a decline of the glomerular filtration rate. Diabetic kidneys are defective in the autophagy process and mitochondrial function and their enhancement of activity alleviates the pathology. In this paper, we developed a mouse model of DN by a combined treatment of a high-fat diet and streptozotocin after unilateral nephrectomy and supplementation with flower or leaf extracts of Abelmoschus manihot (AM) were tested. The preventive effects of the extracts on DN pathology and changes on autophagy and mitochondrial proteins were investigated. DN mice showed a significant increase in fasting blood glucose, plasma creatinine, blood urea nitrogen, and urinary albumin levels. Periodic acid-Schiff and Sirius red staining of the diabetic kidney presented a significant change in glomerular and tubular structures that was associated with podocyte loss and fibrotic protein accumulation. These changes were attenuated by AM extract treatment in DN mice. In addition, hepatic injury, proinflammatory cytokines, and lipid accumulation were decreased by AM extracts in DN mice. As a protective mechanism, AM extracts significantly increased the expression of proteins by regulating autophagy and mitochondrial dynamics, which potentially prevented the kidney and liver from accumulating pathogenic proteins and dysfunctional mitochondria, which alleviated the progression of DN. PMID- 30405078 TI - Genome Instability Induced by Low Levels of Replicative DNA Polymerases in Yeast. AB - Most cells of solid tumors have very high levels of genome instability of several different types, including deletions, duplications, translocations, and aneuploidy. Much of this instability appears induced by DNA replication stress. As a model for understanding this type of instability, we have examined genome instability in yeast strains that have low levels of two of the replicative DNA polymerases: DNA polymerase alpha and DNA polymerase delta (Polalpha and Poldelta). We show that low levels of either of these DNA polymerases results in greatly elevated levels of mitotic recombination, chromosome rearrangements, and deletions/duplications. The spectrum of events in the two types of strains, however, differs in a variety of ways. For example, a reduced level of Poldelta elevates single-base alterations and small deletions considerably more than a reduced level of Polalpha. In this review, we will summarize the methods used to monitor genome instability in yeast, and how this analysis contributes to understanding the linkage between genome instability and DNA replication stress. PMID- 30405079 TI - Evaluation of 99 Pesticide Residues in Major Agricultural Products from the Western Highlands Zone of Cameroon Using QuEChERS Method Extraction and LC-MS/MS and GC-ECD Analyses. AB - There is no information available on pesticide residue levels in major food commodities harvested in Cameroon, especially from the western highlands region, the food basket of the country. Hence, this study evaluated the residues of 99 pesticides in 72 samples of 12 agricultural products collected in the region, using QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) method extraction, and analyzed by liquid chromatography tandem mass spectrometry (LC MS/MS) and gas chromatography with electron capture detection (GC-ECD). This method was suitable for detecting the targeted compounds: For 81 pesticides by LC MS/MS, the limit of quantification (LOQ) was between 0.0004 and 0.0537 mg/kg; and for 18 halogenated pesticides by GC-ECD, it ranged from 0.0012 to 0.2180 mg/kg. The residues of 62 pesticides, including 12 banned compounds, were found in the samples. Insecticides (39.7%) were the most prevalent group, with all the samples containing at least one pesticide. Twenty-one pesticides (34.4%) exceeded their European Union maximum residue limits (MRLs) and 22 pesticides (34.4%) were found in all 6 sampling locations. Malathion and p,p'-DDT were the most distributed pesticides, found in almost all the samples and sampling sites. Food items with the highest rates of positive results were chili pepper (23.2%), white pepper (20.2%), kidney beans (17.3%), and soybeans (17.2%). Samples with residues above their MRLs represented 38% of all the positive analyses; chili pepper (6.4%) and kidney beans (5.5%) were found to have the most residues above their MRLs. The most critical food commodities were kidney beans, soybeans, chili pepper, and maize. This data presents scientific evidence that investigation into continuous monitoring and good regulation of pesticide usage in Cameroon is needed, and paves the way for health risks analysis. PMID- 30405080 TI - Low-Power Low-Cost Wireless Flood Sensor for Smart Home Systems. AB - This paper presents the design of a wireless flood sensor to detect the presence of water on home floors, providing early warning of water leaks. A wireless sensor network has been deployed to gather the measurements from the sensor nodes. A control central coordinates the network and processes the data. Users can remotely inquire for the presence of water, status of the batteries for a specific node, the type of liquid and information about its functionality and alarms, thanks to a proprietary software application. The alerts are also communicated to the user within the home through an audible siren. The designed device is optimized in terms of costs, ease of deployment and maintenance, thus making it widely acceptable to end users. PMID- 30405081 TI - Valorization of Tomato Processing by-Products: Fatty Acid Extraction and Production of Bio-Based Materials. AB - A method consisting of the alkaline hydrolysis of tomato pomace by-products has been optimized to obtain a mixture of unsaturated and polyhydroxylated fatty acids as well as a non-hydrolysable secondary residue. Reaction rates and the activation energy of the hydrolysis were calculated to reduce costs associated with chemicals and energy consumption. Lipid and non-hydrolysable fractions were chemically (infrared (IR) spectroscopy, gas chromatography/mass spectrometry (GC MS)) and thermally (differential scanning calorimetry (DSC), thermogravimetric analysis (TGA)) characterized. In addition, the fatty acid mixture was used to produce cutin-based polyesters. Freestanding films were prepared by non-catalyzed melt-polycondensation and characterized by Attenuated Total Reflected-Fourier Transform Infrared (ATR-FTIR) spectroscopy, solid-state nuclear magnetic resonance (NMR), DSC, TGA, Water Contact Angles (WCA), and tensile tests. These bio-based polymers were hydrophobic, insoluble, infusible, and thermally stable, their physical properties being tunable by controlling the presence of unsaturated fatty acids and oxygen in the reaction. The participation of an oxidative crosslinking side reaction is proposed to be responsible for such modifications. PMID- 30405082 TI - Transcriptomic and Genomic Approaches for Unravelling Candida albicans Biofilm Formation and Drug Resistance-An Update. AB - Candida albicans is an opportunistic fungal pathogen, which causes a plethora of superficial, as well as invasive, infections in humans. The ability of this fungus in switching from commensalism to active infection is attributed to its many virulence traits. Biofilm formation is a key process, which allows the fungus to adhere to and proliferate on medically implanted devices as well as host tissue and cause serious life-threatening infections. Biofilms are complex communities of filamentous and yeast cells surrounded by an extracellular matrix that confers an enhanced degree of resistance to antifungal drugs. Moreover, the extensive plasticity of the C. albicans genome has given this versatile fungus the added advantage of microevolution and adaptation to thrive within the unique environmental niches within the host. To combat these challenges in dealing with C. albicans infections, it is imperative that we target specifically the molecular pathways involved in biofilm formation as well as drug resistance. With the advent of the -omics era and whole genome sequencing platforms, novel pathways and genes involved in the pathogenesis of the fungus have been unraveled. Researchers have used a myriad of strategies including transcriptome analysis for C. albicans cells grown in different environments, whole genome sequencing of different strains, functional genomics approaches to identify critical regulatory genes, as well as comparative genomics analysis between C. albicans and its closely related, much less virulent relative, C. dubliniensis, in the quest to increase our understanding of the mechanisms underlying the success of C. albicans as a major fungal pathogen. This review attempts to summarize the most recent advancements in the field of biofilm and antifungal resistance research and offers suggestions for future directions in therapeutics development. PMID- 30405083 TI - Erratum: Zare, A. et al. RIPK2: New Elements in Modulating Inflammatory Breast Cancer Pathogenesis. Cancers, 2018, 10, 184. AB - The authors wish to make the following correction to their paper [...]. PMID- 30405084 TI - Real Evaluations Tractability using Continuous Goal-Directed Actions in Smart City Applications. AB - One of the most important challenges of Smart City Applications is to adapt the system to interact with non-expert users. Robot imitation frameworks aim to simplify and reduce times of robot programming by allowing users to program directly through action demonstrations. In classical robot imitation frameworks, actions are modelled using joint or Cartesian space trajectories. They accurately describe actions where geometrical characteristics are relevant, such as fixed trajectories from one pose to another. Other features, such as visual ones, are not always well represented with these pure geometrical approaches. Continuous Goal-Directed Actions (CGDA) is an alternative to these conventional methods, as it encodes actions as changes of any selected feature that can be extracted from the environment. As a consequence of this, the robot joint trajectories for execution must be fully computed to comply with this feature-agnostic encoding. This is achieved using Evolutionary Algorithms (EA), which usually requires too many evaluations to perform this evolution step in the actual robot. The current strategies involve performing evaluations in a simulated environment, transferring only the final joint trajectory to the actual robot. Smart City applications involve working in highly dynamic and complex environments, where having a precise model is not always achievable. Our goal is to study the tractability of performing these evaluations directly in a real-world scenario. Two different approaches to reduce the number of evaluations using EA, are proposed and compared. In the first approach, Particle Swarm Optimization (PSO) based methods have been studied and compared within the CGDA framework: naive PSO, Fitness Inheritance PSO (FI-PSO), and Adaptive Fuzzy Fitness Granulation with PSO (AFFG-PSO). The second approach studied the introduction of geometrical and velocity constraints within the CGDA framework. The effects of both approaches were analyzed and compared in the "wax" and "paint" actions, two CGDA commonly studied use cases. Results from this paper depict an important reduction in the number of required evaluations. PMID- 30405086 TI - Computerized Ultrasonic Imaging Inspection: From Shallow to Deep Learning. AB - For many decades, ultrasonic imaging inspection has been adopted as a principal method to detect multiple defects, e.g., void and corrosion. However, the data interpretation relies on an inspector's subjective judgment, thus making the results vulnerable to human error. Nowadays, advanced computer vision techniques reveal new perspectives on the high-level visual understanding of universal tasks. This research aims to develop an efficient automatic ultrasonic image analysis system for nondestructive testing (NDT) using the latest visual information processing technique. To this end, we first established an ultrasonic inspection image dataset containing 6849 ultrasonic scan images with full defect/no-defect annotations. Using the dataset, we performed a comprehensive experimental comparison of various computer vision techniques, including both conventional methods using hand-crafted visual features and the most recent convolutional neural networks (CNN) which generate multiple-layer stacking for representation learning. In the computer vision community, the two groups are referred to as shallow and deep learning, respectively. Experimental results make it clear that the deep learning-enabled system outperformed conventional (shallow) learning schemes by a large margin. We believe this benchmarking could be used as a reference for similar research dealing with automatic defect detection in ultrasonic imaging inspection. PMID- 30405087 TI - A Unified Deep-Learning Model for Classifying the Cross-Country Skiing Techniques Using Wearable Gyroscope Sensors. AB - The automatic classification of cross-country (XC) skiing techniques using data from wearable sensors has the potential to provide insights for optimizing the performance of professional skiers. In this paper, we propose a unified deep learning model for classifying eight techniques used in classical and skating styles XC-skiing and optimize this model for the number of gyroscope sensors by analyzing the results for five different configurations of sensors. We collected data of four professional skiers on outdoor flat and natural courses. The model is first trained over the flat course data of two skiers and tested over the flat and natural course data of a third skier in a leave-one-out fashion, resulting in a mean accuracy of ~80% over three combinations. Secondly, the model is trained over the flat course data of three skiers and tested over flat course and natural course data of one new skier, resulting in a mean accuracy of 87.2% and 95.1% respectively, using the optimal sensor configuration (five gyroscope sensors: both hands, both feet, and the pelvis). High classification accuracy obtained using both approaches indicates that this deep learning model has the potential to be deployed for real-time classification of skiing techniques by professional skiers and coaches. PMID- 30405085 TI - Aggregation-Induced Emission (AIE) Polymeric Micelles for Imaging-Guided Photodynamic Cancer Therapy. AB - Photodynamic therapy (PDT) is a noninvasive treatment for selectively killing malignant tumor cells. The photosensitizer is a necessary component of photodynamic nanomedicine. Many efforts have been made to develop new photosensitizers for efficient cancer photodynamic therapy. In this work, we report a novel nano photosensitizer, polymeric micelles (AIE-M) with aggregation induced emission characteristic, for photodynamic cancer therapy. AIE-M with sub 20 nm particle size is prepared by the self-assembly of salicylaldazine incorporated amphiphilic polymer (AIE-1), which can produce reactive oxygen species (ROS) with light irradiation in solution. After uptake by cancer cells, AIE-M can specially sojourn in plasma membranes of cancer cells at the early stage and predominantly accumulate in the mitochondria of cancer cell at the late stage. The phototoxicity of AIE-M, resulting from the generation of intracellular ROS with light irradiation, can efficiently cause cancer cells death by apoptosis and necrosis. The advantages of AIE-M as a nano photosensitizer include the small size, highly colloidal stability in the process of preparation and storage, and high cell penetration. The ultra-low Critical Micelle Concentration (CMC) of AIE 1, negligible dark toxicity and super phototoxicity of AIE-M suggest its promising potential for image-guided PDT. PMID- 30405089 TI - Co-Delivery of Gemcitabine and Paclitaxel in cRGD-Modified Long Circulating Nanoparticles with Asymmetric Lipid Layers for Breast Cancer Treatment. AB - Combination chemotherapy is a common clinical practice in cancer treatment. Here, cyclic RGD (arginylglycylaspartic acid) peptide was introduced to the surface of lipid/calcium/phosphate (LCP) asymmetric lipid layer nanoparticles for the co delivery of paclitaxel (PTX) and gemcitabine monophosphate (GMP) (P/G-NPs). The sphere-like morphology of P/G-NPs displays a well-distributed particle size, and high entrapment efficiency and drug loading for both PTX and GMP, with a positive zeta potential. P/G-NPs were stable for up to 15 days. The cellular uptake of these cyclic RGD-modified nanoparticles was significantly higher than that of unmodified nanoparticles over 2 h incubation. Compared with the combination of free PTX and GMP (P/G-Free), P/G-NPs exhibited a longer circulation lifetime and improved absorption for PTX and GMP. Polyethylene glycol was responsible for a higher plasma concentration and a decreased apparent volume of distribution (Vz). Nanoparticles enhanced the drug accumulation in tumors compared with other major organs after 24 h. P/G-NPs nearly halted tumor growth, with little evidence of general toxicity, whereas P/G-Free had only a modest inhibitory effect at 16 mg/kg of GMP and 2.0 mg/kg of PTX. Increased levels of apoptosis within tumors were detected in P/G-NPs group by approximately 43.6% (TUNEL assay). When compared with GMP NPs, PTX NPs, and P/G-Free, P/G-NPs decreased expression of B cell lymphoma-2 and B-cell lymphoma-extra large proteins, and increased expression of cleaved poly-ADP-ribose polymerase-1. Calreticulin expression in tumors also increased upon the co-delivery of PTX and GMP. The antitumor effect of P/G-NPs is more powerful than P/G-Free, GMP NP, or PTX NP alone, without obvious toxicity. PMID- 30405088 TI - Lifestyle Interventions in Overweight and Obese Pregnant or Postpartum Women for Postpartum Weight Management: A Systematic Review of the Literature. AB - Excessive gestational weight gain (GWG) and postpartum weight retention (PPWR) may predispose women to the development of obesity. The objective of this systematic review was to evaluate the effectiveness of lifestyle interventions in overweight or obese pregnant and/or postpartum women for managing postpartum weight up to 2 years after giving birth. Eighteen randomised controlled trials were included (2559 participants) and divided into three categories according to the timing of the intervention: pregnancy only (n = 3), postpartum only (n = 12) and pregnancy and postpartum (n = 3). The intervention duration varied from 10 weeks to 10 months and included diet only (n = 5) or diet and physical activity (n = 13). Seven postpartum only interventions reported significant improvements in postpartum weight when compared to the control group. Most of these interventions were short and intensive, lasting 10-16 weeks. One pregnancy only and one pregnancy and postpartum intervention reported reduced PPWR at 6 months. Nine trials did not report an effect of the intervention on postpartum weight. However, of these, four reported associations between GWG and PPWR. This review suggests that successful postpartum weight management is achievable with intensive lifestyle interventions starting in the postpartum period; however, there is insufficient evidence to conclude whether interventions starting in pregnancy are effective. Larger trials utilising comparative methodologies in the pregnancy and postpartum periods are required to inform the development of targeted strategies preventing PPWR or reducing postpartum weight. PMID- 30405090 TI - Effective Degradation of Rh 6G Using Montmorillonite-Supported Nano Zero-Valent Iron under Microwave Treatment. AB - Nano zero-valent iron has drawn great attention for the degradation of organic dyes due to its high reactivity, large specific surface area, lightweight, and magnetism. However, the aggregation and passivation of iron nanoparticles may prohibit the wide use of it. A new composite material was prepared by loading nano zero-valent iron (nZVI) on montmorillonite (MMT) to overcome the above shortcomings and it was further used for the removal of Rhodamine 6G (Rh 6G) under microwave treatment in the present work. The effects of various parameters, including the initial concentration of Rh 6G, microwave power, and pH value were investigated. The new composite material (nZVI/MMT) showed an excellent degradation ability for removing Rh 6G, and the removal amount reached 500 mg/g within 15 min. The degradation rate reached 0.4365 min-1, significantly higher than most previous reports using other removal methods for Rh 6G. PMID- 30405091 TI - Defect-Induced Tunable Permittivity of Epsilon-Near-Zero in Indium Tin Oxide Thin Films. AB - Defect-induced tunable permittivity of Epsilon-Near-Zero (ENZ) in indium tin oxide (ITO) thin films via annealing at different temperatures with mixed gases (98% Ar, 2% O2) was reported. Red-shift of lambdaENZ (Epsilon-Near-Zero wavelength) from 1422 nm to 1995 nm in wavelength was observed. The modulation of permittivity is dominated by the transformation of plasma oscillation frequency and carrier concentration depending on Drude model, which was produced by the formation of structural defects and the reduction of oxygen vacancy defects during annealing. The evolution of defects can be inferred by means of X-ray diffraction (XRD), atomic force microscopy (AFM), and Raman spectroscopy. The optical bandgaps (Eg) were investigated to explain the existence of defect states. And the formation of structure defects and the electric field enhancement were further verified by finite-difference time domain (FDTD) simulation. PMID- 30405093 TI - A Rare Case of Primary Hyperparathyroidism Caused by a Giant Solitary Parathyroid Adenoma. AB - BACKGROUND Solitary parathyroid adenomas are the leading cause of primary hyperparathyroidism in 0% to 85% of cases. Diagnosis of parathyroid adenoma is based on typical clinical presentation of hypercalcemia, biochemical profile, and modern imaging studies. The purpose of this article is to present the diagnostic and therapeutic approach used for a 73-year-old female patient with a giant parathyroid adenoma measuring 5*2.5*2.5 cm and weighing 30 grams. CASE REPORT A 73-year-old female was referred to the outpatient clinic of our Surgical Department with the diagnosis of primary hyperparathyroidism. The patient suffered from typical symptoms of hypercalcemia such as weakness, bone disease, and recurrent nephrolithiasis; she had a painless cervical mass for 5 months. Primary hyperparathyroidism was confirmed based on the patient's biochemical profile, which showed increased levels of serum calcium and parathyroid hormone. SestaMIBI scintigraphy with 99mTechnetium and cervical ultrasonography revealed a large nodule at the inferior pole of the right lobe of the thyroid gland. Intraoperatively, a giant parathyroid adenoma was found and excised. Additionally, levels of intact parathyroid hormone (IOiPTH) were determined intraoperatively and a 95% reduction was found, 20 minutes after the removal of the adenoma. CONCLUSIONS This is an extremely rare case of a giant solitary parathyroid adenoma. Diagnosis of a giant hyperfunctioning solitary parathyroid adenomas was based on clinical presentation, biochemical profile, and imaging studies. Selective treatment was based on surgical excision combined with IOiPTH levels measurement. PMID- 30405092 TI - Motility Disorders in Celiac Disease and Non-Celiac Gluten Sensitivity: The Impact of a Gluten-Free Diet. AB - Background: There is evidence that digestive motor disorders are frequently present in untreated celiac disease (CD) patients. Similarly, non-celiac gluten sensitivity (NCGS) can be associated with gut motor disorders. In both cases, gut dysmotility can improve or be completely reversed with a gluten-free diet (GFD). Methods: A literature search for motility disorders in CD and NCGS patients was carried out using the online databases PubMed, Medline and Cochrane. Results: Esophageal, gastric, small bowel and gallbladder motor disorders are common in both children and adults with CD. Although the clinical consequences of these disorders are not clearly defined, gastric dysfunction could affect drug absorption and metabolism in the thyroid and neurological conditions associated with CD. The impact of a GFD on motility disorders is, however, controversial. No systematic studies are available on NCGS. NCGS frequently overlaps with irritable bowel syndrome (IBS) and similar pathophysiological mechanisms may be hypothesized. Conclusions: Mucosal damage may affect gut motility in untreated CD through perturbation of hormonal and neuro-immunomodulatory regulation. A persistent low-grade mucosal inflammation could explain the cases of persistent motor disorders despite a GFD. Further studies are needed to definitely assess the role of gut motor disorders in NCGS. PMID- 30405094 TI - Efficacy and Safety of gonadotropin-releasing hormone (GnRH) Agonists Triptorelin Acetate and Cetrorelix Acetate in Assisted Reproduction. AB - BACKGROUND The aim of this study was to compare the efficacy and safety of 2 GnRH agonists - triptorelin acetate and cetrorelix acetate - in assisted reproduction. MATERIAL AND METHODS A total of 182 females who received in vitro fertilization and embryo transfer (IVF+ET) from March 2014 to July 2014 were involved, and their clinical data were retrospectively analyzed. Among them, 91 patients received treatment with short-acting triptorelin (group A) and another 91 patients were treated with cetrorelix acetate (group B). Fasting blood was extracted from each patient on the day of administration of human chorionic gonadotropin (hCG), and serum levels of luteinizing hormone (LH), estradiol (E2), and progesterone (P) were detected using chemiluminescence method. The number of oocytes, fertilization rate, cleavage rate, and number of obtained embryos were recorded and compared. Pregnancy outcomes and adverse events were observed and compared. Expression level of FSH receptor (FSHR) in endometrial tissues was measured by qRT-PCR. RESULTS Serum level of E2 was significantly lower in group B than in group A (p<0.05). Indices, including the number of oocytes, fertilization rate and cleavage rate, number of obtained embryos, and pregnancy rate, were slightly better in group B than in group A, but no significant differences were found. The incidence of ovarian hyperstimulation syndrome (OHSS) was significant higher in group A than in group B (p<0.05). FSHR expression level was significantly lower in group B than in group A. CONCLUSIONS The effect of cetrorelix acetate is superior to that of short-acting triptorelin in assisted reproduction. Our most important finding is that cetrorelix acetate reduced the incidence of OHSS. PMID- 30405095 TI - [Knowledge in child safety for parents of children 1 to 4 years old]. AB - OBJECTIVE: Unintentional injuries are the leading cause of child morbidity and mortality, Emergency Services can be a good place to influence their prevention, guiding and anticipating risk situations. The objective of this work was to determine the knowledge and attitude of parents-caregivers of children from one to four years old about child safety. We evaluate if there are differences according the consultation was for unintentional injury or not. METHODS: Study of cross-sectional surveys performed in an Emergency Health Service during 44 days randomly chosen between two periods (10 / 2015 - 01 / 2016 and 10 / 2016 - 01 / 2017). The parents-caregivers of children between one and four years old were surveyed. For each child with unintentional injury (GROUP1) two other children were included with another reason of consultation (GROUP2). The Framingham Security Survey was used. It was considered that the knowledge and attitude of the parents-caregivers was adequate if the proportion of correct answers was >=75%. The data was analyzed with the statistical program SPSS v 22.0 for Windows. RESULTS: 499 parents-caregivers responded to the survey; 170 belonged to GROUP1 and 329 belonged to GROUP2. The median of correct answers was 27/39 (69.2%) in both groups. The variables where more incorrect answers were detected were: lack of security in front of a fire (409, 82%) and absence of window bars (402, 80.6%). Forty-five (26.5%) parents-caregivers of GROUP1 and 94 (28.6%) of GROUP2 answered correctly>=75% of the questions (p = 0.620); According to the age of children, 34.8% of parents- caregivers of children aged one year, 26.9% of the one aged two years, 26.8% of the ones aged three years and 17.9% of the ones aged four years (p = 0.007) answered correctly the questions. CONCLUSIONS: The knowledge of families to prevent unintentional injuries was low, whether or not it was the reason for consultation. A relaxation in the security measures was detected when increasing the autonomy of the children. PMID- 30405096 TI - Prefibrotic myelofibrosis: treatment algorithm 2018. AB - Prefibrotic myelofibrosis (pre-PMF) is a distinct entity among chronic myeloproliferative neoplasm diagnosed according to the revised 2016 WHO classification. The clinical picture is heterogeneous, ranging from isolated thrombocytosis, mimicking essential thrombocythemia (ET), to symptoms of high risk PMF. Retrospective studies showed that survival of patients with pre-PMF is worse than that of ET and better than overt PMF. Whilst a specific prognostic score is lacking, the International Prognostic Scoring System is able to predict survival in pre-PMF patients, yet failing to separate intermediate-1 and -2 groups, and can be used in clinical practice. Each patient should be evaluated for, and interventions adapted to, both life-expectancy and the risk of bleeding and thrombosis. In low-risk patients with expected long survival, observation only is recommended; in cumulated intermediate-1 and -2 risk cases, whose median survival is projected at more than 10 years, treatment is based on symptoms; in high risk cases, with median survival lower than 5 years, intensive management is required. A pragmatic approach to address the risk of bleeding and thrombosis includes: no treatment or low-dose aspirin in asymptomatic patients; aspirin or oral anticoagulation if previous arterial or venous thrombosis, and hydroxyurea as first-line cytoreduction in case of thrombocytosis or leukocytosis. PMID- 30405097 TI - Longer procoagulant phospholipid-dependent clotting time, lower endogenous thrombin potential and higher tissue factor pathway inhibitor concentrations are associated with increased VTE occurrence in patients with newly diagnosed multiple myeloma: results of the prospective ROADMAP-MM-CAT study. AB - Venous thromboembolism (VTE) is a common complication in newly diagnosed symptomatic multiple myeloma (NDMM) patients. We explored cellular and plasma hypercoagulability in NDMM patients to identify relevant biomarkers that can be used in combination with clinical factors in the development of a risk assessment model (RAM) for VTE. Untreated patients (n = 144) with NDMM were prospectively enrolled, baseline biomarkers prior to anti-myeloma treatment and thromboprophylaxis initiation were obtained. These were compared against values in a group of healthy individuals with similar age and sex distribution. The primary study end point was symptomatic VTE occurrence. At 12-month follow-up cumulative VTE rate was 10.4%. NDMM patients showed biological signs of cellular and plasma hypercoagulability and endothelial cell activation. Procoagulant phospholipid clotting time (Procoagulant-PPL) was shorter, P-selectin levels lower and thrombin generation attenuated overall compared to healthy subjects. Longer Procoag-PPL(r), lower endogenous thrombin potential (ETP), and higher levels of tissue factor pathway inhibitor (TFPI) were associated with VTE occurrence. Multivariate analysis showed that Procoag-PPL(r) and ETP were independent risk factors for VTE. We conclude that Procoag-PPL(r) and ETP can be prospectively incorporated into a RAM for VTE in MM in combination with clinical and disease risk factors. PMID- 30405099 TI - Chiral domain wall motion in unit-cell thick perpendicularly magnetized Heusler films prepared by chemical templating. AB - Heusler alloys are a large family of compounds with complex and tunable magnetic properties, intimately connected to the atomic scale ordering of their constituent elements. We show that using a chemical templating technique of atomically ordered X'Z' (X' = Co; Z' = Al, Ga, Ge, Sn) underlayers, we can achieve near bulk-like magnetic properties in tetragonally distorted Heusler films, even at room temperature. Excellent perpendicular magnetic anisotropy is found in ferrimagnetic X3Z (X = Mn; Z = Ge, Sn, Sb) films, just 1 or 2 unit-cells thick. Racetracks formed from these films sustain current-induced domain wall motion with velocities of more than 120 m s-1, at current densities up to six times lower than conventional ferromagnetic materials. We find evidence for a significant bulk chiral Dzyaloshinskii-Moriya exchange interaction, whose field strength can be systematically tuned by an order of magnitude. Our work is an important step towards practical applications of Heusler compounds for spintronic technologies. PMID- 30405098 TI - Association and cis-mQTL analysis of variants in serotonergic genes associated with nicotine dependence in Chinese Han smokers. AB - Variants in serotonergic genes are implicated in nicotine dependence (ND) in subjects of European and African origin, but their involvement with smoking in Asians is largely unknown. Moreover, mechanisms underlying the ND risk-associated single-nucleotide polymorphisms (SNPs) in these genes are rarely investigated. The Fagerstrom Test for Nicotine Dependence (FTND) score was used to assess ND in 2616 male Chinese Han smokers. Both association and interaction analysis were used to examine the association of variants in the serotonergic genes with FTND. Further, expression and methylation quantitative trait loci (cis-mQTL) analysis was employed to determine the association of individual SNPs with the extent of methylation of each CpG locus. Individual SNP-based association analysis revealed that rs1176744 in HTR3B was marginally associated with FTND (p = 0.042). Haplotype-based association analysis found that one major haplotype, T-T-A-G, formed by SNPs rs3758987-rs4938056-rs1176744-rs2276305, located in the 5' region of HTR3B, showed a significant association with FTND (p = 0.00025). Further, a significant genetic interactive effect affecting ND was detected among SNPs rs10160548 in HTR3A, and rs3758987, rs2276305, and rs1672717 in HTR3B (p = 0.0074). Finally, we found four CpG sites (CpG_4543549, CpG_4543464, CpG_4543682, and CpG_4546888) to be significantly associated with three cis-mQTL SNPs (i.e., rs3758987, rs4938056, and rs1176744) located in our detected haplotype within HTR3B. In sum, we showed SNP rs1176744 (Tyr129Ser) to be associated with ND. Together with the SNPs rs3758987 and rs4938056 in HTR3B, they formed a major haplotype, which had significant association with ND. We further showed these SNPs contribute to ND through four methylated sites in HTR3B. All these findings suggest that variants in the serotonergic system play an important role in ND in the Chinese Han population. More importantly, these findings demonstrated that the involvement of this system in ND is through gene-by-gene interaction and methylation. PMID- 30405101 TI - Macrophages regulate the clearance of living cells by calreticulin. PMID- 30405102 TI - Basal freeze-on generates complex ice-sheet stratigraphy. AB - Large, plume-like internal ice-layer-structures have been observed in radar images from both Antarctica and Greenland, rising from the ice-sheet base to up to half of the ice thickness. Their origins are not yet understood. Here, we simulate their genesis by basal freeze-on using numerical ice-flow modelling and analyse the transient evolution of the emerging ice-plume and the surrounding ice layer structure as a function of both freeze-on rate and ice flux. We find good agreement between radar observations, modelled ice-plume geometry and internal layer structure, and further show that plume height relates primarily to ice-flux and only secondarily to freeze-on. An in-depth analysis, performed for Northern Greenland of observed spatial plume distribution related to ice flow, basal topography and water availability supports our findings regarding ice flux and suggests freeze-on is controlled by ascending subglacial water flow. Our results imply that widespread basal freeze-on strongly affects ice stratigraphy and consequently ice-core interpretations. PMID- 30405100 TI - PRKAA1/AMPKalpha1-driven glycolysis in endothelial cells exposed to disturbed flow protects against atherosclerosis. AB - Increased aerobic glycolysis in endothelial cells of atheroprone areas of blood vessels has been hypothesized to drive increased inflammation and lesion burden but direct links remain to be established. Here we show that endothelial cells exposed to disturbed flow in vivo and in vitro exhibit increased levels of protein kinase AMP-activated (PRKA)/AMP-activated protein kinases (AMPKs). Selective deletion of endothelial Prkaa1, coding for protein kinase AMP-activated catalytic subunit alpha1, reduces glycolysis, compromises endothelial cell proliferation, and accelerates the formation of atherosclerotic lesions in hyperlipidemic mice. Rescue of the impaired glycolysis in Prkaa1-deficient endothelial cells through Slc2a1 overexpression enhances endothelial cell viability and integrity of the endothelial cell barrier, and reverses susceptibility to atherosclerosis. In human endothelial cells, PRKAA1 is upregulated by disturbed flow, and silencing PRKAA1 reduces glycolysis and endothelial viability. Collectively, these results suggest that increased glycolysis in the endothelium of atheroprone arteries is a protective mechanism. PMID- 30405103 TI - Plasma Tie2 is a tumor vascular response biomarker for VEGF inhibitors in metastatic colorectal cancer. AB - Oncological use of anti-angiogenic VEGF inhibitors has been limited by the lack of informative biomarkers. Previously we reported circulating Tie2 as a vascular response biomarker for bevacizumab-treated ovarian cancer patients. Using advanced MRI and circulating biomarkers we have extended these findings in metastatic colorectal cancer (n = 70). Bevacizumab (10 mg/kg) was administered to elicit a biomarker response, followed by FOLFOX6-bevacizumab until disease progression. Bevacizumab induced a correlation between Tie2 and the tumor vascular imaging biomarker, Ktrans (R:-0.21 to 0.47) implying that Tie2 originated from the tumor vasculature. Tie2 trajectories were independently associated with pre-treatment tumor vascular characteristics, tumor response, progression free survival (HR for progression = 3.01, p = 0.00014; median PFS 248 vs. 348 days p = 0.0008) and the modeling of progressive disease (p < 0.0001), suggesting that Tie2 should be monitored clinically to optimize VEGF inhibitor use. A vascular response is defined as a 30% reduction in Tie2; vascular progression as a 40% increase in Tie2 above the nadir. Tie2 is the first, validated, tumor vascular response biomarker for VEGFi. PMID- 30405104 TI - Dynamic ubiquitylation of Sox2 regulates proteostasis and governs neural progenitor cell differentiation. AB - Sox2 is a key transcriptional factor for maintaining pluripotency of stem cells. Sox2 deficiency causes neurodegeneration and impairs neurogenesis. Although the transcriptional regulation of Sox2 has been extensively studied, the mechanisms that control Sox2 protein turnover are yet to be clarified. Here we show that the RING-finger ubiquitin ligase complex CUL4ADET1-COP1 and the deubiquitylase OTUD7B govern Sox2 protein stability during neural progenitor cells (NPCs) differentiation. Sox2 expression declines concordantly with OTUD7B and reciprocally with CUL4A and COP1 levels upon NPCs differentiation. COP1, as the substrate receptor, interacts directly with and ubiquitylates Sox2, while OTUD7B removes polyUb conjugates from Sox2 and increases its stability. COP1 knockdown stabilizes Sox2 and prevents differentiation, while OTUD7B knockdown destabilizes Sox2 and induces differentiation. Thus, CUL4ADET1-COP1 and OTUD7B exert opposite roles in regulating Sox2 protein stability at the post-translational level, which represents a critical regulatory mechanism involved in the maintenance and differentiation of NPCs. PMID- 30405105 TI - Symmetry breakdown of electron emission in extreme ultraviolet photoionization of argon. AB - Short wavelength free-electron lasers (FELs), providing pulses of ultrahigh photon intensity, have revolutionized spectroscopy on ionic targets. Their exceptional photon flux enables multiple photon absorptions within a single femtosecond pulse, which in turn allows for deep insights into the photoionization process itself as well as into evolving ionic states of a target. Here we employ ultraintense pulses from the FEL FERMI to spectroscopically investigate the sequential emission of electrons from gaseous, atomic argon in the neutral as well as the ionic ground state. A pronounced forward-backward symmetry breaking of the angularly resolved emission patterns with respect to the light propagation direction is experimentally observed and theoretically explained for the region of the Cooper minimum, where the asymmetry of electron emission is strongly enhanced. These findings aim to originate a better understanding of the fundamentals of photon momentum transfer in ionic matter. PMID- 30405106 TI - Genetic dissection of the miR-200-Zeb1 axis reveals its importance in tumor differentiation and invasion. AB - The epithelial-to-mesenchymal transition (EMT) is an important mechanism for cancer progression and metastasis. Numerous in vitro and tumor-profiling studies point to the miR-200-Zeb1 axis as crucial in regulating this process, yet in vivo studies involving its regulation within a physiological context are lacking. Here, we show that miR-200 ablation in the Rip-Tag2 insulinoma mouse model induces beta-cell dedifferentiation, initiates an EMT expression program, and promotes tumor invasion. Strikingly, disrupting the miR-200 sites of the endogenous Zeb1 locus causes a similar phenotype. Reexpressing members of the miR 200 superfamily in vitro reveals that the miR-200c family and not the co expressed and closely related miR-141 family is responsible for regulation of Zeb1 and EMT. Our results thus show that disrupting the in vivo regulation of Zeb1 by miR-200c is sufficient to drive EMT, thus highlighting the importance of this axis in tumor progression and invasion and its potential as a therapeutic target. PMID- 30405108 TI - A plant-based diet in overweight individuals in a 16-week randomized clinical trial: metabolic benefits of plant protein. AB - BACKGROUND AND OBJECTIVES: A plant-based diet is an effective strategy in the treatment of obesity. In this 16-week randomized clinical trial, we tested the effect of a plant-based diet on body composition and insulin resistance. As a part of this trial, we investigated the role of plant protein on these outcomes. SUBJECTS AND METHODS: Overweight participants (n = 75) were randomized to follow a plant-based (n = 38) or a control diet (n = 37). Dual X-ray Absorptiometry assessed body composition, Homeostasis Model Assessment (HOMA-IR) assessed insulin resistance, and a linear regression model was used to test the relationship between protein intake, body composition, and insulin resistance. RESULTS: The plant-based vegan diet proved to be superior to the control diet in improving body weight, fat mass, and insulin resistance markers. Only the vegan group showed significant reductions in body weight (treatment effect -6.5 [95% CI -8.9 to -4.1] kg; Gxt, p < 0.001), fat mass (treatment effect -4.3 [95% CI -5.4 to -3.2] kg; Gxt, p < 0.001), and HOMA-IR (treatment effect -1.0 [95% CI -1.2 to 0.8]; Gxt, p = 0.004). The decrease in fat mass was associated with an increased intake of plant protein and decreased intake of animal protein (r = -0.30, p = 0.011; and r = +0.39, p = 0.001, respectively). In particular, decreased % leucine intake was associated with a decrease in fat mass (r = +0.40; p < 0.001), in both unadjusted and adjusted models for changes in BMI and energy intake. In addition, decreased % histidine intake was associated with a decrease in insulin resistance (r = +0.38; p = 0.003), also independent of changes in BMI and energy intake. CONCLUSIONS: These findings provide evidence that plant protein, as a part of a plant-based diet, and the resulting limitation of leucine and histidine intake are associated with improvements in body composition and reductions in both body weight and insulin resistance. PMID- 30405109 TI - Modern slavery and the race to fish. AB - Marine fisheries are in crisis, requiring twice the fishing effort of the 1950s to catch the same quantity of fish, and with many fleets operating beyond economic or ecological sustainability. A possible consequence of diminishing returns in this race to fish is serious labour abuses, including modern slavery, which exploit vulnerable workers to reduce costs. Here, we use the Global Slavery Index (GSI), a national-level indicator, as a proxy for modern slavery and labour abuses in fisheries. GSI estimates and fisheries governance are correlated at the national level among the major fishing countries. Furthermore, countries having documented labour abuses at sea share key features, including higher levels of subsidised distant-water fishing and poor catch reporting. Further research into modern slavery in the fisheries sector is needed to better understand how the issue relates to overfishing and fisheries policy, as well as measures to reduce risk in these labour markets. PMID- 30405107 TI - Establishment and characterization of new tumor xenografts and cancer cell lines from EBV-positive nasopharyngeal carcinoma. AB - The lack of representative nasopharyngeal carcinoma (NPC) models has seriously hampered research on EBV carcinogenesis and preclinical studies in NPC. Here we report the successful growth of five NPC patient-derived xenografts (PDXs) from fifty-eight attempts of transplantation of NPC specimens into NOD/SCID mice. The take rates for primary and recurrent NPC are 4.9% and 17.6%, respectively. Successful establishment of a new EBV-positive NPC cell line, NPC43, is achieved directly from patient NPC tissues by including Rho-associated coiled-coil containing kinases inhibitor (Y-27632) in culture medium. Spontaneous lytic reactivation of EBV can be observed in NPC43 upon withdrawal of Y-27632. Whole exome sequencing (WES) reveals a close similarity in mutational profiles of these NPC PDXs with their corresponding patient NPC. Whole-genome sequencing (WGS) further delineates the genomic landscape and sequences of EBV genomes in these newly established NPC models, which supports their potential use in future studies of NPC. PMID- 30405110 TI - Molecular structure of promoter-bound yeast TFIID. AB - Transcription preinitiation complex assembly on the promoters of protein encoding genes is nucleated in vivo by TFIID composed of the TATA-box Binding Protein (TBP) and 13 TBP-associate factors (Tafs) providing regulatory and chromatin binding functions. Here we present the cryo-electron microscopy structure of promoter-bound yeast TFIID at a resolution better than 5 A, except for a flexible domain. We position the crystal structures of several subunits and, in combination with cross-linking studies, describe the quaternary organization of TFIID. The compact tri lobed architecture is stabilized by a topologically closed Taf5-Taf6 tetramer. We confirm the unique subunit stoichiometry prevailing in TFIID and uncover a hexameric arrangement of Tafs containing a histone fold domain in the Twin lobe. PMID- 30405111 TI - Immunogenicity and protective efficacy against Treponema pallidum in New Zealand rabbits immunized with plasmid DNA encoding flagellin. AB - Plasmid DNA encoding flagellin FlaB3 was used as a vaccination candidate for the evaluation of immunogenicity and protection against Treponema pallidum subsp. pallidum dissemination. First, intramuscular injection of the flagellin encoded by the plasmid DNA into New Zealand rabbits elicited both humoral and cellular immune responses. Total IgG production increased in response to flagellin. In addition, serum IFN-gamma secretion and CD8+ cells were substantially greater in the rabbits immunized with the plasmid encoding flagellin FlaB3 than those in the rabbits immunized with recombinant flagellin. The flagellin encoded by the plasmid DNA induced significant upregulation of serum IL-6 and IL-8 compared to that of the control rabbits. Subsequently, intradermal challenge of the vaccinated New Zealand rabbits with 1 * 107T. pallidum resulted in a significant reduction of the bacterial organ burden in the blood, liver, spleen, and testicles in the flagellin plasmid DNA-vaccinated rabbits. Furthermore, the histopathological analysis demonstrated that the rabbits immunized with the plasmid DNA-encoded flagellin (FlaB3) showed better immune protection. These findings provide evidence that plasmid DNA-encoded flagellin (FlaB3) may be useful as a potential immunization route for future development of a vaccine to inhibit T. pallidum dissemination in related animals. PMID- 30405114 TI - Design and application of volatilizable solid additives in non-fullerene organic solar cells. AB - Most of the high-performance organic solar cells are fabricated with the assistance of high-boiling-point solvent additives to optimize their charge transport properties; this has adverse effects on the OSCs' stability and reproducibility in large-scale production. Here, we design volatilizable solid additives by considering the molecular structure feature of an acceptor-donor acceptor-type non-fullerene acceptor. The application of solid additives can enhance the intermolecular pi-pi stacking of the non-fullerene acceptor and thus facilitate the charge transport properties in the active layers, leading to improved efficiencies of OSCs. Importantly, devices fabricated using volatilizable solid additives exhibit higher stability and reproducibility when compared with the OSCs processed with solvent additives. Our results not only demonstrate an approach of applying volatilizable solid additives to benefit the large-scale production of OSCs but also provide a potential direction for designing specific solid additives for different active layers. PMID- 30405115 TI - Targeting myeloid cells to prevent recurrent stroke in general population: the lesson of hydroxyurea in myeloproliferative neoplasms. PMID- 30405112 TI - Integrating chemical and mechanical signals through dynamic coupling between cellular protrusions and pulsed ERK activation. AB - The Ras-ERK signaling pathway regulates diverse cellular processes in response to environmental stimuli and contains important therapeutic targets for cancer. Recent single cell studies revealed stochastic pulses of ERK activation, the frequency of which determines functional outcomes such as cell proliferation. Here we show that ERK pulses are initiated by localized protrusive activities. Chemically and optogenetically induced protrusions trigger ERK activation through various entry points into the feedback loop involving Ras, PI3K, the cytoskeleton, and cellular adhesion. The excitability of the protrusive signaling network drives stochastic ERK activation in unstimulated cells and oscillations upon growth factor stimulation. Importantly, protrusions allow cells to sense combined signals from substrate stiffness and the growth factor. Thus, by uncovering the basis of ERK pulse generation we demonstrate how signals involved in cell growth and differentiation are regulated by dynamic protrusions that integrate chemical and mechanical inputs from the environment. PMID- 30405113 TI - Cytotoxic activity of Kingella kingae RtxA toxin depends on post-translational acylation of lysine residues and cholesterol binding. AB - Kingella kingae is a member of the commensal oropharyngeal flora of young children. Improvements in detection methods have led to the recognition of K. kingae as an emerging pathogen that frequently causes osteoarticular infections in children and a severe form of infective endocarditis in children and adults. Kingella kingae secretes a membrane-damaging RTX (Repeat in ToXin) toxin, RtxA, which is implicated in the development of clinical infections. However, the mechanism by which RtxA recognizes and kills host cells is largely unexplored. To facilitate structure-function studies of RtxA, we have developed a procedure for the overproduction and purification of milligram amounts of biologically active recombinant RtxA. Mass spectrometry analysis revealed the activation of RtxA by post-translational fatty acyl modification on the lysine residues 558 and/or 689 by the fatty-acyltransferase RtxC. Acylated RtxA was toxic to various human cells in a calcium-dependent manner and possessed pore-forming activity in planar lipid bilayers. Using various biochemical and biophysical approaches, we demonstrated that cholesterol facilitates the interaction of RtxA with artificial and cell membranes. The results of analyses using RtxA mutant variants suggested that the interaction between the toxin and cholesterol occurs via two cholesterol recognition/interaction amino acid consensus motifs located in the C-terminal portion of the pore-forming domain of the toxin. Based on our observations, we conclude that the cytotoxic activity of RtxA depends on post-translational acylation of the K558 and/or K689 residues and on the toxin binding to cholesterol in the membrane. PMID- 30405116 TI - Defective mitochondrial protein import contributes to complex I-induced mitochondrial dysfunction and neurodegeneration in Parkinson's disease. AB - Mitochondria are the prime energy source in most eukaryotic cells, but these highly dynamic organelles are also involved in a multitude of cellular events. Disruption of mitochondrial homeostasis and the subsequent mitochondrial dysfunction plays a key role in the pathophysiology of Parkinson's disease (PD). Therefore, maintenance of mitochondrial integrity through different surveillance mechanisms is critical for neuronal survival. Here, we have studied the mitochondrial protein import system in in vitro and in vivo models of PD. Complex I inhibition, a characteristic pathological hallmark in PD, impaired mitochondrial protein import, which was associated with a downregulation of two key components of the system: translocase of the outer membrane 20 (TOM20) and translocase of the inner membrane 23 (TIM23), both in vitro and in vivo. In vitro, those changes were associated with OXPHOS protein downregulation, accumulation of aggregated proteins inside mitochondria and downregulation of mitochondrial chaperones. Most of these pathogenic changes, including mitochondrial dysfunction and dopaminergic cell death, were abrogated by TOM20 or TIM23 overexpression, in vitro. However, in vivo, while TOM20 overexpression exacerbated neurodegeneration in both substantia nigra (SN) pars compacta (pc) and striatum, overexpression of TIM23 partially protected dopaminergic neurons in the SNpc. These results highlight mitochondrial protein import dysfunction and the distinct role of two of their components in the pathogenesis of PD and suggest the need for future studies to further characterize mitochondrial protein import deficit in the context of PD. PMID- 30405117 TI - Maternal depression during pregnancy and cord blood DNA methylation: findings from the Avon Longitudinal Study of Parents and Children. AB - Up to 13% of women may experience symptoms of depression during pregnancy or in the postpartum period. Depression during pregnancy has been associated with an increased risk of adverse neurodevelopmental outcomes in the child and epigenetic mechanisms could be one of the biological pathways to explain this association. In 844 mother-child pairs from the Avon Longitudinal Study of Parents and Children, we carried out an epigenome-wide association study (EWAS) to investigate associations between prospectively collected data on maternal depression ascertained by the Edinburgh Postnatal Depression Scale in pregnancy and DNA methylation in the cord blood of newborn offspring. In individual site analysis, we identified two CpG sites associated with maternal depression in the middle part of pregnancy. In our regional analysis, we identified 39 differentially methylated regions (DMRs). Seven DMRs were associated with depression at any time point during pregnancy, 7 associated with depression in mid-pregnancy, 23 were associated with depression in late pregnancy, and 2 DMRs were associated with depression throughout pregnancy. Several of these map to genes associated with psychiatric disease and brain development. We attempted replication in The Generation R Study and could not replicate our results. Although our findings in ALSPAC suggest that maternal depression could be associated with cord blood DNA methylation the results should be viewed as preliminary and hypothesis generating until further replicated in a larger sample. PMID- 30405118 TI - Estrogen promotes the onset and development of idiopathic scoliosis via disproportionate endochondral ossification of the anterior and posterior column in a bipedal rat model. AB - This study aimed to verify the effects of estrogen on the onset and development of adolescent idiopathic scoliosis and the mechanisms associated with these effects by constructing a pubescent bipedal rat model. Experiments were conducted to investigate whether scoliosis progression was prevented by a Triptorelin treatment. One hundred twenty bipedal rats were divided into female, OVX (ovariectomy), OVX + E2, Triptorelin, sham, and male groups. According to a spinal radiographic analysis, the scoliosis rates and curve severity of the female and OVX + E2 groups were higher than those in the OVX, Triptorelin, and male groups. The measurements obtained from the sagittal plane of thoracic vertebrae CT confirmed a relatively slower growth of the anterior elements and a faster growth of the posterior elements between T11 and T13 in the female and OVX + E2 groups than in the OVX and Triptorelin groups. Histomorphometry and immunohistochemistry revealed a significantly longer hypertrophic zone of the vertebral cartilage growth plates that expressed more type X collagen and less type II collagen in the OVX and Triptorelin groups than in the female and OVX + E2 groups. Ki67 immunostaining confirmed an increase in the proliferation of vertebral growth plate chondrocytes in the OVX group compared with the female and OVX + E2 groups. In conclusion, estrogen obviously increased the incidence of scoliosis and curve severity in pubescent bipedal rats. The underlying mechanism may be a loss of coupling of the endochondral ossification between the anterior and posterior columns. Triptorelin decreased the incidence of scoliosis and curve magnitudes in bipedal female rats. PMID- 30405119 TI - Dynamic control of proinflammatory cytokines Il-1beta and Tnf-alpha by macrophages in zebrafish spinal cord regeneration. AB - Spinal cord injury leads to a massive response of innate immune cells in non regenerating mammals, but also in successfully regenerating zebrafish. However, the role of the immune response in successful regeneration is poorly defined. Here we show that inhibiting inflammation reduces and promoting it accelerates axonal regeneration in spinal-lesioned zebrafish larvae. Mutant analyses show that peripheral macrophages, but not neutrophils or microglia, are necessary for repair. Macrophage-less irf8 mutants show prolonged inflammation with elevated levels of Tnf-alpha and Il-1beta. Inhibiting Tnf-alpha does not rescue axonal growth in irf8 mutants, but impairs it in wildtype animals, indicating a pro regenerative role of Tnf-alpha. In contrast, decreasing Il-1beta levels or number of Il-1beta+ neutrophils rescue functional regeneration in irf8 mutants. However, during early regeneration, interference with Il-1beta function impairs regeneration in irf8 and wildtype animals. Hence, inflammation is dynamically controlled by macrophages to promote functional spinal cord regeneration in zebrafish. PMID- 30405120 TI - Signature of quantum Griffiths singularity state in a layered quasi-one dimensional superconductor. AB - Quantum Griffiths singularity was theoretically proposed to interpret the phenomenon of divergent dynamical exponent in quantum phase transitions. It has been discovered experimentally in three-dimensional (3D) magnetic metal systems and two-dimensional (2D) superconductors. But, whether this state exists in lower dimensional systems remains elusive. Here, we report the signature of quantum Griffiths singularity state in quasi-one-dimensional (1D) Ta2PdS5 nanowires. The superconducting critical field shows a strong anisotropic behavior and a violation of the Pauli limit in a parallel magnetic field configuration. Current voltage measurements exhibit hysteresis loops and a series of multiple voltage steps in transition to the normal state, indicating a quasi-1D nature of the superconductivity. Surprisingly, the nanowire undergoes a superconductor-metal transition when the magnetic field increases. Upon approaching the zero temperature quantum critical point, the system uncovers the signature of the quantum Griffiths singularity state arising from enhanced quenched disorders, where the dynamical critical exponent becomes diverging rather than being constant. PMID- 30405121 TI - A retrieval-specific mechanism of adaptive forgetting in the mammalian brain. AB - Forgetting is a ubiquitous phenomenon that is actively promoted in many species. How and whether organisms' behavioral goals drive which memories are actively forgotten is unknown. Here we show that processes essential to controlling goal directed behavior trigger active forgetting of distracting memories that interfere with behavioral goals. When rats need to retrieve particular memories to guide exploration, it reduces later retention of other memories encoded in that environment. As with humans, this retrieval-induced forgetting is competition-dependent, cue-independent and reliant on prefrontal control: Silencing the medial prefrontal cortex with muscimol abolishes the effect. cFos imaging reveals that prefrontal control demands decline over repeated retrievals as competing memories are forgotten successfully, revealing a key adaptive benefit of forgetting. Occurring in 88% of the rats studied, this finding establishes a robust model of how adaptive forgetting harmonizes memory with behavioral demands, permitting isolation of its circuit, cellular and molecular mechanisms. PMID- 30405122 TI - Epithelial cells release adenosine to promote local TNF production in response to polarity disruption. AB - Disruption of epithelial integrity contributes to chronic inflammatory disorders through persistent activation of stress signalling. Here we uncover a mechanism whereby disruption of apico-basal polarity promotes stress signalling. We show that depletion of Scribbled (Scrib), a baso-lateral determinant, causes epithelial cells to release adenosine through equilibrative channels into the extracellular space. Autocrine activation of the adenosine receptor leads to transcriptional upregulation of TNF, which in turn boosts the activity of JNK signalling. Thus, disruption of cell polarity feeds into a well-established stress pathway through the intermediary of an adenosine signalling branch. Although this regulatory input could help ensuring an effective response to acute polarity stress, we suggest that it becomes deleterious in situations of low grade chronic disruption by provoking a private inflammatory-like TNF-driven response within the polarity-deficient epithelium. PMID- 30405124 TI - Biological plausibility and stochasticity in scalable VO2 active memristor neurons. AB - Neuromorphic networks of artificial neurons and synapses can solve computationally hard problems with energy efficiencies unattainable for von Neumann architectures. For image processing, silicon neuromorphic processors outperform graphic processing units in energy efficiency by a large margin, but deliver much lower chip-scale throughput. The performance-efficiency dilemma for silicon processors may not be overcome by Moore's law scaling of silicon transistors. Scalable and biomimetic active memristor neurons and passive memristor synapses form a self-sufficient basis for a transistorless neural network. However, previous demonstrations of memristor neurons only showed simple integrate-and-fire behaviors and did not reveal the rich dynamics and computational complexity of biological neurons. Here we report that neurons built with nanoscale vanadium dioxide active memristors possess all three classes of excitability and most of the known biological neuronal dynamics, and are intrinsically stochastic. With the favorable size and power scaling, there is a path toward an all-memristor neuromorphic cortical computer. PMID- 30405123 TI - Thermostable virus portal proteins as reprogrammable adapters for solid-state nanopore sensors. AB - Nanopore-based sensors are advancing the sensitivity and selectivity of single molecule detection in molecular medicine and biotechnology. Current electrical sensing devices are based on either membrane protein pores supported in planar lipid bilayers or solid-state (SS) pores fabricated in thin metallic membranes. While both types of nanosensors have been used in a variety of applications, each has inherent disadvantages that limit its use. Hybrid nanopores, consisting of a protein pore supported within a SS membrane, combine the robust nature of SS membranes with the precise and simple engineering of protein nanopores. We demonstrate here a novel lipid-free hybrid nanopore comprising a natural DNA pore from a thermostable virus, electrokinetically inserted into a larger nanopore supported in a silicon nitride membrane. The hybrid pore is stable and easy to fabricate, and, most importantly, exhibits low peripheral leakage allowing sensing and discrimination among different types of biomolecules. PMID- 30405125 TI - Gene inversion potentiates bacterial evolvability and virulence. AB - Most bacterial genes are encoded on the leading strand, co-orienting the movement of the replication machinery with RNA polymerases. This bias reduces the frequency of detrimental head-on collisions between the two machineries. The negative outcomes of these collisions should lead to selection against head-on alleles, maximizing genome co-orientation. Our findings challenge this model. Using the GC skew calculation, we reveal the evolutionary inversion record of all chromosomally encoded genes in multiple divergent bacterial pathogens. Against expectations, we find that a large number of co-oriented genes have inverted to the head-on orientation, presumably increasing the frequency of head-on replication-transcription conflicts. Furthermore, we find that head-on genes, (including key antibiotic resistance and virulence genes) have higher rates of non-synonymous mutations and are more frequently under positive selection (dN/dS > 1). Based on these results, we propose that spontaneous gene inversions can increase the evolvability and pathogenic capacity of bacteria through head-on replication-transcription collisions. PMID- 30405126 TI - Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits. AB - The role of rare variants in complex traits remains uncharted. Here, we conduct deep whole genome sequencing of 1457 individuals from an isolated population, and test for rare variant burdens across six cardiometabolic traits. We identify a role for rare regulatory variation, which has hitherto been missed. We find evidence of rare variant burdens that are independent of established common variant signals (ADIPOQ and adiponectin, P = 4.2 * 10-8; APOC3 and triglyceride levels, P = 1.5 * 10-26), and identify replicating evidence for a burden associated with triglyceride levels in FAM189B (P = 2.2 * 10-8), indicating a role for this gene in lipid metabolism. PMID- 30405127 TI - Systems glycomics of adult zebrafish identifies organ-specific sialylation and glycosylation patterns. AB - The emergence of zebrafish Danio rerio as a versatile model organism provides the unique opportunity to monitor the functions of glycosylation throughout vertebrate embryogenesis, providing insights into human diseases caused by glycosylation defects. Using a combination of chemical modifications, enzymatic digestion and mass spectrometry analyses, we establish here the precise glycomic profiles of eight individual zebrafish organs and demonstrate that the protein glycosylation and glycosphingolipid expression patterns exhibits exquisite specificity. Concomitant expression screening of a wide array of enzymes involved in the synthesis and transfer of sialic acids shows that the presence of organ specific sialylation motifs correlates with the localized activity of the corresponding glycan biosynthesis pathways. These findings provide a basis for the rational design of zebrafish lines expressing desired glycosylation profiles. PMID- 30405128 TI - Proteome evolution under non-substitutable resource limitation. AB - Resource limitation is a major driver of the ecological and evolutionary dynamics of organisms. Short-term responses to resource limitation include plastic changes in molecular phenotypes including protein expression. Yet little is known about the evolution of the molecular phenotype under longer-term resource limitation. Here, we combine experimental evolution of the green alga Chlamydomonas reinhardtii under multiple different non-substitutable resource limitation regimes with proteomic measurements to investigate evolutionary adaptation of the molecular phenotype. We demonstrate convergent proteomic evolution of core metabolic functions, including the Calvin-Benson cycle and gluconeogenesis, across different resource limitation environments. We do not observe proteomic changes consistent with optimized uptake of particular limiting resources. Instead, we report that adaptation proceeds in similar directions under different types of non-substitutable resource limitation. This largely convergent evolution of the expression of core metabolic proteins is associated with an improvement in the resource assimilation efficiency of nitrogen and phosphorus into biomass. PMID- 30405129 TI - BMI1 enables interspecies chimerism with human pluripotent stem cells. AB - Human pluripotent stem cells (hPSCs) exhibit very limited contribution to interspecies chimeras. One explanation is that the conventional hPSCs are in a primed state and so unable to form chimeras in pre-implantation embryos. Here, we show that the conventional hPSCs undergo rapid apoptosis when injected into mouse pre-implantation embryos. While, forced-expression of BMI1, a polycomb factor in hPSCs overcomes the apoptosis and enables hPSCs to integrate into mouse pre-implantation embryos and subsequently contribute to chimeras with both embryonic and extra-embryonic tissues. In addition, BMI1 also enables hPSCs to integrate into pre-implantation embryos of other species, such as rabbit and pig. Notably, BMI1 high expression and anti-apoptosis are also indicators for naive hPSCs to form chimera in mouse embryos. Together, our findings reveal that the apoptosis is an initial barrier in interspecies chimerism using hPSCs and provide a rational to improve it. PMID- 30405131 TI - Dissipative shock waves generated by a quantum-mechanical piston. AB - The piston shock problem is a prototypical example of strongly nonlinear fluid flow that enables the experimental exploration of fluid dynamics in extreme regimes. Here we investigate this problem for a nominally dissipationless, superfluid Bose-Einstein condensate and observe rich dynamics including the formation of a plateau region, a non-expanding shock front, and rarefaction waves. Many aspects of the observed dynamics follow predictions of classical dissipative-rather than superfluid dispersive-shock theory. The emergence of dissipative-like dynamics is attributed to the decay of large amplitude excitations at the shock front into turbulent vortex excitations, which allow us to invoke an eddy viscosity hypothesis. Our experimental observations are accompanied by numerical simulations of the mean-field, Gross-Pitaevskii equation that exhibit quantitative agreement with no fitting parameters. This work provides an avenue for the investigation of quantum shock waves and turbulence in channel geometries, which are currently the focus of intense research efforts. PMID- 30405130 TI - CDC20B is required for deuterosome-mediated centriole production in multiciliated cells. AB - Multiciliated cells (MCCs) harbor dozens to hundreds of motile cilia, which generate hydrodynamic forces important in animal physiology. In vertebrates, MCC differentiation involves massive centriole production by poorly characterized structures called deuterosomes. Here, single-cell RNA sequencing reveals that human deuterosome stage MCCs are characterized by the expression of many cell cycle-related genes. We further investigated the uncharacterized vertebrate specific cell division cycle 20B (CDC20B) gene, which hosts microRNA-449abc. We show that CDC20B protein associates to deuterosomes and is required for centriole release and subsequent cilia production in mouse and Xenopus MCCs. CDC20B interacts with PLK1, a kinase known to coordinate centriole disengagement with the protease Separase in mitotic cells. Strikingly, over-expression of Separase rescues centriole disengagement and cilia production in CDC20B-deficient MCCs. This work reveals the shaping of deuterosome-mediated centriole production in vertebrate MCCs, by adaptation of canonical and recently evolved cell cycle related molecules. PMID- 30405132 TI - The deubiquitinase MYSM1 dampens NOD2-mediated inflammation and tissue damage by inactivating the RIP2 complex. AB - NOD2 is essential for antimicrobial innate immunity and tissue homeostasis, but require tight regulation to avert pathology. A focal point of NOD2 signaling is RIP2, which upon polyubiquitination nucleates the NOD2:RIP2 complex, enabling signaling events leading to inflammation, yet the precise nature and the regulation of the polyubiquitins coordinating this process remain unclear. Here we show that NOD2 signaling involves conjugation of RIP2 with lysine 63 (K63), K48 and M1 polyubiquitin chains, as well as with non-canonical K27 chains. In addition, we identify MYSM1 as a proximal deubiquitinase that attenuates NOD2:RIP2 complex assembly by selectively removing the K63, K27 and M1 chains, but sparing the K48 chains. Consequently, MYSM1 deficient mice have unrestrained NOD2-mediated peritonitis, systemic inflammation and liver injury. This study provides a complete overview of the polyubiquitins in NOD2:RIP2 signaling and reveal MYSM1 as a central negative regulator restricting these polyubiquitins to prevent excessive inflammation. PMID- 30405133 TI - In-situ observation of plasmon-controlled photocatalytic dehydrogenation of individual palladium nanoparticles. AB - Plasmonic nanoparticle catalysts offer improved light absorption and carrier transport compared to traditional photocatalysts. However, it remains unclear how plasmonic excitation affects multi-step reaction kinetics and promotes site selectivity. Here, we visualize a plasmon-induced reaction at the sub nanoparticle level in-situ and in real-time. Using an environmental transmission electron microscope combined with light excitation, we study the photocatalytic dehydrogenation of individual palladium nanocubes coupled to gold nanoparticles with sub-2 nanometer spatial resolution. We find that plasmons increase the rate of distinct reaction steps with unique time constants; enable reaction nucleation at specific sites closest to the electromagnetic hot spots; and appear to open a new reaction pathway that is not observed without illumination. These effects are explained by plasmon-mediated population of excited-state hybridized palladium hydrogen orbitals. Our results help elucidate the role of plasmons in light driven photochemical transformations, en-route to design of site-selective and product-specific photocatalysts. PMID- 30405135 TI - Whole body PD-1 and PD-L1 positron emission tomography in patients with non-small cell lung cancer. AB - PD-L1 immunohistochemistry correlates only moderately with patient survival and response to PD-(L)1 treatment. Heterogeneity of tumor PD-L1 expression might limit the predictive value of small biopsies. Here we show that tumor PD-L1 and PD-1 expression can be quantified non-invasively using PET-CT in patients with non-small-cell lung cancer. Whole body PD-(L)1 PET-CT reveals significant tumor tracer uptake heterogeneity both between patients, as well as within patients between different tumor lesions. PMID- 30405136 TI - Domestication modifies the volatile emissions produced by male Queensland fruit flies during sexual advertisement. AB - Insects commonly undergo substantial changes during adaptation for laboratory or mass-rearing environments ('domestication') that may have significant implications for inferences from laboratory studies and utility for biological control. We assessed the effect of domestication on the amount and blend of volatiles released during sexual calling by laboratory-reared Bactrocera tryoni males using colonies from three regions of Australia: Brisbane, Cairns and Sydney. For each region, volatiles released by males from a young colony (five or fewer generations) and an old colony (20+ generations) during sexual calling was compared. Males from old colonies released more volatiles than males from young colonies. All components of the blend were more abundant in one or more of the older colonies, although differences varied by compound and by region. To assess changes over generations, the young and old colonies obtained from Brisbane were sampled at 5, 12 and 15 generations (young colony) and 25, 35 and 38 generations (old colony). While the old colony remained unchanged, flies from the young colony released more volatiles at each sequential sampling episode, and became increasingly similar to the old colony. Increased volatile production during domestication may be an adaptive response to crowded rearing conditions in which males need to overcome a chemically noisy environment to be sexually successful. PMID- 30405137 TI - A Deep Neural Network Model using Random Forest to Extract Feature Representation for Gene Expression Data Classification. AB - In predictive model development, gene expression data is associated with the unique challenge that the number of samples (n) is much smaller than the amount of features (p). This "n ? p" property has prevented classification of gene expression data from deep learning techniques, which have been proved powerful under "n > p" scenarios in other application fields, such as image classification. Further, the sparsity of effective features with unknown correlation structures in gene expression profiles brings more challenges for classification tasks. To tackle these problems, we propose a newly developed classifier named Forest Deep Neural Network (fDNN), to integrate the deep neural network architecture with a supervised forest feature detector. Using this built in feature detector, the method is able to learn sparse feature representations and feed the representations into a neural network to mitigate the overfitting problem. Simulation experiments and real data analyses using two RNA-seq expression datasets are conducted to evaluate fDNN's capability. The method is demonstrated a useful addition to current predictive models with better classification performance and more meaningful selected features compared to ordinary random forests and deep neural networks. PMID- 30405134 TI - Overcoming EGFRG724S-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors. AB - The emergence of acquired resistance against targeted drugs remains a major clinical challenge in lung adenocarcinoma patients. In a subgroup of these patients we identified an association between selection of EGFRT790M-negative but EGFRG724S-positive subclones and osimertinib resistance. We demonstrate that EGFRG724S limits the activity of third-generation EGFR inhibitors both in vitro and in vivo. Structural analyses and computational modeling indicate that EGFRG724S mutations may induce a conformation of the glycine-rich loop, which is incompatible with the binding of third-generation TKIs. Systematic inhibitor screening and in-depth kinetic profiling validate these findings and show that second-generation EGFR inhibitors retain kinase affinity and overcome EGFRG724S mediated resistance. In the case of afatinib this profile translates into a robust reduction of colony formation and tumor growth of EGFRG724S-driven cells. Our data provide a mechanistic basis for the osimertinib-induced selection of EGFRG724S-mutant clones and a rationale to treat these patients with clinically approved second-generation EGFR inhibitors. PMID- 30405138 TI - Kauniolide synthase is a P450 with unusual hydroxylation and cyclization elimination activity. AB - Guaianolides are an important class of sesquiterpene lactones with unique biological and pharmaceutical properties. They have been postulated to be derived from germacranolides, but for years no progress has been made in the elucidation of their biosynthesis that requires an unknown cyclization mechanism. Here we demonstrate the isolation and characterization of a cytochrome P450 from feverfew (Tanacetum parthenium), kauniolide synthase. Kauniolide synthase catalyses the formation of the guaianolide kauniolide from the germacranolide substrate costunolide. Unlike most cytochrome P450s, kauniolide synthase combines stereoselective hydroxylation of costunolide at the C3 position, with water elimination, cyclization and regioselective deprotonation. This unique mechanism of action is supported by in silico modelling and docking experiments. The full kauniolide biosynthesis pathway is reconstructed in the heterologous hosts Nicotiana benthamiana and yeast, paving the way for biotechnological production of guaianolide-type sesquiterpene lactones. PMID- 30405139 TI - US10 Protein Is Crucial but not Indispensable for Duck Enteritis Virus Infection in Vitro. AB - To investigate the function of the duck enteritis virus (DEV) tegument protein US10, we generated US10 deletion and revertant mutants (DeltaUS10 and US10FRT) via two-step RED recombination based on an infectious BAC clone of DEV CHv-BAC-G (BAC-G). In multistep growth kinetic analyses, DeltaUS10 showed an approximately 100-fold reduction in viral titer, while the genome copies decreased only 4-fold compared to those of BAC-G. In one-step growth kinetic analyses, there were no significant differences in genome copies among BAC-G, DeltaUS10 and US10FRT, but DeltaUS10 still showed a 5- to 20-fold reduction in viral titer, and the replication defect of DeltaUS10 was partially reversed by infection of US10 expressing cells. The transcription levels of Mx, OASL, IL-4, IL-6 and IL-10 in DeltaUS10-infected duck embryo fibroblasts (DEFs) were significantly upregulated, while TLR3 was downregulated compared with those in BAC-G-infected DEFs. Taken together, these data indicated that US10 is vital for DEV replication and is associated with transcription of some immunity genes. PMID- 30405141 TI - Bio-inspired Z-scheme g-C3N4/Ag2CrO4 for efficient visible-light photocatalytic hydrogen generation. AB - Due to low charge separation efficiency and poor stability, it is usually difficult for single-component photocatalysts such as graphitic carbon nitride (g C3N4) and silver chromate (Ag2CrO4) to fulfill photocatalytic hydrogen production efficiently. Z-scheme charge transport mechanism that mimics the photosynthesis in nature is an effective way to solve the above problems. Inspired by photosynthesis, we report Ag2CrO4 nanoparticles-decorated g-C3N4 nanosheet as an efficient photocatalyst for hydrogen evolution reaction (HER) with methanol as sacrificial agent. The formation of Z-scheme g-C3N4/Ag2CrO4 nanosheets photocatalysts could inhibit the recombination of photogenerated electron-hole pairs, promote the generation of hydrogen by photosplitting of water. The experiment results indicate that g-C3N4/Ag2CrO4 nanocomposites present enhanced photocatalytic activity and stability in the H2 evolution of water splitting. And the nanocomposites g-C3N4/Ag2CrO4(23.1%) show the 14 times HER efficiency compared to that of bare g-C3N4. PMID- 30405140 TI - Brain volumetric alterations accompanied with loss of striatal medium-sized spiny neurons and cortical parvalbumin expressing interneurons in Brd1+/- mice. AB - Schizophrenia is a common and severe mental disorder arising from complex gene environment interactions affecting brain development and functioning. While a consensus on the neuroanatomical correlates of schizophrenia is emerging, much of its fundamental pathobiology remains unknown. In this study, we explore brain morphometry in mice with genetic susceptibility and phenotypic relevance to schizophrenia (Brd1+/- mice) using postmortem 3D MR imaging coupled with histology, immunostaining and regional mRNA marker analysis. In agreement with recent large-scale schizophrenia neuroimaging studies, Brd1+/- mice displayed subcortical abnormalities, including volumetric reductions of amygdala and striatum. Interestingly, we demonstrate that structural alteration in striatum correlates with a general loss of striatal neurons, differentially impacting subpopulations of medium-sized spiny neurons and thus potentially striatal output. Akin to parvalbumin interneuron dysfunction in patients, a decline in parvalbumin expression was noted in the developing cortex of Brd1+/- mice, mainly driven by neuronal loss within or near cortical layer V, which is rich in corticostriatal projection neurons. Collectively, our study highlights the translational value of the Brd1+/- mouse as a pre-clinical tool for schizophrenia research and provides novel insight into its developmental, structural, and cellular pathology. PMID- 30405142 TI - Piezoelectric Accelerator. AB - Here we propose the conception of small-size piezoelectric accelerator of charged particles that operates due to the piezoelectric effect at varying mechanical force applied to piezoelectrics in vacuum. The accelerating voltage and the energy of accelerated particles are estimated. In the proof-of-principle experiment we demonstrate the effect of the emission of X-ray radiation at the mechanical compression of piezoelectric ceramics in vacuum. The compression leads to the appearance of charges and potentials on the surfaces of the piezoelectrics and also to the arising of the electric field in vacuum. Electrons are accelerated in the electric field, strike the matter and produce the X-ray radiation. In the experiment, we have observed emission of the characteristic and bremsstrahlung X-ray radiation of energy up to 60 keV due to the compression of piezoelectric ceramics in vacuum. This means that electrons are accelerated in the piezoelectric accelerator up to the energy at least of 60 keV. The agreement of calculated and experimental data confirms the conception. Advantages of the piezoelectric accelerator and possibilities of its development and applications are discussed. PMID- 30405143 TI - Ultrafast laser printing of self-organized bimetallic nanotextures for multi wavelength biosensing. AB - Surface-enhanced spectroscopy (SES) techniques, including surface-enhanced photoluminescence (SEPL), Raman scattering (SERS) and infrared absorption (SEIRA), represent powerful biosensing modalities, allowing non-invasive label free identification of various molecules and quantum emitters in the vicinity of nanotextured surfaces. Enhancement of multi-wavelength (vis-IR) excitation of analyte molecules of interest atop a single textured substrate could pave the way toward ultimate chemosensing performance and further widespread implementation of the SES-based approaches in various crucial areas, such as point-ofcare diagnostics. In this paper, an easy-to-implement ultrafast direct laser printing via partial spallation of thermally-thick silver films and subsequent large-scale magnetron deposition of nanometer-thick Au layers of variable thickness was implemented to produce bimetallic textured surfaces with the cascaded nanotopography. The produced bimetallic textures demonstrate the strong broadband plasmonic response over the entire visible spectral range. Such plasmonic performance was confirmed by convenient spectroscopy-free Red-Green-Blue (RGB) color analysis of the dark-field (DF) scattering images supported by numerical calculations of the electromagnetic (EM) "near-fields", as well as comprehensive DF spectroscopic characterization. Bimetallic laser-printed nanotextures, which can be easily printed at ultrafast (square millimeters per second) rate, using galvanometric scanning, exhibited strong enhancement of the SEPL (up to 75-fold) and SERS (up to 106 times) yields for the organic dye molecules excited at various wavelengths. Additionally, comprehensive optical and sensing characterization of the laser-printed bimetallic surface structures allows substantiating the convenient spectroscopy-free RGB color analysis as a valuable tool for predictive assessment of the plasmonic properties of the various irregularly and quasi-periodically nanotextured surfaces. PMID- 30405144 TI - Publisher Correction: Longitudinal analysis of biomarker data from a personalized nutrition platform in healthy subjects. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30405145 TI - Segmentation of the Proximal Femur from MR Images using Deep Convolutional Neural Networks. AB - Magnetic resonance imaging (MRI) has been proposed as a complimentary method to measure bone quality and assess fracture risk. However, manual segmentation of MR images of bone is time-consuming, limiting the use of MRI measurements in the clinical practice. The purpose of this paper is to present an automatic proximal femur segmentation method that is based on deep convolutional neural networks (CNNs). This study had institutional review board approval and written informed consent was obtained from all subjects. A dataset of volumetric structural MR images of the proximal femur from 86 subjects were manually-segmented by an expert. We performed experiments by training two different CNN architectures with multiple number of initial feature maps, layers and dilation rates, and tested their segmentation performance against the gold standard of manual segmentations using four-fold cross-validation. Automatic segmentation of the proximal femur using CNNs achieved a high dice similarity score of 0.95 +/- 0.02 with precision = 0.95 +/- 0.02, and recall = 0.95 +/- 0.03. The high segmentation accuracy provided by CNNs has the potential to help bring the use of structural MRI measurements of bone quality into clinical practice for management of osteoporosis. PMID- 30405147 TI - Inscribing the core memories of killers. PMID- 30405148 TI - The brain-immune cells axis controls tissue specific immunopathology. AB - During viral infections, cell death can be induced as a direct result of cytopathic virus replication in various cell types and tissues or as an immune response of the host to the infectious agent. This leads to an infiltration of inflammatory cells, causing subsequent tissue damage. The balance between effective elimination of the pathogen and prevention of fatal tissue damage is decisive for life. The host has developed various mechanisms to inhibit excessive immune responses. PMID- 30405149 TI - Mediator contributes to IgH locus VDJ rearrangements by promoting usage of most distal V segments. PMID- 30405146 TI - Microbiome shifts with onset and progression of Sea Star Wasting Disease revealed through time course sampling. AB - The recent outbreak of Sea Star Wasting Disease (SSWD) is one of the largest marine epizootics in history, but the host-associated microbial community changes specific to disease progression have not been characterized. Here, we sampled the microbiomes of ochre sea stars, Pisaster ochraceus, through time as animals stayed healthy or became sick and died with SSWD. We found community-wide differences in the microbiomes of sick and healthy sea stars, changes in microbial community composition through disease progression, and a decrease in species richness of the microbiome in late stages of SSWD. Known beneficial taxa (Pseudoalteromonas spp.) decreased in abundance at symptom onset and through disease progression, while known pathogenic (Tenacibaculum spp.) and putatively opportunistic bacteria (Polaribacter spp. and Phaeobacter spp.) increased in abundance in early and late disease stages. Functional profiling revealed microbes more abundant in healthy animals performed functions that inhibit growth of other microbes, including pathogen detection, biosynthesis of secondary metabolites, and degradation of xenobiotics. Changes in microbial composition with disease onset and progression suggest that a microbial imbalance of the host could lead to SSWD or be a consequence of infection by another pathogen. This work highlights the importance of the microbiome in SSWD and also suggests that a healthy microbiome may help confer resistance to SSWD. PMID- 30405150 TI - Of ethnicity, environment, and microbiota. PMID- 30405151 TI - Insights on the crosstalk between dendritic cells and helper T cells in novel genetic etiology for mendelian susceptible mycobacterial disease. PMID- 30405153 TI - Yeast thioredoxin reductase Trr1p controls TORC1-regulated processes. AB - The thioredoxin system plays a predominant role in the control of cellular redox status. Thioredoxin reductase fuels the system with reducing power in the form of NADPH. The TORC1 complex promotes growth and protein synthesis when nutrients, particularly amino acids, are abundant. It also represses catabolic processes, like autophagy, which are activated during starvation. We analyzed the impact of yeast cytosolic thioredoxin reductase TRR1 deletion under different environmental conditions. It shortens chronological life span and reduces growth in grape juice fermentation. TRR1 deletion has a global impact on metabolism during fermentation. As expected, it reduces oxidative stress tolerance, but a compensatory response is triggered, with catalase and glutathione increasing. Unexpectedly, TRR1 deletion causes sensitivity to the inhibitors of the TORC1 pathway, such as rapamycin. This correlates with low Tor2p kinase levels and indicates a direct role of Trr1p in its stability. Markers of TORC1 activity, however, suggest increased TORC1 activity. The autophagy caused by nitrogen starvation is reduced in the trr1Delta mutant. Ribosomal protein Rsp6p is dephosphorylated in the presence of rapamycin. This dephosphorylation diminishes in the TRR1 deletion strain. These results show a complex network of interactions between thioredoxin reductase Trr1p and the processes controlled by TOR. PMID- 30405154 TI - Hyponatremia in children with respiratory infections: a cross-sectional analysis of a cohort of 3938 patients. AB - Hyponatremia can be a life-threatening illness among hospitalized children. The aims of this study were to evaluate the incidence and risk factors of hyponatremia in 3938 children who were admitted to the Cheil General Hospital and Women's Health Care Center with respiratory infections. Clinical data were collected, and multiplex RT-PCR analyses were done for various microorganisms. Hyponatremia was observed in 531 (13.5%) patients. The incidence of hyponatremia differed according to the respiratory tract infection (P < 0.0001) and microorganism (P = 0.001). In children with hyponatremia, the age at admission was significantly older (P < 0.0001), male gender was more frequent (P = 0.019), CRP was higher (P < 0.0001), and coinfection with multiple organisms was more common (P = 0.001) than in children without hyponatremia. In multivariate analyses, an older age at admission (P = 0.006), male gender (P = 0.004), and increased CRP (P < 0.0001) were independent risk factors. Sodium levels correlated negatively with WBC (P = 0.037), CRP (P < 0.0001), and number of hospital days (P = 0.020). The AUC values of age (0.586, P < 0.0001), CRP (0.599, P < 0.0001), and blood urea nitrogen (0.559, P < 0.0001) were all significant predictors of hyponatremia. This study is the first to show that the incidence of hyponatremia differs according to infecting microorganism and radiological findings. PMID- 30405152 TI - Loss of Sirt2 increases and prolongs a caerulein-induced pancreatitis permissive phenotype and induces spontaneous oncogenic Kras mutations in mice. AB - Mice lacking Sirt2 spontaneously develop tumors in multiple organs, as well as when expressed in combination with oncogenic KrasG12D, leading to pancreatic tumors. Here, we report that after caerulein-induced pancreatitis, Sirt2 deficient mice exhibited an increased inflammatory phenotype and delayed pancreatic tissue recovery. Seven days post injury, the pancreas of Sirt2-/- mice display active inflammation, whereas wild-type mice had mostly recovered. In addition, the pancreas from the Sirt2-/- mice exhibited extensive tissue fibrosis, which was still present at six weeks after exposure. The mice lacking Sirt2 also demonstrated an enhanced whole body pro-inflammatory phenotype that was most obvious with increasing age. Importantly, an accumulation of a cell population with spontaneous cancerous KrasG12D mutations was observed in the Sirt2-/- mice that is enhanced in the recovering pancreas after exposure to caerulein. Finally, transcriptome analysis of the pancreas of the Sirt2-/- mice exhibited a pro-inflammatory genomic signature. These results suggest that loss of Sirt2, as well as increased age, enhanced the immune response to pancreatic injury and induced an inflammatory phenotype permissive for the accumulation of cells carrying oncogenic Kras mutations. PMID- 30405155 TI - Magnetoresistive biosensors with on-chip pulsed excitation and magnetic correlated double sampling. AB - Giant magnetoresistive (GMR) sensors have been shown to be among the most sensitive biosensors reported. While high-density and scalable sensor arrays are desirable for achieving multiplex detection, scalability remains challenging because of long data acquisition time using conventional readout methods. In this paper, we present a scalable magnetoresistive biosensor array with an on-chip magnetic field generator and a high-speed data acquisition method. The on-chip field generators enable magnetic correlated double sampling (MCDS) and global chopper stabilization to suppress 1/f noise and offset. A measurement with the proposed system takes only 20 ms, approximately 50* faster than conventional frequency domain analysis. A corresponding time domain temperature correction technique is also presented and shown to be able to remove temperature dependence from the measured signal without extra measurements or reference sensors. Measurements demonstrate detection of magnetic nanoparticles (MNPs) at a signal level as low as 6.92 ppm. The small form factor enables the proposed platform to be portable as well as having high sensitivity and rapid readout, desirable features for next generation diagnostic systems, especially in point-of-care (POC) settings. PMID- 30405156 TI - Integrative Bone Metabolomics-Lipidomics Strategy for Pathological Mechanism of Postmenopausal Osteoporosis Mouse Model. AB - Osteoporosis, characterized by bone mass reduction and increased fractures, has become a global health problem that seriously affects the health of people, especially postmenopausal women; however, the current pathogenesis of postmenopausal osteoporosis (PMOP) has not been thoroughly elucidated to date. In this study, bilateral ovariectomy was performed to establish an OVX mouse model of osteoporosis. UPLC-Q-TOF-MS-based lipidomics in combination with metabolomics were used to analyze the femur tissue of osteoporosis mice. We found that 11 polar metabolites and 93 lipid metabolites were significantly changed and were involved in amino acid metabolism, nucleotide metabolism and lipid metabolism. Among the lipids, fatty acyls, glycerolipids, glycerophospholipids, sphingolipids and sterols showed robust changes. These results revealed that several metabolic disorders caused by changes in the hormone levels in OVX, especially disordered lipid metabolism, are closely related to the imbalance between bone resorption and formation and may underlie the development of PMOP. The data generated via lipidomics and metabolomics presented in this study shows good applicability and wide coverage in the construction of the metabolic profile of bone tissue. Therefore, this approach may provide the pathway focusing and data support at the metabolite level for the in-depth mechanism of PMOP. PMID- 30405157 TI - Growth Mechanisms and Electronic Properties of Vertically Aligned MoS2. AB - Thin films of layered semiconductors emerge as highly promising materials for energy harvesting and storage, optoelectronics and catalysis. Their natural propensity to grow as oriented crystals and films is one of their distinct properties under recent focal interest. Specifically, the reaction of transition metal films with chalcogen vapor can result in films of vertically aligned (VA) layers, while metal-oxides react with chalcogens in vapor phase to produce horizontally aligned crystals and films. The growth mechanisms of vertically oriented films are not yet fully understood, as well as their dependence on the initial metal film thickness and growth conditions. Moreover, the resulting electronic properties and the role of defects and disorder had not yet been studied, despite their critical influence on catalytic and device performance. In this work, we study the details of oriented growth of MoS2 with complementary theoretical and experimental approaches. We present a general theoretical model of diffusion-reaction growth that can be applied to a large variety of layered materials synthesized by solid-vapor reaction. Moreover, we inspect the relation of electronic properties to the structure of vertically aligned MoS2 and shed light on the density and character of defects in this material. Our measurements on Si-MoS2 p-n hetero-junction devices point to the existence of polarizable defects that impact applications of vertical transition-metal dichalcogenide materials. PMID- 30405158 TI - Spin-wave duplexer studied by finite-element micromagnetic simulation. AB - We conceptually designed a robust nano-scale waveguide structure suitable for potential use as a spin-wave duplexer that allows signal propagation only of selected narrow-band frequencies and duplex transmission in a three-port device comprising a receiver, a transmitter, and their common antenna. The waveguide structure combines three different arms and a circular ring, both made of nanostrip waveguides and a single magnetic material for reliably controllable propagations of spin waves. We attribute the observed duplex transmission of spin waves of narrow pass bands to scattering of spin waves by edge solitons placed at contact areas between the arms and the circular ring. This work proposes the first concept of nano-scale magnonic duplexers operating beyond GHz-frequency ranges. PMID- 30405159 TI - Catalase, superoxide dismutase and ascorbate-glutathione cycle enzymes confer drought tolerance of Amaranthus tricolor. AB - The study was performed to explore physiological, non-enzymatic and enzymatic detoxification pathways of reactive oxygen species (ROS) in tolerance of Amaranthus tricolor under drought stress. The tolerant genotype VA13 exhibited lower reduction in growth, photosynthetic pigments, relative water content (RWC) and negligible increment in electrolyte leakage (EL), lower increment in proline, guaiacol peroxidase (GPOX) activity compared to sensitive genotype VA15. This genotype also had higher catalase (CAT), superoxide dismutase (SOD), remarkable and dramatic increment in ascorbate-glutathione content, ascorbate-glutathione redox and ascorbate-glutathione cycle enzymes activity compared to sensitive genotype VA15. The negligible increment of ascorbate-glutathione content, ascorbate-glutathione redox and ascorbate-glutathione cycle enzymes activities and dramatic increment in malondialdehyde (MDA), hydrogen peroxide (H2O2) and EL were observed in the sensitive genotype VA15. SOD contributed superoxide radical dismutation and CAT contributed H2O2 detoxification in both sensitive and tolerant varieties, however, these had a great contribution in the tolerant variety. Conversely, proline and GPOX accumulation were higher in the sensitive variety compared to the tolerant variety. Increase in ascorbate-glutathione cycle enzymes activities, CAT, ascorbate-glutathione content, SOD, and ascorbate glutathione redox clearly evident that CAT, ascorbate-glutathione cycle and SOD played a significant activity in ROS detoxification of tolerant A. tricolor variety. PMID- 30405160 TI - MRI-guided intrathecal transplantation of hydrogel-embedded glial progenitors in large animals. AB - Disseminated diseases of the central nervous system such as amyotrophic lateral sclerosis (ALS) require that therapeutic agents are delivered and distributed broadly. Intrathecal route is attractive in that respect, but to date there was no methodology available allowing for optimization of this technique to assure safety and efficacy in a clinically relevant setting. Here, we report on interventional, MRI-guided approach for delivery of hydrogel-embedded glial progenitor cells facilitating cell placement over extended surface of the spinal cord in pigs and in naturally occurring ALS-like disease in dogs. Glial progenitors used as therapeutic agent were embedded in injectable hyaluronic acid based hydrogel to support their survival and prevent sedimentation or removal. Intrathecal space was reached through lumbar puncture and the catheter was advanced under X-ray guidance to the cervical part of the spine. Animals were then transferred to MRI suite for MRI-guided injection. Interventional and follow up MRI as well as histopathology demonstrated successful and predictable placement of embedded cells and safety of the procedure. PMID- 30405161 TI - Cellular signaling and gene expression profiles evoked by a bivalent macrocyclic peptide that serves as an artificial MET receptor agonist. AB - Non-native ligands for growth factor receptors that are generated by chemical synthesis are applicable to therapeutics. However, non-native ligands often regulate cellular signaling and biological responses in a different manner than native ligands. Generation of surrogate ligands comparable to native ligands is a challenging need. Here we investigated changes in signal transduction and gene expression evoked by a bivalent macrocyclic peptide (aMD5-PEG11) capable of high affinity binding to the MET/hepatocyte growth factor (HGF) receptor. Binding of aMD5-PEG11 to the MET extracellular region was abolished by deletion of the IPT3 IPT4 domain, indicating the involvement of IPT3-IPT4 in the binding of aMD5-PEG11 to the MET receptor. aMD5-PEG11 induced dimerization and activation of the MET receptor and promoted cell migration that was comparable to induction of these activities by HGF. Signal activation profiles indicated that aMD5-PEG11 induced phosphorylation of intracellular signaling molecules, with a similar intensity and time dependency as HGF. In 3-D culture, aMD5-PEG11 as well as HGF induced epithelial tubulogenesis and up-regulated the same sets of functionally classified genes involved in multicellular organism development. Thus, a non native surrogate ligand that consisted of a bivalent macrocyclic peptide can serve as an artificial MET receptor agonist that functionally substitutes for the native ligand, HGF. PMID- 30405162 TI - Conserved Noncoding Sequences Boost ADR1 and SP1 Regulated Human Swiprosin-1 Promoter Activity. AB - Swiprosin-1 is expressed in various types of cells or tissues of different species. To investigate the mechanisms underlying Swiprosin-1 expression pattern, we analyzed the promoter activity of 2-kilobase genomic sequences located at 5' flanking region of the Swiprosin-1 gene. The -2000/+41 bp of 5' flanking untranslated promoter region of Swiprosin-1 gene was constitutively transactivated without significant effect of PMA, A23187, or PMA/A23187 stimulation in Jurkat T cells. Further, we identified 5' deletant of proximal promoter region (-100/+41 to -70/+41) plays a pivotal role in activating the Swiprosin-1 gene in Jurkat T cells. Our studies also verified that ADR1 and Sp1 transcription factors were located between -70 and -100 locus of 5' flanking proximal promoter region, which is critical for the Swiprosin-1 promoter activity. ADR1 and Sp1 were shown to bind the regions of -82, -79, -76, -73 and 70 and; -79, -78 and -77, respectively, within the proximal promoter region of Swiprosin-1. Finally conserved noncoding sequences (CNS) -1, -2 and -3 were located between the exon 1 and exon 2 of Swiprosin-1 gene and synergistically transactivated the Swiprosin-1 promoter. In summary, Swiprosin-1 was constitutively expressed in Jurkat T cells by the coordinate action of ADR1 and SP1 transcription factors at the transcriptional level and CNS further boost the proximal region of Swiprosin-1 promoter activity. Our findings provide novel insights that the transcriptional regulation of Swiprosin-1 by targeting ADR1 and Sp1 binding sites may be helpful in exploring novel therapeutic strategies for advanced immune or other disorders. PMID- 30405163 TI - High energy oxidation and organosolv solubilization for high yield isolation of cellulose nanocrystals (CNC) from Eucalyptus hardwood. AB - Cellulose nanocrystals (CNC) have been widely used as responsive materials, chiral templates, and tough nano-composites due to its unparalleled properties. Acid and enzyme hydrolyses are extensively employed to prepare CNC. These traditional approaches exhibit inherent limitations of corrosion hazards, time consuming process, and/or low yield. Herein, irradiation oxidation and organosolv solubilization are conducted to cause rapid degradation with simultaneous crystallization of cellulose to achieve approx. 87% yield of CNC. The morphology, spectroscopic, and stability properties of the as-prepared CNC are characterized through UV-vis spectroscopy, zetal potential, XRD, TEM, DLS, GPC, FT-IR and TGA techniques. The resultant CNC suspension presents unique property with high stability after 9 months storage at 4 degrees C. Moreover, CNC liquid crystal phase is successfully generated by addition of anions or cations solution to the CNC aqueous dispersion without stirring. The innovative approach in this work opens an avenue to obtain CNC directly from lignocellulosic biomass through irradiation oxidation and organosolv solubilization without acid hydrolysis and washing procedure. PMID- 30405164 TI - Author Correction: Obstetric outcomes in pregnant women with and without depression: population-based comparison. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30405166 TI - Interplay between MexAB-OprM and MexEF-OprN in clinical isolates of Pseudomonas aeruginosa. AB - MexAB-OprM and MexEF-OprN are Pseudomonas aeruginosa efflux pumps involved in the development of antibiotic resistance. Several studies developed with laboratory strains or using a few clinical isolates have reported that the regulation system of MexEF-OprN is involved in the final levels of MexAB-OprM expression. Therefore, this study was aimed to determine the interplay between MexAB-OprM and MexEF-OprN in 90 out of 190 P. aeruginosa clinical isolates with an efflux pump overexpression phenotype. Regarding oprD, 33% (30/90) of isolates displayed relevant modifications (RM) defined as frameshift or premature stop, both related to carbapenem resistance. On the other hand, 33% of the isolates displayed RM in nalC, nalD or mexR, which were significantly associated with multidrug resistance (MDR), non-susceptibility to carbapenems, OprD alterations and strong biofilm production. Meanwhile, the RM in MexS were associated with presence of pigment (p = 0.004). Otherwise, when all the regulators were analysed together, the association between RM in MexAB-OprM regulators and MDR was only significant (p = 0.039) when mexS was the wild type. These data show the modulatory effect of MexEF-OprN on MexAB-OprM in a clinical population of P. aeruginosa. Further studies may contribute to design of novel molecules acting on this interplay to fight against antimicrobial resistance. PMID- 30405167 TI - Curvature induced quantum phase transitions in an electron-hole system. AB - In this work, we study the effect of introducing a periodic curvature on nanostructures, and demonstrate that the curvature can lead to a transition from a topologically trivial state to a non-trivial state. We first present the Hamiltonian for an arbitrarily curved nanostructure, and introduce a numerical scheme for calculating the bandstructure of a periodically curved nanostructure. Using this scheme, we calculate the bandstructure for a sinusoidally curved two dimensional electron gas. We show that the curvature can lead to a partner switching reminiscent of a topological phase transition at the time reversal invariant momenta. We then study the Bernevig-Hughes-Zhang (BHZ) Hamiltonian for a two-dimensional quantum well. We show that introducing a curvature can lead to the emergence of topological surface states. PMID- 30405165 TI - A versatile method for the UVA-induced cross-linking of acetophenone- or benzophenone-functionalized DNA. AB - Bioconjugation, biosensing, bioimaging, bionanomaterials, etc., are only a few examples of application of functionalized DNA. Since base-modified nucleic acids contribute not only to a broad range of biotechnological fields but also to the understanding of various cellular processes, it is crucial to design novel modifications with unique properties. Here, we demonstrate the utilization of N4 cytidine modified oligonucleotides, which contain reactive acetophenone (AP) or benzophenone (BP) groups, for the UV-induced cross-linking. We find that terminal deoxynucleotidyl transferase-mediated 3'-tailing using AP/BP-containing modified nucleotides generates photoactive DNA, suitable for a straightforward covalent cross-linking with both interacting proteins and a variety of well-known solid polymeric supports. Moreover, we show that AP/BP-functionalization of nucleic acid molecules induces an efficient cross-linking upon exposure to UVA light. Our findings reveal that 3'-tailed single-stranded DNA bearing AP/BP-moieties is easily photoimmobilized onto untreated polystyrene, polypropylene, polylactate, polydimethylsiloxane, sol-gel and borosilicate glass substrates. Furthermore, we demonstrate that such immobilized DNA probes can be further used for successful hybridization of complementary DNA targets. Our results establish novel N4 cytosine nucleobase modifications as photoreactive labels and suggest an effortless approach for photoimmobilization of nucleic acids. PMID- 30405168 TI - Communicating Two States in Perovskite Revealed by Time-Resolved Photoluminescence Spectroscopy. AB - Organic-inorganic perovskite as a promising candidate for solar energy harvesting has attracted immense interest for its low-cost preparation and extremely high quantum efficiency. However, the fundamental understanding of the photophysics in perovskite remains elusive. In this work, we have revealed two distinct states in MAPbI3 thin films at low temperature through time-resolved photoluminescence spectroscopy (TRPL). In particular, we observed a photo-induced carrier injection from the high energy (HE) state to the low energy (LE) state which has a longer lifetime. The strong interaction between the two states, evidenced by the injection kinetics, can be sensitively controlled through the excitation power. Understanding of the interacting two-states not only sheds light on the long PL lifetime in perovskite but also helps to understand the different behavior of perovskite in response to different excitation power. Further efforts in modifying the low energy state could significantly improve the quantum efficiency and lead to novel application in optoelectronics based on perovskite. PMID- 30405169 TI - Dynamic recognition and linkage specificity in K63 di-ubiquitin and TAB2 NZF domain complex. AB - Poly-ubiquitin (poly-Ub) is involved in various cellular processes through the linkage-specific recognition of Ub-binding domains (UBD). In this study, using molecular dynamics (MD) simulation together with an enhanced sampling method, we demonstrated that K63-linked di-Ub recognizes the NZF domain of TAB2, a zinc finger UBD, in an ensemble of highly dynamic structures that form from the weak interactions between UBD and the flexible linker connecting the two Ubs. However, the K63 di-Ub/TAB2 NZF complex showed a much more compact and stable ensemble than the non-native complexes, linear di-Ub/TAB2 NZF and K33 di-Ub/TAB2 NZF, that were modeled from linear di-Ub/HOIL-1L NZF and K33 di-Ub/TRABID NZF1, respectively. We further demonstrated the importance of the length and position of the Ub-Ub linker in the results of MD simulations of K63 di-Ub/TAB2 NZF by changing the Ub linkage from the native K63 to four different non-native linkages, linear, K6, K11, and K48, while maintaining inter-molecular contacts in the native complex. No systems with non-native linkage maintained the native binding configuration. These simulation results provide an atomistic picture of the linkage specific recognition of poly-Ubs leading to the biological functions such as cellular colocalization of various component proteins in the signal transduction pathways. PMID- 30405170 TI - Scaffold-Hopping from Synthetic Drugs by Holistic Molecular Representation. AB - The discovery of novel ligand chemotypes allows to explore uncharted regions in chemical space, thereby potentially improving synthetic accessibility, potency, and the drug-likeness of molecules. Here, we demonstrate the scaffold-hopping ability of the new Weighted Holistic Atom Localization and Entity Shape (WHALES) molecular descriptors compared to seven state-of-the-art molecular representations on 30,000 compounds and 182 biological targets. In a prospective application, we apply WHALES to the discovery of novel retinoid X receptor (RXR) modulators. WHALES descriptors identified four agonists with innovative molecular scaffolds, populating uncharted regions of the chemical space. One of the agonists, possessing a rare non-acidic chemotype, revealed high selectivity on 12 nuclear receptors and comparable efficacy as bexarotene on induction of ATP binding cassette transporter A1, angiopoietin like protein 4 and apolipoprotein E. The outcome of this research supports WHALES as an innovative tool to explore novel regions of the chemical space and to detect novel bioactive chemotypes by straightforward similarity searching. PMID- 30405172 TI - Structural effects and lymphocyte activation properties of self-assembled polysaccharide nanogels for effective antigen delivery. AB - The success of immunotherapeutic vaccines is often limited by their inability to activate the cytotoxic T lymphocyte (CTL)-inducing Th1 pathway. We investigated the ability of self-assembled nanogels (CHP or CH-CDex) to activate this pathway, and characterised them chemically and biologically. Once loaded with antigen (ovalbumin, OVA) their OVA encapsulation and dissociation rates suggested the possibility of effective antigen delivery. The DC2.4 dendritic cell line took up either vaccine time-dependently, but both vaccines required CpG DNA for class I MHC presentation. The nanogel vaccines interacted with RAW264.7, a Balb/c mouse derived macrophage cell line, and co-localised with lysosomes, suggesting their endocytotic internalization in RAW264.7. Both vaccines activated CTLs better than OVA alone. Unlike OVA alone, the nanogel vaccines induced IgG2a antibody production in mice, whereas the former induced IgG1 antibodies. OVA-nanogel delivery to the draining lymph nodes (DLNs) was higher than that for OVA alone, reaching a deeper medullary area. Furthermore, Langerin+ CD103+ DCs interacted with the nanogel vaccines effectively, which is a subset of cross-presentation DC, in the DLNs. The nanogel vaccines each had good anti-tumour efficacy in OVA tumour-bearing mice compared with the OVA alone. Thus, CHP and CH-CDex nanogels should be investigated further because of the great potential they offer for immunotherapy. PMID- 30405171 TI - Social context modulates digestive efficiency in greylag geese (Anser anser). AB - In group-living animals, social context is known to modulate physiology, behaviour and reproductive output as well as foraging and nutritional strategies. Here we investigate the digestive efficiency of 38 individuals belonging to different social categories of a semi-feral and individually marked flock of greylag geese (Anser anser). During 9 consecutive days in winter 2017, when the ground was fully covered with snow (i.e. no grass or other natural forage available) and the accessible food was standardized, 184 individual droppings were collected and analysed to estimate the apparent digestibility of organic matter (ADOM). Lignin was used as an indigestible internal marker in the food and droppings. The digestive efficiency was higher in pairs with offspring as compared to pairs without offspring or unpaired birds. Furthermore, individuals with high ADOM were more likely to breed successfully in the following season than those with low ADOM. Our findings demonstrate that social status modulates digestive efficiency, probably via a chain of physiological mechanisms including a dampened stress response in individuals enjoying stable social relationships with and social support by their family members (i.e. their own pair-partner and offspring). Our findings underline the importance of the social network in modulating physiology, such as digestive efficiency, and ultimately reproductive success. PMID- 30405173 TI - Drought-induced shift in tree response to climate in floodplain forests of Southeastern Europe. AB - Floodplain forests are the most rapidly disappearing ecosystem in the world, especially in temperate regions of Europe where anthropogenic influence has been pronounced throughout history. Research on primeval forests is crucial to further our understanding of their natural dynamics and interaction with climate but is limited by the lack of such preserved forests. The aim of this study was to investigate how a primeval floodplain forest in Southeastern Europe has responded to climate variability during the last 250 years through comparison of tree growth and climate, canopy disturbance and recruitment dynamic of two dominant tree species with different tolerances to flooding/drought. Our analysis revealed induced stress caused by several consecutive severe drought events in the 1940s, which led to a significant increase in sensitivity to increasing temperatures and decreasing river water levels. This trend is particularly pronounced in pedunculate oak. Age structure analysis revealed one larger episode of oak regeneration culminating after periods of intense growth release. Such period co occurs with summer drought, which is part of a complex system of natural disturbances and a significant natural driver of the cyclical regeneration of primeval oak ecosystems. PMID- 30405176 TI - Stop, don't prune me! PMID- 30405175 TI - Author Correction: Maintenance, reserve and compensation: the cognitive neuroscience of healthy ageing. AB - In the originally published version of article, there were two errors in the references. The reference "Nilsson, J. & Lovden, M. Naming is not explaining: future directions for the "cognitive reserve" and "brain maintenance" theories. Alzheimer's Res. Ther. 10, 34 (2018)" was missing. This reference has been added as REF. 14 in the HTML and PDF versions of the article and cited at the end of the sentence "However, over the years, these terms have been used inconsistently, creating confusion and slowing progress." on page 701 and at the end of the sentence "If reserve is defined merely as the factor that individuals with greater reserve have and then this factor is used to explain why some individuals have greater reserve, the argument is clearly circular." on page 704. The reference list has been renumbered accordingly. In addition, in the original reference list, REF. 91 was incorrect. The reference should have read "Cabeza, R. Hemispheric asymmetry reduction in older adults. The HAROLD model. Psychol. Aging 17, 85-100 (2002)". This reference, which is REF. 92 in the corrected reference list, has been corrected in the HTML and PDF versions of the article. PMID- 30405174 TI - Functional recovery of a subtropical evergreen-deciduous broadleaved mixed forest following clear cutting in central China. AB - Ecosystem functioning is largely dependent on the functional traits of its component species. Most of the previous researches on ecosystem recovery have mainly focused on taxonomic composition but less attention is concentrated on functional community composition. Here, we examine the dynamic trend of functional community composition along a recovery chronosequence following clear cutting in subtropical evergreen-deciduous broadleaved mixed forest. Results showed that with the process of recovery, the functional composition changed from a community with high specific leaf area (CWM_ SLA), leaf nitrogen concentration (CWM_ LNC) and leaf phosphorus (CWM_ LPC) but low leaf thickness (CWM_ LT) and stem tissue density (CWM_ STD) to that with low CWM_ SLA, CWM_ LNC and CWM_ LPC but high CWM_ LT and CWM_ STD. Functional traits of evergreen and deciduous species were significantly different in each stage. Light availability and soil phosphorus were the most important influencing factors during the recovery. Our study suggests that the subtropical evergreen-deciduous broadleaved mixed forest is gradually shifting from a resource acquisitive to a resource conservative assemblage, in which evergreen species will become more and more dominant. Any management or conservation planning upon the forest ecosystem should integrate this dynamic trend of functional change. PMID- 30405177 TI - Sensory prediction errors, not performance errors, update memories in visuomotor adaptation. AB - Sensory prediction errors are thought to update memories in motor adaptation, but the role of performance errors is largely unknown. To dissociate these errors, we manipulated visual feedback during fast shooting movements under visuomotor rotation. Participants were instructed to strategically correct for performance errors by shooting to a neighboring target in one of four conditions: following the movement onset, the main target, the neighboring target, both targets, or none of the targets disappeared. Participants in all conditions experienced a drift away from the main target following the strategy. In conditions where the main target was shown, participants often tried to minimize performance errors caused by the drift by generating corrective movements. However, despite differences in performance during adaptation between conditions, memory decay in a delayed washout block was indistinguishable between conditions. Our results thus suggest that, in visuomotor adaptation, sensory predictions errors, but not performance errors, update the slow, temporally stable, component of motor memory. PMID- 30405178 TI - Purified Inactivated Zika Vaccine Candidates Afford Protection against Lethal Challenge in Mice. AB - In response to the 2016 global public health emergency of international concern announced by the World Health Organization surrounding Zika virus (ZIKV) outbreaks, we developed a purified inactivated Zika virus vaccine (PIZV) candidate from ZIKV strain PRVABC59, isolated during the outbreak in 2015. The virus isolate was plaque purified, creating six sub-isolated virus stocks, two of which were selected to generate PIZV candidates for preclinical immunogenicity and efficacy evaluation in mice. The alum-adjuvanted PIZV candidates were highly immunogenic in both CD-1 and AG129 mice after a 2-dose immunization. Further, AG129 mice receiving 2 doses of PIZV formulated with alum were fully protected against lethal ZIKV challenge and mouse immune sera elicited by the PIZV candidates were capable of neutralizing ZIKVs of both African and Asian genetic lineages in vitro. Additionally, passive immunization of naive mice with ZIKV immune serum showed strong positive correlation between neutralizing ZIKV antibody (NAb) titers and protection against lethal challenge. This study supported advancement of the PIZV candidate toward clinical development. PMID- 30405179 TI - Impact of the secondary plant metabolite Cucurbitacin B on the demographical traits of the melon aphid, Aphis gossypii. AB - Cucurbitacin B is a natural triterpene present in plants of Cucurbitaceae family, which are among the host plants for melon aphid, Aphis gossypii. In present study we characterized the effects of two cucurbitacin B concentrations on the biological parameters of adults (F0) and of juveniles and adults of their progeny (F1). The results showed that cucurbitacin B at 25 ppm significantly reduced the adult longevity and fecundity of both F0 and F1 generation. Exposure of F0 generation to 25 ppm though reduced the demographic traits of F1 including the intrinsic rate of increase r (day-1), generation time T (day), finite rate of increase lambda (day-1), however, only net reproductive rate R0 (offspring/individual) decreased significantly. While 100 ppm reduced not only the longevity and fecundity of F0 generation but also the longevity of F1 generation. Fecundity of F1 was not affected by 100 ppm of cucurbitacin B, however, R0 (offspring/individual) and T (day) of F1 generation were lower than the control population. These results support the hypothesis that high contents of cucurbitacin B caused negative impact on melon aphid and could be used as a lead for classical selection of resistant varieties of plants that are main hosts for the melon aphid. PMID- 30405180 TI - Comparison Between Metabolic Syndrome and the Framingham Risk Score as Predictors of Cardiovascular Diseases Among Kazakhs in Xinjiang. AB - Metabolic syndrome (MS) and Framingham risk score (FRS) can be used for predicting the risk of developing cardiovascular diseases (CVD). Previous studies that compared FRS and MS have focused on high-income urban areas. This study focused on the comparison between FRS and MS when used in nomadic minorities in mountain areas. Moreover, an applicable tool for predicting the risk of developing CVD was identified. 2,286 participants who were recruited from the far west of China were followed-up for a median of 5.49 years. MS and FRS were compared in terms of their ability in predicting development of CVD using Cox regression and receiver operating characteristic curve. After each component of MS was appraised, its area under the curve (AUC) was 0.647. When age was included, the AUC of MS risk score increased from 0.647 to 0.758 (P < 0.001). After adjusting for age, the AUC of FRS decreased from 0.732 to 0.582 (P < 0.001). The association between CVD and each quintile of MS risk score that included age was more significant than that between FRS and CVD under the same exposed condition. In conclusion, MS risk score that included age may be a better predictor of CVD among Kazakhs. PMID- 30405181 TI - A study of fractal dimension as a quality indicator of hairtail (Trichiurus haumela) samples during frozen storage. AB - Hairtail fish samples were stored at different freezing temperatures of -5 degrees C, -20 degrees C, -40 degrees C and -80 degrees C. To establish an effective quality evaluation approach for hairtail samples during frozen storage, fractal dimension was used to observe the porous microstructure that resulted from the ice crystal formation in frozen hairtail meat. The results showed that the initial value of fractal dimension of all the samples was 1.968. After frozen storage, the fractal dimension of samples at -5 degrees C, -20 degrees C, -40 degrees C and -80 degrees C decreased to 1.539, 1.682, 1.856 and 1.896, respectively. Traditional quality indicators such as water activity, color and textural properties (i.e., hardness, springiness and chewiness) also exhibited a similar decreasing trend, and the rate of change decreased with a decrease in storage temperature. The relationships were analyzed, and these traditional quality indicators were correlated with the fractal dimension with determined correlation coefficients within +/-0.900. Moreover, based on the fractal dimension model, the first-order kinetic equation of fractal dimension variation during storage was [Formula: see text], which can be used to predict the shelf life of preserved hairtails at different storage temperatures. The results demonstrated fractal dimension was a novel and feasible method to evaluate the quality of hairtails in frozen storage. PMID- 30405182 TI - Increased frequency of systemic pro-inflammatory Vdelta1+ gammadelta T cells in HIV elite controllers correlates with gut viral load. AB - gammadelta T cells predominate in the intestinal mucosa and help maintain gut homeostasis and mucosal immunity. Although HIV infection significantly alters these cells, what drives these perturbations is unclear. Growing evidence suggests that impaired intestinal immune function in HIV leads to chronic immune activation and disease progression. This occurs even in HIV controllers - individuals with undetectable HIV viremia without antiretroviral therapy (ART). We show that Vdelta1+ cells, a subset of gammadelta T cells described as being important in intestinal barrier function, increase in frequency in HIV-infected individuals, including HIV controllers. These cells resemble terminally differentiated effector memory cells, producing the pro-inflammatory cytokines IFNgamma, TNFalpha, and MIP-1beta upon stimulation. Importantly, pro-inflammatory Vdelta1+ cell frequency correlates with levels of HIV RNA in intestinal tissue but not in plasma. This study supports a model in which local viral replication in the gut in HIV controllers disrupts the phenotype and function of Vdelta1+ cells, a cell type involved in the maintenance of epithelial barrier integrity, and may thereby contribute to systemic immune activation and HIV disease progression. PMID- 30405183 TI - Altered Populations of Unconventional T Cell Lineages in Patients with Langerhans Cell Histiocytosis. AB - Langerhans cell histiocytosis (LCH) lesions are defined by the presence of CD1a+/CD207+ myeloid cells, but many other immune cells are present including unconventional T cells, which have powerful immunoregulatory functions. Unconventional T cell lineages include mucosal-associated invariant T (MAIT) cells, type I natural killer T (NKT) cells and gamma-delta (gammadelta) T cells, which are associated with many inflammatory conditions, although their importance has not been studied in LCH. We characterized their phenotype and function in blood and lesions from patients with LCH, and identified a deficiency in MAIT cell frequency and abnormalities in the subset distributions of gammadelta T cells and NKT cells. Such abnormalities are associated with immune dysregulation in other disease settings and are therefore potentially important in LCH. Our study is the first to recognize alterations to MAIT cell proportions in patients with LCH. This finding along with other abnormalities identified amongst unconventional T cells could potentially influence the onset and progression of LCH, thereby highlighting potential targets for new immune based therapies. PMID- 30405184 TI - A novel alkaline protease from alkaliphilic Idiomarina sp. C9-1 with potential application for eco-friendly enzymatic dehairing in the leather industry. AB - Alkaline proteases have a myriad of potential applications in many industrial processes such as detergent, food and feed production, waste management and the leather industry. In this study, we isolated several alkaline protease producing bacteria from soda lake soil samples. A novel serine alkaline protease (AprA) gene from alkaliphilic Idiomarina sp. C9-1 was cloned and expressed in Escherichia coli. The purified AprA and its pre-peptidase C-terminal (PPC) domain truncated enzyme (AprA-PPC) showed maximum activity at pH 10.5 and 60 degrees C, and were active and stable in a wide range of pH and temperature. Ca2+ significantly improved the thermostability and increased the optimal temperature to 70 degrees C. Furthermore, both AprA and AprA-PPC showed good tolerance to surfactants and oxidizing and reducing agents. We found that the PPC domain contributed to AprA activity, thermostability and surfactant tolerance. With casein as substrate, AprA and AprA-PPC showed the highest specific activity of 42567.1 U mg-1 and 99511.9 U mg-1, the Km values of 3.76 mg ml-1 and 3.98 mg ml 1, and the Vmax values of 57538.5 U mg-1 and 108722.1 U mg-1, respectively. Secreted expression of AprA-PPC in Bacillus subtilis after 48 h cultivation resulted in yield of 4935.5 U ml-1 with productivity of 102.8 U ml-1 h-1, which is the highest reported in literature to date. Without adding any lime or sodium sulfide, both of which are harmful pollutants, AprA-PPC was effective in dehairing cattle hide and skins of goat, pig and rabbit in 8-12 h without causing significant damage to hairs and grain surface. Our results suggest that AprA-PPC may have great potentials for ecofriendly dehairing of animal skins in the leather industry. PMID- 30405185 TI - Vaccines to treat opioid use disorders and to reduce opioid overdoses. PMID- 30405186 TI - Intermittent intake of rapid cocaine injections promotes the risk of relapse and increases mesocorticolimbic BDNF levels during abstinence. AB - Cocaine is thought to be more addictive when it reaches the brain rapidly. We predicted that variation in the speed of cocaine delivery influences the likelihood of addiction in part by determining the risk of relapse after abstinence. Under an intermittent-access schedule, rats pressed a lever for rapid (injected over 5 s) or slower (90 s) intravenous cocaine injections (0.5 mg/kg/injection). Control rats self-administered food pellets. A tone-light cue accompanied each self-administered reward. The 5s- and 90s-rats took a similar average amount of cocaine. One or 45 days after withdrawal from cocaine/forced abstinence, lever-pressing behaviour was extinguished during a 6-h session. Immediately thereafter, cue- or cocaine (10 mg/kg, i.p.)-induced reinstatement was assessed for 1 h. One or 45 days after withdrawal, only 5s-rats showed significant cocaine-induced reinstatement of reward-seeking behaviour. In both cocaine groups, cue-induced reinstatement behaviour was more pronounced after 45 days than after 1 day of withdrawal from cocaine, indicating incubation of conditioned drug craving. However, cue-induced reinstatement after extended abstinence was greatest in the 5s-rats. Brain-derived neurotrophic factor (BDNF) activity in the brain regulates reinstatement behaviour. Thus, 24 h after reinstatement tests, we measured BDNF protein concentrations in mesocorticolimbic regions. Only 5s-rats showed time-dependent increases in BDNF concentrations in the prelimbic cortex, nucleus accumbens core and ventral tegmental area after withdrawal from cocaine (day 45 > day 1). Thus, rapidly rising brain cocaine levels might facilitate addiction by evoking changes in the brain that intensify drug craving after abstinence, and these changes persist long after the last bout of cocaine use. PMID- 30405187 TI - Brain structural connectivity and neuroticism in healthy adults. AB - Understanding the neural correlates of the neurotic brain is important because neuroticism is a risk factor for the development of psychopathology. We examined the correlation between brain structural networks and neuroticism based on NEO Five-Factor Inventory (NEO-FFI) scores. Fifty-one healthy participants (female, n = 18; male, n = 33; mean age, 38.5 +/- 11.7 years) underwent the NEO-FFI test and magnetic resonance imaging (MRI), including diffusion tensor imaging and 3D T1WI. Using MRI data, for each participant, we constructed whole-brain interregional connectivity matrices by deterministic tractography and calculated the graph theoretical network measures, including the characteristic path length, global clustering coefficient, small-worldness, and betweenness centrality (BET) in 83 brain regions from the Desikan-Killiany atlas with subcortical segmentation using FreeSurfer. In relation to the BET, neuroticism score had a negative correlation in the left isthmus cingulate cortex, left superior parietal, left superior temporal, right caudal middle frontal, and right entorhinal cortices, and a positive correlation in the bilateral frontal pole, left caudal anterior cingulate cortex, and left fusiform gyrus. No other measurements showed significant correlations. Our results imply that the brain regions related to neuroticism exist in various regions, and that the neuroticism trait is likely formed as a result of interactions among these regions. This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network) from the Ministry of Education, Science, Sports and Culture of Japan. PMID- 30405189 TI - Chemical controls on the propagation rate of fracture in calcite. AB - Calcite (CaCO3) is one of the most abundant minerals in the Earth's crust, and it is susceptible to subcritical chemically-driven fracturing. Understanding chemical processes at individual fracture tips, and how they control the development of fractures and fracture networks in the subsurface, is critical for carbon and nuclear waste storage, resource extraction, and predicting earthquakes. Chemical processes controlling subcritical fracture in calcite are poorly understood. We demonstrate a novel approach to quantify the coupled chemical-mechanical effects on subcritical fracture. The calcite surface was indented using a Vickers-geometry indenter tip, which resulted in repeatable micron-scale fractures propagating from the indent. Individual indented samples were submerged in an array of aqueous fluids and an optical microscope was used to track the fracture growth in situ. The fracture propagation rate varied from 1.6 * 10-8 m s-1 to 2.4 * 10-10 m s-1. The rate depended on the type of aqueous ligand present, and did not correlate with the measured dissolution rate of calcite or trends in zeta-potential. We postulate that chemical complexation at the fracture tip in calcite controls the growth of subcritical fracture. Previous studies indirectly pointed to the zeta-potential being the most critical factor, while our work indicates that variation in the zeta-potential has a secondary effect. PMID- 30405188 TI - Proton minibeam radiation therapy widens the therapeutic index for high-grade gliomas. AB - Proton minibeam radiation therapy (pMBRT) is a novel strategy which has already shown a remarkable reduction in neurotoxicity as to compared with standard proton therapy. Here we report on the first evaluation of tumor control effectiveness in glioma bearing rats with highly spatially modulated proton beams. Whole brains (excluding the olfactory bulb) of Fischer 344 rats were irradiated. Four groups of animals were considered: a control group (RG2 tumor bearing rats), a second group of RG2 tumor-bearing rats and a third group of normal rats that received pMBRT (70 Gy peak dose in one fraction) with very heterogeneous dose distributions, and a control group of normal rats. The tumor-bearing and normal animals were followed-up for 6 months and one year, respectively. pMBRT leads to a significant tumor control and tumor eradication in 22% of the cases. No substantial brain damage which confirms the widening of the therapeutic window for high-grade gliomas offered by pMBRT. Additionally, the fact that large areas of the brain can be irradiated with pMBRT without significant side effects, would allow facing the infiltrative nature of gliomas. PMID- 30405190 TI - Camouflaged Nanosilver with Excitation Wavelength Dependent High Quantum Yield for Targeted Theranostic. AB - The present study shows the thorough investigations on optical properties and hydrodynamic diameters of glutathione (GSH) stabilized nanosilver clusters (AgNC) at different stages of synthesis and engineering for the optimized absolute quantum yield to generate fluorescent images of Dalton Lymphoma Ascites (DLA) tumour bearing mice. The initial increment of quantum yield was wavelength dependent and finally it became 0.509 which was due to the camouflaging or entrapment of AgNC in macrophages membranes. The potentiality of macrophages membrane camouflaged silver nanoclusters (AgM) was reflected in the cell viability assay and confocal based live dead cell assay where the AgM has better cell killing effect compared to AgNC with reduced dosage and in vivo mice imaging generated the clear visualization at the tumour sites. Therefore, from the present study, it can be considered that the camouflaged nanosilver can be used for targeted theranostic applications. PMID- 30405191 TI - Differential Effects of a Glucagon-Like Peptide 1 Receptor Agonist in Non Alcoholic Fatty Liver Disease and in Response to Hepatectomy. AB - Non-alcoholic fatty liver disease (NAFLD) is associated with post-operative liver failure (PLF) and impaired liver regeneration. We investigated the effects of a glucagon-like peptide-1 (GLP-1) receptor agonist on NAFLD, PLF and liver regeneration in mice fed chow diet or methionine/choline-deficient diet (MCD) or high fat diet (HFD). Fc-GLP-1 decreased transaminases, reduced intrahepatic triglycerides (TG) and improved MCD-induced liver dysfuction. Macrophage/Kupffer cell-related markers were also reduced although Fc-GLP-1 increased expression of genes related to natural killer (NK), cytotoxic T lymphocytes and hepatic stellate cell (HSC) activation. After partial hepatectomy (PH), survival rates increased in mice receiving Fc-GLP-1 on chow or MCD diet. However, the benefit of Fc-GLP-1 on NASH-like features was attenuated 2 weeks post-PH and liver mass restoration was not improved. At this time-period, markers of NK cells and cytotoxic T lymphocytes were further elevated in Fc-GLP-1 treated mice. Increased HSC related gene expression in livers was observed together with decreased retinyl ester content and increased retinal and retinoic acid, reflecting HSC activation. Similar effects were found in mice fed HFD receiving Fc-GLP-1. Our results shed light on the differential effects of a long-acting GLP-1R agonist in improving NAFLD and PLF, but not enhancing liver regeneration in mice. PMID- 30405192 TI - Surface potential and thin film quality of low work function metals on epitaxial graphene. AB - Metal films deposited on graphene are known to influence its electronic properties, but little is known about graphene's interactions with very low work function rare earth metals. Here we report on the work functions of a wide range of metals deposited on n-type epitaxial graphene (EG) as measured by Kelvin Probe Force Microscopy (KPFM). We compare the behaviors of rare earth metals (Pr, Eu, Er, Yb, and Y) with commonly used noble metals (Cr, Cu, Rh, Ni, Au, and Pt). The rare earth films oxidize rapidly, and exhibit unique behaviors when on graphene. We find that the measured work function of the low work function group is consistently higher than predicted, unlike the noble metals, which is likely due to rapid oxidation during measurement. Some of the low work function metals interact with graphene; for example, Eu exhibits bonding anomalies along the metal-graphene perimeter. We observe no correlation between metal work function and photovoltage, implying the metal-graphene interface properties are a more determinant factor. Yb emerges as the best choice for future applications requiring a low-work function electrical contact on graphene. Yb films have the strongest photovoltage response and maintains a relatively low surface roughness, ~5 nm, despite sensitivity to oxidation. PMID- 30405193 TI - Disease severity enhancement by an esterase from non-phytopathogenic yeast Pseudozyma antarctica and its potential as adjuvant for biocontrol agents. AB - The phylloplane yeast Pseudozyma antarctica secretes an esterase, named PaE, and xylanase when cultivated with xylose. We previously observed that the lipophilic layer of Micro-Tom tomato leaves became thinner after the culture filtrate treatment. The leaves developed reduced water-holding ability and became wilted. In this study, the purified enzymes were spotted on Micro-Tom leaves. PaE, but not xylanase, thinned the lipophilic layer of leaves and decreased leaf resistance to the phytopathogenic fungus Botrytis cinerea. Disease severity increased significantly in detached leaves and potted plants treated with the culture filtrate and B. cinerea spores compared with those treated with inactivated enzyme and B. cinerea alone. Spore germination ratios, numbers of penetrating fungal hyphae in the leaves, and fungal DNA contents also increased significantly on the detached leaves. Japanese knotweed (Fallopia japonica), a serious invasive alien weed in Europe and North America, also became susceptible to infection by the rust pathogen Puccinia polygoni-amphibii var. tovariae following the culture filtrate treatment. The culture filtrate treatment increased disease development in plants induced by both phytopathogenic fungi. Our results suggest that P. antarctica culture filtrate could be used as an adjuvant for sustainable biological weed control using phytopathogenic fungi. PMID- 30405194 TI - Rapid adaptation in phoretic mite development time. AB - Strong ecological selection can erode genetic variation and render populations unable to deal with changes in ecological conditions. In the adaptation of the phoretic mite Poecilochirus carabi to its host, the burying beetle Nicrophorus vespilloides, the timing of reproduction is crucial. Safe mite development is only possible during the beetles' brood care; mites that develop too slowly will have virtually zero fitness. If the strong specialisation in development time leaves no room for standing genetic variation to remain, changes in beetle brood care are disastrous. Beetle brood care depends on temperature and is thus vulnerable to changing climate. Accidental host switches to another beetle species with shorter brood care would also have negative effects on the mites. Only sufficient standing genetic variation could allow mismatched mite lines to survive and adapt. To test whether such rapid adaptation is possible in principle, we artificially selected on mite generation time. We were able to speed up, but not to slow down, mite development. We conclude that there is enough standing genetic variation in development time to allow P. carabi to quickly adapt to new host species or climate conditions, which could potentially lead to the evolution of new mite species. PMID- 30405196 TI - The Cut and the Building of Psychoanalysis, Volume II: Sigmund Freud and Sandor Ferenczi, by Carlo Bonomi, Routledge, London & New York, 2018, 285pp. PMID- 30405195 TI - Contrasting streamflow regimes induced by melting glaciers across the Tien Shan - Pamir - North Karakoram. AB - The glacierized Tien Shan - Pamir - Karakoram mountain complex supplies water to about 42 million people. Yet, the knowledge about future glacial runoff in response to future climate is limited. Here, we address this issue using a hydrological model, that includes the three components of glacial runoff: ice melt, snowmelt and the runoff of rainfall over ice. The model is forced by climate projections of the CMIP5 models. We find that the three components exhibit different long-term trajectories, sometimes opposite in sign to the long term trend in glacier impacts. For the eastern slope basins, streamflow is projected to increase by 28% (ranging from 9 to 44%, from climate model variation (CMV)) by the late 21st century, under the representative concentration pathway, RCP8.5. Ice melt contributes 39% (25 to 65%, CMV) of the total streamflow increase. However, streamflow from the western slopes is projected to decrease by 5% (-24 to 16%, CMV), due to the smaller contribution of ice melt, less precipitation and higher evapotranspiration. Increasing water supply from the eastern slopes suggests more water availability for currently degraded downstream ecosystems in the Xinjiang province of China, while the likely decreasing streamflow in Central Asian rivers on the western slopes indicates new regulations will be needed. PMID- 30405197 TI - Balint Matters: Psychosomatics and the Art of Assessment, by Jonathan Sklar, Routledge, Abingdon and New York, 2018, 232pp. PMID- 30405198 TI - Political Divide in the Consulting Room. AB - This paper addresses a treatment relationship that tests the analyst's capacity for empathy within an impinging political context. It involves a Ferenczian "relaxation of technique" within the analytic frame, while the analytic couple attempts to negotiate a polarized transference and countertransference. Specifically, within a long-term treatment imbued with positive transference, my patient becomes openly outraged by my insensitive anti-Trump remarks. Increasing confrontations around the expression of political views illuminate our otherness. He complains of psychic ostracism within a liberal cultural context, which tolerates no divergence from mainstream liberal ideas or discourse. I come to embody the oppressive other: the liberal "thought police", "silencing" him for his perspective. Empathic breaches between us take center stage: how I don't see the world as he does, and don't see or hear him. PMID- 30405199 TI - Closed-type pre-treatment device for point-of-care testing of sputum. AB - The procedures and protocols for the pre-treatment of sputum specimens, mainly used for the diagnosis of pneumonia, are complex, labor intensive, and require skilled specialists working in a biosafety containment laboratory because of sample infectivity. In this study, we developed the first portable, low-power pre treatment device that carries out all sputum pre-treatment procedures (liquefaction, homogenization, dissolution, and inactivation) in an enclosed space. Designed to simultaneously employ chemical and mechanical dissolution in the enclosed chamber, this device eliminates the risk of transmission and improves the effectiveness of sputum dissolution and pathogen detection. This device is expected to allow for the pre-treatment of infectious sputum specimens outside of a biosafety containment laboratory. Used in conjunction with automated genome extraction and detection systems, this device should make the on-site diagnosis using infectious sputum specimens possible. PMID- 30405200 TI - Evolution of six novel ORFs in the plastome of Mankyua chejuense and phylogeny of eusporangiate ferns. AB - In this paper, three plastomes of Mankyua chejuense, Helminthostachys zeylanica, and Botrychium ternatum in Ophioglossaceae were completely sequenced in order to investigate the plastome evolution and phylogeny of eusporangiate ferns. They were similar to each other in terms of length and the gene orders; however, six unknown open reading frames (ORFs) were found between rps4 and trnL-UAA genes in M. chejuense. Similar sequence regions of six ORFs of M. chejuense were found at the plastomes of Ophioglossum californicum and H. zeylanica, as well as the mitochondrial genome (mitogenome) of H. zeylanica, but not in B. ternatum. Interestingly, the translated amino acid sequences of three ORFs were more similar to the proteins of distantly related taxa such as algae and bacteria than they were to proteins in land plants. It is likely that the six ORFs region arose from endosymbiotic gene transfer (EGT) or horizontal gene transfer (HGT), but further study is needed to verify this. Phylogenetic analyses suggested that Mankyua was resolved as the earliest diverging lineage and that Ophioglossum was subsequently diverged in Ophioglossaceae. This result supports why the plastome of M. chejuense have contained the most ancestral six ORFs in the family. PMID- 30405202 TI - Evidences for a shared history for spectacled salamanders, haplotypes and climate. AB - The so-called glacial refugia, formed during the Pleistocene climatic oscillations, played a major role in shaping the distribution of European species, triggering migrations or isolating populations. Many of these events were recently investigated by genetic data, mainly for the European Last Glacial stage, in the Iberic, Italian and Greek-Balkan peninsulas. The amphibian genus Salamandrina, the most ancient living salamandrid lineage, was widespread in Europe until the climatic oscillations of Miocene probably forced it to shelter in the only suitable territory at that time, the Apennines. Nowadays this genus is endemic of peninsular Italy with two parapatric species, S. perspicillata and S. terdigitata, sharing an area of secondary contact formed after the Last Glacial Maximum. Climate is generally identified as the key factor for the interpretation of genetic data. In this research, we directly measure climate influences on the two Salamandrina known species through Ensemble Modelling techniques and post-modelling GIS analyses, integrating updated genetic data in this process. Our results confirm the hypotheses of southwards (and subsequent northwards) shifts, identify glacial refugia and corridors used for the post glacial re-colonization. Finally, we map a contact zone deserving more sampling effort to disentangle the introgression and hybridization observed. PMID- 30405201 TI - Maternal High-Fat Diet Programs Offspring Liver Steatosis in a Sexually Dimorphic Manner in Association with Changes in Gut Microbial Ecology in Mice. AB - The contributions of maternal diet and obesity in shaping offspring microbiome remain unclear. Here we employed a mouse model of maternal diet-induced obesity via high-fat diet feeding (HFD, 45% fat calories) for 12 wk prior to conception on offspring gut microbial ecology. Male and female offspring were provided access to control or HFD from weaning until 17 wk of age. Maternal HFD-associated programming was sexually dimorphic, with male offspring from HFD dams showing hyper-responsive weight gain to postnatal HFD. Likewise, microbiome analysis of offspring cecal contents showed differences in alpha-diversity, beta-diversity and higher Firmicutes in male compared to female mice. Weight gain in offspring was significantly associated with abundance of Lachnospiraceae and Clostridiaceae families and Adlercreutzia, Coprococcus and Lactococcus genera. Sex differences in metagenomic pathways relating to lipid metabolism, bile acid biosynthesis and immune response were also observed. HFD-fed male offspring from HFD dams also showed worse hepatic pathology, increased pro-inflammatory cytokines, altered expression of bile acid regulators (Cyp7a1, Cyp8b1 and Cyp39a1) and serum bile acid concentrations. These findings suggest that maternal HFD alters gut microbiota composition and weight gain of offspring in a sexually dimorphic manner, coincident with fatty liver and a pro-inflammatory state in male offspring. PMID- 30405204 TI - Water drainage from Kushiro Coal Mine decreased on the day of all M >= 7.5 earthquakes and increased thereafter. AB - The amount of water drainage from Kushiro Coal Mine in Hokkaido, Japan decreased on the day of all M >= 7.5 earthquakes with epicenters within 300 km of the mine during the monitoring period and increased after these earthquakes. This is a valuable finding which would give us a clue to understand pre- and post-seismic rockmass behaviors and contribute for progress in earthquake prediction in future. PMID- 30405205 TI - Selected Abstracts from the 2018 NCRI Cancer Conference of National Cancer Research Institute. AB - Scottish Event Campus, Glasgow, Sunday 4 - Tuesday 6 November 2018 Attendees of the 2018 NCRI Cancer Conference will be able to contact corresponding authors through the Conference App and e-poster platform at the Conference.W: https://conference.ncri.org.uk : E: conference@ncri.org.ukOrganised by the National Cancer Research Institute, which is a partnership of 19 cancer research funders, the NCRI Cancer Conference provides a platform for researchers, clinicians, people affected by cancer and industry representatives to come together to discuss, present and showcase high-quality research. Sponsorship Statement: Publication of this supplement was sponsored by Roche. All content was reviewed and approved by the NCRI Scientific Committee, which held full responsibility for the abstract selection. PMID- 30405203 TI - Dnmt1 has an essential function despite the absence of CpG DNA methylation in the red flour beetle Tribolium castaneum. AB - Epigenetic mechanisms, such as CpG DNA methylation enable phenotypic plasticity and rapid adaptation to changing environments. CpG DNA methylation is established by DNA methyltransferases (DNMTs), which are well conserved across vertebrates and invertebrates. There are insects with functional DNA methylation despite lacking a complete set of Dnmts. But at least one of the enzymes, DNMT1, appears to be required to maintain an active DNA methylation system. The red flour beetle, Tribolium castaneum, lacks Dnmt3 but possesses Dnmt1 and it has been controversial whether it has a functional DNA methylation system. Using whole genome bisulfite sequencing, we did not find any defined patterns of CpG DNA methylation in embryos. Nevertheless, we found Dnmt1 expressed throughout the entire life cycle of the beetle, with mRNA transcripts significantly more abundant in eggs and ovaries. A maternal knockdown of Dnmt1 caused a developmental arrest in offspring embryos. We show that Dnmt1 plays an essential role in T. castaneum embryos and that its downregulation leads to an early developmental arrest. This function appears to be unrelated to DNA methylation, since we did not find any evidence for this modification. This strongly suggests an alternative role of this protein. PMID- 30405206 TI - Intra-articular administration of IkappaBalpha kinase inhibitor suppresses mouse knee osteoarthritis via downregulation of the NF-kappaB/HIF-2alpha axis. AB - Activation of NF-kappaB signaling promotes osteoarthritis (OA) through the transcriptional induction of Hif-2alpha and catabolic enzymes. This study sought to examine whether inhibiting IkappaBalpha kinase (IKK) could suppress the development of surgically-induced OA of the knee in a mouse model. We employed BMS-345541 (4(2'-aminoethyl) amino-1, 8-dimethylimidazo (1,2-a) quinoxaline) as a selective inhibitor of the subunits of IKK. OA was created by resecting the medial collateral ligament and the medial meniscus in the knees of mice. The mice were then treated with an intra-articular injection of BMS-345541 (50 nM to 500 uM) or vehicle three times a week for 8 weeks. We found that the intra-articular administration of 500 nM and 5 uM BMS-345541 significantly suppressed OA development. In the BMS-345541-treated cartilage, there was a decrease in the phosphorylation of IkappaBalpha and the expression of Hif-2alpha, Mmp13, and Adamts5. In human articular chondrocytes, the IL-1beta-enhanced expression of Hif 2alpha and catabolic factors were decreased by BMS-345541 treatment in dose dependent manner. We conclude that the intra-articular administration of BMS 345541 at some concentrations may suppress the development of OA by downregulating signaling through the NF-kappaB-Hif-2alpha axis. PMID- 30405208 TI - Genomic mosaicism in the pathogenesis and inheritance of a Rett syndrome cohort. AB - PURPOSE: To determine the role of mosaicism in the pathogenesis and inheritance of Rett and Rett-like disorders. METHODS: We recruited 471 Rett and Rett-like patients. Panel-sequencing targeting MECP2, CDKL5, and FOXG1 was performed. Mosaicism was quantified in 147 patients by a Bayesian genotyper. Candidates were validated by amplicon sequencing and digital PCR. Germline mosaicism of 21 fathers with daughters carrying pathogenic MECP2 variants was further quantified. RESULTS: Pathogenic variants of MECP2/CDKL5/FOXG1 were found in 324/471 (68.7%) patients. Somatic MECP2 mosaicism was confirmed in 5/471 (1.1%) patients, including 3/18 males (16.7%) and 2/453 females (0.4%). Three of the five patients with somatic MECP2 mosaicism had mosaicism at MECP2-Arg106. Germline MECP2 mosaicism was detected in 5/21 (23.8%) fathers. CONCLUSION: This is the first systematic screening of somatic and paternal germline MECP2 mosaicism at a cohort level. Our findings indicate that somatic MECP2 mosaicism contributes directly to the pathogenicity of Rett syndrome, especially in male patients. MECP2-Arg106 might be a mosaic hotspot. The high proportion of paternal germline MECP2 mosaicism indicates an underestimated mechanism underlying the paternal origin bias of MECP2 variants. Finally, this study provides an empirical foundation for future studies of genetic disorders caused by de novo variations of strong paternal origin. PMID- 30405207 TI - Valproate reduces neuroinflammation and neuronal death in a rat chronic constriction injury model. AB - Valproate (VPA) is a well-known drug for treating epilepsy and mania, but its action in neuropathic pain is unclear. We used a chronic constriction injury (CCI) model to explore whether VPA prevents neuropathic pain-mediated inflammation and neuronal death. Rats were treated with or without VPA. CCI + VPA rats were intraperitoneally injected with VPA (300 mg/kg/day) from postoperative day (POD) 1 to 14. We measured paw withdrawal latency (PWL) and paw withdrawal threshold (PWT) 1 day before surgery and 1, 3, 7, 14 days after CCI and harvested the sciatic nerves (SN), spinal cord (SC) and dorsal root ganglia (DRG) on POD 3, 7, and 14. PWL and PWT were reduced in CCI rats, but increased in CCI + VPA rats on POD 7 and POD 14. VPA lowered CCI-induced inflammatory proteins (pNFkappaB, iNOS and COX-2), pro-apoptotic proteins (pAKT/AKT and pGSK-3beta/GSK-3beta), proinflammatory cytokines (TNF-alpha and IL-1beta) and nuclear pNFkappaB activation in the SN, DRG and SC in CCI rats. COX-2 and pGSK-3 proteins were decreased by VPA on immunofluorescence analysis. VPA attenuated CCI-induced thermal and mechanical pain behaviors in rats in correlation with anti neuroinflammation action involving reduction of pNFkappaB/iNOS/COX-2 activation and inhibition of pAKT/pGSK-3beta-mediated neuronal death from injury to peripheral nerves. PMID- 30405209 TI - Metabolic rate of major organs and tissues in young adult South Asian women. AB - BACKGROUND/OBJECTIVES: Major organ-specific and tissue-specific metabolic rate (Ki) values were initially estimated using in vivo methods, and values reported by Elia (Energy metabolism: tissue determinants and cellular corollaries, Raven Press, New York, 1992) were subsequently supported by statistical analysis. However, the majority of work to date on this topic has addressed individuals of European descent, whereas population variability in resting energy metabolism has been reported. We aimed to estimate Ki values in South Asian females. SUBJECTS/METHODS: This cross-sectional study recruited 70 healthy young women of South Asian ancestry. Brain and organs were measured using magnetic resonance imaging, skeletal muscle mass by dual-energy X-ray absorptiometry, fat mass by the 4-component model, and whole-body resting energy expenditure by indirect calorimetry. Organ and tissue Ki values were estimated indirectly using regression analysis through the origin. Preliminary analysis suggested overestimation of heart mass, hence the modeling was repeated with a literature based 22.5% heart mass reduction. RESULTS: The pattern of derived Ki values across organs and tissues matched that previously estimated in vivo, but the values were systematically lower. However, adjusting for the overestimation of heart mass markedly improved the agreement. CONCLUSIONS: Our results support variability in Ki values among organs and tissues, where some are more metabolically "expensive" than others. Initial findings suggesting lower organ/tissue Ki values in South Asian women were likely influenced by heart mass estimation bias. The question of potential ethnic variability in organ-specific and tissue-specific energy metabolism requires further investigation. PMID- 30405211 TI - Cytidine deaminase enzymatic activity is a prognostic biomarker in gemcitabine/platinum-treated advanced non-small-cell lung cancer: a prospective validation study. AB - BACKGROUND: Cytidine deaminase (CDA) plays a crucial role in the degradation of gemcitabine. In our previous retrospective study, CDA enzymatic activity was the strongest prognostic biomarker of the activity and efficacy of platinum/gemcitabine combinations. The aim of this prospective study was to validate the prognostic role of CDA activity in the first-line treatment of advanced non-small-cell lung cancer. METHODS: A total of 124 untreated patients received standard doses of platinum/gemcitabine. CDA activity was baseline measured in plasma samples by spectrophotometric assay. RESULTS: Using the median CDA level as cut-off, in the patients with high versus low CDA activity the response rate was 25.0% (95% CI, 14.7-37.8) and 54.1% (95% CI, 40.8-66.9), P = 0.0013; the 6-month progression rate was 34.5% (95% CI, 22.6-46.6) and 54.1% (95% CI, 40.9-65.6), HR = 2.01 (95% CI, 1.32-3.06), P < 0.001; the 1-year survival rate was 23.3% (95% CI, 13.6-34.6) and 57.3% (95% CI, 43.9-68.6), HR = 2.20 (95% CI, 1.46-3.34), P = 0.0002, respectively. CDA activity resulted to be an independent prognostic factor for progression and survival at multivariate analysis. CONCLUSIONS: This study validated prospectively the prognostic role of the CDA activity and should prompt larger and adequately designed randomised prospective studies to establish the predictive impact of this test in improving the outcome of selected patients. PMID- 30405212 TI - Tenofovir disoproxil fumarate discontinuation for renal outcomes: any room for treatment personalization? AB - Tenofovir disoproxil fumarate (TDF) is a very effective antiviral drug that has been associated with tubular dysfunction. The aim of this study was to analyze the demographic, pharmacokinetic, and pharmacogenetic variables associated with TDF discontinuation for renal outcomes in stable HIV-positive patients using multivariable analyses. Three hundred and four patients were included (73% male, with median age and eCrCl of 45.3 years and 90.9 mL/min, respectively). After a median follow-up of 28.3 months, 27 patients discontinued TDF for renal adverse events [persistent urinary abnormalities (n = 21) or eCrCl < 60 mL/min (n = 6)] providing an incidence of 3.77 events per 100 patient-year. The probability of TDF discontinuation was higher with several features (male gender, older age, not Caucasians ancestry, absence of intravenous drug abuse, protease inhibitors, previous indinavir, HCV-positivity, lower CD4 cell count, detectable HIV-RNA, lower eCrCl, spot-urine proteinuria) and higher tenofovir concentrations but not genetic variants. Tenofovir plasma concentrations were prognostic of TDF discontinuation for renal adverse events suggesting that dose-adjustment may be warranted for long-term safety. PMID- 30405210 TI - Effects of CRISPR/Cas9 dosage on TICAM1 and RBL gene mutation rate, embryonic development, hatchability and fry survival in channel catfish. AB - The current study was conducted to assess the effects of microinjection of different dosages of guide RNA (gRNA)/Cas9 protein on the mutation rate, embryo survival, embryonic development, hatchability and early fry survival in channel catfish, Ictalurus punctatus. Guide RNAs targeting two of the channel catfish immune-related genes, toll/interleukin 1 receptor domain-containing adapter molecule (TICAM 1) and rhamnose binding lectin (RBL) genes, were designed and prepared. Three dosages of gRNA/Cas9 protein (low, 2.5 ng gRNA/7.5 ng Cas9, medium, 5 ng gRNA/15 ng Cas9 and high, 7.5 ng gRNA/22.5 ng Cas9) were microinjected into the yolk of one-cell embryos. Mutation rate increased with higher dosages (p < 0.05). Higher dosages increased the mutation frequency in individual embryos where biallelic mutations were detected. For both genes, microinjection procedures increased the embryo mortality (p < 0.05). Increasing the dosage of gRNA/Cas9 protein increased the embryo mortality and reduced the hatching percent (p < 0.05). Embryonic development was delayed when gRNAs targeting RBL gene were injected. Means of fry survival time were similar for different dosages (p > 0.05). The current results lay the foundations for designing gene editing experiments in channel catfish and can be used as a guide for other fish species. PMID- 30405213 TI - Tumour-targeting bacteria engineered to fight cancer. AB - Recent advances in targeted therapy and immunotherapy have once again raised the hope that a cure might be within reach for many cancer types. Yet, most late stage cancers are either insensitive to the therapies to begin with or develop resistance later. Therapy with live tumour-targeting bacteria provides a unique option to meet these challenges. Compared with most other therapeutics, the effectiveness of tumour-targeting bacteria is not directly affected by the 'genetic makeup' of a tumour. Bacteria initiate their direct antitumour effects from deep within the tumour, followed by innate and adaptive antitumour immune responses. As microscopic 'robotic factories', bacterial vectors can be reprogrammed following simple genetic rules or sophisticated synthetic bioengineering principles to produce and deliver anticancer agents on the basis of clinical needs. Therapeutic approaches using live tumour-targeting bacteria can either be applied as a monotherapy or complement other anticancer therapies to achieve better clinical outcomes. In this Review, we summarize the potential benefits and challenges of this approach. We discuss how live bacteria selectively induce tumour regression and provide examples to illustrate different ways to engineer bacteria for improved safety and efficacy. Finally, we share our experience and insights on oncology clinical trials with tumour-targeting bacteria, including a discussion of the regulatory issues. PMID- 30405215 TI - Human disease mutations highlight the inhibitory function of TIM-3. PMID- 30405217 TI - Quenching our thirst for universality. PMID- 30405214 TI - Publisher Correction: Maladaptive cortical hyperactivity upon recovery from experimental autoimmune encephalomyelitis. AB - In the version of this article initially published, Inigo Ruiz de Azua's name was miscategorized. His given name is Inigo and his surname is Ruiz de Azua. This has been corrected in the HTML coding. PMID- 30405219 TI - Chinese pilot project tracks progress towards SDGs. PMID- 30405220 TI - Mentorship training curbs academic abuse. PMID- 30405221 TI - Nobel notes value of basic research for new drugs. PMID- 30405222 TI - Open data are a boon for underfunded researchers. PMID- 30405223 TI - Dams threaten world's largest inland fishery. PMID- 30405225 TI - A population of luminous accreting black holes with hidden mergers. AB - Major galaxy mergers are thought to play an important part in fuelling the growth of supermassive black holes1. However, observational support for this hypothesis is mixed, with some studies showing a correlation between merging galaxies and luminous quasars2,3 and others showing no such association4,5. Recent observations have shown that a black hole is likely to become heavily obscured behind merger-driven gas and dust, even in the early stages of the merger, when the galaxies are well separated6-8 (5 to 40 kiloparsecs). Merger simulations further suggest that such obscuration and black-hole accretion peaks in the final merger stage, when the two galactic nuclei are closely separated9 (less than 3 kiloparsecs). Resolving this final stage requires a combination of high-spatial resolution infrared imaging and high-sensitivity hard-X-ray observations to detect highly obscured sources. However, large numbers of obscured luminous accreting supermassive black holes have been recently detected nearby (distances below 250 megaparsecs) in X-ray observations10. Here we report high-resolution infrared observations of hard-X-ray-selected black holes and the discovery of obscured nuclear mergers, the parent populations of supermassive-black-hole mergers. We find that obscured luminous black holes (bolometric luminosity higher than 2 * 1044 ergs per second) show a significant (P < 0.001) excess of late stage nuclear mergers (17.6 per cent) compared to a sample of inactive galaxies with matching stellar masses and star formation rates (1.1 per cent), in agreement with theoretical predictions. Using hydrodynamic simulations, we confirm that the excess of nuclear mergers is indeed strongest for gas-rich major merger hosts of obscured luminous black holes in this final stage. PMID- 30405226 TI - Observation of universal dynamics in a spinor Bose gas far from equilibrium. AB - Predicting the dynamics of quantum systems far from equilibrium represents one of the most challenging problems in theoretical many-body physics1,2. While the evolution of a many-body system is in general intractable in all its details, relevant observables can become insensitive to microscopic system parameters and initial conditions. This is the basis of the phenomenon of universality. Far from equilibrium, universality is identified through the scaling of the spatio temporal evolution of the system, captured by universal exponents and functions. Theoretically, this has been studied in examples as different as the reheating process in inflationary Universe cosmology3,4, the dynamics of nuclear collision experiments described by quantum chromodynamics5,6, and the post-quench dynamics in dilute quantum gases in non-relativistic quantum field theory7-11. However, an experimental demonstration of such scaling evolution in space and time in a quantum many-body system has been lacking. Here we observe the emergence of universal dynamics by evaluating spatially resolved spin correlations in a quasi one-dimensional spinor Bose-Einstein condensate12-16. For long evolution times we extract the scaling properties from the spatial correlations of the spin excitations. From this we find the dynamics to be governed by an emergent conserved quantity and the transport of spin excitations towards low momentum scales. Our results establish an important class of non-stationary systems whose dynamics is encoded in time-independent scaling exponents and functions, signalling the existence of non-thermal fixed points10,17,18. We confirm that the non-thermal scaling phenomenon involves no fine-tuning of parameters, by preparing different initial conditions and observing the same scaling behaviour. Our analogue quantum simulation approach provides the basis with which to reveal the underlying mechanisms and characteristics of non-thermal universality classes. One may use this universality to learn, from experiments with ultracold gases, about fundamental aspects of dynamics studied in cosmology and quantum chromodynamics. PMID- 30405227 TI - Universal dynamics in an isolated one-dimensional Bose gas far from equilibrium. AB - Understanding the behaviour of isolated quantum systems far from equilibrium and their equilibration is one of the most pressing problems in quantum many-body physics1,2. There is strong theoretical evidence that sufficiently far from equilibrium a wide variety of systems-including the early Universe after inflation3-6, quark-gluon matter generated in heavy-ion collisions7-9, and cold quantum gases4,10-14-exhibit universal scaling in time and space during their evolution, independent of their initial state or microscale properties. However, direct experimental evidence is lacking. Here we demonstrate universal scaling in the time-evolving momentum distribution of an isolated, far-from-equilibrium, one dimensional Bose gas, which emerges from a three-dimensional ultracold Bose gas by means of a strong cooling quench. Within the scaling regime, the time evolution of the system at low momenta is described by a time-independent, universal function and a single scaling exponent. The non-equilibrium scaling describes the transport of an emergent conserved quantity towards low momenta, which eventually leads to the build-up of a quasi-condensate. Our results establish universal scaling dynamics in an isolated quantum many-body system, which is a crucial step towards characterizing time evolution far from equilibrium in terms of universality classes. Universality would open the possibility of using, for example, cold-atom set-ups at the lowest energies to simulate important aspects of the dynamics of currently inaccessible systems at the highest energies, such as those encountered in the inflationary early Universe. PMID- 30405228 TI - Universal prethermal dynamics of Bose gases quenched to unitarity. AB - Understanding strongly correlated phases of matter, such as the quark-gluon plasma and neutron stars, and in particular the dynamics of such systems, for example, following a Hamiltonian quench (a sudden change in some Hamiltonian parameter, such as the strength of interparticle interactions) is a fundamental challenge in modern physics. Ultracold atomic gases are excellent quantum simulators for these problems, owing to their tunable interparticle interactions and experimentally resolvable intrinsic timescales. In particular, they provide access to the unitary regime, in which the interactions are as strong as allowed by quantum mechanics. This regime has been extensively studied in Fermi gases1,2. The less-explored unitary Bose gases3-11 offer possibilities12 such as universal physics controlled solely by the gas density13,14 and new forms of superfluidity15-17. Here, through momentum- and time-resolved studies, we explore degenerate and thermal homogeneous Bose gases quenched to unitarity. In degenerate samples, we observe universal post-quench dynamics in agreement with the emergence of a prethermal state18-24 with a universal non-zero condensed fraction22,24. In thermal gases, the dynamic and thermodynamic properties generally depend on the gas density and the temperature, but we find that they can still be expressed in terms of universal dimensionless functions. Surprisingly, we find that the total quench-induced correlation energy is independent of the gas temperature. These measurements provide quantitative benchmarks and challenges for the theory of unitary Bose gases. PMID- 30405231 TI - Bottom-up biology. PMID- 30405229 TI - Why a European agency post can be an excellent destination for researchers. PMID- 30405232 TI - How biologists are creating life-like cells from scratch. PMID- 30405233 TI - Gut reaction. PMID- 30405235 TI - Farewell to Kepler, India's neutrino observatory and an Ebola warning. PMID- 30405234 TI - Ulcerative colitis: towards remission. PMID- 30405236 TI - Abiotic synthesis of amino acids in the recesses of the oceanic lithosphere. AB - Abiotic hydrocarbons and carboxylic acids are known to be formed on Earth, notably during the hydrothermal alteration of mantle rocks. Although the abiotic formation of amino acids has been predicted both from experimental studies and thermodynamic calculations, its occurrence has not been demonstrated in terrestrial settings. Here, using a multimodal approach that combines high resolution imaging techniques, we obtain evidence for the occurrence of aromatic amino acids formed abiotically and subsequently preserved at depth beneath the Atlantis Massif (Mid-Atlantic Ridge). These aromatic amino acids may have been formed through Friedel-Crafts reactions catalysed by an iron-rich saponite clay during a late alteration stage of the massif serpentinites. Demonstrating the potential of fluid-rock interactions in the oceanic lithosphere to generate amino acids abiotically gives credence to the hydrothermal theory for the origin of life, and may shed light on ancient metabolisms and the functioning of the present-day deep biosphere. PMID- 30405237 TI - Superfluorescence from lead halide perovskite quantum dot superlattices. AB - An ensemble of emitters can behave very differently from its individual constituents when they interact coherently via a common light field. After excitation of such an ensemble, collective coupling can give rise to a many-body quantum phenomenon that results in short, intense bursts of light-so-called superfluorescence1. Because this phenomenon requires a fine balance of interactions between the emitters and their decoupling from the environment, together with close identity of the individual emitters, superfluorescence has thus far been observed only in a limited number of systems, such as certain atomic and molecular gases and a few solid-state systems2-7. The generation of superfluorescent light in colloidal nanocrystals (which are bright photonic sources practically suited for optoelectronics8,9) has been precluded by inhomogeneous emission broadening, low oscillator strength, and fast exciton dephasing. Here we show that caesium lead halide (CsPbX3, X = Cl, Br) perovskite nanocrystals10-13 that are self-organized into highly ordered three-dimensional superlattices exhibit key signatures of superfluorescence. These are dynamically red-shifted emission with more than 20-fold accelerated radiative decay, extension of the first-order coherence time by more than a factor of four, photon bunching, and delayed emission pulses with Burnham-Chiao ringing behaviour14 at high excitation density. These mesoscopically extended coherent states could be used to boost the performance of opto-electronic devices15 and enable entangled multi-photon quantum light sources16,17. PMID- 30405238 TI - Efficient and stable emission of warm-white light from lead-free halide double perovskites. AB - Lighting accounts for one-fifth of global electricity consumption1. Single materials with efficient and stable white-light emission are ideal for lighting applications, but photon emission covering the entire visible spectrum is difficult to achieve using a single material. Metal halide perovskites have outstanding emission properties2,3; however, the best-performing materials of this type contain lead and have unsatisfactory stability. Here we report a lead free double perovskite that exhibits efficient and stable white-light emission via self-trapped excitons that originate from the Jahn-Teller distortion of the AgCl6 octahedron in the excited state. By alloying sodium cations into Cs2AgInCl6, we break the dark transition (the inversion-symmetry-induced parity forbidden transition) by manipulating the parity of the wavefunction of the self trapped exciton and reduce the electronic dimensionality of the semiconductor4. This leads to an increase in photoluminescence efficiency by three orders of magnitude compared to pure Cs2AgInCl6. The optimally alloyed Cs2(Ag0.60Na0.40)InCl6 with 0.04 per cent bismuth doping emits warm-white light with 86 +/- 5 per cent quantum efficiency and works for over 1,000 hours. We anticipate that these results will stimulate research on single-emitter-based white-light-emitting phosphors and diodes for next-generation lighting and display technologies. PMID- 30405239 TI - Cryo-EM structures of a human ABCG2 mutant trapped in ATP-bound and substrate bound states. AB - ABCG2 is a transporter protein of the ATP-binding-cassette (ABC) family that is expressed in the plasma membrane in cells of various tissues and tissue barriers, including the blood-brain, blood-testis and maternal-fetal barriers1-4. Powered by ATP, it translocates endogenous substrates, affects the pharmacokinetics of many drugs and protects against a wide array of xenobiotics, including anti cancer drugs5-12. Previous studies have revealed the architecture of ABCG2 and the structural basis of its inhibition by small molecules and antibodies13,14. However, the mechanisms of substrate recognition and ATP-driven transport are unknown. Here we present high-resolution cryo-electron microscopy (cryo-EM) structures of human ABCG2 in a substrate-bound pre-translocation state and an ATP bound post-translocation state. For both structures, we used a mutant containing a glutamine replacing the catalytic glutamate (ABCG2EQ), which resulted in reduced ATPase and transport rates and facilitated conformational trapping for structural studies. In the substrate-bound state, a single molecule of estrone-3 sulfate (E1S) is bound in a central, hydrophobic and cytoplasm-facing cavity about halfway across the membrane. Only one molecule of E1S can bind in the observed binding mode. In the ATP-bound state, the substrate-binding cavity has collapsed while an external cavity has opened to the extracellular side of the membrane. The ATP-induced conformational changes include rigid-body shifts of the transmembrane domains, pivoting of the nucleotide-binding domains (NBDs), and a change in the relative orientation of the NBD subdomains. Mutagenesis and in vitro characterization of transport and ATPase activities demonstrate the roles of specific residues in substrate recognition, including a leucine residue that forms a 'plug' between the two cavities. Our results show how ABCG2 harnesses the energy of ATP binding to extrude E1S and other substrates, and suggest that the size and binding affinity of compounds are important for distinguishing substrates from inhibitors. PMID- 30405240 TI - Dopamine enhances signal-to-noise ratio in cortical-brainstem encoding of aversive stimuli. AB - Dopamine modulates medial prefrontal cortex (mPFC) activity to mediate diverse behavioural functions1,2; however, the precise circuit computations remain unknown. One potentially unifying model by which dopamine may underlie a diversity of functions is by modulating the signal-to-noise ratio in subpopulations of mPFC neurons3-6, where neural activity conveying sensory information (signal) is amplified relative to spontaneous firing (noise). Here we demonstrate that dopamine increases the signal-to-noise ratio of responses to aversive stimuli in mPFC neurons projecting to the dorsal periaqueductal grey (dPAG). Using an electrochemical approach, we reveal the precise time course of pinch-evoked dopamine release in the mPFC, and show that mPFC dopamine biases behavioural responses to aversive stimuli. Activation of mPFC-dPAG neurons is sufficient to drive place avoidance and defensive behaviours. mPFC-dPAG neurons display robust shock-induced excitations, as visualized by single-cell, projection-defined microendoscopic calcium imaging. Finally, photostimulation of dopamine terminals in the mPFC reveals an increase in the signal-to-noise ratio in mPFC-dPAG responses to aversive stimuli. Together, these data highlight how dopamine in the mPFC can selectively route sensory information to specific downstream circuits, representing a potential circuit mechanism for valence processing. PMID- 30405241 TI - Structures of the intermediates of Kok's photosynthetic water oxidation clock. AB - Inspired by the period-four oscillation in flash-induced oxygen evolution of photosystem II discovered by Joliot in 1969, Kok performed additional experiments and proposed a five-state kinetic model for photosynthetic oxygen evolution, known as Kok's S-state clock or cycle1,2. The model comprises four (meta)stable intermediates (S0, S1, S2 and S3) and one transient S4 state, which precedes dioxygen formation occurring in a concerted reaction from two water-derived oxygens bound at an oxo-bridged tetra manganese calcium (Mn4CaO5) cluster in the oxygen-evolving complex3-7. This reaction is coupled to the two-step reduction and protonation of the mobile plastoquinone QB at the acceptor side of PSII. Here, using serial femtosecond X-ray crystallography and simultaneous X-ray emission spectroscopy with multi-flash visible laser excitation at room temperature, we visualize all (meta)stable states of Kok's cycle as high resolution structures (2.04-2.08 A). In addition, we report structures of two transient states at 150 and 400 us, revealing notable structural changes including the binding of one additional 'water', Ox, during the S2->S3 state transition. Our results suggest that one water ligand to calcium (W3) is directly involved in substrate delivery. The binding of the additional oxygen Ox in the S3 state between Ca and Mn1 supports O-O bond formation mechanisms involving O5 as one substrate, where Ox is either the other substrate oxygen or is perfectly positioned to refill the O5 position during O2 release. Thus, our results exclude peroxo-bond formation in the S3 state, and the nucleophilic attack of W3 onto W2 is unlikely. PMID- 30405242 TI - Palaeolithic cave art in Borneo. AB - Figurative cave paintings from the Indonesian island of Sulawesi date to at least 35,000 years ago (ka) and hand-stencil art from the same region has a minimum date of 40 ka1. Here we show that similar rock art was created during essentially the same time period on the adjacent island of Borneo. Uranium-series analysis of calcium carbonate deposits that overlie a large reddish-orange figurative painting of an animal at Lubang Jeriji Saleh-a limestone cave in East Kalimantan, Indonesian Borneo-yielded a minimum date of 40 ka, which to our knowledge is currently the oldest date for figurative artwork from anywhere in the world. In addition, two reddish-orange-coloured hand stencils from the same site each yielded a minimum uranium-series date of 37.2 ka, and a third hand stencil of the same hue has a maximum date of 51.8 ka. We also obtained uranium-series determinations for cave art motifs from Lubang Jeriji Saleh and three other East Kalimantan karst caves, which enable us to constrain the chronology of a distinct younger phase of Pleistocene rock art production in this region. Dark-purple hand stencils, some of which are decorated with intricate motifs, date to about 21-20 ka and a rare Pleistocene depiction of a human figure-also coloured dark purple has a minimum date of 13.6 ka. Our findings show that cave painting appeared in eastern Borneo between 52 and 40 ka and that a new style of parietal art arose during the Last Glacial Maximum. It is now evident that a major Palaeolithic cave art province existed in the eastern extremity of continental Eurasia and in adjacent Wallacea from at least 40 ka until the Last Glacial Maximum, which has implications for understanding how early rock art traditions emerged, developed and spread in Pleistocene Southeast Asia and further afield. PMID- 30405244 TI - Predictable and precise template-free CRISPR editing of pathogenic variants. AB - Following Cas9 cleavage, DNA repair without a donor template is generally considered stochastic, heterogeneous and impractical beyond gene disruption. Here, we show that template-free Cas9 editing is predictable and capable of precise repair to a predicted genotype, enabling correction of disease-associated mutations in humans. We constructed a library of 2,000 Cas9 guide RNAs paired with DNA target sites and trained inDelphi, a machine learning model that predicts genotypes and frequencies of 1- to 60-base-pair deletions and 1-base pair insertions with high accuracy (r = 0.87) in five human and mouse cell lines. inDelphi predicts that 5-11% of Cas9 guide RNAs targeting the human genome are 'precise-50', yielding a single genotype comprising greater than or equal to 50% of all major editing products. We experimentally confirmed precise-50 insertions and deletions in 195 human disease-relevant alleles, including correction in primary patient-derived fibroblasts of pathogenic alleles to wild-type genotype for Hermansky-Pudlak syndrome and Menkes disease. This study establishes an approach for precise, template-free genome editing. PMID- 30405243 TI - Type 9 secretion system structures reveal a new protein transport mechanism. AB - The type 9 secretion system (T9SS) is the protein export pathway of bacteria of the Gram-negative Fibrobacteres-Chlorobi-Bacteroidetes superphylum and is an essential determinant of pathogenicity in severe periodontal disease. The central element of the T9SS is a so-far uncharacterized protein-conducting translocon located in the bacterial outer membrane. Here, using cryo-electron microscopy, we provide structural evidence that the translocon is the T9SS protein SprA. SprA forms an extremely large (36-strand) single polypeptide transmembrane beta barrel. The barrel pore is capped on the extracellular end, but has a lateral opening to the external membrane surface. Structures of SprA bound to different components of the T9SS show that partner proteins control access to the lateral opening and to the periplasmic end of the pore. Our results identify a protein transporter with a distinctive architecture that uses an alternating access mechanism in which the two ends of the protein-conducting channel are open at different times. PMID- 30405247 TI - Capillary assisted deposition of carbon nanotube film for strain sensing. AB - Advances in stretchable electronics offer the possibility of developing skin-like motion sensors. Carbon nanotubes (CNTs), owing to their superior electrical properties, have great potential for applications in such sensors. In this paper, we report a method for deposition and patterning of CNTs on soft, elastic polydimethylsiloxane (PDMS) substrates using capillary action. Micropillar arrays were generated on PDMS surfaces before treatment with plasma to render them hydrophilic. Capillary force enabled by the micropillar array spreads CNT solution evenly on PDMS surfaces. Solvent evaporation leaves a uniform deposition and patterning of CNTs on PDMS surfaces. We studied the effect of the CNT concentration and micropillar gap size on CNT coating uniformity, film conductivity, and piezoresistivity. Leveraging the piezoresistivity of deposited CNT films, we further designed and characterized a device for the contraction force measurement. Our capillary assisted deposition method of CNT films showed great application potential in fabrication of flexible CNT thin films for strain sensing. PMID- 30405245 TI - The metabolite BH4 controls T cell proliferation in autoimmunity and cancer. AB - Genetic regulators and environmental stimuli modulate T cell activation in autoimmunity and cancer. The enzyme co-factor tetrahydrobiopterin (BH4) is involved in the production of monoamine neurotransmitters, the generation of nitric oxide, and pain1,2. Here we uncover a link between these processes, identifying a fundamental role for BH4 in T cell biology. We find that genetic inactivation of GTP cyclohydrolase 1 (GCH1, the rate-limiting enzyme in the synthesis of BH4) and inhibition of sepiapterin reductase (the terminal enzyme in the synthetic pathway for BH4) severely impair the proliferation of mature mouse and human T cells. BH4 production in activated T cells is linked to alterations in iron metabolism and mitochondrial bioenergetics. In vivo blockade of BH4 synthesis abrogates T-cell-mediated autoimmunity and allergic inflammation, and enhancing BH4 levels through GCH1 overexpression augments responses by CD4- and CD8-expressing T cells, increasing their antitumour activity in vivo. Administration of BH4 to mice markedly reduces tumour growth and expands the population of intratumoral effector T cells. Kynurenine-a tryptophan metabolite that blocks antitumour immunity-inhibits T cell proliferation in a manner that can be rescued by BH4. Finally, we report the development of a potent SPR antagonist for possible clinical use. Our data uncover GCH1, SPR and their downstream metabolite BH4 as critical regulators of T cell biology that can be readily manipulated to either block autoimmunity or enhance anticancer immunity. PMID- 30405246 TI - Design of amidobenzimidazole STING receptor agonists with systemic activity. AB - Stimulator of interferon genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen-derived and self DNA1. The development of compounds that modulate STING has recently been the focus of intense research for the treatment of cancer and infectious diseases and as vaccine adjuvants2. To our knowledge, current efforts are focused on the development of modified cyclic dinucleotides that mimic the endogenous STING ligand cGAMP; these have progressed into clinical trials in patients with solid accessible tumours amenable to intratumoral delivery3. Here we report the discovery of a small molecule STING agonist that is not a cyclic dinucleotide and is systemically efficacious for treating tumours in mice. We developed a linking strategy to synergize the effect of two symmetry-related amidobenzimidazole (ABZI)-based compounds to create linked ABZIs (diABZIs) with enhanced binding to STING and cellular function. Intravenous administration of a diABZI STING agonist to immunocompetent mice with established syngeneic colon tumours elicited strong anti-tumour activity, with complete and lasting regression of tumours. Our findings represent a milestone in the rapidly growing field of immune-modifying cancer therapies. PMID- 30405248 TI - Nonsuicidal self-injury: Implications for research and management. PMID- 30405249 TI - Strength and weakness of the guidelines of Rights of Persons with Disabilities Act, 2016 (dated January 5, 2018): With respect to the persons with neurodevelopmental disorders. PMID- 30405250 TI - Research on opioid substitution therapy in India: A brief, narrative review. AB - Opioid dependence is a significant clinical and public health issue in India. Opioid substitution therapy (OST) is the most evidence-based treatment for opioid dependence. Although available in India for about three decades now, Indian research on this treatment modality has not been adequately reviewed so far. We conducted a narrative review of Indian research on OST. We conducted an online search for relevant literature in the peer-reviewed journals as well as the general online search for books and monographs. We present the findings of the review in the form of description of literature according to certain identified themes. Considering that methadone has became available in India, only recently, the Indian research on OST predominantly features buprenorphine as the agent. Effectiveness of OST among Indian opioid-dependent patients has been well established through prospective, experimental designs as well as through naturalistic studies using retrospective, chart-review approach. Naturalistic and observational postmarketing surveillance studies have demonstrated the safety of buprenorphine and methadone when used as OST. There are certain areas in which more research on OST will be beneficial for Indian clinicians as well as policy makers. However, the quantum of evidence base that exists in India is more than adequate to justify the scale-up of this modality of treatment. A conducive policy environment for scaling-up OST is need of the hour. PMID- 30405251 TI - Opioid substitution therapy: Legal challenges. AB - Drug dependence syndrome is a medical condition classified as a multifactorial health disorder that often follows the course of a relapsing and remitting chronic disease. Opioid substitution therapy (OST) is one of the established standard treatments for opioid dependence syndrome. OST, a process in which opioid-dependent injecting drug users, is provided with long-acting opioid agonist medications for a long period under medical supervision along with psychosocial interventions. OST service provider may have to deal with issues of license/registration/recognition/permission under various legislations such as the Drugs and Cosmetic Act, 1940; Narcotic Drugs and Psychotropic Substances Act, 1985; Rights of person with disability Act, 2016 and Mental Healthcare Act, 2017 depending on the drug prescribed, type of services provided, procuring, transportation, storage, and prescribing these narcotics and psychotropic medicines. The narcotics and psychotropic drugs are administered through various ministries and departments causing huge confusion, lack of coordination, overlapping roles and responsibilities, and various laws/rules and gives an opportunity for the abdication of the responsibilities. The "public mental health issue," where the number of opioid users in the country is approximately two million and opioid dependence syndrome is approximately 0.5 million. The number of beds in the public governed deaddiction centers is abysmally low, number of psychiatrist, or trained medical practitioners in OST are also few in number to face this humongous challenge. Against this background, this article focuses on the legal issues surrounding the OST. PMID- 30405252 TI - Factors affecting quality of life of caregivers of children diagnosed with autism spectrum disorder. AB - Context: Since autism spectrum disorder (ASD) is a lifelong disease and because of its nature, the negative effects of the disease on the quality of life (QoL) of caregivers as well as patients are incontrovertible. Aims: It was aimed to evaluate the effect of the variables related to both parents and children on the QoL scores of the parents of the children with ASD. Settings and Design: This is a causality analysis study. Subjects and Methods: Questionnaire on sociodemographic/disease-related variables, QoL in Autism Questionnaire-Parent Version (QoLA-P), autism behavior checklist and Clinical Global Impression scale were assessed of 162 patients with ASD. Statistical Analysis Used: Unpaired t- test, Mann-Whitney U test, Kruskal-Wallis test, and one-way ANOVA test were used for comparing groups. The parameters found to be statistically significant for QoLA-P in different analyses were included as the independent variable in the logistic regression analysis. The backward (variable elimination) model was selected as the model in the analysis. Results: The causality has been established may be stated as the severity of autism, the presence of psychiatric disorder in the mother/father, attendance of the child at school, duration since the diagnosis of autism, and the child's medication use. Conclusions: Autism affects the QoL of caregivers. The intervention of treatment by considering the factors that affect the QoL positively or negatively may increase the QoL of caregivers. PMID- 30405253 TI - Can positive parenting program (Triple P) be useful to prevent child maltreatment? AB - Objective: This study aimed to determine the effect of the positive parenting program (Triple P) on child maltreatment, children's behaviors, and coping strategies of mothers. Materials and Methods: This study was the pretest-posttest quasiexperimental design. Secondary care state hospital located in the Cappadocia region between January and February 2016. This study was conducted with mothers (n: 138) of children aged between 4 and 12 years, 126 mothers were available to finish the study. Triple P was provided to the mothers in totally three sessions as once per a week. Mothers filled the scales and parent-child information form before the intervention and just after the intervention. Parent-child information form, child behavior checklist, and ways of coping inventory were administered to the mothers. Results: It was determined that after the training, mean scores obtained by the children from the subscales of anxiety, social problems, somatic complaints, attention problems, rule-breaking, and aggressive behaviors decreased (P < 0.05) and desperate approach and submissive approach mean scores of the mothers decreased (P < 0.001) whereas their social support mean scores increased (P < 0.05). In addition, the mothers, who stated that they were frequently looking angry (17.4%), yelling (24.6%), sometimes humiliating (27.7%) to their children, and injured their faces (6.3%) in the past 1 month, said that they did these behaviors to their children at lower rate at the end of the training (3.9%, 17.4%, 19.8%, and 0.0%, respectively). Conclusions: It was determined that Triple P was effective in reducing children's behavioral problems and improving mothers' strategies of coping with stress and contributed the reduction of emotional and physical abuse applied to children. It is recommended to ensure the continuity of these training programs. PMID- 30405255 TI - Consultation-liaison psychiatry services: A survey of medical institutes in India. AB - Aim: The aim of this study was to evaluate the consultation-liaison psychiatry (CLP) training and services in India. Methodology: An online survey was conducted involving at least one faculty member from the department of psychiatry working in various institutes providing postgraduate training in psychiatry. Results: A total of 90 faculty members from different postgraduate institutes across the country participated in the online survey. In three-fourth of the institutes, the CLP services were provided in the form of on-call services with a three-tier system (i.e., CLP team comprising of faculty member, a senior resident, and a junior resident) existing in only about one-third of the institutes. In majority (60%) of the institutes, junior resident was the first-line person responding to the call of other specialists. On an average, CLP teams receive 7.33 calls per day from various clinical departments with a range of 0-20. Among the three most common psychiatric syndromes seen in CLP setting, delirium figured as one of the three most common diagnoses among 79 (87.8%) institutes, and this was followed by substance use disorders (70%), self-harm (60%), and depression (38.9%). Specific CLP posting for junior and senior residents exists only in 28.9% and 12.2% of the institutes, respectively. Joint academic activities with other departments are conducted in 42.2% of the institutes. Regarding research, very few research projects are carried out in the area of CLP. Majority of the participants felt that CLP should be given equal importance or more importance than other subspecialties such as child psychiatry, addiction psychiatry, and geriatric psychiatry in postgraduate training programs. Almost all the participants felt that having good knowledge of CLP helps in managing psychiatric patients in better way. All the participants reported that improving focus on CLP psychiatry will help in reducing stigma attached to mental illnesses and improve the training of postgraduates and the undergraduates. Conclusions: There is a need to improve the CLP services, training program, and research in various medical institutes to provide good mental healthcare to medically ill patients. PMID- 30405254 TI - Efficacy of buprenorphine and clonidine in opioid detoxification: A hospital- based study. AB - Background: The need for effective and accepted method for opioid detoxification is ever increasing. Sublingual buprenorphine and oral clonidine have been effective in opioid detoxification. As often, there is a great variation in the dosage of buprenorphine and clonidine prescribed by the clinicians; hence, there is a felt need to find an effective dosage for a favorable outcome of opioid detoxification. Objective: The objective of this study was to compare the effectiveness of different doses of sublingual buprenorphine and clonidine in opioid detoxification. Materials and Methods: A total of 100 patients with the diagnosis of opioid dependence as per the international classification of diseases-10 criteria were recruited for this study. Participants were assigned randomly into four groups - low-dose clonidine, high-dose clonidine, low-dose sublingual buprenorphine, and high sublingual dose buprenorphine using a computer generated random number table, resulting in 25, 26, 23, and 26 patients in each group, respectively. Results: The four groups had comparable scores on all the items of "stages of change readiness and treatment eagerness scale" for the assessment of motivation at baseline. Progressive decrease in withdrawal score was seen in all the groups on "clinical opiate withdrawal scale" and "subjective opiate withdrawal scale." Conclusion: From the current study, we can infer that both low and high doses of buprenorphine and clonidine are comparable regarding controlling withdrawal. PMID- 30405256 TI - Correlation of cognitive functions with emotional dysregulation in alcohol dependence: A preliminary study. AB - Context and Aims: Dysfunction of cognition and emotion is known in alcohol dependence; however, their relationship in alcohol dependence is unknown. Thus, this study aimed to know the level of emotional dysregulation and cognitive functions and their correlation in patients with alcohol dependence. Materials and Methods: In this hospital-based cross-sectional study, 120 patients with alcohol dependence were consecutively recruited and assessed with sociodemographic and clinical pro forma, Montreal Cognitive Assessment (MoCA), and Difficulty in Emotional Regulation Scale-Short Form (DERS-SF). Statistical Analysis: Descriptive statistical, Kruskal-Wallis H, and regression analysis. Results: Results revealed a mild level of cognitive impairment (mean MoCA score = 0 23.76) and high levels of emotional dysregulation (mean DERS-SF score = 0 26.90). On linear regression analysis (R 2 = 0.266, df = 0 1, F = 0 42.782, P =0.000), the score on MoCA had statistically significant negative association with score on DERS-SF (P = 0.001). Conclusions: Cognitive impairment and emotional dysregulation are inversely related in patients with alcohol dependence. Improving the dysfunction may improve the outcome of alcohol dependence. PMID- 30405257 TI - Psychopathology and coping mechanisms in parents of children with intellectual disability. AB - Background: Raising a child with intellectual disability (ID) can add to parenting stress significantly. This stress can manifest into psychopathologies such as anxiety and depression. The aims of the study were to assess psychopathology and coping mechanisms in parents of children with ID. Materials and Methods: A total of 100 consecutive consenting parents of children with ID were interviewed from child psychiatry outpatient department of a municipal-run tertiary care teaching hospital. A semi-structured pro forma, symptom checklist 90 revised (SCL90R) and Mechanism of Coping Scale (MOCS) were used for assessment. Results: Mean age for the parents was 37.02 (+/-7.35) years, and for the children, it was 8.29 (+/-3.11) years. There were 60 mothers and 61 parents of a male child among sample. Eighty-five of parents considered their child's ID to be a major concern in their life. Depression had highest mean among psychopathologies. Mothers had higher score for depression and Interpersonal sensitivity. Parental psychopathology did not differ significantly with severity of ID of child. Global severity index of SCL90R correlated negatively with age of parents (P = 0.015) and positively with fatalism (P = 0.004), expressive-action (P < 0.000) and passivity (P = 0.001) coping mechanisms. Conclusion: Depression is the most common psychopathology especially among mothers of child with ID. Psychopathology is independent of severity of ID and worsens with coping mechanisms like fatalism, expressive-action, and escape-avoidance. A child with ID should be seen and treated as a family unit giving enough attention to parent's psychological needs as well. PMID- 30405258 TI - How valid is Obsessive-Compulsive Inventory-Revised Scale Among Sri Lankan adults? AB - Background: Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder with a lifetime prevalence of 1.9%-3.0% in the general population. It is an easily missed diagnosis. Although several paper-based tools have been developed, none are culturally validated for Sri Lankans to screen for OCD at field level. Aims: This study aimed to translate and assess the validity and reliability of obsessive-compulsive inventory-revised scale (OCI-R) for Sri Lankan adults. Setting and Design: This study was a case-control study. Materials and Methods: This was conducted among 89 OCD patients and 89 controls recruited from the National Hospital of Sri Lanka to assess the criterion validity of OCI-R (an 18 item tool on common OCD symptoms using six subscales), by applying it and the gold standard (clinical diagnosis made by two independent consultant psychiatrists) to the same patient simultaneously. Before this, the tool was translated into local language (Sinhala) by bilingual experts and two psychiatrists using the forward-backward translation method. Receiver operating characteristics (ROC) curve was drawn to determine the cutoff value to identify OCD in Sri Lanka. Results: The translated tool demonstrated the following: sensitivity 84.4%, specificity 85.6%, positive predictive value 85.4%, negative predictive value 84.6%, and positive and negative likelihood ratios of 5.86 and 0.18, respectively. The cutoff value for diagnosing OCD was 21 according to the ROC curve. Internal consistency (Cronbach's alpha reliability coefficient) of all six domains and the total scale showed values exceeding Nunnally's criteria of 0.7. Conclusions: Sinhala version of the OCI-R scale was identified as a valid and reliable screening instrument to be applied in Sri Lankan adults. PMID- 30405259 TI - Cross-sectional study of psychiatric morbidity in patients with melasma. AB - Context: Patients with dermatological problems have higher prevalence of psychiatric illnesses than the general population. Melasma, hyperpigmentation of skin over sun-exposed areas, has bidirectional cause-effect relationship with depression and stress through psycho-neuro-endocrine pathways. Aims: The aim of this study is to study the psychiatric morbidity and perceived stress in patients with melasma and statistically compare objective study parameters with those without melasma. Settings and Design: This cross-sectional descriptive study was carried out in Tertiary hospital in urban setting, jointly by psychiatrist and dermatologist. Methods and Materials: The study involved 50 consecutive patients with melasma and 30 relatives of patients coming to dermatology clinic not having any skin disorder. Cases were assessed by psychiatrist as per the International Classification of Diseases-10 Diagnostic Criteria for Research, Cohen's 4 item perceived stress scale, Disability Assessment Scale 2.0 by WHO and Hospital Anxiety Depression Scale (HADS) and Dermatologist calculated melasma area severity index score (MASI). Results: Majority patients were females (88%) in the reproductive age group. The most common psychiatric morbidity seen in 42% cases was major depressive disorder. Adjustment disorder (26%) was the second most common diagnosis. Nonparametric analysis using Mann-Whitney U test revealed significantly more perceived stress (P = 0.001), more disability (P = 0.000) and anxiety-depression on HADS (P = 0.0 16) in cases than in their relatives. Limitations: This was a hospital-based study and thus melasma patients in the community are not represented. Small sample size, less number of controls, lack of structured diagnostic interview are other limitations of this study. Conclusions: There is high psychiatric comorbidity (76%) of depressive and stress disorders, higher functional disability and perceived stress in patients with melasma compared to controls. PMID- 30405260 TI - Effectiveness of adjunctive repetitive transcranial magnetic stimulation in management of treatment-resistant depression: A retrospective analysis. AB - Background: There is limited number of studies from India investigating role of repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant depression (TRD). This clinic-based study reports on the efficacy of rTMS as an add-on treatment in patients suffering from TRD. Materials and Methods: Twenty two right-handed patients suffering from major depressive disorder who failed to respond to adequate trials of at least two antidepressants drugs in the current episode received rTMS as an augmenting treatment. High-frequency (Hf) rTMS at 110% of the estimated resting motor threshold (MT) was given over the left dorsolateral prefrontal cortex (DLPFC). A total of 15 sessions were given over 3 weeks with 3000 pulses per session. The outcome was assessed based on the changes in scores of Hamilton Rating Scale for Depression or Montgomery-Asberg Depression Rating Scale. Results: There was a significant reduction in final assessment scores after rTMS intervention as compared to baseline with almost 50% of the participants showing response in either scale. Conclusion: Hf rTMS applied over left DLPFC is an effective add-on treatment strategy in patients with TRD. PMID- 30405261 TI - C-reactive protein, brain-derived neurotrophic factor, interleukin-2, and stressful life events in drug-naive first-episode and recurrent depression: A cross-sectional study. AB - Aims: The aim of the study is to assess and compare serum C-reactive protein (CRP), brain derived neurotrophic factor (BDNF), and interleukin-2 (IL-2) levels in patients with first-episode depression (FED), recurrent depressive disorder (RDD), and healthy controls (HCs) and to determine the relationship between the above-specified inflammatory markers, severity of depression, and stressful life events. Materials and Methods: Consecutive drug-naive patients with FED and RDD (n = 85) and 50 HCs were studied. Serum concentrations of CRP, brain-derived nerve growth factor (BDNF), and IL-2 were measured. All participants were assessed using Mini-International Neuropsychiatric Interview Plus, Beck's depression inventory, and presumptive stressful life events scale. Results: The FED and RDD groups had statistically significant lower serum concentration of BDNF and higher IL-2 compared to the HC group, whereas no statistically significant difference was observed with regard to CRP level. No statistically significant differences were observed with regard to the severity of depression and serum concentrations of CRP, BDNF, and IL-2 in the FED and RDD groups. No significant correlation was found between severity of depression and serum concentration of CRP, BDNF, and IL-2 in both the groups. Serum CRP concentration was significantly higher in patients with >=2 stressful life events. No significant difference was observed between number of stressful life events and BDNF and IL-2 in patients with depression. Conclusion: FED and RDD are associated with lower serum concentration of BDNF and higher IL-2 compared to the HCs, whereas there appears no difference with regard to CRP level. Multicentric studies are needed to further elucidate the role of inflammatory markers in depression. PMID- 30405262 TI - Use of Social Networking Site and Mental Disorders among Medical Students in Kolkata, West Bengal. AB - Background: Use of social networking sites (SNS) and prevalence of anxiety and depression among the young population is on the rise. Objectives: The aim of this study is to assess the pattern of use of SNS and the prevalence of anxiety and depression among medical students as well as to examine the relation, if any, between the use of SNS and anxiety and depression. Methods: A cross-sectional study was conducted among 200 undergraduate students of a medical college in Kolkata, West Bengal during 2017. Information on individual characteristics and use of SNS of medical students were collected using a structured questionnaire. Anxiety and depression were measured using State-Trait Anxiety Inventory (STAI) and becks depression inventory (BDI). Prevalence was expressed in percentage and association was examined with Mann-Whitney U-test. Results: More than 90% of students use more than one SNS or instant messaging system. One-third remained active in SNSs all through the day and around 80% for >=4 h. Use of SNSs during odd hours was reported by 55% participants, and 23.5% expressed their inability to spend a day without SNSs. Nearly 24% reported depression and 68.5% had state anxiety. STAI and BDI scores were significantly (P < 0.05) higher among students who used SNSs for 4 h or more, used it during odd hours or stated inability to spend a day without SNSs than their counterparts. Conclusion: The use of SNS by medical students was pervasive. More use of SNSs and dependence on it were associated with anxiety and depression. PMID- 30405263 TI - Behavioral activation and behavioral inhibition sensitivities in patients with substance use disorders: A study from India. AB - Introduction: Addictive disorders are an epiphenomenon of underlying vulnerabilities. Research over the past decades into these vulnerabilities has distinguished internalizing and externalizing spectra as two distinct personality factors underlying substance use disorders (SUDs). In this study, we explore the behavioral activation and inhibition factors in patients with SUD. Materials and Methods: A total of 240 patients with SUD were recruited for the study. Behavioral inhibition system-behavioral activation/approach system (BIS-BAS) scale was used to assess the three domains of the behavioral activation, namely drive, fun seeking and reward responsiveness, and the behavioral inhibition as a single domain. BIS and BAS subscale total scores, inter-domain correlation, factor structure, and difference in the early-onset and late-onset SUD subgroup scores were calculated. Results: The drive, fun seeking, and reward responsiveness showed a moderate degree of correlation among each other ranging from 0.30 to 0.36. The behavioral inhibition subscale had a modest correlation r = 0.26 with the reward responsiveness subdomain of behavioral activation. The factor structure remained valid at two- and four-factor solutions apart from few items with inconsistent loading. The early-onset n = 209 (87.1%) and late-onset n = 31 (12.9%) SUD subgroup analysis showed a statistically significant difference in the mean scores of drive and fun-seeking subscales with P < 0.05. Discussion and Conclusions: Behavioral activation and inhibition remain two valid personality factors in patients with SUDs. Patients with early onset of SUD have a significantly higher behavioral activation scores in the drive, and fun-seeking subfactors suggesting a higher externalizing tendency. PMID- 30405264 TI - New legislation, new frontiers: Indian psychiatrists' perspective of the mental healthcare act 2017 prior to implementation. AB - Context: The mental healthcare act 2017 represents a complete overhaul of Indian mental health legislation. Aims: The aim of this study was to establish the opinions of Indian psychiatrists regarding the new act. Settings: Mental health professionals in Bihar and Jharkhand were interviewed. Design: A focus group design was utilized. Materials and Methods: Key questions explored the positive and negative aspects of the act and the management of the transitional phase. All focus groups were recorded and transcribed. Analysis: Data were coded and analyzed using an inductive approach. Results: Many positive aspects of the new legislation were identified especially relating to rights, autonomy, and the decriminalization of suicide. However, psychiatrists have significant concerns that the new legislation may negatively impact patients and increase stigma. Psychiatrists held varying views on the proposed licensing and inspection of general hospital psychiatric units. Conclusions: Careful evaluation of the new legislation is needed as the concerns raised warrant ongoing monitoring. PMID- 30405265 TI - A case of craniopharyngioma presenting as rapidly progressive dementia. AB - Rapidly progressive dementia (RPD) is generally obvious to family member but often difficult for physicians to pinpoint the underlying pathology. Some common causes, such as prion's disease, Alzheimer's disease, central nervous system vasculitis, or infection, might present with disease-specific signs or symptoms where many etiologies do not produce such warning signs. Here, we are presenting a case who attended the psychiatric clinic for decreased motivation to do work, easy fatigability, infrequent falls, recent memory impairment, increased appetite, polydipsia and polyuria, and provisionally diagnosed with RPD. Magnetic resonance imaging revealed solid cystic lesion in suprasellar location involving hypothalamus, optic chiasma, and optic tracts, compressing the floor of the third ventricle suggestive of craniopharyngioma which is one of the very few reports in literature. PMID- 30405268 TI - Olfactory groove meningioma masquerading as psychiatric disturbances. PMID- 30405267 TI - Buprenorphine-based opioid substitution therapy in India: A few observations, thoughts, and opinions. AB - The most evidence-based treatment for opioid dependence is opioid agonist maintenance treatment also known as opioid substitution therapy (OST). However, there are some critical, yet unaddressed issues of buprenorphine-based substitution therapy, especially in the Indian context. These comprise of generalizability of the evidence for OST, especially for natural and pharmaceutical opioids and for all age groups, optimum dose and duration of OST, and mode of treatment delivery including the frequency of dispensing. Notwithstanding the use of buprenorphine-naloxone combination, abuse and diversion are serious but often underreported problems. There is an urgent need for health services research in India on OST, focusing on these aspects. Rather than directly copying from Western models, it is important to try to understand the useful and safe program and policy options likely to be applicable in the Indian setting, with our own assets as well as vulnerabilities. PMID- 30405266 TI - Gulliver's world: Persistent lilliputian hallucinations as manifestation of Charles Bonnet syndrome in a case of cataract and normal pressure hydrocephalus. AB - Charles Bonnet Syndrome (CBS) typically occurs in elderly people with peripheral vision impairment, or interruptions in the connections from eyes to visual cortex. The heterogeneity of presentations and causal mechanisms warrants clinical caution. In this report, we describe a case of CBS developing in the form of Lilliputian Hallucinations in an elderly gentleman, on the background of cataract and normal pressure hydrocephalus, the complexities arising out of such aetiogenesis, and its management. We emphasize upon the fact that CBS might develop through two concurrent mechanisms in a given individual. Treating one of these would mean persistent symptoms, and failing to recognize these would lead to continued morbidity. PMID- 30405269 TI - Successful treatment of bipolar disorder by resection of lung tumor: A case report. PMID- 30405270 TI - Fluoxetine-induced pseudocyesis in a patient with obsessive-compulsive disorder: A case report. PMID- 30405271 TI - Somnambulism associated with the use of clonidine: A case report and review of the literature. PMID- 30405272 TI - "Precision psychiatry": A promising direction so far. PMID- 30405273 TI - Rapid and Quantitative De-tert-butylation for Poly(acrylic acid) Block Copolymers and Influence on Relaxation of Thermoassociated Transient Networks. AB - The synthesis of charged polymers often requires the polymerization of protected monomers, followed by a polymer-analogous reaction to the polyelectrolyte product. We present a mild, facile method to cleave tert-butyl groups from poly(tert-butyl acrylate) blocks that yields poly(acrylic acid) (pAA) blocks free of traces of the ester. The reaction utilizes a slight excess of HCl in hexafluoroisopropanol (HFIP) at room temperature and runs to completion within 4 h. We compare deprotection in HFIP with the common TFA/DCM method and show that the latter does not yield clean pAA. We show the effect of complete tert-butyl cleavage on a ABA triblock copolymer, where poly(N-isopropylacrylamide) (pNIPAM) is A and pAA is B, by means of viscosimetry, DLS, and SAXS on solutions above overlap. The pNIPAM blocks dehydrate, and their increased self-affinity above the lower critical solution temperature (LCST) results in network formation by the triblocks. This manifests itself as an increase in viscosity and a slowing down of the first-order correlation function in light scattering. However, this stickering effect manifests itself exclusively when the pAA block is tert-butyl free. Additionally, SAXS shows that the conformational properties of tert-butyl free pAA copolymers are markedly different from those with residual esters. Thus, we illustrate a surprising effect of hydrophobic impurities that act across blocks and assert the usefulness of HCl/HFIP in pAA synthesis. PMID- 30405274 TI - Stereoselective Synthesis of 5-O-Carbamoylpolyoxamic Acid by [2,3]-Wittig-Still Rearrangement. AB - Stereoselective [2,3]-Wittig rearrangement of E- and Z-allylic stannyl ethers derived from an isopropylidene L-threitol derivative has been investigated. The E isomer exhibited best diastereoselectivity and the resulting rearrangement product has been converted to protected polyoxamic acid, an amino acid component of many bioactive polyoxins. PMID- 30405275 TI - Synthetic studies of antitumor macrolide laulimalide: a stereoselective synthesis of the C17-C28 segment. AB - A stereoselective synthesis of the C17-C28 segment of the potent antitumor macrolide, laulimalide has been accomplished. The key steps are a ring-closing olefin metathesis to construct the dihydropyran unit, nucleophilic addition of an alkynyl anion to the Weinreb amide, stereoselective reduction of the resulting ketone to set the C20-hydroxyl stereochemistry, and elaboration of the C21-C22 trans-olefin geometry. PMID- 30405276 TI - Elucidating the multi-targeted anti-amyloid activity and enhanced islet amyloid polypeptide binding of beta-wrapins. AB - beta-wrapins are engineered binding proteins stabilizing the beta-hairpin conformations of amyloidogenic proteins islet amyloid polypeptide (IAPP), amyloid beta, and alpha-synuclein, thus inhibiting their amyloid propensity. Here, we use computational and experimental methods to investigate the molecular recognition of IAPP by beta-wrapins. We show that the multi-targeted, IAPP, amyloid-beta, and alpha-synuclein, binding properties of beta-wrapins originate mainly from optimized interactions between beta-wrapin residues and sets of residues in the three amyloidogenic proteins with similar physicochemical properties. Our results suggest that IAPP is a comparatively promiscuous beta-wrapin target, probably due to the low number of charged residues in the IAPP beta-hairpin motif. The sub micromolar affinity of beta-wrapin HI18, specifically selected against IAPP, is achieved in part by salt-bridge formation between HI18 residue Glu10 and the IAPP N-terminal residue Lys1, both located in the flexible N-termini of the interacting proteins. Our findings provide insights towards developing novel protein-based single- or multi-targeted therapeutics. PMID- 30405278 TI - Clinical Profile and Outcome of Patients with Acute Poisoning Admitted in Intensive Care Unit of Tertiary Care Center in Eastern Nepal. AB - Background: Acute poisoning is a common health-care problem requiring admission in the intensive care unit (ICU) in the developing countries. The study was conducted to assess the epidemiological parameters of acute poisoning and factors affecting clinical course and outcome of the patients in ICU in the eastern part of Nepal. Methodology: This was a prospective observational study conducted at ICU of tertiary care hospital in the eastern part of Nepal for the duration of 2 years. All the acute poisoning cases admitted in the ICU were studied for epidemiological profiles, poisoning characteristics, and various clinical factors affecting the outcome of the patients. Results: Eighty-five patients with acute poisoning were included in the study. Suicidal attempt leading to acute poisoning was seen in majority of the young population. Majority of the poisoning was due to the organophosphorous compounds (43.5%). Patients with organophosphorous poisoning had a significantly longer duration of ICU stay (P = 0.020). The survival of the patients was significantly affected by age, duration of presentation to the hospital, Glasgow Coma Scale, Sequential Organ Failure Assessment score, need for mechanical ventilation, duration of ICU stay, hepatic failure, coagulopathy, and need for vasoactive drugs (P < 0.05). The independent predictors of mortality observed in the study were age, delayed presentation to the hospital, hepatic failure, and need for mechanical ventilation. Conclusion: Organophosphorous poisoning was the most common acute poisoning in young population leading to the ICU admission. Older age, delayed initiation of the resuscitative measures, need for mechanical ventilation, and hepatic failure significantly affected the mortality. PMID- 30405277 TI - Temperature-related mortality impacts under and beyond Paris Agreement climate change scenarios. AB - The Paris Agreement binds all nations to undertake ambitious efforts to combat climate change, with the commitment to Bhold warming well below 2 degrees C in global mean temperature (GMT), relative to pre-industrial levels, and to pursue efforts to limit warming to 1.5 degrees C". The 1.5 degrees C limit constitutes an ambitious goal for which greater evidence on its benefits for health would help guide policy and potentially increase the motivation for action. Here we contribute to this gap with an assessment on the potential health benefits, in terms of reductions in temperature-related mortality, derived from the compliance to the agreed temperature targets, compared to more extreme warming scenarios. We performed a multi-region analysis in 451 locations in 23 countries with different climate zones, and evaluated changes in heat and cold-related mortality under scenarios consistent with the Paris Agreement targets (1.5 and 2 degrees C) and more extreme GMT increases (3 and 4 degrees C), and under the assumption of no changes in demographic distribution and vulnerability. Our results suggest that limiting warming below 2 degrees C could prevent large increases in temperature related mortality in most regions worldwide. The comparison between 1.5 and 2 degrees C is more complex and characterized by higher uncertainty, with geographical differences that indicate potential benefits limited to areas located in warmer climates, where direct climate change impacts will be more discernible. PMID- 30405279 TI - Early pH Change Predicts Intensive Care Unit Mortality. AB - Aim of the Study: Metabolic acidosis is associated with increased mortality in critically ill patients. We hypothesized that early correction of acidosis of presumed metabolic origin results in improved outcomes. Patients and Methods: We conducted a prospective, observational study from February 2015 to June 2016 in a 12 bed mixed intensive care unit (ICU) of a 1000 bed tertiary care hospital in the north of India. ICU patients aged above 18 years with an admission pH >=7.0 to <7.35 of presumed metabolic origin were included. Arterial blood gas parameters including pH, PaO2, PaCO2, HCO3 -, Na+, K+, Cl-, anion gap (AG), base excess, and lactate at 0, 6, and 24 h along with other standard laboratory investigations were recorded. The primary outcome was to assess the impact of early pH changes on mortality at day 28 of ICU. Results: A total of 104 patients with 60.6% males and 91.3% medical patients were included in the study. Sepsis of lung origin (60.6%) was the predominant etiology. By day 28, 68 (65.4%) patients had died. Median age was 49.5 years, weight 61.7 kg, Sequential Organ Failure Assessment, and Acute Physiologic and Chronic Health Evaluation II scores were 16 and 12, respectively. Nonsurvivors had a higher vasopressor index (P < 0.01), lactate and central venous oxygen saturation (P < 0.05), and lower pH (P < 0.05). A pH correction/change of >=1.16% during the first 24 h had the best receiver operating characteristic for predicting survival at day 28, with area under the curve (95% confidence interval, 0.72 [0.62-0.82], P < 0.05) compared to HCO3 -, BE, lactate, and AG. Conclusions: Metabolic acidosis is associated with higher mortality in ICU. The rate of change in pH may better predict ICU mortality than other metabolic indices. PMID- 30405280 TI - Critical Illness Scoring Systems: Sequential Organ Failure Assessment, Acute Physiology and Chronic Health Evaluation II, and Quick Sequential Organ Failure Assessment to Predict the Clinical Outcomes in Scrub Typhus Patients with Organ Dysfunctions. AB - Background and Aim: Scrub typhus (ST) is an acute infectious disease of variable severity caused by Orientia (formerly Rickettsia) tsutsugamushi. The disease can be complicated by organ dysfunctions and the case fatality rate (CFR) is approximately 15%, which further rises with the development of severe complications. We studied the clinical features of the ST and the performance of critical illness scoring systems (CISSs) - Acute Physiology and Chronic Health Evaluation (APACHE) II, sequential organ failure assessment (SOFA), and quick SOFA (qSOFA) in predicting the clinical outcomes in complicated ST (cST) patients admitted to the emergency department. Study Design and Methods: A prospective observational study was done in 50 patients diagnosed to have cST with one or more organ dysfunctions. Clinical features and laboratory parameters were recorded and the patients were followed up until the end of their stay in the hospital. APACHE II, SOFA, and qSOFA scores at admission were calculated and were analyzed in predicting the clinical outcomes. Results: The median SOFA, APACHE II, and qSOFA scores of the cohort were 7 (interquartile range [IQR] = 13-22), 8 (IQR = 5-11), and 2 (IQR = 1-3), respectively. The median duration of in-hospital stay was 9 (IQR 5-11) days and overall CFR was 8%. On bivariate analysis, both SOFA (P = 0.031) and qSOFA (P = 0.001) predicted mortality. However, only SOFA score correlated with the in-hospital stay duration (Pearson's correlation = 0.311, P = 0.028). Conclusion: Among the three CISSs studied, the SOFA score correlated with in-hospital stay duration and mortality, whereas the qSOFA score formed a simple as well as a convenient tool in predicting the mortality in patients of cST with organ dysfunction. PMID- 30405281 TI - Spectrum of Diseases/conditions Exhibiting Hemostatic Abnormalities in Patients Admitted to a Medical Intensive Care Unit of a Tertiary Care Hospital. AB - Background and Aims: In a medical intensive care unit (MICU), many patients develop hemostatic abnormalities, ranging from abnormal clotting tests to frank bleeding. The aim of this study was to assess the etiology of diseases that present with bleeding, its common bleeding manifestations, incidence, MICU stay, mortality, and transfusion requirements in an Indian setup and also to assess if the Acute Physiology and Chronic Health Evaluation II (APACHE II) score can be used as a predictor for blood transfusion requirements. Materials and Methods: Between July 2013 and August 2014, 200 patients with clinically significant bleeding admitted in the MICU were prospectively evaluated. Detailed history, examination, laboratory investigations, APACHE II score, and requirement of blood products were also noted. The endpoints were discharge or death. Results: The spectrum of diseases that presented with bleeding was 47 patients with malaria (23.5%) followed by 36 acute undifferentiated febrile illness (18.0%), 33 dengue (16.5%), 30 leptospirosis (15.0%), 31 acute fulminant hepatitis (15.5%), 14 sepsis (7.0%), and the rest nine miscellaneous causes. The most common bleeding manifestation observed was hematuria in 62/200 (31%). Among the patients studied, 126 expired (63%) and 74 survived (37%). Of the 200 patients, 48/200 (24%) received packed cells, 78/200 (39%) fresh frozen plasma, and 82/200 (41%) platelets. Conclusions: Tropical diseases formed the majority of admissions with bleeding manifestations. Thrombocytopenia is an important marker to predict mortality and also has a significant association with MICU stay. APACHE II score was found to be a good predictor of blood transfusion requirements. PMID- 30405282 TI - Clinical and Laboratory Features Associated with Acute Kidney Injury in Severe Malaria. AB - Introduction: Critically ill severe malaria constitutes one of the major hospital admissions in Indian setting. Clinical studies identifying the factors associated with acute kidney injury (AKI) in malaria are lacking. This study aimed to identify these factors. Methods: This prospective observational study was conducted in a tertiary care center of North India. All adult patients with severe malaria were studied during 2012-2014. Results: The study included 79 patients and AKI was observed in 36 patients. Of these 79 patients, 52.7% were Plasmodium falciparum positive and 47.2% were Plasmodium vivax positive. In AKI patients, thrombocytopenia and jaundice were the most common other complications seen. Among P. vivax malarial patients, 17 (36%) patients had AKI. Features associated with AKI among patients admitted with P. vivax malaria were as follows: tachycardia (adjusted relative risk [RR]: 3.9; 95% confidence interval [CI]: 1.1-13.7), direct hyperbilirubinemia (adjusted RR: 4.7; 95% CI: 1.4-15.2), anemia (adjusted RR: 6; 95% CI: 1.7-22.4), and sepsis (adjusted RR: 3.3; 95% CI: 1.1-13.7). The presence of tachycardia, acidosis, cerebral malaria, acute respiratory distress syndrome/acute lung injury, hypotensive shock, and poor Glasgow Coma Scale were associated with higher mortality in patients with AKI. Patients who required mechanical ventilation and/or vasopressor support had higher mortality. Conclusion: P. vivax is an important cause of severe malaria with AKI in our setting. Various other clinical features are associated with AKI and related mortality. PMID- 30405283 TI - A Multicentric, Prospective, Observational Antibacterial Utilization Study in Indian Tertiary Referral Centers. AB - Rationale: Antibacterials are largely prescribed to the intensive care unit (ICU) patients due to high prevalence of infections. However, appropriate use of antibacterials is imperative; since the misuse of antibacterials increases antibacterial resistance and ultimately, it has negative impact on health care and economic system. Hence, continuous antibacterials prescription assessments are very important to judge and improve prescription patterns. The present work was carried out at public and private hospitals to assess the differences in antibacterial prescribing pattern. Methods: The present study was conducted at three public and two private hospitals over the period of 14 months. Demographic and drug use details were captured daily from patients admitted to medical ICUs to assess the World Health Organization indicators. Results: A total of 700 patients were enrolled across the five centers (140 per center), among them 424 were male and 276 were female. Average number of drugs and antibacterials prescribed at public hospitals are significantly higher than the private hospital. However, percentage of antibacterial agents prescribed at public hospitals was significantly lower than the private hospitals (P = 0.0381). Private hospitals had significantly lower percentage of antibacterial agents prescribed by generic name (P < 0.0001). Differences in change of antibacterial agents required were not statistically significantly different (P = 0.1888); however, significant difference was observed in percentage of patients who received antibacterial treatment as per sensitivity pattern (P = 0.0385) between public and private hospitals. Significantly higher mortality was observed in public hospitals compared to private hospitals (<0.0001). Conclusions: More generic prescriptions and more number of prescriptions as per the sensitivity pattern are required at each public and private hospital. PMID- 30405284 TI - Timing of Renal Replacement Therapy in Acute Kidney Injury: Shedding New Light on an Old Controversy. AB - Critically ill patients with severe acute kidney injury (AKI-D) require renal replacement therapy (RRT) increasingly. However, the optimal timing of initiation of RRT for non-life-threatening indications of AKI remains unknown. There is a debate as to whether different philosophies of RRT initiation (early vs. delayed) confer a survival benefit. Lowering the threshold for RRT initiation, however, inevitably leads to more critically ill patients receiving unnecessary RRT. The relevant proportion of nonprogressing early stage AKI patients with spontaneous kidney recovery is a matter of severe concern because RRT has potentially lethal complications and is expensive. Moreover, these patients should be excluded from randomized trials. The furosemide stress test in critically ill patients with early stages of AKI serves as a novel tubular function test to identify those patients with severe and progressive AKI-D. Future trials to validate findings of a promising pilot study are warranted. PMID- 30405285 TI - Diagnostic Usefulness of Serum Albumin as a Predictor of Diabetic Ketoacidosis. AB - Context: Diabetes mellitus is one of the most prevalent diseases worldwide. One of the acute complications of diabetes mellitus is diabetic ketoacidosis. It becomes essential for the healthcare physicians to identify the individuals who are likely to be prone to the development of ketosis. Serum albumin levels may be a cost-effective and simple parameter to prognosticate the risk of ketosis. Aims: This study was done to find a relationship between serum albumin levels and ketonuria. Settings and Design: After ethical approval, this prospective case control study was carried out in patients diagnosed as type-2 diabetes mellitus. Subjects and Methods: Serum albumin levels were measured by bromo cresol green method. Measurement of urine ketones was done manually using dipsticks, a semi quantitative manual method. Statistical Analysis Used: Student's t-test was used to compare continuous variables and Chi-square test for categorical variables. Pearson's correlation was done to establish correlation. Results: In the normoalbuminemic group, 72% were ketones negative and only 28% had positive ketones in urine, while in the hypoalbuminemic group, 50.7% had negative urine ketones and 49.3% had positive ketonuria. The mean value for ketones in urine was 9.7 mg/dL in the hypoalbuminemic group, but it was only 4.3 mg/dL in the normoalbuminemic group. Pearson's correlation between serum albumin and urine ketone levels was performed and the r-value was found to be -0.305. Conclusions: Serum albumin levels may predict the occurrence of ketosis in diabetic patients. PMID- 30405286 TI - Bilateral Phrenic Nerve Palsy in a Diabetic Causing Respiratory Failure. AB - Neuropathy is one of the major reasons of morbidity in diabetes mellitus (DM). We presented a 64-year-old male who was a case of type 2 DM for >6 years. He presented with orthopnea and respiratory failure secondary to bilateral phrenic neuropathy and resultant diaphragmatic palsy. Clinical examination, ultrasound, and nerve conduction studies confirmed the bilateral involvement of the phrenic nerves. Phrenic neuropathy may be an important, albeit a rare complication of diabetes, and hence, diaphragmatic dysfunction associated with diabetic phrenic neuropathy should be considered in any patient with unexplained breathlessness, orthopnea, and respiratory failure. PMID- 30405288 TI - Calming the Electrical Storm: Use of Stellate Ganglion Block and Thoracic Epidural in Intractable Ventricular Tachycardia. AB - Imbalances in the autonomic nervous system contribute to ventricular tachyarrhythmias. Sympatholysis with thoracic epidural analgesia or a stellate ganglion block attenuates myocardial excitability and the proarrhythmic effects of sympathetic hyperactivity. PMID- 30405287 TI - Methotrexate-Induced Toxic Epidermal Necrolysis: A Rare Case Report and Review of Literature. AB - Acute lymphoblastic leukemia (ALL) is the most common malignancy in pediatric patients, and it is characterized by the presence of malignant lymphoblasts within the bone marrow and peripheral blood. The treatment of ALL involves induction, consolidation, reinduction, and maintenance therapy. Consolidation therapy in ALL-Berlin-Frankfurt-Munster 90 protocol involves the use of high-dose methotrexate (HDMTX, 5 g/m2) over 24 h as continuous infusion. The adverse effects due to HDMTX include renal dysfunction in 2%-12% patients, which can lead to increased systemic MTX exposure, leading to further myelosuppression, mucositis, hepatotoxicity, skin toxicity, and, in severe cases, multiorgan failure. Dermatologic toxicity due to MTX includes morbilliform drug rash, photoreactivation, photoenhancement, and skin hyperpigmentation. Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) are rare and possibly fatal reaction which can occur with MTX. Here, we describe a patient with B-cell ALL who developed TEN after administration of HDMTX. PMID- 30405289 TI - Anti-Voltage-Gated Potassium Channel Antibody Syndrome: A Rare Cause of Hyponatremia in Intensive Care Unit. AB - Hyponatremia causing seizure is a common cause for admission in the critical care unit. Here, we describe a peculiar case of seizure due to hyponatremia, associated with anti-voltage-gated potassium channel antibody syndrome. This case emphasizes that how a proper workup can unveil unusual but potentially treatable causes of hyponatremia. The hallmark of this syndrome is that neurological symptoms may relapse or progress if the disorder is not recognized in time. This case report emphasizes the point that how a keen observation may decode subtle signs of the grave but potentially treatable pathologies. PMID- 30405290 TI - Refractory Status Asthmaticus: A Case for Unconventional Therapies. AB - Status Asthmaticus is a common reason for Emergency Room visits in children. Most of the asthma flares are successfully managed by use of beta agonist and steroids. If these therapies fail to halt the progression of asthma, a number of medical therapies may be used to treat it. However, the data supporting the use of these therapies are conflicting. We present successful use of Extracorporeal Membrane Oxygenation and isoflurane in a child with Refractory Status Asthmaticus. PMID- 30405291 TI - Artesunate-Induced Severe Autoimmune Hemolytic Anemia in Complicated Malaria. AB - Autoimmune hemolytic anemia (AIHA) is a very rare cause of anemia in a case of malaria and drug-induced AIHA is even rarer. A 50-year old patient with a history of fever for 8 days was diagnosed with a case of complicated malaria with mixed infection having initial parasite index of 45%. He showed good response on initial therapy with artesunate (parasite count reduced to <1%) but his haemoglobin (Hb) continued to drop from 12 g% to 4.9 g% over a course of 11 days. Direct coombs test was positive with reduced haptoglobin and increased lactate dehydrogenase suggesting AIHA. The patient was put on steroids and transfused with saline washed O-negative blood. He gradually recovered over 8 weeks with Hb level rising up to 12 g%. This is a rare case of AIHA following treatment of severe malaria with parenteral artesunate suggesting of the drug immune-related mechanism. PMID- 30405292 TI - "BROAD Effect: Bradycardia in Obstructive Airway Disease"An Unusual Phenomenon: A Case Report. AB - Non Invasive Ventilation (NIV) is frequently used in Obstructive Airway Disease (OAD) especially COPD (Chronic Obstructive Pulmonary Disease). Patients often get hypoxic or retain carbon dioxide during attempts to feed the patient orally or trial of intermittent support. However, patient developing sudden bradycardia by mere taking off the mask and reverting to sinus rhythm as soon as mask is put back is extremely rare. We present one such case that was also a treatment challenge for us. Recurrent bradycardia in COPD, with repeatability on discontinuation of Non Invasive Ventilation (NIV) is an extremely rare condition with not much reports/studies in the medical literature. The mechanisms leading to such an event are poorly understood. To the best of our knowledge, it's the first case to be reported from India. PMID- 30405293 TI - Targeting the Venous Confluence of Pirogoff for Central Venous Cannulation Insertion, When Internal Jugular Vein Cannulation is Difficult: A Three-Step Approach. PMID- 30405294 TI - Angiotensin II and the Natriuretic and Blood Pressure Response to Mental Stress in African Americans. AB - Objective: To test the hypothesis that Angiotensin II (Ang II) is a contributing factor to the response pattern in African Americans (AAs) who retain rather than excrete sodium during mental stress. Design/Study Participants: Double-blind, randomized, cross-over trial of 87 healthy AAs aged 18 to 50 years. Interventions: The study participants received either a placebo or irbesartan, (150 mg PO), an Ang II receptor antagonist, for seven days prior to stress testing. Urinary sodium excretion (UNaV) and systolic blood pressure (SBP) were collected prior to and throughout a mental stress protocol (rest and stress period). Setting: A southeastern university. Main Outcome Measures: Ang II, SBP, and sodium retention. Results: During the placebo condition, 62 participants showed the expected increase in UNaV (excreters) while 25 participants reduced UNaV during stress (retainers). Irbesartan retainers demonstrated a reversal in the direction of their natriuretic response, now increasing UNaV in response to stress (? UNaV of -.094 mmol/min with placebo vs .052 mmol/min on irbesartan; P<.001). In excreters, irbesartan reduced SBP levels during both rest (-2.36 mm Hg; P=.03) and stress (-4.59;P<.0001), and an even more pronounced reduction in SBP was demonstrated by retainers on treatment during both rest (-4.29 mm Hg; P=.03) and stress (-6.12; P<.001). Conclusions: Ang II contributes to sodium retention in retainers. Furthermore, our findings indicate that suppression of Ang II has a beneficial effect on SBP during rest and stress in this population. PMID- 30405295 TI - Effect of Race on Outcomes Following Early Coronary Computed Tomographic Angiography or Standard Emergency Department Evaluation for Acute Chest Pain. AB - Objective: To examine racial differences in outcomes with coronary computed tomographic angiography (CCTA) vs standard emergency department (ED) evaluation for chest pain. Design: Retrospective analysis of the prospective, randomized, multicenter Rule Out Myocardial Ischemia/Infarction by Computer Assisted Tomography (ROMICAT-II) trial. Setting: ED at nine hospitals in the United States. Participants: 940 patients who were Caucasian or African American (AA) presenting to the ED with chest pain. Interventions: CCTA or standard ED evaluation. Main Outcome Measures: Length of stay, hospital admission, direct ED discharge, downstream testing and repeat ED visit or hospitalization for recurrent chest pain at 28 days. Safety end points: missed acute coronary syndrome (ACS) and cumulative radiation exposure during the index visit and follow-up period. Results: 659 (66%) patients self-identified as Caucasian and 281 (28%) self-identified as AA. AA were younger and more often female compared with Caucasians, had a higher prevalence of hypertension (64% vs 49%, P<.001) and diabetes (23% vs 14%, P<.001) and a lower prevalence of hyperlipidemia (28% vs 51%, P<.001). ACS was more frequent among Caucasians (10% vs 2%, P<.001). Randomization to CCTA resulted in a reduction in median LOS for Caucasians (7.4 vs 24.7 hours, P<.001) and AA (8.9 vs. 26.3, P<.001; P-interaction=.88). Both AA and Caucasian patients experienced greater radiation exposure and more downstream testing with CCTA compared with standard evaluation. Conclusions: Early CCTA reduced median LOS for both AA and Caucasian patients presenting to the ED with chest pain by approximately 17 hours compared with standard evaluation. PMID- 30405296 TI - Impaired Homocysteine Metabolism Associated with High Plasma Interleukin-17A Levels, a Pro-Atherogenic Marker, in an Endogamous Population of North India. AB - Background: Impaired homocysteine metabolism (IHM; hyperhomocysteinemia) has been linked with many complex disorders like cardiovascular diseases and immunological disturbances. However, studies understanding IHM in light of pro- and anti- atherogeneic markers like Interleukin-17A & -10 (IL-17A & IL-10) and Forkhead box p3 (Foxp3, a master transcription factor) are scarce. Aim: In our present study, we aimed to understand the relation of IHM with plasma IL-17A and IL-10 levels and Foxp3 mRNA expression in peripheral blood mononuclear cells (PBMCs) from an endogamous population (Jats of Haryana, North India) with high prevalence of IHM without the concurrence of significant adverse cardiovascular outcomes. Methods: Forty (40) clinically healthy individuals, unrelated up to first cousins, were recruited and were subjected to demographic, physiological and anthropometric profiling, followed by intravenous blood sample collection (fasting) and lipid profiling. Plasma homocysteine levels were estimated and individuals with homocysteine levels >= 15umol/L and <15umol/L were categorized as the impaired homocysteine metabolism group (IHM, n=30) and normal homocysteine metabolism group (NHM, n=10) respectively. Plasma folate and vitamin B12 and MTHFR C677T (methylenetetrahydrofolate reductase) polymorphism were detected. Relative mRNA expression of Foxp3 in PBMCs (normalized to 18S) was quantitated using SyBR green technology. Plasma IL-10 & 17 levels were estimated by ELISA assays. Results and Conclusions: None of the physiological, anthropometric and lipid variables were different between the two groups. Foxp3 mRNA expression levels were relatively lower, and plasma IL-10 levels were found to be comparable among IHM and NHM group. However, significantly higher IL-17A levels and relatively high LDL cholesterol levels were present in the IHM group as compared with NHM. Our findings suggest that the Jats of Haryana, North India, exhibiting high levels of homocysteine, might also carry the high IL-17A -pro-atherogenic marker, suggesting an increasing burden of pre-morbid condition. This apparently does not reach to significant mortality/morbidity attributed to the counter action or balancing act of IL-10 (an anti-atherogenic marker). This further suggests environment-influenced epigenetic control mechanisms of the targeted genes in the present population. PMID- 30405297 TI - Race/Ethnicity-Specific Associations between Smoking, Serum Leptin, and Abdominal Fat: The Multi-Ethnic Study of Atherosclerosis. AB - Objective: Smoking is a well-known cardiovascular risk factor associated with weight loss. We aimed to evaluate the association between smoking, serum leptin levels, and abdominal fat. Design: Cross-sectional. Setting: Data from examinations 2 or 3 (2002-2005) of the Multi-Ethnic Study of Atherosclerosis (MESA). Participants: 1,875 asymptomatic, community-dwelling adults. Main Outcome Measures: We used multivariable linear regression models to assess the race/ethnicity-specific associations between smoking, serum logeleptin levels, and computed tomography ascertained abdominal fat. Results were adjusted for demographic and relevantclinical covariates. Results: Participants (mean age 64.5+/-9.6 years; 50.6% women; 42.2% former, 11.4% current smokers) were White (40.1%), Hispanic (25.8%), African American (21.1%), and Chinese (13.0%). Overall, median (25th - 75th percentile) leptin levels were significantly lower among current (11.14 ng/mL; 4.13 - 26.18) and former smokers (11.68 ng/mL; 4.72 - 27.57), as compared with never smokers (15.61 ng/mL; 3.05 - 30.12) (P<.001). The difference in median leptin levels between current and never smokers were significantly higher for Hispanics (Delta9.64 ng/mL) and African Americans (Delta8.81 ng/mL) than Whites (Delta2.10 ng/mL) and Chinese (Delta4.70 ng/mL) (P<.001). After adjustment for total abdominal fat, loge-leptin levels remained lower for former (-.14 [-.22 - -.07]) and current (-.17 [-.28 - -.05]) smokers, compared with never smokers. Results differed by race/ethnicity, with significantly lower loge-leptin levels observed only among current and former African Americans and Hispanic smokers, compared with their never smoker counterparts. (Ps for interaction <.05). Conclusions: Among smokers, leptin levels significantly vary by race/ethnicity. Former and current smoking are associated with lower leptin levels, although this may be restricted to Hispanics and African Americans. PMID- 30405299 TI - Addressing Hepatitis C within a Southwest Tribal Community. AB - Objective: The objective was to identify and treat segments of the local population at greatest risk for viral hepatitis C (HCV) infections. Design: The tribal-based HCV initiatives included community involvement and outreach and HCV data were mined and analyzed. Medical records were reviewed, and new HCV tribal health policies and procedures were developed. Results: A total of 251 tribal members (63.7% male) were diagnosed with HCV and had a positive confirmatory test between the years 2009 and 2014. Through community-based outreach efforts, 85 HCV patients were successfully contacted for education, field-testing, referral and follow-up, an increase of more than 300%. Conclusions: The tribe increased ways to monitor HCV risk factors and communicable disease pathways. PMID- 30405298 TI - John Henryism and Perceived Health among Hemodialysis Patients in a Multiracial Brazilian Population: the PROHEMO. AB - Purpose: John Henryism (JH) is a strong behavioral predisposition to engage in high-effort coping with difficult socioenvironmental stressors. We investigated associations between JH and perceived general health (GH) among maintenance hemodialysis (MHD) patients in a multiracial Brazilian population. Design: The 12 item John Henryism Acting Coping (JHAC) Scale was completed by 525 patients enrolled in The Prospective Study of the Prognosis of Hemodialysis Patients (PROHEMO) in Salvador (Bahia) Brazil. JH scores could range from 12 to 60. The low and high JH groups were determined by a median split (<52 vs >=52). The 36 Item Short Form Health Survey was used to determine GH score (range 0-100; higher means better health). Linear regression with extensive adjustments was used to test associations. Results: Mean age was 48.3+/-13.7 years; 38.7% were female; 11.4% were White, 29.1% were Black and 59.4% were mixed race. JH was positively associated with higher GH in the whole sample (adjusted difference [AdjDif]=7.14, 95% CI= 2.98, 11.3) and similarly in men and women. A strong positive association between JH and GH was observed in non-Whites but not in Whites; (AdjDif in Blacks =16.4, 95% CI=8.37, 24.4). Also, a strong positive association between JH and GH was observed for patients aged <60 years (AdjDif =9.04, 95% CI = 4.46, 13.6) but not for older patients. Conclusions: The results indicate that MHD patients engaged in high-effort coping with socioenvironmental stressors as demonstrated by high JH tend to feel more positively about their overall health. This seems to be especially the case for non-White and younger patients. PMID- 30405300 TI - Review: Partner Support and Physical Activity among Mexican American Women. AB - Objective: Global recommendations on physical activity for noncommunicable disease prevention can be promoted using partner support strategies among women of Mexican descent and other ethnicities. Design/Methods: This systematic review utilized a multifaceted ecological approach by focusing comprehensively on community, individual, and social factors influencing physical activity. PubMed, SAGE Publications, EBSCO, ResearchGate, the Cochrane Library and Google Scholar search engines were used to find research on physical activity, with inclusion criteria of Mexican American women, aged >= 18 years, comprising at least 50% of study population sizes. Main Outcome Measures: An initial search of 232 articles with subsequent searches from reference lists led to selection of a mixture of qualitative (3), mixed methods (3), and intervention (1) studies reporting partner support for physical activity as perceived by women. Results: Primarily, studies have conceptualized physical activity as leisure time activities. Few studies have considered multiple ecological factors in examining influences of physical activity among women. Importantly, how women perceive support for physical activity received from partners has been shown to influence their levels of activity. Conclusions: Conceptualization of physical activity restricted only to leisure time eliminates other domains that a broader definition of the term encompasses. Future studies are needed to investigate partner support influences on the overall physical activity of Mexican American women within a larger ecological context. Careful attention to partner support for physical activity engagement can help ameliorate and prevent chronic diseases both nationally and around the world. PMID- 30405301 TI - Commentary: Race and Ethnicity in Biomedical Research - Classifications, Challenges, and Future Directions. AB - The use of race and ethnicity in biomedical research has been a subject of debate for the past three decades. Initially the two major race categories were: White and Black, leaving other minorities uncounted or inappropriately misclassified. As the science of health disparities evolves, more sophisticated and detailed information has been added to large databases. Despite the addition of new racial classifications, including multi-racial denominations, the quality of the data is limited to the data collection process and other social misconceptions. Although race is viewed as an imposed or ascribed status, ethnicity is an achieved status, making it a more challenging variable to include in biomedical research. Ambiguity between race and ethnicity often exists, ultimately affecting the value of both variables. To better understand specific health outcomes or disparities of groups, it is necessary to collect subgroup-specific data. Cultural perceptions and practices, health experiences, and susceptibility to disease vary greatly among broad racial-ethnic groups and requires the collection of nuanced data to understand. Here, we provide an overview of the classification of race and ethnicity in the United States over time, the existing challenges in using race and ethnicity in biomedical research and future research directions. PMID- 30405302 TI - Breast Cancer Outcomes in a Racially and Ethnically Diverse Cohort of Insured Women. AB - Background: It is unknown how subsequent breast cancer outcomes vary by biologic subtype and race/ethnicity in a diverse cohort of breast cancer survivors. Methods: We conducted a prospective cohort study of 6,154 insured breast cancer survivors (AJCC TNM stages 0-IV) diagnosed between 1996-2007 and followed them through 1/1/2010 for subsequent breast cancer events (recurrence, contralateral breast cancer, metastasis, mortality). We compared subsequent breast cancer rates by race/ethnicity groups and biologic subtype (luminal A, luminal B, HER2 enriched, and triple negative). We calculated hazard ratios (HRs) with 95% CIs using multivariable Cox proportional hazards models, adjusted for sociodemographics, cancer treatments, and tumor characteristics. Results: The cohort was diverse: 62.4% non-Hispanic White, 13.2% Hispanic, 14.9% African American, and 9.5% Asian. We identified 1,456 subsequent breast cancer events over 22,830 person-years. Although certain Asian women had higher crude subsequent breast cancer rates compared with Whites, within each biologic subtype category, these disparities disappeared in the multivariable analyses. After accounting for race/ethnicity, compared with women with luminal A tumors (reference), women with luminal B (adjusted HR=3.65, 95% CI: 3.08-4.32), HER2 enriched (adjusted HR=2.81, 95% CI: 2.25-3.51) and triple negative (adjusted HR=1.25, 95% CI: 1.01-1.54) tumors had statistically increased risks of subsequent breast cancer. Factors that were statistically significantly associated with increased risk included higher stage, larger tumor size, positive lymph nodes, and no adjuvant endocrine or chemotherapy (all P<.025). Discussion: Our data suggest that disparities in subsequent breast cancer outcomes were more strongly associated with tumor characteristics and non-use of adjuvant treatments than race/ethnicity. PMID- 30405303 TI - Perspective: Sistas In Science - Cracking the Glass Ceiling. AB - In this perspective, we describe our experience as women of color scientists from diverse backgrounds and similar struggles embarking upon the National Heart, Lung and Blood Institute-funded program called PRIDE (Programs to Increase Diversity among Underrepresented Minorities Engaged in Health-Related Research). Under the leadership of our mentor and friend, Betty Pace, MD, a renowned and successful African American physician-scientist, the PRIDE Program was designed to address the difficulties experienced by junior-level minority investigators in establishing independent research programs and negotiating tenure and full professor status at academic institutions. The strength of PRIDE's innovative formula was pairing us with external senior mentors and, importantly, allowing us to serve as peer mentors to each other. We believe this "Sister's Keeper" paradigm is one solution for women to overcome their limitations and extend understandings and best practices worldwide for science, medicine, and global health. PMID- 30405304 TI - Commentary: Training and Mentoring the Next Generation of Health Equity Researchers: Insights from the Field. AB - During August 30-31, 2017, the National Heart, Lung, and Blood Institute's Center for Translation Research and Implementation Science (CTRIS) hosted a two-day workshop with thought leaders and experts in the fields of implementation science, prevention science, health inequities research, and training and research workforce development. The workshop addressed critical challenges and compelling questions from the NHLBI Strategic Vision, as well as the Department of Health and Human Services' Action Plan to Reduce Racial and Ethnic Health Disparities. Participants discussed: best practices for designing and executing implementation research training programs; approaches to increase participation in implementation research to address health inequities; innovative training methods and models, including team science approaches; and best practices for developing and sustaining a cadre of mentors for individuals who conduct implementation research. As part of this workshop, the Saunders-Watkins Memorial Lecture, named posthumously for Dr. Elijah Saunders, a Baltimore cardiologist, and Dr. Levi Watkins, a Baltimore cardiothoracic surgeon, was established. Both men dedicated their lives to patient care, teaching, research, and community service. The lecture honors them for their pioneering efforts to advance health equity for medically underserved communities in the United States and around the globe, at a time when it was neither popular nor safe to do so. The lecture is also designed to stimulate a future generation of researchers committed to advancing health equity research and the elimination of health iniquities. The inaugural lecture was delivered by Lisa A. Cooper, MD, MPH, Bloomberg Distinguished Professor and James F. Fries Professor of Medicine at Johns Hopkins University, and inaugural recipient of the American Heart Association's Watkins Saunders Award, which recognizes excellence in clinical, medical, and community work focused on diminishing health care disparities in Maryland. This article captures the essence of that lecture. PMID- 30405305 TI - Correction: Inhibition of DNA Methyltransferases and Histone Deacetylases Induces Bone Marrow-derived Multipotent Adult Progenitor Cells to Differentiate into Endothelial Cells. AB - [This corrects the article on p. 60 in vol. 20, PMID: 20521387.]. PMID- 30405306 TI - Perturbation analysis in finite LD-QBD processes and applications to epidemic models. AB - In this paper, we adapt arguments from the paper by Caswell [11] to level dependent quasi-birth-and-death (LD-QBD) processes, which constitute a wide class of structured Markov chains. A LD-QBD process has the special feature that its space of states can be structured by levels (groups of states), so that a tridiagonal-by-blocks structure is obtained for its infinitesimal generator. For these processes, a number of algorithmic procedures exist in the literature in order to compute several performance measures while exploiting the underlying matrix structure; among others, these measures are related to first-passage times to a certain level L(0) and hitting probabilities at this level, the maximum level visited by the process before reaching states of level L(0), and the stationary distribution. For the case of a finite number of states, our aim here is to develop analogous algorithms to the ones analyzing these measures, for their perturbation analysis. This approach uses matrix calculus and exploits the specific structure of the infinitesimal generator, which allows us to obtain additional information during the perturbation analysis of the LD-QBD process by dealing with specific matrices carrying probabilistic insights of the dynamics of the process. We illustrate the approach by means of applying multi-type versions of SI and SIS epidemic models to the spread of antibiotic-sensitive and antibiotic-resistant bacterial strains in a hospital ward. PMID- 30405307 TI - Set screw homogenization of murine ocular tissue, including the whole eye. AB - Purpose: To compare methods for homogenizing the mouse whole eye or retina for RNA extraction. Methods: We tested five homogenization techniques for the whole eye and the retina. Two established shearing techniques were a version of the Potter-Elvehjem homogenizer, which uses a plastic pellet pestle in a microfuge tube, and a Dounce homogenizer. Two modern bead-beating methods used commercially manufactured devices, the Next Advance Bullet Blender and the Qiagen TissueLyser LT. The last method involved vortex mixing multiple samples simultaneously in a buffer containing a stainless-steel set screw, a novel approach. RNA was extracted from the tissue after each technique was used. Degradation of RNA was measured with the RNA integrity number (RIN score) after electrophoresis on an Agilent BioAnalyzer RNA LabChip. Nucleic acid yields were measured with ultraviolet (UV) spectroscopy in a BioTek Synergy H1 Hybrid plate reader. The purity of the nucleic acids was assessed with the mean absorbance ratio (A260/A280). The preparation time per sample was measured with a digital stopwatch. Costs of necessary consumables were calculated per ten samples. Results: The RIN scores for all homogenization methods and both tissue types ranged from 7.75+/-0.64 to 8.78+/-0.18; none were statistically significantly different. The total RNA yield per whole eye from the bead-based methods ranged from 7,700 to 9,800 ng and from 3,000 to 4,600 ng for the pellet pestle and Dounce shearing methods, respectively. The total RNA yield per retina from the bead-based methods ranged from 4,600 to 8,400 ng and from 2,200 to 7,400 ng for the pellet pestle and Dounce shearing methods, respectively. Homogenization was faster using the bead-based methods (about 15 min for ten samples) because multiple samples could be run simultaneously compared to the shearing methods that require samples be homogenized individually (about 45-60 min per ten samples). The costs in consumables for the methods tested ranged from $2.60 to $14.70 per ten samples. The major differences in overall costs come in the form of one-time equipment purchases, which can range from one hundred to thousands of dollars. The bead-based methods required less technician involvement and had less potential for sample contamination than the shearing methods. Conclusions: The purity and quality of RNA were similar across all methods for both tissue types. The novel set screw method and the two bead-based methods (bullet blender and TissueLyser) outperformed the two shearing methods (the pellet pestle and Dounce techniques) in total RNA yields for the whole eye. Although the bullet blender, TissueLyser, and set screw methods produced comparable levels of RNA yield, purity, and quality, the set screw method was less expensive. Researchers seeking the efficiency of sophisticated bead homogenization equipment without the high equipment costs might consider this novel method. PMID- 30405309 TI - Bryocyclopsasetus sp. n. and the presence of Bryocyclopsmuscicola (Menzel, 1926) from Thailand (Crustacea, Copepoda, Cyclopoida, Cyclopidae). AB - The description of Bryocyclopsasetus sp. n. and the record of B.muscicola (Menzel, 1926) from Thailand are presented. The new species is most similar to B.maewaensis Watiroyram, Brancelj & Sanoamuang, 2012, the cave-dwelling species described from northern and western Thailand. They share morphological characteristics, such as the free margin of the anal operculum which is ovated and serrate, the same setae and the spines formulae on P1-P4Exp-2 (setae: 5.5.5.4; spines: 3.3.3.3) and Enp-2 of P1-P2, P4 (setae formula 3.4.3) in both sexes. The new species is easily distinguished from B.maewaensis due to typical divergent caudal rami, the absence of coxal seta on P1, and the absence of blunt tipped setae on P2-P3Exp-2. A dichotomous key to the species of Bryocyclops group I sensuLindberg (1953) is proposed. PMID- 30405308 TI - Complete mitochondrial genome of Echinophylliaaspera (Scleractinia, Lobophylliidae): Mitogenome characterization and phylogenetic positioning. AB - Lack of mitochondrial genome data of Scleractinia is hampering progress across genetic, systematic, phylogenetic, and evolutionary studies concerning this taxon. Therefore, in this study, the complete mitogenome sequence of the stony coral Echinophylliaaspera (Ellis & Solander, 1786), has been decoded for the first time by next generation sequencing and genome assembly. The assembled mitogenome is 17,697 bp in length, containing 13 protein coding genes (PCGs), two transfer RNAs and two ribosomal RNAs. It has the same gene content and gene arrangement as in other Scleractinia. All genes are encoded on the same strand. Most of the PCGs use ATG as the start codon except for ND2, which uses ATT as the start codon. The A+T content of the mitochondrial genome is 65.92% (25.35% A, 40.57% T, 20.65% G, and 13.43% for C). Bayesian and maximum likelihood phylogenetic analysis have been performed using PCGs, and the result shows that E.aspera clustered closely with Sclerophylliamaxima (Sheppard & Salm, 1988), both of which belong to Lobophylliidae, when compared with species belonging to Merulinidae and other scleractinian taxa used as outgroups. The complete mitogenome of E.aspera provides essential and important DNA molecular data for further phylogenetic and evolutionary analyses of corals. PMID- 30405310 TI - Anenteotermescherubimi sp. n., a tiny dehiscent termite from Central Africa (Termitidae: Apicotermitinae). AB - Anenteotermescherubimi Scheffrahn, sp. n. is described from workers and male imagos collected in Cameroon and Republic of the Congo. This is the smallest soldierless termite known from Africa. As with many soldierless and soil-feeding termite species, the enteric valve morphology is a robust and essential diagnostic character for An.cherubimi. Preserved workers display pre-autothysis morphology and the effects of abdominal autothysis. PMID- 30405311 TI - A synopsis of Estonian myriapod fauna (Myriapoda: Chilopoda, Diplopoda, Symphyla and Pauropoda). AB - The data on Estonian Myriapoda are scattered in various publications and there has been no overview of the fauna up to the present. A critical summary of the previous information on Estonian Myriapoda is given, supplemented by new records and distribution maps. Altogether, 5784 specimens from 276 collecting sites were studied. To the hitherto recorded 14 centipede species are added Lithobiusmelanops, L.microps, Geophiluscarpophagus, G.flavus, Strigamiatranssilvanica and Stenotaenialinearis, a probably introduced species. Of the 27 published Estonian millipede species, the data on two species proved erroneous, and two new species were recorded (Craspedosomaraulinsii and Cylindroiulusbritannicus). Two previously recorded millipede species - Brachyiuluspusillus and Mastigophorophyllonsaxonicum - were not found in the recent samples, the latter may have become more rare or extinct. Pauropoda and Symphyla lack previous reliable records. Combined with published data, the number of myriapod species known from Estonia is now set at 52. Some changes in species distribution and frequencies were detected comparing the published data with new records. Some data about habitat preferences of the more common species are also given. The majority of species have a western Palaearctic distribution, while six species are at the northern limit of their ranges. PMID- 30405312 TI - New Atanatolica species from Ecuador (Trichoptera, Leptoceridae). AB - Four new species of Atanatolica Mosely are described from Ecuador: A.andina sp. n., A.angulata sp. n., A.curvata sp. n., and A.decouxi sp. n. These species belong to the A.dominicana group and constitute new records of the genus from Chimborazo, Imbabura, and Napo Provinces. Additionally, A.andina sp. n. represents the highest elevation recorded for any species in the genus at 3900 m. Size class data are also presented suggesting continuous larval growth for the probable larva of A.decouxi sp. n., described and illustrated here. A new distribution record is provided for A.manabi from Carchi Province. PMID- 30405313 TI - Six new species and a new record of Linan Hlavac in China, with a key to species (Coleoptera, Staphylinidae, Pselaphinae). AB - Six new species of the genus Linan Hlavac are described from central to southern China: L.arcitibialis sp. n. (Hubei), L.denticulatus sp. n. (Guizhou), L.divaricatus sp. n. (Jiangxi), L.geneolatus sp. n. (Guizhou), L.mangshanus sp. n. (Hunan), and L.mulunensis sp. n. (Guangxi), with illustrations of habitus and major diagnostic characters. Linanmegalobus Yin & Li, originally described from Guizhou, is newly recorded in Hubei. An updated key to and a distributional map of all 16 known species are provided. PMID- 30405314 TI - Contribution to the genus Filipinolotis Miyatake, 1994 (Coleoptera, Coccinellidae, Sticholotidini). AB - The genus Filipinolotis Miyatake has been reviewed in this study. Descriptions and illustrations of two species (F.latefasciata Miyatake and F.purpuratorotunda Wang, Zhang & Slipinski, sp. n.) in the Luzon island of the Philippines, are given. The male genitalia of F.latefasciata are described for the first time. A key to known species is also provided. PMID- 30405315 TI - A review of the genus Apronopa van Achterberg (Hymenoptera, Braconidae, Alysiinae) with a key to species. AB - A review of the genus Apronopa van Achterberg, 1980 with illustrated re descriptions of the known species and a key for their identification is provided. PMID- 30405316 TI - Are Thyroid Autoimmune Diseases Associated with Cardiometabolic Risks in a Population with Normal Thyroid-Stimulating Hormone? AB - Background: The interrelation between thyroid autoimmunity and cardiovascular risks is complex and has not been confirmed. This study aimed at evaluating whether there exists a relationship between thyroid autoimmune diseases (AITDs) and cardiometabolic risks in a large population with normal thyroid-stimulating hormone (TSH) levels. Methods: The data was obtained from a cross-sectional study (SPECT-China study). This study enrolled 9082 subjects (3948 males and 5134 females) above 18 years with normal TSH levels. AITD was defined according to the positivity of TPOAb and TgAb as well as thyroid ultrasonography (US) findings. Results: After full adjustment, TPOAb and/or TgAb positivity (TPO/TgAb (+)) was significantly associated with higher BMI, waist circumference (WC), and HbA1c only in women (P = 0.004, 0.026 and 0.032, respectively), while both TPO/TgAb positivity and US positivity (TPO/TgAb (+) and US (+)) were positively associated with BMI and WC in both genders (P = 0.002 and 0.020 in men; P < 0.001and <0.001 in women). TPO/TgAb (+) and US (+) were positively associated with HOMA-IR in women (P = 0.021) as well. Binary logistic analysis showed that AITDs had increased risks of central obesity, hyperlipidemia, and metabolic syndrome only in women (all P < 0.05). Moreover, TPO/TgAb (+) and US (+) were associated with an increased risk of obesity for both genders (P = 0.014 in men and P = 0.006 in women). Conclusions: Thyroid autoimmunity was positively associated with HbA1c, HOMA-IR, obesity, central obesity, hyperlipidemia, and metabolic syndrome, especially in women. This highlighted that AITDs may be potential risk factors for cardiometabolic disorders even if one's TSH was within the reference range. PMID- 30405318 TI - Lipids and Atherogenic Indices Fluctuation in Rheumatoid Arthritis Patients on Long-Term Tocilizumab Treatment. AB - Rheumatoid arthritis (RA) patients are at high risk of cardiovascular (CV) events, and the chronic inflammatory state may generate quantitative and qualitative changes in lipoprotein fractions. The anti-IL-6 receptor tocilizumab (TCZ), even if effective in inflammation and joint damage prevention, determined significant alterations to RA patients' lipid levels in randomized controlled trials, but real-world data are lacking. We evaluated the changes in lipid fraction levels and disease activity in a longitudinal cohort of RA patients on long-term treatment with tocilizumab (TCZ) in a community setting. We retrospectively selected 40 naive-biologic RA patients on treatment with intravenous TCZ compared to 20 RA patients on methotrexate treatment as the control group. Total cholesterol (Tot-Chol), low-density lipoproteins (LDL), high density lipoprotein (HDL), and triglyceride (TG) levels were measured at the baseline and at 12, 24, and 52 weeks thereafter. At the same points, 28-joint disease activity score (DAS28), clinical disease activity index (CDAI), and EULAR clinical responses were also assessed. During the first 24 weeks, we observed in TCZ-treated patients a progressive statistically significant (p < 0.001) increase in Tot-Chol, LDL, HDL, and TG, which returned close to the baseline at 52 weeks. But no changes in the lipid-related CV risk indices Tot-Chol/HDL and LDL/HDL ratios and the atherogenic index (log10 TG/HDL) were detectable. Notably, we observed a statistically significant negative correlation between changes in lipid fractions and DAS28 or CDAI. The prolonged treatment with TCZ was associated to a transient increase in cholesterol's fractions during the first 6 months of treatment, with inverse correlation to disease activity, but with no impact on surrogate lipid indices of atherogenic risk. These findings may aid clinicians in interpreting the RA patient's lipid profile in daily clinical practice. PMID- 30405317 TI - MicroRNA Expression Profile of Whole Blood Is Altered in Adenovirus-Infected Pneumonia Children. AB - Human adenovirus (Adv) infection is responsible for most community-acquired pneumonia in infants and children, which results in significant morbidity and mortality in children every year. MicroRNAs (miRNAs) are associated with viral replication and host immune response. Knowing the miRNA expression profile will help understand the role of miRNAs in modulating the host response to adenovirus infection and possibly improve the diagnosis of adenovirus-infected pneumonia. In our study, total RNA extracted from whole blood of adenovirus-infected pneumonia children and healthy controls were analyzed by small RNA deep sequencing. Expression profiles of whole blood microRNAs were altered and distinctly different in adenovirus-infected children. The top 3 upregulated miRNA (hsa-miR 127-3p, hsa-miR-493-5p, and hsa-miR-409-3p) were identified in adenovirus infected children and provided a clear distinction between infected and healthy individuals. Potential host target genes were predicated and validated by qRT-PCR to study the impact of microRNAs on the host genes. Most of the target genes were involved in the MAPK signaling pathway and innate immune response. These highly upregulated microRNAs may have crucial roles in Adv pathogenesis and are potential biomarkers for adenovirus-infected pneumonia. PMID- 30405319 TI - Proteasome Activity and C-Reactive Protein Concentration in the Course of Inflammatory Reaction in Relation to the Type of Abdominal Operation and the Surgical Technique Used. AB - Surgical tissue damage and the accompanying inflammatory response lead to proteasome activation, initiation of damaged protein degradation, and induction of acute-phase inflammatory response. The aim of this study was to investigate the rate of change in proteasome chymotrypsin-like (ChT-L) activity and C reactive protein concentration depending on the degree of tissue damage and their correlation with prealbumin concentrations in children before and after abdominal surgery. This experimental study included children who underwent abdominal surgery between 2015 and 2017. Plasma prealbumin concentrations and C-reactive protein levels (CRP) were determined by standard biochemical laboratory procedures. Proteasome activity was assessed using a Suc-Leu-Leu-Val-Tyr-AMC peptide substrate. Elevation of plasma proteasome activity was noted in children after laparoscopic and open abdominal surgeries. However, 20S proteasome activity in children undergoing conventional open surgery was significantly higher (P < 0.05) than in patients subjected to laparoscopy. At the same time, an increase in the CRP level was observed. However, there was no correlation between C-reactive protein concentrations and the type of abdominal surgery while there was a correlation observed in the case of proteasomes. Proteasome activity correlates with the degree of surgical tissue damage and prealbumin concentrations. More invasive surgery leads to a stronger activation of the proteasome involved in removing proteins that were damaged due to the surgical procedure. Proteasomes are more specific markers because there is a correlation between proteasome activity and the type of abdominal surgery in contrast to C-reactive protein concentrations which are not different in response to surgery performed in regard to ovarian cysts or cholelithiasis. PMID- 30405321 TI - Prediction and experimental validation of solid solutions and isopolymorphs of cytosine/5-flucytosine. AB - A computational search for polymorphs of cytosine, 5-flucytosine and a 1 : 1 mixture of the two substances not only rationalised the preferred packing arrangements but also enabled the finding and characterisation of cytosine/5 flucytosine solid solutions. The structures of the new solid forms were determined by combining laboratory powder X-ray diffraction data and computational modelling. PMID- 30405322 TI - Geographic Variability of Active Ingredients in Spice as an Indicator of Mechanisms of Distribution and Manufacture Within Alaska. AB - Designer drugs, like Spice, are synthetic psychoactive analogs of illegal substances with understudied health effects since they have traditionally been sold in packages labeled "not for human consumption" and the molecular structures can be specifically altered to circumvent legislation. Recent legislation has focused on regulating packaging and has reduced, but not eliminated, the distribution of Spice in Alaska. Legally obtained Spice samples from three geographic regions in Alaska were analyzed using liquid injection gas chromatography-mass spectrometry (GC-MS). Most (70%) of the samples contained illegal cannabinoids that have been regulated by the Drug Enforcement Agency and 47% contained multiple active ingredients. We hypothesized that the heterogeneity of the active ingredients between brands and across regions could be used to indicate small- or larger-scale manufacturing, and the results indicate multiple manufacturing scales. Evidence for small-scale manufacturing included inconsistent packaging, several of which contained similar active ingredient profiles in different brands purchased from a single store. Evidence for large scale production was also found with some brands having consistent active ingredient profiles across regions. This study provides preliminary data for the geographic variability of active ingredients in Spice as an indicator of mechanisms of manufacture and distribution to inform legislators and law enforcement and help prioritizing resource allocation in an effort to quell Spice use in Alaska. PMID- 30405320 TI - IL-17 Receptor Signaling Negatively Regulates the Development of Tubulointerstitial Fibrosis in the Kidney. AB - Chronic inflammation has an important role in the development and progression of most fibrotic diseases, for which no effective treatments exist. Tubulointerstitial fibrosis (TF) is characterized by irreversible deposition of fibrous tissue in chronic kidney diseases. Prolonged injurious stimuli and chronic inflammation regulate downstream events that lead to TF. In recent years, interleukin-17 (IL-17) has been strongly linked to organ fibrosis. However, the role of IL-17 receptor signaling in TF is an active area of debate. Using the unilateral ureteral obstruction (UUO) mouse model of TF, we show that IL-17 receptor A-deficient mice (Il17ra-/- ) exhibit increased TF in the obstructed kidney. Consequently, overexpression of IL-17 restored protection in mice with UUO. Reduced renal expression of matrix-degrading enzymes results in failure to degrade ECM proteins, thus contributing to the exaggerated TF phenotype in Il17ra -/- mice. We demonstrate that the antifibrotic kallikrein-kinin system (KKS) is activated in the obstructed kidney in an IL-17-dependent manner. Accordingly, Il17ra-/- mice receiving bradykinin, the major end-product of KKS activation, prevents TF development by upregulating the expression of matrix-degrading enzymes. Finally, we show that treatment with specific agonists for bradykinin receptor 1 or 2 confers renal protection against TF. Overall, our results highlight an intriguing link between IL-17 and activation of KKS in protection against TF, the common final outcome of chronic kidney conditions leading to devastating end-stage renal diseases. PMID- 30405323 TI - The effect of Zipfian frequency variations on category formation in adult artificial language learning. AB - Successful language acquisition hinges on organizing individual words into grammatical categories and learning the relationships between them, but the method by which children accomplish this task has been debated in the literature. One proposal is that learners use the shared distributional contexts in which words appear as a cue to their underlying category structure. Indeed, recent research using artificial languages has demonstrated that learners can acquire grammatical categories from this type of distributional information. However, artificial languages are typically composed of a small number of equally frequent words, while words in natural languages vary widely in frequency, complicating the distributional information needed to determine categorization. In a series of three experiments we demonstrate that distributional learning is preserved in an artificial language composed of words that vary in frequency as they do in natural language, along a Zipfian distribution. Rather than depending on the absolute frequency of words and their contexts, the conditional probabilities that words will occur in certain contexts (given their base frequency) is a better basis for assigning words to categories; and this appears to be the type of statistic that human learners utilize. PMID- 30405324 TI - Cutaneous Metastasis of Gastroenteropancreatic Neuroendocrine Tumors (GEP-Nets). AB - Background: Gastroenteropancreatic neuroendocrine tumors are neoplasms commonly found within the gastrointestinal tract that originate from endocrine cells. These are slow progressive tumors and often metastasize to other elements of the gastrointestinal tract including the liver. Consequently, these tumors release hormones including serotonin and/or histamine that are responsible for the symptoms including intermittent flushing and diarrhea. Metastasis of gastroenteropancreatic neuroendocrine tumors, although rare, is possible and may extend to local lymph nodes and viscera. Case report: Our patient was a 69-year old female who initially presented with postprandial abdominal pain, nausea, vomiting, and later was diagnosed with gastroenteropancreatic neuroendocrine tumors following surgical resection in 2014. Restaging after surgery showed regional lymph node involvement and hepatic metastasis. Of note she did not have a pre-operative computed tomography scan. She was started on octreotide, and later switched to lanreotide. In the interim, she did not have any positive findings on serial octreoscans depicting the skin lesion that was performed in the interim period every six months. However, she noticed a cutaneous mass in the upper right flank mass in 2016, which was followed up by a dermatologist. In 2017, the mass grew in size and hence biopsied which showed neuroendocrine tumors consistent with her primary tumor. Discussion: Gastroenteropancreatic neuroendocrine tumors often metastasize to lymph nodes and liver but rarely can involve the skin and present as firm papules as found in our patient. Cutaneous metastasis of gastroenteropancreatic neuroendocrine tumors often has high morbidity and mortality and is usually associated with a primary lesion in the bronchopulmonary system. However, as demonstrated in this case report, cutaneous metastasis can originate from the gastrointestinal tract, including the small intestine as well. PMID- 30405325 TI - Pancrelipase-Induced Hypersensitivity Reaction: Case Report and Review of Literature. AB - Introduction: Drug-induced exanthems are commonly associated with NSAIDs, antibiotics, and anti-epileptics. Pancrelipase is frequently used for conditions resulting in pancreatic exocrine insufficiency. Published case reports of pancrelipase hypersensitivity focus on the respiratory manifestations. Case Report: Here we report a case of skin hypersensitivity resulting from pancrelipase use. To further assess this association, we used a Naranjo nomogram, which determines the likelihood that an adverse drug reaction is the result of the drug itself. Our patient had a score of seven, suggesting our patient had a probably adverse drug reaction. Discussion: As pancrelipase is a commonly prescribed drug, clinicians should be aware of the potential hypersensitivity skin reactions associated with pancrelipase. PMID- 30405326 TI - Neuroethics of Non-primary Brain Computer Interface: Focus on Potential Military Applications. AB - The field of neuroethics has had to adapt rapidly in the face of accelerating technological advancement; a particularly striking example is the realm of Brain Computer Interface (BCI). A significant source of funding for the development of new BCI technologies has been the United States Department of Defense, and while the predominant focus has been restoration of lost function for those wounded in battle, there is also significant interest in augmentation of function to increase survivability, coordination, and lethality of US combat forces. While restoration of primary motor and sensory function (primary BCI) has been the main focus of research, there has been marked progress in interface with areas of the brain subserving memory and association. Non-Primary BCI has a different subset of potential applications, each of which also carries its own ethical considerations. Given the amount of BCI research funding coming from the Department of Defense, it is particularly important that potential military applications be examined from a neuroethical standpoint. PMID- 30405327 TI - Behavioral and Pharmacokinetic Profile of Indole-Derived Synthetic Cannabinoids JWH-073 and JWH-210 as Compared to the Phytocannabinoid Delta9-THC in Rats. AB - Synthetic cannabinoid compounds are marketed as "legal" marijuana substitutes, even though little is known about their behavioral effects in relation to their pharmacokinetic profiles. Therefore, in the present study we assessed the behavioral effects of systemic treatment with the two synthetic cannabinoids JWH 073 and JWH-210 and the phytocannabinoid Delta9-THC on locomotor activity, anxiety-like phenotype (in the open field) and sensorimotor gating (measured as prepulse inhibition of the acoustic startle response, PPI), in relation to cannabinoid serum levels. Wistar rats were injected subcutaneously (sc.) with JWH 073 (0.1, 0.5, or 5 mg/kg), JWH-210 (0.1, 0.5, or 5 mg/kg), Delta9-THC (1 or 3 mg/kg) or vehicle (oleum helanti) in a volume of 0.5 ml/kg and tested in the open field and PPI. Although JWH-073, JWH-210, Delta9-THC (and its metabolites) were confirmed in serum, effects on sensorimotor gating were absent, and locomotor activity was only partially affected. Delta9-THC (3 mg/kg) elicited an anxiolytic like effect as suggested by the increased time spent in the center of the open field (p < 0.05). Our results further support the potential anxiolytic-like effect of pharmacological modulation of the endocannabinoid system. PMID- 30405329 TI - Teaching Computational Reproducibility for Neuroimaging. AB - We describe a project-based introduction to reproducible and collaborative neuroimaging analysis. Traditional teaching on neuroimaging usually consists of a series of lectures that emphasize the big picture rather than the foundations on which the techniques are based. The lectures are often paired with practical workshops in which students run imaging analyses using the graphical interface of specific neuroimaging software packages. Our experience suggests that this combination leaves the student with a superficial understanding of the underlying ideas, and an informal, inefficient, and inaccurate approach to analysis. To address these problems, we based our course around a substantial open-ended group project. This allowed us to teach: (a) computational tools to ensure computationally reproducible work, such as the Unix command line, structured code, version control, automated testing, and code review and (b) a clear understanding of the statistical techniques used for a basic analysis of a single run in an MR scanner. The emphasis we put on the group project showed the importance of standard computational tools for accuracy, efficiency, and collaboration. The projects were broadly successful in engaging students in working reproducibly on real scientific questions. We propose that a course on this model should be the foundation for future programs in neuroimaging. We believe it will also serve as a model for teaching efficient and reproducible research in other fields of computational science. PMID- 30405328 TI - Neuroprotective Natural Molecules, From Food to Brain. AB - The prevalence of neurodegenerative disorders is increasing; however, an effective neuroprotective treatment is still remaining. Nutrition plays an important role in neuroprotection as recently shown by epidemiological and biochemical studies which identified food components as promising therapeutic agents. Neuroprotection includes mechanisms such as activation of specific receptors, changes in enzymatic neuronal activity, and synthesis and secretion of different bioactive molecules. All these mechanisms are focused on preventing neuronal damage and alleviating the consequences of massive cell loss. Some neuropathological disorders selectively affect to particular neuronal populations, thus is important to know their neurochemical and anatomical properties in order to design effective therapies. Although the design of such treatments would be specific to neuronal groups sensible to damage, the effect would have an impact in the whole nervous system. The difficult overcoming of the blood brain barrier has hampered the development of efficient therapies for prevention or protection. This structure is a physical, enzymatic, and influx barrier that efficiently protects the brain from exogenous molecules. Therefore, the development of new strategies, like nanocarriers, that help to promote the access of neuroprotective molecules to the brain, is needed for providing more effective therapies for the disorders of the central nervous system (CNS). In order both to trace the success of these nanoplatforms on the release of the bioactive cargo in the CNS and determinate the concentration at trace levels of targets biomolecules by analytical chemistry and concretely separation instrumental techniques, constitute an essential tool. Currently, these techniques are used for the determination and identification of natural neuroprotective molecules in complex matrixes at different concentration levels. Separation techniques such as chromatography and capillary electrophoresis (CE), using optical and/or mass spectrometry (MS) detectors, provide multiples combinations for the quantitative and qualitative analysis at basal levels or higher concentrations of bioactive analytes in biological samples. Bearing this in mind, the development of food neuroprotective molecules as brain therapeutic agents is a complex task that requires the intimate collaboration and engagement of different disciplines for a successful outcome. In this sense, this work reviews the new advances achieved in the area toward a better understanding of the current state of the art and highlights promising approaches for brain neuroprotection. PMID- 30405330 TI - Opioid Deaths: Trends, Biomarkers, and Potential Drug Interactions Revealed by Decision Tree Analyses. AB - Opioid abuse is now the primary cause of accidental deaths in the United States. Studies over several decades established the cyclical nature of abused drugs of choice, with a current resurgence of heroin abuse and, more recently, fentanyl's emergence as a major precipitant of drug-related deaths. To better understand abuse trends and to explore the potential lethality of specific drug-drug interactions, we conducted statistical analyses of forensic toxicological data from the Wayne County Medical Examiner's Office from 2012-2016. We observed clear changes in opioid abuse over this period, including the rapid emergence of fentanyl and its analogs as highly significant causes of lethality starting in 2014. We then used Chi-square Automatic Interaction Detector (CHAID)-based decision tree analyses to obtain insights regarding specific drugs, drug combinations, and biomarkers in blood most predictive of cause of death or circumstances surrounding death. The presence of the non-opioid drug acetaminophen was highly predictive of drug-related deaths, likely reflecting the abuse of various combined acetaminophen-opioid formulations. The short-lived cocaine adulterant levamisole was highly predictive of a short post-cocaine survival time preceding sudden non-drug-related death. The combination of the opioid methadone and the antidepressant citalopram was uniformly linked to drug death, suggesting a potential drug-drug interaction at the level of a pathophysiological effect on the heart and/or drug metabolism. The presence of fentanyl plus the benzodiazepine midazolam was diagnostic for in-hospital deaths following serious medical illness and interventions that included these drugs. These data highlight the power of decision tree analyses not only in the determination of cause of death, but also as a key surveillance tool to inform drug abuse treatment and public health policies for combating the opioid crisis. PMID- 30405331 TI - Cannabis and the Anxiety of Fragmentation-A Systems Approach for Finding an Anxiolytic Cannabis Chemotype. AB - Cannabis sativa is a medicinal herb with a diverse range of chemotypes that can exert both anxiolytic and anxiogenic effects on humans. Medical cannabis patients receiving organically grown cannabis from a single source were surveyed about the effectiveness of cannabis for treating anxiety. Patients rated cannabis as highly effective overall for treating anxiety with an average score of 8.03 on a Likert scale of 0 to 10 (0 = not effective, 10 = extremely effective). Patients also identified which strains they found the most or least effective for relieving their symptoms of anxiety. To find correlations between anxiolytic activity and chemotype, the top four strains voted most and least effective were analyzed by HPLC-MS/MS to quantify cannabinoids and GC-MS to quantify terpenes. Tetrahydrocannabinol (THC) and trans-nerolidol have statistically significant correlations with increased anxiolytic activity. Guiaol, eucalyptol, gamma terpinene, alpha-phellandrene, 3-carene, and sabinene hydrate all have significant correlations with decreased anxiolytic activity. Further studies are needed to better elucidate the entourage effects that contribute to the anxiolytic properties of cannabis varieties. PMID- 30405332 TI - Multimodal Music Perception Engages Motor Prediction: A TMS Study. AB - Corticospinal excitability (CSE) in humans measured with Transcranial Magnetic Stimulation (TMS) is generally increased by the perception of other people's actions. This perception can be unimodal (visual or auditory) or multimodal (visual and auditory). The increase in TMS-measured CSE is typically prominent for muscles involved in the perceived action (muscle specificity). There are two main classes of accounts for this phenomenon. One suggests that the motor system mirrors the actions that the observer perceives (the resonance account). The other suggests that the motor system predicts the actions that the observer perceives (the predictive account). To test these accounts (which need not be mutually exclusive), subjects were presented with four versions of three-note piano sequences: sound only, sight only, audiovisual, and audiovisual with sound lagging behind (the prediction violation condition). CSE was measured in two hand muscles used to play the notes. CSE increased reliably in one muscle only for the prediction violation condition, in line with the predictive account, while the other muscle demonstrated CSE increase for all conditions, in line with the resonance account. This finding supports both predictive coding accounts as well as resonance accounts of motor facilitation during action perception. PMID- 30405333 TI - Gray Matter Atrophy Is Associated With Cognitive Impairment in Patients With Presbycusis: A Comprehensive Morphometric Study. AB - Presbycusis (PC) is characterized by bilateral sensorineural hearing loss at high frequencies and speech-perception difficulties in noisy environments and has a strikingly detrimental impact on cognitive function. As the neural consequences of PC may involve the whole brain, we hypothesized that patients with PC would show structural alterations not only in the auditory cortex but also in the cortexes involved in cognitive function. The purpose of this study was to use surface-based morphometry (SBM) analysis to elucidate whole-brain structural differences between patients with PC and age-matched normal hearing controls. Three-dimensional T1-weighted MR images of 26 patients with mild PC and 26 age-, sex- and education-matched healthy controls (HCs) were acquired. All participants underwent a battery of neuropsychological tests. Our results revealed gray matter atrophy in several auditory cortical areas, nodes of the default mode network (DMN), including the bilateral precuneus and inferior parietal lobule, the right posterior cingulate cortex (PCC), and the right insula of patients with PC compared to that in the HCs. Our findings also revealed that hearing loss was associated with reduced gray matter volume in the right primary auditory cortex of patients with PC. Moreover, structural alterations in the nodes of the DMN were associated with cognitive impairments in PC patients. Additionally, this study provides evidence that a thicker right insula is associated with better speech perception in patients with PC. Based on these findings, we argue that the onset of PC seems to trigger its own cascade of conditions, including a need for increased cognitive resources during speech comprehension, which might lead to auditory and cognition-related cortical reorganization. PMID- 30405334 TI - Training LSTM Networks With Resistive Cross-Point Devices. AB - In our previous work we have shown that resistive cross point devices, so called resistive processing unit (RPU) devices, can provide significant power and speed benefits when training deep fully connected networks as well as convolutional neural networks. In this work, we further extend the RPU concept for training recurrent neural networks (RNNs) namely LSTMs. We show that the mapping of recurrent layers is very similar to the mapping of fully connected layers and therefore the RPU concept can potentially provide large acceleration factors for RNNs as well. In addition, we study the effect of various device imperfections and system parameters on training performance. Symmetry of updates becomes even more crucial for RNNs; already a few percent asymmetry results in an increase in the test error compared to the ideal case trained with floating point numbers. Furthermore, the input signal resolution to the device arrays needs to be at least 7 bits for successful training. However, we show that a stochastic rounding scheme can reduce the input signal resolution back to 5 bits. Further, we find that RPU device variations and hardware noise are enough to mitigate overfitting, so that there is less need for using dropout. Here we attempt to study the validity of the RPU approach by simulating large scale networks. For instance, the models studied here are roughly 1500 times larger than the more often studied multilayer perceptron models trained on the MNIST dataset in terms of the total number of multiplication and summation operations performed per epoch. PMID- 30405337 TI - Elevated Resting State Gamma Oscillatory Activities in Electroencephalogram of Patients With Post-herpetic Neuralgia. AB - In acute and ongoing pain, the spontaneous oscillatory activity of electroencephalogram (EEG) has been characterized by suppression of alpha band oscillations and enhancement of gamma band oscillations. In pathological chronic pain which is more severe and common in clinic practice, it is of great interest to investigate the oscillatory activity especially at the broad gamma frequency bands. Our present study explored the resting state oscillatory activities of EEG in patients with post-herpetic neuralgia (PHN) over 3 months which is a typical neuropathic pain model in clinical researches. It was found that the PHN patients showed anxiety and depression revealed by Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) examinations. Power spectrum analysis revealed that the power at gamma frequency band (from 40 to 70 Hz) of EEG was significantly higher in the PHN patients, and positively correlated with pain intensity, anxiety, and depression indexes. Further, increased gamma activity derived from the prefrontal cortex and the cerebellum were revealed by cluster-based sensor level and the beamforming source level analyses. These results suggest the enhanced gamma oscillatory activity in the prefrontal cortex and cerebellum is a characteristic marker in chronic neuropathic pain patients. PMID- 30405336 TI - Attention-Related Brain Activation Is Altered in Older Adults With White Matter Hyperintensities Using Multi-Echo fMRI. AB - Cognitive decline is often undetectable in the early stages of accelerated vascular aging. Attentional processes are particularly affected in older adults with white matter hyperintensities (WMH), although specific neurovascular mechanisms have not been elucidated. We aimed to identify differences in attention-related neurofunctional activation and behavior between adults with and without WMH. Older adults with moderate to severe WMH (n = 18, mean age = 70 years), age-matched adults (n = 28, mean age = 72), and healthy younger adults (n = 19, mean age = 25) performed a modified flanker task during multi-echo blood oxygenation level dependent functional magnetic resonance imaging. Task-related activation was assessed using a weighted-echo approach. Healthy older adults had more widespread response and higher amplitude of activation compared to WMH adults in fronto-temporal and parietal cortices. Activation associated with processing speed was absent in the WMH group, suggesting attention-related activation deficits that may be a consequence of cerebral small vessel disease. WMH adults had greater executive contrast activation in the precuneous and posterior cingulate gyrus compared to HYA, despite no performance benefits, reinforcing the network dysfunction theory in WMH. PMID- 30405338 TI - Rectifying Resistive Memory Devices as Dynamic Complementary Artificial Synapses. AB - Brain inspired computing is a pioneering computational method gaining momentum in recent years. Within this scheme, artificial neural networks are implemented using two main approaches: software algorithms and designated hardware architectures. However, while software implementations show remarkable results (at high-energy costs), hardware based ones, specifically resistive random access memory (RRAM) arrays that consume little power and hold a potential for enormous densities, are somewhat lagging. One of the reasons may be related to the limited excitatory operation mode of RRAMs in these arrays as adjustable passive elements. An interesting type of RRAM was demonstrated recently for having alternating (dynamic switching) current rectification properties that may be used for complementary operation much like CMOS transistors. Such artificial synaptic devices may be switched dynamically between excitatory and inhibitory modes to allow doubling of the array density and significantly reducing the peripheral circuit complexity. PMID- 30405335 TI - Comparative and Evolutionary Aspects of Gonadotropin-Inhibitory Hormone and FMRFamide-Like Peptide Systems. AB - Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that was found in the brain of Japanese quail when investigating the existence of RFamide peptides in birds. GnIH was named because it decreased gonadotropin release from cultured anterior pituitary, which was located in the hypothalamo-hypophysial system. GnIH and GnIH precursor gene related peptides have a characteristic C terminal LPXRFamide (X = L or Q) motif that is conserved in jawed vertebrates. Orthologous peptides to GnIH are also named RFamide related peptide or LPXRFamide peptide from their structure. A G-protein coupled receptor GPR147 is the primary receptor for GnIH. Similarity-based clustering of neuropeptide precursors in metazoan species indicates that GnIH precursor of vertebrates is evolutionarily related to FMRFamide precursor of mollusk and nematode. FMRFamide peptide is the first RFamide peptide that was identified from the ganglia of the venus clam. In order to infer the evolutionary history of the GnIH-GnIH receptor system we investigate the structural similarities between GnIH and its receptor and well studied nematode Caenorhabditis elegans (C. elegans) FMRFamide-like peptides (FLPs) and their receptors. We also compare the functions of FLPs of nematode with GnIH of chordates. A multiple sequence alignment and phylogenetic analyses of GnIH, neuropeptide FF (NPFF), a paralogous peptide of GnIH, and FLP precursors have shown that GnIH and NPFF precursors belong to different clades and some FLP precursors have structural similarities to either precursor. The peptide coding regions of FLP precursors in the same clade align well with those of GnIH or NPFF precursors. Alignment of GnIH (LPXRFa) peptides of chordates and FLPs of C. elegans grouped the peptides into five groups according to the last C-terminal amino acid sequences, which were MRFa, LRFa, VRFa, IRFa, and PQRFa. Phylogenetic analysis of receptors suggested that GPR147 has evolutionary relationships with FLP receptors, which regulate reproduction, aggression, locomotion, and feeding. GnIH and some FLPs mediate the effect of stress on reproduction and behavior, which may also be a conserved property of these peptide systems. Future studies are needed to investigate the mechanism of how neuropeptide precursor genes are mutated to evolve new neuropeptides and their inheritance. PMID- 30405339 TI - Liraglutide Activates mTORC1 Signaling and AMPA Receptors in Rat Hippocampal Neurons Under Toxic Conditions. AB - The aim of the present study was to determine whether treatment with liraglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist, would alter mammalian target of rapamycin complex 1 (mTORC1) signaling and/or alpha-amino-3-hydroxy-5 methylisoxazole-4-propionic acid (AMPA) receptor activity under dexamethasone induced toxic conditions. Western blot analyses were performed to assess changes in mTORC1-mediated proteins, brain-derived neurotrophic factor (BDNF), and various synaptic proteins (PSD-95, synapsin I, and GluA1) in rat hippocampal cultures under toxic conditions induced by dexamethasone, which causes hippocampal cell death. Hippocampal dendritic outgrowth and spine formation were measured using immunostaining procedures. Dexamethasone significantly decreased the phosphorylation levels of mTORC1 as well as its downstream proteins. However, treatment with liraglutide prevented these reductions and significantly increased BDNF expression. The increase in BDNF expression was completely blocked by rapamycin and 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7 sulfonamide (NBQX). Liraglutide also recovered dexamethasone-induced decreases in the total length of hippocampal dendrites and reductions in spine density in a concentration-dependent manner. However, the positive effects of liraglutide on neural plasticity were abolished by the blockade of mTORC1 signaling and AMPA receptors. Furthermore, liraglutide significantly increased the expression levels of PSD-95, synapsin I, and GluA1, whereas rapamycin and NBQX blocked these effects. The present study demonstrated that liraglutide activated mTORC1 signaling and AMPA receptor activity as well as increased dendritic outgrowth, spine density, and synaptic proteins under toxic conditions in rat primary hippocampal neurons. These findings suggest that GLP-1 receptor (GLP-1R) activation by liraglutide may affect neuroplasticity through mTORC1 and AMPA receptors. PMID- 30405340 TI - Improving Real-Time Lower Limb Motor Imagery Detection Using tDCS and an Exoskeleton. AB - The aim of this work was to test if a novel transcranial direct current stimulation (tDCS) montage boosts the accuracy of lower limb motor imagery (MI) detection by using a real-time brain-machine interface (BMI) based on electroencephalographic (EEG) signals. The tDCS montage designed was composed of two anodes and one cathode: one anode over the right cerebrocerebellum, the other over the motor cortex in Cz, and the cathode over FC2 (using the International 10 10 system). The BMI was designed to detect two MI states: relax and gait MI; and was based on finding the power at the frequency which attained the maximum power difference between the two mental states at each selected EEG electrode. Two different single-blind experiments were conducted, E1 and a pilot test E2. E1 was based on visual cues and feedback and E2 was based on auditory cues and a lower limb exoskeleton as feedback. Twelve subjects participated in E1, while four did so in E2. For both experiments, subjects were separated into two equally-sized groups: sham and active tDCS. The active tDCS group achieved 12.6 and 8.2% higher detection accuracy than the sham group in E1 and E2, respectively, reaching 65 and 81.6% mean detection accuracy in each experiment. The limited results suggest that the exoskeleton (E2) enhanced the detection of the MI tasks with respect to the visual feedback (E1), increasing the accuracy obtained in 16.7 and 21.2% for the active tDCS and sham groups, respectively. Thus, the small pilot study E2 indicates that using an exoskeleton in real-time has the potential of improving the rehabilitation process of cerebrovascular accident (CVA) patients, but larger studies are needed in order to further confirm this claim. PMID- 30405341 TI - Modulation of Working Memory Using Transcranial Electrical Stimulation: A Direct Comparison Between TACS and TDCS. AB - Transcranial electrical stimulation (TES) has been considered a promising tool for improving working memory (WM) performance. Recent studies have demonstrated modulation of networks underpinning WM processing through application of transcranial alternating current (TACS) as well as direct current (TDCS) stimulation. Differences between study designs have limited direct comparison of the efficacy of these approaches, however. Here we directly compared the effects of theta TACS (6 Hz) and anodal TDCS on WM, applying TACS to the frontal-parietal loop and TDCS to the dorsolateral prefrontal cortex (DLPFC). WM was evaluated using a visual 2-back WM task. A within-subject, crossover design was applied (N = 30) in three separate sessions. TACS, TDCS, and sham stimulation were administered in a counterbalanced order, and the WM task was performed before, during, and after stimulation. Neither reaction times for hits (RT-hit) nor accuracy differed according to stimulation type with this study design. A marked practice effect was noted, however, with improvement in RT-hit irrespective of stimulation type, which peaked at the end of the second session. Pre-stimulation RT-hits in session three returned to the level observed pre-stimulation in session two, irrespective of stimulation type. The participants who received sham stimulation in session one and had therefore improved their performance due to practice alone, had thus reached a plateau by session two, enabling us to pool RT hits from sessions two and three for these participants. The pooling allowed implementation of a within-subject crossover study design, with a direct comparison of the effects of TACS and TDCS in a subgroup of participants (N = 10), each of whom received both stimulation types, in a counterbalanced order, with pre-stimulation performance the same for both sessions. TACS resulted in a greater improvement in RT-hits than TDCS (F(2,18) = 4.31 p = 0.03). Our findings suggest that future work optimizing the application of TACS has the potential to facilitate WM performance. PMID- 30405343 TI - Microscale Inorganic LED Based Wireless Neural Systems for Chronic in vivo Optogenetics. AB - Billions of neurons in the brain coordinate together to control trillions of highly convoluted synaptic pathways for neural signal processing. Optogenetics is an emerging technique that can dissect such complex neural circuitry with high spatiotemporal precision using light. However, conventional approaches relying on rigid and tethered optical probes cause significant tissue damage as well as disturbance with natural behavior of animals, thus preventing chronic in vivo optogenetics. A microscale inorganic LED (MU-ILED) is an enabling optical component that can solve these problems by facilitating direct discrete spatial targeting of neural tissue, integration with soft, ultrathin probes as well as low power wireless operation. Here we review recent state-of-the art MU-ILED integrated soft wireless optogenetic tools suitable for use in freely moving animals and discuss opportunities for future developments. PMID- 30405342 TI - Connecting Openness and the Resting-State Brain Network: A Discover-Validate Approach. AB - In personality neuroscience, the openness-brain association has been a topic of interest. Previous studies usually started from difference in openness trait and used it to infer brain functional activity characteristics, but no study has used a "brain-first" research strategy to explore that association based on more objective brain imaging data. In this study, we used a fully data-driven approach to discover and validate the association between openness and the resting-state brain network. We collected data of 120 subjects as a discovery sample and 56 subjects as a validation sample. The Neuroticism Extraversion Openness Five Factor Inventory (NEO-FFI) was used to measure the personality characteristics of all the subjects. Using an exploratory approach based on independent component analysis of resting-state functional magnetic resonance imaging (fMRI) data, we identified a parietal network that consisted of the precuneus and inferior parietal lobe. The inter-subject similarity of the parietal memory network exhibited significant associations with openness trait, and this association was validated using the 56-subject independent sample. This finding connects the openness trait to the characteristics of a neural network and helps to understand the underlying biology of the openness trait. PMID- 30405344 TI - Axonal Injury Induces ATF3 in Specific Populations of Sacral Preganglionic Neurons in Male Rats. AB - Compared to other neurons of the central nervous system, autonomic preganglionic neurons are unusual because most of their axon lies in the periphery. These axons are vulnerable to injury during surgical procedures, yet in comparison to peripheral neurons and somatic motor neurons, the impact of injury on preganglionic neurons is poorly understood. Here, we have investigated the impact of axotomy on sacral preganglionic neurons, a functionally diverse group of neurons required for micturition, defecation, and sexual function. We have previously observed that after axotomy, the injury-related transcription factor activating transcription factor-3 (ATF3) is upregulated in only half of these neurons (Peddie and Keast, 2011: PMID: 21283532). In the current study, we have investigated if this response is constrained to particular subclasses of preganglionic neurons that have specific functions or signaling properties. Seven days after unilateral pelvic nerve transection, we quantified sacral preganglionic neurons expressing ATF3, many but not all of which co-expressed c Jun. This response was independent of soma size. Subclasses of sacral preganglionic neurons expressed combinations of somatostatin, calbindin, and neurokinin-1 receptor, each of which showed a similar response to injury. We also found that in contrast to thoracolumbar preganglionic neurons, the heat shock protein-25 (Hsp25) was not detected in naive sacral preganglionic neurons but was upregulated in many of these neurons after axotomy; the majority of these Hsp25 neurons expressed ATF3. Together, these studies reveal the molecular complexity of sacral preganglionic neurons and their responses to injury. The simultaneous upregulation of Hsp25 and ATF3 may indicate a distinct mechanism of regenerative capacity after injury. PMID- 30405346 TI - Editorial: Axonopathy in Neurodegenerative Disease. PMID- 30405345 TI - MicroRNA-122 Mimic Improves Stroke Outcomes and Indirectly Inhibits NOS2 After Middle Cerebral Artery Occlusion in Rats. AB - Aim: Our previous study demonstrated miR-122 mimic decreased NOS2 expression in blood leucocytes and improved stroke outcomes when given immediately after middle cerebral artery occlusion (MCAO) in rats. Since NOS2 is associated with neuro inflammation in stroke and decreasing NOS2 expression alone in leucocytes is insufficient to improve stroke outcomes, we hypothesized that miR-122 mimic may also decrease NOS2 expression in brain microvascular endothelial cells (BMVECs) even at extended time windows. Methods: We administered PEG-liposome wrapped miR 122 mimic (2.4 mg/kg, i.v.) 0 or 6 h after MCAO, and assessed stroke volume and NOS2 expression in BMVECs 24 h following MCAO in rats. Luciferase reporter assays were used to determine if miR-122 binds to 3' untranslated regions (3'UTR) of NOS2. Results: The data showed that miR-122 mimic decreased infarct volumes and decreased MCAO-induced NOS2 over-expression in BMVECs. However, miR-122 did not bind to 3'UTR of NOS2 in the luciferase assays. Conclusion: The data show the 6-h period of therapeutic efficacy of miR-122 mimic which could relate to indirect knockdown of NOS2 in both BMVECs and leucocytes. PMID- 30405347 TI - Default Mode Network Complexity and Cognitive Decline in Mild Alzheimer's Disease. AB - The human resting-state is characterized by spatially coherent brain activity at a low temporal frequency. The default mode network (DMN), one of so-called resting-state networks, has been associated with cognitive processes that are directed toward the self, such as introspection and autobiographic memory. The DMN's integrity appears to be crucial for mental health. For example, patients with Alzheimer's disease or other psychiatric conditions show disruptions of functional connectivity within the brain regions of the DMN. However, in prodromal or early stages of Alzheimer's disease, physiological alterations are sometimes elusive, despite manifested cognitive impairment. While functional connectivity assesses the signal correlation between brain areas, multi-scale entropy (MSE) measures the complexity of the blood-oxygen level dependent signal within an area and thus might show local changes before connectivity is affected. Hence, we investigated alterations of functional connectivity and MSE within the DMN in fifteen mild Alzheimer's disease patients as compared to fourteen controls. Potential associations of MSE with functional connectivity and cognitive abilities [i.e., mini-mental state examination (MMSE)] were assessed. A moderate decrease of DMN functional connectivity between posterior cingulate cortex and right hippocampus in Alzheimer's disease was found, whereas no differences were evident for whole-network functional connectivity. In contrast, the Alzheimer's disease group yielded lower global DMN-MSE than the control group. The most pronounced regional effects were localized in left and right hippocampi, and this was true for most scales. Moreover, MSE significantly correlated with functional connectivity, and DMN-MSE correlated positively with the MMSE in Alzheimer's disease. Most interestingly, the right hippocampal MSE was positively associated with semantic memory performance. Thus, our results suggested that cognitive decline in Alzheimer's disease is reflected by decreased signal complexity in DMN nodes, which might further lead to disrupted DMN functional connectivity. Additionally, altered entropy in Alzheimer's disease found in the majority of the scales indicated a disturbance of both local information processing and information transfer between distal areas. Conclusively, a loss of nodal signal complexity potentially impairs synchronization across nodes and thus preempts functional connectivity changes. MSE presents a putative functional marker for cognitive decline that might be more sensitive than functional connectivity alone. PMID- 30405349 TI - Trehalose Activates CRE-Dependent Transcriptional Signaling in HT22 Mouse Hippocampal Neuronal Cells: A Central Role for PKA Without cAMP Elevation. AB - Cyclic adenosine 3',5'monophosphate (cAMP) regulated element binding protein (CREB) is a transcription factor involved in many different signaling processes including memory storage and retrieval. The mouse hippocampal neuronal cell line HT22 is widely used as a model system for neuronal cell death and cellular signal pathway investigations. For the present work a variant of HT22 with a stably expressed CRE-luciferase (CRE-luc) reporter (HT22CRE) is introduced, characterized and used to investigate cAMP-dependent and independent CRE dependent signal processes. Trehalose (Mykose or 1-alpha-Glucopyranosyl-1-alpha glucopyranosid) is a naturally occurring disaccharide consisting of two alpha,alpha',1,1-glycosidic connected glucose molecules in a wide range of organisms but usually not found in mammals. Trehalose has been shown to activate autophagy, a process which regulates the degradation and recycling of proteins and organelles. The exact processes how trehalose application works on mammalian neuronal cells is not yet understood. The present work shows that trehalose application dose-dependently elevates CRE-luc activity in HT22 cells and acts synergistically with cAMP-elevating agents. In this pathway cAMP-dependent protein kinase (PKA) appears to be the most important factor and the stress kinase p38 and protein tyrosine kinases (PTKs) act as modulators. PMID- 30405348 TI - Mapping Transgene Insertion Sites Reveals Complex Interactions Between Mouse Transgenes and Neighboring Endogenous Genes. AB - Transgenic mouse lines are routinely employed to label and manipulate distinct cell types. The transgene generally comprises cell-type specific regulatory elements linked to a cDNA encoding a reporter or other protein. However, off target expression seemingly unrelated to the regulatory elements in the transgene is often observed, it is sometimes suspected to reflect influences related to the site of transgene integration in the genome. To test this hypothesis, we used a proximity ligation-based method, Targeted Locus Amplification (TLA), to map the insertion sites of three well-characterized transgenes that appeared to exhibit insertion site-dependent expression in retina. The nearest endogenous genes to transgenes HB9-GFP, Mito-P, and TYW3 are Cdh6, Fat4 and Khdrbs2, respectively. For two lines, we demonstrate that expression reflects that of the closest endogenous gene (Fat4 and Cdh6), even though the distance between transgene and endogenous gene is 550 and 680 kb, respectively. In all three lines, the transgenes decrease expression of the neighboring endogenous genes. In each case, the affected endogenous gene was expressed in at least some of the cell types that the transgenic line has been used to mark and study. These results provide insights into the effects of transgenes and endogenous genes on each other's expression, demonstrate that mapping insertion site is valuable for interpreting results obtained with transgenic lines, and indicate that TLA is a reliable method for integration site discovery. PMID- 30405351 TI - Extracellular Degradation Into Adenosine and the Activities of Adenosine Kinase and AMPK Mediate Extracellular NAD+-Produced Increases in the Adenylate Pool of BV2 Microglia Under Basal Conditions. AB - Cumulating evidence has indicated NAD+ deficiency as a common central pathological factor of multiple diseases and aging. NAD+ supplement is highly protective in various disease and aging models, while two key questions have remained unanswered: (1) Does extracellular NAD+ also produce its effects through its degradation product adenosine? (2) Does extracellular NAD+ produce the protective effects by affecting cells under pathological insults only, or by affecting both normal cell and the cells under pathological insults? Since extracellular NAD+ can be degraded into adenosine, and endogenous adenosine levels are in the nanomolar range under physiological conditions, extracellular NAD+ may produce its effects through its degradation into adenosine. In this study we used BV2 microglia as a cellular model to test our hypothesis that NAD+ treatment can increase the intracellular adenylate pool under basal conditions through its extracellular degradation into adenosine. Our study has shown that extracellular NAD+ is degraded into adenosine extracellularly, which enters BV2 microglia through equilibrative nucleoside transporters under basal conditions. The intracellular adenosine is converted to AMP by adenosine kinase, which increases the intracellular ATP levels by both activating AMPK and increasing the intracellular adenylate pool. Collectively, our study has suggested a novel mechanism underlying the protective effects of NAD+ administration, which is mediated by extracellular NAD+ degradation into adenosine as well as the activities of adenosine kinase and AMPK. Our findings have also suggested that NAD+ administration in various disease and aging models may also produce its effects by affecting the microglia that are not under pathological insults. PMID- 30405350 TI - Metabotropic Glutamate Receptor 7: A New Therapeutic Target in Neurodevelopmental Disorders. AB - Neurodevelopmental disorders (NDDs) are characterized by a wide range of symptoms including delayed speech, intellectual disability, motor dysfunction, social deficits, breathing problems, structural abnormalities, and epilepsy. Unfortunately, current treatment strategies are limited and innovative new approaches are sorely needed to address these complex diseases. The metabotropic glutamate receptors are a class of G protein-coupled receptors that act to modulate neurotransmission across many brain structures. They have shown great promise as drug targets for numerous neurological and psychiatric diseases. Moreover, the development of subtype-selective allosteric modulators has allowed detailed studies of each receptor subtype. Here, we focus on the metabotropic glutamate receptor 7 (mGlu7) as a potential therapeutic target for NDDs. mGlu7 is expressed widely throughout the brain in regions that correspond to the symptom domains listed above and has established roles in synaptic physiology and behavior. Single nucleotide polymorphisms and mutations in the GRM7 gene have been associated with idiopathic autism and other NDDs in patients. In rodent models, existing literature suggests that decreased mGlu7 expression and/or function may lead to symptoms that overlap with those of NDDs. Furthermore, potentiation of mGlu7 activity has shown efficacy in a mouse model of Rett syndrome. In this review, we summarize current findings that provide rationale for the continued development of mGlu7 modulators as potential therapeutics. PMID- 30405352 TI - Overexpression of Kcnmb2 in Dorsal CA1 of Offspring Mice Rescues Hippocampal Dysfunction Caused by a Methyl Donor-Rich Paternal Diet. AB - BK channels are known regulators of neuronal excitability, synaptic plasticity, and memory. Our previous study showed that a paternal methyl donor-rich diet reduced the expression of Kcnmb2, which encodes BK channel subunit beta 2, and caused memory deficits in offspring mice. To explore the underlying cellular mechanisms, we investigated the intrinsic and synaptic properties of CA1 pyramidal neurons of the F1 offspring mice whose fathers were fed with either a methyl donor-rich diet (MD) or regular control diet (CD) for 6 weeks before mating. Whole-cell patch-clamp recordings of CA1 pyramidal neurons revealed a decrease in intrinsic excitability and reduced frequency of inhibitory post synaptic currents in MD F1 mice compared to the CD F1 controls. AAV-based overexpression of Kcnmb2 in dorsal CA1 ameliorated changes in neuronal excitability, synaptic transmission, and plasticity in MD F1 mice. Our findings thus indicate that a transient paternal exposure to a methyl donor-rich diet prior to mating alters Kcnmb2-sensitive hippocampal functions in offspring animals. PMID- 30405353 TI - Modulation of Hyperpolarization-Activated Inward Current and Thalamic Activity Modes by Different Cyclic Nucleotides. AB - The hyperpolarization-activated inward current, Ih, plays a key role in the generation of rhythmic activities in thalamocortical (TC) relay neurons. Cyclic nucleotides, like 3',5'-cyclic adenosine monophosphate (cAMP), facilitate voltage dependent activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels by shifting the activation curve of Ih to more positive values and thereby terminating the rhythmic burst activity. The role of 3',5'-cyclic guanosine monophosphate (cGMP) in modulation of Ih is not well understood. To determine the possible role of the nitric oxide (NO)-sensitive cGMP-forming guanylyl cyclase 2 (NO-GC2) in controlling the thalamic Ih, the voltage dependency and cGMP/cAMP-sensitivity of Ih was analyzed in TC neurons of the dorsal part of the lateral geniculate nucleus (dLGN) in wild type (WT) and NO-GC2 deficit (NO-GC2-/-) mice. Whole cell voltage clamp recordings in brain slices revealed a more hyperpolarized half maximal activation (V1/2) of Ih in NO-GC2-/- TC neurons compared to WT. Different concentrations of 8-Br-cAMP/8-Br-cGMP induced dose-dependent positive shifts of V1/2 in both strains. Treatment of WT slices with lyase enzyme (adenylyl and guanylyl cyclases) inhibitors (SQ22536 and ODQ) resulted in further hyperpolarized V1/2. Under current clamp conditions NO GC2-/- neurons exhibited a reduction in the Ih-dependent voltage sag and reduced action potential firing with hyperpolarizing and depolarizing current steps, respectively. Intrathalamic rhythmic bursting activity in brain slices and in a simplified mathematical model of the thalamic network was reduced in the absence of NO-GC2. In freely behaving NO-GC2-/- mice, delta and theta band activity was enhanced during active wakefulness (AW) as well as rapid eye movement (REM) sleep in cortical local field potential (LFP) in comparison to WT. These findings indicate that cGMP facilitates Ih activation and contributes to a tonic activity in TC neurons. On the network level basal cGMP production supports fast rhythmic activity in the cortex. PMID- 30405354 TI - Hydroxysafflor Yellow A (HSYA) Improves Learning and Memory in Cerebral Ischemia Reperfusion-Injured Rats via Recovering Synaptic Plasticity in the Hippocampus. AB - Hydroxysafflor yellow A (HSYA) is the major active chemical component of the safflower plant flower, which is widely used in Chinese medicine for cerebrovascular and cardiovascular disease treatment. Recent studies have demonstrated that HSYA exerts neuroprotective effect on cerebral ischemia, such as neuronal anti-apoptosis, antioxidant activity and oxygen free radical scavenging. However, whether and how HSYA has a protective effect on cognitive impairment induced by cerebral ischemia reperfusion remains elusive. In the present study, by using the middle cerebral artery occlusion (MCAO) model, we found that 8 mg/kg and 16 mg/kg HSYA administration by common carotid artery (CCA) injection improved impaired cognitive function in Morris water maze (MWM) and passive avoidance tasks, but not 4 mg/kg HSYA treatment, suggesting that HSYA treatment in a certain concentration can improve cognitive impairment in MCAO rats. Furthermore, we found that 8 mg/kg HSYA treatment rescued the impaired long term potentiation (LTP) in hippocampus of MCAO rats. Taken together, these results for the first time demonstrate that HSYA has the capacity to protect cognitive function and synaptic plasticity against cerebral ischemia-reperfusion injury, and provide a new insight that HSYA may be a promising alternative for recovery of cognitive dysfunction after brain ischemic injury. PMID- 30405356 TI - Dietary Zinc Supplementation Prevents Autism Related Behaviors and Striatal Synaptic Dysfunction in Shank3 Exon 13-16 Mutant Mice. AB - The SHANK family of synaptic proteins (SHANK1-3) are master regulators of the organizational structure of excitatory synapses in the brain. Mutations in SHANK1 3 are prevalent in patients with autism spectrum disorders (ASD), and loss of one copy of SHANK3 causes Phelan-McDermid Syndrome, a syndrome in which Autism occurs in >80% of cases. The synaptic stability of SHANK3 is highly regulated by zinc, driving the formation of postsynaptic protein complexes and increases in excitatory synaptic strength. As ASD-associated SHANK3 mutations retain responsiveness to zinc, here we investigated how increasing levels of dietary zinc could alter behavioral and synaptic deficits that occur with ASD. We performed behavioral testing together with cortico-striatal slice electrophysiology on a Shank3 -/- mouse model of ASD (Shank3 ex13-1616-/-), which displays ASD-related behaviors and structural and functional deficits at striatal synapses. We observed that 6 weeks of dietary zinc supplementation in Shank3 ex13 16-/- mice prevented ASD-related repetitive and anxiety behaviors and deficits in social novelty recognition. Dietary zinc supplementation also increased the recruitment of zinc sensitive SHANK2 to synapses, reduced synaptic transmission specifically through N-methyl-D-aspartate (NMDA)-type glutamate receptors, reversed the slowed decay tau of NMDA receptor (NMDAR)-mediated currents and occluded long term potentiation (LTP) at cortico-striatal synapses. These data suggest that alterations in NMDAR function underlie the lack of NMDAR-dependent cortico-striatal LTP and contribute to the reversal of ASD-related behaviors such as compulsive grooming. Our data reveal that dietary zinc alters neurological function from synapses to behavior, and identifies dietary zinc as a potential therapeutic agent in ASD. PMID- 30405357 TI - Clonal Glial Response in a Multiple Sclerosis Mouse Model. AB - Multiple sclerosis (MS) is an autoimmune disease causing central nervous system (CNS) demyelination and axonal injury. In the last years the importance of astrocytes in MS is rapidly increasing, recognizing astrocytes as highly active players in MS pathogenesis. Usually the role assigned to astrocytes in MS lesions has been the formation of the glial scar, but now their implication during lesion formation and the immune response increasingly recognized. Since astrocytes are a heterogeneous cell population with diverse roles in the CNS, the aim of this study was to analyze the putative clonal response of astrocytes in a demyelinating scenario. To undertake this aim, we used the induced experimental autoimmune encephalomyelitis (EAE) as a murine model for MS in previously electroporated mice with in vivo multicolor lineage tracing system, the StarTrack methodology. Our data revealed a variety of morphological changes that were different among distinct clones. In many cases, cells of the same clone responded equally to the injury, while in other cases clonally-related cells responded differently to the injury. Therefore, whereas some clones exhibited a strong morphological alteration, other clones located at similar distances to the lesion were apparently unresponsive. Thus, at present there is no compelling evidences that clonal relationship influences the position or function of astrocytes in the EAE model. Further, the coexistence of different astroglial clonal responses to the bran injury reveals the significance of development to determine the astrocyte features that respond to brain injuries. PMID- 30405358 TI - Intravitreal AAV-Delivery of Genetically Encoded Sensors Enabling Simultaneous Two-Photon Imaging and Electrophysiology of Optic Nerve Axons. AB - Myelination of axons by oligodendrocytes is a key feature of the remarkably fast operating CNS. Oligodendrocytes not only tune axonal conduction speed but are also suggested to maintain long-term axonal integrity by providing metabolic support to the axons they ensheath. However, how myelinating oligodendrocytes impact axonal energy homeostasis remains poorly understood and difficult to investigate. Here, we provide a method of how to study electrically active myelinated axons expressing genetically encoded sensors by combining electrophysiology and two-photon imaging of acutely isolated optic nerves. We show that intravitreal adeno-associated viral (AAV) vector delivery is an efficient tool to achieve functional sensor expression in optic nerve axons, which is demonstrated by measuring axonal ATP dynamics following AAV-mediated sensor expression. This novel approach allows for fast expression of any optical sensor of interest to be studied in optic nerve axons without the need to go through the laborious process of producing new transgenic mouse lines. Viral mediated biosensor expression in myelinated axons and the subsequent combination of nerve recordings and sensor imaging outlines a powerful method to investigate oligodendroglial support functions and to further interrogate cellular mechanisms governing axonal energy homeostasis under physiological and pathological conditions. PMID- 30405355 TI - Phenolic Compounds Characteristic of the Mediterranean Diet in Mitigating Microglia-Mediated Neuroinflammation. AB - Neuroinflammation is a pathological feature of quite a number of Central Nervous System diseases such as Alzheimer and Parkinson's disease among others. The hallmark of brain neuroinflammation is the activation of microglia, which are the immune resident cells in the brain and represents the first line of defense when injury or disease occur. Microglial activated cells can adopt different phenotypes to carry out its diverse functions. Thus, the shift into pro inflammatory/neurotoxic or anti-inflammatory/neuroprotective phenotypes, depending of the brain environment, has totally changed the understanding of microglia in neurodegenerative disease. For this reason, novel therapeutic strategies which aim to modify the microglia polarization are being developed. Additionally, the understanding of how nutrition may influence the prevention and/or treatment of neurodegenerative diseases has grown greatly in recent years. The protective role of Mediterranean diet (MD) in preventing neurodegenerative diseases has been reported in a number of studies. The Mediterranean dietary pattern includes as distinctive features the moderate intake of red wine and extra virgin olive oil, both of them rich in polyphenolic compounds, such as resveratrol, oleuropein and hydroxytyrosol and their derivatives, which have demonstrated anti-inflammatory effects on microglia on in vitro studies. This review summarizes our understanding of the role of dietary phenolic compounds characteristic of the MD in mitigating microglia-mediated neuroinflammation, including explanation regarding their bioavailability, metabolism and blood-brain barrier. PMID- 30405359 TI - Using Pox-Neuro (Poxn) Mutants in Drosophila Gustation Research: A Double-Edged Sword. AB - In Drosophila, Pox-neuro (Poxn) is a member of the Paired box (Pax) gene family that encodes transcription factors with characteristic paired DNA-binding domains. During embryonic development, Poxn is expressed in sensory organ precursor (SOP) cells of poly-innervated external sensory (p-es) organs and is important for specifying p-es organ identity (chemosensory) as opposed to mono innervated external sensory (m-es) organs (mechanosensory). In Poxn mutants, there is a transformation of chemosensory bristles into mechanosensory bristles. As a result, these mutants have often been considered to be entirely taste-blind, and researchers have used them in this capacity to investigate physiological and behavioral functions that act in a taste-independent manner. However, recent studies show that only external taste bristles are transformed in Poxn mutants whereas all internal pharyngeal taste neurons remain intact, raising concerns about interpretations of experimental results using Poxn mutants as taste-blind flies. In this review, we summarize the value of Poxn mutants in advancing our knowledge of taste-enriched genes and feeding behaviors, and encourage revisiting some of the conclusions about taste-independent nutrient-sensing mechanisms derived from these mutants. Lastly, we highlight that Poxn mutant flies remain a valuable tool for probing the function of the relatively understudied pharyngeal taste neurons in sensing meal properties and regulating feeding behaviors. PMID- 30405360 TI - Overall Assay of Neuronal Signal Propagation Pattern With Long-Term Potentiation (LTP) in Hippocampal Slices From the CA1 Area With Fast Voltage-Sensitive Dye Imaging. AB - Activity-dependent changes in the input-output (I-O) relationship of a neural circuit are central in the learning and memory function of the brain. To understand circuit-wide adjustments, optical imaging techniques to probe the membrane potential at every component of neurons, such as dendrites, axons and somas, in the circuit are essential. We have been developing fast voltage sensitive dye (VSD) imaging methods for quantitative measurements, especially for single-photon wide-field optical imaging. The long-term continuous measurements needed to evaluate circuit-wide modifications require stable and quantitative long-term recordings. Here, we show that VSD imaging (VSDI) can be used to record changes in circuit activity in association with theta-burst stimulation (TBS) induced long-term potentiation (LTP) of synaptic strength in the CA1 area. Our optics, together with the fast imaging system, enabled us to measure neuronal signals from the entire CA1 area at a maximum frame speed of 0.1 ms/frame every 60 s for over 12 h. We also introduced a method to evaluate circuit activity changes by mapping the variation in recordings from the CA1 area to coordinates defined by the morphology of CA1 pyramidal cells. The results clearly showed two types of spatial heterogeneity in LTP induction. The first heterogeneity is that LTP increased with distance from the stimulation site. The second heterogeneity is that LTP is higher in the stratum pyramidale (SP)-oriens region than in the stratum radiatum (SR). We also showed that the pattern of the heterogeneity changed according to the induction protocol, such as induction by TBS or high frequency stimulation (HFS). We further demonstrated that part of the heterogeneity depends on the I-O response of the circuit elements. The results show the usefulness of VSDI in probing the function of hippocampal circuits. PMID- 30405361 TI - The Influence of a Memory Delay on Spatial Coding in the Superior Colliculus: Is Visual Always Visual and Motor Always Motor? AB - The memory-delay saccade task is often used to separate visual and motor responses in oculomotor structures such as the superior colliculus (SC), with the assumption that these same responses would sum with a short delay during immediate "reactive" saccades to visual stimuli. However, it is also possible that additional signals (suppression, delay) alter visual and/or motor response in the memory delay task. Here, we compared the spatiotemporal properties of visual and motor responses of the same SC neurons recorded during both the reactive and memory-delay tasks in two head-unrestrained monkeys. Comparing tasks, visual (aligned with target onset) and motor (aligned on saccade onset) responses were highly correlated across neurons, but the peak response of visual neurons and peak motor responses (of both visuomotor (VM) and motor neurons) were significantly higher in the reactive task. Receptive field organization was generally similar in both tasks. Spatial coding (along a Target-Gaze (TG) continuum) was also similar, with the exception that pure motor cells showed a stronger tendency to code future gaze location in the memory delay task, suggesting a more complete transformation. These results suggest that the introduction of a trained memory delay alters both the vigor and spatial coding of SC visual and motor responses, likely due to a combination of saccade suppression signals and greater signal noise accumulation during the delay in the memory delay task. PMID- 30405362 TI - Colocalization of Tectal Inputs With Amygdala-Projecting Neurons in the Macaque Pulvinar. AB - Neuropsychological and neuroimaging studies have suggested the presence of a fast, subcortical route for the processing of emotionally-salient visual information in the primate brain. This putative pathway consists of the superior colliculus (SC), pulvinar and amygdala. While the presence of such a pathway has been confirmed in sub-primate species, it has yet to be documented in the primate brain using conventional anatomical methods. We injected retrograde tracers into the amygdala and anterograde tracers into the colliculus, and examined regions of colocalization of these signals within the pulvinar of the macaque. Anterograde tracers injected into the SC labeled axonal projections within the pulvinar, primarily within the oral, lateral and medial subdivisions. These axonal projections from the colliculus colocalized with cell bodies within the pulvinar that were labeled by retrograde tracer injected into the lateral amygdala. This zone of overlap was most notable in the medial portions of the medial (PM), oral (PO) and inferior pulvinar (PI), and was often densely concentrated in the vicinity of the brachium of the SC. These data provide an anatomical basis for the previously suggested pathway mediating fast processing of emotionally salient information. PMID- 30405363 TI - Cell Densities in the Mouse Brain: A Systematic Review. AB - The mouse brain is the most extensively studied brain of all species. We performed an exhaustive review of the literature to establish our current state of knowledge on cell numbers in mouse brain regions, arguably the most fundamental property to measure when attempting to understand a brain. The synthesized information, collected in one place, can be used by both theorists and experimentalists. Although for commonly-studied regions cell densities could be obtained for principal cell types, overall we know very little about how many cells are present in most brain regions and even less about cell-type specific densities. There is also substantial variation in cell density values obtained from different sources. This suggests that we need a new approach to obtain cell density datasets for the mouse brain. PMID- 30405365 TI - Vestibulo-Hippocampal Function Is Enhanced and Brain Structure Altered in Professional Ballet Dancers. AB - Background and Objective: Life-long balance training has been shown to affect brain structure, including the hippocampus. Data are missing in this respect on professional ballet dancers of both genders. It is also unknown whether transfer effects exist on general balancing as well as spatial orientation abilities, a function mainly supported by the hippocampus. We aimed to assess differences in gray matter (GM) structure, general balancing skills, and spatial orientation skills between professional ballet dancers and non-dancers. Methods: Nineteen professional ballet dancers aged 18-35 (27.5 +/- 4.1 years; 10 females) and nineteen age-matched non-dancers (26.5 +/- 2.1 years; 10 females) were investigated. Main outcomes assessed were the score of a 30-item clinical balance test (CBT), the average error distance (in centimeters) on triangle completion task, and difference in GM density as seen by voxel-based morphometric analysis (VBM, SPM). Results: Ballet group performed significantly better on all conditions of the CBT and in the wheelchair (vestibular-dependent) condition of the spatial orientation test. Larger GM volumes for ballet dancers were observed in the right hippocampus, parahippocampal gyrus, insula, and cingulate motor cortex, whereas both larger and smaller volumes were detected within cerebellum bilaterally in comparison to non-dancers. Conclusion: Our results indicate that life-long ballet training could lead to better clinically relevant balancing abilities as well as vestibular-dependent spatial orientation capabilities; both of the benefits might be caused by positive influence of ballet training on the vestibular system function, and-possibly-its connectivity with temporal lobe regions responsible for vestibular-dependent orienting in space. PMID- 30405364 TI - Functional Diversity of Thalamic Reticular Subnetworks. AB - The activity of the GABAergic neurons of the thalamic reticular nucleus (TRN) has long been known to play important roles in modulating the flow of information through the thalamus and in generating changes in thalamic activity during transitions from wakefulness to sleep. Recently, technological advances have considerably expanded our understanding of the functional organization of TRN. These have identified an impressive array of functionally distinct subnetworks in TRN that participate in sensory, motor, and/or cognitive processes through their different functional connections with thalamic projection neurons. Accordingly, "first order" projection neurons receive "driver" inputs from subcortical sources and are usually connected to a densely distributed TRN subnetwork composed of multiple elongated neural clusters that are topographically organized and incorporate spatially corresponding electrically connected neurons-first order projection neurons are also connected to TRN subnetworks exhibiting different state-dependent activity profiles. "Higher order" projection neurons receive driver inputs from cortical layer 5 and are mainly connected to a densely distributed TRN subnetwork composed of multiple broad neural clusters that are non-topographically organized and incorporate spatially corresponding electrically connected neurons. And projection neurons receiving "driver-like" inputs from the superior colliculus or basal ganglia are connected to TRN subnetworks composed of either elongated or broad neural clusters. Furthermore, TRN subnetworks that mediate interactions among neurons within groups of thalamic nuclei are connected to all three types of thalamic projection neurons. In addition, several TRN subnetworks mediate various bottom-up, top-down, and internuclear attentional processes: some bottom-up and top-down attentional mechanisms are specifically related to first order projection neurons whereas internuclear attentional mechanisms engage all three types of projection neurons. The TRN subnetworks formed by elongated and broad neural clusters may act as templates to guide the operations of the TRN subnetworks related to attentional processes. In this review article, the evidence revealing the functional TRN subnetworks will be evaluated and will be discussed in relation to the functions of the various sensory and motor thalamic nuclei with which these subnetworks are connected. PMID- 30405366 TI - Cannabis Therapeutics and the Future of Neurology. AB - Neurological therapeutics have been hampered by its inability to advance beyond symptomatic treatment of neurodegenerative disorders into the realm of actual palliation, arrest or reversal of the attendant pathological processes. While cannabis-based medicines have demonstrated safety, efficacy and consistency sufficient for regulatory approval in spasticity in multiple sclerosis (MS), and in Dravet and Lennox-Gastaut Syndromes (LGS), many therapeutic challenges remain. This review will examine the intriguing promise that recent discoveries regarding cannabis-based medicines offer to neurological therapeutics by incorporating the neutral phytocannabinoids tetrahydrocannabinol (THC), cannabidiol (CBD), their acidic precursors, tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), and cannabis terpenoids in the putative treatment of five syndromes, currently labeled recalcitrant to therapeutic success, and wherein improved pharmacological intervention is required: intractable epilepsy, brain tumors, Parkinson disease (PD), Alzheimer disease (AD) and traumatic brain injury (TBI)/chronic traumatic encephalopathy (CTE). Current basic science and clinical investigations support the safety and efficacy of such interventions in treatment of these currently intractable conditions, that in some cases share pathological processes, and the plausibility of interventions that harness endocannabinoid mechanisms, whether mediated via direct activity on CB1 and CB2 (tetrahydrocannabinol, THC, caryophyllene), peroxisome proliferator-activated receptor-gamma (PPARgamma; THCA), 5-HT1A (CBD, CBDA) or even nutritional approaches utilizing prebiotics and probiotics. The inherent polypharmaceutical properties of cannabis botanicals offer distinct advantages over the current single-target pharmaceutical model and portend to revolutionize neurological treatment into a new reality of effective interventional and even preventative treatment. PMID- 30405367 TI - Neutrophil-Mediated Endogenous Analgesia Contributes to Sex Differences in Oral Cancer Pain. AB - The incidence of oral cancer in the United States is increasing, especially in young people and women. Patients with oral cancer report severe functional pain. Using a patient cohort accrued through the New York University Oral Cancer Center and immune-competent mouse models, we identify a sex difference in the prevalence and severity of oral cancer pain. A neutrophil-mediated endogenous analgesic mechanism is present in male mice with oral cancer. Local naloxone treatment potentiates cancer mediator-induced orofacial nociceptive behavior in male mice only. Tongues from male mice with oral cancer have significantly more infiltrating neutrophils compared to female mice with oral cancer. Neutrophils isolated from the cancer-induced inflammatory microenvironment express beta endorphin and met-enkephalin. Furthermore, neutrophil depletion results in nociceptive behavior in male mice. These data suggest a role for sex-specific, immune cell-mediated endogenous analgesia in the treatment of oral cancer pain. PMID- 30405369 TI - Linalool Odor-Induced Anxiolytic Effects in Mice. AB - In folk medicine, it has long been believed that odorous compounds derived from plant extracts can have anxiolytic effects. Among them, linalool, one of the terpene alcohols in lavender extracts, has been reported to have the anxiolytic effects. However, the anxiolytic nature of the linalool odor itself as well as its potential action through the olfactory system has not been thoroughly examined. In this study, we examined the anxiolytic effects of linalool odor with light/dark box test and with elevated plus maze (EPM), and found that linalool odor has an anxiolytic effect without motor impairment in mice. The effect was not observed in anosmic mice, indicating that it was triggered by olfactory input evoked by linalool odor. Furthermore, the effect was antagonized by flumazenil, indicating that the linalool odor-induced anxiolytic effect was mediated by gamma aminobutyric acid (GABA)ergic transmission via benzodiazepine (BDZ)-responsive GABAA receptors. These results provide information about the potential central neuronal mechanisms underlying the odor-induced anxiolytic effects and the foundation for exploring clinical application of linalool odor in anxiety treatments. PMID- 30405368 TI - Gentle Handling Attenuates Innate Defensive Responses to Visual Threats. AB - Innate defensive responses to threats are essential for animal survival. The complexity and variability of innate defensive behaviors can be due to individual experiences, environmental factors, and internal states. However, it is not completely understood if the gentle handling involved in sensory processing affects innate defensive responses to visual threats. Here, we report attenuation of innate defensive responses after gentle handling accompanied by de-excitation of the intermediate layer (IL) and deep layer (DL) of the superior colliculus (SC) but not of the superficial layer (SL). Our theoretical analysis of the c-Fos network revealed an increased correlation in module 1, which maybe generally functionally associated with fear emotional, a decreased correlation in module 2, which maybe generally functionally associated with sensory processing. The IL of the SC appeared to have the highest correlation with the two modules. We verified the dynamic activities of the IL of SC in response to overhead looming stimulus using fiber photometry. Retrograde labeling of 18 regions of interest (ROIs) showed that the IL received significant inputs from the cortical areas, thalamus, hypothalamus, and brainstem. These data suggest the sensory processing involved in the modulatory roles of the SC in innate fear processing. PMID- 30405370 TI - The Role of Estrogen Receptor beta (ERbeta) in the Establishment of Hierarchical Social Relationships in Male Mice. AB - Acquisition of social dominance is important for social species including mice, for preferential access to foods and mates. Male mice establish social rank through agonistic behaviors, which are regulated by gonadal steroid hormone, testosterone, as its original form and aromatized form. It is well known that estrogen receptors (ERs), particularly ER alpha (ERalpha), mediate effects of aromatized testosterone, i.e., 17beta-estradiol, but precise role played by ER beta (ERbeta) is still unclear. In the present study, we investigated effects of ERbeta gene disruption on social rank establishment in male mice. Adult male ERbeta knockout (betaERKO) mice and their wild type (WT) littermates were paired based on genotype- and weight-matched manner and tested against each other repeatedly during 7 days experimental period. They underwent 4 trials of social interaction test in neutral cage (homogeneous set test) every other day. Along repeated trials, WT but not betaERKO pairs showed a gradual increase of agonistic behaviors including aggression and tail rattling, and a gradual decrease of latency to social rank determination in tube test conducted after each trial of the social interaction test. Analysis of behavioral transition further suggested that WT winners in the tube test showed one-sided aggression during social interaction test suggesting WT pairs went through a process of social rank establishment. On the other hand, a dominant-subordinate relationship in betaERKO pairs was not as apparent as that in WT pairs. Moreover, betaERKO mice showed lower levels of aggressive behavior than WT mice in social interaction tests. These findings collectively suggest that ERbeta may play a significant role in the establishment and maintenance of hierarchical social relationships among male mice. PMID- 30405371 TI - Attention Bias Test Differentiates Anxiety and Depression in Sheep. AB - Negative affective states such as anxiety and depression pose a risk to animal welfare, however, practical tests for assessing these states in animals are limited. In humans, anxious individuals are shown to pay more attention toward threatening information than non-anxious individuals, known as an attention bias. Previously, an attention bias test was developed and validated as a measure of anxious states in sheep, where more anxious sheep showed increased attention toward a threat (dog) and were more vigilant than Control animals. Studies in humans suggest that attention biases also occur in depressed individuals, with observations of attention biases toward threats, as well as biases away from positive stimuli. Given these findings, we hypothesized that an attention bias test for sheep could also be used to assess states of depression. We predicted that Merino ewes in pharmacologically induced Depressed (para chlorophenylalanine) and Anxious (m-chlorophenylpiperazine) states would show greater attention toward a threat than Control animals (saline), but that the Depressed sheep would show relatively less interest in a positive stimulus (photograph of a conspecific). During testing, Depressed sheep paid more attention toward the threat and less toward the photograph than Control animals as predicted (Analyses of Variance, P < 0.05, n = 16 per treatment). Interestingly, Anxious sheep showed an attention bias in the opposite direction, paying more attention toward the photograph and less toward the threat than Control animals (P < 0.05). Both Anxious and Depressed sheep were more vigilant than Control animals (P = 0.002). These results suggest the attention bias test can be used to measure and differentiate states of depression and anxiety in livestock. The bidirectional nature of the attention bias identified between treatments highlights the importance of measuring multiple behaviors in the test and considering the context in which the test is applied. This will enable a clearer characterization of the affective state of an animal, as an aspect of its welfare. PMID- 30405372 TI - Altered Eye-Movement Patterns During Text Reading in Obsessive-Compulsive Disorder and Internet Gaming Disorder. AB - Obsessive-compulsive disorder (OCD) and internet gaming disorder (IGD), which are similar in that both involve repetitive behaviors and related with cognitive dysfunctions, frequently begin in early adolescence, which is a critical period for learning. Although the deterioration in cognitive functioning caused by these conditions may have adverse effects on information processing, such as text reading, there has been no comprehensive research on the objective indicators of altered reading patterns in these patients. Therefore, we evaluated eye-movement patterns during text reading in patients with OCD or IGD. In total, 20 patients with OCD, 28 patients with IGD and 24 healthy controls (HCs) participated in the reading task using an eye tracker. We compared the fixation durations (FDs), saccade amplitudes and eye-movement regressions of the three groups during reading. We explored relationships between the parameters reflecting altered reading patterns and those reflecting the severity of clinical symptoms. The average FDs and forward saccade amplitudes did not differ significantly among the groups. There were more eye-movement regressions in patients with OCD than in patients with IGD and HCs. No correlation was found between altered eye-movement patterns during reading and the severity of clinical symptoms in any of the patient groups. The significantly increased number of regressions (NRs) in the OCD group during reading may reflect these patients' difficulties with inferential information processing, whereas the reading pattern in the IGD group is relatively intact. These findings suggest that patients with OCD and patients with IGD have different eye-movement patterns during reading reflecting distinct cognitive impairments in the two patient groups. PMID- 30405373 TI - Analysis of Human Brain Structure Reveals that the Brain "Types" Typical of Males Are Also Typical of Females, and Vice Versa. AB - Findings of average differences between females and males in the structure of specific brain regions are often interpreted as indicating that the typical male brain is different from the typical female brain. An alternative interpretation is that the brain types typical of females are also typical of males, and sex differences exist only in the frequency of rare brain types. Here we contrasted the two hypotheses by analyzing the structure of 2176 human brains using three analytical approaches. An anomaly detection analysis showed that brains from females are almost as likely to be classified as "normal male brains," as brains from males are, and vice versa. Unsupervised clustering algorithms revealed that common brain "types" are similarly common in females and in males and that a male and a female are almost as likely to have the same brain "type" as two females or two males are. Large sex differences were found only in the frequency of some rare brain "types." Last, supervised clustering algorithms revealed that the brain "type(s)" typical of one sex category in one sample could be typical of the other sex category in another sample. The present findings demonstrate that even when similarity and difference are defined mathematically, ignoring biological or functional relevance, sex category (i.e., whether one is female or male), is not a major predictor of the variability of human brain structure. Rather, the brain types typical of females are also typical of males, and vice versa, and large sex differences are found only in the prevalence of some rare brain types. We discuss the implications of these findings to studies of the structure and function of the human brain. PMID- 30405374 TI - Differential Subjective Experiences in Learners and Non-learners in Frontal Alpha Neurofeedback: Piloting a Mixed-Method Approach. AB - In a neurofeedback paradigm, trainees learn to willfully control their brain dynamics. How this is realized remains an open question. We evaluate the hypothesis that learning success is associated with a specific phenomenology. To address this proposal, we combined quantitative and qualitative analyses of a short neurofeedback training (NFT) session during which participants enhanced mid frontal alpha power and were then subsequently interviewed about their experiences. We analyzed the electrophysiological data to determine learning success and classify trainees as learners and non-learners. The subjective experiences differed between the two groups and are best described along a trying sensing continuum, with non-learners engaging effortfully with the task (e.g., "I will it [the bar] to move") whereas learners reported more sensing of their inner (e.g., "Something inside my stomach") and outer environment (e.g., "I was aware of the sound of the beeps"). In the process of piloting this mixed-method approach, we developed a classification system for the verbal reports. This system provides an explicit analytic framework which might guide future studies that aim to investigate the association between subjective experiences and NFT protocols. PMID- 30405375 TI - Abstract Representations of Emotions Perceived From the Face, Body, and Whole Person Expressions in the Left Postcentral Gyrus. AB - Emotions can be perceived through the face, body, and whole-person, while previous studies on the abstract representations of emotions only focused on the emotions of the face and body. It remains unclear whether emotions can be represented at an abstract level regardless of all three sensory cues in specific brain regions. In this study, we used the representational similarity analysis (RSA) to explore the hypothesis that the emotion category is independent of all three stimulus types and can be decoded based on the activity patterns elicited by different emotions. Functional magnetic resonance imaging (fMRI) data were collected when participants classified emotions (angry, fearful, and happy) expressed by videos of faces, bodies, and whole-persons. An abstract emotion model was defined to estimate the neural representational structure in the whole brain RSA, which assumed that the neural patterns were significantly correlated in within-emotion conditions ignoring the stimulus types but uncorrelated in between-emotion conditions. A neural representational dissimilarity matrix (RDM) for each voxel was then compared to the abstract emotion model to examine whether specific clusters could identify the abstract representation of emotions that generalized across stimulus types. The significantly positive correlations between neural RDMs and models suggested that the abstract representation of emotions could be successfully captured by the representational space of specific clusters. The whole-brain RSA revealed an emotion-specific but stimulus category independent neural representation in the left postcentral gyrus, left inferior parietal lobe (IPL) and right superior temporal sulcus (STS). Further cluster based MVPA revealed that only the left postcentral gyrus could successfully distinguish three types of emotions for the two stimulus type pairs (face-body and body-whole person) and happy versus angry/fearful, which could be considered as positive versus negative for three stimulus type pairs, when the cross-modal classification analysis was performed. Our study suggested that abstract representations of three emotions (angry, fearful, and happy) could extend from the face and body stimuli to whole-person stimuli and the findings of this study provide support for abstract representations of emotions in the left postcentral gyrus. PMID- 30405376 TI - Eyes-Open and Eyes-Closed Resting States With Opposite Brain Activity in Sensorimotor and Occipital Regions: Multidimensional Evidences From Machine Learning Perspective. AB - Studies have demonstrated that there are widespread significant differences in spontaneous brain activity between eyes-open (EO) and eyes-closed (EC) resting states. However, it remains largely unclear whether spontaneous brain activity is effectively related to EO and EC resting states. The amplitude, local functional concordance, inter-hemisphere functional synchronization, and network centrality of spontaneous brain activity were measured by the fraction amplitude of low frequency fluctuation (fALFF), regional homogeneity (ReHo), voxel-mirrored homotopic connectivity (VMHC) and degree centrality (DC), respectively. Using the public Eyes-open/Eyes-closed dataset, we employed the support vector machine (SVM) and bootstrap technique to establish linking models for the fALFF, ReHo, VMHC and DC dimensions. The classification accuracies of linking models are 0.72 (0.59, 0.82), 0.88 (0.79, 0.97), 0.82 (0.74, 0.91) and 0.70 (0.62, 0.79), respectively. Specifically, we observed that brain activity in the EO condition is significantly greater in attentional system areas, including the fusiform gyrus, occipital and parietal cortex, but significantly lower in sensorimotor system areas, including the precentral/postcentral gyrus, paracentral lobule (PCL) and temporal cortex compared to the EC condition from the four dimensions. The results consistently indicated that spontaneous brain activity is effectively related to EO and EC resting states, and the two resting states are of opposite brain activity in sensorimotor and occipital regions. It may provide new insight into the neural substrate of the resting state and help computational neuroscientists or neuropsychologists to choose an appropriate resting state condition to investigate various mental disorders from the resting state functional magnetic resonance imaging (fMRI) technique. PMID- 30405377 TI - Influence of Audiovisual Training on Horizontal Sound Localization and Its Related ERP Response. AB - The objective was to investigate the influence of audiovisual training on horizontal sound localization and the underlying neurological mechanisms using a combination of psychoacoustic and electrophysiological (i.e., event-related potential, ERP) measurements on sound localization. Audiovisual stimuli were used in the training group, whilst the control group was trained using auditory stimuli only. Training sessions were undertaken once per day for three consecutive days. Sound localization accuracy was evaluated daily after training, using psychoacoustic tests. ERP responses were measured on the first and last day of tasks. Sound localization was significantly improved in the audiovisual training group when compared to the control group. Moreover, a significantly greater reduction in front-back confusion ratio for both trained and untrained angles was found between pre- and post-test in the audiovisual training group. ERP measurement showed a decrease in N1 amplitude and an increase in P2 amplitude in both groups. However, changes in late components were only found in the audiovisual training group, with an increase in P400 amplitude and decrease in N500 amplitude. These results suggest that the interactive effect of audiovisual localization training is likely to be mediated at a relatively late cognitive processing stage. PMID- 30405378 TI - Effect of Visual Information on Active Touch During Mirror Visual Feedback. AB - Several studies have demonstrated that observation of a dummy or mirror-reflected hand being stroked or moving at the same time as the hidden hand evokes a feeling that the dummy hand is one's own, such as the rubber hand illusion (RHI) and mirror visual feedback (MVF). Under these conditions, participants also report sensing the tactile stimulation applied to the fake hands, suggesting that tactile perception is modulated by visual information during the RHI and MVF. Previous studies have utilized passive stimulation conditions; however, active touch is more common in real-world settings. Therefore, we investigated whether active touch is also modulated by visual information during an MVF scenario. Twenty-three participants (13 men and 10 women; mean age +/- SD: 21.6 +/- 2.0 years) were required to touch a polyurethane pad with both hands synchronously, and estimate the hardness of the pad while observing the mirror reflection. When participants observed the mirror reflection of the other hand pushing a softer or harder pad, perceived hardness estimates were significantly biased toward softer or harder, respectively, even though the physical hardness of the pad remained constant. Furthermore, perceived hardness exhibited a strong correlation with finger displacement of the mirrored, but not hidden, hand. The modulatory effects on perceived hardness diminished when participants touched the pad with both hands asynchronously or with their eyes closed. Moreover, participants experienced ownership of the mirrored hand when they touched the pad with both hands synchronously but not asynchronously. These results indicate that hardness estimates were modulated by observation of the mirrored hand during synchronous touch conditions. The present study demonstrates that, similar to passive touch, active touch is also modulated by visual input. PMID- 30405379 TI - Differences in Neurocognitive Mechanisms Underlying the Processing of Center Embedded and Non-embedded Musical Structures. AB - In music, chords are organized into hierarchical structures based on recursive or embedded syntax. How the brain extracts recursive grammar is a central question in musical cognition and other cognitive neuroscience, but the precise mechanism remains unclear. By analyzing event related potentials (ERPs) and neural oscillatory activity, the present study investigated neurocognitive mechanisms underlying the processing of center-embedded structure in music by examining the differences in center-embedded and non-embedded structure processing and evaluating how these differences are affected by musical proficiency. Based on Western musical proficiency, the subjects were divided into two groups, non experts and experts. The results revealed that for non-experts, the processing of center-embedded structure elicited greater early right-anterior negativity (ERAN) and N5 components as well as, reduced alpha and gamma activities than did the non embedded structure. For experts, no significant difference in the ERP response was observed between the processing of non-embedded and center-embedded structures; however, the processing of center-embedded structure elicited increased beta activity compared to non-embedded structure. These findings indicate that listeners different in proficiency would rely on different cognitive neural mechanisms in music processing with the syntactic complexity increases. PMID- 30405380 TI - Retroactive Attentional Shifts Predict Performance in a Working Memory Task: Evidence by Lateralized EEG Patterns. AB - Shifts of attention within working memory based on retroactive (retro-) cues were shown to facilitate performance in working memory tasks. Although posterior asymmetries in the EEG, such as the contralateral delay activity (CDA), have been used to study the active storage of lateralized working memory representations, results on the relation of such asymmetric effects to retro-cue benefits remain inconclusive. We recorded EEG in a retro-cue working memory task with lateralized items and a continuous performance response. Following either a selective or neutral retro-cue, participants adjusted the orientation of a central memory probe to the cued item. Selective retro-cues elicited an early posterior contralateral negativity (PCN), anterior directing attention negativity (ADAN) and a later modulation of CDA indicating that active storage was concentrated on the cued information. By dividing all trials into three within-condition performance quantiles, we could further show that high working memory accuracy was associated with a sustained increase of the CDA effect following the retro cue. These results suggest that focusing resources on the active storage of relevant representations is an important factor regarding retro-cue benefits in working memory tasks. PMID- 30405381 TI - On the Motion of Spikes: Turbulent-Like Neuronal Activity in the Human Basal Ganglia. AB - Neuronal signals are usually characterized in terms of their discharge rate, a description inadequate to account for the complex temporal organization of spike trains. Complex temporal properties, which are characteristic of neuronal systems, can only be described with the appropriate, complex mathematical tools. Here, I apply high order structure functions to the analysis of neuronal signals recorded from parkinsonian patients during functional neurosurgery, recovering multifractal properties. To achieve an accurate model of such multifractality is critical for understanding the basal ganglia, since other non-linear properties, such as entropy, depend on the fractal properties of complex systems. I propose a new approach to the study of neuronal signals: to study spiking activity in terms of the velocity of spikes, defining it as the inverse function of the instantaneous frequency. I introduce a neural field model that includes a non linear gradient field, representing neuronal excitability, and a diffusive term to consider the physical properties of the electric field. Multifractality is present in the model for a range of diffusion coefficients, and multifractal temporal properties are mirrored into space. The model reproduces the behavior of human basal ganglia neurons and shows that it is like that of turbulent fluids. The results obtained from the model predict that passive electric properties of neuronal activity, including ephaptic coupling, are far more relevant to the human brain than what is usually considered: passive electric properties determine the temporal and spatial organization of neuronal activity in the neural tissue. PMID- 30405384 TI - Editorial: Time Perception and Dysfunction: Clinical and Practical Implications. PMID- 30405382 TI - Older Adolescents and Young Adults With Autism Spectrum Disorder Have Difficulty Chaining Motor Acts When Performing Prehension Movements Compared to Typically Developing Peers. AB - It is known that motor actions performed by individuals with autism spectrum disorders (ASD) are clumsy and a previous study revealed that children with ASD of around 8 years old showed less smooth movement and dysfunction of appropriate usage of online vision for grip aperture control. The present study investigates whether and how the kinematic properties of reach-to-grasp movements in older adolescents and adults with ASD [mean (+/-SD) age: 18.3 +/- 2.1] differ from those in typically developing (TD) peers [mean (+/-SD) age: 19.1 +/- 2.2]. Revealing the kinematic properties of reach-to-grasp movements in older adolescents and adults with ASD is indispensable in determining the developmental trajectory of this motor behavior in individuals with ASD. While wearing liquid crystal shutter goggles, participants reached for and grasped a cylinder with a diameter of either 4 or 6 cm. Two visual conditions were tested: a full vision (FV) condition (the goggles remained transparent during the movement) and a no vision (NV) condition (the goggles were closed immediately after the movement was initiated). These two visual conditions were either alternated with each trial in a single experimental session (alternated condition) or blocked within the session (blocked condition). We found that the reaching movement smoothness calculated as a normalized jerk score (i.e., index of skilled, coordinated human movements) of ASD participants did not differ significantly from that of TD peers although ASD participants showed smoother reaching in the alternated condition than in the blocked condition. The influence of online vision and its visual condition schedule on grip aperture during the in-flight phase was remarkably similar between the ASD and TD groups. Furthermore, we found that ASD group experienced a significant longer transition period from grasping end (i.e., stable holding when touching the surface of the object) to uplift initiation than the TD group. The results suggest that (1) deficits in movement smoothness and the use of online vision for motor control are rectified by the time individuals with ASD reach late adolescence and (2) older adolescents and adults with ASD still have difficulties chaining motor acts. PMID- 30405383 TI - Lower Beta: A Central Coordinator of Temporal Prediction in Multimodal Speech. AB - How the brain decomposes and integrates information in multimodal speech perception is linked to oscillatory dynamics. However, how speech takes advantage of redundancy between different sensory modalities, and how this translates into specific oscillatory patterns remains unclear. We address the role of lower beta activity (~20 Hz), generally associated with motor functions, as an amodal central coordinator that receives bottom-up delta-theta copies from specific sensory areas and generate top-down temporal predictions for auditory entrainment. Dissociating temporal prediction from entrainment may explain how and why visual input benefits speech processing rather than adding cognitive load in multimodal speech perception. On the one hand, body movements convey prosodic and syllabic features at delta and theta rates (i.e., 1-3 Hz and 4-7 Hz). On the other hand, the natural precedence of visual input before auditory onsets may prepare the brain to anticipate and facilitate the integration of auditory delta theta copies of the prosodic-syllabic structure. Here, we identify three fundamental criteria based on recent evidence and hypotheses, which support the notion that lower motor beta frequency may play a central and generic role in temporal prediction during speech perception. First, beta activity must respond to rhythmic stimulation across modalities. Second, beta power must respond to biological motion and speech-related movements conveying temporal information in multimodal speech processing. Third, temporal prediction may recruit a communication loop between motor and primary auditory cortices (PACs) via delta to-beta cross-frequency coupling. We discuss evidence related to each criterion and extend these concepts to a beta-motivated framework of multimodal speech processing. PMID- 30405385 TI - Generalized Cross-Frequency Decomposition: A Method for the Extraction of Neuronal Components Coupled at Different Frequencies. AB - Perceptual, motor and cognitive processes are based on rich interactions between remote regions in the human brain. Such interactions can be carried out through phase synchronization of oscillatory signals. Neuronal synchronization has been primarily studied within the same frequency range, e.g., within alpha or beta frequency bands. Yet, recent research shows that neuronal populations can also demonstrate phase synchronization between different frequency ranges. An extraction of such cross-frequency interactions in EEG/MEG recordings remains, however, methodologically challenging. Here we present a new method for the robust extraction of cross-frequency phase-to-phase synchronized components. Generalized Cross-Frequency Decomposition (GCFD) reconstructs the time courses of synchronized neuronal components, their spatial filters and patterns. Our method extends the previous state of the art, Cross-Frequency Decomposition (CFD), to the whole range of frequencies: it works for any f 1 and f 2 whenever f 1:f 2 is a rational number. GCFD gives a compact description of non-linearly interacting neuronal sources on the basis of their cross-frequency phase coupling. We successfully validated the new method in simulations and tested it with real EEG recordings including resting state data and steady state visually evoked potentials (SSVEP). PMID- 30405387 TI - Learning Inverse Statics Models Efficiently With Symmetry-Based Exploration. AB - Learning (inverse) kinematics and dynamics models of dexterous robots for the entire action or observation space is challenging and costly. Sampling the entire space is usually intractable in terms of time, tear, and wear. We propose an efficient approach to learn inverse statics models-primarily for gravity compensation-by exploring only a small part of the configuration space and exploiting the symmetry properties of the inverse statics mapping. In particular, there exist symmetric configurations that require the same absolute motor torques to be maintained. We show that those symmetric configurations can be discovered, the functional relations between them can be successfully learned and exploited to generate multiple training samples from one sampled configuration-torque pair. This strategy drastically reduces the number of samples required for learning inverse statics models. Moreover, we demonstrate that exploiting symmetries for learning inverse statics models is a generally applicable strategy for online and offline learning algorithms. We exemplify this by two different learning approaches. First, we modify the Direction Sampling approach for learning inverse statics models online, in a plain exploratory fashion, from scratch and without using a closed-loop controller. Second, we show that inverse statics mappings can be efficiently learned offline utilizing lattice sampling. Results for a 2R planar robot and a 3R simplified human arm demonstrate that their inverse statics mappings can be learned successfully for the entire configuration space. Furthermore, we demonstrate that the number of samples required for learning inverse statics mappings for 2R and 3R manipulators can be reduced at least by factors of approximately 8 and 16, respectively-depending on the number of discovered symmetries. PMID- 30405386 TI - Mapping the Human Brain in Frequency Band Analysis of Brain Cortex Electroencephalographic Activity for Selected Psychiatric Disorders. AB - There are still no good quantitative methods to be applied in psychiatric diagnosis. The interview is still the main and most important tool in the psychiatrist work. This paper presents the results of electroencephalographic research with the subjects of a group of 30 patients with psychiatric disorders compared to the control group of healthy volunteers. All subjects were solving working memory task. The digit-span working memory task test was chosen as one of the most popular tasks given to subjects with cognitive dysfunctions, especially for the patients with panic disorders, depression (including the depressive phase of bipolar disorder), phobias, and schizophrenia. Having such cohort of patients some results for the subjects with insomnia and Asperger syndrome are also presented. The cortical activity of their brains was registered by the dense array EEG amplifier. Source localization using the photogrammetry station and the sLORETA algorithm was then performed in five EEG frequency bands. The most active Brodmann Areas are indicated. Methodology for mapping the brain and research protocol are presented. The first results indicate that the presented technique can be useful in finding psychiatric disorder neurophysiological biomarkers. The first attempts were made to associate hyperactivity of selected Brodmann Areas with particular disorders. PMID- 30405388 TI - Retromer in Synaptic Function and Pathology. AB - The retromer complex mediates export of select transmembrane proteins from endosomes to the trans-Golgi network (TGN) or to the plasma membrane. Dysfunction of retromer has been linked with slowly progressing neurodegenerative disorders, including Alzheimer's and Parkinson's disease (AD and PD). As these disorders affect synapses it is of key importance to clarify the function of retromer dependent protein trafficking pathways in pre- and postsynaptic compartments. Here we discuss recent insights into the roles of retromer in the trafficking of synaptic vesicle proteins, neurotransmitter receptors and other synaptic proteins. We also consider evidence that implies synapses as sites of early pathology in neurodegenerative disorders, pointing to a possible role of synaptic retromer dysfunction in the initiation of disease. PMID- 30405390 TI - Frailty and Cognitive Impairment in Predicting Mortality Among Oldest-Old People. AB - Backgrounds: Frailty and cognitive impairment are critical geriatric syndromes. In previous studies, both conditions have been identified in old-age adults as increased risk factors for mortality. However, the combined effect of these two syndromes in predicting mortality among people with advanced age is not well understood. Thus, we used Chinese community cohort to determine the impact of the combined syndromes on the oldest-old people. Methods: Our present study is part of an ongoing project on Longevity and Aging in Dujiangyan, which is a community study on a 90+ year cohort in Sichuan Province in China. Participants were elderly people who completed baseline health assessment in 2005 followed by a collection of mortality data in 2009. Frailty and cognitive function were assessed with 34-item Rockwood Frailty Index and the Mini-Mental Status Examination, respectively, and the combined effect(s) of these two parameters on death was examined using the Cox proportional hazard regression model. Results: This study consisted of a total of 705 participants (age = 93.6 +/- 3.3 years; 67.4% females), of which 53.8% died during a four-year follow-up period. The prevalence of frailty, cognitive impairment, and the overlap of these two syndromes was 63.7, 74.2, and 50.3%, respectively. Our data showed that the subjects with combined frailty and cognitive impairment were associated with increased risk of death (age, gender, education level, and other potential confounders adjusted); the hazard ratio was 2.13 (95% confidence interval 1.39, 3.24), compared with the control group. However, neither frailty alone nor cognitive impairment alone increased the risk of death in these individuals. Conclusion: The combined frailty and cognitive impairment, other than the independently measured syndromes (frailty or cognitive impairment alone), was a significant risk factor for death among the oldest-old Chinese people. PMID- 30405391 TI - Epigenetics of Delirium and Aging: Potential Role of DNA Methylation Change on Cytokine Genes in Glia and Blood Along With Aging. AB - Background: Delirium in elderly patients is common and dangerous. Major risk factors include aging and exogenous insults, such as infection or surgery. In animal models, aging enhances pro-inflammatory cytokine release from microglia in response to exogenous insults. The epigenetic mechanism DNA methylation (DNAm) regulates gene expression and changes with age. Older individuals may have methylation changes that influence the increased cytokine upon insult, but the degree to which aging affects DNAm of cytokine genes is not fully understood. Methods: The relationship between DNAm and aging of pro-inflammatory cytokine genes (TNF-alpha, IL1-beta, IL-6) was investigated using methylation array data in two cohorts. Brain and blood samples were collected from a neurosurgery cohort (NSG) of 21 subjects who underwent brain resection. A second cohort, the Grady Trauma Project (GTP), included blood samples from 265 subjects. Results: In the NSG cohort, a significant negative correlation between age and DNAm in brain was found at a CpG in IL-6. With the GTP dataset, significant negative correlations between age and DNAm were seen at most of the CpGs in TNF-alpha. Also, TNF-Alpha expression increases with age. These GTP DNAm correlations were also nominally significant in NSG blood samples. In neuronal negative NSG brain tissue, a similar negative trend was observed. Conclusions: With aging, a decrease in DNAm of cytokines gene CpGs in glia and blood was seen. As this can affect their expression, additional research is needed to fully elucidate the role of DNAm in aging and how it may influence the pathogenesis of delirium. PMID- 30405392 TI - Functional Connectivity Within the Executive Control Network Mediates the Effects of Long-Term Tai Chi Exercise on Elders' Emotion Regulation. AB - Previous research has identified the effects of tai chi exercise on elders' executive control or on their emotion regulation. However, few works have attempted to reveal the relationships between tai chi, executive control, and emotion regulation in the same study. The current resting-state study investigated whether the impact of tai chi on elders' emotion regulation was mediated by the resting-state functional connectivity within the executive control network. A total of 26 elders with long-term tai chi experience and 26 demographically matched healthy elders were recruited. After the resting-state scan, both groups were required to complete a series of questionnaires, including the Five Facets Mindfulness Questionnaire (FFMQ), and a sequential decision task, which offered an index of the subjects' emotion-regulation ability by calculating how their emotional response could be affected by the objective outcomes of their decisions. Compared to the control group, the tai chi group showed higher levels of non-judgment of inner experiences (a component of the FFMQ), stronger emotion regulation ability, and a weaker resting-state functional connectivity between the dorsolateral prefrontal cortex (DLPFC) and the middle frontal gyrus (MFG). Moreover, the functional connectivity between the DLPFC and the MFG in the tai chi group fully mediated the impact of non-judgment of inner experience on their emotion-regulation ability. These findings highlighted that the modulation of non judgment of inner experience on long-term tai chi practitioners' emotion regulation was achieved through decreased functional connectivity within the executive control network. PMID- 30405393 TI - A Nonlinear Simulation Framework Supports Adjusting for Age When Analyzing BrainAGE. AB - Several imaging modalities, including T1-weighted structural imaging, diffusion tensor imaging, and functional MRI can show chronological age related changes. Employing machine learning algorithms, an individual's imaging data can predict their age with reasonable accuracy. While details vary according to modality, the general strategy is to: (1) extract image-related features, (2) build a model on a training set that uses those features to predict an individual's age, (3) validate the model on a test dataset, producing a predicted age for each individual, (4) define the "Brain Age Gap Estimate" (BrainAGE) as the difference between an individual's predicted age and his/her chronological age, (5) estimate the relationship between BrainAGE and other variables of interest, and (6) make inferences about those variables and accelerated or delayed brain aging. For example, a group of individuals with overall positive BrainAGE may show signs of accelerated aging in other variables as well. There is inevitably an overestimation of the age of younger individuals and an underestimation of the age of older individuals due to "regression to the mean." The correlation between chronological age and BrainAGE may significantly impact the relationship between BrainAGE and other variables of interest when they are also related to age. In this study, we examine the detectability of variable effects under different assumptions. We use empirical results from two separate datasets [training = 475 healthy volunteers, aged 18-60 years (259 female); testing = 489 participants including people with mood/anxiety, substance use, eating disorders and healthy controls, aged 18-56 years (312 female)] to inform simulation parameter selection. Outcomes in simulated and empirical data strongly support the proposal that models incorporating BrainAGE should include chronological age as a covariate. We propose either including age as a covariate in step 5 of the above framework, or employing a multistep procedure where age is regressed on BrainAGE prior to step 5, producing BrainAGE Residualized (BrainAGER) scores. PMID- 30405389 TI - Phyto-Therapeutic and Nanomedicinal Approaches to Cure Alzheimer's Disease: Present Status and Future Opportunities. AB - Alzheimer's disease (AD) is characterized by cognitive inability manifested due to the accumulation of beta-amyloid, formation of hyper phosphorylated neurofibrillary tangles, and a malfunctioned cholinergic system. The degeneration integrity of the neuronal network can appear long after the onset of the disease. Nanotechnology-based interventions have opened an exciting area via theranostics of AD in terms of tailored nanomedicine, which are able to target and deliver drugs across the blood-brain barrier (BBB). The exciting interface existing between medicinal plants and nanotechnology is an emerging marvel in medicine, which has delivered promising results in the treatment of AD. In order to assess the potential applications of the medicinal plants, their derived components, and various nanomedicinal approaches, a review of literature was deemed as necessary. In the present review, numerous phytochemicals and various feats in nanomedicine for the treatment of AD have been discussed mechanistically for the first time. Furthermore, recent trends in nanotechnology such as green synthesis of metal nanoparticles with reference to the treatment of AD have been elaborated. Foreseeing the recent progress, we hope that the interface of medicinal plants and nanotechnology will lead to highly effective theranostic strategies for the treatment of AD in the near future. PMID- 30405395 TI - Corroboration of a Major Role for Herpes Simplex Virus Type 1 in Alzheimer's Disease. AB - Strong evidence has emerged recently for the concept that herpes simplex virus type 1 (HSV1) is a major risk for Alzheimer's disease (AD). This concept proposes that latent HSV1 in brain of carriers of the type 4 allele of the apolipoprotein E gene (APOE-epsilon4) is reactivated intermittently by events such as immunosuppression, peripheral infection, and inflammation, the consequent damage accumulating, and culminating eventually in the development of AD. Population data to investigate this epidemiologically, e.g., to find if subjects treated with antivirals might be protected from developing dementia-are available in Taiwan, from the National Health Insurance Research Database, in which 99.9% of the population has been enrolled. This is being extensively mined for information on microbial infections and disease. Three publications have now appeared describing data on the development of senile dementia (SD), and the treatment of those with marked overt signs of disease caused by varicella zoster virus (VZV), or by HSV. The striking results show that the risk of SD is much greater in those who are HSV-seropositive than in seronegative subjects, and that antiviral treatment causes a dramatic decrease in number of subjects who later develop SD. It should be stressed that these results apply only to those with severe cases of HSV1 or VZV infection, but when considered with the over 150 publications that strongly support an HSV1 role in AD, they greatly justify usage of antiherpes antivirals to treat AD. Three other studies are described which directly relate to HSV1 and AD: they deal respectively with lysosomal changes in HSV1-infected cell cultures, with evidence for a role of human herpes virus type 6 and 7 (HHV6 and HHV7) in AD, and viral effects on host gene expression, and with the antiviral characteristics of beta amyloid (Abeta). Three indirectly relevant studies deal respectively with schizophrenia, relating to antiviral treatment to target HSV1, with the likelihood that HSV1 is a cause of fibromyalgia (FM), and with FM being associated with later development of SD. Studies on the link between epilepsy, AD and herpes simplex encephalitis (HSE) are described also, as are the possible roles of APOE-epsilon4, HHV6 and HSV1 in epilepsy. PMID- 30405394 TI - The Barcelona Brain Health Initiative: A Cohort Study to Define and Promote Determinants of Brain Health. AB - The Barcelona Brain Health Initiative (BBHI) is an ongoing prospective longitudinal study focused on identifying determinants of brain health. The main objectives are: (i) to characterize lifestyle, cognitive, behavioral and environmental markers related to a given individual's cognitive and mental functions in middle to old age, (ii) to assess the biological determinants predictive of maintenance of brain health, and (iii) to evaluate the impact of a controlled multi-dimensional lifestyle intervention on improving and maintaining brain health. The BBHI cohort consists of >4500 healthy participants aged 40-65 years followed through online questionnaires (Phase I) assessing participants' self-perceived health and lifestyle factors in seven different domains: overall health, physical exercise, cognitive activity, sleep, nutrition, social interactions, and life purpose. In Phase II a sub-group of 1,000 individuals is undergoing detailed in-person evaluations repeated at two-yearly intervals. These evaluations will provide deep phenotyping of brain function, including medical, neurological and psychiatric examinations, assessment of physical fitness, neuropsychological assessments, structural and functional brain magnetic resonance imaging, electroencephalography and perturbation-based non-invasive brain stimulation evaluations of brain activity, as well as collection of biological samples. Finally, in Phase III a further sub-group of 500 participants will undergo a similar in-person assessment before and after a multi-dimensional intervention to optimize lifestyle habits and evaluate its effects on cognitive and brain structure and function. The intervention group will receive remote supervision through an ICT-based solution, with the support of an expert in health and lifestyle coaching strategies aimed at promoting adherence. On the other hand, the control group will not have this coaching support, and will only receive education and recommendations about healthy habits. Results of this three part initiative shall critically contribute to a better understanding of the determinants to promote and maintain brain health over the lifespan. PMID- 30405396 TI - Task-Based Cognitive Fatigability for Older Adults and Validation of Mental Fatigability Subscore of Pittsburgh Fatigability Scale. AB - Cognitive fatigue and cognitive fatigability are distinct constructs. Cognitive fatigue reflects perception of cognitive fatigue outside of the context of activity level and duration and can be reliably assessed via established instruments such as the Fatigue Severity Scale (FSS) and the Modified Fatigue Impact Scale (MFIS). In contrast, cognitive fatigability reflects change in fatigue levels quantified within the context of the level and duration of cognitive activity, and currently there are no reliable measures of cognitive fatigability. A recently published scale, the Pittsburgh Fatigability Scale (PFS), attempts to remedy this problem with a focus on the aged population. While the physical fatigability subscore of PFS has been validated using physical activity derived measures, the mental fatigability subscore of PFS remains to be tested against equivalent measures derived from cognitive activities. To this end, we recruited 35 older, healthy adult participants (mean age 73.77 +/- 5.9) to complete the PFS as well as a prolonged continuous performance of a Stroop task (>2 h). Task-based assessments included time-on-task changes in self reported fatigue scores (every 20 min), reaction time, and pupil diameter. Defining subjective fatigability, behavioral fatigability, and physiologic/autonomic fatigability to be the slope of change over time-on-task in the above three assessed variables, we found that the PFS mental subscore was not correlated with any of the three task-based fatigability measures. Instead, the PFS mental subscore was correlated with trait level fatigue measures FSS (rho = 0.63, p < 0.001), and MFIS cognitive subsection (rho = 0.36, p = 0.03). This finding suggested that the PFS mental fatigability subscore may not be an adequate measure of how fatigued one becomes after a given amount of mental work. Further development efforts are needed to create a self-report scale that reliably captures cognitive fatigability in older adults. PMID- 30405397 TI - A Single Bout of Aerobic Exercise Improves Motor Skill Consolidation in Parkinson's Disease. AB - Background: Motor learning is impaired in Parkinson's disease (PD), with patients demonstrating deficits in skill acquisition (online learning) and consolidation (offline learning) compared to healthy adults of similar age. Recent studies in young adults suggest that single bouts of aerobic exercise (AEX), performed in close temporal proximity to practicing a new motor task, may facilitate motor skill learning. Thus, we aimed at investigating the effects of a single bout of aerobic cycling on online and offline learning in PD patients. Methods: 17 PD patients (Hoehn and Yahr 1 - 2.5, age: 64.4 +/- 6.2) participated in this crossover study. Immediately prior to practicing a novel balance task, patients either performed 30 min of (i) moderate intensity (60-70% VO2max) aerobic cycling, or (ii) seated rest (order counterbalanced). The task required patients to stabilize a balance platform (stabilometer) in a horizontal position for 30 s. For each experimental condition, patients performed 15 acquisition trials, followed by a retention test 24 h later. We calculated time in balance (platform within +/- 5 degrees from horizontal) for each trial, and analyzed within- and between-subjects differences in skill acquisition (online learning) and skill retention (offline learning) using mixed repeated-measures ANOVA. Results: We found that the exercise bout had no effect on performance level or online gains during acquisition, despite affecting the time course of skill improvements (larger initial and reduced late skill gains). Aerobic cycling significantly improved offline learning, as reflected by larger 24-h skill retention compared to the rest condition. Conclusion: Our results suggest that a single bout of moderate-intensity AEX is effective in improving motor skill consolidation in PD patients. Thus, acute exercise may represent an effective strategy to enhance motor memory formation in this population. More work is necessary to understand the underlying mechanisms, the optimal scheduling of exercise, and the applicability to other motor tasks. Further, the potential for patients in later disease stages need to be investigated. The study was a priori registered at ClinicalTrials.gov (NCT03245216). PMID- 30405398 TI - Early Introduction of cART Reverses Brain Aging Pattern in Well-Controlled HIV Infection: A Comparative MR Spectroscopy Study. AB - Introduction: The aim of this study was to compare age-related changes in chronically infected, asymptomatic HIV-positive patients under combination antiretroviral therapy (cART), with age-, gender-, and educational-level-matched healthy subjects, using multi-voxel magnetic-resonance spectroscopy (MRS). Methods: There were 66 chronically infected HIV-positive subjects and 65 age-, gender-, and educational-level-matched control subjects, divided into four groups according to the age: group 1 (20-29 years old), group 2 (30-39), group 3 (40-49) and group 4 (50-59). MRS was performed and ratios of N-acetyl-aspartate (NAA)/creatine (Cr) were analyzed in ten locations of the supracallosal gray matter. For the comparison of NAA/Cr ratios in healthy and HIV-positive subjects, ANCOVA with age and education as covariates was performed. Correlations of NAA/Cr ratios with duration of cART were performed using Pearson's correlation test. Statistical significance was set at p < 0.05. Results: The NAA/Cr ratios were decreased in the 20-29-year-old HIV-positive subjects in 8/10 locations (p < 0.005) compared to the healthy controls, while in the 50-59-year-old groups they were significiantly lower only in one location (p = 0.004). There were significant positive correlations of NAA/Cr levels with the duration of cART in the oldest group of HIV-positive subjects, while in the youngest group there were no significant correlations. Conclusion: The aging pattern in chronic HIV infection under cART is accentuated rather than accelerated. There is an initial HIV-related neuronal damage with a significant decline in NAA/Cr ratios; after the initiation of cART, however, NAA/Cr ratios increase continuously to become similar to healthy aging individuals, probably due to beneficial effect of long standing cART. Summary: Brain aging in chronic HIV infection under cART is accentuated, with an initial HIV-related neuronal damage followed by a subtle NAA/Cr increase after the initiation of cART. Under cART, in advanced age, NAA/Cr ratios become similar to healthy aging individuals. PMID- 30405399 TI - Altered Functional Interactions of Inhibition Regions in Cognitively Normal Parkinson's Disease. AB - Deficient inhibitory control in Parkinson's disease (PD) is often observed in situations requiring inhibition of impulsive or prepotent behaviors. Although activation of the right-hemisphere frontal-basal ganglia response inhibition network is partly altered in PD, disturbances in interactions of these regions are poorly understood, especially in patients without cognitive impairment. The present study investigated context-dependent connectivity of response inhibition regions in PD patients with normal cognition and control participants who underwent fMRI while performing a stop signal task. PD participants were tested off antiparkinsonian medication. To determine if functional disturbances depended on underlying brain structure, aberrant connectivity was correlated with brain volume and white-matter tissue diffusivity. We found no group differences in response inhibition proficiency. Yet the PD group showed functional reorganization in the long-range connectivity of inhibition regions, despite preserved within network connectivity. Successful inhibition in PD differed from the controls by strengthened connectivity of cortical regions, namely the right dorsolateral prefrontal cortex, pre-supplementary motor area and right caudal inferior frontal gyrus, largely with ventral and dorsal attention regions, but also the substantia nigra and default mode network regions. Successful inhibition in controls was distinguished by strengthened connectivity of the right rostral inferior frontal gyrus and subcortical inhibition nodes (right caudate, substantia nigra, and subthalamic nucleus). In both groups, the strength of context-dependent connectivity correlated with various indices of response inhibition performance. Mechanisms that may underlie aberrantly stronger context specific connectivity include reduced coherence within reorganized systems, compensatory mechanisms, and/or the reorganization of intrinsic networks. In PD, but not controls, abnormally strengthened connectivity was linked to individual differences in underlying brain volumes and tissue diffusivity, despite no group differences in structural variables. The pattern of structural-functional associations suggested that subtle decreases in tissue diffusivity of underlying tracts and posterior cortical volumes may undermine the enhancement of normal cortical-striatal connectivity or cause strengthening in cortical-cortical connectivity. These novel findings demonstrate that functionally reorganized interactions of inhibition regions predates the development of inhibition deficits and clinically significant cognitive impairment in PD. We speculate that altered interactions of inhibition regions with attention-related networks and the dopaminergic system may presage future decline in inhibitory control. PMID- 30405400 TI - Infection Augments Expression of Mechanosensing Piezo1 Channels in Amyloid Plaque Reactive Astrocytes. AB - A defining pathophysiological hallmark of Alzheimer's disease (AD) is the amyloid plaque; an extracellular deposit of aggregated fibrillar Abeta1-42 peptides. Amyloid plaques are hard, brittle structures scattered throughout the hippocampus and cerebral cortex and are thought to cause hyperphosphorylation of tau, neurofibrillary tangles, and progressive neurodegeneration. Reactive astrocytes and microglia envelop the exterior of amyloid plaques and infiltrate their inner core. Glia are highly mechanosensitive cells and can almost certainly sense the mismatch between the normally soft mechanical environment of the brain and very stiff amyloid plaques via mechanosensing ion channels. Piezo1, a non-selective cation channel, can translate extracellular mechanical forces to intracellular molecular signaling cascades through a process known as mechanotransduction. Here, we utilized an aging transgenic rat model of AD (TgF344-AD) to study expression of mechanosensing Piezo1 ion channels in amyloid plaque-reactive astrocytes. We found that Piezo1 is upregulated with age in the hippocampus and cortex of 18-month old wild-type rats. However, more striking increases in Piezo1 were measured in the hippocampus of TgF344-AD rats compared to age-matched wild type controls. Interestingly, repeated urinary tract infections with Escherichia coli bacteria, a common comorbidity in elderly people with dementia, caused further elevations in Piezo1 channel expression in the hippocampus and cortex of TgF344-AD rats. Taken together, we report that aging and peripheral infection augment amyloid plaque-induced upregulation of mechanoresponsive ion channels, such as Piezo1, in astrocytes. Further research is required to investigate the role of astrocytic Piezo1 in the Alzheimer's brain, whether modulating channel opening will protect or exacerbate the disease state, and most importantly, if Piezo1 could prove to be a novel drug target for age-related dementia. PMID- 30405401 TI - Differential Effect of Retroactive Interference on Object and Spatial Memory in the Course of Healthy Aging and Neurodegeneration. AB - Objective: In subjects with mild cognitive impairment (MCI), interference during memory consolidation may further degrade subsequent recall of newly learned information. We investigated whether spatial and object memory are differentially susceptible to interference. Method: Thirty-nine healthy young subjects, 39 healthy older subjects, and 12 subjects suffering from MCI encoded objects and their spatial position on a 4-by-5 grid. Encoding was followed by either: (i) a pause; (ii) an interference task immediately following encoding; or (iii) an interference task following encoding after a 6-min delay. Type of interference (no, early, delayed) was applied in different sessions and order was counterbalanced. Twelve minutes after encoding, subjects saw objects previously presented or new ones. Subjects indicated whether they recognized the object, and if so, the objects' position during encoding. Results: Interference during consolidation provoked a negative effect on spatial memory in young more than older controls. In MCI, object but not spatial memory was affected by interference. Furthermore, a shift from fine- to coarse-grained spatial representation was observed in MCI. No differential effect of early vs. late interference (EI vs. LI) in either of the groups was detected. Conclusions: Data show that consolidation in healthy aging and MCI differs from consolidation in young controls. Data suggest differential processes underlying object and spatial memory and that these are differentially affected by aging and MCI. PMID- 30405402 TI - Motor Learning Improvement Remains 3 Months After a Multisession Anodal tDCS Intervention in an Aging Population. AB - Healthy aging is associated with decline of motor function that can generate serious consequences on the quality of life and safety. Our studies aim to explore the 3-month effects of a 5-day multisession anodal transcranial direct current stimulation (a-tDCS) protocol applied over the primary motor cortex (M1) during motor sequence learning in elderly. The present sham-controlled aging study investigated whether tDCS-induced motor improvements previously observed 1 day after the intervention persist beyond 3 months. A total of 37 cognitively intact aging participants performed five consecutive daily 20-min sessions of the serial-reaction time task (SRTT) concomitant with either anodal (n = 18) or sham (n = 19) tDCS over M1. All participants performed the Purdue Pegboard Test and transcranial magnetic stimulation (TMS) measures of cortical excitability were collected before, 1 day after and 3 months after the intervention. The last follow-up session also included the execution of the trained SRTT. The main findings are the demonstration of durable effects of a 5-day anodal tDCS intervention at the trained skill, while the active intervention did not differ from the sham intervention at both the untrained task and on measures of M1 disinhibition. Thus, the current article revealed for the first time the durability of functional effects of a-tDCS combined with motor training after only 5 days of intervention in an aging population. This finding provides evidence that the latter treatment alternative is effective in achieving our primary motor rehabilitation goal, that is to allow durable motor training effects in an aging population. PMID- 30405404 TI - Berberine Attenuated Proliferation, Invasion and Migration by Targeting the AMPK/HNF4alpha/WNT5A Pathway in Gastric Carcinoma. AB - Background: Recent epidemiologic studies have found that patients with diabetes have a higher risk of gastric cancer (GC), and the long-term use of metformin is associated with a lower risk of gastric cancer. It is believed that blocking tumor energy metabolic alterations is now emerging as a new therapeutic approach of cancer. Berberine, a natural isoquinoline alkaloid, could modulate lipid metabolism and glucose homeostasis by regulating the expression of HNF4alpha in many metabolic diseases. Here, we investigated the effect of Berberine on GC and its possible molecular mechanism through targeting HNF4alpha. Methods and Results: (1) AGS and SGC7901 gastric cancer cells were treated with Berberine (BBR). We found that in AGS and SGC7901 cell, BBR inhibited cell proliferation in a time- and dose-dependent manner through downregulating C-myc. BBR also induced G0-G1 phase arrest with the decreased expression of cyclin D1. Moreover, BBR attenuated the migration and invasion by downregulating MMP-3. (2) The lentivirus infection was used to silence the expression of HNF4alpha in SGC7901 cell. The results demonstrated that the knockdown of HNF4alpha in SGC7901 slowed cells proliferation, induced S phase arrest and dramatically attenuated gastric cancer cells' metastasis and invasion. (3) We performed GC cells perturbation experiments through BI6015 (an HNF4alpha antagonist), AICAR (an AMPK activator), Compound C (AMPK-kinase inhibitor), metformin and BBR. Our findings indicated that BBR downregulated HNF4alpha while upregulating p-AMPK. Moreover, the inhibition of HNF4alpha by BBR was AMPK dependent. (4) Then the LV-HNF4alpha-RNAi SGC7901 cell model was used to detect the downstream of HNF4alpha in vitro. The results showed that the knockdown of HNF4alpha significantly decreased WNT5A and cytoplasmic beta-catenin, but increased E-cadherin in vitro. Berberine also downregulated WNT5A and cytoplasmic beta-catenin, the same as LV-HNF4alpha-RNAi and BI6015 in GC cells. (5) Finally, the SGC7901 and LV-HNF4alpha-RNAi SGC7901 mouse-xenograft model to evaluate the effect of BBR and HNF4alpha gene on GC tumor growth. The result illustrated that BBR and knockdown of HNF4alpha suppressed tumor growth in vivo, and BBR decreased HNF4alpha, WNT5A and cytoplasmic beta-catenin levels, the same effect as HNF4alpha knockout in vivo. Conclusion: BBR not only had proliferation inhibition effect, attenuated the invasion and migration on GC cell lines, but also suppressed the GC tumor growth in vivo. The anti-gastric cancer mechanism of BBR might be involved in AMPK HNF4alpha-WNT5A signaling pathway. HNF4alpha antagonists, such as BBR, could be a promising anti-gastric cancer treatment supplement. PMID- 30405403 TI - In silico Prediction, Characterization, Molecular Docking, and Dynamic Studies on Fungal SDRs as Novel Targets for Searching Potential Fungicides Against Fusarium Wilt in Tomato. AB - Vascular wilt of tomato caused by Fusarium oxysporum f.sp. lycopersici (FOL) is one of the most devastating diseases, that delimits the tomato production worldwide. Fungal short-chain dehydrogenases/reductases (SDRs) are NADP(H) dependent oxidoreductases, having shared motifs and common functional mechanism, have been demonstrated as biochemical targets for commercial fungicides. The 1,3,6,8 tetra hydroxynaphthalene reductase (T4HNR) protein, a member of SDRs family, catalyzes the naphthol reduction reaction in fungal melanin biosynthesis. We retrieved an orthologous member of T4HNR, (complexed with NADP(H) and pyroquilon from Magnaporthe grisea) in the FOL (namely; FOXG_04696) based on homology search, percent identity and sequence similarity (93% query cover; 49% identity). The hypothetical protein FOXG_04696 (T4HNR like) had conserved T-G-X-X X-G-X-G motif (cofactor binding site) at N-terminus, similar to M. grisea (1JA9) and Y-X-X-X-K motif, as a part of the active site, bearing homologies with two fungal keto reductases T4HNR (M. grisea) and 17-beta-hydroxysteroid dehydrogenase from Curvularia lunata (teleomorph: Cochliobolus lunatus PDB ID: 3IS3). The catalytic tetrad of T4HNR was replaced with ASN115, SER141, TYR154, and LYS158 in the FOXG_04696. The structural alignment and superposition of FOXG_04696 over the template proteins (3IS3 and 1JA9) revealed minimum RMSD deviations of the C alpha atomic coordinates, and therefore, had structural conservation. The best protein model (FOXG_04696) was docked with 37 fungicides, to evaluate their binding affinities. The Glide XP and YASARA docked complexes showed discrepancies in results, for scoring and ranking the binding affinities of fungicides. The docked complexes were further refined and rescored from their docked poses through 50 ns long MD simulations, and binding free energies (DeltaGbind) calculations, using MM/GBSA analysis, revealed Oxathiapiprolin and Famoxadone as better fungicides among the selected one. However, Famoxadone had better interaction of the docked residues, with best protein ligand contacts, minimum RMSD (high accuracy of the docking pose) and RMSF (structural integrity and conformational flexibility of docking) at the specified docking site. The Famoxadone was found to be acceptable based on in silico toxicity and in vitro growth inhibition assessment. We conclude that the FOXG_04696, could be employed as a novel candidate protein, for structure-based design, and screening of target fungicides against the FOL pathogen. PMID- 30405406 TI - Effect of Puerarin Regulated mTOR Signaling Pathway in Experimental Liver Injury. AB - It is known that excessive hepatocellular apoptosis is a typical characteristic of hepatic disease, and is regulated by the mammalian target of rapamycin (mTOR) signaling pathway. As the main active component of Kudzu (Pueraria lobata) roots, which is frequently used to treat hepatic diseases, Puerarin (Pue) has been reported to alleviate and protect against hepatic injury. However, it is unclear whether Pue can inhibit mTOR signaling to prevent excessive apoptosis in the treatment of hepatic diseases. In the present study, Pue effectively ameliorated pathological injury of the liver, decreased serum enzyme (ALT, AST, gamma-GT, AKP, DBIL, and TBIL) levels, regulated the balance between pro-inflammatory (TNF alpha, IL-1beta, IL-4, IL-6, and TGF-beta1) and anti-inflammatory cytokines (IL 10), restored the cell cycle and inhibited hepatocellular apoptosis and caspase-3 expression in rats with liver injury induced by 2-AAF/PH. Pue inhibited p-mTOR, p AKT and Raptor activity, and increased Rictor expression in the liver tissues of rats with experimental liver injury. These results indicated that Pue effectively regulated the activation of mTOR signaling pathway in the therapeutic and prophylactic process of Pue on experimental liver injury. PMID- 30405408 TI - Impact of Global DNA Methylation in Treatment Outcome of Colorectal Cancer Patients. AB - Background: Global DNA methylation has an impact in cancer pathogenesis and progression. This study aimed at investigating the impact of global DNA methylation in treatment outcome of Colorectal Cancer (CRC). Patients and Methods: Global DNA methylation was measured by LC/MS/MS in peripheral blood leucocytes of 102, 48, and 32 Egyptian CRC patients at baseline and after 3 and 6 months of Fluoropyrimidine (FP) therapy respectively, in addition to 32 normal healthy matched in age and sex. The genetic expressions of DNA methyl transferases (DNMTs) were determined and correlated with patients' survival using univariate and multivariate methods of analyses. Results: Egyptian CRC patients had significant global hypomethylation of 5mC level and 5mC % with overexpression of DNMT3A and DNMT3B. Significant higher 5mC levels were shown in patients > 45 years, male gender, T2 tumors, stage II, negative lymph nodes, and absence of metastasis. FP therapy significantly reduced DNA methylation particularly in the subgroups of patients with high DNA methylation level at baseline and good prognostic features. After 3 years of follow up, patients with 5mC % > 8.02% had significant poor overall survival (OS) while, significant better event-free survival (EFS) was found in patients with 5mC level > 0.55. High initial CEA level and presence of metastasis were significantly associated with hazards of disease progression and death. Conclusion: Global DNA methylation has a significant impact on the treatment outcome and survival of Egyptian CRC patients treated with FP- based therapy. PMID- 30405407 TI - Confused Connections? Targeting White Matter to Address Treatment Resistant Schizophrenia. AB - Despite development of comprehensive approaches to treat schizophrenia and other psychotic disorders and improve outcomes, there remains a proportion (approximately one-third) of patients who are treatment resistant and will not have remission of psychotic symptoms despite adequate trials of pharmacotherapy. This level of treatment response is stable across all stages of the spectrum of psychotic disorders, including early phase psychosis and chronic schizophrenia. Our current pharmacotherapies are beneficial in decreasing positive symptomology in most cases, however, with little to no impact on negative or cognitive symptoms. Not all individuals with treatment resistant psychosis unfortunately, even benefit from the potential pharmacological reductions in positive symptoms. The existing pharmacotherapy for psychosis is targeted at neurotransmitter receptors. The current first and second generation antipsychotic medications all act on dopamine type 2 receptors with the second generation drugs also interacting significantly with serotonin type 1 and 2 receptors, and with varying pharmacodynamic profiles overall. This focus on developing dopaminergic/serotonergic antipsychotics, while beneficial, has not reduced the proportion of patients experiencing treatment resistance to date. Another pharmacological approach is imperative to address treatment resistance both for response overall and for negative symptoms in particular. There is research suggesting that changes in white matter integrity occur in schizophrenia and these may be more associated with cognition and even negative symptomology. Here we review the evidence that white matter abnormalities in the brain may be contributing to the symptomology of psychotic disorders. Additionally, we propose that white matter may be a viable pharmacological target for pharmacoresistant schizophrenia and discuss current treatments in development for schizophrenia that target white matter. PMID- 30405409 TI - Systems-Mapping of Herbal Effects on Complex Diseases Using the Network Perturbation Signatures. AB - The herbs have proven to hold great potential to improve people's health and wellness during clinical practice over the past millennia. However, herbal medicine for the personalized treatment of disease is still under investigation owing to the complex multi-component interactions in herbs. To reveal the valuable insights for herbal synergistic therapy, we have chosen Traditional Chinese Medicine (TCM) as a case to illustrate the art and science behind the complicated multi-molecular, multi-genes interaction systems, and how the good practices of herbal combination therapy are applicable to personalized treatment. Here, we design system-wide interaction map strategy to provide a generic solution to establish the links between diseases and herbs based on comprehensive testing of molecular signatures in herb-disease pairs. Firstly, we integrated gene expression profiles from 189 diseases to characterize the disease pathological feature. Then, we generated the perturbation signatures from the huge chemical informatics data and pharmacological data for each herb, which were represented the targets affected by the ingredients in the herb. So that we could assess the effects of herbs on the individual. Finally, we integrated the data of 189 diseases and 502 herbs, yielding the optimal herbal combinations for the diseases based on the strategy, and verifying the reliability of the strategy through the permutation testing and literature verification. Furthermore, we propose a novel formula as a candidate therapeutic drugs of rheumatoid arthritis and demonstrate its therapeutic mechanism through the systematic analysis of the influencing targets and biological processes. Overall, this computational method provides a systematic approach, which blended herbal medicine and omics data sets, allowing for the development of novel drug combinations for complex human diseases. PMID- 30405410 TI - Salvianolic Acid B Promotes the Survival of Random-Pattern Skin Flaps in Rats by Inducing Autophagy. AB - Random-pattern skin flap transplantation is frequently applied in plastic and reconstructive surgery. However, the distal part of the flap often suffers necrosis due to ischemia. In this study, the effects of salvianolic acid B (Sal B) on flap survival were evaluated, and the underlying mechanisms were investigated. Sal B improved the survival area, reduced tissue edema, and increased the number of microvessels in skin flaps after 7 days, whereas an autophagy inhibitor (3-methyladenine) reversed the Sal B-induced increase in flap viability. In addition, Sal B stimulated angiogenesis, inhibited apoptosis, reduced oxidative stress, and upregulated autophagy in areas of ischemia. Moreover, the effects of Sal B on angiogenesis, apoptosis, and oxidative stress were reversed by autophagy inhibition. Overall, our findings suggest that Sal B has pro-angiogenesis, anti-apoptosis, and anti-oxidative stress effects by stimulating autophagy, which enhances the survival of random-pattern skin flaps. PMID- 30405411 TI - Pharmacokinetics, Bioavailability, and Tissue Distribution Study of Angoroside C and Its Metabolite Ferulic Acid in Rat Using UPLC-MS/MS. AB - Angoroside C is a phenylpropanoid glycoside compound isolated from the dried root of Scrophularia ningpoensis Hemsl., which possesses the effects of preventing ventricular remodeling, reducing pulmonary oedema, and reducing blood pressure, as well as having the properties of anti-platelet aggregation, hepatoprotection and anti-nephritis, etc. However, few investigations have been conducted on the absorption, distribution, metabolism, and excretion (ADME) study of angoroside C. Thus, a fast ultra-high performance liquid chromatography-tandem quadrupole mass spectrometry (UPLC-MS/MS) method was established for the determination of angoroside C and its metabolite ferulic acid in rat plasma and tissue homogenate. The two analytes were extracted from the biosamples using a simple protein precipitation with acetonitrile. The developed method was validated and successfully applied to the pharmacokinetics, bioavailability and tissue distribution study after the intragastric administration of angoroside C (100 mg/kg) or the intravenous administration of angoroside C (5 mg/kg), respectively. The results showed that angoroside C can be absorbed extremely quickly (T max = 15 min), can be eliminated very rapidly (t 1/2 = 1.26 h), and its oral bioavailability is only about 2.1%. Furthermore, angoroside C was extensively distributed in all main organs (liver, heart, spleen, lung, kidney, and brain), and the highest concentration was detected in the lung 15 min after oral administration. This paper also indicated that angoroside C could be converted to the active metabolite ferulic acid in vivo. The maximum concentrations of ferulic acid in the kidney occurred at 6 h after oral administration. In summary, this study explored some of the pharmacokinetic characteristics of angoroside C in vivo, and the data produced could provide a basis for the further investigation of angoroside C. PMID- 30405405 TI - Antioxidant and Oxidative Stress: A Mutual Interplay in Age-Related Diseases. AB - Aging is the progressive loss of organ and tissue function over time. Growing older is positively linked to cognitive and biological degeneration such as physical frailty, psychological impairment, and cognitive decline. Oxidative stress is considered as an imbalance between pro- and antioxidant species, which results in molecular and cellular damage. Oxidative stress plays a crucial role in the development of age-related diseases. Emerging research evidence has suggested that antioxidant can control the autoxidation by interrupting the propagation of free radicals or by inhibiting the formation of free radicals and subsequently reduce oxidative stress, improve immune function, and increase healthy longevity. Indeed, oxidation damage is highly dependent on the inherited or acquired defects in enzymes involved in the redox-mediated signaling pathways. Therefore, the role of molecules with antioxidant activity that promote healthy aging and counteract oxidative stress is worth to discuss further. Of particular interest in this article, we highlighted the molecular mechanisms of antioxidants involved in the prevention of age-related diseases. Taken together, a better understanding of the role of antioxidants involved in redox modulation of inflammation would provide a useful approach for potential interventions, and subsequently promoting healthy longevity. PMID- 30405412 TI - Calein C, a Sesquiterpene Lactone Isolated From Calea Pinnatifida (Asteraceae), Inhibits Mitotic Progression and Induces Apoptosis in MCF-7 Cells. AB - Breast cancer is the most common cancer in women worldwide. Estrogen receptor positive (ER+) breast cancer represents approximately 75% of diagnosed cases, while 15-20% of them are triple-negative (TN). Although there have been improvements in the therapeutic approach, the mortality rate remains elevated. Thus, it is necessary to identify new chemotherapeutic agents. The present study aimed to evaluate the effects of calein C, a sesquiterpene lactone isolated from Calea pinnatifida, on breast cancer cell lines MCF-7 (ER+), Hs578T (TN) and MDA MB-231 (TN). Calein C significantly reduced the viability of all cell lines; however, MCF-7 cells were more responsive than MDA-MB-231 or Hs578T cells. Thus, the MCF-7 cell line was selected for further investigation. We demonstrated that calein C inhibited cell cycle progression in MCF-7 cells at M-phase. Increased frequency of mitosis was observed in calein C-treated samples compared to the control group, especially of the cell population in initial stages of the mitosis. These events were associated with the ability of calein C to modulate expression levels of critical regulators of mitosis progression. We observed a significant reduction in the relative mRNA abundance of PLK1 and AURKB along with a concomitant increase in CDKN1A (p21) in treated samples. In addition, calein C induced apoptosis in MCF-7 cells due to, at least in part, its ability to reduce the BCL2/BAX ratio. Therefore, our data provide evidence that calein C is an important antimitotic agent and should be considered for further in vivo investigations. PMID- 30405414 TI - Lack of Effects of Extended Sessions of Transcranial Direct Current Stimulation (tDCS) Over Dorsolateral Prefrontal Cortex on Craving and Relapses in Crack Cocaine Users. AB - Background: Non-invasive brain stimulation such as transcranial direct current stimulation (tDCS) has been investigated as additional therapeutic tool for drug use disorder. In a previous study, we showed that five sessions of tDCS applied bilaterally over the dorsolateral prefrontal cortex (dlPFC) reduced craving to the use of crack-cocaine in inpatients from a specialized clinic. In the present study, we examine if an extended number of sessions of the same intervention would reduce craving even further and affect also relapses to crack-cocaine use. Methods: A randomized, double-blind, sham-controlled, clinical trial with parallel arms was conducted (https://clinicaltrials.gov/ct2/show/NCT02091167). Crack-cocaine patients from two private and one public clinics for treatment of drug use disorder were randomly allocated to two groups: real tDCS (5 cm * 7 cm, 2 mA, for 20 min, cathodal over the left dlPFC and anodal over the right dlPFC, n = 19) and sham-tDCS (n = 16). Real or sham-tDCS was applied once a day, every other day, in a total of 10 sessions. Craving was monitored by a 5-item obsessive compulsive drinking scale once a week (one time before, three times during and once after brain stimulation) over about 5 weeks and relapse was monitored after their discharge from clinics for up to 60 days. Results: Craving scores progressively decreased over five measurements in both sham- and real tDCS groups. Corrected Hedges' within-group (initial and final) effect sizes of craving scores were of 0.77 for the sham-tDCS and of 0.97 for the real tDCS group. The between-groups effect size was of 0.34, in favor of the real tDCS group over sham-tDCS group. Relapse rates were high and quite similar between groups in the 30- and 60-days follow-up after discharge from the hospital. Conclusion: Extended repetitive bilateral tDCS over the dlPFC had no add-on effects over regular treatment when considering craving and relapses to the crack cocaine use in a sample of crack-cocaine patients with severe use disorder. Different tDCS montages targeting other cortical regions and perhaps additional extension of sessions need to be investigated to reach more efficiency in managing craving and relapses to crack-cocaine use. PMID- 30405413 TI - Naturally Occurring Acetylcholinesterase Inhibitors and Their Potential Use for Alzheimer's Disease Therapy. AB - Alzheimer's disease (AD) is a main cause of dementia, accounting for up to 75% of all dementia cases. Pathophysiological processes described for AD progression involve neurons and synapses degeneration, mainly characterized by cholinergic impairment. This feature makes acetylcholinesterase inhibitors (AChEi) the main class of drugs currently used for the treatment of AD dementia phase, among which galantamine is the only naturally occurring substance. However, several plant species producing diverse classes of alkaloids, coumarins, terpenes, and polyphenols have been assessed for their anti-AChE activity, becoming potential candidates for new anti-AD drugs. Therefore, this mini-review aimed to recapitulate last decade studies on the anti-AChE activity of plant species, their respective extracts, as well as isolated compounds. The anti-AChE activity of extracts prepared from 54 plant species pertaining 29 families, as well as 36 isolated compounds were classified and discussed according to their anti-AChE pharmacological potency to highlight the most prominent ones. Besides, relevant limitations, such as proper antioxidant assessment, and scarcity of toxicological and clinical studies were also discussed in order to help researchers out with the bioprospection of potentially new AChEi. PMID- 30405415 TI - PBF509, an Adenosine A2A Receptor Antagonist With Efficacy in Rodent Models of Movement Disorders. AB - Adenosine A2A receptor (A2AR) antagonists have emerged as complementary non dopaminergic drugs to alleviate Parkinson's disease (PD) symptomatology. Here, we characterize a novel non-xhantine non-furan A2AR antagonist, PBF509, as a potential pro-dopaminergic drug for PD management. First, PBF509 was shown to be a highly potent ligand at the human A2AR, since it antagonized A2AR agonist mediated cAMP accumulation and impedance responses with KB values of 72.8 +/- 17.4 and 8.2 +/- 4.2 nM, respectively. Notably, these results validated our new A2AR-based label-free assay as a robust and sensitive approach to characterize A2AR ligands. Next, we evaluated the efficacy of PBF509 reversing motor impairments in several rat models of movement disorders, including catalepsy, tremor, and hemiparkinsonism. Thus, PBF509 (orally) antagonized haloperidol mediated catalepsy, reduced pilocarpine-induced tremulous jaw movements and potentiated the number of contralateral rotations induced by L-3,4 dihydroxyphenylalanine (L-DOPA) in unilaterally 6-OHDA-lesioned rats. Moreover, PBF509 (3 mg/kg) inhibited L-DOPA-induced dyskinesia (LID), showing not only its efficacy on reversing parkinsonian motor impairments but also acting as antidyskinetic agent. Overall, here we describe a new orally selective A2AR antagonist with potential utility for PD treatment, and for some of the side effects associated to the current pharmacotherapy (i.e., dyskinesia). PMID- 30405417 TI - FosB mRNA Expression in Peripheral Blood Lymphocytes in Drug Addicted Patients. AB - FosB gene heterodimerizes with Jun family proteins to form activator protein 1 (AP-1) complexes that bind to AP-1 sites in responsive genes to regulate transcription in all cells. The genic expression of FosB seems to be modified after long time exposure to drugs of abuse and these changes may be involved in craving and addicted behavior. This study investigated the FosB mRNA expression in peripheral blood lymphocytes of drug addicted patients using real-time PCR approach. Thus, patients with crack-cocaine use disorder (CUD, n = 10), alcohol use disorder (AUD, n = 12), and healthy non-addicted subjects (CONT, n = 12) were assessed. FosB mRNA expression was reduced by 1.15-fold in CUD and 2.17-fold in AUD when compared to CONT. Hedge's effect size gs over log FosB/Act was of 0.66 for CUD and of 0.30 for AUD when compared to controls. This study showed that FosB mRNA expression was detected in lymphocytes from peripheral blood for the first time, and it was less expressed in drug addicted patients. This molecular technique may constitute a potential peripheral marker for substance use disorder. PMID- 30405416 TI - Polypharmacology or Promiscuity? Structural Interactions of Resveratrol With Its Bandwagon of Targets. AB - Resveratrol (3, 4', 5-trihydroxy-trans-stilbene) is a natural phytoalexin found in grapes and has long been thought to be the answer to the "French Paradox." There is no shortage of preclinical and clinical studies investigating the broad therapeutic activity of resveratrol. However, in spite of many comprehensive reviews published on the bioactivity of resveratrol, there has yet to be a report focused on the variety and complexity of its structural binding properties, and its multi-targeted role. An improved understanding of disease mechanisms at the systems level has enabled targeted polypharmacology to mature into a rational drug discovery approach. Unlike traditional hit-to-lead campaigns that typically optimize activity and selectivity for a single target, polypharmacological drugs aim to selectively target multiple proteins, while avoiding critical off target interactions. This strategy bears promise of improved efficacy and reduced clinical attrition. This review seeks to investigate whether the bioactivity of resveratrol is due to a polypharmacological effect or promiscuity of the phenolic small molecule by examining the modes of binding with its diverse collection of protein targets. We focused on annotated targets, identified via the ChEMBL database, and matched these targets to a representative structure deposited in the Protein Data Bank (PDB), as crystal structures are most informative in understanding modes of binding at the atomic level. We discuss the structural aspects of resveratrol itself that permits binding to multiple proteins in various signaling pathways. Furthermore, we suggest that resveratrol's bioactivity is a result of scaffold promiscuity rather than polypharmacology, and the variety of binding modes across targets display little similarity in the pattern of target interaction. PMID- 30405418 TI - Da-Bu-Yin-Wan Improves the Ameliorative Effect of DJ-1 on Mitochondrial Dysfunction Through Augmenting the Akt Phosphorylation in a Cellular Model of Parkinson's Disease. AB - Da-Bu-Yin-Wan (DBYW) is recorded originally in China over six centuries ago, and it is used to treat Parkinson's disease (PD) clinically in recent decades. DJ-1 is a homodimeric protein linked to early-onset PD, and found in the mitochondria. In addition, DJ-1 could protect the cells by regulating gene transcription and modulating the Akt signal pathways. Therefore, in this research, we aimed to investigate the ameliorative effect of DBYW on mitochondria in the view of the DJ 1 and Akt signaling. Rat adrenal pheochromocytoma cell line PC-12 was transfected with the plasmid pcDNA3-Flag-DJ-1 (pDJ-1). Subsequently, PC-12 cells were exposed to the PD-related mitochondrial toxin (1-methyl-4-phenylpyridinium) without/with the DBYW. After transfected with the plasmid pDJ-1, the 1-methyl-4 phenylpyridinium-induced toxicity was decreased, and the DJ-1 expression in protein level was increased. DJ-1 overexpression not only increased the mitochondrial mass, but also improved the total ATP content. Moreover, Akt phosphorylation was augmented by DJ-1 overexpression. Additionally, DBYW enhanced the above effects. Conclusively, these findings indicate that DBYW promotes the ameliorative effects of DJ-1 on mitochondrial dysfunction at least through augmenting the Akt phosphorylation in 1-methyl-4-phenylpyridinium-treated PC-12 cells. PMID- 30405421 TI - The Effect of Chinese Medicine on Lipid and Glucose Metabolism in Acute Myocardial Infarction Through PPARgamma Pathway. AB - Aim: Danqi Pill (DQP), a Chinese medicine frequently prescribed in China, has been approved to improve cardiac function by regulating cardiac energy metabolism in heart failure (HF) after acute myocardial infarction (AMI) patients. The aim of this study was to explore whether the mechanism of DQP is associated to the lipid and glucose metabolism mediated via PPARgamma (peroxisome proliferator activated receptor gamma) pathway both in vivo and in vitro. Materials and Methods: Model of HF after AMI was established with ligation of left anterior descending artery on Sprague-Dawley (SD) rats. Twenty-eight days after treatment, hematoxylin-eosin (HE) staining was applied to visualize cardiomyocyte morphological changes. High performance liquid chromatography (HPLC) was performed to assess the contents of adenosine phosphates in heart. Positron emission tomography and computed tomography (PET-CT) was conducted to evaluate the cardiac glucose metabolism. Expressions of key molecules such as PPARgamma, sterol carrier protein 2 (SCP2) and long chain acyl CoA dehydrogenase (ACADL) were measured by Western blotting (WB) and immunohistochemistry (IHC). Oxygen glucose deprivation-reperfusion (OGD/R)-induced H9C2 injury cardiomyocyte model was adopted for potential mechanism research in vitro. Results: Treatment with DQP rescued hearts from structural and functional damages as well as inflammatory infiltration. Levels of adenosine triphosphate (ATP) and energy charge (EC) in DQP group were also up-regulated compared to model group. Further results demonstrated that critical enzymes both in lipid metabolism and glucose metabolism compromised in model group compared to sham group. Intriguingly, DQP could up-regulate critical enzymes including ACADL and SCP2 in lipid metabolism accompanying with promoting effect on molecules in glycolysis simultaneously. Results on upstreaming signaling pathway demonstrated that DQP could dramatically increase the expressions of PPARgamma. In vitro study suggested the efficacy of DQP could be blocked by T0070907, a selective PPARgamma inhibitor. Conclusion: DQP has cardioprotective effect in improving cardiac function and energy metabolism through regulating lipid and glucose metabolism. The effects may be mediated by PPARgamma pathway. PMID- 30405419 TI - Investigating Different Mechanisms of Action in Combination Therapy for Influenza. AB - Combination therapy for influenza can have several benefits, from reducing the emergence of drug resistant virus strains to decreasing the cost of antivirals. However, there are currently only two classes of antivirals approved for use against influenza, limiting the possible combinations that can be considered for treatment. However, new antivirals are being developed that target different parts of the viral replication cycle, and their potential for use in combination therapy should be considered. The role of antiviral mechanism of action in the effectiveness of combination therapy has not yet been systematically investigated to determine whether certain antiviral mechanisms of action pair well in combination. Here, we use a mathematical model of influenza to model combination treatment with antivirals having different mechanisms of action to measure peak viral load, infection duration, and synergy of different drug combinations. We find that antivirals that lower the infection rate and antivirals that increase the duration of the eclipse phase perform poorly in combination with other antivirals. PMID- 30405422 TI - Icariside II Ameliorates Cognitive Impairments Induced by Chronic Cerebral Hypoperfusion by Inhibiting the Amyloidogenic Pathway: Involvement of BDNF/TrkB/CREB Signaling and Up-Regulation of PPARalpha and PPARgamma in Rats. AB - Chronic cerebral hypoperfusion (CCH) is regarded as a high-risk factor for cognitive decline of vascular dementia (VD) as it is conducive to induce beta amyloid (Abeta) aggregation. Icariside II (ICS II), a plant-derived flavonoid compound, has showed neuroprotective effect on animal models of Alzheimer's disease (AD) by decreasing Abeta levels. Here, we assessed the effect of ICS II on CCH-induced cognitive deficits and Abeta levels in rats, and the possible underlying mechanisms were also explored. It was disclosed that CCH induced by bilateral common carotid artery occlusion (BCCAO) caused cognitive deficits, neuronal injury and increase of Abeta1-40 and Abeta1-42 levels in the rat hippocampus, while oral administration of ICS II for 28 days abolished the above deficits in the hippocampus of BCCAO rats. Meanwhile, ICS II significantly decreased the expression of beta-amyloid precursor protein (APP) and beta-site amyloid precursor protein cleavage enzyme 1 (BACE1), as well as increased the expression of a disintegrin and metalloproteinase domain 10 (ADAM10) and insulin degrading enzyme (IDE). ICS II also activated peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma, enhanced the expression of brain-derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TrkB), levels of Akt and cAMP response element binding protein (CREB) phosphorylation. Together, these findings suggested that ICS II attenuates CCH-induced cognitive deficits by inhibiting the amyloidogenic pathway via involvement of BDNF/TrkB/CREB signaling and up-regulation of PPARalpha and PPARgamma in rats. PMID- 30405420 TI - Targeted Intracellular Delivery of Antibodies: The State of the Art. AB - A dominant area of antibody research is the extension of the use of this mighty experimental and therapeutic tool for the specific detection of molecules for diagnostics, visualization, and activity blocking. Despite the ability to raise antibodies against different proteins, numerous applications of antibodies in basic research fields, clinical practice, and biotechnology are restricted to permeabilized cells or extracellular antigens, such as membrane or secreted proteins. With the exception of small groups of autoantibodies, natural antibodies to intracellular targets cannot be used within living cells. This excludes the scope of a major class of intracellular targets, including some infamous cancer-associated molecules. Some of these targets are still not druggable via small molecules because of large flat contact areas and the absence of deep hydrophobic pockets in which small molecules can insert and perturb their activity. Thus, the development of technologies for the targeted intracellular delivery of antibodies, their fragments, or antibody-like molecules is extremely important. Various strategies for intracellular targeting of antibodies via protein-transduction domains or their mimics, liposomes, polymer vesicles, and viral envelopes, are reviewed in this article. The pitfalls, challenges, and perspectives of these technologies are discussed. PMID- 30405423 TI - Semaphorins and Their Receptors: From Axonal Guidance to Atherosclerosis. AB - Semaphorins are a large family of secreted, transmembrane, or GPI-anchored proteins initially identified as axon guidance cues signaling through their receptors, neuropilins, and plexins. Emerging evidence suggests that beyond the guidance, they also function in a broad spectrum of pathophysiological conditions, including atherosclerosis, a vascular inflammatory disease. Particular semaphorin members have been demonstrated to participate in atherosclerosis via eliciting endothelial dysfunction, leukocyte infiltration, monocyte-macrophage retention, platelet hyperreactivity, and neovascularization. In this review, we focus on the role of those semaphorin family members in the development of atherosclerosis and highlight the mechanistic relevance of semaphorins to atherogenesis. PMID- 30405425 TI - Comparison of Aerobic Scope for Metabolic Activity in Aquatic Ectotherms With Temperature Related Metabolic Stimulation: A Novel Approach for Aerobic Power Budget. AB - Considering that swim-flume or chasing methods fail in the estimation of maximum metabolic rate and in the estimation of Aerobic Scope (AS) of sedentary or sluggish aquatic ectotherms, we propose a novel conceptual approach in which high metabolic rates can be obtained through stimulation of organism metabolic activity using high and low non-lethal temperatures that induce high (HMR) and low metabolic rates (LMR), This method was defined as TIMR: Temperature Induced Metabolic Rate, designed to obtain an aerobic power budget based on temperature induced metabolic scope which may mirror thermal metabolic scope (TMS = HMR-LMR). Prior to use, the researcher should know the critical thermal maximum (CT max) and minimum (CT min) of animals, and calculate temperature TIMR max (at temperatures -5-10% below CT max) and TIMR min (at temperatures +5-10% above CT min), or choose a high and low non-lethal temperature that provoke a higher and lower metabolic rate than observed in routine conditions. Two sets of experiments were carried out. The first compared swim-flume open respirometry and the TIMR protocol using Centropomus undecimalis (snook), an endurance swimmer, acclimated at different temperatures. Results showed that independent of the method used and of the magnitude of the metabolic response, a similar relationship between maximum metabolic budget and acclimation temperature was observed, demonstrating that the TIMR method allows the identification of TMS. The second evaluated the effect of acclimation temperature in snook, semi-sedentary yellow tail (Ocyurus chrysurus), and sedentary clownfish (Amphiprion ocellaris), using TIMR and the chasing method. Both methods produced similar maximum metabolic rates in snook and yellowtail fish, but strong differences became visible in clownfish. In clownfish, the TIMR method led to a significantly higher TMS than the chasing method indicating that chasing may not fully exploit the aerobic power budget in sedentary species. Thus, the TIMR method provides an alternative way to estimate the difference between high and low metabolic activity under different acclimation conditions that, although not equivalent to AS may allow the standardized estimation of TMS that is relevant for sedentary species where measurement of AS via maximal swimming is inappropriate. PMID- 30405424 TI - Modeling Skeletal Muscle Laminopathies Using Human Induced Pluripotent Stem Cells Carrying Pathogenic LMNA Mutations. AB - Laminopathies are a clinically heterogeneous group of disorders caused by mutations in LMNA. The main proteins encoded by LMNA are Lamin A and C, which together with Lamin B1 and B2, form the nuclear lamina: a mesh-like structure located underneath the inner nuclear membrane. Laminopathies show striking tissue specificity, with subtypes affecting striated muscle, peripheral nerve, and adipose tissue, while others cause multisystem disease with accelerated aging. Although several pathogenic mechanisms have been proposed, the exact pathophysiology of laminopathies remains unclear, compounded by the rarity of these disorders and lack of easily accessible cell types to study. To overcome this limitation, we used induced pluripotent stem cells (iPSCs) from patients with skeletal muscle laminopathies such as LMNA-related congenital muscular dystrophy and limb-girdle muscular dystrophy 1B, to model disease phenotypes in vitro. iPSCs can be derived from readily accessible cell types, have unlimited proliferation potential and can be differentiated into cell types that would otherwise be difficult and invasive to obtain. iPSC lines from three skeletal muscle laminopathy patients were differentiated into inducible myogenic cells and myotubes. Disease-associated phenotypes were observed in these cells, including abnormal nuclear shape and mislocalization of nuclear lamina proteins. Nuclear abnormalities were less pronounced in monolayer cultures of terminally differentiated skeletal myotubes than in proliferating myogenic cells. Notably, skeletal myogenic differentiation of LMNA-mutant iPSCs in artificial muscle constructs improved detection of myonuclear abnormalities compared to conventional monolayer cultures across multiple pathogenic genotypes, providing a high-fidelity modeling platform for skeletal muscle laminopathies. Our results lay the foundation for future iPSC-based therapy development and screening platforms for skeletal muscle laminopathies. PMID- 30405426 TI - Prevalence of Non-responders for Blood Pressure and Cardiometabolic Risk Factors Among Prehypertensive Women After Long-Term High-Intensity Interval Training. AB - Background: Exercise is known to improve cardiometabolic outcomes; however, results are typically reported as mean values, and there is wide interindividual variability in terms of response that has not been explored in populations at risk for hypertension. Our aim was to investigate both the effects on and the prevalence of non-responders (NRs) for decreasing blood pressure (BP) and other risk factors among prehypertensive women after long-term high-intensity interval training (HIIT). A secondary aim was to report potential variables that can predict decreases in BP after HIIT. Methods: Sedentary overweight/obese women (age 35.9 +/- 5.4 year; body mass index [BMI] 30.9 +/- 6.2 kg/m2) were assigned to a prehypertensive (PreHTN; N = 44) or normotensive (NT; N = 40) group according to their ambulatory BP at baseline. Subjects underwent a thrice-weekly 16-week HIIT program (7-10 * 1 min exercise with 2 min of rest). Training-induced changes in body composition and cardiovascular, metabolic, strength, and endurance performance markers were measured, and the prevalence of NRs was reported as a percentage. All outcomes were analyzed by multivariable regression. Results: Statistically significant (P < 0.05) decreases in systolic BP (SBP) were detected in the PreHTN group (Delta -8 mmHg) compared with baseline, whereas the NT group (Delta + 3 mmHg) showed a non-significant increase in SBP. Diastolic BP (DBP) was significantly decreased in the PreHTN group (Delta -5.8 mmHg) and non significantly decreased (Delta -2 mmHg) in the NT group. Also, there were significant differences (P < 0.0001) in the prevalence of NRs based on SBP between the PreHTN and NT groups (11.4 vs. 68.8%), but similar prevalence of NRs based on DBP. SBP alone was a powerful predictive factor for a beneficial SBP reduction, explaining 51.2% of the results, which was similar to other more complex models tested. Conclusion: The prevalence of NRs based on SBP and DBP was different between prehypertensive and normotensive subjects after 16 weeks of HIIT. Other comorbidities such as body composition and metabolic outcomes showed almost similar modifications between prehypertensive and normotensive subjects, being the most basic predictive factor for BP reduction baseline SBP, which we refer to as 'BP health status' (51.2%). This improvement in BP was accompanied by other known improvements of HIIT on body composition, metabolic and endurance performance in both study cohorts. Trial Registration: ClinicalTrials.gov ID: NCT03000140 (Register 20 December, 2016). PMID- 30405428 TI - Commentary: Contextualising Maximal Fat Oxidation During Exercise: Determinants and Normative Values. PMID- 30405427 TI - Female Mice Have Higher Angiogenesis in Perigonadal Adipose Tissue Than Males in Response to High-Fat Diet. AB - Background: Impaired capillary growth (angiogenesis) in skeletal muscle and adipose tissue contributes to the development of metabolic disorders in obese males. This association remains unexplored in females, despite mounting evidence that endothelial cells have sex-specific transcriptional profiles. Therefore, herein we assessed whether males and females show distinct angiogenic capacities in response to diet-induced obesity. Methods: Age-matched male and female mice were fed normal chow or high-fat obesogenic diets for 16 weeks. At the end of diet period, systemic glucose disposal was assessed as well as insulin sensitivity of skeletal muscle and visceral adipose tissue. Capillary content and the expression of angiogenic regulators were also evaluated in these tissues. Results: When placed on a high-fat diet, female mice gained less weight than males and showed a metabolic phenotype similar to NC-fed mice, contrasting with the impaired whole-body glucose metabolism observed in high-fat-fed males. However, high-fat-feeding elevated serum lipid levels similarly in male and female mice. Although skeletal muscle of high-fat-fed female mice had higher insulin sensitivity than male counterparts, no sex difference was detected in muscle capillarization. Metabolic functions of perigonadal white adipose tissue (pgWAT) were retained in high-fat-fed females, as evidenced by smaller adipocytes with preserved insulin sensitivity, greater responsiveness to isoproterenol, higher expression of Adiponectin and a lower ratio of Leptin:Adiponectin mRNA. An enhanced browning phenotype was detected in HF-fed female adipocytes with upregulation of Ucp1 expression. PgWAT from high-fat-fed females also showed augmented capillary number and expression of endothelial cell markers, which was associated with elevated mRNA levels of pro-angiogenic mediators, including vascular endothelial growth factor A (Vegfa) and its receptor (Vegfr2), the Notch ligand Jagged-1 (Jag1) and Angiopoietin-2 (Angpt2). Conclusion: Taken together, our findings provide novel evidence that visceral adipose tissue of female mice display greater levels of pro-angiogenic factors and vascularity than males in response to high-fat diet. This phenotype is associated with preserved metabolic homeostasis at both tissue and systemic levels. Our study discloses that a thus far-unappreciated sex-specific difference in the regulation of adipose angiogenesis may contribute to an individual's susceptibility to developing adipose dysfunction and obesity-related metabolic disturbances. PMID- 30405429 TI - Local Mammary Glucose Supply Regulates Availability and Intracellular Metabolic Pathways of Glucose in the Mammary Gland of Lactating Dairy Goats Under Malnutrition of Energy. AB - As glucose is the regulator of both the milk yield and mammary oxidative status, glucose supply is considered to play important nutritional and physiological role on mammary gland (MG) metabolism. However, inconsistent results were observed from different infusion methods to evaluate the effect of glucose on MG glucose metabolism. Thus, precise method should be developed to learn how availability and intracellular metabolic pathways of glucose in the MG are altered by the direct mammary glucose supply. In addition, limited information is available on the role of mammary glucose supply in milk synthesis in lactating ruminants under an energy-deficient diet. Direct glucose supply to the MG was implemented in the current study through the external pudendal artery infusion under an energy deficient diet. Six doses of glucose (0, 20, 40, 60, 80, and 100 g/d) were infused through the external pudendal arteries, which is the main artery to the MG, to six lactating goats fed with basal diet meeting 81% energy requirement in a 6 * 6 Latin square design. Milk and lactose yields were both quadratically increased with increased glucose infusion, whereas the milk yield changed inconsistently with the increased energy balance (EB), indicating local glucose supply, rather than EB, improved milk production. Glucose fluxes in the MG were significantly increased and correlated with mammary plasma flow. However, the ratio of lactose yield to glucose absorbed by the MG was significantly decreased. The increased glucose fluxes in the MG and changed glucose-related metabolites in milk indicated that the glucose availability and intracellular metabolic pathways was regulated by local mammary glucose. Acute glycolysis consumed the superfluous glucose and induced accumulation of oxygen radicals in the MG during over supplied glucose conditions. The present study provided insight to optimal glucose supply to the MG during the lactation. PMID- 30405430 TI - Influence of Magnitude and Duration of Altered Gravity and Readaptation to 1 g on the Structure and Function of the Utricle in Toadfish, Opsanus tau. AB - Gravity has remained constant during animal evolution and the neural sensory systems detecting acceleration forces have remained remarkably conserved among vertebrates. The utricular organ senses the sum of inertial force due to head translation and head tilt relative to gravitational vertical. Change in gravitational force would be expected to have profound effects on how an organism maintains equilibrium. We characterize the physiology of utricular afferents to applied accelerations in the oyster toadfish, Opsanus tau, in normal 1 g to establish benchmarks, after 1-32-day exposures to 2.24 g (resultant) via centrifugation (hypergravity, HG), after 4- and 16-day exposures to 1.12 g (resultant), and following 1-8 days recovery to HG exposures to study re adaptation to 1 g. Afferents were also examined during activation of efferent vestibular pathway. Centrifugation at 2.24 g included 228 degrees /s constant angular velocity component, and thus horizontal canal afferent responses to yaw rotation were recorded as an internal control in each fish. Afferents studied after 228 degrees /s rotation for 4 and 16 days without centripetal acceleration, called On-Center-Control, were indistinguishable from their control counterparts. Principal response to HG was an adjustment of afferent sensitivity as a function of magnitude and duration of exposure: an initial robust increase at 3-4 days followed by a significant decrease from 16 to 32 days. Initial increase observed after 4 days of HG took >4 days in 1 g to recover, and the decrease observed after 16 days of HG took >2 days to readapt to 1 g. Hair cells in striola and medial extrastriola macula regions were serially reconstructed in 3D from thin sections using transmission electron microscopy in control fish and fish exposed to 4 and 16 days of HG. Despite the highly significant differences in afferent physiology, synaptic body counts quantified in the same fish were equivalent in their inter-animal variability and averages. No clear role of the efferent pathway as a feedback mechanism regulating afferent behavior to HG was found. Transfer from 1 g to HG imparts profound effects on gravitational sensitivity of utricular afferents and the accompanying transfer from the HG back to the 1 g resembles in part (as an analog) the transfer from 1 g to the micrograms. PMID- 30405432 TI - Shining New Light on the Structural Determinants of Cardiac Couplon Function: Insights From Ten Years of Nanoscale Microscopy. AB - Remodelling of the membranes and protein clustering patterns during the pathogenesis of cardiomyopathies has renewed the interest in spatial visualisation of these structures in cardiomyocytes. Coincidental emergence of single molecule (super-resolution) imaging and tomographic electron microscopy tools in the last decade have led to a number of new observations on the structural features of the couplons, the primary sites of excitation-contraction coupling in the heart. In particular, super-resolution and tomographic electron micrographs have revised and refined the classical views of the nanoscale geometries of couplons, t-tubules and the organisation of the principal calcium handling proteins in both healthy and failing hearts. These methods have also allowed the visualisation of some features which were too small to be detected with conventional microscopy tools. With new analytical capabilities such as single-protein mapping, in situ protein quantification, correlative and live cell imaging we are now observing an unprecedented interest in adapting these research tools across the cardiac biophysical research discipline. In this article, we review the depth of the new insights that have been enabled by these tools toward understanding the structure and function of the cardiac couplon. We outline the major challenges that remain in these experiments and emerging avenues of research which will be enabled by these technologies. PMID- 30405431 TI - Novel Insights Into the Role of Glycans in the Pathophysiology of Glomerular Endotheliosis in Preeclampsia. AB - The polysaccharide heparan sulfate is ubiquitously expressed as a proteoglycan in extracellular matrices and on cell surfaces. In the glomerular filtration barrier, the action of the heparan sulfate is directly related to the function of glomerular filtration, mostly attributed to the sulfated domains that occur along the polysaccharide chain, as evidenced by fact that release of fragments of heparan sulfate by heparanase significantly increases the permeability of albumin passage through the glomerular endothelium, event that originates proteinuria. This review aims to show the importance of the structural domains of heparan sulfate in the process of selective permeability and to demonstrate how these domains may be altered during the glomerular inflammation processes that occur in preeclampsia. PMID- 30405434 TI - Two Novel Short Peptidoglycan Recognition Proteins (PGRPs) From the Deep Sea Vesicomyidae Clam Archivesica packardana: Identification, Recombinant Expression and Bioactivity. AB - Vesicomyidae clams are common species living in cold seeps, which incorporates symbiotic bacteria into their body maintaining endosymbiosis relationship. As members of pattern recognition receptor (PRR) family, peptidoglycan recognition proteins (PGRPs) recognize pathogen associated molecular patterns and play an important role in innate immunity. In present study, two short PGRPs (ApPGRP-1 and -2) were first identified from Vesicomyidae clam Archivesica packardana. Sequences analysis showed that they have both conserved Zn2+ binding sites (H-H C) and amidase catalytic sites (H-Y-H-T-C), and phylogenetic tree indicated that they clustered with short PGRPs of other molluscs. PGN assay showed that ApPGRPs could bind Lys-type PGN from Staphylococcus aureus and Dap-type PGN from Bacillus subtilis, and revealed amidase activity with selective zinc ion dependence. rApPGRP-1 and -2 (recombinant ApPGRP-1 and -2) could bind six bacteria with a broad spectrum and had both zinc-dependent and -independent bactericidal activity. ApPGRPs had the complete functions of effectors and partial functions of receptors from PGRPs. Further analyses showed that ApPGRPs from A. packardana might be involved in the endosymbiosis relationship between the host clam and endosymbiotic bacteria as a regulator. The results of these experiments suggested that ApPGRPs were involved in cold seep clams' immune response. This study provides basic information for further research on the immune mechanisms of deep sea organisms. PMID- 30405435 TI - Isolation of High-Purity Extracellular Vesicles by the Combination of Iodixanol Density Gradient Ultracentrifugation and Bind-Elute Chromatography From Blood Plasma. AB - Background: Extracellular vesicles (EVs) (isolated from blood plasma) are currently being extensively researched, both as biomarkers and for their therapeutic possibilities. One challenging aspect to this research is the efficient isolation of high-purity EVs from blood plasma in quantities sufficient for in vivo experiments. In accordance with this challenge, the aim of this study was to develop an isolation method in which to separate the majority of EVs from major impurities such as lipoprotein particles and the abundant plasma proteins albumin and fibrinogen. Methods: Samples of rat blood were centrifuged to remove cells, platelets, large EVs and protein aggregates without prior filtration. Density gradient ultracentrifugation was performed by loading plasma sample onto 50, 30, and 10% iodixanol layers and then centrifuged at 120,000 *g for 24 h. Ten fractions (F1-10) were collected from top to bottom. Fractions with the highest EV content were further purified by ultracentrifugation, size exclusion, or bind elute chromatography. Efficiency and purity were assessed by Western blots. Morphology and size distribution of particles were examined by dynamic light scattering and electron microscopy (EM). Results: The highest band intensities of EV markers Alix, Tsg101 and CD81 were detected by Western blot in F6 of small scale DGUC (61.5 +/- 10.4%; 48.1 +/- 5.8%; 41.9 +/- 3.8%, respectively) at a density of 1.128-1.174 g/mL, where the presence of vesicles with a mean diameter of 38 +/- 2 nm was confirmed by EM and DLS. Only 1.4 +/- 0.5% of LDL and chylomicron marker, 3.0 +/- 1.3% of HDL marker, and 9.9 +/- 0.4% of albumin remained in the EV-rich F6. However, 32.8 +/- 1.5% of the total fibrinogen beta was found in this fraction. Second-step purification by UC or SEC did not improve EV separation, while after BEC on HiScreen Capto Core 700 albumin and lipoprotein contamination were below detection limit in EV-rich fractions. However, BEC decreased efficiency of EV isolation, and fibrinogen was still present in EV-rich fractions. Conclusion: This is the first demonstration that DGUC is able to markedly reduce the lipoprotein content of EV isolates while it separates EVs with high efficiency. Moreover, isolation of lipoprotein- and albumin-free EVs from blood plasma can be achieved by DGUC followed by BEC, however, on the expense of reduced EV yield. PMID- 30405433 TI - The Role of Sodium in Diabetic Cardiomyopathy. AB - Cardiovascular complications are the major cause of mortality and morbidity in diabetic patients. The changes in myocardial structure and function associated with diabetes are collectively called diabetic cardiomyopathy. Numerous molecular mechanisms have been proposed that could contribute to the development of diabetic cardiomyopathy and have been studied in various animal models of type 1 or type 2 diabetes. The current review focuses on the role of sodium (Na+) in diabetic cardiomyopathy and provides unique data on the linkage between Na+ flux and energy metabolism, studied with non-invasive 23Na, and 31P-NMR spectroscopy, polarography, and mass spectroscopy. 23Na NMR studies allow determination of the intracellular and extracellular Na+ pools by splitting the total Na+ peak into two resonances after the addition of a shift reagent to the perfusate. Using this technology, we found that intracellular Na+ is approximately two times higher in diabetic cardiomyocytes than in control possibly due to combined changes in the activity of Na+-K+ pump, Na+/H+ exchanger 1 (NHE1) and Na+-glucose cotransporter. We hypothesized that the increase in Na+ activates the mitochondrial membrane Na+/Ca2+ exchanger, which leads to a loss of intramitochondrial Ca2+, with a subsequent alteration in mitochondrial bioenergetics and function. Using isolated mitochondria, we showed that the addition of Na+ (1-10 mM) led to a dose dependent decrease in oxidative phosphorylation and that this effect was reversed by providing extramitochondrial Ca2+ or by inhibiting the mitochondrial Na+/Ca2+ exchanger with diltiazem. Similar experiments with 31P-NMR in isolated superfused mitochondria embedded in agarose beads showed that Na+ (3-30 mM) led to significantly decreased ATP levels and that this effect was stronger in diabetic rats. These data suggest that in diabetic cardiomyocytes, increased Na+ leads to abnormalities in oxidative phosphorylation and a subsequent decrease in ATP levels. In support of these data, using 31P-NMR, we showed that the baseline beta ATP and phosphocreatine (PCr) were lower in diabetic cardiomyocytes than in control, suggesting that diabetic cardiomyocytes have depressed bioenergetic function. Thus, both altered intracellular Na+ levels and bioenergetics and their interactions may significantly contribute to the pathology of diabetic cardiomyopathy. PMID- 30405437 TI - Leg Press vs. Smith Machine: Quadriceps Activation and Overall Perceived Effort Profiles. AB - First aim was describing Smith machine squat and leg press exercise as nominal load, knee extensors activity, and rating of perceived exertion. Second aim was developing predictive equations to provide same muscular activation and same perceived exertion nominal loads during the two exercises. To do that, vastus lateralis and vastus medialis activation, as their summed surface electromyography signal integrals, and overall perceived exertions were measured at different nominal loads during Smith machine squat and leg press exercise in adult male athletes experienced in weight training. Correlation and multistep stepwise analyses were performed. Then, two different results-driven predictive equations to provide same electromyography signals and same perceived exertion nominal loads were developed. The same electromyography signal equation results were less accurate (i.e., less predictive) due to high inter-individual differences, whereas the same perceived exertion equation results were more accurate, because perceived exertion is more related to the Smith machine squat and leg press exercise overall level of exertion than to the two single muscles that were investigated. In conclusion, these two equations represented an initial attempt to provide athletes and coaches with a new tool to mutually convert equivalent nominal loads during Smith machine squat and leg press exercise over a training period. PMID- 30405436 TI - Sex Differences in the Temporal Recovery of Neuromuscular Function Following Resistance Training in Resistance Trained Men and Women 18 to 35 Years. AB - To investigate sex differences in the temporal recovery of neuromuscular function following resistance training (RT), eleven men and eight women 18-35 years completed a single RT bout (barbell back-squats, 80 % 1RM, 5 sets * 5 reps, 25 % duty cycle, then 1 set * max reps). Measures of muscle function (isometric, concentric, eccentric knee extensor strength, and countermovement jump (CMJ) height), serum creatine kinase activity (CK) and lower-body muscle pain were assessed before RT (0 h), +4 h, +24 h, +48 h, and +72 h post-RT. Data are mean % change from PRE (SD) and effect size (omega2, d). Men and women had similar RT experience (men, 2.1 (0.8) years vs. women 2.4 (1.0) years, P = 0.746, and d = 0.3) and 1RM strength per kg lean mass (men, 1.9 (0.2) kg?kg-1 vs. women, 1.8 (0.3) kg?kg-1, P = 0.303, and d = 0.3). A 36 (12)% increase in lower-body muscle pain was reported following RT (P < 0.05, d > 0.9). There was an absence of any overt change in CK [+24 h, 74 (41) IU?L-1; pooled mean (SD)]. Decrements in knee extensor strength and CMJ height were observed +4 to +72 h for both men and women (P < 0.05, omega2 = 0.19-0.69). Sex differences were apparent for CMJ height (+24 h men, -10 (6)% vs. women, -20 (11)%, P < 0.001, and d = 1.8) and isokinetic concentric strength (+24 h men, -10 (13)% vs. women -25 (14)%, P = 0.006, and d = 1.8), with a more pronounced loss and prolonged recovery in women compared to men (e.g., CMJ + 72 h men, -3 (6)% vs. women, -13 (12)%, P = 0.051, and d = 1.1). We conclude that the different temporal recovery patterns between men and women are not explicable by differences in muscle strength, RT performance, experience, muscle damage or fatigability. PMID- 30405439 TI - Acute Effects of an Ergometer-Based Dryland Alpine Skiing Specific High Intensity Interval Training. AB - Introduction: To establish an alpine ski racing (ASR) specific dryland high intensity training protocol (HIT), we set out to analyze cardiorespiratory and metabolic responses of three ASR specific HIT modes using a ski ergometer compared with a running HIT. Methods: Ten healthy international FIS level subjects (18 +/- 1 years) performed an incremental running VO2max test, three different ASR specific HIT modes [slalom (SL), giant slalom (GS), and SL/GS mix] and a running HIT with measurements of VO2, heart rate (HR), blood lactate, and rate of perceived exertion (RPE). The HIT protocols included 15 * 1-min intervals with >90% HRmax and 30 s active rest. Furthermore, one elite alpine skier performed an 8-week, 17 session HIT block using the SL/GS mixed mode. Results: Running HIT resulted in greater VO2peak and whole-body RPE compared with the three ASR-specific HIT modes. During all four exercise modes participants were able to reach exercise intensities high enough to be classified as HIT (>90% HRmax and >89% VO2max). Legs RPE was similar between the four HIT modes, while arms RPE was higher for the ski-specific HIT. For all studied parameters, similar results for the three skiing specific HIT modes were observed. The 8-week HIT block was feasible for the athlete and resulted in an 11% increase in VO2max at unchanged peak power output. Conclusion: Across all HIT protocols high cardiorespiratory and metabolic responses were achieved. Therefore, the ASR specific HIT was shown to be feasible, thus could offer new possibilities for endurance training in elite alpine skiers. It is suggested to use the SL/GS mixed mode in terms of movement variety. The reduced VO2 in the ski-specific modifications can be attributed to the concentric and eccentric muscle activity resulting in mechanical hindrance for O2 extraction. The long-term effectiveness of ASR specific HIT in elite alpine skiers needs to be proven in a future study. PMID- 30405438 TI - Arrhythmogenic Substrates for Atrial Fibrillation in Obesity. AB - Global obesity rates have nearly tripled since 1975. This obesity rate increase is mirrored by increases in atrial fibrillation (AF) that now impacts nearly 10% of Americans over the age of 65. Numerous epidemiologic studies have linked incidence of AF and obesity and other obesity-related diseases, including hypertension and diabetes. Due to the wealth of epidemiologic data linking AF with obesity-related disease, mechanisms of AF pathogenesis in the context of obesity are an area of ongoing investigation. However, progress has been somewhat slowed by the complex phenotype of obesity; separating the effects of obesity from those of related sequelae is problematic. While the initiation of pathogenic pathways leading to AF varies with disease (including increased glycosylation in diabetes, increased renin angiotensin aldosterone system activation in hypertension, atrial ischemia in coronary artery disease, and sleep apnea) the pathogenesis of AF is united by shared mediators of altered conduction in the atria. We suggest focusing on these downstream mediators of AF in obesity is likely to yield more broadly applicable data. In the context of obesity, AF is driven by the interrelated processes of inflammation, atrial remodeling, and oxidative stress. Obesity is characterized by a constant low-grade inflammation that leads to increased expression of pro-inflammatory cytokines. These cytokines contribute to changes in cardiomyocyte excitability. Atrial structural remodeling, including fibrosis, enlargement, and fatty infiltration is a prominent feature of AF and contributes to the altered conduction. Finally, obesity impacts oxidative stress. Within the cardiomyocyte, oxidative stress is increased through both increased production of reactive oxygen species and by downregulation of scavenging enzymes. This increased oxidative stress modulates of cardiomyocyte excitability, increasing susceptibility to AF. Although the initiating insults vary, inflammation, atrial remodeling, and oxidative stress are conserved mechanisms in the pathophysiology of AF in the obese patients. In this review, we highlight mechanisms that have been shown to be relevant in the pathogenesis of AF across obesity-related disease. PMID- 30405441 TI - Intrapartum Fetal Heart Rate: A Possible Predictor of Neonatal Acidemia and APGAR Score. AB - Background: Predicting perinatal outcomes based on patterns of fetal heart rate (FHR) remains a challenge. The aim of this study was to evaluate intrapartum FHR variability as predictor for neonatal acidemia and APGAR score. Methods: This was a retrospective observational study of 552 childbirths. Multivariable linear regression models were used to assess the association between FHR variability and each of the following outcomes: arterial cord blood pH and base deficit, Apgar 1, and 5 scores. Variables used for adjustment were maternal age, comorbidities (gestational diabetes, preeclampsia, maternal fever, and hypertension), parity, gravidity, uterine contractions, and newborn gestational age, and weight at birth. Results: The following factors were associated with an increased risk of metabolic acidosis and low Apgar scores at birth: increased mean and coefficient of variation (CV) of the FHR, type of delivery and decreased parity. Each 10 beat/min increase in the FHR was associated with an increase of 0.43 mEq/L in the base deficit, and a decrease of 0.01 in the pH, 0.2 in the Apgar 1, and 0.14 in the Apgar 5 scores. Each 10% increase in the CV of the FHR was associated with an increase of 4.05 mEq/L in the base deficit and a decrease of 0.13 in the pH, 1.31 in the Apgar 1, and 0.86 in the Apgar 5 scores. Conclusion: These data suggest the intrapartum FHR variability is physiologically relevant and can be used for predicting the acidemia and Apgar scores at birth of the newborn infants without severe cases of morbidity and from uncomplicated pregnancies. PMID- 30405440 TI - Mitochondria, Oxidative Stress and Innate Immunity. AB - Canonical functions of mitochondria include the regulation of cellular survival, orchestration of anabolic and metabolic pathways, as well as reactive oxygen species (ROS) signaling. Recent discoveries, nevertheless, have demonstrated that mitochondria are also critical elements to stimulate innate immune signaling cascade that is able to intensify the inflammation upon cytotoxic stimuli beyond microbial infection. Here we review the expanding research field of mitochondria and oxidative stress in innate immune system to highlight the new mechanistic insights and discuss the pathological relevance of mitochondrial dysregulation induced aberrant innate immune responses in a growing list of sterile inflammatory diseases. PMID- 30405442 TI - Barttin Regulates the Subcellular Localization and Posttranslational Modification of Human Cl-/H+ Antiporter ClC-5. AB - Dent disease 1 (DD1) is a renal salt-wasting tubulopathy associated with mutations in the Cl-/H+ antiporter ClC-5. The disease typically manifests with proteinuria, hypercalciuria, nephrocalcinosis, and nephrolithiasis but is characterized by large phenotypic variability of no clear origin. Several DD1 cases have been reported lately with additional atypical hypokalemic metabolic alkalosis and hyperaldosteronism, symptoms usually associated with another renal disease termed Bartter syndrome (BS). Expression of the Bartter-like DD1 mutant ClC-5 G261E in HEK293T cells showed that it is retained in the ER and lacks the complex glycosylation typical for ClC-5 WT. Accordingly, the mutant abolished CLC ionic transport. Such phenotype is not unusual and is often observed also in DD1 ClC-5 mutants not associated with Bartter like phenotype. We noticed, therefore, that one type of BS is associated with mutations in the protein barttin that serves as an accessory subunit regulating the function and subcellular localization of ClC-K channels. The overlapping symptomatology of DD1 and BS, together with the homology between the proteins of the CLC family, led us to investigate whether barttin might also regulate ClC-5 transport. In HEK293T cells, we found that barttin cotransfection impairs the complex glycosylation and arrests ClC-5 in the endoplasmic reticulum. As barttin and ClC-5 are both expressed in the thin and thick ascending limbs of the Henle's loop and the collecting duct, interactions between the two proteins could potentially contribute to the phenotypic variability of DD1. Pathologic barttin mutants differentially regulated trafficking and processing of ClC-5, suggesting that the interaction between the two proteins might be relevant also for the pathophysiology of BS. Our findings show that barttin regulates the subcellular localization not only of kidney ClC-K channels but also of the ClC-5 transporter, and suggest that ClC-5 might potentially play a role not only in kidney proximal tubules but also in tubular kidney segments expressing barttin. In addition, they demonstrate that the spectrum of clinical, genetic and molecular pathophysiology investigation of DD1 should be extended. PMID- 30405443 TI - Dietary Genistein Alleviates Lipid Metabolism Disorder and Inflammatory Response in Laying Hens With Fatty Liver Syndrome. AB - This study investigated the molecular mechanism underlying the effect of dietary genistein (GEN) on fatty liver syndrome (FLS) in laying hens. Hens in the control group (CG) were fed a high-energy and low-choline (HELC) diet to establish the FLS model. The livers of the FLS hens were friable and swollen from hemorrhage. Hepatic steatosis and inflammatory cell infiltration were present around the liver blood vessels. Hens in the low-genistein (LGE) and high-genistein (he) groups were fed GEN at 40 and 400 mg/kg doses, respectively, as supplements to the HELC diet. GEN at 40 mg/kg significantly increased gonadotropin-releasing hormone (GnRH) mRNA expression in the hypothalamus, the serum estrogen (E2) level, and the laying rate, whereas 400 mg/kg of GEN decreased GnRH expression and the laying rate without significantly affecting E2, suggesting that high-dose GEN adversely affected the reproductive performance. Either high- or low-dose GEN treatment could alleviate metabolic disorders and inflammatory responses in FLS hens. GEN significantly decreased the serum ALT, creatinine, triglyceride (TG), total cholesterol (TC), and free fatty acid (FFA) levels. Accordingly, the TG and long-chain fatty acid (LCFA) levels, including long-chain saturated fatty acids (LSFAs) and monounsaturated fatty acids (MUFAs), and the n-6:n-3 polyunsaturated fatty acid (PUFA) ratio in the liver were reduced after the GEN treatments, whereas the levels of C22:0, n-3 family fatty acids, C20:3n6, and C20:4n6 were increased. These results indicated that dietary GEN downregulated the expression of genes related to fatty acid synthesis [sterol regulatory element-binding protein 1 (SREBP1c), liver X receptor alpha (LXRalpha), fatty acid synthase (FAS), and acetyl coenzyme A synthetase (ACC)] and the fatty acid transporter (FAT). Furthermore, GEN treatments upregulated the transcription of genes related to fatty acid beta-oxidation [peroxisome proliferator-activated receptor (PPAR)alpha, PPARdelta, ACOT8, ACAD8, and ACADs] in the liver and reduced PPARgamma and AFABP expression in abdominal fat. Dietary GEN alleviated inflammatory cell infiltration in the livers of FLS hens and downregulated TNF alpha, IL-6, and IL-1beta expression. Moreover, GEN treatment increased SOD activity and decreased malondialdehyde activity in the liver. In conclusion, GEN supplementation in the feed inhibited fatty acid synthesis and enhanced beta oxidation in the liver through the PPAR-ACAD/ACOT and PPAR-LXRalpha-SREBP1c ACC/FAS/FAT pathways. Dietary GEN alleviated metabolic disorder and inflammation in the FLS hens by improving the antioxidant capacity and fatty acid profile. PMID- 30405444 TI - Fibroblast Growth Factor 23 Expression Is Increased in Multiple Organs in Mice With Folic Acid-Induced Acute Kidney Injury. AB - Fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis and vitamin D metabolism. In patients with acute kidney injury (AKI), FGF23 levels rise rapidly after onset of AKI and are associated with AKI progression and increased mortality. In mouse models of AKI, excessive rise in FGF23 levels is accompanied by a moderate increase in FGF23 expression in bone. We examined the folic acid induced AKI (FA-AKI) mouse model to determine whether other organs contribute to the increase in plasma FGF23 and assessed the vitamin D axis as a possible trigger for increased Fgf23 gene expression. Twenty-four hours after initiation of FA-AKI, plasma intact FGF23 and 1,25(OH)2D were increased and kidney function declined. FA-treated mice developed renal inflammation as shown by increased Tnf and Tgfb mRNA expression. Fgf23 mRNA expression was 5- to 15-fold upregulated in thymus, spleen and heart of FA-treated mice, respectively, but only 2-fold in bone. Ectopic renal Fgf23 mRNA expression was also detected in FA-AKI mice. Plasma FGF23 and Fgf23 mRNA expression in thymus, spleen, heart, and bone strongly correlated with renal Tnf mRNA expression. Furthermore, Vdr mRNA expression was upregulated in spleen, thymus and heart and strongly correlated with Fgf23 mRNA expression in the same organ. In conclusion, the rapid rise in plasma FGF23 in FA-AKI mice is accompanied by increased Fgf23 mRNA expression in multiple organs and increased Vdr expression in extra osseous tissues together with increased plasma 1,25(OH)2D and inflammation may trigger the rise in FGF23 in FA-AKI. PMID- 30405445 TI - Normative Values for Heart Rate Variability Parameters in School-Aged Children: Simple Approach Considering Differences in Average Heart Rate. AB - Background: Heart rate variability (HRV) analysis is a clinical tool frequently used to characterize cardiac autonomic status. The aim of this study was to establish normative values for short-term HRV parameters by considering their main determinants in school-aged children. Methods: Five-minute electrocardiograms were taken from 312 non-athlete children (153 boys) at age of 6 to 13 years for computation of conventional time- and frequency-domain HRV parameters. Heart rate (HR), respiratory rate, age, body mass index, and sex were considered as their potential determinants. Multiple regression analysis revealed that HR was the principal predictor of all standard HRV indices. To develop their universal normative limits, standard HRV parameters were corrected for prevailing HR. Results: The HRV correction for HR yielded the parameters which became independent on both sex and HR, and only poorly dependent on age (with small effect size). Normal ranges were calculated for both time- and frequency-domain indices (the latter computed with either fast Fourier transform and autoregressive method). To facilitate recalculation of standard HRV parameters into corrected ones, a calculator was created and attached as a Supplementary Material that can be downloaded and used for both research and clinical purposes. Conclusion: This study provides HRV normative values for school-aged children which have been developed independently of their major determinants. The calculator accessible in the Supplementary Material can considerably simplify determination if HRV parameters accommodate within normal limits. PMID- 30405447 TI - Compound Danshen Dripping Pill Inhibits Retina Cell Apoptosis in Diabetic Rats. AB - Scope: Diabetic retinopathy (DR) is a severe microvascular complication of diabetes. Previous clinical trials have shown that Compound Danshen Dripping Pill (CDDP) improves DR symptoms. However, the mechanism involved remains unclear. Procedures: Rats fed a high-fat diet and injected with streptozotocin (STZ) were used as an experimental type 2 diabetes rodent model. CDDP was administered to two groups of diabetic rats at 0.2 and 0.4 g/kg/day via gastric gavage for 12 weeks. After the 12 weeks of treatment, retinal function was evaluated by electroretinography (ERG). Histological staining and TdT-mediated dUTP nick-end labeling (TUNEL) assays were also performed. Retinal genome expression was determined by gene array. Results: We found that CDDP moderated ERG and histological abnormalities in diabetic rats, independent of blood glucose level. A gene array showed that CDDP changed 262 genes significantly in the diabetic retina. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that differentially expressed genes in the CDDP-treated groups were involved mainly in the apoptosis pathway. Moreover, CDDP reduced the number of TUNEL positive cells in the diabetic retinas. CDDP prevented the reduction in Bcl-2 expression and the increase in BCL-2 associated X (Bax) and caspase-3 (Casp3) expression in diabetic rats. Conclusion: Our results suggest that CDDP exerts its neuroprotective functions by inhibiting cell apoptosis in diabetic rats. PMID- 30405448 TI - Neuromuscular Fatigue Does Not Impair the Rate of Force Development in Ballistic Contractions of Submaximal Amplitudes. AB - The effect of muscle fatigue on rate of force development (RFD) is usually assessed during tasks that require participants to reach as quickly as possible maximal or near-maximal force. However, endurance sports require athletes to quickly produce force of submaximal, rather than maximal, amplitudes. Thus, this study investigated the effect of muscle fatigue induced by long-distance running on the capacity to quickly produce submaximal levels of force. Twenty-one male amateur runners were evaluated before and shortly after a half-marathon race. Knee extensors force was recorded under maximal voluntary and electrically evoked contractions. Moreover, a series of ballistic contractions at different submaximal amplitudes (from 20 to 100% of maximal voluntary force) was obtained, by asking the participants to reach submaximal forces as fast as possible. The RFD was calculated for each contraction. After the race, maximal voluntary activation, resting doublet twitch, maximal force, and RFD during maximal contraction decreased (-12, -12, -21, and -19%, respectively, all P-values < 0.0001). Nevertheless, the RFD values measured during ballistic contractions up to 60% of maximal force were unaffected (all P-values > 0.4). Long-distance running impaired the capacity to quickly produce force in ballistic contractions of maximal, but not of submaximal, amplitudes. Overall, these findings suggest that central and peripheral fatigue do not affect the quickness to which muscle contracts across a wide range of submaximal forces. This is a relevant finding for running and other daily life activities that rely on the production of rapid submaximal contractions rather than maximal force levels. PMID- 30405446 TI - Triggering Endogenous Cardiac Repair and Regeneration via Extracellular Vesicle Mediated Communication. AB - A variety of paracrine signals create networks within the myocardium and mediate intercellular communications. Indeed, paracrine stimulation of the endogenous regenerative program of the heart, mainly based on resident cardiac progenitor cell (CPC) activation together with cardiomyocyte proliferation, has become increasingly relevant for future cardiac medicine. In the last years, it has been shown that extracellular vesicles (EV), including exosomes (Ex), are powerful conveyors of relevant biological effects. EV have been proposed not only as promising therapeutic tool for triggering cardiac regeneration and improving repair, but also as means of better understanding the physiological and pathological relationships between specific cardiac components, including cardiomyocytes and fibroblasts. Actually, EV from different kinds of exogenous stem cells have been shown to mediate beneficial effects on the injured myocardium. Moreover, endogenous cells, like CPC can instruct cardiovascular cell types, including cardiomyocytes, while cardiac stromal cells, especially fibroblasts, secrete EV that modulate relevant aspects of cardiomyocyte biology, such as hypertrophy and electrophysiological properties. Finally, cardiomyocytes too may release EV influencing the function of other cardiac cell types. Therefore, EV-based crosstalk is thought to be important in both physiology and pathology, being involved in the responses of the heart to noxious stimuli. In this review we will discuss the role of EV in both regulating cardiac homeostasis and driving heart regeneration. In particular, we will address their role in: (i) providing cardio-protection and enhancing cardiac repair mechanisms; (ii) CPC biology; and (iii) influencing adult cardiomyocyte behavior. PMID- 30405449 TI - Chronic Alcohol Treatment-Induced GABA-Aalpha5 Histone H3K4 Trimethylation Upregulation Leads to Increased GABA-Aalpha5 Expression and Susceptibility to Alcohol Addiction in the Offspring of Wistar Rats. AB - Gamma-aminobutyric acid (GABA)-Aalpha5 is considered to be associated with alcohol-induced memory deficits. However, whether it participates in the formation of alcohol addiction or in the regulation of its susceptibility is unknown. Here, we used a chronic alcohol treatment model to obtain alcohol addicted Wistar rats. Long-term alcoholism increased the expression of prefrontal cortex GABA-Aalpha5 by inducing its histone H3K4 trimethylation, and these changes could be hereditary and lead to increased vulnerability to alcohol addiction in offspring. This study indicates the risk of long-term alcoholism in future generations, emphasizes the importance of GABA-Aalpha5 in the formation of alcohol addiction and the regulation of its susceptibility, and provides new evidence regarding the mechanisms underlying alcohol addiction. PMID- 30405450 TI - Co-design of eHealth Interventions With Children and Young People. AB - Co-design, defined as collective creativity across the entire design process, can lead to the development of interventions that are more engaging, satisfying, and useful to potential users. However, using this methodology within the research arena requires a shift from traditional practice. Co-design of eHealth interventions with children and young people has additional challenges. This review summarizes the applied core principles of co-design and recommends techniques for undertaking co-design with children and young people. Three examples of co-design during the development of eHealth interventions (Starship Rescue, a computer game for treating anxiety in children with long-term physical conditions, a self-monitoring app for use during treatment of depression in young people, and HABITS, the development of an emotional health and substance use app, and eHealth platform for young people) are provided to illustrate the value and challenges of this contemporary process. PMID- 30405451 TI - "Opening a Door to a New Life": The Role of Forgiveness in Healing From Moral Injury. AB - For military veterans struggling with moral injury, forgiveness can become both an animating concern and a potential path to healing. In this perspective piece, we draw on our clinical work and research findings to examine why forgiveness matters to veterans who feel guilt and shame about their actions in war, what type of forgiveness is attainable and meaningful, and what role clinicians can play in facilitating forgiveness. We conclude by reflecting on the potential, as well as the limits and tensions, of forgiveness work in the context of military moral injury. PMID- 30405452 TI - Physiological Basis of the Couvade Syndrome and Peripartum Onset of Bipolar Disorder in a Man: A Case Report and a Brief Review of the Literature. AB - Rapid hormonal changes during pregnancy as well as psycho-social stressors accompanying parenthood have often been associated with peripartum mood episodes in women with bipolar disorder or with not yet clinically expressed bipolar diathesis. Yet, little is known about the correlation of peripartum onset of bipolar disorder in men. We present the case of a man with bipolar disorder with peripartum onset and subsequent episodes following the peripartum initiation of the disease, as well as the association of the couvade syndrome, as a pathological response to a man due to hormonal shifts observed in males cohabiting with a pregnant female. The patient had his first depressive episode during the peripartum period of his spouse, followed by two mixed episodes with psychotic features that leaded to his compulsory psychiatric evaluation and subsequent hospitalization and the diagnosis of Bipolar Disorder I. There is a well-known correlation between the peripartum period and mood disturbances to the point of inducing full blown episodes, suggesting of a bipolar disorder initiation or mood episodes relapsing in female patients already diagnosed with bipolar disorder. Due to the patient's psychological disturbances and the phenomenology of his symptoms, mainly concerning the psychotic features accompanying his episodes, we discuss the possible underlying biological correlates as a triggering mechanism, that might overlap the manifestation of the Couvade Syndrome as well as the initiation or relapse of Bipolar Disorder in males. It seems that males are not less influenced by hormonal and psycho-social factors posed upon them during the peripartum period of their cohabiting female spouse. PMID- 30405453 TI - Mental Training for Better Achievement: Effects of Verbal Suggestions and Evaluation (of Effectiveness) on Cognitive Performance. AB - Objective: There is only some literature regarding the influence of verbal suggestions on cognitive performance in healthy volunteers. For example, the performance in a knowledge test was enhanced when participants were told that they had subliminally received the correct answer. However, enhancing cognitive performance only via verbal suggestions without prior conditioning phases has not yet been examined. The goal of our study was therefore to investigate the effects of a mental training based on verbal suggestions compared to a control training on cognitive performance in a student population using a balanced-placebo-design. Methods: In total, 103 participants were randomly assigned either to listening to a 20 min audio-taped mental training or to a 20 min philosophy lecture (control training) via headphones. Participants were individually tested before and after the training concerning their cognitive performance. Information about the type of training were varied in both intervention conditions ("You are part of our experimental condition and you will receive an effective mental training" or "You are part of our control group and you will receive the control condition"). At the end of the assessment, participants were asked what kind of training they believed they had received and how effective they would rate the received training. Results: Overall, the cognitive performance improved in all participants, F (1, 99) = 490.01, p < 0.001. Contrary to our hypotheses, we found no interaction of the type of training and type of instruction on the cognitive performance. Participants who rated the received training as being effective at the end of the experiment (regardless if it was the mental or the control training), have before experienced a greater improvement in their cognitive performance [F (2,100) = 7.26, p = 0.001] and showed higher scores in the ability to absorb [F (2, 99) = 3.75, p = 0.027]. Conclusion: The subjects' own experiences in the task might have influenced the rating of the training rather than the actual training or the information they receive regarding the type of training. This finding underlines the relevance of enhancing the subjective beliefs and self-efficacy in situations where cognitive attention processes are important and of individually tailoring mental trainings. PMID- 30405454 TI - Understanding and Predicting Antidepressant Response: Using Animal Models to Move Toward Precision Psychiatry. AB - There are two important gaps of knowledge in depression treatment, namely the lack of biomarkers predicting response to antidepressants and the limited knowledge of the molecular mechanisms underlying clinical improvement. However, individually tailored treatment strategies and individualized prescription are greatly needed given the huge socio-economic burden of depression, the latency until clinical improvement can be observed and the response variability to a particular compound. Still, individual patient-level antidepressant treatment outcomes are highly unpredictable. In contrast to other therapeutic areas and despite tremendous efforts during the past years, the genomics era so far has failed to provide biological or genetic predictors of clinical utility for routine use in depression treatment. Specifically, we suggest to (1) shift the focus from the group patterns to individual outcomes, (2) use dimensional classifications such as Research Domain Criteria, and (3) envision better planning and improved connections between pre-clinical and clinical studies within translational research units. In contrast to studies in patients, animal models enable both searches for peripheral biosignatures predicting treatment response and in depth-analyses of the neurobiological pathways shaping individual antidepressant response in the brain. While there is a considerable number of animal models available aiming at mimicking disease-like conditions such as those seen in depressive disorder, only a limited number of preclinical or truly translational investigations is dedicated to the issue of heterogeneity seen in response to antidepressant treatment. In this mini-review, we provide an overview on the current state of knowledge and propose a framework for successful translational studies into antidepressant treatment response. PMID- 30405455 TI - Metabolic and Microbiota Measures as Peripheral Biomarkers in Major Depressive Disorder. AB - Advances in understanding the role of the microbiome in physical and mental health are at the forefront of medical research and hold potential to have a direct impact on precision medicine approaches. In the past 7 years, we have studied the role of microbiota-brain communication on behavior in mouse models using germ-free mice, mice exposed to antibiotics, and healthy specific pathogen free mice. Through our work and that of others, we have seen an amazing increase in our knowledge of how bacteria signal to the brain and the implications this has for psychiatry. Gut microbiota composition and function are influenced both by genetics, age, sex, diet, life experiences, and many other factors of psychiatric and bodily disorders and thus may act as potential biomarkers of the gut-brain axis that could be used in psychiatry and co-morbid conditions. There is a particular need in major depressive disorder and other mental illness to identify biomarkers that can stratify patients into more homogeneous groups to provide better treatment and for development of new therapeutic approaches. Peripheral outcome measures of host-microbe bidirectional communication have significant translational value as biomarkers. Enabling stratification of clinical populations, based on individual biological differences, to predict treatment response to pharmacological and non-pharmacological interventions. Here we consider the links between co-morbid metabolic syndrome and depression, focusing on biomarkers including leptin and ghrelin in combination with assessing gut microbiota composition, as a potential tool to help identify individual differences in depressed population. PMID- 30405456 TI - Gastrointestinal and Psychiatric Symptoms Among Children and Adolescents With Autism Spectrum Disorder. AB - Individuals with autism spectrum disorder (ASD) are at heightened risk of psychiatric comorbidities across the lifespan, including elevated rates of internalizing, externalizing, and self-injurious behaviors. Identification of medical comorbidities that contribute to these concerns may elucidate mechanisms through which psychiatric concerns arise, as well as offer additional avenues for intervention. Gastrointestinal (GI) conditions are of particular interest, as they are prevalent among those with ASD, may share genetic or neurobiological etiologies with the core features of ASD, and are linked with psychiatric difficulties in the general population. In this paper, we draw on data from nearly 2,800 children and adolescents with ASD within the Simons Simplex Collection to characterize the unique contributions of (1) autism symptoms, (2) psychosocial factors (child's age, sex, verbal and nonverbal IQ, adaptive behavior, race, and household income), and (3) GI concerns with respect to multiple psychiatric outcomes. Multiple regression models revealed unique contributions of ASD symptoms and multiple psychosocial factors such as verbal IQ, adaptive behavior, and family income to internalizing, externalizing, and self-injurious behavior. In general, higher levels of psychiatric symptoms were associated with more ASD symptoms, higher verbal IQ, lower adaptive behavior skills, and lower family income. Furthermore, levels of GI symptoms accounted for unique variance in psychiatric outcomes over and above these other factors, linking increased GI problems with increased psychiatric symptoms in children with ASD. Taken together, results indicate that the presence and quantity of GI symptoms should be considered when evaluating psychiatric and behavioral concerns among children with ASD, and that treatment of GI conditions may be an important component in alleviating a broad array of mental health concerns in this group. PMID- 30405457 TI - Increased Inhibition of the Amygdala by the mPFC may Reflect a Resilience Factor in Post-traumatic Stress Disorder: A Resting-State fMRI Granger Causality Analysis. AB - Purpose: To determine whether effective connectivity of the amygdala is altered in traumatized subjects with and without post-traumatic stress disorder (PTSD). Materials and Methods: Resting-state functional MRI data were obtained for 27 patients with typhoon-related PTSD, 33 trauma-exposed controls (TEC), and 30 healthy controls (HC). Effective connectivity of the bilateral amygdala was examined with Granger causality analysis and then compared between groups by conducting an analysis of variance. Results: Compared to the HC group, both the PTSD group and the TEC group showed increased effective connectivity from the amygdala to the medial prefrontal cortex (mPFC). The TEC group showed increased effective connectivity from the mPFC to the amygdala relative to the HC group. Compared to the TEC group, the PTSD group showed increased effective connectivity from the amygdala to the supplementary motor area (SMA), whereas decreased effective connectivity was detected from the SMA to the amygdala. Both the PTSD group and the TEC group showed decreased effective connectivity from the superior temporal gyrus (STG) to the amygdala relative to the HC group. Compared to the HC group, the TEC group showed increased effective connectivity from the amygdala to the dorsolateral prefrontal cortex (dlPFC), while both the PTSD group and the TEC group showed decreased effective connectivity from the dlPFC to the amygdala. The PTSD group showed decreased effective connectivity from the precuneus to the amygdala relative to both control groups, but increased effective connectivity from the amygdala to the precuneus relative to the HC group. Conclusion: Trauma leads to an increased down-top excitation from the amygdala to the mPFC and less regulation of the amygdala by the dlPFC. The results suggest that increased inhibition of the amygdala by the mPFC may reflect a resilience factor, and altered amygdala-SMA and amygdala-STG effective connectivity may reflect compensatory mechanisms of brain function. These data raise the possibility that insufficient inhibition of the amygdala by the mPFC might lead to PTSD in those who have been exposed to traumatic incidents, and may inform future therapeutic interventions. PMID- 30405458 TI - Poorer Integration of Local Orientation Information Occurs in Students With High Schizotypal Personality Traits. AB - Contour integration is impaired in schizophrenia patients, even at the first episode, but little is known about visual integration abilities prior to illness onset. To examine this issue, we compared undergraduate students high and low in schizotypal personality traits, reflecting putative liability to psychosis, on two psychophysical tasks assessing local and global stages of the integration process. The Radial Frequency Jittered Orientation Tolerance (RFJOT) task measures tolerance to orientation noise at the local signal level, when judging global stimulus orientation, whilst the Radial Frequency Integration Task (RFIT) measures the ability to globally integrate the local signals that have been extracted during shape discrimination. Positive schizotypy was assessed with the Perceptual Aberration (PAb) scale from the Wisconsin Schizotypy Scales-Brief. On the RFJOT task, the High PAb group (n = 55) tolerated statistically significantly less noise (d = -0.494) and had a lower proportion of correct responses (d = 0.461) than the Low PAb group (n = 77). For the RFIT there was no statistically significant difference in integration abilities between the High and Low PAb groups. High and Low PAb groups also differed on other positive and disorganized (but not negative) schizotypy traits, hence poorer performance on the RFJOT may not be solely related to unusual perceptual experiences. These findings suggest that difficulties with local noise tolerance but not global integration occur in healthy young adults with high levels of schizotypal personality traits, and may be worth investigating as a marker of risk for schizophrenia. PMID- 30405460 TI - Aberrant Anterior Thalamic Radiation Structure in Bipolar Disorder: A Diffusion Tensor Tractography Study. AB - Disrupted white matter (WM) integrity in the anterior thalamic radiation (ATR) has been identified in individuals with bipolar disorder (BD). We explored whether structural WM aberration in the ATR could be visually evaluated by diffusion tensor tractography (DTT). The study comprised 114 participants, including 57 patients with BD and 57 healthy controls (HCs). A poorly visualized ATR reflects an abnormal WM structure. We defined a poorly visualized ATR as one in which at least one ATR fiber bundle failed to reach to the boundary between gray and white matter. Poor ATR visualization occurred significantly more frequently in the left ATR of those with BD than in HCs (P = 0.042). Furthermore, we adjusted the fractional anisotropy (FA) value and when evaluation of a given ATR changed from good to poor, we defined that value as the optimal FA threshold. In the right ATR, we successfully classified BD and HCs with 71.1% accuracy (sensitivity = 89.5% and specificity = 52.6%) and an area under the curve of 0.76 using the optimal FA threshold of 0.28. The present results suggest that the optimal FA threshold can serve as a biological marker that distinguishes individuals with BD from HCs. Thus, visual evaluation of the ATR by DTT may prove to be a useful adjunctive diagnostic tool for BD in clinical practice. PMID- 30405459 TI - Inferior Frontal Gyrus Volume Loss Distinguishes Between Autism and (Comorbid) Attention-Deficit/Hyperactivity Disorder-A FreeSurfer Analysis in Children. AB - Objective: Autism spectrum (ASD) and attention-deficit/hyperactivity disorder (ADHD) are neurodevelopmental disorders with a high rate of comorbidity. To date, diagnosis is based on clinical presentation and distinct reliable biomarkers have been identified neither for ASD nor ADHD. Most previous neuroimaging studies investigated ASD and ADHD separately. Method: To address the question of structural brain differences between ASD and ADHD, we performed FreeSurfer analysis in a sample of children with ADHD (n = 30), with high-functioning ASD (n = 14), with comorbid high-functioning ASD and ADHD (n = 15), and of typically developed controls (TD; n = 36). With FreeSurfer, an automated brain imaging processing and analyzing suite, we reconstructed the cerebral cortex and calculated gray matter volumes as well as cortical surface parameters in terms of cortical thickness and mean curvature. Results: A significant main effect of the factor ADHD was detected for the left inferior frontal gyrus (Pars orbitalis) volume, with the ADHD group exhibiting smaller Pars orbitalis volumes. Dimensional measures of autism (SRS total raw score) and ADHD (DISYPS-II FBB-ADHD score) had no significant influence on the left Pars orbitalis volume. Both, ASD and ADHD tended to have an effect on cortical thickness or mean curvature, which did not survive correction for multiple comparisons. Conclusion: Our results underline that ADHD rather than ASD is associated with volume loss in the left inferior frontal gyrus (Pars orbitalis). This area might play a relevant role in modulating symptoms of inattention and/or impulsivity in ADHD. The effect of comorbid ADHD in ASD samples and vice versa, on cortical thickness and mean curvature, requires further investigation in larger samples. PMID- 30405461 TI - Support Vector Machine Classification of Obsessive-Compulsive Disorder Based on Whole-Brain Volumetry and Diffusion Tensor Imaging. AB - Magnetic resonance imaging (MRI) methods have been used to detect cerebral anatomical distinction between obsessive-compulsive disorder (OCD) patients and healthy controls (HC). Machine learning approach allows for the possibility of discriminating patients on the individual level. However, few studies have used this automatic technique based on multiple modalities to identify potential biomarkers of OCD. High-resolution structural MRI and diffusion tensor imaging (DTI) data were acquired from 48 OCD patients and 45 well-matched HC. Gray matter volume (GMV), white matter volume (WMV), fractional anisotropy (FA), and mean diffusivity (MD) were extracted as four features were examined using support vector machine (SVM). Ten brain regions of each feature contributed most to the classification were also estimated. Using different algorithms, the classifier achieved accuracies of 72.08, 61.29, 80.65, and 77.42% for GMV, WMV, FA, and MD, respectively. The most discriminative gray matter regions that contributed to the classification were mainly distributed in the orbitofronto-striatal "affective" circuit, the dorsolateral, prefronto-striatal "executive" circuit and the cerebellum. For WMV feature and the two feature sets of DTI, the shared regions contributed the most to the discrimination mainly included the uncinate fasciculus, the cingulum in the hippocampus, corticospinal tract, as well as cerebellar peduncle. Based on whole-brain volumetry and DTI images, SVM algorithm revealed high accuracies for distinguishing OCD patients from healthy subjects at the individual level. Computer-aided method is capable of providing accurate diagnostic information and might provide a new perspective for clinical diagnosis of OCD. PMID- 30405463 TI - Commentary: Mechanical Pain Thresholds and the Rubber Hand Illusion. PMID- 30405462 TI - Chronic Stress Disturbs Metabolome of Blood Plasma and Urine in Diabetic Rats. AB - About 30% of diabetes patients suffer from varying degrees of depression. Diabetes itself is associated with abnormal carbohydrate and energy metabolism. Whether chronic stress-induced depression-like behavior impacts the metabolome of blood plasma and urine in diabetes is not clear. This study aimed to investigate the effect of chronic stress on metabolome of plasma and urine in spontaneously diabetic Goto-Kakizaki (GK) rats. The GK rats were subjected to 8 weeks' chronic unpredictable mild stress (CUMS) to induce depression-like behavior. Metabolome analysis of blood plasma and urine using liquid chromatography mass spectrometry (LC/MS) was performed. Multivariate data analysis was used to evaluate the data. Behavior and biochemical assay confirmed the successful establishment of CUMS induced depression-like behavior model in rats. Disturbance of 20 plasma metabolites and 16 urine metabolites were altered in CUMS-induced depression GK rats as compared to control ones. These disturbed metabolites were involved in fatty acid metabolism, sphingolipid metabolism, phenylalanine metabolism, citrate cycle, glycolysis, glutathione metabolism, and nicotinate and nicotinamide metabolism. This study suggest that chronic stress-induced depression-like behavior may further disturb diabetes-itself energy metabolome. The plasma and urine lipid metabolites monitoring may be useful for early detection of depression in patients with diabetes mellitus. PMID- 30405464 TI - Metacognitive Beliefs Predict Greater Mental Contamination Severity After an Evoking Source. AB - Mental contamination occurs when individuals experience feelings of internal dirtiness and distress in the absence of physical contact with a contaminant. Women who experience sexual trauma frequently report mental contamination. The self-regulatory executive function (S-REF) model proposes that metacognitive beliefs contribute to the appraisal and regulation of thinking, leading to expectations that metacognitive beliefs would predict greater mental contamination severity following an evoking source. Women who reported directly experiencing sexual trauma (N = 102) completed self-report measures of metacognitive beliefs and covariates during an online study session, and subsequently completed a task that evoked mental contamination during a follow-up in-person study session. Metacognitive beliefs surrounding the uncontrollability and danger of thoughts, cognitive confidence, and the need to control thoughts positively correlated with mental contamination severity following the evoking source. Metacognitive beliefs surrounding the uncontrollability and danger of thoughts predicted greater mental contamination severity following the evoking source in multivariate analyses that statistically controlled for baseline mental contamination severity, trait anxiety, and overlap among the metacognitive beliefs. The present results provide preliminary support for the S-REF model as a potential framework for conceptualizing mental contamination. PMID- 30405465 TI - Editorial: Language Acquisition in Diverse Linguistic, Social and Cognitive Circumstances. PMID- 30405466 TI - How Do French-English Bilinguals Pull Verb Particle Constructions Off? Factors Influencing Second Language Processing of Unfamiliar Structures at the Syntax Semantics Interface. AB - An important challenge in bilingualism research is to understand the mechanisms underlying sentence processing in a second language and whether they are comparable to those underlying native processing. Here, we focus on verb-particle constructions (VPCs) that are among the most difficult elements to acquire in L2 English. The verb and the particle form a unit, which often has a non compositional meaning (e.g., look up or chew out), making the combined structure semantically opaque. However, bilinguals with higher levels of English proficiency can develop a good knowledge of the semantic properties of VPCs (Blais and Gonnerman, 2013). A second difficulty is that in a sentence context, the particle can be shifted after the direct object of the verb (e.g., The professor looked it up). The processing is more challenging when the object is long (e.g., The professor looked the student's last name up). This shifted structure favors syntactic processing at the expense of VPC semantic processing. We sought to determine whether or not bilinguals' reading time (RT) patterns would be similar to those observed for native monolinguals (Gonnerman and Hayes, 2005) when reading VPCs in sentential contexts. French-English bilinguals were tested for English language proficiency, working memory and explicit VPC semantic knowledge. During a self-paced reading task, participants read 78 sentences with VPCs that varied according to parameters that influence native speakers' reading dynamics: verb-particle transparency, particle adjacency and length of the object noun phrase (NP; 2, 3, or 5 words). RTs in a critical region that included verbs, NPs and particles were measured. Results revealed that RTs were modulated by participants' English proficiency, with higher proficiency associated with shorter RTs. Examining participants' explicit semantic knowledge of VPCs and working memory, only readers with more native-like knowledge of VPCs and a high working memory presented RT patterns that were similar to those of monolinguals. Therefore, given the necessary lexical and computational resources, bilingual processing of novel structures at the syntax-semantics interface follows the principles influencing native processing. The findings are in keeping with theories that postulate similar representations and processing in L1 and L2 modulated by processing difficulty. PMID- 30405467 TI - Lift Me Up by Looking Down: Social Comparison Effects of Narratives. AB - Stories are a powerful means to change recipients' views on themselves by being transported into the story world and by identifying with story characters. Previous studies showed that recipients temporarily change in line with a story and its characters (assimilation). Conversely, assimilation might be less likely when recipients are less identified with story protagonists or less transported into a story by comparing themselves with a story character. This may lead to changes, which are opposite to a story and its characters (contrast). In two experiments, we manipulated transportation and experience taking via two written reviews (Experiment 1; N = 164) and by varying the perspective of the story's narrator (Experiment 2; N = 79) of a short story about a negligent student. Recipients' self-ratings in comparison to others, motives, and problem-solving behavior served as dependent variables. However, neither the review nor the perspective manipulation affected transportation or experience taking while reading the story. Against our expectations, highly transported recipients (in Study 1) and recipients with high experience taking (in Study 2) showed more persistency working on an anagram-solving task, even when controlling for trait conscientiousness. Our findings are critically discussed in light of previous research. PMID- 30405468 TI - Some Pieces Are Missing: Implicature Production in Children. AB - Until at least 4 years of age, children, unlike adults, interpret some as compatible with all. The inability to draw the pragmatic inference leading to interpret some as not all, could be taken to indicate a delay in pragmatic abilities, despite evidence of other early pragmatic skills. However, little is known about how the production of these implicature develops. We conducted a corpus study on early production and perception of the scalar term some in British English. Children's utterances containing some were extracted from the dense corpora of five children aged 2;00 to 5;01 (N = 5,276), and analysed alongside a portion of their caregivers' utterances with some (N = 9,030). These were coded into structural and contextual categories allowing for judgments on the probability of a scalar implicature being intended. The findings indicate that children begin producing and interpreting implicatures in a pragmatic way during their third year of life, shortly after they first produce some. Their production of some implicatures is low but matches their parents' input in frequency. Interestingly, the mothers' production of implicatures also increases as a function of the children's age. The data suggest that as soon as they acquire some, children are fully competent in its production and mirror adult production. The contrast between the very early implicature production we find and the relatively late implicature comprehension established in the literature calls for an explanation; possibly in terms of the processing cost of implicature derivation. Additionally, some is multifaceted, and thus, implicatures are infrequent, and structurally and contextually constrained in both populations. PMID- 30405469 TI - Naturalizing Phenomenology: A Must Have? AB - Quite a few cognitive scientists are working toward a naturalization of phenomenology. Looking more closely at the relevant literature, however, the 'naturalizing phenomenology' proposals show the presence of different conceptions, assumptions, and formalisms, further differentiated by different philosophical and/or scientific concerns. This paper shows that the original Husserlian stance is deeper, clearer and more advanced than most supposed contemporary improvements. The recent achievements of experimental phenomenology show how to 'naturalize' phenomenology without destroying the guiding assumptions of phenomenology. The requirements grounding the scientific explanation of subjective experience are discussed, such as the nature of the stimuli, their variables, and their manipulation by properly phenomenological methods. PMID- 30405470 TI - Toward a Unification of the Arts. AB - This article presents a manifesto for the scientific exploration of the arts in their totality, rather than conceiving of each artform independently on its own terms. In order to achieve this, I present an analytical procedure that is comprised of two related steps. The first step is to identify instances of sharing in the production mechanisms across artforms, for example the occurrence of rhythmic structure in music, dance, and poetry. The second is to examine how this sharing creates "affordances for combinations," making it possible for music to be set to a poem or for dance movements to be choreographed to music. By elucidating the neurocognitive mechanisms of sharing across arts domains and the affordances that they offer for creating combinations, it should be possible to achieve a unification of the arts. PMID- 30405471 TI - Use a Spoon as a Spade?: Changes in the Upper and Lower Alpha Bands in Evaluating Alternate Object Use. AB - Previous electrophysiological research on human creative cognition has related creative ideation to increased activity in the alpha band, an effect which mainly reflects increased general attentional demands. Research on alpha unrelated to creativity has revealed different functional roles of the upper (semantic processes) and lower (attentional processes) alpha sub-bands. At the same time, the need to dissect creative thinking into specific cognitive operations, such as, semantic processing, re-representation, or conceptual expansion has become evident. The main aim of the reported study was to test whether increased semantic processing demands linked to creating conceptual re-representations of objects required for evaluating alternate uses modulate activity in the upper and/or lower alpha sub-bands. For this purpose, we performed an alternate use evaluation task (AUeT), in which participants saw word pairs representing common uses, alternate uses, and unrelated word pairs, and evaluated whether a given use was common or uncommon (question 1), and how usable it was (question 2). Such an approach allowed us to examine the time-course of semantic processing involved in evaluating alternate uses. Additionally, the results could be contrasted with event-related potential (ERP) studies on creative language and semantic processing. We assumed that demands related to access and integration of semantic information needed to create a re-representation of objects (alternate uses) would be larger than in the case of common uses, which do not require creating a re-representation. This should be reflected in more activity in the alpha band in response to alternate than common uses, which was observed in the analysis of the upper alpha band over parieto-occipital sites. In the lower alpha band, more activity over the left than right anterior sites was observed for alternate uses, which might reflect increased attentional demands. Additionally, in the ERP analysis, alternate uses evoked larger N400 (400-500 ms) amplitudes than common uses, a pattern that extended to later time windows (500-1,000 ms). Overall, the results indicate increased semantic processing demands in alternate use evaluation, possibly linked to the creation of conceptual re-representations. PMID- 30405472 TI - Prognostic Value of Motor Timing in Treatment Outcome in Patients With Alcohol- and/or Cocaine Use Disorder in a Rehabilitation Program. AB - Introduction: Individuals with Substance Use Disorder (SUD) often have cognitive deficits in multiple domains, including motor timing deficits, with recovery times of up to 1 year. Cognitive deficits influence treatment outcomes and abstinence. To our knowledge, timing deficits have not been investigated with regard to treatment outcome and relapse. Methods: This prospective study tested the prognostic value of motor timing in SUD with regard to treatment outcome. The study sample consisted of 74 abstinent in-patients at a private treatment programme for drug/alcohol dependence at the Momentum Mental Healthcare clinic in Somerset West, South Africa, diagnosed with alcohol and/or cocaine dependence. Participants were tested at three points: (i) Within 72 hours of the start of the treatment programme (ii) after completion of the treatment programme at 8 weeks (measure of treatment response) through filling out self-report questionnaires and experimental motor task testing, and (iii) a third visit followed through a telephonic interview at 12-months (measure of relapse). Results: Motor timing alone predicted 27 percent of the variance in alcohol self-efficacy score change, and 25 percent variance in cocaine self-efficacy change scores at treatment completion. Specifically, spatial errors, synchronization errors and inter- response interval errors of a spatial tapping task at baseline predicted self efficacy in alcohol self-efficacy. Cocaine self-efficacy was predicted by spatial errors and contact times of a spatial tapping task at very high tempi (300 ms) only. The high rate of dropout at 12 months post-treatment did not allow for further analysis of the prognostic value of motor timing on relapse. Conclusions: The results of this investigation show us that motor timing holds prognostic value with regard to treatment outcomes. Motor timing predictors for relapse require further investigation going forward. PMID- 30405473 TI - The Prevalence of Left-Handedness Is Higher Among Individuals With Developmental Coordination Disorder Than in the General Population. AB - Many medical, psychiatric and neurological conditions have been characterized by a high prevalence of left-handedness or mixed-handedness. Several studies have indicated an elevated frequency of left-handedness in children with Developmental Coordination Disorder (DCD). However, there have been few studies explicitly exploring this relationship. The assumption is that the prevalence of left handedness in individuals with DCD is higher compared with the prevalence in the general population and resembles the prevalence described in children with other developmental disorders. Computerized searches were conducted in PubMed, PsycInfo and CINAHL databases. Thirty-eight studies were identified and included in the present review, containing handedness distributions across 1071 persons with DCD and 1,045 controls. The distribution of DCD participants across handedness categories was proved to be significantly different from that of the control group, with 14.7 and 8.1% left-handers, respectively. The prevalence of left handedness within the DCD-group is lower than that reported for ASD, and larger than in dyslexia. The elevated levels of left-handedness within the different developmental disorders supports the notion of an association between the different diagnoses. However, the present results are not sufficient to conclude anything about a common cause or underlying factor via the male hormone testosterone. The present results could act as a starting point for testing the hypothesis of such a common factor, as one of the requirements is an elevated prevalence of left-handedness, and without such considerable doubt would be cast upon the hypothesis. PMID- 30405474 TI - The Assessment of Grief in Refugees and Post-conflict Survivors: A Narrative Review of Etic and Emic Research. AB - Background: Prolonged grief disorder (PGD) is a new mental health disorder that will be recognized by the World Health Organization's disorder classification, the ICD-11, in 2018. Current assessment measures of PGD are largely based on North American and European conceptualizations of grief (etic i.e., from the perspective of the observer). However, research is emerging from communities outside of the Global North, in particular, conflict-exposed communities, exploring local models (emic i.e., from within the cultural group), assessment measures and symptoms of grief. Several reviews have found that refugees have higher rates of mental illness, defined by etic standards as depression, post traumatic stress disorder (PTSD), anxiety disorders and psychotic symptoms. Yet, presently there are no reviews documenting the assessment of PGD in refugees and post conflict survivors. Method: This narrative review will provide an overview of studies that assess grief in refugees to (1) identify current assessment measures of grief in refugees (i.e., type and frequency of questionnaires used, whether Global North-based, etic, or locally developed, emic, and the level of cultural adaptation) and (2) to document the variety and rate of grief symptoms identified with Global North standard measures and/or local measures (i.e., the endorsement of standard symptom items and the identification of culturally specific symptoms of grief). Results: This review revealed 24 studies that assessed disordered grief in refugee or post conflict samples. Studies were heterogeneous in their assessment methods; the majority (n = 17) used an etic approach, four used a combined etic/emic approach, and three used a predominantly emic approach. The rate of disordered grief was high depending on cultural adaptation approach (31-76%) and when standard etic measures were used the disordered grief rate was 32%. Conclusion: These findings will help to guide future studies to provide accurate assessment of grief in refugee and post conflict populations and has implications for improving cultural knowledge in clinical practice. PMID- 30405475 TI - Altered Neuronal Responses During an Affective Stroop Task in Adolescents With Conduct Disorder. AB - Conduct disorder (CD) is a psychiatric disorder of childhood and adolescence which has been linked to deficient emotion processing and regulation. The behavioral and neuronal correlates targeting the interaction of emotion processing and response inhibition are still under investigation. Whole-brain event-related fMRI was applied during an affective Stroop task in 39 adolescents with CD and 39 typically developing adolescents (TD). Participants were presented with an emotional stimulus (negative/neutral) followed by a Stroop task with varying cognitive load (congruent/incongruent/blank trials). fMRI analysis included standard preprocessing, region of interest analyses (amygdala, insula, ventromedial prefrontal cortex) and whole-brain analyses based on a 2(group) * 2(emotion) * 3(task) full-factorial ANOVA. Adolescents with CD made significantly more errors, while reaction times did not significantly differ compared to TD. Additionally, we observed a lack of downregulation of left amygdala activity in response to incongruent trials and increased anterior insula activity for CD relative to TD during affective Stroop task processing [cluster-level family-wise error-corrected (p < 0.05)]. Even though no three-way interaction (group * emotion * task) interaction was detected, the findings presented still provide evidence for altered neuronal underpinnings of the interaction of emotion processing and response inhibition in CD. Moreover, our results may corroborate previous evidence of emotion dysregulation as a core dysfunction in CD. Future studies shall focus on investigating the interaction of emotion processing and response inhibition in CD subgroups (e.g., variations in callous-unemotional traits, impulsivity, or anxiety). PMID- 30405477 TI - Defining Extreme Sport: Conceptions and Misconceptions. AB - One feature of how sport is defined is the distinction between extreme and non extreme sport. BASE jumping is an example of an "extreme sport" because it involves a high degree of risk, whilst swimming is classified as "non-extreme" because the risks involved are minimal. This broad definition falls short of identifying the extent of risk and ignores the psychological, social-demographic and life style variables associated with engagement in each sport. PMID- 30405476 TI - On Dynamic Pitch Benefit for Speech Recognition in Speech Masker. AB - Previous work demonstrated that dynamic pitch (i.e., pitch variation in speech) aids speech recognition in various types of noises. While this finding suggests dynamic pitch enhancement in target speech can benefit speech recognition in noise, it is of importance to know what noise characteristics affect dynamic pitch benefit, and who will benefit from enhanced dynamic pitch cues. Following our recent finding that temporal modulation in noise influences dynamic pitch benefit, we examined the effect of speech masker characteristics on dynamic pitch benefit. Specifically, the first goal of the study was to test the hypothesis that dynamic pitch benefit varies depending on the availability of pitch cues in the masker and the intelligibility of masker. The second goal of this study was to investigate whether older listeners as a group can benefit from dynamic pitch for speech recognition in speech maskers. In addition, individual factors of hearing loss and working memory capacity were examined for their impact on older listeners' dynamic pitch benefit. Twenty-three younger listeners with normal hearing and 37 older listeners with varying levels of hearing sensitivity participated the study, in which speech reception thresholds were measured with sentences in speech maskers. While we did not find an effect of masker characteristics on dynamic pitch benefit, the results showed older listeners can benefit from dynamic pitch for recognizing speech in speech maskers. The data also suggest that among those older listeners with hearing loss, dynamic pitch benefit is stronger for individuals with higher working memory capacity. This can be attributed to their ability to exploit facilitated lexical access in processing of degraded speech signal. PMID- 30405478 TI - The Effect of Speech Variability on Tonal Language Speakers' Second Language Lexical Tone Learning. AB - Speech variability facilitates non-tonal language speakers' lexical tone learning. However, it remains unknown whether tonal language speakers can also benefit from speech variability while learning second language (L2) lexical tones. Researchers also reported that the effectiveness of speech variability was only shown on learning new items. Considering that the first language (L1) and L2 probably share similar tonal categories, the present study hypothesizes that speech variability only promotes the tonal language speakers' acquisition of L2 tones that are different from the tones in their L1. To test this hypothesis, the present study trained native Mandarin (a tonal language) speakers to learn Cantonese tones with either high variability (HV) or low variability (LV) speech materials, and then compared their learning performance. The results partially supported this hypothesis: only Mandarin subjects' productions of Cantonese low level and mid level tones benefited from the speech variability. They probably relied on the mental representations in L1 to learn the Cantonese tones that had similar Mandarin counterparts. This learning strategy limited the impact of speech variability. Furthermore, the results also revealed a discrepancy between L2 perception and production. The perception improvement may not necessarily lead to an improvement in production. PMID- 30405479 TI - Effects of Exogenous Auditory Attention on Temporal and Spectral Resolution. AB - Previous research in the visual domain suggests that exogenous attention in form of peripheral cueing increases spatial but lowers temporal resolution. It is unclear whether this effect transfers to other sensory modalities. Here, we tested the effects of exogenous attention on temporal and spectral resolution in the auditory domain. Eighteen young, normal-hearing adults were tested in both gap and frequency change detection tasks with exogenous cuing. Benefits of valid cuing were only present in the gap detection task while costs of invalid cuing were observed in both tasks. Our results suggest that exogenous attention in the auditory system improves temporal resolution without compromising spectral resolution. PMID- 30405480 TI - The Mediating Role of Conceptions of Learning in the Relationship Between Metacognitive Skills/Strategies and Academic Outcomes Among Middle-School Students. AB - This study investigated the mediating role of conceptions of learning in the relationship between metacognitive skills/strategies and academic outcomes among middle-school students. The self-report "Learning Conceptions Questionnaire" (LCQ) and "Metacognitive questionnaire on the method of study" (QMS-in Italian) were administered to 136 middle-school students and their academic outcomes were collected. Correlation analyses revealed that within metacognitive skills/strategies only self-assessment was positively correlated with academic outcomes. Mediation analysis indicated that a conception of learning as internal attribution of success and failure was significantly involved as mediator in the relationship between metacognitive skills/strategies and academic outcomes. This study permitted to advance our knowledge about the relationship between metacognitive skills/strategies and academic outcomes and it has opened the way to practical implications. PMID- 30405481 TI - The Multiple Determinants of Maternal Parenting Stress 12 Months After Birth: The Contribution of Antenatal Attachment Style, Adverse Childhood Experiences, and Infant Temperament. AB - Parenting stress can influence caregiving behavior negatively, which in turn may harm children's development. Identifying precursors of parenting stress, preferably beginning during pregnancy and throughout the first year of life, is therefore important. The present study aims to provide novel knowledge on this issue through a detailed examination of the association between maternal attachment style and later parenting stress. Moreover, we examine the role of several additional risk factors, specificially the mothers' own adverse childhood experiences (ACE), as well as infants' temperamental characteristics. Data from a community based longitudinal study of 1,036 Norwegian mothers, collected during pregnancy and 12 months after childbirth, were used. Results showed that attachment style in pregnancy predicted parenting stress 1 year after birth. In addition, it was demonstrated that the mothers' own ACEs predicted postnatal parenting stress, and that attachment style operated as a mediator of this association. A significant association between perceived infant temperament and parenting stress was also found. The study illustrates the importance of understanding the multifactorial antecedents of parenting stress. The results may inform early intervention efforts aimed at supporting mothers and their partners in the potentially difficult transition period around childbirth. PMID- 30405482 TI - Subjective Discomfort of TMS Predicts Reaction Times Differences in Published Studies. PMID- 30405483 TI - Unintended Negative Effects of the Legitimacy-Seeking Behavior of Social Enterprises on Employee Attitudes. AB - In an emerging field such as social enterprise, it is important for an organization to secure legitimacy to obtain resources and sustain its business. Specifically, when a government distributing subsidies does not have adequate information to decide which organization is trustworthy, it is the legitimacy seeking activities of a social enterprise that determines who receives a subsidy; this, in turn, decides which organization will survive. One of the most effective ways to gain legitimacy is to explicitly emphasize in the public promotion that the organization devotes to its social mission. In the case of Work Integration Social Enterprises (WISEs), an organization emphasizes its social employment of the disadvantaged individuals. However, we argue that social enterprises' public promotion that emphasizes social employment can lower the expected wage, job satisfaction, and organizational commitment of the employees who are hired due to their disadvantaged social status. This is because such obvious promotional messages makes the employees more keenly aware of their disadvantaged status; as a result, this reinforces their self-prejudice that they are not competitive enough in the labor market. We test our hypotheses in the context of South Korean WISEs and found general support for our arguments. PMID- 30405485 TI - Cats Parallel Great Apes and Corvids in Motor Self-Regulation - Not Brain but Material Size Matters. AB - The inhibition of unproductive motor movements is regarded as a fundamental cognitive mechanism. Recently it has been shown that species with large absolute brain size or high numbers of pallial neurons, like great apes and corvids, show the highest performance on a task purportedly measuring this mechanism: the cylinder task. In this task the subject must detour a perpendicularly oriented transparent cylinder to reach a reward through a side opening, instead of directly reaching for it and bumping into the front, which is regarded as an inhibitory failure. Here we test domestic cats, for the first time, and show that they can reach the same levels as great apes and corvids on this task, despite having much smaller brains. We tested subjects with apparatuses that varied in size (cylinder length and diameter) and material (glass or plastic), and found that subjects performed best on the large cylinders. As numbers of successes decreased significantly when the cylinders were smaller, we conducted additionally two experiments to discern which properties (length of the transparent surface, goal distance from the surface, size of the side opening) affects performance. We conclude that sensorimotor requirements, which differ between species, may have large impact on the results in such seemingly simple and apparently comparable tests. However, we also conclude that cats have comparably high levels of motor self-regulation, despite the differences between tests. PMID- 30405484 TI - Contribution of Developmental Psychology to the Study of Social Interactions: Some Factors in Play, Joint Attention and Joint Action and Implications for Robotics. AB - Children exchange information through multiple modalities, including verbal communication, gestures and social gaze and they gradually learn to plan their behavior and coordinate successfully with their partners. The development of joint attention and joint action, especially in the context of social play, provides rich opportunities for describing the characteristics of interactions that can lead to shared outcomes. In the present work, we argue that human-robot interactions (HRI) can benefit from these developmental studies, through influencing the human's perception and interpretation of the robot's behavior. We thus endeavor to describe some components that could be implemented in the robot to strengthen the feeling of dealing with a social agent, and therefore improve the success of collaborative tasks. Focusing in particular on motor precision, coordination, and anticipatory planning, we discuss the question of complexity in HRI. In the context of joint activities, we highlight the necessity of (1) considering multiple speech acts involving multimodal communication (both verbal and non-verbal signals), and (2) analyzing separately the forms and functions of communication. Finally, we examine some challenges related to robot competencies, such as the issue of language and symbol grounding, which might be tackled by bringing together expertise of researchers in developmental psychology and robotics. PMID- 30405486 TI - Reconstruction of Autobiographical Memories of Violent Sexual-Affective Relationships Through Scientific Reading on Love: A Psycho-Educational Intervention to Prevent Gender Violence. AB - Violence in sexual-affective relationships among teens and young people is recognized as a social, educational, and health problem that has increased worldwide in recent years. Educational institutions, as central developmental contexts in adolescence, are key in preventing and responding to gender violence through implementing successful actions. In order to scientifically support that task, the research reported in this article presents and discusses a psycho educational intervention focused on autobiographical memory reconstruction that proved to be successful in raising young women's critical consciousness about the force of the coercive discourse upon sexual-affective experiences and memories. We examined among a sample of young women (n = 32, age range 17-30) whether reading a scholarly text about love, the Radical Love book, modified autobiographical memories of violent sexual-affective relationships in line with preventing future victimization. This group was compared with a control group (n = 31, age range 17-30). Memory reports were collected before and after the reading and coded to analyze their content, both quantitatively and qualitatively. Memory quality features were assessed with the Memory Quality Questionnaire (MMQ). A focus group was also conducted to examine the personal impact of the intervention on participants. Compared with controls, the experimental group had stronger critical memories (of episodes involving violence), an average decrease in positive emotions induced by recall, and an average increase in negative emotions. The results show the effectiveness of the reading intervention designed in relation to gender violence prevention, as they indicate the ability of the psycho-educational action to debilitate the force of the coercive discourse in young women's memories. The findings both advance knowledge on the reconstructive nature of autobiographical memories of violent sexual-affective relationships in female youth and indicate the potential of memory-based interventions as an instrument to prevent and reduce gender violence in school contexts. Teachers and teaching staff, and educational psychologists, among others, can benefit from these results by expanding the tools they have to address gender violence among female adolescents and youth. PMID- 30405487 TI - Bidialectalism and Bilingualism: Exploring the Role of Language Similarity as a Link Between Linguistic Ability and Executive Control. AB - The notion of bilingual advantages in executive functions (EF) is based on the assumption that the demands posed by cross-language interference serve as EF training. These training effects should be more pronounced the more cross language interference bilinguals have to overcome when managing their two languages. In the present study, we investigated the proposed link between linguistic and EF performance using the similarity between the two languages spoken since childhood as a proxy for different levels of cross-language interference. We assessed the effect of linearly increasing language dissimilarity on linguistic and EF performance in multiple tasks in four groups of young adults (aged 18-33): German monolinguals (n = 24), bidialectals (n = 25; German and Swiss German dialect), bilinguals speaking two languages of the same Indo-European ancestry (n = 24; e.g., German-English), or bilinguals speaking two languages of different ancestry (n = 24; e.g., German-Turkish). Bayesian linear mixed effects modeling revealed substantial evidence for a linear effect of language similarity on linguistic accuracy, with better performance for participants with more similar languages and monolinguals. However, we did not obtain evidence for the presence of a similarity effect on EF performance. Furthermore, language experience did not modulate EF performance, even when testing the effect of continuous indicators of bilingualism (e.g., age of acquisition, proficiency, daily foreign language usage). These findings question the theoretical assumption that life-long experience in managing cross-language interference serves as EF training. PMID- 30405488 TI - Does Extreme Language Control Training Improve Cognitive Control? A Comparison of Professional Interpreters, L2 Teachers and Monolinguals. AB - There is currently a lively debate in the literature whether bilingualism leads to enhanced cognitive control or not. Recent evidence suggests that knowledge of more than one language does not always suffice for the manifestation of a bilingual cognitive control advantage. As a result, ongoing research has focused on modalities of bilingual language use that may interact with the bilingual advantage. In this study, we explored the cognitive control performance of simultaneous interpreters. These highly proficient bilinguals comprehend information in one language while producing in the other language, which is a complex skill requiring high levels of language control. In a first experiment, we compared professional interpreters to monolinguals. Data were collected on interference suppression (flanker task), prepotent response inhibition (Simon task), and short-term memory (digit span task). The results showed that the professional interpreters performed similarly to the monolinguals on all measures. In Experiment 2, we compared professional interpreters to monolinguals and second language teachers. Data were collected on interference suppression (advanced flanker task), prepotent response inhibition (advanced flanker task), attention (advanced flanker task), short-term memory (Hebb repetition paradigm), and updating (n-back task). We found converging evidence for our finding that experience in interpreting may not lead to superior interference suppression, prepotent response inhibition, and short-term memory. In fact, our results showed that the professional interpreters performed similarly to both the monolinguals and the second language teachers on all tested cognitive control measures. We did, however, find anecdotal evidence for a (small) advantage in short-term memory for interpreters relative to monolinguals when analyzing composite scores of both experiments together. Taken together, the results of the current study suggest that interpreter experience does not necessarily lead to general cognitive control advantages. However, there may be small interpreter advantages in short-term memory, suggesting that this might be an important cognitive control aspect of simultaneous interpreting. The results are discussed in the light of ongoing debates about bilingual cognitive control advantages. PMID- 30405490 TI - Materialism, Self-Objectification, and Capitalization of Sexual Attractiveness Increase Young Chinese Women's Willingness to Consider Cosmetic Surgery. AB - Research reveals significant positive associations between materialism and cosmetic surgery consideration, yet little is known about why this relationship exists. To address this question, the present study examined potential mediators of the links between materialism and cosmetic surgery consideration. A sample of 336 Chinese undergraduate women completed measures of materialism, self objectification, capitalization of sexual attractiveness, and cosmetic surgery consideration. Correlational analysis showed that materialism, self objectification, and capitalization of sexual attractiveness were significantly positively correlated with cosmetic surgery consideration. The results of path analyses revealed that higher materialism predicted more willingness to consider cosmetic surgery, both directly and indirectly via higher self-objectification and capitalization of sexual attractiveness. PMID- 30405492 TI - From Growth Mindset to Grit in Chinese Schools: The Mediating Roles of Learning Motivations. AB - Growth mindset and grit have attracted much attention in educational research recently. Yet the underlying mechanisms that relate these variables to each other as well as to other variables remain largely unclear. This study investigates the relationships among growth mindset, learning motivations, and grit. We recruited a total of 1,842 students (884 males and 958 females) from third to ninth grade in a Chinese city. Results from the structural equation model analyzing the students' responses showed that learning motivations partially mediate the relationship between growth mindset and grit. Specifically, intrinsic motivation and identified regulation of extrinsic motivation are positively associated with growth mindset and grit, while external regulation of extrinsic motivation is negatively associated with them. Additionally, introjected regulation of extrinsic motivation is uncorrelated with these two variables. This study furthers the understanding of the underlying mechanisms through which growth mindset and grit positively impact education. PMID- 30405491 TI - Left-Side Bias Is Observed in Sequential Matching Paradigm for Face Processing. AB - The left-side bias refers to how a chimeric face is created from the left side of a face (from the viewer's perspective) and its mirror image are considered more similar to the original face than a chimeric face created from the right side of the same face and its mirror image. Previous studies investigated the left-side bias by using the chimeric stimuli task, where the original face and chimeric face were presented simultaneously. However, it remains unclear whether left-side bias effect is observed when the original face and chimeric face are presented sequentially. We completed two experiments using the sequential matching paradigm to investigate this issue. The results from both Experiment 1 and 2 showed that participants judged the identical proportion of the left chimeric face and original face was significantly higher than that of the right chimeric face and original face, which implies that the left-side bias effect can be observed in the sequential matching paradigm for face processing. PMID- 30405493 TI - Looking at the Process: Examining Creative and Artistic Thinking in Fashion Designers on a Reality Television Show. AB - We examine creativity from a qualitative process rather than a quantitative product perspective. Our focus is on "habits of mind" (thinking dispositions) used during the creative process, and the categories we used were those of the eight Studio Habits of Mind observed in visual arts classrooms (Hetland et al., 2007, 2013). Our source of data was footage from a popular reality television show, Project Runway, in which nascent fashion designers are given garment design challenges. An entire season of the show (14 episodes) was transcribed and coded for the presence of eight Studio Habits of Mind. We found abundant evidence of all eight of these thinking dispositions in all portions of the show. We argue that the creative thinking occurring during fashion design bears strong resemblances to that which occurs in the art studio-classroom. Qualitatively created frameworks, like those of the Studio Habits of Mind, can be used to inform our understanding of creative behavior in various disciplines. PMID- 30405494 TI - Commentary: Metacognition and Perspective-Taking in Alzheimer's Disease: A Mini Review. PMID- 30405495 TI - World Single Age Records in Running From 5 km to Marathon. AB - This study investigated the relationship between race times and age, in 1-year intervals, by using the world single age records, from 5 km to marathon running (i. e., 5 km, 4 miles, 8, 10, 12, 15 km, 10 miles, 20 km, half-marathon, 25 km, 30 km, and marathon). For each race, a regression model was fitted. Effects of sex, alone and in interaction with age, and the effect of country of origin on performance were examined in a multi-variable model. The relationship between age and race time was modeled through a 4th order-polynomial function. Women achieved their best half-marathon and marathon race time, respectively, 1 year and 3 years earlier in life than men. On the contrary, in the other races, the best women performances were achieved later in life than men (i.e., 4 miles and 30 km: 2 years later, 8 km: 3 years later, 15-20-25 km: 1 year later, 10 miles: 4 years) or at the same age (i.e., 5, 10, 12 km). Moreover, age of peak performance did not change monotonically with the distance of race. For all races, except 12 km, sex differences had an absolute maximum at old ages and a relative maximum near the age of peak performance. From 8 km onward, estimated sex differences were increasing with increasing race distance. Regarding country, runners from Canada were slower than runners from the United States of America in 5 km by 00:10:05 h:min:s (p < 0.001) and in half-marathon by 00:18:43 h:min:s (p < 0.01). On the contrary, in marathon, they were 00:18:43 h:min faster (p < 0.05). Moreover, in 10 miles, runners from Great Britain were 00:02:53 h:min:s faster (p < 0.05) than runners from the United States of America. In summary, differences seem to exist in the age of peak performance between women and men and for nearly all distances sex differences showed an absolute maximum at old ages and relative maximum near the age of peak performance. Thus, these findings highlight the need for sex specific training programs, especially near the age of peak performance and for elder runners. PMID- 30405496 TI - Development and Validation of the Chinese Modesty Scale (CMS). AB - This paper describes the development and method of validation of the Chinese Modesty Scale (CMS). Based on Wang's dualistic model for value and instrumental modesty, our study employed a review of the literature, in-depth interviews, open ended investigations, and feedback from experts. An initial 14-item scale for analyzing the issue of "Chinese modesty" was developed. Then we explored the dimensions and final items of this CMS using item analysis and exploratory factor analysis (EFA) with sample 1 (n = 406). After that, we conducted a confirmatory factor analysis (CFA) to replicate the factor structure obtained through EFA with a refined, independent, 12-item scale (n = 662). Results confirmed the dualistic model (for value and instrumental modesty) on which this scale was based. That is, we found that there are two kinds of "Chinese modesty": value modesty and instrumental modesty. As a valid, reliable scale, the CMS can therefore be used to measure the "Chinese modesty" of/in different age groups. PMID- 30405489 TI - Toward the Language Oscillogenome. AB - Language has been argued to arise, both ontogenetically and phylogenetically, from specific patterns of brain wiring. We argue that it can further be shown that core features of language processing emerge from particular phasal and cross frequency coupling properties of neural oscillations; what has been referred to as the language 'oscillome.' It is expected that basic aspects of the language oscillome result from genetic guidance, what we will here call the language 'oscillogenome,' for which we will put forward a list of candidate genes. We have considered genes for altered brain rhythmicity in conditions involving language deficits: autism spectrum disorders, schizophrenia, specific language impairment and dyslexia. These selected genes map on to aspects of brain function, particularly on to neurotransmitter function. We stress that caution should be adopted in the construction of any oscillogenome, given the range of potential roles particular localized frequency bands have in cognition. Our aim is to propose a set of genome-to-language linking hypotheses that, given testing, would grant explanatory power to brain rhythms with respect to language processing and evolution. PMID- 30405497 TI - A False Trail to Follow: Differential Effects of the Facial Feedback Signals From the Upper and Lower Face on the Recognition of Micro-Expressions. AB - Micro-expressions, as fleeting facial expressions, are very important for judging people's true emotions, thus can provide an essential behavioral clue for lie and dangerous demeanor detection. From embodied accounts of cognition, we derived a novel hypothesis that facial feedback from upper and lower facial regions has differential effects on micro-expression recognition. This hypothesis was tested and supported across three studies. Specifically, the results of Study 1 showed that people became better judges of intense micro-expressions with a duration of 450 ms when the facial feedback from upper face was enhanced via a restricting gel. Additional results of Study 2 showed that the recognition accuracy of subtle micro-expressions was significantly impaired under all duration conditions (50, 150, 333, and 450 ms) when facial feedback from lower face was enhanced. In addition, the results of Study 3 also revealed that blocking the facial feedback of lower face, significantly boosted the recognition accuracy of subtle and intense micro-expressions under all duration conditions (150 and 450 ms). Together, these results highlight the role of facial feedback in judging the subtle movements of micro-expressions. PMID- 30405498 TI - Tablet Apps to Support First School Inclusion of Children With Autism Spectrum Disorders (ASD) in Mainstream Classrooms: A Pilot Study. AB - The inclusion of children with autism spectrum disorders (ASD) in mainstream classrooms is dramatically impeded by their difficulties in socio-adaptive behaviors. This paper presents a package of mobile applications consisting of both assistive and cognitive rehabilitation applications to support first school inclusion of children with ASD. These applications have been tested in a 3-month intervention in mainstream schools and at home, involving 50 participants (30 children with ASD, half of which was equipped and 20 equipped children with intellectual deficiencies). Benefits on socio-adaptive behaviors and social response in school settings, and socio-cognitive functioning have been assessed. The main results showed that equipped children with ASD improved their socio adaptive behaviors and their social-response in school settings. Both equipped groups increased their socio-cognitive functioning. PMID- 30405499 TI - Effects of Facial Expression and Facial Gender on Judgment of Trustworthiness: The Modulating Effect of Cooperative and Competitive Settings. AB - People often judge trustworthiness based on others' faces (e.g., facial expression and facial gender). However, it is unclear whether social context plays a moderating role in forming trustworthiness judgments. Based on the emotions as social information (EASI) model, differing contexts may impact the effect of facial expression; however, there is no evidence demonstrating that differing contexts will or will not influence the effect of facial gender. In this study, we used two experiments to examine how facial expression and facial gender affect facial trustworthiness judgments and whether the effects on facial trustworthiness judgments are consistent in cooperative and competitive settings. Twenty-seven undergraduates (14 female; M age = 21.81 years, SD = 2.66) participated in experiment 1. The results showed significant main effects of facial expression and facial gender as well as the interaction between them. To examine the social context effect, 28 undergraduates (18 female; M age = 20.93 years, SD = 2.94) participated in experiment 2. The results showed the main effects of facial expression, facial gender, and social context. Moreover, there was a significant interaction between facial gender and facial expression and a marginally significant interaction between social context and facial expression. These results suggest that in the process of judging facial trustworthiness, individuals' judgments are affected by both facial expression and facial gender. Furthermore, the effect of facial gender on facial trustworthiness judgments presents cross-situational stability, and the role of facial expression is influenced by the settings. These findings support and expand the EASI model. PMID- 30405500 TI - Feldenkrais 'Functional Integration' Increases Body Contact Surface in the Supine Position: A Randomized-Controlled Experimental Study. AB - Feldenkrais 'Functional Integration' (FI) is a widely used type of body work with a focus on the continuous integration of body sensations and awareness with movement. The method is, amongst others, known for improving balance in aging populations, but also for its ability to relax muscles. With participants treated in the supine position FI is potentially changing the surface area of the body in contact with the surface on which a participant is lying. So far, no prior study has assessed this claim. We evaluated objectively and subjectively if a treatment with FI would induce changes in pressure and contact surface of the body on the mat. Thirty volunteers received an individual treatment with FI, in a randomized order on both sides of the body. Pressure and contact surface was documented with the Xsensor-Measurement-System. Subjective sensations were assessed with a self report scale. Due to two parallel assessments alpha-level was adjusted to alpha = 0.025. We found that pressure and contact surface of the body on the mat significantly changed after the treatment (factor time: p < 0.0001, etap2 = 0.90). We also found that pressure and contact surface increased significantly on the left side for the group that started with the left side first (time * group p = 0.016; etap2 = 0.62), but less so on the right side for the group that started with the right side first (time * group: p = 0.056) although there was still a substantial effect size ( etap2 = 0.54). The subjective reports confirmed the physical measurements. In conclusion our results demonstrate for the first time that the treatment with the Feldenkrais method changes muscle tone leading to a more relaxed supine position with respect to pressure and contact surface on the mat. PMID- 30405501 TI - Enhancing Collaborative Ideation in Organizations. AB - Extensive research and theory has focused on organizational innovation and the organizational factors that influence that innovation. Research on teams has highlighted a similar set of factors as important for team innovation. However, these literatures have not provided a clear picture of the key factors that influence the collaborative idea exchange processes that occur in teams and organizations. The literature on collaborative ideation has provides a useful theoretical and empirical basis for understanding these processes and the conditions required for optimizing creativity in group interactions. We provide the theoretical and empirical basis for a pragmatic approach to enhancing collaborative innovation processes in various organizational settings and highlight additional research needs and future directions. PMID- 30405502 TI - On a Strategy of Advancement of TMS Based Methods for Studying NCC. PMID- 30405503 TI - Retrieval-Induced Forgetting as Motivated Cognition. AB - Recalling information from a particular category can reduce one's memory capability for related, non-retrieved information. This is known as the retrieval induced forgetting effect (RIF; Anderson et al., 1994). The present paper reviews studies that show that the RIF effect is motivated. More specifically, we describe research showing that the need for closure (NFC; the motivation to attain epistemic certainty; Kruglanski and Webster, 1996) generally enhances the RIF, because this prevents uncertainty and confusion from the intrusion of unwanted memories during selective-retrieval. However, when the content of the to be-forgotten information serves the retriever's goals, NFC reduces RIF. Overall, the present findings are consistent with the view that motivation can affect the magnitude of RIF effects which, in turn, can serve as a mechanism for reaching preferred conclusions. PMID- 30405504 TI - Math Self-Efficacy and STEM Intentions: A Person-Centered Approach. AB - Research pertaining to STEM interest and persistence continues to be a top priority in the educational research arena. The current study employed a person centered approach to examine the impact of math self-efficacy and various distal predictors, such as individuals' demographic information, beliefs about math, and social group identification, on STEM interest and intentions. Specifically, we conducted a latent profile analysis (LPA), thereby inferring three homogeneous subgroups of individuals or latent classes from their response patterns on the 18 item sources of math self-efficacy measure. Our analyses showed that individuals' ethnicity, implicit theories of math ability, and other group orientation were predictive of class membership (Mastery, Moderate, and Unconfident). We also found that there were significant differences in interest in STEM subjects, interest in STEM activities, individuals' majors, and retention grade point average across the three latent classes. Our findings support the importance of math self-efficacy in choice of major as well as overall academic performance regardless of whether a student is in a STEM field or a non-STEM field. PMID- 30405505 TI - A Longitudinal Multilevel Study of the "Social" Genotype and Diversity of the Phenotype. AB - Sociability and social domain-related behaviors have been associated with better well-being and endogenous oxytocin levels. Inspection of the literature, however, reveals that the effects between sociability and health outcomes, or between sociability and genotype, are often weak or inconsistent. In the field of personality psychology, the social phenotype is often measured by error-prone assessments based on different theoretical frameworks, which can partly explain the inconsistency of the previous findings. In this study, we evaluated the generalizability of "sociability" measures by partitioning the population variance in adulthood sociability using five indicators from three personality inventories and assessed in two to four follow-ups over a 15-year period (n = 1,573 participants, 28,323 person-observations; age range 20-50 years). Furthermore, we tested whether this variance partition would shed more light to the inconsistencies surrounding the "social" genotype, by using four genetic variants (rs1042778, rs2254298, rs53576, rs3796863) previously associated with a wide range of human social functions. Based on our results, trait (between individual) variance explained 23% of the variance in overall sociability, differences between sociability indicators explained 41%, state (within individual) variance explained 5% and measurement errors explained 32%. The genotype was associated only with the sociability indicator variance, suggesting it has specific effects on sentimentality and emotional sharing instead of reflecting general sociability. PMID- 30405507 TI - Reincarnating the Identity Theory. AB - The mind/brain identity theory is often thought to be of historical interest only, as it has allegedly been swept away by functionalism. After clarifying why and how the notion of identity implies that there is no genuine problem of explaining how the mental derives from something else, we point out that the identity theory is not necessarily a mind/brain identity theory. In fact, we propose an updated form of identity theory, or embodied identity theory, in which the identities concern not experiences and brain phenomena, but experiences and organism-environment interactions. Such an embodied identity theory retains the main ontological insight of its parent theory, and by invoking organism environment interactions, it has powerful resources to motivate why the relevant identities hold, without posing further unsolvable problems. We argue that the classical multiple realization argument against identity theory is built on not recognizing that the main claim of the identity theory concerns the relation between experience and descriptions of experience, instead of being about relations between different descriptions of experience and we show how an embodied identity theory provides an appropriate platform for making this argument. We emphasize that the embodied identity theory we propose is not ontologically reductive, and does not disregard experience. PMID- 30405506 TI - How Does Observational Learning Produce Placebo Effects? A Model Integrating Research Findings. AB - There is a growing body of evidence proving that observational learning, in addition to classical conditioning and verbal suggestions, may induce both placebo analgesia and nocebo hyperalgesia. However, much less is known about the mechanisms and factors influencing placebo effects induced by observational learning. The paper critically reviews the research findings in the field in the context of Bandura's social learning theory. We apply Bandura's taxonomy of the sources of social learning (behavioral, symbolic, and verbal modeling) and discuss the results of previous studies. Critical points in the placebo effects induced by observational learning are identified. We discuss aspects of behavior presented by the model (both verbal and non-verbal) involved in the formation of placebo effects induced by observational learning as well as the role of expectancies in this process. As a result, we propose a model that integrates the existing research findings. The model shows the main ways of transmission of pain related information from the model to the observer. It highlights the role of expectancies and the individual characteristics of the observer in formation of placebo analgesia and nocebo hyperalgesia induced by observational learning. Finally, we propose future research directions based on our model. PMID- 30405508 TI - Response: Commentary: Cognitive Behavioral Therapy vs. Eye Movement Desensitization and Reprocessing for Treating Panic Disorder: A Randomized Controlled Trial. PMID- 30405509 TI - Semantic Similarity to Known Second Language Words Impacts Learning of New Meanings. AB - Second language (L2) learners need to continually learn new L2 words as well as additional meanings of previously learned L2 words. The present study investigated the influence of semantic similarity on the growth curve of learning of artificially paired new meanings of previously known L2 words in Chinese English bilinguals. The results of a translation recognition task showed that related meanings are learned faster and more accurately than unrelated meanings. The advantage of learning related new meaning persisted and increased for a week after learning the new meanings. These results suggest that semantic similarities impact the learning of new meanings for known L2 words, and that the shared features between previously known and new meanings of a word facilitate the process of incorporating the related new meaning into the lexical semantic network. Our results are discussed under the framework of the connectionist model. PMID- 30405510 TI - Vascular Protection of Hydrogen Sulfide on Cerebral Ischemia/Reperfusion Injury in Rats. AB - This study was undertaken to demonstrate the vascular protection of exogenous and endogenous hydrogen sulfide (H2S) on cerebral ischemia/reperfusion (I/R) injury. The effect of H2S on cerebrovascular dysfunction in middle cerebral artery (MCA) and neuronal damage were measured after cerebral I/R induced by transient middle cerebral artery occlusion (MCAO) in cystathionine c-lyase (CSE) knockdown and wild-type rats. The effect of sodium hydrosulfide (NaHS, donor of exogenous H2S), L-cysteine (L-Cys, substrate of endogenous H2S), and endothelium cells on the responses of isolated MCA derived from non-ischemic rats was also evaluated to assess the underlying mechanism of H2S-mediate cerebral vasodilation. The results revealed that the contraction and dilation of MCA profoundly decreased after cerebral I/R. The vascular dysfunction became more grievous in CSE knockdown rats than in wild-type rats. Interestingly, this vascular dysfunction was significantly alleviated by NaHS supplementation. Moreover, both NaHS and L cysteine could induce remarkable relaxation in the isolated MCA, which was eliminated by co-application of potassium channel blockers ChTx and Apamin, or endothelial removal. By contrast, adding endothelium cells cultured in vitro together with ACh into the luminal perfusate could mimic non-NO and non-PGI2 relaxation in endothelium-denuded MCA, once CSE was knocked down from endothelium cells, and its effect on vasorelaxation was abolished. Furthermore, the indexes of neuronal injury were measured after cerebral I/R to confirm the neuroprotection of H2S, and we found that the neurological scores, cerebral infarction volume, brain water content, malondialdehyde content, and serum lactate dehydrogenase activity (a marker of cellular membrane integrity) were significantly higher in CSE knockdown rats than in normal control rats. It is not surprising that NaHS could alleviate the cerebral injury. These findings revealed that H2S has a protective effect on cerebral I/R injury via its upregulation of the endothelium-dependent contraction and dilation function of cerebral vessels, which may be related to activating potassium channel. PMID- 30405511 TI - Clinical Findings in a Multicenter MRI Study of Mild TBI. AB - Background: Uncertainty continues to surround mild traumatic brain injury (mTBI) diagnosis, symptoms, prognosis, and outcome due in part to a lack of objective biomarkers of injury and recovery. As mTBI gains recognition as a serious public health epidemic, there is need to identify risk factors, diagnostic tools, and imaging biomarkers to help guide diagnosis and management. Methods: One hundred and eleven patients (15-50 years old) were enrolled acutely after mTBI and followed with up to four standardized serial assessments over 3 months. Each encounter included a clinical exam, neuropsychological assessment, and magnetic resonance imaging (MRI). Chi-square and linear mixed models were used to assess changes over time and determine potential biomarkers of mTBI severity and outcome. Results: The symptoms most frequently endorsed after mTBI were headache (91%), not feeling right (89%), fatigue (86%), and feeling slowed down (84%). Of the 104 mTBI patients with a processed MRI scan, 28 (27%) subjects had white matter changes which were deemed unrelated to age, and 26 of these findings were deemed unrelated to acute trauma. Of the neuropsychological assessments tested, 5 and 6-Digit Backward Recall, the modified Balance Error Scoring System (BESS), and Immediate 5-Word Recall significantly improved longitudinally in mTBI subjects and differentiated between mTBI subjects and controls. Female sex was found to increase symptom severity scores (SSS) at every time point. Age >= 25 years was correlated with increased SSS. Subjects aged >= 25 also did not improve longitudinally on 5-Digit Backward Recall, Immediate 5-Word Recall, or Single-Leg Stance of the BESS, whereas subjects < 25 years improved significantly. Patients who reported personal history of depression, anxiety, or other psychiatric disorder had higher SSS at each time point. Conclusions: The results of this study show that 5- and 6-Digit Backward Recall, the modified BESS, and Immediate 5-Word Recall should be considered useful in demonstrating cognitive and vestibular improvement during the mTBI recovery process. Clinicians should take female sex, older age, and history of psychiatric disorder into account when managing mTBI patients. Further study is necessary to determine the true prevalence of white matter changes in people with mTBI. PMID- 30405512 TI - Robotic Arm Rehabilitation in Chronic Stroke Patients With Aphasia May Promote Speech and Language Recovery (but Effect Is Not Enhanced by Supplementary tDCS). AB - Objective: This study aimed to determine the extent to which robotic arm rehabilitation for chronic stroke may promote recovery of speech and language function in individuals with aphasia. Methods: We prospectively enrolled 17 individuals from a hemiparesis rehabilitation study pairing intensive robot assisted therapy with sham or active tDCS and evaluated their speech (N = 17) and language (N = 9) performance before and after a 12-week (36 session) treatment regimen. Performance changes were evaluated with paired t-tests comparing pre- and post-test measures. There was no speech therapy included in the treatment protocol. Results: Overall, the individuals significantly improved on measures of motor speech production from pre-test to post-test. Of the subset who performed language testing (N = 9), overall aphasia severity on a standardized aphasia battery improved from pre-test baseline to post-test. Active tDCS was not associated with greater gains than sham tDCS. Conclusions: This work indicates the importance of considering approaches to stroke rehabilitation across different domains of impairment, and warrants additional exploration of the possibility that robotic arm motor treatment may enhance rehabilitation for speech and language outcomes. Further investigation into the role of tDCS in the relationship of limb and speech/language rehabilitation is required, as active tDCS did not increase improvements over sham tDCS. PMID- 30405513 TI - Multimodal Neuroimaging Approach to Variability of Functional Connectivity in Disorders of Consciousness: A PET/MRI Pilot Study. AB - Behavioral assessments could not suffice to provide accurate diagnostic information in individuals with disorders of consciousness (DoC). Multimodal neuroimaging markers have been developed to support clinical assessments of these patients. Here we present findings obtained by hybrid fludeoxyglucose (FDG )PET/MR imaging in three severely brain-injured patients, one in an unresponsive wakefulness syndrome (UWS), one in a minimally conscious state (MCS), and one patient emerged from MCS (EMCS). Repeated behavioral assessment by means of Coma Recovery Scale-Revised and neurophysiological evaluation were performed in the two weeks before and after neuroimaging acquisition, to ascertain that clinical diagnosis was stable. The three patients underwent one imaging session, during which two resting-state fMRI (rs-fMRI) blocks were run with a temporal gap of about 30 min. rs-fMRI data were analyzed with a graph theory approach applied to nine independent networks. We also analyzed the benefits of concatenating the two acquisitions for each patient or to select for each network the graph strength map with a higher ratio of fitness. Finally, as for clinical assessment, we considered the best functional connectivity pattern for each network and correlated graph strength maps to FDG uptake. Functional connectivity analysis showed several differences between the two rs-fMRI acquisitions, affecting in a different way each network and with a different variability for the three patients, as assessed by ratio of fitness. Moreover, combined PET/fMRI analysis demonstrated a higher functional/metabolic correlation for patients in EMCS and MCS compared to UWS. In conclusion, we observed for the first time, through a test-retest approach, a variability in the appearance and temporal/spatial patterns of resting-state networks in severely brain-injured patients, proposing a new method to select the most informative connectivity pattern. PMID- 30405514 TI - Cerebral Autoregulation Is Disrupted Following a Season of Contact Sports Participation. AB - Repetitive subconcussive head impacts across a season of contact sports participation are associated with a number of deficits in brain function. To date, no research has investigated the effect of such head impact exposure on dynamic cerebral autoregulation (dCA). To address this issue, 179 elite, junior level (age 19.6 +/- 1.5 years) contact sport (ice hockey, American football) athletes were recruited for pre-season testing. Fifty-two non-concussed athletes returned for post-season testing. Fifteen non-contact sport athletes (age 20.4 +/ 2.2) also completed pre- and postseason testing. dCA was assessed via recordings of beat-by-beat mean arterial pressure (MAP) and middle cerebral artery blood velocity (MCAv) using finger photoplethysmography and transcranial Doppler ultrasound, respectively, during repetitive squat-stand maneuvers at 0.05 and 0.10 Hz. Transfer function analysis was used to determine Coherence (correlation), Gain (response amplitude), and Phase (response latency) of the MAP MCAv relationship. Results showed that in contact sport athletes, Phase was reduced (p = 0.027) and Gain increased (p < 0.001) at post-season compared to pre season during the 0.10 Hz squat-stand maneuvers, indicating cerebral autoregulatory impairment in both the latency and magnitude of the response. Changes in Phase were greater in athletes experiencing higher numbers and severity of head impacts. By contrast, no changes in dCA were observed in non contact sport controls. Taken together, these results demonstrate that repetitive subconcussive head impacts occurring across a season of contact sports participation are associated with exposure-dependent impairments in the cerebrovascular pressure-buffering system capacity. It is unknown how long these deficits persist or if they accumulate year-over-year. PMID- 30405516 TI - A Practical Score for Prediction of Outcome After Cerebral Venous Thrombosis. AB - Background: Most patients with cerebral venous thrombosis (CVT) have independent survival in the short term. However, identification of high-risk individuals with an unfavorable outcome is a challenging task. We aimed to develop a CVT grading scale (CVT-GS) to aid in the short-term clinical decision-making. Methods: We included 467 consecutive patients with CVT who were hospitalized from 1981 to 2015 in two third-level referral hospitals. Factors associated with 30-day mortality were selected with bivariate analyses to integrate a Cox proportional hazards model to determine components of the final scoring. After the scale was configured, the prognostic performance was tested for prediction of short-term death or moderately impaired to death [modified Rankin scale (mRS) > 2]. CVT-GS was categorized as mild, moderate or severe for the prediction of 30-day fatality rate and a probability of mRS > 2. Results: The 30-day case fatality rate was 9.0%. The CVT-GS (0-13 points; more points predicting poorer outcomes) was composed of parenchymal lesion size > 6 cm (3 points), bilateral Babinski signs (3 points), male sex (2 points), parenchymal hemorrhage (2 points), and level of consciousness (coma: 3 points, stupor: 2, somnolence: 1, and alert: 0). CVT was categorized as mild (0-2 points, 0.4% fatality rate), moderate (3-7 points, 9.9% fatality rate), or severe (8-13 points, 61.4% fatality rate). The CVT-GS had an accuracy of 91.6% for the prediction of 30-day mortality and 85.3% for mRS > 2. Conclusions: CVT-GS is a practical clinical tool for prediction of outcome after CVT. This score may aid in clinical decision-making and could serve to stratify patients enrolled in clinical trials. PMID- 30405515 TI - Vacuolated PAS-Positive Lymphocytes on Blood Smear: An Easy Screening Tool and a Possible Biomarker for Monitoring Therapeutic Responses in Late Onset Pompe Disease (LOPD). AB - Background: Primary aim was to investigate the diagnostic value of PAS-positive vacuolated lymphocytes on blood smear in Late Onset Pompe Disease (LOPD) patients and, secondly, to evaluate its potential utility in monitoring treatment effects. Methods: We examined blood smear of 26 LOPD patients. We evaluated 10 treated and 16 untreated LOPD patients. Among the latter group, 7 patients later initiated ERT and were tested again 6 months after start. Blood smear was also sampled from 82 controls and 19 patients with other muscle glycogenoses (MGSDs). PAS staining was used to evaluate: (1) presence of lymphocytes with glycogen-filled vacuoles, (2) quantification of vacuolated lymphocytes. Results: We found that PAS-positive lymphocytes were significantly higher in LOPD patients than in controls or other MGSDs (p < 0.05 and p < 0.001, respectively). ROC curve for discriminating between untreated LOPD patients and controls yielded an AUC of 1.00 (95%CI 1.00 1.00; p < 0.0001). PAS-positive lymphocyte cutoff level of >10 yielded sensitivity of 100% (95%CI 78-100%), specificity of 100% (95%CI 96-100%), and positive predictive value of 100%. Patients studied before and after ERT showed a dramatic decrease of PAS-positive vacuolated lymphocytes number (p = 0.016). In other MGSDs, PAS-positive lymphocytes were significantly lower that untreated LOPD patients but higher than controls. Conclusions: Our data suggest that the Blood Smear Examination (BSE) for PAS-positive lymphocytes quantification could be used as a simple and sensitive test for a quick screening of suspected Pompe disease. The quantification of vacuolated lymphocytes appears to be also a valuable tool for monitoring the efficacy of treatment in LOPD patients. PMID- 30405518 TI - Increased Corticomuscular Coherence and Brain Activation Immediately After Short Term Neuromuscular Electrical Stimulation. AB - Neuromuscular Electrical Stimulation (NMES) is commonly used in motor rehabilitation for stroke patients. It has been verified that NMES can improve muscle strength and activate the brain, but the studies on how NMES affects the corticomuscular connection are limited. Some studies found an increased corticomuscular coherence (CMC) after a long-term NMES. However, it is still unknown about CMC during NMES, as relatively pure EMG is very difficult to obtain with the contamination of NMES current pulses. In order to approach the condition during NMES, we designed an experiment with short-term NMES and immediately captured data within 100 s. The repetition of wrist flexion was used to realize static muscle contractions for CMC calculation and dynamic contractions for event related desynchronization (ERD). The result of 13 healthy participants showed that maximal values (p = 0.0020) and areas (p = 0.0098) of CMC and beta ERD were significantly increased immediately after NMES. It was concluded that a short term NMES can still reinforce corticomuscular functional connection and brain activation related to motor task. This study verified the immediate strengthen of corticomuscular changes after NMES, which was expected to be the basis of long term neural plasticity induced by NMES. PMID- 30405517 TI - Neuroprotection in Traumatic Brain Injury: Mesenchymal Stromal Cells can Potentially Overcome Some Limitations of Previous Clinical Trials. AB - Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. In the last 30 years several neuroprotective agents, attenuating the downstream molecular and cellular damaging events triggered by TBI, have been extensively studied. Even though many drugs have shown promising results in the pre-clinical stage, all have failed in large clinical trials. Mesenchymal stromal cells (MSCs) may offer a promising new therapeutic intervention, with preclinical data showing protection of the injured brain. We selected three of the critical aspects identified as possible causes of clinical failure: the window of opportunity for drug administration, the double-edged contribution of mechanisms to damage and recovery, and the oft-neglected role of reparative mechanisms. For each aspect, we briefly summarized the limitations of previous trials and the potential advantages of a newer approach using MSCs. PMID- 30405520 TI - Transplantation of Embryonic Neural Stem Cells and Differentiated Cells in a Controlled Cortical Impact (CCI) Model of Adult Mouse Somatosensory Cortex. AB - Traumatic brain injury (TBI) is a major cause of death worldwide. Depending on the severity of the injury, TBI can reflect a broad range of consequences such as speech impairment, memory disturbances, and premature death. In this study, embryonic neural stem cells (ENSC) were isolated from E14 mouse embryos and cultured to produce neurospheres which were induced to generate differentiated cells (DC). As a cell replacement treatment option, we aimed to transplant ENSC or DC into the adult injured C57BL/6 mouse cortex controlled cortical impact (CCI) model, 7 days post-trauma, in comparison to saline injection (control). The effect of grafted cells on neuroinflammation and neurogenesis was investigated at 1 and 4 weeks post-transplantation. Results showed that microglia were activated following mild CCI, but not enhanced after engraftment of ENSC or DC. Indeed, ipsilateral lesioned somatosensory area expressed high levels of Iba-1+ microglia within the different groups after 1 and 4 weeks. On the other hand, treatment with ENSC or DC demonstrated a significant reduction in astrogliosis. The levels of GFAP expressing astrocytes started decreasing early (1 week) in the ENSC group and then were similarly low at 4 weeks in both ENSC and DC. Moreover, neurogenesis was significantly enhanced in ENSC and DC groups. Indeed, a significant increase in the number of DCX expressing progenitor cells was observed at 1 week in the ENSC group, and in DC and ENSC groups at 4 weeks. Furthermore, the number of mature neuronal cells (NeuN+) significantly increased in DC group at 4 weeks whereas they decreased in ENSC group at 1 week. Therefore, injection of ENSC or DC post-CCI caused decreased astrogliosis and suggested an increased neurogenesis via inducing neural progenitor proliferation and expression rather than neuronal maturation. Thus, ENSC may play a role in replacing lost cells and brain repair following TBI by improving neurogenesis and reducing neuroinflammation, reflecting an optimal environment for transplanted and newly born cells. PMID- 30405521 TI - Movement Speed-Accuracy Trade-Off in Parkinson's Disease. AB - Patients with Parkinson's disease (PD) often have difficulties generating rhythmic movements, and also difficulties on movement adjustments to accuracy constraints. In the reciprocal aiming task, maintaining a high accuracy comes with the cost of diminished movement speed, whereas increasing movement speed disrupts end-point accuracy, a phenomenon well known as the speed-accuracy trade off. The aim of this study was to examine how PD impacts speed-accuracy trade-off during rhythmic aiming movements by studying the structural kinematic movement organization and to determine the influence of dopamine replacement therapy on continuous movement speed and accuracy. Eighteen patients with advanced idiopathic Parkinson's disease performed a reciprocal aiming task, where the difficulty of the task was manipulated through target width. All patients were tested in two different sessions: ON-medication and OFF-medication state. A control group composed of healthy age-matched participants was also included in the study. The following variables were used for the analyses: Movement time, Error rate, effective target width, and Performance Index. Percentage of acceleration time and percentage of non-linearity were completed with kinematics patterns description using Rayleigh-Duffing model. Both groups traded off speed against accuracy as the constraints pertaining to the latter increased. The trade off was more pronounced with the PD patients. Dopamine therapy allowed the PD patients to move faster, but at the cost of movement accuracy. Surprisingly, the structural kinematic organization did not differ across group nor across medication condition. These results suggest that PD patients, when involved in a reciprocal aiming task, are able to produce rhythmic movements. PD patients' overall slowing down seems to reflect a global adaptation to the disease in the absence of a structurally altered kinematic organization. PMID- 30405522 TI - Noisy Galvanic Vestibular Stimulation Sustainably Improves Posture in Bilateral Vestibulopathy. AB - Patients with bilateral vestibulopathy (BV) suffer from persistent postural imbalance, leading to a marked decrease in quality of life and a higher risk of falls. However, so far, the effective treatments for BV are very limited. We examined whether long-term noisy galvanic vestibular stimulation (nGVS) keeps improving body balance after the cessation of the stimulus in BV patients. Thirteen BV patients received nGVS for 30 min with a lower intensity than the intensity at which they feel any cutaneous sensations, and their postural movement was monitored for 6 h after the stimuli. The same session was repeated at 14-day intervals. Stance tasks on two legs were performed with eyes closed. The velocity of the center of pressure (COP) movement, the area enclosed by the COP movement, and the root mean square of the displacement of the COP were measured. The power spectrum of the COP movement was assessed. Subjective improvement of body balance was graded as worsened (-2), slightly worsened (-1), unchanged (0), slightly improved (+1) and improved (+2) in comparison with that without nGVS. In each session, the velocity of the COP movement was significantly improved for 6 h after the stimulus had ceased (P < 0.01). Concomitantly, the mean frequency of the COP power spectrum was significantly reduced in the anterior-posterior axis (P < 0.05). Subjective symptoms of imbalance were improved during the post-stimulation effect (P < 0.05). nGVS leads to an improvement in body balance that lasts for several hours after the end of the stimulus in BV patients with a reduction in the high-frequency components of their postural movement. This trial was registered with the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMINCTR: UMIN000028054). PMID- 30405523 TI - APT Weighted MRI as an Effective Imaging Protocol to Predict Clinical Outcome After Acute Ischemic Stroke. AB - To explore the capability of the amide-proton-transfer weighted (APTW) magnetic resonance imaging (MRI) in the evaluation of clinical neurological deficit at the time of hospitalization and assessment of long-term daily functional outcome for patients with acute ischemic stroke (AIS). We recruited 55 AIS patients with brain MRI acquired within 24-48 h of symptom onset and followed up with their 90 day modified Rankin Scale (mRS) score. APT weighted MRI was performed for all the study subjects to measure APTW signal quantitatively in the acute ischemic area (APTWipsi) and the contralateral side (APTWcont). Change of the APT signal between the acute ischemic region and the contralateral side (DeltaAPTW) was calculated. Maximum APTW signal (APTWmax) and minimal APTW signal (APTWmin) were also acquired to demonstrate APTW signals heterogeneity (APTWmax-min). In addition, all the patients were divided into 2 groups according to their 90-day mRS score (good prognosis group with mRS score <2 and poor prognosis group with mRS score >=2). In the meantime, DeltaAPTW of these groups was compared. We found that DeltaAPTW was in good correlation with National Institutes of Health Stroke Scale (NIHSS) score (R 2 = 0.578, p < 0.001) and 90-day mRS score (R 2 = 0.55, p < 0.001). There was significant difference of DeltaAPTW between patients with good prognosis and patients with poor prognosis. Plus, APTWmax-min was significantly different between two groups. These results suggested that APT weighted MRI could be used as an effective tool to assess the stroke severity and prognosis for patients with AIS, with APTW signal heterogeneity as a possible biomarker. PMID- 30405519 TI - Diagnosis and Treatment of NMO Spectrum Disorder and MOG-Encephalomyelitis. AB - Neuromyelitis optica spectrum disorders (NMOSD) are autoantibody mediated chronic inflammatory diseases. Serum antibodies (Abs) against the aquaporin-4 water channel lead to recurrent attacks of optic neuritis, myelitis and/or brainstem syndromes. In some patients with symptoms of NMOSD, no AQP4-Abs but Abs against myelin-oligodendrocyte-glycoprotein (MOG) are detectable. These clinical syndromes are now frequently referred to as "MOG-encephalomyelitis" (MOG-EM). Here we give an overview on current recommendations concerning diagnosis of NMOSD and MOG-EM. These include antibody and further laboratory testing, MR imaging and optical coherence tomography. We discuss therapeutic options of acute attacks as well as longterm immunosuppressive treatment, including azathioprine, rituximab, and immunoglobulins. PMID- 30405524 TI - Basis of Shoulder Nerve Entrapment Syndrome: An Ultrasonographic Study Exploring Factors Influencing Cross-Sectional Area of the Suprascapular Nerve. AB - As changes in nerves' shape and size are common ultrasonographic findings of entrapment neuropathy, measurement of the nerve cross-sectional area (CSA) becomes the mostly used indicator to differentiate normality from pathology. Recently, more US research has been conducted to measure the shape of the suprascapular notch and the diameter of the suprascapular nerve. Because the suprascapular nerve is paramount for various shoulder disorders, the present study aims to establish normal values of suprascapular nerve sizes at different levels as well as to investigate potential influence of participants' characteristics on the CSA measurements. The present study used a cross-sectional design investigating the CSA values of the suprascapular nerve from the supraclavicular region to spinoglenoid notch. We employed the inside-epineurium and outside-epineurium methods to quantify CSA of cervical roots (C5 and C6) and the suprascapular nerve on US imaging. Univariate comparisons of nerve sizes among different age and gender groups were carried out. Multivariate analysis was performed to analyze the impact of participants' characteristics on nerve CSA. Repeated measurement analysis of variance was conducted to examine segmental variations of CSA of the suprascapular nerve from its origin to infraspinatus fossa. Our study included 60 healthy adults with 120 shoulders and had three major findings: (1) the inside-epineurium method was more reliable than the outside-epineurium approach for CSA measurements due to higher intra- and inter rater reliability, (2) women had smaller sizes for cervical nerve roots and for the most proximal segment of the suprascapular nerves, and (3) using the outside epineurium method, the suprascapular nerve CSA was larger in its distal division than the portion proximal to the mid-clavicular line. In conclusion, the inside epineurium method has better reliability for nerve CSA assessment but the outside epineurium method is needed for quantifying the size of distal suprascapular nerve. Gender difference in CSA values should be considered during evaluation of the most proximal nerve segment. Using the outside-epineurium method, the distal suprascapular nerve would be estimated larger than its proximal portion and the segmental discrepancy should be not misinterpreted as pathology. PMID- 30405525 TI - Neurological Complications in Young Infants With Acute Bacterial Meningitis. AB - We aimed to evaluate the occurrence, treatment, and outcomes of neurological complications after bacterial meningitis in young infants. A case series study from a retrospective cohort from two tertiary-level medical centers in Taiwan between 2007 and 2016 was conducted. Eighty-five young infants aged < 90 days with bacterial meningitis were identified. 25 (29.4%) were born at preterm. Group B Streptococcus (GBS) and Escherichia coli caused 74.1% of identified cases. Despite the majority (90.6%) initially received microbiologically appropriate antibiotics, 65 (76.5%) had experienced at least one neurological complication identified at a median of 6 days (range: 1-173) after onset of bacterial meningitis. The most common neurological complication was seizure (58.8%), followed by subdural effusion (47.1%), ventriculomegaly (41.2%), subdural empyema (21.2%), hydrocephalus (18.8%), ventriculitis (15.3%), periventricular leukomalacia (11.8%), and encephalomalacia (10.6%). Nine patients (10.6%) died (including 4 had critical discharge on request) and 29/76 (38.2%) of the survivors had major neurological sequelae at discharge. Nighteen (22.4%) received surgical intervention due to these complications. After multivariate logistic regression, initial seizure (adjusted odds ratio [aOR]: 4.76, 95% confidence interval [CI]: 1.7-13.0, P = 0.002) and septic shock (aOR: 6.04; 95% CI: 1.35 27.0, P = 0.019) were independent predictors for final unfavorable outcomes. Conclusions: Neurological complications and sequelae are common in young infants after bacterial meningitis. Patients presented with early seizure or septic shock can be an early predictor of final unfavorable outcomes and require close monitoring. Further research regarding how to improve clinical management and outcomes is warranted. PMID- 30405526 TI - Effects of High-intensity Robot-assisted Hand Training on Upper Limb Recovery and Muscle Activity in Individuals With Multiple Sclerosis: A Randomized, Controlled, Single-Blinded Trial. AB - Background : Integration of robotics and upper limb rehabilitation in people with multiple sclerosis (PwMS) has rarely been investigated. Objective: To compare the effects of robot-assisted hand training against non-robotic hand training on upper limb activity in PwMS. To compare the training effects on hand dexterity, muscle activity, and upper limb dysfunction as measured with the International Classification of Functioning. Methods: This single-blind, randomized, controlled trial involved 44 PwMS (Expanded Disability Status Scale:1.5-8) and hand dexterity deficits. The experimental group (n = 23) received robot-assisted hand training; the control group (n = 21) received non-robotic hand training. Training protocols lasted for 5 weeks (50 min/session, 2 sessions/week). Before (T0), after (T1), and at 1 month follow-up (T2), a blinded rater evaluated patients using a comprehensive test battery. Primary outcome: Action Research Arm Test. Secondary outcomes: Nine Holes Peg Test; Fugl-Meyer Assessment Scale-upper extremity section; Motricity Index; Motor Activity Log; Multiple Sclerosis (MS) Quality of Life-54; Life Habits assessment-general short form and surface electromyography. Results: There were no significant between-group differences in primary and secondary outcomes. Electromyography showed relevant changes providing evidence increased activity in the extensor carpi at T1 and T2. Conclusion: The training effects on upper limb activity and function were comparable between the two groups. However, robot-assisted training demonstrated remarkable effects on upper limb use and muscle activity. https://clinicaltrials.gov NCT03561155. PMID- 30405527 TI - Leptin Selectively Regulates Nutrients Metabolism in Nile Tilapia Fed on High Carbohydrate or High Fat Diet. AB - Leptin is known to inhibit appetite and promote energy metabolism in vertebrates. Leptin resistance (LR) commonly occurs in diet-induced obesity (DIO) in mammals. However, the roles of leptin in the energy homeostasis in DIO animals with LR remain unclear. Here we first verified the high expression of leptin in subcutaneous adipose tissue (SCAT) as in liver in Nile tilapia. Furthermore, we produced two types of DIO Nile tilapia by using a high-carbohydrate diet (HCD) or a high-fat diet (HFD), and confirmed the existence of LR in both models. Notably, we found that HCD-DIO fish retained leptin action in the activation of lipid metabolism and showed LR in glucose metabolism regulation, while this selective leptin action between lipid and glucose metabolism was reversed in HFD-DIO fish. Fasting the fish for 1 week completely recovered leptin actions in the regulation of lipid and glucose metabolism. Therefore, leptin may retain more of its activities in animals with LR than previously believed. Evolutionally, this selective regulation of leptin in nutrients metabolism could be an adaptive mechanism in animals to store surplus calories when different types of food are abundant. PMID- 30405528 TI - The Essential Role of SIRT1 in Hypothalamic-Pituitary Axis. AB - The endocrine system plays an essential role in the physiological adaptation to malnutrition. The adaptive response of various hormones directs the energy utilization toward the survival functions and away from growth and reproduction. Particularly, the hypothalamic pituitary axis plays an integral and a central role in the regulation of endocrine organs. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase that is activated in response to calorie restriction (CR). SIRT1 is involved in cellular processes via the deacetylation of histone as well as various transcription factors and signal transduction molecules and thereby modulates the endocrine/metabolic functions. There is much evidence to demonstrate clearly that SIRT1 in the hypothalamus, pituitary gland, and other target organs modifies the synthesis, secretion, and activities of hormones and in turn induces the adaptive responses. In this review, we discussed the role of SIRT1 in the hypothalamic pituitary axis and its pathophysiological significance. PMID- 30405529 TI - The Discovery of Insulin: An Important Milestone in the History of Medicine. AB - The discovery of insulin represents an authentic breakthrough, characterized, at the same time, by contrasts, controversies and disputes among scholars, as well as by great disappointments, failures and hopes. It is the story of famous, almost famous and little known people, of serendipities, discoveries and re discoveries. The discovery of insulin has been a milestone and has truly revolutionized both the therapy and the prognosis of the diabetes, one of the diseases most studied in the history of medicine, whose first mentions trace back to a collection of ancient Egyptian, Indian and Chinese textbooks. As stated by Colwell, the introduction of insulin has heralded the end of the so-called "pre insulin era" or "frustration era", paving the way for a new era and clinical advancements. The current review offers a broad, comprehensive overview of main steps culminating into insulin discovery, including recent advancements such as personalized and individualized insulin therapy. PMID- 30405530 TI - Adiponectin, Leptin and Visfatin in Hypoxia and its Effect for Weight Loss in Obesity. AB - Rationale: Hypoxia induces leptin gene expression in human adipocytes via hypoxia inducible factors (HIF-alpha/beta). Under ambient moderate hypoxia, leptin in adipocytes is elevated for at least 14 days. Leptin is supposedly involved in the reduced food intake, increased utilization of fatty acids for energy production and possible weight loss observed at high altitudes. Literature on adiponectin and visfatin in high altitude is inconsistent with reports of elevated levels and non-elevated levels. Exercise in hypoxia studies in obese subjects have shown a significant weight loss after up to 3 weeks, but it is unclear if this effect holds up for longer time periods. Therefore, we aimed to investigate 32 obese subjects completing 52 exercise and rest sessions within 8 months at either moderate or sham hypoxia and to analyze leptin, adiponectin, and visfatin mRNA expression at different time points of exposure. Methods: Abdominal subcutaneous fat biopsies were taken from 32 obese subjects before, after 3 months and after 8 months of intervention. Subjects were randomly divided into two groups and exercised at moderate intensity at two different study sites twice a week. The IG was exposed to normobaric hypoxia (FiO2: 14.0 +/- 0.2%,) at exercise and at rest (FiO2: 12.0 +/- 0.2%) and the CG to sham hypoxia. Quantitative real-time polymerase chain reaction (qPCR) was used in order to determine mRNA-levels of leptin, adiponectin, and visfatin. Results: No differences in leptin levels after 3 and 8 months compared to baseline and between groups were found. There was no significant difference regarding adiponectin or visfatin at any time point compared to baseline in the hypoxia group, but an increase after 3 months was seen in the control group at normoxia compared to the hypoxia group (adiponectin: p = 0.029 and visfatin: p = 0.014). Conclusion: In this first several months' duration randomized sham controlled hypoxia exercise and rest study with obese subjects, we found no time extended leptin mRNA-expression in subjects under hypoxia after 3 and 8 months compared to baseline levels. Moderate exercise in normoxia not in hypoxia leads to elevated adiponectin and visfatin levels after 3 months. PMID- 30405531 TI - Pharmaceutical Impact of Houttuynia Cordata and Metformin Combination on High-Fat Diet-Induced Metabolic Disorders: Link to Intestinal Microbiota and Metabolic Endotoxemia. AB - Purpose: Metformin and Houttuynia cordata are representative anti-diabetic therapeutic agents in western and oriental medicinal fields, respectively. The present study examined the therapeutic effects of houttuynia cordata extract (HCE) and metformin in combination in a dysmetabolic mouse model. Methods: Metabolic disorders were induced in C57BL/6J mice by high fat diet (HFD) for 14 weeks. Results: Combination of metformin and HCE significantly lowered body weight, abdominal fat, perirenal fat, liver and kidney weights, but did not change epididymal fat in HFD-fed animals. Metformin + HCE treatment markedly attenuated the elevated serum levels of TG, TC, AST, ALT, and endotoxin and restored the depleted HDL level. Both HCE and metformin + HCE treatment ameliorated glucose tolerance and high level of fasting blood glucose in association with AMPK activation. Moreover, treatment with HCE + metformin dramatically suppressed inflammation in HFD-fed animals via inhibition of proinflammatory cytokines (MCP-1 and IL-6) and LPS receptor (TLR4). Histopathological findings showed that exposure of HFD-treated animals to metformin + HCE ameliorated fatty liver, shrinkage of intestinal villi and adipocytes enlargement. Furthermore, HCE and metformin + HCE treatments markedly modulated the abundance of gut Gram-negative bacteria, including Escherichia coli and Bacteriodetes fragilis, but not universal Gram-positive bacteria. Conclusions: Overall, HCE and metformin cooperatively exert their therapeutic effects via modulation of gut microbiota, especially reduction of Gram-negative bacteria, resulting in alleviation of endotoxemia. PMID- 30405533 TI - Commentary: Research Gaps in Gestational Diabetes Mellitus: Executive Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop. PMID- 30405532 TI - Metformin and Colorectal Cancer. AB - Colorectal Cancer (CRC) is one of the most frequently encountered neoplasms in humans. The incidence of CRC has been increasing and new strategies for prevention, including chemoprevention, are required to lower its incidence and associated mortality. Metformin is a biguanide compound commonly used for the treatment of diabetes mellitus. Many recent basic research, epidemiological and clinical trial studies have indicated that metformin has benefits not only in diabetes treatment, but also in lowering the risk of developing cancer (including CRC). These studies indicate that metformin may be a candidate chemoprevention agent for CRC. This review article shall discuss the present evidence of metformin treatment and CRC, as well as outline our challenge in the investigation of metformin use in chemoprevention therapy for colorectal tumors. PMID- 30405534 TI - IL-34 Expression Is Reduced in Hashimoto's Thyroiditis and Associated With Thyrocyte Apoptosis. AB - Hashimoto's thyroiditis (HT) is a common autoimmune disease accompanied by lymphocyte infiltration and thyroid tissue destruction. IL-34 was first described in 2008, and its involvement in the development of many autoimmune diseases has been recently identified. However, whether IL-34 is a regulatory factor in HT is unclear. Here, we demonstrate that IL-34 is expressed on thyroid follicular epithelial cells and that IL-34 expression is significantly reduced in thyroid tissue in patients with HT and spontaneous autoimmune thyroiditis (SAT) models. Serum IL-34 levels in patients with HT are also significantly reduced. In addition, IL-34 is associated with thyroid autoantibodies in both thyroid tissue and serum. Furthermore, our data show that IL-34 participates in the apoptosis resistance of thyrocytes in HT induced by CSF-1R and may be a potential indicator for evaluating thyrocyte damage. PMID- 30405536 TI - Ghrelin Receptor Is Required for the Effect of Nesfatin-1 on Glucose Metabolism. AB - Studies of nesfatin-1 in glucose metabolism have become a topic of interest recently, however, the specific receptor for nesfatin-1 has not yet been identified. Some studies hinted at a connection between nesfatin-1 and the ghrelin receptor, growth hormone secretagogue receptor. Therefore, we aimed to study the role of GHSR in the glycemic effects of nesfatin-1 as well as its downstream pathways. We employed C57/BL6 mice (wild type and GHSR knockout mice) eating a normal chow diet and a high fat diet in this study, and the experimental technique included western blot, real-time PCR, immunofluorescence and ELISA. We found that in mice fed a normal chow diet (NCD), nesfatin-1 improved glucose tolerance, up-regulated AKT kinase (AKT) mRNA levels and phosphorylation and GLUT4 membrane translocation in skeletal muscle. These effects were blocked by co injection of GHSR antagonist [D-Lys3]-GHRP-6 and were attenuated in GHSR knockout mice. In mice fed high-fat diet (HFD), nesfatin-1 not only exerted the effects observed in NCD mice, but also suppressed appetite and raised AKT levels in liver tissues that also required GHSR. Peripheral nesfatin-1 suppressed c-fos expression of GHSR immunoreactive neurons induced by fasting in hypothalamic nuclei, indicating that nesfatin-1 inhibited the activation of central GHSR. We concluded that the effects of nesfatin-1 on food intake and glucose metabolism were GHSR-dependent, and that the glycemic effect was associated with AKT and GLUT4. This study should stimulate further exploration of the nesfatin-1 receptor. PMID- 30405535 TI - Stress Effects on the Mechanisms Regulating Appetite in Teleost Fish. AB - The homeostatic regulation of food intake relies on a complex network involving peripheral and central signals that are integrated in the hypothalamus which in turn responds with the release of orexigenic or anorexigenic neuropeptides that eventually promote or inhibit appetite. Under stress conditions, the mechanisms that control food intake in fish are deregulated and the appetite signals in the brain do not operate as in control conditions resulting in changes in the expression of the appetite-related neuropeptides and usually a decreased food intake. The effect of stress on the mechanisms that regulate food intake in fish seems to be mediated in part by the corticotropin-releasing factor (CRF), an anorexigenic neuropeptide involved in the activation of the HPI axis during the physiological stress response. Furthermore, the melanocortin system is also involved in the connection between the HPI axis and the central control of appetite. The dopaminergic and serotonergic systems are activated during the stress response and they have also been related to the control of food intake. In addition, the central and peripheral mechanisms that mediate nutrient sensing capacity and hence implicated in the metabolic control of appetite are inhibited in fish under stress conditions. Finally, stress also affects peripheral endocrine signals such as leptin. In the present minireview, we summarize the knowledge achieved in recent years regarding the interaction of stress with the different mechanisms that regulate food intake in fish. PMID- 30405537 TI - Quantification of a Glucocorticoid Profile in Non-pooled Samples Is Pivotal in Stress Research Across Vertebrates. AB - Vertebrates are faced continuously with a variety of potential stressful stimuli and react by a highly conserved endocrine stress response. An immediate catecholamine mediated response increases plasma glucose levels in order to prepare the organism for the "fight or flight" reaction. In addition, in a matter of minutes after this (nor)adrenaline release, glucocorticoids, in particular cortisol or corticosterone depending on the species, are released through activation of the hypothalamic-pituitary-interrenal (HPI) axis in fish or hypothalamic-pituitary-adrenal (HPA) axis in other vertebrates. These plasma glucocorticoids are well documented and widely used as biomarker for stress across vertebrates. In order to study the role of glucocorticoids in acute and chronic stress and gain in-depth insight in the stress axis (re)activity across vertebrates, it is pivotal to pin-point the involved molecules, to understand the mechanisms of how the latter are synthesized, regulated and excreted, and to grasp their actions on a plethora of biological processes. Furthermore, in-depth knowledge on the characteristics of the tissues as well as on the analytical methodologies available for glucocorticoid quantification is needed. This manuscript is to be situated in the multi-disciplinary research topic of glucocorticoid action across vertebrates which is linked to a wide range of research domains including but not limited to biochemistry, ecology, endocrinology, ethology, histology, immunology, morphology, physiology, and toxicology, and provides a solid base for all interested in stress, in particular glucocorticoid, related research. In this framework, internationally validated confirmation methods for quantification of a glucocorticoid profile comprising: (i) the dominant hormone; (ii) its direct precursors; (iii) its endogenously present phase I metabolites; and (iv) the most abundant more polar excreted exogenous phase I metabolites in non-pooled samples are pivotal. PMID- 30405538 TI - Use of Indigenous Hanseniaspora vineae and Metschnikowia pulcherrima Co fermentation With Saccharomyces cerevisiae to Improve the Aroma Diversity of Vidal Blanc Icewine. AB - Using novel non-Saccharomyces strains is regarded as an effective way to improve the aroma diversity of wines to meet the expectations of consumers. The non Saccharomyces Hanseniaspora vineae and Metschnikowia pulcherrima have good aromatic properties useful for the production of table wine. However, no detailed information is available on their performances in icewine fermentation. In this study, simultaneous and sequential fermentation trials of indigenous M. pulcherrima CVE-MP20 or H. vineae CVE-HV11 with S. cerevisiae (SC45) were performed in 50-L fermenters of Vidal icewine, respectively. The results showed that SC45 cofermented with different non-Saccharomyces strains could generate a distinct aroma quality of icewine compared with four S. cerevisiae strain monocultures as evidenced by principal component analysis (PCA). Mixed fermentation of MP20/SC45 produced higher contents of acetate esters and beta damascenone with lower C6 alcohols relative to SC45 monoculture. Interestingly, HV11/SC45 generated the highest amounts of C6 alcohols [(Z)-3-hexen-1-ol and (E) 3-hexen-1-ol], higher alcohols (isobutanol, isopentanol, and 2-phenylethanol), acetate esters (2-phenethyl acetate and isoamyl acetate), cis-rose oxide, beta damascenone, and phenylacetaldehyde. Compared with simultaneous inoculation, sequential inoculation could achieve higher aroma diversity and produce higher intensity of fruity, flowery, and sweet attributes of icewine as assessed by calculating the odor activity values (OAVs). Our results verified the desired enological characteristics of H. vineae strain in icewine fermentation and also demonstrated that using indigenous non-Saccharomyces and Saccharomyces strains is a feasible way to improve aroma diversity of icewine products, which could provide an alternative way to meet the requirement of wine consumers for diversified aromatic quality. PMID- 30405539 TI - Pleiotropic Roles of ChSat4 in Asexual Development, Cell Wall Integrity Maintenance, and Pathogenicity in Colletotrichum higginsianum. AB - Potassium has an important role to play in multiple cellular processes. In Saccharomyces cerevisiae, the serine/threonine (S/T) kinase Sat4/Hal4 is required for potassium accumulation, and thus, regulates the resistance to sodium salts and helps in the stabilization of other plasma membrane transporters. However, the functions of Sat4 in filamentous phytopathogenic fungi are largely unknown. In this study, ChSat4, the yeast Sat4p homolog in Colletotrichum higginsianum, has been identified. Target deletion of ChSAT4 resulted in defects in mycelial growth and sporulation. Intracellular K+ accumulation was significantly decreased in the ChSAT4 deletion mutant. Additionally, the DeltaChsat4 mutant showed defects in cell wall integrity, hyperoxide stress response, and pathogenicity. Localization pattern analysis indicated ChSat4 was localized in the cytoplasm. Furthermore, ChSat4 showed high functional conservation with the homolog FgSat4 in Fusarium graminearum. Taken together, our data indicated that ChSat4 was important for intracellular K+ accumulation and infection morphogenesis in C. higginsianum. PMID- 30405540 TI - The Endophytic Mycobiome of European Ash and Sycamore Maple Leaves - Geographic Patterns, Host Specificity and Influence of Ash Dieback. AB - The European ash (Fraxinus excelsior) is threatened by the introduced ascomycete Hymenoscyphus fraxineus, the causal agent of ash dieback. Endophytic fungi are known to modulate their host's resistance against pathogens. To understand possible consequences of ash dieback on the endophytic mycobiome, F. excelsior leaves were collected in naturally regenerated forests and the fungal communities analyzed by classic culture and Illumina amplicon sequencing using a newly developed and validated fungal-specific primer. Collections were done in the area infested by ash dieback north of the Alps, and in the disease free area on the south side. Sycamore maple (Acer pseudoplatanus) was additionally collected, as well as the flowering ash (F. ornus), which occurs naturally in the south and shows tolerance to ash dieback. Both cultivation and amplicon sequencing revealed characteristic endophytic fungal communities dominated by several strictly host specific Venturia species. On A. pseudoplatanus, a hitherto undescribed Venturia species was identified. Due to its dominance on F. excelsior, V. fraxini is unlikely to go extinct in case of reduced host densities. A majority of species was not strictly host specific and is therefore likely less affected by ash dieback in the future. Still, shifts in community structure and loss of genetic diversity cannot be excluded. The potentially endangered endophyte Hymenoscyphus albidus was rarely found. In addition to host specificity, species with preferences for leaf laminae or petioles were found. We also detected considerable geographical variation between sampling sites and clear differences between the two sides of the Alps for endophytes of F. excelsior, but not A. pseudoplatanus. Since sycamore maple is not affected by an epidemic, this could point toward an influence of ash dieback on ash communities, although firm conclusions are not possible because of host preferences and climatic differences. Furthermore, the mycobiota of F. excelsior trees with or without dieback symptoms were compared, but no clear differences were detected. Besides methodical refinement, our study provides comprehensive data on the ash mycobiome that we expect to be subject to changes caused by an emerging disease of the host tree. PMID- 30405541 TI - Production of Cold-Active Lipase by Free and Immobilized Marine Bacillus cereus HSS: Application in Wastewater Treatment. AB - Lipases are enzymes that have the potential to hydrolyze triacylglycerol to free fatty acids and glycerol and have various applications. The aim of the present study was to isolate and screen marine bacteria for lipase production, optimize the production, and treat wastewater. A total of 20 marine bacterial isolates were obtained from the Mediterranean Sea and were screened for lipase production. All isolates were found to have lipolytic ability. The differences between the isolates were studied using RAPD-PCR. The most promising lipase producer (isolate 3) that exhibited the highest lipolytic hydrolysis (20 mm) was identified as Bacillus cereus HSS using 16S rDNA analysis and had the accession number MF581790. Optimization of lipase production was carried out using the Plackett Burman experimental design with cotton seed oil as the inducer under shaking conditions at 10 degrees C. The most significant factors that affected lipase production were FeSO4, KCl, and oil concentrations. By using the optimized culture conditions, the lipase activity increased by 1.8-fold compared with basal conditions. Immobilization by adsorption of cells on sponge and recycling raised lipase activity by 2.8-fold compared with free cells. The repeated reuse of the immobilized B. cereus HSS maintained reasonable lipase activity. A trial for the economic treatment of oily wastewater was carried out. Removal efficiencies of biological oxygen demand, total suspended solids, and oil and grease were 87.63, 90, and 94.7%, respectively, which is promising for future applications. PMID- 30405543 TI - Long-Term Nitrogen Fertilization Elevates the Activity and Abundance of Nitrifying and Denitrifying Microbial Communities in an Upland Soil: Implications for Nitrogen Loss From Intensive Agricultural Systems. AB - The continuous use of nitrogen (N) fertilizers to increase soil fertility and crop productivity often results in unexpected environmental effects and N losses through biological processes, such as nitrification and denitrification. In this study, multidisciplinary approaches were employed to assess the effects of N fertilization in a long-term (~20 years) field experiment in which a fertilizer gradient (0, 200, 400, and 600 kg N ha-1 yr-1) was applied in a winter wheat summer maize rotation cropping system in the North China Plain, one of the most intensive agricultural regions in China. The potential nitrification/denitrification rates, bacterial community structure, and abundances of functional microbial communities involved in key processes of the N cycle were assessed during both the summer maize (SM) and winter wheat (WW) seasons. Long-term N fertilization resulted in a decrease in soil pH and an increase in soil organic matter (OM), total N and total carbon concentrations. Potential nitrification/denitrification and the abundances of corresponding functional N cycling genes were positively correlated with the fertilization intensity. High-throughput sequencing of the 16S rRNA gene revealed that the increased fertilization intensity caused a significant decrease of bacterial diversity in SM season, while changed the microbial community composition such as increasing the Bacteroidetes abundance and decreasing Acidobacteria abundance in both SM and WW seasons. The alteration of soil properties markedly correlated with the variation in microbial structure, as soil pH and OM were the most predominant factors affecting the microbial structure in the SM and WW seasons, respectively. Furthermore, consistently with the results of functional gene quantification, functional prediction of microbial communities based on 16S rRNA sequence data also revealed that the abundances of the key nitrificaiton/denitrification groups were elevated by long-term N inputs. Taken together, our results suggested that soil microbial community shifted consistently in both SM and WW seasons toward a higher proportion of N-cycle microbes and exhibited higher N turnover activities in response to long-term elevated N fertilizer. These findings provided new insights into the molecular mechanisms responsible for N loss in intensively N fertilized agricultural ecosystems. PMID- 30405542 TI - Regulatory sRNAs in Cyanobacteria. AB - As the transcriptional and post-transcriptional regulators of gene expression, small RNAs (sRNAs) play important roles in every domain of life in organisms. It has been discovered gradually that bacteria possess multiple means of gene regulation using RNAs. They have been continuously used as model organisms for photosynthesis, metabolism, biotechnology, evolution, and nitrogen fixation for many decades. Cyanobacteria, one of the most ancient life forms, constitute all kinds of photoautotrophic bacteria and exist in almost any environment on this planet. It is believed that a complex RNA-based regulatory mechanism functions in cyanobacteria to help them adapt to changes and stresses in diverse environments. Although lagging far behind other model microorganisms, such as yeast and Escherichia coli, more and more non-coding regulatory sRNAs have been recognized in cyanobacteria during the past decades. In this article, by focusing on cyanobacterial sRNAs, the approaches for detection and targeting of sRNAs will be summarized, four major mechanisms and regulatory functions will be generalized, eight types of cis-encoded sRNA and four types of trans-encoded sRNAs will be reviewed in detail, and their possible physiological functions will be further discussed. PMID- 30405544 TI - Effects of Probiotic Bacillus as an Alternative of Antibiotics on Digestive Enzymes Activity and Intestinal Integrity of Piglets. AB - The previous study in our team found that supplementation of probiotic Bacillus amyloliquefaciens (Ba) instead of antibiotics promote growth performance of piglets. Hence, the present study was carried out to further demonstrate the effect of Ba replacement of antibiotics on digestive and absorption enzyme activity and intestinal microbiota population of piglets. A total of 90 piglets were selected and divided into three groups: G1 group was fed with basal diet supplemented with 150 mg/Kg aureomycin, G2 group was fed with 1 * 108 cfu/Kg Ba and half dose of aureomycin, G3 group was used the diet with 2 * 108cfu/Kg Ba replaced aureomycin. Each treatment had three replications of 10 pigs per pen. Results indicated that Ba replacement significantly increased the activities of amylase, disaccharides and Na+/K+-ATPase. And chymotrypsin activity in different section of intestine was dramatically enhanced in half replacement of aureomycin with Ba. Moreover, Ba replacement maintained the intestinal integrity with the significantly decreased activity of DAO compared with aureomycin group. Besides, supplementation with Ba increased the beta-diversity of intestinal microbiota. Taken together, the current study indicated that diet supplementation with Ba instead of aureomycin increased the growth performance of piglets by improving the digestive and absorb enzyme activities, enhancing the intestinal integrity and regulating the population of intestinal micrbiota. PMID- 30405545 TI - Evidence for an Adaptation of a Phage-Derived Holin/Endolysin System to Toxin Transport in Clostridioides difficile. AB - The pathogenicity locus (PaLoc) of Clostridioides difficile usually comprises five genes (tcdR, tcdB, tcdE, tcdA, tcdC). While the proteins TcdA and TcdB represent the main toxins of this pathogen, TcdR and TcdC are involved in the regulation of their production. TcdE is a holin family protein, members of which are usually involved in the transport of cell wall-degrading enzymes (endolysins) for phage-induced lysis. In the past, TcdE has been shown to contribute to the release of TcdA and TcdB, but it is unclear whether it mediates a specific transport or rather a lysis of cells. TcdE of C. difficile strains analyzed so far can be produced in three isoforms that are initiated from distinct N-terminal ATG codons. When produced in Escherichia coli, we found that the longest TcdE isoform had a moderate effect on cell growth, whereas the shortest isoform strongly induced lysis. The effect of the longest isoform was inhibitory for cell lysis, implying a regulatory function of the N-terminal 24 residues. We analyzed the PaLoc sequence of 44 C. difficile isolates and found that four of these apparently encode only the short TcdE isoforms, and the most closely related holins from C. difficile phages only possess one of these initiation codons, indicating that an N-terminal extension of TcdE evolved in C. difficile. All PaLoc sequences comprised also a conserved gene encoding a short fragment of an endolysin remnant of a phage holin/endolysin pair. We could produce this peptide, which we named TcdL, and demonstrated by bacterial two-hybrid analysis a self interaction and an interaction with TcdB that might serve to mediate TcdE dependent transport. PMID- 30405546 TI - Phloem-Triggered Virus-Induced Gene Silencing Using a Recombinant Polerovirus. AB - The phloem-limited poleroviruses infect Arabidopsis thaliana without causing noticeable disease symptoms. In order to facilitate visual infection identification, we developed virus-induced gene silencing (VIGS) vectors derived from Turnip yellows virus (TuYV). Short sequences from the host gene AtCHLI1 required for chlorophyll biosynthesis [42 nucleotides in sense or antisense orientation or as an inverted-repeat (IR), or an 81 nucleotide sense fragment] were inserted into the 3' non-coding region of the TuYV genome to screen for the most efficient and robust silencing vector. All recombinant viruses produced a clear vein chlorosis phenotype on infected Arabidopsis plants due to the expression inhibition of the AtCHLI1 gene. The introduction of a sense-oriented sequence into TuYV genome resulted in a virus exhibiting a more sustainable chlorosis than the virus containing an IR of the same length. This observation was correlated with a higher stability of the sense sequence insertion in the viral genome. In order to evaluate the impact of the TuYV silencing suppressor P0 in the VIGS mechanism a P0 knock-out mutation was introduced into the recombinant TuYV viruses. They induced a similar but milder vein clearing phenotype due to lower viral accumulation. This indicates that P0 does not hinder the performances of the TuYV silencing effect and confirms that in the viral infection context, P0 has no major impact on the production, propagation and action of the short distance silencing signal in phloem cells. Finally, we showed that TuYV can be used to strongly silence the phloem specific AtRTM1 gene. The TuYV-derived VIGS vectors therefore represent powerful tools to easily detect and monitor TuYV in infected plants and conduct functional analysis of phloem-restricted genes. Moreover this example indicates the potential of poleroviruses for use in functional genomic studies of agronomic plants. PMID- 30405547 TI - The Biogeographical Distribution of Soil Bacterial Communities in the Loess Plateau as Revealed by High-Throughput Sequencing. AB - The rigorous environmental stress of the severely eroded Loess Plateau may have promoted specific soil bacterial communities in comparison to other eco environmental regions. In order to unmask the bacterial diversity and most influential environmental parameters, Illumina MiSeq high throughput sequencing of 16S rRNA from 24 representative soil samples collected across south-east to north-west transect of the Loess Plateau in northern Shaanxi, China was conducted. This high-throughput sequencing revealed a total of 1,411,001 high quality sequences that classified into 38 phyla, 127 classes, >240 orders, and over 650 genera, suggesting a high bacterial richness across the Loess Plateau soils. The seven dominant groups were: Proteobacteria, Actinobacteria, Acidobacteria, Planctomycetes, Gemmatimonadetes, Chloroflexi, and Verrucomicrobi (relative abundance of >5%). Increasing/decreasing soil pH and geographic longitudinal distance correlated significantly with increasing/decreasing bacterial richness and diversity indices. Pairwise correlation analysis showed higher bacterial diversity at longitudinal gradients across 107 degrees 39'-109 degrees 15' (south-east to north-west) in our studied Chinese loess zone. Variation partitioning analysis indicated significant influence of soil characteristics (~40.4%) than geographical distance (at a landscape scale of ~400 km) that was responsible for 13.6% of variation in bacterial community structure from these soils. Overall, contemporary soil characteristics structure the bacterial community in Loess Plateau soil to a greater extent than the spatial distances along the loess transect. PMID- 30405548 TI - Bacterial Abundance and Community Composition in Pond Water From Shrimp Aquaculture Systems With Different Stocking Densities. AB - In shrimp aquaculture, farming systems are carefully managed to avoid rearing failure due to stress, disease, or mass mortality, and to achieve optimum shrimp production. However, little is known about how shrimp farming systems affect biogeochemical parameters and bacterial communities in rearing water, whether high stocking densities (intensive system) will increase the abundance of pathogenic bacteria. In this study, we characterized bacterial communities in shrimp ponds with different population densities. Water quality, such as physical parameters, inorganic nutrient concentrations, and cultivable heterotrophic bacterial abundances, including potential pathogenic Vibrio, were determined in moderate density/semi-intensive (40 post-larvae m-3) and high density/intensive shrimp ponds (90 post-larvae m-3), over the shrimp cultivation time. Free-living and particle-attached bacterial communities were characterized by amplicon sequencing of the 16S rRNA gene. Suspended particulate matter (SPM), salinity, chlorophyll a, pH, and dissolved oxygen differed significantly between semi intensive and intensive systems. These variations contrasted with the equal abundance of cultivable heterotrophic bacteria and inorganic nutrient concentrations. Bacterial communities were dominated by Gammaproteobacteria, Alphaproteobacteria, Flavobacteriia, Bacilli, and Actinobacteria. Halomonas and Psychrobacter were the most dominant genera in the particle-attached fractions, while Salegentibacter, Sulfitobacter, and Halomonas were found in the free-living fractions of both systems. Redundancy analysis indicated that among the observed environmental parameters, salinity was best suited to explain patterns in the composition of both free-living and particle-attached bacterial communities (R 2: 15.32 and 12.81%, respectively), although a large fraction remained unexplained. Based on 16S rRNA gene sequences, aggregated particles from intensive ponds loaded a higher proportion of Vibrio than particles from semi-intensive ponds. In individual ponds, sequence proportions of Vibrio and Halomonas displayed an inverse relationship that coincided with changes in pH. Our observations suggest that high pH-values may suppress Vibrio populations and eventually pathogenic Vibrio. Our study showed that high-density shrimp ponds had a higher prevalence of Vibrio, increased amounts of SPM, and higher phytoplankton abundances. To avoid rearing failure, these parameters have to be managed carefully, for example by providing adequate feed, maintaining pH level, and removing organic matter deposits regularly. PMID- 30405549 TI - Extrusion of Dissolved Oxygen by Exopolysaccharide From Leuconostoc mesenteroides and Its Implications in Relief of the Oxygen Stress. AB - Strains of Leuconostoc are generally facultatively anaerobic and exposure to oxygen might be detrimental; therefore, strategies to combat the oxygen stress are essential for these bacteria to survive and flourish in the oxygenic atmosphere. Despite the extensive applications in industry, the fundamental issues concerning the aerobic life of Leuconostocs remain to be addressed. In this study, we have demonstrated that Leuconostoc mesenteroides CGMCC10064 cultivated in sucrose medium would acquire a growth advantage over that in glucose medium under oxygenic conditions, as reflected by more viable cells and less accumulation of reactive oxygen species. Further analysis showed that the growth advantage was dependent on exopolysaccharide (EPS) synthesized by a secreted glucansucrase. Determination of the dissolved oxygen in the culture suggested that the growth improvement was mediated by extrusion of dissolved oxygen from the aqueous circumstances. Growth experiments performed with the purified EPS showed that supplementation of 5 g/L EPS in the medium could improve the aerobic growth of L. mesenteroides by ~10-fold. Moreover, the purified EPS was also effective in promoting the aerobic growth of oxygen-sensitive Lactobacillus and Bifidobacterium. These results demonstrate that EPS of L. mesenteroides plays a critical role in relief of the oxygen stress, and suggest the potential of the EPS in manufacture as well as preservation of oxygen sensitive probiotics. PMID- 30405550 TI - Genotypic and Phenotypic Characterization of IncX3 Plasmid Carrying bla NDM-7 in Escherichia coli Sequence Type 167 Isolated From a Patient With Urinary Tract Infection. AB - Infections due to New Delhi metallo-beta lactamase (NDM)-7-producing Escherichia coli are infrequent and sporadic. In this study, we report one case of recurrent urinary tract infection caused by bla NDM-7-producing E. coli belonging to phylogenetic group A, sequence type (ST) 167. In this study, we aimed to describe the genotype and phenotype of bla NDM-7-producing E. coli in China. The isolate exhibited resistance to beta-lactam antimicrobials, trimethoprim sulfamethoxazole, quinolones, and aminoglycosides. bla NDM-7 is located on a conjugative plasmid designated pJN05NDM-7 belonging to type IncX3. pJN05NDM-7 was fully sequenced and compared with all publicly available bla NDM-7-harboring plasmids. pJN05NDM-7 is almost identical to pKpN01-NDM7 and pKW53T, although the plasmids are geographically unrelated. The comparison of IncX3 plasmids harboring bla NDM in China showed high similarity, with genetic differences within insertion fragments. Notably, the differences in plasmids of animal and human origin were insignificant, because only one plasmid showed deletion inside the ISAba125 region compared with pJN05NDM7. Our study demonstrates that E. coli carrying IncX3 plasmids play an important role as a reservoir and in the spread of bla NDM. Further studies should be performed to control the dissemination of bla NDM among food animals. PMID- 30405551 TI - Endotoxemia by Porphyromonas gingivalis Injection Aggravates Non-alcoholic Fatty Liver Disease, Disrupts Glucose/Lipid Metabolism, and Alters Gut Microbiota in Mice. AB - Many risk factors related to the development of non-alcoholic fatty liver disease (NAFLD) have been proposed, including the most well-known of diabetes and obesity as well as periodontitis. As periodontal pathogenic bacteria produce endotoxins, periodontal treatment can result in endotoxemia. The aim of this study was to investigate the effects of intravenous, sonicated Porphyromonas gingivalis (Pg) injection on glucose/lipid metabolism, liver steatosis, and gut microbiota in mice. Endotoxemia was induced in C57BL/6J mice (8 weeks old) by intravenous injection of sonicated Pg; Pg was deactivated but its endotoxin remained. The mice were fed a high-fat diet and administered sonicated Pg (HFPg) or saline (HFco) injections for 12 weeks. Liver steatosis, glucose metabolism, and gene expression in the liver were evaluated. 16S rRNA gene sequencing with metagenome prediction was performed on the gut microbiota. Compared to HFco mice, HFPg mice exhibited impaired glucose tolerance and insulin resistance along with increased liver steatosis. Liver microarray analysis demonstrated that 1278 genes were differentially expressed between HFco and HFPg mice. Gene set enrichment analysis showed that fatty acid metabolism, hypoxia, and TNFalpha signaling via NFkappaB gene sets were enriched in HFPg mice. Although sonicated Pg did not directly reach the gut, it changed the gut microbiota and decreased bacterial diversity in HFPg mice. Metagenome prediction in the gut microbiota showed enriched citrate cycle and carbon fixation pathways in prokaryotes. Overall, intravenous injection of sonicated Pg caused impaired glucose tolerance, insulin resistance, and liver steatosis in mice fed high-fat diets. Thus, blood infusion of Pg contributes to NAFLD and alters the gut microbiota. PMID- 30405552 TI - Distribution of Arsenic Resistance Genes in Prokaryotes. AB - Arsenic is a metalloid that occurs naturally in aquatic and terrestrial environments. The high toxicity of arsenic derivatives converts this element in a serious problem of public health worldwide. There is a global arsenic geocycle in which microbes play a relevant role. Ancient exposure to arsenic derivatives, both inorganic and organic, has represented a selective pressure for microbes to evolve or acquire diverse arsenic resistance genetic systems. In addition, arsenic compounds appear to have been used as a toxin in chemical warfare for a long time selecting for an extended range of arsenic resistance determinants. Arsenic resistance strategies rely mainly on membrane transport pathways that extrude the toxic compounds from the cell cytoplasm. The ars operons, first discovered in bacterial R-factors almost 50 years ago, are the most common microbial arsenic resistance systems. Numerous ars operons, with a variety of genes and different combinations of them, populate the prokaryotic genomes, including their accessory plasmids, transposons, and genomic islands. Besides these canonical, widespread ars gene clusters, which confer resistance to the inorganic forms of arsenic, additional genes have been discovered recently, which broadens the spectrum of arsenic tolerance by detoxifying organic arsenic derivatives often used as toxins. This review summarizes the presence, distribution, organization, and redundance of arsenic resistance genes in prokaryotes. PMID- 30405554 TI - Understanding the Biomineralization Role of Magnetite-Interacting Components (MICs) From Magnetotactic Bacteria. AB - Biomineralization is a process that takes place in all domains of life and which usually helps organisms to harden soft tissues by creating inorganic structures that facilitate their biological functions. It was shown that biominerals are under tight biological control via proteins that are involved in nucleation initiation and/or which act as structural skeletons. Magnetotactic bacteria (MTB) use iron biomineralization to create nano-magnetic particles in a specialized organelle, the magnetosome, to align to the geomagnetic field. A specific set of magnetite-associated proteins (MAPs) is involved in regulating magnetite nucleation, size, and shape. These MAPs are all predicted to contain specific 17 22 residue-long sequences involved in magnetite formation. To understand the mechanism of magnetite formation, we focused on three different MAPs, MamC, Mms6 and Mms7, and studied the predicted iron-binding sequences. Using nuclear magnetic resonance (NMR), we differentiated the recognition mode of each MAP based on ion specificity, affinity, and binding residues. The significance of critical residues in each peptide was evaluated by mutation followed by an iron co-precipitation assay. Among the peptides, MamC showed weak ion binding but created the most significant effect in enhancing magnetite particle size, indicating the potency in controlling magnetite particle shape and size. Alternatively, Mms6 and Mms7 had strong binding affinities but less effect in modulating magnetite particle size, representing their major role potentially in initiating nucleation by increasing local metal concentration. Overall, our results explain how different MAPs affect magnetite synthesis, interact with Fe2+ ions and which residues are important for the MAPs functions. PMID- 30405553 TI - Laboratory Diagnosis of Respiratory Tract Infections in Children - the State of the Art. AB - In the pediatric population, respiratory infections are the most common cause of physician visits. Although many respiratory illnesses are self-limiting viral infections that resolve with time and supportive care, it can be critical to identify the causative pathogen at an early stage of the disease in order to implement effective antimicrobial therapy and infection control. Over the last few years, diagnostics for respiratory infections have evolved substantially, with the development of novel assays and the availability of updated tests for newer strains of pathogens. Newer laboratory methods are rapid, highly sensitive and specific, and are gradually replacing the conventional gold standards, although the clinical utility of these assays is still under evaluation. This article reviews the current laboratory methods available for testing for respiratory pathogens and discusses the advantages and disadvantages of each approach. PMID- 30405555 TI - 4-Chlorophenol Oxidation Depends on the Activation of an AraC-Type Transcriptional Regulator, CphR, in Rhodococcus sp. Strain YH-5B. AB - 4-Chlorophenol (4-CP) oxidation plays an essential role in the detoxification of 4-CP. However, oxidative regulation of 4-CP at the genetic and biochemical levels has not yet been studied. To explore the regulation mechanism of 4-CP oxidation, a novel gene cluster, cphRA2A1, involved in biodegradation of 4-CP was identified and cloned from Rhodococcus sp. strain YH-5B by genome walking. The sequence analysis showed that the cphRA2A1 gene cluster encoded an AraC-type transcriptional regulator and a two-component monooxygenase enzyme, while quantitative real-time PCR analysis further revealed that cphR was constitutively expressed and positively regulated the transcription of cphA2A1 genes in response to 4-CP or phenol, as evidenced by gene knockout and complementation experiments. Through the transcriptional fusion of the mutated cphA2A1 promoter with the lacZ gene, it was found that the CphR regulator binding sites had two 15-bp imperfect direct repeats (TGCA-N6-GGNTA) at -35 to -69 upstream of the cphA2A1 transcriptional start site. Notably, the sub-motifs at the -46 to -49 positions played a critical role in the appropriate interaction with the CphR dimer. In addition, it was confirmed that the monooxygenase subunits CphA1 and CphA2, which were purified by His-tag affinity chromatography, were able to catalyze the conversion of 4-CP to 4-chlorocatechol, suggesting that strain YH-5B could degrade 4-CP via the 4-chlorocatechol pathway. This study enhances our understanding of the genetic and biochemical diversity in the transcriptional regulation of 4-CP oxidation in Gram-positive bacteria. PMID- 30405556 TI - Identification of Amino Acids Essential for Viral Replication in the HCMV Helicase-Primase Complex. AB - Promising new inhibitors that target the viral helicase-primase complex have been reported to block replication of herpes simplex and varicella-zoster viruses, but they have no activity against human cytomegalovirus (HCMV), another herpesvirus. The HCMV helicase-primase complex (pUL105-pUL102-pUL70) is essential for viral DNA replication and could thus be a relevant antiviral target. The roles of the individual subunits composing this complex remain to be defined. By using sequence alignment of herpesviruses homologs, we identified conserved amino acids in the putative pUL105 ATP binding site and in the putative pUL70 zinc finger pattern. Mutational analysis of several of these amino acids both in pUL105 and pUL70, proved that they are crucial for viral replication. We also constructed, by homology modeling, a theoretical structure of the pUL105 N-terminal domain which indicates that the mutated conserved amino acids in this domain could be involved in ATP hydrolysis. PMID- 30405557 TI - Viral Respiratory Infections in the Neonatal Intensive Care Unit-A Review. AB - Although infrequent, respiratory viral infections (RVIs) during birth hospitalization have a significant impact on short- and long-term morbidity in term and preterm neonates. RVI have been associated with increased length of hospital stay, severe disease course, unnecessary antimicrobial exposure and nosocomial outbreaks in the neonatal intensive care unit (NICU). Virus transmission has been described to occur via health care professionals, parents and other visitors. Most at risk are infants born prematurely, due to their immature immune system and the fact that they stay in the NICU for a considerable length of time. A prevalence of RVIs in the NICU in symptomatic infants of 6-30% has been described, although RVIs are most probably underdiagnosed, since testing for viral pathogens is not performed routinely in symptomatic patients in many NICUs. Additional challenges are the wide range of clinical presentation of RVIs, their similarity to bacterial infections and the unreliable detection methods prior to the era of molecular biology based technologies. In this review, current knowledge of early-life RVI in the NICU is discussed. Reviewed viral pathogens include human rhinovirus, respiratory syncytial virus and influenza virus, and discussed literature is restricted to reports based on modern molecular biology techniques. The review highlights therapeutic approaches and possible preventive strategies. Furthermore, short- and long-term consequences of RVIs in infants hospitalized in the NICU are discussed. PMID- 30405558 TI - Evidence of Illegitimate Recombination Between Two Pasteurellaceae Plasmids Resulting in a Novel Multi-Resistance Replicon, pM3362MDR, in Actinobacillus pleuropneumoniae. AB - Evidence of plasmids carrying the tetracycline resistance gene, tet(B), was found in the previously reported whole genome sequences of 14 United Kingdom, and 4 Brazilian, isolates of Actinobacillus pleuropneumoniae. Isolation and sequencing of selected plasmids, combined with comparative sequence analysis, indicated that the four Brazilian isolates all harbor plasmids that are nearly identical to pB1001, a plasmid previously found in Pasteurella multocida isolates from Spain. Of the United Kingdom isolates, 13/14 harbor plasmids that are (almost) identical to pTetHS016 from Haemophilus parasuis. The remaining United Kingdom isolate, MIDG3362, harbors a 12666 bp plasmid that shares extensive regions of similarity with pOV from P. multocida (which carries blaROB-1 , sul2, and strAB genes), as well as with pTetHS016. The newly identified multi-resistance plasmid, pM3362MDR, appears to have arisen through illegitimate recombination of pTetHS016 into the stop codon of the truncated strB gene in a pOV-like plasmid. All of the tet(B) carrying plasmids studied were capable of replicating in Escherichia coli, and predicted origins of replication were identified. A putative origin of transfer (oriT) sequence with similar secondary structure and a nic-site almost identical to that of RP4 was also identified in these plasmids, however, attempts to mobilize them from an RP4-encoding E. coli donor strain were not successful, indicating that specific conjugation machinery may be required. PMID- 30405559 TI - Role of Extracellular Carbonic Anhydrase in Dissolved Inorganic Carbon Uptake in Alkaliphilic Phototrophic Biofilm. AB - Alkaline Soda Lakes are extremely productive ecosystems, due to their high dissolved inorganic carbon (DIC) concentrations. Here, we studied the dynamics of the carbonate system, in particular, the role of extracellular carbonic anhydrase (eCA) of an alkaliphilic phototrophic biofilm composed of bacteria enriched from soda lake benthic mats. By using measurements with microsensors and membrane inlet mass spectrometry, combined with mathematical modeling, we show how eCA controls DIC uptake. In our experiments, the activity of eCA varied four-fold, and was controlled by the bicarbonate concentration during growth: a higher bicarbonate concentration led to lower eCA activity. Inhibition of eCA decreased both the net and the gross photosynthetic productivities of the investigated biofilms. After eCA inhibition, the efflux of carbon dioxide (CO2) from the biofilms increased two- to four-fold. This could be explained by the conversion of CO2, leaking from cyanobacterial cells, by eCA, to bicarbonate. Bicarbonate is then taken up again by the cyanobacteria. In suspensions, eCA reduced the CO2 leakage to the bulk medium from 90 to 50%. In biofilms cultivated at low bicarbonate concentration (~0.13 mM), the oxygen production was reduced by a similar ratio upon eCA inhibition. The role of eCA in intact biofilms was much less significant compared to biomass suspensions, as CO2 loss to the medium is reduced due to mass transfer resistance. PMID- 30405560 TI - Transmissible ST3-IncHI2 Plasmids Are Predominant Carriers of Diverse Complex IS26-Class 1 Integron Arrangements in Multidrug-Resistant Salmonella. AB - Diverse mobile genetic elements (MGEs) including plasmids, insertion sequences, and integrons play an important role in the occurrence and spread of multidrug resistance (MDR) in bacteria. It was found in previous studies that IS26 and class 1 integrons integrated on plasmids to speed the dissemination of antibiotic resistance genes in Salmonella. It is aimed to figure out the patterns of specific genetic arrangements between IS26 and class 1 integrons located in plasmids in MDR Salmonella in this study. A total of 74 plasmid-harboring Salmonella isolates were screened for the presence of IS26 by PCR amplification, and 39 were IS26-positive. Among them, 37 isolates were resistant to at least one antibiotic. The thirty-seven antibiotic-resistant isolates were further involved in PCR detection of class 1 integrons and variable regions, and all were positive for class 1 integrons. Six IS26-class 1 integron arrangements with IS26 inserted into the upstream or downstream of class 1 integrons were characterized. Eight combinations of these IS26-class 1 integron arrangements were identified among 31 antibiotic-resistant isolates. Multidrug-resistance plasmids of the IncHI2 incompatibility group were dominant, which all belonged to ST3 by plasmid double locus sequence typing. These 21 IncHI2-positive isolates harbored six complex IS26-class 1 integron arrangement patterns. Conjugation assays and Southern blot hybridizations confirmed that conjugative multidrug-resistance IncHI2 plasmids harbored the different complex IS26-class 1 integron arrangements. The conjugation frequency of IncHI2 plasmids transferring alone was 10-5-10-6, reflecting that different complex IS26-class 1 integron arrangement patterns didn't significantly affect conjugation frequency (P > 0.05). These data suggested that class 1 integrons represent the hot spot for IS26 insertion, forming diverse MDR loci. And ST3-IncHI2 was the major plasmid lineage contributing to the horizontal transfer of composite IS26-class 1 integron MDR elements in Salmonella. PMID- 30405561 TI - Discriminatory Power Evaluation of Nuclear Ribosomal RNA Barcoding Sequences Through Ophiocordyceps sinensis Related Samples. AB - Since the cost of Ophiocordyceps sinensis has increased dramatically and the counterfeits may have adverse effect to health, a rapid and precise species-level DNA barcoding identification system could be a potent approach and significantly enhance the regulatory capacity. The discrimination power of three subunits sequences from nuclear ribosomal RNA gene cluster were determined by Simpson's index of discrimination using 43 wild O. sinensis fruiting bodies, pure cultures, commercial mycelium fermented powder and counterfeits. The internal transcribed spacer (ITS) sequences showed the highest variance and discrimination power among 43 samples, as determined by Simpson's index of discrimination (D = 0.972), followed by large subunit (LSU; D = 0.963) and small subunit (SSU; D = 0.921). ITS-2 sequences showed the highest discrimination power for 43 samples among ITS 1, ITS-2, and 5.8S region of ITS sequences. All O. sinensis samples were grouped into a unique ITS sequence cluster under 95% similarity and two O. sinensis samples and six non-O. sinensis samples showed false claims. Our data showed that the ITS region could provide accurate species identification for O. sinensis samples, especially when macroscopic and microscopic method could not be applied in the highly processed commercial products. Since the authentication of O. sinensis related products is essential to ensure its safety and efficacy, identification of O. sinensis through ITS sequence comparison or unique PCR amplification of the species specific target, such as the ITS region, should be considered in the next revision of Chinese pharmacopeia. PMID- 30405562 TI - The Roles of Two Type VI Secretion Systems in Cronobacter sakazakii ATCC 12868. AB - The type VI secretion system (T6SS), which has been found in 25% of gram-negative bacteria, is a crucial virulence factor in several pathogens. Although T6SS gene loci have been discovered in Cronobacter species, one of the major opportunistic foodborne pathogens, its function has not been elucidated. In this study, the roles of two phylogenetically distinct T6SS gene clusters in Cronobacter sakazakii ATCC12868 were investigated. Analysis of 138 genome sequences of C. sakazakii strains, we found that one T6SS gene cluster (T6SS-1) was ubiquitous in all examined strains, whereas another (T6SS-2) was absent or degenerated in a large proportion of the strains (n = 97). In addition, we confirmed the T6SS-1 antibacterial function through an in-frame deletion in the vasK and hcp genes. Compared with the wild-type strain, the T6SS-2-deficient mutant presented a much stronger colonization of organs when infecting neonatal rats. Thus, we proposed that T6SS-2 plays a role in pathogenic processes. This is the first study to investigate the functions of T6SS in C. sakazakii, and the results will extend our understanding of the pathogenic and phylogenetic characteristics of C. sakazakii. PMID- 30405563 TI - Predicting Influenza Antigenicity by Matrix Completion With Antigen and Antiserum Similarity. AB - The rapid mutation of influenza viruses especially on the two surface proteins hemagglutinin (HA) and neuraminidase (NA) has made them capable to escape from population immunity, which has become a key challenge for influenza vaccine design. Thus, it is crucial to predict influenza antigenic evolution and identify new antigenic variants in a timely manner. However, traditional experimental methods like hemagglutination inhibition (HI) assay to select vaccine strains are time and labor-intensive, while popular computational methods are less sensitive, which presents the need for more accurate algorithms. In this study, we have proposed a novel low-rank matrix completion model MCAAS to infer antigenic distances between antigens and antisera based on partially revealed antigenic distances, virus similarity based on HA protein sequences, and vaccine similarity based on vaccine strains. The model exploits the correlations of viruses and vaccines in serological tests as well as the ability of HAs from viruses and vaccine strains in inferring influenza antigenicity. We also compared the effects of comprehensive 65 amino acids substitution matrices in predicting influenza antigenicity. As a result, we applied MCAAS into H3N2 seasonal influenza virus data. Our model achieved a 10-fold cross validation root-mean-squared error (RMSE) of 0.5982, significantly outperformed existing computational methods like antigenic cartography, AntigenMap and BMCSI. We also constructed the antigenic map and studied the association between genetic and antigenic evolution of H3N2 influenza viruses. Finally, our analyses showed that homologous structure derived amino acid substitution matrix (HSDM) is most powerful in predicting influenza antigenicity, which is consistent with previous studies. PMID- 30405564 TI - Therapeutic Potential of a New Jumbo Phage That Infects Vibrio coralliilyticus, a Widespread Coral Pathogen. AB - Biological control using bacteriophages is a promising approach for mitigating the devastating effects of coral diseases. Several phages that infect Vibrio coralliilyticus, a widespread coral pathogen, have been isolated, suggesting that this bacterium is permissive to viral infection and is, therefore, a suitable candidate for treatment by phage therapy. In this study, we combined functional and genomic approaches to evaluate the therapeutic potential of BONAISHI, a novel V. coralliilyticus phage, which was isolated from the coral reef in Van Phong Bay (Vietnam). BONAISHI appears to be strictly lytic for several pathogenic strains of V. coralliilyticus and remains infectious over a broad range of environmental conditions. This candidate has an unusually large dsDNA genome (303 kb), with no genes that encode known toxins or implicated in lysogeny control. We identified several proteins involved in host lysis, which may offer an interesting alternative to the use of whole bacteriophages for controlling V. coralliilyticus. A preliminary therapy test showed that adding BONAISHI to an infected culture of Symbiodinium sp. cells reduced the impact of V. coralliilyticus on Symbiodinium sp. photosynthetic activity. This study showed that BONAISHI is able to mitigate V. coralliilyticus infections, making it a good candidate for phage therapy for coral disease. PMID- 30405565 TI - Spatial Variability and Co-acclimation of Phytoplankton and Bacterioplankton Communities in the Pearl River Estuary, China. AB - Phytoplankton and bacterioplankton play significant roles in estuarine systems. It is important to demonstrate the spatial variability of bacterial and microalgal communities and understand the co-acclimation of these organisms to different environmental factors. In this study, MiSeq sequencing and morphological identification were applied to analyze the variations in bacterial and microalgal communities in the Pearl River Estuary, respectively. Molecular ecological network analysis was used to investigate the potential interactions between microalgae and bacteria and illustrate the responses of these interactions to environmental gradients. The results revealed that microalgal/bacterial communities in freshwater samples were distinct from those in mesohaline water samples. Microalgae affiliated to the genus Skeletonema dominated the mesohaline water phytoplankton communities, while Melosira was the more abundant genus in freshwater communities. Actinobacteria, Alphaproteobacteria, Betaproteobacteria, and Acidimicrobiia dominated bacterial communities in freshwater samples, while Gammaproteobacteria, Bacilli, and Synechococcophycideae were more abundant in mesohaline water samples. Tightly correlations were observed between phytoplankton and bacterioplankton. These interactions were regarded to be key factors in shaping the community structures. Further, the KEGG database and PICRUSt were used to predict the functions of bacterioplankton in the process of nitrogen cycling. The results indicated that denitrification could play an important role in nitrogen loss and might alleviate the eutrophication in the Pearl River Estuary. Collectively, the results in this study revealed that substantial changes in phytoplankton and bacterioplankton communities were correlated with the gradients of environmental parameters in the Pearl River Estuary. The results also demonstrated that the interactions between phytoplankton and bacterioplankton were important for these organisms to acclimate to changing environments. PMID- 30405566 TI - Comparative Genomics and in vitro Infection of Field Clonal Isolates of Brucella melitensis Biovar 3 Did Not Identify Signature of Host Adaptation. AB - Brucella spp. are responsible for brucellosis, a widespread zoonosis causing reproductive disorders in animals. Species-classification within this monophyletic genus is based on bacteriological and biochemical phenotyping. Traditionally, Brucella species are reported to have a preferential, but not exclusive mammalian host. However, this concept can be challenged since many Brucella species infect a wide range of animal species. Adaptation to a specific host can be a driver of pathogen variation. It is generally thought that Brucella species have highly stable and conserved genomes, however the degree of genomic variation during natural infection has not been documented. Here, we investigated potential genetic diversity and virulence of Brucella melitensis biovar 3 field isolates obtained from a single outbreak but from different host species (human, bovine, small ruminants). A unique MLVA-16 pattern suggested all isolates were clonal. Comparative genomic analyses showed an almost non-existent genetic diversity among isolates (only one SNP; no architectural rearrangements) and did not highlight any signature specific to host adaptation. Similarly, the strains showed identical capacities to enter and replicate in an in vitro model of macrophage infection. In our study, the absence of genomic variability and similar virulence underline that B. melitensis biovar 3 is a broad-host-range pathogen without the need to adapt to different hosts. PMID- 30405567 TI - Impact of Salicylic Acid and PGPR on the Drought Tolerance and Phytoremediation Potential of Helianthus annus. AB - The present study was aimed to isolate and characterize plant growth promoting rhizobacteria (PGPR) from the rhizosphere of rainfed area (Karak) in Pakistan. The influence of isolated rhizobacteria, in association with salicylic acid (SA), physiological attributes, drought tolerance potential, and phytoremediation in drought-stressed sunflower exposed was investigated. The isolated bacteria were named P1 and P2 and characterized on the basis of colony morphology and biochemical traits. Both PGPR P1 and P2 were identified on the basis of 16S-rRNA gene sequencing as Planomicrobium chinense strain P1 (Accession No. MF616408) and Bacillus cereus strain P2 (Accession No. MF616406). The fresh cultures (24 h old) of isolates were used to soak the seeds pre-sowing. SA was foliar applied at three-leaf-stage. Likewise, the 30-days-old seedlings (three leaf stage) were exposed to drought stress. Drought stress was imposed to 30-days-old plants (three-leaf stage) by withholding water supply for the next 15 days until the soil water content reached 10%. The PGPR and/or SA treatment resulted in significant accumulation of Cd (84%), Pb (66%), and Ni (65%) in the rhizosphere. PGPR also induced accumulation of Cd and Ni in plant shoot. Combined treatment of PGPR and SA increased the Cu (21%), Co (11%), and Zn (8%) accumulation but decreased (12%) the Fe accumulation as compared to coinoculation of PGPR P1 and P2. Inoculation of plants with PGPR significantly increased shoot length (60%), root length (68%), root fresh (61%), and dry (63%) biomass under water stress. The inoculated plants had increased chlorophyll (67%), carotenoid (70%), leaf protein (64%), sugar (64%), and phenolic (62%) contents while lower leaf proline (62%) content, malondialdehyde (MDA) (64%), and antioxidant enzymes (67%) which suggest their role in drought tolerance. It is concluded that integrative use of PGPR in combination with SA found to be an efficacious strategy to improve the phytoremediation of heavy metals and plant growth under stressed conditions particularly under water-deficient conditions. PMID- 30405568 TI - Effects of 5-Azacytidine on Growth and Hypocrellin Production of Shiraia bambusicola. AB - Hypocrellins, fungal perylenequinones of Shiraia bambusicola are developed as important photodynamic therapy agents against cancers and viruses. Due to the limitation of the wild resources, the mycelium culture is a promising alternative for hypocrellin production. As DNA methylation has profound effects on fungal growth, development and secondary metabolism, we used both McrBC cleavage and HPLC analysis to reveal the status of DNA methylation of S. bambusicola mycelium. We found that DNA methylation is absent in mycelia, but DNA methylation inhibitor 5-azacytidine (5-AC) still induced the fluffy phenotype and decreased hypocrellin contents significantly. Simultaneously, a total of 4,046 differentially expressed genes were induced by 5-AC, including up-regulated 2,392 unigenes (59.12%) and down-regulated 1,654 unigenes (40.88%). Gene ontology analysis showed 5-AC treatment changed expression of genes involved in membrane composition and oxidation-reduction process. The fluffy phenotype in 5-AC-treated S. bambusicola was closely related to strong promotion of developmental regulator WetA and the repression of the sexual developmental actor VeA and LaeA. It was a surprise finding that 5-AC reduced reactive oxygen species (ROS) production significantly in the mycelia via the inhibition of NADPH oxidase gene (NOX) expression and NOX activity. With the treatment of vitamin C and H2O2, we found that the reduced ROS generation was involved in the down-regulated expression of key genes for hypocrellin biosynthesis and the decreased hypocrellin production. To our knowledge, this is the first attempt to examine DNA methylation level in S. bambusicola. Our results suggested that the mediation of ROS generation could not be ignored in the study using 5-AC as a specific DNA methylation inhibitor. PMID- 30405569 TI - Dynamic Distribution of Gut Microbiota in Goats at Different Ages and Health States. AB - The importance of the gut microbiota (GM) of animals is widely acknowledged because of its pivotal roles in metabolism, immunity, and health maintenance. The level of health can be reflected by the dynamic distribution of GM. In this study, high-throughput sequencing of the bacterial 16S rRNA gene was used to compare the microbial populations from feces in healthy and diarrheic kids, which reflected the dynamic shift of microbiota in kids and investigated differences from adult healthy goats. Healthy kids and goats not only displayed higher species richness but also exhibited higher bacterial diversity than diarrheic kids based on the results of the operational taxonomic unit analysis, alpha diversity, and beta diversity. Firmicutes and Bacteroidetes were the most dominant phyla in all samples. At the genus level, the differences in diversity and abundance between diarrheic kids and the other two groups were gradually observed. In the diarrheic kid intestine, Bacteroides remained the dominant species, and the proportion of Clostridium_sensu_stricto_1 and Paeniclostridium increased, whereas Rikenellaceae_RC9_gut_group, Ruminococcaceae_UCG-005, and Christensenellaceae_R-7_group were significantly reduced. The results showed the differences of GM in diarrheic kids and healthy kids were significant while in kids and goats were not obvious. Differences in the composition of intestinal microbiota may not be the cause of diarrhea, and some changes of bacterial richness may guide our interpretation of diarrhea. This study is the first to investigate the distribution of GM in Boer goats with different ages and health states. Furthermore, this study will provide a theoretical basis for the establishment of a prevention and treatment system for goat diarrhea. PMID- 30405570 TI - CXCR4- and CCR5-Tropic HIV-1 Clones Are Both Tractable to Grow in Rhesus Macaques. AB - A major issue for present HIV-1 research is to establish model systems that reflect or mimic viral replication and pathogenesis actually observed in infected humans. To this end, various strategies using macaques as infection targets have long been pursued. In particular, experimental infections of rhesus macaques by HIV-1 derivatives have been believed to be best suited, if practicable, for studies on interaction of HIV-1 and humans under various circumstances. Recently, through in vitro genetic manipulations and viral cell-adaptations, we have successfully generated a series of HIV-1 derivatives with CXCR4-tropism or CCR5 tropism that grow in macaque cells to various degrees. Of these viruses, those with best replicative potentials can grow comparably with a pathogenic SIVmac in macaque cells by counteracting major restriction factors TRIM5, APOBEC3, and tetherin proteins. In this study, rhesus macaques were challenged with CXCR4 tropic (MN4/LSDQgtu) or CCR5-tropic (gtu + A4CI1) virus. The two viruses were found to productively infect rhesus macaques, being rhesus macaque-tropic HIV-1 (HIV-1rmt). However, plasma viral RNA was reduced to be an undetectable level in infected macaques at 5-6 weeks post-infection and thereafter. While replicated similarly well in rhesus peripheral blood mononuclear cells, MN4/LSDQgtu grew much better than gtu + A4CI1 in the animals. To the best of our knowledge, this is the first report demonstrating that HIV-1 derivatives (variants) grow in rhesus macaques. These viruses certainly constitute firm bases for generating HIV 1rmt clones pathogenic for rhesus monkeys, albeit they grow more poorly than pathogenic SIVmac and SHIV clones reported to date. PMID- 30405571 TI - Microbial Community Dynamics in Mother's Milk and Infant's Mouth and Gut in Moderately Preterm Infants. AB - Mother's own milk represents the optimal source for preterm infant nutrition, as it promotes immune defenses and gastrointestinal function, protects against necrotizing enterocolitis, improves long-term clinical outcome and is hypothesized to drive gut microbiota assembly. Preterm infants at birth usually do not receive their mother's milk directly from the breast, because active suckling and coordination between suckling, swallowing and breathing do not develop until 32-34 weeks gestational age, but actual breastfeeding is usually possible as they grow older. Here, we enrolled moderately preterm infants (gestational age 32-34 weeks) to longitudinally characterize mothers' milk and infants' gut and oral microbiomes, up to more than 200 days after birth, through 16S rRNA sequencing. This peculiar population offers the chance to disentangle the differential contribution of human milk feeding per se vs. actual breastfeeding in the development of infant microbiomes, that have both been acknowledged as crucial contributors to short and long-term infant health status. In this cohort, the milk microbiome composition seemed to change following the infant's latching to the mother's breast, shifting toward a more diverse microbial community dominated by typical oral microbes, i.e., Streptococcus and Rothia. Even if all infants in the present study were fed human milk, features typical of healthy, full term, exclusively breastfed infants, i.e., high percentages of Bifidobacterium and low abundances of Pseudomonas in fecal and oral samples, respectively, were detected in samples taken after actual breastfeeding started. These findings underline the importance of encouraging not only human milk feeding, but also an early start of actual breastfeeding in preterm infants, since the infant's latching to the mother's breast might constitute an independent factor helping the health-promoting assembly of the infant gut microbiome. PMID- 30405572 TI - Antimicrobial Resistance Profile of mcr-1 Positive Clinical Isolates of Escherichia coli in China From 2013 to 2016. AB - Multidrug-resistant (MDR) Escherichia coli poses a great challenge for public health in recent decades. Polymyxins have been reconsidered as a valuable therapeutic option for the treatment of infections caused by MDR E. coli. A plasmid-encoded colistin resistance gene mcr-1 encoding phosphoethanolamine transferase has been recently described in Enterobacteriaceae. In this study, a total of 123 E. coli isolates obtained from patients with diarrheal diseases in China were used for the genetic analysis of colistin resistance in clinical isolates. Antimicrobial resistance profile of polymyxin B (PB) and 11 commonly used antimicrobial agents were determined. Among the 123 E. coli isolates, 9 isolates (7.3%) were resistant to PB and PCR screening showed that seven (5.7%) isolates carried the mcr-1 gene. A hybrid sequencing analysis using single molecule, real-time (SMRT) sequencing and Illumina sequencing was then performed to resolve the genomes of the seven mcr-1 positive isolates. These seven isolates harbored multiple plasmids and are MDR, with six isolates carrying one mcr-1 positive plasmid and one isolate (14EC033) carrying two mcr-1 positive plasmids. These eight mcr-1 positive plasmids belonged to the IncX4, IncI2, and IncP1 types. In addition, the mcr-1 gene was the solo antibiotic resistance gene identified in the mcr-1 positive plasmids, while the rest of the antibiotic resistance genes were mostly clustered into one or two plasmids. Interestingly, one mcr-1 positive isolate (14EC047) was susceptible to PB, and we showed that the activity of MCR-1-mediated colistin resistance was not phenotypically expressed in 14EC047 host strain. Furthermore, three isolates exhibited resistance to PB but did not carry previously reported mcr-related genes. Multilocus sequence typing (MLST) showed that these mcr-1 positive E. coli isolates belonged to five different STs, and three isolates belonged to ST301 which carried multiple virulence factors related to diarrhea. Additionally, the mcr-1 positive isolates were all susceptible to imipenem (IMP), suggesting that IMP could be used to treat infection caused by mcr-1 positive E. coli isolates. Collectively, this study showed a high occurrence of mcr-1 positive plasmids in patients with diarrheal diseases of Guangzhou in China and the abolishment of the MCR-1 mediated colistin resistance in one E. coli isolate. PMID- 30405573 TI - ant(6)-I Genes Encoding Aminoglycoside O-Nucleotidyltransferases Are Widely Spread Among Streptomycin Resistant Strains of Campylobacter jejuni and Campylobacter coli. AB - Thermotolerant Campylobacter species C. jejuni and C. coli are actually recognized as the major bacterial agent responsible for food-transmitted gastroenteritis. The most effective antimicrobials against Campylobacter are macrolides and some, but not all aminoglycosides. Among these, susceptibility to streptomycin is reduced by mutations in the ribosomal RPSL protein or by expression of ANT(6)-I aminoglycoside O-nucleotidyltransferases. The presence of streptomycin resistance genes was evaluated among streptomycin-resistant Campylobacter isolated from humans and animals by using PCR with degenerated primers devised to distinguish ant(6)-Ia, ant(6)-Ib and other ant-like genes. Genes encoding ANT(6)-I enzymes were found in all possible combinations with a major fraction of the isolates carrying a previously described ant-like gene, distantly related and belonging to the new ant(6)-I sub-family ant(6)-Ie. Among Campylobacter isolates, ant(6)-Ie was uniquely found functional in C. coli, as shown by gene transfer and phenotype expression in Escherichia coli, unlike detected coding sequences in C. jejuni that were truncated by an internal frame shift associated to RPSL mutations in streptomycin resistant strains. The genetic relationships of C. coli isolates with ANT(6)-Ie revealed one cluster of strains presented in bovine and humans, suggesting a circulation pathway of Campylobacter strains by consuming contaminated calf meat by bacteria expressing this streptomycin resistance element. PMID- 30405574 TI - Equine Methicillin-Resistant Sequence Type 398 Staphylococcus aureus (MRSA) Harbor Mobile Genetic Elements Promoting Host Adaptation. AB - Continuing introduction of multi-drug resistant, zoonotic pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) in horse clinics challenges the biosafety of employees and animal patients. This study was aimed to determine the occurrence of mobile genetic elements facilitating survival in the early stages of invasive infection in different host species, including humans and horses, in MRSA carried by equine patients admitted to a large horse clinic. A total of 341 equine patients were investigated for carriage of MRSA by hygiene screening directly at hospital admission. MRSA were further investigated by antimicrobial susceptibility testing, whole-genome sequencing and genomic composition, including virulence factors involved in immune evasion and host adaption. From a total of 340 validated specimens from equine nostrils, 3.5% yielded positive results for MRSA. All MRSA were found to be closely related belonging to sequence type (ST) 398_t011 with up to four additional antimicrobial resistances. All MRSA harbored a specific Staphylococcal Pathogenicity Island (SaPIbov5) involved in facilitating survival in ruminant and equine plasma. Moreover, a beta-hemolysin (hlb) converting PhiSa3 phage encoding the human specific Immune Evasion Cluster (IEC) was present in 72% of the isolates. An equid-specific leukotoxin encoded by a further temperate phage (Saeq1) was only rarely detected (22%). Despite the absence of beta-hemolysin production for all IEC-positive ST398, a prominent hemolysis zone was demonstrable on sheep blood agar. Thus, IEC might remain undetected among the ST398 lineage, since the presence of IEC is commonly associated with reduction of hemolysis in S. aureus belonging to other genetic backgrounds. Here we describe MRSA-ST398 harboring different mobile genetic elements encoding variants of immune evasion factors and toxins previously shown to contribute to S. aureus invasive diseases in specific host species or ecologic niches. We suggest these combinations contribute to the adaptation of MRSA belonging to ST398 with respect to epidemic spread across different habitats and hosts, and may therefore confer a host "generalist" phenotype. PMID- 30405575 TI - Phage-Borne Depolymerases Decrease Klebsiella pneumoniae Resistance to Innate Defense Mechanisms. AB - Klebsiella pneumoniae produces capsular polysaccharides that are a crucial virulence factor protecting bacteria against innate response mechanisms of the infected host. Simultaneously, those capsules are targeted by specific bacteriophages equipped with virion-associated depolymerases able to recognize and degrade these polysaccharides. We show that Klebsiella phage KP32 produces two capsule depolymerases, KP32gp37 and KP32gp38, with a high specificity for the capsular serotypes K3 and K21, respectively. Together, they determine the host spectrum of bacteriophage KP32, which is limited to strains with serotype K3 and K21. Both depolymerases form a trimeric beta-structure, display moderate thermostability and function optimally under neutral to alkaline conditions. We show that both depolymerases strongly affect the virulence of K. pneumoniae with the corresponding K3 and K21 capsular serotypes. Capsule degradation renders the otherwise serum-resistant cells more prone to complement-mediated killing with up to four log reduction in serum upon exposure to KP32gp37. Decapsulated strains are also sensitized for phagocytosis with a twofold increased uptake. In addition, the intracellular survival of phagocytized cells in macrophages was significantly reduced when bacteria were previously exposed to the capsule depolymerases. Finally, depolymerase application considerably increases the lifespan of Galleria mellonella larvae infected with K. pneumoniae in a time- and strain-dependent manner. In sum, capsule depolymerases are promising antivirulence compounds that act by defeating a major resistance mechanism of K. pneumoniae against the innate immunity. PMID- 30405576 TI - SakA and MpkC Stress MAPKs Show Opposite and Common Functions During Stress Responses and Development in Aspergillus nidulans. AB - Stress activated MAP kinases (SAPKs) of the Hog1/Sty1/p38 family are specialized in transducing stress signals. In contrast to what is seen in animal cells, very few fungal species contain more than one SAPK. Aspergillus nidulans and other Aspergilli contain two SAPKs called SakA/HogA and MpkC. We have shown that SakA is essential for conidia to maintain their viability and to survive high H2O2 concentrations. H2O2 induces SakA nuclear accumulation and its interaction with transcription factor AtfA. Although SakA and MpkC show physical interaction, little is known about MpkC functions. Here we show that DeltampkC mutants are not sensitive to oxidative stress but in fact MpkC inactivation partially restores the oxidative stress resistance of DeltasakA mutants. DeltampkC mutants display about twofold increase in the production of fully viable conidia. The inactivation of the SakA upstream MAPKK PbsB or the simultaneous elimination of sakA and mpkC result in virtually identical phenotypes, including decreased radial growth, a drastic reduction of conidiation and a sharp, progressive loss of conidial viability. SakA and to a minor extent MpkC also regulate cell-wall integrity. Given the roles of MpkC in conidiation and oxidative stress sensitivity, we used a functional MpkC::GFP fusion to determine MpkC nuclear localization as an in vivo indicator of MpkC activation during asexual development and stress. MpkC is mostly localized in the cytoplasm of intact conidia, accumulates in nuclei during the first 2 h of germination and then becomes progressively excluded from nuclei in growing hyphae. In the conidiophore, MpkC nuclear accumulation increases in vesicles, metulae and phialides and decreases in older conidia. Oxidative and osmotic stresses induce MpkC nuclear accumulation in both germinating conidia and hyphae. In all these cases, MpkC nuclear accumulation is largely dependent on the MAPKK PbsB. Our results indicate that SakA and MpkC play major, distinct and sometimes opposing roles in conidiation and conidiospore physiology, as well as common roles in response to stress. We propose that two SAPKs are necessary to delay (MpkC) or fully stop (SakA) mitosis during conidiogenesis and the terminal differentiation of conidia, in the highly prolific phialoconidiation process characteristic of the Aspergilli. PMID- 30405577 TI - Reduced Chlorine in Drinking Water Distribution Systems Impacts Bacterial Biodiversity in Biofilms. AB - In drinking water distribution systems (DWDS), a disinfectant residual is usually applied to limit bacterial regrowth. However, delivering water with no or reduced chlorine residual could potentially decrease the selection for antimicrobial resistant microorganisms, favor bacterial regrowth and result in changes in bacterial populations. To evaluate the feasibility of water reduction in local DWDS while ensuring water safety, water quality was measured over 2 months in two different networks, each of them harboring sub-areas with normal and reduced chlorine. Water quality remained good in chlorine reduced samples, with limited development of total flora and absence of coliforms. Furthermore, 16S rRNA amplicon-based metagenomics was used to investigate the diversity and the composition of microbial communities in the sub-networks. Taxonomic classification of sequence reads showed a reduced bacterial diversity in sampling points with higher chlorine residuals. Chlorine disinfection created more homogeneous bacterial population, dominated by Pseudomonas, a genus that contains some major opportunistic pathogens such as P. aeruginosa. In the absence of chlorine, a larger and unknown biodiversity was unveiled, also highlighted by a decreased rate of taxonomic classification to the genus and species level. Overall, this experiment in a functional DWDS will facilitate the move toward potable water delivery systems without residual disinfectants and will improve water taste for consumers. PMID- 30405579 TI - The Prospects of an Active Vaccine Against Asthma Targeting IL-5. AB - Allergen-specific T helper type 2 (Th2) responses followed by eosinophilic inflammation of the lung are important causes of allergic asthma. Interleukin-5 (IL-5) is a master regulator of eosinophil differentiation as well as activation. Blocking IL-5 using monoclonal antibodies (mAbs) against IL-5 is a powerful way to improve asthmatic symptoms in patients with an eosinophilic component of the disease. We have previously shown that vaccination against IL-5 can abrogate eosinophilic inflammation of the lung in allergic mice. More recently, we have demonstrated that eosinophil-mediated skin disease in horses with insect bite hypersensitivity can be strongly reduced by vaccination against IL-5. Here we would like to propose the development of a similar vaccine for the treatment of asthma in humans. PMID- 30405578 TI - Immunomodulatory Function of HBeAg Related to Short-Sighted Evolution, Transmissibility, and Clinical Manifestation of Hepatitis B Virus. AB - Hepatitis B virus (HBV) infection, a global public health problem can be asymptomatic, acute or chronic and can lead to serious consequences of infection, including cirrhosis, and hepatocellular carcinoma. HBV, a partially double stranded DNA virus, belongs to the family Hepadnaviridae, and replicates via reverse transcription of an RNA intermediate. This reverse transcription is catalyzed by a virus-encoded polymerase that lacks proof reading ability, which leads to sequence heterogeneity. HBV is classified into nine genotypes and at least 35 subgenotypes, which may be characterized by distinct geographical distributions. This HBV diversification and distinct geographical distribution has been proposed to be the result of the co-expansion of HBV with modern humans, after their out-of-Africa migration. HBeAg is a non-particulate protein of HBV that has immunomodulatory properties as a tolerogen that allows the virus to establish HBV infection in vivo. During the natural course of infection, there is seroconversion from a HBeAg-positive phase to a HBeAg-negative, anti-HBe-positive phase. During this seroconversion, there is loss of tolerance to infection and immune escape-HBeAg-negative mutants can be selected in response to the host immune response. The different genotypes and, in some cases, subgenotypes develop different mutations that can affect HBeAg expression at the transcriptional, translational and post-translational levels. The ability to develop mutations, affecting HBeAg expression, can influence the length of the HBeAg-positive phase, which is important in determining both the mode of transmission and the clinical course of HBV infection. Thus, the different genotypes/subgenotypes have evolved in such a way that they exhibit different modes of transmission and clinical manifestation of infection. Loss of HBeAg may be a sign of short-sighted evolution because there is loss of tolerogenic ability of HBeAg and HBeAg negative virions are less transmissible. Depending on their ability to lead to HBeAg seroconversion, the genotype/subgenotypes exhibit varying degrees of short sighted evolution. The "arms race" between HBV and the immune response to HBeAg is multifaceted and its elucidation intricate, with transmissibility and persistence being important for the survival of the virus. We attempt to shed some light on this complex interplay between host and virus. PMID- 30405580 TI - Expression Patterns, Genomic Conservation and Input Into Developmental Regulation of the GGDEF/EAL/HD-GYP Domain Proteins in Streptomyces. AB - To proliferate, antibiotic-producing Streptomyces undergo a complex developmental transition from vegetative growth to the production of aerial hyphae and spores. This morphological switch is controlled by the signaling molecule cyclic bis (3',5') di-guanosine-mono-phosphate (c-di-GMP) that binds to the master developmental regulator, BldD, leading to repression of key sporulation genes during vegetative growth. However, a systematical analysis of all the GGDEF/EAL/HD-GYP proteins that control c-di-GMP levels in Streptomyces is still lacking. Here, we have FLAG-tagged all 10 c-di-GMP turnover proteins in Streptomyces venezuelae and characterized their expression patterns throughout the life cycle, revealing that the diguanylate cyclase (DGC) CdgB and the phosphodiesterase (PDE) RmdB are the most abundant GGDEF/EAL proteins. Moreover, we have deleted all the genes coding for c-di-GMP turnover enzymes individually and analyzed morphogenesis of the mutants in macrocolonies. We show that the composite GGDEF-EAL protein CdgC is an active DGC and that deletion of the DGCs cdgB and cdgC enhance sporulation whereas deletion of the PDEs rmdA and rmdB delay development in S. venezuelae. By comparing the pan genome of 93 fully sequenced Streptomyces species we show that the DGCs CdgA, CdgB, and CdgC, and the PDE RmdB represent the most conserved c-di-GMP-signaling proteins in the genus Streptomyces. PMID- 30405581 TI - Bacterial Diversity and the Geochemical Landscape in the Southwestern Gulf of Mexico. AB - Marine sediments are an example of one of the most complex microbial habitats. These bacterial communities play an important role in several biogeochemical cycles in the marine ecosystem. In particular, the Gulf of Mexico has a ubiquitous concentration of hydrocarbons in its sediments, representing a very interesting niche to explore. Additionally, the Mexican government has opened its oil industry, offering several exploration and production blocks in shallow and deep water in the southwestern Gulf of Mexico (swGoM), from which there are no public results of conducted studies. Given the higher risk of large-scale oil spills, the design of contingency plans and mitigation activities before oil exploitation is of growing concern. Therefore, a bacterial taxonomic baseline profile is crucial to understanding the impact of any eventual oil spill. Here, we show a genus level taxonomic profile to elucidate the bacterial baseline, pointing out richness and relative abundance, as well as relationships with 79 abiotic parameters, in an area encompassing ~150,000 km2, including a region where the exploitation of new oil wells has already been authorized. Our results describe for the first time the bacterial landscape of the swGoM, establishing a bacterial baseline "core" of 450 genera for marine sediments in this region. We can also differentiate bacterial populations from shallow and deep zones of the swGoM based on their community structure. Shallow sediments have been chronically exposed to aromatic hydrocarbons, unlike deep zones. Our results reveal that the bacterial community structure is particularly enriched with hydrocarbon-degrading bacteria in the shallow zone, where a greater aromatic hydrocarbon concentration was determined. Differences in the bacterial communities in the swGoM were also observed through a comprehensive comparative analysis relative to various marine sediment sequencing projects, including sampled sites from the Deep Water Horizon oil spill. This study in the swGoM provides clues to the bacterial population adaptation to the ubiquitous presence of hydrocarbons and reveals organisms such as Thioprofundum bacteria with potential applications in ecological surveillance. This resource will allow us to differentiate between natural conditions and alterations generated by oil extraction activities, which, in turn, enables us to assess the environmental impact of such activities. PMID- 30405582 TI - Responses of Nitrogen-Cycling Microorganisms to Dazomet Fumigation. AB - The influence of soil fumigation on microorganisms involved in transforming nitrogen remains little understood, despite the use of fumigants for many decades to control soil-borne pathogens and plant-parasitic nematodes. We used real-time PCR (quantitative polymerase chain reaction) and 16S rRNA gene amplicon sequencing techniques to monitor changes in the diversity and community structure of microorganisms associated with nitrogen transfer after the soil was fumigated with dazomet (DZ). We also examined nitrous oxide (N2O) emissions from these microorganisms present in fumigated fluvo-aquic soil and lateritic red soil. Fumigation with DZ significantly reduced the abundance of 16S rRNA and nitrogen cycling functional genes (nifH, AOA amoA, AOB amoA, nxrB, narG, napA, nirK, nirS, cnorB, qnorB, and nosZ). At the same time, N2O production rates increased between 9.9 and 30 times after fumigation. N2O emissions were significantly correlated with NH4+ , dissolved amino acids and microbial biomass nitrogen, but uncorrelated with functional gene abundance. Diversity indices showed that DZ temporarily stimulated bacterial diversity as well as caused a significant change in bacterial community composition. For example, DZ significantly decreased populations of N2-fixing bacteria Mesorhizobium and Paenibacillus, nitrifiers Nitrosomonas, and the denitrifiers Bacillus, Pseudomonas, and Paracoccus. The soil microbial community had the ability to recover to similar population levels recorded in unfumigated soils when the inhibitory effects of DZ fumigation were no longer evident. The microbial recovery rate, however, depended on the physicochemical properties of the soil. These results provided useful information for environmental safety assessments of DZ in China, for improving our understanding of the N-cycling pathways in fumigated soils, and for determining the potential responses of different N-cycling groups after fumigation. PMID- 30405583 TI - Oyster Farming, Temperature, and Plankton Influence the Dynamics of Pathogenic Vibrios in the Thau Lagoon. AB - Vibrio species have been associated with recurrent mass mortalities of juvenile oysters Crassostrea gigas threatening oyster farming worldwide. However, knowledge of the ecology of pathogens in affected oyster farming areas remains scarce. Specifically, there are no data regarding (i) the environmental reservoirs of Vibrio populations pathogenic to oysters, (ii) the environmental factors favoring their transmission, and (iii) the influence of oyster farming on the persistence of those pathogens. This knowledge gap limits our capacity to predict and mitigate disease occurrence. To address these issues, we monitored Vibrio species potentially pathogenic to C. gigas in 2013 and 2014 in the Thau Lagoon, a major oyster farming region in the coastal French Mediterranean. Sampling stations were chosen inside and outside oyster farms. Abundance and composition of phyto-, microzoo-, and mesozooplankton communities were measured monthly. The spatial and temporal dynamics of plankton and Vibrio species were compared, and positive correlations between plankton species and vibrios were verified by qPCR on isolated specimens of plankton. Vibrio crassostreae was present in the water column over both years, whereas Vibrio tasmaniensis was mostly found in 2013 and Vibrio aestuarianus was never detected. Moreover, V. tasmaniensis and V. crassostreae were found both as free-living or plankton attached vibrios 1 month after spring mortalities of the oyster juveniles. Overall, V. crassostreae was associated with temperature and plankton composition, whereas V. tasmaniensis correlated with plankton composition only. The abundance of Vibrio species in the water column was similar inside and outside oyster farms, suggesting important spatial dispersion of pathogens in surrounding areas. Remarkably, a major increase in V. tasmaniensis and V. crassostreae was measured in the sediment of oyster farms during cold months. Thus, a winter reservoir of pathogenic vibrios could contribute to their ecology in this Mediterranean shellfish farming ecosystem. PMID- 30405584 TI - Cervicovaginal Fungi and Bacteria Associated With Cervical Intraepithelial Neoplasia and High-Risk Human Papillomavirus Infections in a Hispanic Population. AB - The human cervicovaginal microbiota resides at an interface between the host and the environment and may affect susceptibility to disease. Puerto Rican women have high human papillomavirus (HPV) infection and cervical cancer rates. We hypothesized that the population structure of the cervicovaginal bacterial and fungal biota changed with cervical squamous intraepithelial lesions and HPV infections. DNA was extracted from cervix, introitus, and anal sites of 62 patients attending high-risk San Juan clinics. The 16S rRNA V4 region and ITS-2 fungal regions were amplified and sequenced using Illumina technology. HPV genotyping was determined by reverse hybridization with the HPV SPF10-LiPA25 kit. HPV prevalence was 84% of which ~44% subjects were infected with high-risk HPV, ~35% were co-infected with as many as 9 HPV types and ~5% were infected with exclusively low-risk HPV types. HPV diversity did not change with cervical dysplasia. Cervical bacteria were more diverse in patients with CIN3 pre cancerous lesions. We found enrichment of Atopobium vaginae and Gardnerella vaginalis in patients with CIN3 lesions. We found no significant bacterial biomarkers associated with HPV infections. Fungal diversity was significantly higher in cervical samples with high-risk HPV and introitus samples of patients with Atypical Squamous Cells of Undetermined Significance (ASCUS). Fungal biomarker signatures for vagina and cervix include Sporidiobolaceae and Sacharomyces for ASCUS, and Malassezia for high-risk HPV infections. Our combined data suggests that specific cervicovaginal bacterial and fungal populations are related to the host epithelial microenvironment, and could play roles in cervical dysplasia. PMID- 30405585 TI - The Botrytis cinerea Xylanase BcXyl1 Modulates Plant Immunity. AB - Botrytis cinerea is one of the most notorious pathogenic species that causes serious plant diseases and substantial losses in agriculture throughout the world. We identified BcXyl1 from B. cinerea that exhibited xylanase activity. Expression of the BcXyl1 gene was strongly induced in B. cinerea infecting Nicotiana benthamiana and tomato plants, and BcXyl1 deletion strains severely compromised the virulence of B. cinerea. BcXyl1 induced strong cell death in several plants, and cell death activity of BcXyl1 was independent of its xylanase activity. Purified BcXyl1 triggered typically PAMP-triggered immunity (PTI) responses and conferred resistance to B. cinerea and TMV in tobacco and tomato plants. A 26-amino acid peptide of BcXyl1 was sufficient for elicitor function. Furthermore, the BcXyl1 death-inducing signal was mediated by the plant LRR receptor-like kinases (RLKs) BAK1 and SOBIR1. Our data suggested that BcXyl1 contributed to B. cinerea virulence and induced plant defense responses. PMID- 30405587 TI - Viability of Lactobacillus plantarum on Fresh-Cut Chitosan and Alginate-Coated Apple and Melon Pieces. AB - There is an increasing trend toward foods with probiotics; the awareness of healthy diet and wellbeing is the leading cause of this increase. As a result, food producers and stakeholders require new probiotic products. The increased incidence of lactose intolerance and the new lifestyles (vegan and vegetarian styles) have led to a renewed interest in non-dairy probiotic carriers. The use of biopolymeric matrices to develop active food packaging carrying probiotics has been studied and proposed as an alternative method to design new solutions. The main topic of this paper was the design of fresh-cut fruits (apples and melons) as carriers for a promising Lactobacillus plantarum; fruit pieces were coated with either alginate or chitosan. Apple (Granny Smith) and melon pieces (Cucumis melo, var. Cantalupensis) were preliminary treated with an anti-browning solution (citric and ascorbic acids). Then, fruit pieces were dipped in a solution containing L. plantarum c19 (9 log cfu/ml) and coated with alginate or chitosan. Samples without probiotic and/or coatings were used as controls. All samples were stored at 4 degrees C for 14 days under air or modified atmosphere (65% N2, 30% CO2, and 5% O2); the following analyses were done: pH, color, O2, and CO2 in the head space, microbiology (mesophilic bacteria, lactic acid bacteria, yeasts, and molds). The most important results can be summarized as follows: (a) Alginate coating showed better performances than chitosan-coating, as it did not affect the viability of L. plantarum. (b) The inoculation of probiotics in the controls negatively affected the color, but the coating was able to counteract this effect. This paper supports the combination of edible coatings and probiotic as a promising way to design new fruit-based functional foods; further investigations are required to study the effect of this combination on the sensory scores. PMID- 30405586 TI - The GbsR Family of Transcriptional Regulators: Functional Characterization of the OpuAR Repressor. AB - Accumulation of compatible solutes is a common stress response of microorganisms challenged by high osmolarity; it can be achieved either through synthesis or import. These processes have been intensively studied in Bacillus subtilis, where systems for the production of the compatible solutes proline and glycine betaine have been identified, and in which five transporters for osmostress protectants (Opu) have been characterized. Glycine betaine synthesis relies on the import of choline via the substrate-restricted OpuB system and the promiscuous OpuC transporter and its subsequent oxidation by the GbsAB enzymes. Transcription of the opuB and gbsAB operons is under control of the MarR-type regulator GbsR, which acts as an intracellular choline-responsive repressor. Modeling studies using the X-ray structure of the Mj223 protein from Methanocaldococcus jannaschii as the template suggest that GbsR is a homo-dimer with an N-terminal DNA-reading head and C-terminal dimerization domain; a flexible linker connects these two domains. In the vicinity of the linker region, an aromatic cage is predicted as the inducer-binding site, whose envisioned architecture resembles that present in choline and glycine betaine substrate-binding proteins of ABC transporters. We used bioinformatics to assess the phylogenomics of GbsR-type proteins and found that they are widely distributed among Bacteria and Archaea. Alignments of GbsR proteins and analysis of the genetic context of the corresponding structural genes allowed their assignment into four sub-groups. In one of these sub-groups of GbsR-type proteins, gbsR-type genes are associated either with OpuA-, OpuB-, or OpuC-type osmostress protectants uptake systems. We focus here on GbsR-type proteins, named OpuAR by us, that control the expression of opuA-type gene clusters. Using such a system from the marine bacterium Bacillus infantis, we show that OpuAR acts as a repressor of opuA transcription, where several compatible solutes (e.g., choline, glycine betaine, proline betaine) serve as its inducers. Site-directed mutagenesis studies allowed a rational improvement of the putative inducer-binding site in OpuAR with respect to the affinity of choline and glycine betaine binding. Collectively, our data characterize GbsR-/OpuAR-type proteins as an extended sub-group within the MarR-superfamily of transcriptional regulators and identify a novel type of substrate-inducible import system for osmostress protectants. PMID- 30405588 TI - Characterization of Diversity and Probiotic Efficiency of the Autochthonous Lactic Acid Bacteria in the Fermentation of Selected Raw Fruit and Vegetable Juices. AB - The diversity of indigenous lactic acid bacteria (LAB) in fermented broccoli, cherry, ginger, white radish, and white-fleshed pitaya juices was analyzed using culture-independent and -dependent approaches. The major properties of selected probiotic strains, including dynamic variations in pH, viable cell counts, antibiotic resistance, bacterial adhesion to hydrophobic compounds, and survivability during simulated gastrointestinal transit, were investigated using broccoli as the fermentation substrate. In broccoli and ginger juices, the genus Lactobacillus occupied the dominant position (abundances of 79.0 and 30.3%, respectively); in cherry and radish juices, Weissella occupied the dominant position (abundances of 78.3 and 83.2%, respectively); and in pitaya juice, Streptococcus and Lactococcus occupied the dominant positions (52.2 and 37.0%, respectively). Leuconostoc mesenteroides, Weissella cibaria/soli/confusa, Enterococcus gallinarum/durans/hirae, Pediococcus pentosaceus, Bacillus coagulans, and Lactococcus garvieae/lactis subspecies were identified by partial 16S rRNA gene sequencing. In general, the selected autochthonous LAB isolates displayed no significant differences in comparison with commercial strains with regard to growth rates or acidification in fermented broccoli juice. Among all the isolates, L. mesenteroides B4-25 exhibited the highest antibiotic resistance profile (equal to that of L. plantarum CICC20265), and suitable adhesion properties (adhesion of 13.4 +/- 5.2% ~ 36.4 +/- 3.2% and 21.6 +/- 1.4% ~ 69.6 +/ 2.3% to ethyl acetate and xylene, respectively). Furthermore, P. pentosaceus Ca 4 and L. mesenteroides B-25 featured the highest survival rates (22.4 +/- 2.6 and 21.2 +/- 1.4%, respectively), after simulated gastrointestinal transit. These results indicated a high level of diversity among the autochthonous bacterial community in fermented fruit and vegetable juices, and demonstrated the potential of these candidate probiotics for applications in fermentation. PMID- 30405589 TI - Microbiomes Associated With Foods From Plant and Animal Sources. AB - Food microbiome composition impacts food safety and quality. The resident microbiota of many food products is influenced throughout the farm to fork continuum by farming practices, environmental factors, and food manufacturing and processing procedures. Currently, most food microbiology studies rely on culture dependent methods to identify bacteria. However, advances in high-throughput DNA sequencing technologies have enabled the use of targeted 16S rRNA gene sequencing to profile complex microbial communities including non-culturable members. In this study we used 16S rRNA gene sequencing to assess the microbiome profiles of plant and animal derived foods collected at two points in the manufacturing process; post-harvest/pre-retail (cilantro) and retail (cilantro, masala spice mixes, cucumbers, mung bean sprouts, and smoked salmon). Our findings revealed microbiome profiles, unique to each food, that were influenced by the moisture content (dry spices, fresh produce), packaging methods, such as modified atmospheric packaging (mung bean sprouts and smoked salmon), and manufacturing stage (cilantro prior to retail and at retail). The masala spice mixes and cucumbers were comprised mainly of Proteobacteria, Firmicutes, and Actinobacteria. Cilantro microbiome profiles consisted mainly of Proteobacteria, followed by Bacteroidetes, and low levels of Firmicutes and Actinobacteria. The two brands of mung bean sprouts and the three smoked salmon samples differed from one another in their microbiome composition, each predominated by either by Firmicutes or Proteobacteria. These data demonstrate diverse and highly variable resident microbial communities across food products, which is informative in the context of food safety, and spoilage where indigenous bacteria could hamper pathogen detection, and limit shelf life. PMID- 30405590 TI - Enzymatic Bioweathering and Metal Mobilization From Black Slate by the Basidiomycete Schizophyllum commune. AB - Schizophyllum commune is a filamentous basidiomycete causing white-rot in many wood species with the help of a broad range of enzymes including multicopper oxidases such as laccases and laccase-like oxidases. Since these enzymes exhibit a broad substrate range, their ability to oxidatively degrade black slate was investigated. Both haploid monokaryotic, and mated dikaryotic strains were able to grow on black slate rich in organic carbon as sole carbon source. On defined media, only the monokaryon showed growth promotion by addition of slate. At the same time, metals were released from the slate and, after reaching a threshold concentration, inhibited further growth of the fungus. The proteome during decomposition of the black slate showed induction of proteins potentially involved in rock degradation and stress resistance, and the gene for laccase-like oxidase mco2 was up-regulated. Specifically in the dikaryon, the laccase gene lcc1 was induced, while lcc2 as well as mco1, mco3, and mco4 expression levels remained similar. Spectrophotometric analysis revealed that both life forms were able to degrade the rock and produce smaller particles. PMID- 30405592 TI - Marek's Disease Virus Activates the PI3K/Akt Pathway Through Interaction of Its Protein Meq With the P85 Subunit of PI3K to Promote Viral Replication. AB - It is known that viruses can active the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway in host cells to support cell survival and viral replication; however, the role of PI3K/Akt signaling in the pathogenic mechanisms induced by Marek's disease virus (MDV) which causes a neoplastic Marek's disease in poultry, remains unknown. In this study, we showed that MDV activated the PI3K/Akt pathway in chicken embryo fibroblasts (CEFs) at the early phase of infection, whereas treatment with a PI3K inhibitor LY294002 prior to MDV infection decreased viral replication and DNA synthesis. Flow cytometry analysis showed that inhibition of the PI3K/Akt pathway could significantly increase apoptosis in MDV-infected host cells, indicating that activation of PI3K/Akt signaling could facilitate viral replication through support of cell survival during infection. Evaluation of the underlying molecular mechanism by co-immunoprecipitation and laser confocal microscopy revealed that a viral protein Meq interacted with both p85alpha and p85beta regulatory subunits of PI3K and could induce PI3K/Akt signaling in Meq overexpressing chicken fibroblasts. Our results showed, for the first time, that MDV activated PI3K/Akt signaling in host cells through interaction of its Meq protein with the regulatory p85 subunit of PI3K to delay cell apoptosis and promote viral replication. This study provides clues for further studies of the molecular mechanisms underlying MDV infection and pathogenicity for the host. PMID- 30405591 TI - Identification of Amino Acid Residues Responsible for Inhibition of Host Gene Expression by Influenza A H9N2 NS1 Targeting of CPSF30. AB - H9N2 influenza A viruses (IAV) are considered low pathogenic avian influenza viruses (LPAIV). These viruses are endemic in poultry in many countries in Asia, the Middle East and parts of Africa. Several cases of H9N2-associated infections in humans as well as in pigs have led the World Health Organization (WHO) to include these viruses among those with pandemic potential. To date, the processes and mechanisms associated with H9N2 IAV adaptation to mammals are poorly understood. The non-structural protein 1 (NS1) from IAV is a virulence factor that counteracts the innate immune responses. Here, we evaluated the ability of the NS1 protein from A/quail/Hong Kong/G1/97 (HK/97) H9N2 to inhibit host immune responses. We found that HK/97 NS1 protein counteracted interferon (IFN) responses but was not able to inhibit host gene expression in human or avian cells. In contrast, the NS1 protein from earlier H9N2 IAV strains, including the first H9N2 A/turkey/Wisconsin/1/1966 (WI/66), were able to inhibit both IFN and host gene expression. Using chimeric constructs between WI/66 and HK/97 NS1 proteins, we identified the region and amino acid residues involved in inhibition of host gene expression. Amino acid substitutions L103F, I106M, P114S, G125D and N139D in HK/97 NS1 resulted in binding to the 30-kDa subunit of the cleavage and polyadenylation specificity factor (CPSF30) and, in consequence, inhibition of host gene expression. Notably, changes in the same amino acid residues resulted in the lack of inhibition of host gene expression by WI/66 NS1. Importantly, our results identified a new combination of amino acids required for NS1 binding to CPSF30 and inhibition of host gene expression. These results also confirm previous studies demonstrating strain specific differences in the ability of NS1 proteins to inhibit host gene expression. PMID- 30405593 TI - Growth in Hyper-Concentrated Sweet Whey Triggers Multi Stress Tolerance and Spray Drying Survival in Lactobacillus casei BL23: From the Molecular Basis to New Perspectives for Sustainable Probiotic Production. AB - Lactobacillus casei BL23 has a recognized probiotic potential, which includes immune modulation, protection toward induced colitis, toward induced colon cancer and toward dissemination of pathogens. In L. casei, as well as in other probiotics, both probiotic and technological abilities are highly dependent (1) on the substrate used to grow bacteria and (2) on the process used to dry and store this biomass. Production and storage of probiotics, at a reasonable financial and environmental cost, becomes a crucial challenge. Food-grade media must be used, and minimal process is preferred. In this context, we have developed a "2-in-1" medium used both to grow and to dry L. casei BL23, considered a fragile probiotic strain. This medium consists in hyper-concentrated sweet whey (HCSW). L. casei BL23 grows in HCSW up to 30% dry matter, which is 6 times-concentrated sweet whey. Compared to isotonic sweet whey (5% dry matter), these growth conditions enhanced tolerance of L. casei BL23 toward heat, acid and bile salts stress. HCSW also triggered intracellular accumulation of polyphosphate, of glycogen and of trehalose. A gel-free global proteomic differential analysis further evidenced overexpression of proteins involved in pathways known to participate in stress adaptation, including environmental signal transduction, oxidative and metal defense, DNA repair, protein turnover and repair, carbohydrate, phosphate and amino acid metabolism, and in osmoadaptation. Accordingly, HCSW cultures of L. casei BL23 exhibited enhanced survival upon spray drying, a process known to drastically affect bacterial viability. This work opens new perspectives for sustainable production of dried probiotic lactobacilli, using food industry by-products and lowering energy costs. PMID- 30405594 TI - Identification of wysPII as an Activator of Morphological Development in Streptomyces albulus CK-15. AB - Wuyiencin is produced by Streptomyces albulus var. wuyiensis and used widely in agriculture to control a variety of fungal diseases, such as cucumber downy mildew, strawberry powdery mildew, and tomato gray mold. As an industrially produced biopesticide, reducing production costs is very important for popularization of this approach. To obtain a rapidly growing strain that effectively shortens the fermentation time, we investigated the effects of knockout and overexpression of the wysPII gene, a member of the LuxR regulatory gene family, in S. albulus strain CK-15. The DeltawysPII mutant exhibited a reduced rate of growth and sporulation. The time taken to reach the greatest mycelial biomass was approximately 18 h shorter in the ooPII (wysPII overexpressing) strain compared with that of the wild-type (WT) strain. In addition, the time to reach the greatest wuyiencin production was 56 h in the ooPII strain compared with 62 h in the WT strain. Furthermore, wysPII was shown to act as an activator of morphological development without affecting wuyiencin production. Thus, the ooPII strain can be used to reduce costs and increase efficiency in industrial fermentation processes for wuyiencin production. PMID- 30405595 TI - Dietary Exposure to the Environmental Chemical, PFOS on the Diversity of Gut Microbiota, Associated With the Development of Metabolic Syndrome. AB - The gut microbiome is a dynamic ecosystem formed by thousands of diverse bacterial species. This bacterial diversity is acquired early in life and shaped over time by a combination of multiple factors, including dietary exposure to distinct nutrients and xenobiotics. Alterations of the gut microbiota composition and associated metabolic activities in the gut are linked to various immune and metabolic diseases. The microbiota could potentially interact with xenobiotics in the gut environment as a result of their board enzymatic capacities and thereby affect the bioavailability and toxicity of the xenobiotics in enterohepatic circulation. Consequently, microbiome-xenobiotic interactions might affect host health. Here, we aimed to investigate the effects of dietary perfluorooctane sulfonic acid (PFOS) exposure on gut microbiota in adult mice and examine the induced changes in animal metabolic functions. In mice exposed to dietary PFOS for 7 weeks, body PFOS and lipid contents were measured, and to elucidate the effects of PFOS exposure, the metabolic functions of the animals were assessed using oral glucose-tolerance test and intraperitoneal insulin-tolerance and pyruvate-tolerance tests; moreover, on Day 50, cecal bacterial DNA was isolated and subject to 16S rDNA sequencing. Our results demonstrated that PFOS exposure caused metabolic disturbances in the animals, particularly in lipid and glucose metabolism, but did not substantially affect the diversity of gut bacterial species. However, marked modulations were detected in the abundance of metabolism associated bacteria belonging to the phyla Firmicutes, Bacteroidetes, Proteobacteria, and Cyanobacteria, including, at different taxonomic levels, Turicibacteraceae, Turicibacterales, Turicibacter, Dehalobacteriaceae, Dehalobacterium, Allobaculum, Bacteroides acidifaciens, Alphaproteobacteria, and 4Cod-2/YS2. The results of PICRUSt analysis further indicated that PFOS exposure perturbed gut metabolism, inducing notable changes in the metabolism of amino acids (arginine, proline, lysine), methane, and a short-chain fatty acid (butanoate), all of which are metabolites widely recognized to be associated with inflammation and metabolic functions. Collectively, our study findings provide key information regarding the biological relevance of microbiome-xenobiotic interactions associated with the ecology of gut microbiota and animal energy metabolism. PMID- 30405596 TI - Discovery of Diverse Rodent and Bat Pestiviruses With Distinct Genomic and Phylogenetic Characteristics in Several Chinese Provinces. AB - Bats and rodents are widely distributed worldwide and can be native or intermediate reservoirs of many important zoonotic viruses. Pestiviruses are a group of virus species of the genus Pestivirus under the family Flaviviridae that can infect a wide variety of artiodactylous hosts, including swine and ruminants. Two classic types of pestiviruses, bovine viral diarrhea virus and classical swine fever virus, are important causative agents of mild-to-severe disease in bovine and swine hosts, respectively, and cause tremendous economic losses in these industries. Recent reports revealed that bats and rodents could also act as natural hosts of pestiviruses and an atypical porcine pestivirus, which cause disease in piglets, showed a close genetic relationship with a specific bat pestivirus, RaPestV-1. This study aimed to describe the detection and characterization of novel pestiviruses from bats and rodents in different locations by analyzing the available bat and rodent virome data from throughout China. Two bat pestivirus species and four rodent pestivirus species that are distinct from other known viruses were identified and sequenced. These viruses were identified from two bat species and four rodent species in different Chinese provinces. There were two distinct lineages present in these viruses, that differ from artiodactylous pestivirus. These findings expand our understanding of the genetic diversity of pestiviruses in bats and rodents and suggest the presence of a diverse set of pestiviruses in non-artiodactylous hosts. This study may provide new insight for the prevention of future viral disease outbreaks originating from bats and rodents. PMID- 30405597 TI - Real Time Monitoring of NADPH Concentrations in Corynebacterium glutamicum and Escherichia coli via the Genetically Encoded Sensor mBFP. AB - Analyses of intracellular NADPH concentrations are prerequisites for the design of microbial production strains and process optimization. mBFP was described as metagenomics derived, blue fluorescent protein showing NADPH-dependent fluorescence. Characterization of mBFP showed a high specificity for binding of NADPH (K D 0.64 mM) and no binding of NADH, the protein exclusively amplified fluorescence of NADPH. mBFP catalyzed the NADPH-dependent reduction of benzaldehyde and further aldehydes, which fits to its classification as short chain dehydrogenase. For in vivo NADPH analyses a codon-optimized gene for mBFP was introduced into Corynebacterium glutamicum WT and the phosphoglucoisomerase deficient strain C. glutamicum Deltapgi, which accumulates high levels of NADPH. For determination of intracellular NADPH concentrations by mBFP a calibration method with permeabilized cells was developed. By this means an increase of intracellular NADPH concentrations within seconds after the addition of glucose to nutrient-starved cells of both C. glutamicum WT and C. glutamicum Deltapgi was observed; as expected the internal NADPH concentration was significantly higher for C. glutamicum Deltapgi (0.31 mM) when compared to C. glutamicum WT (0.19 mM). Addition of paraquat to E. coli cells carrying mBFP led as expected to an immediate decrease of intracellular NADPH concentrations, showing the versatile use of mBFP as intracellular sensor. PMID- 30405598 TI - Interpretation of Serological Complement Biomarkers in Disease. AB - Complement system aberrations have been identified as pathophysiological mechanisms in a number of diseases and pathological conditions either directly or indirectly. Examples of such conditions include infections, inflammation, autoimmune disease, as well as allogeneic and xenogenic transplantation. Both prospective and retrospective studies have demonstrated significant complement related differences between patient groups and controls. However, due to the low degree of specificity and sensitivity of some of the assays used, it is not always possible to make predictions regarding the complement status of individual patients. Today, there are three main indications for determination of a patient's complement status: (1) complement deficiencies (acquired or inherited); (2) disorders with aberrant complement activation; and (3) C1 inhibitor deficiencies (acquired or inherited). An additional indication is to monitor patients on complement-regulating drugs, an indication which may be expected to increase in the near future since there is now a number of such drugs either under development, already in clinical trials or in clinical use. Available techniques to study complement include quantification of: (1) individual components; (2) activation products, (3) function, and (4) autoantibodies to complement proteins. In this review, we summarize the appropriate indications, techniques, and interpretations of basic serological complement analyses, exemplified by a number of clinical disorders. PMID- 30405599 TI - A Metalloprotease Homolog Venom Protein From a Parasitoid Wasp Suppresses the Toll Pathway in Host Hemocytes. AB - Parasitoid wasps depend on a variety of maternal virulence factors to ensure successful parasitism. Encapsulation response carried out by host hemocytes is one of the major host immune responses toward limiting endoparasitoid wasp offspring production. We found that VRF1, a metalloprotease homolog venom protein identified from the endoparasitoid wasp, Microplitis mediator, could modulate egg encapsulation in its host, the cotton bollworm, Helicoverpa armigera. Here, we show that the VRF1 proenzyme is cleaved after parasitism, and that the C-terminal fragment containing the catalytic domain enters host hemocytes 6 h post parasitism. Furthermore, using yeast two-hybrid and pull-down assays, VRF1 is shown to interact with the H. armigera NF-kappaB factor, Dorsal. We also show that overexpressed of VRF1 in an H. armigera cell line cleaved Dorsal in vivo. Taken together, our results have revealed a novel mechanism by which a component of endoparasitoid wasp venom interferes with the Toll signaling pathway in the host hemocytes. PMID- 30405601 TI - Abnormal T Cell Frequencies, Including Cytomegalovirus-Associated Expansions, Distinguish Seroconverted Subjects at Risk for Type 1 Diabetes. AB - We analyzed T cell subsets from cryopreserved PBMC obtained from the TrialNet Pathway to Prevention archives. We compared subjects who had previously seroconverted for one or more autoantibodies with non-seroconverted, autoantibody negative individuals. We observed a reduced frequency of MAIT cells among seroconverted subjects. Seroconverted subjects also possessed decreased frequencies of CCR4-expressing CD4 T cells, including a regulatory-like subset. Interestingly, we found an elevation of CD57+, CD28-, CD127-, CD27- CD8 T cells (SLEC) among seroconverted subjects that was most pronounced among those that progressed to disease. The frequency of these SLEC was strongly correlated with CMV IgG abundance among seroconverted subjects, associated with IA-2 levels, and most elevated among CMV+ seroconverted subjects who progressed to disease. Combined, our data indicate discrete, yet profound T cell alterations are associated with islet autoimmunity among at-risk subjects. PMID- 30405600 TI - An RORgammat Oral Inhibitor Modulates IL-17 Responses in Peripheral Blood and Intestinal Mucosa of Crohn's Disease Patients. AB - Background and Aims: Despite the negative results of blocking IL-17 in Crohn's disease (CD) patients, selective modulation of Th17-dependent responses warrants further study. Inhibition of retinoic acid-related orphan receptor gamma (RORgammat), the master regulator of the Th17 signature, is currently being explored in inflammatory diseases. Our aim was to determine the effect of a novel oral RORgammat antagonist (BI119) in human CD and on an experimental model of intestinal inflammation. Methods: 51 CD patients and 11 healthy subjects were included. The effects of BI119 were tested on microbial-stimulated peripheral blood mononuclear cells (PBMCs), intestinal crypts and biopsies from CD patients. The ability of BI119 to prevent colitis in vivo was assessed in the CD4+CD45RBhigh T cell transfer model. Results: In bacterial antigen-stimulated PBMCs from CD patients, BI119 inhibits Th17-related genes and proteins, while upregulating Treg and preserving Th1 and Th2 signatures. Intestinal crypts cultured with supernatants from BI119-treated commensal-specific CD4+ T cells showed decreased expression of CXCL1, CXCL8 and CCL20. BI119 significantly reduced IL17 and IL26 transcription in colonic and ileal CD biopsies and did not affect IL22. BI119 has a more profound effect in ileal CD with additional significant downregulation of IL23R, CSF2, CXCL1, CXCL8, and S100A8, and upregulation of DEFA5. BI119 significantly prevented development of clinical, macroscopic and molecular markers of colitis in the T-cell transfer model. Conclusions: BI119 modulated CD-relevant Th17 signatures, including downregulation of IL23R while preserving mucosa-associated IL-22 responses, and abrogated experimental colitis. Our results provide support to the use of RORgammat antagonists as a novel therapy to CD treatment. PMID- 30405602 TI - Human NK Cells Develop an Exhaustion Phenotype During Polar Degranulation at the Aspergillus fumigatus Hyphal Synapse. AB - Pulmonary aspergillosis is an opportunistic fungal infection affecting immunocompromised individuals. Increasing understanding of natural killer (NK) cell immunobiology has aroused considerable interest around the role of NK cells in pulmonary aspergillosis in the immunocompromised host. Murine studies indicate that NK cells play a critical role in pulmonary clearance of A. fumigatus. We show that the in vitro interaction between NK cells and A. fumigatus induces partial activation of NK cell immune response, characterised by low-level production of IFN-gamma, TNF-alpha, MIP-1alpha, MIP-1beta, and RANTES, polarisation of lytic granules and release of fungal DNA. We observed a contact dependent down-regulation of activatory receptors NKG2D and NKp46 on the NK cell surface, and a failure of full granule release. Furthermore, the NK cell cytokine mediated response to leukaemic cells was impaired in the presence of A. fumigatus. These observations suggest that A. fumigatus-mediated NK cell immunoparesis may represent an important mechanism of immune evasion during pulmonary aspergillosis. PMID- 30405603 TI - Elevated Systemic and Parasite-Antigen Stimulated Levels of Type III IFNs in a Chronic Helminth Infection and Reversal Following Anthelmintic Treatment. AB - Type III IFNs are important players in immunity to viral and bacterial infections. However, their association with helminth infections has not been examined. To explore the association of Type III IFNs with Strongyloides stercoralis (Ss) infection, we examined the systemic levels of IFN lambda-1, IFN lambda-2 and IFN lambda-3, IL-10, and CXCL10/IP-10 in Ss infected (INF, n = 44), helminth-uninfected (UN, n = 44) and in post-treatment INF individuals. We also examined the levels of IFN lambda-1, IFN lambda-2 and IFN lambda-3, IL-10, and CXCL10/IP-10 in whole blood culture supernatants stimulated with Ss somatic antigens, or PPD or LPS. Finally, we performed correlations of systemic Type III IFN levels with absolute numbers of dendritic cell subsets. Ss infection is characterized by elevated systemic levels of IFN lambda-1, IFN lambda-2 and IFN lambda-3, IL-10, and CXCL10/IP-10 in comparison to UN individuals and a significant reduction following anthelmintic treatment. Ss infection is also characterized by elevated levels of unstimulated or Ss antigen stimulated levels of IFN lambda-1, IFN lambda-2 and IFN lambda-3, CXCL10/IP-10 and a significant reduction following treatment. In addition, Ss infection is characterized by increased numbers of plasmacytoid and myeloid dendritic cells in comparison to UN individuals, with a significant reduction following anthelmintic treatment of INF individuals. Finally, Ss infection exhibits a significant positive correlation between the systemic levels of IFN lambda-2 and IFN lambda-3 and the numbers of plasmacytoid dendritic cells. Thus, Ss infection is characterized by elevations in systemic and antigen-induced levels of Type III IFNs, which is positively associated with the numbers of plasmacytoid dendritic cells and reversed upon anthelmintic treatment. PMID- 30405604 TI - Bordetella pertussis Whole Cell Immunization, Unlike Acellular Immunization, Mimics Naive Infection by Driving Hematopoietic Stem and Progenitor Cell Expansion in Mice. AB - Hematopoietic stem and progenitor cell (HSPC) compartments are altered to direct immune responses to infection. Their roles during immunization are not well described. To elucidate mechanisms for waning immunity following immunization with acellular vaccines (ACVs) against Bordetella pertussis (Bp), we tested the hypothesis that immunization with Bp ACVs and whole cell vaccines (WCVs) differ in directing the HSPC characteristics and immune cell development patterns that ultimately contribute to the types and quantities of cells produced to fight infection. Our data demonstrate that compared to control and ACV-immunized CD-1 mice, immunization with an efficacious WCV drives expansion of hematopoietic multipotent progenitor cells (MPPs), increases circulating white blood cells (WBCs), and alters the size and composition of lymphoid organs. In addition to MPPs, common lymphoid progenitor (CLP) proportions increase in the bone marrow of WCV-immunized mice, while B220+ cell proportions decrease. Upon subsequent infection, increases in maturing B cell populations are striking in WCV-immunized mice. RNAseq analyses of HSPCs revealed that WCV and ACV-immunized mice vastly differ in developing VDJ gene segment diversity. Moreover, gene set enrichment analyses demonstrate WCV-immunized mice exhibit unique gene signatures that suggest roles for interferon (IFN) induced gene expression. Also observed in naive infection, these IFN stimulated gene (ISG) signatures point toward roles in cell survival, cell cycle, autophagy, and antigen processing and presentation. Taken together, these findings underscore the impact of vaccine antigen and adjuvant content on skewing and/or priming HSPC populations for immune response. PMID- 30405605 TI - Antibody Epitope Specificity for dsDNA Phosphate Backbone Is an Intrinsic Property of the Heavy Chain Variable Germline Gene Segment Used. AB - Analysis of protein sequences by the informational spectrum method (ISM) enables characterization of their specificity according to encoded information represented with defined frequency (F). Our previous data showed that F(0.367) is characteristic for variable heavy chain (VH) domains (a combination of variable (V), diversity (D) and joining (J) gene segments) of the anti-phosphocholine (PC) T15 antibodies and mostly dependent on the CDR2 region, a site for PC phosphate group binding. Because the T15 dsDNA-reactive U4 mutant also encodes F(0.367), we hypothesized that the same frequency may also be characteristic for anti-DNA antibodies. Data obtained from an analysis of 60 spontaneously produced anti-DNA antibody VH domain sequences supported our hypothesis only for antibodies, which use V gene segment in germline configuration, such as S57(VH31), MRL-DNA22, and VH11, members of the VH1 (J558) and VH7 (S107) gene families. The important finding is that out of seven V gene segments used by spontaneous anti-DNA antibodies, F(0.367) is only expressed by the germline configuration of these three V gene segments. The data suggest that antibody specificity for the phosphate group moiety delineated as F(0.367) is the intrinsic property of the V germline gene segments used, whereas paratope/epitope interaction with antigens bearing this epitope, such as PC or dsDNA, requires corresponding antibody VH conformation that is susceptible to somatic mutation(s). PMID- 30405606 TI - Complement C3 Produced by Macrophages Promotes Renal Fibrosis via IL-17A Secretion. AB - Complement synthesis in cells of origin is strongly linked to the pathogenesis and progression of renal disease. Multiple studies have examined local C3 synthesis in renal disease and elucidated the contribution of local cellular sources, but the contribution of infiltrating inflammatory cells remains unclear. We investigate the relationships among C3, macrophages and Th17 cells, which are involved in interstitial fibrosis. Here, we report that increased local C3 expression, mainly by monocyte/macrophages, was detected in renal biopsy specimens and was correlated with the severity of renal fibrosis (RF) and indexes of renal function. In mouse models of UUO (unilateral ureteral obstruction), we found that local C3 was constitutively expressed throughout the kidney in the interstitium, from which it was released by F4/80+macrophages. After the depletion of macrophages using clodronate, mice lacking macrophages exhibited reductions in C3 expression and renal tubulointerstitial fibrosis. Blocking C3 expression with a C3 and C3aR inhibitor provided similar protection against renal tubulointerstitial fibrosis. These protective effects were associated with reduced pro-inflammatory cytokines, renal recruitment of inflammatory cells, and the Th17 response. in vitro, recombinant C3a significantly enhanced T cell proliferation and IL-17A expression, which was mediated through phosphorylation of ERK, STAT3, and STAT5 and activation of NF-kB in T cells. More importantly, blockade of C3a by a C3aR inhibitor drastically suppressed IL-17A expression in C3a-stimulated T cells. We propose that local C3 secretion by macrophages leads to IL-17A-mediated inflammatory cell infiltration into the kidney, which further drives fibrogenic responses. Our findings suggest that inhibition of the C3a/C3aR pathway is a novel therapeutic approach for obstructive nephropathy. PMID- 30405607 TI - MUC1 Mucin: A Putative Regulatory (Checkpoint) Molecule of T Cells. AB - T lymphocytes are at the center of inducing an effective adaptive immune response and maintaining homeostasis. T cell responses are initiated through interactions between antigen presenting cells (APCs) and T cells. The type and strength of signals delivered through the T cell receptor (TCR) may modulate how the cells respond. The TCR-MHC (T cell receptor-major histocompatibility complex molecules) complex dictates the specificity, whereas co-stimulatory signals induced by interaction of various accessory cell surface molecules strengthen and optimize T cell responses. Multiple immune regulatory mechanisms brought about by co inhibitory molecules expressed on T cells play a key role in orchestrating successful and non-damaging immunity. These co-inhibitory molecules are also referred to as initiators of immune check-points or co-inhibitory pathways. Knowledge of co-inhibitory pathways associated with activated T lymphocytes has allowed a better understanding of (a) the inflammatory and anti-inflammatory processes associated with infectious diseases and autoimmune diseases, and (b) mechanisms by which tumors evade immune attack. Many of these regulatory pathways are non-redundant and function in a highly concerted manner. Targeting them has provided effective approaches in treating cancer and autoimmune diseases. For this reason, it is valuable to identify any co-inhibitory molecules that affect these pathways. MUC1 mucin (CD227) has long been known to be expressed by epithelial cells and overexpressed by a multitude of adenocarcinomas. As long ago as 1998 we made a surprising discovery that MUC1 is also expressed by activated human T cells and we provided the first evidence of the role of MUC1 as a novel T cell regulator. Subsequent studies from different laboratories, as well as ours, supported an immuno-regulatory role of MUC1 in infections, inflammation, and autoimmunity that corroborated our original findings establishing MUC1 as a novel T cell regulatory molecule. In this article, we will discuss the experimental evidence supporting MUC1 as a putative regulatory molecule or a "checkpoint molecule" of T cells with implications as a novel biomarker and therapeutic target in chronic diseases such as autoimmunity, inflammation and cancer, and possibly infections. PMID- 30405608 TI - Acute Toxoplasma Gondii Infection in Cats Induced Tissue-Specific Transcriptional Response Dominated by Immune Signatures. AB - RNA-sequencing was used to detect transcriptional changes in six tissues of cats, seven days after T. gondii infection. A total of 737 genes were differentially expressed (DEGs), of which 410 were up-regulated and 327 were down-regulated. The liver exhibited 151 DEGs, lung (149 DEGs), small intestine (130 DEGs), heart (123 DEGs), brain (104 DEGs), and spleen (80 DEGs)-suggesting tissue-specific transcriptional patterns. Gene ontology and KEGG analyses identified DEGs enriched in immune pathways, such as cytokine-cytokine receptor interaction, Jak STAT signaling pathway, NOD-like receptor signaling pathway, NF-kappa B signaling pathway, MAPK signaling pathway, T cell receptor signaling pathway, and the cytosolic DNA sensing pathway. C-X-C motif chemokine 10 (CXCL10) was involved in most of the immune-related pathways. PI3K/Akt expression was down-regulated in all tissues, except the spleen. The genes for phosphatase, indoleamine 2,3 dioxygenase, Hes Family BHLH Transcription Factor 1, and guanylate-binding protein 5, playing various roles in immune defense, were co-expressed across various feline tissues. Multivariate K-means clustering analysis produced seven gene clusters featuring similar gene expression patterns specific to individual tissues, with lung tissue cluster having the largest number of DEGs. These findings suggest the presence of a broad immune defense mechanism across various tissues in cats against acute T. gondii infection. PMID- 30405609 TI - Intranasal Vaccination With Lipoproteins Confers Protection Against Pneumococcal Colonisation. AB - Streptococcus pneumoniae is endowed with a variety of surface-exposed proteins representing putative vaccine candidates. Lipoproteins are covalently anchored to the cell membrane and highly conserved among pneumococcal serotypes. Here, we evaluated these lipoproteins for their immunogenicity and protective potential against pneumococcal colonisation. A multiplex-based immunoproteomics approach revealed the immunogenicity of selected lipoproteins. High antibody titres were measured in sera from mice immunised with the lipoproteins MetQ, PnrA, PsaA, and DacB. An analysis of convalescent patient sera confirmed the immunogenicity of these lipoproteins. Examining the surface localisation and accessibility of the lipoproteins using flow cytometry indicated that PnrA and DacB were highly abundant on the surface of the bacteria. Mice were immunised intranasally with PnrA, DacB, and MetQ using cholera toxin subunit B (CTB) as an adjuvant, followed by an intranasal challenge with S. pneumoniae D39. PnrA protected the mice from pneumococcal colonisation. For the immunisation with DacB and MetQ, a trend in reducing the bacterial load could be observed, although this effect was not statistically significant. The reduction in bacterial colonisation was correlated with the increased production of antigen-specific IL-17A in the nasal cavity. Immunisation induced high systemic IgG levels with a predominance for the IgG1 isotype, except for DacB, where IgG levels were substantially lower compared to MetQ and PnrA. Our results indicate that lipoproteins are interesting targets for future vaccine strategies as they are highly conserved, abundant, and immunogenic. PMID- 30405610 TI - Molecular Signature of Aluminum Hydroxide Adjuvant in Ovine PBMCs by Integrated mRNA and microRNA Transcriptome Sequencing. AB - There have been few in vivo studies on the effect of aluminum hydroxide adjuvant and its influence on the immune response to vaccination. In this study, lambs received a parallel subcutaneous treatment with either commercial vaccines containing aluminum hydroxide or an equivalent dose of this compound only with the aim of identifying the activated molecular signature. Blood samples were taken from each animal at the beginning and at the end of the experiment and PBMCs isolated. Total RNA and miRNA libraries were prepared and sequenced. After alignment to the Oar3.1 reference genome and differential expression with 3 programs, gene enrichment modeling was performed. For miRNAs, miRBase and RNAcentral databases were used for detection and characterization. Three expression comparisons were made: vaccinated animals at the beginning and at the end of the treatment, adjuvanted animals at the same times, and animals of both treatments at the end of the experiment. After exposure to both treatments, a total of 2,473; 2,980 and 429 differentially expressed genes were identified in vaccinated animals, adjuvanted animals and animals at the end of both treatments, respectively. In both adjuvant and vaccine treated animals the NF-kappaB signaling pathway was enriched. On the other hand, it can be observed a downregulation of cytokines and cytokine receptors in the adjuvanted group compared to the vaccinated group at the final time, suggesting a milder induction of the immune response when the adjuvant is alone. As for the miRNA analysis, 95 miRNAs were detected: 64 previously annotated in Ovis aries, 11 annotated in Bos taurus and 20 newly described. Interestingly, 6 miRNAs were differentially expressed in adjuvant treated animals, and 3 and 1 in the other two comparisons. Lastly, an integrated miRNA-mRNA expression profile was developed, in which a miRNA-mediated regulation of genes related to DNA damage stimulus was observed. In brief, it seems that aluminum-containing adjuvants are not simple delivery vehicles for antigens, but also induce endogenous danger signals that can stimulate the immune system. Whether this contributes to long-lasting immune activation or to the overstimulation of the immune system remains to be elucidated. PMID- 30405611 TI - Incubation of Immune Cell Grafts With MAX.16H5 IgG1 Anti-Human CD4 Antibody Prolonged Survival After Hematopoietic Stem Cell Transplantation in a Mouse Model for Fms Like Tyrosine Kinase 3 Positive Acute Myeloid Leukemia. AB - Despite the constant development of innovative therapeutic options for hematological malignancies, the gold-standard therapy regimen for curative treatment often includes allogeneic hematopoietic stem cell transplantation (HSCT). The graft-vs.-leukemia effect (GVL) is one of the main therapeutic goals that arises from HSCT. On the other hand, graft-vs.-host disease (GVHD) is still one of the main and most serious complications following allogeneic HSCT. In acute myeloid leukemia (AML), HSCT together with high-dose chemotherapy is used as a treatment option. An aggressive progression of the disease, a decreased response to treatment, and a poor prognosis are connected to internal tandem duplication (ITD) mutations in the Fms like tyrosine kinase 3 (FLT3) gene, which affects around 30% of AML patients. In this study, C3H/HeN mice received an allogeneic graft together with 32D-FLT3ITD AML cells to induce acute GVHD and GVL. It was examined if pre-incubation of the graft with the anti-human cluster of differentiation (CD) 4 antibody MAX.16H5 IgG1 prevented the development of GVHD and whether the graft function was impaired. Animals receiving grafts pre incubated with the antibody together with FLT3ITD AML cells survived significantly longer than mice receiving untreated grafts. The observed prolonged survival due to MAX.16H5 incubation of immune cell grafts prior to transplantation may allow an extended application of additional targeted strategies in the treatment of AML. PMID- 30405613 TI - PEGylated Domain I of Beta-2-Glycoprotein I Inhibits the Binding, Coagulopathic, and Thrombogenic Properties of IgG From Patients With the Antiphospholipid Syndrome. AB - APS is an autoimmune disease in which antiphospholipid antibodies (aPL) cause vascular thrombosis and pregnancy morbidity. In patients with APS, aPL exert pathogenic actions by binding serum beta-2-glycoprotein I (beta2GPI) via its N terminal domain I (DI). We previously showed that bacterially-expressed recombinant DI inhibits biological actions of IgG derived from serum of patients with APS (APS-IgG). DI is too small (7 kDa) to be a viable therapeutic agent. Addition of polyethylene glycol (PEGylation) to small molecules enhances the serum half-life, reduces proteolytic targeting and can decrease immunogenicity. It is a common method of tailoring pharmacokinetic parameters and has been used in the production of many therapies in the clinic. However, PEGylation of molecules may reduce their biological activity, and the size of the PEG group can alter the balance between activity and half-life extension. Here we achieve production of site-specific PEGylation of recombinant DI (PEG-DI) and describe the activities in vitro and in vivo of three variants with different size PEG groups. All variants were able to inhibit APS-IgG from: binding to whole beta2GPI in ELISA, altering the clotting properties of human plasma and promoting thrombosis and tissue factor expression in mice. These findings provide an important step on the path to developing DI into a first-in-class therapeutic in APS. PMID- 30405614 TI - Epigenetic Regulation via Altered Histone Acetylation Results in Suppression of Mast Cell Function and Mast Cell-Mediated Food Allergic Responses. AB - Mast cells are highly versatile cells that perform a variety of functions depending on the immune trigger, context of activation, and cytokine stimulus. Antigen-mediated mast cell responses are regulated by transcriptional processes that result in the induction of numerous genes contributing to mast cell function. Recently, we also showed that exposure to dietary agents with known epigenetic actions such as curcumin can suppress mast cell-mediated food allergy, suggesting that mast cell responses in vivo may be epigenetically regulated. To further assess the effects of epigenetic modifications on mast cell function, we examined the behavior of bone marrow-derived mast cells (BMMCs) in response to trichostatin A (TSA) treatment, a well-studied histone deacetylase inhibitor. IgE mediated BMMC activation resulted in enhanced expression and secretion of IL-4, IL-6, TNF-alpha, and IL-13. In contrast, pretreatment with TSA resulted in altered cytokine secretion. This was accompanied by decreased expression of FcepsilonRI and mast cell degranulation. Interestingly, exposure to non-IgE stimuli such as IL-33, was also affected by TSA treatment. Furthermore, continuous TSA exposure contributed to mast cell apoptosis and a decrease in survival. Further examination revealed an increase in I-kappaBalpha and a decrease in phospho-relA levels in TSA-treated BMMCs, suggesting that TSA alters transcriptional processes, resulting in enhancement of I-kappaBalpha transcription and decreased NF-kappaB activation. Lastly, treatment of wild-type mice with TSA in a model of ovalbumin-induced food allergy resulted in a significant attenuation in the development of food allergy symptoms including decreases in allergic diarrhea and mast cell activation. These data therefore suggest that the epigenetic regulation of mast cell activation during immune responses may occur via altered histone acetylation, and that exposure to dietary substances may induce epigenetic modifications that modulate mast cell function. PMID- 30405615 TI - Immune Protection of SIV Challenge by PD-1 Blockade During Vaccination in Rhesus Monkeys. AB - Though immune correlates for protection are still under investigation, potent cytotoxic T lymphocyte responses are desirable for an ideal HIV-1 vaccine. PD-1 blockade enhances SIV-specific CD8+ T cells. However, little information has been reported about how it affects the immunogenicity and protection of prophylactic SIV vaccines in nonhuman primates. Here, we show that PD-1 blockade during vaccination substantially improved protective efficacy in SIV challenged macaques. The PD-1 pathway was blocked using a monoclonal antibody specific to human PD-1. Administration of this antibody effectively augmented and sustained vaccine-induced SIV-specific T cell responses for more than 42 weeks after first immunization in rhesus monkeys, as compared with SIV vaccination only. Importantly, after intrarectally repeated low-dosage challenge with highly pathogenic SIVmac239, monkeys with PD-1 blockade during vaccination achieved full protection against incremental viral doses of up to 50,000 TICD50. These findings highlight the importance of PD-1 blockade during vaccination for the development of HIV vaccines. PMID- 30405612 TI - Role of TRAFs in Signaling Pathways Controlling T Follicular Helper Cell Differentiation and T Cell-Dependent Antibody Responses. AB - Follicular helper T (TFH) cells represent a highly specialized CD4+ T cell subpopulation that supports the generation of germinal centers (GC) and provides B cells with critical signals promoting antibody class switching, generation of high affinity antibodies, and memory formation. TFH cells are characterized by the expression of the chemokine receptor CXCR5, the transcription factor Bcl-6, costimulatory molecules ICOS, and PD-1, and the production of cytokine IL-21. The acquisition of a TFH phenotype is a complex and multistep process that involves signals received through engagement of the TCR along with a multitude of costimulatory molecules and cytokines receptors. Members of the Tumor necrosis factor Receptor Associated Factors (TRAF) represent one of the major classes of signaling mediators involved in the differentiation and functions of TFH cells. TRAF molecules are the canonical adaptor molecules that physically interact with members of the Tumor Necrosis Factor Receptor Superfamily (TNFRSF) and actively modulate their downstream signaling cascades through their adaptor function and/or E3 ubiquitin ligase activity. OX-40, GITR, and 4-1BB are the TRAF dependent TNFRSF members that have been implicated in the differentiation and functions of TFH cells. On the other hand, emerging data demonstrate that TRAF proteins also participate in signaling from the TCR and CD28, which deliver critical signals leading to the differentiation of TFH cells. More intriguingly, we recently showed that the cytoplasmic tail of ICOS contains a conserved TANK binding kinase 1 (TBK1)-binding motif that is shared with TBK1-binding TRAF proteins. The presence of this TRAF-mimicking signaling module downstream of ICOS is required to mediate the maturation step during TFH differentiation. In addition, JAK-STAT pathways emanating from IL-2, IL-6, IL-21, and IL-27 cytokine receptors affect TFH development, and crosstalk between TRAF-mediated pathways and the JAK-STAT pathways can contribute to generate integrated signals required to drive and sustain TFH differentiation. In this review, we will introduce the molecular interactions and the major signaling pathways controlling the differentiation of TFH cells. In each case, we will highlight the contributions of TRAF proteins to these signaling pathways. Finally, we will discuss the role of individual TRAF proteins in the regulation of T cell-dependent humoral responses. PMID- 30405616 TI - Pseudomonas aeruginosa in Chronic Lung Infections: How to Adapt Within the Host? AB - Bacteria that readily adapt to different natural environments, can also exploit this versatility upon infection of the host to persist. Pseudomonas aeruginosa, a ubiquitous Gram-negative bacterium, is harmless to healthy individuals, and yet a formidable opportunistic pathogen in compromised hosts. When pathogenic, P. aeruginosa causes invasive and highly lethal disease in certain compromised hosts. In others, such as individuals with the genetic disease cystic fibrosis, this pathogen causes chronic lung infections which persist for decades. During chronic lung infections, P. aeruginosa adapts to the host environment by evolving toward a state of reduced bacterial invasiveness that favors bacterial persistence without causing overwhelming host injury. Host responses to chronic P. aeruginosa infections are complex and dynamic, ranging from vigorous activation of innate immune responses that are ineffective at eradicating the infecting bacteria, to relative host tolerance and dampened activation of host immunity. This review will examine how P. aeruginosa subverts host defenses and modulates immune and inflammatory responses during chronic infection. This dynamic interplay between host and pathogen is a major determinant in the pathogenesis of chronic P. aeruginosa lung infections. PMID- 30405617 TI - Human Monocytic Suppressive Cells Promote Replication of Mycobacterium tuberculosis and Alter Stability of in vitro Generated Granulomas. AB - Tuberculosis (TB) has tremendous public health relevance. It most frequently affects the lung and is characterized by the development of unique tissue lesions, termed granulomas. These lesions encompass various immune populations, with macrophages being most extensively investigated. Myeloid derived suppressor cells (MDSCs) have been recently identified in TB patients, both in the circulation and at the site of infection, however their interactions with Mycobacterium tuberculosis (Mtb) and their impact on granulomas remain undefined. We generated human monocytic MDSCs and observed that their suppressive capacities are retained upon Mtb infection. We employed an in vitro granuloma model, which mimics human TB lesions to some extent, with the aim of analyzing the roles of MDSCs within granulomas. MDSCs altered the structure of and affected bacterial containment within granuloma-like structures. These effects were partly controlled through highly abundant secreted IL-10. Compared to macrophages, MDSCs activated primarily the NF-kappaB and MAPK pathways and the latter largely contributed to the release of IL-10 and replication of bacteria within in vitro generated granulomas. Moreover, MDSCs upregulated PD-L1 and suppressed proliferation of lymphocytes, albeit with negligible effects on Mtb replication. Further comprehensive characterization of MDSCs in TB will contribute to a better understanding of disease pathogenesis and facilitate the design of novel immune based interventions for this deadly infection. PMID- 30405620 TI - CD24 Expression and B Cell Maturation Shows a Novel Link With Energy Metabolism: Potential Implications for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. AB - CD24 expression on pro-B cells plays a role in B cell selection and development in the bone marrow. We previously detected higher CD24 expression and frequency within IgD+ naive and memory B cells in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) compared with age-matched healthy controls (HC). Here, we investigated the relationship between CD24 expression and B cell maturation. In vitro stimulation of isolated B cells in response to conventional agonists were used to follow the dynamics of CD24 positivity during proliferation and differentiation (or maturation). The relationship between CD24 expression to cycles of proliferation and metabolism in purified B cells from HC was also investigated using phospho-flow (phosphorylation of AMPK-pAMPK), 1proton nuclear magnetic resonance and Mitotracker Far-red (Mitochondrial mass-MM). In vitro, in the absence of stimulation, there was an increased percentage of CD24+ viable B cells in ME/CFS patients compared to HC (p < 0.05) following 5 days culture. Following stimulation with B cell agonists, percentage of CD24+B cells in both naive and memory B cell populations decreased. P < 0.01). There was a negative relationship between percentage of CD24+B cells with MM (R2 = 0.76; p < 0.01), which was subsequently lost over sequential cycles of proliferation. There was a significant correlation between CD24 expression on B cells and the usage of glucose and secretion of lactate in vitro. Short term ligation of the B cell receptor with anti-IgM antibody significantly reduced the viability of CD24+ memory B cells compared to those cross-linked by anti-IgD or anti-IgG antibody. A clear difference was found between naive and memory B cells with respect to CD24 expression and pAMPK, most notably a strong positive association in IgD+IgM+ memory B cells. In vitro findings confirmed dysregulation of CD24-expressing B cells from ME/CFS patients previously suggested by immunophenotype studies of B cells from peripheral blood. CD24-negative B cells underwent productive proliferation whereas CD24+ B cells were either unresponsive or susceptible to cell death upon BCR-engagement alone. We suggest that CD24 expression may reflect variations in energy metabolism on different B cell subsets. PMID- 30405619 TI - The Combination Therapy of Dietary Galacto-Oligosaccharides With Budesonide Reduces Pulmonary Th2 Driving Mediators and Mast Cell Degranulation in a Murine Model of House Dust Mite Induced Asthma. AB - Background: Dietary non-digestible galacto-oligosaccharides (GOS) suppress allergic responses in mice sensitized and challenged with house dust mite (HDM). Budesonide is the standard therapy for allergic asthma in humans but is not always completely effective. Aim: To compare the efficacy of budesonide or different doses of GOS alone or with a combination therapy of budesonide and GOS on HDM-allergic responses in mice. Methods:BALB/c mice were sensitized and challenged with HDM, while fed a control diet or a diet supplemented with 1 or 2.5 w/w% GOS, and either or not oropharyngeally instilled with budesonide. Systemic and local inflammatory markers, such as mucosal mast cell protease-1 (mMCP-1) in serum, pulmonary CCL17, CCL22, and IL-33 concentrations and inflammatory cell influx in the bronchoalveolar lavage fluid (BALF) were determined. Results: Budesonide or GOS alone suppressed the number of eosinophils in the BALF of HDM allergic mice whereas budesonide either or not combined with GOS lowered both eosinophil and lymphocyte numbers in the BALF of HDM-allergic mice. Both 1 w/w% and 2.5 w/w% GOS and/or budesonide suppressed serum mMCP-1 concentrations. However, budesonide nor GOS alone was capable of reducing Th2 driving chemokines CCL17, CCL22 and IL-33 protein levels in supernatants of lung homogenates of HDM allergic mice, whereas the combination therapy did. Moreover, IL-13 concentrations were only significantly suppressed in mice treated with budesonide while fed GOS. A similar tendency was observed for the frequency of GATA3+CD4+ Th2 and CD4+RORgammat+ Th17 cells in the lungs of the allergic mice. Conclusion: Dietary intervention using GOS may be a novel way to further improve the efficacy of anti-inflammatory drug therapy in allergic asthma by lowering Th2 driving mediators and mast cell degranulation. PMID- 30405621 TI - A Single-Cell Sequencing Guide for Immunologists. AB - In recent years there has been a rapid increase in the use of single-cell sequencing (scRNA-seq) approaches in the field of immunology. With the wide range of technologies available, it is becoming harder for users to select the best scRNA-seq protocol/platform to address their biological questions of interest. Here, we compared the advantages and limitations of four commonly used scRNA-seq platforms in order to clarify their suitability for different experimental applications. We also address how the datasets generated by different scRNA-seq platforms can be integrated, and how to identify unknown populations of single cells using unbiased bioinformatics methods. PMID- 30405622 TI - Complement Component C1q as Serum Biomarker to Detect Active Tuberculosis. AB - Background: Tuberculosis (TB) remains a major threat to global health. Currently, diagnosis of active TB is hampered by the lack of specific biomarkers that discriminate active TB disease from other (lung) diseases or latent TB infection (LTBI). Integrated human gene expression results have shown that genes encoding complement components, in particular different C1q chains, were expressed at higher levels in active TB compared to LTBI. Methods: C1q protein levels were determined using ELISA in sera from patients, from geographically distinct populations, with active TB, LTBI as well as disease controls. Results: Serum levels of C1q were increased in active TB compared to LTBI in four independent cohorts with an AUC of 0.77 [0.70; 0.83]. After 6 months of TB treatment, levels of C1q were similar to those of endemic controls, indicating an association with disease rather than individual genetic predisposition. Importantly, C1q levels in sera of TB patients were significantly higher as compared to patients with sarcoidosis or pneumonia, clinically important differential diagnoses. Moreover, exposure to other mycobacteria, such as Mycobacterium leprae (leprosy patients) or BCG (vaccinees) did not result in elevated levels of serum C1q. In agreement with the human data, in non-human primates challenged with Mycobacterium tuberculosis, increased serum C1q levels were detected in animals that developed progressive disease, not in those that controlled the infection. Conclusions: In summary, C1q levels are elevated in patients with active TB compared to LTBI in four independent cohorts. Furthermore, C1q levels from patients with TB were also elevated compared to patients with sarcoidosis, leprosy and pneumonia. Additionally, also in NHP we observed increased C1q levels in animals with active progressive TB, both in serum and in broncho-alveolar lavage. Therefore, we propose that the addition of C1q to current biomarker panels may provide added value in the diagnosis of active TB. PMID- 30405618 TI - Adapted Immune Responses of Myeloid-Derived Cells in Fatty Liver Disease. AB - Non-alcoholic fatty liver disease (NAFLD) is considered to be one of the most frequent chronic liver diseases worldwide and is associated with an increased risk of developing liver cirrhosis and hepatocellular carcinoma. Hepatic macrophages, mainly comprising monocyte derived macrophages and tissue resident Kupffer cells, are characterized by a high diversity and plasticity and act as key regulators during NAFLD progression, in conjunction with other infiltrating myeloid cells like neutrophils or dendritic cells. The activation and polarization of myeloid immune cells is influenced by dietary components, inflammatory signals like danger-associated molecular patterns (DAMPs) or cytokines as well as gut-derived inflammatory factors such as pathogen-associated molecular patterns (PAMPs). The functionality of myeloid leukocytes in the liver is directly linked to their inflammatory polarization, which is shaped by local and systemic inflammatory mediators such as cytokines, chemokines, PAMPs, and DAMPs. These environmental signals provoke intracellular adaptations in myeloid cells, including inflammasome and transcription factor activation, inflammatory signaling pathways, or switches in cellular metabolism. Dietary changes and obesity also promote a dysbalance in intestinal microbiota, which can facilitate intestinal permeability and bacterial translocation. The aim of this review is to highlight recent findings on the activating pathways of innate immune cells during the progression of NAFLD, dissecting local hepatic and systemic signals, dietary and metabolic factors as well as pathways of the gut-liver axis. Understanding the mechanism by which plasticity of myeloid-derived leukocytes is related to metabolic changes and NAFLD progression may provide options for new therapeutic approaches. PMID- 30405623 TI - Integrative Computational Modeling of the Lymph Node Stromal Cell Landscape. AB - Adaptive immune responses develop in secondary lymphoid organs such as lymph nodes (LNs) in a well-coordinated series of interactions between migrating immune cells and resident stromal cells. Although many processes that occur in LNs are well understood from an immunological point of view, our understanding of the fundamental organization and mechanisms that drive these processes is still incomplete. The aim of systems biology approaches is to unravel the complexity of biological systems and describe emergent properties that arise from interactions between individual constituents of the system. The immune system is greater than the sum of its parts, as is the case with any sufficiently complex system. Here, we review recent work and developments of computational LN models with focus on the structure and organization of the stromal cells. We explore various mathematical studies of intranodal T cell motility and migration, their interactions with the LN-resident stromal cells, and computational models of functional chemokine gradient fields and lymph flow dynamics. Lastly, we discuss briefly the importance of hybrid and multi-scale modeling approaches in immunology and the technical challenges involved. PMID- 30405624 TI - Antibodies and Antibody Derivatives: New Partners in HIV Eradication Strategies. AB - Promptly after primoinfection, HIV generates a pool of infected cells carrying transcriptionally silent integrated proviral DNA, the HIV-1 reservoir. These cells are not cleared by combined antiretroviral therapy (cART), and persist lifelong in treated HIV-infected individuals. Defining clinical strategies to eradicate the HIV reservoir and cure HIV-infected individuals is a major research field that requires a deep understanding of the mechanisms of seeding, maintenance and destruction of latently infected cells. Although CTL responses have been classically associated with the control of HIV replication, and hence with the size of HIV reservoir, broadly neutralizing antibodies (bNAbs) have emerged as new players in HIV cure strategies. Several reasons support this potential role: (i) over the last years a number of bNAbs with high potency and ability to cope with the extreme variability of HIV have been identified; (ii) antibodies not only block HIV replication but mediate effector functions that may contribute to the removal of infected cells and to boost immune responses against HIV; (iii) a series of new technologies have allowed for the in vitro design of improved antibodies with increased antiviral and effector functions. Recent studies in non-human primate models and in HIV-infected individuals have shown that treatment with recombinant bNAbs isolated from HIV-infected individuals is safe and may have a beneficial effect both on the seeding of the HIV reservoir and on the inhibition of HIV replication. These promising data and the development of antibody technology have paved the way for treating HIV infection with engineered monoclonal antibodies with high potency of neutralization, wide coverage of HIV diversity, extended plasma half-life in vivo and improved effector functions. The exciting effects of these newly designed antibodies in vivo, either alone or in combination with other cure strategies (latency reversing agents or therapeutic vaccines), open a new hope in HIV eradication. PMID- 30405627 TI - Effect of Tyrosin Kinase Inhibitors on NK Cell and ILC3 Development and Function. AB - Tyrosin kinase inhibitors (TKI) sharply improved the prognosis of Chronic Myeloid Leukemia (CML) and of Philadelphia+ Acute Lymphoblastic Leukemia (Ph+ALL) patients. However, TKI are not curative because of the development of resistance and lack of complete molecular remission in the majority of patients. Clinical evidences would support the notion that patient's immune system may play a key role in preventing relapses. In particular, increased proportions of terminally differentiated CD56+CD16+CD57+ NK cells have been reported to be associated with successful Imatinib therapy discontinuation or with a deep molecular response in Dasatinib-treated patients. In view of the potential role of NK cells in immune response against CML, it is important to study whether any TKI have an effect on the NK cell development and identify possible molecular mechanism(s) by which continuous exposure to in vitro TKI may influence NK cell development and repertoire. To this end, CD34+ hematopoietic stem cells (HSC) were cultured in the absence or in the presence of Imatinib, Nilotinib, or Dasatinib. We show that all compounds exert an inhibitory effect on CD56+ cell recovery. In addition, Dasatinib sharply skewed the repertoire of CD56+ cell population, leading to an impaired recovery of CD56+CD117-CD16+CD94/NKG2A+EOMES+ mature cytotoxic NK cells, while the recovery of CD56+CD117+CD94/NKG2A-RORgammat+ IL-22-producing ILC3 was not affected. This effect appears to involve the Dasatinib-mediated inhibition of Src kinases and, indirectly, of STAT5-signaling activation in CD34+ cells during first days of culture. Our studies, reveal a possible mechanism by which Dasatinib may interfere with the proliferation and maturation of fully competent NK cells, i.e., by targeting signaling pathways required for differentiation and survival of NK cells but not of ILC3. PMID- 30405625 TI - Human and Murine Evidence for Mechanisms Driving Autoimmune Photosensitivity. AB - Ultraviolet (UV) light is an important environmental trigger for systemic lupus erythematosus (SLE) patients, yet the mechanisms by which UV light impacts disease are not fully known. This review covers evidence in both human and murine systems for the impacts of UV light on DNA damage, apoptosis, autoantigen exposure, cytokine production, inflammatory cell recruitment, and systemic flare induction. In addition, the role of the circadian clock is discussed. Evidence is compared in healthy individuals and SLE patients as well as in wild-type and lupus-prone mice. Further research is needed into the effects of UV light on cutaneous and systemic immune responses to understand how to prevent UV-light mediated lupus flares. PMID- 30405628 TI - Pharmacological Inhibition of Toll-Like Receptor-4 Signaling by TAK242 Prevents and Induces Regression of Experimental Organ Fibrosis. AB - Systemic sclerosis (SSc) is a poorly understood heterogeneous condition with progressive multi-organ fibrosis. Recent genetic and genomic evidence suggest a pathogenic role for dysregulated innate immunity and toll-like receptor (TLR) activity in SSc. Levels of both TLR4, as well as certain endogenous TLR ligands, are elevated in skin and lung tissues from patients with SSc and correlate with clinical disease parameters. Conversely, genetic targeting of TLR4 or its endogenous "damage-associated" ligands ameliorates progressive tissue fibrosis. Targeting TLR4 signaling therefore represents a pharmacological strategy to prevent intractable fibrosis. We examined the effect of TAK242, a small molecule TLR4 inhibitor, in preclinical fibrosis models and in SSc fibroblasts. TAK242 treatment prevented, promoted regression of, bleomycin-induced dermal and pulmonary fibrosis, and reduced the expression of several pro-fibrotic mediators. Furthermore, TAK242 ameliorated peritoneal fibrosis and reduced spontaneous hypodermal thickness in TSK/+ mice. Importantly, TAK242 abrogated collagen synthesis and myofibroblasts differentiation in explanted constitutively active SSc fibroblast. Altogether, these findings identify TAK242 as an anti-fibrotic agent in preclinical models of organ fibrosis. TAK242 might potentially represent a novel strategy for the treatment of SSc and other fibrotic diseases. PMID- 30405626 TI - IL-33/ST2 Axis in Organ Fibrosis. AB - Interleukin 33 (IL-33) is highly expressed in barrier sites, acting via the suppression of tumorigenicity 2 receptor (ST2). IL-33/ST2 axis has long been known to play a pivotal role in immunity and cell homeostasis by promoting wound healing and tissue repair. However, it is also involved in the loss of balance between extensive inflammation and tissue regeneration lead to remodeling, the hallmark of fibrosis. The aim of the current review is to critically evaluate the available evidence regarding the role of the IL-33/ST2 axis in organ fibrosis. The role of the axis in tissue remodeling is better understood considering its crucial role reported in organ development and regeneration. Generally, the IL 33/ST2 signaling pathway has mainly anti-inflammatory/anti-proliferative effects; however, chronic tissue injury is responsible for pro-fibrogenetic responses. Regarding pulmonary fibrosis mature IL-33 enhances pro-fibrogenic type 2 cytokine production in an ST2- and macrophage-dependent manner, while full-length IL-33 is also implicated in the pulmonary fibrotic process in an ST2-independent, Th2 independent fashion. In liver fibrosis, evidence indicate that when acute and massive liver damage occurs, the release of IL-33 might act as an activator of tissue-protective mechanisms, while in cases of chronic injury IL-33 plays the role of a hepatic fibrotic factor. IL-33 signaling has also been involved in the pathogenesis of acute and chronic pancreatitis. Moreover, IL-33 could be used as an early marker for ulcer-associated activated fibroblasts and myofibroblast trans-differentiation; thus one cannot rule out its potential role in inflammatory bowel disease-associated fibrosis. Similarly, the upregulation of the IL-33/ST2 axismay contribute to tubular cell injury and fibrosis via epithelial to mesenchymal transition (EMT) of various cell types in the kidneys. Of note, IL-33 exerts a cardioprotective role via ST2 signaling, while soluble ST2 has been demonstrated as a marker of myocardial fibrosis. Finally, IL-33 is a crucial cytokine in skin pathology responsible for abnormal fibroblast proliferation, leukocyte infiltration and morphologic differentiation of human endothelial cells. Overall, emerging data support a novel contribution of the IL 33/ST2 pathway in tissue fibrosis and highlight the significant role of the Th2 pattern of immune response in the pathophysiology of organ fibrosis. PMID- 30405629 TI - Comparative Glycomics of Immunoglobulin A and G From Saliva and Plasma Reveals Biomarker Potential. AB - The N-glycosylation of immunoglobulin (Ig) G, the major antibody in the circulation of human adults, is well known for its influence on antibody effector functions and its alterations with various diseases. In contrast, knowledge on the role of glycans attached to IgA, which is a key immune defense agent in secretions, is very scarce. In this study we aimed to characterize the glycosylation of salivary (secretory) IgA, including the IgA joining chain (JC), and secretory component (SC) and to compare IgA and IgG glycosylation between human plasma and saliva samples to gain a first insight into oral cavity-specific antibody glycosylation. Plasma and whole saliva were collected from 19 healthy volunteers within a 2-h time window. IgG and IgA were affinity-purified from the two biofluids, followed by tryptic digestion and nanoLC-ESI-QTOF-MS(/MS) analysis. Saliva-derived IgG exhibited a slightly lower galactosylation and sialylation as compared to plasma-derived IgG. Glycosylation of IgA1, IgA2, and the JC showed substantial differences between the biofluids, with salivary proteins exhibiting a higher bisection, and lower galactosylation and sialylation as compared to plasma-derived IgA and JC. Additionally, all seven N-glycosylation sites, characterized on the SC of secretory IgA in saliva, carried highly fucosylated and fully galactosylated diantennary N-glycans. This study lays the basis for future research into the functional role of salivary Ig glycosylation as well as its biomarker potential. PMID- 30405630 TI - Novel Chimeric Protein Vaccines Against Clostridium difficile Infection. AB - Clostridium difficile infection (CDI) is the leading cause of world-wide nosocomial acquired diarrhea in adults. Active vaccination is generally accepted as a logical and cost-effective approach to prevent CDI. In this paper, we have generated two novel chimeric proteins; one designated Tcd169, comprised of the glucosyltransferase domain (GT), the cysteine proteinase domain (CPD), and receptor binding domain (RBD) of TcdB, and the RBD of TcdA; the other designated Tcd169FI, which contains Salmonella typhimurium flagellin (sFliC) and Tcd169. Both proteins were expressed in and purified from Bacillus megaterium. Point mutations were made in the GT (W102A, D288N) and CPD (C698) of TcdB to ensure that Tcd169 and Tcd169FI were atoxic. Immunization with Tcd169 or Tcd169Fl induced protective immunity against TcdA/TcdB challenge through intraperitoneal injection, also provided mice full protection against infection with a hyper virulent C. difficile strain (BI/NAP1/027). In addition, inclusion of sFlic in the fusion protein (Tcd169Fl) enhanced its protective immunity against toxin challenge, reduced C. difficile numbers in feces from Tcd169Fl-immunized mice infected C. difficile. Our data show that Tcd169 and Tcd169FI fusion proteins may represent alternative vaccine candidates against CDI. PMID- 30405631 TI - IgG Glyco-Engineering to Improve IVIg Potency. AB - Intravenous immunoglobulins (IVIg) are used in the treatment of different autoimmune and inflammatory diseases, such as immune thrombocytopenia and hemolytic anemia. One of the modes of action of IVIg is preventing phagocytosis of autoantibody-opsonized blood cells by saturation of the Fc-gamma receptors of macrophages in spleen and liver. IgG contains a fixed glycan, which is in most cases biantennary, at the asparagine residue at position 297 in the Fc tail. This glycan consists of a core structure of N-acetyl glucosamine (GlcNAc) and mannose groups, variably extended with core fucose, bisecting GlcNAc as well as terminal galactose and sialic acid. This structural glycan influences the binding affinity of IgG to Fc-gamma receptors. By glyco-engineering, we generated monoclonal IgG antibodies with different Fc-tail glycans and tested both their opsonizing and blocking capacity in a phagocytosis assay of IgG-opsonized erythrocytes with human monocyte-derived macrophages. In contrast to a lack of effect in opsono phagocytosis, these IgG glycovariants differentially inhibited the uptake of opsonized erythrocytes. The level of bisecting GlcNAc and galactosylation had unexpectedly larger impact than core fucosylation, and suggest that targeted modifications different from the core fucose may well improve the immunomodulating efficacy of IVIg treatment. PMID- 30405633 TI - Donor NKG2C Copy Number: An Independent Predictor for CMV Reactivation After Double Cord Blood Transplantation. AB - Cytomegalovirus (CMV) remains a major cause of morbidity following allogeneic hematopoietic stem cell transplant. Natural killer cells expressing NKG2C have been shown to play a role in the immune surveillance of human CMV. We studied NKG2C copy number in the donor graft and the risk of CMV reactivation after double umbilical cord blood transplantation (DUCBT) in 100 CMV seropositive DUCBT recipients and their corresponding cord blood (CB) grafts (n = 200). In the setting of DUCBT, the combined graft may contain 0-4 functional copies of NKG2C gene. Sixteen patients received a combined graft with 1 or 2 NKG2C copies and 84 patients were recipients of a combined graft with 3 or 4 NKG2C copies. The 6 month cumulative incidence of CMV reactivation for the two groups was 93.7 and 58.4%, respectively (p = 0.0003). In multivariate analysis, low NKG2C copies in the graft was an independent predictor of CMV reactivation (HR = 2.72, CI = 1.59 4.64; p < 0.0001). Our study points to an important role for donor NKG2C for protection against CMV reactivation after DUCBT. These novel findings may help identify patients at a higher risk of CMV reactivation after DUCBT. Donor NKG2C genotype may be used as a potential criterion in the algorithm for graft selection for DUCBT. PMID- 30405632 TI - Phenotype, Polyfunctionality, and Antiviral Activity of in vitro Stimulated CD8+ T-Cells From HIV+ Subjects Who Initiated cART at Different Time-Points After Acute Infection. AB - Since anti-HIV treatment cannot cure the infection, many strategies have been proposed to eradicate the viral reservoir, which still remains as a major challenge. The success of some of these strategies will rely on the ability of HIV-specific CD8+ T-cells (CD8TC) to clear reactivated infected cells. Here, we aimed to investigate the phenotype and function of in vitro expanded CD8TC obtained from HIV+ subjects on combination antiretroviral therapy (cART), either initiated earlier (median = 3 months postinfection, ET: Early treatment) or later (median = 20 months postinfection, DT: Delayed treatment) after infection. Peripheral blood mononuclear cells from 12 DT and 13 ET subjects were obtained and stimulated with Nef and Gag peptide pools plus IL-2 for 14 days. ELISPOT was performed pre- and post-expansion. CD8TC memory/effector phenotype, PD-1 expression, polyfunctionality (CD107a/b, IFN-gamma, IL-2, CCL4 (MIP-1beta), and/or TNF-alpha production) and antiviral activity were evaluated post expansion. Magnitude of ELISPOT responses increased after expansion by 103 times, in both groups. Expanded cells were highly polyfunctional, regardless of time of cART initiation. The memory/effector phenotype distribution was sharply skewed toward an effector phenotype after expansion in both groups although ET subjects showed significantly higher proportions of stem-cell and central memory CD8TCs. PD-1 expression was clustered in HIV-specific effector memory CD8TCs, subset that also showed the highest proportion of cytokine-producing cells. Moreover, PD-1 expression directly correlated with CD8TC functionality. Expanded CD8TCs from DT and ET subjects were highly capable of mediating antiviral activity, measured by two different assays. Antiviral function directly correlated with the proportion of fully differentiated effector cells (viral inhibition assay) as well as with CD8TC polyfunctionality and PD-1 expression (VITAL assay). In sum, we show that, despite being dampened in subjects on cART, the HIV-specific CD8TC response could be selectively stimulated and expanded in vitro, presenting a high proportion of cells able to carry-out multiple effector functions. Timing of cART initiation had an impact on the memory/effector differentiation phenotype, most likely reflecting how different periods of antigen persistence affected immune function. Overall, these results have important implications for the design and evaluation of strategies aimed at modulating CD8TCs to achieve the HIV functional cure. PMID- 30405635 TI - Asparaginyl Endopeptidase (Legumain) Supports Human Th1 Induction via Cathepsin L Mediated Intracellular C3 Activation. AB - Autocrine activation of the complement receptors C3aR and CD46 by complement activation components C3a and C3b produced through C3 cleavage by the protease cathepsin L (CTSL) during T cell stimulation is a requirement for IFN-gamma production and Th1 induction in human CD4+ T cells. Thus, lack of autocrine CD46 activation, such as in CD46-deficient patients, is associated with defective Th1 responses and recurrent infections. We have identified LGMN [the gene coding for legumain, also known as asparaginyl endopeptidase (AEP)] as one of the key genes induced by CD46 co-stimulation during human CD4+ T cell activation. AEP processes and activates a range of proteins, among those alpha1-thymosin and CTSL, which both drive intrinsically Th1 activity-but has so far not been described to be functionally active in human T cells. Here we found that pharmacological inhibition of AEP during activation of human CD4+ T cells reduced CTSL activation and the CTSL-mediated generation of intracellular C3a. This translated into a specific reduction of IFN-gamma production without affecting cell proliferation or survival. In line with these findings, CD4+ T cells isolated from Lgmn -/- mice also displayed a specific defect in IFN-gamma secretion and Th1 induction. Furthermore, we did not observe a role for AEP-driven autocrine alpha1-thymosin activation in T cell-derived IFN-gamma production. These data suggest that AEP is an "upstream" activator of the CTSL-C3-IFN-gamma axis in human CD4+ T cells and hence an important supporter of human Th1 induction. PMID- 30405634 TI - gammadelta T Cells in Antimalarial Immunity: New Insights Into Their Diverse Functions in Protection and Tolerance. AB - Uniquely expressing diverse innate-like and adaptive-like functions, gammadelta T cells exist as specialized subsets, but are also able to adapt in response to environmental cues. These cells have long been known to rapidly proliferate following primary malaria infection in humans and mice, but exciting new work is shedding light into their diverse functions in protection and following repeated malaria infection. In this review, we examine the current knowledge of functional specialization of gammadelta T cells in malaria, and the mechanisms dictating recognition of malaria parasites and resulting proliferation. We discuss gammadelta T cell plasticity, including changing interactions with other immune cells during recurrent infection and potential for immunological memory in response to repeated stimulation. Building on recent insights from human and murine experimental studies and vaccine trials, we propose areas for future research, as well as applications for therapeutic development. PMID- 30405636 TI - Editorial: Antibody Fc Engineering: Towards Better Therapeutics. PMID- 30405638 TI - LIGHT/TNFSF14 as a New Biomarker of Bone Disease in Multiple Myeloma Patients Experiencing Therapeutic Regimens. AB - We have previously shown that through the production of high LIGHT levels, immune cells contribute to both osteoclastogenesis and bone destruction in Multiple Myeloma (MM)-related bone disease. With the aim of further exploring the mechanisms underlying the development of MM-related bone disease, here we focused on a possible role of LIGHT in MM patients with active bone disease despite the treatment received. We detected LIGHT over-expression by circulating CD14+ monocytes from MM patients still showing active bone disease, despite the treatment. In addition, we found over-expression of receptor activator of nuclear factor kappa-B ligand (RANKL), whose pro-osteoclastogenic role is well-known, in T-lymphocytes isolated from the same patients. Although the percentages of circulating osteoclast progenitors, CD14+CD16+ monocytes, were higher in all the MM patients than in the controls spontaneous osteoclastogenesis occurred only in the cultures derived from PBMCs of MM patients with unresponsive bone disease. Of note, in the same cultures osteoclastogenesis was partially or completely inhibited, in a dose-dependent manner, by the addition of RANK-Fc or anti-LIGHT neutralizing antibody, demonstrating the contribution of both LIGHT and RANKL to the enhanced osteoclast formation observed. In addition, high serum levels of TRAP5b and CTX, the two markers of osteoclast activity, were detected in MM patients with bone disease not responsive to treatment. In conclusion, our study indicates a prominent role of LIGHT in the crosstalk among osteoclasts and immune cells, co-involved together with RANKL in the pathophysiological mechanisms leading to MM-related bone disease. This TNF superfamily member may thus be a possible new therapeutic target in MM-related bone disease. PMID- 30405637 TI - A Task Force Against Local Inflammation and Cancer: Lymphocyte Trafficking to and Within the Skin. AB - The skin represents a specialized site for immune surveillance consisting of resident, inflammatory and memory populations of lymphocytes. The entry and retention of T cells, B cells, and ILCs is tightly regulated to facilitate detection of pathogens, inflammation and tumors cells. Loss of individual or multiple populations in the skin may break tolerance or increase susceptibility to tumor growth and spread. Studies have significantly advanced our understanding of the role of skin T cells and ILCs at steady state and in inflammatory settings such as viral challenge, atopy, and autoimmune inflammation. The knowledge raised by these studies can benefit to our understanding of immune cell trafficking in primary melanoma, shedding light on the mechanisms of tumor immune surveillance and to improve immunotherapy. This review will focus on the T cells, B cells, and ILCs of the skin at steady state, in inflammatory context and in melanoma. In particular, we will detail the core chemokine and adhesion molecules that regulate cell trafficking to and within the skin, which may provide therapeutic avenues to promote tumor homing for a team of lymphocytes. PMID- 30405640 TI - Ultrasensitive Quantification of Cytokine Proteins in Single Lymphocytes From Human Blood Following ex-vivo Stimulation. AB - In this study we demonstrate the feasibility of direct, quantitative measurement of cytokine proteins in single human CD8 lymphocytes from fresh peripheral blood of healthy donors following a brief ex vivo stimulation. Cytokine-secreting cells were identified using cell surface "catch" reagents and single cell data were obtained by sorting of individual cytokine-secreting cells into 96 well plates containing lysis buffer followed by analysis using ultrasensitive immunoassays for interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha). CD8 cells negative for cytokine production, as determined by the cell surface catch reagents were used as negative controls. Furthermore, studies were undertaken to compare the mean fluorescence intensity (MFI) values of cytokine staining by flow cytometry with the quantification of cytokines using the current method. This study demonstrates that it is feasible to quantify cytokines from individual primary cells. A shift from qualitative to quantitative determinations of cytokine protein levels in single cells will permit more precise and reproducible studies of heterogeneity in the immune system and can be accomplished with readily available instrumentation. PMID- 30405639 TI - CAR-T Cells and Oncolytic Viruses: Joining Forces to Overcome the Solid Tumor Challenge. AB - Adoptive transfer of chimeric antigen receptor (CAR)-modified T cells has resulted in unprecedented rates of long-lasting complete responses in patients with leukemia and lymphoma. However, despite the impressive results in patients with hematologic malignancies, CAR-T cells have showed limited effect against solid cancers. New approaches will need to simultaneously overcome the multiple challenges that CAR-T cells encounter in solid tumors, including the immunosuppressive tumor microenvironment and heterogeneity of antigen expression. Oncolytic viruses are lytic and immunogenic anti-cancer agents with the potential to synergize with CAR-T cells for the treatment of solid tumors. In addition, viruses can be further modified to deliver therapeutic transgenes selectively to the tumor microenvironment, which could enhance the effector functions of tumor specific T cells. This review summarizes the major limitations of CAR-T cells in solid tumors and discusses the potential role for oncolytic viruses as partners for CAR-T cells in the fight against cancer. PMID- 30405641 TI - Influenza Vaccine-Induced Antibody Responses Are Not Impaired by Frailty in the Community-Dwelling Elderly With Natural Influenza Exposure. AB - Background: Elderly adults over 65 years of age are recommended to receive seasonal influenza vaccination as they are at a higher risk of infection and its complications than the younger community. The elderly are often stratified according to frailty status where frail individuals are more susceptible to adverse health outcomes than their non-frail counterparts, however, it is not known whether immunity induced by influenza vaccination is impaired in the frail elderly. Study Design: Two hundred and five elderly subjects of Chinese ethnicity in Singapore (mean age 73.3 +/- 5.3 years, 128 females and 77 males) were administered the recommended trivalent inactivated 2013-14 seasonal influenza vaccine (VaxigripTM) containing A/H1N1, A/H3N2, and B strains. The elderly subjects were stratified into three groups according to Fried's frailty criteria (59 frail, 85 pre-frail, 61 robust) and were also ranked by Rockwood's frailty index (RFI). Statistical associations were evaluated between frailty status and pre- and post-vaccination antibody titres in sera measured by Hemagglutination inhibition (HAI) and microneutralization (MN) assays. Immunological responses across frailty strata were also studied in terms of leukocyte cellular distribution, cytokine levels and gene expression. Results: Post-vaccination, 83.4% of the subjects seroconverted for A/H1N1, 80.5% for A/H3N2, and 81% for the B strain. The seroconversion rates were comparable across frailty groups (A/H1N1, ANOVA, p = 0.7910; A/H3N2, ANOVA, p = 0.8356, B, ANOVA, p = 0.9741). Geometric mean titres of HAI and MN as well as seroprotection rates were also similar in all three frailty groups and uncorrelated with RFI (Spearman, r = 0.023, p = 0.738). No statistically significant differences were observed between the frailty groups in vaccine-induced modulation of leukocyte populations, cytokine responses, and gene expression profiles of peripheral blood mononuclear cells (PBMCs). Whereas, post- and pre-vaccination HAI titres were positively correlated after adjusting for age and gender (A/H1N1, R 2 = 0.216, p = 9.1e-11; A/H3N2, R 2 = 0.166, p = 3.4e-8; B, R 2 = 0.104, p = 3.1e-5). With most subjects lacking previous history of influenza vaccination, the pre-vaccination titres were likely due to natural exposure and seen to match the pattern of influenza subtype prevalence in the time period of vaccination. Conclusion: The majority of the elderly subjects seroconverted for seasonal influenza upon vaccination, and importantly, influenza vaccination-induced humoral immune responses and seroprotection were similar across the frailty strata, indicating that frail individuals may also benefit from influenza vaccination. Pre-existing antibodies due to natural exposure appeared to positively influence vaccine-induced antibody responses. PMID- 30405643 TI - The Photoperiod-Insensitive Allele Ppd-D1a Promotes Earlier Flowering in Rht12 Dwarf Plants of Bread Wheat. AB - The gibberellin-responsive dwarfing gene Rht12 can significantly reduce plant height without changing seedling vigor and substantially increase ear fertility in bread wheat (Triticum aestivum. L). However, Rht12 delays heading date and anthesis date, hindering the use of Rht12 in wheat improvement. To promote early flowering of the Rht12 dwarf plants, the photoperiod-insensitive allele Ppd-D1a was introduced through a cross between Jinmai47 (Ppd-D1a) and Karcagi (Rht12). The results showed that Ppd-D1a can rescue the delaying effect of Rht12 on flowering time and promote earlier flowering by 9.0 days (163.2 degrees Cd) in the Rht12 dwarf plants by shortening the late reproduction phase. Plant height was reduced by Rht12 (43.2%) and Ppd-D1a (10.9%), achieving dwarf plants with higher lodging resistance. Ear fertility, like the grain number per spike, was significantly increased by Rht12 (21.3%), while it was reduced by Ppd-D1a (6.5%). However, thousand kernel weight was significantly reduced by Rht12 (12.9%) but significantly increased by Ppd-D1a (16.9%). Finally, plant yield was increased by 16.4 and 8.2%, and harvest index was increased by 24.9 and 15.4% in the Rht12 dwarf lines and tall lines with Ppd-D1a, respectively. Clearly, there was an additive interaction between Rht12 and Ppd-D1 and the introduction of Ppd-D1a advanced the flowering time and improved the yield traits of Rht12 dwarf plants, suggesting that the combination of Rht12 and Ppd-D1a would be conducive to the successful use of Rht12 in wheat breeding programs. PMID- 30405644 TI - Timing of Water Deficit Limits Maize Kernel Setting in Association With Changes in the Source-Flow-Sink Relationship. AB - The kernel setting of maize varies greatly because of the timing and intensity of water deficits. This variation can limit leaf productivity (source), the translocation of assimilated sugars (flow), and yield formation (sink). To explain the decline in kernel setting of maize under water deficits from the perspective of source-flow-sink, a 3-year experiment was conducted under a rain shelter. Five water regimes were studied. One regime included well-irrigated (CK) treatment. Four regimes involved water deficits: irrigation was withheld during the 6- to 8-leaf stage (V6-8), the 9- to 12-leaf stage (V9-12), the 13-leaf stage to tasseling stage (V13-T), and the silking stage to blister stage (R1-2). Water deficit effects on kernel setting began when the water deficit occurred at V9 and became more significant with time. Kernel weight was reduced by 12 and 11% when there were water deficits during V9-12 and V13-T, respectively. This was the result of reduced leaf area (limited source) and an altered vascular bundle in the ear peduncles (limited assimilate flow). The reduced vascular bundle number, rather than the ear peduncle cross-sectional area, significantly affected the final kernel weight when exposed to a water deficit prior to the silking stage. The water deficits prior to and close to the flowering stage significantly reduced ear kernel number; that is, 14 and 19% less during V13-T and R1-2, respectively, compared with the kernel number during the CK treatment. This reflects a smaller sink under water deficit conditions. Additionally, ovary size was reduced the most in the V13-T water deficit compared with other treatments. After rewatering, the water deficit before or during flowering stage continued to have residual effects on grain-filling in the late growth period. The grain filling rate decreased under the V9-12 water deficit; the grain-filling duration shortened under the R1-2 water deficit; and both negative effects occurred under the V13-T water deficit. This study clearly indicated that (1) the water deficit during the vegetative organ rapid growth period both limited leaf source development and assimilate flow and slowed down kernel development, and (2) the water deficit just before and during flowering reduced kernel sink. Deficits at both times could retard grain-filling and reduce maize yield. The results of the present study might guide irrigation practices in irrigated maize or inform the management of sowing time in rainfed maize, to desynchronize the water deficit and the plant's reactions to such deficits at different stages. PMID- 30405642 TI - Human Metapneumovirus: Mechanisms and Molecular Targets Used by the Virus to Avoid the Immune System. AB - Human metapneumovirus (hMPV) is a respiratory virus, first reported the year 2001. Since then, it has been described as one of the main etiological agents that causes acute lower respiratory tract infections (ALRTIs), which is characterized by symptoms such as bronchiolitis, wheezing and coughing. Susceptible population to hMPV-infection includes newborn, children, elderly and immunocompromised individuals. This viral agent is a negative-sense, single stranded RNA enveloped virus, that belongs to the Pneumoviridae family and Metapneumovirus genus. Early reports-previous to 2001-state several cases of respiratory illness without clear identification of the responsible pathogen, which could be related to hMPV. Despite the similarities of hMPV with several other viruses, such as the human respiratory syncytial virus or influenza virus, mechanisms used by hMPV to avoid the host immune system are still unclear. In fact, evidence indicates that hMPV induces a poor innate immune response, thereby affecting the adaptive immunity. Among these mechanisms, is the promotion of an anergic state in T cells, instead of an effective polarization or activation, which could be induced by low levels of cytokine secretion. Further, the evidences support the notion that hMPV interferes with several pattern recognition receptors (PRRs) and cell signaling pathways triggered by interferon associated genes. However, these mechanisms reported in hMPV are not like the ones reported for hRSV, as the latter has two non-structural proteins that are able to inhibit these pathways. Several reports suggest that viral glycoproteins, such as G and SH, could play immune-modulator roles during infection. In this work, we discuss the state of the art regarding the mechanisms that underlie the poor immunity elicited by hMPV. Importantly, these mechanisms will be compared with those elicited by other common respiratory viruses. PMID- 30405645 TI - Genome-Wide Association Study Identifies Candidate Genes Related to Seed Oil Composition and Protein Content in Gossypium hirsutum L. AB - Cotton (Gossypium spp.) is a leading natural fiber crop and an important source of vegetable protein and oil for humans and livestock. To investigate the genetic architecture of seed nutrients in upland cotton, a genome-wide association study (GWAS) was conducted in a panel of 196 germplasm resources under three environments using a CottonSNP80K chip of 77,774 loci. Relatively high genetic diversity (average gene diversity being 0.331) and phenotypic variation (coefficient of variation, CV, exceeding 3.9%) were detected in this panel. Correlation analysis revealed that the well-documented negative association between seed protein (PR) and oil may be to some extent attributable to the negative correlation between oleic acid (OA) and PR. Linkage disequilibrium (LD) was unevenly distributed among chromosomes and subgenomes. It ranged from 0.10 0.20 Mb (Chr19) to 5.65-5.75 Mb (Chr25) among the chromosomes and the range of Dt subgenomes LD decay distances was smaller than At-subgenomes. This panel was divided into two subpopulations based on the information of 41,815 polymorphic single-nucleotide polymorphism (SNP) markers. The mixed linear model considering both Q-matrix and K-matrix [MLM(Q+K)] was employed to estimate the association between the SNP markers and the seed nutrients, considering the false positives caused by population structure and the kinship. A total of 47 SNP markers and 28 candidate quantitative trait loci (QTLs) regions were found to be significantly associated with seven cottonseed nutrients, including protein, total fatty acid, and five main fatty acid compositions. In addition, the candidate genes in these regions were analyzed, which included three genes, Gh_D12G1161, Gh_D12G1162, and Gh_D12G1165 that were most likely involved in the control of cottonseed protein concentration. These results improved our understanding of the genetic control of cottonseed nutrients and provided potential molecular tools to develop cultivars with high protein and improved fatty acid compositions in cotton breeding programs through marker-assisted selection. PMID- 30405647 TI - Genome-Wide Identification, Expression Profiling, and Functional Validation of Oleosin Gene Family in Carthamus tinctorius L. AB - Carthamus tinctorius L., commonly known as safflower, is an important oilseed crop containing oil bodies. Oil bodies are intracellular organelles in plant cells for storing triacylglycerols (TAGs) and sterol esters. Oleosins are the most important surface proteins of the oil bodies. We predicted and retrieved the sequences of eight putative C. tinctorius oleosin (Ctoleosin) genes from the genome database of safflower. The bioinformatics analyses revealed the size of their open reading frames ranging from 414 to 675 bp, encoding 137 to 224 aa polypeptides with predicted molecular weights of 14.812 to 22.155 kDa, all containing the typical "proline knot" motif. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) determined the spatiotemporal expression pattern of Ctoleosin genes, which gradually increased and peaked during flowering and seed ripening, and decreased thereafter. To validate their role in plant development, we transformed and overexpressed these eight putative Ctoleosin genes in Arabidopsis. Overexpressing Ctoleosins did not affect leaf size, although silique length was altered. Arabidopsis transformed with Ctoleosin3, 4, and 5 grew longer siliques than did the wild-type plants, without altering seed quantity. The 100-grain weight of the transgenic Arabidopsis seeds was slightly more than that of the wild-type seeds. The seed germination rates of the plants overexpressing Ctoleosin4 and 6 were slightly lower as compared with that of the wild-type Arabidopsis, whereas that in the other transgenic lines were higher than that in the wild-type plants. The overexpression of Ctoleosin genes elevated the oil content in the seeds of transgenic Arabidopsis. Our findings not only provide an approach for increasing the oil content, but also for elucidating the intricate mechanisms of oil body synthesis. PMID- 30405646 TI - Both NaCl and H2O2 Long-Term Stresses Affect Basal Cytosolic Ca2+ Levels but Only NaCl Alters Cytosolic Ca2+ Signatures in Arabidopsis. AB - Salinity is one of the formidable environmental factors that affect plant growth and development and constrain agricultural productivity. Experimentally imposed short-term NaCl treatment triggers a transient increase in cytosolic free Ca2+ concentration ([Ca2+]i) via Ca2+ influx across the plasma membrane. Salinity stress, as well as other stresses, induces the production of reactive oxygen species (ROS), such as H2O2. It is well established that short-term H2O2 treatment also triggers a transient increase in [Ca2+]i. However, whether and how long-term NaCl and H2O2 treatments affect the basal levels of [Ca2+]i as well as plant responses to additional NaCl and H2O2 stresses remain poorly understood. Using an aequorin-based Ca2+ imaging assay, we found that the long-term treatment of Arabidopsis seedlings with both moderate NaCl and H2O2 in the growth media reduced the basal [Ca2+]i levels. Interestingly, we found that the long-term treatment with NaCl, but not H2O2, affected the responses of plants to additional NaCl stress, and remarkably the roots displayed enhanced responses while the leaves showed reduced responses. These findings suggest that plants adapt to the long-term NaCl stress, while H2O2 might be an integrator of many stresses. PMID- 30405649 TI - Approach to Higher Wheat Yield in the Huang-Huai Plain: Improving Post-anthesis Productivity to Increase Harvest Index. AB - Both increased harvest index (HI) and increased dry matter (DM) are beneficial to yield; however, little is known about the priority of each under different yield levels. This paper aims to determine whether HI or DM is more important and identify the physiological attributes that act as indicators of increased yield. Two field experiments involving different cultivation patterns and water-nitrogen modes, respectively, were carried out from 2013 to 2016 in Huang-Huai Plain, China. Plant DM, leaf area index (LAI), and radiation interception (RI) were measured. Increased yield under low yield levels <7500 kg ha-1 was attributed to an increase in both total DM and HI, while increases under higher yield levels >7500 kg ha-1 were largely dependent on an increase in HI. Under high yield levels, HI showed a significant negative correlation with total DM and a parabolic relationship with net accumulation of DM during filling. Higher net accumulation of DM during filling helped slow down the decrease in HI, thereby maintaining a high value. Moreover, net DM accumulation during filling was positively correlated with yield, while post-anthesis accumulation showed a significant linear relationship with leaf area potential (LAP, R 2 = 0.404-0.526) and radiation interception potential (RIP, R 2 = 0.452-0.576) during grain filling. These findings suggest that the increase in LAP and RIP caused an increase in net DM accumulation after anthesis. Under DM levels >13,000 kg ha-1 at anthesis, maintaining higher LAI and RI in lower layers during grain formation contributed to higher yield. Furthermore, the ratio of upper- to lower-layer RI showed a second-order curve with yield during filling, with an increase in the optimal range with grain development. Pre-anthesis translocation amount, translocation ratios and contribution ratios also showed second-order curves under high yield levels, with optimal values of 3000-4500 kg ha-1, 25-35, and 30 50%, respectively. These results confirm the importance of HI in improving the yield, thereby providing a theoretical basis for wheat production in the Huang Huai Plain. PMID- 30405648 TI - Impacts of Paraburkholderia phytofirmans Strain PsJN on Tomato (Lycopersicon esculentum L.) Under High Temperature. AB - Abnormal temperatures induce physiological and biochemical changes resulting in the loss of yield. The present study investigates the impact of the PsJN strain of Paraburkholderia phytofirmans on tomato (Lycopersicon esculentum Mill.) in response to heat stress (32 degrees C). The results of this work showed that bacterial inoculation with P. phytofirmans strain PsJN increased tomato growth parameters such as chlorophyll content and gas exchange at both normal and high temperatures (25 and 32 degrees C). At normal temperature (25 degrees C), the rate of photosynthesis and the photosystem II activity increased with significant accumulations of sugars, total amino acids, proline, and malate in the bacterized tomato plants, demonstrating that the PsJN strain had a positive effect on plant growth. However, the amount of sucrose, total amino acids, proline, and malate were significantly affected in tomato leaves at 32 degrees C compared to that at 25 degrees C. Changes in photosynthesis and chlorophyll fluorescence showed that the bacterized tomato plants were well acclimated at 32 degrees C. These results reinforce the current knowledge about the PsJN strain of P. phytofirmans and highlight in particular its ability to alleviate the harmful effects of high temperatures by stimulating the growth and tolerance of tomato plants. PMID- 30405650 TI - The Xylulose 5-Phosphate/Phosphate Translocator Supports Triose Phosphate, but Not Phosphoenolpyruvate Transport Across the Inner Envelope Membrane of Plastids in Arabidopsis thaliana Mutant Plants. AB - The xylulose 5-phosphate/phosphate translocator (PTs) (XPT) represents a link between the plastidial and extraplastidial branches of the oxidative pentose phosphate pathway. Its role is to retrieve pentose phosphates from the extraplastidial space and to make them available to the plastids. However, the XPT transports also triose phosphates and to a lesser extent phosphoenolpyruvate (PEP). Thus, it might support both the triose phosphate/PT (TPT) in the export of photoassimilates from illuminated chloroplasts and the PEP/PT (PPT) in the import of PEP into green or non-green plastids. In mutants defective in the day- and night-path of photoassimilate export from the chloroplasts (i.e., knockout of the TPT [tpt-2] in a starch-free background [adg1-1])the XPT provides a bypass for triose phosphate export and thereby guarantees survival of the adg1-1/tpt-2 double mutant. Here we show that the additional knockout of the XPT in adg1-1/tpt 2/xpt-1 triple mutants results in lethality when the plants were grown in soil. Thus the XPT can functionally support the TPT. The PEP transport capacity of the XPT has been revisited here with a protein heterologously expressed in yeast. PEP transport rates in the proteoliposome system were increased with decreasing pH values below 7.0. Moreover, PEP transport determined in leaf extracts from wild type plants showed a similar pH-response, suggesting that in both cases PEP2- is the transported charge-species. Hence, PEP import into illuminated chloroplasts might be unidirectional because of the alkaline pH of the stroma. Here the consequence of a block in PEP transport across the envelope was analyzed in triple mutants defective in both PPTs and the XPT. PPT1 is knocked out in the cue1 mutant. For PPT2 two new mutant alleles were isolated and established as homozygous lines. In contrast to the strong phenotype of cue1, both ppt2 alleles showed only slight growth retardation. As plastidial PEP is required e.g., for the shikimate pathway of aromatic amino acid synthesis, a block in PEP import should result in a lethal phenotype. However, the cue1-6/ppt2-1/ppt2-1 triple mutant was viable and even exhibited residual PEP transport capacity. Hence, alternative ways of PEP transport must exist and are discussed. PMID- 30405651 TI - Fusarium Wilt of Banana: Current Knowledge on Epidemiology and Research Needs Toward Sustainable Disease Management. AB - Banana production is seriously threatened by Fusarium wilt (FW), a disease caused by the soil-borne fungus Fusarium oxysporum f. sp. cubense (Foc). In the mid twentieth century FW, also known as "Panama disease", wiped out the Gros Michel banana industry in Central America. The devastation caused by Foc race 1 was mitigated by a shift to resistant Cavendish cultivars, which are currently the source of 99% of banana exports. However, a new strain of Foc, the tropical race 4 (TR4), attacks Cavendish clones and a diverse range of other banana varieties. Foc TR4 has been restricted to East and parts of Southeast Asia for more than 20 years, but since 2010 the disease has spread westward into five additional countries in Southeast and South Asia (Vietnam, Laos, Myanmar, India, and Pakistan) and at the transcontinental level into the Middle East (Oman, Jordan, Lebanon, and Israel) and Africa (Mozambique). The spread of Foc TR4 is of great concern due to the limited knowledge about key aspects of disease epidemiology and the lack of effective management models, including resistant varieties and soil management approaches. In this review we summarize the current knowledge on the epidemiology of FW of banana, highlighting knowledge gaps in pathogen survival and dispersal, factors driving disease intensity, soil and plant microbiome and the dynamics of the disease. Comparisons with FW in other crops were also made to indicate possible differences and commonalities. Our current understanding of the role of main biotic and abiotic factors on disease intensity is reviewed, highlighting research needs and futures directions. Finally, a set of practices and their impact on disease intensity are discussed and proposed as an integrative management approach that could eventually be used by a range of users, including plant protection organizations, researchers, extension workers and growers. PMID- 30405653 TI - Overexpression of a Transcription Factor Increases Lipid Content in a Woody Perennial Jatropha curcas. AB - Vegetable oil is an important renewable resource for dietary consumption for human and livestock, and more recently for biodiesel production. Lipid traits in crops are controlled by multiple quantitative trait loci (QTLs) and each of them has a small effect on lipid traits. So far, there is limited success to increase lipid yield and improve lipid quality in plants. Here, we reported the identification of a homolog of APETALA2 (AP2) transcription factor WRINKLED1 (JcWRI1) from an oleaginous plant Jatropha curcas and characterized its function in Jatropha and Arabidopsis thaliana. Using physical mapping data, we located JcWRI1 in a QTL region specifying high oleate and lipid content in Jatropha. Overexpression of JcWRI1 in Jatropha elevated seed lipid content and increased seed mass. Lipid profile in seeds of over-expression plants showed higher oleate content which will be beneficial to improve biodiesel quality. Overexpression of JcWRI1 activated lipid-related gene expression and JcWRI1 was shown to directly bind to the AW-box of promoters of some of these genes. In conclusion, we were able to increase seed lipid content and improve seed lipid quality in Jatropha by manipulating one key transcription factor JcWRI1. PMID- 30405654 TI - A Comparison of Landraces vs. Modern Varieties of Lettuce in Organic Farming During the Winter in the Mediterranean Area: An Approach Considering the Viewpoints of Breeders, Consumers, and Farmers. AB - The interest of farmers in growing lettuce landraces is increasing, as landrace varieties prove particularly appealing to consumers striving to purchase natural, local, and high-quality produce. Although high genetic diversity exists in the landrace gene pool, this has scarcely been studied, thus hindering landrace utilization in agriculture. In this study, we analyzed the genetic diversity and the agronomic and quality traits of lettuce landraces in organic agrosystems, by characterizing 16 landraces and 16 modern varieties. We compared 29 morphological descriptors, and several traits relating to agronomic behavior (total and commercial weight, resistance to Bremia lactucae) and quality (color, chlorophyll, dry matter, and total sugars). Trials were conducted in two localities and managed following organic farming practices. Moreover, farmers and consumers participated in the phenotyping of accessions by scoring yield, resistance to B. lactucae, appearance, and taste acceptance. Results show that cultivar group, rather than the genetic origin (modern vs. landrace), is the major source of variation for all agronomic and quality traits. Batavia and Butterhead were highly homogeneous cultivar groups, while Cos accessions showed a much higher intra-varietal diversity. There was also a clear separation between modern and landrace varieties of Oak leaf. Fifteen out of the 16 evaluated landraces presented a high susceptibility to the particular B. lactucae race isolated from the experimental field - a new race not reported before. Breeding programs intended to introgress genetic resistance to this pathogen are a major priority to recover the cultivation of lettuce landraces. Principal component analysis (PCA), conducted on all quantitative data, showed a clear differentiation between modern varieties and landraces, mostly related to their commercial weight and susceptibility to B. lactucae. These seem the most important traits influencing farmer and consumer evaluations. Farmers showed a high capacity for characterizing the samples and agreed with consumers when scoring for the external appearance. It is proposed that farmers and consumers should be included in the phenotyping platforms in future research projects aiming for recovery of landraces. PMID- 30405655 TI - Impacts of Atmospheric CO2 and Soil Nutritional Value on Plant Responses to Rhizosphere Colonization by Soil Bacteria. AB - Concerns over rising atmospheric CO2 concentrations have led to growing interest in the effects of global change on plant-microbe interactions. As a primary substrate of plant metabolism, atmospheric CO2 influences below-ground carbon allocation and root exudation chemistry, potentially affecting rhizosphere interactions with beneficial soil microbes. In this study, we have examined the effects of different atmospheric CO2 concentrations on Arabidopsis rhizosphere colonization by the rhizobacterial strain Pseudomonas simiae WCS417 and the saprophytic strain Pseudomonas putida KT2440. Rhizosphere colonization by saprophytic KT2440 was not influenced by sub-ambient (200 ppm) and elevated (1,200 ppm) concentrations of CO2, irrespective of the carbon (C) and nitrogen (N) content of the soil. Conversely, rhizosphere colonization by WCS417 in soil with relatively low C and N content increased from sub-ambient to elevated CO2. Examination of plant responses to WCS417 revealed that plant growth and systemic resistance varied according to atmospheric CO2 concentration and soil-type, ranging from growth promotion with induced susceptibility at sub-ambient CO2, to growth repression with induced resistance at elevated CO2. Collectively, our results demonstrate that the interaction between atmospheric CO2 and soil nutritional status has a profound impact on plant responses to rhizobacteria. We conclude that predictions about plant performance under past and future climate scenarios depend on interactive plant responses to soil nutritional status and rhizobacteria. PMID- 30405652 TI - Plant Growth-Promoting Rhizobacteria: Context, Mechanisms of Action, and Roadmap to Commercialization of Biostimulants for Sustainable Agriculture. AB - Microbes of the phytomicrobiome are associated with every plant tissue and, in combination with the plant form the holobiont. Plants regulate the composition and activity of their associated bacterial community carefully. These microbes provide a wide range of services and benefits to the plant; in return, the plant provides the microbial community with reduced carbon and other metabolites. Soils are generally a moist environment, rich in reduced carbon which supports extensive soil microbial communities. The rhizomicrobiome is of great importance to agriculture owing to the rich diversity of root exudates and plant cell debris that attract diverse and unique patterns of microbial colonization. Microbes of the rhizomicrobiome play key roles in nutrient acquisition and assimilation, improved soil texture, secreting, and modulating extracellular molecules such as hormones, secondary metabolites, antibiotics, and various signal compounds, all leading to enhancement of plant growth. The microbes and compounds they secrete constitute valuable biostimulants and play pivotal roles in modulating plant stress responses. Research has demonstrated that inoculating plants with plant growth promoting rhizobacteria (PGPR) or treating plants with microbe-to-plant signal compounds can be an effective strategy to stimulate crop growth. Furthermore, these strategies can improve crop tolerance for the abiotic stresses (e.g., drought, heat, and salinity) likely to become more frequent as climate change conditions continue to develop. This discovery has resulted in multifunctional PGPR-based formulations for commercial agriculture, to minimize the use of synthetic fertilizers and agrochemicals. This review is an update about the role of PGPR in agriculture, from their collection to commercialization as low-cost commercial agricultural inputs. First, we introduce the concept and role of the phytomicrobiome and the agricultural context underlying food security in the 21st century. Next, mechanisms of plant growth promotion by PGPR are discussed, including signal exchange between plant roots and PGPR and how these relationships modulate plant abiotic stress responses via induced systemic resistance. On the application side, strategies are discussed to improve rhizosphere colonization by PGPR inoculants. The final sections of the paper describe the applications of PGPR in 21st century agriculture and the roadmap to commercialization of a PGPR-based technology. PMID- 30405656 TI - Actinorhizal Signaling Molecules: Frankia Root Hair Deforming Factor Shares Properties With NIN Inducing Factor. AB - Actinorhizal plants are able to establish a symbiotic relationship with Frankia bacteria leading to the formation of root nodules. The symbiotic interaction starts with the exchange of symbiotic signals in the soil between the plant and the bacteria. This molecular dialog involves signaling molecules that are responsible for the specific recognition of the plant host and its endosymbiont. Here we studied two factors potentially involved in signaling between Frankia casuarinae and its actinorhizal host Casuarina glauca: (1) the Root Hair Deforming Factor (CgRHDF) detected using a test based on the characteristic deformation of C. glauca root hairs inoculated with F. casuarinae and (2) a NIN activating factor (CgNINA) which is able to activate the expression of CgNIN, a symbiotic gene expressed during preinfection stages of root hair development. We showed that CgRHDF and CgNINA corresponded to small thermoresistant molecules. Both factors were also hydrophilic and resistant to a chitinase digestion indicating structural differences from rhizobial Nod factors (NFs) or mycorrhizal Myc-LCOs. We also investigated the presence of CgNINA and CgRHDF in 16 Frankia strains representative of Frankia diversity. High levels of root hair deformation (RHD) and activation of ProCgNIN were detected for Casuarina-infective strains from clade Ic and closely related strains from clade Ia unable to nodulate C. glauca. Lower levels were present for distantly related strains belonging to clade III. No CgRHDF or CgNINA could be detected for Frankia coriariae (Clade II) or for uninfective strains from clade IV. PMID- 30405657 TI - Identification of Soil Bacterial Isolates Suppressing Different Phytophthora spp. and Promoting Plant Growth. AB - Bacterial isolates obtained from the rhizosphere of Arabidopsis and a plantless compost potting mix was screened for anti-oomycete activity against Phytophthora capsici, Phytophthora citricola, Phytophthora palmivora, and Phytophthora cinnamomi. Three out of 48 isolates exhibited more than 65% inhibition against all tested Phytophthora species and were selected for further studies. These strains, named UQ154, UQ156, and UQ202, are closely related to Bacillus amyloliquefaciens, Bacillus velezensis, and Acinetobacter sp., respectively, based on 16S rDNA sequence analysis. The isolates were evaluated for their ability to fix nitrogen, solubilize phosphate, as well as for siderophore, indoleacetic acid, cell wall degrading enzymes and biofilm production. Their plant growth promoting activities were evaluated by measuring their effect on the germination percentage, root and shoot length, and seedling vigor of lettuce plants. All of these traits were significantly enhanced in plants grown from seeds inoculated with the isolates compared with control plants. Moreover, bacteria-inoculated P. capsici-infected chili plants exhibited improved productivity based on CO2 assimilation rates. Both real-time quantitative PCR and disease severity index revealed significant decreases in pathogen load in infected chili root tissues when plants were previously inoculated with the isolates. Biocontrol activity may result from the secretion of diketopiperazines as identified by Gas chromatography-mass spectrometry analysis of bacterial cultures' extracts. Collectively, this work demonstrates the potential of bacterial isolates to control Phytophthora infection and promote plant growth. They can, therefore be considered as candidate microbial biofertilizers and biopesticides. PMID- 30405658 TI - WHIRLY1 Occupancy Affects Histone Lysine Modification and WRKY53 Transcription in Arabidopsis Developmental Manner. AB - Single-stranded DNA-binding proteins (SSBs) are assumed to involve in DNA replication, DNA repairmen, and gene transcription. Here, we provide the direct evidence on the functionality of an Arabidopsis SSB, WHIRLY1, by using loss- or gain-of-function lines. We show that WHIRLY1 binding to the promoter of WRKY53 represses the enrichment of H3K4me3, but enhances the enrichment of H3K9ac at the region contained WHIRLY1-binding sequences and TATA box or the translation start region of WRKY53, coincided with a recruitment of RNAPII. In vitro ChIP assays confirm that WHIRLY1 inhibits H3K4me3 enrichment at the preinitiation complex formation stage, while promotes H3K9ac enrichment and RNAPII recruitment at the elongation stage, consequently affecting the transcription of WRKY53. These results further explore the molecular actions underlying SSB-mediated gene transcription through epigenetic regulation in plant senescence. PMID- 30405659 TI - Germination and Early Seedling Development in Quercus ilex Recalcitrant and Non dormant Seeds: Targeted Transcriptional, Hormonal, and Sugar Analysis. AB - Seed germination and early seedling development have been studied in the recalcitrant species Quercus ilex using targeted transcriptional, hormonal, and sugar analysis. Embryos and seedlings were collected at eight morphologically defined developmental stages, S0-S7. A typical triphasic water uptake curve was observed throughout development, accompanied by a decrease in sucrose and an increase in glucose and fructose. Low levels of abscisic acid (ABA) and high levels of gibberellins (GAs) were observed in mature seeds. Post-germination, indole-3-acetic acid (IAA), increased, whereas GA remained high, a pattern commonly observed during growth and development. The abundance of transcripts from ABA-related genes was positively correlated with the changes in the content of the phytohormone. Transcripts of the drought-related genes Dhn3 and GolS were more abundant at S0, then decreased in parallel with increasing water content. Transcripts for Gapdh, and Nadh6 were abundant at S0, supporting the occurrence of an active metabolism in recalcitrant seeds at the time of shedding. The importance of ROS during germination is manifest in the high transcript levels for Sod and Gst, found in mature seeds. The results presented herein help distinguish recalcitrant (e.g., Q. ilex) seeds from their orthodox counterparts. Our results indicate that recalcitrance is established during seed development but not manifest until germination (S1-S3). Post-germination the patterns are quite similar for both orthodox and recalcitrant seeds. PMID- 30405660 TI - Developmental Plasticity of the Major Alkyl Cannabinoid Chemotypes in a Diverse Cannabis Genetic Resource Collection. AB - Cannabis is a chemically diverse domesticated plant genus which produces a unique class of biologically active secondary metabolites referred to as cannabinoids. The affinity and selectivity of cannabinoids to targets of the human endocannabinoid system depend on alkyl side chain length, and these structural activity relationships can be utilized for the development of novel therapeutics. Accurate early screening of germplasm has the potential to accelerate selection of chemical phenotypes (chemotypes) for pharmacological exploitation. However, limited attempts have been made to characterize the plasticity of alkyl cannabinoid composition in different plant tissues and throughout development. A chemotypic diversity panel comprised of 99 individuals from 20 Cannabis populations sourced from the Ecofibre Global Germplasm Collection (ecofibre.com.au and anandahemp.com) was used to examine alkyl cannabinoid variation across vegetative, flowering and maturation stages. A wide range of di /tri-cyclic as well as C3-/C5-alkyl cannabinoid composition was observed between plants. Chemotype at the vegetative and flowering stages was found to be predictive of chemotype at maturation, indicating a low level of plasticity in cannabinoid composition. Chemometric cluster analysis based on composition data from all three developmental stages categorized alkyl cannabinoid chemotypes into three classes. Our results suggest that more extensive chemical and genetic characterization of the Cannabis genepool could facilitate the metabolic engineering of alkyl cannabinoid chemotypes. PMID- 30405661 TI - Development of Wheat With Hypoimmunogenic Gluten Obstructed by the Gene Editing Policy in Europe. AB - Coeliac Disease (CD) is an auto-immune reaction to gluten in 1-2% of the human population. A gluten-free (GF) diet, excluding wheat, barley, and rye, is the only remedy. This diet is difficult to adhere to, partly because wheat gluten is added to many processed products for their viscoelastic properties. In addition, GF products are less healthy and expensive. Wheat products containing only hypoimmunogenic gluten proteins would be a desirable option. Various gluten peptides that trigger CD have been characterized. A single wheat variety contains around hundred gluten genes, producing proteins with varying numbers of epitopes. Gene editing using CRISPR/Cas9 can precisely remove or modify the DNA sequences coding for immunogenic peptides. Wheat with hypoimmunogenic gluten thus exemplifies the potential of gene editing for improving crops for human consumption where conventional breeding cannot succeed. We describe here, in relation to breeding hypoimmunogenic wheat varieties, the inconsistencies of applying GM regulation in Europe for gene-edited plants while mutation breeding derived plants are exempted. We explain that healthy products derived from this new technology may become available in the United States, Canada, Argentina and other countries but not in Europe, because of strict regulation of unintended GM risk at the expense of reduction the existing immunogenicity risks of patients. We argue that regulation of gene-edited plants should be based on scientific evidence. Therefore, we strongly recommend implementing the innovation principle. Responsible Research and Innovation, involving stakeholders including CD patient societies in the development of gene-editing products, will enable progress toward healthy products and encourage public acceptance. PMID- 30405662 TI - Warm Season Grain Legume Landraces From the South of Europe for Germplasm Conservation and Genetic Improvement. AB - Currently, there is a high concern from consumers regarding food quality, with emphasis on the origin of food sources. We here review the current situation of beans (Phaseolus spp.) and cowpea (Vigna unguiculata (L.) Walp.) landraces in the South of Europe focusing on morpho-agronomic and genetic diversity and physiological adaptation to the different agrosystems, including the symbiotic association with rhizobia. Despite the reduction in the production and consumption of grain legumes in Southern Europe, the variability of common bean, runner bean and cowpea landraces in this region is adequately preserved ex situ in germplasm banks and in breeder collections in Portugal, Spain, Italy and Greece; however, on-farm (in situ) conservation in isolated areas mainly in gardens and small fields for farmers own consumption and local markets is not guaranteed. This variability can be used for the genetic improvement of varieties, which will result in environmental-friendly improved legumes for a sustainable production in the South of Europe as well as in other regions of the World. PMID- 30405663 TI - Physiological and Biochemical Responses of Cucumis melo L. Chloroplasts to Low Phosphate Stress. AB - Phosphorus (P) is a limiting plant soil nutrient. Long-term low inorganic phosphate (Pi) irreversibly damages plant cells and hinders plant growth. Plants have evolved several adaptive biochemical, physiological, and developmental responses to low-Pi stress. However, little is known about chloroplast responses to low-Pi stress. In this study, we used physiological and biochemical analyses to investigate melon chloroplast responses to low-Pi stress. The results indicated that low-Pi stress impeded melon seedling growth and reduced its dry matter content by inhibiting the photosynthesis. Low-Pi stress reduced the P content in shoots, which inhibited ATP synthase (ATP-ase) activity, and disturbed the proton and electron transport efficiency on chloroplast photosynthetic electron transport chain. In addition, low-Pi stress induced reactive oxygen species (ROS) production in the leaves, which caused membrane peroxidation. Therefore, redox homeostasis was not maintained, and the melon leaves presented with symptoms of photooxidative stress. To mitigate photoinhibition, the melon plants initiated non-photochemical chlorophyll fluorescence quenching (NPQ) initiated by acidification of the thylakoid lumen to dissipate excess excitation energy, significantly improved ROS-scavenging enzyme activity. Based on these experimental results, we concluded that low Pi inhibited photosystem activity and caused photooxidative stress and photoinhibition. To alleviate these negative effects, the plant activated its NPQ mechanism, alternative electron transport pathways, and antioxidant system to protect its chloroplasts. PMID- 30405665 TI - Marker-Assisted Breeding of Improved Maternal Haploid Inducers in Maize for the Tropical/Subtropical Regions. AB - For efficient production of doubled haploid (DH) lines in maize, maternal haploid inducer lines with high haploid induction rate (HIR) and good adaptation to the target environments is an important requirement. In this study, we present second generation Tropically Adapted Inducer Lines (2GTAILs), developed using marker assisted selection (MAS) for qhir1, a QTL with a significant positive effect on HIR from the crosses between elite tropical maize inbreds and first generation Tropically Adapted Inducers Lines (TAILs). Evaluation of 2GTAILs for HIR and agronomic performance in the tropical and subtropical environments indicated superior performance of 2GTAILs over the TAILs for both HIR and agronomic performance, including plant vigor, delayed flowering, grain yield, and resistance to ear rots. One of the new inducers 2GTAIL006 showed an average HIR of 13.1% which is 48.9% higher than the average HIR of the TAILs. Several other 2GTAILs also showed higher HIR compared to the TAILs. While employing MAS for qhir1 QTL, we observed significant influence of the non-inducer parent on the positive effect of qhir1 QTL on HIR. The non-inducer parents that resulted in highest mean HIR in the early generation qhir1+ families also gave rise to highest numbers of candidate inducers, some of which showed transgressive segregation for HIR. The mean HIR of early generation qhir1+ families involving different non-inducer parents can potentially indicate recipient non-inducer parents that can result in progenies with high HIR. Our study also indicated that the HIR associated traits (endosperm abortion rate, embryo abortion rate, and proportion of haploid plants among the inducer plants) can be used to differentiate inducers vs. non-inducers but are not suitable for differentiating inducers with varying levels of haploid induction rates. We propose here an efficient methodology for developing haploid inducer lines combining MAS for qhir1 with HIR associated traits. PMID- 30405664 TI - Responses of the Endophytic Bacterial Communities of Juncus acutus to Pollution With Metals, Emerging Organic Pollutants and to Bioaugmentation With Indigenous Strains. AB - Plants and their associated bacteria play a crucial role in constructed wetlands. In this study, the impact of different levels of pollution and bioaugmentation with indigenous strains individually or in consortia was investigated on the composition of the endophytic microbial communities of Juncus acutus. Five treatments were examined and compared in where the wetland plant was exposed to increasing levels of metal pollution (Zn, Ni, Cd) and emerging pollutants (BPA, SMX, CIP), enriched with different combinations of single or mixed endophytic strains. High levels of mixed pollution had a negative effect on alpha diversity indices of the root communities; moreover, the diversity indices were negatively correlated with the increasing metal concentrations. It was demonstrated that the root communities were separated depending on the level of mixed pollution, while the family Sphingomonadaceae exhibited the higher relative abundance within the root endophytic communities from high and low polluted treatments. This study highlights the effects of pollution and inoculation on phytoremediation efficiency based on a better understanding of the plant microbiome community composition. PMID- 30405666 TI - Current Advances in Molecular Basis and Mechanisms Regulating Leaf Morphology in Rice. AB - Yield is majorly affected by photosynthetic efficiency. Leaves are essential structure for photosynthesis and their morphology especially size and shape in a plant canopy can affect the rate of transpiration, carbon fixation and photosynthesis. Leaf rolling and size are considered key agronomic traits in plant architecture that can subsidize yield parameters. In last era, a number of genes controlling leaf morphology have been molecularly characterized. Despite of several findings, our understanding toward molecular mechanism of leaf rolling and size are under-developed. Here, we proposed a model to apprehend the physiological basis of different genes organized in a complex fashion and govern the final phenotype of leaf morphology. According to this leaf rolling is mainly controlled by regulation of bulliform cells by SRL1, ROC5, OsRRK1, SLL2, CLD1, OsZHD1/2, and NRL1, structure and processes of sclerenchyma cells by SLL1 and SRL2, leaf polarity by ADL1, RFS and cuticle formation by CFL1, and CLD1. Many of above mentioned and several other genes interact in a complex manner in order to sustain cellular integrity and homeostasis for optimum leaf rolling. While, leaf size is synchronized by multifarious interaction of PLA1, PLA2, OsGASR1, and OsEXPA8 in cell division, NAL1, NAL9, NRL1, NRL2 in regulation of number of veins, OsCOW1, OsPIN1, OsARF19, OsOFP2, D1 and GID in regulation of phytohormones and HDT702 in epigenetic aspects. In this review, we curtailed recent advances engrossing regulation and functions of those genes that directly or indirectly can distress leaf rolling or size by encoding different types of proteins and genic expression. Moreover, this effort could be used further to develop comprehensive learning and directing our molecular breeding of rice. PMID- 30405667 TI - Metabolomics Analysis of Soybean Hypocotyls in Response to Phytophthora sojae Infection. AB - Soybean is one of the most important economic and oil crops across the world. Phytophthora root rot (PRR), caused by Phytophthora sojae (P. sojae), is a major disease in most soybean-growing regions worldwide. Here, we investigated metabolic changes in hypocotyls of two soybean lines, Nannong 10-1 (resistant line, R) and 06-070583 (susceptible line, S), at two time points (12 and 36 hpi) after P. sojae infection and metabolic differences between the R line and the S line. In total, 90 differentially accumulated metabolites (DAMs) were identified after P. sojae infection; the levels of 50 metabolites differed between the R line and the S line. There are 28 DAMs that not only differentially accumulated between the R line and the S line but also differentially accumulated after P. sojae infection. Based on the changes of these DAMs in response to P. sojae infection in different lines and at different timepoints, and the differences in the contents of these DAMs between the R line and the S line, we speculated that DAMs, including sugars (monosaccharides and oligosaccharides), organic acids (oxalic acid, cumic acid), amino acid derivatives, and other secondary metabolites (mannitol, octanal, hypoxanthine, and daidzein etc.) may participate in the metabolic-level defense response of soybean to P. sojae. In this study, an integrated pathway-level analysis of transcriptomics (obtained by RNA-Seq) and metabolomics data illustrated the poor connections and interdependencies between the metabolic and transcriptional responses of soybean to P. sojae infection. This work emphasizes the value of metabolomic studies of plant-pathogen interactions and paves the way for future research of critical metabolic determinants of the soybean-P. sojae interaction. PMID- 30405669 TI - Development and Validation of an Effective CRISPR/Cas9 Vector for Efficiently Isolating Positive Transformants and Transgene-Free Mutants in a Wide Range of Plant Species. AB - The CRISPR/Cas9 technique is a highly valuable tool in creating new materials for both basic and applied researches. Previously, we succeeded in effectively generating mutations in Brassica napus using an available CRISPR/Cas9 vector pKSE401, while isolation of Cas9-free mutants is laborious and inefficient. Here, we inserted a fluorescence tag (sGFP) driven by the constitutive 35S promoter into pKSE401 to facilitate a visual screen of mutants. This modified vector was named pKSE401G and tested in several dicot plant species, including Arabidopsis, B. napus, Fragaria vesca (strawberry), and Glycine max (soybean). Consequently, GFP-positive plants were readily identified through fluorescence screening in all of these species. Among these GFP-positive plants, the average mutation frequency ranged from 20.4 to 52.5% in Arabidopsis and B. napus with stable transformation, and was 90.0% in strawberry and 75.0% in soybean with transient transformation, indicating that the editing efficiency resembles that of the original vector. Moreover, transgene-free mutants were sufficiently identified in Arabidopsis in the T2 generation and B. napus in the T1 generation based on the absence of GFP fluorescence, and these mutants were stably transmissible to next generation without newly induced mutations. Collectively, pKSE401G provides us an effective tool to readily identify positive primary transformants and transgene-free mutants in later generations in a wide range of dicot plant species. PMID- 30405668 TI - LysM Receptor-Like Kinase and LysM Receptor-Like Protein Families: An Update on Phylogeny and Functional Characterization. AB - Members of plant specific families of receptor-like kinases (RLKs) and receptor like proteins (RLPs), containing 3 extracellular LysMs have been shown to directly bind and/or to be involved in perception of lipo-chitooligosaccharides (LCO), chitooligosaccharides (CO), and peptidoglycan (PGN), three types of GlcNAc containing molecules produced by microorganisms. These receptors are involved in microorganism perception by plants and can activate different plant responses leading either to symbiosis establishment or to defense responses against pathogens. LysM-RLK/Ps belong to multigenic families. Here, we provide a phylogeny of these families in eight plant species, including dicotyledons and monocotyledons, and we discuss known or putative biological roles of the members in each of the identified phylogenetic groups. We also report and discuss known biochemical properties of the LysM-RLK/Ps. PMID- 30405671 TI - Contributions of Three Starch Branching Enzyme Isozymes to the Fine Structure of Amylopectin in Rice Endosperm. AB - Three starch branching enzyme (BE) isozymes, BEI, BEIIa, and BEIIb, are involved in starch biosynthesis in rice endosperm. Past in vivo and in vitro studies have suggested that each BE isozyme plays a distinct role in forming the fine structure of amylopectin. To elucidate more details of their roles, we prepared DNA constructs in which all the possible combinations of the expressions of these three isozymes were suppressed in developing rice endosperm. Analysis of the chain-length distributions of amylopectin produced under these various conditions confirmed the contributions of the individual BE isozymes to the fine structure of amylopectin in rice endosperm. Among these isozymes, the impact of loss of BEIIb activity on amylopectin fine structure was most remarkable and indicated that it plays a specific role in the synthesis of short chains with a 6-13 degree of polymerization (DP). The contribution of BEI to the amylopectin synthesis was unclear when only BEI activity was reduced. It was clear, however, when both BEI and BEIIb activities were substantially inhibited. The DP11-22 intermediate chains were markedly reduced in the DeltaBEI/BEIIb line compared with the DeltaBEIIb line, indicating that BEI plays a distinct role in the synthesis of these intermediate chains. Although no substantial change in amylopectin chain profile was detected in the DeltaBEIIa line, the role of BEIIa could be deciphered by analyzing amylopectin fine structure from the DeltaBEI/BEIIa/BEIIb line in comparison to that from DeltaBEI/BEIIb line. This strongly suggests that BEIIa compensates for the role of BEI, rather than that of BEIIb, by forming intermediate chains of DP11-22. In addition, the new possibility that BEIIa is involved in the formation of starch granules in rice endosperm was suggested because the onset temperature for gelatinization of starch granules in the DeltaBEIIa/BEIIb line was significantly higher than that in the DeltaBEIIb line. In summary, the present study highlights the distinct roles of BEI, BEIIa, and BEIIb in the synthesis of amylopectin in developing rice endosperm. PMID- 30405670 TI - Recent Advances in the Transcriptional Regulation of Secondary Cell Wall Biosynthesis in the Woody Plants. AB - Plant cell walls provide structural support for growth and serve as a barrier for pathogen attack. Plant cell walls are also a source of renewable biomass for conversion to biofuels and bioproducts. Understanding plant cell wall biosynthesis and its regulation is of critical importance for the genetic modification of plant feedstocks for cost-effective biofuels and bioproducts conversion and production. Great progress has been made in identifying enzymes involved in plant cell wall biosynthesis, and in Arabidopsis it is generally recognized that the regulation of genes encoding these enzymes is under a transcriptional regulatory network with coherent feedforward and feedback loops. However, less is known about the transcriptional regulation of plant secondary cell wall (SCW) biosynthesis in woody species despite of its high relevance to biofuels and bioproducts conversion and production. In this article, we synthesize recent progress on the transcriptional regulation of SCW biosynthesis in Arabidopsis and contrast to what is known in woody species. Furthermore, we evaluate progress in related emerging regulatory machineries targeting transcription factors in this complex regulatory network of SCW biosynthesis. PMID- 30405672 TI - Engineering Non-cellulosic Polysaccharides of Wood for the Biorefinery. AB - Non-cellulosic polysaccharides constitute approximately one third of usable woody biomass for human exploitation. In contrast to cellulose, these substances are composed of several different types of unit monosaccharides and their backbones are substituted by various groups. Their structural diversity and recent examples of their modification in transgenic plants and mutants suggest they can be targeted for improving wood-processing properties, thereby facilitating conversion of wood in a biorefinery setting. Critical knowledge on their structure-function relationship is slowly emerging, although our understanding of molecular interactions responsible for observed phenomena is still incomplete. This review: (1) provides an overview of structural features of major non cellulosic polysaccharides of wood, (2) describes the fate of non-cellulosic polysaccharides during biorefinery processing, (3) shows how the non-cellulosic polysaccharides impact lignocellulose processing focused on yields of either sugars or polymers, and (4) discusses outlooks for the improvement of tree species for biorefinery by modifying the structure of non-cellulosic polysaccharides. PMID- 30405673 TI - Prediction of Lime Tolerance in Rhododendron Based on Herbarium Specimen and Geochemical Data. AB - Rhododendrons are typically known to be calcifuges that cannot grow well in lime soils. Data on lime tolerance of different taxa in Rhododendron are scarce. Habitats of naturally distributed specimens of genus Rhododendron were compiled as Chinese text-based locations from the Chinese Virtual Herbarium. The locations were then geocoded into latitude/longitude pairs and subsequently connected to soil characteristics including pH and CaCO3 from the Harmonized World Soil Database (HWSD). Using the upper quartile values of pH > 7.2 and CaCO3 > 2% weight in topsoil as threshold, we predicted the lime tolerant taxa. A dataset of 31,146 Rhododendron specimens including the information on taxonomy, GPS locations and soil parameters for both top- and subsoil was built. The majority of the specimens were distributed in soils with moderately acidic pH and without presence of CaCO3. 76 taxa with potential lime tolerance were predicted out of 525 taxa. The large scale data analysis based on combined data of geocoded herbarium specimens and HWSD allows identification of valuable Rhododendron species, subspecies or botanical varieties with potential tolerance to lime soils with higher pH. The predicted tolerant taxa are valuable resources for an in depth evaluation of lime tolerance or for further use in horticulture and breeding. PMID- 30405674 TI - Functional Characterization of Two Class II Diterpene Synthases Indicates Additional Specialized Diterpenoid Pathways in Maize (Zea mays). AB - As a major staple food, maize (Zea mays) is critical to food security. Shifting environmental pressures increasingly hamper crop defense capacities, causing expanded harvest loss. Specialized labdane-type diterpenoids are key components of maize chemical defense and ecological adaptation. Labdane diterpenoid biosynthesis most commonly requires the pairwise activity of class II and class I diterpene synthases (diTPSs) that convert the central precursor geranylgeranyl diphosphate into distinct diterpenoid scaffolds. Two maize class II diTPSs, ANTHER EAR 1 and 2 (ZmAN1/2), have been previously identified as catalytically redundant ent-copalyl diphosphate (CPP) synthases. ZmAN1 is essential for gibberellin phytohormone biosynthesis, whereas ZmAN2 is stress-inducible and governs the formation of defensive kauralexin and dolabralexin diterpenoids. Here, we report the biochemical characterization of the two remaining class II diTPSs present in the maize genome, COPALYL DIPHOSPHATE SYNTHASE 3 (ZmCPS3) and COPALYL DIPHOSPHATE SYNTHASE 4 (ZmCPS4). Functional analysis via microbial co expression assays identified ZmCPS3 as a (+)-CPP synthase, with functionally conserved orthologs occurring in wheat (Triticum aestivum) and numerous dicot species. ZmCPS4 formed the unusual prenyl diphosphate, 8,13-CPP (labda-8,13-dien 15-yl diphosphate), as verified by mass spectrometry and nuclear magnetic resonance. As a minor product, ZmCPS4 also produced labda-13-en-8-ol diphosphate (LPP). Root gene expression profiles did not indicate an inducible role of ZmCPS3 in maize stress responses. By contrast, ZmCPS4 showed a pattern of inducible gene expression in roots exposed to oxidative stress, supporting a possible role in abiotic stress responses. Identification of the catalytic activities of ZmCPS3 and ZmCPS4 clarifies the first committed reactions controlling the diversity of defensive diterpenoids in maize, and suggests the existence of additional yet undiscovered diterpenoid pathways. PMID- 30405675 TI - Aerial Imagery Analysis - Quantifying Appearance and Number of Sorghum Heads for Applications in Breeding and Agronomy. AB - Sorghum (Sorghum bicolor L. Moench) is a C4 tropical grass that plays an essential role in providing nutrition to humans and livestock, particularly in marginal rainfall environments. The timing of head development and the number of heads per unit area are key adaptation traits to consider in agronomy and breeding but are time consuming and labor intensive to measure. We propose a two step machine-based image processing method to detect and count the number of heads from high-resolution images captured by unmanned aerial vehicles (UAVs) in a breeding trial. To demonstrate the performance of the proposed method, 52 images were manually labeled; the precision and recall of head detection were 0.87 and 0.98, respectively, and the coefficient of determination (R 2) between the manual and new methods of counting was 0.84. To verify the utility of the method in breeding programs, a geolocation-based plot segmentation method was applied to pre-processed ortho-mosaic images to extract >1000 plots from original RGB images. Forty of these plots were randomly selected and labeled manually; the precision and recall of detection were 0.82 and 0.98, respectively, and the coefficient of determination between manual and algorithm counting was 0.56, with the major source of error being related to the morphology of plants resulting in heads being displayed both within and outside the plot in which the plants were sown, i.e., being allocated to a neighboring plot. Finally, the potential applications in yield estimation from UAV-based imagery from agronomy experiments and scouting of production fields are also discussed. PMID- 30405676 TI - Which Genes in a Typical Intertidal Seagrass (Zostera japonica) Indicate Copper-, Lead-, and Cadmium Pollution? AB - Healthy seagrasses are considered a prime indicator of estuarine and coastal ecosystem function; however, as the only group of flowering plants recolonizing the sea, seagrasses are frequently exposed to anthropogenic heavy metal pollutants, which are associated with high levels of molecular damage. To determine whether biologically relevant concentrations of heavy metals cause systematic alterations in RNA expression patterns, we performed a gene expression study using transcriptome analyses (RNA-seq). We exposed the typical intertidal seagrass Zostera japonica to 0 and 50 MUM of copper (Cu), lead (Pb), and cadmium (Cd) under laboratory conditions. A total of 18,266 differentially expressed genes (DEGs) were identified, of which 2001 co-expressed genes directly related by Cu, Pb, and Cd stress. We also examined the effects of short-term heavy metal Cu, Pb, and Cd pulses on the accumulation of metals in Z. japonica and showed metal concentrations were higher in the shoots than in roots. Twelve differentially expressed genes were further analyzed for expression differences using real-time quantitative polymerase chain reaction (RT-qPCR). Our data suggest that as coastal seawater pollution worsens, the sensitive genes identified in this study may be useful biomarkers of sublethal effects and provide fundamental information for Z. japonica resistant gene engineering. PMID- 30405677 TI - The MAP3K-Coding QUI-GON JINN (QGJ) Gene Is Essential to the Formation of Unreduced Embryo Sacs in Paspalum. AB - Apomixis is a clonal mode of reproduction via seeds, which results from the failure of meiosis and fertilization in the sexual female reproductive pathway. In previous transcriptomic surveys, we identified a mitogen-activated protein kinase kinase kinase (N46) displaying differential representation in florets of sexual and apomictic Paspalum notatum genotypes. Here, we retrieved and characterized the N46 full cDNA sequence from sexual and apomictic floral transcriptomes. Phylogenetic analyses showed that N46 was a member of the YODA family, which was re-named QUI-GON JINN (QGJ). Differential expression in florets of sexual and apomictic plants was confirmed by qPCR. In situ hybridization experiments revealed expression in the nucellus of aposporous plants' ovules, which was absent in sexual plants. RNAi inhibition of QGJ expression in two apomictic genotypes resulted in significantly reduced rates of aposporous embryo sac formation, with respect to the level detected in wild type aposporous plants and transformation controls. The QGJ locus segregated independently of apospory. However, a probe derived from a related long non-coding RNA sequence (PN_LNC_QGJ) revealed RFLP bands cosegregating with the Paspalum apospory-controlling region (ACR). PN_LNC_QGJ is expressed in florets of apomictic plants only. Our results indicate that the activity of QGJ in the nucellus of apomictic plants is necessary to form non-reduced embryo sacs and that a long non-coding sequence with regulatory potential is similar to sequences located within the ACR. PMID- 30405679 TI - Somatic Embryogenesis and Plant Regeneration From Primordial Shoot Explants of Picea abies (L.) H. Karst. Somatic Trees. AB - The recalcitrance of adult conifer tissues has prevented vegetative propagation of trees with known and desired characteristics. Somatic embryogenesis (SE) initiation protocol, recently developed for white spruce (Picea glauca, Klimaszewska et al., 2011), was applied in order to examine the feasibility, frequency and timing of SE induction from primordial shoots (PS) of Norway spruce (P. abies). In total, 39 genotypes were screened from 2015 to 2017 using 4-6 years old trees of SE origin as explant donors. Two genotypes responded: 11Pa3794 produced six proliferating embryonal mass (EM) sublines and 11Pa4066 produced 23 EM sublines. SE initiations occurred at the beginning of April, when the temperature sum (d.d.) started to accumulate, and at the end of October or beginning of November when the chilling unit (ch.u.) sum was over 500. EM sublines from both genotypes contained numerous early somatic embryos as detected by acetocarmine staining. The sublines of 11Pa4066 produced the mean of 78.6 +/- 12.8 cotyledonary somatic embryos /g FW, but 11Pa3794 produced only a few cotyledonary somatic embryos that were able to germinate. The original EM lines (from which the trees were regenerated) had produced the same number of somatic embryos in 2011 maturations, which was approximately 120 somatic embryos /g FW. Microsatellite analyses conducted with both responsive genotypes confirmed the genetic stability of the EM sublines compared with the donor trees growing in the field. SE protocol developed for white spruce PS explants was also suitable for PS of Norway spruce if the explants were in the responsive developmental stage. PMID- 30405678 TI - H2O2 Signature and Innate Antioxidative Profile Make the Difference Between Sensitivity and Tolerance to Salt in Rice Cells. AB - Salt tolerance is a complex trait that varies between and within species. H2O2 profiles as well as antioxidative systems have been investigated in the cultured cells of rice obtained from Italian rice varieties with different salt tolerance. Salt stress highlighted differences in extracellular and intracellular H2O2 profiles in the two cell cultures. The tolerant variety had innate reactive oxygen species (ROS) scavenging systems that enabled ROS, in particular H2O2, to act as a signal molecule rather than a damaging one. Different intracellular H2O2 profiles were also observed: in tolerant cells, an early and narrow peak was detected at 5 min; while in sensitive cells, a large peak was associated with cell death. Likewise, the transcription factor salt-responsive ethylene responsive factor 1 (TF SERF1), which is known for being regulated by H2O2, showed a different expression profile in the two cell lines. Notably, similar H2O2 profiles and cell fates were also obtained when exogenous H2O2 was produced by glucose/glucose oxidase (GOX) treatment. Under salt stress, the tolerant variety also exhibited rapid upregulation of K+ transporter genes in order to deal with K+/Na+ impairment. This upregulation was not detected in the presence of oxidative stress alone. The importance of the innate antioxidative profile was confirmed by the protective effect of experimentally increased glutathione in salt-treated sensitive cells. Overall, these results underline the importance of specific H2O2 signatures and innate antioxidative systems in modulating ionic and redox homeostasis for salt stress tolerance. PMID- 30405680 TI - Fitness Cost of Transgenic cry1Ab/c Rice Under Saline-Alkaline Soil Condition. AB - The environmental release and biosafety of transgenic Bt crops have attracted global attention. China has a large area of saline-alkali land, which is ideal for large-scale production of Bt transgenic rice. Therefore an understanding of the fitness of Bt transgenic rice in saline-alkaline soils and the ability to predict its long-term environmental effects are important for the future sustainable use of these crops. In the present study, we aimed to evaluate the fitness of cry1Ab/c transgenic rice in both farmland and natural ecosystems. Transgenic cry1Ab/c rice Huahui1, for which a national biosafety certificate was obtained, was grown on normal farmland and saline-alkaline soils in a glass greenhouse. The expression pattern of exogenous Cry1Ab/c protein, and vegetative and reproductive fitness of rice were assessed. The expression of the exogenous Cry1Ab/c protein in the transgenic rice grown on saline-alkaline soil was lower than that in the strain grown on farmland soil. Under both the soil conditions, vegetative growth abilities, as evaluated by tiller number and biomass, and reproductive growth abilities, as measured by filled grain number and filled grain weight per plant, showed a significantly higher fitness cost for Huahui1 than that for the parental rice Minghui63 grown under the same soil conditions. In saline-alkaline soil, the fitness cost of Huahui1was moderately higher than that of Minghui63. Therefore, the ecological risk of cry1Ab/c transgenic rice is not expected to be higher than that of parental rice Minghui63 if the former escapes into natural saline-alkaline soil. The results of the present study provide a scientific basis to improve environmental safety assessment of the insect-resistant transgenic rice strain Huahui1 before commercialization. PMID- 30405682 TI - Non-syndromic Cleft Lip and Palate Polymorphisms Affect Normal Lip Morphology. AB - Non-syndromic cleft lip with or without palate (NSCL/P) is a frequent malformation of the facial region. Genetic variants (SNPs) within nineteen loci have been previously associated with NSCL/P in GWAS studies of European individuals. These common variant SNPs may have subtler effects on the morphology of the lip and face in unaffected individuals. Several studies have investigated the genetic influences on facial morphology using land-marking methods, but these landmarks are sparse in the lip region. The aim of this study is to assess for associations between the nineteen NSCL/P SNPs and normal lip phenotypes, using a detailed categorical scale. Three-dimensional laser scanned facial images were obtained of 4,747 subjects recruited from the Avon Longitudinal Study of Parents and Children (ALSPAC) and genetic data was available for 3,643 of them. A polygenetic risk score (PRS) combining the nineteen NSCL/P SNPs was associated with V-shaped Cupid's bow (P = 3 * 10-4) and narrow philtrum (P = 2 * 10-4) phenotypes. Analysis of individual SNPs found strong evidence for association between rs227731 and skeletal II pattern (P = 5 * 10-6). This study finds that known NSCL/P SNPs affect lip phenotypes in the general population, and an increased PRS is associated with narrow philtrum and V-shaped Cupid's bow. However, the difference in NSCL/P PRS between people with and without certain lip features is unlikely to be great enough to serve as a useful marker of NSCL/P risk. PMID- 30405681 TI - Imputation-Based Whole-Genome Sequence Association Study Reveals Constant and Novel Loci for Hematological Traits in a Large-Scale Swine F2 Resource Population. AB - The whole-genome sequences of progenies with low-density single-nucleotide polymorphism (SNP) genotypes can be imputed with high accuracy based on the deep coverage sequences of key ancestors. With this imputation technology, a more powerful genome-wide association study (GWAS) can be carried out using imputed whole-genome variants and the phenotypes of interest to overcome the shortcomings of low-power detection and the large confidence interval derived from low-density SNP markers in classic association studies. In this study, 19 ancestors of a large-scale swine F2 White Duroc * Erhualian population were deeply sequenced for their genome with an average coverage of 25*. Considering 98 pigs from 10 different breeds with high-quality deep sequenced genomes, we imputed the whole genomic variants of 1020 F2 pigs genotyped by the PorcineSNP60 BeadChip with high accuracy and obtained 14,851,440 sequence variants after quality control. Based on this, 87 novel quantitative traits loci (QTLs) for 18 hematological traits at three different physiological stages of the F2 pigs were identified, among which most of the novel QTLs have been repeated in two of the three stages. Literature mining pinpointed that the FGF14 and LCLAT1 genes at SSC11 and SSC3 may affect the MCH at day 240 and MCV at day 18, respectively. The present study shows that combining high-quality imputed genomic variants and correlated phenomic traits into GWAS can improve the capability to detect QTL considerably. The large number of different QTLs for hematological traits identified at multiple growth stages implies the complexity and time specificity of these traits. PMID- 30405684 TI - Editorial: Arterial Aging and Age-Associated Arterial Diseases. PMID- 30405683 TI - Uncovering the Changing Gene Expression Profile of Honeybee (Apis mellifera) Worker Larvae Transplanted to Queen Cells. AB - The reproductive division of labor, based on caste differentiation in social insects, is of great significance in evolution. Generally, a healthy bee colony consists of a queen and numerous workers and drones. Despite being genetically identical, the queen and workers exhibit striking differences in morphology, behavior, and lifespan. The fertilized eggs and larvae selectively develop into queen and worker bees depending on the local nutrition and environment. Bee worker larvae that are transplanted within 3 days of age to queen cells of a bee colony can develop into queens with mature ovaries. This phenomenon is important to understand the regulatory mechanisms of caste differentiation. In this study, we transplanted worker larvae (Apis mellifera) at the age of 1 (L1), 2 (L2), and 3 days (L3) into queen cells until the age of 4 days. Subsequently, genetic changes in these larvae were evaluated. The results revealed that the number of differentially expressed genes (DEGs) in L1 vs. L3 was more than that in L1 vs. L2. Furthermore, many of the genes that were downregulated are mostly involved in metabolism, body development, reproductive ability, and longevity, indicating that these functions decreased with the age of transplantation of the larvae. Moreover, these functions may be critical for worker larvae to undergo the developmental path to become queens. We also found that the DEGs of L1 vs. L2 and L1 vs. L3 were enriched in the MAPK, FoxO, mTOR, Wnt, TGF-beta Hedgehog Toll and Imd, and Hippo signaling pathways. Gene ontology analysis indicated that some genes are simultaneously involved in different biological pathways; through these genes, the pathways formed a mutual regulatory network. Casein kinase 1 (CK 1) was predicted to participate in the FoxO, Wnt, Hedgehog, and Hippo signaling pathways. The results suggest that these pathways cross talked through the network to modify the development of larvae and that CK 1 is an important liaison. The results provide valuable information regarding the regulatory mechanism of environmental factors affecting queen development, thus, amplifying the understanding of caste differentiation in bees. PMID- 30405685 TI - Mutational Evolution of Pseudomonas aeruginosa Resistance to Ribosome-Targeting Antibiotics. AB - The present work examines the evolutionary trajectories of replicate Pseudomonas aeruginosa cultures in presence of the ribosome-targeting antibiotics tobramycin and tigecycline. It is known that large number of mutations across different genes - and therefore a large number of potential pathways - may be involved in resistance to any single antibiotic. Thus, evolution toward resistance might, to a large degree, rely on stochasticity, which might preclude the use of predictive strategies for fighting antibiotic resistance. However, the present results show that P. aeruginosa populations evolving in parallel in the presence of antibiotics (either tobramycin or tigecycline) follow a set of trajectories that present common elements. In addition, the pattern of resistance mutations involved include common elements for these two ribosome-targeting antimicrobials. This indicates that mutational evolution toward resistance (and perhaps other properties) is to a certain degree deterministic and, consequently, predictable. These findings are of interest, not just for P. aeruginosa, but in understanding the general rules involved in the evolution of antibiotic resistance also. In addition, the results indicate that bacteria can evolve toward higher levels of resistance to antibiotics against which they are considered to be intrinsically resistant, as tigecycline in the case of P. aeruginosa and that this may confer cross-resistance to other antibiotics of therapeutic value. Our results are particularly relevant in the case of patients under empiric treatment with tigecycline, which frequently suffer P. aeruginosa superinfections. PMID- 30405686 TI - AP-1 (bZIP) Transcription Factors as Potential Regulators of Metallothionein Gene Expression in Tetrahymena thermophila. AB - Metallothioneins (MT) are multi-stress proteins mainly involved in metal detoxification. MT gene expression is normally induced by a broad variety of stimulus and its gene expression regulation mainly occurs at a transcriptional level. Conserved motifs in the Tetrahymena thermophila MT promoters have been described. These motifs show a consensus sequence very similar to AP-1 sites, and bZIP type transcription factors might participate in the MT gene expression regulation. In this research work, we characterize four AP-1 transcription factors in each of four different analyzed Tetrahymena species, detecting a high conservation among them. Each AP-1 molecule has its counterpart in the other three Tetrahymena species. A comparative qRT-PCR analysis of these AP-1 genes have been carried out in different T. thermophila strains (including metal adapted, knockout and/or knockdown strains among others), and under different metal-stress conditions (1 or 24 h Cd2+, Cu2+, or Pb2+ treatments). The possible interaction of these transcription factors with the conserved AP-1 motifs present in MT promoters has been corroborated by protein-DNA interaction experiments. Certain connection between the expression patterns of the bZIP and MT genes seems to exist. For the first time, and based on our findings, a possible gene expression regulation model including both AP-1 transcription factors and MT genes from the ciliate T. thermophila has been elaborated. PMID- 30405687 TI - Global Transcriptome Analysis During Adipogenic Differentiation and Involvement of Transthyretin Gene in Adipogenesis in Cattle. AB - Adipose tissue plays central role in determining the gustatory quality of beef, but traditional Chinese beef cattle have low levels of fat content. We applied RNA-seq to study the molecular mechanisms underlying adipocyte differentiation in Qinchuan cattle. A total of 18,283 genes were found to be expressed in preadipocytes and mature adipocytes, respectively. 470 of which were significantly differentially expressed genes (DEGs) [false discovery rate (FDR) values < 0.05 and fold change >= 2]. In addition, 4534 alternative splicing (AS) events and 5153 AS events were detected in preadipocytes and adipocytes, respectively. We constructed a protein interaction network, which suggested that collagen plays an important role during bovine adipogenic differentiation. We characterized the function of the most down-regulated DEG (P < 0.001) among genes we have detected by qPCR, namely, the transthyretin (TTR) gene. Overexpression of TTR appears to promote the expression of the peroxisome proliferator activated receptor gamma (PPARgamma) (P < 0.05) and fatty acid binding Protein 4 (FABP4) (P < 0.05). Hence, TTR appears to be involved in the regulation of bovine adipogenic differentiation. Our study represents the comprehensive approach to explore bovine adipocyte differentiation using transcriptomic data and reports an involvement of TTR during bovine adipogenic differentiation. Our results provide novel insights into the molecular mechanisms underlying bovine adipogenic differentiation. PMID- 30405688 TI - Analysing the Expression of Eight Clock Genes in Five Tissues From Fasting and Fed Sows. AB - In a previous study, we observed that circadian clock genes are differentially expressed in the skeletal muscle of fasting and fed sows. The goal of the current work was to investigate if these genes are also differentially expressed in tissues containing the central (hypothalamus) and peripheral (duodenum, dorsal fat, muscle, and liver) clocks. As animal material, we used 12 sows that fasted 12 h before slaughtering (T0) and 12 sows that were fed ad libitum 7 h prior slaughtering (T2). Tissue samples were collected immediately after slaughter and total RNA was subsequently extracted. The expression of the ARNTL, BHLHE40, CRY2, NPAS2, NR1D1, PER1, PER2, and SIK1 genes was measured by quantitative reverse transcription PCR. The numbers of clock genes showing differential expression before and after feeding varied depending on the tissue i.e., four in dorsal fat and duodenum, six in skeletal muscle, and seven in the liver. In contrast, none of the eight analysed genes displayed a significant differential expression in hypothalamus, the tissue where the central clock resides. This result supports that the differential expression of clock genes in the four tissues mentioned above is probably induced by nutrition and not by the central clock entrained by light. Moreover, we have observed that the NPAS2 and ARNTL genes display positive log2(FC) values in the five tissues under analysis, whilst the CRY2, PER1 (except dorsal fat) and PER2 (except hypothalamus) genes generally show negative log2(FC) values. Such result might be explained by the existence of a negative feedback loop between the ARNTL/NPAS2 and CRY/PER genes. Collectively, these results support that nutrition plays an important role in modulating the timing of porcine peripheral circadian clocks. Such regulation could be essential for coordinating the subsequent metabolic response to nutrient supply. PMID- 30405689 TI - Deep Learning-Based Multi-Omics Data Integration Reveals Two Prognostic Subtypes in High-Risk Neuroblastoma. AB - High-risk neuroblastoma is a very aggressive disease, with excessive tumor growth and poor outcomes. A proper stratification of the high-risk patients by prognostic outcome is important for treatment. However, there is still a lack of survival stratification for the high-risk neuroblastoma. To fill the gap, we adopt a deep learning algorithm, Autoencoder, to integrate multi-omics data, and combine it with K-means clustering to identify two subtypes with significant survival differences. By comparing the Autoencoder with PCA, iCluster, and DGscore about the classification based on multi-omics data integration, Autoencoder-based classification outperforms the alternative approaches. Furthermore, we also validated the classification in two independent datasets by training machine-learning classification models, and confirmed its robustness. Functional analysis revealed that MYCN amplification was more frequently occurred in the ultra-high-risk subtype, in accordance with the overexpression of MYC/MYCN targets in this subtype. In summary, prognostic subtypes identified by deep learning-based multi-omics integration could not only improve our understanding of molecular mechanism, but also help the clinicians make decisions. PMID- 30405691 TI - The Site Frequency/Dosage Spectrum of Autopolyploid Populations. AB - The Site Frequency Spectrum (SFS) and the heterozygosity of allelic variants are among the most important summary statistics for population genetic analysis of diploid organisms. We discuss the generalization of these statistics to populations of autopolyploid organisms in terms of the joint Site Frequency/Dosage Spectrum and its expected value for autopolyploid populations that follow the standard neutral model. Based on these results, we present estimators of nucleotide variability from High-Throughput Sequencing (HTS) data of autopolyploids and discuss potential issues related to sequencing errors and variant calling. We use these estimators to generalize Tajima's D and other SFS based neutrality tests to HTS data from autopolyploid organisms. Finally, we discuss how these approaches fail when the number of individuals is small. In fact, in autopolyploids there are many possible deviations from the Hardy Weinberg equilibrium, each reflected in a different shape of the individual dosage distribution. The SFS from small samples is often dominated by the shape of these deviations of the dosage distribution from its Hardy-Weinberg expectations. PMID- 30405692 TI - Hacking Aging: A Strategy to Use Big Data From Medical Studies to Extend Human Life. AB - Age is the most important single factor associated with chronic diseases and ultimately, death. The mortality rate in humans doubles approximately every eight years, as described by the Gompertz law of mortality. The incidence of specific diseases, such as cancer or stroke, also accelerates after the age of about 40 and doubles at a rate that mirrors the mortality-rate doubling time. It is therefore, entirely plausible to think that there is a single underlying process, the driving force behind the progressive reduction of the organism's health leading to the increased susceptibility to diseases and death; aging. There is, however, no fundamental law of nature requiring exponential morbidity and mortality risk trajectories. The acceleration of mortality is thus the most important characteristics of the aging process. It varies dramatically even among closely related mammalian species and hence appears to be a tunable phenotype. Here, we follow how big data from large human medical studies, and analytical approaches borrowed from physics of complex dynamic systems can help to reverse engineer the underlying biology behind Gompertz mortality law. With such an approach we hope to generate predictive models of aging for systematic discovery of biomarkers of aging followed by identification of novel therapeutic targets for future anti-aging interventions. PMID- 30405693 TI - Network and Pathway Analysis of Toxicogenomics Data. AB - Toxicogenomics is the study of the molecular effects of chemical, biological and physical agents in biological systems, with the aim of elucidating toxicological mechanisms, building predictive models and improving diagnostics. The vast majority of toxicogenomics data has been generated at the transcriptome level, including RNA-seq and microarrays, and large quantities of drug-treatment data have been made publicly available through databases and repositories. Besides the identification of differentially expressed genes (DEGs) from case-control studies or drug treatment time series studies, bioinformatics methods have emerged that infer gene expression data at the molecular network and pathway level in order to reveal mechanistic information. In this work we describe different resources and tools that have been developed by us and others that relate gene expression measurements with known pathway information such as over-representation and gene set enrichment analyses. Furthermore, we highlight approaches that integrate gene expression data with molecular interaction networks in order to derive network modules related to drug toxicity. We describe the two main parts of the approach, i.e., the construction of a suitable molecular interaction network as well as the conduction of network propagation of the experimental data through the interaction network. In all cases we apply methods and tools to publicly available rat in vivo data on anthracyclines, an important class of anti-cancer drugs that are known to induce severe cardiotoxicity in patients. We report the results and functional implications achieved for four anthracyclines (doxorubicin, epirubicin, idarubicin, and daunorubicin) and compare the information content inherent in the different computational approaches. PMID- 30405694 TI - Historical Refugia and Isolation by Distance of the Mud Snail, Bullacta exarata (Philippi, 1849) in the Northwestern Pacific Ocean. AB - Many phylogeographic studies on marine organisms in the Northwestern Pacific have supported for the biogeographic hypotheses that isolation in the marginal seas of this region during the Pleistocene glaciation lower sea level led to population genetic divergence, and thus population expansion was a common phenomenon when the sea level rebounded. However, most of these studies were based on maternally inherited mitochondrial DNA markers with limited sample sites and therefore, were unable to reveal detailed pictures encompassing paternal line information covering of the entire range. In this study, we used the mitochondrial cytochrome c oxidase subunit I (COI) and nine nuclear microsatellite loci to investigate the phylogeography of the mud snail, Bullacta exarata (Philippi, 1849), a species endemic to the Northwestern Pacific. We sampled 14 natural populations spanning across 3800 km of the Chinese coastline, essentially covering most of the species distribution range. COI analysis identified a total of 149 haplotypes separated into two distinct groups with nine mutation steps, revealing a prominent phylogeographic structure. Nuclear microsatellite data also demonstrated a similar but weaker genetic structure. The estimated time to the most recent common ancestor between the two COI haplogroups is at ~0.89 Ma, indicating that B. exarata populations survived the Pleistocene glaciation in the Sea of Japan and the Okinawa Trough, two marginal seas around the species range. The consistent significant patterns of isolation by distance of both COI and microsatellites suggests that limited mobility of adults and short planktonic stage of larvae may have played an important role in promoting or maintaining the genetic differentiation of B. exarata. Results from population demographic analyses support population expansion late in the Pleistocene era. PMID- 30405696 TI - The Korean Baekdudaegan Mountains: A Glacial Refugium and a Biodiversity Hotspot That Needs to Be Conserved. PMID- 30405695 TI - Lack of Association of rs1192415 in TGFBR3-CDC7 With Visual Field Progression: A Cohort Study in Chinese Open Angle Glaucoma Patients. AB - To investigate the association of known candidate genes with the visual field (VF) progression of primary open angle glaucoma (POAG) in a Han Chinese population. We included 440 POAG patients in this study. Fourteen previously reported single nucleotide polymorphisms (SNPs) at five different gene regions (TGFBR3-CDC7, TMCO1, CDKN2B-AS1, ATOH7, and SIX1/SIX6) were genotyped. Age at diagnosis, gender, intraocular pressure (IOP), mean defect (MD) of VF, vertical cup disk ratio (VCDR), best corrected visual acuity (BCVA), central corneal thickness (CCT), and axial length (AL) were recorded at baseline. Patients were followed up for 5 years to evaluate VF progression over time. Clinical information and allele frequencies of 14 SNPs were compared between patients who progressed and who did not within 5 years by multivariate logistic regression. Survival analysis was performed to evaluate the contribution of the associated SNP by cox regression. Greater MD (P < 0.0001), increased VCDR (P = 0.0001), higher IOP (P = 0.0003), worse BCVA (P = 0.002), and older age (P = 0.030) at the baseline were associated with VF progression. Both multivariate logistic regression and cox regression survival analysis showed none of the 14 SNPs statistically associated with VF progression adjusted with age at diagnosis, gender, baseline MD, follow-up IOP, CCT, and AL. There were lack of association of SNPs at TGFBR3-CDC7, TMCO1, ATOH7, CDKN2B-AS1, SIX1/SIX6 loci with VF progression in POAG patients in Han Chinese. Further studies are needed to evaluate the association of genetic variants with VF progression. PMID- 30405697 TI - Distinctions in Fine-Scale Spatial Genetic Structure Between Growth Stages of Picea jezoensis Carr. AB - Conifers in northern forests, such as fir and spruce, preferably regenerate on coarse woody debris, including fallen logs, stumps, and snags. In northern Japan, the sub-boreal conifer species Picea jezoensis is completely dependent on coarse woody debris for seedling establishment. To understand the fine-scale spatial genetic structure (FSGS) of this species, a 5-ha plot was established in central Hokkaido, and 531 individual trees were categorized into four life-stages (seedling, sapling, juvenile, and mature) on the basis of age and size. The FSGS of the established seedlings and later growth stages was investigated using 11 nuclear simple sequence repeat loci. A STRUCTURE analysis of seedlings and saplings established on fallen logs revealed that genetically related individuals were spatially localized between adjacent logs. We also found a significant FSGS in early life-stages based on a decline in the kinship coefficient calculated between individuals over shorter to longer spatial distances. Furthermore, the estimation of dispersal kernels indicated the frequent occurrence of short distance seed dispersal. These results indicated that genetically related seedlings and saplings regenerated on the same or nearby fallen logs. In contrast to the results for the early stages, mature-stage trees showed no significant FSGS. We ran a simulation to examine the hypothesis that the FSGS could be eliminated by demographic thinning during life history processes. We calculated values for simulated offspring generated under three sets of conditions; i.e., by removing (i) inbred individuals, (ii) randomly chosen individuals, and (iii) all individuals on the specific fallen logs. However, the results for the FSGS were significant for all simulated data sets. This indicated that inbreeding depression, stochastic loss, or eradication of establishment sites by local disturbances alone could not explain the lack of FSGS among mature-stage trees. Therefore, it is possible that the colonization history of mature trees present on the study site might differ from that of the current offspring. PMID- 30405690 TI - Mechanisms Underlying the Environmentally Induced Plasticity of Leaf Morphology. AB - The primary function of leaves is to provide an interface between plants and their environment for gas exchange, light exposure and thermoregulation. Leaves have, therefore a central contribution to plant fitness by allowing an efficient absorption of sunlight energy through photosynthesis to ensure an optimal growth. Their final geometry will result from a balance between the need to maximize energy uptake while minimizing the damage caused by environmental stresses. This intimate relationship between leaf and its surroundings has led to an enormous diversification in leaf forms. Leaf shape varies between species, populations, individuals or even within identical genotypes when those are subjected to different environmental conditions. For instance, the extent of leaf margin dissection has, for long, been found to inversely correlate with the mean annual temperature, such that Paleobotanists have used models based on leaf shape to predict the paleoclimate from fossil flora. Leaf growth is not only dependent on temperature but is also regulated by many other environmental factors such as light quality and intensity or ambient humidity. This raises the question of how the different signals can be integrated at the molecular level and converted into clear developmental decisions. Several recent studies have started to shed the light on the molecular mechanisms that connect the environmental sensing with organ-growth and patterning. In this review, we discuss the current knowledge on the influence of different environmental signals on leaf size and shape, their integration as well as their importance for plant adaptation. PMID- 30405698 TI - Dynamic Changes in the Global MicroRNAome and Transcriptome Identify Key Nodes Associated With Ovarian Development in Chickens. AB - The analysis of gene expression patterns during ovarian follicle development will advance our understanding of avian reproductive physiology and make it possible to improve laying performance. To gain insight into the molecular regulation of ovarian development, a systematic profiling of miRNAs and mRNAs at four key stages was conducted, using ovarian tissues from hens at 60 days of age (A), 100 days (B), 140 days-not yet laying (C), and 140 days-laying (D). Comparisons of consecutive stages yielded 73 differentially expressed miRNAs (DEMs) (14 for B vs. A, 8 for C vs. B, and 51 for D vs. C) and 2596 differentially expressed genes (DEGs) (51 for B vs. A, 20 for C vs. B, and 2579 for D vs. C). In addition, 174 DEMs (22 for C vs. A, 74 for D vs. A, and 78 for D vs. B) and 3205 DEGs (118 for C vs. A, 2284 for D vs. A, and 2882 for D vs. B) were identified between nonconsecutive stages. Some DEGs are involved in the Wnt and TGF-beta signaling pathways, which are known to affect ovarian development and ovulation. An integrative analysis of the miRNA and mRNA profiles identified 3166 putative miRNA-mRNA regulatory pairs containing 84 DEMs and 1047 DEGs. Functional annotation of the networks provides strong evidence that the miRNA regulatory networks may play vital roles in ovarian development and ovulation. Ten DEMs and 10 genes were validated by real-time quantitative PCR. The candidate miRNA-mRNA pairs gga-miR-200a-3p-SFRP4, gga-miR-101-3p-BMP5, gga-miR-32-5p-FZD4, and gga-miR 458b-5p-CTNNB1 potentially associated with ovarian development. PMID- 30405699 TI - IDH1: Linking Metabolism and Epigenetics. AB - Mutations in genes encoding enzymes of the tricarboxylic acid cycle often contribute to cancer development and progression by disrupting cell metabolism and altering the epigenetic landscape. This is exemplified by the isoforms of isocitrate dehydrogenase (IDH1/2), which metabolize isocitrate to alpha Ketoglutarate (alpha-KG). Gain of function mutations in IDH1 or IDH2 result in reduced levels of alpha-KG as a result of increased formation of D-2 Hydroxyglutarate (2-HG). alpha-KG is an essential co-factor for certain histone and DNA demethylases, while 2-HG is a competitive inhibitor. These IDH1/2 mutations are thought to result in hypermethylated histones and DNA which in turn alters gene expression and drives cancer progression. While this model seems to be generally accepted in the field, the exact molecular mechanisms still remain elusive. How much of this model has been rigorously demonstrated and what is just being assumed? Are the effects genome-wide or focused on specific loci? This Perspective aims at elucidating the key questions that remain to be addressed, the experimental techniques that could be used to gain further insight into the molecular mechanisms involved and the additional consequences of these mutations beyond DNA and protein methylation. PMID- 30405701 TI - Commentary: Nuclear dynamics of the Set1C subunit Spp1 prepares meiotic recombination sites for break formation. PMID- 30405700 TI - Molecular Evolution and Stress and Phytohormone Responsiveness of SUT Genes in Gossypium hirsutum. AB - Sucrose transporters (SUTs) play key roles in allocating the translocation of assimilates from source to sink tissues. Although the characteristics and biological roles of SUTs have been intensively investigated in higher plants, this gene family has not been functionally characterized in cotton. In this study, we performed a comprehensive analysis of SUT genes in the tetraploid cotton Gossypium hirsutum. A total of 18 G. hirsutum SUT genes were identified and classified into three groups based on their evolutionary relationships. Up to eight SUT genes in G. hirsutum were placed in the dicot-specific SUT1 group, while four and six SUT genes were, respectively, clustered into SUT4 and SUT2 groups together with members from both dicot and monocot species. The G. hirsutum SUT genes within the same group displayed similar exon/intron characteristics, and homologous genes in G. hirsutum At and Dt subgenomes, G. arboreum, and G. raimondii exhibited one-to-one relationships. Additionally, the duplicated genes in the diploid and polyploid cotton species have evolved through purifying selection, suggesting the strong conservation of SUT loci in these species. Expression analysis in different tissues indicated that SUT genes might play significant roles in cotton fiber elongation. Moreover, analyses of cis-acting regulatory elements in promoter regions and expression profiling under different abiotic stress and exogenous phytohormone treatments implied that SUT genes, especially GhSUT6A/D, might participate in plant responses to diverse abiotic stresses and phytohormones. Our findings provide valuable information for future studies on the evolution and function of SUT genes in cotton. PMID- 30405702 TI - SNPs Associated With Testosterone Levels Influence Human Facial Morphology. AB - Many factors influence human facial morphology, including genetics, age, nutrition, biomechanical forces, and endocrine factors. Moreover, facial features clearly differ between males and females, and these differences are driven primarily by the influence of sex hormones during growth and development. Specific genetic variants are known to influence circulating sex hormone levels in humans, which we hypothesize, in turn, affect facial features. In this study, we investigated the effects of testosterone-related genetic variants on facial morphology. We tested 32 genetic variants across 22 candidate genes related to levels of testosterone, sex hormone-binding globulin (SHGB) and dehydroepiandrosterone sulfate (DHEAS) in three cohorts of healthy individuals for which 3D facial surface images were available (Pittsburgh 3DFN, Penn State and ALSPAC cohorts; total n = 7418). Facial shape was described using a recently developed extension of the dense-surface correspondence approach, in which the 3D facial surface was partitioned into a set of 63 hierarchically organized modules. Each variant was tested against each of the facial surface modules in a multivariate genetic association-testing framework and meta-analyzed. Additionally, the association between these candidate SNPs and five facial ratios was investigated in the Pittsburgh 3DFN cohort. Two significant associations involving intronic variants of SHBG were found: both rs12150660 (p = 1.07E-07) and rs1799941 (p = 6.15E-06) showed an effect on mandible shape. Rs8023580 (an intronic variant of NR2F2-AS1) showed an association with the total and upper facial width to height ratios (p = 9.61E-04 and p = 7.35E-04, respectively). These results indicate that testosterone-related genetic variants affect normal range facial morphology, and in particular, facial features known to exhibit strong sexual dimorphism in humans. PMID- 30405703 TI - A Human Gonadal Cell Model From Induced Pluripotent Stem Cells. AB - Sertoli cells are main players in the male gonads development and their study may shed light on 46,XY disorders of sex development (DSD). Mature primary Sertoli cells are incapable of proliferating in prolonged in vitro cultures and the available Sertoli cell models have several limitations since they derive from mouse or human cancer tissues. We differentiated human fibroblasts (HFs)-derived induced pluripotent stem cells into Sertoli-like cells (SLC) and, in order to characterize this new Sertoli cell model, we performed gene expression analyses by NextGeneration Sequencing techniques. This approach revealed that our putative SLC have reduced expression of pluripotency markers and expressed Sertoli cell markers such as SRY-Related HMG-Box 9 (SOX9), vimentin (VIM), and claudin-11 (CLDN-11). More in detail, the transcriptional profile analysis suggested that these cells are in an early stage of Sertoli cells maturation. Harnessing the power of induced pluripotent stem cells, we were able to generate SLC that show genetic and functional similarities to human Sertoli cells (HSerCs). SLC could become an excellent source of patient-specific Sertoli cells that could be of paramount benefit for both basic research and personalized medicine in sex development and reproductive medicine. PMID- 30405704 TI - Emerging Roles of Fibroblast Growth Factor 10 in Cancer. AB - Whilst cross-talk between stroma and epithelium is critical for tissue development and homeostasis, aberrant paracrine stimulation can result in neoplastic transformation. Chronic stimulation of epithelial cells with paracrine Fibroblast Growth Factor 10 (FGF10) has been implicated in multiple cancers, including breast, prostate and pancreatic ductal adenocarcinoma. Here, we examine the mechanisms underlying FGF10-induced tumourigenesis and explore novel approaches to target FGF10 signaling in cancer. PMID- 30405706 TI - Using Compact Coevolutionary Algorithm for Matching Biomedical Ontologies. AB - Over the recent years, ontologies are widely used in various domains such as medical records annotation, medical knowledge representation and sharing, clinical guideline management, and medical decision-making. To implement the cooperation between intelligent applications based on biomedical ontologies, it is crucial to establish correspondences between the heterogeneous biomedical concepts in different ontologies, which is so-called biomedical ontology matching. Although Evolutionary algorithms (EAs) are one of the state-of-the-art methodologies to match the heterogeneous ontologies, huge memory consumption, long runtime, and the bias improvement of the solutions hamper them from efficiently matching biomedical ontologies. To overcome these shortcomings, we propose a compact CoEvolutionary Algorithm to efficiently match the biomedical ontologies. Particularly, a compact EA with local search strategy is able to save the memory consumption and runtime, and three subswarms with different optimal objectives can help one another to avoid the solution's bias improvement. In the experiment, two famous testing cases provided by Ontology Alignment Evaluation Initiative (OAEI 2017), i.e. anatomy track and large biomed track, are utilized to test our approach's performance. The experimental results show the effectiveness of our proposal. PMID- 30405707 TI - A Hybrid Model for Forecasting Sunspots Time Series Based on Variational Mode Decomposition and Backpropagation Neural Network Improved by Firefly Algorithm. AB - The change of the number of sunspots has a great impact on the Earth's climate, agriculture, communications, natural disasters, and other aspects, so it is very important to predict the number of sunspots. Aiming at the chaotic characteristics of monthly mean of sunspots, a novel hybrid model for forecasting sunspots time-series based on variational mode decomposition (VMD) and backpropagation (BP) neural network improved by firefly algorithm (FA) is proposed. Firstly, a set of intrinsic mode functions (IMFs) are obtained by VMD decomposition of the monthly mean time series of the sunspots. Secondly, the firefly algorithm is introduced to initialize the weights and thresholds of the BP neural network, and a prediction model is established for each IMF. Finally, the predicted values of these components are calculated to obtain the final predict results. Comparing BP model, FA-BP model, EMD-BP model, and VMD-BP model, the simulation results show that the proposed algorithm has higher prediction accuracy and can be used to forecast the time series of sunspots. PMID- 30405705 TI - Regulation of FGF10 Signaling in Development and Disease. AB - Fibroblast Growth Factor 10 (FGF10) is a multifunctional mesenchymal-epithelial signaling growth factor, which is essential for multi-organ development and tissue homeostasis in adults. Furthermore, FGF10 deregulation has been associated with human genetic disorders and certain forms of cancer. Upon binding to FGF receptors with heparan sulfate as co-factor, FGF10 activates several intracellular signaling cascades, resulting in cell proliferation, differentiation, and invasion. FGF10 activity is modulated not only by heparan sulfate proteoglycans in the extracellular matrix, but also by hormones and other soluble factors. Despite more than 20 years of research on FGF10 functions, context-dependent regulation of FGF10 signaling specificity remains poorly understood. Emerging modes of FGF10 signaling regulation will be described, focusing on the role of FGF10 trafficking and sub-cellular localization, heparan sulfate proteoglycans, and miRNAs. Systems biology approaches based on quantitative proteomics will be considered for globally investigating FGF10 signaling specificity. Finally, current gaps in our understanding of FGF10 functions, such as the relative contribution of receptor isoforms to signaling activation, will be discussed in the context of genetic disorders and tumorigenesis. PMID- 30405708 TI - Kernel Entropy Component Analysis with Nongreedy L1-Norm Maximization. AB - Kernel entropy component analysis (KECA) is a newly proposed dimensionality reduction (DR) method, which has showed superiority in many pattern analysis issues previously solved by principal component analysis (PCA). The optimized KECA (OKECA) is a state-of-the-art variant of KECA and can return projections retaining more expressive power than KECA. However, OKECA is sensitive to outliers and accused of its high computational complexities due to its inherent properties of L2-norm. To handle these two problems, we develop a new extension to KECA, namely, KECA-L1, for DR or feature extraction. KECA-L1 aims to find a more robust kernel decomposition matrix such that the extracted features retain information potential as much as possible, which is measured by L1-norm. Accordingly, we design a nongreedy iterative algorithm which has much faster convergence than OKECA's. Moreover, a general semisupervised classifier is developed for KECA-based methods and employed into the data classification. Extensive experiments on data classification and software defect prediction demonstrate that our new method is superior to most existing KECA- and PCA-based approaches. Code has been also made publicly available. PMID- 30405710 TI - Spatial Integration of Somatosensory Inputs during Sensory-Motor Plasticity Phenomena Is Normal in Focal Hand Dystonia. AB - Background: Surround inhibition is a system that sharpens sensation by creating an inhibitory zone around the central core of activation. In the motor system, this mechanism probably contributes to the selection of voluntary movements, and it seems to be lost in dystonia. Objectives. To explore if sensory information is abnormally processed and integrated in focal hand dystonia (FHD) and if surround inhibition phenomena are operating during sensory-motor plasticity and somatosensory integration in normal humans and in patients with FHD. Methods. We looked at the MEP facilitation obtained after 5 Hz repetitive paired associative stimulation of median (PAS M), ulnar (PAS U), and median + ulnar nerve (PAS MU) stimulation in 8 normal subjects and 8 FHD. We evaluated the ratio MU/(M + U) * 100 and the spatial and temporal somatosensory integration recording the somatosensory evoked potentials (SEPs) evoked by a dual nerve input. Results: FHD had two main abnormalities: first, the amount of facilitation was larger than normal subjects; second, the spatial specificity was lost. The MU/(M + U) * 100 ratio was similar in healthy subjects and in FHD patients, and the somatosensory integration was normal in this subset of patients. Conclusions. The inhibitory integration of somatosensory inputs and the somatosensory inhibition are normal in patients with focal dystonia as well as lateral surrounding inhibition phenomena during sensory-motor plasticity in FHD. PMID- 30405711 TI - Application of Teledermoscopy in the Diagnosis of Pigmented Lesions. AB - Background: Dermatology, due to the peculiar characteristic of visual diagnosis, is suitable for the application of modern telemedicine techniques, such as mobile teledermoscopy. Objectives: To evaluate the feasibility and reliability of the technique for the diagnosis of pigmented lesions. Methods: Through the storage and routing method, 41 pigmented lesions were analyzed. After the selection of the lesions during the outpatient visit, the clinical and dermatoscopic images were obtained by the resident physician through the cellphone camera and sent to the assistant dermatologist by means of an application for exchange of messages between mobile platforms. Firstly, the assistant dermatologist described the visualized dermatoscopic structures and defined its diagnosis and conduct, based solely on the evaluation of the clinical and dermatoscopic images, without having the knowledge of the anamnesis data. Afterwards, the same assistant dermatologist evaluated the patient face to face, defining the dermatoscopic structures, diagnosis, and conduct. The data obtained through teledermoscopy and face-to-face assessments were compared and accuracy was defined as the concordance between the diagnoses. Results: A match rate of 90% between teledermoscopic and face-to-face diagnosis was demonstrated (McNemar's statistical analysis, whose p value was 0.1366, showed no evidence to support the inferiority of the teledermoscopic method). PMID- 30405712 TI - Use of Expectation Disconfirmation Theory to Test Patient Satisfaction with Asynchronous Telemedicine for Diabetic Retinopathy Detection. AB - Objective: The purpose of the study is to extend research on patient satisfaction with telemedicine services by employing the theoretical framework of Expectation Disconfirmation Theory (EDT) for diabetic retinopathy screenings focusing on rural patients. Method: Adult subjects (n=220) with diabetes were recruited from a single family practice office in rural Iowa. Subjects completed a "pre" survey concerning their forward-looking perceptions of telemedicine prior to using telemedicine for detection of diabetic retinopathy and a "post" survey after they received recommendations from the distant ophthalmologists. Results: All hypotheses of the EDT model were supported. Patient satisfaction is influenced by both patients' expectations (P<.001) and disconfirmation of expectations (P<.001), and patient satisfaction has a positive impact on patient preference for telemedicine services (P<.001). Overall, patients who received telemedicine services were highly satisfied with telemedicine and developed a favorable disposition towards telemedicine services. Conclusions: The EDT model is a viable framework to study patient satisfaction of telemedicine services. While previous feasibility studies have shown that telemedicine for diabetic retinopathy screenings yields diagnostic efficacy, this study applies a theoretical framework to demonstrate the viability of telemedicine for diabetic retinopathy screenings in rural areas. PMID- 30405709 TI - Visual Features in Alzheimer's Disease: From Basic Mechanisms to Clinical Overview. AB - Alzheimer's disease (AD) is the leading cause of dementia worldwide. It compromises patients' daily activities owing to progressive cognitive deterioration, which has elevated direct and indirect costs. Although AD has several risk factors, aging is considered the most important. Unfortunately, clinical diagnosis is usually performed at an advanced disease stage when dementia is established, making implementation of successful therapeutic interventions difficult. Current biomarkers tend to be expensive, insufficient, or invasive, raising the need for novel, improved tools aimed at early disease detection. AD is characterized by brain atrophy due to neuronal and synaptic loss, extracellular amyloid plaques composed of amyloid-beta peptide (Abeta), and neurofibrillary tangles of hyperphosphorylated tau protein. The visual system and central nervous system share many functional components. Thus, it is plausible that damage induced by Abeta, tau, and neuroinflammation may be observed in visual components such as the retina, even at an early disease stage. This underscores the importance of implementing ophthalmological examinations, less invasive and expensive than other biomarkers, as useful measures to assess disease progression and severity in individuals with or at risk of AD. Here, we review functional and morphological changes of the retina and visual pathway in AD from pathophysiological and clinical perspectives. PMID- 30405713 TI - Clinical, Genetics, and Bioinformatic Characterization of Mutations Affecting an Essential Region of PLS3 in Patients with BMND18. AB - Background: Bone mineral density quantitative trait locus 18 (BMND18, OMIM #300910) is a type of early-onset osteogenesis imperfecta (OI) caused by loss-of function mutations in the PLS3 gene, which encodes plastin-3, a key protein in the formation of actin bundles throughout the cytoskeleton. Here, we report a patient with PLS3 mutation caused BMND18 and evaluated all the reported disease causing mutations by bioinformatic analysis. Methods: Targeted gene sequencing was performed to find the disease-causing mutation in our patient. Bioinformatic analyses mainly including homology modelling and molecular dynamics stimulation were conducted to explore the impact of the previously reported mutations on plastin-3. Results: Gene sequencing showed a novel nonsense mutation (c.745G > T, p.E249X), which locates at a highly conserved region containing residues p.240 266 (LOOP-1) in the PLS3 gene. Further bioinformatic analyses of the previously reported mutations revealed that LOOP-1 is predicted to physically connect the calponin-homology 1 (CH1) and CH2 domains of the ABD1 fragment and spatially locates within the interface of ABD1 and ABD2. It is crucial to the conformation transition and actin-binding function of plastin-3. Conclusions: This report identified a novel mutation that truncates the PLS3 gene. Moreover, bioinformatic analyses of the previous reported mutations in PLS3 gene lead us to find a critical LOOP-1 region of plastin-3 mutations at which may be detrimental to the integral conformation of plastin-3 and thus affect its binding to actin filament. PMID- 30405714 TI - Prognostic Factors Predicting Poor Outcome in Cancer Patients with Febrile Neutropenia in the Emergency Department: Usefulness of qSOFA. AB - Background/Aims: Febrile neutropenia is considered as one of the most important and potentially life-threatening oncologic emergencies, which requires prompt medical assessment and treatment with antibiotics. This was a single-center retrospective study that investigated the prognostic factors predicting poor outcome in patients with cancer who presented with febrile neutropenia at the emergency department (ED). Methods: The medical records of patients diagnosed with febrile neutropenia in the ED from January 2014 to December 2017 were reviewed. Patients aged >18 years who were diagnosed with a malignancy were included in the analysis. Febrile neutropenia was defined as an absolute neutrophil count < 1,000/mm3 with a temperature greater than 38 degrees C. Patients were divided into two groups: those who were admitted at the intensive care unit (ICU) or those who died in the hospital (case group) and those who were admitted at general wards and were discharged (control group). The two groups were compared to determine the factors associated with poor prognosis. Results: We identified 104 patients (25 and 79 from the case and control groups, respectively) with cancer who presented with febrile neutropenia at the ED during the study period. Lower blood pressure, platelet count, and HCO3 - level, higher CRP and creatinine level, and the presence of bacteremia were more commonly observed in the case group than in the control group. In the multiple logistic regression analysis, the following independent predictors significantly correlated with ICU admission and in-hospital mortality: quick sequential (sepsis related) organ failure assessment (qSOFA) score (odds ratio [OR]: 4.62; 95% confidence interval [CI]: 1.17-18.22; p=0.285), hemoglobin level (OR: 0.51; 95% CI: 0.33-0.78; p=0.002), total bilirubin level (OR: 7.69; 95% CI: 1.29-45.8; p=0.025), and respiratory tract infection (OR: 29.65; 95% CI: 3.81-230.7; p=0.0012). Conclusions: The qSOFA can be a useful bedside tool for patients with cancer who present with febrile neutropenia at the ED. Moreover, it can help emergency physicians in identifying patients at risk of poor prognosis and in initiating prompt empirical antimicrobial therapy. Further studies must be conducted to validate the efficacy of the qSOFA in these patients in the ED. PMID- 30405715 TI - Evaluation of Sterilisation Techniques for Regenerative Medicine Scaffolds Fabricated with Polyurethane Nonbiodegradable and Bioabsorbable Nanocomposite Materials. AB - An effective sterilisation technique that maintains structure integrity, mechanical properties, and biocompatibility is essential for the translation of new biomaterials to the clinical setting. We aimed to establish an effective sterilisation technique for a biodegradable (POSS-PCL) and nonbiodegradable (POSS PCU) nanocomposite scaffold that maintains stem cell biocompatibility. Scaffolds were sterilised using 70% ethanol, ultraviolet radiation, bleach, antibiotic/antimycotic, ethylene oxide, gamma irradiation, argon plasma, or autoclaving. Samples were immersed in tryptone soya broth and thioglycollate medium and inspected for signs of microbial growth. Scaffold surface and mechanical and molecular weight properties were investigated. AlamarBlue viability assay of adipose derived stem cells (ADSC) seeded on scaffolds was performed to investigate metabolic activity. Confocal imaging of rhodamine phalloidin and DAPI stained ADSCs was performed to evaluate morphology. Ethylene oxide, gamma irradiation, argon plasma, autoclaving, 70% ethanol, and bleach were effective in sterilising the scaffolds. Autoclaving, gamma irradiation, and ethylene oxide led to a significant change in the molecular weight distribution of POSS-PCL and gamma irradiation and ethylene oxide to that of POSS-PCU (p<0.05). UV, ethanol, gamma irradiation, and ethylene oxide caused significant changes in the mechanical properties of POSS-PCL (p<0.05). Argon was associated with significantly higher surface wettability and ADSC metabolic activity (p<0.05). In this study, argon plasma was an effective sterilisation technique for both nonbiodegradable and biodegradable nanocomposite scaffolds. Argon plasma should be further investigated as a potential sterilisation technique for medical devices. PMID- 30405716 TI - Regulatory T Cells and Profile of FOXP3 Isoforms Expression in Peripheral Blood of Patients with Myelodysplastic Syndromes. AB - We have investigated the frequencies of regulatory T cells and the level of FOXP3 isoforms expression in peripheral blood of patients with myelodysplastic syndromes and found the significant reduction of regulatory T cells at all stages of the disease. At the same time in untreated patients, we observed the shift in the FOXP3 isoforms expression profile towards the full-length molecule possibly due to inflammation. Based on the already known information about the potentially higher functional activity of FOXP3 molecule lacking exon 2, we have also hypothesized that our finding may explain the high risk of autoimmune disorders in this disease. PMID- 30405717 TI - Antifungal Susceptibility and Biofilm Production of Candida spp. Isolated from Clinical Samples. AB - Objective: The study aims to speciate clinical Candida isolates and detect their biofilm-forming ability and antifungal resistance. Methods: All the Candida spp. isolated from different clinical samples like pus, urine, blood, and body fluid were included in the study. Biofilm production was tested by the microtiter plate method. Antifungal susceptibility was studied by the disk diffusion method. Patient's demographic details such as age, sex, and clinical information were collected. Presence of other risk factors such as diabetes mellitus, history of antibiotic use, and any urinary tract instrumentations was also recorded. Results: Among 90 Candida species isolated, most predominant species was found to be C. albicans (45.5%) followed by C. tropicalis (28.88%), C. krusei (20%), C. glabrata (3.33%), and C. parapsilosis (2.22%). Candida spp. were isolated from urine (43%), BAL/sputum (18.88%), high vaginal swab (8.88%), suction tips (7.77%), blood and wound swabs (6.66%), pus (3.33%), bile aspirate (2.22%), and deep tissue (1.11%). A larger number of females were affected than males, and the age group of 51 to 60 years was more susceptible to candidiasis. A higher number of C. albicans isolates produced biofilm followed by C. parapsilosis, C. tropicalis, and C. krusei. However, C. glabrata showed no biofilm production in our study. All Candida isolates were 100% sensitive to amphotericin B. Voriconazole was the next effective drug with 81.11% susceptibility. 24.44% of strains were resistant to fluconazole. Conclusion: Speciation of Candida isolates, detection of ability to form the biofilm, and monitoring of antifungal susceptibility testing are necessary for appropriate treatment. PMID- 30405718 TI - Hydrogen Peroxide-Induced DNA Damage and Repair through the Differentiation of Human Adipose-Derived Mesenchymal Stem Cells. AB - Human adipose-derived mesenchymal stem cells (hADMSCs) are recognized as a potential tool in cell tissue therapy because of their capacity to proliferate and differentiate in vitro. Several studies have addressed their use in regenerative medicine; however, little is known regarding their response to DNA damage and in particular to the reactive oxygen species (ROS) that are present in the microenvironment of implantation. In this study, we used the ROS-inducing agent hydrogen peroxide to explore the responses of (1) hADMSCs and (2) derived terminally differentiated adipocytes to oxidatively generated DNA damage. Using single cell gel electrophoresis, a dose-related increase was found for both DNA breaks and oxidative lesions (formamidopyrimidine DNA glycosylase-sensitive sites) upon exposure of hADMSCs to hydrogen peroxide. DNA repair capacity of hADMSCs was affected in cells exposed to 150 and 200 MUM of hydrogen peroxide. An increase in the basal levels of DNA breaks and oxidative DNA lesions was observed through adipocyte differentiation. In addition, hydrogen peroxide-induced DNA damage increased through adipocyte differentiation; DNA repair capacity also decreased. This study is the first follow-up report on DNA repair capacity during adipogenic differentiation. Remarkably, in terminally differentiated adipocytes, DNA breakage repair is abolished while the repair of DNA oxidative lesions remains efficient. PMID- 30405721 TI - The Stem Cell Niche: Interactions between Stem Cells and Their Environment. PMID- 30405719 TI - N6-Methyladenosine in RNA and DNA: An Epitranscriptomic and Epigenetic Player Implicated in Determination of Stem Cell Fate. AB - Vast emerging evidences are linking the base modifications and determination of stem cell fate such as proliferation and differentiation. Among the base modification markers extensively studied, 5-methylcytosine (5-mC) and its oxidative derivatives (5-hydroxymethylcytosine (5-hmC), 5-formylcytosine (5-fC), and 5-carboxylcytosine (5-caC)) dynamically occur in DNA and RNA and have been acknowledged as important epigenetic markers involved in regulation of cellular biological processes. N6-Methyladenosine modification in DNA (m6dA), mRNA (m6A), tRNA, and other noncoding RNAs has been defined as another important epigenetic and epitranscriptomic marker in eukaryotes in recent years. The mRNA m6A modification has been characterized biochemically, molecularly, and phenotypically, including elucidation of its methyltransferase complexes (m6A writer), demethylases (m6A eraser), and direct interaction proteins (readers), while limited information on the DNA m6dA is available. The levels and the landscapes of m6A in the epitranscriptomes and epigenomes are precisely and dynamically regulated by the fine-tuned coordination of the writers and erasers in accordance with stages of the growth, development, and reproduction as naturally programmed during the lifespan. Additionally, progress has been made in appreciation of the link between aberrant m6A modification in stem cells and diseases, like cancers and neurodegenerative disorders. These achievements are inspiring scientists to further uncover the epigenetic mechanisms for stem cell development and to dissect pathogenesis of the multiple diseases conferred by development aberration of the stem cells. This review article will highlight the research advances in the role of m6A methylation modifications of DNA and RNA in the regulation of stem cell and genesis of the closely related disorders. Additionally, this article will also address the research directions in the future. PMID- 30405720 TI - Dynamism, Sensitivity, and Consequences of Mesenchymal and Stem-Like Phenotype of Cancer Cells. AB - There are remarkable similarities in the description of cancer stem cells (CSCs) and cancer cells with mesenchymal phenotype. Both cell types are highly tumorigenic, resistant against common anticancer treatment, and thought to cause metastatic growth. Moreover, cancer cells are able to switch between CSC and non CSC phenotypes and vice versa, to ensure the necessary balance within the tumor. Likewise, cancer cells can switch between epithelial and mesenchymal phenotypes via well-described transition (EMT/MET) that is thought to be crucial for tumor propagation. In this review, we discuss whether, and to which extend, the CSCs and mesenchymal cancer cells are overlapping phenomena in terms of mechanisms, origin, and implication for cancer treatment. As well, we describe the dynamism of both phenotypes and involvement of the tumor microenvironment in CSC reversion and in EMT. PMID- 30405722 TI - Differentiation Potential of Human Wharton's Jelly-Derived Mesenchymal Stem Cells and Paracrine Signaling Interaction Contribute to Improve the In Vitro Maturation of Mouse Cumulus Oocyte Complexes. AB - In vitro maturation (IVM) in cumulus oocyte complexes (COCs) can be improved by the presence of human Wharton's jelly-derived MSCs (hWJ-MSCs), under specific culture conditions. COCs were cultured in twelve different culture systems, composed of four stock media, stock media conditioned with hWJ-MSCs, and stock media in which the oocytes were indirectly cocultured with the hWJ-MSCs. The rates of maturation to meiosis II were compared among the groups. G2-PLUS and coculture with DMEM-F12 were the most efficient systems for the maturation of COCs. The fertilization rate and rate of development to the blastocyst stage were compared between these two groups. Moreover, hWJ-MSC-conditioned media showed no benefits for the COC-IVM. The analysis of OCT4 expression of hWJ-MSCs in G1-PLUS, TYH, and G2-PLUS showed a downregulation of OCT4 by 25.9, 24.7, and 6.6%, respectively, compared to that in hWJ-MSCs cultured in DMEM-F12. Finally, we have demonstrated that two prerequisites appeared to be necessary for the hWJ-MSCs to improve the IVM of COCs: hWJ-MSCs' differentiation potential and the presence of coordinated paracrine interaction between the stem cells and COCs. Under the appropriate conditions, the paracrine factors produced in the coculture system with DMEM-F12 may help to develop synthetic media for successful in vitro culture of COCs. PMID- 30405723 TI - Limbal Stem Cell Transplantation: Clinical Results, Limits, and Perspectives. AB - Limbal stem cell deficiency (LSCD) is a clinical condition characterized by damage of cornea limbal stem cells, which results in an impairment of corneal epithelium turnover and in an invasion of the cornea by the conjunctival epithelium. In these patients, the conjunctivalization of the cornea is associated with visual impairment and cornea transplantation has poor prognosis for recurrence of the conjunctivalization. Current treatments of LSCD are aimed at replacing the damaged corneal stem cells in order to restore a healthy corneal epithelium. The autotransplantation of limbal tissue from the healthy, fellow eye is effective in unilateral LSCD but leads to depauperation of the stem cell reservoir. In the last decades, novel techniques such as cultivated limbal epithelial transplantation (CLET) have been proposed in order to reduce the damage of the healthy fellow eye. Clinical and experimental evidence showed that CLET is effective in inducing long-term regeneration of a healthy corneal epithelium in patients with LSCD with a success rate of 70%-80%. Current limitations for the treatment of LSCD are represented by the lack of a marker able to unequivocally identify limbal stem cells and the treatment of total, bilateral LSCD which requires other sources of stem cells for ocular surface reconstruction. PMID- 30405724 TI - Intravenous Transplantation of Mesenchymal Stem Cells Reduces the Number of Infiltrated Ly6C+ Cells but Enhances the Proportions Positive for BDNF, TNF 1alpha, and IL-1beta in the Infarct Cortices of dMCAO Rats. AB - The resident microglial and infiltrating cells from peripheral circulation are involved in the pathological processes of ischemia stroke and may be regulated by mesenchymal stem/stromal cell (MSC) transplantation. The present study is aimed at differentiating the neurotrophic and inflammatory roles played by microglial vs. infiltrating circulation-derived cells in the acute phase in rat ischemic brains and explore the influences of intravenously infused allogeneic MSCs. The ischemic brain injury was induced by distal middle cerebral artery occlusion (dMCAO) in SD rats, with or without MSC infusion in the same day following dMCAO. Circulation-derived infiltrating cells in the brain were identified by Ly6C, a majority of which were monocytes/macrophages. Without MSC transplantation, among the infiltrated Ly6C+ cells, some were positive for BDNF, IL-1beta, or TNF-alpha. Following MSC infusion, the overall number of Ly6C+ infiltrated cells was reduced by 50%. In contrast, the proportions of infiltrated Ly6C+ cells coexpressing BDNF, IL-1beta, or TNF-alpha were significantly enhanced. Interestingly, Ly6C+ cells in the infarct area could produce either neurotrophic factor BDNF or inflammatory cytokines (IL-1beta or TNF-alpha), but not both. This suggests that the Ly6C+ cells may constitute heterogeneous populations which react differentially to the microenvironments in the infarct area. The changes in cellular composition in the infarct area may have contributed to the beneficial effect of MSC transplantation. PMID- 30405726 TI - Zebularine Promotes Hepatic Differentiation of Rabbit Bone Marrow Mesenchymal Stem Cells by Interfering with p38 MAPK Signaling. AB - Demethylating agent zebularine is reported to be capable of inducing differentiation of stem cells by activation of methylated genes, though its function in hepatocyte differentiation is unclear. p38 signal pathway is involved in differentiation of hepatocytes and regulating of DNA methyltransferases 1 (DNMT1) expression. However, little is known about the impact of zebularine on bone marrow mesenchymal stem cells (BMMSCs) and p38 signaling during hepatic differentiation. The present study investigated the effects of zebularine on hepatic differentiation of rabbit BMMSCs, as well as the role of p38 on DNMT1 and hepatic differentiation, with the aim of developing a novel strategy for improving derivation of hepatocytes. BMMSCs were treated with zebularine at concentrations of 10, 20, 50, and 100 MUM in the presence of hepatocyte growth factor; changes in the levels of hepatic-specific alpha-fetoprotein and albumin were detected and determined by RT-PCR, WB, and immunofluorescence staining. Expression of DNMT1 and phosphorylated p38 as well as urea production and ICG metabolism was also analyzed. Zebularine at concentrations of 10, 20, and 50 MUM could not affect cell viability after 48 h. Zebularine treatment leads to an inhibition of DNMT activity and increase of hepatic-specific proteins alpha fetoprotein and albumin in BMMSCs in vitro; zebularine addition also induced expression of urea production of and ICG metabolism. p38 signal was activated in BMMSCs simulated with HGF; inhibition of p38 facilitated the synthesis of DNMT1 and albumin in cells. Zebularine restrained DNMT1 and phosphorylated p38 which were induced by HGF. Therefore, this study demonstrated that treatment with zebularine exhibited terminal hepatic differentiation of BMMSCs in vitro in association with hepatocyte growth factor; p38 pathway at least partially participates in zebularine-induced hepatic differentiation of rabbit BMMSCs. PMID- 30405727 TI - Palliative Care in Congenital Syndrome of the Zika Virus Associated with Hospitalization and Emergency Consultation: Palliative Care and Congenital Syndrome of Zika. AB - Background: Congenital syndrome of Zika virus (CSZV) is associated with neuromotor and cognitive developmental disorders, limiting the independence and autonomy of affected children and high susceptibility to complications, so palliative care needs to be discussed and applied. Aim: To identify factors associated with emergency visits and hospitalizations of patients with CSZV and clinical interventions performed from the perspective of palliative care. Design: This is a cross-sectional study with bidirectional longitudinal component. Data were collected between May and October 2017 through the review of medical records and interviews with relatives of patients hospitalized. Setting/Participants: The study was developed in a tertiary care hospital involving patients with confirmed CSZV born as of August 2015 and followed up until October 2017. Patients under investigation were excluded. Results: 145 patients were followed up at the specialized outpatient clinic, 92 (63.5%) were consulted at least once in the emergency room, and 49% had already been hospitalized, with the main reason being neurological causes, while 24.1% had never required any emergency visit or hospitalization. No risk factors were associated with the occurrence of consultations or hospitalizations. Such events happened at an early age and were accompanied by a high number of invasive procedures and interventions. An approach in palliative care was only identified in two hospitalized patients. Conclusions: For the patient with known severe malformations caused by congenital infection by the Zika virus with indication of palliative care, this approach could be used in order to allow life without suffering and disproportionate invasive method. PMID- 30405725 TI - Genetic Markers Can Predict Chondrogenic Differentiation Potential in Bone Marrow Derived Mesenchymal Stromal Cells. AB - The precise predictions of the differentiation direction and potential of mesenchymal stromal cells (MSCs) are an important key to the success of regenerative medicine. The expression levels of fate-determining genes may provide tools for predicting differentiation potential. The expression levels of 95 candidate marker genes and glycosaminoglycan (GAG) contents after chondrogenic induction in 10 undifferentiated ilium and 5 jaw MSC cultures were determined, and their correlations were analyzed. The expression levels of eight genes before the induction of chondrogenic MSC differentiation were significantly correlated with the GAG levels after induction. Based on correlation patterns, the eight genes were classified into two groups: group 1 genes (AURKB, E2F1, CDKN2D, LIF, and ACLY), related to cell cycle regulation, and group 2 genes (CD74, EFEMP1, and TGM2), involved in chondrogenesis. The expression levels of the group 2 genes were significantly correlated with the ages of the cell donors. The expression levels of CDKN2D, CD74, and TGM2 were >10-fold higher in highly potent MSCs (ilium MSCs) than in MSCs with limited potential (jaw MSCs). Three-dimensional (3D) scatter plot analyses of the expression levels of these genes showed reduced variability between donors and confirmed predictive potential. These data suggest that group 2 genes are involved in age-dependent decreases in the chondrogenic differentiation potential of MSCs, and combined 3D analyses of the expression profiles of three genes, including two group 2 genes, were predictive of MSC differentiation potential. PMID- 30405728 TI - Antibacterial and Antibiofilm Efficacy of Antimicrobial Photodynamic Therapy Against Intracanal Enterococcus faecalis: An In Vitro Comparative Study with Traditional Endodontic Irrigation Solutions. AB - Objectives: Enterococcus faecalis (E. faecalis), an infecting microorganism of the root canals, is difficult to eliminate during endodontic therapy. In this study, the effect of root canal disinfection with sodium hypochlorite (NaOCl) and chlorhexidine (CHX) was evaluated on planktonic and biofilm forms of E. faecalis in comparison with antimicrobial photodynamic therapy (aPDT) as an alternative strategy for root canal disinfection. Materials and Methods: In this study, E. faecalis (ATCC 29212) was used. The experimental procedures included aPDT with curcumin (CUR) and indocyanine green (ICG) as photosensitizers, irrigation with 5.25% NaOCl, 0.2% and 2.0% CHX solutions as traditional endodontic irrigating solutions, and the control group. The antibacterial and anti-biofilm potentials were assessed by counting the colony forming units and also using the crystal violet assay, respectively. Results: According to the results, E. faecalis biofilm was disrupted by 65.3%, 81.0% and 92.6% using 0.2% CHX, 2.0% CHX, and 5.25% NaOCl, respectively (P<0.05). In addition, CUR- and ICG-mediated aPDT displayed a significant reduction in E. faecalis count (90.2% and 82.5%, respectively) and its biofilm (83.6% and 75.2%, respectively) in comparison to the control group (P<0.05). Conclusions: APDT has a high potential for elimination of E. faecalis and is almost equivalent to NaOCl and CHX. It can be used as an adjucnt to conventional endodontic irrigating solutions. PMID- 30405729 TI - Microleakage of an Enhanced Resin-Modified Glass Ionomer Restorative Material in Primary Molars. AB - Objectives: Resin composites, glass ionomers (GIs), or a combination of these materials have gradually replaced silver amalgam in pediatric dentistry. The purpose of this study was to compare the microleakage of Class II (box only) cavity restorations with ACTIVA Bioactive Restorative Glass, resin-modified GI (RMGI), and composite in primary molars. Materials and Methods: A total of 65 primary molars with at least one intact proximal surface were selected in this in vitro study. After debridement of each tooth, Class II (box only) cavities were prepared. Based on the type of the restorative material and the application of etching and bonding adhesives, the samples were categorized into five groups: (1) composite; (2) RMGI (Fuji II LC)+conditioner; (3) RMGI (Fuji II LC); (4) enhanced RMGI (ACTIVA Bioactive Restorative Glass)+etching/bonding; and (5) ACTIVA Bioactive Restorative Glass. The restored teeth were thermocycled for 2000 cycles. After embedding in an acrylic resin, the degree of dye penetration at axial and gingival walls was assessed using a stereomicroscope. The data were statistically analyzed by analysis of variance (ANOVA) and Tukey's test. Results: Resin-based composite (RBC) Z250 showed the least microleakage, while RMGI showed maximum microleakage at axial walls. The mean degree of microleakage at gingival margins was the lowest in RBC Z250 and ACTIVA+etching/bonding groups and the highest in RMGI+conditioner and RMGI groups. Conclusions: The microleakage of ACTIVA Bioactive Restorative material in the absence or presence of etching and bonding could be comparable to the microleakage of composites. PMID- 30405730 TI - Marginal Integrity of Cervical Restorations with Caries-Affected Dentinal Walls: Effect of Contamination with Hemostatic Agents. AB - Objectives: The aim of this study was to compare the microleakage in normal and caries-affected dentin (CAD) and to investigate the effect of three hemostatic agents on the microleakage of Class V composite resin restorations in CAD. Materials and Methods: Ninety-six Class V non-beveled cavities were prepared in 48 third molars at 1 mm below the cementoenamel junction (CEJ) in the cervical margin with the occlusogingival size of 2 mm, mesiodistal dimension of 3 mm, and a depth of 1.5 mm. Next, the teeth were divided into 8 groups (n=12): G1-4 included normal dentin (N) substrate, while G5-8 were exposed to mineralization/demineralization cycles to produce CAD substrate. Groups 1 and 5 were the controls. ViscoStat was used in groups 2 and 6, ViscoStat Clear was used in groups 3 and 7, while trichloroacetic acid (TCA) was used in groups 4 and 8. The cavities were restored with composite resin. The samples were sectioned after thermocycling and immersion in 2% fuchsin for 24 hours. The degree of dye penetration was evaluated under a stereomicroscope at 40* magnification. Data were evaluated using Kruskal-Wallis and Mann-U-Whitney tests in SPSS 15 software (alpha=0.05). Results: Significant differences were recorded on the mean microleakage of different groups (P=0.047). There was a significant difference in the mean dentinal microleakage between N and CAD groups (P=0.014). The dentinal microleakage in group 3 was significantly higher than that in groups 4 to 8. Conclusions: According to the results, CAD showed less microleakage in comparison with intact dentin. ViscoStat Clear caused a greater microleakage than did ViscoStat or TCA. PMID- 30405731 TI - Effect of Different Irrigants Applied After Post Space Preparation on Push-Out Bond Strength of a Self-Etch Resin Cement. AB - Objectives: The aim was to investigate the effect of intracanal irrigants and agents on the bond strength of intraradicular fiber posts to dentin. Materials and Methods: Root canals of 72 decoronated single-rooted premolars were cleaned, shaped, and obturated with gutta-percha and AH26. The specimens were incubated at 37 degrees C and 100% humidity for seven days. Next, the coronal 10 mm of the canals were prepared to receive size 2 D.T. Light fiber post, and the specimens were randomly allocated into six groups according to the irrigants used after post space preparation: normal saline (control group), 5.25% sodium hypochlorite (NaOCl)/15 seconds, 17% ethylenediaminetetraacetic acid (EDTA)/60 seconds, 2% chlorhexidine (CHX)/5 minutes, MTAD/5 minutes, and acid-etching/15 seconds. All canals were rinsed with normal saline and dried. Fiber posts were cemented using Panavia F2.0. After 24 hours, two mid-root slices of 1mm thickness were obtained from each specimen. Push-out bond strength test was performed in a universal testing machine at 0.5mm/minute. The maximum applied load was recorded, and the bond strength was calculated in megapascal (MPa). Data were analyzed by one-way analysis of variance (ANOVA) and Tukey's test. Results: The mean shear bond strengths of etched (53.21+/-12.11 MPa), MTAD (52.47+/-14.75 MPa) and EDTA (49.08+/-10.19 MPa) groups were significantly higher than that of the control group (39.82+/-10.04 MPa). The difference was marginally significant for CHX group (49.8+/-13.57 MPa) and not significant for NaOCl group (47.15+/-17.64 MPa). Conclusions: Etching or irrigating the root canals with MTAD or EDTA after post space preparation increases the bond strength of Panavia F2.0 to dentin. PMID- 30405732 TI - Effect of Er,Cr (YSGG Laser Root Conditioning on the Success of Root Coverage with Subepithelial Connective Tissue Graft): A Randomized Clinical Trial with a 6 Month Follow-Up. AB - Objectives: Finding predictable approaches for root surface biomodification is an important challenge in the treatment of gingival recession. This study sought to assess the root coverage percentage by subepithelial connective tissue graft (SCTG) following root surface conditioning with erbium, chromium: yttrium scandium gallium garnet (Er,Cr:YSGG) laser. Materials and Methods: In this split mouth, randomized clinical trial, 30 teeth with Miller's Class I and II gingival recession were treated with SCTG (the Langer and Langer technique) with (case group) or without (control group) root surface conditioning with Er,Cr:YSGG laser (wavelength=2780 nm, power=0.75 W, H mode, repetition rate=20 Hz). Recession depth (RD), recession width (RW), clinical attachment level (CAL), and probing depth (PD) were assessed at the baseline (one week before surgery) and at 2 and 6 months postoperatively. The amount of root coverage was quantified in the two groups. Data were analyzed using Friedman test and Wilcoxon signed-rank test. Results: No significant difference was noted between the case and control groups in any parameter (P>0.05). Significant improvement occurred in all the measured parameters in the two groups after surgery (P<0.05). The mean root coverage at the end of the study period was 87% and 80% in the case and control groups, respectively (P=0.244), and complete root coverage was achieved in 66% and 60% of the samples in the case and control groups, respectively. Conclusions: Root surface conditioning by Er,Cr:YSGG laser improved the mean root coverage and the percentage of complete root coverage. However, these changes were not statistically significant. PMID- 30405733 TI - Evaluation of Enamel and Dentinal Microleakage in Class II Silorane-Based and Methacrylate-Based Resin Composite Restorations Using Specific and Nonspecific Adhesives. AB - Objectives: The aim of this study was to evaluate enamel and dentinal microleakage in Class II cavities restored with silorane- and methacrylate-based resin composites using specific and nonspecific adhesives. Materials and Methods: Thirty-six caries-free human premolars were used. Two Class II cavities were prepared on each tooth. The gingival floor was set at 1 mm above (on the mesial surface) and at 1 mm below (on the distal surface) the cementoenamel junction (CEJ). The samples were randomly divided into four groups, and the cavities were restored with a methacrylate-based composite (FiltekTM P60) and a silorane-based composite (FiltekTM P90) with specific and nonspecific adhesives. Microleakage was tested using a standardized dye penetration method. All samples were examined under a stereomicroscope, and microleakage scores were statistically analyzed using Kruskal-Wallis and Mann-Whitney-U tests. One sample from each group was examined under a scanning electron microscope (SEM) to determine the bonding area. Results: No significant difference was found between the groups in terms of the enamel microleakage (P=0.086). There was a significant difference between the groups with regard to dentinal microleakage (P=0.003). No significant reduction in microleakage was observed in groups restored with FiltekTM P90 composite using its specific adhesive compared to those restored with FiltekTM P60 composite using its specific adhesive (P=0.626). Conclusions: The results indicated that the application of methacrylate- and silorane-based composites with specific or nonspecific adhesives had no impact on enamel microleakage, but it affected dentinal microleakage, and specific adhesives showed less microleakage. It seems that a phosphate-methacrylate-based intermediate resin is required to bond dimethacrylate adhesive to silorane-based composites. PMID- 30405735 TI - Full Arch All-on-4 Fixed Implant-Supported Prostheses with 8.5 Years of Follow Up: A Case Report. AB - Typically, full arch reconstruction of edentulous ridges requires five to 10 dental implants; however, some patients demanding fixed implant-supported prostheses are not able to medically or economically afford complex bone grafts and/or a greater number of implants. These situations could pivot the treatment plan toward the All-on-4 protocol. Nevertheless, due to less implant support in this treatment option, mechanical and biological complications might arise. This article describes the treatment of a fully edentulous patient with two types of fixed implant-supported prostheses on four dental implants along with the following complications. PMID- 30405734 TI - Effects of Pretreatment Exposure to Dental Practice Using a Smartphone Dental Simulation Game on Children's Pain and Anxiety: A Preliminary Double-Blind Randomized Clinical Trial. AB - Objectives: Studies on modeling a pre-exposure technique for the prevention of anxiety in children are rare, and there is no study on interactive modeling using computer games. We assessed the effect of playing a dental simulation game before operation on pain and anxiety in 4- to 7-year-old children during their first dental treatment session. Materials and Methods: In this double-blind randomized clinical trial, 50 children needing unilateral pulpotomy and placement of stainless-steel crowns (SSC) on mandibular primary first molars were enrolled and randomly divided into experimental (a simulation game) and control (no intervention) groups. The experimental group played the game twice a day for two weeks before the scheduled visit. At the dental session, their pre- and post operative pains were recorded using the Wong-Baker Facial Rating Scale (W-BFRS). Also, heart rate (HR; as an indicator of anxiety) was measured using a finger pulse oximeter at six treatment stages: (1) baseline (at the initial session, two weeks before treatment) and (2-6) during different stages of treatment. Effects of playing the simulation on pain and HR were analyzed using t-test and repeated measures two-way analysis of covariance (ANCOVA). Results: Game playing significantly reduced the HR (P=0.031). The interaction of playing with the treatment period was also significant (P=0.004). When the groups were compared in each of the six time points, the experimental group showed reduced HR during anesthetic injection and cavity preparation using a high-speed handpiece (P<0.003). Conclusions: Based on the results, playing certain dental simulation games before the first dental visit might reduce the anxiety felt during anesthetic injections and drilling. PMID- 30405736 TI - Pharmacologic Effect of Miao Medicine Illicium simonsii Maxim. on Collagen Induced Arthritis in Rats. AB - Objectives: To study the pharmacologic effect and mechanism of action of Miao medicine Illicium simonsii Maxim. (ISM) in treating rheumatoid arthritis. Methods: Sixty rats were randomly divided to six groups: normal control (normal), collagen-induced arthritis (CIA) model (model), CIA + tripterygium glycosides (TG), CIA + ISM high dose oral (ISM-H), CIA + ISM low-dose oral (ISM-L), and CIA + ISM topical application (ISM-T). The treatment doses were selected based on published reports and folk medicine practice. The outcome measurements included paw swelling, joint pathology, organ index, blood count, T helper 17 (Th17) cell count, and interleukin-6 (IL-6) level. Results: Compared to the CIA model group, all treatment groups showed a significant reduction in paw swelling, blood vessel pathology, Th17 cell count, and IL-6 levels (p < 0.05 or p < 0.01). All treatment groups showed alleviated foot swelling and lower total number of white blood cells, and these effects were observed earlier with oral ISM than topical ISM. The effect of ISM was weaker than that of TG. In addition, less organ damage was observed with topical ISM than oral ISM but better than TG. Conclusions: These results suggest that, by downregulating Th17 cells, ISM inhibits the production of Il-6, thereby alleviating the proliferation of endothelial and rheumatoid-like cells and leukocytosis in CIA rats, ultimately eliminating foot swelling. PMID- 30405739 TI - Biological Activities of Four Adaptogenic Plant Extracts and Their Active Substances on a Rotifer Model. AB - Rotifers have been widely used as well-characterized models of aging, since their multiorgan character makes them suitable as in vivo toxicological and lifespan models. Here we report the assessment of four adaptogenic plants and their extracts for the first time in this model. The effects on rotifer viability of extracts and characteristic active markers of Panax ginseng, Withania somnifera, Leuzea carthamoides, and Rhodiola rosea were tested in vivo. The crude extracts were nontoxic to Philodina acuticornis bdelloid rotifers; however, the pure substances of the plants influenced negatively the viability. Ginsenoside Rb1 and secondary metabolites of Withania somnifera exerted deleterious effect on the animals. The aglycone tyrosol and cinnamyl alcohol (from Rhodiola rosea) were more toxic than their glycosides salidroside and rosavin. Although the 20-OH ecdysone and ajugasterone C (from Leuzea carthamoides) are chemically very similar, the latter was less toxic. PMID- 30405737 TI - The Therapeutic Effect of the Chinese Herbal Medicine, Rehmanniae Radix Preparata, in Attention Deficit Hyperactivity Disorder via Reversal of Structural Abnormalities in the Cortex. AB - Rehmanniae radix preparata is extracted from wine-steaming the Rehmannia root, a scrophulariaceae plant. It has been used for thousands of years with effects of nourishing kidney-yin, benefiting essence and filling marrow based on traditional Chinese medicine (TCM) theory. Rehmanniae radix preparata has antioxidant, antisenescence, anti-inflammatory, and neuroprotective properties. It is the most popular Traditional Chinese medicinal compound (TCMC) used in attention deficit hyperactivity disorder (ADHD) therapy. However, few studies have been conducted exploring the effects and potential mechanisms of Rehmanniae radix preparata alone on ADHD. Recent studies have shown that Rehmanniae radix preparata inhibits spontaneous activity in mice, improves learning and memory in rats following thalamic arcuate nucleus injury, and exhibits antidepressant effects. Catalpol, an active component of Rehmanniae radix preparata, elevates brain-derived neurotrophic factor (BDNF), and attenuates neuronal apoptosis and energy metabolism failure. ADHD is characterized by hyperactivity-impulsivity and impairments in learning and memory. Its pathomechanism is closely related to structural abnormalities in the cortex that is mediated by dysfunction in neuronal development, apoptosis, and energy metabolism. We hypothesize that Rehmanniae radix preparata may be effective at treating ADHD by alleviating neurodevelopmental abnormalities, neuronal apoptosis, and energy metabolism failure. PMID- 30405741 TI - Randomized, Double-Blind, Placebo-Controlled Study of Modified Erzhi Granules in the Treatment of Menopause-Related Vulvovaginal Atrophy. AB - Objective: To evaluate the clinical therapeutic efficacy and safety of modified Erzhi granules (MEG) in patients with menopause-related vulvovaginal atrophy (VVA). Methods: This randomized, double-blind, placebo-controlled study comprised two groups, including the treatment and control groups. Patients receive MEG and placebo for 12 weeks, respectively. Vaginal health score (VHS), vaginitis score, vaginal maturation index (VMI), female sexual function index (FSFI), and modified Kupperman Index (modified KI) were used as efficacy endpoints and assessed at baseline, 4, 8, and 12 weeks during administration, and 4 weeks after drug withdrawal. At baseline and 12 weeks, serum estradiol (E2), follicle stimulating hormone (FSH), pelvic ultrasound, breast ultrasound, and other safety parameters were measured, recording adverse events. Results: At 12 weeks, VHS, percentage of superficial cells in the vaginal epithelium and FSFI were significantly increased, while vaginitis score, percentage of basal cells in the vaginal epithelium, and modified KI were significantly decreased in comparison with baseline and control group (all P<0.05); these differences persisted for up to 4 weeks after drug withdrawal. The placebo group showed no significant change during treatment compared with baseline values (p>0.05). Serum E2 and FSH levels, endometrial thickness, and breast thickness in all patients were within the normal ranges before and after treatment, with no serious adverse reactions observed. Conclusion: MEG significantly alleviates menopause-related vulvovaginal atrophy, with no overt adverse effects on the endometrium, breast, hepatic, and renal functions. PMID- 30405740 TI - alpha-Mangostin Alleviated Lipopolysaccharide Induced Acute Lung Injury in Rats by Suppressing NAMPT/NAD Controlled Inflammatory Reactions. AB - alpha-Mangostin (MAN) is a bioactive xanthone isolated from mangosteen. This study was designed to investigate its therapeutic effects on acute lung injury (ALI) and explore the underlying mechanisms of action. Rats from treatment groups were subject to oral administration of MAN for 3 consecutive days beforehand, and then ALI was induced in all the rats except for normal controls via an intraperitoneal injection with lipopolysaccharide. The severity of disease was evaluated by histological examination and hematological analysis. Protein expressions in tissues and cells were examined with immunohistochemical and immunoblotting methods, respectively. The levels of cytokines and nicotinamide adenine dinucleotide (NAD) were determined using ELISA and colorimetric kits, respectively. It was found that MAN treatment significantly improved histological conditions, reduced leucocytes counts, relieved oxidative stress, and declined TNF-alpha levels in ALI rats. Meanwhile, MAN treatment decreased expressions of nicotinamide phosphoribosyltransferase (NAMPT) and Sirt1 both in vivo and in vitro, which was accompanied with a synchronized decline of NAD and TNF-alpha. Immunoblotting assay further showed that MAN downregulated HMGB1, TLR4, and p-p65 in RAW 264.7 cells. MAN induced declines of both HMGB1/TLR4/p-p65 and TNF-alpha were substantially reversed by cotreatment with nicotinamide mononucleotide or NAD. These results suggest that downregulation of NAMPT/NAD by MAN treatments contributes to the alleviation of TLR4/NF-kappaB-mediated inflammations in macrophage, which is essential for amelioration of ALI in rats. PMID- 30405738 TI - Plant-Derived Products for Treatment of Vascular Intima Hyperplasia Selectively Inhibit Vascular Smooth Muscle Cell Functions. AB - Natural products are used widely for preventing intimal hyperplasia (IH), a common cardiovascular disease. Four different cells initiate and progress IH, namely, vascular smooth muscle, adventitial and endothelial cells, and circulation or bone marrow-derived cells. Vascular smooth muscle cells (VSMCs) play a critical role in initiation and development of intimal thickening and formation of neointimal hyperplasia. In this review, we describe the different originating cells involved in vascular IH and emphasize the effect of different natural products on inhibiting abnormal cellular functions, such as VSMC proliferation and migration. We further present a classification for the different natural products like phenols, flavonoids, terpenes, and alkaloids that suppress VSMC growth. Abnormal VSMC physiology involves disturbance in MAPKs, PI3K/AKT, JAK-STAT, FAK, and NF-kappaB signal pathways. Most of the natural isolate studies have revealed G1/S phase of cell cycle arrest, decreased ROS production, induced cell apoptosis, restrained migration, and downregulated collagen deposition. It is necessary to screen optimal drugs from natural sources that preferentially inhibit VSMC rather than vascular endothelial cell growth to prevent early IH, restenosis following graft implantation, and atherosclerotic diseases. PMID- 30405742 TI - Anti-Inflammatory Activity of Rg3-Enriched Korean Red Ginseng Extract in Murine Model of Sepsis. AB - Ginseng has therapeutic effects on various bodily disorders ranging from minor inflammation to major cardiovascular diseases. In our study, we explored the anti inflammatory effects of Rg3-enriched red ginseng extract (Rg3-RGE), a ginsenoside belonging to the panaxadiol group. We employed nitric oxide assay (NO) and 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), western blot, and hematoxylin and eosin staining (H&E) to elucidate the anti-inflammatory activity of Rg3-RGE. Rg3-RGE potently suppressed NO production in the murine macrophage cell line, RAW 264.7 cells, without any cytotoxicity across dosages. Additionally, it inhibited the mRNA expression of proinflammatory mediators and cytokines like iNOS, COX-2, IL-1beta, IL-6, and TNF-alpha. Moreover it also inhibited the levels of malondialdehyde levels in serum of septic shock mice. Immunoblot analysis showed that Rg3-RGE induced anti-inflammatory signal transduction via the NF-kappaB and MAPK pathways. A remarkable attenuation of inflammation by oral treatment with Rg3-RGE in mice was observed in the survival study. The in vivo study using a septic shock mouse model also showed similar results as the in vitro study. Our findings suggest that Rg3-RGE can potentially be a potent anti-inflammatory agent that likely mediates its anti-inflammatory effects via the NF-kappaB and MAPK pathways. PMID- 30405743 TI - Efficacy and Safety of Ginkgo Biloba Pills for Coronary Heart Disease with Impaired Glucose Regulation: Study Protocol for a Series of N-of-1 Randomized, Double-Blind, Placebo-Controlled Trials. AB - Background: Coronary heart disease has become a serious challenge to China with its high prevalence and mortality. The impaired glucose regulation is prevalent in patients with cardiovascular disease. However, there are few drugs that interfere early with impaired glucose regulation. Ginkgo biloba extract not only is a commonly used drug for cardiovascular diseases, but also has a significant effect in reducing blood sugar. Therefore, this study used a single-case randomized controlled trial to explore the efficacy of Ginkgo biloba pills in the treatment of coronary heart disease patients with impaired glucose regulation. Methods/Design: This is a randomized, double-blind, placebo-controlled, three period crossover trial for a single subject. A total of 12 subjects will be recruited in this trial. The trial is divided into three cycles, and one cycle has two treatment periods. Ginkgo biloba pills and placebo will be randomized during the treatment period. The test period will last for 58 weeks and subjects will take 48 weeks. Subjects will be selected by the researcher strictly in accordance with the inclusion and exclusion criteria. Discussion: Ginkgo biloba preparations are widely used in cardiovascular diseases both at home and abroad due to their definite curative effect, few side effects, various dosage forms, and convenient and safe use. Diabetes mellitus is a high-risk factor for the occurrence of cardiovascular disease. Therefore, it is of great significance to control the impaired glucose regulation and slow down the development of diabetes and reduce the incidence and mortality of cardiovascular diseases. This trial is registered with ClinicalTrials.gov (ID: NCT03483779). PMID- 30405744 TI - Safety of Acupuncture in Patients Taking Newer Oral Anticoagulants: A Retrospective Chart Review Study. AB - Anticoagulant therapy is used to reduce the risk of thromboembolic events in patients with atrial fibrillation. Warfarin has been the traditional anticoagulant but is difficult to use because of its narrow therapeutic window. Recently, newer oral anticoagulants (NOACs) have been developed. However, bleeding continues to be a significant complication. The objective of this study was to assess the safety of acupuncture in patients taking NOACs. The medical records in the Stroke Center at Kyung Hee University Korean Medicine Hospital were retrospectively reviewed to identify patients who had received acupuncture between January 2017 and September 2017. The patients were divided into groups according to whether they were taking an NOAC, an antiplatelet agent, or no anticoagulant therapy. Bleeding-related side effects that occurred immediately after removal of acupuncture needles were recorded. Three hundred and sixteen patients underwent 10,177 acupuncture sessions during the study period. Microbleeding (bleeding that ceased within 30 s) occurred at a rate of 3.9% in the NOAC group, 5.6% in the antiplatelet group, and 5.1% in the control group. There were no between-group differences in the microbleeding rate. No serious adverse events, including major bleeding, were detected. These findings indicate that acupuncture is safe in patients taking NOACs. PMID- 30405745 TI - Total Flavone of Rhododendron Improves Cerebral Ischemia Injury by Activating Vascular TRPV4 to Induce Endothelium-Derived Hyperpolarizing Factor-Mediated Responses. AB - Background: Total flavonoids of Rhododendron (TFR) is extracted from Rhododendron, a herbal medicine widely used in China. The main components are flavone compounds such as warfarin, rutin, quercetin, and hyperoside. We investigated the role of TRPV4 channel in the TFR induced endothelium-dependent hyperpolarizing factor- (EDHF-) mediated responses against ischemia/reperfusion injury (IR) in cerebral IR (CIR) rats. Methods: The morphological changes of cerebral cortex, the relaxation of cerebral basal artery (CBA), and cell membrane potential recording were studied in CIR rats. The outward potassium current in smooth muscle cell was recorded by whole-cell patch clamp recording. The protein expression of TRPV4, SKca, and IKca was determined. Confocal laser was used to measure the Ca2+ fluorescence intensity. Results: After treatment with TFR, the number of pyramidal cells in brain tissue increased and the number of empty or lightly stained cells decreased and these effects were eliminated by using HC 067047, Apamin, or TRAM-34. TFR induced and EDHF-mediated dilatation and hyperpolarization in CBA were also attenuated by using these inhibitors. The increased outward current density elicited by TFR in acutely isolated CBA smooth muscle cells was abolished by using TRAM-34 and Apamin. TFR upregulated the protein expression of TRPV4, SKca, and IKca that was also eliminated by these inhibitors. Laser scanning showed that the increased mean fluorescence intensity of Ca2+ by CIR was decreased by using TFR and that this effect was again eliminated by the above inhibitors. Conclusions: We conclude that in the CBA of the CIR rats the protective effect of TFR on ischemic cerebrovascular injury may be related to the activation of the TRPV4 in both endothelium and smooth muscle by increasing its expression and activity. The activation of TRPV4 channel in the endothelium may be linked to the opening of endothelial IKca/SKca channels that induces EDHF-mediated relaxation and hyperpolarization in the smooth muscle cell. In addition, the activation of TRPV4 in the smooth muscle cell in CBA may be linked with the activation of BKCa channel through a TRPV4-dependent pathway, reduce Ca2+ concentration in the cell, and relaxes the vessel. These findings may form a new therapeutic target for protection of ischemic brain injury and facilitate the use of Chinese medicine in brain protection. PMID- 30405747 TI - Mechanobiological Analysis of Molar Teeth with Carious Lesions through the Finite Element Method. AB - The analysis of the distribution of stress in dental organs is a poorly studied area. That is why computational mechanobiological analysis at the tissue level using the finite element method is very useful to achieve a better understanding of the biomechanics and the behaviour of dental tissues in various pathologies. This knowledge will allow better diagnoses, customize treatment plans, and establish the basis for the development of better restoration materials. In the present work, through the use of high-fidelity biomodels, computational mechanobiological analyses were performed on four molar models affected with four different degrees of caries, which are subjected to masticatory forces. With the analyses performed, it is possible to observe that the masticatory forces that act on the enamel are not transmitted to the dentin and to the bone and periodontal ligament to protect the nerve, as it happens in a healthy dental organ. With the presence of decay, these forces are transmitted partly to the pulp. The reactions to the external loads on the dental organs depend on the advances of the carious lesion that they present, since the distribution of stresses is different in a healthy tooth. PMID- 30405746 TI - Real-Time Evaluation of the Signal Processing of sEMG Used in Limb Exoskeleton Rehabilitation System. AB - As an important branch of medical robotics, a rehabilitation training robot for the hemiplegic upper limbs is a research hotspot of rehabilitation training. Based on the motion relearning program, rehabilitation technology, human anatomy, mechanics, computer science, robotics, and other fields of technology are covered. Based on an sEMG real-time training system for rehabilitation, the exoskeleton robot still has some problems that need to be solved in this field. Most of the existing rehabilitation exoskeleton robotic systems are heavy, and it is difficult to ensure the accuracy and real-time performance of sEMG signals. In this paper, we design a real-time training system for the upper limb exoskeleton robot based on the EMG signal. It has four main characteristics: light weight, portability, high precision, and low delay. This work includes the structure of the rehabilitation robotic system and the method of signal processing of the sEMG. An experiment on the accuracy and time delay of the sEMG signal processing has been done. In the experimental results, the recognition accuracy of the sEMG is 94%, and the average delay time is 300 ms, which meets the accuracy and real time requirements. PMID- 30405750 TI - Tumor suppression by Tegafur combined with Barbadian in S-180 tumor-bearing mice. AB - The aim of this study was to discuss the antitumor effect of Tegafur combined with Barbadian on S-180 tumor-bearing mice. A murine tumor model was prepared by subcutaneous injection of S-180 sarcoma cells to the armpit of the right limb of healthy female SPF KM mice. The 24 tumor-bearing mice were randomly divided into 4 groups: Combination therapy group of Tegafur and Barbadian, Barbadian group, Tegafur group and normal saline control group. Corresponding test substances were given to each group by intragastric administration, respectively, 0.2 ml/mouse, once/day, continuous 5 days, interval for 2 days, recorded as 1 period, 3 periods were continuously performed. Antitumor rate, immune cells, blood biochemistry and inflammatory mediators and other indexes were then respectively measured. Result showed that the antitumor rate for the Combination group was 78%; Barbadian group, 72%; and Tegafur group, -89%. White blood cells (WBC) in Barbadian group was significantly higher than that in the control group (P<0.01); lymphocytes (LYMPH), Barbadian group was significantly higher than that in the control group (P<0.01), Tegafur group was significantly lower than the control group (P<0.01); monocytes (MONO), all drug groups were significantly higher than the control group (P<0.01); neutrophils (NEUT), combination group (P<0.01) and Barbadian group (P<0.05) were significantly higher than the control group; blood sugar for the combination (P<0.05) and Barbadian (P<0.01) groups were significantly higher than the control group, while the Tegafur group was significantly lower than the control group (P<0.01). Cholesterol and BUN in the Tegafur group were significantly higher than that in control group (P<0.05). For IL-1, the combination and Barbadian groups were significantly higher than the control group (P<0.05), while for IL-6, all the drug groups were significantly higher than the control group (P<0.05). TNF-alpha in the Tegafur group was significantly lower than that in the control group (P<0.05). In conclusion, the combination of Tegafur and Barbadian has the significant effect of inhibiting mice S-180 sarcoma. The single use of chemotherapeutic drug Tegafur has no significant inhibitory effect on mice S-180 sarcoma. The single use of Barbadian has good antitumor effect and can resist the significant decrease of lymphocytes caused by the chemotherapeutic drug Tegafur. Thus, Barbadian has a good antitumor effect and can protect the immune system of the body, making it a viable treatment option. PMID- 30405748 TI - Expression of somatostatin and its receptor 1-5 in endometriotic tissues and cells. AB - The present study aimed to detect the expression of somatostatin (SS) and SS receptor (SSTR)1-5 in tissues from patients with endometriosis (EMS). Reverse transcription-quantitative polymerase chain reaction analysis was applied to examine the expression of somatostatin gene in ectopic endometrial cells (EECs). The expression of somatostatin receptor 1-5 in the ectopic endometrium (EE), eutopic endometrium and normal endometrium and their association with EMS staging were determined by immunohistochemistry. The results indicated that the expression of SS in EECs was significantly higher compared with that in the control group. SSTR1-5 were expressed in the EE tissues from 30 patients with EMS, and the positive rates were 43.3, 70.0, 53.3, 50.0 and 96.7%, respectively, which were closely associated with EMS staging of the patients. The positive rates of SSTR1-5 expression in the eutopic endometrium from 12 patients with EMS were 33.3, 41.7, 58.3, 58.3 and 83.3%, respectively, while the positive rates of SSTR1-5 expression in the normal endometrium from 14 women without EMS were 7.1, 7.1, 21.4, 28.6 and 64.3%, which were lower than the positive rates of SSTR1-5 in the EE (43.3, 70, 53.3, 50 and 96.7%) and eutopic endometrial cells (33.3, 41.7, 58.3, 58.3 and 83.3%). In conclusion, SS was highly expressed in EECs. SSTR1-5 were expressed in the ectopic as well as eutopic endometrium, and low or moderate expression of SSTR1-4 and high expression of SSTR5 were detected in the ectopic and eutopic endometrial tissues, while low expression of SSTR1-4 and partial expression of SSTR5 were detected in normal endometrium. The positive rates of expression of SSTR1-5 in the EE cells and eutopic endometrium were higher than those in the normal endometrium. The expression of all the subtypes of SSTR in the EE tissues was closely associated with EMS staging. PMID- 30405749 TI - Effects of let-7c on the proliferation of ovarian carcinoma cells by targeted regulation of CDC25a gene expression. AB - MicroRNAs serve a role in the development of ovarian cancer (OC). The present study investigated whether let-7c is able to regulate the proliferation of OC cells by targeting cell division cycle 25A (CDC25a). The reverse transcription quantitative polymerase chain reaction was performed to detect the expression of let-7c in OC specimens. Let-7c agomir was transfected into OC cells, and the proliferation and apoptosis of OC cells were detected. A dual-luciferase assay and western blotting were performed to analyze whether CDC25a was the target gene of let-7c as well as its interaction site. The results revealed that, in OC tissue, let-7c was downregulated when compared with normal ovarian tissue. A Cell Counting Kit-8 (CCK8) assay, colony formation assay and flow cytometry demonstrated that increased expression of let-7c was able to inhibit the proliferation and increase the apoptosis of OC cells. Western blotting revealed that upregulated let-7c is able to decrease the expression of CDC25a, and a dual luciferase assay and a recovery assay demonstrated that let-7c was able to regulate the expression of the 3' untranslated region of CDC25a. Therefore, the roles of let-7c in inhibiting the proliferation and promoting the apoptosis of OC cells may be realized through the regulation of the expression of CDC25a. The results of the present study revealed that let-7c may be a novel target in the diagnosis and treatment of OC. PMID- 30405751 TI - Effects of PLK1 on proliferation, invasion and metastasis of gastric cancer cells through epithelial-mesenchymal transition. AB - Effects of polo-like kinase (PLK1) on proliferation, migration and invasion capacities of gastric cancer cells through epithelial-mesenchymal transition (EMT) were investigated. Small-interfering ribonucleic acid (siRNA) with targeted interference in PLK1 gene was designed and transfected into gastric cancer MGC 803 cells via Lipofectamine to inhibit the expression of PLK1 gene in MGC-803 cells. The proliferation of MGC-803 cells was detected via methyl thiazolyl tetrazolium (MTT) assay. The mRNA and protein expression of PLK1 and EMT-related marker (E-cadherin) was detected via real-time polymerase chain reaction and western blot analysis, respectively. The effects of interference in PLK1 gene on migration and invasion of MGC-803 cells were studied via wound healing assay and Transwell chamber assay, respectively. Results of MTT assay showed that compared with that in control group, the cell proliferation in PLK1 siRNA group was significantly inhibited (p<0.01). Compared with those in control group, the mRNA and protein expression of PLK1 in PLK1 siRNA group was significantly decreased (p<0.01), but the mRNA and protein expression of E-cadherin was obviously upregulated (p<0.01). Results of wound healing assay and invasion assay showed that the capacity of migration and invasion of MGC-803 cells in PLK1 siRNA group was significantly inhibited compared with those in control group (p<0.01). In conclusion, PLK1 enhances the proliferation, migration and invasion of gastric cancer MGC-803 cells through affecting EMT. PMID- 30405753 TI - Expression and significance of miR-24 and miR-101 in patients with advanced gastric cancer. AB - Clinical significance of micro ribonucleic acid (miR)-24 and miR-101 were investigated by evaluating the expression of miR-24 and miR-101 in the tissues of patients with advanced gastric cancer. A total of 247 gastric cancer tissue specimens and 150 cancer-adjacent normal tissues (>5 cm away from the tumor) from patients with advanced gastric cancer who underwent surgical resection in the Surgical Oncology Department of Tianjin Union Medical Centre (Tianjin, China) from April 2013 to May 2016 were collected. The expression of miR-24 and miR-101 in gastric cancer and cancer-adjacent normal tissues were detected via reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and the correlation of the levels of miR-24 and miR-101 in gastric cancer tissues with their clinical and pathological features were explored. The expression level of miR-24 in gastric cancer tissues was significantly higher than that in cancer adjacent normal tissues (t=10.26, p<0.01), while the expression level of miR-101 was significantly lower (t=13.940, p<0.01). The expression of miR-24 and miR-101 in gastric cancer was correlated with the pathological differentiation degree of the tumor, lymph node metastasis and depth of infiltration (p<0.05). The multivariate Cox regression analysis revealed that miR-24 and miR-101 were independent prognostic factors affecting the overall survival of patients (p<0.01). The results indicated that the expression of miR-24 is upregulated and that of miR-101 is downregulated in gastric cancer tissues. miR-24 and miR-101 may promote the occurrence, development, infiltration and metastasis of gastric cancer, and can be indicators for the prognosis of patients with gastric cancer. PMID- 30405752 TI - Expression of PD-L1 and SOX2 during rectal tumourigenesis: Potential mechanisms for immune escape and tumour cell invasion. AB - Immunoediting is defined as a process whereby tumour cells develop the capacity to escape immune cell recognition. Accumulating evidence suggests that cancer stem-like cells (CSCs) have an enhanced capacity to interact with the immune system. The expression of CSCs and immune cell-associated markers has been demonstrated to change with disease progression from premalignant lesions to invasive cancer. The present study investigated the expression of putative CSC and immune cell-associated markers in different stages of progression from dysplasia to invasive malignancy in rectal lesions. Immunohistochemistry was performed for the CSC markers Lgr5 and SOX2 and the immune-associated markers CD8, Foxp3 and PD-L1 in 79 cases of endoscopically-excised rectal lesions, ranging from low grade adenoma (LG) to invasive adenocarcinoma (AdCa). CD8 and Foxp3 expression significantly increased with advances in disease progression [AdCa vs. LG: Odds ratio (OR) 4.33; 95% confidence interval (CI), 1.16-16.3; P=0.03 and OR, 40.5; 95% CI, 6.57-249.6; P<0.0001, respectively]. An increase in programmed death-ligand 1 (PD-L1) expression was also observed with disease progression (OR, 24.0; 95% CI, 4.23-136.2; P=0.0003). The expression of sex determining region Y-box 2 (SOX2) did not correlate with disease progression, although an elevated expression was observed in areas with high grade dysplasia. Increased PD-L1 expression may be a mechanism by which tumour cells evade immune recognition, facilitating tumour cell invasion in rectal cancer. The expression of SOX2 in areas with high grade dysplasia may indicate the de-differentiation of tumour cells, or the activation of migration pathways for invasion. PMID- 30405755 TI - Effects of NOTCH1 signaling inhibitor gamma-secretase inhibitor II on growth of cancer stem cells. AB - The present study aimed to observe the effect of the Notch1 signaling inhibitor gamma-secretase inhibitor II (GSI II) on the growth and differentiation of tumor cells. The tumor cell line U87 was grown in serum-free media, and cell growth was evaluated using immunofluorescence. Single-cell wall-adherent growing conditions were prepared, GSI II was added, and the differentiation and growth of single tumor cells was evaluated. Immunofluorescence demonstrated positive results for the expression of Nestin and cluster of differentiation 133. The cell proliferation rate was reduced following the addition of GSI II (P<0.05). GSI II may significantly inhibit the proliferation and differentiation of U87 tumor stem cells. PMID- 30405754 TI - SERINC2-knockdown inhibits proliferation, migration and invasion in lung adenocarcinoma. AB - Serine incorporator 2 (SERINC2) is a member of the SERINC family of transmembrane proteins that incorporate serine into membrane lipids during synthesis. In the present study, the biological function of SERINC2 in lung adenocarcinoma cells was investigated. The data from a previous study and the publicly available Oncomine database were analysed regarding the expression levels of SERINC2 mRNA in lung adenocarcinoma. A lentiviral-based short hairpin RNA (shRNA) was used to suppress SERINC2 expression in lung cancer cells. The effect of SERINC2 expression on lung cancer proliferation was determined using cell counting kit-8 and colony formation assays. The influence on invasion and migration was examined in vitro using Transwell and wound-healing assays, respectively. Phosphorylated protein kinase B (p-AKT) expression levels were assessed by immunoblotting. According to a previous study and Oncomine, expression levels of SERINC2 mRNA are significantly upregulated in tumour tissues compared with those in healthy tissues in patients with lung adenocarcinoma. SERINC2-knockdown by lentiviral based shRNA inhibited the proliferation, migration and invasion of the H1650 and A549 cells. In addition, p-AKT expression levels were significantly decreased following SERINC2-knockdown. In conclusion, SERINC2-knockdown suppresses lung adenocarcinoma proliferation, migration and invasion through a mechanism that may be associated with phosphatidylinositol 3-kinase/AKT signalling. Based on these findings, SERINC2 serves an important role in the progression of lung adenocarcinoma. PMID- 30405756 TI - Downregulation of 5-hydroxytryptamine receptor 3A expression exerts an anticancer activity against cell growth in colorectal carcinoma cells in vitro. AB - 5-hydroxytryptamine receptor 3A (HTR3A) is an important member of the 5-HT family, which has been suggested to contribute to human tumor development. However, the functions of HTR3A in human cancer, particularly in colorectal carcinoma (CRC) have not been well-characterized. Reverse transcription quantitative polymerase was performed to detect endogenous HTR3A expression in 6 CRC cell lines. HTR3A was then knocked down via a lentivirus-mediated shRNA system to detect the effect of HTR3A silencing on cell proliferation and apoptosis by MTT, colony formation, flow cytometry and western blotting assays in CRC. HTR3A was expressed at different levels in the 6 CRC cell lines. In addition, HTR3A knockdown inhibited CRC cell proliferation and colony formation, resulting in cell cycle arrest and the promotion of cell apoptosis. Additionally, the expression levels of apoptosis-associated proteins including BAD and BAX were increased, while Bcl-2 expression was decreased following HTR3A knockdown. In summary, the data of the present study indicated that HTR3A serves an important role in colon carcinogenesis, but in-depth studies of the mechanisms underlying these data are required to demonstrate whether it may be used as a novel target for CRC therapy. PMID- 30405757 TI - A dosimetric study on radiation-induced hypothyroidism following intensity modulated radiotherapy in patients with nasopharyngeal carcinoma. AB - The objective of the present study was to investigate the association between thyroid gland-dosimetric parameters and hypothyroidism induced by intensity modulated radiotherapy in patients with nasopharyngeal carcinoma (NPC). A total of 52 patients with NPC treated in the Department of Radiation Oncology of The Affiliated Hospital of Xuzhou Medical University, from May 2008 to December 2016 were retrospectively enrolled in the present study and divided into two groups based on thyroid function: The euthyroid and hypothyroid groups. The association between hypothyroidism and clinical or dosimetric parameters were analyzed. Females had a significantly increased probability of suffering from radiation induced hypothyroidism (RIHT), compared with males (P=0.010). The occurrence of RIHT was significantly negatively associated with thyroid volume prior to radiotherapy (P=0.048). Furthermore, the mean dose (Dmean) and V50 in the hypothyroidism group were significantly increased, compared with the euthyroidism group (P=0.017 and P=0.023, respectively). During the treatment optimization period, dose constraints associated with the thyroid gland demonstrated a significantly protective effect on thyroid function compared with the unconstrained group (P=0.034). According to the receiver operating characteristic curves, the threshold value was 5,160 cGy for Dmean and 54.5% for V50. The 3-year cumulative incidence of RIHT was 67.8% when the Dmean value was >5,160 cGy and 44.6% when the Dmean was <5,160 cGy (log rank test, P=0.036). Furthermore, the 3 year cumulative incidence was 66.1% when the V50 was >54.5%, and 29.9% when the V50 was <54.5% (log rank test, P=0.025). In conclusion, RIHT is associated with radiation dose, particularly with Dmean and V50 of the thyroid gland. Dose constraints associated with the thyroid gland significantly reduced the incidence of hypothyroidism compared with the unconstrained group. PMID- 30405758 TI - Th17 response in patients with cervical cancer. AB - Persistent infection by high-risk human papillomavirus (HR-HPV) is the main risk factor for uterine cervical cancer (UCC). However, viral infection alone is not sufficient for the development and progression of premalignant cervical lesions for cancer. In previous years it has been suggested that the adaptive immune response triggered by the differentiation of naive helper T cells in Th17 cells may serve an important role in disease development. It has been hypothesized that Th17 cells may be involved in the promotion of UCC, as high levels of interleukin 17 (IL17) expression have been detected in the mucosa of the uterine cervix of patients affected by the disease. However, the role of Th17 cells in the tumor development and progression remains unclear. It is believed that the immune response of the Th17 type during persistent infection of the genital tract with HR-HPV triggers chronic inflammation with a long duration with the production of IL17 and other pro-inflammatory cytokines, creating a favorable environment for tumor development. These cytokines are produced by immune system cells in addition to tumor cells and appear to function by modulating the host immune system, resulting in an immunosuppressive response as opposed to inducing an effective protective immune response, thus contributing to the growth and progression of the tumor. In the present review, the latest advances are presented about the function of Th17 cells and the cytokines produced by them in the development and progression of UCC. PMID- 30405760 TI - MicroRNA-195 as a diagnostic biomarker in human cancer detection: A meta analysis. AB - MicroRNAs (miRNAs/miRs) show great promise as novel cancer biomarkers. Several studies have revealed an association between abnormal miRNA expression and the risk of various cancer types. However, the diagnostic accuracy and reliability of miRNAs remains unclear. The present meta-analysis was performed to summarize the overall diagnostic performance of miR-195 for cancer. The PubMed, Cochrane Library, Wanfang and China National Knowledge Infrastructure databases were searched for associated literature published until December 10, 2017. Eligible studies were selected using multiple search strategies based on study selection criteria. Measures, including sensitivity and specificity, of the performance of miR-195 as a cancer diagnostic tool were pooled using bivariate meta-analysis models. All analyses were performed using Stata 14.0. The pooled analysis included 8 studies comprising 735 cases and 547 controls. The pooled diagnostic results calculated from all studies were as follows: Sensitivity, 0.79 [95% confidence interval (CI), 0.69-0.87]; specificity, 0.84 (95% CI, 0.68-0.93); positive likelihood ratio, 4.9 (95% CI, 2.50-9.50); negative likelihood ratio, 0.25 (95% CI, 0.18-0.35); diagnostic odds ratio, 20 (95% CI, 10.00-38.00); and area under the curve, 0.87 (95% CI, 0.84-0.90). Deeks' funnel plot asymmetry test suggested no potential publication bias (P=0.53). The present meta-analysis indicated that miR-195 could be a reliable non-invasive biomarker for the diagnosis of cancer. Further large-scale prospective studies are necessary to confirm the present findings and the clinical value of miR-195 for future diagnostics. PMID- 30405759 TI - Progress in the chemotherapeutic treatment of osteosarcoma. AB - Osteosarcoma (OS) is the most common type of primary bone tumor in children and adolescents and has been associated with a high degree of malignancy, early metastasis, rapid progression and poor prognosis. However, the use of adjuvant chemotherapy improves the prognosis of patients with OS. OS chemotherapy is based primarily on the use of adriamycin, cisplatin (DDP), methotrexate (MTX), ifosfamide (IFO), epirubicin (EPI) and other drugs. Previous studies have revealed that the survival rate for patients with OS appears to have plateaued: 5 year survival rates remain close to 60%, even with the use of combined chemotherapy. The most limiting factors include complications and fatal toxicity associated with chemotherapy agents, particularly high-dose MTX (HD-MTX), for which high toxicity and great individual variation in responses have been observed. Docetaxel (TXT) is a representative member of the relatively recently developed taxane class of drugs, which function to inhibit OS cell proliferation and induce apoptosis. Recently, more clinical studies have reported that TXT combined with gemcitabine (GEM) is effective in the treatment of OS (relapse/refractory and progressive), providing evidence in support of potential novel treatment strategies for this patient population. However, there is still no global consensus on this type of chemotherapy approach. The present review summarizes current studies surrounding progress in the chemotherapeutic treatment of OS and discusses the advantages and potential feasibility of TXT+GEM in the treatment of OS. PMID- 30405761 TI - Filamin A inhibits tumor progression through regulating BRCA1 expression in human breast cancer. AB - Filamin A (FlnA) is an actin cross-linking protein. Previous studies have demonstrated its role in tumor progression in a wide range of cancer types. It has been reported that FlnA interacts with the DNA damage response protein, breast cancer gene 1 (BRCA1), which is a tumor suppressor gene. However, to the best of our knowledge, there are no studies evaluating the association of these genes in human carcinomas. In the present study, the immunohistochemistry of a tissue microarray was used to investigate the clinical significance of FlnA and BRCA1 expression in pathological specimens collected from 424 patients treated for breast cancer. In addition, FlnA and BRCA1 expression was downregulated in the breast cancer cell line, MCF-7, through FlnA RNA interference. FlnA expression was exhibited by cancer tissues collected from 137 patients with breast cancer, which also exhibited high expression of BRCA1 and were associated with a relatively long survival time. A significant association was identified between FlnA protein expression and tumor size, and between FlnA protein expression and progesterone receptor expression. These results suggest that BRCA1 expression could be regulated by FlnA in the breast cancer cell line, MCF-7. Overall, the present study demonstrates that FlnA expression was associated with BRAC1 expression and tumor size in breast cancer, which provides important implications for future study of FlnA in the progression of human breast cancer. PMID- 30405763 TI - A gene mutation in RNA-binding protein 10 is associated with lung adenocarcinoma progression and poor prognosis. AB - RBM10 regulates the expression of various genes, which are often mutated in male lung adenocarcinoma. The present study confirmed the association of the RBM10 mutation at exon 10 with the clinicopathological data and prognosis of lung adenocarcinoma. The effect of mutant RBM10 on regulating lung cancer cell growth and invasion was investigated in vitro. Tissue specimens from 50 patients with lung adenocarcinoma were subjected to Sanger sequencing for RBM10 exon 10 mutations. Lung adenocarcinoma cells were transfected with pcDNA3.1 carrying wild type RBM10 cDNA or exon mutation cDNA for cell viability, apoptosis and invasion assays. RBM10 exon 10 mutations were identified in 11 out of 50 patients, with a high frequency in male patients [c.763 C>T, p.Arg241Cys for 33.3% (10/30)] and were significantly associated with the American Joint Committee on Cancer stage (P=0.005), lymph node metastasis (P=0.019) and shorter 5-year survival rate compared with the wild type RBM10 (36.4% vs. 46.5%; P=0.019). Multivariate analysis revealed that RBM10 exon 10 mutation was an independent prognostic factor (HR=3.787; P=0.033). RBM10 exon 10 mutation at c.763 C>T significantly promoted tumor cell proliferation and invasion capacity, whereas wild type RBM10 inhibited tumor cell invasion in vitro. In conclusion, RBM 10 mutation at exon 10 (c.763 C>T) occurs frequently and is an independent prognostic predictor in lung adenocarcinoma. PMID- 30405762 TI - Synergistic antitumor effect of the combination of a dual cancer-specific oncolytic adenovirus and cisplatin on lung cancer cells. AB - The effect of the combination of a recombinant adenovirus (ATV) expressing a specific apoptin protein and cisplatin on human lung cancer cells (A549 cells) was determined. The inhibitory effects of ATV and cisplatin, ATV alone, or cisplatin alone on the migration and invasion of A549 cells were evaluated in vitro using cell proliferation, wound healing, Transwell migration and Matrigel invasion assays. The tumor inhibition effect on A549 cells in vivo was assessed by observing the tumor growth and survival rate of nude mice with subcutaneous tumor xenografts grown from implanted A549 cells after treatment with ATV, cisplatin, or ATV combined with cisplatin. The proliferation (P<0.01), migration (P<0.01), and invasion (P<0.01) on A549 cells was suppressed significantly by ATV, cisplatin, and ATV and cisplatin, in a dose- and time-dependent manner. The inhibition of tumor growth in transplanted nude mice in the ATV combined with cisplatin group was significantly higher than that displayed in the other groups, and the survival rate of the combined treatment group was significantly higher than that of the group treated with cisplatin alone. The results indicated that the combined application of ATV and cisplatin could reduce toxicity and showed a synergistic effect in reducing tumor growth and increasing survival. Thus, there is a potential research value in treating tumors using the combination of ATV and cisplatin, which provides a foundation for future preclinical studies on this antitumor treatment. PMID- 30405764 TI - MicroRNA-661 expression is upregulated in pancreatic ductal adenocarcinoma and promotes cell proliferation. AB - Deregulation of microRNA (miRNA/miR) expression has been implicated in the development of pancreatic ductal adenocarcinoma (PDAC). However, the role of miR 661 in PDAC remains unknown. In the present study, it was revealed that miR-661 expression was significantly upregulated in PDAC tissues compared with that in adjacent normal tissues by using reverse transcription-quantitative polymerase chain reaction assays. Higher miR-661 expression revealed a positive association with lymph node metastasis, an advanced T stage and a poor prognosis in patients with PDAC. Furthermore, ectopic expression of miR-661 significantly promoted the cell proliferation ability in PDAC cell lines, and simultaneously promoted Wnt signaling pathway-related protein expression of beta-catenin, transcription factor 4 and cyclin D1 in vitro. However, the downregulation of miR-661 revealed reverse effects. Thus, the results of the present study indicated that miR-661 may function as a prognostic marker and provide insight for pancreatic cancer treatment. PMID- 30405765 TI - Hesperidin exhibits in vitro and in vivo antitumor effects in human osteosarcoma MG-63 cells and xenograft mice models via inhibition of cell migration and invasion, cell cycle arrest and induction of mitochondrial-mediated apoptosis. AB - The objective of the present study was to investigate the anticancer properties of hesperidin against human osteosarcoma MG-63 cells. Its effects on apoptosis, cell migration, cell invasion and cell cycle arrest, and its effects on tumor volume and weight were also evaluated in the present study. MTS assay was used to study the cytotoxic effects of the compound on cell viability. Effects on apoptosis and cell cycle arrest were evaluated by flow cytometry. In vitro wound healing assay and Matrigel assay were performed to study the effects of hesperidin on cell migration and cell invasion, respectively. Hesperidin exerted dose-dependent and time-dependent growth inhibitory effects on cervical cancer cells with IC50 values of 33.5, 23.8 and 17.6 uM, respectively, at 24, 48 and 72 h time intervals. Hesperidin led to early and late apoptosis induction in these cells. Hesperidin-treated cells also led to G2/M phase cell cycle arrest, which exhibited strong dose-dependence. Hesperidin treatment also led to inhibition of cell migration and invasion. PMID- 30405766 TI - High expression of GALNT7 promotes invasion and proliferation of glioma cells. AB - Polypeptide-N-acetyl-galactosaminlytransferase 7 (GALNT7), a member of the GalNAc transferase family, has not been previously evaluated as a prognostic factor of glioblastoma (GBM) or low-grade glioma (LGG). Based on The Cancer Genome Atlas database and bioinformatics analyses, the expression of GALNT7 was demosntrated to be higher in GBM and LGG tissues than in normal brain tissue. The expression levels of GANLT7 were associated with age, tumor grade, survival rate, disease free survival time and overall survival time. Gene correlation and gene-set enrichment analyses suggested that GALNT7 may affect the proliferative and invasive abilities of glioma cells through multiple signaling pathways, including regulation of the actin cytoskeleton, natural killer cell-mediated cytotoxicity, the janus kinase-signal transducer and activator of transcription (STAT) signaling pathway, cell adhesion molecules and extracellular matrix receptor interaction pathways. Furthermore, 5 target genes of GALNT7 involved in these signaling pathways were identified, including Crk, Rac family small GTPase 1, STAT3, poliovirus receptor and Tenascin C. In summary, high expression of GALNT7 was associated with poor prognosis of glioma, and may be used as an effective biomarker of glioma. PMID- 30405768 TI - Fractional uptake of circulating tumor cells into liver-lung compartments during curative resection of periampullary cancer. AB - Circulating tumor cells (CTCs) are able to predict outcome in patients with breast, colon and prostate cancer and appear to be promising biomarkers of pancreatic carcinoma. The aim of the present study was to demonstrate a statistically significant portal-arterial difference of CTCs during curative resection of periampullary cancer. A commercially available instrument (IsofluxR) was used to quantify blood content of CTC in 10 patients with periampullary cancer according to preoperative diagnostics. Portal and arterial blood samples (~8 ml each) were simultaneously collected intra-operatively following surgical dissection prior to division of the pancreas for tumor removal. Quantitative CTC analyses were performed according to standardized protocols for immune-magnetic enrichment of CTC. Flow cytometry was applied for qualitative evaluations of various CTC markers in 7 patients. There was a statistically significant difference in the number of CTCs collected in the portal blood [58+/-14 cells per 100 ml; mean +/- standard error (SE)] vs. arterial blood [24+/-7 cells per 100 ml (SE), P<0.025]. A fractional uptake of >=40% across liver and lung compartments of assumed malignant CTC was estimated to correspond to the appearance of ~410 tumor cells per minute during pancreatic resections based on estimated hepatic blood flow, measured tumor cell mass and tumor cell proliferation activity. Complications in the collection of portal blood were not observed. A significant uptake across liver or lung compartments of potentially malignant tumor CTCs from periampullary carcinoma may represent a model to capture, define and characterize cell clones with metastatic potential in liver and lung tissues following surgical resection. PMID- 30405767 TI - Regulating glioma stem cells by hypoxia through the Notch1 and Oct3/4 signaling pathway. AB - To investigate the effects of hypoxia on the features of cancer stem cells in the glioma cancer U87 cell line and underlying mechanism, stem cell markers and features in U87 were studied under the hypoxic and normoxic culture conditions by reverse transcription-quantitative polymerase chain reaction, western blot analysis, MTT, a colony formation test and flow cytometry. Compared to the normoxic group, the cluster of differentiation 133+ phenotype, clone formation rate and cell vitality were significantly elevated in U87 cells cultured in a hypoxic microenvironment. Also, the mRNA and protein expression of neurogenic locus notch homolog protein 1 (Notch1) and Oct3/4 were significantly elevated in U87 cells cultured in a hypoxic microenvironment, however, transcription factor SOX-2 expression was not significantly changed. These results indicate that hypoxia can promote the proliferation of glioma stem cells and maintain the characteristics of stem cells through the activation of Notch1 and Oct3/4 or Notch1 activation, affecting the biological characteristics of glioma cells. PMID- 30405769 TI - Imbalanced expression pattern of steroid receptor coactivator-1 and -3 in liver cancer compared with normal liver: An immunohistochemical study with tissue microarray. AB - Steroids affect normal and pathological functions of the liver through receptors, which require coactivators for their transcriptional activation. Steroid receptor coactivator (SRC)-1 and SRC-3 have been demonstrated to be regulated in numerous cancers; however, their expression profiles in liver cancer including hepatocellular carcinoma (HCC) and cholangiocellular carcinoma (CCC) remain unclear. Using tissue microarray immunohistochemistry, normal liver tissue and HCC tissue exhibited immunoreactivity of SRC-1, which were predominantly localized within extranuclear components; in CCC, they were detected within the cell nuclei; SRC-3 was also detected in the cell nuclei. Furthermore, no altered expression of SRC-1 and SRC-3 was observed in liver cancer compared with normal liver tissue; however, in CCC, the expression of SRC-3 was significantly increased compared with that detected in HCC. Importantly, although expression of SRC-1 and SRC-3 did not reveal any significant differences (30 vs. 40%) in normal liver tissue, HCC and CCC expression of SRC-1 was significantly decreased compared with that of SRC-3 (9.3 vs. 36%, and 6.7 vs. 67.7% for HCC and CCC, respectively). Further comparative analysis revealed that this discrepancy was detected in males with liver cancer, across all ages of HCC cases, younger CCC cases and all stages of liver cancer. The results suggested the presence of an imbalanced expression pattern of SRC-1 and SRC-3 from normal liver tissue to liver cancer (decreased SRC-1 and increased SRC-3), which may affect hepatic function and therefore promote liver carcinogenesis. PMID- 30405770 TI - Application of novel targeted molecular imaging probes in the early diagnosis of upper urinary tract epithelial carcinoma. AB - Imaging techniques of upper tract urothelial carcinoma (UTUC) are presently limited. Upconversion particles (UCPs) could be used to target tumors for imaging. The present study aimed to assess the value of a nano-UCP as a diagnostic probe for deep tumor tissue, including UTUC. Polymer-coated water soluble UCPs were synthesized. The pH Low Insertion Peptide (pHLIP) polypeptide was synthesized using the solid phase method. The silane shell surface was modified to present amino or carboxyl groups. Succinimidyl 4-(N maleimidomethyl)cyclohexane-1-carboxylate was used for the coupling of the polypeptide to the UCPs. An animal model of subcutaneous tumor was established in 4-week old nude mice using UTUC cells. Urinary tract epithelial cancer T24 cells were injected into the diaphragm below the heart. PHLIP-UCP solution (1 ml) was injected into the abdominal cavity of each animal. Optical detection was performed using a small animal living body multispectral imaging system. UCPs dispersed in chloroform emitted no light under natural light, while they emitted a green light when excited with a 980-nm laser. The maximum emission wavelength of Ho3+-doped UCPs was ~550 nm and the red emission region was ~650 nm. As the coated UCPs possessed a tendency to agglomerate and precipitate, the yield of the UCPs in the aqueous phase was reduced. Tumors could be successfully imaged in tumor-bearing mice. NaYF4: Yb, Ho3+ UPCs could be used for the detection of UTUC, thus further studies are required to determine if it could be used in larger animals with deeper tumors. PMID- 30405771 TI - miR-145-5p inhibits the proliferation and migration of bladder cancer cells by targeting TAGLN2. AB - MicroRNA-145-5p (miR-145-5p) is found to be involved in tumor development and progression. However, there are few studies on the effects of miR-145-5p on bladder cancer (BC). The role of miR-145-5p in BC was predicted by analysis of cell proliferation and migration in this study. The miR-145-5p and transgelin-2 (TAGLN2) expressions were evaluated via reverse transcription-quantitative PCR (RT-qPCR) or western blot analysis. The MTT and Transwell assay assessed cell proliferation and migration. TAGLN2 targeted to miR-145-5p was determined using luciferase assays. The results showed that the miR-145-5p downregulation was found in BC. miR-145-5p overexpression inhibited cell proliferation and migration in BC. Moreover, miR-145-5p directly targeted TAGLN2, and TAGLN2 expression was increased in BC. In addition, the high expression of TAGLN2 promoted cell proliferation and migration in BC. miR-145-5p appeared to regulate TAGLN2 in BC, and it also inhibited the cell proliferation and migration. The novel miR-145 5p/TAGLN2 axis may provide new therapeutic implications for BC. PMID- 30405772 TI - The SOX2OT/miR-194-5p axis regulates cell proliferation and mobility of gastric cancer through suppressing epithelial-mesenchymal transition. AB - Recent studies reported that long noncoding RNAs (LncRNAs) were involved in tumorigenesis of various human cancer types, including gastric cancer (GC) through targeting microRNAs (miRNAs/miRs). The present study investigated the biological functions of LncRNA SOX2 overlapping transcript (SOX2OT)/miR-194-5p axis and its underlying mechanism in the tumor progression of GC. The results showed that relative expression of LncRNA SOX2OT was highly upregulated while the expression of miR-194-5p was down-regulated in GC tissues and cell lines (MGC 803, SGC-7901, MKN-74). Knockdown of SOX2OT inhibited cell proliferation, invasion and migration of GC cells (MGC803, MKN-74) through reducing epithelial mesenchymal transition (EMT). Moreover, miR-194-5p was predicted to be one of the targets of SOX2OT through bioinformatics analysis and was verified by luciferase reporter assay. miR-194-5p expression was negatively regulated by SOX2OT expression in GC cells and miR-194-5p inhibitor was found to counteract the inhibitory effects of SOX2OT short hairpin (sh)RNA on cell proliferation and mobility through enhancing EMT in GC cells. Taken together, the in vitro experiments revealed that knockdown of SOX2OT inhibited cell proliferation and mobility through suppressing EMT via targeting miR-194-5p in GC. In addition, results from in vivo experiments showed that knockdown of SOX2OT suppressed GC tumor growth and matrix metalloproteinase (MMP)-2 and MMP-9 expression through inhibiting EMT. Besides that, relative expression of miR-194-5p was increased in sh-SOX2OT group compared with sh-NC group. In summary, our study elucidated that the SOX2OT/miR-194-5p axis participated in the tumor progression of GC through regulation of EMT both in vitro and in vivo. Hence, targeting the SOX2OT/miR-194 5p axis may aid in establishing novel strategies for therapy of GC. PMID- 30405773 TI - MicroRNA-140-5p suppresses cell proliferation and invasion in gastric cancer by targeting WNT1 in the WNT/beta-catenin signaling pathway. AB - MicroRNAs have been suggested as potential regulators in gastric cancer (GC) development through affecting the expression of their target genes. Previous studies have demonstrated that miR-140-5p is downregulated in GC. However, the underlying functional role of miR-140-5p in GC remains largely unknown. The present study revealed that miR-140-5p expression was significantly decreased in 60 GC tissues, compared with corresponding adjacent non-tumor tissues. A lower miR-140-5p expression was significantly associated with lymph node metastasis and an advanced Tumor-Node-Metastasis stage in patients with GC. Furthermore, patients with a lower miR-140-5p expression exhibited shorter disease-free survival and overall survival times. Gain- and loss-of-function assays revealed that increased miR-140-5p expression significantly inhibited GC cell proliferation and invasion ability, as well as the Wnt/beta-catenin signaling pathway by decreasing WNT1 and beta-catenin expression. However, decreasing miR 140-5p expression had the opposite effects. Bioinformatics methods and dual luciferase reporter assays revealed that WNT1 was a direct target of miR-140-5p. miR-140-5p suppressed cell proliferation and invasion by regulating WNT1 expression. Therefore, the results of the present study demonstrated that miR-140 5p may serve as a potential prognostic marker and therapeutic target in patients with GC. PMID- 30405774 TI - Knockdown of LETM1 inhibits proliferation and metastasis of human renal cell carcinoma cells. AB - The leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) has been reported to serve an important role in a number of human malignancies and is correlated with poor prognosis. However, little is known about the role of LETM1 in renal cell carcinoma (RCC). In the present study, the expression levels of LETM1 were investigated in RCC cell lines (Caki-1, 786-O, OS-RC-2, A498 and ACHN) and the HK-2 normal human renal tubular epithelial cell line. Short interfering RNA (siRNA) was used to knock down the expression of LETM1 in 786-O and A498 cells. The results indicated that the constitutive expression of LETM1 was notably upregulated in RCC cell lines. Knockdown of LETM1 significantly decreased cell proliferation, migration and invasion. Mechanistically, it was revealed that the knockdown of LETM1 expression sharply downregulated the protein expression of beta-Catenin, Cyclin D1 and c-Myc in 786-O and A498 cells. In conclusion, these results suggest that knockdown of LETM1 exhibits tumor suppressive effects, at least in part by controlling the downstream Wnt/beta-Catenin signaling pathway. Therefore, LETM1 may act as a novel therapeutic target for the treatment of RCC. PMID- 30405775 TI - MicroRNA-143 regulates cell migration and invasion by targeting GOLM1 in cervical cancer. AB - Accumulated research has revealed that the abnormal expression of microRNAs play a crucial role in tumorigenesis, potentially serving as therapeutic biomarkers in multiple tumors including cervical cancer. However, the expression level, biological role and the underlying mechanism of miRNA-143 in cervical cancer remain unclear. In the current study, we analyzed the miRNA-143 and golgi membrane protein 1 (GOLM1) expression in cervical cancer tissues and cells to explore their effects on cervical cancer occurrence and metastasis. Reverse transcription-quantitative PCR (RT-qPCR) was used to detect the miRNA-143 expression in cervical cancer tissues and cells. Following transfection, cell Transwell assays, western blot analysis and luciferase reporter assays were carried out in human cervical cancer cells. Results demonstrated that the miRNA 143 expression was dramatically decreased in both cervical cancer tissue samples and cells in contrast with the control group. We also found that the miRNA-143 expression negatively correlated with the GOLM1 expression in cervical cancer tissues and miRNA-143 inhibited cell invasion and migration via targeting GOLM1 in cervical cancer. PMID- 30405776 TI - Identification of novel long non-coding RNA in diffuse intrinsic pontine gliomas by expression profile analysis. AB - Diffuse intrinsic pontine glioma (DIPG) is one of the most devastating types of pediatric cancer. Accumulating evidence suggests that the dysregulated expression of long non-coding (lnc)-RNAs is associated with various pathologies of the CNS. However, the expression patterns and prognostic roles of lncRNAs in DIPG have not yet been systematically determined. In the present study, lncRNA expression profiles were obtained from the Gene Expression Omnibus (GEO) database using the lncRNA-mining approach and a differential expression analysis for lncRNAs was performed between DIPG and low-grade brainstem glioma and DIPG and normal pediatric brainstem tissue. Using a two-tailed t-test, 58 and 197 lncRNAs were found to be significantly deferentially expressed (Fold change >2 or <0.5, FDR adjusted P<0.05). To identify the prognostic value of these 255 differentially expressed lncRNAs, univariate and multivariate Cox proportional hazards regression analysis were performed and a 9-lncRNA signature as a potential biomarker for predicting the prognosis of DIPG was constructed. Kaplan-Meier curve analysis showed that patients in the high-risk group exhibited a reduced survival time compared with patients in the low-risk group (median survival of 230 vs. 460 days, log-rank test P<0.001). Moreover, this lncRNA-signature could be used as an independent prognostic marker for DIPG patient survival. The present study provided novel candidates for the investigation of potential diagnostic or prognostic biomarkers and/or therapeutic targets of DIPG, as well as a novel insight into the underlying mechanisms of DIPG. PMID- 30405777 TI - Screening of differentially methylated genes in breast cancer and risk model construction based on TCGA database. AB - Differentially methylated genes in breast cancer were screened out and a prognostic risk model of breast cancer was constructed. RNA-seq data and methylation data for breast cancer-related level 3 were downloaded from The Cancer Genome Atlas (TCGA), and MethylMix R package was used to screen out differentially methylated genes in cancer tissues and normal tissues. DAVID was used to analyze the GO enrichment of differentially methylated genes, ConsensusPathDB to analyze the PATHWAY pathways of differentially methylated genes, the single factor, multivariate Cox analysis and Akaike Information Criterion (AIC) to construct the prognostic risk model of breast cancer, and the ROC curve to judge the clinical application value of the risk model. Two hundred and fifty-seven differentially methylated genes were successfully screened out in cancer tissues and normal tissues; 39 related to GO enrichments and 19 related to PATHWAY pathways were found; the best prognostic risk model was obtained, risk score = QRFP (degree of methylation) * (-3.657) + S100A16 * (-3.378) + TDRD1 * ( 4.001) + SMO * (3.548); it was determined from each sample that the median value of the risk score was 0.936; using it as the cut-off value, the five-year survival rate in high-risk group of patients was 72.4% (95% CI, 62.7-83.6%), and that in low-risk group of patients was 86.6% (95% CI, 78.6-95.3%). The difference in the survival rate between the high-risk and low-risk groups was significant (P<0.001). The AUC of ROC curve was 0.791, so the model had a good clinical application value. This study successfully found multiple breast cancer-related methylation genes, the relationship between them and the course and prognosis of breast cancer was analyzed. Moreover, a prognostic risk model was constructed, which facilitated the expansion of the current study on the role of methylation in the occurrence and development of breast cancer. PMID- 30405778 TI - Aclidinium inhibits proliferation and metastasis of ovarian cancer SKOV3 cells via downregulating PI3K/AKT/mTOR signaling pathway. AB - Aclidinium, a muscarinic antagonist, is generally used to treat the respiratory system diseases whereas it is not clear whether aclidinium has therapeutic effect in ovarian cancer (OC). The aim of this study was to investigate the impact of aclidinium on OC and its potential mechanism. CCK-8 was employed to test the potential effect of aclidinium on SKOV3 cell proliferation. Transwell migration and invasion assay was performed to assess the influence of aclidinium on SKOV3 cell metastasis and invasion. Furthermore, flow cytometry apoptotic analysis was used to evaluate the effect of aclidinium on cell apoptosis. Finally, western blotting was applied to determine the changes of key proteins in apoptosis and PI3K/AKT/mTOR signaling pathway induced by aclidinium. The study showed that aclidinium had antiproliferative activity on SKOV3 cells. Simultaneously, aclidinium could significantly inhibit the number of migrated and invaded SKOV3 cells and markedly increased the SKOV3 cell apoptosis rate. Mechanistically, the expression of PI3K/AKT/mTOR signaling pathway related proteins were significantly inhibited in aclidinium treated SKOV3 cells. Our findings proposed a clue for further OC studies in preclinical and clinical treatment and aclidinium may be useful for the treatment of OC in the future. PMID- 30405779 TI - Cytoplasmic CD133 expression correlates with histologic differentiation and is a significant prognostic factor in extrahepatic bile duct cancer and gallbladder cancer. AB - Prominin-1 (CD133) is one of the most important stem cell markers among various malignant tumor types, but the clinicopathological significance of CD133 expression in intrahepatic cholangiocarcinoma remains controversial. To the best of our knowledge, there have been no reports on extrahepatic bile duct cancer (EHBDCA) and gallbladder cancer (GBCA). The present study examined the clinicopathological significance of CD133 expression in EHBDCA and GBCA. Immunohistochemistry was used to evaluate CD133 expression in resected specimens obtained from 82 patients with EHBDCA and GBCA, and this expression was compared with the clinicopathological parameters and survival data of the patients. Cytoplasmic CD133 expression was identified in 20 patients, and its incidence was significantly associated with histopathological grade (P=0.035), pT factor (P=0.020) and recurrence (P=0.046). Survival analysis revealed that cytoplasmic CD133 expression in patients was significantly associated with a poorer overall survival (OS) and relapse-free survival (RFS) compared with those without cytoplasmic expression (5-year OS rate, 11.6% vs. 39.1%; 3-year RFS rate, 12.5% vs. 42.0%, respectively). Multivariate analysis revealed that cytoplasmic CD133 expression was an independent prognostic factor for OS and RFS (P=0.0036 and P<0.0001, respectively). To the best of our knowledge, this is the first report demonstrating that cytoplasmic CD133 expression was associated with histologic differentiation, cancer progression, recurrence and poor prognosis in EHBDCA and GBCA. CD133 expression may be a useful marker for clinical prognosis in patients with EHBDCA and GBCA. PMID- 30405780 TI - A comprehensive gene mutation analysis of liquid biopsy samples from patients with metastatic colorectal cancer to the ovary: A case report. AB - Liquid biopsies of circulating tumor DNA (ctDNA) can detect molecular alterations, including tumor-specific mutations, and have recently been used as a non-invasive diagnostic, prognostic, and predictive tool. However, this technique is not commonly used in the gynecological field. Gene mutation profiling of liquid biopsy samples was performed using CAncer Personalized Profiling by deep Sequencing (CAPP-Seq), a novel next-generation sequencing-based approach to ultrasensitive ctDNA detection, in order to make it possible to molecularly diagnose metastatic colorectal cancer to the ovary. Liquid biopsy (plasma) samples and formalin-fixed paraffin-embedded tumor samples were obtained from two patients with ovarian tumors, who had a history of surgery for colorectal cancer, and comprehensive gene mutation profiling was conducted using CAPP-Seq. In patient 1, mutations were identified in the same three regions in both the ovarian tumor and preoperative plasma sample (in the KRAS G13D, APC E1306*, and TP53 H193Y genes). In patient 2, mutation was identified in the same one region in all the primary colorectal tumor, the ovarian tumor, and preoperative plasma sample (in APC R216* gene). These mutations are well-known genetic signatures of colorectal cancer, suggesting that the ovarian tumor was metastatic. Tthe gene mutation patterns of colorectal cancer were examined by subjecting liquid biopsy samples from patients with suspected metastatic ovarian tumors to CAPP-Seq. Gene mutation profiling of liquid biopsy samples can contribute to the preoperative differential diagnosis of metastatic ovarian cancer and its subsequent personalized treatment. PMID- 30405782 TI - Wentilactone A induces cell apoptosis by targeting AKR1C1 gene via the IGF 1R/IRS1/PI3K/AKT/Nrf2/FLIP/Caspase-3 signaling pathway in small cell lung cancer. AB - Wentilactone A (WA), a marine-derived compound, inhibits proliferation of NCI H446, as demonstrated by previous research; however, the anti-SCLC mechanism underlying WA was not fully investigated. The present study aimed to investigate the anti-SCLC mechanism underlying WA in vitro and in vivo. Cell Counting Kit-8 was used to assay cell growth, flow cytometry was conducted to analyze cell apoptosis and nude mice xenografts were used to examine SCLC growth following WA treatment. Bioinformatics was used for verification of the target gene of WA. Reverse transcription-quantitative polymerase chain reaction and western blot were used to examine aldo-keto reductase family 1 member C1 (AKR1C1) mRNA and protein levels, and AKR1C1-associated proteins prior to and following WA treatment. Cell growth, apoptosis and growth of nude mice xenografts were assayed prior to and following transfection with AKR1C1 knockdown or overexpression carriers, respectively. It was determined that AKR1C1 was a target gene of WA. Decreased AKR1C1 expression and WA treatment promoted apoptosis in SCLC via the insulin like growth factor-1 receptor/insulin receptor substrate 1/phosphoinositide 3-kinase/AKT/nuclear factor-erythroid 2-associated factor 2/Fas-associated death domain-like interleukin-1-converting enzyme-like inhibitory protein/Caspase-3 pathway. WA attenuated the proliferation and induced the apoptosis of SCLC cells in vitro and in vivo by targeting the AKR1C1 gene. WA may be a novel AKR1C1-targeted drug candidate for the treatment of SCLC in the future. PMID- 30405781 TI - Aberrant expression of glycogen synthase kinase-3beta in human breast and head and neck cancer. AB - Glycogen Synthase Kinase-3beta (GSK-3beta), a serine/threonine protein kinase, has been implicated as a potential therapeutic target in human cancer. The objective of the present study was to evaluate aberrant expression of GSK-3beta as a potential biomarker in human breast and head and neck cancers. Nuclear/cytosolic fractionation, immunoblotting and immunohistochemical staining was used to study the expression of GSK-3beta in human breast and head and neck cancer. Aberrant nuclear accumulation of GSK-3beta in five human breast cancer cell lines was demonstrated and in 89/128 (70%) human breast carcinomas, whereas no detectable expression of GSK-3beta was found in benign breast tissue. Nuclear GSK-3beta expression was associated with HER-2 positive tumors (P=0.02) and non triple negative breast carcinomas (P=0.0001), although nuclear GSK-3beta was observed in some samples across all breast cancer subtypes. Aberrant nuclear expression of GSK-3beta was found in 11/15 (73%) squamous cell head and neck carcinomas, whereas weak or no detectable expression of GSK-3beta was found in benign salivary gland and other benign head and neck tissues. These results support the hypothesis that aberrant nuclear GSK-3beta may represent a potential target for the clinical treatment of human breast and squamous cell carcinoma. PMID- 30405783 TI - Lectin histochemical analysis of uterine natural killer cells in normal, hydatidiform molar and invasive molar pregnancy. AB - Uterine natural killer (uNK) cells have been hypothesized to serve a role in controlling trophoblast invasion and proliferation. The aim of the present study was to identify the distribution and number of uNK cells in normal pregnancy (NP), partial mole (PM), complete mole (CM) and invasive mole (IM). uNK cells were detected using dolichos biflorus agglutinin lectin immunohistochemistry in decidual and villous tissues from early NP (n=15), late NP (n=15), PM (n=22), CM (n=20) and IM (n=10). A scaled eye piece was used for cell counting to obtain semi-quantitative results. It was revealed that uNK cells were mainly located in the uterine deciduas of early NP. As pregnancy progressed, the number of decidual uNK cells significantly decreased. Decidual uNK cells of PM, CM and IM were located near blood vessel endothelial cells. No significant differences were detected with respect to the numbers of decidual uNK between early NP and PM. However, the number of decidual uNK cells was significantly reduced in CM and IM compared with early NP. The populations of decidual uNK cells were not significantly different between CM and IM. No uNK cells were detected in the villi of PM, CM or IM. The decrease of decidual uNK cells in late NP, CP and IM, compared with early NP, suggested that uNK cells served an important role in controlling trophoblast invasion and proliferation. PMID- 30405784 TI - EMT induced by loss of LKB1 promotes migration and invasion of liver cancer cells through ZEB1-induced YAP signaling. AB - Liver cancer cells often exhibit mesenchymal phenotypes, a critical phenotypic alteration of cancer cells termed the epithelial-mesenchymal transition (EMT). To examine whether liver kinase B1 (LKB1) serves a potential role in EMT in liver carcinogenesis, in the present study, it was determined that the expression of LKB1 decreased in the hepatocellular carcinoma (HCC) cell line, compared with a normal liver cell line. LKB1 overexpression decreased cell motility and invasiveness. Furthermore, the loss of LKB1 induced the expression of several EMT marker proteins, including that of Zinc Finger E-Box Binding Homeobox 1 (ZEB1). Notably, the expression of Yes-associated protein (YAP) was positively associated with that of ZEB1 in LKB1-knockdown cells with a mesenchymal phenotype. Here, we describe the direct regulation of the Hippo pathway effector YAP by ZEB1. The findings of the present study demonstrate that ZEB1 regulates the expression of YAP and regulates the expression of downstream target genes to promote malignant progression. PMID- 30405785 TI - miR-491-5p inhibits osteosarcoma cell proliferation by targeting PKM2. AB - Increasing evidence has indicated that microRNAs (miRNAs/miRs) are associated with tumorigenesis and the development of numerous cancer types. Previous studies have suggested miRNA-491-5p is downregulated in osteosarcoma (OS) and functions as a tumor suppressor. However, the biological roles and underlying mechanisms associated with miR-491-5p function in OS require further exploration. In the present study, it was demonstrated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) that miR-491-5p was downregulated in 36 pairs of OS tissues, compared with in adjacent normal bone tissues. Furthermore, CCK-8 and colony formation assays indicated that miR-491-5p mimics suppressed OS cell proliferation. However, an miR-491-5p inhibitor enhanced cell proliferation. In addition, luciferase reporter assays, RT-qPCR and western blot analysis demonstrated that PKM2 was a direct target of miR-491-5p. The miR-491-5p mimic inhibited the mRNA and protein expression of PKM2, while the miR-491-5p inhibitor promoted PKM2 mRNA and protein expression. In addition, PKM2 overexpression reversed the proliferation-inhibiting effects of miR-491-5p in OS cells. Therefore, these results indicated that miR-491-5p serves as a tumor suppressor in OS cells, which may be important in OS treatment. PMID- 30405786 TI - MicroRNA 141 represses nasopharyngeal carcinoma growth through inhibiting BMI1. AB - Distant metastasis is the primary cause of mortality in patients with nasopharyngeal carcinoma (NPC). Unveiling the mechanism of metastasis will aid in shedding light on the clinical therapeutic strategies in NPC treatment. The present study revealed that the expression of microRNA 141 (miR-141) was downregulated in NPC tumor cells, particularly in metastatic ones. Ectopic expression of miR-141 blocked the proliferative and invasive ability of the tumor cells in vitro, and inhibited NPC tumor growth in vivo. Mechanistic studies identified that BMI1 served as the direct target of miR-141, and overexpression of BMI1 reversed the tumor repressor effect of miR-141. Prognostic analysis revealed that this miR-141/BMI1 signaling axis correlated with the clinical stage of patients with NPC. The study of miR-141 provided novel insight into the mechanism of NPC progression, which was correlated with the stage and metastatic state of patients. This miR-141/BMI1 axis may serve as a novel pharmacological target in NPC treatment. PMID- 30405787 TI - Barrier-to-autointegration factor 1: A novel biomarker for gastric cancer. AB - China is a country with a high incidence of gastric cancer (GC), where the GC incidence and the resultant mortality rates account for 50% of those worldwide. Surgical resection remains the primary treatment for GC. However, postoperative patients have a poor prognosis as the majority of patients present with metastases at the time of diagnosis. Therefore, the identification of novel treatment targets is required. The present study aimed to determine the effects of barrier-to-autointegration factor 1 (BANF1) on the clinical features and prognosis of GC, which may aid in discovering a novel tumor diagnostic biomarker and treatment target. The BANF1 gene expression profiles for normal and gastric tumor tissues were downloaded from the Gene Expression Omnibus GSE54129 data set to analyse the expression of BANF1 at the mRNA levels. Then, online survival analysis was performed using the GC database with the Kaplan-Meier Plotter (http://kmplot.com/analysis/) data. To examine the association between BANF1 and clinical features and prognosis, 132 postoperative GC pathological specimens were collected for immunohistochemical analyses. In the GSE54129 data sets, BANF1 expression at the mRNA level was significantly higher in the tumor tissue compared with that in the normal tissue. The same result was obtained in following the immunohistochemical analyses. In addition, BANF1 expression was associated with the patient age, tumor differentiation and infiltration depth. The survival time of BANF1 high-expression patients was shorter compared with that of the low-expression patients, and tumor differentiation status and tumor node metastasis stage were independent prognostic factors of the overall survival of patients with GC. The results of the present study suggest that BANF1 is associated with the clinical features and prognosis of GC. It may be a novel indicator of tumor prognosis and a potential therapeutic target for GC. PMID- 30405788 TI - Upregulation of circRNA_0000285 serves as a prognostic biomarker for nasopharyngeal carcinoma and is involved in radiosensitivity. AB - Despite significant medical advancement, nasopharyngeal carcinoma (NPC) remains one of the most difficult types of cancer to detect and treat. Circular RNA (circRNA) signatures may be used as prognostic and predictive factors for cancer. Previous studies indicated that the biological role of circular homeodomain interacting protein kinase 3 (HIPK3) has cancer type-specificity. The HIPK3 gene locus formats three circRNA isoforms: circRNA_100783, circRNA_0000285 and circRNA_100782. However, their roles in NPC remain unknown. In the present study, whether these circRNAs could be used as a biomarker for NPC diagnosis and predicting treatment response was investigated. Reverse transcription quantitative polymerase chain reaction was performed to measure the levels of circRNA_100783, circRNA_0000285 and circRNA_100782 in NPC and adjacent tissues. In addition, the circRNA_0000285 levels were further confirmed in serum samples from patients with NPC and healthy controls. The results demonstrated that circRNA_0000285, but not circRNA_100782 and circRNA_100783, was significantly increased in NPC tissues and serum samples from patients with NPC, compared with adjacent tissues and serum samples from healthy controls, respectively. Furthermore, circRNA_0000285 expression was increased in patients with radioresistant NPC, compared with patients with radiosensitive NPC. Further analysis demonstrated that circRNA_0000285 was significantly associated with tumor size (P<0.001), differentiation (P=0.022), lymph node metastasis (P=0.035), distant metastasis (P=0.022) and Tumor-Node-Metastasis stage (P<0.001). Additionally, univariate and multivariate analyses indicated that circRNA_0000285 may be an independent prognostic factor for the outcome of patients with NPC. The present data indicated that circRNA_0000285 may be a novel biomarker for NPC and is involved in NPC radiosensitivity. PMID- 30405789 TI - Osteosarcoma in patients below 25 years of age: An observational study of incidence, metastasis, treatment and outcomes. AB - Only few systematic and comprehensive studies have focused on osteosarcoma in children and adolescents. In the present study, 3,085 patients with osteosarcoma were identified in the Surveillance, Epidemiology and End Results Program database. The patients were <25 years of age and diagnosed between 1973 to 2012. A retrospective study was performed to investigate the factors associated with tumor incidence, metastasis, treatment and survival. The results indicated that the incidence of osteosarcoma was higher in male patients compared with female patients. In addition, the incidence rate of osteosarcoma was higher among male and female patients between the ages of 10 and 19. Osteosarcoma located in the chest and pelvic bones was associated with metastatic disease; however, metastasis in two histological types, parosteal and periosteal, was infrequent. Survival analysis revealed the following were associated with poor outcomes: Sex, patients diagnosed between 1973 and 1982, distant metastasis, treatment without surgery or with radiation, a tumor with a poorly differentiated or undifferentiated grade, tumor size >=100 mm, and a tumor in the pelvic bones. Patient's whose histologic type was parosteal osteosarcoma and whose tumor was located in one of the limbs, or who underwent local or radical excision, exhibited a good survival outcome. Survival outcomes were ranked according to the type of surgery, from best to worst, as follows: Local excision, radical excision, amputation and no surgery. In summary, the incidence of osteosarcoma is higher in male patients compared with female patients. Furthermore, individuals between the ages of 10 and 19 have a higher risk of osteosarcoma. Osteosarcoma located in the chest and pelvic bones has a high risk of metastasis. Limb-salvage surgery may be the optimal treatment approach for non-metastatic osteosarcoma. PMID- 30405790 TI - Ganoderic acid A exerts antitumor activity against MDA-MB-231 human breast cancer cells by inhibiting the Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway. AB - Breast cancer is a common malignant tumor among females, with triple-negative breast cancer being an important type accounting for 15-20% of all breast cancer cases. Triple-negative breast cancer is one of the most aggressive types of cancer without standard adjuvant chemotherapy. Ganoderic acid A (GA-A) is one of the major bioactive Ganoderma triterpenoids isolated from Ganoderma, which are recognized for their preventative and therapeutic effects. In the present study, the antineoplastic effect of GA-A on human breast cancer was investigated and the pro-apoptotic function of Janus kinase (JAK)2 and signal transducer and activator of transcription (STAT)3 on the function of GA-A was revealed. GA-A treatment inhibited the invasion of MDA-MB-231 cells. In addition, GA-A exhibited significant antitumor activity by enhancing the apoptotic index and reactive oxygen species production. In the present study, GA-A was identified to directly inhibit JAK2 phosphorylation and STAT3 downstream activation. In addition, GA-A suppressed STAT3 target gene expression, including B cell lymphoma-extra-large and Myeloid cell leukemia 1, resulting in elevated levels of proteins associated with mitochondrial apoptosis in addition to inhibitors of cyclin-dependent kinase. GA-A, in combination with AG490, a JAK2/STAT3 inhibitor, further decreased MDA-MB-231 cell viability. In conclusion, GA-A treatment inhibited breast cancer cell viability via JAK2/STAT3 downregulation and may regulate associated targets to serve an anti-MDA-MB-231 role, including mitochondrial apoptosis and regulating the expression of cell-cycle-associated factors. PMID- 30405791 TI - Synthesis and pharmacological evaluation of novel epidermal growth factor receptor inhibitors against prostate tumor cells. AB - The aim of the present study was to investigate the activities of novel synthetic epidermal growth factor receptor (EGFR) inhibitors (ZINC05463076, ZINC2102846 and ZINC19901103) against prostate tumors, in vitro models and investigate the potential underlying mechanisms. A panel of prostate tumor cell lines (LNCaP, DU 145, PC-3 and LNCaP-AI cells) were used to evaluate antitumor activity of ZINC05463076, ZINC2102846, and ZINC19901103 in vitro. Cell growth and clonal formation were determined by MTT assay and Soft agar colony formation assay, respectively. An EGFR kinase assay following treatment of the compounds was performed by ELISA. Cell cycle-regulating proteins, including cyclin-dependent kinase (CDK)1, CKD2, CKD4 and inhibitory effects of these compounds on downstream signaling were analyzed by western blotting. Flow cytometry was performed to investigate apoptosis and cell cycle phases of the treated cells. It was revealed that all compounds synthesized in the present study demonstrated significant EGFR inhibition abilities, compared with approved EGFR inhibitor drug gefitinib. Treatment of LNCaP, DU-145, PC3 and LNCaP-AI cells with these compounds revealed cell proliferation inhibition and colony formation suppression dose-dependently in vitro. The agents impaired phosphorylation of EGFR and extracellular signal regulated kinase 1/2 and suppressed their downstream signaling. In addition, these novel synthetic agents decreased the expression level of survivin, which may induce G1 cell cycle phase arrest and cell apoptosis in PCa cells subsequently. Collectively, ZINC05463076, ZINC2102846 and ZINC19901103 exhibited significant antitumor activity in human prostate tumors in vitro, by inhibiting EGFR and promoting apoptosis, which suggested a rationale for clinical development in prostate tumor therapy. PMID- 30405793 TI - Lipid rafts regulate the lamellipodia formation of melanoma A375 cells via actin cytoskeleton-mediated recruitment of beta1 and beta3 integrin. AB - Lipid rafts, distinct liquid-ordered plasma membrane microdomains, have been shown to regulate tumor cell migration by internalizing and recycling cell surface proteins. The present study reports that lipid rafts are a prerequisite for lamellipodia formation, which is the first step in the processes of tumor cell migration. The results from the wound-healing assay and immunostaining indicated that lipid rafts were asymmetrically distributed to the leading edge of migrating melanoma A375 cells during lamellipodia formation. When the integrity of lipids rafts was disrupted, lamellipodia formation was inhibited. The investigation of possible molecular mechanisms indicated that lipid rafts recruited beta1 and beta3 integrins, two important adhesion proteins for cell migration, to the lamellipodia. However, the different distribution characteristics of beta1 and beta3 integrins implied disparate functions in lamellipodia formation. Further immunostaining experiments showed that the actin cytoskeleton was responsible for lipid raft-mediated beta1 and beta3 integrin distribution in the lamellipodia. Together, these findings provide novel insights into the regulation of lipid rafts in lamellipodia formation, and suggest that lipid rafts may be novel and attractive targets for cancer therapy. PMID- 30405792 TI - Low expression of miR-199 in hepatocellular carcinoma contributes to tumor cell hyper-proliferation by negatively suppressing XBP1. AB - Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide, and microRNAs (miRs) are considered to serve important functions in the pathogenesis of HCC by regulating the expression of specific target genes. The present study was conducted to investigate the role of miR-199 and its putative target X-box binding protein 1 (XBP1) in HCC, as well as of the downstream gene cyclin D. The expression levels of miR-199, XBP1 and cyclin D were detected in clinical HCC specimens. The effect of miR-199 on the regulation of HCC cell proliferation and its underlying mechanism were examined in Hep3B2.1 7 cells, through expression assays and measurement of cell proliferation (via Cell Counting Kit-8, and 5-ethynyl-2'-deoxyuridine and DAPI double-staining assays) coupled with gain- and lose- of function experiments. The expression of XBP1 and cyclin D was significantly increased in HCC tissues when compared with adjacent non-HCC tissues, while the expression of miR-199 was decreased. Exogenous miR-199 significantly suppressed the expression of XBP1 and cyclin D in Hep3B2.1-7 cells. However, the expression of XBP1 and cyclin D significantly increased on treatment with miR-199 inhibitor. Consistently, Hep3B2.1-7 cells co transfected with a wild type reporter plasmid [XBP1-3'untranslated region (UTR) WT] and exogenous miR-199 exhibited lower relative luciferase enzyme activity than cells co-transfected with negative control miRNA and XBP1-3'UTR-WT, while cells co-transfected with mutated plasmid (XBP1-3'UTR-MU) and miR-199 exhibited no change. It was further observed that knockdown of XBP1 by small interfering RNA significantly decreased the expression of cyclin D in Hep3B2.1-7 cells. Additionally, exogenous miR-199 decreased the proliferation of Hep3B2.1-7 cells, which was contrary to the effect of miR-199 inhibitor. In conclusion, it was demonstrated that miR-199 negatively regulated the expression of XBP1 by directly binding to its 3'UTR and that XBP1 impacted cyclin D expression, which was associated with the cell cycle regulation in Hep3B2.1-7 cells. These findings suggested that a miR-199/XBP1/cyclin D axis may serve an important role in the pathogenesis of HCC. PMID- 30405794 TI - HDAC inhibitor apicidin suppresses murine oral squamous cell carcinoma cell growth in vitro and in vivo via inhibiting HDAC8 expression. AB - Apicidin, a cyclic peptide histone deacetylase (HDAC) inhibitor, has been demonstrated to exhibit antitumor activity in a number of human cancer types. The present study examined the antitumor activity of apicidin in murine oral squamous cell carcinoma (OSCC) cells. Inhibition of cell proliferation and the expression of selective HDACs were determined in apicidin-treated AT-84 murine OSCC cells. A C3H mouse model with subcutaneous injection of AT-84 cells was used to assess the in vivo effect of apicidin on tumor growth. Apicidin-induced cell growth inhibition and selectively reduced HDAC8 expression in AT-84 cells. Induction of apoptosis and autophagy was observed in apicidin-treated AT-84 cells. Apicidin notably inhibited tumor growth by up to 46% relative to the control group at the end of a 14-day period in a murine tumor model. The immunohistochemistry results in tumor tissues indicated that apicidin inhibited cell proliferation and induced apoptosis and autophagy in AT-84 cell-derived tumor tissues. Overexpression of HDAC8 was observed in the nucleus and cytoplasm in tumor tissues and apicidin significantly inhibited the level of HDAC8 expression, compared with the vehicle group. These results indicated that apicidin inhibited cell proliferation through HDAC8 inhibition in murine OSCC cells in vitro and in vivo. The present study indicated that apicidin may be an effective therapeutic agent for OSCC. PMID- 30405795 TI - Short-term curative effect and safety of propranolol combined with laser in the treatment of infantile hemangiomas. AB - Short-term curative effect and safety of propranolol combined with laser in the treatment of infantile hemangiomas was studied, so as to provide reference for clinical treatment. A total of 100 cases of infantile hemangiomas admitted to the Affiliated Hospital of Jining Medical University from October 2014 to June 2016 were selected into this study. According to the random number table method, they were divided into the control group and the observation group, with 50 cases in each group. The infant patients in the control group were treated with laser alone, and the infant patients in the observation group were treated with propranolol combined with laser. The healing time, the number of times of laser therapy, the short-term curative effect, the changes in serum inflammatory factors before and after treatment and the incidence of adverse reactions were compared between the two groups of infant patients. The healing time and the times of laser therapy of the infant patients in the observation group were less than those of the infant patients in the control group, and the differences were statistically significant (p<0.05). The short-term curative effect of the observation group (98%) was higher than that of the control group (82%), and the difference was statistically significant (p<0.05). The levels of serum inflammatory factors interleukin (IL)-2, IL-6 and IL-10 in the two groups of infant patients after treatment were lower than those before treatment, and the levels in the observation group were lower than those in the control group, and the differences were statistically significant (p<0.05). Propranolol combined with laser in the treatment of infantile hemangiomas has remarkable short-term curative effects. It can effectively reduce the levels of inflammatory factors, shorten the healing time and reduce the number of times of laser therapy. It is safe and worthy of clinical promotion. PMID- 30405796 TI - miR-34a targets BCL-2 to suppress the migration and invasion of sinonasal squamous cell carcinoma. AB - Sinonasal squamous cell carcinomas (SN-SCC) are rare tumors with low survival rate. It was reported that miR-34a expression is low in many cancers and acted as a tumor suppressor. But the biological function of miR-34a in SN-SCC has hardly been reported. Therefore, we explored the role and underlying mechanism of miR 34a in the migration and invasion of SN-SCC. Western blot analysis and RT-PCR were carried out to examine B-cell lymphoma-2 (BCL-2) and miR-34a expression in SN-SCC. Transwell assay was performed to test the SN-SCC migratory and invasive ability. Luciferase reporter assay was carried out to verify the target of miR 34a. Results demonstrated that miR-34a expression was lower in SN-SCC tissues and cells than normal SN-SCC. Re-expression of miR-34a inhibited cell migration and invasion, while had the opposite effect on inhibition of miR-34a. We also found that BCL-2 expression was higher in SN-SCC and silencing BCL-2 curbed the development of SN-SCC. BCL-2 was found to be a target of miR-34a and negatively correlated with miR-34a expression. Furthermore, BCL-2 attenuated the miR-34a inhibitory effect on SN-SCC cell migration and invasion. In short, these data demonstrated that miR-34a inhibited SN-SCC cell migration and invasion through targeting BCL-2. PMID- 30405797 TI - Therapeutic effects of lenvatinib in combination with rAd-p53 for the treatment of non-small cell lung cancer. AB - The aim of the present study was to analyze the effects of the combined treatment of lenvatinib and adenoviral delivered p53 gene (rAd-p53) on non-small cell lung cancer (NSCLC) cells and a total of 120 patients with NSCLC. The therapeutic effects of gene therapy of rAd-p53 and target therapy of Lenvatinib were investigated in NSCLC patients. The anti-tumor effects of combined treatment of llenvatinib and rAd-p53 was administered orally once-daily in NSCLC patients. Patients with NSCLC were divided into three groups and received lenvatinib (n=40), rAd-p53 (n=40) or combined treatment of lenvatinib and rAd-p53 (n=40) for a total of 30 days. Results showed that p53 was down-regulated and VEGFR, FGFR and PDGFR-beta were up-regulated in NSCLC tissues compared to adjacent normal tissues. Combined treatment of Lenvatinib and rAd-p53 markedly inhibited NSCLC cell growth, migration and invasion, and promoted apoptosis compared to either lenvatinib or rAd-p53 alone. The most common treatment-related adverse events included hypertension, diarrhea, nausea, proteinuria and body weight loss. Outcomes indicated that combined treatment of lenvatinib and rAd-p53 markedly inhibited tumor growth compared to lenvatinib and rAd-p53 alone for NSCLC patients. Combined treatment of lenvatinib and rAd-p53 did not exhibit drug accumulation after 30-day treatment. In conclusion, these outcomes indicate that combined treatment of lenvatinib and rAd-p53 may be an efficient therapeutic schedule for the treatment of NSCLC patients. PMID- 30405798 TI - Invasive bronchial fibroblasts derived from asthmatic patients activate lung cancer A549 cells in vitro. AB - Epidemiological data suggests that there are functional links between bronchial asthma and lung carcinogenesis. Bronchial fibroblasts serve a prominent role in the asthmatic process; however, their involvement in lung cancer progression remains unaddressed. To estimate the effect of the asthmatic microenvironment on the invasiveness of lung cancer cells, the present study compared the behavior of human non-small cell lung cancer A549 cells exposed to the signals from human bronchial fibroblasts (HBFs) derived from non-asthmatic donors (NA HBFs) and from asthmatic patients (AS HBFs). NA HBFs did not significantly affect A549 motility, whereas AS HBFs and the media conditioned with AS HBF/A549 co-cultures increased Snail-1/connexin43 expression and motility of A549 cells. In contrast to NA HBFs, which formed A549-impenetrable lateral barriers, alpha-SMA+ AS HBFs actively infiltrated A549 monolayers and secreted chemotactic factors that arrested A549 cells within AS HBF/A549 contact zone. However, small sub-populations of A549 cells could release from this arrest and colonize distant regions of AS HBF monolayers. These data indicated that the interactions between lung cancer cells and HBFs in asthmatic bronchi may facilitate the colonization of lung tumors by fibroblasts. It further stabilizes the tumor microenvironment and potentially facilitates collective colonization of novel bronchial loci by cancer cells. Potential mechanistic links between the asthmatic process and lung cancer progression suggest that bronchial asthma should be included in the list of potential prognostic markers for lung cancer therapy. PMID- 30405799 TI - Ethnicity based variation in expression of E-cadherin in patients with squamous cell carcinoma of the oral tongue. AB - The oral tongue is the most common site for tumours within the oral cavity. Despite intense research, there has been no improvement in the survival rate for patients with oral tongue squamous cell carcinoma (OTSCC) during the last decades. Differences between oral cancer patients based on ethno-geographical distribution have been reported. The present study used immunohistochemistry to evaluate commonly used markers of cancer cell phenotypes, E-cadherin, beta catenin and cytokeratins 5 and 19, in 120 patients with OTSCC. To evaluate the impact of ethnicity, patients from Sweden and Italy were included. A higher proportion of Swedish patients exhibited high expression of E-cadherin in their tumours (P=0.039), and high levels of E-cadherin in Swedish OTSCC patients that had succumbed to their disease were associated with poor prognosis. These data demonstrated differences in the pathological characteristics of OTSCC between two different European populations. The findings emphasise the need to take ethnicity/geographical location of patients into account when comparing results from different studies of OTSCC. PMID- 30405800 TI - Low dose dinaciclib enhances doxorubicin-induced senescence in myeloma RPMI8226 cells by transformation of the p21 and p16 pathways. AB - Multiple myeloma (MM) is a hematological malignancy that lacks a cure. However, novel combination therapy is a current anti-MM strategy. Doxorubicin (DOX) is a type of anthracycline which is a first-line chemotherapeutic for treating MM and induces senescence in many types of cancer. Dinaciclib is a potent, small molecule CDK inhibitor with promise for treating several types of cancer in I/II phase clinical trials. In the present study the anticancer effects and underlying mechanisms of dinaciclib combined with DOX in MM RPMI-8226 cells were investigated. Results indicated that DOX induced cell viability inhibition, cell cycle arrest and senescence. Furthermore, DOX resulted in increased alterations in DNA damage-related proteins such as p-ATM, p-Chk2, p-p53, p21 and gammaH2AX, but not p16. Notably, the combination of dinaciclib and DOX inhibited cell growth and promoted senescence by transforming the suppressive effects of the ATM/Chk2/p53/p21 signaling pathway and enhancing the p16 signaling pathway. Thus, low-dose dinaciclib enhanced anti-MM effects mediated by DOX via transformation of p21-p16 signaling pathways, leading to accelerated senescence, but not apoptosis. The present findings suggest this approach may be a promising therapeutic strategy for the treatment of MM. PMID- 30405801 TI - Analyses and treatment of simultaneous bi-lineage malignancies of myeloid leukemia and lymphoma: Two case reports and a literature review. AB - The present study reports two cases of concurrently diagnosed T-lymphoblastic lymphoma (T-LBL) and chronic myeloid leukemia (CML). The literature review revealed that myeloid leukemia may appear secondary to Hodgkin lymphoma or non Hodgkin lymphoma. However, simultaneous bi-lineage hematologic malignancies are rarely seen and the prognosis is worse than single lineage lymphoma or myeloid leukemia. There were no standard therapies. All simultaneous bi-lineage malignancies of myeloid leukemia and lymphoma reported in Pubmed were combined with the present two cases, to analyses its pathogenesis, features and treatment. It was concluded that the prognosis of bi-lineage hematologic malignancies was poor, however allogeneic hematopoietic stem cell transplantation could improve survival (P=0.033). PMID- 30405802 TI - Association of PTEN expression with liver function and inflammatory changes in patients with liver cancer after chemotherapy. AB - This study investigated the effects of phosphatase and tensin homolog deleted on chromosome ten (PTEN) expression on liver function classification, serum tumor markers and liver function of patients with liver cancer. A total of 63 patients with primary liver cancer treated in Xiangya Hospital (Changsha, China) were retrospectively analyzed. The difference in the PTEN expression levels in normal liver cells and liver cancer cells was compared via immunohistochemistry. According to the expression level of PTEN in the patient's pathological report, patients were divided into PTEN-positive and PTEN-negative groups. The expression level of each tumor marker in serum of patients was observed, and the association of PTEN expression level with the serum tumor markers was analyzed. Moreover, the changes in liver function and inflammatory factors before and after chemotherapy were compared. Finally, the relationship between the PTEN expression level and Child-Pugh grading of the liver function was detected. Compared with that in normal liver cells, the positive expression rate of PTEN protein in liver cancer cells was significantly decreased (P<0.05). No significant difference was found in the expression levels of serum tumor markers, except alpha-fetoprotein (AFP) in liver cancer patients between PTEN-positive and PTEN-negative group, indicating that PTEN expression has no significant effects on serum tumor markers. The levels of albumin (ALB), alkaline phosphatase (ALP) and prothrombin activity (PTA) were decreased significantly after chemotherapy compared with those before chemotherapy (P<0.05). Besides, the levels of inflammatory factors were remarkably reduced after chemotherapy. PTEN expression was negatively associated with liver function grading, and the higher the PTEN expression, the lower the liver function grading was. The low expression of PTEN has a certain association with the occurrence and grading of liver cancer. PTEN gene has guiding significance in predicting the occurrence, development and prognosis of liver cancer. PMID- 30405803 TI - Expression of miRNA-206 and miRNA-145 in breast cancer and correlation with prognosis. AB - Correlation between microRNA (miRNA)-206 and miRNA-145 expression and prognosis in breast cancer was investigated. Breast cancer specimens and paracancerous tissues of 372 breast cancer patients who underwent surgical resection in the First Affiliated Hospital of Shantou University Medical College from September 2010 to September 2014 were included. qRT-PCR was used to detect the expression of miR-206 and miR-145 in breast cancer and paracancerous tissues, and patients were divided into high and low expression groups according to the median expression level to plot survival curve. Expression levels of miR-145 and miR-206 in breast cancer tissues were 2.24+/-1.23 and 0.76+/-0.24, respectively. Expression level of miR-145 was significantly lower, while expression level of miR-206 was significantly higher in tumor tissues than in paracancerous tissues (p<0.05). The 3-year survival rates of miR-145 low expression group and miR-206 high expression group were also lower than that of miR-145 high expression group and miR-206 low expression group, respectively (p<0.05). Expression of miR-206 is upregulated and expression of miR-145 is downregulated in breast cancer, which may have an impact on the prognosis of patients. miR-206 and miR-145 may serve as important indicators to predict prognosis of patients with breast cancer in the future. PMID- 30405804 TI - Serum levels of candidate microRNA diagnostic markers differ among the stages of non-small-cell lung cancer. AB - Circulating microRNAs (miRNAs) are promising markers for cancer diagnosis and prognosis. Numerous studies evaluating miRNAs as markers for non-small cell lung cancer (NSCLC) have been conducted in recent years; however, the majority of candidate markers proposed via individual studies were inconsistent and no marker miRNAs for the diagnosis of early stage NSCLC have been established. In the present study, miR-145, miR-20a, miR-21 and miR-223, which were previously reported as candidate diagnostic markers of NSCLC, were re-evaluated. The serum levels of these miRNAs were quantified in 56 patients with stage I-IV NSCLC using the TaqMan microRNA assays and separately compared the levels at each stage with those in 26 control patients. The level of miR-145 was significantly reduced in patients with NSCLC, regardless of clinical stage, and its level increased following tumor resection in patients with stage I-II disease. These results indicate that miR-145 is relevant as a diagnostic marker for stages I-IV NSCLC. Additionally, the levels of miR-20a and miR-21 demonstrated notable differences among patients at different clinical stages. These miRNAs distinguished patients in a number of, but not all, stages of NSCLC from cancer-free control patients. These results indicated that it is essential to analyze miRNA levels at each stage separately in order to evaluate marker miRNAs for NSCLC diagnosis. PMID- 30405805 TI - A potential common role of the Jumonji C domain-containing 1A histone demethylase and chromatin remodeler ATRX in promoting colon cancer. AB - Jumonji C domain-containing 1A (JMJD1A) is a histone demethylase and epigenetic regulator that has been implicated in cancer development. In the current study, its mRNA and protein expression was analyzed in human colorectal tumors. It was demonstrated that JMJD1A levels were increased and correlated with a more aggressive phenotype. Downregulation of JMJD1A in human HCT116 colorectal cancer cells caused negligible growth defects, but robustly decreased clonogenic activity. Transcriptome analysis revealed that JMJD1A downregulation led to multiple changes in HCT116 cells, including inhibition of MYC- and MYCN-regulated pathways and stimulation of the TP53 tumor suppressor response. One gene identified to be stimulated by JMJD1A was alpha-thalassemia/mental retardation syndrome X-linked (ATRX), which encodes for a chromatin remodeler. The JMJD1A protein, but not a catalytically inactive mutant, activated the ATRX gene promoter and JMJD1A also affected levels of dimethylation on lysine 9 of histone H3. Similar to JMJD1A, ATRX was significantly overexpressed in human colorectal tumors and correlated with increased disease recurrence and lethality. Furthermore, ATRX downregulation in HCT116 cells reduced their growth and clonogenic activity. Accordingly, upregulation of ATRX may represent one mechanism by which JMJD1A promotes colorectal cancer. In addition, the data presented in this study suggest that the current notion of ATRX as a tumor suppressor is incomplete and that ATRX might context dependently also function as a tumor promoter. PMID- 30405806 TI - Identification of the key genes and pathways in prostate cancer. AB - Prostate cancer (PCa) is one of the most common malignancies in men globally. The aim of the present study was to identify the key genes and pathways involved in the occurrence of PCa. Gene expression profile (GSE55945) was downloaded from Gene Expression Omnibus, and the differentially expressed genes (DEGs) were identified. Subsequently, Gene ontology analysis, KEGG pathway analysis and protein-protein interaction (PPI) analysis of DEGs were performed. Finally, the identified key genes were confirmed by immunohistochemistry. The GO analysis results showed that the DEGs were mainly participated in cell cycle, cell division, cell development and cell junction. The KEGG pathway analysis showed that the DEGs were mainly enriched in proteoglycans in cancer, endocytosis, focal adhesion and hippo signaling pathway. The PPI analysis results showed that RPS21, FOXO1, BIRC5, POLR2H, RPL22L1 and NPM1 were the key genes involved in the occurrence of PCa, and the Module analysis indicated that the occurrence of PCa was associated with cell cycle, oocyte meiosis and ribosome biogenesis. IHC result showed that the expression of RPS21, BIRC5, POLR2H, RPL22L1 and NPM1 were significantly upregulated in PCa, while the expression of FOXO1 was significantly downregulated in PCa, matching with the bioinformatics analysis. Taken together, several key genes and pathways were identified involved in PCa, which might provide the potential biomarker for prognosis, diagnosis and drug targets. PMID- 30405807 TI - Mapping of new skin tumor susceptibility loci by a phenotype-driven congenic approach. AB - As cancer susceptibility varies among mouse strains, mouse models are powerful tools for the identification of genes responsible for cancer development. Several cancer susceptibility loci have been mapped by genetic analysis using cancer resistant and cancer-susceptible mouse strains. However, only a few corresponding genes for these loci have been identified, because most of the cancer susceptibility loci are low-penetrance alleles. We reported previously that wild derived PWK mice showed no tumor development on treatment with the two-stage skin carcinogenesis protocol [induced by 7.12-dimethylbenz(a)anthracene (DMBA)/12-O tetradecanoylphorbol-13-acetate (TPA)], and that this phenotype is dominant resistant when crossed with the highly susceptible strain FVB. From the analysis of the F1 backcross generation between PWK and FVB, we have mapped the new significant locus Skts-fp1 on chromosome 4. In the present study, congenic strains were generated with the PWK resistance allele in the FVB background using a phenotype-driven approach, and sought to narrow down the candidate loci and find the responsible gene(s). One of the resistant mice in the N6 generation carried the remaining PWK allele on chromosomes 4, 7 and 11, and an association study using the progeny of this mouse suggested that the locus on chromosome 11 may affect the cancer susceptibility locus on chromosome 7. On the other hand, no skin tumor susceptibility locus was mapped on chromosome 11 as examined in N2 progeny. These findings suggest that there is at least one tumor-resistance gene on chromosome 7, the function of which could be regulated by gene(s) located on chromosome 11. PMID- 30405808 TI - Evaluation of positive ductal margins of biliary tract cancer in intraoperative histological examination. AB - At present the only method available to confirm microscopic infiltration of cancer into ductal margins during surgery, is intraoperative histological examination. In the present study, the status of the surgical margins and postoperative course were evaluated to determine any correlation between remnant carcinoma and postoperative survival. All consecutive patients who underwent resection for biliary tract cancer between January 2004 and May 2012 were identified from a database. Positive margin cases were divided into two groups, invasive carcinoma and carcinoma in situ (CIS). Immunohistochemical staining targeting Ki67 and p53 for positive margins was performed. Cases of major vessel invasion were significantly increased in the positive group compared with the negative group. The recurrence rate was significantly lower in the CIS group compared with the invasive group. The survival rate was significantly increased in the CIS group compared with the invasive group. The expression levels of p53 and Ki67 were significantly increased in the invasive group compared with the CIS group. No statistical correlations were observed between the expression of p53 or Ki67 and the survival or recurrence of disease. In the positive group, resected margin status was the principal factor associated with recurrence-free survival according to Cox-regression analysis. In conclusion, the status of the resected margins in the positive group was the most important factor for postoperative survival and recurrence in cholangiocarcinoma, not immunohistochemical staining targeting Ki67 and p53. PMID- 30405809 TI - Nitric oxide functions in stromal cell-derived factor-1-induced cytoskeleton changes and the migration of Jurkat cells. AB - Stromal cell-derived factor-1 (SDF-1) regulates multiple cell signal pathways in a variety of cellular functions, including cell migration, proliferation, survival and angiogenesis. SDF-1-induced chemotaxis is an important step of lymphocyte migration. However, the molecular mechanisms that modulate SDF-1 mediated lymphocyte migration are not well identified. Nitric oxide (NO) has been found to function as a signaling molecule in a number of signaling pathways, including migration. In the present study, the potential role of NO in SDF-1 induced migration and the association between NO and the cytoskeletal changes of Jurkat cells was investigated. The present study demonstrated that Jurkat cells induced the production of NO by SDF-1 stimulation, using Griess reaction method and western blot analysis, and that NO was involved in SDF-1-induced rearrangement and polymerization of the cytoskeleton, using NOS inhibitor L-NMMA. Furthermore, NO was required for the migration of Jurkat cells. The research suggested that NO signaling pathways exerted a critical role in SDF-1-induced cytoskeleton changes and the migration of Jurkat cells. This work provides insight into the migration mechanism of acute lymphoblastic leukemia and provides an effective theoretical basis for therapy strategies for acute lymphoblastic leukemia. PMID- 30405810 TI - Precursor B cell lymphoid blast crisis of chronic myeloid leukemia with novel chromosomal abnormalities: A case report. AB - Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder. It is characterized by the presence of the Philadelphia (Ph) chromosome, t(9;22)(q34.1;q11.2), which carries the BCR-ABL1 fusion gene. Tyrosine kinase inhibitors (TKIs) have markedly changed the treatment approach of CML and have become the first-line agents for almost all CML patients. However, certain patients experience resistance to these medications, which occurs through several mechanisms, including the accumulation of TKI-resistant chromosomal abnormalities. The present study reports a case of a 27-year-old Saudi male with CML receiving TKI treatment, who presented with precursor B-cell lymphoblastic crisis demonstrating the presence of the novel combined chromosomal abnormalities; non-Ph der(22), i(9) and der(20), carrying the BCR-ABL1 fusion gene. This case report adds to the literature on novel TKI-resistance-conferring chromosomal abnormalities and links them to precursor B-cell lymphoblastic crisis. PMID- 30405812 TI - Negative lymph node at station 108 is a strong predictor of overall survival in esophageal cancer. AB - A negative lymph node (NLN) may represent a stronger predictor for the overall survival (OS) rate of patients with esophageal squamous cell carcinoma (ESCC), when compared with a positive LN (PLN). The present study aimed to investigate which LN station, containing the NLN, was associated with OS rate. A retrospective review was conducted in 216 patients with ESCC and a forward stepwise Cox regression model analysis was used to assess the relationship between clinical parameters and OS rate. Patients were divided into subgroups according to the status of the LN at station 108. Survival analysis was performed using the Kaplan-Meier method. The ratio of albumin-to-globulin (AGR), and of lymphocytes to neutrophil granulocytes (LNR) in the subgroups were also investigated. Overall, 105p (the PLN number at station 105), 108p, 109p and 7p were confirmed to be risk factors for OS rate (all P<0.05). Conversely, 108n (the NLN number at station 108) was identified as a protective factor for OS rate [hazard ratio (HR) 0.457, P=0.001]. Survival analysis demonstrated that patients with an NLN identified at the station 108 had an improved OS rate compared with those with a PLN identified at station 108 (P=0.006). Patients with only an NLN identified at station 108 had the best OS rate among all the sub-groups examined, and the AGR of this group of patients was higher than those of the other groups. The LN status at station 108 may indicate the prognosis of patients with ESCC, and an NLN may reflect the reaction of the immune system to tumor metastasis in these patients. PMID- 30405811 TI - miR-221 regulates proliferation and apoptosis of ovarian cancer cells by targeting BMF. AB - To observe the expression of microRNA-221 (miR-221) in ovarian cancer tissues and its effect and associated mechanism on proliferation and apoptosis in the ovarian cancer SKOV3 cell line. The expression of miR-221 and B-cell lymphoma 2 modifying factor (BMF) mRNA in ovarian cancer and para-carcinoma tissues was detected by reverse transcription-quantitative polymerase chain reaction, the expression of BMF was detected by western blot. MicroRNA.org online predicted that BMF was the possible target gene of miR-221, and the regulatory association was validated by a dual-luciferase reporter gene assay. SKOV3 cells were divided into 8 transfection groups: Anti-miR-negative control (NC); anti-miR-221; phosphorylated internal ribosome entry site 2 (pIRES2)-blank, pIRES2-BMF, small interfering (si) NC, si-BMF, anti-miR-221+si-BMF and anti-miR-221+pIRES2-BMF groups. Cell proliferation was detected by EdU staining flow cytometry. The effect of transfection on cell apoptosis was detected by Annexin V/PI double staining, and the activity of caspase-3 was detected by spectrophotometry. The effect of anti miR-221 or pIRES2-BMF transfection on SKOV3 cell proliferation was detected by MTT assay and flow cytometry, and the effect on apoptosis was detected by the Annexin V/PI double staining. Compared with para-cancer tissues, the miR-221 expression was significantly upregulated (P<0.001), the BMF mRNA expression was significantly downregulated (P<0.001), and the expression of BMF proteins was significantly downregulated in the ovarian cancer tissues. Dual-luciferase reporter gene assay confirmed a targeted regulatory association between miR-221 and BMF. The anti-miR-221 or pIRES2-BMF transfection significantly upregulated BMF expression in SKOV3 cells, significantly decreased cell proliferation and significantly increased cell apoptosis. The overexpression of BMF may enhance the proapoptotic and proliferation-inhibition effect of anti-miR-221 on SKOV3 cells. The transfection of si-BMF significantly promoted cell proliferation, reduced cell apoptosis and attenuated the proapoptotic and proliferation-inhibition effect of anti-miR-221 on cells. The expression of miR-221 was significantly upregulated and the expression of BMF was significantly down-regulated in ovarian cancer tissues. The overexpression of miR-221 antagonized the apoptosis of ovarian cancer SKOV3 cell and promoted the cell proliferation by targeted inhibition of the expression of BMF, which may serve a role in the pathogenesis of ovarian cancer. PMID- 30405813 TI - Increased expression of Na+/H+ exchanger isoform 1 predicts tumor aggressiveness and unfavorable prognosis in epithelial ovarian cancer. AB - Na+/H+ exchanger isoform 1 (NHE1), which is a regulator of intracellular and extracellular pH via ion exchange, has been demonstrated to serve an important role in cell differentiation, migration and invasion in solid tumors and hematological malignancies. However, the potential role of NHE1 in epithelial ovarian cancer (EOC) remains unclear. In the present study, the expression pattern and the prognostic value of NHE1 were investigated in EOC. EOC tissues, non-cancerous tumors and normal ovarian tissues were collected, and the expression levels of NHE1 were determined using the reverse transcription quantitative polymerase chain reaction, western blotting and immunohistochemistry. The expression pattern of NHE1 was also evaluated in ovarian cancer cell lines using western blotting and immunofluorescence. In addition, the association between the NHE1 expression pattern and the clinicopathological features and the clinical prognosis of patients with EOC was also analyzed. The expression levels of NHE1 were identified to be significantly increased in EOC tissues compared with non-cancerous tumors and normal ovarian tissues (P<0.05). Furthermore, the increased expression of NHE1 was associated with an advanced International Federation of Gynecology and Obstetrics stage (FIGO III-IV; P<0.001) and the presence of high-grade carcinoma (grades 2-3, P<0.001). Overexpressed NHE1 was identified as a risk factor of shorter PFS (P<0.001) and OS (P<0.001). A multivariate Cox's regression analysis revealed that NHE1 was an independent prognostic factor for the prediction of the outcome of patients with EOC. NHE1 may, therefore, serve as a potential therapeutic target to inhibit tumor aggressiveness. PMID- 30405814 TI - The effect of centromere protein U silencing by lentiviral mediated RNA interference on the proliferation and apoptosis of breast cancer. AB - Centromere protein U (CENPU) is a novel transcriptional repressor that is associated with different types of cancer. However, its function in breast cancer is poorly understood. In the present study, it was identified that CENPU was highly expressed in breast cancer tissues compared with expression in normal breast tissues (P=0.001). Furthermore, the CENPU mRNA level in tumors was often elevated, compared with the matched adjacent normal breast cancer tissue specimens in the dataset from The Cancer Genome Atlas database (n=106; P<0.001). To understand the function of CENPU in human breast carcinogenesis, its effects on the proliferation, apoptosis and cell cycle progression of MDA-MB-231 cells were examined using the lentiviral-mediated CENPU knockdown approach. The RNA and protein expression levels in the transfected cells were monitored using reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. The mRNA and protein expression levels of the CENPU gene were significantly lower in the CENPU-shRNA transfected cells than in the control (P<0.01), indicating successful gene expression knockdown. Post-transfection, cell counting and MTT analysis revealed that the proliferation activity was significantly suppressed in CENPU knockdown cells relative to the control (P<0.01). Additionally, fluorescence activated cell sorting analysis revealed that the (G2+S) phase fraction was significantly declined in CENPU knockdown cells relative to the control; while the G1 phase fraction was significantly increased (P<0.01) and the percentage of the apoptotic cells was significantly increased (P<0.01). In conclusion, downregulation of CENPU gene expression may inhibit cell proliferation and cell cycle progression, and increase the apoptosis of the breast cancer cells. These results suggested a possible function of this protein in breast cancer pathogenesis and prognosis. PMID- 30405815 TI - Gene networks in basal cell carcinoma of the eyelid, analyzed using gene expression profiling. AB - Basal cell carcinoma (BCC) is the most frequent malignant tumor of the eyelid; it progresses slowly and rarely metastasizes. However, BCC of the eyelid is partially invasive and can extend to the surrounding ocular adnexa even if appropriate treatment is performed. To understand the molecular mechanism underlying its pathogenesis, global gene expression analysis of surgical tissue samples of BCC of the eyelid (n=2) and normal human epidermal keratinocytes was performed using a GeneChip(r) system. The histopathological examination of surgically removed eyelid tissues showed the tumor nest composed with small basaloid. In the samples from patients 1 and 2, 687 and 713 genes were identified, respectively, demonstrating >=5.0-fold higher expression than that noted in normal human epidermal keratinocytes. For the 640 genes with upregulated expression in both patient samples, Ingenuity(r) pathway analysis showed that the gene network in BCC of the eyelid included many BCC-associated genes, such as the following: BCL2 apoptosis regulator; Patched-1; and SRY-box 9. In addition, unique gene networks related to cancer cell growth, tumorigenesis, and cell survival were identified. These results of integrating microarray analyses provide further insights into the molecular mechanisms involved in BCC of the eyelid and may provide a therapeutic approach for this disease. PMID- 30405816 TI - Acidosis promotes cell apoptosis through the G protein-coupled receptor 4/CCAAT/enhancer-binding protein homologous protein pathway. AB - The aim of the present study was to investigate the effects of acidosis on the apoptosis of renal epithelial and endothelial cells, and the molecular pathways responsible for this. A human proximal tubular cell line, HK-2, and human umbilical vein endothelial cells (HUVECs), were transfected with control or G protein-coupled receptor 4 siRNA for 36 h. Cells were exposed to normal (pH 7.4) or acidic (pH 6.4) media. Western blot analysis was used to assess the protein expression levels of G protein-coupled receptor 4 (GPR4), CCAAT/enhancer-binding protein homologous protein (CHOP) and cleaved caspase-3. Cell apoptosis was examined using the TUNEL assay and the lactate dehydrogenase (LDH) release assay. Using these techniques, it was demonstrated that acidosis increased the protein expression levels of GPR4, CHOP, cleaved caspase-3 and intracellular cyclic adenosine monophosphate levels in hypoxia/reoxygenation (HR)-treated cell lines. Knockdown of GPR4 in HK-2 cells and HUVECs markedly reduced the protein expression levels of acidosis-mediated GPR4, CHOP and cleaved caspase-3, as well as the rate of cell apoptosis. Therefore, the results of the present study suggested that acidosis promotes the apoptosis of HK-2 cells and HUVECs by regulating the GPR4/CHOP pathway. PMID- 30405817 TI - Hyperthermia enhances the sensitivity of pancreatic cancer SW1990 cells to gemcitabine through ROS/JNK signaling. AB - Pancreatic cancer (PC) is a highly aggressive type of cancer. Gemcitabine (GEM) is a standard chemotherapeutic treatment of advanced PC; however, it requires improvement, and more effective therapeutic methods must be further explored. In the present study, hyperthermia combined with GEM was used on the PC cell line SW1990. The results revealed that mild hyperthermia (at 42 degrees C) effectively increased the inhibitory effect of GEM on cell viability, as determined using an MTT assay, and increased the effect of GEM-induced apoptosis, as determined using an Annexin V-fluorescein isothiocyanate/propidium iodide assay, in PC SW1990 cells. Additionally, it resulted in increased S-phase arrest, downregulated the expression of the anti-apoptosis protein B-cell lymphoma 2 and upregulated the expression of the pro-apoptosis protein Bcl-2-associated X protein, cleaved caspase-3 and cleaved caspase-9, as determined using a reverse transcription quantitative polymerase chain reaction and western blot analysis. Furthermore, it was revealed that hyperthermia resulted in the rapid generation of reactive oxygen species (ROS) and substantial activation of c-Jun-N-terminal kinase (JNK). The introduction of ROS and JNK inhibitors suppressed hyperthermia-induced apoptosis in GEM-treated cells, suggesting that hyperthermia increased GEM cytotoxicity in PC SW1990 cells by inducing apoptosis via the ROS/JNK signaling pathway. PMID- 30405818 TI - High levels of glioma tumor suppressor candidate region gene 1 predicts a poor prognosis for prostate cancer. AB - Glioma tumor suppressor candidate region gene 1 (GLTSCR1) is associated with the progression of oligodendroglioma. However, there has been little study of GLTSCR1 in prostate cancer. In the present study, the association between the expression of GLTSCR1, and the progression and prognosis of tumors in patients with prostate cancer was assessed. An immunohistochemical analysis was performed using a human tissue microarray for GLTSCR1 at the protein expression level and the immunostaining results were evaluated against clinical variables of patients with prostate cancer. Subsequently, The Cancer Genome Atlas (TCGA) was used to validate the analysis results at the mRNA level and to study the prognostic value of GLTSCR1 in prostate cancer. Immunohistochemistry and TCGA data analysis revealed that GLTSCR1 expression in the prostate cancer tissues was significantly higher than that in the benign prostate tissues (immunoreactivity score, P=0.015; mRNA levels: cancer, 447.7+/-6.45 vs. benign, 343.5+/-4.21; P<0.001). Additionally, the increased GLTSCR1 protein expression was associated with certain clinical variables in the prostate cancer tissues, including advanced clinical stage (P<0.001), enhanced tumor invasion (P=0.003), lymph node metastasis (P=0.003) and distant metastasis (P=0.001). TCGA data revealed similar results, demonstrating that the upregulation of GLTSCR1 mRNA expression was associated with the Gleason score (P<0.001), enhanced tumor invasion (P=0.011), lymph node metastasis (P=0.001) and distant metastasis (P=0.002). Furthermore, Kaplan-Meier analysis suggested that among all patients, high GLTSCR1 expression indicated a decreased overall survival (P=0.028) and biochemical recurrence (BCR) free survival (P=0.004), compared with patients with low GLTSCR1 expression. Finally, multivariate analysis revealed that the expression of GLTSCR1 was an independent predictor of poor BCR-free survival (P=0.049). The present study suggested that the increased expression of GLTSCR1 was associated with the progression of prostate cancer. Furthermore, GLTSCR1 may be a novel biomarker that is able to predict the clinical outcome in prostate cancer patients. PMID- 30405819 TI - Anticancer effects of curcumin on nude mice bearing lung cancer A549 cell subsets SP and NSP cells. AB - Curcumin is a key polyphenolic curcuminoid extracted from the root of turmeric rhizome Curcuma longa Linn, which is a frequently used Chinese herb for the treatment of cancer. The aim of the present study was to investigate the mechanism of the inhibitory effects of curcumin on nude mice with lung cancer A549 cell subsets side population (SP) and non-SP (NSP) cells. BALB/c mice were subcutaneously injected with the tumor cells of A549 SP or NSP subsets consisting of 1*109 cells/l (0.2 ml in total). After 16 days of inoculation with A549, the mice were intraperitoneally injected with curcumin (100 mg/kg, 0.2 ml) once every other day, eight times in total. A series of assays were performed to detect the effects of curcumin on: i) Tumor weight and size; ii) Notch and hypoxia inducible factor 1 (HIF-1) mRNA expression by quantitative polymerase chain reaction; and iii) vascular endothelial growth factor (VEGF) and nuclear factor-kappaB (NF kappaB) by immunohistochemistry. It was determined that curcumin decreased the tumor weight and size, downregulated the expression of Notch and HIF-1 mRNA and suppressed the VEGF and NF-kappaB expression. These results indicated that curcumin inhibited lung cancer growth through the regulation of angiogenesis mediated by VEGF signaling. PMID- 30405820 TI - Overexpression of sigma-1 receptor in MCF-7 cells enhances proliferation via the classic protein kinase C subtype signaling pathway. AB - Sigma-1 receptor (sigma-1R), a 25-kDa integral membrane protein, is expressed at a high density in various tumor cell lines and its ligands mediate tumor cell proliferation. However, the effect of this receptor on proliferation and the associated intracellular molecules in tumors remains unclear. The present study aimed to investigate the effect of sigma-1R overexpression on MCF-7 cell proliferation and the associated intracellular molecules that serve a key role in this process. The sigma-1R proliferative function was examined by comparing the proliferation rates of a sigma-1R-overexpressing line, MCF-41 with a sigma-1R defective line, MCF-7, in culture media with various serum concentrations. The results demonstrated that MCF-41 cells grew significantly faster compared with MCF-7 cells, indicating a proliferation-enhancing receptor function. This proliferation-enhancing effect was completely eliminated by adding a PKC inhibitor to the culture media for MCF-41 cells. To identify which PKC subtype affects the proliferative function of sigma-1R, five inhibitors of PKC subtypes or enzymes involved in the PKC signaling cascade were introduced to MCF-7 and MCF 41 cell culture media and their effects on cell proliferation were compared. It was revealed that only the classic PKC subtype inhibitor, GF109203*, significantly inhibited MCF-41 cell proliferation compared with the MCF-7 line. In conclusion, among PKC iso-enzymes only classic PKC subtype enzymes serve an important role in sigma-1R overexpression enhancing MCF-7 cell proliferation. PMID- 30405821 TI - Cross regulation of signaling pathways in gastrointestinal stromal tumor. AB - The Sonic hedgehog (Shh) signaling pathway may be interrelated with other signaling pathways, such as the phosphoinositide 3-kinase (PI3K) and mitogen activated protein kinase (MAPK) pathways in gastrointestinal stromal tumor (GIST). The present study investigated the interaction among Shh, PI3K and MAPK signaling pathways in GIST cells. The expression of PI3K, MAPK and Shh signaling pathways in GIST-H1 cells were upregulated by endothelial growth factor (EGF) and recombinant Shh (N-shh) stimulation, and were downregulated by specific inhibitors of each signaling pathway. The proliferation rate of GIST-H1 cells were significantly increased under EGF or N-shh treatment (P<0.01). In addition, this effect was partially prevented by the pretreatment of the inhibitors of these signaling pathways. In summary, a cross regulation exists among the Shh, PI3K and MAPK signaling pathways in GIST-H-1 cells. The combined use of the inhibitors of these signaling pathways is a potentially novel option for GIST targeted therapy. PMID- 30405822 TI - Intervenolin suppresses gastric cancer cell growth through the induction of TSP-1 secretion from fibroblast-like stromal cells. AB - Fibroblast-like stromal cells modulate the growth of cancer cells, both positively and negatively. Growth modulation is achieved through the secretion of regulatory factors as well as by proteins within the extracellular matrix. Those cellular interactions present attractive targets for cancer chemotherapy. It was demonsrated a novel natural compound, intervenolin (ITV), inhibited the in vitro growth of human gastric cancer cells when co-cultured with stromal cells. Importantly, the inhibition was enhanced by the presence of stromal cells. The present study reported a mechanism of ITV action. Human gastric fibroblast-like stromal cells (Hs738) were treated with ITV. The resultant conditioned medium (ITV CM) inhibited the growth of human gastric cancer cells and suppressed the level of c-Myc protein. This result suggested that ITV negatively modulated cancer cell growth by upregulating the secretion of factors originating from stromal cells in the co-culture system. To better understand the mechanism, ITV CM was subjected to proteomic analysis. The data revealed that one of the candidate regulators was thrombospondin-1 (TSP-1). Recombinant human TSP-1 protein inhibited the growth of gastric cancer cells. Moreover, the growth inhibitory activities of ITV CM as well as that of recombinant TSP-1 were blocked by neutralizing antibody targeting TSP-1. These results suggested that ITV inhibited the growth of gastric cancer cells through its modulation of stromal cell function. PMID- 30405823 TI - Hsa-miR-376c-3p targets Cyclin D1 and induces G1-cell cycle arrest in neuroblastoma cells. AB - High-risk neuroblastoma is the most aggressive form of cancer in children. The estimated survival of children with high-risk neuroblastoma is 40-50% compared with low and intermediate risk neuroblastoma, which is >98 and 90-95%, respectively. In addition, patients with high-risk neuroblastoma often experience relapse following intensive treatments with standard chemotherapeutic drugs. Therefore alternative strategies are required to address this problem. MicroRNAs (miRNAs/miRs) are small, endogenously expressed non-coding RNAs, which when deregulated have been demonstrated to serve significant roles in the tumorigenesis of a number of different types of cancer. Results from a previous deep sequencing study identified 22 downregulated miRNAs from the 14q32 miRNA cluster differentially expressed in neuroblastoma cell lines isolated from 6 patients at diagnosis and at relapse following intensive treatments. miR-376c-3p is one of the 22 miRNAs that was downregulated in the majority of the cell lines isolated from patients post treatment. The present study employed reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to quantify the basic expression of miR-376c-3p in 6 neuroblastoma cell lines. The functional role of miR-376c-3p in the neuroblastoma cell lines was evaluated by alamar blue cell viability and propidium iodide-flow cytometric assays. In addition, luciferase reporter assays, RT-qPCR and western blotting were performed to identify and quantify the targets of miR-376c-3p in neuroblastoma cell lines. Ectopic expression of miR-376c-3p led to significant inhibition of cell viability and G1-cell cycle arrest in multiple neuroblastoma cell lines by reducing the expression of cyclin D1, an oncogene critical for neuroblastoma pathogenesis. The results of the present study provide novel insights into the functional role of miR-376c-3p and suggest new approaches for the treatment of neuroblastoma. PMID- 30405824 TI - Plk1 promotes the migration of human lung adenocarcinoma epithelial cells via STAT3 signaling. AB - Polo-like kinase (Plk)1 contributes to the development of human cancer via multiple mechanisms, such as promoting the migration of cancer cells. However, the mechanistic basis for the regulation of cell migration by Plk1 remains unknown. To address this question, the present study investigated the effect of Plk1 inhibition on the migration of human lung adenocarcinoma epithelial A549 cells and the molecular factors involved. A549 cells were treated with the Plk1 inhibitor, BI2536, and cell migration was evaluated with the wound-healing assay. The expression of matrix metallopeptidase (MMP)2, vascular endothelial growth factor (VEGF)A, total and phosphorylated signal transducer and activator of transcription (STAT)3 was assessed by western blotting and reverse transcription polymerase chain reaction following Plk1 knockdown and/or STAT3 overexpression. The interaction between Plk1 and STAT3 was evaluated by co-immunoprecipitation. The levels of MMP2 and VEGFA were decreased by treatment with Plk1 inhibitor. The phosphorylation of STAT3, which acts upstream of MMP2 and VEGFA, was also decreased by Plk1 knockdown, an effect that was abrogated by STAT3 overexpression. In addition, Plk1 was detected to bind with STAT3 either directly or as part of a complex by co-immunoprecipitation experiments. These results indicated that Plk1 may promote the migration of A549 cells via regulation of STAT3 signaling. PMID- 30405825 TI - Effect of five novel 5-substituted tetrandrine derivatives on P-glycoprotein mediated inhibition and transport in Caco-2 cells. AB - Tetrandrine (Tet) is a potent inhibitor that reverses P-glycoprotein-mediated multidrug resistance (MDR). A number of novel 5-substituted tetrandrine derivatives were synthesized by the authors. The present study aimed at identifying potential P-gp inhibitor candidates, and intracellular uptake and efflux experiments and Caco-2 cell-based Transwell transport studies were performed. It was demonstrated that all five test compounds were able to inhibit efflux and increase intracellular uptake of the P-gp substrate, rhodamine-123 (Rho-123); the test compounds were P-gp inhibitors. The transepithelial transport experiment indicated that the secretory (basolateral-to-apical) of Rho-123 decreased, the absorption (apical-to-basolateral) increased and the transport efflux ratio (ER) reduced in the presence of the five compounds. Among the compounds, fluobenzene-Tet (TF) exhibited similar inhibitory effect as Tet. Although the other four test compounds exhibited weaker inhibitory effects than Tet and TF, the compounds exhibited stronger inhibitory effects compared with the reference compound verapamil. The study demonstrated that the five novel 5 substituted tetrandrine derivatives are able to act as inhibitors of P-gp to overcome P-gp-mediated drug resistance. PMID- 30405826 TI - Effects of FOXM1 inhibition and ionizing radiation on melanoma cells. AB - Metastatic melanoma can be highly refractory to conventional radiotherapy and chemotherapy but combinatorial-targeted therapeutics are showing greater promise on improving treatment efficacy. Previous studies have shown that knockdown of Forkhead box M1 (FOXM1) can sensitize various tumor types to radiation-induced cell death. The effect of combining radiation with a small molecule FOXM1 inhibitor, Siomycin A, on growth, death and migration of a metastatic melanoma cell line (SK-MEL-28) that overexpresses this pleiotropic cell cycle regulator was investigated. Siomycin A (SIOA) was found to be a strong inducer of apoptosis, and inhibitor of proliferation and migration in a scratch wound assay in this cell line. Induction of apoptosis occurred at concentrations >1 uM in association with reductions in the constitutive FOXM1 and anti-apoptotic B-cell lymphoma 2 protein levels found in these cells. Single doses of ionizing radiation (0-40 Gy) delivered by linear accelerator caused inhibition of growth and migration without significant induction of cell death. Pretreatment with SIOA did not increase the sensitivity of this melanoma cell line to radiation as observed in other tumor types. These data confirm that as a single agent, SIOA is an effective inducer of cell death and inhibitor of migration in metastatic melanoma cells expressing constitutive FOXM1. In combination with radiation, SIOA pre-treatment, however, may not be of added benefit. PMID- 30405827 TI - Carcinogenesis-related changes in iron metabolism in chronic obstructive pulmonary disease subjects with lung cancer. AB - Chronic obstructive pulmonary disease (COPD) is often accompanied by lung cancer. In our previous work, it was observed that matrix metalloproteinase-3 and haptoglobin (HP) polymorphisms were potential markers of enhanced susceptibility to lung cancer development among male COPD subjects. Here, results are reported on blood serum levels of several proteins involved in iron metabolism, inflammation and the oxidative stress response compared between the same groups of subjects. The blood serum levels of tumor necrosis factor alpha (TNFalpha), transferrin, hepcidin, ferritin, soluble transferrin receptor and 8-oxo-2' deoxyguanosine were compared, as well as total iron-binding capacity (TIBC) and ceruloplasmin ferroxidase activity in two groups of subjects: Male COPD patients (54 subjects) and male COPD patients diagnosed with lung cancer (53 subjects). Statistically significant differences were identified between the two groups in transferrin and TNFalpha levels, as well as in TIBC; all three parameters were lower in the group consisting of COPD patients diagnosed with lung cancer (P<0.01). It was also revealed that HP genotype 1/2 was concomitant with low transferrin blood level in subjects with COPD; this apparent dependence was absent in the COPD + cancer subjects. The results indicate a role of iron metabolism in the susceptibility to lung cancer in COPD-affected subjects. They also emphasize the importance of individual capacity for an effective response to oxidative stress during the pathogenic process as HP is a plasma protein that binds free hemoglobin and its polymorphism results in proteins with altered hemoglobin-binding capacity and different antioxidant and iron-recycling functions. PMID- 30405828 TI - Dihydroartemisinin triggers c-Myc proteolysis and inhibits protein kinase B/glycogen synthase kinase 3beta pathway in T-cell lymphoma cells. AB - Recent studies have revealed a positive therapeutic effect of dihydroartemisinin (DHA) on tumor cells. However, the underlying mechanism of this has not yet been elucidated. The present study examined the potential therapeutic role and mechanism of DHA in T-cell lymphoma cells. It was revealed that DHA inhibited the proliferation of Jurkat and HuT-78 T-cell lymphoma cells in a concentration- and time-dependent manner. Furthermore, DHA reduced c-Myc protein expression at the transcriptional level, and induced the phosphorylation of c-Myc and the degradation of c-Myc oncoprotein levels. DHA treatment resulted in decreased phosphorylation of protein kinase B (Akt) and glycogen synthase 3beta (GSK3beta) in T-cell lymphoma cells. In addition, DHA treatment induced cell apoptosis, which was accompanied by an increased ratio of Bax/Bcl-2. Taken together, the results of the present study suggested that DHA may exert its antitumor role by accelerating c-Myc proteolysis and inhibiting the Akt/GSK3beta pathway in T-cell lymphoma cells. PMID- 30405829 TI - Utilizing ethacrynic acid and ciclopirox olamine in liver cancer. AB - Once aberrantly activated, the Wnt/beta-catenin pathway may result in uncontrolled proliferation and eventually cancer. Efforts to counter and inhibit this pathway are mainly directed against beta-catenin, as it serves a role on the cytoplasm and the nucleus. In addition, specially-generated lymphocytes are recruited for the purpose of treating liver cancer. Peripheral blood mononuclear lymphocytes are expanded by the timely addition of interferon gamma, interleukin (IL)-1beta, IL-2 and anti-cluster of differentiation 3 antibody. The resulting cells are called cytokine-induced killer (CIK) cells. The present study utilised these cells and combine them with drugs inhibiting the Wnt pathway in order to examine whether this resulted in an improvement in the killing ability of CIK cells against liver cancer cells. Drugs including ethacrynic acid (EA) and ciclopirox olamine (CPX) were determined to be suitable candidates, as determined by previous studies. Drugs were administered on their own and combined with CIK cells and then a cell viability assay was performed. These results suggest that EA-treated cells demonstrated apoptosis and were significantly affected compared with untreated cells. Unlike EA, CPX killed normal and cancerous cells even at low concentrations. Subsequent to combining EA with CIK cells, the potency of killing was increased and a greater number of cells died, which proves a synergistic action. In summary, EA may be used as an anti-hepatocellular carcinoma drug, while CPX possesses a high toxicity to cancerous as well as to normal cells. It was proposed that EA should be integrated into present therapeutic methods for cancer. PMID- 30405830 TI - Oncological and renal outcomes of segmental ureterectomy vs. radical nephroureterectomy for upper tract urothelial carcinoma. AB - Segmental ureterectomy (SU) represents a promising alternative for the treatment of upper tract urothelial carcinomas (UTUCs) as it is a less invasive procedure and guarantees the preservation of renal units. The present study evaluated oncological outcomes and renal functions following SU when compared with radical nephroureterectomy (RNU). A total of 26 patients with UTUCs who underwent SU (n=12) or RNU (n=14) were retrospectively evaluated. SU was performed in patients with clinically unifocal disease. In the SU group, the following surgeries were carried out: 7 direct ureterocystoneostomy, 1 reimplantation on psoas hitch bladder, 1 reimplantation on Boari flap bladder, 2 ureteral end-to-end anastomosis and 1 subtotal ureterectomy. In the SU group, tumors were low grade urothelial carcinoma (UC) in 6 patients, high grade UC in 5 patients and high grade UC with squamous cell differentiation in 1 patient, as well as <=pT1 in 5, >=pT2 in 6 and pTis in 1 patient; 'p' refers to the pathological state. The 5 year overall, cancer-specific, recurrence free and metastasis free survival in the SU group were 77.8, 87.5, 34.4 and 80.8%, respectively, which all exhibited no significant differences when compared with those of the RNU group. With regard to renal function, postoperative estimated glomerular filtration rates were preserved in the SU group. The present study demonstrated that SU does not result in poorer cancer control when compared with RNU. Thus, SU is an acceptable alternative to RNU in selected cases, as it is less invasive and preserves renal functions. PMID- 30405831 TI - Genetic polymorphisms in CDH1 are associated with endometrial carcinoma susceptibility among Chinese Han women. AB - The cadherin 1 (CDH1) gene plays critical roles in the epithelial-mesenchymal transition process, potentially offering us a glimpse into the development of endometrial carcinoma (EC). The present study aimed to identify whether genetic variants in CDH1 affect EC susceptibility in Chinese Han women, using a strategy combining haplotype-tagging single nucleotide polymorphisms (htSNPs) association analysis with fine-scale mapping. A total of 9 htSNPs in CDH1 were genotyped among 516 cases and 706 age-matched cancer-free controls. Logistic regression analyses revealed 3 htSNPs (rs17715799, rs6499199 and rs13689) to be associated with increased EC risk and 3 htSNPs (rs12185157, rs10431923 and rs4783689) with decreased EC risk. Furthermore, 14 newly imputed SNPs of CDH1 were identified to be associated with EC risk (P<0.05) using genotype imputation analysis. Notably, multivariate logistic analysis demonstrated that rs13689, rs10431923 and rs10431924 could affect EC susceptibility independently (P<=0.001). Subsequent Generalized Multifactor Dimensionality Reduction analysis revealed several best fitting models for predicting EC risk, including SNP-SNP interactions among rs7100190, rs12185157, rs10431923, rs7186053, rs6499199, rs4783689, rs13689, rs6499197 and rs10431924, and SNP-environment interactions between related SNPs and number of childbirth. Moreover, functional annotations suggest that the majority of these susceptible variants may carry potential biological functions that affect certain gene regulatory elements. In summary, this study suggested that the genetic polymorphisms of CDH1 were indeed associated with EC susceptibility on several levels. If further additional functional studies could verify these findings, these genetic variants may serve as future personalized markers for the early prediction of endometrial cancer in Chinese Han women. PMID- 30405832 TI - Variants in the 3'-untranslated region of CUL3 is associated with risk of esophageal squamous cell carcinoma. AB - Background: Esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers in China. Recently, a study identified that cullin 3 (CUL3) was significantly mutated and deleted in ESCC. We then hypothesis that germline variants in CUL3 may also associated with the susceptibility of ESCC. Variants in the gene 3'-untranslated region (3'-UTR) may associate with gene expression by altering miRNAs binding. Material and Methods: We systematically searched for variants in the 3'-UTR of CUL3 using the Ensembl database. Taqman SNP Genotyping Assay was performed in 638 ESCC cases and 546 controls to examine the association between the rs2396092 and the risk of ESCC. The eQTL analysis for CUL3 were conducted by using the GTEx database. Results: We identified that the rs2396092 was significantly associated with the susceptibility of ESCC. Compared with the TT genotype carriers, the CT genotype and CC genotype carriers were correlated with risk of ESCC with odds ratio being 1.33 (95% CI: 1.04-1.70, P=0.0222) and 1.63 (95% CI: 1.07-2.50, P=0.0241), respectively. Different genotypes of rs2396092 was also shown to be correlated with altered CUL3 expression. Conclusion: The results emphasize the importance of CUL3 in the development of ESCC and may contribute to the personalized prevention of this cancer in the future. PMID- 30405833 TI - miRNA-21 and miRNA-223 expression signature as a predictor for lymph node metastasis, distant metastasis and survival in kidney renal clear cell carcinoma. AB - Purpose: The aim of this study was to generate a novel miRNA expression signature to effectively assess nodal metastasis, distant metastasis and predict prognosis for patients with kidney renal clear cell carcinoma (KIRC) and explore its potential mechanism of affecting the prognosis. Method: Using expression profiles downloaded from the Cancer Genome Atlas database, we identified multiple miRNAs with differential expression between KIRC and paired normal tissues. The diagnostic values of the differentially expressed miRNAs for nodal metastasis and distant metastasis were evaluated by Receiver Operating Characteristic (ROC) curve analysis. Then, we evaluated the impact of miRNAs on overall survival (OS) by univariate and multivariate COX regression analyzes. This analysis was ultimately used to construct a miRNA signature that effectively assessed nodal metastasis, distant metastasis and predicted prognosis. The functional enrichment analysis of the miRNAs included in the signatures was used to explore its potential molecular mechanism in KIRC. Results: Based on our cutoff criteria (P < 0.05 and |log2FC| > 1.0), we identified 104 differentially expressed microRNAs (miRNAs), including 43 that were up-regulated in KIRC tissues and 61 that were down-regulated. We found 12 miRNAs were potentially diagnostic biomarkers of nodal metastasis and distant metastasis by ROC curve analysis. Two miRNAs (miRNA 21 and miRNA-223) were significant miRNAs independently associated with OS based on Cox univariate and multivariate analysis. We generated a signature index based on expression of these two miRNAs, and the two-miRNA signature is promising as a biomarker for diagnosing nodal metastasis, distant metastasis and predicting 5 year survival rate of KIRC with areas under the curve (AUC)=0.738, 0.659 and 0.731, respectively. Patients were stratified into high-risk and low-risk groups, according to median of the signature prognosis indexes. Patients in the high-risk group had significantly shorter survival times than those in the low-risk group (P = 0.000). The functional enrichment analysis suggested that the target genes of two miRNAs may be involved in various pathways related to cancer, p53 signaling pathway, apoptosis, and MAPK signaling pathway. Conclusion: The two miRNA signature could assess nodal metastasis, distant metastasis and predict survival of KIRC. As a promising prediction tool, the mechanism of the two miRNAs in KIRC deserves further study. PMID- 30405834 TI - MiR-543 promotes cell proliferation and metastasis of renal cell carcinoma by targeting Dickkopf 1 through the Wnt/beta-catenin signaling pathway. AB - Background: Renal cell carcinoma (RCC) is a common malignancy with high morbidity. MicroRNAs (miRNAs) have been demonstrated to be critical post transcriptional regulators in tumorigenesis. This study aimed to investigate the effect of miR-543 on the proliferation and metastasis of RCC. Material and Methods: The expression of miR-543 was examined in clinical samples and RCC cell lines. A498 and 786-O cell lines were employed and transfected with miR-543 inhibitor or miR-543 mimics. The correlation between miR-543 and DKK-1 was determined by luciferase reporter assay. Cell viability and cell cycle were determined by CCK8 and flow cytometry assay. Cell migration and invasion capacity were examined by transwell assay. The protein level of DKK1, beta-catenin and pGSK-3beta were analyzed by western blotting. Results: miR-543 was found to be up regulated in RCC cell lines. Further studies identified DKK-1 as a direct target of miR-543. Moreover, miR-543 overexpression suppressed the expression of DKK-1, and promoted cell proliferation, migration and invasion capacity, while knockdown of miR-543 abrogated above results. MiR-543 knockdown also decreased beta-catenin and pGSK-3beta levels. In vivo assay verified that miR-543 acts as an oncogene through the regulation of DKK-1 and Wnt/beta-catenin signaling pathway. Conclusion: Our study indicated that miR-543 negatively regulate the expression of DKK-1 in vitro. MiR-543 promotes malignancy phenotypes of RCC both in vitro and in vivo. This regulatory effect of miR-543 may be associated with Wnt/beta catenin signaling pathway. Therefore, miR-543 could be used as a biomarker for predicting the progression of RCC. PMID- 30405835 TI - Luteolin exerts an anticancer effect on gastric cancer cells through multiple signaling pathways and regulating miRNAs. AB - Accumulating studies confirmed that luteolin, a common dietary flavonoid which is widely distributed in plants and has diverse beneficial biological function, including anti-oxidant, anti-inflammation and anticancer properties. However, the detail mechanisms of luteolin on GC are poorly understood. Here, we investigated the anticancer effect of luteolin in GC cells in vitro and in vivo. Luteolin reduced the cell viability in a time and dose-dependent manner. Luteolin significantly inhibited cell cycle progress, colony formation, proliferation, migration, invasion and promoted apoptosis in vitro and in vivo. Luteolin also regulated these biological effects associated regulators. Mechanically, luteolin treatment regulated Notch1, PI3K, AKT, mTOR, ERK, STAT3 and P38 signaling pathways and modulated a series of miRNAs expression. These findings provide novel insight into the molecular function of luteolin which suggest its potential as a therapeutic agent for human GC. PMID- 30405836 TI - Neoadjuvant Chemotherapy with Fluorouracil plus Nedaplatin or Cisplatin for Locally Advanced Nasopharyngeal Carcinoma: a Retrospective Study. AB - The present study aimed to evaluate the efficacy, toxicity and long-term outcome of nedaplatin or cisplatin combined with 5-fluorouracil neoadjuvant chemotherapy (NF or PF regimen) followed by concurrent chemoradiotherapy (CCRT) for treatment of locally advanced nasopharyngeal carcinoma (NPC). In this study, a total of 186 patients with locally advanced NPC between January 2009 and November 2011 in our center were retrospectively analyzed. 103 cases were received NF neoadjuvant chemotherapy followed by nedaplatin concurrent intensity-modulated radiotherapy (IMRT), and 83 cases were received PF neoadjuvant chemotherapy followed by cisplatin concurrent IMRT. Overall survival (OS), progression-free survival (PFS), local relapse-free survival (LRFS), regional relapse-free survival (RRFS) and distant metastasis-free survival (DMFS), as well as acute toxicities were monitored. Results showed that there were no significant differences in 5-year OS, PFS, LRFS, RRFS and DMFS between NF and PF groups. NF group had a higher incidence of grade 3-4 neutropenia (46.6% vs. 31.3%, P=0.035) and thrombocytopenia (17.5% vs. 7.3%, P=0.042) compared with PF group. However, NF group was less common to suffer from grade 3-4 nausea (1.9% vs. 24.1%, P<0.001), vomiting (0% vs. 13.3%, P<0.001) and weight loss (0% vs. 4.8%, P=0.025). In multivariate analysis, N stage was an independent factor for OS, PFS, RRFS and DMFS. In conclusion, neoadjuvant chemotherapy with fluorouracil plus nedaplatin followed by nedaplatin concurrent with IMRT exhibited similar efficacy but more tolerable toxicity than cisplatin setting, which might be an effective and safe choice for treatment of locally advanced NPC. PMID- 30405837 TI - How much margin do we need for pelvic lymph nodes irradiation in the era of IGRT? AB - Background and purpose: Image guided radiotherapy (IGRT) without 6 degree of freedom couch can only correct the translational setup errors of pelvic radiotherapy. But errors introduced by rotation and deformation of CTV can't be adjusted in most of IGRT systems. This article is to evaluate these errors and to provide recommendations on the margin needed in the era of IGRT. Material and methods: 218 patients who received pelvic radiotherapy in PUMC Hospital from 2012 to 2014 were included. A simulation CT and a CBCT were acquired for every patient. 3D and 6D registrations of CT and CBCT were applied. 9 bony landmarks were marked and distances of each landmark between CT and CBCT were measured in three directions. Results: Without image guidance, movements of landmarks in the directions of LR, AP and SI were 0.4 +/- 2.5 mm, 1.3 +/- 3.8 mm and 1.5 +/- 5.0 mm respectively, with 3D-registration, movements were 0.0 +/- 1.5 mm, 0.7+/- 2.8 mm and 0.6+/- 3.2 mm, and with 6D-registration, movements were 0.0 +/- 0.5 mm, 0.2 +/- 1.0 mm and 0.2 +/- 1.1 mm in each direction. Conclusions: IGRT could reduce setup errors. IGRT with 6D treatment couches could further reduce setup errors compared to 3D couches. For centers without IGRT, we suggest CTV-PTV margins of 6 mm, 9 mm and 12 mm in LR, AP and SI directions respectively, margins of 3 mm, 6.5 mm and 7 mm for the use of daily IGRT with 3D couch and 2 mm, 3 mm and 3 mm for 6D couch. PMID- 30405838 TI - The prognostic value of long noncoding RNA ZEB1-AS1 on clinical outcomes in human cancer. AB - Background: Although growing evidence have demonstrated that long non-coding RNA ZEB1-AS1 was aberrantly expressed in various types of cancers and can be used as a prognostic marker in cancer, the results remain inconclusive. Therefore, we performed this meta-analysis to evaluate the prognostic value of ZEB1-AS1 in human cancer. Methods: A literature survey was conducted for all eligible studies by searching the following online databases: PubMed and Embase. The pooled odds ratios (ORs) or hazard ratios (HRs) with a 95 % confidence interval (95 % Cl) were computed to demonstrate its prognostic value. Results: A total of 14 studies with 1096 individuals were included to evaluate the association of ZEB1-AS1 with clinicopathological features and overall survival (OS). In the pooled analyses stratified by clinicopathological features, ZEB1-AS1 expression was significantly related to depth of tumor (OR=2.92, 95% CI 1.22-7.02), poor histological differentiation (OR=2.72, 95% CI: 1.92-3.86), lymph node metastasis (OR=3.93, 95% CI: 2.65-5.84), distant metastasis (OR=5.34, 95% CI: 2.85-10.02) and tumor stage (OR=2.46, 95% CI 1.42-4.24), but not to tumor size (OR=1.25, 95% CI 0.79-1.96). Altered ZEB1-AS1 expression was found to be an indicator of worse prognosis in OS (HR = 1.94, 95% CI: 1. 66-2.22) among tumor patients. Conclusions: High ZEB1 AS1expression was associated poor clinical outcome and it can serve as a novel predictive biomarker in various cancers. PMID- 30405840 TI - Survival analysis for lung adenosquamous carcinoma patients with brain metastasis. AB - Purpose: We retrospectively collected consecutive survival data of lung adenosquamous cell carcinoma (ASC) patients with brain metastasis (BM) in our institute and discussed the factors related to prognosis of these patients. Patients and Methods: A total of 42 patients diagnosed as lung ASC with BM between July 1, 2008 and December 31, 2010 at the Department of Respiratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University were retrospectively reviewed. Time to BM (TTB) and overall survival (OS) data were analyzed. OS1 was calculated from the time ASC was diagnosed until the death of a patient. OS2 was defined as the duration from BM was first identified to the death of a patient. 1-year, 2-year and 3-year survival rates were also computed. Univariate and multivariate survival analysis was performed using Kaplan-Meier methods and Cox regression. Results: The median TTB for all patients was 5.7 months [95% confidence interval (CI): 0.8 - 10.6 months]. The median OS1 was 13.8 months (95%CI: 11.2 - 16.4 months). TTB longer than 12 months [adjusted HR: 0.15 (95%CI: 0.05 -0.48 vs. TTB<= 6 months, P=0.001); 0.22 (95%CI: 0.07- 0.71, vs. TTB 6-12 months, P=0.010) and resection for BM lesions [adjusted hazard ratio (HR): 0.47 (95%CI: 0.24 - 0.94 vs. not resected, P=0.032)] were independent predictors for a longer OS1. The median OS2 was 7.9 months (95%CI: 4.5 - 11.3 months). Treatment cycles more than 3 [adjusted HR: 0.41 (95%CI: 0.20 - 0.83 vs. treatment cycles <3, P=0.013)] was an independent predictor for a longer OS2. Conclusions: This study shows that resection of BM if possible, and standard chemo radiotherapy in patients with multiple BM lesions is associated with longer overall survival. PMID- 30405839 TI - Oncogenic virus-induced aerobic glycolysis and tumorigenesis. AB - Enhanced glycolysis under normoxic conditions is known as aerobic glycolysis or the Warburg effect and is a hallmark of many tumors. Viral infection may also induce aerobic glycolysis as it is required for replication and survival. Tumor viruses inducing aerobic glycolysis and lactate production during latent infection suggest a potential role of virus-induced glycolysis in tumorigenesis. Virus or virus-encoded proteins regulate glucose uptake and lactate export, increase the activity of glycolytic enzymes, and modulate glucose metabolic signals. Accumulating evidence suggests that virus-induced glycolysis may facilitate cell growth, transformation, migration, and invasion, but its significance in tumorigenesis remains unclear. We summarize the effects of oncogenic viruses on the metabolic shift to aerobic glycolysis and discuss the possible association of this metabolic reprogramming with tumor development and progression. PMID- 30405841 TI - Preoperative Serum and Intra-platelet Serotonin in Prognosis: Useful or Useless? PMID- 30405842 TI - LncRNA GACAT1 Promotes Gastric Cancer Cell Growth, Invasion And Migration By Regulating MiR-149-mediated Of ZBTB2 And SP1. AB - Long non-coding RNAs (lncRNAs) were involved in the progression of gastric cancer (GC). In our study, we have determined that GACAT1 expression was upregulated in GC. Overexpression of GACAT1 promoted GC cell proliferation, invasion and migration. We also determined that miR-149 directly interacts with the target site on GACAT1. Furthermore, we investigated that miR-149 downregulated ZBTB2 and SP1 expressions which were induced by GACAT1, miR-149 inhibited GC cell growth and invasion mediated by GACAT1. In conclusion, we found that miR-149 downregulated ZBTB2 and SP1 expressions, and inhibited GC cell progression mediated by GACAT1. Therefore, we indicated that GACAT1 and miR-149 may be potential therapeutic targets for GC. PMID- 30405843 TI - Nucleolar stress: is there a reverse version? AB - The nucleolus is a dynamic structure that has roles in various physiological and pathophysiological processes. Perturbations on many aspects of the nucleolar functions are thought to cause "nucleolar stress", which occurs in response to a variety of chemotherapeutic drugs. The main characteristic changes of nucleolar stress include: 1) reduction of the size and volume of the nucleolus; 2) inhibition of RNA Pol I-mediated rRNA synthesis; and 3) nucleoplasmic translocation of nucleolar stress-related proteins. In studying the apoptosis inducing effect of the natural compound lovastatin (LV) on breast cancer stem cells, we unexpectedly uncovered a novel form of nucleolar stress, which we call "reverse nucleolar stress". In our system, the canonical nucleolus stress inducer doxorubicin caused nucleoplasmic translocation of the nucleolar protein NPM and complete abolishment of Nolc1, an NPM-interacting protein and an activator of rRNA transcription. In contrast, the reverse nucleolar stress induced by LV is manifested as a more localized perinucleolar distribution of NPM and an increase in the protein level of Nolc1. Furthermore, translocation of the ribosomal protein RPL3 from the cytoplasm to the nucleolus and increased AgNOR staining were observed. These changes characterize a novel pattern of nucleolar stress doubtlessly distinguishable from the canonical one. The functional consequences of reverse nucleolar stress are not clear at present but may presumably be related to cell death or even normalization of the stressed cell. The discovery of reverse nucleolar stress opens up a new area of research in molecular and cellular biology and might have important implications in cancer therapy. PMID- 30405844 TI - Breast cancer stem cell markers CD44 and ALDH1A1 in serum: distribution and prognostic value in patients with primary breast cancer. AB - Background: CD44 and ALDH1 have been recognized as the most widely used markers to identify breast cancer stem cells (BCSCs). However, limited to tissue sample and rare population, BCSCs have always been not easily detected. We aimed to measure CD44 and ALDH1A1 (major contributor to ALDH1 activity) levels in serum and explore the prognostic value in primary breast cancer patients. Methods: This study included 140 primary breast cancer patients with stage I-III. Serum samples were collected before surgery and stored at -80 degrees. CD44 and ALDH1A1 were measured by chemiluminescent assay. Results: High serum CD44 levels (>= 417.4 ng/mL) were correlated with postmenopausal status (P = 0.006), estrogen receptor negativity (P = 0.025), progesterone receptor negativity (P = 0.002) and adjuvant chemotherapy (P = 0.003). The mean serum CD44 levels of luminal group (406.4 +/- 68.3 ng/mL) were significantly lower than triple negative group (506.8 +/- 175.5 ng/mL) (P < 0.001). There was no correlation between serum ALDH1A1 levels and molecular subtypes. Multivariate analysis revealed that high serum CD44 level (>= 417.4 ng/mL), was an independent factor for PFS (P = 0.019) and OS (P = 0.008). However, serum ALDH1A1 has no impact on either PFS (P = 0.613) or OS (P = 0.441). Conclusion: Serum CD44 was an independent prognostic indicator in primary breast cancer. However, serum ALDH1A1 has no impact on survivals and might not be an appropriate candidate to predict prognosis for breast cancer. PMID- 30405845 TI - Activated Tumor-infiltrating Fibroblasts Predict Worse Prognosis in Breast Cancer Patients. AB - Purpose: Activated tumor-infiltrating fibroblasts were significantly associated with survival of cancer patients. However, they are heterogeneous population, and the prognostic role of these cells in human breast cancer still remains controversial. Herein, we performed the meta-analysis to better understand the role of these cells in prognosis prediction for breast cancer patients. Methods: We searched PubMed and EBSCO to identify the studies evaluating the association of intratumoral activated fibroblast density detected by immunohistochemical (IHC) method and overall survival (OS) and/or disease-free survival (DFS) in breast cancer patients, then computed extracted data into hazard ratios (HRs) for OS, DFS and clinicopathological features such as lymph node metastasis, TNM stage with STATA 12.0. Results: A total of 3680 patients with breast cancer from 15 published studies were incorporated into this meta-analysis. We found that the infiltration of activated fibroblasts significantly decreased overall survival (OS) and disease-free survival (DFS) in patients. In stratified analyses, high density of FSP-1+ or podoplanin+ fibroblasts was significantly associated with worse OS; while alpha-SMA+ or podoplanin+ fibroblast infiltration was associated with worse DFS in breast cancer. In addition, elevated number of activated tumor infiltrating fibroblasts significantly correlated with lymph node metastasis and poor tumor differentiation of patients. Conclusion: The infiltration of activated fibroblasts, especially the FSP-1+ or podoplanin+ fibroblasts leads to worse clinical outcome in breast cancer patients, implicating that it is a valuable prognostic biomarker and targeting it may have a potential for effective treatment. PMID- 30405847 TI - Human papillomavirus 16 E7 oncoprotein alters the expression profiles of circular RNAs in Caski cells. AB - Cervical cancer is one of the most common cancer in female worldwide. The expression of high-risk human papillomavirus E7 oncogene is necessary for the maintenance of malignant phenotypes and transformation. Accumulating studies of this protein has been explored in cervical cancer, however, there are fewer studies on how E7 expression affects the expression of global circular RNA. CircRNA, a promising biomarker and even therapeutic target, has become a star molecular in research after miRNA and long non-coding RNA. Our aim of this study was to investigate the global circRNA levels modulated by HPV E7 expression and identified the potential consequences for mechanism studies. Here we investigated the expression profiles of circRNAs by transfecting E7 siRNA in Caski cells with high-throughput microarray technology. In total, we identified 526 dysregulated circRNAs with fold change >=2 or<=0.5, and p< 0.05. Among them, 352 were up regulated and 174 were down-regulated. In addition, 8 selected circRNAs confirmed using qRT-PCR was in line with the results of microarray analysis. Furthermore, bioinformatic analyses indicated that differently expressed circRNAs might implicate in the mTOR signaling pathway, proline metabolism and glutathione metabolism. In conclusion, this study showed the expression profiles of circRNAs regulated by HPV16 E7 in cervical cancer cells and provides novel insights into the new potential candidates for future mechanism studies. PMID- 30405846 TI - Paired box 2 promotes progression of endometrial cancer via regulating cell cycle pathway. AB - Background: Human paired box 2 (PAX2) plays a key role in cell fate, early patterning and organogenesis. Methods: We investigated the function of PAX2 on the biological behavior of endometrial cancer in vitro and in vivo and to explore the regulation mechanism, stable knocking-down and over-expression PAX2 endometrial cancer cell lines were established. CCK-8 and transwell assays were applied to determine proliferation, invasion and migration ability. Cell cycle distribution was analyzed by flow cytometry. Affymetrix GeneChip(r) human Exon 1.0 ST arrays was used to screen the downstream target genes of PAX2. Results: PAX2 significantly enhanced proliferation and invasiveness. In addition, PAX2 influenced the expression of cyclin-dependent kinase 1(CDK1), which play pivotal roles in cell cycle pathway. When CDK1 was knocked down, and the cell proliferation promotion role of PAX2 was attenuated dramatically to a level comparable with the control groups. Conclusions: PAX2, though influencing the expression of CDK1, promotes the proliferation, enhances the mobility of endometrial cancer cells, thus exerts an important role in the carcinogenesis of endometrial cancer. PAX2 may be a potential therapeutic target for endometrial cancer. PMID- 30405849 TI - miR-29b negatively regulates MMP2 to impact gastric cancer development by suppress gastric cancer cell migration and tumor growth. AB - MicroRNAs (miRNAs) are important regulators and associated with the development of many different types of cancer, including gastric cancer. However, their pathophysiologic role and their relevance to tumorigenesis, invasion and metastasis are still unknown. In our current study, we performed microRNA array and found that 28 of miRNAs were differentially expressed in INF type of gastric cancer. Among 28 miRNAs, miR-29b was one of the most significantly down-regulated miRNA. Further bioinformatics analysis showed that MMP2 was a potential target of miR-29b. Interestingly, luciferase analysis showed that miR-29b negatively regulates MMP2 by binding with the miRNA response element (MRE) on the 3'UTR of MMP2. In addition, overexpression of miR-29b significantly decreased the mRNA and protein level of MMP2 and the activity of MMP2 to suppress gastric cancer cell migration. Moreover, lentivirus mediated overexpression of miR-29b dramatically suppressed the ability of BGC823 cells to form colonies in vitro and their ability to develop tumor in vivo in nude mice. Finally, our qPCR and western blot analysis showed that miR-29b was significantly reduced in clinical gastric cancer tissue, whereas MMP2 protein was significantly up-regulated, suggesting that this aberrant down-regulation of miR-29b might be associated with the abnormal regulation of MMP2 and the development of gastric cancer. Significant apparent was also found between miR-29b expression and TNM staging, lymph node status, tumor differentiation and Ming classification. Together, our data suggest an important regulatory role of miR-29b in the development of gastric cancer. Thus, miR-29b and MMP2 might be important diagnostic or therapeutic targets for human tumor diseases. PMID- 30405848 TI - MicroRNA-34 family in breast cancer: from research to therapeutic potential. AB - MicroRNA (miRNA)-34 family (miR-34s), including miR-34a/b/c, is the most well studied non-coding RNAs that regulate gene expression post-transcriptionally. The miR-34s mediates the tumor suppressor function of p53 in the pathogenesis of breast cancer by targeting different oncogenes. This review focuses on the anti oncogenic regulation of the miR-34s, emphasizing the major signaling pathways that are involved in the modulation of miR-34s in breast cancer. Moreover, it highlights how epigenetic modification by the p53/miR-34s axis regulates the proliferation, invasiveness, chemoresistance, and sternness of breast cancer. A better understanding of the molecular mechanisms of miR-34s will open new opportunities for the development of novel therapeutic strategies and define a new approach in identifying potential biomarkers for early diagnosis of breast cancer. PMID- 30405850 TI - EZH2 Expression is increased in BAP1-mutant renal clear cell carcinoma and is related to poor prognosis. AB - Aim: BAP1 is frequently mutated in clear cell renal cell carcinoma (ccRCC) with a definitive role still unclear. Methods: In silico analysis of BAP1-mutant and wild-type gene enrichment and functional annotation in TCGA-KIRC dataset was performed. Target gene was studied based on functional clustering and was knowledge-based. Validation using in-house pathological sections were performed immunohistochemically. In vitro and in vivo studies on target gene were performed. Results: The TCGA ccRCC dataset included 534 ccRCC samples. BAP1 was frequently mutated and more frequently downregulated in ccRCC compared to normal kidney tissue or benign renal tumors. In the analysis between samples with BAP1 mutation (N = 33) and pan-negative (N = 33), we found that cancers with BAP1 mutation was significantly enriched for 14 pathways, of which 3 were DNA repair pathways, in which EZH2 played a role. CcRCC patients with lower BAP1 expression had poor prognosis and showed higher EZH2 expression, which also conferred worsened survival. Genetic and pharmaceutical inhibition of EZH2 not only inhibited BAP1-mutatn ccRCC cell viability and invasion but also abrogated genetic replenishing of BAP1 expression. Validation cohort encompassing 62 ccRCC samples confirmed the worsened phenotype for cases with higher EZH2 expression and significant positive correlation between expressions of EZH2 and BAP1. EZH2 inhibitor also inhibited tumor growth in xenograft mouse model with BAP1-mutated ccRCC cells with unremarkable toxicity. Conclusion: CcRCC with decreased BAP1 level has poor prognosis and is associated with higher EZH2 expression. Inhibition of EZH2 in BAP1-mutated entity holds promise for further investigation. PMID- 30405851 TI - Research progress on the impact of radiation on TKI resistance mechanisms in NSCLC. AB - Resistance to tyrosine kinase inhibitor (TKI) therapy is often accompanied by various genetic alterations, and radiation is an important weapon for changing the DNA of tumor cells. In radiotherapy combined with TKI therapy for non-small cell lung cancer (NSCLC), the two treatment strategies affect and interact with each other, resulting in complex tumor resistance mechanisms. Accordingly, tumor progression management after radiotherapy combined with TKI therapy should be different from that after TKI therapy alone. However, current clinical practice is entirely based on the resistance mechanisms of simple TKI therapy. Therefore, it is imperative to investigate the impact of radiation on the mechanism of TKI resistance. However, due to the complexity of the resistance mechanisms under the combined effect of both therapies, such studies remain extremely challenging and time-consuming. PMID- 30405852 TI - Oestrogen Inhibits VEGF Expression And Angiogenesis In Triple-Negative Breast Cancer By Activating GPER-1. AB - Triple-negative breast cancer (TNBC) is the most malignant type of breast cancer with ample vascularisation and high vascular endothelial growth factor (VEGF) expression. The sex steroid hormone oestrogen is involved in several cellular activities associated with TNBC regulation. However, the role of oestrogen in VEGF expression and angiogenesis in TNBC remains unclear. In this study, we found that treatment with 17beta-oestradiol (E2) inhibited VEGF mRNA and protein expression in the TNBC cell lines MDA-MB-468 and MDA-MB-436. To further elaborate on the phenomenon of E2-regulated angiogenesis, we showed that conditioned medium from the TNBC cell line MDA-MB-468 treated with E2 inhibits the tube formation ability of human umbilical vein endothelial cells (HUVECs). Additionally, the G protein-coupled oestrogen receptor-1 (GPER-1)-specific agonist G-1 has a function similar to that of E2. While G-15, the selective antagonist of GPER-1, notably reversed the inhibitory effects of E2 and G-1 on VEGF expression and tube formation, suggesting that GPER-1 is involved in the E2-induced angiogenesis suppression in TNBC cells. Moreover, E2 inhibited in vivo tumour growth and angiogenesis and reduced the expression levels of VEGF, NF-kappaB/p65, STAT3, and the endothelial marker CD34 in MDA-MB-468 xenograft tumours. Our findings provide important evidence that E2 can inhibit VEGF expression and angiogenesis in TNBC by activating GPER-1, offering additional insight into tumour angiogenesis and targets for drug intervention in TNBC. PMID- 30405853 TI - Multiplex Cell-Free DNA Reference Materials for Quality Control of Next Generation Sequencing-Based In Vitro Diagnostic Tests of Colorectal Cancer Tolerance. AB - Background: Liquid biopsies based on next-generation sequencing (NGS) assays are confronted with more opportunities and challenges. Widespread clinical implementation of NGS-based cancer in vitro diagnostic tests (IVDs) highlighted the urgency to establish reference materials (RMs) which could provide full control of the process from nucleic acid extraction to test report generation. Quality control based on cell-free DNA (cfDNA) RMs is especially important for liquid biopsies. Methods: Here, we used genomic DNA from thirteen cell lines to establish four negative cfDNA RMs (N1-N4) and four multiplex cfDNA RMs (L1-L4) at serial allelic frequencies ranging from approximately 2% to 0.1%. All the cfDNA RMs were quantified and validated via both droplet digital polymerase chain reaction (ddPCR) and NGS. These RMs were distributed to eight domestic manufacturers to collaboratively evaluate the performance of several domestic NGS based cancer IVDs covering four major NGS platforms (NextSeq, HiSeq, Ion Proton, and BGISEQ). Results: Each multiplex RM has eleven colorectal cancer-related mutations, including six KRAS mutations (G12S, G12C, G12D, G12A, G12V, and G13D), three NRAS mutations (G12D, Q61R, and Q61K), one PIK3CA mutation (H1047R), and one BRAF mutation (V600E). Each mutation in the cfDNA RMs was quantified and validated via both ddPCR and NGS, showing the good relevance of mutant allelic frequency. These RMs were distributed to eight domestic manufacturers for collaborative evaluation. All eight manufacturers provided similar results by domestic NGS-based cancer IVDs, except for manufacturer #5. The coefficient of variation (CV) was increased with decreasing mutant allelic frequency, and poor repetition occurred when the allelic frequency was lower than 0.5%. Conclusions: These results indicated that these cfDNA RMs would be pivotal for NGS-based cancer IVDs, especially for liquid biopsies of colorectal cancer-related mutations and would guide the further development of RMs covering more onco related mutations. PMID- 30405854 TI - Association between a Single Nucleotide Polymorphism in the 3'-UTR of ARHGEF18 and the Risk of Nonidiopathic Pulmonary Arterial Hypertension in Chinese Population. AB - ARHGEF18 has been identified as upregulated in the lung tissues of rat models of pulmonary artery hypertension introduced by hypoxia or monocrotaline (MCT). We used online SNP function prediction tools to screen the candidate SNPs that might be associated with the regulation of the ARHGEF18 expression. The result suggested that rs3745357 located in the 3'-untranslated region of ARHGEF18 is probably a genetic modifier in the process. In the present study, we aimed to investigate the association between ARHGEF18 rs3745357 polymorphism and nonidiopathic pulmonary arterial hypertension susceptibility (niPAH). A total of 293 participants were included in the case-control study (117 patients and 176 healthy controls). The rs3745357 variant was discriminated by using cleaved amplification polymorphism (CAP) sequence-tagged site technology. Although the overall allele and genotype frequencies of rs3745357 in niPAH patients were close to those of the control group, significant differences have been identified when we further divided the niPAH patients into subgroups with or without coronary heart disease (CHD). Rs3745357 C allele frequency was significantly higher in niPAH patients without CHD history (p = 0.001), while the frequency was significantly lower in niPAH patients with CHD history (p = 0.017) when compared to control subjects. The distribution of genotype frequencies was also quite different. After adjustment by gender and age, significant differences were found between patients with CHD history and controls. The results suggest that the ARHGEF18 rs3745357 variant may be used as a marker for the genetic susceptibility to niPAH. PMID- 30405855 TI - Adipsin, MIP-1b, and IL-8 as CSF Biomarker Panels for ALS Diagnosis. AB - Amyotrophic lateral sclerosis (ALS) is an aggressive neurodegenerative disorder that selectively attacks motor neurons in the brain and spinal cord. Despite important advances in the knowledge of the etiology and progression of the disease, there are still no solid grounds in which a clinician could make an early objective and reliable diagnosis from which patients could benefit. Diagnosis is difficult and basically made by clinical rating scales (ALSRs and El Escorial). The possible finding of biomarkers to aid in the early diagnosis and rate of disease progression could serve for future innovative therapeutic approaches. Recently, it has been suggested that ALS has an important immune component that could represent either the cause or the consequence of the disease. In this report, we analyzed 19 different cytokines and growth factors in the cerebrospinal fluid of 77 ALS patients and 13 controls by decision tree and PanelomiX program. Results showed an increase of Adipsin, MIP-1b, and IL-6, associated with a decrease of IL-8 thresholds, related with ALS patients. This biomarker panel analysis could represent an important aid for diagnosis of ALS alongside the clinical and neurophysiological criteria. PMID- 30405856 TI - Identification of Core Biomarkers Associated with Outcome in Glioma: Evidence from Bioinformatics Analysis. AB - Glioma is the most common neoplasm of the central nervous system (CNS); the progression and outcomes of which are affected by a complicated network of genes and pathways. We chose a gene expression profile of GSE66354 from GEO database to search core biomarkers during the occurrence and development of glioma. A total of 149 samples, involving 136 glioma and 13 normal brain tissues, were enrolled in this article. 1980 differentially expressed genes (DEGs) including 697 upregulated genes and 1283 downregulated genes between glioma patients and healthy individuals were selected using GeoDiver and GEO2R tool. Then, gene ontology (GO) analysis as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were carried out using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Moreover, Cytoscape with Search Tool for the Retrieval of Interacting Genes (STRING) and Molecular Complex Detection (MCODE) plug-in was employed to imagine protein-protein interaction (PPI) of these DEGs. The upregulated genes were enriched in cell cycle, ECM receptor interaction, and p53 signaling pathway, while the downregulated genes were enriched in retrograde endocannabinoid signaling, glutamatergic synapse, morphine addiction, GABAergic synapse, and calcium signaling pathway. Subsequently, 4 typical modules were discovered by the PPI network utilizing MCODE software. Besides, 15 hub genes were chosen according to the degree of connectivity, including TP53, CDK1, CCNB1, and CCNB2, the Kaplan-Meier analysis of which was further identified. In conclusion, this bioinformatics analysis indicated that DEGs and core genes, such as TP53, might influence the development of glioma, especially in tumor proliferation, which were expected to be promising biomarkers for diagnosis and treatment of glioma. PMID- 30405858 TI - Amino Acid-Based Metabolic Panel Provides Robust Prognostic Value Additive to B Natriuretic Peptide and Traditional Risk Factors in Heart Failure. AB - Metabolic disturbances represent functional perturbation in peripheral tissues and predict outcomes in patients with heart failure (HF). This study developed an amino acid-based metabolic panel and sought to see whether this panel could add diagnostic and prognostic value to currently used B-type natriuretic peptide (BNP) measurements. Mass spectrometry and ultra-performance liquid chromatography were performed on 1288 participants, including 129 normal controls and 712 patients at HF stages A to D in the initial cohort and 447 stage C patients in the validation cohort. Patients were followed up for composite events (death/HF related rehospitalization). Histidine, ornithine, and phenylalanine were 3 metabolites found strongly significant to identify patients at stage C and were adopted to develop the HOP panel. Compared to BNP, HOP had better value in discriminating the patients at different stages, especially in elderly patients and those with atrial fibrillation, high body mass index, or kidney dysfunction. HOP was correlated with the distance of 6 min walking distance better than BNP. For prognosis, HOP predicted composite events in patients at stages C and D, independent of log (BNP), age, sex, left ventricular ejection fraction, New York Heart Association functional class, HF stage, diabetes mellitus, chronic kidney disease, hypertension, hemoglobin, and albumin. Higher BNP (>=750 pg/mL) along with higher HOP (>=14) robustly predicted lower event-free survival compared to all others [hazard ratio = 3.15 (2.23-4.46), p < 0.001]. The prognostic value of HOP was confirmed in the validation cohort. In conclusion, aiming for clinical applications, this study proved that the HOP panel provides diagnostic and prognostic value additive to BNP and traditional risk factors. PMID- 30405857 TI - Usefulness of the Adipokines as Biomarkers of Ischemic Cardiac Dysfunction. AB - Cardiovascular disease is the leading cause of death among both women and men, but there is still a great percentage of misdiagnosis and lack of clearly defined criteria. Advances in biomolecular science have proven the crucial role of inflammation and, more importantly, the role of adipokines in mediating all stages of coronary artery disease. It has also been suggested that regional fat deposits, more precisely from thoracic region, have a major influence on the development of coronary artery disease by creating a local proatherogenic environment. The immune system closely interacts with metabolic risk factors to initiate, promote, and further aggravate the atherosclerotic lesions on the arterial wall all with the "help" of adipokines. So nowadays, research extensively focuses on uncovering biomarkers that would provide an increased chance of detecting subclinical cardiac distress and also add a consistent value to current guideline-imposed risk criteria. PMID- 30405859 TI - A Noninvasive Score to Predict Liver Fibrosis in HBeAg-Positive Hepatitis B Patients with Normal or Minimally Elevated Alanine Aminotransferase Levels. AB - Noninvasive fibrosis tests are highly needed but have not been well studied in chronic hepatitis B patients with normal or minimally elevated alanine aminotransferase (ALT) levels. This study is aimed at developing a noninvasive score system to predict liver fibrosis in these patients. HBeAg-positive chronic hepatitis B patients with ALT levels of <80 IU/l and liver histology (n = 290) were assigned to training (n = 203) or validation (n = 87) groups. Training group patients were divided into nonsignificant (F0-1) and significant fibrosis (F2-4) according to METAVIR stages. Logistic regression was performed to identify factors for liver fibrosis and develop a score system. The capacity of the score to identify the severity of fibrosis was displayed by receiver operating characteristic curve (ROC) and area under ROC (AUROC) values. Multivariate logistic regression showed that HBeAg (ratios of the sample to the cutoff values (S/CO)) and liver stiffness measurement (LSM; kilopascals (kPa)) were independent factors of liver fibrosis. A score system composed of HBeAg and LSM by assigning a point of 1, 2, or 3 to different HBeAg and LSM levels, respectively, was developed. The scores 2-3, 4, and 5-6 of the sum of HBeAg and LSM points indicated nonsignificant, indeterminate, and significant fibrosis, respectively. The score system had an AUROC of 0.880 and showed similar performance in validation group patients. The accuracy for identifying significant and nonsignificant fibrosis was 77.14% in validation group patients and 71.26% in the entire group of patients. It is suggested that this noninvasive score system can accurately predict hepatic fibrosis and may reduce the need for liver biopsy in HBeAg-positive patients with normal or minimally elevated ALT levels. PMID- 30405861 TI - Preconditioning Contractions Suppress Muscle Pain Markers after Damaging Eccentric Contractions. AB - Inexperienced vigorous exercise, including eccentric contraction (ECC), causes muscle pain and damage. Similar prior light exercise suppresses the development of muscle pain (repeated-bout effect), but the molecular mechanisms behind this are not sufficiently understood. In this study, the influence of a nondamaging preconditioning ECC load (Precon) on muscle pain-related molecules and satellite cell-activating factors was investigated at the mRNA expression level. Nine-week old male Wistar rats (n=36) were divided into 2 groups: a group receiving only a damaging ECC (100 contractions) load (non-Precon) and a group receiving a nondamaging ECC (10 contractions) load 2 days before receiving the damaging ECC load (Precon). ECC was loaded on the left leg, and the right leg was regarded as the intact control (CTL). The medial head of the gastrocnemius muscle from all rats was excised 2 or 4 days after the damaging ECC loading, and the relative mRNA expression levels of muscle pain- and satellite cell-related molecules were quantitated using real-time RT PCR. Precon suppressed increases in MHC-embryonic and MHC-neonatal mRNA expressions. Enhancement of HGF, Pax7, MyoD, and myogenin mRNA expression was also suppressed, suggesting that Precon decreased the degree of muscle damage and no muscle regeneration or satellite cell activation occurred. Similarly, increases in mRNA expression of muscle pain-related molecules (BKB2 receptor, COX-2, and mPGEC-1) were also suppressed. This study clearly demonstrated that at the mRNA level, prior light ECC suppressed muscle damage induced by later damaging ECC and promoted recovery from muscle pain. PMID- 30405863 TI - Remote arterial vasculitis as a possible complication of Phosphorus-32 Radiosynovectomy. AB - Patients with hemophilia suffer from repeated episodes of hemarthrosis leading to chronic inflammation and synovitis. Radiosynovectomy is an effective nonsurgical modality that can reduce inflammation, pain, and hemarthrosis in such cases. We describe an adolescent male with severe Hemophilia A, who developed arterial vasculitis and perivasculitis targeting the brachiocephalic, right common carotid, and right subclabvian arteries occurring within few days after difficult Phosphorus-32 radiosynovectomy, possibly as a complication of the procedure. Despite prophylaxis with recombinant FVIII therapy, he developed chronic synovitis and underwent radionuclide synovectomy with P-32 injection to the left ankle and right knee. Five days later, he developed pain in the lower right neck and right upper chest. Computed tomography and magnetic resonance imaging and angiography demonstrated inflammation involving the arteries of the right thoracic inlet. Geiger-Mueller meter indicated increased radioactivity not only in the left ankle and right knee but also in the right upper chest. Detection of radioisotope at the right thoracic inlet corresponding to the area of vasculitis was indicative of likely deposition of the P-32 isotope in an area exposed to maximum cardiac output and increased blood flow, leading to subclavian, carotid, and innominate arteritis with surrounding edema. PMID- 30405862 TI - 18F-PET/CT imaging of metastasis to the thyroid gland: Imaging findings and effect on patient management. AB - Purpose: While metastasis to the thyroid from a primary cancer remote to the thyroid is uncommon, current imaging techniques have improved detection of these intrathyroid metastases. The purpose of this study was to evaluate the 18F-PET/CT appearance of intrathyroid metastases and assess the impact of detection on patient management. Methods: The 18F-PET/CT appearance of intrathyroid metastasis, including standardized uptake value (SUV), disease extent, and the effect on patient management following diagnosis were retrospectively reviewed. Inclusion criteria included 18F-PET/CT imaging and diagnosis of the intrathyroid metastasis matching the remote primary tumor. Results: Intrathyroid metastasis were detected in 24 patients. The intrathyroid metastases presented on 18F-PET/CT as focal nodular uptake (n = 21), multiple nodular uptake (n = 2), or diffuse uptake/infiltration of the thyroid gland (n = 1). The SUV ranged between 3.9 and 42 (median 12.5 +/- 7.5); in 2 patients, the FDG-avidity was minimal. On 18F PET/CT, distant metastases were present outside the neck (n = 18), or limited to the neck (n = 6). In 2 of these 6 patients, the thyroid was the only site of metastatic disease. Due to the metastatic disease, the therapy was changed in 23 of 24 patients; 1 patient was lost to follow-up. Conclusion: In any patient with a previous or current history of an extrathyroid malignancy, an 18FDG-avid thyroid mass or diffuse infiltration of the thyroid on 18F-PET/CT should be considered a potential intrathyoid metastasis until proven otherwise. Knowledge of an intrathyroid metastasis may impact patient management, especially if the thyroid or neck are the only sites of metastatic disease. PMID- 30405860 TI - Systematic Review on Resting-State EEG for Alzheimer's Disease Diagnosis and Progression Assessment. AB - Alzheimer's disease (AD) is a neurodegenerative disorder that accounts for nearly 70% of the more than 46 million dementia cases estimated worldwide. Although there is no cure for AD, early diagnosis and an accurate characterization of the disease progression can improve the quality of life of AD patients and their caregivers. Currently, AD diagnosis is carried out using standardized mental status examinations, which are commonly assisted by expensive neuroimaging scans and invasive laboratory tests, thus rendering the diagnosis time consuming and costly. Notwithstanding, over the last decade, electroencephalography (EEG) has emerged as a noninvasive alternative technique for the study of AD, competing with more expensive neuroimaging tools, such as MRI and PET. This paper reports on the results of a systematic review on the utilization of resting-state EEG signals for AD diagnosis and progression assessment. Recent journal articles obtained from four major bibliographic databases were analyzed. A total of 112 journal articles published from January 2010 to February 2018 were meticulously reviewed, and relevant aspects of these papers were compared across articles to provide a general overview of the research on this noninvasive AD diagnosis technique. Finally, recommendations for future studies with resting-state EEG were presented to improve and facilitate the knowledge transfer among research groups. PMID- 30405865 TI - CT-guided navigated microwave ablation (MWA) of an unfavorable located breast cancer metastasis in liver segment I. AB - For percutaneous minimally-invasive local ablation therapies of malignant lesions within the liver computed tomography (CT) fluoroscopy or ultrasound (US) can be applied for the positioning of ablation probes. However, lesions in liver segment I and in the upper part of liver segment VIII are difficult to reach with CT fluoroscopy and US guidance even for experienced interventionalists as steep and transcostal access paths may be needed. In addition, there is always the risk to lacerate crucial vessels near the liver hilus. We report on the use of a CT-based stereotactic navigation system (CAS-One, CAScination AG, Bern, Switzerland) for the precise positioning of the ablation probe to perform a percutaneous stereotactic image-guided microwave ablation of a breast cancer liver metastasis in liver segment I that was unreachable with conventional CT or US guidance. Based on the initial planning scan and image-to-patient registration a precise positioning of the probe was possible sparing vital structures like the directly adjacent vulnerable vessels. The ablation was performed without complications fully covering the metastatic lesion with the ablation zone. To this day, there was no recurring tumor 18 months after the intervention. PMID- 30405864 TI - Eagle's syndrome: a case report and CT pictorial review. AB - Eagle's syndrome (ES) refers to symptomatic elongation of the ossified styloid process. A styloid process greater than 2.5 cm in length should be considered abnormal; however, an elongated styloid process is not sufficient for a diagnosis of ES; only an abnormal styloid process in association with symptoms can confirm the syndrome. In this case report, we discuss a 54-year-old man who has come to our attention with various symptoms: dysphagia to both solids and liquids, difficulty swallowing, neck pain, and a foreign body sensation during bilateral neck rotation and mouth opening. The diagnosis is performed radiologically because conventional radiographs have many potential disadvantages, whereas, computed tomography (CT) scans and reconstructions allow the length and angulation of the styloid process to be measured and the relationship between the elongated styloid processes and adjacent anatomical structures to be evaluated. Moreover, CT allows for differential diagnosis and provides detailed information needed for surgical planning. PMID- 30405866 TI - Post-traumatic superior mesenteric venous thrombosis with subsequent extension to the portal vein. AB - Acute superior mesenteric vein thrombosis was first described in 1935 by Warren and Eberhardt. It is a potentially life-threatening condition, as it can lead to bowel ischemia and, ultimately, infarction. Its etiology may be primary or secondary to acquired prothrombotic conditions. Early recognition of mesenteric venous thrombosis is important, but can be challenging due to its nonspecific clinical presentation. Contrast-enhanced computed tomography is currently the gold standard for diagnosis. Systemic anticoagulation and surgical resection of the necrotic segment are the two main treatments. Here, we describe a case of acute post-traumatic superior mesenteric vein thrombosis, which was treated with systemic anticoagulation and resection of the ischemic bowel segment, with subsequent extension of the thrombosis to the portal vein. PMID- 30405867 TI - Hypoplasia of right renal vein with aberrant drainage into ipsilateral spermatic vein: Case report. AB - The objective of this study was to describe a case of marked hypoplasia of the right renal vein with drainage into ipsilateral gonadal vein. A 66-year-old man, known for hypertension and previous smoking, underwent an abdominal ultrasound exam, which detected a juxtarenal aortic aneurysm. Computed tomography scan confirmed the presence of the aortic aneurysm; furthermore it showed an abnormal right kidney venous drainage consistent in a dilated and tortuous vein, which originated at the hilar region, heading caudally and joining the right spermatic vein at level of aortic carrefour. A thin vein-located more cranially with mild and late contrast enhancement-was also demonstrated from right kidney hilum to inferior vena cava, probably representing a remnant of the right main renal vein. To our knowledge, this anatomic variant was never reported in the peer-reviewed literature. PMID- 30405869 TI - Atomic Layer Deposition of Zinc Oxide: Study on the Water Pulse Reactions from First-Principles. AB - Atomic layer deposition (ALD) of zinc oxide thin films has been under intense research in the past few years. The most common precursors used in this process are diethyl zinc (DEZ) and water. The surface chemistry related to the growth of a zinc oxide thin film via atomic layer deposition is not entirely clear, and the ideal model of the process has been contradicted by experimental data, e.g., the incomplete elimination of the ethyl ligands from the surface and the non-negative mass change during the water pulse. In this work we investigate the surface reactions of water during the atomic layer deposition of zinc oxide. The adsorption and ligand-exchange reactions of water are studied on ethyl-saturated surface structures to grasp the relevant surface chemistry contributing to the deposition process. The complex ethyl-saturated surface structures are adopted from a previous publication on the DEZ/H2O-process, and different configurations are sampled using ab initio molecular dynamics in order to find a suitable minimum structure. Water molecules are found to adsorb exothermically onto the ethyl-covered surface at all the ethyl concentrations considered. We do not observe an adsorption barrier for water at 0 K; however, the adsorption energy for any additional water molecules decreases rapidly at high ethyl concentrations. Ligand-exchange reactions are studied at various surface ethyl coverages. The water pulse ligand-exchange reactions have overall larger activation energies than surface reactions for diethyl zinc pulse. For some of the configurations considered, the reaction barriers may be inaccessible at the process conditions, suggesting that some ligands may be inert toward ligand exchange with water. The activation energies for the surface reactions show only a weak dependence on the surface ethyl concentration. The sensitivity of the adsorption of water at high ethyl coverages suggests that at high ligand coverages the kinetics may be somewhat hindered due to steric effects. Calculations on the ethyl-covered surfaces are compared to a simple model containing a single monoethyl zinc group. The calculated activation energy for this model is in line with calculations done on the complex model, but the adsorption of water is poorly described. The weak adsorption bond onto a single monoethyl zinc is probably due to a cooperative effect between the surface zinc atoms. A cooperative effect between water molecules is also observed; however, the effect on the activation energies is not as significant as has been reported for other ALD processes. PMID- 30405868 TI - Shape-based separation of micro-/nanoparticles in liquid phases. AB - The production of particles with shape-specific properties is reliant upon the separation of micro-/nanoparticles of particular shapes from particle mixtures of similar volumes. However, compared to a large number of size-based particle separation methods, shape-based separation methods have not been adequately explored. We review various up-to-date approaches to shape-based separation of rigid micro-/nanoparticles in liquid phases including size exclusion chromatography, field flow fractionation, deterministic lateral displacement, inertial focusing, electrophoresis, magnetophoresis, self-assembly precipitation, and centrifugation. We discuss separation mechanisms by classifying them as either changes in surface interactions or extensions of size-based separation. The latter includes geometric restrictions and shape-dependent transport properties. PMID- 30405870 TI - Oxygen Evolution Reaction Kinetic Barriers on Nitrogen-Doped Carbon Nanotubes. AB - We investigate kinetic barriers for the oxygen evolution reaction (OER) on singly and doubly nitrogen-doped single-walled carbon nanotubes (NCNTs) using the climbing image nudged elastic band method with solvent effects represented by a 45-water-molecule droplet. The studied sites were chosen based on a previous study of the same systems utilizing a thermodynamic model which ignored both solvent effects and kinetic barriers. According to that model, the two studied sites, one on a singly nitrogen-doped CNT and the other on a doubly doped CNT, were approximately equally suitable for OER. For the four-step OER process, however, our reaction barrier calculations showed a clear difference in the rate determining *OOH formation step between the two systems, with barrier heights differing by more than 0.4 eV. Thus, the simple thermodynamic model may alone be insufficient for identifying optimal OER sites. Of the remaining three reaction steps, the two H2O forming ones were found to be barrierless in all cases. We also performed solvent-free barrier calculations on NCNTs and undoped CNTs. Substantial differences were observed in the energies of the intermediates when the solvent was present. In general, the observed low activation energy barriers for these reactions corroborate both experimental and theoretical findings of the utility of NCNTs for OER catalysis. PMID- 30405871 TI - A Method to Improve the Imaging Quality in Dual-Wavelength Digital Holographic Microscopy. AB - A digital hologram-optimizing method was proposed to improve the imaging quality of dual-wavelength digital holographic microscopy (DDHM) by reducing the phase noise level. In our previous work, phase noise reduction was achieved by dual wavelength digital image-plane holographic microscopy (DDIPHM). In the optimization method in this paper, the phase noise was further reduced by enhancing the real-image term and suppressing effects of the zero-order term in the frequency spectrum of a digital hologram. Practically, the carrier frequency of the real-image term has the correspondence with interference fringes in the hologram. Mathematically, the first order intrinsic mode function (IMF1) in bidimensional empirical mode decomposition (BEMD) has similar characteristics to the grayscale values of ideal interference fringes. Therefore, with the combination of DDIPHM and BEMD, by utilizing the characteristics of IMF1, the digital hologram was optimized with purified interference fringes, enhancing the real-image term simultaneously. Finally, the validity of the proposed method was verified by experimental results on a microstep. PMID- 30405872 TI - Development of an Artificial Finger-Like Knee Loading Device to Promote Bone Health. AB - This study presents the development of an innovative artificial finger-like device that provides position specific mechanical loads at the end of the long bone and induces mechanotransduction in bone. Bone cells such as osteoblasts are the mechanosensitive cells that regulate bone remodelling. When they receive gentle, periodic mechanical loads, new bone formation is promoted. The proposed device is an under-actuated multi-fingered artificial hand with 4 fingers, each having two phalanges. These fingers are connected by mechanical linkages and operated by a worm gearing mechanism. With the help of 3D printing technology, a prototype device was built mostly using plastic materials. The experimental validation results show that the device is capable of generating necessary forces at the desired frequencies, which are suitable for the stimulation of bone cells and the promotion of bone formation. It is recommended that the device be tested in a clinical study for confirming its safety and efficacy with patients. PMID- 30405873 TI - Role of Natural Antioxidants from Functional Foods in Neurodegenerative and Metabolic Disorders. PMID- 30405874 TI - Downregulated Expression of Solute Carrier Family 26 Member 6 in NRK-52E Cells Attenuates Oxalate-Induced Intracellular Oxidative Stress. AB - Solute carrier family 26 member 6 (Slc26a6), which is mainly expressed in the intestines and kidneys, is a multifunctional anion transporter that is crucial in the transport of oxalate anions. This study is aimed at investigating the effect of Slc26a6 expression on oxalate-induced cell oxidation and crystal formation. Lentivirus transfection was used to upregulate or downregulate Slc26a6 expression in NRK cells. Cell viability and apoptosis, reactive oxygen species (ROS) and malondialdehyde (MDA) generation, and superoxide dismutase (SOD) activity were measured. Crystal adhesion and the cell ultrastructure were observed using light and transmission electron microscopy (TEM). Three groups of rats, normal control, lentivirus-vector, and lentivirus-small interfering RNA (lv-siRNA) groups, were used, and after lentivirus transfection, they were fed 1% ethylene glycol (EG) and 0.5% ammonium chloride (NH4Cl) for 2 weeks. Dihydroethidium (DHE), terminal deoxynucleotidyl transferase (TdT) deoxyuridine dUTP nick-end labeling (TUNEL), and von Kossa staining were performed, and nuclear factor kappaB (NFkappaB) and osteopontin (OPN) expression were measured. In the vitro study, compared to the control group, downregulated Slc26a6 NRK cells showed alleviation of the cell viability decrease, cell apoptosis rate, ROS generation, and SOD activity decrease after oxalate treatment. Crystal adhesion and vesicles were significantly less after oxalate exposure than in the untreated controls. Rats infected with lentivirus-siRNA exhibited attenuated SOD generation, cell apoptosis, and crystal formation in the kidneys. Increased phosphorylation of NFkappaB and OPN was involved in the pathological process. In conclusion, the results of the present study indicate that reducing the expression of Slc26a6 in the kidney may be a potential strategy for preventing stone formation. PMID- 30405875 TI - Exercise-Induced Reductive Stress Is a Protective Mechanism against Oxidative Stress in Peripheral Blood Mononuclear Cells. AB - Eccentric exercise is a well-studied modality that induces oxidative stress and muscle damage. Furthermore, it promotes inflammatory response in which peripheral blood mononuclear cells (PBMCs) are the major mediators. Although free radicals are necessary in a specific range of concentrations, yet unknown, it remains unclear whether reductive redox status (i.e., increased antioxidant defenses and impaired free radical generation) is beneficial or not. Thus, the aim of the present investigation was to examine the effects of reductive stress and the impact of reduced glutathione (GSH) baseline values on the ability of PBMCs to counteract oxidative stress induced by a potent oxidative agent. PBMCs were isolated from the blood of subjects who performed eccentric exercise and treated with t-BOOH for 24 h. The subjects were clustered in the reductive and the oxidative group on the basis of increased or decreased GSH concentration postexercise compared to preexercise values, respectively. According to our results in PBMCs, lipid peroxidation levels as depicted by thiobarbituric acid reactive substances (TBARS) remained unchanged in the reductive group contrary to the observed enhancement in the oxidative group. In addition, GSH concentration and catalase activity increased in the reductive group, whereas they were not affected in the oxidative group. In conclusion, the effects of an oxidizing agent on the redox status of PBMCs isolated from the blood of athletes after acute eccentric exercise are dependent on the baseline values of GSH in erythrocytes. Otherwise, reductive stress defined by increased GSH levels is a protective mechanism, at least when followed by an oxidative stimulus. PMID- 30405876 TI - Vildagliptin Attenuates Hepatic Ischemia/Reperfusion Injury via the TLR4/NF kappaB Signaling Pathway. AB - The Toll-like receptor-4 (TLR4)/nuclear factor kappa B (NF-kappaB) signaling pathway is vital in the pathogenesis of hepatic ischemia/reperfusion (HIR) injury. Dipeptidyl peptidase-4 (DPP4) inhibitors exert protective effects on IR injury of the kidney, heart, and lung; however, their effect on the liver is still unknown. Thus, the purpose of this study was to examine whether pretreatment with vildagliptin (Vilda), a DPP4 inhibitor, produces hepatic protection against IR injury and to investigate its influence on TLR4/NF-kappaB signaling in a rat model. Thirty male Wistar rats were divided into 3 groups: the sham group: subjected to a sham operation and received normal saline; the HIR group: subjected to HIR and received normal saline; and the Vilda + HIR group: subjected to HIR with pretreatment of 10 mg/kg/day Vilda for 10 days intraperitoneally. Hepatic ischemia lasted for 45 minutes followed by 3-hour reperfusion; then blood and liver samples were collected for biochemical and histopathological examination. The HIR group produced a significant increase in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatic malondialdehyde (MDA), nitric oxide (NO), and tumor necrosis factor alpha (TNF alpha) levels and a significant reduction in the hepatic catalase level in comparison to the sham group. Moreover, a significant upregulation of gene and protein expressions of TLR4, NF-kappaB, and high-mobility group box-1 (HMGB1) along with caspase-3 protein expression was observed in the HIR group when compared with the sham group. Histopathological examination of the liver from the HIR group showed necrosis, sinusoidal congestion, hemorrhage, and hepatocyte degeneration. Administration of Vilda ameliorated the biochemical and histopathological changes caused by HIR. Vildagliptin showed for the first time a hepatoprotective effect in HIR injury through downregulation of TLR4/NF kappaB/HMGB1 and caspase-3 hepatic expressions. PMID- 30405877 TI - Modulation of Oxidative Status by Normoxia and Hypoxia on Cultures of Human Dermal Fibroblasts: How Does It Affect Cell Aging? AB - Reactive oxygen species (ROS) production in the skin is among the highest compared to other organs, and a clear correlation exists between ROS production and skin aging. Many attempts are underway to reduce oxidative stress in the skin by topical treatment or supplementation with antioxidants/cosmeceuticals, and cultures of human dermal fibroblasts (HDF) are widely used for these studies. Here, we examined the influence of oxygen tension on cell aging in HDF and how this impacted ROS production, the enzymatic and nonenzymatic antioxidant response system, and the efficacy of this defense system in limiting DNA damage and in modulating gene expression of proteins involved in the extracellular matrix, linked to skin aging. We investigated a selection of parameters that represent and reflect the behavior of cellular responses to aging and oxygen tension. Serial passaging of HDF under normoxia (21%) and hypoxia (5%) leads to cell aging as confirmed by beta-galactosidase activity, p16 expression, and proliferation rate. However, in HDF under 21% O2, markers of aging were significantly increased compared to those under 5% O2 at matched cell passages despite having lower levels of intracellular ROS and higher levels of CoQ10, total GSH, SOD1, SOD3, and mitochondrial superoxide anion. miRNA-181a, which is known to be upregulated in HDF senescence, was also analyzed, and indeed, its expression was significantly increased in old cells at 21% O2 compared to those at 5% O2. Upregulation of MMP1 and downregulation of COL1A1 along with increased DNA damage were also observed under 21% O2 vs 5% O2. The data highlight that chronic exposure to atmospheric 21% O2 is able to trigger hormetic adaptive responses in HDF that however fail, in the long term, to prevent cellular aging. This information could be useful in further investigating molecular mechanisms involved in adaptation of skin fibroblasts to oxidative stress and may provide useful hints in addressing antiaging strategies. PMID- 30405879 TI - Bevacizumab as a chemoprotectant: reducing oxaliplatin induced hepatic sinusoidal injury. PMID- 30405878 TI - Role of Oxidative Stress in the Pathology and Management of Human Tuberculosis. AB - Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis, is the leading cause of mortality worldwide due to a single infectious agent. The pathogen spreads primarily via aerosols and especially infects the alveolar macrophages in the lungs. The lung has evolved various biological mechanisms, including oxidative stress (OS) responses, to counteract TB infection. M. tuberculosis infection triggers the generation of reactive oxygen species by host phagocytic cells (primarily macrophages). The development of resistance to commonly prescribed antibiotics poses a challenge to treat TB; this commonly manifests as multidrug resistant tuberculosis (MDR-TB). OS and antioxidant defense mechanisms play key roles during TB infection and treatment. For instance, several established first-/second-line antitubercle antibiotics are administered in an inactive form and subsequently transformed into their active form by components of the OS responses of both host (nitric oxide, S-oxidation) and pathogen (catalase/peroxidase enzyme, EthA). Additionally, M. tuberculosis has developed mechanisms to survive high OS burden in the host, including the increased bacterial NADH/NAD+ ratio and enhanced intracellular survival (Eis) protein, peroxiredoxin, superoxide dismutases, and catalases. Here, we review the interplay between lung OS and its effects on both activation of antitubercle antibiotics and the strategies employed by M. tuberculosis that are essential for survival of both drug-susceptible and drug-resistant bacterial subtypes. We then outline potential new therapies that are based on combining standard antitubercular antibiotics with adjuvant agents that could limit the ability of M. tuberculosis to counter the host's OS response. PMID- 30405880 TI - Genome-wide association analysis identifies SNPs predictive of in vitro leukemic cell sensitivity to cytarabine in pediatric AML. AB - Cytarabine has been an integral part of acute myeloid leukemia (AML) chemotherapy for over four decades. However, development of resistance and high rates of relapse is a significant impediment in successfully treating AML. We performed a genome-wide association analysis (GWAS) and identified 113 (83 after adjusting for Linkage Disequilibrium) SNPs associated with in vitro cytarabine chemosensitivity of diagnostic leukemic cells from a cohort of 50 pediatric AML patients (p<10-4). Further evaluation of diagnostic leukemic cell gene-expression identified 19 SNP-gene pairs with a concordant triad of associations: i)SNP genotype with cytarabine sensitivity (p<0.0001), ii) gene-expression with cytarabine sensitivity (p<0.05), and iii) genotype with gene-expression (p<0.1). Two genes from SNP-gene pairs, rs1376041-GPR56 and rs75400242-IGF1R, were functionally validated by siRNA knockdown in AML cell lines. Consistent with association of rs1376041 and gene-expression in AML patients siRNA mediated knock down of GPR56 increased cytarabine sensitivity of AML cell lines. Similarly for IGF1R, knockdown increased the cytarabine sensitivity of AML cell lines consistent with results in AML patients. Given both IGF1R and GPR56 are promising drug-targets in AML, our results on SNPs driving the expression/function of these genes will not only enhance our understanding of cytarabine resistance but also hold promise in personalizing AML for targeted therapies. PMID- 30405881 TI - High expression level of CD44v8-10 in cancer stem-like cells is associated with poor prognosis in esophageal squamous cell carcinoma patients treated with chemoradiotherapy. AB - Background: Strong reactive oxygen species (ROS) suppression in cancer stem-like cell components in various solid tumors is associated with therapeutic resistance. In this study, we investigated the influence of CD44v8-10 expression on the overall survival of esophageal squamous cell carcinoma (E-SCC) patients after definitive chemoradiotherapy (dCRT) and on radio-sensitivities of E-SCC cell lines treated with or without sulfasalazine, a CD44v8-10-xCT-GSH axis inhibitor. Methods: Seventy-three patients with E-SCC who received dCRT were examined retrospectively. CD44v8-10 expression was analyzed immunohistochemically using paraffin-blocked pre-dCRT biopsy specimens obtained by esophagoscopy and was expressed as a histo-score (H-score). The relationship between the H-score and overall survival was analyzed. From human E-SCC cell lines (T.T, T.Tn, or Kyse-3650), we collected CD44v8-10High and CD44v8-10Low subpopulations using a cell sorter. Water-soluble tetrazolium salt-8 (WST), glutathione-SH (GSH) and ROS assays were performed to compare the effect of sulfasalazine on the radio sensitivities of these subpopulations in T.Tn and Kyse-3650. Results: High CD44v8 10 expression was independently associated with poor prognosis in E-SCC patients treated with dCRT (hazard ratio = 2.906, 95% CI = 1.277-6.611, p = 0.011). In CD44v8-10High cells of each cell line, sulfasalazine decreased cellular GSH levels, resulting in increased radiation-induced ROS and reduced cell viability. In contrast, sulfasalazine had no significant effects in CD44v8-10Low cells. Conclusion: High CD44v8-10 expression was an independent prognostic factor in E SCC patients treated with dCRT. CD44v8-10-xCT-GSH axis inhibition sensitized CD44v8-10High E-SCC cells to ROS-inducing treatments such as radiotherapy. Targeting CD44v8-10-xCT-GSH axis may improve the prognosis of post-dCRT E-SCC patients. PMID- 30405882 TI - The anti-psychotic drug pimozide is a novel chemotherapeutic for breast cancer. AB - Pimozide, an antipsychotic drug of the diphenylbutylpiperidine class, has been shown to suppress cell growth of breast cancer cells in vitro. In this study we further explore the inhibitory effects of this molecule in cancer cells. We found that Pimozide inhibited cell proliferation in a dose- and time-dependent manner in MDA-MB-231 breast cancer cells and A549 lung cancer cells. Furthermore, we found that Pimozide also promoted apoptosis as demonstrated by cell cycle arrest and induction of double-strand DNA breaks but did not result in any effect in the non-transformed MCF10A breast cell line. In order to shed new lights into the molecular pathways affected by Pimozide, we show that Pimozide downregulated RAN GTPase and AKT at both protein and mRNA levels and inhibited the AKT signaling pathway in MDA-MB-231 breast cancer cells. Pimozide also inhibited the epithelial mesenchymal transition and cell migration and downregulated the expression of MMPs. Administration of Pimozide showed a potent in vivo antitumor activity in MDA-MB-231 xenograft animal model and reduced the number of lung metastases by blocking vascular endothelial growth factor receptor 2. Furthermore, Pimozide inhibited myofibroblast formation as evaluated by the reduction in alpha-smooth muscle actin containing cells. Thus, Pimozide might inhibit tumor development by suppressing angiogenesis and by paracrine stimulation provided by host reactive stromal cells. These results demonstrate a novel in vitro and in vivo antitumor activity of Pimozide against breast and lung cancer cells and provide the proof of concept for a putative Pimozide as a novel approach for cancer therapy. PMID- 30405883 TI - Variability in genes regulating vitamin D metabolism is associated with vitamin D levels in type 2 diabetes. AB - Mortality rate is increased in type 2 diabetes (T2D). Low vitamin D levels are associated with increased mortality risk in T2D. In the general population, genetic variants affecting vitamin D metabolism (DHCR7 rs12785878, CYP2R1 rs10741657, GC rs4588) have been associated with serum vitamin D. We studied the association of these variants with serum vitamin D in 2163 patients with T2D from the "Sapienza University Mortality and Morbidity Event Rate (SUMMER) study in diabetes". Measurements of serum vitamin D were centralised. Genotypes were obtained by EcoTM Real-Time PCR. Data were adjusted for gender, age, BMI, HbA1c, T2D therapy and sampling season. DHCR7 rs12785878 (p = 1 x 10-4) and GC rs4588 (p = 1 x 10-6) but not CYP2R1 rs10741657 (p = 0.31) were significantly associated with vitamin D levels. One unit of a weighted genotype risk score (GRS) was strongly associated with vitamin D levels (p = 1.1 x 10-11) and insufficiency (<30 ng/ml) (OR, 95%CI = 1.28, 1.16-1.41, p = 1.1 x 10-7). In conclusion, DHCR7 rs12785878 and GC rs4588, but not CYP2R1 rs10741657, are significantly associated with vitamin D levels. When the 3 variants were considered together as GRS, a strong association with vitamin D levels and vitamin D insufficiency was observed, thus providing robust evidence that genes involved in vitamin D metabolism modulate serum vitamin D in T2D. PMID- 30405885 TI - Aldoxorubicin and Temozolomide combination in a xenograft mice model of human glioblastoma. AB - Glioblastoma Multiforme (GBM) is still an incurable disease. The front-line Temozolomide (TMZ)-based therapy suffers from poor efficacy, underlining the need of new therapies. Preclinically, Aldoxorubicin (Aldox), a novel prodrug of Doxorubicin (Dox), has been successfully tested against GBM, encouraging the study of its association with other agents. For the first time, we evaluated the effectiveness of Aldox combined to TMZ in preclinical models of GBM. Our in vitro results demonstrated that the anti-glioma effect of Aldox was more marked than TMZ and their combination increased the killing effect of the anthracycline in TMZ-resistant GBM cells. Moreover, unlike Dox, Aldox was able to accumulate in P glycoprotein (P-gp)-overexpressed cells due to a negative regulation of the P-gp function. We also compared efficacy and safety of weekly administrations of Aldox (16 mg/kg), with or without TMZ (0.9 mg/kg, daily injections), in the U87 xenograft mouse model. Aldox therapy induced a moderate tumor volume inhibition (TVI) and an increased survival rate (+12.5% vs vehicle). On the other hand, when combined to TMZ, Aldox caused a significant TVI (P=0.0175 vs vehicle) and delayed the mortality during the experimental period, although TVI and endpoint survival percentage (+37.5% vs vehicle) were not significantly different from TMZ alone. Our preliminary data showed that Aldox exerts anti-glioma effects in vitro and in vivo. It also enhances its antitumor activity when combined with TMZ, resulting in a superior efficacy compared to the single agents, without adverse side effects. PMID- 30405884 TI - Exosomal survivin facilitates vesicle internalization. AB - Survivin, a member of the inhibitor of apoptosis (IAP) protein family plays a significant role in cell fate and function. It is significantly overexpressed in tumor cells and has been identified in most cancer cell types. A novel extracellular population has recently been identified and its function is still unknown. Emerging evidence continues to shed light on the important role the tumor microenvironment (TME) has on tumor survival and progression. This new population of survivin has been seen to enhance the tumor phenotype when internalized by recipient cells. In this paper, we sought to better understand the mechanism by which survivin is taken up by cancer cells and the possible role it plays in this phenomenon. We isolated the exosomal carriers of extracellular survivin and using a lipophilic stain, PKH67, we tracked their uptake with immunofluorescence and flow cytometry. We found that by blocking exosomal survivin, exosome internalization is reduced, signifying a novel function for this protein. We also discovered that the common membrane receptors, transferrin receptor, endothelin B receptor, insulin receptor alpha, and membrane glucocorticoid receptor all facilitate exosomal internalization. This understanding further clarifies the protein-protein interactions in the TME that may influence tumor progression and identifies additional potential chemotherapeutic targets. PMID- 30405887 TI - Generation and characterization of novel recombinant anti-hERG1 scFv antibodies for cancer molecular imaging. AB - Modern molecular imaging techniques have greatly improved tumor detection and post-treatment follow-up of cancer patients. In this context, antibody-based imaging is rapidly becoming the gold standard, since it combines the unique specificity of antibodies with the sensitivity of the different imaging technologies. The aim of this study was to generate and characterize antibodies in single chain Fragment variable (scFv) format directed to an emerging cancer biomarker, the human ether-a-go-go-related gene-1 (hERG1) potassium channel, and to obtain a proof of concept for their potential use for in vivo molecular imaging. The anti-hERG1scFv was generated from a full length monoclonal antibody and then mutagenized, substituting a Phenylalanine residue in the third framework of the VH domain with a Cysteine residue. The resulting scFv-hERG1-Cys showed much higher stability and protein yield, increased affinity and more advantageous binding kinetics, compared to the "native" anti-hERG1scFv. The scFv-hERG1-Cys was hence chosen and characterized: it showed a good binding to the native hERG1 antigen expressed on cells, was stable in serum and displayed a fast pharmacokinetic profile once injected intravenously in nude mice. The calculated half-life was 3.1 hours and no general toxicity or cardiac toxic effects were detected. Finally, the in vivo distribution of an Alexa Fluor 750 conjugated scFv hERG1-Cys was evaluated both in healthy and tumor-bearing nude mice, showing a good tumor-to-organ ratio, ideal for visualizing hERG1-expressing tumor masses in vivo. In conclusion, the scFv-hERG1-Cys possesses features which make it a suitable tool for application in cancer molecular imaging. PMID- 30405888 TI - MEK/CDK4,6 co-targeting is effective in a subset of NRAS, BRAF and 'wild type' melanomas. AB - Targeted therapy has become a cornerstone for the treatment of melanoma patients. Targeting NRAS function is particularly challenging. To date, only single MEK inhibitor treatment was able to show minimal clinical efficacy. The discovery that co-targeting of MEK and CDK4,6 has antitumor activity created excitement for patients and clinicians; however, it is largely unknown if only NRAS mutant patients might benefit from MEK/CDK4,6 blockade. In this study we investigate response patterns of NRAS, BRAF mutant and 'wild type' melanoma cells in vitro and in vivo when challenged with inhibitors of MEK, CDK4,6 and the combination of both. Data revealed, that in vitro growth response patterns of cells treated with the MEK/CDK4,6 combination correspond to in vivo efficacy of MEK/CDK4,6 co targeting in melanoma xenograft models. Strikingly, this was consistently observed in NRAS and BRAF mutant, as well as in 'wild type' melanoma cells. Additionally, cells displaying elevated p-Rb levels after single MEK inhibition, showed more effective growth reduction with MEK/CDK4,6 co-targeting compared to single MEK inhibitor treatment in vivo. Findings indicate that combined MEK/CDK4,6 inhibition could offer an effectively therapeutic modality in a subset of BRAF and NRAS mutant, as well as 'wild type' melanoma patients. PMID- 30405886 TI - Mechanisms through which lithocholic acid delays yeast chronological aging under caloric restriction conditions. AB - All presently known geroprotective chemical compounds of plant and microbial origin are caloric restriction mimetics because they can mimic the beneficial lifespan- and healthspan-extending effects of caloric restriction diets without the need to limit calorie supply. We have discovered a geroprotective chemical compound of mammalian origin, a bile acid called lithocholic acid, which can delay chronological aging of the budding yeast Saccharomyces cerevisiae under caloric restriction conditions. Here, we investigated mechanisms through which lithocholic acid can delay chronological aging of yeast limited in calorie supply. We provide evidence that lithocholic acid causes a stepwise development and maintenance of an aging-delaying cellular pattern throughout the entire chronological lifespan of yeast cultured under caloric restriction conditions. We show that lithocholic acid stimulates the aging-delaying cellular pattern and preserves such pattern because it specifically modulates the spatiotemporal dynamics of a complex cellular network. We demonstrate that this cellular network integrates certain pathways of lipid and carbohydrate metabolism, some intercompartmental communications, mitochondrial morphology and functionality, and liponecrotic and apoptotic modes of aging-associated cell death. Our findings indicate that lithocholic acid prolongs longevity of chronologically aging yeast because it decreases the risk of aging-associated cell death, thus increasing the chance of elderly cells to survive. PMID- 30405889 TI - Synergistic antitumor effect of a gamma-secretase inhibitor PF-03084014 and sorafenib in hepatocellular carcinoma. AB - As a multi-kinase inhibitor, sorafenib is beneficial in around 30% of hepatocellular carcinoma (HCC) patients; however, HCC patients develop acquired drug resistance quickly. Clinical benefits of sorafenib, in combination with transarterial chemoembolization (TACE), radiotherapy, and other chemodrugs are limited. We investigated the efficacy and mechanisms of Notch signaling inhibition as adjuvant to sorafenib in HCC spheroid-derived in vitro and in vivo tumor models, using the gamma-secretase inhibitor (GSI), PF-03084014. The combination of PF-03084014 plus sorafenib inhibited proliferation and self renewal of HCC spheroids (stem-like cancer cells). PF-03084014 significantly enhanced antitumor activity of sorafenib; both agents at low dose reached synergistic tumor growth suppression of HCC spheroid-derived orthotopic tumors. The Notch1-Snail1 signaling pathway contributed to sorafenib resistance via increasing epithelial-mesenchymal transition (EMT) and EMT-mediated cancer stem cell (CSC) features, such as increased expression of Snail1, N-cadherin, ABCG2, and the stem cell related genes Nanog and Oct4, and decreased expression of E cadherin. Anti-tumor activity of the combination therapy was associated with decreased expression of survival signals (Mek/Erk, PI3K/Akt) and reduced microvessel density. PF-03084014 plus sorafenib targets Notch1-Snail1 signaling to reverse EMT and EMT-mediated CSC stemness in the tumors. These synergistic effects provide a rationale to utilize GSIs, in combination with sorafenib, as a new therapeutic strategy for the treatment of HCC. PMID- 30405891 TI - Correction: Regulation of Aldo-keto-reductase family 1 B10 by 14-3-3epsilon and their prognostic impact of hepatocellular carcinoma. AB - [This corrects the article DOI: 10.18632/oncotarget.5734.]. PMID- 30405892 TI - Correction: Interaction between physical activity, PITX1 rs647161 genetic polymorphism and colorectal cancer risk in a Korean population: a case-control study. AB - [This corrects the article DOI: 10.18632/oncotarget.24136.]. PMID- 30405893 TI - Spatio-temporal asymmetry of local wind fields and its impact on short-term wind forecasting. AB - The massive amounts of spatio-temporal data collected in today's wind farms have created a necessity for accurate spatio-temporal models. Despite the growing recognition for non-separable spatio-temporal models, a significant reliance on separable, symmetric models is still the norm in today's renewable industry. We discover that the broad use of separable models is due to the handling of wind data in a setting that does not reveal their fine-scale spatio-temporal structure. The contribution of this research is two-fold. First, we devise a special pair of spatio-temporal "lens" that allows us to see the fine-scale spatio-temporal variations and interactions, and subsequently, we conclude that local wind fields exhibit strong signs of non-separability and asymmetry. Using one year of turbine-specific wind measurements, we show that asymmetry can in fact be detected in more than 93% of the time. Second, making use of the spatio temporal lens, we propose an enhanced procedure for short-term wind speed forecast. Substantial improvements in forecast accuracy in both wind speed and wind power were observed. When combined with certain intelligent methods such as support vector machine, additional improvements are possible. PMID- 30405894 TI - Vitamin D and its receptor polymorphisms: New possible prognostic biomarkers in leukemias. AB - Several factors such as chromosomal translocations, gene mutations, and polymorphisms are involved in the pathogenesis of leukemia/lymphoma. Recently, the role of vitamin D (VD) and vitamin D receptor (VDR) polymorphisms in hematologic malignancies has been considered. In this review, we examine the possible role of VD levels, as well as VDR polymorphisms as prognostic biomarkers in leukemia/lymphoma. Relevant English language literature were searched and retrieved from Google Scholar search engine (1985-2017). The following keywords were used: vitamin D, vitamin D receptor, leukemia, lymphoma, and polymorphism. Increased serum levels of VD in patients with leukemia are associated with a better prognosis. However, low VD levels are associated with a poor prognosis, and VDR polymorphisms in various leukemias can have prognostic value. VD biomarker can be regarded as a potential prognostic factor for a number of leukemias, including acute myeloblastic leukemia (AML), chronic lymphoblastic leukemia (CLL), and diffuse large B-cell lymphoma (DLBCL). There is a significant relationship between different polymorphisms of VDR (including Taq I and Fok I) with several leukemia types such as ALL and AML, which may have prognostic value. PMID- 30405890 TI - Effect of therapies-mediated modulation of telomere and/or telomerase on cancer cells radiosensitivity. AB - Cancer is one of the leading causes of death in the world. Many strategies of cancer treatment such as radiotherapy which plays a key role in cancer treatment are developed and used nowadays. However, the side effects post-cancer radiotherapy and cancer radioresistance are two major causes of the limitation of cancer radiotherapy effectiveness in the cancer patients. Moreover, reduction of the limitation of cancer radiotherapy effectiveness by reducing the side effects post-cancer radiotherapy and cancer radioresistance is the aim of several radiotherapy-oncologic teams. Otherwise, Telomere and telomerase are two cells components which play an important role in cancer initiation, cancer progression and cancer therapy resistance such as radiotherapy resistance. For resolving the problems of the limitation of cancer radiotherapy effectiveness especially the cancer radio-resistance problems, the radio-gene-therapy strategy which is the use of gene-therapy via modulation of gene expression combined with radiotherapy was developed and used as a new strategy to treat the patients with cancer. In this review, we summarized the information concerning the implication of telomere and telomerase modulation in cancer radiosensitivity. PMID- 30405896 TI - Normal hearing young adults with mild tinnitus: Reduced inhibition as measured through sensory gating. AB - Decreased central inhibition, possibly related to hearing loss, may contribute to chronic tinnitus. However, many individuals with normal hearing thresholds report tinnitus, suggesting that the percept in this population may arise from sources other than peripheral deafferentation. One measure of inhibition is sensory gating. Sensory gating involves the suppression of non-novel input, and is measured through cortical auditory evoked potential (CAEP) responses to paired stimuli. In typical gating function, amplitude suppression is observed in the second CAEP response when compared to the first CAEP response, illustrating inhibitory activity. Using this measure, we investigated central inhibitory processes in normal hearing young adults with and without mild tinnitus to determine whether inhibition may be a contributing factor to the tinnitus percept. Results showed that gating function was impaired in the tinnitus group, with the CAEP Pa component significantly correlated with tinnitus severity. Further exploratory analyses were conducted to evaluate variability in gating function within the tinnitus group, and findings showed that high CAEP amplitude suppressors demonstrated gating performance comparable to adults without tinnitus, while low amplitude suppressors exhibited atypical gating function. PMID- 30405895 TI - Expression of CD markers in JAK2V617F positive myeloproliferative neoplasms: Prognostic significance. AB - Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized by the presence of JAK2V617F mutation. Thrombohemorrhagic as well as autoimmune or inflammatory phenomena are common clinical outcomes of these disorders. Recent studies have shown that abnormality in frequency and function of blood cells manifested by an alteration in CD markers' expression patterns play a key role in these complications. So, there may be a relationship between CD markers' expressions and prognosis of JAK2V617F positive MPNs. Therefore, in this review, we have focused on these abnormalities from the perspective of changing expressions of CD markers and assessment of the relationship between these changes with prognosis of JAK2V617F positive MPNs. It can be stated that the abnormal expression of a large number of CD markers can be used as a prognostic biomarker for clinical outcomes including thrombohememorrhagic events, as well as autoimmune and leukemic transformation in JAK2V617F positive MPNs. Considering the possible role of CD markers' expressions in JAK2V617F MPNs prognosis, further studies are needed to confirm the relationship between the expression of CD markers with prognosis to be able to find an appropriate therapeutic approach via targeting CD markers. PMID- 30405897 TI - Gaussian Modelling Characteristics of Peripheral Arterial Pulse: Difference between Measurements from the Three Trimesters of Healthy Pregnancy. AB - Arterial pulse wave analysis has been attempted to monitor the maternal physiological changes of circulatory system during pregnancy. This study aimed to quantify the difference of Gaussian modelling characteristics derived from radial pulses measured from the three trimesters of healthy pregnant women. Radial pulses were recorded from seventy pregnant women between gestational week 11-13, week 20-22, and then week 37-39. They were then normalized and decomposed into three independent Gaussian waves for deriving four key modelling characteristic parameters: including the peak time interval (T) and peak amplitude ratio (R) between the first and second Gaussian waves (T 1,2 and R 1,2), and their corresponding values between the first and third Gaussian waves (T 1,3 and R 1,3). Post hoc multiple comparisons after analysis of variance was then applied to study the within-subject differences in Gaussian modelling characteristics between the three trimesters. The key results were that T 1,2 and T 1,3 increased significantly (T 1,2: 12.8 +/- 1.3 vs 13.2 +/- 1.3, p < 0.05; T 1,3: 39.5 +/- 4.3 vs 45.4 +/- 5.1, p < 0.001), and R 1,3 decreased significantly from the first to second trimester (0.60 +/- 0.15 vs 0.53 +/- 0.11, p < 0.001). From the second to third trimester, T 1,2 decreased significantly (13.2 +/- 1.3 vs 12.8 +/- 1.2, p < 0.01), and T 1,3 and R 1,3 decreased slightly but nonsignificantly. Since larger T 1,2 and T 1,3 and smaller R 1,3 are associated with more compliant peripheral arteries, our results indicated that peripheral arteries become more compliant from the first to second trimester and then have a tendency of returning to baseline during normal pregnancy. In conclusion, this study has quantitatively demonstrated significant changes of Gaussian modelling characteristics derived from radial pulses at the three trimesters of normal pregnant women, suggesting that these modelling characteristics could be used as parameters in monitoring maternal physiological changes during normal pregnancy. PMID- 30405899 TI - Software Framework for the Creation and Application of Personalized Bone and Plate Implant Geometrical Models. AB - Computer-Assisted Orthopaedic Surgery (CAOS) defines a set of techniques that use computers and other devices for planning, guiding, and performing surgical interventions. The important components of CAOS are accurate geometrical models of human bones and plate implants, which can be used in preoperational planning or for surgical guiding during an intervention. Software framework which is introduced in this study is based on the Model-View-Controller (MVC) architectural pattern, and it uses 3D models of bones and plate implants developed by the application of the Method of Anatomical Features (MAF). The presented framework may be used for preoperative planning processes and for the production of personalized plate implants. The main idea of the research was to develop a novel integrated software framework which will provide improved personalized healthcare to the patient, and at the same time, provide the surgeon with more control over the patient's treatment and recovery. PMID- 30405900 TI - Meta-Analysis of the Relationship between the APOE Gene and the Onset of Parkinson's Disease Dementia. AB - Purpose: To clarify the relationship between certain genotypes or alleles of the APOE gene and the onset risk of Parkinson's disease dementia (PDD). Methods: The PubMed, Cochrane, Embase, CBM, CNKI, and Wanfang databases were searched to identify all case-control studies and cohort studies published before October 30, 2017, that investigated the association between the APOE gene and the onset of PDD. Manual information retrieval was also performed. All studies that met the quality requirements were included in a meta-analysis performed using RevMan 5.3 software. Results: The meta-analysis included 17 studies, with a total of 820 patients in the PDD group and 1,922 in the non-PDD group. The influence of the APOE gene on PDD onset was analyzed from three aspects: five genotypes vs. epsilon3/3, epsilon2+/epsilon4+ vs. epsilon3/3, and epsilon4+ vs. epsilon4-. The risk factors for PDD may include the genotypes epsilon3/4 (OR 1.47, 95% CI 1.14 1.89) and epsilon4/4 (OR 2.93, 95% CI 1.20-7.14). In patients with PDD, there was no significant difference in the distribution of epsilon2+ vs. epsilon3/3 (OR 1.35, 95% CI 0.97-1.87, P=0.07). The risk of PDD was 1.61 times greater in epsilon4+ compared with epsilon3/3 (OR 1.61, 95% CI 1.24-2.08, P=0.0003). As the results indicated that epsilon2+ did not play a role as a risk factor or a protective factor, we divided the population into epsilon4+ and epsilon4- for the meta-analysis and found that, among patients with Parkinson's disease, the dementia risk of those with epsilon4+ was 1.72 times greater than that of those with epsilon4- (OR 1.72, 95% CI 1.41-2.10, P < 0.00001). Subgroup analysis in accordance with different geographical regions revealed that epsilon4+ was a risk factor for PDD in people from all regions. Conclusions: Among the APOE genotypes, epsilon2+ is neither a risk factor nor a protective factor for PDD, while epsilon4+ is a risk factor for PDD. The present results are applicable to Asian, European, and American patients with Parkinson's disease. Regarding the single APOE genotypes, epsilon3/4 and epsilon4/4 may be risk factors for PDD; however, further studies with large sample sizes are needed to verify this. PMID- 30405898 TI - Review of Catheter-Associated Urinary Tract Infections and In Vitro Urinary Tract Models. AB - Catheter-associated urinary tract infections (CAUTIs) are one of the most common nosocomial infections and can lead to numerous medical complications from the mild catheter encrustation and bladder stones to the severe septicaemia, endotoxic shock, and pyelonephritis. Catheters are one of the most commonly used medical devices in the world and can be characterised as either indwelling (ID) or intermittent catheters (IC). The primary challenges in the use of IDs are biofilm formation and encrustation. ICs are increasingly seen as a solution to the complications caused by IDs as ICs pose no risk of biofilm formation due to their short time in the body and a lower risk of bladder stone formation. Research on IDs has focused on the use of antimicrobial and antibiofilm compounds, while research on ICs has focused on preventing bacteria entering the urinary tract or coming into contact with the catheter. There is an urgent need for in vitro urinary tract models to facilitate faster research and development for CAUTI prevention. There are currently three urinary tract models that test IDs; however, there is only a single very limited model for testing ICs. There is currently no standardised urinary tract model to test the efficacies of ICs. PMID- 30405901 TI - An observational study of Chinese adults with relapsed/refractory Philadelphia negative acute lymphoblastic leukemia. AB - Aim: Chinese adults with relapsed/refractory Philadelphia chromosome-negative B cell precursor acute lymphoblastic leukemia (Ph- ALL) have poor outcomes. Patients & methods: We conducted a nationwide, retrospective, observational study to assess outcomes in this patient population. Results: Of the 270 enrolled patients, 31% of patients at last salvage achieved complete remission (CR) or CR with partial hematologic recovery (CRh), with median time to CR/CRh of 30 days and median CR/CRh duration of 2.7 months. The CR/CRh rate was more favorable with earlier versus later lines of salvage (41, 24 and 17% at first, second and third or later salvages, respectively). Conclusion: This dataset serves as an important reference of real-world outcomes using currently available chemotherapy regimens for high-risk Chinese adults with relapsed/refractory Ph- ALL. PMID- 30405902 TI - Nuclear transport inhibition in acute myeloid leukemia: recent advances and future perspectives. AB - Selective inhibitors of nuclear export (SINE) are emerging as a potentially efficacious therapeutic strategy for overcoming resistance to conventional chemotherapy for acute myeloid leukemia. SINE specifically block the protein Exportin 1, also known as chromosomal region maintenance 1, leading to nuclear retention of cargo proteins, including several tumor suppressor proteins. Selinexor, a first generation SINE, is currently in early phase clinical studies in various combinations with promising antileukemic and pro-apoptotic activity. Here we discuss the mechanism of action of SINEs and further elaborate on the clinical data available from the various trials in acute myeloid leukemia. PMID- 30405903 TI - Computer aided design of FtsZ targeting oligopeptides?. AB - FtsZ is a protein involved in the bacterial division process and is thus an emerging target for antibacterial drugs. The network of interactions between FtsZ monomers necessary for exploitation of its biological function are studied here with molecular dynamics and free energy calculations. The results obtained led to the design of FtsZ targeting peptides which exhibited activity against the function of FtsZ in vitro. PMID- 30405904 TI - Artificial intelligence, machine learning and health systems. PMID- 30405905 TI - Effects of D-Lysine Substitutions on the Activity and Selectivity of Antimicrobial Peptide CM15. AB - Despite their potent antimicrobial activity, the usefulness of antimicrobial peptides (AMPs) as antibiotics has been limited by their toxicity to eukaryotic cells and a lack of stability in vivo. In the present study we examined the effects of introducing D-lysine residues into a 15-residue hybrid AMP containing residues 1-7 of cecropin A and residues 2-9 of melittin (designated CM15). Diastereomeric analogs of CM15 containing between two and five D-lysine substitutions were evaluated for their antimicrobial activity, lysis of human erythrocytes, toxicity to murine macrophages, ability to disrupt cell membranes, and protease stability. All of the analogs caused rapid permeabilization of the Staphylococcus aureus cell envelope, as indicated by uptake of SYTOX green. CM15 also permeabilized the plasma membrane of RAW264.7 macrophages, but this was substantially diminished for the D-lysine containing analogs. The introduction of D-lysine caused moderate decreases in antimicrobial activity for all analogs studied. However, D-Lys substitution produced a much more pronounced reduction in toxicity to eukaryotic cells, leading to marked improvements in antimicrobial efficacy for some analogs. Circular dichroism studies indicated a progressive loss of helical secondary structure upon introduction of D-lysine residues, and there was a good correspondence between helical content and eukaryotic cell cytotoxicity. Overall, these studies show that the biological activity of CM15 analogs containing D-lysine depends on both the number and position of D-Lys substitutions, and that such substitutions can dramatically lower toxicity to eukaryotic cells with only minimal decreases in antimicrobial activity. PMID- 30405906 TI - Tear Ferning Test and Pathological Effects on Ocular Surface before and after Topical Cyclosporine in Vernal Keratoconjunctivitis Patients. AB - Background: Vernal keratoconjunctivitis (VKC) is a rare ocular surface inflammatory disease that affects mainly boys in the first decade of life. Clinical observations show that it generally regresses spontaneously with the onset of puberty, but therapeutic measures must be taken before then to control the course of the disease. Purpose: To evaluate the role of the lacrimal mucous component in VKC patients and compare tear ferning test (TFT) modifications, MUC5AC levels in tears, and density of conjunctival goblet cells to clinical characteristics before and after treatment with cyclosporine A (CY) in eye drops. Methods: Forty-seven patients affected by VKC and 30 healthy subjects aged between 3 and 16 years of life were enrolled. All individuals were submitted to complete eye examination and skin prick test (SPT) for the most common allergens. Then, they were subjected to collection of the tears and to impression cytology to evaluate TFT, MUC5AC levels, and conjunctival goblet cell density, before and after treatment with CY in eye drops. Results: Comparing the VKC group vs. the control group at baseline, a significant alteration in the degree of the ferns was found, indicating a pathological condition of the lacrimal mucous layer. In addition, an increased number of goblet cells were observed in the patients. The concentration of lacrimal secretory mucins (MUC5AC) did not show significant differences between the 2 groups. Patients treated with CY have reported improvements of some signs and symptoms of disease activity, including TFT, and a tendency of conjunctival goblet cell density to normalise. Conclusions: The results obtained demonstrated for the first time a significant alteration of the lacrimal mucin component evaluated in the VKC group, and an improvement of the latter after CY therapy. PMID- 30405907 TI - Efficacy and Safety of an Aflibercept Treat-and-Extend Regimen in Treatment-Naive Patients with Macular Oedema Secondary to Central Retinal Vein Occlusion (CRVO): A Prospective 12-Month, Single-Arm, Multicentre Trial. AB - Objectives: To evaluate efficacy and safety of an aflibercept treat-and-extend (TAE) regimen in patients with macular oedema (MO) secondary to central retinal vein occlusion (CRVO). Design Setting and Patients: Phase IV, prospective, open label, single-arm trial in 11 Spanish hospitals. Treatment-naive patients with <6 month diagnosis of MO secondary to CRVO and best-corrected visual acuity (BCVA) of 73-24 ETDRS letters were included between 23 January 2015 and 17 March 2016. Intervention: Intravitreal aflibercept 2 mg monthly (3 months) followed by proactive individualized dosing. Main Outcomes: Mean change in BCVA after 12 months. Results: 24 eyes (24 patients) were included; mean (SD) age: 62.8 (15.0) years; 54.2% male; median (IQR) time since diagnosis: 7.6 (3.0, 15.2) days. Mean BCVA scores significantly improved between baseline (56.0 (16.5)) and Month 12 (74.1 (17.6)); mean (95% CI) change: 14.8 (8.2, 21.4); P=0.0001. Twelve (50.0%) patients gained >=15 ETDRS letters. Foveal thickness improved between baseline (mean: 569.4 (216.8) um) and Month 12 (mean 257.4 (48.4) um); P < 0.0001. At Month 12, 8.3% patients had MO. The mean (SD) number of injections: 8.3 (3.0). No treatment-related AEs were reported. Five (20.8%) patients experienced ocular AEs. Two nonocular serious AEs were reported. Conclusions: An aflibercept TAE regimen improves visual acuity in patients with MO secondary to CRVO over 12 months with good tolerability. PMID- 30405908 TI - Development of Regional Disparities in Alzheimer's Disease Mortality in the Slovak Republic from 1996 to 2015. AB - Alzheimer's disease-subsequently as AD in the text-represents a chronic neurodegenerative disease discussed very often in the recent period. It involves the G30 diagnosis expressing exactly AD and also the F00 diagnosis epitomising dementia in AD. The Slovak Republic has a very various population in terms of the disparities of the population localisation. The analysis is executed on the basement of the standardised mortality rate. It is calculated for the individual districts of the Slovak Republic to get a detailed spatial view and for each year of the explored period from 1996 to 2015 to get a time development. It has a considerably rising tendency. Therefore, the regional disparities of the standardised mortality rate of AD are analysed from an angle of view of its similarity, by its measurement in a form of a Euclidean distance approach. The results of the analysis offer the heat maps as the distance matrices in a graphic form and the maps of the individual districts too. These outputs reveal a very heterogeneous structure of the standardised mortality rate. Another graphic outcome demonstrates a distribution of its values among the districts throughout the whole Slovak Republic for the whole observed period. The results offer a comparison among the districts of the Slovak Republic too. The highest values and also the lowest values are reached in the different districts for the both sexes. Even, one district reaches the opposite result for the individual sexes. The age structure of the deceased population on the G30 diagnosis is also executed and the extreme values from an angle of a view of the districts are picked up. There are evident high differentiations between the individual districts of the Slovak Republic. The conclusion section involves the several key points and the potential suggestions for further research. PMID- 30405909 TI - Value of Assessing Autonomic Nervous Function by Heart Rate Variability and Heart Rate Turbulence in Hypertensive Patients. AB - Purpose: To explore the relationship between blood pressure control and autonomic nervous function assessing by heart rate variability (HRV) and heart rate turbulence (HRT) in hypertensive patients. Methods: A total of 120 consecutive hypertensive patients and 80 nonhypertensive patients (N-HP group) were enrolled in this study. The hypertensive patients were divided into controlled blood pressure and uncontrolled blood pressure groups according to their blood pressure on admission. All subjects underwent 24-hour Holter monitoring. This study compared HRV and HRT in nonhypertensive and hypertensive patients and hypertensive patients with controlled and uncontrolled blood pressure. HRV parameters include square root of mean of the sum of squares of successive NN interval differences (rMSSD), number of successive NN intervals differing by > 50ms divided by the total number of successive NN intervals (pNN50), very low frequency (VLF) at frequency between 0.0033 and 0.04 Hz, low frequency (LF) at frequency between 0.04 and 0.15 Hz, and high frequency (HF) at frequency between 0.15 and 0.4 Hz. Turbulence slope (TS) belongs to HRT parameters. Results: TS, rMSSD, pNN50, VLF, LF, and HF values were significantly lower in the HP group than in the N-HP group. Multiple logistic regression analysis showed that reduced TS, rMSSD, pNN50, LF, and HF values were risk factors of hypertension. TS, rMSSD, pNN50, VLF, LF, and HF values were significantly lower in hypertensive patients with uncontrolled blood pressure than in hypertensive patients with controlled blood pressure. Multiple logistic regression analysis showed that reduced TS, rMSSD, pNN50, VLF, LF, and HF values were risk factors for uncontrolled blood pressure. Conclusions: This study indicates impaired autonomic nervous function in hypertensive patients, especially in hypertensive patients with uncontrolled blood pressure despite guideline recommended antihypertensive medications. PMID- 30405910 TI - Zinc Deficiency and the Recurrence of Clostridium difficile Infection after Fecal Microbiota Transplant: A Retrospective Cohort Study. AB - Background: Fecal microbiota transplant (FMT) is an effective therapy for recurrent Clostridium difficile infection (CDI). However, in 12% of patients treated with FMT, CDI recurs within one month. Zinc deficiency predicts increased diarrheal frequency in malnourished children, but little is known about its association with FMT outcome. We hypothesized that zinc levels were an independent predictor of CDI recurrence after FMT. Methods: We performed a retrospective cohort study of 80 patients (mean age, 66; 59 women) receiving FMT for CDI from 9/2013-9/2016 at a tertiary care center. Zinc levels were measured within 90 days before FMT. The primary outcome was CDI recurrence within 90 days after FMT. We controlled for risk factors for FMT failure using Cox regression. We also analyzed the effect of zinc supplementation in individuals with deficiency. Results: Forty-nine subjects had a normal zinc level, and 31 had a low level (<0.66 ug/mL). CDI recurred in 3/49 (6%) patients with normal zinc and 5/31 (16%) patients with low zinc (HR = 11.327, 95% CI = 2.162-59.336, p=0.004). Among low zinc subjects, 2 of 25 (8%) that received zinc supplements and 3 of 6 (50%) that did not receive zinc supplements had recurrence of CDI (HR = 0.102, 95% CI = 0.015-0.704, p=0.021). Conclusion: Zinc deficiency was associated with increased CDI recurrence after FMT. Among zinc-deficient patients, supplementation was associated with reduced recurrence. Further study is needed to determine whether zinc deficiency represents a pathophysiologic mechanism and target for therapy. PMID- 30405911 TI - Evaluating an Education Program to Reduce Indeterminate QuantiFERON Gold In-Tube Results. AB - Background: The QuantiFERON Gold In-Tube (QFT-G) assay is used to identify individuals with tuberculosis infection and gives quantitative and qualitative results including positive, negative, or indeterminate results (that cannot be interpreted clinically). Several factors, including immunosuppression and preanalytical factors, have been suggested to be significantly associated with indeterminate QFT-G results. An online education program was designed and implemented to reduce the rate of indeterminate QFT-G test results at Houston Methodist Hospital (HMH). Methods: Data from patients' electronic medical records having indeterminate QFT-G results between 01/2015 and 05/2016 at HMH in Houston, TX, were administratively extracted for (1) medical unit where QFT-G phlebotomy was performed, (2) demographics, and (3) ICD-9/10 diagnosis codes. Unit nurses identified with high proportions of indeterminate QFT-G results were emailed a link to an online pretest educational program with a QFT-G blood collection and handling presentation, and a posttest assessment. Results: Of the 332 nurses emailed, 94 (28.4%) voluntarily completed both tests within the 6-month time allotted. The nurses that completed the education program had a significantly higher posteducation test score than on the pretest (70.2% versus 55.3%, p<0.001, effect size=0.82). Improved posttest score was seen in 67.0% of participants. No reduction in the proportion of indeterminate test results was seen overall at HMH in the 6 months after education. Conclusions: A targeted education program was able to successfully increase nurses' knowledge of blood collection and handling procedures for the QFT-G test, but no association was found between the improvement of posttest score and indeterminate QFT-G test results. PMID- 30405912 TI - Glomerulonephritis Pattern at a Jordanian Tertiary Care Center. AB - Aim: To determine the prevalence and frequency of different pathological patterns of glomerulonephritis (GN) in adolescent (age >= 11 years) and adult Jordanian patients. Materials and Methods: A retrospective analysis of all clinical and pathological reports of Jordanian patients who had native renal biopsies at the University of Jordan hospital between January 2007 and March 2018 to assess the prevalence and pathological pattern of GN. The data were analyzed statistically using descriptive statistics, the chi-squared test, and Fisher's exact tests. The level of significance was set at P < 0.05. Results: Two hundred and nine patients (88 males and 121 females) had native kidney biopsies diagnosed as having GN; the mean age at the time of biopsy was 36.0 +/- 14.9 years. Primary GN (51.2%) was more common than secondary GN (48.8%). The most common GN was lupus nephritis (LN) (33.5%), followed by membranous nephropathy (MGN) (15.3%), and diabetic nephropathy (DN) (11.0%). Furthermore, IgA nephropathy was noted in 8.1% of cases. LN was the most common among the secondary GN and occurred in 49.6% of females; MGN was the most common primary GN and occurred in 22.7% of males. There was a statistically significant difference between males and females in the prevalence of LN and MGN (P < .001 and P = .011, respectively). LN was also dominant in all age groups expect for the >=60 years group, which tended to exhibit DN (40%). Conclusion: LN is the most common GN type in Jordan, followed by MGN and DN. MGN is the predominant primary GN with a higher prevalence among males; LN is the predominant secondary GN and tends to occur in Jordanian females. The GN patterns in this study shifted from membranoproliferative GN to MGN in Jordan, which revealed a shift towards similar patterns exhibited in developed countries. Furthermore, DN is the most frequent GN in the elderly. PMID- 30405913 TI - The Role of Wearable Devices in Multiple Sclerosis. AB - Multiple sclerosis (MS) is the most common neurological disorder in young adults. The prevalence of walking impairment in people with MS (pwMS) is estimated between 41% and 75%. To evaluate the walking capacity in pwMS, the patient reported outcomes (PROs) and performance-based tests (i.e., the 2-minute walk test, the 6-minute walk test, the Timed 25-Foot Walk Test, the Timed Up and Go Test, and the Six Spot Step Test) could be used. However, some studies point out that the results of both performance-based tests and objective measures (i.e., by accelerometer) could not reflect patient reports of walking performance and impact of MS on daily life. This review analyses different motion sensors embedded in smartphones and motion wearable device (MWD) that can be useful to measure free-living walking behavior, to evaluate falls, fatigue, sedentary lifestyle, exercise, and quality of sleep in everyday life of pwMS. Caveats and limitations of MWD such as variable accuracy, user adherence, power consumption and recharging, noise susceptibility, and data management are discussed as well. PMID- 30405915 TI - Serum Cortisol as a Predictor of Major Adverse Pulmonary Event in Emergency Department Acutely Dyspneic Patients. AB - Cortisol is a steroid hormone released from the adrenal glands in response to stressful conditions. Elevated cortisol levels have been described in stress, but it is unclear whether these are associated with adverse outcomes. In this study, we assess whether cortisol levels drawn in patients presenting with dyspnea to the ED were a predictor of major adverse pulmonary event (MAPE). In 87 patients presenting with dyspnea to the ED, cortisol levels were determined. Patients were then assessed to determine the following MAPE: endotracheal intubation (ETI) in the ED, admission to the intensive care unit (ICU), and in-hospital all-cause mortality. Forty-four patients (50.6%) were female and 33 (37.9%) were diagnosed with heart failure. Cortisol levels in patients with and without MAPE were 34.3MUg/dL and 23.8MUg/dL, respectively (p<0.001). Also, cortisol levels were found higher in patients intubated in the ED than nonintubated patients (54.2MUg/dL vs 25.7MUg/dL, p<0.001), higher in patients admitted to the ICU (38.7MUg/dL vs 24 MUg/dL, p<0.001), and higher in patients who died in hospital (50MUg/dL vs 24.3MUg/dL, p<0.001). The area under the ROC curve using cortisol to detect any component of MAPE-ETI or ICU admission or in-hospital all-cause mortality-was 0.76 (95% CI, 0.65-0.84). A cortisol value of 31.4MUg/dL had sensitivity of 70.8% and specificity of 79.4% for predicting MAPE. Patients in the MAPE group had higher serum cortisol levels than those without any MAPE. Cortisol may be used as a marker to predict MAPE in nontraumatic acutely dyspneic adult patients on ED admission. PMID- 30405914 TI - Prediction of Preterm Birth: Maternal Characteristics, Ultrasound Markers, and Biomarkers: An Updated Overview. AB - There is not a single or combined screening method for preterm birth with high sensitivity which will truly identify the women at risk for preterm birth while also with high specificity to prevent unnecessary interventions and high treatment costs. Measurement of cervical length is the most cost-effective method that is used in clinical practice. Bedside tests have also been developed for detecting markers like fetal fibronectin, insulin-like growth factor binding protein-1 (IGFBP-1), interleukin-6, and placental alpha-macroglobulin-1. Taking the maternal history, health condition, and sociodemographical factors into consideration is recommended. Ultrasound markers apart from cervical length measurements as uterocervical angle and placental strain ratio are studied. Investigations on metabolomics, proteomics, and microRNA profiling have brought a new aspect on this subject. Maybe in the future, with clear identification of women at true risk for preterm birth, development of more effective preventive strategies will not be unfeasible. PMID- 30405916 TI - CDK9 Expression Shows Role as a Potential Prognostic Biomarker in Breast Cancer Patients Who Fail to Achieve Pathologic Complete Response after Neoadjuvant Chemotherapy. AB - Failure to achieve pathologic complete response is associated with poor prognosis in breast cancer patients following neoadjuvant chemotherapy (NACT). However, prognostic biomarkers for clinical outcome are unclear in this patient population. Cyclin-dependent kinase 9 (CDK9) is often dysregulated in breast cancer, and its deficiency results in genomic instability. We reviewed the records of 84 breast cancer patients from Emory University's Winship Cancer Institute who had undergone surgical resection after NACT and had tissue available for tissue microarray analysis (TMA). Data recorded included disease presentation, treatment, pathologic response, overall survival (OS), locoregional recurrence free survival (LRRFS), distant-failure free survival (DFFS), recurrence-free survival (RFS), and event-free survival (EFS). Immunohistochemistry was performed on patient samples to determine CDK9 expression levels after NACT. Protein expression was linked with clinical data to determine significance. In a Cox proportional hazards model, using a time dependent covariate to evaluate the risk of death between groups beyond 3 years, high CDK9 expression was significantly associated with an increase in OS (HR: 0.26, 95% CI: 0.07-0.98, p=0.046). However, Kaplan-Meier curves for OS, LRRFS, DFFS, RFS, and EFS did not reach statistical significance. The results of this study indicate that CDK9 may have a potential role as a prognostic biomarker in patients with breast cancer following NACT. However, further validation studies with increased sample sizes are needed to help elucidate the prognostic role for CDK9 in the management of these patients. PMID- 30405917 TI - Excisional Biopsy of the Pyogenic Granuloma in Very High-Risk Patient. AB - Oral surgery to remove pyogenic granuloma in a high-risk patient is reported. A 47-year-old man with gastroesophageal reflux disease, diabetes mellitus II, dyslipidemia, and chronic coronary insufficiency (myocardial infarction within 2 years) with episodes of unstable angina was submitted to an excisional biopsy of hemorrhagic lesion in the lingual right mandibular gingiva. During dental treatment, the arterial blood pressure, oxygen saturation, heart rate, and electrocardiogram were monitored. Local anesthesia was performed with 0.45 ml of 3% prilocaine with 0.03 IU/ml felypressin. The anticoagulant therapy was not interrupted. No local or systemic complications were noticed during or after the surgery. PMID- 30405918 TI - A Hiccup in Hiccup Management: Cardiac Arrest from Previously Undiagnosed Congenital Long QT Syndrome. AB - We report the case of a person who went into cardiac arrest after being given chlorpromazine for hiccups and was subsequently diagnosed with congenital Long QT Syndrome. Long QT Syndrome is an uncommon, congenital condition that carries a high risk of sudden cardiac death. Clinicians need to recognize the risk that chlorpromazine may prolong the QTc and prepare to manage potential complications. PMID- 30405919 TI - Simultaneous Pheochromocytoma, Paraganglioma, and Papillary Thyroid Carcinoma without Known Mutation. AB - Background: Pheochromocytoma/paraganglioma is a rare tumor from neuroendocrine cells. 1/3rd of cases have germline mutations. Papillary thyroid carcinoma (PTC) is a common neoplasm from follicular cells of the thyroid. We report a case of pheochromocytoma/paraganglioma and PTC with negative testing for common mutations. Case: 32-year-old male with incidental liver mass during laparoscopy for acute appendicitis. His symptoms included abdominal pain and profuse axillary hyperhidrosis. MRI showed an 11x12x14 cm cystic and solid mass in right adrenal gland, and 3.4x2.9x3.8 cm mass in porta hepatis. Urine metanephrines was elevated. After preoperative alpha-blockade, patient underwent total right adrenalectomy. Pathology report confirmed diagnosis of pheochromocytoma. According to the Grading system for Adrenal Pheochromocytoma and Paraganglioma (GAPP), tumor's score was 9, indicating poorly differentiated tumor. Ki67 index 5% and S100 were negative. Postoperatively, plasma free metanephrines normalized but plasma free normetanephrines remained elevated. Based on this biochemical profile, presence of paraganglioma was suspected. CT showed 4.2x3.5 cm round soft tissue mass in porta hepatis which increased in size from previous MRI. Simultaneously, PET scan identified a 1.5 cm thyroid mass. Calcitonin level was normal. Fine-needle aspiration was consistent with PTC. Resection of the mass and total thyroidectomy were performed with confirmation of paraganglioma S100 positive and PTC. Normetanephrines decreased to 283 (<148 pg/mL); free metanephrines remained normal. Gene mutation of EGLN1, FH, KIF1B, MEN1, NF1, RET, SDHAF2, SDHC, SDHD, TMEM127, VHL, and SDHA was negative. Conclusion: Whether paraganglioma/pheochromocytoma/PTC combination is coincidental or resulted from an underlying unknown mutation cannot be excluded. PMID- 30405920 TI - Infected Renal Cyst as a Complication of Dropped Gallstones during Laparoscopic Cholecystectomy. AB - Dropped gallstones are a relatively common complication, occurring in 3% to 32% of laparoscopic cholecystectomies performed, depending on various intraoperative risk factors. However, complications arising from dropped gallstones are relatively rare, occurring in fewer than 1% of such patients, and can include abscesses and inflammatory masses confined to the subhepatic space, presenting days to years later. We report a patient who developed an infected renal cyst as a result of dropped gallstones, which created a fistula from the duodenum to a previously simple right renal cyst, which was initially identified on an abdominal CT scan. Dropped gallstones can result in substantial morbidity in a minority of patients following cholecystectomy performed for cholecystitis, and a high clinical as well as radiological index of suspicion may be required for accurate early recognition and treatment. PMID- 30405921 TI - West Nile Encephalitis, an Unusual Infection in a Chronic Lymphocytic Leukemia Patient. AB - CNS involvement by CLL is a rare occurrence, usually happening in the context of a transformation to a more aggressive lymphoma in what is known as Richter's transformation. We report a patient with active CLL who developed confusion and was found to have West Nile encephalitis that initially mimicked CNS involvement by CLL. The patient recovered with supportive treatment and later restarted ibrutinib therapy. This case illustrates the importance of maintaining a broad differential among cancer patients with new onset confusion as well as that of questioning malignant infiltration of CNS when there is concomitant active CNS infection. PMID- 30405922 TI - An Unprecedented Case of p190 BCR-ABL Chronic Myeloid Leukemia Diagnosed during Treatment for Multiple Myeloma: A Case Report and Review of the Literature. AB - We report the case of a 76-year-old man who was diagnosed as having chronic myeloid leukemia (CML) with p190 BCR-ABL while receiving treatment for symptomatic multiple myeloma (MM). The diagnosis of MM was based on the presence of serum M-protein, abnormal plasma cells in the bone marrow, and lytic bone lesions. The patient achieved a partial response to lenalidomide and dexamethasone treatment. However, 2 years after the diagnosis of MM, the patient developed leukocytosis with granulocytosis, anemia, and thrombocytopenia. Bone marrow examination revealed Philadelphia chromosomes and chimeric p190 BCR-ABL mRNA. Fluorescence in situ hybridization also revealed BCR-ABL-positive neutrophils in the peripheral blood, which suggested the emergence of CML with p190 BCR-ABL. The codevelopment of MM and CML is very rare, and this is the first report describing p190 BCR-ABL-type CML coexisting with MM. Moreover, we have reviewed the literature regarding the coexistence of these diseases. PMID- 30405923 TI - An X-Linked Hyper-IgM Patient Followed Successfully for 23 Years without Hematopoietic Stem Cell Transplantation. AB - When caring for patients with life-limiting diseases, improving survival and optimizing quality of life are the primary goals. For patients with X-linked hyper-IgM syndrome (XHIGM), the treatment modality has to be decided for a particular patient regarding hematopoietic stem cell transplantation or intravenous immunoglobulin replacement therapy with P. jiroveci prophylaxis. A seven-year-old male patient was admitted with recurrent upper and lower respiratory tract infections and recurrent otitis media. His initial immunologic evaluation revealed low IgG and normal IgA and IgM levels with normal lymphocyte phenotyping and inadequate specific antibody responses. He was diagnosed as common variable immunodeficiency and began to receive intravenous immunoglobulin (IVIG) (0.5 gm/kg) with four-week intervals. During follow-up for 23 years under IVIG therapy, he was extremely well and never had severe infections. In 2017, targeted next generation sequencing was performed in order to understand his molecular pathology. A previously described hemizygous c.31C>T(p.Arg11Ter) mutation was found in CD40LG gene. The mother was heterozygous carrier for this mutation and his sister did not have any mutation. Flow cytometric analysis for CD40LG expression on activated T cells showed highly decreased, but not absent, CD40LG expression. In conclusion, diagnostic delay is a clinical problem for patients with CD40LG deficiency, because of low or normal IgM levels, showing that all the hypogammaglobulinemic patients, not only with high serum IgM levels, but also with normal to low IgM levels, have to be examined for CD40LG expression on activated T lymphocytes. Secondly, type of CD40LG mutations leads to enormous interpatient variations regarding serum IgM levels, CD40LG levels on activated T cells, age at diagnosis, severity of clinical findings, and follow-up therapies with or without hematopoietic stem cell therapy. PMID- 30405924 TI - First Case of Pleural Empyema Caused by Staphylococcus simulans: Review of the Literature. AB - Staphylococcus simulans is a coagulase-negative organism, mainly an animal pathogen. Reports of human infection have been infrequent, mainly in patients with repeated animal contact. We report the first case of pleural empyema in an elderly woman. S. simulans tends to cause more severe infection because of a biofilm layer which helps in adherence and colonization of smooth surfaces, especially prosthetic devices, shunts, and catheters. The challenging problem even after CoNS isolation and identification is the assessment of their clinical relevance. Major factors that inhibit the penetration of antibiotics is the large sized effusions/empyema, thickness of pleura, and the nature of antibiotic itself. Source control for septic patients remains the cornerstone of treatment along with optimal antimicrobial coverage. Staphylococcus simulans, a coagulase negative staphylococcus, is emerging as an important cause of virulent infections with high mortality in humans. Given its propensity for multidrug resistance, including vancomycin, there is an imperative for early and accurate identification of the isolate. Despite aggressive treatment, the patient succumbed to her illness. PMID- 30405925 TI - Acute Abdomen due to Mutual Tangle of Two Small Paratubal Cysts. AB - A 30-year-old woman (gravida 0) visited our hospital with a complaint of right lower abdominal pain. Transvaginal ultrasonography revealed a 5-cm swollen right ovary, which was suspected to be a mature cystic teratoma. Pelvic examination revealed moderate pain. Contrast-enhanced computed tomography showed a 44-mm cystic mass containing fat and calcified material in the right pelvis. Since torsion was suspected, emergent laparoscopic surgery was performed. Intraoperative findings were a swollen right ovary without torsion or congestion. Two small pedunculated 1- and 2-cm diameter paratubal cysts that grew from almost the same place of the ampulla of the right fallopian tube were observed. The thin stalk of the 1-cm paratubal cyst was entangled around the stalk of the 2-cm paratubal cyst, with its head congested. Through a small abdominal laparoscopic incision, the tumor of the right ovary and the two paratubal cysts were excised. Histopathological examination revealed that the right ovarian tumor was a mature cystic teratoma, and the two paratubal cysts had no malignancy. This case showed that only a 2-cm tumor with congestion caused the acute abdomen. PMID- 30405926 TI - Conservative Management of Abnormally Invasive Placenta Previa after Midtrimester Foetal Demise. AB - We present the case of a midtrimester intrauterine foetal demise (IUFD) in the context of abnormally invasive placentation. This was a grade 4 placenta previa with placenta increta in a patient requesting fertility conservation and was managed conservatively without immediate surgical intervention. The patient spontaneously delivered the fetus after 33 days, followed by a large obstetric haemorrhage requiring immediate laparotomy and hysterotomy. Her uterus was preserved and she went on to recover without further significant complication. While conservative management of morbidly adherent placentas has been well documented, there are no published cases of this strategy in the context of IUFD and fertility preservation. PMID- 30405927 TI - Severe Hypocalcemia and Hypomagnesemia with Denosumab in Advanced Chronic Kidney Disease: Case Report and Literature Review. AB - Background: Denosumab has become the preferred agent over zolendronic acid to help prevent skeletal-related events in patients with metastatic bone disease and multiple myeloma because it is approved for use in those with kidney dysfunction. However, denosumab has been linked to cases of hypocalcemia, particularly in those with advanced kidney disease. Case Presentation: We present the case of a patient with metastatic prostate cancer and chronic kidney disease due to obstructive nephropathy who developed severe hypocalcemia and hypomagnesemia after denosumab injection, which required intensive care unit admission, aggressive calcium supplementation, and hemodialysis assistance. We reviewed the evidence behind the safety profile of denosumab in chronic kidney disease, and we also looked at additional factors that may precipitate severe hypocalcemia with denosumab in advanced kidney disease. Conclusion: We believe that denosumab should be avoided in advanced chronic kidney disease due to the potential life threatening, severe hypocalcemia that has been observed. PMID- 30405928 TI - Acute Posterior Multifocal Placoid Pigment Epitheliopathy Associated with Gastrointestinal Stromal Tumor and Hurthle Cell Tumor. AB - Acute posterior multifocal placoid pigment epitheliopathy (APMPEE) is a chorioretinal inflammatory disease of unknown origin. Patients usually present with a rapid loss of central/paracentral vision over the course of a week in both eyes. The fundus exhibits rapid appearance of multiple deep subretinal yellow white, flat lesions at the RPE/choriocapillaris level. This in turn causes changes of both the ellipsoid zone and RPE which can result in permanent central vision loss. The pathogenesis is controversial but is associated with a recent viral illness and can involve the central nervous system with concern for cerebral vasculitis. Rare reports of APMPEE associated with systemic vasculitis such as Wegener's granulomatosis and malignancy such as clear cell renal carcinoma have been reported. We report a case of APMPEE with concurrent diagnosis of gastrointestinal stromal tumor and Hurthle cell tumor. While such association may well be coincidental, the near simultaneous presentation raised our suspicion for potential association. PMID- 30405929 TI - Endovascular Management of a Refractory Pseudoaneurysm of the Sternocleidomastoid Artery Caused by Attempted Internal Jugular Central Line Placement with Long-Term Follow-Up: A Case Report and Review. AB - Introduction: This case report shows successful treatment of a refractory sternocleidomastoid branch of the superior thyroid artery (SBSTA) pseudoaneurysm using endovascular glue embolization in a patient who refused surgery. Case Presentation: A 63-year-old female with multiple comorbidities presented with a firm 7 cm tender mass located in the right neck. Ultrasound showed pseudoaneurysm and a 7 * 3.3 * 4 cm multilobular hematoma in the location of the previous central line. CTA showed a corresponding heterogeneous mass. Serial imaging demonstrated enlargement over 2 weeks. Angiogram showed contrast blush off of the SBSTA. Management and Outcome: SBSTA was embolized using glue. Repeat angiogram showed embolization and no contrast blush. One month later, the mass was no longer pulsatile but present on physical exam. CTA showed decreased size. 8 months later, her neck was soft without mass. Discussion: Pseudoaneurysms of the external carotid artery are rare and usually due to trauma. Pseudoaneurysms after central line placement are documented, but most are complications of femoral central lines. A handful of cases of superior thyroid artery pseudoaneurysms due to several etiologies are reported, but none involving the SBSTA. Therapeutic options include surveillance, compression, thrombin injection, embolization, and surgery. Endovascular management offers an alternative for patients unwilling or unable to undergo open surgery. PMID- 30405930 TI - Nasal Chondromesenchymal Hamartoma: Rare Case Report in an Elderly Patient and Brief Review of Literature. AB - Hamartomas are considered a mixture of nonneoplastic tissue, which may be indigenous to a different location in the body. As such, they may be epithelial, mesenchymal, or mixed. In the sinonasal region, the following hamartomatous lesions are considered to lie on a spectrum and include respiratory epithelial adenomatoid hamartoma (REAH), chondro-osseous respiratory epithelial adenomatoid hamartoma (COREAH), and nasal chondromesenchymal hamartoma (NCMH). To our knowledge, less than 50 cases of sinonasal hamartomas have been reported in the English literature so far with NCMH being very rare and primarily a tumor in infancy, with only 2 cases reported in individuals older than 16 years of age. We report a highly unusual case of a NCMH in the right maxillary sinus of a 70-year old female. PMID- 30405931 TI - Hirschsprung's Associated Enterocolitis (HAEC) Personalized Treatment with Probiotics Based on Gene Sequencing Analysis of the Fecal Microbiome. AB - Approximately 40% of children with Hirschsprung's disease (HD) suffer from Hirschsprung's associated enterocolitis (HAEC) despite correct surgery. Disturbances of the intestinal microbiome may play a role. Treatment with probiotics based on individual analyses of the fecal microbiome has not been published for HD patients with recurrent HAEC yet. A boy with trisomy 21 received transanal pull-through at the age of 6 months for rectosigmoid HD. With four years, he suffered from recurrent episodes of HAEC. The fecal microbiome was measured during three healthy and three HAEC episodes by next-generation sequencing. The patient was started on daily probiotics for 3 months; the fecal microbiome was measured weekly. The fecal microbiome differed significantly between healthy and HAEC episodes. HAEC episodes were associated with significant decreases of Actinobacteria and significant increases of Bacteroidetes and Proteobacteria. Probiotic treatment led to a significant increase of alpha diversity and a significant increase of Bifidobacterium and Streptococcus as well as decreases of Rikenellaceae, Pseudobutyrivibrio, Blautia, and Lachnospiraceae. A longitudinal observation of the microbiome has never been performed following correction of Hirschsprung's disease. Probiotic treatment significantly changed the fecal microbiome; the alterations were not limited to strains contained in the administered probiotics. PMID- 30405932 TI - A Case of Multiple Myeloma Misdiagnosed as Seronegative Rheumatoid Arthritis and Review of Relevant Literature. AB - Multiple myeloma (MM) is a malignant plasma cell proliferation producing large numbers of monoclonal immunoglobulins. Typical MM symptoms include anemia, renal failure, hypercalcemia, and bone pain. Atypical symptoms have rarely been reported in the literature. We report a case of a 58-year-old male who presented with symmetrical inflammatory polyarthritis and was misdiagnosed with seronegative rheumatoid arthritis (RA). After failing many RA treatments and with further workup, the diagnosis of MM was made. This rare manifestation of MM carries a diagnostic challenge and causes a significant delay in treating such patients. Here, we report this unusual initial presentation with review of several cases in the English literature describing similar presentations. PMID- 30405933 TI - Pharmacokinetics and UPLC-MS/MS of Delsoline in Mouse Whole Blood. AB - Delsoline, a major alkaloid of Delphinium anthriscifolium Hance, has both a curare-like effect and a ganglion-blocking effect and is used to relieve muscle tension or hyperkinesia. A ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was established for the determination of delsoline in mouse blood, and the pharmacokinetics of delsoline after intravenous administration (1 mg/kg) and intragastric administration (9, 6, and 3 mg/kg) were studied. Gelsenicine served as an internal standard, and a UPLC BEH C18 chromatographic column was used. The mobile phase consisted of acetonitrile and 0.1% formic acid; the gradient elution flow rate was 0.4 mL/min. The MRM model was used for the quantitative analysis of delsoline m/z 468.3?108.1 and the internal standard m/z 327.1?296.1. Mouse blood samples were treated with acetonitrile precipitation to remove proteins. In the concentration range of 0.1 1000 ng/mL, delsoline in mouse blood showed a good linearity (r 2 > 0.995), and the lower limit of quantitation was 0.1 ng/mL. The intraday precision relative standard deviation (RSD) was below 14%, and the interday precision RSD was below 15%. The accuracy ranged between 94.3% and 110.1%, the average recovery was above 90.8%, and the matrix effect ranged between 97.0% and 102.5%. The UPLC-MS/MS method was sensitive, rapid, and selective in the study of pharmacokinetics of delsoline. The absolute bioavailability of delsoline was 20.9%. PMID- 30405934 TI - Our heritage and beyond. PMID- 30405935 TI - Early Wound Healing Score: a system to evaluate the early healing of periodontal soft tissue wounds. AB - Purpose: Numerous indices have been proposed to analyse wound healing in oral soft tissues, but each has specific shortcomings. A new method of analysis, the Early Wound Healing Score (EHS), was evaluated in the present study. The aim was to assess more accurately early healing by primary intention of surgical incisions in periodontal soft tissues. Methods: Twenty-one patients were treated with different surgical procedures comprising 1 or 2 vertical releasing incisions as part of a surgical access flap. Twenty-four hours after surgery, early wound healing at the vertical releasing incisions was assessed using the EHS. This score assessed clinical signs of re-epithelialization (CSR), clinical signs of haemostasis (CSH), and clinical signs of inflammation (CSI). Since complete wound epithelialization was the main outcome, the CSR score was weighted to be 60% of the total final score. Accordingly, a score of 0, 3, or 6 points was possible for the assessment of CSR, whereas scores of 0, 1, or 2 points were possible for CSH and CSI. Higher values indicated better healing. Accordingly, the score for ideal early wound healing was 10. Results: Thirty vertical releasing incisions were assessed in 21 patients. At 24 hours after incision, 16 vertical releasing incisions (53.33%) received the maximum score of CSR, while 6 cases (20%) received an EHS of 10. None of the cases received 0 points. Conclusion: The EHS system may be a useful tool for assessing early wound healing in periodontal soft tissue by primary intention after surgery. PMID- 30405936 TI - Estrogen reinforces barrier formation and protects against tumor necrosis factor alpha-induced barrier dysfunction in oral epithelial cells. AB - Purpose: Epithelial barrier dysfunction is involved in the pathophysiology of periodontitis and oral lichen planus. Estrogens have been shown to enhance the physical barrier function of intestinal and esophageal epithelia, and we aimed to investigate the effect of estradiol (E2) on the regulation of physical barrier and tight junction (TJ) proteins in human oral epithelial cell monolayers. Methods: HOK-16B cell monolayers cultured on transwells were treated with E2, an estrogen receptor (ER) antagonist (ICI 182,780), tumor necrosis factor alpha (TNFalpha), or dexamethasone (Dexa), and the transepithelial electrical resistance (TER) was then measured. Cell proliferation was measured by the cell counting kit (CCK)-8 assay. The levels of TJ proteins and nuclear translocation of nuclear factor (NF)-kappaB were examined by confocal microscopy. Results: E2 treatment increased the TER and the levels of junctional adhesion molecule (JAM) A and zonula occludens (ZO)-1 in a dose-dependent manner, without affecting cell proliferation during barrier formation. Treatment of the tight-junctioned cell monolayers with TNFalpha induced decreases in the TER and the levels of ZO-1 and nuclear translocation of NF-kappaB. These TNFalpha-induced changes were inhibited by E2, and this effect was completely reversed by co-treatment with ICI 182,780. Furthermore, E2 and Dexa presented an additive effect on the epithelial barrier function. Conclusions: E2 reinforces the physical barrier of oral epithelial cells through the nuclear ER-dependent upregulation of TJ proteins. The protective effect of E2 on the TNFalpha-induced impairment of the epithelial barrier and its additive effect with Dexa suggest its potential use to treat oral inflammatory diseases involving epithelial barrier dysfunction. PMID- 30405937 TI - Clinical and microbiological effects of the supplementary use of an erythritol powder air-polishing device in non-surgical periodontal therapy: a randomized clinical trial. AB - Purpose: This study was undertaken to evaluate the clinical and microbiological effects of an erythritol powder air-polishing device (EPAP) as a supplement to scaling and root planing (SRP) therapy in patients with moderate chronic periodontitis. Methods: Clinical and microbiological evaluations were performed at 21 sites treated with SRP (control) and 21 sites treated with SRP+EPAP (test). All examinations were performed before treatment, 1 month after treatment, and 3 months after treatment. Results: There were no significant clinical differences between the test group and the control group. Microbiological analysis revealed that the relative expression level of Porphyromonas gingivalis was significantly lower in the test group than in the control group at 1 month after treatment. Clinical and microbiological results showed improvements at 1 month compared to baseline; in contrast, the results at 3 months after treatment were worse than those at 1 month after treatment. Conclusions: In this study, both SRP and SRP+EPAP were clinically and microbiologically effective as non-surgical periodontal treatments. In particular, the SRP+EPAP group showed an antimicrobial effect on P. gingivalis, a keystone bacterium associated with the onset of chronic periodontitis, in a short-term period. Periodic periodontal therapy, at intervals of at least every 3 months, is important for sustaining the microbiological effects of this treatment. PMID- 30405939 TI - Panoramic radiography can be an effective diagnostic tool adjunctive to oral examinations in the national health checkup program. AB - Purpose: We investigated correlations between the findings of oral examinations and panoramic radiography in order to determine the efficacy of using panoramic radiographs in screening examinations. Methods: This study included patients who visited dental clinics at National Health Insurance Service (NHIS) Ilsan Hospital for checkups during 2009-2015 and underwent panoramic radiographic examinations within 1 year prior to the oral examinations. Among the 48,006 patients who received checkups, 1,091 were included in this study. The data were evaluated using the Cohen kappa and interrater agreement coefficients. Accuracy, sensitivity, and specificity were calculated using data from the panoramic radiographs as true positive diagnoses. Results: The interrater agreement coefficient for occlusal caries was 28.8%, and the Cohen kappa coefficient was 0.043 between the oral and panoramic radiographic examinations. Root caries and subgingival calculus were only found on the radiographs, while gingival inflammation was found only by the oral examinations. The oral examinations had a specificity for detecting occlusal dental caries of 100%, while their sensitivity for proximal dental caries and supragingival calculus was extremely low (14.0% and 18.3%, respectively) compared to the panoramic radiographic examinations. The oral examinations showed a relatively low sensitivity of 66.2% and a specificity of 43.7% in detecting tooth loss compared with panoramic radiography. Conclusions: Panoramic radiography can provide information that is difficult to obtain in oral examinations, such as root caries, furcation involvement, and subgingival calculus, which are factors that can directly affect the survival rate of teeth. It therefore seems reasonable and necessary to add panoramic radiography to large-scale health checkup programs such as that provided by the NHIS. PMID- 30405940 TI - Simplified nonsurgical treatment of peri-implantitis using chlorhexidine and minocycline hydrochloride. AB - Purpose: The present study investigated the outcomes of a newly-developed, simple, and practical nonsurgical treatment modality suitable for most forms of intrabony defects around failing dental implants using intrasulcular delivery of chlorhexidine solution and minocycline hydrochloride (HCl). Methods: Forty-five dental implants in 20 patients diagnosed with peri-implantitis were included. At baseline and the study endpoint, the probing pocket depth (PPD), clinical attachment level (CAL), and the presence of bleeding on probing (BOP) at 6 sites around each implant were recorded. The radiographic osseous defect morphology at the mesial or distal proximal aspect of each implant was classified as 1) narrow or wide and 2) shallow or deep. For a comparative analysis of bone changes according to the defect morphology, the distance from the implant shoulder to the most coronal bone-to-implant contact point (DIB) at the mesial and distal aspects of each implant was measured at baseline and the endpoint. Patients were scheduled to visit the clinic every 2-4 weeks for intrasulcular irrigation of chlorhexidine and delivery of minocycline HCl. Results: We observed statistically significant decreases in PPD, CAL, and BOP after treatment. At the endpoint, bone levels increased in all defects, regardless of the osseous morphology of the intrabony defect. The mean DIB change in deep defects was significantly greater than that in shallow defects. Although the mean bone gain in narrow defects was greater than in wide defects, the difference was not statistically significant. Conclusions: We propose that significant and sustainable improvements in both clinical and radiographic parameters can be expected when intrabony defects around dental implants are managed through a simple nonsurgical approach involving combined intrasulcular chlorhexidine irrigation and local delivery of minocycline HCl. PMID- 30405938 TI - Biomimetic characteristics of mussel adhesive protein-loaded collagen membrane in guided bone regeneration of rabbit calvarial defects. AB - Purpose: The aim of the present study was to evaluate the biocompatibility and barrier function of mussel adhesive protein (MAP)-loaded collagen membranes in guided bone regeneration (GBR). Methods: Eight male New Zealand white rabbits were used. Four circular defects (diameter: 8 mm) were created in the calvarium of each animal. The defects were randomly assigned to 1) a negative control group, 2) a cyanoacrylate (CA)-loaded collagen membrane group (the CA group), 3) a MAP-loaded collagen membrane group (the MAP group), and 4) a group that received a polycaprolactone block with MAP-loaded collagen membrane (the MAP-PCL group). Specimens were harvested at 2 weeks (n=4) and 8 weeks (n=4) postoperatively for observational histology and histometric analysis. Results: In the histologic analysis, MAP was completely absorbed without any byproducts. In contrast, some of the CA adhesive remained, showing an inflammatory reaction, at 8 weeks. In the MAP-PCL group, the MAP-loaded collagen membranes served as a barrier membrane despite their fast degradation in GBR. No significant difference was found in the amount of new bone between the MAP-PCL and MAP groups (1.82+/ 0.86 mm2 and 2.60+/-0.65 mm2, respectively). Conclusions: The MAP-loaded collagen membrane functioned efficiently in this rabbit calvarial GBR model, with excellent biocompatibility. Further research is needed to assess clinical applications in defect types that are more challenging for GBR than those used in the current model. PMID- 30405941 TI - Three Single Nucleotide Polymorphisms of LOXL1' in a Turkish Population with Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma. AB - Objectives: To investigate the three single nucleotide polymorphisms (SNPs) (rs3825942, rs1048661, and rs2165241) of the LOXL1 gene in pseudoexfoliation syndrome (XFS) and pseudoexfoliation glucoma (XFG) in the Turkish population. Materials and Methods: DNA was obtained from blood samples of 48 XFS, 58 XFG, and 171 control subjects. Three LOXL1 SNPs (rs3825942, rs1048661, rs2165241) were investigated with real time PCR, a probe-based genotyping method, and melting curve analysis. Results: All three SNPs of LOXL1 were significantly associated with XFS (rs3825942 p=3.54x10-6, odds ratio [OR]=infinity; rs1048661 p=0.008, OR=2.18; rs2165241 p=8.69x10-9, OR=4.30) and XFG (rs3825942 p=3.41x10-7, OR=infinity; rs1048661 p=1.75x10-5, OR=3.78; rs2165241 p=3.85x10-11 OR=4.90). No significant differences were observed between the XFS and XFG groups for any of the SNPs. The GG genotype of rs3825942 was more valuable for distinguishing pseudoexfoliative cases from healthy individuals. The homozygous TT genotype of rs2165241 was associated with 6-fold increased XFS risk (p=8.15x10-8, OR=6.32) and 7-fold increased XFG risk (p=1.45x10-10 OR=7.95). The GGT haplotype consisting of all three risk alleles was associated with a 7.45-fold higher risk of XFS/XFG (p=8.65x10-14, OR=7.45). Presence of T allele of rs2165241 conferred 3 times higher risk for men than women (p=6.78x10-5, OR=3.202). Conclusion: LOXL1 SNPs are associated with increased risk for pseudoexfoliation in the Turkish population. T allele of rs2165241 was found to be the most important characterized risk factor for our cohort. All SNP distributions were similar to other European and American populations. PMID- 30405942 TI - Does Fluid Temperature Affect Corneal Endothelium-Descemet Membrane Scroll Formation? An In Vitro Study. AB - Objectives: To investigate whether unfolding time of Descemet membrane (DM) graft rolls changes at various fluid temperatures. Materials and Methods: The study was prospective, ex vivo, and experimental. The study was conducted at the tertiary center for corneal disease in Adana Numune Training and Research Hospital between June 2014 and June 2015. DMs were divided into 4 categories according to baseline roll tightness and these were distributed among 4 different groups using 4 different balanced salt solution (BSS) temperatures (8, 16, 23, and 36 degrees C). Sixteen donor corneas were obtained from the hospital eye bank. Results: DM roll formations may vary according to the donor cornea received. Some form tighter rolls while others can form a more open roll. No differences in roll tightness were observed in any of the DM rolls after 5 or 10 minutes in the different BBS temperatures. In all groups, neither tightening nor opening was observed in DM roll formations. Conclusion: Different BSS temperatures were found to have no effects on DM unfolding time in this study. PMID- 30405943 TI - Evaluation of Anterior Segment Parameters in Pseudoexfoliative Glaucoma, Primary Angle-Closure Glaucoma, and Healthy Eyes. AB - Objectives: To evaluate anterior segment parameters measured by dual Scheimpflug corneal topography in pseudoexfoliative glaucoma (PEXG), primary angle-closure glaucoma (PACG), and healthy eyes. Materials and Methods: One hundred forty-three eyes of 86 patients were included in this study. Forty-seven eyes of 38 patients with PEXG, 30 eyes of 15 patients with PACG, and 66 eyes of 33 healthy subjects were evaluated. Patients who underwent previous ophthalmic surgery and contact lens wearers were excluded. After full ophthalmological examination, mean central corneal thickness (CCT), white-to-white horizontal corneal diameter (WTW), pupillary diameter (PD), anterior chamber volume (ACV), anterior chamber depth (ACD), and mean anterior chamber angle were measured by dual Scheimpflug corneal topography and compared between the three groups. Statistical analyses were done using Statistical Package for Social Sciences for Windows 18.0 program. Results: No statistical difference was found in mean age or gender among the study groups (p>0.05). There were also no statistical differences in CCT, WTW, or PD among the groups (p=0.568, p=0.064, p=0.321, respectively). ACV, ACD, and mean anterior chamber angle values were significantly lower in the PACG group compared to the other groups (p=0.000 for all). There was no statistically significant difference in these measurements between the PEXG and normal eyes. Conclusion: ACV and depth and mean anterior chamber angle were statistically different (lower) in PACG when compared with PEXG and healthy eyes. Dual Scheimpflug corneal topography can be used as an objective method for the measurement of anterior segment parameters in glaucoma. PMID- 30405945 TI - Evaluation of the Relationship Between Age-related Macular Degeneration and Refractive Error, Socio-demographic Features, and Biochemical Variables in a Turkish Population. AB - Objectives: To investigate the relationship between age-related macular degeneration (AMD) and refractive error and axial length, as well as the socio demographic characteristics and biochemical variables that may affect this relationship. Materials and Methods: A total of 196 eyes of 98 patients over 50 years of age who were diagnosed with AMD at our clinic were included in this cross-sectional study. Early and late AMD findings were categorized according to the age-related eye disease study grading scale. Objective refractive error was measured by autorefractometer, confirmed by subjective examination, and spherical equivalent was calculated. Refractive errors of -0.50 D to 0.50 D were classified as emmetropia, <-0.50 D as myopia, and >0.50 D as hyperopia. Axial length was measured by ultrasonic biometry and values <=23.00 mm were classified as short, >23.00 and <24.00 mm as normal, and >=24.00 mm as long axial length. Demographic, systemic, and biochemical parameters of all patients were also investigated. Results: Hypermetropic refractive error and shorter axial length were significantly more common than the other groups (p<0.01). No differences were observed between early and late stage groups in terms of refractive error and axial length. Patients with myopia had significantly lower values for total cholesterol, triglyceride, fasting blood glucose, and proportion of smokers. Rates of oral nutritional supplement use and fish consumption were significantly higher in the early AMD group. The most common comorbidity among the AMD patients in our study was essential hypertension. Conclusion: Hyperopic refractive error and shorter axial length were found to be associated with AMD. Longitudinal studies including larger patient numbers are needed to elucidate the causal and temporal relationship between hyperopic refractive error and AMD. PMID- 30405944 TI - Real-World Outcomes of Anti-VEGF Treatment for Neovascular Age-Related Macular Degeneration in Turkey: A Multicenter Retrospective Study, Bosphorus Retina Study Group Report No: 1. AB - Objectives: To evaluate the real-world outcomes of intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment in neovascular age-related macular degeneration (nAMD) patients. Materials and Methods: Multicenter, retrospective, interventional, non-comparative study. The records of nAMD patients treated with an anti-VEGF agent on a pro re nata treatment regimen basis between January 2013 and December 2015 were reviewed. The patients who completed a follow-up period of 12 months were included. Primary outcome measures of this study were the visit and injection numbers during the first year. Results: Eight hundred eighty eyes of 783 patients met the inclusion criteria for the study. Mean number of visits at month 12 was 6.9+/-2.5 (range: 1-15). Mean number of injections at month 12 was 4.1+/-1.9 (range: 1-11). Mean visual acuity at baseline and months 3, 6, and 12 was 0.90+/-0.63 LogMAR (range: 0.0-3.0), 0.79+/ 0.57 LogMAR (range: 0.0-3.0), 0.76+/-0.57 LogMAR (range: 0.0-3.0), and 0.79+/ 0.59 LogMAR (range: 0.0-3.0), respectively. Mean central retinal thickness at baseline and months 6 and 12 was 395+/-153 MUm (range: 91-1582), 330+/-115 MUm (range: 99-975), and 332+/-114 MUm (range: 106-1191), respectively. Conclusion: The numbers of visits and injections were much lower than ideal and were insufficient with the pro re nata treatment regimen. PMID- 30405946 TI - Short-term Efficacy of Micropulse Yellow Laser in Non-center-involving Diabetic Macular Edema: Preliminary Results. AB - Objectives: The aim of this study was to evaluate the efficacy of micropulse yellow laser (MPL) on best corrected visual acuity (BCVA) and retinal thickness in patients with non-center-involving diabetic macular edema (DME). Materials and Methods: We retrospectively reviewed 9 eyes of 8 patients with non-center involving DME who underwent MPL treatment between January 2015 and December 2016. BCVA (logMAR) and retinal thickness were evaluated before and 3 months after treatment. Maximum retinal thickness was determined manually from simultaneous spectral-domain optical coherence tomography images and recorded. The change in the measurements from before to after treatment was analyzed statistically. Results: Of the 8 patients, 3 were female and 5 were male. The mean age was 52.8 years. Two of the 9 eyes had received previous intravitreal anti-vascular endothelial growth factor injection(s). Median BCVA was improved 3 months after treatment, although the difference was not statistically significant (0.34 logMAR before and 0.29 logMAR after treatment). BCVA was improved in 4 eyes while it showed no change in the remaining 5 eyes. The mean retinal thickness was 470.6 MUm at baseline and 416 MUm at 3 months after MPL treatment (p=0.01). Retinal thickness decreased in all eyes after treatment. Conclusion: In this study, parafoveal retinal thickness showed significant decrease after MPL treatment in patients with DME. The limited increase in BCVA may be due to the inclusion of a low number of patients and only those with non-center-involving macular edema. MPL may be used as an alternative to conventional argon laser in non-center involving DME. PMID- 30405947 TI - Binocular Indirect Ophthalmoscopy Complements Non-contact Wide-field Imaging with Optos to Treat a Baby Outside ETROP Guidelines. AB - We report a male premature baby who was born at 24 weeks gestation weighing 600 grams. There was bilateral stage 2, zone 2 retinopathy of prematurity (ROP) without plus disease at 38 weeks postmenstrual age. Ultra-wide-field Optomap images obtained 1 week later showed no change in ROP stage. At 40 weeks postmenstrual age, stage 3, zone 2 ROP was detected using binocular indirect ophthalmoscopy and documented using Optos. Minor tortuosity and dilation of vessels was interpreted as pre-plus disease. One week later, at 41 weeks postmenstrual age, Optomap images identified progressive extraretinal fibroproliferation in the nasal quadrant. As a result, the baby was treated with fundus laser photocoagulation. PMID- 30405948 TI - Bilateral Serous Macular Detachment After Attempted Suicide with Pregabalin. AB - A 24-year-old female presented with bilateral vision loss following attempted suicide with pregabalin. Her best-corrected visual acuity (BCVA) was 20/40 in the right eye and 20/50 in the left eye. The bilateral visual disturbance was associated with serous macular detachment. Fundus examination of both eyes showed foveal serous retinal detachment, which was confirmed by optical coherence tomography. Topical nepafenac 0.1% eye drops were started as single drop every 8 hours for 4 weeks. One month later, the serous macular detachment had regressed and BCVA increased to 20/20 in both eyes. To the best of our knowledge, this is the first reported case of bilateral serous macular detachment presumably caused by pregabalin intoxication. PMID- 30405949 TI - Toxocara Neuroretinitis Associated with Raw Meat Consumption. AB - Neuroretinitis characterized by optic disc edema and star-like exudates in the macula was detected in a patient who presented with sudden unilateral painless vision loss and had a history of raw meat consumption. The patient tested seropositive for Toxocara. Combination therapy with steroid and albendazole resulted in an increase in visual acuity and complete resolution of clinical signs. PMID- 30405950 TI - Multimodal Imaging in Pachychoroid Neovasculopathy: A Case Report. AB - Pachychoroid neovasculopathy (PNV) is a form of type 1 neovascularization characterized by dilated choroidal vessels in areas of increased choroidal thickness. In this article, we describe a patient diagnosed with PNV. A 50-year old male with a 2-month history of blurred vision was referred to our clinic. His best corrected visual acuity was 20/100 in both eyes. Retinal pigment epithelium alterations, which were more prominent in fundus autofluorescence, were detected in both eyes on dilated fundus examination. Characteristic findings of PNV were detected in fundus fluorescein angiography, indocyanine green angiography, spectral domain optical coherence tomography, and optical coherence tomography angiography. PMID- 30405951 TI - Clinical Features and Surgical Results in Harada-Ito Surgery Patients. AB - Symptomatic excyclotorsion is an important clinical problem, especially in acquired superior oblique muscle palsy. Excyclotorsion can disrupt the fusion and cause torsional diplopia. Harada-Ito surgery (HI) is a widely used method for treating excyclotorsions. This method relieves the torsional diplopia by increasing the effect of the incyclotorsion. In this study, we aimed to report the clinical features of patients with torsional diplopia due to acquired trochlear nerve palsy and the results of HI surgery in these patients. PMID- 30405952 TI - Topography and Higher Order Corneal Aberrations of the Fellow Eye in Unilateral Keratoconus. PMID- 30405953 TI - Meniscal Root Repairs. AB - Meniscal root tears are substantial injuries that usually require surgical management. If left untreated, meniscal root tears can lead to the rapid onset of osteoarthritis similar to that seen after a total meniscectomy. Meniscal root tears often go unnoticed on magnetic resonance imaging and arthroscopy, in large part because meniscal root anatomy and its biomechanical importance have been defined only recently. In a transtibial meniscal root repair, the current clinical standard of care, the root is reattached to its native attachment site on the tibial plateau, restoring tibiofemoral contact mechanics. While this video article shows a posterior medial root repair technique, the same anatomic, biomechanical, and surgical principles apply to a posterior lateral meniscal root attachment. The principal steps in this procedure include (1) verifying the presence of a posterior medial meniscal root tear with arthroscopic visualization and probing, (2) inspecting the root tear and debriding the root attachment site to bone with a curet, (3) arthroscopic release of any adhesions that cause retraction of the meniscal root to a nonanatomic position, (4) drilling of two separate transtibial tunnels that extend down to the anteromedial portion of the tibia, (5) placing an accessory portal to pass the sutures, (6) placing two simple sutures through the torn meniscal root and shuttling them down the tibial tunnels, and (7) tying the sutures over a surgical button on the anteroproximal portion of the tibia with the knee flexed 90 degrees . Postoperatively, patients remain non-weight-bearing for six weeks. Passive knee flexion from 0 degrees to 90 degrees is allowed for the first two weeks. After two weeks, motion is increased as tolerated. Patients initiate weight-bearing at postoperative week six and commence the use of a stationary bicycle. Resistive exercises are slowly progressed, and the patient should avoid squatting as well as squatting and lifting for four months. Patients are expected to return to normal physical activity within four to six months postoperatively. PMID- 30405954 TI - Arthrodesis of the Hallux Metatarsophalangeal Joint. AB - Introduction: Arthrodesis of the first metatarsophalangeal joint is the most reliable surgical option, with a low complication rate, for hallux rigidus from end-stage osteoarthritis. Step 1 Surgical Approach: Make a medial approach, following the mid-axis of the joint. Step 2 Joint Preparation: Using a cup-cone configuration provides excellent bone exposure, construct stability, and metatarsophalangeal joint congruity. Step 3 Positioning of Arthrodesis: Fix the toe in 5 degrees to 10 degrees of valgus and elevated 5 mm from the floor to achieve desired dorsiflexion. Step 4 Application of Implants: Achieve a stable construct with a crossed lag screw and a dorsal locking plate (a hybrid construct). Step 5 Closure: Perform a standard soft-tissue closure. Step 6 Postoperative Care: Allow weight-bearing as tolerated after two weeks and impact exercises only after bone healing has been shown on radiographs, which can take up to ten weeks. Results: Arthrodesis of the metatarsophalangeal joint in the hallux provides good results in terms of patient satisfaction and function, as demonstrated in many studies, most of them retrospective.IndicationsContraindicationsPitfalls & Challenges. PMID- 30405955 TI - Key Procedures: On the Cutting Edge for Teaching Surgical Techniques. PMID- 30405956 TI - Direct Anterior Hip Exposure for Total Hip Arthroplasty. AB - Total hip arthroplasty through the direct anterior approach provides the only true internervous access to the hip joint. The indications are the same as those for total hip replacement performed through any other approach. If necessary, the approach can be extended proximally or distally and can be used for complex primary cases as well as for revision cases. The principal steps in the procedure include (1) preoperative planning to help the surgeon restore leg length and lateral offset and assess for possible surgical pitfalls; (2) positioning of the patient supine on a regular orthopaedic table with a bump beneath the pelvis and an additional arm-board to support the opposite leg; (3) a longitudinal skin incision starting 3 cm lateral and distal to the anterior superior iliac spine and continuing along the muscles to the tensor fasciae latae; (4) creation of an intermuscular portal by making a longitudinal incision along the interval between the tensor fasciae latae and the sartorius muscles and performing blunt dissection medial to the tensor fasciae latae; (5) exposure of the capsule by cauterizing or ligating the ascending branches of the lateral circumflex artery and removing the precapsular fat pad; (6) anterior capsulectomy and double osteotomy, done by incising the capsule along the neck and perpendicular to the neck at its attachment, excising the anterior aspect of the capsule, and then performing one osteotomy at the subcapital level and another at the base of the neck; (7) acetabular preparation and cup implantation, performed by incising the medial part of the capsule, removing the labrum and osteophytes, using standard or offset reamers for the acetabulum, and implanting the cup according to standard anatomical landmarks; (8) proximal femoral release by removing the superolateral aspect of the capsule and releasing the posterior aspect of the capsule to elevate the femur; and (9) femoral preparation and implantation, done by opening the femoral canal, broaching with a double offset broacher, and inserting the femoral component into the space created by the broachers. In a randomized, prospective, controlled trial comparing the direct anterior with the direct lateral approach1, we showed better functional outcomes with the direct anterior approach at six weeks after the surgery. At two years, the outcomes were similar between the groups. PMID- 30405957 TI - Placement of an Intramedullary Nail for the Treatment of Proximal Ulnar Fractures. AB - Introduction: The fixation of olecranon fractures with intramedullary olecranon nails has been demonstrated to be an effective treatment option that may result in decreased soft-tissue irritation. Step 1 Positioning and Approach: Proper positioning of the patient during this procedure allows for improved access to the fracture and increased accessibility for fluoroscopy. Step 2 Reduce the Fracture: Reduce and provisionally hold the fracture following a limited periosteal elevation. Step 3 Ream the Olecranon and Place the Nail: The olecranon is then reamed, and the intramedullary nail is inserted. Step 4 Insert the Screw: Place proximal interlocking screws using the targeting system. Step 5 Close the Wound: Close the wound with subdermal sutures and either staples or interrupted nylon horizontal mattress sutures. Results: A total of twenty-eight patients with unstable olecranon fractures were treated with intramedullary olecranon nailing in our series, and union was achieved in all patients by eight weeks.IndicationsContraindicationsPitfalls & Challenges. PMID- 30405958 TI - Medial and Lateral Meniscal Inside-Out Repairs. AB - Meniscal tears differ in terms of pattern and location. If left untreated, a meniscal tear can lead to the development of osteoarthritis and increased pain, swelling, and functional limitations. Tears in the vascularized outer two-thirds of the meniscus can often be successfully repaired with use of an inside-out technique. Vertical mattress sutures stabilize the meniscal tear in place, allowing for proper healing. The principal steps in the procedure include (1) assessing the location and pattern of the tear arthroscopically, (2) performing a medial or lateral meniscal repair incision in the proper anatomic location, (3) passing the sutures in a vertical mattress pattern through the torn meniscus, and (4) tying the sutures while verifying sufficient reduction of the tear arthroscopically. Postoperatively, patients remain non-weight-bearing for the course of six weeks. Passive knee flexion from 0 degrees to 90 degrees is allowed for the first two weeks. After two weeks, motion is increased as tolerated. At six weeks postoperatively, patients are allowed to progress to weight-bearing as tolerated and initiate the use of a stationary bicycle. They should avoid squatting, sitting cross-legged, and squatting and lifting for four months postoperatively to avoid substantial stress on the healing meniscus. After four months, sports-specific activities are initiated. Patients are expected to return to normal physical activity within four to six months postoperatively. PMID- 30405960 TI - Proximal Tibial Valgus Osteotomy: Lateral Closing Wedge. AB - Valgus-producing high tibial osteotomy (HTO) is a well-accepted treatment modality in active patients with varus malalignment and symptomatic medial unicompartmental osteoarthritis (OA) of the knee. One of the key factors for long term success of the osteotomy is the achievement of an even distribution of the mechanical load on the knee joint by obtaining an ideal alignment of the lower extremity mechanical axis. Proper surgical techniques are very important, and lateral closing wedge proximal tibial valgus osteotomy (CWO) is highly effective in achieving the desired overcorrection of 3 degrees to 7 degrees of valgus. The major steps of CWO are (1) preoperative planning, in which the frontal plane varus knee deformity is assessed on a standard whole-leg radiograph; (2) a transverse anterolateral incision from the tubercle toward the posterior aspect of the proximal part of the fibular head; (3) exposure and snaring of the common peroneal nerve; (4) resection of the anterior aspect of the proximal part of the fibular head; (5) use of a calibrated slotted wedge resection guide to perform the osteotomy proximal to the tuberosity under fluoroscopic guidance; (6) removal of an osseous wedge and closure of the osteotomy site, with the medial opposite cortex acting as a hinge; and (7) fixation of the osteotomy site with two step staples. Complications (e.g., nonunion, deep infection, and peroneal neuropathy) are rare. At follow-up, CWO has been shown to improve knee function and reduce pain. Male patients with early-onset knee OA have an almost ten times lower probability of failure of a CWO than women with more degenerative disease. The survival rate, with knee replacement as the end point, is approximately 75% at ten years following CWO. CWO postpones primary total knee arthroplasty (TKA) for a median of seven years, and there is low-quality evidence that osteotomy does not compromise subsequent knee replacement. PMID- 30405959 TI - Single and Dual-Incision Fasciotomy of the Lower Leg. AB - Introduction: Compartment syndrome of the leg is an orthopaedic emergency and can be treated with single or dual-incision fasciotomy, allowing for necessary decompression of all four compartments. Step 1 Single-Incision Technique Position the Patient: Place the patient supine with a bump underneath the ipsilateral buttock. Step 2 Single-Incision Technique Make the Skin Incision: An incision centered over the posterolateral aspect of the leg provides access to all four compartments of the leg. Step 3 Single-Incision Technique Decompress the Superficial Posterior Lateral and Anterior Compartments: Make longitudinal fascial incisions, approximately the length of the skin incision, in the superficial posterior, lateral, and then anterior compartments. Step 4 Single Incision Technique Decompress the Deep Posterior Compartment: Using the lateral intermuscular septum as a guide to reach the posterolateral aspect of the fibula, release the fascial attachment of the deep posterior compartment from the fibula. Step 5 Single-Incision Technique Postoperative Protocol: After appropriate operative fixation and/or debridement of nonviable tissue, dress the wounds with a VAC device. Step 1 Dual-Incision Technique Position the Patient: Position the patient, administer antibiotics, and prepare and drape the limb as described in Step 1 for the single-incision technique. Step 2 Dual-Incision Technique Make the Anterolateral Skin Incision: Make an incision centered over the anterolateral aspect of the leg to provide access to the anterior and lateral compartments of the leg. Step 3 Dual-Incision Technique Decompress the Anterior and Lateral Compartments: Make a longitudinal fascial incision in the anterior compartment anterior to the intermuscular septum and a separate longitudinal incision for decompression of the lateral compartment posterior to the intermuscular septum. Step 4 Dual-Incision Technique Make the Posteromedial Skin Incision: Make an incision centered over the posteromedial aspect of the leg to provide access to the superficial and deep posterior compartments of the leg. Step 5 Dual-Incision Technique Decompress the Superficial and Deep Posterior Compartments: Through the posteromedial skin incision, identify both the deep and the superficial posterior compartments and incise their fascia longitudinally for adequate decompression. Step 6 Dual-Incision Technique Postoperative Protocol: Follow the same postoperative protocol as outlined in Step 5 for the single-incision technique. Results: Both the single and the dual-incision techniques are effective for relieving elevated intracompartmental pressures to prevent myonecrosis.IndicationsContraindicationsPitfalls & Challenges. PMID- 30405961 TI - Posterior Arthroscopic Subtalar Arthrodesis. AB - Introduction: Although subtalar joint arthrodesis may be achieved through open or arthroscopic approaches, we have found that posterior arthroscopic subtalar arthrodesis has technical advantages compared with other approaches. Step 1 Preoperative Assessment and Planning: Clinically assess the foot and ankle with regard to remaining motion, previous scarring, and associated deformities, ensuring that no concomitant procedure will be needed in the supine position. Step 2 Positioning of the Patient: Use spinal or general anesthesia. Step 3 Placement of the Posterolateral Portal Lateral to the Achilles Tendon: Place the posterolateral portal lateral to the Achilles tendon at the level of the tip of the lateral malleolus, according to the original technique described by van Dijk et al. Step 4 Placement of the Posteromedial Portal Medial to the Achilles Tendon: Place the posteromedial portal medial to the Achilles tendon at the level of the tip of the lateral malleolus. Step 5 Exposure of the Subtalar Joint by Removing the Fatty Tissue and Part of the Posterior Joint Capsule: With the help of the shaver, look for the landmarks of the posterior arthroscopy, going from the posterolateral part of the subtalar joint toward the flexor hallucis longus tendon, which is medially located, while exposing the tibiotalar joint. Step 6 Debridement and Microfracturing of the Posterior Facet of the Subtalar Joint: Sometimes an accessory portal, just anterior to the tip of the external malleolus, may be needed to achieve a distraction of the anterior part of the subtalar posterior facet. Step 7 Use of Bone Graft: To perform this concomitant step, which generally is not necessary, use an arthroscopic forceps to insert a 5 by 20-mm autograft or allograft in the subtalar joint. Step 8 Fixation of the Subtalar Joint Using Two Cannulated Screws and Fluoroscopy: Use two cannulated screws with a 7.3-mm diameter; we prefer stabilization screws to compression screws. Step 9 Additional Surgical Procedures: Always clean out the posterior compartment of the ankle during the PASTA procedure, as is done during surgical treatment for posterior impingement syndrome, and note that both posterior impingement syndrome and subtalar degenerative changes may thereby be easily addressed through this procedure. Step 10 Postoperative Care: A short posterior leg splint is worn for three to ten days, followed by another non-weight-bearing cast for another three weeks. Results: Since the appearance of the original article, a total of forty-one unilateral subtalar joints in twenty-five men and sixteen women, seen between May 2007 and December 2012, with isolated subtalar arthritis or talocalcaneal coalition without any other major hindfoot arthritis were treated by posterior arthroscopic subtalar arthrodesis, and all subtalar joints except for two were considered radiographically fused at the first attempt after an average of 6.7 weeks (range, six to ten weeks).IndicationsContraindicationsPitfalls & Challenges. PMID- 30405962 TI - Open Reduction and Internal Fixation of Both-Bones Forearm Fractures. AB - Compared with closed reduction or older fixation methods, open reduction and compression plate fixation has dramatically improved the outcomes of displaced diaphyseal forearm fractures. However, the procedure can be technically demanding, with implant choice, surgical approach, accuracy of reduction, and sufficient fracture stability to allow early postoperative motion all having been shown to affect outcome. The procedure is performed with the following steps:The patient is positioned supine on the operating room table with the arm on a hand table and a tourniquet applied to the upper arm.After skin preparation and draping, a longitudinal incision is made over the volar aspect of the forearm between the flexor carpi radialis tendon and the radial artery, centered over the radial fracture site.The interval between the flexor carpi radialis and the radial artery is developed, and, depending on the location, the deeper musculature is reflected from the bone adjacent to the fracture site, which is debrided of hematoma, irrigated, and cleaned.The fracture is reduced and is provisionally fixed with a Kirschner wire, or lag screw if possible. A small fragment compression plate that provides at least three bicortical screws proximal and distal to the fracture is selected and is applied with one screw each proximally and distally.After provisional fixation of the radius, a similar process is carried out for the ulna, with use of an approach along the subcutaneous border between the flexor carpi ulnaris and extensor carpi ulnaris. Then the forearm is carefully examined clinically and radiographically to ensure accurate reduction of the fractures and motion/stability of the elbow and wrist.The remainder of the screws are inserted, the fascia of the forearm is not closed, and a standard closure of subcutaneous tissue and skin is performed.Open fractures of the forearm can typically be treated with irrigation, debridement, and immediate fixation. A volar approach is preferred over a dorsal approach for most radial fractures to minimize the risk to the posterior interosseous nerve. Anatomic reduction, especially restoration of the radial bow, is critical for restoration of motion and function. Bone-grafting is rarely indicated, even in comminuted fractures. A rapid return to function, union rates of >=95%, restoration of forearm strength and stability, and low complication rates have been reported in multiple studies of this technique. PMID- 30405963 TI - Transtrapezial Approach for Fixation of Acute Scaphoid Fractures. AB - Introduction: The transtrapezial approach for fixation of acute scaphoid fractures facilitates precise percutaneous placement of a screw along the central axis of the scaphoid, which has been shown to be biomechanically superior. Step 1 Position the Patient Surgeon and Fluoroscopy Equipment: Correctly position the patient, surgeon, and fluoroscopy equipment before starting the procedure. Step 2 Mark the Skin: Mark the central axis of the scaphoid on the skin along the anteroposterior and lateral (optional) planes as the markings allow visual control for insertion of the guidewire. Step 3 Stab Incision: Make a volar stab incision over the distal half of the trapezium. Step 4 Insert the Guidewire: Insert the guidewire through the trapezium along the central axis of the scaphoid, which is the critical step of the procedure. Step 5 Drilling: Drill the trapezium and the distal cortex of the scaphoid to allow easy insertion of the screw. Step 6 Length Measurement: Precisely measure the scaphoid length to determine the appropriate screw length. Step 7 Insert the Screw: Insert the selected screw over the guidewire. Results: In our report on the first results of this technique in forty-one patients with an acute nondisplaced scaphoid waist fracture, all fractures united within ten weeks (mean, 6.4 weeks) and the modified Mayo wrist score was good (four patients) or excellent (thirty-seven patients) at a mean follow-up of thirty-six months (range, fourteen to sixty eight months).IndicationsContraindicationsPitfalls & Challenges. PMID- 30405964 TI - Lateral Elbow Exposures: The Extensor Digitorum Communis Split Compared with the Kocher Approach. AB - Introduction: In comparison with the frequently used modified Kocher approach, the extensor digitorum communis (EDC) splitting approach allows improved access to the anterior half of the radial head, which is most commonly fractured, while reducing the risk of iatrogenic injury to the lateral collateral ligament. Step 1 Make the Incision Modified Kocher Approach: Make an oblique 7-cm lateral incision beginning at the proximal edge of the lateral epicondyle and extending distally over the center of the radial head toward the posterior ulnar border of the extensor carpi ulnaris muscle belly. Step 2 Develop the Interval Between the Anconeus and the Extensor Carpi Ulnaris: Identify and develop the intermuscular interval between the anconeus and the extensor carpi ulnaris. Step 3 Perform the Lateral Elbow Capsulotomy: Longitudinally incise the lateral elbow capsule and annular ligament anterior to the lateral ulnar collateral ligament. Step 4 The Extended Modified Kocher Approach: Extend the exposure by elevating the common extensor origin (extensor carpi radialis brevis, EDC, and extensor carpi ulnaris) proximally off the lateral epicondyle and reflect it anteriorly. Step 5 Make the Incision EDC Splitting Approach: Make a longitudinal oblique 5 to 6-cm lateral incision beginning at the proximal edge of the lateral epicondyle and extending distally over the radial head toward the Lister tubercle. Step 6 Identify and Split the EDC: The EDC tendon is identified and bisected longitudinally starting proximally at its origin on the lateral epicondyle and extending 20 mm distally from the radiocapitellar joint. Step 7 Perform the Lateral Elbow Capsulotomy: The annular ligament and joint capsule are then incised collinear with the EDC split anterior to the equator of the capitellum. Step 8 Extended EDC Splitting Approach: Extend the exposure by detaching the anterior half of the EDC tendon and the extensor carpi radialis brevis tendon from the lateral epicondyle. Step 9 Layered Closure: Perform an interrupted layered closure. Results: In our recent cadaveric study, we quantitatively compared the modified Kocher and EDC splitting approaches in order to determine which provided the greatest exposure of the anterior aspect of the radial head, which is most commonly fractured.IndicationsContraindicationsPitfalls & Challenges. PMID- 30405965 TI - Depth-Based, Motion-Stabilized Colorization of Microscope-Integrated Optical Coherence Tomography Volumes for Microscope-Independent Microsurgery. AB - Purpose: We develop and assess the impact of depth-based, motion-stabilized colorization (color) of microscope-integrated optical coherence tomography (MIOCT) volumes on microsurgical performance and ability to interpret surgical volumes. Methods: Color was applied in real-time as gradients indicating axial position and stabilized based on calculated center of mass. In a test comparing colorization versus grayscale visualizations of prerecorded intraoperative volumes from human surgery, ophthalmologists (N = 7) were asked to identify retinal membranes, the presence of an instrument, its contact with tissue, and associated deformation of the retina. In a separate controlled trial, trainees (N = 15) performed microsurgical skills without conventional optical visualization and compared colorized versus grayscale MIOCT visualization on a stereoptic screen. Skills included thickness identification, instrument placement, and object manipulation, and were assessed based on time, performance metrics, and confidence. Results: In intraoperative volume testing, colorization improved ability to differentiate membrane from retina (P < 0.01), correctly identify instrument contact with membrane (P = 0.03), and retinal deformation (P = 0.01). In model microsurgical skills testing, trainees working with colorized volumes were faster (P < 0.01) and more correct (P < 0.01) in assessments of thickness for recessed and elevated objects, were less likely to inadvertently contact a surface when approaching with an instrument (P < 0.01), and uniformly more confident (P < 0.01 for each) in conducting each skill. Conclusions: Depth-based colorization enables effective identification of retinal membranes and tissue deformation. In microsurgical skill testing, it improves user efficiency, and confidence in microscope-independent, OCT-guided model surgical maneuvers. Translational Relevance: Novel depth-based colorization and stabilization technology improves the use of intraoperative MIOCT. PMID- 30405966 TI - Assessment of a mouse xenograft model of primary colorectal cancer with special reference to perfluorooctane sulfonate. AB - Colorectal cancer ranks third among the most commonly diagnosed cancers in the United States. Current therapies have a range of side effects, and the development of a reliable animal model to speed the discovery of safe effective preventative therapies would be of great value. A cross-sectional study in a large Appalachian population recently showed an association between low circulating levels of perfluorooctane sulfonate (PFOS) and a reduced prevalence of colorectal cancer. A study using APCmin (C57BL/6J-ApcMin/J) mice prone to familial adenomatous polyposis found PFOS was protective when exposure occurred during tumor development. To test the possible benefit of PFOS on spontaneous colorectal cancer, we developed a mouse model utilizing primary patient colorectal cancer implants into NSG (NOD.Cg-PrkdcscidIl2rgtm1Wjl /Sz) mice. Study goals included: (1) to assess potential factors supporting the successful use of colorectal cancer from heterogeneous tumors for PDX studies; and, (2) evaluate PFOS as a therapy in tumor matched pairs of mice randomized to receive PFOS or vehicle. The time in days for mice to grow primary tumors to 5 mm took almost 2 months (mean = 53.3, se = 5.7, range = 17-136). Age of mice at implantation, patient age, gender and race appeared to have no discernable effect on engraftment rates. Engraftment rates for low and high-grade patient tumors were similar. PFOS appeared to reduce tumor size dramatically in one group of tumors, those from the right ascending colon. That is, by 5 weeks of treatment in two mice, PFOS had eliminated their 52.4 mm3 and 124.6 mm3 masses completely, an effect that was sustained for 10 weeks of treatment; in contrast, their corresponding matched vehicle control mice had tumors that grew to 472.7 mm3 and 340.1 mm3 in size respectively during the same period. In a third xenograft mouse, the tumor growth was dramatically blunted although not eliminated, and compared favorably to their matched vehicle controls over the same period. These preliminary findings suggested that this mouse model may be advantageous for testing compounds of potential value in the treatment of colorectal cancer, and PFOS may have utility in selected cases. PMID- 30405967 TI - Home sick: impacts of migratory beekeeping on honey bee (Apis mellifera) pests, pathogens, and colony size. AB - Honey bees are important pollinators of agricultural crops and the dramatic losses of honey bee colonies have risen to a level of international concern. Potential contributors to such losses include pesticide exposure, lack of floral resources and parasites and pathogens. The damaging effects of all of these may be exacerbated by apicultural practices. To meet the pollination demand of US crops, bees are transported to areas of high pollination demand throughout the year. Compared to stationary colonies, risk of parasitism and infectious disease may be greater for migratory bees than those that remain in a single location, although this has not been experimentally established. Here, we conducted a manipulative experiment to test whether viral pathogen and parasite loads increase as a result of colonies being transported for pollination of a major US crop, California almonds. We also tested if they subsequently transmit those diseases to stationary colonies upon return to their home apiaries. Colonies started with equivalent numbers of bees, however migratory colonies returned with fewer bees compared to stationary colonies and this difference remained one month later. Migratory colonies returned with higher black queen cell virus loads than stationary colonies, but loads were similar between groups one month later. Colonies exposed to migratory bees experienced a greater increase of deformed wing virus prevalence and load compared to the isolated group. The three groups had similar infestations of Varroa mites upon return of the migratory colonies. However, one month later, mite loads in migratory colonies were significantly lower compared to the other groups, possibly because of lower number of host bees. Our study demonstrates that migratory pollination practices has varying health effects for honey bee colonies. Further research is necessary to clarify how migratory pollination practices influence the disease dynamics of honey bee diseases we describe here. PMID- 30405968 TI - Structure, dynamics and predicted functional role of the gut microbiota of the blue (Haliotis fulgens) and yellow (H. corrugata) abalone from Baja California Sur, Mexico. AB - The GI microbiota of abalone contains a highly complex bacterial assemblage playing an essential role in the overall health of these gastropods. The gut bacterial communities of abalone species characterized so far reveal considerable interspecific variability, likely resulting from bacterial interactions and constrained by the ecology of their abalone host species; however, they remain poorly investigated. Additionally, the extent to which structural changes in the microbiota entail functional shifts in metabolic pathways of bacterial communities remains unexplored. In order to address these questions, we characterized the gut microbiota of the northeast Pacific blue (Haliotis fulgens or HF) and yellow (Haliotis corrugata or HC) abalone by 16S rRNA gene pyrosequencing to shed light on: (i) their gut microbiota structure; (ii) how bacteria may interact among them; and (iii) predicted shifts in bacterial metabolic functions associated with the observed structural changes. Our findings revealed that Mycoplasma dominated the GI microbiome in both species. However, the structure of the bacterial communities differed significantly in spite of considerable intraspecific variation. This resulted from changes in predominant species composition in each GI microbiota, suggesting host-specific adaptation of bacterial lineages to these sympatric abalone. We hypothesize that the presence of exclusive OTUs in each microbiota may relate to host-specific differences in competitive pressure. Significant differences in bacterial diversity were found between species for the explored metabolic pathways despite their functional overlap. A more diverse array of bacteria contributed to each function in HC, whereas a single or much fewer OTUs were generally observed in HF. The structural and functional analyses allowed us to describe a significant taxonomic split and functional overlap between the microbiota of HF and HC abalone. PMID- 30405970 TI - Ontogenetic changes in swimming speed of silver carp, bighead carp, and grass carp larvae: implications for larval dispersal. AB - Bighead, silver, and grass carps are invasive in the waterways of central North America, and grass carp reproduction in tributaries of the Great Lakes has now been documented. Questions about recruitment potential motivate a need for accurate models of egg and larval dispersal. Quantitative data on swimming behaviors and capabilities during early ontogeny are needed to improve these dispersal models. We measured ontogenetic changes in routine and maximum swimming speeds of bighead, grass, and silver carp larvae. Daily measurements of routine swimming speed were taken for two weeks post-hatch using a still camera and the LARVEL program, a custom image-analysis software. Larval swimming speed was calculated using larval locations in subsequent image frames and time between images. Using an endurance chamber, we determined the maximum swimming speed of larvae (post-gas bladder inflation) for four to eight weeks post-hatch. For all species, larval swimming speeds showed similar trends with respect to ontogeny: increases in maximum speed, and decreases in routine speed. Maximum speeds of bighead and grass carp larvae were similar and generally faster than silver carp larvae. Routine swimming speeds of all larvae were highest before gas bladder inflation, most likely because gas bladder inflation allowed the fish to maintain position without swimming. Downward vertical velocities of pre-gas bladder inflation fish were faster than upward velocities. Among the three species, grass carp larvae had the highest swimming speeds in the pre-gas bladder inflation period, and the lowest speeds in the post-gas bladder inflation period. Knowledge of swimming capability of these species, along with hydraulic characteristics of a river, enables further refinement of models of embryonic and larval drift. PMID- 30405969 TI - Elaborate plumage patterning in a Cretaceous bird. AB - Integumentary patterns and colors can differentiate species, sexes, and life changes and can inform on habitat and ecology. However, they are rarely preserved in the fossil record. Here, we report on an extremely well-preserved specimen of the Cretaceous bird Confuciusornis with unprecedented complexity, including small spots on the wings, crest, and throat. Morphological and chemical evidence suggest that these patterns are produced by melanin, but unusual preservation prevents assignment of specific colors. Based on comparisons with extant birds, these patterns were likely used for camouflage, although other functions including sexual signaling cannot be ruled out. Our data show that even more elaborate plumage patterns than the spangles in Anchiornis and stripes in Sinosauropteryx were present at a relatively early stage of avian evolution, showing the significance of coloration and patterning to feather evolution. PMID- 30405971 TI - Dynamic proteomic changes in soft wheat seeds during accelerated ageing. AB - Previous research demonstrated that soft wheat cultivars have better post-harvest storage tolerance than harder cultivars during accelerated ageing. To better understand this phenomenon, a tandem mass tag-based quantitative proteomic analysis of soft wheat seeds was performed at different storage times during accelerated ageing (germination ratios of 97%, 45%, 28%, and 6%). A total of 1,010 proteins were differentially regulated, of which 519 and 491 were up- and downregulated, respectively. Most of the differentially expressed proteins were predicted to be involved in nutrient reservoir, enzyme activity and regulation, energy and metabolism, and response to stimulus functions, consistent with processes occurring in hard wheat during artificial ageing. Notably, defense associated proteins including wheatwin-2, pathogenesis-related proteins protecting against fungal invasion, and glutathione S-transferase and glutathione synthetase participating in reactive oxygen species (ROS) detoxification, were upregulated compared to levels in hard wheat during accelerated ageing. These upregulated proteins might be responsible for the superior post-harvest storage tolerance of soft wheat cultivars during accelerated ageing compared with hard wheat. Although accelerated ageing could not fully mimic natural ageing, our findings provided novel dynamic proteomic insight into soft wheat seeds during seed deterioration. PMID- 30405972 TI - Evaluation of soil intervention values in mine tailings in northern Chile. AB - The aim of this work is to show a methodological proposal for the analysis of soil intervention values in mine tailings in order to determine the intervention requirements in the commune of Andacollo in northern Chile. The purpose of this analysis is to guide the intervention policies of both private and public organizations. The evaluation method is based on the Dutch legislation. The usability of the proposed methods depends on the available geochemical data from soil samples; in particular, we tackle the case when information regarding clay percentage in the soil is not available. We use the concepts of a threshold factor and an adjusted threshold factor to calculate a weighted intervention ranking. In order to illustrate the utility of this methodological proposal, a case study is carried out with the prescribed approach. In particular, this work presents an analysis of the elements of environmental significance related to the mining activity (Hg, Cd, Pb, As, Cu, Ni, Zn, Cr) in the commune of Andacollo, Coquimbo Region, Chile. The analyzed samples are used to determine where the intervention of tailing deposits is necessary and where a solution to these environmental liabilities is required as soon as possible. Out of the 81 samples evaluated, it was found that 18 require a potential intervention, and of these samples, seven of them are associated with abandoned tailings that, in some cases, are located close to the town center itself, one sample is associated with active tailings and the other 10 with inactive tailings. PMID- 30405973 TI - imGLAD: accurate detection and quantification of target organisms in metagenomes. AB - Accurate detection of target microbial species in metagenomic datasets from environmental samples remains limited because the limit of detection of current methods is typically inaccessible and the frequency of false-positives, resulting from inadequate identification of regions of the genome that are either too highly conserved to be diagnostic (e.g., rRNA genes) or prone to frequent horizontal genetic exchange (e.g., mobile elements) remains unknown. To overcome these limitations, we introduce imGLAD, which aims to detect (target) genomic sequences in metagenomic datasets. imGLAD achieves high accuracy because it uses the sequence-discrete population concept for discriminating between metagenomic reads originating from the target organism compared to reads from co-occurring close relatives, masks regions of the genome that are not informative using the MyTaxa engine, and models both the sequencing breadth and depth to determine relative abundance and limit of detection. We validated imGLAD by analyzing metagenomic datasets derived from spinach leaves inoculated with the enteric pathogen Escherichia coli O157:H7 and showed that its limit of detection can be comparable to that of PCR-based approaches for these samples (~1 cell/gram). PMID- 30405974 TI - A trait-based ecology to assess the acclimation of a sperm-dependent clonal fish compared to its sexual host. AB - Background: Survival in temporally or spatially changing environments is a prerequisite for the perpetuation of a given species. In addition to genetic variation, the role of epigenetic processes is crucial in the persistence of organisms. For instance, mechanisms such as developmental flexibility enable the adjustment of the phenotype of a given individual to changing conditions throughout its development. However, the extent of factors other than genetic variability, like epigenetic processes, in the production of alternative phenotype and the consequences in realized ecological niches is still unclear. Methods: In this study, we compared the extent of realized niches between asexual and sexual individuals from different environments. We used a trait-based ecology approach exploiting trophic and locomotive structures to infer the environment that each biotype actually used. More specifically, we compared the morphology of the all-female clonal and sperm-dependent fish Chrosomus eos-neogaeus to that of their sexual host species C. eos in common garden and natural conditions. Results: Transfer from natural to controlled conditions resulted in a similar shift in measured morphology for clonal and sexual individuals suggesting comparable level of flexibility in both kinds of organisms. However, clonal, but not sexual, individuals displayed a consistent phenotype when reared in uniform conditions indicating that in absence of genetic variation, one phenotype corresponds to one niche. This contrasted with results from natural conditions where clones were morphologically as variable as sexual individuals within a sampled site. In addition, similar phenotypic changes for both clonal and sexual individuals were observed among the majority of sampled sites, indicating that they responded similarly to the same environments. Discussion: Our results indicated that clones can efficiently use different niches and may evolve in a range of environmental conditions comparable to that of a sexual species, thus underlying the importance of factors other than genetic variability, like epigenetic processes, for coping with environmental heterogeneity. PMID- 30405975 TI - Classification of Alzheimer's Disease, Mild Cognitive Impairment and Normal Control Subjects Using Resting-State fMRI Based Network Connectivity Analysis. AB - This paper proposes a robust method for the Alzheimer's disease (AD), mild cognitive impairment (MCI), and normal control subject classification under size limited fMRI data samples by exploiting the brain network connectivity pattern analysis. First, we select the regions of interest (ROIs) within the default mode network and calculate the correlation coefficients between all possible ROI pairs to form a feature vector for each subject. Second, we propose a regularized linear discriminant analysis (LDA) approach to reduce the noise effect due to the limited sample size. The feature vectors are then projected onto a one dimensional axis using the proposed regularized LDA. Finally, an AdaBoost classifier is applied to carry out the classification task. The numerical analysis demonstrates that the purposed approach can increase the classification accuracy significantly. Our analysis confirms the previous findings that the hippocampus and the isthmus of the cingulate cortex are closely involved in the development of AD and MCI. PMID- 30405976 TI - An Adaptive Seismocardiography (SCG)-ECG Multimodal Framework for Cardiac Gating Using Artificial Neural Networks. AB - To more accurately trigger data acquisition and reduce radiation exposure of coronary computed tomography angiography (CCTA), a multimodal framework utilizing both electrocardiography (ECG) and seismocardiography (SCG) for CCTA prospective gating is presented. Relying upon a three-layer artificial neural network that adaptively fuses individual ECG- and SCG-based quiescence predictions on a beat by-beat basis, this framework yields a personalized quiescence prediction for each cardiac cycle. This framework was tested on seven healthy subjects (age: 22 48; m/f: 4/3) and eleven cardiac patients (age: 31-78; m/f: 6/5). Seventeen out of 18 benefited from the fusion-based prediction as compared to the ECG-only based prediction, the traditional prospective gating method. Only one patient whose SCG was compromised by noise was more suitable for ECG-only-based prediction. On average, our fused ECG-SCG-based method improves cardiac quiescence prediction by 47% over ECG-only-based method; with both compared against the gold standard, B-mode echocardiography. Fusion-based prediction is also more resistant to heart rate variability than ECG-only- or SCG-only-based prediction. To assess the clinical value, the diagnostic quality of the CCTA reconstructed volumes from the quiescence derived from ECG-, SCG- and fusion based predictions were graded by a board-certified radiologist using a Likert response format. Grading results indicated the fusion-based prediction improved diagnostic quality. ECG may be a sub-optimal modality for quiescence prediction and can be enhanced by the multimodal framework. The combination of ECG and SCG signals for quiescence prediction bears promise for a more personalized and reliable approach than ECG-only-based method to predict cardiac quiescence for prospective CCTA gating. PMID- 30405977 TI - A New Method for Diaphragmatic Maximum Relaxation Rate Ultrasonographic Measurement in the Assessment of Patients With Diaphragmatic Dysfunction. AB - Measurements of ultrasound diaphragmatic motion, amplitude, force, and velocity of contraction may provide important and essential information about diaphragmatic fatigue, weakness, or paralysis. In this paper, we propose and evaluate a semi-automated analysis system for measuring the diaphragmatic motion and estimating the maximum relaxation rate (MRR_SAUS) from ultrasound M-mode images of the diaphragmatic muscle. The system was evaluated on 27 M-mode ultrasound images of the diaphragmatic muscle [20 with no resistance (NRES) and 7 with resistance (RES)]. We computed semi-automated ultrasound MRR measurements on all NRES/RES images, using the proposed system (MRR_SAUS = 3.94 +/- 0.91/4.98 +/- 1.98 [1/s]), and compared them with the manual measurements made by a clinical expert (MRR_MUS = 2.36 +/- 1.19/5.8 +/- 2.1 [1/s],) and those made by a reference manual method (MRR_MB = 3.93 +/- 0.89/3.73 +/- 0.52 [1/sec], performed manually with the Biopac system. MRR_SAUS and MRR_MB measurements were not statistically significantly different for NRES and RES subjects but were significantly different with the MRR-MUS measurements made by the clinical expert. It is anticipated that the proposed system might be used in the future in the clinical practice in the assessment and follow up of patients with diaphragmatic weakness or paralysis. It may thus potentially help to understand post-operative pulmonary dysfunction or weaning failure from mechanical ventilation. Further validation and additional experimentation in a larger sample of images and different patient groups is required for further validating the proposed system. PMID- 30405978 TI - A Ballistographic Approach for Continuous and Non-Obtrusive Monitoring of Movement in Neonates. AB - Continuously monitoring body movement in preterm infants can have important clinical applications since changes in movement-patterns can be a significant marker for clinical deteriorations including the onset of sepsis, seizures, and apneas. This paper proposes a system and method to monitor body movement of preterm infants in a clinical environment using ballistography. The ballistographic signal (BSG) is acquired using a thin and a film-like sensor that is placed underneath an infant. Manual annotations based on video-recordings served as a reference standard for identifying movement. We investigated the performance of multiple features, constructed from the BSG waveform, to discriminate movement from no movement based on data acquired from 10 preterm infants. Since routine cardiorespiratory monitoring is prone to movement artifacts, we also compared the application of these features on the simultaneously acquired cardiorespiratory waveforms, i.e., the electrocardiogram, the chest impedance, and the photoplethysmogram. The BSG-based-features consistently outperformed those based on the routinely acquired cardiorespiratory waveforms. The best performing BSG-based feature-the signal instability index-had a mean (standard deviation) effect size of 0.90 (0.06), as measured by the area under the receiver operating curve. The proposed system for monitoring body movement is robust to noise, non-obtrusive, and has high performance in clinical settings. PMID- 30405979 TI - Screening for Atrial Fibrillation During Automatic Blood Pressure Measurements. AB - Atrial fibrillation (Afib) contributes significantly to overall cardiovascular risk. Widespread screening for Afib in primary care is sometimes performed by palpation, but suffers from low accuracy and is dependent on clinician experience. Algorithms implemented on oscillometric blood pressure devices can detect Afib with high sensitivity and specificity, but information on factors affecting accuracy is scant. Concurrent diagnostic electrocardiogram (ECG) and oscillometry were measured in participants in ECG clinics at two sites. Root mean squared successive difference (RMSSD) and irregularity index (Irrx) were calculated from oscillometric data and used to train logistic regression classifiers. Monte Carlo cross validation with 20 splits was performed to estimate confidence intervals for mean sensitivity and specificity, with various weightings, in the absence or presence of ectopics, and with or without repeated measurements. 707 measurements, including 168 Afib, were collected from 569 participants with mean (standard deviation) age of 63 (16) years. Sensitivity/specificity of RMSSD and Irrx were 0.982/0.908 and 0.986/0.960 respectively when ectopics were included. Excluding ectopics from the data improved specificity by up to 5%. Nevertheless, based on this performance and after accounting for prevalence of Afib in the population aged over 60 years, and estimated costs of healthcare, oscillometric screening for Afib in this age group could return a positive net health-economic benefit. PMID- 30405980 TI - Investigating the Efficacy of Anatomical Silicone Models Developed from a 3D Printed Mold for Perineal Repair Suturing Simulation. AB - There is a scarcity of affordable, validated, standardized and anatomically correct silicone perineum models for the rehearsal of postpartum laceration repair. The purpose of this technical report is to describe and validate evidence for a silicone, perineal repair model created from a 3D printed mold for medical resident training and clinical skills maintenance. A pre-existing model from an open-source royalty-free website was purchased and converted using Fusion360TM (Autodesk Inc., San Rafael, CA, USA) into a stereolithography (.stl) file and altered to produce a negative mold. Using a spatula, a fine silicone layer was first applied inside the mold, followed by a small piece of flesh-colored mesh netting material within the perineal surface area, fitting the width of the mold. The mesh was pressed into the thin layer of silicone, which was meant to provide anatomical structure to prevent the sutures from tearing through the silicone. The remainder of the silicone mix was then poured into the mold, which required three hours to fully set before being removed from the mold. Twelve silicone models were produced and used during a one-hour workshop at the Rural and Remote Conference by 16 obstetrics and gynecology residents and practicing rural physicians, and four facilitators. At the end of the workshop, the participants were provided with a qualitative survey and asked to rate the perceived realism and educational effectiveness of the silicone perineum model as compared to pre existing simulation models that they have used previously. The overall workshop participant feedback was positive, noting that the models provided more realistic visualization for the suturing simulation of first- and second-degree perineal injuries. The silicone models were considered to be useful in simulation training when attempting first- and second-degreeperineum suturing techniques within a confined space. The overall feedback was positive, noting that they provided more realistic visualization experience compared to pre-existing simulation models, such as beef tongues and synthetic sponges. The feedback from the participants and facilitators included thoughts about how to add additional mesh to the silicone model so the subcutaneous and vaginal plane sutures would hold, as well as increase the size of the vaginal canal size to more accurately represent a postpartum repair. There were also suggestions to alter the colour of the model to be flesh-toned as opposed to pink, to more accurately simulate human tissue. Silicone perineum models, created from a 3D printed mold, are an economical training tool as compared to commercially available, cost prohibitive models. They also provide anatomically accurate simulation training opportunities for residents to learn and maintain clinical skills in perineal repair, as compared to beef tongues and synthetic sponges, which have previously been used in obstetrics and gynecology simulation-based medical education. PMID- 30405981 TI - A Case of Paraneoplastic Guillain-Barre Syndrome Associated with Squamous Cell Carcinoma of the Lung. AB - We report a case of a 61-year-old man with a history of squamous cell carcinoma of the lung presenting with rapidly progressive symmetric ascending weakness with areflexia. The weakness was quickly followed by respiratory decompensation requiring intubation. Lumbar puncture yielded cerebrospinal fluid with elevated protein (177 mg/dL), normal glucose (61 mg/dL), normal red blood cell count (0 per/ul), and normal white blood cell count (0 per/uL). Emergent magnetic resonance imaging of cervical, thoracic, and lumbar spine did not show evidence of metastatic disease, fracture, subluxation, or other causes of cord compression. The patient was diagnosed with acute inflammatory polyneuropathy, also known as Guillain-Barre syndrome. Despite treatment with a five-day course of intravenous immunoglobulin and a subsequent five-day course of plasmapheresis, the patient did not recover respiratory function and died 48 days after diagnosis. To our knowledge, this is the first documented case of Guillain-Barre occurring concomitantly with squamous cell carcinoma of the lung. PMID- 30405982 TI - Calcified Diverticula in the Setting of Per Rectal Bleed. AB - Diverticula and calcification of tissue are both common processes; however, when occurring synergistically, they present a rare phenomenon. Our case of a 62-year old female with frank blood per rectum revealed calcified diverticula on a non contrast computed tomography (CT) scan. This is a diagnosis of exclusion having ruled out differentials such as calcified fecaliths, ingestion of radiopaque liquids, pills or objects, calcified infectious cysts, and neoplastic masses. After resuscitation and stabilization of the patient, the subsequent priority shifted to the assessment of the rebleeding risk. With calcification being a rare occurrence with diverticula, it is unclear how this constant irritating nidus will affect the chances of rebleeding. Thus, for this particular phenomenon, patients with calcified diverticula should be monitored with dedicated surveillance to ascertain rebleeding rates. PMID- 30405983 TI - Synchronous Colonic Adenocarcinoma and Metastatic Lobular Carcinoma in a Colectomy Specimen: A Rare Finding. AB - Invasive lobular carcinoma is the second-most-common subtype of invasive breast carcinoma. Its metastatic pattern is different compared to invasive carcinoma-no special type. It metastasizes more often to the gastrointestinal tract, peritoneum, pleura, and ovaries. The extrahepatic gastrointestinal tract metastases occur mostly in the stomach and small intestine and less often in the colon and rectum. We present a case description of an 87-year-old woman admitted to our hospital with hematochezia, abdominal discomfort, fatigue, and weight loss. A colonoscopy revealed an exophytic tumor of the sigmoid colon. Metastatic disease was not found in imaging studies. A low anterior resection was performed. The pathologic examination revealed a collision tumor consisting of a poorly differentiated adenocarcinoma of the colon and metastatic lobular carcinoma. The diagnosis was challenging due to the lack of a previous history. Also, the diffuse architectural pattern and signet ring cells found may be in primary signet ring carcinoma of the colon as well as in carcinomas from other anatomical sites. Immunohistochemistry was helpful in making the diagnosis. A review of the literature revealed that this is the fourth case of metastatic breast carcinoma coexisting with colonic adenocarcinoma. PMID- 30405984 TI - Radiologic Evaluation of Chronic Vertebral Compression Fractures and Role of Vertebral Augmentation. AB - The literature has classified chronic vertebral compression fractures (VCF) as those still "symptomatic" four or more months after onset. Pain is regarded as the predominant chronic symptom; however, radiologic changes are important in evaluating fracture progression. This review examines a series of patients with chronic fractures and both persistence of spinal pain combined with radiologic changes, such as worsening collapse, spinal angulation, the development of vertebral edema and clefts, as well as the development of new fractures at adjacent spinal levels. In patients with clear progressive radiologic changes in addition to pain, vertebral augmentation on an average of 9.3 months after injury was effective in reducing the pain and stabilizing these more chronic osteoporotic fractures. A comparison of the pre- and post-procedure visual analog scale score (VAS) indicated an average of 66% reduction in pain. There are several reasons for the development of chronic symptomatic fractures. Most commonly, interventional treatment is delayed in a patient already diagnosed with VCF after a long period of conservative treatment, yet pain persists, or the initial clinical and radiologic evaluation misses the fracture, leading to a delay in diagnosis and treatment. In this report, management in these patients and the role of late vertebral augmentation for chronic symptomatic fractures is clarified based on the findings of various radiologic changes seen on both initial and follow-up radiologic studies. PMID- 30405985 TI - Improvement of Chronic Idiopathic Urticaria With Levothyroxine: A Case Report and Review of Literature. AB - There is an increased association between chronic urticaria (CU) and thyroid autoantibodies. We presented a case of a patient suffering from CU and newly diagnosed Hashimoto's thyroiditis in which levothyroxine therapy completely resolved the symptoms of urticaria. A 58-year-old female with a past medical history of recurrent urticaria presented with complaints of fatigue and weight gain. Laboratory investigations showed a high thyroid stimulating hormone (TSH) level and a low free thyroxine (T4) level. She had elevated levels of antithyroid peroxidase (anti-TPO) and anti-thyroglobulin antibodies (anti-TG). She was diagnosed as a case of Hashimoto's thyroiditis and started on levothyroxine therapy. She noticed that her uncontrolled recurrent urticaria started to get better and after a few months of therapy, she stopped taking her topical ointments and antihistamines. The reason for the association between positive serological tests for thyroid autoimmunity and CU is unclear. The resolution of chronic urticaria with levothyroxine in our patient with Hashimoto's thyroiditis suggests a common underlying mechanism between the two pathologies. PMID- 30405986 TI - Genetic Predisposition to Infectious Disease. AB - In contemporary medical practice, approaches to infectious disease management have been primarily rooted in a pathogen-centered model. However, host genetics also contribute significantly to infectious disease burden. The fast expansion of bioinformatics techniques and the popularization of the genome-wide association study (GWAS) in recent decades have allowed for rapid and affordable high throughput genomic analyses. This review focuses on the host model of infectious disease with particular emphasis placed on the genetic variations underlying observed infectious disease predisposition. First, we introduce observational twin-twin concordance studies of diseases such as poliomyelitis, tuberculosis, and hepatitis which suggest the important role of host genetics. We review the well-established links between specific genetic alterations and predisposition to malaria (P. falciparum and P. vivax), Creutzfeldt-Jacob disease (CJD), human immunodeficiency virus (HIV), and Norwalk virus. Finally, we discuss the novel findings yielded by modern GWAS studies, which suggest the strong contribution of immunologic variation in the major histocompatibility complex (MHC) to host genetic infectious disease susceptibility. Future large-scale genomic studies hold promise in providing insights into immunology-pathogen links and may allow for the development of personalized genomic approaches to infectious disease prevention and treatment. PMID- 30405987 TI - Role of Electroconvulsive Therapy in Major Depressive Disorder with Borderline Personality Disorder: Case Report and Literature Review. AB - Major depressive disorder (MDD) becomes difficult to treat when the patient has a comorbid personality disorder. For such patients, even a combination of psychotherapy and pharmacotherapy has been ineffective. Electroconvulsive therapy (ECT) has been the first line of therapy for the treatment-resistant depression. We used this mode of therapy for a patient who had MDD along with borderline personality disorder and had failed trials of multiple medications and psychotherapy. ECT was very successful in our patient. PMID- 30405988 TI - Delayed Chronotropic Response due to Autonomic Imbalance Presenting as Dyspnea on Early Exertion: A Complication of Bariatric Surgery. AB - Bariatric surgery has shown promising outcomes in improving overall morbidity and mortality in morbidly obese patients. Cardiovascular risk reduction from weight loss is well known in the literature. However, little is highlighted about the cardiovascular complications of massive and rapid weight loss associated with bariatric surgery. These complications result mainly from autonomic imbalance manifesting as increased parasympathetic tone and a decrease in sympathetic response. This imbalance is a consequence of hormonal changes associated with massive weight loss. We present a unique case which is a demonstration of the aforementioned changes. Our patient presented with dyspnea during an early phase of exercise with the resolution of symptoms with the continuation of exercise. PMID- 30405989 TI - Patent Foramen Ovale in Cryptogenic Stroke and Migraine with Aura: Does Size Matter? AB - INTRODUCTION: There is an association between cryptogenic strokes and patent foramen ovale (PFO), as well as between migraines with aura and PFO. The purpose of the current study was to compare shunt characteristics in the stroke and migraine populations. METHODS: We retrospectively evaluated the degree of the shunt in 68 consecutive patients with cryptogenic stroke (n=33) or migraines with aura (n=35) evaluated in a single transcranial Doppler laboratory. All patients underwent an intravenous injection of agitated saline, followed by the insonation of the middle cerebral artery to determine the degree of the right-to-left shunt. We graded the shunt size according to the number of emboli: Grade I, none; Grade II, 1-10; Grade III, 11-100; and Grade IV, >100. Grades I and II were considered low-grade shunts, and Grades III and IV were considered high-grade. RESULTS: In the 14-month study period, we found 31 high-grade shunts and 37 low-grade shunts. Among migraines with aura patients, 27 (77%) had high-grade shunts, whereas only 4 patients (12%) with cryptogenic stroke had high-grade shunts. These percentages were significantly different between groups (Fisher's exact test, p<0.0001). CONCLUSIONS: In a standardized laboratory using uniform methods, we found a significant difference in shunt size associated with PFO between cryptogenic stroke and migraine with aura patients. We hypothesize that in migraines with aura, venous admixture with arterial blood is the main mechanism by which PFO contributes to the condition. In contrast, cryptogenic strokes associated with PFO are more likely to arise from an atrial septal clot within the PFO space. PMID- 30405990 TI - A Prospective Study on the Diagnostic Value of Hyperbilirubinemia as a Predictive Factor for Appendicular Perforation in Acute Appendicitis. AB - Background Appendicitis is one of the most common surgical emergency in general surgical practices. Early and prompt diagnosis is necessary to avoid life threatening complications associated with it. The diagnosis is mainly clinically aided by imaging techniques. The physiological obstruction of the bile flow associated with appendicular pathology leads to hyperbilirubinemia, which can be used as a predictive factor of appendicular perforation. Method This prospective study was conducted in the department of general surgery in Madras Medical College and Rajiv Gandhi Government Hospital, Chennai, from January 2012 to November 2012. A total of 378 patients with the features of acute appendicitis or appendicular perforation admitted in the emergency surgical ward were included. Results Out of 378 of the study population, 18% had appendicular perforation and 82% had acute appendicitis. Out of 67 perforations, 60 patients have hyperbilirubinemia (90%) whereas out of 311 patients with appendicitis, only 89 (29%) of them had elevated bilirubin. Hyperbilirubinemia with a cutoff point of 0.9 mg% for appendicitis patients has a sensitivity of 89.6%, specificity of 71.4%, a positive predictive value of 27%, and a negative predictive value of 96.9%. Hyperbilirubinemia with a cutoff point of >1.3 mg% for appendicular perforation has a sensitivity of 80%, specificity of 89%, a positive predictive value of 93%, and a negative predictive value of 96%. Conclusions Hyperbilirubinemia with bilirubin levels more than 1.3 mg% are highly predictive of appendicular perforation and, hence, aid in prompt diagnosis. This can be combined with a clinical diagnosis and imaging for an accurate and precise diagnosis. PMID- 30405991 TI - Clinical Management of Root Resorption: A Report of Three Cases. AB - Root resorption is a pathological condition that may be an endodontic challenge if not diagnosed and treated correctly. The recent advances in the imaging technologies and material science have enabled the clinician to visualize the structural changes accurately and repair them with materials providing favourable seal ability. In this article, we report three cases of root resorption with different presentations which were diagnosed with the help of cone beam computed tomography (CBCT) and successfully managed. The series highlights the importance of diagnosis in unusual clinical situations and recommends early commencement of optimal management for longevity of tooth for health and function. PMID- 30405992 TI - Occupational Physical Activity in Young Adults and Stroke: Was It Due to My Job? AB - The association of physical activity and stroke among working young adults and vice versa has increasingly empathized in recent years. Lack of physical activity, along with many other modifiable risk factors, such as hypertension, obesity, atherosclerosis, and diabetes, contributes through vascular dysfunction to the development of adverse cerebrovascular events in the future and has always been a topic of interest in the fields of neurology and stroke rehabilitation. We wrote this review article to elaborate on this relationship in detail. This article suggests that the physical activity role in stroke development and the rehabilitation process has a diverse role, where individuals with low physically active occupations are prone to develop a stroke more readily in comparison with other workers who have a moderate amount of physical activity in their jobs; however, less mobility appeared to be harmful too soon after stroke. In addition, we elucidate the effects of physical activity on sympathetic activity and remodeling of vascular response. Alterations in the neuroendocrine system include several factors. This includes harmful changes caused by increasing levels of epinephrine and norepinephrine. These changes are seen with stress-induced cerebrovascular injury and are often elevated in post-stroke patients. In contrast, post-stroke patients engaged in physical activity may prevent these harmful neurotrophic factors by reducing the elevated levels of epinephrine and norepinephrine. However, we need more studies in the near future to further explore this association process. Therefore, we recommend more research to explore the relationship of occupation-related factors and adverse stroke outcomes. PMID- 30405993 TI - Point-of-care Ultrasonography for Detecting the Etiology of Unexplained Acute Respiratory and Chest Complaints in the Emergency Department: A Prospective Analysis. AB - Introduction Point-of-care ultrasound (POCUS) is increasingly used as a diagnostic tool in emergency departments. As the number and type of POCUS protocols expand, there is a need to validate their efficacy in comparison with current diagnostic standards. This study compares POCUS to chest radiography in patients with undifferentiated respiratory or chest complaints. Methods A prospective convenience sample of 59 adult patients were enrolled from those presenting with unexplained acute respiratory or chest complaints (and having orders for chest radiography) to a single emergency department in an academic tertiary-care hospital. After a brief educational session, a medical student, blinded to chest radiograph results, performed and interpreted images from the modified Rapid Assessment of Dyspnea in Ultrasound (RADiUS) protocol. The images were reviewed by a blinded ultrasound fellowship-trained emergency physician and compared to chest radiography upon chart review. The primary "gold standard" endpoint diagnosis was the diagnosis at discharge. A secondary analysis was performed using the chest computed tomography (CT) diagnosis as the endpoint diagnosis in the subset of patients with chest CTs. Results When using diagnosis at discharge as the endpoint diagnosis, the modified RADiUS protocol had a higher sensitivity (79% vs. 67%) and lower specificity (71% vs. 83%) than chest radiography. When using chest CT diagnosis as the endpoint diagnosis (in the subset of patients with chest CTs), the modified RADiUS protocol had a higher sensitivity (76% vs. 65%) and lower specificity (71% vs. 100%) than chest radiography. The medical student performed and interpreted the 59 POCUS scans with 92% accuracy. Conclusion The sensitivity and specificity of POCUS using the modified RADiUS protocol was not significantly different than chest radiography. In addition, a medical student was able to perform the protocol and interpret scans with a high level of accuracy. POCUS has potential value for diagnosing the etiology of undifferentiated acute respiratory and chest complaints in adult patients presenting to the emergency department, but larger clinical validation studies are required. PMID- 30405994 TI - Does the Venus de Milo have a Spinal Deformity? AB - The Venus de Milo, an ancient Greek statue, has been viewed as one of the most celebrated pieces of art in Western culture. It was sculpted during the Hellenistic period between 150 and 50 BC and is believed to be the work of Alexandros of Antioch. The sculpture is thought to depict Aphrodite, the Greek goddess of love and beauty. When assembled, the two halves of the sculpture meet in an almost horizontal line that is purposefully obscured by a roll of garment around the hips. It has been noted that the midline of the statue's face is displaced slightly. German anatomist von Henke observed that Venus's pelvis is obliquely positioned and that there is a leg length discrepancy. These findings lead him and others to posit that the Venus de Milo might have a subtle spinal deformity. In this review, we examine the literature regarding this famous statue and evidence that the model of the statue might have had a deformity of the vertebral column. PMID- 30405995 TI - Anomalous Origin of Left Anterior Descending Artery and Left Circumflex Artery from Right Coronary Sinus with Malignant Left Anterior Descending Artery Course: Role of Coronary CT Angiography Derived Fractional Flow Reserve in Decision Making. AB - Congenital coronary anomalies are uncommon and are mostly asymptomatic; however, patients may have symptoms depending on the origin and course of anomalous artery. Very rarely, coronary anomalies can also lead to life-threatening complications especially in young athletes. A malignant course of the left main (LM) or left anterior descending (LAD) artery between aorta and pulmonary artery is considered the most significant risk factor for such complications. Various noninvasive tests are available to evaluate myocardial ischemia due to anomalous coronary artery. Coronary computed tomography (CT) angiogram derived fractional flow reserve (CT-FFR) is a noninvasive diagnostic test which has shown promising results in the hemodynamic assessment of obstructive coronary artery disease. However, its role in coronary anomalies has not been studied. We present a case of a 22-year-old male who presented with atypical chest pain and was found to have anomalous origin of left anterior descending (LAD) artery and left circumflex (LCX) artery from right coronary sinus. LAD had a malignant course for which CT-FFR was done which was hemodynamically nonsignificant. The decision was made to manage the patient conservatively. PMID- 30405996 TI - Prolonged Post-electroconvulsive Therapy Delirium: An Unusual Presentation. AB - Electroconvulsive therapy (ECT) is an effective but underutilized modality for the treatment of depression unresponsive to antidepressants. Mild to moderate cognitive impairment is a commonly encountered adverse effect but it normally resolves within hours. We report a case of post-ECT delirium lasting over a course of 14 days with succeeding sessions. Modification of ECT protocol by spacing the intervals of subsequent sessions and switching from bilateral brief pulse to unilateral ultra-brief pulse was found to be effective in reducing the confusion. PMID- 30405997 TI - Corrective Osteotomy for Coronal Plane Malunion of the Medial Femoral Condyle. AB - Medial femoral condyle malunion in the coronal plane is a very rare injury. In this presented case, we performed intra-articular corrective osteotomy for a malunited medial femoral condyle in the coronal plane of a 22-year-old man and obtained good functional and radiographic results. Corrective osteotomy for a malunited medial Hoffa fracture is technically very challenging, but intra articular corrective osteotomy for these malunited fractures offers a good outcome and should be considered as a salvage treatment. PMID- 30405998 TI - Outcomes of Kidney Transplantation by Using the Technique of Renal Artery Anastomosis First. AB - Introduction The surgical technique for kidney transplantation has been well established: the renal vein is anastomosed first, followed by renal artery anastomosis. Alternatively, the renal artery can be anastomosed first and then the renal vein for kidney transplantation. However, there is a lack of data on the outcomes of kidney transplantation by using this alternative approach. The objective of this paper was to review the outcomes of kidney transplant by using this approach. Methods A review of 205 consecutive kidney transplants was conducted. All kidney transplants were performed by doing renal artery anastomosis first and then the renal vein. Data were collected, including vascular/urological complications and kidney graft function. Results All transplants were performed successfully with no occurrence of renal artery/vein thrombosis and urine leakage. There were five cases of renal artery stenosis that were managed with endovascular intervention. There was no recurrence on follow up. One ureteric stenosis required surgical reconstruction. Conclusions This alternative vascular anastomotic technique is efficient and safe. It avoids flip flopping the kidney graft during the vessel anastomoses and may be more practical in minimally invasive surgery for a kidney transplant due to the space constraint. PMID- 30405999 TI - Psychophysiological Reactivity and PTSD Symptom Severity among Young Women. AB - Mixed findings with regard to cardiovascular reactivity (CVR) and posttraumatic stress disorder (PTSD) have suggested a need to further explore the nature of this relationship and factors that might explain differences in reactivity across and within samples. In the present study, the severity of PTSD symptoms was investigated in relation to CVR among young women. In addition, we examined whether severity within PTSD symptom clusters and level of dissociative symptoms were related to CVR. Heart rate, systolic and diastolic blood pressure, cardiac output (CO) and total peripheral resistance (TPR) reactivity in response to an oral speaking task were assessed for 58 young trauma-exposed civilian women with varying levels of PTSD symptomatology (from no symptoms to high severity of PTSD). The PTSD severity sub-scores for the DSM-V symptom clusters and total PTSD severity were based on structured interview (Clinician Administered PTSD Scale), and dissociative symptoms were assessed using the Dissociative Experiences Scale. Severity of total PTSD symptoms was associated with greater CO reactivity (r = .48, p < .01) and lower TPR reactivity (r = -.50, p < .01). Significant associations were not observed for heart rate or blood pressure. Results did not vary according to severity of symptoms within PTSD symptom cluster, with correlations for CO reactivity ranging from .40 to .49 and correlations for TPR reactivity ranging from -.40 to -.50 within symptom clusters. Dissociative symptoms were not significantly correlated with the CVR measures. Results partially supported the expectation that PTSD severity is one factor that would be associated with CVR, and suggest that reactivity for the underlying components of blood pressure (CO and TPR) provide additional information in probing stress reactivity in PTSD. PMID- 30406000 TI - Successful recovery of associated interstitial nephritis and focal segmental glomerulosclerosis in patients with HCV and HIV treated with sofosbuvir and daclatasvir and revision of literature. AB - In this report, we describe the coexistence of two rare and debated complications of hepatitis C virus (HCV) infection: interstitial nephritis, with associated focal glomerulosclerosis, and autoimmune hepatitis, in a 55-year-old HIV/HCV coinfected woman. The patient was treated for the immune-mediated manifestations with mycophenolate mofetil, which she continued for 9 years, as symptoms relapsed at every attempt to discontinue immunosuppression. The patient finally cleared HCV infection thanks to new direct-acting agents and could discontinue immunosuppressive therapy maintaining stable conditions and laboratory parameters after 24-weeks follow-up. PMID- 30406001 TI - Staurosporine Induces the Generation of Polyploid Giant Cancer Cells in Non-Small Cell Lung Carcinoma A549 Cells. AB - Cultivation of A549 non-small-cell lung carcinoma (NSCLC) cells in the presence of staurosporine (SSP) leads to a reduction or a lack of proliferation in a concentration-dependent manner. This inhibition of proliferation is accompanied by the generation of polyploid giant cancer cells (PGCCs) that are characterized by cell flattening, increased cell size, polyploidy, and polynucleation as determined by crystal violet staining, BrdU and DiI labelling, and flow cytometry as well as video time-lapse analysis. Continuous SSP treatment of A549 cells can preserve PGCCs for at least two months in a resting state. Upon removal of SSP, A549 PGCCs restart to divide and exhibit a proliferation pattern and cellular morphology indistinguishable from cells where PGCCs originally derived from. Thus, SSP-treated A549 cells represent a simple and reliable experimental model for the reversible generation of PGCCs and their subsequent experimental analysis. PMID- 30406004 TI - Identifying subgroups of Black, Hispanic and Asian men at increased risk for comorbid depression and overweight or obesity. AB - Comorbid depression and overweight or obesity increase risk for developing many chronic diseases. Investigating men of color without using a non-Hispanic White male reference group will capture a more nuanced picture of how socio-demographic factors contribute to increased risk for comorbid depression and overweight or obesity among and between men of color. This study used the U.S.-based 2014 National Health Interview Survey (n = 1363) in May 2018 to examine associations between race/ethnicity and comorbid overweight or obesity and depression in men. Men were more likely to be obese or overweight and depressed if they were older (31-54 years old and 55+) [OR = 2.387, 95% CI: 1.526, 3.873, p = 0.000; OR = 2.220, 95% CI: 1.355, 3.635, p = 0.002], Black [OR = 2.745, 95% CI: 1.622, 4.646, p < 0.001], Hispanic [OR = 2.967, 95% CI: 1.762, 4.995, p < 0.001], or earned $35,000-$74,999 [OR = 1.987, 95% CI: 1.255-3.152, p = 0.004]. We identified socio demographic sub-groups of men at increased risk for comorbid depression and overweight or obesity. Examining intra-group differences among men of color will help clinicians and researchers to address more nuanced socio-demographic characteristics of groups of men who are more at risk for developing a chronic disease. PMID- 30406003 TI - Impact of warning labels on sugar-sweetened beverages on parental selection: An online experimental study. AB - Sugar-sweetened beverages (SSBs) are one of the largest added sugar sources to diets in the UK and USA, particularly among young people. Warning labels, including calorie information labels, could reduce SSB consumption but uncertainty surrounds the labels that are most effective. This study assessed the impact of labels containing (a) each of two image-based warnings and (b) calorie information, singly and together, on SSB selection by parents of 11-16-year-olds living in the UK. Using a 3 (disease image, sugar content image, no image) * 2 (calorie information, no calorie information) between-subjects experimental design, 2002 participants were randomised to see beverages with one of six labels and selected one for their child to consume. The primary outcome was the proportion of participants selecting an SSB. Data were collected in December 2017. Logistic regressions showed SSB selection was lower when labels contained an image-based warning (35%), compared to not having any label (49%) or just calorie information (43.5%). The disease image lowered selection more than the sugar image (32% vs 40.5%). Providing calorie information with the disease image had no additional impact on selection (33%) but enhanced the impact of the sugar image (36%). Image-based warning labels discourage SSB selection by parents for their children. Images depicting health consequences of excess sugar consumption have larger effects than those depicting sugar content. Calorie information does not add to the effect of the former but does to that of the latter. Field studies are needed to assess the impact of SSB warning labels in real-life settings. PMID- 30406002 TI - Epidermal Growth Factor Receptor Gene in Non-Small-Cell Lung Cancer: The Importance of Promoter Polymorphism Investigation. AB - Recently, epidermal growth factor receptor (EGFR) was a key molecule in investigation of lung cancer, and it was a target for a new therapeutic strategy, based on molecular analyses. In this review, we have summarized some issues considering the role of EGFR in lung cancer, its coding gene, and its promoter gene polymorphisms (SNPs) -216G/T and -191C/A in non-small-cell lung cancer (NSCLC). The position of the SNPs indicates their significant role in EGFR regulation. The accumulation of knowledge regarding SNPs lately suggests their significant and important role in the onset of carcinogenesis, the prediction of the onset of metastases, the response to therapy with TKI inhibitors, and the onset of toxic effects of the applied therapy. Based on this, we suggest further studies of the relationship of clinical significance to SNPs in patients with lung tumors. PMID- 30406005 TI - Associations between screen time and lower psychological well-being among children and adolescents: Evidence from a population-based study. AB - Previous research on associations between screen time and psychological well being among children and adolescents has been conflicting, leading some researchers to question the limits on screen time suggested by physician organizations. We examined a large (n = 40,337) national random sample of 2- to 17-year-old children and adolescents in the U.S. in 2016 that included comprehensive measures of screen time (including cell phones, computers, electronic devices, electronic games, and TV) and an array of psychological well being measures. After 1 h/day of use, more hours of daily screen time were associated with lower psychological well-being, including less curiosity, lower self-control, more distractibility, more difficulty making friends, less emotional stability, being more difficult to care for, and inability to finish tasks. Among 14- to 17-year-olds, high users of screens (7+ h/day vs. low users of 1 h/day) were more than twice as likely to ever have been diagnosed with depression (RR 2.39, 95% CI 1.54, 3.70), ever diagnosed with anxiety (RR 2.26, CI 1.59, 3.22), treated by a mental health professional (RR 2.22, CI 1.62, 3.03) or have taken medication for a psychological or behavioral issue (RR 2.99, CI 1.94, 4.62) in the last 12 months. Moderate use of screens (4 h/day) was also associated with lower psychological well-being. Non-users and low users of screens generally did not differ in well-being. Associations between screen time and lower psychological well-being were larger among adolescents than younger children. PMID- 30406007 TI - The dual burden of malnutrition in the United States and the role of non-profit organizations. AB - The dual burden of malnutrition (obesity or a non-communicable disease coupled with malnutrition) is prevalent in more than half of all malnourished households that reside in the US. Non-profit organizations should make a conscientious effort to not serve products high in sugar and saturated fat, and low in fiber. Instead, they should diligently serve nutrient-dense foods rich in produce, whole grains and omega 3 fatty acids to minimize health disparities prevalent in LSES households. Nonprofit organizations have the potential to decrease health disparities nationally by feeding health sustaining products such as whole grains, fresh produce and lean proteins. This commentary lists feasible options for organizations to serve healthier options and reduce health disparities such as implementing nutrition policies, capitalizing on donations and securing partnerships. PMID- 30406006 TI - The global burden of multiple chronic conditions: A narrative review. AB - Globally, approximately one in three of all adults suffer from multiple chronic conditions (MCCs). This review provides a comprehensive overview of the resulting epidemiological, economic and patient burden. There is no agreed taxonomy for MCCs, with several terms used interchangeably and no agreed definition, resulting in up to three-fold variation in prevalence rates: from 16% to 58% in UK studies, 26% in US studies and 9.4% in Urban South Asians. Certain conditions cluster together more frequently than expected, with associations of up to three-fold, e.g. depression associated with stroke and with Alzheimer's disease, and communicable conditions such as TB and HIV/AIDS associated with diabetes and CVD, respectively. Clusters are important as they may be highly amenable to large improvements in health and cost outcomes through relatively simple shifts in healthcare delivery. Healthcare expenditures greatly increase, sometimes exponentially, with each additional chronic condition with greater specialist physician access, emergency department presentations and hospital admissions. The patient burden includes a deterioration of quality of life, out of pocket expenses, medication adherence, inability to work, symptom control and a high toll on carers. This high burden from MCCs is further projected to increase. Recommendations for interventions include reaching consensus on the taxonomy of MCC, greater emphasis on MCCs research, primary prevention to achieve compression of morbidity, a shift of health systems and policies towards a multiple-condition framework, changes in healthcare payment mechanisms to facilitate this change and shifts in health and epidemiological databases to include MCCs. PMID- 30406008 TI - Impact of gaining or maintaining excessive weight in infancy on markers of metabolic homeostasis in young children: A longitudinal study in Chilean children. AB - Childhood obesity in Chile is one of the highest in the world. The objective of this study was to assess the impact of excessive weight gained or maintained over a 3-year period, on markers of metabolic homeostasis in young children. This is a longitudinal study which includes 243 children followed from 4 to 7 years. We assessed BMI, body fat percentage, waist circumference (WC), waist-hip ratio (WHR), waist-height (WH) and trunk fat as well as the following metabolic parameters: glucose, insulin, triglycerides, total cholesterol, LDL, HDL and metabolic risk score. Kruskal- Wallis was used to assess differences in metabolic markers by nutritional status and logistic regression to determine the effect of maintaining or gaining excess weight over the 3-year period, compared with children who maintained a normal weight. Children who were obese at both ages compared with those who were normal weight, had a significantly higher WC, serum concentrations of total fat, total cholesterol, triglycerides, LDL cholesterol and metabolic risk score (P < 0.05). Children who were overweight or obese at 4 and 7 years, had a greater risk of having a high WC (OR: 3.37; P = 0.03), total cholesterol (OR: 4.17; P < 0.003), triglycerides (OR: 1.96; P = 0.04); thus a higher metabolic risk score (OR: 3.21; P = 0.003). Excess weight maintained over time in early childhood, significantly increases the risk of having higher serum biomarkers of cardiovascular risk, which in turn determines the magnitude of cardiovascular and metabolic risks later in life. PMID- 30406010 TI - Social determinants of smoke exposure during pregnancy: Findings from waves 1 & 2 of the Population Assessment of Tobacco and Health (PATH) Study. AB - Maternal smoking during pregnancy (MSDP) and secondhand smoke (SHS) exposure are associated with a myriad of negative health effects for both mother and child. However, less is known regarding social determinants for SHS exposure, which may differ from those of maternal smoking during pregnancy (MSDP). To identify social determinants for SHS exposure only, MSDP only, and MSDP and SHS exposure, data were obtained from all pregnant women (18-54 years; N = 726) in waves 1 and 2 of the Population Assessment of Tobacco and Health Study (2014-2015). Multiple logistic regressions were conducted using SAS 9.4. Smoke exposure during pregnancy was common; 23.0% reported SHS exposure only, 6.1% reported MSDP only, and 11.8% reported both SHS exposure and MSDP. Results demonstrate that relationships between smoke exposure during pregnancy and social determinants vary by type of exposure. Women at risk for any smoke exposure during pregnancy include those who are unmarried and allow the use of combustible tobacco products within the home. Those who are at higher risk for SHS exposure include those who are younger in age, and those who are earlier in their pregnancy. Those who are at higher risk for maternal smoking include those with fair/poor mental health status and those who believe that others' view tobacco use more positively. These results suggest the need for implementing more comprehensive policies that promote smoke-free environments. Implementing these strategies have the potential to improve maternal and fetal health outcomes associated with tobacco smoke exposure. PMID- 30406009 TI - Effects of the social norms intervention The GOOD Life on norm perceptions, binge drinking and alcohol-related harms: A cluster-randomised controlled trial. AB - The study aimed to investigate if the school-based social norms intervention The GOOD Life was effective in reducing misperceptions, heavy alcohol use and alcohol related harms among Danish pupils aged 13-17 years. In total 38 schools were included in a cluster-randomised controlled trial and allocated to either intervention (n = 641) or control group (n = 714) during 2015/2016. Both groups completed an online survey before the intervention and 3 months after baseline. The GOOD Life intervention provided normative feedback tailored for each school grade using three communication channels: classroom sessions, posters and web application. Outcome measures were overestimation of peers' lifetime binge drinking, binge drinking (5 or more drinks on one occasion) and alcohol-related harms. Intervention effects at follow-up were examined using multilevel logistic regression models. Pupils in the intervention group were less likely to overestimate peers' lifetime binge drinking compared to those in the control group (OR: 0.52, 95%CI: 0.33-0.83) and were less likely to report two or more alcohol-related harms (OR: 0.59, 95%CI: 0.37-0.93). Overall, no significant effect of the intervention was found on binge drinking. However, among pupils stating it would be ok, if they drank more (n = 296), a preventive effect was found on binge drinking four or more times during the last 30 days (OR: 0.37, 95%CI: 0.15-0.95). Additionally, the intervention effect on overestimation was higher among pupils who reported binge drinking at baseline. Receiving the intervention had a positive effect on norm perceptions and alcohol-related harms. We also found that the intervention effect differed by baseline status of alcohol use. PMID- 30406011 TI - Recurrent respiratory papillomatosis with lung involvement. AB - Recurrent respiratory papillomatosis (RRP) is a rare disease caused by human papillomavirus. Aggressive forms of RRP require repeated cytoreductive surgery to restore airway patency. Tracheal disease is even less common and lung parenchyma is involved in less than 1% of patients. We present reports of three cases of RRP with progressive lung disease in adult patients. PMID- 30406012 TI - An unusual case of hypercapnic respiratory failure. AB - Asphyxiating thoracic dystrophy (ATD also known as Jeune syndrome) is a very rare disorder with an incidence in the United States of 1 case per 100,000-130,000 live births. Chronic alveolar hypoventilation leading to concurrent hypoxia is the main cause of morbidity and mortality in these patients due to its complications. A 22-year-old male with past medical history of ATD and severe kyphoscoliosis presented with progressively worsening shortness of breath for several days. Past surgical history was significant for multiple reconstructive sternal surgeries, his first surgery was at the age of two. His chest exam was without wheezing and was notable for symmetrically decreased breath sounds. Arterial blood gas showed PH 7.17, PCO2 155, PO2 95 and O2 saturation of 97% on 2 L nasal cannulae. PA and lateral chest xrays showed a long and severely narrow thoracic cavity. 2D echocardiography showed left ventricular ejection fraction of 55% and evidence of severe pulmonary hypertension. CT chest angiography showed severe dilatation of the pulmonary artery in comparison to ascending aorta and significant right ventricular enlargement. Right heart catheterization confirmed these findings with a mean pulmonary arterial pressure of 61 mmHg. Within several days of hospitalization, patient developed acute worsening of his chronic hypercapnic respiratory failure thought to be due to worsening of pulmonary arterial hypertension with right heart failure. This in return was attributed to underlying ventilatory failure secondary to severe thoracic dystrophy. ATD is an autosomal recessive genetic disorder. Mutations in the IFT80 gene, which encode for an intraflagellar protein, cause this protein to be defective. Clinically, ATD is characterized by a small, narrow chest and variable limb shortness. While ATD is compatible with life, respiratory failure and infections are often fatal during infancy. Patients that survive past the age of 2 have seen respiratory complications resolve due to less pronounced thoracic malformations, but in our case the main cause of worsening pulmonary function was the degree of pulmonary arterial hypertension and right heart failure. Patients with ATD usually develop progressive hypercapnic respiratory failure due to an abnormally small thorax. Surgical options include lateral thoracic expansion or sternal and chest wall reconstruction. However, these surgeries only add a few years to survival without a definitive cure. PMID- 30406013 TI - Disseminated varicella-zoster virus infection with abdominal pain possibly caused by pirfenidone: A case report. AB - We report a case of chronic hypersensitivity pneumonitis treated with pirfenidone in a 76-year-old woman who complained of acute-onset abdominal pain and rashes. The patient was diagnosed with disseminated varicella-zoster virus (VZV) infection, and pirfenidone was discontinued. Her condition improved in one month. Pirfenidone may induce disseminated VZV infection. PMID- 30406014 TI - Epilepsy in patients with long QT syndrome type 1: A Norwegian family. AB - The congenital long QT syndrome (cLQTS) is an inherited cardiac disorder and is associated with sudden cardiac death. We describe a Norwegian family with mutations within the KCNQ1 gene causing cLQTS type 1 (LQT1) and epilepsy. The index patient had Jervell and Lange-Nielsen-syndrome (JLNS) with deafness and recurrent episodes of cardiac arrhythmia. The mother and the brother have Romano Ward syndrome (RWS) with recurrent arrhythmias. Whereas the father has focal epilepsy and genetically verified LQT1, the sister has both focal epilepsy and RWS. Our findings are consistent with the notion that mutations in the KCNQ1 gene can cause epilepsy. PMID- 30406015 TI - Lobular panniculitis associated with chikungunya fever: A case report. AB - Chikungunya fever is a mosquito-borne viral disease classically characterized by an acute onset of fever, arthralgia, and skin rash. In this article, we report the acute febrile illness of an adult female with arthropathy and morbilliform eruptions. The patient developed panniculitis lesions on both shins. This report aims to describe an infrequent cutaneous presentation of chikungunya fever. PMID- 30406016 TI - Successful outpatient management of Campylobacter fetus bacteremia in an immunocompetent patient with endovascular involvement. AB - We describe a case of Campylobacter fetus bacteremia with endovascular involvement in an immunocompetent female patient. The patient was treated with high dose ciprofloxacin as an outpatient and recovered well. PMID- 30406017 TI - A rare x-ray image of emphysematous cystitis. PMID- 30406018 TI - Congenital bladder diverticulum in a child: Surgical steps of extra-vesical excision. PMID- 30406019 TI - The mysterious gross haematuria in patient on Leflunomide: A case report and literature review. PMID- 30406020 TI - Acetochlor poisoning presenting as acute genital edema: A case report. PMID- 30406021 TI - In-vivo & in-vitro toxicity test of molecularly engineered PCMS: A potential drug for wireless remote controlled treatment. AB - PC, PCM, PCS, and PCMS are our designed & synthesized ~8 nm PAMAM dendrimer (P) based organic supramolecular systems, for example, PCMS has 32 molecular motors (M), 4 pH sensors (S) and 2 multi-level molecular electronic switches (C). We have reported earlier following a preliminary in-vitro test that the synthesized PCMS can selectively target cancer cell nucleotides if triggered wirelessly by an electromagnetic pulse. Here to further verify its drug potential, we have studied the preliminary efficacy, toxicity, and pharmacokinetics of P derivatives (PC, PCM, PCMS) in-vivo and in-vitro. We used ethanol-induced gastric inflammation model and cultured human gastric epithelial cells AGS to examine to the toxicity of PAMAM dendrimers cell permeability and toxicity, in (a) the cultured human gastric epithelium cells (AGS), and in (b) the gastric ulcer mice model. Here we report that the toxicity of PAMAM dendrimer (>G3.5) P can be reduced by adding C, M and S. Gastric ulcer is the primary stage of the manifestation of acute inflammation, even gastric epithelial cancer. Ethanol causes ulceration (ulcer index 30), thus upregulates both pro and active MMP-9. A 50 MUl PCMS dose prior to ethanol administration reduces ulceration by ~80% and downregulates MMP-9 and prevents oxidative damages of gastric tissue by ECM remodeling. Alcohol's inflammation of mouse stomach causes up-regulation of both pro and active MMP-9, resulting in oxidative damages of gastric tissue by ECM remodeling. PCMS in particular dose window reverses & alters ECM remodeling, thus, neutralizing alcohol-induced inflammation & generation of ROS. PMID- 30406023 TI - Standard method for microCT-based additive manufacturing quality control 4: Metal powder analysis. AB - X-ray micro computed tomography (microCT) can be applied to analyse powder feedstock used in additive manufacturing. In this paper, we demonstrate a dedicated workflow for this analysis method, specifically for Ti6Al4V powder typically used in commercial powder bed fusion (PBF) additive manufacturing (AM) systems. The methodology presented includes sample size requirements, scan conditions and settings, reconstruction and image analysis procedures. We envisage this method will support standardization in powder analysis in the additive manufacturing community. This is aimed at ultimately improving the quality of additively manufactured parts, through the identification of impurities and defects in powders. *MicroCT analysis of metal powders for additive manufacturing*Method describes a standard workflow simplifying usage of the technique*Sample requirements and image analysis workflow is described. PMID- 30406022 TI - Antidotes for aluminum phosphide poisoning - An update. AB - Aluminum phosphide (AlP), an inexpensive solid fumigant, is frequently used for grain conservation despite its alleged high toxicity. Increased utilization of AlP for agricultural and non-agricultural purposes during the last four decades has resulted in increment of AlP-attributed poisoning numbers. Moreover, due to its limitless accessibility in developing countries, AlP has been increasingly used for suicide. Moisture-exposed AlP undergoes a chemical reaction producing phosphine gas, which in turn inhibits cytochrome oxidase and impedes cellular oxygen consumption. Lethality remains elevated reaching rates of >50% and no effective antidote is available. Nevertheless, experimental and clinical studies suggested that magnesium sulfate, melatonin, N-acetylcysteine, glutathione, sodium selenite, vitamin C and E, triiodothyronine, liothyronine, vasopressin, milrinone, Laurus nobilis L., 6-aminonicotinamide, boric acid, acetyl-L-carnitine and coconut oil, may serve as antidotes by reducing the deleterious oxidative properties of AlP. This article reviews the afore-mentioned chemicals suggested to specifically treat AlP poisoning and discusses their protective mechanisms and main outcomes. PMID- 30406024 TI - On the Use of Multivariate Methods for Analysis of Data from Biological Networks. AB - Data analysis used for biomedical research, particularly analysis involving metabolic or signaling pathways, is often based upon univariate statistical analysis. One common approach is to compute means and standard deviations individually for each variable or to determine where each variable falls between upper and lower bounds. Additionally, p-values are often computed to determine if there are differences between data taken from two groups. However, these approaches ignore that the collected data are often correlated in some form, which may be due to these measurements describing quantities that are connected by biological networks. Multivariate analysis approaches are more appropriate in these scenarios, as they can detect differences in datasets that the traditional univariate approaches may miss. This work presents three case studies that involve data from clinical studies of autism spectrum disorder that illustrate the need for and demonstrate the potential impact of multivariate analysis. PMID- 30406025 TI - Intake of Non-steroidal Anti-inflammatory Drugs and the Risk of Prostate Cancer: A Meta-Analysis. AB - Background: Epidemiological evidences regarding the association between the use of non-steroidal anti-inflammatory drugs (NSAIDs) and the risk of prostate cancer (PC) is still controversial. Therefore, we conducted a meta-analysis to explore the controversy that exists. Methods: Electronic databases including Medline, EMBASE, Web of Science, Cochrane Library, BIOSIS, Scopus, CBM, CNKI, WANFANG, and CQVIP were used to search for and identify eligible studies published until December 31, 2017. Pooled effect estimates for the relative risk (RR) were computed through fixed-effects or random-effects models as appropriate. Publication bias was evaluated by Egger's and Begg's tests and potential sources of heterogeneity were investigated in subgroup analyses. Results: A total of 43 observational studies were eligible for this meta-analysis. A protective effect was identified for the intake of any NSAIDs on the risk of PC (pooled RR = 0.89, 95% CI = 0.81-0.98). Moreover, the long-term intake of NSAIDs (>=5 years rather than >=4 years) was associated with reduced PC incidence (pooled RR = 0.882, 95% CI = 0.785-0.991). Aspirin intake was also associated with a 7.0% risk reduction of PC (pooled RR = 0.93, 95% CI = 0.89-0.96). The inverse association became stronger for advanced PC and PC with a Gleason score >=7 compared to the association with total PC. Interestingly, it was the daily dose (>=1 pill/day) rather than, long-term aspirin intake (>=4 or >=5 years) that was associated with reduced PC incidence (pooled RR = 0.875, 95% CI = 0.792-0.967). The pooled effects for non-aspirin NSAIDs demonstrated no significantly adverse or beneficial effects on total PC, advanced PC, or PC with Gleason score >=7, though all pooled RRs were >1. Conclusions: Our findings suggested a protective effect of the intake of any NSAIDs on the risk of PC, especially in those who took the NSAIDs for a long period. Moreover, aspirin intake was also associated with a decreased risk of PC, and there was a dose related association between aspirin intake and the risk of PC, while no significant effects of long-term aspirin intake were found on the PC incidence. PMID- 30406026 TI - miR-182 and miR-183 Promote Cell Proliferation and Invasion by Targeting FOXO1 in Mesothelioma. AB - Dysregulation of miR-182 and miR-183 has been implicated in the progression of several human cancers. Our previous study showed that miR-182 and miR-183 are upregulated in malignant mesothelioma. However, their biological functions remain unclear. We performed in-situ hybridization to analyze the expression of miR-182 and miR-183 in human tissues. Functional analysis was performed by treatment of two mesothelioma cell lines (ACC-MESO1 and CRL-5915) with miR-182 and miR-183 inhibitors. RT-PCR and western blot analysis were conducted to analyze the expression of FOXO1, a known target of both miR-182 and miR-183. Mesothelioma cells treated with FOXO1 siRNA and miR-182/183 inhibitors were also analyzed by evaluating cell proliferation and invasion, as well as expression of FOXO1 and its downstream targets. We confirmed miR-182 expression in 25/29 cases and miR 183 expression in 29/29 cases of human mesothelioma tissue by in-situ hybridization. Notably, inhibition of miR-182 or miR-183 reduced cell proliferation, invasion, migration, and adhesion abilities of mesothelioma cells. Surprisingly, transfection with both miR-182 and miR-183 inhibitors showed even more effects on cell progression. Furthermore, FOXO1 was identified as a target of miR-182 and miR-183 in mesothelioma cells. Inhibition of miR-182 and miR-183 reduced cell proliferation ability via upregulation of FOXO1 and its downstream targets, namely, p27. Moreover, inhibition of miR-182 and miR-183 reduced the cell invasion properties of mesothelioma cells. Our findings indicated that miR 182 and miR-183 promote mesothelioma cell progression via downregulation of FOXO1 and p27. Targeting the miR-182/183-FOXO1 axis could serve as a novel treatment against malignant mesothelioma. PMID- 30406027 TI - Hematologic Tumor Cell Resistance to the BCL-2 Inhibitor Venetoclax: A Product of Its Microenvironment? AB - BCL-2 family proteins regulate the intrinsic pathway of programmed cell death (apoptosis) and play a key role in the development and health of multicellular organisms. The dynamics of these proteins' expression and interactions determine the survival of all cells in an organism, whether the healthy cells of a fully competent immune system or the diseased cells of an individual with cancer. Anti apoptotic proteins like BCL-2, BCL-XL, and MCL-1 are well-known for maintaining tumor cell survival and are therefore attractive drug targets. The BCL-2 selective inhibitor venetoclax has been approved for use in chronic lymphocytic leukemia and is now being studied in a number of other hematologic malignancies. As clinical data mature, hypotheses have begun to emerge regarding potential mechanisms of venetoclax resistance. Here, we review accumulating evidence that lymphoid microenvironments play a key role in determining hematologic tumor cell sensitivity to venetoclax. PMID- 30406028 TI - Interaction Between Prediabetes and the ABO Blood Types in Predicting Postsurgical Esophageal Squamous Cell Carcinoma-Specific Mortality: The FIESTA Study. AB - Background: We aimed to investigate the interaction between prediabetes and the ABO blood types in predicting esophageal squamous cell carcinoma (ESCC)-specific mortality by analysing data from the FIESTA study on normal/prediabetic patients with ESCC. Methods: Total 1,857 normal/prediabetic patients with ESCC who underwent three-field lymphadenectomy between January 2000 and December 2010 and survived hospitalization were analyzable, with follow-up beginning in 2000 and ending in 2015. Results: At the end of the follow-up, there were 1,161 survivors and 696 non-survivors. The follow-up time ranged from 0.5 to 180 months. The cumulative survival rates in normal patients were obviously better than in prediabetic patients. The cumulative survival rates were significantly higher in normal patients than in prediabetic patients for the blood types O and A (Log rank test P < 0.05), while no significance was detected for the blood types B and AB. Adjusted risk estimates for ESCC-specific mortality for prediabetic patients relative to normal patients were statistically significant in the blood type B- group (hazard ratio [HR]: 1.71; 95% confidence interval [CI]: 1.33-2.20; P < 0.001), but not in the blood type B+ group (HR: 1.12; 95% CI: 0.77-1.64; P = 0.5544). Conclusions: Our findings indicate that prediabetes can predict the significant risk of ESCC-specific mortality in Chinese Han patients with the blood types O and A. PMID- 30406029 TI - Developments in Blood-Brain Barrier Penetrance and Drug Repurposing for Improved Treatment of Glioblastoma. AB - Glioblastoma (GBM) is one of the most common, deadly, and difficult-to-treat adult brain tumors. Surgical removal of the tumor, followed by radiotherapy (RT) and temozolomide (TMZ) administration, is the current treatment modality, but this regimen only modestly improves overall patient survival. Invasion of cells into the surrounding healthy brain tissue prevents complete surgical resection and complicates treatment strategies with the goal of preserving neurological function. Despite significant efforts to increase our understanding of GBM, there have been relatively few therapeutic advances since 2005 and even fewer treatments designed to effectively treat recurrent tumors that are resistant to therapy. Thus, while there is a pressing need to move new treatments into the clinic, emerging evidence suggests that key features unique to GBM location and biology, the blood-brain barrier (BBB) and intratumoral molecular heterogeneity, respectively, stand as critical unresolved hurdles to effective therapy. Notably, genomic analyses of GBM tissues has led to the identification of numerous gene alterations that govern cell growth, invasion and survival signaling pathways; however, the drugs that show pre-clinical potential against signaling pathways mediated by these gene alterations cannot achieve effective concentrations at the tumor site. As a result, identifying BBB-penetrating drugs and utilizing new and safer methods to enhance drug delivery past the BBB has become an area of intensive research. Repurposing and combining FDA-approved drugs with evidence of penetration into the central nervous system (CNS) has also seen new interest for the treatment of both primary and recurrent GBM. In this review, we discuss emerging methods to strategically enhance drug delivery to GBM and repurpose currently-approved and previously-studied drugs using rational combination strategies. PMID- 30406030 TI - Immune Checkpoints and Innovative Therapies in Glioblastoma. AB - Targeting the Immune Checkpoint molecules (ICs; CTLA-4, PD-1, PD-L1/2, and others) which provide inhibitory signals to T cells, dramatically improves survival in hard-to-treat tumors. The establishment of an immunosuppressive environment prevents endogenous immune response in glioblastoma; therefore, manipulating the host immune system seems a reasonable strategy also for this tumor. In glioma patients the accumulation of CD4+/CD8+ T cells and Treg expressing high levels of CTLA-4 and PD-1, or the high expression of PD-L1 in glioma cells correlates with WHO high grade and short survival. Few clinical studies with IC inhibitors (ICis) were completed so far. Notably, the first large scale randomized trial (NCT 02017717) that compared PD-1 blockade and anti-VEGF, did not show an OS increase in the patients treated with anti-PD-1. Several factors could have contributed to the failure of this trial and must be considered to design further clinical studies. In particular the possibility of targeting at the same time different ICs was pre-clinically tested in an animal model were inhibitors against IDO, CTLA-4 and PD-L1 were combined and showed persistent and significant antitumor effects in glioma-bearing mice. It is reasonable to hypothesize that the immunological characterization of the tumor in terms of type and level of expressed IC molecules on the tumor and TIL may be useful to design the optimal ICi combination for a given subset of tumor to overcome the immunosuppressive milieu of glioblastoma and to efficiently target a tumor with such high cellular complexity. PMID- 30406031 TI - Genomic Network-Based Analysis Reveals Pancreatic Adenocarcinoma Up-Regulating Factor-Related Prognostic Markers in Cervical Carcinoma. AB - We previously showed that PAUF is involved in tumor development and metastases in cervical cancer. This study was conducted to discover novel molecular markers linked with PAUF in cervical cancer using genomic network analysis and to assess their prognostic value in cervical cancer. Three PAUF-related genes were identified using in-silico network-based analysis of the open genome datasets. To assess the expression of these genes and their relationship to the outcome of cervical cancer, immunohistochemical analysis was performed using cervical cancer TMA. The associations of the identified proteins with clinicopathologic characteristics and prognosis were examined. AGR2, BRD7, and POM121 were identified as interconnected with PAUF through in-silico network-based analysis. AGR2 (r = 0.213, p < 0.001) and POM121 (r = 0.135, p = 0.013) protein expression were positively correlated with PAUF. BRD7High and AGR2Low were significantly associated with favorable disease-free survival (DFS) (p = 0.009 and p < 0.001, respectively), and in combination with PAUFHigh, even more significantly favorable DFS observed (p < 0.001 for both). In multivariate analysis, AGR2High (HR = 3.16, p = 0.01) and BRD7High (HR = 0.5, p = 0.025) showed independent prognostic value for DFS. In a random survival forest (RSF) model, the combined clinical and molecular variable model predicted DFS with significantly improved power compared with that of the clinical variable model (C-index of 0.79 vs. 0.75, p < 0.001). In conclusion, AGR2 and BRD7 expression have prognostic significance in cervical cancer and provide opportunities for improved treatment options. Genomic network-based approaches using the cBioPortal may facilitate the discovery of additional biomarkers for the prognosis of cervical cancer and may provide new insights into the biology of cervical carcinogenesis. PMID- 30406032 TI - Incidence of Long-Term Esophageal Dilation With Various Treatment Approaches in the Older Head and Neck Cancer Population. AB - Purpose: Treatments for locoregionally advanced head and neck cancer (LAHNC) negatively impact swallowing function, but the long-term incidence of severe toxicity requiring esophageal dilation is not well-documented in the population. The aim of this study was to compare the incidence of long-term esophageal dilation across varying treatments for LAHNC. Methods and Materials: We identified 5,223 patients with LAHNC diagnosed from 2000 to 2009 in the SEER Medicare database. We compared the incidence of esophageal dilation for surgery alone vs. surgery plus adjuvant radiotherapy (RT) and chemoradiotherapy (CRT) vs. definitive RT or CRT. Results: The cumulative incidence of esophageal dilation for all sites at 10 years, according to treatment group were as follows: CRT, 14% (95% confidence interval (CI), 12-17%); definitive RT, 13% (95% CI, 10-16%); surgery alone, 5% (95% CI, 3-7%); surgery and CRT, 15% (95% CI, 11-19%); surgery and adjuvant RT: 10% (95% CI, 8-13%). There was no significant difference in the incidence of esophageal dilation between surgery plus adjuvant RT/CRT or definitive RT/CRT (p = 0.37), but the incidence was significantly increased in both groups compared to surgery alone (p = 0.003). On multivariable analysis, chemotherapy was associated with significantly increased incidence of esophageal dilation (HR 2.9, 95% CI 1.5-5.5, p < 0.001) in oropharyngeal cancers. Conclusions: The incidence of esophageal dilation is similar in LAHNC patients undergoing RT with or without surgery. Chemoradiotherapy increases the long-term risk of esophageal dilation events over surgery alone. PMID- 30406033 TI - LMO1 Gene Polymorphisms Reduce Neuroblastoma Risk in Eastern Chinese Children: A Three-Center Case-Control Study. AB - Background: Neuroblastoma, a neuroendocrine tumor, stems from the developing sympathetic nervous system. Previous genome-wide association studies (GWASs) have discovered a number of neuroblastoma susceptibility genes in Caucasians including LIM domain only 1 (LMO1). Objective: We conducted a three-center case-control study including 313 cases and 716 controls with the purpose to evaluate the association between five GWAS-identified LMO1 variants (rs110419 A>G, rs4758051 G>A, rs10840002 A>G, rs204938 A>G, and rs2168101 G>T) and neuroblastoma susceptibility in eastern Chinese children. Methods: Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. False positive report possibility (FPRP) analysis was performed to check whether significant results were noteworthy. Results: Significant associations with neuroblastoma risk were found for four (rs110419, rs4758051, rs10840002, and rs2168101) out of the five polymorphisms. Combined analysis demonstrated that carriers of 4-5 protective genotypes had a significantly decreased risk of neuroblastoma in comparison those with 0-3 protective genotypes (adjusted OR = 0.51, 95% CI = 0.39-0.68, P < 0.0001). Haplotype analysis of the five SNPs yield four significant haplotypes associated with neuroblastoma susceptibility. Conclusion: In conclusion, we confirmed LMO1 polymorphisms may reduce neuroblastoma risk in eastern Chinese populations. PMID- 30406034 TI - Biglycan Regulates MG63 Osteosarcoma Cell Growth Through a LPR6/beta-Catenin/IGFR IR Signaling Axis. AB - Biglycan, a small leucine rich proteoglycan (SLRP), is an important participant in bone homeostasis and development as well as in bone pathology. In the present study biglycan was identified as a positive regulator of MG63 osteosarcoma cell growth (p <= 0.001). IGF-I was shown to increase biglycan expression (p <= 0.01), whereas biglycan-deficiency attenuated significantly both basal and IGF-I induced cell proliferation of MG63 cells (p <= 0.001; p <= 0.01, respectively). These effects were executed through the IGF-IR receptor whose activation was strongly attenuated (p <= 0.01) in biglycan-deficient MG63 cells. Biglycan, previously shown to regulate Wnt/beta-catenin pathway, was demonstrated to induce a significant increase in beta-catenin protein expression evident at cytoplasmic (p <= 0.01), membrane (p <= 0.01), and nucleus fractions in MG63 cells (p <= 0.05). As demonstrated by immunofluorescence, increase in beta-catenin expression is attributed to co-localization of biglycan with the Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6) resulting in attenuated beta catenin degradation. Furthermore, applying anti-beta-catenin and anti-pIGF-IR antibodies to MG-63 cells demonstrated a cytoplasmic and to the membrane interaction between these molecules that increased upon exogenous biglycan treatment. In parallel, the downregulation of biglycan significantly inhibited both basal and IGF-I-dependent ERK1/2 activation, (p <= 0.001). In summary, we report a novel mechanism where biglycan through a LRP6/beta-catenin/IGF-IR signaling axis enhances osteosarcoma cell growth. PMID- 30406035 TI - The Antitumor Activities of Marsdenia tenacissima. AB - Marsdenia tenacissima (MT), a traditional Chinese herbal medicine, has long been used for thousands of years to treat asthma, tracheitis, rheumatism, etc. An increasing number of recent studies have focused on the antitumor effects of MT. The effects of MT on cancer are the result of various activated signaling pathways and inhibiting factors and the high expression levels of regulatory proteins. MT can inhibit different cancer types including non-small cell lung cancer (NSCLC), malignant tumors, hepatic carcinoma, and so on. This article mainly focuses on the activities and mechanisms of MT. In addition, the efficacy and toxicity of MT are also discussed. Further studies of MT are required for improved medicinal utilization. PMID- 30406036 TI - The Correlation Between Hepatitis B Virus Precore/Core Mutations and the Progression of Severe Liver Disease. AB - Viral mutations acquired during the course of chronic hepatitis B virus (HBV) infection are known to be associated with the progression and severity of HBV related liver disease. This study of HBV-infected Saudi Arabian patients aimed to identify amino acid substitutions within the precore/core (preC/C) region of HBV, and investigate their impact on disease progression toward hepatocellular carcinoma (HCC). Patients were categorized according to the severity of their disease, and were divided into the following groups: inactive HBV carriers, active HBV carriers, liver cirrhosis patients, and HCC patients. Two precore mutations, W28* and G29D, and six core mutations, F24Y, E64D, E77Q, A80I/T/V, L116I, and E180A were significantly associated with the development of cirrhosis and HCC. Six of the seven significant core mutations that were identified in this study were located within immuno-active epitopes; E77Q, A80I/T/V, and L116I were located within B-cell epitopes, and F24Y, E64D, and V91S/T were located within T cell epitopes. Multivariate risk analysis confirmed that the core mutations A80V and L116I were both independent predictors of HBV-associated liver disease progression. In conclusion, our data show that mutations within the preC/C region, particularly within the immuno-active epitopes, may contribute to the severity of liver disease in patients with chronic hepatitis. Furthermore, we have identified several distinct preC/C mutations within the study population that affect the clinical manifestation and progression of HBV-related disease. The specific identity of HBV mutations that are associated with severe disease varies between different ethnic populations, and so the specific preC/C mutations identified here will be useful for predicting clinical outcomes and identifying the HBV-infected patients within the Saudi population that are at high risk of developing HCC. PMID- 30406037 TI - Entamoeba histolytica Calreticulin Induces the Expression of Cytokines in Peripheral Blood Mononuclear Cells Isolated From Patients With Amebic Liver Abscess. AB - Calreticulin (CRT) is a highly conserved protein in the endoplasmic reticulum that plays important roles in the regulation of key cellular functions. Little is known about the participation of E. histolytica CRT (EhCRT) in the processes of pathogenicity or in the modulation of the host immune response. The aim of this study was to evaluate the role of CRT in the proliferation and the cytokine profile in peripheral blood mononuclear cells (PBMCs) from patients with amebic liver abscess (ALA) during the acute phase (AP-ALA) of the disease compared to patients during the resolution phase (R-ALA). The PBMCs from each participant were cocultured with EhCRT and tested by the colorimetric method to evaluate their proliferation index (PI). The supernatants were subjected to an enzyme linked immunosorbent assay (ELISA) to evaluate the concentration of cytokines. The mean values of all groups were compared using the independent t-test. When the PIs of individuals without diagnosis of liver abscess (NEG) were compared, there were no statistically significant differences in the proliferation of PBMCs between patients with AP-ALA and R-ALA when stimulated with EhCRT or concanavalin A (ConA). However, the levels of interleukins [IL-6, IL-10, granulocyte colony stimulating factor (GCSF), and transforming growth factor beta1 (TGFbeta1)] were higher in patients with AP-ALA, whereas in patients with R-ALA, higher levels of interferon gamma (IFNgamma) were detected. These results suggest that EhCRT acts as a mitogen very similar to the activity of ConA. In addition, EhCRT is an excellent immunogen for the specific activation of PBMCs, inducing the differential expression of ILs depending on the outcome of disease, determining the type of immune response: a Th2 cytokine profile during the acute phase and a Th1 profile during the resolution phase. PMID- 30406038 TI - Metagenomic Analysis of Flaviviridae in Mosquito Viromes Isolated From Yunnan Province in China Reveals Genes From Dengue and Zika Viruses. AB - More than 6,000 mosquitoes of six species from six sites were collected and tested for their virome using metagenomics sequencing and bioinformatic analysis. The identified viral sequences belonged to more than 50 viral families. The results were verified by PCR of selected viruses in all mosquitoes, followed by phylogenetic analysis. In the present study, we identified the partial dengue virus (DENV), Zika virus (ZIKV), and Japanese encephalitis virus (JEV) sequences in mosquitoes. Metagenomic analysis and the PCR amplification revealed three DENV sequences, one of which encodes a partial envelope protein. Two ZIKV sequences both encoding partial nonstructural protein 3 and one JEV sequence encoding the complete envelope protein were identified. There was variability in the viral titers of the newly isolated virus JEV-China/YN2016-1 of different passage viruses. The newly identified Zika virus gene from ZIKV-China/YN2016-1 was an Asian genotype and shared the highest nucleotide sequence identity (97.1%) with a ZIKV sequence from Thailand isolated in 2004. Phylogenetic analysis of ZIKV China/YN2016-1 and ZIKV-China/YN2016-2 with known Flavivirus genes indicated that ZIKV has propagated in Yunnan province, China. PMID- 30406040 TI - In vitro Activity of Pentamidine Alone and in Combination With Aminoglycosides, Tigecycline, Rifampicin, and Doripenem Against Clinical Strains of Carbapenemase Producing and/or Colistin-Resistant Enterobacteriaceae. AB - Enterobacteriaceae cause different types of community- and hospital-acquired infections. Moreover, the spread of multidrug-resistant Enterobacteriaceae is a public health problem and the World Health Organization pointed them among the pathogens in which the search of new antibiotics is critical. The objective of this study was to analyze the in vitro activity of pentamidine alone and in combination with gentamicin, tobramycin, amikacin, tigecycline, rifampicin, or doripenem against eight clinical strains of carbapenemase-producing and/or colistin-resistant Enterobacteriaceae: five carbapenemase-producing Klebsiella pneumoniae, one carbapenemase-producing Escherichia coli, and two colistin resistant Enterobacter cloacae. MIC and MBC were determined following standard protocols. MIC results were interpreted for all the antibiotics according to the EUCAST breakpoints but for rifampicin in which the French FSM breakpoint was used. Bactericidal and synergistic activity of pentamidine alone and in combination with antibiotics at concentrations of 1xMIC was measured by time-kill curves. For one selected strain, K. pneumoniae OXA-48/CTX-M-15 time-kill curves were performed also at 1/2xMIC of pentamidine. All studies were performed in triplicate. Pentamidine MIC range was 200-800 MUg/mL. The 50, 12.5, 62.5, 87.5, and 62.5% of the strains were susceptible to gentamicin, tobramycin, amikacin, tigecycline, and doripenem, respectively. Only the two E. cloacae strains were susceptible to rifampicin. Pentamidine alone at 1xMIC showed bactericidal activity against all strains, except for the E. cloacae 32 strain. The bactericidal activity of pentamidine alone was also observed in combination. The combinations of pentamidine were synergistic against E. cloacae 32 with amikacin and tobramycin at 24 h and with tigecycline at 8 h. Pentamidine plus rifampicin was the combination that showed synergistic activity against more strains (five out of eight). Pentamidine plus doripenem did not show synergy against any strain. At 1/2xMIC, pentamidine was synergistic with all the studied combinations against the K. pneumoniae OXA-48/CTX-M-15 strain. In summary, pentamidine alone and in combination shows in vitro activity against carbapenemase-producing and/or colistin-resistant Enterobacteriaceae. Pentamidine appears to be a promising option to treat infections caused by these pathogens. PMID- 30406042 TI - Identification of Anti-staphylococcal and Anti-biofilm Compounds by Repurposing the Medicines for Malaria Venture Pathogen Box. AB - There has been an alarming increase in infections caused by antimicrobial resistant pathogens. These infections are responsible for more than half a million deaths globally each year. Staphylococcus aureus is one of the deadliest bacterial pathogen responsible for nosocomial and community acquired infections. The open-access Pathogen Box (PBox) provides a potential platform to identify new treatment options against antibiotic-resistant bacteria by repurposing it. In this study, we have screened the PBox library comprised of ~400 compounds to identify novel anti-staphylococcal compounds. in vitro antimicrobial screening using S. aureus isolates, ATCC 29213 (methicillin-sensitive) and ATCC 700699 (methicillin-resistant) revealed 13 compounds which showed highly potent antibacterial activity against both planktonic and biofilm state. The 13 compounds were not found cytotoxic to mouse macrophage cell line, RAW264.7. Out of the 13 compounds, only MMV687251 and MMV676477 revealed structural similarity with vancomycin by comparing their atomic pair fingerprints using Tanimoto coefficient method. The structural similarities may indicate similar mode of action like vancomycin for the two compounds. Our result showed that PBox compounds offer a promising lead for the development of new anti-staphylococcal treatment options. PMID- 30406041 TI - Metagenomic Sequencing From Mosquitoes in China Reveals a Variety of Insect and Human Viruses. AB - We collected 8,700 mosquitoes in three sites in China, which belonged to seven species. Their viromes were tested using metagenomic sequencing and bioinformatic analysis. The abundant viral sequences were detected and annotated belonging to more than 50 viral taxonomic families. The results were verified by PCR, followed by phylogenetic analysis. In the present study, we identified partial viral genes of dengue virus (DENV), a novel circovirus (CCV), densovirus (DNV), Japanese encephalitis virus (JEV), and Wuhan mosquito virus (WMV) in mosquitoes. Metagenomic analysis and PCR amplification revealed three DENV sequences, which were as homologous to the NS3 gene of DENV from Singapore isolated in 2005, with at least 91% nucleotide (nt) identity. Seven fragments of JEV encoding structural proteins were identified belonging to genotype I. They all shared high homology with structural protein genes of JEV isolated from Laos in 2009. The production of infectious virus particles of the newly isolated virus YunnanJEV2017-4 increased after passage from the BHK-21 cell line to the Vero cell line. Novel circovirus-related genes were identified and as being related to an unnamed gene of a mosquito circovirus (MCCV) sequence from the USA isolated in 2011, with at least 41% nt identity: this distant relationship suggests that the parent virus might belong to a novel circovirus genus. Additionally, numerous known viruses and some unknown viruses were also detected in mosquitoes from Yunnan province, China, which will be tested for propagation. PMID- 30406039 TI - Autophagy, EVs, and Infections: A Perfect Question for a Perfect Time. AB - Autophagy, a highly conserved process, serves to maintain cellular homeostasis in response to an extensive variety of internal and external stimuli. The classic, or canonical, pathway of autophagy involves the coordinated degradation and recycling of intracellular components and pathogenic material. Proper regulation of autophagy is critical to maintain cellular health, as alterations in the autophagy pathway have been linked to the progression of a variety of physiological and pathological conditions in humans, namely in aging and in viral infection. In addition to its canonical role as a degradative pathway, a more unconventional and non-degradative role for autophagy has emerged as an area of increasing interest. This process, known as secretory autophagy, is gaining widespread attention as many viruses are believed to use this pathway as a means to release and spread viral particles. Moreover, secretory autophagy has been found to intersect with other intracellular pathways, such as the biogenesis and secretion of extracellular vesicles (EVs). Here, we provide a review of the current landscape surrounding both degradative autophagy and secretory autophagy in relation to both aging and viral infection. We discuss their key features, while describing their interplay with numerous different viruses (i.e. hepatitis B and C viruses, Epstein-Barr virus, SV40, herpesviruses, HIV, chikungunya virus, dengue virus, Zika virus, Ebola virus, HTLV, Rift Valley fever virus, poliovirus, and influenza A virus), and compare secretory autophagy to other pathways of extracellular vesicle release. Lastly, we highlight the need for, and emphasize the importance of, more thorough methods to study the underlying mechanisms of these pathways to better advance our understanding of disease progression. PMID- 30406043 TI - Toxoplasma Does Not Secrete the GRA16 and GRA24 Effectors Beyond the Parasitophorous Vacuole Membrane of Tissue Cysts. AB - After invasion, Toxoplasma resides in a parasitophorous vacuole (PV) that is surrounded by the PV membrane (PVM). Once inside the PV, tachyzoites secrete dense granule proteins (GRAs) of which some, such as GRA16 and GRA24, are transported beyond the PVM likely via a putative translocon. However, once tachyzoites convert into bradyzoites within cysts, it is not known if secreted GRAs can traffic beyond the cyst wall membrane. We used the tetracycline inducible system to drive expression of HA epitope tagged GRA16 and GRA24 after inducing stage conversion and show that these proteins are not secreted beyond the cyst wall membrane. This suggests that secretion of GRA beyond the PVM is not important for the tissue cyst stage of Toxoplasma. PMID- 30406044 TI - Proteomic Profiling of Burkholderia thailandensis During Host Infection Using Bio Orthogonal Noncanonical Amino Acid Tagging (BONCAT). AB - Burkholderia pseudomallei and B. mallei are the causative agents of melioidosis and glanders, respectively, and are often fatal to humans and animals. Owing to the high fatality rate, potential for spread by aerosolization, and the lack of efficacious therapeutics, B. pseudomallei and B. mallei are considered biothreat agents of concern. In this study, we investigate the proteome of Burkholderia thailandensis, a closely related surrogate for the two more virulent Burkholderia species, during infection of host cells, and compare to that of B. thailandensis in culture. Studying the proteome of Burkholderia spp. during infection is expected to reveal molecular mechanisms of intracellular survival and host immune evasion; but proteomic profiling of Burkholderia during host infection is challenging. Proteomic analyses of host-associated bacteria are typically hindered by the overwhelming host protein content recovered from infected cultures. To address this problem, we have applied bio-orthogonal noncanonical amino acid tagging (BONCAT) to B. thailandensis, enabling the enrichment of newly expressed bacterial proteins from virtually any growth condition, including host cell infection. In this study, we show that B. thailandensis proteins were selectively labeled and efficiently enriched from infected host cells using BONCAT. We also demonstrate that this method can be used to label bacteria in situ by fluorescent tagging. Finally, we present a global proteomic profile of B. thailandensis as it infects host cells and a list of proteins that are differentially regulated in infection conditions as compared to bacterial monoculture. Among the identified proteins are quorum sensing regulated genes as well as homologs to previously identified virulence factors. This method provides a powerful tool to study the molecular processes during Burkholderia infection, a much-needed addition to the Burkholderia molecular toolbox. PMID- 30406045 TI - The Human Gut Colonizer Blastocystis Respires Using Complex II and Alternative Oxidase to Buffer Transient Oxygen Fluctuations in the Gut. AB - Blastocystis is the most common eukaryotic microbe in the human gut. It is linked to irritable bowel syndrome (IBS), but its role in disease has been contested considering its widespread nature. This organism is well-adapted to its anoxic niche and lacks typical eukaryotic features, such as a cytochrome-driven mitochondrial electron transport. Although generally considered a strict or obligate anaerobe, its genome encodes an alternative oxidase. Alternative oxidases are energetically wasteful enzymes as they are non-protonmotive and energy is liberated in heat, but they are considered to be involved in oxidative stress protective mechanisms. Our results demonstrate that the Blastocystis cells themselves respire oxygen via this alternative oxidase thereby casting doubt on its strict anaerobic nature. Inhibition experiments using alternative oxidase and Complex II specific inhibitors clearly demonstrate their role in cellular respiration. We postulate that the alternative oxidase in Blastocystis is used to buffer transient oxygen fluctuations in the gut and that it likely is a common colonizer of the human gut and not causally involved in IBS. Additionally the alternative oxidase could act as a protective mechanism in a dysbiotic gut and thereby explain the absence of Blastocystis in established IBS environments. PMID- 30406047 TI - Response: Commentary: Reducing Viability Bias in Analysis of Gut Microbiota in Preterm Infants at Risk of NEC and Sepsis. PMID- 30406046 TI - Supplementation With 2'-FL and scGOS/lcFOS Ameliorates Rotavirus-Induced Diarrhea in Suckling Rats. AB - Rotavirus (RV) is considered to be the most common cause of gastroenteritis among infants aged less than 5 years old. Human milk bioactive compounds have the ability to modulate the diarrheic process caused by several intestinal pathogens. This study aimed to evaluate the potential protective role of a specific human milk oligosaccharide, 2'-fucosyllactose (2'-FL), a mixture of the prebiotic short chain galacto-oligosaccharides and long-chain fructo-oligosaccharides 9:1 (GOS/FOS) and their combination (2'-FL+GOS/FOS) on RV-induced diarrhea in suckling rats. The nutritional intervention was performed from the second to the sixteenth day of life by oral gavage and on day 5 an RV strain was orally administered to induce infection. Fecal samples were scored daily to assess the clinical pattern of severity, incidence and duration of diarrhea. Blood and tissues were obtained at day 8 and 16 in order to evaluate the effects on the epithelial barrier and the mucosal and systemic immune responses. In the assessment of severity, incidence and duration of diarrhea, both 2'-FL and GOS/FOS displayed a beneficial effect in terms of amelioration. However, the mechanisms involved seemed to differ: 2'-FL displayed a direct ability to promote intestinal maturation and to enhance neonatal immune responses, while GOS/FOS induced an intestinal trophic effect and an RV-blocking action. The combination of 2'-FL and GOS/FOS showed additive effects in some variables. Therefore, it could be a good strategy to add these compounds in combination to infant formulas, to protect against human RV-induced diarrhea in children. PMID- 30406048 TI - Limited Correlation of Shotgun Metagenomics Following Host Depletion and Routine Diagnostics for Viruses and Bacteria in Low Concentrated Surrogate and Clinical Samples. AB - The etiologic cause of encephalitis, meningitis or meningo-encephalitis is unknown in up to 70% of cases. Clinical shotgun metagenomics combined with host depletion is a promising technique to identify infectious etiologies of central nervous system (CNS) infections. We developed a straightforward eukaryotic host nucleic acid depletion method that preserves intact viruses and bacteria for subsequent shotgun metagenomics screening of clinical samples, focusing on cerebrospinal fluid (CSF). A surrogate CSF sample for a CNS infection paradigm was used to evaluate the proposed depletion method consisting of selective host cell lysis, followed by enzymatic degradation of the liberated genomic DNA for final depletion with paramagnetic beads. Extractives were subjected to reverse transcription, followed by whole genome amplification and next generation sequencing. The effectiveness of the host depletion method was demonstrated in surrogate CSF samples spiked with three 1:100 dilutions of Influenza A H3N2 virus (qPCR Ct-values 20.7, 28.8, >42/negative). Compared to the native samples, host depletion increased the amount of the virus subtype reads by factor 7127 and 132, respectively, while in the qPCR negative sample zero vs. 31 (1.4E-4 %) virus subtype reads were detected (native vs. depleted). The workflow was applied to thirteen CSF samples of patients with meningo-/encephalitis (two bacterial, eleven viral etiologies), a serum of an Andes virus infection and a nose swab of a common cold patient. Unlike surrogate samples, host depletion of the thirteen human CSF samples and the nose swab did not result in more reads indicating presence of damaged pathogens due to, e.g., host immune response. Nevertheless, previously diagnosed pathogens in the human CSF samples (six viruses, two bacteria), the serum, and the nose swab (Human rhinovirus A31) were detected in the depleted and/or the native samples. Unbiased evaluation of the taxonomic profiles supported the diagnosed pathogen in two native CSF samples and the native and depleted serum and nose swab, while detecting various contaminations that interfered with pathogen identification at low concentration levels. In summary, damaged pathogens and contaminations complicated analysis and interpretation of clinical shotgun metagenomics data. Still, proper consideration of these issues may enable future application of metagenomics for clinical diagnostics. PMID- 30406049 TI - Bacteriophage Therapy: Clinical Trials and Regulatory Hurdles. AB - Increasing reports of antimicrobial resistance and limited new antibiotic discoveries and development have fuelled innovation in other research fields and led to a revitalization of bacteriophage (phage) studies in the Western world. Phage therapy mainly utilizes obligately lytic phages to kill their respective bacterial hosts, while leaving human cells intact and reducing the broader impact on commensal bacteria that often results from antibiotic use. Phage therapy is rapidly evolving and has resulted in cases of life-saving therapeutic use and multiple clinical trials. However, one of the biggest challenges this antibiotic alternative faces relates to regulations and policy surrounding clinical use and implementation beyond compassionate cases. This review discusses the multi-drug resistant Gram-negative pathogens of highest critical priority and summarizes the current state-of-the-art in phage therapy targeting these organisms. It also examines phage therapy in humans in general and the approaches different countries have taken to introduce it into clinical practice and policy. We aim to highlight the rapidly advancing field of phage therapy and the challenges that lie ahead as the world shifts away from complete reliance on antibiotics. PMID- 30406050 TI - Genotyping of Aspergillus fumigatus in Formalin-Fixed Paraffin-Embedded Tissues and Serum Samples From Patients With Invasive Aspergillosis. AB - Invasive aspergillosis (IA) is a deep tissue infection with a high mortality occurring mostly in immunocompromised patients. To investigate the pathology of patients with IA it may be important to determine the genotype of the invasive isolate of Aspergillus, however available tissues for study are often formalin fixed paraffin embedded (FFPE). Although DNA has been successfully isolated from such tissues for species identification, genotyping of Aspergillus species on such tissues has not yet been performed. In this study we aimed to determine the genotype of Aspergillus fumigatus in FFPE tissue and serum samples from five patients with invasive aspergillosis using nine highly polymorphic short tandem repeat (STRAf) loci. FFPE lung and bronchial biopsies from all patients were successfully typed. By comparing the latter result with non-FFPE materials from non-sterile samples such as sputum, bronchoalveolar lavage and lung abscess, we found identical genotypes within three patients, while the two other patients had a dominant genotype shared among all sample types. Genotyping of serum samples was successful in two serum samples with galactomannan ratios of 4 and 5.6, but failed in serum samples with galactomannan levels <0.5. In addition, testing a subset of these materials with the AsperGenius multiplex qPCR assay, we did not find azole resistance mutations. With this STRAf assay, A. fumigatus from FFPE tissue and serum was successfully genotyped, allowing retrospective examination of A. fumigatus in culture negative patients with IA. PMID- 30406051 TI - New records of non-indigenous molluscs from the eastern Mediterranean Sea. AB - We report new findings of non-indigenous Indo-Pacific molluscs from shallow water habitats off Israel, Greece and Egypt, eastern Mediterranean Sea. The bivalves Pillucina vietnamica Zorina, 1978 and Alveinus miliaceus (Issel, 1869) were collected from sandy bottoms off Israel, whereas Gregariella cf. ehrenbergi (Issel, 1869) was recovered from a buoy originating from Port Said, Egypt, and stranded on the Israeli coast. The three species are first records for the Mediterranean Sea. Additionally, we report range extensions for several gastropods: Varicopeza pauxilla (A. Adams, 1855) is recorded from Israel, Phidiana militaris (Alder and Hancock, 1864) from southern Israel (Ashqelon), and Viriola cf. bayani Jousseaume, 1884 from Israel and Crete. Shells and valves of an unidentified lucinid bivalve morphologically distinct from any known Mediterranean species were found along the Israeli Mediterranean shore. PMID- 30406053 TI - One Menu Please: Parents Want Affordable, Right-sized Portions for Their Children in Restaurants. AB - One contributing factor to the obesity epidemic is the large portion sizes served in restaurants. However, no study has looked at the parents' desire for smaller portioned meals for their children at restaurants in the U.S. This study examined parents' preference for restaurants to offer smaller, lower-priced child portions for their children and reasons for the preference. Multivariable logistic regression was used to estimate adjusted odds ratios (ORs) for the association between preference for child portions and variables on parental sociodemographic characteristics and weight status. About 70% of parents said they would prefer that restaurants offer smaller, lower-priced child portions of all menu offerings. The adjusted odds of preferring child portions were significantly higher among Hispanic parents (OR, 1.95 vs. non-Hispanic whites) but significantly lower among parents with lower education (<= high school, OR, 0.64; some college, OR, 0.69 vs. college graduate) and parents residing in the Midwest or West (Midwest, OR, 0.61; West, OR, 0.58 vs. South). The most common reason for preferring child portions of all meals was "wanting my child to eat healthier foods that are not offered on the children's menu" (72%). These findings can be used to encourage restaurants and other venues to consider offering child portions of healthier menu items. PMID- 30406054 TI - Evaluation of Mineral Contents of Multi-Vitamin and Minerals Currently Sold in South Korea. AB - Dietary supplements are popular worldwide and their use has been increasing. The purpose of this study was to evaluate the mineral contents of multi-vitamins and minerals (MVMs) in most commonly sold among dietary supplements. Ninety popular MVM supplements sold in South Korea were surveyed regarding their characteristics and ingredients including minerals listed on the labels through off-line and on line search. Daily mineral contents of the MVM supplements were compared with Korean Dietary Reference Intakes (DRIs) by target populations. The average price of 90 MVM supplements was $41.3 per bottle, with a price of $0.9 per day and the average number of minerals contained per supplement was 4.7. A total 14 minerals were found in the MVM supplements including calcium, phosphorus, sodium, potassium, and magnesium. Nine minerals (e.g. calcium, magnesium, and iron) were included in more than 30% of the MVM supplements examined. When daily mineral dose of MVMs was compared to DRIs, calcium was the lowest (34.0% of recommended intake [RI]) and chromium was the highest (218.7% of adequate intake [AI]), and zinc, copper, selenium, and chromium were also higher than their RI or AI levels. The daily mineral contents of the 90 MVM supplements were below the tolerable upper-intake level, but some minerals were higher than RI or AI with high variance among products. Therefore, there is a great need to educate the public for the adequate selection and use of MVM supplements based on the contents of MVM supplements and individual's mineral intake derived from the diet. PMID- 30406052 TI - Diabetes and Alzheimer's Disease: Mechanisms and Nutritional Aspects. AB - Blood glucose homeostasis is well maintained by coordinated control of various hormones including insulin and glucagon as well as cytokines under normal conditions. However, chronic exposure to diabetic environment with high fat/high sugar diets and physical/mental stress can cause hyperglycemia, one of main characteristics of insulin resistance, metabolic syndrome, and diabetes. Hyperglycemia impairs organogenesis and induces organ abnormalities such as cardiac defect in utero. It is a risk factor for the development of metabolic diseases in adults. Resulting glucotoxicity affects peripheral tissues and vessels, causing pathological complications including diabetic neuropathy, nephropathy, vessel damage, and cardiovascular diseases. Moreover, chronic exposure to hyperglycemia can deteriorate cognitive function and other aspects of mental health. Recent reports have demonstrated that hyperglycemia is closely related to the development of cognitive impairment and dementia, suggesting that there may be a cause-effect relationship between hyperglycemia and dementia. With increasing interests in aging-related diseases and mental health, diabetes related cognitive impairment is attracting great attention. It has been speculated that glucotoxicity can result in structural damage and functional impairment of brain cells and nerves, hemorrhage of cerebral blood vessel, and increased accumulation of amyloid beta. These are potential mechanisms underlying diabetes-related dementia. Nutrients and natural food components have been investigated as preventive and/or intervention strategy. Among candidate components, resveratrol, curcumin, and their analogues might be beneficial for the prevention of diabetes-related cognitive impairment. The purposes of this review are to discuss recent experimental evidence regarding diabetes and cognitive impairment and to suggest potential nutritional intervention strategies for the prevention and/or treatment of diabetes-related dementia. PMID- 30406055 TI - Pickle Consumption is Associated with Body Mass Index and Blood Pressure among Iranian Female College Students: a Cross-Sectional Study. AB - Pickle is consumed in high amount among Iranians. Pickle consumption may be related to body mass index (BMI) and blood pressure (BP) but limited evidence exist in this regard. The aim of current study was to determine the association between pickle consumption and risk of overweight, central obesity and BP among Isfahanian female youths. A cross-sectional study was conducted on 289 female students aged 18-27 years randomly selected from students of Isfahan University of Medical Sciences, Isfahan, Iran. Diet was assessed by a validated and reliable food-frequency questionnaire. Mean pickle consumption was 15.1 +/- 2.2 g/day. Individuals in the highest tertile of pickle consumption had a significantly higher BMI, systolic and diastolic BP (p = 0.001, 0.03, and 0.03, respectively), whereas we did not observe significant association for waist circumference (p = 0.21). Total energy intake (p = 0.02) and consumption of carbohydrate (p = 0.01), protein (p = 0.03), and fat (p = 0.05) in the upper tertile was higher than lower tertiles. There was a significant association between pickle consumption and obesity and BP among Iranian female youths. Further prospective studies are needed to confirm this association. PMID- 30406056 TI - Food Habits, Dietary Intake, and Body Composition in Children with Cerebral Palsy. AB - This study aimed to determine meal-related factors affecting nutritional status, dietary intake, and body composition of children with cerebral palsy (CP). This study was conducted on 16 children with and 16 children without CP, aged 4 to 12 years, through a survey on general characteristics, body composition, eating habits, and nutrient intake. In the case of children with CP, comparisons were made according to classification into types of paralysis (hemiplegia, paraplegia, and quadriplegia). With respect to stature, the percentile of those surveyed was within normal range; however, children with CP were in a significantly lower percentile (p < 0.05) than healthy children. Regarding problems of dietary life, while usually brain-damaged children with CP have an overeating problem, seriously brain-damaged children with CP cannot have a meal by themselves; this was significantly different among the groups (p < 0.01). Regarding average intake of vitamin D and calcium, children with and without CP had a lower intake than required, with no significant difference between the groups. The evaluation of the nutrient status of children with and children without CP showed that children with CP were slow in stature development, and intake of vitamin D and calcium were less than required; therefore, it is necessary to provide education on adequate intake of nutrients. Since CP leads to frequent external intervention to having meals, it is required of parents and teachers to undergo training on adequate eating habits and attitudes. PMID- 30406057 TI - Effects of Maternal and Post-Weaning High-Fat Diet on Leptin Resistance and Hypothalamic Appetite Genes in Sprague Dawley Rat Offspring. AB - The defective satiation signaling may contribute to the etiology of obesity. We investigated how dietary modification during maternal (pregnancy and lactation) and post-weaning affects obesity, insulin resistance (IR) and hypothalamic appetite responses in offspring in adulthood. Pregnant female SD rats were randomly allocated to either maternal high-fat diet (43% energy from fat) or control diet (12% energy from fat) until the end of suckling. After weaning for additional 4 weeks, half of the offsprings were continuously fed the same diet as the dam (C-C and H-H groups); the remainder received the counterpart diet (C-H and H-C groups). The long-term high-fat diet during maternal and post-weaning period (H-H group) led to susceptibility to obesity and IR through the significant increases of hypothalamic orexigenic genes compared to the maternal and post-weaning control diet group (C-C group). In contrast, the hypothalamic expression levels of anorexigenic genes, apolipoprotein E, leptin receptor, and activated signal transducer and activator of transcription protein 3 were significantly lower in H-H group with elevations in circulating insulin and leptin and body fat mass. However, dietary changes after weaning (H-C and C-H groups) partially modified these conditions. These results suggest that maternal and post-weaning diet conditions can potentially disrupt hypothalamic neuronal signal irrelevantly, which is essential for leptin's regulation of energy homeostasis and induce the risk of offspring to future metabolic disorders. PMID- 30406058 TI - Effect of Pre-meal Water Consumption on Energy Intake and Satiety in Non-obese Young Adults. AB - I determined whether water consumption reduces energy intake and affects satiety in non-obese young adults. The final subjects consisted of 15 individuals (8 women and 7 men) with average ages of 26.4 and 23.5 years for women and men, respectively. When subjects drank water before eating a test meal, they ate a lower amount of the test meal compared to eating test meals under waterless and postload water conditions (preload water: 123.3 g vs. waterless: 161.7 g or postload water: 163.3 g, p < 0.05). Water consumption after eating a test meal did not affect energy intake. When the subjects drank water before eating a test meal, despite consuming a lower amount, the subjects did not feel significantly less satiety than eating meals under waterless or postload water conditions. The finding that pre-meal water consumption led to a significant reduction in meal energy intake in young adults suggests that pre-meal water consumption may be an effective weight control strategy, although the mechanism of action is unknown. PMID- 30406059 TI - Diet Modification Based on the Enhanced Recovery After Surgery Program (ERAS) in Patients Undergoing Laparoscopic Colorectal Resection. AB - The enhanced recovery after surgery (ERAS) program aims to maximize the recovery of patients by minimizing pre- and postoperative complications and stress. The program recommends providing preoperative carbohydrate (CHO) supplements and starting an early postoperative diet to reduce the fasting duration. Based on these recommendations, we implemented preoperative CHO supplementation and initiated an early postoperative diet in patients undergoing laparoscopic colorectal resection. We observed 3 patients as follows: a non-ERAS case, preoperative ERAS case, and pre- and postoperative ERAS case. The preoperative well-being and compliance of patients improved after implementation of the ERAS program. Moreover, the length of hospital stay was reduced. Therefore, we consider that the ERAS program may be helpful for the recovery of patients undergoing laparoscopic colorectal resection. PMID- 30406060 TI - Vasculopathy, Immunodeficiency, and Bone Marrow Failure: The Intriguing Syndrome Caused by Deficiency of Adenosine Deaminase 2. AB - Deficiency of adenosine deaminase 2 (DADA2) is a monogenic form of systemic vasculopathy that often presents during early childhood. Linked to biallelic mutations in ADA2 (previously CECR1), DADA2 was initially described as a syndrome of recurrent fever, livedo racemosa, early-onset strokes, and peripheral vasculopathy that resembles polyarteritis nodosum. However, the wide spectrum of clinical findings and heterogeneity of disease, even among family members with identical mutations, is increasingly recognized. Evidence of systemic inflammation and vasculopathy is not uniformly present in DADA2 patients and some can remain asymptomatic through adulthood. Humoral immunodeficiency characterized by low immunoglobulin levels and increased risk of infection is another common feature of DADA2. Variable cytopenias including pure red cell aplasia that mimics Diamond-Blackfan anemia can also be primary manifestations of DADA2. How defects in a single gene translate into these heterogeneous presentations remains to be answered. In this review, we will summarize lessons learned from the pleiotropic clinical manifestations of DADA2. PMID- 30406061 TI - MicroRNA 27b-3p Modulates SYK in Pediatric Asthma Induced by Dust Mites. AB - The PI3K-AKT pathway is known to regulate cytokines in dust mite-induced pediatric asthma. However, the underlying molecular steps involved are not clear. In order to clarify further the molecular steps, this study investigated the expression of certain genes and the involvement of miRNAs in the PI3K-AKT pathway, which might affect the resultant cytokine-secretion. in-vivo and in vitro ELISA, qRT-PCR and microarrays analyses were used in this study. A down expression of miRNA-27b-3p in dust mite induced asthma group (group D) was found by microarray analysis. This was confirmed by qRT-PCR that found the miRNA-27b-3p transcripts that regulated the expression of SYK and EGFR were also significantly decreased (p < 0.01) in group D. The transcript levels of the SYK and PI3K genes were higher, while those of EGFR were lower in the former group. Meanwhile, we found significant differences in plasma concentrations of some cytokines between the dust mite-induced asthma subjects and the healthy controls. On the other hand, this correlated with the finding that the transcripts of SYK and its downstream PI3K were decreased in HBE transfected with miRNA-27b-3p, but were increased in HBE transfected with the inhibitor in vitro. Our results indicate that the differential expression of the miRNAs in dust mite-induced pediatric asthma may regulate their target gene SYK and may have an impact on the PI3K-AKT pathway associated with the production of cytokines. These findings should add new insight into the pathogenesis of pediatric asthma. PMID- 30406062 TI - Genetic Testing for Steroid-Resistant-Nephrotic Syndrome in an Outbred Population. AB - Background: Steroid-resistant nephrotic syndrome (SRNS) is a leading cause of end stage kidney disease in children and young adults. Despite advances in genomic science that have led to the discovery of >50 monogenic causes of SRNS, there are no clear guidelines for genetic testing in clinical practice. Methods: Using high throughput sequencing, we evaluated 492 individuals from 181 families for mutations in 40 known SRNS genes. Causative mutations were defined as missense, truncating, and obligatory splice site variants with a minor allele frequency <1% in controls. Non-synonymous variants were considered pathogenic if determined to be deleterious by at least two in silico models. We further evaluated for differences in age at disease onset, family history of SRNS or chronic kidney disease, race, sex, renal biopsy findings, and extra-renal manifestations in subgroups with and without disease causing variants. Results: We identified causative variants in 40 of 181 families (22.1%) with SRNS. Variants in INF2, COL4A3, and WT1 were the most common, accounting for over half of all causative variants. Causative variants were identified in 34 of 86 families (39.5%) with familial disease and 6 of 95 individuals (6.3%) with sporadic disease (chi2 p < 0.00001). Family history was the only significant clinical predictor of genetic SRNS. Conclusion: We identified causative mutations in almost 40% of all families with hereditary SRNS and 6% of individuals with sporadic disease, making family history the single most important clinical predictors of monogenic SRNS. We recommend genetic testing in all patients with SRNS and a positive family history, but only selective testing in those with sporadic disease. PMID- 30406063 TI - Neuroprotective Effect of IRL-1620, an Endothelin B Receptor Agonist, on a Pediatric Rat Model of Middle Cerebral Artery Occlusion. AB - Objective: The purpose of this study was to determine the potential neuroprotective effect of endothelin B (ETB) receptor agonist IRL-1620 treatment in a pediatric model of ischemic stroke. Design: A prospective, animal model study. Setting: An experimental laboratory. Subjects: Three-month-old male Wistar Han rats. Interventions: The rats underwent permanent middle cerebral artery occlusion (MCAO). At 2, 4, and 6 h post MCAO, they were treated with saline, IRL 1620 (5 MUg/kg, IV), and/or ETB antagonist BQ788 (1 mg/kg, IV). Measurements and Main Results: The rats were evaluated over the course of 7 days for neurological and motor deficit, cerebral blood flow (CBF), and infarct volume. Young rats treated with IRL-1620 following MCAO improved significantly in neurological and motor assessments as compared to the vehicle-treated group, as measured by neurological score (P = 0.00188), grip test (P < 0.0001), and foot-fault error (P = 0.0075). CBF in the infarcted hemisphere decreased by 45-50% in all groups immediately following MCAO. After 7 days, CBF in the infarcted hemisphere of the IRL-1620 group increased significantly (P = 0.0007) when compared to the vehicle treated group (+2.3 +/- 23.3 vs. -45.4 +/- 10.2%). Additionally, infarct volume was significantly reduced in IRL-1620-treated rats as compared to vehicle-treated rats (P = 0.0035, 41.4 +/- 35.4 vs. 115.4 +/- 40.9 mm3). Treatment with BQ788 blocked the effects of IRL-1620. Conclusions: IRL-1620 significantly reduced neurological and motor deficit as well as infarct volume while increasing CBF in a pediatric rat model of cerebral ischemia. These results indicate that selective ETB receptor stimulation may provide a novel therapeutic strategy in the treatment of pediatric ischemic stroke as has been demonstrated in adult ischemic stroke. PMID- 30406064 TI - Congenital Heart Disease Increases Mortality in Neonates With Necrotizing Enterocolitis. AB - Background: Studies on the influence of congenital heart disease (CHD) on neonates with necrotizing enterocolitis (NEC) have produced varied results. We therefore examined the influence of CHD on NEC outcomes. Methods: We carried out a retrospective single-center study including infants with confirmed NEC, treated between 2004 and 2017. We excluded patients with isolated patent ductus arteriosus or pulmonary hypertension (n = 45) and compared outcomes of patients with hemodynamically relevant CHD (n = 38) and those without CHD (n = 91). Results: Patients with CHD were more mature than those without CHD [gestational age, median, 95% confidence interval (CI95), 37.1, 34.5-37.2w, vs. 32.6, 31.9 33.3w; P < 0.01]. The presence of CHD did not influence the frequencies of severe disease (overall 21% Bell stage III), nor surgical interventions (overall 30%), the occurrence of intestinal complications (overall 13%), nor the duration of hospitalization (overall 38 days in survivors). The overall mortality as well as NEC-related mortality was increased with the presence of CHD, being 50% (19 out of 38) and 13% (5 out of 38), respectively, when compared to patients without CHD, being 8% (7 out of 91) and 3% (3 out of 91). The presence of CHD and of advanced NEC stage III were independent predictors of NEC-associated fatalities with multivariable odds ratios (CI95) of 7.0, 1.3-39.5 for CHD, and of 3.4, 1.6 7.5 for stage III disease. Conclusions: While some outcome parameters in neonates with NEC remained unaffected by the presence of CHD, the mortality risk for patients with CHD was seven times higher than without CHD. PMID- 30406065 TI - Oxygen Delivery and Oxygen Consumption in Pediatric Fluid Refractory Septic Shock During the First 42 h of Therapy and Their Relationship to 28-Day Outcome. AB - Background: In septic shock, both oxygen delivery (DO2) and oxygen consumption (VO2) are dysfunctional. The current therapeutic regimens are geared to normalize global oxygen delivery (DO2) to tissues via goal directed therapies but mortality remains high at 10-20%. Methods: We studied cardiac index (CI), systemic vascular resistance index (SVRI), central venous oxygen saturation (ScvO2), central venous pressure (CVP), peripheral oxygen saturation (SpO2), mean blood pressure (MBP), body temperature, blood lactate, base excess and hemoglobin concentration (Hb) in a cohort of children admitted in "fluid-refractory" severe septic shock to pediatric intensive care, over 4.5-years. We calculated their 6 h global oxygen delivery (DO2) and global oxygen consumption (VO2) over the first 42 h and looked at factors associated with VO2/DO2 ratio (i.e., global oxygen extraction, gO2ER) and 28-day mortality. Results: Sixty-two children mean age (SD) 7.19 (5.44) years were studied. Fifty-seven (93%) children were sedated and mechanically ventilated and all received adrenaline or noradrenaline or both and added milrinone in 6 (9.6%). At 28 days, 9 (14.5%) were dead. The global oxygen extraction ratio (gO2ER) was consistently lower amongst the survivors and independently predicted mortality (ROC AUC = 0.75). A lactate level of 4 mmol/l or above, when associated with a concurrent metabolic acidosis predicted mortality with a sensitivity of 100% (95% CI 90.5-100) and a specificity of 67.7% (95% CI 62.2-72.9). A gO2ER of 0.48 or above on admission to the PICU was associated with death with a 66.7% sensitivity (95%CI 29.9-92.5) and 90.5% specificity (95%CI 79.3-96.8). A global O2ER of >0.48 combined with a concurrent blood lactate >4.0 mmol/l at any time within the first 42 h of therapy predicted death with a sensitivity of 63.9% (95% CI, 46.2-79.1) and specificity of 97.8% (95% CI, 95.7-99.0). A radar plot identified MBP-CVP difference, and CI as additional goals of therapy that may offer a survival benefit. Conclusions: Global O2ER of >0.48 with a concurrent blood lactate >4.0 mmol/l in children with metabolic acidosis was an independent factor associated with death in fluid resistant septic shock. Trends of gO2ER seem useful to recognize survivors and non-survivors early in the illness. PMID- 30406066 TI - Off-Label Use of Ataluren in Four Non-ambulatory Patients With Nonsense Mutation Duchenne Muscular Dystrophy: Effects on Cardiac and Pulmonary Function and Muscle Strength. AB - About 15% of Duchenne muscular dystrophy (DMD) cases are caused by point mutations leading to premature stop codons and disrupted synthesis of the dystrophin protein. Stop codon read-through therapy is available with the drug Ataluren (Translarna(r) by PTC Therapeutics). Following positive results in ambulatory nmDMD (non-sense mutation Duchenne muscular dystrophy) patients, Ataluren received conditional approval in ambulant nmDMD patients by the EMA in 2014. However, there are limited data on non-ambulatory nmDMD patients treated with Ataluren. Here, we report our experience in four non-ambulatory nmDMD patients. Routine investigations included cardiac function, pulmonary function tests and muscle strength. We compared changes in left ventricular fractional shorting, forced volume vital capacity and BMI from two defined time periods (18 26-month period prior to and after Ataluren start). Mean age at loss of ambulation was 10.1 +/- 0.5 years, mean age when initiating Ataluren treatment 14.1 +/- 1.4 years. Serial echocardiography, pulmonary lung function tests, and assessment of muscle strength indicated mild attenuation of disease progression after initiation of Ataluren treatment. A possible side effect of Ataluren was a reduction in BMI. There were no adverse clinical effects or relevant abnormalities in routine laboratory values. We conclude that Ataluren appears to mildly ameliorate the clinical course in our patients with a good safety profile. However, larger clinical trials are required to assess the role of Ataluren and its long-term impact on disease progression in non-ambulant nmDMD patients. PMID- 30406067 TI - Digital Delivery of Meditative Movement Training Improved Health of Cigarette Smoke-Exposed Subjects. AB - Many FA who flew prior to the ban on smoking in commercial aircraft exhibit an unusual pattern of long-term pulmonary dysfunction. This randomized controlled study tested the hypothesis that digitally delivered meditative movement (MM) training improves chronic obstructive pulmonary disease (COPD)-related symptoms in flight attendants (FA) who were exposed to second-hand cigarette smoke (SHCS) while flying. Phase I of this two-phase clinical trial was a single-arm non randomized pilot study that developed and tested methods for MM intervention; we now report on Phase II, a randomized controlled trial comparing MM to a control group of similar FA receiving health education (HE) videos. Primary outcomes were the 6-min walk test and blood levels of high sensitivity C-reactive protein (hs CRP). Pulmonary, cardiovascular, autonomic and affective measures were also taken. There were significant improvements in the 6-min walk test, the Multidimensional Assessment of Interoceptive Awareness (MAIA) score, and the COPD Assessment Test. Non-significant trends were observed for increased dehydroepiandrosterone sulfate (DHEAS) levels, decreased anxiety scores and reduced blood hs-CRP levels, and increased peak expiratory flow (PEF). In a Survey Monkey questionnaire, 81% of participants who completed pre and post testing expressed mild to strong positive opinions of the study contents, delivery, or impact, while 16% expressed mild negative opinions. Over the course of the year including the study, participant adoption of the MM practices showed a significant and moderately large correlation with overall health improvement; Pearson's R = 0.62, p < 0.005. These results support the hypothesized benefits of video-based MM training for this population. No adverse effects were reported. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02612389. PMID- 30406069 TI - Validation and Factor Analysis of the Child and Youth Resilience Measure for Indigenous Australian Boarding School Students. AB - Introduction: Resilience is a strengths-based construct that is useful for understanding differences in health and wellbeing among youth. There are a range of validated survey instruments available to measure resilience for Aboriginal and Torres Strait Islander (hereafter respectfully Indigenous) youth. However, standard international instruments should only be used if they have been subjected to a rigorous cross-cultural adaptation process and psychometric evaluation in the target population to ensure their validity. The aim of the study was to validate an adapted Child and Youth Resilience Measure (CYRM-28) within a sample of Indigenous Australian boarding school students. Method: The CYRM-28, augmented with an additional 11 site specific items was administered to a purposive sample of Australian Indigenous boarding school students (n = 233) as part of the broader T4S survey instrument that captures demographic information and measures resilience, psychological distress and risk, and service usage. Confirmatory factor analysis was undertaken to verify the relationship between the observed variables with the theoretical constructs of the CYRM-28 and previous findings on the factor structure. Cronbach alpha was also calculated to assess the internal consistency of the CYRM-28 within this sample. Results: Survey data were not a good fit for any previously identified models of the CYRM 28, although the inclusion of a site-specific variable improved the overall fit statistics. Two separate scales were confirmed that capture the sources and expressions of resilience for Indigenous Australian boarding school students. This structure is different to previous findings in relation to the CYRM-28, but consistent with conceptualizations of resilience as a dynamic process. Conclusions: The findings are useful in guiding the future use of the CYRM-28 instrument, explorations of Indigenous youth resilience, and for services working with Indigenous youth in out of home care situations. They highlight contextual differences in the measurement of resilience and the importance of validating standard instruments that have been subjected to rigorous cross-cultural adaptation processes. The two scales offer practical guidance to human services working with Indigenous youth on strategies to build and monitor resilience in Indigenous Australian youth and contribute to the emergent understanding of their resilience. PMID- 30406068 TI - Metabolomic Markers of Phthalate Exposure in Plasma and Urine of Pregnant Women. AB - Phthalates are known endocrine disruptors and found in almost all people with several associated adverse health outcomes reported in humans and animal models. Limited data are available on the relationship between exposure to endocrine disrupting chemicals and the human metabolome. We examined the relationship of metabolomic profiles in plasma and urine of 115 pregnant women with eleven urine phthalate metabolites measured at 26 weeks of gestation to identify potential biomarkers and relevant pathways. Targeted metabolomics was performed by selected reaction monitoring liquid chromatography and triple quadrupole mass spectrometry to measure 415 metabolites in plasma and 151 metabolites in urine samples. We have chosen metabolites with the best defined peaks for more detailed analysis (138 in plasma and 40 in urine). Relationship between urine phthalate metabolites and concurrent metabolomic markers in plasma and urine suggested potential involvement of diverse pathways including lipid, steroid, and nucleic acid metabolism and enhanced inflammatory response. Most of the correlations were positive for both urine and plasma, and further confirmed by regression and PCA analysis. However, after the FDR adjustment for multiple comparisons, only 9 urine associations remained statistically significant (q-values 0.0001-0.0451), including Nicotinamide mononucleotide, Cysteine T2, Cystine, and L-Aspartic acid. Additionally, we found negative associations of maternal pre-pregnancy body mass index (BMI) with more than 20 metabolomic markers related to lipid and amino-acid metabolism and inflammation pathways in plasma (p = 0.01-0.0004), while Mevalonic acid was positively associated (p = 0.009). Nicotinic acid, the only significant metabolite in urine, had a positive association with maternal BMI (p = 0.002). In summary, when evaluated in the context of metabolic pathways, the findings suggest enhanced lipid biogenesis, inflammation and altered nucleic acid metabolism in association with higher phthalate levels. These results provide new insights into the relationship between phthalates, common in most human populations, and metabolomics, a novel approach to exposure and health biomonitoring. PMID- 30406070 TI - Nurse-Led Diabetes Self-Management Education Improves Clinical Parameters in Ethiopia. AB - Background: Unlike in developed countries, the clinical effectiveness of diabetes self-management education (DSME) is not well-studied in the African context. Thus, this study sought to determine effects of DSME on clinical outcomes among type 2 diabetic (T2DM) patients in Ethiopia. Methods: Before-and-after controlled study design was employed, with random assignment of 116 T2DM adult patients to a nurse-led DSME group and 104 to a treatment-as-usual (comparison) group. A nurse led DSME with six sessions supported with illustrative pictures handbooks and fliers was customized to local conditions and delivered by trained nurses over 9 months. Our primary outcome was a change in the proportion of people with target glycated hemoglobin (HbA1c <= 7%). We used chi-square test and mixed model analysis. Results: Seventy-eight (67%) and 64 (62%) participants assigned to intervention and comparison, respectively completed the study, and included in the final analysis. Mean HbA1c was significantly reduced by 2.88% within the intervention group and by 2.57% within the comparison group. However, change in the proportion of participants with target HbA1c and end-line mean HbA1c difference between the groups were not significant. Adjusted end-line fasting blood sugar (FBS), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were significantly lower in the intervention group, by 27 +/- 9 mg/dL, 12 +/- 3, and 8 +/- 2 mmHg, respectively. Conclusion: After 9 months of nurse-led DSME, HbA1c was significantly reduced within both groups but there was no significant difference in HbA1c between groups. The intervention also showed some clinically significant effects on blood pressure and FBS. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT03185689, retrospectively registered on June 14, 2017 on ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03185689. PMID- 30406071 TI - Predictors of Physical Activity in Middle Childhood. A Fixed-Effects Regression Approach. AB - Background: Moderate-to-vigorous physical activity (MVPA) has a range of health benefits across the life span. Although many putative determinants of children's MVPA have been identified, their causal status is uncertain due to difficulties in adjusting for potential confounders. Objective: To inform promotion of children's MVPA we therefore aimed to examine well-known child-, family- and contextual predictors of MVPA in middle childhood, by applying a fixed effects regression approach, which rules out the influence of all unmeasured time invariant confounders. Methods: Two birth cohorts of children living in the city of Trondheim, Norway were invited to participate (82.0% consented). The participants were followed-up biennially from age 6 to 10 years (n = 800) between 2009 and 2014. MVPA in children was recorded by accelerometers and child-, family and contextual factors were obtained through interviews and questionnaires. Predictors included (i) child-level factors: the child's time outdoors, organized sports participation, athletic self-concept, self-reported screen time and objectively measured sedentariness; (ii) family factors: self-reported parental MVPA and actively transporting the child to school; and (iii) contextual factors: parental socio-economic status (SES), access to playgrounds and ballparks, traffic safety, and having a garden. A three-wave prospective study was conducted with a hybrid fixed effects regressions analysis adjusting for all time-invariant confounders to examine predictors of MVPA. Results: Children evidenced increased MVPA when they spent more time outside, spent less time being sedentary and when the family had a garden and lived in a traffic-safe area. Conclusion: Adjusting for measured time-varying and all unmeasured time-invariant confounders renders many previously identified child and family factors without impact on MVPA in children. However, several contextual factors may promote MVPA in middle childhood, and efforts to facilitate children being outside in environments that promote physical activity (e.g., being outside, in gardens, or otherwise traffic safe areas) may prove important. PMID- 30406072 TI - Socioeconomic Inequalities in the Risk Factors of Noncommunicable Diseases Among Women of Reproductive Age in Sub-saharan Africa: A Multi-Country Analysis of Survey Data. AB - Background: Understanding the socioeconomic discordance associated with the risk factors of non-communicable diseases (NCDs) can help direct effective interventions to end its persistent occurrence. We examined the prevalence of high blood pressure, overweight/obesity, alcohol consumption and tobacco use among women and compared across wealth quintiles in sub-Saharan Africa countries. Methods: This study included 454,080 women of reproductive age (15-49 years) from the current Demographic and Health Survey (DHS) conducted between 2008/09-2017 across 33 sub-Saharan Africa countries. The outcome variables were high blood pressure, overweight/obesity, alcohol consumption and tobacco use. The prevalence of the risk factors of NCDs and sample characteristics across different levels of wealth quintiles were examined. Furthermore, socioeconomic inequalities were measured using concentration index (CI) and Lorenz curve considering urban-rural differentials. Results: The prevalence of high blood pressure and overweight/obesity were 1.2-17.3% and 6.7-44.5% respectively with significant wealth quintile differences. More so, alcohol consumption prevalence was 4.1 47.3% and tobacco use was 0.3-9.9%. The overall prevalence of high blood pressure was 5.5%, overweight/obesity accounted for about 23.1%, alcohol consumption and tobacco users were 23.9 and 2.4%, respectively. The socioeconomic inequalities in high blood pressure (CI = 0.1352, p < 0.001); overweight/obesity (CI = 0.2285, p < 0.001), and alcohol consumption (CI = 0.0278, p < 0.001) were significantly more in the higher socioeconomic group, compared to the lower socioeconomic group. In contrast, the prevalence of tobacco use (CI = -0.2551, p < 0.001) was significantly more in the lower socioeconomic group, compared to the higher socioeconomic group. The test for differences in rural vs. urban concentration indices for high blood pressure, overweight/obesity, alcohol consumption, and tobacco use were statistically significant in all the health indicators (p < 0.05). Conclusion: An effective intervention should incorporate a high-risk approach to terminate risk distribution by directing resources to key population women. To improve the benefit to risk ratio and enhance the cost effectiveness of preventive health programmes, it is paramount to understand the worth of equity based strategies. Integrating equity elements to interventions is a key measure toward ensuring that policies and programmes meet their milestones. Government should strengthen living standards, literacy and healthcare system to curtail the increasing prevalence of the risk factors of NCDs. PMID- 30406073 TI - Parental Intention to Support the Use of Computerized Cognitive Training for Children With Genetic Neurodevelopmental Disorders. AB - Children with genetic neurodevelopmental disorders (NDDs) such as Down syndrome, Prader-Willi syndrome, and Fragile X syndrome may show a range of cognitive impairments, including impairments in executive functions (EF). EF are related to general intelligence, academic achievement, and literacy and mathematical skills. EF deficits are linked to a variety of clinically and socially important behaviors. Therefore, methods for improving EF in children with NDDs could be beneficial. One method for improving EF is through cognitive training. Research on commercial brain training programmes and video games suggests that EF can be improved through training, both in healthy adults and in children with NDDs. Computerized cognitive training (CCT) therefore represents a potentially viable intervention for children with NDDs. For training to be effective, it is important that an appropriate regimen is followed. Since children are likely to engage with training at home, the intentions of their parents to support them are therefore important. However, no research has investigated the attitudes of parents of children with NDDs to CCT. To address this, we developed a questionnaire based on the theory of planned behavior, which states that a person's intention to engage in a behavior is predicted by (1) their attitude toward the behavior, (2) their perception of subjective norms regarding the behavior (i.e., perceived social pressure), and (3) their perceived control over the behavior. The questionnaire was completed by parents of children with NDDs; 58 unique responses were retained for analyses. Parents reported low levels of knowledge of CCTs, and low levels of experience with CCTs (both their own experience and their child's experience). However, our results also show that parents of children with NDDs have positive beliefs about the potential of CCT to benefit their children and intend to support the use of CCT by their children. Linear modeling showed that, of the three constructs of the theory of planned behavior, only attitudes significantly predicted intention. Finally, parents' beliefs about the benefits of CCT correlated positively with positive attitudes toward such training. We also found limited evidence that parents of boys have more positive attitudes regarding CCT than parents of girls. PMID- 30406074 TI - Science Has to Take Responsibility. 10 Years World Health Summit-The Road to Better Health for All. PMID- 30406075 TI - Water-Borne Perovskite Quantum Dot-Loaded, Polystyrene Latex Ink. AB - Highly lipophilic nanocrystals (NCs) of cesium lead halides were successfully embedded in polystyrene (PS) particles by deliberately controlling the swelling of the PS particles in the mixtures of good and bad organic solvents. The resulting composite particles were readily transferred into water via simple stepwise solvent exchange, which yielded water-borne perovskite NC-based inks with outstanding structural and chemical stability in aqueous media. Minimal change in the photoluminescence (PL) of the NCs loaded in the PS particles was visible after 1 month of incubation of the composite particles in water in a broad pH range from 1 to 14, which could otherwise be hardly realized. Loading into the PS particles also made the NCs highly stable against polar organic solvents, such as ethanol, intense light irradiation, and heat. The NC PL intensity slightly changed after the composite particles were heated at 75 degrees C and under irradiation of strong blue light (@365 nm) for 1 h. Furthermore, the PS matrices could effectively inhibit the exchange of halide anions between two differently sized perovskite NCs loaded therein, thereby offering a considerable technical advantage in the application of multiple perovskite NCs for multicolor display in the future. PMID- 30406076 TI - Control of Uniaxial Negative Thermal Expansion in Layered Perovskites by Tuning Layer Thickness. AB - Uniaxial negative thermal expansion (NTE) is known to occur in low n members of the A n+1B n O3n+1 Ruddlesden-Popper (RP) layered perovskite series with a frozen rotation of BO6 octahedra about the layering axis. Previous work has shown that this NTE arises due to the combined effects of a close proximity to a transition to a competing phase, so called "symmetry trapping", and highly anisotropic elastic compliance specific to the symmetry of the NTE phase. We extend this analysis to the broader RP family (n = 1, 2, 3, 4, ..., infinity), demonstrating that by changing the fraction of layer interface in the structure (i.e., the value of 1/n) one may control the anisotropic compliance that is necessary for the pronounced uniaxial NTE observed in these systems. More detailed analysis of how the components of the compliance matrix develop with 1/n allows us to identify different regimes, linking enhancements in compliance between these regimes to the crystallographic degrees of freedom in the structure. We further discuss how the perovskite layer thickness affects the frequencies of soft zone boundary modes with large negative Gruneisen parameters, associated with the aforementioned phase transition, that constitute the thermodynamic driving force for NTE. This new insight complements our previous work-showing that chemical control may be used to switch from positive to negative thermal expansion in these systems-since it makes the layer thickness, n, an additional design parameter that may be used to engineer layered perovskites with tuneable thermal expansion. In these respects, we predict that, with appropriate chemical substitution, the n = 1 phase will be the system in which the most pronounced NTE could be achieved. PMID- 30406077 TI - Facile Fabrication of Sandwich Structural Membrane With a Hydrogel Nanofibrous Mat as Inner Layer for Wound Dressing Application. AB - A common problem existing in wound dressing is to integrate the properties of against water erosion while maintaining a high water-uptake capacity. To tackle this issue, we imbedded one layer of hydrogel nanofibrous mat into two hydrophobic nanofibrous mats, thereafter, the sandwich structural membrane (SSM) was obtained. Particularly, SSM is composed of three individual nanofibrous layers which were fabricated through sequential electrospinning technology, including two polyurethane/antibacterial agent layers, and one middle gelatin/rutin layer. The obtained SSM is characterized in terms of morphology, component, mechanical, and functional performance. In addition to the satisfactory antibacterial activity against Staphylococcus aureus and Escherichia coli, and antioxidant property upon scavenging DPPH free radicals, the obtained SSM also shows a desirable thermally regulated water vapor transmission rate. More importantly, such SSM can be mechanically stable and keep its intact morphology without appearance damage while showing a high water-absorption ratio. Therefore, the prepared sandwich structural membrane with hydrogel nanofibrous mat as inner layer can be expected as a novel wound dressing. PMID- 30406078 TI - Enhanced Sub-ppm NH3 Gas Sensing Performance of PANI/TiO2 Nanocomposites at Room Temperature. AB - PANI/TiO2 nanocomposites spheres were synthesized using a simple and efficient one-step hydrothermal process. The morphology and structure of PANI/TiO2 nanocomposites spheres were investigated by X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) techniques. The PANI/TiO2 nanocomposite sphere-based sensor exhibits good selectivity, sensitivity (5.4 to 100 ppm), repeatability, long-term stability and low detection limit (0.5 ppm) to ammonia at room temperature (20 +/- 5 degrees C). It also shows a good linearity relationship in the range of 0.5-5 and 5-100 ppm. The excellent NH3 sensing performance is mainly due to the formation of the p-n heterostructure in the nanocomposites. PMID- 30406079 TI - Developing Paper Based Diagnostic Technique to Detect Uric Acid in Urine. AB - Urinary or serum uric acid concentration is an indicator of chronic kidney condition. An increase in uric acid concentration may indicate renal dysfunction. Reliable instantaneous detection of uric acid without requiring sophisticated laboratory and analytical instrumentation, such as: chromatographic and spectrophotometric methods, would be invaluable for patients with renal complication. This paper reports the early development of a simple, low-cost, instantaneous and user-friendly paper based diagnostic device (PAD) for the qualitative and quantitative detection of uric acid in urine. A colorimetric detection technique was developed based on the intensity of Prussian blue color formation on paper in presence of uric acid; the reaction rate of corresponding chemical reactions on paper surface was also studied. Based on the colorimetric signal produced on paper surface, a calibration curve was developed to detect unknown concentration of uric acid in urine. The effect of temperature on formation of color signal on paper surface was also analyzed. In this study, estimation of urinary uric acid using MATLAB coding on a windows platform was demonstrated as the use of software application and digital diagnostics. This paper-based technique is faster and less expensive compared to traditional detection techniques. The paper-based diagnostic can be integrated with a camera of smart phone, tablet computer or laptop and an image processing application (using windows/android/IOS platform) as a part of digital diagnostics. Therefore, with proper calibration, the paper-based technique can be compatible and economical to the sophisticated detection techniques used to detect urinary uric acid. PMID- 30406080 TI - Coculture of Marine Streptomyces sp. With Bacillus sp. Produces a New Piperazic Acid-Bearing Cyclic Peptide. AB - Microbial culture conditions in the laboratory, which conventionally involve the cultivation of one strain in one culture vessel, are vastly different from natural microbial environments. Even though perfectly mimicking natural microbial interactions is virtually impossible, the cocultivation of multiple microbial strains is a reasonable strategy to induce the production of secondary metabolites, which enables the discovery of new bioactive natural products. Our coculture of marine Streptomyces and Bacillus strains isolated together from an intertidal mudflat led to discover a new metabolite, dentigerumycin E (1). Dentigerumycin E was determined to be a new cyclic hexapeptide incorporating three piperazic acids, N-OH-Thr, N-OH-Gly, beta-OH-Leu, and a pyran-bearing polyketide acyl chain mainly by analysis of its NMR and MS spectroscopic data. The putative PKS-NRPS biosynthetic gene cluster for dentigerumycin E was found in the Streptomyces strain, providing clear evidence that this cyclic peptide is produced by the Streptomyces strain. The absolute configuration of dentigerumycin E was established based on the advanced Marfey's method, ROESY NMR correlations, and analysis of the amino acid sequence of the ketoreductase domain in the biosynthetic gene cluster. In biological evaluation of dentigerumycin E (1) and its chemical derivatives [2-N,16-N-deoxydenteigerumycin E (2) and dentigerumycin methyl ester (3)], only dentigerumycin E exhibited antiproliferative and antimetastatic activities against human cancer cells, indicating that N-OH and carboxylic acid functional groups are essential for the biological activity. PMID- 30406082 TI - Carbothermal Synthesis of Nitrogen-Doped Graphene Composites for Energy Conversion and Storage Devices. AB - Metal oxides and carbonaceous composites are both promising materials for electrochemical energy conversion and storage devices, such as secondary rechargeable batteries, fuel cells and electrochemical capacitors. In this study, Fe3O4 nanoparticles wrapped in nitrogen-doped (N-doped) graphene nanosheets (Fe3O4@G) were fabricated by a facile one-step carbothermal reduction method derived from Fe2O3 and liquid-polyacrylonitrile (LPAN). The unique two dimensional structure of N-doped graphene nanosheets, can not only accommodate the volume changes during lithium intercalation/extraction processes and suppress the particles aggregation but also act as an electronically conductive matrix to improve the electrochemical performance of Fe3O4 anode, especially the rate capability. What's more, by etching Fe3O4@G to remove the iron-based oxide template, porous N-doped graphene composites (NGCs) were prepared and presented abundant pore structure with high specific surface area, delivering a specific capacitance of 172 F.g-1 at 0.5 A.g-1. In this way, Fe2O3 was both template and activator to adjust the pore size of graphene. And the effect of specific surface area and pore size tuned by the Fe2O3 activator were also revealed. PMID- 30406081 TI - Functional Hydrogels With Tunable Structures and Properties for Tissue Engineering Applications. AB - Tissue engineering (TE) has been used as an attractive and efficient process to restore the original tissue structures and functions through the combination of biodegradable scaffolds, seeded cells, and biological factors. As a unique type of scaffolds, hydrogels have been frequently used for TE because of their similar 3D structures to the native extracellular matrix (ECM), as well as their tunable biochemical and biophysical properties to control cell functions such as cell adhesion, migration, proliferation, and differentiation. Various types of hydrogels have been prepared from naturally derived biomaterials, synthetic polymers, or their combination, showing their promise in TE. This review summarizes the very recent progress of hydrogels used for TE applications. The strategies for tuning biophysical and biochemical properties, and structures of hydrogels are first introduced. Their influences on cell functions and promotive effects on tissue regeneration are then highlighted. PMID- 30406084 TI - Characterization of Solid-State Drug Polymorphs and Real-Time Evaluation of Crystallization Process Consistency by Near-Infrared Spectroscopy. AB - Herein, we aimed to develop a strategy for evaluating the consistency of pharmaceutically important crystallization processes in real time, focusing on two typical cases of polymorphism. Theoretical analysis using a combination of 13C solid-state nuclear magnetic resonance spectroscopy with other polymorphism analysis techniques identified a number of marker signals, the changes of which revealed the presence of two or more structural orientations (lattices and/or molecular conformations) in both cefazolin sodium pentahydrate (alpha-CEZ-Na) and cephathiamidine (CETD). The proportions of these forms were shown to be batch dependent and were defined as critical quality attributes (CQAs) to evaluate process consistency. Subsequently, real-time analysis by chemometrics-assisted near-infrared spectroscopy (NIR) was used to obtain useful information corresponding to CQAs. The pretreated spectra of representative samples were transformed by first derivative and vector normalization methods and used to calculate standard deviations at each wavelength and thus detect significant differences. As a result, vibrational responses of H2O, CH3, and CH2 moieties (at 5,280, 4,431, and 4,339 cm-1, respectively) were shown to be sensitive to the CQAs of alpha-CEZ-Na, which allowed us to establish a highly accurate discrimination model. Moreover, signals of H2O, CONH, and COOH moieties (at 5,211, 5,284, and 5,369 cm-1, respectively) played the same role in the case of CETD, as confirmed by theoretical results. Thus, we established a technique for the rapid evaluation of crystallization process consistency and deepened our understanding of crystallization behavior by using NIR in combination with polymorphism analysis techniques. PMID- 30406083 TI - Multicomponent Reactions Accelerated by Aqueous Micelles. AB - Multicomponent reactions are powerful synthetic tools for the efficient creation of complex organic molecules in an one-pot one-step fashion. Moreover, the amount of solvents and energy needed for separation and purification of intermediates is significantly reduced what is beneficial from the green chemistry issues point of view. This review highlights the development of multicomponent reactions conducted using aqueous micelles systems during the last two decades. PMID- 30406085 TI - A Brief Overview of Two Major Strategies in Diversity-Oriented Synthesis: Build/Couple/Pair and Ring-Distortion. AB - In the interdisciplinary research field of chemical biology and drug discovery, diversity-oriented synthesis (DOS) has become indispensable in the construction of novel small-molecule libraries rich in skeletal and stereochemical diversity. DOS aims to populate the unexplored chemical space with new potential bioactive molecules via forward synthetic analysis. Since the introduction of this concept by Schreiber, DOS has evolved along with many significant breakthroughs. It is therefore important to understand the key DOS strategies to build molecular diversity with maximized biological relevancy. Due to the length limitations of this mini review, we briefly discuss the recent DOS plans using build/couple/pair (B/C/P) and ring-distortion strategies for the synthesis of major biologically relevant target molecules like natural products and their related compounds, macrocycles, and privileged structures. PMID- 30406086 TI - Gas Sensing Performances of ZnO Hierarchical Structures for Detecting Dissolved Gases in Transformer Oil: A Mini Review. AB - Power transformer is one of the critical and expensive apparatus in high voltage power system. Hence, using highly efficient gas sensors to real-time monitor the fault characteristic gases dissolved in transformer oil is in pressing need to ensure the smooth functionalization of the power system. Till date, as a semiconductor metal oxide, zinc oxide (ZnO) is considered as the promising resistive-type gas sensing material. However, the elevated operating temperature, slow response, poor selectivity and stability limit its extensive applications in the field of dissolved gases monitoring. In this respect, rigorous efforts have been made to offset the above-mentioned shortcomings by multiple strategies. In this review, we first introduce the various ZnO hierarchical structures which possess high surface areas and less aggregation, as well as their corresponding gas sensing performances. Then, the primary parameters (sensitivity, selectivity and stability) which affect the performances of ZnO hierarchical structures based gas sensors are discussed in detail. Much more attention is particularly paid to the improvement strategies of enhancing these parameters, mainly including surface modification, additive doping and ultraviolet (UV) light activation. We finally review gas sensing mechanism of ZnO hierarchical structure based gas sensor. Such a detailed study may open up an avenue to fabricate sensor which achieve high sensitivity, good selectivity and long-term stability, making it a promising candidate for transformer oil monitor. PMID- 30406087 TI - Activation of Electrophile/Nucleophile Pair by a Nucleophilic and Electrophilic Solvation in a SNAr Reaction. AB - Nucleophilic aromatic substitution reactions of 4-chloroquinazoline toward aniline and hydrazine were used as a model system to experimentally show that a substrate bearing heteroatoms on the aromatic ring as substituent is able to establish intramolecular hydrogen bond which may be activated by the reaction media and/or the nature of the nucleophile. PMID- 30406088 TI - Advances in Organic Solvent Nanofiltration Rely on Physical Chemistry and Polymer Chemistry. AB - The vast majority of industrial chemical synthesis occurs in organic solution. Solute concentration and solvent recovery consume ~50% of the energy required to produce chemicals and pose problems that are as relevant as the synthesis process itself. Separation and purification processes often involve a phase change and, as such, they are highly energy-intensive. However, novel, energy-efficient technologies based on polymer membranes are emerging as a viable alternative to thermal processes. Despite organic solvent nanofiltration (OSN) could revolutionize the chemical, petrochemical, food and pharmaceutical industry, its development is still in its infancy for two reasons: (i) the lack of fundamental knowledge of elemental transport phenomena in OSN membranes, and (ii) the instability of traditional polymer materials in chemically challenging environments. While the latter issue has been partially solved, the former was not addressed at all. Moreover, the few data available about solute and solvent transport in OSN membranes are often interpreted using inappropriate theoretical tools, which contributes to the spread of misleading conclusions in the literature. In this review we provide the state of the art of organic solvent nanofiltration using polymeric membranes. First, theoretical models useful to interpret experimental data are discussed and some misleading conclusions commonly reported in the literature are highlighted. Then, currently available materials are reviewed. Finally, materials that could revolutionize OSN in the future are identified. Among the possible applications of OSN, isomers separation could open a new era in chemical engineering and polymer science in the years to come. PMID- 30406089 TI - Building a Bird: Musculoskeletal Modeling and Simulation of Wing-Assisted Incline Running During Avian Ontogeny. AB - Flapping flight is the most power-demanding mode of locomotion, associated with a suite of anatomical specializations in extant adult birds. In contrast, many developing birds use their forelimbs to negotiate environments long before acquiring "flight adaptations," recruiting their developing wings to continuously enhance leg performance and, in some cases, fly. How does anatomical development influence these locomotor behaviors? Isolating morphological contributions to wing performance is extremely challenging using purely empirical approaches. However, musculoskeletal modeling and simulation techniques can incorporate empirical data to explicitly examine the functional consequences of changing morphology by manipulating anatomical parameters individually and estimating their effects on locomotion. To assess how ontogenetic changes in anatomy affect locomotor capacity, we combined existing empirical data on muscle morphology, skeletal kinematics, and aerodynamic force production with advanced biomechanical modeling and simulation techniques to analyze the ontogeny of pectoral limb function in a precocial ground bird (Alectoris chukar). Simulations of wing assisted incline running (WAIR) using these newly developed musculoskeletal models collectively suggest that immature birds have excess muscle capacity and are limited more by feather morphology, possibly because feathers grow more quickly and have a different style of growth than bones and muscles. These results provide critical information about the ontogeny and evolution of avian locomotion by (i) establishing how muscular and aerodynamic forces interface with the skeletal system to generate movement in morphing juvenile birds, and (ii) providing a benchmark to inform biomechanical modeling and simulation of other locomotor behaviors, both across extant species and among extinct theropod dinosaurs. PMID- 30406090 TI - A Simple Algorithm for Assimilating Marker-Based Motion Capture Data During Periodic Human Movement Into Models of Multi-Rigid-Body Systems. AB - Human movement analysis is often performed with a model of multi-rigid-body system, whereby reflective-marker-based motion capture data are assimilated into the model for characterizing kinematics and kinetics of the movements quantitatively. Accuracy of such analysis is limited, due to motions of the markers on the skin relative to the underlying skeletal system, referred to as the soft tissue artifact (STA). Here we propose a simple algorithm for assimilating motion capture data during periodic human movements, such as bipedal walking, into models of multi-rigid-body systems in a way that the assimilated motions are not affected by STA. The proposed algorithm assumes that STA time profiles during periodic movements are also periodic. We then express unknown STA profiles using Fourier series, and show that the Fourier coefficients can be determined optimally based solely on the periodicity assumption for the STA and kinematic constraints requiring that any two adjacent rigid-links are connected by a rotary joint, leading to the STA-free assimilated motion that is consistent with the multi-rigid-link model. To assess the efficiency of the algorithm, we performed a numerical experiment using a dynamic model of human gait composed of seven rigid links, on which we placed STA-affected markers, and showed that the algorithm can estimate the STA accurately and retrieve the non-STA-affected true motion of the model. We also confirmed that our STA-removal processing improves accuracy of the inverse dynamics analysis, suggesting the usability of the proposed algorithm for gait analysis. PMID- 30406091 TI - Poroelastic Modeling of Highly Hydrated Collagen Hydrogels: Experimental Results vs. Numerical Simulation With Custom and Commercial Finite Element Solvers. AB - This study presents a comparison between the performances of two Finite Element (FE) solvers for the modeling of the poroelastic behavior of highly hydrated collagen hydrogels. Characterization of collagen hydrogels has been a widespread challenge since this is one of the most used natural biomaterials for Tissue Engineering (TE) applications. V-Biomech(r) is a free custom FE solver oriented to soft tissue modeling, while Abaqus(r) is a general-purpose commercial FE package which is widely used for biomechanics computational modeling. Poroelastic simulations with both solvers were compared to two experimental protocols performed by Busby et al. (2013) and Chandran and Barocas (2004), also using different implementations of the frequently used Neo-Hookean hyperelastic model. The average differences between solvers outputs were under 5% throughout the different tests and hydrogel properties. Thus, differences were small enough to be considered negligible and within the variability found experimentally from one sample to another. This work demonstrates that constitutive modeling of soft tissues, such as collagen hydrogels can be achieved with either V-Biomech or Abaqus standard options (without user-subroutine), which is important for the biomechanics and biomaterials research community. V-Biomech has shown its potential for the validation of biomechanical characterization of soft tissues, while Abaqus' versatility is useful for the modeling and analysis of TE applications where other complex phenomena may also need to be captured. PMID- 30406092 TI - Hydrogen Peroxide-Based Fluorometric Assay for Real-Time Monitoring of SAM Dependent Methyltransferases. AB - Methylated chemicals are widely used as key intermediates for the syntheses of pharmaceuticals, fragrances, flavors, biofuels and plastics. In nature, the process of methylation is commonly undertaken by a super-family of S-adenosyl methionine-dependent enzymes known as methyltransferases. Herein, we describe a novel high throughput enzyme-coupled assay for determining methyltransferase activites. Adenosylhomocysteine nucleosidase, xanthine oxidase, and horseradish peroxidase enzymes were shown to function in tandem to generate a fluorescence signal in the presence of S-adenosyl-L-homocysteine and Amplex Red (10-acetyl-3,7 dihydroxyphenoxazine). Since S-adenosyl-L-homocysteine is a key by-product of reactions catalyzed by S-adenosyl methionine-dependent methyltransferases, the coupling enzymes were used to assess the activities of EcoRI methyltransferase and a salicylic acid methyltransferase from Clarkia breweri in the presence of S adenosyl methionine. For the EcoRI methyltransferase, the assay was sensitive enough to allow the monitoring of DNA methylation in the nanomolar range. In the case of the salicylic acid methyltransferase, detectable activity was observed for several substrates including salicylic acid, benzoic acid, 3-hydroxybenzoic acid, and vanillic acid. Additionally, the de novo synthesis of the relatively expensive and unstable cosubstrate, S-adenosyl methionine, catalyzed by methionine adenosyltransferase could be incorporated within the assay. Overall, the assay offers an excellent level of sensitivity that permits continuous and reliable monitoring of methyltransferase activities. We anticipate this assay will serve as a useful bioanalytical tool for the rapid screening of S-adenosyl methionine-dependent methyltransferase activities. PMID- 30406093 TI - Perspective on Improving Environmental Monitoring of Biothreats. AB - For more than a decade, the United States has performed environmental monitoring by collecting and analyzing air samples for a handful of biological threat agents (BTAs) in order to detect a possible biological attack. This effort has faced numerous technical challenges including timeliness, sampling efficiency, sensitivity, specificity, and robustness. The cost of city-wide environmental monitoring using conventional technology has also been a challenge. A large group of scientists with expertise in bioterrorism defense met to assess the objectives and current efficacy of environmental monitoring and to identify operational and technological changes that could enhance its efficacy and cost-effectiveness, thus enhancing its value. The highest priority operational change that was identified was to abandon the current concept of city-wide environmental monitoring because the operational costs were too high and its value was compromised by low detection sensitivity and other environmental factors. Instead, it was suggested that the focus should primarily be on indoor monitoring and secondarily on special-event monitoring because objectives are tractable and these operational settings are aligned with likelihood and risk assessments. The highest priority technological change identified was the development of a reagent less, real-time sensor that can identify a potential airborne release and trigger secondary tests of greater sensitivity and specificity for occasional samples of interest. This technological change could be transformative with the potential to greatly reduce operational costs and thereby create the opportunity to expand the scope and effectiveness of environmental monitoring. PMID- 30406094 TI - A Cortical Thickness Mapping Method for the Coxal Bone Using Morphing. AB - As human body finite element models become more integrated with the design of safety countermeasures and regulations, novel models need to be developed that reflect the variation in the population's anthropometry. However, these new models may be missing information which will need to be translated from existing models. During the development of a 5th percentile female occupant model (F05), cortical thickness information of the coxal bone was unavailable due to resolution limits in the computed tomography (CT) scans. In this study, a method for transferring cortical thickness information from a source to a target model with entirely different geometry and architecture is presented. The source and target models were the Global Human Body Models Consortium (GHBMC) 50th percentile male (M50) and F05 coxal bones, respectively. To project the coxal bone cortical thickness from the M50 to the F05, the M50 model was first morphed using a Kriging method with 132 optimized control points to the F05 anthropometry. This technique was found to be accurate with a mean nodal discrepancy of 1.27 mm between the F05 and morphed M50 (mM50) coxal bones. Cortical thickness at each F05 node was determined by taking the average cortical thickness of every mM50 node, non-linearly weighted by its distance to the F05 nodes. The non-linear weighting coefficient, beta, had a large effect on the accuracy and smoothness of the projected cortical bone thickness. The optimal projection had beta = 4 and was defined when the tradeoff between projection accuracy and smoothness was equal. Finally, a quasi-static pelvis compression was simulated to examine to effect of beta. As beta, increased from 0 to 4, the failure force decreased by ~100 N, whereas the failure displacement increased by 0.9 mm. Results from quasi-static compression tests of the F05 pelvis were comparable to experimental results. This method could be applied to other anatomical regions where cortical thickness variation is important, such as the femur and ribs and is not limited to GHBMC-family models. Furthermore, this process will aid the development of subject-specific finite element models where accurate cortical bone thickness measurements cannot be obtained. PMID- 30406096 TI - Readiness for Environmental Release of Genetically Engineered (GE) Plants in Uganda. AB - Research and development of genetically engineered (GE) crops in Uganda was initiated in 2003 with the launch of a national agricultural biotechnology center at Kawanda in central Uganda. The country has now approved 17 field experiments for GE plants, which were first established in 2006 with the planting of a banana confined field trial that evaluated performance of plants modified to express resistance to black sigatoka disease. Researchers leading the GE experiments have indicated that some of these GE plants are ready for environmental release that is moving beyond confined field testing toward commercialization. The government of Uganda, over the past two decades, has supported processes to put in place an effective national biosafety framework including establishment of a supportive policy environment; creation of a clear institutional framework for handling applications and issuance of permits; building critical capacity for risk analysis; and providing options for public engagement during decision-making. Uganda is ready to make a biosafety decision regarding environmental release of GE plants based on the level of capacity built, progress with priority GE crop research in the country, and the advancement in biosafety systems. Enactment of a national biosafety law that provides for a coordinated framework for implementation by the relevant regulatory agencies will strengthen the system further. In addition, product developers need to submit applications for biosafety approval for environmental release of GE crops so that mechanisms are tested and improved through practice. PMID- 30406097 TI - Changes in Vitreoretinal Adhesion With Age and Region in Human and Sheep Eyes. AB - While several studies have qualitatively investigated age- and region-dependent adhesion between the vitreous and retina, no studies have directly measured the vitreoretinal strength of adhesion. In this study, we developed a rotational peel device and associated methodology to measure the maximum and steady-state peel forces between the vitreous and the retina. Vitreoretinal adhesion in the equator and posterior pole were measured in human eyes from donors ranging 30 to 79 years of age, and in sheep eyes from premature, neonatal, young lamb, and young adult sheep. In human eyes, maximum peel force in the equator (7.24 +/- 4.13 mN) was greater than in the posterior pole (4.08 +/- 2.03 mN). This trend was especially evident for younger eyes from donors 30 to 39 years of age. After 60 years of age, there was a significant decrease in the maximum equatorial (4.69 +/- 2.52 mN, p = 0.016) and posterior pole adhesion (2.95 +/- 1.25 mN, p = 0.037). In immature sheep eyes, maximum adhesion was 7.60 +/- 3.06 mN, and did not significantly differ between the equator and posterior pole until young adulthood. At this age, the maximum adhesion in the equator nearly doubled (16.67 +/- 7.45 mN) that of the posterior pole, similar to the young adult human eyes. Light microscopy images suggest more disruption of the inner limiting membrane (ILM) in immature sheep eyes compared to adult sheep eyes. Interestingly, in human eyes, ILM disruption was significantly greater in the posterior pole (p < 0.05) and in people over 60 years of age (p < 0.02). These findings supplement the current discussion surrounding age-related posterior vitreous detachment, and the risk factors and physiological progressions associated with this condition. In addition, these data further our understanding of the biomechanical mechanisms of vitreoretinal adhesion, and can be used to develop age- appropriate computational models simulating retinal detachment, hemorrhaging, or retinal trauma. PMID- 30406098 TI - Cellular Response to Surface Morphology: Electrospinning and Computational Modeling. AB - Surface properties of biomaterials, such as chemistry and morphology, have a major role in modulating cellular behavior and therefore impact on the development of high-performance devices for biomedical applications, such as scaffolds for tissue engineering and systems for drug delivery. Opportunely designed micro- and nanostructures provides a unique way of controlling cell biomaterial interaction. This mini-review discusses the current research on the use of electrospinning (extrusion of polymer nanofibers upon the application of an electric field) as effective technique to fabricate patterns of micro- and nano-scale resolution, and the corresponding biological studies. The focus is on the effect of morphological cues, including fiber alignment, porosity and surface roughness of electrospun mats, to direct cell migration and to influence cell adhesion, differentiation and proliferation. Experimental studies are combined with computational models that predict and correlate the surface composition of a biomaterial with the response of cells in contact with it. The use of predictive models can facilitate the rational design of new bio-interfaces. PMID- 30406099 TI - Defining Skin Fibroblastic Cell Types Beyond CD90. PMID- 30406095 TI - Gene Co-expression Network Reveals Potential New Genes Related to Sugarcane Bagasse Degradation in Trichoderma reesei RUT-30. AB - The biomass-degrading fungus Trichoderma reesei has been considered a model for cellulose degradation, and it is the primary source of the industrial enzymatic cocktails used in second-generation (2G) ethanol production. However, although various studies and advances have been conducted to understand the cellulolytic system and the transcriptional regulation of T. reesei, the whole set of genes related to lignocellulose degradation has not been completely elucidated. In this study, we inferred a weighted gene co-expression network analysis based on the transcriptome dataset of the T. reesei RUT-C30 strain aiming to identify new target genes involved in sugarcane bagasse breakdown. In total, ~70% of all the differentially expressed genes were found in 28 highly connected gene modules. Several cellulases, sugar transporters, and hypothetical proteins coding genes upregulated in bagasse were grouped into the same modules. Among them, a single module contained the most representative core of cellulolytic enzymes (cellobiohydrolase, endoglucanase, beta-glucosidase, and lytic polysaccharide monooxygenase). In addition, functional analysis using Gene Ontology (GO) revealed various classes of hydrolytic activity, cellulase activity, carbohydrate binding and cation:sugar symporter activity enriched in these modules. Several modules also showed GO enrichment for transcription factor activity, indicating the presence of transcriptional regulators along with the genes involved in cellulose breakdown and sugar transport as well as other genes encoding proteins with unknown functions. Highly connected genes (hubs) were also identified within each module, such as predicted transcription factors and genes encoding hypothetical proteins. In addition, various hubs contained at least one DNA binding site for the master activator Xyr1 according to our in silico analysis. The prediction of Xyr1 binding sites and the co-expression with genes encoding carbohydrate active enzymes and sugar transporters suggest a putative role of these hubs in bagasse cell wall deconstruction. Our results demonstrate a vast range of new promising targets that merit additional studies to improve the cellulolytic potential of T. reesei strains and to decrease the production costs of 2G ethanol. PMID- 30406102 TI - Editorial: Cell Adhesion and Migration in the Development of Multicellular Organisms. PMID- 30406100 TI - Stem/Progenitor Cells and Their Therapeutic Application in Cardiovascular Disease. AB - Cardiovascular disease is the leading cause of death in the world. The stem/progenitor cell-based therapy has emerged as a promising approach for the treatment of a variety of cardiovascular diseases including myocardial infarction, stroke, peripheral arterial disease, and diabetes. An increasing number of evidence has shown that stem/progenitor cell transplantation could replenish damaged cells, improve cardiac and vascular functions, and repair injured tissues in many pre-clinical studies and clinical trials. In this review, we have outlined the major types of stem/progenitor cells, and summarized the studies in applying these cells, especially endothelial stem/progenitor cells and their derivatives, in the treatment of cardiovascular disease. Here the strategies used to improve the stem/progenitor cell-based therapies in cardiovascular disease and the challenges with these therapies in clinical applications are also reviewed. PMID- 30406101 TI - DNMT3B Functions: Novel Insights From Human Disease. AB - DNA methylation plays important roles in gene expression regulation and chromatin structure. Its proper establishment and maintenance are essential for mammalian development and cellular differentiation. DNMT3B is the major de novo DNA methyltransferase expressed and active during the early stage of embryonic development, including implantation. In addition to its well-known role to methylate centromeric, pericentromeric, and subtelomeric repeats, recent observations suggest that DNMT3B acts as the main enzyme methylating intragenic regions of active genes. Although largely studied, much remains unknown regarding how these specific patterns of de novo CpG methylation are established in mammalian cells, and which are the rules governing DNMT3B recruitment and activity. Latest evidence indicates that DNMT3B recruitment is regulated by numerous mechanisms including chromatin modifications, transcription levels, non coding RNAs, and the presence of DNA-binding factors. DNA methylation abnormalities are a common mark of human diseases involving chromosomal and genomic instabilities, such as inherited disease and cancer. The autosomal recessive Immunodeficiency, Centromeric instability and Facial anomalies syndrome, type I (ICF-1), is associated to hypomorphic mutations in DNMT3B gene, while its altered expression has been correlated with the development of tumors. In both cases, this implies that abnormal DNA hypomethylation and hypermethylation patterns affect gene expression and genomic architecture contributing to the pathological states. We will provide an overview of the most recent research aimed at deciphering the molecular mechanisms by which DNMT3B abnormalities are associated with the onset and progression of these pathologies. PMID- 30406103 TI - Setting Eyes on the Retinal Pigment Epithelium. AB - The neural component of the zebrafish eye derives from a small group of cells known as the eye/retinal field. These cells, positioned in the anterior neural plate, rearrange extensively and generate the optic vesicles (OVs). Each vesicle subsequently folds over itself to form the double-layered optic cup, from which the mature eye derives. During this transition, cells of the OV are progressively specified toward three different fates: the retinal pigment epithelium (RPE), the neural retina, and the optic stalk. Recent studies have shown that folding of the zebrafish OV into a cup is in part driven by basal constriction of the cells of the future neural retina. During folding, however, RPE cells undergo an even more dramatic shape conversion that seems to entail the acquisition of unique properties. How these changes occur and whether they contribute to optic cup formation is still poorly understood. Here we will review present knowledge on RPE morphogenesis and discuss potential mechanisms that may explain such transformation using examples taken from embryonic Drosophila tissues that undergo similar shape changes. We will also put forward a hypothesis for optic cup folding that considers an active contribution from the RPE. PMID- 30406107 TI - Translating Science Into Business Innovation: The Case of Open Food and Nutrition Data Hackathons. AB - In this article, we explore the use of hackathons and open data in corporations' open innovation portfolios, addressing a new way for companies to tap into the creativity and innovation of early-stage startup culture, in this case applied to the food and nutrition sector. We study the first Open Food Data Hackdays, held on 10-11 February 2017 in Lausanne and Zurich. The aim of the overall project that the Hackdays event was part of was to use open food and nutrition data as a driver for business innovation. We see hackathons as a new tool in the innovation manager's toolkit, a kind of live crowdsourcing exercise that goes beyond traditional ideation and develops a variety of prototypes and new ideas for business innovation. Companies then have the option of working with entrepreneurs and taking some the ideas forward. PMID- 30406104 TI - Initial Steps in Mammalian Autophagosome Biogenesis. AB - During the last decade, autophagy has been pointed out as a central process in cellular homeostasis with the consequent implication in most cellular settings and human diseases pathology. At present, there is significant data available about molecular mechanisms that regulate autophagy. Nevertheless, autophagy pathway itself and its importance in different cellular aspects are still not completely clear. In this article, we are focused in four main aspects: (a) Induction of Autophagy: Autophagy is an evolutionarily conserved mechanism induced by nutrient starvation or lack of growth factors. In higher eukaryotes, autophagy is a cell response to stress which starts as a consequence of organelle damage, such as oxidative species and other stress conditions. (b) Initiation of Autophagy; The two major actors in this signaling process are mTOR and AMPK. These multitasking protein complexes are capable to summarize the whole environmental, nutritional, and energetic status of the cell and promote the autophagy induction by means of the ULK1-Complex, that is the first member in the autophagy initiation. (c) ULK1-Complex: This is a highly regulated complex responsible for the initiation of autophagosome formation. We review the post transductional modifications of this complex, considering the targets of ULK1. (d)The mechanisms involved in autophagosome formation. In this section we discuss the main events that lead to the initial structures in autophagy. The BECN1 Complex with PI3K activity and the proper recognition of PI3P are one of these. Also, the transmembrane proteins, such as VMP1 and ATG9, are critically involved. The membrane origin and the cellular localization of autophagosome biogenesis will be also considered. Hence, in this article we present an overview of the current knowledge of the molecular mechanisms involved in the initial steps of mammalian cell autophagosome biogenesis. PMID- 30406105 TI - The Impact of Fibromyalgia in Spondyloarthritis: From Classification Criteria to Outcome Measures. AB - The term spondyloarthritis (SpA) encompasses a broad clinical spectrum characterized by chronic inflammatory conditions affecting the sacroiliac joints, the spine but also peripheral joints and tendons and being additionally associated with the involvement of organs, such as bowel, eye and skin (1). Musculoskeletal pain is a key symptom in SpA. However, although low back pain and/or joint pain are characteristic for SpA, undifferentiated pain at different enthesial sites may also be a concomitant or even the first clinical presentation in some patients (2). In addition, fatigue is another important symptom often reported by patients with SpA, which substantially affects the quality of life (QoL) (3). Fibromyalgia (FM) is the most common diagnosis in patients complaining of chronic diffuse pain with fatigue and may occur alone or in association with chronic inflammatory diseases (4). The prevalence of FM ranges from 2 to 8% in the general population and it can reach up to over 50% in patients with other rheumatic and musculoskeletal diseases (RMDs) (5-7). FM has been identified as the most disabling RMD, based on the patients' perception that their medical condition is not properly recognized (8). This is also due to the poor knowledge about its pathogenesis, and therefore the lack of reliable biomarkers reveals a major unmet need requiring to be addressed in further research studies. Over the last decade, an increasing body of evidence described the impact of FM in SpA highlighting the pitfalls for correct classification, appropriate differential diagnosis and assessment of outcome measures in both conditions. The purpose of this review is to provide an overview of currently available data with regard to the coexistence and reciprocal features of FM and SpA. PMID- 30406108 TI - Bioaccessibility of Biofortified Sweet Potato Carotenoids in Baby Food: Impact of Manufacturing Process. AB - Orange-fleshed sweet potato (OFSP), a biofortified crop rich in beta-carotene, can be used as a component of baby food recipes in order to tackle vitamin A deficiency in children <6 years old. In this work, the impact of formulation (addition of pumpkin, oil, and egg yolk) and industrial heat processing (pasteurization, sterilization) on carotenoid content and bioaccessibility was evaluated in an OFSP-based baby puree. A commercial OFSP baby food product from Brazil and a homemade OFSP puree were used as references. The losses of all-trans beta-carotene ranged from 16 to 21% (pasteurization, homemade) to 32% (sterilization). Because of higher particle sizes and despite a higher content in carotenoids, the homemade puree had a lower bioaccessibility (i.e., micellar transfer using in vitro digestion: 0.50%) compared with the sterilized and commercial purees (5.3-6.2%). Taking into account bioaccessibility and applying a 50% conversion to retinol, a 115 g baby portion of the sterilized OFSP-puree formulated with 2% oil provided 31.4% of the daily vitamin A requirement (RDA) for children under 6 years. In comparison, 115 g of homemade OFSP-puree provided only 3.5% of the RDA. Addition of pumpkin to OFSP did not improve the percentage of RDA. Interestingly, the incorporation of an emulsifier (egg yolk powder) before cooking could improve the percentage of provision by a factor of 2.7. These results showed that reaching a balance between formulation and processing is determinant to maximize carotenoid bioaccessibility of carotenoids from OFSP based baby food. PMID- 30406106 TI - Recent Advances in Endothelial Colony Forming Cells Toward Their Use in Clinical Translation. AB - The term "Endothelial progenitor cell" (EPC) has been used to describe multiple cell populations that express endothelial surface makers and promote vascularisation. However, the only population that has all the characteristics of a real "EPC" is the Endothelial Colony Forming Cells (ECFC). ECFC possess clonal proliferative potential, display endothelial and not myeloid cell surface markers, and exhibit pronounced postnatal vascularisation ability in vivo. ECFC have been used to investigate endothelial molecular dysfunction in several diseases, as they give access to endothelial cells from patients in a non invasive way. ECFC also represent a promising tool for revascularization of damaged tissue. Here we review the translational applications of ECFC research. We discuss studies which have used ECFC to investigate molecular endothelial abnormalities in several diseases and review the evidence supporting the use of ECFC for autologous cell therapy, gene therapy and tissue regeneration. Finally, we discuss ways to improve the therapeutic efficacy of ECFC in clinical applications, as well as the challenges that must be overcome to use ECFC in clinical trials for regenerative approaches. PMID- 30406109 TI - Prognostic Significance of Solitary Lymphnode Metastasis and Micrometastasis in Gastric Cancer. AB - Gastric cancer (GC) used to be one of the most common malignancies in the world and still is the second leading cause of malignancy-related death in the Far East. The most significant factors that were found to be associated with the clinical outcome in patients with non-metastatic (M0) gastric cancer is tumor's depth of invasion, the presence and the extend of lymphnode involvement, as well as the histological type according to Lauren (intestinal or diffuse). Although it is generally accepted that D2 gastrectomy is the procedure of choice to achieve adequate oncologic excision, there are quite many concerns for its use in patients with early gastric cancer (EGC), where No or N1 specimens are frequently reported. The last two decades, with the evolvement of cancer cell detection techniques, the attend of the medical community is focused on GC patients with solitary lymphnode metastasis (SLN) or micrometastasis (mM). There is a discussion whether SLN should be attributed as the "real" sentinel node (SN) and its projection on patients' survival. The aim of this study is to review the recent literature and attempt to clarify the clinical significance of SLN in gastric cancer. PMID- 30406110 TI - Open Intraperitoneal Onlay Mesh (IPOM) Technique for Incisional Hernia Repair. AB - In an Expert Consensus Guided by Systematic Review the panel agreed that for open elective incisional hernia repair sublay mesh location is preferred, but open intraperitoneal onlay mesh (IPOM) may be useful in certain settings. Accordingly, the available literature on the open IPOM technique was searched and evaluated. Material and Methods: A systematic search of the available literature was performed in July 2018 using Medline, PubMed, and the Cochrane Library. Forty five publications were identified as relevant for the key question. Results: Compared to laparoscopic IPOM, the open IPOM technique was associated with significantly higher postoperative complication rates and recurrence rates. For the open IPOM with a bridging situation the postoperative complication rate ranges between 3.3 and 72.0% with a mean value of 20.4% demonstrating high variance, as did the recurrence rate of between 0 and 61.0% with a mean value of 12.6%. Only on evaluation of the upward-deviating maximum values and registry data is a trend toward better outcomes for the sublay technique demonstrated. Through the use of a wide mesh overlap, avoidance of dissection in the abdominal wall and defect closure it appears possible to achieve better outcomes for the open IPOM technique. Conclusion: Compared to the laparoscopic technique, open IPOM is associated with significantly poorer outcomes. For the sublay technique the outcomes are quite similar and only tendentially worse. Further studies using an optimized open IPOM technique are urgently needed. PMID- 30406112 TI - DNA Sliding Clamps as Therapeutic Targets. AB - Chromosomal DNA replication is achieved by an assembly of multi-protein complexes at the replication fork. DNA sliding clamps play an important role in this assembly and are essential for cell viability. Inhibitors of bacterial (beta clamp) and eukaryal DNA clamps, proliferating cell nuclear antigen (PCNA), have been explored for use as antibacterial and anti-cancer drugs, respectively. Inhibitors for bacterial beta-clamps include modified peptides, small molecule inhibitors, natural products, and modified non-steroidal anti-inflammatory drugs. Targeting eukaryotic PCNA sliding clamp in its role in replication can be complicated by undesired effects on healthy cells. Some success has been seen in the design of peptide inhibitors, however, other research has focused on targeting PCNA molecules that are modified in diseased states. These inhibitors that are targeted to PCNA involved in DNA repair can sensitize cancer cells to existing anti-cancer therapeutics, and a DNA aptamer has also been shown to inhibit PCNA. In this review, studies in the use of both bacterial and eukaryotic sliding clamps as therapeutic targets are summarized. PMID- 30406111 TI - The Role of PI3K in Met Driven Cancer: A Recap. AB - The Receptor Tyrosine Kinase (RTK) Met, overexpressed or mutated in cancer, plays a major role in cancer progression and represents an attractive target for cancer therapy. However RTK inhibitors can lead to drug resistance, explaining the necessity to develop therapies that target downstream signaling. Phosphatidylinositide 3-kinase (PI3K) is one of the most deregulated pathways in cancer and implicated in various types of cancer. PI3K signaling is also a major signaling pathway downstream of RTK, including Met. PI3K major effectors include Akt and "mechanistic Target of Rapamycin" (mTOR), which each play key roles in numerous and various cell functions. Advancements made due to the development of molecular and pharmaceutical tools now allow us to delve into the roles of each independently. In this review, we summarize the current understanding we possess of the activation and role of PI3K/Akt/mTOR, downstream of Met, in cancer. PMID- 30406113 TI - Omega-3 PUFA vs. NSAIDs for Preventing Cardiac Inflammation. PMID- 30406114 TI - Multicellular Interactions in 3D Engineered Myocardial Tissue. AB - Cardiovascular disease is a leading cause of death in the US and many countries worldwide. Current cell-based clinical trials to restore cardiomyocyte (CM) health by local delivery of cells have shown only moderate benefit in improving cardiac pumping capacity. CMs have highly organized physiological structure and interact dynamically with non-CM populations, including endothelial cells and fibroblasts. Within engineered myocardial tissue, non-CM populations play an important role in CM survival and function, in part by secreting paracrine factors and cell-cell interactions. In this review, we summarize the progress of engineering myocardial tissue with pre-formed physiological multicellular organization, and present the challenges toward clinical translation. PMID- 30406115 TI - The Role of Cerebral Embolic Protection Devices During Transcatheter Aortic Valve Replacement. AB - Transcatheter aortic valve replacement is the therapy of choice for patients with severe aortic stenosis who have prohibitive or high surgical risk. However, the benefit of TAVR is attenuated by the occurrence of major disabling stroke which is associated with increased mortality and early-reduced quality of life. Despite advances in TAVR technology, stroke remains a serious complication that is associated with significant negative outcomes. The majority of these occur in the acute phase following TAVR where cerebral embolic events are frequent. Cerebral embolic protection devices (CEPD) have been developed to minimize the risk of peri-procedural ischemic stroke during TAVR. CEPD have the potential to reduce intraprocedural burden of new silent ischemic injury. In this review we outline the etiology and incidence of stroke in TAVR population, and systematically review current evidence for cerebral embolic protection devices. PMID- 30406118 TI - Integrating Trap-Neuter-Return Campaigns Into a Social Framework: Developing Long Term Positive Behavior Change Toward Unowned Cats in Urban Areas. AB - Cat management is often discussed in terms of population reduction, with trap neuter-return (TNR) campaigns commonly organized to manage unowned urban cat populations. However, long-term effectiveness is only possible if positive neutering practices are continued by local residents. Here we discuss how implementing TNR within a wider framework of social engagement has the potential to tackle cat overpopulation and instill long-term positive behavior change toward them. We demonstrate how community engagement pre-TNR can help establish a baseline of the attitudes, knowledge and behavior concerning cats. Using a case study, we explore whether this information can be linked with positive intended behavior based on intentions to arrange for neutering of unowned cats. Structural equation modeling indicated that negative attitudes toward cats and reduced knowledge around neutering reduced the likelihood of positive intended behavior. This result was underpinned by the indirect effects of perceptions of unowned cats and reduced understanding of their needs. Utilizing these results alongside an understanding of the values and motivation of the community allows for tailored and targeted education and intervention. In turn, this addresses the underlying knowledge gaps and perceptions regarding cat welfare. This framework can help address the challenge of cat management because it: (1) takes an integrative approach to identifying the motivations of communities to take responsibility for unowned cats; (2) changes the structure of the social environment, encouraging positive neutering practices for unowned cats. In turn this improves the impact and longevity of TNR campaigns whilst promoting positive welfare change for unowned and owned cats; and (3) appreciates that opinions are likely to vary hugely between areas, therefore providing an adaptable community level approach. PMID- 30406119 TI - Presence of Probst Bundles Indicate White Matter Remodeling in a Dog With Corpus Callosum Hypoplasia and Dysplasia. AB - Corpus callosum abnormalities (CCA) rarely occur in dogs and are related to hypo/adypsic hypernatremia and seizures. Hypoplasia and dysplasia of the corpus callosum (CC) with concomitant lobar holoprosencephaly is the most common variant. It is currently uncertain using conventional MRI if canine CCA reflects the failure of commissural fibers to develop or the failure of the commissural fibers to cross hemispheres. Diffusion tensor imaging was performed in a 4-year old Staffordshire mix breed dog with CCA and an age-matched healthy Beagle. In comparison to the control dog, CC tractography of the affected dog depicted only axonal tracts corresponding to the temporal CC fibers. The cingulum bundles appeared supernumerary with unorganized architecture, extending into the ipsilateral cerebral cortex, and therefore strongly suggested homology to Probst bundles reported in humans with CCA. The presence of Probst bundles in canine CCA could represent compensatory neuroplasticity-mediated networking and may contribute the fair prognosis reported in affected dogs. PMID- 30406116 TI - Endothelial-Vascular Smooth Muscle Cells Interactions in Atherosclerosis. AB - Atherosclerosis is a chronic progressive inflammatory process that can eventually lead to cardiovascular disease (CVD). Despite available treatment, the prevalence of atherosclerotic CVD, which has become the leading cause of death worldwide, persists. Identification of new mechanisms of atherogenesis are highly needed in order to develop an effective therapeutic treatment. The blood vessels contain two primary major cell types: endothelial cells (EC) and vascular smooth muscle cells (VSMC). Each of these performs an essential function in sustaining vascular homeostasis. EC-VSMC communication is essential not only to development, but also to the homeostasis of mature blood vessels. Aberrant EC-VSMC interaction could promote atherogenesis. Identification of the mode of EC-VSMC crosstalk that regulates vascular functionality and sustains homeostasis may offer strategic insights for prevention and treatment of atherosclerotic CVD. Here we will review the molecular mechanisms underlying the interplay between EC and VSMC that could contribute to atherosclerosis. We also highlight open questions for future research directions. PMID- 30406120 TI - Sampling Methodology to Maximize the Efficient Use of National Abattoir Surveillance: Using Archived Sera to Substantiate Freedom From Bluetongue Virus Infection in Ireland. AB - In recent years, there has been increasing recognition of the value of multiple data sources available to fulfill surveillance objectives, and the use of these has been applied to address many questions relating to animal health surveillance. In Ireland, we face a slightly different problem, namely, best use of an existing surveillance resource (serological samples collected over many years from cull cows at slaughter), which has been used to substantiate freedom from Brucella abortus following its successful eradication in 2009. In this study, we evaluate a sampling methodology to use this resource to substantiate freedom from bluetongue virus (BTV) infection. An examination of the degree to which cull cows were resident in the same herd throughout the midge biting season showed that, of 50,640 samples collected between 17 October and 23 December 2016, 80.2% were from animals resident in the same herd between 01 April 2016 and 2 months prior to their slaughter date, 74.1% for 1 month prior, 70.1% for 2 weeks prior, 66.4% for 1 week prior, and 56.4% up to 1 day prior to slaughter. An examination was made of the degree to which individual samples within the same 88 well frozen storage block came from geographically clustered herds, whether from a concentration of animals from the same herd in a single block, or from clustering around the slaughterhouse where the samples were taken. On the basis of these analyses, a sampling strategy was derived aimed at minimizing the number of storage blocks which needed to be thawed, whilst ensuring a large enough and representative sample, geographically stratified according to the bovine population of 51 squares, each 45 * 45 km, covering the entirety of Ireland. None of the 503 samples tested were positive for BTV, providing reassurance of national BTV freedom. More broadly, the study demonstrates the use of abattoir based serological samples collected for one large scale surveillance programme in surveillance for other bovine infections. PMID- 30406117 TI - Chicken Gut Microbiota: Importance and Detection Technology. AB - Sustainable poultry meat and egg production is important to provide safe and quality protein sources in human nutrition worldwide. The gastrointestinal (GI) tract of chickens harbor a diverse and complex microbiota that plays a vital role in digestion and absorption of nutrients, immune system development and pathogen exclusion. However, the integrity, functionality, and health of the chicken gut depends on many factors including the environment, feed, and the GI microbiota. The symbiotic interactions between host and microbe is fundamental to poultry health and production. The diversity of the chicken GI microbiota is largely influenced by the age of the birds, location in the digestive tract and diet. Until recently, research on the poultry GI microbiota relied on conventional microbiological techniques that can only culture a small proportion of the complex community comprising the GI microbiota. 16S rRNA based next generation sequencing is a powerful tool to investigate the biological and ecological roles of the GI microbiota in chicken. Although several challenges remain in understanding the chicken GI microbiome, optimizing the taxonomic composition and biochemical functions of the GI microbiome is an attainable goal in the post genomic era. This article reviews the current knowledge on the chicken GI function and factors that influence the diversity of gut microbiota. Further, this review compares past and current approaches that are used in chicken GI microbiota research. A better understanding of the chicken gut function and microbiology will provide us new opportunities for the improvement of poultry health and production. PMID- 30406122 TI - Laparoscopic Artificial Insemination Technique in Small Ruminants-A Procedure Review. AB - Laparoscopic artificial insemination (LAI) is an intrauterine method of insemination, especially utilized in the small ruminant species to bypass their unique anatomically tortuous cervix. There are several advantages of LAI that include efficient use of processed semen leading to higher pregnancy rates. Success of LAI programs depends on proper implementation of estrus synchronization programs, patient selection and thorough knowledge of the reproductive physiology. In addition, proper equipment and surgical expertise help in reducing patient morbidity and mortality rates. LAI can be associated with several complications as a result of inadequate patient preparation, poor technique or equipment failure. Hence, a thorough planning is essential to carry out the procedure safely and with consistent success rates. Addition of LAI to a small ruminant/food animal practice can be quite profitable and professionally fulfilling, as long as an appropriate investment in equipment and adequate training of veterinarians and technical staff is implemented. Though the technique for performing LAI has been mentioned briefly through various research articles, this article serves as the first comprehensive review of the technique, equipment used, associated complications and useful practical tips that could serve as a guideline for clinicians interested in adding this service to their practice. The article also contains some novel research supported ideas to provide laparoscopic insufflation that have been recently developed. PMID- 30406121 TI - In silico Comparison of Test-and-Cull Protocols for Bovine Tuberculosis Control in France. AB - Whole depopulation of cattle herds (WHD) confirmed infected by bovine tuberculosis (bTB) has led since the 1950s to a drop of herd incidence in France below 0.1% in 2000, justifying the current officially bTB free (OTF) status of the country. However, this protocol is expensive, ethically questionable, and difficult for breeders to accept because the number of confirmed animals in an infected herd is often very low. A test-and-cull protocol combining at least three screening sessions of the entire herd followed by the slaughter of all the non-negative animals has been used for some years. The aim of this work was to evaluate in silico the epidemiological effectiveness, the public costs and the acceptability to farmers of this test-and-cull protocol as well as of several ones. A stochastic compartmental model of within-herd bTB spread was used. Six test-and-cull protocols were compared: two versions of the official protocol and four alternatives with varying delays between screenings, and varying tests used. Protocols were simulated for an average French beef herd, and compared to WHD. Three key indicators were computed: the failure probability of the protocol (a failure being defined as an herd recovering its OTF status recovery while still infected, indicator of epidemiological effectiveness), its overall public cost and the percentage of farmers who would have dropped it to switch to WHD (indicator of acceptability to farmers). Failure probability ranged from 1.4 to 12.4% and was null (by definition) for WHD. The median cost varied between 2.7 and 78 K? for the test-and-cull protocols, vs. 120 K? for WHD. The percentage of dropout ranged from 7.8 to 22%. The optimal tradeoff between epidemiological effectiveness, public costs, and acceptability to farmers was obtained for protocols with an increased delay (6 months instead of 2 in the currently used protocol) between the last two screening sessions, with either 3 or 2 screening sessions. This study may help improving the official test-and-cull protocol applied in France under European Union regulation, by suggesting alternative protocols, very effective, cheaper, and more acceptable than WHD. PMID- 30406123 TI - 30-day mortality after the start of systemic anticancer therapy for lung cancer: is it really a useful performance indicator? AB - Systemic treatment is the standard treatment for unresectable stage III and IV lung cancer. Nevertheless, a 5-10% death rate has been described within 30 days after the last systemic treatment, suggesting that these patient did not benefit. We analysed the 30-day mortality after start of systemic therapy. Data were retrieved from the Netherlands National Cancer Registry. From 2010 to 2015, 26 277 patients were included. 56% were men. The median age was 65 years and 31% of patients were aged >=70 years. 27% involved small cell lung cancer and 73% nonsmall cell lung cancer. Overall mortality within 30 days after the start of systemic treatment was 6.2%. Multivariable analysis established the prognostic influence of age, histology, number of metastatic sites and type of systemic treatment. Chemotherapy was administered in 77 hospitals, treating each 15-161 lung cancer patients with systemic therapy annually. None of the hospitals had a significantly higher 30-day mortality according to hierarchical multivariable analysis, controlling for case-mix. In the Netherlands, the 30-day mortality rate after start of systemic therapy for lung cancer patients was comparable with earlier reports. Hospital volume did not influence the 30-day mortality rate. 30 day mortality rate is not a meaningful indicator to monitor quality of care. PMID- 30406124 TI - Reflux in idiopathic pulmonary fibrosis: treatment informed by an integrated approach. AB - After MDT work-up and review, gastro-oesophageal reflux and pulmonary aspiration were found to be common in IPF patients; surgery was recommended in only 10% http://ow.ly/rO3T30lU17o. PMID- 30406125 TI - Azithromycin treatment modifies airway and blood gene expression networks in neutrophilic COPD. AB - Long-term, low-dose azithromycin reduces exacerbation frequency in chronic obstructive pulmonary disease (COPD), yet the mechanism remains unclear. This study characterised genome-wide gene expression changes in patients with neutrophilic COPD following long-term, low-dose azithromycin treatment. Patients with neutrophilic COPD (>61% or >162*104 cells per mL sputum neutrophils) were randomised to receive either azithromycin or placebo for 12 weeks. Sputum and blood were obtained before and after 12 weeks of treatment. Gene expression was defined using microarrays. Networks were analysed using the Search Tool for the Retrieval of Interacting Gene database. In sputum, 403 genes were differentially expressed following azithromycin treatment (171 downregulated and 232 upregulated), and three following placebo treatment (one downregulated and two upregulated) compared to baseline (adjusted p<0.05 by paired t-test, fold-change >1.5). In blood, 138 genes were differentially expressed with azithromycin (121 downregulated and 17 upregulated), and zero with placebo compared to baseline (adjusted p<0.05 by paired t-test, fold-change >1.3). Network analysis revealed one key network in both sputum (14 genes) and blood (46 genes), involving interferon-stimulated genes, human leukocyte antigens and genes regulating T-cell responses. Long-term, low-dose azithromycin is associated with downregulation of genes regulating antigen presentation, interferon and T-cell responses, and numerous inflammatory pathways in the airways and blood of neutrophilic COPD patients. PMID- 30406126 TI - Asthma severity and fertility outcome in women with polycystic ovary syndrome: a registry-based study. AB - Recent research suggests that women with polycystic ovary syndrome (PCOS) have a higher risk of asthma. However, the severity of asthma, use of antiasthma medication and effect on fertility have yet to be investigated. In a case-control cross-sectional registry study using the Danish National Patient Register and other Danish registries, asthma prevalence, asthma severity, antiasthma medication use and fertility outcome were investigated among two groups of women with PCOS (n=1358 and n=17 123) and a healthy control group (n=5340). Both asthma prevalence (OR 1.45, 95% CI 1.24-1.70) and mean daily inhaled corticosteroid dose were higher among women with PCOS compared with healthy controls, whereas asthma severity was the same in women with and without PCOS. Women with PCOS and asthma had more in vitro fertilisation treatments than women in the control group with asthma, but the numbers of children per woman and spontaneous abortions were the same. Women with PCOS have a higher prevalence of asthma and a higher use of inhaled corticosteroids, whereas asthma severity is the same in women with and without PCOS. Asthma is associated with more in vitro fertilisation treatments in women with PCOS. PMID- 30406127 TI - Transcriptomic Changes in Broiler Chicken Hypothalamus during Growth and Development. AB - The hypothalamus plays an overarching role that is reflected in the physiological processes observed in the entire organism. The hypothalamus regulates selected metabolic processes and activities of the autonomic nervous system. The avian hypothalamus due to the structural complexity is not well described and has a slightly different function than the mammalian hypothalamus that is the subject of numerous studies. The present study evaluated activities of hypothalamic genes in fast-growing chickens during development (at the 1st day and 3rd and 6th weeks after hatching). The hypothalamic transcriptomes for 3- and 6-week-old cockerels were analysed using an RNA sequencing method in next-generation sequencing (NGS) technology. The differentially expressed gene analysis was conducted using DESeq2 software. In younger 22-day-old cockerels, 389 genes showed higher expression (fold change > 1.5) than that in 45-day-old birds. These genes played a role in several biological processes because they encoded proteins involved in integrin signalling, regulation of hormone levels, camera-type eye development, and blood vessel development. Moreover, surprisingly in the hypothalamus of 3-week-old cockerels, transcripts were identified for proteins involved in both anorexigenic (POMC, NMU) and orexigenic (PMCH, ALDH1A1, LPL, and GHRH) pathways. The RNA-seq results were confirmed by qPCR methods. In summary, the intensive growth of 3 week-old chickens was reflected in hypothalamic activities because the genes associated with the somatotropin axis and regulation of satiety centre showed increased expression. PMID- 30406128 TI - Risk Evaluation of Azithromycin-Induced QT Prolongation in Real-World Practice. AB - Background: Azithromycin exposure has been reported to increase the risk of QT prolongation and cardiovascular death. However, findings on the association between azithromycin and cardiovascular death are controversial, and azithromycin is still used in actual practice. Additionally, quantitative assessments of risk have not been performed, including the risk of QT prolongation when patients are exposed to azithromycin in a real-world clinical setting. Therefore, in this study, we aimed to evaluate the risk of exposure to azithromycin on QT prolongation in a real-world clinical setting using a 21-year medical history database of a tertiary medical institution. Methods: We analyzed the electrocardiogram results and relevant electronic health records of 402,607 subjects in a tertiary teaching hospital in Korea from 1996 to 2015. To evaluate the risk of QT prolongation of azithromycin, we conducted a case-control analysis using amoxicillin for comparison. Multiple logistic regression analysis was performed to correct for age, sex, accompanying drugs, and disease. Results: The odds ratio (OR) for QT prolongation (QTc>450 ms in male and >460 ms in female) on azithromycin exposure was 1.40 (95% confidence interval [CI], 1.23-1.59), and the OR for severe QT prolongation (QTc>500 ms) was 1.43 (95% CI, 1.13-1.82). On the other hand, the ORs on exposure to amoxicillin were 1.06 (95% CI, 0.97-1.15) and 0.88 (95% CI, 0.70-1.09). In a subgroup analysis, the risk of QT prolongation in patients aged between 60 and 80 years was significantly higher when they are exposed to azithromycin. Conclusions: The risk of QT prolongation was increased when patients, particularly the elderly aged 60-79 years, were exposed to azithromycin. Therefore, clinicians should pay exercise caution using azithromycin or consider using other antibiotics, such as amoxicillin, instead of azithromycin. PMID- 30406129 TI - Nucleolar Division in the Promastigote Stage of Leishmania major Parasite: A Nop56 Point of View. AB - Nucleogenesis is the cellular event responsible for the formation of the new nucleoli at the end of mitosis. This process depends on the synthesis and processing of ribosomal RNA (rRNA) and, in some eukaryotes, the transfer of nucleolar material contained in prenucleolar bodies (PNBs) to active transcription sites. The lack of a comprehensive description of the nucleolus throughout the cell cycle of the human pathogen Leishmania major prompted us to analyze the distribution of nucleolar protein 56 (Nop56) during interphase and mitosis in the promastigote stage of the parasite. By in silico analysis we show that the orthologue of Nop56 in L. major (LmNop56) contains the three characteristic Nop56 domains and that its predicted three-dimensional structure is also conserved. Fluorescence microscopy observations indicate that the nucleolar localization of LmNop56 is similar, but not identical, to that of the nucleolar protein Elp3b. Notably, unlike other nucleolar proteins, LmNop56 remains associated with the nucleolus in nonproliferative cells. Moreover, epifluorescent images indicate the preservation of the nucleolar structure throughout the closed nuclear division. Experiments performed with the related parasite Trypanosoma brucei show that nucleolar division is carried out by an analogous mechanism. PMID- 30406130 TI - Enhanced Production of Polymyxin E in Paenibacillus polymyxa by Replacement of Glucose by Starch. AB - Polymyxin E or colistin, produced by Paenibacillus polymyxa, is an important antibiotic against Gram-negative pathogens. The objective of this study is to evaluate the effect of starch in fermentation medium on colistin biosynthesis in P. polymyxa. The results indicated that replacement of glucose by starch stimulated colistin production and biosynthesis rate. Overall, the stimulation extent was starch concentration-dependent. As expected, addition of starch induced the expression of amyE encoding amylase and increased amylase activity in fermentation solution. Additionally, replacement of glucose by starch resulted in residue reducing sugar and pH of fermentation mixture low relative to glucose as the sole sugar source. At the molecular level, it was found that replacement of glucose by starch has enhanced the relative expression level of ccpA encoding catabolite control protein A. Therefore, the repression of starch utilization by glucose could be probably relieved. In addition, use of starch stimulated the expression of regulatory gene spo0A but repressed the expression of another regulatory gene abrB. As a result, the expression of genes directly involved in colistin biosynthesis and secretion increased, indicating that at the transcriptional level spo0A and abrB played opposite roles in regulating colistin biosynthesis in P. polymyxa. Taken together, our data demonstrated that starch instead of glucose can promote colistin production probably by affecting the expression of colistin biosynthesis-related genes, as well as reducing the repression of glucose to a secondary metabolic product. PMID- 30406131 TI - Outcome of Irrigation and Debridement after Failed Two-Stage Reimplantation for Periprosthetic Joint Infection. AB - Introduction: Two-stage revision is the gold standard for the treatment of deep implant infection after knee or hip arthroplasty. Irrigation and debridement may be a treatment option for failed 2-stage revisions in cases where a reinfection occurs within 30 days or the symptoms exist not longer than 3 weeks and is appealing because of its low morbidity. We determined the incidence of recurrent infections following irrigation and debridement for failed two-stage revision hip and knee arthroplasty. Methods: We performed a single center retrospective review of periprosthetic hip and knee infections treated with a two-stage procedure from 2002 to 2010. All patients that subsequently underwent irrigation and debridement for a subsequent infection were selected for the current study. Results: 440 two stage revisions were performed between 2002 and 2010. Fifty-one two-stage revisions failed (11.6%). Nineteen failed two-stage revisions were treated with irrigation and debridement; 12 (63.2%) patients remained free of infection at follow-up (mean follow-up: 39 months; range, 24-90 months), infection persisted in 6 patients (31.6%), and 1 patient died (5.3%). Conclusions: Success rates of irrigation and debridement for failed two-stage procedures are similar to the success rates of irrigation and debridement in primary implant infections. According to the current paper, irrigation and debridement are an acceptable treatment for acute reinfections after failed two-stage revision if performed within the first 30 postoperative days after failed two-stage procedure or if symptoms are present for less than 3 weeks in the presence of a susceptible organism. PMID- 30406132 TI - The Economic Impact of Cutaneous Leishmaniasis in Sri Lanka. AB - Cutaneous leishmaniasis (CL) is a neglected tropical disease which affects mainly the poorest communities in developing countries. Considering the limited published information on economic impact of CL in Sri Lanka, the current study was conducted with the objective of revealing the nature and magnitude of the economic impact of CL in three selected disease endemic regions in Kurunegala District, Sri Lanka. The patient records of CL notified of relevant Medical Officer of Health (MOH) office during 2013- 2016 were obtained. Patient households were visited and data collection was done using an interviewed administered questionnaire. The majority of patients (57%) were economically active at the time of infection. Of them, 65% were the only contributors to household economy. Total median costs including both direct and indirect costs were 66.85 USD (Rs. 10,831) (IQR = 57.26 - 86.78 USD), while total median economic loss to households was 61.27 USD (Rs. 9,927) (IQR= 49.61- 75.04 USD). From provider perspective, total median cost per patient was 22.83 USD (Rs. 3,696). The mean total economic loss was denoted as 65.26 USD (Rs. 10,572) which is about 5.4% of the annual household income and 20.9% of the mean annual per capita income of the study population. Although economic impact of CL infection is not catastrophic according to current interpretation, the infection may have significant economic impacts on households when considering the mean economic loss to household as a percentage of the mean annual per capita income of the population. PMID- 30406133 TI - Finite Element Analysis and Biomechanical Testing to Analyze Fracture Displacement of Alveolar Ridge Splitting. AB - The alveolar ridge splitting technique enables reconstruction of atrophied alveolar ridges prior implantation. However, in cases of severe atrophy, there is an unpredictable risk of fracturing the buccal lamella during the expansion. Currently, there is no preoperative assessment to predict the maximum distraction of the lamella. The aim of this study was to develop a biomechanical model to mimic the alveolar ridge splitting and a finite element (FE) model to predict the experimental results. The biomechanical testing was conducted on porcine mandibles. To build the FE model high resolution peripheral quantitative computer tomography scans of one specimen was performed after the osteotomy outline, but before the lamella displacement. A servo-electric testing machine was used for the axial tension test to split the lamellae. Results showed, in line with clinical observations, that the lamellae broke primarily at the base of the splits with a median displacement of 1.27 mm. The FE model could predict fracture force and fracture displacement. Fracture force showed a nonlinear correlation with the height of the bone lamella. In conclusion, good correspondence between mechanical testing and virtual FE analysis showed a clinically relevant approach that may help to predict maximum lamella displacement to prevent fractures in the future. PMID- 30406135 TI - Necrotizing Enterocolitis in Moderate Preterm Infants. AB - Necrotizing enterocolitis (NEC) is a devastating morbidity usually seen in preterm infants, with extremely preterm neonates (EPT <=28 weeks) considered at highest risk. Moderately preterm infants (MPT 28-34 weeks) constitute a large percentage of NICU admissions. In our retrospective data analysis of NEC in a single regional perinatal center, NEC was observed in 10% of extremely EPT and 7% of MPT, but only 0.7% of late-preterm/term admissions. There was an inverse relationship between postnatal age at onset of NEC and gestational age at birth. Among MPT infants with NEC, maternal hypertensive disorders (29%) and small for gestational age (SGA-15%) were more common than in EPT infants (11.6 and 4.6%, resp.). Congenital gastrointestinal anomalies were common among late preterm/term infants with NEC. SGA MPT infants born to mothers with hypertensive disorders are particularly at risk and should be closely monitored for signs of NEC. Identifying risk factors specific to each gestational age may help clinicians to tailor interventions to prevent NEC. PMID- 30406134 TI - Targeted Molecular Magnetic Resonance Imaging Detects Brown Adipose Tissue with Ultrasmall Superparamagnetic Iron Oxide. AB - The peptide (CKGGRAKDC-NH2) specifically targets the brown adipose tissue (BAT). Here we applied this peptide coupled with polyethylene glycol (PEG)-coated ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles to detect BAT in vivo by magnetic resonance imaging (MRI). The peptide was conjugated with PEG coated USPIO nanoparticles to obtain targeted USPIO nanoprobes. Then the nanoprobes for BAT were evaluated in mice. T2*-weighted images were performed, precontrast and postcontrast USPIO nanoparticles. Finally, histological analyses proved the specific targeting. The specificity of targeted USPIO nanoprobes was observed in mice. The T2* relaxation time of BAT in the targeted group decreased obviously compared to the controls (P<0.001). Prussian blue staining and transmission electron microscope confirmed the specific presence of iron oxide. This study demonstrated that peptide (CKGGRAKDC-NH2) coupled with PEG-coated USPIO nanoparticles could identify BAT noninvasively in vivo with MRI. PMID- 30406136 TI - Occurrence and Multilocus Genotyping of Giardia duodenalis in Yunnan Black Goats in China. AB - Giardia duodenalis is an important zoonotic parasite which can parasitize in the intestines of humans and various animals. However, the information about the prevalence and genetic diversity of G. duodenalis in goats in China is limited. It is yet to be known whether Yunnan black goats, a unique goat breed in subtropical Yunnan province, southwestern China, are infected with G. duodenalis. Thus, a total of 907 fecal samples were collected from Yunnan black goats in five regions in Yunnan province, to estimate the prevalence and genotypes of G. duodenalis using a PCR-based approach. The G. duodenalis prevalence is 4.2% (38/907) in Yunnan black goats by nested amplification of the beta-giardin (bg) gene, and the genotypes are identified as assemblage E, with 5 novel subtypes (E11-E15). Multilocus sequence typing revealed that 11, 18, and 38 samples were amplifiable on tpi (triose phosphate isomerase), gdh (glutamate dehydrogenase), and bg locus, respectively, and identified three novel multilocus genotypes (MLGs): MLGE9-MLGE11. To our knowledge, this is the first report of G. duodenalis prevalence and genotypes in Yunnan black goats in China, which extended the host range of G. duodenalis and provided basic data for controlling G. duodenalis infection in Yunnan black goats. PMID- 30406138 TI - Cytotoxicological Investigation of the Essential Oil and the Extracts of Cotula cinerea and Salvia verbenaca from Morocco. AB - The objective of this work was to investigate the cytotoxicological effect of the extracts (hexane, ethyl acetate, and n-butanol) of Cotula cinerea and Salvia verbenaca in addition to the essential oil of Cotula cinerea. These plants are widely used in the Moroccan traditional folk medicine. The cytotoxic effect was explored against two cancer cell lines, Vero and RD, using the colorimetric MTT assay. The obtained results showed that the cytotoxicity differed according to the used extract with an efficient effect of Cotula cinerea extracts compared to Salvia verbenaca. A potent cytotoxicity was thus observed for the Cotula cinerea hexane extract which inhibited the growth of RD cell line at the lowest IC50 value (57.21+/-3.43 ug/mL). This was followed by the ethyl acetate extract and the essential oil with moderate effects against RD cell line and showed IC50 values of 187.52+/-6.27 ug/mL and 173.05+/-4.46 ug/mL, respectively. On the other hand, different results were obtained and Cotula cinerea essential oil was the most cytotoxic with the lowest IC50 value (72.72+/-2.18 ug/mL) against Vero cell line. In the same conditions, higher concentrations were needed in the case of Salvia verbenaca extracts. The results of this study showed thus that Cotula cinerea essential oil and hexane extract showed significant cytotoxic effects against RD and Vero cell lines, respectively, and could be considered as novel source of antitumor agents. This study is expected to be beneficial for clinical and traditional applications for Cotula cinerea as a remedy against cancer and opens new perspectives for further investigations on other types of cancer cell lines. PMID- 30406140 TI - Technetium-99 Conjugated with Methylene Diphosphonate Ameliorates Glucocorticoid Induced Osteoporosis by Inhibiting Osteoclastogenesis. AB - Technetium-99 conjugated with methylene diphosphonate (99Tc-MDP) is an effective anti-inflammatory drug in treating rheumatoid arthritis (RA) for over 15 years in China. However, as a special form of bisphosphonate, the antiosteoporotic effect of 99Tc-MDP is unclear. We systematically investigated the effects of 99Tc-MDP on cancellous and cortical bone, respectively, in glucocorticoid induced osteoporosis (GIO) animal models. Forty-eight Sprague-Dawley rats were randomly divided into six groups: blank, negative control, high dose, medium dose, low dose, and positive control groups. After dexamethasone was given to all groups except the blank group to induce osteoporosis, the rats in different groups were treated with saline, MDP, or different doses of 99Tc-MDP. After treatment, all rats were sacrificed, and their tibiae and femora were analyzed with microcomputed tomography (micro-CT), histology and biomechanics. Micro-CT analyses showed that (1) 99Tc-MDP reversed glucocorticoid induced bone microarchitecture destruction by increasing BV/TV, Tb.Th, and Tb.N and decreasing BS/BV, Tb.Sp, and TBPf; (2) effect of 99Tc-MDP increased as its dosage increased; and (3) 99Tc-MDP could improve cortical bone thickness while MDP failed to do so. Micro-CT spatial structure analysis and histology also yielded consistent results, indicating that 99Tc-MDP increased trabecular number and connectivity morphologically. Secondly, biomechanics revealed that 99Tc-MDP can enhance the extrinsic stiffness of bone by changing bone geometry. Finally, 99Tc-MDP could inhibit osteoclastogenesis in PBMCs in human. In conclusion, 99Tc-MDP exerted antiosteoporotic effect by improving both cancellous and cortical bone, as well as increasing extrinsic bone stiffness which might be attributed to the its inhibition of osteoclast differentiation. The antiosteoporotic effect of 99Tc-MDP may suggest a potential clinical application for patients with GIO. PMID- 30406139 TI - CT Myocardial Perfusion Imaging: A New Frontier in Cardiac Imaging. AB - The past two decades have witnessed rapid and remarkable technical improvement of multidetector computed tomography (CT) in both image quality and diagnostic accuracy. These improvements include higher temporal resolution, high-definition and wider detectors, the introduction of dual-source and dual-energy scanners, and advanced postprocessing. Current new generation multidetector row (>=64 slices) CT systems allow an accurate and reliable assessment of both coronary epicardial stenosis and myocardial CT perfusion (CTP) imaging at rest and during pharmacologic stress in the same examination. This novel application makes CT the unique noninvasive "one-stop-shop" method for a comprehensive assessment of both anatomical coronary atherosclerosis and its physiological consequences. Myocardial CTP imaging can be performed with different approaches such as static arterial first-pass imaging, and dynamic CTP imaging, with their own advantages and disadvantages. Static CTP can be performed using single-energy or dual-energy CT, employing qualitative or semiquantitative analysis. In addition, dynamic CTP can obtain quantitative data of myocardial blood flow and coronary flow reserve. The purpose of this review was to summarize all available evidence about the emerging role of myocardial CTP to identify ischemia-associated lesions, focusing on technical considerations, clinical applications, strengths, limitations, and the more promising future fields of interest in the broad spectra of ischemic heart disease. PMID- 30406141 TI - Discovery of a Novel Microtubule Targeting Agent as an Adjuvant for Cancer Immunotherapy. AB - For an activating immunotherapy such as adjuvants, a compound that can prolong immune stimulation may enhance efficacy. We leveraged data from two prior high throughput screens with NF-kappaB and interferon reporter cell lines to identify 4H-chromene-3-carbonitriles as a class of compounds that prolonged activation in both screens. We repurchased 23 of the most promising candidates. Out of these compounds we found #1 to be the most effective agent in stimulating the release of cytokines and chemokines from immune cells, including murine primary bone marrow derived dendritic cells. Mechanistically, #1 inhibited tubulin polymerization, and its effect on immune cell activation was abolished in cells mutated in the beta-tubulin gene (TUBB) encoding the site where colchicine binds. Treatment with #1 resulted in mitochondrial depolarization followed by mitogen activated protein kinase activation. Because tubulin polymerization modulating agents have been used for chemotherapy to treat malignancy and #1 activated cytokine responses, we hypothesized that #1 could be effective for cancer immunotherapy. Intratumoral injection of #1 delayed tumor growth in a murine syngeneic model of head and neck cancer. When combined with PD-1 blockade, tumor growth slowed in the injected tumor nodule and there was an abscopal effect in an uninjected nodule on the contralateral flank, suggesting central antitumor immune activation. Thus, we identified a new class of tubulin depolymerizing agent that acts as both an innate and an adaptive immune activating agent and that limits solid tumor growth when used concurrently with a checkpoint inhibitor. PMID- 30406142 TI - First Paleogenetic Evidence of Probable Syphilis and Treponematoses Cases in the Brazilian Colonial Period. AB - Despite interest in the origins of syphilis, paleopathological analysis has not provided answers, and paleogenetic diagnosis remains a challenge. Even venereal syphilis has low infectivity which means there are few circulating bacteria for most of the individual's life. Human remains recovered from the Nossa Senhora do Carmo Church (17th to 19th centuries) and the Praca XV Cemetery (18th to 19th centuries), Rio de Janeiro, Brazil, were subjected to Treponema paleogenetic analysis. Historical data point to endemic treponemal infections in the city, including venereal syphilis. Based on the physiopathology of Treponema pallidum infection, 25 samples, mostly from skull remains of young adults, with no visible paleopathological evidence of treponematoses, were analyzed. PCR with three molecular targets, tpp47, polA, and tpp15, were applied. Ancient DNA tpp15 sequences were recovered from two young adults from each archaeological site and revealed the polymorphism that characterizes T. p. subsp. pallidum in a female up to 18 years old, suggesting a probable case of syphilis infection. The results indicated that the epidemiological context and the physiopathology of the disease should be considered in syphilis paleogenetic detection. The findings of Treponema sp. aDNA are consistent with historical documents that describe venereal syphilis and yaws as endemic diseases in Rio de Janeiro. Data on the epidemiological characteristics of the disease and its pathophysiology offer new perspectives in paleopathology. PMID- 30406143 TI - Single versus Double Skin Preparation for Infection Prevention in Proximal Humeral Fracture Surgery. AB - Preoperative skin preparation plays a major role in preventing postoperative infections. This study aims to compare a single skin preparation (povidone iodine) with a double skin preparation (chlorhexidine gluconate followed by povidone iodine). Forty patients affected by proximal humeral fracture were included in the study. The day of surgery the two skin preparation strategies were performed in the same shoulder, divided into two areas, at the level of the deltopectoral approach. Skin swabs were collected from each area and subjected to microbiological analysis. Both skin preparations significantly reduced the positive culture rate. Coagulase-negative staphylococci (CoNS) dropped from 92.5% to 40% and to 7.5% after the single and double skin preparation (p<0.001), respectively. The positivity rate was reduced from 50% to 17.5% (p=0.002) and from 27.5% to 0% (p= 0.001) for Propionibacterium acnes and Staphylococcus aureus, respectively, with no difference between the two preparations. The double skin preparation had a more significant effect on bacterial load against CoNS compared to the single skin preparation (p<0.001 versus p= 0.015). In conclusion, both the approaches reduced S. aureus and P. acnes skin load, whereas the double skin preparation is more effective than the single one against CoNS. In light of our findings, preoperative strategies able to reduce bacterial load could potentially increase the final efficacy of perioperative traditional skin preparations. PMID- 30406144 TI - Comprehensive Validation of Snapback Primer-Based Melting Curve Analysis to Detect Nucleotide Variation in the Codon 12 and 13 of KRAS Gene. AB - Background: KRAS genotyping in tumor samples is a decisive clinical test for the anti-EGFR therapy management. However, the complexity of KRAS mutation landscape across different cancer types and the mosaic effect caused by cancer cellularity and heterogeneity make the choice of KRAS genotyping method a challenging topic in the clinical practice. Methods: We depicted the landscape of somatic KRAS mutation in 7,844 primary tumors and 10,336 metastatic tumors across over 30 types of cancer using the Cancer Genome Atlas (TCGA) and Integrated Mutation Profiling of Actionable Cancer Targets (MSKCC-IMPACT) databases, respectively. A snapback primer assay based on melting curve analysis was developed to detect the most common somatic mutations in KRAS codons 12 and 13. The sensitivity and accuracy of the method was validated by genotyping 100 colorectal cancer (CRC) samples, in comparison with Sanger sequencing and T-A cloning sequencing. Results: Pancreas adenocarcinoma (somatic mutation frequency 90.6%), colorectal adenocarcinoma (42.5%), and lung adenocarcinoma (32.6%) are the top three most KRAS mutant primary cancer types. The metastatic tumors showed a higher prevalence (90.99% versus 66.31%) and diversity of KRAS mutation compared with the primary tumors. Mutations in codons 12 and 13 are the predominant genetic alteration in KRAS (84.15% for TCGA and 86.13% for MSK-IMPACT). Moreover, KRAS mutation is highly correlated with the overall survival of patients with metastatic cancer. The snapback primer assay showed a more favorable performance in enriching and detecting the KRAS codon 12 and 13 mutation (1% mutation load) compared with Sanger sequencing (20% mutation load and 7% false-negative rate). Conclusions: KRAS mutation pattern is highly diverse among different cancer types and is associated with the survival of patients with metastatic cancers. The snapback primer assay is a reliable, sensitive method to detect the major mutant KRAS alleles, which might facilitate the effective cancer treatment decisions. PMID- 30406145 TI - Inoculation with Efficient Nitrogen Fixing and Indoleacetic Acid Producing Bacterial Microsymbiont Enhance Tolerance of the Model Legume Medicago truncatula to Iron Deficiency. AB - The aim of this study was to assess the effect of symbiotic bacteria inoculation on the response of Medicago truncatula genotypes to iron deficiency. The present work was conducted on three Medicago truncatula genotypes: A17, TN8.20, and TN1.11. Three treatments were performed: control (C), direct Fe deficiency (DD), and induced Fe deficiency by bicarbonate (ID). Plants were nitrogen-fertilized (T) or inoculated with two bacterial strains: Sinorhizobium meliloti TII7 and Sinorhizobium medicae SII4. Biometric, physiological, and biochemical parameters were analyzed. Iron deficiency had a significant lowering effect on plant biomass and chlorophyll content in all Medicago truncatula genotypes. TN1.11 showed the highest lipid peroxidation and leakage of electrolyte under iron deficiency conditions, which suggest that TN1.11 was more affected than A17 and TN8.20 by Fe starvation. Iron deficiency affected symbiotic performance indices of all Medicago truncatula genotypes inoculated with both Sinorhizobium strains, mainly nodules number and biomass as well as nitrogen-fixing capacity. Nevertheless, inoculation with Sinorhizobium strains mitigates the negative effect of Fe deficiency on plant growth and oxidative stress compared to nitrogen-fertilized plants. The highest auxin producing strain, TII7, preserves relatively high growth and root biomass and length when inoculated to TN8.20 and A17. On the other hand, both TII7 and SII4 strains improve the performance of sensitive genotype TN1.11 through reduction of the negative effect of iron deficiency on chlorophyll and plant Fe content. The bacterial inoculation improved Fe-deficient plant response to oxidative stress via the induction of the activities of antioxidant enzymes. PMID- 30406146 TI - Identification of Six Potentially Long Noncoding RNAs as Biomarkers Involved Competitive Endogenous RNA in Clear Cell Renal Cell Carcinoma. AB - Background. Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma (RCC), usually is representative of metastatic heterogeneous neoplasm that links with poor prognosis, but the pathogenesis of ccRCC remains unclear. Currently, numerous evidences prove that long noncoding RNAs (lncRNAs) are considered as competing endogenous RNA (ceRNA) to participate in cellular processes of tumors. Therefore, to investigate the underlying mechanisms of ccRCC, the expression profiles of lncRNAs, miRNAs, and mRNAs were downloaded from the Cancer Genome Atlas (TCGA) database. A total of 1526 differentially expressed lncRNAs (DElncRNAs), 54 DEmiRNAs, and 2352 DEmRNAs were identified. To determine the connection of them, all DElncRNAs were input to the miRcode database. The results indicated that 85 DElncRNAs could connect with 9 DEmiRNAs in relation to our study. Then, databases of TargetScan and miRDB were used to search for targeted genes with reference to DEmiRNAs. The results showed that 203 out of 2352 targeted genes were identified in our TCGA set. Subsequently, ceRNA network was constructed according to Cytoscape and the targeted genes were functionally analyzed to elucidate the mechanisms of DEmRNAs. The results of survival analysis and regression analysis indicated that 6 DElncRNAs named COL18A1-AS1, WT1-AS, LINC00443, TCL6, AL356356.1, and SLC25A5-AS1 were significantly correlative with the clinical traits of ccRCC patients and could be served as predictors for ccRCC. Finally, these findings were validated by quantitative RT-PCR (qRT-PCR). Based on these discoveries, we believe that this identified ceRNA network will provide a novel perspective to elucidate ccRCC pathogenesis. PMID- 30406137 TI - Cellular and Molecular Heterogeneity Associated with Vessel Formation Processes. AB - The microvasculature heterogeneity is a complex subject in vascular biology. The difficulty of building a dynamic and interactive view among the microenvironments, the cellular and molecular heterogeneities, and the basic aspects of the vessel formation processes make the available knowledge largely fragmented. The neovascularisation processes, termed vasculogenesis, angiogenesis, arteriogenesis, and lymphangiogenesis, are important to the formation and proper functioning of organs and tissues both in the embryo and the postnatal period. These processes are intrinsically related to microvascular cells, such as endothelial and mural cells. These cells are able to adjust their activities in response to the metabolic and physiological requirements of the tissues, by displaying a broad plasticity that results in a significant cellular and molecular heterogeneity. In this review, we intend to approach the microvasculature heterogeneity in an integrated view considering the diversity of neovascularisation processes and the cellular and molecular heterogeneity that contribute to microcirculatory homeostasis. For that, we will cover their interactions in the different blood-organ barriers and discuss how they cooperate in an integrated regulatory network that is controlled by specific molecular signatures. PMID- 30406147 TI - The Influence of Body Mass Composition on the Postural Characterization of School Age Children and Adolescents. AB - Introduction: In recent years a significant increase in the percentage of children with postural problems has been observed. It is necessary to focus on preventing the phenomenon and on analysis of existing postural defects. Aim: The aim of this work was to assess the potential relationship between body mass composition and body posture in school-age children. Material and Methods: 464 school-age children ranging from 6 to 16 years (234 boys and 230 girls) were qualified for the study. Body mass composition was assessed using the analyzer Tanita MC 780 MA. Assessment of body posture was performed using Zebris system. All the results were analyzed with statistical methods. The accepted level of significance was p<0.05. Results: Analyses of the disparities between the girls and the boys showed statistically significant differences in all of the body mass components and in obliquity of the pelvis/shoulder. The boys were characterized by higher contents of muscle tissue (p<0.001), bone tissue (p<0.001), fatless tissue (p<0.001), and body water (p<0.001) as well as a greater obliquity angle (p=0.018). The girls, on the other hand, were found with higher content of fatty tissue (p<0.001). The children with lower content of muscle tissue (p=0.030), fatless tissue (p=0.030), water (p=0.030), and higher content of fatty tissue measured in kg (p=0.027) were characterized by greater pelvic obliquity. Conclusion: The current study shows evidence that sex, as a strongly differentiating factor, determines body mass composition and the occurrence of suboptimal postures only in the pelvic area. Body mass composition differentiates body posture of the study group. The content of fatty tissue influences the occurrence of suboptimal postures in the scapula and pelvic area in the frontal plane. The content of muscle tissue is associated with faulty postures in the scapula and pelvic area in the frontal plane. PMID- 30406148 TI - The Management of Acute Anterior Uveitis Complicating Spondyloarthritis: Present and Future. AB - Spondyloarthropathies (SpA) encompass a group of chronic inflammatory diseases sharing common genetic and clinical features, including the association with HLA B27 antigen, the involvement of both the axial and the peripheral skeleton, the presence of dactylitis, enthesitis, and typical extra-articular manifestations such as psoriasis, inflammatory bowel disease, and acute anterior uveitis (AAU). The latter is commonly reported as a noninfectious acute inflammation of the anterior uveal tract and its adjacent structures. AAU may affect more than 20% of SpA patients representing the most common extra-articular manifestation of the disease. Considering the potential consequences of untreated AAU, early diagnosis and aggressive treatment are crucial to avoid complications of remittent or chronic eye inflammation, such as visual loss and blindness. The management of SpA has dramatically improved over the last decades due to the development of new treat-to-target strategies and to the introduction of biologic disease modifying antirheumatic drugs (bDMARDs), particularly tumor necrosis factor alpha inhibitors (TNFis), currently used for the treatment of nonresponder patients to conventional synthetic agents. Along with the improvement of musculoskeletal features of SpA, bDMARDs provided an additional effect also in the management of AAU in those patients who are failures to topical and systemic conventional therapies. Nowadays, five TNFis, one interleukin-17, and one interleukin 12/23 blocker are licensed for the treatment of SpA, with different proven efficacy in preventing and treating ocular involvement. The aim of this review is to summarize the current options and to analyze the future perspectives for the management of SpA-associated AAU. PMID- 30406149 TI - Association of Resistin Gene Polymorphisms with Oral Squamous Cell Carcinoma Progression and Development. AB - Oral squamous cell carcinoma (OSCC) accounts for over 90% of malignant neoplasms of the mouth. In Taiwan, OSCC is the fourth most common male cancer and the fourth leading cause of male cancer death. Resistin (RETN) is an adipokine that is associated with obesity, inflammation, and various cancers. Here, we examine the association between four single nucleotide polymorphisms (SNPs) of the RETN gene (rs3745367, rs7408174, rs1862513, and rs3219175) and OSCC susceptibility as well as clinical outcomes in 935 patients with OSCC and in 1200 cancer-free healthy controls. We found that, in 1465 smokers, RETN polymorphisms carriers with the betel-nut chewing habit had a 6.708-10.882-fold greater risk of having OSCC compared to RETN wild-type carriers without the betel-nut chewing habit. Patients with OSCC who had A/A homozygous of RETN rs3219175 polymorphism showed a high risk for an advanced tumor size (> T2), compared to those patients with G/G homozygotes. In addition, A/T/G/G haplotype significantly increased the risks for OSCC by 1.376-fold. This study is the first to examine the risk factors associated with RETN SNPs in OSCC progression and development in Taiwan. PMID- 30406150 TI - Determinants of Change in Glycemic Status in Individuals with Prediabetes: Results from a Nationwide Cohort Study in Germany. AB - Previous studies investigating determinants of changes in glycemic status among individuals with prediabetes mainly focused on glucose-defined prediabetes. In this study, we examined determinants of a regression to normoglycemia or a progression to diabetes among individuals with HbA1c-defined prediabetes. The study included 817 participants (18-79 years) with prediabetes (HbA1c 5.7-6.4% (39-47 mmol/mol)) at baseline. Glycemic status at follow-up was categorized as diagnosed diabetes (self-reported physician diagnosis or antidiabetic medication), undiagnosed diabetes (HbA1c >= 6.5% (>=48 mmol/mol)), prediabetes (as defined at baseline), and normoglycemia (HbA1c < 5.7% (<39 mmol/mol)). Determinants of glycemic changes were identified by multinomial logistic regression (OR (95% CI)), with those remaining in the prediabetic state as reference. During a mean follow-up time of 12.0 years, 33.8% of the participants reverted to normoglycemia, 7.2% progressed to undiagnosed diabetes, 12.8% progressed to diagnosed diabetes, and 46.2% remained prediabetic. Determinants of a regression to normoglycemia were female sex (male vs. female: 0.67 (0.46; 0.98)) and higher HDL cholesterol levels (1.17 (1.02; 1.35) per 10 mg/dl). Determinants of a progression to undiagnosed or diagnosed diabetes were higher values of BMI (1.10 (1.02; 1.18); 1.13 (1.06; 1.21) per kg/m2), waist circumference (1.04 (1.01; 1.07); 1.06 (1.03; 1.09) per cm), alanine aminotransferase (1.06 (1.03; 1.09); 1.07 (1.03; 1.10) per U/l), and gamma glutamyl transferase (1.02 (1.00; 1.03); 1.03 (1.01; 1.04) per U/l). Higher age (1.04 (1.02; 1.06) per year), female sex (male vs. female: 0.56 (0.33; 0.97)), and parental history of diabetes (yes vs. no: 1.82 (1.05; 3.15)) were further associated with a progression to diagnosed diabetes, whereas higher triglyceride levels (1.03 (1.01; 1.06) per 10 mg/dl) were associated with a progression to undiagnosed diabetes. In conclusion, among the investigated determinants, potentially modifiable anthropometric and metabolic markers were associated with glycemic changes in individuals with HbA1c-defined prediabetes. The findings of this study demonstrate the need for more refined case finding strategies for diabetes prevention. PMID- 30406151 TI - Spironolactone Protects against Diabetic Cardiomyopathy in Streptozotocin-Induced Diabetic Rats. AB - Spironolactone (SPR) has been shown to protect diabetic cardiomyopathy (DCM), but the specific mechanisms are not fully understood. Here, we determined the cardioprotective role of SPR in diabetic mice and further explored the potential mechanisms in both in vivo and in vitro models. Streptozotocin- (STZ-) induced diabetic rats were used as the in vivo model. After the onset of diabetes, rats were treated with either SPR (STZ + SPR) or saline (STZ + NS) for 12 weeks; nondiabetic rats were used as controls (NDCs). In vitro, H9C2 cells were exposed to aldosterone, with or without SPR. Cardiac structure was investigated with transmission electron microscopy and pathological examination; immunohistochemistry was performed to detect nitrotyrosine, collagen-1, TGF beta1, TNF-alpha, and F4/80 expression; and gene expression of markers for oxidative stress, inflammation, fibrosis, and energy metabolism was detected. Our results suggested that SPR attenuated mitochondrial morphological abnormalities and sarcoplasmic reticulum enlargement in diabetic rats. Compared to the STZ + NS group, cardiac oxidative stress, fibrosis, inflammation, and mitochondrial dysfunction were improved by SPR treatment. Our study showed that SPR had cardioprotective effects in diabetic rats by ameliorating mitochondrial dysfunction and reducing fibrosis, oxidative stress, and inflammation. This study, for the first time, indicates that SPR might be a potential treatment for DCM. PMID- 30406152 TI - The Application of Nanoparticle-Based Drug Delivery Systems in Checkpoint Blockade Cancer Immunotherapy. AB - Tumor is the most serious threat to human beings. Although war against cancer has been launched over forty years, cancer treatment is still far away from being satisfactory. Immunotherapy, especially checkpoint blockade immunotherapy, is a rising star that shows a promising future. To fulfill the requirement of depleting primary tumor and inhibiting tumor metastasis and recurrence, many researchers combined checkpoint blockade immunotherapy with other treatment strategies to extend the treatment outcome. Photodynamic therapy could induce immunogenic cell death, and checkpoint blockade could further accelerate the immunity; therefore, combining these two strategies publishes many papers. Additionally, photothermal therapy and immunotherapy were also utilized for combining with checkpoint blockade, which were also reviewed in this paper. Furthermore, antibodies, siRNA, and small molecule inhibitors are developed to block the checkpoint; therefore, we categorized the papers into three sections, combination nanoparticles with checkpoint blockade antibody, combination nanoparticles with checkpoint blockade siRNA, and combination nanoparticles with small molecule checkpoint inhibitors, and related researches were summarized. In conclusion, the combination nanoparticle with checkpoint blockade cancer immunity is a promising direction that may fulfill the requirement of cancer treatment. PMID- 30406154 TI - MicroRNA-96 Promotes Schistosomiasis Hepatic Fibrosis in Mice by Suppressing Smad7. AB - Infection with Schistosoma causes aberrant expression of host microRNAs (miRNAs), and normalizing the levels of dysregulated miRNAs can attenuate pathology. Here, we show that the host miRNA, miR-96, is markedly upregulated during the progression of hepatic schistosomiasis. We demonstrate that elevation of miR-96 induces hepatic fibrosis in infected mice by suppressing the expression of its target gene, Smad7. We show that infection with Schistosoma induces the expression of transforming growth factor beta1 (TGF-beta1), which in turn upregulates the expression of miR-96 through SMAD2/3-DROSHA-mediated post transcriptional regulation. Furthermore, inhibition of miR-96 with recombinant adeno-associated virus 8 (rAAV8)-mediated delivery of Tough Decoy RNAs in mice attenuated hepatic fibrosis and prevented lethality following schistosome infection. Taken together, our data highlight the potential for rAAV8-mediated inhibition of miR-96 as a therapeutic strategy to treat hepatic schistosomiasis. PMID- 30406155 TI - Evaluation, treatment, and analysis of a rare case of motor speech systems dyscoordination syndrome. AB - This report describes an unusual presentation of a voice disorder arising from inability to coordinate the three components of motor speech: respiration, phonation, and articulation. These systems were individually intact, as demonstrated by laryngoscopy, motor speech examination, and treatment methods achieving success under controlled conditions. Following initial programming of his deep brain stimulation (DBS) device, a 62-year-old male, diagnosed with Parkinson's disease (PD) 14 years previously, abruptly experienced a vocal disorder characterized by pressed, very low frequency creaky voice produced on held breath. Evaluation and therapy sessions revealed intact respiration, phonation, and articulation as component systems of motor speech, while indicating a severe deficit in coordinating these systems for articulated speech. Performance varied with mode of vocal production. Vowel prolongation and singing were normal in contrast to severe impairment when respiration and phonation were integrated with articulated speech. A listening study utilizing speech samples from five spoken modes-conversation, repetition, formulaic expressions, continuously phonated material and singing, yielded higher intelligibility on sung and continuously phonated phrases, confirming clinical impressions. Acoustic measures of fundamental frequency, vowel quality (harmonic-to-noise ratios) and duration supported the intelligibility results. Repetition and conversation were similarly impaired, suggesting that the disability was not attributable to the basal ganglia. This case reveals the role of higher order management of respiration, articulation, and voice for speech and describes a successful treatment utilizing breath control. PMID- 30406153 TI - On the Dual Role of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 (CEACAM1) in Human Malignancies. AB - Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a glycoprotein belonging to the carcinoembryonic antigen (CEA) family that is expressed on a wide variety of cells and holds a complex role in inflammation through its alternate splicing and generation of various isoforms, mediating intricate mechanisms of modulation and dysregulation. Initially regarded as a tumor suppressor as its expression shows considerable downregulation within the epithelia in the early phases of many solid cancers, CEACAM1 has been linked lately to the progression of malignancy and metastatic spread as various papers point to its role in tumor progression, angiogenesis, and invasion. We reviewed the literature and discussed the various expression patterns of CEACAM1 in different types of tumors, describing its structure and general biologic functions and emphasizing the most significant findings that link this molecule to poor prognosis. The importance of understanding the role of CEACAM1 in cell transformation stands not only in this adhesion molecule's value as a prognostic factor but also in its promising premise as a potential new molecular target that could be exploited as a specific cancer therapy. PMID- 30406156 TI - 6-hydroxydopamine (6-OHDA) Oxidative Stress Assay for Observing Dopaminergic Neuron Loss in Caenorhabditis elegans. AB - The nematode Caenorhabditis elegans is a powerful genetic model that can be used to investigate neuronal death. Research using C. elegans has been crucial to characterize cell death programmes that are conserved in mammals. Many neuronal signaling components, such as those mediating dopaminergic neurotransmission, are preserved as well. Dopaminergic neurons are progressively lost in Parkinson's disease and an important risk factor to develop this disease appears to be oxidative stress, the increased occurrence of highly reactive oxygen species. Oxidative stress-induced dopaminergic neurodegeneration is mimicked in animal models by treatment with 6-hydroxydopamine (6-OHDA), a dopamine analog, which is specifically taken up into dopaminergic neurons. After exposing C. elegans to 6 OHDA, the loss of fluorescently labeled dopaminergic neurons can be easily monitored. An organisms' sensitivity to oxidative stress is thought to be influenced by basal levels of intrinsic oxidative stress and the ability to counteract oxidative stress and oxidative stress-induced damage. The C. elegans '6-OHDA model' led to the discovery of novel genes that are required to protect dopaminergic neurons and it has helped to determine the effects of conserved cell death and cell engulfment pathways in dopaminergic neurodegeneration. Here, we describe a simple protocol that allows for the easy detection of dopaminergic neuron loss after 6-OHDA treatment in C. elegans. PMID- 30406157 TI - An Image Analysis Pipeline to Quantify Emerging Cracks in Materials or Adhesion Defects in Living Tissues. AB - Microcracks in materials reflect their mechanical properties. The quantification of the number or orientation of such cracks is thus essential in many fields, including engineering and geology. In biology, cracks in soft tissues can reflect adhesion defects, and the analysis of their pattern can help to deduce the magnitude and orientation of tensions in organs and tissues. Here, we describe a semi-automatic method amenable to analyze cell separations occurring in the epidermis of Arabidopsis thaliana seedlings. Our protocol is applicable to any image exhibiting small cracks, and thus also adapted to the analysis of emerging cracks in animal tissues and materials. PMID- 30406158 TI - Testing for Assortative Mating by Diet in Drosophila melanogaster. AB - Experimental studies of the evolution of reproductive isolation in real time are a powerful way to reveal the way that fundamental processes, such as mate choice, initiate divergence. Mate choice, while frequently described in females, can occur in either sex, and can be affected by the genetics or environment of an individual. Here we describe simple protocols for assessing mating outcomes in fruit flies, which in this context can be used to assess reproductive isolation derived from rearing on different diets over multiple generations. PMID- 30406159 TI - Mammalian Cell-derived Vesicles for the Isolation of Organelle Specific Transmembrane Proteins to Conduct Single Molecule Studies. AB - Cell-derived vesicles facilitate the isolation of transmembrane proteins in their physiological membrane maintaining their structural and functional integrity. These vesicles can be generated from different cellular organelles producing, housing, or transporting the proteins. Combined with single-molecule imaging, isolated organelle specific vesicles can be employed to study the trafficking and assembly of the embedded proteins. Here we present a method for organelle specific single molecule imaging via isolation of ER and plasma membrane vesicles from HEK293T cells by employing OptiPrep gradients and nitrogen cavitation. The isolation was validated through Western blotting, and the isolated vesicles were used to perform single molecule studies of oligomeric receptor assembly. PMID- 30406160 TI - 3D X-Ray Imaging of Continuous Objects beyond the Depth of Focus Limit. AB - X-ray ptychography is becoming the standard method for sub-30 nm imaging of thick extended samples. Available algorithms and computing power have traditionally restricted sample reconstruction to 2D slices. We build on recent progress in optimization algorithms and high performance computing to solve the ptychographic phase retrieval problem directly in 3D. Our approach addresses samples that do not fit entirely within the depth of focus of the imaging system. Such samples pose additional challenges because of internal diffraction effects within the sample. We demonstrate our approach on a computational sample modeled with 17 million complex variables. PMID- 30406162 TI - Data solubility and parameters of adjustments (alpha and beta) of phenanthrene in supercritical CO2 employing the modified Redlich-Kwong equation. AB - This article contains data related to the research article entitled "Calculation method for determining Phenanthrene solubility in supercritical CO2 employing Redlich-Kwong modified equation" (Colpas et al., 2018) [1]. The presented data gives information on the physical properties of the solute and the solvent. The experimental solubilities of phenanthrene in equilibrium and those calculated using the modified Redlich-Kwong equation with the inclusion of the adjustment parameters alpha and beta are shown, see Colpas et al. (2018) [1] and "Modified Redlich-Kwong equation of state for supercritical carbon dioxide" (Heidaryan and Jarrahian, 2013) [7]. The mean squared error (MSE) was calculated for the supercritical Phenanthrene-CO2 system at different temperatures above the critical point of the solvent. PMID- 30406161 TI - Cathepsin K inhibition preserves compressive load in lumbar vertebrae of osteoporotic monkeys. AB - Anti-resorptive drugs treat bone loss by blocking osteoclast activity through a variety of mechanisms of action. Once significant bone loss has occurred, the ability to restore biomechanical function may differ based on the drug chosen. To assess this question, bisphosphonate (alendronate, ALN) and cathepsin K inhibitor (MK-0674, CatKi) were employed in treatment mode to compare the relative changes to cancellous bone microstructure and mechanical properties in ovariectomized (OVX) cynomolgus monkeys. Lumbar vertebrae (LV) bone mineral density (BMD) values taken two years post-surgery prior to drug treatment show a 10-15% decrease (p < 0.05) for all OVX animals. OVX animals were then treated with vehicle (VEH), ALN (0.03 mg/kg weekly), or CatKi MK-0674 (0.6 or 2.5 mg/kg daily, CatKi-L and H respectively) for two years and compared to a control Sham surgery group. Ex-vivo microcomputed tomography (MUCT) of LV2 and compression testing of LV4-6 were used to measure cancellous bone microstructure and changes in bone mechanics, respectively. After two years of treatment, ALN-treated animals showed no significant difference in MUCT or biomechanical parameters when compared to Veh. However, treatment with CatKi-H resulted in a 30% increase in yield and peak loads, and apparent peak and yield stress as compared to Veh (p < 0.05) and gave average mechanical values greater than the Sham sample. Treatment with CatKi-L exhibited a similar trend of increase to CatKi-H (p < 0.08). Intriguingly, these changes were realized despite no significant differences in mean values of trabecular bone morphologic parameters. Together these data suggest matrix-level changes in bone composition that are unique to the CatK inhibition mechanism, resulting in the preservation of bone compressive load with treatment. PMID- 30406163 TI - Whole-rock and mineral chemical data from a profile of the ~900 Ma Niutishan Fe Ti-rich sill in XuZhou, North China. AB - In this article, the geochemical data of a ~900 Ma mafic sill from Xuzhou, North China are reported. These datasets include 37 whole-rock major and trace element data, and 21 major element data on plagioclase, 20 major element data on clinopyroxene crystals, 10 major element data on apatite crystals, 7 major element data of preserved coexisting titano-magnetite and ilmenite grains, 36 major element data on different types of ilmenite crystals, 13 major element and 11 trace element data on titanite. These data are associated with Su et al. "Petrogenesis of a ~900 Ma mafic sill from Xuzhou, North China: Implications for the genesis of Fe-Ti-rich rocks" (Su et al., 2018), and in which their characters and variations were interpreted and discussed. PMID- 30406164 TI - Dataset of chlorophyll content estimation of Coffea Canephora using Red and Near Infrared consumer-grade camera. AB - This dataset presents a series of broad Red and Near-Infrared (NIR) bands obtained from consumer-grade camera in estimating chlorophyll contents in Robusta coffee (Coffea Canephora) plants at the leaf level. A total of 600 leaves were measured using direct-leaf tools namely SPAD-502 chlorophyll meter, Spectrometer, and modified consumer-grade camera using a 665 nm long-pass external filter. PMID- 30406165 TI - Spherical particles derived from TMV virions enhance the protective properties of the rabies vaccine. AB - In this study the ability of spherical particles (SPs) obtained from the tobacco mosaic virus (TMV) virions to enhance the immunogenic potential of the vaccine was evaluated. TMV SPs were shown to increase the protective properties of the widely used effective Russian adjuvant-free rabies vaccine, composed of killed rabies virions. The results of the NIH potency test showed enhancement of protectivity, that is comparable with the effect of the incomplete Freund's adjuvant on the same vaccine. PMID- 30406166 TI - Data on the bisphenol A adsorption from aqueous solutions on PAC and MgO~PAC crystals. AB - The compounds of endocrine disrupting are one of the important pollutants in the environment. These pollutants, even at extremely low concentrations, have significant effects on humans, animals and the environment. The main goal of this work was to study the performance activated carbon coated with MgO in the bisphenol A adsorption from aqueous solutions. The leading variables investigated were initial concentration of bisphenol A (20-100 mg/L), PAC and MgO~PAC (2-6 g), contact time (10-60 min), and pH (3-11). The residue concentration of bisphenol A was measured by temperature High-Performance Liquid Chromatography. The maximum adsorption of bisphenol A over PAC and MgO~PAC crystals was 9.2 mg/g and 22.28 mg/g, respectively. Based on BET, the surface area of PAC and MgO~PAC crystals were found to be 450.3 m2/g and 378.21 m2/g, respectively. By increasing initial concentration of bisphenol A, the adsorption decreased. The study findings showed that the Langmuir model and the pseudo-second-order model were a fit model to the experimental data, respectively. PMID- 30406167 TI - Data to model the prognosticators of luxury consumption: A partial least squares structural equation modelling approach (PLS-SEM). AB - This article presents raw inferential statistical data that determined the impact of exclusivity, materialism, perceived quality and brand consciousness on luxury consumption. The data were collected from consumers within the Cape Town metropolitan area. A quantitative research method was used to analyse the data. Structured questionnaires were distributed to consumers within the Cape Town metropolitan area of South Africa. Reliability and validity were confirmed. Structural equation modelling (SEM) using the Smart PLS software, version 3, was used to present the data. The SEM path analysis shows the estimates of the interconnectedness of the major constructs in the data. The outcomes obtained from this dataset show the relationship between exclusivity, perceived quality and brand consciousness had a positive and a significant impact on luxury consumption. However, materialism proved to have a negative and insignificant influence on luxury consumption. PMID- 30406168 TI - Data on the levels of Melamine- migration from Melamine- ware products and effect of food type and time on it. AB - Nowadays, Melamine- containers is widely use to because of heat- resistant. Due to the effects of Melamine- on human health, constant and long-term usage of Melamine- containers can be a source of Melamine- exposure to human body. The objective of this research was to measure the levels of Melamine- migration from Melamine- ware-products into foods at different test conditions and Effect of food type and Time on it. Spectrophotometer UV/VIS method was used to detect the limits of Melamine- and the method was based on the in the complex of Melamine- formaldehyde and Uranin (a ketone group).The limit of detection (LOD) of the method was 0.2 (ug/ml) which is functional for measuring. Migration was less than the standard level of European Union (30 ug/ml). In this study, 3% acetic acid, distilled water and 15% ethanol were used as simulants. The results showed the temperature is an important factor in Melamine- migration and in 97% of cases, with increasing temperature from 30 to 90 there is a significant increase (P < 0.05) in Melamine- migration furthermore migration from acidic simulants was more than alcoholic and neutral ones (p < 0.001). PMID- 30406169 TI - Penile basal cell carcinoma in a black kidney transplant recipient. PMID- 30406171 TI - Oral prednisone: A unique and effective treatment for actinic lichen planus. PMID- 30406170 TI - Widespread presentation and spontaneous regression of porokeratotic eccrine ostial and dermal duct nevus. PMID- 30406172 TI - A case of rituximab-induced pyoderma gangrenosum. PMID- 30406173 TI - A case of primary cutaneous malakoplakia in a cardiac transplant recipient. PMID- 30406174 TI - Linkage analysis of multiplex Caribbean Hispanic families loaded for unexplained early-onset cases identifies novel Alzheimer's disease loci. AB - Introduction: Less than 10% of early-onset Alzheimer's disease (EOAD) is explained by known mutations. Methods: We conducted genetic linkage analysis of 68 well-phenotyped Caribbean Hispanic families without clear inheritance patterns or mutations in APP, PSEN1, and PSEN2 and with two or more individuals with EOAD. Results: We identified 16 (logarithm of odds > 3.6) linked regions, including eight novel loci for EOAD (2p15, 5q14.1, 11p15.1, 13q21.22, 13q33.1, 16p12.1, 20p12.1, and 20q11.21) and eight regions previously associated with late-onset Alzheimer's disease. The strongest signal was observed at 16p12.1 (25 cM, 33 Mb; heterogeneity logarithm of odds = 5.3), ~3 Mb upstream of the ceroid lipofuscinosis 3 (CLN3) gene associated with juvenile neuronal ceroid lipofuscinosis (JNCL), which functions in retromer trafficking and has been reported to alter intracellular processing of the amyloid precursor protein. Discussion: This study supports the notion that the genetic architectures of unexplained EOAD and late-onset AD overlap partially, but not fully. PMID- 30406175 TI - Diagnostic performance of Elecsys immunoassays for cerebrospinal fluid Alzheimer's disease biomarkers in a nonacademic, multicenter memory clinic cohort: The ABIDE project. AB - Introduction: We compared the automated Elecsys and manual Innotest immunoassays for cerebrospinal fluid (CSF) Alzheimer's disease biomarkers in a multicenter diagnostic setting. Methods: We collected CSF samples from 137 participants in eight local memory clinics. Amyloid beta(1-42) (Abeta42), total tau (t-tau), and phosphorylated tau (p-tau) were centrally analyzed with Innotest and Elecsys assays. Concordances between methods were assessed. Results: Biomarker results strongly correlated between assays with Spearman's rho 0.94 for Abeta42, 0.98 for t-tau, and 0.98 for p-tau. Using Gaussian mixture modeling, cohort-specific cut points were estimated at 1092 pg/mL for Abeta42, 235 pg/mL for t-tau, and 24 pg/mL for p-tau. We found an excellent concordance of biomarker abnormality between assays of 97% for Abeta42 and 96% for both t-tau and p-tau. Discussion: The high concordances between Elecsys and Innotest in this nonacademic, multicenter cohort support the use of Elecsys for CSF Alzheimer's disease diagnostics and allow conversion of results between methods. PMID- 30406176 TI - Unsupervised online neuropsychological test performance for individuals with mild cognitive impairment and dementia: Results from the Brain Health Registry. AB - Introduction: The purpose of this study is to compare online neuropsychological test performance of older adults across self-reported diagnoses of being cognitively normal, mild cognitive impairment, and dementia due to Alzheimer's disease and to determine the association of memory concerns and family history of dementia on cognitive performance. Methods: Participants completed the Cogstate Brief Battery unsupervised at home. Results: Data from 6463 participants over the age of 55 years were analyzed. Adults with the diagnosis of mild cognitive impairment and Alzheimer's disease were associated with poorer performance on all cognitive tests than cognitively normal adults (P < .05 for all), and online cognitive test performance significantly improved diagnostic classification (P < .001). Poorer performance on all cognitive measures was associated with memory concern (P < .001 for all) but not family history of dementia. Discussion: Our results provide preliminary support for the use of cognitive tests taken online without supervision as a means to improve the efficiency of participant screening and recruitment for clinical trials. PMID- 30406178 TI - Distal Dendritic Enrichment of HCN1 Channels in Hippocampal CA1 Is Promoted by Estrogen, but Does Not Require Reelin. AB - HCN1 compartmentalization in CA1 pyramidal cells, essential for hippocampal information processing, is believed to be controlled by the extracellular matrix protein Reelin. Expression of Reelin, in turn, is stimulated by 17beta-estradiol (E2). In this study, we therefore tested whether E2 regulates the compartmentalization of HCN1 in CA1 via Reelin. In organotypic entorhino hippocampal cultures, we found that E2 promotes HCN1 distal dendritic enrichment via the G protein-coupled estrogen receptor GPER1, but apparently independent of Reelin, because GST-RAP, known to reduce Reelin signaling, did not prevent E2 induced HCN1 enrichment in distal CA1. We therefore re-examined the role of Reelin for the regulation of HCN1 compartmentalization and could not detect effects of reduced Reelin signaling on HCN1 distribution in CA1, either in the (developmental) slice culture model or in tamoxifen-inducible conditional reelin knockout mice during adulthood. We conclude that for HCN1 channel compartmentalization in CA1 pyramidal cells, Reelin is not as essential as previously proposed, and E2 effects on HCN1 distribution in CA1 are mediated by mechanisms that do not involve Reelin. Because HCN1 localization was not altered at different phases of the estrous cycle, gonadally derived estradiol is unlikely to regulate HCN1 channel compartmentalization, while the pattern of immunoreactivity of aromatase, the final enzyme of estradiol synthesis, argues for a role of local hippocampal E2 synthesis. PMID- 30406181 TI - Correction: Jiang et al., NCS-Rapgef2, the Protein Product of the Neuronal Rapgef2 Gene, Is a Specific Activator of D1 Dopamine Receptor-Dependent ERK Phosphorylation in Mouse Brain (eNeuro September/October 2017, 4(5) e0248-17.2017 1-17 https://doi.org/10.1523/ENEURO.0248-17.2017). AB - [This corrects the article DOI: 10.1523/ENEURO.0248-17.2017.]. PMID- 30406179 TI - The Role of Interleukin-10 in Mediating the Effect of Immune Challenge on Mouse Gonadotropin-Releasing Hormone Neurons In Vivo. AB - Immune challenge alters neural functioning via cytokine production. Inflammation has profound impact on the central regulation of fertility, but the mechanisms involved are not clearly defined. The anti-inflammatory cytokine interleukin (IL) 10 is responsible for balancing the immune response in the brain. To examine whether IL-10 has an effect on the function of the gonadotropin-releasing hormone (GnRH) neurons, we first examined the effect of immune responses with distinct cytokine profiles, such as the T cell-dependent (TD) and T cell-independent (TI) B-cell response. We investigated the effect of the TD and TI immune responses on ERK1/2 phosphorylation in GnRH neurons by administering fluorescein isothiocyanate/keyhole limpet hemocyanin (KLH-FITC) or dextran-FITC to female mice. Although dextran-FITC had no effect, KLH-FITC induced ERK1/2 phosphorylation in GnRH neurons after 6 d. KLH-FITC treatment increased the levels of IL-10 in the hypothalamus (HYP), but this treatment did not cause lymphocyte infiltration or an increase in the levels of proinflammatory cytokines. In IL-10 knock-out (KO) mice, KLH-FITC-induced ERK1/2 phosphorylation in the GnRH neurons was absent. We also showed that in IL-10 KO mice, the estrous cycle was disrupted. Perforated patch-clamp recordings from GnRH-GFP neurons, IL 10 immunohistochemistry, and in vitro experiments on acute brain slices revealed that IL-10 can directly alter GnRH neuron firing and induce ERK1/2 phosphorylation. These observations demonstrate that IL-10 plays a role in influencing signaling of GnRH neurons in the TD immune response. These results also provide the first evidence that IL-10 can directly alter the function of GnRH neurons and may help the maintenance of the integrity of the estrous cycle. PMID- 30406180 TI - Porf-2 = Arhgap39 = Vilse: A Pivotal Role in Neurodevelopment, Learning and Memory. AB - Small GTP-converting enzymes, GTPases, are essential for the efficient completion of many physiological and developmental processes. They are regulated by GTPase activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs). Arhgap39, also known as preoptic regulatory factor-2 (Porf-2) or Vilse, a member of the Rho GAP group, was first identified in 1990 in the rat CNS. It has since been shown to regulate apoptosis, cell migration, neurogenesis, and cerebral and hippocampal dendritic spine morphology. It plays a pivotal role in neurodevelopment and learning and memory. Homologous or orthologous genes are found in more than 280 vertebrate and invertebrate species, suggesting preservation through evolution. Not surprisingly, loss of the Arhgap39/Porf-2 gene in mice manifests as an embryonic lethal condition. Although Arhgap39/Porf-2 is highly expressed in the brain, it is also widely distributed throughout the body, with potential additional roles in oncogenesis and morphogenesis. This review summarizes, for the first time, the known information about this gene under its various names, in addition to considering its transcripts and proteins. The majority of findings described have been made in rats, mice, humans, and fruit flies. This work surveys the known functions, functional mediators, variables modifying expression and upstream regulators of expression, and potential physiological and pathological roles of Arhgap39/Porf-2 in health and disease. PMID- 30406182 TI - Simultaneous Assessment of Homonymous and Heteronymous Monosynaptic Reflex Excitability in the Adult Rat. AB - In order to successfully perform motor tasks such as locomotion, the central nervous system must coordinate contractions of antagonistic and synergistic muscles across multiple joints. This coordination is largely dependent upon the function of proprioceptive afferents (PAs), which make monosynaptic connections with homonymous motoneurons. Homonymous pathways have been well studied in both health and disease but their collateral fibers projecting to heteronymous, synergistic muscles receive relatively less attention. This is surprising given that PA collaterals have significant effects on the excitability of heteronymous motoneurons, and that their synaptic terminal density is activity dependent. It is likely that the relative lack of literature is due to the lack of a preparation which allows synergistic heteronymous pathways to be assessed in vivo. Here, we describe a method to simultaneously evoke homonymous and heteronymous (synergistic) monosynaptic reflexes (MSRs) and study their modulation by descending pathways in adult rats. Through stimulation of the medial plantar nerve, we were able to produce an H reflex in the intrinsic foot (IF) muscles of the hind paw with a latency of 10.52 +/- 3.8 ms. Increasing the stimulus intensity evoked a robust signal with a monosynaptic latency (11.32 +/- 0.35 ms), recorded in the ipsilateral gastrocnemius (Gs). Our subsequent analyses suggest that Gs motoneurons were activated via heteronymous afferent collaterals from the medial plantar nerve. These reflexes could be evoked bilaterally and were modulated by conditioning stimuli to the cortex (Cx) and reticular formation. Interestingly, cortical stimulation was equally efficient at modulating both ipsilateral and contralateral reflexes, indicating that cortical modulation of lumbar sensory afferents lacks the laterality demonstrated by studies of cortical muscle activation. This technique represents a novel, relatively simple way to assess heteronymous afferent pathways in normal motor control as well as in models of motor disorders where adaptive and maladaptive plasticity of PAs and descending systems affects functional outcomes. PMID- 30406177 TI - Inflammation as a central mechanism in Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by cognitive decline and the presence of two core pathologies, amyloid beta plaques and neurofibrillary tangles. Over the last decade, the presence of a sustained immune response in the brain has emerged as a third core pathology in AD. The sustained activation of the brain's resident macrophages (microglia) and other immune cells has been demonstrated to exacerbate both amyloid and tau pathology and may serve as a link in the pathogenesis of the disorder. In the following review, we provide an overview of inflammation in AD and a detailed coverage of a number of microglia-related signaling mechanisms that have been implicated in AD. Additional information on microglia signaling and a number of cytokines in AD are also reviewed. We also review the potential connection of risk factors for AD and how they may be related to inflammatory mechanisms. PMID- 30406185 TI - Erratum: Mattan et al., Motivation Modulates Brain Networks in Response to Faces Varying in Race and Status: A Multivariate Approach (eNeuro July/August 2018, 5(4) e0039-18.2018 1-13 https://doi.org/10.1523/ENEURO.0039-18.2018). AB - [This corrects the article DOI: 10.1523/ENEURO.0039-18.2018.]. PMID- 30406184 TI - Partial, Rather than Full, BACE1 Inhibition May Be a Better Therapeutic Strategy for Alzheimer's Disease Due to Effects of Complete Loss of BACE1 Activity on Adult Hippocampal Neurogenesis. AB - Highlighted Research Paper: BACE1 Regulates Proliferation and Neuronal Differentiation of Newborn Cells in the Adult Hippocampus in Mice by, Zena K. Chatila, Eunhee Kim, Clara Berle, Enjana Bylykbashi, Alexander Rompala, Mary K. Oram, Drew Gupta, Sang Su Kwak, Young Hye Kim, Doo Yeon Kim, Se Hoon Choi, and Rudolph E. Tanzi. PMID- 30406183 TI - Distinctive Structural and Molecular Features of Myelinated Inhibitory Axons in Human Neocortex. AB - Numerous types of inhibitory neurons sculpt the performance of human neocortical circuits, with each type exhibiting a constellation of subcellular phenotypic features in support of its specialized functions. Axonal myelination has been absent among the characteristics used to distinguish inhibitory neuron types; in fact, very little is known about myelinated inhibitory axons in human neocortex. Here, using array tomography to analyze samples of neurosurgically excised human neocortex, we show that inhibitory myelinated axons originate predominantly from parvalbumin-containing interneurons. Compared to myelinated excitatory axons, they have higher neurofilament and lower microtubule content, shorter nodes of Ranvier, and more myelin basic protein (MBP) in their myelin sheath. Furthermore, these inhibitory axons have more mitochondria, likely to sustain the high energy demands of parvalbumin interneurons, as well as more 2',3'-cyclic nucleotide 3' phosphodiesterase (CNP), a protein enriched in the myelin cytoplasmic channels that are thought to facilitate the delivery of nutrients from ensheathing oligodendrocytes. Our results demonstrate that myelinated axons of parvalbumin inhibitory interneurons exhibit distinctive features that may support the specialized functions of this neuron type in human neocortical circuits. PMID- 30406187 TI - As Soon as You Taste It: Evidence for Sequential and Parallel Processing of Gustatory Information. AB - The quick and reliable detection and identification of a tastant in the mouth regulate nutrient uptake and toxin expulsion. Consistent with the pivotal role of the gustatory system, taste category information (e.g., sweet, salty) is represented during the earliest phase of the taste-evoked cortical response (Crouzet et al., 2015), and different tastes are perceived and responded to within only a few hundred milliseconds, in rodents (Perez et al., 2013) and humans (Bujas, 1935). Currently, it is unknown whether taste detection and discrimination are sequential or parallel processes, i.e., whether you know what it is as soon as you taste it. To investigate the sequence of processing steps involved in taste perceptual decisions, participants tasted sour, salty, bitter, and sweet solutions and performed a taste-detection and a taste-discrimination task. We measured response times (RTs) and 64-channel scalp electrophysiological recordings and tested the link between the timing of behavioral decisions and the timing of neural taste representations determined with multivariate pattern analyses. Irrespective of taste and task, neural decoding onset and behavioral RTs were strongly related, demonstrating that differences between taste judgments are reflected early during chemosensory encoding. Neural and behavioral detection times were faster for the iso-hedonic salty and sour tastes than their discrimination time. No such latency difference was observed for sweet and bitter, which differ hedonically. Together, these results indicate that the human gustatory system detects a taste faster than it discriminates between tastes, yet hedonic computations may run in parallel (Perez et al., 2013) and facilitate taste identification. PMID- 30406186 TI - Maternal Immune Activation Alters Adult Behavior, Gut Microbiome and Juvenile Brain Oscillations in Ferrets. AB - Maternal immune activation (MIA) has been identified as a causal factor in psychiatric disorders by epidemiological studies in humans and mechanistic studies in rodent models. Addressing this gap in species between mice and human will accelerate the understanding of the role of MIA in the etiology of psychiatric disorders. Here, we provide the first study of MIA in the ferret (Mustela putorius furo), an animal model with a rich history of developmental investigations due to the similarities in developmental programs and cortical organization with primates. We found that after MIA by injection of PolyIC in the pregnant mother animal, the adult offspring exhibited reduced social behavior, less eye contact with humans, decreased recognition memory, a sex-specific increase in amphetamine-induced hyperlocomotion, and altered gut microbiome. We also studied the neurophysiological properties of the MIA ferrets in development by in-vivo recordings of the local field potential (LFP) from visual cortex in five- to six-week-old animals, and found that the spontaneous and sensory-evoked LFP had decreased power, especially in the gamma frequency band. Overall, our results provide the first evidence for the detrimental effect of MIA in ferrets and support the use of the ferret as an intermediate model species for the study of disorders with neurodevelopmental origin. PMID- 30406188 TI - Sex Differences in the Rapid Cell Signaling Mechanisms Underlying the Memory Enhancing Effects of 17beta-Estradiol. AB - Little is known about how 17beta-estradiol (E2) mediates memory formation in males. In ovariectomized (OVX) mice, bilateral dorsal hippocampal (DH) infusion of E2 enhances memory consolidation in object recognition (OR) and object placement (OP) tasks in a manner dependent on activation of extracellular signal regulated kinase (ERK) and Akt signaling. Here, bilateral DH E2 infusion enhanced memory consolidation in both tasks among OVX female, gonadally-intact male, and castrated male mice, suggesting comparable facilitation of memory consolidation in both sexes, independent of testicular hormones in males. Contrary to previous reports in OVX mice, E2 did not increase DH ERK or Akt phosphorylation in males, nor did the ERK inhibitor U0126 [1,4-diamino-2,3-dicyano-1,4-bis (o aminophenylmercapto) butadiene] prevent E2 from enhancing memory consolidation among intact and castrated males. These data suggest that ERK activation is not necessary for E2 to enhance memory consolidation in males, and compared with previous reports in females, reveal novel sex differences in the cell-signaling pathways through which E2 facilitates memory consolidation. To explore the mechanisms underlying E2-induced memory enhancements in males, phosphorylation of the transcription factor cAMP response element binding protein (CREB) in the DH was assessed. E2 increased phospho-CREB levels in both sexes, yet U0126 did not block these increases in castrated or intact males, indicating that E2 regulates CREB phosphorylation in males via an ERK-independent mechanism. Collectively, these findings suggest that the beneficial effects of hippocampal E2 on memory consolidation in males and females are mediated by different molecular mechanisms, which has important implications for the development of treatments to reduce memory dysfunction in men and women. PMID- 30406189 TI - Targeted Activation of Cholinergic Interneurons Accounts for the Modulation of Dopamine by Striatal Nicotinic Receptors. AB - Striatal dopamine (DA) is a major player in action selection and reinforcement. DA release is under strong local control by striatal ACh acting at axonal nicotinic ACh receptors (nAChRs) on DA axons. Striatal nAChRs have been shown to control how DA is released in response to ascending activity from DA neurons, and they also directly drive DA release following synchronized activity in a small local cholinergic network. The source of striatal ACh has been thought to arise solely from intrinsic cholinergic interneurons (ChIs), but recent findings have identified a source of cholinergic inputs to striatum from brainstem nuclei, the pedunculopontine nucleus (PPN) and laterodorsal tegmentum (LDT). Here, we used targeted optogenetic activation alongside DA detection with fast-scan cyclic voltammetry to test whether ChIs alone and/or brainstem afferents to the striatum can account for how ACh drives and modulates DA release in rat striatum. We demonstrate that targeted transient light activation of rat striatal ChIs drives striatal DA release, corroborating and extending previous observations in mouse to rat. However, the same light stimulation targeted to cholinergic brainstem afferents did not drive DA release, and nor did it modulate DA release activated subsequently by electrical stimulation, whereas targeted activation of ChIs did so. We were unable to obtain any evidence for DA modulation by PPN/LDT stimulation. By contrast, we could readily identify that striatal ChIs alone are sufficient to provide a source of ACh that powerfully regulates DA via nAChRs. PMID- 30406190 TI - Strategic and Dynamic Temporal Weighting for Perceptual Decisions in Humans and Macaques. AB - Perceptual decision-making is often modeled as the accumulation of sensory evidence over time. Recent studies using psychophysical reverse correlation have shown that even though the sensory evidence is stationary over time, subjects may exhibit a time-varying weighting strategy, weighting some stimulus epochs more heavily than others. While previous work has explained time-varying weighting as a consequence of static decision mechanisms (e.g., decision bound or leak), here we show that time-varying weighting can reflect strategic adaptation to stimulus statistics, and thus can readily take a number of forms. We characterized the temporal weighting strategies of humans and macaques performing a motion discrimination task in which the amount of information carried by the motion stimulus was manipulated over time. Both species could adapt their temporal weighting strategy to match the time-varying statistics of the sensory stimulus. When early stimulus epochs had higher mean motion strength than late, subjects adopted a pronounced early weighting strategy, where early information was weighted more heavily in guiding perceptual decisions. When the mean motion strength was greater in later stimulus epochs, in contrast, subjects shifted to a marked late weighting strategy. These results demonstrate that perceptual decisions involve a temporally flexible weighting process in both humans and monkeys, and introduce a paradigm with which to manipulate sensory weighting in decision-making tasks. PMID- 30406191 TI - Zic4-Lineage Cells Increase Their Contribution to Visual Thalamic Nuclei during Murine Embryogenesis If They Are Homozygous or Heterozygous for Loss of Pax6 Function. AB - Our aim was to study the mechanisms that contribute to the development of discrete thalamic nuclei during mouse embryogenesis (both sexes included). We characterized the expression of the transcription factor coding gene Zic4 and the distribution of cells that expressed Zic4 in their lineage. We used genetic fate mapping to show that Zic4-lineage cells mainly contribute to a subset of thalamic nuclei, in particular the lateral geniculate nuclei (LGNs), which are crucial components of the visual pathway. We observed that almost all Zic4-lineage diencephalic progenitors express the transcription factor Pax6 at variable location-dependent levels. We used conditional mutagenesis to delete either one or both copies of Pax6 from Zic4-lineage cells. We found that Zic4-lineage cells carrying either homozygous or heterozygous loss of Pax6 contributed in abnormally high numbers to one or both of the main lateral geniculate nuclei (LGNs). This could not be attributed to a change in cell production and was likely due to altered sorting of thalamic cells. Our results indicate that positional information encoded by the levels of Pax6 in diencephalic progenitors is an important determinant of the eventual locations of their daughter cells. PMID- 30406192 TI - Role of the K+-Cl- Cotransporter KCC2a Isoform in Mammalian Respiration at Birth. AB - In central respiratory circuitry, synaptic excitation is responsible for synchronizing neuronal activity in the different respiratory rhythm phases, whereas chloride-mediated inhibition is important for shaping the respiratory pattern itself. The potassium chloride cotransporter KCC2, which serves to maintain low intraneuronal Cl- concentration and thus render chloride-mediated synaptic signaling inhibitory, exists in two isoforms, KCC2a and KCC2b. KCC2 is essential for functional breathing motor control at birth, but the specific contribution of the KCC2a isoform remains unknown. Here, to address this issue, we investigated the respiratory phenotype of mice deficient for KCC2a. In vivo plethysmographic recordings revealed that KCC2a-deficient pups at P0 transiently express an abnormally low breathing rate and a high occurrence of apneas. Immunostainings confirmed that KCC2a is normally expressed in the brainstem neuronal groups involved in breathing (pre-Botzinger complex, parafacial respiratory group, hypoglossus nucleus) and is absent in these regions in the KCC2a-/- mutant. However, in variously reduced in vitro medullary preparations, spontaneous rhythmic respiratory activity is similar to that expressed in wild type preparations, as is hypoglossal motor output, and no respiratory pauses are detected, suggesting that the rhythm-generating networks are not intrinsically affected in mutants at P0. In contrast, inhibitory neuromodulatory influences exerted by the pons on respiratory rhythmogenesis are stronger in the mutant, thereby explaining the breathing anomalies observed in vivo. Thus, our results indicate that the KCC2a isoform is important for establishing proper breathing behavior at the time of birth, but by acting at sites that are extrinsic to the central respiratory networks themselves. PMID- 30406193 TI - What, If Anything, Is Rodent Prefrontal Cortex? AB - Prefrontal cortex (PFC) means different things to different people. In recent years, there has been a major increase in publications on the PFC, especially using mice. However, inconsistencies in the nomenclature and anatomical boundaries of PFC areas has made it difficult for researchers to compare data and interpret findings across species. We conducted a meta-analysis of publications on the PFC of humans and rodents and found dramatic differences in the focus of research on these species. In addition, we compared anatomical terms and criteria across several common rodent brain atlases and found inconsistencies among, and even within, leading atlases. To assess the impact of these issues on the research community, we conducted a survey of established PFC researchers on their use of anatomical terms and found little consensus. We report on the results of the survey and propose an alternative scheme for interpreting data from rodent studies, based on structural analysis of the corpus callosum and nomenclature used in research on the anterior cingulate cortex (ACC) of primates. PMID- 30406194 TI - COMT Inhibition Alters Cue-Evoked Oscillatory Dynamics during Alcohol Drinking in the Rat. AB - Alterations in the corticostriatal system have been implicated in numerous substance use disorders, including alcohol use disorder (AUD). Adaptations in this neural system are associated with enhanced drug-seeking behaviors following exposure to cues predicting drug availability. Therefore, understanding how potential treatments alter neural activity in this system could lead to more refined and effective approaches for AUD. Local field potentials (LFPs) were acquired simultaneously in the prefrontal cortex (PFC) and nucleus accumbens (NA) of both alcohol preferring (P) and Wistar rats engaged in a Pavlovian conditioning paradigm wherein a light cue signaled the availability of ethanol (EtOH). On test days, the catechol-o-methyl-transferase (COMT) inhibitor tolcapone was administered prior to conditioning. Stimulus-evoked voltage changes were observed following the presentation of the EtOH cue in both strains and were most pronounced in the PFC of P rats. Phase analyses of LFPs in the theta band (5 11 Hz) revealed that PFC-NA synchrony was reduced in P rats relative to Wistars but was robustly increased during drinking. Presentation of the cue resulted in a larger phase reset in the PFC of P rats but not Wistars, an effect that was attenuated by tolcapone. Additionally, tolcapone reduced cued EtOH intake in P rat but not Wistars. These results suggest a link between corticostriatal synchrony and genetic risk for excessive drinking. Moreover, inhibition of COMT within these systems may result in reduced attribution of salience to reward paired stimuli via modulation of stimulus-evoked changes to cortical oscillations in genetically susceptible populations. PMID- 30406195 TI - Functional Categories of Visuomotor Neurons in Macaque Frontal Eye Field. AB - Frontal eye field (FEF) in macaque monkeys contributes to visual attention, visual-motor transformations and production of eye movements. Traditionally, neurons in FEF have been classified by the magnitude of increased discharge rates following visual stimulus presentation, during a waiting period, and associated with eye movement production. However, considerable heterogeneity remains within the traditional visual, visuomovement, and movement categories. Cluster analysis is a data-driven method of identifying self-segregating groups within a dataset. Because many cluster analysis techniques exist and outcomes vary with analysis assumptions, consensus clustering aggregates over multiple analyses, identifying robust groups. To describe more comprehensively the neuronal composition of FEF, we applied a consensus clustering technique for unsupervised categorization of patterns of spike rate modulation measured during a memory-guided saccade task. We report 10 functional categories, expanding on the traditional 3 categories. Categories were distinguished by latency, magnitude, and sign of visual response; the presence of sustained activity; and the dynamics, magnitude and sign of saccade-related modulation. Consensus clustering can include other metrics and can be applied to datasets from other brain regions to provide better information guiding microcircuit models of cortical function. PMID- 30406196 TI - Projection Patterns of Corticofugal Neurons Associated with Vibrissa Movement. AB - Rodents actively whisk their vibrissae, which, when they come in contact with surrounding objects, enables rodents to gather spatial information about the environment. Cortical motor command of whisking is crucial for the control of vibrissa movement. Using awake and head-fixed rats, we investigated the correlations between axonal projection patterns and firing properties in identified layer 5 neurons in the motor cortex, which are associated with vibrissa movement. We found that cortical neurons that sent axons to the brainstem fired preferentially during large-amplitude vibrissa movements and that corticocallosal neurons exhibited a high firing rate during small vibrissa movements or during a quiet state. The differences between these two corticofugal circuits may be related to the mechanisms of motor-associated information processing. PMID- 30406197 TI - Inhibition of Pyramidal Neurons in the Basal Amygdala Promotes Fear Learning. AB - The basolateral amygdala complex, which contains the lateral (LA) and basal (BA) subnuclei, is a critical substrate of associative learning related to reward and aversive stimuli. Auditory fear conditioning studies in rodents have shown that the excitation of LA pyramidal neurons, driven by the inhibition of local GABAergic interneurons, is critical to fear memory formation. Studies examining the role of the BA in auditory fear conditioning, however, have yielded divergent outcomes. Here, we used a neuron-specific chemogenetic approach to manipulate the excitability of mouse BA neurons during auditory fear conditioning. We found that chemogenetic inhibition of BA GABA neurons, but not BA pyramidal neurons, impaired fear learning. Further, either chemogenetic stimulation of BA GABA neurons or chemogenetic inhibition of BA pyramidal neurons was sufficient to generate the formation of an association between a behavior and a neutral auditory cue. This chemogenetic memory required presentation of a discrete cue, and was not attributable to an effect of BA pyramidal neuron inhibition on general freezing behavior, locomotor activity, or anxiety. Collectively, these data suggest that BA GABA neuron activation and the subsequent inhibition of BA pyramidal neurons play important role in fear learning. Moreover, the roles of inhibitory signaling differ between the LA and BA, with excitation of pyramidal neurons promoting memory formation in the former, and inhibition of pyramidal neurons playing this role in the latter. PMID- 30406198 TI - Microglia Enhance Synapse Activity to Promote Local Network Synchronization. AB - Microglia are highly motile immunoreactive cells that play integral roles in the response to brain infection and damage, and in the progression of various neurological diseases. During development, microglia also help sculpt neural circuits, via both promoting synapse formation and by targeting specific synapses for elimination and phagocytosis. Microglia are also active surveyors of neural circuits in the mature, healthy brain, although the functional consequences of such microglia-neuron contacts under these conditions is unclear. Using in vivo imaging of neurons and microglia in awake mice, we report here the functional consequences of microglia-synapse contacts. Direct contact between a microglial process and a single synapse results in a specific increase in the activity of that contacted synapse, and a corresponding increase in back-propagating action potentials along the parent dendrite. This increase in activity is not seen for microglia-synapse contacts when microglia are activated by chronic lipopolysaccharide (LPS) treatment. To probe how this microglia-synapse contact affects neural circuits, we imaged across larger populations of motor cortical neurons. When microglia were again activated by LPS (or partially ablated), there was a decrease in the extent to which neuronal activity was synchronized. Together, our results demonstrate that interactions between physiological or resting microglia and synapses in the mature, healthy brain leads to an increase in neuronal activity and thereby helps to synchronize local populations of neurons. Our novel findings provide a plausible physical basis for understanding how alterations in immune status may impact on neural circuit plasticity and on cognitive behaviors such as learning. PMID- 30406199 TI - Electrical Microstimulation of Visual Cerebral Cortex Elevates Psychophysical Detection Thresholds. AB - Sensory prostheses can restore aspects of natural sensation by delivering electrical current directly into sensory circuits. An effective sensory prosthetic should be capable of generating reliable real-time perceptual signals for hours each day over many years. However, we still know little regarding the stability of percepts produced by electrical microstimulation of cerebral sensory cortex when stimulation is delivered repeatedly over long periods. Developing methods that yield highly sensitive and reliable assessments of a subject's sensitivity to stimulation is important for developing prosthetic devices that can mimic the constant stream of information inherent in daily experience. Here, we trained rhesus monkeys to report electrical microstimulation of their primary visual cortex (V1) and measured how repeated stimulation affected the minimal electrical current needed to generate a percept (behavioral detection threshold). Using adaptive staircase procedures with a two-alternative forced-choice (2AFC) detection task, we obtained highly reliable detection threshold measures with as few as 100 trials. Using either chronically implanted or acutely inserted microelectrodes, we found that repeated electrical microstimulation elevated detection thresholds, with effects persisting between daily testing sessions. Our results demonstrate task designs that can support rapid and reliable measurements of detection thresholds, and point to the need for validation that detection thresholds in targeted structures will be sufficiently stable in the face of the amount of chronic stimulation that will be required for effective sensory prosthetics. PMID- 30406201 TI - A swarm of slippery micropropellers penetrates the vitreous body of the eye. AB - The intravitreal delivery of therapeutic agents promises major benefits in the field of ocular medicine. Traditional delivery methods rely on the random, passive diffusion of molecules, which do not allow for the rapid delivery of a concentrated cargo to a defined region at the posterior pole of the eye. The use of particles promises targeted delivery but faces the challenge that most tissues including the vitreous have a tight macromolecular matrix that acts as a barrier and prevents its penetration. Here, we demonstrate novel intravitreal delivery microvehicles-slippery micropropellers-that can be actively propelled through the vitreous humor to reach the retina. The propulsion is achieved by helical magnetic micropropellers that have a liquid layer coating to minimize adhesion to the surrounding biopolymeric network. The submicrometer diameter of the propellers enables the penetration of the biopolymeric network and the propulsion through the porcine vitreous body of the eye over centimeter distances. Clinical optical coherence tomography is used to monitor the movement of the propellers and confirm their arrival on the retina near the optic disc. Overcoming the adhesion forces and actively navigating a swarm of micropropellers in the dense vitreous humor promise practical applications in ophthalmology. PMID- 30406200 TI - Enlarged Optic Nerve Axons and Reduced Visual Function in Mice with Defective Microfibrils. AB - Glaucoma is a leading cause of irreversible vision loss due to retinal ganglion cell (RGC) degeneration that develops slowly with age. Elevated intraocular pressure (IOP) is a significant risk factor, although many patients develop glaucoma with IOP in the normal range. Mutations in microfibril-associated genes cause glaucoma in animal models, suggesting the hypothesis that microfibril defects contribute to glaucoma. To test this hypothesis, we investigated IOP and functional/structural correlates of RGC degeneration in mice of either sex with abnormal microfibrils due to heterozygous Tsk mutation of the fibrilin-1 gene (Fbn1Tsk /+). Although IOP was not affected, Fbn1Tsk /+ mice developed functional deficits at advanced age consistent with glaucoma, including reduced RGC responses in electroretinogram (ERG) experiments. While RGC density in the retina was not affected, the density of RGC axons in the optic nerve was significantly reduced in Fbn1Tsk /+ mice. However, reduced axon density correlated with expanded optic nerves, resulting in similar numbers of axons in Fbn1Tsk /+ and control nerves. Axons in the optic nerves of Fbn1Tsk /+ mice were significantly enlarged and axon diameter was strongly correlated with optic nerve area, as has been reported in early pathogenesis of the DBA/2J mouse model of glaucoma. Our results suggest that microfibril abnormalities can lead to phenotypes found in early-stage glaucomatous neurodegeneration. Thinning of the elastic fiber-rich pia mater was found in Fbn1Tsk /+ mice, suggesting mechanisms allowing for optic nerve expansion and a possible biomechanical contribution to determination of axon caliber. PMID- 30406202 TI - Dynamic assembly of liquid crystalline graphene oxide gel fibers for ion transport. AB - Colloidal dispersions with liquid crystallinity hold great promise for fabricating their superstructures. As an example, when graphene oxide (GO) sheets are assembled in the liquid crystalline state, they can turn into ordered macroscopic forms of GO such as fibers via the wet spinning process. Here, we report that by reinforcing intersheet interactions, GO liquid crystals (LCs) turn into mechanically robust hydrogels that can be readily drawn into highly aligned fibrillar structures. GO hydrogel fibers with highly aligned sheets (orientation factor, f = 0.71) exhibit more than twice the ionic conductivity compared to those with partially aligned structures (f = 0.01). The hierarchically interconnected two-dimensional nanochannels within these neatly aligned GOLC hydrogel fibers may facilitate controlled transport of charge carriers and could be potentially explored as cables for interconnecting biosystems and/or human made devices. PMID- 30406203 TI - A novel ternary heterostructure with dramatic SERS activity for evaluation of PD L1 expression at the single-cell level. AB - Surface-enhanced Raman scattering (SERS) probes based on a charge transfer (CT) process with high stability and reproducibility are powerful tools under open-air conditions. However, the key problem ahead of practical usage of CT-based SERS technology is how to effectively improve sensitivity. Here, a novel ternary heterostructure SERS substrate, Fe3O4@GO@TiO2, with a significant enhancement factor of 8.08 * 106 was first synthesized. We found the remarkable enhanced effect of SERS signal to be attributed to the resonance effect of CuPc, CT between GO and TiO2, and enrichment from a porous TiO2 shell. In addition, we developed a robust SERS probe with good recyclability under visible light illumination on Fe3O4@GO@TiO2 nanocomposites toward ultrasensitive detection of cancer cells down to three cells. We have now successfully applied this probe for in situ quantification and imaging of programmed cell death receptor ligand 1 (PD L1) on triple-negative breast cancer cell surface at the single-cell level and for monitoring the expression variation of PD-L1 during drug treatment. PMID- 30406204 TI - Correlative 3D x-ray fluorescence and ptychographic tomography of frozen-hydrated green algae. AB - Accurate knowledge of elemental distributions within biological organisms is critical for understanding their cellular roles. The ability to couple this knowledge with overall cellular architecture in three dimensions (3D) deepens our understanding of cellular chemistry. Using a whole, frozen-hydrated Chlamydomonas reinhardtii cell as an example, we report the development of 3D correlative microscopy through a combination of simultaneous cryogenic x-ray ptychography and x-ray fluorescence microscopy. By taking advantage of a recently developed tomographic reconstruction algorithm, termed GENeralized Fourier Iterative REconstruction (GENFIRE), we produce high-quality 3D maps of the unlabeled alga's cellular ultrastructure and elemental distributions within the cell. We demonstrate GENFIRE's ability to outperform conventional tomography algorithms and to further improve the reconstruction quality by refining the experimentally intended tomographic angles. As this method continues to advance with brighter coherent light sources and more efficient data handling, we expect correlative 3D x-ray fluorescence and ptychographic tomography to be a powerful tool for probing a wide range of frozen-hydrated biological specimens, ranging from small prokaryotes such as bacteria, algae, and parasites to large eukaryotes such as mammalian cells, with applications that include understanding cellular responses to environmental stimuli and cell-to-cell interactions. PMID- 30406206 TI - Improving supersonic flights with femtosecond laser filamentation. AB - When a flying object becomes supersonic, a concomitant increase in drag leads to a considerable rise in fuel consumption. We show experimentally that an embarked terawatt femtosecond laser can significantly decrease this drag. We measured a 50% transient reduction of drag on a test model placed in a supersonic wind tunnel at Mach 3. This effect was initiated by the thin hot air column created in front of the supersonic object by filamentation of the laser pulse. We also show that this technique offers possibilities for steering. PMID- 30406205 TI - Discovery of log-periodic oscillations in ultraquantum topological materials. AB - Quantum oscillations are usually the manifestation of the underlying physical nature in condensed matter systems. Here, we report a new type of log-periodic quantum oscillations in ultraquantum three-dimensional topological materials. Beyond the quantum limit (QL), we observe the log-periodic oscillations involving up to five oscillating cycles (five peaks and five dips) on the magnetoresistance of high-quality single-crystal ZrTe5, virtually showing the clearest feature of discrete scale invariance (DSI). Further, theoretical analyses show that the two body quasi-bound states can be responsible for the DSI feature. Our work provides a new perspective on the ground state of topological materials beyond the QL. PMID- 30406207 TI - Compliant and stretchable thermoelectric coils for energy harvesting in miniature flexible devices. AB - With accelerating trends in miniaturization of semiconductor devices, techniques for energy harvesting become increasingly important, especially in wearable technologies and sensors for the internet of things. Although thermoelectric systems have many attractive attributes in this context, maintaining large temperature differences across the device terminals and achieving low-thermal impedance interfaces to the surrounding environment become increasingly difficult to achieve as the characteristic dimensions decrease. Here, we propose and demonstrate an architectural solution to this problem, where thin-film active materials integrate into compliant, open three-dimensional (3D) forms. This approach not only enables efficient thermal impedance matching but also multiplies the heat flow through the harvester, thereby increasing the efficiencies for power conversion. Interconnected arrays of 3D thermoelectric coils built using microscale ribbons of monocrystalline silicon as the active material demonstrate these concepts. Quantitative measurements and simulations establish the basic operating principles and the key design features. The results suggest a scalable strategy for deploying hard thermoelectric thin-film materials in harvesters that can integrate effectively with soft materials systems, including those of the human body. PMID- 30406208 TI - Upper Ureteric Stricture Secondary to Celiac Plexus Block Managed by Robotic Ureterocalicostomy. AB - Introduction: Ureterocalicostomy is a well-established procedure of choice for recurrent pelviureteric junction (PUJ) obstruction refractory to endoscopic management, failed pyeloplasty, completely intrarenal pelvis, and iatrogenic upper ureteral stricture with significant peripelvic fibrosis. Robotic ureterocalicostomy is the procedure of choice in such scenarios where meticulous dissection and accurate anastomotic suturing is required. Case Presentation: We report the case of an 18-year-old male, who underwent celiac plexus block for pain management of chronic calcific pancreatitis and presented with pain in the epigastric region and the right flank. A CT and subsequent nephrostogram revealed an upper ureteral defect (corrosive stricture) of ~4 cm at the level of PUJ. Robotic ureterocalicostomy was performed. We discuss the clinical presentation, evaluation, and management along with literature review. Conclusion: Iatrogenic ureteral strictures are not uncommon in urological practice, but an upper ureteral stricture secondary to celiac plexus block is a rarity. Adequate evaluation and timely intervention by reconstructive surgery, robotic ureterocalicostomy in this case, yield satisfactory results. PMID- 30406209 TI - The Causal Effects of Education on Health Outcomes in the UK Biobank. PMID- 30406210 TI - Single dose partial breast irradiation using an MRI linear accelerator in the supine and prone treatment position. AB - Background: In selected patients with early-stage and low-risk breast cancer, an MRI-linac based treatment might enable a radiosurgical, non-invasive alternative for current standard breast conserving therapy. Aim: To investigate whether single dose accelerated partial breast (APBI) to the intact tumor in both the prone and supine radiotherapy positions on the MRI-linac is dosimetrically feasible with respect to predefined coverage and organs at risk (OAR) constraints. Material & methods: For 20 patients with cTis or low-risk cT1N0M0 non-lobular breast carcinoma, previously treated with single dose preoperative APBI in the supine (n = 10) or prone (n = 10) position, additional intensity modulated radiotherapy plans with 7 coplanar beams in the presence of a 1.5T magnetic field were generated. A 20 Gy and 15 Gy dose was prescribed to the gross tumor and clinical target volume, respectively. The percentage of plans achieving predefined organ at risk (OAR) constraints, currently used in clinical practice, was assessed. Dosimetry differences between the prone versus supine approach and the MRI-linac versus clinically delivered plans were evaluated. Results: All MRI linac plans met the coverage and predefined OAR constraints. The prone approach appeared to be more favorable with respect to the chest wall, and ipsilateral lung dose compared to the supine position. No dosimetric differences were observed for the ipsilateral breast. No treatment position was clearly more beneficial for the skin or heart, since dosimetry varied among parameters. Overall, the MRI-linac and clinical plans were comparable, with minor absolute dosimetric differences. Conclusion: MRI-linac based single dose APBI to the intact tumor is a promising and a dosimetrically feasible strategy in patients with low-risk breast cancer. Preliminary OAR dosimetry favored the prone radiotherapy position. PMID- 30406211 TI - The FGF1/CPP-C chimera protein protects against intestinal adverse effects of C ion radiotherapy without exacerbating pancreatic carcinoma. AB - Background and purpose: Carbon ion (C-ion) beams are concentrated to irradiate pancreatic carcinoma in the upper abdomen; however, this radiotherapy potentially causes adverse reactions in the gastrointestinal tract. FGF1 is a candidate radioprotector for radiation-induced intestinal damage, but may promote the malignancy of pancreatic cancer. An FGF1/CPP-C chimeric protein was created to enhance the intracellular signaling mode of FGF1 instead of FGFR signaling. The present study investigated the effects of FGF1/CPP-C on the intestinal adverse reactions of C-ion radiotherapy as well as its influence on the malignancy of pancreatic cancer. Materials and methods: FGF1/CPP-C was administered intraperitoneally to BALB/c mice without heparin 12 h before total body irradiation (TBI) with low-LET C-ion (17 keV/MUm) at 6-8 Gy. Several radioprotective effects were examined in the jejunum. The invasion and migration of the human pancreatic carcinoma cell lines MIAPaCa-2 and PANC-1 were assessed using Boyden chambers after cultures with FGF1/CPP-C. Results: The FGF1/CPP-C treatment promoted crypt survival after C-ion irradiation at 7-8 Gy significantly more than the FGF1 treatment. FGF1/CPP-C also inhibited C-ion radiotherapy induced apoptosis and reduced gammaH2AX foci in crypt cells more than FGF1. However, FGF1/CPP-C inhibited the downstream signaling pathways of FGFRs and suppressed the activation of cell-cycle regulatory molecules in the intestine until 4 h after TBI. Furthermore, IEC6 cells were arrested in G2M after cultures with FGF1/CPP-C or FGF1, suggesting that DNA repair after irradiation is promoted by FGF1/CPP-C-induced G2M arrest. In contrast, FGF1/CPP-C appeared to be internalized into MIAPaCa-2 and PANC-1 cells more efficiently than FGF1. Therefore, FGF1/CPP-C reduced the in vitro proliferation, invasion, and migration of MIAPaCa-2 and PANC-1 cells significantly more than FGF1 through the cellular internalization of FGF1. Conclusion: These results suggest that the intracellular signaling mode of FGF1/CPP-C attenuates the intestinal adverse effects of C-ion radiotherapy without enhancing the malignancy of pancreatic carcinoma. PMID- 30406212 TI - Ultrastructural Characterization of Flashing Mitochondria. AB - Mitochondria undergo spontaneous transient elevations in matrix pH associated with drops in mitochondrial membrane potential. These mitopHlashes require a functional respiratory chain and the profusion protein optic atrophy 1, but their mechanistic basis is unclear. To gain insight on the origin of these dynamic events, we resolved the ultrastructure of flashing mitochondria by correlative light and electron microscopy. HeLa cells expressing the matrix-targeted pH probe mitoSypHer were screened for mitopHlashes and fixed immediately after the occurrence of a flashing event. The cells were then processed for imaging by serial block face scanning electron microscopy using a focused ion beam to generate ~1,200 slices of 10 nm thickness from a 28 MUm * 15 MUm cellular volume. Correlation of live/fixed fluorescence and electron microscopy images allowed the unambiguous identification of flashing and nonflashing mitochondria. Three dimensional reconstruction and surface mapping revealed that each tomogram contained two flashing mitochondria of unequal sizes, one being much larger than the average mitochondrial volume. Flashing mitochondria were 10-fold larger than silent mitochondria but with a surface to volume ratio and a cristae volume similar to nonflashing mitochondria. Flashing mitochondria were connected by tubular structures, formed more membrane contact sites, and a constriction was observed at a junction between a flashing mitochondrion and a nonflashing mitochondrion. These data indicate that flashing mitochondria are structurally preserved and bioenergetically competent but form numerous membrane contact sites and are connected by tubular structures, consistent with our earlier suggestion that mitopHlashes might be triggered by the opening of fusion pores between contiguous mitochondria. PMID- 30406213 TI - Selectivity Conversion of Protease Inhibitory Antibodies. AB - Background: Proteases are one of the largest pharmaceutical targets for drug developments. Their dysregulations result in a wide variety of diseases. Because proteolytic networks usually consist of protease family members that share high structural and catalytic homology, distinguishing them using small molecule inhibitors is often challenging. To achieve specific inhibition, this study described a novel approach for the generation of protease inhibitory antibodies. As a proof of concept, we aimed to convert a matrix metalloproteinase (MMP)-14 specific inhibitor to MMP-9 specific inhibitory antibodies with high selectivity. Methods: An error-prone single-chain Fv (scFv) library of an MMP-14 inhibitor 3A2 was generated for yeast surface display. A dual-color competitive FACS was developed for selection on MMP-9 catalytic domain (cdMMP-9) and counter-selection on cdMMP-14 simultaneously, which were fused/conjugated with different fluorophores. Isolated MMP-9 inhibitory scFvs were biochemically characterized by inhibition assays on MMP-2/-9/-12/-14, proteolytic stability tests, inhibition mode determination, competitive ELISA with TIMP-2 (a native inhibitor of MMPs), and paratope mutagenesis assays. Results: We converted an MMP-14 specific inhibitor 3A2 into a panel of MMP-9 specific inhibitory antibodies with dramatic selectivity shifts of 690-4,500 folds. Isolated scFvs inhibited cdMMP-9 at nM potency with high selectivity over MMP-2/-12/-14 and exhibited decent proteolytic stability. Biochemical characterizations revealed that these scFvs were competitive inhibitors binding to cdMMP-9 near its reaction cleft via their CDR H3s. Conclusions: This study developed a novel approach able to convert the selectivity of inhibitory antibodies among closely related protease family members. This methodology can be directly applied for mAbs inhibiting many proteases of biomedical importance. PMID- 30406215 TI - Does daughter deficit promote paternal substance use? Evidence from China. AB - Background: China and various other countries have experienced unbalanced sex ratios in the marriage market, which triggers intense competition and pressure to get married. Meanwhile, China has more smokers and drinkers than any other countries in the world. This paper provides evidence on smoking and alcohol use as a stress coping strategy for the competitive marriage market. Methods: This paper utilizes two household longitudinal datasets from rural China-a national survey and a regional survey-to examine paternal substance use in response to skewed sex ratios of their children's generation. The longitudinal feature of the two datasets enables us to explore within household variation in smoking and alcohol use. Sex ratios are matched using a 1% sample of the 2000 China Population Census. Results: Strikingly, paternal smoking and alcohol use are more intense for families with a son living in communities with higher sex ratios. In contrast, those with a daughter do not demonstrate this pattern. Coping with the marriage market pressure is a plausible pathway linking the observed skewed sex ratios and intense substance use. Conclusions: High male-to-female sex ratios promote smoking and alcohol drinking among fathers with sons. Considering the highly competitive marriage market in the coming decade and the prevalent substance use that generates lasting health impacts and large negative externalities to society, policies that address the skewed sex ratios could lead to substantial welfare gains. PMID- 30406214 TI - Frontiers and Opportunities: Highlights of the 2nd Annual Conference of the Chinese Antibody Society. AB - The Chinese Antibody Society (CAS) convened the second annual conference in Cambridge, MA, USA on 29 April 2018. More than 600 members from around the world attended the meeting. Invited speakers discussed the latest advancements in therapeutic antibodies with an emphasis on the progress made in China. The meeting covered a vast variety of topics including the current status of therapeutic antibodies, the progress of immuno-oncology, and biosimilars in China. The conference presentations also included the development of several novel antibodies such as antibodies related to weight loss, T-cell receptor mimicking antibodies that target intracellular antigens, and tumor-targeting antibodies that utilize both innate and adaptive immune pathways. At the meeting, the CAS announced the launch of its official journal-Antibody Therapeutics-in collaboration with Oxford University Press. The conference was concluded by a panel discussion on how to bring a therapeutic drug developed in China to the USA for clinical trials. PMID- 30406216 TI - Space-Charge Layers in All-Solid-State Batteries; Important or Negligible? AB - All-solid state batteries have the promise to increase the safety of Li-ion batteries. A prerequisite for high-performance all-solid-state batteries is a high Li-ion conductivity through the solid electrolyte. In recent decades, several solid electrolytes have been developed which have an ionic conductivity comparable to that of common liquid electrolytes. However, fast charging and discharging of all-solid-state batteries remains challenging. This is generally attributed to poor kinetics over the electrode-solid electrolyte interface because of poorly conducting decomposition products, small contact areas, or space-charge layers. To understand and quantify the role of space-charge layers in all-solid-state batteries a simple model is presented which allows to asses the interface capacitance and resistance caused by the space-charge layer. The model is applied to LCO (LiCoO2) and graphite electrodes in contact with an LLZO (Li7La3Zr2O12) and LATP (Li1.2Al0.2Ti1.8(PO4)3) solid electrolyte at several voltages. The predictions demonstrate that the space-charge layer for typical electrode-electrolyte combinations is about a nanometer in thickness, and the consequential resistance for Li-ion transport through the space-charge layer is negligible, except when layers completely depleted of Li-ions are formed in the solid electrolyte. This suggests that space-charge layers have a negligible impact on the performance of all-solid-state batteries. PMID- 30406218 TI - The role of beta-elimination for the clinical activity of hypomethylating agents and cyclophosphamide analogues. AB - A beta-elimination reaction generally involves the cleavage of a sigma (sigma) bond at the position beta (beta) to a pair of electrons that departs a molecule via a nucleophilic leaving group, subsequently leading to the formation of a new pi (pi) bond. We describe the importance of beta-elimination reactions in the mechanisms of action of two classes of chemotherapeutic agents. First, we evaluate the chemical steps resulting in formation of 5-methyl-cytosine and its disassociation from DNA methytransferase (DNMT) by beta-elimination reaction. When carbon 5 (C5) of cytosine is substituted with a nitrogen atom (N) in 5-aza cytosine analogues, the critical beta-elimination reaction cannot proceed, which results in the permanent attachment of 5-aza-cytosine to DNMT. The net outcome is entrapment of the DNMT by 5-aza-cytosine analogues and its eventual degradation, leading to DNA hypomethylation. Second, we analyze the critical role of beta elimination reaction in the activation of cyclophosphamide and ifosfamide. The incapability of undergoing beta-elimination results in reduction of the cytotoxic activity of these agents. It appears that the conversion of aldehyde group, in aldophosphamide metabolites of cyclophosphamide and ifosfamide, to carboxyl group by aldehyde dehydrogenase makes the protons on the carbon atom attached to carboxyl group not acidic enough that can be removed under physiologic conditions via initiation of the critical beta-elimination reaction. This ultimately culminates in selective cytotoxic effect of these agents against lymphocytes but not hematopoietic and other stem cells with high aldehyde dehydrogenase content. PMID- 30406220 TI - Miniature Elastomeric Valve Design for Safe Direct Current Stimulator. AB - For safety reasons, commercial neural implants use charge-balanced biphasic pulses to interact with target neurons using metal electrodes. Short biphasic pulses are used to avoid irreversible electrochemical reactions at the electrode tissue interfaces. Biphasic pulses are effective at exciting neurons, but quite limited in inhibiting their activity. In contrast, direct current can both excite and inhibit neurons, however delivered to metal electrodes, it causes toxic electrochemical reactions. We recently introduced Safe Direct Current Stimulator (SDCS) technology, which can excite or inhibit neurons without violating the safety criteria. Instead of direct current, SDCS generates an ionic direct current (iDC) from a biphasic input signal using a network of fluidic channels and mechanical valves. A key enabler towards transforming SDCS concept from a benchtop design to an implantable neural prosthesis is the design of a miniature valve. In this work, we present poly-dimethylsiloxane (PDMS) based elastomeric valves, squeeze valve (SV) and plunger valve (PV) capable of being actuated using a shape memory alloy wire. PMID- 30406217 TI - Oxygen Reduction Reaction Electrocatalysts Derived from Iron Salt and Benzimidazole and Aminobenzimidazole Precursors and Their Application in Microbial Fuel Cell Cathodes. AB - In this work, benzimidazole (BZIM) and aminobenzimidazole (ABZIM) were used as organic-rich in nitrogen precursors during the synthesis of iron-nitrogen-carbon (Fe-N-C) based catalysts by sacrificial support method (SSM) technique. The catalysts obtained, denoted Fe-ABZIM and Fe-BZIM, were characterized morphologically and chemically through SEM, TEM, and XPS. Moreover, these catalysts were initially tested in rotating ring disk electrode (RRDE) configuration, resulting in similar high electrocatalytic activity toward oxygen reduction reaction (ORR) having low hydrogen peroxide generated (<3%). The ORR performance was significantly higher compared to activated carbon (AC) that was the control. The catalysts were then integrated into air-breathing (AB) and gas diffusion layer (GDL) cathode electrode and tested in operating microbial fuel cells (MFCs). The presence of Fe-N-C catalysts boosted the power output compared to AC cathode MFC. The AB-type cathode outperformed the GDL type cathode probably because of reduced catalyst layer flooding. The highest performance obtained in this work was 162 +/- 3 MUWcm-2. Fe-ABZIM and Fe-BZIM had similar performance when incorporated to the same type of cathode configuration. Long-term operations show a decrease up to 50% of the performance in two months operations. Despite the power output decrease, the Fe-BZIM/Fe-ABZIM catalysts gave a significant advantage in fuel cell performance compared to the bare AC. PMID- 30406219 TI - Electronics for a Safe Direct Current Stimulator. AB - Commercially available neuroprostheses, while successful and effective, are limited in their functionality by their reliance on pulsatile stimulation. Direct current (DC) has been shown to have great potential for the purposes of neuromodulation; however, direct current cannot be applied directly to neurons due to the charge injection thresholds of electrodes. We are developing a Safe Direct Current Stimulator (SDCS) that applies ionic direct current (iDC) without inducing toxic electrochemical reactions. The current design of the SDCS uses a series of eight valves in conjunction with four electrodes to rectify ionic current in microfluidic channels. This paper outlines the design, implementation, and testing of the electronics of the SDCS. These electronics will ultimately be interfaced with a separate microfluidic circuit in the device prototype. Testing the outputs of the electronics confirmed adherence to its design requirements. The completion of the SDCS electronics enables the further development of iDC as a mechanism for neuromodulation. PMID- 30406221 TI - Two aggregation-induced emission (AIE)-active reaction-type probes: for real-time detecting and imaging of superoxide anions. AB - Fluorescent probes are powerful tools for investigating reactive oxygen species (ROS) in living organisms. The overproduced "primary" ROS of superoxide anions (O2-) cause a chain of oxidative damage. In order to monitor O2- level fluctuations in living cells, we synthesized two reaction-type probes of TPA-DHP 1,2,3 and TPA-PPA-1,2,3, which were composed of an electron-rich triphenylamine (TPA) and the very active functional groups of dihydropyridine (DHP) and pyridinium (PPA). Intriguingly, DHP and PPA were able to carry out easy proton abstractions and nucleophilic reactions in the presence of O2-, resulting in the corresponding products with sharp wavelength shifts, and elevated fluorescence intensities. Therefore, undesirable background fluorescence interference can be reduced during the monitoring and imaging process. Meanwhile, the developed dual channel monitoring strategy not only provides observations of the O2- level fluctuations, but could also be employed to image the dynamic accumulation process of probes in the different cell organelles. Therefore, the design could provide a simple, accurate and universal platform for biological applications in future research work. PMID- 30406223 TI - AFM assessing of nanomechanical fingerprints for cancer early diagnosis and classification: from single cell to tissue level. AB - Cancer development and progression are closely associated with changes both in the mechano-cellular phenotype of cancer and stromal cells and in the extracellular matrix (ECM) structure, composition, and mechanics. In this paper, we review the use of atomic force microscopy (AFM) as a tool for assessing the nanomechanical fingerprints of solid tumors, so as to be potentially used as a diagnostic biomarker for more accurate identification and early cancer grading/classification. The development of such a methodology is expected to provide new insights and a novel approach for cancer diagnosis. We propose that AFM measurements could be employed to complement standard biopsy procedures, offering an objective, novel and quantitative diagnostic approach with the properties of a blind assay, allowing unbiased evaluation of the sample. PMID- 30406224 TI - Confocal Raman micro-spectral evidence and physicochemical evaluation of triamterene salts. AB - Discrimination of active pharmaceutical ingredients (APIs) existing as neutral molecules or salts is essential and complicated. However, the discrimination of pharmaceutical salts by confocal Raman micro-spectroscopy remains relatively poorly understood. In this paper, four new salts of triamterene (Tri) cocrystallized with nicotinic acid (NA), benzoic acid (BA), p-toluenesulfonic acid (TA), or isonicotinic acid (INA) were prepared and characterized comprehensively by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), polarized light microscopy (PLM), and dynamic vapor sorption (DVS). Ionized pteridine is identified by marker peaks in the confocal Raman micro-spectra that are characteristic of C[double bond, length as m-dash]N. The single crystal structures of Tri-NA.H2O and Tri-TA further demonstrate that a proton transfers from the carboxylic group of NA or TA to the pyrimidine N1 atom of Tri and their salts formation take place. The intrinsic dissolution rate (IDR) and apparent equilibrium solubility of these four salts are improved compared to the pure Tri component, especially for Tri-BA. This study provides a valuable insight into pharmaceutical salt discrimination by vibrational spectroscopy and presents that the combination of Tri with an acid can be a possible and promising alternative formulation of Tri. PMID- 30406225 TI - Graphene oxide-phenalenyl composite: transition metal-free recyclable and catalytic C-H functionalization. AB - An efficient route towards a heterogeneous transition metal-free catalytic C-H functionalization using a covalently linked graphene oxide-phenalenyl conjugate is described herein (28 examples, which include a core of some biologically relevant biaryl and hetero-biaryls). It is an environmentally benign, economical and heterogeneous platform, whose catalytic activity can easily be regenerated through a simple washing-drying technique and the catalytic activity can be retained even after 10 cycles. PMID- 30406226 TI - Nanomaterials for luminescent detection of water and humidity. AB - The rapid and sensitive detection of water or humidity has attracted wide interest because of their considerable significance in the chemical industry and other fields. Nanotechnology offers potential tools in the construction of various luminescent nanosensors for sensing water or relative humidity (RH). In this review, we present the recent advances in different luminescent nanomaterials, namely, luminescent copper nanoclusters, carbon quantum dots, metal-organic frameworks, covalent organic frameworks and other nanomaterials, in the detection of water and RH. Also, the challenges and opportunities are discussed. PMID- 30406227 TI - AIE active piperazine appended naphthalimide-BODIPYs: photophysical properties and applications in live cell lysosomal tracking. AB - Piperazine appended naphthalimide-BODIPYs (NPB1-NPB4) exhibiting solvatochromism and aggregation-induced emission with a large Stokes shift (up to 146 nm) have been described. Separation of naphthalimide and BODIPY fluorophores by piperazine in these conjugates creates a donor-acceptor system and induces twisted intramolecular charge transfer, in addition to photoinduced electron transfer. The crucial role of naphthalimide, the alkyl chain length, the piperazine ring, and the solid-state packing on AIE has been extensively investigated by various studies. Superior cell permeability coupled with bio-compatibility of these conjugates offers a unique opportunity for their potential applications in live cell lysosomal tracking. PMID- 30406229 TI - Rovibrational quantum dynamics of the vinyl radical and its deuterated isotopologues. AB - Rotational-vibrational states up to 3200 cm-1, beyond the highest-lying stretching fundamental, are computed variationally for the vinyl radical (VR), H2Cbeta[double bond, length as m-dash]CalphaH, and the following deuterated isotopologues of VR: CH2[double bond, length as m-dash]CD, CHD[double bond, length as m-dash]CH, and CD2[double bond, length as m-dash]CD. The height of the CalphaH tunneling rocking barrier of VR, partially responsible for the complex nuclear dynamics of VR and its isotopologues, is determined to be 1641 +/- 25 cm 1 by the focal-point analysis approach. The definitive nuclear-motion computations performed utilize two previously published potential energy hypersurfaces and reveal interesting energy-level and tunneling patterns characterizing the internal motions of the four isotopologues. A full assignment, including symmetry labels, of the vibrational states computed for CH2[double bond, length as m-dash]CH is provided, whenever feasible, based on the analysis of wave functions and the related one- and two-mode reduced density matrices. The computed vibrational states of CH2[double bond, length as m-dash]CD and CD2[double bond, length as m-dash]CD are characterized up to slightly above the top of the barrier. Interestingly, it is the interplay of the nu6 (formally CH2 rock) and nu7 (formally CH rock) modes that determines the tunneling dynamics; thus, the description of tunneling in VR needs, as a minimum, the consideration of two in-plane bending motions at the two ends of the molecule. When feasible, the computed results are compared to their experimental counterparts as well as to previous computational results. Corrections to the placement of the nu4 and nu6 fundamentals of VR are proposed. Tunneling switching, a unique phenomenon characterizing tunneling in slightly asymmetric effective double-well potentials, is observed and discussed for CHD[double bond, length as m-dash]CH. Despite the extensive tunneling dynamics, the rotational energy-level structure of VR exhibits rigid-rotor-type behavior. PMID- 30406230 TI - Influences of carboxyl functionalization of intercalators on exfoliation of graphite oxide: a molecular dynamics simulation. AB - In this study, the influences of the carboxyl functionalization of intercalators on exfoliation of graphite oxide were analyzed using molecular dynamics (MD) simulations. Molecular models of four-layered graphene oxide (GO) sheets, four different solvents (ethanol, dimethylformamide, tetrahydrofuran, and N-methyl-2 pyrrolidone), and four different intercalators (anthracene, 2 anthracenecarboxylic acid, 2,3-anthracenedicarboxylic acid, and 2,6 anthracenedicarboxylic acid) were used in the MD simulations. A separation simulation of GO sheets was performed to determine the point at which the GO sheets begin to exfoliate. An insertion simulation was used to obtain the minimum kinetic energy required for exfoliation and to calculate GO-solvent and GO intercalator interaction energies. As the simulation result, GO-solvent and GO intercalator interactions affected the minimum kinetic energy required for exfoliation. Having more carboxyl functional groups on the anthracene improved both the GO-intercalator interaction and the efficiency of the intercalators during exfoliation. These results reveal that increasing the interaction energy between the GO sheets and the insertion molecules is an efficient way to improve the performance of the solvents and the intercalators for the exfoliation of GO sheets. PMID- 30406232 TI - Correction: A ratiometric fluorescent probe for peroxynitrite prepared by de novo synthesis and its application in assessing the mitochondrial oxidative stress status in cells and in vivo. AB - Correction for 'A ratiometric fluorescent probe for peroxynitrite prepared by de novo synthesis and its application in assessing the mitochondrial oxidative stress status in cells and in vivo' by Dong-Ye Zhou et al., Chem. Commun., 2018, 54, 11590-11593. PMID- 30406233 TI - On-surface transmetalation of metalloporphyrins. AB - Increasing the complexity of 2D metal-organic networks has led to the fabrication of structures with interesting magnetic and catalytic properties. However, increasing complexity by providing different coordination environments for different metal types imposes limitations on their synthesis if the controlled placement of one metal type into one coordination environment is desired. Whereas metal insertion into free-base porphyrins at the vacuum/solid interface has been thoroughly studied, providing detailed insight into the mechanisms at play, the chemical interaction of a metal atom with a metallated porphyrin is rarely investigated. Herein, the breadth of metalation reactions is augmented towards the metal exchange of a metalloporphyrin through the deliberate addition of atomic metal centers. The cation of Fe(ii)-tetraphenylporphyrins can be replaced by Co in a redox transmetalation-like reaction on a Au(111) surface. Likewise, Cu can be replaced by Co. The reverse reaction does not occur, i.e. Fe does not replace Co in the porphyrin. This non-reversible exchange is investigated in detail by X-ray absorption spectroscopy complemented by scanning tunneling microscopy. Density functional theory illuminates possible reaction pathways and leads to the conclusion that the transmetalation proceeds through the adsorption of initially metallic (neutral) Co onto the porphyrin and the expulsion of Fe towards the surface accompanied by Co insertion. Our findings have important implications for the fabrication of porphyrin layers on surfaces when subject to the additional deposition of metals. Mixed-metal porphyrin layers can be fabricated by design in a solvent-free process, but conversely care must be taken that the transmetalation does not proceed as an undesired side reaction. PMID- 30406234 TI - Freezing of micrometer-sized liquid droplets of pure water evaporatively cooled in a vacuum. AB - Freezing processes are reported for pure-water droplets generated in a vacuum in the size range of 49-71 MUm in diameter. The process is characterized for each size by measurement of a freezing curve, where the fraction of frozen droplets is evaluated as a function of time. The 49 MUm droplet was found to freeze at a time between 7.0 and 7.9 ms after being generated at room temperature, where the fraction of frozen droplets increased from 5% to 95%; the freezing time was thus distributed statistically within 1 ms. The freezing time was retarded by about 3 ms as the size increases from 49 to 71 MUm, while the rise time of the freezing curve was almost unchanged. Numerical simulation of a cooling curve, i.e., the temperature of a droplet as a function of time, revealed that the droplets in the present size range are frozen at almost the same temperature between 233 and 236 K. The freezing curves measured in the experiment were well reproduced by numerical simulation based on the simulated cooling curves combined with the temperature dependence of the volume-based homogeneous ice nucleation rates of pure water reported previously. It was also found that a droplet is disintegrated into a few fragments upon freezing, which suggests formation of a frozen shell in the outer region of a droplet. PMID- 30406235 TI - Design of smart targeted and responsive drug delivery systems with enhanced antibacterial properties. AB - The use of antibiotics has been an epoch-making invention in the past few decades for the treatment of infectious diseases. However, the intravenous injection of antibiotics lacking responsiveness and targeting properties has led to low drug utilization and high cytotoxicity. More importantly, it has also caused the development and spread of drug-resistant bacteria due to repeated medication and increased dosage. The differences in the microenvironments of the bacterial infection sites and normal tissues, such as lower pH, high expression of some special enzymes, hydrogen peroxide and released toxins, etc., are usually used for targeted and controlled drug delivery. In addition, bacterial surface charges, antigens and the surface structures of bacterial cell walls are all different from normal tissue cells. Based on the special bacterial infection microenvironments and bacteria surface properties, a series of drug delivery systems has been constructed for highly efficient drug release. This review summarizes the recent progress in targeted and responsive drug delivery systems for enhanced antibacterial properties. PMID- 30406236 TI - Inelastic vibrational dynamics of CS in collision with H2 using a full dimensional potential energy surface. AB - We report a six-dimensional (6D) potential energy surface (PES) for the CS-H2 system computed using high-level electronic structure theory and fitted using a hybrid invariant polynomial method. Full-dimensional quantum close-coupling scattering calculations have been carried out using this potential for rotational and, for the first time, vibrational quenching transitions of CS induced by H2. State-to-state cross sections and rate coefficients for rotational transitions in CS from rotational levels j1 = 0-5 in the ground vibrational state are compared with previous theoretical results obtained using a rigid-rotor approximation. For vibrational quenching, state-to-state and total cross sections and rate coefficients were calculated for the vibrational transitions in CS(v1 = 1,j1) + H2(v2 = 0,j2) -> CS(v1' = 0,j1') + H2(v2' = 0,j2') collisions, for j1 = 0-5. Cross sections for collision energies in the range 1 to 3000 cm-1 and rate coefficients in the temperature range of 5 to 600 K are obtained for both para-H2 (j2 = 0) and ortho-H2 (j2 = 1) collision partners. Application of the computed results in astrophysics is also discussed. PMID- 30406237 TI - Versatile heteroleptic bis-terdentate Cr(iii) chromophores displaying room temperature millisecond excited state lifetimes. AB - Substitution of Ru(ii)-based chromophores with cheaper Cr(iii)-based complexes in optically active metallo-supramolecular architectures is limited by the lack of synthetic strategies leading to heteroleptic Cr(iii)-polypyridyl complexes with long excited-state lifetimes. Herein, we report on a versatile method yielding heteroleptic bis(terdentate) Cr(iii) complexes with room temperature millisecond range excited-state lifetimes, tuneable electronic and photophysical properties and easy anchoring possibilities. PMID- 30406238 TI - A signal amplification strategy and sensing application using single gold nanoelectrodes. AB - In this work, a label-free electrochemical apta-nanosensor was fabricated on a single gold nanodisk electrode (AuNDE) for thrombin sensing with high sensitivity via a novel signal amplification strategy. This recognition platform was fabricated via self-assembly of helper DNA (HP-DNA), thrombin-binding aptamer (TBA) and gold nanoparticle (AuNP)-DNA complexes to form a sandwich structure on the AuNDE surface. A novel signal amplification strategy via designed AuNP-DNA complexes was introduced using Ru(NH3)63+ as the signal reporter based on the electrostatic interaction. In the presence of thrombin, the strong interaction between the TBA and target led to the dissociation of sandwich DNA complexes from the AuNDE, which resulted in the reduction current of Ru(NH3)63+. This proposed sensing platform showed a wide detection range of 0.1 pM-5 nM and a low detection limit of 0.02 pM. Considering the small overall dimensions and high sensitivity, this nanosensor can be potentially applied for bioanalysis in living biosystems. PMID- 30406239 TI - The interplay between single particle anisotropy and interparticle interactions in ensembles of magnetic nanoparticles. AB - This paper aims to analyze the competition of single particle anisotropy and interparticle interactions in nanoparticle ensembles using a random anisotropy model. The model is first applied to ideal systems of non-interacting and strongly dipolar interacting ensembles of maghemite nanoparticles. The investigation is then extended to more complex systems of pure cobalt ferrite CoFe2O4 (CFO) and mixed cobalt-nickel ferrite (Co,Ni)Fe2O4 (CNFO) nanoparticles. Both samples were synthetized by the polyol process and exhibit the same particle size (DTEM ~ 5 nm), but with different interparticle interaction strengths and single particle anisotropy. The implementation of the random anisotropy model allows investigation of the influence of single particle anisotropy and interparticle interactions, and sheds light on their complex interplay as well as on their individual contribution. This analysis is of fundamental importance in order to understand the physics of these systems and to develop technological applications based on concentrated magnetic nanoparticles, where single and collective behaviors coexist. PMID- 30406240 TI - A novel sponge-like 2D Ni/derivative heterostructure to strengthen microwave absorption performance. AB - One of the major hurdles of Ni-based microwave absorbing materials is the preparation of two-dimensional (2D) Ni flakes that can improve magnetic anisotropy to tune complex permeability. In this study, we successfully synthesized porous 2D sponge-like Ni/derivative heterostructures composed of Ni, NiO and Ni(OH)2 through a controllable hydrogen reduction method. Thanks to the larger grain size of the Ni/derivative heterostructure prepared at 600 degrees C (Ni-600) under hydrogen flow, good magnetic properties and high magnetic loss could be obtained, which is beneficial for the enhancement of microwave absorption properties. For the Ni-600 samples, the minimal reflection loss (RL) is -37.3 dB at 7.1 GHz and the effective bandwidth (RL < -10 dB, 90% microwave dissipation) could be tuned in the range of 4.5-18.0 GHz with the thickness of 1.5-4.5 mm. High attenuation ability, including dielectric loss and magnetic loss, and good impedance matching are the requirements for excellent microwave absorption properties. In addition, the porous 2D heterostructure flake structure also significantly contributes to microwave absorption. Multiple reflections and scattering caused by the porous flakes, interfacial polarizations in the heterostructures, tunable impedance matching in the porous structure, strong natural resonance induced by the 2D flakes and plentiful micro-capacitors in the separate flakes account for the enhanced microwave absorption performance. This study demonstrates a fresh exploration of designing novel electromagnetic wave absorbing materials. PMID- 30406242 TI - Delithiation/lithiation behaviors of three polymorphs of LiVOPO4. AB - LiVOPO4 is an attractive high-voltage cathode with rich polymorphs (alpha, beta and alphaI). We present here a comparison of the behaviors of three LiVOPO4 polymorphs during delithiation/lithiation. Experimental and computational work suggests that alpha-LiVOPO4 suffers from more severe conductivity problems among the three forms. For the first time, our preliminary studies on lithiated beta Li2VOPO4 demonstrate that the orthorhombic structure of beta-LiVOPO4 could be retained after lithiation, which is consistent with the finding for the other two forms. PMID- 30406243 TI - Correction: Tunable hydrodynamics: a field-frequency phase diagram of a non equilibrium order-to-disorder transition. AB - Correction for 'Tunable hydrodynamics: a field-frequency phase diagram of a non equilibrium order-to-disorder transition' by Somayeh Khajehpour Tadavani et al., Soft Matter, 2017, 13, 7412-7424. PMID- 30406244 TI - Enhanced parylene-C fluorescence as a visual marker for neuronal electrophysiology applications. AB - Parylene-C is a popular polymer material in biomedical applications, with excellent physicochemical properties and microfabrication capability. Like many aromatic polymers, parylene-C also has autofluorescence, which was usually taken as a negative background noise in biomedical detection studies. However, the fluorescence intensity of thin-film (<1 MUm) parylene-C was relatively weak, which may be a big limitation in visualization. In this work, we reported a simple annealing method to significantly enhance the fluorescence and achieve sufficient intensity as a visual marker. We studied the behaviors and mechanisms of the enhanced parylene-C fluorescence, then verified the feasibility and reliability of parylene-C for preparing fluorescent pipettes in targeted neuronal electrophysiology, where fluorescent guidance was strongly needed. The powerful parylene-C fabrication technique enables a precisely-controlled conformal coating along with a mass production capability, which further resulted in high-quality electrophysiological recordings of both cultured hippocampal neurons and acute hippocampal brain slices. Moreover, the enhanced parylene-C fluorescence can also be applied in more general biological operations, such as designable fluorescent micro-patterns for visualization in broader biomedical fields. PMID- 30406245 TI - Reversible pH switchable oxidase-like activities of MnO2 nanosheets for a visual molecular majority logic gate. AB - Although the enzyme-like activities of MnO2 nanosheets have been investigated, effective strategies for modulating their activities are still lacking. Herein, inspired by the pH-dependent activity of natural enzymes, we demonstrate that the oxidase-like activities of the MnO2 nanosheets are pH switchable and reversible. The MnO2 nanosheets show oxidase-like activities in an acidic medium, which can catalyze the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) to form blue oxidized TMB (oxTMB), while the corresponding activities are greatly weakened under alkaline conditions. The reaction mechanism is attributed to the fact that the MnO2 nanosheets can be transformed into hexagonal Na4MnO4 with a low reaction activity in an alkaline environment. Using the pH switchable oxidase-like activities of the MnO2 nanosheets and other reaction processes, we construct a visual three-input molecular majority logic gate with a single-vote veto function. In addition, an OR-INH cascade logic circuit is successfully realized as well. PMID- 30406246 TI - Superwettable nanodendritic gold substrates for direct miRNA SERS detection. AB - By combining a superwettable interface with a nanodendritic gold structure, we have fabricated a superwettable nanodendritic gold substrate for direct SERS detection of multiple concentrations of miRNAs. The nanodendritic gold substrate provides numerous hotspots for Raman signal enhancement, and the superwettable interface ensures the immobilization of droplets in superhydrophilic microwells, which hold great potentials for applications in disease diagnostics. PMID- 30406247 TI - Interpreting the Raman OH/OD stretch band of ice from isotopic substitution and phase transition effects. AB - Understanding the OD/OH stretch band (ODSB/OHSB) features for the Raman spectra of ice remains a challenge. This study measures the ODSB/OHSB for isotopically substituted D2O/H2O (with volume ratio VD2O/VH2O of 1/0, 4/1, 1/1, 1/4 and 0/1) ice Ih, and compares them with those for liquid water and ices in various phases. The data show that istopic substitution (IS) narrows the ODSB/OHSB of ice from both the low-frequency and the high-frequency side to the middle of the OD/OH stretch regions, but in contrast, IS enhances the high-frequency part of the ODSB/OHSB for liquid water. The ODSB/OHSB features of ice and their dependences on IS and phase transition can be understood basically from the concept that ice has diverse HB configurations that depend on the ice lattice form and the proton (dis)order and essentially determine the intermolecular vibrational couplings in ice. Combined with a Gaussian fitting analysis, more details for the HB configurations in ice are revealed: tetrahedral HB profiles, which are responsible for the main peak, are dominant and non-tetrahedral ones, which bring about the high-frequency shoulders, are also important. On IS, the proportion of tetrahedral HB profiles sees a dramatic decrease. PMID- 30406248 TI - Synthesis of chiral seven-membered beta-substituted lactams via Rh-catalyzed asymmetric hydrogenation. AB - Rh/bisphosphine-thiourea ligand (ZhaoPhos)-catalyzed asymmetric hydrogenation of seven-membered beta-substituted alpha,beta-unsaturated lactams was successfully developed to prepare various chiral seven-membered beta-substituted lactams with good to excellent results (up to >99% conversion, 99% yield, and >99% ee). PMID- 30406249 TI - Atmospheric chemistry of iodine anions: elementary reactions of I-, IO-, and IO2- with ozone studied in the gas-phase at 300 K using an ion trap. AB - Using a radio-frequency ion trap to study ion-molecule reactions under isolated conditions, we report a direct experimental determination of reaction rate constants for the sequential oxidation of iodine anions by ozone at room temperature (300 K). The results are R1: I- + O3 -> IO- + O2, k1 = (7 +/- 2) * 10 12 cm3 s-1; R2: IO- + O3 -> IO2- + O2, k2 = (10 +/- 2) * 10-9 cm3 s-1; R3: IO2- + O3 -> IO3- + O2, k3 = (16 +/- 2) * 10-9 cm3 s-1. More oxidized forms such as IO4- and IO5- were not observed. Additionally, we performed quantum chemical calculations to elucidate the energetics of these oxidation reactions. PMID- 30406250 TI - The development of a new approach toward lanthanide-based OLED fabrication: new host materials for Tb-based emitters. AB - To develop the recently proposed approach toward host selection for lanthanide based emitters, four phosphine oxides PO = PO1-PO4 were investigated which are able to both increase the electron mobility and to sensitize terbium luminescence. New highly soluble and brightly luminescent terbium complexes TbCl3(PO).H2O and Tb(pobz)3(PO).(CH3)2CO (pobz- = phenoxybenzoate) with a quantum yield of up to 100% were synthesized and thoroughly characterized. To study the electroluminescence properties of these materials, a series of solution-processed OLED devices were fabricated and their heterostructures were selected based on the HOMO and LUMO energies of PO1-PO4, which were carefully assessed by the combination of DFT and TDDFT methods. Thus, the effectiveness of the proposed approach was proved, and the influence of the anionic ligand was shown. The maximum OLED luminance reached 75 Cd m-2, which is a high value for solution processed OLEDs based on terbium complexes. PMID- 30406251 TI - Ambient condition retention of band-gap tuning in MAPbI3 induced by high pressure quenching. AB - In the present work, we show a successful approach to achieve stable structural and optical changes induced by pressure on bulk amounts of MAPI after pressure release. Such effects on the optical properties resemble those achieved in situ (e.g., in diamond anvil cells) but are retained and stabilized under ambient conditions thanks to a partial quenching of the high-pressure state. PMID- 30406252 TI - The HKrCCHCO2 complex: an ab initio and matrix-isolation study. AB - We report an experimental and theoretical study on new noble-gas hydride complex HKrCCHCO2, which is the first known complex of a krypton hydride with carbon dioxide. This species was prepared by the annealing-induced H + Kr + CCHCO2 reaction in a krypton matrix, the CCHCO2 complexes being produced by UV photolysis of propiolic acid (HCCCOOH). The H-Kr stretching mode of the HKrCCHCO2 complex at 1316 cm-1 is blue-shifted by 74 cm-1 from the most intense H-Kr stretching band of HKrCCH monomer. The observed blue shift indicates the stabilization of the H-Kr bond upon complexation, which is characteristic of complexes of noble-gas hydrides. This spectral shift is slightly larger than that of the HKrCCHC2H2 complex (+60 cm-1) and significantly larger than that of the HXeCCHCO2 complex (+32 and +6 cm-1). On the basis of comparison with ab initio computations at the MP2 and CCSD(T) levels of theory, the experimentally observed absorption is assigned to the quasi-parallel configuration of the HKrCCHCO2 complex. The calculated complexation-induced spectral shift of the H-Kr stretching band (60.4 or 72.7 cm-1 from the harmonic calculations at the MP2 and CCSD(T) levels, respectively) agrees well with the experimental value. PMID- 30406253 TI - Investigations into the DNA-binding mode of doxorubicinone. AB - Cancer treatment is one of the major challenges facing the modern biomedical profession. Development of new small-molecule chemotherapeutics requires an understanding of the mechanism of action for these treatments, as well as the structure-activity relationship. Study of the well-known DNA-intercalating agent, doxorubicin, and its aglycone, doxorubicinone, was undertaken using a variety of spectroscopic and calorimetric techniques. It was found that, despite conservation of the planar, aromatic portion of doxorubicin, the agylcone does not intercalate; it instead likely binds to the DNA minor-groove. PMID- 30406254 TI - Atomistic insights into the adsorption and stimuli-responsive behavior of poly(N isopropylacrylamide)-graphene hybrid systems. AB - Non-covalent functionalization of graphene materials with responsive polymers is a promising approach for synthesizing new, hybrid composites with improved dispersibility and functional properties. However, the interplay between various components of the hybrid systems, their structural configurations, and stimuli responsive behavior are not yet well understood at the atomic level. Here, we investigate the temperature-responsive behavior of physisorbed poly(N isopropylacrylamide) (PNIPAM) on to graphene (G) and graphene oxide (GO) sheets in aqueous solution using large scale molecular dynamics simulations. It was observed that PNIPAM can be spontaneously anchored to the surfaces of both G and GO at 290 K with a macromolecular coil shape. However, the configuration of PNIPAM on G is markedly different in comparison with that on GO, leading to its distinct thermoresponsive behavior. Specifically, the adsorption on G gives rise to an increase in the temperature of the coil-to-globule transition when compared to the native polymer, the origin of which can be interpreted in terms of the interactions and the solvation behavior. The results obtained here are of significance to the design and manipulation of graphene-based stimuli-responsive hybrid systems with optimal functional properties. PMID- 30406255 TI - Improving health systems through innovation in population health and health services research. PMID- 30406256 TI - How to improve success of technology projects in health and social care. AB - Technologies are often viewed as the route to better, safer and more efficient care, but technology projects rarely deliver all the anticipated benefits. This is usually because they are too complex - and because the complexity is suboptimally handled. This article summarises a new framework to improve the success of technology projects: the nonadoption, abandonment, scale-up, spread and sustainability (NASSS) framework. The framework is based on a narrative systematic review and empirical work, and addresses the different domains in technology projects and how different aspects of complexity may be handled in each of them. PMID- 30406257 TI - Increasing the use of research in population health policies and programs: a rapid review. AB - BACKGROUND AND OBJECTIVES: Although the body of literature on factors that impede and enhance the use of research in policy making continues to expand, there is limited evidence about strategies that are effective at fostering the use of research in population health policy and programs. Building on previous reviews, we reviewed the published literature to identify and assess papers describing intervention studies that had outcome measures relating to research use. STUDY TYPE: Rapid review. METHODS: We searched four academic databases and Google Scholar to identify papers published between 2009 and 2015. Our focus was on strategies relevant to population health policy and program delivery. For studies that tested strategies to increase the use of research, we extracted details about the intervention, participants, study sites and methods, and primary and other outcomes. RESULTS: We identified 14 articles reporting on 13 intervention studies. The studies were relatively weak methodologically and together provide few indications of effect. Only one study used an experimental design and one other used pre-/post-test design; the remaining studies were characterised by an absence of control groups, small sample sizes, and self-report data. Of the 13 studies: four intervention studies were related to the theme 'relevant, useful, accessible research'; five studies (described in six papers) tested strategies that facilitated interaction between researchers and research users; three studies assessed strategies aimed at enhancing the capacity of organisations to use research; and one intervention study was related to the theme 'funding research infrastructure and research projects'. CONCLUSION: The level of evidence for the effectiveness of strategies to improve the use of research in policy making is low, and there remains a need for well-designed empirical studies that evaluate interventions. In the absence of strong evidence, efforts to enhance research use should be tailored to organisational needs and may incorporate capability development, improved access to targeted research summaries and syntheses, and greater interaction and collaboration with researchers. PMID- 30406258 TI - What do we know about alcohol mixed with energy drink (AmED) use in Australia? Expanding local evidence. AB - OBJECTIVES: Despite continued health concerns associated with the practice of consuming alcohol mixed with energy drinks (AmED), few Australian studies have examined the popularity of this combination or attempted to characterise AmED consumers. The purpose of this paper is to replicate two previously used survey approaches to consolidate a national picture of AmED consumption in Australia. METHODS: The survey approaches used were: an online survey with a convenience sample of New South Wales (NSW), Australia, residents (n = 1931; 63.7% female; median age 23.0 years); and street intercept surveys in regional and metropolitan entertainment precincts in NSW (n = 1265; 58.2% male; median age 21.0 years). Analyses explored the rates and frequency of AmED use across both samples, and the sociodemographic and substance use predictors of AmED consumption in the past 12 months. RESULTS: More than 90% of participants in both samples reported alcohol consumption in the past 12 months, with approximately 40% of current drinkers also reporting AmED use in the past 12 months. Three-quarters of participants interviewed in entertainment precincts reported alcohol consumption in the previous 12 hours, with one in six of these also reporting AmED consumption in the past 12 hours. AmED users across both samples were more likely than alcohol-only consumers to be younger and male, and to report riskier substance use practices. CONCLUSIONS: Health promotion activities are warranted to promote awareness of energy drink guidelines, and the potential harms of exceeding these guidelines, among alcohol consumers. In addition, health workers should consider enquiring about AmED use as an indicator of risk related to substance use. PMID- 30406259 TI - Design and delivery of an innovative speech pathology service-learning program for primary school children in Far West NSW, Australia. AB - BACKGROUND: Children growing up in Australian rural communities have more communication impairments than their urban counterparts. Communication impairments, if left unresolved in school starters, lead to long-term learning and behavioural problems. Rural communities are disadvantaged by a scarcity of health professionals. METHODS: Supervised speech pathology students on rural clinical placement provided speech, language and communication screening, assessment and therapy to children starting kindergarten in Broken Hill, New South Wales, Australia. The students collected service outcome data for children in the program. RESULTS: Analysis of the outcome data demonstrated improvements in communication impairments for approximately one-quarter of the children. CONCLUSION: The service-learning program used in this study is designed to facilitate implementation in other locations. The model resulted in some improvement in communication impairments. It has the potential to revolutionise undergraduate student learning placements, as well as address the chronic health professional shortage in rural Australia. PMID- 30406260 TI - Translational Research Grants Scheme (TRGS): a new approach to strengthening health system research capacity. AB - BACKGROUND: Bridging the 'gap' between research evidence and the complexities of policy and practice is central to health improvement. The Translational Research Grants Scheme (TRGS) in New South Wales (NSW), Australia, is a funding scheme aimed at reducing the time between research generation and translation to policy and practice. The TRGS is also an important part of NSW Health's efforts to harness and strengthen research capacity to improve health service delivery. METHODS: A document review and interviews (n = 12) with key stakeholders were undertaken following the first round of TRGS funding in November 2016. The communications from continuing quality improvement processes over the three funding rounds have provided further insight. RESULTS AND DISCUSSION: A total of 53 projects have been funded under the scheme, with recipients across many NSW Health organisations. NSW Health has committed more than $24 million to date. Round one of the TRGS was received well by the policy makers, Local Health Districts and research stakeholders interviewed. Of particular note were: the requirement for Chief Executives to demonstrate strong support for the implementation of findings; requirements to partner with state-wide policy leads and clinical networks; and capacity-building outcomes of the scheme. The ongoing quality improvement processes indicate that the program continues to be well received, with improvements to partnership arrangements, and an acknowledgement of the challenge that arises because the scheme, by nature of its capacity building aim, attracts proposals from a range of research experience. LESSONS LEARNT: The TRGS is filling an important gap in the research funding landscape in NSW and is well regarded by stakeholders. To ensure that the TRGS is achieving its intended aims, an evaluation of the impact of the scheme will take place during 2018-19. PMID- 30406261 TI - Codesign of the Population Health Information Management System to measure reach and practice change of childhood obesity programs. AB - INTRODUCTION: Childhood obesity prevalence is an issue of international public health concern and governments have a significant role to play in its reduction. The Healthy Children Initiative (HCI) has been delivered in New South Wales (NSW), Australia, since 2011 to support implementation of childhood obesity prevention programs at scale. Consequently, a system to support local implementation and data collection, analysis and reporting at local and state levels was necessary. The Population Health Information Management System (PHIMS) was developed to meet this need. Design and development: A collaborative and iterative process was applied to the design and development of the system. The process comprised identifying technical requirements, building system infrastructure, delivering training, deploying the system and implementing quality measures. Use of PHIMS: Implementation of PHIMS resulted in rapid data retrieval and reporting against agreed performance measures for the HCI. The system has 150 users who account for the monitoring and reporting of more than 6000 HCI intervention sites (early childhood services and primary schools). LESSONS LEARNT: Developing and implementing PHIMS presented a number of complexities including: applying an information technology (IT) development methodology to a traditional health promotion setting; data access and confidentiality issues; and managing system development and deployment to intended timelines and budget. PHIMS was successfully codesigned as a flexible, scalable and sustainable IT solution that supports state-wide HCI program implementation, monitoring and reporting. PMID- 30406262 TI - Partnering to prevent chronic disease: reflections and achievements from The Australian Prevention Partnership Centre. AB - OBJECTIVES: To accelerate the use of evidence in policy and practice through cross-sectoral, multidisciplinary partnership research, founded on shared governance and coproduction. Type of program or service: A National Health and Medical Research Council (NHMRC) Partnership Centre for Better Health. METHODS: We present our views and experiences based on the first 5 years of operation of The Australian Prevention Partnership Centre. RESULTS: We have undertaken an ambitious and complex 5-year program of work taking a systems approach to prevention research, and have grown the size and reach of the collaboration to become a focus for prevention research in Australia. We have progressed towards reaching our objectives. However, there have been challenges including trust building between stakeholders, the complexities of incorporating coproduction into every research project, and the production of research that is implementable within different policy environments. LESSONS LEARNT: Working within the partnership model has provided the time, resources and flexibility to coproduce policy-relevant, timely research. PMID- 30406263 TI - A priority-driven, policy-relevant research program to support a response to blood-borne viruses and sexually transmissible infections in NSW, Australia. AB - OBJECTIVES: Strong collaboration between researchers, policy makers and practitioners supports the use of research evidence in policy and practice. Strategies for increasing the use of evidence in policy development and implementation include creating more opportunities for closer collaboration between researchers and policy makers, ensuring research syntheses are more accessible to policy makers, and increasing workforce capacity to utilise evidence. Type of program or service: The BBV & STI Research, Intervention and Strategic Evaluation Program, 2014-2019 (BRISE) is a coherent and integrated program that delivers policy-relevant research, strategic advice, capacity building and communications to support the response to blood-borne viruses (BBV) and sexually transmissible infections (STI) in New South Wales (NSW), Australia. BRISE has five key objectives: generate high-quality research; maximise the use of research; build research capacity; communication and marketing; and governance and management. RESULTS: BRISE facilitates the coproduction of research where researchers and policy makers are meaningfully involved in all stages of research priority setting and codesign from development to application, building an understanding of the way evidence is generated to allow for greater integration between research and use of evidence. LESSONS LEARNT: Bringing multiple research projects together under a single contract and budget provided the NSW Ministry of Health (the Ministry) with cost efficiencies and streamlined contract management and project reporting. A flexible work plan allowed for a mix of longer-term (up to 5-year) projects and shorter projects that were responsive to emerging policy relevant research priorities. The Ministry became involved in the production of collaborative research as a research partner, rather than solely a research 'funder'. The joint management of research projects involving a policy officer from the Ministry provided opportunities for individuals to build on their research capabilities and literacy. Collaborative priority setting and project work, and increased research literacy, improved the likelihood that research generated would then be used in policy and practice. PMID- 30406264 TI - The Prevention Research Support Program: supporting innovation in research, translation and capability building. AB - OBJECTIVES: The Prevention Research Support Program (PRSP) is a New South Wales (NSW) Ministry of Health funding scheme. The scheme aims to build capability, and strengthen prevention and early intervention research that is important to the NSW public health system (NSW Health) and that leads to improved health and reduced health inequities for the people of NSW. This paper describes how PRSP funding has supported recipients to produce high-quality, policy-relevant research, and increase the impact of research on policy and practice. Type of program: The PRSP is a competitive funding program that supports NSW research organisations that conduct prevention and early intervention research that aligns with NSW Health priorities. The objectives of the PRSP are to: increase high quality and internationally recognised prevention research in NSW; support the generation of research evidence that addresses NSW Health prevention priorities, including cross-government priorities; encourage the adoption of research evidence in relevant policies, programs and services in NSW; and build the prevention research capability of NSW Health staff and the NSW Health system. METHODS: Funding recipients provide information about their research, translation and capability building achievements in their funding applications and submit annual progress reports. Data from these sources were aggregated to illustrate trends in indicators of research excellence over time. Prior to the most recent call for applications, the program was reviewed. The review included consultations with funding recipients, policy and practice partners, and key funding stakeholders. Stakeholders' perceptions of the benefits and challenges associated with the PRSP were drawn from the consultation data. RESULTS: PRSP funding recipients demonstrate considerable increases over time on several indicators of research excellence, including peer-reviewed journal publications, grant income, and research students supervised. Recipients use a range of strategies to ensure dialogue with health system partners, and report research impacts at the local, state, national and international levels. PRSP funding also supports the development of research capability. LESSONS LEARNT: The PRSP is a unique scheme that is highly valued by both funding recipients and health system stakeholders. The continuity of funding provided under the scheme enables recipients to adopt a strategic approach to their research and develop innovative strategies to support its conduct and use. PMID- 30406265 TI - Utility of the World Health Organization Disability Asessment Schedule and the World Health Organization minimal generic set of domains of functioning and health in spinal cord injury. AB - OBJECTIVE: To compare easy-to-use International Classification of Functioning, Disability and Health (ICF)-based measures of functioning with the level and severity of spinal cord injury. METHODS: Cross-sectional study. Patients (n = 142) and their significant others completed the 12-item World Health Organization Disability Assessment Schedule (WHODAS 2.0) questionnaire. A physician at the university hospital outpatient clinic assessed functioning with the 7-item World Health Organization (WHO) minimal generic set. RESULTS: The patient and proxy WHODAS sum score was rated severe with decreasing severity in groups with complete and partial tetraplegia and paraplegia, respectively. Working ability was rated most severely impaired in the tetraplegic groups. Between-group differences were also found in mobility, household tasks, and self-care. Mobility was found to be associated with lesion severity; life activities, participation and friendships with lesion level; and self-care and WHODAS sum score with both lesion severity and level. Depending on the level and severity of spinal cord injury, a moderate to strong correlation was found between the sum scores of the 2 tools, and mostly very strong correlations between patient and proxy assessments of functioning. CONCLUSION: Both generic ICF-based tools, despite their briefness, seemed to be useful as they were able to differentiate various levels and severities of spinal cord injury. We recommend using the 12-item WHODAS 2.0 when planning individualized services for patients with spinal cord injury. PMID- 30406266 TI - Usefulness of an unstable board balance test to accurately identify community dwelling elderly individuals with a history of falls. AB - OBJECTIVE: To determine the usefulness of an un-stable board balance test in identifying a fall history among high-functioning community-dwelling elderly individuals. DESIGN: Case-control study. SUBJECTS: Sixty-one community-dwelling elderly aged >= 65 years and having the capacity to walk independently without an assistive device. METHODS: Subjects completed 3 balance performance tests: the Unstable Board Balance Test, Functional Reach Test, and Timed Up and Go. For analysis, subjects were classified as fallers or non-fallers based on the history of falls over the previous year, and performance outcomes were compared between the 2 groups. Subjects classified as fallers were then matched 1:1 with non fallers (for sex, age, body weight and height), and the optimal cut-off score and area under the receiver operating characteristic curve (AUC) for each test were calculated. RESULTS: Functional reach test and Timed Up and Go did not reliably discriminate between fallers and non-fallers. In contrast, the score on the unstable board balance test was significantly different between the 2 groups (p = 0.040). Among all 3 tests, AUC was largest for the unstable board balance test (0.78), with superior sensitivity (0.67) and specificity (0.87). CONCLUSION: For high-functioning elderly subjects, the unstable board balance test was useful in discriminating between fallers and non-fallers. PMID- 30406267 TI - Impact of unilateral spatial neglect with or without other cognitive impairments on independent gait recovery in stroke survivors. AB - OBJECTIVE: To investigate the impact of unilateral spatial neglect with or without other cognitive impairments on recovery of independent gait in stroke survivors. DESIGN: A prospective cohort study. SUBJECTS: Ninety-four stroke survivors in an inpatient rehabilitation ward. METHODS: The presence of unilateral spatial neglect was assessed by the visuospatial perception score of the Stroke Impairment Assessment Set, and other cognitive impairments were assessed by Mini-Mental State Examination. Participants were categorized into 3 groups: group 1, unilateral spatial neglect with other cognitive impairments; group 2, unilateral spatial neglect without other cognitive impairments; and group 3, non-unilateral spatial neglect. The outcome was the walking score of the Functional Independence Measure (FIM) at discharge (score >= 6 or <= 5). RESULTS: Multivariate logistic regression analysis (reference, group 3) showed that the presence of unilateral spatial neglect with other cognitive impairments (group 1) had a significant association with dependence of gait (p = 0.003), and the odds ratio (95% confidence interval) was 5.55 (1.19-23.04). In contrast, there was no significant relationship between the presence of unilateral spatial neglect without other cognitive impairments (group 2) and dependence of gait (p = 0.207). CONCLUSION: The presence of unilateral spatial neglect without other cognitive impairments is not a significant factor for regaining independent gait. In contrast, unilateral spatial neglect becomes a strong negative factor when combined with other cognitive impairments. PMID- 30406268 TI - Therapeutic and economic effects of multimodal back exercise: A controlled multicentre study. AB - To compare the cost-effectiveness of a multimodal back exercise programme for non specific back pain with that of standard treatment. Medical costs were measured in euros (EUR) and effectiveness was measured using Graded Chronic Pain Status (GCPS). A controlled multicentre study (39 sites) with a 6-month intervention phase and follow-up at 6, 12 and 18 months. The study included 1,829 participants in an intervention group and 495 individuals in a control group. The multimodal back exercise programme comprises 36 exercise sessions for optimizing the spine stabilizing muscles and everyday motor func-tions. The patients were given a home training programme at the end of the intervention programme. The back exercise programme resulted in a significant reduction, of 0.4, in back pain grade on the GCPS after 2 years, compared with standard treat-ment, and reduced medical costs by 763 EUR. The exercise programme was therapeutically effective for GCPS back pain grades 1-4 and produced cost savings in the case of grade 4 GCPS. The multimodal back exercise programme was therapeutically effective for back pain (grades 1-2) and pain-related functional impairment (grades 3-4). It resulted in reduced costs for chronic back pain causing high pain-induced functional impairment (grade 4). The therapeutic and economic effects of the programme increase with the grade of back pain. PMID- 30406269 TI - [Functional rehabilitation of severe laryngopharyngeal injuries after near-lethal suicide attempt by hanging]. AB - BACKGROUND: Hanging is a common method of suicide with an estimated mortality rate of about 70%. Survival of patients with severe laryngopharyngeal injuries after strangulation is not common. However, clinical findings of patients reaching the hospital alive may be minimal. A rapid onset of multidisciplinary diagnostic and therapeutic management is mandatory, followed by psychiatric treatment and functional rehabilitation. CASE PRESENTATION AND RESULTS: Two uncommon cases after severe laryngopharyngeal injury due to near-lethal suicide attempt by hanging demonstrate the emergency management and reconstructive surgery. Subsequent tracheal cannula management and swallowing therapy to full recovery are described. In addition, a proposal for an interdisciplinary treatment algorithm for those patients is presented. CONCLUSION: Minimal external clinical findings after near-lethal suicide attempts by hanging do not exclude severe internal injuries of the upper aerodigestive tract structures. After reconstructive surgery an appropriate tracheal cannula management and an early and intensive swallowing therapy parallel to the psychiatric treatment is mandatory to restore voice, airway and deglutition. PMID- 30406270 TI - [Anteromedial maxillectomy for improvement of nasal breathing : Advanced procedure in surgery of the lateral nasal wall]. AB - The aim of classical surgical correction for nasal breathing impairment is to harmonically extend the physiological space in the nose by an operation of the nasal septum and inferior nasal turbinate. In this way the airflow character should be maintained and the mucosa protected in order not to endanger the respiratory function of the nose. This article presents an operative approach developed stepwise a few years ago in which the different operative steps are carried out depending on the individual anatomical situation and the underlying mucosal disease. The focus is on partial anteromedial maxillectomy. PMID- 30406271 TI - "Pseudo" T1-weighted appearance of the brain on FLAIR: unmasking the extent of gray matter involvement on susceptibility-weighted imaging in chronic toluene abuse. PMID- 30406272 TI - Black bone MRI with 3D reconstruction for the detection of skull fractures in children with suspected abusive head trauma. AB - PURPOSE: The purpose of this study was to determine the accuracy of "black bone" (BB) MRI for the detection of skull fractures in children with potential abusive head trauma. METHODS: A total of 34 pediatric patients were evaluated for potential abusive head trauma. All patients had both a non-contrast head CT (HCT) with multiplanar reformatted images and 3D volumetric reformatted images where available (gold standard) for fracture diagnosis and BB of the head with multiplanar reformatted images and 3D volumetric images. BB was performed using an ultrashort TE pointwise encoding time reduction with radial acquisition (PETRA) sequence at 1.5 T or 3 T. BB datasets were post-processed and 3D images created using Fovia's High Definition Volume Rendering(r) software. Two board certified pediatric neuroradiologists independently reviewed the HCT and BB imaging, blinded to the findings from the other modality. RESULTS: Median patient age was 4 months (range 1.2-30 months). A total of 20 skull fractures in six patients (18% incidence of skull fractures) were detected on HCT. BB demonstrated 83% sensitivity (95%[CI] 36-99%), 100% specificity (95%[CI] 88-100%), 100% PPV (95%[CI] 46-100%), 97% NPV (95%[CI] 82-99%), and 97% accuracy (95%[CI] 85-99%) for diagnosis of a skull fracture. BB detected 95% (19/20) of the skull fractures detected by CT. CONCLUSION: A black bone MRI sequence may provide high sensitivity and specificity for detection of skull fractures in pediatric patients with abusive head trauma. PMID- 30406273 TI - Catheter-independent suture probe canaloplasty with suprachoroidal drainage. AB - PURPOSE: To introduce the novel technique of suture probe canaloplasty with suprachoroidal drainage (SCD) as a catheter-independent and cost-saving method to perform non-penetrating glaucoma surgery. METHODS: Prospective interventional study with a 12-month follow-up. A standard 6/0 polypropylene suture is twisted in a special manner to create a double helix with a small loop at its end. Then canaloplasty with SCD is performed, but instead of using the standard canaloplasty catheter, Schlemm's canal is probed with the twisted suture. After 360 degrees probing, a 10/0 polypropylene suture is thread through the loop and the twisted 6/0 suture is pulled backwards through Schlemm's canal. The 10/0 suture in Schlemm's canal is tied firmly and hyaluronic acid is injected into the suprachoroidal space. RESULTS: In total, 74 eyes that underwent suture probe canaloplasty with SCD were included. In 57 cases, probing of Schlemm's canal with the twisted 6/0 suture succeeded. Seventeen eyes had adhesions in Schlemm's canal which made probing with the suture impossible so that the surgeon switched in 12 cases to microcatheter-guided canaloplasty with SCD. While this was successful in five further cases, the adhesions seemed surely not be overcome and SCD with collagen sheet implantation was directly performed. In four additional cases after successful probing, the suture cut through trabecular meshwork; hence a 360 degrees suture trabeculotomy was performed. After successful suture probe canaloplasty with SCD, intraocular pressure (IOP) decreased by 39.2% (from 19.8 +/- 4.3 mmHg with 3.4 +/- 0.7 different IOP-lowering eye drops to 12.0 +/- 1.9 mmHg with 0.6 +/- 0.9 eye drops). Three patients did not achieve sufficient IOP levels and, therefore, underwent 360 degrees suture trabeculotomy during follow up. No serious or sight-threatening complications occurred. CONCLUSION: Suture probe canaloplasty + SCD yields the opportunity to conduct canaloplasty with SCD more cost-effectively with a safety profile and IOP-lowering effect comparable to conventional canaloplasty. In cases where probing with the suture fails. there still remains the option to use a conventional microcatheter or to switch to SCD with collagen sheet implantation. PMID- 30406274 TI - New clinical ultrahigh-resolution SD-OCT using A-scan matching algorithm. AB - PURPOSE: A new clinical ultrahigh-resolution spectral domain optical coherence tomography (UHR-SD-OCT) system using an original averaging technique named "A scan matching algorithm" was developed. The aim of this study was to determine whether our new UHR-SD-OCT system can obtain clearer sectional images of the retina than conventional standard resolution SD-OCT systems (SR-SD-OCT). METHODS: We recorded horizontal B-scan images of 42 normal eyes using our new UHR-SD-OCT device (Bi-MU, Kowa) and a conventional SR-SD-OCT (Spectralis, Heidelberg). To evaluate the clarity of the interdigitation zone (IZ) subjectively, the integrity of IZ was divided into three types by two raters. To evaluate the clarity of the IZ objectively, a peak height score (PHS) was calculated at five different points of the macula using the longitudinal reflectivity profile. RESULTS: The mean (+/- SD) of the subjective visibility score of the IZ in the UHR-SD-OCT images was 2.64 +/- 0.54 which was significantly higher than the 2.46 +/- 0.46 in the SR-SD OCT images (P = 0.02). The PHS was also significantly higher for the UHR-SD-OCT than for the SR-SD-OCT images at all five locations (all P < 0.01). CONCLUSION: The results indicate that the newly developed clinical UHR-SD-OCT instrument using the A-scan matching algorithm can obtain clearer images of the IZ, and they suggest that this device should be clinically useful in detecting finer structural abnormalities of the outer retina. PMID- 30406275 TI - Propofol-sparing effect of different concentrations of dexmedetomidine : Comparison of gender differences. AB - BACKGROUND: The pharmacodynamics of propofol are closely linked to gender. Dexmedetomidine can decrease propofol needs during propofol anesthesia. The aim of this study was to compare the gender differences on the calculated effect site median effective concentration (EC50) of propofol for loss of consciousness (LOC) after pretreatment with different concentrations of dexmedetomidine. METHODS: In this study 60 male and 60 female patients were randomly allocated to receive dexmedetomidine at target plasma concentrations of 0.0 ng/ml (0.0 group), 0.4 ng/ml (0.4 group), 0.6 ng/ml (0.6 group) and 0.8 ng/ml (0.8 group). Propofol was administered after dexmedetomidine had been intravenously infused for 15 min. The propofol infusion was targeted to provide an initial effect-site concentration of 1.0 MUg/ml, followed by increments by 0.2 MUg/ml when the effect-site concentration and target concentration of propofol were in equilibrium until LOC was established, where LOC was defined by the observer's assessment of alertness/sedation scale (OAA/S) score < 2. RESULTS: The calculated effect-site EC50 of propofol LOC was higher in males than in females in the 0.0, 0.4, 0.6, and 0.8 groups (2.43 vs. 2.17, 1.99 vs. 1.82, 1.72 vs. 1.56 and 1.50 vs. 1.32 MUg/ml, respectively, all p < 0.05). The hypnotic interaction between dexmedetomidine and propofol could be described with an additive model of pharmacodynamic interaction. CONCLUSION: Gender significantly influenced the calculated effect-site EC50 of propofol for LOC after pretreatment with different concentrations of intravenous dexmedetomidine. It was concluded that an additive interaction could describe the results seen. Thus, gender has to be considered when these drugs are co-administered. PMID- 30406276 TI - [Prehospital plasma transfusion in civilian trauma patients in hemorrhagic shock]. PMID- 30406277 TI - Deciphering biased inverse agonism of cangrelor and ticagrelor at P2Y12 receptor. AB - P2Y12 receptor (P2Y12-R) is one of the major targets for drug inhibiting platelet aggregation in the treatment/prevention of arterial thrombosis. However, the clinical use of P2Y12-R antagonists faces some limitations, such as a delayed onset of action (clopidogrel) or adverse effect profile (ticagrelor, cangrelor), justifying the development of a new generation of P2Y12-R antagonists with a better clinical benefit-risk balance. Although the recent concept of biased agonism offers the possibility to alleviate undesirable adverse effects while preserving therapeutic outcomes, it has never been explored at P2Y12-R. For the first time, using highly sensitive BRET2-based probes, we accurately delineated biased ligand efficacy at P2Y12-R in living HEK293T cells on G protein activation and downstream effectors. We demonstrated that P2Y12-R displayed constitutive Gi/o-dependent signaling that is impaired by the R122C mutation, previously associated with a bleeding disorder. More importantly, we reported the biased inverse agonist efficacy of cangrelor and ticagrelor that could underlie their clinical efficacy. Our study points out that constitutive P2Y12-R signaling is a normal feature of the receptor that might be essential for platelets to respond faster to a vessel injury. From a therapeutic standpoint, our data suggest that the beneficial advantages of antiplatelet drugs might be more related to inverse agonism at P2Y12-R than to antagonism of ADP-mediated signaling. In the future, deciphering P2Y12-R constitutive activity should allow the discovery of more selective biased P2Y12-R blockers demonstrating therapeutic advantages over classical antiplatelet drugs by improving therapeutic outcomes and concomitantly relieving undesirable adverse effects. PMID- 30406278 TI - Overexpression of Three Duplicated BnPCS Genes Enhanced Cd Accumulation and Translocation in Arabidopsis thaliana Mutant cad1-3. AB - Phytochelatins are widely known to chelate heavy metal in vacuole and decrease plant damage. Phytochelatin synthase gene (PCS), which is involved in phytochelatins synthesis, is commonly designated as a key gene for phytoremediation. In our study, we cloned three duplicated BnPCS genes from Brassica napus and transformed them into Arabidopsis thaliana AtPCS1 mutant cad1 3, respectively. Three transgene lines and cad1-3 were subjected to a cascade of concentrations of cadmium (Cd) treatment. Evaluation of morphological and physiological measurement results show that transgene lines possess higher Cd tolerance and resistance than A. thaliana mutant cad1-3. The analysis of PCs and Cd contents in root and shoot collectively indicated that transgenic plants promoted Cd accumulation and translocation. In conclusion, all the three BnPCS transgene lines enhanced Cd tolerance, accumulation and translocation, which could provide gene resources for phytoremediation. PMID- 30406279 TI - Association of Serum Sclerostin with Bone Sclerostin in Chronic Kidney Disease is Lost in Glucocorticoid Treated Patients. AB - The osteocytic protein sclerostin inhibits bone turnover. Serum sclerostin rises early in chronic kidney disease (CKD), but if this reflects osteocyte sclerostin production is unclear, since sclerostin is also expressed in extra-skeletal tissue. Glucocorticoid treatment impacts on serum sclerostin, but the effect on the association between serum and bone sclerostin is unknown. We sought to determine whether serum sclerostin reflects bone sclerostin in different CKD stages and how this association is influenced by glucocorticoid treatment. In a cross-sectional analysis, we investigated serum sclerostin, bone sclerostin by immunohistochemistry, and bone histomorphometry in iliac crest bone biopsies from 43 patients with CKD 3-5D, including 14 dialysis patients and 22 transplanted patients (18 kidney, 4 other). Thirty-one patients were on glucocorticoid treatment at time of biopsy. Patients with low bone turnover (bone formation rate < 97 um2/mm2/day; N = 13) had higher median serum sclerostin levels (224.7 vs. 141.7 pg/ml; P = 0.004) and higher bone sclerostin, expressed as sclerostin positive osteocytes per bone area (12.1 vs. 5.0 Scl+ osteocytes/B.Ar; P = 0.008), than patients with non-low bone turnover (N = 28). In linear regression analyses, correcting for age, gender, dialysis status and PTH, serum sclerostin was only associated with bone sclerostin in patients not treated with glucocorticoids (r2 = 0.6, P = 0.018). For the first time, we describe that female CKD patients have higher median bone sclerostin than males (11.7 vs. 5.7 Scl+ osteocytes/B.Ar, P = 0.046), despite similar serum sclerostin levels and bone histo-morphometric parameters. We conclude that glucocorticoid treatment appears to disrupt the association of serum sclerostin with bone sclerostin in CKD. PMID- 30406280 TI - Comparison of elicitor-based effects on metabolic responses of Taxus * media hairy roots in perfluorodecalin-supported two-phase culture system. AB - KEY MESSAGE: Two lines of Taxus * media hairy roots harbouring or not the TXS transgene demonstrated diverse gene expression and taxane yield during cultivation in PFD-supported two liquid-phase culture system. Two lines of Taxus * media hairy roots were subjected to single or twice-repeated supplementation with methyl jasmonate, sodium nitroprusside, L-phenylalanine, and sucrose feeding. One line harboured transgene of taxadiene synthase (ATMA), while the second (KT) did not. Both hairy root lines were cultured in two-phase culture systems containing perfluorodecalin (PFD) in aerated or degassed form. The relationship between TXS (taxadiene synthase), BAPT (baccatin III: 3-amino, 3 phenylpropanoyltransferase), and DBTNBT (3'-N-debenzoyl-2-deoxytaxol-N benzoyltransferase) genes and taxane production was analysed. The ATMA and KT lines differed in their potential for taxane accumulation, secretion, and taxane profile. In ATMA biomass, both paclitaxel and baccatin III were detected, while in KT roots only paclitaxel. The most suitable conditions for taxane production for ATMA roots were found in single-elicited supported with PFD-degassed cultures (2 473.29 +/- 263.85 ug/g DW), whereas in KT roots in single-elicited cultures with PFD-aerated (470.08 +/- 25.15 ug/g DW). The extracellular levels of paclitaxel never exceeded 10% for ATMA roots, while for KT increased up to 76%. The gene expression profile was determined in single-elicited cultures supported with PFD-degassed, where in ATMA roots, the highest taxane yield was obtained, while in KT the lowest one. The gene expression pattern in both investigated root lines differed substantially what resulted in taxane yield characterized particular lines. The highest co-expression of TXS, BAPT and DBTNBT genes noted for ATMA roots harvested 48 h after elicitation corresponded with their higher ability for taxane production in comparison with the effects observed for KT roots. PMID- 30406282 TI - Prognoses after self-harm in youth: exploring the gender factor. AB - PURPOSE: Gender differences in youth self-harm are sparsely studied regarding long-term prognoses. We aimed to study the gender differences in effects of adolescent self-harm in early adult life in four domains: 1/family situation, 2/education and employment, 3/mental illness and suicidal behaviour, and 4/suicide and all-cause mortality. METHOD: A register-based cohort study including all Swedish residents aged 20 during 2001-2005 was performed. Exposure was self-harm at ages 10-20, and outcomes were death and suicide and past-year records of self-harm, marital status/children, education/employment, and mental health at age 30. We used logistic regression for dichotomous outcomes, and Cox regression models for time-dependent outcomes. An interaction term was introduced to detect significant gender effects, in which case we performed stratified analyses. RESULTS: Subjects with self-harm before age 20 had a poorer prognosis for all studied outcomes, and risk estimates were similar for men and women for most outcomes including suicide. Significant interaction terms (ITs) were found, revealing gender differences, for being married (pIT 0.0003; ORmen 0.6, ORwomen 0.9), being a parent (pIT < 0.0001; ORmen 0.7, ORwomen 1.1), receiving unemployment support (pIT < 0.0001; ORmen 2.4, ORwomen 1.8), and death from any cause (pIT 0.006; ORmen 10.6, ORwomen 7.4). CONCLUSIONS: Adolescent self-harm was associated with later life adversities and affected men more than women regarding prognoses for unemployment and certain aspects of the family situation. We found no gender difference for the effect of self-harm on the risk of suicide. Future suicide risk should not be underestimated in young self-harming women. PMID- 30406281 TI - Understanding the Impacts of Surface Compositions on the In-Vitro Dissolution and Aerosolization of Co-Spray-Dried Composite Powder Formulations for Inhalation. AB - PURPOSE: Dissolution behavior of dry powder inhaler (DPI) antibiotic formulations in the airways may affect their efficacy especially for poorly-soluble antibiotics such as azithromycin. The main objective of this study was to understand the effects of surface composition on the dissolution of spray dried azithromycin powders by itself and in combination with colistin. METHODS: Composite formulations of azithromycin (a poorly water-soluble molecule) and colistin (a water-soluble molecule) were produced by spray drying. The resultant formulations were characterized for particle size, morphology, surface composition, solid-state properties, solubility and dissolution. RESULTS: The results demonstrate that surfaces composition has critical impacts on the dissolution of composite formulations. Colistin was shown to increase the solubility of azithromycin. For composite formulations with no surface colistin, azithromycin released at a similar dissolution rate as the spray-dried azithromycin alone. An increase in surface colistin concentration was shown to accelerate the dissolution of azithromycin. The dissolution of colistin from the composite formulations was significantly slower than the spray-dried pure colistin. In addition, FTIR spectrum showed intermolecular interactions between azithromycin and colistin in the composite formulations, which could contribute to the enhanced solubility and dissolution of azithromycin. CONCLUSIONS: Our study provides fundamental understanding of the effects of surface concentration of colistin on azithromycin dissolution of co-spray-dried composite powder formulations. PMID- 30406283 TI - Systemic autoimmune diseases are associated with an increased risk of obsessive compulsive disorder: a nationwide population-based cohort study. AB - PURPOSE: Studies suggested autoimmunity plays a role in the etiology of obsessive compulsive disorder (OCD). The purpose of this study was to determine if a history of systemic autoimmune diseases (SADs) is associated with an increased risk of subsequent onset of OCD. METHODS: Patients with or without SADs were identified in the Taiwan National Health Insurance Program. The SADs cohort consisted of 63,165, while the comparison cohort consisted of 315,825 patients. The incidence rates of OCD with a maximum follow-up period of 10 years between patients with and without SADs were compared using a Cox proportional hazard model to estimate the hazard ratio (HR) and 95% confidence interval (95% CI). RESULTS: The major finding was the discovery of a higher incidence of subsequent OCD among patients with SADs (HR: 1.85; 95% CI 1.41-2.43) after adjusted for other demographic characteristics. Specifically, the risk of OCD was observed to be significant increase in systemic lupus erythematosus (1.65, 1.07-2.54) dermatomyositis (3.25, 1.04-10.17), and Sjogren's syndrome (2.38, 1.53-3.72). Also, this study revealed some potential risk factors for developing OCD, including younger age (less than or equal to 50-year-old) and some comorbidities (alcohol use disorder, liver cirrhosis, and malignancies). Conversely, this study found that steroid use was a potential protective factor for the development of OCD. CONCLUSIONS: This study confirms that SADs are associated with higher incidence of OCD, suggesting that abnormal autoimmune process is associated with increased expression of psychiatric disturbances. PMID- 30406284 TI - Trends in prescriptions for sedative-hypnotics among Korean adults: a nationwide prescription database study for 2011-2015. AB - PURPOSE: This study investigated prescriptions for sedative-hypnotics via data obtained from the Health Insurance Review and Assessment (HIRA) service. METHODS: Data on sedative-hypnotic prescriptions from the HIRA service of the Republic of Korea were analyzed from 2011 to 2015. We included prescriptions for subjects > 18 years of age from hospitals and community healthcare centers. In addition, subgroup analyses with a subsample restricted to prescriptions from patients with diagnostic codes F510 (nonorganic insomnia) or G470 (insomnia) were performed. After analyzing the number of prescriptions by individual pharmacy items, the prescription codes were grouped as: (1) benzodiazepines; (2) non-benzodiazepines, including zolpidem; (3) antidepressants; and (4) antipsychotics. We calculated the monthly percent change in the number of prescriptions by drug group using Joinpoint regression. RESULTS: Among the sedative-hypnotic groups, benzodiazepines were the most commonly prescribed drugs in Korea during the study period. As a single sedative-hypnotic item, zolpidem was the most frequently prescribed medication for patients with insomnia. Prescriptions for all groups of sedative-hypnotics increased significantly during the study period. When stratified by age group, antipsychotic prescriptions increased significantly by 0.19-0.21% per month among men and women aged 50-59 years and > 70 years. Prescriptions for antidepressants in 30-39-year-old men increased significantly by 0.20%. CONCLUSIONS: Benzodiazepine prescriptions as well as those for antipsychotics and antidepressants to treat insomnia increased during 2011-2015 in Korea. Monitoring the use of sedative-hypnotics at the national level is necessary, especially in the elderly population. PMID- 30406285 TI - A dose-escalation study of docetaxel, oxaliplatin, and S-1 (DOS) as a first-line therapy for patients with unresectable metastatic gastric cancer. AB - PURPOSE: The aim of this study was to determine the recommended dose (RD) for a docetaxel/oxaliplatin/S-1 (DOS) regimen in patients with unresectable gastric cancer and to preliminarily evaluate its efficacy. METHODS: Previously untreated patients with histologically proven unresectable metastatic gastric cancer were enrolled (n = 16). Docetaxel and oxaliplatin were administered intravenously on day 8 and S-1 was administered orally twice a day on days 1-14. Each cycle was repeated every 3 weeks. Dose-limiting toxicities (DLTs) were evaluated during the first treatment cycle. Three dose escalations of DOS were employed in this study: level 1 (50/100/80 mg/m2), level 2 (50/130/80 mg/m2), and level 3 (60/130/80 mg/m2). RESULTS: According to the 3 + 3 dose-escalating schedule, we determined that the RD and maximum tolerated dose for this regimen were level 1 and level 2, respectively. The DLTs were grade 3 diarrhea and febrile neutropenia. The overall response rate was 78% (7/9) for patients with measurable lesions and consisted of two complete responses and five partial responses. Five patients underwent conversion surgery. The median follow-up time was 19 months with median survival time and progression-free survival being 19.6 months and 7.6 months, respectively. CONCLUSIONS: The results from this study demonstrated the safety and tolerability of DOS in unresectable metastatic gastric cancer patients and revealed promising preliminary efficacy with a high conversion rate. A phase II trial of DOS regimen using the identified RD is ongoing. PMID- 30406286 TI - The relationship between serum indoxyl sulfate and the renal function after catheter ablation of atrial fibrillation in patients with mild renal dysfunction. AB - Indoxyl sulfate (IS), a protein-bound uremic toxin, induces renal disorders and atrial fibrillation (AF). It is well known that renal dysfunction is a risk factor for AF and radiofrequency catheter ablation (RFCA) improves the renal function. However, the improvement in the renal function after RFCA in patients with early stage chronic kidney disease (CKD) and the serial changes in the IS level have not been fully elucidated. This study aimed to investigate whether IS affects the improvement in the renal function. A total of 91 consecutive patients with mild kidney dysfunction (CKD stage I-II) who underwent RFCA and maintained sinus rhythm were prospectively enrolled. The plasma IS level and estimated glomerular filtration rate (eGFR) were determined before, 3 months, and 1 year after RFCA. The patients were divided according to the IS quartiles (Q1-4; < 0.4, 0.4-0.7, 0.7-1.2, and > 1.2 MUg/ml). There was no significant difference in the eGFR among the IS quartiles. A significantly higher eGFR improvement rate was obtained for IS-Q4 than the other quartiles (p = 0.039). The IS-Q4 IS level significantly decreased at 1 year after RFCA (1.8 +/- 0.8 to 1.2 +/- 0.7 MUg/ml, p < 0.01). The multivariable logistic model revealed that a high-IS level (IS-Q4) was an independent predictor of an eGFR improvement (OR 3.33; 95% CI 1.16-9.59; p = 0.026). A high-IS level reduction after RFCA improved the renal function in AF patients with mild kidney dysfunction. PMID- 30406287 TI - Acknowledgment of Reviewers 2016 and 2017. PMID- 30406288 TI - Impact of endoscopic ultrasonography on diagnosis of pancreatic cancer. AB - Accumulated evidence has revealed that endoscopic ultrasonography (EUS) has had a great impact on the clinical evaluation of pancreatic cancers. EUS can provide high-resolution images of the pancreas with a quality regarded as far surpassing that achieved on transabdominal ultrasound (US), computed tomography (CT), or magnetic resonance imaging (MRI). EUS is particularly useful for the detection of small pancreatic lesions, while EUS and its related techniques such as contrast enhanced EUS (CE-EUS), EUS elastography, and EUS-guided fine needle aspiration (EUS-FNA) are also useful in the differential diagnosis of solid or cystic pancreatic lesions and the staging (T-staging, N-staging, and M-staging) of pancreatic cancers. In the diagnosis of pancreatic lesions, CE-EUS and EUS elastography play a complementary role to conventional EUS. When sampling is performed using EUS-FNA, CE-EUS and EUS elastography provide information on the target lesions. Thus, conventional EUS, CE-EUS, EUS elastography, and EUS-FNA are essential in the clinical investigation of pancreatic cancer. PMID- 30406289 TI - Patient- versus physician-reported outcomes in prostate cancer patients receiving hypofractionated radiotherapy within a randomized controlled trial. AB - PURPOSE: The risk of developing acute radiotherapy(RT)-induced side effects may increase with hypofractionated RT. To detect treatment-related side effects, patient-reported outcomes (PROs) might be more reliable than physician-reported outcomes. Therefore, we tried to evaluate the rate of agreement between urinary and gastrointestinal (GI) side effects and the prevalence of side effects reported by patients and by physicians. METHODS: Data from a randomized controlled trial (RCT) comparing two hypofractionated RT schedules were used. Urinary (nocturia, incontinence, frequency, dysuria, and urgency) and GI (obstruction, diarrhea, vomiting, nausea, bloating, hemorragia, and incontinence) symptoms measured by the EORTC QLQ-C30 and PR-25 were used for PROs. The same symptoms were scored by the physician using the Common Terminology Criteria Adverse Events v4.0. Outcomes were reported at baseline, end of treatment, month 1, and month 3. PROs and physician-reported outcomes were converted in two categories (0 = no symptoms; 1 = symptoms of any severity) and were correlated using the kappa (kappa) correlation statistics. Values below 0.40 were considered low agreement. In addition, the prevalence of symptoms was calculated. RESULTS: Data from 160 patients were used. The mean value for Cohen's kappa was 0.31 (ranging between 0.04 and 0.55) and 0.23 (ranging between 0.04 and 0.47) for urinary and GI symptoms, respectively. Except for three symptoms at baseline, all symptoms reported by patients were higher than those reported by physicians. CONCLUSION: There is low agreement between symptoms reported by patients and physicians, with high rates of underreporting by the physician. PMID- 30406290 TI - Assessment of a guideline-based heart substructures delineation in left-sided breast cancer patients undergoing adjuvant radiotherapy : Quality assessment within a randomized phase III trial testing a cardioprotective treatment strategy (SAFE-2014). AB - BACKGROUND AND PURPOSE: In our institute, breast cancer patients undergoing adjuvant treatment are included in a protocol aimed to reduce cardiovascular morbidity (SAFE-2014, NCT2236806), assessing preclinical heart damage with heart speckle-tracking ultrasound. To develop a dose constraint related to subclinical heart damage, a reliable delineation of heart substructures based on a pre existing guideline was made. PATIENTS AND METHODS: Heart substructures of 16 left sided breast cancer patients included in the SAFE protocol were delineated by five operators. For each substructure, a multi-contour delineation based on a majority vote algorithm (MCD) was created. A consensus-based delineation (CBD) was developed by an independent team of two blinded operators. Dice similarity coefficients (DSC) between volumes delineated by different operators and the MCD were collected and reported, as well as DSC between CBD and MCD. RESULTS: Mean DSCs between heart chambers delineated by each operator and the corresponding MCDs ranged between 0.78 and 0.96. Mean DSC between substructures delineated by all single operators and the corresponding MCD ranged between 0.84 and 0.94. Mean DSC between CBD and the corresponding MCD ranged from 0.89 to 0.97. CONCLUSION: Results showed low inter-observer variability of heart substructure delineation. This constitutes an external validation of the contouring atlas used, allowing a reliable dosimetric assessment of these volumes within the SAFE-2014 trial. PMID- 30406291 TI - Brief Psychoeducation Program to Enhance Recovery Knowledge and Attitudes of Mental Health Service Providers and Users: Randomized Controlled Trials. AB - Recovery-oriented transformation of mental health service systems not only necessitates changes in mental health policies and practices, it also requires an adoption of recovery-oriented mindset, which includes knowledge and attitudes, among service providers. It is also important that service users are informed about the changes and can fully participate in the process. The present study developed and evaluated the efficacy of a recovery psychoeducation program in enhancing recovery-oriented knowledge and attitudes among mental health service providers and users in Hong Kong. In study 1, 111 service providers were randomly assigned to 2-day psychoeducation group or control group. Results showed that participants in psychoeducation group had significantly better recovery knowledge and more positive attitudes towards recovery after the intervention than the control counterparts. The effect of the recovery psychoeducation program on recovery attitudes was fully mediated by the improvement in recovery knowledge. In study 2, 93 people with mental illness were randomized into 2-week psychoeducation group or control group. Participants in the psychoeducation group had a significant improvement in the level of recovery-oriented knowledge immediately after the workshops, but the effect could not be sustained at follow up. To transform into a recovery-oriented service system, having an effective program to orient service providers and users to recovery is essential. This study provided initial support to the use of a brief psychoeducational program for recovery-oriented knowledge enhancement. Given the short-term efficacy and feasibility of the interventions, service leaders and managers in different clinical and social service settings should consider implementing the programs as part of staff and users' service orientation to build a recovery-supporting workforce and empower their service users early in the recovery process. PMID- 30406292 TI - Changes in responsiveness to allatostatin treatment accompany shifts in stress reactivity in young worker honey bees. AB - Exposing honey bees to isopentylacetate (IPA) can cause stress-related changes in learning performance. In bees of foraging age, IPA's effects on learning are mimicked by C-type allatostatins (AstCC, AstCCC) injected into the brain. Here we ask whether allatostatins induce a similar response in young (6-day-old) bees and if so, whether their effects on learning performance are modulated by queen mandibular pheromone (QMP). We found that young bees exposed to IPA responded less to the conditioned stimulus during training than controls (Type 1-like stress response). AstCC treatment induced a similar response, but only in bees maintained without QMP. Bees exposed to QMP responded to AstCC with increased odour responsiveness and odour generalisation in the 1-h memory test (Type 2-like response). Type 2-like responses could be induced also by the A-type allatostatin, AstA. However, in bees exposed to QMP, AstA-induced odour generalisation was absent. Effects of AstCCC treatment in young bees were weak, indicating that responsiveness to this peptide changes with age. Our findings are consistent with the hypothesis that honey bee allatostatins play a role in stress reactivity, but suggest in addition that allatostatin signalling is age dependent and susceptible to modulation by pheromone released by the queen bee. PMID- 30406293 TI - [Sense and benefits of screening procedures]. PMID- 30406294 TI - [Screening instruments: more light than shade]. PMID- 30406295 TI - The role of the NADH-dependent nitrite reductase, Nir, from Escherichia coli in fermentative ammonification. AB - Nitrate and nitrite reduction are of paramount importance for nitrogen assimilation and anaerobic metabolism, and understanding the specific roles of each participating reductase is necessary to describe the biochemical balance that dictates cellular responses to their environments. The soluble, cytoplasmic siroheme NADH-nitrite reductase (Nir) in Escherichia coli is necessary for nitrate/nitrite assimilation but has also been reported to either "detoxify" nitrite, or to carry out fermentative ammonification in support of anaerobic catabolism. Theoretically, nitrite detoxification would be important for anaerobic growth on nitrate, during which excess nitrite would be reduced to ammonium. Fermentative ammonification by Nir would be important for maximization of non-respiratory ATP production during anaerobic growth in the presence of nitrite. Experiments reported here were designed to test the potential role of Nir in fermentative ammonification directly by growing E. coli along with mutant strains lacking Nir or the respiratory nitrite reductase (Nrf) under anaerobic conditions in defined media while monitoring nitrogen utilization and fermentation metabolites. To focus on the role of Nir in fermentative ammonification, pH control was used in most experiments to eliminate nitrite toxicity due to nitric acid formation. Our results demonstrate that Nir confers a significant benefit during fermentative growth that reflects fermentative ammonification rather than detoxification. We conclude that fermentative ammonification by Nir allows for the energetically favorable fermentation of glucose to formate and acetate. These results and conclusions are discussed in light of the roles of Nir in other bacteria and in plants. PMID- 30406296 TI - Pharmacological properties of marine macroalgae-associated heterotrophic bacteria. AB - The rich diversity of marine macroalgae and their associated bacterial flora represent a potential reservoir of bioactive compounds with valuable biotechnological and pharmaceutical use. Heterotrophic bacteria associated with the intertidal macroalgae were isolated and evaluated for their pharmacological properties using various in vitro models. Among 148 cultivable isolates, more than 50% were dominated by gamma-Proteobacteria and Firmicutes, wherein 53 of them showed consistent antibacterial activity against a broad spectrum of clinically significant pathogens. The bacteria were characterized by extensive microbiological, molecular and chemical identification tools. The heterotrophs Bacillus amyloliquefaciens MTCC 12716 and Shewanella algae MTCC 12715 isolated from a red marine macroalga Hypnea valentiae exhibited potential anti-infective properties against multidrug-resistant pathogens, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis (minimum inhibitory concentration of 6.25-12.5 ug/mL). The organic extract of B. amyloliquefaciens displayed significantly greater antioxidative properties (IC90 < 1 mg/mL) and the activities showed considerable positive correlation (r2 > 0.8, P < 0.05) with the inhibitory activities against angiotensin converting enzyme-I, pro-inflammatory cyclooxygenases and 5-lipoxygenase, dipeptidyl peptidase-4 and hydroxymethylglutaryl coenzyme A reductase, which were associated with hypertension, inflammation, diabetes, and hypercholesterolemia, respectively. The applications of nuclear magnetic resonance-based fingerprinting to analyze the characteristic signals in the solvent extracts and to correlate them with the pharmaceutical properties were underlined. The heterotrophic bacterium B. amyloliquefaciens MTCC 12716 might, therefore, serve as a potential therapeutic candidate to develop products with wide pharmaceutical applications. PMID- 30406297 TI - Magnesium Extravaganza: A Critical Compendium of Current Research into Cellular Mg2+ Transporters Other than TRPM6/7. AB - Magnesium research has boomed within the last 20 years. The real breakthrough came at the start of the new millennium with the discovery of a plethora of possible Mg homeostatic factors that, in particular, included putative Mg2+ transporters. Until that point, Mg research was limited to biochemical and physiological work, as no target molecular entities were known that could be used to explore the molecular biology of Mg homeostasis at the level of the cell, tissue, organ, or organism and to translate such knowledge into the field of clinical medicine and pharmacology. Because of the aforementioned, Mg2+ and Mg homeostasis, both of which had been heavily marginalized within the biomedical field in the twentieth century, have become overnight a focal point of many studies ranging from primary biomedical research to translational medicine.The amount of literature concerning cellular Mg2+ transport and cellular Mg homeostasis is increasing, together with a certain amount of confusion, especially about the function(s) of the newly discovered and, in the majority of instances, still only putative Mg2+ transporters/Mg2+ homeostatic factors. Newcomers to the field of Mg research will thus find it particularly difficult to orient themselves.Here, we briefly but critically summarize the status quo of the current understanding of the molecular entities behind cellular Mg2+ homeostasis in mammalian/human cells other than TRPM6/7 chanzymes, which have been universally accepted as being unspecific cation channel kinases allowing the flux of Mg2+ while constituting the major gateway for Mg2+ to enter the cell. PMID- 30406299 TI - Rheumatology in Egypt: back to the future. AB - Medical knowledge in ancient Egypt had a remarkable reputation since rulers of other empires used to request the pharaoh to send them their best physician to treat their beloved ones. Many rheumatologic conditions as giant-cell arteritis, reactive arthritis and other forms of spondyloarthritis have been identified in ancient Egyptian materials. Rheumatologists in Egypt are enormously expanding and mastering the tools that aid them in enhancing the management of rheumatic diseases. More Egyptian rheumatologists are actively participating in the annual European League Against Rheumatism (EULAR) and American College of Rheumatology conferences and those attached to well known state of the art centers are increasing. EULAR certified Egyptian MSUS trainers are effectively performing regionally. This review throws light on the rheumatology practice in Egypt, its progress from ancient times passing through Egyptian medical healthcare services, education systems for rheumatologists, rheumatology associations, an overview on the spectrum of rheumatic diseases through publications in the field till future perspectives. Rheumatology in Egypt is an actively growing and dynamic specialty of medicine with considerable contributions to the world's literature. These days, persistent efforts are mandatory to raise the standard of clinical and basic research, to optimize clinical practice with regard to new biologics, to develop tailored and targeted therapies for the rheumatic diseases, and to meet the medical demands of the exponentially increasing Egyptian population. Opportunities and challenges discussed high-lighten future perspectives needed to boost the rheumatology practice in Egypt. PMID- 30406298 TI - Colorimetric zearalenone assay based on the use of an aptamer and of gold nanoparticles with peroxidase-like activity. AB - An aptamer based colorimetric assay is described for the determination of zearalenone (ZEN). It is based on the inhibition of the peroxidase-mimicking activity of gold nanoparticles (AuNPs) by the ZEN aptamer. However, in the presence of ZEN, the aptamer is bound by ZEN and can no longer inhibit the peroxidase-mimicking activity of AuNPs. The color change of solution is related to ZEN concentration and observed with bare eyes. Under optimal conditions, the absorbance (at 630 nm) increases linearly in the ZEN concentration range of 10 250 ng.mL-1, and the limit of detection is 10 ng.mL-1. The specificity of the assay was verified by studying the effect of potential interferents. The recoveries from ZEN spiked corn and corn oil range from 92 to 110%, and the relative standard deviations are between 2.4 and 6.4%. The results are in good agreement with those obtained by an ELISA. Graphical abstract Schematic presentation of colorimetric assay for rapid and sensitive determination of zearalenone (ZEN) based on the inhibition of ZEN aptamer on the the peroxidase like activity of gold nanoparticle (AuNPs). PMID- 30406300 TI - Web-Based Educational Seminars Compare Favorably with In-House Seminars for Bariatric Surgery Patients. AB - BACKGROUND: Comprehensive preparative patient education is a key element in bariatric patient success. The primary objective of this study was to compare attrition rates, demographics, and surgery outcomes between patients who participated in the online vs in-house preparative seminars. METHODS: A retrospective chart review was performed involving patients who chose to participate in online vs in-house educational seminar between July of 2014 and December of 2016. The patients were divided into two groups based on their choice of educational seminar and tracked to see how many made it to an initial visit and to surgery. In those who had bariatric surgery, data was collected on age, type of insurance, length of stay (LOS), longest follow-up, and change in body mass index. RESULTS: Total of 1230 patients were included in this study. There was no difference in attrition rate to initial consultation visit (29.1% vs 29.9%), but there was a statistically higher attrition to surgery in the in-house seminar attendees (72.9%) compared to online participants (66.6%, p < 0.05). Between January 2015 and December 2016, 291 patients underwent primary bariatric surgery. The online group was on average 3 years younger which was statistically significant. There were no differences in LOS, longest follow-up, and weight loss at 12 months between the groups. CONCLUSION: When comparing attrition rates and bariatric surgery outcomes, no overall difference was noted between patients who received web- or hospital-based preparative education. Bariatric programs should provide access to online seminars to attract younger population and save resources and cost. PMID- 30406301 TI - Pancreatic Tail Bleeding and Leakage After Sleeve Gastrectomy in a Patient with High Body Mass Index: a Case Report. PMID- 30406302 TI - New associations of the Multidimensional Prognostic Index. AB - BACKGROUND: The multidimensional prognostic index (MPI) is a validated, sensitive, and specific prognosis estimation tool based on a comprehensive geriatric assessment (CGA). The MPI accurately predicts mortality after 1 month and 1 year in older, multimorbid patients with acute disease or relapse of chronic conditions. OBJECTIVE: To evaluate whether the MPI predicts indicators of healthcare resources, i.e. grade of care (GC), length of hospital stay (LHS) and destination after hospital discharge in older patients in an acute medical setting. MATERIAL AND METHODS: In this study 135 hospitalized patients aged 70 years and older underwent a CGA evaluation to calculate the MPI on admission and discharge. Accordingly, patients were subdivided in low (MPI-1, score 0-0.33), moderate (MPI-2, score 0.34-0.66) and high (MPI-3, score 0.67-1) risk of mortality. The GC, LHS and the discharge allocation were also recorded. RESULTS: The MPI score was significantly related to LHS (p = 0.011) and to GC (p < 0.001). In addition, MPI-3 patients were significantly more often transferred from other hospital settings (p = 0.007) as well as significantly less likely to be discharged home (p = 0.04) than other groups. CONCLUSION: The CGA-based MPI values are significantly associated with use of indicators of healthcare resources, including GC, LHS and discharge allocation. These findings suggest that the MPI may be useful for resource planning in the care of older multimorbid patients admitted to hospital. PMID- 30406303 TI - The relationship between confidence and accuracy with verbal and verbal + numeric confidence scales. AB - Police departments often use verbal confidence measures (highly confident, somewhat confident) with a small number of values, whereas psychologists measuring the confidence-accuracy relationship typically use numeric scales with a large range of values (20-point or 100-point scales). We compared verbal and verbal + numeric confidence scales for two different lineups, using either two or four levels of confidence. We found strong confidence-accuracy relationships that were unaffected by the nature of the scale at the highest level of confidence. High confidence corresponded to high accuracy with both two- and four-level scales, and the scale type (verbal only or verbal + numeric) did not matter. Police using a simple scale of "highly confident" and "somewhat confident" can, according to our results, rest assured that high confidence indicates high accuracy on a first identification from a lineup. In addition, our two lineups differed greatly in difficulty, yet the confidence-accuracy relationship was quite strong for both lineups, although somewhat lower for the more difficult lineup. PMID- 30406304 TI - The Jewish doctors involved in the development of health resorts in eastern Galicia at the late 19th and early 20th century (Central and Eastern Europe). AB - BACKGROUND: The involvement of Jewish doctors and scientists in the development of health resorts in eastern Galicia (part of the Austrian monarchy after 1772, and since 1918 as part of independent Poland, now part of Ukraine) is unquestionable; however, awareness of this fact is not that common. Meanwhile, also due to their work and activity, small borderland resorts became important medical, cultural and social centers of the region. The involvement of Jewish doctors in the development of Galician health resorts resulted from, among others, the rich and multi-layered tradition and integration of Judaism with the hygiene regulations and moral principles of the religion. The eastern Galicia health resort culture, architecture, style of how free time was spent, along with treatment and disease prevention, contributed to a European identity in the region. AIM: This article constitutes an attempt to restore the memory of places and people who created the phenomenon of Galician health resorts, an important social amenity and whose contribution to this process is completely forgotten or omitted. Most of the physicians mentioned in this article died in concentration camps or were murdered by the Nazis. METHODS: The article is based on the analysis of source texts drawn up in the German and Polish languages, including biographical archives, books, scientific articles, ego documents and press reports from the decades before WW I. RESULTS: On the European level, eastern Galicia resorts were new resorts and the development took place mainly around 1900. The Jewish community constitutively contributed to the medical, economic and cultural development of the resorts. Its role in creating a resort culture is related both to the activity of the Jewish intelligentsia and wealthy bourgeoisie, as well as local craftsmen, tavern owners or shopkeepers. It resulted from a wealthy and multi-layered Jewish tradition and the integration of Judaism with the orders of hygiene and moral principles of religion. PMID- 30406305 TI - Explaining the neural activity distribution associated with discrete movement sequences: Evidence for parallel functional systems. AB - To explore the effects of practice we scanned participants with fMRI while they were performing four-key unfamiliar and familiar sequences, and compared the associated activities relative to simple control sequences. On the basis of a recent cognitive model of sequential motor behavior (C-SMB), we propose that the observed neural activity would be associated with three functional networks that can operate in parallel and that allow (a) responding to stimuli in a reaction mode, (b) sequence execution using spatial sequence representations in a central symbolic mode, and (c) sequence execution using motor chunk representations in a chunking mode. On the basis of this model and findings in the literature, we predicted which neural areas would be active during execution of the unfamiliar and familiar keying sequences. The observed neural activities were largely in line with our predictions, and allowed functions to be attributed to the active brain areas that fit the three above functional systems. The results corroborate C-SMB's assumption that at advanced skill levels the systems executing motor chunks and translating key-specific stimuli are racing to trigger individual responses. They further support recent behavioral indications that spatial sequence representations continue to be used. PMID- 30406306 TI - Frequency of helping friends and helping strangers is explained by different neural signatures. AB - Acts of helping friends and strangers are part of everyday life. However, people vary significantly with respect to how often they help others and with respect to whom they actually help on a day-to-day basis. Despite everyday helping being so pervasive, these individual differences are poorly understood. Here, we used source-localized resting electroencephalography to measure objective and stable individual differences in neural baseline activation in combination with an ecologically valid method that allows assessment of helping behavior in the field. Results revealed that neural baseline activation in the right dorsolateral prefrontal cortex (DLPFC) - a brain region associated with self-control and strategic social behavior - predicts the daily frequency of helping friends, whereas the daily frequency of helping strangers was predicted by neural baseline activation in the dorsomedial prefrontal cortex (DMPFC) - a brain region associated with social cognition processes. These findings offer evidence that distinct neural signatures and associated psychological and cognitive processes may underlie the propensity to help friends and strangers in daily life. PMID- 30406307 TI - Recurrent kidney stones in a family with a mitochondrial disorder due to the m.3243A>G mutation. PMID- 30406308 TI - Osteoporosis Conference 2018 Birmingham, UK 2 - 4 December 2018 Abstracts. PMID- 30406309 TI - Medication-related osteonecrosis of the jaw after tooth extraction in cancer patients: a multicenter retrospective study. AB - : Root amputation, immunosuppressive therapy, mandibular tooth extraction, pre existing inflammation, and longer duration of treatment with bone-modifying agents were significantly associated with an increased risk of medication-related osteonecrosis of the jaw. Hopeless teeth should be extracted without drug holiday before the development of inflammation in cancer patients receiving high-dose bone-modifying agents. INTRODUCTION: No studies have comprehensively analyzed the influence of pre-existing inflammation, surgical procedure-related factors such as primary wound closure, demographic factors, and drug holiday on the incidence of medication-related osteonecrosis of the jaw (MRONJ). The purpose of this study was to retrospectively investigate the relationships between these various factors and the development of MRONJ after tooth extraction in cancer patients receiving high-dose bone-modifying agents (BMAs) such as bisphosphonates or denosumab. METHODS: Risk factors for MRONJ after tooth extraction were evaluated with univariate and multivariate analyses. The following parameters were investigated in all patients: demographics, type and duration of BMA use, whether BMA use was discontinued before tooth extraction (drug holiday), the duration of such discontinuation, the presence of pre-existing inflammation, and whether additional surgical procedures (e.g., incision, removal of bone edges, root amputation) were performed. RESULTS: We found that root amputation (OR = 22.62), immunosuppressive therapy (OR = 16.61), extraction of mandibular teeth (OR = 12.14), extraction of teeth with pre-existing inflammation, and longer duration (>= 8 months) of high-dose BMA (OR = 7.85) were all significantly associated with MRONJ. CONCLUSIONS: Tooth extraction should not necessarily be postponed in cancer patients receiving high-dose BMA. The effectiveness of a short-term drug holiday was not confirmed, as drug holidays had no significant impact on MRONJ incidence. Tooth extraction may be acceptable during high-dose BMA therapy until 8 months after initiation. PMID- 30406310 TI - Prognostic value of a new semiquantitative score system for adenosine stress myocardial perfusion by CMR. AB - OBJECTIVES: Cardiovascular magnetic resonance (CMR) provides information on myocardial ischemia through stress perfusion studies. In clinical practice, the grading of induced perfusion defects is performed by visual estimation of their extension. The aim of our study is to devise a score of the degree of ischemia and to test its prognostic value. METHODS: Between 2009 and 2011, patients with diagnosed or suspected coronary artery disease underwent stress perfusion CMR. A score of ischemic burden was calculated on the basis of (1) stress-induced perfusion defect, (2) persistence, (3) transmurality, and (4) stress-induced contractile defect. Follow-up was censored after 4 years and primary end-point was defined by a composite of death, heart failure episode, acute coronary syndrome, and ventricular arrhythmias. Univariate and multivariate logistic regressions were used to assess the strength of the association between the CMR ischemic variables, and the composite outcome. RESULTS: Forty-four of the 128 patients (34%) presented with adverse events, while 84 (66%) did not. Sixty-one patients (48%) had negative perfusion studies while 67 (52%) showed perfusion defect. Patients with positive perfusion studies and adverse events (n = 39) had higher number of segments with persistent defect (3.3 vs 1.3, p = 0.001) and highest score (19.6 vs 13.3 p = 0.012) than patients with positive perfusion studies and absence of events (n = 28). The number of segments with persistent defect showed the strongest predictive value of adverse events (OR 1.54; CI 1.19 2.00; p < 0.001). CONCLUSIONS: The score of ischemic burden proposed herein has prognostic value. Persistence of a perfusion defect has the strongest impact on prognosis. KEY POINTS: * Cardiovascular magnetic resonance provides information on myocardial ischemia by visual estimation of the presence of perfusion defects induced by stress. * There is not a standardized method for grading perfusion defects which, in practice, is performed by visual estimation of their extension. * As proven in this study, the integration of several parameters of perfusion defects (in addition to extension) into a semiquantitative score has prognostic value. PMID- 30406311 TI - Predictive value of sarcopenia and visceral obesity for postoperative pancreatic fistula after pancreaticoduodenectomy analyzed on clinically acquired CT and MRI. AB - OBJECTIVE: To evaluate predictive values of sarcopenia and visceral obesity measured from preoperative CT/MRIs for postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy in patients with periampullary malignancies. METHODS: From the prospectively constructed surgical registry, we included adult patients treated with pancreaticoduodenectomy. Based on CT/MRIs, body morphometric analysis was performed to evaluate the visceral obesity and sarcopenia, based on the areas of visceral fat and skeletal muscle measured at the L3 vertebrae level. We retrieved various perioperative factors from registry. As outcomes of postoperative complications, we evaluated POPF and major complications based on the Clavien-Dindo classification. Multivariate logistic regression analyses were performed. RESULTS: From a total of 284 patients (163 males, 121 females) who met the inclusion/exclusion criteria, POPF, major complications, and 60-day mortality occurred in 52 (18.3%), 34 (12.0%), and 6 (2.1%), respectively. Sarcopenia and visceral obesity were noted in 123 (75.5%) and 66 (40.5%) of men and 68 (56.2%) and 53 (43.8%) of women, respectively. Combination of sarcopenia and obesity (sarcopenic obesity) was noted in 31.9% (52/163) of men and in 26.4% (32/121) of women. In multivariate logistic regression analyses, sarcopenic obesity was the only independent predictor for POPF (OR 2.65, 95% CI 1.43-4.93), and the vascular resection during pancreaticoduodenectomy was the only independent predictor for severe complications (OR 3.75, 95% CI 1.61-8.70). CONCLUSION: Sarcopenic obesity might be highly predictive for POPF. Body morphometric analysis in preoperative CT/MRI combined with assessment of perioperative clinical features may help to identify high-risk patients and determine perioperative management strategies. KEY POINTS: * Sarcopenic obesity might be predictive for postoperative pancreatic fistula after pancreaticoduodenectomy. * The vascular resection during pancreaticoduodenectomy might be predictive of major complications. * Body morphometric analysis might be helpful for identifying high-risk patients. PMID- 30406312 TI - Dual-energy CT for liver iron quantification in patients with haematological disorders. AB - OBJECTIVES: To retrospectively quantify liver iron content in haematological patients suspected of transfusional haemosiderosis using dual-energy CT (DECT) and correlate with serum ferritin levels and estimated quantity of transfused iron. METHODS: One hundred forty-seven consecutive dual-source dual-energy non contrast chest-CTs in 110 haematologic patients intended primarily for exclusion of pulmonary infection between September 2016 and June 2017 were retrospectively evaluated. Image data was post-processed with a software prototype. After material decomposition, an iron enhancement map was created and freehand ROIs were drawn including most of the partially examined liver. The virtual iron content (VIC) was calculated and expressed in milligram/millilitre. VIC was correlated with serum ferritin and estimated amount of transfused iron. Scans of patients who had not received blood products were considered controls. RESULTS: Forty-eight (32.7%) cases (controls) had not received any blood transfusions whereas 67.3% had received one transfusion or more. Median serum ferritin and VIC were 138.0 MUg/dl (range, 6.0-2628.0 MUg/dl) and 1.33 mg/ml (range, - 0.94-7.56 mg/ml) in the post-transfusional group and 27.0 MUg/dl (range, 1.0-248.0 MUg/dl) and 0.61 mg/ml (range, - 2.1-2.4) in the control group. Correlation between serum ferritin and VIC was strong (r = 0.623; p < 0.001) as well as that between serum ferritin and estimated quantity of transfused iron (r = 0.681; p < 0.001). CONCLUSIONS: Hepatic VIC obtained via dual-energy chest-CT examinational protocol strongly correlates with serum ferritin levels and estimated amount of transfused iron and could therefore be used in the routine diagnosis for complementary evaluation of transfusional haemosiderosis. KEY POINTS: * Virtual liver iron content was measured in routine chest-CTs of haematological patients suspected of having iron overload. Chest-CTs were primarily intended for exclusion of pulmonary infection. * Measurements correlate strongly with the most widely used blood marker of iron overload serum ferritin (after exclusion of infection) and the amount of transfused iron. * Liver VIC could be used for supplemental evaluation of transfusional haemosiderosis in haematological patients. PMID- 30406313 TI - Predicting the grade of hepatocellular carcinoma based on non-contrast-enhanced MRI radiomics signature. AB - PURPOSE: This study was conducted in order to investigate the value of magnetic resonance imaging (MRI)-based radiomics signatures for the preoperative prediction of hepatocellular carcinoma (HCC) grade. METHODS: Data from 170 patients confirmed to have HCC by surgical pathology were divided into a training group (n = 125) and a test group (n = 45). The radiomics features of tumours based on both T1-weighted imaging (WI) and T2WI were extracted by using Matrix Laboratory (MATLAB), and radiomics signatures were generated using the least absolute shrinkage and selection operator (LASSO) logistic regression model. The predicted values of pathological HCC grades using radiomics signatures, clinical factors (including age, sex, tumour size, alpha fetoprotein (AFP) level, history of hepatitis B, hepatocirrhosis, portal vein tumour thrombosis, portal hypertension and pseudocapsule) and the combined models were assessed. RESULTS: Radiomics signatures could successfully categorise high-grade and low-grade HCC cases (p < 0.05) in both the training and test datasets. Regarding the performances of clinical factors, radiomics signatures and the combined clinical and radiomics signature (from the combined T1WI and T2WI images) models for HCC grading prediction, the areas under the curve (AUCs) were 0.600, 0.742 and 0.800 in the test datasets, respectively. Both the AFP level and radiomics signature were independent predictors of HCC grade (p < 0.05). CONCLUSIONS: Radiomics signatures may be important for discriminating high-grade and low-grade HCC cases. The combination of the radiomics signatures with clinical factors may be helpful for the preoperative prediction of HCC grade. KEY POINTS: * The radiomics signature based on non-contrast-enhanced MR images was significantly associated with the pathological grade of HCC. * The radiomics signatures based on T1WI or T2WI images performed similarly at predicting the pathological grade of HCC. * Combining the radiomics signature and clinical factors (including age, sex, tumour size, AFP level, history of hepatitis B, hepatocirrhosis, portal vein tumour thrombosis, portal hypertension and pseudocapsule) may be helpful for the preoperative prediction of HCC grade. PMID- 30406314 TI - WNT5A supports viability of senescent human dental follicle cells. AB - The osteogenic differentiation of dental follicle cells (DFCs) is inhibited by the onset of cellular senescence, but the cause for this is largely unknown. Recently it was shown that WNT5a, which is an inductor of the non-canonical WNT pathway, stimulates both cellular senescence and osteogenic differentiation of different cell types. In this study, we investigated the role of WNT5a for viability and osteogenic differentiation in human DFCs after the induction of cellular senescence. DFCs were cultivated until the induction of cellular senescence. The induction of cellular senescence was confirmed by beta galactosidase staining, estimation of population doubling time, and slightly telomere length shortening. After induction of cellular senescence, the expression of WNT5A and the potential to induce the osteogenic differentiation decreased. Inhibition of WNT5A by specific siRNAs had significant effect on the viability of DFCs. Cell proliferation was reduced, whereas both cellular senescence and cell death were increased in DFCs. However, an inhibition of WNT5A did only slightly effect the osteogenic differentiation of DFCs. Our results suggest that WNT5A supports viability during both cell proliferation and osteogenic differentiation of DFCs. PMID- 30406316 TI - Importance of Compliance Audits for a Pediatric Complicated Appendicitis Clinical Practice Guideline. AB - Clinical practice guidelines (CPG) have been shown to decrease practice variation, reduce resource use, and improve patient outcomes. The purpose of this study was to audit compliance of a pediatric complicated appendicitis CPG to identify areas for continued improvement. A comprehensive complicated appendicitis CPG was implemented in a children's hospital system. Outcomes were compared for 48 months pre- (01/2012 to 12/2015) and 28 months post implementation (01/2016 to 04/2018). A detailed compliance audit was nested within the post-implementation period in 60 consecutive patients from 11/2017 to 03/2018. Feedback was provided to care providers throughout the audit. Overall, 2370 children with complicated appendicitis were identified (1366 pre-CPG and 1004 post-CPG). The CPG resulted in decrease in mean length of stay from 5.3 days to 4.5 days (p = 0.751), postoperative returns to the system (13.0% to 10.1%, p = 0.030), and readmissions (5.3% to 4.3%, p = 0.237). Central line use decreased from 11.2% to 5.5% (p < 0.001) and antibiotic selection improved from 47.0% to 84.1% (p < 0.001). On audit, only 15% (9/60) had full CPG compliance and 49% (29/60) received recommended antibiotic durations. Compliance increased from 7% to 23% with audit-derived feedback. After stratifying by appendicitis severity, audits resulted in improved antibiotic duration compliance for patients with severe appendicitis (38.1% to 66.7%, p = 0.07) and postoperative ambulation for patients with lower grade disease (37.5% to 83.3%, p = 0.06). Audit cycles on a complicated appendicitis CPG and feedback to providers improved CPG compliance and more granular outcomes of interest. PMID- 30406317 TI - Anterograde colonic irrigations by percutaneous endoscopic caecostomy in refractory colorectal functional disorders. AB - PURPOSE: In case reports or small studies, percutaneous endoscopic caecostomy (PEC) has been proposed as an alternative to the Malone intervention to perform antegrade colonic enemas. Our goal was to assess the feasibility, efficacy, and tolerance of PEC in a large group of patients with refractory colorectal functional disorders. METHODS: From September 2006 to April 2014, all patients undergoing PEC for constipation, fecal incontinence, and incontinence after rectal resection in two expert centers were studied. The PEC procedure consisted in anchoring the caecum to the abdominal wall (caecopexy) and placing a specifically designed tube in the colonic lumen to perform antegrade enemas. The quality of life (GIQLI), constipation (Kess), and incontinence (Cleveland) scores were assessed before PEC and at 3, 6, 12, and 24 months. RESULTS: A total of 69 patients were included. GIQLI scores were significantly improved in constipation group (n = 43), incontinence group (n = 19), and rectal resection group (n = 10). In the constipation group, Kess score decreased from 25.9 before PEC to 20.6 at 2 years (p = 0.01). In the incontinence and post-rectal resection groups, Cleveland scores decreased from 14.3 before PEC to 2.7 at 6 months (p = 0.01) and to 10.4 at 2 years (p = 0.04). Overall, PEC was considered successful by patients in 58%, 74%, and 90% of cases, in constipation, incontinence, and rectal resection groups, respectively. Chronic pain (52%) at the catheter site was the most frequent complication. CONCLUSIONS: Percutaneous endoscopic caecostomy for antegrade colonic enemas improves significantly the quality of life of patients with colorectal disorder refractory to medical treatment. PMID- 30406318 TI - Neuroendoscopic biopsy: analysis of a series of 80 patients. AB - Neuroendoscopy enables diagnostic biopsy of intraventricular and/or paraventricular tumors and the simultaneous treatment of associated hydrocephalus in selected cases. The objective of this paper was to analyze the effectiveness and safety of this procedure. This retrospective study included 80 patients between 2 months and 78 years old diagnosed with intraventricular and/or paraventricular expansive lesion who underwent neuroendoscopic biopsy from 2004 to 2016. Collected variables were gender, age at diagnosis, clinical presentation, tumor location, surgical technique, management of hydrocephalus, pathological findings, procedure-related complications, and follow-up time. Neuroendoscopic biopsy was performed in 80 patients. Mean age at diagnosis was 27 years, and 52.5% were men. According to the Depreitere Classification, 71 were level I (conclusive diagnosis), 1 level III (problematic categorization), and 8 level IV (non-interpretable diagnosis). The most frequent diagnosis was grade I astrocytoma (14%). Diagnostic success per patient was 88.7%. Sixty-nine patients had hydrocephalus at diagnosis, 37 of whom were treated with endoscopic third ventriculostomy (ETV), with septostomy (SPT) in 14, and only SPT in 4. Twenty eight patients underwent ventricular peritoneal shunt (VPS), with SPT in 20. The ETV success rate was 70.9%. The complication rate per patient was 11%: five patients presented intraventricular hemorrhage, three of whom died; one patient presented cerebrospinal fluid fistula; three presented transient oculomotor impairment. Postoperative follow-up was from 1 month to 12.4 years (mean 45 months). Neuroendoscopy is an effective procedure for the pathological diagnosis of intraventricular and paraventricular tumors, allowing the treatment of associated hydrocephalus. Nevertheless, it is not exempt from serious complications and requires proper training. PMID- 30406319 TI - Adding dextran to local anesthetic enhances analgesia. PMID- 30406320 TI - Assessment of Capacity to Meet Lancet Commission on Global Surgery Indicators in the Federal Capital Territory, Abuja, Nigeria. AB - BACKGROUND: This is a baseline assessment of surgical capacity in the Federal Capital Territory (FCT), in preparation for the creation of a National Surgical, Obstetric, Anesthesia, and Nursing Plan. METHODS: In October 2017, all 10 of the 11 secondary hospitals in FCT that provide surgical and/or obstetric care were surveyed using a modified World Health Organization Hospital Assessment Tool and a qualitative semi-structured hospital interview tool of the medical Director (MdD). This project received approval from the Nigeria Federal Ministry of Health and the FCT Department of Health and Human Services. RESULTS: The number of inpatient beds ranged from 35 to 140, and the number of admissions ranged from 1200 to 6400 patients per year. The mean number of surgeries performed in 2016 by these hospitals was 783 (range 235-1601). Cesarean section was the most common surgical procedure at each hospital. Only five hospitals regularly performed laparotomies. Only three hospitals regularly performed fixation of open fractures. Of 152 surgical, obstetric, and anesthesia providers, all hospitals had at least one consultant obstetrician, but only four hospitals had a general surgeon and three hospitals had a consultant anesthesiologist. Deficient physical space for inpatient admissions was the most common concern of MdDs. CONCLUSIONS: The FCT reaches the target for 2-h access, with 80% of patients (on average) reaching the hospital within 2 h. However, SAO provider density, surgical volume, and tracking of the perioperative mortality rate were low. Data were lacking to comment on protection against impoverishing and catastrophic expenditures. PMID- 30406321 TI - Correction to: Hypophosphatemia as a Predictor of Organ-Specific Complications Following Gastrointestinal Surgery: Analysis of 8034 Patients. AB - In the original version of this article, Martin R. Weiser's last name was spelled incorrectly. It is correct as reflected here. The original article has been updated. PMID- 30406315 TI - A Precision Medicine Approach to Cerebral Edema and Intracranial Hypertension after Severe Traumatic Brain Injury: Quo Vadis? AB - PURPOSE OF REVIEW: Standard clinical protocols for treating cerebral edema and intracranial hypertension after severe TBI have remained remarkably similar over decades. Cerebral edema and intracranial hypertension are treated interchangeably when in fact intracranial pressure (ICP) is a proxy for cerebral edema but also other processes such as extent of mass lesions, hydrocephalus, or cerebral blood volume. A complex interplay of multiple molecular mechanisms results in cerebral edema after severe TBI, and these are not measured or targeted by current clinically available tools. Addressing these underpinnings may be key to preventing or treating cerebral edema and improving outcome after severe TBI. RECENT FINDINGS: This review begins by outlining basic principles underlying the relationship between edema and ICP including the Monro-Kellie doctrine and concepts of intracranial compliance/elastance. There is a subsequent brief discussion of current guidelines for ICP monitoring/management. We then focus most of the review on an evolving precision medicine approach towards cerebral edema and intracranial hypertension after TBI. Personalization of invasive neuromonitoring parameters including ICP waveform analysis, pulse amplitude, pressure reactivity, and longitudinal trajectories are presented. This is followed by a discussion of cerebral edema subtypes (continuum of ionic/cytotoxic/vasogenic edema and progressive secondary hemorrhage). Mechanisms of potential molecular contributors to cerebral edema after TBI are reviewed. For each target, we present findings from preclinical models, and evaluate their clinical utility as biomarkers and therapeutic targets for cerebral edema reduction. This selection represents promising candidates with evidence from different research groups, overlap/inter-relatedness with other pathways, and clinical/translational potential. We outline an evolving precision medicine and translational approach towards cerebral edema and intracranial hypertension after severe TBI. PMID- 30406322 TI - Serum C-reactive protein level after ventral hernia repair with mesh reinforcement can predict infectious complications: a retrospective cohort study. AB - PURPOSE: Infectious complications (ICs) after mesh-reinforced ventral hernioplasty often lead to prolonged and complicated hospitalizations. As early diagnosis and management can mitigate complications, early prediction is important. Our aim was to determine whether postoperative blood tests are valuable predictors of IC. METHODS: We retrospectively analyzed 373 patients who underwent conventional ventral hernioplasty with mesh augmentation between 2008 and 2011. The clinical outcome was correlated with postoperative serum C-reactive protein (CRP) and white blood cell counts (WBC) and assessed by area under the curve (AUC) analysis of the receiver operating characteristics curve. RESULTS: ICs occurred in 51 (13.7%) patients, who required further management. Among these, 48 patients developed a procedure-related complication, the most frequent being surgical site infection (n = 44). The infections appeared after a median postoperative delay of 12 days. Serum CRP was superior to WBC in the prediction of a complicated course. A maximum CRP < 105 mg/L on postoperative day (POD) 2 or 3 had the highest negative predictive value (NPV; 100%) in ruling out ICs [positive predictive value (PPV) 29%; sensitivity 100%; specificity 55%]. The PPV for occurrence of IC improved each day after surgery, reaching up to 46% on POD 5 or 6 for a CRP cut-off of 63.2 mg/L (NPV 93%; sensitivity 69%; specificity 83%). The AUC was 0.80 at both time points. CONCLUSIONS: Our results indicate that postoperative serum CRP allows for early prediction of the postoperative course. Low CRP during the initial PODs is associated with lower risk of ICs. Higher levels on POD 5 or 6 behoove close surveillance. PMID- 30406323 TI - Total or partial removal of infected mesh? Invited comment. PMID- 30406324 TI - Laparoscopic transperitoneal inguinal hernioplasty (TAPP) after radical open retropubic prostatectomy: special features and clinical outcomes. AB - Purpose Laparoscopic transperitoneal endoscopic (TAPP) and totally extraperitoneal (TEP) hernia repair have been well established in primary and recurrent inguinal hernias [1]. Only few studies [2-5] evaluate the surgical outcome of patients with inguinal hernias after radical prostatectomy, using the TAPP or TEP procedure. But controversies remain including its feasibility, safety and recurrence rate. The mesh size to be used and the necessity of a complete dissection of the scared retropubic space are discussed controversially. Long term follow-up studies are missing. Methods After introducing the technique of a laparoscopic transperitoneal endoscopic hernioplasty (TAPP) at the hospital in October 1992, this approach had been recommended to all adult patients with inguinal and femoral hernias. In our single-center study, the medical records of all 5,764 patients with 7,010 inguinal and femoral hernias, operated from 1993 until 2009, were enrolled in a retrospective analysis. A TAPP procedure was performed in 6,582 hernias (Peitsch, Surg Endosc 28:671-682, 2014). During that period, 48 patients with 55 inguinal hernias on average of 3.7 years (3 months-14 years) after prior open radical retropubic prostatectomy underwent hernia surgery (92.7% TAPP). The age of these patients, time required for surgery, hernia location (medial, lateral, combined and bilateral), the perioperative (30-day complications "Clavien Classification") and late complications with a median postoperative follow-up time of 8.0 years (2-17 years) were analyzed and compared with the data of the control group (all TAPP procedures for inguinal and femoral hernias). Results Patients with inguinal hernias after radical open retropubic prostatectomy were older as patients of the control group (70.3 vs. 59.1 years) and the medial time required for surgery was significantly longer (72.9 vs. 41.3 min). Less frequent were bilateral inguinal hernias (25.5 vs. 35.8%), medial inguinal hernias (Hernia classification Nyhus Type 3A) with 5.5 vs. 17.9% and femoral hernias (0 vs. 4.9%). No hernia patient after radical prostatectomy and only 0.1% of the control group (n = 6582 hernias) had a conversion to an anterior open repair. One patient after radical prostatectomy needed a laparoscopic drainage of a hemato-seroma 48 h postoperatively (1/51). The rate of late postoperative complications was low. 4.8% of patients reported of groin pain and 2.4% of testicular pain longer than 28 days postoperatively. The hernia recurrence rate of 2.4% (1/42 TAPP) was not significantly different from the control group (1.8%, 16/896 hernias). Conclusions In the hands of surgeons with large experiences in endoscopic laparoscopic hernia repair, the laparoscopic transperitoneal hernioplasty (TAPP) after previous radical open retropubic prostatectomy is safe and effective with low intra- and postoperative complications and low hernia recurrences (2.4%). A TAPP technique with closure of hernia gaps larger than 1 * 1 cm with non-absorbable surgical sutures and a mesh size of 13 * 13-15 cm is requested. A complete sharp dissection of the retropubic scared tissue for mesh implantation is not mandatory. PMID- 30406325 TI - Using quilting sutures in decreasing seroma formation after managing large ventral hernias: a comparative study. AB - PURPOSE: The aim of this study was to evaluate using quilting sutures in a prospective randomized controlled manner the decrease in the incidence of seroma formation among patients subjected to ventral hernia repair. METHODS: The study was a prospective randomized controlled study. 370 patients with large ventral hernias were randomly distributed among two groups. Group A (control group) included 180 patients in whom the repair was done without quilting sutures. Group B (quilting group) included 190 patients, all performed with quilting. Method of dissection was unified as far as possible. All cases had an attached closed suction drain that was removed after two successive days of output <= 50 cc. The output of the suction drain was recorded; accumulation of clinically detected seroma after 1, 2 and 4 weeks of removal of the drain was monitored. RESULTS: There was no statistical difference between both groups as regards the demographic data and the hernia characteristics. There was significantly smaller amount of output of the drains in every day of the first five postoperative days as well as the total amount of the output before drain removal in favor of the quilting group. Drains were removed earlier in group B. The incidence of clinically detected seroma was less in group B as well. CONCLUSIONS: Quilting sutures is an effective and easy technique to reduce post-ventral hernia seroma accumulation. PMID- 30406326 TI - Correction to: Systematic review of pre-clinical chronic myeloid leukaemia. AB - The author would like to correct the error in the publication of the original article. The corrected detail is given below for your reading. PMID- 30406327 TI - Correction to: A phase II study of lenalidomide consolidation and maintenance therapy after autologous PBSCT in patients with multiple myeloma. AB - In the original publication of this article, "Conflict of interest" was published incorrectly. The corrected "Conflict of interest" is given below for your reading. PMID- 30406328 TI - Oral Health Status of Refugee Children in Montreal. AB - This study aimed to assess the oral health status of refugee children in comparison with that of Canadian children. In addition, we investigated the extent to which demographic factors are associated with caries experience in this population. Children with a confirmed refugee status and Canadian children (control group) matched for age and sex composed the study population. A comprehensive review of dental charts was completed to assess children's demographic data, caries experience, oral hygiene and gingival health status. The majority of refugee children had never seen a dentist before their arrival to Canada. Refugee children had significant higher dmft/DMFT scores than Canadian children (7.29 +/- 5.1 and 4.47 +/- 5, respectively; p < 0.0001). Furthermore, individual factors, such as refugee status (OR = 5.08; 95% CI = 2.31-11.1) and child age (OR = 2.17; 95% CI = 1.04-4.51) were significantly associated with caries experience. Access to appropriate dental care to refugee children should be a key priority for health care providers and policy makers. PMID- 30406329 TI - Indocyanine green fluorescence-navigated laparoscopic metastasectomy for peritoneal metastasis of hepatocellular carcinoma: a case report. AB - BACKGROUND: Indocyanine green (ICG) can selectively accumulate in primary hepatocellular carcinoma (HCC) and its extrahepatic metastases. ICG fluorescence imaging is an extremely sensitive intraoperative tool for detecting HCC foci and can be used to detect impalpable tumors in laparoscopic surgery. Here, we report a case of a 75-year-old man who underwent peritoneal metastasis resection of HCC using a laparoscopic near-infrared imaging system and ICG fluorescence-navigated surgery. CASE PRESENTATION: A 75-year-old man was referred to our department for peritoneal metastasis resection of HCC. Two years before admission, he had undergone transarterial embolization and segmentectomy of segment 6 with open surgery for ruptured HCC. Computed tomography revealed a 12-mm peritoneal metastatic lesion on the abdominal wall near the cut surface of the liver. No other metastases were observed; resection of the solitary metastasis was scheduled. ICG (0.5 mg/kg body weight) was intravenously injected, 72 h preoperatively. An endoscopic, ICG near-infrared fluorescence imaging system revealed clear green fluorescence, indicating peritoneal metastasis of HCC on the abdominal wall. The tumor was resected with adequate surgical margin by partially resecting the liver and diaphragm, followed by histological confirmation as peritoneal metastasis of HCC. No recurrence was observed after 12 months of follow-up. CONCLUSIONS: ICG fluorescence can be useful in laparoscopic surgery for identifying peritoneal metastasis. PMID- 30406330 TI - Long working hours are inversely related to sick leave in the following 3 months: a 4-year registry study. AB - PURPOSE: The aim of this study was to investigate the effects of long working hours (>= 12 h shifts) on sick leave using objective records of shift work exposure and of sick leave. METHODS: A total of 1538 nurses (mean age 42.5, SD 12.0; response rate 42%) participated. Payroll and archival sick leave data over a 4-year period were retrieved from employers' records and aggregated over every third calendar month. A multilevel negative binomial model was used to investigate the effects of exposure to long working hours, on subsequent sick leave rates the following 3 months. Covariates included prior sick leave, number of shifts worked, night and evening shifts, personality, and demographic characteristics. RESULTS: Exposure to long working hours was associated with fewer sick leave days in the subsequent 3 months [adjusted model, incidence rate ratio (IRR) = 0.946, 95% CI 0.919-0.973, p < 0.001]. The interaction long working hours by a number of work days showed that sick leave days the subsequent 3 months was higher by long shifts when number of shifts was high compared to when number of shifts was low [adjusted model, IRR 1.002, 95% CI 1.000-1.004, p < 0.05]. DISCUSSION: Long working hours was associated with fewer sick leave days. The restorative effects of extra days off with long working hours are discussed as possible explanations to this relationship. PMID- 30406331 TI - Is effort-reward imbalance at work associated with different domains of health functioning? Baseline results from the French CONSTANCES study. AB - PURPOSE: Despite its importance a comprehensive assessment of health functioning has rarely been included in epidemiological investigations of work-related health outcomes. In this study, we analyzed associations of a health-adverse psychosocial work environment with a comprehensive set of subjective and objective measures of health functioning that cover the three domains of affective, cognitive, and physical functioning. METHODS: Baseline data from the French CONSTANCES cohort study were used with a sample of 24,327 employed men and women aged 45-60. Psychosocial work environment was measured by the short version of the effort-reward imbalance (ERI) questionnaire. Measures of health functioning were depressive symptoms, semantic fluency, verbal memory, walking speed, standing balance and lung function. RESULTS: First, we replicated main psychometric properties of the ERI questionnaire in the French cohort. Second, ERI scales revealed consistent associations with depressive symptoms, but less consistent links to cognitive and physical function. Among men, we observed an association of stressful work with reduced lung function. CONCLUSIONS: This study demonstrated consistent associations of stressful work in terms of effort-reward imbalance with affective functioning in a large sample of male and female employees. Relationships with physical functioning were less consistent and restricted to men, and cognitive functioning was only marginally associated with stressful work. We also established the psychometric properties of the French short version of the ERI questionnaire, thus offering a tool for guiding and harmonizing further research in this field. PMID- 30406332 TI - Heatwave and work-related injuries and illnesses in Adelaide, Australia: a case crossover analysis using the Excess Heat Factor (EHF) as a universal heatwave index. AB - PURPOSE: Heatwaves, or extended periods of extreme heat, are predicted to increase in frequency, intensity and duration with climate change, but their impact on occupational injury has not been extensively studied. We examined the relationship between heatwaves of varying severity and work-related injuries and illnesses. We used a newly proposed metric of heatwave severity, the Excess Heat Factor (EHF), which accounts for local climate characteristics and acclimatization and compared it with heatwaves defined by daily maximum temperature. METHODS: Work-related injuries and illnesses were identified from two administrative data sources: workers' compensation claims and work-related ambulance call-outs for the years 2003-2013 in Adelaide, Australia. The EHF metrics were obtained from the Australian Bureau of Meteorology. A time stratified case-crossover regression model was used to examine associations between heatwaves of three levels of severity, workers' compensation claims, and work-related ambulance call-outs. RESULTS: There was an increase in work-related ambulance call-outs and compensation claims during low and moderately severe heatwaves as defined using the EHF, and a non-significant decline during high severity heatwaves. Positive associations were observed during moderate heatwaves in compensation claims made by new workers (RR 1.31, 95% CI 1.10-1.55), workers in medium-sized enterprises (RR 1.15, 95% CI 1.01-1.30), indoor industries (RR 1.09, 95% CI 1.01-1.17), males (RR 1.13, 95% CI 1.03-1.23) and laborers (RR 1.21, 95% CI 1.04-1.39). CONCLUSIONS: Workers should adopt appropriate precautions during moderately severe heatwaves, when the risks of work-related injuries and illnesses are increased. Workplace policies and guidelines need to consider the health and safety of workers during heatwaves with relevant prevention and adaptation measures. PMID- 30406333 TI - The first report on serotyping of bluetongue virus in small ruminants of Khyber Pakhtunkhwa province, Pakistan. AB - Bluetongue virus (BTV), a member of Orbivirus genus (family Reoviridae), is a non contagious infection of domestic and wild ruminants. The current study was designed to detect various serotypes of BTV in small ruminants of Khyber Pakhtunkhwa (KPK) province of Pakistan, along with their effects on hemato biochemical parameters. A total of 408 serum samples in four districts (Mansehra, Abbottabad, Swabi, and Kohat) of KPK from small ruminants were screened based on competitive ELISA (cELISA). A total of 204 (50%) samples were found positive for BTV group-specific antibodies. The seropositive samples were processed for the detection of BTV serotypes through real-time polymerase chain reaction (qPCR). Out of 204 cELISA-positive samples, 60 (29.41%) were found positive through qPCR. Three serotypes [6, 8, 9] were detected from Mansehra District and two from Kohat [2, 8] and Abbottabad [6, 8], while only one from Swabi [8]. The serotype "8" was found consistently in all the four study districts. A significant (p < 0.05) increase in the level of blood urea nitrogen (BUN) and alkaline phosphatase (ALP) was recorded in goats, whereas aspartate aminotransferase (AST) in sheep infected with BTV, compared to healthy animals. The hematological parameters showed significantly (p < 0.05) raised total leucocyte count (TLC) in both sheep and goats, whereas only hematocrit (HCT) value was increased significantly (p < 0.05) in infected sheep. This is the first report on serotyping of BTV among small ruminants in Pakistan. PMID- 30406334 TI - Factors Influencing the Risk of Becoming Sexually Active Among HIV Infected Adolescents in Kampala and Kisumu, East Africa. AB - About 2.1 million adolescents aged 10-19 years are living with HIV, 80% of them in sub-Saharan Africa. Early sexual activity remains an important risk factor for HIV transmission and potentially result in negative health consequences including onward transmission of sexually transmitted infections. Cross-sectional data of 580 adolescents living with HIV (ALHIV) aged 13-17 years (317 girls and 263 boys) from Kenya and Uganda were analyzed to assess factors associated with risk to become sexually active. Factors associated with risk of sexual intercourse were identified using Kaplan-Meier survival curves and Cox regression with gender stratified bi-and multivariable models. Slightly more females (22%) than males (20%) reported they have had sex. Multivariable models showed that being aware of one's own HIV infection, and receiving antiretroviral treatment were negatively associated with risk of becoming sexually active, while subjective norms conducive to sexuality, and girls' poor health experience increased the risk. In the final multi-variable models, schooling was protective for girls, but not for boys. Being more popular with the opposite sex was negatively associated with the outcome variable only for girls, but not for boys. This study expands the knowledge base on factors associated with onset of sexual activity among ALHIV, potentially informing positive prevention interventions. PMID- 30406336 TI - The Relationship Between Hiatal Hernia and Cricopharyngeus Muscle Dysfunction. AB - Although the precise etiology of cricopharyngeus muscle (CPM) dysfunction (CPMD) is uncertain, many have hypothesized that a hypertrophied CPM may develop as a protective compensation against gastroesophageal reflux disease (GERD). The purpose of this investigation was to evaluate the association between CPMD and the presence of hiatal hernia (HH) in an attempt to elucidate the potential etiology of CPMD. The charts of individuals who underwent video fluoroscopic esophagrams between 01/01/14 and 10/30/16 were reviewed from an electronic database. A group of 50 subjects with reported HH were identified and age- and gender-matched to an individual without HH. The prevalence of CPMD was compared between groups. The mean (+/- SD) age of the HH cohort was 64 (+/- 13.4) years and 64 (+/- 12.8) years for the group without HH (p > 0.05). Thirty-eight percent was male. The frequency of CPMD in the HH group was 78% versus 58% in the non-HH group (p < 0.05). Individuals with a HH were 2.57 times more likely to have evidence of CPMD (95% CI 1.07- 6.15). Although these data suggest an association between GERD and CPMD, further research is required before a causal relationship can be presumed. PMID- 30406337 TI - New generation cancer therapy: right direction for sure with some uncertainty. PMID- 30406335 TI - Short Message Service (SMS) Surveys Assessing Pre-exposure Prophylaxis (PrEP) Adherence and Sexual Behavior are Highly Acceptable Among HIV-Uninfected Members of Serodiscordant Couples in East Africa: A Mixed Methods Study. AB - Short message service (SMS) surveys are a promising data collection method and were used to measure sexual behavior and adherence to HIV pre-exposure prophylaxis (PrEP) among HIV-uninfected partners of serodiscordant couples enrolled in a sub-study of the Partners Demonstration Project (an open-label study of integrated antiretroviral therapy and PrEP for HIV prevention in Kenya and Uganda). Questionnaires were completed by 142 participants after study exit. Median age was 29 years; 69% were male. Ninety-five percent (95%) felt SMS surveys were "easy" or "very easy", 74% reported no challenges, and 72% preferred SMS surveys over in-person study visits. Qualitative interviews involving 32 participants confirmed the ease of responding to SMS surveys. Participants also indicated that surveys acted as reminders for adherence to PrEP and condom use and were experienced as support from the study. SMS surveys were generally found to be acceptable in this population and provided real-time context of PrEP use. PMID- 30406338 TI - Substance use and internalizing symptoms among high school students and access to health care services: results from a population-based study. AB - OBJECTIVES: To examine co-occurring mental health problems among a population based sample of high school students in Ontario, Canada, to understand their prevalence, associated risk factors, and relationship with mental health service access and utilization. METHODS: The data were derived from the 2013 Ontario Student Drug Use and Health Survey, a biennial survey of students attending publicly funded Ontario schools, from a subsample of students who completed both the internalizing and substance use portions of the survey (n = 2945). Rates of co-occurring problems were calculated for the previous 12 months. Service use for students with co-occurring problems was also calculated for the past 12 months. Odds ratios were estimated using binary logistic regression models correcting for the survey design. RESULTS: In an adjusted model, youth with internalizing symptoms were 2.40 times more likely and youth with substance use problems were 2.24 times more likely to have accessed mental health services during the past 12 months than youth without these problems. Youth with co-occurring internalizing and substance use problems were 6.74 times more likely (95% CI 4.66-9.76, p < 0.001) to have accessed mental health services during the past year compared with youth without co-occurring problems, but only 52.8% of youth with co-occurring problems (95% CI 45.6-59.9%) used mental health services. CONCLUSIONS: The findings suggest that just over half of Ontario students in grades 9 through 12 who have co-occurring internalizing and substance use problems are utilizing mental health services. Further research should examine the factors related to service use in this population in order to better inform policy and program development. PMID- 30406339 TI - Mild cognitive impairment in long-term brain tumor survivors following brain irradiation. AB - INTRODUCTION: There is no accepted classification of cognitive impairment in cancer survivors. We assess the extent of mild cognitive impairment (MCI) syndrome in brain tumor survivors using criteria adapted from the National Institute on Aging and the Alzheimer's Association (NIA-AA). METHODS: We retrospectively reviewed the cognitive data of brain tumor survivors post radiation therapy (RT) enrolled from 2008 to 2011 in a randomized trial of donepezil versus placebo for cognitive impairment. One hundred and ninety eight adult survivors with primary or metastatic brain tumors who were >= 6 months post RT were recruited at 24 sites in the United States. Cognitive function was assessed at baseline, 12 and 24 weeks post-randomization. For this analysis, we used baseline data to identify MCI and possible dementia using adapted NIA-AA criteria. Cases were subtyped into four groups: amnestic MCI-single domain (aMCI sd), amnestic MCI-multiple domain (aMCI-md), non-amnestic MCI-single domain (naMCI-sd), and non-amnestic MCI-multiple domain (naMCI-md). RESULTS: One hundred and thirty one of 197 evaluable patients (66%) met criteria for MCI. Of these, 13% were classified as aMCI-sd, 58% as aMCI-md, 19% as naMCI-sd, and 10% as naMCI md. Patients with poorer performance status, less education, lower household income and those not working outside the home were more likely to be classified as MCI. CONCLUSION: Two-thirds of post-RT brain tumor survivors met NIA-AA criteria for MCI. This taxonomy may be useful when applied to brain tumor survivors because it defines cognitive phenotypes that may be differentially associated with course, treatment response, and risk factor profiles. PMID- 30406340 TI - Environmental behaviors of PAHs in Ordovician limestone water of Fengfeng coal mining area in China. AB - In this study, we collected a total of 15 Ordovician limestone (OL) water, 4 shallow groundwater, 3 mine water, 2 surface water, and 2 coal bedrock water samples, aiming to analyze the characteristics of distributions and sources of polycyclic aromatic hydrocarbons (PAHs) in OL water in a typical exploited coal mine named as Fengfeng mining area. Firstly, the PAHs behaviors and characteristics in different types of water of the mining area were investigated and summarized. And then, the hydrogen and oxygen isotopes were combined with isomer ratio method to determine the characteristics, sources, and behaviors of PAHs in OL water, respectively. Results showed that the concentration of PAHs ranged from 0.06 to 0.56 ng/L in OL water of Fengfeng Mine. Among them, the dominant 2-4 cyclic PAHs, including Nap, Phe, Flt, and Flu, were detected at a low concentration level with high detection rate. Characteristic compound ratios Ant/(Ant + Phe) and Flt/(Flt + Pyr) showed that the PAHs were derived from the combustion of the coal and biomass. The results of deltaD/delta18O and deltaD/Phe testing showed that the PAHs in most OL water came from rainfall infiltration recharge with coal and biomass combustion products in exposed bedrock area at high altitude. The PAHs of some polluted areas were derived from leakage recharge of shallow groundwater, mine water, and coal bedrock water. PMID- 30406341 TI - Blue light-emitting diode in healthy vaginal mucosa-a new therapeutic possibility. AB - A healthy female genital mucosa has an ecosystem that remains in balance through interactions between endogenous and exogenous factors. The light-emitting diode (LED) is a device that emits light at different wavelengths, with varying color and effects. Blue light in humans is most commonly used for antimicrobial purposes and has been already applied to treat facial acne and gastric bacteria. Although blue LED therapy in humans has been reported, its properties against vaginal infections have not yet been investigated. This study aims to test the safety and effects of 401 +/- 5 nm blue LED on healthy vaginal mucosa. Phase I clinical trial involving 10 women between 18 and 45 years old with healthy vaginal mucosa. The participants were illuminated by 401 +/- 5 nm blue LED for 30 min and anamnesis, oncotic cytology, and pH measurement were made again after 21/28 days of treatment. In the re-evaluation, adverse effects were investigated. The mean age was 27 +/- 5.4 years and one of the women was excluded due to interruption of use of oral contraceptives. Oncotic cytology done before and after therapy showed that the composition of the microflora remained normal in all participants. Vaginal pH remained unchanged in eight of the women and had a reduction in one woman (5.0-4.0). No adverse effects were observed during or after illumination. 401 +/- 5 nm blue LED did not generate any adverse effects or pathogenic changes in the microflora and vaginal pH. The effects of 401 +/- 5 nm blue LED still need to be tested in vulvovaginal pathogens. Trial registration number: NCT03075046. PMID- 30406342 TI - Ensemble Technique for Prediction of T-cell Mycobacterium tuberculosis Epitopes. AB - Development of an effective machine-learning model for T-cell Mycobacterium tuberculosis (M. tuberculosis) epitopes is beneficial for saving biologist's time and effort for identifying epitope in a targeted antigen. Existing NetMHC 2.2, NetMHC 2.3, NetMHC 3.0 and NetMHC 4.0 estimate binding capacity of peptide. This is still a challenge for those servers to predict whether a given peptide is M. tuberculosis epitope or non-epitope. One of the servers, CTLpred, works in this category but it is limited to peptide length of 9-mers. Therefore, in this work direct method of predicting M. tuberculosis epitope or non-epitope has been proposed which also overcomes the limitations of above servers. The proposed method is able to work with variable length epitopes having size even greater than 9-mers. Identification of T-cell or B-cell epitopes in the targeted antigen is the main goal in designing epitope-based vaccine, immune-diagnostic tests and antibody production. Therefore, it is important to introduce a reliable system which may help in the diagnosis of M. tuberculosis. In the present study, computational intelligence methods are used to classify T-cell M. tuberculosis epitopes. The caret feature selection approach is used to find out the set of relevant features. The ensemble model is designed by combining three models and is used to predict M. tuberculosis epitopes of variable length (7-40-mers). The proposed ensemble model achieves 82.0% accuracy, 0.89 specificity, 0.77 sensitivity with repeated k-fold cross-validation having average accuracy of 80.61%. The proposed ensemble model has been validated and compared with NetMHC 2.3, NetMHC 4.0 servers and CTLpred T-cell prediction server. PMID- 30406343 TI - Longitudinal Associations Between Fatigue and Perceived Work Ability in Cancer Survivors. AB - Purpose To examine the associations between changes of fatigue and changes of perceived work ability in cancer survivors. Furthermore, to examine the effects of physical job demands on these associations. Methods Data from a feasibility study on a multidisciplinary intervention to enhance return to work in patients with cancer receiving chemotherapy was used. Fatigue (Multidimensional Fatigue Inventory) and perceived work ability (first item of the Work Ability Index) were assessed at baseline, and after 6, 12, and 18 months. Change scores (S1, S2, S3) from each assessment to the next were calculated, thus encompassing three separate time periods of 6 months. Regression analyses were used to quantify associations between change of perceived work ability and (model 1) change of general fatigue, and (model 2) change of mental and physical fatigue for each 6 month period separately. For model 2, interaction effects of perceived physical job demands were studied. Results A total of 89 participants were included for analysis, among which 84% with a diagnosis of breast cancer. On average, in model 1, a reduction of five points on general fatigue was associated with an improvement of one point in perceived work ability in all three 6-month periods. Model 2 showed, similarly, that change of physical fatigue (S1 and S2: B = - 0.225; p < .001 and B = - 0.162; p = .012) and change of mental fatigue (S3: B = 0.177; p = .027) were significantly inversely associated with change of perceived work ability. Interaction effects were not significant. Conclusion The inverse, longitudinal association between fatigue and perceived work ability supports previous findings from cross-sectional studies and shows potential occupational impact of targeting fatigue in cancer rehabilitation. PMID- 30406344 TI - Investigation of feeding behaviour in C. elegans reveals distinct pharmacological and antibacterial effects of nicotine. AB - Caenorhabditis elegans is an informative model to study the neural basis of feeding. A useful paradigm is one in which adult nematodes feed on a bacterial lawn which has been pre-loaded with pharmacological agents and the effect on pharyngeal pumping rate scored. A crucial aspect of this assay is the availability of good quality bacteria to stimulate pumping to maximal levels. A potential confound is the possibility that the pharmacological agent impacts bacterial viability and indirectly influences feeding rate. Here, the actions of nicotine on pharyngeal pumping of C. elegans and on the Escherichia coli bacterial food source were investigated. Nicotine caused an immediate and concentration-dependent inhibition of C. elegans pharyngeal pumping, IC50 4 mM (95% CI = 3.4 mM to 4.8 mM). At concentrations between 5 and 25 mM, nicotine also affected the growth and viability of E. coli lawns. To test whether this food depletion by nicotine caused the reduced pumping, we modified the experimental paradigm. We investigated pharyngeal pumping stimulated by 10 mM 5-HT, a food 'mimic', before testing if nicotine still inhibited this behaviour. The IC50 for nicotine in these assays was 2.9 mM (95% CI = 3.1 mM to 5.1 mM) indicating the depletion of food lawn does not underpin the potency of nicotine at inhibiting feeding. These studies show that the inhibitory effect of nicotine on C. elegans pharyngeal pumping is mediated by a direct effect rather than by its poorly reported bactericidal actions. PMID- 30406345 TI - Comparison of Reference Genes for Transcriptional Studies in Postmortem Human Brain Tissue Under Different Conditions. PMID- 30406347 TI - Is it appropriate to use anticoagulants for thromboprophylaxis after knee arthroscopy? PMID- 30406346 TI - Development of Bacillus amyloliquefaciens as a high-level recombinant protein expression system. AB - Bacillus amyloliquefaciens K11 is a hyperproducer of extracellular neutral protease, which can produce recombinant homologous protein steadily and is amenable to scale up to high-cell density fermentation. The present study aims to genetically modify strain K11 as a highly efficient secretory expression system for high-level production of heterologous proteins. Using B. amyloliquefaciens K11 and alkaline protease gene BcaprE as the expression host and model gene, the gene expression levels mediated by combinations of promoters PamyQ, PaprE and Pnpr and signal peptides SPamyQ, SPaprE and SPnpr were assessed on shake flask level. The PamyQ-SPaprE was found to be the best secretory expression cassette, giving the highest enzyme activities of extracellular BcaprE (13,800 +/- 308 U/mL). Using the same expression system, the maltogenic alpha-amylase Gs-MAase and neutral protease BaNPR were successfully produced with the enzyme activities of 19. +/- 0.2 U/mL and 17,495 +/- 417 U/mL, respectively. After knocking out the endogenous neutral protease-encoding gene Banpr, the enzyme activities of BcaprE and Gs-MAase were further improved by 25.4% and 19.4%, respectively. Moreover, the enzyme activities of BcaprE were further improved to 30,200 +/- 312 U/mL in a 15 L fermenter following optimization of the fermentation conditions. In the present study, the genetically engineered B. amyloliquefaciens strain 7-6 containing PamyQ-SPaprE as the secretory expression cassette was developed. This efficient expression system shows general applicability and represents an excellent industrial strain for the production of heterologous proteins. PMID- 30406348 TI - A narrative review of the cardiovascular risks associated with concomitant aspirin and NSAID use. AB - The concomitant use of low-dose aspirin for cardioprotection and non-steroidal anti-inflammatory agents for pain relief is prevalent, particularly in the elderly for whom cardiovascular disease and pain are common co-morbidities. Non selective non-steroidal anti-inflammatory drugs (NSAIDs) are known to interfere with the antiplatelet effect of aspirin through competitive binding with COX-1. While the clinical significance of this interference is still unclear, this review sought to assess the body of literature which has evaluated the potential attenuation of the anti-platelet effect of aspirin when dosed concomitantly with an NSAID. This review supports that the pharmacodynamic interaction between aspirin and non-selective NSAIDs occurs, but finds that the interaction varies amongst agents, and is highly dependent on numerous factors including: dose timing, dose of aspirin, and dose of the NSAID in question. Recent findings suggest that patient factors, such as body weight may also be indicators of aspirin's cardiovascular effectiveness. Ultimately, the clinical decision making for concomitant NSAID and low-dose aspirin regimens remains at the patient level. PMID- 30406350 TI - Platelet number and graft function predict intensive care survival in allogeneic stem cell transplantation patients. AB - Despite significant advances in the treatment of complications requiring intensive care unit (ICU) admission, ICU mortality remains high for patients after allogeneic stem cell transplantation. We evaluated the role of thrombocytopenia and poor graft function in allogeneic stem cell recipients receiving ICU treatments along with established prognostic ICU markers in order to identify patients at risk for severe complications. At ICU admission, clinical and laboratory data of 108 allogeneic stem cell transplanted ICU patients were collected and retrospectively analyzed. Platelet counts (<= 50,000/MUl, p < 0.0005), hemoglobin levels (<= 8.5 mg/dl, p = 0.019), and leukocyte count (<= 1500/MUl, p = 0.025) along with sepsis (p = 0.002) and acute myeloid leukemia (p < 0.0005) correlated significantly with survival. Multivariate analysis confirmed thrombocytopenia (hazard ratio (HR) 2.79 (1.58-4.92, 95% confidence interval (CI)) and anemia (HR 1.82, 1.06-3.11, 95% CI) as independent mortality risk factors. Predominant ICU diagnoses were acute respiratory failure (75%), acute kidney injury (47%), and septic shock (30%). Acute graft versus host disease was diagnosed in 42% of patients, and 47% required vasopressors. Low platelet (<= 50,000/MUl) and poor graft function are independent prognostic factors for impaired survival in critically ill stem cell transplanted patients. The underlying pathophysiology of poor graft function is not fully understood and currently under investigation. High-risk patients may be identified and ICU treatments stratified according to allogeneic stem cell patients' individual risk profiles. In contrast to previous studies involving medical or surgical ICU patients, the fraction of thrombocytopenic patients was larger and low platelets were a better differentiating factor in multivariate analysis than any other parameter. PMID- 30406351 TI - Preface. PMID- 30406352 TI - Longitudinal investigation of cognitive deficits in breast cancer patients and their gray matter correlates: impact of education level. AB - Cognitive deficits are a major complaint in breast cancer patients, even before chemotherapy. Comprehension of the cerebral mechanisms related to cognitive impairment in breast cancer patients remains difficult due to the scarcity of studies investigating both cognitive and anatomical imaging changes. Furthermore, only some of the patients experienced cognitive decline following chemotherapy, yet few studies have identified risk factors for cognitive deficits in these patients. It has been shown that education level could impact cognitive abilities during the recovery phase following chemotherapy. Our main aim was to longitudinally evaluate cognitive and anatomical changes associated with cancer and chemotherapy in breast cancer patients. Our secondary aim was to assess the impact of education level on cognitive performances and gray matter (GM) atrophy in these patients. Twenty patients were included before chemotherapy (T1), 1 month (T2) and 1 year (T3) after chemotherapy. Twenty-seven controls without a history of cancer were assessed at T1 and T3 only. Cluster groups based on education level were defined for both groups and were further compared. Comparison between patients and controls revealed deficits in patients on verbal episodic memory retrieval at T1 and T3 and on executive functions at T3. After chemotherapy, breast cancer patients had GM atrophy that persisted or recovered 1 year after chemotherapy depending on the cortical areas. Increase in GM volumes from T1 to T3 were also found in both groups. At T2, patients with a higher level of education compared to lower level exhibited higher episodic memory retrieval and state anxiety scores, both correlating with cerebellar volume. This higher level of education group exhibited hippocampal atrophy. Our results suggest that, before chemotherapy, cancer-related processes impact cognitive functioning and that this impact seems exacerbated by the effect of chemotherapy on certain brain regions. Increase in GM volumes after chemotherapy were unexpected and warrant further investigations. Higher education level was associated, 1 month after the end of chemotherapy, with greater anxiety and hippocampal atrophy despite a lack of cognitive deficits. These results suggest, for the first time, the occurrence of compensation mechanisms that may be linked to cognitive reserve in relationship to state anxiety. This identification of factors, which may compensate cognitive impairment following chemotherapy, is critical for patient care and quality of life. PMID- 30406353 TI - Regional growth trajectories of cortical myelination in adolescents and young adults: longitudinal validation and functional correlates. AB - Adolescence is a time of continued cognitive and emotional evolution occurring with continuing brain development involving synaptic pruning and cortical myelination. The hypothesis of this study is that heavy myelination occurs in cortical regions with relatively direct, predetermined circuitry supporting unimodal sensory or motor functions and shows a steep developmental slope during adolescence (12-21 years) until young adulthood (22-35 years) when further myelination decelerates. By contrast, light myelination occurs in regions with highly plastic circuitry supporting complex functions and follows a delayed developmental trajectory. In support of this hypothesis, cortical myelin content was estimated and harmonized across publicly available datasets provided by the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) and the Human Connectome Project (HCP). The cross-sectional analysis of 226 no-to-low alcohol drinking NCANDA adolescents revealed relatively steeper age-dependent trajectories of myelin growth in unimodal primary motor cortex and flatter age dependent trajectories in multimodal mid/posterior cingulate cortices. This pattern of continued myelination showed smaller gains when the same analyses were performed on 686 young adults of the HCP cohort free of neuropsychiatric diagnoses. Critically, a predicted correlation between a motor task and myelin content in motor or cingulate cortices was found in the NCANDA adolescents, supporting the functional relevance of this imaging neurometric. Furthermore, the regional trajectory slopes were confirmed by performing longitudinally consistent analysis of cortical myelin. In conclusion, coordination of myelin content and circuit complexity continues to develop throughout adolescence, contributes to performance maturation, and may represent active cortical development climaxing in young adulthood. PMID- 30406349 TI - An Overview of 3D Printing Technologies for Soft Materials and Potential Opportunities for Lipid-based Drug Delivery Systems. AB - PURPOSE: Three-dimensional printing (3DP) is a rapidly growing additive manufacturing process and it is predicted that the technology will transform the production of goods across numerous fields. In the pharmaceutical sector, 3DP has been used to develop complex dosage forms of different sizes and structures, dose variations, dose combinations and release characteristics, not possible to produce using traditional manufacturing methods. However, the technology has mainly been focused on polymer-based systems and currently, limited information is available about the potential opportunities for the 3DP of soft materials such as lipids. METHODS: This review paper emphasises the most commonly used 3DP technologies for soft materials such as inkjet printing, binder jetting, selective laser sintering (SLS), stereolithography (SLA), fused deposition modeling (FDM) and semi-solid extrusion, with the current status of these technologies for soft materials in biological, food and pharmaceutical applications. RESULT: The advantages of 3DP, particularly in the pharmaceutical field, are highlighted and an insight is provided about the current studies for lipid-based drug delivery systems evaluating the potential of 3DP to fabricate innovative products. Additionally, the challenges of the 3DP technologies associated with technical processing, regulatory and material issues of lipids are discussed in detail. CONCLUSION: The future utility of 3DP for printing soft materials, particularly for lipid-based drug delivery systems, offers great advantages and the technology will potentially support patient compliance and drug effectiveness via a personalised medicine approach. PMID- 30406354 TI - The relationship between the morphological axis and the kinematic axis of the proximal radius. AB - PURPOSE: Surgical procedures for impaired forearm rotation such as for chronic radial head dislocation remain controversial. We hypothesized that the morphological axis of the proximal radius is important for stable forearm rotation, and we aimed to clarify the relationship between the morphological axis and the kinematic axis of the proximal radius using four-dimensional computed tomography (4DCT). METHODS: Ten healthy volunteers were enrolled. Four dimensional CT of the dominant forearm during supination and pronation was obtained. The rotation axis of forearm rotation was calculated from all frames during supination and pronation. The principle axis of inertia, which represents the most stable rotation axis of a rigid body, was calculated for the proximal radius by extending its surface data incrementally by 1% from the proximal end. The angle between the kinematic rotation axis and the morphological rotation axis of each length was calculated. RESULTS: The rotation axis of the forearm was positioned on the radial head 0.0 mm radial and 0.4 mm posterior to the center of the radial head proximally and 2.0 mm radial and 1.2 mm volar to the fovea of the ulnar head distally. The principle axis at 15.9% of the length of the proximal radius coincided with the forearm rotation axis (kinematic axis). Individual differences were very small (SD 1.4%). CONCLUSION: Forearm rotation was based on the axis at 16% of the length of the proximal radius. This portion should be aligned in cases of severe morphological deformity of the radial head that cause "rattling motion" of the radial head after reduction procedures. PMID- 30406355 TI - Fibular groove morphology and measurements on MRI: correlation with fibularis tendon abnormalities. AB - PURPOSE: Fibular (peroneal) groove morphology may influence fibularis tendon pathology, including tendinosis, tears, and luxation. The study goal was to evaluate the inter-reader agreement of morphologic characterization and measures of the fibular groove at two different levels on MRI and correlation with fibularis tendon pathology. MATERIALS AND METHODS: 47 ankle MRIs in patients without lateral ankle pain were reviewed by two musculoskeletal radiologists. Fibular groove morphology and various measurements were assessed at both the level of the tibial plafond and 1 cm proximal to the tip of the lateral malleolus. Fibularis tendon pathology and other variants were also recorded. Intraclass correlation (ICC) and kappa statistic (kappa) were applied to assess inter-observer agreement. Receiver operating characteristic (ROC) and area under the curve (AUC) analysis were performed to determine correlation between fibular groove morphometry and fibularis (peroneus) brevis tendon tears. RESULTS: Between readers, there was fair-to-excellent agreement (ICC = 0.61-0.95) for performed fibular groove measurements and moderate-to-very good agreement for identification and description of fibular groove and fibularis tendon morphology and pathology and normal variants in this region (kappa = 0.46-1), with the exception of fibular groove morphology at 1 cm proximal to the lateral malleolar tip (kappa = 0.34). Individually, no measurement or description of pathology could discriminate between patients with or without fibularis brevis tendon tears except fibularis brevis tendinosis (AUC = 0.87 for reader 1). CONCLUSION: There is overall moderate-to-excellent inter-reader agreement for various measurements and descriptors of fibular groove and fibularis tendon morphometry and pathology, including novel measurements introduced in this study. PMID- 30406356 TI - Characteristics and outcome of newborn admitted with acute bilirubin encephalopathy to a tertiary neonatal intensive care unit. AB - BACKGROUND: Acute bilirubin encephalopathy (ABE) still represents a significant cause of morbidity and mortality throughout the world, especially in developing countries. We aimed to determine the prevalence of ABE based on the Johnson bilirubin-induced neurologic dysfunction (BIND) score and to describe the discharge outcomes. METHODS: We prospectively studied all newborns >= 35 weeks with ABE by evaluating signs of mental sensorium, muscle tone, and cry patterns over 1 year. RESULTS: 12% (81 out of 674) of the newborns admitted for neonatal hyperbilirubinemia had a BIND score > 1. Their admission age was 6 +/- 4.1 days; total serum bilirubin (TSB) was 31.2 +/- 10 mg/dL (range 17.5-75.2). Of these newborns, 40.7% and 21% had evidence of haemolysis and sepsis, respectively. Overall mortality was 9.9%; 58% of the newborns showed signs of mild-to-moderate BIND at discharge, while 32.1% survived with an apparently normal outcome. Admission BIND score was significantly correlated with admission TSB (r = 0.476, P < 0.001). Similarly, BIND score at discharge was correlated with admission TSB (r = 0.442, P < 0.001) and admission BIND score (r = 0.888, P < 0.001). The regression model showed that admission TSB (P < 0.001) and maternal illiteracy (P = 0.034) were predictors of the BIND score at admission, while admission BIND score was the best indicator of the discharge score (P < 0.001). CONCLUSIONS: ABE is still a major problem in our community. Admission TSB and maternal illiteracy are good predictors of bilirubin encephalopathy at admission and discharge. PMID- 30406357 TI - Thyroid hormones, metabolic syndrome and Vitamin D in middle-aged and older euthyroid subjects: a preliminary study. AB - AIM: To explore the relationship between thyroid hormones, Vitamin D (Vit.D) serum concentrations and metabolic syndrome (MetS) in euthyroid subjects. METHODS: 123 community-dwelling subjects were enrolled. According to thyroid stimulating hormone (TSH) values the sample was divided into: (1) group 1 (TSH <= 2 mU/L); (2) group 2 (TSH > 2 mU/L). RESULTS: Group 2 showed higher percentage of subjects with MetS (p = 0.003) and hypertension (p = 0.031), higher values of waist circumference (WC) (p = 0.007), parathyroid hormone (p = 0.016), glycaemia (p = 0.045), triglycerides (p = 0.034) and free T4 (fT4) (p = 0.013). Correlation analysis showed several weak significant correlations: MetS with TSH (r = 0.202, p = 0.031) and fT3 (r = - 0.206, p = 0.028); THS with body mass index (r = 0.187, p = 0.047) and hypertension (r = 0.199, p = 0.034); Vit.D with WC (r = - 0.185, p = 0.04). CONCLUSIONS: Our results showed a possible association between thyroid hormones and MetS. Visceral fat and insulin resistance may be an interesting link between Vit.D and TSH levels. PMID- 30406358 TI - Cut-off for the Life-Space Assessment in persons with cognitive impairment. AB - BACKGROUND: A version of the Life-Space Assessment in persons with cognitive impairment (LSA-CI) has recently been developed. AIMS: To establish a cut-off value for the newly developed Life-Space Assessment in persons with cognitive impairment (LSA-CI). METHODS: In a cross-sectional study including 118 multimorbid, older persons with cognitive impairment, life-space mobility (LSM) was documented by the LSA-CI. The analysis was rationalized by Global Positioning System (GPS)-based measures of spatial distance from home. A receiver-operating characteristic (ROC) curve was created and the cut-off point for the LSA-CI was identified with the Youden's Index. RESULTS: ROC curve analysis indicated a critical value of 26.75 (within a range of 0-90) to differentiate between low and high LSM with a sensitivity of 78.1% and specificity of 84.2%. DISCUSSION: Diagnostic interpretation of the ROC curves revealed that low and high LSM groups can be differentiated with the proposed cut-off. CONCLUSIONS: The proposed LSA-CI cut-off score can be recommended to tailor clinical interventions and evaluate change over time. PMID- 30406359 TI - The shifting self in aging. AB - BACKGROUND AND AIMS: This study investigated the ability of older adults to shift between self-images. METHODS: We designed a shifting-self task in which older adults and younger adults were invited to produce statements describing their physical self (e.g., "I am tall") and psychological self (e.g., "I am cheerful"). Participants were invited to shift between physical-self statements and psychological-self statements and, on a control task, to produce two blocks of physical-self statements and psychological-self statements. They also performed a typical shifting task (i.e., the plus-minus task). RESULTS: Analysis showed slower completion time on the shifting-self task in older adults than in younger adults. Time to complete the shifting-self task was longer than that for the control task in both older and younger adults. Performances on the shifting-self task were significantly correlated with performances on the plus-minus task. DISCUSSION: We hypothesized that older adults take more time to shift between self-images because they enjoy self-stability. In other words, the tendency of older adults to shift between self-images more slowly than younger adults might be because they have more consistent or stable self-concepts, and are therefore less inclined to "change" their self-images. PMID- 30406360 TI - The RECIST criteria compared to conventional response evaluation after peptide receptor radionuclide therapy in patients with neuroendocrine neoplasms. AB - OBJECTIVE: The Response Evaluation Criteria In Solid Tumors (RECIST) is the most used radiological method for evaluating response after peptide receptor radionuclide therapy (PRRT) in patients with neuroendocrine tumors. This method may give too positive estimates of response in slow growing tumors as it allows a substantial increase in tumor size before patients are classified as having progressive disease. We wanted to compare RECIST with a conventional method in routine use for estimating treatment effect based on defining any unequivocal increase in size of tumor load as progressive disease. We also wanted to investigate whether any differences had clinical implications. METHODS: Patients treated with 177Lutetium-DOTA-octreotate having at least one follow-up radiological response evaluation were included. Radiological examinations were retrospectively evaluated by RECIST and compared to the radiological evaluations performed at regular follow-up examinations. RESULTS: Seventy-nine patients were included, 33 (42%) were women, median age 65 years. The primary tumors was located in the small intestine in 35 (44%) and the in the pancreas in 27 (34%) of the patients. Indication for treatment was progressive disease in 71 (90%) patients. Based on RECIST, 67 (85%) patients had objective response or stable disease as best effect versus 59 (75%) patients based on the conventional method (p < 0.001). Median progression free survival was 33 months estimated by RECIST and 28 months estimated with the conventional method (p < 0.001). Eight (10%) patients received tumor-targeted therapy due to progressive disease based on the conventional method while still having stable disease according to RECIST. CONCLUSION: Response evaluation after PRRT with RECIST gave more positive estimates for treatment effects compared to a method where any equivocal change in tumor load was regarded as significant. These differences had clinical implications. PMID- 30406361 TI - Phase I/IIa PET imaging study with 89zirconium labeled anti-PSMA minibody for urological malignancies. AB - OBJECTIVE: We conducted the present phase I/IIa positron emission tomography (PET) imaging study with 89Zr conjugated with desferroxamine-IAB2M (89Zr-Df IAB2M), an anti-prostate-specific membrane-antigen minibody, to assess its safety and feasibility in patients with urological cancer. METHODS: 89Zr-Df-IAB2M was synthetized by IBA Molecular (Somerset, NJ, USA) and transported by air to Tsukuba Molecular Imaging Center (Tsukuba, Ibaraki, Japan).17 patients received 74 MBq (2 mCi) of 89Zr-Df-IAB2M at total mass doses of 10 mg. Whole-body and plasma clearance, normal-organ and lesion uptake, and radiation absorbed dose were estimated. We also preliminarily tested the performance of 89Zr-immuno-PET imaging for 13 patients with prostate cancer and 4 patients with other urological cancer. RESULTS: The administration of 89Zr-Df-IAB2M was well-tolerated, and no infusion-related reactions were observed in any patient. No adverse events were noted in the laboratory parameters, vital signs, or other parameters. The plasma clearance was biphasic, with an initial rapid phase (t 1/2 fast: 10.1 +/- 3.4 h) followed by a slow phase (t 1/2 slow: 49.0 +/- 22.7 h). The half-life of radioactivity in the whole body (WB t1/2) was 237 +/- 9 h. The highest absorbed radiation dose was 1.67 mGy/MBq, observed in the liver and kidney. The effective dose was 0.68 +/- 0.08 mSv/MBq. The radiation dose rate at 0.5 m distance from the patient was 8.67 uSv/h on day 1, and decreased to 2.26 uSv/h at 5 days after injection. Both bone and lymph node metastases were detected with 89Zr-Df-IAB2M by 24 or 48 h imaging. CONCLUSIONS: Administration of 89Zr-Df-IAB2M was well tolerated and safe in terms of adverse events and radiation exposure and protection. 89Zr-Df-IAB2M is feasible for usage by long-distance transportation. Further studies are warranted for analysis of its use for tumor lesion detection (UMIN000015356). PMID- 30406362 TI - Biomaterials for Regenerative Medicine: Historical Perspectives and Current Trends. AB - Biomaterials are key components in tissue engineering and regenerative medicine applications, with the intended purpose of reducing the burden of disease and enhancing the quality of life of a large number of patients. The success of many regenerative medicine strategies, such as cell-based therapies, artificial organs, and engineered living tissues, is highly dependent on the ability to design or produce suitable biomaterials that can support and guide cells during tissue healing and remodelling processes. This chapter presents an overview about basic research concerning the use of different biomaterials for tissue engineering and regenerative medicine applications. Starting from a historical perspective, the chapter introduces the basic principles of designing biomaterials for tissue regeneration approaches. The main focus is set on describing the main classes of biomaterials that have been applied in regenerative medicine, including natural and synthetic polymers, bioactive ceramics, and composites. For each class of biomaterials, some of the most important physicochemical and biological properties are presented. Finally, some challenges and concerns that remain in this field are presented and discussed. PMID- 30406363 TI - Identification of molecular signatures involved in radiation-induced lung fibrosis. AB - In radiotherapy, radiation (IR)-induced lung fibrosis has severe and dose limiting side effects. To elucidate the molecular effects of IR fibrosis, we examined the fibrosis process in irradiated mouse lung tissues. High focal IR (90 Gy) was exposed to a 3-mm volume of the left lung in C57BL6 mice. In the diffused irradiation, 20 Gy dose delivered with a 7-mm collimator almost covered the entire left lung. Histological examination for lung tissues of both irradiated and neighboring regions was done for 4 weeks after irradiation. Long-term effects (12 months) of 20Gy IR were compared on a diffuse region of the left lung and non irradiated right lung. Fibrosis was initiated as early as 2 weeks after IR in the irradiated lung region and neighboring region. Upregulation of gtse1 in both 90Gy irradiated and neighboring regions was observed. Upregulation of fgl1 in both 20Gy diffused irradiated and non-irradiated lungs was identified. When gtse1 or flg1 was knock-downed, TGFbeta or IR-induced epithelial-mesenchymal transition was inhibited, accompanied with the inhibition of cellular migration, suggesting fibrosis responsible genes. Immunofluorescence analysis using mouse fibrotic lung tissues suggested that fibrotic regions showed increased expressions of Gtse1 and Fgl1, indicating novel molecular signatures of gtse1and fgl1 for IR-induced lung fibrosis. Even though their molecular mechanisms and IR doses or irradiated volumes for lung fibrosis may be different, these genes may be novel targets for understanding IR-induced lung fibrosis and in treatment strategies. KEY MESSAGES: Upregulation of gtse1 by 90Gy focal irradiation and upregulation of fgl1 by 20Gy diffused irradiation are identified in mouse lung fibrosis model. Gtse1 and Fgl1 are involved in radiation or TGFbeta-induced epithelial-mesenchymal transition. Radiation-induced fibrotic regions of mouse lungs showed increased expressions of Gtse1 and Fgl1. Gtse1 and Fgl1 are suggested to be novel targets for radiation induced lung fibrosis. PMID- 30406364 TI - Survivorship care visits in a high-risk population of breast cancer survivors. AB - PURPOSE: Breast cancer survivors face numerous challenges after diagnosis and treatment. Several models have been developed to attempt to improve quality of care. Here, we describe characteristics and outcomes of patients who participated in survivorship visits (SV) at Johns Hopkins (JH). METHODS: We retrospectively reviewed charts of breast cancer patients who participated in an optional SV 1-3 months after completing locoregional therapy and initial systemic therapy. We report patient demographics, comorbidities, tumor characteristics, treatments, and responses to symptom questionnaires. We compared the characteristics of SV participants to stage I-III analytical cases in the 2010-2015 JH Cancer Registry (JHCR). RESULTS: We identified 87 women with stage I-III breast cancer who participated in SVs from 2010 to 2016. Compared to patients in the JHCR (n = 2942), SV participants were younger, more likely to be African American and more likely to have a higher TNM stage, hormone receptor-negative disease, and HER2 positive disease. They were more likely to have received chemotherapy and radiation therapy. They also have similar recurrence rates despite the SV cohort's shorter median follow-up time. Among SV participants, the prevalence of comorbidities including peripheral neuropathy, anemia, lymphedema, anxiety, deep vein thrombosis, and depression increased significantly from time of diagnosis to most recent follow-up. CONCLUSIONS: Compared to the JHCR cohort, SV participants had higher risk cancers and a high frequency of comorbidities potentially associated with breast cancer and therapy. These high-risk patients may benefit most from specific interventions targeting survivorship care, and their experiences may help improve care delivery models. PMID- 30406365 TI - Racial/ethnic disparities in inflammatory breast cancer survival in the Michigan Cancer Surveillance Program. AB - PURPOSE: While racial disparities in inflammatory breast cancer (IBC) incidence are fairly well documented, with black women having significantly higher rates compared to white women; less is known about whether IBC prognosis differs by race/ethnicity. Therefore, the objective of this study was to assess racial/ethnic disparities in survival among women diagnosed with IBC in the Michigan Cancer Surveillance Program (MCSP) from 1998 to 2014. METHODS: We examined the frequency and percentage of breast cancer cases coded to the various IBC codes in the MCSP registry over the study period. We used age-adjusted and multivariable Cox Proportional hazard regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of race/ethnicity with all-cause mortality. RESULTS: Using a comprehensive case definition of IBC, 1324 IBC patients were identified from women diagnosed with invasive breast cancer in the MCSP [Non-Hispanic Black (NHB) = 227; Non-Hispanic White (NHW) = 984; Hispanic = 86; other = 27]. The percentage of all breast cancer cases defined as IBC in the MCSP registry differs considerably across registry codes from 0.02 to 1.1%. We observed significantly higher risk of death among NHB compared with NHW [HR (95% CI), 1.21 (1.01-1.45)], while no significant survival differences were observed between NHW and Hispanics or other racial/ethnic minorities. CONCLUSIONS: A comprehensive case definition should be utilized to avoid underestimation of IBC and to better understand this aggressive disease. Further research is needed to identify underlying causes and develop effective interventions to reduce IBC survival disparities between NHB and NHW women. PMID- 30406366 TI - Poor adherence to early childhood blood pressure measurement guidelines in a large pediatric healthcare system. AB - BACKGROUND: Children who were born prematurely, those with a very low birthweight, or who have survived the neonatal intensive care unit (NICU) are at risk for the development of hypertension and chronic kidney disease (CKD), and thus require blood pressure screening less than 3 years of age, per American Academy of Pediatrics (AAP) 2004 and 2017 guidelines. METHODS: We reviewed the practice patterns of a large pediatric health care system and assessed adherence to the AAP clinical practice guidelines on blood pressure measurements in children less than 3 years of age for hypertension and CKD with the following risk factors: prematurity, very low birthweight, and a neonatal intensive care setting encounter. This retrospective chart review included a total of 9965 patients with a median gestational age of 34 weeks. RESULTS: Overall, 38% of patients had at least one blood pressure measured less than 3 years of age. Primary care accounted for 41% of all outpatient encounters and 4% of all blood pressure measurements. Surgical specialties (i.e., ophthalmology, otolaryngology, and orthopedics) accounted for many non-primary care visits and were less likely than medical specialties (i.e., cardiology and nephrology) to obtain a blood pressure measurement (p < 0.0001). CONCLUSIONS: This study of a large healthcare system's practice revealed a lack of basic screening for hypertension in a population known to be at risk for hypertension and CKD. PMID- 30406367 TI - An unusual cause of nephrotic syndrome: Questions. PMID- 30406368 TI - An unusual cause of nephrotic syndrome: Answers. PMID- 30406369 TI - How to improve response to rituximab treatment in children with steroid-dependent nephrotic syndrome: answer to Drs. Fujinaga and Nishino. PMID- 30406370 TI - Non-alkaloidal composition of Ephedra Herb is influenced by differences in habitats. AB - Ephedra Herb is a crude drug defined as the terrestrial stem of Ephedra sinica, E. intermedia, or E. equisetina. It is often used to treat headaches, bronchial asthma, nasal inflammation, and the common cold. In this study, we isolated characteristic non-alkaloidal constituents from the extracts and identified them in relation to the habitat of Ephedra Herb. Extracts were prepared from Ephedra Herb collected from Inner Mongolia and Gansu. High-performance liquid chromatography was performed to quantitatively analyse the amount of ephedrine alkaloids in each extract. We compared the chemical compositions of the extracts by thin layer chromatography (TLC) to find spot characteristics depending on the habitat. 1H-NMR, 13C-NMR, and 2D-NMR spectra of the samples were also examined. The ephedrine content of all extracts satisfied the quality standard stated in the Japanese Pharmacopoeia. Nonetheless, we found each notable constituent characteristic to the Ephedra Herbs from both habitats. In order to identify them, Ephedra Herb extracts were separated by column chromatography, resulting in the isolation of (+/-)-alpha-terpineol-beta-D-O-glucopyranoside (1) and (E)-7 hydroxy-3,7-dimethyloct-2-en-1-yl-beta-D-O-glucopyranoside (2) as the characteristic constituents in Ephedra Herb from Inner Mongolia. Epheganoside (3), a new eudesmane-type sesquiterpene glycoside, and scopoletin (4) were found to be the characteristic constituents in Ephedra Herb from Gansu. The results obtained from this study can be used to distinguish between the habitats of Ephedra Herb. PMID- 30406371 TI - Two-photon based imaging reveals mechanisms of tissue damage. PMID- 30406372 TI - pKa measurements for the SAMPL6 prediction challenge for a set of kinase inhibitor-like fragments. AB - Determining the net charge and protonation states populated by a small molecule in an environment of interest or the cost of altering those protonation states upon transfer to another environment is a prerequisite for predicting its physicochemical and pharmaceutical properties. The environment of interest can be aqueous, an organic solvent, a protein binding site, or a lipid bilayer. Predicting the protonation state of a small molecule is essential to predicting its interactions with biological macromolecules using computational models. Incorrectly modeling the dominant protonation state, shifts in dominant protonation state, or the population of significant mixtures of protonation states can lead to large modeling errors that degrade the accuracy of physical modeling. Low accuracy hinders the use of physical modeling approaches for molecular design. For small molecules, the acid dissociation constant (pKa) is the primary quantity needed to determine the ionic states populated by a molecule in an aqueous solution at a given pH. As a part of SAMPL6 community challenge, we organized a blind pKa prediction component to assess the accuracy with which contemporary pKa prediction methods can predict this quantity, with the ultimate aim of assessing the expected impact on modeling errors this would induce. While a multitude of approaches for predicting pKa values currently exist, predicting the pKas of drug-like molecules can be difficult due to challenging properties such as multiple titratable sites, heterocycles, and tautomerization. For this challenge, we focused on set of 24 small molecules selected to resemble selective kinase inhibitors-an important class of therapeutics replete with titratable moieties. Using a Sirius T3 instrument that performs automated acid-base titrations, we used UV absorbance-based pKa measurements to construct a high quality experimental reference dataset of macroscopic pKas for the evaluation of computational pKa prediction methodologies that was utilized in the SAMPL6 pKa challenge. For several compounds in which the microscopic protonation states associated with macroscopic pKas were ambiguous, we performed follow-up NMR experiments to disambiguate the microstates involved in the transition. This dataset provides a useful standard benchmark dataset for the evaluation of pKa prediction methodologies on kinase inhibitor-like compounds. PMID- 30406373 TI - Hyperresponsiveness to interferon gamma exposure as a response mechanism to anti PD-1 therapy in microsatellite instability colorectal cancer. AB - Colorectal cancer (CRC) with high-level microsatellite instability (MSI-H) tends to be associated with a better response to programmed death receptor-1 (PD-1) blockade than does microsatellite stable CRC. However, emerging evidence makes the use of programmed death ligand-1 (PD-L1) as a biomarker problematic. Here, we sought to characterize the interactions between PD-L1 expression and the response to PD-1 blockade therapy in BALB/c mice with a subcutaneous tumor challenge. We further focused on interferon gamma (IFNgamma)-induced PD-L1 expression in an in vitro setting to evaluate the responsiveness to IFNgamma exposure and the specific signaling of PD-1 in HCT116 and SW480 cell lines. In this study, enhanced PD-L1 expression increased survival in CT26 cells, and PD-1 blockade increased the CTL profile and apoptotic cells in mice with CRC. Our in vitro findings showed that PD-L1 expression was significantly upregulated by a low-dose IFNgamma treatment, and the MSI-H cell line might exhibit hyperresponsiveness to IFNgamma exposure partly through the JAK-STAT pathway. These results suggest that intrinsic PD-L1 in cooperation with extrinsic IFNgamma exposure in CRC may be more responsive to anti-PD-1 therapy, mainly through the CTL profile in the tumor microenvironment. PMID- 30406374 TI - Apoptosis of tumor-infiltrating T lymphocytes: a new immune checkpoint mechanism. AB - Immunotherapy based on checkpoint inhibitors is providing substantial clinical benefit, but only to a minority of cancer patients. The current priority is to understand why the majority of patients fail to respond. Besides T-cell dysfunction, T-cell apoptosis was reported in several recent studies as a relevant mechanism of tumoral immune resistance. Several death receptors (Fas, DR3, DR4, DR5, TNFR1) can trigger apoptosis when activated by their respective ligands. In this review, we discuss the immunomodulatory role of the main death receptors and how these are shaping the tumor microenvironment, with a focus on Fas and its ligand. Fas-mediated apoptosis of T cells has long been known as a mechanism allowing the contraction of T-cell responses to prevent immunopathology, a phenomenon known as activation-induced cell death, which is triggered by induction of Fas ligand (FasL) expression on T cells themselves and qualifies as an immune checkpoint mechanism. Recent evidence indicates that other cells in the tumor microenvironment can express FasL and trigger apoptosis of tumor-infiltrating lymphocytes (TIL), including endothelial cells and myeloid derived suppressor cells. The resulting disappearance of TIL prevents anti-tumor immunity and may in fact contribute to the absence of TIL that is typical of "cold" tumors that fail to respond to immunotherapy. Interfering with the Fas FasL pathway in the tumor microenvironment has the potential to increase the efficacy of cancer immunotherapy. PMID- 30406375 TI - The nature of the human T cell response to the cancer antigen 5T4 is determined by the balance of regulatory and inflammatory T cells of the same antigen specificity: implications for vaccine design. AB - The oncofoetal antigen 5T4 is a promising T cell target in the context of colorectal cancer, as demonstrated by a recent clinical study where 5T4-specific T cell responses, induced by vaccination or cyclophosphamide, were associated with a significantly prolonged survival of patients with metastatic disease. Whilst Th1-type (IFN-gamma+) responses specific to 5T4, and other oncofoetal antigens, are often readily detectable in early stage CRC patients and healthy donors, their activity is suppressed as the cancer progresses by CD4+CD25hiFoxp3+ regulatory T cells (Treg) which contribute to the immunosuppressive environment conducive to tumour growth. This study mapped the fine specificity of Th1 and Treg cell responses to the 5T4 protein. Surprisingly, both immunogenic peptides and those recognised by Tregs clustered in the same HLA-DR transcending epitope rich hotspots within the 5T4 protein. Similarly, regions of low Th1-cell immunogenicity also did not contain peptides capable of stimulating Tregs, further supporting the notion that Treg and Th1 cells recognise the same peptides. Understanding the rules which govern the balance of Th1 and Treg cells responding to a given peptide specificity is, therefore, of fundamental importance to designing strategies for manipulating the balance in favour of Th1 cells, and thus the most effective anti-cancer T cell responses. PMID- 30406376 TI - Neuroprotective effects of matrine on scopolamine-induced amnesia via inhibition of AChE/BuChE and oxidative stress. AB - The present study was designed to evaluate the effects of matrine (MAT) on scopolamine (SCOP)-induced learning and memory impairment. After successive oral administration of MAT to mice for three days at doses of 0.4, 2, and 10 mg/kg, we assessed improvements in learning and memory and investigated the mechanism of action of SCOP-induced amnesia. Donepezil at a dose of 3 mg/kg was used as a standard memory enhancer. MAT significantly improved SCOP-induced learning and memory impairment in novel object recognition and Y-maze tests at doses of 0.4, 2, and 10 mg/kg. Furthermore, MAT inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities and decreased oxidative stress in the brain, as evidenced by increased total antioxidant capacity, total superoxide dismutase levels, and catalase activities as well as decreased malondialdehyde levels. Additionally, there was a significant negative correlation between the percentage of spontaneous alternation in the Y maze and AChE activity in the cortex and hippocampus. MAT ameliorated SCOP-induced amnesia by the inhibition of both AChE/BuChE activities and oxidative stress. This study provides further evidence to encourage the development of MAT as a drug for the prevention or treatment of Alzheimer's disease. PMID- 30406377 TI - Gender difference and correlation between sexuality, thyroid hormones, cognitive, and physical functions in elderly fit. AB - PURPOSE: Sexuality in the elderly is related to psycho-physical well-being. Aim of this study was to analyze the correlation between sexual health, thyroid hormones, cognitive functions, and physical fitness in elderly population. METHODS: Fifty-one fit adults were recruited (age: 71.9 +/- 5.3 years, 26 females and 25 males). Sexuality was evaluated using the Changes in Sexual Functioning Questionnaire-short form (CSFQ-14) and the Sexual Attitude Scale (SAS). Thyroid function was assessed by measuring serum TSH, FT3, and FT4. Cognitive functions and depressive symptoms were evaluated by the Mini Mental State Examination (MMSE) test and Geriatric Depression Scale (GDS) scores. Subjects' physical fitness was evaluated using the following tests: Short Physical Performance Battery (SPPB), Handgrip test (HG), Timed Up and Go test (TUG), and 2-Minute step test (ST). RESULTS: CSFQ-14 positively correlated with MMSE (p < 0.05) and negatively with GDS (p < 0.05), while thyroid function was not correlated with sexuality, in both genders. A negative relationship between FT4 vs. weight, FT3 vs. HG and FT3/FT4 ratio vs. ST were found (p = 0.05) in females, while in males, it occurred for TSH vs. TUG (p < 0.05); a positive relationship existed in females between FT4 vs. ST (p < 0.05). Finally, CSFQ-14 was significantly correlated with SPPB (p < 0.05), CST, TUG, and ST (p < 0.01), in both genders. CONCLUSION: We demonstrated a strict relationship between active sexuality, preserved cognitive function and appropriate physical fitness in elderly subjects, independently from gender. Our preliminary data suggest that in elderly fit population, peripheral thyroxin deiodination may be a useful predictor of better physical performance and more successful aging. PMID- 30406378 TI - Evaluating the effects of mobile health intervention on weight management, glycemic control and pregnancy outcomes in patients with gestational diabetes mellitus. AB - PURPOSE: To explore the effects of mobile health (mHealth) intervention on pregnancy weight management, blood glucose control and pregnancy outcomes. METHODS: A total of 124 patients with gestational diabetes mellitus (GDM) were selected. Patients were randomly divided into two groups. The 60 patients in the control group received standard outpatient treatment, while the remaining 64 patients received a nurse's online guidance both through a mobile medical App installed on their phone and through regular offline clinical treatment in the mHealth group. Patients were treated for an average of 13 weeks and general conditions, compliance, blood glucose, glycosylated hemoglobin, weight gain, pregnancy, and neonatal outcomes were monitored in both groups longitudinally. RESULTS: The mHealth group demonstrated higher levels of compliance (83.3 +/- 12.5% vs. 70.4 +/- 10.1%, t = - 6.293, df = 122, p < 0.001), lower frequency of outpatient service (8.1 +/- 1.3 vs. 11.2 +/- 1.1, t = 14.285, df = 122, p < 0.001), lower hemoglobin A1C before delivery (4.7 +/- 0.2 vs. 5.3 +/- 0.3, t = 13.216, df = 122, p < 0.001) as well as the rates of off-target measurements both fasting (4.6 +/- 0.4% vs. 8.3 +/- 0.6%, t = 40.659, df = 122, p < 0.001) and 2 h post-prandial (7.9 +/- 0.7% vs. 14.7 +/- 0.8%, t = 50.746, df = 122, p < 0.001). Weight gain in the mHealth group was less than control group (3.2 +/- 0.8 vs. 4.8 +/- 0.7, t = 11.851, df = 122 p < 0.001). CONCLUSION: Mobile health intervention management of gestational diabetes mellitus improves patients' compliance and blood glucose control, and reduces weight gain, thereby reducing the rates of complications in both pregnant women and fetuses during delivery during pregnancy. PMID- 30406379 TI - The female prostate sign. PMID- 30406380 TI - Differences in early imaging features and pattern of progression on CT between intrahepatic biliary metastasis of colorectal origin and intrahepatic non-mass forming cholangiocarcinoma in patients with extrabiliary malignancy. AB - PURPOSE: To assess the differences in early imaging features and progression pattern on CT between intrahepatic biliary metastasis (IBM) and non-mass-forming cholangiocarcinoma (NMFC) in patients with extrabiliary malignancy. METHODS: This retrospective study included 35 patients who were surgically and pathologically confirmed with IBM (n = 14) or NMFC (n = 21) at the time of or after surgery for extrabiliary malignancy. Two observers evaluated the following aspects of biliary lesions on initial or follow-up CT images: location, characteristics of intrahepatic duct (IHD) dilatation, presence of duct wall thickening, and periductal infiltration lesion or periductal expansile mass. RESULTS: All IBMs were associated with colorectal cancer (p = 0.032). As early imaging features on CT, smooth tapered localized IHD dilatation without duct wall thickening and peripheral duct involvement were observed significantly more often in IBM, and IHD dilatation with abrupt tapering or irregularity of transition site and bile duct wall thickening were significantly more common in NMFC (all p < 0.05). Regarding progression pattern, periductal expansile mass was present only in IBM, whereas periductal infiltrative lesion was present only in NMFC (p < 0.001). CONCLUSION: In the differentiation between IBM and NMFC in patients with extrabiliary malignancy, the differences in early imaging features and progression pattern of the two diseases revealed in this study would be helpful for diagnosis. PMID- 30406381 TI - Robotic duodeno-duodenostomy creation in a pediatric patient with idiopathic duodenal stricture. AB - Duodenal stenosis is one of the leading causes of duodenal obstruction in the pediatric population, usually diagnosed in newborns and in Down syndrome patients. It has historically been treated with duodeno-duodenostomy, an operation that is now commonly performed laparoscopically. We present a case of a 10-year-old child with a rare chromosomal abnormality who was diagnosed with a duodenal stricture after presenting with failure to thrive and inability to tolerate tube feeds. Duodeno-duodenostomy was performed using the da Vinci(r) robot, allowing for improved intra-operative range of motion and control during anastomosis creation, with the same cosmetic benefits of laparoscopic surgery, and subsequent improvement in symptoms postoperatively. This case highlights the utility of robotic surgery in complex operations in the pediatric population. PMID- 30406382 TI - Applications of Focused Ultrasound in Cerebrovascular Diseases and Brain Tumors. AB - Oncology and cerebrovascular disease constitute two of the most common diseases afflicting the central nervous system. Standard of treatment of these pathologies is based on multidisciplinary approaches encompassing combination of interventional procedures such as open and endovascular surgeries, drugs (chemotherapies, anti-coagulants, anti-platelet therapies, thrombolytics), and radiation therapies. In this context, therapeutic ultrasound could represent a novel diagnostic/therapeutic in the armamentarium of the surgeon to treat these diseases. Ultrasound relies on mechanical energy to induce numerous physical and biological effects. The application of this technology in neurology has been limited due to the challenges with penetrating the skull, thus limiting a prompt translation as has been seen in treating pathologies in other organs, such as breast and abdomen. Thanks to pivotal adjuncts such as multiconvergent transducers, magnetic resonance imaging (MRI) guidance, MRI thermometry, implantable transducers, and acoustic windows, focused ultrasound (FUS) is ready for prime-time applications in oncology and cerebrovascular neurology. In this review, we analyze the evolution of FUS from the beginning in 1950s to current state-of-the-art. We provide an overall picture of actual and future applications of FUS in oncology and cerebrovascular neurology reporting for each application the principal existing evidences. PMID- 30406383 TI - Diagnosis and Treatment of Mitochondrial Myopathies. AB - Mitochondrial myopathies are progressive muscle conditions caused primarily by the impairment of oxidative phosphorylation (OXPHOS) in the mitochondria. This causes a deficit in energy production in the form of adenosine triphosphate (ATP), particularly in skeletal muscle. The diagnosis of mitochondrial myopathy is reliant on the combination of numerous techniques including traditional histochemical, immunohistochemical, and biochemical testing combined with the fast-emerging molecular genetic techniques, namely next-generation sequencing (NGS). This has allowed for the diagnosis to become more effective in terms of determining causative or novel genes. However, there are currently no effective or disease-modifying treatments available for the vast majority of patients with mitochondrial myopathies. Existing therapeutic options focus on the symptomatic management of disease manifestations. An increasing number of clinical trials have investigated the therapeutic effects of various vitamins, cofactors, and small molecules, though these trials have failed to show definitive outcome measures for clinical practice thus far. In addition, new molecular strategies, specifically mtZFNs and mtTALENs, that cause beneficial heteroplasmic shifts in cell lines harboring varying pathogenic mtDNA mutations offer hope for the future. Moreover, recent developments in the reproductive options for patients with mitochondrial myopathies mean that for some families, the possibility of preventing transmission of the mutation to the next generation is now possible. PMID- 30406384 TI - Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches. AB - Ryanodine receptor type 1-related myopathies (RYR1-RM) are the most common class of congenital myopathies. Historically, RYR1-RM classification and diagnosis have been guided by histopathologic findings on muscle biopsy. Main histological subtypes of RYR1-RM include central core disease, multiminicore disease, core-rod myopathy, centronuclear myopathy, and congenital fiber-type disproportion. A range of RYR1-RM clinical phenotypes has also emerged more recently and includes King Denborough syndrome, RYR1 rhabdomyolysis-myalgia syndrome, atypical periodic paralysis, congenital neuromuscular disease with uniform type 1 fibers, and late onset axial myopathy. This expansion of the RYR1-RM disease spectrum is due, in part, to implementation of next-generation sequencing methods, which include the entire RYR1 coding sequence rather than being restricted to hotspot regions. These methods enhance diagnostic capabilities, especially given historic limitations of histopathologic and clinical overlap across RYR1-RM. Both dominant and recessive modes of inheritance have been documented, with the latter typically associated with a more severe clinical phenotype. As with all congenital myopathies, no FDA-approved treatments exist to date. Here, we review histopathologic, clinical, imaging, and genetic diagnostic features of the main RYR1-RM subtypes. We also discuss the current state of treatments and focus on disease-modulating (nongenetic) therapeutic strategies under development for RYR1 RM. Finally, perspectives for future approaches to treatment development are broached. PMID- 30406385 TI - Long-term outcomes following surgical repair of giant paraoesophageal hiatus hernia. AB - INTRODUCTION: There are limited data regarding long-term outcomes after surgical repair of giant paraoesophageal hiatus hernia (GPHH). The aim of this study was to assess symptomatic recurrence and patient-reported outcomes following GPHH repair. METHODS: 178 patients undergoing elective (127) and emergency (51) GPHH repair between 1994 and 2015 were identified from the prospectively collected Lothian Surgical Audit database. Electronic patient records were used to determine rate of clinical recurrence. A postal questionnaire was used to assess modified DeMeester, 'Gastrointestinal Symptom Rating Scale' symptom scores, breathing and exercise tolerance, and patient satisfaction. RESULTS: Median follow-up was 35 months (range 12-238). 15 (8.4%) patients developed a clinical recurrence and 13 (7.3%) underwent a further operation. The clinical recurrence rates were similar in patients followed-up less than 5 years and beyond 5 years [10/128 (7.8%) vs 5/50 (10%)]. Mortality rate was 1.6% for elective compared with 16.7% for emergency procedures (P < 0.001). Completed questionnaires were received from 95 (78.5%) of 121 eligible patients. Mean symptom scores were low (Modified DeMeester 2.6). 83.7% of patients reported a good or excellent outcome, and 97.8% believed they had made the correct decision to undergo surgery. CONCLUSIONS: Surgical repair of GPHH is associated with high levels of patient satisfaction and good overall symptom outcome. There is a clinical recurrence rate of 8.4%, which does not significantly increase with long-term follow-up. PMID- 30406387 TI - Robotic pelvic dissection as surgical treatment of complicated diverticulitis in elective settings: a comparative study with fully laparoscopic procedure. AB - BACKGROUND: Recently, minimally invasive treatment of complicated sigmoid diverticulitis is becoming a valid alternative to standard procedures. Robotic approach may be useful to allow more precise dissection in arduous pelvic dissection as in complicated diverticulitis. The aim of this study is to investigate effectiveness, potential benefits and short-term outcomes of robotic assisted laparoscopic surgical resection, compared with fully laparoscopic resection in complicated diverticulitis. METHODS: Between January 2009 and December 2017, 156 consecutive patients with history of complicated diverticular disease were referred to our Department of General, Mininvasive and Robotic Surgery. All patients underwent elective colonic resections performed by the same colorectal surgeon and followed a perioperative ERAS program. Demographic and clinical features, surgical data, postoperative data, 30-day morbidity and mortality, VAS for surgeon's compliance were evaluated. RESULTS: One hundred and fifty-six consecutive patients underwent elective colonic resection: 92 fully laparoscopic (FL) colorectal resections and 64 procedures with robotic hybrid approach (RHA). Conversion rate was none in the RHA group versus 6.5% in the FL group, because of poor vision due to bowel distension, inflammatory pseudotumor and peritoneal adhesions. No 30-day mortality was observed. Mean operative time was 167.5 +/- 54.4 min (80-420) in the FL group and 172.5 +/- 55.64 min (110-325) in the RHA group (p 0.079), mean intraoperative blood loss was 144.6 +/- 40.6 ml (40-200) with the FL technique and 138.4 +/- 28.3 ml (20-185) with the RHA (p 0.295). Mean hospital stay for FL was 5 +/- 4.1 days (range 3-45) and 5 +/- 2.7 days (range 3-20) for RHA (p 0.974). Overall postoperative morbidity rate was 21.6% in the FL group and 12.3% in the RHA (p 0.067). Major postoperative morbidity (Clavien-Dindo 3 and 4) represented 13% and 4.6%, respectively (p 0.091). VAS for surgeon's compliance revealed a better performance in the robotic arm (p 0.059). CONCLUSIONS: This preliminary study highlights the potential benefits of robotic-assisted laparoscopy in colorectal resections for complicated diverticular disease in terms of surgical efficacy, postoperative morbidity and better surgeon's compliance. PMID- 30406386 TI - Effects of dexamethasone on postoperative urinary retention after laparoscopic inguinal hernia repair. AB - BACKGROUND: Postoperative urinary retention (POUR) is a complication of laparoscopic inguinal hernia repair (LIHR). Previous research has identified predictive factors of POUR, such as age and history of benign prostatic hyperplasia (BPH). There is currently limited work on preventative measures. We hypothesize dexamethasone, a steroid, reduces POUR rates following LIHR due to its mechanism. METHODS: Consecutive patients (n = 979) undergoing LIHR from 2009 to 2017 at a single institution were selected from a prospectively managed database. All procedures were performed by four general surgeons. Only male patients were selected, as the majority of POUR occurs in males. Patients were retroactively chart reviewed and divided into two groups, dexamethasone use (n = 623) and no dexamethasone use (n = 356). Perioperative factors were compared between groups with Chi-square and independent samples t tests. Univariable and multivariable logistic regression analysis was used to assess whether dexamethasone use was associated with POUR. A subgroup analysis was performed on the dexamethasone group to determine any dose-dependent effects. RESULTS: We found a significant difference in POUR between the dexamethasone group and no dexamethasone group (3.7% vs. 9.8%, p = 0.0001). Patients in the dexamethasone group had a shorter length of stay, and were less likely to have BPH or a Foley placed (all p < 0.05). Age and BMI were similar between groups. Multivariable analysis showed that the use of dexamethasone was associated with a reduced risk of POUR (OR 0.52, 95% CI 0.2-0.97, p = 0.0386), while controlling for factors such as age and BPH. A subgroup analysis examined the effect of dexamethasone per unit (mg) increase. There was no significant association between dexamethasone dose and POUR rates (OR 1.07, 95% CI 0.82-1.38, p = 0.6241). CONCLUSIONS: Patients who received dexamethasone showed a lower rate of POUR regardless of dose. These results suggest dexamethasone can be administered to reduce POUR in males undergoing LIHR. PMID- 30406388 TI - Re-framing the question: Should hydroxyethyl starch be used in clinical practice? PMID- 30406389 TI - A proteomics-metabolomics approach indicates changes in hypothalamic glutamate GABA metabolism of adult female rats submitted to intrauterine growth restriction. AB - PURPOSE: Intrauterine growth restriction (IUGR) has been shown to induce the programming of metabolic disturbances and obesity, associated with hypothalamic derangements. The present study aimed at investigating the effects of IUGR on the protein and metabolite profiles of the hypothalamus of adult female rats. METHODS: Wistar rats were mated and either had ad libitum access to food (control group) or received only 50% of the control intake (restricted group) during the whole pregnancy. Both groups ate ad libitum throughout lactation. At 4 months of age, the control and restricted female offspring was euthanized for blood and tissues collection. The hypothalami were processed for data independent acquisition mass spectrometry-based proteomics or targeted mass spectrometry based metabolomics. RESULTS: The adult females submitted to IUGR showed increased glycemia and body adiposity, with normal body weight and food intake. IUGR modulated significantly 28 hypothalamic proteins and 7 hypothalamic metabolites. The effects of IUGR on hypothalamic proteins and metabolites included downregulation of glutamine synthetase, glutamate decarboxylase, glutamate dehydrogenase, isocitrate dehydrogenase, alpha-ketoglutarate, and up-regulation of NADH dehydrogenase and phosphoenolpyruvate. Integrated pathway analysis indicated that IUGR affected GABAergic synapse, glutamate metabolism, and TCA cycle, highly interconnected pathways whose derangement has potentially multiple consequences. CONCLUSION: The present findings suggested that the effects of IUGR on GABA/glutamate-glutamine cycle may be involved in the programming of obesity and hyperglycemia in female rats. PMID- 30406391 TI - Acknowledgment of Reviewers 2016 and 2017. PMID- 30406390 TI - Challenges are opportunities. PMID- 30406392 TI - A randomized double-blind placebo-controlled trial showing rifaximin to improve constipation by reducing methane production and accelerating colon transit: A pilot study. AB - OBJECTIVE: Gut microbe-derived methane may slow colon transit causing chronic constipation (CC). Effect of rifaximin on breath methane and slow-transit CC was evaluated. METHOD: Bristol stool form, frequency, colon transit time (CTT), and breath methane were evaluated in 23 patients with CC (10 patients with constipation-predominant irritable bowel syndrome [IBS-C], 13 functional constipation, Rome III) and m-ethane production compared with 68 non-constipating IBS. Methane-producing CC (basal >= 10 PPM and/or post-lactulose rise by > 10 PPM) was randomized (double-blind) to rifaximin (400-mg thrice/day, 2-weeks) or placebo. Stool forms, frequency, breath methane, and CTT were recorded afterward. RESULTS: CC patients tended to be methane producer more often (13/23 [56.5%] vs. 25/68 [36.5%], p = 0.07) and had greater area under curve (AUC) for methane (2415 [435-23,580] vs. 1335 [0-6562.5], p = 0.02) than non-constipating IBS. Methane producers (8/13 [61.5%]) and 5/10 (50%) non-producers had abnormal CTT (marker retention: 36-h, 53 [0-60] vs. 19 [8-56], p = 0.06; 60-h, 16 [0-57] vs. 13 [3 56], p = 0.877). Six and 7/13 methane producers were randomized to rifaximin and placebo, respectively. Rifaximin reduced AUC for methane more (6697.5 [1777.5 23,580] vs. 2617.5 [562.5-19,867.5], p = 0.005) than placebo (3945 [2415 12,952.5] vs. 3720 [502.5-9210], p = 0.118) at 1 month. CTT normalized in 4/6 (66.7%) on rifaximin (36-h retention, 54 [44-57] vs. 36 [23-60], p = 0.05; 60-h, 45 [3-57] vs. 14 [11-51], p = 0.09) but none on placebo (p = 0.02) (36-h, 31 [0 60] vs. 25 [0-45], p = 0.078; 60-h, 6 [0-54] vs. 12 [0-28], p = 0.2). Weekly stool frequency (3 [1-9] and 7 [1-14], p = 0.05) and forms improved with rifaximin than placebo. CONCLUSION: Rifaximin improves CC by altering methane production and colon transit. TRIAL REGISTRATION: Clinical Trial Registry, India: REF/2012/01/003216 ? ?. PMID- 30406393 TI - Removal of aluminium from aqueous solution by four wild-type strains of Aspergillus niger. AB - This paper provides a unique comparison of the performance of four wild-type Aspergillus niger strains in remediation of aluminium(III)-contaminated aqueous solutions. The direct fungal aluminium removal via biosorption and bioaccumulation was compared among all fungal strains, including bioaccumulation efficiency during dynamic and static cultivation. Our results indicate that aluminium bioaccumulation by living biomass outperformed biosorption, although biosorption by non-living biomass is a less time-demanding process. Among others, only one strain significantly differed regarding comparison of dynamic and static bioaccumulation. In this case, a significantly higher removal performance was achieved under dynamic cultivation conditions at initial aluminium(III) concentrations over 2.5 mg L-1. Although the fungal sensitivity towards aluminium(III) differed among selected fungal strains, there was no apparent correlation between the strains' removal performance and their adaptive mechanisms. PMID- 30406394 TI - Prehospital triage for mass casualty incidents using the META method for early surgical assessment: retrospective validation of a hospital trauma registry. AB - BACKGROUND: In mass casualty incidents (MCI), death usually occurs within the first few hours and thus early transfer to a trauma centre can be crucial in selected cases. However, most triage systems designed to prioritize the transfer to hospital of these patients do not assess the need for surgery, in part due to inconclusive evidence regarding the value of such an assessment. Therefore, the aim of the present study was to evaluate the capacity of a new triage system-the Prehospital Advanced Triage Method (META)-to identify victims who could benefit from urgent surgical assessment in case of MCI. METHODS: Retrospective, descriptive, observational study of a multipurpose cohort of patients included in the severe trauma registry of the Gregorio Maranon University General Hospital (Spain) between June 1993 and December 2011. All data were prospectively evaluated. All patients were evaluated with the META system to determine whether they met the criteria for urgent transfer. The META defines patients in need of urgent surgical assessment: (a) All penetrating injuries to head, neck, torso and extremities proximal to elbow or knee, (b) Open pelvic fracture, (c) Closed pelvic fracture with mechanical or haemodynamic instability and (d) Blunt torso trauma with haemodynamic instability. Patients who fulfilled these criteria were designated as "Urgent Evacuation for Surgical Assessment" (UESA) cases; all other cases were designated as non-UESA. The following variables were assessed: patient status at the scene; severity scales [RTS, Shock index, MGAP (Mechanism, Glasgow coma scale, Age, pressure), GCS]; need for surgery and/or interventional procedure to control bleeding (UESA); and mortality. The two groups (UESA vs. non UESA) were then compared. RESULTS: A total of 1882 cases from the database were included in the study. Mean age was 39.2 years and most (77%) patients were male. UESA patients presented significantly worse on-scene hemodynamic parameters (systolic blood pressure and heart rate) and greater injury severity (RTS, shock index, and MGAP scales). No differences were observed for respiratory rate, need for orotracheal intubation, or GCS scores. The anatomical injuries of patients in the UESA group were less severe but these patients had a greater need for urgent surgery and higher mortality rates. CONCLUSION: These findings suggest that the META triage classification system could be beneficial to help identify patients with severe trauma and/or in need of urgent surgical assessment at the scene of injury in case of MCI. These findings demonstrate that, in this cohort, the META fulfils the purpose for which it was designed. PMID- 30406395 TI - Increased center of pressure trajectory of the finger during precision grip task in stroke patients. AB - The aim of this study was to assess the spatial stability of stroke patients while holding a freely movable object. Twenty-two acute stroke patients with mild hand impairment performed a grip and lift task using the thumb and index finger. The displacement of the center of pressure (COP) trajectory, the grip force (GF) and several clinical parameters were monitored. Although the GF was not different between paretic and nonparetic hands, the COP trajectory of the paretic index finger was increased. Moreover, the COP trajectories of the thumb and index finger in hemorrhagic patients were longer than those in ischemic patients. These discrepancies between kinetic parameters suggest that different aspects of grip force control may be considered in patients with mild stroke. PMID- 30406396 TI - Establishment of wildflower fields in poor quality landscapes enhances micro parasite prevalence in wild bumble bees. AB - The current worldwide pollinator decline is caused by the interplay of different drivers. Several strategies have been undertaken to counteract or halt this decline, one of which is the implementation of wildflower fields. These supplementary flowers provide extra food resources and have proven their success in increasing pollinator biodiversity and abundance. Yet such landscape alterations could also alter the host-pathogen dynamics of pollinators, which could affect the populations. In this study, we investigated the influence of sown wildflower fields on the prevalence of micro-parasites and viruses in the wild bumble bee Bombus pascuorum, one of the most abundant bumble bee species in Europe and the Netherlands. We found that the effect of sown wildflower fields on micro-parasite prevalence is affected by the composition of the surrounding landscape and the size of the flower field. The prevalence of micro-parasites increases with increasing size of sown wildflower fields in landscapes with few semi-natural landscape elements. This effect was not observed in landscapes with a high amount of semi-natural landscape elements. We elaborate on two mechanisms which can support these findings: (1) "transmission hot spots" within the altered flower-networks, which could negatively impact hosts experiencing an increased exposure; (2) improved tolerance of the hosts, withstanding higher parasite populations. PMID- 30406397 TI - An in-depth review of the methods, findings, and theories associated with odor evoked autobiographical memory. AB - Over the past nearly 35 years, there has been sporadic interest in what has commonly come to be known as the Proust phenomenon, whereby autobiographical memories are retrieved and experienced differently when evoked by odors as compared with other types of cues, such as words, images or sounds. The purpose of this review is threefold. First, we provide a detailed analysis of the methods used to investigate Proust effects. Second, we review and analyze the various findings from the literature and determine what we feel to be the most important and stable findings. Third, we provide a series of previously postulated and new hypotheses that attempt to account for the various findings. Given the early stage of research, the current review aims to provide a measure of organization to the field, as well serve as a guide for how future investigations may address the topic. We conclude with the recommendation that research in this area shift its focus from establishing the phenomenon towards explaining its causes. PMID- 30406398 TI - Multiple Myeloma of the Young - a Single Center Experience Highlights Future Directions. AB - Multiple myeloma is quite uncommon in the young population. We performed a retrospective review in our database from 2006 to 2015 to examine the clinical features, outcomes and survival of multiple myeloma patients <=40 years old. Among 312 newly diagnosed patients we found sixteen (5.1%) who were 40 years old or younger. Their characteristics including M-protein type, genetical alterations, clinical symptoms and disease stage were as various as those in the older population. All but two young patients underwent autologous stem cell transplantation after the induction treatment. Their response to treatment did not differ markedly from the older patients. We also compared the survival data of patiens <=40 years and > 40 years old. The 5-year progression-free survival were 48% and 35%, the 5-year overall survival were 83% and 53% respectively, the latter showing a significant advantage for the younger population. 70% of the young patients received maintenance or consolidation therapy after the initial treatment. Although several effective new therapies have been introduced recently, there is still an unmet need for curative treatment options for young and fit multiple myeloma patients. PMID- 30406399 TI - Metastatic Spread from Abdominal Tumor Cells to Parathymic Lymph Nodes. AB - Metastatic studies on rats showed that after subrenal implantation of tumor cells under the capsule of the kidney or subhepatic implantation under Glisson's capsule of the liver generated primary tumors in these organs. It was assumed that tumor cells that escaped through the disrupted peripheral blood vessels of primary tumors entered the peritoneal cavity, crossed the diaphragm, and appeared in the thoracal, primarily in the parathymic lymph nodes. This explanation did not answer the question whether distant lymph nodes were reached via the blood stream from the primary tumor or through the thoracal lymphatic vessels. In this work, we investigated the metastatic pathway in C3H/HeJ mice, after direct intraperitoneal administration of murine SCC VII cells bypassing the hematogenic spread of tumor cells. The direct pathway was also mimicked by intraperitoneal injection of Pelican Ink colloidal particles, which appeared in the parathymic lymph nodes, similarly to the tumor cells that caused metastasis in the parathymic lymph nodes and in the thymic tissue. The murine peritoneal-parathymic lymph node route indicates a general mechanism of tumor progression from the abdominal effusion. This pathway starts with the growth of abdominal tumors, continues as thoracal metastasis in parathymic lymph nodes and may proceed as mammary lymph node metastasis. PMID- 30406400 TI - The Long Noncoding RNA HOST2 Promotes Gemcitabine Resistance in Human Pancreatic Cancer Cells. AB - Our study was aimed to identify the fundamental role of lncRNA HOST2 in gemcitabine resistance regulation in human pancreatic cancer cells. The levels of HOST2 in pancreatic cancer cell lines were measured by quantitative real-time PCR (qRT-PCR). Due to high expression and strong gemcitabine resistance, Hs766T and AsPC-1 cell lines were selected to be knockdown the expression of HOST2 by transfection sh-HOST2. After manipulation of HOST2, the cell proliferation induced by gemcitabine was examined by CCK-8 assay. Next, colony formation ability of Hs766T and AsPC-1 cell lines was determined by clone-forming assay. At last, the relationship between HOST2 and cell apoptosis in Hs766T and AsPC-1 cell lines was evaluated by flow cytometry. QRT-PCR revealed that HOST2 was overexpressed in six pancreas neoplasm cell lines compared with normal cell lines HPDE6-C7. HOST2 expression levels in group resistant to gemcitabine were higher than the group sensitive to gemcitabine. Additionally, CCK-8 assay verified that cell proliferation was inhibited by sh-HOST2 with or without gemcitabine treatment. Furthermore, clone-forming assay revealed that colony formation ability was weakened by down-regulated HOST2 with or without gemcitabine treatment. Flow cytometry revealed that cell apoptosis induced by gemcitabine was promoted by sh-HOST2. In conclusion, down-regulated HOST2 inhibited proliferation and promoted apoptosis of pancreas cancer cells with or without gemcitabine treatment. Thus, HOST2 is a potential therapeutic target for gemcitabine chemoresistance in pancreatic neoplasms. PMID- 30406401 TI - The Effect of CD86 Expression on the Proliferation and the Survival of CLL Cells. AB - Micro-environment plays important role in the pathogenesis of CLL by providing protective niche for CLL cells. Several molecules play important role in communication between CLL cells and immune cells like CD86.Some of the data suggest that CLL patients with high CD86 level need earlier treatments and cells with higher CD86 expression has higher proliferation rate but the role of CD86 in the survival and proliferation of CLL cells is unclear. We investigated the effect of CD86 expression to CLL cells in 50 peripheral blood and 15 lymph node biopsy samples from CLL patients. Our results showed that the expressions of CD86 increased significantly after 7 day culturing in medium, or in the presence of bone marrow stromal cells (BMSCs). We found positive correlation between CD86 and CD23 expression (p < 0.05), but no correlation with other markers. Furthermore, no correlation were found between the CD86 expression and the proliferation of CLL cells. Analysis of clinical data showed that cases with high CD86 expression had lower level of serum lymphocyte count (p < 0.04) at the time of the diagnosis. CD86 shows multiple appearances in the lymph nodes containing pseudofollicules, but no correlation was found between CD86 positivity, and Ki67 positivity. Our results suggest that the use of CD86 molecule as a proliferation marker for CLL is highly questionable. However, the CD86 molecule may interfere with the immune system of patients with CLL by activating and depleting immune functions. That can be the reason why CD86 positivity may mean worse prognosis. PMID- 30406402 TI - Intensive targeting of regulatory competence genes by transposable elements in streptococci. AB - Competence for natural transformation is a widespread developmental process of streptococci. By allowing the uptake and recombination of exogenous naked DNA into the genome, natural transformation, as transposable elements, plays a key role in the plasticity of bacterial genomes. We previously analysed the insertion sites of IS1548, an insertion sequence present in Streptococcus agalactiae and S. pyogenes, and showed that some targeted loci are involved in competence induction. In this work, we investigated on a large scale if loci coding for early competence factors (ComX and the two pheromone-dependent signalling systems ComCDE and ComRS) of streptococci are especially targeted by transposable elements. The transposable elements inserted in regions surrounding these genes and housekeeping genes used for Multilocus Sequence Typing (MLST) were systematically searched for. We found numerous insertion events in the close vicinity of early competence genes, but only very few into the MLST loci. The incidence of transposable elements, mainly insertion sequences, is particularly high in the intergenic regions surrounding comX alleles in numerous species belonging to most streptococcal groups. The identification of scarce disruptive insertions inside early competence genes indicates that the maintenance of competence is essential for streptococci. The specific association of transposable elements with intergenic regions bordering the main regulatory genes of competence may impact on the induction of transformability and so, on the genome plasticity and adaptive evolution of streptococci. This widespread phenomenon brings new perspectives on our understanding of competence regulation and its role in the bacterial life cycle. PMID- 30406403 TI - 2018 Fetal Cardiac Symposium Abstracts Presented on July 12-13, 2018 Rush University Medical Center, Chicago, IL. PMID- 30406404 TI - Relationship between VEGF-related gene polymorphisms and brain morphology in treatment-naive patients with first-episode major depressive disorder. AB - Vascular endothelial growth factor (VEGF) is involved in the development of major depressive disorder (MDD). Recently, a genome-wide association study has revealed that four VEGF-related single nucleotide polymorphisms (SNPs) (i.e., rs4416670, rs6921438, rs6993770 and rs10738760) were independently associated with circulating VEGF levels. The current study investigated the relationship between brain volume and these four SNPs in first-episode drug-naive MDD patients. A total of 38 first-episode drug-naive MDD patients and 39 healthy subjects (HS) were recruited and underwent high-resolution T1-weighted imaging. Blood samples were collected from all the participants for serum VEGF assays and VEGF-related SNPs genotyping. Genotype-diagnosis interactions related to whole-brain cortical thickness and hippocampal subfield volumes were evaluated for the four SNPs. The results revealed a genotype-diagnosis interaction only for rs6921438 (i.e., the MDD patients and HS with the G/G genotype versus the MDD patients and HS with A carrier genotype) in the subiculum of the left hippocampus (p < 0.05), and not the other SNPs. There was a volume reduction in the left subiculum of G/G genotype patients compared with the other groups. The "hypochondriasis" scores of the HAMD-17 scale were significantly higher in the G/G genotype patients than the A-carrier genotype patients. The association was observed between VEGF-related SNP rs6921438 and subiculum atrophy in first-episode drug-naive MDD patients. PMID- 30406405 TI - Bone marrow washout for multilevel vertebroplasty in multiple myeloma spinal involvement. Technical note. AB - INTRODUCTION: Vertebral involvement is found in a high percentage of multiple myeloma (MM) patients, often requiring multilevel surgical treatment to reduce pain and disability and to receive prompt access to oncological care. We describe the clinical use of washout technique for multilevel vertebroplasty in MM patients with diffuse spinal involvement. The aim of this technique is to reduce the risk of pulmonary fat embolism after cement injection and possibly to increment the amount of cement and treated levels in one surgical stage. METHODS: Three patients were treated with the washout technique prior to multilevel vertebroplasty for thoracolumbar diffuse spinal involvement in multiple myeloma. We describe the surgical technique and review the pertinent literature. RESULTS: The technique is clinically safe and effective in reducing pain, without significant complications. Two six-level vertebroplasties were performed in one case, allowing a larger amount of cement injected and a prompt start of the oncological treatment. CONCLUSIONS: Multilevel vertebroplasty in MM patients with diffuse spinal involvement carries the advantages of reducing pain, avoid repeated surgeries and faster return to oncological regimen. Cardiovascular complications, including pulmonary embolism, are rare but can have fatal consequences. It is mainly due to bone marrow mobilization during cement injection and the risk increases with the amount of cement injected and the number of treated levels. Despite multilevel treatment at the same stage, we did not observe any significant complication in our series. Further studies are needed to confirm the preliminary results of this technique. These slides can be retrieved under electronic supplementary material. PMID- 30406406 TI - Tunnel placement in ACL reconstruction surgery: smaller inter-tunnel angles and higher peak forces at the femoral tunnel using anteromedial portal femoral drilling-a 3D and finite element analysis. AB - PURPOSE: Recent studies have emphasized the importance of anatomical ACL reconstruction to restore normal knee kinematics and stability. Aim of this study is to evaluate and compare the ability of the anteromedial (AM) and transtibial (TT) techniques for ACL reconstruction to achieve anatomical placement of the femoral and tibial tunnel within the native ACL footprint and to determine forces within the graft during functional motion. As the AM technique is nowadays the technique of choice, the hypothesis is that there are significant differences in tunnel features, reaction forces and/or moments within the graft when compared to the TT technique. METHODS: Twenty ACL-deficient patients were allocated to reconstruction surgery with one of both techniques. Postoperatively, all patients underwent a computed tomography scan (CT) allowing 3D reconstruction to analyze tunnel geometry and tunnel placement within the native ACL footprint. A patient specific finite element analysis (FEA) was conducted to determine reaction forces and moments within the graft during antero-posterior translation and pivot-shift motion. RESULTS: With significantly shorter femoral tunnels (p < 0.001) and a smaller inter-tunnel angle (p < 0.001), the AM technique places tunnels with less variance, close to the anatomical centre of the ACL footprints when compared to the TT technique. Using the latter, tibial tunnels were more medialised (p = 0.007) with a higher position of the femoral tunnels (p = 0.02). FEA showed the occurrence of higher, but non-significant, reaction forces in the graft, especially on the femoral side and lower, however, statistically not significant, reaction moments using the AM technique. CONCLUSION: This study indicates important, technique-dependent differences in tunnel features with changes in reaction forces and moments within the graft. LEVEL OF EVIDENCE: II. PMID- 30406407 TI - Midbody of the medial meniscus as a reference of preservation in partial meniscectomy for complete discoid lateral meniscus. AB - PURPOSE: To evaluate the postoperative size of discoid lateral meniscus using magnetic resonance imaging (MRI) after partial meniscectomy relative to the size of medial meniscus midbody. METHODS: This study included 48 patients who underwent arthroscopic partial meniscectomy with or without repair for symptomatic complete discoid meniscus. The intraoperative size of midbody of medial meniscus was used as a reference for partial meniscectomy. MRIs were performed pre- and postoperatively. Quantitative evaluations of the height, width, extrusion of the meniscus, and relative percentage of extrusion in the coronal and sagittal planes were completed. Demographic data, preoperative shift, type of shift, and operative technique were analyzed while considering the remaining meniscus. Logistic regression analyses were used. RESULTS: The mean remaining discoid meniscal width in the coronal plane of MRI was not significantly different from the width of midbody of medial meniscus (9.1 +/- 4.2 mm vs. 9.4 +/- 1.4 mm, n.s.) Absolute meniscal extrusion and relative percentage of extrusion in the coronal plane and the ratio of t meniscus in sagittal plane of the final MRI were significantly increased as compared with the preoperative MRI. Preoperative shift was a risk factor for the reduction of remaining meniscal width (odds ratio 11.997, p = 0.016, 95% CI 1.586-90.737). CONCLUSION: The size of midbody of medial meniscus could be a reference for partial meniscectomy in symptomatic complete discoid meniscus. Preoperative shift represents a risk factor for decreased remaining meniscal width. These findings could be helpful in ensuring appropriate surgical planning and explaining poor prognostic factors. LEVEL OF EVIDENCE: Prospective cohort study, Level II. PMID- 30406408 TI - Anterior cruciate ligament reconstruction is associated with greater tibial tunnel widening when using a bioabsorbable screw compared to an all-inside technique with suspensory fixation. AB - PURPOSE: To compare clinical outcomes and tunnel widening following anterior cruciate ligament reconstruction (ACLR) performed with an all-inside technique (Group A) or with a bioabsorbable tibial screw and suspensory femoral fixation (Group B). METHODS: Tunnel widening was assessed using computed tomography (CT) and a previously validated analytical best fit cylinder technique at approximately 1-year following ACLR. Clinical follow-up comprised evaluation with IKDC, KSS, Tegner, Lysholm scores, and knee laxity assessment. RESULTS: The study population comprised 22 patients in each group with a median clinical follow-up of 24 months (range 21-27 months). The median duration between ACLR and CT was 13 months (range 12-14 months). There were no significant differences in clinical outcome measures between groups. There were no differences between groups with respect to femoral tunnel widening. However, there was a significantly larger increase in tibial tunnel widening, at the middle portion, in Group B (2.4 +/- 1.5 mm) compared to Group A (0.8 +/- 0.4 mm) (p = 0.027), and also at the articular portion in Group B (1.5 +/- 0.8 mm) compared to Group A (0.8 +/- 0.8 mm) (p = 0.027). CONCLUSION: Tibial tunnel widening after ACLR using hamstring tendon autograft is significantly greater with suspensory femoral fixation and a bioabsorbable tibial interference screw when compared to an all-inside technique at a median follow-up of 2 years. The clinical relevance of this work lies in the rebuttal of concerns arising from biomechanical studies regarding the possibility of increased tunnel widening with an all-inside technique. LEVEL OF EVIDENCE: III. PMID- 30406409 TI - N- and O-Doped Carbon Dots for Rapid and High-Throughput Dual Detection of Trace Amounts of Iron in Water and Organic Phases. AB - In this work, we report a dual use of highly fluorescent N- and O-doped carbon dots (CDs) for rapid and high-throughput trace analysis of iron in water and organic phases. The CDs are rapidly synthesized in a sealed vessel via microwave irradiation within 5 min, and they exhibit high quantum yields of 80% with sensitive quenching responses to iron contents. Combined with a microplate fluorescence reader, a rapid and high-throughput assay for ions is further developed. The whole process from the CD synthesis to the detection output can be accomplished within 15 min. The limits of detection for Fe3+ in aqueous solution and ferrocene in organic gasoline are determined down to 0.05 mM. Furthermore, this method has been successfully used to determine the level of irons in real gasoline for quality evaluation. The results have an excellent agreement with atomic absorption spectrophotometric measurements. The CD-based facile assay with lower cost, use of less sample, and higher-throughput holds great promise as a powerful tool for iron detection in water and organic phase samples. PMID- 30406410 TI - Fitness costs associated with multiple resistance to dicamba and atrazine in Chenopodium album. AB - MAIN CONCLUSION: Detrimental pleiotropic effects of resistance mutation(s) were observed for multiple-resistant phenotypes (resistant to both atrazine and dicamba). The multiple-resistant phenotypes had lower growth rates and less capacity for vegetative growth compared to the phenotypes only resistant to atrazine. The fitness costs that are conferred by herbicide resistance alleles can affect the rate of herbicide resistance evolution within populations. We evaluated the direct fitness costs involved with multiple resistance to dicamba and atrazine (R1 and R2) in Chenopodium album by comparing the performance of multiple-resistant phenotypes to those phenotypes that were only resistant to atrazine (S1 and S2). The R1 and R2 phenotypes were consistently shorter and produced less dry matter than the S1 and S2 phenotypes. The R1 and R2 phenotypes were shown to have lower relative growth rates (RGR) and net assimilation rates (NAR) than the S1 and S2 phenotypes at an early stage of growth. However, there was no significant difference in RGR between the R1 and R2 and, S1 and S2 phenotypes at a later stage of growth, though the R1 and R2 phenotypes still had a lower NAR at this later stage. Further investigations using a neighbouring crop competition approach showed that the R1 and R2 phenotypes were weaker competitors, and exhibited significantly less capacity for vegetative growth compared to the S1 and S2 phenotypes during competition. Overall, the results of this study revealed multiple- resistance to atrazine and dicamba endowed a significant fitness penalty to C. album, and it is possible that the frequency of multiple-resistant individuals would gradually decline once selection pressure from herbicides was discontinued. PMID- 30406411 TI - Efficacy of biological agents and compost on growth and resistance of tomatoes to late blight. AB - MAIN CONCLUSION: This study identified biocontrol measures for improving plant quality and resistance under biotic stress caused by the most devastating pathogen in tomato production. The management of plant diseases are dependent on a variety of factors. Two important variables are the soil quality and its bacterial/fungal community. However, the interaction of these factors is not well understood and remains problematic in producing healthy crops. Here, the effect of oak-bark compost, Bacillus subtilis subsp. subtilis, Trichoderma harzianum and two commercial products (FZB24 and FZB42) were investigated on tomato growth, production of metabolites and resistance under biotic stress condition (infection with Phytophthora infestans). Oak-bark compost, B. subtilis subsp. subtilis, and T. harzianum significantly enhanced plant growth and immunity when exposed to P. infestans. However, the commercial products were not as effective in promoting growth, with FZB42 having the weakest protection. Furthermore, elevated levels of anthocyanins did not correlate with enhanced plant resistance. Overall, the most effective and consistent plant protection was obtained when B. subtilis subsp. subtilis was combined with oak-bark compost. In contrast, the combination of T. harzianum and oak-bark compost resulted in increased disease severity. The use of compost in combination with bio-agents should, therefore, be evaluated carefully for a reliable and consistent tomato protection. PMID- 30406412 TI - Assessment of the use of ethanol instead of MTBE as an oxygenated compound in Mexican regular gasoline: combustion behavior and emissions. AB - The energy reforms implemented in Mexico promote the use of ethanol in gasoline but exclude the country's ozone nonattainment areas oxygenated with methyl-tert butyl ether (MTBE) in view that further scientific studies are required. To address a potential implementation scenario in areas of ozone high VOC-sensitive regimes, the impact on performance and emissions characteristics between the regular MTBE fuel available and a formulated gasoline containing 10% v/v ethanol having similar Reid vapor pressure (RVP) were compared in a single cylinder spark ignited engine and a set of tier I vehicles. Included in the assessment were the "criteria" pollutants (THC, CO, and NOx), toxic compounds, and speciated hydrocarbons in order to calculate the ozone-forming potential (OFP). The change in combustion speed of ethanol fuel vs. regular gasoline seems to be small and depends mainly on base gasoline formulation. Vehicle dynamometer testing showed no statistically significant differences in the average THC, CO, and NOx results when comparing both fuels. Statistically significant differences were seen in total speciated hydrocarbons, total carbonyls emitted, the increases in acetaldehyde emissions, and the decreases in OFP with E10. The results show roughly 20% increase in evaporative emissions when E10 is used, but the OFP of the emissions is lower than that of the Metropolitan Area of Mexico City fuel (MAMC). The increase in the oxygen content using ethanol fuel seems to have no deleterious effect on the vintage of vehicles tested. Taking into consideration that the evaporative emissions standard in Mexico is less stringent than that in other countries, the substitution of the actual regular gasoline for ethanol fuels should uphold the least volatile AA class in areas with ozone problems. PMID- 30406413 TI - Ayahuasca improves emotion dysregulation in a community sample and in individuals with borderline-like traits. AB - BACKGROUND: Research suggests that mindfulness-based interventions may improve mindfulness-related capacities (e.g., decentering, non-judging, and non-reacting) and emotion regulation. Previously, our group reported that ayahuasca could be a potential analogue of mindfulness practice. The main aim of the current study was to examine the effects of ayahuasca on emotional regulation and mindfulness related capacities. Secondarily, we sought to explore the effects of ayahuasca on individuals with borderline personality disorder (BPD) traits. METHOD: This is an observational study of 45 volunteers who participated in an ayahuasca session. The volunteers completed various self-report instruments designed to measure emotional dysregulation (Difficulties in Emotion Regulation Scale (DERS)) and mindfulness traits (Five Facet Mindfulness Questionnaire (FFMQ)-Short Form and Experiences Questionnaire (EQ)) prior to and 24 h after the ayahuasca session. The volunteers were divided into two subgroups based on their score on the McLean Screening Instrument for BPD (MSI-BPD). Twelve participants were grouped into the BPD-like traits subgroup while the rest of them were included in the non-BPD-like subgroup. We performed within-subjects and between-group analyses. RESULTS: Overall, the participants showed significant improvements on the FFMQ subscales observing, acting with awareness, non-judging, and non-reacting and also significantly improved on decentering (EQ scale) and on the DERS subscales emotional non-acceptance, emotional interference, and lack of control. The BPD like subgroup also showed significant improvements on the DERS subscales emotional interference and lack of control but not in mindfulness capacities. CONCLUSIONS: These findings suggest a potential therapeutic effect for ayahuasca in emotion regulation and mindfulness capacities (including decentering, acceptance, awareness, and sensitivity to meditation practice). Based on these results, we believe that ayahuasca therapy could be of value in clinical populations, such as individuals with BPD, affected by emotion dysregulation. PMID- 30406414 TI - Non-contrast three-dimensional gradient recalled echo Dixon-based magnetic resonance angiography/venography in children. AB - Magnetic resonance imaging (MRI) has been considered a valuable diagnostic tool for noninvasive imaging of the vasculature in children and adults for more than two decades. While a variety of non-contrast MRI methods have been described for imaging of both arteries and veins (e.g., time-of-flight, phase contrast, and balanced steady-state free precession imaging), contrast-enhanced magnetic resonance angiography/venography are the most commonly employed vascular imaging techniques due to their high spatial and contrast resolutions and general reliability. In this technical innovation article, we describe a novel 3-D respiratory-triggered gradient recalled echo Dixon-based MR angiography/MR venography technique that provides high-resolution anatomical imaging of the vasculature of the neck, body and extremities without the need for intravenous contrast material or breath-holding. PMID- 30406416 TI - Female Pelvic Medicine & Reconstructive Surgery (FPMRS) challenges on behalf of the collaborative research in pelvic surgery consortium (CoRPS): managing complicated cases series 2: management of urinary incontinence in a neurogenic patient. AB - Discussion and management of incontinence in a patient with spina bifida by four international experts followed by a literature review. PMID- 30406417 TI - A MnO2 nanosheet-based ratiometric fluorescent nanosensor with single excitation for rapid and specific detection of ascorbic acid. AB - Ascorbic acid (AA) detection in biological sample and food sample is critical for human health. Herein, a MnO2 nanosheet (MnO2-NS)-based ratiometric fluorescent nanosensor has been developed for high sensitive and specific detection of AA. The MnO2-NS presents peroxidase-like activity and can oxidize non-fluorescent substrate of o-phenylenediamine (OPDA) into fluorescent substrate, presenting maximum fluorescence at 568 nm (F568). If MnO2-NS is premixed with AA, the MnO2 NS is then decomposed as Mn2+ by AA, decreasing the fluorescent intensity of F568. Meantime, AA is oxidized as dehydroascorbic acid (DHAA), which can react with OPDA to generate fluorescent substrate. A new fluorescence response is found at 425 nm (F425). The dual fluorescent responses can be excited with a universal excitation wavelength, simplifying the detection procedure. With F425/F568 as readout, limit of detection for AA reaches as low as 10.0 nM. Satisfactory recoveries are found for AA detection in serum and diverse beverages. The ratiometric strategy significantly eliminates false-negative and false-positive results, providing a cost-effective, rapid, and reliable way for AA detection in real sample. PMID- 30406419 TI - Parental overprotection and youth suicide behavior in low- and middle-income countries: a multilevel analysis of cross-national data. AB - OBJECTIVES: Research on youth suicide behavior has emphasized parent-child relations as a critical protective factor. This study investigates whether "too much" regulation of children, i.e., overprotection, may actually increase the likelihoods of youth suicide intent and plan. METHODS: Data are drawn from the subset of the Global School-based Student Health Survey (2000-2012), consisting of children living in 48 low- and middle-income countries. Two-level hierarchical linear models are fitted to examine the potential curvilinear (U-shaped) association between parental monitoring and suicide behavior among youth. RESULTS: Adjusting for individual- and country-level covariates, significant support is found for non-monotonicity specifically among boys: Greater parental involvement in male children's lives lowers both suicide ideation and suicide plan to some extent but, after certain thresholds, increases the odds of both outcomes. Results for girls, however, are much less pronounced. CONCLUSIONS: In resource-poor countries marked by some of the highest teenage suicide rates in the world, overprotective parenting style is found to have negative and gendered consequences on the mental health of youth. More research is needed to confirm its replicability in economically more developed societies. PMID- 30406415 TI - Phenotypic and Genetic Characteristics of Lipodystrophy: Pathophysiology, Metabolic Abnormalities, and Comorbidities. AB - PURPOSE OF REVIEW: This article focuses on recent progress in understanding the genetics of lipodystrophy syndromes, the pathophysiology of severe metabolic abnormalities caused by these syndromes, and causes of severe morbidity and a possible signal of increased mortality associated with lipodystrophy. An updated classification scheme is also presented. RECENT FINDINGS: Lipodystrophy encompasses a group of heterogeneous rare diseases characterized by generalized or partial lack of adipose tissue and associated metabolic abnormalities including altered lipid metabolism and insulin resistance. Recent advances in the field have led to the discovery of new genes associated with lipodystrophy and have also improved our understanding of adipose biology, including differentiation, lipid droplet assembly, and metabolism. Several registries have documented the natural history of the disease and the serious comorbidities that patients with lipodystrophy face. There is also evolving evidence for increased mortality rates associated with lipodystrophy. Lipodystrophy syndromes represent a challenging cluster of diseases that lead to severe insulin resistance, a myriad of metabolic abnormalities, and serious morbidity. The understanding of these syndromes is evolving in parallel with the identification of novel disease causing mechanisms. PMID- 30406418 TI - A competitive colorimetric chloramphenicol assay based on the non-cross-linking deaggregation of gold nanoparticles coated with a polyadenine-modified aptamer. AB - A competitive colorimetric assay has been established to detect chloramphenicol (CAP). It is based on the use of colloidal and electrostatically stabilized aptamer-modified gold nanoparticles (GNPs). The CAP aptamer is modified by a sequence of 5 adenosine groups to anchor it on the surface of GNPs. It can competitively capture two compounds, viz. D-(-)-threo-2-amino-1-(4-nitrophenyl) 1,3-propanediol (CAP-base, with a positive charge) and CAP (which is uncharged). The capture of the positively charged CAP-base triggers the aggregation of modified GNPs in salt-containing solution, and this causes a color change from red to purple. However, in the presence of CAP and CAP-base, the capture of the uncharged CAP weakens this color change by a competing process for capture. Thus, the concentration of CAP is associated with the degree of deaggregation of GNPs and can be quantified by the ratio of absorbances at 620 nm and 520 nm. The assay has a 22 nM limit of detection in acidic solution, and the response is linear in the range of 0.20 to 3.20 MUM CAP concentration. This assay was successfully applied to the determination of CAP in spiked environmental water samples. Conceivably, this method has a wide scope in that it may be applied to a wide range of analytes if respective aptamers are available. Graphical abstract Schematic presentation of a competitive non-cross linking deaggregating method for detecting chloramphenicol. The surface charge of polyA-Apt@GNPs and its aggregation degree (purple) are determined by the charge of target. (CAP-base: precursor of CAP; PolyA-Apt@GNPs: 5'-polyA-modified DNA aptamer functionalized gold nanoparticles.). PMID- 30406420 TI - Sex-Based Differences in Chronic Total Occlusion Management. AB - ?: Chronic total occlusions (CTOs) are an important and increasingly recognized subgroup of coronary lesions, documented in at least 30%, but up to 52% of patients with coronary artery disease (CAD) undergoing coronary angiography. Percutaneous coronary intervention (PCI) of these lesions is increasingly pursued, with excellent success rates. PURPOSE OF REVIEW: It is known that gender differences exist in the presentation of CAD, as well as in clinical outcomes after routine PCI; however, it is not well described how these differences pertain to management of CTOs. This review summarizes the available data regarding sex-based differences in CTO management and outcomes. RECENT FINDINGS: Women comprise approximately 20% of CTO registry and trial participants. As has been demonstrated in PCI studies, women comprise a minority of patients in CTO PCI registries and trials. Sex-based differences exist in complication rates, collateral formation, and outcomes and need further evaluation in future studies. PMID- 30406421 TI - Intracranial Ewing sarcoma with whole genome study. AB - INTRODUCTION: Ewing sarcoma (ES) as a primary intracranial tumor is very rare. Recently, CNS embryonal tumors with ES-like genomic change have been reported. Patients and methods We report a case of intracranial Ewing sarcoma in a 13-year old girl who complained of headache and migraine. The tumor had developed in the right middle cranial fossa with a mass effect on the brain with impending transuncal herniation. RESULTS: Undifferentiated small round cell morphology with completely negative results for friend leukemia integration 1 transcription factor (Fli-1) and a nonspecific cytoplasmic CD99-positive staining pattern mislead the diagnosis as central nervous system (CNS) embryonal tumor, NOS. However, whole genome sequencing (WGS) revealed Ewing sarcoma (EWS)-Fli-1 gene fusion, which was confirmed by fluorescence in situ hybridization study and the diagnosis was revised to ES. CONCLUSIONS: This case is a true intracranial but extra-axial ES confirmed by WGS. We report this case of intracranial ES to demonstrate the importance of marker gene studies using FISH or NGS. PMID- 30406422 TI - The accuracy and trending ability of cardiac index measured by the fourth generation FloTrac/Vigileo systemTM and the Fick method in cardiac surgery patients. AB - To compare the accuracy and trending ability of the cardiac index (CI) measured by FloTrac/VigileoTM (CIFT) or derived by the Fick equation (CIFick) using E CAiOVX (enables continuous monitoring of oxygen consumption) with that measured by thermodilution (CITD) in patients with off-pump coronary artery bypass surgery. Twenty-two patients undergoing elective off-pump coronary artery bypass surgery were included. CIFT and CIFick were determined simultaneously at six time points during off-pump coronary artery bypass surgery. At each time-point, phenylephrine (50 ug) was administered to increase systematic vascular resistance, with CI measured before and after administration (CITD used as reference method). Agreement of each method was evaluated by Bland-Altman analysis, while trending ability was evaluated by four-quadrant plot analysis and polar plot analysis. By Bland-Altman analysis, CIFT and CIFick showed percentage errors of 49.5% and 78.6%, respectively, compared with CITD. Subgroup analysis showed a percentage error between COFT and COTD of 28.9% in patients with a CI >= 2.4 L/min/m2, and 78.1% in patients with a CI >= 2.4 L/min/m2. The concordance rate of four-quadrant plot analysis was 93.3% for CIFT and 66.7% for CIFick in datasets where CITD >= 2.4 L/min/m2 before and after phenylephrine administration were included. CIFT and CIFick had wide limits of agreement with CITD, and were below acceptable limits for tracking phenylephrine-induced CI changes. However, subgroup analysis showed improved accuracy and trending ability of CIFT when only points where CITD >= 2.4 L/min/m2 were included, while there was no improvement in CIFick accuracy or trending ability. PMID- 30406423 TI - Gorongosa and Sasagamine: intra-species behavioral variation in baboons and Japanese monkeys. PMID- 30406424 TI - BRAF mutation testing in melanoma: results from a German observational multicenter study. AB - Quality control of BRAF mutation testing methods used in routine practice is crucial for optimal treatment selection. In this prospective study, we assessed the impact of patient/sample characteristics on BRAF mutation testing results in patients with melanoma, during clinical practice. Data were collected on routine testing practices and documented mutation status in patients with melanoma stages IIIB, IIIC, or IV across 28 diagnostic pathology centers in Germany. Patient/sample data collected included: patient age, location of primary melanoma and metastases, origin of sample, melanoma subtype, and quality of tissue. Statistical influence of patient/sample characteristics on BRAF mutation rate was assessed using multiple logistic regression analyses and statistical models developed to predict the probability of BRAF mutations for individual patient cohorts. Data/samples from 642 patients with melanoma were analyzed. BRAF mutations were documented in 241/642 patients (37.5%). The primary statistical model to predict BRAF mutation rates included: age (continuous), origin of sample, method of mutation analysis, and quality of tissue. Analyses of post hoc collected data identified major deviations between documented mutation rates included in this study vs. routinely recorded mutation rates for three centers. When samples from these centers were excluded, the influence of testing method was no longer statistically significant. The final model included patient age, origin of sample (including metastasis location), and quality of tissue. Once validated in an independent population, this type of model could allow pathology centers to compare the performance of their testing methods with what would be expected based on patient, tumor, and sample characteristics. PMID- 30406425 TI - Osteoporosis in postmenopausal women in this decade: a bibliometric assessment of current research and future hotspots. AB - : Postmenopausal osteoporosis (PMOP) has already become a major public health problem. However, there was no bibliometric analysis estimating the evolutionary process of PMOP research. PURPOSE: This study aimed to assess its scientific activity. METHODS: Publications on PMOP were retrieved from Science Citation Index-Expanded (SCI-E) of the Web of Science (WoS) from 2008 to 2018. VOSviewer software was used for data mining and visualization. The quantity of papers, number of citations, citation frequency per year, and H-index were assessed and compared among different countries, institutes, and researchers. RESULTS: A total of 11,142 papers were included and were cited 184,416 times. The USA contributed the most papers (3162), the most citations (83,270 times), and the highest H index (115). Canada ranked first for the number of papers per million populations and per trillion GDP. Seven of the top ten funding agencies were industries. The key words were stratified into four clusters: cluster 1 ("basic research"), cluster 2 ("diagnosis"), cluster 3 ("treatment"), and cluster 4 ("others"). Average appearing years (AAY) of key words in cluster 1 were the largest compared to those in clusters 2 and 3. For hotspots, "miRNA" showed a relatively latest AAY of 2017.63, followed by "abaloparatide" and "adipokine". CONCLUSION: We concluded that the USA and Europe were the most productive regions on PMOP, with a high prevalence of articles supported by pharmaceutical companies. Key word focus gradually shifted from "diagnosis" to "treatment" and then to precision medicine orientated "basic research". It is recommended to pay attention to potential research hotspots, such as "miRNA," "abaloparatide," and "adipokine". PMID- 30406426 TI - Factors associated with the time to first palliative care consultation in Lebanese cancer patients. AB - INTRODUCTION: Early palliative care is recommended for cancer patients. However, palliative care consults (PCC) are often delayed in Lebanon. The aim of this study was to identify the factors associated with timing of PCC and their impact on the place of death. METHODS: This is a retrospective, single institution, study conducted at Hotel Dieu de France University Hospital in Lebanon. The clinical and demographic characteristics of oncology patients who received PCC were obtained. Cox and logistic regression models were used to evaluate the factors determining the time to first PCC and location of death, respectively. RESULTS: Two hundred and ten patients were included in our analyses with a median age of 69 years (range 22-92 years). The median survival times were: overall survival 18.7 months, time to first PCC 17.9 months, and survival post-PCC 0.6 months. Among patients who were followed-up at home, the median time spent at home was 0.6 months. Late PCC were associated with a childless status (HR = 0.57, 95%CI = 0.37-0.86, p = 0.007), awareness of the diagnosis (HR = 0.64, 95%CI = 0.45-0.91, p = 0.013), and lack of palliative home care (HR = 0.42, 95%CI = 0.25 0.65, p < 0.001). Older patients (OR = 1.03, 95%CI = 1.01-1.05, p = 0.026) and those who had been followed up at home during the PCC (OR = 160.56, 95%CI = 21.39 1205.50, p < 0.001) were significantly more likely to have died at home as opposed to the hospital. DISCUSSION: Cancer patients often receive PCC only shortly before their death. PCC for Lebanese cancer patients were found to be significantly delayed in patients that are childless, knowledgeable of their diagnosis, and lack home palliative care. PMID- 30406427 TI - Optogenetic Long-Term Depression Induction in the PVT-CeL Circuitry Mediates Decreased Fear Memory. AB - The dysregulation of fear learning and abnormal activities of cerebral networks may contribute to the etiologies of anxiety disorders. Although it has been proposed that decreased activity in the paraventricular nucleus of the thalamus (PVT) to the lateral central nucleus of amygdala (CeL) pathway could induce an attenuation of learned fear, no study has shown the effect of the direct optogenetic activation of PVT projecting CeL neurons in vivo on unconditioned fear-related behaviors or learned fear expression. The mechanisms that control the neuronal activity of the PVT-CeL pathway involved in anxiety are rare. Here, we found that CeL neurons have varied responses to optogenetic excitation of PVT terminals in the CeL: neurons with relative high excitability(~ 30%), neurons with relative low excitability(~ 60%), and neurons with no excitability (~ 10%). We next explored the role of the PVT-CeL pathway in unconditioned and conditioned fear-related behaviors by using optogenetics and anxiety assays in freely moving mice. We observed that temporally precise optogenetic activation of the CeL projecting PVT neurons had no effect on unconditioned fear-related behaviors on the elevated plus maze test and the open field test. But optogenetic activation of the CeL-projecting PVT neurons increased conditioned fear expression. We then found that optogenetic long-term depression (LTD) induction in the CeL receiving PVT afferents effectively exerted a persistent attenuation of learned fear. The percentage of neurons with relative high excitability was decreased by the LTD induction, and the percentage of neurons with relative low excitability was increased by the LTD induction. Taking these results together, we identify that increased activity of the PVT-CeL pathway could lead to as excessive learned fear. The CeL neurons with relative high responses to the photo-stimulation of PVT afferents in the CeL may be the key neurons that regulate the output of learned fear expression. Our optogenetic LTD protocol may inspire the development of novel treatments for anxiety disorders involving deep brain stimulation to induce plasticity at relevant brain areas. PMID- 30406428 TI - ESCRT Proteins Control the Dendritic Morphology of Developing and Mature Hippocampal Neurons. AB - The proper shape of dendritic arbors of different types of neurons determines their proper communication within neuronal networks. The shape of dendritic arbors is acquired during a complex and multistep process called dendritogenesis. In most cases, once proper morphology is achieved, it remains stable throughout the lifespan, with the exception of rare events during which dendrites are abruptly pruned. The endosomal sorting complex required for transport (ESCRT) is multisubunit machinery that is involved in various cellular processes when membrane scission is needed. ESCRT subcomplexes regulate dendrite pruning in Drosophila neurons. However, the contribution of ESCRT components to the dendritogenesis of mammalian neurons and control of dendrite stability remains poorly defined. In the present study, we found that ESCRT-0, ESCRT-I, ESCRT-II, and ESCRT-III and Vps4 are required for proper dendrite morphology under basal culture conditions and for accelerated dendritogenesis in response to phosphoinositide 3-kinase (PI3K) activation. The knockdown of Vps28 (ESCRT-I) and Vps25 (ESCRT-II) resulted in downregulation of the activity of mechanistic/mammalian target of rapamycin complex 1. We also demonstrated that Vps28, Vps24, and Vps25 are required for dendrite stabilization in mature neurons. PMID- 30406429 TI - Prevalence and quantification of contamination of knitted cotton outer gloves during hip and knee arthroplasty surgery. AB - INTRODUCTION: Knitted cotton outer gloves offer protection against surgical glove perforation and provide improved grip on instruments. These gloves absorb blood and other fluids during surgery, and may therefore also accumulate contaminating bacteria. To date, there is no published data on microbial contamination of such gloves during surgery. METHODS: Knitted cotton outer gloves used in primary and revision hip and knee arthroplasty from two Swiss hospitals were analysed by quantitative bacteriology. Samples were subjected to sonication and vortexing, followed by membrane filtration of the sonicate. Membranes were incubated under aerobic and anaerobic culture conditions, respectively, for 21 days. Total microbial load for each pair of gloves was determined by colony-forming units (CFU) count. Strain identification was performed with MALDI-TOF. RESULTS: A total of 43 pairs of gloves were collected from continuous series of surgeries. Under aerobic culture conditions, total CFU counts ranged 0-1103, 25 (58%) samples remaining sterile, and 4 (9%) yielding > 100 CFU. Under anaerobic culture conditions, total CFU counts ranged 0-3579, 22 (51%) samples remaining sterile, 6 (14%) yielding > 100 CFU. The only covariate significantly associated with the level of contamination was the provider hospital (p < 0.0001 for aerobic and p = 0.007 for anaerobic cultures). Strain identification revealed only skin commensals, mainly coagulase-negative staphylococci and Propionibacterium spp. CONCLUSION: While contamination of surgical latex gloves is a well-known issue, no study has examined so far contamination of knitted cotton outer gloves. No or very low microbial contamination could be identified in the majority of the knitted cotton outer gloves assayed. However, a relevant proportion showed contamination far higher than estimated minimal thresholds for implant-associated infection. Clinical relevance of these findings remains to be established. PMID- 30406430 TI - A Novel Methodology for Extracting and Evaluating Therapeutic Movements in Game Based Motion Capture Rehabilitation Systems. AB - Virtual rehabilitation yields outcomes that are at least as good as traditional care for improving upper limb function and the capacity to carry out activities of daily living. Due to the advent of low-cost gaming systems and patient preference for game-based therapies, video game technology will likely be increasingly utilized in physical therapy practice in the coming years. Gaming systems that incorporate low-cost motion capture technology often generate large datasets of therapeutic movements performed over the course of rehabilitation. An infrastructure has yet to be established, however, to enable efficient processing of large quantities of movement data that are collected outside of a controlled laboratory setting. In this paper, a methodology is presented for extracting and evaluating therapeutic movements from game-based rehabilitation that occurs in uncontrolled and unmonitored settings. By overcoming these challenges, meaningful kinematic analysis of rehabilitation trajectory within an individual becomes feasible. Moreover, this methodological approach provides a vehicle for analyzing large datasets generated in uncontrolled clinical settings to enable better predictions of rehabilitation potential and dose-response relationships for personalized medicine. PMID- 30406432 TI - ? PMID- 30406431 TI - Choledochal malformations: global research, scientific advances and key controversies. AB - Choledochal malformations (CMs) represent a spectrum of relatively rare and complex congenital anomalies, characterized by abnormal dilatation of the biliary tract in the absence of any acute obstruction. Today, almost 20% of CMs can be detected in-utero using maternal ultrasonography. Formal scientometric analysis was used to identify where modern CM research is taking place and perhaps where our attention should be directed in the future. Thus, this article offers a comprehensive review of recent scientific advances relating to CMs including the current understanding of etiology and classification, whilst also discussing key controversies such as risk of malignant transformation and the role of newer modalities of surgical treatment. Although laparoscopic excision of CMs and biliary reconstruction is nowadays feasible and safe, care should be taken before dispensing with standard open techniques, which have minimal complication rates and proven long-term benefit. PMID- 30406433 TI - ? PMID- 30406434 TI - ? PMID- 30406435 TI - The "Reading the Mind in the Eyes" Test in Autism-Spectrum Disorders Comparison with Healthy Controls: A Systematic Review and Meta-analysis. AB - We conducted a meta-analysis of 18 studies to establish whether a relation exists between Reading the Mind in the Eye Test (RMET) performance and intelligence quotient (IQ) in individuals diagnosed with autism-spectrum disorders (ASD) and controls, taking into account relevant characteristics such as age, gender, and autism quotient. Our findings indicate that RMET performance was better in controls compared with those diagnosed with ASD. We found that RMET performance is dependent on full and verbal IQ and age in controls. However, RMET performance is negatively correlated with performance IQ in individuals diagnosed with ASD. These results suggest that the methodology applied by ASD when taking the RMET is different from control individuals and might depend less on verbal abilities. PMID- 30406436 TI - The Association of the Broader Autism Phenotype with Emotion-Related Behaviors in Mothers of Children With and Without Autism Spectrum Traits. AB - Broader autism phenotype (BAP) characteristics (pragmatic language deficits, aloofness, and rigidity) are prevalent in families of individuals with autism spectrum disorder (ASD) and may influence emotion-related behaviors. The current study analyzed associations among BAP characteristics with emotion-related behaviors in mothers of children with and without ASD. Twenty-seven mothers completed BAP and emotion regulation (ER) questionnaires. Maternal affect was coded during an interaction task. BAP rigidity negatively correlated with the ER strategy reappraisal. BAP total and pragmatic scores positively correlated with observed negative affect. Associations remained significant in step-wise regressions that controlled for other BAPQ subscale scores. Findings suggest that pragmatic difficulties may interfere with positive mother-child interactions and mothers with high rigidity may benefit from learning adaptive ER strategies. PMID- 30406437 TI - Diagnosing Autism Spectrum Disorder in Children with Low Mental Age. AB - Autism Spectrum Disorder (ASD) diagnostic tools are not designed for mental ages (MA) below 12 months. Autism Diagnostic Observation Schedule (ADOS) and Childhood Autism Rating Scale (CARS) were examined in 2-year-olds with ASD-low MA (n = 53), Global Developmental Delay (GDD; n = 175), and ASD-higher MA (n = 425). ADOS and CARS demonstrated similar agreement with clinical diagnosis, but ADOS over classified ASD in low MA, whereas CARS both over- and under-classified. All ADOS items differentiated GDD from ASD. Elementary social behaviors (e.g., eye contact, social interest) were similar across ASD groups, although advanced skills (e.g., pointing, play) were more impaired in ASD-low MA. ASD-low MA, a severe presentation, may require a modified ADOS algorithm to account for developmental delays. PMID- 30406438 TI - Maintaining lower limb access with the HeRO device. AB - Central venous catheters (CVC) remain a mainstay of vascular access particularly for incident patients,?but lead to central vein stenosis (CVS) in up to 1 in 6 patents. This often leads to establishing dialysis access in the groin which in turn may result in development of CVS in the lower body, although this is poorly reported. The HeRO device was designed to address CVS by bypassing the stenosed veins with a nitinol-reinforced silicone tube into the right atrium, which acts as an outflow conduit attached to an arterial inflow. The efficacy and safety of the HeRO device in the upper limb is well established, but there is no data on its use in the lower limb. We describe 2 cases of HeRO in the lower limb, one primary and one secondary, which remain in use. Lower limb HeRO is feasible in the lower limb and can work well either as de novo (to achieve vascular access) or as a salvage procedure (to maintain vascular access). PMID- 30406439 TI - In-Silico Bioprospecting: Finding Better Enzymes. AB - Enzymes are essential biological macromolecules, which catalyse chemical reactions and have impacted the human civilization tremendously. The importance of enzymes as biocatalyst was realized more than a century ago by eminent scientists like Kuhne, Buchner, Payen, Sumner, and the last three decades has seen exponential growth in enzyme industry, mainly due to the revolution in tools and techniques in molecular biology, biochemistry and production. This has resulted in high demand of enzymes in various applications like food, agriculture, chemicals, pharmaceuticals, cosmetics, environment and research sector. The cut-throat competition also pushes the enzyme industry to constantly discover newer and better enzymes regularly. The conventional methods to discover enzymes are generally costly, time consuming and have low success rate. Exploring the exponentially growing biological databases with the help of various computational tools can increase the discovering process, with less resource consumption and higher success rate. Present review discusses this approach, known as in-silico bioprospecting, which broadly involves computational searching of gene/protein databases to find novel enzymes. PMID- 30406440 TI - Ribosome Display: A Potent Display Technology used for Selecting and Evolving Specific Binders with Desired Properties. AB - Ribosome display is a powerful engineering research tool for the high-throughput selection of peptides or proteins, which results in the generation of high performance binders against nearly any antigen of interest. As a cell-free display system, ribosome display has been well developed with many outstanding achievements for over 20 years. Compared with other related display techniques, ribosome display shows unique advantages and development prospects. This tool has been successfully exploited for the selection of functional and specific binders in vitro. This review provides a comprehensive survey of the applications of ribosome display in screening or evolving functional proteins as well as in diagnostics and therapeutics. Previous papers on ribosome display failed to comprehensively review evolutionary strategies for proteins. In the present paper, we review all existing evolutionary strategies that have been combined with ribosome display. We also discuss shortcomings, improvement strategies, and research tendency. PMID- 30406441 TI - [Magnetic resonance-guided focused ultrasound : A new option for tremor treatment]. PMID- 30406442 TI - Cancer Evolution as the New Frontier of Precision Medicine. AB - New experimental breast cancer therapies directed against novel targets are currently in clinical These experimental agents are likely to be effective for a niche of breast cancers with specific "driver mutations". The ability to perform comprehensive molecular profiling of individual tumors has rapidly expanded over the last few years, and new DNA sequencing technologies require relatively limited quantities of fresh or archived paraffin-embedded or snap-frozen tumor tissue and provide rapid turnaround of sequencing results within a few weeks or less. All these technologies provide an unprecedented opportunity to identify patients with rare "driver" molecular alternations that are candidates for proof of-concept clinical trials with matched targeted therapy, in the context of basket trials. The aim of this chapter on molecular profiling is to summarize the known recurrent molecular alterations in breast cancer that are potentially amenable to investigational targeted therapy, to provide an overview of the existing technological platforms for molecular profiling and ongoing or planned institutional/national screening initiatives and to outline a vision for molecular screening that may be integrated into the future activities of breast cancer research. PMID- 30406443 TI - Neuropharmacology of Synthetic Cathinones. AB - Synthetic cathinones are derivatives of the naturally occurring compound cathinone, the main psychoactive ingredient in the khat plant Catha edulis. Cathinone is the beta-keto analog of amphetamine, and all synthetic cathinones display a beta-keto moiety in their structure. Several synthetic cathinones are widely prescribed medications (e.g., bupropion, Wellbutrin(r)), while others are problematic drugs of abuse (e.g., 4-methylmethcathinone, mephedrone). Similar to amphetamines, synthetic cathinones are psychomotor stimulants that exert their effects by impairing the normal function of plasma membrane transporters for dopamine (DAT), norepinephrine (NET), and 5-HT (SERT). Ring-substituted cathinones like mephedrone are transporter substrates that evoke neurotransmitter release by reversing the normal direction of transporter flux (i.e., releasers), whereas pyrrolidine-containing cathinones like 3,4-methylenedioxypyrovalerone (MDPV) are potent transporter inhibitors that block neurotransmitter uptake (i.e., blockers). Regardless of molecular mechanism, all synthetic cathinones increase extracellular monoamine concentrations in the brain, thereby enhancing cell-to-cell monoamine signaling. Here, we briefly review the mechanisms of action, structure-activity relationships, and in vivo pharmacology of synthetic cathinones. Overall, the findings show that certain synthetic cathinones are powerful drugs of abuse that could pose significant risk to users. PMID- 30406444 TI - Evaluation of the Predictive and Prognostic Values of Stromal Tumor-Infiltrating Lymphocytes in HER2-Positive Breast Cancers treated with neoadjuvant chemotherapy. AB - BACKGROUND: Stromal tumor-infiltrating lymphocytes (sTILs) have been identified as a predictive biomarker for response to neoadjuvant chemotherapy (NAC) and prognosis in human epidermal growth factor receptor 2 (HER2)-positive breast cancers. However, standardized scoring methods for use in clinical practice need to be established, and the optimal threshold of sTILs to predict pathological complete response (pCR) and prognosis in HER2+ breast cancers has not yet been defined. OBJECTIVE: The predictive and prognostic values of sTILs in patients with HER2-positive breast cancer treated with NAC were evaluated, with the aim to explore the optimal thresholds of sTILs and to investigate the feasibility of scoring methods in clinical practice. PATIENTS AND METHODS: A total of 143 core needle biopsy specimens of HER2-positive invasive breast cancers obtained from Chinese patients who had been treated with trastuzumab-based NAC followed by surgery between 2009 and 2015 were extracted from the pathology database of Fudan University Shanghai Cancer Center. sTIL levels in the pre-NAC core needle biopsy specimens were scored using methods recommended by the International TILs Working Group 2014. The associations between sTILs and pCR, disease-free survival (DFS), and overall survival (OS) were evaluated, and the optimal thresholds for predictive and prognostic values of sTILs were analyzed. RESULTS: First, sTILs were associated with a higher pCR rate in HER2-positive breast cancers. Univariate (per 10% sTILs: odds ratio [OR] 1.05, 95% confidence interval [CI] 1.02-1.08, p = 0.001) and multivariate regression analyses (per 10% sTILs: OR 1.04, 95% CI 1.00-1.07, p = 0.034) indicated that sTILs as a continuous variable were a significant predictor of pCR in HER2-positive breast cancers. Receiver operating characteristics (ROC) curve analysis showed that a 20% threshold best distinguished the pCR subgroup from the non-pCR subgroup. The dichotomized sTILs with a threshold set at 20% was a strong predictor of pCR in the univariate (OR 0.25, 95% CI 0.12-0.52, p < 0.001) and multivariate analyses (OR 0.35, 95% CI 0.14-0.87, p = 0.024). Second, sTILs were associated with better prognosis in HER2-positive breast cancers. Univariate (DFS: hazard ratio [HR] 0.91, 95% CI 0.88-0.95, p < 0.001; OS: HR 0.88, 95% CI 0.83-0.94, p < 0.001), and multivariate analyses (DFS: HR 0.93, 95% CI 0.90-0.97, p < 0.001; OS: HR 0.92, 95% CI 0.86 0.98, p = 0.009) suggested that sTILs as a continuous variable had a strong predictive value for improved DFS and OS. As a binary variable with a threshold of 20%, univariate (DFS: HR 6.60, 95% CI 2.91-14.95, p < 0.001; OS: HR 10.29, 95% CI 2.37-44.66, p = 0.002) and multivariate analyses (DFS: HR 3.87, 95% CI 1.65 9.12, p = 0.002; OS: HR 4.74, 95% CI 1.02-22.01, p = 0.047) indicated that patients with >= 20% sTILs had a significantly better prognosis than the patients with < 20% sTILs. CONCLUSIONS: Our study indicates that baseline sTILs scored by methods recommended by the International TILs Working Group in pre-NAC core needle biopsy specimens are significantly correlated with pCR and prognosis in HER2-positive breast cancers. A 20% threshold for sTILs may be a feasible diagnostic marker to predict pCR to NAC and prognosis in patients with HER2 positive breast cancers. PMID- 30406445 TI - Gene variants identified by whole-exome sequencing in 33 French women with premature ovarian insufficiency. AB - PURPOSE: To investigate the potential genetic etiology of premature ovarian insufficiency (POI). METHODS: Whole-exome sequencing (WES) was done on DNA samples from women diagnosed with POI. Mutations identified were analyzed by in silico tools and were annotated according to the guidelines of the American College of Medical Genetics and Genomics. Plausible variants were confirmed by Sanger sequencing. RESULTS: Four of the 33 individuals (12%) carried pathogenic or likely pathogenic variants, and 6 individuals carried variants of unknown significance. The genes identified with pathogenic or likely pathogenic variants included PMM2, MCM9, and PSMC3IP. CONCLUSIONS: WES is an efficient tool for identifying gene variants in POI women; however, interpretation of variants is hampered by few exome studies involving ovarian disorders and the need for trio sequencing to determine inheritance and to detect de novo variants. PMID- 30406446 TI - Monozygotic twinning in the IVF era: is it time to change existing concepts? PMID- 30406447 TI - A successful treatment with 5 methyltetrahydrofolate of a 677 TT MTHFR woman suffering premature ovarian insufficiency post a NHL (non-Hodgkin's lymphoma) and RPL (repeat pregnancy losses). PMID- 30406448 TI - Could polymorphisms of some hormonal receptor genes, involved in folliculogenesis help in predicting patient response to controlled ovarian stimulation? AB - PURPOSE: The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in selected genes, responsible for hormonal regulation of folliculogenesis, are associated with response to controlled ovarian hyperstimulation (COH) and clinical characteristics of women enrolled in in vitro fertilization (IVF) programs. METHODS: In a cross-sectional study, 60 (IVF) patients underwent COH by using gonadotropin-releasing hormone (GnRH) antagonist and recombinant follicle-stimulating hormone (rFSH) protocol. Patients were classified into three groups: poor-responders (according to Bologna criteria), normo-responders (<= 15 oocytes), and hyper-responders (> 15 oocytes). Genotyping of SNPs AMH rs10407022, AMHR rs3741664, FSHR rs1394205 and rs6166, and ESR1 rs2234693 was performed using high-resolution melting analysis (HRMA). Basal FSH (bFSH), estradiol (E2), and anti-Mullerian hormone (AMH) were measured by enzyme linked immunosorbent assay (ELISA). RESULTS: Patients with GG genotype of FSHR rs1394205 had significantly lower AMH level (P = 0.016) and required higher rFSH dose per oocyte compared to women with AA or AG genotype (P = 0.036). We also found higher frequency of GG genotype of FSHR rs1394205 in poor- (76.5%) than in hyper-responders (37.5%, P = 0.002). Patients with AA genotype of FSHR rs6166 had higher level of measured bFSH compared to those with AG or GG genotypes (P = 0.043). Women with GG genotype of AMHR rs3741664 required higher rFSH dose in comparison with patients carrying genotypes AA or AG (P = 0.028). CONCLUSIONS: The GG genotype at position rs1394205 is associated with poor ovarian response to COH. Patients with this genotype may require higher doses of rFSH for ovulation induction. PMID- 30406449 TI - Enhancement of corn stover conversion to carboxylates by extrusion and biotic triggers in solid-state fermentation. AB - Solid-state fermentation is a potential technology for developing lignocellulosic biomass-based biorefineries. This work dealt with solid-state fermentation for carboxylates production from corn stover, as building blocks for a lignocellulosic feedstock-based biorefinery. The effect of extrusion pretreatment, together with the action of a microbial consortia and hydrolytic enzymes as biotic triggers, was investigated on corn stover conversion, microbial metabolic pathways, and populations. The extrusion caused changes in the physical and morphological characteristics, without altering the biochemical composition of the corn stover. Extrusion also led to remarkable differences in the composition of the indigenous microbial population of the substrate. Consequently, it affected the structure of community developed after fermentation and the substrate conversion yield, which increased by 118% (from 23 +/- 4 gCOD/kgVSi obtained with raw substrate to 51 +/- 1 gCOD/kgVSi with extruded corn stover) with regard to self-fermentation experiments. The use of activated sludge as inoculum further increased the total substrate conversion into carboxylates, up to 60 +/- 2 gCOD/kgVSi, and shaped the microbial communities (mainly composed of bacteria from the Clostridia and Bacteroidia classes) with subsequent homogenization of the fermentation pathways. The addition of hydrolytic enzymes into the reactors further increased the corn stover conversion, leading to a maximum yield of 142 +/- 1 gCOD/kgVSi. Thus, extrusion pretreatment combined with the use of an inoculum and enzyme addition increased by 506% corn stover conversion into carboxylates. Beside biomass pretreatment, the results of this study indicated that biotic factor greatly impacted solid-state fermentation by shaping the microbial communities and related metabolic pathways. PMID- 30406450 TI - Gongronella sp. w5 elevates Coprinopsis cinerea laccase production by carbon source syntrophism and secondary metabolite induction. AB - When sucrose was used as the carbon source, the Basidiomycete Coprinopsis cinerea showed poor growth and low laccase activity in pure culture, but greatly enhanced the level of laccase activity (>1800 U/L) during coculture with the Mucoromycete Gongronella sp. w5. As a result, the mechanism of laccase overproduction in coculture was investigated by starting from clarifying the function of sucrose. Results demonstrated that Gongronella sp. w5 in the coculture system hydrolyzed sucrose to glucose and fructose by an intracellular invertase. Fructose rather than glucose was supplied by Gongronella sp. w5 as the readily available carbon source for C. cinerea, and contributed to an alteration of its growth behavior and a basal laccase secretion of 110.6 +/- 3.3 U/L. On the other hand, separating Gongronella sp. w5 of C. cinerea by transfer into dialysis tubes yielded the same level of laccase activity as without separation, indicating that enhanced laccase production probably resulted from the metabolites in the fermentation broth. Further investigation showed that the ethyl acetate-extracted metabolites generated by Gongronella sp. w5 induced C. cinerea laccase production. One of the laccase-inducing compounds namely p-hydroxybenzoic acid (HBA) was purified and identified from the extract. When using HBA as the inducer and fructose as the carbon source in monoculture, C. cinerea observed similar high laccase activity to that in coculture, and zymograms revealed the same expression of laccase Lcc9 as the main and Lcc1 and Lcc5 as the minor enzymes. Overall, our experiments verified that Gongronella sp. w5 elevates Coprinopsis cinerea laccase production by carbon source syntrophism and secondary metabolite induction. PMID- 30406451 TI - Stimulatory effects of novel glucosylated lactose derivatives GL34 on growth of selected gut bacteria. AB - Previously we structurally characterized five glucosylated lactose derivatives (F1-F5) with a degree of polymerization (DP) of 3-4 (GL34), products of Lactobacillus reuteri glucansucrases, with lactose and sucrose as substrates. Here, we show that these GL34 compounds are largely resistant to the hydrolytic activities of common carbohydrate-degrading enzymes. Also, the ability of single strains of gut bacteria, bifidobacteria, lactobacilli, and commensal bacteria, to ferment the GL34 compounds was studied. Bifidobacteria clearly grew better on the GL34 mixture than lactobacilli and commensal bacteria. Lactobacilli and the commensal bacteria Escherichia coli Nissle and Bacteroides thetaiotaomicron only degraded the F2 compound alpha-D-Glcp-(1 -> 2)-[beta-D-Galp-(1 -> 4)-]D-Glcp, constituting around 30% w/w of GL34. Bifidobacteria digested more than one compound from the GL34 mixture, varying with the specific strain tested. Bifidobacterium adolescentis was most effective, completely degrading four of the five GL34 compounds, leaving only one minor constituent. GL34 thus represents a novel oligosaccharide mixture with (potential) synbiotic properties towards B. adolescentis, synthesized from cheap and abundantly available lactose and sucrose. PMID- 30406452 TI - [Immunotherapy]. PMID- 30406453 TI - ? PMID- 30406454 TI - ? PMID- 30406455 TI - ? PMID- 30406456 TI - ? PMID- 30406457 TI - ? PMID- 30406458 TI - ? PMID- 30406459 TI - ? PMID- 30406461 TI - Microshear bond strength of different restorative materials to teeth with molar incisor-hypomineralisation (MIH): a pilot study. AB - AIM: To compare the microshear bond strength of resin based composite (RBC) and resin modified glass ionomer cement (RMGIC) restorations when bonded to teeth with molar incisor hypomineralisation (MIH). METHODS: Eleven first permanent molars with MIH were included in this study. Teeth were sectioned mesio-distally producing a total of 22 surfaces for testing. Each specimen was placed inside a plastic ring with the flattened surface in contact with a glass slab. The plastic ring was filled with autopolymerising acrylic resin to imbed the specimen leaving the enamel surface exposed. Each surface was then bonded to 0.96 mm diameter RBC and light cured RMGIC following the manufacturers' instructions. Microshear bond testing was performed after 24 h storage in distilled water at 37 degrees C. A Bisco shear tester was used to apply shear stress of 1 mm/min until failure. Wilcoxon signed-rank paired-test was used for comparison of bond strength values. RESULTS: Microshear bond strength of RBC (30.80 +/- 8.19 MPa) was significantly higher than that of RMGIC (11.13 +/- 6.91 MPa) when bonded to hypomineralised permanent first molars (p < 0.001). CONCLUSION: The microshear bond strength of RBC is significantly higher than that of RMGIC when bonded to MIH affected teeth. Therefore, RBC can be recommended as the restoration of choice for teeth with MIH whenever the clinical scenario allows. PMID- 30406460 TI - Pharmaceutical Potential of a Novel Chitosan Derivative Schiff Base with Special Reference to Antibacterial, Anti-Biofilm, Antioxidant, Anti-Inflammatory, Hemocompatibility and Cytotoxic Activities. AB - PURPOSE: Chitosan and its derivatives possess several unique properties relevant in the field of pharmaceutics and medicinal chemistry. This study aimed to evaluate the pharmaceutical performance of an innovative chitosan derivative, methyl acrylate chitosan bearing p-nitrobenzaldehyde (MA*CS*pNBA) Schiff base. METHODS: The antibacterial activity of MA*CS*pNBA was tested against multi-drug resistant (MDR) Gram-negative and Gram-positive bacteria using agar-well diffusion method. Anti-biofilm formation was analyzed using a microtitre plate. Antioxidant assays were performed to assess the scavenging activity of MA*CS*pNBA using DPPH, hydrogen peroxide, superoxide together with its reducing power activity. Anti-inflammatory activity was evaluated by albumin denaturation, membrane stabilization, and proteinase inhibition methods. MA*CS*pNBA was tested for its hemolytic efficiency on human erythrocytes. Cytotoxicity of MA*CS*pNBA was evaluated by MTT assay. RESULTS: MA*CS*pNBA showed a significant performance as an antibacterial candidate against MDR bacteria, anti-biofilm, antioxidant and anti-inflammatory biomaterial, evidencing hemocompatibility and no cytotoxicity. It exhibited a significant negative correlation with biofilm formation by the MDR PA-09 strain. Biological activities were found to be significantly concentration dependent. CONCLUSIONS: the newly chitosan derivative MA*CS*pNBA showed to be promising for pharmaceutical applications, expanding the treatment ways toward skin burn infections since it allied excellent antibacterial, anti-biofilm, antioxidant, anti-inflammatory, hemocompatibility and absence of cytotoxic activities. PMID- 30406462 TI - VEGF, Microvessel Density, and CD44 as Inflammation Markers in Peri-implant Healthy Mucosa, Peri-implant Mucositis, and Peri-implantitis: Impact of Age, Smoking, PPD, and Obesity. AB - Several biologic processes affect the supporting peri-implant tissue leading to implant failure and complications, mainly referred to inflammation that is still poorly investigated in the peri-implant soft tissues. Our aim was to investigate in peri-implant healthy mucosa, peri-implant mucositis, and peri-implantitis the expression of some angiogenesis markers highly associated with inflammation, and evaluate its relationships with age, smoking, peri-implant pocket depth (PPD), and body max index (BMI). Moreover, we wanted to study the impact of these clinical parameters in the disease pathogenesis. Forty-eight total patients were recruited. Sixteen had at least one successfully osteointegrated dental implant (group A) and 32 had at least one osseointegrated implant in need of a peri implant treatment for inflammatory/infectiveous reasons: precisely 16 for mucositis (group B) and 16 for peri-implantitis (group C). VEGF, CD34, and CD44 immunohistochemical expression was evaluated in the interproximal biopsies of marginal peri-implant tissue and correlated with the clinical parameters. A significant difference between groups in mean PPD was found, while the distribution by age, gender, smoking, and BMI resulted similar. Group C had significantly higher levels of VEGF, CD34, and CD44 expression compared to the other groups. VEGF, CD34, CD44, and peri-implant pocket depth were all positively correlated. Our study revealed that peri-implantitis is a condition characterized by unique and distinctive features. Our results supported that PPD has a great impact on the peri-implantitis and it is closely related to the inflammation marker expression. The identification of specific biomarkers might help in choosing distinct treatment approaches for target individuals. PMID- 30406463 TI - MicroRNA let-7c Improves LPS-Induced Outcomes of Endometritis by Suppressing NF kappaB Signaling. AB - Endometritis is a common inflammatory disease which endangers human and animal reproductive health. MicroRNA (miRNA) let-7c plays an important role in the inflammatory process; however, the regulatory underlying mechanism of let-7c in endometritis is unclear. In this study, we confirmed that let-7c was significantly reduced in LPS-induced mouse endometritis model, and overexpression of let-7c was able to effectively reduce uterine tissue damage caused by lipopolysaccharide (LPS), and then, a LPS-induced bovine endometrial epithelial cell (BEND) line was used to mimic the inflammatory model in vitro. Our data showed that overexpression of let-7c significantly reduced the expression of pro inflammatory cytokines in BEND cells induced by LPS. Meanwhile, immunofluorescence and western blotting results showed that let-7c significantly inhibited LPS-induced phosphorylation of NF-kappaB, thereby inhibiting downstream pro-inflammatory cytokine expression. Taken together, our results suggested that let-7c ameliorates LPS-induced endometritis by attenuating the expression of pro inflammatory cytokines via inhibition of the activation of NF-kappaB. PMID- 30406464 TI - Environmental Problems of Mining Waste Disposal Sites in Russia. AB - The exploitation of mineral deposits is followed by the formation of huge amounts of wastes, which have strong negative impacts on the surrounding environment. This paper presents the results of the compilation of data on general environmental problems in sites of waste disposal from mining and ore processing in Russia, based on the analysis of published data and own research. The own research of the authors relates to the estimation of the environmental hazards of mining waste using geochemical investigations and biotesting, as well as the development of the classification of technogenic mineral resources counting the reasons of the accumulation of precious components in them and findings on their environmental impact. The influence of waste disposal was determined as significant and diverse, leading to the transformation of all natural compartments surrounding waste disposal sites. The situation is especially aggravated when there are some mining and processing facilities within one relatively small territory. As a result, strong influence zones are formed. These zones have pronounced geochemical features reflecting the specificity of extracted rocks and produced raw materials. The analyzed information can serve as a basis for the development of nature protection measures for the mining waste disposal sites in Russia. Such measures using modern technical means for monitoring can minimize environmental damage from technogenic mineral formations. PMID- 30406465 TI - Variability of bio-climatology indicators in the Southwest China under climate warming during 1961-2015. AB - Southwest China (SWC), characterized by complex climate, undulating topography, intertwined mountains and basins, and diverse ecosystem, is a global hotspot in biodiversity. SWC also is sensitive to climate change, the effects of which can be expressed through alterations in bio-climatology indicators. In this study, we investigated the trends of the key bio-climatology indicators, including mean temperature of the warmest month (TWM), mean temperature of the coldest month (TCM), accumulated temperature above 5 degrees C (AT5) and 10 degrees C (AT10), number of days with daily mean temperature above 5 degrees C (DT5) and 10 degrees C (DT10), annual precipitation (P), precipitation days (DP), and moisture index (MI). The 105 meteorological stations data from 1961 to 2015 were selected to examine the trend of these indexes in SWC. The results suggested that TWM and TCM both experienced a significant upward trend, with the more pronounced increase in TCM than that in TWM. TWM increased by 0.011 degrees C year-1 and TCM increased by 0.025 degrees C year-1. AT5, AT10, DT5, and DT10 also exhibited increasing trend, with AT10 > AT5 and DT10 > DT5, and the trend in DT was found to be less significant than that in AT. The increment of AT5, AT10, DT5, and DT10 were 6.452 degrees C year-1, 7.158 degrees C year-1, 0.164 days year-1, and 0.263 days year-1, respectively. P, DP, and MI showed a downward trend, among which DP experienced a significant decrease with - 1.018 days year-1. In general, SWC tends to be drier and warmer, which may alter the structure and function of the local ecosystem, further then affect the role as a global diversity hotspot. PMID- 30406466 TI - Limb Blood Flow Restriction Plus Mild Aerobic Exercise Training Protects the Heart Against Isoproterenol-Induced Cardiac Injury in Old Rats: Role of GSK 3beta. AB - The present study was conducted to evaluate the effect of blood flow restriction (BFR) training on cardiac resistance to isoproterenol (ISO) induced heart injury in old rats and examined the hypothesis that BFR training may interfere with age associated impairment of mitochondria by the inhibitory phosphorylation of GSK 3beta at Ser9. Old male Wistar rats were divided into the following six groups: CTL (control), ISO (isoproterenol-treated), Sh + ISO (sham-operated plus ISO), BFR + ISO (blood flow restriction plus ISO), Sh-Ex + ISO (sham-operated subjected to exercise and ISO), and BFR-Ex + ISO (blood flow restriction along with exercise and ISO). 10 weeks of exercise training was considered. Then, cardiac injury was induced and physiological, histological, and biochemical parameters were recorded and assessed. Compared to CTL group, isoproterenol administration significantly reduced the systolic arterial pressure (SAP), left-ventricular systolic pressure (LVSP), and +/- dp/dt max (P < 0.05). BFR training improved these parameters in the way that BFR-Ex + ISO group had higher SAP, LVSP and +/- dp/dt max (P < 0.05) and lower LVEDP (left-ventricular end diastolic pressure) (P < 0.01) than untrained and Sh-Ex + ISO groups. The pS9-GSK-3beta and pS9-GSK 3beta/GSK-3beta ratio were increased in the BFR-Ex + ISO group compared to CTL, ISO, Sh + ISO, and BFR + ISO groups (P < 0.05). The level of plasma cardiac Troponin-I and the severity of the injuries were significantly reduced in BFR-Ex + ISO group versus other cardiac damaged groups. In conclusion, our findings clearly confirmed the cardio-protective effect of BFR training against ISO induced myocardial injury. Increased phosphorylated GSK-3beta and angiogenesis in this model of exercise justify the resistance of old hearts facing stressful situations. PMID- 30406467 TI - Cardiotoxicity of Pesticides: Are Africans at Risk? AB - Cardiovascular disease has maintained the unenviable position as the number one cause of death in the world. It is now clear that the traditional risk factors of cardiovascular disease are driven by primary factors like globalisation, urbanisation, industrialisation and agricultural practices. Pesticide use is an integral component of modern and improved agriculture. The abuse and misuse of these chemicals has caused significant poisoning worldwide and particularly in low- and middle-income countries where Africa belongs. This review surveys the widening population of people poisoned by pesticides in Africa and examines the possibility of pesticide-induced cardiotoxicity. The exposed group includes workers in pesticide industries, transporters of these chemicals, farmers, farm workers who apply these pesticides, vendors and sellers of farm produce and consumers of foodstuffs that are treated with pesticides as well as persons who consume water and inhale air filled with pesticides. There are numerous animal model studies that employ electrocardiography, echocardiography, enzyme studies and histopathology to demonstrate pesticide-induced cardiotoxicity in many parts of the world. There are also case reports and epidemiological data of pesticide induced cardiovascular intoxication in man. With the increasing reports of pesticide-induced central system nervous toxicity in Africa, there are enough reasons to suspect cardiovascular system poisoning as well. The poorly developed clinical toxicology specialty may explain the low index of suspicion of pesticide induced cardiovascular diseases. With the pervading ignorance, indiscriminate sale, unguarded use, lack of adequate legislation, inadequate enforcement of legal institutes associated with pesticide use in Africa, there is no doubt that the increasing prevalence and incidence of cardiovascular diseases may partly be due to exposure to these chemicals. Africans may after all be at risk of pesticide-induced cardiotoxicity, but more studies will be required to examine the pattern of cardiotoxicity as well as factors that modulate its occurence. PMID- 30406468 TI - Picea wilsonii transcription factor NAC2 enhanced plant tolerance to abiotic stress and participated in RFCP1-regulated flowering time. AB - KEY MESSAGE: Picea wilsonii transcription factor PwNAC2 enhanced plant tolerance to salt and drought stress through multiple signaling pathway and interacted with PwRFCP1 to participate in flowering regulation. NAC is one of the largest transcription factor families in plants, however, its role is not yet fully understood. Here, we identified a transcription factor PwNAC2 in Picea wilsonii, which localized in nucleus with transcriptional activity in C-terminal region and can form homodimer by itself. Expression analysis by real-time PCR showed that PwNAC2 was induced by multiple abiotic stresses and phytohormones stimuli. PwRFCP1 (Resemble-FCA-contain-PAT1 domain), an interaction protein of PwNAC2 was screened via yeast two hybrid. Luciferase complementation assay confirmed the interaction in vivo and bimolecular fluorescence complementation assay showed the interaction in nucleus. PwNAC2 overexpression retarded Arabidopsis hypocotyls growth which is closely related to light, whereas promotion of hypocotyls growth by PwRFCP1 is independent on light. Under drought or salt treatment, overexpression of PwNAC2 in Arabidopsis showed more vigorous seed germination and significant tolerance for seedlings by ROS scavenging, reducing of membrane damage, slower water loss and increased stomatal closure. ABA or CBF-pathway marker genes were substantially higher in PwNAC2 transgenic Arabidopsis. Overexpression of PwRFCP1 promotes flowering in transgenic Arabidopsis, whereas PwNAC2 delayed flowering by altering the expression of FT, SOC1 and FLC. In addtioin, PwRFCP1 overexpression plants showed no higher tolerance to stress treatment than Col-0. Collectively, our results indicate that PwNAC2 enhanced plant tolerance to abiotic stress through multiple signaling pathways and participated in PwRFCP1-regulated flowering time. PMID- 30406470 TI - Statement of the BVA, the DOG, and the RG on treatment of choroidal neovascularization in diseases other than neovascular age-related macular degeneration : Dated Ocotber 2017. PMID- 30406471 TI - [Contact lens complications : Diagnosis and treatment]. AB - Contact lens complications are all pathological alterations of the eyes caused by wearing contact lenses. Clinical manifestations particularly affect the cornea and conjunctiva. A differentiation is made between undesired manifestations and disease conditions that at least temporarily make the further wearing of contact lenses impossible. The decisive factor is that for every irritation of the anterior segment of the eye the possibility of contact lens complications is considered and investigated. This article describes the most important contact lens types, the physiology and pathology of corneal metabolism, clinical manifestations and the corresponding treatment. PMID- 30406469 TI - Trithorax-group protein ATX5 mediates the glucose response via impacting the HY1 ABI4 signaling module. AB - KEY MESSAGE: Trithorax-group Protein ARABIDOPSIS TRITHORAX5 modulates the glucose response. Glucose is an evolutionarily conserved modulator from unicellular microorganisms to multicellular animals and plants. Extensive studies have shown that the Trithorax-group proteins (TrxGs) play essential roles in different biological processes by affecting histone modifications and chromatin structures. However, whether TrxGs function in the glucose response and how they achieve the control of target genes in response to glucose signaling in plants remain unknown. Here, we show that the Trithorax-group Protein ARABIDOPSIS TRITHORAX5 (ATX5) affects the glucose response and signaling. atx5 loss-of-function mutants display glucose-oversensitive phenotypes compared to the wild-type (WT). Genome wide RNA-sequencing analyses have revealed that ATX5 impacts the expression of a subset of glucose signaling responsive genes. Intriguingly, we have established that ATX5 directly controls the expression of HY1 by trimethylating H3 lysine 4 of the Arabidopsis Heme Oxygenase1 (HY1) locus. Glucose signaling causes the suppression of ATX5 activity and subsequently reduces the H3K4me3 levels at the HY1 locus, thereby leading to the increased expression of ABSCISIC ACID INSENSITIVE4 (ABI4). This result suggests that an important ATX5-HY1-ABI4 regulatory module governs the glucose response. This idea is further supported by genetic evidence showing that an atx5 hy1-100 abi4 triple mutant showed a similar glucose-insensitive phenotype as compared to that of the abi4 single mutant. Our findings show that a novel ATX5-HY1-ABI4 module controls the glucose response in Arabidopsis thaliana. PMID- 30406472 TI - [Transepithelial photorefractive keratectomy : Results and clinical experiences]. AB - OBJECTIVE: To analyze and assess the refractive outcome after transepithelial photorefractive keratectomy (TransPRK). MATERIAL AND METHODS: The treatment was performed with the AMARIS 1050RS laser (SCHWIND eye-tech-solutions GmbH, Kleinostheim, Germany). The method used an aspheric, aberration-neutral ablation profile and a standardized epithelial tissue removal of 55 um in the center and 65 um at a radius of 4 mm as well as SmartPulse technology. Only spherical and/or cylindrical refraction values were treated. Only untreated eyes with preoperative best corrected visual acuity equal to or better than 0.8 were included in the cohort. Follow-up examinations were performed after 1 and 4 days, after 1 and 3 months and after 1 year RESULTS: A total of 939 consecutive TransPRK laser treatments performed in the period from December 2014 to December 2016 were retrospectively analyzed. The mean age of the patients was 34 years. The preoperative sphere had a range of -7.75 D up to +3.00 D and cylinders up to 5.00 D. The 3-month follow-up control was performed in 728 eyes (77.5%). The predictability showed 89% of eyes within the target correction of less than 0.50 D and 99% of eyes less than 1.00 D. The astigmatic correction showed 91% of eyes with less than 0.50 D. In the safety 1% of eyes showed a visual loss of 2 Snellen lines because of haze. In 26 eyes (2.7%) follow-up treatment was performed with renewed TransPRK laser treatment, in the myopic cohort in 1.8% and in the hyperopic cohort in 13.0%. A residual refraction occurred in 20 eyes without haze and 6 eyes showed a residual refraction with signs of haze. CONCLUSION: The TransPRK led to similar results to intrastromal refractive surgery techniques but with fewer clinical complications. PMID- 30406474 TI - Interactions Between Antiepileptic and Antibiotic Drugs: A Systematic Review and Meta-Analysis with Dosing Implications. AB - INTRODUCTION: Qualitative studies on drug-drug interactions (DDIs) between anticonvulsants and antibiotics report pharmacokinetic changes that may increase the clinical risks in terms of adverse drug reactions (ADRs) and efficacy. However, no studies have provided a systematic and quantitative analysis of anticonvulsant-antibiotic pharmacokinetic DDIs. To provide such indications, we systematically and critically reviewed the literature on anticonvulsant antibiotic DDIs in terms of quantitative pharmacokinetic changes and related ADRs. We also investigated less-known interactions for the possible occurrence of clinically relevant events. METHODS: We conducted a systematic review of all reports of DDIs between anticonvulsants and antibiotics assessing pharmacokinetic parameters published until 9 June 2017. RESULTS: We were able to meta-analyse the effect of macrolides on carbamazepine area under the concentration-time curve from time zero to infinity [AUCinfinity] (+ 34.5 ug/mL*h, p = 0.005, n = 38), clearance (- 2.88 mL/min, p < 0.001, n = 46) and trough plasma concentration [Ct] (+ 8.0 ug/mL, p = 0.002, n = 23), and of carbapenems on valproic acid Ct (- 42.9 ug/mL, p < 0.001, n = 262). Pharmacokinetic parameters with other DDIs were insufficiently reported to allow a statistical analysis. CONCLUSIONS: Therapeutic drug monitoring in patients receiving long-term antiepileptic therapies may help, in specific conditions, to improve safety while preserving efficacy. Such a procedure would also increase scientific information on how pharmacokinetic variations are associated with ADR occurrence, and possibly epileptological outcomes for those DDIs for which available information is suggestive of a relevant effect but is not yet sufficient to draw conclusions. PMID- 30406473 TI - A case of radiation-associated angiosarcoma after breast cancer. AB - BACKGROUND: Radiation-associated angiosarcoma (RAAS) is a rare subtype of secondary angiosarcoma that is characterized by rapid proliferation and extensive tissue infiltration. Although various treatments for RAAS (such as surgery, chemotherapy, and radiation therapy) have been reported, there is no consensus as to which approach is the best. CASE PRESENTATION: A 76-year-old woman presented with right breast cancer (T1N0M0, stage I) 9 years ago. She had undergone breast conserving surgery and sentinel lymph node biopsy and was receiving adjuvant chemotherapy and radiation therapy for the malignancy. Six years after presenting with the tumor, she developed pigmented skin and was diagnosed with a RAAS; this angiosarcoma recurred three times within 2 years. The angiosarcoma was resected each of the three times, after which adjuvant radiation therapy was performed. At 76 years old, the patient developed a new mass on her chest skin in the vicinity of the scar. Angiosarcoma was diagnosed following a pathology report, which resulted in a second diagnosis of recurrent RAAS again since the diagnostic criteria were met. After extensive resection of the irradiated area, the patient has remained free of angiosarcoma for the last 3 years. CONCLUSION: Resection of the entire irradiated field is critical for successful treatment of RAAS. PMID- 30406475 TI - A Systematic Review on the Effect of HIV Infection on the Pharmacokinetics of First-Line Tuberculosis Drugs. AB - INTRODUCTION: Contrasting findings have been published regarding the effect of human immunodeficiency virus (HIV) on tuberculosis (TB) drug pharmacokinetics (PK). OBJECTIVES: The aim of this systematic review was to investigate the effect of HIV infection on the PK of the first-line TB drugs (FLDs) rifampicin, isoniazid, pyrazinamide and ethambutol by assessing all published literature. METHODS: Searches were performed in MEDLINE (through PubMed) and EMBASE to find original studies evaluating the effect of HIV infection on the PK of FLDs. The included studies were assessed for bias and clinical relevance. PK data were extracted to provide insight into the difference of FLD PK between HIV-positive and HIV-negative TB patients. This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and its protocol was registered at PROSPERO (registration number CRD42017067250). RESULTS: Overall, 27 studies were eligible for inclusion. The available studies provide a heterogeneous dataset from which consistent results could not be obtained. In both HIV-positive and HIV-negative TB groups, rifampicin (13 of 15) and ethambutol (4 of 8) peak concentration (Cmax) often did not achieve the minimum reference values. More than half of the studies (11 of 20) that included both HIV-positive and HIV-negative TB groups showed statistically significantly altered FLD area under the concentration-time curve and/or Cmax for at least one FLD. CONCLUSIONS: HIV infection may be one of several factors that reduce FLD exposure. We could not make general recommendations with respect to the role of dosing. There is a need for consistent and homogeneous studies to be conducted. PMID- 30406476 TI - Bladder and ureteral injuries during benign hysterectomy: an observational cohort analysis in New York State. AB - PURPOSE: Hysterectomy (Hys) is the most common non-urologic surgery associated with iatrogenic genitourinary (GU) injury. We present the largest known population-based evaluation of GU injury related to benign Hys. METHODS: The New York Statewide Planning and Research Cooperative System (SPARCS) was queried by ICD-9 and CPT codes. SPARCS for women from 1995 to 2014, who underwent laparoscopic or robotic Hys (minimally invasive surgery = MIS), abdominal Hys (AH), and vaginal Hys (VH) for benign diagnoses. Bladder and ureteral repairs were captured based on the procedure codes. Codes for ureteroneocystotomy (UNC) were compared to any other ureteral repairs, to elucidate injury patterns. Statistical analysis was conducted using Chi squared test, ANOVA, Mann-Whitney test and Poisson Regression and multivariable analysis were performed. RESULTS: 516,340 women underwent Hys for a benign etiology. 69% were AH, 25% VH, and 6% were MIS. 7490 patients (1.45%) had a concomitant GU injury. Compared to VH, MIS and AH were associated with greater odds of bladder and ureteral injury (p < 0.001). MIS and AH, compared to VH, were associated with reduced odds of UNC compared to complex reconstruction (OR 0.27, p < 0.001 and OR 0.12, p < 0.00, respectively). The injured cohort had higher total mean charges ($29,889 vs $15,808) and length of hospitalization (6.32 vs 3.56 days) (p < 0.001). CONCLUSIONS: Bladder and ureteral injuries during hysterectomy are uncommon in contemporary practice and are lower than historical rates. GU injury increases hospitalization cost. VH is associated with the lowest rate of GU injury, and thus appears to be a valuable approach, when feasible. PMID- 30406477 TI - Development and external validation of a pathological nodal staging score for patients with clear cell renal cell carcinoma. AB - OBJECTIVES: To develop and externally validate a model that quantifies the likelihood that a pathologically node-negative patient with clear cell renal cell carcinoma (cRCC) has, indeed, no lymph node metastasis (LNM). PATIENTS AND METHODS: Data from 1389 patients treated with radical nephrectomy (RN) and lymph node dissection (LND) were analyzed. For external validation, we used data from 2270 patients in the Surveillance, Epidemiology and End Results (SEER) database. We estimated the sensitivity of pathologic nodal staging using a beta-binomial model and developed a pathological nodal staging score (pNSS), which represents the probability that a patient is correctly staged as node negative as a function of the number of examined lymph nodes (LNs). RESULTS: The mean and median number of LNs removed were 7.0 and 5.0 (standard deviation, SD 6.6; interquartile range, IQR 7.0) in the development cohort and 5.6 and 2.0 (SD 8.6, IQR 5.0) in the validation cohort, respectively. The probability of missing a positive LN decreased with increasing number of LNs examined. In both the validation and the development cohort, the number of LNs needed for correctly staging a patient as node negative increased with higher pathological tumor stage and Fuhrman grade. CONCLUSIONS: The number of examined LNs needed for adequate nodal staging in cRCC depends on pathological tumor stage and Fuhrman grade. We developed here and then externally validated a pNSS, which could help to refine patient counseling, decision-making regarding risk-stratified surveillance regimens and inclusion criteria for clinical trials of adjuvant therapy. PMID- 30406478 TI - An Expandable Mechanopharmaceutical Device (2): Drug Induced Granulomas Maximize the Cargo Sequestering Capacity of Macrophages in the Liver. AB - PURPOSE: Drug-induced liver injuries (DILI) comprise a significant proportion of adverse drug reactions leading to hospitalizations and death. One frequent DILI is granulomatous inflammation from exposure to harmful metabolites that activate inflammatory pathways of immune cells of the liver, which may act as a barrier to isolate the irritating stimulus and limit tissue damage. METHODS: Paralleling the accumulation of CFZ precipitates in the liver, granulomatous inflammation was studied to gain insight into its effect on liver structure and function. A structural analog that does not precipitate within macrophages was also studied using micro-analytical approaches. Depleting macrophages was used to inhibit granuloma formation and assess its effect on drug bioaccumulation and toxicity. RESULTS: Granuloma-associated macrophages showed a distinct phenotype, differentiating them from non-granuloma macrophages. Granulomas were induced by insoluble CFZ cargo, but not by the more soluble analog, pointing to precipitation being a factor driving granulomatous inflammation. Granuloma associated macrophages showed increased activation of lysosomal master-regulator transcription factor EB (TFEB). Inhibiting granuloma formation increased hepatic necrosis and systemic toxicity in CFZ-treated animals. CONCLUSIONS: Granuloma associated macrophages are a specialized cell population equipped to actively sequester and stabilize cytotoxic chemotherapeutic agents. Thus, drug-induced granulomas may function as drug sequestering "organoids" -an induced, specialized sub-compartment- to limit tissue damage. PMID- 30406479 TI - The Role of Botulinum Toxin Injections for Esophageal Motility Disorders. AB - PURPOSE OF REVIEW: The advancement of high-resolution esophageal manometry has led to improvement in the diagnosis of esophageal motility disorders. We reviewed the recent medical literature regarding the use of botulinum toxin (BTx) injections in the esophagus and the indications, current outcomes, and reported complications of this therapy. RECENT FINDINGS: The response rates of BTx injection therapy vary depending on the esophageal motility disorder. Studies have shown that response is transient in achalasia patients and given the more effective therapies available, it is only recommended in patients who are not surgical candidates. In nonachalasia patients, studies of BTx injections have demonstrated improvement in dysphagia symptoms in patients with spastic disorders, though studies are small and largely retrospective. The available literature showed a variable response to BTx in esophagogastric junction outlet obstruction (EGJOO) and non-cardiac chest pain patients. Despite advances in diagnosing esophageal motility disorders, there is a need for further research in patient selection for esophageal BTx, dose and injection location, and disease specific outcomes. Placebo-controlled trials are crucial to evaluate BTx efficacy and duration of response. Esophageal-directed BTx injections are beneficial in improving dysphagia in spastic motility disorders and in achalasia patients who are elderly or have multiple co-morbidities. There is a lack of evidence to support use in patients with EGJOO and non-cardiac chest pain, or for young or healthy achalasia patients. PMID- 30406480 TI - Prospective Assessment of Liver Function by an Enzymatic Liver Function Test to Estimate Short-Term Survival in Patients with Liver Cirrhosis. AB - BACKGROUND: MELD attempts to objectively predict the risk of mortality of patients with liver cirrhosis and is commonly used to prioritize organ allocation. Despite the usefulness of the MELD, updated metrics could further improve the accuracy of estimates of survival. AIMS: To assess and compare the prognostic ability of an enzymatic 13C-based liver function test (LiMAx) and distinct markers of liver function to predict 3-month mortality of patients with chronic liver failure. METHODS: We prospectively investigated liver function of 268 chronic liver failure patients without hepatocellular carcinoma. Primary study endpoint was liver-related death within 3 months of follow-up. Prognostic values were calculated using Cox proportional hazards and logistic regression analysis. RESULTS: The Cox proportional hazard model indicated that LiMAx (p < 0.001) and serum creatinine values (p < 0.001) were the significant parameters independently associated with the risk of liver failure-related death. Logistic regression analysis revealed LiMAx and serum creatinine to be independent predictors of mortality. Areas under the receiver-operating characteristic curves for MELD (0.86 [0.80-0.92]) and for a combined score of LiMAx and serum creatinine (0.83 [0.76-0.90]) were comparable. CONCLUSIONS: Apart from serum creatinine levels, enzymatic liver function measured by LiMAx was found to be an independent predictor of short-term mortality risk in patients with liver cirrhosis. A risk score combining both determinants allows reliable prediction of short-term prognosis considering actual organ function. Trial Registration Number (German Clinical Trials Register) # DRKS00000614. PMID- 30406481 TI - Risk factors for recurrent percutaneous nephrostomy catheter-related infections. AB - PURPOSE: Percutaneous nephrostomy (PCN) catheters are mainly indicated for urinary tract obstructions. Unfortunately, the rate for infection and recurrence remains elevated. Our objective was to identify the risk factors leading to recurrent PCN-related infections (PCNI) in cancer patients. METHODS: We retrospectively reviewed 571 patients who underwent initial PCN catheter placement at our institution. Of these, we identified patients with a definite PCNI and catheter exchange, with a minimum 30-day follow-up. We defined PCNI as presence of a urine culture positive for bacteria (>= 104 CFU/mL) plus symptoms of urinary tract infection. A PCNI was considered recurrent if the same organism was isolated. Antibiotics were considered concordant if they were active against all identified organisms. RESULTS: A total of 81 patients (14%) developed an initial PCNI. Of 47 patients with 30-day follow-up, 10 patients (21%) were identified as having a recurrent PCNI. In terms of demographic characteristics, clinical manifestations, and microbiological data, there was no statistically significant difference between the recurrent and non-recurrent groups. However, in multivariate logistic regression analysis, two factors were independently associated with a decrease in recurrent PCNI: concordant antibiotic use (OR 0.04; p = 0.008) and PCN catheter exchange within 4 days of infection (OR 0.1; p = 0.048). CONCLUSIONS: To decrease the high rate of recurrent infections, associated costs, and potential delay in further chemotherapy, we recommend that once antimicrobial susceptibility test results are available and the patient is known to be receiving concordant antimicrobials, clinicians proceed with immediate PCN catheter exchange, ideally within the first 4 days of the infection. PMID- 30406482 TI - The effects of intraoperative ICG fluorescence angiography in laparoscopic low anterior resection: a propensity score-matched study. AB - BACKGROUND: It remains unclear whether indocyanine green (ICG) angiography could reduce the rate of postoperative anastomotic leakage (AL) following rectal surgery. The aim was to determine whether intraoperative ICG angiography could decrease symptomatic AL following laparoscopic low anterior resection (LAR). METHODS: This is a retrospective study of 149 patients with rectal cancer who underwent laparoscopic LAR at a single institution. Propensity score matching (PSM) was employed to compare groups with and without ICG angiography. RESULTS: Before PSM, the symptomatic AL rate was 10.4% (5/48) in patients with ICG angiography, compared with 6.9% (7/101) in cases without ICG angiography (P = 0.52). In patients with ICG angiography, poor perfusion of the proximal colon judged by ICG angiography led to additional colon resection in 27.1% (13/48). Symptomatic AL occurred in 30.8% (4/13) of the patients who had revision of the transection site, whereas it occurred in only 2.9% (1/35) of the patients who did not need revision of the transection site (P = 0.015). After PSM, the symptomatic AL rate was 8.8% (3/34) in patients with ICG angiography, compared with 14.7% (5/34) in cases without ICG angiography (P = 0.71). In univariate analysis, high BMI, preoperative chemotherapy, and lateral lymph node dissection were significantly associated with symptomatic AL. Multivariate analysis indicated that only lateral lymph node dissection remained significantly associated with AL (odds ratio, 10.05; 95% confidence interval, 1.75-58.61; P = 0.011). CONCLUSIONS: Intraoperative ICG angiography is useful for prediction of AL following laparoscopic LAR. PMID- 30406483 TI - Barriers to Surgical Resection of Pancreatic Adenocarcinoma. PMID- 30406484 TI - Breast Reconstruction in an Underserved Population: A Retrospective Study. AB - BACKGROUND: Breast reconstruction can help restore the shape and appearance of breasts after surgery. Studies have shown that minority and uninsured patients are less likely to receive breast reconstruction after mastectomy. OBJECTIVE: We sought to determine if post-mastectomy reconstruction varied by patient ethnicity and insurance status in a medically underserved population. METHODS: This was a retrospective study of mastectomy patients seen at Bellevue Hospital Center, a safety-net hospital in New York City, between January 2010 and December 2015. The Chi square test was used to compare patient characteristics versus type of reconstruction chosen and likelihood of reconstruction. Logistic regression was used to examine likelihood of reconstruction, controlling for patient insurance status, race, age, stage at presentation, and contralateral prophylactic mastectomy. RESULTS: Of the 750 patients included in the database, 220 underwent mastectomy. Overall, 73.6% of our patient population received breast reconstruction. Patients with Medicare insurance were less likely to get reconstruction compared with patients with other types of insurance (37.5%, p = 0.04). Hispanic patients were most likely to receive reconstruction (89.1%), followed by Black patients (80%) and Asian patients (66.7%) [p = 0.03]. There were no significant associations between patient race or stage at presentation and type of reconstruction. In a multivariate logistic regression, advancing age was associated with a decreased likelihood of reconstruction (adjusted odds ratio 0.91, p < 0.001). CONCLUSIONS: In our underserved patient population, patients received breast reconstruction at rates higher than the national average. Institutional availability of patient navigators and preoperative counseling may contribute to more equal access to breast reconstruction. PMID- 30406485 TI - ASO Author Reflections: Acellular Dermal Matrix Reduces Myofibroblasts in Capsule Tissue. PMID- 30406486 TI - ASO Author Reflections: Metastatic Melanoma to the Large Bowel. PMID- 30406487 TI - ASO Author Reflections: The Role of Post-mastectomy Radiation Therapy in the Setting of Nodal Micrometastases. PMID- 30406488 TI - Biochemical and Skeletal Outcomes of Parathyroidectomy for Normocalcemic (Incipient) Primary Hyperparathyroidism. AB - BACKGROUND: Normocalcemic (incipient) primary hyperparathyroidism (PHPT) is characterized by inappropriately elevated parathyroid hormone (PTH) levels in the setting of normal serum calcium. The biochemical and skeletal outcomes after parathyroidectomy for normocalcemic PHPT are not well-described. METHODS: All patients who underwent parathyroidectomy for normocalcemic PHPT at a single institution were retrospectively reviewed (2006-2016). Pre- and postoperative calcium, PTH, and bone mineral density (BMD) were compared between patients with normalized versus persistently elevated PTH levels > 6 months after parathyroidectomy. Multivariable Cox regression was used to identify risk factors associated with persistently elevated PTH levels after parathyroidectomy. RESULT: Parathyroidectomy was performed in 71 patients with normocalcemic PHPT, of whom 38 (53.5%) had multi-gland disease. No patients became hypercalcemic, with a median follow-up of 23.1 months. Persistently elevated PTH levels were noted in 33 (46.5%) patients. In multivariable analysis, preoperative PTH > 100 pg/mL was associated with persistently elevated PTH levels after parathyroidectomy. In 38 patients with available pre- and postoperative BMD measurements, the mean preoperative BMD improved + 5.6% (p < 0.01) in patients with normalized PTH, while no significant change was observed in patients with persistently elevated PTH levels (- 2.2%, p = 0.47). CONCLUSIONS: Elevated PTH levels are common after parathyroidectomy for normocalcemic PHPT. Improvements in BMD may be predicated on long-term normalized PTH levels following surgery. PMID- 30406489 TI - Effect of Epigallo-Catechin-3-Gallate on Lipid Metabolism Related Gene Expression and Yolk Fatty Acid Profiles of Laying Hens Exposed to Vanadium. AB - As the understanding of the pathways involved in such effect are quite limited, we investigated the gene pathways that modulate lipid metabolism in layers and the fatty acid profiles of the yolk of layers that were challenged with dietary vanadium (V) and supplemented with epigallo-catechin-3-gallate (EGCG). For this purpose, a total of 120 hens were divided into four groups which were fed the following experimental diets for a period of 8 weeks: control (basal diet), V10 (control + 10 mg/kg V), EGCG130 (V10 + 130 mg/kg EGCG), and EGCG217 (V10 + 217 mg/kg EGCG). Blood total cholesterol, triglyceride, glucose, and very low-density lipoprotein-cholesterol concentration were lower in V10, EGCG130, and EGCG217 groups compared to the control group, while total cholesterol and triglyceride content in blood were lower in the EGCG217 group than in V10 group (P < 0.05). Hens consumed V10 diet had the highest triglyceride content in liver among treatments, whereas EGCG130 and EGCG217 groups had lower values when compared to those observed in the control group (P < 0.01). Dietary inclusion of V increased yolk polyunsaturated fatty acid (PUFA) and total unsaturated fatty acid (UFA) content compared to the control group (P < 0.05), whereas the addition of either 130 or 217 mg/kg EGCG in V containing diet resulted in similar yolk PUFA and UFA contents with those observed in the control group. Treatment with V alone upregulated the expression of hepatic fatty acid synthase (FAS) and sterol regulator element-binding protein 1 (SREBP1), while EGCG downregulated FAS and SREBP1 expressions in contrast to V10 treatments (P < 0.01). Liver gene expression peroxisome proliferator-activated receptor gamma (PPARgamma) was lower in the V10 than in the control group while EGCG inclusion groups upregulated their expression (P < 0.05). In conclusion, the data gathered in this study indicate that dietary V and EGCG alter the layers' lipid metabolism and fat deposition pattern in egg yolk, which might be associated with their modulatory effect on lipogenesis-related gene (FAS, SREBP1, and PPARgamma) expression. PMID- 30406490 TI - Expression Profiles of Selenium-Related Genes in Human Chondrocytes Exposed to T 2 Toxin and Deoxynivalenol. AB - The combination of excess mycotoxin exposure and selenium deficiency has been widely considered as a cause of Kashin-Beck disease (KBD). The present study aimed to investigate the expression profiles of selenium-related genes in human chondrocytes after exposure to T-2 toxin and deoxynivalenol (DON) and to preliminarily identify the potential biological functions of the identified genes. Gene expression profiling was performed on human chondrocytes treated with 0.01 MUg/ml T-2 toxin and 1.0 MUg/ml DON by using Affymetrix Human Gene Arrays. The 1660 selenium-related genes were derived from the Comparative Toxicogenomics Database. Gene-term enrichment analysis was conducted by the DAVID gene annotation tool. Our results showed that 69 and 191 selenium-related genes were differentially expressed after T-2 toxin and DON treatment, respectively. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that these identified genes were involved in various biological functions, such as the GO terms in response to oxidative stress, cell cycle arrest, and apoptotic process and the KEGG metabolic, FoxO signaling, and p53 signaling pathways. Our results may help explain the mechanisms of interaction between mycotoxins and selenium following human chondrocyte damage and reveal the potential roles of environmental risk factors in cartilage lesions during KBD development. PMID- 30406491 TI - Treatment outcomes and prognostic factors of medication-related osteonecrosis of the jaw: a case- and literature-based review. AB - OBJECTIVES: The purpose of this study was to investigate the treatment outcomes and prognostic factors of medication-related osteonecrosis of the jaw (MRONJ) in Japanese patients. PATIENTS AND METHODS: Among 409 cases, treatment outcomes and prognostic factors were investigated in 275 patients. In statistical analyses, the 1-year cumulative curative rate was calculated with the Kaplan-Meier method, and significance was examined with the Wilcoxon test. Cox's proportional hazards regression analysis was used for the multivariate analysis. RESULTS: Resolution of the disease was achieved in 137 out of 275 MRONJ patients (49.8%). One-year cumulative curative rates were 39.8% in stage 1 patients, 26.3% in stage 2, and 19.0% in stage 3. The 1-year cumulative curative rates of treatment interventions were 17.2% for conservative treatment, 34.5% for sequestrectomy, and 40.7% for extended surgery including bone resection and segmental resection. As the prognostic factors of treatment outcomes, the type of medication, stage of MRONJ, and type of surgical intervention were identified as independent factors in a multivariate analysis. CONCLUSION: These results suggest that surgical interventions may lead to a good prognosis in MRONJ patients. CLINICAL RELEVANCE: This study indicated that surgical intervention for MRONJ might lead to improvement of prognosis and quality of life in MRONJ patients. PMID- 30406492 TI - The Impact of Spiritual Care Education on Anxiety in Family Caregivers of Patients with Heart Failure. AB - Heart failure (HF) has been emerging as a general health problem over recent decades. Spiritual care is a type of support service provided to patients suffering from HF. Spiritual care intervention in nursing is a unique aspect of care, which cannot be replaced by psychosocial care. Considering the importance of anxiety for caregivers of patients with HF, the present study aimed to examine the effect of spiritual intervention on anxiety in caregivers of patients with HF in Ilam, Iran. This research is a semi-experimental study, 71 caregivers of patients with HF were randomly assigned to experimental group (n = 34) and control (n = 37) group. Beck Anxiety Inventory, which consisted of 21 items and scored based on a 4-point Likert scale ranging from zero to three, was employed to collect data. The scores range from zero to 63 with the higher scores indicating the higher level of anxiety. The experimental group received spiritual intervention over six 45-minute sessions in a period of 2 weeks (14 days; three times a week; every other day). Data were analyzed using descriptive and inferential statistics run in the SPSS software version 16. The result showed a difference between the level of anxiety in two groups after the intervention (P = 0.001). Anxiety level in the experimental group three weeks after intervention (27.88 +/- 7.10) was significant in comparison with before intervention (45.06 +/ 5.79) (P = 0.001). According to the results, the spiritual intervention reduced the anxiety level in the caregivers of patients with HF. Nurses are recommended to provide such necessary training to caregivers in order to provide the grounds for reducing their anxiety. PMID- 30406493 TI - Religion, Spirits, Human Agents and Healing: A Conceptual Understanding from a Sociocultural Study of Tehuledere Community, Northeastern Ethiopia. AB - This paper explores the relationship among religion, spirits and healing in the Tehuledere community in the northeastern part of Ethiopia and focuses on how this knowledge can inform primary healthcare reform. The study employed qualitative ethnographic methods. Participatory observation, over a total of 5 months during the span of 1 year, was supplemented by focus group discussions (96 participants in 10 groups) and in-depth interviews (n = 20) conducted with key informants. Data were analyzed thematically using narrative strategies. The present study revealed that members of the study community perceive health, illness and healing as being given by God. Many of the Tehuledere people attribute illness to the wrath of supernatural forces. Healing is thought to be mitigated by divine assistance obtained through supplication and rituals and through the healing interventions of nature spirit actors. We found that the health, illnesses and healing were inextricably linked to religious and spiritual beliefs. Our findings suggest that religious and spiritual elements should be considered when drafting and implementing primary healthcare strategies for the study communities and similar environments and populations around the globe. PMID- 30406494 TI - Probability assessment of vegetation vulnerability to drought based on remote sensing data. AB - Drought is one of the important factors causing vegetation degradation. Determination of areas with vegetation more sensitive to drought can be effective in drought risk management. Considering the ability to describe vegetation conditions, vegetation health index (VHI) was used to determine the probability of vegetation vulnerability to drought and to provide the map of Iran showing sensitive areas to drought. This study tries to express the probability of vegetation vulnerability to drought in four main climatic classes including hyper arid, arid, semi-arid and semi-humid, and humid in Iran. Temperature condition index (TCI) and vegetation condition index (VCI) were calculated using land surface temperature (LST) derived from the MOD11A2 product and normalized different vegetation index (NDVI) obtained from MOD13A2 product, MODIS sensor. Combining these two indices, VHI was calculated for late of March, April, May, and June during 2000-2017. VHI was classified into five classes representing the drought intensity. Then, the probability of occurrence (%) of each class was calculated and multiplied with weight of each class, varying from 0 to 40 based on drought intensity. Finally, probability of vegetation vulnerability index (PVVI) was calculated by summing of the values obtained for each class. The results showed that PVVI was higher in arid and hyper-arid areas than that in other areas in the four studied periods. The highest mean values of PVVI in humid as well as semi-arid and semi-humid classes were found in April as 59.87 and 62.4, respectively, while the highest mean values of PVVI in arid and hyper-arid classes were observed in May as 70.98 and 68.13, respectively. In total, our results showed that PVVI is affected by different climatic and topographic conditions, and it suggested that this index be used to determine the probability of vegetation vulnerability. PMID- 30406495 TI - Initial verification of data from a clinical database of gastroenterological surgery in Japan. AB - PURPOSES: To evaluate the reliability of data collected from the gastroenterological section of the National Clinical Database of Japan (NCD), which began registrations in 2011 with ten surgical subspecialty societies. METHODS: During 2014 and 2015, 1,136,700 cases involving 115 procedures at 4374 hospitals were registered in the gastroenterological surgery section of the NCD. After a test audit using the 2014 data, 17 hospitals were selected for the first audit and data verification for 2015. The data accuracy of patient demographics, surgical outcomes, and processes was assessed using 45 items from the cases registered, in comparison with the medical records. RESULTS: In the first audit of the 2015 data, case registration accuracy verification involved 338 patients (99.4% of the extracted cases). The data accuracy with the maximum postoperative variables was > 95%. Accuracy of the mortality and status 30 days after the surgery was high (> 99%) with a sensitivity of 1.00 and a specificity of 1.00. Among the six complications studied, the recorded cases had high specificity but lower sensitivity (0.70-0.89). CONCLUSIONS: We verified the data from the gastroenterological section of the NCD and found high accuracy of data entry. PMID- 30406496 TI - Association of serum markers of oxidative stress with myocardial infarction and stroke: pooled results from four large European cohort studies. AB - Oxidative stress contributes to endothelial dysfunction and is involved in the pathogenesis of myocardial infarction (MI) and stroke. However, associations of biomarkers of oxidative stress with MI and stroke have not yet been addressed in large cohort studies. A nested case-control design was applied in four population based cohort studies from Germany, Czech Republic, Poland and Lithuania. Derivatives of reactive oxygen metabolites (d-ROMs) levels, as a proxy for the reactive oxygen species burden, and total thiol levels (TTL), as a proxy for the reductive capacity, were measured in baseline serum samples of 476 incident MI cases and 454 incident stroke cases as well as five controls per case individually matched by study center, age and sex. Statistical analyses were conducted with multi-variable adjusted conditional logistic regression models. d ROMs levels were associated with both MI (odds ratio (OR), 1.21 [95% confidence interval (CI) 1.05-1.40] for 100 Carr units increase) and stroke (OR, 1.17 [95% CI 1.01-1.35] for 100 Carr units increase). TTL were only associated with stroke incidence (OR, 0.79 [95% CI 0.63-0.99] for quartiles 2-4 vs. quartile 1). The observed relationships were stronger with fatal than with non-fatal endpoints; association of TTL with fatal MI was statistically significant (OR, 0.69 [95% CI 0.51-0.93] for 100 MUmol/L-increase). This pooled analysis of four large population-based cohorts suggests an important contribution of an imbalanced redox system to the etiology of mainly fatal MI and stroke events. PMID- 30406497 TI - An initial experience with intraoperative O-Arm for deep brain stimulation surgery: can it replace post-operative MRI? AB - Deep brain stimulation (DBS) is used to treat movement disorders, severe psychiatric disorders, and neuropathic pain, among other diseases. Advanced neuroimaging techniques allow direct or indirect localization of the target site, which is verified in many centers by the intraoperative recording of unitary neuronal activity. Intraoperative image acquisition technology (e.g., O-Arm) is increasingly used for accurate electrode positioning throughout the surgery. The aim of our study is to analyze the initial experience of our team in the utilization of O-Arm for planning DBS and monitoring its precision and accuracy throughout the procedure. The study included 13 patients with movement disorders. All underwent DBS with the intraoperative O-arm image acquisition system (iCT) and Medtronic StealthStation S7 cranial planning system, placing a total of 25 electrodes. For each patient, we calculated the difference between real and theoretic x, y, z coordinates, using the paired Student's t test to evaluate absolute and directional differences and the one-sample Student's t test to analyze differences in Euclidean distances. No statistically significant differences were found in absolute, directional, or Euclidean distances between intended and actual x, y, and z coordinates, based on iCT scan. Our experience confirms that utilization of the O-Arm system in DBS provides accurate and precise verification of electrode placements throughout the procedure. Recent studies found no significant differences between iCT and postoperative MRI, the current gold standard. Further prospective studies are warranted to test the elimination of postoperative MRI when this system is used. PMID- 30406498 TI - Antithrombotic therapy and intracranial bleeding in subjects with sporadic brain arteriovenous malformations: preliminary results from a retrospective study. PMID- 30406499 TI - T cells in IgA nephropathy: role in pathogenesis, clinical significance and potential therapeutic target. AB - BACKGROUND: Immunoglobulin A nephropathy (IgAN), the most frequent cause of primary glomerulonephritis worldwide, is an autoimmune disease with complex pathogenesis. In this review, we focus on T cells and summarize knowledge about their involvement in pathophysiology and treatment of IgAN METHODS: We reviewed the literature for (1) alterations of T cell subpopulations in IgAN, (2) experimental and clinical proofs for T cells' participation in IgAN pathogenesis, (3) clinical correlations with T cell-associated alterations, and (4) influence of drugs used in IgAN therapy on T cell subpopulations. RESULTS: We found that IgAN is characterized by higher proportions of circulatory Th2, Tfh, Th17, Th22 and gammadelta T cells, but lower Th1 and Treg cells. We discuss genetic and epigenetic makeup that may contribute to this immunological phenotype. We found that Th2, Th17 and Tfh-type interleukins contribute to elevated synthesis of galactose-deficient IgA1 (Gd-IgA1) and that the production of anti-Gd-IgA1 autoantibodies may be stimulated by Tfh cells. We described the roles of Th2, Th17, Th22 and Treg cells in the renal injury and summarized correlations between T cell-associated alterations and clinical features of IgAN (proteinuria, reduced GFR, hematuria). We detailed the impact of immunosuppressive drugs on T cell subpopulations and found that the majority of drugs have nonoptimal influence on T cells in IgAN patients. CONCLUSIONS: T cells play an important role in IgAN pathogenesis and are correlated with its clinical severity. Clinical trials with the drugs targeting the reported alterations of the T-cell compartment are highly desirable. PMID- 30406500 TI - JAK2/STAT3/BMP-2 axis and NF-kappaB pathway are involved in erythropoietin induced calcification in rat vascular smooth muscle cells. AB - BACKGROUND: Vascular calcification is common in chronic kidney disease (CKD) patients, while erythropoietin (EPO) is widely used in the treatment of renal anemia in CKD patients, whether there is a link between the two is still not clear. METHODS: The primary rat vascular smooth muscle cells (VSMCs) and CKD rats were treated with EPO and the calcium deposition was observed by alizarin red staining, von Kossa staining and calcium quantification. Activation of JAK2/STAT3/BMP-2 axis and NF-kappaB signaling pathways was investigated by Western blotting. RESULTS: EPO-induced calcium deposition in VSMCs and significantly potentiated calcification in CKD rats. Furthermore, EPO activated JAK2/STAT3/BMP-2 axis, NF-kappaB pathway and the pro-calcification effect of EPO was partially blocked by the STAT3 inhibitor (Cryptotanshinone) or NF-kappaB inhibitor (BAY 11-7082), respectively, in vitro. CONCLUSION: EPO could promote VSMCs calcification in vitro and in vivo and this effect may be achieved through the JAK2/STAT3/BMP-2 axis and NF-kappaB pathway. PMID- 30406501 TI - Foreign-body reaction to lanthanum on gastric mucosa. PMID- 30406502 TI - Immunotherapy for Urothelial Carcinoma: Current Evidence and Future Directions. AB - PURPOSE OF REVIEW: Until recently, effective treatment options for patients with advanced urothelial carcinoma were limited to platinum-based chemotherapy. In the post-platinum setting and for patients ineligible for cisplatin, minimally effective second-line chemotherapy was used and outcomes were poor. The approval of immune checkpoint inhibitors has significantly changed the treatment landscape of urothelial carcinoma. Here, we review current data demonstrating their efficacy in advanced disease and ongoing trials investigating novel combination strategies. RECENT FINDINGS: Since May 2016, five agents targeting the programmed cell death 1 (PD-1) pathways have been approved for use after progression on platinum-based chemotherapy. Further, atezolizumab and pembrolizumab are approved for use in cisplatin-ineligible patients with high programmed death-ligand 1 (PD L1) expression. Preliminary studies have shown their safety and efficacy as neoadjuvant therapy in muscle-invasive bladder cancer. Several ongoing trials are investigating these agents in combination with radiation therapy, platinum-based chemotherapy, other immune checkpoint inhibitors, and targeted agents. Immune checkpoint inhibitors have demonstrated durable efficacy in patients with advanced urothelial carcinoma as first- and second-line therapy. Ongoing studies will help define the optimal sequence, combination strategies, and predictive biomarkers of response. PMID- 30406504 TI - Survival of a Male Infant with a Familial Xp11.4 Deletion Causing Ornithine Transcarbamylase Deficiency. AB - Ornithine transcarbamylase (OTC) deficiency is well known to cause severe neonatal hyperammonemia in males with absent enzyme activity. In families with large deletions of the X chromosome involving OTC and other contiguous genes, male infants appear to have an even more severe course. Notably, there are no published reports of these males surviving to liver transplant, even in cases where the diagnosis was known or suspected at birth. We describe two male newborns and their mother who all have a 1.5-Mb deletion of Xp11.4 encompassing the genes TSPAN7, OTC, and part of RPGR. The first child succumbed to his illness on his fourth day of life. His younger brother was diagnosed prenatally, and with early aggressive treatment, he survived the neonatal period. He suffered multiple life-threatening complications but stabilized and received a liver transplant at 7 months of age. This report demonstrates both the possibility of survival and the complications in caring for these patients. PMID- 30406503 TI - A Novel Vision-Enhancing Technology for Low-Vision Impairments. AB - Ocular disorders such as vitreoretinal pathologies are widespread, especially in older adults. In particular, degenerative diseases of the retina such as macular senile degenerations are on the rise and affect millions of people with hundreds of thousands of new cases each year. These diseases can cause profoundly disabling visual impairments, in some cases severely compromising the central and/or the peripheral vision in one or both eyes. In this paper, we present a novel vision aids technology that allows for correcting or attenuating the perception of visual field defects due to ocular pathologies of diverse origins or traumas by using techniques of 3D visualisation, eye tracking, and image processing. The presented technology is mainly conceived for providing vision aids that can significantly improve the quality of life of people with this kind of visual disorders. As well, it could be employed for supporting the diagnosis of ocular dysfunctions and for monitoring the progression of diseases. The technology shown in this work is protected by an International Application in Patent Cooperation Treaty (PCT). PMID- 30406505 TI - Enzyme Replacement Therapy in Pregnant Women with Fabry Disease: A Case Series. AB - Fabry disease is a rare inherited lysosomal storage disorder caused by the deficiency of the enzyme alpha-galactosidase A. There is uncertainty regarding the safety of enzyme replacement therapy during pregnancy. We describe the course and outcome of seven pregnancies in six patients with Fabry disease who continued or reinitiated enzyme replacement therapy during pregnancy. No adverse events, in both mothers and children, were observed. PMID- 30406507 TI - Gaining from discretization of continuous data: The correspondence analysis biplot approach. AB - According to Stevens's classification of measurement, continuous data can be either ratio or interval scale data. The relationship between two continuous variables is assumed to be linear and is estimated with the Pearson correlation coefficient, which assumes normality between the variables. If researchers use conventional statistics (t test or analysis of variance) or factor analysis of correlation matrices to study gender or race differences, the data are assumed to be continuous and normally distributed. If continuous data are discretized, they become ordinal; thus, discretization is widely considered to be a downgrading of measurement. However, discretization is advantageous for data analysis, because it provides interactive relationships between the discretized variables and naturally measured categorical variables such as gender and race. Such interactive relationship information between categories is not available with the ratio or interval scale of measurement, but it is useful to researchers in some applications. In the present study, Wechsler intelligence and memory scores were discretized, and the interactive relationships were examined among the discretized Wechsler scores (by gender and race). Unlike in previous studies, we estimated category associations and used correlations to enhance their interpretation, and our results showed distinct gender and racial/ethnic group differences in the correlational patterns. PMID- 30406506 TI - Formal representation of ambulatory assessment protocols in HTML5 for human readability and computer execution. AB - Ambulatory assessment (AA) is a research method that aims to collect longitudinal biopsychosocial data in groups of individuals. AA studies are commonly conducted via mobile devices such as smartphones. Researchers tend to communicate their AA protocols to the community in natural language by describing step-by-step procedures operating on a set of materials. However, natural language requires effort to transcribe onto and from the software systems used for data collection, and may be ambiguous, thereby making it harder to reproduce a study. Though AA protocols may also be written as code in a programming language, most programming languages are not easily read by most researchers. Thus, the quality of scientific discourse on AA stands to gain from protocol descriptions that are easy to read, yet remain formal and readily executable by computers. This paper makes the case for using the HyperText Markup Language (HTML) to achieve this. While HTML can suitably describe AA materials, it cannot describe AA procedures. To resolve this, and taking away lessons from previous efforts with protocol implementations in a system called TEMPEST, we offer a set of custom HTML5 elements that help treat HTML documents as executable programs that can both render AA materials, and effect AA procedures on computational platforms. PMID- 30406508 TI - Synthesizing effects for multiple outcomes per study using robust variance estimation versus the three-level model. AB - Primary studies increasingly report information that can be used to provide multiple effect sizes. Of interest in this study, primary studies might compare a treatment and a control group on multiple related outcomes that result in multiple dependent effect sizes to be synthesized. There are a number of ways to handle the resulting within-study "multiple-outcome" dependency. The present study focuses on use of the multilevel meta-analysis model (Van den Noortgate, Lopez-Lopez, Marin-Martinez, & Sanchez-Meca, 2013) and robust variance estimation (Hedges, Tipton, & Johnson, 2010) for handling this dependency, as well as for estimating outcome-specific mean effect sizes. We assessed these two approaches under various conditions that differed from each other in within-study sample size; the number of effect sizes per outcome; the number of outcomes per study; the number of studies per meta-analysis; the ratio of variances at Levels 1, 2, and 3; and the true correlation between pairs of effect sizes at the between study level. Limitations and directions for future research are discussed. PMID- 30406509 TI - Lip creams with propolis special extract GH 2002 0.5% versus aciclovir 5.0% for herpes labialis (vesicular stage) : Randomized, controlled double-blind study. AB - A lip cream with special propolis extract GH 2002 at a concentration of 0.5% (199 patients) was tested against aciclovir 5% (198 patients) in the treatment of episodes of herpes labialis under double-blind conditions. Upon inclusion, all patients were in the vesicular phase. Application was five times daily of approximately 0.2 g of cream to the entire upper and lower lip. The primary parameter was the difference in time between groups to complete encrustation or epithelization of the lesions. Secondary endpoints were the course of typical herpes symptoms (pain, burning and itching, tension and swelling), the global assessment of efficacy and the safety of application. The predefined clinical situation was reached after a (median) 3 days with propolis and 4 days with aciclovir (p < 0.0001). Significant differences in favor of propolis were also found for all secondary parameters. No allergic reactions, local irritations or other adverse events occurred. PMID- 30406510 TI - Are predictors of reading impairment in isolated cleft similar to those in idiopathic dyslexia? AB - Children with isolated cleft of the lip and/or palate (iCL/P) are at increased risk for reading impairment. The purpose of this study was to evaluate the impact of early risk factors (hearing, speech, and early literacy) on reading performance compared to unaffected participants with average (uAR) and impaired (uIR) reading. Reading achievement and early literacy skills were evaluated across three groups (27 iCL/P, 32 uAR, and 33 uIR). All participants were males, ages 8-11 years old. Those with history of head trauma/injury or major medical/mental health conditions were excluded. Group differences in achievement and early literacy skills were evaluated with ANCOVAs. Participants with impaired reading achievement (at or below 25th Percentile) were identified. Medical record reviews for participates with iCL/P were conducted and audiology and speech ratings recorded. Correlations were calculated between achievement, early literacy, hearing, and speech. Participants with iCL/P had significantly elevated risk for reading impairment (37%); this risk differed by cleft type (0% iCL, 55% iCLP, and 60% iCP). Achievement for participants with iCP was similar to the uIR group. Early literacy risk resulted in lower achievement scores for both iCL/P and unaffected participants. History of inadequate hearing and speech did not significantly impact early literacy or achievement measures. There is a high risk of reading impairment for children with iCL/P-highest for those with iCLP and iCP. Early literacy predictors of reading outcome are similar for iCL/P and idiopathic dyslexia. Current screening and intervention methods are supported. PMID- 30406511 TI - The 24-month outcomes of intravitreal aflibercept combined with photodynamic therapy for polypoidal choroidal vasculopathy. AB - PURPOSE: This study was prospectively carried out to clarify the effectiveness of visual and anatomical outcomes under combination therapy of intravitreal aflibercept (IVA) and verteporfin photodynamic therapy (vPDT) in over 24 months. STUDY DESIGN: A single-arm prospective exploratory study. METHODS: Twenty-six eyes of 26 treatment naive PCV patients were enrolled in this study. The primary outcome measures were the changes in best corrected visual acuity (BCVA) and the complete polyp regression rate. The secondary outcome measures included central retinal thickness assessed by optical coherence tomography. RESULTS: The patients showed significant improvement in BCVA by 0.14 logMAR units at 12 months and 0.11 logMAR units at 24 months from baseline (both p < 0.01). The mean central retinal thickness also significantly decreased at 12 months (p < 0.001) and at 24 months (p = 0.001). Complete regression of polypoidal lesions was achieved by 15 out of 20 eyes (75%) at 12 months and 11 out of 20 eyes (55%) at 24 months. The mean treatment number was 2.9 courses of IVA and 1.5 courses of vPDT and the mean retreatment free interval after initial therapy was 12.8 months during follow up of 24 months. The complete data from all predetermined examinations were observed in 17 out of 26 enrolled patients (65%) in this study. CONCLUSION: In this study, combination therapy of IVA and vPDT yielded visual and anatomical improvements in treatment-naive PCV patients over a 24-month follow-up period. PMID- 30406512 TI - Impact of Tumor Burden on Quantitative [68Ga] DOTATOC Biodistribution. AB - PURPOSE: As has been previously reported, the somatostatin receptor (SSTR) imaging agent [68Ga]-labeled 1,4,7,10-tetraazacyclododecane-N,N',N",N''' tetraacetic acid-d-Phe(1)-Tyr(3)-octreotate ([68Ga]DOTATATE) demonstrates lower uptake in normal organs in patients with a high neuroendocrine tumor (NET) burden. Given the higher SSTR affinity of [68Ga] DOTATATE, we aimed to quantitatively investigate the biodistribution of [68Ga]-labeled 1,4,7,10 tetraazacyclododecane-N,N',N",N'''-tetraacetic acid-d-Phe(1)-Tyr(3)-octreotide ([68Ga]DOTATOC) to determine a potential correlation between uptake in normal organs and NET burden. PROCEDURES: Of the 44 included patients, 36/44 (82 %) patients demonstrated suspicious radiotracer uptake on [68Ga] DOTATOC positron emission tomography (PET)/X-ray computed tomography (CT). Volumes of interest (VOIs) were defined for tumor lesions and normal organs (spleen, liver, kidneys, adrenals). Mean body weight corrected standardized uptake value (SUVmean) for normal organs was assessed and was used to calculate the corresponding mean specific activity uptake (Upt: fraction of injected activity per kg of tissue). For the entire tumor burden, SUVmean, maximum standardized uptake value (SUVmax), and the total mass (TBM) was calculated and the decay corrected tumor fractional uptake (TBU) was assessed. A Spearman's rank correlation coefficient was used to determine the correlations between normal organ uptake and tumor burden. RESULTS: The median SUVmean was 18.7 for the spleen (kidneys, 9.2; adrenals, 6.8; liver, 5.6). For tumor burden, the median values were SUVmean 6.9, SUVmax 35.5, TBM 42.6 g, and TBU 1.2 %. With increasing volume of distribution, represented by lean body mass and body surface area (BSA), Upt decreased in kidneys, liver, and adrenal glands and SUVmean increased in the spleen. Correlation improved only for both kidneys and adrenals when the influence of the tumor uptake on the activity available for organ uptake was taken into account by the factor 1/(1-TBU). TBU was neither predictive for SUVmean nor for Upt in any of the organs. The distribution of organ Upt vs. BSA/(1-TBU) were not different for patients with minor TBU (<3 %) vs. higher TBU (>7 %), indicating that the correlations observed in the present study are explainable by the body size effect. High tumor mass and uptake mitigated against G1 NET. CONCLUSIONS: There is no significant impact on normal organ biodistribution with increasing tumor burden on [68Ga] DOTATOC PET/CT. Potential implications include increased normal organ dose with [177Lu DOTA]0-D-Phe1-Tyr3-Octreotide and decreased absolute lesion detection with [68Ga] DOTATOC in high NET burden. PMID- 30406513 TI - Spatial Concordance of Tumor Proliferation and Accelerated Repopulation from Pathologic Images to 3'-[18F]Fluoro-3'-Deoxythymidine PET Images: a Basic Study Guided for PET-Based Radiotherapy Dose Painting. AB - PURPOSE: To assess tumor cell proliferation and repopulation during fractionated radiotherapy and investigate the spatial concordance of cell proliferation and repopulation according to the uptake of 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT). PROCEDURES: Mice bearing A549 xenograft tumors were assigned to five irradiated groups, including 3 fraction (f)/6 days (d), 6f/12d, 9f/18d, 12f/24d, and 18f/36d with 2 Gy/f irradiations performed every other day and one non irradiated group. Serial [18F]FLT positron emission tomography (PET) scans were performed at different time points as the groups finished the radiotherapy. The maximum of standard uptake values (SUVmax) were measured to confirm the likely time of tumor repopulation. A layer-by-layer comparison between SUVmax of PET images and Ki-67 LI of pathology images, including the thresholds at which maximum overlap occurred between FLT-segmented areas and cell proliferation areas were conducted to evaluate the spatial correlation. RESULTS: The SUVmax decreased in the 3f/6d group (P = 0.000) compared to the non-irradiated group, increased in the 6f/12d group and then gradually reduced with prolonged treatment. Proliferation changes in 6f/12d group on pathology images were also confirmed. Significant correlations were found between the SUVmax and Ki-67 LI in each in vitro tumor of cell proliferation group and accelerated repopulation group (both of the P < 0.001). Furthermore, the mean overlap region rates (ORRs) were 56.21 % and 57.82 % in the proliferation group and repopulation group, respectively. The data represented the preferable registration. CONCLUSIONS: [18F]FLT PET is a promising imaging surrogate of tumor proliferative response to fractionated radiotherapy and may help make an adaptive radiation oncology treatment plan to realize radiotherapy dose painting. PMID- 30406515 TI - [Management of community acquired pneumonia]. PMID- 30406516 TI - ? PMID- 30406514 TI - Dairy Consumption and Cardiometabolic Diseases: Systematic Review and Updated Meta-Analyses of Prospective Cohort Studies. AB - PURPOSE OF REVIEW: Dairy products contain both beneficial and harmful nutrients in relation to cardiometabolic diseases. Here, we provide the latest scientific evidence regarding the relationship between dairy products and cardiometabolic diseases by reviewing the literature and updating meta-analyses of observational studies. RECENT FINDINGS: We updated our previous meta-analyses of cohort studies on type 2 diabetes, coronary heart disease (CHD), and stroke with nine studies and confirmed previous results. Total dairy and low-fat dairy (per 200 g/d) were inversely associated with a 3-4% lower risk of diabetes. Yogurt was non-linearly inversely associated with diabetes (RR = 0.86, 95% CI: 0.83-0.90 at 80 g/d). Total dairy and milk were not associated with CHD (RR~1.0). An increment of 200 g of daily milk intake was associated with an 8% lower risk of stroke. The latest scientific evidence confirmed neutral or beneficial associations between dairy products and risk of cardiometabolic diseases. PMID- 30406517 TI - ? PMID- 30406518 TI - ? PMID- 30406519 TI - ? PMID- 30406520 TI - ? PMID- 30406521 TI - ? PMID- 30406523 TI - ? PMID- 30406522 TI - ? PMID- 30406524 TI - ? PMID- 30406525 TI - ? PMID- 30406526 TI - [The new S3-guideline gestational diabetes]. PMID- 30406527 TI - [Update H. pylori therapy]. PMID- 30406528 TI - [Drug treatment for dizziness]. PMID- 30406529 TI - [Lifestyle modifications - neglected component of antihypertensive treatment]. PMID- 30406530 TI - [Modern stepped care treatment of arterial hypertension]. PMID- 30406531 TI - ? PMID- 30406532 TI - ? PMID- 30406533 TI - ? PMID- 30406534 TI - ? PMID- 30406535 TI - ? PMID- 30406536 TI - ? PMID- 30406537 TI - ? PMID- 30406538 TI - ? PMID- 30406539 TI - ? PMID- 30406540 TI - ? PMID- 30406541 TI - ? PMID- 30406542 TI - ? PMID- 30406543 TI - ? PMID- 30406546 TI - ? PMID- 30406545 TI - ? PMID- 30406544 TI - ? PMID- 30406547 TI - ? PMID- 30406548 TI - ? PMID- 30406549 TI - ? PMID- 30406550 TI - ? PMID- 30406551 TI - ? PMID- 30406552 TI - ? PMID- 30406553 TI - ? PMID- 30406554 TI - ? PMID- 30406555 TI - ? PMID- 30406556 TI - ? PMID- 30406557 TI - ? PMID- 30406558 TI - ? PMID- 30406559 TI - ? PMID- 30406560 TI - ? PMID- 30406561 TI - ? PMID- 30406562 TI - ? PMID- 30406563 TI - ? PMID- 30406565 TI - Autoantibody and metalloproteinase activity in early arthritis. AB - OBJECTIVES: The aim of the study was to evaluate the frequency of anti-mutated citrullinated vimentin antibodies (a-Sa), anti-citrullinated alpha-enolase peptide 1 antibodies (a-CEP-1), anti-filaggrin antibodies (AFAs), heterogeneous nuclear ribonucleoprotein compies/anti-RA33-antibodies (a-hnRNP/RA33), anti carbamylated protein antibodies (a-CarP), and metalloproteinase (MMPs) activity in patients with early inflammatory arthritis (EIA). METHODS: Seventy-four patients with EIA: 51 diagnosed with RA (rheumatoid arthritis) and 23 with UA (undifferentiated arthritis), and 20 healthy volunteers were enrolled to the study. Inflammatory markers, rheumatoid factor (RF), and antibodies mentioned above were assessed in all patients. RESULTS: In the EIA group, we observed significantly higher concentration of a-CEP-1 (65.8 +/- 111.6 RU/mL) than in controls (2.0 +/- 0.0 RU/mL). In RF(+) RA patients, we observed higher concentration of a-Sa and a-CEP-1 than in other groups. A-Sa were positive in 69% of RF(+) RA, 37% of RF(-) RA, 26% of UA patients and in 10% of controls. A-CEP-1 were positive in 77% of RF(+) RA patients, in 56% of RF(-) RA patients, in 8.7% of UA patients, but they were negative in controls. In patients with RF(+) RA, positive a-CarP were present statistically significantly more often than in RF ( ) RA patients. No statistically significant difference in frequency of a hnRNP/RA33 and AFA between RF(+) RA, RF(-) RA, and UA was observed. CONCLUSIONS: Our results suggest that a-CEP-1 may help in differentiation between RF(-) RA and UA. a-CEP-1 and a-Sa may be useful while diagnosing EIA. a-CarP may be used in differentiation of RA RF(-) and UA. However, a follow-up study is needed to evaluate the prognostic value of analyzed antibodies. PMID- 30406564 TI - Optimization of the parameters that affect the synthesis of magnetic copolymer styrene-divinilbezene to be used as efficient matrix for immobilizing lipases. AB - The parameters that effect the synthesis of poly(styrene-co-divinylbenzene) magnetized with magnetite (STY-DVB-M) by polymerization emulsion were assessed in order to obtain magnetic beads to be used as matrix for lipase immobilization. The combined effect of polyvinyl alcohol (PVA) concentration and agitation was studied using response surface methodology. A 22 full-factorial design was employed for experimental design and analysis of the results. The optimum PVA concentration and agitation were found to be 1 wt% and 400 rpm, respectively. These conditions allow attaining the best particle size distribution of the synthesized particles (80% between 80 and 24 mesh). The performance of the magnetic beads was tested as a matrix for immobilizing two microbial lipases (Lipases from Burkholderia cepacia-BCL and Pseudomonas fluorescens-AKL) by physical adsorption and high immobilization yields (> 70%) and hydrolytic activities (? 1850 U g-1) were attained. The properties of free and immobilized lipases were searched and compared. Similar performance regarding the analyzed parameters (biochemical properties, kinetic constants and thermal stability) were obtained. Moreover, both immobilized lipases were found to be able to catalyze the transesterification of coconut oil with ethanol to produce fatty acid ethyl esters (FAEE). Further study showed that the B. cepacia immobilized lipase could be used seven times without significant decrease of activity, revealing half-life time of 970 h. PMID- 30406566 TI - Quantifying Social Reinforcement Among Family Members on Adherence to Medications for Chronic Conditions: a US-Based Retrospective Cohort Study. AB - BACKGROUND: More than 50% of patients are non-adherent to medications, often without an easily identifiable reason to clinicians. No study has quantified the extent to which health behaviors like medication-taking are correlated within families using national or routinely collected data for a range of conditions. OBJECTIVE: To examine how an individual's health behaviors are influenced by those of their family members, particularly in adherence to medications for chronic conditions. DESIGN: Retrospective cohort study. PATIENTS: Using claims from a large nationwide insurer, we identified patients initiating medications for one of five chronic conditions with a family member who also recently filled one of these medications. MAIN MEASURES: The primary exposure was whether family members were fully adherent (defined as a proportion of days covered >= 80%) before the patient's date of initiation. The outcome of interest was whether patients were fully adherent in the 12 months after initiation. Baseline demographic and clinical characteristics were also measured before initiation. We used multivariable modified Poisson regression to examine the association between prior family adherence and subsequent patient adherence. KEY RESULTS: Among 254,144 patients, rates of full adherence among patients whose family members were and were not fully adherent were 37.3% and 26.9%, respectively (adjusted relative risk [aRR] 1.29, 95%CI 1.28-1.31). The association was stronger when both used cardiometabolic medications (aRR 1.35, 95%CI 1.32-1.37). Similarly, patients were also 38% more likely to be adherent if they and their family members used a medication for the same condition (aRR 1.38, 95%CI 1.35-1.40). CONCLUSIONS: Adherence among family members appeared to be highly correlated, suggesting positive reinforcement by family or the sharing of unmeasured behaviors or characteristics associated with better adherence. Regardless, information about prior adherence among family members from routinely collected data could potentially inform adherence prediction or intervention efforts. PMID- 30406567 TI - Primary Care Transformation and Physician Burnout. PMID- 30406568 TI - A Cross-sectional Survey Using Clinical Vignettes to Examine Overdose Risk Assessment and Willingness to Prescribe Naloxone. PMID- 30406570 TI - Terminal. PMID- 30406569 TI - Physician Empathy Is Not Associated with Laboratory Outcomes in Diabetes: a Cross sectional Study. AB - BACKGROUND: One widely cited study suggested a link between physician empathy and laboratory outcomes in patients with diabetes, but its findings have not been replicated. While empathy has a positive impact on patient experience, its impact on other outcomes remains unclear. OBJECTIVE: To assess associations between physician empathy and glycosylated hemoglobin (HgbA1c) as well as low-density lipoprotein (LDL) levels in patients with diabetes. DESIGN: Retrospective cross sectional study. PARTICIPANTS: Patients with diabetes who received care at a large integrated health system in the USA between January 1, 2011, and May 31, 2014, and their primary care physicians. MAIN MEASURES: The main independent measure was physician empathy, as measured by the Jefferson Scale of Empathy (JSE). The JSE is scored on a scale of 20-140, with higher scores indicating greater empathy. Dependent measures included patient HgbA1c and LDL. Mixed effects linear regression models adjusting for patient sociodemographic characteristics, comorbidity index, and physician characteristics were used to assess the association between physician JSE scores and their patients' HgbA1c and LDL. KEY RESULTS: The sample included 4176 primary care patients who received care with one of 51 primary care physicians. Mean physician JSE score was 118.4 (standard deviation (SD) = 12). Median patient HgbA1c was 6.7% (interquartile range (IQR) = 6.2-7.5) and median LDL concentration was 83 (IQR = 66-104). In adjusted analyses, there was no association between JSE scores and HgbA1c (beta = - 0.01, 95%CI = - 0.04, 0.02, p = 0.47) or LDL (beta = 0.41, 95%CI = - 0.47, 1.29, p = 0.35). CONCLUSION: Physician empathy was not associated with HgbA1c or LDL. While interventions to increase physician empathy may result in more patient centered care, they may not improve clinical outcomes in patients with diabetes. PMID- 30406571 TI - Keeping Pace with the Expanding Role of Health Coaching. PMID- 30406572 TI - Tissue engineering the cancer microenvironment-challenges and opportunities. AB - Mechanosensing is increasingly recognised as important for tumour progression. Tumours become stiff and the forces that normally balance in the healthy organism break down and become imbalanced, leading to increases in migration, invasion and metastatic dissemination. Here, we review recent advances in our understanding of how extracellular matrix properties, such as stiffness, viscoelasticity and architecture control cell behaviour. In addition, we discuss how the tumour microenvironment can be modelled in vitro, capturing these mechanical aspects, to better understand and develop therapies against tumour spread. We argue that by gaining a better understanding of the microenvironment and the mechanical forces that govern tumour dynamics, we can make advances in combatting cancer dormancy, recurrence and metastasis. PMID- 30406573 TI - Molecular characterization and expression changes of cytoglobin genes in response to hypoxia in a Tibetan schizothoracine fish, Schizopygopsis pylzovi. AB - Schizopygopsis pylzovi, an endemic fish of the subfamily Schizothoracinae, is comparatively well adapted to dissolved oxygen fluctuations in the aqueous environments of the Qinghai-Tibetan Plateau. Here, we cloned the complete cDNA of cytoglobin 1 and 2 (Cygb1 and Cygb2) from S. pylzovi and then investigated transcriptional changes of both genes in the selected tissues in response to hypoxia. Both the two genes had the standard exon-intron structure of vertebrate Mb genes but lacked an exon at downstream of the H helix (HC11.2) as seen in mammals. We applied severe hypoxia (4 h at PO2 = 3.6% saturation) and moderate hypoxia (72 h at PO2 = 36.0% saturation) to adult S. pylzovi. Under severe hypoxia, the Cygb1 mRNA levels decreased significantly in the liver, kidney, and brain, but increased significantly in the heart, while the Cygb2 mRNA levels downregulated significantly in the muscle and liver. But, the transcriptional activity of Cygb1 in muscle and that of Cygb2 in the kidney, brain, and heart remained almost unchanged. Under moderate hypoxia, the transcriptional activities of both genes in muscle and brain were turned down quickly after onset hypoxia, while in the liver, kidney, and heart, the transcriptional activities of both genes showed a short-term upregulation in different time periods of hypoxia exposure. Our data suggest that both the Cygb1 and Cygb2 in S. pylzovi are hypoxia-induced genes, and the responses of the transcription regulation of Cygb1 and Cygb2 genes to hypoxia are tissue specific and also depend on the hypoxia regime, which are different from that of other fish species. PMID- 30406574 TI - Apathy and health-related quality of life in nursing home residents. AB - PURPOSE: To explore the association between apathy and health-related quality of life (HRQoL) from resident and proxy perspectives and whether cognition and depression moderate this relationship. METHODS: Secondary analyses with baseline data from a cluster randomized trial on the effects of a care program for depression in Nursing Homes (NHs) were conducted. For HRQoL, the Visual Analogue Scale (VAS) and the Dutch version of the European Quality of Life (EQ-5D) were administered to 521 NH residents, and to professional caregivers reporting from the perspective of the NH resident (Resident-Proxy) and from their own perspective (Proxy-Proxy). Utility scores (U) were calculated for the three perspectives. Apathy, depression, and cognition were measured using the 10-item Apathy Evaluation Scale, the Cornell Scale for Depression in Dementia, and the standardized Mini-Mental State Examination, respectively. RESULTS: Mixed models adjusted for clustering within NH units revealed that apathy was negatively associated with HRQoL both from the Resident-Proxy perspective (EQ-5D VAS: estimated effect, - 0.31, P < 0.001; EQ-5D Utility: - 0.30, P < 0.001) and from the Proxy-Proxy perspective (VAS: - 0.29, P < 0.001; U: - 0.03, P < 0.001), but not from the Resident-Resident perspective (VAS: - 0.05, P = 0.423; Utility: - 0.08, P = 0.161). Controlling for depression and cognition and their interaction terms with apathy did not change the results. CONCLUSION: Apathy is negatively associated with NH resident HRQoL as reported by proxies. Depression and cognitive functioning do not moderate this association. NH residents do not self report a relationship between apathy and HRQoL. More research is needed to understand caregiver and NH resident attitudes and underlying assumptions regarding apathy and HRQoL. PMID- 30406575 TI - NGS sequencing reveals that many of the genetic variations in transgenic rice plants match the variations found in natural rice population. AB - BACKGROUND: As the transformation process can induce mutations in host plants, molecular characterization of the associated genomic changes is important not only for practical food safety but also for understanding the fundamental theories of genome evolution. OBJECTIVES: To investigate a population-scale comparative study of the genome-wide spectrum of sequence variants in the transgenic genome with the variations present in 3000 rice varieties. RESULTS: On average, we identified 19,273 SNPs (including Indels) per transgenic line in which 10,729 SNPs were at the identical locations in the three transgenic rice plants. We found that these variations were predominantly present in specific regions in chromosomes 8 and 10. Majority (88%) of the identified variations were detected at the same genomic locations as those in natural rice population, implying that the transgenic induced mutations had a tendency to be common alleles. CONCLUSION: Genomic variations in transgenic rice plants frequently occurred at the same sites as the major alleles found in the natural rice population, which implies that the sequence variations occur within the limits of a biological system to ensure survival. PMID- 30406576 TI - Learning Curve in Robot-Assisted Laparoscopic Liver Resection. AB - BACKGROUND: The objective of this study was to evaluate the learning curve effect on the safety and feasibility of robot-assisted liver resection (RALR). METHODS: In 140 consecutive cases, all data about demographic, surgical procedure, postoperative course were collected prospectively and analyzed. Risk-adjusted cumulative sum model was used for determining the learning curve based on the need for conversion. RESULTS: Among all 140 patients, no patients suffered from any organ dysfunction postoperatively and the operative mortality was 0%. The CUSUM analysis showed that at the 30th consecutive patient, the open conversion rate reached to the average value, and it further improved thereafter. In the last 70 patients, only 3 patients (4.3%) required conversion and 7 patients (10%) needed blood transfusion. Only 1 patient (1.3%) out of 79 patients with HCC had a positive resection margin. Univariate analyses showed the following risk factors associated with significantly higher risks of conversion (P < 0.05): tumor number > 1, lesions in segments 1/4a/7/8, right posterior sectionectomy, and lesions which were beyond the indications of the Louisville statement. Multivariate logistic analysis revealed that both tumor number > 1 (OR: 2.10, P < 0.05) and right posterior sectionectomy (OR: 11.19, P < 0.01) were risk factors of conversion. CONCLUSIONS: The robotic approach for hepatectomy is safe and feasible. A learning curve effect was demonstrated in this study after the 30th consecutive patient. The long-term oncological outcomes of robotic hepatectomy still need further investigation. PMID- 30406577 TI - Tips and Tricks of Performing Surgically Inserted TAP Catheters for Hepatectomy. PMID- 30406578 TI - Evolving the Paradigm of Early Drain Removal Following Pancreatoduodenectomy. AB - BACKGROUND: Recent data illustrates improved outcomes when adhering to early drain removal following pancreatoduodenectomy (PD). This study aims to explore the potential benefits of expanding the timeframe for early drain removal. METHODS: Six hundred forty PDs were originally managed by selective drain placement and early removal. Outcomes were reappraised in the framework of a novel proposal; intraoperative drains were omitted based on a low-risk profile (Fistula Risk Score 0-2), followed by drain removal at PODs 1, 3, and 5 if drain fluid amylase (DFA) fell below specific cutoffs based on optimized negative predictive values (NPV) for clinically relevant postoperative pancreatic fistula (CR-POPF). Characteristics of the remaining cohort with drains in situ on POD5 were examined using multivariable analysis (MVA). RESULTS: Intraoperative FRS would preclude drains from 230 (35.9%) negligible/low-risk cases with a cohort CR POPF rate of 1.7%. Of the remaining patients, 30.5% would have drains removed on POD1 based on a DFA threshold of 300 IU/L (NPV = 98.4%), demonstrating a 1.6% CR POPF rate. On POD3, drains could be removed in the residual cohort from 21.1% of patients with DFA <= 150 IU/L (NPV = 96.6%), reflecting a 3.4% CR-POPF rate. On POD5, a DFA threshold of 50 IU/L (NPV = 84%) identified 16.3% more patients whose drains could be removed. The remaining cohort (POD5 DFA > 50 IU/L), "enriched" for fistula development and reflecting just 18.4% of the original patients, displays a 61% CR-POPF rate. Among these patients on POD5, a DFA threshold > 2000 IU/L best predicted subsequent CR-POPF (PPV = 89.5%), and MVA revealed a positive association between pancreatic cancer/pancreatitis (OR = 4.37, p = 0.022) and longer operations (OR = 3.74, p = 0.014) with CR-POPF development. CONCLUSION: Early drain removal is a dynamic concept and can be employed throughout the postoperative time course using conditional thresholds to better identify patients at risk for CR-POPF. PMID- 30406579 TI - Erosion Rate of the Magnetic Sphincter Augmentation Device Is Much Higher for Anal Incontinence than for Antireflux. PMID- 30406581 TI - Evaluation of the potential of sewage sludge as a valuable fertilizer for wheat (Triticum aestivum L.) crops. AB - A greenhouse experiment was performed to assess the soil heavy metal pools, growth, yield, and heavy metal uptake of wheat plants (Triticum aestivum L.) that are grown at different rates in soils supplemented with sewage sludge (SS). The experimental design was completely randomized, with six replicates per treatment. The application of SS significantly increased the soil organic matter content. Generally, most growth parameters, as well as the biomass of treated wheat, were significantly increased with the amendment of SS, up to the addition rate of 40 g kg-1. The content of all heavy metals (except Cr in grains and Pb in spikes) significantly increased in different tissues of treated wheat with the increasing rate of SS application. However, all heavy metal concentrations (except for Al, Cr, Fe, and Mn in the roots) were normal and did not overcome the phytotoxic levels. The wheat was recognized by a bioaccumulation factor < 1.0 for most of the heavy metals. The translocation factor for all of the heavy metals was < 1.0. Therefore, the SS utilized in the present study could be used as a valuable organic fertilizer in wheat cultivation areas in Saudi Arabia and could also act as an eco-friendly method for the recycling of SS. PMID- 30406580 TI - In Vivo Osteocyte Mechanotransduction: Recent Developments and Future Directions. AB - PURPOSE OF REVIEW: Mechanical loading is an essential stimulus for skeletal tissues. Osteocytes are primarily responsible for sensing mechanical stimuli in bone and for orchestrating subsequent responses. This is critical for maintaining homeostasis, and responding to injury/disease. The osteocyte mechanotransduction pathway, and the downstream effects it mediates, is highly complex. In vivo models have proved invaluable in understanding this process. This review summarizes the commonly used models, as well as more recently developed ones, and describes how they are used to address emerging questions in the field. RECENT FINDINGS: Minimally invasive animal models can be used to determine mechanisms of osteocyte mechanotransduction, at the cell and molecular level, while simultaneously reducing potentially confounding responses such as inflammation/wound-healing. The details of osteocyte mechanotransduction in bone are gradually becoming clearer. In vivo model systems are a key tool in pursing this question. Advances in this field are explored and discussed in this review. PMID- 30406582 TI - Modeling daily water temperature for rivers: comparison between adaptive neuro fuzzy inference systems and artificial neural networks models. AB - River water temperature is a key control of many physical and bio-chemical processes in river systems, which theoretically depends on multiple factors. Here, four different machine learning models, including multilayer perceptron neural network models (MLPNN), adaptive neuro-fuzzy inference systems (ANFIS) with fuzzy c-mean clustering algorithm (ANFIS_FC), ANFIS with grid partition method (ANFIS_GP), and ANFIS with subtractive clustering method (ANFIS_SC), were implemented to simulate daily river water temperature, using air temperature (Ta), river flow discharge (Q), and the components of the Gregorian calendar (CGC) as predictors. The proposed models were tested in various river systems characterized by different hydrological conditions. Results showed that including the three inputs as predictors (Ta, Q, and the CGC) yielded the best accuracy among all the developed models. In particular, model performance improved considerably compared to the case where only Ta is used as predictor, which is the typical approach of most of previous machine learning applications. Additionally, it was found that Q played a relevant role mainly in snow-fed and regulated rivers with higher-altitude hydropower reservoirs, while it improved to a lower extent model performance in lowland rivers. In the validation phase, the MLPNN model was generally the one providing the highest performances, although in some river stations ANFIS_FC and ANFIS_GP were slightly more accurate. Overall, the results indicated that the machine learning models developed in this study can be effectively used for river water temperature simulation. PMID- 30406583 TI - Indoor phthalates from household dust in Qatar: implications for non-dietary human exposure. AB - Phthalates are ubiquitous semi-volatile organic compounds in the indoor environment present in various consumer products such as cosmetics, polyvinylchloride (PVC) flooring, food packing, and many others. Indoor phthalate concentrations were investigated in 15 buildings including 11 homes, 3 laboratories, and 1 from a hospital in Qatar. Dust samples were collected from vacuum cleaning bags usually used for cleaning homes, labs, and hospitals. The main objectives of this study was to determine the occurrence and concentration of phthalates in dust in Qatar and consequently to estimate the non-dietary human exposure. Eleven phthalates was analyzed. The major identified phthalate compounds at homes in Qatar were bis(2-ethylhexyl) phthalate unlabeled (DEHP) and diisononyl phthalate (DINP) at a geometric mean of 288 MUg/g (median 395 MUg/g) and 106 MUg/g (median 101 MUg/g) accounting for 57% and 23% of the total measured phthalates, respectively. The major phthalate compounds found in the first lab building were DEHP and DINP with a median of 4861 MUg/g and 943 MUg/g, respectively, accounting for 82% and 16% of the total phthalates. For the second lab building, the major phthalates were DEHP with a median of 466 MUg/g, accounting for 20% of the total phthalates measured, and DINP median of 1725 MUg/g, accounting for 71% of the total measured phthalates. The dust sample tested from hospital building had DEHP as the major phthalate compound with a median of 793 MUg/g, accounting for 4.0% of the total measured phthalates, and DINP with a median of 19,626 MUg/g, accounting for 94%. The estimated human non dietary exposure for children, adults, and toddlers was based on phthalate concentrations (median) and found to be 225 ng/kg bw/day for children, 2328 ng/kg bw/day for adults, and 2099 ng/kg bw/day for toddlers. PMID- 30406584 TI - Performances of Pichia kudriavzevii in decolorization, biodegradation, and detoxification of C.I. Basic Blue 41 under optimized cultural conditions. AB - The aim of this study was to evaluate the performances of Pichia kudriavzevii CR Y103 yeast strain for the decolorization, biodegradation, and detoxification of cationic dye C.I. Basic Blue 41, a toxic compound to aquatic life with long lasting effects. Under optimized cultural conditions (10.0-g L-1 glucose, 0.2-g L 1 yeast extract, and 1.0-g L-1 (NH4)2SO4), the yeast strain was able to decolorize 97.86% of BB41 (50 mg L-1) at pH 6 within 4 h of incubation at 30 degrees C under shaken conditions (12,238.00-MUg h-1 average decolorization rate) and 100% within 12 h. The UV-Vis spectral analysis, high-performance liquid chromatography (HPLC), and Fourier-transform infrared spectroscopy (FTIR) analysis confirmed the complete decolorization and degradation of the BB41 dye by P. kudriavzevii CR-Y103. Also, other seven yeast strains, isolated from soil, as P. kudriavzevii (CR-Y108, CR-Y119, and CR-Y112), Candida tropicalis CR-Y128, Cyberlindnera saturnus CR-Y125, and Candida solani CR-Y124 have shown a promising decolorizing potential of azo-dye BB41 (99.89-76.09% decolorization). Phytotoxicity, cytotoxicity, and genotoxicity assays on Trifolium pratense and Triticum aestivum seedlings confirmed the high toxicity of BB41 dye (500 ppm), with inhibition on germination rate (%), root and shoot elongation, decreasing of mitoxic index value (with 34.03% in T. pratense and 40.25% in T. aestivum), and increasing the frequency of chromosomal aberrations (6.87 times in T. pratense and 6.25 times in T. aestivum), compared to control. The same biomarkers indicated the nontoxic nature of the BB41 degraded metabolite (500 ppm) obtained after P. kudriavzevii CR-Y103 treatment. Moreover, the healthy monkey kidney cells (Vero cells) had a low sensitivity to BB41 biodegraded products (250 MUg mL 1) (MTT cell viability assay) and revealed minor DNA damage (comet assay) compared to BB41 dye treatment. These findings show that P. kudriavzevii could be used in eco-friendly bioremediation technologies, applicable for reducing the toxicity of basic azo-dyes containing wastewaters. PMID- 30406585 TI - Effects of different composting strategies on methane, nitrous oxide, and carbon dioxide emissions and nutrient loss during small-scale anaerobic composting. AB - Composting is considered as one of the main sustainable methods for the treatment of livestock manure. In this study we investigated the effects of additives (urea and rice straw) on methane (CH4), nitrous oxide (N2O), and carbon dioxide (CO2) emissions using a traditional Chinese pig slurry composting method over an 81-day period, as well as examining total organic carbon and total nitrogen loss. Four common treatment strategies were examined in this study: a control (MC), urea nitrogen addition (MN), composting using rice straw cover (MScover), and compost mixed with rice straw (MSmix). Our results indicate that the addition of urea resulted in the lowest total CH4 emissions and the highest N2O emissions. MScover treatment had the highest and most significant effect on CH4 emissions, while MSmix treatment had the lowest CO2 emissions. Carbon lost through CH4 and CO2 released during the experiment was 0.1-0.9 and 2.4-3.9% of total carbon loss, respectively, and nitrogen lost through N2O release was 11.1-17.9% of total nitrogen. In general, although MSmix, MScover, and MN treatments increased global warming potential by 21.4, 41.6, and 50.9% per kg of pig slurry, respectively, no statistical differences between the four treatments were recorded. By considering carbon and nitrogen conservation, as well as the improvement of the quality of compost and the mitigation of greenhouse gases (GHGs), the small-scale composting method of pig slurry alone is an acceptable environmentally friendly strategy for use in China. PMID- 30406586 TI - beta-Pinene moderates Cr(VI) phytotoxicity by quenching reactive oxygen species and altering antioxidant machinery in maize. AB - We examined the possible role of monoterpene beta-pinene in providing protection against Cr(VI) toxicity in maize (Zea mays). Treatment with beta-pinene (10 MUM) significantly alleviated Cr(VI) accumulation and recuperated Cr(VI) caused decline in root and coleoptile growth in maize. beta-Pinene addition caused a decline in Cr(VI)-induced accumulation of superoxide anion, hydroxyl ion, hydrogen peroxide and confirmed by in-situ detection of ROS using histochemical localization. It suggested that the beta-pinene quenches/neutralizes enhanced ROS generated under Cr(VI) exposure. beta-Pinene also reduced Cr(VI)-induced electrolyte leakage, thereby suggesting its role in membrane stabilization. Further, beta-pinene regulated the activity of scavenging enzymes, thereby suggesting a role in modulating Cr(VI)-induced oxidative damage. In conclusion, our results suggest that the addition of beta-pinene has a protective role against Cr(VI) stress and provides resistance to maize against Cr(VI) toxicity. PMID- 30406587 TI - Decreasing farm number benefits the mitigation of agricultural non-point source pollution in China. AB - Agricultural non-point source pollution causes global warming and the deterioration of air and water quality. It is difficult to identify and monitor the emission sources of agricultural pollution due to the large number of farms in China. Many studies focus on the technological aspect of achieving agricultural sustainability, but its socioeconomic aspect is poorly understood. Here, we report how group size (number of farms in a certain region) affects agricultural pollution governance through conducting a social science experiment. We found that when communication was allowed among group members, a small group size facilitated cooperation. Although deviations from the cooperation equilibrium occurred with time in all groups, the smaller the group size, the slower the cooperation equilibrium became frangible. These findings suggest that reducing number of farms and extending the length of farm property rights can benefit the mitigation of agricultural non-point pollution in China. Social science experiments can be a useful tool to understand the socioeconomic aspect of agricultural sustainability. PMID- 30406588 TI - Removal of particulate matter and trace elements from ambient air by urban greenery in the winter season. AB - Particulate matter (PM) is one of the most harmful inhaled pollutants. When PM is emitted into the atmosphere, the only possible method for cleaning ambient air is through vegetation acting as biological filters for pollutants. However, in winter periods when the concentration of PM is usually the highest, the efficiency of plants is very low. The aim of this work was therefore to examine the accumulation of PM and selected trace elements (TE) by three species, evergreen coniferous Taxus baccata L. and Pinus nigra Arn., and deciduous Carpinus betulus L. during the winter season. The highest amounts of PM accumulated on the foliage of P. nigra, while TE on the leaves of C. betulus. Most of the PM accumulated on plant foliage belonged to the large fraction size (10-100 MUm) and was deposited on the surface of foliage (SPM). The concentration of four TE (Ni, Pb, Cd, and Sb) was higher in PM accumulated on foliage, while in the case of three other TE (Zn, Cr and Mg), their concentration was higher in plant tissue. The TE were recorded in all PM size fractions and were rather equally distributed between surface PM (SPM) and in-wax PM (WPM). These findings have implications for urban plantings in countries with short vegetative season, where tolerant conifer species and deciduous species which keep foliage through winter should be included in urban forest plantings due to their efficiency in the removal of pollutants from the air. PMID- 30406589 TI - Evaluation of mercury phytoavailability in Oxisols. AB - Mercury is a metal which is potentially toxic for the environment. Many factors control its retention in the soil, such as cation exchange capacity, pH, clay content, organic matter, and redox potential. It is important to know the phytotoxic effects of soil Hg to prevent environmental contamination and its entry into the food chain. Several analytical methods are used to measure metal phytoavailability in soils, but none has been reported for Hg in Oxisols, the most common soil class in Brazil and a very important soil class throughout the tropics. The aim of this study was to select the chemical extractor that best correlated the Hg levels in plants and the Oxisols. The soils used were classified as Dystrophic Red-Yellow Oxisol (LVAd) and Dystroferric Red Oxisol (LVdf), which were collected in the 0-0.2-m soil layer. The species selected for cultivation were a monocotyledon, oat (Avena sativa L. cv. Sao Carlos) and a eudicotyledon, common bean (Phaseolus vulgaris L. cv. Madreperola). Each test plot was composed of a 500 cm3 pot filled with soil samples contaminated with HgCl2. Treatments were arranged in a completely randomized design, with four replications. The experiment was conducted for 30 days. Mercury contents were separately extracted with the following extractors: USEPA 3051A, Mehlich-1, Mehlich-3, DTPA, and water. Mercury was determined by hydride generation atomic absorption spectroscopy. The extracted contents were correlated with the contents in the tissues of the plants' aerial part by the Pearson correlation. Although it is not considered a standard procedure to evaluate metal phytoavailable contents, the method that presented the best correlations between soil Hg and plant Hg was USEPA 3051A (r = 0.75*). As expected, the worst correlation was with water (r = 0.57* for common bean and r = 0,05ns for oat). PMID- 30406590 TI - Developing an electric vehicle urban driving cycle to study differences in energy consumption. AB - This paper develops a methodology for constructing a representative electric vehicle (EV) urban driving cycle as a basis for studying the differences in estimated energy consumption, taking Xi'an as an example. The test route is designed in accordance with the overall topological structure of the urban roads in the study region and the results of a traffic flow survey. Wavelet decomposition and reconstruction are utilized to preprocess the original data. Principal component analysis (PCA) is used to reduce the number of the kinetic parameters. The fuzzy C-means (FCM) clustering algorithm is used to cluster the driving segments. A representative EV urban driving cycle is constructed in accordance with the time proportions of three classes of driving segments and the correlation coefficients of the characteristic parameters. Finally, the differences in energy consumption estimates obtained using the constructed Xi'an EV urban driving cycle (XA-EV-UDC) and the international driving cycles are studied. The comparison shows that when international driving cycles are used to estimate the energy consumption and driving range of EVs, large relative errors will result, with energy consumption errors of 9.65 to 21.17% and driving range errors of 20.10 to 38.14%. Therefore, to accurately estimate energy consumption and driving range of EVs under real-world driving conditions, representative EV driving cycles for each typical city and region should be constructed. PMID- 30406591 TI - Process development of silica extraction from RHA: a cradle to gate environmental impact approach. AB - India is one of the major rice-producing countries. Rice husk is a major agricultural by-product from rice production, which is used as a fuel in boilers. Its use as fuel produces huge amounts of silica-rich rice husk ash (RHA). This paper aims at providing an overall assessment of environmental impacts associated with the extraction of silica from RHA-a process developed by our study group. The functional unit used in this study is production of 100 kg of silica. The analysis included the extraction and transportation of other raw materials; RHA was assumed to be processed at the site. The study was conducted in accordance with the international ISO 14040 procedural framework. LCA is performed using GaBi Education software, and five midpoint indicators are chosen to assess the environmental impacts of silica extraction. The overall climate change (CC) of the extraction process is 7.26 kg CO2 equivalent per kg of silica produced. A high contribution of calcination to CC is attributed to the use of electricity. The comprehensive environmental impacts of silica-rich RHA resulting from processing of RHA and improvement options to achieve sustainable production are presented. The negative impacts that can be avoided during silica extraction are also discussed. It is observed that calcination is a major contributor to the overall environmental indicators. The work also stresses on the use of renewable energy for electricity generation, which would help in decreasing the overall greenhouse gas emissions during extraction while ensuring waste utilization. PMID- 30406592 TI - Developing air exchange rate models by evaluating vehicle in-cabin air pollutant exposures in a highway and tunnel setting: case study of Tehran, Iran. AB - The passengers inside vehicles could be exposed to high levels of air pollutants particularly while driving on highly polluted and congested traffic roadways. In order to study such exposure levels and its relation to the cabin ventilation condition, a monitoring campaign was conducted to measure the levels inside the three most common types of vehicles in Tehran, Iran (a highly air polluted megacity). In this regard, carbon monoxide (CO) and particulate matter (PM) were measured for various ventilation settings, window positions, and vehicle speeds while driving on the Resalat Highway and through the Resalat Tunnel. Results showed on average in-cabin exposure to particle number and PM10 for the open windows condition was seven times greater when compared to closed windows and air conditioning on. When the vehicle was passing through the tunnel, in-cabin CO and particle number increased 100 and 30%, respectively, compared to driving on highway. Air exchange rate (AER) is a significant factor when evaluating in-cabin air pollutants level. AER was measured and simulated by a model developed through a Monte Carlo analysis of uncertainty and considering two main affecting variables, vehicle speed and fan speed. The lowest AER was 7 h-1 for the closed window and AC on conditions, whereas the highest AER was measured 70 h-1 for an open window condition and speed of 90 km h-1. The results of our study can assist policy makers in controlling in-cabin pollutant exposure and in planning effective strategies for the protection of public health. PMID- 30406593 TI - Influence of salinity cycles in bioreactor performance and microbial community structure of membrane-based tidal-like variable salinity wastewater treatment systems. AB - A membrane bioreactor and two hybrid moving bed bioreactor-membrane bioreactors were operated for the treatment of variable salinity wastewater, changing in cycles of 6-h wastewater base salinity and 6-h maximum salinity (4.5 and 8.5 mS cm-1 electric conductivity, which relate to 2.4 and 4.8 g L-1 NaCl, respectively), under different hydraulic retention times (6, 9.5, and 12 h) and total solids concentrations (2500 and 3500 mg L-1). The evaluation of the performance of the systems showed that COD removal performance was unaffected by salinity conditions, while BOD5 and TN removals were significantly higher in the low-salinity scenario. The microbial community structure showed differences with respect to salinity conditions for Eukarya, suggesting their higher sensitivity for salinity with respect to Prokarya, which were similar at both salinity scenarios. Nevertheless, the intra-OTU distribution of consistently represented OTUs of Eukarya and Prokarya was affected by the different salinity maximums. Multivariate redundancy analyses showed that several genera such as Amphiplicatus (0.01-5.90%), Parvibaculum (0.27-1.19%), Thiothrix (0.30-1.19%), Rhodanobacter (2.81-5.85%), Blastocatella (0.21-2.01%), and Nitrobacter (0.80-0.99%) were positively correlated with BOD5 and TN removal, and the ecological roles of these were proposed. All these genera were substantially more represented under low salinity conditions (10-500% higher relative abundance), demonstrating that they might be of importance for the treatment of variable salinity wastewater. Evaluation of Eukarya OTUs showed that many of them lack a consistent taxonomic classification, which highlights the lack of knowledge of the diversity and ecological role of Eukaryotes in saline wastewater treatment processes. The results obtained will be of interest for future design and operation of salinity wastewater treatment systems particularly because little is known on the effect of variable salinity conditions in wastewater treatment. PMID- 30406594 TI - Improving of the Mg-Co nanoferrites efficiency for crude oil adsorption from aqueous solution by blending them with chitosan hydrogel. AB - The efficiency of the as-prepared Mg0.25Co0.75Fe2O4 spinel nanoparticles for adsorption of crude oil from aqueous solution was improved by blending them with chitosan hydrogel (CH) prepared using epichlorohydrin as cross-linker resulting (CH/Mg0.25Co0.75Fe2O4) nanocomposites. Mg0.25Co0.75Fe2O4 nanocrystals was prepared by the chemical co-precipitation method and characterized by using X-ray diffraction (XRD), infrared spectroscopy (FT-IR), scanning electron microscope (SEM), transmission electron microscope (TEM), and differential thermal analysis (DTA)/thermogravimetric analysis (TGA). DTA/TGA results showed that the net weight loss of the samples heated from room temperature up to 1000 degrees C lies in the range 2.2-26.5% weight, where the maximum weight loss appeared at 100 degrees C and 614 degrees C. The blending nanocomposites prepared, were characterized by FT-IR and SEM micrographs. The effect of the nanoparticles ratio on the water uptake of nanocomposites and their capability to adsorb the crude oil was estimated by the gravimetric method. TEM results showed that the average nanoparticle size (Z) of Mg0.25Co0.75Fe2O4 is 30.06 nm and the SEM illustrated the presence of a very clear and rough layer of pores which are homogenously arranged structures that could play an important role in the adsorption and stability of crude oil on polymers. The adsorption ability of crude oil from waste water on the CH/Mg0.25Co0.75Fe2O4 nanocomposites hydrogel was reported and it was found that the CH/Mg0.25Co0.75Fe2O4 with 95/5% ratio showed the improvement in the oil adsorption (72.5%) than the 0/100% one (50.2%). As a consequence, it is highly suggested that the potential of blending CH with Mg0.25Co0.75Fe2O4 to obtain CH/Mg0.25Co0.75Fe2O4 for enhancing crude oil adsorption in oily waste water treatment with a low cost. PMID- 30406595 TI - Production, characterization and effectiveness of cellulose acetate functionalized ZnO nanocomposite adsorbent for the removal of Se (VI) ions from aqueous media. AB - In this study, ZnO functionalized cellulose acetate nanocomposite (ZnO/CA NC) was synthesized using a simple chemical approach found to have a high surface area of 657.34 m2/g and utilized as adsorbents for the removal of Se (VI) from aqueous solutions. Investigations on X-ray diffraction (XRD) revealed that ZnO nanocomposite has a smaller crystallite size compared to ZnO nanoparticles which facilitated for reduced agglomeration confirmed by scanning electron microscopy (SEM). The ensuing properties of ZnO/CA NC displayed high maximum adsorption capacity of 160.5 mg/g for Se (VI) ions. Inner-sphere surface complexes on ZnO/CA NC under prevailing conditions for Se (VI) were discussed using FTIR spectroscopical results. In order to evaluate the removal efficiency, the effects of adsorbent dosage, pH, and temperature were thoroughly investigated. The amount of Se (VI) ions adsorbed on ZnO/CA NC was also determined by zeta potential. The fractional removal of pollutants (Se (VI)) was done using mass transfer model. In addition, prominent adsorption capacity was also tested utilizing concurrent anions (SO42-, Cl-, and F-) with reference to Se (VI) and cost prudent regenerability of adsorbent by NaOH solution was ascertained with anti interference and recovery steps. ZnO/CA NC was obtained by simple chemical methodology and high surface adsorption capacities supply an encouraging technique for Se (VI) removal in water treatment applications. PMID- 30406596 TI - Antibiotics in hospital effluents: occurrence, contribution to urban wastewater, removal in a wastewater treatment plant, and environmental risk assessment. AB - The study presented the occurrence of antibiotics in 16 different hospital effluents, the removal of antibiotics in urban wastewater treatment plant (WWTP), and the potential ecotoxicological risks of the effluent discharge on the aquatic ecosystem. The total concentration of antibiotics in hospital effluents was ranged from 21.2 +/- 0.13 to 4886 +/- 3.80 ng/L in summer and from 497 +/- 3.66 to 322,735 +/- 4.58 ng/L in winter. Azithromycin, clarithromycin, and ciprofloxacin were detected the highest concentrations among the investigated antibiotics. The total antibiotic load to the influent of the WWTP from hospitals was 3.46 g/day in summer and 303.2 g/day in winter. The total antibiotic contribution of hospitals to the influent of the WWTP was determined as 13% in summer and 28% in winter. The remaining 87% in summer and 72% in winter stems from the households. The total antibiotic removal by conventional physical and biological treatment processes was determined as 79% in summer, whereas it decreased to 36% in winter. When the environmental risk assessment was performed, azithromycin and clarithromycin in the effluent from the treatment plant in winter posed a high risk (RQ > 10) for the aquatic organisms (algae and fish) in the receiving environment. According to these results, the removal efficiency of antibiotics at the WWTP is inadequate and plant should be improved to remove antibiotics by advanced treatment processes. PMID- 30406597 TI - 13q22.1-q32.1 Microdeletion Syndrome. PMID- 30406598 TI - What do people think about genetics? A systematic review. AB - Genetics is increasingly becoming a part of modern medical practice. How people think about genetics' use in medicine and their daily lives is therefore essential. Earlier studies indicated mixed attitudes about genetics. However, this might be changing. Using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) as a guideline, we initially reviewed 442 articles that looked at awareness, attitudes, knowledge, and perception of risks among the general and targeted recruitment populations. After fitting our criteria (from the last 5 years, conducted in the USA, non-provider populations, quantitative results reported, and assessed participants 18 years and older), finally 51 eligible articles were thematically coded and presented in this paper. Awareness is reported as relatively high in the studies reviewed. Attitudes are mixed but with higher proportions reporting positive attitudes towards genetic testing and counseling. Self-reported knowledge is reasonably high, specifically with the effects of specific programs developed to raise knowledge levels of the general and targeted recruited populations. Perception of risk is somewhat aligned with actual risk. With the reasonable positive reports of genetic awareness and knowledge, there is similar positive attitude and perception of risk, supporting the need for continued dissemination of such knowledge. Given interest in incorporating community participation in genomic educational strategies, we provide this review as a baseline from which to launch community specific educational supports and tools. PMID- 30406599 TI - Combined Application of Entomopathogenic Nematodes and Insecticides in the Control of Leaf-Miner Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae) on Tomato. AB - The present research aimed to investigate the compatibility of entomopathogenic nematodes (EPNs) and registered insecticides for the control of Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae) in the tomato crop, as well as the susceptibility of pupae of T. absoluta to EPNs combined with different percentages below the recommended dose of compatible chemical insecticides in laboratory conditions and in the greenhouse. The species of EPN used was Heterorhabditis amazonensis JPM4. The insecticides used were Actara(r), Premio(r), and Warrant(r). In the compatibility test between the EPNs and insecticides, the viability and infectivity of the nematodes after contact with the insecticides were evaluated. An assessment of the efficacy of the combined application of different doses of the insecticides and the EPNs on T. absoluta was carried out in the laboratory and greenhouse. The efficacy of the combined application of the insecticides and the EPNs on T. absoluta via soil was carried out at application intervals of 1 and 2 weeks. The EPNs were compatible with the three insecticides tested. In the laboratory, there was an additive effect of the combined application of insecticides and H. amazonensis as the dose of the products increased. In the greenhouse assay, the combined application of EPNs and insecticides induced mortality above 48%, and the combined application of EPNs and Warrant(r) 75% presented 60% of mortality. The weekly and fortnightly applications were effective in controlling T. absoluta, and there was no difference between the insecticides tested when applied together with the nematodes. PMID- 30406600 TI - Decrease of inhibitory synaptic currents of locus coeruleus neurons via orexin type 1 receptors in the context of naloxone-induced morphine withdrawal. AB - Acute opioid withdrawal syndrome is a series of neurological symptoms caused by the abrupt cessation of the chronic administration of opioids such as morphine. The locus coeruleus (LC) in the brain stem receives a dense projection of orexinergic fibers from the hypothalamus and is a candidate site for the expression of the somatic aspects of morphine withdrawal. Previous studies have shown that orexin-A contributes to the behavioral symptoms of naloxone-induced morphine withdrawal, partly by reducing the activity of GABAergic neurons, suggesting that orexin-A may negatively modulate fast GABAergic neurotransmission during morphine withdrawal. We used whole-cell patch-clamp recordings of LC neurons in brainstem slices to investigate the effect of orexin-A on bicuculline sensitive GABAergic inhibitory postsynaptic currents (IPSCs) during naloxone induced morphine withdrawal. Male Wistar rats (P14-P21) were given morphine (20 mg/kg, i.p.) daily for seven consecutive days to create dependency on the drug. The application of naloxone (1 uM) to brain slices of morphine-treated rats reduced the amplitude of evoked IPSCs (eIPSCs) as well as spontaneous IPSCs (sIPSCs) frequency but did not change sIPSCs amplitude. Orexin-A (100 nM) significantly enhanced the suppressive effect of naloxone on eIPSCs amplitude and sIPSCs frequency but had no effect on the presence of the orexin type 1 receptor (OX1R) antagonist, SB-334867. Orexin-A alone had no significant effect on eIPSCs and sIPSCs in the absence of naloxone. In summary, our results show that orexin A, via OX1R, potentiates the suppressive effect of naloxone on GABAergic IPSCs of LC neurons in morphine-treated rats. We conclude that orexins may have a critical role in regulating GABAergic neurotransmission to LC neurons during naloxone induced morphine withdrawal. PMID- 30406601 TI - Magnetic resonance imaging in patients with cardiac implantable electronic devices. AB - In recent years the prevalence of implantation of a cardiac implantable electronic device (CIED) has increased due to expanding implantation indications and prolonged life expectancy. Diagnostic strategies increasingly employ magnetic resonance imaging (MRI) to aid therapeutic strategies. In earlier guidelines, MRI was contra-indicated in patients with CIEDs, mainly due to previous reports of severe complications. With the development of MRI-conditional CIEDs and recent evidence concerning non-MRI-conditional CIEDs, MRIs in CIED patients can be safely performed in many hospitals.However, there are several questions that need to be addressed. Which patients can we scan? How can the scans be performed safely? And last but not least, can cardiac MRI provide diagnostic yield in patients with CIEDs?Current European guidelines are rather outdated and vague about patient selection and practical issues. There are national guidelines on this topic but several issues need extra attention and those are addressed in this point of view. It is important to create an environment with proper patient selection without unnecessary MRI scans in CIED patients, but also without unnecessary fear of complications, preventing access to MRI in patients who can benefit from this powerful diagnostic tool. PMID- 30406602 TI - Imaging for cardiac resynchronisation therapy requires cardiac magnetic resonance. PMID- 30406603 TI - Reply to the letter from Bhagirath et al.: Imaging for cardiac resynchronisation therapy requires cardiac magnetic resonance. PMID- 30406604 TI - Tuberous sclerosis complex: new insights into clinical and therapeutic approach. AB - Tuberous sclerosis complex (TSC) is a complex disease with many different clinical manifestations. Despite the common opinion that TSC is a rare condition, with a mean incidence of 1/6000 live births and a prevalence of 1/20,000, it is increasingly evident that in reality this is not true. Its clinical sequelae span a range of multiple organ systems, in particular the central nervous system, kidneys, skin and lungs. The management of TSC patients is heavily burdensome in terms of time and healthcare costs both for the families and for the healthcare system. Management options include conservative approaches, surgery, pharmacotherapy with mammalian target of rapamycin inhibitors and recently proposed options such as therapy with anti-EGFR antibody and ultrasound-guided percutaneous microwaves. So far, however, no systematically accepted strategy has been found that is both clinically and economically efficient. Thus, decisions are tailored to patients' characteristics, resource availability and clinical and technical expertise of each single center. This paper reviews the pathophysiology and the clinical (diagnostic-therapeutic) management of TSC. PMID- 30406605 TI - Infusion of autologous bone marrow derived mononuclear stem cells potentially reduces urinary markers in diabetic nephropathy. AB - BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. Previous studies demonstrated safety and efficacy of autologous bone marrow-derived mononuclear cells (ABM-MNCs) in induced type-1 diabetes mellitus (T1DM) rats. However, the effect of ABM-MNCs on urinary markers of DN in humans is not well studied. We evaluated the therapeutic effect of ABM MNCs on the urinary markers microalbuminuria (MAU), urinary type-IV collagen and urinary neutrophil gelatinase-associated lipocalin (uNGAL) in T1DM patients with and without nephropathy. METHODS: This prospective open-label pilot study included 15 patients with T1DM, who had completed 2 visits within 6 months. Patients were divided into two groups according to the presence (DN, n = 7) and absence of nephropathy (T1DM, n = 8). ABM-MNCs were injected at each visit as per study protocol. Routine laboratory data, diabetes tests (fasting serum C-peptide and insulin, glycated hemoglobin, fasting and postprandial glucose), 24-h MAU and urinary type-IV collagen were measured at each visit. uNGAL levels were studied before and after 3 days of ABM-MNCs infusion at each visit. RESULTS: Mean age of patients was 29.2 +/- 10.4 years, 33% were male, and 27% of the overall group had hypertension. MAU was significantly reduced in the overall group (- 26.0%, p = 0.037), including in DN (- 83.2%, p = 0.021). A short-term significant reduction of uNGAL levels was observed 3 days after ABM-MNCs administration during the both the 1st visit (median 13.4 vs. 9.5 ng/ml, p = 0.027) and 2nd visit (median 8.8 vs. 6.4 ng/ml, p = 0.042) in both groups. However this reduction did not remain significant at the 6-month follow-up. Urinary type-IV collagen did not respond significantly to ABM-MNCs infusion. CONCLUSION: Infusion of autologous bone marrow-derived mononuclear cells significantly reduced levels of MAU in DN patients. Further studies with larger sample size are needed to confirm these observations. PMID- 30406606 TI - Cardiovascular risk in renal transplant recipients. AB - Successful kidney transplantation offers patients with end-stage renal disease the greatest likelihood of survival. However, cardiovascular disease poses a major threat to both graft and patient survival in this cohort. Transplant recipients are unique in their accumulation of a wide range of traditional and non-traditional cardiovascular risk factors. Hypertension, diabetes, dyslipidaemia and obesity are highly prevalent in patients with end-stage renal disease. These risk factors persist following transplantation and are often exacerbated by the drugs used for immunosuppression in organ transplantation. Additional transplant-specific factors such as poor graft function and proteinuria are also associated with increased cardiovascular risk. However, these transplant-related factors remain unaccounted for in current cardiovascular risk prediction models, making it challenging to identify transplant recipients with highest risk. With few interventional trials in this area specific to transplant recipients, strategies to reduce cardiovascular risk are largely extrapolated from other populations. Aggressive management of traditional cardiovascular risk factors remains the cornerstone of prevention, though there is also a potential role for selecting immunosuppression regimens to minimise additional cardiovascular injury. PMID- 30406607 TI - Pneumonectomy-related small omega (omega) sign and increased pulmonary uptake in myocardial perfusion imaging. PMID- 30406608 TI - Evaluation of the effect of reducing administered activity on assessment of function in cardiac gated SPECT. AB - BACKGROUND: We previously optimized several reconstruction strategies in SPECT myocardial perfusion imaging (MPI) with low dose for perfusion-defect detection. Here we investigate whether reducing the administered activity can also maintain the diagnostic accuracy in evaluating cardiac function. METHODS: We quantified the myocardial motion in cardiac-gated stress 99m-Tc-sestamibi SPECT studies from 163 subjects acquired with full dose (29.8 +/- 3.6 mCi), and evaluated the agreement of the obtained motion/thickening and ejection fraction (EF) measures at various reduced dose levels (uniform reduction or personalized dose) with that at full dose. We also quantified the detectability of abnormal motion via a receiver-operating characteristics (ROC) study. For reconstruction we considered both filtered backprojection (FBP) without correction for degradations, and iterative ordered-subsets expectation-maximization (OS-EM) with resolution, attenuation and scatter corrections. RESULTS: With dose level lowered to 25% of full dose, the obtained results on motion/thickening, EF and abnormal motion detection were statistically comparable to full dose in both reconstruction strategies, with Pearson's r > 0.9 for global motion measures between low dose and full dose. CONCLUSIONS: The administered activity could be reduced to 25% of full dose without degrading the function assessment performance. Low dose reconstruction optimized for perfusion-defect detection can be reasonable for function assessment in gated SPECT. PMID- 30406609 TI - Automated dynamic motion correction using normalized gradient fields for 82rubidium PET myocardial blood flow quantification. AB - BACKGROUND: Patient motion can lead to misalignment of left ventricular (LV) volumes-of-interest (VOIs) and subsequently inaccurate quantification of myocardial blood flow (MBF) and flow reserve (MFR) from dynamic PET myocardial perfusion images. We aimed to develop an image-based 3D-automated motion correction algorithm that corrects the full dynamic sequence for translational motion, especially in the early blood phase frames (~ first minute) where the injected tracer activity is transitioning from the blood pool to the myocardium and where conventional image registration algorithms have had limited success. METHODS: We studied 225 consecutive patients who underwent dynamic rest/stress rubidium-82 chloride (82Rb) PET imaging. Dynamic image series consisting of 30 frames were reconstructed with frame durations ranging from 5 to 80 seconds. An automated algorithm localized the RV and LV blood pools in space and time and then registered each frame to a tissue reference image volume using normalized gradient fields with a modification of a signed distance function. The computed shifts and their global and regional flow estimates were compared to those of reference shifts that were assessed by three physician readers. RESULTS: The automated motion-correction shifts were within 5 mm of the manual motion correction shifts across the entire sequence. The automated and manual motion correction global MBF values had excellent linear agreement (R = 0.99, y = 0.97x + 0.06). Uncorrected flows outside of the limits of agreement with the manual motion-corrected flows were brought into agreement in 90% of the cases for global MBF and in 87% of the cases for global MFR. The limits of agreement for stress MBF were also reduced twofold globally and by fourfold in the RCA territory. CONCLUSIONS: An image-based, automated motion-correction algorithm for dynamic PET across the entire dynamic sequence using normalized gradient fields matched the results of manual motion correction in reducing bias and variance in MBF and MFR, particularly in the RCA territory. PMID- 30406610 TI - Validation and Extension of a Fluid-Structure Interaction Model of the Healthy Aortic Valve. AB - PURPOSE: The understanding of the optimum function of the healthy aortic valve is essential in interpreting the effect of pathologies in the region, and in devising effective treatments to restore the physiological functions. Still, there is no consensus on the operating mechanism that regulates the valve opening and closing dynamics. The aim of this study is to develop a numerical model that can support a better comprehension of the valve function and serve as a reference to identify the changes produced by specific pathologies and treatments. METHODS: A numerical model was developed and adapted to accurately replicate the conditions of a previous in vitro investigation into aortic valve dynamics, performed by means of particle image velocimetry (PIV). The resulting velocity fields of the two analyses were qualitatively and quantitatively compared to validate the numerical model. In order to simulate more physiological operating conditions, this was then modified to overcome the main limitations of the experimental setup, such as the presence of a supporting stent and the non physiological properties of the fluid and vessels. RESULTS: The velocity fields of the initial model resulted in good agreement with those obtained from the PIV, with similar flow structures and about 90% of the computed velocities after valve opening within the standard deviation of the equivalent velocity measurements of the in vitro model. Once the experimental limitations were removed from the model, the valve opening dynamics changed substantially, with the leaflets opening into the sinuses to a much greater extent, enlarging the effective orifice area by 11%, and reducing greatly the vortical structures previously observed in proximity of the Valsalva sinuses wall. CONCLUSIONS: The study suggests a new operating mechanism for the healthy aortic valve leaflets considerably different from what reported in the literature to date and largely more efficient in terms of hydrodynamic performance. This work also confirms the crucial role that numerical approaches, complemented with experimental findings, can play in overcoming some of the limitations inherent in experimental techniques, supporting the full understanding of complex physiological phenomena. PMID- 30406611 TI - [Editor's Comment]. PMID- 30406612 TI - ? PMID- 30406613 TI - ? PMID- 30406614 TI - ? PMID- 30406615 TI - ? PMID- 30406616 TI - ? PMID- 30406617 TI - ? PMID- 30406618 TI - [Milestones of Thyroid Surgery]. AB - Thyroid surgery has been developping to a safe surgery including minimally invasive treatment options meeting high safety standards up to now. This fascinating development is displayed in a medical-historical context based on the current state of surgical and medical-historical research. The increasing comprehension of thyroid diseases and treatments including their perioperative sequelae and complications is interpreted in this historical context. Newly implemented minimally invasive thyroid operations differ by access modalities and pathes and led to higher patient comforts regarding the wounds and scar formation. Future surgical techniques and new access pathes have to meet at least the present high safety and quality standards in thyroid surgery and nuclear medicine. PMID- 30406619 TI - [Vocal Changes and Laryngeal Modifications in the Elderly (Presbyphonia and Presbylarynx)]. AB - In about 20 % of the population older than 60 years of age, voice problems (presbyphonia) are manifest, often combined with hearing deficits (presbyacusis), swallowing disorders (presbyphagia), dizziness (presbyvertigo) and/or impaired vision (presbyopia).The singing voice is afflicted more often, earlier and more severely than the speaking voice. But it is not just the vocal quality and capacity that are affected. Due to reduced pulmonary function, the breathing impetus is also weakened. As a result of the descending of the larynx, resonance properties of the vocal tract change in seniors, and there is increased risk of aspiration.Vocal deficits are caused by age-related morphological changes in the larynx (presbylarynx). These alterations concern both the ectolaryngeal skeleton and the endolaryngeal soft tissues (particularly the vocal folds). The vocalis muscle atrophies and becomes hypotonic, which becomes clinically apparent as vocal fold bowing and spindle-shaped glottic chink with loss of air during phonation. The laryngeal mucosa dries out (laryngitis sicca).Vocal rehabilitation in the elderly includes both general and voice-specific therapeutic options. Underlying internal and neurological diseases (e. g. reflux, neurodegenerative or cerebrovascular affections), as well as side effects of drugs must be considered. A healthy lifestyle without pathogenic agents promotes good function of phonatory and respiratory organs. As far as voice therapy is concerned, glottal attack exercises can improve glottal closure during phonation, and relaxation exercises may reduce supraglottic hyperfunctional compression. In special cases with large glottic chink, phonosurgical augmentation of the vocal folds may enhance glottal closure and vocal strength. Vocal hygiene (e. g. regular airway moisturisation) complements voice exercises.In the elderly, singing has proven pychosocial benefits (improvement of well-being and social participation) and verified positive immunological effects (salivary IgA increase). PMID- 30406620 TI - ? PMID- 30406621 TI - [From the Expert's Office: The meaning of olfactory bulb volume measurements in evaluating olfactory loss]. PMID- 30406622 TI - ? PMID- 30406623 TI - ? PMID- 30406624 TI - Hip Taping Positively Alters Running Kinematics in Asymptomatic Females. AB - Greater functional knee valgus (FKV) is thought to contribute to a greater risk of sustaining overuse running injuries. The hip is commonly implicated in greater functional knee valgus, but no studies have investigated the effects of hip taping on running kinematics. The present study investigated whether or not hip taping altered hip and knee kinematics compared to sham and no taping in female runners demonstrating excessive functional knee valgus. Lower limb stance-phase kinematics were collected from 23 female runners using three-dimensional motion capture. Participants performed over ground running at 3.5 m/s and 5.0 m/s. Three taping conditions (no tape; sham tape; hip tape) were tested. Statistical inference was performed using Statistical Parametric Mapping Hotelling's paired t tests, with post-hoc paired t-tests. Hip taping significantly decreased hip adduction and internal rotation angles throughout stance phase by up to 7 degrees , compared to sham and no taping. Hip taping significantly increased knee adduction, internal rotation, flexion, and reduced peak knee flexion angles, compared to no tape. Hip taping reduced excessive hip motion by clinically meaningful magnitudes, and also benefited knee frontal and transverse plane kinematics at the slower running speed. Hip taping may provide an immediate solution in correcting FKV in running. PMID- 30406625 TI - An Electronic Medical Record in Pediatric Medical Education: Survey of Medical Students' Expectations and Experiences. AB - OBJECTIVE: This study sought to quantitatively characterize medical students' expectations and experiences of an electronic health record (EHR) system in a hospital setting, and to examine perceived and actual impacts on learning. METHODS: Medical students from July to December 2016 at a tertiary pediatric institution completed pre- and postrotation surveys evaluating their expectations and experience of using an EHR during a pediatric medicine rotation. Survey data included past technology experience, EHR accessibility, use of learning resources, and effect on learning outcomes and patient-clinician communication. RESULTS: Students generally reported high computer self-efficacy (4.16 +/- 0.752, mean +/- standard deviation), were comfortable with learning new software (4.08 +/- 0.771), and expected the EHR to enhance their overall learning (4.074 +/- 0.722). Students anticipated the EHR to be easy to learn, use, and operate, which was consistent with their experience (pre 3.86 vs. post 3.90, p = 0.56). Students did not expect nor experience that the EHR reduced their interaction, visual contact, or ability to build rapport with patients. The EHR did not meet expectations to facilitate learning around medication prescribing, placing orders, and utilizing online resources. Students found that the EHR marginally improved feedback surrounding clinical contributions to patient care from clinicians, although not to the expected levels (pre 3.50 vs. post 3.17, p < 0.01). CONCLUSION: Medical students readily engaged with the EHR, recognized several advantages in clinical practice, and did not consider their ability to interact with patients was impaired. There was widespread consensus that the EHR enhanced their learning and clinician's feedback, but not to the degree they had expected. PMID- 30406627 TI - [Care of Patients During Emergency Caesarian Section - Evaluation of Quality Characteristics from the Patients Point of View]. AB - BACKGROUND: An emergency caesarian section can be a terrifying experience for expectant mothers. Fear for her own life as well as her unborn child's is a traumatic event that can result in the development of post-traumatic stress disorder (PTSD). The aim of this survey was to define scales and items that describe the quality of care of parturients in cases of emergency caesarian section. METHODS: A pool of items was developed via a 2-step online Delphi survey administered to women who had undergone an emergency caesarian section. The resulting parameters were evaluated for relevance and validity in a larger patient collective. Lastly, we identified factors that could be grouped into relevant scales. RESULTS: After validating the results of the Delphi survey, 5 scales with 18 items were identified. They encompassed the following dimensions: "team external effect," "mother's level of information," "subjective evaluation," "personal integrity," and "after-care." These items could explain 58.2% of total variance and provide a stable factorial solution (KMO 0.76). CONCLUSION: To our knowledge, this is the first time a German criteria checklist has been developed to evaluate the care of expectant mothers undergoing an emergency caesarian section. This checklist can be used in addition to medical outcomes to measure quality of care. Further studies are needed to evaluate practical implementation and its impact on patient care. PMID- 30406626 TI - [Guideline for the Diagnosis and Treatment of Asthma - Guideline of the German Respiratory Society and the German Atemwegsliga in Cooperation with the Paediatric Respiratory Society and the Austrian Society of Pneumology]. PMID- 30406628 TI - Metabolic Syndrome as a Predictor of Adrenal Functional Status: A Discriminant Multivariate Analysis Versus Logistic Regression Analysis. AB - Patients harboring adrenal tumors are characterized by higher prevalence of metabolic syndrome (MetS) components and a higher incidence of cardiovascular complications, especially in cases of subclinical or overt hormonal hypersecretion. Early detection and referral of those patients in tertiary centers could prevent unfavorable outcomes. In this cross-sectional, retrospective study, we evaluated 111 consecutive patients with adrenal incidentalomas and 14 patients with known hypersecretory adrenal lesions (autonomous cortisol secretion, primary aldosteronism, and pheochromocytoma), who were investigated in our clinic. Based on the different distribution of MetS components in patients with non-functional and functional adrenal lesions we introduced a predictive model of hormonal hypersecretion using those components. We performed multivariate discriminant analysis and compared predictive results with conventional multiple logistic regression analysis. Diabetes, impaired glucose tolerance, impaired fasting glucose, hypertension, body mass index, HDL cholesterol levels, triglyceride levels, drug treatment for lipid disorder (statins, fenofibrate, and fish oils, alone or in combination), and maximal adrenal lesion diameter were used as discriminating covariates. Multivariate discriminant function exhibited a sensitivity of 77.27% and specificity of 73.08% in predicting adrenal hormonal hypersecretion. Receiver operating characteristic curve of discriminant predictive function had an area under the curve value of 0.785, S.E. 0.04. Logistic function delivered comparable results. MetS components exhibit a good predictive feature of hormonal hypersecretion in patients with adrenal tumors. Predictive functions may help in the search for an easy and generally available algorithm to validly predict the functional activity of adrenal masses. PMID- 30406629 TI - Flexible traction method for endoscopic resection by using an endoscopic hand suturing technique. PMID- 30406630 TI - "Candy cane" syndrome: a report of a mini-invasive endoscopic treatment using OverStitch, a novel endoluminal suturing system. PMID- 30406631 TI - Endoscopic retrieval of a migrated pancreatic stent using a handmade catheter with a guidewire loop. PMID- 30406632 TI - Bridge-to-surgery gallbladder drainage with a lumen-apposing metal stent in malignant distal biliary obstruction: a choice tailored for the surgeon. PMID- 30406633 TI - Retrograde single-balloon enteroscopy for the removal of a mollusc shell retained in the ileum of a patient with active Crohn's disease. PMID- 30406635 TI - Endoscopic removal of dental prosthesis impacted in the duodenal papilla. PMID- 30406634 TI - Endoscopic ultrasound-guided hepaticogastrostomy combined with novel uncovered metal stent. PMID- 30406636 TI - Thoracoscopic and endoscopic cooperative surgery (TECS): a novel less invasive technique for resection of gastric tube cancer after esophagectomy. PMID- 30406637 TI - Endoscopic exchange of a lumen-apposing metal stent after endoscopic ultrasound guided gastroenterostomy in severe acute pancreatitis. PMID- 30406638 TI - Cannabis for the treatment of ulcerative colitis. AB - BACKGROUND: Cannabis and cannabinoids are often promoted as treatment for many illnesses and are widely used among patients with ulcerative colitis (UC). Few studies have evaluated the use of these agents in UC. Further, cannabis has potential for adverse events and the long-term consequences of cannabis and cannabinoid use in UC are unknown. OBJECTIVES: To assess the efficacy and safety of cannabis and cannabinoids for the treatment of patients with UC. SEARCH METHODS: We searched MEDLINE, Embase, WHO ICTRP, AMED, PsychINFO, the Cochrane IBD Group Specialized Register, CENTRAL, ClinicalTrials.Gov and the European Clinical Trials Register from inception to 2 January 2018. Conference abstracts and references were searched to identify additional studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing any form or dose of cannabis or its cannabinoid derivatives (natural or synthetic) to placebo or an active therapy for adults (> 18 years) with UC were included. DATA COLLECTION AND ANALYSIS: Two authors independently screened search results, extracted data and assessed bias using the Cochrane risk of bias tool. The primary outcomes were clinical remission and relapse (as defined by the primary studies). Secondary outcomes included clinical response, endoscopic remission, endoscopic response, histological response, quality of life, C-reactive protein (CRP) and fecal calprotectin measurements, symptom improvement, adverse events, serious adverse events, withdrawal due to adverse events, psychotropic adverse events, and cannabis dependence and withdrawal effects. We calculated the risk ratio (RR) and corresponding 95% confidence interval for dichotomous outcomes. For continuous outcomes, we calculated the mean difference (MD) and corresponding 95% CI. Data were pooled for analysis when the interventions, patient groups and outcomes were sufficiently similar (determined by consensus). Data were analyzed on an intention-to-treat basis. GRADE was used to evaluate the overall certainty of evidence. MAIN RESULTS: Two RCTs (92 participants) met the inclusion criteria. One study (N = 60) compared 10 weeks of cannabidiol capsules with up to 4.7% D9 tetrahydrocannabinol (THC) with placebo capsules in participants with mild to moderate UC. The starting dose of cannabidiol was 50 mg twice daily increasing to 250 mg twice daily if tolerated. Another study (N = 32) compared 8 weeks of therapy with two cannabis cigarettes per day containing 0.5 g of cannabis, corresponding to 23 mg THC/day to placebo cigarettes in participants with UC who did not respond to conventional medical treatment. No studies were identified that assessed cannabis therapy in quiescent UC. The first study was rated as low risk of bias and the second study (published as an abstract) was rated as high risk of bias for blinding of participants and personnel. The studies were not pooled due to differences in the interventional drug.The effect of cannabidiol capsules (100 mg to 500 mg daily) compared to placebo on clinical remission and response is uncertain. Clinical remission at 10 weeks was achieved by 24% (7/29) of the cannabidiol group compared to 26% (8/31) in the placebo group (RR 0.94, 95% CI 0.39 to 2.25; low certainty evidence). Clinical response at 10 weeks was achieved in 31% (9/29) of cannabidiol participants compared to 22% (7/31) of placebo patients (RR 1.37, 95% CI 0.59 to 3.21; low certainty evidence). Serum CRP levels were similar in both groups after 10 weeks of therapy. The mean CRP in the cannabidiol group was 9.428 mg/L compared to 7.638 mg/L in the placebo group (MD 1.79, 95% CI -5.67 to 9.25; moderate certainty evidence). There may be a clinically meaningful improvement in quality of life at 10 weeks, measured with the IBDQ scale (MD 17.4, 95% CI -3.45 to 38.25; moderate certainty evidence). Adverse events were more frequent in cannabidiol participants compared to placebo. One hundred per cent (29/29) of cannabidiol participants had an adverse event, compared to 77% (24/31) of placebo participants (RR 1.28, 95% CI 1.05 to1.56; moderate certainty evidence). However, these adverse events were considered to be mild or moderate in severity. Common adverse events included dizziness, disturbance in attention, headache, nausea and fatigue. None (0/29) of the cannabidiol participants had a serious adverse event compared to 13% (4/31) of placebo participants (RR 0.12, 95% CI 0.01 to 2.11; low certainty evidence). Serious adverse events in the placebo group included worsening of UC and one complicated pregnancy. These serious adverse events were thought to be unrelated to the study drug. More participants in the cannabidiol group withdrew due to an adverse event than placebo participants. Thirty-four per cent (10/29) of cannabidiol participants withdrew due to an adverse event compared to 16% (5/31) of placebo participants (RR 2.14, 95% CI 0.83 to 5.51; low certainty evidence). Withdrawls in the cannabidiol group were mostly due to dizziness. Withdrawals in the placebo group were due to worsening UC.The effect of cannabis cigarettes (23 mg THC/day) compared to placebo on mean disease activity, CRP levels and mean fecal calprotectin levels is uncertain. After 8 weeks, the mean disease activity index score in cannabis participants was 4 compared with 8 in placebo participants (MD -4.00, 95% CI -5.98 to -2.02). After 8 weeks, the mean change in CRP levels was similar in both groups (MD -0.30, 95% CI -1.35 to 0.75; low certainty evidence). The mean fecal calprotectin level in cannabis participants was 115 mg/dl compared to 229 mg/dl in placebo participants (MD -114.00, 95% CI 246.01 to 18.01). No serious adverse events were observed. This study did not report on clinical remission, clinical response, quality of life, adverse events or withdrawal due to adverse events. AUTHORS' CONCLUSIONS: The effects of cannabis and cannabidiol on UC are uncertain, thus no firm conclusions regarding the efficacy and safety of cannabis or cannabidiol in adults with active UC can be drawn.There is no evidence for cannabis or cannabinoid use for maintenance of remission in UC. Further studies with a larger number of patients are required to assess the effects of cannabis in UC patients with active and quiescent disease. Different doses of cannabis and routes of administration should be investigated. Lastly, follow-up is needed to assess the long term safety outcomes of frequent cannabis use. PMID- 30406639 TI - Rutosides for prevention of post-thrombotic syndrome. AB - BACKGROUND: Post-thrombotic syndrome (PTS) is a long-term complication of deep venous thrombosis (DVT) that is characterised by pain, swelling, and skin changes in the affected limb. One in three patients with DVT will develop post-thrombotic sequelae within five years. The current standard care for the prevention of PTS following DVT is elastic compression stockings. Rutosides are a group of compounds derived from horse chestnut (Aesculus hippocastanum), a traditional herbal remedy for treating oedema formation in chronic venous insufficiency (CVI). However, it is not known whether rutosides are effective and safe in the prevention of PTS. This is the second update of the review first published in 2013. OBJECTIVES: To determine the effectiveness and safety of rutosides for prevention of post-thrombotic syndrome (PTS) in patients with deep vein thrombosis (DVT), compared to placebo, no intervention, or reference medication. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 21 August 2018. SELECTION CRITERIA: We planned to include trials of rutosides versus any alternative (placebo, no intervention, or reference medication) in the prevention of PTS in patients with DVT. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and intended to extract information from the trials. MAIN RESULTS: No studies were identified comparing rutosides versus any alternative in the prevention of PTS. AUTHORS' CONCLUSIONS: As there were no studies identified in this review there is currently insufficient evidence to determine the effectiveness and safety of rutosides for prevention of PTS in patients with DVT. Some studies suggest that rutosides may provide short-term relief of PTS symptoms. However, there is nothing published on their use as a preventative therapy for PTS. High quality randomised controlled trials of rutoside versus any alternative are required to build the evidence base in this area. PMID- 30406641 TI - New SNP variants of MARVELD2 (DFNB49) associated with non-syndromic hearing loss in Chinese population. AB - Non-syndromic hearing loss (NSHL) is a common defect in humans. Variants of MARVELD2 at the DFNB49 locus have been shown to cause bilateral, moderate to profound NSHL. However, the role of MARVELD2 in NSHL susceptibility in the Chinese population has not been studied. Here we conducted a case-control study in an eastern Chinese population to profile the spectrum and frequency of MARVELD2 variants, as well as the association of MARVELD2 gene variants with NSHL. Our results showed that variants identified in the Chinese population are significantly different from those reported in Slovak, Hungarian, and Czech Roma, as well as Pakistani families. We identified 11 variants in a cohort of 283 NSHL cases. Through Sanger sequencing and bioinformatics analysis, we found that c.730G>A variant has detrimental effects in the eastern Chinese population, and may have relatively high correlation with NSHL pathogenicity. PMID- 30406640 TI - Rutosides for treatment of post-thrombotic syndrome. AB - BACKGROUND: Post-thrombotic syndrome (PTS) is a long-term complication of deep venous thrombosis (DVT) that is characterised by pain, swelling, and skin changes in the affected limb. One in three patients with DVT will develop post-thrombotic sequelae within five years. Rutosides are a group of compounds derived from horse chestnut (Aesculus hippocastanum), a traditional herbal remedy for treating oedema formation in chronic venous insufficiency (CVI). However, it is not known whether rutosides are effective and safe in the treatment of PTS. This is the second update of the review first published in 2013. OBJECTIVES: To determine the effectiveness (improvement or deterioration in symptoms) and safety of rutosides for treatment of post-thrombotic syndrome (PTS) in patients with DVT compared to placebo, no intervention, elastic compression stockings (ECS) or any other treatment. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 21 August 2018. SELECTION CRITERIA: Two review authors independently assessed studies for inclusion. Studies were included to allow the comparison of rutosides versus placebo or no treatment, rutosides versus ECS, and rutosides versus any other treatment. Two review authors extracted information from the trials. Disagreements were resolved by discussion. DATA COLLECTION AND ANALYSIS: Data were extracted using designated data extraction forms. The Cochrane 'Risk of bias' tool was used for all included studies to assist in the assessment of quality. Primary outcome measures were the occurrence of leg ulceration over time (yes or no) and any improvement or deterioration of post-thrombotic syndrome (yes or no). Secondary outcomes included reduction of oedema, pain, recurrence of DVT or pulmonary embolism, compliance with therapy, and adverse effects. All of the outcome measures were analysed using Mantel-Haenzel fixed-effect model odds ratios. The unit of analysis was the number of patients. We used GRADE to assess the quality of the evidence for each outcome. MAIN RESULTS: Ten reports of nine studies were identified following searching and three studies with a total of 233 participants met the inclusion criteria. Overall quality of evidence using the GRADE approach was low, predominantly due to the lack of both participant and researcher blinding in the included studies. The quality of the evidence was further limited as only three small studies contributed to the review findings. A subjective scoring system was used to obtain the symptoms of PTS so it was important that the assessors were blinded to the intervention. One study compared rutosides with placebo, one study compared rutosides with ECS and rutosides plus ECS versus ECS alone, and one study compared rutosides with an alternative venoactive remedy. Occurrence of leg ulceration was not reported in any of the included studies. There was no clear evidence to support a difference in PTS improvement between the rutosides or placebo/no treatment groups (OR 1.29, 95% CI 0.69 to 2.41; 164 participants; 2 studies; low-quality evidence); or between the rutosides and ECS groups (OR 0.80, 95% CI 0.31 to 2.03; 80 participants; 1 study ; low-quality evidence). Results from one small study reported less PTS improvement in the rutosides group compared to an alternative venoactive remedy (OR 0.18, 95% CI 0.04 to 0.94; 29 participants; 1 study; low-quality evidence). There was no clear evidence to support a difference in PTS deterioration when comparing rutosides with placebo/no treatment (OR 0.61, 95% CI 0.19 to 1.90; 80 participants; 1 study); with ECS (OR 0.61, 95% CI 0.19 to 1.90; 80 participants; 1 study); or an alternative venoactive remedy (OR 0.19, 95% CI 0.01 to 4.24; 29 participants; 1 study). No clear evidence of a difference in adverse effects between the rutosides and placebo/no treatment groups was seen ('mild side effects' reported in 7/41 and 5/42 respectively). In the study comparing rutosides with ECS, 2/80 could not tolerate ECS and 6/80 stopped medication due to side effects. The study comparing rutosides with an alternative venoactive remedy did not comment on side effects AUTHORS' CONCLUSIONS: There was no evidence that rutosides were superior to the use of placebo or ECS. Overall, there is currently limited low-quality evidence that 'venoactive' or 'phlebotonic' remedies such as rutosides reduce symptoms of PTS. Mild side effects were noted in one study. The three studies included in this review provide no evidence to support the use of rutosides in the treatment of PTS. PMID- 30406642 TI - Can virtual learning environments be used as research platforms? AB - BACKGROUND: Many higher education institutions use virtual learning environments (VLEs), with one in seven students learning exclusively online. The use of online research methods and approaches has also gained momentum over the past decade. AIM: To explore the use of VLEs for qualitative research. DISCUSSION: Using VLEs for purposes beyond teaching and learning functions offers various opportunities, providing a method of collecting data that has minimal costs, requires few resources, offers maximum flexibility, has apt technical support and engages participants. However, it also has several challenges. CONCLUSION: This study supports the proposed potential value and appropriateness of using VLEs to collect data. The function of VLEs may be significantly widened at reasonable cost and challenge. Work in this regard is encouraged. IMPLICATION FOR PRACTICE: VLEs may be used in nurse education research, which stands to benefit from this opportunity at reasonable cost and challenge. PMID- 30406643 TI - The carbamate aldicarb altered the gut microbiome, metabolome and lipidome of C57BL/6J mice. AB - The gut microbiome is highly involved in numerous aspects of host physiology, from energy harvest to stress response, and can confer many benefits to the host. The gut microbiome development could be affected by genetic and environmental factors, including the pesticides. The carbamate insecticide aldicarb has been extensively used in agriculture, which raises serious public health concern. However, the impact of aldicarb on the gut microbiome, host metabolome and lipidome has not been well studied yet. Herein, we use multi-omics approaches, including16S rRNA sequencing, shotgun metagenomics sequencing, metabolomics and lipidomics, to elucidate aldicarb-induced toxicity in the gut microbiome and the host metabolic homeostasis. We demonstrated that aldicarb perturbed the gut microbiome development trajectory, enhanced gut bacterial pathogenicity, altered complex lipid profile, induced oxidative stress, protein degradation and DNA damage. The brain metabolism was also disturbed by the aldicarb exposure. These findings may provide a novel understanding of the toxicity of carbamate insecticides. PMID- 30406644 TI - Machine-Learning Prediction of CO Adsorption in Thiolated, Ag-Alloyed Au Nanoclusters. AB - We propose a machine-learning model, based on the random-forest method, to predict CO adsorption in thiolate protected nanoclusters. Two phases of feature selection and training, based initially on the Au25 nanocluster, are utilized in our model. One advantage to a machine-learning approach is that correlations in defined features disentangle relationships among the various structural parameters. For example, in Au25, we find that features based on the distribution of Ag atoms relative to the CO adsorption site are the most important in predicting adsorption energies. Our machine-learning model is easily extended to other Au-based nanoclusters, and we demonstrate predictions about CO adsorption on Ag-alloyed Au36 and Au133 nanoclusters. PMID- 30406645 TI - Acid-Treated PEDOT:PSS Polymer and TiO2 Nanorod Schottky Junction Ultraviolet Photodetectors with Ultrahigh External Quantum Efficiency, Detectivity, and Responsivity. AB - Vertically aligned TiO2 nanorods (NRs) were synthesized on a fluorine-doped tin oxide-deposited glass substrate by the hydrothermal method. A Schottky junction ultraviolet photodetector was fabricated by spin-coating of the poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) polymer on TiO2 NRs. For the improvement of device performance, the electrical conductivity of the polymer was increased by adding dimethyl sulfoxide (DMSO) and concentrated H2SO4 acid. The diode parameters, i.e., work function, series resistance, and ideality factor, were studied for all devices. Photoresponse behavior of the TiO2 nanorod/PEDOT:PSS junction was studied upon illumination of white light of intensity 80 mW/cm2. Our acid-treated sample demonstrated the highest photocurrent value, which is 10 times larger than that of DMSO-treated and 39 times larger than that of the untreated sample. Our acid-treated device showed superior external quantum efficiency (~12 560%), responsivity (~34.43 A/W), and detectivity (~1.6 * 1011 Hz1/2/W) at ~340 nm wavelength under -1 V bias. PMID- 30406646 TI - Laser-Induced Transformable BiS@HSA/DTX Multiple Nanorods for Photoacoustic/Computed Tomography Dual-Modal Imaging Guided Photothermal/Chemo Combinatorial Anticancer Therapy. AB - Suboptimal intratumor accumulation and poorly controllable release of encapsulated drugs remain unresolved challenges hampering further advancement of nanomedicines in cancer therapy. Herein, we conceived near-infrared (NIR) laser triggered transformable BiS@HSA/DTX multiple nanorods (mNRs), which were made of small bundles of bismuth sulfide nanorods (BiS NRs) coated with docetaxel (DTX) inlaid human serum albumin (HSA). The BiS@HSA/DTX mNRs had a lateral size of approximately 100 nm and efficiently accumulated in the tumor microenvironment upon systemic administration in tumor-bearing nude mice. NIR laser irradiation of the tumor area caused rapid disassembly of the BiS@HSA/DTX mNRs into individual HSA-coated BiS nanorods (BiS@HSA iNRs) and triggered the release of DTX from the HSA corona, due to the local temperature increase generated by BiS NRs via the photothermal effect. The laser-induced transformation into BiS@HSA iNRs facilitated their penetration and increased the retention time in tumor. The spatiotemporal delivery behavior of the BiS@HSA/DTX mNRs could be monitored by photoacoustic/computed tomography dual-modal imaging in vivo. Furthermore, because of the excellent photothermal conversion properties of BiS NRs and laser triggered DTX release from BiS@HSA/DTX mNRs, efficient tumor combinatorial therapy was achieved via concurrent hyperthermia and chemotherapy in mice treated with BiS@HSA/DTX mNRs upon NIR laser irradiation. PMID- 30406648 TI - Evaluation of Heavy- and Medium-Duty On-Road Vehicle Emissions in California's South Coast Air Basin. AB - Emission measurements were collected from heavy-duty (HDVs) and medium-duty vehicles (MDVs) at the Peralta weigh station long-term measurement site near Anaheim, CA, in 2017. Two Fuel Efficiency Automobile Test units sampled elevated and ground-level exhaust vehicles totaling 2 315 measurements. HDVs (1844 measurements) exhibited historical reductions in fuel specific oxides of nitrogen (NOx) from the 2008 measurements (55%) with increased use of exhaust gas recirculation and selective catalytic reduction systems. However, as these technologies have aged, the in-use benefits have declined. Infrared % opacity measurements of tailpipe soot decreased 14% since 2012 with increased diesel particulate filter (DPF) use, DPF longevity, and fleet turnover. Sixty-three percent of the HDV fleet in 2017 was chassis model year 2011+ compared to only 12% in 2012. The observed MDV fleet (471 measurements) was 1.4 years older than the HDV fleet with average NOx 14% higher. A significant reduction in MDV NOx occurred ~2 model years prior to similar HDV reductions (2014 versus 2016 chassis model year). MDV chassis model years 2014+ were able to meet their corresponding NOx laboratory certification standards in-use, whereas HDVs remain slightly above this threshold. Similar MDV NOx emission trends were also observed in data previously collected in Chicago, IL. PMID- 30406649 TI - Importance of the Nucleophilic Property of Tea Polyphenols. AB - Tea is the second most popular beverage in the world after water. Vast accumulative evidence attest that tea consumption may promote human health, such as antioxidant, anti-obesity, and anticancer activities. Therefore, tea phytochemicals have drawn exceeding attention from researchers in structure confirmation, formation mechanism, component clarification, and bioactivity screening of interested constituents. Particularly, most investigations of chemical or biochemical reactions of catechins have concentrated on the B ring of the C6-C3-C6 skeleton. Hence, in this perspective, we reviewed the profound findings of the carbon-carbon (C-C) connection from the unambiguous characterization of novel A-ring addition derivatives of tea catechins, including catechin-carbonyl and catechin-theanine conjugates and the C-C formation mechanisms, and offered our view of the potential effects of catechin-carbonyl interactions on flavor generation and bioactive action in tea. PMID- 30406647 TI - From Catalysis to Cancer: Toward Structure-Activity Relationships for Benzimidazol-2-ylidene-Derived N-Heterocyclic-Carbene Complexes as Anticancer Agents. AB - The promise of the metal(arene) structure as an anticancer pharmacophore has prompted intensive exploration of this chemical space. While N-heterocyclic carbene (NHC) ligands are widely used in catalysis, they have only recently been considered in metal complexes for medicinal applications. Surprisingly, a comparatively small number of studies have been reported in which the NHC ligand was coordinated to the RuII(arene) pharmacophore and even less with an OsII(arene) pharmacophore. Here, we present a systematic study in which we compared symmetrically substituted methyl and benzyl derivatives with the nonsymmetric methyl/benzyl analogues. Through variation of the metal center and the halido ligands, an in-depth study was conducted on ligand exchange properties of these complexes and their biomolecule binding, noting in particular the stability of the M-CNHC bond. In addition, we demonstrated the ability of the complexes to inhibit the selenoenzyme thioredoxin reductase (TrxR), suggested as an important target for anticancer metal-NHC complexes, and their cytotoxicity in human tumor cells. It was found that the most potent TrxR inhibitor diiodido(1,3 dibenzylbenzimidazol-2-ylidene)(eta6-p-cymene)ruthenium(II) 1bI was also the most cytotoxic compound of the series, with the antiproliferative effects in general in the low to middle micromolar range. However, since there was no clear correlation between TrxR inhibition and antiproliferative potency across the compounds, TrxR inhibition is unlikely to be the main mode of action for the compound type and other target interactions must be considered in future. PMID- 30406650 TI - Identification of Spherical and Nonspherical Proteins by a Solid-State Nanopore. AB - The three-dimensional structure of a protein plays an important role in protein dynamics in the biological system of human. By now, it remains a challenge to characterize and quantify the shape of a protein at the single-molecule level. The nanopores, as a novel single-molecule sensor, has been widely applied in many fields such as DNA sequencing and human diseases diagnosis. In this paper, we investigated the translocation of spherelike con.A and the prolate bovine serum albumin (BSA) under an electric field by a solid-state nanopore. By analyzing the ionic current, the con.A and the BSA could be characterized and differentiated due to their intrinsic shape difference. Because the prolate BSA will have the preferred orientations for a higher electric field, when it is residing inside the nanopore, multiple ionic current blockade levels will be observed. While for the spherical con.A, there is only one ionic current blockade level. The method presented here will be potentially applied to fingerprint a single protein as a new method having the features of low cost and high throughput in the near future. PMID- 30406651 TI - Metabolomics of Green-Tea Catechins on Vascular-Endothelial-Growth-Factor Stimulated Human-Endothelial-Cell Survival. AB - Neovascularization causes serious oculopathy related to upregulation of vascular endothelial-growth factor (VEGF) causing new capillary growth via endothelial cells. Green-tea-extract (GTE) constituents possess antiangiogenesis properties. We used VEGF to induce human umbilical-vein endothelial cells (HUVECs) and applied GTE, epigallocatechin gallate (EGCG), and mixtures of different compositions of purified catechins (M1 and M2) to evaluate their efficacies of inhibition and their underlying mechanisms using cell-cycle analysis and untargeted metabolomics techniques. GTE, EGCG, M1, and M2 induced HUVEC apoptosis by 22.1 +/- 2, 20.0 +/- 0.7, 50.7 +/- 8.5, and 69.8 +/- 4.1%, respectively. GTE exerted a broad, balanced metabolomics spectrum, involving suppression of the biosynthesis of cellular building blocks and oxidative-phosphorylation metabolites as well as promotion of the biosynthesis of membrane lipids and growth factors. M2 mainly induced mechanisms associated with energy and biosynthesis suppression. Therefore, GTE exerted mechanisms involving both promotion and suppression activities, whereas purified catechins induced extensive apoptosis. GTE could be a more promising antineovascularization remedy for ocular treatment. PMID- 30406652 TI - Total Synthesis and Absolute Stereochemical Assignment of Microgrewiapine A and Its Stereoisomers. AB - Total synthesis of both enantiomers of (-)-(2 S,3 R,6 S)- and (+)-(2 R,3 S,6 R) microgrewiapine A along with (+)-microcosamine A and (-)-6- epi-microgrewiapine A from chiral 1-(alpha-methylbenzyl)-aziridine-2-carboxylate was accomplished for the first time. Key steps involved in this synthesis include one-pot reductive ring-opening of aziridine, debenzylation, intramolecular N-alkylation to obtain the key piperidine ring, and Julia-Kociensky olefination. The absolute configuration of natural microgrewiapine A is assigned as (+)-(2 R,3 S,6 R), which is opposite to the originally proposed structure by comparing optical rotation data of both synthetic enantiomers. PMID- 30406653 TI - Treating the Poly(3,4-ethylenedioxythiophene):Poly(styrenesulfonate) Surface with Hydroquinone Enhances the Performance of Polymer Solar Cells. AB - The introduction of poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) as a standard hole transport layer greatly increased the efficiency of early organic solar cells. However, because PEDOT:PSS has a metallic property, it can still form a barrier by means of metal-semiconductor contact at its interface with the photoactive layer. In this study, we modified the PEDOT:PSS surface with hydroquinone (HQ) to remove that barrier. HQ treatment of the PEDOT:PSS surface lowered the hole transport barrier at the interface between the PEDOT:PSS and the active layer. In addition, because of the secondary doping effect of HQ, the sheet resistance of the PEDOT:PSS surface decreased by almost 2 orders of magnitude. As a result, the device fabricated with the HQ-modified PEDOT:PSS showed a 28% increase in efficiency compared to the device without HQ treatment. Modifying the PEDOT:PSS surface with HQ solution is an easy way to effectively boost the performance of polymer solar cells. PMID- 30406654 TI - Low-Cost Automatic Sensor for in Situ Colorimetric Detection of Phosphate and Nitrite in Agricultural Water. AB - This study proposed a low-cost sensor for in situ automatic monitoring of phosphate and nitrite in agricultural water environments, involving a series of "Fish-Bite" reservoirs, multiple reagent capsules, and a colorimetric sensor. The Fish-Bite reservoir is an alternative to the pumps, valves, and filters that are widely used for water sample collection and also offers a closed cell for chromogenic reactions afterward. Up to two capsules can be embedded in each reservoir to support chromogenic reactions that use two different reagents in sequence. From the results of calibration tests in the laboratory, the limit of detection was found to be approximately 0.01 mg/L for both phosphate and nitrite, with a linear range of 0.01-1.00 mg/L for phosphate and 0.01-0.20 mg/L for nitrite. Furthermore, an in situ experiment was successfully carried out in an irrigation canal beside farmland to demonstrate the practicability and robustness of the device. The averaged concentrations of phosphate and nitrite were 0.0113 mg/L and 0.0383 mg/L, respectively. The relative deviations were 20.2% and 11.7%, respectively, referred to results obtained by using the standard spectrophotometric methods. With the advantages of being robust, fast, and low cost, this in situ device is promising for the formation of agricultural sensor networks. PMID- 30406656 TI - Fecal Microbiota Responses to Bran Particles Are Specific to Cereal Type and In Vitro Digestion Methods That Mimic Upper Gastrointestinal Tract Passage. AB - Although in vitro studies to identify interactions between food components and the colonic microbiota employ distinct methods to mimic upper gastrointestinal (GI) tract digestion, the effects of differences in protocols on fermentation have not been rigorously addressed. Here, we compared two widely used upper GI tract digestion methods on four different cereal brans in fermentations by fecal microbiota to test the hypotheses that (1) different methods are varyingly efficient in removing accessible starches and proteins from dietary components and (2) these result in cereal-specific differences in fermentation by fecal microbiota. Our results supported both hypotheses, in that the methods differed significantly in bran starch and protein retention and that the effects were cereal-specific. Furthermore, these differences impacted fermentation by the fecal microbiota of healthy donors, altering both short-chain fatty acid production and microbial community composition. These data suggest that digestion methods should be standardized across laboratories for in vitro fiber fermentation studies. PMID- 30406657 TI - Reaction Mechanism for the Hydrogen Evolution Reaction on the Basal Plane Sulfur Vacancy Site of MoS2 Using Grand Canonical Potential Kinetics. AB - We develop the grand canonical potential kinetics (GCP-K) formulation based on thermodynamics from quantum mechanics calculations to provide a fundamental basis for understanding heterogeneous electrochemical reactions. Our GCP-K formulation arises naturally from minimizing the free energy using a Legendre transform relating the net charge of the system and the applied voltage. Performing this macroscopic transformation explicitly allows us to make the connection of GCP-K to the traditional Butler-Volmer kinetics. Using this GCP-K based free energy, we show how to predict both the potential and pH dependent chemistry for a specific example, the hydrogen evolution reaction (HER) at a sulfur vacancy on the basal plane of MoS2. We find that the rate-determining steps in both acidic and basic conditions are the Volmer reaction in which the second hydrogen atom is adsorbed from the solution. Using the GCP-K formulation, we show that the stretched bond distances change continuously as a function of the applied potential. This shows that the main reason for the higher activity in basic conditions is that the transition state is closer to the product, which leads to a more favorable Tafel slope of 60 mV/dec. In contrast if the transition state were closer to the reactant, where the transfer coefficient is less than 0.5 we would obtain a Tafel slope of almost 150 mV/dec. Based on this detailed understanding of the reaction mechanism, we conclude that the second hydrogen at the chalcogenide vacant site is the most active toward the hydrogen evolution reaction. Using this as a descriptor, we compare it to the other 2H group VI metal dichalcogenides and predict that vacancies on MoTe2 will have the best performance toward HER. PMID- 30406655 TI - The High Chemofidelity of Metal-Catalyzed Hydrogen Atom Transfer. AB - The implementation of any chemical reaction in a structurally complex setting ( King , S. M. J. Org. Chem. 2014 , 79 , 8937 ) confronts structurally defined barriers: steric environment, functional group reactivity, product instability, and through-bond electronics. However, there are also practical barriers. Late stage reactions conducted on small quantities of material are run inevitably at lower than optimal concentrations. Access to late-stage material limits extensive optimization. Impurities from past reactions can interfere, especially with catalytic reactions. Therefore, chemical reactions on which one can rely at the front lines of a complex synthesis campaign emerge from the crucible of total synthesis as robust, dependable, and widely applied. Trost conceptualized "chemoselectivity" as a reagent's selective reaction of one functional group or reactive site in preference to others ( Trost , B. M. Science 1983 , 219 , 245 ). Chemoselectivity and functional group tolerance can be evaluated quickly using robustness screens ( Collins , K. D. Nat. Chem. 2013 , 5 , 597 ). A reaction may also be characterized by its "chemofidelity", that is, its reliable reaction with a functional group in any molecular context. For example, ketone reduction by an electride (dissolving metal conditions) exhibits high chemofidelity but low chemoselectivity: it usually works, but many other functional groups are reduced at similar rates. Conversely, alkene coordination chemistry effected by pi Lewis acids can exhibit high chemoselectivity ( Trost , B. M. Science 1983 , 219 , 245 ) but low chemofidelity: it can be highly selective for alkenes but sensitive to the substitution pattern ( Larionov , E. Chem. Commun. 2014 , 50 , 9816 ). In contrast, alkenes undergo reliable, robust, and diverse hydrogen atom transfer reactions from metal hydrides to generate carbon-centered radicals. Although there are many potential applications of this chemistry, its functional group tolerance, high rates, and ease of execution have led to its rapid deployment in complex synthesis campaigns. Its success derives from high chemofidelity, that is, its dependable reactivity in many molecular environments and with many alkene substitution patterns. Metal hydride H atom transfer (MHAT) reactions convert diverse, simple building blocks to more stereochemically and functionally dense products ( Crossley , S. W. M. Chem. Rev. 2016 , 116 , 8912 ). When hydrogen is returned to the metal, MHAT can be considered the radical equivalent of Bronsted acid catalysis-itself a broad reactivity paradigm. This Account summarizes our group's contributions to method development, reagent discovery, and mechanistic interrogation. Our earliest contribution to this area-a stepwise hydrogenation with high chemoselectivity and high chemofidelity-has found application to many problems. More recently, we reported the first examples of dual-catalytic cross couplings that rely on the merger of MHAT cycles and nickel catalysis. With time, we anticipate that MHAT will become a staple of chemical synthesis. PMID- 30406658 TI - Breaking the Magic Border of One Second for Slow Magnetic Relaxation of Cobalt Based Single Ion Magnets. AB - Instead of assembling complex clusters and/or expensive lanthanide-based systems as single ion magnets, we are focusing on mononuclear cobalt(II) systems among which the complex under study, [Co( pydca)( dmpy)]2.H2O (1), shows a field supported slow magnetic relaxation on the order of seconds at low temperature ( pydca = pyridine-2,6-dicarboxylato, dmpy = 2,6-dimethanolpyridine). The low frequency relaxation time is as slow as tau(LF) = 1.35(6) s at T = 1.9 K and BDC = 0.4 T. The properties of 1 are compared to the previously reported nickel and copper analogues which were the first examples of single ion magnets in the family of Ni(II) and Cu(II) complexes. PMID- 30406659 TI - Ferroelectric Polarization Rotation in Order-Disorder-Type LiNbO3 Thin Films. AB - The direction of ferroelectric polarization is prescribed by the symmetry of the crystal structure. Therefore, rotation of the polarization direction is largely limited, despite the opportunity it offers in understanding important dielectric phenomena such as piezoelectric response near the morphotropic phase boundaries and practical applications such as ferroelectric memory. In this study, we report the observation of continuous rotation of ferroelectric polarization in order disorder-type LiNbO3 thin films. The spontaneous polarization could be tilted from an out-of-plane to an in-plane direction in the thin film by controlling the Li vacancy concentration within the hexagonal lattice framework. Partial inclusion of monoclinic-like phase is attributed to the breaking of macroscopic inversion symmetry along different directions and the emergence of ferroelectric polarization along the in-plane direction. PMID- 30406660 TI - Cellular Uptake and Intracellular Antioxidant Activity of Zein/Chitosan Nanoparticles Incorporated with Quercetin. AB - In this work, zein/chitosan nanoparticles (ZCPs-Q) were developed for encapsulating quercetin to overcome its lower water solubility and instability, and to concomitantly enhance its cellular uptake and intracellular antioxidant activity. This strategy enhanced quercetin solubility 753.6 and 9.95 times in water and PBS (7.4), respectively, and quercetin encapsulated in ZCPs remained stable after UV irradiation and heat treatment. ZCPs-Q could significantly attenuate AAPH induced erythrocyte hemolysis through the inhibition of ROS generation. It restored intracellular antioxidant enzyme (SOD and GSH-Px) activities to normal levels and inhibited intracellular malondialdehyde (MDA) formation. Simultaneously, ZCPs-Q showed a strong antioxidant activity in HepG2 cells with an EC50 value of 31.18 MUg/mL, which was lower than free quercetin's 41.02 MUg/mL. ZCPs enhanced the uptake efficiency of quercetin in Caco-2 cells, which contributed to the improvement of cellular antioxidant activities (CAA) evaluated with the CAA assay and AAPH-induced erythrocyte hemolysis assay. The designed route is particularly suitable for the encapsulation of water-insoluble nutraceuticals and for enhancing cell uptake and CAA. PMID- 30406661 TI - First Report of Plant-Derived beta-Sitosterol with Antithrombotic, in Vivo Anticoagulant, and Thrombus-Preventing Activities in a Mouse Model. AB - Inhibitors of thrombin, a key enzyme in the blood coagulation cascade, are of great interest because of their selective specificity and effectiveness in anticoagulation therapy against cardiovascular disorders. The natural soybean phytosterol, beta-sitosterol (BSS) demonstrated anticoagulant activity by dose dependent inhibition of thrombin in an uncompetitive manner with a Ki value of 0.267 MUM as well as by partial inhibition of thrombin-catalyzed platelet aggregation with a half-maximal inhibitory concentration (IC50) value of 10.45 +/ 2.88 MUM against platelet-rich plasma and 9.2 +/- 1.2 MUM against washed platelets. An in silico study indicated binding of BSS to thrombin, which was experimentally verified by spectrofluorometric and isothermal calorimetric analyses. Under in vitro conditions, BSS demonstrated thrombolytic activity by activating plasminogen, albeit it is devoid of protease (fibrinogenolytic) activity. BSS was noncytotoxic to mammalian cells, nonhemolytic, demonstrated its in vivo anticoagulant activity when administered orally, and inhibited k carrageen-induced thrombus formation in the tails of mice. Our results suggest that dietary supplementation of BSS may help to prevent thrombosis-associated cardiovascular disorders. PMID- 30406662 TI - Base-Mediated Direct Transformation of N-Propargylamines into 2,3,5 Trisubstituted 1 H-Pyrroles. AB - An efficient and base-mediated intramolecular cyclization of N-propargylamines for the synthesis of structurally diversified pyrroles in high yield has been described. The developed methodology is broadly applicable and is tolerated by a variety of functional groups. Key intermediates of natural product discoipyrrole C as well as HMG-CoA-reductase inhibitor have been successfully synthesized using developed chemistry. The proposed mechanism was supported by control experiments. PMID- 30406663 TI - Catalytic [3 + 3]-Cycloaddition for Regioselective Preparation of Tricyclic Oxadiazines. AB - Agrochemically useful and structurally important, functionally rich tricyclic oxadiazines were synthesized in very good yields with excellent diastereoselectivities through a catalytic [3 + 3]-cycloaddition from the readily available p-quinols, azomethine imines, and a catalytic amount of Bronsted base (KO tBu). PMID- 30406664 TI - Topological Insulator-Based van der Waals Heterostructures for Effective Control of Massless and Massive Dirac Fermions. AB - Three dimensional (3D) topological insulators (TIs) are an important class of materials with applications in electronics, spintronics and quantum computing. With the recent development of truly bulk insulating 3D TIs, it has become possible to realize surface dominated phenomena in electrical transport measurements e.g. the quantum Hall (QH) effect of massless Dirac fermions in topological surface states (TSS). However, to realize more advanced devices and phenomena, there is a need for a platform to tune the TSS or modify them e.g. gap them by proximity with magnetic insulators, in a clean manner. Here we introduce van der Waals (vdW) heterostructures in the form of topological insulator/insulator/graphite to effectively control chemical potential of the TSS. Two types of gate dielectrics, normal insulator hexagonal boron nitride (hBN) and ferromagnetic insulator Cr2Ge2Te6 (CGT) are utilized to tune charge density of TSS in the quaternary TI BiSbTeSe2. hBN/graphite gating in the QH regime shows improved quantization of TSS by suppression of magnetoconductivity of massless Dirac fermions. CGT/graphite gating of massive Dirac fermions in the QH regime yields half-quantized Hall conductance steps and a measure of the Dirac gap. Our work shows the promise of the vdW platform in creating advanced high quality TI-based devices. PMID- 30406665 TI - Loss of SETD2 Induces a Metabolic Switch in Renal Cell Carcinoma Cell Lines toward Enhanced Oxidative Phosphorylation. AB - SETD2, a histone H3 lysine trimethyltransferase, is frequently inactivated and associated with recurrence of clear cell renal cell carcinoma (ccRCC). However, the impact of SETD2 loss on metabolic alterations in ccRCC is still unclear. In this study, SETD2 null isogenic 38E/38F clones derived from 786-O cells were generated by zinc finger nucleases, and subsequent metabolic, genomic, and cellular phenotypic changes were analyzed by targeted metabolomics, RNA sequencing, and biological methods, respectively. Our results showed that compared with parental 786-O cells, 38E/38F cells had elevated levels of MTT/Alamar blue levels, ATP, glycolytic/mitochondrial respiratory capacity, citrate synthase (CS) activity, and TCA metabolites such as aspartate, malate, succinate, fumarate, and alpha-ketoglutarate. The 38E/38F cells also utilized alternative sources beyond pyruvate to generate acetyl-CoA for the TCA cycle. Moreover, 38E/38F cells showed disturbed gene networks mainly related to mitochondrial metabolism and the oxidation of fatty acids and glucose, which was associated with increased PGC1alpha, mitochondrial mass, and cellular size/complexity. Our results indicate that SETD2 deficiency induces a metabolic switch toward enhanced oxidative phosphorylation in ccRCC, which can be related to PGC1alpha-mediated metabolic networks. Therefore, this current study lays the foundation for the further development of a global metabolic analysis of cancer cells in individual patients, which ultimately will have significant potential for the discovery of novel therapeutics and precision medicine in SETD2 inactivated ccRCC. PMID- 30406666 TI - Personality traits and cognitive function in old-adults with type-2 diabetes. AB - OBJECTIVES: Personality may constitute an important domain of influence on cognitive function in old-adults. We assessed the relationship of personality traits and cognitive performance in individuals with Type-2 Diabetes (T2D), and explored possible mediators. METHOD: The sample includes 377 dementia-free subjects with T2D participating in the Israel Diabetes and Cognitive Decline study who underwent assessment of cognition and personality (mean age 72 +/- 4y; 42% females). We assessed the relationships of personality traits with episodic memory, semantic categorization, attention/working memory, executive function and overall cognition using linear regression models adjusting for age, education, sex, BMI, T2D duration, Hemoglobin A1C (HbA1C), hypertension, c-reactive protein, total- to HDL-cholesterol ratio and ApoEE4 genotype. A post-hoc mediation analysis was conducted with HbA1C, proportion of days covered (PDC) by T2D prescription claims and depressive symptoms. RESULTS: After adjustment for multiple covariates, high neuroticism levels were associated with poorer performance overall (beta= -0.16 +/- 0.05; p = 0.001) and with poorer episodic memory, attention/working memory, and semantic categorization (beta= -0.14 +/- 0.05; p = 0.007, beta= -0.12 +/- 0.05; p = 0.017 and beta= -0.12 +/- 0.05; p = 0.018, respectively). High scores on openness to experience were associated with better global cognition (beta = 0.11 +/- 0.05; p = 0.026), executive functions (beta = 0.13 +/- 0.05; p = 0.013) and semantic categorization (beta = 0.17 +/- 0.05; p = 0.001, respectively). Depressive symptoms mediated the association of neuroticism with executive function, and the association of openness with executive function and overall cognition. CONCLUSION: Personality may play an important role in cognitive health among elderly subjects with T2D. Future studies should address the mechanisms underlying these relationships and specifically the potential role of depressive symptoms which may be in the causal pathway between personality traits and cognitive outcomes. PMID- 30406667 TI - How do inpatient psychiatric nurses make sense of and respond to behaviours in dementia? An Interpretative Phenomenological Analysis. AB - OBJECTIVES: Existing literature demonstrates that nurses' understanding of behaviours in dementia influences their responses to persons with dementia. However, there is limited research on the psychological processes involved in how nurses make sense of the behaviours and how these impact on responding, and a dearth of such literature from inpatient acute dementia settings. This study explored how inpatient psychiatric nurses make sense of and respond to behaviours in dementia. METHOD: This study employed Interpretative Phenomenological Analysis (IPA), a qualitative method that explores in detail how participants make sense of their experiences. Eight inpatient psychiatric nurses were recruited from two inpatient services within a National Health Service Mental Health Trust. Semi structured interviews were conducted to gain an in depth understanding of their experience. Transcripts of the interviews were then analysed using IPA. RESULTS: Four interrelated themes were identified: 'Effort to sense make', 'Pressures of the organisation', 'Balancing personal and professional selves: The underlying emotional connection'; and '"Looking back on it..."'. CONCLUSIONS: The study highlighted that sense making is a dynamic process, which occurs through a range of psychological processes and can change moment by moment dependent on the influences on the nurse. It demonstrated that nurses need to be supported to move flexibly through a range of emotional connections, which were found to underlie the negotiations made at work and influence sense making and responding. Nurses may benefit from space to reflect and formulate their understanding of clients, but further research is required to determine the effectiveness of this. PMID- 30406668 TI - Is the association between social network types, depressive symptoms and life satisfaction mediated by the perceived availability of social support? A cross sectional analysis using the Canadian Longitudinal Study on Aging. AB - OBJECTIVES: The objectives of this study were to examine: 1) whether the relationship between social network types, depressive symptoms and life satisfaction is mediated by different types of perceived social support; and, 2) whether social support plays a mediational role for married versus unmarried older adults. METHODS: The study was based on national, baseline data (Tracking Cohort) from the Canadian Longitudinal Study on Aging for participants aged 65 to 85 (N = 8782). Five social network types derived from cluster analysis were used as predictors in the mediation analyses, with the four social support subscales of the Medical Outcomes Survey (MOS) Social Support Survey (tangible, emotional, positive social interactions, and affectionate) included as mediators, and depressive symptoms and life satisfaction as outcome variables. Socio-demographic and physical health variables were included as covariates. RESULTS: Significant indirect effects emerged, with less diverse social network structures generally associated with less social support which, in turn, was related to more depressive symptoms and lower life satisfaction. However, different findings emerged for different types of social support, for participants who were married and unmarried, and for depressive symptoms versus life satisfaction. CONCLUSION: Our findings suggest that restricted social networks that are reflective of social isolation, as well as those that are intermediate in terms of their diversity can create gaps in perceived social support and, consequently, can negatively impact mental health and life satisfaction. PMID- 30406669 TI - Tephrosia apollinea seed: a new rich source of essential polyunsaturated fatty acids, tocopherols, sterols, and squalene. AB - Tephrosia apollinea is a legume species, native to southwest Asia and northeast Africa, rich in bioactive flavonoids (hydrophilic compounds). T. apollinea seeds were not considered previously as a potential source of lipophilic compounds such as: essential fatty acids, tocopherols, sterols, and squalene, hence, the present study were performed. The oil yield in T. apollinea seeds amounted to 11.8% dw. The T. apollinea seed oil was predominated by the polyunsaturated fatty acids - linoleic (26.8%) and alpha-linolenic (22.7%). High levels were recorded also for oleic (27.6%) and palmitic (14.9%) acids. Four tocopherols and one tocotrienol, with the domination of gamma-tocopherol (98%) were identified in T. apollinea seed oil. The beta-sitosterol (59%), Delta5-stigmasterol (21%) and campesterol (9%) were detected as main sterols in T. apollinea seed oil. The total content of tocochromanols, sterols, carotenoids and squalene in the T. apollinea seed oil was 256.7, 338.1, 12.5 and 1103.8 mg/100 g oil, respectively. T. apollinea seeds oil, due to the high concentration of lipophilic bioactive compounds can find a potential application in the food, cosmetic and pharmaceutical industry. PMID- 30406670 TI - Social factors relating to depression among older people in Japan: analysis of longitudinal panel data from the AGES project. AB - OBJECTIVES: Preventing the onset of depression among older people in Japan requires clarifying the social determinants of depression by using longitudinal data, while also taking biological and psychological factors into account. Identification of such determinants may enable more active intervention through social policy. We aimed to reveal the social factors related to depression in Japan's older people and consider associated policy implications. METHOD: Panel data obtained from a longitudinal survey (Wave 1 to Wave 2) of 3464 elderly subjects, aged 65 years or more, as part of the Aichi Gerontological Evaluation Study (AGES) project was employed. The outcome variable was depression, as evaluated by the Geriatric Depression Scale. Frequency of meeting with friends, social support, hobbies, participation in organizations, life events, illness, self-rated health, instrumental activities of daily living, and sense of coherence were entered as explanatory variables within a logit model for each gender. RESULTS: Of the subjects without mental illness or depression at Wave 1, 14% had become depressed by Wave 2. In both men and women, life events predicted increased odds of depression, while sense of coherence predicted reduced odds. The frequency of meeting with friends, hobbies, and self-rated health predicted reduced odds of depression in men, while age predicted increased odds in women. CONCLUSION: Overall, social interaction is important for preventing depression in Japan, and that the establishment of a system capable of promoting social interaction and providing care to the elderly during life events may be a useful social policy approach to preventing depression. PMID- 30406671 TI - Neogenkwanine I from the flower buds of Daphne genkwa with its stereostructure confirmation using quantum calculation profiles and antitumor evaluation. AB - Neogenkwanine I (1), a new daphnane-type diterpene with 4,7-ether group, along with four known ones (2-5), were isolated from Daphne genkwa. The structure including absolute configurations of 1 was established on the basis of NMR, 13C NMR and ECD calculations and CD exciton chirality analysis. 13C-NMR and ECD calculations of daphnane-type diterpenes were reported here for the first time. All of the diterpenes were screened for their cytotoxic activities against MCF-7 and Hep3B cell lines. The cytotoxicity structure- activity relationship of compounds was illustrated with the absence of ortho-ester group of daphnane-type diterpenes. PMID- 30406672 TI - Neurons in ventral tegmental area tonically inhibit sympathetic outflow to brown adipose tissue; possible mediation of thermogenic signals from lateral habenula. AB - The lateral habenula (LHb), a nucleus involved in the response to salient, especially adverse, environmental events, is implicated in brown adipose tissue (BAT) thermogenesis caused by these events. LHb-elicited thermogenesis involves a neural pathway to the lower brainstem sympathetic control center in the medullary raphe. There are no direct connections from the LHb to the medullary raphe. LHb mediated behavioral responses involve inhibitory control over the dopamine neurons in the ventral tegmental area (VTA), mediated via an excitatory drive from the LHb to GABAergic neurons in the tail of the VTA. We hypothesized that inhibition of the VTA is also involved in LHb-mediated BAT thermogenesis. To test this hypothesis, inhibition of neurons in the VTA with muscimol increased BAT sympathetic nerve discharge by 22.0+/-9.2 dBMUV (n=24, p<0.0001) and BAT temperature by 1.2+/-0.1 oC (p<0.001). This response was abolished by inhibition of the medullary raphe neurons with muscimol. BAT thermogenesis initiated with focal injections of bicuculline into the LHb was reversed by subsequent blockade of GABAA receptors in the VTA with bicuculline. These results suggest that, at least in anesthetized rats, neurons in the VTA tonically inhibit BAT thermogenesis via a link, presently unknown, to the medullary raphe. Removal of this VTA-initiated inhibition is an important mechanism whereby LHb neurons activate BAT thermogenesis. PMID- 30406673 TI - Gender differences in patient and system delay for primary percutaneous coronary intervention: current trends in a Swiss ST-segment elevation myocardial infarction population. AB - BACKGROUND:: Women with ST-segment elevation myocardial infarction (STEMI) experience greater delays for percutaneous coronary intervention-facilitated reperfusion than men. Whether women and men benefit equally from current strategies to reduce ischaemic time and whether there are gender differences in factors determining delays is unclear. METHODS:: Patient delay (symptom onset to first medical contact) and system delay (first medical contact to percutaneous coronary intervention-facilitated reperfusion) were compared between women ( n=967) and men ( n=3393) in a Swiss STEMI treatment network. Trends from 2000 to 2016 were analysed, with additional comparisons between three time periods (2000 2005, 2006-2011 and 2012-2016). Factors predicting delays and hospital mortality were determined by multivariate regression modelling. RESULTS:: Female gender was independently associated with greater patient delay ( P=0.02 vs. men), accounting for a 12% greater total ischaemic time among women in 2012-2016 (median 215 vs. 192 minutes, P<0.001 vs. men). From 2000-2005 to 2012-2016, median system delay was reduced by 18 and 25 minutes in women and men, respectively ( P<0.0001 for trend, P=n.s. for gender difference). Total occlusion of the culprit artery, stent thrombosis, a Killip class of 3 or greater, and presentation during off hours predicted delays in men, but not in women. A Killip class of 3 or greater and age, but not gender or delays, were independently associated with hospital mortality. CONCLUSIONS:: STEMI-related ischaemic time in women remains greater than in men due to persistently greater patient delays. In contrast to men, clinical signs of ongoing chest discomfort do not predict delays in women, suggesting that female STEMI patients are less likely to attribute symptoms to a condition requiring urgent treatment. PMID- 30406674 TI - Is Antibiotic Prophylaxis Necessary Before Dental Procedures in Patients Post Total Ankle Arthroplasty? AB - BACKGROUND:: The need for dental antibiotic prophylaxis after orthopedic surgery remains unclear. Current recommendations are based on patients with total hip and total knee arthroplasties. We investigated available evidence regarding the need for dental antibiotic prophylaxis in patients post foot and ankle surgery, specifically total ankle arthroplasty. Additionally, we examined the microbiology behind the risk of transient bacteremia from dental procedures and whether this leads to an increased risk for postoperative infection in foot and ankle surgery. METHODS:: We performed a MEDLINE literature review of English articles between 1980 and 2018 on patients with prosthetic joints undergoing dental work, and studies evaluating hematogenous prosthetic joint infection (PJI) and dental antibiotic prophylaxis. We additionally included articles on PJI post total ankle arthroplasty, as well as committee guidelines. RESULTS:: There is no literature at present that evaluates transient bacteremia with dental procedures in patients following foot and ankle surgery. The data on this topic are isolated to PJI rates in the context of hip and total knee arthroplasty. This is of particular interest as rates of total ankle arthroplasty PJI have been reported to be 2- to 4-fold higher than in hip and total knee arthroplasty. CONCLUSION:: The concern for postoperative infection due to transient bacteremia without dental antibiotic prophylaxis can be extrapolated to patients undergoing foot and ankle surgeries. Some data suggest that oral cavity bacteria can seed a prosthetic joint, though no clear relationship has been demonstrated. Similar risk factors have been identified between hip and knee PJI and total ankle arthroplasty. In light of the absence of scrutiny of and guidelines on this topic in foot and ankle surgery, it may be advisable to apply similar principles to decision-making in patients after foot and ankle surgery. LEVEL OF EVIDENCE:: Level III, systematic review. PMID- 30406675 TI - Iridoid glycosides from the fruits of Cornus officinalis. AB - Four new iridoid glycosides named cornusphenosides A-D (1-4) were isolated from an ethanol extract of the fruits of Cornus officinalis (shan zhu yu). The structures of these compounds were elucidated on the basis of spectroscopic data (UV, IR, HRESIMS, and 1D and 2D NMR) and chemical evidence. The neuroprotective effects of compounds 1-4 were also assessed in vitro.GRAPHICAL ABSTRACT[Formula: see text]. PMID- 30406676 TI - A guide for proper utilisation of stable isotope reference materials. AB - Many scientific publications about stable isotope ratios suffer from flawed practices regarding calibration and normalisation of raw delta values in conjunction with prescribed delta values of reference materials. Violations of the identical treatment principle with regards to samples and standards (i.e. reference materials) and lack of adherence to SI-mandated and IUPAC-recommended nomenclature exacerbate the widespread problem of lackadaisical analytical practice and reporting. Science is supposed to strive for exactness, whereas ambiguity and jargon confound interdisciplinary communication. This contribution aims to expose typical misconceptions and avoidable errors and offers guidance toward the reproducible generation of isotope data, isotopic scale normalisation, and proper data reporting. We offer a comprehensive overview of sources of light stable isotope reference materials to best match sample matrices encountered by stable isotope practitioners with chemically similar reference materials. PMID- 30406677 TI - Violence against health-care workers in a conflict affected city. AB - The problem of aggression towards health care staff is global. It negatively impacts on their psychological and physical well-being, and on their performance. This study was set to explore the exposure of healthcare personnel city to different forms of violence and the influence of this violence on their work and life. A sample of 700 healthcare workers was collected from six major hospitals and 20 primary health care centers in Baghdad. The questionnaire inquired about exposure to any sort of violence including insult, assaults, and displacement, being arrested, kidnapped, and intentionally injured or threatened at the workplace. More than 85% of respondents reported exposure to violence. The most important reason for violence was the poor medical services and lack of hospital supplies (22.1%). Young doctors were significantly more exposed to violence, especially verbal, mostly during the day. A significant association was seen between exposure to physical violence, male gender and short duration of experience. The most significant source of violence was the patient's relatives. There is an overwhelming surge of violence against health workers that may adversely reflect on their performance. Passing legislation that protects health workers against violence is an urgent need at this time of unrest. PMID- 30406678 TI - Survival after refractory cardiogenic shock is comparable in patients with Impella and veno-arterial extracorporeal membrane oxygenation when adjusted for SAVE score. AB - OBJECTIVES:: Survival after different short-term mechanical circulatory support is difficult to compare because various systems are used and patient disease severity is most often not adjusted for. This study compares the outcome after the use of Impella and veno-arterial extracorporeal membrane oxygenation (VA ECMO) in refractory cardiogenic shock, adjusted for disease severity through the survival after the VA-ECMO (SAVE) score. METHODS:: Patients with refractory shock treated with either VA-ECMO or Impella between January 2003 and August 2015 were included. Data were analysed to assess short and long-term survival and complications. The SAVE score was calculated for the two groups and outcome was compared adjusted for the SAVE score. RESULTS:: There was no difference between VA-ECMO patients ( n=46) and Impella patients ( n=48) in mean age or renal failure. ECMO patients were more often intubated and had lower diastolic blood pressure at device implantation. ECMO patients had a lower SAVE score (-0.4 (6.5)) compared to Impella patients (4.1 (5.4)). There was no difference in intensive care unit survival between ECMO patients 65% (52-80) or Impella patients 63% (55-79), or long-term survival between groups. When stratified into worse (III-IV) or better SAVE class (I-II) there was no difference in survival between the groups. CONCLUSIONS:: Short and long-term survival is not measurably different among patients treated with Impella or VA-ECMO due to refractory cardiogenic shock, after adjustment for disease severity through the SAVE score. PMID- 30406679 TI - Awareness of disease in Alzheimer's disease: what do patients realize about their own condition? AB - OBJECTIVE: We aim to assess different objects of awareness of disease of people with Alzheimer's disease (AD) in mild and moderate stages Method: Semi-structured interviews were conducted with 34 participants with AD and qualitative analyses were used to analyze the participants' reports. RESULTS: Cognitive impairment was the most peserved area of awareness. The participants' explanations were mainly categorized as biological/genetic and psychosocial causes. Also, awareness of social/emotional functioning and interpersonal relationships were generally well preserved in this group. Among those who noticed some alterations in social life, there were reports of the feeling of being exposed and how some cognitive symptoms interfere with their functioning. In the emotional state domains, most of the participants reported more sadness than before the onset of dementia. Although most participants noticed a change in routine and the impact on daily life, many did not notice the need of help for general tasks. CONCLUSION: Our results underpin that most people with AD were able to provide their own subjective report of their experience of living with a disease. Participants' self-reports demonstrated the differences across domains, and this information may contribute to a better understanding of awareness of disease in AD. PMID- 30406680 TI - A computational study of the EN 1078 impact test for bicycle helmets using a realistic subject-specific finite element head model. AB - In the present study, the free fall impact test in accordance with the EN1078 standard for certification of bicycle helmets is replicated using numerical simulations. The impact scenario is simulated using an experimentally validated, patient-specific head model equipped with and without a bicycle helmet. Head accelerations and intracranial biomechanical injury metrics during the impacts are recorded. It is demonstrated that wearing the bicycle helmet during the impact reduces biomechanical injury metrics, with the biggest reduction seen in the metric for skull fracture. PMID- 30406682 TI - The detrimental effect of academic procrastination on subsequent grades: the mediating role of coping over and above past achievement and working memory capacity. AB - BACKGROUND: Academic procrastination is common among university students and its effect on their achievement is worrisome. Although procrastination is often depicted as self-regulation failure, research still needs to examine the self regulatory mechanisms involved in the relationship between procrastination and achievement. OBJECTIVES: In this prospective study, we sought to (a) unravel the unique effect of academic procrastination on university grades, (b) examine the mediating role of task-oriented and disengagement-oriented coping as a self regulatory pathway toward achievement, (c) control for the potential confounding influence of past achievement and working memory capacity. METHODS: A sample of 258 university students completed self-report measures of academic procrastination and coping, and performed tests of working memory. Their semester grade point average was collected at the end of the semester. RESULTS: Results of structural equation modeling showed that academic procrastination negatively predicted subsequent academic achievement, even after controlling for high school achievement and working memory capacity. Furthermore, indirect effects revealed that task- and disengagement-oriented coping explained 70% of the total effect. CONCLUSION: These findings outline that the effect of academic procrastination cannot be reduced to a history of academic difficulties or limited cognitive ability and that coping plays an important role in the procrastination - achievement relationship. PMID- 30406681 TI - Mindfulness and psychoeducation to manage stress in amnestic mild cognitive impairment: A pilot study. AB - OBJECTIVES: Amnestic mild cognitive impairment (aMCI) often corresponds to the prodromal stage of Alzheimer disease (AD). The aMCI stage represents a crucial time window to apply preventive interventions in an attempt to delay cognitive decline. Stress, one of AD's modifiable risk factors frequently co-occurring with aMCI, stands out as a key intervention target. The goal of this study was to assess the impacts of two non-pharmacological interventions, mindfulness and psychoeducation, on stress at the psychological and physiological levels among aMCI older adults. METHODS: Forty-eight aMCI participants were randomized between a mindfulness-based intervention (MBI) and a psychoeducation-based intervention (PBI) for eight weekly sessions. Anxiety symptoms, perceived stress levels, cortisol awakening response (CAR), and coping strategies were assessed pre- and post-intervention. Mindfulness attitudes and time dedicated to at-home meditative practices were evaluated in the MBI group. RESULTS: The main results revealed a slight reduction of the CAR among MBI participants who practiced meditation at home the most and a decrease in perceived stress levels in the PBI group. Both interventions enhanced problem-focused coping strategies. CONCLUSION: In sum, this pilot study supports the potential of MBI and PBI to reduce stress at the physiological and psychological level, respectively, and increase coping strategies in older adults at risk for AD. PMID- 30406683 TI - Efficacy and Safety of Microneedling for the Treatment of Cutaneous Warts. PMID- 30406684 TI - Combining molecular docking and molecular dynamics studies for modelling Staphylococcus aureus MurD inhibitory activity. AB - The ATP-dependent bacterial MurD enzyme catalyses the formation of the peptide bond between cytoplasmic intermediate UDP-N-acetylmuramoyl-L-alanine and D glutamic acid. This is essential for bacterial cell wall peptidoglycan synthesis in both Gram-positive and Gram-negative bacteria. MurD is recognized as an important target for the development of new antibacterial agents. In the present study we prepared the 3D-stucture of the catalytic pocket of the Staphylococcus aureus MurD enzyme by homology modelling. Extra-precision docking, binding free energy calculation by the MM-GBSA approach and a 40 ns molecular dynamics (MD) simulation of 2-thioxothiazolidin-4-one based inhibitor $1 was carried out to elucidate its inhibition potential for the S. aureus MurD enzyme. Molecular docking results showed that Lys19, Gly147, Tyr148, Lys328, Thr330 and Phe431 residues are responsible for the inhibitor-protein complex stabilization. Binding free energy calculation revealed electrostatic solvation and van der Waals energy components as major contributors for the inhibitor binding. The inhibitor modelled S. aureus protein complex had a stable conformation in response to the atomic flexibility and interaction, when subjected to MD simulation at 40 ns in aqueous solution. We designed some molecules as potent inhibitors of S. aureus MurD, and to validate the stability of the designed molecule D1-modelled protein complex we performed a 20 ns MD simulation. Results obtained from this study can be utilized for the design of potent S. aureus MurD inhibitors. PMID- 30406685 TI - Effectiveness of denosumab on back pain-related disability and quality-of-life in patients with vertebral fragility fractures. AB - BACKGROUND: Denosumab is a fully human IgG2 monoclonal antibody that, neutralizing the receptor activator of nuclear factor kappa-Beta ligand (RANKL), inhibits the osteoclast-mediated bone resorption. It is yet to be defined if denosumab can reduce osteoporosis-related disability and improve health-related quality-of-life (HRQoL) in patients with fragility fractures. OBJECTIVE: To assess the effectiveness of denosumab in reducing back pain related disability and improving HRQoL in osteoporotic post-menopausal women with vertebral fractures. RESEARCH DESIGN AND METHODS: A real practice prospective study was carried out, enrolling women over 50 years with a post-menopausal osteoporosis that experienced at least one vertebral fracture receiving subcutaneous denosumab (60 mg, every 6 months), calcium carbonate (500-1000 mg/day) and cholecalciferol (800 IU/day) for 1 year. Back pain related disability was assessed as the primary outcome using the Spine Pain Index (SPI); secondary outcomes were: SF-12 (Physical Health Composite Score, PCS, and Mental Health Composite Score, MCS), and EuroQol-5D (EuroQol-5D-3L index and EuroQol-Visual Analog Scale, EQ-VAS). All outcome measures were assessed at baseline (T0), after 6 months (T1), and after 12 months (T2) of treatment. Trabecular Bone Score (TBS), lumbar spine (LS) and femoral neck (FN) BMD at T0 and T2 were also evaluated. RESULTS: This study included 140 post-menopausal women, mean age = 70.60 (SD = 8.81) years. There were statistically significant differences after 12 months (T2-T0) in all outcomes assessed: SPI (p < 0.001), SF-12 PCS (p < 0.001), SF-12 MCS (p < 0.001), EQ-5D-3L index (p = 0.039), and EQ-VAS (p = 0.003). Moreover, there was a significant improvement of both LS BMD (p < 0.001) and FN BMD (p < 0.001). No local or systemic adverse events, including new vertebral fractures, osteonecrosis of the jaw and atypical femur fractures, were reported. CONCLUSIONS: The data demonstrated that denosumab was effective in reducing back pain related disability and in improving HRQoL in post-menopausal women with vertebral fractures. PMID- 30406686 TI - Naringenin prevents doxorubicin-induced toxicity in kidney tissues by regulating the oxidative and inflammatory insult in Wistar rats. AB - This study is undertaken to investigate the effects of naringenin on doxorubicin- (Dox) induced nephrotoxicity in Wistar rats. Dox 10 mg/kg body weight was administered intraperitoneally once and naringenin 50 and 100 mg/kg body weight was administered orally daily for 21 d. Dox-induced oxidative stress lead to steep elevation in blood urea nitrogen (BUN), creatinine, lactate dehydrogenase (LDH), and kidney injury molecule-1 (KIM-1), compared to control, treatment with naringenin preserved kidney functions. With Dox treatment significant decrease in antioxidant enzymes with increase in malondialdehyde (MDA) compared to control was observed. Naringenin treatment reversed these values compared to Dox in kidney tissue. Dox treatment showed increased tissue nitric oxide levels naringenin treatment decreased nitric oxide (NO) in kidney tissue. Furthermore, Dox-induced inflammatory burst as indicated by up-regulation of nuclear factor kappaB (NF-kappaB), tumour necrosis factor-alpha (TNF-alpha) tissue levels and prostaglandin-E2 (PGE-2). All such events were normalised back to normal by naringenin treatment. PMID- 30406687 TI - A new formulation of levothyroxine engineered to meet new specification standards. AB - BACKGROUND: Small variations in the dose of levothyroxine have been associated with marked variations in thyroid function in people with hypothyroidism. Accordingly, regulators have identified levothyroxine as a "narrow therapeutic index" drug subject to more stringent regulations compared with other drugs, in terms of the accuracy and stability of the amount of active drug in each tablet (typically required to be 95-105% of the labelled amount over its full shelf life), and its bioavailability geometric mean ratios (90% confidence intervals between 90-111.1%, including 100%). REVIEW: This review describes a reformulation of a widely used levothyroxine product (Euthyrox.*). The new tablet fulfils all criteria according to the new specification regulations for dosage accuracy over a shelf life of 3 years in all climate zones, and for bioequivalence compared to the conventional formulation used for many years. In addition, a clinical trial demonstrated equivalent exposure between three different tablet strengths of the new formulation, amounting to the same total dose (dose form proportionality). As a consequence, switching from the conventional to the new formulation can be undertaken on a 1:1 dose-for-dose basis, without re-titration or additional thyroid function testing. CONCLUSION: The new formulation, which is more stable, will assist in the accurate dosage and titration of levothyroxine in the management of hypothyroidism. PMID- 30406688 TI - Eveningness diurnal preference associated with poorer socioemotional cognition and social functioning among healthy adolescents and young adults. AB - Recently there has been growing interest in associations between sleep, emotion, and social functioning. Less is known about relationships between chronotype preference and socioemotional cognition and functioning, particularly among adolescents, who experience dramatic normative shifts in diurnal preference, affective functioning, and social competence. Fifty-five healthy adolescents and young adults completed a self-report chronotype preference measure, a computerized measure of socioemotional cognition, and a semi-structured clinical interview assessing interpersonal functioning. Greater eveningness preference was associated with poorer socioemotional cognition and social functioning in this age group. Future studies should assess these relationships across development and using objective measures of circadian timing. PMID- 30406689 TI - Synthesis and biological evaluation of picroside derivatives as hepatoprotective agents. AB - Picrorhizae Rhizoma as a hepatoprotective herb, has been applied for thousands of years, and picroside was proved to be its active constituent. In this study, twelve derivatives of picroside were synthesized and the hepatoprotective activity of the derivatives was evaluated on SMMC-7721 cells. Six out of the derivatives had shown a better protective effect on H2O2-induced SMMC-7221 cells than picroside, and the activity of two derivatives (2 and 4) was stronger than that of the reference compound, silybin. Compound 2 shown the strongest protective effect (EC50 = 6.064 +/- 1.295 MUM). PMID- 30406690 TI - Excelsanone, a new isoflavonoid from Erythrina excelsa (Fabaceae), with in vitro antioxidant and in vitro cytotoxic effects on prostate cancer cells lines. AB - A new isoflavonoid, excelsanone (2), was isolated from the ethyl acetate extract of Erythrina excelsa stem bark, together with three known compounds namely 6,8 diprenylgenistein (3), beta-sitosterol (1) and sitosteryl-beta-D-glucopyranoside (4). Their structures were elucidated using spectroscopic methods (HR-ESI-MS, NMR and IR) and by comparison with some literature data. The antioxidant activity of crude extracts and two isolated compounds was evaluated using free radical scavenging (DPPH) and Ferric Reducing Ability Power (FRAP) methods with catechin as standard. The results of the radical scavenging activity showed that excelsanone (2) has a moderate potential with an IC50 of 1.31 mg/ml. The cytotoxicity of compounds 2 and 3 as well as the ethyl acetate extract was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two prostate cancer cell lines (DU145 and PC3). Excelsanone (2) induced a greater cytotoxicity in all tested cell lines, with a significant inhibition of DU145 cells growth in a concentration-dependent manner. PMID- 30406691 TI - The role of centrality to self-concept in moderating the associations between injury perceptions and outcomes. AB - OBJECTIVES: To test the centrality of injury to self-concept as a moderator of the associations between injury perceptions and outcomes. METHODS: Two concurrent studies on samples of injured individuals. MEASURES: The centrality of injury to one's self concept was measured by the degree of self-injury separation (PRISM); injury perceptions were measured by the injury perception questionnaire; and outcomes by standard scales of self-assessed health, physical, emotional and social functioning, vitality, depression, anxiety and somatisation. Regression analyses examined the significance of adding the interactions between injury centrality and injury perceptions to explained outcome variance, beyond their separate contributions. RESULTS: Both injury centrality and injury perceptions significantly explained variance in patients' functioning and well-being. Injury centrality moderated the associations between various injury perceptions and outcomes, especially pronounced for emotional representations of the injury. As hypothesised, the effects of injury perceptions on outcomes were stronger among patients for whom the injury was central to their self-concept compared to patients who perceived the injury as peripheral to their self-concept. CONCLUSIONS: 'Centrality to the self' is a moderator of the impact of perceptions on outcomes of injuries. The findings suggest ways to tailor interventions to sub groups of injured patients based on injury centrality to their self-concept. PMID- 30406692 TI - A qualitative analysis of the vaccine intention-behaviour relationship: parents' descriptions of their intentions, decision-making behaviour and planning processes towards HPV vaccination. AB - OBJECTIVE: The objective of this study is to identify factors influencing the vaccine intention-behaviour relationship. DESIGN: A total of 445 parents who received a brief intervention to promote HPV vaccination were categorized based on their intentions post-intervention (yes/unsure/eventually/never) and subsequent adolescents' vaccine status (yes/no). Fifty-one of these parents participated in qualitative interviews. MAIN OUTCOME MEASURES: Parents described their intentions, decision-making and planning processes towards vaccination. Framework analysis was used to analyse the data. RESULTS: Parents in the 'Yes/Yes' category were knowledgeable about HPV/vaccine, described strong, stable intentions, considered themselves the primary decision-makers about vaccination and said they vaccinated immediately. 'Yes/No' parents described strong intentions and thought their adolescent was vaccinated OR described hesitant intentions, seeking advice/agreement from others and noting barriers to vaccination without solutions. 'Unsure/Yes' parents described their intentions as strengthening with information from credible sources and identified strategies for overcoming barriers. 'Unsure/No' and 'Eventually/No' parents had misinformation/negative beliefs regarding vaccination, described being ambivalent or non-supportive of vaccination and cited barriers to vaccination. 'Never/No' parents held negative beliefs about vaccination, described strong, stable intentions to NOT vaccinate, deferring the decision to others, and reported no planning towards vaccination. CONCLUSIONS: Intention characteristics and planning processes could moderate the vaccine intention-behaviour relationship, potentially serving as targets for future vaccine strategies. PMID- 30406693 TI - Comment on 'Gut microbiota characterisation in obese patients before and after bariatric surgery'. PMID- 30406694 TI - Two alkaline motifs in the Lactobacillus salivarius Lv72 OppA surface are important to its adhesin function. AB - Glycosaminoglycans are involved in the attachment of Lactobacillus salivarius Lv72, a strain of vaginal origin, to HeLa cell cultures, indicating that they play a fundamental role in the attachment of mutualistic bacteria to the epithelium lining cavities where the normal microbiota thrives. The bacterial OppA protein has been proposed as an adhesin involved in this adherence since, once purified, it significantly interferes with attachment of the lactobacilli to HeLa cell cultures. In this article, the role of OppA is confirmed through the determination of its location at the cell surface and its ability to promote Lactobacillus casei and Lactococcus lactis adherence to eukaryotic cell cultures upon cloning and expression of oppA in these bacteria. The OppA sequence showed five potential domains for glycosaminoglycan-binding, and structural modelling of the protein showed that two of them were located in the vicinity of an OppA superficial groove whose width approached the diameter of the helical form of heparin in solution. Their involvement in the binding was demonstrated through substitution of critical basic amino acids by acidic ones, which resulted in loss of affinity for heparan sulphate and chondroitin sulphate depending on the domain mutated, suggesting that there might be a certain degree of specialisation. In addition, circular dichroism analysis showed that the spectrum changes induced by OppA-heparan sulphate binding were attenuated by the variant proteins, indicating that these motifs are the OppA recognition domains for the eukaryotic cell surface. PMID- 30406695 TI - Protective effect of Lactobacillus reuteri KUB-AC5 against Salmonella Enteritidis challenge in chickens. AB - Poultry is an important high-quality food and protein source for humans. However, chicken is considered a primary source of foodborne diseases, especially Salmonella Enteritidis infection. Reducing Salmonella contamination in live poultry will thus lower the risk to consumers. Our previous studies reported that Lactobacillus reuteri KUB-AC5 can produce a substance with antimicrobial activity against pathogenic bacteria, especially Salmonella. In vivo testing revealed that this strain greatly influenced the ileal microbiota by improving chicken gastrointestinal health and inhibiting certain pathogenic bacteria. However, its activity against Salmonella in chicken is unknown. This study investigated the effects of the probiotic L. reuteri KUB-AC5 at various concentrations against Salmonella and the microbiota status in the gastrointestinal tract of broiler chickens. Four treatments groups were used: negative-control group (no Salmonella challenge), positive-control group (Salmonella challenge), and 5 or 7 log cfu probiotic supplementation to Salmonella-challenged chickens. The resultant microbial diversities at the growing and finisher stages were not significantly different among the groups (P>0.05). However, a high dosage of KUB-AC5 maintained similar microbial diversity in Salmonella-challenged chickens as observed in the non-challenged group in the early stage. The exposure Salmonella can affect the microbial diversity that consequently contributes to the disease progression in chicken. Low and high dosages of KUB-AC5 eliminated S. Enteritidis from the ileum and caecum at 14, 21 and 35 days of age. A high-dose of KUB-AC5 also enhanced Lactobacillaceae levels in the growing stage in both the ileum and caecum and suppressed Enterobacteriaceae levels in the finisher stage on day 35, whereas these effects were not observed in the low dose of KUB-AC5 or control groups. These results support the potential value of high-dose L. reuteri KUB-AC5 supplementation for three days after hatching in preventing Salmonella infection in chickens. PMID- 30406696 TI - Regulatory T cells and Toll-like receptor 2 and 4 mRNA expression in infants with colic treated with Lactobacillus reuteri DSM17938. AB - Regulatory T cells induce immune homeostasis and the expression of Toll like receptors (TLRs); subsequent inflammatory cytokine release may be involved. Recent studies have shown a microbial imbalance in the gut of colicky infants (with a prevalence of gram-negative bacteria, such as Escherichia coli), and accumulating evidence has shown the efficacy of a probiotic (Lactobacillus reuteri) in breastfed subjects, but the underlying mechanism remains undefined. The study enrolled 59 infants younger than 60 days, of whom 34 subjects had colic and 25 were healthy controls. With a double-blind, placebo-controlled randomised study performed in our unit from October 2016 to July 2017, infants with colic were randomly assigned to receive oral daily L. reuteri DSM17938 (1*108 cfu) or placebo for 28 days. Peripheral blood was collected to assess the expression of FoxP3, TLR2 and TLR4 mRNA using real-time TaqMan RT-PCR at baseline and after the study period. Our findings showed increased mRNA expression of the transcription factor forkhead box P3 (FoxP3) in infants treated with L. reuteri DSM 17938 for 28 days (P<0.009) and increased TLR2 and TLR4 mRNA expression in both treated and placebo subjects. After L. reuteri administration for 28 days in infants with colic, we observed a significant decrease in daily crying time (302.3+/-19.86 min/day on day 0 vs 76.75+/-22.15 min/day on day 28, P=0.001). This study provides evidence that the observed increase in FoxP3 expression and reduction in crying time might be responses to probiotic treatment, while the increase in TLR2 and TLR4 mRNA expression might be related to age. Exploiting these new findings may lead to an unprecedented level of therapeutic control over immune tolerance using probiotics. PMID- 30406697 TI - LGR4 protects hepatocytes from injury in mouse. AB - Leucine-rich repeat G-protein-coupled receptors (LGRs) and their endogenous ligands R-spondin1-4 (Rspo) are critical in embryonic development and in maintenance of stem cells. The functions of the Rspo-LGR system in differentiated cells remain uncharacterized. In this study, the expression profiles of LGRs and Rspos were characterized in mature hepatocytes. A liver-specific knockout of LGR4 in mouse was generated and used to study hepatic ischemia and reperfusion induced injury (HIRI) as well as LPS/D-Gal induced liver injury. We demonstrated that in adult liver, LGR4 is expressed in hepatocytes and responds to Rspo1 with internalization. Rspo1 is responsive to various nutritional states and to mTOR signaling. Activation of LGR4 by Rspo1 significantly reduced TNFalpha-induced cell death, and levels of NFkappaB-p65 and caspase 3 in cultured hepatocytes. Knockdown of hepatic LGR4rendered hepatocytes more vulnerable to TNFalpha-induced damage in cultured primary cells and in the setting of HIRI and LPS/D-Gal induced liver injury. Rspo1 potentiated both basal and Wnt3a-induced stabilization of beta-catenin. Disruption of beta-catenin signaling reversed the protective effects of Rspo1 on TNFalpha-induced hepatocyte toxicity. LGR4knockdown increased nuclear translocation of NFkappaB-p65 in response to acute injury. Overexpression of IKKbeta attenuated the protective effects of Rspo1 on TNFalpha-induced cell death. In conclusion, the Rspo1/LGR4 system represents a novel pathway for cytoprotection, and modulation of stress-induced tissue damage. PMID- 30406698 TI - Zinc Ameliorates Intestinal Barrier Dysfunctions in Shigellosis by Reinstating Claudin-2 and -4 on the Membranes. AB - Whether zinc(Zn2+) regulates barrier functions by modulating tight junction (TJ) proteins when pathogens such as Shigella alter epithelial permeability is still un-resolved. We investigated the potential benefits of Zn2+ in restoring impaired barrier function in vivo in Shigella infected mouse tissue and in vitro T84 cell monolayers. Basolateral Shigella infection triggered time dependent decrease in trans-epithelial resistance (TER) followed by an increase in paracellular permeability of FITC-labelled dextran and altered ion selectivity. This lead to ion and water loss into the intestinal lumen. Immunofluorescence studies revealed redistribution of claudin-2 and -4 to an intracellular location, and accumulation of these proteins in the cytoplasm following infection. Zn2+ ameliorated this perturbed barrier by redistribution of claudin -2 and -4 back to the plasma membrane and by modulating the phosphorylation state of TJ proteins through ERK1/2 dependency. Zn2+ prevents elevation of IL-6 and IL-8. Mice challenged with Shigella showed that oral Zn2+supplementation diminished diverse pathophysiological symptoms of shigellosis. Claudin-2 and -4 were susceptible to Shigella infection resulting in altered barrier function and increased levels of IL-6 and IL-8. Zn2+ supplementation ameliorated this barrier dysfunction, and the inflammatory response involving ERK mediated change of phosphorylation status for claudin-2 and -4. Thus, Zn2+ may have potential therapeutic value in inflammatory diarrhea and shigellosis. PMID- 30406699 TI - Molecular Characterization of a Precision-Cut Rat Liver Slice Model for the Evaluation of Anti-Fibrotic Compounds. AB - Precision-cut liver tissue slice (PCLS) contains all major cell types of the liver parenchyma and preserves the original cell-cell and cell-matrix contacts. It represents a promising ex vivo model to study liver fibrosis and test the anti fibrotic effect of experimental compounds in a physiologic environment. In this study using RNAquencing we demonstrated that various pathways functionally related to fibrotic mechanisms were dysregulated in PCLSs derived from rats subjected to bile duct ligation. The Alk5 inhibitor SB525334, nintedanib and sorafenib each reversed a subset of genes dysregulated in fibrotic PCLSs and of those genes we identified 608 genes whose expression was reversed by all three compounds. These genes define a molecular signature characterizing many aspects of liver fibrosis pathology and its attenuation in the model. A panel of 12 genes and 4 secreted biomarkers including procollagen I, HA, IGFBP5 and WISP1, were further validated as efficacy endpoints for the evaluation of anti-fibrotic activity of experimental compounds. Finally, we showed that blockade of alphaV integrins with a small molecule inhibitor attenuated the fibrotic phenotype in the model. Overall, our results suggest that the rat fibrotic PCLS model may represent a valuable system for target validation and to determine the efficacy of experimental compounds. PMID- 30406700 TI - Adnexal torsion in symptomatic women: a single-centre retrospective study of diagnosis and management. AB - This retrospective study aimed to evaluate the sonographic diagnosis and management strategy of symptomatic adnexal torsion at a teaching hospital in Hyderabad, India. All women with abdominal pain and preoperative or operative diagnosis of adnexal torsion from January 2011 to December 2015 were included. A total of 76 women with 78 episodes were included; 28 (36%) occurred during pregnancy. The ovarian mass (in 71%) and pregnancy (in 35%) constituted the most common risk factors. The overall sensitivity, specificity, positive predictive value, negative predictive value and the accuracy of ultrasound were 75%, 27%, 86%, 15% and 68%, respectively. Ultrasonography was more sensitive in detecting torsions in the non-pregnant subgroup but had a higher specificity during pregnancy. An oophorectomy was performed in 9% of the women due to gangrene. Benign paraovarian cysts and teratomas were the most frequent lesions to undergo torsion. The obstetric outcome was good, the miscarriage rate being 5%. Impact statement What is already known on this subject? Adnexal torsion presents a diagnostic and therapeutic challenge. There are various sonographic criteria that aid in the clinical diagnosis. Discoloured ovaries do not routinely warrant removal. What the results of this study add? The sonographic diagnosis is inaccurate in a third of the cases. Torsion without the involvement of the ovary does not exhibit any of the classic ultrasound findings other than a torted pedicle and therefore a sonographic diagnosis may be difficult. Discoloured ovaries had a normal appearance at future surgeries, reinforcing the concept that an oophorectomy (after detorsion) should be the exception rather than the rule even if the ovary is bluish black. What the implications are of these findings for clinical practice and/or further research? Training in pelvic ultrasound to complement clinical judgement and regular audits of treatment must be conducted in order to minimise pitfalls in diagnosis and management. An ultrasound examination cannot be used as a sole diagnostic criterion to confirm or exclude torsion and a clinical assessment takes precedence. PMID- 30406701 TI - Defluoridation of synthetic and industrial wastewater by using acidic activated alumina adsorbent: characterization and optimization by response surface methodology. AB - Excessive contamination of fluoride in wastewater is the cause of several chronic health problems. For this purpose, an adsorbent was prepared from alumina by acidic activation using sulfuric acid. The current research aims to find the maximum fluoride adsorption (%) from synthetic and industrial wastewater at optimum process parameters by using response surface methodology (RSM). All batch scale experiments were carried out according to the statistical-design order. Central composite design (CCD) was applied to ascertain the effect of adsorbent dose, pH, initial fluoride concentration and temperature on fluoride adsorption (%). Maximum fluoride removal was predicted based on the quadratic model developed. Validation of the model was done with negligible error. The regression coefficient of the model was found to be 0.96. From the analysis of variance (ANOVA), the factors with the greatest effect on the adsorption of fluoride were identified. Under optimized condition, the adsorbent dose 13.89 g L-1, pH 5.52, temperature 25 degrees C and initial fluoride concentration 18.67 mg L-1 resulted in 96% of maximum fluoride adsorption. Under the same optimized parameters, the fluoride adsorption from industrial wastewater found to be 92.10%. PMID- 30406703 TI - Response to: vaginal birth in breech presentation in morbidly obese woman. PMID- 30406702 TI - A rare pseudo tumour in the extraembryonic coelom in first trimester of pregnancy: ultrasound and pathology. PMID- 30406704 TI - The rare cause of childhood bleeding - recurrent Mullerian papilloma. PMID- 30406705 TI - The use of zeolite-based additives for immobilising iron during pressure filtration of coal refuse slurry. AB - Pressure filtration of coal refuse slurry has the potential to provide a concentrated solids stream that can be stacked, thereby offering multiple environmental benefits. However, potential leachates from the solids stream can impact the environment. In that context, this study performed preliminary investigations of the application of zeolite-based additives to adsorb metals leaching from coal refuse slurry at low pH. Additives were added to the coal refuse slurry, which was filtered using bench- and lab-scale pressure filtration units. Results indicated that the overall filtrate flux and cake moisture characteristics were not significantly affected by the addition of additives up to 20% (by weight of solids). It was shown that adsorption as high as 80% was achieved by using the additives to capture iron. It was concluded that the finer additive with less silicon content was more effective in capturing iron. The results showed that the thickener feed stream leached out less iron than the thickener underflow stream. The adsorption process was not significantly affected by slight variations in initial iron concentration in the solution. The use of lower pH water on the filter cakes treated with the additive showed minimal release of iron and manganese into the aqueous phase. PMID- 30406706 TI - Bilateral gonadal artery injury after peripartum hysterectomy. PMID- 30406707 TI - FEVR findings in patients with Loeys-Dietz syndrome type II. AB - BACKGROUND: Loeys-Dietz syndrome (LDS) is a connective tissue disorder that has phenotypic overlap with Marfan syndrome. In LDS, the aortic root dissections can be more aggressive and occur at a younger age than Marfan syndrome. MATERIALS AND METHODS: Review of two cases. RESULTS: A 7-year old boy with history of LDS was found to have a vitreous hemorrhage in the right eye. Further examination showed findings of Familial Exudative Vitreoretinopathy (FEVR). Both eyes were found to have peripheral non-perfusion and neovascularization. A non-related 25-month-old boy with no molecularly confirmed connective tissue disorder was found to have bilateral peripheral non-perfusion and bilateral tractional retinal detachments. The boy was clinically diagnosed with Larsen syndrome, Ehlers-Danlos syndrome kyphoscoliotic form, and Marfan syndrome before presentation. The FEVR lead to consideration of LDS that was molecularly confirmed. Consequently, he was monitored for aortic root dilation. CONCLUSION: FEVR findings may lead to diagnosis of LDS and patients with LDS may present with proliferative retinopathy. PMID- 30406708 TI - No preventive or therapeutic efficacy of infliximab against macrophage activation syndrome due to systemic juvenile idiopathic arthritis. PMID- 30406709 TI - The potential of tumor-derived exosomes for noninvasive cancer monitoring: an update. AB - INTRODUCTION: Liquid biopsy platforms are being actively developed in the biomarker field. Extracellular vesicles (EVs), especially the tumor-derived exosome (TEX) subsets of EVs, represent a platform that allows for molecular and genetic profiling of parent tumor cells. TEX are ubiquitous in body fluids of cancer patients and are promising clinically relevant surrogates of cancer cells. Areas covered: Isolation from body fluids of cancer patients and subsetting of exosomes based on immunoaffinity capture offers a means of evaluating proteins, lipids, nucleic acids and other molecular contents that are a characteristic of TEX and exosomes produced by reprogrammed normal cells. The same liquid biopsy can inform about the status of a tumor and simultaneously evaluate the competency of immune cells to mediate anti-tumor activities. Expert commentary: TEX and reprogrammed non-TEX isolated from plasma of cancer patients have the potential to become non-invasive biomarkers of cancer diagnosis, prognosis and response to therapies. PMID- 30406710 TI - Severe refractory bilateral shoulder dystocia released with digital hooking (Bourgeois-Siegemundin) manoeuvre. PMID- 30406711 TI - The Psychological Risk of Minimal Risk Activities: A Pre- and Posttest Study Using the Self-Assessment Manikin. AB - It is difficult to apply U.S. Federal Code of Regulation's criterion for "minimal risk," because benchmarks of minimal risk have not been quantified. Our goal was to examine the psychological risks of several day-to-day activities. Using the Self-Assessment Manikin (SAM), we assessed the state valence and arousal of 432 patients and employees at a large Midwestern Department of Veterans Affairs medical facility before and after they had their blood drawn, saw their primary care physician or mental health provider, or took part in an exercise class. Exercise was associated with near-large to large salutary effects (Cohen's d = 0.76-1.17); other effects were small or moderate in positive directions (Cohen's d = 0.02-0.51). Our findings are a promising start toward establishing benchmarks and quantifying the psychological harms of minimal risk activities. Estimates such as these may help researchers determine whether their own research exceeds minimal risk. PMID- 30406712 TI - A case of a contained uterine rupture. PMID- 30406713 TI - Mental Health Issues and Substance Use in the United States: Pulling the Power Levers. AB - BACKGROUND: Promising treatment avenues have been developed and studied that align well with the skills of psychiatric-mental health (PMH) nurses. The treatments are relationship-driven, nimble and accessible, and recovery-guided. They emphasize a whole-person approach with care delivered by a team of experts working in a contextually coordinated way. AIMS: To describe the challenges facing the United States with regard to mental illness and substance use disorders and the ways in which PMH nurses can use their skills to mitigate these challenges. METHOD: Published research and government reports were reviewed to obtain current mental health and substance use data. RESULTS: The number of people not being treated for mental illnesses-particularly serious mental illness, major depressive episode, and suicidal thoughts-has not improved since 2009. Although inroads have been made in reducing the rate of smoking in the United States, we are facing an opioid crisis. There are limited data on marijuana use, but it is apparent that many Americans use cannabis routinely. According to the Substance Abuse and Mental Health Administration, approximately 44.7 million people need mental health treatment and 20.1 million Americans need substance use treatment, but only 10% to 30% receive it. CONCLUSIONS: PMH nurses must take a leading role in retooling the therapeutic relationship and partnering with clients, families, and caregivers to improve the quality of life and well being of those dealing with mental illness and substance use disorders. To accomplish this essential task, the PMH nursing workforce must be robust and distributed throughout the United States. PMID- 30406714 TI - A Systematic Review Summarizing the State of Evidence on Bullying in Childhood Cancer Patients/Survivors. AB - BACKGROUND: One in four school-aged children is bullied. However, the risk may be greater for childhood cancer patients/survivors (diagnosed <18 years), because of symptoms of the disease and treatment that may prejudice peers. While the serious consequences of bullying are well documented in the general population, bullying may have even greater impact in children with cancer due to the myriad of challenges associated with treatment and prolonged school absence. OBJECTIVE: To summarize the state of evidence on bullying in childhood cancer patients/survivors; specifically, the rate and types of bullying experienced and the associated factors. METHOD: We searched five electronic databases from inception to February 2018 for original research articles reporting on bullying in childhood cancer patients/survivors. RESULTS: We identified 29 eligible articles, representing 1,078 patients/survivors ( M = 14.35 years). Self-reports from patients/survivors revealed a considerably higher rate of bullying (32.2%) compared with the general population (25%). Our review identified little information on the factors associated with bullying in patients/survivors. However, the bullying described tended to be verbal and was often related to the physical side effects of treatment, indicating that differences in appearance may prejudice peers. It was further suggested that educating the child's classmates about cancer may prevent bullying. CONCLUSIONS: Our findings confirm that bullying is a significant challenge for many childhood cancer patients/survivors. Additional studies are needed to identify factors that may influence the risk of bullying, which will inform the development of evidence-based interventions and guidelines to prevent bullying in childhood cancer patients/survivors. PMID- 30406715 TI - A Comparison of Violence Victimization and Polyvictimization Experiences Among Sexual Minority and Heterosexual Adolescents and Young Adults. AB - Despite recent civil rights advances for sexual minority communities in the United States, disparities in violence victimization have increased in recent years. Polyvictimization, the experience of multiple types of violence, is common in the United States and may result in mental and physical health consequences above and beyond single-type victimization. However, disparities in polyvictimization among sexual minority young people remain understudied. The purpose of this article was to determine whether there were disparities in monovictimization and polyvictimization among sexual minority young people compared with their heterosexual peers. Data for this article were from The National Longitudinal Study of Adolescent to Adult Health, a nationally representative cohort study started in 1994. Participants reported their experiences with eight types of violence across child abuse, criminal assault, intimate partner violence (IPV), and sexual assault domains. We categorized individuals with no violence victimization as nonvictims, individuals with one form of victimization as monovictims, and individuals with multiple types of victimization as polyvictims. We then compared experiences of each type of victimization and overall monovictimization and polyvictimization by sexual orientation ( n = 9,828). Among females, the proportions of individuals experiencing victimization by sexual orientation were significantly different for all forms of violence. Among males, criminal assault, IPV resulting in injury, and nonphysically and physically forced sexual assault differed by sexual orientation. Compared with 100% heterosexual peers, individuals who were mostly heterosexual had significantly increased odds of monovictimization and polyvictimization compared with no victimization. Bisexual individuals had significantly increased odds of polyvictimiztion, and mostly/100% homosexual individuals had significantly increased odds of monovictimization. Multiple victimization experiences may be a pathway to lifetime health disparities, so our findings may explain many of the health disparities experienced in sexual minority communities. It will be critical to develop and evaluate intervention and prevention programs to eliminate these disparities. PMID- 30406716 TI - Genetic polymorphism of glial cell-derived neurotrophic factor (GDNF) in male infertility. PMID- 30406717 TI - Attachment style and changes in systemic inflammation following migration to a new country among international students. AB - Attachment style may influence the acculturation process by shaping the types of social relationships that individuals form and maintain. Social relationship quantity and quality have been linked to chronic low-grade systemic inflammation, an immune process associated with risk for age-related diseases. The goal of this study was to investigate whether attachment style moderates the change in systemic inflammation during the early phases of the acculturation process, a period associated with rapid changes in social functioning. In this 5-month longitudinal study, 58 new international students completed the Adult Attachment Scale and provided blood samples for C-reactive protein (CRP) analysis shortly after arrival in the host country as well as 2 and 5 months later. Results indicated that individuals with higher attachment anxiety experienced larger increases in CRP over time. During a period of rapid changes in social functioning, attachment anxiety promotes immune changes that may increase health risk over time. PMID- 30406718 TI - A Cytogenetic Profile of Radiation Damage. AB - Most of the important biological effects associated with the exposure to ionizing radiations are mirrored at the chromosomal level. In all cases, changes in the levels of cytogenetic effects are associated with changes in absorbed dose, dose rate and radiation quality. Some of the complexities associated with the quantitative description of such changes in response can be circumvented by appealing to concepts embodied in what has been called the "mean inactivation dose". Additional metrics designed to provide LET-dependent "signatures" of damage have been employed with moderate degrees of success. These, along with some alternative approaches, are discussed in an effort to stimulate discussion, and to further work leading to a better understanding of mechanisms involved in the production and significance of chromosome aberrations after exposure to ionizing radiations. PMID- 30406719 TI - Maternal sensitivity during infancy and the regulation of startle in preschoolers. AB - Caregiving insensitivity and fear dysregulation predict anxiety symptoms in children. It is unclear, however, whether sensitive parental care during infancy predicts fear regulation later in childhood. To address this question, we asked whether observed maternal sensitivity, measured at 6 months, predicts 42-month old children's laboratory-induced fear responses (n=213) during a fear-eliciting episode. We predicted that higher levels of maternal sensitivity would be associated with greater fear regulation. We operationalized fear regulation as decreases in fear over repeated trials of a novel, potentially frightening, stimulus. Two aspects of fear responses were considered: expressed fear and startle. Expressed fear scores did not decrease over time but children exhibited less startle behavior in the second half of the task. Maternal sensitivity predicted this startle attenuation across trials. These findings highlight the contribution of maternal sensitivity during infancy to the development of fear regulation in early childhood, further suggesting its influence on offspring anxiety problems. PMID- 30406720 TI - Longitudinal associations between attachment quality in infancy, C-reactive protein in early childhood, and BMI in middle childhood: preliminary evidence from a CPS-referred sample. AB - In the current pilot study, we examined whether insecure or disorganized attachment was associated with elevated inflammation (i.e. C-reactive protein [CRP]) in children with histories of child protective services (CPS) involvement, and whether early childhood CRP predicted body mass index (BMI) in middle childhood. Participants included 45 CPS-referred children and 39 low-risk comparison children, for whom we assessed levels of CRP in early childhood (Mean age = 4.9 years). For the CPS-referred children, who were drawn from an ongoing longitudinal study, we had attachment classifications (assessed during infancy with the Strange Situation) and BMI data (assessed during early and middle childhood); these data were not available for the low-risk comparison group. CPS referred children who had insecure or disorganized attachments during infancy had higher levels of CRP in early childhood than CPS-referred children who had secure attachments, who had similar levels of CRP to low-risk comparison children. Among CPS-referred children, early childhood CRP predicted age 8 BMI, controlling for BMI at age 4. Findings offer preliminary support for the association between attachment quality and inflammation in early childhood, which may have implications for later physical health. PMID- 30406721 TI - A preliminary investigation of attachment style and inflammation in African American young adults. AB - Individuals' social experiences are associated with their mental health, physical health, and even mortality. Over the last 30 years, researchers have examined the ways in which these social experiences might be associated with chronic inflammation - a component underlying many of the chronic diseases of aging. Little research, however, has examined the role of adults' attachment style as a specific social component that might be associated with inflammation. In the present study, we utilized data from a sample of 59 African-American adults from the Maryland Adolescent Development in Context Study (MADICS) to examine the links between attachment avoidance and attachment anxiety and C-reactive protein (CRP) and interleukin (IL)-6. After controlling for demographic characteristics, body mass index, and depressive symptoms, attachment avoidance and anxiety were associated with IL-6 but not CRP. This study adds to the growing body of research identifying the wide range of social experiences associated with inflammation and further suggests that attachment relationship experiences may have implications for biological processes relevant to many chronic diseases of aging. PMID- 30406722 TI - Attachment and physical health: introduction to the special issue. AB - Over the last 40 years, researchers have made considerable progress identifying the ways in which attachment security shapes individuals' social and emotional functioning. In recent years, new investigations have shed light on connections between attachment and physiological systems in the body. The goal of this special issue is to focus attention on how attachment may be related to biological markers that relate to physical health, including inflammation, cortisol, and cardiometabolic risk. The papers in this special issue, highlighted in this introduction, demonstrate that these links may exist across the lifespan. We conclude with several examples of extensions of this work might emerge in the years to come. PMID- 30406723 TI - Pressurized liquid extraction of six tetracyclines from agricultural soils. AB - Veterinary antibiotics used in agriculture can be introduced into the environment through land application of animal manure, accumulating in soils and groundwaters and posing a significant risk to human health and animal well-being. As the analysis of tetracyclines in soil is challenging due to their strong interaction with soil minerals and organic carbon, the objective of this study was to develop a reliable and reproducible method for quantitative analysis of chlortetracycline and oxytetracycline, and their respective metabolites in soils. A method based on pressurized liquid extraction (PLE) with in-cell clean-up was developed for the extraction of chlortetracycline and oxytetracycline and four likely metabolites from a set of four soils. Optimized conditions included a cell size of 22 mL, soil loading of 5 g, pH of 8.0, methanol:water ratio of 3:1, 50 degrees C, and two cycles. Soil extracts were analysed by high-performance liquid chromatography (HPLC) coupled with ion trap mass spectrometry (MS). Recoveries of seven tetracyclines from soil ranged from 41% to 110%. The limits of detection for tetracyclines were 0.08-0.3 ug g-1 soil, and intra- and inter-day variation ranged from 0.12-0.34%. The proposed PLE method is suitable for quantification of tetracyclines in agricultural soils at typical concentrations expected in contaminated environments. PMID- 30406724 TI - Maternal attachment avoidance is linked to youth diurnal cortisol slopes in children with asthma. AB - Prior evidence suggests that an individual's attachment orientation is linked to the health and health-related biology of his/her romantic relationship partners. The current study examined whether this effect extends to parent-child relationships. Specifically, we investigated the association between maternal attachment anxiety and avoidance and diurnal cortisol of offspring. In a sample of 138 youth with asthma and their primary caregivers, caregivers reported their attachment orientations, and their children (aged 10-17) supplied four saliva samples per day over four days to assess diurnal cortisol patterns. Growth curve analyses revealed no links to caregiver attachment anxiety, but caregiver attachment avoidance was significantly associated with children's diurnal cortisol slopes, such that greater attachment avoidance predicted flatter diurnal cortisol slopes. Maternal warmth did not mediate this link. These results support the possibility that an individual's adult attachment orientation may "get under the skin" of family members to influence their health-related biology. Future research should seek to determine the causal direction of this association and mechanisms of this effect. PMID- 30406725 TI - Clinical observation of regular intermittent epidural injection combined with different puncture points in suppressing breakthrough pain in labour analgesia. AB - The aim of the current study was to evaluate the clinical effects of the regular intermittent epidural injection combined with different puncture points (RIEI dPP) in suppressing breakthrough pain during a labour analgesia. A total of 90 primipara were randomly divided into three groups (n = 30): Group L2-3 (A), Group L3-4 (B) and Group L4-5 (C). The analgesic pump parameters were set as: impact dose 8 mL, locking time 15 minutes, background dose 0, and the additional impact dose 8 mL after each hour intermittence. The pain's visual analogue scale (VAS), breakthrough pain, maximum block segment, modified Bromage score, labour duration and the neonatal Apgar score were recorded and compared. Compared with the pre analgesia time, the VAS scores were found to be significantly decreased in the three groups (p < .05), but there were significant differences among the three groups (p > .05). During analgesia, the maximum block segment in Group C was more significantly reduced than in the other two groups (p > .05), but there was no significant difference in the breakthrough pain among the three groups (p > .05). The comparison of other indexes among the three groups showed there was no significant difference (p > .05). RIEI-dPP at L2-3, L3-4 and L4-5 during labour analgesia can effectively inhibit breakthrough pain. Impact Statement What is already known on this subject? According to human anatomical features, the injection speed and capacity are the prerequisite for obtaining the ideal block range. Experiments confirm that a more uniform and wider drug distribution can be achieved by epidural intermittent rapid infusion with higher injection pressure than a continuous infusion with low injection pressure. Compared with the continuous epidural administration mode, the regular intermittent epidural injection mode can better inhibit breakthrough pain with a lower amount of anaesthetic. What the results of this study add? Similar labour analgesic effects can be achieved by regular intermittent epidural injection mode with different puncture points. What the implications are of these findings for clinical practice and/or further research? Compared with a continuous infusion, a regular intermittent epidural injection can achieve a more uniform drug distribution in the epidural space, so the block range can be more extensive, which can not only reduce the amount of anaesthetic but also effectively reduce the incidence of breakthrough pain. However, the selection of an intervertebral puncture site still lacks a uniform standard. The outcomes of this study can directly verify that regular intermittent epidural injection at L2-3, L3-4 and L4-5 can effectively inhibit breakthrough pain and achieve good analgesic effects, so selecting the intervertebral space with clear anatomical structure positioning and easier puncture pathway can benefit a labour analgesia. PMID- 30406726 TI - Non-targeted HIV testing in the emergency department: not just how but where. AB - INTRODUCTION: The emergency department (ED) has the potential to enhance early HIV diagnosis through HIV testing programs. How these are implemented is a subject of debate. Areas covered: We describe the main HIV testing approaches: diagnostic testing, targeted screening, and non-targeted screening, and review ED based non-targeted HIV screening studies conducted after 2006 among >=5000 patients. As well as examining how testing is offered, we focus on where it is offered, through the patient's journey from registration, via triage and the waiting room, to the bedside. Barriers to the testing offer, acceptance and performance were examined at each location. While testing offer rates were higher at registration and triage, compared to the waiting room and bedside, this was sometimes at the expense of testing acceptance and performance. Variables affecting testing rates included type of consent, employment of external staff and type of testing: fourth generation serological testing versus rapid testing. Expert commentary: These large studies shed light on the importance of where as well as how HIV testing is performed, and the ways in which the 'where' can influence non-targeted screening yields. This perspective enables testing approaches to be tailored to specific ED settings in order to maximize testing rates. PMID- 30406727 TI - Assessment of medical students' leadership traits in a problem/case-based learning program. AB - BACKGROUND: Healthcare delivery is shifting to team-based care and physicians are increasingly relied upon to lead and participate in healthcare teams. Educational programs to foster the development of leadership qualities in medical students are needed to prepare future physicians for these roles. OBJECTIVE: Evaluate the development of leadership attributes in medical students during their first 2 years of medical school while participating in leadership training integrated into a problem/case-based learning program utilizing the Leadership Traits Questionnaire assessment tool. DESIGN: Ninety-eight students enrolled at Zucker School of Medicine participated in Patient-Centered Explorations in Active Reasoning, Learning and Synthesis (PEARLS), a hybrid problem/case-based learning program, during the first and second years of medical school. The Leadership Traits Questionnaire, designed to measure 14 distinct leadership traits, was utilized. It was administered to students, peers in students' PEARLS groups and their faculty facilitators. Participants completed questionnaires at three-time points during the study. Likert scale data obtained from the questionnaire was analyzed using a two-level Hierarchal Linear Model. RESULTS: Complete data sets were available for 84 students. Four traits, including self-assured, persistent, determined, and outgoing, significantly increased over time by measurements of both peer and facilitator-rated assessments. Six additional traits significantly increased over time by measurement of facilitator-rated assessment. By contrast, a majority of student self-rated assessments trended downward during the study. CONCLUSIONS: Medical students demonstrated development of several important leadership traits during the first 2 years of medical school. This was accomplished while participating in the PEARLS program and without the addition of curricular time. Future work will examine the impact of third year clerkships on leadership traits. PMID- 30406728 TI - Relationship Between Sleep Quality, Depression Symptoms, and Blood Glucose in Pregnant Women. AB - Sleep quality during pregnancy affects maternal/child health. We aimed to assess changes in sleep quality during pregnancy and determine its relationship to maternal mood, blood glucose, and work schedule among primiparous women. We conducted a prospective/longitudinal/observational study. Ninety-two pregnant women were recruited from Midwestern hospital. Mood and sleep quality data were collected using Edinburgh Postnatal Depression Scale/Pittsburgh Sleep Quality Index at Gestational Weeks 22 and 32. Forty-three women completed the study. Twenty-six women (63%) were African American and the mean age was 23.64 ( SD = 3.82) years. Rate of poor sleep quality increased during pregnancy with 25% of women had scores indicative of depression symptoms. Poor sleep quality score was related to mood scores ( p < .05) and work schedule. Blood glucose was not significantly related to sleep duration. In conclusion, poor sleep quality during pregnancy was associated with poor mood and work schedule, suggesting that interventions targeting mental health and lifestyles are needed. PMID- 30406729 TI - Cross-validation of the screening scale in an adult protective services sample. AB - Adult Protective Services (APS) professionals are often called on to assess decision-making capacity when investigating financial exploitation. Previous research found that in consecutive APS cases, a decision-making screening scale (LFDSS) also detected financial exploitation. The purpose of this study was to apply the clinical cutoff scores derived from the previous study to a new sample of APS cases. Using a sample of 105 participants, from APS workers across 5 counties this study investigated the clinical utility of the LFDSS to detect financial exploitation based on ratings by APS professionals using the scale. Results demonstrate that the LFDSS has excellent internal consistency and clinical utility properties. This paper provides support for use of the LFDSS as a reliable and valid instrument. Instructions for use of the LFDSS are included in the article, along with information about online support tools. PMID- 30406731 TI - Medical school dropouts: regrettable or required? PMID- 30406730 TI - Impact of the final adjective in the Medical Student Performance Evaluation on determination of applicant desirability. AB - BACKGROUND: The Medical Student Performance Evaluation (MSPE) is a primary source of information used by residency programs in their selection of trainees. The MSPE contains a narrative description of the applicant's performance during medical school. In 2002, the Association of American Medical Colleges' guideline for preparation of the MSPE recommended inclusion of a comparative summative assessment of the student's overall performance relative to his/her peers (final adjective). OBJECTIVE: We hypothesize that the inclusion of a final adjective in the MSPE affects a reviewer's assessment of the applicant's desirability more than the narrative description of performance and designed a study to evaluate this hypothesis. DESIGN: Fifty-six faculty members from the Departments of Pediatrics and Medicine with experience reviewing MSPEs as part of the intern selection process reviewed two pairs of mock MSPE letters. In each pair, the narrative in one letter was superior to that in the other. Two final adjectives describing relative class ranks were created. Each subject was first presented with a pair of letters with mismatched final adjective (study), i.e., the letter with the stronger narrative was presented with the weaker final adjective and vice versa. The subject was then presented with a second pair of letters without final adjectives (control). Subjects ranked the relative desirability of the two applicants in each pair. RESULTS: The proportion of rankings congruent with the strength of the narratives under study and control conditions were compared. Subjects were significantly less likely to rank the applicants congruent with the strength of the narratives when the strength of the final adjectives conflicted with the strength of the narrative; 42.9% of study letters were ranked congruent with the narrative versus 82.1% of controls (p = 0.0001). CONCLUSION: The MSPE final adjective had a greater impact than the narrative description of performance on the determination of applicant desirability. ABBREVIATIONS: MSPE: Medical Student Performance Evaluation; AAMC: Association of American Medical Colleges; BCM: Baylor College of Medicine. PMID- 30406732 TI - Investigation of neurodegenerative and inflammatory processes in sleep bruxism. AB - OBJECTIVE: The present study aimed to evaluate the anxiety and optical coherence tomography (OCT) findings in patients with sleep bruxism (SB) and to develop objective measurements to assess the neurodegenerative and inflammatory processes associated with this disease. METHODS: A group of 40 SB patients were compared with a control group consisting of 40 healthy individuals (without SB). Anxiety results and the OCT measurements of retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), and choroidal thickness were assessed in both groups. RESULTS: Anxiety values in the bruxism group were significantly higher than those in the control group. The measurements of RNFL, IPL, and GCL in the bruxism group were significantly lower than the control group, whereas the choroidal thickness was significantly higher. CONCLUSION: According to literature, this is the first study that analyzed the changes in the retinal structures in bruxism, which revealed that SB is a neurodegenerative and inflammatory process. PMID- 30406733 TI - Influence of single nucleotide polymorphism in IL-27 and IL-33 genes on breast cancer. PMID- 30406734 TI - Development and Spanish translation of the Weinberg Center Risk and Abuse Prevention Screen (WC-RAPS). AB - Barriers for enhanced detection, identification, and reporting of elder abuse include the paucity of appropriate, valid, easily administered screening tools. This article describes the qualitative methods used in the development of the Weinberg Center Risk and Abuse Prevention Screen (WC-RAPS), and of its Spanish version. Focus groups and cognitive interviews were instrumental in identifying problematic items, underscoring potential response errors, and informing about putative causes for divergent interpretations of item-intent. Seven of the 11 original items were modified, a double-barreled item was segregated into two, one item deleted, and three additional items included to create the final 13 WC-RAPS items. The multi-step approach implemented for the Spanish conversion evidenced deviation from the original intended meaning for one item. The readability for English and Spanish versions was also assessed. Screening for elder abuse, if implemented systematically can be instrumental in identifying unrecognized abuse and preventing reoccurrence. PMID- 30406735 TI - Purification and characterization of thermostable cellobiohydrolase from Thermotoga petrophila. AB - BACKGROUND: Cellulose, being the most abundant biopolymer found in nature, can be utilized for bioethanol production to cater the future energy needs. Due to increased usage of fossil fuel it has been predicted that fossil fuel reserves may be depleted by year 2050. These concerns need serious attention and focus should be diverted to renewable fuels that are based on natural resources. Cellulases including exoglucanase (cellobiohydrolases) are the key enzymes that are produced by cellulolytic micro-organisms for the biodegradation of natural resource (cellulose) into fermentable reducing sugars. Many members of genus Clostridium possess supramolecular structures known as cellulosomes which contain various cellulases. Cellulase are composed of catalytic subunits that include endoglucanase, beta-glucosidase and cellobiohydrolases which concurrently can catalyse and subsequently convert cellulose into glucose and other sugars. After the action of cellulases, the sugars can be conveniently converted into bioethanol. OBJECTIVE: In the present study, characterization of a thermostable cellobiohydrolase enzyme from Thermotoga petrophila was carried out. The main purpose of this study is the utilization of thermostable cellobiohydrolase along with other cellulases in the process of saccharification of the cellulosic biomass to produce fermentable sugars that could in turn be converted into bioethanol which is the fuel of the future. METHOD: In this article, we propose a framework for achieving our a forementioned object. We started with the cloning of thermophilic cellobiohydrolase gene in mesophilic hosts to ease enzyme production. After cloning of cellobiohydrolase gene, submerged fermentation was performed for intracellular enzyme production. Microbial pellet obtained after centrifugation was sonicated and subjected to ammonium sulphate precipitation. The fraction obtained was purified to isoelectric homogeneity through ion exchange chromatography. Finally SDS analysis of purified cellobiohydrolase was carried out alongwith its characterization, kinetics and thermodynamics studies. RESULTS: Purification fold of 4.05 was obtained along with enzyme activity and specific activity of 11.5 U ml-1 min-1 and 66.5 U mg-1, respectively. The molecular mass of purified recombinant enzyme was 37 kDa as calculated by means of SDS-PAGE analysis. The enzyme showed 50% residual activity at 90oC and also at a wide pH range of 4-10. The enzyme retained its activity in the presence of most of the metal ions except Fe+2, Hg+2 and Pb+2. EDTA has an inhibitory effect on the function of the enzyme. The catalytic activity of the enzyme was maintained in the presence of the organic solvents. The enzyme had a Km and Vmax of 4.6 mM and 25.64+/-1.87 uM min-1 for PNP-beta-D-cellobioside under optimal conditions. CONCLUSION: The present study demonstrated that cellobiohydrolase produced from Thermotoga petrophila can be employed in many industries like paper and pulp and food processing. Most recent application of the cellobiohydrolases is their utilization in the production of bioethanol. PMID- 30406736 TI - Pharmaceutical Mixtures: Still A Concern For Human And Environmental Health. AB - In the present work, recent data onto the sources, occurrence and fate of human use pharmaceutical active compounds (PhACs) in the aquatic environment have been reviewed. Since PhACs and their metabolites are usually present as mixtures in the environment at very low concentrations, , a particular emphasis was placed onto the PhACs mixtures, as well as on their short-term and long-term effects against human and environmental health. Moreover, a general overview of the main conventional as well as of the latest trends in wastewaters decontaminant technologies was outlined. Advantages and disadvantages of current processes were also pointed-out. It appears that numerous gaps still exist in the current knowledge related to this field of interest, and further studies should be conducted at global level in order to ensure a more efficient monitorisation of the presence of PhACs and their metabolites into the aquatic environment and to develop new mitigation measures. PMID- 30406737 TI - The Importance of Food Perception in Food Choices and Nutrition. PMID- 30406738 TI - Patent Selections. PMID- 30406740 TI - Systematic Review of Food Addiction as Measured With the Yale Food Addiction Scale: Implications for the Food Addiction Construct. AB - BACKGROUND: The concept of food addiction attracts much interest by the scientific community. Research is mainly based on the Yale Food Addiction Scale (YFAS), a tool developed to assess food addiction. Substance use disorder criteria have been used to develop this scale. Objective The aim of this paper was to review the clinical significance of food addiction diagnoses made with the YFAS and to discuss the results in light of the current debate on behavioral addictions. Method We performed a systematic review of the studies that assessed food addiction with the YFAS published between January 2014 and July 2017 by searching the electronic databases PsycINFO, MEDLINE, and PsycARTICLES. Results Sixty publications were included in the analysis. Thirty-three studies examined nonclinical samples and 27 examined clinical samples. All studies used YFAS scoring results to define food addiction. The prevalence of food addiction according to the YFAS varied largely by the studied samples. In general, a higher body mass index and the presence of eating disorders (EDs), especially binge eating disorder (BED), were associated with higher YFAS scores. Conclusion The concept of food addiction has not been established to this day although it can be grouped with other EDs such as BED. More research is needed to understand this behavior and the differences between food addiction and other EDs. The criteria for food addiction should be revisited in light of the concepts currently used to examine behavioral addictions. PMID- 30406741 TI - Pyrrolopyrazoles; Synthesis, Evaluation and Pharmacological Screening as Antidepressant Agents. AB - : * Background: Pyrroles and fused pyrroles are of great interest as biologically active compounds, among these activities; antidepressant activity is of special concern. OBJECTIVE: Synthesis of a series of pyrrolopyrazoles and their pyrimidine derivatives and their characterization using spectral data to be monitored for antidepressant activity using behavioral techniques. METHOD: A control group provided by the vehicle i.p., positive control group received fluoxetine as standard and all other groups were administered the tested compounds. The groups were subjected to tail suspension test (TST) to determine the antidepressant activity compared with fluoxetine as standard drug. The compounds exhibiting antidepressant activity were then used to analyze changes in serotonin (5HT) level in the brain of albino mice. RESULTS: TST results showed that both [pyrazoles & pyrazlopyrimidines] derivatives exhibit promising anti depressant activity. Conclusion compounds [pyrazoles & pyrazlopyrimidines] show promising antidepressant activity possibly mediated by the increased levels of 5HT. PMID- 30406743 TI - Nutritional status and related factors of schoolchildren in Corum, Turkey. AB - OBJECTIVE: We aimed to determine nutritional status and related factors among schoolchildren in Corum, Central Anatolia, Turkey. DESIGN: Schoolchildren's height and weight were measured to calculate BMI and BMI Z-scores. Height, weight and BMI Z-scores were analysed and nutritional status classified according to the WHO. SETTING: Central Anatolia, Turkey.ParticipantsSchoolchildren aged 5-17 years (n 1684) participated in study. RESULTS: Of children, 4.2% were stunted, 6.9% thin, 13.8% overweight and 6.6% were obese. Proportions of stunting, thinness and overweight/obesity were significantly higher in children aged >10 years (78.6, 75.0 and 64.9%, respectively) than in those aged <=10 years (21.4, 25.0 and 35.1%, respectively; all P <0.001). Median (range) birth weight and breast feeding duration in children with stunting (2750 (1400-3600)g; 10 (0-36) months) were significantly lower and shorter, respectively, than those of normal height (3200 (750-5500)g; 15 (0-72) months) and tall children (3500 (2500-4900)g; 18 (0 36) months; P <0.001, <0.001, 0.011 and 0.016, respectively). The same relationship was observed in thin children (3000 (1000-4500)g; 12 (0-36) months) compared with normal-weight (3200 (750-5500)g; 15 (0-72) months) and overweight/obese children (3300 (1200-5500)g; 16 (0-48) months; P=0.026, <0.001, 0.045 and 0.011, respectively). CONCLUSIONS: Overweight and obesity are health problems that must be addressed in schoolchildren. Adolescents also have a risk of double malnutrition. Promoting normal birth weight and encouraging long duration of breast-feeding are important to support normal growth in children. PMID- 30406742 TI - Using social media to assess the consumer nutrition environment: comparing Yelp reviews with a direct observation audit instrument for grocery stores. AB - OBJECTIVE: To examine the feasibility of using social media to assess the consumer nutrition environment by comparing sentiment expressed in Yelp reviews with information obtained from a direct observation audit instrument for grocery stores. DESIGN: Trained raters used the Nutrition Environment Measures Survey in Stores (NEMS-S) in 100 grocery stores from July 2015 to March 2016. Yelp reviews were available for sixty-nine of these stores and were retrieved in February 2017 using the Yelp Application Program Interface. A sentiment analysis was conducted to quantify the perceptions of the consumer nutrition environment in the review text. Pearson correlation coefficients (rho) were used to compare NEMS-S scores with Yelp review text on food availability, quality, price and shopping experience. SETTING: Detroit, Michigan, USA.ParticipantsNone. RESULTS: Yelp reviews contained more comments about food availability and the overall shopping experience than food price and food quality. Negative sentiment about food prices in Yelp review text and the number of dollar signs on Yelp were positively correlated with observed food prices in stores (rho=0.413 and 0.462, respectively). Stores with greater food availability were rated as more expensive on Yelp. Other aspects of the food store environment (e.g. overall quality and shopping experience) were captured only in Yelp. CONCLUSIONS: While Yelp cannot replace in-person audits for collecting detailed information on the availability, quality and cost of specific food items, Yelp holds promise as a cost-effective means to gather information on the overall cost, quality and experience of food stores, which may be relevant for nutrition outcomes. PMID- 30406744 TI - The EcoCyc Database. AB - EcoCyc is a bioinformatics database available at EcoCyc.org that describes the genome and the biochemical machinery of Escherichia coli K-12 MG1655. The long term goal of the project is to describe the complete molecular catalog of the E. coli cell, as well as the functions of each of its molecular parts, to facilitate a system-level understanding of E. coli. EcoCyc is an electronic reference source for E. coli biologists and for biologists who work with related microorganisms. The database includes information pages on each E. coli gene product, metabolite, reaction, operon, and metabolic pathway. The database also includes information on E. coli gene essentiality and on nutrient conditions that do or do not support the growth of E. coli. The website and downloadable software contain tools for analysis of high-throughput data sets. In addition, a steady-state metabolic flux model is generated from each new version of EcoCyc and can be executed via EcoCyc.org. The model can predict metabolic flux rates, nutrient uptake rates, and growth rates for different gene knockouts and nutrient conditions. This review outlines the data content of EcoCyc and of the procedures by which this content is generated. PMID- 30406745 TI - The Relevance of Irreversible Loss of Brain Function as a Reliable Sign of Death. AB - BACKGROUND: There is an ongoing need for clear explanation of the diagnostic entity called "irreversible loss of brain function" (ILBF), as the absolute reliability of this diagnosis and its significance continue to be widely misunderstood. The determination of death as an objective medical-scientific matter is often not clearly distinguished from various other aspects of death, such as its metaphysical and cultural aspects and the ways in which the living deal with the dead. METHODS: This review is based on articles retrieved by a selective literature search in the PubMed database and on guidelines and standardized diagnostic protocols from Germany and abroad. RESULTS: ILBF can be caused by brain ischemia or anoxia or by any other type of brain disease or injury leading to an elevation of the intracranial pressure above the blood pressure and thereby to an arrest of the cerebral circulation. All situations in which brain function is merely reduced but not abolished, or only temporarily but not permanently abolished, can be clearly differentiated from ILBF through the use of standard diagnostic procedures as recommended in the relevant guidelines. Biological features that are common to all human beings underlie the medical criteria for the determination of death. The most important elements of the determination of death are irreversibility of the loss of brain function, loss of integration of bodily functions into a single living being, and loss of ability for any self-reflection or any independent interaction with the environment. CONCLUSION: ILBF is a reliable sign that a human being is dead. There has never been even one known case of incorrect determination of ILBF after proper application of the standardized diagnostic procedures that are set down in the guideline according to S16 of the German Transplantation Law. PMID- 30406746 TI - A Guinea Pig as a Source of Infection. PMID- 30406747 TI - Unanswered Questions. PMID- 30406748 TI - In Reply. PMID- 30406749 TI - No Obvious Association. PMID- 30406750 TI - The Mikulicz Line as a Parameter. PMID- 30406751 TI - In Reply. PMID- 30406752 TI - O2 saturation target of 96-100% should be abandoned. PMID- 30406753 TI - In Reply. PMID- 30406754 TI - STEMI Equivalent in Ventricular Pacemaker Rhythm. PMID- 30406755 TI - The Neurophysiology and Treatment of Motion Sickness. AB - BACKGROUND: Seasickness and travel sickness are classic types of motion illness. Modern simulation systems and virtual reality representations can also induce comparable symptoms. Such manifestations can be alleviated or prevented by various measures. METHODS: This review is based on pertinent publications retrieved by a PubMed search, with special attention to clinical trials and review articles. RESULTS: Individuals vary in their susceptibility to autonomic symptoms, ranging from fatigue to massive vomiting, induced by passive movement at relatively low frequencies (0.2 to 0.4 Hz) in situations without any visual reference to the horizontal plane. Younger persons and women are considered more susceptible, and twin studies have revealed a genetic component as well. The various types of motion sickness are adequately explained by the intersensory conflict model, incorporating the vestibular, visual, and proprioceptive systems and extended to include consideration of postural instability and asymmetry of the otolith organs. Scopolamine and H1-antihistamines, such as dimenhydrinate and cinnarizine, can be used as pharmacotherapy. The symptoms can also be alleviated by habituation through long exposure or by the diminution of vestibular stimuli. CONCLUSION: The various types of motion sickness can be treated with general measures to lessen the intersensory conflict, behavioral changes, and drugs. PMID- 30406756 TI - Location location location: an exploration of disparities in access to publicly listed pre-exposure prophylaxis clinics in the United States. AB - PURPOSE: HIV pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV transmission. Finding a PrEP provider, however, can be a barrier to accessing care. This study explores the distribution of publicly listed PrEP-providing clinics in the United States. METHODS: Data regarding 2094 PrEP-providing clinics come from PrEP Locator, a national database of PrEP-providing clinics. We compared the distribution of these PrEP clinics to the distribution of new HIV diagnoses within various geographical areas and by key populations. RESULTS: Most (43/50) states had less than one PrEP-providing clinic per 100,000 population. Among states, the median was two clinics per 1000 PrEP-eligible men who have sex with men. Differences between disease burden and service provision were seen for counties with higher proportions of their residents living in poverty, lacking health insurance, identifying as African American, or identifying as Hispanic/Latino. The Southern region accounted for over half of all new HIV diagnoses but only one-quarter of PrEP-providing clinics. CONCLUSIONS: The current number of PrEP-providing clinics is not sufficient to meet needs. In addition, PrEP-providing clinics are unevenly distributed compared to disease burden, with poor coverage in the Southern divisions and areas with higher poverty, uninsured, and larger minority populations. PrEP services should be expanded and targeted to address disparities. PMID- 30406757 TI - A first case of human herpesvirus-6B reactivation, confirmed by next-generation sequencing, in allopurinol-induced hypersensitivity syndrome in China. PMID- 30406758 TI - Nevus cells of cardiofaciocutaneous syndrome bear BRAF germ-line and somatic double mutations. PMID- 30406759 TI - Prognostic role of platelet to lymphocyte and lymphocyte to monocyte ratios in advanced melanoma treated with anti-programmed death-1. PMID- 30406760 TI - Sensory perception and nerve fibre innervation in patients with keloid scars: an investigative study. PMID- 30406761 TI - Quantitative assessment of metabolic tumor burden in molecular subtypes of primary breast cancer with FDG PET/CT. AB - PURPOSE: We aimed to quantitatively evaluate volumetric metabolic tumor burden including metabolic tumor volume and total lesion glycolysis in different molecular subtypes of breast cancer using 18F-fluorodeoxyglucose (FDG) positron emission tomography/ computed tomography (PET/CT). METHODS: This study involved 99 female patients with pathologic diagnosis of primary breast cancer, who underwent 18F-FDG PET/CT before any therapy. Patients were divided into subtypes of luminal A, luminal B, ERBB2+, and basal-like based on the immunohistochemistry results. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) before and after correction for lean body mass were achieved and compared. Correlations between metabolic tumor burden and Ki-67 were analyzed and diagnostic performances of volumetric metabolic parameters were evaluated. RESULTS: TLG values were significantly different between each molecular subtype, while MTV values were not. Values of TLG were significantly reduced after normalizing for lean body mass in each subtype. Both of them showed correlations with Ki-67 and presented high diagnostic ability in identifying patients with basal-like breast cancer from the rest. TLGs before and after normalizing for the lean body mass had similar diagnostic performances in differentiating patients of basal-like subtype from the rest. CONCLUSION: Metabolic tumor burden could comprehensively reflect tumor metabolic differences of molecular subtypes of breast cancer, and it can serve to help differentiate patients with basal-like breast cancer. PMID- 30406763 TI - Percutaneous glue embolization for recalcitrant iatrogenic portal hemorrhage. AB - N-butyl cyanoacrylate glue is well established as a transcatheter or direct injection embolic agent. Herein, targeted glue embolization was performed by direct needle injection into peripheral portal branches and along the surface of the liver to directly treat actively extravasating portal venous injury. In both cases, hemodynamically unstable patients underwent exploratory laparotomy, which was not able to definitively treat the hemorrhage. Subsequently, emergent visceral angiography and indirect portography revealed active portal phase extravasation. Transhepatic direct needle injection of the peripheral portal active extravasation with glue was successful in both cases and the patients stabilized, demonstrating this as an efficacious salvage approach. PMID- 30406764 TI - Ureteral protection during microwave ablation of renal cell carcinoma: combined use of pyeloperfusion and hydrodissection. AB - A 56-year-old female with past medical history of thrombotic microangiopathy presented to her physician with nonspecific abdominal pain. A magnetic resonance imaging scan was obtained, which revealed a 3.1 cm mass arising from medial lower pole of the left kidney that was subsequently shown to be renal cell carcinoma by percutaneous biopsy. Because of her history of thrombotic microangiopathy and other comorbidities, she was deemed a nonsurgical candidate and was therefore referred to interventional radiology for thermal ablation. Computed tomography (CT)-guided microwave ablation was performed with the combined use of pyeloperfusion and hydrodissection for maximal ureteral protection. Follow-up unenhanced CT scan obtained one month after ablation showed a normal collecting system without evidence of hydronephrosis or urinoma. PMID- 30406762 TI - Nephrotoxicity of gadolinium-based contrast in the setting of renal artery intervention: retrospective analysis with 10-year follow-up. AB - PURPOSE: We aimed to determine the incidence rate and potential risk factors for postcontrast acute kidney injury (PC-AKI) as well as the long-term clinical implications on dialysis and mortality in patients with chronic kidney disease (CKD) who underwent renal artery stent placement exclusively with gadolinium based contrast agents. METHODS: This retrospective study reviewed 412 patients with CKD who underwent renal artery stent placement. Sixty-eight patients underwent intervention exclusively with gadolinium-based contrast agents and were analyzed. Criteria for PC-AKI included either an absolute serum creatinine increase >0.3 mg/dL or percentage increase in serum creatinine >50% within 48 hours of intervention. Logistic regression analysis was performed to identify risk factors for PC-AKI. The cumulative proportion of patients who died or went on to hemodialysis was determined using Kaplan-Meier survival analysis. RESULTS: The incidence of PC-AKI was 14.7%. The rate of AKI decreased for every 1 unit increase in glomerular filtration rate ( GFR, odds ratio [OR]=0.91, P = 0.047). Prehydration was associated with a lower PC-AKI rate (OR=0.17; P = 0.015). Acute kidney injury after intervention was associated with an increased rate of dialysis (Hazard ratio [HR]=4.51, P = 0.002) and mortality (HR=2.52; P = 0.027). CONCLUSION: Gadolinium-based contrast agents are potentially nephrotoxic when used for endovascular intervention in patients with CKD. The risk of PC-AKI increased with lower GFR and decreased with prehydration. Dialysis and mortality risk were increased in patients who developed PC-AKI. PMID- 30406766 TI - Edge-insensitive magnetism and half metallicity in graphene nanoribbons. AB - Realizing magnetism in graphene nanostructures is a decade-long challenge. The magnetic edge state and half metallicity in zigzag graphene nanoribbons are particularly promising (Son et al 2006 Nature 444 347). However, its experimental realization has been hindered by the stringent requirement of the mono hydrogenated zigzag edge. Using first-principle calculations, we predict that free-carrier doping can overcome this challenge and realize ferromagnetism and half-metallicity in narrow graphene nanoribbons of general types of edge structures. This magnetism exists within the density range of gate-doping experiments (~1013 cm-2) and has large spin polarization energy up to 17 meV per carrier, which induces a Zeeman splitting equivalent to an external magnetic field of a few hundred Tesla. Moreover, we trace the formation of this edge insensitive magnetism to the quantum confinement of the electronic state near the band edge and reveal the scaling law of magnetism versus the ribbon width. Our findings suggest that combining doping with quantum confinement could be a general tool to realize transition-metal-free magnetism in light-element nanostructures. PMID- 30406767 TI - Second-harmonic generation as a probe for structural and electronic properties of buried GaP/Si(0 0 1) interfaces. AB - Optical second-harmonic generation is demonstrated to be a sensitive probe of the buried interface between the lattice-matched semiconductors gallium phosphide and silicon with (0 0 1) orientation. Ex situ rotational anisotropy measurements on GaP/Si heterostructures show a strong isotropic component of the second-harmonic response not present for pure Si(0 0 1) or GaP(0 0 1). The strength of the overlaying anisotropic response directly correlates with the quality of the interface as determined by atomically resolved scanning transmission electron microscopy. Systematic comparison of samples fabricated under different growth conditions in metal-organic vapor phase epitaxy reveals that the anisotropy for different polarization combinations can be used as a selective fingerprint for the occurrence of anti-phase domains and twins. This all-optical technique can be applied as an in situ and non-invasive monitor even during growth. PMID- 30406765 TI - Abnormal subcortical activity in congenital mirror movement disorder with RAD51 mutation. AB - PURPOSE: Congenital mirror movement disorder (CMMD) is characterized by unintended, nonsuppressible, homologous mirroring activity contralateral to the movement on the intended side of the body. In healthy controls, unilateral movements are accompanied with predominantly contralateral cortical activity, whereas in CMMD, in line with the abnormal behavior, bilateral cortical activity is observed for unilateral motor tasks. However, task-related activities in subcortical structures, which are known to play critical roles in motor actions, have not been investigated in CMMD previously. METHODS: We investigated the functional activation patterns of the motor components in CMMD patients. By using linkage analysis and exome sequencing, common mutations were revealed in seven affected individuals from the same family. Next, using functional magnetic resonance imaging (fMRI) we investigated cortical and subcortical activity during manual motor actions in two right-handed affected brothers and sex, age, education, and socioeconomically matched healthy individuals. RESULTS: Genetic analyses revealed heterozygous RAD51 c.401C>T mutation which cosegregated with the phenotype in two affected members of the family. Consistent with previous literature, our fMRI results on these two affected individuals showed that mirror movements were closely related to abnormal cortical activity in M1 and SMA during unimanual movements. Furthermore, we have found previously unknown abnormal task related activity in subcortical structures. Specifically, we have found increased and bilateral activity during unimanual movements in thalamus, striatum, and globus pallidus in CMMD patients. CONCLUSION: These findings reveal further neural correlates of CMMD, and may guide our understanding of the critical roles of subcortical structures for unimanual movements in healthy individuals. PMID- 30406768 TI - Exact equations for averaged electromagnetic field and its fluctuations at wave multiple scattering by plane periodic array of magnetic microelements. AB - Electromagnetic wave (EM) multiple scattering by a plane periodic array of magnetic microelements in free space is considered analytically by natural subdividing of the EM wave into the averaged and fluctuation components. Each magnetic element is characterized by magnetic susceptibility tensor and shape. An exact Dyson integral equation is derived for the magnetic field Floquet-Bloch amplitude in-plane averaged over an array unit cell. The mass operator of the Dyson equation is expressed via the T-scattering operator of the array unit cell that satisfies a type of the Lippmann-Schwinger equation. We showed that magnetic field fluctuations are generated by the Bragg-Laue diffraction of an averaged magnetic field on the periodic array and are described inside the array as waves propagating with the Laue wave vectors equal to the difference between the in plane wave vector of the incident magnetic field and the reciprocal lattice wave vector. We derived, for the first time, an exact quadrature to calculate magnetic field fluctuations from their averaged value. These general results are illustrated by a simple Born approximation. In particular, we revealed a mechanism of discrete waveguide excitation by an incident plane EM wave via the averaged EM wave Brag-Laue diffraction on the magnetic microelement array in the quasi-static approach when the wavelength of incident EM is much larger than the sizes of magnetic elements and periods of the array. The mode energy excitation coefficient at normal incidence of the plane EM wave on the array is evaluated. PMID- 30406769 TI - Optimizing special quasirandom structure (SQS) models for accurate functional property prediction in disordered 2D alloys. AB - 2D materials such as MXenes have garnered attention in a wide field of applications ranging from energy to environment to medical. Properties of 2D materials can be tailored via alloying and in some cases, solid-solutions (disordered alloys) are formed. To predict the disordered alloy properties via first-principles, the model structure needs to imitate the random arrangements of alloyants and yet remains computationally tractable. Using density functional theory and the cluster expansion method, we investigate the accuracy of using of special quasirandom structures (SQSs) for predicting disordered 2D alloy properties, evaluating the effect of SQS supercell size on the prediction quality of formation energies, elastic properties, and structural parameters. We illustrate the findings with 5 different disordered binary [Formula: see text] MXene alloy systems (where M = Ti and M' = Zr, Hf, V, Nb, or Ta), demonstrating that SQSs around 6-8 times the primitive cell (N = 6-8) are sufficient to attain convergence in the property predictions versus supercell size. For formation energies, SQSs with N > 4 are found to reproduce the formation energies of the fully disordered phase within ~2.5 meV. For the simulation of the experimentally-synthesized TiNbCO2, we find convergence in structural parameters and elastic tensors at N ~ 6. We traced the convergence of the predictions to the convergence in the band structure-related properties via analysis of the electronic densities-of-states and the projected crystal overlap Hamilton population. Our findings suggest that modest sized SQSs would reproduce the properties of disordered MXene alloys. The results should help guide the investigations of structure-property relationships in other disordered 2D materials as well. PMID- 30406770 TI - Tumor Volume Reduction After Gemcitabine Plus Cisplatin Induction Chemotherapy in Locally Advanced Nasopharyngeal Cancer: Comparison with Paclitaxel and Cisplatin Regimens. AB - BACKGROUND Gemcitabine plus cisplatin (GP) is a novel regimen of induction chemotherapy (IC) for treating locoregional advanced nasopharyngeal cancer (NPC). This retrospective study aimed to compare the efficacy of GP and TP (paclitaxel plus cisplatin) regimens in tumor volume reduction after IC. MATERIAL AND METHODS Between January 2014 and July 2017, 44 patients with III-IVB stage NPC received GP IC followed by concurrent chemoradiotherapy. These patients were matched with 44 patients receiving TP IC according to clinical characteristics. The gross tumor volume of the primary site and positive lymph nodes were delineated by magnetic resonance imaging before and after IC, as well as the nasopharyngeal air cavities. The changes in tumor volume and nasopharyngeal air cavity after IC were calculated and compared between the 2 groups. Treatment toxicities and early survival outcomes were also reported. RESULTS There were no differences in the initial tumor volume and nasopharyngeal cavity between the 2 groups. The volume changes after IC for the primary site, lymph nodes, and nasopharyngeal cavity were 31.4 (range, -0.97-75.8), 4.68 (range, -7.08-22.06), and 2.62 (range, 0.1 7.63) mL for GP and 23.36 (range, -59.14-83.58), 4.7 (range, -11.21-48.61), and 1.47 (range, -2.47-6.17) mL for TP, respectively. All comparisons favored the GP regimen. The toxicities of the 2 regimens were comparable and no survival differences were observed at follow-up (median, 18.7 months). CONCLUSIONS Changes in the tumor volume and nasopharyngeal air cavity showed that the GP regimen was significantly more effective than the TP regimen in tumor burden reduction. However, whether the advantages of GP can translate into survival benefits requires further investigation. PMID- 30406771 TI - A HElium NanoDroplet Isolation (HENDI) investigation of the weak hydrogen bonding in the propyne dimer (CH3CCH)2. AB - A HElium Nanodroplet Isolation (HENDI) experiment was performed to explore the absorption spectra of the propyne monomer (CH3CCH), dimer and (CH3CCH)>=3 multimers in the vicinity of the CH stretch region nu1 of the monomer. Ab initio calculations were performed at the MP2 level to document the potential energy surface of the dimer. This provided the necessary parameters to simulate the absorption spectrum of the dimer and thus facilitate the interpretation of the experiment. The central result was to observe three isomers of the dimer, hence reflecting the complexity of the weak CHpi H-bonding when several H-donors are at play. PMID- 30406772 TI - Optimizing decision tree structures for spectral histopathology (SHP). AB - This paper reviews methods to arrive at optimum decision tree or label tree structures to analyze large SHP datasets. Supervised methods of analysis can utilize either sequential or (flat) multi-classifiers depending on the variance in the data, and on the number of spectral classes to be distinguished. For small number of spectral classes, multi-classifiers have been used in the past, but for the analysis of datasets containing large numbers (~20) of disease or tissue types, mixed decision tree structures were found to be advantageous. In these mixed structures, discrimination into classes and subclasses is achieved via hierarchical decision/label tree structures. PMID- 30406773 TI - Correction: A gold isocyanide complex with a pendant carboxy group: orthogonal molecular arrangements and hypsochromically shifted luminescent mechanochromism. AB - Correction for 'A gold isocyanide complex with a pendant carboxy group: orthogonal molecular arrangements and hypsochromically shifted luminescent mechanochromism' by Tomohiro Seki et al., Chem. Commun., 2018, 54, 11136-11139. PMID- 30406774 TI - Near-infrared fluorescence imaging for vascular visualization and fungal detection in plants. AB - We found that heptamethine dye IR-820 showed distinct emission peaks in both the NIR-Ia and NIR-Ib windows. IR-820 yielded images of vascular structures in the NIR-Ib window with unprecedented details. NIR-Ib fluorescence imaging was useful not only for studying plant transpiration, but also for detecting and differentiating fungal pathogens. PMID- 30406775 TI - Molecular simulations reveal that a short helical loop regulates thermal stability of type I cohesin-dockerin complexes. AB - The cellulosome provides a fully worked out example of evolved radical nanotechnology. Improved understanding, and first steps toward re-engineering this biological nanomachine, is providing design rules for the formulation of advanced synthetic materials that can harness molecular flexibility and sticking interactions for applications in clean energy, environmental monitoring, and miniaturized devices. Computer simulations provide atomic scale insights into the mechanical stability of the component protein units, flexibility of short peptides that tether the units into scaffolds, and thermodynamic stability of protein-protein and protein-carbohydrate complexes, complementing and in some cases directing experiments. In the present work, a systematic computational study of cohesin-dockerin pairs, the strongly-bound protein complexes that glue the cellulosome nano-architecture in place, reveals that a short alpha-helix in the middle of the smaller dockerin protein becomes disordered at elevated temperatures and weakens cohesin-dockerin binding in mesophilic species. In thermophilic species, a more extensive and more thermally resistant H-bond network ensures the structure remains ordered at elevated temperatures of up to 400 K. The simulations predict that simply grafting the most crucial eight residue peptide sequence into the mesophilic complex can, for one species and one of two possible binding modes, potentially create a new thermally resistant complex, providing leads for future experiments to re-engineer designer cellulosomes that can withstand elevated temperatures and so provide clean, renewable biocatalysts. PMID- 30406776 TI - A high-density collagen xerogel thread prevents the progression of peritoneal fibrosis. AB - Peritoneal fibrosis is often provoked by peritoneal dialysis and is an essential precursor condition to the development of encapsulating peritoneal sclerosis. This study aimed to determine the efficacy of a high-density collagen xerogel thread (CXT) for the prevention of peritoneal fibrosis. Female ICR mice received intraperitoneal injections of chlorhexidine gluconate (CG) every other day to induce peritoneal fibrosis. For evaluation, the insertion of CXT or infusion of atelocollagen gel into the peritoneal cavity was conducted on the day before CG injection. For comparison, no collagen treatment after CG injection, and abdominal puncture without CG injection were also performed. Peritoneal fibrosis and inflammation were significantly suppressed by CXT for a long period. CXT prevented mesothelial epithelial-mesenchymal transition, myofibroblast emergence, and inflammatory cell invasion in the peritonitis tissue. In the early phase, atelocollagen gel modulated the expression of the fibrosis-associated protein transforming growth factor (TGF)-beta, connective tissue growth factor (CTGF), and CD105 in the peritoneum under CG-induced inflammation, while CXT did not. In contrast, CXT regulated the expression of CTGF and CD105 in the late phase and maintained antimicrobial protein REG3G at the same level as the Sham group in the early and late phases. Although the precise mechanism remains to be clarified, these findings suggest that CXT may have the potential to be developed as a simple therapeutic device to prevent peritoneal fibrosis, a severe complication in patients undergoing long-term peritoneal dialysis. PMID- 30406777 TI - An in situ SERS study of ionic transport and the Joule heating effect in plasmonic nanopores. AB - Understanding the ionic transport behaviour as well as temperature change caused by the Joule heating effect is important for the application of plasmonic nanopores. To explore the basic properties of ionic transport through nanopores, we assemble gold nanoparticles on the tip of a glass nanopipette to form a hydrophilic gold porous structure (hydro-GPS) that exhibits high Raman activity. PMID- 30406778 TI - One-step construction of molecular complexity by tert-butyl nitrite (TBN) initiated cascade alpha,beta-sp3 C-H bond difunctionalization and C-N bond cleavage. AB - TBN-initiated cascade multifunctionalization of inert C-H and C-N bonds in N arylazacycles has been realized under transition-metal free conditions, in which the synthetically useful oxime, N-NO and aldehyde functional groups were constructed in only one synthetic step. PMID- 30406779 TI - Electronic and thermoelectric properties of Zn and Se double substituted tetrahedrite. AB - The influence of Zn and Se double substitution on the electronic and thermoelectric properties of tetrahedrite was investigated in this study. The samples Cu11Zn1Sb4S13-xSex (x = 0.25, 0.5, 0.75, 1, and 2) were prepared via solid state synthesis followed by field assisted sintering. The density functional theory (DFT) results showed that Se substitution introduces additional bands near the Fermi level (EF), with lower effective mass compared to Zn (only) substituted sample Cu11Zn1Sb4S13. Consequently, the electrical resistivity decreased with the increase in Se content which is attributed to the enhanced charge carrier mobility caused by the more dispersive Se states as indicated by DFT results. But the Seebeck coefficient was invariant with x, due to the enhancement of the density of states (DOS) at EF. The overall effect was an increase in power factor of the Cu11Zn1Sb4S13-xSex samples compared to Cu11Zn1Sb4S13. The Zn2+ substitution at the Cu1+ tetrahedral site resulted in a decrease of the carrier thermal conductivity due to the decrease in charge carrier concentration. Whereas Se substitution resulted in the decrease of lattice thermal conductivity due to additional phonon scattering caused by the S Se mass difference. Simultaneous optimization of the power factor and thermal conductivity could thus be achieved via double substitution at Cu and S sites. A maximum thermoelectric figure of merit (zT) of 0.86 at 673 K was exhibited by the Cu11Zn1Sb4S12.75Se0.25 sample due to its relatively high power factor among the samples (0.9 mW m-1 K-2 at 673 K) coupled with very low total thermal conductivity (0.67 W m-1 K-1 at 673 K). PMID- 30406780 TI - Water as a modulator in the synthesis of surface-mounted metal-organic framework films of type HKUST-1. AB - Thin films of nanoporous metal-organic frameworks, MOFs, are widely used for various purposes, ranging from molecular separation to electronic and optical applications. Ultrathin MOF films prepared in a controlled layer-by-layer fashion, also referred to as surface-mounted MOFs or SURMOFs, have attracted particular attention. While many aspects of SURMOF synthesis have been investigated and optimized, the impact of growth modulators, which are well established in bulk MOF synthesis, has so far received only a little attention in the context of layer-by-layer approaches. Here, we investigate the impact of water as a growth modulator during the synthesis of thin MOF films of type HKUST 1. We find that water has a tremendous impact on the crystallinity and on the defect-density of the prepared MOF films. The use of the optimized water concentrations allows considerable improvement in the SURMOF crystallinity and at the same time reduces their defect density. This study shows that water is an important modulator in MOF thin film growth and can be used to tune the material from a low defect to high defect state. PMID- 30406786 TI - Determining the lipid specificity of insoluble protein transmembrane domains. AB - While the specificity of protein-lipid interactions is a key feature in the function of biological membranes, studying the specifics of these interactions is challenging because most membrane proteins are insoluble in water due to the hydrophobic nature of their transmembrane domains (TMDs). Here, we introduce a method that overcomes this solubility limitation and identifies the affinity profile of protein TMDs to specific lipid formulations. Using 5 human TMDs as a sample group, our results demonstrate that TMDs are highly selective and that these specific lipid-TMD interactions can involve either a single lipid, or the combination of multiple lipid species. PMID- 30406781 TI - Cytotoxicity of sesquiterpene alkaloids from Nuphar plants toward sensitive and drug-resistant cell lines. AB - Multi-drug resistance (MDR) is a critical problem in cancer chemotherapy. MDR causes the overexpression of ATP-binding cassette (ABC) transporters and mutations in tumor suppressor genes and oncogenes. To tackle this issue, in this study, we focused on Nuphar plants, which have been traditionally used as food. Sesquiterpene alkaloids (1-3) were isolated from N. japonicum and dimeric sesquiterpene thioalkaloids (4-10) were isolated from N. pumilum. P-glycoprotein overexpressing CEM/ADR5000 cells were cross-resistant to 6,6' dihydroxythiobinupharidine (10). Using in silico molecular docking, we calculated the binding energies and simulated the interactions of these compounds with the corresponding amino acid residues at the binding site of P-gp. In addition, we investigated the cytotoxicity of these compounds towards cell lines overexpressing other ABC transporters (BCRP, ABCB5), cell lines with a knocked out tumor suppressor gene TP53 or cell lines overexpressing a deletion-activated EGFR oncogene. These cell lines were sensitive or only minimally cross-resistant to these compounds compared with their corresponding wild-type cell lines. PMID- 30406787 TI - Infrared photodissociation spectroscopy of ion-radical networks in cationic dimethylamine complexes. AB - Infrared photodissociation spectroscopy was employed to establish the general trends in the stepwise growth motif of cationic dimethylamine (DMA)n+ (n = 4-13) complexes. Electronic structure calculations were performed to identify the structure of the low-lying isomers and to assign the observed spectral features. The results showed the preference of the formation of the proton-transferred (CH3)2NH2+ ion core. The (CH3)2NH2+-[(CH3)2N] ion-radical pair contact and the ion-radical separated pair could coexist at n = 4. The [(CH3)2N] radical is separated from the (CH3)2NH2+ ion core by one DMA molecule at n = 4-6 and by two or more DMA molecules in the larger clusters. This suggests that the (CH3)2NH2+ [(CH3)2N] ion-radical contact pair is not stable in the subsequent radiation induced processes of DMA, and the [(CH3)2N] radical is released from the charged site in the cationic DMA networks. PMID- 30406788 TI - Computer simulation study of the solvation of lithium ions in ternary mixed carbonate electrolytes: free energetics, dynamics, and ion transport. AB - A ternary mixture of ethylmethyl carbonate (EMC), dimethyl carbonate (DMC), and ethylene carbonate (EC) is a common solvent used in lithium ion batteries. The effect of cyclic ethylene carbonate (EC) on the solvation structure, free energetics and related dynamics of the ternary mixed carbonate electrolyte with lithium hexafluorophosphate (Li+PF6-) salt is systematically investigated by molecular dynamics simulations. The EC co-solvent tends to decrease the structural heterogeneity and solvent fluctuation in the solvation of Li+ ions. Despite the large difference in dielectric constants according to the EC concentration, the effective polarity of ternary mixed electrolytes, measured as the solvation-induced stabilization of Li+ ions, is marginally affected by EC co solvent. As the EC concentration chiEC increases, the solvation structural relaxation of Li+ ions accelerates in the subpicosecond regime, whereas the diffusional motion of ions slows down. The viscosity of the electrolyte solution and the solvation structure changed by EC co-solvent contribute to the ionic conductivity in an opposite manner, and as a result, the ionic conductivity of the electrolyte solution exhibits non-monotonic behavior according to chiEC. PMID- 30406789 TI - Assigning a structural motif using spontaneous molecular dipole orientation in thin films. AB - Spontaneous orientation of molecular dipoles has been observed to produce bulk electric fields, termed 'spontelectric' fields, in a broad variety of molecular solid thin films formed by condensation from the gas phase. Such spontelectric fields are found in cis-methyl formate (cis-MF) and the present work combines observation of these fields with high quality ab initio studies of cis-MF monomers and dimers. This enables a prediction of the structural motif within the unit cell of the crystalline phase of solid cis-MF, showing it to be a non-polar dimer. Dimer formation at deposition temperatures of >90 K is therefore cited to contribute to the observed collapse of the spontelectric field at these temperatures. This is the first time that such a structural prediction has been made using observations of spontelectric behaviour as a key indicator. PMID- 30406790 TI - An ultraviolet and electric field activated photopolymer-ferroelectric nanoparticle composite for the performance enhancement of triboelectric nanogenerators. AB - For the development of high performance triboelectric generators (TENGs), it is required to have facile methods to adjust the triboelectric properties of the friction surfaces. In this work, we present the surface charge density modulation of the photopolymer-ferroelectric nanoparticle composite surface by applying ultraviolet (UV) and electric field. By using the photopolymer, the triboelectric surface property was modulated by exposure to UV. In addition, lithographic surface patterning can be easily adopted to enlarge the frictional surface area as well. Furthermore, the use of the PP allows a facile integration of ferroelectric nanoparticles (NPs) in the form of a nanocomposite structure, which can effectively increase the surface charge density by spontaneous dipole coupling of NPs embedded in the PP layer. As a result, approximately 4-fold higher output power has been achieved by applying this approach. The developed TENGs have also demonstrated superior mechanical durability, generating consistent outputs during 104 cyclic frictional contacts. The approach proposed here is a simple and reliable way to enhance the output performance of TENGs. PMID- 30406791 TI - Structural design considerations of solution-processable graphenes as interfacial materials via a controllable synthesis method for the achievement of highly efficient, stable, and printable planar perovskite solar cells. AB - Solution-processable graphenes (represented by reduced graphene oxides, rGOs) have shown promising abilities as HTLs in perovskite solar cells (PeSCs). However, there has been no attempt to systematically tailor the characteristics of rGOs to the specifications of PeSCs. Furthermore, the applications of rGO HTLs have been limited to the spin-coating system, which is incompatible with roll-to roll manufacturing. Here, with the aid of a polymer-graphene hybrid structure and a controllable synthesis method, we successfully developed a much more feasible rGO HTL and demonstrated highly efficient, stable, and printable p-i-n planar PeSCs with facile one-step processing. The characteristics of the developed polyacrylonitrile-grafted rGOs (PRGOs) were optimized by varying the synthesis conditions including the gamma-radiation intensity (200, 400, and 600 kGy) and the concentration of the acrylonitrile (AN) precursor (2, 4, and 6 wt%). It is revealed that the PRGO synthesized with a lower AN concentration and a higher irradiation intensity (PRGO_2-600) is the most suitable one for PeSC HTL. PRGO_2 600 effectively raises the average power conversion efficiencies (PCEs) of PeSCs by ~36% compared to those of conventional PeSCs using PEDOT:PSS HTL. The comprehensive investigations confirm that the enhanced device efficiency stems from (1) the favorable interlayer characteristics of the PRGO itself and (2) the well-crystallized perovskite layer grown on the PRGO. In addition to the PCE, thechemically inert PRGOs can also maintain their electrical properties over time and retard the decomposition of perovskite films, thereby prolonging the operation time of PeSCs in the atmosphere. More importantly, the applicability of the PRGO HTL is clearly verified even in the roll-to-roll compatible slot-die coating system, exhibiting comparable performances to those of the spin-coating system. PMID- 30406792 TI - Elucidation of the intrinsic optical properties of hydrogen-bonded and protonated flavin chromophores by photodissociation action spectroscopy. AB - A model system of the flavin chromophore was synthesized and investigated for its intrinsic optical properties by gas phase action spectroscopy using an ion storage ring. An ammonium group was anchored to this flavin chromophore to allow its transfer to the gas phase by electrospray ionization and for studying the influence of hydrogen bonding and a nearby positive charge. According to calculations one of the hydrogen atoms of the ammonium group favorably forms an intramolecular ionic hydrogen bond to one of the oxygen atoms of the flavin chromophore, and this interaction was found to cause a blueshift of the S0 -> S1 transition and a redshift of the S0 -> S2 transition. For comparison, the S0 -> S1 transition shows little solvent dependence (only in regard to the degree of fine structure). In addition, the influence of protonation of the flavin chromophore was elucidated by experimental and theoretical studies of a simple flavin system. While the position of the S0 -> S1 absorption was at identical positions in the gas phase for the intramolecularly hydrogen-bonded and protonated flavin systems, the S0 -> S2 absorption was further redshifted for the protonated species. This redshift resulting from protonation was also observed in solution. PMID- 30406793 TI - Rh-Catalyzed aminative dearomatization of 2-naphthols. AB - A direct aminative dearomatization of 2-naphthols was achieved. In the presence of 1 mol% Rh2(esp)2 and 3 equivalents of O-(2,4-dinitrophenyl)hydroxylamine (DPH) as readily available aminating reagents, the reactions of 2-naphthols afforded unprotected alpha-amino-beta-naphthalenones in good yields under mild reaction conditions. The conditions were compatible with gram-scale reaction, and the product could undergo diverse transformations. PMID- 30406794 TI - Carbon-encapsulated multi-phase nanocomposite of W2C@WC1-x as a highly active and stable electrocatalyst for hydrogen generation. AB - The major challenges related to the activity, stability, and cost of electrocatalysts are being increasingly raised to achieve highly efficient and cost-effective hydrogen generation. Herein, multiphase nanocomposites of W2C@WC1 x encapsulated within graphitic carbon layers were prepared via a facile and effective process of electrical explosion of wires and subsequent heat treatment to serve as a highly active and stable electrocatalyst without any noble metal for hydrogen generation. The single-phase comprising less than 15 nm WC1-x nanoparticles embedded in a lump of amorphous carbon were successfully synthesized via the EEW process in oleic acid used as a carbon source at room temperature. Subsequent heat treatment facilitates the desired phase transition of WC1-x to W2C without the formation of any secondary phases, maintaining the initial particle size and simultaneously eliminating excess amorphous carbon adhered to the nanoparticles. The few graphitic carbon layer-encapsulated nanoparticles with the main W2C phase prepared by this simple method exhibit high efficiency for hydrogen generation with a low overpotential of 240 mV at a current density of 10 mA cm-2 and a low Tafel slope of 86 mV dec-1. Moreover, the overpotential is well maintained at a constantly injected current density of 10 mA cm-2 for 100 h with a low eta100/etai value of 1.03 (etai: initial overpotential, eta100: overpotential after 100 h), demonstrating superior catalytic stability in acidic media. This work proposes and evaluates a facile strategy for the synthesis of highly efficient electrocatalysts based on metal carbides without noble metals. PMID- 30406795 TI - Using light, X-rays and electrons for evaluation of the nanostructure of layered materials. AB - As a case study for the evaluation of the nanostructure of layered materials, we report on results of the comprehensive characterization of high-energy ball milled layered molybdenum disulfide (2H-MoS2) on different length scales. Analysis of X-ray powder diffraction patterns (XRPDs) including the Debye background at low scattering angles caused by uncorrelated single or few-layer MoS2 slabs (full scattering model), yield much more precise data about the average stacking degree than routine XRPD evaluation, and an estimation of the amount of single layer material is possible. Reflections with super Lorentzian line shape can be satisfactorily modeled assuming different stacking sequences induced by the mechanical forces exerted during the high-energy ball-mill process. An advanced analysis of UV-Vis spectra to determine layer number and lateral crystallite size, which was recently developed for liquid exfoliation materials, is used for the first time, and the results demonstrate the universal applicability of the approach. The data obtained with this analysis support the main findings of evaluation of the XRPD data. Both methods clearly evidence that increasing the duration of high-energy ball-mill treatment leads to an increase of material with decreasing average stacking and a reduction of the lateral size of the slabs. Finally, high-resolution transmission electron microscopy enabled identification of defects which can hardly be detected in XRPDs or in UV-Vis spectra. PMID- 30406796 TI - Thermally induced structural transformations of linear coordination polymers based on aluminum tris(diorganophosphates). AB - The thermal transitions of inorganic-organic hybrid polymers composed of linear aluminum tris(diorganophosphate) chains with a general formula of catena Al[O2P(OR)2]3 (where R = C1-C8 alkyl group or phenyl moiety) have been studied by means of DSC, powder XRD, TGA and TG-QMS, as well as optical spectroscopy. DSC and XRD reveal that most of them undergo reversible structural transformations in the solid state between -100 and 200 degrees C caused by the changes in conformation of their organic substituents; however, a translational displacement of the rigid polymeric chains occurs only in the case of the derivative bearing long 2-ethylhexyl groups, which becomes liquid at about 140 degrees C. The thermal decomposition of the studied polymers begins between 200 and 265 degrees C depending on the type of organic substituent R decorating their aluminophospate core. TGA combined with mass spectrometry of the evolved gaseous products shows that the pyrolytic decomposition of Al[O2P(OR)2]3 proceeds either through beta elimination of olefin (for compounds with C2-C8 aliphatic ligands), or a homolytic cleavage of the P-OR bond (for methyl and phenyl derivatives); both processes are accompanied by condensation of the newly formed POH groups and liberation of water. Powder XRD, FTIR and SEM analyses of the solid residues indicate that thermolysis of Al[O2P(OR)2]3 accompanied by olefin elimination leads to the formation of condensed aluminum phosphates, mainly aluminum cyclohexaphosphate, exhibiting porous morphology. On the other hand, thermal degradation of methyl or phenyl derivatives results in amorphous aluminophosphate residues, and the latter contains conducting carbonaceous phases. PMID- 30406797 TI - Comparative study of the strongest solid Lewis acids known: ACF and HS-AlF3. AB - Aluminium chlorofluoride (ACF) and high-surface aluminium fluoride (HS-AlF3) were analyzed by a set of characterization methods to assess their acidic properties: NH3-TPD, CO adsorption followed by DRIFTS, CD3CN-PAS-FTIR and MAS NMR spectroscopy after 15N-pyridine adsorption. Both catalysts contain very strong and medium-strong Lewis acid sites as confirmed by CO adsorption, in which small differences arise from the morphological properties of each catalyst, with ACF being microporous and HS-AlF3 mesoporous. Shifts of the CO vibration band of up to 77 cm-1 were observed, which account for very strong Lewis acid sites. In addition, very strong Lewis acid sites could be identified by CD3CN-PAS for both catalysts, exhibiting a shift of 95 cm-1 from free nitrile, the highest ever reported for a solid Lewis acid. PMID- 30406798 TI - A near-infrared fluorescent probe for monitoring leucine aminopeptidase in living cells. AB - Leucine aminopeptidase (LAP), one of the important cancer-related biomarkers, is significantly over-expressed in many malignant tumor cells. Developing an effective fluorescent probe for high-specificity and in situ trapping of endogenous LAP in living samples is still challenging. In this project, we report a water-soluble near-infrared (NIR) fluorescent probe (CHMC-M-Leu) for specific monitoring of LAP in vitro and in vivo. The novel fluorescent probe (CHMC-M-Leu) contains a NIR-emitting fluorophore (CHMC-M) as the reporter and l-leucine as the enzyme-active trigger moiety which are linked together by a p-aminobenzyl alcohol (PABA) section. Upon exposure to LAP, the fluorescence at 625 nm gets impressively enhanced, which belongs to the near-infrared region and is beneficial for imaging in vivo. Furthermore, the novel fluorescent probe exhibits fast response and highly chemoselective detection of LAP in various bio-related species. In addition, CHMC-M-Leu shows favourable cellular uptake and was successfully used to monitor endogenous LAP in living cells. PMID- 30406799 TI - Highly conductive porous graphene/sulfur composite ribbon electrodes for flexible lithium-sulfur batteries. AB - Flexible batteries have become an indispensable component of emerging devices, such as wearable, foldable electronics and sensors. Although various flexible batteries have been explored based on one-dimensional and two-dimensional platforms, developing a high energy density electrode with high structural integrity remains challenging. Herein, a scalable, one-pot wet spinning strategy is used to synthesize a flexible porous cathode for lithium-sulfur batteries (LSBs) for the first time, which consists of reduced graphene oxide (rGO), graphene crumples (GCs) and sulfur powders. The electrode structures are tailored using GCs with different dimensions and functional features that are critical to its robustness under mechanical deformation and electrolyte penetration into the battery components. The optimized rGO/GC/S composite ribbon cathodes deliver a high capacity of 524 mA h g-1 after 100 cycles at a current rate of 0.2 C. A shape-conformable battery prototype comprising an rGO/GC/S cathode and a lithium anode demonstrates a stable discharge characteristic under repeated bending/flattening cycles. The LSB prototype supported by an elastomer presents stable discharge behavior with high mechanical robustness against an extension of up to 50%. The above-mentioned findings shed new light on developing sulfur cathodes for flexible, high performance LSBs based on the rational design of graphene structures. PMID- 30406804 TI - Electronic density distribution of Mn-N bonds by a tuning effect through partial replacement of Mn by Co or Ni in a sodium-rich hexacyanoferrate and its influence on the stability as a cathode for Na-ion batteries. AB - This study evaluates the effect of equimolar substitution of manganese by cobalt or nickel in hexacyanoferrate (HCF) open frameworks as electrode materials for Na ion batteries. As the stability of Mn-N bonds is crucial to obtain long term stability and cyclability of manganese (Mn-HCF), the samples were analyzed thoroughly using several spectroscopic and structural methods. The XPS and infrared experiments reveal that the charge density around Fe is modulated by the presence of Co or Ni, which is associated with their high polarizing power, leading to decreased cell distortion as revealed by XRD. The Rietveld refinement demonstrated that the octahedra built by 3d metals and the cyanide nitrogen were distorted with the axial bond distances being larger than the equatorial distances. This octahedral distortion promotes the spin behavior of 3/2 for Mn2+ confirmed by magnetic experiments; the arising of this spin state is attributed to d orbital splitting determined by UV-Vis experiments. Therefore, the changes upon Mn substitution are related to the modification of the covalent character of Mn-N bonds, modulated by the effect of the Ni and Co polarizing power. All these properties improve the electrochemical stability of the Ni or Co substituted materials as Na-ion batteries, leading to higher capacity retention even at higher C-rates (5C) and good capacity recovery, in comparison with those obtained for Mn-HCF. PMID- 30406805 TI - Correction to: Industry-funded versus non-profit-funded critical care research: a meta-epidemiological overview. AB - The original article can be found online. PMID- 30406806 TI - Innovation and safety in critical care: should we collaborate with the industry? Pro. PMID- 30406807 TI - Innovation and safety in critical care: should we collaborate with the industry? Con. PMID- 30406808 TI - [Robot-assisted minimally invasive esophagectomy]. PMID- 30406809 TI - Comment on 'Exercise training decreases pancreatic fat content and improves beta cell function regardless of baseline glucose tolerance: a randomised controlled trial'. Reply to Amini P and Moharamzadeh S [letter]. PMID- 30406810 TI - [What does dermatology have to do with andrology?] PMID- 30406811 TI - [Andrological consultation in new systemic oncological therapies with small molecules]. AB - Small molecules are rapidly broadening the spectrum of systemic oncologic therapies. Targets of those drugs are-among others-tyrosine and serine/threonine kinases like VEGF-R, EGF-R, Bcr-Abl, c-kit, JAK, CDK as well as BRAF and MEK. Clinical data of potential risks to male fertility are still very limited and are generally only available for older preparations. In addition, they are often multikinase inhibitors, so that even small molecules with the same (main) target are not completely comparable. For fertility protection, sperm cryopreservation should be offered to men seeking fatherhood before starting targeted therapy. PMID- 30406813 TI - Synovitis following anterior cruciate ligament reconstruction using the LARS device. AB - PURPOSE: The Ligament Augmentation and Reconstruction System (LARS(r)) has been at the forefront of a recent revival in the use of synthetic ligaments for ACL reconstruction. However, despite promising short-to-mid-term results its role has been approached with caution due to a high number of major complications in previous synthetic graft designs including mechanical failures, synovitis and osteoarthritis. This study aims to report on the incidence of synovitis in a series of patients undergoing second-look surgery following LARS ACL reconstruction. METHODS: A retrospective analysis was performed of a single surgeon's series of 12 patients that underwent second-look arthroscopic surgery following primary LARS ACL surgery for indications including mechanical symptoms (meniscal tears/cyclops lesions/chondral flaps) and/or symptomatic instability secondary to LARS failure. In all cases an examination under anaesthesia (EUA) was performed, and a qualitative assessment of the synovium was carried out and graded as normal, reactive or inflammatory. A synovial biopsy was performed in all knees with visible evidence of synovitis and in all cases of LARS failure. RESULTS: The second-look arthroscopy was performed at a mean of 23 months (7-66) after the index surgery. In 6 (50%) knees the LARS device had failed necessitating removal and revision ACL reconstruction, while in the remaining 6 knees the LARS was still intact. Arthroscopic evaluation of the synovium revealed a normal appearance in 8 knees (67%) and reactive synovitis in 4 knees (23%); of these 4 knees, one had an intact LARS device and 3 had failed LARS. Histological examination from these 4 knees and the 3 knees with graft failures without visible synovitis revealed chronic hypertrophic synovitis (moderate 2, mild 5) in all cases with rare giant cells, consistent with a reaction to foreign body material. CONCLUSIONS: Foreign body synovitis is a common finding in our series of patients undergoing a repeat arthroscopy following a LARS ACL reconstruction. The histological diagnosis of synovitis was more frequently encountered than an arthroscopic appearance of synovitis. Whilst the results of this case series cannot support a direct causative link between LARS failure and the development of synovitis, this study highlights the need to remain vigilant about the risk of reactive synovitis following LARS ACL reconstruction due to exposure of the knee to foreign body material. LEVEL OF EVIDENCE: Level IV, case series. PMID- 30406812 TI - [Sexually transmitted infections and male fertility]. AB - BACKGROUND: Sexually transmitted infections (STI) are common worldwide and can cause impairment of fertility. In women pelvic inflammatory disease with subsequent tubal sterility is well-documented but the influence of STI on male fertility is still controversely discussed OBJECTIVE: The effects of various bacterial and viral STI on male fertility are discussed. MATERIAL AND METHODS: An evaluation of the international literature up to 30 April 2018 was carried out including studies on larger collectives from the Asiatic region. RESULTS: There is still an inconsistent picture of the influence of various bacterial and viral STI on male fertility. Direct or indirect evidence of the impact of a pathogen alone on the quality of ejaculates could not be clearly demonstrated; however, there are indications of a negative effect by Mycoplasma and Ureaplasma species in large Asiatic collectives. The transmission of viral pathogens, such as human papillomavirus (HPV), herpes simplex virus (HSV) and hepatitis B virus (HBV) possible impairs the success of assisted reproductive techniques. In contrast, manifest inflammatory processes of the male genital tract caused by STI (in particular Chlamydia and gonococci) or human immunodeficiency virus (HIV) infections often result in impairment of sperm qualtity. CONCLUSION: In cases of male fertility disorders a microbiological clarification is recommended. Further studies on the effect of STI on male fertility in larger collectives are necessary, particularly for Caucasian populations. The utilization of existing preventive measures, such as screening for Chlamydia in young women and HPV vaccination also for young males, should be intensively promoted. PMID- 30406814 TI - Metallothionein Induced Time Dependent Histomorphometric Analysis of Clarias gariepinus Exposed to Cadmium. AB - Cadmium (Cd), an extremely toxic heavy metal is extensively used in modern era because of its constructive chemical and physical properties. Recently Cd contamination was estimated in India's major cities fresh water ecosystem, which may have firm impact on human health. Hence, this study was aimed to detect the time dependent effect of cadmium in fresh water fish C. gariepinus, a bioindicator species of water pollution. In a controlled environment, fishes were exposed to cadmium for different duration and analyzed for Cd accumulation. Cd induced toxicity was assessed by estimating metallothionein biomarker protein of heavy metal toxicity and histomorphometric changes in liver and kidney. Our results revealed that fish exposed to Cd induced apoptosis in fish tissues via induction of caspases and in contrast the metallothionein was also increased consistently with different doses of Cd exposure. Hence we conclude Cd induced structural damages to fishes are attributed to induction of caspases and estimating MT level in tissues can be effective biomarker to analyze the effect of acute environmental exposure to Cd. PMID- 30406815 TI - Academic cosmetic gynecology and energy-based therapies: ambiguities, explorations, and FDA advisories. PMID- 30406816 TI - Should we combine vaginal prolapse surgery with continence surgery? AB - The risk of postoperative stress urinary incontinence (SUI) can be reduced by combining prolapse repair with continence surgery. However, more women face a serious adverse event (SAE) after vaginal prolapse surgery combined with a midurethral sling (MUS). It is difficult to predict a woman's individual postoperative SUI and SAE risk; therefore, weighing the benefits and risks of combination surgery is complex. We offer a concept that might help in considering combination surgery. According to this concept, women whose risk of needing subsequent surgery for postoperative SUI is on average 9% are likely to benefit from combination surgery. PMID- 30406817 TI - Selective resetting position and heading estimations while driving in a large scale immersive virtual environment. AB - Two experiments investigated how self-motion cues and landmarks interact in determining a human's position and heading estimations while driving in a large scale virtual environment by controlling a gaming wheel and pedals. In an immersive virtual city, participants learned the locations of five buildings in the presence of two proximal towers and four distal scenes. Then participants drove two streets without viewing these buildings, towers, or scenes. When they finished driving, either one tower with displacement to the testing position or the scenes that had been rotated reappeared. Participants pointed in the directions of the five buildings. The least squares fitting method was used to calculate participants' estimated positions and headings. The results showed that when the displaced proximal tower reappeared, participants used this tower to determine their positions, but used self-motion cues to determine their headings. When the rotated distal scenes reappeared, participants used these scenes to determine their headings. If they were instructed to continuously keep track of the origin of the path while driving, their position estimates followed self motion cues, whereas if they were not given instructions, their position estimates were undetermined. These findings suggest that when people drive in a large-scale environment, relying on self-motion cues, path integration calculates headings continuously but calculates positions only when they are required; relying on the displaced proximal landmark or the rotated distal scenes, piloting selectively resets the position or heading representations produced by path integration. PMID- 30406818 TI - Surgical excision and not chemotherapy is the most powerful modality in treating synovial sarcoma: the UK's North East experience. AB - BACKGROUND AND PURPOSE: We reviewed our experience of synovial sarcoma to identify factors predictive of local recurrence and overall survival, the impact of chemotherapy and outcomes after surgical excision alone. MATERIALS AND METHODS: 81 patients were treated between 1997 and 2014 of mean age 39 years (8 78). Tumours were in the extremity in 55 (67%). 9 patients presented with metastases and 10 with unresectable disease. Mean follow-up was 3.7 years (SD 3.8). Treatment groups were palliative, surgery only, surgery and radiotherapy, or surgery with chemotherapy (with or without radiotherapy). RESULTS: Local recurrence-free survival (LRFS) was 73% at 5 years, and 68% at 10 and 15 years. In multivariate analysis, positive surgical margins were an independent predictor of LRFS. Overall survival (OS) was 50% at 5 years for all patients, and 62% at 5 years for those treated with curative intent. Larger tumour size and non extremity locations were predictors of poorer OS. Patients who had chemotherapy did not have significantly better OS or LRS than others. INTERPRETATION: These results show that where feasible, curative resection should not be delayed for chemotherapy. Treatment with surgery only can be associated with good outcomes in selected patients with smaller extremity tumours; although our series is small. PMID- 30406819 TI - Randomized trial of an increased dose of calcium channel blocker or angiotensin II type 1 receptor blocker as an add-on intensive depressor therapy in type 2 diabetes mellitus patients with uncontrolled essential hypertension: the ACADEMIE Study. AB - There is a lack of data on how to treat hypertensive patients with diabetes when treatment with medium doses of calcium channel blocker and angiotensin II type 1 receptor blocker (ARB) is insufficient to achieve the target blood pressure (BP). A total of 121 participants with type 2 diabetes and uncontrolled essential hypertension, who were receiving medium doses of amlodipine (5 mg/day) and ARB, were enrolled. Participants were randomized to receive either a high dose of amlodipine (10 mg/day) plus a medium dose of ARB (high-AML) or a medium dose of amlodipine (5 mg/day) plus a high dose of ARB (high-ARB). The depressor effects of these two regimens were monitored using a telemonitoring home BP-measuring system. Fifty-four patients were excluded after an observation period, and the remaining 67 eligible participants were randomized into the two groups; 42 which had a record of their home BP for analysis. The change in morning home systolic and diastolic BP was greater in the high-AML than in the high-ARB (systolic BP; - 7.9 mmHg vs. + 2.7 mmHg; p = 0.0002, diastolic BP; - 3.9 mmHg vs. + 0.6 mmHg; p = 0.0007). In addition, the home systolic and diastolic BP before going to bed and office systolic BP were significantly reduced from week 0 only in the high-AML. An increased dose of amlodipine, but not ARB, reduced home morning BP in hypertensive patients with type 2 diabetes who were already receiving combination therapy with medium doses of amlodipine and ARB. PMID- 30406820 TI - Reduced resistance to sediment-trapping turfs with decline of native kelp and establishment of an exotic kelp. AB - Understanding the strength and type of interactions among species is vital to anticipate how ecosystems will respond to ongoing anthropogenic stressors. Here, we examine the ecological function of native (Ecklonia radiata) and invasive (Undaria pinnatifida) kelps in resisting shifts to sediment-trapping turf on reefs within the highly urbanized temperate Port Phillip Bay (PPB), Australia. Short-term (30 days) and long-term (232 days) manipulations demonstrated that kelp laminae can clear and maintain the substratum free of turfs, while conversely, removal of kelp leads to a proliferation of turfs. Analyses looking at the relationship between total length of E. radiata and U. pinnatifida and the area cleared of turf algae showed that the clearing effect of E. radiata over a year was greater than that of U. pinnatifida due to the annual die-back of the invasive. A natural experiment (608 days) identified that ongoing sea urchin (Heliocidaris erythrogramma) grazing led to native kelp bed decline, facilitating turf dominance. Even though U. pinnatifida establishes once native beds are disturbed, its ecological function in clearing turf is weaker than E. radiata, given its annual habit. In PPB, turfs represent the more persistent and problematic algal group and are likely changing the structure, function, and energy flows of shallow temperate reefs in this urbanised embayment. PMID- 30406821 TI - Long-term trends in the foraging ecology and habitat use of an endangered species: an isotopic perspective. AB - Evaluating long-term drivers of foraging ecology and population productivity is crucial for providing ecological baselines and forecasting species responses to future environmental conditions. Here, we examine the trophic ecology and habitat use of North Atlantic leatherback turtles (St. Croix nesting population) and investigate the effects of large-scale oceanographic conditions on leatherback foraging dynamics. We used bulk and compound-specific nitrogen isotope analysis of amino acids (CSIA-AA) to estimate leatherback trophic position (TP) over an 18 year period, compare these estimates with TP estimates from a Pacific leatherback population, and elucidate the pre-nesting habitat use patterns of leatherbacks. Our secondary objective was to use oceanographic indices and nesting information from St. Croix leatherbacks to evaluate relationships between trophic ecology, nesting parameters, and regional environmental conditions measured by the North Atlantic Oscillation (NAO) and Atlantic Multidecadal Oscillation. We found no change in leatherback TP over time and no difference in TP between Atlantic and Pacific leatherbacks, indicating that differences in trophic ecology between populations are an unlikely driver of the population dichotomy between Pacific and Atlantic leatherbacks. Isotope data suggested that St. Croix leatherbacks inhabit multiple oceanic regions prior to nesting, although, like their conspecifics in the Pacific, individuals exhibit fidelity to specific foraging regions. Leatherback nesting parameters were weakly related to the NAO, which may suggest that positive NAO phases benefit St. Croix leatherbacks, potentially through increases in resource availability in their foraging areas. Our data contribute to the understanding of leatherback turtle ecology and potential mechanistic drivers of the dichotomy between populations of this protected species. PMID- 30406822 TI - Locally distributed multicentric plasmacytomas in the ileum secondary to lymphoma chemoimmunotherapy. PMID- 30406823 TI - The effect of rho kinase inhibition on morphological and electrophysiological maturity in iPSC-derived neurons. AB - Induced pluripotent stem cell (iPSC)-derived neurons permit the study of neurogenesis and neurological disease in a human setting. However, the electrophysiological properties of iPSC-derived neurons are consistent with those observed in immature cortical neurons, including a high membrane resistance depolarized resting membrane potential and immature firing properties, limiting their use in modeling neuronal activity in adult cells. Based on the proven association between inhibiting rho kinase (ROCK) and increased neurite complexity, we seek to determine if short-term ROCK inhibition during the first 1 2 weeks of differentiation would increase morphological complexity and electrophysiological maturity after several weeks of differentiation. While inhibiting ROCK resulted in increased neurite formation after 24 h, this effect did not persist at 3 and 6 weeks of age. Additionally, there was no effect of ROCK inhibition on electrophysiological properties at 2-3, 6, or 12 weeks of age, despite an increase in evoked and spontaneous firing and a more hyperpolarized resting membrane potential over time. These results indicate that while there is a clear effect of time on electrophysiological maturity, ROCK inhibition did not accelerate maturity. PMID- 30406824 TI - Distribution of FMRFamide-related peptides and co-localization with glutamate in Cupiennius salei, an invertebrate model system. AB - FMRFamide-related proteins have been described in both vertebrate and invertebrate nervous systems and have been suggested to play important roles in a variety of physiological processes. One proposed function is the modulation of signal transduction in mechanosensory neurons and their associated behavioral pathways in the Central American wandering spider Cupiennius salei; however, little is known about the distribution and abundance of FMRFamide-related proteins (FaRPs) within this invertebrate system. We employ immunohistochemistry, Hoechst nuclear stain and confocal microscopy of serial sections to detect, characterize and quantify FMRFamide-like immunoreactive neurons throughout all ganglia of the spider brain and along leg muscle. Within the different ganglia, between 3.4 and 12.6% of neurons showed immunolabeling. Among the immunoreactive cells, weakly and strongly labeled neurons could be distinguished. Between 71.4 and 81.7% of labeled neurons showed weak labeling, with 18.3 to 28.6% displaying strong labeling intensity. Among the weakly labeled neurons were characteristic motor neurons that have previously been shown to express gamma-aminobutyric acid or glutamate. Ultrastructural investigations of neuromuscular junctions revealed mixed presynaptic vesicle populations including large electron-dense vesicles characteristic of neuropeptides. Double labeling for glutamate and FaRPs indicated that a subpopulation of neurons may co-express both neuroactive compounds. Our findings suggest that FaRPs are expressed throughout all ganglia and that different neurons have different expression levels. We conclude that FaRPs are likely utilized as neuromodulators in roughly 8% of neurons in the spider nervous system and that the main transmitter in a subpopulation of these neurons is likely glutamate. PMID- 30406826 TI - Three-dimensional force analysis of surgical manipulations at the long process of the incus. AB - PURPOSE: Surgical manipulation with application of inappropriate force may damage middle ear structures leading to hearing loss. This work analyzes the forces applied in simulated otosurgical exercises in a laboratory set-up by measuring the spatial components of applied forces with objective assessment criteria. With these criteria, the individual force characteristics applied by the surgeon can be quantified and an objective feedback can be given about their surgical maneuvers. METHODS: A natural size model of the human incus was mounted on a load cell to measure the spatial forces in all three directions during different manipulation tasks performed under the microscope by ten surgeons from our department having different levels of experience in otosurgery. The motions of the incus model and the instrument tip were recorded simultaneously with a video camera. RESULTS: Independent of surgical experience, a three-dimensional force pattern could be detected with components transverse to the desired force directions. The measured forces applied by trainees showed larger variations in magnitude, in spatial distribution and in temporal course than those applied by experienced surgeons. A better repeatability of identical tasks, constancy of force patterns and low peak force values could be seen in the group of experienced surgeons. CONCLUSIONS: The laboratory system presented in this study using simultaneous video and 3-D force registration allows the objective assessment of surgical manipulations, e.g., at the long process of the incus. Training with video and force feedback provides information about surgical techniques and skill development of surgeons and has the potential to shorten the learning curve and to diminish intra-operative risks to patients. PMID- 30406825 TI - [Leadless endocardial ultrasound based left ventricular stimulation : WISE CRT System: alternative to conventional methods]. AB - There are still several limitations in delivering cardiac resynchronisation therapy (CRT). After 6 months, 20-40% of patients fail to have clinical benefit due to various reasons. Endocardial stimulation rather than conventional epicardial pacing has been shown to be more physiological, improves electrical stimulation of the left ventricle (LV), has less dispersion of electrical activity and results in better resynchronisation. The WiSETM CRT System ("Wireless stimulation endocardial system"; EBR Systems, Sunnyvale, CA, USA) provides an option for wireless, LV endocardial pacing triggered by a conventional right ventricular pacing spike from a co-implant. The feasibility of the WiSETM CRT System has been successfully demonstrated in a population of failed cardiac resynchronisation patients with either failed implantation of a conventional system, nonresponse to conventional therapy or upgrade from pacemaker or defibrillator, where a conventional system was not an option. The WiSETM CRT System is an innovative technology with promising safety, performance and preliminary efficacy. PMID- 30406827 TI - Bifunctional in vivo role of laccase exploited in multiple biotechnological applications. AB - Laccases are multicopper enzymes present in plants, fungi, bacteria, and insects, which catalyze oxidation reactions together with four electron reduction of oxygen to water. Plant, bacterial, and insect laccases have a polymerizing role in nature, implicated in biosynthesis of lignin, melanin formation, and cuticle hardening, respectively. On the other hand, fungal laccases carry out both polymerizing (melanin synthesis and fruit body formation) as well as depolymerizing roles (lignin degradation). This bifunctionality of fungal laccases can be attributed to the presence of multiple isoforms within the same as well as different genus and species. Interestingly, by manipulating culture conditions, these isoforms with their different induction patterns and unique biochemical characteristics can be expressed or over-expressed for a targeted biotechnological application. Consequently, laccases can be considered as one of the most important biocatalyst which can be exploited for divergent industrial applications viz. paper pulp bleaching, fiber modification, dye decolorization, bioremediation as well as organic synthesis. The present review spotlights the role of fungal laccases in various antagonistic applications, i.e., polymerizing and depolymerizing, and co-relating this dual role with potential industrial significance. PMID- 30406828 TI - Left inferior parietal and posterior temporal cortices mediate the effect of action observation on semantic processing of objects: evidence from rTMS. AB - Previous studies showed that motor information related to tool use (i.e., functional actions) could affect processing of objects semantic properties, whereas motor information related to grasping or moving tool (i.e., structural actions) cannot. However, little is known about the neural correlates mediating such interaction between motor and semantic information. Here, healthy participants performed a semantic judgment task requiring identification of semantic relations among objects, after observing a functional, a structural or a pointing action prime. In a within-subject design, during prime presentation the participants underwent repetitive transcranial magnetic stimulation (rTMS) over the left supramarginal gyrus (SMG), the left posterior middle temporal gyrus (pMTG) or received sham stimulation. Results showed that in the sham condition observing functional actions (vs. structural and pointing actions) favoured processing of semantic relations based on function similarity (i.e., taxonomic relations), but not of relations based on co-occurrence within an event schema (i.e., thematic relations). Moreover, stimulation of both left SMG and pMTG abolished the effect of functional action primes worsening subsequent judgment about taxonomic relations, and this effect was greater after pMTG stimulation. rTMS did not affect processing of thematic semantic relations. We suggest that action observation triggers activation of functional motor information within left inferior parietal cortex, and that integration between functional motor and conceptual information in left temporal cortex could impact high-level semantic processing of tools. PMID- 30406829 TI - Individual movement features during prism adaptation correlate with after-effects and interlimb transfer. AB - The human nervous system displays such plasticity that we can adapt our motor behavior to various changes in environmental or body properties. However, how sensorimotor adaptation generalizes to new situations and new effectors, and which factors influence the underlying mechanisms, remains unclear. Here we tested the general hypothesis that differences across participants can be exploited to uncover what drives interlimb transfer. Twenty healthy adults adapted to prismatic glasses while reaching to visual targets with their dominant arm. Classic adaptation and generalization across movement directions were observed but transfer to the non-dominant arm was not significant and inter individual differences were substantial. Interlimb transfer resulted for some participants in a directional shift of non-dominant arm movements that was consistent with an encoding of visuomotor adaptation in extrinsic coordinates. For some other participants, transfer was consistent with an intrinsic coordinate system. Simple and multiple regression analyses showed that a few kinematic parameters such as peak acceleration (or peak velocity) and variability of movement direction were correlated with interlimb transfer. Low peak acceleration and low variability were related to extrinsic transfer, while high peak acceleration and high variability were related to intrinsic transfer. Motor variability was also positively correlated with the magnitude of the after-effect systematically observed on the dominant arm. Overall, these findings on unconstrained movements support the idea that individual movement features could be linked to the sensorimotor adaptation and its generalization. The study also suggests that distinct movement characteristics may be related to different coordinate frames of action representations in the nervous system. PMID- 30406830 TI - [MIF in kidney diseases : A story of Dr. Jekyll and Mr. Hyde (German version)]. AB - BACKGROUND: Macrophage migration-inhibitory factor (MIF) is a cytokine best known for its proinflammatory and disease-aggravating role in a number of conditions, including atherosclerosis, autoimmune diseases, sepsis, and glomerulonephritides. OBJECTIVES: In our studies we aimed to define the role of MIF on local renal resident cells, in particular the renal epithelium. RESULTS: We have shown that MIF exerts local effects on glomerular cells, in particular the parietal epithelial cells and mesangial cells, promoting their pathological proliferation and aggravating disease course of a murine model of immune-mediated glomerulonephritis. In contrast, in a large set of animal and in vitro experiments, we have shown that in the setting of chronic kidney disease, MIF had an unexpected and potent antifibrotic and anti-inflammatory effect. This was mediated by enhanced regeneration and reduced cell-cycle arrest of tubular epithelial cells. Finally, in a combined approach using clinical studies, animal models, and in vitro experiments, we have shown that MIF is also renoprotective in the setting of acute kidney injury. In this setting, MIF-modulated programmed cell death of tubular cells and thereby reduced necroinflammation and kidney injury. CONCLUSIONS: Taken together, MIF has a dual role in kidney diseases, promoting (auto)immune glomerular diseases and limiting tubular cell injury in the setting of acute and chronic kidney diseases. These data suggest potential safety issues of systemic MIF targeted therapies, but also open new therapeutic options by targeting MIF or its analogues to tubular cells. PMID- 30406831 TI - [TILGen study-immunological targets in patients with breast cancer : Influence of tumor-infiltrating lymphocytes]. AB - BACKGROUND: The interaction of our immune system with breast cancer (BC) cells prompted the investigation of tumor-infiltrating lymphocytes (TILs) and targeted, tumor antigen-specific immunotherapy. OBJECTIVES: Correlation between TILs and pathological complete response (pCR) after neoadjuvant systemic therapy (NACT). Tumor-specific antigens (TSAs) in HER2+ and triple negative BC and establishment of TSA-specific therapies within the interdisciplinary TILGen study. METHODS: Illustration of the TILGen study design. Assessment of TILs and correlation with pCR within this BC study. RESULTS: pCR was achieved in 38.4% (56/146) and associated with estrogen receptor/progesterone receptor negative (ER-/PR-) and HER2+ tumors. Lymphocytic predominant BC (LPBC) was found in 16.4% (24/146), particularly in ER-/PR- (ER-: 27.3% vs. ER+: 9.9%, PR-: 22.3% vs. PR+: 8.2%), large, and poorly differentiated BC. TILs were significantly correlated with pCR in multivariate analysis. In LPBC, pCR was achieved in 66.7%, whereas it was 32.8% in non-LPBC. CONCLUSIONS: First results confirm the influence of the human immune system on the response to NACT in HER2+ and triple negative BC. TSA specific immunotherapy might improve the outcome in BC patients but there is an urgent need for comprehensive studies to further investigate this issue. PMID- 30406833 TI - Highlights of the special scientific sessions of the 45th Annual Scientific Meeting of the International Skeletal Society (ISS) 2018, Berlin, Germany. PMID- 30406832 TI - Comprehensive analysis of oxylipins in human plasma using reversed-phase liquid chromatography-triple quadrupole mass spectrometry with heatmap-assisted selection of transitions. AB - Oxylipins, a subclass of lipid mediators, are metabolites of various polyunsaturated fatty acids with crucial functions in regulation of systemic inflammation. Elucidation of their roles in pathological conditions requires accurate quantification of their levels in biological samples. We refined an ultra-performance liquid chromatography-multiple reaction monitoring-mass spectrometry (UPLC-MRM-MS)-based workflow for comprehensive and specific quantification of 131 endogenous oxylipins in human plasma, in which we optimized LC mobile phase additives, column, and gradient conditions. We employed heatmap assisted strategy to identify unique transitions to improve the assay selectivity and optimized solid phase extraction procedures to achieve better analyte recovery. The method was validated according to FDA guidelines. Overall, 94.4% and 95.7% of analytes at tested concentrations were within acceptable accuracy (80-120%) and precision (CV < 15%), respectively. Good linearity for most analytes was obtained with R2 > 0.99. The method was also validated using a standard reference material-SRM 1950 frozen human plasma to demonstrate inter-lab compatibility. Graphical abstract ?. PMID- 30406834 TI - Alkaptonuria-an atypical case: multi-modality imaging review. AB - Alkaptonuria is a rare inborn metabolic disorder due to a mutation in the homogentisic acid oxidase enzyme (HGO) gene on chromosome 3q. As HGO is deficient in alkaptonuria patients, there is an accumulation of homogentisic acid in the blood and urine. Homogentisic acid gets deposited in the soft tissues, tendons, cartilages, large joints and intervertebral discs. Ochronosis usually affects the dorsolumbar spine and typically spares the cervical spine and sacroiliac joints. However, in this case of isolated ochronosis, we report co-existent extensive cervical spine degenerative changes and cervical vertebral fusion, which has not been described in the literature so far. PMID- 30406835 TI - Single-shot CT after wrist trauma: impact on detection accuracy and treatment of fractures. AB - OBJECTIVE: To evaluate accuracy of fracture detection and therapeutic impact of a single-shot CT protocol as a primary imaging tool in all patients with clinical suspicion of wrist injury, and evaluate the resulting impact on therapy. MATERIALS AND METHODS: We performed a single-institution study on all patients with suspicion of fractures of the wrist and carpus. All patients underwent conventional radiography, thereafter single-shot wrist CT, and then 1-year follow up. Physicians and radiologists prospectively scored likelihood of fracture presence on a five-point scale before and after CT. Three surgeons proposed a treatment regimen (functional, cast, reduction, or operative) based on clinical and radiological data, first with knowledge of conventional radiography, and then with knowledge of CT. The reference standard for fracture presence was based on all data. We performed receiver operating characteristic (ROC) analyses and calculated proportion of wrists with treatment changes due to CT imaging. RESULTS: Ninety-eight patients participated (63% female, mean age 53, range, 18 87 years old) with 100 wrist CTs. Conventional radiography detected true-positive fractures in 45, and CT in 61 wrists. The areas under the curve for fracture detection were 0.85 (95% CI 0.77-0.93) for conventional radiography and 0.97 (95% CI 0.93-1.00) for CT. Treatment changed in 24 (24%, 95% CI 16-33%) - 31 (31%, 95% CI 23-41%) wrists, mostly involving a decrease in the rate of cast immobilization. CONCLUSIONS: Single-shot CT in patients with clinical suspicion of wrist injury increases accuracy of fracture detection. This has a significant impact therapy in this population, mainly on cast immobilization. TRIAL REGISTRATION: We registered the study at www.clinicaltrials.gov , NL43482.091.13. PMID- 30406837 TI - Isolation and characterisation of mouse intestinal mesoangioblasts. AB - AIMS AND OBJECTIVES: Children suffering from intestinal failure (IF) endure considerable morbidity and overall have poor survival rates, complicated by the shortage of organs available for transplantation. Therefore, new therapeutic approaches are pivotal if outcomes are to be improved. Over the past years, tissue engineering (TE) has emerged as a possible alternative treatment for many congenital and acquired conditions. TE aims at creating bioengineered organs by means of combining scaffolds with appropriate cell types, which in the intestine are organised within a multilayer structure. In order to generate functional intestine, this cellular diversity and organisation will need to be recreated. While the cells for the epithelial, neural and vascular compartments have been well defined, so far, less attention has been put on the muscular compartment. More recently, mesoangioblasts (MABs) have been identified as a novel source for tissue regeneration since they are able to give rise to vascular and other mesodermal derivatives. To date MABs have not been successfully isolated from intestinal tissue. Therefore, our aim was to demonstrate the possibility of isolating MABs from adult mouse small intestine. MATERIALS AND METHODS: All experiments were carried out using small intestinal tissues from C57BL/6J mice. We applied an established protocol for MAB isolation from the isolated neuromuscular layer of the small intestine. Cultured cells were stained for Ki67 to assess proliferation rates as well as for a panel of pericyte markers to determine their phenotype. RESULTS: Cells were successfully isolated from gut biopsies. Cultured cells showed good proliferative capacity and positivity for at least three pericytes markers found in vessels of the gut neuromuscular wall: neuron-glial antigen 2, alkaline phosphatase and platelet-derived growth factor beta. CONCLUSION: This proof-of-principle study lays the foundation for further characterization of MABs as a possible cell source for intestinal smooth muscle regeneration and TE. PMID- 30406836 TI - Fact or myth? The long shared common wall between the fistula and the urethra in male anorectal malformation with urethral bulbar fistula. AB - AIM: It has long been considered surgical dogma that the length of the shared common wall (CW) between a fistula and the urethra in males with anorectal malformation (ARM) and rectourethral bulbar fistula (RUBF) is considerably longer than in males with ARM and rectourethral prostatic fistula (RUPF). This belief has led surgeons who perform laparoscopic-assisted anorectoplasty (LAARP) for RUPF to avoid LAARP for RUBF for risk of potential injury to the urethra or incomplete removal of the fistula. In this study, we compared CW between RUBF and RUPF using distal colostography (DCG) and direct intraoperative measurements. METHODS: DCG of rectourethral fistula patients (n = 63; RUBF: n = 44; RUPF: n = 19) were used to measure CW retrospectively. Results were expressed as a ratio of the height of L4; i.e., CW:L4. If less than 0.7, the CW was classified as being "short"; if 0.71-1.4, as being "medium"; and if greater than 1.41, as being "long". CW that could not be measured was classified as indeterminate. 24 of these patients also had CW measured intraoperatively during LAARP as previously described. The results obtained using both techniques were also compared. RESULTS: Surprisingly, CW:L4 in RUBF patients was short in 47.7%, medium in 27.3%, long in 20.5%, and indeterminate in 4.5% on DCG, equivalent to mean lengths of 7 mm, 8.5 mm, and 10.3 mm obtained using direct intraoperative measurement for short, medium, and long CW:L4 categories, respectively. CW:L4 in RUPF was short in 73.6%, medium in 10.5%, and long in 5.2% on DCG, while mean intraoperative measurements were 5 mm, 7 mm, and 10 mm, respectively. Differences in CW measured intraoperatively were not significantly different between RUBF and RUPF (p = NS). CONCLUSION: From our findings, 47.7% of CWs in RUBF were short using two independent methods, with only 20.5% being long. Thus, LAARP should be considered actively for treating selected RUBF cases and not be excluded on the basis of CW length. PMID- 30406838 TI - Oral administration of irinotecan in patients with solid tumors: an open-label, phase I, dose escalating study evaluating safety, tolerability and pharmacokinetics. AB - BACKGROUND: Oral drug formulations have several advantages compared to intravenous formulation. Apart from patient convenience and favorable pharmacoeconomics, they offer the possibility of frequent drug administration at home. In this study, we present a new oral irinotecan formulation designed as an enteric coated immediate release tablet which in pre-clinical studies has shown good exposure with low variability. METHODS: A phase I, dose escalating study to assess safety, tolerability, pharmacokinetics and efficacy of an oral irinotecan formulation and to establish the maximum tolerated dose (MTD). Each treatment cycle was once-daily irinotecan for 14 days followed by 1 week rest. RESULTS: 25 patients were included across four cohorts; 3 patients were included in cohort 1 (20 mg/m2), 7 patients were included in cohort 2 (30 mg/m2), 3 patients were included in cohort 3 (25 mg/m2) and 12 patients were included in cohort 4 (21 mg/m2). Median age was 67 years, 52% were performance status (PS) 0 while 48% were PS 1. Median number of prior therapies was 3 (range 1-6). MTD was established at 21 mg/m2. No responses were observed. Nine patients (36%) had stable disease (SD), lasting median 19 weeks (range 7-45 weeks). Among these five patients had previously received irinotecan. No grade 3/4 hematologic toxicities were reported. Totally six patients experienced grade 1/2 anemia, three patients had grade 1/2 leucopenia and 1 patient had grade 1 thrombocytopenia. Most common non-hematological grade 1 and 2 adverse events were nausea, fatigue, diarrhea, vomiting and cholinergic syndrome. Grade 3 toxicities included diarrhea, fatigue, nausea and vomiting, no grade 4 events were reported. PK data showed consistent daily exposures during treatment at days 1 and 14 and no drug accumulation. SN-38 interpatient variability was in the same range as after infusion. CONCLUSIONS: Oral irinotecan was generally well tolerated; side effects were manageable and similar in type to those observed with intravenous irinotecan. Hematological toxicities were few and only grade 1/2. In this heavily pre-treated patient population, oral irinotecan demonstrated activity even among patients previously treated with irinotecan. PMID- 30406839 TI - Steroidal dimer by001 inhibits proliferation and migration of esophageal cancer cells via multiple mechanisms. AB - OBJECTIVE: To investigate the potential inhibitory effects of structurally novel steroidal dimer by001 in esophageal cancer in vitro. METHODS: The cytotoxicity of by001 on esophageal, gastric, neuroblastoma and prostate cancer cells was examined MTT assay and colony formation assay. By001 induced apoptosis and production of intracellular reactive oxygen species on esophageal cancer cells Ec109, TE-1 and human normal gastric epithelial cells GES-1 was detected by flow cytometry. The effect of by001 on mitochondrial membrane potential was detected by fluorescence microscope through JC-1 staining. The level of intracellular reactive oxygen species was measured by fluorescence microscope and flow cytometry via DCFH-DA staining. The effect of by001 on members of Bcl-2 family, Fas, LC3, PARP and caspases was determined by Western blot. The effect of by001 on migration was measured by transwell assay. RESULTS: By001 effectively inhibited proliferation of esophageal, gastric, neuroblastoma and prostate cancer cells in a time- and concentration-dependent manner in vitro. By001 reduced the number and the size of colonies at low micromolar concentrations, elevated cellular ROS levels and caused mitochondrial dysfunction in esophageal cancer cells. Molecular mechanistic studies showed that by001 triggered apoptosis through regulating members of Bcl-2 family and Fas. CONCLUSIONS: These findings suggested that by001 may inhibited proliferation of esophageal cancer cells through mitochondria and death receptor-mediated apoptotic pathways, autophagy induction, as well as suppressed migration of esophageal cancer cells. PMID- 30406840 TI - Exposure-response relationship of olaratumab for survival outcomes and safety when combined with doxorubicin in patients with soft tissue sarcoma. AB - PURPOSE: Olaratumab is a recombinant human IgG1 monoclonal antibody against PGDFRalpha. Olaratumab plus doxorubicin improved survivalversus doxorubicin in an open-label, randomised phase 2 soft tissue sarcoma (STS) trial. We characterised the olaratumab exposure-response relationship for progression-free survival (PFS), overall survival (OS), and safety. METHODS: PFS and OS data from the 133 patients enrolled in the phase 2 study were analysed using time-to-event modelling. The effect of olaratumab on PFS/OS was explored using the trough serum concentration after cycle 1 (Cmin1) and the average concentration throughout treatment (Cavg). The rate of treatment-emergent adverse events (TEAEs) was compared across olaratumab exposure quartiles. RESULTS: PFS and OS were described by models with an exponential hazard function and inhibitory EMAX functions to describe the effect of olaratumab, regardless of the PK endpoint. The olaratumab EC50s for PFS (ECmin150 = 82.0 ug/mL, ECavg50 = 179 ug/mL) and OS (ECmin150 = 66.1 ug/mL, ECavg50 = 134 ug/mL) corresponded to the median and 25th percentile of Cmin1/Cavg in the study, respectively. Maximum predicted improvement in the hazard ratio for OS and PFS was approximately 75% and 60%, respectively. There was no change in the rate of TEAEs with increasing olaratumab serum levels. CONCLUSIONS: PFS/OS benefits occurred without a rate change in TEAEs across quartiles. Maximum benefit in OS was achieved in the upper three quartiles and a potential of early disease progression in the lower quartile of olaratumab serum exposure. These results prompted a loading dose strategy in the ongoing phase 3 STS trial. PMID- 30406841 TI - Translation, cross-cultural adaptation, and validation of the Italian version of the Oxford Shoulder Instability Score. AB - PURPOSE: The Oxford Shoulder Instability Score (OSIS) is self-reported outcome measurement developed to evaluate shoulder instability taking into account also adaptive strategies. Valid, reliable, reproducible, and user-friendly translations of outcome measure instruments are needed to allow comparisons of international study results. METHODS: The Italian translation and cultural adaptation of the OSIS were completed using a "translation-back translation" method and the final version was administered to a sample of 25 consecutive Italian-speaking patients. The psychometric properties of this adaptation were evaluated in terms of feasibility, reliability, construct validity, and responsiveness. RESULTS: No major differences occurred between the OSIS translations into Italian and back into English, and no content- or linguistic related difficulties were reported. The Cronbach's alpha for the total OSIS was 0.897. Intraclass correlation coefficient value for inter-rater reliability was 0.805, while for intra-rater reliability was 0.586. Spearman rank correlation coefficient between the OSIS and the Rowe score was 0.548 (p = 0.005) and between OSIS-I and SF-12 was 0.488 (p = 0.013). CONCLUSIONS: The Italian version of the OSIS is a reliable, valid, and reproducible outcome measure for clinical evaluation of patients affected by shoulder instability, which remains simple and user-friendly as the original version. LEVEL OF EVIDENCE: Prospective cohort study, Level II. CLINICAL RELEVANCE: The availability of a validated translation of the OSIS will help surgeon to share their data on shoulder instability diagnostic and treatment in a more reproducible and comparable fashion. PMID- 30406842 TI - Surgical treatment of thoracic disc herniation: an overview. AB - BACKGROUND: Surgical treatment of thoracic disc herniation (TDH) is technically demanding due to its proximity to the spinal cord. METHODS: Literature review. RESULTS: Symptomatic TDH is a rare condition predominantly localized between T8 and L1. Surgical indications include intractable back or radicular pain, neurological deficits, and myelopathy signs. Giant calcified TDH (> 40% spinal canal occupation) are frequently associated with myelopathy, intradural extension, and post-operative complications. Careful pre-operative planning helps reduce the risk of complications. Pre-operative CT and MRI identify the hernia's location and size, calcifications, and intradural extension. The approach must provide adequate dural sac visualization with minimal manipulation of the cord. Non-anterior approaches are favoured if they provide at least equal exposure than anterior approach owing to higher risk of pulmonary morbidity associated with anterior approach. A transthoracic approach is recommended for central calcified herniated discs. A posterolateral approach is often suitable for non-calcified lateralized TDH. Thoracoscopic approaches are less invasive but have a substantial learning curve. Retropleural mini-thoracotomy is an acceptable alternative. Pre-operative identification of the pathological level is confirmed by intra-operative level check. Intra-operative cord monitoring is preferable but warrant further studies. Magnification and adequate lightening of the surgical field are paramount (microscope, thoracoscopy). Intra-operative CT scan with navigation is becoming increasingly popular since it provides real-time control on the decompression. Indications of fusion consist of pre-operative back pain, Scheuermann's disease, multilevel resection, wide vertebral body resection (> 50%), and herniation at thoracolumbar junction. Neurological deterioration, dural tear, and subarachnoid-pleural fistula are the most severe complications. CONCLUSION: Further improvements are still warranted in thoracic spine surgery despite the advent of minimally invasive techniques. Intra-operative CT scan will probably enhance the safety of the TDH surgery. PMID- 30406843 TI - Tricholoma matsutake may take more nitrogen in the organic form than other ectomycorrhizal fungi for its sporocarp development: the isotopic evidence. AB - Tricholoma matsutake is an ectomycorrhizal (ECM) fungus capable of in vitro saprotrophic growth, but the sources of C and N used to generate sporocarps in vivo are not well understood. We examined natural abundance isotope data to investigate this phenomenon. For this purpose, C, N and their stable isotopes (13C, 15N) content of fungal sporocarps and their potential nutrient sources (i.e., foliage, litter, fine roots, wood, and soil) were investigated from two well-studied sites in Finland and Japan. Our results show that delta13C values of T. matsutake and other fungal groups are consistent with those of most studies, but a very high delta15N value (16.80/00 +/- 2.3) is observed in T. matsutake. Such isotopic pattern of fungal delta15N suggests that matsutake has a greater proteolytic potential to digest chemically complex 15N-enriched organic matter and hydrophobic hyphae. This assumption is further supported by a significant and positive correlation between delta13Ccap-stipe and delta15Ncap-stipe exclusively in T. matsutake, which suggests common C and N sources (protein) possible for isotopically enriched cap. The 13C increase of caps relative to stipe presumably reflects greater contents of 13C-enriched protein than 13C-depleted chitin. We conclude that T. matsutake is a typical ECM fungus which obtains for its sporocarp development for both C and N from a common protein source (vs. photosynthetic carbon) present in soil organic matter. PMID- 30406844 TI - Robot-assisted single-port surgery for mediastinal tumors. AB - We successfully performed totally endoscopic single-port robotic surgery. A 50 year-old man with a mediastinal tumor underwent robot-assisted tumor resection. Only one port was placed on the right side of the chest, and a robotic endoscope and two robotic instruments were inserted through the port. The instruments were crossed while avoiding collision. Single-port robotic surgery for a mediastinal tumor using the cross-arm technique was safely achieved with good clinical results and excellent cosmetic results. PMID- 30406845 TI - Thinking the future of child and adolescent psychiatry: what are we talking about? PMID- 30406846 TI - LPHN3 gene variations and susceptibility to ADHD in Chinese Han population: a two stage case-control association study and gene-environment interactions. AB - Polymorphisms in latrophilin 3 (LPHN3) were recently reported to be associated with attention-deficit/hyperactivity disorder (ADHD), and subsequently other researchers tried to replicate the findings in different populations. This study was aimed to confirm the role of the LPHN3 in ADHD and explore the potential interactions with environmental risk factors in Chinese Han population. We examined the association of LPHN3 with ADHD in a population of 473 ADHD children and 585 controls. As a supplement of ADHD diagnosis, Conners Parent Symptom Questionnaire (PSQ) was used to evaluate ADHD symptoms. Blood lead levels (BLLs) were measured by atomic absorption spectrophotometry and other potential environmental risk factors were determined via a questionnaire filled out by the parents. Finally, after validation in an independent sample (284 cases and 390 controls), we observed significant associations between LPHN3 variants rs1868790 and ADHD risk in combined stage within codominant model [TA/AA: OR (95% CI) = 1.636 (1.325-2.021)], dominant model [OR (95% CI) = 1.573 (1.288-1.922)], and additive model [OR (95% CI) = 1.535 (1.266-1.862)]. Furthermore, rs1868790 significantly interacted with BLLs and maternal stress to modify ADHD susceptibility (P < 0.05), and rs1868790 was found to be related with ADHD symptoms (P < 0.05). Expression quantitative trait loci analysis further indicated that rs1868790 took part in the regulation of LPHN3 gene expression. As the first study to comprehensively explore the role of LPHN3 in ADHD in Chinese children, our research suggests that LPHN3 gene has a significant effect on the ADHD in a Chinese population. PMID- 30406847 TI - Diagnostic efficacy of dual-focus endoscopy with narrow-band imaging using simplified dyad criteria for superficial esophageal squamous cell carcinoma. AB - BACKGROUND: Our previous studies have shown the diagnostic utility of a newly developed dual-focus endoscope with narrow-band imaging (DF-NBI) and simplified dyad criteria for detection of superficial esophageal squamous cell carcinoma (SESCC). This clinical trial aimed to study the diagnostic efficacy of DF-NBI with dyad criteria for detecting SESCC compared to white light imaging (WLI). METHODS: This was a single-arm prospective comparative trial. We enrolled 170 consecutive high-risk patients for esophageal squamous cell carcinoma. Patients were initially examined with WLI by one independent endoscopist and then the other performed DF-NBI blinded to the WLI diagnosis to avoid a carry-over effect. Lesions showing proliferation and/or various shapes of intrapapillary capillary loops (IPCL) under DF-NBI (i.e., dyad criteria) were endoscopically diagnosed as SESCC including high-grade intraepithelial neoplasia. The primary endpoint was sensitivity of WLI and DF-NBI for detecting SESCC. The secondary endpoints were the diagnostic performance (i.e., specificity and accuracy) and inter/intra observer concordance of DF-NBI with dyad criteria. RESULTS: A total 77 SESCCs were detected. The sensitivity of DF-NBI for SESCC was significantly higher than that of WLI (91% vs. 51%, P < 0.001). The specificity and accuracy of WLI and DF NBI using dyad criteria were 100% vs. 84%, and 86% vs. 86%, respectively. Various shapes and proliferation of IPCL showed the highest value in inter-observer and intra-observer agreements (kappa = 0.77 and 0.82, respectively). CONCLUSION: DF NBI combined with dyad criteria may be a promising technique with a high sensitivity for diagnosis of SESCC and high inter/intra-observer agreement. PMID- 30406849 TI - A rapid introduction to neurological biochemistry using Drosophila melanogaster. AB - Short, cost-effective teaching activities are a useful way of providing an integrated view on biological processes. Here we describe a brief, hands-on workshop that allows pre-university students to explore their understanding of a neurological pathway from its chemical bases to phenotype. The workshop effectively introduces the students to data collection and analysis in an enjoyable way and at an appropriate level, determined by an end of session feedback survey. The design of the workshop can be adapted and scaled to generate diverse sessions such as university teaching practicals or summer school training workshops. PMID- 30406848 TI - Relation Between Stress Granules and Cytoplasmic Protein Aggregates Linked to Neurodegenerative Diseases. AB - ?: A hallmark of neurodegenerative diseases is the accumulation of cytoplasmic protein aggregates in neurons of affected subjects. Among recently identified elements of these aggregates are RNA-binding proteins (RBPs) involved in RNA metabolism and alternative splicing and have in common the presence of low complexity domains (LCD) that are prone to self-assemble and form aggregates. The mechanism of cytoplasmic protein aggregation remains elusive. Stress granules (SGs) that are micrometric RNA-protein assemblies located in the cytoplasm of cells exposed to environmental stress are suspected to play the role of seeds. The review sheds light on the recent experimental results that suggest a link between SGs and cytoplasmic protein aggregates but also propose other routes for the formation of these aggregates. PURPOSE OF REVIEW: To analyze the potential relationship between cytoplasmic protein aggregates in neurons of affected subjects and stress granules. RECENT FINDINGS: Liquid phase separation explains how protein and RNA could assemble in membraneless compartments, notably SGs. These results highlight the importance of RBPs with LCD in the SG assembly. Maturation of SGs and in particular the dense core is a potential source of insoluble protein aggregates. Several lines of evidence linked stress granule dynamics to pathogenic protein aggregates. (i) Proteins that accumulate in cytoplasmic aggregates are also SG components. (ii) Neurons are specifically exposed to stress events due to their high metabolism and long lifespan. (iii) Diseases linked protein mutations affect the SG dynamics. (iv) SG dense core could be a breeding ground for protein aggregates. However, we should also keep in mind that SGs are not the only RNA-protein assembly in the cytoplasm; the RNA transport granules could also play a role in the formation of insoluble protein aggregates. PMID- 30406850 TI - The Evolving Role of the Cardiologist in the Management of Type 2 Diabetes. AB - PURPOSE OF REVIEW: To evaluate the treatment of type 2 diabetes from a cardiologist's view. RECENT FINDINGS: A new era in the treatment of type 2 diabetes began for the cardiologist in 2015 with the publication of the EMPA-REG outcome trial finding a significant reduction in CV death with empagliflozin (oral sodium-glucose co-transporter-2 [SGLT2] inhibitor) in patients with type 2 diabetes at increased cardiovascular risk. Shortly thereafter, the injectable glucagon-like peptide agonists (GLP-1) liraglutide and semaglutide found a significant reduction in composite major cardiovascular events (CV death, non fatal MI, or stroke). Both classes have demonstrated significant renal protection when added to usual care. Moreover, there may be some exciting new benefits of SGLT2 inhibitors for patients with heart failure. These research studies are underway. These two new classes of cardiovascular drugs for type 2 diabetes usher in a new era for the cardiologist who sees greater than 50% of patients with diabetes. The off-target effect of these agents is different as with all new cardiovascular compounds. While safety profiles in these populations are consistent with the known effects of these classes, new off-target effects have been seen with some agents in this class. Ongoing collaboration between cardiologists and other care providers remains important in the implementation of the evidence and care of patients with type 2 diabetes. PMID- 30406851 TI - Predictors of incisional hernia in adult liver transplant recipients. AB - PURPOSE: Incisional hernia is a complication following abdominal operation. Patients undergoing liver transplantation have a high risk of developing incisional hernia because of immunosuppression. The purpose of this study was to evaluate incisional hernia after liver transplantation and to identify risk factors for hernia formation in those patients. METHODS: We retrospectively reviewed 1044 adult patients with more than 2 years of follow-up in patients who underwent liver transplantation from January 2000 to December 2015. RESULTS: Incisional hernia was identified in 79 patients with more than 2 years of follow up. The overall incisional hernia rate was 7.6%. The mean age and body mass index (BMI) of the patients with incisional hernia were 55 +/- 9 years and 25.3 +/- 3.7 kg/m2, respectively. No significant differences in gender, diagnosis, diabetes, Child-Pugh score, model for end-stage liver disease (MELD) score, donor type, hepatorenal syndrome, varix bleeding, ascites, hepatic encephalopathy, ventilator use, spontaneous bacterial peritonitis (SBP), or bile leakage were found between patients who did and did not develop incisional hernia. Patients with acute rejection before hernia development were more to have herniated patients hernia (p < 0.05). CONCLUSION: Age greater than 55 years and high BMI were significant risk factors. We identified risk factors for the development of incisional hernia. Based on these risk factors, attention should be paid to incisional hernia in older and obese patients. PMID- 30406852 TI - A novel 450-nm blue laser system for surgical applications: efficacy of specific laser-tissue interactions in bladder soft tissue. AB - Low-power blue laser allows clean cutting with little bleeding and no undesired coagulations in adjacent tissues; however, studies on high-power blue laser soft tissue ablation properties, including vaporization and coagulation, have not been reported yet. The purpose of this study is to evaluate and analyze the ablation efficacy and coagulation properties of bladder epithelium tissues with a 30-W 450 nm wavelength blue laser. Well-designed ex vivo experiments compared blue laser and 532-nm LBO green laser, both with laser power up to 30 W, for porcine bladder tissue vaporization and coagulation at different experimental parameter settings. At working distance of 1 mm and sweeping speed of 1.5 mm/s, the vaporization efficiency of blue laser and green laser was 5.14mm3/s and 1.20mm3/s, while the depth of coagulation layer was 460 +/- 70 MUm and 470 +/- 80 MUm, respectively. We found both blue laser and green laser have excellent efficacy of tissue vaporization and similar tissue coagulation properties. Moreover, in a set of in vivo experiments simulated laser transurethral resection (TUR) surgery on dogs, we found both blue laser and green laser exhibited similar and satisfactory vaporization and coagulation outcomes. Taken together, our results demonstrate that a 450-nm wavelength high-power diode blue laser, like 532-nm wavelength green laser, is capable to produce high efficient tissue vaporization, low-laser tissue penetration, good tissue coagulation, and has low thermal damage to adjacent tissues. Therefore, a 30-W blue diode laser could be a new and safe alternative for surgeries of superficial bladder diseases. PMID- 30406853 TI - S100A12 and vascular endothelial growth factor can differentiate Blau syndrome and familial Mediterranean fever from systemic juvenile idiopathic arthritis. AB - OBJECTIVES: Systemic juvenile idiopathic arthritis (sJIA) has recently become regarded as one of the autoinflammatory syndromes (AIS). However, other AIS, such as familial Mediterranean fever (FMF) and Blau syndrome, have been initially misdiagnosed as sJIA because of the clinical similarities. Making the correct diagnosis in the early stage of these AIS is desirable. Therefore, we evaluated serum S100A12 and vascular endothelial growth factor (VEGF) levels to determine if they could be biomarkers for differentiating these AIS. METHOD: Serum S100A12 and VEGF levels were examined in patients with Blau syndrome (n = 4), FMF (n = 4), and sJIA (n = 11) in the active and inactive phases. RESULTS: In the active phase, S100A12 levels were significantly higher in patients with sJIA and FMF compared with those with Blau syndrome (p < 0.001). VEGF levels of patients with sJIA were significantly higher than those of patients with others (p = 0.001). In the inactive phase, there was no significant difference in VEGF levels. However, colchicine-resistant patients or patients without treatment with FMF showed high levels of S100A12 compared with others. CONCLUSIONS: Measuring both serum S100A12 and VEGF levels may be useful for differentiating patients with Blau syndrome and FMF from those with sJIA at the early stage. PMID- 30406854 TI - Performance assessment of artificial neural networks and support vector regression models for stream flow predictions. AB - Water resources planning, development, and management need reliable forecasts of river flows. In past few decades, an important dimension has been introduced in the prediction of the hydrologic phenomenon through artificial intelligence-based modeling. In this paper, the performance of three artificial neural network (ANN) and four support vector regression (SVR) models was investigated to predict streamflows in the Upper Indus River. Results from ANN models using three different optimization techniques, namely Broyden-Fletcher-Goldfarb-Shannon, Conjugate Gradient, and Back Propagation algorithms, were compared with one another. A further comparison was made between these ANNs and four types of SVR models which were based on linear, polynomial, radial basis function, and sigmoid kernels. Past 30 years' monthly data for precipitation, temperature, and streamflow obtained from Pakistan Surface Water Hydrology Department Lahore were used for this purpose. Three types of input combinations with respect to the main input variables (temperature, precipitation, and stream flow) and several types of input combinations with respect to time lag were tested. The best input for ANN and SVR models was identified using correlation coefficient analysis and genetic algorithm. The performance of the ANN and SVR models was evaluated by mean bias error, Nash-Sutcliffe efficiency, root mean square error, and correlation coefficient. The efficiency of the Broyden-Fletcher-Goldfarb-Shannon ANN model was found to be much better than that of other models, while the SVR model based on radial basis function kernel predicted stream flows with comparatively higher accuracy than the other kernels. Finally, long-term predictions of streamflow have been made by the best ANN model. It was found that stream flow of Upper Indus River has a decreasing trend. PMID- 30406856 TI - Metal concentrations and source identification in Chilean public children's playgrounds. AB - This study is focused on four Biobio region cities, Concepcion, Talcahuano, Los Angeles, and Tome; these cities flourished very close to different industrial activities. We determined a pseudo total concentration of seven heavy metals (Cr, Ni, Cu, Zn, As, Cd, and Pb) in playground soils through inductively coupled plasma-mass spectrometry (ICP-MS). Principal components analysis (PCA) revealed that contamination in soils comes from three principal sources. Firstly, industrial and burning activities; secondly, the use of phytosanitary and chemical products; and thirdly, vehicular traffic emissions. Zn and Cu are the most abundant analyzed elements in all the playground's soils. Concepcion reflected the lowest values of pollutants and Talcahuano the highest, reflecting the industrial effects. The average values of the analyzed elements were Cr = 32.90 mg kg-1; Ni = 23.76 mg kg-1; Cu = 31.51 mg kg-1; Zn = 63.69 mg kg-1; As = 19.51 mg kg-1; Cd = 0.50 mg kg-1; and Pb = 17.59 mg kg-1. Anomalously high values of some elements were found Cu = 462.73 mg kg-1, Zn = 364.39 mg kg-1, As = 34.7 mg kg-1 in Talcahuano, Cd = 1.6 mg kg-1 in Tome, and Pb = 55.59 mg kg-1 in Los Angeles. Nevertheless, according to international guideline values of pollutants (VROM 2000 and ADEC 2010) there is no risk for children in any playground studied but all playgrounds are a potential risk for the environment. It points out the necessity to continue studying and monitoring Chilean urban playground to prevent health problems in the population. Graphical abstract. PMID- 30406857 TI - Dietary Fiber and Gastrointestinal Disease: an Evolving Story. PMID- 30406858 TI - Stakeholder Perspectives on Implementing Cognitive Behavioral Social Skills Training on Assertive Community Treatment Teams. AB - This study examined stakeholder perceptions of the "fit" between cognitive behavioral social skills training (CBSST) and assertive community treatment (ACT) when implementing CBSST into existing community-based ACT teams. Focus group feedback was collected from a diverse set of stakeholders (i.e., clients, providers, supervisors, agency administrators, public sector representatives, and intervention developers). Results identified perceived client and provider benefits for integrating CBSST into ACT while highlighting the importance of purposeful adaptations, training, and implementation tools to facilitate structural and values fit between CBSST and ACT. Study findings will inform future endeavors to implement CBSST and other relevant EBPs into ACT. Trial Registry: ClinicalTrials.gov #NCT02254733. PMID- 30406860 TI - Whipple's Disease: A Well-Done Outcome to a Rare Disease. PMID- 30406855 TI - Untangling PTSD and TBI: Challenges and Strategies in Clinical Care and Research. AB - PURPOSE OF REVIEW: Traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) can result from similar injuries and can result in similar symptoms, such as problems with sleep, concentration, memory, and mood. Although PTSD and persistent sequelae due to a TBI (PST) have generally been viewed as pragmatically confounded but conceptually separable entities, we examine emerging evidence emphasizing the breadth of overlap in both clinical presentation and underlying pathophysiology between PST and PTSD. RECENT FINDINGS: New evidence underscores the poor specificity of symptoms to etiology and emphasizes the potential, after both physical brain injury and traumatic stress, for changes in each of the three interacting systems that coordinate the body's response to the experience or expectation of major injury-the immune, endocrine, and neuromodulatory neurotransmitter systems. A view of PTSD and PST sharing common pathophysiologic elements related to the CNS response to acute injury or threat carries important implications for research and clinical care. PMID- 30406859 TI - Radiographic Progression in Ankylosing Spondylitis: From Prognostication to Disease Modification. AB - PURPOSE OF REVIEW: Pain, functional limitation, and spinal damage are the three main domains that have significant impact on various aspects of axial spondyloarthritis (axSpA). RECENT FINDINGS: Several randomized controlled trials (RCTs) showed a beneficial effect of non-steroid ant-inflammatory drugs (NSAIDs) and biologic treatments on pain and function. The effect of available treatments on spinal damage is still of interest and is being studied. In this article, we review the literature on radiographic progression in axSpA. We discuss the natural course of spinal progression, predictors of spinal damage, and the effect of lifestyle changes and medications on radiographic progression in axSpA. PMID- 30406862 TI - The effects of irreversible electroporation on the stomach wall after ablating hepatic tissues. AB - This study aimed to evaluate the effect of irreversible electroporation (IRE) on the stomach wall after IRE was applied on liver tissues adjacent to the anterior wall of the stomach. IRE ablation was performed in eight Tibet mini-pigs with three lesions per pig. The IRE electrodes were inserted into the liver tissues situated close to the anterior wall of the stomach. As for the control group, the IRE electrodes were also inserted into the liver tissues for three lesions in four Tibet mini-pigs but did not turn on the current. Serum aminotransferase and WBC levels clearly increased in all the IRE ablated animals by Day 1 and decreased gradually thereafter. The gross postmortem examination at 7 days post IRE revealed a whitish lesion with sharp demarcation on the serosal surface of the stomach, but we could not find any signs of ablation or just find a small, slightly reddish lesion at the Day-28 examination. On the Day-7 histopathological examination, inflammation and fibrosis were observed in the serosal layer of the stomach in each animal and mild inflammation of the myofibers was found in only two pigs. All the stomach layers returned to normalcy by 28 days post-IRE. Thus, IRE ablation of hepatic tissues situated close to the stomach wall cannot lead to stomach perforation. IRE is therefore a safe procedure for ablating hepatic tumors that are adjacent to the stomach. PMID- 30406861 TI - JAK Inhibitors in Rheumatology: Implications for Paediatric Syndromes? AB - PURPOSE OF REVIEW: Given the recent increase in the profile and use of Janus kinase inhibitors (JAKinibs) in adult patients with rheumatic diseases, we aimed to review the current evidence accruing for use in paediatric rheumatology patients. RECENT FINDINGS: Significant advances have been made in the management of rheumatic diseases in the past two decades. The introduction of biologic agents in both adults and children has provided significant improvements to patient outcomes and led to better quality of life. Moreover, responses to similar agents allude to common effector pathways operating across juvenile and adult synovitis especially. However, inefficacy and intolerance of these agents leads to a subset of children with limited treatment options. Since 2012, Janus kinase (JAK) inhibitors (JAKinibs), a novel group of oral small molecule inhibitors, have demonstrated their efficacy in several forms of adult inflammatory arthritis, such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA). There are hopes that these successes will be transferable to the paediatric population. In the following review, we discuss the development and progress of JAKinibs in this regard. PMID- 30406864 TI - Nucleoli in embryos: a central structural platform for embryonic chromatin remodeling? AB - Nucleoli are the site of ribosomal RNA production and subunit assembly. In contrast to active nucleoli in somatic cells, where three basic sub-compartments can be observed, mammalian oocytes and early embryos contain atypical nucleoli termed "nucleolus-like bodies" or "nucleolus precursor bodies", respectively. Unlike their somatic counterparts, these structures are composed of dense homogenous fibrillar material and exhibit no polymerase activity. Irrespective of these unusual properties, they have been shown to be absolutely essential for embryonic development, as their microsurgical removal results in developmental arrest. Historically, nucleolus-like and nucleolus precursor bodies have been perceived as passive storage sites of nucleolar material, which is gradually utilized by embryos to construct fully functional nucleoli once they have activated their genome and have started to produce ribosomes. For decades, researchers have been trying to elucidate the composition of these organelles and provide the evidence for their repository role. However, only recently has it become clear that the function of these atypical nucleoli is altogether different, and rather than being involved in ribosome biogenesis, they participate in parental chromatin remodeling, and strikingly, the artificial introduction of a single NPB component is sufficient to rescue the developmental arrest elicited by the NPB removal. In this review, we will describe and summarize the experiments that led to the change in our understanding of these unique structures. PMID- 30406863 TI - Nuclear and chloroplast DNA phylogeography suggests an Early Miocene southward expansion of Lithocarpus (Fagaceae) on the Asian continent and islands. AB - BACKGROUND: Most genera of Fagaceae are thought to have originated in the temperate regions except for the genus Lithocarpus, the stone oaks. Lithocarpus is distributed in subtropical and tropical Asia, and its ancestral population is hypothesized to be distributed in tropical regions in Borneo and Indochina. Borneo and the nearby islands (the Greater Sunda Islands) were connected to the Malay Peninsula and Indochina prior to the Pliocene epoch and formed the former Sundaland continent. The Southeast Asian Lithocarpus, is thought to have dispersed between continental Asia and the present Sundaland. The drastic climate changes during the Pliocene and Pleistocene epochs which caused periodic sea level changes is often used to explain the cause of its diversity. The aim of this study was to establish phylogenetic relationships by analyzing nuclear (nrDNA) and chloroplast (cpDNA) DNA in order to describe and analyze the origin, causes of diversification and historical biogeography of Lithocarpus. RESULTS: Phylogeny reconstructed through the multiple-species coalescent method with nrDNA and cpDNA revealed that the continental-Asian taxa were clustered at the basal lineages. The derived lineages of tropical Lithocarpus, with the inference of a subtropical ancestral state, imply a southward migration in the Early Miocene period with subsequent in situ diversification in the Greater Sunda Islands. The gradual decrease in temperature since the Middle Miocene period is proposed as a cause of the increase in the net diversification rate. CONCLUSIONS: The historical ancestral origin of Lithocarpus has been suggested to be mainland Asia. Southward migration in the Early Miocene period with subsequent in situ diversification could explain the current diversity of stone oaks in Southeast Asia. This study also considered the multiple origins of stone oaks currently indigenous to the subtropical islands offshore and near mainland China. Our results provide phylogenetic evidence for a subtropical origin of Asian stone oaks and reveal the process of diversification and how it fits into the timeline of major geologic and climatic events rather than local, episodic, rate-shifting events. PMID- 30406865 TI - An End-to-end System for Automatic Characterization of Iba1 Immunopositive Microglia in Whole Slide Imaging. AB - Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide. Detailed studies of the microglial response after TBI require high throughput quantification of changes in microglial count and morphology in histological sections throughout the brain. In this paper, we present a fully automated end-to-end system that is capable of assessing microglial activation in white matter regions on whole slide images of Iba1 stained sections. Our approach involves the division of the full brain slides into smaller image patches that are subsequently automatically classified into white and grey matter sections. On the patches classified as white matter, we jointly apply functional minimization methods and deep learning classification to identify Iba1-immunopositive microglia. Detected cells are then automatically traced to preserve their complex branching structure after which fractal analysis is applied to determine the activation states of the cells. The resulting system detects white matter regions with 84% accuracy, detects microglia with a performance level of 0.70 (F1 score, the harmonic mean of precision and sensitivity) and performs binary microglia morphology classification with a 70% accuracy. This automated pipeline performs these analyses at a 20-fold increase in speed when compared to a human pathologist. Moreover, we have demonstrated robustness to variations in stain intensity common for Iba1 immunostaining. A preliminary analysis was conducted that indicated that this pipeline can identify differences in microglia response due to TBI. An automated solution to microglia cell analysis can greatly increase standardized analysis of brain slides, allowing pathologists and neuroscientists to focus on characterizing the associated underlying diseases and injuries. PMID- 30406866 TI - Activity-Based Protein Profiling-Enabling Multimodal Functional Studies of Microbial Communities. AB - Microorganisms living in community are critical to life on Earth, playing numerous and profound roles in the environment and human and animal health. Though their essentiality to life is clear, the mechanistic underpinnings of community structure, interactions, and functions are largely unexplored and in need of function-dependent technologies to unravel the mysteries. Activity-based protein profiling offers unprecedented molecular-level characterization of functions within microbial communities and provides an avenue to determine how external exposures result in functional alterations to microbiomes. Herein, we illuminate the current state and prospective contributions of ABPP as it relates to microbial communities. We provide details on the design, development, and validation of probes, challenges associated with probing in complex microbial communities, provide some specific examples of the biological applications of ABPP in microbes and microbial communities, and highlight potential areas for development. The future of ABPP holds real promise for understanding and considerable impact in microbiome studies associated with personalized medicine, precision agriculture, veterinary health, environmental studies, and beyond. PMID- 30406867 TI - Cryptococcal Titan Cells: When Yeast Cells Are All Grown up. AB - Cryptococcus neoformans is a human pathogenic yeast that causes hundreds of thousands of deaths worldwide among susceptible individuals, in particular, HIV+ patients. This yeast has developed several adaptation mechanisms that allow replication within the host. During decades, this yeast has been well known for a very peculiar and unique structure that contributes to virulence, a complex polysaccharide capsule that surrounds the cell wall. In contrast to other fungal pathogens, such as Candida albicans or Aspergillus fumigatus, the role of morphological transitions has not been studied in the virulence of Cryptococcus neoformans since this yeast does not form hyphae during infection. However, in the last years, different groups have described the ability of this fungus to change its size during infection. In particular, Cryptococcus can form "titan cells," which are blastoconidia of an abnormal large size. Since their discovery, there is increasing evidence that these cells contribute, not only to long-term persistence in the host, but they can also actively participate in the development of the disease. Recently, several groups have simultaneously described different media that induce the appearance of titan cells in laboratory conditions. Using these conditions, new inducing factors and signaling pathways involved in this transition have been described. In this article, we will review the main phenotypic features of these cells, factors, and transduction pathways that induce cell growth, and how titan cells contribute to the disease caused by this pathogen. PMID- 30406868 TI - Can low b value diffusion weighted imaging evaluate the character of cerebrospinal fluid dynamics? AB - PURPOSE: We aimed to investigate whether low b value diffusion-weighted imaging (DWI) can show the change of cerebrospinal fluid (CSF) dynamics. MATERIALS AND METHODS: The subjects of this retrospective study consisted of patients with ventricular dilatation (n = 50) and controls (n = 50). The CSF signal intensity on the b = 500 s/mm2 DWI was evaluated by a scoring method in the lateral, 3rd and 4th ventricles, the cerebral sulci and the Sylvian fissure. The signal void findings adjacent to the septum pellucidum were also evaluated. RESULTS: The CSF signal intensities were significantly less in lateral ventricle and 3rd ventricle of the ventricular dilatation subjects. In controls, the score for the signal void in the Sylvian fissure showed a significant positive correlation with age. However, other areas did not show a significant correlation with age. The appearance of the characteristic signal void adjacent to the septum pellucidum showed a significant correlation with ventricular dilatation. CONCLUSION: Our current study suggests that the CSF signal intensity on the b = 500 s/mm2 DWI may show the changes in CSF dynamics and might be useful to evaluate the overlook of CSF dynamics. PMID- 30406869 TI - Impact of pre-diagnosis depressive symptoms and health-related quality of life on treatment choice for ductal carcinoma in situ and stage I breast cancer in older women. AB - PURPOSE: To examine whether pre-diagnosis patient-reported health-related quality of life (HRQOL) and depressive symptoms are associated with local treatment for older women with ductal carcinoma in situ (DCIS) and stage I breast cancer (BC). METHODS: Using the SEER-MHOS dataset, we identified women >= 65 years old with DCIS or stage I BC diagnosed 1998-2011 who completed surveys <= 24 months before diagnosis. Depressive symptoms were measured by major depressive disorder (MDD) risk and HRQOL was measured by Physical and Mental Component Summary scores (PCS and MCS, respectively) of the SF-36/VR-12. Associations with treatment choice (breast-conserving surgery [BCS] and radiation therapy [RT], BCS alone, mastectomy) were assessed with multivariable multinomial logistic regression, controlling for patient characteristics. RESULTS: We identified 425 women with DCIS and 982 with stage I BC. Overall, 20.4% endorsed depressive symptoms placing them at risk for MDD pre-diagnosis; mean MCS and PCS scores were 52.3 (SD = 10.1) and 40.5 (SD = 11.5), respectively. Among women with DCIS, those at risk for MDD were more likely to receive BCS (adjusted odds ratio [AOR] 2.04, 95% CI 1.04 4.00, p = 0.04) or mastectomy (AOR 1.88, 95% CI 0.91-3.86, p = 0.09) compared to BCS + RT. For DCIS, MCS score was not associated with treatment; higher PCS score was associated with decreased likelihood of receiving mastectomy versus BCS + RT (AOR 0.71 per 10-point increase, 95% CI 0.54-0.95, p = 0.02). For BC, none of the measures were significantly associated with treatment. CONCLUSION: Older women at risk for MDD before DCIS diagnosis were less likely to receive RT after BCS, compared to BCS alone or mastectomy. PMID- 30406870 TI - Prior bariatric surgery lowers complication rates following spine surgery in obese patients. AB - BACKGROUND: Bariatric surgery (BS) is an increasingly common treatment for morbid obesity that has the potential to effect bone and mineral metabolism. The effect of prior BS on spine surgery outcomes has not been well established. The aim of this study was to assess differences in complication rates following spinal surgery for patients with and without a history of BS. METHODS: Retrospective analysis of the prospectively collected New York State Inpatient Database (NYSID) years 2004-2013. BS patients and morbidly obese patients (non-BS) were divided into cervical and thoracolumbar surgical groups and propensity score matched for age, gender, and invasiveness and complications compared. RESULTS: One thousand nine hundred thirty-nine spine surgery patients with a history of BS were compared to 1625 non-BS spine surgery patients. The average time from bariatric surgery to spine surgery is 2.95 years. After propensity score matching, 740 BS patients were compared to 740 non-BS patients undergoing thoracolumbar surgery, with similar comorbidity rates. The overall complication rate for BS thoracolumbar patients was lower than non-BS (45.8% vs 58.1%, P < 0.001), with lower rates of device-related (6.1% vs 23.2%, P < 0.001), DVT (1.2% vs 2.7%, P = 0.039), and hematomas (1.5% vs 4.5%, P < 0.001). Neurologic complications were similar between BS patients and non-BS patients (2.3% vs 2.7%, P = 0.62). For patients undergoing cervical spine surgery, BS patients experienced lower rates of bowel issues, device-related, and overall complication than non-BS patients (P < 0.05). CONCLUSIONS: Bariatric surgery patients undergoing spine surgery experience lower overall complication rates than morbidly obese patients. This study warrants further investigation into these populations to mitigate risks associated with spine surgery for bariatric patients. PMID- 30406871 TI - Incidence and clinical significance of postoperative delirium after brain tumor surgery. AB - BACKGROUND: Delirium is an acute and reversible deterioration of mental state. Postoperative delirium (POD) can develop after surgical procedures and is associated with impaired health status and worse recovery. So far, there is little data about postoperative delirium after brain surgery. The aim of this study was to evaluate frequency, risk factors, and prognostic value of POD in predicting short-term postoperative outcomes after brain tumor surgery. METHODS: Five-hundred and twenty-two patients who underwent elective brain tumor surgery in 2010-2017 were included in this prospective study. Patients were monitored for POD using the Confusion Assessment Method for the ICU (CAM-ICU) for 2 to 7 days after the surgery. At hospital discharge, outcomes were evaluated using the Glasgow Outcome Scale (GOS). RESULTS: POD was diagnosed in 22 (4.2%) patients. Risk factors of POD were low level of hemoglobin, poor functional status at time of admission, low education level and older age (65 years and older). POD incidence was not associated with brain tumor laterality, location, extent of resection, histological diagnosis, or affected brain lobe. POD was associated with greater risk for unfavorable outcomes at hospital discharge (OR = 5.3; 95% CI [2.1-13.4], p = 0.001). CONCLUSIONS: POD is not a common complication after elective brain tumor surgery. Older age, poor functional status, low education level and anemia are associated with greater POD risk. Extent of surgical intervention and brain tumor location are not associated with POD risk. POD is associated with worse outcome at hospital discharge. PMID- 30406872 TI - Long-term performance of a UASB reactor treating acid mine drainage: effects of sulfate loading rate, hydraulic retention time, and COD/SO42- ratio. AB - Acid mine drainage (AMD) is among the most serious threats to water and the typical alkali-based treatment costs are high. This study's main objective was the establishment of a highly efficient biological process using an upflow anaerobic sludge blanket (UASB) reactor to treat AMD based on a shorter hydraulic retention time (HRT) and lower organic matter input. The process was evaluated for a long-term operation (739 days) in terms of the influence of HRT (14-24 h), metal addition, sulfate loading rate (0.5-2.6 g SO42- l-1 d-1), and the COD/SO42- ratio (0.67-1.0) using ethanol as the only electron donor at a pH of 4.0. Neutral effluent pH was achieved throughout the time apart from operational modifications. The reduction in HRT from 24 to 16 h and an increase in the sulfate loading rate (SLR) up to 2.25 g SO42- l-1 d-1 improved the sulfate removal to (92.1 +/- 1.8)% with 80% chemical oxygen demand (COD) removal. However, the sulfate reduction was less than 80% when the HRT and SLR was changed to 14 h and 2.6 g SO42- l-1 d-1, respectively. The oxidation of organic matter by sulfate reduction was greater than 50% regardless of the conditions imposed but the use of ethanol to treat AMD was more efficient when either the HRT was 16 h (1.5 g SO42- l-1 d-1) in the presence of Fe, Zn, and Cu or the HRT was 14 h (2.6 g SO42- l-1 d-1) but the COD/SO42- ratio was reduced to 0.67. The fully optimized conditions of the UASB reactor were set at an HRT of 16 h, SLR of 1.5 g SO42- l-1 d-1, and a COD/SO42- ratio of 1.0. PMID- 30406873 TI - Risk Perceptions and Barriers to Protective Behavior Use Among Chemical Tank Cleaners: An Exploratory Study. AB - Chemical tank cleaners' occupational diseases and injuries are largely unknown due to a lack of monitoring and limited research. Their potential exposure to highly corrosive chemicals-including sodium hypochlorite, sodium hydroxide, and ferric chloride-suggests that tank cleaners represent an at-risk occupational group. This pilot study explored tank cleaners' risk perceptions and barriers to using personal protective equipment and other protective behaviors in their workplace. Data sources included a survey (n = 29) and interviews (n = 9) with sodium hypochlorite tank cleaners in the United States. Although sodium hypochlorite may become reactive under high temperatures, 12 questionnaire respondents indicated not being concerned about high temperatures within the tank, and 15 were not concerned about exposure via ingestion. Analyses of survey and interview results provide evidence of inadequate training among tank cleaners, their lack of understanding of basic chemical properties and routes of exposure, and limited access to and an incomplete understanding of how to properly use personal protective equipment, particularly respiratory protection. These findings can inform researchers, educators, and safety engineers in developing future studies, interventions, and training to improve tank cleaners' health and safety. PMID- 30406874 TI - Triiodothyronine Promotes Cell Proliferation of Breast Cancer via Modulating miR 204/Amphiregulin. AB - Breast cancer (BC) severely threatens women's life, and Triiodothyronine (T3) shows a positive role on BC cell proliferation, while the potential mechanism underlying it is still unclear. T3 was used to stimulate BC cell lines MCF-7 and T47-D. Real-time PCR was performed to determine the expression of miRNAs, while western blot was used to measure protein expression of Amphiregulin (AREG), AKT and p-AKT. The interaction between miR-204 and AREG was determined using luciferase reporter assay. MTT was performed to detect cell viability. The expression of miR-204 was decreased, while AREG and p-AKT was increased in T3 stimulated BC cell lines. T3 stimulation promoted cell viability. miR-204 targets AREG to regulate its expression. T3 promoted expression of AREG and p-AKT, while miR-204 overexpression reversed the effect of T3, however, pcDNA-AREG transfection abolished the effect of miR-204 mimic. T3 promoted cell viability of BC cells via modulating the AKT signaling pathway. The detailed mechanism was that the down-regulated miR-204 that induced by T3 stimulation promoted the expression of AREG, the up-regulated AREG activated AKT signaling pathway, while the activated AKT signaling promoted cell proliferation. PMID- 30406875 TI - Radiation Therapy Reduced Blood Levels of LDH, HIF-1alpha, and miR-210 in OSCC. AB - Radiation Therapy (RT) is a treatment option for a large number of neoplasias. However, the effect of RT on the level of hypoxia markers is poorly understood. The present study aimed to investigate the effect of RT on the levels of hypoxic markers in Oral squamous cell carcinoma (OSCC). Evaluation of HIF-1alpha and miR 210 levels in OSCC was performed. Then a proteomic analysis was performed to identify candidate hypoxic targets of RT. To validate proteomic studies, the effect of RT on HIF-1alpha, miR-210, PDH-A and LDH-A levels under hypoxia was assessed by qRT-PCR. The impact of RT in hypoxia markers was evaluated in patients to confirm in vitro results. An increase in the HIF-1alpha levels was observed in OSCC. RT reduced OSCC cell proliferation and migration. Interestingly, hypoxia could revert the effect of radiation on OSCC phenotype. However, proteomics analyses suggested that LDH is one of the critical targets of RT even in hypoxia. Moreover, RT decreased HIF-1alpha, miR-210, and LDH even in hypoxia. The current study demonstrated that hypoxia could revert the effects of RT in the OSCC context. However, RT reduces the levels HIF-1alpha, miR-210 and LDH in vivo and in vitro. The consequences of RT in blood should be carefully investigated. PMID- 30406876 TI - A sweet fever. PMID- 30406877 TI - Stevens-Johnson syndrome. PMID- 30406878 TI - Re-enchanting the body: overcoming the melancholy of anatomy. AB - I argue here that Weberian disenchantment is manifest in the triumph of instrumental reason and the expansion of analytic enquiry, which now dominates not simply those sciences upon which medicine depends, but medical practice itself. I suggest ways that analytic enquiry, also referred to here as anatomical reasoning, are part of a particular ideology-a way of seeing, speaking about, and inhabiting the world-that often fails to serve the health of patients because it is incapable of "seeing" them in the moral sense described by Iris Murdoch and others. I use the work of James Elkins and Wendell Berry to call for the recovery of a way of seeing the human body as both other and more than an object of scientific enquiry and social control. PMID- 30406880 TI - Correction to: Strategies for Predicting Response to Checkpoint Inhibitors. AB - The original version of this article unfortunately contained a mistake. The conflict of interest statement was incorrect. The corrected statement is given below. PMID- 30406879 TI - Correction to: Fidaxomicin for the treatment of Clostridium difficile infection (CDI) in at-risk patients with inflammatory bowel disease, fulminant CDI, renal impairment or hepatic impairment: a retrospective study of routine clinical use (ANEMONE). AB - The article "Fidaxomicin for the treatment of Clostridium difficile infection (CDI) in at-risk patients with inflammatory bowel disease, fulminant CDI, renal impairment or hepatic impairment: a retrospective study of routine clinical use (ANEMONE)", written by M.J.G.T. Vehreschild et al., was originally published at Springerlink on 11 August 2018 without open access. PMID- 30406881 TI - Shear stress and blood trauma under constant and pulse-modulated speed CF-VAD operations: CFD analysis of the HVAD. AB - Modulation of pump speed has been proposed and implemented clinically to improve vascular pulsatility in continuous flow ventricular assist device patient. The flow dynamics of the HVAD with a promising asynchronous pump speed modulation and its potential risk for device-induced blood trauma was investigated numerically. The boundary conditions at the pump inlet and outlet were defined using the pressure waveforms adapted from the experimentally recorded ventricular and arterial pressure waveforms in a large animal ischemic heart failure (IHF) model supported by the HVAD operated at constant and modulated pump speeds. Shear stress fields and hemolysis indices were derived from the simulated flow fields. The overall features of the computationally generated flow waveforms at simulated constant and pulse-modulated speed operations matched with those of the experimentally recorded flow waveforms. The simulations showed that the shear stress field and hemolysis index vary throughout the cardiac cycle under the constant speed operation, and also as a function of modulation profile under modulated speed operation. The computational model did not demonstrate any differences in the time average hemolysis index between constant and modulated pump speed operations, thereby predicting pulse-modulated speed operation may help to restore vascular pulsatility without any further increased risk of blood trauma. Graphical abstract The streamline inside the HVAD pump and the wall shear stress distribution on the impeller surface at six discrete time instants over one cardiac cycle under constant speed operation (3000 rpm) (a) and under pulse modulated speed operation (b). c Computationally predicted flow rate waveform under pulse-modulated speed operation. d Computationally predicted time-varying HI generated by the HVAD pump under the two operation modes constant speed (dash line) and pulse-modulated speed (solid line). These figures indicate that the pulse-modulated speed operation may help to restore vascular pulsatility without any further increased risk of blood trauma. PMID- 30406883 TI - High frequency deep transcranial magnetic stimulation acutely increases beta endorphins in obese humans. AB - PURPOSE: In obesity, metabolic and voluntary factors regulate appetite, and a dysregulation of the reward pathway was demonstrated in all addiction disorders. Deep transcranial magnetic stimulation (dTMS) is already used to modulate cerebral dopamine activation in neuro-psychiatric diseases. We presently assess the acute effect of high frequency (HF) and low frequency (LF) dTMS on the modulation of the main neuropeptides and neurotransmitters involved in the reward pathway in obese subjects. METHODS: This study was designed as a double-blind, sham-controlled, randomized clinical trial. Thirty-three obese patients (9 males, 24 females, age 48.1 +/- 10.6, BMI 36.4 +/- 4.7) were enrolled in the study. All patients were studied during a single dTMS session and blood aliquots were drawn before and after a single dTMS session. Metabolic and neuro-endocrine parameters were evaluated before and after: (1) 18 Hz dTMS (HF, 13 patients); (2) 1 Hz dTMS (LF, 10 patients); (3) Sham treatment (Sham, 10 patients). RESULTS: No statistically significant variations in metabolic parameters, systolic and diastolic blood pressure, and heart rate were shown acutely. HF showed a significant increase of beta-endorphin compared to other groups (p = 0.048); a significant increase of ghrelin in LF (p = 0.041) was also demonstrated. CONCLUSIONS: A single session of HF dTMS treatment determines in obese subjects an acute increase of beta-endorphin level, indicating an activation of the reward pathway. The present findings constitute proof of principle for a potential application of this methodology in obesity treatment. PMID- 30406884 TI - Effects of exenatide and liraglutide on postchallenge glucose disposal in individuals with normal glucose tolerance. AB - PURPOSE: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are categorized as short- or long-acting types, but information regarding differences in the effects of these two types on postprandial glucose disposal has been limited. We have now investigated the effects of exenatide and liraglutide (short- and long-acting GLP 1RAs, respectively) on glucose disposal during an oral glucose tolerance test (OGTT). METHODS: Fourteen healthy volunteers with normal glucose tolerance underwent three OGTTs, which were performed without pharmacological intervention or after a single administration of exenatide or liraglutide at 30 min and 10 h, respectively, before test initiation. The three OGTTs were performed with intervals of at least 7 days between successive tests and within a period of 2 months. RESULTS: Exenatide, but not liraglutide, markedly decelerated the peak of both plasma glucose and serum insulin levels during the OGTT, with the peaks of both glucose and insulin concentrations occurring at 150 min after test initiation with exenatide compared with 30 min in the control condition or with liraglutide. Exenatide and liraglutide reduced the area under the curve for plasma glucose levels during the OGTT by similar extents, whereas that for serum insulin levels was reduced only by exenatide. CONCLUSIONS: Our results suggest that exenatide decelerates the increase in plasma glucose levels through inhibition of glucose absorption and that it exerts an insulin-sparing action after glucose challenge. PMID- 30406885 TI - Long-term control of Paget's disease of bone with low-dose, once-weekly, oral bisphosphonate preparations, in a "real world" setting. AB - PURPOSE: Bisphosphonates are the mainstay of the treatment of Paget's disease of bone (PDB). Clinical practice guidelines recommend treatment with intravenous zoledronic acid or high-dose oral nitrogen bisphosphonates (N-BPs). We present our long-term experience treating PDB patients with lower than recommended oral doses of N-BPs, equivalent to once-weekly doses used for treating osteoporosis. METHODS: PDB patients were seen, between 1990 and 2015 at the endocrine clinic of an academic medical center. Diagnosis was established according to accepted criteria. Patients were initially treated with alendronate 70 mg/week or risedronate 35 mg/week. Whenever the initial dose failed to produce remission, the dosage was increased to twice a week the respective dose. RESULTS: Patients were followed for a mean of 11.9 years (range: 1.7-24.8). Out of 96 treatment courses with N-BPs, 89% were with alendronate and 11% with risedronate. Remission was achieved in 84% of the courses with alendronate 70 mg/week. 90% of those who did not achieve remission subsequently responded to 140 mg/week. Out of the 8 treatment courses with risedronate 35 mg/week, 87% achieved remission, and the 2 patients who did not achieve remission subsequently responded to 70 mg/week. The median duration of remissions following 3-4 months courses of alendronate 70 mg/week or risedronate 35 mg/week was 8.8 months (IQR: 5.5, 14.8). CONCLUSION: In a large proportion of "real world" PDB patients, remission can be achieved with once-weekly, "osteoporosis doses" of alendronate or risedronate. PMID- 30406882 TI - Modulation of S. aureus and P. aeruginosa biofilm: an in vitro study with new coumarin derivatives. AB - Coumarin is an important heterocyclic molecular framework of bioactive molecules against broad spectrum pathological manifestations. In the present study 18 new coumarin derivatives (CDs) were synthesized and characterized for antibiofilm activity against two model bacteria such as Staphylococcus aureus and Pseudomonas aeruginosa. It was observed that all the CDs executed significant effect in moderating activities against both planktonic and biofilm forms of these selected bacteria. Hence, to interpret the underlying probable reason of such antibiofilm effect, in-silico binding study of CDs with biofilm and motility associated proteins of these organisms were performed. All CDs have shown their propensity for occupying the native substrate binding pocket of each protein with moderate to strong binding affinities. One of the CDs such as CAMN1 showed highest binding affinity with these proteins. Interestingly, the findings of in-silico studies coincides the experimental results of antibiofilm and motility affect of CDs against both S. aureus and P. aeruginosa. Moreover, in-silico studies suggested that the antibiofilm activity of test CDs may be due to the interference of biofilm and motility associated proteins of the selected model organisms (PilT from P. aeruginosa and TarK, TarO from S. aureus). The detailed synthesis, characterization, methodology and results of biological screening along with computational studies have been reported. This study could be of greater interest in the context of the development of new anti-bacterial agent in the future. PMID- 30406886 TI - Technique of robotic left hepatectomy : how we approach it. AB - Minimally invasive technique has been adopted as the standard of care in many surgical fields within general surgery. Hepatobiliary surgery, however, is lacking behind due to the complex nature of the operation and concerns of major bleeding. Several centers suggested that inherent limitations of conventional laparoscopy precludes its wide adoption. Robotic technique provides solutions to these limitations. In this study, we report our standardized technique of robotic left hepatectomy. We discuss aspects of robotic hepatectomy and describe our standardized approach for robotic left hepatectomy. A video is attached to this article. A 76-year-old man with a 4.5 cm biopsy-proven hepatocellular carcinoma was taken to the operating room for a robotic left hepatectomy. His past medical and surgical history was only consistent with hypertension and diabetes. Robotic extrahepatic glissonian pedicle approach was applied to gain inflow control. Left hepatic artery and portal vein were individually dissected and isolated prior to division. An intraoperative robotic ultrasound was utilized to ensure negative resection margins. Left hepatic vein was transected intrahepatically using a laparoscopic Endo GIA stapler. Segment 2,3, and part of 4 were removed. Operative time was 180 min without intraoperative complications. Estimated blood loss was less than 50 cc. The patient was discharged home on postoperative day 3. The use of robotic technology during complex hepatic resections such as left hepatectomy is safe and feasible. This approach provides an alternative technique in minimally invasive liver surgery. PMID- 30406887 TI - Rationale of using multiplex polymerase chain reaction (PCR) panels for etiological diagnosis of infective diarrhea in the tropics. PMID- 30406888 TI - Diclofenac induced apoptosis via altering PI3K/Akt/MAPK signaling axis in HCT 116 more efficiently compared to SW480 colon cancer cells. AB - Diclofenac is a preferential cyclooxygenase 2 inhibitor (COX-2) and member of non steroidal anti-inflammatory drugs (NSAIDs). Inflammation is one of the main reason of poor prognosis of colon cancer cases; thereby NSAIDs are potential therapeutic agents in colon cancer therapy. In this study, our aim to understand the potential molecular targets of diclofenac, which may propose new therapeutic targets in HCT 116 (wt p53) and SW480 (mutant p53R273H) colon cancer cells. For this purpose, we identified different response against diclofenac treatment through expression profiles of PI3K/Akt/MAPK signaling axis. Our hypothesis was diclofenac-mediated apoptosis is associated with inhibition of PI3K/Akt/MAPK signaling axis. We found that sub-cytotoxic concentration of diclofenac (400 uM) promoted further apoptosis in HCT 116 cells compared to SW480 colon cancer cells. Diclofenac triggered dephosphorylation of PTEN, PDK, Akt, which led to inhibition of PI3K/Akt survival axis in HCT 116 colon cancer cells. However, diclofenac showed lesser effect in SW480 colon cancer cells. In addition, diclofenac further activated p44/42, p38 and SAPK/JNK in HCT 116 cells compared to SW480 cells. PMID- 30406889 TI - Allyl isothiocyanate attenuates oxidative stress and inflammation by modulating Nrf2/HO-1 and NF-kappaB pathways in traumatic brain injury in mice. AB - Traumatic brain injury (TBI) is the leading cause of mortality and morbidity in young adults and children in the industrialized countries; however, there are presently no FDA approved therapies. TBI results in oxidative stress due to the overproduction of reactive oxygen species and overwhelming of the endogenous antioxidant mechanisms. Recently, it has been reported that antioxidants including phytochemicals have a protective role against oxidative damage and inflammation after TBI. To analyze the effects of a naturally occurring antioxidant molecule, allyl isothiocyanate (AITC), on the nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa B (NF-kappaB) signaling pathways in TBI, a cryogenic injury model was induced in mice. Here, we showed that AITC administered immediately after the injury significantly decreased infarct volume and blood-brain barrier (BBB) permeability. Protein levels of proinflammatory cytokines interleukin-1beta (IL1beta) and interleukin-6 (IL6), glial fibrillary acidic protein (GFAP) and NF-kappaB were decreased, while Nrf2, growth-associated protein 43 (GAP43) and neural cell adhesion molecule levels were increased with AITC when compared with vehicle control. Our results demonstrated that the antioxidant molecule AITC, when applied immediately after TBI, provided beneficial effects on inflammatory processes while improving infarct volume and BBB permeability. Increased levels of plasticity markers, as well as an antioxidant gene regulator, Nrf2, by AITC, suggest that future studies are warranted to assess the protective activities of dietary or medicinal AITC in clinical studies. PMID- 30406890 TI - Correction to: Bone Marrow Derived Pluripotent Cells are Pericytes which Contribute to Vascularization. AB - Please note the following errors in the original version. PMID- 30406891 TI - Spirituality Needs in Chronic Pain Patients: A Cross-Sectional Study in a General Hospital in Malaysia. AB - Evidence-based practices that rely upon pain relieving medications and interventional strategies for symptom alleviation in chronic pain survivors have shown modest benefits. The recent emphasis of spiritual care as a new dimension of treatment strategy incorporated within the biopsychosocial model has inspired new hopes to mediate mental and physical health for illness coping. This study aimed to explore the factors associated with spirituality needs among chronic pain patients in a general hospital in Malaysia. An analytical cross-sectional study was conducted among 117 chronic pain patients in a general hospital in Malaysia. Clinical features and assessments were evaluated by an experienced pain physician and retrieved from patient medical records. An interviewer-administered questionnaire that consisted of items on socio-demographics, the validated 19 items spiritual needs questionnaire and the visual analog scale was utilized. Multivariate linear regression analysis was conducted to identify the factors associated with spiritual needs in chronic pain patients. Patients had higher actively giving score as compared to other spirituality need domains. Central neuropathic pain (beta = 1.691, p = 0.040) predicted existential. Renal problems (beta = 5.061, p = 0.019) highly predicted religiosity; followed by head pain (beta = 3.774, p = 0.036), central neuropathic pain (beta = 2.730, p = 0.022), heart problems (beta = 1.935, p = 0.041), income (beta = 0.001, p = 0.003), living arrangement (beta = - 3.045, p = 0.022), face (beta = - 3.223, p = 0.005) and abdominal (beta = - 4.745, p = 0.0001) pains. Predictors of inner peace include renal problems (beta = 3.752, p = 0.021), shoulder pain (beta = 1.436, p = 0.038) and pain duration (beta = - 0.012, p = 0.027). Predictors of actively giving were renal problems (beta = 3.803, p = 0.001), central neuropathic pain (beta = 1.448, p = 0.017), heart problems (beta = 1.004, p = 0.042), income (beta = 0.001, p = 0.0001), age (beta = - 0.046, p = 0.004) and abdominal pain (beta = 2.617, p = 0.0001). Chronic pain patients had higher actively giving score compared to other spirituality needs. Their spirituality needs were significantly influenced by pain type, duration and site, co-existing medical conditions and socio-demographics. PMID- 30406892 TI - [Cancer screening in Germany: availability and participation]. AB - In Germany, approximately 227,000 women and 249,000 men developed cancer in 2014, and nearly 223,000 patients died from the disease that year. Many cancers are curable or have a very good prognosis when they are diagnosed at an early stage. This is where the concept of early detection examinations comes into play.This article describes the current conditions of and participation in examinations for the early detection of cervical, breast, skin, prostate, and colon cancer as provided by Germany's statutory health services. Participation was derived from claims data from the statutory health insurance system as well as from Germany's mammography screening program (MSP). The survey "German Health Update" (GEDA 2014/2015-EHIS) served as an additional data source. According to the claims data and considering the intended intervals, participation quotas among insured persons who are entitled to participate lie between 16% (colonoscopy) and 48% (Pap test). In 2015, 51.5% of invited women participated in the MSP. The results according to self-reports of the GEDA survey lie in part substantially higher. The results according to the claims data, the MSP, as well as the self-reports suggest that a large part of the population utilizes the examinations. Colon and cervical cancer examinations will be expanded as organized and quality-assured early detection programs with regular invitations and information on benefits and risks. These efforts should contribute to reaching eligible people who have thus far not participated. PMID- 30406893 TI - The Effects of Soy Milk Enriched with Lactobacillus casei and Omega-3 on the Tibia and L5 Vertebra in Diabetic Rats: a Stereological Study. AB - Bone fragility, despite relatively high BMD values, is an important complication related to insulin resistance and oxidative stress in diabetes mellitus type 1. The present study aimed to compare the effects of soy milk (SM), soy milk containing Lactobacillus casei (PSM), and soy milk enriched with Lactobacillus casei and omega-3 (OPSM) on the stereology of the tibia and vertebra, and antioxidant activity in type 1 diabetic rats. Sixty-five male Sprague Dawley rats were randomly assigned into 5 groups of 13 animals each. Diabetes was induced by a single injection of STZ (60 mg/kg); two control groups (non-diabetic: CN and diabetic: CD) were selected and then fed with 1 mL of distilled water. Three treatment groups were fed 1 ml of SM, PSM, and OPSM via intragastric gavage for 60 days. Treatment with SM, PSM, and OPSM significantly decreased (P < 0.05) the number of the osteoclasts in both tibia and L5 vertebra, and plasma alkaline phosphatase level. Also, the osteoblast number, calcium level, catalase activity, and total antioxidant capacity were increased in the SM, PSM, and OPSM groups compared to the STZ group. OPSM had the greatest effects on the stereological and biochemical parameters compared to the SM and PSM groups. Soy milk combination with Lactobacillus casei and omega-3 can ameliorate the stereological changes in the tibia and vertebra. In addition, this combination increased the antioxidant activity and improved the redox homeostasis in diabetic rats. These results suggest the potential role of soy milk containing Lactobacillus casei enriched with omega-3 in preventing and delaying osteoporosis in diabetic patients. PMID- 30406894 TI - Population Health Adaptation Approaches to the Increasing Severity and Frequency of Weather-Related Disasters Resulting From our Changing Climate: A Literature Review and Application to Charleston, South Carolina. AB - PURPOSE OF REVIEW: Recent changes in our planetary climate have and will continue to challenge historical knowledge and risk assumptions for weather-related disasters. While the public health community is rapidly working to develop epidemiological approaches and tools to mitigate and adapt to these weather related disasters, recent high-profile events have exposed gaps in knowledge and response efforts. Limited work has been done to assess the climate readiness of the local public health and healthcare community as it pertains to local response planning and adaptation measures in the event of a weather-related disaster. The purpose of this paper is to review the existing literature related to climate change, weather-related disasters, and population health approaches to adapt to climate-related changes in weather-related disasters at the local level. We highlight a brief case study to illustrate an example of a local approach to adaptation planning in a coastal community. RECENT FINDINGS: Few studies have put forth quantitative disaster epidemiology tools to aid public health officials in preparing for and responding to these weather-related disaster events. There is a general lack of understanding within the public health community about the epidemiological tools which are available to assist local communities in their preparation for, response to, and recovery from weather-related disasters. Cities around the nation are already working to assess their vulnerability and resilience to weather-related disasters by including climate change in emergency preparedness plans and developing adaptation strategies, as well as equipping local hospitals, health departments and other critical public health systems with climate information. But more work is needed and public health funding is lagging to support local and state-level efforts in preparing for and adapting to weather related disasters in the context of a changing climate. Our population health disaster preparedness programs need to be adapted to address the increasing risks to local public health resulting from our changing climate. PMID- 30406895 TI - Hydrolytic enzymes mediated lipid-DNA catabolism and altered gene expression of antioxidants under combined application of lead and simulated acid rain in Fenugreek (Trigonella foenum graecum L.) seedlings. AB - Understanding ill effects of simultaneous existence of various abiotic stresses, commonly observed due to various anthropogenic activities and global climate change these days, over plants growth, metabolic activity and yield responses are important for continued agricultural productivity and food security. In the present study, seedlings of Fenugreek (Trigonella foenum graecum L.) were subjected to lead (Pb, 1200 ppm) and/or simulated acid rain (SAR, pH 3.5) for 30 days, and were then analysed. The results revealed reduced growth, and total lipid and DNA contents, while enhanced Pb accumulation, biological concentration factor, biological accumulation coefficient, translocation factor, lipase activity, and levels of free fatty acid, conjugated diene, lipid hydroperoxide, DNA oxidation and DNase activity under Pb and/or SAR exposure. Additionally, activities and gene expression levels of antioxidants (superoxide dismutase, catalase, guaiacol peroxidase and ascorbate peroxidase) were enhanced in response to applied treatments. The results also suggested that inhibitions/ accelerations determined under joint addition of Pb and SAR were comparatively more profound than those measured under their single application. Additionally, root was more sensitive to Pb treatment, compared to both leaf and shoot. Hence, under simultaneous presence of two or more number of abiotic stresses, the strategy opted by plants for survival is chiefly governed by the interaction between prevailing stressors, which is then conceived by plants as a new state of stress. PMID- 30406897 TI - Hydrochemical assessment of surface and ground waters used for drinking and irrigation in Kardeh Dam Basin (NE Iran). AB - Water quality for drinking and irrigation usage was examined in Kardeh dam basin in NE Iran. Thirty-two surface and groundwater samples were collected and analyzed for major ions of Ca2+, Mg2+, Na+, K+, HCO3-, CO32-, SO42- and Cl- by using standard analytical methods of titration and atomic absorption spectrophotometry at geochemistry laboratory of Ferdowsi University of Mashhad. Dominant cation in most of the water samples are Ca2+ and Mg2+, and dominant anion is HCO3-. Water quality index (WQI) was calculated based on physicochemical parameters such as pH, EC and major ions. The WQI values were less than 100 (maximum permissible value) for all samples and suitable for drinking usage; nevertheless, water quality decreased from northwest toward the southeast of studied area. Also, based on modified NSFWQI, the water resources were classified into average and good categories, which are suitable for irrigation uses. More than 40% of the samples are not suitable for irrigation uses based on magnesium hazard values. Carbonate rocks have the main effect on hydrogeochemical facies and the water quality in studied area. According to drinking and irrigation indices, water quality is reducing from upstream toward downstream to the southeast of the basin. PMID- 30406896 TI - Modulation of growth, ascorbate-glutathione cycle and thiol metabolism in rice (Oryza sativa L. cv. MTU-1010) seedlings by arsenic and silicon. AB - Arsenic is a carcinogenic metalloid, exists in two important oxidation states arsenate (As-V) and arsenite (As-III). The influence of arsenate with or without silicate on the growth and thiol metabolism in rice (Oryza sativa L. cv. MTU 1010) seedlings were investigated. Arsenate was more toxic for root growth than shoot growth where the root lengths were short, characteristically fragile and root tips turned brown. The multiple comparison analysis using Tukey's HSD (honest significant difference) tests indicated that the rate of arsenate accumulation and its conversion to arsenite by arsenate reductase were significantly increased in all arsenate treated seedlings while in seedlings treated jointly with arsenate and silicate, arsenate accumulation and its conversion to arsenite decreased. Silicate content was detected in the seedlings treated with silicate alone and under co-application of arsenate with silicate. In the test seedlings arsenic toxicity increased ascorbate and glutathione contents along with the activities of their regulatory enzymes, viz., ascorbate peroxidase, glutathione reductase, glutathione peroxidase and glutathione-s transferase to reduce the toxicity level induced by arsenic whereas ascorbate oxidase activity was decreased to maintain sufficient ascorbate pool under arsenate treatment. Phytochelatins production were increased in both root and shoot of the test seedlings under arsenate exposure to alter the detrimental effects of arsenic by chelation with arsenite and their subsequent sequestration into vacuole. Thus, joint application of silicate along with arsenate showed significant alterations on all the parameters tested compared to arsenate treatment alone due to less availability of arsenic in the tissue leading to better growth and metabolism in rice seedlings. Thus use of silicon in arsenic contaminated medium may help to grow rice with improved vigour. PMID- 30406898 TI - Development of scientifically justified proposals on the prevention and treatment of environmentally determined constitutional growth delay in children in the West Kazakhstan region. AB - Environmental pollution in many regions of Kazakhstan poses a threat to the growth and development of local children. For children living the near the Aral Sea, chrome processing and gas processing regions, we undertook a medical examination, including physical and sexual development parameters, laboratory studies (complete blood count, urinalysis, blood chemistry), bone age, blood levels of microelements (chromium, manganese, nickel, lead, copper) and hormones [thyroid (T3, T4, TSH), sexual (LH, FSH), growth (STH, IGF-1)], in consultation with relevant specialist doctors. Statistical analysis showed a significant prevalence of short stature among children living, on average, 22.9 versus 7.8% in the control region. Children in these regions have high blood levels of toxic chromium, manganese, lead and nickel compounds. The main causes of short stature in children living in the Aral Sea, chrome processing and oil and gas processing regions are cerebral-endocrine pathologies, hereditary diseases, somatogenic diseases, constitutional growth delay, a toxic chemical load and ecologically determined short stature. A working classification of short stature in children living in the Aral Sea, chrome processing and gas processing regions, including ecologically dependent short stature, has been developed. The scheme of medical and recreational measures for children living in the Aral Sea, chrome processing and gas processing regions was proposed. PMID- 30406899 TI - Contractile protein biochemistry in the Pollard Lab in Baltimore. AB - We describe our search for the molecular mechanisms of cell motility with personal recollections of bucket biochemistry in Tom Pollards Lab at the Johns Hopkins, circa 1980. PMID- 30406900 TI - Cognitive Behavior Therapy and Metacognitive Therapy: Moderators of Treatment Outcomes for Children with Generalized Anxiety Disorder. AB - Although cognitive behavioral therapy (CBT) is effective for childhood anxiety disorders, approximately 40% of youth remain anxious after treatment. Metacognitive therapy (MCT-c) for children with generalized anxiety disorder (GAD) has shown promising effects. The present study aimed to examine if CBT and MCT-c show differential effects in children with primary GAD based on baseline characteristics, in a quasi-experimental design. To investigate which treatment is most beneficial for whom, three potential moderators: age, symptom severity, and comorbid social anxiety were examined. Sixty-three children aged 7-14 completed CBT or MCT-c. Participants were assessed before and after treatment. Both CBT and MCT-c were highly effective in treatment of childhood GAD. None of the selected variables significantly moderated treatment outcomes. Subgroups of children with high symptom severity and social anxiety comorbidity showed trends of responding better to CBT. Methodologically stronger studies are needed to facilitate a better adaptation of treatment for children with GAD. PMID- 30406901 TI - Fremanezumab: First Global Approval. AB - Fremanezumab-vfrm (hereafter referred to as fremanezumab) [AJOVYTM] is a fully humanized monoclonal antibody (IgG2Deltaa) developed by Teva Pharmaceuticals to selectively target calcitonin gene-related peptide (a vasodilatory neuropeptide involved in the pathophysiology of migraine). Its use has been associated with significant reductions in migraine frequency, the requirement for acute headache medication use and headache-related disability compared with placebo in multinational, phase III studies, and in September 2018 fremanezumab was approved by the US FDA for the preventive treatment of migraine in adults. A regulatory assessment for fremanezumab as a preventive treatment of migraine in adults is underway in the EU. Fremanezumab is also undergoing phase III development for the preventive treatment of cluster headache (although a phase III chronic cluster headache study has been suspended due to the results of a prespecified futility analysis) and phase II development for the preventive treatment of post-traumatic headache disorder. This article summarizes the milestones in the development of fremanezumab leading to this first approval in the USA for the preventive treatment of migraine in adults. PMID- 30406902 TI - Dolutegravir/Rilpivirine: A Review in HIV-1 Infection. AB - Dolutegravir/rilpivirine (Juluca(r)) is the first two-drug single-tablet regimen (STR) to be approved for the treatment of HIV-1 infection in adults. The fixed dose STR combines the integrase strand transfer inhibitor dolutegravir with the non-nucleoside reverse transcriptase inhibitor rilpivirine. In two phase III non inferiority trials (SWORD-1 and SWORD-2) in treatment-experienced patients already virologically suppressed on their current antiretroviral (ART) regimen, switching to once-daily dolutegravir plus rilpivirine maintained virological suppression over 48 weeks. Switching to a two-drug regimen of dolutegravir plus rilpivirine was also associated with high rates of virological suppression in real-world observational studies. Switching to once-daily dolutegravir plus rilpivirine was generally well tolerated and associated with more favourable renal and bone parameters than remaining on the current ART regimen. Longer-term, dolutegravir plus rilpivirine demonstrated durable maintenance of virological suppression and remained generally well tolerated for up to 100 weeks. Thus, dolutegravir/rilpivirine provides a convenient alternative treatment option for some adults with HIV-1 infection and no history of virological failure who are already virologically suppressed on (and wish to switch from) their current ART regimen. PMID- 30406903 TI - Human Ductal Carcinoma In Situ: from the Eyes of a Beholder. PMID- 30406905 TI - Assuring the quality of programmatic assessment: Moving beyond psychometrics. PMID- 30406904 TI - Aiming for agency and authenticity in assessment. PMID- 30406906 TI - Efficacy and Safety of Eltrombopag for Aplastic Anemia: A Systematic Review and Meta-analysis. AB - BACKGROUND AND OBJECTIVES: Eltrombopag seems to be effective in treating patients with aplastic anemia in several clinical trials. This paper aims to perform the first meta-analysis analyzing the efficacy and safety of eltrombopag for aplastic anemia. METHODS: Literatures were retrieved from PubMed, EMBASE, OVID, Web of Science, Cochrane, Wanfang, http://clinicaltrials.gov and World Health Organization International Clinical Trials Registry Platform search portal from establishment to July 2018. Using Stata statistical software version 12.0, subgroup analyses and sensitivity analyses were conducted. RESULTS: The overall hematologic response rate is 88% (95% CI 83-94%) for patients treated with eltrombopag plus immunosuppressive therapy, and 47% (95% CI 38-56%) for patients with refractory aplastic anemia using eltrombopag alone. Karyotype abnormality rates include an overall rate of 10% (95% CI 7-14%), a subtotal rate of 8% (95% CI 3-13%) for patients who are treated with eltrombopag plus immunosuppressive therapy without using antithymocyte globulin before, and a subtotal rate of 17% (95% CI 10-24%) for patients with refractory aplastic anemia treated with eltrombopag alone. CONCLUSIONS: With different treatments and in different conditions eltrombopag showed a distinctive effect for aplastic anemia. However, clone evolution and adverse events were associated with treatment. PMID- 30406907 TI - Characteristics and prognosis of patients with non-immunoglobulin-M monoclonal gammopathy of undetermined significance: a retrospective study. AB - Non-immunoglobulin (Ig)-M monoclonal gammopathy of undetermined significance (MGUS) is a precursor lesion with the potential to evolve into a malignant plasma cell neoplasm. The prevalence of MGUS differs by ethnicity and is lower in the Japanese population than in the Western population. However, there is limited evidence about the clinical course of MGUS in Asian races. The present study aims at elucidating the clinical course and prognosis of Japanese patients with non IgM MGUS in the clinical setting. We retrospectively examined 1009 patients with non-IgM MGUS identified by screening procedures. The median overall survival of these patients was > 20 years, and only one-fifth patients died of plasma cell neoplasms. The cumulative incidence of plasma cell neoplasms requiring treatment was 19%. Multivariate analysis revealed that immunoparesis and female gender were independent factors affecting treatment requirement. Although the characteristics and clinical course of patients with non-IgM MGUS obtained in this study were found to be essentially similar to those of previous studies, we report here for the first time that female gender is a significant independent factor for requiring treatment. PMID- 30406908 TI - Ferroptosis and Its Role in Diverse Brain Diseases. AB - Ferroptosis is a recently identified, iron-regulated, non-apoptotic form of cell death. It is characterized by cellular accumulation of lipid reactive oxygen species that ultimately leads to oxidative stress and cell death. Although first identified in cancer cells, ferroptosis has been shown to have significant implications in several neurologic diseases, such as ischemic and hemorrhagic stroke, Alzheimer's disease, and Parkinson's disease. This review summarizes current research on ferroptosis, its underlying mechanisms, and its role in the progression of different neurologic diseases. Understanding the role of ferroptosis could provide valuable information regarding treatment and prevention of these devastating diseases. PMID- 30406910 TI - MHC Class I Molecules and PirB Shape Neuronal Morphology by Affecting the Dendritic Arborization of Cortical Neurons. AB - Neuronal MHC class I proteins have been previously reported to regulate synaptic plasticity. Several reports indicate MHC class I proteins are expressed early during development of the nervous system, suggesting they may also play a role in neuronal development. Using cultured cortical neurons, we show MHC class I proteins aggregate at specific sites in neuronal cell bodies, which overlap with the actin cytoskeleton. Knockout of MHC class I in cultured neurons increases total dendritic length and the number of branch points. These effects are abolished by reintroducing MHC class I expression. Similarly, blocking of MHC class I proteins or PirB by an MHCI antibody or a soluble PirB ectodomain respectively, mimics the knock out phenotype of increased dendritic branching. This effect is correlated with decreased phosphorylation of both LIMK and cofilin, suggesting it may be mediated by an induction of cofilin activity. Finally, layer II and III cortical neurons in the sensorimotor region of an MHC class I deficiency mouse model show increased dendritic growth and branching. Altogether, our results suggest MHC class I plays a role in inhibiting or limiting the degree of dendrite arborization during the development of cortical neurons. PMID- 30406911 TI - Social Connectedness and Loneliness Mediate the Association Between Autistic Traits and Internalizing Symptoms Among Young Adults. AB - Adults with autism and subclinical autistic traits report greater internalizing problems than their peers, but the psychological processes underlying these associations are not well understood. The current study used structural equation modeling to examine whether social experiences (social connectedness and loneliness) mediate the link between autistic traits and internalizing symptoms among 821 college students. Those with higher total Broader Autism Phenotype Questionnaire (BAPQ) scores reported lower social connectedness, which related to greater loneliness, and, in turn, greater anxious and depressive symptoms. Relations with specific BAPQ subscales were also examined. Results indicate that, among young adults, stronger subclinical autistic traits relate to greater mental health and social difficulties and point to the important role of social experiences in mental health adjustment. PMID- 30406912 TI - Effects of Delay, Question Type, and Socioemotional Support on Episodic Memory Retrieval by Children with Autism Spectrum Disorder. AB - Twenty-seven autistic children and 32 typically developing (TD) peers were questioned about an experienced event after a two-week delay and again after a two-month delay, using the Revised National Institute of Child Health and Human Development (NICHD) Investigative Interview Protocol. Recall prompts elicited more detailed and more accurate responses from children than recognition prompts. Autistic children recalled fewer correct narrative details than TD peers when questioned using open invitations, cued invitations, and directive questions. Nonetheless, they were as accurate as TD peers when responding to all types of prompts. The informativeness and accuracy of children's reports remained unchanged over time. Social support was beneficial when children were interviewed for the first time but not after a longer delay. PMID- 30406913 TI - Anxiety and Interpretation of Ambiguity in Autistic Children, Typical Children and Their Mothers. AB - Anxiety is highly prevalent in autistic children. Yet interpretation biases implicated in anxiety in non-autistic individuals have received little research attention in this group. Twenty-two autistic children and 25 typical children completed an ambiguous scenarios interview and questionnaire-based measures of anxiety. A subsample of mothers completed parent-report and adult relevant versions of the interview and anxiety questionnaires. Autistic children self reported similar interpretations of ambiguous scenarios, and similar levels of anxiety, to their typical peers. In contrast, mothers of autistic children reported greater levels of anxiety, and more negative interpretations of ambiguous scenarios in both their children and themselves, relative to mothers of typical children. These data highlight the importance of including autistic children's self-reports when measuring and treating anxiety. PMID- 30406914 TI - Motion-Capture Patterns of Voluntarily Mimicked Dynamic Facial Expressions in Children and Adolescents With and Without ASD. AB - Research shows that neurotypical individuals struggle to interpret the emotional facial expressions of people with Autism Spectrum Disorder (ASD). The current study uses motion-capture to objectively quantify differences between the movement patterns of emotional facial expressions of individuals with and without ASD. Participants volitionally mimicked emotional expressions while wearing facial markers. Recorded marker movement was grouped by expression valence and intensity. We used Growth Curve Analysis to test whether movement patterns were predictable by expression type and participant group. Results show significant interactions between expression type and group, and little effect of emotion valence on ASD expressions. Together, results support perceptions that expressions of individuals with ASD are different from-and more ambiguous than those of neurotypical individuals'. PMID- 30406915 TI - Assessment of Non-vitamin K Oral Anticoagulants Use in a Tertiary Care Center in the USA: A Chart Review of 909 Patients. AB - BACKGROUND: Non-vitamin K oral anticoagulants (NOACs) have emerged as an attractive alternative to vitamin K antagonists for various thromboembolic indications. However, prescribed NOAC doses are often inconsistent with drug labeling and prescribers might not consider the potential risks associated with concomitant use of other drugs, which can compromise NOACs' safety and effectiveness. METHODS: A retrospective chart review was conducted in a tertiary care center in USA over a 4-month period. We studied patients whose home medications included NOACs and assessed the appropriateness as per drug labeling, taking into consideration relevant clinical factors and concomitant drug intake. RESULTS: A total of 909 patients with a mean age of 70.6 +/- 13.1 years, out of which 51.6% were males, were included. The majority of patients received NOACs for stroke prevention in atrial fibrillation (AF) (70.5%), or deep venous thrombosis/pulmonary embolism (DVT/PE) treatment (13.5%). The most common drug prescribed was apixaban (57.8%) followed by rivaroxaban (34.0%), and less frequently dabigatran (7.7%). Inappropriate dosing was significantly more frequent among older patients, those taking NOACs for AF, those taking a higher number of home medications, and those with a lower creatinine clearance. Seven hundred and six patients (77.67%) had at least one drug-NOAC interaction, out of which 515 were rated major interactions. Antiplatelets, amiodarone, non-steroidal anti-inflammatory medications, and calcium channel blockers were the most commonly interacting drugs. CONCLUSION: A significant number of patients received NOACs at doses inconsistent with the package labeling or had clinically significant drug-drug interactions with NOACs. Efforts are warranted to improve appropriate dosing and avoid significant drug interactions. PMID- 30406916 TI - The prognostic and predictive role of hyponatremia in patients with advanced non small cell lung cancer (NSCLC) with bone metastases. AB - PURPOSE: Hyponatremia and bone metastasis (BMs) are known as negative prognostic factors in patients affected by metastatic non-small cell lung cancer (NSCLC). Hyponatremia is associated with higher risk of osteoporosis and bone fracture, but no data are available about the relationship between hyponatremia and bone metastasis. This study aims to analyze the prognostic impact of hyponatremia in NSCLC patients with bone metastases. METHODS: We retrospectively collected data about advanced NSCLC patients. Survival curves were estimated using Kaplan-Meier method, and comparisons were made using chi-square test. RESULTS: Six hundred forty-seven patients were enrolled into the study. BMs were present in 264 patients (41%) at diagnosis, while hyponatremia appeared in 237 (37%) patients during the first-line treatment. Patients without BMs had a median overall survival (mOS) of 15.9 months (95% CI 14.1-17.9) versus 11.4 months (95% CI 9.4 13.4) for patients with BMs (p = 0.001). Eunatremic patients had a better outcome (mOS 16.3 months, 95% CI 14.6-18.0 vs 10.3 months, 95% I 7.6-12.8, p = 0.003). Considering the two variables, patients with BMs and hyponatremia had a mOS of 10.1 months (95% CI 4.3-15.9), patients with hyponatremia without BMs 11.9 months (95% CI 11.4-12.4), while mOS was 13.1 months (95% CI 12.0-14.2) for eunatremic patients with BMs versus 17.1 months (95% CI 15.2-19.1) in eunatremic patients without BMs (p = 0.0020). Hyponatremic patients developed metachronous BMs significantly earlier (3.73 vs 5.76 months, p = 0.0187). CONCLUSIONS: Our study showed that hyponatremia is an important prognostic factor and it should be necessarily considered to enhance the management of NSCLC patients with BMs. PMID- 30406917 TI - The role of wrist monitors to measure blood pressure in older adults. AB - BACKGROUND: Arterial hypertension is a common condition in older adults with increasing data about blood pressure (BP) targets and antihypertensive treatment in this population. Recent studies have opened new discussions about the different usual and unusual methods of blood pressure monitoring. However, there are no evidence-based recommendations whether BP should be measured at upper arms or at wrist, which seems to be more comfortable in older and frail people. AIMS: The purpose of this study was to test the quality of wrist BP monitors as diagnostic method in older adults. METHODS: BP measurements at both upper arms and at both wrists were compared under standardized conditions in 605 patients >= 75 years. Differences in wrist and upper arm BP were, furthermore, correlated with various diagnoses and parameters including ankle-brachial-index (ABI). RESULTS: In patients of 75-80 years, there were no differences in BP measurements at upper arms compared to wrists whereas in patients > 80 years, BP measurements at wrists were significantly lower than at upper arms. In both age groups BP measured at wrist was significantly lower in patients with ABI < 0.9. CONCLUSIONS: BP wrist monitors could be considered as a serious alternative in adults of 75-80 years or in older persons with normal ABI values. PMID- 30406918 TI - Autophagy and its role in pulmonary hypertension. AB - Pulmonary hypertension (PH) is a very common kind of pulmonary vascular disease, which can cause a heavier burden on patient's quality of life, even lead to death. Yet, the mechanism of PH is incomprehensive and not so clear nowadays. In recent years, more and more studies show that autophagy plays a pivotal role in the development of PH. Some modalities target on the formation or maturation of autophagosome that has emerged from our increasing knowledge of autophagy machinery, which may prevent or eliminate the process of PH. The deciphering of molecular selectivity of autophagy has also been a source of novel modulators that act specifically on selective forms of autophagy. Tremendous recent progress has opened a new possibility for modulating autophagy in complex diseases. Thus, autophagy may become a prospective choice for treatment of PH. Herein, we reviewed the literatures and discussed the role of autophagy in the development and treatment of PH. PMID- 30406919 TI - Association between tongue and lip motor functions and mixing ability in complete denture wearers. AB - BACKGROUND: Masticatory performance of elderly complete denture wearers is low, which may lead to restriction on intakes of several foods such as fresh fruit or raw vegetables. AIM: The aim of this study was to investigate the relationship between tongue motor function, lip motor function, and mixing ability in complete denture wearers. MATERIALS AND METHODS: Participants comprised 54 complete denture wearers with a mean age of 77.1 years. Maximum tongue pressure and oral diadochokinesis were measured to evaluate tongue and lip motor functions. A color changeable, chewing gum was used to evaluate mixing ability. The relationship between tongue and lip motor functions and mixing ability was assessed using stepwise multiple regression analysis. RESULTS: The stepwise multiple regression analysis identified maximum tongue pressure, the number of repetitions of the syllable "ka", and gender as significant predictors for mixing ability among complete denture wearers. DISCUSSION: The elderly edentulous individuals mainly used tongue motor function in oral motor functions for mixing color-changeable chewing gums, which might be ascribable to wearing complete dentures. CONCLUSIONS: Under the limited conditions of this study, factors relating to tongue motor function, tongue pressure and the number of repetitions of the syllable "/ka"/ significantly contributed to the mixing ability of complete denture wearers. It was suggested that tongue motor function had positive effect on the mixing ability of complete denture wearers. PMID- 30406921 TI - Standardised quality control and quality assurance activities in radiology across Australia and New Zealand: in search of the Holy Grail. PMID- 30406920 TI - The Charlson Comorbidity and Barthel Index predict length of hospital stay, mortality, cardiovascular mortality and rehospitalization in unselected older patients admitted to the emergency department. AB - BACKGROUND AND AIMS: The Charlson Comorbidity Index (CCI) is the most widely used assessment tool to report the presence of comorbid conditions. The Barthel index (BI) is used to measure performance in activities of daily living. We prospectively investigated the performance of CCI or BI to predict length of hospital stay (LOS), mortality, cardiovascular (CV) mortality and rehospitalization in unselected older patients on admission to the emergency department (ED). We also studied the association of CCI or BI with costs. METHODS: We consecutively enrolled 307 non-surgical patients >= 68 years presenting to the ED with a wide range of comorbid conditions. Baseline characteristic, clinical presentation, laboratory data, echocardiographic parameters and hospital costs were compared among patients. All patients were followed up for mortality, CV mortality and rehospitalization within the following 12 months. A multivariate analysis was performed. RESULTS: Mortality was increased for patients having a higher CCI or BI with a hazard ratio around 1.17-1.26 or 0.75-0.81 (obtained for different models) for one or ten point increase in CCI or BI, respectively. The prognostic impact of a high CCI or BI on CV mortality and rehospitalization was also significant. In a multiple linear regression using the same independent variables, CCI and BI were identified as a predictor of LOS in days. Multiple linear regression analysis did not confirm an association between CCI and costs, but for BI after adjusting for multiple factors. CONCLUSION: CCI and BI independently predict LOS, mortality, CV mortality, and rehospitalization in unselected older patients admitted to ED. PMID- 30406922 TI - AFOMP policy number 6: code of ethics for medical physicists in AFOMP Countries. AB - This policy statement, which is the sixth of a series of documents prepared by the Asia-Oceania Federation of Organizations for Medical Physics (AFOMP) Professional Development Committee, gives guidance on how medical physicists in AFOMP countries should conduct themselves in an ethical manner in their professional practice (Ng et al. in Australas Phys Eng Sci Med 32:175-179, 2009; Round et al. in Australas Phys Eng Sci Med 33:7-10, 2010; Round et al. in Australas Phys Eng Sci Med 34:303-307, 2011; Round et al. in Australas Phys Eng Sci Med 35:393-398, 2012; Round et al. in Australas Phys Eng Sci Med 38:217-221, 2015). It was developed after the ethics policies and codes of conducts of several medical physics societies and other professional organisations were studied. The policy was adopted at the Annual General Meeting of AFOMP held in Jaipur, India, in November 2017. PMID- 30406923 TI - A prospective study of weekly intensity modulated radiation therapy plan adaptation for head and neck cancer: improved target coverage and organ at risk sparing. AB - This prospective study of weekly CT scanning and plan adaption during H&N IMRT reports on the frequency of plan adaptations based on dosimetric differences between original and re-optimised IMRT plans. The volumetric and geometric change occurring in target volumes and salivary glands is also described. Ten H&N cancer patients underwent weekly planning CT imaging and re-optimisation of the IMRT plan if PTV or OAR coverage was unacceptable. Comparisons of PTV and parotid gland dosimetry between the original and adaptive plans were made. Parotid and submandibular gland volume changes and shift were calculated. Eight of ten patients required one or more plan adaptations, with 41% of adaptations occurring by fraction ten. Salivary glands reduced in volume, with a medial shift of the lateral border of the parotid gland and a superior shift of the submandibular gland. Change in PTV coverage did not correlate with weight loss or nutritional score. Inadequate PTV coverage, requiring plan adaptation, occurs early in the course of IMRT. A weekly Adaptive RT (ART) protocol results in significant improvement of PTV coverage. Implementation of a clinical ART protocol should include imaging and dose calculation within the first ten fractions. PMID- 30406924 TI - Deciphering forest change: Linking satellite-based forest cover change and community perceptions in a threatened landscape in India. AB - Global conservation efforts have traditionally focused on biodiversity hotspots and other priority landscapes. However, large areas outside priority sites have high conservation value and are referred to as neglected landscapes. The Eastern Ghats of India is an unexplored forest landscape of high conservation value with several endemic and threatened species reported, and is also home to many indigenous forest-dwelling communities. However, it remains a neglected area for conservation and only 3.53% of this landscape is protected. Here, we examine the effectiveness of protected areas in neglected landscapes in preventing forest degradation, and how community perceptions can be used to understand satellite based landscape change analyses at village level. This study was conducted in Papikonda National park (PNP) and its unprotected buffers in India's Eastern Ghats. Forest degradation was higher in the buffer (32%) than inside PNP (12%) between 1991 and 2014. Communities attributed shifting cultivation, plantations and over-extraction of forest resources as being the major drivers of forest degradation. Community observations of change were not significantly correlated with spatial measures of change. Forest degradation was higher outside the PA at a landscape level and inside the PA at the village level, therefore the PA was effective in reducing degradation at the landscape level but not at the village level inside the PA. We further discuss the role of community observations in interpreting forest degradation in neglected forest landscapes. PMID- 30406925 TI - Assessing transformative capacity for sustainable urban regeneration: A comparative study of three South Korean cities. AB - Urban regeneration forms a key approach for coping with persistent sustainability problems in cities. In practice, however, it is often driven by motives other than sustainability transformation. This paper explores the preconditions that allow urban regeneration approaches to become transformative, and suggests a methodology to support this shift in practice. It does so by assessing the capacity available to prepare for, initiate, and steer a path-deviant sustainability transformation of urban areas in three South Korean cities, jointly with stakeholders. The findings reflect how local policy largely supports a conservative development pathway, favored by national government, sidelining especially ecological implications. Major deficits exist regarding systems thinking, sustainability foresight, and social learning processes, while collective visioning, intermediation, community empowerment, and repositioning science could become instant drivers. In conclusion, assessing transformative capacity offers a crucial lever to design urban-regeneration approaches for unlearning dominant development paradigms and to experimentally reconfigure urban social-ecological-technological systems. PMID- 30406926 TI - Prolonged Exposure to Silver Nanoparticles Results in Oxidative Stress in Cerebral Myelin. AB - Currently, silver nanoparticles (AgNPs) are frequently used in a wide range of medical and consumer products. Substantial usage of AgNPs is considered to create substantive risks to both the environment and the human health. Since there is increasing evidence that the main mechanism of toxicity of AgNPs relates to oxidative stress, in the current study we investigate oxidative stress-related biochemical parameters in myelin isolated from adult rat brain subjected to a low dose of AgNPs. Animals were exposed for 2 weeks to 0.2 mg/kg b.w. of small (10 nm) AgNPs stabilized in citrate buffer or silver citrate established as a control to compare the effects of particulate and ionic forms of silver. We observe enhanced peroxidation of lipids and decreased concentrations of protein and non protein -SH groups in myelin membranes. Simultaneously, expression of superoxide dismutase, a free radical scavenger, is increased whereas the process of protein glutathionylation, being a cellular protective mechanism against irreversible oxidation, is found to be inefficient. Results indicate that oxidative stress induced alterations in myelin membranes may be the cause of ultrastructural disturbances in myelin sheaths. PMID- 30406927 TI - Actinomyces spp. bloodstream and deep vein thrombus infections in people who inject drugs. AB - INTRODUCTION: Actinomyces spp. cause several well-described syndromes including cervicofacial and pelvic infections. Actinomyces spp. infection as an opportunistic infection among people who inject drugs has rarely been described with few case reports published. METHODS AND RESULTS: Here we describe four people who inject drugs admitted with Actinomyces spp. infections, all with an overlapping syndrome and who presented a challenge to both diagnose and to manage. DISCUSSION: This case series highlights the potential to overlook Actinomyces spp. infection in people who inject drugs and aims to increase clinician awareness of diagnosis, empirical and directed treatment, and potential complications of this infection. PMID- 30406928 TI - Identification a novel insertion PHEX mutation in a sporadic patient with hypophosphatemic rickets. PMID- 30406929 TI - Autoimmune thyroid diseases are more common in patients with prolactinomas: a retrospective case-control study in an Italian cohort. AB - BACKGROUND: Prolactin may exert immunological effects. Over the years, a higher prevalence of autoimmune thyroid diseases (ATD) has been reported in patients with prolactinomas (PRLs) in areas with sufficient iodine intake. PURPOSE: The aim of our study was to evaluate the prevalence of ATD [Graves' disease (GD) and chronic autoimmune thyroiditis (AIT)] in a retrospective cohort of Italian patients with PRLs compared to a sex-matched control group, represented by subjects with non-functioning pituitary adenoma (NFPA) or empty sella (ES). MATERIALS AND METHODS: We enrolled 149 patients (108 F/41 M) with PRLs (110 micro/39 macro) and 143 subjects (100 F/43 M) with NFPA (n = 96, 56 micro/40 macro) or ES (n = 47), with normal serum prolactin. Neck ultrasound and thyroid function tests (anti-thyroid antibodies, TSH, FT3 and FT4) were performed in all patients. RESULTS: In PRLs, median serum prolactin was significantly higher (98.3 vs. 8.9 ng/ml, p <= 0.0001), while age was lower (34 vs. 46 years, p <= 0.001) compared to controls. The prevalence of ATD was 13.4% (20/149) in PRLs (1 GD and 19 AIT) compared to 6.3% (9/143) in the controls (p = 0.042). At the multivariate analysis, serum prolactin was the only independent factor predicting ATD. Thyroid volume (12.5 +/- 5.9 ml vs. 12.8 +/- 10 ml, p = 0.47) and the presence of uni- or multinodular goiter (29.5% vs. 35%, p = 0.35) did not differ between PRLs and control groups. CONCLUSIONS: Our data in an area with mild iodine deficiency confirm a higher prevalence of ATD in patients with prolactinomas. PMID- 30406930 TI - Clinical characteristics and outcomes of open globe injuries in Japan. AB - PURPOSE: To describe the epidemiology and clinical outcomes of open globe injuries (OGIs) in Japan over 10 years, and examine preoperative factors influencing the visual prognosis after surgery. STUDY DESIGN: Retrospective, observational, multicenter case-series study. METHODS: Patients' data were entered into a computerized database for review and statistical analyses. The following parameters were assessed; age, gender, initial and final visual acuity, duration between onset and surgery, presence of lens in the eye, characteristics of injury, presence of ocular complications, and number of surgeries. RESULTS: The records of 374 eyes with OGI were enrolled. The average age of the patients was 56.8 +/- 22.1 years, and the majority of patients were men (73.5%). Compared to the overall cohort, work-related OGI was the most common, associated with significantly better final visual acuity, whereas patients with fall-down OGI showed significantly worse final visual acuity (P < 0.05). Among the types of injury, both the initial and final visual acuity were significantly worse in the rupture group than in the laceration group. Multiple liner regression analyses revealed that the final visual acuity was significantly associated with initial visual acuity, type of injury (rupture), retinal detachment, and proliferative vitreoretinopathy. CONCLUSION: To predict the visual outcome in patients with OGI, ophthalmologists need to pay attention not only to the initial visual acuity but also to initial ocular conditions, such as the presence of ocular complications. PMID- 30406931 TI - Splenic flexure mobilization in rectal cancer surgery: do we always need it? AB - Splenic flexure (SFM) in rectal cancer surgery is a crucial step which may increase the difficulty of the operation. The aim of this retrospective single center study is to demonstrate if the selective omission of SFM during anterior rectal resection can reduce the complexity of the operation, without affecting post-operative and oncologic outcomes. Data of 112 consecutive rectal resections for cancer from March 2010 to March 2017 were analyzed and divided into two groups: SFM and No-SFM. A sub-analysis was then performed for laparoscopy and traditional cases. Post-operative and oncologic outcomes, including overall (OS) and cancer-related survival (CRS), were analyzed and compared. SFM was performed in 42% of cases and laparoscopy was used in 73.2%. Operative time resulted significantly lower in the No-SFM group (190 vs. 225 min, p = 0.01). In laparoscopy in the No-SFM group, operative time and post-operative stay were significantly lower (205.5 vs. 222.5 min, p = 0.04; 9 vs. 10 days, p = 0.01). Most of the open resections were performed without SFM (35.4% vs. 14.9%, p = 0.02). No statistical significant differences were found in OS and CRS in the two groups. We support the hypothesis that every surgeon should carry out an accurate intra-operative evaluation to perform a selective SFM. When possible, SFM can be safely avoided with no additional risks in terms of post-operative and oncologic outcomes. PMID- 30406932 TI - Cytoreductive surgery followed by HIPEC repetition for secondary ovarian cancer recurrence. AB - Secondary and tertiary cytoreductive surgery was associated with improved overall survival in platinum-sensitive recurrent ovarian cancer (ROC). Hyperthermic intraoperative intra-peritoneal chemotherapy (HIPEC) is considered an attractive method in the treatment of ROC to deliver chemotherapy with enhanced effect directly at the tumor site. However, another deserving aspect is the feasibility and the oncologic role of HIPEC repetition. Twelve patients affected by secondary ovarian cancer recurrence previously submitted to cytoreduction followed by HIPEC were enrolled for the present study to receive tertiary cytoreduction followed by HIPEC repetition. The median operative time, including time for HIPEC procedure, was 360 min (range 240-540). Average EBL was 325 ml (from 100 to 500 ml). The median hospital stay was of 5 days, from 4 to 10. Low-grade post operatory complications occurred in 2 patients (16.6%) and high-grade complication in 1 case (8.3%). Our study report encouraging data about safety of HIPEC repetition in ovarian cancer treatment. PMID- 30406933 TI - Laparoscopic resection of splenic flexure colon cancers: a retrospective multi center study with 117 cases. AB - The objective is to investigate the short- and long-term outcomes of laparoscopic resections of splenic flexure colon cancers in three Italian high-volume centers. The laparoscopic resection of splenic flexure colon cancers is a challenging procedure and has not been completely standardized, mainly due to the technical difficulty, the arduous identification of major blood vessels, and the problems associated with anastomosis construction. In this retrospective cohort observational study, a consecutive series of patients treated in three Italian high-volume centers with elective laparoscopic resection of the splenic flexure for cancer is analyzed. The observational period was from January 2008 to August 2017. Patient demographics and clinical features, operative data, and short- and long-term outcomes were prospectively recorded in a specific database and were retrospectively analyzed. During the observation period, 117 patients were selected. Conversion to open surgery was necessary in 15 patients (12.8%). Of 102 complete laparoscopic procedures, multi-visceral resection was performed in 13 cases (12.7%). Postoperative surgical complications occurred in 13 patients (12.7%), with 3 cases of anastomotic leak (2.9%) and 3 cases of re-operation (2.9%). The postoperative mortality in this population was null. The 5-year overall survival rate was 84.3%, and the 5-year disease-free survival rate was 87.8%. Laparoscopic resection of the splenic flexure is feasible and safe in high volume centers. Compared to the results of other laparoscopic colonic resections, the short- and long-term outcomes are similar, but the conversion rate is higher. PMID- 30406935 TI - Significance of congestive heart failure as a cause of pleural effusion: Pilot data from a large multidisciplinary teaching hospital. AB - BACKGROUND: Epidemiological data on the causes of pleural effusion (PE) are scarce. Data on the local prevalence of various causes of PE may play a crucial role in the management strategy of patients with PE. The aim of the study was to investigate the causes of PE and to assess 30-day mortality rate in unselected adult patients treated in a large, multidisciplinary hospital. METHODS: Retrospective analysis of medical records, including chest radiographs, of 2835 consecutive patients admitted to the hospital was performed. Radiograhic signs of PE were found in 195 of 1936 patients in whom chest radigraphs were available. These patients formed the study group. RESULTS: The leading causes of PE were as follows: congestive heart failure (CHF; 37.4%), pneumonia (19.5%), malignancy (15.4%), liver cirrhosis (4.2%) and pulmonary embolism. The cause of PE in 6.7% patients was not established. There was a significant predominance of small volume PE as compared to a moderate or large volume PEs (153, 28 and 14 patients, respectively). Almost 80% of patients with CHF presented with small volume PE, while almost 50% of patients with malignant PE demonstrated moderate or large volume PE. Thirty-day mortality rate ranged from 0% for tuberculous pleurisy to 40% for malignant PE (MPE). CONCLUSIONS: Pleural effusion was found in 10.1% of patients treated in a large multidisciplinary hospital. CHF was the leading cause of PE. Although 30-day mortality in patients with CHF was relatively high, it was lower than that in parapneumonic PE and MPE. PMID- 30406934 TI - Transanal total mesorectal excision (TaTME): single-centre early experience in a selected population. AB - Total mesorectal excision (TME) represents the key principle in the surgical treatment of rectal cancer. Transanal mesorectal excision was introduced as a complement to conventional surgery to overcome its technical difficulties. The aim of this study was to evaluate the early surgical results following the introduction of this novel technique at our Unit. Between January and May 2016, 12 patients diagnosed with mid-low rectal adenocarcinoma were enrolled into this study and evaluated with regards demography, histopathology, peri-operative data and postoperative complications. The tumor was located in the middle rectum in 6 patients (50%), in the lower rectum in 6 patients (50%). Mean operative time was 356.5 +/- 76.2 min (range 240-494). Eleven out 12 patients (91.6%) had less than 200 mL of intraoperative blood loss. Mean hospital stay was 10.9 +/- 4.6 days (range 5-19). No mortality was recorded. Intraoperative complications were recorded in 1, while early post-operative complications (< 30 days) were observed in 5 patients (41.6%). Histopathology showed in all cases an intact mesorectum. Mean number of lymphnodes harvested was 13.6 +/- 6.6 (range 4-29). Distal and circumferential margin was, respectively, of 20.8 +/- 14.2 mm (range 2-45 mm) and 16.1 +/- 7.6 mm (range 3-30 mm). The comparative analysis showed significant differences concerning mean operative time (p = 0.0473) and estimated blood loss (p = 0.0367). This study confirms this technique is safe and feasible, but more evidence to support its use over conventional laparoscopic surgery is needed. PMID- 30406936 TI - Impact of routine invasive strategy on outcomes in patients with non-ST segment elevation myocardial infarction during 2005-2014: A report from the Polish Registry of Acute Coronary Syndromes (PL-ACS). AB - BACKGROUND: Non-ST-segment-elevation myocardial infarction (NSTEMI) has become the most frequently encountered type of MI. The patient clinical profile and management has evolved over the past decade. As there is still a scarcity of data on the latest trends in NSTEMI, changes herein were observed and assessed in the treatment and outcomes in Poland between 2005 and 2014. METHODS: A total of 197,192 patients with NSTEMI who enrolled in the Polish Registry of Acute Coronary Syndromes (PL-ACS) between 2005 and 2014 were analyzed. In-hospital and 12-month mortality were assessed. RESULTS: Coronary angiography use increased from 35.8% in 2005-2007 to 90.7% in 2012-2014 (p < 0.05), whereas percutaneous coronary intervention increased from 25.7% in 2005-2007 to 63.6% in 2012-2014 (p < 0.05). There was a 50% reduction in in-hospital mortality (from 5.6% in 2005 2007 to 2.8% in 2012-2014; p < 0.05) and a 30% reduction in one-year mortality (from 19.4% in 2005-2007 to 13.7% in 2012-2014; p < 0.05). A multivariate analysis confirmed an immense impact of invasive strategy on patient prognosis during in-hospital observation with an odds ratio (OR) of 0.31 (95% confidence interval [CI] 0.29-0.33; p < 0.05) as well as during the 12-month observation with an OR of 0.51 (95% CI 0.49-0.52; p < 0.05). CONCLUSIONS: Over the past 10 years, an important advance in the management of NSTEMI has taken place in Poland. Routine invasive strategy resulted in a significant decrease in mortality rates in all groups of NSTEMI patients. PMID- 30406937 TI - Randomized controlled clinical trials versus real-life atrial fibrillation patients treated with oral anticoagulants. Do we treat the same patients? AB - BACKGROUND: The aim of the study was to compare clinical characteristics of real life AF patients with populations included in randomized clinical trials (ROCKET AF and RE-LY). METHODS: The analysis included 3528 patients who are participants of the ongoing, multicentre, retrospective CRAFT study. The study is registered in ClinicalTrials.gov: NCT02987062. The study is based on a retrospective analysis of hospital records of AF patients treated with vitamin K antagonists (VKAs) (acenocoumarol, warfarin) and non-vitamin K oral anticoagulants (NOACs) (dabigatran, rivaroxaban). CHADS2 score was used for risk of stroke stratification. RESULTS: VKA was prescribed in 1973 (56.0%), while NOAC in 1549 (44.0%), including dabigatran - 504 (14.3%) and rivaroxaban - 1051 (29.8%), of the 3528 patients. VKA patients in the CRAFT study were at significantly lower risk of stroke (CHADS2 1.9 +/- 1.3), compared with the VKA population from the RE LY (2.1 +/- 1.1) and the ROCKET-AF (3.5 +/- 1.0). Patients in the CRAFT study treated with NOAC (CHADS2 for patients on dabigatran 150 mg - 1.3 +/- 1.2 and on rivaroxaban - 2.2 +/- 1.4) had lower risk than pts from the RE-LY (2.2 +/- 1.2) and the ROCKET AF (3.5 +/- 0.9). CONCLUSIONS: Real-world patients had a lower risk of stroke than patients included in the RE-LY and ROCKET AF trials. PMID- 30406938 TI - Catheter ablation of atrial fibrillation: current status, techniques, outcomes and challenges. AB - Atrial fibrillation (AF) is the most common human arrhythmia. Interventional treatment with catheter ablation is meanwhile an established technique that is increasingly applied and has become one of the main treatment modalities in patients with AF. Ablation results in significant improvement of symptoms and quality of life. There is up to now no clear evidence of an impact of the procedure on hard clinical endpoints except in patients with heart failure who seem to benefit significantly from ablation. Cornerstone of the procedure is achievement of pulmonary vein isolation. Radiofrequency energy is the main applied energy source but cryoballoon ablation has emerged as a safe and effective alternative to RF ablation. Additional ablation strategies and novel technical features have been proposed but without unequivocal proof of clinical benefit. Most promising of these seems to be substrate mapping of the left atrium with substrate modification in areas with low voltage as an adjunct to pulmonary vein isolation. Complication rates remains considerable despite accumulated experience and can be partly reduced by application of preventive measures. PMID- 30406939 TI - Do we differ in indications and demographics in cardiac resynchronization recipients in Poland? Insights from the European CRT Survey II Registry. AB - BACKGROUND: Multiple randomized clinical trials have proved that cardiac resynchronization therapy (CRT) reduces morbidity and mortality in appropriately selected patients with congestive heart failure and is recommended for such patients as per the European Society of Cardiology (ESC) guidelines. AIMS: In this paper we compare indications and demographics in cardiac resynchronization recipients in Poland and other European countries. METHODS: In 2015 and 2016, physicians from 42 European countries participated in the second edition of the European Cardiac Resynchronization Therapy Survey. For 14 months, 288 implant centres gathered data on 11088 patients regarding demography, indications, implanting methods, and guidance compatibility from patients receiving CRT. RESULTS: The survey indicated a vast group of patients as having qualified for CRT implantation (some of them with relatively weak guidance recommendations) and showed essential variety in clinical practice when national data was benchmarked. CONCLUSIONS: As far as demographic data from the survey is concerned, it can be generally assumed that patients receiving CRT were mainly men with depressed left ventricular ejection fraction (mostly less than 35%), with left bundle branch block (LBBB), and an intrinsic QRS duration of more than 150 ms. This was observed for both Poland and other European countries and fulfils the guidance criteria for CRT implantation. On the other hand, some devices were implanted in patients beyond the guideline recommendations. For these procedures, the decision regarding CRT implantation relies mainly on the physicians' experience. PMID- 30406940 TI - Inflammatory markers and left ventricular diastolic dysfunction in a family-based population study. AB - BACKGROUND: Heart failure affects patients with normal left ventricular systolic function (heart failure with preserved ejection fraction, HFPEF) and those with reduced ejection fraction (HFREF). The treatment of HFPEF remains an unresolved issue. AIM: The purpose of this study was to determinate the relationship between inflammatory markers and left ventricular diastolic dysfunction (LVDD) in a family-based population study. METHODS: In 303 participants from the general population (55% women, median age 49 years and 45% men, median age 40 years) we assessed echocardiography examination and measured inflammatory markers in serum: C-reactive protein (CRP), myeloperoxidase (MPO) and interleukin 6 (IL-6). RESULTS: The correlation of IL-6 concentration was observed for peak of the transmitral late diastolic velocity (A) and S/D ratio (p<0.01). Moreover significant correlation between IL-6 was shown to have an effect on E/A ratio and early diastolic peak velocities of the mitral annulus displacement (E'). The association of IL-6 concentration was noted with the peak of transmitral early diastolic velocities (E) and the the E/E' ratio (p<0.05) in men. In addition, the CRP concentration was shown to have an effect on E/A ratio in women (p<0.05). Moreover significant correlation between the CRP concentration and S/D ratio was observed in both women (p<0.01) and men (p<0.05). No significant correlation was observed between the level of MPO and LVDD parameters. Additionally only one predictive model for E' was depended on IL-6, age and heart rate in the men was found (p<0.001, R2=0.611). CONCLUSIONS: The above results suggest that inflammation may lead to the onset of LVDD probably via vascular endothelial dysfunction. PMID- 30406941 TI - Depressive symptoms and cardiovascular diseases in Polish adult population. Results of NATPOL2011 study. AB - BACKGROUND: Poland is a country of high cardiovascular risk. Because the depression was found to be a predictor of coronary artery disease and the prevalence of depressive symptoms raised worldwide, so the monitoring of depressive symptoms in a population is desirable. AIM: to evaluate the prevalence of depressive symptoms (DS) in relation to the socio-demographic status, and selected types of cardiovascular diseases in the adult Polish population. METHODS: A country representative random sample of 2413 subjects, aged 18-79, was examined in 2011. Rates of self-reported cardiovascular conditions including hypertension (HT), coronary artery disease (CAD), previous myocardial infarction (MI), heart failure (HF), atrial fibrillation (AF) and stroke (ST) were assessed by a questionnaire and the prevalence of DS by a Beck depression inventory (BDI), separately in men and women. DS were defined as BDI score >= 10pts. RESULTS: DS were found in 23.4% of men and 33.4% of women (p < 0.0001). The prevalence of DS increased with age, from 16.5% in the youngest group of men to 48.3% in the oldest group of women. We found that DS were significantly more prevalent in subjects suffering from HT, CAD, ST, AF and diabetes, and also after MI in women. The rates of DS in women with a history of MI or stroke were extremely high (76.3% and 83.3% respectively). Only age and primary education level were associated with DS, as was a history of stroke in women. DS were more often found in older and in primary educated persons. CONCLUSIONS: Depressive symptoms were more prevalent in women compared to men, and were significantly and independently associated with age and primary education level in both genders, and a history of stroke in women. PMID- 30406942 TI - Updated 2018 NICE guidance on venous thromboembolism - does evidence from root cause analysis of hospital-associated thrombosis support the additional investment required? PMID- 30406943 TI - Essential characteristics of pharmacogenomics study publications. AB - Pharmacogenomics (PGx) can be seen as a model for biomedical studies: it includes all disease areas of interest, spans in vitro studies to clinical trials, while focusing on the relationships between genes and drugs and the resulting phenotypes. This review will examine different characteristics of PGx study publications and provide examples of excellence in framing PGx questions and reporting their resulting data in a way that maximizes the knowledge that can be built upon them. This article is protected by copyright. All rights reserved. PMID- 30406944 TI - A phase II trial of eltrombopag for patients with chronic lymphocytic leukaemia (CLL) and thrombocytopenia. PMID- 30406945 TI - Cumulative anthracycline exposure and risk of cardiotoxicity; a Danish nationwide cohort study of 2440 lymphoma patients treated with or without anthracyclines. AB - Cardiotoxicity is a known risk of anthracycline treatment. However, the relative contribution of anthracyclines to the development of congestive heart failure (CHF), when included in a poly-chemotherapy regimen, is unclear. We examined cardiotoxicity in adult patients with diffuse large B-cell lymphoma and follicular lymphoma undergoing first-line immunochemotherapy from 2000-2012. In total, 2440 patients without previous heart disease were identified from the Danish Lymphoma Registry, of which 1994 (81.7%) were treated with anthracycline containing chemotherapy [R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) or R-CHOEP (R-CHOP + etoposide)] and 446 (18.3%) were treated without anthracyclines (reference group). Compared to the reference group, the adjusted hazard ratio of CHF after 3-5 cycles of R-CHOP/CHOEP was 5.0 [95% confidence interval (CI) 1.4; 18.5], 6 cycles 6.8 (95% CI 2.0; 23.3) and >6 cycles 13.4 (95% CI 4.0; 45.0). The cumulative 5-year risk of CHF with all-cause mortality as competing risk was 4.6% after 3-5 cycles of R-CHOP/CHOEP, 4.5% after 6 and 7.9% after more than 6 cycles. Cumulative 5-year risk for patients treated without anthracyclines was 0.8%. Using anthracyclines in first-line lymphoma treatment increases risk of CHF in patients without previous history of heart disease. In particular, treatment with >6 cycles of R-CHOP/CHOEP is associated with a significant increase in CHF rate. PMID- 30406947 TI - Eosinophilic polymorphic and pruritic eruption associated with radiotherapy: case report and overview of disease characteristics. PMID- 30406946 TI - Complex and monosomal karyotype are distinct cytogenetic entities with an adverse prognostic impact in paediatric acute myeloid leukaemia. A NOPHO-DBH-AML study. AB - Data on occurrence, genetic characteristics and prognostic impact of complex and monosomal karyotype (CK/MK) in children with acute myeloid leukaemia (AML) are scarce. We studied CK and MK in a large unselected cohort of childhood AML patients diagnosed and treated according to Nordic Society for Paediatric Haematology and Oncology (NOPHO)-AML protocols 1993-2015. In total, 800 patients with de novo AML were included. CK was found in 122 (15%) and MK in 41 (5%) patients. CK and MK patients were young (median age 2.1 and 3.3 years, respectively) and frequently had FAB M7 morphology (24% and 22%, respectively). Refractory disease was more common in MK patients (15% vs. 4%) and stem cell transplantation in first complete remission was more frequent (32% vs. 19%) compared with non-CK/non-MK patients. CK showed no association with refractory disease but was an independent predictor of an inferior event-free survival (EFS; hazard ratio [HR] 1.43, P = 0.03) and overall survival (OS; HR 1.48, P = 0.01). MK was associated with a poor EFS (HR 1.57, P = 0.03) but did not show an inferior OS compared to non-MK patients (HR 1.14, P = 0.62). In a large paediatric cohort, we characterized AML with non-recurrent abnormal karyotype and unravelled the adverse impact of CK and MK on prognosis. PMID- 30406949 TI - Guided root canal preparation using cone beam computed tomography and optical surface scans - an observational study of pulp space obliteration and drill path depth in 50 patients. AB - AIM: To report the precision of guided access cavity preparations in relation to demographical and dental variables in 50 patients. METHODOLOGY: This observational study was carried out during the period 2014-2017. The patients were consecutive referrals to a private endodontic practice. The inclusion criteria were as follows: (i) pulp space obliteration associated with signs of apical periodontitis (PAI score >3 or sensitive to percussion, (ii) teeth with pulp space obliteration in need of a post, where the referring dentist had attempted or failed to negotiate the obliterated root canal (and it was not possible to negotiate using the operating microscope within a reasonable time frame) and (iii) a surgical intervention was not justified. A published methodology for guided endodontics was used. Measures on demographical and previous dental history were analysed and related to drill path precision, being evaluated on radiographs as optimal (centre of the root canal) or acceptable (peripheral/tangential). The chi-square test was used for analyses of correlation between predictor variables and binary logistic regression analysis using backward elimination with degree of obliteration, guided access cavity preparation depth and precision as dependent variables. Significance level was 0.05. RESULTS: Thirty-one female (median age 65 year) and 19 males (median age 69 year) were enrolled. Overall, 88% (n = 44) of the teeth had pulp space obliteration associated with signs of apical periodontitis, whereas the remaining teeth were in need of a post. The pulp space obliterations were longer in maxillary compared with mandibular teeth (P = 0.024). The performance of the drill path in mandibular teeth versus maxillary teeth resulted in a significantly greater number of optimal precision scores (P = 0.033), and when a previous attempt at access and canal negotiation had occurred versus no attempt (P = 0.009). Even in cases with the worst outcome, the technique was still successful clinically. CONCLUSIONS: The clinical implementation of guided root canal treatment in fifty serial cases of single-rooted teeth with pulp space obliteration was associated with a precision that in all cases led to the location and negotiation of the root canal and completion of the treatment. PMID- 30406948 TI - Treatment policy estimands for recurrent event data using data collected after cessation of randomised treatment. AB - In the past, many clinical trials have withdrawn subjects from the study when they prematurely stopped their randomised treatment and have therefore only collected 'on-treatment' data. Thus, analyses addressing a treatment policy estimand have been restricted to imputing missing data under assumptions drawn from these data only. Many confirmatory trials are now continuing to collect data from subjects in a study even after they have prematurely discontinued study treatment as this event is irrelevant for the purposes of a treatment policy estimand. However, despite efforts to keep subjects in a trial, some will still choose to withdraw. Recent publications for sensitivity analyses of recurrent event data have focused on the reference-based imputation methods commonly applied to continuous outcomes, where imputation for the missing data for one treatment arm is based on the observed outcomes in another arm. However, the existence of data from subjects who have prematurely discontinued treatment but remained in the study has now raised the opportunity to use this 'off-treatment' data to impute the missing data for subjects who withdraw, potentially allowing more plausible assumptions for the missing post-study-withdrawal data than reference-based approaches. In this paper, we introduce a new imputation method for recurrent event data in which the missing post-study-withdrawal event rate for a particular subject is assumed to reflect that observed from subjects during the off-treatment period. The method is illustrated in a trial in chronic obstructive pulmonary disease (COPD) where the primary endpoint was the rate of exacerbations, analysed using a negative binomial model. PMID- 30406950 TI - Pulmonary arterial hypertension: In Asia, as elsewhere, still a lethal disease despite modern treatment. PMID- 30406951 TI - Ether-soluble Cu53 Nanoclusters as an Effective Precursor of High-quality CuI Films for Optoelectronic Applications. AB - An effective strategy is developed to synthesize high-nuclearity Cu clusters, [Cu53(RCOO)10(C=CtBu)20Cl2H18]+ (Cu53), which is the largest Cu(I)/Cu(0) cluster reported to date. Cu powder and Ph2SiH2 are employed as the reducing agents in the synthesis. As revealed by single-crystal diffraction, Cu53 is arranged as a four-concentric-shell Cu3@Cu10Cl2@Cu20@Cu20 structure, possessing an atomic arrangement of concentric M12 icosahedral and M20 dodecahedral shells which popularly occurs in Au/Ag nanoclusters. Surprisingly, Cu53 can be dissolved in diethyl ether and spin coated to form uniform nanoclusters film on organo-lead halide perovskite. The cluster film can subsequently be converted into high quality CuI film via in-situ iodination at room temperature. The as-fabricated CuI film proves to be an excellent hole-transport layer for fabricating highly stable CuI-based perovskite solar cells (PSCs) with 14.3% of efficiency. PMID- 30406953 TI - Waldenstrom macroglobulinaemia terminating in acute lymphoblastic leukaemia after treatment with fludarabine. PMID- 30406952 TI - A novel complete blood count-based score to screen for myelodysplastic syndrome in cytopenic patients. AB - The diagnosis of myelodysplastic syndromes (MDS) is often challenging, time- and resource-consuming. A thorough analysis of complete blood count (CBC) parameters could, however, help to screen for MDS among other causes of cytopenia. To test this hypothesis, 109 newly-diagnosed MDS patients and 399 cytopenic patients older than 50 years with confirmed absence of MDS were enrolled in a prospective study. Multiparametric analysis highlighted three CBC parameters that were significantly different between the two cohorts: mean corpuscular volume, absolute neutrophil count and median neutrophil complexity and width of dispersion of the events measured (Ne-WX), which were used to define an MDS-CBC score. This score enables the prediction of MDS with 86% sensitivity and 88% specificity. The MDS-CBC score excluded MDS in 89% of cytopenic controls. Moreover, high score values at MDS diagnosis significantly correlated with decreased event-free (P = 0.02) and overall survival (P = 0.01). The power of this score was confirmed in an independent validation cohort (MDS n = 34, cytopenic controls n = 28). The MDS-CBC score is an easy and fast tool to exclude or suspect MDS in unselected patients with cytopenia of unknown reasons at the time of analysis, by prompting blood smear examination. It may thus improve allocation of further MDS-specific work-up in patients with cytopenia at the time of CBC assessment. PMID- 30406954 TI - Non-invasive ventilation or high-flow oxygen therapy: When to choose one over the other? AB - It has been found that high-flow oxygen therapy (HFOT) can reduce mortality of patients admitted to intensive care unit (ICU) for de novo acute respiratory failure (ARF) as compared to non-invasive ventilation (NIV). HFOT might therefore be considered as a first-line strategy of oxygenation in these patients. The beneficial effects of HFOT may be explained by its good tolerance and by physiological characteristics including delivery of high FiO2 , positive end expiratory pressure (PEEP) effect and continuous dead space washout contributing to decreased work of breathing. In contrast, NIV should be used cautiously in patients with de novo ARF due to high tidal volumes promoted by pressure support and that may potentially worsen pre-existing lung injury. Although recent studies have reported no benefit and even deleterious effects of NIV in immunocompromised patients with ARF, the experts have recommended its use as a first-line strategy. In patients with acute-on-chronic respiratory failure and respiratory acidosis, it has been clearly shown that NIV is the best strategy of oxygenation. However, HFOT seems able to reverse respiratory acidosis and further studies are needed to evaluate whether HFOT could represent an alternative to standard oxygen. Although NIV is recommended to treat ARF in post-operative patients or to prevent post extubation respiratory failure in ICU, recent large-scale randomized studies suggest that HFOT could be equivalent to NIV. While recent recommendations have been established from studies comparing NIV with standard oxygen, new studies are needed to compare NIV versus HFOT in order to better define the appropriate indications for both treatments. PMID- 30406955 TI - Impacts on in-event, ambulance and emergency department services from patients presenting from a mass gathering event: A retrospective analysis. AB - OBJECTIVE: The aim of this study was to describe the in-event, ambulance and ED impacts of patient presentations from an Australian mass gathering event (MGE) including patient demographics, provision of care, length of stay and discharge disposition. METHODS: This research was set at one MGE in Australia. The MGE had one first aid post and one in-event health team staffed by doctors, nurses and paramedics. A retrospective analysis of patient care records from providers of in event, ambulance and ED services was undertaken. Data analysis included descriptive and inferential statistics. RESULTS: Of the 20 000 MGE participants, 197 (0.99% [95% CI 0.86-1.13], 9.85/1000) presented for in-event first aid care, with 24/197 (12.2% [95% CI 8.33-17.49], 1.2/1000) referred to in-event health professionals. Fifteen of the referred patients (62.5% [95% CI 42.71-78.84]) returned to the MGE following administration of intravenous fluids (n = 13) and/or anti-emetics (n = 11). Seven (29.2% [95% CI 14.92-49.17], 0.35/1000) were referred to ambulance paramedic care, requiring endotracheal intubation (n = 1) and airway adjuncts (n = 3) prior to transportation to ED; these patients had an ED median length of stay of 7 h (5.5-12.5) receiving imaging and ventilator support. Five were discharged from ED, one required an operation and another required intensive care unit admission. CONCLUSIONS: There was an impact on in event, ambulance and ED services from this MGE but the in-event model of care may have limited ambulance usage and ED visits. The ED length of stay was greater than the national median, perhaps reflecting the appropriateness of transport and nature of care requirements while in the ED. PMID- 30406956 TI - Advances in Chimeric Antigen Receptor (CAR)-T Cell Therapies for Solid Tumors. AB - In 2017, the United States Food and Drug Administration (FDA) approved the first two novel cellular immunotherapies using synthetic, engineered receptors known as chimeric antigen receptors (CAR), tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta), expressed by patient-derived T cells for the treatment of hematological malignancies expressing the B-cell surface antigen CD19 in both pediatric and adult patients. This approval marked a major milestone in the use of antigen-directed 'living drugs' for the treatment of relapsed or refractory blood cancers, and with these two approvals, there is increased impetus to expand not only the target antigens but also the tumor types that can be targeted. This state-of-the-art review will focus on the challenges, advances, and novel approaches being utilized to implement CAR-T cell immunotherapy for the treatment of solid tumors. This article is protected by copyright. All rights reserved. PMID- 30406957 TI - Non-invasive transcutaneous auricular vagus nerve stimulation prevents postoperative ileus and endotoxemia in mice. AB - BACKGROUND: The cholinergic anti-inflammatory pathway comprises the perception of peripheral inflammation by afferent sensory neurons and reflex activation of efferent vagus nerve activity to regulate inflammation. Activation of this pathway was shown to reduce the inflammatory response and improve outcome of postoperative ileus (POI) and sepsis in rodents. Herein, we tested if a non invasive auricular electrical transcutaneous vagus nerve stimulation (tVNS) affects inflammation in models of POI or endotoxemia. METHODS: Mice underwent tVNS or sham stimulation before and after induction of either POI by intestinal manipulation (IM) or endotoxemia by lipopolysaccharide administration. Some animals underwent a preoperative right cervical vagotomy. Neuronal activation of the solitary tract nucleus (NTS) and the dorsal motor nucleus of the vagus nerve (DMV) were analyzed by immunohistological detection of c-fos+ cells. Gene and protein expression of IL-6, MCP-1, IL-1beta as well as leukocyte infiltration and gastrointestinal transit were analyzed at different time points after IM. IL-6, TNFalpha, and IL-1beta serum levels were analyzed 3 hours after lipopolysaccharide administration. RESULTS: tVNS activated the NTS and DMV and reduced intestinal cytokine expression, reduced leukocyte recruitment to the manipulated intestine segment, and improved gastrointestinal transit after IM. Endotoxemia-induced IL-6 and TNF-alpha release was also reduced by tVNS. The protective effects of tVNS on POI and endotoxemia were abrogated by vagotomy. CONCLUSION: tVNS prevents intestinal and systemic inflammation. Activation of the DMV indicates an afferent to efferent central circuitry of the tVNS stimulation and the beneficial effects of tVNS depend on an intact vagus nerve. tVNS may become a non-invasive approach for treatment of POI. PMID- 30406958 TI - CRISPR/Cas9 mutagenesis in Volvox carteri. AB - Volvox carteri and other volvocine green algae comprise an excellent model for investigating developmental complexity and its origins. Here we describe a method for targeted mutagenesis in V. carteri using CRISPR/Cas9 components expressed from transgenes. We used V. carteri nitrate reductase gene (nitA) regulatory sequences to conditionally express Streptococcus pyogenes Cas9, and V. carteri U6 RNA gene regulatory sequences to constitutively express single-guide RNA (sgRNA) transcripts. V. carteri was bombarded with both the Cas9 vector and with one of several sgRNA vectors programmed to target different test genes (glsA, regA, and invA), and transformants were selected for expression of a hygromycin-resistance marker present on the sgRNA vector. Hygromycin-resistant transformants grown with nitrate as sole nitrogen source (inducing for nitA) were tested for Cas9 and sgRNA expression, and for ability to generate progeny with expected mutant phenotypes. Some transformants of a Somatic Regenerator (Reg) mutant strain receiving sgRNA plasmid with glsA protospacer sequence yielded progeny (at a rate of ~.01%) with a Gonidialess (Gls) phenotype similar to that observed for previously described glsA mutants, and sequencing of the glsA gene in independent mutants revealed short deletions within the targeted region of glsA, indicative of Cas9-directed non-homologous end joining. Similarly, bombardment of a morphologically wild type strain with the Cas9 plasmid and sgRNA plasmids targeting regA or invA yielded regA and invA mutant transformants/progeny, respectively (at rates of 0.1%-100%). The capacity to make precisely directed frameshift mutations should greatly accelerate the molecular genetic analysis of development in V. carteri, and of developmental novelty in the volvocine algae. This article is protected by copyright. All rights reserved. PMID- 30406959 TI - Transarterial radioembolization with yttrium-90 of unresectable primary hepatic malignancy in children. AB - BACKGROUND: Primary malignant liver tumors are rare, accounting for 1% to 2% of all childhood cancers. When chemotherapy fails, transarterial radioembolization with yttrium-90 (TARE-Y90) may offer an alternative therapy as a bridge to surgical resection or liver transplant or for palliation. METHODS: We conducted a retrospective review of 10 pediatric patients with histologically confirmed primary liver malignancy who received treatment with TARE-Y90. RESULTS: The median age at treatment was 5.5 years (range, 2-18 years). Median patient survival from initial diagnosis was 12.5 months (range, 10-28 months), and median patient survival after TARE-Y90 was 4 months (range, 2-20 months). Retreatment was well tolerated in three of 10 patients, with these patients demonstrating the longest survival times (range, 17-20 months). One patient was transplanted 6 weeks after TARE-Y90. By RECIST 1.1 criteria of all target lesions, eight of nine patients had stable disease, and one of nine had progressive disease. By mRECIST criteria (requiring postcontrast arterial phase imaging), two of seven patients had a partial response, four of seven had stable disease, and one of seven had progressive disease. CONCLUSION: TARE-Y90 of unresectable primary liver malignancy is both technically feasible and demonstrates an anticancer effect, and retreatment is well tolerated. TARE-Y90 could be considered as adjunctive therapy in pediatric patients with unresectable hepatic malignancies and could be used as a bridge to surgical resection or liver transplant. More research is required to determine the efficacy of this treatment in children and to define the clinical scenarios where benefit is likely to be optimized. PMID- 30406960 TI - Personalized Hydrogels for Engineering Diverse Fully Autologous Tissue Implants. AB - Despite incremental improvements in the field of tissue engineering, no technology is currently available for producing completely autologous implants where both the cells and the scaffolding material are generated from the patient, and thus do not provoke an immune response that may lead to implant rejection. Here, a new approach is introduced to efficiently engineer any tissue type, which its differentiation cues are known, from one small tissue biopsy. Pieces of omental tissues are extracted from patients and, while the cells are reprogrammed to become induced pluripotent stem cells, the extracellular matrix is processed into an immunologically matching, thermoresponsive hydrogel. Efficient cell differentiation within a large 3D hydrogel is reported, and, as a proof of concept, the generation of functional cardiac, cortical, spinal cord, and adipogenic tissue implants is demonstrated. This versatile bioengineering approach may assist to regenerate any tissue and organ with a minimal risk for immune rejection. PMID- 30406961 TI - Psychiatric disorders, substance use, and executive functioning in older probationers. AB - Background: Although the number of older people serving community sentences (probation) after conviction for a criminal offence in England and Wales has increased rapidly since about 2006, this population has received little research attention. Aim: To examine the mental health, substance use, and executive functioning of older probationers. Methods: Thirty-two male probationers aged 50 years and older were recruited from probation services in the Thames Valley, England, and administered validated semistructured interviews for psychiatric disorders, symptom checklists for depression and substance use, cognitive impairment screens, and neuropsychological tests of executive functioning (examining verbal fluency and response inhibition). Results: We found that older probationers presented with a high prevalence of mental health difficulties (overall caseness n = 22; 69%, 95% CI [53-85]) that exceed estimates in the older general population. Prevalences of depression (25%) or alcohol abuse or dependence (19%) were found to be high. In comparison with normative data, however, older probationers did not present with deficits in tested executive functioning. Conclusions and implications for practice: Mental health and substance use problems were more prominent than cognitive deficits in this sample of older probationers. Further work should include older community controls to inform service planning and to determine how these mental health factors interact with offending. PMID- 30406963 TI - Four weeks of exercise early in life reprograms adult skeletal muscle insulin resistance caused by paternal high fat diet. AB - KEY POINTS: Paternal high fat diet/obesity before mating can negatively influence the metabolism of offspring. Exercise only early in life has a remarkable effect to reprogram adult rat offspring exposed to detrimental insults before conception. Exercise only early in life normalized adult whole body and muscle insulin resistance due to having a high fat fed/obese father. Unlike the effects on the muscle, early exercise did not normalise the reduced adult pancreatic beta cell mass due to having a high fat fed/obese father. Early life exercise training may be able to reprogram the individual whose father was obese, inducing long lasting beneficial effects on health. ABSTRACT: Paternal high fat diet (HFD) impairs female rat offspring glucose tolerance, pancreatic morphology and insulin secretion. We examined whether only 4 weeks of exercise early in life could reprogram these negative effects. Male Sprague-Dawley rats consumed a HFD for 10 weeks before mating with chow-fed dams. Female offspring remained sedentary or performed moderate intensity treadmill exercise (5 days/week, 60 min/day, 20 m/min) from 5 to 9 weeks of age. Paternal HFD impaired (P<0.05) adult offspring whole body insulin sensitivity (intraperitoneal insulin sensitivity test) and skeletal muscle ex vivo insulin sensitivity and TBC1D4 phosphorylation. It also lowered beta-cell mass and reduced in vivo insulin secretion in response to an intraperitoneal glucose tolerance test. Early life exercise in offspring reprogrammed the negative effects of paternal HFD on whole body insulin sensitivity, skeletal muscle ex vivo insulin-stimulated glucose uptake and TBC1D4 phosphorylation and increased GLUT4 protein. However, early exercise did not normalise the reduced pancreatic beta-cell mass or insulin secretion. In conclusion, only 4 weeks of exercise early in life in female rat offspring reprograms reductions in insulin sensitivity in adulthood caused by a paternal high fat diet without affecting pancreatic beta-cell mass or insulin secretion. This article is protected by copyright. All rights reserved. PMID- 30406964 TI - Stressful life events and psychiatric comorbidity in acne-a case control study. AB - INTRODUCTION: Possibility of a causal influence of emotional stress, on the course of various skin diseases, has been postulated. However, it is still inconclusive about the role of stressful life events in acne. In this background, the present study was carried out to know its role in acne. METHODS: Consecutive one hundred patients who were diagnosed with acne vulgaris in the age group of 12 to 45 years were included. Age and sex matched controls were taken. A semistructured proforma was used to collect sociodemographic details. Stressful life events were assessed using presumptive stressful life event scale. Anxiety was evaluated using Hamilton Anxiety Rating scale and Depression by Hamilton Depression Rating Scale. RESULTS: There was no difference in total stressful life events in past one year between patients and controls. The undesirable life event was present in 65 patients and 50 controls, this difference was statistically significant. Getting married or appearing for exams were the most common stressful life event in patients. Forty patients had comorbid psychiatric illness whereas in controls comorbidity was in 24 and this difference was statistically significant. DISCUSSION: The undesirable stressful life events and psychiatric comorbidity were more in acne patients than in controls. PMID- 30406962 TI - Compositional response of Amazon forests to climate change. AB - Most of the planet's diversity is concentrated in the tropics, which includes many regions undergoing rapid climate change. Yet, while climate-induced biodiversity changes are widely documented elsewhere, few studies have addressed this issue for lowland tropical ecosystems. Here we investigate whether the floristic and functional composition of intact lowland Amazonian forests have been changing by evaluating records from 106 long-term inventory plots spanning 30 years. We analyse three traits that have been hypothesized to respond to different environmental drivers (increase in moisture stress and atmospheric CO2 concentrations): maximum tree size, biogeographic water-deficit affiliation and wood density. Tree communities have become increasingly dominated by large statured taxa, but to date there has been no detectable change in mean wood density or water deficit affiliation at the community level, despite most forest plots having experienced an intensification of the dry season. However, among newly recruited trees, dry-affiliated genera have become more abundant, while the mortality of wet-affiliated genera has increased in those plots where the dry season has intensified most. Thus, a slow shift to a more dry-affiliated Amazonia is underway, with changes in compositional dynamics (recruits and mortality) consistent with climate-change drivers, but yet to significantly impact whole community composition. The Amazon observational record suggests that the increase in atmospheric CO2 is driving a shift within tree communities to large-statured species and that climate changes to date will impact forest composition, but long generation times of tropical trees mean that biodiversity change is lagging behind climate change. PMID- 30406966 TI - Handouts 2.0: enhanced capabilities and continued relevance. PMID- 30406965 TI - Maturation of pre-40S particles in yeast and humans. AB - The synthesis of ribosomal subunits in eukaryotes requires the interplay of numerous maturation and assembly factors (AFs) that intervene in the insertion of ribosomal proteins within pre-ribosomal particles, the ribosomal subunit precursors, as well as in pre-ribosomal RNA (rRNA) processing and folding. Here, we review the intricate nuclear and cytoplasmic maturation steps of pre-40S particles, the precursors to the small ribosomal subunits, in both yeast and human cells, with particular emphasis on the timing and mechanisms of AF association with and dissociation from pre-40S particles and the roles of these AFs in the maturation process. We highlight the particularly complex pre-rRNA processing pathway in human cells, compared to yeast, to generate the mature 18S rRNA. We discuss the information gained from the recently published cryo-electron microscopy atomic models of yeast and human pre-40S particles, as well as the checkpoint/quality control systems that seem to operate to probe functional sites within yeast cytoplasmic pre-40S particles. This article is categorized under: RNA Processing > rRNA Processing Translation > Ribosome Biogenesis. PMID- 30406968 TI - The role of ultrasound teaching in the undergraduate medical curriculum. PMID- 30406967 TI - Low additive effect of hydroxychloroquine on Japanese patients with systemic lupus erythematosus taking calcineurin inhibitor. AB - AIM: To assess for any additive value of hydroxychloroquine (HCQ) in Japanese patients with systemic lupus erythematosus (SLE) depending on calcineurin inhibitors (CNIs). METHODS: We retrospectively evaluated patients with SLE who visited our hospital from 2015 to 2016 and were taking prednisolone (PSL) at <20 mg/d and one immunosuppressant (IS). Patients were divided into two groups depending on HCQ use and the groups were compared for changes in SLE Disease Activity Index (SLEDAI), prednisolone (PSL) dose, and cumulative flare rate between patients who were treated and not treated with CNI. RESULTS: Among the 103 patients evaluated, 19 (18.4%) were treated with HCQ. On analysis of all patients, SLEDAI, PSL doses, and cumulative flare rate were significantly reduced in patients who received HCQ compared to those who did not (P = 0.04, P = 0.01, and P = 0.03, respectively). Regarding IS use, we found less additive therapeutic effect in CNI users than in users of other ISs in terms of reduction in SLEDAI and PSL dose (P = 0.05 and P < 0.01, respectively). CONCLUSIONS: The addition of HCQ reduced disease activity, PSL dose, and flares in Japanese SLE patients but conferred less additive clinical efficacy when added to CNIs. PMID- 30406969 TI - Local regression and control of T1-2 nasopharyngeal carcinoma treated with intensity-modulated radiotherapy. AB - OBJECTIVE: To observe the local regression and control in T1-2 nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiotherapy (IMRT) and to analyze the related influencing factors. METHODS: Between January 2006 and June 2014, 247 consecutive T1-2 NPC patients treated with IMRT were retrospectively analyzed, with 126 (51.0%) N0-1 disease and 121 (49.0%) N2-3 disease. Among them, 72.9% received platinum-based chemotherapy. The prescribed dose to gross tumor volume was 66 Gy/30 fractions. RESULTS: By the end of IMRT, the chemoradiotherapy (CRT) group had higher local complete response (CR) rate compared with IMRT alone group (92.2% vs 74.6%, P < 0.001), but no significant difference was discovered in 5-year local control (LC) rate (95.1% vs 94.9%, P = 0.968). Of the rest 31 patients with residual nasopharyngeal lesions after IMRT, those received boost irradiation (67.7%) also showed no improvement in 5-year LC rate compared with the observational group (95.0% vs 100.0%, P = 0.307). With a median follow-up of 63 months, the estimated 5-year LC rate for the whole group was 95.1% (T1 vs T2: 95.9% vs 94.7%, P = 0.186). Prognostic factors for LC were found neither in univariate nor in multivariate analysis. Advanced N stage was found to be the only adverse prognostic factor for all the other survivals. CONCLUSIONS: Excellent LC could be achieved in T1-2 NPC treated with IMRT. The addition of chemotherapy may offer short-term response benefit, but no significant LC benefit, so did boost irradiation. Attention should be attached to advanced N stage, the exploration of the recurrence-related factors, and the necessities of the additional treatment. PMID- 30406970 TI - Combination therapy with F5/35 fiber chimeric conditionally replicative adenoviruses expressing IL-24 enhances the antitumor effect of temozolomide against melanoma. AB - BACKGROUND: Temozolomide (TMZ) is widely used to treat melanoma; however, response rates to TMZ are low because of rapid and frequent resistance. Conditionally, replicative adenoviruses (CRAds) are an effective and promising approach. The receptor for adenovirus is coxsackie-adenovirus receptor (CAR), which is poorly expressed in most cells. However, CD46, which is the receptor of species B adenoviruses (Ads), is highly expressed in many cells. METHODS: We constructed CRAd F5/35-ZD55-IL-24, which uses the viral receptors CAR and CD46 for entry into cells. We investigated the antitumor effect of F5/35-ZD55-IL-24 in combination with TMZ to treat melanoma in vitro and in vivo. RESULTS: The ?results indicated that F5/35-ZD55-IL-24 in combination with TMZ produced additive or synergistic antitumor and pro-apoptotic effects in melanoma cells. The combination of F5/35-ZD55-IL-24 and TMZ significantly inhibited the growth of melanoma in vivo. In addition, the antitumor effect of F5/35-ZD55-IL-24 was superior to that of ZD55-IL-24 and ZD55-IL-24 combined with TMZ. CONCLUSIONS: The use of F5/35-ZD55-IL-24 in conjunction with TMZ is a promising approach for anti melanoma therapy. Our results indicated that F5/35-ZD55-IL-24 in combination with TMZ produced additive or synergistic antitumor effect and pro-apoptotic effect in melanoma cells highly expressed CD46. The combination of F5/35-ZD55-IL-24 and TMZ significantly inhibited the growth of melanoma in vivo. We also found the antitumor effect of F5/35-ZD55-IL-24 was superior to ZD55-IL-24, the combination of F5/35-ZD55-IL-24 and TMZ had a more significant antitumor effect than ZD55-IL 24 combining with TMZ. PMID- 30406971 TI - Management of Dumbbell and Paraspinal Tumors of the Thoracic Spine Using a Single stage Posterolateral Approach: Case Series. AB - This study investigated the surgical results of a single-stage posterolateral approach with arc incision, unilateral laminectomy, and costotransversectomy for the management of dumbbell tumors and paraspinal tumors of the thoracic spine. From January 2010 to March 2017, 14 patients with dumbbell tumors or paraspinal tumors of the thoracic spine who underwent resection with single-stage posterolateral approach were followed up and analyzed retrospectively. The operations were performed using a single-stage posterolateral approach with arc incision, unilateral laminectomy, and costotransversectomy without any instrumentation. We reviewed the scores of clinical symptoms and imaging results, including postoperative MRI and reconstructed 3D-CT images. Gross total removal was achieved in 13 patients, and subtotal removal was achieved in 1 case. Histopathology revealed schwannoma in 9 patients, angiolipoma in 1 patient, and paraganglioma and mixed hemangioma in 2 patients each. No significant operative or postoperative complications occurred in any patient. The 14 patients were followed up for 14-68 months (mean 39.4 months). At the final follow-up, no obvious spinal deformity or tumor recurrence was found in any patient except one with paraganglioma. Single-stage posterolateral approach is a good alternative surgical method for removing dumbbell tumors and paraspinal tumors of the thoracic spine without necessitating a subsequent anterior operation. PMID- 30406972 TI - Tranexamic Acid Plus Low-dose Epinephrine Reduces Blood Loss in Total Knee Arthroplasty: A Systematic Review and Meta-analysis. AB - The present study assessed the effectiveness of the combined administration of tranexamic acid (TXA) plus low-dose epinephrine in primary total knee arthroplasty (TKA). We searched the following Chinese electronic databases: China National Knowledge Infrastructure and WanFang Data. We also searched the following English electronic databases: PubMed, Embase, Web of Science, and Central Register of Controlled Trials. To search for additional eligible studies, we also used Google's search engine. All randomized controlled trials (RCT) comparing TXA plus low-dose epinephrine (Combined group) and TXA alone in TKA were systematically searched. The primary outcomes were total blood loss, hidden blood loss, the requirement for transfusion, maximum hemoglobin (Hb) drop, and deep venous thrombosis (DVT). Drainage volume, operation time, length of stay, hospital for special surgery (HSS) score, and range of motion (ROM) were considered as secondary outcomes. Subgroup analyses were performed to assess the benefits of using a tourniquet and the application routes of topical or intravenous TXA between the two groups. Statistical analysis was assessed using RevMan 5.3 software. Four independent RCT were included involving 426 patients, with 213 patients in the Combined group and 213 patients in the TXA alone group. In the Combined group there was significant reduction in total blood loss (MD, 204.70; 95% CI, -302.76 to -106.63; P < 0.0001), hidden blood loss (MD, 185.63; 95% CI, -227.56 to -143.71; P < 0.00001), drainage volume (MD, 93.49; 95% CI, 117.24 to -69.74; P < 0.00001), and maximum Hb drop (MD, 5.33, 95% CI, -6.75 to 3.91; P < 0.00001). No statistical differences were found postoperatively in terms of the requirement for transfusion (risk ratio, 0.52; 95% CI, 0.26-1.04; P = 0.06), operation time (MD, 0.85; 95% CI, -2.62 to 4.31; P = 0.63), length of stay (MD, -0.02; 95% CI, -0.52 to 0.47; P = 0.93), HSS score (MD, 0.78; 95% CI, 0.36 to 1.92; P = 0.18), and ROM (MD, 1.40; 95% CI, -1.01 to 3.81; P = 0.26), and not increasing the risk of DVT (risk ratio, 1.00; 95% CI, 0.33 to 3.02; P = 1.00) in the two groups. This meta-analysis demonstrated that the administration of tranexamic acid plus low-dose epinephrine is a safe and efficacious treatment to reduce total blood loss, hidden blood loss, drainage volume, and maximum Hb drop in primary TKA, without increasing the risk of DVT in primary THA. PMID- 30406973 TI - Characteristics of accidental injuries from power tools treated at two emergency departments in Queensland. AB - OBJECTIVE: Injuries are a major burden on the Australian healthcare system. Power tool usage is a common cause of accidental injury. A better understanding of the trends of power tool injuries will inform prevention strategies and potentially mitigate costs. METHODS: The ED databases from two level 1 hospitals were reviewed for presentations between 2005 and 2015 resulting from accidental injury with power tools. A subgroup of patients presenting to one hospital between 2016 and 2017 were interviewed about the activities and circumstances that led to their injuries, and followed up 3 months later to assess outcomes. RESULTS: A total of 4057 cases of accidental injury from power tool use were identified. Power saws and grinders contributed to 54% of injuries. Most injuries were located on an upper limb (48%) or the head and neck (30%). Over half (54%) of all head injuries were associated with metal and wood fragments to the eye from grinders, drills and saws. Hospital admission rates were highest for patients aged >60 years. Injuries to females were <5% of all presentations, but 40% of those caused by lawnmowers. Among the 200 patients interviewed, lapses in concentration during use, and modification and inappropriate use of a power tool were the main contributors to injury. Recovery periods >3 months were common. CONCLUSIONS: Accidental injuries from power tool use have a considerable impact on ED resources and can affect the long-term quality of life of those injured. Effective education about safe usage and protection may prevent many injuries. PMID- 30406974 TI - Mitochondrial and nuclear disease panel (Mito-aND-Panel): Combined sequencing of mitochondrial and nuclear DNA by a cost-effective and sensitive NGS-based method. AB - BACKGROUND: The diagnosis of mitochondrial disorders is challenging because of the clinical variability and genetic heterogeneity of these conditions. Next Generation Sequencing (NGS) technology offers a robust high-throughput platform for nuclear and mitochondrial DNA (mtDNA) analyses. METHOD: We developed a custom Agilent SureSelect Mitochondrial and Nuclear Disease Panel (Mito-aND-Panel) capture kit that allows parallel enrichment for subsequent NGS-based sequence analysis of nuclear mitochondrial disease-related genes and the complete mtDNA genome. Sequencing of enriched mtDNA simultaneously with nuclear genes was compared with the separated sequencing of the mitochondrial genome and whole exome sequencing (WES). RESULTS: The Mito-aND-Panel permits accurate detection of low-level mtDNA heteroplasmy due to a very high sequencing depth compared to standard diagnostic procedures using Sanger sequencing/SNaPshot and WES which is crucial to identify maternally inherited mitochondrial disorders. CONCLUSION: We established a NGS-based method with combined sequencing of the complete mtDNA and nuclear genes which enables a more sensitive heteroplasmy detection of mtDNA mutations compared to traditional methods. Because the method promotes the analysis of mtDNA variants in large cohorts, it is cost-effective and simple to setup, we anticipate this is a highly relevant method for sequence-based genetic diagnosis in clinical diagnostic applications. PMID- 30406975 TI - Is This Mine to Keep? Three-dimensional Printing Enables Active, Personalized Learning in Anatomy. AB - Understanding orbital anatomy is important for optometry students, but the learning resources available are often fragile, expensive, and accessible only during scheduled classes. Drawing on a constructivist, personalized approach to learning, this study investigated students' perceptions of an alternative learning resource: a three-dimensional (3D) printed model used in an active learning task. A human skull was three-dimensionally scanned and used to produce a 3D printed model for each student. Students actively participated in model creation by tracing suture lines and coloring individual orbital bones during a practical class, then keeping the model for future study. Students' perceptions of the 3D orbital model were examined through a questionnaire: the impact the model had on their learning; perceptions of the 3D orbit compared to traditional resources; and utility of having their own personalized model. The 3D orbit was well received by the student cohort. Participants (n = 69) preferred the 3D orbit as a resource for learning orbital bone anatomy compared to traditional learning resources, believing the model helped them to understand and visualize the spatial relationships of the bones, and that it increased their confidence to apply this knowledge. Overall, the participants liked that they co-created the model, could touch and feel it, and that they had access to it whenever they liked. Three-dimensional printing technology has the potential to enable the creation of effective learning resources that are robust, low-cost and readily accessible to students, and should be considered by anyone wishing to incorporate personalized resources to their multimodal teaching repertoire. PMID- 30406976 TI - Shade Stability of Polymer Infiltrated and Resin Nano Ceramic Crowns after Dynamic Chewing Simulation. AB - OBJECTIVE: Investigation of the shade stability of polymer-infiltrated and resin nano ceramic crowns before and after artificial aging. METHOD: 40 identical crowns of each of the materials VITA Enamic (VE) and Lava Ultimate (LU) were manufactured. Half of the crowns went through a dynamic chewing simulation (CS) with thermocycling. Material subgroups: 1. VE, 2. VE/CS, 3. LU, 4. LU/CS (each n=20). These were divided into 4 groups (n=5) and distributed in usual stain solutions. The shade of each crown was measured occlusally and vestibularly before and after insertion using a spectrophotometer (n=5). The data were analyzed using ANOVA and Tukey's test (p<=0.05). RESULTS: Sum scores (SSC) of the occlusal DeltaE values: LU/CS: 7.99, VE: 5.75 VE/CS: 5.44, LU: 5.17. The total sum of the SSC yielded, for the materials: SSCtotal(VE): 20.0 and SSCtotal(LU): 24.0. SIGNIFICANCE: Occlusally, there were significant shade differences for VE/CS (p=0.025) and LU/CS (p=0.014) between red wine and distilled water. LU/CS is significantly more clearly stained occlusally by coffee in comparison to the other three material subgroups (VE: p=0.007, LU: p=0.026, VE/CS: p=0.013). CONCLUSIONS: The shade stability of VITA Enamic crowns is superior to that of Lava Ultimate crowns. Only Lava Ultimate is affected by chewing simulation. PMID- 30406977 TI - Sunitinib Alone or after Nephrectomy in Renal Cancer. PMID- 30406978 TI - Sunitinib Alone or after Nephrectomy in Renal Cancer. PMID- 30406979 TI - A Phase 3 Trial of l-Glutamine in Sickle Cell Disease. PMID- 30406980 TI - A Phase 3 Trial of l-Glutamine in Sickle Cell Disease. PMID- 30406981 TI - Vitamin D Supplementation in Pregnancy and Lactation and Infant Growth. PMID- 30406982 TI - Long-Lasting and Easy-to-Use Rewritable Paper Fabricated by Printing Technology. AB - Nowadays, urged by the high demand to reduce paper consumption, rewritable paper receives more and more attention. However, it is a great challenge to conveniently fabricate the rewritable paper which has long legible time of information and is easy to use simultaneously. Here, we report a new type of long lasting rewritable paper based on color-memorizing thermochromic dye and photothermal-converting toner, which is fabricated by a two-step printing process. The rewritable paper demonstrates excellent rewriting performances (legible time > 6 months and reversibility > 100 times). The thermochromic effect is based on a temperature-driven phase change mechanism, accompanied by a lactone ring tautomerism of crystal violet lactone. The color of the rewritable paper rapidly changes from blue to colorlessness when the temperature is higher than 65 degrees C, and the colorless state can be maintained at room temperature. The color returns to blue when the temperature is lower than -10 degrees C. By using an electrothermal pen, a thermal printer, and near infrared (NIR) light, characters and images with high resolution can be handwritten, thermal-printed, and photoprinted on the rewritable paper. The written/printed information can be cleaned under lower temperature or can be quickly erased by NIR light. This rewritable paper is easy for large-scale production and will have promising opportunities in practical applications, such as long-lasting information recording and reading, rewritable label, reprintable displays, and so on. PMID- 30406983 TI - Correction to "Broadband Absorption Enhancement in Polymer Solar Cells Using Highly Efficient Plasmonic Heterostructured Nanocrystals". PMID- 30406984 TI - Recent Advances in Chromatography for Pharmaceutical Analysis. PMID- 30406985 TI - Propeller-Shaped, Triarylamine-Rich, and Dopant-Free Hole-Transporting Materials for Efficient n-i-p Perovskite Solar Cells. AB - By introducing six triarylamine groups to a hexaphenylbenzene (HPB) or a hexakis(2-thienyl)benzene (HTB) core, two propeller-shaped, triarylamine-rich, and low-cost hole-transporting materials (HTMs), which are termed as HPB-OMe and HTB-OMe, respectively, with considerable hole mobility, were obtained by easy synthetic routes. Solid-state planar perovskite CH3NH3PbI3 solar cells (PSCs) with two new HTMs showed high power conversion efficiencies (12.9% for HPB-OMe and 17.3% for HTB-OMe in forward scans) under standard 100 mW cm-2 AM 1.5G illumination without doping. A comparison of matched-degree of energy levels, hole-transporting ability, photovoltaic conversion efficiencies, and recombination of the two HTMs indicated that developing multi-triarylamine- and thiophene-rich molecules provides candidate and efficient dopant-free HTMs for PSCs. PMID- 30406986 TI - Crystal Structure of the Siderophore Binding Protein BauB Bound to an Unusual 2:1 Complex Between Acinetobactin and Ferric Iron. AB - The critical role that iron plays in many biochemical processes has led to an elaborate battle between bacterial pathogens and their hosts to acquire and withhold this critical nutrient. Exploitation of iron nutritional immunity is being increasingly appreciated as a potential antivirulence therapeutic strategy, especially against problematic multidrug resistant Gram-negative pathogens such as Acinetobacter baumannii. To facilitate iron uptake and promote growth, A. baumannii produces a nonribosomally synthesized peptide siderophore called acinetobactin. Acinetobactin is unusual in that it is first biosynthesized in an oxazoline form called preacinetobactin that spontaneously isomerizes to the final isoxazolidinone acinetobactin. Interestingly, both isomers can bind iron and both support growth of A. baumannii. To address how the two isomers chelate their ferric cargo and how the complexes are used by A. baumannii, structural studies were carried out with the ferric acinetobactin complex and its periplasmic siderophore binding protein BauB. Herein, we present the crystal structure of BauB bound to a bis-tridentate (Fe3+L2) siderophore complex. Additionally, we present binding studies that show multiple variants of acinetobactin bind BauB with no apparent change in affinity. These results are consistent with the structural model that depicts few direct polar interactions between BauB and the acinetobactin backbone. This structural and functional characterization of acinetobactin and its requisite binding protein BauB provides insight that could be exploited to target this critical iron acquisition system and provide a novel approach to treat infections caused by this important multidrug resistant pathogen. PMID- 30406987 TI - Correction to "Switching from Controlled Ring-Opening Polymerization (cROP) to Controlled Ring-Closing Depolymerization (cRCDP) by Adjusting the Reaction Parameters That Determine the Ceiling Temperature". PMID- 30406988 TI - Sequential Formation of Analyte Ions Originated from Bulk Alloys for Ambient Mass Spectrometry Analysis. AB - Rapid chemical decoding of bulk alloys to obtain both organic and elemental composition is of sustainable interest in multiple disciplines. Herein, an analytical strategy inherited from electrochemistry and mass spectrometry (MS) was developed for direct molecular characterization of alloys. While the organics on the alloy surface were simply extracted into the solvent for ESI-MS analysis, the components in the bulk alloy were successively converted into metal ions at appropriate electrolysis potentials, which were online chelated with specific ligands for ESI-MS analysis. A single sample analysis took only a few seconds since no other sample pretreatment was required, and a detection limit of 0.1 ppb was achieved for a component in alloy with low sample consumption (<1.0 mg). Proof-of-concept application indicated that the presented method has unique capability for successive analysis of organic and metallic components in liquids (e.g., engine oil), solids (e.g., alloy), and tunable spatial resolution (~1.0 to (1.0 * 10-5) cm2) for molecular characterization of bulk alloys. PMID- 30406989 TI - Substrate Determinants for Unwinding Activity of the DExH/D-Box Protein RNA Helicase A. AB - RNA helicase A (RHA) as a member of the DExH/D-box subgroup of helicase superfamily II is involved in virtually all aspects of RNA metabolism. It exhibits robust RNA helicase activity in vitro. However, little is known about the molecular and physical determinants for RHA substrate recognition and RHA translocation along the nucleic acids. Here, our nondenaturing polyacrylamide gel electrophoresis (PAGE)-based unwinding assays of chemical and structural modified substrates indicate that RHA translocates efficiently along the 3' overhang of RNA, but not DNA, with a requirement of covalent continuity. Ribose-phosphate backbone lesions on both strands of the nucleic acids, especially on the 3' overhang of the loading strand, affect RHA unwinding significantly. Furthermore, RHA requires RNA on the 3' overhang which directly or indirectly connects with the duplex region to mediate productive unwinding. Collectively, these findings propose a basic mechanism of the substrate determinants for RHA backbone tracking during duplex unwinding. PMID- 30406990 TI - Mass Spectrometry Genotyping of Human Papillomavirus Based on High-Efficiency Selective Enrichment of Nanoparticles. AB - This work developed a novel spermine-modified nanodiamonds (SP-NDs)-based method to selectively enrich oligonucleotides for matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) of human papillomavirus (HPV) virus. Our results showed that SP-NDs can effectively extract and enrich DNA oligonucleotides from sodium dodecyl sulfonate and urea solution. In addition, SP-NDs can also selectively extract oligonucleotides from enzymes digestion products of polymerase chain reaction-restriction fragment mass polymorphism (PCR-RFMP) of HPV virus. Then, the extract can be detected by MALDI TOF MS directly without further purification. According to the MS results, the HPV genotyping can be achieved. More importantly, with SP-NDs extraction, clinical samples infected with HPV genotype 16 and 18 can be identified. The described method shows great advantages of simplicity, high selectivity, and good reliability in real clinical samples. Due to our methods improvement on DNA enrichment, extraction and purification, the PCR-based MALDI-TOF MS for the analysis of oligonucleotides maybe become more rapid, sensitive, and high throughput, is promising for analysis for DNA methylation, single-nucleotide polymorphisms, and other virus typing. PMID- 30406991 TI - Mechanism of Fluorinated Anthranilate-Induced Growth Inhibition in Mycobacterium tuberculosis. AB - The biosynthesis of tryptophan in Mycobacterium tuberculosis is initiated by the transformation of chorismate to anthranilate, catalyzed by anthranilate synthase (TrpE/TrpG). Five additional enzymes are required to complete tryptophan biosynthesis. M. tuberculosis strains auxotrophic for tryptophan, an essential amino acid in the human diet, are avirulent. Thus, tryptophan synthesis in M. tuberculosis has been suggested as a potential drug target, and it has been reported that fluorinated anthranilate is lethal to the bacillus. Two mechanisms that could explain the cellular toxicity were tested: (1) the inhibition of tryptophan biosynthesis by a fluorinated intermediate or (2) formation of fluorotryptophan and its subsequent effects. Here, M. tuberculosis mc2 6230 cultures were treated with anthranilates fluorinated at positions 4, 5, and 6. These compounds inhibited bacterial growth on tryptophan-free media with 4 fluoroanthranilate being more potent than 5-fluoroanthranilate or 6 fluoroanthranilate. LC-MS based analysis of extracts from bacteria treated with these compounds did not reveal accumulation of any of the expected fluorinated intermediates in tryptophan synthesis. However, in all cases, significant levels of fluorotryptophan were readily observed, suggesting that the enzymes involved in the conversion of fluoro-anthranilate to fluorotryptophan were not being inhibited. Inclusion of tryptophan in cultures treated with the fluoro anthranilates obviated the cellular toxicity. Bacterial growth was also inhibited in a dose-dependent manner by exposure to tryptophan substituted with fluorine at positions 5 or 6. Thus, the data suggest that fluorotryptophan rather than fluoro anthranilate or intermediates in the synthesis of fluorotryptophan causes the inhibition of M. tuberculosis growth. PMID- 30406992 TI - Role of Human Aldo-Keto Reductases in the Metabolic Activation of the Carcinogenic Air Pollutant 3-Nitrobenzanthrone. AB - 3-Nitrobenzanthrone (3-NBA) is a potent mutagen and suspected human carcinogen detected in diesel exhaust particulate and ambient air pollution. It requires metabolic activation via nitroreduction to promote DNA adduct formation and tumorigenesis. NAD(P)H:quinone oxidoreductase 1 (NQO1) has been previously implicated as the major nitroreductase responsible for 3-NBA activation, but it has recently been reported that human aldo-keto reductase 1C3 (AKR1C3) displays nitroreductase activity toward the chemotherapeutic agent PR-104A. We sought to determine whether AKR1C isoforms could display nitroreductase activity toward other nitrated compounds and bioactivate 3-NBA. Using discontinuous enzymatic assays monitored by UV-HPLC, we determined that AKR1C1-1C3 catalyze three successive two-electron nitroreductions toward 3-NBA to form the reduced product 3-aminobenzanthrone (3-ABA). Evidence of the nitroso- and hydroxylamino- intermediates were obtained by UPLC-HRMS. Km, kcat, and kcat/ Km values were determined for recombinant AKR1C and NQO1 and compared. We found that AKR1C1, AKR1C3, and NQO1 have very similar apparent catalytic efficiencies (8 vs 7 min-1 mM-1) despite the higher kcat of NQO1 (0.058 vs 0.012 min-1). AKR1C1-1C3 possess a Km much lower than that of NQO1, which suggests that they may be more important than NQO1 at the low concentrations of 3-NBA to which humans are exposed. Given that inhalation represents the primary source of 3-NBA exposure, we chose to evaluate the relative importance of AKR1C1-1C3 and NQO1 in human lung epithelial cell lines. Our data suggest that the combined activities of AKR1C1-1C3 and NQO1 contribute equally to the reduction of 3-NBA in A549 and HBEC3-KT cell lines and together represent approximately 50% of the intracellular nitroreductase activity toward 3-NBA. These findings have significant implications for the metabolism of nitrated polycyclic aromatic hydrocarbons and suggest that the hitherto unrecognized nitroreductase activity of AKR1C enzymes should be further investigated. PMID- 30406993 TI - Cobweb-like Structural Stimuli-Responsive Composite with Oil Warehouse and Transportation System for Oil Storage and Recyclable Smart-Lubrication. AB - Despite recent advances in the stimuli-responsive composites for oil storage and smart lubrication, achieving the high oil storage and recyclable smart lubrication remains a challenge. Herein, a novel cobweb-like structural system consisting of oil warehouse and transportation system was designed and prepared and it shows high capacity of oil storage and recyclable smart-lubrication. Hollow SiO2 microspheres grated of KH550 and porous polyimide (PPI) were used as oil warehouse and pipeline, respectively, to build the smart system. Because of the novel structure, the composites can keep both high oil-content and oil retention. Applying stimuli on materials resulted in lubricants releasing on the contact surface which can reduce the friction and wear during sliding. However, removing stimuli, the capillary force induced the sucking back of lubricant into the interior of composites through interconnected small pores of PPI. On the basis of high oil storage and stimuli-responsive performance, the composites can be used for recyclable smart-lubrication. The composites showed remarkable lubricating properties (coefficient of friction 0.056 and Ws 3.55 * 10-7 mm3 N-1 m-1) when the content of KHSM (hollow silica microspheres grated of KH550 (3 Aminopropyltriethoxysilane)) was 1.5 wt % by subjecting it to macroscopic pin-on disc friction tests. Therefore, cobweb-like structural composites with oil warehouse and transportation system hold the promise for formulating of high oil storage and recyclable smart-lubrication. PMID- 30406994 TI - A Residue outside the Binding Site Determines the Galpha Binding Specificity of GoLoco Motifs. AB - GoLoco motif-containing proteins regulate the nucleotide-binding state of Galpha proteins in various signaling pathways. As guanine nucleotide dissociation inhibitors (GDIs), they bind Galpha.GDP and inhibit GDP to GTP exchange. GoLoco proteins show binding selectivity toward different members of the Galpha family. Although the Galphai1.GDP/RGS14 crystal structure explains the specific binding selectivity of the RGS14 GoLoco domain well, the mechanism of selective binding has not been understood for the more general features of short GoLoco domains found in tandem arrays in proteins like GPSM2/LGN/ dPins and GPSM1/AGS3. We explored the mechanism of differential interactions of GoLoco protein LGN with hGalphai3 and hGalphao. By combining mutagenesis experiments and molecular dynamics simulations, we identified a residue (Asp229 in hGalphai3) away from the binding interface that remarkably affects the interaction between LGN and hGalphai/o. A negatively charged residue at this position is required for high binding affinity. This affinity regulation mechanism was further verified by the cases of hGalphai2 and dGalphao, suggesting that this pathway is conserved among members of the Galpha family. PMID- 30406995 TI - Rossmann-Fold Methyltransferases: Taking a "beta-Turn" around Their Cofactor, S Adenosylmethionine. AB - Methyltransferases (MTases) are superfamilies of enzymes that catalyze the transfer of a methyl group from S-adenosylmethionine (SAM), a nucleoside-based cofactor, to a wide variety of substrates such as DNA, RNA, proteins, small molecules, and lipids. Depending upon their structural features, the MTases can be further classified into different classes; we consider exclusively the largest class of MTases, the Rossmann-fold MTases. It has been shown that the nucleoside cofactor-binding Rossmann enzymes, particularly the nicotinamide adenine dinucleotide (NAD)-, flavin adenine dinucleotide (FAD)-, and SAM-binding MTases enzymes, share common binding motifs that include a Gly-rich loop region that interacts with the cofactor and a highly conserved acidic residue (Asp/Glu) that interacts with the ribose moiety of the cofactor. Here, we observe that the Gly rich loop region of the Rossmann MTases adapts a specific type II' beta-turn in the proximity of the cofactor (<4 A), and it appears to be a key feature of these superfamilies. Additionally, we demonstrate that the conservation of this beta turn could play a critical role in the enzyme-cofactor interaction, thereby shedding new light on the structural conformation of the Gly-rich loop region from Rossmann MTases. PMID- 30406996 TI - Role of CSE-Produced H2S on Cerebrovascular Relaxation via RhoA-ROCK Inhibition and Cerebral Ischemia-Reperfusion Injury in Mice. AB - The role of CSE-produced H2S on cerebrovascular relaxation and cerebral ischemia reperfusion (I/R) injury was investigated using CSE knockout (CSE-/-) and wild type (CSE+/+) mice. The relaxation of the cerebral basilar artery (BA) to CSE produced H2S and its mechanism were detected. The results revealed that both NaHS, a donor of exogenous H2S, and ROCK inhibitor Y27632 could induce significant relaxation of the BA, but the relaxation of the BA to NaHS was significantly attenuated by Y27632. In addition, removal of endothelium could reduce the relaxation of the BA to Y27632; CSE knockout also significantly attenuated Y27632-induced BA relaxation with endothelium rather than without endothelium. By contrast, the contraction of the BA from CSE-/- mice to RhoA agonist LPA or U46619 was stronger than that from CSE+/+ mice. Furthermore, RhoA activity and ROCK protein expression remarkably increased in the BA vascular smooth muscle cells (VSMCs) from CSE-/- mouse, which were inhibited by NaHS pretreatment. These findings revealed that the CSE-produced H2S induced cerebrovascular relaxation is generated from endothelial cells and the mechanism of vascular relaxation may relate to inhibition of RhoA-ROCK pathway. We next sought to confirm the protective effect of CSE-produced H2S on cerebral I/R injury produced by middle cerebral artery occlusion and bilateral common carotid artery occlusion in mice. We investigated the changes of neurological deficit, cerebral infarct, brain water content, LDH decrease, MDA increase as well as impairment of learning and memory function. The results showed that the cerebral injury became more grievous in CSE-/-mice than that in CSE+/+mice, which could be remarkably alleviated by NaHS pretreatment. PMID- 30406997 TI - Toward Mechanically Stable Silicon-Based Anodes Using Si/SiO x@C Hierarchical Structures with Well-Controlled Internal Buffer Voids. AB - Low conductivity and structural degradation of silicon-based anodes lead to severe capacity fading, which fundamentally hinders their practical application in Li-ion batteries. Here, we report a scalable Si/SiO x@C anode architecture, which is constructed simultaneously by sintering a mixture of SiO/sucrose in argon atmosphere, followed by acid etching. The obtained structure features highly uniform Si nanocrystals embedded in silica matrices with well-controlled internal nanovoids, with all of them embraced by carbon shells. Because of the improvement of the volumetric efficiency for accommodating Si active spices and electrical properties, this hierarchical anode design enables the promising electrochemical performance, including a high initial reversible capacity (1210 mAh g-1), stable cycling performance (90% capacity retention after 100 cycles), and good rate capability (850 mAh g-1 at 2.0 A g-1 rate). More notably, the compact heterostructures derived from micro-SiO allow high active mass loading for practical applications and the facile and scalable fabrication strategy makes this electrode material potentially viable for commercialization in Li-ion batteries. PMID- 30406998 TI - New Helicene-Type Hole-Transporting Molecules for High-Performance and Durable Perovskite Solar Cells. AB - Three azahelicene derivatives with electron-rich bis(4-methoxyphenyl)amino or bis( p-methoxyphenyl)aminophenyl groups at the terminals were deliberately designed, synthesized, and characterized as hole-transporting materials (HTMs) for perovskite solar cells (PSCs). Optical and thermal properties, energy level alignments, film morphologies, hole extraction ability, and hole mobility were studied in detail. PSCs using the newly synthesized molecules as HTMs were fabricated. A maximum power conversion efficiency (PCE) of 17.34% was observed for the bis( p-methoxyphenyl)amino-substituted derivative (SY1) and 16.10% for the bis( p-methoxyphenyl)aminophenyl-substituted derivative (SY2). Longer-chain substituent such as hexyloxy group greatly diminishes the efficiency. In addition, the dopant-free devices fabricated with SY1 as the HTM shows an average PCE of 12.13%, which is significantly higher than that of spiro-OMeTAD (7.61%). The ambient long-term stability test revealed that after 500 h, the devices prepared from SY1 and SY2 retained more than 96% of its initial performance, which is much improved than the reference device with standard spiro-OMeTAD as the HTM under the same conditions. Detailed material cost analysis reveals that the material cost for SY1 is less than 8% of that for spiro-OMeTAD. These results provide a useful direction for designing a new class of HTMs to prepare highly efficient and more durable PSCs. PMID- 30406999 TI - Strain Engineering in Highly Wrinkled CVD Graphene/Epoxy Systems. AB - Chemical vapor deposition (CVD) is regarded as a promising fabrication method for the automated, large-scale, production of graphene and other two-dimensional materials. However, its full commercial exploitation is limited by the presence of structural imperfections such as folds, wrinkles, and even cracks that downgrade its physical and mechanical properties. For example, as shown here by means of Raman spectroscopy, the stress transfer from an epoxy matrix to CVD graphene is on average 30% of that of exfoliated monolayer graphene of over 10 MUm in dimensions. However, in terms of electrical response, the situation is reversed; the resistance has been found here to decrease by the imposition of mechanical deformation possibly due to the opening up of the structure and the associated increase of electron mobility. This finding paves the way for employing CVD graphene/epoxy composites or coatings as conductive "networks" or bridges in cases for which the conductivity needs to be increased or at least retained when the system is under deformation. The tuning/control of such systems and their operative limitations are discussed here. PMID- 30407000 TI - The Mg-Rich Phase NdNiMg15: Structural and Magnetic Properties. AB - The intermetallic NdNiMg15 is the Mg-richest phase (more than 88 atom % of Mg) discovered in the Mg-Nd-Ni system. Its structure was determined by X-ray diffraction on single crystal with the following crystal data: tetragonal system, P4/ nmm, Z = 2, a = 10.0602(1) A, c = 7.7612(2) A, dcalc = 2.40 g.cm-3. Its structure is made of a three-dimensional framework of magnesium atoms showing channels filled by one-dimensional chain consisting of alternating Nd and Ni atoms along the c-axis. Anti-ferromagnetic ordering was observed with TN = 9 K, which is remarkably high considering the long distances between magnetic atoms, that is, Nd atoms. The effective magnetic moment MUeff is equal to 3.58 MUB, which is consistent with magnetic Nd3+ ions and weakly or nonmagnetic Ni atoms. Below TN, the M( H) curves show field-induced metamagnetic transitions at critical fields increasing with decreasing temperatures. The magnetic structure of NdNiMg15 was determined from neutron powder diffraction data by considering the propagation vector k = (1/2 1/2 0). This magnetic structure consists in ferromagnetic chains along the c-axis of Nd atoms carrying moments, only separated by Ni atoms. The chains are ferromagnetically coupled within planes perpendicular to the [110] direction, and these planes are anti-ferromagnetically coupled to neighboring planes forming a checkerboard-like magnetic structure. PMID- 30407001 TI - Hydrogen Insertion in the Intermetallic GdScGe: A Drastic Reduction of the Dimensionality of the Magnetic and Transport Properties. AB - Intermetallic phases have been investigated with respect to their ability to accept small atoms in interstitial sites without changing the host structure. Among those, the intermetallic compounds crystallizing in the tetragonal CeScSi type structure are able to absorb hydrogen atoms. These compounds are of particular interest because they can show electride-like character and, therefore, can be exploited as new catalysts. Here we report the case of GdScGe which uptakes hydrogen at 623 K and under a H2 gas pressure between 0.5 and 4 MPa. The formation of the hydride GdScGeH, with H atoms entering into the [Gd4] tetrahedra, preserves the host structure but induces an anisotropic volume expansion with a strong increase of the c-parameter and a slight decrease of the a-parameter. Interestingly, we show for the first time for this family of materials that hydrogen insertion reduces the dimensionality of the magnetic and transport properties from 3D to quasi-2D which results in a vanishing of the ferromagnetic order ( TC = 350 K for GdScGe) and a change of the metallic conduction behavior to a nonmetallic one. As evidenced by density functional theory calculations, such drastic effects are accounted for through the Gd-H chemical bonding effect and the oxidizing effect of H whereas the volume expansion plays only a minor role. PMID- 30407003 TI - Programming Protein Polymerization with DNA. AB - A strategy that utilizes DNA for controlling the association pathway of proteins is described. This strategy uses sequence-specific DNA interactions to program energy barriers for polymerization, allowing for either step-growth or chain growth pathways to be accessed. Two sets of mutant green fluorescent protein (mGFP)-DNA monomers with single DNA modifications have been synthesized and characterized. Depending on the deliberately controlled sequence and conformation of the appended DNA, these monomers can be polymerized through either a step growth or chain-growth pathway. Cryo-electron microscopy with Volta phase plate technology enables the visualization of the distribution of the oligomer and polymer products, and even the small mGFP-DNA monomers. Whereas cyclic and linear polymer distributions were observed for the step-growth DNA design, in the case of the chain-growth system linear chains exclusively were observed, and a dependence of the chain length on the concentration of the initiator strand was noted. Importantly, the chain-growth system possesses a living character whereby chains can be extended with the addition of fresh monomer. This work represents an important and early example of mechanistic control over protein assembly, thereby establishing a robust methodology for synthesizing oligomeric and polymeric protein-based materials with exceptional control over architecture. PMID- 30407002 TI - Amplified Visualization of Protein-Specific Glycosylation in Zebrafish via Proximity-Induced Hybridization Chain Reaction. AB - The visualization of glycosylation states of specific proteins in vivo is of great importance for uncovering their roles in disease development. However, the ubiquity of glycosylation makes probing the glycans on a certain protein as difficult as looking for a needle in a haystack. Herein, we demonstrate a proximity-induced hybridization chain reaction (HCR) strategy for amplified visualization of protein-specific glycosylation. The strategy relies on designing two kinds of DNA probes, glycan conversion probes and protein recognition probes, which are attached to glycans and target proteins, respectively. Upon sequential binding to the targets, the proximity-induced hybridization between two probes occurs, which leads to the structure-switching of protein recognition probes, followed by triggering of HCR assembly. This strategy has been used to visualize tyrosine-protein kinase 7-specific sialic acid in living CEM cells and zebrafish and to monitor its variation during drug treatment. It provides a potential tool for investigating protein-specific glycosylation and researching the relation between dynamic glycans state and disease process. PMID- 30407004 TI - Pesticides in Brazil: A Viewpoint about the Poison Law. PMID- 30407005 TI - Halogenated Meroditerpenoids from a South Pacific Collection of the Red Alga Callophycus serratus. AB - A detailed examination of the red alga Callophycus serratus collected in Tonga led to the isolation of six new halogenated meroditerpenoids: callophycol C (1), callophycoic acid I (2), iodocallophycols E (3) and F (4), iodocallophycoic acid B (5), and callophycoic acid J (6). Of these, compounds 3-5 are new iodinated additions to the growing family of Callophycus meroditerpenoids. The relative configurations of compounds 1-6 were deduced by analyses of 1D NOE data and 1H-1H scalar coupling constants, and 3-6 are proposed to differ from the closely related compounds reported in the literature, iodocallophycoic acid A and iodocallophycols A-D. Iodocallophycol E (3) exhibited moderate cytotoxicity against the promyelocytic leukemia cell line HL-60 with an IC50 value of 6.0 MUM. PMID- 30407006 TI - Stereoselective Construction of Pyrazinoindoles and Oxazinoindoles via Ring Opening/Pictet-Spengler Reaction of Aziridines and Epoxides with 3-Methylindoles and Carbonyls. AB - A highly efficient and stereoselective route to access 1,3-disubstituted 1,2,3,4 tetrahydropyrazino[1,2- a]indoles and 3,4-dihydro-1H-[1,4]oxazino[4,3- a]indoles with excellent stereoselectivity (de, ee >99%) via base mediated ring opening of aziridines/epoxides with 3-methylindoles followed by BF3.OEt2 catalyzed Pictet Spengler reaction is accomplished. Interestingly, PTSA promoted cyclization led to the formation of oxidized 3,4-dihydropyrazino[1,2- a]indoles in excellent yields via an unprecedented Pictet-Spengler-detosylation cascade. PMID- 30407007 TI - A Steroid-Type Antioxidant Targeting the Keap1/Nrf2/ARE Signaling Pathway from the Soft Coral Dendronephthya gigantea. AB - Four new steroids, named 7-dehydroerectasteroid F (1), 11alpha-acetoxyarmatinol A (2), 22,23-didehydroarmatinol A (3), and 3-O-acetylhyrtiosterol (4), together with 11 previously described analogues, were isolated from a South China Sea collection of the soft coral Dendronephthya gigantea. The structures of the new steroids were elucidated by comprehensive spectroscopic analysis and by comparison with previously reported data. Compound 1 showed potent protection against H2O2-induced oxidative damage in neuron-like PC12 cells by promoting nuclear translocation of Nrf2 and enhancing the expression of HO-1. 1 represents the first steroid-type antioxidant from marine organisms. PMID- 30407008 TI - Ingestion and Chronic Effects of Car Tire Tread Particles on Freshwater Benthic Macroinvertebrates. AB - Micronized particles released from car tires have been found to contribute substantially to microplastic pollution, triggering the need to evaluate their effects on biota. In the present study, four freshwater benthic macroinvertebrates were exposed for 28 days to tread particles (TP; 10-586 MUm) made from used car tires at concentrations of 0, 0.1, 0.3, 1, 3, and 10% sediment dry weight. No adverse effects were found on the survival, growth, and feeding rate of Gammarus pulex and Asellus aquaticus, the survival and growth of Tubifex spp., and the number of worms and growth of Lumbriculus variegatus. A method to quantify TP numbers inside biota was developed and here applied to G. pulex. In bodies and faces of G. pulex exposed to 10% car tire TP, averages of 2.5 and 4 tread particles per organism were found, respectively. Chemical analysis showed that, although car tire TP had a high intrinsic zinc content, only small fractions of the heavy metals present were bioavailable. PAHs in the TP-sediment mixtures also remained below existing toxicity thresholds. This combination of results suggests that real in situ effects of TP and TP-associated contaminants when dispersed in sediments are probably lower than those reported after forced leaching of contaminants from car tire particles. PMID- 30407009 TI - VIETHERB: A Database for Vietnamese Herbal Species. AB - Vietnam carries a highly diverse data of traditional medicine, in which various combinations of herbs were widely used as remedies for many types of diseases. Poor hand-writing records and current text-based databases, however, perplex the conventionalizing and evaluating process of the canonical therapeutic effects. In efforts to reorganize the valuable information, we provide VIETHERB database (http://vietherb.com.vn/) for herbs documented in Vietnamese traditional medicines. This database is constructed with temerity to provide users with information of herbs and other side information including metabolites, diseases, morphologies, and geographical locations for each individual species. Our data in this release consists of 2881 species, 10887 metabolites, 458 geographical locations, and 8046 therapeutic effects. The number of binary relationships of species-metabolite, species-therapeutic effect, species-morphology, and species distribution are 17602, 2718, 11943, and 16089 respectively. The information of Vietnamese herbal species can be easily accessed or queried using their scientific names. Searching for species share side information can be simply done by clicking on the data. The database primarily serves as open sources facilitating users in studies on computer-aided drug design, statistical learning, and other experimental sciences. PMID- 30407010 TI - Correction to Scalable Electron Correlation Methods. 4. Parallel Explicitly Correlated Local Coupled Cluster with Pair Natural Orbitals (PNO-LCCSD-F12). PMID- 30407011 TI - Long Exciton Dephasing Time and Coherent Phonon Coupling in CsPbBr2Cl Perovskite Nanocrystals. AB - Fully inorganic cesium lead halide perovskite nanocrystals (NCs) have shown to exhibit outstanding optical properties such as wide spectral tunability, high quantum yield, high oscillator strength as well as blinking-free single photon emission, and low spectral diffusion. Here, we report measurements of the coherent and incoherent exciton dynamics on the 100 fs to 10 ns time scale, determining dephasing and density decay rates in these NCs. The experiments are performed on CsPbBr2Cl NCs using transient resonant three-pulse four-wave mixing (FWM) in heterodyne detection at temperatures ranging from 5 to 50 K. We found a low-temperature exciton dephasing time of 24.5 +/- 1.0 ps, inferred from the decay of the photon-echo amplitude at 5 K, corresponding to a homogeneous line width (fwhm) of 54 +/- 5 MUeV. Furthermore, oscillations in the photon-echo signal on a picosecond time scale are observed and attributed to coherent coupling of the exciton to a quantized phonon mode with 3.45 meV energy. PMID- 30407012 TI - Photoredox Generated Vinyl Radicals: Synthesis of Bisindoles and beta-Carbolines. AB - A photoredox catalyzed approach enabling use of alkynes as surrogate of 2 oxoaldehydes/1,2-diones is reported. The method overcomes the difficulty associated with application of unsubstituted aliphatic alpha-oxoaldehydes, which has hitherto limited their general use. Indoles, tryptamine, and tryptophan methyl ester participated in the reaction to give a variety of alpha-oxo based analogues. Quantum yield investigations support a radical chain mechanism. PMID- 30407013 TI - Probing Ligand-Induced Cooperative Orbital Redistribution That Dominates Nanoscale Molecule-Surface Interactions with One-Unit-Thin TiO2 Nanosheets. AB - Understanding the general electronic principles underlying molecule-surface interactions at the nanoscale is crucial for revealing the processes based on chemisorption, like catalysis, surface ligation, surface fluorescence, etc. However, the electronic mechanisms of how surface states affect and even dominate the properties of nanomaterials have long remained unclear. Here, using one-unit thin TiO2 nanosheet as a model surface platform, we find that surface ligands can competitively polarize and confine the valence 3d orbitals of surface Ti atoms from delocalized energy band states to localized chemisorption bonds, through probing the surface chemical interaction at the orbital level with near-edge X ray absorption fine structure (NEXAFS). Such ligand-induced orbital redistributions, which are revealed by combining experimental discoveries, quantum calculations, and theoretical analysis, are cooperative with ligand coverages and can enhance the strength of chemisorption and ligation-induced surface effects on nanomaterials. The model and concept of nanoscale cooperative chemisorption reveal the general physical principle that drives the coverage dependent ligand-induced surface effects on regulating the electronic structures, surface activity, optical properties, and chemisorption strength of nanomaterials. PMID- 30407014 TI - Clean Block Copolymer Microparticles from Supercritical CO2: Universal Templates for the Facile and Scalable Fabrication of Hierarchical Mesostructured Metal Oxides. AB - Metal oxide microparticles with well-defined internal mesostructures are promising materials for a variety of different applications, but practical routes to such materials that allow the constituent structural length scales to be precisely tuned have thus far been difficult to realize. Herein, we describe a novel platform methodology that utilizes self-assembled block copolymer (BCP) microparticles synthesized by dispersion polymerization in supercritical CO2 (scCO2) as universal structure directing agents for both hydrolytic and nonhydrolytic sol-gel routes to metal oxides. Spherically structured poly(methyl methacrylate- block-4-vinylpyridine) (PMMA- b-P4VP) BCP microparticles are translated into a series of the corresponding organic/inorganic composites and pure inorganic derivatives with a high degree of fidelity for the metal oxides TiO2 and LiFePO4. The final products are comprised of particles close to 1 MUm in size with a highly ordered internal morphology of interconnected spheres between 20-40 nm in size. Furthermore, our approach is readily scalable, enabling grams of pure or carbon-coated TiO2 and LiFePO4, respectively, to be fabricated in a facile two step route involving ambient temperature mixing and drying stages. Given that both length scales within these BCP microparticles can be controlled independently by minor variations in the reagent quantities used, the present general strategy could represent a milestone in the design and synthesis of hierarchical metal oxides with completely tunable dimensions. PMID- 30407016 TI - Decoration of Coiled-Coil Peptides with N-Cysteine Peptide Thioesters As Cyclic Peptide Precursors Using Copper-Catalyzed Azide-Alkyne Cycloaddition (CuAAC) Click Reaction. AB - The development of a copper-catalyzed azide-alkyne cycloaddition (CuAAC) protocol for the decoration of coiled coils with N-cysteine peptide thioesters as cyclic peptide precursors is presented. The reaction conditions include tert-butanol/PBS as the solvent and CuSO4/THPTA/ascorbate as the catalytic system. During these studies, partial formylation of N-terminal cysteine peptides is observed. Mechanistic analysis leads to identification of the formyl source and, hence, to the development of reaction conditions, under which the undesired side reaction was suppressed. PMID- 30407015 TI - Rhodium(III)-Catalyzed Redox-Neutral Cascade [3 + 2] Annulation of N Phenoxyacetamides with Propiolates via C-H Functionalization/Isomerization/Lactonization. AB - A Rh(III)-catalyzed cascade [3 + 2] annulation of N-phenoxyacetamides with propiolates under mild conditions using the internal oxidative O-N bond as the directing group has been achieved. This catalytic system provides a regio- and stereoselective access to benzofuran-2(3 H)-ones bearing exocyclic enamino motifs with exclusive Z configuration selectivity, acceptable to good yields and good functional group compatibility. Mechanistic investigations by experimental and density functional theory studies suggest that a consecutive process of C-H functionalization/isomerization/lactonization is likely to be involved in the reaction. PMID- 30407017 TI - Extended Sialylated O-Glycan Repertoire of Human Urinary Glycoproteins Discovered and Characterized Using Electron-Transfer/Higher-Energy Collision Dissociation. AB - A relatively novel activation technique, electron-transfer/higher-energy collision dissociation (EThcD) was used in the LC-MS/MS analysis of tryptic glycopeptides enriched with wheat germ agglutinin from human urine samples. We focused on the characterization of mucin-type O-glycopeptides. EThcD in a single spectrum provided information on both the peptide modified and the glycan carried. Unexpectedly, glycan oxonium ions indicated the presence of O-acetyl, and even O-diacetyl-sialic acids. B and Y fragment ions revealed that (i) in core 1 structures the Gal residue featured the O-acetyl-sialic acid, when there was only one in the glycan; (ii) several glycopeptides featured core 1 glycans with disialic acids, in certain instances O-acetylated; (iii) the disialic acid was linked to the GalNAc residue whatever the degree of O-acetylation; (iv) core 2 isomers with a single O-acetyl-sialic acid were chromatographically resolved. Glycan fragmentation also helped to decipher additional core 2 oligosaccharides: a LacdiNAc-like structure, glycans carrying sialyl LewisX/A at different stages of O-acetylation, and blood antigens. A sialo core 3 structure was also identified. We believe this is the first study when such structures were characterized from a very complex mixture and were linked not only to a specific protein, but also the sites of modifications have been determined. PMID- 30407018 TI - Phosphoric Acid Catalyzed [4 + 1]-Cycloannulation Reaction of ortho-Quinone Methides and Diazoketones: Catalytic, Enantioselective Access toward cis-2,3 Dihydrobenzofurans. AB - A highly straightforward route to enantiomerically highly enriched cis-2,3 dihydrobenzofurans has been achieved via addition of alpha-diazocarbonyl compounds to in situ generated o-QMs catalyzed by a chiral Bronsted acid. This catalytic strategy provides a direct access to 2,3-dihydrobenzofurans in high yields and with up to 91:9 dr and 99:1 er at ambient temperature. Moreover, a unique phenonium-type rearrangement accounts for product formation with an inverted 2,3-substitution pattern. PMID- 30407019 TI - Barriers for Extrusion of a Guest from the Interior Binding Cavity of a Host: Gas Phase Experimental and Computational Results for Ion-Capped Decamethylcucurbit[5]uril Complexes. AB - Factors affecting the extrusion of guests from metal ion-capped decamethylcucurbit[5]uril (mc5) molecular container complexes are investigated using both collision-induced dissociation techniques and molecular mechanics simulations. For guests without polar bonds, the extrusion barrier increases with increasing guest volume. This is likely because escape of larger guests requires more displacement of the metal ion caps and, thus, more disruption of the ion dipole interactions between the ion caps and the electronegative rim oxygens of mc5. However, guests larger than the optimum size for encapsulation displace the ion caps prior to collision-induced dissociation, resulting in less stable complexes and lower dissociation thresholds. The extrusion barriers obtained for guests with polar bonds are smaller than those obtained for similarly sized guests without polar bonds. This is likely because the partial charges on the guest allow electrostatic interactions with the ion cap and rim oxygens of mc5 during extrusion, thus stabilizing the extrusion transition state and reducing the extrusion barrier. Results from this study demonstrate simple principles to consider for designing host-guest complexes with specific guest-loss behaviors. Similar trends are observed between the experimental and computational results, demonstrating that molecular mechanics simulations can be used to approximate the relative stability of mc5 molecular container complexes and likely those of other similar complexes. PMID- 30407020 TI - Exceedingly Fast, Direct Access to Dihydroisoquinolino[1,2- b]quinazolinones through a Ruthenium(II)-Catalyzed Redox-Neutral C-H Allylation/Hydroamination Cascade. AB - A ruthenium(II)-catalyzed redox-neutral synthesis of dihydroisoquinoline-fused quinazolinone derivatives has been accomplished through the merger of C-H activation and alkene difunctionalization using quinazolinone as an inherent directing group. This intermolecular reaction proceeds rapidly and is complete within 10 min, providing the annulation product in high yields without any stoichiometric metal oxidant. Mechanistically, this tandem reaction proceeds through directed ortho C-H allylation followed by hydroamination with the proximal -CONH group, to furnish 6-methyl-5,6-dihydro-8 H-isoquinolino[1,2- b]quinazolin-8-ones in a single operation. The carboxylic acid additive has a dual role in the formation of active catalyst and protodemetalation. PMID- 30407021 TI - Catalytic Asymmetric Mannich Type Reaction with Tri-/Difluoro- or Trichloroacetaldimine Precursors. AB - A highly efficient catalytic asymmetric Mannich type reaction of CF3-, CF2H-, or CCl3-acetaldimine precursors by a chiral primary amine is presented. This protocol provides facile access to chiral CF3-, CF2H-, or trichloroethyl amines in excellent yields and high enantioselectivity (up to 99% yield, up to >99% ee). PMID- 30407022 TI - Memory for temporal order in action is slow developing, sensitive to deviant input, and supported by foundational cognitive processes. AB - Executing actions in a specific order is a critical component of many action sequences that children must acquire, the majority of which are learned through observation and imitation of others. Although a wealth of evidence indicates that children can process and represent temporal order in memory, relatively little is known about the development of this ability and the cognitive mechanisms that support it in the context of imitation. The present research investigated 4- through 8-year-old children's ability to learn the temporal order of novel, arbitrary action sequences via imitation. On Day 1, children observed and imitated four instances each for two different multistep sequences. One sequence was easy and the other was difficult, in terms of categorizing the items used in each instance. For one sequence, the experimenter also performed one instance in a deviant temporal order, which occurred either early or late in learning. Memory generalization for each sequence was assessed on Day 2. Results indicated significant effects of age and sequence difficulty on children's ability to recall the individual actions as well as the standard order. Experiencing the deviant order also uniquely disrupted children's ability to generalize the order. Experiencing the deviant early in learning globally lowered children's memory for both sequences. Thus, children's ability to learn temporal order develops slowly over childhood, is supported by foundational cognitive processes that operate in a hierarchical fashion, and is highly sensitive to variable temporal input. These results have implications for theories of imitation and cultural learning more broadly. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407023 TI - Child-present and child-themed marital conflict in daily life of parents of children with and without autism spectrum disorder. AB - Parents of 5- to 12-year-old children (half had been diagnosed with autism spectrum disorder [ASD] and half were typically developing) provided reports of the most significant marital conflict of the day and ratings of child behaviors problems on a daily basis for 14 days. Mothers and fathers in the ASD group reported having more conflicts in daily life with any children present and more conflicts with the target child present than their counterparts with typically developing children did. Fathers (but not mothers) in the ASD group reported more conflicts as including child-related themes, although parents across the groups did not differ in their reporting marital conflict that specifically discussed the study's target child. Results from multilevel modeling revealed within-person associations between child presence during marital conflict and parents' emotions; specifically, child presence was related to lower dyadic positivity and higher dyadic anger, according to both mothers and fathers. In addition, results identified significant, positive within-person associations between child presence during marital conflict and discussing certain conflict topics (increased likelihoods of discussing any children and the study's target children). These direct associations were found consistently across mothers' and fathers' reports, and did not vary across ASD and comparison families. Multilevel models focused on implications of the marital conflict for the study's target children generally found child presence during conflict and discussion of child themed conflict topics to predict higher levels of behavior problems in daily life. One moderating effect was identified, with child presence during conflict related to higher behavior problems according to mothers in the ASD group but not those in the comparison group. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407024 TI - Measuring early learning and development across cultures: Invariance of the IDELA across five countries. AB - Relatively little research has addressed whether conceptual frameworks of early learning generalize across different national contexts. This article reports on a cross-country measurement invariance analysis of the International Development and Early Learning Assessment (IDELA). The IDELA is a direct assessment tool for 3- to 6-year-old children, intended to measure Early Literacy, Early Numeracy, Motor, and Social-Emotional development. Its generalizability is evaluated using samples from 5 countries: Afghanistan (N = 2,629); Bolivia (N = 480); Ethiopia (N = 682); Uganda (N = 504); and Vietnam (N = 675). The 4-domain model of the IDELA was supported in each country, although the domains were highly correlated. Measurement invariance analysis revealed that most IDELA items do not provide a basis for comparing children's development over the 5 countries. This research supports the use of the IDELA for program evaluation and within-country monitoring purposes, but cautions against its use for international comparisons. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407025 TI - Dual-task costs in working memory: An adversarial collaboration. AB - Theories of working memory often disagree on the relationships between processing and storage, particularly on how heavily they rely on an attention-based limited resource. Some posit separation and specialization of resources resulting in minimal interference to memory when completing an ongoing processing task, while others argue for a greater overlap in the resources involved in concurrent tasks. Here, we present four experiments that investigated the presence or absence of dual-task costs for memory and processing. The experiments were carried in an adversarial collaboration in which researchers from three opposing theories collaboratively designed a set of experiments and provided differential predictions in line with each of their models. Participants performed delayed recall of aurally and visually presented letters and an arithmetic verification task either as single tasks or with the arithmetic verification task between presentation and recall of letter sequences. Single- and dual-task conditions were completed with and without concurrent articulatory suppression. A consistent pattern of dual-task and suppression costs was observed for memory, with smaller or null effects on processing. The observed data did not fit perfectly with any one framework, with each model having partial success in predicting data patterns. Implications for each of the models are discussed, with an aim for future research to investigate whether some combination of the models and their assumptions can provide a more comprehensive interpretation of the pattern of effects observed here and in relevant previous studies associated with each theoretical framework. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407026 TI - Distress intolerance moderation of neurophysiological markers of response inhibition after induced stress: Relations with cannabis use disorder. AB - Cannabis use is prevalent but only a minority of regular users develop cannabis use disorder (CUD); thus, CUD risk identification among current cannabis users is vital for targeted intervention development. Existing data suggest that high distress intolerance (DI), an individual difference reflective of the ability to withstand negative affect, is linked to CUD, possibly via stress-elicited impairment of response inhibition but this has never been explicitly tested. Frequent cannabis users with high and low DI completed a go/no-go task during EEG recording before and after a laboratory stressor. Relations between DI, cannabis use-related problems, and behavioral as well as neurophysiological markers of response inhibition functioning were assessed. DI significantly moderated the effect of the stressor on the conflict-monitoring but not evaluative phase of response inhibition as measured by N2 and P3a amplitude, respectively. Unexpectedly, cannabis users with high DI demonstrated stressor-elicited enhancement rather than impairment of conflict-monitoring neural activity, which was related to faster reaction time (RT) and decreased past-month cannabis problems. Enhanced inhibition-related modulation of P3a amplitude was generally associated with increased cannabis problems regardless of acute stress. Results did not provide support for stress-elicited impairment in cognitive control as a mechanism linking high DI and CUD, though some support was found for the relevance of inhibition-related neural activity to CUD. Stress-elicited enhancement of conflict-monitoring neural activity during response inhibition may reflect an adaptive neural response among cannabis users with high DI that protects against CUD in this at-risk group. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407027 TI - Alcohol, tobacco, and marijuana expectancies as predictors of substance use initiation in adolescence: A longitudinal examination. AB - Outcome expectancies have been found to be predictive of substance use. While development of expectancies may be dynamic during adolescence, it is unknown whether the rate of change (slope) in substance use expectancies is a risk factor for use onset across multiple substance use domains. The present study tested the hypothesis that the slope of positive and negative alcohol, tobacco, and marijuana use expectancies during mid-adolescence (9th-10th grade) would predict use onset of each respective substance during late adolescence (11th-12th grade). Data from 3,396 ethnically diverse high school students were collected across eight waves of assessment and analyzed within a latent growth modeling framework. Results revealed that the slopes of positive substance use expectancies among never-users of each respective substance predicted increased odds of onset (Alcohol: ORB = 7.73, p < .001; Tobacco: ORB = 5.58, p < .001; Marijuana: ORB = 2.49, p = .001). Only the slope of negative marijuana expectancies predicted increased odds of onset (Marijuana: ORB = .44, p = .04). Baseline level of positive and negative substance use outcome expectancies were also generally found to be associated with onset. For three common drugs used by adolescents, change in substance use expectancies during the first two years of high school may be a marker of risk propensity for substance use onset. Change in expectancies may be an important target in substance use prevention, with research indicating that expectancy challenge and life skills interventions being potentially efficacious. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407028 TI - Decomposing the causes of the socioeconomic status-health gradient with biometrical modeling. AB - The consistent relationship between socioeconomic status (SES) and health has been widely covered in the media and scientific journals, which typically argue that physical-health inequalities are caused by material disadvantage directly or indirectly (e.g., chronic environmental-stress, health care resources, etc.). Such explanations do not explain the finely stratified health differences across the entire range of SES. Recent theories have helped address such limitations, but implicate multiple different explanatory pathways. For example, differential epidemiology articles have argued that individual differences are the "fundamental cause" of the gradient (Gottfredson, 2004). Alternatively, variants of allostatic load theory (McEwen & Stellar, 1993), such as the Risky Families model (Repetti, Taylor, & Seeman, 2002) implicate the early home-environment. These theory-driven pathways align with interpretations associated with biometrical models; yet, little research has applied biometrical modeling to understanding the sources of the gradient. Our study presents several innovations and new research findings. First, we use kinship information from a large national family dataset, the NLSY79, whose respondents are approximately representative of United States adolescents in 1979. Second, we present the first biometrical analysis of the relationships between SES and health that uses an overall SES measure. Third, we separate physical and mental health, using excellent measurement of each construct. Fourth, we use a bivariate biometrical model to study overlap between health and SES. Results suggest divergent findings for physical and mental health. Biometrical models indicate a primarily genetic etiology for the link between SES and physical health, and a primarily environmental etiology for the link between SES and mental health. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407029 TI - What's the harm? Internalized prejudice and cultural betrayal trauma in ethnic minorities. AB - The differential contexts that ethnic minorities face as a result of lower societal status impact outcomes of trauma. Cultural betrayal trauma theory (CBTT) is a contextualized framework that was created to examine trauma in minority populations. According to CBTT, due to societal inequality, within-group trauma in minority populations is a cultural betrayal that contributes to outcomes. In addition to looking at typically studied abuse outcomes (e.g., posttraumatic stress disorder), CBTT also predicts cultural outcomes, such as internalized prejudice, changes in ethnic identity, and (intra)cultural pressure (e.g., silencing victims of intraracial trauma to protect the minority ingroup from discriminatory individuals and systems of the dominant culture). No prior studies have examined cultural outcomes in CBTT. It was hypothesized that intraracial trauma (aka, cultural betrayal trauma) would be associated with cultural outcomes in a sample of ethnic minority college students. Participants (N = 296; 60.5% female; age: M = 20.12, SD = 2.81) were ethnic minority college students (35.0% Asian, 24.7% Hispanic-Latino American, 14.2% Other, 13.2% Black-African American, 5.7% Native Hawaiian or Other Pacific Islander, 3.4% American Indian-Alaska Native, and 3.4% Middle Eastern) attending a predominantly White university. Participants completed self-report questionnaires assessing trauma and outcomes online. Separate hierarchical linear regression analyses suggested that when controlling for age, gender, ethnicity, and interracial trauma, intraracial trauma predicted internalized prejudice, (intra)cultural pressure, and changes in identification with ethnic identity. These findings have implications for cultural competency in clinical interventions for minority victims of trauma. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407030 TI - Effects of virtual walking on spinal cord injury-related neuropathic pain: A randomized, controlled trial. AB - PURPOSE: This study is an examination of the efficacy of a virtual walking protocol to treat spinal cord injury (SCI)-related pain. METHOD: A total of 59 individuals with SCI and neuropathic pain (NP) were randomly assigned to receive 20 min of virtual walking, the treatment condition, or virtual wheeling, the control condition. Although having NP was a requirement to participate in the study, participants also underwent pain classification of up to 3 worst pain sites to also examine the effects of virtual walking on nonneuropathic pain. Pain outcomes included changes in pain severity across all pain types, NP unpleasantness, and severity of various sensory qualities of NP. DESIGN: This was a randomized, controlled, single-blinded trial. RESULTS: There was no significant difference in change in pain between groups, though there was a significant pre- to posttreatment reduction across all pain types in the virtual walking condition, but not the control condition. Specific to NP, there was a significant reduction in pain unpleasantness, but not neuropathic pain intensity. NP experienced as "cold," "deep," and with increased skin sensitivity were significantly reduced following virtual walking compared with the control condition. CONCLUSION: Results from this trial suggest that virtual walking treatment may benefit certain aspects of NP, such as associated unpleasantness, as well as certain sensory qualities of that pain. Efficacy of this treatment modality to reduce overall pain severity remains unclear, and may be modulated by other injury, individual, or personality characteristics. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407031 TI - The effects of integrated single- and dual-task training on automaticity and attention allocation in Parkinson's disease: A secondary analysis from a randomized trial. AB - OBJECTIVE: People with Parkinson's disease (PwPD) demonstrate impaired automaticity of motor and cognitive tasks, with unclear prioritization strategies when exposed to dual-task situations. However, no randomized trials have investigated the effects of training on automaticity and prioritization strategies in this population. The purpose of this study was to investigate the effects of training on the automaticity of gait and cognitive processing in PwPD and the allocation of attention between gait and a cognitive task. METHOD: One hundred PwPD were randomized to 10 weeks of challenging gait and balance training (including single and dual-task conditions) or to a control group (care as usual). Outcome measure was the absolute dual-task interference (difference between single- and dual-tasks) for gait and cognitive parameters. Differences between baseline and follow-up were compared between the groups. The Mann-Whitney U test was used to assess potential differences. Significance level was set to p = .05. The direction and magnitude of nonparametric effect sizes were used to investigate attention allocation. RESULTS: No significant between-groups differences were found regarding any gait parameter. The training group significantly improved the dual-task interference of the cognitive task. The direction of between-groups effect sizes indicated that the training group primarily allocated attention to the cognitive task, whereas the control group appeared to prioritize gait. CONCLUSIONS: The results indicate that challenging training can improve automaticity of cognitive processing during walking. This may have a beneficiary effect on the ability to ambulate safely in the community, thereby improving independence and the quality of life in this population. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407032 TI - Social learning of goal-directed actions in dogs (Canis familiaris): Imitation or emulation? AB - A goal-directed action is composed of two main elements on which the observer may focus its attention: the movement performed (i.e., the action) and the outcome (i.e., the goal). In a social learning situation, consequently, the observer may imitate the action of the model or emulate the result of its action. In humans and primates, the tendency to selectively engage in any of these two processes is considered to be dependent upon the availability and saliency of information about the goal, implying the capacity to recognize the goals of others' actions. Dogs are skillful in learning socially from humans, and, when trained with the Do as I Do method, they imitate human actions. Here, we tested trained dogs for engaging in imitation or emulation based on information about the goal. We found that dogs observing the demonstration of an object-related action in the absence of a clear goal tended to solve the task by matching the body movement of the human demonstrator. In contrast, when they could observe the exact same movement, but the goal was apparent, they attempted to solve the task by their own means, that is, by emulation, instead of imitating the demonstrated action. These results provide experimental evidence for dogs being able to recognize the goals of others and adjust their behavior accordingly, relying flexibly on imitation or emulation. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407033 TI - Does limited working memory capacity underlie age differences in associative long term memory? AB - Past research has consistently shown that episodic memory (EM) declines with adult age and, according to the associative-deficit hypothesis, the locus of this decline is binding difficulties. We investigated the importance of establishing and maintaining bindings in working memory (WM) for age differences in associative EM. In Experiment 1 we adapted the presentation rate of word pairs for each participant to achieve 67% correct responses during a WM test of bindings in young and older adults. EM for the pairs was tested thereafter in the same way as WM. Equating WM for bindings between young and older adults reduced, but did not fully eliminate, the associative EM deficit in the older adults. In Experiment 2 we varied the set size of word pairs in a WM test, retaining the mean presentation rates for each age group from Experiment 1. If a WM deficit at encoding causes the EM deficit in older adults, both WM and EM performance should decrease with increasing set size. Against this prediction, increasing set size did not affect EM. We conclude that reduced WM capacity does not cause the EM deficit of older adults. Rather, both WM and EM deficits are reflections of a common cause, which can be compensated for by longer encoding time. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407034 TI - Age-related differences in prefrontal-hippocampal connectivity are associated with reduced spatial context memory. AB - Altered functional connectivity between dorsolateral prefrontal cortex (DLPFC), posterior hippocampus (HC) and other brain regions with advanced age may contribute to age-related differences in episodic memory. In the current fMRI study of spatial context memory, we used seed connectivity analysis to test for age-related differences in the correlations between activity in DLPFC and HC seeds, and the rest of the brain, in an adult life span sample. In young adults, we found that connectivity between right DLPFC and other prefrontal cortex regions, parietal cortex, precuneus, and ventral visual cortices during encoding was positively related to performance. Positive seed connectivity among these regions, and negative connectivity with posterior HC at retrieval was also positively correlated with retrieval accuracy in young adults. In older adults, activity in right DLPFC was positively correlated with activity in this same set of brain regions, and with posterior HC during encoding and retrieval. Interestingly, this pattern of seed connectivity in older adults was negatively correlated with retrieval accuracy. Thus, age-related differences in context memory may be related to altered frontal-parietal and visual cortical interactions with posterior HC. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407036 TI - Partners' depressive symptoms moderate the effects of expressive suppression. AB - Suppressing emotional expressions can hide one's needs from relationship partners and thus prevent partners from providing support. Nevertheless, suppressing expressions may help people maintain more favorable evaluations of partners who are ultimately unsupportive because people may attribute a lack of support to partners being unaware of their needs. Thus, given that depressive symptoms reduce provisions of support, people with partners experiencing depressive symptoms may remain more satisfied to the extent that they previously suppressed emotional expressions. We tested these ideas in 1 experiment, 1 cross-sectional study, and 1 longitudinal study. In Study 1, participants imagined either expressing or suppressing their emotions, imagined their partner was either supportive or unsupportive to their needs, and reported their perceptions of their partner. In Studies 2 and 3, newlywed couples reported their depressive symptoms, their marital satisfaction, and the extent to which they suppressed their emotional expressions cross-sectionally (Study 2) or every year for 2 years (Study 3). Results revealed that people with unsupportive partners or partners high in depressive symptoms made more benevolent attributions for their partners' unsupportive behavior and remained more satisfied with their partners to the extent that they suppressed their emotional expressions; however, people with supportive partners or partners low in depressive symptoms became more dissatisfied with their partners to the extent that they suppressed their emotional expressions. These results highlight the benefits of dyadic theoretical perspectives by revealing that qualities of the partner moderate the effects of expressive suppression. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407035 TI - Effectiveness of a brief adjunctive yoga intervention for short-term mood and psychiatric symptom change during partial hospitalization. AB - OBJECTIVE: Evidence concerning the effectiveness of yoga in partial hospital programs is limited. Yet, partial hospitals provide treatment at a critical juncture by bridging inpatient and outpatient care. The present study tested the effectiveness of a single-session group yoga intervention for short-term mood and psychiatric symptom change in participants attending a 1- to 2-week partial hospital program. METHOD: Participants included 104 partial hospital patients who participated in the single-session yoga intervention and completed a measure of positive/negative affect before and after the group. Participants, as well as partial hospital patients who did not attend the yoga intervention (n = 438), completed measures of depression and anxiety symptoms at admission and discharge from the program. At discharge, they also rated their perceived improvement and the overall quality of the care they received. RESULTS: Participants who attended the yoga intervention experienced significant improvements in positive and negative affect during the group. They did not show greater improvements in symptoms of anxiety or depression over the course of treatment compared to individuals who did not attend the group. Yoga intervention participants nonetheless gave higher ratings to the quality of the care they received. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Findings demonstrated that attending a single yoga session during partial hospitalization was associated with short-term mood benefits, and with enhanced overall perceptions of treatment. Further research is needed to determine the conditions under which participation in yoga during partial hospitalization could contribute to symptom change in this context. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407037 TI - Maternal perceptions of paternal investment are associated with relationship satisfaction and breastfeeding duration in humans. AB - This study examined potential pathways in the associations between breastfeeding and mothers' relationship satisfaction, including her satisfaction with father involvement (FI) and parity, among mothers not working outside the home at 6 months. Mothers (n = 222) completed questionnaires at 4 time-points, 3 to 24 months postpartum as part of a longitudinal cohort study. In this study, we were interested in two main outcome variables: mothers' relationship satisfaction with their partner (RS) and continuation of breastfeeding after 3 months. Our first analysis revealed that breastfeeding at 3 months postpartum predicted decreased RS at 6 months postpartum, which was mediated by mothers' dissatisfaction with FI in infant caretaking at 6 months postpartum. These associations depended on mothers' parity: Multiparous breastfeeding mothers were the most dissatisfied with FI. Second, mothers' satisfaction with FI at 6 months also predicted increased RS at 24 months through increased RS at 12 months, but not through FI at 18 months. Third, we found that high dissatisfaction with FI at 6 months was the only significant predictor for the discontinuation of breastfeeding from 3 to 6 months postpartum. Our results suggest that multiparous breastfeeding mothers might be more dissatisfied with FI in caregiving than nonbreastfeeding mothers and primiparous breastfeeding mothers. Furthermore, mothers' satisfaction with FI seems a potent predictor of overall RS up to 24 months postpartum and the continuation of breastfeeding from 3 to 6 months postpartum, regardless of parity. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407038 TI - Union stability among mothers and stepfathers: Contributions of stepfathers and biological fathers. AB - A substantial proportion of unmarried mothers with young children live with new partners (stepfathers), and the stability of these unions is important to outcomes for mothers and children. This study examined effects of both step- and biological fathers' co-parenting, parenting, and financial contributions on union stability among mothers and stepfathers. Data were from the Fragile Families and Child Wellbeing Study (N = 370), and the sample included mothers with 3-year-old children who were mostly unmarried and low-income. Results from discrete-time event history analysis indicated that mothers' residential unions with stepfathers were more stable when stepfathers were working and less stable when biological fathers paid formal child support. Results from interactions in the model showed that differences in the likelihood of dissolution between working and nonworking stepfathers were greater when stepfathers had more supportive co parenting relationships with mothers and when stepfathers engaged in activities with the child more often. Findings suggest that economic contributions of both biological and stepfathers affect the stability of mother-stepfather residential unions, and stepfathers' co-parenting and parenting contributions may provide additional protection against union dissolution, particularly when stepfathers are working. Prevention and intervention programs could benefit these fragile families by attending to economic contributions of both fathers and stepfathers and helping stepfathers develop roles as co-parents and parents in this context. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407039 TI - Competing indirect effects in a comparative psychotherapy trial for generalized anxiety disorder. AB - In a randomized trial for generalized anxiety disorder, cognitive-behavioral therapy (CBT) and CBT integrated with motivational interviewing (MI) promoted comparable worry reduction at posttreatment, whereas MI-CBT outperformed CBT over 12-month follow-up (Westra, Constantino, & Antony, 2016). Secondary analyses revealed competing mediators of the long-term treatment effect: MI-CBT related to lower patient resistance to the treatment, which promoted lower follow-up worry, whereas CBT related to greater increases in patient friendly submissiveness (FS), or compliance, which also promoted lower follow-up worry (that suppressed an even greater long-term advantage of MI-CBT). In this study, we tested these competing, though theoretically consistent, variables as mediators of the nonsignificant treatment effect on posttreatment worry, as there could also be treatment specific means to arriving to these comparable ends. Eighty-five patients received 15 sessions of MI-CBT or CBT. Therapists rated patient FS through treatment, observers rated resistance at midtreatment, and patients rated worry at posttreatment. Bootstrap analyses indicated that MI-CBT patients exhibited less resistance, which promoted lower posttreatment worry, whereas CBT patients had greater increases in FS, which also promoted lower worry. CBT and MI-CBT achieved comparable posttreatment outcomes through separate indirect paths that each conferred an advantage for one treatment over the other (and had canceled out a direct treatment effect immediately after therapy). The composite trial findings have significance for understanding different pathways to personal change in both the short- and long terms, and for the importance of testing indirect effects both when direct treatment effects do and do not emerge. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407040 TI - The vicissitudes of conducting psychodynamic research in a naturalistic setting. AB - This article reports on our experiences conducting naturalistic research as clinician-researchers in a training setting within a public safety-net hospital. The naturalistic, practice-based context has presented various challenges to the research process, including the following: supporting research with limited finances, establishing continuity of research personnel, designating time for research within an intensive clinical training program, responding to difficulties obtaining data, seeking consultation for advanced data analysis, organizing the writing process, and determining order of authorship. In addition, in mixed-methods research of psychodynamic psychotherapy, each of these challenges has interacted with the inherent challenges of qualitative research. We describe the systemic and project-specific challenges of conducting such research, as well as practical strategies that we have used to overcome them, with the aim of helping other clinician-researchers facilitate naturalistic research. The challenges reflect the problem of being "stuck" in the gap that this special section of Psychotherapy is examining, although the strategies serve as optimistic reminders that this type of work is indeed possible. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407041 TI - Say it as it is: Consequences of voice directness, voice politeness, and voicer credibility on voice endorsement. AB - To gain endorsement from their managers, should employees be direct with explicit change suggestions, or should they be indirect with questions and hints? We draw on psychological threat and communication clarity theories to offer competing hypotheses with respect to the association between voice directness and managerial endorsement. We then further draw from social judgment research to theorize whether the relationship between voice directness and managerial endorsement might be modified by voicer politeness and voicer credibility. The results of an experimental study and two field studies show that being direct about change-oriented suggestions is associated with more frequent managerial endorsement when voicers are credible (Studies 1 and 2 in the United States) or polite (Study 3 in China). We discuss implications of these findings, limitations, and directions for future research. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407042 TI - Job crafting revisited: Implications of an extended framework for active changes at work. AB - Employees often self-initiate changes to their jobs, a process referred to as job crafting, yet we know little about why and how they initiate such changes. In this paper, we introduce and test an extended framework for job crafting, incorporating individuals' needs and regulatory focus. Our theoretical model posits that individual needs provide employees with the motivation to engage in distinct job-crafting strategies-task, relationship, skill, and cognitive crafting-and that work-related regulatory focus will be associated with promotion or prevention-oriented forms of these strategies. Across three independent studies and using distinct research designs (Study 1: N = 421 employees; Study 2: N = 144, using experience sampling data; Study 3: N = 388, using a lagged study design), our findings suggest that distinct job-crafting strategies, and their promotion- and prevention-oriented forms, can be meaningfully distinguished and that individual needs (for autonomy, competence, and relatedness) at work differentially shape job-crafting strategies. We also find that promotion- and prevention-oriented forms of job-crafting vary in their relationship with innovative work performance, and we find partial support for work-related regulatory focus strengthening the indirect effect of individual needs on innovative work performance via corresponding forms of job crafting. Our findings suggest that both individual needs and work-related regulatory focus are related to why and how employees will choose to craft their jobs, as well as to the consequences job crafting will have in organizations. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407043 TI - It's about time - A longitudinal adaptation model of high-performance work teams. AB - Work teams have become an essential part of organizations, but how implementation of work teams influences performance outcomes over time still remains unclear. This study aims to explore this issue by examining implementation of high performance work teams (HPWTs) in a manufacturing context. We draw upon team development and adaptation literature and organizational change literature to propose a 2-phase adaptation model whereby the growth rates of performance outcomes initially decline after implementation of HPWTs and later increase and become higher than the rates before implementation. Over a 4-year period, a field quasi-experiment was conducted in 20 plants producing automation and control equipment for a Fortune 500 firm and collected monthly data regarding plant-level labor productivity and inventory turnover before and after implementation of HPWTs. Results based on piecewise growth modeling indicate that the growth rate of labor productivity declines immediately after conversion to HPWTs and recovers to the original level but not higher, whereas the growth rate of inventory turnover does not decline significantly but shows a long-term improvement. We discuss the effects of HPWT implementation on the 2 dependent variables and provide implications for practices and future research. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407044 TI - Sleepy, sluggish, worried, or down? The distinction between self-reported sluggish cognitive tempo, daytime sleepiness, and internalizing symptoms in youth with attention-deficit/hyperactivity disorder. AB - Sluggish cognitive tempo (SCT) consists of symptoms of slowness, sluggishness, daydreaming, and low motivation. SCT has been linked to attention deficit/hyperactivity disorder (ADHD), internalizing symptoms, and daytime sleepiness. Although there is clear evidence that SCT and ADHD symptoms are distinct constructs, the distinction between SCT, anxiety/depression, and daytime sleepiness is less clear. Prior research has largely relied upon parent-report to evaluate potential overlap between SCT, sleep, and anxiety/depression, despite best practice suggesting that self-report should be used to assess internalizing symptoms. The present study used adolescent self-report to evaluate whether SCT was distinct from daytime sleepiness, anxiety, and depression. Participants were 285 middle school students comprehensively diagnosed with ADHD. Ten confirmatory factor analyses were conducted: four 1-factor models, three 2-factor models, one 3-factor model, one 4-factor model, and a higher order model. Results showed that SCT was indeed distinct from all tested constructs, with the four-factor model including self-report of SCT, anxiety, depression, and daytime sleepiness meeting adequate model fit criteria. All models including SCT as its own factor had improved model fit over models with SCT in a combined factor with another construct. Implications for the assessment and treatment of SCT are discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407045 TI - Peer specialists in suicide prevention: Possibilities and pitfalls. AB - The emergence of peer specialists with histories of suicidality in mental health care services is a recent but scarcely researched societal phenomenon. The current study aimed to explore how peer specialists who have experienced suicidality (either attempted suicide or suicidal ideation) use their experiences to contribute to suicide prevention in mental health care services. Qualitative interviews with 20 peer specialists who have personally dealt with suicidality in their past were conducted. Interviewees perceived their work to have unique value in terms of their approach to making contact with suicidal care consumers on an emotional level, which was perceived to lead to less reluctance on the part of suicidal care consumers to talk about suicidality, as well as affect feelings of being acknowledged and heard. However, the lack of professional distance was perceived to carry several risks, including burdening clients with the peer specialists' own suicidal experiences, perceived reluctance of coworkers to let peer specialists work with suicidal clients, and the burden of working with suicidal clients for the peer specialists. Specific conditions that were perceived to be needed in order to work with suicidal clients consisted of personal distance to own process of recovery and suicidality, establishing boundaries with the team or colleagues for the peer specialists' work concerning suicide risk assessment, safety, privacy, and sharing responsibility. Further discussion between mental health care clinicians and peer specialists regarding the role of the peer specialist in suicide prevention is needed to further clarify and optimize their role. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407046 TI - Perceived helpfulness of peer-delivered trauma specific treatment: A randomized controlled trial. AB - Peer providers have been associated with positive outcomes in behavioral health, but little is known about the perceived helpfulness of their services. We used a mixed-methods randomized controlled trial to compare the perceived helpfulness of seeking safety (SS) led by peer providers compared to its delivery by licensed behavioral health clinicians (including both a licensed alcohol and drug abuse counselor and licensed clinical mental health counselor). Participants (N = 278) rated the helpfulness of 12 SS topics at the end of every session. A subset (n = 245) of participants also rated the helpfulness of SS overall and its treatment components; 3 and 6 months following their first SS group. We also collected qualitative data to inform our understanding of the ways perceived helpfulness varied among participants in peer-led (PL) and clinician-led (CL) groups. Ratings of overall and topic-specific helpfulness were high among both groups, and while ratings were slightly higher among participants in PL groups, the difference was not significant. Participants in PL-SS rated certain treatment components significantly more helpful compared to participants in CL-SS, including the focus on learning coping skills (81.6% PL vs. 64.9% CL, p = .020) and safety as a priority of treatment (81.6% PL vs. 61.5% CL, p = .006). Because of the homogeneity of helpfulness ratings, the relationship between perceived helpfulness and treatment retention and outcomes could not be examined. Future research on this association is warranted. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407047 TI - State-wide university implementation of an online platform for eating disorders screening and intervention. AB - The Internet-based Healthy Body Image (HBI) Program platform uses online screening to identify individuals at low risk for, high risk for, or with an eating disorder (ED) and then directs users to tailored, evidence-based online/mobile interventions or referral to in-person care to address individuals' risk/clinical status. We examined findings from the first state-wide deployment of HBI over the course of 3 years in Missouri public universities, sponsored by the Missouri Eating Disorders Council and the Missouri Mental Health Foundation. First, the screen was completed 2,454 times, with an average of 2.5% of the undergraduate student body on each campus taking the screen. Second, ED risk level in the participating students was high-over 56% of students screened were identified as being at high risk for ED onset or having a clinical/subclinical ED. Third, uptake for the HBI online/mobile interventions ranged from 44-51%, with higher rates of uptake in the high-risk compared with low-risk group. Fourth, results showed that, for students with a clinical/subclinical ED, use of the clinical mobile application Student Bodies-Eating Disorders intervention resulted in significantly decreased restrictive eating and binge eating. Neither vomiting nor diet pill/laxative use was found to decrease, but reports of these behaviors were very low. This is the first deployment of a comprehensive online platform for screening and delivering tailored interventions to a population of individuals with varying ED risk and symptom profiles in an organized care setting. Implications for future research and sustaining and broadening the reach of HBI are discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407049 TI - Mobile app interventions for military and veteran families: Before, during, and after deployment. AB - Deployment to foreign wars leads to many challenges for military families. Unique risk factors for behavioral and psychological problems have been identified before, during, and after the deployment of a loved one. This brief report outlines these challenges and risk factors at each stage of the deployment process and describes mobile applications that may be beneficial in addressing them. The mobile applications, Babies on the Homefront, The Big Moving Adventure, and Sandboxx, were identified as relevant for addressing the parenting, communication, and relocation difficulties experienced by military families before and during the deployment process. Parenting 2GO, PTSD Coach, and PTSD Family Coach were identified as being relevant for addressing the difficulties with the reintegration of service members into the family unit. The potential for the clinical use of these apps are considered and discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407048 TI - Cultural considerations in using mobile health in clinical care with military and veteran populations. AB - Traditional cultural models typically address factors like ethnicity, language, and race as important concerns pertaining to treatment efficacy, but over the years, professionals have expanded the focus to include gender, sexual orientation, age, socioeconomic status, and other aspects of identity and experience, including military cultural issues. As the integration of mobile health increases in clinical care, another important cultural factor that can impact care is technological culture. Differences in perception of technological competence by patient and provider can impact the provider's ability to effectively connect with the patient and fully leverage tools to support evidence based treatment. In this article, we describe provider- and patient-level cultural issues in the provision of clinical care in the military and veteran populations and how the development of cultural competency in technological culture can improve patient care. We apply traditional models in the development of cultural competency to technological culture as well as provide recommendations for providers in Department of Defense and Department of Veterans Affairs health care systems that may be relevant to outside clinicians as well. Key factors are addressed when considering the cultural issues involved in the clinical integration of mobile health in the military and veteran populations. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407050 TI - Peer support in an outpatient program for veterans with posttraumatic stress disorder: Translating participant experiences into a recovery model. AB - Veterans returning from recent conflicts present with increased rates of posttraumatic stress disorder (PTSD), and veterans from prior service eras continue to seek trauma-based services. Peer support for veterans with PTSD has the potential to resolve ongoing challenges in access and engagement in mental health care. Assessing the value of peer support services requires a thorough understanding of the expected role and the empirical mechanisms of peer support participation in PTSD recovery. To better understand these mechanisms, this study interviewed 29 veteran participants from an established peer support program (PSP), located in the Central Valley of the Veterans Affairs (VA) Palo Alto Health Care System (VAPAHCS) in Northern California. A domain analysis of narrative transcripts generated 34 codes through a grounded theory method. Codes were organized into the following thematic categories: the perceived role of the PSP, supportive experiences of the PSP, global gains from the PSP, and limitations to PSP and further mental health engagement. These results were synthesized into a theoretical model that identifies improved functioning and reduced distress as the expected outcomes of PSP-mediated recovery and illustrates the continuum from in-group experiences to these outcomes. Our results suggest that PSP-mediated recovery is defined as acceptance of PTSD into daily life and identity, rather than resolution of symptoms. This conceptualization has implications for peer support provider training, PSP integration into health care settings, and future outcome analyses on the effectiveness of PSPs. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407051 TI - Getting closer? Differences remain in neuropsychological assessments converted to mobile devices. AB - Dementia is an increasing concern in today's aging society. Despite the limited evidence for dementia screening at a population level, a push to improve diagnosis and the expansion of technology usage within health-care settings has led to the rising popularity of computerized neuropsychological assessment devices (CNADs). Some CNADs are completely new tests, others are direct translations of traditional pen-and-paper cognitive functioning tests. This study is an investigation of the equivalence between two existing pen-and-paper tests and their translated versions on mobile platforms. In this small-scale study (N = 42), the scores on two multidomain assessments-Saint Louis University Mental State Examination (SLUMS; Feliciano et al., 2013) and Cambridge University Pen to Digital Equivalence assessment (CUPDE; Ruggeri, Maguire, Andrews, Martin, & Menon, 2016)-were significantly different, even with multiple design iterations, when participants were matched by age and score on an independent screening tool, the Self-Administered Gerocognitive Exam (SAGE), t(13) = 2.55, p < .05, d = .680. There was no relationship between the Color Trails Task (CTT; D'Elia, Satz, Uchiyama, & White, 1996; Maj et al., 1993) and its mobile translation, the electronic CTT (eCTT), rho = -.144, n = 21, p = .533. Though no difference was identified between the eCTT and the modified pen-and-paper CTT (pCTT) scores, t(13) = .092, p = .928, there was no relationship between eCTT and pCTT, r = .139, n = 14, p = .635. Outcome scores of mobile-based assessments appear to remain distinct from the established norms of traditional assessments, adding to existing concerns associated with population-screening programs via mobile applications. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407052 TI - Raw-score equivalence of computer-assisted and paper versions of WISC-V. AB - The adaptation of individually administered psychological tests from paper to app based administration formats can present unique threats to the construct and raw score equivalence of the paper and digital formats. We discuss these potential threats and describe a study evaluating the equivalence of paper and digital versions of the Wechsler Intelligence Scale for Children, fifth edition (WISC-V), which has been adapted to an app-based testing platform called Q-interactive. The present study (N = 350) used an equivalent-groups design to assess the raw-score equivalence of 18 WISC-V subtests that were designed with the intent of minimizing format effect. Effect sizes in standard deviation units were small, ranging from -0.20 to 0.20 (mean absolute value = 0.09), and format effects were unrelated to ability level, age, sex, or parent education. These results suggest that when tests are designed or adapted with digital-paper equivalence as a goal, digital-paper raw-score equivalence can be achieved across a variety of construct domains. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407053 TI - Perceived barriers and facilitators to implementation of peer support in Veterans Health Administration Primary Care-Mental Health Integration settings. AB - Peer support is increasingly recognized as consistent with the goals of integrated primary care and is being implemented in primary care settings as a patient-centered approach that increases patient activation and access to care. Within the Veterans Health Administration (VHA), peer support specialists (PSSs) have traditionally worked in specialty mental health settings and only recently started working in Primary Care-Mental Health Integration (PC-MHI) settings. Prior research has identified implementation challenges, such as role confusion, when integrating peer support into new settings. In this qualitative descriptive study, we conducted semistructured interviews on perceived barriers and facilitators to implementing peer support in PC-MHI with 25 key stakeholders (7 PSSs, 6 PSS supervisors, 6 PC-MHI providers, and 6 primary care providers). We used conventional content analysis to code responses within four a priori implementation categories: barriers, initial facilitators, long-term facilitators, and leadership support. Perceived barriers included poor program functioning, inadequate administrative support, role confusion, and negative stakeholder attitudes. Key perceived facilitators of initializing and maintaining peer support were similar; administrative support was emphasized followed by program functioning and team cohesion. Stakeholder buy-in and access/visibility were perceived to facilitate initial implementation, whereas evidence of success was believed to facilitate maintenance. Stakeholder buy-in and administrative support were considered key elements of leadership support. Results were consistent with prior research from specialty mental health settings, but identified unique considerations for PC-MHI settings, particularly clarifying the PSS role based on local PC-MHI needs, obtaining buy-in, and facilitating integration of PSSs into the primary care team. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407054 TI - Parent-therapist alliance and technology use in behavioral parent training: A brief report. AB - Researchers propose that technology has the capacity to promote therapeutic alliance; however, clinicians worry the opposite is true. Behavioral parent training (BPT), an approach that is reliant on the parent as the mechanism of change, is the standard of care for early-onset (3-8 years old) behavior disorders. Importantly, behavior disorders are among the most common reasons parents seek mental health services for their children; therefore, BPT affords an ideal context within which to better understand the potential interrelationship between technology and therapeutic alliance. To this end, this study examined the link between smartphone-enhancements to 1 BPT program and parent-therapist alliance in 9 families of children with early-onset behavior disorders. Findings suggest relative differences in patterns of alliance and use of the smartphone enhancements within the technology-enhanced group, patterns that have implications for better understanding the impact of technology on the therapeutic process, the deployment of existing technology-enhanced services, and the development of future technology-enhanced services. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407055 TI - Behavioral and cognitive intervention strategies delivered via coached apps for depression: Pilot trial. AB - Depression is common in primary care settings, but barriers prevent many primary care patients from initiating treatment. Smartphone apps stand as a possible means to overcome such barriers. However, there is limited evidence to understand the use and efficacy of these apps. The purpose of the current study was to pilot an evaluation of the usage and efficacy of apps for depression based upon behavioral or cognitive intervention skills, compared to a wait-list control. Thirty adults with depression were randomized to the use of either a behavioral app (Boost Me) or a cognitive app (Thought Challenger) or to a wait-list control. Boost Me and Thought Challenger participants received 6 weeks of the respective intervention along with weekly coaching sessions, with a 4-week follow-up period; wait-list control participants received no interventions for 10 weeks. A repeated measures analysis of variance was conducted to examine depression over time and across treatment groups; t tests compared app usage across groups. Depression scores changed significantly over time (p < .001), with group differences occurring between Thought Challenger and wait-list control participants (p = .03). Boost Me was used significantly more than was Thought Challenger (p = .02); however, there was no evidence to suggest correlations between usage and changes in depression (ps > .05). The present study provides initial support that intervention strategies for depression delivered via apps with human support can impact symptoms and may promote continued use over 6 weeks. This pilot also demonstrates the feasibility of future research regarding the delivery of behavioral and cognitive intervention strategies via apps. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407056 TI - PTSD coach mobile application with brief telephone support: A pilot study. AB - The number of health care mobile applications (MAs) has increased drastically in recent years, but research on efficacy and approaches to provide MA intervention is lacking. The PTSD Coach was designed to help individuals with posttraumatic stress disorder (PTSD) symptoms to understand and manage symptoms. Use of MA tends to drop off quickly; this pilot study tested the use of the PTSD Coach with brief telephone support by paraprofessionals. A total of 29 participants with elevated PTSD symptoms recruited from Veterans Affairs primary care clinics completed baseline and 4-month follow-up surveys including the PTSD Checklist, Patient Health Questionnaire for depressive symptoms, and Quality of Life Enjoyment and Satisfaction Questionnaire. Participants received PTSD Coach MA intervention plus paraprofessional brief telephone support reported the phone support was helpful and greater than 70% of participants maintained use of the MA throughout the 3-month intervention period. Results indicated that participants showed significant improvement on PTSD reexperiencing symptoms, depressive symptoms, and quality of life after intervention. The PTSD Coach MA plus brief telephone support is a promising approach for primary care patients managing psychiatric symptoms. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407057 TI - Smartphone apps for psychological health: A brief state of the science review. AB - In this brief state of the science review, we provide a synopsis of the literature on psychological health mobile applications (apps) and discuss the impact of mobile technology on psychological health practice. We describe the variety of psychological health app uses from self-management, skills training, and supportive care to symptom tracking and data collection; and we summarize the current evidence for the efficacy and effectiveness of psychological health apps. Finally, we offer some pragmatic suggestions for evaluating psychological health apps for quality and clinical utility. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407058 TI - Peer specialists: Exploring the influence of program structure on their emerging role. AB - Although peer specialists play an increasing role in mental health service delivery, little is known about the best program structures for maximizing effective service delivery. This study reports on qualitative data from a larger study on peer specialists working with veterans in a Veterans Affairs homelessness program who were dually diagnosed with substance abuse and mental health concerns. Peer specialists were trained to deliver a recovery support program that is carried out weekly over 9 months and includes 20 structured sessions using a workbook and 20 unstructured, individually planned sessions. A sample of 20 veterans who were in the program were interviewed, along with 8 case managers and 3 peer specialists involved with the program. Interview transcripts were coded for 3 elements of program structure: time, content, and delivery. Results show that the program structure allowed flexibility for individual needs and that the workbook sessions were useful. Veterans ascribed value to the peer specialist delivering the content, compared to working alone on the material. Deliberate use of unstructured time with the peer specialist was seen as reducing isolation, increasing community integration, and encouraging recovery activities. The weekly, dependable nature of the program was seen as highly positive, whereas the 9-month duration was seen as too short. All groups interviewed expressed satisfaction with the program, although the case managers reported some reservations related to supervision and boundaries. Results suggest that, compared to completely structured or unstructured approaches that are common for peer specialist services, a middle level of structure for peer specialist programs could be a useful alternative. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407060 TI - Customizing a clinical app to reduce hazardous drinking among veterans in primary care. AB - Within the Veterans Health Administration (VHA), 15-30% of patients seen in primary care are identified as hazardous drinkers, yet the vast majority of these patients receive no intervention. Time constraints on providers and patient-level barriers to in-person treatment contribute to this problem. The scientific literature provides a compelling case that mobile-based interventions can reduce hazardous drinking and underscores the role of peer support in behavioral change. Here, we describe the benefits of using a clinical app-Step Away-to treat hazardous drinking among VHA primary care patients as well as an approach to customizing the app to maximize its engagement and effectiveness with this population. We highlight the value of integrating use of Step Away with telephone support from a trained VHA peer support specialist. This type of integrated approach may provide the key therapeutic components necessary to generate an effective and easily implemented alcohol use intervention that can be made available to VHA primary care patients who screen positive for hazardous drinking but are unwilling or unable to attend in-person treatment. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407059 TI - Real-time demonstration of a mHealth app designed to reduce college students hazardous drinking. AB - Heavy alcohol use is a serious health issue in the United States with consequences such as illness, injury, and death. College students are among the most vulnerable to problems associated with risky drinking. This demographic is known as the Net Generation because members have grown up with digital technologies such as smartphones and apps. Thus, mobile health (mHealth) applications, successful in the delivery of health information and interventions to tech-savvy individuals, are a promising means of reaching them. To that end, we developed a smartphone application (SmarTrek) that targets college students and aims to reduce risky alcohol use. SmarTrek features are easy to use and have interactive components including text messages that incorporate motivational interviewing and ecological momentary interventions. We conducted iterative theater testing, field testing, and focus groups to evaluate the acceptability of SmarTrek with college students. We identified salient issues that might arise from SmarTrek use and modified the app based on feedback from participants. Participants were assigned to 2 groups (Group 1 [n = 4] and Group 2 [n = 6]). At baseline, participants completed 2 standardized surveys. Following their field testing, each group of participants was then invited to a focus group session of the app in which they provided feedback. The majority of participants (90%) agreed that SmarTrek was easy to use and that the information provided was useful and had a positive effect on decreasing their drinking. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407061 TI - Brain mechanisms controlling Pavlovian fear conditioning. AB - A key insight of associative learning theory is that learning depends on the actions of prediction error: a discrepancy between the actual and expected outcomes of a conditioning trial. This view of learning has inspired, and in turn been supported by, work in the neurosciences ranging from single unit recording and neuroimaging studies to pharmacological, chemogenetic, and optogenetic interventions. Here we review evidence describing how error-correcting learning rules are instantiated in the activity of distributed neural circuits controlling the effectiveness of unconditioned stimuli during Pavlovian fear conditioning. We show that these prediction error signals, controlling variations in event processing, are fundamental to Pavlovian fear association formation. We also argue that variations in event processing are embedded within multiplexed learning signals and that a coherent understanding of the nature and relationships between these multiple signals at specific times during the conditioning trial is needed. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407062 TI - The nature of phenotypic variation in Pavlovian conditioning. AB - Pavlovian conditioning procedures result in dramatic individual differences in the topography of learnt behaviors in rats: When the temporary insertion of a lever into an operant chamber is paired with food pellets, some rats (known as sign-trackers) predominantly interact with the lever, while others (known as goal trackers) predominantly approach the food well. Two experiments examined the sensitivity of these two behaviors to changing reinforcement contingencies in groups of male and female rats exhibiting the different phenotypes (i.e., sign trackers and goal-trackers). In both phenotypes, behavior oriented to the food well was more sensitive to contingency changes (e.g., a reversal in which of two levers was reinforced) than was lever-oriented behavior. That is, the nature of the two behaviors differed independently of the rats in which they were manifest. These results indicate that the behavioral phenotypes reflect the parallel operation of a stimulus-stimulus associative process that gives rise to food-well activity and a stimulus-response process that gives rise to lever-oriented activity, rather than the operation of a single process (e.g., stimulus-stimulus) that generates both behaviors. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407064 TI - Extinction makes acquisition context-specific in conditioned taste aversion regardless of the context where acquisition and testing take place. AB - Retrieval of a flavor-illness association has been found to show contextual dependence when the association is learned after a nontarget flavor-illness association has been extinguished in what has been named as the extinction makes acquisition context-specific (EMACS) effect. Four experiments were designed to further explore the EMACS effect in conditioned taste aversion. Experiments 1 and 2 replicated the EMACS effect using rats that did not experience extinction, and rats that underwent extinction of a different flavor as controls. Experiments 3 and 4 found that the experience of extinction with the nontarget Flavor X in a given context (A) led to context-specificity of performance to the target Flavor Y both, when Y was trained in a highly familiar context (B) and tested in the context where X had been trained (Context A, Experiment 3), and when the test was conducted in a less familiar context (C) where no cues or outcomes were presented before (Experiment 4). These results are consistent with the idea that the experience of extinction encourages organism's attention to the contexts, making retrieval of new learning context-specific. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407063 TI - Stimulus control of actions and habits: A role for reinforcer predictability and attention in the development of habitual behavior. AB - Goal-directed actions are instrumental behaviors whose performance depends on the organism's knowledge of the reinforcing outcome's value. In contrast, habits are instrumental behaviors that are insensitive to the outcome's current value. Although habits in everyday life are typically controlled by stimuli that occasion them, most research has studied habits using free-operant procedures in which no discrete stimuli are present to occasion the response. We therefore studied habit learning when rats were reinforced for lever pressing on a random interval 30-s schedule in the presence of a discriminative stimulus (S) but not in its absence. In Experiment 1, devaluing the reinforcer with taste aversion conditioning weakened instrumental responding in a 30-s S after 4, 22, and 66 sessions of instrumental training. Even extensive practice thus produced goal directed action, not habit. Experiments 2 and 3 contrastingly found habit when the duration of S was increased from 30 s to 8 min. Experiment 4 then found habit with the 30-s S when it always contained a reinforcer; goal-directed action was maintained when reinforcers were earned at the same rate but occurred in only 50% of Ss (as in the previous experiments). The results challenge the view that habits are an inevitable consequence of repeated reinforcement (as in the law of effect) and instead suggest that discriminated habits develop when the reinforcer becomes predictable. Under those conditions, organisms may pay less attention to their behavior, much as they pay less attention to signals associated with predicted reinforcers in Pavlovian conditioning. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407065 TI - Log versus linear timing in human temporal bisection: A signal detection theory study. AB - Using signal detection theory, we investigated whether human participants represent time linearly or logarithmically in a bisection task. Participants saw a stimulus 1.0 to 1.5 s in duration, and then judged whether the stimulus duration was closer to 1.0 s or to 1.5 s, and how sure they were of their response. Whereas the mean of the subjective stimulus duration was a linear function of the objective stimulus duration, participants produced remarkably different psychophysical functions-linear for some participants, concave for others, and convex for still others. Hence, the appropriate question might not be whether humans encode time linearly or logarithmically, but for which participants and under which conditions is time encoded linearly, logarithmically, or even exponentially. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407066 TI - Reward shifts in forced-choice and free-choice autoshaping with rats. AB - Successive negative contrast (SNC) involves a disruption of behavior when the paired reward is unexpectedly reduced from a large to a small amount, relative to a control always receiving the small amount. Five experiments with rats explored SNC in the Pavlovian autoshaping procedure in which a retractable lever is paired with the delivery of food pellets. In Experiment 1, a 12-to-2 pellet downshift either early in training (after 3 sessions) or late in training (after 20 sessions) yielded no significant evidence of SNC either in terms of lever pressing or goal entries. Experiment 2 showed that presession feeding (another form of reward devaluation) suppressed lever pressing in nonreinforced tests early in training. However, no statistical evidence of lever pressing suppression was found late in training. Presession feeding also suppressed lever pressing late in training if the test session included reinforcements. Experiment 3, using reward downshift, showed that adding a nontarget lever produced no statistical evidence of response suppression to the target lever during the downshift. Lever pressing to the target lever increased and goal entries tended to decrease after a 12-to-2 pellet downshift. Using a within-subject design and two target levers with distinct reward values (Experiment 4), reward downshift produced evidence of lever pressing enhancement in single-lever trials, but lever pressing suppression and a switch in preference to the unshifted lever in nonreinforced free-choice trials. Experiment 5 replicated these within-subject SNC effects, but found only modest evidence for a successive positive contrast effect in free-choice behavior. These results suggest that autoshaping in rats may induce response invigoration in forced-choice situations, but response suppression in free-choice situations. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407067 TI - Short-term memory in habituation and dishabituation of newborn chicks' freezing response. AB - Cognitive models of habituation and dishabituation postulate that the latter is attributable to the perturbation of the model of the repeated stimulation stored in short-term memory (STM) by the occurrence of a new stimulus, called dishabituator. However, although both behavioral phenomena depend on STM, previous studies in Aplysia have found that dishabituation seems to require further steps of development of the STM system to emerge. Here, we addressed whether this is a universal condition for the appearance of the 2 forms of learning, namely whether dishabituation must necessarily follow habituation. To this aim, we studied habituation and dishabituation of the freezing response to a sudden acoustic stimulation in newly hatched chicks (1 day old vs. 3 days old). The results showed that in chicks, dishabituation was fully present a few hours after hatching, a pattern of results indicating that, in this precocial avian species, habituation and dishabituation share the same developmental trajectory and the underlying STM mechanisms are simultaneously operative soon after birth. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30407068 TI - Understanding Parental Ethnotheories and Practices About Healthy Eating: Exploring the Developmental Niche of Preschoolers. AB - PURPOSE:: To understand parental ethnotheories (ie, belief systems) and practices about preschoolers' healthy eating guided by the developmental niche framework. DESIGN:: Qualitative hermeneutic phenomenology. SETTING:: Home. PARTICIPANTS:: Participants were 20 parents of preschool-age children ages 3 to 5 years, recruited from a quantitative investigation. A majority of the participants were white, female, married, well educated, and working full time. METHODS:: Participants who completed the quantitative survey were asked to provide their contact information if they were willing to be interviewed. From the pool of participants who expressed their willingness to participate in the interviews, 20 participants were selected using a random number generator. In-person semistructured interviews were conducted until data saturation (n = 20). Thematic analysis was performed. RESULTS:: Three themes and 6 subthemes emerged: theme 1 parental ethnotheories about healthy eating included subthemes of knowledge about healthy eating, motivations to promote healthy child development through healthy eating, and sources of knowledge about healthy eating (eg, doctors, social media, government guidelines, positive family-of-origin experiences); theme 2-parental ethnotheories that supported organization of children's physical and social settings included structured mealtime routines and food socialization influences (eg, grandparents, siblings, and childcare programs); and theme 3-parental ethnotheories that supported children's learning about healthy eating included parent-child engagement, communication, and encouragement in food-related activities (eg, meal preparation, visiting farmer's market, grocery shopping, gardening, cooking, baking). CONCLUSION:: Findings advance the literature on parental practices about healthy eating. Parental ethnotheories (eg, beliefs, motivations, knowledge, and skills) matter. Developmental niche of preschoolers (ie, physical and social settings, childrearing practices, and parental ethnotheories) constitutes an interactive system in which ethnotheories serve as guides to parental practices. Fostering nutrition education and parent-child engagement, communication, and encouragement in food-related activities are recommended to promote children's healthy eating in daily routines. PMID- 30407069 TI - Cardiac involvement in critically ill patients with leptospirosis: A prospective study using myocardial deformation imaging. AB - BACKGROUND:: Myocardial inflammation often complicates leptospirosis, a re emerging global zoonosis. Leptospirosis associated myocardial dysfunction is equivocal and the pattern of cardiac involvement may not differ from that of sepsis associated myocarditis. METHODS:: We prospectively compared cardiac involvement in 113 intensive care unit patients with severe leptospirosis to 31 patients with sepsis syndrome using a comprehensive assessment comprising of clinical presentation, electrocardiography, two-dimensional echocardiography (with global longitudinal strain calculation), and cardiac biomarker evaluation. Binomial logistic regression was performed to identify independent predictors of left ventricular systolic dysfunction in leptospirosis. RESULTS:: Compared to sepsis syndrome, leptospirosis patients were younger, had higher body mass index measurements and were more likely to be smokers. Electrocardiography abnormalities were common and similar in both groups. Myocardial systolic dysfunction was common in both groups (leptospirosis: 55.86% vs sepsis syndrome: 51.61%, p=0.675) with subclinical left ventricular systolic dysfunction (characterized by abnormal global longitudinal strain and normal left ventricular ejection fraction) being most frequent followed by isolated right ventricular systolic dysfunction, isolated left ventricular systolic dysfunction, and bi ventricular systolic dysfunction (leptospirosis: 31.43%, 18.42%, 13.16%, 10.53%, respectively; sepsis syndrome: 22.22%, 12.00%, 12.00%, 8.00%, respectively ( p>0.05 for each comparator)). Leptospirosis patients had a trend towards greater troponin-T elevation (61.0% vs 40.0%, p=0.057). ST-segment elevation and elevated troponin were independent predictors of reduced left ventricular ejection fraction in leptospirosis. CONCLUSIONS:: Cardiac involvement in leptospirosis appears to be similar to that of sepsis syndrome, with myocardial systolic dysfunction being common. As such, clinical vigilance pertaining to cardiac status is paramount in these high-risk patients. PMID- 30407070 TI - Battle Over Herb-Induced Liver Injury: Low Prevalence Confirmed through Secondary Evaluation and Research Team's Clarifying Rebuttal to Unwarranted Public Claims. PMID- 30407071 TI - Organisational impact of the National Disability Insurance Scheme transition on mental health care providers: the experience in the Australian Capital Territory. AB - OBJECTIVES:: Concerns raised about the appropriateness of the National Disability Insurance Scheme (NDIS) in Australia for people with mental illness have not been given full weight due to a perceived lack of available evidence. In the Australian Capital Territory (ACT), one of the pilot sites of the Scheme, mental health care providers across all relevant sectors who were interviewed for a local Atlas of Mental Health Care described the impact of the scheme on their service provision. METHODS:: All mental health care providers from every sector in the ACT were contacted. The participation rate was 92%. We used the Description and Evaluation of Services and Directories for Long Term Care to assess all service provision at the local level. RESULTS:: Around one-third of services interviewed lacked funding stability for longer than 12 months. Nine of the 12 services who commented on the impact of the NDIS expressed deep concern over problems in planning and other issues. CONCLUSIONS:: The transition to NDIS has had a major impact on ACT service providers. The ACT was a best-case scenario as it was one of the NDIS pilot sites. PMID- 30407072 TI - Comparison of public mother-baby psychiatric units in Australia: similarities, strengths and recommendations. AB - BACKGROUND:: Mother-baby units are innovative and important models of care that allow inpatient treatment of postpartum maternal mental disorders whilst preserving and promoting the attachment relationship with their young infants. OBJECTIVES:: To report data across five public mother-baby units in Australia in order to explore similarities and distinguishing features of each model. METHOD:: Each unit also provided 12 months of data on key characteristics of their unit. RESULTS:: Despite the geographic differences, the diagnostic profiling, length of stay, and child protection involvement were similar across the units. CONCLUSIONS:: Acute care for perinatal mental illness offered in public mother baby units in Australia shows consistency across units, raising concerns for where such treatment is unavailable. PMID- 30407073 TI - Switch-associated adverse events: focus on olanzapine. AB - OBJECTIVES:: Switching between different antipsychotic therapies is a frequent occurrence in the management of patients with schizophrenia and other psychotic disorders. This paper provides a review of the principles of antipsychotic switching and discusses pharmacological principles underlying adverse events that occur while switching olanzapine to another antipsychotic medication. It offers suggestions for management of switch-associated adverse events in clinical settings. CONCLUSIONS:: Few publications explore olanzapine switch-related adverse events, the underlying pharmacological principles and appropriate switching strategies to minimise the risk of adverse events. There is still a need for further studies to verify existing knowledge and assist in the development of 'gold standard' guidelines that outline appropriate switching strategies and duration of the switching process to reduce and avoid adverse events. PMID- 30407074 TI - Wind-Driven Saltation: An Overlooked Challenge for Life on Mars. AB - Numerous studies have demonstrated that the martian surface environment is hostile to life because of its rough radiation climate and the reactive chemistry of the regolith. Physical processes such as erosion and transport of mineral particles by wind-driven saltation have hitherto not been considered as a life hazard. We report a series of experiments where bacterial endospores (spores of Bacillus subtilis) were exposed to a simulated saltating martian environment. We observed that 50% of the spores that are known to be highly resistant to radiation and oxidizing chemicals were destroyed by saltation-mediated abrasion within one minute. Scanning electron micrographs show that the spores were not only damaged by abrasion but were eradicated during the saltation process. We suggest that abrasion mediated by wind-driven saltation should be included as a factor that defines the habitability of the martian surface environment. The process may efficiently protect the martian surface from forward contamination with terrestrial microbial life-forms. Abrasion mediated by wind-driven saltation should also be considered as a major challenge to indigenous martian surface life if it exists/existed. PMID- 30407075 TI - Gestational Trophoblastic Tumors: A Timely Review of Diagnostic Pathology. AB - CONTEXT.-: Gestational trophoblastic tumors include 3 distinct entities: gestational choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. Accurate diagnosis is important for clinical management of the patient. OBJECTIVE.-: To review clinical features and pathologic diagnosis of gestational trophoblastic tumors. DATA SOURCES.-: Literature and personal experience are the sources for this study. CONCLUSIONS.-: Trophoblastic tumors are rare encounters in modern medicine, as a result of clinical practice of molar surveillance programs and early chemotherapeutic intervention for persistent gestational trophoblastic neoplasia. Diagnostic recognition of these tumors requires a high index of suspicion, awareness of their histologic characteristics, and appropriate application of immunohistochemical and molecular biomarkers. Recent attention has been given to a few precursor lesions of gestational trophoblastic tumors, including early/in situ choriocarcinoma and atypical placental site nodule. PMID- 30407076 TI - Cerebral toxoplasmosis in a patient with prolonged CD4 lymphopenia post autologous hemopoietic stem cell transplant. PMID- 30407077 TI - Evaluation of the Effectiveness of a 3-Year, Teacher-Led Healthy Lifestyle Program on Eating Behaviors Among Adolescents Living in Day School Hostels in Malaysia. AB - BACKGROUND:: Independence gained during adolescence may be associated with unhealthy eating behaviors. Although malnutrition among adolescents is evident, studies on eating behaviors among adolescents are scarce. OBJECTIVE:: To determine the effectiveness of a teacher-led Healthy Lifestyle Program on eating behaviors among adolescents in Malaysia. METHODS:: This was a cluster randomized controlled trial (conducted in 2012 to 2014), with 100 schools randomly selected from 721 schools, then assigned to 50 intervention schools and 50 control schools. A Healthy Eating and Be Active among Teens (HEBAT) module was developed for pretrained teachers to deliver a Healthy Lifestyle Program on eating behaviors among adolescents. Eating behaviors of the respondents was determined using Eating Behaviors Questionnaire. Linear Mixed Model analysis and chi2 test were used to determine within- and between-group effects of studied variables. RESULTS:: A total of 4277 respondents participated in this study, with 2635 samples involved in the final analysis, comprised of 921 intervention and 1714 control respondents. There were 32.4% (36.4%) males and 67.6% (63.6%) females in the intervention (control) group. Mean age was comparable between the groups (intervention = 12.98 years; control = 12.97 years). Majority of the respondents skipped meals at baseline (intervention = 74.7%; control = 79.5%). After the program, intervention respondents had higher consumption frequency of lunch, dinner, and mid-morning snack but a lower consumption frequency of late-evening snack and meal skipping behaviors than their control counterparts. CONCLUSION:: The teacher-led Healthy Lifestyle Program was effective in reducing meal-skipping behaviors among Malaysian adolescents. PMID- 30407078 TI - Early life adversity, use of specialist care and unmet specialist care need among children. AB - Adverse childhood experiences (ACEs) are linked to increased utilization of health care among adults; however, the impact of ACEs on nonmental health specialist care has been largely overlooked. To address this, data from the 2011 2012 National Survey of Children's Health ( n = 89,357) were used to assess the health of children aged 0-17 living with a parent or guardian. Use of specialist care among children in the past 12 months was the outcome of interest and experiencing any one of nine ACEs was the independent variable of interest. After adjusting for confounders in logistic regression modeling, children who experience specific ACEs had higher odds of receiving specialist care. All ACEs were associated with higher unmet need of specialist care, and each additional ACE was independently associated with higher odds of needing specialist care among those who had not received it. This study provides evidence of that experiencing specific ACEs lead to increased demand of nonmental health specialist services among children and adds to the growing body of research indicating that individual ACE items may be differentially associated with health care utilization or not associated with health-care utilization at all. PMID- 30407079 TI - Case-control study on intestinal intussusception: implications for anti-rotavirus vaccination. AB - BACKGROUND: Intussusception represents the most common cause of abdominal emergency among young children but nearly 75% of cases are still considered idiopathic. RESEARCH DESIGN AND METHODS: A case-control study was conducted among Sicilian children aged 0-59 months with a hospital admission for intussusception between 2009 and 2015 to identify factors associated with intussusception onset. RESULTS: Overall, 125 cases and 190 controls were recruited for the study. Birth order (OR 1.49, 95%CI: 1.10, 2.02, P = 0.02) and having had gastroenteritis or having taken antibiotics during the 30 days prior to hospitalization (OR 11.55, 95%CI: 3.23, 41.23, P < 0.001; 3.09, 95%CI: 1.17, 8.12, P = 0.009, respectively) were significantly associated with intussusception. On the other hand, exclusive breastfeeding for at least two months was a protective factor (OR 0.48, 95%CI: 0.23, 0.99, P = 0.009). Anti-rotavirus vaccination did not correlate with risk of intussusception (OR 0.96, 95% CI: 0.41, 2.25, P = 0.92). CONCLUSIONS: These findings increase the awareness of intussusception among clinical and public health service providers to obtain a better susceptibility profile. Moreover, identifying children at higher risk of intussusception could be useful in vaccination counselling to intercept early symptoms and to reduce the number of serious cases. PMID- 30407080 TI - Age modifies the association between driver's body mass index and death following motor vehicle crashes. AB - OBJECTIVE: We explored the association between body mass index (BMI) and the odds of a driver being fatally injured in a motor vehicle crash (MVC) after controlling for driver, crash, and vehicle factors known to independently contribute to injury severity. We hypothesized that BMI would be related to risk of fatal injury after controlling for other risk factors but that BMI would also interact with age. METHOD: We analyzed crashes involving 2 passenger type vehicles (1998-2015) from the Fatality Analysis Reporting System using binary logistic regression (with generalized estimating equations) to compute odds ratios and 95% confidence intervals of fatality by BMI status. RESULTS: Our results indicate that BMI status confers varying levels of risk at different ages. For example, a very low BMI of 18 increased the odds of fatality (relative to BMI = 21.75) more at age 85 (adjusted odds ratio [aOR] = 1.17, 95% confidence interval [CI], 1.09, 1.26) than at age 25 (aOR = 1.03, 95% CI, 1.01, 1.06). Similarly, a very high BMI of 42.5 increased the odds of fatality (relative to BMI = 21.75) more at age 85 (aOR = 2.17, 95% CI, 1.64, 2.87) than at age 25 (aOR = 1.33, 95% CI, 1.21, 1.45). Conversely, a moderate BMI of 27.5 was protective for drivers aged 85 (aOR = 0.94, 95% CI, 0.88, 0.99) but had no effect for drivers aged 25 (aOR = 1.00, 95% CI, 0.98, 1.02). We also found that a higher BMI was associated with higher odds of wearing a seat belt improperly or not wearing one at all. CONCLUSION: The relationship between BMI and fatality risk needs to be considered by policymakers, public health officials, and vehicle manufacturers to ensure that vehicles are safe for all occupants regardless of their weight, size, or shape. PMID- 30407081 TI - Validation of a Simulated Commercial Frying Process to Control Salmonella in Donuts. AB - This study validated a typical commercial donut frying process as an effective kill-step against a 7-serovar Salmonella cocktail (Newport, Typhimurium, Senftenberg, Tennessee, and three dry food isolates) when contamination was introduced through inoculated flour. The bread and pastry flour mix (3:1) was inoculated with the Salmonella cocktail, and subsequently dried back to original preinoculation moisture content, achieving a Salmonella population of 7.6 log CFU/g. Inoculated flour was used to prepare a typical commercial donut batter, which was fried using 375 degrees F (190.6 degrees C) oil temperature. No viable Salmonella was detected using an enrichment plating protocol in the donuts after 2 min of frying, resulting in >7-log reduction in Salmonella population. The internal donut temperature increased from ~30 degrees C to ~119 degrees C at the end of 2 min of frying. The water activities of the donut crumb and crust after 2 min of frying, followed by 30 min of ambient air cooling, were 0.944 and 0.852, respectively. The donut pH after ambient-air cooling was 5.51. The D- and z values of the Salmonella cocktail in donut dough were determined using thermal death-time disks and temperature-controlled water baths. The D-values of the cocktail were 8.6, 2.9, and 2.1 min at 55 degrees C, 58 degrees C, and 61 degrees C, respectively, whereas the z-value was 10 degrees C. This study validated that >7-log reduction could be achieved if donuts are fried for at least 2 min in the oil at 190.6 degrees C, and calculated D- and z-values present the heat resistance of Salmonella in donut dough at the start of the frying processes. However, results from this study should not be extrapolated when donut composition and frying parameters are changed significantly. PMID- 30407082 TI - Detection and Molecular Characteristics of Toxoplasma gondii DNA in Retail Raw Meat Products in Poland. AB - Raw and undercooked meat are regarded as important sources of Toxoplasma gondii infection of people in Europe; however, data concerning this issue in Poland are still insufficient. The aim of this study was to determine the prevalence of T. gondii DNA isolated from raw meat products retailed in Poland. The molecular characteristics of detected DNA were also performed. Samples of cured bacon, raw or smoked sausages, ham, and minced meat were examined for the presence of T. gondii DNA. Samples were digested by pepsin solution, followed by the DNA isolation. Nested and real-time polymerase chain reaction (PCR) was performed based on the amplification of 35-fold-repetitive B1 fragment gene of T. gondii. For selected B1-positive samples, multiplex PCR was performed using SAG1, SAG2 (5'-SAG2 and 3'-SAG2), altSAG2, SAG3, GRA6, BTUB, C29-2, and L358 genetic markers. Amplicons were sequenced and analyzed with NCBI database. Among 3223 examined samples, 175 (5.4%) were PCR positive. The highest percentages of positive results were found for samples originating from south-east regions of Poland-Podkarpackie (17.9%), Malopolskie (12.6%), and Lubelskie (10.8%) (p < 0.001). The percentages of positive results for particular types of meat products sausages, smoked meat products, ham, and minced meat-ranged from 4.5% to 5.8% and the differences between them were not significant (p > 0.05). Sequence analysis of selected B1-positive samples demonstrated mostly the alleles of clonal type III (49.0%), and less-type II (17.3%), and type I (10.2%) based on nine used genetic markers. The combinations of types I/II or II/III or I/III alleles at different loci were also found in 23.5% of cases. Detection of T. gondii DNA in raw meat products may indicate the potential health threat for consumers in Poland; however, for complete risk assessment of T. gondii infection, the additional studies, including detection of live parasite, are needed. PMID- 30407083 TI - Performance-based visual field testing for drivers with glaucoma: A pilot study. AB - OBJECTIVE: Conventional visual field (VF) tests are limited in predicting on-road driving performance of individuals with glaucoma. We developed a new performance based VF test in a driving simulator for individuals with glaucoma. The aim was to evaluate the psychometric properties of the newly developed test. METHODS: In this pilot study, 17 drivers with glaucoma aged 65.24 +/- 9.69 and 13 control drivers aged 61.27 +/- 11.45 completed the performance-based VF task. Construct validity was determined by comparing performance on the new task with results on conventional visual and perimetry tests including Humphrey Visual Field Analyzer, Keystone Vision Screener, and Useful Field of View (UFOV). Concurrent validity was evaluated by comparing performance on the new task with on-road driving performance, scored using the Test Ride for Investigating Practical fitness-to drive (TRIP). Ten individuals (7 with glaucoma and 3 controls) participated in the test-retest reliability assessment. RESULTS: Drivers with glaucoma identified fewer symbols (P = .047) and took longer to respond to the symbols (P = .048) compared to controls. In the glaucoma group, correct responses on the performance based VF test correlated strongly (r = -0.51, P = .046) with UFOV divided attention. Both glaucoma and control groups achieved submaximal to maximal scores on the TRIP (median [Q1-Q3], glaucoma: 193 [191-196]; controls: 196 [195-196]; P = .16). No strong correlations were found between scores on the performance-based VF test and on-road driving performance in glaucoma. The intraclass correlation coefficients ranged between 0.77 for response time and 0.92 for correct responses, indicating good to excellent test-retest reliability. CONCLUSIONS: We established the construct validity and test-retest reliability of the performance based VF test. Future studies should include a larger sample with more severe driving difficulties to demonstrate the concurrent validity between performance based VF testing and on-road driving performance in glaucoma. PMID- 30407084 TI - Assimilative and accommodative coping in older adults with and without sensory impairment: four-year change and prospective relations with affective well-being. AB - OBJECTIVES: Sensory impaired older adults may be particularly dependent on coping strategies such as assimilation (or tenacious goal pursuit [TGP]) and accommodation (or flexible goal adjustment [FGA]) to secure high levels of well being. We investigated if late-life changes in these coping strategies and prospective associations of TGP and FGA with affective well-being vary according to sensory impairment status. METHOD: Our study sample consisted of 387 adults aged 72-95 years (M = 82.50 years, SD =4.71 years) who were either visually impaired (VI; n = 121), hearing impaired (HI; n = 116), or sensory unimpaired (UI; n = 150). One hundred sixty-eight individuals were reassessed after approximately 4 years. RESULTS: Both VI and HI revealed a decrease in TGP, whereas TGP remained stable in UI. For FGA, a significant increase in HI was observed, whereas a significant decline emerged in UI. Controlling for age, gender, and cognitive abilities, higher TGP at baseline was significantly associated with higher negative affect 4 years later in VI. Moreover, the positive association between baseline FGA and subsequent positive affect was stronger in HI than in UI older adults. CONCLUSION: Our findings suggest that older adults with sensory impairments reveal trajectories of assimilative and accommodative coping and associations of TGP and FGA with affective well-being that are different from sensory unimpaired individuals. PMID- 30407085 TI - Optimizing quality of life in perimenopause: lessons from the East. AB - As global life expectancy improves, women are expected to spend more than one third of their lives in the status of menopause. In China, many women suffer from menopausal symptoms during this period, which impacts their well-being and quality of life. However, most Chinese women simply endure menopausal symptoms. Since the Chinese Menopause Society was founded in 1999, several versions of the guidelines for menopause management and menopausal hormone therapy (MHT) have been published; international cooperation has strengthened; menopause-related activities have been advocated; and popular knowledge of menopause and MHT has gradually improved. Medical workers, menopausal women, and the general population have come to realize that MHT is the most effective treatment for menopausal symptoms and could improve quality of life. In addition to MHT, non-hormone management (traditional Chinese medicine, lifestyle changes, social/psychological interventions, dietary management, etc.) of menopausal symptoms is an important consideration, especially in situations when MHT is contra-indicated. This review summarizes the literature and research studies to help health care acknowledge the population and prevent underuse of effective therapies or use of inappropriate or ineffective therapies, which, in turn, is expected to improve public health management and women's quality of life. More efforts should be made to better disseminate the knowledge on perimenopausal management among Chinese women. PMID- 30407086 TI - A State-of-the-Science Review of Mercury Biomarkers in Human Populations Worldwide between 2000 and 2018. AB - BACKGROUND: The Minamata Convention on Mercury provided a mandate for action against global mercury pollution. However, our knowledge of mercury exposures is limited because there are many regions and subpopulations with little or no data. OBJECTIVE: We aimed to increase worldwide understanding of human exposures to mercury by collecting, collating, and analyzing mercury concentrations in biomarker samples reported in the published scientific literature. METHOD: A systematic search of the peer-reviewed scientific literature was performed using three databases. A priori search strategy, eligibility criteria, and data extraction steps were used to identify relevant studies. RESULTS: We collected 424,858 mercury biomarker measurements from 335,991 individuals represented in 312 articles from 75 countries. General background populations with insignificant exposures have blood, hair, and urine mercury levels that generally fall under [Formula: see text], [Formula: see text], and [Formula: see text], respectively. We identified four populations of concern: a) Arctic populations who consume fish and marine mammals; b) tropical riverine communities (especially Amazonian) who consume fish and in some cases may be exposed to mining; c) coastal and/or small island communities who substantially depend on seafood; and d) individuals who either work or reside among artisanal and small-scale gold mining sites. CONCLUSIONS: This review suggests that all populations worldwide are exposed to some amount of mercury and that there is great variability in exposures within and across countries and regions. There remain many geographic regions and subpopulations with limited data, thus hindering evidence-based decision making. This type of information is critical in helping understand exposures, particularly in light of certain stipulations in the Minamata Convention on Mercury. https://doi.org/10.1289/EHP3904. PMID- 30407087 TI - Validity and the reliability of the Turkish version of the control of allergic rhinitis and asthma test for children (CARATKids). AB - AIM: Asthma occurs in association with allergic rhinitis. Control of Allergic Rhinitis and Asthma Test for Children (CARATKids) is a questionnaire to assess control of both diseases. The aim of this study was to assess the validity and reliability of the CARATKids in Turkish children aged 6-12 years. METHODS: After a cultural adaptation process, children with asthma and allergic rhinitis were recruited. CARATKids, childhood Asthma Control Test, total nasal symptom score, visual analog scale scores for asthma and rhinitis, peak nasal inspiratory flow and peak expiratory flow values were obtained at baseline and after 4-6 weeks. The patients were classified according to the control level for asthma and rhinitis and stable/unstable groups. Discriminative properties, internal consistency, test-retest reliability, responsiveness, validity and minimal clinically important difference (MCID) were assessed. Receiver operating characteristic curve analysis was performed. RESULTS: About 174 patients were included. The Cronbach's alpha was 0.841. Correlation coefficients between CARATKids and external measures of control were 0.42-0.77, and between the score changes of CARATKids and external measures of control it was 0.56-0.78. Guyatt's responsiveness index was -1.88, within-patient change of CARATKids score was significant. The intra-class correlation coefficient was 0.973. The MCID was 4. A cutoff score of <=5 on the CARATKids had a sensitivity of 100% to distinguish the controlled groups according to both the GINA and ARIA. CONCLUSION: CARATKids is a reliable and valid tool to assess asthma and allergic rhinitis control in Turkish children. A score of <=5 on CARATKids defines controlled disease for both diseases simultaneously. PMID- 30407088 TI - Understanding the Link between Anxiety and a Neural Marker of Anxiety (The Error Related Negativity) in 5 to 7 Year-Old Children. AB - Despite growing evidence that an elevated error-related negativity (ERN) is a risk marker for anxiety, it is unclear what psychological construct underlies this association. To address this gap, we devised a 9-item self-report scale for assessing error sensitivity (i.e. the fear of making mistakes) in children. The Child Error Sensitivity Index was administered to 97 children ages 5-7 years old and demonstrated good internal reliability and convergent validity. The Child Error Sensitivity Index related to the ERN, and the relationship between the ERN and child anxiety symptoms was mediated by scores on the Child Error Sensitivity Index. PMID- 30407089 TI - Implementation and monitoring of decisions by pharmacy and therapeutics committees in South African public sector hospitals. AB - INTRODUCTION: The National Drug Policy in South Africa has achieved its objective in establishing and strengthening Pharmacy and Therapeutics Committees (PTCs) in all hospitals. However, little is known about the implementation of decisions by PTCs and the monitoring thereof. Consequently, there is a need to investigate this. Areas covered: We sought to address this via an online survey distributed to pharmacists working in public sector hospitals across South Africa with perceived functioning PTCs, with a 32.3% response rate to the survey. Expert commentary: Membership of all PTCs included a pharmacist, who in most cases (51.2%) held the secretariat position. Principal PTC activities were encouraging rational medicine use (RMU) (86,0%), pharmacovigilance (82.6%) and implementing standard treatment guidelines (STGs) (77.9%). Only a third (37.5%) stated that they were using indicators to monitor PTC performance. Where collected, indicator data were mostly used for providing feedback to PTCs (83.3%). Most hospitals (95.1%) implemented PTC decisions; however, 62.0% mentioned guidelines on implementing PTC decisions did not exist in their hospital. The majority of respondents (65.4% and 83.8%, respectively) indicated PTC decisions were evaluated and reviewed in their hospitals. Overall, a high percentage of respondents stated the main activities of PTCs were to enhance RMU as well as implement STGs. However, guidelines on implementation of decisions by PTCs are currently lacking and most PTCs were not monitoring their performance. This needs to be addressed. PMID- 30407090 TI - Birthplace is a risk factor for exchange transfusion in outborn infants admitted for jaundice in Myanmar: a case-control study. AB - AIM: To evaluate the role of pathway to admission for jaundice among the risk factors for exchange transfusion in outborn infants in a low resource setting. METHODS: This retrospective case-control study (1:1 ratio) was carried out at the Yankin Children's Hospital in Yangon (Myanmar). All cases were neonates admitted for treatment of jaundice between March 2013 and February 2014 and who required an exchange transfusion. Each control was the next noncase neonate admitted for treatment of jaundice and treated with phototherapy. Infant characteristics, pathways of admission and clinically relevant factors for exchange transfusion were collected. RESULTS: One hundred thirty-four cases and 134 controls were included in the study. Among cases, home was the most common place of birth while public hospital was the most frequent source of referral. Among controls, private/public hospitals were the commonest places of birth and referral. At multivariable analysis, homebirth was associated with increased likelihood of receiving exchange transfusion at admission (OR 3.30, 95% C.I. 1.31-8.56). CONCLUSION: Homebirth was an independent risk factor for exchange transfusion at admission for jaundice in a low-resource setting. Appropriate health education of pregnant women and traditional/home birth attendants may contribute to reduce the need for exchange transfusion in low-resource settings. PMID- 30407091 TI - Physical Presence, Social Presence, and Anxiety in Participants with Social Anxiety Disorder During Virtual Cue Exposure. AB - Although social anxiety disorders (SADs) are increasingly treated by means of virtual cue exposure, the mechanisms leading to sufficient anxiety levels and thus to a success of virtual reality exposure therapy are still poorly understood. Also, most studies with SAD participants fail to evaluate social presence, although it may be a more appropriate indicator for virtual social stress scenarios than physical presence. Hence, for the first time, this study sets out to examine the link between social presence, physical presence, and emotional responses to phobogenic virtual social stimuli. A group of n = 12 participants with SAD and n = 12 healthy controls were exposed to three social tasks in an interactive virtual environment (VE). Self-report measures of physical and social presence as well as state anxiety were used alongside heart rate measures to evaluate the virtual experience. Results show significantly higher anxiety levels-both self-report and physiological-in SAD participants than in controls. Also, socially anxious subjects reported to experience more copresence and mutual attention as well as a higher sense of being in the VE than their healthy peers. In sum, social presence experiences may be more predicative of the anxiety response in SAD individuals than physical presence. Especially attentional processes seem to crucially shape the interplay between presence and affective responses. PMID- 30407092 TI - A comparison of the efficacy of immunomodulatory-free regimens in relapsed or refractory multiple myeloma: a network meta-analysis. AB - Treatment history influences the outcomes of subsequent therapies in patients with relapsed or refractory multiple myeloma (RRMM) and needs to be considered when deciding which treatment to use next. To assess the relative merits of immunomodulatory (IMiD)-free treatments, a systematic literature review (SLR) was conducted to identify relevant randomized controlled trials in patients with RRMM. A network meta-analysis (NMA) was performed to assess various IMiD-free regimens, including bortezomib and dexamethasone (Vd)-based treatments, and to explore differences in patient outcomes. The SLR identified 52 articles, from which four trials were ultimately included in the base-case NMA. The NMA showed that daratumumab plus Vd (DVd) provided a significant advantage in prolonging progression-free survival. Similar trends were observed for overall survival and overall response. Across all outcomes, DVd had the highest probability of being the best treatment. These findings suggest that DVd may provide superior clinical outcomes for RRMM patients suitable for IMiD-free regimens. PMID- 30407093 TI - Positive sentinel node in luminal A-like breast cancer patients - implications for adjuvant chemotherapy? AB - BACKGROUND: In luminal A-like breast cancer, the indication for adjuvant chemotherapy still is largely based on lymph nodestatus. Sentinel node (SN) positive patients who are no longer recommended an axillary lymph node dissection (ALND) risk undertreatment, especially if they have >=4 lymph node metastases (LNMs). AIM: To quantify the group of SN positive luminal A-like patients with >=4 LNMs and to investigate if the ratio between positive SNs and examined SNs (SN ratio) can provide information of the axillary tumor burden. MATERIAL AND METHODS: Nearly 370 patients between 2014-2016 in Western Sweden with a clinically node-negative invasive breast cancer treated with both SNB and subsequent ALND were included. SNB findings were compared to ALND findings and the ability of the SN ratio to describe the axillary tumor burden was evaluated using multivariable analysis. RESULTS: In total,17.6% of patients with luminal A like tumors had >=4 LNMs. The SN ratio was statistically significant for predicting >=4 LNMs among luminal A-like patients (p = .013, OR 1.89 (95% CI 1.14 3.12) per 0.1 increment in SN ratio). CONCLUSIONS: One sixth of patients with SN positive luminal A-like tumors risk undertreatment. The SN ratio may aid in identifying many of these patients. PMID- 30407094 TI - A framework for exposure characterization and gamma dosimetry at the NMBU FIGARO irradiation facility. AB - PURPOSE: The FIGARO low dose 60Co gamma irradiation facility at the Norwegian University of Life Sciences, As, Norway, is dedicated to the study of effects on living organisms from acute or chronic ionizing radiation exposures, either alone or in combination with other stressors such as UV radiation, metals or radionuclides. Here, we present a framework of working guidelines and computer software for characterization of absorbed dose rates and accumulated doses to organisms exposed within the continuous gamma field at FIGARO. The aims of the framework are to ensure gamma exposures are well characterized, that results from exposures are correctly interpreted in terms of absorbed dose rates and accumulated doses, and that sufficient information is available so that exposures can be reproduced later or at other facilities. METHODS: The software of the framework includes a Geant4 application for Monte Carlo radiation transport simulations and tools for dose planning, recording and reporting. The working guidelines are prepared for expert users who provide simulated, calculated or estimated absorbed dose rates and for regular users who conduct exposure experiments and are responsible for record keeping. To demonstrate the developed framework, we use a case study where 14 freshwater microcosms are exposed to four levels of gamma dose rates at FIGARO. CONCLUSION: The framework guides users towards good dosimetry practices. Lessons learned could be transferable to other gamma irradiation facilities. PMID- 30407095 TI - Long-term effect of all-trans retinoic acid and arsenic trioxide sequential maintenance in patients with acute promyelocytic leukemia. AB - The specific prognostic factors and the long-term effects of different treatment options in APL remain unclear. In this retrospective study, 70 APL patients were treated with ATRA + DNR/DA or ATRA + ATO regimens for induction therapy and DA or ATRA + ATO for consolidation and maintenance therapy. The prognostic factors and treatment effects on outcome were analyzed. Results showed that the 5-year OS in low-intermediate risk and high risk groups were 95.63% and 100%, and the 5-year RFS were 95.34% and 100%, respectively, the early mortality rate was 4.28%. No significant difference was found on OS and RFS with different regimens, but side effects and treatment-related mortality rates were lower in ATRA + ATO group. CD34 expression, FLT3-ITD mutation and PML-RARA isoform had no significance on OS and RFS. In conclusion, cytogenetic and molecular abnormalities had no influence on effect of APL patients; ATRA + ATO sequential maintenance may alleviate complications, treatment-related mortality, and the previously high risk factors. PMID- 30407096 TI - Improvement of thyroid function in POEMS syndrome after combination therapy of lenalidomide and dexamethasone. AB - Hypothyroidism is the most common endocrine disorder in POEMS syndrome. In this single-center prospective study, 36 patients with newly diagnosed POEMS syndrome were treated with lenalidomide (10 mg daily for 21 days) and dexamethasone (40mg once per week) for 12 cycles. Hypothyroidism was demonstrated in 58.5% (24/41) at baseline, including 25% (6/24) of clinical hypothyroidism and 75% (18/24) of subclinical hypothyroidism. After 12-month treatment, the percentages of clinical hypothyroidism and subclinical hypothyroidism had decreased 11.8% and 27.2%, respectively. Percentage of euthyroidism had increased from 41.5% to 80.5%. There was a strong relation between VEGF response and thyroid function improvement (p = .028). Patients with clinical hypothyroidism at baseline had an inferior 1-year OS (50% vs. 100%, p < .043) than euthyroidism and subclinical hypothyroidism groups. Clinical hypothyroidism was associated with decreased overall survival and this combination treatment was effective in improving thyroid function in POEMS syndrome. PMID- 30407097 TI - Effects of rapamycin in combination with fludarabine on primary chronic lymphocytic leukemia cells. PMID- 30407099 TI - Perceptions of a Breast Cancer Survivorship Intervention: Pearls of Wisdom from Young African American Women. AB - PURPOSE: African American (AA) women ages 20-44 develop breast cancer at higher rates compared with Caucasian women. These young survivors (<45 years) also have disparate quality of life (QOL). Little is known about survivorship information needs of young AA survivors. The purpose of this study was to explore young AA survivors' perceptions of an existing QOL intervention for breast cancer survivors, identifying information needs to address using a targeted intervention. METHODS: Two semistructured interviews were conducted with each of 15 young AA survivors who had completed breast cancer treatment. This article focuses on the second interview in which young AA survivors reviewed intervention materials and described their perceptions of the intervention. Content analysis was used to identify themes, which were validated by participants. RESULTS: Participants (n: 15; mean age at study entry: 35 years) reported that the existing evidence-based intervention discussed relevant but general survivorship information. They suggested adapting the information for young AA survivors: addition of content geared toward finances, how to better communicate to manage dating and relationships, how to engage in healthful activities, and how to find local resources for any stage of survivorship. Furthermore, they suggested multiple modes of information delivery and inclusion of diverse imagery. CONCLUSION: Engaging young AA survivors yielded pearls of wisdom, highlighting the general nature of an existing intervention and suggesting adaptations to meet young AA survivors' information needs. Applying such pearls can be a powerful method to target survivorship interventions for this disparate group of cancer survivors. PMID- 30407098 TI - Factors associated with immunotherapy selection in patients with advanced melanoma. AB - AIM: To explore factors associated with pembrolizumab (PEMBRO) versus ipilimumab + nivolumab (IPI+NIVO) selection in advanced melanoma. MATERIALS & METHODS: Total of 12 academic and satellite clinics contributed to this study. Descriptive and logistic regression analyses were conducted to explore associations between clinical characteristics and treatment choice. Results: Total of 400 patients were included: 200 PEMBRO and 200 IPI+NIVO. Patients were significantly more likely to receive PEMBRO versus IPI+NIVO if they had poorer Eastern Cooperative Oncology Group score, 2-4 versus 0-1 (odds ratio [OR]: 6.6; 95% CI: 3.0-14.7), if they were PD-L1 positive (OR: 4.5; 95% CI: 1.9-10.4) or had BRAF wild-type tumor (OR: 2.2; 95% CI: 1.4-3.6). CONCLUSION: Patient factors are significantly associated with treatment selection in advanced melanoma. Outcomes comparisons should take this into consideration. PMID- 30407100 TI - Selective Serotonin Reuptake Inhibitors and Persistent Pulmonary Hypertension of the Newborn: An Update Meta-Analysis. AB - BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) is a serious condition associated with substantial mortality and morbidity. Previous studies have suggested a possible link between maternal selective serotonin reuptake inhibitor (SSRI) use and the risk of PPHN. This study aimed to provide an up-to date review and meta-analysis of the topic. METHODS: Using the search terms [SSRI OR SSRIs OR selective serotonin reuptake inhibitors OR antidepressant OR Prozac OR fluoxetine OR Lexapro OR escitalopram] AND [pregnancy OR maternal OR newborn OR persistent pulmonary hypertension OR PPHN OR neonat* OR fet*], a preliminary search on the PubMed, Medline, EMBASE, Web of Science, and Google Scholar database yielded 7327 articles published in English between January 1, 1960 and October 1, 2017. RESULTS: A total of 9 cohort and case-control studies, with a total of 7,540,265 subjects were systematically reviewed. Random-effects meta analysis of eight studies revealed a significantly increased risk of PPHN with maternal SSRI use during pregnancy, with a pooled OR of 1.516 (95% confidence interval: 1.035-1.997, p < 0.001). Overall, the absolute increase in risk of PPHN with SSRI use appears small, with an absolute risk difference of 0.619 per 1000 livebirths and a number needed to harm of 1615 women. CONCLUSIONS: Current evidence suggests that there were significantly greater odds of PPHN with SSRI use during pregnancy. However, the clinical significance of this association remains modest and likely outweighed by the potential benefits of treatment of perinatal depression. The risk of PPHN associated with SSRI therapy might not warrant the recommendation to withdraw antidepressant therapy, as evidence from other studies show that untreated perinatal depression presents additional adverse maternal and fetal outcomes. Given the increasing prevalence of maternal depression and consequent use of antidepressant medications, further research with robust longitudinal or randomized, controlled studies and mechanistic investigations are needed. PMID- 30407101 TI - What does good FISHing look like in MDS? PMID- 30407102 TI - The Case for Patient Navigation in Lung Cancer Screening in Vulnerable Populations: A Systematic Review. AB - Patient navigation has been proposed to combat cancer disparities in vulnerable populations. Vulnerable populations often have poorer cancer outcomes and lower levels of screening, adherence, and treatment. Navigation has been studied in various cancers, but few studies have assessed navigation in lung cancer. Additionally, there is a lack of consistency in metrics to assess the quality of navigation programs. The authors conducted a systematic review of published cancer screening studies to identify quality metrics used in navigation programs, as well as to recommend standardized metrics to define excellence in lung cancer navigation. The authors included 26 studies evaluating navigation metrics in breast, cervical, colorectal, prostate, and lung cancer. After reviewing the literature, the authors propose the following navigation metrics for lung cancer screening programs: (1) screening rate, (2) compliance with follow-up, (3) time to treatment initiation, (4) patient satisfaction, (5) quality of life, (6) biopsy complications, and (7) cultural competency. PMID- 30407103 TI - Acute myeloid leukemia in the elderly: what constitutes treatment value? AB - Treatment options for patients with acute myeloid leukemia (AML), who are unfit for induction chemotherapy are unsatisfactory. Overall survival (OS) superiority has not been demonstrated in randomized controlled trials (RCT) in this population, challenging the value of available therapies. We sought to assess the relative value of approved therapies using value-assessment tools. Clinical, safety, quality-of-life (QOL), supportive care, and resource utilization outcomes data were abstracted from RCTs and examined using value-assessment frameworks. Three RCTs, one each of azacitidine, decitabine, and low-dose cytarabine were identified. OS was not statistically significant and secondary outcomes including response rates, rates of transfusion independence, the frequency of hospitalizations and changes in QOL were reported differently across trials. Value-assessment tools considered OS as the primary efficacy endpoint without consideration to response rates. The NCCN Evidence BlocksTM were most successful in considering secondary endpoints. With the move toward value-based care, understanding how these value tools apply to AML patients is critical. PMID- 30407104 TI - Natural clays with an inherent uranium component that nevertheless sequester uranium from contaminated water. AB - Clays present a cost effective and sustainable method for removing uranium and heavy metals from drinking water because of their cation exchange capabilities. However, managing muddy suspensions is problematic; therefore, clay pellets as presented in this article are a promising alternative. Three standard clays and two regional clays were evaluated for sorption, both in powder form and in pellet structure for comparison. The objective was to evaluate individual sorption processes and assess the effect on uranium sorption due to the process of altering the clay powder to produce pellets. The sorption capacity of the pellets is sufficiently large to not only sorb the intrinsic non-bonded uranium but to continue to sorb uranium from contaminated water. Furthermore, the uranyl cation was also removed preferentially in the presence of Pb2+ and Cd2+ heavy metal cations, hydronium ions, and more importantly the naturally occurring cations, Na1+, Ca2+, and Mg2+ that occur in abundant concentrations. Clay pellets as well as powders reduced uranium concentrations, and in extreme cases from 450 ppb, 15 times the Environmental Protection Agency maximum contaminant level to non detectable limits. Clay pellets are excellent candidates for the safe and manageable removal of uranium and heavy metals to produce potable water. PMID- 30407105 TI - Synthesis and characterization of antibacterial bio-nano films for food packaging. AB - This study prepared antibacterial nanocomposite films for food packaging from Montmorillonite, which was modified by quaternary ammonium salts such as cetyltrimethylammonium bromide (CT), hexadecyl-tributyl phosphonium bromide (HD) and corn starch (CS). After this, it determined the antimicrobial activity of CS nanofilms against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) bacteria. Dispersion of silicate layers and starch nanocomposite films was analyzed by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT IR) and scanning electron microscopy (SEM), and the results indicated that presence of quaternary ammonium salts enhanced clay dispersion, and the starch films incorporated with quaternary ammonium salts would provide potential use in food packaging as nanostructural materials. The nanofilms that were obtained based on the results of the antibacterial analysis were confirmed to have much stronger antibacterial properties than those in similar studies in the literature. PMID- 30407106 TI - Behavioral Economics and Breast Cancer Screening: Looking Beyond Patient Cost. PMID- 30407107 TI - Review of Cardiovascular Drugs in Pregnancy. AB - Cardiovascular disease is now the leading cause of pregnancy-related deaths in the United States. Increasing maternal mortality in the United States underscores the importance of proper cardiovascular management. Significant physiological changes during pregnancy affect the heart's ability to respond to pathological processes such as hypertension and heart failure. These physiological changes further affect the pharmacokinetic and pharmacodynamic properties of cardiac medications. During pregnancy, these changes can significantly alter medication efficacy and metabolism. This article systematically reviews the literature on safety, efficacy, pharmacokinetics, and pharmacodynamics of cardiovascular drugs used for hypertension and heart failure during pregnancy and lactation. The 2017 American College of Cardiology/American Heart Association hypertension guidelines recommend transitioning pregnant patients to methyldopa, nifedipine, or labetalol. Heart failure medications, including beta-blockers, furosemide, and digoxin, are relatively safe and can be used effectively. Medications that block the renin angiotensin-aldosterone system have been shown to be beneficial in the general population; however, they are teratogenic and, therefore, contraindicated in pregnancy. Cardiovascular medications can also enter breast milk and, therefore, care must be taken when selecting drugs during the lactation period. A summary of the safety of drugs during pregnancy and lactation from an online resource, LactMed by the National Library of Medicine's TOXNET database, is included. High-risk pregnant patients with cardiovascular disease require a multispecialty team of doctors, including health care providers from obstetrics and gynecology, maternal fetal medicine, internal medicine, cardiovascular disease specialists, and specialized pharmacology expertise. PMID- 30407108 TI - The Experience of Being Aware of Disease Status in Women with Recurrent Ovarian Cancer: A Phenomenological Study. AB - BACKGROUND: Awareness of disease status has been identified as a factor in the treatment decision-making process. Women with recurrent ovarian cancer are facing the challenge of making treatment decisions throughout the disease trajectory. It is not understood how women with ovarian cancer perceive their disease and subsequently make treatment decisions. PURPOSE: The purpose of this phenomenological study was to understand the lived experience of women with recurrent ovarian cancer, how they understood their disease and made their treatment decisions. METHODS: A qualitative design with a descriptive phenomenological method was used to conduct 2 in-depth interviews with 12 women (n = 24 interviews). Each interview was ~60 minutes and was digitally recorded and professionally transcribed. Data collection focused on patients' understanding of their disease and how patients participated in treatment decisions. A modified version of Colaizzi's method of phenomenological reduction guided data analysis. RESULTS: Three themes emerged to describe the phenomenon of being aware of disease status: (1) perceiving recurrent ovarian cancer as a chronic illness, (2) perceived inability to make treatment decisions, and (3) enduring emotional distress. CONCLUSIONS AND IMPLICATIONS: This study revealed how 12 women conceptualized recurrent ovarian cancer as a chronic disease and their perceived inability to make treatment decisions because of lack of information and professional qualifications, resulting in enduring emotional distress. Future research should replicate the study to confirm the persistence of the themes for racially, ethnically, and religiously diverse patient samples and to improve understanding of awareness of disease status and decision-making processes of patients. PMID- 30407109 TI - Risky Sexual Behaviors and Repeat Induced Abortion Among Unmarried Young Women in China: Results from a Large, Nationwide, Population-Based Sample. AB - BACKGROUND: Young women are disadvantaged with respect to their ability to access contraception, which puts them at especially high risk of repeat induced abortion. This study aims to estimate the prevalence of repeat induced abortion and to identify its association with risky sexual behaviors among unmarried young women in China. MATERIALS AND METHODS: Data were obtained from the Survey of Youth Access to Reproductive Health in China and collected using probability proportionate to size sampling. Population numbers and prevalence of repeat induced abortion by characteristics were calculated among 11,076 unmarried young women aged 15-24 years. Univariate logistic regression, multivariate logistic regression, and logistic regression with propensity score-based weighting were used to elucidate the associations of each risky sexual behavior with repeat induced abortion among sexually active young women. RESULTS: The prevalence of repeat induced abortion was 0.8% (95% confidence interval [CI]: 0.7-1.0) among unmarried young women (11,076) and it accounted for 21.3% of those who had ever had induced abortion. Among sexually active young women, the prevalence of abortion was 4.40% (95% CI: 3.6-5.4). Condom nonuse during the first sexual experience (odds ratio = 2.72, 95% CI: 1.55-4.76), sexual activity with multiple partners (9.71, 5.61-16.81), being forced to have sexual intercourse (4.46, 1.44 13.76), casual sex (5.77, 3.28-10.13), commercial sex (4.51, 2.01-10.12), condom nonuse during the most recent sexual encounter (2.01, 1.31-3.08), and having any of the above behaviors (5.68, 2.26-14.28) were associated with repeat abortion. CONCLUSIONS: Risky sexual behaviors were associated with repeat abortion among unmarried young women in China. The findings highlight the need for reproductive health promotion programs for unmarried young women in China and other similar settings. PMID- 30407110 TI - DNA Aptamers for the Malignant Transformation Marker CD24. AB - Cluster of differentiation 24 (CD24) is a cell surface glycoprotein, which is largely present on hematopoietic cells and many types of solid tumor cells. CD24 is known to be involved in a wide range of downstream signaling pathways and neural development, yet the underlying mechanisms are poorly understood. Moreover, its production correlates with poor cancer prognosis, and targeting of CD24 with different antibodies has been shown to inhibit disease progression. Nucleic acid aptamers are oligonucleotides that are selected from random DNA or RNA libraries for high affinity and specific binding to a certain target. Thus, they can be used as an alternative to antibodies. To gain an insight on CD24 role and its interaction partners, we performed several SELEX (systematic evolution of ligands by exponential enrichment) experiments to select CD24-specfiic DNA aptamers. We found that the cell-SELEX approach was the most useful and that using HT-29 cell line presenting CD24 along with CD24 knockdown HT-29 cells has selected six aptamers. For the selected aptamers, we determined dissociation constants in the nanomolar range (18-709 nM) using flow cytometry. These aptamers can be applied as diagnostic tools to track cancer progression and bear a potential for therapeutic use for inhibiting signaling pathways that promote the metastatic process. PMID- 30407111 TI - HMGB1 Antagonist, Box A, Reduces TLR4, RAGE, and Inflammatory Cytokines in the Cornea of P. aeruginosa-Infected Mice. AB - PURPOSE: High mobility group box 1 (HMGB1) contributes to adverse disease outcome in Pseudomonas aeruginosa keratitis. This study tests Box A, an HMGB1 antagonist, in a model of the disease. METHODS: C57BL/6 mice (B6) were injected subconjunctivally (1 day before infection) with Box A or phosphate-buffered saline (PBS), infected with P. aeruginosa strain ATCC 19660, and injected intraperitoneally with Box A or PBS at 1 and 3 days postinfection (p.i.). Clinical scores, photographs with a slit lamp camera, real-time polymerase chain reaction (RT-PCR), western blot, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), myeloperoxidase (MPO), and bacterial plate count were used to assess disease outcome. In separate experiments, the therapeutic potential of Box A was tested as described above, but with treatment begun at 6 h p.i. RESULTS: Box A versus PBS prophylactic treatment significantly reduced clinical scores, MPO activity, bacterial load, and expression of TLR4, RAGE, IL 1beta, CXCL2, and TNF-alpha in the infected cornea. Box A blocked co-localization of HMGB1/TLR4 in infiltrated cells in the stroma at 3 and 5 days p.i., but only at 5 days p.i. for HMGB1/RAGE. Box A versus PBS therapeutic treatment significantly reduced clinical scores, MPO activity, bacterial load, and protein levels of IL-1beta, CXCL2, and IL-6 in the infected cornea. CONCLUSION: Overall, Box A lessens the severity of Pseudomonas keratitis in mice by decreasing expression of TLR4, RAGE (their interaction with HMGB1), IL-1beta, CXCL2 (decreasing neutrophil infiltrate), and bacterial plate count when given prophylactically. Therapeutic treatment was not as effective at reducing opacity (disease), but shared similar features with pretreatment of the mice. PMID- 30407112 TI - Laparoscopic Magnet-Assisted Percutaneous Endoscopic Gastrostomy Placement. AB - BACKGROUND: There are various methods to place a gastrostomy tube. We report a laparoscopic method to place a standard percutaneous endoscopic gastrostomy (PEG) tube without the use of endoscopy. METHODS: Laparoscopic magnet-assisted PEG placement was carried out using an orogastric tube attached with a magnet that is used to retrieve the PEG wire that has been percutaneously placed into the stomach. RESULTS: Four pediatric patients (mean age 31 months) underwent a PEG tube placement using the laparoscopic magnet-assisted PEG tube insertion technique during 2017. There were no immediate and long-term tube placement complications. Retrieval of the PEG wire using the magnet-tipped orogastric tube was successful in all patients. CONCLUSION: Laparoscopic magnet-assisted PEG tube placement allows precise PEG tube placement without the need for endoscopy. PMID- 30407113 TI - Residue levels and spatial distribution of phthalate acid esters in water and sediment from urban lakes of Guangzhou, China. AB - The residue levels and composition profiles of phthalate acid esters (PAEs) in water and sediment samples were investigated in eight urban lakes of Guangzhou, China. A total of 23 water and 16 sediment samples were collected. Results showed that all target PAEs were detected with dimethyl phthalate and di(2-ethylhexyl) phthalate as the most abundant compounds. The total concentrations of PAEs from different urban lakes were in the range of 273-1173 ng/L for water and 16.5-242 ng/g for sediments, with the geometric mean of 515 ng/L and 75.0 ng/g, respectively. Zhongshan Park Lake and Liwan Lake were the most highly contaminated with PAEs in water and in sediment, respectively. The spatial distribution of PAEs exhibited that distribution coefficients of PAEs between sediment and water are consistent with hydrophilicity of PAEs, and pollution levels and characteristics of PAEs in different lakes had a close relationship with the geographical location of the lake, industrial and commercial types, population density, and the association between the lake and the Pearl River. According to Pearson correlation analysis, PAEs would be derived from similar or identical sources. Risk assessment suggested that the exposure of PAEs in Guangzhou has a moderate toxicity at the current level. PMID- 30407114 TI - The endogenous opioid system modulates defensive behavior evoked by Crotalus durissus terrificus: Panicolytic-like effect of intracollicular non-selective opioid receptors blockade. AB - BACKGROUND:: There is a controversy regarding the key role played by opioid peptide neurotransmission in the modulation of panic-attack-related responses. AIMS:: Using a prey versus rattlesnakes paradigm, the present work investigated the involvement of the endogenous opioid peptide-mediated system of the inferior colliculus in the modulation of panic attack-related responses. METHODS:: Wistar rats were pretreated with intracollicular administration of either physiological saline or naloxone at different concentrations and confronted with rattlesnakes ( Crotalus durissus terrificus). The prey versus rattlesnake confrontations were performed in a polygonal arena for snakes. The defensive behaviors displayed by prey (defensive attention, defensive immobility, escape response, flat back approach and startle) were recorded twice: firstly, over a period of 15 min the presence of the predator and a re-exposure was performed 24 h after the confrontation, when animals were exposed to the experimental enclosure without the rattlesnake. RESULTS:: The intramesencephalic non-specific blockade of opioid receptors with microinjections of naloxone at higher doses decreased both anxiety (defensive attention and flat back approach) and panic attack-like (defensive immobility and escape) behaviors, evoked in the presence of rattlesnakes and increased non-defensive responses. During the exposure to the experimental context, there was a decrease in duration of defensive attention. CONCLUSIONS:: These findings suggest a panicolytic-like effect of endogenous opioid receptors antagonism in the inferior colliculus on innate (panic attack) and conditioned (anticipatory anxiety) fear in rats threatened by rattlesnakes. PMID- 30407115 TI - Comparative Analysis of Carbapenem-Resistant Acinetobacter baumannii Sequence Types in Southern Brazil: From the First Outbreak (2007-2008) to the Endemic Period (2013-2014). AB - Acinetobacter baumannii is considered an important pathogen of clinical significance that is responsible for a wide range of nosocomial infections. Carbapenem resistance among A. baumannii isolates has increased dramatically in the Past years because of the emergence and dissemination of specific epidemic clones. We aimed to characterize the population structure of A. baumannii isolates from Porto Alegre city, Southern Brazil, in two distinct periods: during the first carbapenem-resistant A. baumannii (CRAB) outbreak (2007-2008) and 5 years later when the CRAB reached endemic levels (2013-2014). The study included 49 CRAB isolates collected in two periods: 2007-2008 (31 isolates) and 2013-2014 (18 isolates). Multilocus sequence typing (MLST) was performed according to Institute Pasteur, followed by eBURST analysis. PCR was used to detect integrase gene, blaNDM, and oxacillinase genes, and also to detect the ISAba1 element upstream blaOXA-23. The eBURST analysis identified the clonal complexes (CCs) CC15, CC32, CC79, CC216, CC221, and CC464 in the first period (2007-2008) and CC1, CC2, CC15, CC79, and CC162 during the endemic period (2013-2014). Molecular analysis by MLST identified 13 new sequence types. As we found A. baumannii with the blaOXA-23 gene of several CCs, it can be concluded that the increase of CRAB infections are not related to a specific clone. Furthermore, the high-risk CC15 and CC79 were related to the first CRAB outbreak and these CCs persisted up to 2014 in Porto Alegre city. The international clones CC1 and CC2 were observed for the first time in only the second period (2013-2014), alerting to the emergence of these clones in Southern Brazil. PMID- 30407117 TI - The Evolution of the Concept of Transference. PMID- 30407116 TI - Clinicopathologic Analysis of Oral Squamous Cell Carcinoma After 125I Interstitial Brachytherapy. AB - Oral squamous cell carcinoma is a common malignancy in the head and neck region. Brachytherapy after radical surgery has achieved much progress as a cancer adjuvant treatment. This study focused on the pathologic characteristics of the patients with oral squamous cell carcinoma who underwent seed implantation after radical surgery, and the relationship of these characteristics with prognosis. Thus, 76 patients with oral squamous cell carcinoma, who were treated with surgery and subsequently with iodine 125 (125I) radioactive seed implantation, were recruited in this study. We summarized the demographic information, tumor size, location, clinical stage, prognosis, and pathologic characteristics, and discussed the correlations between prognosis and histologic features of oral squamous cell carcinoma after seed implantation. The data showed that the median age was 64 years old, the male/female ratio was 47/29, and the frequent location of the carcinoma was the tongue (35.5%). The median follow-up time was 126 months, and of the patients, 52 (68.4%) exhibited recurrent tumors. The 5-year survival rate was 81.5%, and the local control rate in 6 months was 95.3%. Microscopically, 25 cases demonstrated lymph node metastasis, there was obvious necrosis in 13 cases, and 55 cases exhibited confirmed adjacent tissue invasion including muscle, gland, vessel, nerve, and bone infiltration. Among those, vascular infiltration (13 cases) was significantly correlated with tumor recurrence ( P < .05). This study suggests that detailed pathologic diagnosis and microscopic description, especially of vascular infiltration, was valuable in the prognosis prediction of brachytherapy. PMID- 30407118 TI - Henry Bate's Tabule Machlinenses: the earliest astronomical tables by a Latin author. AB - The known works of the medieval astronomer/astrologer Henry Bate (1246-after 1310) include a set of planetary mean motion tables for the meridian of his Flemish hometown Mechelen. These tables survive in three manuscripts representing two significantly different recensions, but have never been examined for their principles of construction or underlying parameters. Such analysis reveals that Bate employed an unusual value for the length of the tropical year (c.365 1/4 - 1/112 days), which was probably derived by comparing ancient and contemporary observations of the vernal equinox. In addition, there are clear signs that Bate kept revising his parameters for the mean motions of Venus and the three superior planets, none of which can be traced back to earlier sources. Together with some of Bate's preserved statements, these findings support the conclusion that the Tabule Machlinenses were unique among the astronomical tables produced in medieval Latin Christendom for using independently derived parameters that were the result of new observations. Bate's achievement connects him to a wider milieu of astronomers operating in late-thirteenth-century Paris, who put an increased emphasis on observation and the critical examination of received data. PMID- 30407119 TI - Soft Radio-Frequency Identification Sensors: Wireless Long-Range Strain Sensors Using Radio-Frequency Identification. AB - Increasing amounts of attention are being paid to the study of Soft Sensors and Soft Systems. Soft Robotic Systems require input from advances in the field of Soft Sensors. Soft sensors can help a soft robot to perceive and to act upon its immediate environment. The concept of integrating sensing capabilities into soft robotic systems is becoming increasingly important. One challenge is that most of the existing soft sensors have a requirement to be hardwired to power supplies or external data processing equipment. This requirement hinders the ability of a system designer to integrate soft sensors into soft robotic systems. In this article, we design, fabricate, and characterize a new soft sensor, which benefits from a combination of radio-frequency identification (RFID) tag design and microfluidic sensor fabrication technologies. We designed this sensor using the working principle of an RFID transporter antenna, but one whose resonant frequency changes in response to an applied strain. This new microfluidic sensor is intrinsically stretchable and can be reversibly strained. This sensor is a passive and wireless device, and as such, it does not require a power supply and is capable of transporting data without a wired connection. This strain sensor is best understood as an RFID tag antenna; it shows a resonant frequency change from approximately 860 to 800 MHz upon an applied strain change from 0% to 50%. Within the operating frequency, the sensor shows a standoff reading range of >7.5 m (at the resonant frequency). We characterize, experimentally, the electrical performance and the reliability of the fabrication process. We demonstrate a pneumatic soft robot that has four microfluidic sensors embedded in four of its legs, and we describe the implementation circuit to show that we can obtain movement information from the soft robot using our wireless soft sensors. PMID- 30407120 TI - Chain-Like Granular Jamming: A Novel Stiffness-Programmable Mechanism for Soft Robotics. AB - The ability to regulate the mechanical stiffness in a large range could be extremely important for soft robots to interact with the environment more effectively. In this article, we propose a novel chain-like granular jamming mechanism to achieve a large range of stiffness variation instantly, based on a method that is totally different from existing vacuum-based granular jamming systems. Theoretical modeling is introduced to find the best combination of granules to form the chain-like structure (CLS) and experiments are conducted to demonstrate it. The experimental results indicate that the novel jamming structure is able to achieve a stiffness variation range as large as 50.7 folds. To further validate the effectiveness of the CLS, a soft-rigid hybrid actuator based on the jamming structure is proposed and an integrated fabrication method is provided. Furthermore, an anthropomorphic hand based on the hybrid actuators is developed and the experimental results show that the hand is not only versatile enough to manipulate various objects with different weights, material properties, shapes, and surface characteristics at the soft state, like existing soft grippers, but also can lift heavy objects (1.5 kg in a cylindrical grasping gesture and 3.52 kg in a hook gesture) at the rigid state, which could be difficult for other soft grippers. Finally, the hand is integrated into our homemade service robot, significantly improving the practicability and safety of the robot when serving humans. PMID- 30407121 TI - Identification of promoter P cadR, in silico characterization of cadmium resistant gene cadR and molecular cloning of promoter P cadR from Pseudomonas aeruginosa BC15. AB - Cadmium (Cd) remediation in Pseudomonas aeruginosa is achieved through the function of two vital genes, cadA and cadR, that code for P-type ATPase (CadA) and transcription regulatory protein (CadR), respectively. Although numerous studies are available on these metal-sensing and regulatory proteins, the promoter of these genes, metal sensing and binding ability, are poorly understood. The present work is aimed at the characterization of the CadR protein, identification of the P cadR promoter and protein-promoter-metal binding affinity using bioinformatics and to validate the results by cloning the P cadR promoter in Escherichia coli DH5alpha. The promoter regions and its curvature were identified and analysed using PePPER software (University of Groningen, The Netherland) and the Bendit program (Version: v.1.0), respectively. Using Phyre, the three-dimensional structure of CadR was modelled, and the structure was validated by Ramachandran plots. The DNA-binding domain was present in the N terminal region of CadR. A dimeric interface was observed in helix-turn-helix and metal ion-binding sites at the C-terminal. Docking studies showed higher affinity of Cd to both CadR (Atomic contact energy = -15.04 kcal/Mol) and P cadR (Atomic contact energy = -40.18 kcal/Mol) when compared to other metal ions. CadR with P cadR showed the highest binding affinity (Atomic contact energy= -250.40 kcal/Mol) when compared with P cadA. In vitro studies using green fluorescent protein tagged with P cadR ( gfp-P cadR) cloned in E. coli-expressed gfp protein in a concentration-dependent manner upon Cd exposure. Based on our in silico studies and in vitro molecular cloning analysis, we conclude that P cadR and CadR are active only in the presence of Cd. The CadR protein has the highest binding affinity with P cadR. As it became apparent that the cadR gene regulates the P cadR activity in the presence of Cd with high specificity, and the cadR and P cadR can be used as a biological tool for development of a microbial biosensor. PMID- 30407122 TI - Local Toxicity of Topically Administrated Thermoresponsive Systems: In Vitro Studies with In Vivo Correlation. AB - Thermoresponsive materials have the ability to respond to a small change in temperature-a property that makes them useful in a wide range of applications and medical devices. Although very promising, there is only little conclusive data about the cytotoxicity and tissue toxicity of these materials. This work studied the biocompatibility of three Food and Drug Administration approved thermoresponsive polymers: poly( N-isopropyl acrylamide), poly(ethylene glycol) poly(propylene glycol)-poly(ethylene glycol) tri-block copolymer, and poly(lactic acid-co-glycolic acid) and poly(ethylene glycol) tri-block copolymer. Fibroblast NIH 3T3 and HaCaT keratinocyte cells were used for the cytotoxicity testing and a mouse model for the in vivo evaluation. In vivo results generally showed similar trends as the results seen in vitro, with all tested materials presenting a satisfactory biocompatibility in vivo. pNIPAM, however, showed the highest toxicity both in vitro and in vivo, which was explained by the release of harmful monomers and impurities. More data focusing on the biocompatibility of novel thermoresponsive biomaterials will facilitate the use of existing and future medical devices. PMID- 30407124 TI - Weight Loss Strategies Used by Army Reserve Officer Training Corps Cadets: Implication for Student Health and Wellness Services. AB - BACKGROUND: Maintaining a healthy weight is a military requirement for the Reserve Officer Training Corps (ROTC) cadets. Male and female soldiers often have different approaches to maintaining a healthy weight and mobile health (m-health) tools can be harnessed and tailored to the needs of individual cadets. OBJECTIVES: This study examined gender differences in technology use, weight loss strategies, information needed to maintain a healthy weight, and willingness to participate in m-health research and programs. MATERIALS AND METHODS: A self administered survey was completed by 404 cadets from ROTC programs in Florida in 2017. RESULTS: Most owned smartphones and used them as their primary internet access. Women had significantly lower body mass index than men (p = 0.037). Most used healthy weight loss strategies, including increasing physical activity, reducing sweets, and reducing fried foods. Women were more likely than men to reduce fried foods (p < 0.0003) and sweets (p = 0.020). Most reported a willingness to participate in m-health weight management research and programs, with women more willing to do so (p = 0.038). Most were willing to participate in m-health programs that used text messages, food/activity/sleep apps, smart watches/fitness trackers, and stress management/anxiety apps. Women were more willing to participate in programs that used apps for stress/anxiety management (p = 0.004) and to track food/activity/sleep (p < 0.0001). Most needed information on eating healthy on a budget and eating healthy on-the-run. CONCLUSIONS: Opportunities exist for college health and wellness professionals to use a variety of m-health tools and apps to promote general health and wellness and to help cadets achieve and maintain a healthy weight. PMID- 30407123 TI - Real-Time Tumor-Tracking Radiotherapy and General Stereotactic Body Radiotherapy for Adrenal Metastasis in Patients With Oligometastasis. AB - BACKGROUND:: Precise local radiotherapy for adrenal metastasis can prolong the useful life of patients with oligometastasis. The aim of this retrospective, 2 center study was to establish the safety and effectiveness of real-time tumor tracking radiotherapy and general stereotactic body radiotherapy in treating patients with adrenal metastatic tumors. MATERIALS AND METHODS:: Thirteen lesions in 12 patients were treated with real-time tumor-tracking radiotherapy (48 Gy in 8 fractions over 2 weeks) and 8 lesions in 8 patients were treated with general stereotactic body radiotherapy (40-50 Gy in 5-8 fractions over 2 weeks or 60-70 Gy in 10 fractions over 2 weeks). Overall survival rates, local control rates, and adverse effects were analyzed. RESULTS:: The actuarial overall survival rates for all patients at 1 and 2 years were 78.5% and 45.8%, respectively, with a median follow-up of 17.5 months, and the actuarial local control rates for all tumors at 1 and 2 years were 91.7% and 53.0%, respectively, with a median follow up of 9 months. A complete local tumor response was obtained in 3 tumors treated by real-time tumor-tracking radiotherapy (lung adenocarcinomas with diameters of 35, 40, and 60 mm). There was a statistically significant difference in the local control between the groups treated by real-time tumor-tracking radiotherapy (100% at 1 year) and general stereotactic body radiotherapy (50% at 1 year; P < .001). No late adverse reactions at Grade 2 or higher were reported for either treatment group. CONCLUSIONS:: This study showed that although both treatments are safe and effective, the real-time tumor-tracking radiotherapy is more effective than general stereotactic body radiotherapy in local control for adrenal metastasis. PMID- 30407125 TI - A Soft Retraction System for Surgery Based on Ferromagnetic Materials and Granular Jamming. AB - In recent years, minimally invasive surgery (MIS) has gained wider acceptance among surgeons. MIS requires high skills for the operators, mainly due to its intrinsic technical limitations. Tissue manipulation and retraction remain the most challenging tasks; more specifically liver, stomach, and intestine are the organs mostly involved in retraction tasks for abdominal procedures. The literature reports an increasing interest toward dedicated solutions for abdominal tissue retraction tasks. To overcome the limitations of commercial systems and research prototypes, the aim of this study is the design, the realization, and the validation of a retraction system that is simple, reliable, easy to use, safe, and broadly compatible with MIS. The proposed retractor has two main components: (1) a soft central part with variable stiffness obtained by exploiting the granular jamming phenomenon for assuring, at the same time, safe introduction into the abdominal cavity and stable retraction and (2) two iron cylinders located at the two extremities of the device for anchoring the retractor to the abdominal wall by using the magnetic attraction force between these components and two external permanent magnets. System design has been performed by deeply investigating granular jamming principle and ferromagnetic properties of iron elements. Ex vivo and in vivo assessment has been carried out with the final aim to identify the most appropriate design of each retractor component and to demonstrate the advantages of using a soft system with variable stiffness during a retraction task. PMID- 30407126 TI - Mentally Disordered Firesetters: An Examination of Risk Factors. AB - OBJECTIVE: In this study, we examined the risk-related characteristics of mentally disordered patients who had either been (1) involved in a firesetting incident or (2) involved in a nonfiresetting comparison incident while under the care of the National Health Service (NHS). METHOD: A total of 132 participants were recruited from an NHS Care Group in England (66 mentally disordered firesetters, 66 mentally disordered comparisons). Logistic regression was used to model the ability of static, dynamic, and incident-related factors in predicting whether a patient had set a fire (including gender-sensitive subanalyses), whether a patient firesetter was male or female, and a one-time or repeat firesetter. RESULTS: We identified a cluster of variables that predicted firesetting status. We also identified key factors that predicted female patient firesetters relative to female patient controls who engaged in other undesirable behaviors and male patient firesetters. A cluster of variables predictive of repeat versus one-time firesetting also emerged. CONCLUSIONS: Findings are discussed in relation to further development of risk-related firesetting theory. PMID- 30407127 TI - Agile and Resilient Insect-Scale Robot. AB - A key challenge in bioinspired insect-scale running robots is to make them both agile and resilient. In this study, we develop a dielectric elastomer actuated soft robot that mimics inchworms. We use an elastomer to make the soft body, a stretchable dielectric to provide electrostatic actuation of high power density, and multizone actuation to achieve ratcheting locomotion. We fabricate the body, muscles, and feet in a single piece, with no internal open space. The robot runs four times its body length per second and turns at a radius about three times its body length in 0.3 s. The robot survives compression 30,000 times its own weight and survives collision with a rigid surface at a speed of 30 m/s. The robot can climb a slope of 30 degrees . Walking on a horizontal plane, the robot carries a payload four times its own weight. The robot can operate on land, underwater, and in vacuum. The simplicity in design and fabrication will enable the robot to serve as a model system to investigate insect-scale actuation and locomotion, as well as the social behavior of swarms of robots. The robot also provides a platform to integrate wireless charging, mobile communication, and stretchable electronics. PMID- 30407128 TI - "It seems kinda like a different language to us": Homeless youths' attitudes and experiences pertaining to condoms and contraceptives. AB - Homeless youth become pregnant or involved in pregnancies at high rates. There are many ways by which unintended pregnancies may be prevented, including the use of condoms and other contraceptives. However, there is a dearth of research regarding contraceptive use among this vulnerable youth population, and especially through lenses that consider homeless youths' diverse gender identities, expressions, and sexualities. This study qualitatively explores homeless youths' attitudes and experiences regarding condom and other contraceptive use. Data were obtained from interviews with 30 youth experiencing homelessness, ages 18-21. Youth reported inconsistent use of condoms and other contraceptives, which youth often attributed to their perceptions of contraceptive inaccessibility and exorbitant cost. Most youth also did not know where to obtain contraceptive information and services, and reported transportation barriers and fear of being stigmatized in health care settings, particularly in relation to their gender identities and sexualities. Findings suggest that reproductive and sexual health information and services are urgently needed by all homeless young people, and from low-barrier, non-judgmental, and empathetic sources. PMID- 30407129 TI - Predictors of death anxiety among patients with heart disease. AB - OBJECTIVE: This research examines whether or not socio-demographic factors and hope predict death anxiety among patients with heart disease. MATERIALS AND METHODS: Our sample consisted of 500 respondents who were hospitalized in a medical institution in Iran. Data were collected using the Templer Death Anxiety Scale (TDAS) and the Herth Hope Index (HHI). RESULTS: The results of current study indicated that higher economic status, having one's main source of income from friends, increased age, increased religious belief, and increased hope were associated with lower death anxiety. CONCLUSION: These results highlight that improving hope, and religiosity among cardiac patients may be an effective means by which to reduce their death anxiety. PMID- 30407130 TI - Factors affecting smoke and crystalline silica exposure among wildland firefighters. AB - Smoke exposure data among U.S. wildland firefighters for carbon monoxide, respirable particulate and respirable crystalline silica are presented from a field surveillance program between 2009 and 2012. Models to predict fireline average exposure to each inhalation hazard were developed and fit to the available data. The models identify factors to consider when defining similar exposure groups and designing future data collection. Task-based rather than shift-average data collection is important because the work activity representing the majority of fireline time, the position up- or downwind of the fire, and the proportion of time this combination represented were significant factors in the model for carbon monoxide, and all but wind position were significant for respirable particulate matter. The wind position versus the fire was not important for respirable quartz exposure. The crew type was an important factor in each model. PMID- 30407131 TI - Endovascular management of ruptured abdominal aortic aneurysms and acute aortic dissections. AB - The management of vascular emergencies is dependent on rapid identification and confirmation of the diagnosis with concurrent patient stabilization prior to immediate transfer to the operating suite. A variety of technological advances in diagnostic imaging as well as the advent of minimally invasive endovascular interventions have shifted the contemporary treatment algorithms of such pathologies. This review provides a comprehensive discussion on the current state and future trends in the management of ruptured abdominal aortic aneurysms as well as acute aortic dissections. PMID- 30407132 TI - Central nervous system modulates the neuromechanical delay in a broad range for the control of muscle force. AB - Force is generated by muscle units according to the neural activation sent by motor neurons. The motor unit is therefore the interface between the neural coding of movement and the musculotendinous system. Here we propose a method to accurately measure the latency between an estimate of the neural drive to muscle and force. Furthermore, we systematically investigate this latency, which we refer to as the neuromechanical delay (NMD), as a function of the rate of force generation. In two experimental sessions, eight men performed isometric finger abduction and ankle dorsiflexion sinusoidal contractions at three frequencies and peak-to-peak amplitudes {0.5, 1, and 1.5 Hz; 1, 5, and 10 of maximal force [%maximal voluntary contraction (MVC)]}, with a mean force of 10% MVC. The discharge timings of motor units of the first dorsal interosseous (FDI) and tibialis anterior (TA) muscle were identified by high-density surface EMG decomposition. The neural drive was estimated as the cumulative discharge timings of the identified motor units. The neural drive predicted 80 +/- 0.4% of the force fluctuations and consistently anticipated force by 194.6 +/- 55 ms (average across conditions and muscles). The NMD decreased nonlinearly with the rate of force generation ( R2 = 0.82 +/- 0.07; exponential fitting) with a broad range of values (from 70 to 385 ms) and was 66 +/- 0.01 ms shorter for the FDI than TA ( P < 0.001). In conclusion, we provided a method to estimate the delay between the neural control and force generation, and we showed that this delay is muscle dependent and is modulated within a wide range by the central nervous system. NEW & NOTEWORTHY The motor unit is a neuromechanical interface that converts neural signals into mechanical force with a delay determined by neural and peripheral properties. Classically, this delay has been assessed from the muscle resting level or during electrically elicited contractions. In the present study, we introduce the neuromechanical delay as the latency between the neural drive to muscle and force during variable-force contractions, and we show that it is broadly modulated by the central nervous system. PMID- 30407133 TI - Impulsivity and Active Inference. AB - This article characterizes impulsive behavior using a patch-leaving paradigm and active inference-a framework for describing Bayes optimal behavior. This paradigm comprises different environments (patches) with limited resources that decline over time at different rates. The challenge is to decide when to leave the current patch for another to maximize reward. We chose this task because it offers an operational characterization of impulsive behavior, namely, maximizing proximal reward at the expense of future gain. We use a Markov decision process formulation of active inference to simulate behavioral and electrophysiological responses under different models and prior beliefs. Our main finding is that there are at least three distinct causes of impulsive behavior, which we demonstrate by manipulating three different components of the Markov decision process model. These components comprise (i) the depth of planning, (ii) the capacity to maintain and process information, and (iii) the perceived value of immediate (relative to delayed) rewards. We show how these manipulations change beliefs and subsequent choices through variational message passing. Furthermore, we appeal to the process theories associated with this message passing to simulate neuronal correlates. In future work, we will use this scheme to identify the prior beliefs that underlie different sorts of impulsive behavior-and ask whether different causes of impulsivity can be inferred from the electrophysiological correlates of choice behavior. PMID- 30407134 TI - Grasping Neurons in the Ventral Premotor Cortex of Macaques Are Modulated by Social Goals. AB - Although it is established that F5 neurons can distinguish between nonsocial goals such as bringing food to the mouth for eating or placing it in a container, it is not clear whether they discriminate between social and nonsocial goals. Here, we recorded single-unit activity in the ventral premotor cortex of two female macaques and used a simple reach-to-grasp motor task in which a monkey grasped an object with a precision grip in three conditions, which only differed in terms of their final goal, that is, a subsequent motor act that was either social (placing in the experimenter's hand ["Hand" condition]) or nonsocial (placing in a container ["Container" condition] or bringing to the mouth for eating ["Mouth" condition]). We found that, during the execution of the grasping motor act, the response of a sizable proportion of F5 motor neurons was modulated by the final goal of the action, with some having a preference for the social goal condition. Our results reveal that the representation of goal-directed actions in ventral premotor cortex is influenced by contextual information not only extracted from physical cues but also from cues endowed with biological or social value. Our study suggests that the activity of grasping neurons in the premotor cortex is modulated by social context. PMID- 30407135 TI - C957T-mediated Variation in Ligand Affinity Affects the Association between 11C raclopride Binding Potential and Cognition. AB - The dopamine (DA) system plays an important role in cognition. Accordingly, normal variation in DA genes has been found to predict individual differences in cognitive performance. However, little is known of the impact of genetic differences on the link between empirical indicators of the DA system and cognition in humans. The present work used PET with 11C-raclopride to assess DA D2-receptor binding potential (BP) and links to episodic memory, working memory, and perceptual speed in 179 healthy adults aged 64-68 years. Previously, the T allele of a DA D2-receptor single-nucleotide polymorphism, C957T, was associated with increased apparent affinity of 11C-raclopride, giving rise to higher BP values despite similar receptor density values between allelic groups. Consequently, we hypothesized that 11C-raclopride BP measures inflated by affinity rather than D2-receptor density in T-allele carriers would not be predictive of DA integrity and therefore prevent finding an association between 11C-raclopride BP and cognitive performance. In accordance with previous findings, we show that 11C-raclopride BP was increased in T-homozygotes. Importantly, 11C-raclopride BP was only associated with cognitive performance in groups with low or average ligand affinity (C-allele carriers of C957T, n = 124), but not in the high-affinity group (T-homozygotes, n = 55). The strongest 11C raclopride BP-cognition associations and the highest level of performance were found in C-homozygotes. These findings show that genetic differences modulate the link between BP and cognition and thus have important implications for the interpretation of DA assessments with PET and 11C-raclopride in multiple disciplines ranging from cognitive neuroscience to psychiatry and neurology. PMID- 30407136 TI - Glucocorticoids, Noradrenergic Arousal, and the Control of Memory Retrieval. AB - Glucocorticoids and noradrenaline can enhance memory consolidation but impair memory retrieval. Beyond their effects on quantitative memory performance, these major stress mediators bias the engagement of multiple memory systems toward "habitual" control during learning. However, if and how glucocorticoids and noradrenaline may also affect which memory system is recruited during recall, thereby affecting the control of retrieval, remain largely unknown. To address this question, we trained healthy participants in a probabilistic classification learning task, which can be supported both by cognitive and habitual strategies. Approximately 24 hr later, participants received a placebo, hydrocortisone, yohimbine (an alpha2-adrenoceptor antagonist increasing noradrenergic stimulation), or both drugs before they completed a recall test for the probabilistic classification learning task. During training, all groups showed a practice-dependent shift toward more habitual strategies, reflecting an "automatization" of behavior. In the recall test, after a night of sleep, this automatization was even more pronounced in the placebo group, most likely due to offline consolidation processes and with beneficial effects on recall performance. Hydrocortisone or yohimbine intake abolished this further automatization, preventing the shift to a more efficient memory system and leading, in particular in the hydrocortisone group, to impaired recall performance. Our results suggest that glucocorticoids and noradrenergic stimulation may modulate the engagement of different strategies at recall and link the well-known stress hormone-induced retrieval deficit to a change in the system controlling memory retrieval. PMID- 30407137 TI - Diagnosis of non-effusive feline infectious peritonitis by reverse transcriptase quantitative PCR from mesenteric lymph node fine-needle aspirates. AB - OBJECTIVES: The aim of this study was to evaluate a feline coronavirus (FCoV) reverse transcriptase quantitative PCR (RT-qPCR) on fine-needle aspirates (FNAs) from mesenteric lymph nodes (MLNs) collected in sterile saline for the purpose of diagnosing non-effusive feline infectious peritonitis (FIP) in cats. METHODS: First, the ability of the assay to detect viral RNA in MLN FNA preparations compared with MLN biopsy preparations was assessed in matched samples from eight cats. Second, a panel of MLN FNA samples was collected from a series of cats representing non-effusive FIP cases (n = 20), FCoV-seropositive individuals (n = 8) and FCoV seronegative individuals (n = 18). Disease status of the animals was determined using a combination of gross pathology, histopathology and/or 'FIP profile', consisting of serology, clinical pathology and clinical signs. RESULTS: Viral RNA was detected in 18/20 non-effusive FIP cases; it was not detected in two cases that presented with neurological FIP. Samples from 18 seronegative non FIP control cats and 7/8 samples from seropositive non-FIP control cats contained no detectable viral RNA. Thus, as a method for diagnosing non-effusive FIP, MLN FNA RT-qPCR had an overall sensitivity of 90.0% and specificity of 96.1%. CONCLUSIONS AND RELEVANCE: In cases with a high index of suspicion of disease, RT qPCR targeting FCoV in MLN FNA can provide important information to support the ante-mortem diagnosis of non-effusive FIP. Importantly, viral RNA can be reliably detected in MLN FNA samples in saline submitted via the national mail service. When applied in combination with biochemistry, haematology and serological tests in cases with a high index of suspicion of disease the results of this assay may be used to support a diagnosis of non-effusive FIP. PMID- 30407138 TI - Feline histoplasmosis presenting with bone and joint involvement: clinical and diagnostic findings in 25 cats. AB - OBJECTIVES: The aim of this study was to describe clinical and diagnostic findings in cats with bone and joint disease associated with histoplasmosis. METHODS: Medical records from between 2011 and 2017 were reviewed. Inclusion criteria required: (1) diagnosis of histoplasmosis by cytology, histology, urine or serum Histoplasma antigen testing, or culture; and (2) lameness or joint effusion as a presenting complaint or physical examination finding. RESULTS: Twenty-five cases met the inclusion criteria. Four had incomplete records, but available data were included when applicable. Lameness was a presenting complaint in 17/21 cats and was the only complaint in 9/21 cats. Initial diagnosis was made by cytology in 22/25 cats and by culture, urine antigen and necropsy in one case each. Diagnostic cytology samples included synovial fluid (n = 13), lymph node (n = 5), skin (n = 2), lung (n = 1) and bone (n = 1). Two additional cases had synovial fluid examined but no organisms present. Inflammation was present in all synovial fluid samples examined. Biopsy was obtained in two cats and histologic diagnoses included osteomyelitis with no infectious organisms identified and severe lymphoplasmacytic synovitis suggestive of feline periosteal proliferative polyarthritis. Histoplasma urine antigen test was positive in 7/12 cats. CONCLUSIONS AND RELEVANCE: Inflammatory arthritis is common in cats with histoplasmosis, with lameness a common presenting complaint. Organisms are found in synovial fluid cytology in most cases. If not, appropriate additional diagnostics must be pursued. PMID- 30407140 TI - Letter from the editor. PMID- 30407139 TI - 64-multidetector CT anatomical assessment of the feline bronchial and pulmonary vascular structures. AB - OBJECTIVES: The aim of the study was to provide a detailed anatomical study of the feline bronchial and vascular structures by using CT angiography (CTA). METHODS: Adult cats with no respiratory clinical signs were enrolled in a CTA protocol to provide an anatomical study of the thorax. The dimensions, number of branches and branching pattern (monopodial vs dichotomic) of both bronchial and pulmonary vascular structures were evaluated under positive inspiration apnoea. A linear generalised estimating equations analysis (Spearman's rho) was used to identify statistical correlation between tracheal diameter, age and body weight of the cats. RESULTS: Fourteen cats met the inclusion criteria. The pulmonary arteries had larger diameters than the pulmonary veins, and the pulmonary veins had larger diameters than the bronchial structures. A higher number of segmental bronchial and pulmonary vascular branches was observed in the left caudal lung lobe than in the other lobes. The monopodial branching pattern of both bronchial and pulmonary vascular structures was predominant in all cats of our study (100%) in cranial, caudal and right middle lung lobes, while a dichotomic branching pattern of the bronchial and pulmonary vascular structures of the accessory lung lobe was seen in 13 cats (93%). Thirteen cats (93%) had three pulmonary vein ostia, and one cat (7%) also presented with an additional left intermediate pulmonary vein ostium. Variation in the number of segmental pulmonary vein branches was noted in the right caudal lung lobe. There was no statistical correlation between tracheal diameter, age and weight. CONCLUSIONS AND RELEVANCE: Architecture of the feline bronchovascularr structures belongs to a mixed type of monopodial and dichotomic branching pattern. In cats, the pulmonary venous drainage system predominately presents three pulmonary vein ostia. Variations in the type of formation and the number of branches of the pulmonary venous drainage system were noted. PMID- 30407141 TI - Human Vaccines & Immunotherapeutics: News. PMID- 30407142 TI - Direct-to-consumer advertising effects on nurse-patient relationship, authority, and prescribing appropriateness. AB - BACKGROUND:: Discussing direct-to-consumer advertising of prescription drugs during a visit could affect prescribing practices and provider-patient relationship. RESEARCH OBJECTIVES:: The study examines advanced practice nurse prescribers' perceptions of direct-to-consumer advertising and its effects on nurse-patient relationship, prescriptive authority, and appropriateness of patient clinical requests. RESEARCH DESIGN:: A cross-sectional survey design was implemented. PARTICIPANTS AND RESEARCH CONTEXT:: The random sample consisted of 316 nurses (27.17% response rate) in one of the Midwestern states in the United States. Pearson's chi-square analysis and multiple/multinomial logistic regression analyses were used. ETHICAL CONSIDERATIONS:: Permission to conduct the study was obtained from the university's Institutional Review Board. Participation was voluntary, and measures were taken to protect the anonymity and confidentiality of consenting participants. FINDINGS:: Most nurses (69%) believed that patients were "poor or very poor" at assessing the relevance of drug advertisements, 61% reported that the increase in drugs advertisements directed at patient was "a bad or a very bad thing," and only 16% thought the advertisements were accurate to "a very or to a great extent." Improved nurse patient relationship was associated with factors such as the patient not bringing printed material, seeking nurse's opinion only, taking responsibility for their health, and not challenging nurse's prescriptive authority. DISCUSSION:: Advertising discussion during a visit could improve as well as pose a challenge to a nurse-patient relationship and nurse's prescriptive authority. CONCLUSION:: The positives of discussing advertising information can be maximized and the negatives minimized through enhanced interpersonal nurse-patient communication. PMID- 30407144 TI - Data and tissue research without patient consent: A qualitative study of the views of research ethics committees in New Zealand. AB - PURPOSE: Secondary use of clinical tissue and data is an increasingly important platform for health research. Many jurisdictions allow research ethics committees (RECs) or institutional review boards (IRBs) the flexibility to waive the requirement for patient consent for secondary research. But most RECs/IRBs conduct their meetings "behind closed doors" and their decision-making processes are opaque to researchers and academics. The purpose of this study was to assess how New Zealand RECs weigh the potentially competing goals of enabling research and protecting patients' rights. METHODS: We used a participatory observation approach involving observation sessions (3), focus groups (4), and individual interviews (2) with members of the national-level health and disability ethics committees (HDECs) in 2016. RESULTS: Twenty-four HDEC members participated (75% participation rate). Participants described the core ethical issues as consent, public benefit, and potential harms (to both collectives and individuals). Participants felt the weight of responsibility in waiving patients' right to consent. Time pressure and a lack of specificity in the guidelines resulted in increased anxiety and stress. Participants' comments demonstrate multiple different methods for defining and assessing public benefit. CONCLUSION: IRB/REC members have rich experience of moral reasoning regarding research ethics, especially in areas where the official guidance is underdeveloped. Their insights can contribute to the academic literature and suggest improvements in the review process and in ethical regulation and guidelines. PMID- 30407145 TI - Acute Histopathologic Findings Related to Needle Puncture Trauma during Subcutaneous Injection in the Sprague-Dawley Rat Model. AB - It is important to detect injection site reactions during the nonclinical phases of drug development. However, differentiating between normal changes following needle trauma and changes due to the toxicity of injected drugs can be challenging. Therefore, we used the Sprague-Dawley rat model to evaluate the pathological findings expected following a single subcutaneous injection of normal saline. Rats were subcutaneously administered with normal saline, and the injection sites were examined microscopically. Inflammation was evident in most of the injection sites, mostly in minimal severity. Parakeratosis/epithelial crust was also seen in several sites, and necrosis was observed in a minority of the cases. These findings indicate that needle puncture trauma can present with some degree of inflammation and necrosis. Although limited to a specific time point and strain, this study shows that inflammation following subcutaneous injection can be attributed in part to the needle trauma and not necessarily to the drug itself. PMID- 30407143 TI - Nurse participation in legal executions: An ethics round-table discussion. AB - A paper was published in 2003 discussing the ethics of nurses participating in executions by inserting the intravenous line for lethal injections and providing care until death. This paper was circulated on an international email list of senior nurses and academics to engender discussion. From that discussion, several people agreed to contribute to a paper expressing their own thoughts and feelings about the ethics of nurses participating in executions in countries where capital punishment is legal. While a range of opinions were presented, these opinions fell into two main themes. The first of these included reflections on the philosophical obligations of nurses as caregivers who support those in times of great need, including condemned prisoners at the end of life. The second theme encompassed the notion that no nurse ever should participate in the active taking of life, in line with the codes of ethics of various nursing organisations. This range of opinions suggests the complexity of this issue and the need for further public discussion. PMID- 30407146 TI - The Emergence of Microphysiological Systems (Organs-on-chips) as Paradigm changing Tools for Toxicologic Pathology. AB - Microphysiological systems (MPS), commonly known as organs-on-chips, are a rapidly advancing technology that promises to impact many areas of medical and toxicological pathology. In this minireview, the history of MPS and its potential utility in safety assessment are described with the toxicologic pathologist in mind. Several MPS development focus areas are defined, and recent progress in the area is highlighted. MPS will likely become an important tool for the toxicologic pathologist as part of our role in the safety assessment process within the pharmaceutical, biotechnology, medical device, and cosmetic and agrichemical industries. PMID- 30407147 TI - Functional and Morphological Characteristics of Pancreatic Islet Lesions Induced by Quinolone Antimicrobial Agent Gatifloxacin in Rats. AB - We characterized pancreatic islet lesions induced by several quinolones using functional and morphological examinations of the pancreatic islets in male rats orally administered gatifloxacin, lomefloxacin, or levofloxacin at 300 mg/kg for 14 consecutive days. Consequently, in contrast to lomefloxacin or levofloxacin, gatifloxacin increased serum glucose and glycosylated albumin on day 14 and elevated serum glucose tended to decrease insulin in the intravenous glucose tolerance test. Microscopically, only gatifloxacin induced cytoplasmic vacuoles containing eosinophilic homogenous contents in islet cells. Immunohistochemical examination revealed that vacuolated islet cells were positively stained for insulin, demonstrating they were pancreatic beta cells. Electron microscopy showed that the cytoplasmic vacuoles represented dilated cisterna of the rough endoplasmic reticulum filled with electron-lucent materials in pancreatic beta cells. Moreover, insulin secretory granules were drastically decreased in vacuolated islet cells, suggesting impaired insulin synthesis and/or transport. This gatifloxacin-induced pancreatic toxicity in rats was considered to be associated with high pancreatic drug distribution. These results demonstrated that gatifloxacin provoked functional and morphological pancreatic beta cell alteration associated with impaired insulin synthesis and/or transport, leading to hyperglycemia. PMID- 30407148 TI - A Comparison of Spontaneous Tumors in Tg.rasH2 Mice in 26-week Carcinogenicity Studies Conducted at a Single Test Facility during 2004 to 2012 and 2013 to 2018. AB - This article presents the historical control data of spontaneous tumors in Tg.rasH2 published in 2013 (2004-2012) and compares and contrasts it to more recent data collected from 2013 to 2018, reporting differences in the average percentage incidences or incidence ranges as well as the incidence of new tumors. In 2013, we published a comprehensive review of spontaneous tumors in Tg.rasH2 mice used in 26-week carcinogenicity studies, which included data from control dose groups from 26 studies and a total of 710 mice per sex. The total database, now including the more recent data, has nearly doubled the number of animals, completing to date a total of 52 studies in males and 51 studies in females for a total of 1,615 male mice and 1,560 female mice, respectively. In this article, we compare the data collected from 2004 to 2012 against the data collected from 2013 to 2018 and the overall tumor incidence change. PMID- 30407149 TI - Perpetrator Risk Markers for Intimate Terrorism and Situational Couple Violence: A Meta-Analysis. AB - Johnson developed a typology of intimate partner violence (IPV) which includes two different categories of violence: situational couple violence (SCV) and intimate terrorism (IT). Johnson proposed that IT is more likely to be found in clinical samples (e.g., batterer intervention programs or domestic violence shelters) compared to nonclinical (general population) samples. This meta analysis ( n = 149 studies; k = 216 effect sizes) examines differences in the strengths of IPV risk markers in clinical and nonclinical samples of male perpetrators and female victims. All variables (communication and conflict resolution, demand-withdraw patterns, relationship dissatisfaction, controlling behaviors, jealousy, patriarchal beliefs, power in the relationship, and stalking) were expected to be significantly related to IPV for both clinical and nonclinical populations. However, specific variables indicative of IT (control, jealousy, patriarchal beliefs, power, and stalking) were expected to be more strongly associated with clinical samples compared to nonclinical samples. As expected, most variables were significant for clinical and nonclinical populations, and IT risk markers (control, power, jealousy, and patriarchal beliefs) were significantly stronger risk markers for IPV in clinical samples. These results indicate that Johnson's typology may be conceptualized as representing a continuum of violence, with IT being more severe due to the controlling nature of the violence. Sample type needs to be considered when research about IPV is disseminated, as different degrees of IPV (IT vs. SCV) may be present depending on sample type. Implications from this study include the need to differentiate the level of violence and to tailor intervention for IPV appropriately. PMID- 30407150 TI - Prevalence and risk factors of human polyomavirus infections in non-malignant tonsils and gargles: the SPLIT study. AB - The prevalence of 13 polyomaviruses (PyVs) in the tonsil brushings and gargles of immunocompetent children and adults was assessed. Patients undergoing tonsillectomy for benign indications were recruited in 19 centres in France. After resection, the entire outer surface of the right and left halves of the tonsils was brushed extensively. Gargles were also collected prior to surgery in selected adults. A species-specific multiplex assay was used to detect the DNA of 13 PyVs. In tonsil brushings (n=689), human PyV 6 (HPyV6) and Merkel cell PyV (MCPyV) were the most prevalent (~15 %), followed by trichodysplasia spinulosa associated PyV (TSPyV), BKPyV, Washington University PyV (WUPyV) and human PyV 9 (HPyV9) (1 to 5 %), and human PyV 7 (HPyV7), John Cunningham PyV (JCPyV) and Simian virus 40 (SV40) (<1 %), while no Karolinska Institute PyV (KIPyV), Malawi PyV (MWPyV), human PyV 12 (HPyV12) or Lyon IARC PyV (LIPyV) were detected. The prevalence of TSPyV and BKPyV was significantly higher in children versus adults, whereas for HPyV6 the opposite was found. HPyV6 and WUPyV were significantly more prevalent in men versus women. In gargles (n=139), MCPyV was the most prevalent (~40 %), followed by HPyV6, HPyV9 and LIPyV (2 to 4 %), and then BKPyV (~1 %), while other PyVs were not detected. MCPyV and LIPyV were significantly more prevalent in gargles compared to tonsil brushings, in contrast to HPyV6. We described differing patterns of individual PyV infections in tonsils and gargles in a large age-stratified population. Comparison of the spectrum of PyVs in paired tonsil samples and gargles adds to the current knowledge on PyV epidemiology, contributing towards a better understanding of PyV acquisition and transmission and its potential role in head and neck diseases. PMID- 30407152 TI - Avoiding routine postoperative voiding cystourethrogram: Predicting radiologic success for endoscopically treated vesicoureteral reflux. AB - INTRODUCTION: Variability in the success rates for the endoscopic correction of vesicoureteral reflux (VUR) has prompted a debate regarding the use of routine postoperative voiding cystourethrogram (VCUG). This study examines the predictive performance of intraoperative mound morphology (IMM) and the presence of a postoperative ultrasound mound (PUM) on radiologic success, as well as investigates the role of using these two predictive factors as a composite tool to predict VUR resolution after endoscopic treatment. METHODS: This retrospective study included children with primary VUR who underwent endoscopic correction with a double HIT technique and dextranomer/hyaluronic acid copolymer. IMM was assessed intraoperatively. The presence of a PUM and VUR resolution were assessed by postoperative ultrasound (US) and VCUG, respectively. Radiologic success was defined as VUR resolution. RESULTS: A total of 70 children (97 ureters) were included in the study. The overall radiologic success rate was 83.5%. There was no statistically significant association between radiologic success and IMM (85.2% with excellent and 87.5% with "other" morphology; p=0.81). The sensitivity and specificity of PUM for radiologic success in this study was 98% and 71%, respectively, while the sensitivity and specificity of the combined prediction model were 81.9% and 85.7%, respectively. CONCLUSIONS: We objectively demonstrated that IMM was a poor predictor of radiologic success and should be used with caution. In addition, the performance of a combined prediction model was inferior to the presence of a PUM alone. As such, selective use of postoperative VCUG may be guided solely by the presence of a PUM. PMID- 30407151 TI - Oral steroids for hearing loss associated with otitis media with effusion in children aged 2-8 years: the OSTRICH RCT. AB - BACKGROUND: Children with hearing loss associated with otitis media with effusion (OME) are commonly managed through surgical intervention, hearing aids or watchful waiting. A safe, inexpensive, effective medical treatment would enhance treatment options. Small, poorly conducted trials have found a short-term benefit from oral steroids. OBJECTIVE: To determine the clinical effectiveness and cost effectiveness of a 7-day course of oral steroids in improving hearing at 5 weeks in children with persistent OME symptoms and current bilateral OME and hearing loss demonstrated by audiometry. DESIGN: Double-blind, individually randomised, placebo-controlled trial. SETTING: Ear, nose and throat outpatient or paediatric audiology and audiovestibular medicine clinics in Wales and England. PARTICIPANTS: Children aged 2-8 years, with symptoms of hearing loss attributable to OME for at least 3 months, a diagnosis of bilateral OME made on the day of recruitment and audiometry-confirmed hearing loss. INTERVENTIONS: A 7-day course of oral soluble prednisolone, as a single daily dose of 20 mg for children aged 2 5 years or 30 mg for 6- to 8-year-olds, or matched placebo. MAIN OUTCOME MEASURES: Acceptable hearing at 5 weeks from randomisation. Secondary outcomes comprised acceptable hearing at 6 and 12 months, tympanometry, otoscopic findings, health-care consultations related to OME and other resource use, proportion of children who had ventilation tube (grommet) surgery at 6 and 12 months, adverse effects, symptoms, functional health status, health-related quality of life, short- and longer-term cost-effectiveness. RESULTS: A total of 389 children were randomised. Satisfactory hearing at 5 weeks was achieved by 39.9% and 32.8% in the oral steroid and placebo groups, respectively (absolute difference of 7.1%, 95% confidence interval -2.8% to 16.8%; number needed to treat = 14). This difference was not statistically significant. The secondary outcomes were consistent with the picture of a small or no benefit, and we found no subgroups that achieved a meaningful benefit from oral steroids. The economic analysis showed that treatment with oral steroids was more expensive and accrued fewer quality-adjusted life-years than treatment as usual. However, the differences were small and not statistically significant, and the sensitivity analyses demonstrated large variation in the results. CONCLUSIONS: OME in children with documented hearing loss and attributable symptoms for at least 3 months has a high rate of spontaneous resolution. Discussions about watchful waiting and other interventions will be enhanced by this evidence. The findings of this study suggest that any benefit from a short course of oral steroids for OME is likely to be small and of questionable clinical significance, and that the treatment is unlikely to be cost-effective and, therefore, their use cannot be recommended. FUTURE WORK: Studies exploring optimal approaches to sharing natural history data and enhancing shared decision-making are needed for this condition. TRIAL REGISTRATION: Current Controlled Trials ISRCTN49798431 and EudraCT 2012 005123-32. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 61. See the NIHR Journals Library website for further project information. PMID- 30407153 TI - Robotic surgery improves transfusion rate and perioperative outcomes using a broad implementation process and multiple surgeon learning curves. AB - INTRODUCTION: Data from a randomized trial suggest transfusion rates are similar for robotic and open prostatectomy. The objective of this study was to compare perioperative outcomes of robotic and open prostatectomy at a Canadian academic centre. METHODS: A retrospective review of all prostatectomies performed by all surgeons at The Ottawa Hospital between 2009 and 2016 was completed. Cases and outcomes were identified using an administrative data warehouse. Extracted data included patient factors (age, body mass index, American Society of Anesthesiologists score, Elixhauser comorbidity score), operative factors (length of operation, surgical approach, anesthesia type) and perioperative outcomes (length of recovery room and hospital stay, transfusion rate, hospital cost). Baseline characteristics and outcomes were compared between robotic and open surgical approaches. The primary outcome was transfusion during the index admission. RESULTS: A total of 1606 prostatectomies were performed by 12 surgeons during the study period (840 robotic, 766 open). The rate of transfusion was lower in patients undergoing robotic compared to open surgery (0.6% vs. 11.2%; p<0.001). The robotic prostatectomy cohort had a shorter length of stay in the recovery room (155.7 vs. 231.1 minutes; p<0.001) and shorter length of hospital admission (1.4 vs. 2.8 days; p<0.001). Hospital costs per case were approximately $800 more for robotic prostatectomy ($11 475 vs. $10 656; p<0.001). CONCLUSIONS: This hospital-wide analysis revealed that robotic prostatectomy is associated with a lower transfusion rate compared to the open approach. Further studies emphasizing patient-reported outcomes are needed. PMID- 30407154 TI - Contemporary management of renal trauma in Canada: A 10-year experience at a level 1 trauma centre. AB - INTRODUCTION: Contemporary Canadian renal trauma data is lacking. Our objective is to describe 10-year outcomes of renal trauma at a Canadian level 1 trauma centre using a conservative approach. METHODS: The Alberta Trauma Registry at the University of Alberta was used to identify renal trauma patients from October 2004 to December 2014. Hospital records and imaging were reviewed to identify clinicoradiographical factors, including patient age, gender, Injury Severity Score (ISS), American Association of the Surgery for Trauma (AAST) grade, computerized tomography (CT) findings, urological interventions, length of stay, transfusion and death rates. Descriptive statistics, Chi-square, and t-tests were used when appropriate. RESULTS: A total of 368 renal trauma patients were identified. Mechanism of injury was blunt trauma in 89.1% of cases, mean age was 36.2 years, and mean ISS was 30.8 (+/-13.6). AAST grade distribution was 16.6% (Grade I), 22.8% (Grade II), 36.4% (Grade III), 20.9% (Grade IV), and G3.3% (Grade V). Overall, 9.5% (35) of patients required urological intervention for a total of 40 treatments, including ureteral stenting (3.0%), angioembolization (3.3%), percutaneous drainage (0.3%), or open intervention including nephrectomy (2.4%) and renorraphy (0.5%). No Grade 1 or 2 injuries required intervention, while 1.5%, 31.2%, and 75.0% of Grade 3, 4, and 5 injuries did, respectively. The overall renal salvage rate was 97.6%, which did not differ by mechanism of injury (p=0.25). Patients with penetrating trauma were more likely to require urological intervention (20.0% vs. 8.2%; p=0.04). Of the high-grade (III-V) renal injuries identified, 15.7% (35/223) required urological intervention, 4.9% (11) required open surgical intervention, and only 4.0% (9) of patients with high-grade renal injury required nephrectomy. CONCLUSIONS: The trend towards conservative treatment of renal trauma in Canada appears well-supported even in a severely injured patient population, as over 90% of patients avoid urological intervention and only 3% require operative intervention resulting in renal salvage rates of 97.6%. PMID- 30407155 TI - Identification of subgroups of metastatic castrate-resistant prostate cancer (mCRPC) patients treated with abiraterone plus prednisone at low vs. high risk of radiographic progression: An analysis of COU-AA-302. AB - INTRODUCTION: Radiographic imaging is used to monitor disease progression for men with metastatic castrate-resistant prostate cancer (mCRPC). The optimal frequency of imaging, a costly and limited resource, is not known. Our objective was to identify predictors of radiographic progression to inform the frequency of imaging for men with mCRPC. METHODS: We accessed data for men with chemotherapy naive mCRPC in the abiraterone acetate plus prednisone (AA-P) group of a randomized trial (COU-AA-302) (n=546). We used Cox proportional hazards modelling to identify predictors of time to progression. We divided patients into groups based on the most important predictors and estimated the probability of radiographic progression-free survival (RPFS) at six and 12 months. RESULTS: Baseline disease and change in prostate-specific antigen (PSA) at eight weeks were the strongest determinants of RPFS. The probability of RPFS for men with bone only disease and a >=50% fall in PSA was 93% (95% confidence interval [CI] 87-96) at six months and 80% (95% CI 72-86) at 12 months. In contrast, the probability of RPFS for men with bone and soft metastasis and <50% fall in PSA was 55% (95% CI 41-67) at six months and 34% (95% CI 22-47) at 12 months. These findings should be externally validated. CONCLUSIONS: Patients with chemotherapy naive mCRPC treated with first-line AA-P can be divided into groups with significantly different risks of radiographic progression based on a few clinically available variables, suggesting that imaging schedules could be individualized. PMID- 30407156 TI - A new model for delivering care for lower urinary tract symptoms. AB - INTRODUCTION: Lower urinary tract symptoms (LUTS) are being treated in secondary care settings, resulting in delayed access for all patients. The objectives of this study were to examine the effects of an integrated delivery model on 1) the volume of care delivered in the secondary care setting; and 2) the use of potentially unnecessary care associated with LUTS. METHODS: This study was based on a retrospective analysis of administrative data collected before and after the integrated LUTS clinic was introduced in Calgary, Alberta. Two cohorts of patients diagnosed with one of four conditions associated with LUTS were defined: 1) the year prior to the introduction of the integrated LUTS clinic; and 2) the year after. To measure their utilization of care, patients' healthcare records between the clinic, emergency department, and hospital were linked. The integrated LUTS clinic involved a multidisciplinary care team, co-located with a common electronic medical record system using a pre-established clinical pathway. RESULTS: After the introduction of the integrated LUTS clinic, there was a significant increase in the proportional number of patients receiving followup care at the clinic and a significant decrease in the proportional number of patients receiving a cystoscopy or being admitted to the hospital. There was no change in the number of patients visiting the emergency department. CONCLUSIONS: An integrated delivery model can be successfully implemented in secondary care for delivering chronic care. The integrated LUTS clinic improved access to care for patients and reduced their use of unnecessary services. PMID- 30407157 TI - Standardized reporting templates with mandatory reporting fields and "pick-list" options improve use of Prostate Imaging and Data Reporting System version 2 in clinical practice: A plan-do-study-act analysis. PMID- 30407158 TI - Is there an increased risk of an infected prosthetic joint after cystoscopy or transurethral prostatectomy? PMID- 30407160 TI - Forearm Metastases as Unsuspected First Manifestations of Lung Adenocarcinoma. AB - An 83-year-old male who was a former smoker had pain on the left forearm accompanied with progressive swallowing in the last four to five months. Imaging studies revealed a cystic necrotic mass on the flexor digitorum superficialis muscle (biopsy: striated muscle tissue infiltrated by an adenocarcinoma). A whole body computerized tomography (CT) scan demonstrates the presence of two lung masses that were suspicious of malignancy. Diagnosed as having stage IV lung adenocarcinoma (cT4NxM1b, IASLC TNM 8th [3]), he received chemotherapy with a carboplatin/pemetrexed-based regimen and local palliative radiation for the control of arm pain. PMID- 30407159 TI - Squamous Cell Carcinoma Arising in Zenker's Diverticulum: A Case Report and Review of the Literature. AB - The occurrence of squamous cell carcinoma (SCC) arising in a Zenker's diverticulum is a very rare incident. Complete excision of the diverticulum is considered as the procedure of choice for SCC in the pharyngeal pouch. Histopathological assessment of the pouch is the only modality to rule out SCC. Here, we report a case of a 71-year-old male with 20 years of history of Zenker's diverticulum, who recently presented with a history of weight and appetite loss. A barium swallow confirmed Zenker's pouch, the patient underwent diver ticulectomy and cricopharyngeal myotomy; a histopathological examination of the specimen revealed a fungating mass of SCC within the pouch. This report highlights the suggestion of considering SCC not only in patients with a long history of Zenker's diverticulum but also when there is a clinical suspicion with new symptoms for a more aggressive management for diagnosis and complete excision of the pouch. PMID- 30407161 TI - Association of Acromegaly and Central Sleep Apnea Syndrome. AB - Acromegaly is usually characterized by the excessive secretion of growth hormone (GH) after the closure of epiphyseal plaques, resulting from functional pituitary adenomas. The most common manifestations of acromegaly are acral and soft tissue overgrowth, diabetes mellitus, hypertension, and heart and respiratory failure. In patients, obstruction of the upper airway may develop due to enlargement of the tongue and thickening of the tissues of the larynx; consequently, obstructive sleep apnea syndrome (OSAS) occurs commonly in acromegaly. Previous studies have shown an association between acromegaly and central sleep apnea syndrome (CSAS). Some of these described patients described showed that an elevation in the GH level may cause a defect in the respiratory drive. Most systemic diseases seen in acromegaly require effective treatment. We believe that it is necessary to perform effective treatments by examining respiratory disorders in sleep. PMID- 30407162 TI - Unexpected Pregnancy during Treatment of Multidrug-resistant Tuberculosis. AB - Several drugs used in the treatment of multidrug-resistant tuberculosis (MDR-TB) have been reported as teratogenic. Treatment of such cases during gestation is disputable. Some experts favor the termination of pregnancy, whereas others suggest reducing the dose of teratogenic drugs or even suspending the regimen during pregnancy. There have been no clinical trials on the subject, but case reports and case series show excellent outcomes for children exposed during pregnancy to second-line agents, indicating that aggressive management of gestational MDR-TB may benefit not only the mother but also the fetus. We present a case of pregnancy in a teenager while she was under treatment for MDR-TB and continued with full treatment and nevertheless delivered a healthy child. PMID- 30407164 TI - Positive anti-MOG antibodies in a patient with Sjogren's syndrome and transverse myelitis. AB - Twenty percent of patients with Sjogren's syndrome experience associated neurological disease. Transverse myelitis (TM) frequently forms part of a neuromyelitis optica spectrum disorder associated with the presence of anti aquaporin 4 (AQP4) antibodies. We report the first described case of a patient who developed TM and the presence of a newly recognized antibody, anti-myelin oligodendrocyte protein (MOG), who went on to develop Sjogren's syndrome. AQP4 and MOG antibodies should be tested to guide prognostically the chances of further relapse as well as the type and duration of immunotherapy in patients with coexisting Sjogren's syndrome and TM. PMID- 30407163 TI - Duration of Stay of Patients with Community-Acquired Pneumonia in Influenza Season. AB - OBJECTIVES: There is a seasonal variation in the incidence of some infectious diseases. We analyzed the impact of influenza season (IS) on duration of stay (DOS) and some other characteristics of patients with community-acquired pneumonia (CAP). MATERIALS AND METHODS: In our retrospective cohort study, we analyzed data of 369 patients with CAP. RESULTS: The mean patient age was 65.5+/ 16.69 years, and 267 (72.4%) patients were male. There was no difference between patients with CAP admitted to hospital and intensive care unit during IS and non influenza season (NIS) with respect to age, mortality, and DOS. There was no difference in leukocyte and neutrophil counts, C-reactive protein level, and erythrocyte sedimentation rate in different seasons. Although most comorbid disease rates were similar, only cancer, especially lung cancer, was more prevalent in NIS. Bilateral CAP confirmed using thorax computed tomography was more frequent in IS. CONCLUSION: Although more patients with bilateral pneumonias were hospitalized in IS, DOS was not different between IS and NIS. PMID- 30407165 TI - Tuberculin test conversion in patients with chronic inflammatory arthritis receiving biological therapy. AB - OBJECTIVE: The blockade of inflammatory mediators produced by biological therapies is associated with an increased risk of opportunistic infections, as for example Mycobacterium tuberculosis (MT). Given the endemic situation of tuberculosis (TB) in some countries and immunosuppression/anergy of patients with chronic inflammatory arthritis, we wonder whether it is necessary to monitor the MT infection after starting the biological treatment. To evaluate the frequency of the tuberculin skin test (TST) conversion and its association with an active TB infection and other disease variables. METHODS: Patients with rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), and spondyloarthritis (SpA) receiving treatment with anti-TNF, tocilizumab, and/or abatacept agents were included into the study. Patients had to have a negative TST (<5 mm) at the baseline, and a second TST was performed 2-22 months after the initiation of biologic therapy. The TST conversion was considered as a variation >=5 mm between the two TSTs performed within an interval between 2 months and 2 years. RESULTS: A total of 85 patients were included into the study, and 78.8% were women, with a median schooling duration of 12 years. A total of 74.1% of patients had RA, 16.5% psoriatic arthritis, and 4.7% AIJ and ankylosing spondylitis. Regarding treatment, 75.3% received anti-TNF therapy (31.8% etanercept, 21.2% adalimumab, 17.6% infliximab, 3.5% golimumab, and 1.2% certolizumab), 15.3% tocilizumab, and 9.4% abatacept. Eight patients (9.4%) developed a TST conversion. The shift was more frequent in men (62.5%) than in women (37.5%) (p=0.009), and in those with a prolonged disease duration (X 226+/-109 vs X130+/-105 [p=0.017]). This association remained after adjusting for other variables. All patients who developed a TST conversion received prophylactic isoniazid, and only one patient with other risk factors developed active TB. CONCLUSION: The frequency of a TST conversion in patients with chronic inflammatory arthritis was low and was associated with male gender and longer disease duration. PMID- 30407166 TI - Novel presentations of periodic fever syndromes: Discrepancies between genetic and clinical diagnoses. AB - OBJECTIVE: The Periodic fever syndromes (PFS) are a group of disorders of the innate immune system. We investigated patients diagnosed with PFS at the Dartmouth Hitchcock Pediatric Rheumatology Clinic. METHODS: Case acquisition was performed by reviewing ICD 9/10 coded records for familial Mediterranean fever (ICD 9 277.31), laboratory test records for PFS genetic screening, and clinic records between 1/1/2011 and 12/31/2017. RESULTS: Twenty-seven cases had clinical evaluations including PFS genetic screening. Clinical diagnoses included familial Mediterranean fever (FMF) (10 cases), Muckle-Wells (2 cases), tumor necrosis factor receptor associated periodic syndrome (TRAPS) (4 cases), hyper IgD syndrome (HIDS) (1 case), Crohn's Disease (1 case), systemic onset juvenile idiopathic arthritis (SoJIA) (1 case), fever of unknown origin (FUO) (1 case), periodic fever adenitis pharyngitis aphthous ulcer (PFAPA) (6 cases), and cold induced urticaria (1 case). Fifteen cases were associated with a genetic cause. Seven of the 10 FMF cases were confirmed genetically and were either heterozygous or compound heterozygotes. Both cases of Muckle-Wells had either a compound heterozygote for CIAS 1 or a NOD gene mutation. Both TRAPS cases presented atypically with patients developing systemic lupus erythematosus (SLE) or being asymptomatic. Two patients had novel syndromes. One FMF patient had a TRNT1 gene mutation who responded to intravenous immunoglobulin (IVIg) and colchicine after failing multiple treatments. The other had SoJIA with a LPIN 2 gene mutation but responded to colchicine. Only one of the 15 genetically proven cases had classical presentation and genetics (HIDS secondary to a mevalonate kinase (MVK) gene mutation). CONCLUSION: PFS screening was helpful in over half of the cases to develop therapeutic treatment plans. Given the atypical clinical presentations seen with genetically determined PFS, extensive genetic testing is indicated for all patients presenting with a PFS, excluding classical PFAPA syndrome. PMID- 30407167 TI - Sporadic late onset nemaline myopathy (SLONM) in an adult presenting with progressive muscle weakness. AB - Sporadic late onset nemaline myopathy (SLONM) is a rare, intractable acquired myopathy that is characterised by progressive muscle weakness and the presence of nemaline rods in myofibres. Unlike the congenital form of nemaline myopathy (NM), there are only few case reports and series on SLONM in the scientific literature. We present a case report of SLONM in a 62-year-old male from a rural town in Western Australia, without any of the conditions often associated with SLONM such as monoclonal gammopathy of uncertain significance or HIV infection. SLONM should be considered in the differential diagnosis of progressive proximal muscle weakness in an adult. PMID- 30407169 TI - On the wave zone of synchrotron radiation. AB - The extension of the wave zone of synchrotron radiation is studied. PMID- 30407168 TI - The HEPS project. AB - The High Energy Photon Source (HEPS), a 6 GeV green-field diffraction-limited storage ring light source, will be built in Beijing, China. The HEPS design has been evolving for about ten years, and is now mostly finished and ready for construction. The storage ring is based on a modified hybrid seven-bend achromat (7BA) design, where bending magnets with reverse bending angles and longitudinal gradients are adopted to reach an ultralow natural emittance of 34.2 pm with a circumference of 1360.4 m. The central slice of the dipole in the middle of the modified hybrid 7BA, with flexible magnetic field, is used as the source of the bending-magnet beamline. Moreover, alternating high- and low-beta sections are specially designed to generate and deliver X-ray synchrotron radiation with high brightness of 5 * 1022 photons s-1 mm-2 mrad-2 (0.1% bandwidth)-1. Here, the HEPS storage ring design and solutions to the challenges inherent in this ultralow emittance design are presented. PMID- 30407170 TI - Synchrotron radiation loss of a laser accelerator based on an inverse electron cyclotron resonance maser. AB - A laser accelerator based on an electron cyclotron resonance maser is described. Important losses that give rise to saturation length and saturation power are included in the analysis. The results are compared with results from an inverse free-electron laser accelerator. PMID- 30407172 TI - Rocking curve and spatial coherence properties of a long X-ray compound refractive lens. AB - Semi-analytical theory of a long set of X-ray compound refractive lenses (CRLs) based on recurrence relations is developed further. The geometrical aperture, angular divergence of incident radiation and source size were accurately taken into account. Using this theory it is possible to calculate the width of the rocking curve of a long (40.7 cm) Be CRL which coincides with experimental data obtained earlier. By this approach the transverse coherence length for the X-ray beam after passing a set of CRLs of arbitrary complexity has been estimated. It is shown that at the focus this coherence length is equal to a diffraction limited beam size (beam size in the case of a point source) and has minimal difference with the real beam size. PMID- 30407171 TI - Time-resolved pair distribution function analysis of disordered materials on beamlines BL04B2 and BL08W at SPring-8. AB - A dedicated apparatus has been developed for studying structural changes in amorphous and disordered crystalline materials substantially in real time. The apparatus, which can be set up on beamlines BL04B2 and BL08W at SPring-8, mainly consists of a large two-dimensional flat-panel detector and high-energy X-rays, enabling total scattering measurements to be carried out for time-resolved pair distribution function (PDF) analysis in the temperature range from room temperature to 873 K at pressures of up to 20 bar. For successful time-resolved analysis, a newly developed program was used that can monitor and process two dimensional image data simultaneously with the data collection. The use of time resolved hardware and software is of great importance for obtaining a detailed understanding of the structural changes in disordered materials, as exemplified by the results of commissioned measurements carried out on both beamlines. Benchmark results obtained using amorphous silica and demonstration results for the observation of sulfide glass crystallization upon annealing are introduced. PMID- 30407174 TI - Subpixel resolution in CdTe Timepix3 pixel detectors. AB - Timepix3 (256 * 256 pixels with a pitch of 55 um) is a hybrid-pixel-detector readout chip that implements a data-driven architecture and is capable of simultaneous time-of-arrival (ToA) and energy (ToT: time-over-threshold) measurements. The ToA information allows the unambiguous identification of pixel clusters belonging to the same X-ray interaction, which allows for full one-by one detection of photons. The weighted mean of the pixel clusters can be used to measure the subpixel position of an X-ray interaction. An experiment was performed at the European Synchrotron Radiation Facility in Grenoble, France, using a 5 um * 5 um pencil beam to scan a CdTe-ADVAPIX-Timepix3 pixel (55 um * 55 um) at 8 * 8 matrix positions with a step size of 5 um. The head-on scan was carried out at four monochromatic energies: 24, 35, 70 and 120 keV. The subpixel position of every single photon in the beam was constructed using the weighted average of the charge spread of single interactions. Then the subpixel position of the total beam was found by calculating the mean position of all photons. This was carried out for all points in the 8 * 8 matrix of beam positions within a single pixel. The optimum conditions for the subpixel measurements are presented with regards to the cluster sizes and beam subpixel position, and the improvement of this technique is evaluated (using the charge sharing of each individual photon to achieve subpixel resolution) versus alternative techniques which compare the intensity ratio between pixels. The best result is achieved at 120 keV, where a beam step of 4.4 um +/- 0.86 um was measured. PMID- 30407173 TI - Towards chemically neutral carbon cleaning processes: plasma cleaning of Ni, Rh and Al reflective optical coatings and thin Al filters for free-electron lasers and synchrotron beamline applications. AB - The choice of a reflective optical coating or filter material has to be adapted to the intended field of application. This is mainly determined by the required photon energy range or by the required reflection angle. Among various materials, nickel and rhodium are common materials used as reflective coatings for (soft) X ray mirrors. Similarly, aluminium is one of the most commonly used materials for extreme ultraviolet and soft X-ray transmission filters. However, both of these types of optics are subject to carbon contamination, which can be increasingly problematic for the operation of the high-performance free-electron laser and synchrotron beamlines. As an attempt to remove this type of contamination, an inductively coupled plasma source has been used in conjunction with N2/O2/H2 and N2/H2 feedstock gas plasmas. Results from the chemical surface analysis of the above materials before and after plasma treatment using X-ray photoelectron spectroscopy are reported. It is concluded that a favorable combination of an N2/H2 plasma feedstock gas mixture leads to the best chemical surface preservation of Ni, Rh and Al while removing the carbon contamination. However, this feedstock gas mixture does not remove C contamination as rapidly as, for example, an N2/O2/H2 plasma which induces the surface formation of NiO and NiOOH in Ni and RhOOH in Rh foils. As an applied case, the successful carbon removal from ultrathin Al filters previously used at the FERMI FEL1 using an N2/H2 plasma is demonstrated. PMID- 30407175 TI - Ultrahigh-vacuum organic molecular-beam deposition system for in situ growth and characterization. AB - A compact ultrahigh-vacuum molecular-beam deposition system has been developed for the in situ synthesis of organic thin films and multilayers. The system incorporates all the features (heater, thickness monitor, evaporators) necessary for controlled organic thin-film growth. It can be used independently, or it can be docked to the in situ growth system and transferred to other instruments of the PGM beamline, thus allowing extensive film preparation and characterization. A manipulator dedicated to specimen preparation and organic-film deposition with temperature control between 200 K and ~800 K has been developed. The design and performance of the system are reported with emphasis on a novel solution of masks developed to achieve position-dependent film deposition. To demonstrate the enhanced capabilities of the PGM beamline in the growth and in the characterization of electronic-structure studies of organic molecular films and their heterostructures through synchrotron-based spectroscopies, this paper presents some preliminary results of a study of Fe-phthalocyanine growth on Si substrates and on in situ prepared La0.67Sr0.33MnO3 buffer layers on SrTiO3 single crystal. PMID- 30407176 TI - Flexible sample cell for real-time GISAXS, GIWAXS and XRR: design and construction. AB - Since the properties of functional materials are highly dependent on their specific structure, and since the structural changes, for example during crystallization, induced by coating and annealing processes are significant, the study of structure and its formation is of interest for fundamental and applied science. However, structure analysis is often limited to ex situ determination of final states due to the lack of specialized sample cells that enable real-time investigations. The lack of such cells is mainly due to their fairly complex design and geometrical restrictions defined by the beamline setups. To overcome this obstacle, an advanced sample cell has been designed and constructed; it combines automated doctor blading, solvent vapor annealing and sample hydration with real-time grazing-incidence wide- and small-angle scattering (GIWAXS/GISAXS) and X-ray reflectivity (XRR). The sample cell has limited spatial requirements and is therefore widely usable at beamlines and laboratory-scale instruments. The cell is fully automatized and remains portable, including the necessary electronics. In addition, the cell can be used by interested scientists in cooperation with the Institute for Crystallography and Structural Physics and is expandable with regard to optical secondary probes. Exemplary research studies are presented, in the form of coating of P3HT:PC61PM thin films, solvent vapor annealing of DRCN5T:PC71BM thin films, and hydration of supported phospholipid multilayers, to demonstrate the capabilities of the in situ cell. PMID- 30407177 TI - In situ observation of phase changes of a silica-supported cobalt catalyst for the Fischer-Tropsch process by the development of a synchrotron-compatible in situ/operando powder X-ray diffraction cell. AB - In situ characterization of catalysts gives direct insight into the working state of the material. Here, the design and performance characteristics of a universal in situ synchrotron-compatible X-ray diffraction cell capable of operation at high temperature and high pressure, 1373 K, and 35 bar, respectively, are reported. Its performance is demonstrated by characterizing a cobalt-based catalyst used in a prototypical high-pressure catalytic reaction, the Fischer Tropsch synthesis, using X-ray diffraction. Cobalt nanoparticles supported on silica were studied in situ during Fischer-Tropsch catalysis using syngas, H2 and CO, at 723 K and 20 bar. Post reaction, the Co nanoparticles were carburized at elevated pressure, demonstrating an increased rate of carburization compared with atmospheric studies. PMID- 30407178 TI - Rigorous calculations and synchrotron radiation measurements of diffraction efficiencies for tender X-ray lamellar gratings: conical versus classical diffraction. AB - When reflection gratings are operated at grazing incidence in the extreme off plane configuration and the incident beam trajectory is parallel to the grooves, the diffraction into the first order can be more efficient than in the classical orientation. This situation is referred to as the conical diffraction case. In the classical configuration the grooves are perpendicular to the incident beam and thus an efficiency-reducing shadowing effect will be observed at very grazing angles. It was recently shown that a laminar grating could provide symmetric and relatively high efficiencies in conical diffraction for diffraction even of photons with large energies of the order of 4 and 6 keV. For photon energies in the tender X-ray range, accurate computing tools for the calculation of diffraction efficiencies from gratings with simple coatings have not been available. Promising results for this spectral range now require the development of tools for modelling the diffraction efficiency expected in optical instrumentation, in which the provision of high efficiency in the indicated spectral range is mandatory. This is the case when weak sources are to be investigated, like in space science. In this study it will be shown that scalar calculations are not appropriate for this purpose, while newly introduced rigorous calculations based on the boundary integral equation method, implemented in the PCGrate(r) code, can provide predictions that are in agreement with observed diffraction efficiencies. The agreement is achieved by modelling the exact surface profile. This applies for both the conical diffraction configuration and for the classical in-plane configuration, in which a significantly lower efficiency was obtained. Even though the profile of the presented grating was not perfect, but significantly distorted, the calculations show that efficiency-wise the structure provided already more than 75% of the ideally expected efficiency for conical diffraction. This is a very promising result for further optimization of diffraction gratings for use in the tender X ray range. PMID- 30407179 TI - Site occupancy of Fe2+, Fe3+ and Ti4+ in titanomagnetite determined by valence difference contrast in synchrotron X-ray resonant scattering. AB - A synchrotron X-ray diffraction study of a single crystal of titanomagnetite shows that the cation distribution of Fe2+, Fe3+ and Ti4+ is of the inverse spinel type. The valence-difference contrast (VDC) method of resonant scattering was applied at a wavelength of lambda = 1.7441 A (E = 7.1085 keV) within the pre edge of the Fe K absorption spectrum, utilizing the large difference in the real part of anomalous scattering factors, between -7.45 and -6.50, for Fe2+ and Fe3+, respectively. The most plausible atomic arrangement in Ti0.31Fe2.69O4 obtained from our analysis is [Fe3+1.00]A[Fe3+0.38Fe2+1.31Ti4+0.31]BO4, where A and B in an AB2O4-type structure correspond to the tetrahedral and octahedral sites, respectively. This result suggests that titanomagnetite has the complete inverse spinel structure continuously from the end-member of magnetite, even in the case of relatively high Ti content. The physical properties may be described by the Neel model, which claims that Fe3+ preferentially occupies the tetrahedral site, within a Ti-poor half-region of the solid solution. Based on the ordering scheme the magnetic structure of titanomagnetite is considered to be analogous to that of magnetite. The combination of circularly polarized X-rays and a horizontal type four-circle diffractometer used in this VDC technique has the advantage of increasing the experimental accuracy and freedom with the simultaneous reduction of experimental noise. PMID- 30407180 TI - Elaborations on Mossbauer rotor experiments with synchrotron radiation and with usual resonant sources. AB - A comparative analysis of Mossbauer experiments in a rotating system between a recent application using synchrotron radiation [Friedman et al. (2016). Eur. Phys. Lett. 114, 50010; Friedman et al. (2017). J. Synchrotron Rad. 24, 661-666] and usual sources of resonant radiation is carried out. The principal methodological difference between these experiments can be related to the fact that in the former set of experiments the source of the resonant radiation rests in a laboratory frame whereas for the latter set of experiments the source is attached to a rotating system. It is concluded that the utilization of ordinary Mossbauer sources remains the most promising path for further research appertaining to the Mossbauer effect in rotating systems. PMID- 30407181 TI - Depth-dependent atomic valence determination by synchrotron techniques. AB - The properties of many materials can be strongly affected by the atomic valence of the contained individual elements, which may vary at surfaces and other interfaces. These variations can have a critical impact on material performance in applications. A non-destructive method for the determination of layer-by-layer atomic valence as a function of material thickness is presented for La0.7Sr0.3MnO3 (LSMO) thin films. The method utilizes a combination of bulk- and surface-sensitive X-ray absorption spectroscopy (XAS) detection modes; here, the modes are fluorescence yield and surface-sensitive total electron yield. The weighted-average Mn atomic valence as measured from the two modes are simultaneously fitted using a model for the layer-by-layer variation of valence based on theoretical model Hamiltonian calculations. Using this model, the Mn valence profile in LSMO thin film is extracted and the valence within each layer is determined to within an uncertainty of a few percent. The approach presented here could be used to study the layer-dependent valence in other systems or extended to different properties of materials such as magnetism. PMID- 30407182 TI - Implications of X-ray beam profiles on qualitative and quantitative synchrotron micro-focus X-ray fluorescence microscopy. AB - Synchrotron radiation X-ray fluorescence microscopy is frequently used to investigate the spatial distribution of elements within a wide range of samples. Interrogation of heterogeneous samples that contain large concentration ranges has the potential to produce image artefacts due to the profile of the X-ray beam. The presence of these artefacts and the distribution of flux within the beam profile can significantly affect qualitative and quantitative analyses. Two distinct correction methods have been generated by referencing the beam profile itself or by employing an adaptive-thresholding procedure. Both methods significantly improve qualitative imaging by removing the artefacts without compromising the low-intensity features. The beam-profile correction method improves quantitative results but requires accurate two-dimensional characterization of the X-ray beam profile. PMID- 30407184 TI - Phosphorus K-edge XANES spectroscopy has probably often underestimated iron oxyhydroxide-bound P in soils. AB - Phosphorus (P) K-edge X-ray absorption near-edge structure (XANES) spectra of orthophosphate (oPO4) bound to soil FeIII minerals (e.g. ferrihydrite, goethite) show a pre-edge signal at 2148-2152 eV. It is unknown whether organic P bound to FeIII oxyhydroxides also show this feature. Otherwise, Fe-bound soil P may be underestimated by P K-edge XANES spectroscopy, because a large portion of Fe oxyhydroxide-bound P in soils is organic P. K-edge XANES spectra were obtained for different organic P compounds present in soils [inositol hexaphosphate (IHP), glucose-6-phosphate (G6P), adenosine triphosphate (ATP)] after sorption to ferrihydrite or goethite and compared with spectra of oPO4 adsorbed to these minerals. P sorption to ferrihydrite increased in the sequence IHP ? G6P < oPO4 < ATP. P sorption to goethite increased in the sequence G6P < oPO4 ? ATP = IHP. Pre edge signals in P K-edge XANES spectra of organic P adsorbed to Fe oxyhydroxides were markedly smaller compared with those of oPO4 adsorbed to these minerals and absent for FeIII oxyhydroxide-bound ATP as well as goethite-bound IHP. Linear combination fitting (LCF) performed on spectra of IHP, G6P or ATP adsorbed to ferrihydrite or goethite, using only spectra of FeIII oxyhydroxide-bound oPO4 as reference compounds for Fe-bound P, erroneously assigned >93% (ferrihydrite) or >41% (goethite) of Fe-bound P to non-Fe-bound P species. Inclusion of FeIII oxyhydroxide-bound IHP as reference compounds markedly increased the recovery of oxyhydroxide-bound organic P. Thus, Fe-bound soil P has probably often been underestimated by LCF in soil XANES studies where IHP adsorbed to ferrihydrite and to goethite were not included as reference compounds. PMID- 30407183 TI - Ultralow-temperature device dedicated to soft X-ray magnetic circular dichroism experiments. AB - A new ultralow-temperature setup dedicated to soft X-ray absorption spectroscopy and X-ray magnetic circular dichroism (XMCD) experiments is described. Two experiments, performed on the DEIMOS beamline (SOLEIL synchrotron), demonstrate the outstanding performance of this new platform in terms of the lowest achievable temperature under X-ray irradiation (T = 220 mK), the precision in controlling the temperature during measurements as well as the speed of the cooling-down and warming-up procedures. Moreover, owing to the new design of the setup, the eddy-current power is strongly reduced, allowing fast scanning of the magnetic field in XMCD experiments; these performances lead to a powerful device for X-ray spectroscopies on synchrotron-radiation beamlines facilities. PMID- 30407185 TI - XAS/DRIFTS/MS spectroscopy for time-resolved operando investigations at high temperature. AB - The combination of complementary techniques in the characterization of catalysts under working conditions is a very powerful tool for an accurate and in-depth comprehension of the system investigated. In particular, X-ray absorption spectroscopy (XAS) coupled with diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) and mass spectroscopy (MS) is a powerful combination since XAS characterizes the main elements of the catalytic system (selecting the absorption edge) and DRIFTS monitors surface adsorbates while MS enables product identification and quantification. In the present manuscript, a new reactor cell and an experimental setup optimized to perform time-resolved experiments on heterogeneous catalysts under working conditions are reported. A key feature of this setup is the possibility to work at high temperature and pressure, with a small cell dead volume. To demonstrate these capabilities, performance tests with and without X-rays are performed. The effective temperature at the sample surface, the speed to purge the gas volume inside the cell and catalytic activity have been evaluated to demonstrate the reliability and usefulness of the cell. The setup capability of combining XAS, DRIFTS and MS spectroscopies is demonstrated in a time-resolved experiment, following the reduction of NO by Rh nanoparticles supported on alumina. PMID- 30407187 TI - Counting-loss correction for X-ray spectra using the pulse-repairing method. AB - Facing the technical problem of pulse distortion caused by frequent resetting in the latest high-performance silicon drift detectors, which work under high counting-rate conditions, a method has been used to remove false peaks in order to obtain a precise X-ray spectrum, the essence of which eliminates distorted pulses. Aiming at solving the problem of counting-loss generated by eliminating distorted pulses, this paper proposes an improved method of pulse repairing. A 238Pu source with activity of 10 mCi was used as the measurement object, and the energy spectrum obtained by the pulse repairing method was compared with that obtained by the pulse elimination method. The ten-measurement results show that the pulse repairing method can correct the counting-loss caused by the pulse elimination method and increase peak area, which is of great significance for obtaining a precise X-ray energy spectrum. PMID- 30407186 TI - Ultra-small-angle X-ray photon correlation spectroscopy using the Eiger detector. AB - Successful implementation of the single-photon-counting Eiger 500k pixel array detector for sub-millisecond X-ray photon correlation spectroscopy (XPCS) measurements in the ultra-small-angle scattering region is reported. The performance is demonstrated by measuring the dynamics of dilute silica colloids in aqueous solvents when the detector is operated at different counter depths, 4, 8 and 12 bit. In the fastest mode involving 4 bit parallel readout, a stable frame rate of 22 kHz is obtained that enabled measurement of intensity-intensity autocorrelation functions with good statistics down to the 50 us range for a sample with sufficient scattering power. The high frame rate and spatial resolution together with large number of pixels of the detector facilitate the investigation of sub-millisecond dynamics over a broad length scale by multispeckle XPCS. This is illustrated by an example involving phoretic motion of colloids during the phase separation of the solvent. PMID- 30407188 TI - Track analysis of a synchrotron X-ray photoelectric nanoradiator by in situ fluorescence imaging of reactive oxygen species: comparative study of gold and iron oxide nanoparticles. AB - The emission of fluorescent X-rays and low-energy electrons by mid-/high-Z nanoparticles upon irradiation with either X-ray photons or high-energy ion beams is referred to as the nanoradiator effect (NRE). A track analysis of NRE was performed using reactive oxygen species (ROS) gels, to which macrophages containing gold nanoparticles (AuNPs) were attached, together with single-cell irradiation of the intracellular nanoparticles from a microbeam of synchrotron X rays, and the range and distribution of ^?bulletOH and O2^{ ?bullet - } produced were compared with those of the Fe-nanoradiator by magnetite nanoparticles (FeONP, Fe3O4). The Au-nanoradiator generated ROS fluorescence to a greater depth and wider angle with respect to the incident X-rays than that of the Fe nanoradiator. The ROS-oxidant fluorescence intensity ratios of ^?bulletOH to O2^{ ?bullet - } were different for the AuNPs and FeONPs, reflecting different relative yields of electrons and fluorescent X-rays from NRE. In the region immediately (<100 um) below the irradiated cell, ^?bulletOH-radicals were distributed mainly along two or three tracks in the depth direction in the FeONP- or AuNP-ROS gel. In contrast, O2^{ ?bullet - } was scattered more abundantly in random directions in the AuNP-ROS gel than in the FeONP-ROS gel. Track analysis of X-ray photoelectric nanoradiator radiation showed a different range of dose distribution and relative emission compositions between Au- and Fe-nanoradiators, suggesting more extensive damage beyond a single cell containing AuNPs than one containing FeONPs. PMID- 30407189 TI - Responsive alignment for X-ray tomography beamlines. AB - X-ray computed tomography (CT) is an imaging technique intended to obtain the internal structure and three-dimensional representation of a sample. In general, parallel-beam CT reconstruction algorithms require a precise angular alignment and knowledge of the exact axis of rotation position. Highly brilliant X-ray sources with ever-increasing data-acquisition rates demand optimized alignment techniques to avoid compromising in situ data analysis. This paper presents a method to automatically align the angular orientation and linear position of the rotation axis in a tomography setup, correlating image features from different X ray projections. PMID- 30407190 TI - A comparison of parametric and integrative approaches for X-ray fluorescence analysis applied to a Stroke model. AB - Synchrotron X-ray fluorescence imaging enables visualization and quantification of microscopic distributions of elements. This versatile technique has matured to the point where it is used in a wide range of research fields. The method can be used to quantitate the levels of different elements in the image on a pixel-by pixel basis. Two approaches to X-ray fluorescence image analysis are commonly used, namely, (i) integrative analysis, or window binning, which simply sums the numbers of all photons detected within a specific energy region of interest; and (ii) parametric analysis, or fitting, in which emission spectra are represented by the sum of parameters representing a series of peaks and other contributing factors. This paper presents a quantitative comparison between these two methods of image analysis using X-ray fluorescence imaging of mouse brain-tissue sections; it is shown that substantial errors can result when data from overlapping emission lines are binned rather than fitted. These differences are explored using two different digital signal processing data-acquisition systems with different count-rate and emission-line resolution characteristics. Irrespective of the digital signal processing electronics, there are substantial differences in quantitation between the two approaches. Binning analyses are thus shown to contain significant errors that not only distort the data but in some cases result in complete reversal of trends between different tissue regions. PMID- 30407191 TI - Simultaneous X-ray radioscopy/tomography and energy-dispersive diffraction applied to liquid aluminium alloy foams. AB - High-speed X-ray imaging in two dimensions (radioscopy) and three dimensions (tomography) is combined with fast X-ray diffraction in a new experimental setup at the synchrotron radiation source BESSY II. It allows for in situ studies of time-dependent phenomena in complex systems. As a first application, the foaming process of an aluminium alloy was studied in three different experiments. Radioscopy, optical expansion measurements and diffraction were used to correlate the change of foam morphology to the various phases formed during heating of an AlMg15Cu10 alloy to 620 degrees C in the first experiment. Radioscopy was then replaced by tomography. Acquiring tomograms and diffraction data at 2 Hz allows even more details of foam evolution to be captured, for example, bubble size distribution. In a third experiment, 4 Hz tomography yields dynamic insights into fast phenomena in evolving metal foam. PMID- 30407192 TI - Experimental feasibility of dual-energy computed tomography based on the Thomson scattering X-ray source. AB - Unlike large-scale and expensive synchrotron radiation facilities, the Thomson scattering X-ray source can provide quasi-monochromatic, energy-tunable and high brightness X-ray pulses with a small footprint and moderate cost, making it an excellent candidate for dual-energy and multi-energy imaging at laboratories and hospitals. Here, the first feasibility study on dual-energy computed tomography (CT) based on this type of light source is reported, and the effective atomic number and electron-density distribution of a standard phantom consisting of polytetrafluoroethylene, water and aluminium is derived. The experiment was carried out at the Tsinghua Thomson scattering X-ray source with peak energies of 29 keV and 68 keV. Both the reconstructed effective atomic numbers and the retrieved electron densities of the three materials were compared with their theoretical values. It was found that these values were in agreement by 0.68% and 2.60% on average for effective atomic number and electron density, respectively. These results have verified the feasibility of dual-energy CT based on the Thomson scattering X-ray source and will further expand the scope of X-ray imaging using this type of light source. PMID- 30407193 TI - Diffraction apparatus and procedure in tomography X-ray diffraction imaging for biological cells at cryogenic temperature using synchrotron X-ray radiation. AB - X-ray diffraction imaging is a technique for visualizing the structure of biological cells. In X-ray diffraction imaging experiments using synchrotron radiation, cryogenic conditions are necessary in order to reduce radiation damage in the biological cells. Frozen-hydrated biological specimens kept at cryogenic temperatures are also free from drying and bubbling, which occurs in wet specimens under vacuum conditions. In a previous study, the diffraction apparatus KOTOBUKI-1 [Nakasako et al. (2013), Rev. Sci. Instrum. 84, 093705] was constructed for X-ray diffraction imaging at cryogenic temperatures by utilizing a cryogenic pot, which is a cooling device developed in low-temperature physics. In this study a new cryogenic pot, suitable for tomography experiments, has been developed. The pot can rotate a biological cell over an angular range of +/-170 degrees against the direction of the incident X-ray beam. Herein, the details and the performance of the pot and miscellaneous devices are reported, along with established experimental procedures including specimen preparation. The apparatus has been used in tomography experiments for visualizing the three-dimensional structure of a Cyanidioschyzon merolae cell with an approximate size of 5 um at a resolution of 136 nm. Based on the experimental results, the necessary improvements for future experiments and the resolution limit achievable under experimental conditions within a maximum tolerable dose are discussed. PMID- 30407194 TI - Automatic projection image registration for nanoscale X-ray tomographic reconstruction. AB - Novel developments in X-ray sources, optics and detectors have significantly advanced the capability of X-ray microscopy at the nanoscale. Depending on the imaging modality and the photon energy, state-of-the-art X-ray microscopes are routinely operated at a spatial resolution of tens of nanometres for hard X-rays or ~10 nm for soft X-rays. The improvement in spatial resolution, however, has led to challenges in the tomographic reconstruction due to the fact that the imperfections of the mechanical system become clearly detectable in the projection images. Without proper registration of the projection images, a severe point spread function will be introduced into the tomographic reconstructions, causing the reduction of the three-dimensional (3D) spatial resolution as well as the enhancement of image artifacts. Here the development of a method that iteratively performs registration of the experimentally measured projection images to those that are numerically calculated by reprojecting the 3D matrix in the corresponding viewing angles is shown. Multiple algorithms are implemented to conduct the registration, which corrects the translational and/or the rotational errors. A sequence that offers a superior performance is presented and discussed. Going beyond the visual assessment of the reconstruction results, the morphological quantification of a battery electrode particle that has gone through substantial cycling is investigated. The results show that the presented method has led to a better quality tomographic reconstruction, which, subsequently, promotes the fidelity in the quantification of the sample morphology. PMID- 30407195 TI - Towards synchrotron phase-contrast lung imaging in patients - a proof-of-concept study on porcine lungs in a human-scale chest phantom. AB - In-line free propagation phase-contrast synchrotron tomography of the lungs has been shown to provide superior image quality compared with attenuation-based computed tomography (CT) in small-animal studies. The present study was performed to prove the applicability on a human-patient scale using a chest phantom with ventilated fresh porcine lungs. Local areas of interest were imaged with a pixel size of 100 um, yielding a high-resolution depiction of anatomical hallmarks of healthy lungs and artificial lung nodules. Details like fine spiculations into surrounding alveolar spaces were shown on a micrometre scale. Minor differences in artificial lung nodule density were detected by phase retrieval. Since we only applied a fraction of the X-ray dose used for clinical high-resolution CT scans, it is believed that this approach may become applicable to the detailed assessment of focal lung lesions in patients in the future. PMID- 30407197 TI - Feasibility study of phase-contrast X-ray laminography using X-ray interferometry. AB - For fine observation of laminar samples, phase-contrast X-ray laminography using X-ray interferometry was developed. An imaging system fitted with a two-crystal X ray interferometer was used to perform the observations, and the sectional images were calculated by a three-dimensional iterative reconstruction method. Obtained images of an old flat slab of limestone from the Carnic Alps depicted fusulinids in the Carboniferous period with 3 mg cm-3 density resolution, and those of carbon paper used for a fuel-cell battery displayed the inner fibrous structures clearly. PMID- 30407196 TI - Three-dimensional characterization of the microstructure in rabbit patella patellar tendon interface using propagation phase-contrast synchrotron radiation microtomography. AB - Understanding the three-dimensional ultrastructure morphology of tendon-to-bone interface may allow the development of effective therapeutic interventions for enhanced interface healing. This study aims to assess the feasibility of propagation phase-contrast synchrotron radiation microtomography (PPC-SRuCT) for three-dimensional characterization of the microstructure in rabbit patella patellar tendon interface (PPTI). Based on phase retrieval for PPC-SRuCT imaging, this technique is capable of visualizing the three-dimensional internal architecture of PPTI at a cellular high spatial resolution including bone and tendon, especially the chondrocytes lacuna at the fibrocartilage layer. The features on the PPC-SRuCT image of the PPTI are similar to those of a histological section using Safranin-O staining/fast green staining. The three dimensional microstructure in the rabbit patella-patellar tendon interface and the spatial distributions of the chondrocytes lacuna and their quantification volumetric data are displayed. Furthermore, a color-coding map differentiating cell lacuna in terms of connecting beads is presented after the chondrocytes cell lacuna was extracted. This provides a more in-depth insight into the microstructure of the PPTI on a new scale, particularly the cell lacuna arrangement at the fibrocartilage layer. PPC-SRuCT techniques provide important complementary information to the conventional histological method for characterizing the microstructure of the PPTI, and may facilitate in investigations of the repair mechanism of the PPTI after injury and in evaluating the efficacy of a different therapy. PMID- 30407198 TI - A modified discrete tomography for improving the reconstruction of unknown multi gray-level material in the 'missing wedge' situation. AB - Full angular rotational projections cannot always be acquired in tomographic reconstructions because of the limited space in the experimental setup, leading to the 'missing wedge' situation. In this paper, a recovering 'missing wedge' discrete algebraic reconstruction technique algorithm (rmwDART) has been proposed to solve the 'missing wedge' problem and improve the quality of the three dimensional reconstruction without prior knowledge of the material component's number or the material's values. By using oversegmentation, boundary extraction and mathematical morphological operations, 'missing wedge' artifact areas can be located. Then, in the iteration process, by updating the located areas and regions, high-quality reconstructions can be obtained from the simulations, and the reconstructed images based on the rmwDART algorithm can be obtained from soft X-ray nano-computed tomography experiments. The results showed that there is the potential for discrete tomography. PMID- 30407199 TI - Laser-heating system for high-pressure X-ray diffraction at the Extreme Conditions beamline I15 at Diamond Light Source. AB - In this article, the specification and application of the new double-sided YAG laser-heating system built on beamline I15 at Diamond Light Source are presented. This system, combined with diamond anvil cell and X-ray diffraction techniques, allows in situ and ex situ characterization of material properties at extremes of pressure and temperature. In order to demonstrate the reliability and stability of this experimental setup over a wide range of pressure and temperature, a case study was performed and the phase diagram of lead was investigated up to 80 GPa and 3300 K. The obtained results agree with previously published experimental and theoretical data, underlining the quality and reliability of the installed setup. PMID- 30407200 TI - The wave optical whole process design of the soft X-ray interference lithography beamline at SSRF. AB - A new spatially coherent beamline has been designed and constructed at the Shanghai Synchrotron Radiation Facility. Here, the design of the beamline is introduced and the spatial coherence is analyzed throughout the whole process by wave optics. The simulation results show good spatial coherence at the endstation and have been proven by experiment results. PMID- 30407201 TI - Sirepo: an open-source cloud-based software interface for X-ray source and optics simulations. AB - Sirepo, a browser-based GUI for X-ray source and optics simulations, is presented. Such calculations can be performed using SRW (Synchrotron Radiation Workshop), which is a physical optics computer code, allowing simulation of entire experimental beamlines using the concept of a 'virtual beamline' with accurate treatment of synchrotron radiation generation and propagation through the X-ray optical system. SRW is interfaced with Sirepo by means of a Python application programming interface. Sirepo supports most of the optical elements currently used at beamlines, including recent developments in SRW. In particular, support is provided for the simulation of state-of-the-art X-ray beamlines, exploiting the high coherence and brightness of modern light source facilities. New scientific visualization and reporting capabilities have been recently implemented within Sirepo, as well as automatic determination of electron beam and undulator parameters. Publicly available community databases can be dynamically queried for error-free access to material characteristics. These computational tools can be used for the development and commissioning of new X ray beamlines and for testing feasibility and optimization of experiments. The same interface can guide simulation on a local computer, a remote server or a high-performance cluster. Sirepo is available online and also within the NSLS-II firewall, with a growing number of users at other light source facilities. Our open source code is available on GitHub. PMID- 30407202 TI - Low-cost disposable high-pressure setup for in situ X-ray experiments. AB - A low-cost, flexible and fast method to create disposable sample cells suitable for in situ catalytic or material synthesis studies based on standard quartz capillaries, heat-shrinkable tubing and standard Swagelok components is described. PMID- 30407203 TI - Demanding an end to tuberculosis: treatment of tuberculosis infection among persons living with and without HIV. AB - PURPOSE OF REVIEW: More than two billion people are infected with Mycobacterium tuberculosis and few of them are ever offered therapy in spite of such treatment being associated with reduced rates of morbidity and mortality. This article reviews the current recommendations on the diagnosis and treatment of TB infection (or what is commonly referred to as 'prophylaxis' or 'preventive therapy' of latent TB) and discusses barriers to implementation that have led to low demand for this life-saving therapeutic intervention. RECENT FINDINGS: Treatment of infection for both TB and drug-resistant TB is well tolerated and effective, and several new, shorter regimens - including rfiapenitine-based regimens of 1 month and 12 weeks duration - have been shown to be effective. Not all persons infected with TB go on to develop disease and the risk is the highest in the first 2 years after infection. Given this, additional work is needed to better identify those at the highest risk of developing active TB. SUMMARY: Practitioners should offer newer, shorter regimens to persons who are infected with TB and at high risk of developing disease, including people living with HIV and household contacts of people living with TB who are age 5 years and under. This includes individuals who have been exposed to drug-resistant forms of disease. Socioeconomic risk factors may play a key role in the development of TB disease and should also be addressed. PMID- 30407204 TI - The Evolving Practice Patterns of Academic Endocrine Surgeons: A Cross-sectional Analysis of the Faculty Practice Solutions Center Database 2014 to 2017. AB - OBJECTIVE: To examine the evolution of an academic endocrine surgeon's practice over time. SUMMARY BACKGROUND: Amid growing recognition that surgical volume and specialization are linked to better outcomes, endocrine surgery is one of the youngest fields to develop its own formal fellowship training program. However, 3 decades after the emergence of endocrine surgery as a distinct specialty, the medical community and public still have a limited understanding of endocrine surgeons and what they do. METHODS: We performed a cross-sectional analysis of endocrine surgeons identified in the Faculty Practice Solutions Center Database from 2014 to 2017. Trends in annual number of endocrine surgeries performed, number of all surgeries performed, total work relative value units generated, and patient payer mix stratified by years of practice were evaluated. RESULTS: One hundred thirty-nine endocrine surgeons practicing in 103 institutions over 4 years were analyzed. The proportion of endocrine-specific operations increases over time. A typical academic endocrine surgeon meets the high-volume threshold for thyroidectomies early in their career, but does not reach the thresholds for parathyroidectomies or adrenalectomies until after 4 years. Increased productivity as reflected by adjusted work relative value units does increase over the first 15 years of practice, but also decreases as the proportion of endocrine-specific practice increases. The greatest proportion of endocrine surgeons' patients are insured by commercial plans (46%-50%), and payer mix is stable across all levels of practice. CONCLUSIONS: Although endocrine surgeons perform a high-volume of endocrine-specific operations, practice patterns are heterogeneous and suggest that most surgeons have to grow their endocrine specific practice over time. PMID- 30407205 TI - Response to: "Comment on: A National Analysis of Longterm Survival Following Thoracoscopic Versus Open Lobectomy for Stage I Nonsmallcell Lung Cancer". PMID- 30407206 TI - Interleukin-4/interleukin-13 versus interleukin-5: a comparison of molecular targets in biologic therapy for the treatment of severe asthma. AB - PURPOSE OF REVIEW: Asthma is a chronic, inflammatory disorder of the airways caused by a complex interplay of various biologic mechanisms. Several monoclonal antibody therapies targeting interleukin (IL)-4/IL-13 and IL-5 cytokine pathways have been developed for the treatment of severe eosinophilic asthma. As individuals can display biomarkers and clinical features characteristic of several asthma phenotypes, selection of anoptimal biologic can be difficult. RECENT FINDINGS: Dupilumab, a monoclonal antibody that binds to the alpha subunit of the IL-4 receptor (IL-4Ralpha) and has been approved for the treatment of adults with severe atopic dermatitis, has been shown in recent phase 3 trials to also have significant clinical benefits in the asthmatic population irrespective of baseline eosinophil counts. SUMMARY: As monoclonal antibodies targeting either IL-4 or IL-13 cytokines individually have failed to demonstrate significant clinical benefits, biologics that target cytokine receptors may be more efficacious compared to those that target cytokines. Furthermore, inhibition of the IL-4/IL-13 signaling cascades may disrupt a broader Th2 inflammatory response compared to a more selective impairment of eosinophil proliferation and activity via blockage of the IL-5 pathway. Future research with independently funded, head to-head trials of approved biologics is needed to elucidate a favorable therapeutic option. PMID- 30407207 TI - Strategies to reduce corticosteroid-related adverse events in asthma. AB - PURPOSE OF REVIEW: Severe asthmatics, despite the chronic use of high inhaled corticosteroids (ICS) doses and frequent intake of systemic corticosteroids, remains clinically and/or functionally uncontrolled. These patients are also often affected by rhinitis or chronic rhinosinusitis requiring frequent use of intranasal corticosteroids. Therefore, severe asthmatics are exposed to an overload of corticosteroids that is frequently associated with relevant and costly adverse events. This clinical problem and the strategies to overcome it are here summarized. RECENT FINDINGS: Different therapeutic options may help in reducing the corticosteroid load in asthmatics, ranging from allergy immunotherapy (nonsuitable for severe uncontrolled patients), immunosuppressant agents like methotrexate or cyclosporine, novel biologic drugs (mainly anti-IgE, anti-IL5 and anti-IL4-receptor-alpha), and aspirin desensitization (for patients with anti-inflammatory drugs exacerbated respiratory disease). SUMMARY: The evidence of even serious corticosteroid-related adverse events associated with consistent health-care costs, should prompt the entire scientific community and health regulatory authorities to promote actions to increase the use of well tolerated and effective strategies to reduce the corticosteroid need in asthmatics; the most promising option seems to be the add-on use of biologic agents. PMID- 30407208 TI - Coronary plaque erosion developing in an area of high endothelial shear stress: insights from serial optical coherence tomography imaging. PMID- 30407209 TI - Are two internal thoracic grafts better than one in patients with peripheral vascular disease? AB - BACKGROUND: The use of two bilateral internal thoracic artery grafting (BITA) was shown to lead to survival benefit. However, operators are reluctant to use BITA with peripheral vascular disease (PVD) because of concerns of increased rates of sternal wound infection and lack of studies supporting survival benefit compared with single internal thoracic artery (SITA) grafting. The aim of this study is to compare outcome BITA grafting versus of SITA and vein grafts in PVD patients. PATIENTS AND METHODS: Six hundred and twenty-one PVD patients who underwent BITA between 1996 and 2011 were compared with 372 patients who underwent SITA. RESULTS: SITA patients were older and more likely more likely to have comorbidities (female, insulin-dependent diabetes, chronic obstructive lung disease, congestive heart failure, previous coronary artery bypass grafting, renal insufficiency, cerebrovascular disease, and emergency operation). Operative mortality (5.1 vs. 4.5%, in the SITA and BITA, respectively, P=0.758), rate of sternal wound infection (5.1 vs. 3.9%, P=0.421), and strokes (4.8 vs. 7.4%, P=0.141) were not significantly different between groups. BITA patients did not have significantly better 10-year survival (52.6 vs. 45.9%, P=0.087) and after propensity score matching (302 well-matched pairs), BITA was not associated with improved survival (hazard ratio: 0.902; 95% confidence interval: 0.742-1.283; P=0.784) (Cox model). CONCLUSION: The routine use of BITA versus SITA in PVD patients does not improve long-term survival. Selective use of BITA in lower risk patients might unmask the benefits of BITA. PMID- 30407210 TI - The relation between ABO blood types and clinical and platelet function parameters in patients who underwent percutaneous coronary intervention. AB - BACKGROUND: ABO blood groups have been associated with venous thromboembolism and arterial thrombosis. Although platelets play key roles in thrombogenesis, the relation between ABO groups and platelets is not well known and was investigated in this study. PATIENTS AND METHODS: ABO blood type information was retrospectively obtained for 206 patients who underwent percutaneous coronary intervention and received dual antiplatelet therapy with aspirin and clopidogrel. Platelet function was measured using VerifyNow system, light transmission aggregometry, thromboxane B2, urinary 11-dehydrothromboxane B2, and vasodilator stimulated phosphoprotein phosphorylation assays. Samples were also tested following treatment with 10 and 30 umol/l of aspirin or 30 and 100 umol/l of P2Y12 inhibitor 2-methylthioadenosine 5'-monophosphate triethylammonium salt hydrate (2-MeSAMP). Forty-four clinical and 30 platelet function parameters were analyzed. Patients were categorized as aspirin or clopidogrel poor responder (PR) according to cutoff levels of each test. RESULTS: Blood type A was significantly associated with myocardial infarction (MI) history [odds ratio (OR)=2.50, 95% confidence interval (CI)=1.37-4.58, P=0.003], higher baseline troponin T and creatine kinase-muscle and brain index, postpercutaneous coronary intervention creatine kinase-muscle and brain index, and platelet reactivity index and being PR against 2-MeSAMP (OR=5.75, 95% CI=1.51-21.90, P=0.010). Blood type O was associated with higher arachidonic acid-induced platelet aggregation and negatively associated with MI history (OR=0.47, 95% CI=0.26-0.84, P=0.010), PRI and being PR against clopidogrel (OR=0.54, 95% CI=0.30-0.99, P=0.043) and 2 MeSAMP (OR=0.16, 95% CI=0.03-0.76, P=0.021). CONCLUSION: Blood type A was found as a risk factor for MI. Higher arachidonic acid-induced aggregation in group O and higher PRI in group A against aspirin and P2Y12 inhibitor treatment, respectively, may suggest alternative antiplatelet therapies for PRs with these blood types. PMID- 30407211 TI - A mitochondrial neurogastrointestinal encephalomyopathy with intestinal pseudo obstruction resulted from a novel splice site mutation. AB - Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is an autosomal recessive disorder characterized by gastrointestinal dysmotility, cachexia, ptosis, peripheral neuropathy and leukoencephalopathy. The diagnosis is often not made until 5-10 years after the onset of symptoms. MNGIE is caused by mutations in thymidine phosphorylase gene TYMP. Here, we present a 19-year-old boy with MNGIE who had a chronic intestinal pseudo-obstruction, and we describe his family history. Genetic analysis revealed a novel homozygous c.765+1G>C intronic mutation which is expected to disrupt splicing of TYMP in the patient. Family screening revealed that the brother was also affected and the mother was a carrier. MNGIE should be considered and genetic testing instigated if individuals with cachexia have neuromuscular complaints or symptoms of chronic intestinal pseudo-obstruction. PMID- 30407212 TI - Clinicopathologic Features of CIC-NUTM1 Sarcomas, a New Molecular Variant of the Family of CIC-fused Sarcomas. AB - CIC-fused sarcomas represent an emerging family of tumors, for long connected to the Ewing family group of tumors, but underlined by distinct CIC fusions with different partners. 3' Fusion partners include DUX4, FOXO4, and, as recently emphasized, NUTM1. In this study, we report the clinicopathologic and molecular features of a series of 6 CIC-NUTM1 sarcomas. Mean age at diagnosis was 6 years (2 to 27 y), and 4 patients were male individuals. Primary tumors were located in the central nervous system (n=3), paravertebral soft tissue and epidural spaces (n=1, each), and lung (n=1). Median overall survival was 17.5 months (7 to 37 mo), and all but one patient died of disease. All tumors displayed classic features of CIC-DUX4 sarcomas with round cell to epithelioid microscopic appearance. Most tumors expressed ETV4 and NUTM1 (n=5/6 and 6/6, respectively), whereas WT1cter was positive in only 2 cases. All tested tumors were positive for break-apart fluorescence in situ hybridization for CIC and NUTM1. Apart from CIC or NUTM1 genomic breakpoints, no other recurrent copy number alteration was seen on genomic profiles. Fusion transcripts were identified by RNA-sequencing on either formalin-fixed paraffin-embedded or frozen material. CIC and NUTM1 breakpoints were located between exons 16 and 20 and exons 2 and 5, respectively. Altogether, CIC-NUTM1 sarcomas represent a new molecular variant of CIC-fused sarcomas with a predilection for the central nervous system and younger pediatric population. Its phenotype may be confused with NUT carcinomas. PMID- 30407213 TI - The Development of a Diabetes Application for Patients With Poorly Controlled Type 2 Diabetes Mellitus. AB - The prevalence of patients with diabetes mellitus has increased in recent years. This has resulted in increased demand for face-to-face diabetes education by diabetes nurse clinicians. The use of mobile-health technologies in diabetes education is an innovative way of learning and has the potential to engage patients and influence positive health behaviors, including meeting desired goals and diabetes-related outcomes. The aim of the study was to develop and test the usability and feasibility of an empirical diabetes application for patients with type 2 diabetes mellitus. The mobile-based, gamified Diabetes Application was developed based on a full systems development life-cycle framework. Eight patients with poorly controlled type 2 diabetes mellitus completed a pilot study that consisted of a postapplication survey to assess the usability and feasibility of the diabetes application. The findings affirmed the usefulness and feasibility of the diabetes application for patients with diabetes mellitus. It increased awareness, enriched knowledge, promoted user engagement, motivated positive behaviors, and affirmed patient belief in diabetes self-management. This article discusses the development and evaluation of the diabetes application, including modifications made based on the results of the pilot study. PMID- 30407214 TI - A Typology of Future Health Services by Exploring Core Concepts and Values: A Q methodology Approach. AB - Recent rapid development of medical and information technology has enabled the use of appropriate techniques for the delivery of healthcare. This project involved prediction of the meaning and structure of future health services, which are now commonly described through various keywords, without establishment of the concepts. The objectives of this study were to identify key concepts and values about future health services and to categorize the prediction of those from the perspectives of the concerned professionals using Q-methodology with 50 selected Q-statements. A total of 53 participants performed the Q-sort task using the 50 statements; collected data were analyzed using an associated program, pc-QUANL. Fifty Q-samples were selected to sort the concepts, and 53 professionals sorted the Q-samples. Six concepts were summarized, namely, the Optimistic Innovation Positive Type, Pessimistic Resistance to Technology-Driven Medicine Type, Intelligent Information Technology Centered Type, Bio-technology Centered Type, Personal Health Data Centered Type, and Customized Care Centered Type. The results could be used in the future design of consumer-centered health services. Advanced technology may accommodate the individual needs of different stakeholders and carve an ecosystem-wide suite of interacting complex adaptive systems. PMID- 30407215 TI - Factors associated with locoregional and metastatic breast cancer at diagnosis in a Southern Portuguese registry in the period 2005-2012. AB - Breast cancer (BC) is the most frequent malignancy in Portuguese women, and more than half of the registered cases live in the south of the country. The main of this study was to characterize patients with locoregional and metastatic incident BC living in the Southern Portuguese and Madeira regions in 2005-2012 according to demographic, clinical and contextual characteristics. Additionally it aimns to find the associations and relative influences of these factors with locoregional or metastatic disease at diagnosis. After a descriptive approach, binary logistic regression models were used to estimate factors related to the presence of metastatic disease at diagnosis. A final multiple regression model was developed and presented graphically as a nomogram. The median age at diagnosis was 60.84 years, being statistically lower in locoregional cases (P<0.001). Most patients presented a locoregional disease (78.4%) of unspecified location (44.5%) and had a ductal carcinoma (73.1%). The Lisbon region represented 50.5% of the analyzed cases. Metastatic disease significantly decreased over the period under analysis (~7%/year). Demographic (age at diagnosis >=50 years), clinical (lobular and 'other' morphologies, unspecified location) and contextual (residence in Portalegre) characteristics were statistically correlated with the presence of metastatic disease at the time of BC diagnosis in univariate logistic regression, with all but the last maintaining their significance in a multivariate model. Cases with metastatic BC disease at diagnosis are decreasing; however, additional information on their characteristics can improve the alignment of public health strategies, thus strengthening this trend, and contributing to the development of a graphically tailored screening tool. PMID- 30407216 TI - Supplementation of p-coumaric acid exhibits chemopreventive effect via induction of Nrf2 in a short-term preclinical model of colon cancer. AB - Suppression of colorectal cancer by means of chemoprevention is gaining great attention owing to promising outcomes with less adverse effects in preclinical and clinical trials. The present study aims to explore the mechanism of chemoprevention by p-coumaric acid (p-CA) in a short-term preclinical model of colon cancer. 1,2-dimethylhydrazine-administered rats supplemented with p-CA showed downregulation of the expression of colonic proteins, namely, cyclin B1, cdc2, and mdm2, which regulate cell cycle, and immediate early response genes, namely, c-fos, c-jun and c-myc, which regulate cell proliferation. Apoptosis induction was also observed in the colon of p-CA-supplemented rats as assessed by the Bax/Bcl-2 ratio. Immunohistochemistry, immunoblotting and real-time polymerase chain reaction analysis revealed that supplementation of p-CA improved the in-vivo detoxification potential by modulating the cytoplasmic-to-nuclear ratio of nuclear factor erythroid 2-related factor 2, favouring the induction of genes responsible for cytoprotection and detoxification. The outcome of these findings suggests that p-CA inhibited polyp formation by improving the process of detoxification and apoptosis in the colon of 1,2-dimethylhydrazine-administered rats. PMID- 30407217 TI - Social skills and relationships in Turner syndrome. AB - PURPOSE OF REVIEW: Summarize the literature on the social skills and relationships of women with Turner syndrome and examine the biological and psychological factors that may contribute to social interaction difficulties. RECENT FINDINGS: Turner syndrome is often associated with impaired social cognitive processing and executive function deficits. These cognitive abnormalities, together with a range of physical differences, may adversely affect social communication skills, which typically begin to impair quality of life during early adolescence. Parental accounts of their daughter's social skills frequently highlight interaction problems, both in the home and beyond; in contrast, self-reports are usually far more positive. At present, we do not know the extent to which such self-reports reflect a lack of social awareness, or a lack of concern about social difficulties. SUMMARY: Women with Turner syndrome are likely to experience social interaction challenges (especially in friendships and relationships) across the lifespan. Providing appropriate guidance and support to them demands a better understanding of their strengths and weaknesses. PMID- 30407218 TI - The role of CXCR2 in acute inflammatory responses and its antagonists as anti inflammatory therapeutics. AB - PURPOSE OF REVIEW: CXCR2 is key stimulant of immune cell migration and recruitment, especially of neutrophils. Alleviating excessive neutrophil accumulation and infiltration could prevent prolonged tissue damage in inflammatory disorders. This review focuses on recent advances in our understanding of the role of CXCR2 in regulating neutrophil migration and the use of CXCR2 antagonists for therapeutic benefit in inflammatory disorders. RECENT FINDINGS: Recent studies have provided new insights into how CXCR2 signaling regulates hematopoietic cell mobilization and function in both health and disease. We also summarize several CXCR2 regulatory mechanisms during infection and inflammation such as via Wip1, T-bet, P-selectin glycoprotein ligand-1, granulocyte-colony-stimulating factor, and microbiome. Moreover, we provide an update of studies investigating CXCR2 blockade in the laboratory and in clinical trials. SUMMARY: Neutrophil homeostasis, migration, and recruitment must be precisely regulated. The CXCR2 signaling pathway is a potential target for modifying neutrophil dynamics in inflammatory disorders. We discuss the recent clinical use of CXCR2 antagonists for controlling inflammation. PMID- 30407219 TI - Is in-office transperineal biopsy the future of prostate cancer diagnosis? PMID- 30407220 TI - Residual stone fragments: clinical implications and technological innovations. AB - PURPOSE OF REVIEW: To summarize the recent literature on the topic of residual stone fragments in particular novel developments in this field. RECENT FINDINGS: The urological position towards residual fragments has shifted in recent years from observation, to active retrieval with innovative methods, to algorithm-based predictions of surgical outcomes. Novel technologies have been described to extract residual fragments through magnetism, a polyethylene endoscopic pouch and a biocompatible stone adhesive. In an effort to have a tighter grip over the outcome of residual fragments, artificial neural networks (ANNs) have been developed to accurately predict surgical outcomes in terms of stone clearance and secondary procedures. SUMMARY: Growing evidence continues to show the term clinically insignificant residual fragments (CIRF) for residual fragments of 4 mm or less to be a misnomer. In fact, only a third of CIRF is spontaneously cleared from the kidney after surgery and may become a cause for reintervention being both costly and significantly affecting patients' well being. Several novel methods which have been developed to extract residual fragments require further in-vivo investigations to confirm their safety and efficacy. ANNs algorithms are increasingly being used to predict surgical outcomes in stone therapy and assist in preoperative patient counselling and decision-making. PMID- 30407221 TI - Ho: YaG laser lithotripsy: recent innovations. AB - PURPOSE OF REVIEW: The aim of this study was to summarize the recent innovations of the holmium laser with special respect to lithotripsy. Therefore, we reviewed and discussed the most recent and pivotal publications on this topic. RECENT FINDINGS: The current literature underlines Holmium:yttrium-aluminium-garnet (Ho:YAG) lithotripsy as a well tolerated and efficient method to treat urinary calculi. Because of modifiable adjustments of pulse energy, pulse frequency, and pulse length, especially with newer generations of holmium lasers, urologists can accurately choose between the 'fragmentation' and 'dusting' technique with its alterations. Recently, the 'Moses mode' as a new feature incorporated in the Lumenis Pulse P120H holmium laser showed less retropulsion with higher rates of stone ablation because of an improved energy transmission from the laser fiber towards the targeted calculus in in-vitro studies. SUMMARY: Based on technological developments, Ho:YAG laser lithotripsy has become more efficient in reducing retropulsion and increasing stone ablation volume. However, despite its widespread use as a lithotripter, a newly developed thulium fiber laser, which has already shown promising results in experimental studies, could become an alternative in future practice. PMID- 30407222 TI - Emerging role for kynurenines in metabolic pathologies. AB - PURPOSE OF REVIEW: So far, the tryptophan catabolites generated in the kynurenine pathway have been mainly studied in relation to oncologic and mental health disorders. The current review provides an update on the emerging biomedical interest for kynurenine pathway activity in the field of energy homeostasis and metabolic diseases. RECENT FINDINGS: Kynurenine pathway enzymes are expressed in tissues relevant for energy homeostasis such as fat, skeletal muscle, liver and endocrine pancreas, blood vessel and heart, and are regulated by nutritional and inflammatory signals. Kynurenine pathway metabolites have been proposed as biomarkers for initiation and progression of atherosclerosis and diabetes. Exercise training activation of kynurenine pathway in skeletal muscles increases lipid metabolism and thermogenesis, and it limits weight gain, inflammation, insulin resistance, and glucose intolerance in rodents fed a high-fat diet. Manipulation of kynurenine pathway metabolism through administration of enzyme inhibitors or kynurenine pathway metabolites can serve as novel therapeutic strategy for atherosclerosis, obesity, glucose intolerance, or impaired insulin secretion. SUMMARY: Although we are far from a complete understanding of the role of kynurenine pathway in the modulation of energy homeostasis, targeting kynurenine pathway harbors high potential to expand the range of therapies to prevent and treat metabolic diseases. PMID- 30407223 TI - Human milk protein vs. formula protein and their use in preterm infants. AB - PURPOSE OF REVIEW: We review the current available evidence on the metabolic fate of human milk proteins and their potential clinical implications for growth and body composition development vs. those of formula proteins in preterm infants. RECENT FINDINGS: The decreased content of human milk protein in preterm mothers throughout lactation might contribute to the reduced growth reported in exclusively human milk-fed infants compared with that of formula-fed infants. Recent studies have demonstrated that preterm infants are capable of degrading human milk proteins regardless of their degree of prematurity or postnatal age, with limited contribution from milk proteases to protein digestion. The nitrogen balance of fortified human milk-fed preterm infants is higher than that of formula-fed preterm infants. Moreover, the growth of human milk-fed preterm infants appears to be accompanied by fat-free mass deposition. SUMMARY: Provided that adequate protein and energy intakes are delivered, human milk enhances protein use rather than oxidation as well as promotes tissue growth, leading to preferential fat-free mass deposition and contributing to the recovery of the body composition in preterm infants. Human milk feeding should be supported and promoted for all preterm mother-infant pairs. PMID- 30407224 TI - The ties that bind: skin, gut and spondyloarthritis. AB - PURPOSE OF REVIEW: This article aims to review recent literature linking epithelial barrier inflammation and arthritis in spondyloarthritis (SpA), with a critical view on how they are bound by genetic, immunological and environmental ties. RECENT FINDINGS: The epithelia-joint axis has become an intense area of both basic and clinical SpA research. The penultimate goal is to understand the immunopathologic links between epithelial inflammation and arthritis in SpA. Inflammatory bowel disease (IBD) and psoriasis (PsO) have strong links to SpA at several levels. Clinically, there is a strong association of IBD, PsO and SpA. Genetically, there are many shared risk factors; however, there are also distinct differences in the genetics of the respective diseases. Immunologically, type 3 immunity, especially interleukin (IL)-17 and IL-23 dysregulation, has been shown to play a central role in IBD, PsO and SpA. Environmentally, a microbial dysbiosis has been noted in each of these diseases, but whether the microbial signature is similar between diseases is not clear, nor is the effect of dysbiosis on the immune response known. SUMMARY: It will be crucial to determine whether the relationship between epithelia inflammation and SpA is truly causal for both the understanding of pathogenesis and for future treatment strategies. PMID- 30407225 TI - Cardiovascular magnetic resonance in the diagnosis and management of cardiac and vascular involvement in the systemic vasculitides. AB - PURPOSE OF REVIEW: Cardiac manifestations in systemic vasculitides, either primary or secondary due to infection, malignancy or autoimmune rheumatic diseases may be life-threatening. Cardiovascular (CVD) magnetic resonance (CMR) has been recently proposed as an ideal noninvasive tool to evaluate systemic vasculitides. In the present article, we present an overview of CMR in the diagnosis and follow-up of cardiac involvement in systemic vasculitides. RECENT FINDINGS: CMR is a noninvasive, nonradiating modality, capable to assess cardiac function, perfusion and tissue characterization that can be of great diagnostic value in both primary and secondary systemic vasculitides. It has been already documented that CMR is superior to other imaging modalities, because it has great versatility and higher spatial resolution that allows the detection of early CVD phenomena occurring during systemic vasculitides. Magnetic resonance angiography and oedema-fibrosis imaging detect early CVD involvement such as acute and/or chronic inflammation, coronary macro-micro-circulation abnormalities and/or small vessel vasculitis. SUMMARY: CMR due to its great versatility gives valuable information about cardiac function, perfusion, type of fibrosis and vascular integrity that may significantly contribute to treatment decisions beyond vascular scores, other disease activity or severity indices or the acute phase response. PMID- 30407226 TI - Nervous system involvement in Behcet's syndrome. AB - PURPOSE OF REVIEW: Neurological involvement in Behcet's syndrome is defined as 'the occurrence of neurological symptoms and signs in a patient who meets the International Diagnostic Criteria for BS not otherwise explained by any other known systemic or neurological disease or treatment, and in whom objective abnormalities consistent with neuro-Behcet's syndrome (NBS) are detected either on neurological examination, neuroimaging studies (magnetic resonance imaging [MRI]), and/or on cerebrospinal fluid (CSF) examination'. Given that the neurological involvement of Behcet's syndrome carries a poor prognosis, we aimed to describe the differential diagnosis of NBS and highlight the different radiological patterns together with the treatment options. RECENT FINDINGS: Two distinct MRI patterns of spinal cord involvement in Behcet's syndrome according to T2-weighted axial images were described: 'Bagel Sign' pattern: a central lesion with hypointense core and hyperintense rim with or without contrast enhancement; and 'Motor Neuron' pattern: a symmetric involvement of the anterior horn cells. Infliximab prevents patients from having further attacks and even led to improvement in the neurological examination. SUMMARY: As the treatment options completely differ, a NBS diagnosis should be carefully made in patients with clinical and MRI features mimicking other central nervous system inflammatory disorders. PMID- 30407227 TI - Editorial: A review of vasculitis 2019: an introduction. PMID- 30407228 TI - Opioid Use in the Postoperative Arena: Global Reduction in Opioids After Surgery Through Enhanced Recovery and Gynecologic Surgery. AB - Enhanced recovery programs aim to reduce surgical stress to improve the patient perioperative experience. Through a combination of multimodal analgesia and maintaining a physiological state, postoperative recovery is improved. Many analgesic adjuncts are available that improve postoperative pain control and limit opioid analgesia requirements. Adjuncts are often used in combination, but different interventions may be incorporated for patient-specific and procedure specific needs. Postoperative pain control can be optimized by continuing nonopioid adjuncts, and prescribing opioid analgesia to address breakthrough pain. Prescribing practices should balance optimizing pain relief, minimizing the risk of chronic pain, while limiting the potential for opioid misuse. PMID- 30407229 TI - Frequent premature ventricular beats in healthy children: when to ignore and when to treat? AB - PURPOSE OF REVIEW: Premature ventricular beats (PVCs) are frequently identified in healthy children with structurally normal hearts and generally have a benign clinical course often disappearing spontaneously. However, a small percentage of children may develop a cardiomyopathy. The purpose of this review is to understand which children may be at risk of development of left ventricular (LV) dysfunction with idiopathic PVCs. RECENT FINDINGS: There is increasing evidence that a ventricular ectopic burden more than 24% in adults may lead to LV dysfunction. Most of the pediatric studies to date are retrospective, small case series from single institutions and have conflicting results regarding a direct correlation of the PVC burden to LV dysfunction. Development of a cardiomyopathy from frequent PVCs in children is likely multifactorial relating to the burden itself, presence of higher levels of ectopy (couplets and runs of ventricular tachycardia) as well as the duration of ventricular ectopy. Understanding the duration of ectopy is often unknown as patients are asymptomatic and the irregular heart beat was identified at a well-child examination. SUMMARY: Asymptomatic children with normal ventricular function and a low ectopy burden can be followed without any intervention and generally reassured. Children with an ectopy burden more than 30% are at some risk of developing LV dysfunction and should be more closely followed with noninvasive imaging. Development of symptoms attributed to the ectopy or signs of increasing LV dimensions or LV dysfunction should be treated with medication or catheter ablation. PMID- 30407230 TI - Epigenetical Targeting of the FOXP3 Gene by S-Adenosylmethionine Diminishes the Suppressive Capacity of Regulatory T Cells Ex Vivo and Alters the Expression Profiles. AB - Regulatory T cells (Treg cells), a subgroup of CD4 lymphocytes, play a crucial role in serving as an immune suppressor and in maintaining peripheral tolerance. As the accumulation of Treg cells in the tumor microenvironment is significantly associated with a decreased survival time of patients, they are considered as an important therapeutic target in the immunotherapy of human cancers. These cells are either derived from the thymus, which are called (CD4CD25CD127) natural Treg cells (nTreg cells), or they are generated from CD4CD25 naive T cells by transforming growth factor-beta 1 and interleukin 2 (IL-2) in the periphery, which are called induced Treg cells (iTreg cells). Although iTreg cells are unstable, nTreg cells stably express forkhead box P3 (FOXP3) protein. Moreover, nTreg cells can be classified as memory (CD45RA) and naive (CD45RA) Treg cells, and this classification is based on the expression of CD45RA. FOXP3, which is a master regulator transcription factor, is essential for the functions of Treg cells, and it is mainly controlled by epigenetic mechanisms. The cyclooxygenase 2 (COX2)/prostaglandin E2 (PGE2) pathway is also reported to contribute to the regulatory functions of tumor-infiltrating Treg cells. As a new approach, we investigated whether S-adenosylmethionine (SAM), a substrate of DNA methyltransferase, attenuates the immune-suppressive capacity of the naive subtype of nTreg cells (CD4CD25CD127CD45RA). Moreover, we examined the effects of PGE2/COX2 pathway blockers on the suppressive capacity of Treg cells. We found that SAM diminished the suppression competency of Treg cells by decreasing the FOXP3 mRNA and protein levels in a dose-dependent manner. SAM increased the DNA methylation of FOXP3 at the first intron site. In addition, SAM decreased the mRNA and protein levels of the IL-10 cytokine, which has suppressive roles in the immune system. Moreover, mRNA levels of interferon gamma (IFNG) were found to be increased. COX2 inhibition and blockage of PGE2 receptors also reduced the protein and mRNA levels of IL-10, but they did not exhibit any significant effect on Treg cells' suppression in the coculture system. Our results show that SAM might be considered and investigated as a promising agent for immunotherapy in the future. PMID- 30407231 TI - Clinicopathologic Correlation With Expression of PD-L1 on Both Tumor Cells and Tumor-infiltrating Immune Cells in Patients With Non-Small Cell Lung Cancer. AB - Our study was to evaluate the concordance of programmed cell death-ligand 1 (PD L1) expression between 22C3 and SP263 assay and explore the association of clinicopathologic features with expression of PD-L1 on both tumor cells (TC) and tumor-infiltrating immune cells (IC). We retrospectively assessed the PD-L1 expression in 305 patients with lung adenocarcinoma or adenosquamous carcinoma by 22C3 and SP263 assay. The association of PD-L1 expression by 22C3 assay with clinicopathologic features was also analyzed. The prevalence of PD-L1 expression by 22C3 assay was 20.7% with a >=50% cutoff and 46.6% with a >=1% cutoff. The concordance rates between 2 PD-L1 assays while using 1%, 5%, 25%, and 50% positive TC as the cutoffs were 91.8%, 93.1%, 95.1% and 99.0%, respectively. For PD-L1 expression on IC, the concordance rate was 93.4% using a 1% cutoff. According to the results of 22C3 assay, high PD-L1 expression (using a >=50% cutoff) on TC was significantly associated with smoking, advanced stage disease, and KRAS mutation. PD-L1 expression on IC was significantly associated with smoking and KRAS mutation. PD-L1 expression on TC and IC were both significantly associated with average number of cigarettes smoked >=20 per day. The 22C3 and SP263 assays were highly concordant for assessment of PD-L1 expression on TC and IC. Patients with KRAS mutation and smoking history, particularly those having a large number of cigarettes smoked per day, were more likely to have PD-L1 expression on both TC and IC. PMID- 30407232 TI - Concluding My Service as Editor in Chief. PMID- 30407233 TI - Symptoms and Experience of Depression Among Chinese Communities in the West: A Scoping Review. AB - Despite the increasing presence of Chinese communities in the West, their experiences of depression and the variations in symptoms or presentation are not well understood. Using Arksey and O'Malley's methodical framework, we conducted a scoping review of the published literature, using electronic databases MEDLINE and PsycINFO, and searched for articles published since 1999. Out of 1177 articles identified, 21 met the inclusion criteria. Thematic synthesis revealed valuable scholarly work on (1) depression rates, migration, and contextual determinants, (2) causation beliefs and help seeking, (3) acculturation and symptoms, (4) presenting symptoms and somatization, and (5) culturally sensitive assessment and care. Overall, this review has identified the importance of contextual determinants in the development of depression, low rates of seeking of professional help, subtle variations in somatization, and knowledge gaps in culturally sensitive care. The findings suggest that, rather than treating migration as a cause of mental distress, the accompanying conditions and events need to be further examined and addressed as potential risk or protective factors. Subtle variations in somatization are also evident, and future scholarly work should examine the notion of cultural scripts-namely, that people attend and react to particular experiences in culturally based ways. For this reason (among others), practice models need to develop strategies for culturally sensitive care, such as co-construction of illness narratives and finding common ground. Given the stigma of mental illness and the low level of seeking professional help, the role of primary care should be expanded. Further studies investigating mental health issues beyond depression are also warranted in the studied community. PMID- 30407234 TI - Pain and Depression: A Systematic Review. AB - BACKGROUND: Pain comorbid with depression is frequently encountered in clinical settings and often leads to significant impaired functioning. Given the complexity of comorbidities, it is important to address both pain and depressive symptoms when evaluating treatment options. AIM: To review studies addressing pain comorbid with depression, and to report the impact of current treatments. METHOD: A systematic search of the literature databases was conducted according to predefined criteria. Two authors independently conducted a focused analysis of the full-text articles and reached a consensus on 28 articles to be included in this review. RESULTS: Overall, studies suggested that pain and depression are highly intertwined and may co-exacerbate physical and psychological symptoms. These symptoms could lead to poor physical functional outcomes and longer duration of symptoms. An important biochemical basis for pain and depression focuses on serotonergic and norepinephrine systems, which is evident in the pain ameliorating properties of serotonergic and norepinephrine antidepressants. Alternative pharmacotherapies such as ketamine and cannabinoids appear to be safe and effective options for improving depressive symptoms and ameliorating pain. In addition, cognitive-behavioral therapy may be a promising tool in the management of chronic pain and depression. CONCLUSION: The majority of the literature indicates that patients with pain and depression experience reduced physical, mental, and social functioning as opposed to patients with only depression or only pain. In addition, ketamine, psychotropic, and cognitive-behavioral therapies present promising options for treating both pain and depression. PMID- 30407235 TI - A Potential Role for the Noncoding Transcriptome in Psychiatric Disorders. AB - Understanding the complexity and regular function of the human brain is an unresolved challenge that hampers the identification of disease-contributing components and mechanisms of psychiatric disorders. It is accepted that the majority of psychiatric disorders result from a complex interaction of environmental and heritable factors, and efforts to determine, for example, genetic variants contributing to the pathophysiology of these diseases are becoming increasingly successful. We also continue to discover new molecules with unknown functions that might play a role in brain physiology. One such class of polymeric molecules is noncoding RNAs; though discovered years ago, they have only recently started to receive careful attention. Furthermore, recent technological advances in the field of molecular genetics and high-throughput sequencing have facilitated the discovery of a broad spectrum of RNAs that show no obvious coding potential but may provide additional layers of complexity and regulation to the molecular mechanisms underlying psychiatric disorders. Their exquisite enrichment and expression profiles in the brain may point to important functions of these RNAs in health and disease. This review will therefore aim to provide insight into the expression of noncoding RNAs in the brain, their function, and potential role in psychiatric disorders. PMID- 30407236 TI - Differential Susceptibility to the Environment and Borderline Personality Disorder. AB - Evolutionary models of psychopathology can shed light on gene-environment interactions. Differential susceptibility to the environment means that heritable traits can have positive or negative effects, depending on environmental context. Thus, traits that increase risk for mental disorders when the environment is negative can be adaptive when the environment is positive. This model can be applied to borderline personality disorder, with predictors such as emotional dysregulation and impulsivity seen as temperamental variations leading to negative effects in an unfavorable environment but to positive effects in a favorable environment. This model may also be useful in conceptualizing the mechanisms of effective therapy for borderline personality disorder. PMID- 30407237 TI - A Case of Emotional Trauma in the Setting of Neurodevelopmental Disability. PMID- 30407238 TI - Behavioral challenges: A novel approach to mental health workers in medical nursing. PMID- 30407239 TI - Dual-Source Dual-Energy CT Portal Venous Phase Abdominal CT Scans in Large Body Habitus Patients: Preliminary Observations on Image Quality and Material Decomposition. AB - PURPOSE: Our objective was to evaluate image quality (IQ) and material decomposition in patients with large body habitus undergoing portal venous phase abdominal computed tomography (CT) scans on dual-source dual-energy CT (dsDECT) scanners. METHODS: This retrospective analysis included 30 scans from consecutive patients (19 males/11 females, mean +/- SD age = 55.3 +/- 17.5 years, range = 27 87 years) with large body habitus (>=90 kg, mean +/- SD weight = 105.4 +/- 12.35, range = 91-145 kg) who underwent portal venous phase abdominal DECT examinations on dsDECT scanner between Jan 2015 and Dec 2015. Qualitative and quantitative evaluation of IQ of DECT data sets (blended, iodine, and virtual noncontrast images) was performed. The patients were categorized into 2 groups (group A, <=104 kg; group B, >104 kg). RESULTS: The mean +/- SD patient body weight in group A was 97.2 +/- 4.5 kg (range = 91-104 kg) and 114.8 +/- 11.7 kg (range = 104.3-145.2 kg) for patients in group B. The diagnostic acceptability of the blended images in patients > 104 kg was lower (3.6 vs 4, <3 in 4/14 vs 0/16, P = 0.03). The extension of visceral anatomy beyond DE field of view (DEFOV) was seen in 60% (28 organs in 18 patients), the most common organs being liver and spleen. The incidence of visceral organs outside DEFOV was significantly higher in patients > 104 kg (18 vs 10, P = 0.03). Outside the DEFOV, blended images demonstrated higher image noise (mean: 14.48, range = 10.09-26.83 vs mean: 9.5, range = 7.3-15.8) P < 0.001) and lower signal-to-noise ratio (mean: 4.15, range = 1.5-7.6 vs mean: 7.5, range = 4.2-9.9) P < 0.001), and material-specific information was not available in this region. Within the DEFOV, the IQ of iodine maps and virtual non-contrast images were diagnostically acceptable with diagnostic acceptability of 3 or greater in nearly all patients. A 40-cm transverse diameter cut-off provided a good predictor of extension of visceral anatomy outside the effective DEFOV. CONCLUSIONS: Dual-source DECT allows diagnostically acceptable IQ and material separation in patients with large body habitus with the major limitation of exclusion of patient anatomy and organs outside the effective dual-energy field of view. PMID- 30407240 TI - Adaptive Nonlocal Means Method for Denoising Basis Material Images From Dual Energy Computed Tomography. AB - We propose an adaptive nonlocal means approach for image-domain material decomposition in low-dose dual-energy micro-computed tomography. The key idea is to create a distribution map for decomposition error and assign a smooth weight for a given pixel. This method is applied to the decomposed images of 3 basis materials: bone, soft tissue, and gold in our applications. We assume that bone and gold cannot coexist in the same pixel and regroup these basis materials into 2 categories. For soft tissue, the proposed algorithm is implemented in a noniterative mode. For bone and gold, an iterative mode is used and followed by a postiteration process. Both our numerical simulation and in vivo preclinical experiment results show that the proposed adaptive nonlocal means outperforms other state-of-the-art denoising algorithms, such as the original nonlocal means and total variation minimization methods. PMID- 30407241 TI - Diagnostic Value of Quantitative Perfusion Computed Tomography Technique in the Assessment of Tumor Response to Sorafenib in Patients With Advanced Hepatocellular Carcinoma. AB - AIM: The aim of this study was to assess the role of dynamic contrast-enhanced perfusion computed tomography (pCT) imaging in the early detection of blood flow changes related to antiangiogenic treatment with sorafenib, in patients with advanced hepatocellular carcinoma (HCC), being the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria the standard of reference. METHODS: Between 2012 and 2016, 43 cirrhotic patients (male, n = 39; female, n = 4) with biopsy-proven multifocal HCC underwent multi-detector-row computed tomography, and pCT examinations were performed before and every 2 months after sorafenib administration. Perfusion CT technique is based on the acquisition of 16 dynamic slices/scan per 40 scans, performed on a 256-slice multi-detector-row computed tomography scanner, after intravenous bolus injection of 50 mL of iodinated contrast agent (350 mg I/mL) at a flow rate of 5 mL/s. According to mRECIST, patients were stratified into complete (CR) or partial response (PR) and stable (SD) or progressive disease (PD). The following pCT parameters were calculated: hepatic perfusion (mL/s per 100 g), time to peak (seconds), arterial perfusion (mL/s), and hepatic perfusion index (%). Perfusion CT values at baseline and first follow-up were reported for all mRECIST groups and then compared between the nonprogressor (CR, PR, SD) and progressor groups (PD). RESULTS: Most pCT values were significantly higher (P < 0.01) between baseline and follow-up in the CR and PR groups, whereas nonsignificant differences were found among SD patients, and a nonsignificant trend (P > 0.05) toward increase was observed among PD patients. Moreover, pCT values were significantly higher (P = 0.05) at baseline in the nonprogressor group compared with the progressor. CONCLUSION: Preliminary results suggest that pCT adds quantitative data of vascularization, thus demonstrating its usefulness in the assessment of therapeutic response to sorafenib in advanced HCC, in line with mRECIST criteria, offering 1-step information on tissue cellularity and vascularization. PMID- 30407242 TI - Assessment of Mass Effect Sign at High-Resolution Computed Tomography in Prediction of Cholesteatoma. AB - OBJECTIVE: The aim of this study was to assess the accuracy of mass effect sign in the diagnosis of cholesteatoma at high-resolution computed tomography (HRCT). METHODS: This prospective study included 32 ears in 24 patients with chronic otitis media who underwent HRCT of the temporal bone. Otoscopic and operative notes were recorded. Image analysis was done both qualitatively and quantitatively. In the qualitative analysis, mass effect was evaluated visually by comparing both ears together in 4 certain anatomical sites. Ossicular erosions, erosion of tegmen tympani, erosion of tympanic segment of facial nerve canal, and the presence of lobulated nondependent opacity were also evaluated. In the quantitative analysis, we calculated the difference between the distances of the described anatomical sites in both ears. RESULTS: Qualitative analysis of mass effect sign showed 97.1% accuracy in detecting cholesteatoma. Ossicular erosions showed 69.2% accuracy in the diagnosis of cholesteatoma. In the quantitative analysis, we found that the cutoff point of 0.45 mm in the difference of aditus measure between both ears showed 85.3% accuracy in differentiating cholesteatoma from otitis media. The cutoff point of 0.75 mm in the differences in supratubal measure showed 86.1% accuracy. The cutoff point of 0.45 mm in the medial to incus measure showed 100% accuracy. CONCLUSION: High resolution computed tomography is highly valuable for the detection of mass effect sign, which has great importance in diagnosing cholesteatoma. PMID- 30407243 TI - Updated Imaging Features of Dysplastic Cerebellar Gangliocytoma. AB - OBJECTIVE: The aim of this study was to perform an updated review of the imaging features of dysplastic cerebellar gangliocytoma (DCG). METHODS: Imaging findings were retrospectively reviewed in 14 patients with DCG. The analysis included size, location, cyst formation, calcification, intralesional hemorrhage, enhancement pattern, and apparent diffusion coefficient (ADC). RESULTS: In addition to revisiting many well-established imaging features of DCG, enhancement was much more common (64.3%) than previously reported, and small enhancing veins were also frequently encountered within or along the periphery of the lesions (50%). Dysplastic cerebellar gangliocytomas had an elevated ADC compared with normal cerebellum (967.8 +/- 115.7 vs 770.4 +/- 47.3 * 10 mm/s; P < 0.0001). CONCLUSIONS: Enhancement on magnetic resonance imaging within DCG should be an accepted imaging finding rather than being viewed as uncommon or atypical. Dysplastic cerebellar gangliocytomas typically have an elevated ADC compared with normal cerebellum, which may assist in differentiation from other posterior fossa neoplasms. PMID- 30407244 TI - Assessment of Liver and Spleen in Children With Gaucher Disease Type 1 With Chemical Shift Imaging. AB - PURPOSE: The aim of this study was to assess of liver and spleen in children with Gaucher disease type 1 with chemical shift imaging. METHODS: Retrospective analysis was conducted on 36 untreated children with Gaucher disease type 1 and 15 age- and sex-matched control children who underwent chemical shift imaging of the abdomen. The hepatic and splenic fat fraction was calculated. The Pediatric Gaucher Severity Scoring System, hematologic parameters, and enzyme assay of the disease were calculated and correlated with hepatic and splenic fat fraction. RESULTS: The mean hepatic fat fraction in Gaucher disease was 14.1 +/- 3.1 (95% confidence interval [CI], 12.9-15.2) was significantly higher (P = 0.001) than that of control subjects 5.2 +/- 0.9 (95% CI, 4.7-5.7). The mean splenic fat fraction in Gaucher disease was 11.2 +/- 2.9 (95% CI, 11.2 +/- 2.9), and that of control was 4.5 +/- 0.9 (95% CI, 4.02-5.2). The thresholds of hepatic and splenic fat fraction used to differentiate patients from control subjects were 0.47 and 0.39 with areas under the curve of 0.947 and 0.999, respectively. The hepatic and splenic fat fraction is correlated with the Pediatric Gaucher Severity Scoring System (r = -0.523, -0.602), hemoglobin concentration (r = -0.491, -0.505), platelet count (r = -0.593, -0.24), beta-glucosidase (r = 0.519, 0.549), and chitotriosidase (r = -0.03, 0.267), respectively. CONCLUSIONS: Hepatic and splenic fat fraction is a promising quantitative imaging parameter for detection and quantification of hepatic and splenic infiltration in children with Gaucher disease and correlated with clinical scoring, hematologic parameters, and enzyme assay of the disease. PMID- 30407245 TI - Mixed Imaging on Port-Venous Phase of Contrast-Enhanced Dual-Source Dual-Energy Computed Tomography: A Measurement Method Based on Couinaud Segments. AB - OBJECTIVE: The aim of this study was to evaluate the changes of the iodine value quantified on the Couinaud segments measured in port-venous phase using the iodine-mixed technique of contrast-enhanced dual-source dual-energy computed tomography (CT) scanning in different Child-Pugh stages of hepatitis B-induced liver cirrhosis. METHODS: Patients clinically diagnosed with hepatitis B-induced cirrhosis were prospectively engaged in our study. Each patient underwent multiphase iodine agent contrast-enhanced dual-source dual-energy CT scanning, and then the iodine-mixed imaging of port-venous phase was postprocessed. Iodine concentration was obtained for each segment based on the Couinaud segments. The volume of each segment and the total of the liver were measured and calculated using the postprocessing software of volume. All the cirrhosis patients were grouped into 3 subgroups based on the Child-Pugh stage method. Patients without cirrhosis were engaged for the control group. The iodine concentration, volume, and iodine storage among groups were analyzed by SPSS version 19.0. Single energy was used for the nonenhanced phase scanning, which was used for the radiation dosage comparison with dual-energy CT scanning. RESULTS: Two hundred three patients were ultimately enrolled in our study, including 148 patients with cirrhosis (Child A, 69; Child B, 51; Child C, 28) and 55 patients without cirrhosis as control subjects. The total volume and iodine storage of cirrhosis group were smaller than those of the control group (P < 0.001). Compared with the control group, the iodine concentration in each segment decreased with progression of cirrhosis. The volume, iodine concentration, and iodine storage of the right hepatic lobe and left medial segment decreased with cirrhosis severity (P < 0.001). There was no significant difference in the volume of right hepatic lobe between Child C group and Child B group, whereas the iodine storage of Child C group was lower than that of Child B group (P < 0.05). The volume and iodine storage of left lateral segment increased with the progression of liver cirrhosis in the Child A and Child B groups (P < 0.05), whereas there was no statistical difference between the Child B and Child C groups, and the iodine storage in the Child C group was lower than that of the Child B group (P < 0.05). The radiation dose of dual-energy scanning was lower than that of single-energy scanning (P < 0.001). The iodine concentration 1.512 mg/mL on the left medial segment reached the most optimal evaluation on cirrhosis, with a sensitivity of 100%, specificity of 0.722, and area under the curve of 0.914. CONCLUSIONS: Iodine concentration in portal phase measurement can evaluate and reflect the severity of cirrhosis. Iodine content segmental quantification can analyze the changes of the liver storage with a progression of cirrhosis. Dual-energy scanning reduced the radiation damage in patients and is valuable for a further study and clinical application. PMID- 30407246 TI - Phase-Contrast Magnetic Resonance Quantification of Aortic Regurgitation in Patients With Turbulent Aortic Flow. AB - OBJECTIVE: This study aimed to assess variability in measurements and accurately quantify aortic regurgitation in patients with coexisting turbulent aortic flow using phase-contrast magnetic resonance. METHODS: All patients (n = 21) underwent phase-contrast magnetic resonance at 2 or more sites: ascending aorta, sinuses of Valsalva, and left ventricular outflow tract. The net flow/minute (NF), forward flow/minute (FF), regurgitant flow/minute (RF), and regurgitant fraction (RF%) were compared with the sum of superior vena cava and descending aortic flow/minute, left ventricular cardiac output, difference between the 2, and percentage difference, respectively. RESULTS: The NF, FF, and RF were significantly different between each site. The combination of FF in the left ventricular outflow tract and NF from the superior vena cava + descending aorta provided the best reliability of RF and regurgitant fraction (intraclass correlation coefficients, 0.881 [95% confidence interval, 0.882-0.878] and 0.838 [95% confidence interval, 0.837-0.838]). CONCLUSION: Combining flow measurements from more than 1 site provides the most accurate quantification of aortic regurgitation in patients with turbulent aortic flow. PMID- 30407247 TI - Transmural Myocardial Scar Assessed by Cardiac Computed Tomography: Predictor of Echocardiographic Versus Clinical Response to Cardiac Resynchronization Therapy? AB - OBJECTIVES: Before cardiac resynchronization therapy (CRT) implantation, cardiac computed tomography (CT) can provide assessment of cardiac venous anatomy and visualize left ventricular (LV) myocardial scar. We hypothesized that localization and burden of transmural myocardial scar verified by cardiac CT are associated with echocardiographic and clinical response to CRT. METHODS: We prospectively included 140 CRT recipients undergoing preimplant cardiac CT. We assessed transmural scar, defined as hypoperfusion involving more than one-half of the myocardial wall in each LV segment using a 17-segment model. Echocardiographic nonresponse was defined as less than 5% absolute improvement in LV ejection fraction at 6 months' follow-up. Clinical nonresponse was defined as 1 or more of the following at 6 months' follow-up: death, heart failure hospitalization, or no improvement in New York Heart Association class and less than 10% increase in 6-minute walk-test distance. RESULTS: Higher burden of myocardial scar was associated with echocardiographic nonresponse (adjusted odds ratio, 3.02; 95% confidence interval, 1.03-8.91; P = 0.045). Scar concordant or adjacent to LV pacing site was associated with echocardiographic nonresponse (adjusted odds ratio, 8.2; 95% confidence interval, 1.51-44.27; P = 0.015). No association between scar and clinical nonresponse was demonstrated. CONCLUSIONS: Higher scar burden and scar in proximity to the LV pacing site assessed by cardiac CT are associated with echocardiographic nonresponse to CRT. Burden and location of scar were not associated with clinical nonresponse. Further large scale studies are needed to assess the potential association between myocardial scar detected by cardiac CT and clinical CRT outcome. PMID- 30407248 TI - Introduction to Dual-Energy Computed Tomography. PMID- 30407249 TI - Assessing the Relationship Between American Heart Association Atherosclerotic Cardiovascular Disease Risk Score and Coronary Artery Imaging Findings. AB - OBJECTIVE: The aim of this study was to characterize the relationship between computed tomography angiography imaging characteristics of coronary artery and atherosclerotic cardiovascular disease (ASCVD) score. METHODS: We retrospectively identified all patients who underwent a coronary computed tomography angiography at our institution from December 2013 to July 2016, then we calculated the 10 year ASCVD score. We characterized the relationship between coronary artery imaging findings and ASCVD risk score. RESULTS: One hundred fifty-one patients met our inclusion criteria. Patients with a 10-year ASCVD score of 7.5% or greater had significantly more arterial segments showing stenosis (46.4%, P = 0.008) and significantly higher maximal plaque thickness (1.25 vs 0.53, P = 0.001). However, among 56 patients with a 10-year ASCVD score of 7.5% or greater, 30 (53.6%) had no arterial stenosis. Furthermore, among the patients with a 10 year ASCVD score of less than 7.5%, 24 (25.3%) had some arterial stenosis. CONCLUSIONS: There is some concordance but not a perfect overlap between 10-year ASCVD risk scores and coronary artery imaging findings. PMID- 30407252 TI - Non-Hodgkin lymphoma risk in adults living with HIV across five continents. AB - OBJECTIVE: To compare non-Hodgkin lymphoma (NHL) incidence rates in adults who started antiretroviral therapy (ART) across the Asia-Pacific, South Africa, Europe, Latin, and North America. METHODS: We included cohort data of adults living with HIV who started ART after 1995 within the framework of the International epidemiology Databases to Evaluate AIDS (IeDEA) and the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE). We used flexible parametric survival models to compare regional NHL rates at 2 years after ART start and to identify risk factors for NHL. RESULTS: We included 210 898 adults with 1.1 million person-years (pys) of follow-up and 1552 incident NHL cases (raw overall incidence rate 142/100 000 pys). After adjusting for age at ART start, first-line ART regimen, calendar period of ART start, and especially current CD4 cell count, NHL rates were similar across regions for most population groups. However, South African women remained at increased risk of developing NHL compared with their European counterparts [adjusted hazard ratio [aHR] 1.79, 95% CI 1.19-2.70]. In Europe, Latin, and North America, NHL risk was highest in MSM (aHR 1.30, 95% CI 1.14-1.48), followed by heterosexual men (referent), and women (aHR 0.66, 95% CI 0.57-0.78). CONCLUSION: The risk of developing NHL is higher in women in South Africa than in Europe and higher in MSM compared with heterosexual men and women. Reasons for these differences remain unclear. Early ART access and regular patient monitoring to avert low CD4 cell counts remain key for NHL prevention. PMID- 30407251 TI - Sex differences in HIV-associated cognitive impairment. AB - OBJECTIVE: We determined whether there are sex differences in the prevalence and profile of HIV-associated neurocognitive impairment, and whether sex moderates the effect of HIV-serostatus on neurocognitive impairment among HIV-positive and HIV-negative individuals. Secondarily, we assessed whether differences were explained by greater biopsychosocial risk factors in HIV-positive women. DESIGN: An observational cohort study. METHODS: Analyses included 1361 HIV-positive (204 women) and 702 HIV-negative (214 women) (ages = 18-79 years) participants from the UCSD HIV Neurobehavioral Research Program. Demographically corrected standardized T-scores from 15 neuropsychological tests were used to calculate domain-specific and global deficit scores (GDS). GDS at least 0.5 defined neurocognitive impairment. Biopsychosocial risk factors included low education, low reading level (education quality), lifetime substance use disorders, depressed mood (clinically significant depressive symptoms and/or current major depressive disorder) and a cumulative syndemic count (sum of biopsychosocial risk factors, range = 0-4). Race-stratified analyses were conducted. Analyses were adjusted for relevant demographic and clinical factors. RESULTS: HIV-associated neurocognitive impairment was more prevalent in women versus men; however, the difference was eliminated after adjustment for reading level. In sex-stratified logistic regressions, the association between HIV-seropositivity and higher likelihood of neurocognitive impairment was stronger in women versus men; however, the association was attenuated in women, but not men, after adjusting for reading level. These results in the overall sample were specific to blacks. Sex differences in the profile of HIV-associated neurocognitive impairment varied by race. CONCLUSION: Women, particularly black women, were most at-risk for HIV associated neurocognitive impairment. Higher rates of HIV-associated neurocognitive impairment in women versus men may reflect differences in educational quality. PMID- 30407253 TI - CD8+ T cells: mechanistic target of rapamycin and eukaryotic initiation factor 2 in elite HIV-1 control. PMID- 30407254 TI - New insight into the mechanisms of achieving antiretroviral therapy-free HIV-1 control. PMID- 30407255 TI - An implicit threat: dolutegravir-induced schizophrenic brief psychotic disorder and persistent cenesthopathy. PMID- 30407257 TI - Transcriptional gene silencing limits CXCR4-associated depletion of bone marrow CD34+ cells in HIV-1 infection: Erratum. PMID- 30407256 TI - Considerations in evaluating infectious morbidity and mortality in HIV-exposed uninfected infants. PMID- 30407258 TI - Irritable bowel syndrome and colonic diverticular disease: overlapping symptoms and overlapping therapeutic approaches. AB - PURPOSE OF REVIEW: Irritable bowel syndrome (IBS) is a common symptomatic disorder in the Western world and colonic diverticula are also prevalent; however, relationships between IBS-type symptoms and diverticula have been a source of much debate. Our goal was to reassess these relationships in the light of new data. RECENT FINDINGS: On removing from consideration clinical scenarios which are directly related to diverticula (i.e., diverticulitis, diverticular hemorrhage, and complications of diverticulitis, such as stricture and fistula), relationships between IBS and diverticula can be seen to revolve around a number of questions. First, are IBS and symptomatic uncomplicated diverticular disease (SUDD) the same condition? Or, in other words is SUDD no more than IBS in an individual who just happens to have diverticula? Although coincident IBS and diverticula inevitably do occur there is some evidence to indicate that SUDD may be somewhat distinctive with SUDD being characterized by more frequent and severe pain. Second, and analogous to interactions between IBS and inflammatory bowel disease or celiac disease, can an episode of acute diverticulitis lead to the de novo development of IBS? There is now epidemiological and pathophysiological evidence to support this occurrence. SUMMARY: Although relationships between uncomplicated diverticular disease and IBS have been reexamined their status remains unclear. As yet, however, none of the newer concepts related to this relationship have led to new therapeutic approaches in IBS or diverticular disease. PMID- 30407259 TI - Excluding irritable bowel syndrome in the inflammatory bowel disease patient: how far to go? AB - PURPOSE OF REVIEW: Irritable bowel syndrome (IBS) is among the most commonly encountered conditions in primary care and gastroenterology. There is ample evidence that an IBS diagnosis based on symptom-based criteria and exclusion of alarm features that would otherwise support diagnostic testing is accurate and durable. For many clinicians, however, IBS remains a diagnosis of exclusion because of concern surrounding missed diagnoses of inflammatory bowel disease (IBD) or other organic gastrointestinal diseases. Using blood and/or fecal biomarker tests to shift the precolonoscopy probability of IBD in patients with symptoms mimicking IBS is becoming an increasingly reasonable practice with improvement in 'preliminary' tests. RECENT FINDINGS: Fecal calprotectin (FCP) testing appears to be the most sensitive preliminary test for discriminating IBD from IBS. Although both fecal lactoferrin and FCP were superior to serum C reactive peptide (CRP) in their diagnostic accuracy, FCP is superior to fecal lactoferrin based on available literature. SUMMARY: In patients with IBS with diarrhea who have not undergone previous extensive evaluation, the ability of screening tests to detect colonic inflammation is improving. FCP and fecal lactoferrin are reliable predictors of colonic inflammation and should be considered for standard testing in patients with IBS-D symptoms to help identify those who would benefit most from colonoscopy. Although predictive, there currently are no fecal or serum tests that can definitively identify or subtype IBD. PMID- 30407260 TI - The dark side of the colon: current issues surrounding the significance, prevalence, detection, diagnosis and management of serrated polyps. AB - PURPOSE OF REVIEW: Hyperplastic polyps, once considered to have no malignant potential, are now recognized to be part of a larger group of polyps known as serrated polyps. Serrated polyps can progress to CRC through an epigenetic pathway known as CpG Island Methylator Phenotype (CIMP), characterized by hypermethylation of specific DNA regions such as the promoter regions of the DNA mismatch repair genes like MLH1. The CIMP pathway is tightly linked with mutations of the oncogene BRAF. There are three subtypes of serrated polyps - hyperplastic polyps, sessile serrated polyps (SSPs) and traditional serrated adenomas (TSAs). TSAs harbor cytologic dysplasia whereas hyperplastic polyps and SSPs are nondysplastic lesions. Currently, only SSPs and TSAs are believed to progress to CRC whereas hyperplastic polyps are thought to be benign with no malignant potential. This article will review the current evidence while highlighting some of the issues regarding serrated polyps. RECENT FINDINGS: One challenge has been pathologically distinguishing hyperplastic polyps from SSPs, which is an important distinction, given the potential for progression of SSPs to CRC. Other challenges regarding serrated polyps include adequate detection and resection. Surveillance guideline recommendations for some serrated polyps have been changed in current guidelines to reflect the malignant potential, recommending closer surveillance intervals than the 10-year follow-up that has been traditionally provided for hyperplastic polyps. SUMMARY: Given the difficulties in diagnosing as well as resecting, it is important for endoscopists to know how to detect, resect and manage follow-up in patients with serrated polyps. PMID- 30407261 TI - Intraoperative Multimodal Monitoring in Pedicle Subtraction Osteotomies of the Lumbar Spine: A Narrative Literature Review. AB - The use of intraoperative multimodal monitoring (IOM) in spinal deformity surgeries is well documented. In particular, pedicle subtraction osteotomy (PSO), a corrective procedure for sagittal deformity of the spine, often involves IOM usage. By providing immediate feedback to the operating surgeon, IOM has the potential to eliminate or at least minimize the risk of iatrogenic neurological injury. However, despite the widespread usage of IOM, there is currently no standardization of IOM usage in complex spine surgeries, including lumbar PSOs, and decisions concerning IOM utilization are often driven by surgeon experience and preference. This creates a state of clinical equipoise, which is further complicated by the varying degrees of benefit that IOM has on patient outcomes depending on the operation and spinal levels involved. For instance, while IOM use in thoracic PSOs has been shown to be effective, there is no established consensus on the net impact of IOM use in PSOs of the lumbar spine. Although IOM has the potential to mitigate neurological damage, it also increases operation time and cost; thus, it should only be used in operations where it will have a net positive impact on patient outcomes. The question thus becomes whether PSO of the lumbar spine is one such operation. To address this, we examine the most frequently used IOM modalities and evaluate their current usage and efficacy in lumbar PSOs. Furthermore, we will also examine the utility of IOM for other surgeries of the lumbar spine, including corrective procedures for idiopathic scoliosis and degenerative scoliosis, and routine lumbar procedures, such as discectomies and decompression surgeries for foraminal and canal stenosis. PMID- 30407263 TI - Does Gender Influence Postoperative Outcomes in Minimally Invasive Transforaminal Lumbar Interbody Fusion? AB - STUDY DESIGN: Retrospective cohort. OBJECTIVE: The objective of this study was to determine if an association exists between gender and postoperative improvements in patient-reported outcomes (PRO) measures following minimally invasive transforaminal lumbar interbody fusion (MIS TLIF). SUMMARY OF BACKGROUND DATA: Current spine literature presents conflicting findings regarding the influence of gender on clinical outcomes. METHODS: Patients undergoing primary, single-level MIS TLIF were retrospectively reviewed. PRO measures including Oswestry Disability Index (ODI) and Visual Analog Scale (VAS) back and leg pain scores were collected preoperatively and 6-week, 12-week, and 6-month postoperatively. Rates of minimum clinically important difference (MCID) achievement were determined at 6-months postoperative. Statistical analysis was performed using Pearson chi analysis or Student t test. RESULTS: In total, 169 patients, 40.83% females and 59.17% males, were included. Females experienced greater inpatient pain scores than males (POD 0: 5.30 vs. 4.69, P=0.041; POD 1: 4.80 vs. 4.13, P=0.019). Females demonstrated significantly greater ODI (43.77 vs. 36.22; P=0.002) and VAS leg (6.20 vs. 5.27; P=0.039) scores than males. No differences in postoperative improvements in ODI, VAS back or VAS leg pain scores were identified between genders, with exception to females demonstrating greater improvement in VAS leg pain at 6 months postoperatively (female: -4.40 vs. male: 3.32; P=0.033). Furthermore, no differences in MCID achievement for PROs were identified between cohorts. CONCLUSIONS: Females demonstrated greater preoperative pain and disability as well as inpatient VAS pain scores compared to males. Furthermore, gender was not associated with differences in length of stay, perioperative complication rates, or narcotics consumption. Improvements in pain and disability, as well as rates of MCID achievement were similar between genders. These findings suggest that gender is not associated with surgical or clinical outcomes and should not be used as a predictor of outcomes following MIS TLIF. LEVEL OF EVIDENCE: Level III. PMID- 30407262 TI - Impact of the Number of Levels on Adverse Events and Length of Stay Following Posterior Lumbar Fusion Procedures. AB - STUDY DESIGN: Retrospective SUMMARY OF BACKGROUND DATA:: Little is known regarding the impact of the number of operative levels on the risk for adverse events following spinal procedures. OBJECTIVE: The objective of this study was to test for associations between the number of operative levels and occurrence of adverse events following posterior lumbar fusion (PLF). METHODS: Patients undergoing 1-, 2-, or 3-level PLFs were identified in the American College of Surgeons National Surgical Quality Improvement Program database. The number of operative levels was tested for association with occurrence of adverse events in the 30-days following the procedure using multivariate regression. Post hoc pairwise comparisons were made between 1- and 2-level and between 2- and 3-level procedures. Analyses were adjusted for differences in baseline characteristics. RESULTS: In total, 8162 underwent 1-level, 3,527 underwent 2-level, and 718 underwent 3-level procedures. Patients undergoing 2-level procedures had a higher rate of anemia requiring blood transfusion than 1-level procedures (23.4% vs. 8.6%; adjusted relative risk [RR]=2.5; P<0.001). Furthermore, patient undergoing 3-level procedures had a higher rate of anemia requiring blood transfusion than 2 level procedures (29.9% vs. 23.4%; adjusted RR=1.3; P<0.001). In addition, patients undergoing 3-level procedures had a longer length of stay than 2-level procedures (4.6 vs. 3.9 d; P<0.001) and 2-level procedures had a longer length of stay than 1-level procedures (3.9 vs. 3.5 d; P<0.001). CONCLUSIONS: Increasing the number of operative levels by one level has minimal impact on the rates of most short-term postoperative adverse events following PLF. This is true both for an increase from 1 to 2 levels and from 2 to 3 levels. While surgeons should consider that an increase in the number of operative levels may increase the risk for blood transfusion and will almost certainly prolong the hospital stay, they need not fear a major increase in the rates of postoperative adverse events. PMID- 30407264 TI - Changes in Proximal Femoral Shape During Fetal Development: Common Mistake in Reliability Analysis. PMID- 30407265 TI - Safe Parameters for Utilizing Magnetic Growth Rods in Patient With a Vagal Nerve Stimulator and Case Report. AB - BACKGROUND: Magnetic growing rods are being utilized more frequently in children with early-onset scoliosis. Many of these children have multiple medical problems and additional medical devices implanted that utilize similar magnetic technology, including vagal nerve stimulator (VNS) devices. There is some concern that the external remote controller (ERC) used to control the magnetic growth rod will interact with these devices during lengthening procedures. We believe there are safe parameters which allow the magnetic growth rod ERC to be utilized in patients with an implanted VNS. METHODS: A VNS device was tested in a simulation with the magnetic growth rods ERC to determine if it would activate/inactivate the device during a lengthening procedure. This study consists of 2 simulations. Simulation 1 evaluates placing the VNS adjacent to the ERC in the same coronal plane. Simulation 2 elevates the ERC placement above the device to simulate the thickness of a torso while increasing the distance of the VNS from the ERC in the coronal plane. RESULTS: The time of exposure of the VNS device to the magnetic field had no correlation with activation. Distance had an effect on device activation. In the coronal plane of the device, activation occurred 43% of the time at 0 cm, 71% at 4 cm, and 5% activation at 8 cm. Greater than 10 cm had no activation. In the sagittal plane with the ERC 8 cm above the device, activation occurred 71% at 0 cm distance, 38% at 2 cm, and no activation occurred at a distance of >4 cm. CONCLUSIONS: Utilization of the magnetic growth rod ERC can be carried out safely in patients with a VNS. Simulations show that an actuator implanted 4 cm from the VNS device in the coronal plane in a child with >8 cm chest wall thickness will not activate the VNS device. When choosing a rod configuration for implantation, the child's chest wall thickness and the ERC placement should be considered. PMID- 30407266 TI - Pediatric Forearm Fractures are Effectively Immobilized With a Sugar-Tong Splint Following Closed Reduction. AB - INTRODUCTION: Following closed reduction and initial casting of pediatric forearm fractures, loss of reduction (LOR) occurs in ~5% to 75% of fractures. Sugar-tong splinting has been shown to maintain acceptable reduction in pediatric distal radius fractures while potentially avoiding issues associated with circumferential casting. We hypothesized that the sugar-tong splint would be an acceptable method for initial immobilization to prevent LOR in distal, mid-shaft, and proximal pediatric forearm fractures. METHODS: This is an IRB-approved, retrospective study. Inclusion criteria included pediatric patients age 4 to 16 years old, open growth plates, with a displaced forearm fracture (radius, ulna, or both bone) that underwent closed reduction. The clinical protocol involved closed reduction and application of a sugar-tong splint by an orthopaedic resident under conscious sedation in the emergency room. Clinical follow-up occurred at 1, 2, 4, and 6-week intervals with a long-arm cast overwrap applied at the initial clinic visit. Primary outcome was radiographic LOR which was defined as a change of >10 degrees of angulation on anterior posterior/lateral projections from initial postreduction radiograph or previous follow-up radiograph. The secondary outcome was the need for further intervention. RESULTS: Sixty-four (38%) patients demonstrated radiographic LOR with 90% of LORs occurring in the first 2 weeks. LOR was significantly more common in distal radius fractures [48/110 (44%)] than with either proximal [2/14 (14%), P=0.04] or mid-shaft radius fractures [7/41 (17%), P=0.004]. There was no difference in LOR by location for ulna fractures [proximal=2/13 (15%), middle=4/38 (11%), distal=20/77 (26%), P>0.08]. There was no difference in radial LOR in patients with isolated radius fractures compared with both bone forearm fracture (17/40 vs. 40/125, P=0.22), or ulnar LOR between isolated ulna and both bone forearm fracture (0/3 vs. 26/125, P>0.99). CONCLUSION: The sugar-tong splint is effective at maintaining reduction of pediatric forearm fractures similar to published rates for casting. While effective at all levels of the forearm, the sugar-tong splint performed best in proximal and mid-shaft forearm fractures. LEVEL OF EVIDENCE: Level IV. PMID- 30407267 TI - C-reactive protein decrease associates with mortality reduction only in heart failure with preserved ejection fraction. AB - AIMS: The prognostic role of high-sensitivity C-reactive protein (hsCRP) in acute heart failure is less well established than for chronic heart failure and the impact of its variation is unknown. We studied the impact of hsCRP variation in acute heart failure and whether it differed according to left ventricular function. METHODS: We analyzed patients prospectively included in an acute heart failure registry. Admission and discharge hsCRP were evaluated as part of the registry's protocol and its relative variation (DeltahsCRP) was assessed. DeltahsCRP during hospitalization = [(admission hsCRP - discharge hsCRP)/admission hsCRP] * 100. Endpoint: all-cause death; follow-up: 3 years. A multivariate Cox-regression model was used to assess the prognostic value of DeltahsCRP (continuous and categorical variable: cut-off 40% decrease); analysis was stratified according to ventricular function. RESULTS: We studied 439 patients: mean age 75 years, 50.1% men and 69.2% had heart failure with reduced ejection fraction (HFrEF). Median discharge hsCRP was 12.4 mg/l and median DeltahsCRP was ~40%. During follow-up 247 patients (56.3%) died: 73 (54.1%) heart failure with preserved ejection fraction (HFpEF) patients and 174 (57.2%) HFrEF patients. The multivariate-adjusted hazard ratio of 3-year mortality in HFpEF patients with hsCRP decrease of at least 40% during hospitalization was 0.56 (95% CI 0.32-0.99). A decrease of at least 40% in hsCRP was not mortality-associated in HFrEF patients. There was interaction between DeltahsCRP and left ventricular ejection fraction. CONCLUSION: A decrease of at least 40% in hsCRP in acute heart failure was associated with a 44% decrease in 3-year death risk in HFpEF patients. No association between DeltahsCRP and prognosis existed in HFrEF patients. Inflammation appears to play a different role according to left ventricular function. PMID- 30407268 TI - Recent developments in asthma in pregnancy. AB - PURPOSE OF REVIEW: Asthma affects up to 13% of pregnancies worldwide and has a varying and unpredictable clinical course during pregnancy. Pharmacological asthma treatment is recommended; however, studies show that some pregnant women with asthma cease their medication in early pregnancy. There is likely a large unmet disease burden arising from asthma in pregnancy. RECENT FINDINGS: Antenatal and asthma guidelines lack sufficient information on asthma management in pregnant women, and implementation of the current guidelines seems inadequate. Prescription databases provide evidence of cessation of asthma medication during pregnancy on a population level. Population-based databases also provide evidence of rare adverse perinatal outcomes. The risk of childhood asthma in the offspring of women with asthma is reduced by adequate control of maternal asthma during pregnancy. Vitamin D sufficiency during pregnancy could also reduce the risk of childhood asthma. SUMMARY: The findings of this review demonstrate the need for improved asthma and antenatal guidelines regarding asthma management during pregnancy, and the need of adequate implementation of these guidelines. Furthermore, adequate asthma control during pregnancy is needed to reduce the risk of childhood asthma. To maintain asthma control, prepregnancy medication should be continued throughout pregnancy and adjusted according to the current treatment steps if required. PMID- 30407269 TI - Familial association of attention-deficit hyperactivity disorder with autoimmune diseases in the population of Sweden. AB - AIMS: In the era of genome-wide association studies, familial risks are used to estimate disease heritability and success in gene identification. We wanted to estimate associations of 42 autoimmune diseases with attention-deficit hyperactivity disorder (ADHD) between individuals and family members. PARTICIPANTS AND METHODS: The availability of a Multigeneration Register in Sweden provides reliable access to family data that covers the last century. An open cohort design of the diseases in individual and family members was obtained through linkage to the Hospital Discharge Register. Standardized incidence ratios were calculated as relative risks for ADHD in family members of affected patients compared with those without affected family members. RESULTS: Among a total of 86 493 patients, 18 153 had a family history of autoimmune diseases. ADHD was associated with 14 autoimmune diseases in the first-degree relatives, including ankylosing spondylitis (standardized incidence ratio:1.13), celiac disease (1.16), Crohn's disease (1.07), diabetes mellitus type 1 (1.19), discoid lupus erythematosus (1.26), glomerular nephritis chronic (1.13), Hashimoto/hypothyroidism (1.11), lupoid hepatitis (1.44), multiple sclerosis (1.11), psoriasis (1.18), Reiter's disease (1.38), rheumatoid arthritis (1.07), Sjogren's syndrome (1.21), and ulcerative colitis (1.05). CONCLUSIONS: Familial associations with several autoimmune diseases suggest genetic sharing and challenge to gene identification. PMID- 30407270 TI - Fall Risk and Utilization of Balance Training for Adults With Symptomatic Knee Osteoarthritis: Secondary Analysis From a Randomized Clinical Trial. AB - BACKGROUND AND PURPOSE: Knee osteoarthritis (KOA) is a common disease that hinders activity participation in older adults. Associated symptoms and physiological changes can increase risk of falling in individuals with KOA. Balance training can decrease fall risks in older adults. Limited evidence exists regarding utilization of balance training in physical therapy (PT) for this population. This secondary data analysis investigated the proportion of participants at high risk for falling in the PhysicAl THerapy vs. INternet-based Exercise Training for Patients with Osteoarthritis (PATH-IN) study and the frequency with which balance training was utilized as an intervention in PT. METHODS: PATH-IN study participants (N = 344) performed the Four-Stage Balance Test and the Timed Up and Go (TUG) test during baseline assessment. Participants were randomly allocated to PT, an Internet-based exercise program, or a control group. Participants were classified as being at high risk for falling if they did not progress to the single-leg stance (SLS) during the Four-Stage Balance Test, were unable to maintain SLS for 5 seconds, or took longer than 13.5 seconds to complete the TUG test. The proportion of participants at high risk for falling was calculated for all participants and separately for those allocated to PT. In addition, PT notes were coded for balance training and the frequency of balance training utilization was calculated. RESULTS AND DISCUSSION: Upon enrollment, 35.5% (N = 122) of all participants and 36.2% (N = 50) of those allocated to PT were at high risk for falling. Of participants allocated to PT with documentation available for coding (N = 118), 35.5% (N = 42) were at high risk for falling. Balance training was provided to 62.7% (N = 74) during at least one PT session. Of those classified as being at high risk for falling, 33.3% (N = 14) did not receive balance training. CONCLUSIONS: The finding of high fall risks in more than one-third of all participants with KOA is consistent with previous reports of a higher risk of falling in this population. Many PT participants did receive some balance training; however, one-third of participants at high risk for falling did not. Balance training for individuals with KOA at high risk for falling may be underutilized. PMID- 30407271 TI - Hip Muscle Strengthening for Knee Osteoarthritis: A Systematic Review of Literature. AB - BACKGROUND AND PURPOSE: Osteoarthritis (OA) of the knee joint results in chronic pain and functional decline among older adults. Hip muscle weakness has been observed in persons with knee OA and is claimed to increase the medial compartment loading on the knee joint. Although individual studies are available, no review has yet integrated the literature on the benefits of hip muscle strengthening for persons with knee OA. This review aims to systematically summarize the current evidence on the effectiveness of hip muscle strengthening on knee pain, lower extremity function, and biomechanical measures of the knee in persons with knee OA. METHODS: An extensive electronic literature search was conducted in the databases PubMed, Scopus, Cumulative Index to Nursing and Allied Health (CINAHL), Cochrane Central Register of Controlled Trials (CENTRAL), and Physiotherapy Evidence Database (PEDro) to identify the published trials in the English language from January 1990 to August 2017. Randomized controlled trials that studied the effectiveness of hip muscle strengthening in persons with knee OA on knee pain, physical function, and biomechanical measures of the knee were considered for inclusion. The key word combinations were knee osteoarthritis, degenerative arthritis, arthralgia, muscle strengthening, and resistance training using the Boolean operators AND, OR. Two reviewers independently performed the study selection, and a third reviewer intervened when the consensus was not attained. Quality assessment of the included studies was carried out using the PEDro scale. RESULTS AND DISCUSSION: The search produced 774 results, among which 81 full-text articles were studied. Five randomized controlled trials of good methodological quality, including 331 participants, were included in the review. The effectiveness of hip muscle strengthening was assessed in isolation, combination, and comparison with other lower extremity exercise. Overall, the studies reported clear benefits of hip muscle strengthening on knee pain, physical function, and hip muscle strength. However, hip muscle strengthening was ineffective in improving the biomechanical measures such as dynamic alignment and knee adduction (also known as valgus) moment. CONCLUSION: The current review identified strong, high-quality evidence to recommend hip muscle strengthening in the conservative management of persons with knee OA. Further research is needed to establish the underlying mechanisms for the clinical benefits. PMID- 30407272 TI - Reliability, Validity, and Ability to Identity Fall Status of the Berg Balance Scale, Balance Evaluation Systems Test (BESTest), Mini-BESTest, and Brief-BESTest in Older Adults Who Live in Nursing Home. AB - BACKGROUND AND PURPOSE: In any given year, 28% to 35% of older adults experience falls. In nursing home environments, the annual rate of falls increases to 30% to 50%. Our objective was to verify and compare the reliability, validity, and ability to identify falls of the Berg Balance Scale (BBS), Balance Evaluation Systems Test (BESTest), Mini-BESTest, and Brief-BESTest for older adults who live in nursing home. METHODS: This was a cross-sectional study. Older adults (n = 49; aged 62-90 years; mean = 77.8; standard deviation = 7.2) were recruited from a nonprofit nursing home. All participants were assessed by 2 physiotherapists using the BBS, BESTest, Mini-BESTest, and Brief-BESTest. The interrater and test retest (7-14 days) reliability were assessed using intraclass correlation coefficients (ICCs [2, 1]). Minimal detectable changes at the 95% confidence level were established. To analyze each test's ability to identify fall status, we used receiver operating characteristic (ROC) curves, whose statistical significance we verified using the area under the ROC curve (AUC) and respective 95% confidence intervals (CIs). The diagnostic likelihood ratios (positive and negative) and 95% CI were used to verify posttest probability. We used Fagan's nomogram to show the posttest probability of each balance test. Validity was assessed using kappa coefficients and the prevalence-adjusted bias-adjusted kappa (PABAK). RESULTS: Interrater and test-retest reliability for the total scores were good to excellent across all 4 tests (ICC interrater value = 0.992-0.994 and ICC test-retest value = 0.886-0.945). All tests were also able to identify fall status (AUC = 0.712-0.762) and were in good agreement with each other (kappa coefficient for individuals with fall risk = 0.679-0.957 and individuals with no fall risk = 0.135-0.143; PABAK = 83.7%-98%). CONCLUSION: All balance tests presented similar reliability, reproducibility, and validity. This suggests that any of these tests can be used in clinical practice. However, the Brief-BESTest is the quickest and easiest test to perform. PMID- 30407273 TI - Attenuation of Spontaneous Baroreceptor Sensitivity following Concussion. AB - INTRODUCTION: Cardiovascular autonomic nervous system (CV-ANS) function is negatively impacted after concussion. The arterial baroreflex buffers pressor and depressor challenges through efferent modulation of cardiac chrono- and inotropism, and peripheral vascular tone. Baroreceptor sensitivity (BRS) reflects the capacity of the CV-ANS to accommodate dynamic metabolic demands in the periphery. The impact of concussion on BRS has yet to be defined. METHODS: CV-ANS assessment (e.g., electrocardiogram and beat-to-beat SBP) was performed the seated upright position at rest within 48 hours (V1) of concussion and 1 week later (V2) in 10 intercollegiate male athletes with concussion and 10 non-injured male athletes. Changes in heart rate (HR), SBP, high and low frequency HR variability (HF- and LF-HRV, respectively), LF-SBP variability and BRS for increasing (BRSn-Up) and decreasing (BRSn-Dn) SBP excursions, and overall BRS (BRSn-Avg) were assessed for differences at V1 and V2. RESULTS: The concussion (age: 20+/-1 years; height: 1.79+/-0.14 meters; weight: 83+/-10 kilograms) and control (age: 20+/-1 years; height: 1.78+/-0.10 meters; weight: 79+/-13 kilograms) groups were matched for demographics. Concussed athletes had a significantly reduced BRSn-Up, BRSn-Dn, and BRSn-Avg compared to controls at V1 or V2; these changes occurred without differences in conventional markers of CV ANS function (e.g., HF-HRV, LF-HRV, LF-SBP), HR or SBP at either visit. CONCLUSIONS: Reduced BRS is a post-concussive consequence of CV-ANS dysfunction during the first post-injury week. Because SBP was similar between groups, it may be speculated that reduced BRS was not afferent in origin, but represents a post injury consequence of the central nervous system after injury. PMID- 30407274 TI - Photoplethysmography Detection of Overreaching. AB - INTRODUCTION: Detecting the onset of functional or non-functional overreaching in endurance athletes is of prior importance to ensure reactive amendment of the scheduled training program. The objective of this study was to assess photoplethysmography (PPG) in overloaded athletes and test whether 1) it would be affected differently in functional overreached (FOR) or non-overreached acutely fatigued (AF) athletes; 2. Specific PPG characteristics would allow timely distinction of FOR and AF. METHODS: Fifteen athletes performed 2-wk baseline (BSL) training followed by 3-wk overload (+45%; OVL) and 2-wk recovery (-20%; RCV). 3000 m running time-trial was used to assess performance at the end of BSL, OVL and RCV and distinguish FOR and AF. PPG was recorded overnight using a wearable sensor, every third night. Overnight means and variances of systolic, diastolic and dicrotic amplitudes and times as well as systolic and diastolic slopes were used to discriminate FOR and AF athletes. RESULTS: Performance was decreased in FOR and improved in AF at the end of OVL. Diastolic time was greater in AF than FOR whilst systolic slope was smaller in AF than FOR during OVL. The variances of systolic, diastolic, dicrotic amplitudes, systolic, diastolic slopes and pulse areas were smaller in AF compared to FOR in the last week of OVL. CONCLUSION: PPG is an efficient tool for the detection of overreaching as it distinguished FOR and AF athletes during OVL (prior performance decrement). This fast-responding method would therefore allow adjusting the daily training content in order to prevent non-functional overreaching. PMID- 30407275 TI - Effectiveness of a Parent-led Physical Activity Intervention in Youth with Obesity. AB - PURPOSE: Prader-Willi Syndrome (PWS) is a complex, rare neuro-behavioral syndrome characterized by excessive fat, hypotonia, poor motor skills, and behavioral and cognitive disabilities. We tested the effectiveness of a home-based physical activity (PA) intervention led by parents in youth with obesity with and without PWS to increase moderate-to-vigorous PA (MVPA) and gross motor proficiency (MP). METHODS: Participants were 111 youth ages 8-16 y (45 with PWS and 66 without PWS, but categorized as obese). A parallel design was used with the control group (C) receiving the intervention after serving as control. Intervention participants (I) completed a PA curriculum four days a week for 24 weeks including warm-up exercises, strengthening exercises, and playground games two days a week and interactive console games two days a week guided by their parents. Pre-post outcomes (baseline to 24 weeks) included MVPA (7-day accelerometry) and MP including upper limb coordination, bilateral coordination, balance, running speed and agility, and muscle strength (Bruininks-Oseretsky Test of Motor Proficiency). RESULTS: The intervention led to no change in MVPA (I-group: 39.6 vs. 38.9 min/day; C-group: 40.6 vs. 38.3 min/day). The intervention led to improvements in body coordination (22.3%; p<0.05), as well as strength and agility (13.7%; p<0.05). Specifically, the I-group showed increases in upper limb coordination (19.1%), bilateral coordination (27.8%), and muscle strength (12.9%) (p<0.05 for all) not observed in the C-group: -0.2%, 2.5%, and -3.2%, respectively. CONCLUSIONS: This parent-guided PA intervention did not increase PA. However, the intervention led to improvements in gross motor skill competency. Providing families with tools and support can lead to implementation of PA routines that contribute to motor skill proficiency in youth with and without PWS. PMID- 30407276 TI - Time Trial Performance Is Sensitive to Low-Volume Autologous Blood Transfusion. AB - PURPOSE: This study tested the hypothesis that autologous blood transfusion (ABT) of ~50% of the red blood cells (RBCs) from a standard 450 ml phlebotomy would increase mean power in a cycling time trial. Additionally, the study investigated whether further ABT of RBCs obtained from another 450 ml phlebotomy would increase repeated cycling sprint ability. METHODS: In a randomized, double-blind, placebo-controlled crossover design (3-month wash-out), nine highly trained male subjects donated two 450 ml blood bags each (BT-trial) or were sham phlebotomized (PLA-trial). Four weeks later, a 650 kcal time trial (n=7) was performed three days before and 2 h after receiving either ~50% (135 ml) of the RBCs or a sham transfusion. On the following day, transfusion of RBCs (235 ml) from the second donation or sham transfusion was completed. A 4*30 s all-out cycling sprint interspersed by 4 min of recovery was performed six days before and three days after the second ABT (n=9). RESULTS: The mean power was increased in time trials from before to after transfusion (P<0.05) in BT (213+/-35 vs. 223+/-38 W; mean+/ SD) but not in PLA (223+/-42 vs. 224+/-46 W). In contrast, the mean power output across the four 30 s sprint bouts remained similar in BT (639+/-35 vs. 644+/-26 W) and PLA (638+/-43 vs. 639+/-25 W). CONCLUSION: ABT of only ~135 ml of RBCs is sufficient to increase mean power in a 650 kcal cycling time trial by ~5% in highly trained men. In contrast, a combined high-volume transfusion of ~135 and ~235 ml of RBCs does not alter 4*30 s all-out cycling performance interspersed with 4 min of recovery. PMID- 30407277 TI - Mitochondrial Pathway Is Involved in Advanced Glycation End Products-Induced Apoptosis of Rabbit Annulus Fibrosus Cells. AB - STUDY DESIGN: Experimental study. OBJECTIVE: The purposes of this study were to evaluate whether advanced glycation end-products (AGEs) induce annulus fibrosus (AF) cell apoptosis and further to explore the mechanism by which this process occurs. SUMMARY OF BACKGROUND DATA: Recent studies revealed that AGEs accumulation is considered an important factor in diabetic intervertebral disc (IVD) degeneration. However, the effect of AGEs on intervertebral disc remains unclear. METHODS: AF cells were treated with various concentrations of AGEs for 3 days. Cell viability and cell proliferation were measured by Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) incorporation assays, respectively. Cell apoptosis was examined by Annexin V/PI apoptosis detection kit and Hoechst 33342. The expression of apoptosis-related proteins, including Bax, Bcl-2, cytochrome c, caspase-3, and caspase-9, was detected by western blotting. In addition, Bax and Bcl-2 mRNA expression levels were detected by RT-PCR. Mitochondrial membrane potential (MMP) and intracellular reactive oxygen species (ROS) production of AF cell were examined by JC-1 staining and DCFH-DA fluorescent probes, respectively. RESULTS: Our results indicated that AGEs had inhibitory effects on AF cell proliferation and induced AF cell apoptosis. The molecular data showed that AGEs significantly up-regulated Bax expression and inhibited Bcl-2 expression. In addition, AGEs increased the release of cytochrome c into the cytosol and enhanced caspase-9 and caspase-3 activation. Moreover, treatment with AGEs resulted in a decrease in MMP and the accumulation of intracellular ROS in AF cells. The antioxidant N-acetyl-L-cysteine significantly reversed AGE-induced MMP decrease and AF cell apoptosis. CONCLUSION: These results suggested that AGEs induce rabbit AF cell apoptosis and mitochondrial pathway may be involved in AGE-mediated cell apoptosis, which may provide a theoretical basis for diabetic IVD degeneration. LEVEL OF EVIDENCE: N/ A.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0. PMID- 30407278 TI - Emphysematous pyelonephritis and cystitis in a patient with uremia and anuria: A case report and literature review. AB - INTRODUCTION: Emphysematous pyelonephritis (EPN) or cystitis (EC) is a severe infection of the urinary tract with high mortality. EPN is uncommon among the patients of end stage of renal failure (ESRD) CASE PRESENTATION:: A 38-year-old male with uremia and anuria who was on hemodialysis was found to have gas formation in the bilateral pelvis, ureters, and urinary bladder by CT scan. The diagnosis was emphysematous pyelonephritis and cystitis. And Foley catheter was placed and bladder irrigation was performed. Escherichia coli infection was identified in urine culture and antibiotic was prescribed accordingly. Gas disappeared completely and the patient recovered uneventfully. CONCLUSION: This is the first case report of asymptomatic EPN and EC in uremic patient, and conservative management was optimistic in this condition. More attention should be paid to EPN and EC happening to ESRD patients. PMID- 30407279 TI - Influence of magnesium sulfate on hemodynamic responses during laparoscopic cholecystectomy: A meta-analysis of randomized controlled studies. AB - BACKGROUND: The impact of magnesium sulfate on hemodynamic responses during laparoscopic cholecystectomy remains controversial. We conduct a systematic review and meta-analysis to explore the influence of magnesium sulfate on hemodynamic responses for laparoscopic cholecystectomy. METHODS: We search PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through June 2018 for randomized controlled trials (RCTs) assessing the effect of magnesium sulfate on hemodynamic responses for laparoscopic cholecystectomy. Meta analysis is performed using the random-effect model. RESULTS: Four RCTs involving 208 patients are included in the meta-analysis. Overall, compared with control group in laparoscopic cholecystectomy, intravenous magnesium sulfate is associated with systolic blood pressure at 30 minutes [Std. MD = -1.34; 95% confidence interval (95% CI) = -1.86 to -0.82; P < .00001], diastolic blood pressure at 30 minutes (Std. MD = -1.40; 95% CI = -1.86 to -0.94; P < .00001), mean arterial pressure at 30 minutes (Std. MD = -1.19; 95% CI = -1.91 to -0.46; P = .001), systolic blood pressure at 10 minutes (Std. MD = -1.61; 95% CI = -2.08 to -1.13; P < .00001), diastolic blood pressure at 10 minutes (Std. MD = -1.54; 95% CI = -2.68 to -0.40; P = .008), heart rate at 30 minutes (Std. MD = -2.09; 95% CI = -2.87 to -1.32; P < .00001), but results in prolonged extubation time (Std. MD = 0.96; 95% CI = 0.18-1.74; P = .02). CONCLUSION: Magnesium sulfate can reduce blood pressure, but with the increase in extubation time for laparoscopic cholecystectomy. PMID- 30407281 TI - Glucose-regulated protein 78 in the aqueous humor in diabetic macular edema patients. AB - In this study, we explored the presence and elevation of glucose-regulated protein 78 (GRP78) in aqueous humor of patients with diabetic macular edema (DME).After comparing DME patients with the controls, we analyzed GRP78 and vascular endothelial growth factor (VEGF) levels in DME patients. We examined factors associated with GRP78 levels in DME patients.GRP78 was detected in aqueous humor with elevated levels in DME patients. Stepwise backward regression analysis showed that GRP78 levels were associated with the VEGF levels and the duration of diabetes (P < .001 and P = .002, respectively). However, no statistical significance was observed between GRP78 levels and the decrease in CST following 3 monthly anti-VEGF treatments in univariate regression analysis (P = .695).We showed that GRP78 is elevated in DME patients. In addition, there is a correlation between GRP78 and VEGF levels in aqueous humor. However, GRP78 levels were not associated with the responsiveness of anti-VEGF in DME patients. PMID- 30407282 TI - Congenital anal atresia with rectovestibular fistula, scoliosis, unilateral renal agenesis, and finger defect (VACTERL association) in a patient with partial bicornuate uterus and distal vaginal atresia: A case report. AB - RATIONALE: Vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect (VACTERL) association and Mullerian duct anomalies are rare conditions. We present a rare condition with the co-occurrence of the VACTERL association and Mullerian duct hypoplasia to characterize patients' clinical presentations, outcomes, and treatment. PATIENT CONCERNS: An 11-year-old girl presented to our hospital with severe lower abdominal pain, lower vaginal atresia with enlargement of the upper vagina and a bicornuate uterus with a Y-shaped uterine cavity filled with hematometra on pelvic magnetic resonance imaging. Her medical history included congenital anal atresia with a rectovestibular fistula, congenital right renal deficiency, congenital right thumb malformation, and scoliosis. DIAGNOSES: 1. Congenital genital tract malformations, a partial bicornuate uterus, and distal vaginal atresia (U3aC0V4); 2. VACTERL association (congenital anal atresia with rectovestibular fistula, scoliosis with hemi vertebra and butterfly vertebra, unilateral renal agenesis, and finger defect). INTERVENTIONS: Colpotomy, laparoscopic exploration, pelvic adhesiolysis, and hysteroscopy were performed. OUTCOMES: Two months after surgery, a pelvic examination showed an unobstructed vagina which was 10 cm long and 2 fingers wide, without adhesion or constriction. LESSONS: Clinicians should have a high index of suspicion when evaluating patients with genital malformations associated with VACTERL. Early diagnosis of distal vaginal atresia with appropriate surgical intervention decreases long-term morbidity. PMID- 30407280 TI - Effect of Endostar combined with chemotherapy in advanced well-differentiated pancreatic neuroendocrine tumors. AB - The aim of the present study was to assess the effect of Endostar and temozolomide or dacarbazine plus 5-fluorouracil (5-FU) in patients with advanced pancreatic neuroendocrine tumors (pNETs).Phase II study of 14 patients with locally advanced or metastatic well-differentiated pNETs treated between April 2013 and September 2016. Patients received temozolomide or dacarbazine plus 5-FU, and Endostar. The primary outcome was the radiographic response rate.All 14 patients had nonfunctional pNETs. Six patients received temozolomide and 8 received dacarbazine + 5-FU, combined with Endostar. Thirteen patients were assessable for treatment response: 1(7%) with complete response, 5 (39%) with partial response, 5 (39%) with stable disease, and 2 (15%) with progression. The median progression-free survival was 12 months. The most common grade 1/2 toxicities were neutropenia (43%) and leucopenia (21%).Endostar combined with temozolomide or dacarbazine + 5-FU was effective in the treatment of advanced pNETs. The combinations were well tolerated. PMID- 30407283 TI - Effectiveness of Chinese herbal medicine Ping Chuan Ke Li for the management of mild/moderate persistent asthma. AB - This study assessed the effectiveness and safety of Chinese herbal medicine Ping Chuan Ke Li (PCKL) for the treatment of patients with mild/ moderate persistent asthma.A total of 108 eligible patients with persistent asthma were included and were divided into a treatment group and a control group in this retrospective study. All 108 patients underwent oral montelukast. Additionally, subjects in the treatment group also received PCKL therapy. All patients in both groups were treated for a total of 1 month. The primary outcome of lung function was evaluated by the forced expiratory volume in one second (FEV1) and FEV1/forced vital capacity (FVC). The secondary outcome of quality of life was assessed by St. George's Respiratory Questionnaire (SGRQ). Moreover, adverse events (AEs) were also recorded in this study. All outcome measurements were assessed after 1 month treatment.After 1-month treatment, patients in the treatment group did not demonstrate better outcome in the improvement of lung function, measured by FEV1 (P =.57, table 2), and FEV1/FVC (P =.29); and enhancement of quality of life, measured by SGRQ scale (total, P =.37; symptom, P =.32; activity, P =.39; impact, P =.83). In addition, no AEs differ between 2 groups.The results of this study showed that Chinese herbal PCKL may not benefit for patients with mild/moderate persistent asthma after 1-month treatment. PMID- 30407284 TI - Anti-PD-1 pembrolizumab induced autoimmune diabetes in Chinese patient: A case report. AB - RATIONALE: Programmed cell death-1 protein (PD-1) antibody is an immune checkpoint inhibitor that triggers anti-tumor response by enhancing immune response. Although PD-1 antibody has been reported effective in some malignant tumor, it can also induce significant immune-related adverse events (irAEs) such as autoimmune diabetes. PATIENT CONCERNS: A 67-year-old male patient with non small cell lung cancer (NSCLS) presented with polydipsia, polyuria, weakness, and weight loss after use of anti-programmed cell death-1 antibody therapy. Hyperglycemia, high serum ketone, low bicarbonate and high anion gap were compatible with the criteria of diabetic ketoacidosis (DKA). DIAGNOSES: Autoimmune diabetes and diabetic ketoacidosis (DKA). The presence of low serum titers of c-peptide, high blood glucose together with diabetic ketoacidosis (DKA) that occurs shortly after the use of pembrolizumab strongly supported the diagnosis of anti-PD-1 induced autoimmune diabetes. INTERVENTIONS: The patient stopped using pembrolizumab while continuous subcutaneous insulin infusion (CSII) was started at the same time. The insulin infusion was switched to multiple daily injection (MDI) after he was discharged from hospital. OUTCOMES: The patient is now a well-controlled insulin-dependent patient with palliative care of NSCLS. LESSONS: Autoimmune diabetes induced by anti-programmed cell death-1 (PD 1)/programmed cell death 1 ligand 1 (PD-L1) therapy is a rare, but life threatening immune-related side effect. Physicians should closely monitor diabetes-related indexes of patients who have been undergoing the treatment of anti-PD-1/PD-L1 therapy. PMID- 30407285 TI - Oral tranexamic acid reduces blood loss in total-knee arthroplasty: A meta analysis. AB - BACKGROUND: Postoperative hemorrhage following total-knee arthroplasty (TKA) remains an important topic. The objective of the meta-analysis is to assess the effectiveness of oral antifibrinolytics for blood management in patients undergoing TKA. METHODS: We searched Medline (1966 to August 2018), PubMed (1966 to August 2018), Embase (1980 to August 2018), ScienceDirect (1985 to August 2018), and the Web of Science (1995 to August 2018) for randomized control trials (RCTs). To assess the heterogeneity of study trial and determine the model for analysis (random-effect model or fixed-effect model), I tests and Chi-squared were conducted. We utilized the STATA 12.0 (StataCorp, College Station, TX) to perform all statistical analyses. RESULTS: A total of 5 RCTs met our inclusion criteria. This meta-analysis shows that there are significant differences between the 2 groups regarding total blood loss, hemoglobin reduction, and transfusion rates. In addition, no adverse effects were identified in treatment groups. CONCLUSION: The oral form of antifibrinolytics in TKA is able to significantly decrease blood loss, postoperative hemoglobin reduction, as well as transfusion requirements. No increased risk of postoperative complications was observed. Higher quality RCTs is necessary to confirm our finding. PMID- 30407286 TI - Concomitant breast and axillary lymphangioma in an adult: A case report and a review of the literature. AB - RATIONALE: Lymphangiomas develop in the head, neck, and axilla of patients <2 years old in more than 90% of cases. They are rarely reported in adults. PATIENT CONCERNS: Here, we report on a 37-year-old woman with a firm, hypoechoic 3.3 cm mass in the right upper, outer quadrant of the breast with discomfort, and swelling of the right axillary region. DIAGNOSIS AND INTERVENTIONS: She underwent wide excision of the right breast and axillary lesion and the lesion pathologic finding is lymphangioma of the breast. OUTCOMES: She was in good condition with no signs of postoperative complications and no evidence of recurrence at 6 months postsurgery. LESSONS: Despite the rarity of breast cystic lymphangioma, its evaluation should be considered for prompt diagnosis and definitive treatment to prevent recurrence and complications. Furthermore, this is the first case of concomitant lymphangioma of the breast parenchyma and axillary region. PMID- 30407287 TI - XRCC1 polymorphism and overall survival in ovarian cancer patients treated with platinum-based chemotherapy: A systematic review and MOOSE-compliant meta analysis. AB - OBJECTIVES: Although platinum-based chemotherapy is widely used for advanced ovarian cancer (OC), genetic polymorphisms can influence the chemotherapeutic response. This study investigated the association between XRCC1 polymorphisms Arg194Trp, Arg280His, and Arg399Gln, and overall survival (OS) in OC patients who received platinum-based chemotherapy. METHODS: We systematically searched PubMed, Embase, the Cochrane library, Chinese National Knowledge Infrastructure, Wanfang, and Weipu databases for relevant studies from inception to October, 2017. OS was calculated using a random-effects model. Sensitivity, subgroup, and publication bias analyses were also performed. RESULTS: Five studies involving 1159 OC patients were included. When compared with 194ArgArg, 194TrpTrp (hazard ratio [HR] 1.09, 95% confidence interval [CI] 0.71-1.69, P = .69) and 194TrpArg (HR 1.00, 95% CI 0.78-1.28, P = .98) carriers were not associated with OS. Similarly, compared with 280ArgArg carriers, neither 280HisHis (HR 1.39, 95% CI 0.82 to 2.34, P = .22) nor 280HisArg (HR 0.98, 95% CI 0.73 to -1.31, P = .90) affected OS. Furthermore, there were no significant differences in OS between 399GlnGln (HR 1.00, 95% CI 0.46-2.16, P > .99), 399GlnArg (HR 1.05, 95% CI 0.81-1.37, P = .70), and 399ArgArg. Finally, subgroup analysis suggested that 399GlnGln significantly decreased OS when the percentage of III or IV cases was >80.0% (HR 1.79, 95% CI 1.22-2.62, P = .003), while OS was increased when this percentage was <80.0% (HR 0.47, 95% CI 0.28-0.79, P = .004). CONCLUSIONS: This study indicated that XRCC1 Arg194Trp, Arg280His, and Arg399Gln did not affect OS after platinum-based chemotherapy in OC patients. However, disease status could affect the relationship between Arg399Gln and OS in these patients. PMID- 30407288 TI - New methods for specialized subjective and high-precision objective evaluation of constricted ears: A pilot study. AB - The effects of therapy on constricted ears are evaluated subjectively and objectively. However, previous methods are not specific, comprehensive, precise, or effective in diagnosing and predicting surgical outcomes. This study aimed to present a personalized, subjective evaluation scale and new objective indices utilizing a digital method for the accurate evaluation of constricted ears.Nine consecutive patients with constricted ears were selected. To perform subjective evaluations, the patients' parents were contacted by telephone within 3 to 6 months after surgery and asked to answer questions using a scale. To perform objective evaluations, the constricted and normal ears of each patient were scanned using a 3-dimensional scanner before and 14 days after surgery. The vertical height of the auricle (VHA), transverse diameter of the auricle, minimum length of the helix (MLH), length of the inner auricle (LIA), and transverse diameter of the inner auricle were calculated using Mimics software. The Wilcoxon matched pairs signed-rank test was used for data analysis.High satisfaction scores were reported. The folds of the ear and helix had the highest median scores, whereas the crus of the antihelix had the lowest. The difference in LIA and postoperative MLH was greater than that in VHA and preoperative MLH. The mean values of the 5 indices of the normal ear were greater than those of the indices of the preoperative constricted ear (P < .05).The specialized subjective scale reported in this study allows comprehensive and personalized assessment of constricted ears. The new objective indices are more effective than existing methods and the digital measurement method is precise and reliable. These methods will allow the treatment of constricted ears to be better evaluated, leading to improvements in patient management and treatment selection. PMID- 30407289 TI - Learning curves for robotic pancreatic surgery-from distal pancreatectomy to pancreaticoduodenectomy. AB - This study sought to identify the learning curves of console time (CT) for robotic pancreaticoduodenectomy (RPD) and robotic distal pancreatectomy (RDP). Perioperative outcomes were compared between the early group of surgeries performed early in the learning curve and the late group of surgeries performed after the learning curve.Pancreaticoduodenectomy (PD) is a technically demanding and challenging procedure carrying a high morbidity.Data for RDP and RPD were prospectively collected for analysis. The learning curve was assessed by cumulative sum (CUSUM). Based on CUSUM analyses, patients were divided into the early group and the late group.There were 70 RDP and 61 RPD cases. It required 37 cases to overcome the learning curve for RDP and 20 cases for RPD. The median console time was significantly shorter in the late group for both RDP (112 minutes vs 225 minutes, P < .001) and RPD (360 minuntes vs 520 minutes, P < .001). Median blood loss was significantly less in the late group for both RDP (30 cc vs 100 cc, P = .003) and RPD (100 cc vs 200 cc, P < .001). No surgical mortality occurred in either group. Clinically relevant pancreatic fistula rate was 22.9% for RDP (32.4% in the early group vs 12.1% in the late group, P = .043), and 11.5% for RPD (0 in early group vs 17.1% in late group, P = .084).This study demonstrates that the RPD learning curve is 20 cases with prior experience of RDP and confirms the safety and feasibility of both RPD and RDP. Practice and familiarity with the robotic platform are likely to contribute to significant shortening of the learning curve in robotic pancreatic surgery, while knowledge and experience, in addition to practical skills, are also essential to minimize the potential surgical risks of RPD. PMID- 30407290 TI - Propranolol eye drops in patients with corneal neovascularization. AB - RATIONALE: Studies performed in animal models of corneal neovascularization suggested the possible efficacy of a treatment with propranolol. Corneal neovascularization is one of the most feared complications of Stevens-Johnson syndrome that frequently involves ocular surface. We report the first 2 patients with severe ocular neo-vascularization treated with different degrees of success, with propranolol eye drops. PATIENT CONCERNS: Two patients with corneal neovascularization complicating the Stevens-Johnson syndrome, not responsive to steroids and cyclosporine, were treated with propranolol eye drops. DIAGNOSES: Corneal neovascularization was detected by ophthalmoscopic evaluation. INTERVENTIONS: Topical treatment with propranolol eye drops at different concentrations. OUTCOMES: Both patients reported dramatic subjective benefits (reduction of photophobia and discomfort) without adverse effects, and in the patient with a less advanced disease, an objective reduction of neovascularization and an improved visual acuity was observed. LESSONS: This experience suggests that propranolol might be an inexpensive, safe and effective treatment in counteracting the progression of corneal neovascularization. PMID- 30407291 TI - A comparison of the effects between 2 computerized cognitive training programs, Bettercog and COMCOG, on elderly patients with MCI and mild dementia: A single blind randomized controlled study. AB - BACKGROUND: A computerized cognitive rehabilitation program can be used to treat patients with mild cognitive impairment or dementia. We developed a new computerized cognitive rehabilitation program (Bettercog) that contained various treatment programs for cognitive training for mild cognitive impairment or dementia. This study was conducted to compare the clinical efficacy of Bettercog and computer-assisted cognitive rehabilitation (COMCOG) that has had clinical efficacy previously proven in patients with mild cognitive impairment or dementia. METHODS: Randomized, single-blind comparison pilot study of 20 elderly patients with cognitive decline-eight men and 12 women-with an average age of 74.3 years. Bettercog trains not only memory and attention but also orientation, calculation, executive function, language, comprehension, and spatiotemporal abilities. To retain subjects' interest, pictures, animations, and game elements were introduced. The subjects were divided into COMCOG and Bettercog groups by random assignment and underwent 12 sessions of a computerized cognitive rehabilitation program for three weeks. In a separate space, an independent clinical psychologist conducted the Seoul Neuropsychological Screening Battery 2nd edition (SNSB-II), Korean Mini-Mental State Examination (K-MMSE), Clinical Dementia Rating (CDR), and the Korean version of the Modified Barthel Index (K MBI) before and after treatment. RESULTS: There was no significant difference between the two groups in baseline age, sex, illiteracy, years of education, and scores on the K-MMSE, CDR, SNSB-II, and K-MBI. In the posttreatment cognitive assessment, the K-MMSE scores of patients treated with Bettercog improved from 19.2 +/- 3.9 to 21.3 +/- 4.0 (P = .005). In the memory domain of the SNSB-II, the percentile score improved from 15.3 +/- 24.5 to 24.2 +/- 30.7 (P = .026). However, there was no statistically significant difference in the final K-MMSE, CDR, and SNSB-II scores between the two treatment groups. In both groups, K-MBI scores improved statistically significantly after treatment. CONCLUSIONS: Through this preliminary study, we verified that the newly developed computerized cognitive rehabilitation program is effective in improving cognitive function. However, 12 sessions are not enough to administer a variety of cognitive rehabilitation content to patients. It is, therefore, necessary to conduct a large-scale study using a computerized cognitive rehabilitation program that has various cognitive content. PMID- 30407292 TI - Beneficial effects of combined administration of Clopidogrel and Aspirin on the levels of proinflammatory cytokines, cardiac function, and prognosis in ST segment elevation myocardial infarction: A comparative study. AB - OBJECTIVE: Both Aspirin and Clopidogrel are considered as effective drugs in decreasing ischemic events, which potentially contribute to a promising application regarding the cardiovascular events. In the present study, we evaluated the efficacy of the combination of both Clopidogrel and Aspirin to determine the influence among inflammatory factors, cardiac function, and treatment outcome of patients suffering from ST-segment elevation myocardial infarction (STEMI) in the Hebei province of China. METHODS: To compare the efficacy of this combination therapy with a single Aspirin treatment, we experimented in 68 patients with the administration of both Clopidogrel and Aspirin as well as another 68 patients administered only with Aspirin. An enzyme linked immunosorbent assay was used to measure the expression of inflammatory factors, thereby evaluating the effect on inflammation. In addition, a series of indexes related to cardiac function and renal function were monitored by use of a color Doppler ultrasound and an automatic biochemical analyzer, respectively. Myocardial injury-related indicators were detected. A multivariate logistic regression analysis was performed so we could identify potential risk factors. In addition, both postoperative hemorrhages and cardiac events were observed to evaluate the treatment outcome of patients with STEMI. RESULTS: Initially, the treatment outcome revealed a better efficacy in patients treated with the combination of both Clopidogrel and Aspirin, with the patients also showing more obviously alleviated myocardial injury, better cardiac and renal functions with lower serum levels of inflammatory factors. The lower incidence of postinfarction angina, recurrent myocardial infarction, stroke, and death also provide evidence that patients showed a better outcome after treatment with both Clopidogrel and Aspirin. CONCLUSION: Taken together, the combination therapy of Clopidogrel and Aspirin provided a better improvement on both the cardiac function and outcome of STEMI patients in the Hebei province of China, with reduced inflammation as well. PMID- 30407293 TI - Clinicopathologic characteristics in patients with upper third gastric cancer following radical surgical treatment: A retrospective cohort study. AB - The incidences of upper third gastric cancer (UTGC) have been increasing. However, the prognostic factors for UTGC following radical surgical treatment remains largely unknown. This study was to investigate prognostic factors for overall survival (OS), lymph node metastasis and recurrence of UTGC.Clinicopathologic data of 126 UTGC patients who underwent radical surgical treatment were retrospectively analyzed. OS and univariate analysis were determined by Kaplan-Meier analysis and the significance of the difference between curves was calculated with the log-rank test. The Cox proportional hazards regression model was applied to perform multivariate analysis. Receiver operating characteristic (ROC) curve analysis was used to determine the prognostic accuracy.The 1-, 3-, and 5-year OS for patients with UTGC were 81%, 47.6%, and 38.6% respectively. Univariate analysis showed that tumor size (P = .019), tumor invasion depth (P < .001), and lymph node metastasis (P < .001) were the risk factors for 5-year OS. Multivariate analysis identified tumor invasion depth (P < .001) and lymph node metastasis (P < .001) as independent prognostic factors for the 5-year OS in patients with UTGC. In addition, ROC curve analysis showed that tumor invasion depth (P = .017) or lymph node metastasis (P = .001) alone showed significantly effective prognosis for the 5-year OS in patients with UTGC. For UTGC patients with lymph node metastasis, tumor size (P = .023), lym embolism (P = .003), tumor invasion depth (P = .002), and invasion of tunica serosa (P = .004) were the risk factors for the 5-year OS. Multivariate analysis identified tumor size (P = .048), lym embolism (P = .032), tumor invasion depth (P = .004), and invasion of tunica serosa (P = .031) as independent prognostic factors for the 5-year OS. For UTGC patients with distant metastasis or tumor recurrence, univariate and multivariate analyses demonstrated that tumor invasion depth and lymph node metastasis were independent prognostic factors for the 5 year OS.The results suggested that for UPGC patients undergoing the radical surgical treatment, tumor invasion depth and/or lymph node metastasis are the independent prognostic factors for the 5-year OS, lymph node metastasis, distant metastasis and tumor recurrence. PMID- 30407294 TI - Seromucinous hamartoma of inferior turbinate: A case report. AB - RATIONALE: Seromucinous hamartoma is a rare benign glandular proliferation of the sinonasal tract and nasopharynx, and the majority of lesions occur on the posterior nasal septum. PATIENT CONCERNS: The patient had complaints of rhinorrhea, sneezing, and itching for a number of years, and recurrent right nasal bleeding for which the patient underwent endoscopic removal of a right inferior turbinate tumor. The biopsy result was low-grade, non-intestinal type adenocarcinoma, and the patient was referred to our hospital. DIAGNOSIS AND INTERVENTIONS: An endoscopic medial maxillectomy of the right nasal cavity was performed. The histopathological analysis of the nasal mass revealed a seromucinous (glandular) hamartoma. OUTCOMES: The postoperative course was unremarkable. The patient has been followed up regularly for 1 year with no additional treatment and no recurrence. LESSONS: Seromucinous hamartoma of the nasal cavity is extremely rare, especially in anterior portion of nasal cavity. It is important to distinguish seromucinous hamartoma from adenocarcinoma and to maintain regular long-term follow-up. PMID- 30407296 TI - Dermoid cyst of nasal septum in an adult patient: A case report. AB - RATIONALE: Nasal dermoid cysts are rare congenital lesions and may present as a midline nasal swelling. Nasal dermoid cysts usually present at birth and are commonly diagnosed by 3 years of age. An incidentally detected nasal dermoid cyst in an adult patient is extremely rare. PATIENT CONCERN: We report an unusual case of an adult patient with an incidentally diagnosed dermoid cyst of the nasal septum, which presented as a longstanding discharging pit in the nasal columella since childhood. DIAGNOSIS: A preoperative diagnosis of dermoid cyst of the nasal septum was made. INTERVENTION: We performed the external rhinoplasty incision, including a small elliptical incision for removal of the columella pit. OUTCOME: There has been no evidence of recurrence during the 2-year follow-up. LESSONS: An incidentally detected nasal dermoid cyst in an adult patient is extremely rare. The most important point for the preoperative diagnosis of nasal dermoid cysts is to identify the presence or absence of intracranial extension. The treatment of choice for nasal dermoid cysts is complete surgical excision with clear margins. PMID- 30407295 TI - Breathlessness in amyotrophic lateral sclerosis: A case report on the role of osteoporosis in the worsening of respiratory failure. AB - RATIONALE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative multisystem disorder, presenting with limb or bulbar onset. To date, there is no cure for ALS. At some stage of the disease, patients may complain of breathlessness due to respiratory failure, thus needing a noninvasive mechanical ventilation (NIMV) support. However, breathlessness is a symptom that may be induced by different causes that must be taken into consideration in ALS management. PATIENTS CONCERNS: We report the case of an 81-year-old man, with a spinal onset ALS, who was admitted to our clinic to start NIMV because of respiratory involvement. After 3 weeks from NIMV performed at night time, with beneficial effects, he suddenly complained of breathlessness even at rest and in standing position. DIAGNOSIS: Respiratory and cardiac assessments did not show new clinical events, indicating the worsening respiratory function. Due to a history of osteoporosis which was treated with biphosphonates and even though no previous bone trauma or falls were reported, we performed a spine computed tomography scan. The findings indicated multiple dorsal vertebral fractures which was a probable cause for breathlessness. INTERVENTIONS AND OUTCOMES: Considering the neurodegenerative disease associated to respiratory failure, the cardiovascular risk factors and the age, the patient refused to undergo a surgery with kyphoplasty. A spine support was then prescribed, together with analgesic medications, with significant alleviation of pain and breathlessness. LESSONS: The occurrence of breathlessness in a patient with ALS cannot always be related to the bulbar involvement. Other causes should be taken into account, especially when there is sudden worsening of symptoms in spite of good clinical response and compliance to NIMV treatment. PMID- 30407297 TI - Comparison of endoscopic thyroidectomy via a modified axillo-breast approach with the conventional breast approach for treatment of unilateral papillary thyroid microcarcinoma. AB - Endoscopic thyroidectomy (ET) via an axillo-breast (ABA), axillary or breast approach (BA) is effective for treatment of unilateral papillary thyroid microcarcinoma (PTMC). However, several disadvantages still exist, including inconvenience for using endoscopic instruments and poor cosmetic results. Here, we introduced a modified ABA (MABA) to overcome these disadvantages and evaluated its therapeutic outcomes by comparison with conventional BA.Fifty-five patients undergoing ET via MABA (n = 22) or BA (n = 33) for PTMC were retrospectively enrolled between June 2012 and June 2015. Surgical outcomes, including the operation time, blood loss, amount of drainage, number of dissected lymph nodes, complications, cosmetic satisfaction and prognosis (recurrence and survival), were analyzed.The operation time (87.1 +/- 9.3 min vs 93.2 +/- 8.3 min; P = .014) and drainage tube removal time (4.4 +/- 1.0 days vs 5.1 +/- 1.1 days; P = .018) were shorter in the MABA group than those in the BA group. There was less postoperative drainage (54.3 +/- 35.7 mL vs 137.6 +/- 87.0 mL; P < .01) in the MABA group compared with the BA group. No significant differences in the blood loss (15.9 +/- 7.5 mL vs 19.2 +/- 11.7 mL, P = .243) and the number of dissected lymph nodes (1.8 +/- 1.5 vs 2.3 +/- 2.1, P = .309) were observed between the 2 groups. Subcutaneous ecchymosis occurred more frequently in the BA group than that in the MABA group (33.3% vs 9.1%; P = .038). Patients treated by MABA were more satisfied with their cosmetic results than those undergoing BA (100% vs 81.8%; P = .034). At the last follow-up time, all patients were alive although 1 patient in the BA group developed cervical lymph node recurrence ipsilateral to the original tumor at 4 years after surgery. Multivariate logistic regression analysis showed MABA surgery was a protective factor for postoperative complications (OR = 0.209, 95% confidence interval [CI] = 0.054-0.817, P = .024).ET via the MABA strategy may be a good choice for unilateral PTMC because of shorter operation time, fewer complications, greater cosmetic satisfaction, and excellent prognosis. PMID- 30407298 TI - Molecular analysis of hemoglobinopathies in a large ethnic Hakka population in southern China. AB - Thalassemia is an inherited autosomal recessive disorder with microcytic hypochromic anemia resulting from reduced or absent synthesis of 1 or more of the globin chains of hemoglobin. This study provided the insight into prevalence and molecular characterization of thalassemia in Hakka population. 14,524 unrelated subjects were included in our study from January 2015 to November 2017. All the subjects were detected by hematological analysis, hemoglobin electrophoresis analysis, and molecular diagnosis (gap-polymerase chain reaction and flow-through hybridization technology). Data analysis was used to compare allele frequencies between the Hakka populations. Seven thousand four hundred twenty-two cases of microcytosis were found. The percentage of microcytosis in Meizhou, Ganzhou, and Heyuan was 50.91% (6738/13,236), 51.27% (445/868), and 56.90% (239/420), respectively. A total of 5516 mutant chromosomes were identified, including 3775 alpha-thalassemia and 1741 beta-thalassemia. --/alphaalpha was the most common alpha-thalassemia genotype, followed by -alpha/alphaalpha and -alpha/alphaalpha, accounted for 84.92% of alpha-thalassemia genotypes. Twelve kinds of mutations and 26 genotypes in beta-thalassemia were found. IVS-II-654(C->T), CD41-42( TCTT), -28(A->G), and CD17(A->T) alleles accounted for 92.65% of these mutations. IVS-II-654/N, CD41-42/N, -28/N, CD17/N genotypes accounted for 91.53% of beta thalassemia genotypes. 27 fetuses with at-risk pregnancies were subjected to prenatal diagnosis. Five fetuses were Bart's hydrops syndrome and 2 fetuses with beta-thalassemia major. There were some differences in molecular characterization of thalassemia among Hakka people in different areas of southern China. Our results enriched the related information of thalassemia in the region, which provided valuable references for the prevention and control of thalassemia. PMID- 30407299 TI - Genetic polymorphism (rs6776158) in CaSR gene is associated with risk of nephrolithiasis in Chinese population. AB - The objective of this study is to find about the association between calcium sensing receptor (CaSR) genetic variants and susceptibility to nephrolithiasis in the Chinese Han population.This hospital-based case-control study included 319 nephrolithiasis cases and 378 healthy controls subjects. Two SNPs in CaSR were genotyped using the TaqMan assay.We found that subjects carrying the G allele of rs6776158 (AG and GG) had significantly higher risk of nephrolithiasis compared to the AA genotype (P = .015 and .009, respectively).Our results indicate that rs6776158 polymorphism that might elevate the risk of nephrolithiasis in the Chinese population. PMID- 30407300 TI - Efficacy and safety of Xiaofeng powder (xiao feng san) in treating urticaria: A protocol for a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Urticaria is a common skin disease that has a high impact on a patient's daily life. Xiaofeng powder (XFP) is one of the most commonly used Chinese herbal formula in China for urticaria. However, due to the lack of systematic evaluations, its clinical efficacy remains controversial. This meta analysis was performed to evaluate the effect and safety of XFP for urticaria. METHODS: Seven databases, including Cochrane Central Register of Controlled Trials, PubMed, Embase, the Chinese National Knowledge Infrastructure (CNKI), the Chinese Scientific Journal Database (VIP), the Chinese Biomedical Literature Database (CBM), and the Wanfang Database. The period will be from their inception to September 2018. Randomized controlled trials of XFS used separately against conventional Western medicine therapy in patients with urticarial were included. After the methodologic quality was assessed and the valid data were extracted, RevMan 5.3 software was used for the final meta-analysis. RESULTS: The results will provide evidence regarding the efficacy and safety of XFP in treating urticaria. CONCLUSION: The conclusion of our systematic review will provide evidence to judge whether XFP is an effective intervention for patient with urticaria. This systematic review will be disseminated in peer-reviewed publications. The results of the study will provide evidence concerning the efficacy and safety of Xiaofeng Powder (xiao feng san) in treating urticaria. PROSPERO REGISTRATION NUMBER: PROSPERO CRD 42018087260. PMID- 30407301 TI - Soshiho-tang for treating common cold in children younger than 12 years: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Soshiho-tang (SST) is widely used to treat common cold in East Asian countries. Many clinical trials assessing the efficacy and safety of SST formulas for the treatment of pediatric common cold have been reported. The aim of this systematic review is to assess the available clinical evidence on the use of SST formulas in the treatment for common cold in children younger than 12 years. METHODS: Fifteen databases will be searched from their inception until March 2019. We will be including the randomized controlled trials (RCTs) assessing all types of SST formulas used in the treatment of common cold in children younger than 12 years. The methodological qualities of the RCTs will be assessed using the Cochrane Collaboration tool for assessing the risk of bias, while confidence in the cumulative evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation instrument. ETHICS AND DISSEMINATION: This systematic review will be published in a peer-reviewed journal and will also be disseminated electronically and in print. The review will be updated to inform and guide health care practices. PMID- 30407302 TI - Prognostic impact of germinal center B-cell-like and non-germinal center B-cell like subtypes of bone marrow involvement in patients with diffuse large B-cell lymphoma treated with R-CHOP. AB - The prognostic significances of the germinal center B-cell-like (GCB) and non germinal center B-cell-like (non-GCB) types of diffuse large B-cell lymphoma (DLBCL) have been reported to be different. We analyzed the effect of the cell of origin (COO) of bone marrow (BM) involvement in patients with DLBCL who were treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in a single institute.The subtype of BM involvement was evaluated in 633 patients who were diagnosed with primary DLBCL and had been treated with R-CHOP. BM trephine biopsies were analyzed, and immunohistochemical staining of CD20, CD79a, and CD3 was performed. Additional staining of CD10, Bcl 6, and MUM1 was performed to determine the COO based on a previously reported algorithm.BM involvement was present in 81 patients (12.8%). Among them, 30 patients (37.0%) had GCB-type BM involvement and 51 (63.0%) showed non-GCB-type involvement. Kaplan-Meier survival analysis showed that the non-GCB type had the worst progression-free survival (PFS) and overall survival (OS) (P <.001). In multivariate analysis controlled for the International Prognostic Index (IPI) score, non-GCB type was an independent predictor of PFS (P <.004) and OS (P =.042), whereas GCB type was not a prognostic factor independent of the IPI score.Further prognostication based on the COO of BM involvement is a useful indicator of PFS, independent of IPI score. Accurate staging based on the COO should be included in the examination of BM in DLBCL. PMID- 30407303 TI - Prognosis of a rare subtype of thyroid cancer: Spindle cell thyroid carcinoma. AB - Systemic illustrations of spindle cell thyroid cancer (SCTC), based on a large cohort, are few. We investigated the prognosis of SCTC compared to the most common subtypes, papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC).Information of patients with a diagnosis of SCTC, PTC, or FTC, between 2004 and 2013, was obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Patient survival curves were investigated using Kaplan-Meier analyses, log-rank tests, and Cox proportional hazards regression analyses.In a Kaplan-Meier analysis of the entire cohort of thyroid cancer patients, cancer specific survival declined sharply for patients with SCTC, but declined more modestly for patients with PTC and FTC. Unadjusted Cox regression analysis and Kaplan-Meier curve analysis showed that SCTC had a poorer cancer-specific mortality and all-cause mortality compared to PTC and FTC. Similar results were obtained after adjustment for different confounding factors.Our study assessed the prognosis of SCTC, based on a large cohort, compared to PTC and FTC, and found relatively accurate hazard ratios of death rate in SCTC as compared to PTC and FTC. Thus, our findings would provide beneficial insights on patients with SCTC, and aid in treatment decision making, more radical treatment like total thyoridectomy and/or plus central lymph node dissection should be performed for patients with SCTC. PMID- 30407305 TI - Clinical efficacy and safety of traditional Chinese patent medicine for hyperthyroid heart disease: study protocol for a systematic review and meta analysis. AB - BACKGROUND: Hyperthyroid heart disease (HHD), one of the most common complications of hyperthyroidism, is a serious public health problem due to the direct toxic or indirect effects of excessive thyroid hormone on the heart, resulting in high mortality and increasing health care costs. Traditional Chinese patent medicines (TCPMs), developed by combining modernized pharmaceutical technologies with ancient TCM theories, have been widely used in the treatment of HHD. However, the safety and efficacy of TCPMs used in patients with HHD has been uncertain and there has been no standard clinical trial published to confirm this. Thus, we conduct a study to evaluate the safety and efficacy of TCPMs for HHD. METHODS: The reference lists of randomized controlled trials and 8 electronic databases will be independently and systematically searched by 2 review authors in August 2018. Four English databases [EMBASE, PubMed, National Guideline Clearinghouse (NGC), and Cochrane Central Register of Controlled Trials (CENTRAL)] and 4 Chinese databases [Chinese Biomedical Literature Database (CBM), Chinese National Knowledge Infrastructure [CNKI], Wanfang Database, and VIP Database] will be included. The primary outcomes will be assessed according to the effective rate of treatment, electrocardiogram, and thyroid hormone levels. Data synthesis will be precisely computed using the RevManV5.3 software when a data-analysis is allowed. Methodological quality will be assessed according to Cochrane Handbook. RESULTS: This study will provide a high-quality synthesis of current evidence of TCPMs for HHD from different aspects, including the clinical symptoms, thyroid hormone levels, and ECG changes. CONCLUSION: The conclusion of this systematic review will provide evidence to prove whether TCPMs are effective therapeutic intervention for patient with HHD. PMID- 30407304 TI - Clinical characteristics and thromboembolic risk of atrial fibrillation patients with and without congestive heart failure. Results from the CRATF study. AB - Congestive heart failure (CHF) and atrial fibrillation (AF) frequently coexist and are associated with increased risk of cardiovascular events.To compare baseline characteristics, comorbidities and pharmacotherapy in AF patients with concomitant CHF to those without CHF.The study included 3506 real-life AF patients with (37.1%) and without CHF - participants of the multicentre, retrospective MultiCenter expeRience in AFib patients Treated with OAC (CRAFT) trial (NCT02987062).All patients were treated with non-vitamin K antagonist oral anticoagulants (NOAC) or vitamin K antagonists (VKA). The frequency of NOAC among patients with and without CHF was 45.6% and 43.2%, respectively (P = .17). Patients with CHF were older (73.3 vs 64.7 years, P <.001), less likely to be women (37.4% vs 42%, P = .007), had higher CHA2DS2-VASc score (3.8 +/- 1.7 vs 2.6 +/- 1.8, P <.001), more often had permanent AF (53.0% vs 13.4%, P <.001), chronic obstructive pulmonary disease (16.7% vs 4.9%, P <.001), coronary artery disease (64.3% vs 29.8%, P <.001), peripheral vascular disease (65.3% vs 31.4%, P <.001), chronic kidney disease (43.1% vs 10.0%, P <.001), liver fibrosis (5.7% vs 2.6%, P <.001), neoplasm (9.6% vs 7.3%, P = .05), history of composite of stroke, transient ischemic attack or systemic embolization (16.2% vs 10.7%, P <.001), pacemaker (27.4% vs 22.1%, P = .004), implantable cardioverter-defibrillator (22.7% vs 0.8%, P <.001) or transaortic valve implantation (4.0% vs 0.8%, P <.001), cardiac resynchronization therapy (8.7% vs 0.3%, P <.001), composite of kidney transplantation, hemodialysis or creatinine level > 2.26 mg/dL (3.6% vs 0.8%, P <.001) and had less often hypertension (69.4% vs 72.5%, P = .05).Patients with AF and CHF had a higher thromboembolic risk and had more concomitant diseases. PMID- 30407307 TI - Serum electrolyte imbalance and prognostic factors of postoperative death in adult traumatic brain injury patients: A prospective cohort study. AB - Electrolyte imbalances are common in traumatic brain injury. It shares the cause of perioperative morbidity and mortality. Types of intravenous fluid resuscitation, osmotic diuretics, massive blood loss, and intracranial pathology were considered as the potential factors to worsen electrolyte abnormalities in these patients. The aims of this study were to report the incidence of electrolyte imbalance in traumatic brain injured patients and to assess the association between electrolyte imbalance and other prognostic factors to death within 24 hours of the injury.The study was carried out in the northern university, tertiary-care hospital of Thailand. The patients aged from 18 to 65 years old, presented with traumatic brain injury, and needed for emergency craniotomy were included. We excluded the patients who had minor neurosurgical procedures, pregnancy, and undergone cardiopulmonary resuscitation from the Emergency Department.Among 145 patients recruited, 101 (70%) had Glasgow Coma Scale (GCS) score <= 8, 25 (17%) had GCS score 9 to 12, and 19 (13%) had GCS score 13 to 15. The most common diagnosis were subdural hematoma and epidural hematoma, 51% and 36%, respectively. Hypokalemia was the most common electrolyte imbalance at 65.5%. The results of the use of a multivariable logistic regression model show that the odds of postoperative death in TBI patients were increased with high levels of blood glucose, hypernatremia, and acidosis.Hypokalemia was the most common electrolyte imbalance in TBI patients. Hypernatremia, acidosis, and hyperglycemia significantly increased the odds ratio of death in the first 24 hours post TBI. PMID- 30407306 TI - Rate of and time to symptomatic remission in first-episode psychosis in Northern Malawi: A STROBE-compliant article. AB - Although longer duration of untreated psychosis (DUP) is associated with poor response to antipsychotic treatment, it remains unclear whether it independently influences time to symptomatic remission in first-episode psychosis (FEP). This study examined rate of symptomatic remission, and explored if DUP, premorbid functioning, global functioning, insight and socio-demographic characteristics were independently associated with time to symptomatic remission in FEP.This prospective study enrolled 126 FEP patients (aged 18-65) between June 2009 and September 2012. Subjects were followed-up monthly over 18 months after they had received antipsychotic medication. Remission in positive and negative symptoms was defined as in the Remission in Schizophrenia Working Group (RSWG) criteria. Subjects were defined as "in symptomatic remission" if they remitted in both negative and positive symptoms. At baseline, the following explanatory variables were measured: socio-demographic characteristics; DUP as short (<=5 months) and long (>5 months); premorbid functioning as deteriorating, stable poor, and stable good according to Cannon-Spoor Premorbid Adjustment Scale; global functioning as "worst (1-10) to serious (41-50)" and "moderate (51-60) to superior (91-100)," according to the Global Assessment of Functioning Scale; and insight as poor (<=8) and good (>=9) according to the Insight Scale (Birchwood). Univariate and multivariable analyses were used to generate results.Out of 126 subjects, 98 (78%) completed follow-up, of which 70 (71.4%) achieved symptomatic remission within mean duration of 8.05 (4.54) months. Besides, having long DUP and separated/divorced/widowed (adjusted hazard ratio [aHR] = 0.07, 95%CI = [0.01, 0.46]), long DUP and poor insight (aHR = 0.18, 95%CI = [0.04, 0.89]), poor insight and separated/divorced/widowed (aHR = 0.09, 95%CI = [0.01, 0.70]), deteriorating premorbid functioning (aHR = 0.47, 95%CI = [0.23, 0.97]), family history of psychiatric disorders (aHR = 0.52, 95%CI = (0.30, 0.93]), and being male (aHR = 0.47, 95%CI = [0.24, 0.92]) delayed symptomatic remission.These results propose that psychological interventions and social support for mental health problems are warranted and may enhance better response to antipsychotic medications among separated/divorced/widowed patients with long DUP or poor insight, and poor insight patients with long DUP. Deteriorating premorbid functioning, family history of psychiatric disorders and being male continue being important risk factors for poor odds of remission. PMID- 30407308 TI - Immediate versus conventional postoperative tracheal extubation for enhanced recovery after liver transplantation: IPTE versus CTE for enhanced recovery after liver transplantation. AB - INTRODUCTION: To systematically compare immediate postoperative tracheal extubation (IPTE) with conventional tracheal extubation (CTE) and to determine whether IPTE can achieve an enhanced recovery for adult patients underwent liver transplantation (LT) without additional risks. We designed a systematic review and meta-analysis. METHODS: The RCTs, cohorts, case-controls, or case series that explored outcomes of IPTE after LT for adults were involved in our study. The Newcastle-Ottawa scale was used to assess the risk of bias. RESULTS: A total of 15 studies (n = 4144) were included, consisting of 10 studies (retrospective cohorts; n = 3387) for quantitative synthesis and 5 studies (1 prospective cohort, and 4 case series; n = 757) for qualitative synthesis. The pooled estimates suggested IPTE could reduce time to discharge from ICU stay (TDICU) (mean difference [MD] -2.12 days, 95% confidence interval [CI] -3.04 to -1.19 days), time to discharge from the hospital (TDH) (MD -6.43 days, 95% CI -9.53 to 3.33 days), re-intubation rate (RI) (odds ratio [OR] 0.29, 95% CI 0.22-0.39), morbidity rate (MR) (OR 0.15, 95% CI 0.08-0.30) and graft dysfunction rate (GD) (IPTE vs CTE: 0.3% vs 3.8%, P < .01), and had comparable ICU survival rate (ICUS) (OR 6.67 95% CI 1.34-33.35) when compared with CTE after LT. CONCLUSIONS: IPTE can achieve an enhanced recovery for adult patients underwent LT without additional re-intubation, morbidity, and mortality risks. However, further work needs to be done to establish the extent definitively through carefully designed and conducted RCTs. PMID- 30407309 TI - Layer-specific strain analysis of left ventricular myocardium after alcohol septal ablation for hypertrophic obstructive cardiomyopathy. AB - INTRODUCTION: We aimed to explore the layer-specific systolic strain of left ventricular (LV) myocardium in patients with hypertrophic obstructive cardiomyopathy (HOCM) before and after alcohol septal ablation (ASA).The routine 2D (frame rate: >50 Hz) data sets were acquired using GE Vivi7 system for 44 consecutive HOCM patients and 21 matched normal subjects. Fifteen of HOCM patients had serial echocardiograms available for speckle tracking analyses before and 1 year after ASA. 2D strain was analyzed by EchoPAC software.The layer strain from inner to mid-myocardial and outer layers in basal and middle segments in HOCM patients continuously declined. The absolute values of peak systolic strains from the endocardium to mid-myocardium and epicardium in the basal septum of the HOCM group were significantly lower than those of the normal group (P <.01). Meanwhile, the layer systolic strain of LV endocardium in the basal septum increased significantly during a 1-year follow-up (P <.05). CONCLUSIONS: The layer-specific strains of HOCM patients measured by tissue Doppler echocardiography decreased significantly compared to those of normal individuals. The increased specific layer strain of LV endocardium in the basal septum may be a valid marker of echocardiographic improvement in HOCM patients receiving ASA. PMID- 30407310 TI - Qishen Yiqi dripping pills for ischemic heart failure: A protocol for a prospective cohort study. AB - BACKGROUND: The prognosis of ischemic heart failure (IHF) is worse than non-IHM. Improving the management of IHF remains an urgent demand. In recent years, Qishen Yiqi dripping pills (QSYQ), a type of Chinese herbal medicine (CHM), has been popular for IHF combined with standard western medicine. However, relevant scientific evidence from the real clinical practice still is insufficient. The prospective cohort study aims to assess the effectiveness and safety of QSYQ plus standard western medicine for IHF in the real clinical practice. METHODS: It is a multicenter, prospective, observational cohort study. A total of 1200 patients with IHF recruited from 84 hospitals in China will be assigned to exposure group (patients with QSYQ treatment) or non-exposed group (patients without QSYQ treatment) mainly according to patients' preference in real clinical situation. The primary outcomes include New York Heart Association (NYHA) cardiac functional classification and Minnesota Living with Heart Failure Questionnaire (MLHFQ). The secondary outcomes include composite outcomes (all-cause mortality, frequency of re-admission or emergency due to cardiovascular events), left ventricular ejection fraction and cardiothoracic ratio, symptoms and signs obtained by the 4 Tradiational Chinese Medicine (TCM) diagnostic methods. Assessments will be performed at baseline, 1st and 3rd month after enrollment. DISCUSSION: It will provide new evidence on QSYQ for IHF in real clinical practice. STUDY REGISTRATION: This study has been registered on the Chinese Clinical Trial Registry (No: ChiCTR-ONRC-14004407). PMID- 30407311 TI - Ursodeoxycholic acid after common bile duct stones removal for prevention of recurrence: A systematic review and meta-analysis of randomized controlled trials. AB - INTRODUCTION: The recurrence rate of common bile duct stones (CBDS) after removal has been reported to exceed 10% and no established pharmacologic treatment exists for the prevention of recurrent CBDS. Many studies indicated ursodeoxycholic acid (UDCA) has the potential to prevent the recurrence of CBDS. The aim of this systematic review is to evaluate the effects of UDCA for prevention of recurrence after common bile duct stones removal. METHODS AND ANALYSIS: We will systematically screen all randomized controlled trials (RCTs) published through electronically and hand searching. The following search engines including Ovid Medline, EMBASE, Cochrane CENTRAL, Proquest, Scopus, Web of Science, Pubmed, the Chinese Biomedical Literature Database, the China National Knowledge Infrastructure, VIP Information, Wanfang Data. Supplementary sources will be searched including gray literature, conference proceedings, and potential identified publications in OpenGrey.eu and Google Scholar databases. Two reviewers will independently conduct the trial inclusion, data extraction and assess the quality of studies. The recurrence rate of CBDS will be assessed as the primary outcomes. The adverse event that required discontinuation of UDCA intervention and the drop-outs (lost to follow-up) before the end of the study will be measured as secondary outcomes. Methodological quality will be evaluated according to the Cochrane risk of bias. All analyses will be applied by RevMan (version 5.3). RESULTS: This systemic review and meta-analysis will evaluate the effects of UDCA for prevention of recurrence after CBDS removal in RCTs. CONCLUSION: Our study will provide evidence to judge whether UDCA is an effective intervention to prevent the recurrence after CBDS removal. PMID- 30407312 TI - N-acetylcysteine improves oxidative stress and inflammatory response in patients with community acquired pneumonia: A randomized controlled trial. AB - Oxidative stress is considered to be part of the pathogenic mechanism for community-acquired pneumonia (CAP) and is closely linked to inflammation. Attenuation of oxidative stress would be expected to reduce pulmonary damage. Antioxidants have been found to be effective in alleviating lung injury and protecting against damage of other organs.The aim of the study was to compare the effect of adding N-acetylcysteine (NAC) to conventional treatment versus conventional treatment on oxidative stress, inflammatory factors, and radiological changes in CAP patients.Eligible CAP patients at Weihai Municipal Hospital were stratified and randomly assigned to either NAC group or non-NAC group between August 2016 and March 2017. The NAC group received conventional treatment for pneumonia and NAC (1200 mg/d). Thenon-NAC group received conventional therapy. malondialdehyde (MDA), superoxide dismutase (SOD), total antioxidant capacity (TAOC), tumor necrosis factor-alpha (TNF-alpha), and computed tomography (CT) images were evaluated at baseline and after treatment. The primary endpoint indicators were the changes in oxidative stress parameters (MDA, TAOC, SOD) and TNF-alpha after treatment in the NAC group compared with those in the non-NAC group. The secondary endpoint indicator was any difference in CT scores after treatment in the NAC group compared with the non-NAC group.Baseline levels of MDA, TAOC, SOD, and TNF-alpha were similar between the 2 groups before treatment. Plasma levels of MDA and TNF-alpha decreased more (P < .05 MDA:p 0.004, TNF-alpha:p <0.001) in the NAC group than the non-NAC group, and there was a reliable increase in TAOC content (p 0.005). There was no significant difference in increased plasma SOD activity between the groups (p 0.368), and the NAC group did not show a greater improvement from CT scores. No NAC-related adverse effects were observed.Addition of NAC therapy for CAP patients reduced MDA and TNF-alpha and increased TAOC. Treatment with NAC may help to reduce oxidative and inflammatory damage in pneumonia patients. PMID- 30407313 TI - Epidural hematoma after caudal epidural pulsed radiofrequency stimulation: A case report. AB - RATIONALE: Epidural hematoma is a possible complication after neuraxial procedures. Recently, caudal epidural pulsed radiofrequency (PRF) stimulation was reported as an effective method for controlling several types of chronic pain. Herein, we report on a patient who developed a lumbar epidural hematoma after receiving caudal epidural PRF stimulation. PATIENT CONCERNS: A 75-year-old woman, who was taking oral warfarin (2 mg/d), received caudal epidural PRF stimulation for symmetrical neuropathic pain in both legs due to chronic idiopathic axonal polyneuropathy. She did not discontinue warfarin use before undergoing the procedure. Three days and 12 hours after the procedure, motor weakness suddenly manifested in the right leg (manual muscle testing [MMT] = 2-3). DIAGNOSES: Lumbar magnetic resonance imaging (MRI) performed 7 days after the PRF procedure showed a spinal epidural hematoma at the L1 to L5 levels, compressing the thecal sac. The international normalized ratio was 6.1 at the time of the MRI. INTERVENTIONS: Decompressive laminectomy from L1 to L5 with evacuation of the hematoma was performed. OUTCOMES: Three months postoperatively, the motor weakness in the patient's right leg improved to MMT = 4 to 5. LESSONS: This case suggests that clinicians should carefully check if patients are taking an anticoagulant medication and ensure that it is discontinued for an appropriate length of time before a caudal epidural PRF procedure is performed. PMID- 30407315 TI - Spontaneous complete regression of large uterine fibroid after the second vaginal delivery: Case report. AB - RATIONALE: Fibroids are common, hormone-dependent, benign uterine tumors. It is estimated that they occur in 20% to 40% of women during their reproductive years. The prevalence of fibroids among pregnant women is 10.7%. Most fibroids do not increase in size during pregnancy. Pregnancy has a variable and unpredictable effect on fibroid growth. The influence of pregnancy on uterine fibroid size still remains unclear. Researchers evaluating fibroids have reported an inverse association between parity and fibroids, suggestive of a protective effect. Pregnancies that occur while fibroids are small would be protective; whereas pregnancies occurring before fibroid development or after the tumors reach some critical size would not be protective. Herein, the case of a woman with a large uterine fibroid that was spontaneously regressed after a second successful vaginal delivery is reported. To our knowledge, the complete regression of a large fibroid after delivery has not yet been reported. PATIENT CONCERNS: A 35 year-old gravida 1 para 0 woman was referred from a private clinic with a history of pelvic mass, adnexal mass and 19 weeks of amenorrhea. DIAGNOSIS: Ultrasonographic examination indicated a solid mass at the uterine fundus (12.1 * 8.3 cm) suggestive of a uterine fibroid and complex echogenic mass at the right adnexa (7.7 * 6.0 cm). INTERVENTIONS: Usually, cesarean sections are performed after myomectomy due to the risk for rupture when attempting vaginal delivery. So, the patient decided against the myomectomy, because she did not have any myoma-related symptoms after the first vaginal delivery and wanted to have more children via vaginal birth. OUTCOMES: Six months postpartum she becomes pregnant again. The patient had another vaginal birth. Four years after second delivery, the large myoma completely regressed. LESSONS: Fibroids can regress with postpartum involution. Even though fibroid-related pregnancy complication is 10% to 30%, prophylactic myomectomy is not recommended. In addition, given the protective effect of parity, conception and delivery are reasonable option and could allow treatment to be deferred in women planning a pregnancy. PMID- 30407316 TI - Clinical, cytogenetic, and molecular findings in a fetus with ultrasonic multiple malformations, 4q duplication, and 7q deletion: A case report and literature review. AB - RATIONALE: Chromosome deletion/duplication has been reported to be associated with mental disability and dysmorphism according to the accumulated research evidence. PATIENT CONCERNS: A 25-year-old woman underwent amniocentesis for cytogenetic and single-nucleotide polymorphism (SNP) array analysis at 18 weeks of gestation due to the increased Down syndrome risk of 1/13. DIAGNOSES: The fetal chromosomal analysis revealed a seemingly "normal" chromosomal karyotype, but the SNP array results showed a partial duplication of chromosome 4q34.1q35.2 and a deletion of chromosome 7q34q36.3fluorescence in situ hybridization (FISH) analysis showed that the couple had normal chromosome 4 and 7, whereas there was a partial signal fragment of chromosome 4 attached on the long arm of chromosome 7 for the fetus. INTERVENTIONS: The couple finally chose to terminate the pregnancy based on the ultrasonic multiple malformations and the abnormal SNP array results. OUTCOMES: The duplicated/deleted segments of the fetus were de novo. Meanwhile, we consider SHH and XRCC2 as good candidate genes, which may, in part, explain the observed abnormalities for the fetus. LESSONS: The combination of SNP array and FISH analysis can give a molecular chromosomal diagnosis, which will offer more clear cytogenetic diagnosis and genetic counseling. PMID- 30407314 TI - Rhabdomyolysis during myelosuppression in a patient with central nervous system leukemia: A case report. AB - RATIONALE: Rhabdomyolysis is a potentially life-threatening syndrome and is a rare complication in patients with acute leukemia. PATIENT'S CONCERNS: A 20-year old male was admitted to our hospital due to skin ecchymosis in his trunk and lower limbs for 10 days. DIAGNOSES: Based on the precise diagnosis of leukemia, namely cell morphology, immunology, cytogenetics, and molecular biological typing (MICM), the patient was diagnosed with acute T-lymphocytic leukemia (T-ALL). INTERVENTIONS: The patient received hyper-Cyclophosphamide, Vincristine,Adriamycin, Dexamethasone (hyper-CVAD) regimen chemotherapy (methotrexate, pirarubicin, vincristine and dexamethasone alternating with methotrexate and cytarabine) for 3 courses of chemotherapy. After 3 months of treatment, the patient developed intermittent pain, blurred vision, and inarticulate speech. Therefore, the patient was considered as central nervous system leukemia (CNSL) and immediately received 2 courses of chemotherapy with hyper-CVAD-B combined with polyethylene glycol conjugated asparaginase (PEG-ASP). OUTCOMES: On the seventh day after the completion of chemotherapy, the patient was diagnosed with rhabdomyolysis because he complained of perianal pain and hematuria, and his creatine kinase (CK) increased suddenly to 3136 U/L. Finally, the patient died despite all kinds of active rescue. LESSONS: Rhabdomyolysis may occur after chemotherapy of leukemia. When patients developed hematuria, muscle weakness, or even asymptomatic elevation of CK levels, physicians should pay attention to the occurrence of rhabdomyolysis and take active hydration treatment. PMID- 30407317 TI - Selection of the best point and angle of lateral ventricle puncture according to DTI reconstruction of peripheral nerve fibers. AB - This study aims to find accurate angles and depths of lateral ventricle puncture using diffusion tensor imaging (DTI) reconstruction, as well as to provide an optimized and alternative puncturing strategy.A total of 90 computed tomography (CT) images and 30 CT images with DTI were analyzed. The measurements were performed on coronal, sagittal, and horizontal planes. Some distances and angles were measured to determine the best angle and penetration depth during the puncture process. Important landmarks of the lateral ventricle were also measured, and a comparison of the differences between 2 hemispheres was also assessed.It showed that the vertical distance from the superior margin to inferior margin of the lateral ventricle was 22.2 +/- 0.5 mm and the length was 124.1 +/- 2.1 mm. In the frontal horn puncture approach, the penetration depth should be limited between 105.2 and 109.4 mm, the angle should be 71.6 +/- 2.7 degrees . During the occipital horn puncture approach, puncturing depth was from 90.7 to 111.4 mm, and angle was 15.3 +/- 1.8 degrees . Through the parietal lobe puncture approach, which was firstly brought out in this study, the puncturing length should be 124.4 to 130.2 mm and angle was 56.6 +/- 2.0 degrees .The traditional recommended protocol of lateral ventricle puncture is not accurate, the refined lateral ventricle puncture protocol established in this study will reduce injury and remain function. A DTI imaging examination combining with nerve fibers reconstruction were strongly recommended before lateral ventricle puncture, which will help neurosurgeons to determine the best puncturing angles and depth. PMID- 30407318 TI - Pneumocardia and septic pulmonary embolism due to nongas-forming liver abscess: A case report. AB - RATIONALE: Pneumocardia and septic pulmonary embolism are uncommon complications of Klebsiella pneumoniae primary liver abscess (KPLA); however, they may lead to a poor clinical outcome. PATIENT CONCERNS: A 67-year-old woman was admitted to our hospital with fever, chills, cough, and dyspnea for 4 days. She had a previous history of diabetes mellitus. DIAGNOSES: The chest computed tomography (CT) revealed multiple peripheral nodules in both lungs and wedge-shaped peripheral infiltrative lesions abutting the pleura, suggestive of septic pulmonary embolism. An abdominal CT on the following day showed a large liver abscess without gas formation and pneumocardia of the right ventricle. INTERVENTIONS: After the antibiotic therapy of intravenous imipenem and drainage of the liver abscess, our patient made a complete recovery. OUTCOMES: The patient was discharged on the 25th hospital day after full recovery and was doing well on follow-up at 10 months. LESSONS: KPLA is potentially fatal due to the associated serious metastatic complications. Attention must be paid not only to the primary focus of infection but also to infection of other organs. It is important to detect to diagnose the spread of infection accurately, in a timely manner, to improve the prognosis of this condition. PMID- 30407319 TI - Goal-directed fluid therapy does not reduce postoperative ileus in gastrointestinal surgery: A meta-analysis of randomized controlled trials. AB - BACKGROUND: Perioperative goal-directed fluid therapy (GDFT) aiming to maintain individual fluid balance based on sensitive parameters was prevalent in major surgery, especially in enhanced recovery after surgery (ERAS) pathway. This meta analysis was conducted for the purpose of evaluating whether GDFT impacts on occurrence of postoperative ileus and whether its application is worthwhile in gastrointestinal surgery. METHODS: A systematic search of RCTs compared GDFT with other fluid management in patients undergoing gastrointestinal surgery from the PubMed, Web of Science, Embase, Cochrane Library databases was implemented. The primary outcome is incidence of postoperative ileus. Other outcome measures were length of hospital stay (LOS), postoperative morbidity and mortality. Subgroup analysis was planed a prior to verify the definite role of GDFT. RESULTS: 12 trials consisted of 1836 patients were included in the final analysis. GDFT did not influence the occurrence of postoperative ileus (relative risk, RR 0.71, 95% confidence interval, CI 0.47-1.07, P = .10), with moderate heterogeneity (I = 29%, P = .16). No difference was found between GDFT and control groups in LOS (mean difference -0.17 days, 95% CI -0.73 to 0.39, P = .55), total complication rate (RR 0.92, 95% CI 0.81-1.05, P = .23), and 30-day mortality (RR 0.91, 95% CI 0.47-1.75, P = .77). In other secondary outcomes, only wound infection rate was lower in the GDFT group (RR 0.68, 95% CI 0.50-0.93, P = .02). When performed subgroup analysis, GDFT was superior in reduction ileus only when compared with standard therapy or in those outside ERAS. CONCLUSIONS: It is possible that GDFT dose not affect the occurrence of postoperative ileus in gastrointestinal surgery. It scarcely influences postoperative morbidity and mortality as well. However, lower incidence of ileus is observed in GDFT group either outside ERAS or compared with standard fluid therapy. Probably, GDFT may not be necessary in the ERAS pathway or if a hybrid approach is adopted. PMID- 30407320 TI - Age, sex, and the association of chronic kidney disease with all-cause mortality in Buddhist priests: An analysis of the standardized mortality ratio from the Korean Buddhist priests cohort. AB - Buddhist priests lead a unique lifestyle, practicing asceticism, with a vegetarian diet. Such behavior may have an impact on clinical outcomes. Hence, we explored the mortality among Korean Buddhist priests as compared with the general population.This study is a single-center, retrospective study. Among the 3867 Buddhist priests who visited Dongguk University Gyeongju Hospital between January 2000 and February 2016, 3639 subjects were available for mortality data from Statistics Korea. Standardized mortality ratio (SMR) was computed for all causes of death and compared with the general population using national statistics in Korea. Information regarding end-stage renal disease (ESRD) was investigated from the Korean Society of Nephrology registry. Among the 3639 patients, the baseline laboratory results were obtained in 724 patients. Chronic kidney disease (CKD) was defined as dipstick proteinuria >=1 or an estimated glomerular filtration rate <60 mL/min/1.73 m.The mean age was 50.0 +/- 12.5 years, and 51.0% were men. During the follow-up period for 31.1 +/- 35.6 months, 55 (7.6%) patients died. During the follow-up period, 3 (0.4%) and 23 (3.2%) patients developed ESRD and urinary stone, respectively. The SMR for all causes of death was 0.76 (95% confidence interval [CI] 0.57-0.99; men 0.91, 95% CI 0.65-1.23; women 0.52, 95% CI 0.28-0.87). Among 724 patients, 74 (10.2%) patients had CKD. The SMR for non CKD patients (0.61, 95% CI 0.43-0.85) was significantly lower than the general population. Female and patients older than 50 years (0.74, 95% CI 0.55-0.98) had a significantly lower SMR. In the Cox proportional hazards model with adjustment, older age (adjusted HR 1.04, 95% CI 1.10-1.07) and presence of CKD (adjusted HR 2.55, 95% CI 1.07-6.06) were independently associated with increased all-cause mortality.Buddhist priests and especially Buddhist priests without CKD showed a significantly lower mortality compared with the general population. PMID- 30407321 TI - Focal therapy versus robot-assisted partial nephrectomy in the management of clinical T1 renal masses: A systematic review and meta-analysis. AB - BACKGROUND: Robot-assisted partial nephrectomy (RPN) and focal therapy (FT) have both been successfully employed in the management of small renal masses. However, despite this being the era of minimally invasive surgery, few comparative studies exist on RPN and FT. The aim of our study is to review perioperative, renal functional and oncologic outcomes of FT and RPN in cT1 renal masses. METHODS: Literature published in Medline, EMBASE, and Cochrane Library databases up to April 22, 2018, was systematically searched. We included literature comparing outcomes of FT (radiofrequency ablation, cryoablation, microwave ablation, and irreversible electroporation) and RPN. Studies that reported only on laparoscopic partial nephrectomy or open partial nephrectomy, and review articles, editorials, letters, or cost analyses were excluded. In total, data from 1166 patients were included. RESULTS: From 858 total articles, 7 nonrandomized, observational studies were included. Compared with RPN, FT was associated with a significantly lower decrease of estimated glomerular filtration rate (weighted mean difference [WMD] -8.06 mL/min/1.73 m; confidence interval [CI] -15.85 to -0.26; P = .04), and lower estimated blood loss (WMD -49.61 mL; CI -60.78 to -38.45; P < .001). However, patients who underwent FT had a significantly increased risk of local recurrence (risk ratio [RR] 9.89; CI 4.24-23.04; P < .001) and distant metastasis (RR 6.42; CI 1.70-24.33; P = .006). However, operative times, lengths of stay, and complication rates were revealed to be similar between FT and RPN. CONCLUSION: RPN has a substantial advantage in preventing cancer recurrence. However, in the era of minimally invasive surgery, FT has advantages in renal function preservation and less bleeding. Long-term follow-up for survival rates and comparative analysis of microwave ablation and irreversible electroporation are needed to extend FT for patients with significant morbidities and for those who need sufficient renal function preservation with minimal bleeding. PMID- 30407322 TI - Routine coagulation test abnormalities caused by rivaroxaban: A case report. AB - RATIONALE: Rivaroxaban is a non-vitamin K antagonist oral anticoagulant. Current recommendations state that coagulation monitoring is not required, and neither the dose nor dosing interval requires adjustment in response to changes in coagulation parameters when rivaroxaban is used for approved indications. Guidelines mainly discuss the indications for rivaroxaban and non-vitamin K antagonist oral anticoagulants in general; they offer less guidance regarding how to use these medications in specific clinical situations to bridge the gulf between guidelines and clinical practice. PATIENT CONCERNS: An 88-year-old man with a long history of atrial fibrillation presented to the hospital with worsening dyspnea and chest pain. Significantly, he had an estimated glomerular filtration rate of 46.7 mL/min. He was prescribed oral rivaroxaban 20 mg once daily. After 7 days, the patient complained of maroon colored stools. DIAGNOSIS: Laboratory investigations revealed that the patient's prothrombin time (PT) and activated partial thromboplastin time (aPTT) were elevated. Rivaroxaban induced gastrointestinal bleeding was suspected. INTERVENTIONS: Rivaroxaban was discontinued and routine coagulation tests were monitored daily. OUTCOMES: Two days following the discontinuation of the drug, the bleeding was controlled and hemoglobin was normal, but the PT and aPTT remained abnormal. On the third day after discontinuing rivaroxaban, the patient experienced sudden syncope and pulselessness and expired. LESSONS: This case indicates that in real-world situations, a small number of patients may develop changes in both PT and aPTT during rivaroxaban therapy. Therefore, coagulation monitoring should be considered in patients with risk factors for bleeding, such as elderly patients with renal insufficiency. PMID- 30407323 TI - Apatinib for salvage treatment of advanced malignant pleural mesothelioma: A case report. AB - RATIONALE: Malignant Pleural Mesothelioma (MPM) is rare cancer and has a poor prognosis with resistance to chemotherapy or radiotherapy. Until now there is no standard third-line treatment for patients who have failed second-line therapy. PATIENT CONCERNS: A 58-year-old non-smoking female peasant of ethnic Han was admitted to the oncology department of the 363 Hospital with a primary complaint of chest tightness and breathlessness from 3 months ago. DIAGNOSES: Positron emission tomography-computed tomography (PET/CT) examination showed "dirty" pleural and parietal pleural involvement as well as mediastinal and pulmonary hilar lymph node enlargement. Finally, cancer cells were seen after repeated pleural effusion cell examination. Immunohistochemistry confirmed epithelioid of pleural mesothelioma. INTERVENTIONS: Apatinib as a third-line treatment after failure from pemetrexed/cisplatin (PC) as the first-line chemotherapy and gemcitabine/cisplatin (GP) as the second-line chemotherapy. At first, 250 mg/day was given and 1 week later, the dose was increased to 500 mg/day. OUTCOMES: A 5 month progression-free survival was achieved and toxicity included severe hand foot syndrome, mild proteinuria, and hypertension. LESSONS: Apatinib may be a potential therapeutic drug for MPM, particularly as a third-line treatment in cases resistant to chemotherapeutic options. PMID- 30407324 TI - Impact of global spine balance and cervical regional alignment on determination of postoperative cervical alignment after laminoplasty. AB - The aim of this study is to analyze the combined impact of preoperative T1 slope (T1S) and C2-C7 sagittal vertical axis (C2-C7 SVA) on determination of cervical alignment after laminoplasty.Forty patients undergoing laminoplasty for cervical spondylotic myelopathy (CSM) with more than 2 years follow-up were enrolled. Three parameters, including cervical lordosis, T1S, and C2-C7 SVA, were measured by preoperative and postoperative radiographs. Receiver operating characteristics (ROC) curve analysis was used to determine the optimal cut-off values of preoperative T1S and C2-C7 SVA for predicting postoperative loss of cervical lordosis. Patients were classified into 4 categories based on cut-off values of preoperative T1S and C2-C7 SVA. The primary outcome was postoperative C2-C7 SVA. Change in radiographic parameters between 4 groups were compared and analyzed.Optimal cut-off values for predicting loss of cervical lordosis were T1S of 20 degrees and C2-C7 SVA of 22 mm. Patients with small C2-C7 SVA, no matter what the value of T1S, got slight loss of cervical lordosis and increase in C2-C7 SVA. Patients with low T1S and large SVA (T1 <=20 degrees and SVA >22 mm) got postoperative correction of kyphosis and decrease of C2-C7 SVA. However, patients with high T1S and large SVA (T1 >20 degrees and SVA >22 mm) got mean postoperative C2-C7 SVA value of 37.06 mm, close to the threshold value of 40 mm.Determination of cervical alignment after laminoplasty relies on the equilibrium between destruction of cervical structure, kyphotic force, and adaptive compensation of whole spine, lordotic force. Lower T1S means bigger compensatory ability to adjust different severity of cervical sagittal malalignment, and vice versa. PMID- 30407325 TI - Response of germline BRCA2-mutated advanced pancreatic acinar cell carcinoma to olaparib: A case report. AB - RATIONALE: Pancreatic acinar cell carcinoma (PACC) is a relatively rare malignancy of the exocrine pancreas. BRCA2, a cancer susceptibility gene, has been widely studied in breast and ovarian carcinomas as mutation carriers for this gene are at a high risk for cancer development. Olaparib, an oral poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor, has been approved for the treatment of ovarian cancer with any BRCA 1/2 mutations. Herein, we report the first case of a germline BRCA2-mutated unresectable advanced PACC patient who responded well to olaparib treatment. PATIENT CONCERNS: A 59-year-old male with a family history of cancer presented with a persistent epigastric dull pain for 3 months. DIAGNOSIS: The patient was diagnosed with advanced PACC based on computed tomography (CT) scan, laparotomy, and pathology. INTERVENTIONS: Exploratory laparotomy, intratumoral brachytherapy by radioiodine-125 seeds, modified FOLFIRINOX chemotherapy, and targeted therapy with olaparib were administered. OUTCOMES: The patient responded well to olaparib until the occurrence of severe adverse drug reactions, he died as a result of multiple organ failure with an overall survival period of 12 months. LESSONS: As a PARP inhibitor, olaparib has remarkable curative effect not only on breast and ovarian cancers, but also on other malignancies with BRCA mutations. Patients with advanced cancer could benefit from active targeted therapy with improvement in overall survival and quality of life. PMID- 30407326 TI - Management of chronic pain in Ehlers-Danlos syndrome: Two case reports and a review of literature. AB - RATIONALE: Ehlers-Danlos syndromes (EDSs) are a heterogeneous group of heritable connective tissue disorders involving defective collagen synthesis. Patients with EDS are prone for chronic myofascial pain, apart from other comorbidities. Although the initial pathology is commonly nociceptive, progression of EDS leads to neuropathies and central sensitization of pain signals. Overall, approximately 90% or more EDS patients suffer from chronic pain. There are no existing guidelines to manage chronic pain in EDS patients. In this article, we illustrate 2 case reports of EDS patients with chronic pain and review the relevant literature regarding the pathological considerations and management of chronic pain in EDS. PATIENT CONCERNS: Our first patient had worsening multiple joint pains despite treatment with medications and a recent diagnosis of EDS-type 3. The second patient had a complicated history including longstanding EDS and multiple previous surgeries. She was referred due to concern about complex regional pain syndrome (CRPS) in her upper extremity. DIAGNOSES: For the first patient, apart from chronic pain due to her EDS, her history also revealed that she suffered from kinesiophobia. For the second patient, a detailed clinical assessment revealed no signs of CRPS but instead a generalized worsening of EDS symptoms. INTERVENTIONS: Both patients were evaluated by the multidisciplinary team consisting of a pain physician, nurse, pain psychologist, and a kinesiologist. Their treatment involved optimization of daily medications, participation in pain self-management sessions that included cognitive behavioral therapy, graded exercises, coping, and relaxation strategies. OUTCOMES: Both patients demonstrated significantly better pain control and achieved overall improvement in daily living. LESSONS: EDS is a complex illness with a multitude of symptoms. As in our patients, EDS patients also suffer from panic and anxiety disorders that increase the burden of pain. Apart from optimization of medications, EDS patients are best managed by a multidisciplinary approach that includes pain education and life style changes. The caution that they are resistant to local anesthetics is unwarranted. Appropriate pain interventions in selected patients may have a role to decrease pain intensity. PMID- 30407327 TI - Staplers or clips?: A systematic review and meta-analysis of vessel controlling devices for renal pedicle ligation in laparoscopic live donor nephrectomy. AB - BACKGROUND: Controlling of the renal vessels is a critical step in live donor nephrectomy (LDN). Currently, mainly 2 devices, Hem-o-Lok clips and staplers, are utilized to control vessels during LDN. Both of them have advantages and disadvantages. METHODS: This systematic review and meta-analysis was aimed to compare the safety and the efficacy of the 2 devices and to identify the better one in LDN. A systematic search for related publications in the databases of PubMed, Medline, Embase, the Cochrane Library, and Web of Science through February 2018 was performed. Eight studies were selected and evaluated with the Newcastle-Ottawa Scale (NOS). RESULTS: The meta-analysis result showed that utilization of Hem-o-Lok clips resulted in greater amount of estimated blood loss (mean differences [MD]: 40.10; 95% confidence interval [CI] 4.37-75.84) and longer time of warm ischemia (WIT) (MD: 55.61; 95% CI 36.79-74.43) than using staplers. Residual vascular length of grafts in clip group was longer than that in stapler group (MD: 2.51; 95% CI 0.78-4.24). However, the differences in primary outcomes such as device failure rate, death rate, and severe hemorrhage rate, were not significant between these 2 groups. In addition, utilization of Hem-o-Lok clips costed approximate $400 lower than staplers per patient. CONCLUSION: This study revealed that Hem-o-Lok clips and staplers have the similar function in LDN renal ligation, regarding the device failure rate, death rate, and severe hemorrhage rate. However, the surgeons would benefit from the clips in terms of the residue length of vessels, these outstanding features provide operation convenience and flexibility, such as right-sided donor nephrectomies, early vascular bifurcation, and rare vascular variation. In addition, the clips have potential economic advantages. In some developing countries, it would reduce the healthcare expenditure. PMID- 30407328 TI - The effects of a forced-air warming system plus electric blanket for elderly patients undergoing transurethral resection of the prostate: A randomized controlled trial. AB - BACKGROUND: Perioperative inadvertent hypothermia in elderly urology patients undergoing transurethral resection of the prostate (TURP) is a well-known serious complication, as it increases the risk of myocardial ischemia, blood loss, and surgical wound infection. We conducted this prospective randomized controlled trial to evaluate the combined effect of a forced-air warming system and electric blanket in elderly TURP patients. METHODS: Between January 2015 and October 2017, we recruited 443 elderly male patients undergoing elective TURP with subarachnoid blockade (SAB). These were randomly divided into 3 groups: group E (intraoperative warming using electric blankets set to 38 degrees C; n = 128); group F (intraoperative warming using a forced-air warmer set to 38 degrees C; n = 155) and group FE (intraoperative warming using a forced-air warmer plus electric blankets, both set to 38 degrees C; n = 160). The primary outcome was shivering and their grades. Hemodynamic changes, esophageal temperature, recovery time, incidences of adverse effects, and patient and surgeon satisfaction were also recorded. RESULTS: Baseline characteristics showed no significant differences when compared across the 3 groups (P >.05). Compared with groups E and F, both HR and mean arterial pressure (MAP) in group FE were significantly decreased from T6 to T10 (P <.05). Compared with groups E and F, esophageal temperature in group FE increased significantly from T5 to T10 (P <.05). Compared with group E, esophageal temperature in group F was significantly increased from T5 to T10 (P <.05). Compared with groups F and FE, post-anesthesia care unit (PACU) recovery time was longer in group E, while compared with group F, PACU recovery time was shorter in group FE (P <.05). Compared to patients in groups E and F, those in group FE had a significantly lower incidence of arrhythmia and shivering (P <.05). The number of patients with shivering grades 0 to 3 was higher in group E than in other groups, while the number of patients with shivering grade 2 was significantly higher in group F than in group FE (P <.05). Patient and surgeon satisfaction scores were higher in group FE than in groups E and F (P <.05). CONCLUSIONS: Use of a forced-air warming system combined with an electric blanket was an effective method with which to retain warmth among elderly TURP patients. PMID- 30407329 TI - Long-term safety and immunogenicity of the M72/AS01E candidate tuberculosis vaccine in HIV-positive and -negative Indian adults: Results from a phase II randomized controlled trial. AB - OBJECTIVES: To assess the long-term safety and immunogenicity of the M72/ Adjuvant System (AS01E) candidate tuberculosis (TB) vaccine up to 3 years post dose 2 (Y3) in human immunodeficiency virus (HIV)-positive (HIV+) and HIV negative (HIV-) Indian adults. METHODS: This phase II, double-blind, randomised, controlled clinical trial (NCT01262976) was conducted at YRG CARE Medical Centre, in Chennai, India, between January 2011 and June 2015.Three cohorts (HIV+ participants stable on antiretroviral therapy [ART; HIV+ART+], HIV+ ART-naive [HIV+ART-], and HIV- participants) were randomised (1:1) to receive 2 doses of M72/AS01E (M72/AS01E groups) or saline (control groups) 1 month apart and were followed up toY3. Latent TB infection was assessed at screening using an interferon-gamma (IFN-gamma) release assay (IGRA). Safety and immunogenicity results up to Y1 post-vaccination were reported elsewhere. Here, we report serious adverse events (SAEs), humoral and cell-mediated immune (CMI) responses to M72 recorded at Y2 and Y3. RESULTS: Of 240 enrolled and vaccinated participants, 214 completed the long-term follow-up part of the study.In addition to SAEs previously described, between Y1 and Y2 1 M72/AS01E recipient in the HIV+ART+ cohort reported 2 SAEs (sinus cavernous thrombosis and gastroenteritis) that were not considered as causally related to the study vaccine.Vaccination elicited persistent humoral immune responses against M72. At Y3, seropositivity rates were 97.1%, 66.7%, and 97.3% and geometric mean concentrations (GMCs) were 22.0 ELISA units (EU)/mL, 4.9 EU/mL, and 24.3 EU/mL in the HIV+ART+, HIV+ART-, and HIV- cohorts, respectively. Humoral immune response was lowest in the HIV+ART cohort.In M72/AS01E recipients, no notable decrease in the frequency of M72 specific CD4 T-cells expressing >=2 immune markers among interleukin-2 (IL-2), IFN-gamma, tumour necrosis factor alpha (TNF-alpha) and CD40 ligand (CD40L) was observed at Y3 post-vaccination. Median values (interquartile range) of 0.35% (0.13-0.49), 0.05% (0.01-0.10), and 0.15% (0.09-0.22) were recorded in the HIV+ART+, HIV+ART- and HIV- cohorts, respectively. CD4 T-cell response was lowest in the HIV+ART- cohort.No CD8 T-cell response was observed. CONCLUSION: The cellular and humoral immune responses induced by M72/AS01E in HIV+ and HIV- adults persisted up to Y3 post-vaccination. No safety concerns were raised regarding administration of M72/AS01E to HIV+ adults. CLINICAL TRIAL REGISTRATION: NCT01262976 (www.clinicaltrials.gov). PMID- 30407330 TI - Impacts of time interval on 18F-FDG uptake for PET/CT in normal organs: A systematic review. AB - BACKGROUND: To perform a systematic review of the effect of time interval on 2 deoxy-2-[18F] fluoro-D-glucose (18F-FDG) uptake in normal organs. METHODS: PubMed, EMBASE, Ovid, and Cochrane databases were searched to identity all potential eligible literature. The study characteristics and relevant data were extracted and analyzed. We adopted the effect size (ES) and the coefficient of determination (R) to best measure the magnitude of the relation between time interval and 18F-FDG uptake in normal organs. RESULTS: Seven articles and 860 participants were included. The time interval on liver and mediastinal blood pool were relatively medium (R=0.01-0.03, ES = -0.57 and -0.60) but noticeable (R = 0.06, ES = -0.68 and -0.39), respectively. The uptake of 18F-FDG on cerebellum, spleen, bone marrow, muscle, bowel, and adipose remains to be verified as the rare studies. In addition, other factors such as body mass index and blood glucose level appeared to be important which also affect 18F-FDG uptake in normal organs. CONCLUSION: The impact of time interval on SUVs in liver and mediastinal blood pool were relatively medium but clinically noticeable. More studies need to be done to solve the relation between the SUVs of other organs and time interval. PMID- 30407331 TI - TA pharmacopuncture as a primary and independent treatment for frequent sprains occurring over 9 months in a patient with needle sickness: Case report. AB - RATIONALE: Sprains, stretching or tearing of ligaments are common injuries. Clinicians should try to prevent acupuncture-associated vasovagal responses (AAVR) when treating patients with such injuries. In this study, we report the treatment of frequent sprains of various body parts in a patient with a history of AAVR using only TA (a 7-herb extract consisting of Scutellaria baicalensis, Phellodendron amurense, Pulsatilla koreana, Sophora tonkinensis, Aucklandia lappa, Aquilaria agallocha, and Carthamus tinctorius L.) pharmacopuncture. PATIENT CONCERNS: The patient was a 47-year-old woman who was injured 23 times in 9 months. The injuries occurred in the knees, thumb, wrist, ankle, and low back region due to overextension during physical activity or frequent exercise. This patient had great fear of acupuncture after fainting due to her experience with a previous fire needling on an ankle sprain 18 years ago. Therefore, she did not want to undergo conventional acupuncture, including needle retention. DIAGNOSES: With the exception of the bruising and sprain of a knee occurring over 1 week after onset at the initial visit, the injuries were diagnosed as acute sprains of grade 1 with pain without range of movement limitation in various parts of the knee, ankle, thumb, and lower back. Time to onset of these injuries was within 3 days. INTERVENTIONS: The patients received only TA pharmacopuncture at 4 to 6 ouch points (ashi points). The patient returned to work immediately after the conclusion of treatment without any posttreatment such as infrared and hot pack which can help absorbing the extract and calming the injection site. OUTCOME: The treatment was usually completed within 4 sessions, and led to a reduction in pain (visual analog scale [VAS] score of 1). In the absence of mild swelling and warmth or when there was mild pain (VAS score <3) in the affected area, the patient reported reduced pain and smoother joint movement immediately after 1 to 2 sessions. LESSONS: Although our report is a single case study, our results indicate that TA pharmacopuncture can be effective in treating various acute sprains and is a potential acupuncture method for the treatment of patients with AAVR. PMID- 30407332 TI - Impact of nearby smoking on adolescent smoking behavior in Korea. AB - Although youth smoking is a very significant topic, research on youth smoking is limited. More specifically, youth smoking studies are limited to certain schools and regions. In this study, we investigated the association between number of nearby smokers and adolescent smoking behavior.This study used South Korea's representative Youth Risk Behavior Web-based Survey from 2014 to 2016. A total 198,814 adolescents were included in the analysis. Survey logistic regression models were used to examine the association. We also analyzed subgroup models and various combinations of nearby smokers to explain adolescent smoking behavior.Adjusting for variables associated with smoking behavior, multivariate survey logistic regressions revealed that adolescents with more nearby smokers had a greater risk for smoking (1 person: odds ratio [OR], 5.090; 2 persons: OR, 8.405; 3 persons or more: OR, 12.039, all statistically significant). Combinations of nearby smokers also show that the risk of smoking increases as the number of people increases. In particular, smoking increased significantly when with friends.The study found that, as the number of surrounding cigarette smokers increases, the smoking rate in teenagers increases, and there is a tendency to vary according to social status. We recommend that educators and policy makers use a variety of approaches considering social environmental factors in smoking prevention programs and smoking cessation education for adolescents. PMID- 30407333 TI - Management of refractory chronic migraine using ultrasound-guided pulsed radiofrequency of greater occipital nerve: Two case reports. AB - RATIONALE: Although various oral medications and procedures are applied for managing migraine, their efficacy remains limited. To control migraine that does not respond to conventional treatments, we conducted pulsed radiofrequency (PRF) stimulation to the greater occipital nerve (GON) in 2 patients. PATIENT CONCERNS: Patients 1 and 2 complained of chronic throbbing, pulsating, and tight headaches. Their headache intensities scored 8 and 7 on a numeric rating scale (NRS), respectively. Patient 1 experienced the headache bilaterally in the frontal, retro-orbital, parietal, and occipital regions. The initial onset of the symptoms was more than 15 years ago. Patient 2 complained of headaches in the left frontal, retro-orbital, parietal, and occipital regions, which occurred first more than 14 years ago. DIAGNOSES: According to the International Classification of Headache Disorder-3 beta criteria, the patients were diagnosed with chronic migraine. INTERVENTIONS: Oral medications, GON block with bupivacaine and dexamethasone, and botulinum toxin injections did not alleviate the patients' migraine.The PRF stimulation on GON was performed under the guidance of ultrasound, at 5 Hz and 5-millisecond pulsed width for 360 seconds at 45 V. The electrode tip temperature was maintained at or below 42 degrees C. OUTCOMES: Two weeks after applying PRF, the pain was reduced to NRS 3 in both patients, who also reported that the headache became bearable after PRF. The effectiveness of PRF on GON lasted for at least 3 months in both patients, and no adverse effects were observed. LESSONS: Our findings suggested that the application of PRF on GON can be a useful option for treating refractory chronic migraine. PMID- 30407334 TI - Novel homozygous inactivating mutation of the calcium-sensing receptor gene in neonatal severe hyperparathyroidism responding to cinacalcet therapy: A case report and literature review. AB - RATIONALE: Calcium-sensing receptor (CaSR) mutations can cause life-threatening neonatal severe hyperparathyroidism (NSHPT). The medical management of NSHPT is often challenging and complex. Here, we present a case of NSHPT caused by a novel homozygous CaSR mutation. PATIENT CONCERNS: A Chinese female infant presented with poor feeding, constipation, severe hypotonia, and periodic bradycardia. Biochemistry tests revealed markedly elevated serum levels of Ca and parathyroid hormone (PTH). DIAGNOSES: Genetic sequencing revealed a previously undescribed CaSR mutation in exon 3 (c.242T>A; p.I81K). A diagnosis of NSHPT secondary to homozygously inherited familial hypocalciuric hypercalcemia syndrome was established. INTERVENTIONS: Cinacalcet was administered after the common treatments (low-calcium intake, hydration, and furosemide), calcitonin, and pamidronate therapy all failed. OUTCOMES: Serum Ca decreased and stabilized with cinacalcet therapy. During a 10-month follow-up, total calcium was maintained within the high-normal range and PTH was normalized. LESSONS: A trial of cinacalcet therapy might be undertaken in cases of NSHPT while definitive results of the genetic analysis are awaited. PMID- 30407335 TI - Lithium intoxication presenting as altered consciousness and arrhythmia with cardiogenic shock: A case report. AB - RATIONALE: Lithium has been used to treat bipolar disorder. Lithium has a narrow therapeutic index, with a therapeutic level between 0.6 and 1.5 mEq/L. The possible complications of lithium overdose include altered mental status, hand tremor, muscle weakness, nausea, vomiting, diarrhea, seizure, syncope, and arrhythmia. Lithium intoxication can be fatal and is difficult to diagnose in patients without a history of lithium intake. The occurrence of serious cardiac arrhythmias is rare in lithium intoxication. PATIENT CONCERNS: An 81-year-old man was brought to the emergency department because of consciousness disturbance for 2 days. According to his daughter, he had a history of hypertension and diabetes. Recently, his family also observed slurring of speech and easy choking. The physical examination findings were unremarkable. DIAGNOSIS: Blood examination only revealed impaired renal function. Twelve-lead electrocardiography revealed sinus rhythm with first-degree atrioventricular block. Chest radiography revealed mediastinal widening. The blood pressures obtained from the 4 limbs showed no significant differences. Subsequently, brain computed tomography revealed no obvious intracranial lesion. A neurologist was consulted, and a recent ischemic stroke could not be ruled out. While in the observation area, his systolic blood pressure decreased to <90 mm Hg and he showed bradycardia, and 12-lead electrocardiography revealed an AV block and long pulse. Contrast-enhanced chest computed tomography revealed no evidence of aortic dissection. Another family member reported a history of lithium intake for bipolar disorder for >30 years. Blood examination revealed a lithium concentration of 2.65 mEq/L. INTERVENTIONS: A nephrologist was consulted, and emergency hemodialysis was indicated. Dopamine was administered for his shock status via a right neck central venous catheter. OUTCOMES: His lithium level gradually declined after the hemodialysis, and blood pressure and consciousness level improved subsequently. The patient was discharged 9 days later in a stable condition. LESSONS: If an emergency physician encounters a patient with altered consciousness and arrhythmia with cardiogenic shock, the patient's drug intake history should be carefully reviewed to rule out cardiovascular problems on the basis of the patient's clinical condition. PMID- 30407336 TI - Vertigo caused by longus colli tendonitis: A case report and literature review. AB - RATIONALE: Tendinitis of the longus colli muscle is an aseptic inflammatory process leading to acute posterior neck pain, neck stiffness, and dysphagia or odynophagia. We present a patient exhibiting an infrequent symptom, vertigo. This is the first description of the occurrence of vertigo symptoms caused by longus colli tendinitis. PATIENT CONCERNS: A 38-year-old man was diagnosed with vertigo, presenting with a 1-month history of dizziness, palpitations, and numbness in the hands. DIAGNOSIS: Longus colli tendinitis. The diagnosis was established using magnetic resonance imaging fat-suppression sequences. INTERVENTIONS: Treatment with corticosteroid injections and acupotomy. OUTCOMES: The symptoms relieved immediately after the treatment and complete resolution of the symptoms was observed after 1 week. LESSONS: Longus colli tendinitis with vertigo is an under reported condition in the literature and physicians should be aware of its existence. A lack of familiarity with the anatomy of the prevertebral space and its variable radiographic appearance makes the diagnosis of longus colli tendinitis clinically difficult. Misdiagnosis of this condition may lead to unnecessary interventions in vertigo. PMID- 30407338 TI - Glomus tumor of the stomach: A case report. AB - RATIONALE: Glomus tumors (GTs) are a rare disorder originating from the glomus of the anastomoses of small arteries, usually occurring in the subungual region of the fingertips or toes and seldom occurring in the stomach. We unintentionally found a case of a gastric glomus tumor (GGT) without any upper abdominal discomfort. The diagnosis of this disease was mainly by immunohistochemistry. PATIENT CONCERNS: The patient presented to our hospital with intermittent right abdominal pain for 1 month. Abdominal computed tomography showed a nodular enhancement lesion in the gastric antrum. DIAGNOSES: The patient was diagnosed with an ileocecal tumor and a gastric stromal tumor. INTERVENTIONS: Surgical resection of the ileocecal and gastric tumors was performed. OUTCOMES: Pathologic examination of gastric masses revealed GT. The operation was effective, and the patient was discharged from our hospital 7 days after surgery. Upon follow-up at 3 months, the patient was asymptomatic. LESSONS: GTs are submucosal tumors rarely found in the stomach. Surgical resection is a good choice of treatment. The GGT lacked specific clinical and imaging features, and immunohistochemistry was essential in the diagnosis of GGT. PMID- 30407337 TI - Chronic myeloid leukemia extramedullary blast crisis presenting as central nervous system leukemia: A case report. AB - RATIONALE: Childhood chronic myeloid leukemia (CCML) is a malignant disease of granulocyte abnormal hyperplasia that is caused by clonal proliferation of pluripotent stem cells. The condition is relatively rare, accounting for 2.0% to 3.0% of cases of childhood leukemia. In addition, the incidence of extramedullary blast crisis in CCML presenting as central nervous system (CNS) blast crisis remaining chronic phase of the disease in bone marrow is extremely unusual. PATIENT CONCERNS: We report a case of childhood chronic myelogenous leukemia that abandoned treatment, resulting in chronic myelogenous leukemia transforming into extramedullary blast crisis resulting in CNS leukemia, accompanied by the chronic phase of the disease in bone marrow. DIAGNOSES: Chronic myeloid leukemia extramedullary blast crisis presenting as CNS leukemia without blast crisis in bone marrow. INTERVENTIONS: Following high-dose systemic and intrathecal chemotherapy, the patient continued to do well. LESSONS: High-dose systemic and intrathecal chemotherapy is safe and helpful for CCML extramedullary blast crisis. A long-term follow-up is crucial. PMID- 30407340 TI - 3.0T Contrast-enhanced whole-heart coronary magnetic resonance angiography for simultaneous coronary artery angiography and myocardial viability in chronic myocardial infarction: A single-center preliminary study. AB - To evaluate the accuracy of contrast-enhanced whole-heart magnetic resonance coronary angiography at 3.0T for assessing significant stenosis (>=50% lumen diameter reduction) in patients with myocardial infarction, by using conventional coronary artery angiography as the reference standard, and also test the performance of that for the detection and assessment of chronic myocardial infarction (MI), compared with standard delayed-enhancement coronary magnetic resonance (DE-CMR) for the determination of infarct size.We studied 42 consecutive patients (37 men, 5 women, mean age 58.5 +/- 10.7 years) with MI scheduled for conventional coronary angiography. Contrast-enhanced whole-heart coronary magnetic resonance angiography (CMRA) was employed after sublingual nitroglycerin (NTG) with the abdominal banding rolled tightly along the side of ribs. Finally, a 3D phase-sensitive inversion-recovery gradient-echo (3D-PSIR GRE) sequence was performed during free breathing. The assessment of MI sizes on WH-CMRA reconstructed images and 3D-PSIR-GRE images were compared using a paired student t test.The acquisition of CMRA was completed in 40 (95.2%) of 42 patients, with an imaging time averaged at 9.5 +/- 3.1 minutes. The average navigator efficiency was 47%. The sensitivity, specificity, and positive and negative predictive values of whole-heart CMRA for the detection of significant lesions on a segment-by-segment analysis were 91.7% (95% confidence interval [CI] 83.8-96.1), 84.0% (95% CI 80.0-87.4), 57.9% (95% CI 50.0-65.8), 97.7% (95% CI 95.3-98.9), respectively, and on a patient-based analysis 93.5% (95% CI 77.2 98.9), 88.9% (95% CI 50.7-99.4), 96.7% (95% CI 80.9-99.8), and 80.0% (95% CI 44.2 96.5), respectively. Infarcts were generally higher on the CE-CMRA technique compared with the standard technique (18.0 +/- 7.2 cm vs 16.1 +/- 6.4 cm; P < .0001).Contrast-enhanced whole-heart CMRA with 3.0-T not only may permit reliable detection of significant obstructive coronary artery disease in patients with myocardial infarction, but also could identify and quantify the volume of myocardial infarction. This technique could be considered the preferred approach in patients who could not overcome longer scanning times or unable to hold their breath instead of delayed-enhancement magnetic resonance imaging for detection of infarcted myocardium. However, compared with standard imaging, the volume of myocardial infarction is slightly overestimated. PMID- 30407339 TI - Acellular dermal matrix in premature ejaculation: A preliminary study. AB - BACKGROUND: To investigate the efficacy of acellular dermal matrix in penis augmentation (ADMPA) for premature ejaculation (PE). METHODS: A total of 39 patients treated with ADM in penis augmentation from June 2014 to December 2017 were evaluated. Detailed evaluations on PE were conducted before operation and at the 6-month and 2-year follow-up visits after operation. Self-estimated intravaginal ejaculatory latency time (IELT) and 5-item version of the International Index of Erectile Function (IIEF-5) were used to measure the ejaculation and the erectile function for all subjects. RESULTS: Compared to the baseline data, the IELT and IIEF-5 scores were increased, and PE was relieved at 6 months and 2 years after operation. No major complications occurred in the series. Minor complications were resolved with conservative treatment within 3 weeks. The psychosexual impact of the operation was beneficial in the majority of cases. CONCLUSION: Our survey systematically evaluated the effects of ADMPA for PE. ADMPA might be an optional surgical method in patients with PE, especially for those who seek penile augmentation. However, given the small amount of cases involved in this study, further studies on the effect of ADMPA for PE were still needed. PMID- 30407341 TI - Epidemiology of foodborne disease outbreaks from 2011 to 2016 in Shandong Province, China. AB - Foodborne disease is a major public health concern in both developed and developing countries. China has established a nationwide Foodborne Disease Outbreak Surveillance System (FDOSS) for collection and periodic reporting of data on the occurrence and causes of foodborne disease outbreaks in China. Each provincial Centers for Disease Control and Prevention (CDC) conducts the system working.We reviewed foodborne disease outbreaks that occurred during 2011 to 2016 in Shandong Province from the FDOSS. The Wilcoxon test was used to compare the median number of ill persons in outbreaks. All data analysis was performed using Epi Info 7.During 2011 to 2016, Shandong CDC received reports of 1043 foodborne disease outbreaks, resulting in 8078 illnesses, 2442 hospitalizations, and 17 deaths. There were a median of 69 outbreaks annually [interquartile range (IQR) 10-342], resulting in 335 to 3824 illnesses each year. The median outbreak size was 3 persons (IQR 2-7). Hotels (including cruise ships, hotpot restaurants, barbecue shops) were the most common setting. Among the 744 (71.3%) outbreaks with an implicated food or contaminated ingredient reported, 704 (94.6%) could be assigned to one of 17 predefined commodity categories. Of the 280 outbreaks with a known etiology, 117 (41.8%) were caused by poisonous plants and animals and their toxins, 39 (13.9) were caused by nitrite, and 27 (9.6%) were caused by vibrio parahaemolyticus. Of the 491 (47.1%) outbreaks with at least a contributing factor to cause outbreak, 168 (34.2%) were caused by improper processing, and 100 (20.4) were caused by inedible and misuse.Timely investigation, disposal and reporting of foodborne disease outbreaks provides information that might help FDOSS to make full use of efficiency and FDOSS should be continued and strengthened even more in Shandong Province, such as an increase in diagnostic laboratory capacities. PMID- 30407342 TI - A novel subchondral bone-grafting procedure for the treatment of giant-cell tumor around the knee: A retrospective study of 27 cases. AB - The vast majority of giant-cell tumors occur around the knee and characteristically affect the subchondral bone. Thermal damage to the articular cartilage arising from the application of polymethylmethacrylate (PMMA) or extensive intralesional curettage presents a challenging problem to orthopedic surgeons and patients due to compliance issues. For this reason, we developed a new subchondral bone-grafting procedure to restore massive bone defects and reduce degenerative changes in the knee.The aim of this study was to describe the novel subchondral bone-grafting procedure and evaluate clinical outcomes in patients with giant-cell tumors around the knee.This retrospective single-center study included a total of 27 patients with giant-cell tumors in the distal femur and proximal tibia admitted to our department from January 2012 to December 2015 and treated with aggressive intralesional curettage. Eleven males and 16 females were included. All cases underwent subchondral autograft bone grafting followed by bone cement reconstruction and instrument internal fixation. The Musculoskeletal Tumor Society (MSTS) score and short form-36 (SF-36) were applied to assess the functional outcome of the knee joint and quality of life. Tumor recurrence, Kellgren and Lawrence (KL) grade, and the distance of the cement to the articular surface were assessed throughout the sample.All cases were followed up after surgery for an average of 32.9 +/- 7.1 months (range 25-57 months). At the end of the follow-up period, all patients were alive and free from pulmonary metastasis. Complications associated with this surgery occurred only in 1 patient (3.7%), who presented with an incision infection that resolved with regular dressing and antibiotics. No fractures, instrument breakage, or joint fluid leakage occurred. Local recurrence occurred in 1 case (3.7%) at the distal femur after 23 months and was treated by wide resection followed by prosthesis reconstruction. Twenty-four patients (89%) did not develop radiographic findings of osteoarthritis: at the final follow-up 2 patients (7.4%), had progressed to KL1 and 1 patient had progressed to KL2. According to the MSTS scoring system, the functional score of the affected knee joint at the last follow-up ranged from 80% to 97%, with an average of 87.3%. The quality of life parameters assessed by the SF-36 survey at the last follow-up ranged from 47 to 96, with an average of 77.For patients with giant-cell tumor of bone near the knee, subchondral bone grafting combined with bone cement reconstruction is recommended as a feasible and effective treatment modality. PMID- 30407343 TI - Acceptability and consumption of tofu as a meat alternative among secondary school boarders in Enugu State, Nigeria: Implications for nutritional counseling and education. AB - Tofu, a food made of condensed soymilk that originated in China, has both nutritional and health benefits. The main objective of this study was to determine the acceptability and consumption of tofu as a meat alternative among students in boarding secondary schools in Enugu State, Nigeria.In this study, the authors adopted a cross-sectional analytic design. A representative sample of 603 adolescents in the boarding secondary schools took part in the study. Power analysis was conducted to estimate the appropriate sample size for the current study. Correlations analysis, moderation analysis, chi, analysis of variance (ANOVA), and t tests were employed for the analysis of the data.Students' acceptance of the 3 cooking options of tofu (steamed, boiled, and fried) did not significantly differ by gender. It was found that 94.5% of the respondents recognized the benefits of tofu; there is no significant difference between the male and female students on the extent to which they would eat tofu in school; the recognition of benefits of tofu is not significantly associated with acceptance of steamed, boiled, and fried tofu among the students; and the recognition of benefits of tofu is not significantly associated with consumption of tofu among the students. The finding further revealed that gender did not significantly moderate the association between recognition of benefits of tofu and students' acceptability of tofu. Also, it was found that gender did not significantly moderate the association between recognition of benefits of tofu and consumption of tofu among students.Further research is needed to identify the level of tofu acceptability and consumption among adolescents in boarding secondary schools in other states of Nigeria. Further research on factors influencing how recognition of benefits of tofu is associated with its acceptability among the Nigerian student population can have implications for nutritional counseling and regional health. PMID- 30407344 TI - Prognostic value of the systematic immune-inflammation index among patients with operable colon cancer: A retrospective study. AB - The systematic immune-inflammation index (SII) has been used to predict the prognosis of patients with various cancers. This study aimed to determine whether the preoperative SII was associated with postoperative survival among patients with operable colon cancer.This retrospective study included 118 age- and sex matched healthy subjects and 118 patients who underwent radical surgery for colon cancer between January 2011 and December 2013. The preoperative SII was calculated based on counts of neutrophils, lymphocytes, and platelets in the peripheral blood. Pearson correlation analysis was used to analyze the relationships between the SII and carcinoembryonic antigen (CEA) concentration, average length of stay (ALOS), and medical costs during hospitalization. The chi test or Fisher exact test was used to analyze the relationship between the preoperative SII and the postoperative survival rate.The median SII value was 667.75 among patients with colon cancer, which was higher than the value among healthy subjects. A high SII (>667.75) was associated with a large tumor size and advanced TNM stage, although it was not associated with age, sex, tumor location, or pathological grade. Pearson correlation analysis revealed that the SII was positively correlated with serum CEA concentration, ALOS, and medical costs. Relative to a low SII, a high SII was significantly associated with a lower overall survival rate at 3 years and 5 years after surgery.The present study's findings suggest that the preoperative SII is a useful prognostic index for patients with operative colon cancer. PMID- 30407345 TI - Tumor necrosis factor-alpha-308 gene promoter polymorphism associates with survival of cancer patients: A meta-analysis. AB - BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is involved in cancer pathogenesis, and TNF-alpha-308G>A, a single-nucleotide polymorphism, is associated with cancer prognosis; however, different studies have reported inconsistent results. This meta-analysis aimed to determine the correlation between TNF-alpha-308G>A polymorphism and the survival of cancer patients. METHODS: PubMed, Web of Science, Embase, Wanfang database, VIP database, and China National Knowledge Infrastructure database were used to obtain articles on association between TNF-alpha-308G>A polymorphism and cancer survival, published until April 2018. A meta-analysis was carried out using Stata 12.0 software to determine the pooled hazard ratio (HR) and 95% confidence intervals (95% CI). Furthermore, publication bias was assessed, and sensitivity analysis was performed to validate the analysis. RESULTS: In total, 13 retrospective cohort studies including 2559 cancer patients were reviewed to estimate the association between TNF-alpha-308G>A polymorphism and overall survival (OS) of cancer patients. The pooled results suggested that within TNF-alpha-308G>A polymorphism, genotypes GA+AA/GG (HR = 1.39, 95% CI: 0.90-2.14, P < .001, I = 78.1%), GA/GG (HR = 1.06, 95% CI: 0.83-1.36, P = .072, I = 53.5%), and AA/AG+GG (HR = 3.28, 95% CI: 0.92-11.72, P = .001, I = 85.9%) were not associated with the OS of cancer patients. However, interestingly, the HR was greater for patients with the AA genotype than for those with the GG genotype, suggesting an association between TNF-alpha-308G>A polymorphism and OS among cancer patients (AA/GG, HR = 2.16, 95% CI: 1.36-3.43, P = .281, I = 21.5%). CONCLUSION: TNF-alpha-308G>A polymorphism affects the OS of cancer patients and is a potential therapeutic target for cancer. PMID- 30407346 TI - Clinical results of closed versus mini-open reduction with percutaneous pinning for supracondylar fractures of the humerus in children: A retrospective case control study. AB - To compare the clinical outcomes of 2 procedures, closed or mini-open reduction with percutaneous pinning (ORPP), for the treatment of supracondylar fractures of the humerus in children.Patients aged less than 15 years who had undergone surgery for supracondylar fracture of the humerus between 2004 and 2013 were identified. The case records and radiographs from 34 patients were reviewed. Twenty-one patients had undergone closed reduction followed by percutaneous pinning (CRPP), while 13 had undergone mini-open reduction through the anterior approach with percutaneous pinning (mini-ORPP). The average age of the patients at the time of surgery was 5.4 (1-13) years in the CRPP group and 5.4 (2-9) years in the mini-ORPP group. The average age of the patients at the time of surgery was 5.4 (1-13) years in the CRPP group and 5.4 (2-9) years in the mini-ORPP group. Based on the Gartland classification system, the CRPP group included 12 type 2 and 9 type 3 fractures, while the mini-ORPP group included 4 type 2 and 9 type 3 fractures. The average postoperative follow-up duration was 8 (3-21) months in the CRPP group and 10 (3-10) months in the mini-ORPP group. The investigated parameters were postoperative complications, radiographic evaluation, and clinical evaluation, including range of motion (ROM) and Flynn's criteria. To evaluate the deformity of the humerus, Baumann's angle and the carrying angle (CA) were calculated on anteroposterior radiographs.Although no patient showed loss of reduction, deep infection, or neurovascular complications, 1 patient in the CRPP group had a cubitus varus deformity. The average CA loss in the injured elbow compared with the CA of the contralateral side was significantly larger in the CRPP group than the mini-ORPP group. In accordance with Flynn's criteria, the results in the CRPP group were excellent in 12 patients, good in 8, and poor in 1; the results in the mini-ORPP group were excellent in 12, and good in 1.To eliminate the possibility of postoperative cubitus varus deformity, the mini-ORPP is the optimal procedure for supracondylar fracture of the humerus in children. PMID- 30407347 TI - Association between the aspartic acid D-repeat polymorphisms and osteoarthritis susceptibility: An updated systematic review and meta-analyses. AB - OBJECTIVES: Association between the D-repeat of asporin (ASPN) gene and osteoarthritis (OA) was still inconsistent. We performed this meta-analysis to systematically assess the D-repeat polymorphisms in OA susceptibility. METHODS: Relevant studies were enrolled by searching databases. Odd ratios (ORs) with 95% confidence intervals (95% CIs) were used for evaluating the association between ASPN gene and OA. Heterogeneity was calculated using the Q statistic, and three different subgroup analyses were performed on ethnicity, gender, and OA positions respectively. False discovery rate (FDR) was applied to regulate the multiple comparisons. RESULTS: Twelve qualified articles involving 5190 OA patients and 5167 healthy controls were included. With D13 polymorphism, Caucasian male patients have low OA susceptibility (P = .008, PFDR = .024, OR [95% CI] = 0.83 [0.73-0.95]). As to D14 polymorphism, all male patients (P = .0004, PFDR = .001, OR [95% CI] = 1.38 [1.15-1.64]), Asian male patients (P = .01, PFDR = .01, OR [95% CI] = 1.72 [1.11-2.66]), and Caucasian male patients (P = .005, PFDR = .001, OR [95% CI] = 1.32 [1.09-1.60]) have high OA susceptibility. In the pooled population of KOA with D14 polymorphism, overall male patients (P = .03, PFDR = .045, OR [95% CI] = 1.35 [1.02-1.78]) and Asian male patients (P = .01, PFDR = .03, OR [95% CI] = 1.72 [1.11-2.66]) have high OA risk. With D16 polymorphism, Latin America patients may have high OA risk (P = .04, PFDR = .15, OR [95% CI] = 1.43 [1.02-2.01]). CONCLUSION: Our results suggest that D-repeat of ASPN gene is mainly associated with male patients. The D13 polymorphism plays a protective role for OA in Caucasians male individuals while D14 plays a risk factor for KOA in male patients. PMID- 30407349 TI - Lack of antiretroviral therapy is associated with higher risk of neurosyphilis among HIV-infected patients who remain serofast after therapy for early syphilis. AB - Resolution of clinical symptoms and at least 4-fold decline in nontreponemal antibody titers after treatment of syphilis is regarded as "proof of cure." However, a substantial proportion of patients demonstrates <4-fold reduction of titers after recommended therapy (serofast state). It remains unclear whether the serofast state is indicative of persistence of bacteria or only a residual immune response.The aim of the present study was to determine the association between the serofast state and the risk of neurosyphilis in human immunodeficiency virus (HIV)-infected individuals and to identify potential predictors of neurosyphilis.Thirty-three patients with early syphilis and HIV co-infection were included. One year after the recommended treatment of syphilis, all patients who did not achieve proper serologic response underwent lumbar puncture and cerebrospinal fluid (CSF) examination.Twelve months after completing therapy for syphilis, the proportion of patients with serofast state after syphilis therapy was 36.4% (n = 12). Among them, 5 (41.7%) had neurosyphilis. Individuals who remained serofast and had neurosyphilis (n = 5) when compared to those without neurosyphilis (n = 7) were characterized by significantly lower CD4+ cell count and higher HIV RNA levels (P < .05). Moreover, a significantly higher proportion of patients with neurosyphilis was not receiving antiretroviral therapy (ART). The nonreceipt of ART independently increased the risk of neurosyphilis in the analyzed group of serofast HIV-infected patients (odds ratio = 4.5; 95% confidence interval 1.5-13.59, P = .003).Patients co-infected with HIV require careful serologic and clinical follow-up after therapy for syphilis. In all of the patients who do not respond serologically after treatment for syphilis, especially in those who are not receiving ART, lumbar puncture and CSF examination should be considered. PMID- 30407348 TI - Role of preoperative endoscopic clipping in laparoscopic distal gastrectomy for early gastric cancer. AB - In this study, we evaluate the usefulness of preoperative endoscopic clipping for early gastric cancer (EGC) localization in laparoscopic distal gastrectomy.We retrospectively screened all consecutive patients who underwent laparoscopic distal gastrectomy for EGC by 1 surgeon at Chungnam National University Hospital between January 2014 and December 2016. Patients who underwent combined surgery and patients who had tumors at the lower third of the stomach were excluded. Endoscopic clipping was performed prior to surgery by specialized endoscopists. During the operation, endoscopic metal clips were found using surgical devices, and laparoscopic vessel clips were attached on the presumed site; thereafter, intraoperative radiographs were obtained for confirmation.We analyzed a total of 196 patients; of them, 101 were classified into the clipping group (CG) and 95 into the non clipping group (NCG). The 2 groups were comparable regarding their demographic characteristics. The CG showed less additional resection (2 of 101 patients [2.0%] vs 9 of 95 patients [9.4%], P = .021) and better outcomes in terms of the operation time (P = .000), duration of hospital stay (P = .036), and postoperative atelectasis (P = .001) than the NCG.Preoperative endoscopic clipping was helpful in determining the exact resection margin in laparoscopic distal gastrectomy for EGC. PMID- 30407350 TI - Nivolumab therapy for metastatic collecting duct carcinoma after nephrectomy: A case report. AB - RATIONALE: Collecting duct carcinoma (CDC) is a rare type of nonclear renal cell carcinoma, often presenting at an advanced stage of the disease, and standard treatment guidelines have not been established. PATIENT CONCERNS: A 73-year-old man was admitted to our hospital with complaints of fever and lower right back pain. DIAGNOSES: Computed tomography revealed a poorly defined tumor of the right kidney without metastasis. The patient underwent right radical nephrectomy and was diagnosed with clinical stage T1bN0M0 renal cancer; the pathological findings showed collecting duct carcinoma. INTERVENTIONS: After nephrectomy, multiple lung metastases were found in the following month, so first-line chemotherapy of gemcitabine (1000 mg/m on days 1 and 8, every 21 days) and cisplatin (70 mg/m on day 2, every 21 days) was administered. Due to disease progression, targeted therapy with axitinib (10 mg/body) and second-line chemotherapy of paclitaxel (200 mg/m on day 1, every 21 days) and carboplatin (area under the curve of 6 on day 1, every 21 days) were subsequently administered. However, the lung metastases progressed and new metastases spread to the right adrenal gland, liver, and lymph nodes. Based on the high expression of programmed death-ligand 1 in tumor cells, we treated the patient with the immune checkpoint inhibitor nivolumab. OUTCOMES: After 2 courses of treatment, he experienced a partial response and improved performance status, and thus was discharged from the hospital. To date, the patient is on his fifth course of treatment as an outpatient without disease progression. LESSONS: The findings of our study suggest that nivolumab may be effective even if the patient has highly progressive CDC with a low PS, if PD-L1 is highly expressed in the tumor cells. PMID- 30407351 TI - Clinical signs of retroperitoneal abscess from colonic perforation: Two case reports and literature review. AB - RATIONALE: Retroperitoneal colonic perforation is a rare cause of retroperitoneal abscess. It presents, more frequently in frail elderly patients, with heterogeneous signs and symptoms which hamper the clinical diagnosis. Subcutaneous emphysema with pneumomediastinum and iliopsoas muscle abscess are unusual signs. Colonic retroperitoneal perforation may be consequent to diverticulitis or locally advanced colon cancer. Due to the anatomy of the retroperitoneal space and different physiopathology, diverticular perforation may present with air and pus collection; on the other hand perforated colon cancer may cause groin mass and psoas abscess. We reported 2 cases of colonic retroperitoneal perforation from diverticulitis and locally advanced colon cancer, respectively. Aim of this report is to improve differential diagnosis based on clinical signs. PATIENTS' CONCERNS: A 71-year-old man presented with pain in his left side, fatigue, fever, nausea, massive subcutaneous emphysema of the neck, and Blumberg sign in the left iliac fossa. A 67-year-old man presented with abdominal pain, sub-occlusion, left groin mass, left groin, and lower limb pain during walking, negative Blumberg sign. DIAGNOSIS: In the first patient the computerized tomography revealed pneumoperitoneum, gas in the mesosigma, pneumomediastinum, wall thickening of the descending colon, and retroperitoneal collection from diverticular perforation. In the second patient abdominal CT scan found thickening of the sigmoid colon adherent to the iliopsoas and fluid collection. INTERVENTIONS: In the first patient, a left hemicolectomy extending to the transverse colon, followed by a toilette and debridement of the retroperitoneum were performed. In the second patient, tumor of descending colon perforated in the retroperitoneum with iliopsoas abscess was treated with left hemicolectomy and a drainage of the abscess. OUTCOMES: The first patient underwent right colectomy with ileostomy in the 7 postoperative day for large bowel necrosis. He died of sepsis 2 days after. The second patient had regular postoperative and he is still alive. LESSONS: The spread of retroperitoneal abscess in complicated colonic diverticulitis is different from that in advanced colonic cancer. The former can present with a subcutaneous emphysema, the latter with a groin mass. Hence a thorough clinical examination and radiological studies are needed to diagnose these conditions. PMID- 30407352 TI - Acupressure for insomnia: A protocol for systematic review and meta-analysis. AB - BACKGROUND: Insomnia is a public sleep disorder defined as a deficiency of sleep quantity or quality. Acupressure is a low-cost treatment that has potential as an insomnia therapy. METHODS: Four databases will be searched from inception to date. The researchers will screen clinical randomized trials of acupressure and auricular acupuncture for insomnia. The screening of the study, data extraction will be carried out independently by 2 researchers. The specific process will refer to the Cochrane Handbook for Systematic Review. RESULTS: The results of the study will be published in a scientific journal after peer-review. We integrate the latest study about acupressure for insomnia. CONCLUSION: This systematic review will provide evidence for assessing the improvement of acupressure for insomnia. ETHICS AND DISSEMINATION: The systematic review will be published in a peer-reviewed journal. The review will also be disseminated electronically and in print.PROSPERO registration: CRD42018104155. PMID- 30407353 TI - The association between body mass index and the risk of different gastrointestinal cancers: A protocol for an overview of systematic reviews. AB - BACKGROUND: Changes in our lifestyle over the past few decades have led to a significant increase in the worldwide prevalence of both overweight (defined as a body mass index [BMI]>=25 kg/m) and obesity (BMI>=30 kg/m), thus leading to numerous harmful consequences for an individual's health. Several meta-analyses support the link between obesity and different gastrointestinal cancers, but substantial heterogeneity exists between studies. We will synthesize published systematic reviews to evaluate the association between body mass index (BMI) and the incidence and mortality of different gastrointestinal cancers. METHODS: PubMed, EMBASE, and the Cochrane Library will be systematically searched for systematic reviews, meta-analyses, and pooled analyses in July, 2018. Two review authors will independently screen titles and abstracts for relevance, assess full texts for inclusion, carry out data extraction, and appraise methodological quality using AMSTAR checklist and reporting quality using PRISMA statement. The association between BMI and different gastrointestinal cancers will be estimated by computing the pooled relative risk (RR) and its 95% confidence interval (CI), which will be calculated from the adjusted RR, odds ratio, or hazard ratio, and 95% CI offered in the studies. Heterogeneity between studies will be assessed with the I statistic as a measure of the proportion of total variation in estimates that is due to heterogeneity, where I values of 25%, 50%, and 75% correspond to cut-off points for low, moderate, and high degrees of heterogeneity. The random effects model will be used as the pooling method when significant heterogeneity existed and the fixed effect model will be used when no heterogeneity was observed. Possible publication bias will be tested by Begg and Egger test. DISCUSSION: This overview of systematic reviews will provide an accessible, comprehensive synthesis with which to inform clinicians and the development of guidelines for the management of the individuals with high BMI. ETHICS AND DISSEMINATION: Only published secondary data will be used in this study, and therefore ethics approval is not required.PROSPERO registration number: CRD42018107334. PMID- 30407354 TI - Effects of Shuganjianpihuatanxingqi decoction on mild subclinical hypothyroidism: A SPIRIT compliant randomized controlled trial study protocol. AB - INTRODUCTION: Mild subclinical hypothyroidism (SCH) can cause depression, fatigue, cognitive dysfunction, or other hypothyroid symptoms, and even progress to hypothyroidism. The treatment of mild SCH is controversial. Shuganjianpihuatanxingqi decoction (SD) is a frequently prescribed Chinese herbal medicine in patients with mild SCH. However, scientific evidence is needed to confirm the therapeutic effect of SD. METHODS AND ANALYSIS: This study is a randomized, double-blind, and controlled clinical trial. A total of 228 participants with the diagnosis of mild SCH will be randomly assigned to the SD or placebo group in a ratio of 1:1. Participants will receive treatment for 12 weeks and undergo 12-month follow-up. The primary outcome measure is the thyroid stimulating hormone level, and secondary outcomes will be the differences in the results of Thyroid-related Quality of Life Questionnaire, blood lipids, and Traditional Chinese Medicine Symptom Score Scale between baseline and at 12 weeks after intervention. ETHICS AND DISSEMINATION: The study has been approved by Guang'anmen Hospital of China Academy of Chinese Medical Sciences (no.2018-005-ky 01). The trial results will be published via peer-reviewed journals and the Clinical Research Information Service. TRIAL REGISTRATION NUMBER: ChiCTR1800015781 (approval date: 20 April 2018). PMID- 30407355 TI - A case report of metastatic breast cancer initially presenting with esophageal dysphagia. AB - RATIONALE: Breast cancer metastasis to the esophagus is uncommon. To our knowledge, the present case is the first report of breast cancer with dysphagia as the initial symptom. PATIENT CONCERNS: A 62-year-old woman was admitted to our hospital for progressive dysphagia. DIAGNOSES: Endoscopic ultrasound-guided fine needle biopsy of the esophageal lesion found poorly differentiated carcinoma, and surgical resection of the breast nodule revealed invasive ductal carcinoma. INTERVENTIONS: The patient underwent an esophagectomy, and the immunohistochemistry of surgical specimen was identified as metastatic breast cancer. Then patient was treated with chemotherapy and hormone therapy. OUTCOMES: The patient remained symptom-free during 5 months of follow-up examinations. LESSONS: This case indicates that metastatic breast cancer to the esophagus should be considered as a cause of esophageal stricture in older women. PMID- 30407356 TI - Two case reports of neonatal autoantibody-associated congenital heart block. AB - RATIONALE: Neonatal lupus erythematosus (NLE) is an infrequent disease caused by transplacental maternal autoantibodies. The most common effects of NLE include cutaneous involvement and congenital heart block (CHB), although it might involve multiple organs, such as the liver, lungs, blood, and nervous or digestive systems. Izmirly PM1 and Tonello et al recently reported cutaneous manifestations of neonatal lupus and risk of subsequent CHB. The most serious complication of NLE is complete atrioventricular (AV) block. PATIENT CONCERNS: We experienced 2 cases of NLE that were diagnosed in the past year in our Neonatal Intensive Care Unit. These cases showed 2 different clinical spectrums (CHB, multisystemic effects). One case was a 32-week pregnant woman with combined liver damage and fever, and her fetus was premature due to bradycardia and pericardial effusion. The second case was a young pregnant woman who had systemic lupus erythematosus for 2 years and had been taking methylprednisolone and hydroxychloroquine for a long time since her illness. When prenatal testing at 28 weeks of pregnancy showed that the fetus had CHB, the mother began taking dexamethasone. DIAGNOSIS: The first case was diagnosed as NLE with CHB after birth, while the second was diagnosed as NLE with CHB, ductus arteriosus, and atrial septal defect when she was born at 34 weeks. INTERVENTIONS: Both of 2 cases were treated with steroids, intravenous immunoglobulin, and a diuretic. But the second case was treated with isoprenaline in addition to the above. OUTCOMES: Both of the infants was followed up and found to be clinically normal. During the clinic follow-up of the first case, the 8-month-old infant was still asymptomatic with normal growth and development. Her heart rate fluctuated from 40 to 90 beats/minute. LESSONS: Autoimmune CHB is a severe, potentially life-threatening disorder associated with passive transfer of maternal anti-Sjogren's syndrome A/Ro and anti-Sjogren's syndrome B/La autoantibodies. Mothers who are positive for these autoantibodies are recommended to have serial echocardiography and obstetric ultrasonography from the early second trimester. Newborns should be delivered at an early stage of gestation if there is evidence of pericardial effusion, ascites, increasing ventricular ectopy, reduced ventricular shortening fraction, or AV valve regurgitation. Aggressive medical management after birth should be coupled with pacemaker implantation in infants who do not respond to medical therapies alone. PMID- 30407357 TI - Massive idiopathic spontaneous hemothorax complicating anti-N-methyl-d-aspartate receptor encephalitis: A case report. AB - RATIONALE: Spontaneous hemothorax is a subcategory of hemothorax which can be life threatening. The etiology of spontaneous hemothorax can be various, and in some rare cases the causes remained unknown. Hence, it is quite difficult to establish the diagnosis. Here, we report a case of spontaneous hemothorax in a young female patient who was recently diagnosed with anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDAR encephalitis). PATIENT CONCERNS: A 20-year-old female was transferred to emergency department of our hospital from local hospital presented with insomnia, mood lability, tonic-clonic seizure, and decreased level of consciousness. DIAGNOSES: The diagnosis of anti-NMDAR encephalitis was established by detection of cerebrospinal fluid (CSF) and serum antibodies to the NMDA receptor. During the hospital stay, the patient developed massive spontaneous hemothorax and was confirmed by closed-tube thoracostomy. INTERVENTIONS AND OUTCOMES: Video-assisted thoracotomy was performed to evacuate the blood clots and also to obtain pleural biopsy specimen for diagnostic evaluation. However, the reason of hemothorax remained idiopathic. The postoperative status of this patient was uneventful, and she was discharged on postoperative day 45 as her mental status improved markedly. LESSONS: In this case, the patient had both anti- NMDAR encephalitis and autoimmune thyroid disease. Based on it, we suspected that the patient subjected to severe autoimmune response and inflammatory reaction, which might explain the pathologic changes of parietal pleura and visceral pleura. We recommend the suspicion of spontaneous hemothorax should be considered when the patients with autoimmune diseases present with hemorrhage-related signs or symptoms. PMID- 30407358 TI - Retrospective analysis of 52 patients with prolactinomas following endoscopic endonasal transsphenoidal surgery. AB - BACKGROUND: Prolactinomas affect patients' quality of life and even endanger lives. The study aimed to investigate the effect of the endoscopic endonasal transsphenoidal approach (EETA) on 52 patients with prolactinomas. METHODS: A total of 52 patients with prolactinomas who had previously undergone EETA in the People's Hospital of Xinjiang Uygur Autonomous Region between January 2013 and December 2017 were retrospectively analyzed. Factors affecting the extent of resection and postoperative remission rates were also investigated. RESULTS: All the patients were pathologically diagnosed with prolactinomas. Compared with giant adenomas, the total removal rate of microadenomas and macroadenomas was significantly increased (P < .05). In addition, the total removal rate of patients with noninvasive prolactin adenomas was significantly higher than patients with invasive prolactinadenomas (P < .05). Furthermore, there were no significant differences in postoperative remission rates among patients with prolactin adenomas from different ethnic groups (P > .05). Also preoperative administration of bromocriptine and preoperative prolactin (PRL) levels did not significantly affect therapeutic outcomes postsurgery (P > .05). Postoperative menstruation was improved or normalized in 20 (38.5%) female patients, vision was improved or normalized in 15 (28.8%) patients, and headaches were improved or normalized in 22 (42.3%) patients. Sexual function was improved in 2 male patients following surgery. A total of 6 patients exhibited a recurrence following surgery. A number of patients suffered from postoperative complications, including transient diabetes insipidus in 5 (9.6%) patients and postoperative transient cerebrospinal fluid leakage in 2 (3.8%) patients. CONCLUSION: The results of this study demonstrated that tumor size, preoperative PRL levels, and invasion of adenomas represent independent factors that can affect the success of surgery. The results suggested that EETA represents a therapeutic strategy for the treatment of patients with prolactinoma with high remission rates and low complication rates. Therefore, EETA should be considered a primary treatment for patients with prolactinomas who are not responsive to treatment with medical therapy. PMID- 30407359 TI - Human papillomavirus prevalence and behavioral risk factors among HIV-infected and HIV-uninfected men who have sex with men in Taiwan. AB - Human papillomavirus (HPV) infection is associated with cancer and can be prevented through vaccination. Few studies from Taiwan have reported on HPV infection among human immunodeficiency virus (HIV)-infected subjects. The aim of this study was to examine the prevalence of HPV infection among men who have sex with men (MSM) with and without HIV infection in Taiwan, and explore the behavioral risk factors thereof.We conducted a cross-sectional study in Taiwan during 2013 to 2016 to collect data on MSM aged 20 years or older. We used a questionnaire in a face-to-face interview, and subsequently collected oral, anal, and genital specimens from HIV-infected and HIV-uninfected subjects. Multivariate analysis was performed to predict factors associated with high-risk HPV (HR-HPV) positivity.Overall, 279 subjects, including 166 (59.5%) HIV-uninfected and 113 (40.5%) HIV-infected men were enrolled. Compared to HPV-negative subjects, HPV positive subjects had significantly higher rates of receptive anal sex (91.3% vs 75.6%), substance use (22.6% vs 11%), history of sexually transmitted infections (75.7% vs 38.4%), anogenital or oral warts (39.1% vs 6.72%), syphilis (32.2% vs 11.6%), and HIV infection (69.6% vs 20.1%). We detected 489 HPV deoxyribonucleic acid (DNA) types (through 379 viable specimens), of which 43.6%, 5.7%, 56.4%, and 10.4% were HR-HPV type, HPV type 16, low-risk HPV types, and HPV type 6, respectively. In multivariate analysis, HIV-infected subjects had a significantly higher prevalence of HR-HPV infection (adjusted odds ratio, 5.80; 95% confidence interval, 2.57-13.11), compared to HIV-uninfected subjects.These results suggest that the prevalence of HPV infection was high among HIV-infected MSM. Additionally, anal HPV infection was observed to be common among both HIV infected and HIV-uninfected MSM in Taiwan. The prevalence of oral and genital HPV infection, HR-HPV DNA types, and multiple HPV types was higher in HIV-infected subjects than in HIV-uninfected subjects. As only 35% of subjects practiced safe sex, we recommend routine HPV vaccination with 4-valent HPV or 9-valent HPV vaccines for both MSM, and HIV-infected subjects. PMID- 30407361 TI - Different weight shift trainings can improve the balance performance of patients with a chronic stroke: A randomized controlled trial. AB - BACKGROUND: Improving balance ability, increasing walking ability, and reducing the occurrence of falls are important objectives in the rehabilitation of stroke patients. Do the posture balance training and the intervention of lateral wedge insoles to improve of balance function and increase walking ability in patients with a chronic stroke? METHODS: A randomized, controlled trial with concealed allocation, intention-to-treat analysis, and blinded assessors. Participants who had a chronic stroke (onset >6 months) were recruited from the rehabilitation and neurology departments of a hospital in central Taiwan. Subjects were divided into 3 groups: a visual biofeedback balance training group, a lateral wedge group, and a control group; apart from their usual rehabilitation program, and both experimental groups received a 6-week training session program. The primary outcome was the balance computerized adaptive test (balance CAT), and secondary outcome was timed up and go (TUG) test. All subjects were evaluated at the baseline, posttraining (6-week), 1st follow-up (10-week), and 2nd follow-up (18 week). RESULTS: A total of 56 subjects were participated in this study, including 38 males and 18 females. The mean age of the subjects was 59.1 years old, and the mean time was 43.7 months after the onset of the stroke. This study found the interaction in groups and measurement time points reached statistical significance of the balance CAT and TUG test (F = 5.740, P < .001; F = 2.926, P = .011; respectively). In addition, the performance of both the visual biofeedback training and lateral wedge group was superior to that of the control group. CONCLUSION: Six-week visual biofeedback training and intervention of 5 degrees lateral wedge insoles can improve the balance ability of patients with a chronic stroke. TRIAL REGISTRY: http://www.chictr.org.cn, ChiCTR-IPR-15007092. PMID- 30407360 TI - Analysis of cervical human papillomavirus infection in 2300 women in Urumqi, China. AB - This study is to investigate the cervical human papillomavirus (HPV) infection rate in women of Urumqi, China.The epidemiological questionnaire survey was used to study 2300 women in Urumqi with a prospective research method. The second generation hybrid capture assay, cervical liquid-based cytology test, colposcopy, and cervical biopsy were used to screen CC.In 2300 cases, HPV was detected in 385 cases with infection rate of 16.74%. The infection rates of Uygur and Han women were 20.08% and 13.39%, respectively, with significant differences (P <.05). Among all age groups, the infection rate was highest in the age group of 20 to 25 years (with infection rate of 22.22%), followed by the age group of 45 to 49 years (with infection rate of 18.78%). In 8 districts, the highest positive rate was in Saybagh District with infection rate of 24.79%, followed by Urumqi County with infection rate of 19.05%, and the lowest was in Toutunhe District with infection rate of 10.86%. There was no significant difference in HPV infection among all age groups or among 8 districts of Urumqi. HPV infection rates were 10.48%, 84.52%, 92.94%, 100% in chronic cervicitis, low grade and high-grade intraepithelial neoplasia and CC group, respectively. The difference was statistically significant (P <.05).The HPV infection rate of Uygur is higher than that in Han ethnic in Urumqi. The infection rate of HPV increases with the severity of cervical lesions. PMID- 30407362 TI - Coronary artery aneurysm formation after drug-coated balloon treatment of de novo lesions: Two case reports. AB - RATIONALE: The safety and efficacy of drug-coated balloon (DCB) technology have primarily been proven in the treatment of coronary in-stent restenosis. Whereas increasing evidences show that DCB use was feasible in certain de novo coronary lesions. In 2012, Vassilev reported the 1st case in which a coronary aneurysm formed after a DCB was used to treat drug-eluting stent (DES) restenosis. To date, limited information has been reported on coronary artery aneurysm (CAA) development following DCB treatment of de novo lesions. PATIENT CONCERNS: A 42 year-old male underwent delayed coronary angiography due to extensive anterior wall myocardial infarction. After balloon predilation in the mid-left anterior descending (LAD) artery, the residual 30% stenosis without major dissection was treated with a DCB. Angiographic follow-up at 6 and 12 months revealed an aneurysm in the treated area of the LAD artery, with positive vascular remodeling behind this aneurysm. A 54-year-old male with nonstent thrombosis elevation myocardial infarction underwent elective catheterization. Coronary angiography revealed critical stenosis in the LAD and significant narrowing at the distal segments of both the left circumflex artery (LCX) and the nondominant right coronary artery. After predilation of the lesion in the LCX, the residual 30% stenosis was treated with a DCB. The lesion in the LAD was treated with a DCB either. Angiography follow-up at 6 months revealed good results in the LAD; however, an aneurysm was observed in the DCB-treated area of the LCX. DIAGNOSIS: The CAA formation after DCB treatment of de novo lesions. INTERVENTIONS AND OUTCOMES: Because the 2 patients were asymptomatic upon diagnosis, the aneurysms were left untreated. Long-term dual antiplatelet therapy and intense follow-up were recommended. LESSONS: Our cases raise questions regarding the safety of DCB treatment for de novo lesions in real-world contexts. There might be a need to clarify the appropriate doses for drugs coated on DCBs. Although indications for DCB treatment for de novo coronary lesions should not be overly aggressively broadened, the potential role of such treatment in this context merits additional elucidation in future studies. PMID- 30407363 TI - An evidence-based approach to assess the accuracy of intravoxel incoherent motion imaging for the grading of brain tumors. AB - BACKGROUND: Differentiation of high-grade gliomas (HGGs) and low-grade gliomas (LGGs) is an important clinical problem because treatment strategies vary greatly. This study was performed to investigate the potential diagnostic value of incoherent intravoxel motion imaging (IVIM) to distinguish HGG from LGG by meta-analysis. METHODS: A computerized search of the literature was performed using the free-access PubMed database, Web of Science, and Chinese biomedical database, and relevant articles until September 18, 2018 that used IVIM to distinguish HGG from LGG were included. All analyses were performed using Review Manager 5.3 and Stata. Mean difference (MD) at 95% confidence interval (CI) of the apparent diffusion coefficient (ADC), diffusion coefficient value (D), perfusion fraction value (f), and perfusion coefficient value (D*) were summarized. RESULTS: Nine studies were used for general data pooling. In the tumor parenchyma (TP) regions, subgroup analysis revealed D* in HGG is higher than in LGG (MD = 1.19, P = .002), and D in HGG is lower than in LGG (MD = -1.06, P = .001). However, no significant difference in f (MD = 0.89, P = .056) was detected between HGG and LGG. In the white matter regions, HGG had higher D* (MD = 0.76, P = .04) compared with LGG, while no marked differences between the D value (P = .07) and f (P = .09) values. CONCLUSION: The present meta-analysis shows that the ADC, D, and D* values derived from IVIM may be useful in differentiating HGG from LGG. Considering the small sample of this study, we need to be cautious when interpreting the results of this study. Other prospective and large-sample randomized controlled trials were needed to establish the value of IVIM in differentiating HGG from LGG. PMID- 30407364 TI - Vaginal delivery in a pregnant woman with cord prolapse, velamentous cord insertion, and fetal vertex presentation: A case report. AB - RATIONALE: We report a rare case of a pregnant woman with cord prolapse, velamentous cord insertion (VCI), and fetal vertex presentation who completed vaginal delivery. PATIENT CONCERNS: Without having undergone regular antepartum examinations, a 31-year-old pregnant woman, gravida 6, para 4, abortion 1, presented at 37 weeks and 3 days of gestation. She had regular labor pain and bloody show. DIAGNOSES: Cord prolapse during labor and VCI after delivery. INTERVENTIONS: Per vaginal examination at 11:20 PM revealed a fully dilated cervix. Thirty minutes later, artificial rupture of the membrane was performed, and an overt prolapsed cord approximately 10-cm long was palpated in the vagina. Fetal heartbeat decelerated to 60 bpm. After fundal pushing for some minutes, a female baby weighing 2130 g was delivered at 11:54 PM with a pediatrician on standby. Apgar scores were 7 (0 minute), 9 (5 minutes), and 10 (10 minutes). The placenta weighed 870 g and was delivered 5 minutes later, and VCI was discovered. OUTCOMES: Her postpartum course was uncomplicated and both the patient and infant were discharged 3 days later. LESSONS: A pregnant woman with umbilical prolapse, VCI, and a fetal vertex presentation can successfully deliver a baby through the vagina. Factors contributing to the success of the reported vaginal delivery might have been a small fetus, multipara status, and immediate management. PMID- 30407365 TI - Okbyungpoongsan (Yupingfeng) for treating allergic rhinitis: A protocol for the systematic review of controlled trials. AB - BACKGROUND: Okbyungpoongsan (OBPS) is widely used as a treatment for allergic rhinitis (AR) in Far East countries. Many clinical trials have assessed the efficacy and safety of the OBPS formula for treating AR. Here, we systematically will review the clinical evidence for and against administration of OBPS. METHODS AND ANALYSIS: All RCTs of decoctions or modified decoctions will be included. The methodological quality of the RCTs will be analyzed using the Cochrane Collaboration tool for assessing risk of bias, while confidence in the cumulative evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) instrument. ETHICS AND DISSEMINATION: This systematic review will be published in a peer-reviewed journal and will also be disseminated electronically and in print. The review will be updated to provide additional information and guide healthcare practices.Registration number: CRD42017080292. PMID- 30407369 TI - Effect of Coagulation Factor Concentrates on Markers of Endothelial Cell Damage in Experimental Hemorrhagic Shock. AB - BACKGROUND: Plasma-based resuscitation showed protective effects on the endothelial glycocalyx compared to crystalloid resuscitation. There is paucity of data regarding the effect of coagulation factor concentrates (CFC) on the glycocalyx in hemorrhagic shock (HS). We hypothesized that colloid-based resuscitation supplemented with CFCs offers a therapeutic value to treat endothelial damage following HS. METHODS: Eighty-four rats were subjected to pressure controlled (mean arterial pressure (MAP) 30-35 mmHg) and lab guided (targeted cutoff: lactate >2.2. mmol/l and base deficit > 5.5 mmol/l) HS. Animals were resuscitated with fresh frozen plasma (FFP), Human albumin (HA) or Ringer's lactate (RL) and RL or HA supplemented with fibrinogen concentrate (FC) or prothrombin complex concentrate (PCC). Serum epinephrine and the following markers of endothelial damage were assessed at baseline and at the end-of observation (120 minutes after shock was terminated): syndecan-1, heparan sulfate, and soluble vascular endothelial growth factor receptor 1 (sVEGFR 1). RESULTS: Resuscitation with FFP had no effect on sVEGFR1 compared to crystalloid based resuscitation (FFP: 19.3 ng/ml vs. RL: 15.9 ng/ml; RL+FC: 19.7 ng/ml; RL+PCC: 18.9 ng/ml; n.s.). At the end-of-observation, syndecan-1 was similar among all groups. Interestingly, HA+FC treated animals displayed the highest syndecan-1 concentration (12.07 ng/ml). Resuscitation with FFP restored heparan sulfate back to baseline (baseline: 36 ng/ml vs. end-of-observation: 36 ng/ml). CONCLUSION: The current study revealed that plasma-based resuscitation normalized circulating heparan sulfate but not syndecan-1. Co-administration of CFC had no further effect on glycocalyx shedding suggesting a lack of its therapeutic potential. LEVEL OF EVIDENCE: VExperimental in vivo study. PMID- 30407370 TI - Plasma Renin Concentration is Associated with Hemodynamic Deficiency and Adverse Renal Outcome in Septic Shock. AB - BACKGROUND: In septic shock, both systemic vasodilatation and glomerular arteriole dilatation are responsible for the drop in glomerular filtration observed in early acute kidney injury. Angiotensin II has been showed to act on both mechanisms. Our objective was to evaluate the impact of renin angiotensin system activation, on hemodynamic deficiency and renal outcome in patient with septic shock and to assess whether urinary sodium could be a reliable test for high plasma renin concentration screening. METHODS: This was a prospective and observational study. Inclusion criteria were 1) early septic shock (first episode) 2) dose of norepinephrine >= 0.25 MUg/kg/min 3) before the start of substitutive corticosteroids. Plasma renin concentration, plasma aldosterone concentration and urinary sodium were measured at inclusion. Renal outcome, organ deficiency and 28-day survival were followed. RESULTS: Plasma renin concentration was associated with worse hemodynamic deficiency and adverse renal outcome. Natriuresis was associated with shock severity but was not associated with renal outcome. Low natriuresis (< 20 mM) was associated with higher renin concentration. Those 2 variables were only weakly correlated. CONCLUSIONS: Plasma renin concentration is associated with adverse renal outcome, probably through shock severity and insufficient glomerular efferent arterioles vasoconstriction. An association was observed between low natriuresis and high plasma renin concentration. PMID- 30407366 TI - Research Methodologies for Total Worker Health(r): Proceedings From a Workshop. AB - OBJECTIVE: There is growing interest in the NIOSH Total Worker Health program, specifically in the process of designing and implementing safer, health-promoting work and workplaces. A Total Worker Health (TWH) Research Methodology Workshop was convened to discuss research methods and future needs. METHODS: Twenty-six experts in occupational safety and health and related fields reviewed and discussed current methodological and measurement issues and those showing promise. RESULTS: TWH intervention studies face the same challenges as other workplace intervention studies and some unique ones. Examples are provided of different approaches and their applications to TWH intervention studies, and desired developments in the TWH literature. CONCLUSIONS: This report discusses and outlines principles important to building the TWH intervention research base. Rigorous, valid methodologic, and measurement approaches are needed for TWH intervention as well as for basic/etiologic, translational, and surveillance research. PMID- 30407371 TI - The Effect of Nutrition on Early Stress-Induced Hyperglycemia, Serum Insulin Levels, and Exogenous Insulin Administration in Critically Ill Patients with Septic Shock: A Prospective Observational Study. AB - BACKGROUND: Stress-induced hyperglycemia is common among septic shock patients. Nutritional support influences glucose homeostasis but this effect has never been studied in septic shock. We aimed to determine the course of hyperglycemia and serum insulin levels in critically ill septic shock patients and to address the effects of caloric intake on glycemia, insulin levels, and exogenous insulin requirements. METHODS: A prospective observational study of 24 ventilated septic shock patients for 72 hours. Every four hours nutritional variables, exogenous insulin administration, serum insulin, and glucose levels were recorded. RESULTS: Stress-induced hyperglycemia was found in 96.2% of patients. Exogenous insulin requirements increased gradually and were most pronounced at 36 hours (mean 4.64 IU/hr). Total serum insulin levels where lowest at the point of most exogenous insulin requirements (mean 2.75 mIU/L). Total caloric intake and insulin requirements were positively associated (Pearson correlation coefficient 0.210). CONCLUSIONS: In patients with septic shock marked reduced serum insulin levels can be observed during the first 36 hours after ICU admission that have to be compensated by exogenous insulin administration, a phenomenon gradually improving after 36 hours. Feeding is positively associated with exogenous insulin requirements. These results suggest that strategies to manage stress-induced hyperglycemia in patients with septic shock should consider frequent glycemic monitoring, conservative insulin dosing to prevent hypoglycemia when insulin resistance disappears, and slow progressive nutrition support during the early ICU phase as caloric loading may worsen hyperglycemia. This approach may attenuate the risk of glucose variability, hypo- and hyperglycemia and associated poor outcomes. PMID- 30407372 TI - MIR-190B Alleviates Cell Autophagy and Burn-Induced Skeletal Muscle Wasting via Modulating PHLPP1/AKT/FOXO3A Signaling Pathway. AB - INTRODUCTION: Cell autophagy is an important material recycling process and is involved in regulating many vital activities under both physiological and pathological conditions. However, the mechanism of autophagy regulating burn induced skeletal muscle wasting still needs to be elucidated. METHODS: The rat burn model with 30% total body surface area and L6 cell line were used in this study. An immunofluorescence assay was used to detect autophagic levels. miRNA array and real-time PCR were employed to measure miR-190b levels, and its influence on PHLPP1 protein translation was estimated using luciferase reporter assay. The expression levels of autophagy-related proteins were analysed by Western blot. Skeletal muscle wasting was evaluated by the ratio of tibias anterior muscle weight to body weight. RESULTS: Our study demonstrates that burn injury promotes expression of the autophagy-related proteins LC3 and Beclin-1, suppresses expression of Akt and FoxO3a protein phosphorylation, and increases PHLPP1 protein level which is required for Akt dephosphorylation. miR-190b, the regulator of PHLPP1 protein translation, also significantly decreases after burn injury. Ectopic expression of miR-190b in L6 myoblast cell down-regulates PHLPP1 protein expression, elevates Akt and FoxO3a phosphorylation, and subsequently reduces cell autophagy. Finally, suppressing autophagy with 3-MA represses the protein expression of LC3 and Beclin-1 and mitigates burn-induced skeletal muscle wasting. CONCLUSION: Burn injury induced skeletal muscle cell autophagy and subsequently resulted in skeletal muscle wasting via regulating miR 190b/PHLPP1/Akt/FoxO3a signaling pathway. PMID- 30407373 TI - Cardiac Effects of Hyperoxia During Resuscitation from Hemorrhagic Shock in Swine. AB - Hyperoxia (ventilation with FIO2 = 1.0) has vasoconstrictor properties, in particular in the coronary vascular bed, and, hence, may promote cardiac dysfunction. However, we previously showed that hyperoxia attenuated myocardial injury during resuscitation from hemorrhage in swine with coronary artery disease. Therefore, we tested the hypothesis whether hyperoxia would also mitigate myocardial injury and improve heart function in the absence of chronic cardiovascular co-morbidity.After 3 hours of hemorrhage (removal of 30% of the calculated blood volume and subsequent titration of mean arterial pressure to 40mmHg) 19 anesthetized, mechanically ventilated and instrumented pigs received FIO2 = 0.3(control) or hyperoxia(FIO2 = 1.0) during the first 24 hours. Before, at the end of and every 12 hours after shock, hemodynamics, blood gases, metabolism, cytokines and cardiac function (pulmonary artery thermodilution, left ventricular pressure-conductance catheterization) were recorded. At 48 hours, cardiac tissue was harvested for western blotting, immunohistochemistry and mitochondrial respiration.Except for higher left ventricular end-diastolic pressures at 24 hours (hyperoxia 21(17;24),control 17(15;18)mmHg;p = 0.046), hyperoxia affected neither left ventricular function cardiac injury (max. Troponin I at 12 hours: hyperoxia:9(6;23),control:17(11;24)ng mL;p = 0.395), nor plasma cytokines (except for interleukin-1beta: hyperoxia 10(10;10) and 10(10;10)/control 14(10;22), 12(10;15)pg mL, p = 0.023 and 0.021 at 12 and 24 hours, respectively), oxidation and nitrosative stress, and mitochondrial respiration. However, hyperoxia decreased cardiac tissue 3-nitrotyrosine formation (p < 0.001) and inducible nitric oxide synthase expression (p = 0.016). Ultimately, survival did not differ significantly either.In conclusion, in contrast to our previous study in swine with coronary artery disease, hyperoxia did not beneficially affect cardiac function or tissue injury in healthy swine, but was devoid of deleterious side effects. PMID- 30407375 TI - Towards Independent Control of Multiple Magnetic Mobile Microrobots. AB - In this paper, we have developed an approach for independent autonomous navigation of multiple microrobots under the influence of magnetic fields and validated it experimentally. We first developed a heuristics based planning algorithm for generating collision-free trajectories for the microrobots that are suitable to be executed by an available magnetic field. Second, we have modeled the dynamics of the microrobots to develop a controller for determining the forces that need to be generated for the navigation of the robots along the trajectories at a suitable control frequency. Next, an optimization routine is developed to determine the input currents to the electromagnetic coils that can generate the required forces for the navigation of the robots at the controller frequency. We then validated our approach by simulating an electromagnetic system that contains an array of sixty-four magnetic microcoils designed for generating local magnetic fields suitable for simultaneous independent actuation of multiple microrobots. Finally, we prototyped an m m -scale version of the system and present experimental results showing the validity of our approach. PMID- 30407374 TI - Miniature Microwave Notch Filters and Comparators Based on Transmission Lines Loaded with Stepped Impedance Resonators (SIRs). AB - In this paper, different configurations of transmission lines loaded with stepped impedance resonators (SIRs) are reviewed. This includes microstrip lines loaded with pairs of SIRs, and coplanar waveguides (CPW) loaded with multi-section SIRs. Due to the high electric coupling between the line and the resonant elements, the structures are electrically small, i.e., dimensions are small as compared to the wavelength at the fundamental resonance. The circuit models describing these structures are discussed and validated, and the potential applications as notch filters and comparators are highlighted. PMID- 30407376 TI - Particulate Blood Analogues Reproducing the Erythrocytes Cell-Free Layer in a Microfluidic Device Containing a Hyperbolic Contraction. AB - The interest in the development of blood analogues has been increasing recently as a consequence of the increment in the number of experimental hemodynamic studies and the difficulties associated with the manipulation of real blood in vitro because of ethical, economical or hazardous issues. Although one-phase Newtonian and non-Newtonian blood analogues can be found in the literature, there are very few studies related to the use of particulate solutions in which the particles mimic the behaviour of the red blood cells (RBCs) or erythrocytes. One of the most relevant effects related with the behaviour of the erythrocytes is a cell free layer (CFL) formation, which consists in the migration of the RBCs towards the center of the vessel forming a cell depleted plasma region near the vessel walls, which is known to happen in in vitro microcirculatory environments. Recent studies have shown that the CFL enhancement is possible with an insertion of contraction and expansion region in a straight microchannel. These effects are useful for cell manipulation or sorting in lab-on-chip studies. In this experimental study we present particulate Newtonian and non-Newtonian solutions which resulted in a rheological blood analogue able to form a CFL, downstream of a microfluidic hyperbolic contraction, in a similar way of the one formed by healthy RBCs. PMID- 30407377 TI - Design and Performance of a Focus-Detection System for Use in Laser Micromachining. AB - We describe a new approach for locating the focal position in laser micromachining. This approach is based on a feedback system that uses a charge coupled device (CCD) camera, a beam splitter, and a mirror to focus a laser beam on the surface of a work piece. We tested the proposed method for locating the focal position by using Zemax simulations, as well as physically carrying out drilling processes. Compared with conventional methods, this approach is advantageous because: the implementation is simple, the specimen can easily be positioned at the focal position, and the dynamically adjustable scan amplitude and the CCD camera can be used to monitor the laser beam's profile. The proposed technique will be particularly useful for locating the focal position on any surface in laser micromachining. PMID- 30407378 TI - Easily Fabricated Microfluidic Devices Using Permanent Marker Inks for Enzyme Assays. AB - In this communication, we describe microfluidic paper analytical devices (MUPADs) easily fabricated from commercially available Sharpie ink permanent markers on chromatography paper to colorimetrically detect glucose using glucose oxidase (GOx). Here, solutions of horseradish peroxidase (HRP), GOx, and potassium iodide (KI)were directly spotted onto the center of the MUPAD and flowed into samples of glucose that were separately spotted on the MUPAD. Using an XY plotter (Roland DGA Corporation, Irvine, CA USA), several ink marks drawn in the paper act as the hydrophobic barriers, thereby, defining the hydrophilic fluid flow paths of the solutions. Two paper devices are described that act as independent assay zones. The glucose assay is based on the enzymatic oxidation of iodide to iodine whereby a color change from clear to brownish-yellow is associated with the presence of glucose. In these experiments, two designs are highlighted that consist of circular paper test regions fabricated for colorimetric and subsequent quantification detection of glucose. The use of permanent markers for paper patterning is inexpensive and rapid and does not require special laboratory equipment or technical skill. PMID- 30407379 TI - Study on Improving Thickness Uniformity of Microfluidic Chip Mold in the Electroforming Process. AB - Electroformed microfluidic chip mold faces the problem of uneven thickness, which decreases the dimensional accuracy of the mold, and increases the production cost. To fabricate a mold with uniform thickness, two methods are investigated. Firstly, experiments are carried out to study how the ultrasonic agitation affects the thickness uniformity of the mold. It is found that the thickness uniformity is maximally improved by about 30% after 2 h electroforming under 200 kHz and 500 W ultrasonic agitation. Secondly, adding a second cathode, a method suitable for long-time electroforming is studied by numerical simulation. The simulation results show that with a 4 mm width second cathode used, the thickness uniformity is improved by about 30% after 2 h of electroforming, and that with electroforming time extended, the thickness uniformity is improved more obviously. After 22 h electroforming, the thickness uniformity is increased by about 45%. Finally, by comparing two methods, the method of adding a second cathode is chosen, and a microfluidic chip mold is made with the help of a specially designed second cathode. The result shows that the thickness uniformity of the mold is increased by about 50%, which is in good agreement with the simulation results. PMID- 30407380 TI - Single-Capacitor Electret Impact Microgenerator. AB - A new type of electrostatic microgenerator is presented that converts mechanical microvibrational energy into electric energy. The energy conversion mechanism is as follows. External microvibrations are transmitted to the device frame. The thin electret layer sputtered to the silicon substrate surface was fixed on the frame and the moving electrode was fixed by a weak suspension and comes into contact with the electret surface under the action of vibrations. A two-stage impact process is described: coming into contact with the spring stop that models the undulation of the contact surfaces, and direct impact on the electret surface. A numerical modeling of the generator operation is performed and analytic estimates of the generated power are obtained. It is shown that the energy generated by this motor is significantly higher than the energy generated by the classical mechanism based on the excitation of the forced vibrations of the moving plate. Experimental measurements of the microgenerator prototype parameters confirm the results of the theoretical modeling. PMID- 30407381 TI - Aspartate Aminotransferase and Alanine Aminotransferase Detection on Paper-Based Analytical Devices with Inkjet Printer-Sprayed Reagents. AB - General biochemistry detection on paper-based microanalytical devices (PADs) uses pipette titration. However, such an approach is extremely time-consuming for large-scale detection processes. Furthermore, while automated methods are available for increasing the efficiency of large-scale PAD production, the related equipment is very expensive. Accordingly, this study proposes a low-cost method for PAD manufacture, in which the reagent is applied using a modified inkjet printer. The optimal reaction times for the detection of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are shown to be 6 and 7 min, respectively, given AST and ALT concentrations in the range of 5.4 to 91.2 U/L (R2 = 0.9932) and 5.38 to 86.1 U/L (R2 = 0.9944). The experimental results obtained using the proposed PADs for the concentration detection of AST and ALT in real human blood serum samples are found to be in good agreement with those obtained using a traditional spectrophotometric detection method by National Cheng Kung University hospital. PMID- 30407382 TI - Design and Analysis of MEMS Linear Phased Array. AB - A structure of micro-electro-mechanical system (MEMS) linear phased array based on "multi-cell" element is designed to increase radiation sound pressure of transducer working in bending vibration mode at high frequency. In order to more accurately predict the resonant frequency of an element, the theoretical analysis of the dynamic equation of a fixed rectangular composite plate and finite element method simulation are adopted. The effects of the parameters both in the lateral and elevation direction on the three-dimensional beam directivity characteristics are comprehensively analyzed. The key parameters in the analysis include the "cell" number of element, "cell" size, "inter-cell" spacing and the number of elements, element width. The simulation results show that optimizing the linear array parameters both in the lateral and elevation direction can greatly improve the three-dimensional beam focusing for MEMS linear phased array, which is obviously different from the traditional linear array. PMID- 30407384 TI - Temperature Sensing in Modular Microfluidic Architectures. AB - A discrete microfluidic element with integrated thermal sensor was fabricated and demonstrated as an effective probe for process monitoring and prototyping. Elements were constructed using stereolithography and market-available glass bodied thermistors within the modular, standardized framework of previous discrete microfluidic elements demonstrated in the literature. Flow rate dependent response due to sensor self-heating and microchannel heating and cooling was characterized and shown to be linear in typical laboratory conditions. An acid-base neutralization reaction was performed in a continuous flow setting to demonstrate applicability in process management: the ratio of solution flow rates was varied to locate the equivalence point in a titration, closely matching expected results. This element potentially enables complex, three-dimensional microfluidic architectures with real-time temperature feedback and flow rate sensing, without application specificity or restriction to planar channel routing formats. PMID- 30407383 TI - Rapid Detection of Salmonella enterica in Food Using a Compact Disc-Shaped Device. AB - Rapid detection of food-borne pathogens is essential to public health and the food industry. Although the conventional culture method is highly sensitive, it takes at least a few days to detect food-borne pathogens. Even though polymerase chain reaction (PCR) can detect food-borne pathogens in a few hours, it is more expensive and unsatisfactorily sensitive relative to the culture method. We have developed a method to rapidly detect Salmonella enterica by using a compact disc (CD)-shaped device that can reduce reagent consumption in conventional PCR. The detection method, which combines culture and PCR, is more rapid than the conventional culture method and is more sensitive and cheaper than PCR. In this study, we also examined a sample preparation method that involved collecting bacterial cells from food. The bacteria collected from chicken meat spiked with S. enterica were mixed with PCR reagents, and PCR was performed on the device. At a low concentration of S. enterica, the collected S. enterica was cultured before PCR for sensitive detection. After cultivation for 4 h, S. enterica at 1.7 * 104 colony-forming units (CFUs).g-1 was detected within 8 h, which included the time needed for sample preparation and detection. Furthermore, the detection of 30 CFUs.g-1 of S. enterica was possible within 12 h including 8 h for cultivation. PMID- 30407385 TI - Dynamic Electromechanical Coupling of Piezoelectric Bending Actuators. AB - Electromechanical coupling defines the ratio of electrical and mechanical energy exchanged during a flexure cycle of a piezoelectric actuator. This paper presents an analysis of the dynamic electromechanical coupling factor (dynamic EMCF) for cantilever based piezoelectric actuators and provides for the first time explicit expressions for calculation of dynamic EMCF based on arrangement of passive and active layers, layer geometry, and active and passive materials selection. Three main cantilever layer configurations are considered: unimorph, dual layer bimorph and triple layer bimorph. The actuator is modeled using standard constitutive dynamic equations that relate deflection and charge to force and voltage. A mode shape formulation is used for the cantilever dynamics that allows the generalized mass to be the actual mass at the first resonant frequency, removing the need for numerical integration in the design process. Results are presented in the form of physical insight from the model structure and also numerical evaluations of the model to provide trends in dynamic EMCF with actuator design parameters. For given material properties of the active and passive layers and given system overall damping ratio, the triple layer bimorph topology is the best in terms of theoretically achievable dynamic EMCF, followed by the dual layer bimorph. For a damping ratio of 0.035, the dynamic EMCF for an example dual layer bimorph configuration is 9% better than for a unimorph configuration. For configurations with a passive layer, the ratio of thicknesses for the passive and active layers is the primary geometric design variable. Choice of passive layer stiffness (Young's modulus) relative to the stiffness of the material in the active layer is an important materials related design choice. For unimorph configurations, it is beneficial to use the highest stiffness possible passive material, whereas for triple layer bimorph configurations, the passive material should have a low stiffness. In all cases, increasing the transverse electromechanical coupling coefficient of the active material improves the dynamic EMCF. PMID- 30407387 TI - CMOS MEMS Fabrication Technologies and Devices. AB - This paper reviews CMOS (complementary metal-oxide-semiconductor) MEMS (micro electro-mechanical systems) fabrication technologies and enabled micro devices of various sensors and actuators. The technologies are classified based on the sequence of the fabrication of CMOS circuitry and MEMS elements, while SOI (silicon-on-insulator) CMOS MEMS are introduced separately. Introduction of associated devices follows the description of the respective CMOS MEMS technologies. Due to the vast array of CMOS MEMS devices, this review focuses only on the most typical MEMS sensors and actuators including pressure sensors, inertial sensors, frequency reference devices and actuators utilizing different physics effects and the fabrication processes introduced. Moreover, the incorporation of MEMS and CMOS is limited to monolithic integration, meaning wafer-bonding-based stacking and other integration approaches, despite their advantages, are excluded from the discussion. Both competitive industrial products and state-of-the-art research results on CMOS MEMS are covered. PMID- 30407386 TI - Thermocapillarity in Microfluidics-A Review. AB - This paper reviews the past and recent studies on thermocapillarity in relation to microfluidics. The role of thermocapillarity as the change of surface tension due to temperature gradient in developing Marangoni flow in liquid films and conclusively bubble and drop actuation is discussed. The thermocapillary-driven mass transfer (the so-called Benard-Marangoni effect) can be observed in liquid films, reservoirs, bubbles and droplets that are subject to the temperature gradient. Since the contribution of a surface tension-driven flow becomes more prominent when the scale becomes smaller as compared to a pressure-driven flow, microfluidic applications based on thermocapillary effect are gaining attentions recently. The effect of thermocapillarity on the flow pattern inside liquid films is the initial focus of this review. Analysis of the relation between evaporation and thermocapillary instability approves the effect of Marangoni flow on flow field inside the drop and its evaporation rate. The effect of thermocapillary on producing Marangoni flow inside drops and liquid films, leads to actuation of drops and bubbles due to the drag at the interface, mass conservation, and also gravity and buoyancy in vertical motion. This motion can happen inside microchannels with a closed multiphase medium, on the solid substrate as in solid/liquid interaction, or on top of a carrier liquid film in open microfluidic systems. Various thermocapillary-based microfluidic devices have been proposed and developed for different purposes such as actuation, sensing, trapping, sorting, mixing, chemical reaction, and biological assays throughout the years. A list of the thermocapillary based microfluidic devices along with their characteristics, configurations, limitations, and improvements are presented in this review. PMID- 30407388 TI - Love-Mode MEMS Devices for Sensing Applications in Liquids. AB - Love-wave-based MEMS devices are theoretically investigated in their potential role as a promising technological platform for the development of acoustic-wave based sensors for liquid environments. Both single- and bi-layered structures have been investigated and the velocity dispersion curves were calculated for different layer thicknesses, crystallographic orientations, material types and electrical boundary conditions. High velocity materials have been investigated too, enabling device miniaturization, power consumption reduction and integration with the conditioning electronic circuits. The electroacoustic coupling coefficient dispersion curves of the first four Love modes are calculated for four dispersive coupling configurations based on a c-axis tilted ZnO layer on wz BN substrate. The gravimetric sensitivity of four Love modes travelling at a common velocity of 9318 m/s along different layer thicknesses, and of three Love modes travelling at different velocity along a fixed ZnO layer thickness, are calculated in order to design enhanced-performance sensors. The phase velocity shift and attenuation due to the presence of a viscous liquid contacting the device surface are calculated for different thicknesses of a c-axis inclined ZnO layer onto BN half-space. PMID- 30407390 TI - Devices Based on Co-Integrated MEMS Actuators and Optical Waveguide: A Review. AB - The convergence of Micro Electro Mechanical Systems (MEMS) and optics was, at the end of the last century, a fertile ground for a new breed of technological and scientific achievements. The weightlessness of light has been identified very early as a key advantage for micro-actuator application, giving rise to optical free-space MEMS devices. In parallel to these developments, the past 20 years saw the emergence of a less pursued approach relying on guided optical wave, where, pushed by the similarities in fabrication process, researchers explored the possibilities offered by merging integrated optics and MEMS technology. The interest of using guided waves is well known (absence of diffraction, tight light confinement, small size, compatibility with fiber optics) but it was less clear how they could be harnessed with MEMS technology. Actually, it is possible to use MEMS actuators for modifying waveguide properties (length, direction, index of refraction) or for coupling light between waveguide, enabling many new devices for optical telecommunication, astronomy or sensing. With the recent expansion to nanophotonics and optomechanics, it seems that this field still holds a lot of promises. PMID- 30407391 TI - Numerical Investigation of Cell Encapsulation for Multiplexing Diagnostic Assays Using Novel Centrifugal Microfluidic Emulsification and Separation Platform. AB - In the present paper, we report a novel centrifugal microfluidic platform for emulsification and separation. Our design enables encapsulation and incubation of multiple types of cells by droplets, which can be generated at controlled high rotation speed modifying the transition between dripping-to-jetting regimes. The droplets can be separated from continuous phase using facile bifurcated junction design. A three dimensional (3D) model was established to investigate the formation and sedimentation of droplets using the centrifugal microfluidic platform by computational fluid dynamics (CFD). The simulation results were compared to the reported experiments in terms of droplet shape and size to validate the accuracy of the model. The influence of the grid resolution was investigated and quantified. The physics associated with droplet formation and sedimentation is governed by the Bond number and Rossby number, respectively. Our investigation provides insight into the design criteria that can be used to establish centrifugal microfluidic platforms tailored to potential applications, such as multiplexing diagnostic assays, due to the unique capabilities of the device in handling multiple types of cells and biosamples with high throughput. This work can inspire new development of cell encapsulation and separation applications by centrifugal microfluidic technology. PMID- 30407392 TI - Two-Layer Microstructures Fabricated by One-Step Anisotropic Wet Etching of Si in KOH Solution. AB - Anisotropic etching of silicon in potassium hydroxide (KOH) is an important technology in micromachining. The residue deposition from KOH etching of Si is typically regarded as a disadvantage of this technology. In this report, we make use of this residue as a second masking layer to fabricate two-layer complex structures. Square patterns with size in the range of 15-150 MUm and gap distance of 5 MUm have been designed and tested. The residue masking layer appears when the substrate is over-etched in hydrofluoric acid (HF) solution over a threshold. The two-layer structures of micropyramids surrounded by wall-like structures are obtained according to the two different masking layers of SiO2 and residue. The residue masking layer is stable and can survive over KOH etching for long time to achieve deep Si etching. The process parameters of etchant concentration, temperature, etching time and pattern size have been investigated. With well controlled two-layer structures, useful structures could be designed for applications in plasmonic and microfluidic devices in the future. PMID- 30407393 TI - Mental Fatigue Monitoring Using a Wearable Transparent Eye Detection System. AB - We propose mental fatigue measurement using a wearable eye detection system. The system is capable of acquiring movement of the pupil and blinking from the light reflected from the eye. The reflection is detected by dye-sensitized photovoltaic cells. Since these cells are patterned onto the eyeglass and do not require external input power, the system is notable for its lightweight and low power consumption and can be combined with other wearable devices, such as a head mounted display. We performed experiments to correlate information obtained by the eye detection system with the mental fatigue of the user. Since it is quite difficult to evaluate mental fatigue objectively and quantitatively, we assumed that the National Aeronautics and Space Administration Task Load Index (NASA-TLX) had a strong correlation with te mental fatigue. While a subject was requested to conduct calculation tasks, the eye detection system collected his/her information that included position, velocity and total movement of the eye, and amount and frequency of blinking. Multiple regression analyses revealed the correlation between NASA-TLX and the information obtained for 3 out of 5 subjects. PMID- 30407394 TI - Magnetic Bead-Magic Bullet. AB - Microfluidics is assumed to be one of the leading and most promising areas of research since the early 1990s. In microfluidic systems, small spherical magnetic particles with superparamagnetic properties, called magnetic beads, play an important role in the design of innovative methods and tools, especially in bioanalysis and medical sciences. The intention of this review paper is to address main aspects from the state-of-the-art in the area of magnetic bead research, while demonstrating the broad variety of applications and the huge potential to solve fundamental biological and medical problems in the fields of diagnostics and therapy. Basic issues and demands related to the fabrication of magnetic particles and physical properties of nanosize magnets are discussed in Section 2. Of main interest are the control and adjustment of the nanoparticles' properties and the availability of adequate approaches for particle detection via their magnetic field. Section 3 presents an overview of magnetic bead applications in nanomedicine. In Section 4, practical aspects of sample manipulation and separation employing magnetic beads are described. Finally, the benefits related to the use of magnetic bead-based microfluidic systems are summarized, illustrating ongoing questions and open tasks to be solved on the way to an approaching microfluidic age. PMID- 30407396 TI - A New XYZ Compliant Parallel Mechanism for Micro-/Nano-Manipulation: Design and Analysis. AB - Based on the constraint and position identification (CPI) approach for synthesizing XYZ compliant parallel mechanisms (CPMs) and configuration modifications, this paper proposes a new fully-symmetrical XYZ CPM with desired motion characteristics such as reduced cross-axis coupling, minimized lost motion, and relatively small parasitic motion. The good motion characteristics arise from not only its symmetric configuration, but also the rigid linkages between non-adjacent rigid stages. Comprehensive kinematic analysis is carried out based on a series of finite element simulations over a motion range per axis less than +/-5% of the beam length, which reveals that the maximum cross-axis coupling rate is less than 0.86%, the maximum lost motion rate is less than 1.20%, the parasitic rotations of the motion stage (MS) are in the order of 10-5 rad, and the parasitic translations of the three actuated stages (ASs) are in the order of 10-4 of the beam length (less than 0.3% of the motion range), where the beam slenderness ratio is larger than 20. Furthermore, the nonlinear analytical models of the primary translations of the XYZ CPM, including the primary translations of the MS and the ASs, are derived and validated to provide a quick design synthesis. Moreover, two practical design schemes of the proposed XYZ CPM are discussed with consideration of the manufacturability. The practical designs enable the XYZ CPM to be employed in many applications such as micro-/nano positioning, micro-/nano-manufacturing and micro-/nano-assembly. Finally, a spatial high-precision translational system is presented based on the practical design schemes, taking the actuator and sensor integration into account. PMID- 30407397 TI - Scanning Micromirror Platform Based on MEMS Technology for Medical Application. AB - This topical review discusses recent development and trends on scanning micromirrors for biomedical applications. This also includes a biomedical micro robot for precise manipulations in a limited volume. The characteristics of medical scanning micromirror are explained in general with the fundamental of microelectromechanical systems (MEMS) for fabrication processes. Along with the explanations of mechanism and design, the principle of actuation are provided for general readers. In this review, several testing methodology and examples are described based on many types of actuators, such as, electrothermal actuators, electrostatic actuators, electromagnetic actuators, pneumatic actuators, and shape memory alloy. Moreover, this review provides description of the key fabrication processes and common materials in order to be a basic guideline for selecting micro-actuators. With recent developments on scanning micromirrors, performances of biomedical application are enhanced for higher resolution, high accuracy, and high dexterity. With further developments on integrations and control schemes, MEMS-based scanning micromirrors would be able to achieve a better performance for medical applications due to small size, ease in microfabrication, mass production, high scanning speed, low power consumption, mechanical stable, and integration compatibility. PMID- 30407395 TI - CD-Based Microfluidics for Primary Care in Extreme Point-of-Care Settings. AB - We review the utility of centrifugal microfluidic technologies applied to point of-care diagnosis in extremely under-resourced environments. The various challenges faced in these settings are showcased, using areas in India and Africa as examples. Measures for the ability of integrated devices to effectively address point-of-care challenges are highlighted, and centrifugal, often termed CD-based microfluidic technologies, technologies are presented as a promising platform to address these challenges. We describe the advantages of centrifugal liquid handling, as well as the ability of a standard CD player to perform a number of common laboratory tests, fulfilling the role of an integrated lab-on-a CD. Innovative centrifugal approaches for point-of-care in extremely resource poor settings are highlighted, including sensing and detection strategies, smart power sources and biomimetic inspiration for environmental control. The evolution of centrifugal microfluidics, along with examples of commercial and advanced prototype centrifugal microfluidic systems, is presented, illustrating the success of deployment at the point-of-care. A close fit of emerging centrifugal systems to address a critical panel of tests for under-resourced clinic settings, formulated by medical experts, is demonstrated. This emphasizes the potential of centrifugal microfluidic technologies to be applied effectively to extremely challenging point-of-care scenarios and in playing a role in improving primary care in resource-limited settings across the developing world. PMID- 30407399 TI - Microfluidic-Based Droplet and Cell Manipulations Using Artificial Bacterial Flagella. AB - Herein, we assess the functionality of magnetic helical microswimmers as basic tools for the manipulation of soft materials, including microdroplets and single cells. Their ability to perform a range of unit operations is evaluated and the operational challenges associated with their use are established. In addition, we also report on interactions observed between the head of such helical swimmers and the boundaries of droplets and cells and discuss the possibilities of assembling an artificial swimming microorganism or a motorized cell. PMID- 30407400 TI - Oocytes Polar Body Detection for Automatic Enucleation. AB - Enucleation is a crucial step in cloning. In order to achieve automatic blind enucleation, we should detect the polar body of the oocyte automatically. The conventional polar body detection approaches have low success rate or low efficiency. We propose a polar body detection method based on machine learning in this paper. On one hand, the improved Histogram of Oriented Gradient (HOG) algorithm is employed to extract features of polar body images, which will increase success rate. On the other hand, a position prediction method is put forward to narrow the search range of polar body, which will improve efficiency. Experiment results show that the success rate is 96% for various types of polar bodies. Furthermore, the method is applied to an enucleation experiment and improves the degree of automatic enucleation. PMID- 30407398 TI - A Review of Biomedical Centrifugal Microfluidic Platforms. AB - Centrifugal microfluidic or lab-on-a-disc platforms have many advantages over other microfluidic systems. These advantages include a minimal amount of instrumentation, the efficient removal of any disturbing bubbles or residual volumes, and inherently available density-based sample transportation and separation. Centrifugal microfluidic devices applied to biomedical analysis and point-of-care diagnostics have been extensively promoted recently. This paper presents an up-to-date overview of these devices. The development of biomedical centrifugal microfluidic platforms essentially covers two categories: (i) unit operations that perform specific functionalities, and (ii) systems that aim to address certain biomedical applications. With the aim to provide a comprehensive representation of current development in this field, this review summarizes progress in both categories. The advanced unit operations implemented for biological processing include mixing, valving, switching, metering and sequential loading. Depending on the type of sample to be used in the system, biomedical applications are classified into four groups: nucleic acid analysis, blood analysis, immunoassays, and other biomedical applications. Our overview of advanced unit operations also includes the basic concepts and mechanisms involved in centrifugal microfluidics, while on the other hand an outline on reported applications clarifies how an assembly of unit operations enables efficient implementation of various types of complex assays. Lastly, challenges and potential for future development of biomedical centrifugal microfluidic devices are discussed. PMID- 30407401 TI - Development of a Whole Blood Paper-Based Device for Phenylalanine Detection in the Context of PKU Therapy Monitoring. AB - Laboratory-based testing does not allow for the sufficiently rapid return of data to enable optimal therapeutic monitoring of patients with metabolic diseases such as phenylketonuria (PKU). The typical turn-around time of several days for current laboratory-based testing is too slow to be practically useful for effective monitoring or optimizing therapy. This report describes the development of a rapid, paper-based, point-of-care device for phenylalanine detection using a small volume (40 MUL) of whole blood. The quantitative resolution and reproducibility of this device with instrumented readout are described, together with the potential use of this device for point-of-care monitoring by PKU patients. PMID- 30407403 TI - CMOS-NEMS Copper Switches Monolithically Integrated Using a 65 nm CMOS Technology. AB - This work demonstrates the feasibility to obtain copper nanoelectromechanical (NEMS) relays using a commercial complementary metal oxide semiconductor (CMOS) technology (ST 65 nm) following an intra CMOS-MEMS approach. We report experimental demonstration of contact-mode nano-electromechanical switches obtaining low operating voltage (5.5 V), good ION/IOFF (103) ratio, abrupt subthreshold swing (4.3 mV/decade) and minimum dimensions (3.50 MUm * 100 nm * 180 nm, and gap of 100 nm). With these dimensions, the operable Cell area of the switch will be 3.5 MUm (length) * 0.2 MUm (100 nm width + 100 nm gap) = 0.7 MUm2 which is the smallest reported one using a top-down fabrication approach. PMID- 30407404 TI - Height Resolution of Antibody Spots Measured by Spinning-Disk Interferometry on the BioCD. AB - Spinning-disc interferometry (SDI) is a high-speed laser scanning approach to surface metrology that uses common-path interferometry to measure protein spots on a BioCD disk. The measurement sensitivity depends on the scanning pitch and on the time-base. Based on high-resolution laser scanning images of printed antibody spots, we quantify the protein sensitivity as a function of the scan parameters. For smoothly printed antibody spots scanned with a transverse spatial resolution of 1 MUm, the surface height precision for a single 100 MUm diameter protein spot is approximately 1 pm. This detection sensitivity sets the fundamental limit of detection for label-free BioCD biosensors performing immunoassays. PMID- 30407402 TI - Opto-Microfluidic Immunosensors: From Colorimetric to Plasmonic. AB - Optical detection has long been the most popular technique in immunosensing. Recent developments in the synthesis of luminescent probes and the fabrication of novel nanostructures enable more sensitive and efficient optical detection, which can be miniaturized and integrated with microfluidics to realize compact lab-on-a chip immunosensors. These immunosensors are portable, economical and automated, but their sensitivity is not compromised. This review focuses on the incorporation and implementation of optical detection and microfluidics in immunosensors; it introduces the working principles of each optical detection technique and how it can be exploited in immunosensing. The recent progress in various opto-microfluidic immunosensor designs is described. Instead of being comprehensive to include all opto-microfluidic platforms, the report centers on the designs that are promising for point-of-care immunosensing diagnostics, in which ease of use, stability and cost-effective fabrication are emphasized. PMID- 30407406 TI - Combined Forced and Thermocreep Convection through a Long Horizontal Microchannel. AB - This study examines how thermal creep affects the mixed convection in a long horizontal parallel-plate microchannel under a pressure drop and a temperature rise. The analytical solutions of the fully developed thermal-flow fields and the corresponding characteristics are derived based on the Maxwell boundary conditions with thermal creep and presented for the physical properties of air at the standard reference state. The calculated thermal-flow characteristics reveal that thermal creep has an appreciable effect on the velocity slip, flow rate, and heat transfer rate but a negligible effect on the flow drag. Such a creep effect could be further magnified by decreasing the pressure drop or increasing the Knudsen number. PMID- 30407405 TI - Challenges and Opportunities of Centrifugal Microfluidics for Extreme Point-of Care Testing. AB - The advantages offered by centrifugal microfluidic systems have encouraged its rapid adaptation in the fields of in vitro diagnostics, clinical chemistry, immunoassays, and nucleic acid tests. Centrifugal microfluidic devices are currently used in both clinical and point-of-care settings. Recent studies have shown that this new diagnostic platform could be potentially used in extreme point-of-care settings like remote villages in the Indian subcontinent and in Africa. Several technological inventions have decentralized diagnostics in developing countries; however, very few microfluidic technologies have been successful in meeting the demand. By identifying the finest difference between the point-of-care testing and extreme point-of-care infrastructure, this review captures the evolving diagnostic needs of developing countries paired with infrastructural challenges with technological hurdles to healthcare delivery in extreme point-of-care settings. In particular, the requirements for making centrifugal diagnostic devices viable in developing countries are discussed based on a detailed analysis of the demands in different clinical settings including the distinctive needs of extreme point-of-care settings. PMID- 30407407 TI - Surface Free Energy Determination of APEX Photosensitive Glass. AB - Surface free energy (SFE) plays an important role in microfluidic device operation. Photosensitive glasses such as APEX offer numerous advantages over traditional glasses for microfluidics, yet the SFE for APEX has not been previously reported. We calculate SFE with the Owens/Wendt geometric method by using contact angles measured with the Sessile drop technique. While the total SFE for APEX is found to be similar to traditional microstructurable glasses, the polar component is lower, which is likely attributable to composition. The SFE was modified at each stage of device fabrication, but the SFE of the stock and fully processed glass was found to be approximately the same at a value of 51 mJ.m-2. APEX exhibited inconsistent wetting behavior attributable to an inhomogeneous surface chemical composition. Means to produce more consistent wetting of photosensitive glass for microfluidic applications are discussed. PMID- 30407408 TI - Sandwiched Long-Period Fiber Grating Fabricated by MEMS Process for CO2 Gas Detection. AB - This paper presents an optical fiber gas sensor based on sandwiched long-period fiber grating (SLPFG) that is fabricated via the microelectromechanical systems (MEMS) process and coated with amino silica adsorbent for carbon dioxide (CO2) gas sensing. The amine-modified nanoporous silica foams were coated onto the SLPFG for CO2 adsorption. To characterize the CO2 adsorption of the SLPFG sensor, a gas sensing test was conducted with a mixed gas consisting of 15% CO2 and 85% nitrogen at a flow rate of 0.2 L/min. The results showed that the spectra of the SLPFG were varied with the gas flow within 21 min. After that, the transmission spectra of the SLPFG held steady and exhibited no further change. This phenomenon was caused by the adsorption saturation of the amine-modified nanoporous silica foams which were coated onto the SLPFG. During the absorption process, the transmission was increasing by about 11.27 dB (from -23.11 to -11.84 dB), and the increasing rate of transmission was 0.4598 dB/min. Repeatable adsorption and desorption experiment results showed that the SLPFG CO2 gas sensor exhibited good repeatability and a short response time. The recovery rate for each cycle was about 85%, and the required recovery time was short. Therefore, elaborated SLPFG gas sensor could potentially be used as a gas sensor for monitoring CO2 adsorption in the context of various industrial, agricultural, and household applications. PMID- 30407409 TI - A Microfluidic-Based Fabry-Perot Gas Sensor. AB - We developed a micro-gas detector based on a Fabry-Perot (FP) cavity embedded in a microfluidic channel. The detector was fabricated in two steps: a silicon substrate was bonded to a glass slide curved with a micro-groove, forming a microfluidic FP cavity; then an optical fiber was inserted through a hole drilled at the center of the groove into the microfluidic FP cavity, forming an FP cavity. The light is partially reflected at the optical fiber endface and the silicon surface, respectively, generating an interference spectrum. The detection is implemented by monitoring the interference spectrum shift caused by the refractive index change of the FP cavity when a gas analyte passes through. This detection mechanism (1) enables detecting a wide range of analytes, including both organic and inorganic (inertia) gases, significantly enhancing its versatility; (2) does not disturb any gas flow so that it can collaborate with other detectors to improve sensing performances; and (3) ensures a fast sensing response for potential applications in gas chromatography systems. In the experiments, we used various gases to demonstrate the sensing capability of the detector and observed drastically different sensor responses. The estimated sensitivity of the detector is 812.5 nm/refractive index unit (RIU) with a detection limit of 1.2 * 10-6 RIU assuming a 1 pm minimum resolvable wavelength shift. PMID- 30407410 TI - Mathematical Modelling and Simulation Research of Thermal Engraving Technology Based on PMMA Material. AB - We proposed a thermal engraving technology based on heat transfer theory and polymer rheology in microfluidic field. Then, we established a 3D model of the thermal engraving process based on polymethyl methacrylate (PMMA) material. We could employ the model to analyze the influence of temperature and speed on microchannel processing through the finite element simulation. Thus, we gained the optimal processing parameters. The orthogonal experiments were carried out within the parameter ranges obtained by the simulation results. Finally, we fabricated the smooth microchannel, the average roughness of which was 0.3 MUm, by using the optimal parameters. Furthermore, we examined the surface morphology and wettability. Our work provides a convenient technological support for a fast, low-cost, and large-scale manufacturing method of microfluidic chips. PMID- 30407412 TI - Balloon Pump with Floating Valves for Portable Liquid Delivery. AB - In this paper, we propose a balloon pump with floating valves to control the discharge flow rates of sample solutions. Because the floating valves were made from a photoreactive resin, the shapes of the floating valves could be controlled by employing different exposure patterns without any change in the pump configurations. Owing to the simple preparation process of the pump, we succeeded in changing the discharge flow rates in accordance with the number and length of the floating valves. Because our methods could be used to easily prepare balloon pumps with arbitrary discharge properties, we achieved several microfluidic operations by the integration of the balloon pumps with microfluidic devices. Therefore, we believe that the balloon pump with floating valves will be a useful driving component for portable microfluidic systems. PMID- 30407411 TI - Allergy Testing and Drug Screening on an ITO-Coated Lab-on-a-Disc. AB - A lab-on-a-disc (LOAD) is a centrifugal microfluidic set-up based on centrifugal force without using micro-pumps to drive reagents and cells to various chambers through channels and valves for reactions. A LOAD coated with conductive transparent indium tin oxide (ITO) for thermal control was developed to screen allergy-blocking agents. When the acridine orange (AO)-loaded KU-812 human basophilic cells were activated in the LOAD by stimuli, AO trapped in the cytoplasmic granules was released externally as an allergic mediator mimetic to report degranulation. This response was monitored by fluorescence when the released AO in supernatant had been transferred, with a higher spinning speed, from the reaction chamber to detection chamber in the LOAD where AO reacted with exogenous DNA. We report here the principles of the system and an improved LOAD set-up with the ITO-coated glass resistive microheater to run assays at 37 degrees C. By using this platform, we demonstrate here for the first time that triptolide, an active ingredient from the Chinese medicine herb Tripterygium wilfordii Hook f., was able to suppress the fMLP-mediated degranulation in basophils. This serves as an example how LOADs can be used to screen agents to alleviate symptoms of allergy. PMID- 30407413 TI - Fabrication and Measurement of a Suspended Nanochannel Microbridge Resonator Monolithically Integrated with CMOS Readout Circuitry. AB - We present the fabrication and characterization of a suspended microbridge resonator with an embedded nanochannel. The suspended microbridge resonator is electrostatically actuated, capacitively sensed, and monolithically integrated with complementary metal-oxide-semiconductor (CMOS) readout circuitry. The device is fabricated using the back end of line (BEOL) layers of the AMS 0.35 MUm commercial CMOS technology, interconnecting two metal layers with a contact layer. The fabricated device has a 6 fL capacity and has one of the smallest embedded channels so far. It is able to attain a mass sensitivity of 25 ag/Hz using a fully integrable electrical transduction. PMID- 30407414 TI - Capillary Self-Alignment of Microchips on Soft Substrates. AB - Soft micro devices and stretchable electronics have attracted great interest for their potential applications in sensory skins and wearable bio-integrated devices. One of the most important steps in building printed circuits is the alignment of assembled micro objects. Previously, the capillary self-alignment of microchips driven by surface tension effects has been shown to be able to achieve high-throughput and high-precision in the integration of micro parts on rigid hydrophilic/superhydrophobic patterned surfaces. In this paper, the self alignment of microchips on a patterned soft and stretchable substrate, which consists of hydrophilic pads surrounded by a superhydrophobic polydimethylsiloxane (PDMS) background, is demonstrated for the first time. A simple process has been developed for making superhydrophobic soft surface by replicating nanostructures of black silicon onto a PDMS surface. Different kinds of PDMS have been investigated, and the parameters for fabricating superhydrophobic PDMS have been optimized. A self-alignment strategy has been proposed that can result in reliable self-alignment on a soft PDMS substrate. Our results show that capillary self-alignment has great potential for building soft printed circuits. PMID- 30407415 TI - Micromachines Beyond Silicon-Based Technologies: A Letter from the New Editor-in Chief. AB - It is my pleasure to assume the role of the Editor-in-Chief of Micromachines from March 2016.[...]. PMID- 30407416 TI - Dealing with Magnetic Disturbances in Human Motion Capture: A Survey of Techniques. AB - Magnetic-Inertial Measurement Units (MIMUs) based on microelectromechanical (MEMS) technologies are widespread in contexts such as human motion tracking. Although they present several advantages (lightweight, size, cost), their orientation estimation accuracy might be poor. Indoor magnetic disturbances represent one of the limiting factors for their accuracy, and, therefore, a variety of work was done to characterize and compensate them. In this paper, the main compensation strategies included within Kalman-based orientation estimators are surveyed and classified according to which degrees of freedom are affected by the magnetic data and to the magnetic disturbance rejection methods implemented. By selecting a representative method from each category, four algorithms were obtained and compared in two different magnetic environments: (1) small workspace with an active magnetic source; (2) large workspace without active magnetic sources. A wrist-worn MIMU was used to acquire data from a healthy subject, whereas a stereophotogrammetric system was adopted to obtain ground-truth data. The results suggested that the model-based approaches represent the best compromise between the two testbeds. This is particularly true when the magnetic data are prevented to affect the estimation of the angles with respect to the vertical direction. PMID- 30407418 TI - Microstructure-Enhanced Liquid-Liquid Extraction in a Real-Time Fluorescence Detection Microfluidic Chip. AB - Microfluidic system is widely employed in the detection of environmental contaminants and biological specimens. One of the critical issues which limits the applications of microfluidic chips is the limit of detection of trace specimens. Liquid-liquid extraction is of great importance in the preprocessing in microfluidic devices. In this paper, we developed a real-time fluorescence detection microfluidic chip combined with a microstructure-enhanced liquid-liquid laminar extraction technique, which concentrated the trace compound and realized real-time monitoring. Auxiliary microstructures integrated in the microfluidic chip were applied to increase the extraction efficiency, which was proved by the FEM (finite element method) simulation as well. A common fluorescence probe, Rhodamine 6G (Rh6g), was used in the experiment to demonstrate the performance of the microfluidic system. It revealed that the liquid-liquid laminar extraction combined with auxiliary microstructures of a cross shape was an effective method for enrichment. The efficiency of microstructure-enhanced liquid-liquid extraction was increased by 350% compared to the traditional laminar flow extraction. PMID- 30407417 TI - Photochemical Synthesis and Versatile Functionalization Method of a Robust Porous Poly(ethylene glycol methacrylate-co-allyl methacrylate) Monolith Dedicated to Radiochemical Separation in a Centrifugal Microfluidic Platform. AB - The use of a centrifugal microfluidic platform is an alternative to classical chromatographic procedures for radiochemistry. An ion-exchange support with respect to the in situ light-addressable process of elaboration is specifically designed to be incorporated as a radiochemical sample preparation module in centrifugal microsystem devices. This paper presents a systematic study of the synthesis of the polymeric porous monolith poly(ethylene glycol methacrylate-co allyl methacrylate) used as a solid-phase support and the versatile and robust photografting process of the monolith based on thiol-ene click chemistry. The polymerization reaction is investigated, varying the formulation of the polymerisable mixture. The robustness of the stationary phase was tested in concentrated nitric acid. Thanks to their unique "easy-to-use" features, centrifugal microfluidic platforms are potential successful candidates for the downscaling of chromatographic separation of radioactive samples (automation, multiplexing, easy integration in glove-boxes environment, and low cost of maintenance). PMID- 30407420 TI - Experimental Analysis of Porosity and Permeability in Pressed Paper. AB - In this paper, we report an analysis of pressed paper in terms of porosity and permeability. Previously, we reported a pressed paper that exhibits decreased porosity and permeability. Additionally, its applications into programmed sample delivery as well as flow rate control were reported. However, there is a need for a theoretical analysis of pressed paper in terms of porosity and permeability for a more precise design principle and its applications because porosity and permeability are important factors in determining fluidic behavior. Here, we propose a theoretical model for analyzing decreased porosity and permeability in pressed paper. Porosity and permeability of pressed paper were quantitatively calculated using experimental results with a theoretical model. Furthermore, based on the analyzed results of porosity and permeability in pressed paper, a porosity-permeability relationship was investigated. PMID- 30407419 TI - Liquid Core ARROW Waveguides: A Promising Photonic Structure for Integrated Optofluidic Microsensors. AB - In this paper, we introduce a liquid core antiresonant reflecting optical waveguide (ARROW) as a novel optofluidic device that can be used to create innovative and highly functional microsensors. Liquid core ARROWs, with their dual ability to guide the light and the fluids in the same microchannel, have shown great potential as an optofluidic tool for quantitative spectroscopic analysis. ARROWs feature a planar architecture and, hence, are particularly attractive for chip scale integrated system. Step by step, several improvements have been made in recent years towards the implementation of these waveguides in a complete on-chip system for highly-sensitive detection down to the single molecule level. We review applications of liquid ARROWs for fluids sensing and discuss recent results and trends in the developments and applications of liquid ARROW in biomedical and biochemical research. The results outlined show that the strong light matter interaction occurring in the optofluidic channel of an ARROW and the versatility offered by the fabrication methods makes these waveguides a very promising building block for optofluidic sensor development. PMID- 30407421 TI - Digital Micromirror Device (DMD)-Based High-Cycle Torsional Fatigue Testing Micromachine for 1D Nanomaterials. AB - Fatigue behavior of nanomaterials could ultimately limit their applications in variable nano-devices and flexible nanoelectronics. However, very few existing nanoscale mechanical testing instruments were designed for dedicated fatigue experiments, especially for the challenging torsional cyclic loading. In this work, a novel high-cycle torsion straining micromachine, based on the digital micromirror device (DMD), has been developed for the torsional fatigue study on various one-dimensional (1D) nanostructures, such as metallic and semiconductor nanowires. Due to the small footprint of the DMD chip itself and its cable-remote controlling mechanisms, it can be further used for the desired in situ testing under high-resolution optical or electron microscopes (e.g., scanning electron microscope (SEM)), which allows real-time monitoring of the fatigue testing status and construction of useful structure-property relationships for the nanomaterials. We have then demonstrated its applications for testing nanowire samples with diameters about 100 nm and 500 nm, up to 1000 nm, and some of them experienced over hundreds of thousands of loading cycles before fatigue failure. Due to the commercial availability of the DMD and millions of micromirrors available on a single chip, this platform could offer a low-cost and high throughput nanomechanical solution for the uncovered torsional fatigue behavior of various 1D nanostructures. PMID- 30407422 TI - Nonlinear Dynamic Behavior of a Bi-Axial Torsional MEMS Mirror with Sidewall Electrodes. AB - Nonlinear dynamic responses of a Micro-Electro-Mechanical Systems (MEMS) mirror with sidewall electrodes are presented that are in close agreement with previously-reported experimental data. An analysis of frequency responses reveals softening behavior, and secondary resonances originated from the dominant quadratic nonlinearity. The quadratic nonlinearity is an electromechanical coupling effect caused by the electrostatic force. This effect is reflected in our mathematical model used to simulate the dynamic response of the micro-mirror. The effects of increased forcing and decreased damping on the frequency response are investigated as the mirrors are mostly used in vacuum packages. The results can predict MEMS mirror behaviors in optical devices better than previously reported models. PMID- 30407424 TI - An Investigation of Processes for Glass Micromachining. AB - This paper presents processes for glass micromachining, including sandblast, wet etching, reactive ion etching (RIE), and glass reflow techniques. The advantages as well as disadvantages of each method are presented and discussed in light of the experiments. Sandblast and wet etching techniques are simple processes but face difficulties in small and high-aspect-ratio structures. A sandblasted 2 cm * 2 cm Tempax glass wafer with an etching depth of approximately 150 um is demonstrated. The Tempax glass structure with an etching depth and sides of approximately 20 MUm was observed via the wet etching process. The most important aspect of this work was to develop RIE and glass reflow techniques. The current challenges of these methods are addressed here. Deep Tempax glass pillars having a smooth surface, vertical shapes, and a high aspect ratio of 10 with 1-MUm diameter glass pillars, a 2-MUm pitch, and a 10-MUm etched depth were achieved via the RIE technique. Through-silicon wafer interconnects, embedded inside the Tempax glass, are successfully demonstrated via the glass reflow technique. Glass reflow into large cavities (larger than 100 MUm), a micro-trench (0.8-MUm wide trench), and a micro-capillary (1-MUm diameter) are investigated. An additional optimization of process flow was performed for glass penetration into micro-scale patterns. PMID- 30407423 TI - Microfluidic Device to Measure the Speed of C. elegans Using the Resistance Change of the Flexible Electrode. AB - This work presents a novel method to assess the condition of Caenorhabditis elegans (C. elegans) through a resistance measurement of its undulatory locomotion speed inside a micro channel. As the worm moves over the electrode inside the micro channel, the length of the electrode changes, consequently behaving like a strain gauge. In this paper, the electrotaxis was applied for controlling the direction of motion of C. elegans as an external stimulus, resulting in the worm moving towards the cathode of the circuit. To confirm the proposed measurement method, a microfluidic device was developed that employs a sinusoidal channel and a thin polydimethylsiloxane (PDMS) layer with an electrode. The PDMS layer maintains a porous structure to enable the flexibility of the electrode. In this study, 6 measurements were performed to obtain the speed of an early adult stage C. elegans, where the measured average speed was 0.35 (+/-0.05) mm/s. The results of this work demonstrate the application of our method to measure the speed of C. elegans undulatory locomotion. This novel approach can be applied to make such measurements without an imaging system, and more importantly, allows directly to detect the locomotion of C. elegans using an electrical signal (i.e., the change in resistance). PMID- 30407425 TI - A New Analytical Model to Estimate the Voltage Value and Position of the Pull-In Limit of a MEMS Cantilever. AB - In this study, a new analytical model is developed for an electrostatic Microelectromechanical System (MEMS) cantilever actuator to establish a relation between the displacement of its tip and the applied voltage. The proposed model defines the micro-cantilever as a rigid beam supported by a hinge at the fixed end with a spring point force balancing the structure. The approach of the model is based on calculation of the electrostatic pressure centroid on the cantilever beam to localize the equivalent electrostatic point load. Principle outcome of the model is just one formula valid for all displacements ranging from the initial to the pull-in limit position. Our model also shows that the pull-in limit position of a cantilever is approximately 44% of the initial gap. This result agrees well with both simulation results and experimental measurements reported previously. The formula has been validated by comparing the results with former empirical studies. For displacements close to the pull-in limit, the percentage errors of the formula are within 1% when compared with real measurements carried out by previous studies. The formula also gives close results (less than 4%) when compared to simulation outcomes obtained by finite element analysis. In addition, the proposed formula measures up to numerical solutions obtained from several distributed models which demand recursive solutions in structural and electrostatic domains. PMID- 30407426 TI - Challenges in the Use of Compact Disc-Based Centrifugal Microfluidics for Healthcare Diagnostics at the Extreme Point of Care. AB - Since its inception, Compact Disc (CD)-based centrifugal microfluidic technology has drawn a great deal of interest within research communities due to its potential use in biomedical applications. The technology has been referred to by different names, including compact-disc microfluidics, lab-on-a-disk, lab-on-a-CD and bio-disk. This paper critically reviews the state-of-the-art in CD-based centrifugal microfluidics devices and attempts to identify the challenges that, if solved, would enable their use in the extreme point of care. Sample actuation, manufacturing, reagent storage and implementation, target multiplexing, bio particle detection, required hardware and system disposal, and sustainability are the topics of focus. PMID- 30407428 TI - An Analytical Model for CMUTs with Square Multilayer Membranes Using the Ritz Method. AB - Capacitive micromachined ultrasonic transducer (CMUT) multilayer membrane plays an important role in the performance metrics including the transmitting efficiency and the receiving sensitivity. However, there are few studies of the multilayer membranes. Some analytical models simplify the multilayer membrane as monolayer, which results in inaccuracies. This paper presents a new analytical model for CMUTs with multilayer membranes, which can rapidly and accurately predict static deflection and response frequency of the multilayer membrane under external pressures. The derivation is based on the Ritz method and Hamilton's principle. The mathematical relationships between the external pressure, static deflection, and response frequency are obtained. Relevant residual stress compensation method is derived. The model has been verified for three-layer and double-layer CMUT membranes by comparing its results with finite element method (FEM) simulations, experimental data, and other monolayer models that treat CMUTs as monolayer plates/membranes. For three-layer CMUT membranes, the relative errors are ranging from 0.71%-3.51% for the static deflection profiles, and 0.35% 4.96% for the response frequencies, respectively. For the double-layer CMUT membrane, the relative error with residual stress compensation is 4.14% for the central deflection, and -1.17% for the response frequencies, respectively. This proposed analytical model can serve as a reliable reference and an accurate tool for CMUT design and optimization. PMID- 30407427 TI - Surface Tension Directed Fluidic Self-Assembly of Semiconductor Chips across Length Scales and Material Boundaries. AB - This publication provides an overview and discusses some challenges of surface tension directed fluidic self-assembly of semiconductor chips which are transported in a liquid medium. The discussion is limited to surface tension directed self-assembly where the capture, alignment, and electrical connection process is driven by the surface free energy of molten solder bumps where the authors have made a contribution. The general context is to develop a massively parallel and scalable assembly process to overcome some of the limitations of current robotic pick and place and serial wire bonding concepts. The following parts will be discussed: (2) Single-step assembly of LED arrays containing a repetition of a single component type; (3) Multi-step assembly of more than one component type adding a sequence and geometrical shape confinement to the basic concept to build more complex structures; demonstrators contain (3.1) self packaging surface mount devices, and (3.2) multi-chip assemblies with unique angular orientation. Subsequently, measures are discussed (4) to enable the assembly of microscopic chips (10 MUm-1 mm); a different transport method is introduced; demonstrators include the assembly of photovoltaic modules containing microscopic silicon tiles. Finally, (5) the extension to enable large area assembly is presented; a first reel-to-reel assembly machine is realized; the machine is applied to the field of solid state lighting and the emerging field of stretchable electronics which requires the assembly and electrical connection of semiconductor devices over exceedingly large area substrates. PMID- 30407429 TI - Magnetophoretic Sorting of Single Cell-Containing Microdroplets. AB - Droplet microfluidics is a promising tool for single-cell analysis since single cell can be comparted inside a tiny volume. However, droplet encapsulation of single cells still remains a challenging issue due to the low ratio of droplets containing single cells. Here, we introduce a simple and robust single cell sorting platform based on a magnetophoretic method using monodisperse magnetic nanoparticles (MNPs) and droplet microfluidics with >94% purity. There is an approximately equal amount of MNPs in the same-sized droplet, which has the same magnetic force under the magnetic field. However, the droplets containing single cells have a reduced number of MNPs, as much as the volume of the cell inside the droplet, resulting in a low magnetic force. Based on this simple principle, this platform enables the separation of single cell-encapsulated droplets from the droplets with no cells. Additionally, this device uses only a permanent magnet without any complex additional apparatus; hence, this new platform can be integrated into a single cell analysis system considering its effectiveness and convenience. PMID- 30407430 TI - Resonant Varifocal Micromirror with Piezoresistive Focus Sensor. AB - This paper reports a microelectromechanical systems (MEMS) resonant varifocal mirror integrated with piezoresistive focus sensor. The varifocal mirror is driven electrostatically at a resonant frequency of a mirror plate to obtain the wide scanning range of a focal length. A piezoresistor is used to monitor the focal length of the varifocal mirror. The device is made of a silicon-on insulator (SOI) wafer and a glass wafer. A mirror plate and a counter electrode are fabricated by a top silicon layer of the SOI wafer and on the glass wafer, respectively. The piezoresistor is fabricated by ion implantation on a supporting beam of the mirror plate. The stress variation of the beam, which is detected by the piezoresistor, correspond the focal length of the varifocal mirror. The focus length varies from -41 to 35 mm at the resonant frequency of 9.5 kHz. The focal length of the varifocal mirror is monitored by the piezoresistor in real time. PMID- 30407431 TI - Miniaturized Rotary Actuators Using Shape Memory Alloy for Insect-Type MEMS Microrobot. AB - Although several types of locomotive microrobots have been developed, most of them have difficulty locomoting on uneven surfaces. Thus, we have been focused on microrobots that can locomote using step patterns. We are studying insect-type microrobot systems. The locomotion of the microrobot is generated by rotational movements of the shape memory alloy-type rotary actuator. In addition, we have constructed artificial neural networks by using analog integrated circuit (IC) technology. The artificial neural networks can output the driving waveform without using software programs. The shape memory alloy-type rotary actuator and the artificial neural networks are constructed with silicon wafers; they can be integrated by using micro-electromechanical system (MEMS) technology. As a result, the MEMS microrobot system can locomote using step patterns. The insect type MEMS microrobot system is 0.079 g in weight and less than 5.0 mm in size, and its locomotion speed is 2 mm/min. The locomotion speed is slow because the heat of the shape memory alloy conducts to the mechanical parts of the MEMS microrobot. In this paper, we discuss a new rotary actuator compared with the previous model and show the continuous rotation of the proposed rotary actuator. PMID- 30407433 TI - Polymer Magnetic Composite Core Based Microcoils and Microtransformers for Very High Frequency Power Applications. AB - We present a rapid prototyping and a cost effective fabrication process on batch fabricated wafer-level micro inductive components with polymer magnetic composite (PMC) cores. The new PMC cores provide a possibility to bridge the gap between the non-magnetic and magnetic core inductive devices in terms of both the operating frequency and electrical performance. An optimized fabrication process of molding, casting, and demolding which uses teflon for the molding tool is presented. High permeability NiFeZn powder was mixed with Araldite epoxy to form high resistive PMC cores. Cylindrical PMC cores having a footprint of 0.79 mm 2 were fabricated with varying percentage of the magnetic powder on FR4 substrates. The core influence on the electrical performance of the inductive elements is discussed. Inductor chips having a solenoidal coil as well as transformer chips with primary and secondary coils wound around each other have been fabricated and evaluated. A core with 65% powder equipped with a solenoid made out of 25 um thick insulated Au wire having 30 turns, yielded a constant inductance value of 2 uH up to the frequency of 50 MHz and a peak quality factor of 13. A 1:1 transformer with similar PMC core and solenoidal coils having 10 turns yielded a maximum efficiency of 84% and a coupling factor of 96%. In order to protect the solenoids and to increase the mechanical robustness and handling of the chips, a novel process was developed to encapsulate the components with an epoxy based magnetic composite. The effect on the electrical performance through the magnetic composite encapsulation is reported as well. PMID- 30407432 TI - Holographic Fabrication of Designed Functional Defect Lines in Photonic Crystal Lattice Using a Spatial Light Modulator. AB - We report the holographic fabrication of designed defect lines in photonic crystal lattices through phase engineering using a spatial light modulator (SLM). The diffracted beams from the SLM not only carry the defect's content but also the defect related phase-shifting information. The phase-shifting induced lattice shifting in photonic lattices around the defects in three-beam interference is less than the one produced by five-beam interference due to the alternating shifting in lattice in three beam interference. By designing the defect line at a 45 degree orientation and using three-beam interference, the defect orientation can be aligned with the background photonic lattice, and the shifting is only in one side of the defect line, in agreement with the theory. Finally, a new design for the integration of functional defect lines in a background phase pattern reduces the relative phase shift of the defect and utilizes the different diffraction efficiency between the defect line and background phase pattern. We demonstrate that the desired and functional defect lattice can be registered into the background lattice through the direct imaging of designed phase patterns. PMID- 30407434 TI - Minimally Intrusive Optical Micro-Strain Sensing in Bulk Elastomer Using Embedded Fabry-Perot Etalon. AB - A variety of strain sensors have been developed to measure internal deformations of elastomeric structures. Strain sensors measuring extremely small mechanical strain, however, have not yet been reported due mainly to the inherently intrusive integration of the sensor with the test structure. In this work, we report the development of a minimally intrusive, highly sensitive mechanical strain transducer realized by monolithically embedding a Fabry-Perot (FP) etalon into a poly(dimethylsiloxane) (PDMS) block test structure. Due to the extreme sensitivity of the FP resonance condition to the thickness of the spacer layer between the two reflectors, the limit of detection in the mechanical deformation can be as low as ~110 nm with a 632.8 nm laser used as the probing light. The compatibility of PDMS with additive fabrication turned out to be the most crucial enabling factor in the realization of the FP etalon-based strain transducer. PMID- 30407435 TI - Optofluidic Fabry-Perot Micro-Cavities Comprising Curved Surfaces for Homogeneous Liquid Refractometry-Design, Simulation, and Experimental Performance Assessment. AB - In the scope of miniaturized optical sensors for liquid refractometry, this work details the design, numerical simulation, and experimental characterization of a Fabry-Perot resonator consisting of two deeply-etched silicon cylindrical mirrors with a micro-tube in between holding the liquid analyte under study. The curved surfaces of the tube and the cylindrical mirrors provide three-dimensional light confinement and enable achieving stability for the cavity illuminated by a Gaussian beam input. The resonant optofluidic cavity attains a high-quality factor (Q)-over 2800-which is necessary for a sensitive refractometer, not only by providing a sharp interference spectrum peak that enables accurate tracing of the peak wavelengths shifts, but also by providing steep side peaks, which enables detection of refractive index changes by power level variations when operating at a fixed wavelength. The latter method can achieve refractometry without the need for spectroscopy tools, provided certain criteria explained in the details are met. By experimentally measuring mixtures of acetone-toluene with different ratios, refractive index variations of 0.0005 < Deltan < 0.0022 could be detected, with sensitivity as high as 5500 MUW/RIU. PMID- 30407436 TI - A One-Square-Millimeter Compact Hollow Structure for Microfluidic Pumping on an All-Glass Chip. AB - A micro surface tension pump is a new type of low-cost, built-in, all-glass, microfluidic pump on a glass microchip fabricated by one-step glass etching. However, geometric minimization and optimization for practical use are challenging. Here, we report a one-square-millimeter, built-in, all-glass pump controlled by two-way digital gas pressure. The pump consists simply of two joint chambers and a piston between two gas control channels. It does not require pre perfusion for initialization, and can immediately begin to run when a liquid enters its inlet channel. It is also more reliable than conventional micro pumps for practical use due to its ability to restart after the formation of a blocking bubble, which can serve as a valuable troubleshooting procedure. Its volumetric pump output was 0.5-0.7 nL.s-1 under a pump head pressure of 300 Pa. PMID- 30407437 TI - Three-Dimensional Force Measurements During Rapid Palatal Expansion in Sus scrofa. AB - Rapid palatal expansion is an orthodontic procedure widely used to correct the maxillary arch. However, its outcome is significantly influenced by factors that show a high degree of variability amongst patients. The traditional treatment methodology is based on an intuitive and heuristic treatment approach because the forces applied in the three dimensions are indeterminate. To enable optimal and individualized treatment, it is essential to measure the three-dimensional (3D) forces and displacements created by the expander. This paper proposes a method for performing these 3D measurements using a single embedded strain sensor, combining experimental measurements of strain in the palatal expander with 3D finite element analysis (FEA). The method is demonstrated using the maxillary jaw from a freshly euthanized pig (Sus scrofa) and a hyrax-design rapid palatal expander (RPE) appliance with integrated strain gage. The strain gage measurements are recorded using a computer interface, following which the expansion forces and extent of expansion are estimated by FEA. A total activation of 2.0 mm results in peak total force of about 100 N-almost entirely along the direction of expansion. The results also indicate that more than 85% of the input activation is immediately transferred to the palate and/or teeth. These studies demonstrate a method for assessing and individualizing expansion magnitudes and forces during orthopedic expansion of the maxilla. This provides the basis for further development of smart orthodontic appliances that provide real-time readouts of forces and movements, which will allow personalized, optimal treatment. PMID- 30407438 TI - Fabrication of High-Aspect-Ratio 3D Hydrogel Microstructures Using Optically Induced Electrokinetics. AB - We present a rapid hydrogel polymerization and prototyping microfabrication technique using an optically induced electrokinetics (OEK) chip, which is based on a non-UV hydrogel curing principle. Using this technique, micro-scale high aspect-ratio three-dimensional polymer features with different geometric sizes can be fabricated within 1-10 min by projecting pre-defined visible light image patterns onto the OEK chip. This method eliminates the need for traditional photolithography masks used for patterning and fabricating polymer microstructures and simplifies the fabrication processes. This technique uses cross-link hydrogels, such as poly(ethylene glycol) (PEG)-diacrylate (PEGDA), as fabrication materials. We demonstrated that hydrogel micropillar arrays rapidly fabricated using this technique can be used as molds to create micron-scale cavities in PDMS (polydimethylsiloxane) substrates. Furthermore, hollow, circular tubes with controllable wall thicknesses and high-aspect ratios can also be fabricated. These results show the potential of this technique to become a rapid prototyping technology for producing microfluidic devices. In addition, we show that rapid prototyping of three-dimensional suspended polymer structures is possible without any sacrificial etching process. PMID- 30407439 TI - Micro-Shaping of Nanopatterned Surfaces by Electron Beam Irradiation. AB - We show that planar nanopatterned thin films on standard polycarbonate (PC) compact discs (CD) can be micro-shaped in a non-contact manner via direct e-beam exposure. The shape of the film can be controlled by proper selection of the e beam parameters. As an example of application, we demonstrate a two-dimensional (2D) array of micro-lenses/reservoirs conformally covered by an Al 2D nanohole array (NHA) film on a PC CD substrate. It is also shown that such a curvilinear Al NHA layer can be easily transferred onto a flexible polymeric support. The presented technique provides a new tool for creating lab-on-CD architectures and developing multifunctional (flexible) non-planar nanostructured films and surfaces. PMID- 30407440 TI - Shape-Selective Assembly of Anisotropic, Deformable Microcomponents Using Bottom Up Micromanufacturing. AB - A technique for shape-selective directed assembly of anisotropic, deformable, chemically-identical microcomponents onto patterned rigid templates based on shape and size differences is modeled and demonstrated. The assembly method not only controls the selective placement of the components, but also aligns the components with the assembly sites. Unlike the assembly of isotropic (spherical) microcomponents, in which only size differences can be used to discriminate among chemically-identical components to achieve selective placement, differences in both shape and size can enable selectivity in the assembly of anisotropic (non spherical) microcomponents. The present selective directed assembly is driven by shape-matching to a microfabricated template to provide selectivity, uniform chemical surface functionalization to promote assembly, and megasonic excitation to prevent assembly into poorly shape-matched binding sites. A theoretical framework quantifies the predicted selectivity of this approach and predicts that it will be effective for many material combinations, including hydrogels and bio compatible polymers. Experiments demonstrate successful directed assembly of cylindrical, hydrogel colloidal microcomponents with 26 MUm mean diameter and 50 MUm length into silicon templates patterned with hemicylindrical assembly sites. During the assembly, tapered microcomponents with 150 MUm length and a nominal diameter of 26 MUm that decreases along the components' lengths were successfully excluded from hemicylindrical assembly sites. These results provide the first demonstration of selective directed assembly of non-spherical microcomponents by this approach. The assembly shows high local yields in agreement with theory. PMID- 30407441 TI - Optofluidic Device Based Microflow Cytometers for Particle/Cell Detection: A Review. AB - Optofluidic devices combining micro-optical and microfluidic components bring a host of new advantages to conventional microfluidic devices. Aspects, such as optical beam shaping, can be integrated on-chip and provide high-sensitivity and built-in optical alignment. Optofluidic microflow cytometers have been demonstrated in applications, such as point-of-care diagnostics, cellular immunophenotyping, rare cell analysis, genomics and analytical chemistry. Flow control, light guiding and collecting, data collection and data analysis are the four main techniques attributed to the performance of the optofluidic microflow cytometer. Each of the four areas is discussed in detail to show the basic principles and recent developments. 3D microfabrication techniques are discussed in their use to make these novel microfluidic devices, and the integration of the whole system takes advantage of the miniaturization of each sub-system. The combination of these different techniques is a spur to the development of microflow cytometers, and results show the performance of many types of microflow cytometers developed recently. PMID- 30407443 TI - Droplet Velocity in an Electrowetting on Dielectric Digital Microfluidic Device. AB - In many electrowetting on dielectric (EWOD) based microfluidics devices, droplet actuation speed is a crucial performance-controlling parameter. Our present study aims to characterize and study droplet speed in a typical EWOD device. First, a practical droplet speed measurement method has been methodically demonstrated and some related velocity terms have been introduced. Next, influence of electrode shape on droplet speed has been studied and a new design to enhance droplet speed has been proposed and experimentally demonstrated. Instead of using square shaped electrodes, rectangular electrodes with smaller widths are used to actuate droplets. Additionally, different schemes of activating electrodes are studied and compared for the same applied voltage. The experiments show that a particular scheme of activating the array of rectangular electrodes enhances the droplet speed up to 100% in comparison to the droplet speed in a conventional device with square shaped electrodes. PMID- 30407442 TI - Mechanically-Tunable Photonic Devices with On-Chip Integrated MEMS/NEMS Actuators. AB - This article reviews mechanically-tunable photonic devices with on-chip integrated MEMS/NEMS actuators. With related reports mostly published within the last decade, this review focuses on the tuning mechanisms of various passive silicon photonic devices, including tunable waveguides, couplers, ring/disk resonators, and photonic crystal cavities, and their results are selectively elaborated upon and compared. Applications of the mechanisms are also discussed. Future development of mechanically-tunable photonics is considered and one possible approach is based on plasmonics, which can confine light energy in the nano-scale space. Optomechanics is another innovation, derived from the strong coupling of optical and mechanical degrees of freedom. State-of-the-art studies of mechanically-tunable plasmonics and on-chip optomechanics are also selectively reviewed. PMID- 30407444 TI - Carbon Nanotube Paper-Based Electroanalytical Devices. AB - Here, we report on carbon nanotube paper-based electroanalytical devices. A highly aligned-carbon nanotube (HA-CNT) array, grown using chemical vapor deposition (CVD), was processed to form bi-layered paper with an integrated cellulose-based Origami-chip as the electroanalytical device. We used an inverse ordered fabrication method from a thick carbon nanotube (CNT) sheet to a thin CNT sheet. A 200-layered HA-CNT sheet and a 100-layered HA-CNT sheet are explored as a working electrode. The device was fabricated using the following methods: (1) cellulose-based paper was patterned using a wax printer, (2) electrical connection was made using a silver ink-based circuit printer, and (3) three electrodes were stacked on a 2D Origami cell. Electrochemical behavior was evaluated using electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV). We believe that this platform could attract a great deal of interest for use in various chemical and biomedical applications. PMID- 30407446 TI - [Terapias celulares: una nueva era en la batalla contra el cancer]. PMID- 30407445 TI - A Micro Saddle Coil with Switchable Sensitivity for Local High-Resolution Imaging of Luminal Tissue. AB - This paper reports on a micro saddle coil for local high-resolution magnetic resonance imaging (MRI) fabricated by embedding a flexible coil pattern into a polydimethyilsiloxane (PDMS) tube. We can change the sensitivity of the micro coil by deforming the shape of the coil from a saddle-shaped mode to a planar shaped mode. The inductance, the resistance, and the Q-factor of the coil in the saddle-shaped mode were 2.45 MUH, 3.31 Omega, and 39.9, respectively. Those of the planar-shaped mode were 3.07 MUH, 3.92 Omega, and 42.9, respectively. In MRI acquired in saddle-shaped mode, a large visible area existed around the coil. Although the sensitive area was considerably reduced in the planar-shaped mode, clear MRI images were obtained. The signal-to-noise ratios (SNR) of the saddle shaped and planar-shaped modes were 194.9 and 505.9, respectively, at voxel size of 2.0 * 2.0 * 2.0 mm3 and 11.7 and 37.4, respectively, at voxel size of 0.5 * 0.5 * 1.0 mm3. The sensitivity of the saddle-shaped and the planar-shaped modes were about 3 times and 10 times higher, respectively, than those of the medical head coil at both voxel sizes. Thus, the micro saddle coil enabled large-area imaging and highly sensitive imaging by switching the shape of the coil. PMID- 30407448 TI - [La retroalimentacion como compromiso]. PMID- 30407447 TI - [La critica y la educacion medica: hacia un conocimiento liberador. Parte I]. AB - This essay defines the current moment as a civilizatory collapse, consequence of the dominance of limitless profit interests, which has been possible due to the insensitivity and permissiveness of most of the population in the face of extreme social and ecosystemic degradations. In the background of such "anesthesia" there is the predominant education and its key role in the reproduction of prevalent social ideas and practices and in the perpetuation of degrading traits: individualism, exclusionary specialization, passivity, competitiveness, consumerism and vulnerability to media manipulation. With this intellective and interpretive framework, the concept of deep and creative critique was updated in order to deepen the critique of medical education, allowing for the differentiation and contrast of two radically different types of education. Firstly, the passive education, reproductive of the degrading traits of universal validity, whose core is the idea of knowledge comparable to a cumulative rote learning of heteronomous and unrelated information, and by an implicit pedagogy focused on facilitating the consumption and uncritical assimilation of established truths. Secondly, the participatory education (proposal to overcome the passive), where knowledge is the elaboration and re-elaboration of students with the essential mediation of critique. The students construct and reconstruct their own versions of themselves and their context; the implicit pedagogy is condensed in infecting enthusiasm to understand who we are and where we are, and procure conducive environments for critique and the elaboration of a progressively penetrating and liberating knowledge that has shown its feasibility in specific situations. PMID- 30407449 TI - [Sobrevida global de pacientes con leucemia aguda en el Hospital de Especialidades Pediatricas de Chiapas, Mexico]. AB - Background: At the 10th anniversary of the Hospital de Especialidades Pediatricas in Chiapas, Mexico, it was important to assess the 5-year acute leukemia overall survival under the Seguro Popular program (Popular Insurance). Methods: A descriptive and survival study of 210 acute leukemia patients diagnosed and treated during 2008-2012 was performed. Kaplan-Meier survival curves were developed for all patients, each leukemia type (B, T and myeloid) and for B type related to risk group, age, sex, leukocytes, cell markers, DNA index, karyotype, and translocations. Results: Age, gender and proportion of leukemia types (B = 85%; M = 10%; T = 5%), were similar to other parts of the country. At the end of the 5-year treatment, 20% of the patients were alive, 53% had died and 27% had abandoned the treatment. Global survival was 42% (B = 45%; T = 20%; M = 10%) (median: 38.8 months; confidence interval of 95% = 28.9-48.7). Very high-risk median survival was 7.7 versus 47 months. There was no difference between standard and high-risk groups. The initial leukocyte count < 50,000/mL and CD10 positive were related to better B survival; no other variables were related. At the time of death, 29% of patients were in remission. Conclusions: Global survival of acute leukemia at Hospital de Especialidades Pediatricas under the Seguro Popular during its first 5 years was surprisingly poor given the medical resources available through the insurance. Early mortality, death during remission and high desertion rates contributed to these results. A detailed revision of treatment protocols and reasons for abandoning treatment is mandatory. PMID- 30407451 TI - [Aneurisma de arteria testicular: reporte de un caso y revision de la literatura]. AB - Background: Aneurysm of the testicular artery is a rare entity; the term is described as the dilation of any blood vessel in the body. Case report: An 18 year-old patient with a left testicular artery aneurysm, with no family or personal history of medical importance, presented for consultation due to a volume increase of long evolution in the inguinal region, accompanied by sporadic pain with no other symptoms. The testicular artery aneurysm was not detectable preoperatively by ultrasound, which only reported data compatible with left inguinal hernia and varicocele. The diagnosis was made postoperatively by a histopathological study. This case highlights the presentation of a true aneurysm of the testicular artery and the result after definitive surgical treatment. Conclusions: The etiology of the aneurysm and pseudoaneurysm reported in the literature is described after a testicular trauma and, a few cases of congenital origin. The clinical manifestations are pain and an inguinal mass, which can be frequently confused with inguinal hernias or an aggregated pathology. Therefore, the approach of patients with inguinal or testicular pathology should be protocolized and include aneurysm within the differential diagnoses. PMID- 30407450 TI - [Tiempo de respuesta terapeutica al propranolol sistemico en el manejo de hemangiomas subgloticos pediatricos: serie de casos y revision de la literatura]. AB - Background: Airway hemangiomas are congenital neoplasms of low incidence. Its clinical presentation consists of obstruction of the upper airway with progressive dyspnea and stridor and the life of the patient at risk. Infantile hemangiomas have an incidence at birth of 2%, increasing to 9% at 12 months of life. Almost 60% of childhood hemangiomas affect the head and neck region. However, localization in the upper airway is not as frequent and it is only reported in 1.8% of patients with cutaneous hemangiomas. The traditional treatment of laryngeal hemangiomas has been the administration of systemic corticosteroids for long periods, endolaryngeal surgery with CO2 laser, open surgery, tracheostomy or, recently, oral propranolol. Case report: Five cases of subglottic hemangioma treated with systemic propranolol are presented. The therapeutic time of response with the satisfactory control of obstructive symptoms and assurance of the airway was evaluated. In these cases, propranolol was shown to be an effective and safe option for the treatment of laryngeal hemangiomas with a therapeutic response time of 48 to 72 hours. Conclusions: In recent years, the treatment with oral propranolol has become the first therapeutic option due to its high efficacy and safety profile. PMID- 30407452 TI - [Retrasplante cardiaco electivo. Primer caso en Mexico]. AB - Orthotopic cardiac retransplantation is used to treat transplanted cardiac graft end-stage failure. We present the first case of successful elective cardiac retransplantation in Mexico. It was a 25-year old male with heart transplantation who developed graft-resistant chronic vasculopathy. He underwent elective retransplantation in September 2017; complications during postoperative evolution were treated with favorable response. He was discharged owing to improvement at four weeks postoperatively. It is concluded that in adequately selected cases and comprehensively assessed, cardiac retransplantation is an appropriate option to treat cardiac graft failure. PMID- 30407453 TI - [Mortalidad por enfermedad de Alzheimer en Mexico de 1980 a 2014]. AB - Background: Dementias are rarely considered to be a main cause of death; therefore there are only few studies on Alzheimer's mortality covering long periods. Objective: To describe mortality from Alzheimer's disease in Mexico for the period from 1980 to 2014. Method: Cross-sectional study where, with official mortality data in Mexico according to codes 331.0 and G30, respectively, of the 9th and 10th revisions of the International Statistical Classification of Diseases and Related Health Problems, crude and standardized Alzheimer's disease mortality rates were obtained, both nationally and by states. Results: From almost being inexistent, deaths from Alzheimer's disease went to a rate of 65.12 per 1000 females and 43.66 per 1000 males in the 2010-2014 five-year period. Throughout the study period, the age group with highest mortality rates for this cause were those older than 80 years, with 0.29 per 100,000 population in 1980 1984 and 55.02 in 100,000 in the 2010-2014 period. The region with the highest mortality was the northwest, with rates higher than 2.28 per 100,000 population. Conclusions: Mortality from Alzheimer's disease is a public health problem in Mexico with a growing trend, especially among women and older adults. Early diagnostic measures and opportune treatment are required in primary care in order to reduce this problem. PMID- 30407454 TI - [Frecuencia y gravedad de la retinopatia del prematuro en una unidad de cuidados intensivos neonatales]. AB - Introduction: Retinopathy of prematurity (ROP) is a disease where retinal blood vessels do not develop normally and may cause visual damage and blindness. Objective: To determine the frequency and severity of ROP in preterm newborns. Method: A descriptive, comparative study was carried out within the 2009-2013 period. Patients' general characteristics were recorded, including gestational age and postmenstrual age at the moment of ophthalmologic examination, as well as ROP severity and type of treatment. Results: A total of 326 preterm newborns were included: 47.8 % (n = 156) had ROP; in 21.1 % it was severe (stage >= 3). Median gestational age was 28 weeks in preterm newborns with ROP, median birth weight was 1000 g, and median postmenstrual age at ophthalmological examination was 36 weeks. Of the infants with ROP, 71.1 % received treatment: 63.4 % of those who had mild ROP and 100 % of those with severe ROP. Conclusions: ROP frequency was high, higher than that reported in developed countries and similar to that in developing countries. The frequency of severe ROP was also higher. It is necessary for effective programs for the detection and opportune treatment of ROP to be established. PMID- 30407455 TI - [Hospitales del Instituto Mexicano del Seguro Social durante los sismos de septiembre de 2017. Analisis desde la perspectiva del Programa Hospital Seguro]. AB - Introduction: The function of hospitals during major emergency or disaster is vital. Their response capacity depends on their geographic location, adequate organization, structural safety and safety of non-structural elements. After September 2017 earthquakes, self-assessment and Safe Hospital Program assessment results were compared in disabled hospitals belonging to the Mexican Institute of Social Security. Objective: To compare the Hospital Safety Index (HIS) with self assessments carried out by the units. Method: HIS and the Pan-American Health Organization/World Health Organization checklist were used. The comparison was carried out in 3 hospitals that were disabled after September 2017 earthquakes. Results: Variability was observed in HIS, which revealed self-assessment biases: no hospital obtained a HIS score lower than 0.35, although all 3 were disabled in the immediate phase after the seismic events. Conclusions: Result variability depends on who applies the instrument. Quick HIS assessment provides an immediate idea of the probability for a hospital to continue functioning in case of disaster and allows determining mitigation actions to increase health facilities' resilience and safety. PMID- 30407456 TI - [Autopercepcion del peso a traves de figuras corporales en ninos en edad escolar de Piedras Negras, Coahuila, Mexico]. AB - Background: The prevalence of overweight and obesity has increased worldwide. In this context, the lack of awareness of excess weight among overweight and obese children is a public health concern that needs to be explored in the Northern border of Mexico. Methods: Body mass index (BMI) was calculated from children from third to sixth grades of basic education. The Children's Body Image Scale was applied to evaluate perceived and ideal BMI comparing against calculated BMI. We also analyzed the frequency of accurate perceivers of actual weight and discrepancy of ideal weight against calculated BMI. Results: We studied 155 children (43.8% were female) with a mean age of 10.2 years. Accuracy prevalence of BMI perceived respect to calculated BMI was 59.4%. Discrepancy prevalence of ideal BMI respect to calculated BMI was 44.4%. Comparison of perceived BMI respect to calculated BMI showed an overestimation on low weight category (33%) and subestimations in categories of normal weight (12.4%), overweight (85%) and obesity (81.6%). Comparison of ideal BMI respect to calculated BMI showed an absolute overestimation of low weight and underestimations in categories of normal weight, overweight and obesity of 5.6%, 100%, and 97.4%, respectively. Conclusions: The results of this work showed a consistent underestimation of children's body weight, particularly among those classified in categories of overweight and obesity in a demographic context in which the prevalence of both categories was of 38% in this study. PMID- 30407457 TI - Early discharge of pediatric patients with cancer, fever, and neutropenia with low-risk of systemic infection. AB - Background: Ambulatory therapy in low-risk patients with cancer, fever, and neutropenia seems to be a secure and effective alternative. This study aimed to compare the effectiveness and safety of the antimicrobial treatment in early discharge vs. in-hospital treatment in children with cancer and febrile neutropenia (FN) with low risk of invasive bacterial infection (IBI). Methods: Quasi-experimental design with a historical cohort control group. Children with cancer during an episode of FN and low risk of IBI were included. The control group were inpatient children that received intravenous piperacillin/tazobactam. The experimental group was early discharge patients, who received 48 h of IV treatment and were switched to oral treatment. Outcomes: fever resolution, readmissions, and mortality. Results: Eighty low-risk FN episodes were included; the median age was 6 years old (2.6-11 years), and 43 (54%) were female. Main diagnoses were solid tumors (52 patients) and leukemia or lymphoma (28 patients). Forty-three patients received in-hospital treatment, and 37 were selected for early discharge (31 patients received ciprofloxacin and six received amoxicillin/clavulanate). Two patients were readmitted, one due to a relapse of fever with tumor progression and the other due to epistaxis. Adverse effects occurred in 21.6% of the early discharge group and 12% of the inpatient treatment group (p = 0.04). Conclusions: Early discharge in pediatric patients with cancer, fever, and neutropenia is an acceptable and safe alternative for low-risk patients. PMID- 30407458 TI - [Recomendaciones a los cuerpos directivos de las agrupaciones medicas en su relacion con la industria]. AB - Continuing medical education activities are often financially supported by pharmaceutical and device companies. With the purpose to ensure ethics and accountability in the management of this assistance, the Committee of Ethics and Transparency in the Physician-Industry Relationship of the National Academy of Medicine of Mexico formulates recommendations to medical associations' leaders in this text. PMID- 30407459 TI - [Estrategias de afrontamiento para el manejo del estres y su relacion con el nivel de obesidad y calidad de vida en pacientes candidatos a cirugia bariatrica]. AB - Introduction: Stress is a variable that may play an important role in the development of obesity and in the quality of life of patients who are candidates for bariatric surgery, since stress is linked to the consumption of hypercaloric foods, sedentariness and higher incidence of psychological disorders. Objective: To describe the most common types of stress coping strategies in patients who are candidates for bariatric surgery and establish their relationship with body mass index and quality of life perception. Method: One-hundred and one patients with severe obesity who were candidates for bariatric surgery were evaluated by means of the Stress Coping Questionnaire and the Quality of Life and Health Inventory. Results: The most commonly used coping type is action and the most common strategy is focus on problem solving. Five coping strategies were significantly associated with quality of life; there was no significant association with body mass index. Conclusion: There is an association between some coping styles and quality of life in individuals who are candidates for bariatric surgery. PMID- 30407461 TI - [Academicos titulares del ano 2018]. PMID- 30407462 TI - [Relevancia del modelo de preimpresiones en las publicaciones periodicas]. PMID- 30407460 TI - [Ninos con mordeduras de animales hospitalizados en un centro de referencia de Uruguay]. AB - Background: Animal bites are a health problem that can produce lesions of varying severity, with the risk of aesthetic and functional sequelae and infectious complications. The objective of the study was to describe the clinical, epidemiological, treatment and complications of lesions caused by animal bites in children hospitalized in a reference center in Uruguay. Method: Descriptive, retrospective study. All children hospitalized for animal bites between 2014 and 2017 were included. Medical records were reviewed and data, such as the animal involved, injuries, treatments, complications, and if the case was notified to the Ministry of Health, were recorded. Results: A total of 106 children were hospitalized, with a mean age 4.5 years. The animals involved were dogs (80.2%), rodents (8.5%), arachnids (4.7%), and others (6.5%). The majority of the lesions were superficial (80.2%), and 91.5% of the cases were hospitalized in moderate care. The treatments were hygiene (96.2%), suture (70.8%), and antibiotic prophylaxis (81.1%). There were complications in 77.4% of the cases. In three cases, the isolation of the most frequent etiological agent was possible: Streptococcus pyogenes. Notification to the Ministry of Health occurred in 20.7% of the cases. No lethality was recorded. Conclusions: A total of 106 children were hospitalized due to animal bites. The most affected were males under 5 years old. Most of them were bitten at home or nearby. Dogs and rodents were the most involved animals. There were predominantly head and limb lesions, mostly mild and superficial. Complications occurred in 77.4% of cases, mainly infectious and aesthetic-functional. PMID- 30407463 TI - [Academicos honorarios del ano 2018]. PMID- 30407464 TI - [Clasificacion molecular del carcinoma de colon y recto. Una revision corta]. AB - Traditionally, carcinoma classifications have been based on clinical or pathological features. However, with the development of molecular biology in recent decades, more tumors are increasingly being genetically studied and, in several of them, molecular classifications have been created (the most widely studied and used is that for breast cancer). Colon and rectum cancer are no exception. In this short review, the evolution of colon and rectum cancer molecular classification is explained and the consensus conclusions on the subject are addressed. PMID- 30407465 TI - [Enfermedad de Chagas en Mexico]. AB - Chagas disease, which is caused by Trypanosoma cruzi, is considered to be the most serious parasitic disease in America. It is transmitted mainly by triatominae ("kissing bugs"). Mazzoti reported the first two human cases in Mexico. The form of transmission is by parasites entering the organism in feces of the insect, by blood transfusion, from mother to child, by organ transplant and laboratory accidents. In Mexico, 1.1 million people are estimated to be infected; the incidence in 2012 was 0.70 per 1,00,000 population. In 2017, the highest incidence rates were registered in Yucatan, Oaxaca and Hidalgo. The infection causes cardiomyopathies and mega-organs of the digestive tract. Diagnosis in the acute phase is by parasitological approach and, in the chronic phase, by laboratory screening studies. In Mexico's blood banks, screening for Chagas disease is mandatory; from 2007 to 2016, seroprevalence has decreased from 0.40 to 0.32 due to the improvement of donor selection processes and the ad hoc questionnaire. The targets of the parasite are neurons and smooth and myocardial muscle cells. The association of neuronal and smooth muscle destruction defines the presentation of chagas mega-syndromes. Initial manifestations of the disease can go unnoticed; 5% show apparent signs and symptoms and 30% will progress to the chronic asymptomatic phase. Currently available treatments have effect in the acute phase. For the control of Chagas disease, the Specific Action Program for the Prevention and Control of Chagas Disease (PAE Chagas 2013-2018) is available to initiate activities aimed at eliminating transfusion and congenital transmission and controlling vector transmission. The success of medical care depends on oportune detection, early etiological treatment and coverage broadening. On the other hand, monitoring and screening of pregnant women living in risk areas and blood and organ donors universal screening will enable the elimination congenital and transfusion transmission. PMID- 30407466 TI - [Inicio del tratamiento farmacologico de la tuberculosis]. AB - The appearance of new anti-tuberculosis drugs such as bedaquiline and delamanid makes it impossible not to remember that the first strictly controlled medical trials of tuberculosis treatment were published in two rigorously researched outstanding articles that can be qualified as historical. In 1948, streptomycin was formally studied as an efficacious anti-tuberculosis drug. In 1952, another trial compared streptomycin-paramino salicylic acid with isoniazid, by means of which the first bases of pharmacological tuberculosis treatment were established. PMID- 30407467 TI - [Actualidades en la inmunopatologia de la esclerosis multiple]. AB - Multiple sclerosis is a demyelinating inflammatory disease that affects the central nervous system. Its etiology is the result of a complex interaction between genetic and environmental factors that trigger a deregulated immune response, with the resulting inflammation and neuronal/axonal degeneration. Neuroinflammation is triggered when peripheral leukocytes migrate to the central nervous system and release cytokines such as interleukins 1 and 6 (IL-1 and 6) and tumor necrosis factor (TNF), which act on dwelling cells. The innate immune system plays an important role in the onset and progression of the disease by identifying molecular patterns associated with pathogens and damage, which modulate effector and regulatory functions of the cells where they are expressed, in order to direct the specific immune response. Th17 cells favor the disruption of the blood-brain barrier, which enables the migration of leukocytes to the central nervous system and the triggering of the inflammatory cascade; the Th1 profile (IL-1, IL-6) collaborates to perpetuate it. B-cell function is to produce antibodies and cytokines (IL-6, IL-12 and TFN). Knowledge on multiple sclerosis pathophysiology will enable the development of new therapeutic options that impact on natural history of the disease and its prognosis. PMID- 30407468 TI - [Utilidad del complejo soluble de ataque a membrana para determinar actividad clinica de la dermatomiositis y respuesta al tratamiento]. AB - Introduction: Dermatomyositis is an autoimmune disease and the most common idiopathic inflammatory myopathy. During patient follow-up, determining biochemical parameters is required in order to assess for disease activity and treatment efficacy. Objective: To determine the relationship between the degree of activation of the complement system through the soluble membrane attack complex (c5b-9), dermatomyositis clinical activity and its variations with conventional treatment. Method: Forty-five patients with active and inactive dermatomyositis were studied. Chemical parameters and clinical severity were established and correlated with ELISA-determined C5b-9 serum levels. Results: There was positive correlation between dermatomyositis cutaneous and muscular activity and C5b-9 serum levels, which was lower than with traditional biochemical markers. In the case of treatment response, C5b-9 showed significant reduction, similar to clinical severity; with biochemical parameters, the reduction was not significant at one month of treatment with systemic steroids. Conclusions: Serum levels of C5b-9 levels of C5b-9 are higher in patients with dermatomyositis than in healthy subjects; dermatomyositis active and inactive cases were determined by means of their measurement. They can be a reliable parameter of therapeutic response, more accurate than muscle enzymes measurement, particularly creatine phosphokinase. PMID- 30407469 TI - [Implicaciones psiquiatricas y neurologicas en la literatura shakespeariana. Breve analisis]. AB - William Shakespeare (1564-1616) is with no doubt one of the most prolific literary artists of all times; in addition to being an eminent playwright, his works reflect arguments that express medical knowledge, allude to concise descriptions that are relevant to medical practice of that time, and even to current medicine. He wrote between 35 and 38 plays, six lyric works and 154 sonnets (approximately) where finding little more than 700 references to medicine of those days is possible. For this reason, different scholars have analyzed the medical concepts within the Shakespearean literature; some agree that these may be the result of studies of his own, while others suggest that Shakespeare repeated the medical knowledge of some "men of wisdom" of his time. It should be mentioned that the author's contemporary London society lived in an overpopulated, nauseating, sexually promiscuous city that was plagued by pests and waste and continually besieged by epidemics whose treatments many times caused greater evil than benefit (for example, lead-based make-up). Some biographers credit syphilis, alcohol, and depression as the source of Shakespeare's creative production. Despite the myriad of authors who have analyzed the insinuations about medicine in Shakespeare's dramatic accounts, Sigmund Freud (1856-1939) is perhaps the most important; throughout his career he carried out a substantial analysis of the English playwright's works owing to his passion for literature and for this author. PMID- 30407470 TI - Findings of Research Misconduct. PMID- 30407471 TI - ESTER DERIVED TITANIUM ENOLATE ALDOL REACTION: HIGHLY DIASTEREOSELECTIVE SYNTHESIS OF SYN- AND ANTI-ALDOLS. AB - Aldol reactions of bidentate aldehydes and cis-1-arylsulfonamido-2-indanyl ester derived titanium enolates proceed with excellent syn-diastereoselectivities and good to excellent isolated yields. PMID- 30407472 TI - Correction: Reactive polycyclic aromatic hydrocarbon dimerization drives soot nucleation. AB - Correction for 'Reactive polycyclic aromatic hydrocarbon dimerization drives soot nucleation' by M. R. Kholghy et al., Phys. Chem. Chem. Phys., 2018, 20, 10926 10938. PMID- 30407473 TI - Assessment of the targeting specificity of a fluorescent albumin conceived as a preclinical agent of the liver function. AB - In the context of increasing liver diseases, no contrast agent is currently available in Europe and the United States to directly assess the liver function. Only neolactosylated human serum albumin is being clinically used in Asia. In order to perform preclinical studies in the context of liver diseases, we conceived a fluorescent lactosylated albumin for the quantification of liver functional cells (l-Cyal). Precise characterization was achieved in order to determine the amounts of lactose and Cyanine 5 (Cy5) coupled to the albumin. In addition, potential aggregation was characterized by asymmetrical flow field-flow fractionation hyphenated to multi-angle light scattering (AF4-MALS). The optimal functionalized albumin exhibited a mass greater than 87 kDa which corresponds to the addition of 34 lactose moieties per protein and 1-2 Cy5 labels. Also, no significant formation of aggregates could be identified due to the modification of the native albumin. In healthy mice, the accumulation of l-Cyal in the liver and its selectivity for hepatocyte cells were shown by optical imaging and flow cytometry. Administration of l-Cyal to mice bearing liver metastases showed a reduced signal in the liver related to a decrease in the number of hepatocytes. The l-Cyal bioimaging contrast agent could be particularly useful for assessing the state of liver related diseases. PMID- 30407474 TI - Interface engineered surface morphology evolution of Au@Pd core-shell nanorods. AB - Engineering the interfacial structure of bimetallic nanocrystals is an effective method to improve their electrocatalytic performances. Here, we design a facile strategy for controlling the surface morphology evolution of Au@Pd core-shell nanorods by adjusting the solution supersaturation. The Pd shell of the as prepared Au@Pd bimetallic nanorods can be modulated from a (111) facet-exposed island to a (100) facet-exposed conformal shell. The conformal shell structure exhibited enhanced catalytic performance toward the ethanol oxidation reaction, while the core-island structure possessed better catalytic stability. This work provides a facile method for interfacial engineering of bimetallic nanocrystals with desired morphology and properties. PMID- 30407479 TI - Intermolecular structural correlations in model globular and unconcatenated ring polymer liquids. AB - We employ the field theoretic polymer integral equation theory to construct a segment-level theory for the thermodynamics and pair structure of dense liquids of interpenetrating ring polymers and a simple globule model. The latter is defined by a fractal mass distribution on all internal length scales with an exponent equal to the spatial dimension (dF = ds = 3). In an isochoric ensemble the dimensionless compressibility and pressure is predicted to vary exponentially with macromolecular volume fraction. An intermolecular correlation hole exists down to small length scales. This model appears to be useful for a recently studied experimental soft nanoparticle suspension, and also serves as a reference system for our analysis of ring liquids. Motivated by simulations, a two-fractal exponent ring model is adopted for the intramolecular structure factor. At smaller lengths it describes chain-like macromolecules, while on larger scales it corresponds to a space-filling object in the sense that dF = ds = 3. The crossover between these two regimes is of order the entanglement length of the linear chain analog. Based on a constant compressibility ensemble, the effective volume fraction grows at intermediate values of degree of polymerization (N), and crosses over to a very slow logarithmic growth at large N. A weaker intermolecular correlation hole is predicted. The number of nearest neighbor rings increases dramatically at small N, akin to linear chain melts, but then tends to saturate at large N, in accord with simulations. The tools developed may be relevant for other partially interpenetrating soft objects such as core-shell nanogels or microgels. PMID- 30407481 TI - Trajectories of Nonagenarian Health: Gender, Age, and Period Effects. AB - The US population aged 90 years and older is growing rapidly and there are limited data on their health. The Cardiovascular Health Study is a prospective study of black and white adults >=65 years recruited in two waves (1989-90 and 1992-93) from Medicare eligibility lists in Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh, Pennsylvania. We created a synthetic cohort of the 1,889 participants who had reached age 90 at baseline or during follow-up through July 16th, 2015. Participants entered the cohort at 90 years and we evaluated their changes in health after age 90 (median [IQR] follow-up: 3 [1.3-5] years). Measures of health included cardiovascular events, cognitive function, depressive symptoms, prescription medications, self-rated health, and measures of functional status. The mortality rate was high: 19.0 (95% CI: 17.8, 20.3) per 100 person-years in women and 20.9 (95% CI: 19.2, 22.8) in men. Cognitive function and all measures of functional status declined with age; these changes were similar by gender. When we isolated period effects, we found that medications use increased over time. These estimates can help inform future research and health care systems to meet the needs of this growing population. PMID- 30407482 TI - Index suffix-prefix overlaps by (w, k)-minimizer to generate long contigs for reads compression. AB - Motivation: Advanced high-throughput sequencing technologies have produced massive amount of reads data, and algorithms have been specially designed to contract the size of these data sets for efficient storage and transmission. Reordering reads with regard to their positions in de novo assembled contigs or in explicit reference sequences has been proven to be one of the most effective reads compression approach. As there is usually no good prior knowledge about the reference sequence, current focus is on the novel construction of de novo assembled contigs. Results: We introduce a new de novo compression algorithm named minicom. This algorithm uses large k-minimizers to index the reads and subgroup those that have the same minimizer. Within each subgroup, a contig is constructed. Then some pairs of the contigs derived from the subgroups are merged into longer contigs according to a (w; k)-minimizer indexed suffix-prefix overlap similarity between two contigs. This merging process is repeated after the longer contigs are formed until no pair of contigs can be merged. We compare the performance of minicom with two reference-based methods and four de novo methods on 18 data sets (13 RNA-seq data sets and 5 whole genome sequencing data sets). In the compression of single-end reads, minicom obtained the smallest file size for 22 of 34 cases with significant improvement. In the compression of paired-end reads, minicom achieved 20-80% compression gain over the best state-of-the-art algorithm. Our method also achieved a 10% size reduction of compressed files in comparison with the best algorithm under the reads-order preserving mode. These excellent performances are mainly attributed to the exploit of the redundancy of the repetitive substrings in the long contigs. Availability and Implementation: https://github.com/yuansliu/minicom. Supplementary Information: Supplementary data are available at Bioinformatics online. PMID- 30407483 TI - Protective effects of ghrelin on fasting-induced muscle atrophy in aging mice. AB - Sarcopenia is the aging-associated progressive loss of skeletal muscle, however the pathogenic mechanism of sarcopenia is not clear. The orexigenic hormone ghrelin stimulates growth hormone secretion, increases food intake, and promotes adiposity. Here we showed that fasting-induced muscle loss was exacerbated in old ghrelin-null (Ghrl-/-) mice, exhibiting decreased expression of myogenic regulator MyoD and increased expression of protein degradation marker MuRF1, as well as altered mitochondrial function. Moreover, acylated ghrelin (AG) and unacylated ghrelin (UAG) treatments significantly increased mitochondrial respiration capacity in muscle C2C12 cells. Consistently, AG and UAG treatments effectively increased myogenic genes and decreased degradation genes in the muscle in fasted old Ghrl-/- mice, possibly by stimulating insulin and AMPK pathways. Furthermore, Ghrl-/- mice showed a profile of pro-inflammatory gut microbiota, exhibiting reduced butyrate-producing bacteria Roseburia and ClostridiumXIVb. Collectively, our results showed that ghrelin has a major role in the maintenance of aging muscle via both muscle-intrinsic and -extrinsic mechanisms. AG and UAG enhanced muscle anabolism and exerted protective effects for muscle atrophy. Since UAG is devoid of the obesogenic side effect seen with AG, it represents an attractive therapeutic option for sarcopenia. PMID- 30407484 TI - BacPaCS - Bacterial Pathogenicity Classification via Sparse-SVM. AB - Motivation: Bacterial infections are a major cause of illness worldwide. However, most bacterial strains pose no threat to human health and may even be beneficial. Thus, developing powerful diagnostic bioinformatic tools that differentiate pathogenic from commensal bacteria are critical for effective treatment of bacterial infections. Results: We propose a machine-learning approach for classifying human-hosted bacteria as pathogenic or non-pathogenic based on their genome-derived proteomes. Our approach is based on sparse Support Vector Machines (SVM), which autonomously selects a small set of genes that are related to bacterial pathogenicity. We implement our approach as a tool - "Bacterial Pathogenicity Classification via sparse-SVM" (BacPaCS) - which is fully automated and handles datasets significantly larger than those previously used. BacPaCS shows high accuracy in distinguishing pathogenic from non-pathogenic bacteria, in a clinically relevant dataset, comprising only human-hosted bacteria. Among the genes that received the highest positive weight in the resulting classifier, we found genes that are known to be related to bacterial pathogenicity, in addition to novel candidates, whose involvement in bacterial virulence was never reported. Availability: The code and the resulting model are available at: https://github.com/barashe/bacpacs. Supplementary information: Supplementary files, including an appendix, are provided as part of this submission. PMID- 30407485 TI - Whisper: Read sorting allows robust mapping of DNA sequencing data. AB - Motivation: Mapping reads to a reference genome is often the first step in a sequencing data analysis pipeline. The reduction of sequencing costs implies a need for algorithms able to process increasing amounts of generated data in reasonable time. Results: We present Whisper, an accurate and high-performant mapping tool, based on the idea of sorting reads and then mapping them against suffix arrays for the reference genome and its reverse complement. Employing task and data parallelism as well as storing temporary data on disk result in superior time efficiency at reasonable memory requirements. Whisper excels at large NGS read collections, in particular Illumina reads with typical WGS coverage. The experiments with real data indicate that our solution works in about 15% of the time needed by the well-known BWA-MEM and Bowtie2 tools at a comparable accuracy, validated in a variant calling pipeline. Availability: Whisper is available for free from https://github.com/refresh-bio/Whisper or http://sun.aei.polsl.pl/REFRESH/Whisper/. Supplementary Information: Supplementary data are available at Bioinformatics online. PMID- 30407486 TI - Variants in the PSCA gene associated with risk of cancer and non-neoplastic diseases: systematic research synopsis, meta-analysis and epidemiological evidence. AB - Variants in the PSCA gene have been linked with risk of multiple cancers and other diseases. But results have been inconclusive and no systematic research synopsis has been available. We did a comprehensive meta-analysis to investigate associations between variants in this gene and risk of nine cancers and four non neoplastic diseases based on data from 55 publications including 81 961 cases and 442 932 controls. We graded levels of cumulative epidemiological evidence of a significant association using the Venice criteria and false-positive report probability tests. We performed functional annotation for these variants using data from the Encyclopedia of DNA Elements (ENCODE) Project and other public databases. We found that six variants were nominally significantly associated with an increased or reduced risk of three cancers and three non-neoplastic diseases (P<0.05). Cumulative evidence of an association was graded as strong for rs2294008 [odds ratio (OR)=1.32, P=5.1*10-33], rs2976392 (OR=1.29, P=1.8*10-8), rs9297976 (OR=0.75, P=1.4*10-7), rs2976391 (OR=1.38, P=6.1*10-5) and rs138377917 (OR=0.53, P=0.008) with gastric cancer, rs2294008 with bladder cancer (OR=1.15, P =8.0*10-19), gastritis (OR=1.35, P=1.2*10-5), duodenal ulcer (OR=0.68, P=2.4*10 57) and gastric ulcer (OR=0.88, P=1.7*10 -7). Data from the ENCODE Project and other databases showed that these variants and other variants correlated with them might fall in putative functional regions. In conclusion, this study provides summary evidence that variants in the PSCA gene are associated with risk of gastric and bladder cancer, gastritis, as well as duodenal and gastric ulcer and highlights the significant role of this gene in the pathogenesis of these diseases. PMID- 30407487 TI - A Healthy Lifestyle Index in Relation to Risk of Endometrial and Ovarian Cancer Among Women in the Women's Health Initiative Study. AB - Lifestyle-related factors influence risk of endometrial and ovarian cancers, but few studies have examined their joint associations with risk of these cancers. Using multivariable Cox regression models, we assessed the association of a healthy lifestyle index ((HLI) - a composite score (range 0-20) involving diet, alcohol consumption, physical activity, body mass index and smoking; higher scores represent healthier behavior) - with risk of endometrial and ovarian cancers among 108,136 postmenopausal women who were recruited in the Women's Health Initiative study between 1993 and 1998. After a median follow-up of 17.9 years, 1,435 endometrial cancer cases and 904 ovarian cancer cases had been ascertained. Women in the highest quintile of the HLI score had a lower risk of overall, Type I, well-differentiated, moderately differentiated, poorly differentiated, and localized endometrial cancer than those in the lowest quintile (HR>=q5 vs q1: 0.61 (95% CI: 0.51,0.72), 0.60 (0.49.0.72), 0.66 (0.46, 0.96), 0.69 (0.52,0.90), 0.49 (0.34,0.72) and 0.61 (0.50,0.74), respectively). The HLI score had a weak positive association with risk of serous ovarian cancer. Our findings underscore the potential importance of a healthy lifestyle in lowering endometrial cancer risk among postmenopausal women. PMID- 30407489 TI - Measurement error and variant-calling in deep Illumina sequencing of HIV. AB - Motivation: Next-generation deep sequencing of viral genomes, particularly on the Illumina platform, is increasingly applied in HIV research. Yet, there is no standard protocol or method used by the research community to account for measurement errors that arise during sample preparation and sequencing. Correctly calling high and low frequency variants while controlling for erroneous variants is an important precursor to downstream interpretation, such as studying the emergence of HIV drug-resistancemutations, which in turn has clinical applications and can improve patient care. Results: We developed a new variant calling pipeline, hivmmer, for Illumina sequences from HIV viral genomes. First, we validated hivmmer by comparing it to other variant-calling pipelines on real HIV plasmid data sets. We found that hivmmer achieves a lower rate of erroneous variants, and that all methods agree on the frequency of correctly called variants. Next, we compared the methods on an HIV plasmid data set that was sequenced using Primer ID, an amplicon-tagging protocol, which is designed to reduce errors and amplification bias during library preparation. We show that the Primer ID consensus exhibits fewer erroneous variants compared to the variant calling pipelines, and that hivmmer more closely approaches this low error rate compared to the other pipelines. The frequency estimates from the Primer ID consensus do not differ significantly from those of the variant-calling pipelines. Availability: hivmmer is freely available for non-commercial use from https://github.com/kantorlab/hivmmer. Supplementary Information: Supplementary data are available at Bioinformatics online. PMID- 30407488 TI - The Role of Comorbidity on Mortality after Hip Fracture: A Nationwide Norwegian Study of 38,126 Women with Hip Fracture Matched to a General Population Comparison Cohort. AB - Hip fracture patients often have comorbidities. We investigated whether the combination of comorbidity and hip fracture could explain the previously observed excess mortality among hip fracture patients compared to the general population. Using a population-based matched design with 38,126 Norwegian women suffering a hip fracture in the period 2009-2015 and the same number women in a matched comparison cohort, we matched on pre-fracture comorbidity, age, and education. We estimated relative survival, and additive and multiplicative comorbidity-hip fracture interaction. An additive comorbidity-hip fracture interaction of 4-9 per 100 patients was observed mainly during the first year after hip fracture. Among women with high comorbidity, 15 additional deaths per 100 patients were observed and of these, 9 deaths could be attributed to the interaction and 6 to the hip fracture per se. On the relative scale, we observed an increasing heterogeneity in survival by comorbidity over time; survival was reduced by around 40% after 6 years, among patients with high comorbidity while among women with no comorbidity, survival was reduced with 17% (hip fracture vs. no hip fracture). In summary, pre-fracture comorbidity was associated with short-term absolute excess mortality and long-term relative excess mortality. PMID- 30407490 TI - OPA2Vec: combining formal and informal content of biomedical ontologies to improve similarity-based prediction. AB - Motivation: Ontologies are widely used in biology for data annotation, integration, and analysis. In addition to formally structured axioms, ontologies contain meta-data in the form of annotation axioms which provide valuable pieces of information that characterize ontology classes. Annotation axioms commonly used in ontologies include class labels, descriptions, or synonyms. Despite being a rich source of semantic information, the ontology meta-data are generally unexploited by ontology-based analysis methods such. Results: We propose a novel method, OPA2Vec, to generate vector representations of biological entities in ontologies by combining formal ontology axioms and annotation axioms from the ontology metadata. We apply a Word2Vec model that has been pre-trained on either a corpus or abstracts or full-text articles to produce feature vectors from our collected data. We validate our method in two different ways: first, we use the obtained vector representations of proteins in a similarity measure to predict protein-protein interaction on two different datasets. Second, we evaluate our method on predicting gene-disease associations based on phenotype similarity by generating vector representations of genes and diseases using a phenotype ontology, and applying the obtained vectors to predict gene-disease associations using mouse model phenotypes. We demonstrate that OPA2Vec significantly outperforms existing methods for predicting gene-disease associations. Using evidence from mouse models, we apply OPA2Vec to identify candidate genes for several thousand rare and orphan diseases. OPA2Vec can be used to produce vector representations of any biomedical entity given any type of biomedical ontology. Availability: https://github.com/bio-ontology-research-group/opa2vec. PMID- 30407491 TI - Potential Hazards Not Communicated in Safety Data Sheets of Flavoring Formulations, Including Diacetyl and 2,3-Pentanedione. AB - Objectives: Workers using flavoring formulations containing diacetyl and 2,3 pentanedione may be at risk of inhalational exposure, as these volatile hazardous chemicals are emitted from the bulk material, especially at elevated temperatures. However, flavoring formulations that contain diacetyl and 2,3 pentanedione might not list these ingredients because they are generally recognized as safe to ingest, may be part of a proprietary mixture deemed a trade secret, or may not be required to be listed if they are present at <1% composition. The objective of this study was to investigate whether potential inhalational hazards present in flavoring samples were reported as chemical ingredients on their corresponding safety data sheets (SDSs). Methods: A convenience sample of 26 bulk liquid flavorings obtained from two coffee roasting and packaging facilities in the USA was analyzed for 20 volatile organic chemicals present in the headspaces of vials containing flavoring liquids using gas chromatography-mass spectrometry. Flavoring samples were included in the study if headspace analysis results and SDSs were available. Flavoring samples included hazelnut, French vanilla, amaretto, chocolate, and caramel as well as some flavoring mixtures containing added fruit flavors such as cherry and raspberry. The presence of a chemical in the flavoring formulation was then compared to the ingredient list on the SDSs. Results: All the flavoring SDSs contained trade secret designations. None of the SDSs listed diacetyl or 2,3 pentanedione. Headspace analyte concentrations revealed that diacetyl was present in 21 of 26 samples (81%) with a maximum concentration of 5.84 * 104 ug m-3 in flavor 18 (caramel). 2,3-Pentanedione was present in 15 flavors (58%) with a maximum concentration of 3.79 * 105 ug m-3 in flavor 24 (oatmeal cookies). Conclusions: A majority of the flavorings tested had diacetyl, 2,3-pentanedione, or both as volatile constituents in the headspace. These chemicals were not listed on the SDSs, but inclusion of diacetyl and 2,3-pentanedione on SDSs would serve to protect downstream users from unrecognized exposure and potential respiratory disease. The headspace technique presented here is a viable tool to rapidly screen for volatile hazardous chemicals that may be present in flavoring formulations. Facilities that use flavorings should be aware that constituents in flavorings may present a potential inhalational hazard even if not identified as such by the SDS. A precautionary approach is warranted when working with flavorings, including exposure monitoring and effective exposure control strategies such as containment and local exhaust ventilation. PMID- 30407492 TI - dtangle: accurate and robust cell type deconvolution. AB - Motivation: Cell type composition of tissues is important in many biological processes. To help understand cell type composition using gene expression data, methods of estimating (deconvolving) cell type proportions have been developed. Such estimates are often used to adjust for confounding effects of cell type in differential expression analysis (DEA). Results: We propose dtangle, a new cell type deconvolution method. dtangle works on a range of DNA microarray and bulk RNA-seq platforms. It estimates cell type proportions using publicly available, often cross-platform, reference data.We evaluate dtangle on eleven benchmark data sets showing that dtangle is competitive with published deconvolution methods, is robust to outliers and selection of tuning parameters, and is fast. As a case study, we investigate the human immune response to Lyme disease. dtangle's estimates reveal a temporal trend consistent with previous findings and are important covariates for DEA across disease status. Availability: dtangle is on CRAN (cran.r-project.org/package=dtangle) or github (dtangle.github.io). Supplementary Information: Supplementary data are available at Bioinformatics online. PMID- 30407493 TI - High efficiency referential genome compression algorithm. AB - Motivation: With the development and the gradually popularized application of next-generation sequencing technologies (NGS), genome sequencing has been becoming faster and cheaper, creating a massive amount of genome sequence data which still grows at an explosive rate. The time and cost of transmission, storage, processing and analysis of these genetic data have become bottlenecks that hinder the development of genetics and biomedicine. Although there are many common data compression algorithms, they are not effective for genome sequences due to their inability to consider and exploit the inherent characteristics of genome sequence data. Therefore, the development of a fast and efficient compression algorithm specific to genome data is an important and pressing issue. Results: We have developed a referential lossless genome data compression algorithm with better performance than previous algorithms. According to a carefully designed matching strategy selection mechanism, the advantages of local matching and global matching are reasonably combined together to improve the description efficiency of the matched sub-strings. The effects of the length and the position of matched sub-strings to the compression efficiency are jointly taken into consideration. The proposed algorithm can compress the FASTA data of complete human genomes, each of which is about 3G, in about 18 minutes. The compressed file sizes are ranging from dozens of megabytes to about 2 hundred megabytes. The averaged compression ratio is higher than that of the state-of-the art genome compression algorithms, the time complexity is at the same order of the best-known algorithms. Availability: https://github.com/jhchen5/SCCG. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30407494 TI - Shared genetic risk contributes to type 1 and type 2 diabetes etiology. AB - The extent to which shared genetic risk contributes to T1D and T2D etiology is unknown. In this study, we generated T1D association data of 15k samples imputed into the HRC panel which we compared to published T2D association data imputed into 1000 Genomes. The effects of genetic variants on T1D and T2D risk at known loci and genome-wide were positively correlated. Increased risk of T1D and T2D was correlated with higher fasting insulin and glucose level and decreased birth weight, among other correlations. Variants with T1D and T2D association were further enriched in pancreatic, adipose, B cell, and endoderm regulatory elements. We fine-mapped causal variants at known loci and found evidence for co localization at five signals, four of which had same direction of effect. Shared risk variants were associated with quantitative measures of islet function and early growth, and were expression QTLs in relevant tissues. We further identified a shared variant at GLIS3 in islet accessible chromatin with allelic effects on enhancer activity. Our findings identify a shared genetic risk involving effects on islet function as well as insulin resistance, growth and development in the etiology of T1D and T2D, supporting a role for T2D-relevant processes in addition to autoimmunity in T1D risk. PMID- 30407495 TI - The renal immune-inflammatory component of arterial hypertension: Emerging therapeutic strategies. PMID- 30407496 TI - Volumes of the Hippocampal Formation Differentiate Component Processes of Memory in a Community Sample of Homeless and Marginally Housed Persons. AB - Objective: Persons who are homeless or marginally housed exhibit significant cognitive dysfunction, with memory being the most impaired domain. Hippocampal subfield volumes have been found to differentially relate to component processes of memory. The neural correlates of memory have not been previously examined in marginalized persons who are understudied and underserved. We examined whether hippocampal subfields and entorhinal cortex volumes are uniquely related to indices of verbal episodic memory using the Hopkins Verbal Learning Test - Revised. Method: Data was used from a large sample of community dwelling homeless and marginally housed adults (N = 227). Regression analyses were conducted to examine hippocampal subfield volumes (CA1, CA3, CA4, dentate gyrus, subiculum) and entorhinal cortex, and their associations with measures of verbal immediate recall, learning slope, and verbal delayed recall. Results: Greater CA3 subfield volume was associated with better performance on an index of encoding (immediate recall), but only in older individuals. Greater CA1 and subiculum volumes were associated with better performance on immediate and delayed recall (measures that tap into retrieval processes), but not with learning slope (a more pure index of encoding). Entorhinal cortex volume was related to all components of memory beyond total hippocampal volume. Conclusions: Our results suggest common neuroanatomical correlates of memory dysfunction in large sample of marginalized persons, and these are uniquely related to different components of memory. These findings have clinical relevance for marginalized populations and theoretical relevance to the growing literature on functional specialization of the hippocampal subfields. PMID- 30407497 TI - CORRIGENDUM FOR "Advanced Glycation End Products and esRAGE Are Associated With Bone Turnover and Incidence of Hip Fracture in Older Men". PMID- 30407499 TI - CORRIGENDUM FOR "Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society* Clinical Practice Guideline". PMID- 30407498 TI - Impact of Standard Bacterial Vaginosis Treatment on the Genital Microbiota, Immune Milieu, and Ex Vivo Human Immunodeficiency Virus Susceptibility. AB - Background: Genital immunology is a key determinant of human immunodeficiency virus (HIV) susceptibility. Both factors are modulated by bacterial vaginosis (BV) and, to some extent, by Lactobacillus iners, the genital Lactobacillus spp. that predominates in African, Caribbean, and other Black (ACB) women. We conducted a clinical trial to assess the impact of oral metronidazole treatment on the genital immune parameters of HIV acquisition risks in Kenyan women with BV. Methods: The primary endpoint was ex vivo cervical CD4+ T-cell HIV susceptibility after 1 month; secondary endpoints included genital cytokine/chemokine levels, cervical immune cell populations, and the composition of the cervico-vaginal microbiota by 16S ribosomal RNA gene amplicon sequencing. Results: BV resolved (Nugent score <= 3) at 1 month in 20/45 participants, and cervical CD4+ T-cell HIV entry was moderately reduced in all participants, regardless of treatment outcome. Resolution of BV and reduced abundances of BV associated gram-negative taxa correlated with reduced genital interleukin (IL) 1alpha/beta. However, BV resolution and the concomitant colonization by Lactobacillus iners substantially increased several genital chemokines associated with HIV acquisition, including interferon-gamma inducible protein (IP)-10, macrophage inflammatory protein (MIP)-3alpha, and monokine induced by gamma interferon (MIG). In an independent cohort of ACB women, most of whom were BV free, vaginal chemokines were again closely linked with L. iners abundance, though not other Lactobacillus spp. Conclusions: BV treatment reduced genital CD4+ T-cell HIV susceptibility and IL-1 levels, but dramatically increased the genital chemokines that may enhance HIV susceptibility; the latter effect was related to the restoration of an Lactobacillus iners-dominated microbiota. Further studies are needed before treatment of asymptomatic BV can be recommended for HIV prevention in ACB communities. PMID- 30407500 TI - Clusterdv, a simple density-based clustering method that is robust, general and automatic. AB - Motivation: How to partition a data set into a set of distinct clusters is a ubiquitous and challenging problem. The fact that data varies widely in features such as cluster shape, cluster number, density distribution, background noise, outliers and degree of overlap, makes it difficult to find a single algorithm that can be broadly applied. One recent method, clusterdp, based on search of density peaks, can be applied successfully to cluster many kinds of data, but it is not fully automatic, and fails on some simple data distributions. Results: We propose an alternative approach, clusterdv, which estimates density dips between points, and allows robust determination of cluster number and distribution across a wide range of data, without any manual parameter adjustment. We show that this method is able to solve a range of synthetic and experimental data sets, where the underlying structure is known, and identifies consistent and meaningful clusters in new behavioral data. Availability: The clusterdv is implemented in Matlab. Its source code, together with example data sets, are available on: https://github.com/jcbmarques/clusterdv. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30407501 TI - The mortality burden of multidrug-resistant pathogens in India: a retrospective observational study. AB - Background: The threat posed by antibiotic resistance is of increasing concern in low- and middle-income countries (LMICs) as their rates of antibiotic use increase. However, an understanding of the burden of resistance is lacking in LMICs, particularly for multi-drug resistant (MDR) pathogens. Methods: We conducted a retrospective, ten hospital study of the relationship between MDR pathogens and mortality in India. Patient-level antimicrobial susceptibility tests (AST) results for Enterococcus spp., Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. were analyzed for their association with patient mortality outcomes. Results: We analyzed data on 5,103 AST results from 10 hospitals. The overall mortality rate of patients was 13.1% (n = 581), and there was a significant relationship between MDR and mortality. Infections with MDR and XDR E. coli, XDR K. pneumoniae, and MDR A. baumannii were associated with 2-3 times higher mortality. Mortality due to methicillin-resistant S. aureus (MRSA) was significantly higher than susceptible strains when the MRSA isolate was resistant to aminoglycosides. Conclusions: This is one of the largest studies undertaken in an LMIC to measure the burden of antibiotic resistance. We found that MDR bacterial infections pose a significant risk to patients. While consistent with prior studies, the variation in drug resistance and associated mortality outcomes by pathogen is different from that observed in high-income countries and provides a baseline for studies in other LMICs. Future research should aim to elucidate the burden of resistance and the differential transmission mechanisms that drive this public health crisis. PMID- 30407502 TI - Executive Dysfunction in Patients With Korsakoff's Syndrome: A Theory-Driven Approach. AB - Aims: In addition to amnesia, executive deficits are prominent in Korsakoff's syndrome (KS), yet poorly studied. This study investigates the degree of executive dysfunction in patients with KS for the three main executive subcomponents shifting, updating and inhibition using novel, theory-driven paradigms. Short summary: Compared to healthy controls, patients with KS show impairments on the executive subcomponents shifting and updating, but not on inhibition. Methods: Executive functions were measured with six carefully designed tasks in 36 abstinent patients with KS (mean age 62.3; 28% woman) and compared with 30 healthy non-alcoholic controls (mean age 61.8; 40% woman). ANOVAs were conducted to examine group differences and effect sizes were calculated. Results: Compared to healthy controls, patients with KS were impaired on the executive subcomponents shifting and updating. No statistically significant group difference was found on the factor inhibition. Conclusions: Executive dysfunction in long-abstinent patients with alcoholic KS shows a profile in which shifting and updating ability are affected most. It also highlights that executive dysfunction is an important feature of KS and requires more attention in scientific and clinical practice, as these deficits may also affect daily functioning. PMID- 30407503 TI - Inhibition of Phosphodiesterase 4 by FCPR03 Alleviates Chronic Unpredictable Mild Stress-induced Depressive-like Behaviors and Prevents Dendritic Spine Loss in Mice Hippocampi. AB - Background: Phosphodiesterase 4 (PDE4) is a promising target for developing novel antidepressants. However, prototype PDE4 inhibitors show severe side effects, including nausea and vomiting. FCPR03 is a novel PDE4 inhibitor with little emetic potential. In the present study, we investigated the inhibitory effect of FCPR03 on chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors in mice and explored the underlying mechanisms. Methods: The depression model of mice was established by CUMS. Forced swim test (FST), tail suspension test (TST) and sucrose preference test (SPT) were used to assess depressive-like behaviors. Golgi-staining was utilized to analyze dendritic morphology and spine density. The level of cAMP was measured by ELISA assay. Western blot was used to evaluate protein levels of phosphorylated cAMP-response element binding protein (CREB), protein kinase B (Akt), glycogen synthase kinase-3beta (GSK-3beta), brain derived neurotrophic factor (BDNF) in both hippocampus and prefrontal cortex. Postsynaptic density protein 95 (PSD95) and synapsin 1 were also detected by Western blot in the hippocampi. Results: Treatment with FCPR03 (0.5-1.0 mg/kg, i.p.) increased consumption of sucrose in SPT in mice exposed to CUMS. FCPR03 shorten the immobility time in FST and TST without affecting the locomotor activity. Furthermore, CUMS decreased the dendritic spine density and dendritic length in the hippocampus. This change was accompanied by decreased expression of PSD95 and synapsin 1. Interestingly, FCPR03 prevented dendritic spine loss and increased synaptic protein levels. Moreover, the levels of cAMP, phosphorylated CREB and BDNF were elevated in CUMS-challenged mice after treatment with FCPR03. In addition, FCPR03 also enhanced the phosphorylation of both Akt and GSK-3beta in mice exposed to CUMS. Conclusion: The present study suggests that FCPR03 could prevent both depressive-like behaviors and spine loss induced by CUMS in the mice hippocampi. PMID- 30407504 TI - Identification and validation of novel microenvironment-based immune molecular subgroups of head and neck squamous cell carcinoma: implications for immunotherapy. AB - Background: Targeting the immune checkpoint pathway has demonstrated anti-tumor cytotoxicity in treatment-refractory head and neck squamous cell carcinoma (HNSC). To understand the molecular mechanisms underpinning its anti-tumor response, we characterized the immune landscape of HNSC by their tumor and stromal compartments to identify novel immune molecular subgroups. Patients and methods: A training cohort of 522 HNSC samples from the Cancer Genome Atlas profiled by RNA sequencing was analyzed. We separated gene expression patterns from tumor, stromal, and immune cell gene using a non-negative matrix factorization algorithm. We correlated the expression patterns with a set of immune-related gene signatures, potential immune biomarkers, and clinicopathological features. Six independent datasets containing 838 HNSC samples were used for validation. Results: Approximately 40% of HNSCs in the cohort (211/522) were identified to show enriched inflammatory response, enhanced cytolytic activity and active interferon-gamma signaling (all, P < 0.001). We named this new molecular class of tumors the Immune Class. Then we found it contained two distinct microenvironment-based subtypes, characterized by markers of active or exhausted immune response. The Exhausted Immune Class was characterized by enrichment of activated stroma and anti-inflammatory M2 macrophage signatures, WNT/TGF-beta signaling pathway activation and poor survival (all, P < 0.05). An enriched proinflammatory M1 macrophage signature, enhanced cytolytic activity, abundant tumor-infiltrating lymphocytes (TILs), high human papillomavirus (HPV) infection and favorable prognosis was associated with Active Immune Class (all, P < 0.05). The robustness of these immune molecular subgroups was verified in the validation cohorts, and Active Immune Class showed potential response to PD-1 blockade (P = 0.01). Conclusions: This study revealed a novel Immune Class in HNSC; two subclasses characterized by active or exhausted immune responses were also identified. These findings provide new insights into tailoring immunotherapeutic strategies for different HNSC subgroups. PMID- 30407505 TI - Antidepressant Effects of Rhodomyrtone in Mice with Chronic Unpredictable Mild Stress-Induced Depression. AB - Background: Rhodomyrtone is one of the main active compounds derived from Rhodomyrtustomentosa, which belongs to the Myrtaceae family. In the current study, we investigated the properties of rhodomyrtone as a potential drug candidate for the treatment of stress-caused depression. Methods: We assessed the function of rhodomyrtone in chronic unpredictable mild stress (CUMS), a well validated depression model in mice. Depression-like behaviour tests, including a sucrose performance test, social interaction test, and forced swimming test, were used to validate the antidepressant effects of rhodomyrtone. The Morris water maze was used to evaluate the mice's learning and memory ability. Spine density, glycogen synthase kinase-3beta (GSK3beta), brain-derived neurotrophic factor (BDNF), postsynaptic density protein 95 (PSD-95), and apoptosis-associated protein were detected to reveal the underlying mechanism. Results: Rhodomyrtone was found to be able to prevent source consumption decrease, decreased social behaviours, and increase of immobility in the forced swimming test, suggesting a protective effect of rhodomyrtone against depression-like behaviours. Additionally, rhodomyrtone prevented the impairment of spatial memory in mice exposed to CUMS. Rhodomyrtone administration also reversed dendritic spine density defects in CUMS. Furthermore, rhodomyrtone inhibited the increase of GSK3beta activity and reversed the decrease of brain-derived neurotrophic factor and PSD-95 in CUMS mice. Elevated expression of apoptosis-associated protein Bax and cleaved-caspase 3 was also reversed by rhodomyrtone treatment. Conclusions: These results suggested that the antidepressant effect of rhodomyrtone involves the regulation of neurogenesis, neuronal survival, and synaptic plasticity in the hippocampus. PMID- 30407506 TI - Drosophila suzukii (Diptera: Drosophilidae) Oviposition and Adult Emergence in Six Wine Grape Varieties Grown in Virginia. AB - Drosophila suzukii (Matsumura) is a pest of small fruits and grapes in the United States and in its home range of Japan. Physiological and morphological laboratory testing was performed on six commonly grown wine grape varieties in Virginia. Skin thickness, penetration force, and oBrix were analyzed to determine ovipositional preferences. Experiments were performed for three consecutive years from grapes collected at one Virginia vineyard. More eggs were laid in intact Viognier grapes than any other variety. Oviposition into intact grapes was not affected by skin thickness or oBrix; however, oviposition increased when penetration force decreased. An ovipositional choice test determined no varietal preferences. Survivorship from egg to adulthood using uninjured and injured grapes was also assessed to determine varietal suitability as D. suzukii hosts, with more flies emerging from injured grapes than uninjured. However, D. suzukii adults did emerge from intact grapes and at higher percentages than previously recorded in other wine grape studies. All varieties had eggs oviposited into them when injured. Determining the time at which each grape variety became susceptible to oviposition was determined using a D. suzukii bioassay spanning 12 wk using grapes from the green pea stage until ripe. Susceptibility to D. suzukii oviposition was based upon ripening period and penetration force. Early ripening varieties may be more susceptible to D. suzukii oviposition in the field with later maturing, harder fleshed-varieties which may escape D. suzukii oviposition. PMID- 30407507 TI - Complex sex-biased antibody responses: Estrogen receptors bind estrogen response elements centered within immunoglobulin heavy chain gene enhancers. AB - Nuclear hormone receptors including the estrogen receptor (ERalpha) and the retinoic acid receptor regulate a plethora of biological functions including reproduction, circulation, and immunity. To understand how estrogen and other nuclear hormones influence antibody production, we characterized total serum antibody isotypes in female and male mice of C57BL/6J, BALB/cJ, and C3H/HeJ mouse strains. Antibody levels were higher in females compared to males in all strains and there was a female preference for IgG2b production. Sex -biased patterns were influenced by vitamin levels, and by antigen-specificity toward influenza virus or pneumococcus antigens. To help explain sex-biases, we examined the direct effects of estrogen on immunoglobulin heavy chain sterile transcript production among purified, LPS-stimulated B cells. Supplemental estrogen in B cell cultures significantly increased immunoglobulin heavy chain sterile transcripts. Chromatin immunoprecipitation analyses of activated B cells identified significant ERalpha binding to estrogen response elements (ERE) centered within enhancer elements of the immunoglobulin heavy chain locus, including the EMU enhancer and hypersensitive site 1,2 (HS1,2) in the 3' regulatory region. The ERE in HS1,2 was conserved across animal species, and in humans marked a site of polymorphism associated with the estrogen-augmented autoimmune disease, lupus. Taken together, results highlight: (i) important targets of ERalpha in regulatory regions of the immunoglobulin heavy chain locus that influence antibody production, and (ii) the complexity of mechanisms by which estrogen instructs sex-biased antibody production profiles. PMID- 30407508 TI - Emodin rescued hyperhomocysteinemia-induced dementia and Alzheimer's disease-like features in rats. AB - Background: Hyperhomocysteinemia (HHcy) is an independent risk factor for dementia, including Alzheimer's disease (AD). Lowering homocysteine levels with folic acid treatment with or without vitamin B12 was shown few clinical benefits on cognition. Methods: To verify the effect of emodin, a naturally active compound from Rheum officinale, on HHcy-induced dementia, rats were treated with homocysteine injection (HCY, 400 g/kg/day, 2 weeks) via vena caudalis. Afterwards, HCY rats with cognitive deficits were administered intragastric emodin at different concentrations, namely, 0 (HCY-E0), 20 (HCY-E20), 40 (HCY E40) and 80 mg/kg/day (HCY-E80) for 2 weeks. Results: beta-amyloid (Abeta) overproduction, tau hyperphosphorylation and losses of neuron and synaptic proteins were detected in the hippocampi of HCY-E0 rats with cognitive deficits. HCY-E40 and HCY-E80 rats had better behavioural performances. Although it did not reduce the plasma homocysteine level, emodin (especially 80 mg/kg/day) reduced the levels of Abeta and tau phosphorylation, decreased the levels of beta-site amyloid precursor protein-cleaving enzyme 1, and improved the activity of protein phosphatase 2A. In the hippocampi of HCY-E40 and HCY-E80 rats, the neuron numbers, levels of synaptic proteins and phosphorylation of the cAMP responsive element-binding protein at Ser133 were increased; in addition, depressed microglial activation and reduced levels of 5-lipoxygenase, interleukin-6 and tumour necrosis factor alpha were also observed. Lastly, HHcy-induced microangiopathic alterations, oxidative stress and elevated DNA methyltransferases 1 and 3 were rescued by emodin. Conclusions: Emodin represents a novel potential candidate agent for HHcy-induced dementia and AD-like features. PMID- 30407509 TI - Revealing of a novel xylose-binding site of Geobacillus stearothermophilus xylanase by directed evolution. AB - Xylan saccharification is a key step in many important biotechnological applications. Xylose is the main product of xylan degradation and is a major xylanase inhibitor in a bioreactor; however, xylose-binding site of xylanase is not discovered yet. Evolving of xylose-tolerant xylanase variants will reduce the cost of xylanases in industry. Glycoside hydrolase family-10 thermostable Geobacillus stearothermophilus xylanase XT6 is non-competitively inhibited by xylose with inhibition constant ki equals to 12.2 mM. In the absence of X-ray crystallography of xylanase-xylose complex, unbiased random mutagenesis of the whole xylanase gene was done by error-prone PCR constructing a huge library. Screening a part of the library revealed xylose-tolerant mutants having three mutations, M116I, L131P and L133V, clustered in the N-terminus of alpha-helix 3. The best xylose-tolerant mutant showed higher ki and catalytic capability than that of the parent by 3.5 and 3 folds, respectively. In addition, kcat increased 4.5-fold and KM decreased two-fold. The molecular docking of xylose into xylanase XT6 structure showed that xylose binds into a small pocket between N-terminus of alpha-helices 3 and 4 and close to the three mutations. Mobility of alpha-helices 3 and 4, which controls catalysis rate, is restricted by xylose binding and increased by these mutations. PMID- 30407510 TI - The impact of periconceptional maternal lifestyle on clinical features and biomarkers of placental development and function: a systematic review. AB - BACKGROUND: Worldwide, placenta-related complications contribute to adverse pregnancy outcomes, such as pre-eclampsia, fetal growth restriction and preterm birth, with implications for the future health of mothers and offspring. The placenta develops in the periconception period and forms the interface between mother and embryo/fetus. An unhealthy periconceptional maternal lifestyle, such as smoking, alcohol and under- and over-nutrition, can detrimentally influence placental development and function. OBJECTIVE AND RATIONALE: The impact of maternal lifestyle on placental health is largely unknown. Therefore, we aim to summarize the evidence of the impact of periconceptional maternal lifestyle on clinical features and biomarkers of placental development and function throughout pregnancy. SEARCH METHODS: A comprehensive search in Medline, Embase, Pubmed, The Cochrane Library Web of Science and Google Scholar was conducted. The search strategy included keywords related to the maternal lifestyle, smoking, alcohol, caffeine, nutrition (including folic acid supplement intake) and body weight. For placental markers throughout pregnancy, keywords related to ultrasound imaging, serum biomarkers and histological characteristics were used. We included randomized controlled trials and observational studies published between January 2000 and March 2017 and restricted the analysis to singleton pregnancies and maternal periconceptional lifestyle. Methodological quality was scored using the ErasmusAGE tool. A protocol of this systematic review has been registered in PROSPERO International prospective register of systematic reviews (PROSPERO 2016:CRD42016045596). OUTCOMES: Of 2593 unique citations found, 82 studies were included. The median quality score was 5 (range: 0-10). The findings revealed that maternal smoking was associated with lower first-trimester placental vascularization flow indices, higher second- and third-trimester resistance of the uterine and umbilical arteries and lower resistance of the middle cerebral artery. Although a negative impact of smoking on placental weight was expected, this was less clear. Alcohol use was associated with a lower placental weight. One study described higher second- and third-trimester placental growth factor (PlGF) levels after periconceptional alcohol use. None of the studies looked at caffeine intake. Adequate nutrition in the first trimester, periconceptional folic acid supplement intake and strong adherence to a Mediterranean diet, were all associated with a lower resistance of the uterine and umbilical arteries in the second and third trimester. A low caloric intake resulted in a lower placental weight, length, breadth, thickness, area and volume. Higher maternal body weight was associated with a larger placenta measured by ultrasound in the second and third trimester of pregnancy or weighed at birth. In addition, higher maternal body weight was associated with decreased PlGF-levels. WIDER IMPLICATIONS: Evidence of the impact of periconceptional maternal lifestyle on placental health was demonstrated. However, due to poorly defined lifestyle exposures and time windows of investigation, unstandardized measurements of placenta-related outcomes and small sample sizes of the included studies, a cautious interpretation of the effect estimates is indicated. We suggest that future research should focus more on physiological consequences of unhealthy lifestyle during the critical periconception window. Moreover, we foresee that new evidence will support the development of lifestyle interventions to improve the health of mothers and their offspring from the earliest moment in life. PMID- 30407511 TI - Association between BMI and semen quality: an observational study of 3966 sperm donors. AB - STUDY QUESTION: What is the relationship between abnormal BMI and semen quality? SUMMARY ANSWER: Underweight was significantly associated with lower sperm concentration, total sperm number and total motile sperm count, while overweight was significantly associated with lower semen volume, total sperm number and total motile sperm count. WHAT IS KNOWN ALREADY: Abnormal BMI has been associated with lower semen quality, but the results remain somewhat controversial. In addition, most previous studies have focused on the influence of obesity or overweight on semen quality, and evidence on the association between underweight and semen quality is rare. STUDY DESIGN, SIZE, DURATION: This research was an observational study investigating 3966 sperm donors from a large sperm bank in Wuhan city, China. These donors passed the screening for sperm donation and underwent 29 949 semen examinations between 1 January 2013 and 9 April 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: BMI was categorized into four groups: underweight (<18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2) and obese (>=30 kg/m2). Semen volume, sperm concentration, total sperm number, total motility, progressive motility and total motile sperm count were determined by trained clinical technicians. Linear mixed models were used to conduct dose-response analyses between BMI and semen quality parameters. MAIN RESULTS AND THE ROLE OF CHANCE: Underweight was significantly associated with a 3.0% (95% CI: 0.1%, 5.8%), 6.7% (1.9%, 11.3%) and 7.4% (2.2%, 12.4%) reduction in sperm concentration, total sperm number and total motile sperm count, respectively. Overweight was significantly associated with a 4.2% (1.6%, 6.8%), 3.9% (0.9%, 6.9%) and 3.6% (0.2%, 6.9%) reduction in semen volume, total sperm number and total motile sperm count, respectively. Non-linear models including continuous BMI as a natural cubic spline function yielded similar results. LIMITATIONS, REASONS FOR CAUTION: Our study subjects were sperm donors who are typically young and healthy, and therefore not representative of the general male population. Caution should be paid in generalizing our results to other populations. Furthermore, we did not measure the donors' weight repeatedly along with each semen donation; instead, we only measured it once during the screening, which may cause bias due to the variations of weight across time. WIDER IMPLICATIONS OF THE FINDINGS: Our study provides evidence that underweight and overweight are associated with lower semen quality, and highlights the importance of maintaining a normal weight for men. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Health and Family Planning Commission of Hubei Province (Grant number WJ2015MA027), the Hubei Provincial Committee of the Communist Youth League of China, and Center for Global and Regional Environmental Research at the University of Iowa. The authors declare that there are no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A. PMID- 30407512 TI - Short-term Pasteurization of Breast Milk to Prevent Postnatal Cytomegalovirus Transmission in Very Preterm Infants. AB - Background: Postnatally acquired cytomegalovirus (pCMV) infection through breast milk (BM) may cause severe illness and even death, yet BM is advantageous for preterm infants. Therefore, effective methods to prevent its transmission are needed. Objective: To assess the effectiveness of short-term pasteurization (62 degrees C for 5 seconds) in preventing CMV transmission via BM in preterm infants. Design: Prospective interventional bicentric cohort study with infant enrollment between 6/2010 and 1/2012. A cohort from the Tuebingen neonatal intensive care unit (NICU) from 1995-98 served as historical controls. Differences in CMV transmission were compared with reference to the cumulative time at risk for CMV-transmission. Setting: Two German level-3 NICUs. Participants: Eighty-seven preterm infants of 69 CMV IgG-positive mothers with birth weight <1500g or gestational age <32 weeks, and 83 historical controls, were included. Intervention: BM samples were short-term pasteurized from postnatal day four to discharge. Main Outcome and Measure: Primary endpoint was the CMV status at discharge, evaluated by PCR and short-term microculture from urine. Result: Two of 87 (2.3%) study infants had a postnatal CMV transmission. This compared to 17 of 83 (20.5%) controls. Total time under risk for infection was 9.6 years versus 10.0 years in controls, yielding an incidence of 0.21/year (95% CI 0.03 to 0.75/year) vs. 1.70/year (95% CI 0.99 to 2.72/year), respectively. The risk ratio controls vs. study infants was 8.3 (95% CI 2.4 to 52.4) according to Cox proportional hazard model (P=.0003). Conclusion: Short term pasteurization significantly reduces the incidence of pCMV infection through BM in the NICU. Trial Registration: The study was registered with clinicaltrials.gov (NCT01178905). PMID- 30407514 TI - Resistant Hypertension: An Update. PMID- 30407513 TI - Safety and immunogenicity of a heterologous prime-boost Ebola virus vaccine regimen - ChAd3-EBO-Z followed by MVA-EBO-Z in healthy adults in the UK and Senegal. AB - Background: The 2014 West African outbreak of Ebola virus disease highlighted the urgent need to develop an effective Ebola vaccine. Methods: We undertook two Phase I studies assessing safety and immunogenicity of the viral vector MVA-EBO Z, manufactured rapidly on a new duck cell line either alone or in a heterologous prime-boost regimen with ChAd3-EBO-Z followed by MVA-EBO-Z. Adult volunteers in the UK (n = 38) and Senegal (n=40) were vaccinated and an accelerated one week prime-boost regimen was assessed in Senegal. Safety was assessed by active and passive collection of local and systemic adverse events. Results: The standard and accelerated heterologous prime-boost regimes were well-tolerated and elicited potent cellular and humoral immunogenicity in the UK and Senegal, but vaccine induced antibody responses were significantly lower in Senegal. Cellular immune responses measured by flow cytometry were significantly greater in African vaccinees receiving ChAd3 and MVA vaccines in the same rather than the contralateral limb. Conclusions: MVA biomanufactured on an immortalised duck cell line shows potential for very large-scale manufacturing with lower cost of goods. This first trial of MVA-EBO-Z in humans encourages further testing in Phase II studies with the one week prime-boost interval regimen appearing particularly suitable for outbreak control. PMID- 30407515 TI - Second victims in the labor ward: Are Danish midwives and obstetricians getting the support they need? AB - Objective: To describe midwives' and obstetricians' experiences on the level of support from colleagues and managers in Danish labor wards following adverse events. Design, setting and participants: A 2012 National survey of Danish obstetricians and midwives was conducted to assess the level of support received in the workplace. Main outcome measures: Scales on social community at work, social support from colleagues and immediate superiors, and use of support mechanisms on labor wards after serious adverse events were assessed. Results: 2098 midwives and obstetricians were invited to complete the survey (response rate 59%), and the analyses were carried out on the 593 respondents who had been involved in at least one traumatic childbirth at their current place of work. Respondents experienced high levels of social support from colleagues and social community at work, midwives significantly higher than obstetricians, and 95% of respondents had talked to colleagues about an adverse event. Respondents generally experienced low levels of social support and feedback from immediate superiors, and only 49% had talked to their immediate superior about an adverse event. Fifty% believed that the hospital had a clear process through which they could report adverse events, and 44% knew how to access the necessary confidential emotional support at work. Conclusions: Midwives and obstetricians experienced high levels of social support and feedback from colleagues who are the most frequent individuals to consult after adverse events. We strongly suggest developing second victim support programmes with a focus on offering peer support from qualified and trained peers. PMID- 30407516 TI - IMP1 3' UTR shortening enhances metastatic burden in colorectal cancer. AB - The RNA binding protein insulin-like growth factor 2 mRNA binding protein 1 (IMP1) is overexpressed in colorectal cancer (CRC); however, evidence for a direct role for IMP1 in CRC metastasis is lacking. IMP1 is regulated by let-7 microRNA, which binds in the 3' untranslated region (UTR) of the transcript. The availability of binding sites is in part controlled by alternative polyadenylation (APA), which determines 3' UTR length. Expression of the short 3' UTR transcript (lacking all miRNA sites) results in higher protein levels and is correlated with increased proliferation. We used in vitro and in vivo model systems to test the hypothesis that the short 3' UTR isoform of IMP1 promotes CRC metastasis. Herein we demonstrate that 3' UTR shortening increases IMP1 protein expression and that this in turn enhances the metastatic burden to the liver, whereas expression of the long isoform (full length 3' UTR) does not. Increased tumor burden results from elevated tumor surface area driven by cell proliferation and cell survival mechanisms. These processes are independent of classical apoptosis pathways. Moreover, we demonstrate the shifts toward the short isoform are associated with metastasis in patient populations where IMP1 long expression predominates. Overall, our work demonstrates that different IMP1 expression levels result in different functional outcomes in CRC metastasis and that targeting IMP1 may reduce tumor progression in some patients. PMID- 30407517 TI - Support for teams, technology and patient involvement in decision-making associated with support for patient-centred care. AB - Objective: Patient-centred care is recommended to transform healthcare delivery to improve the quality and safety of healthcare. This study aimed to assess the determinants of support for attributes of patient-centred care (PCC) from Canadian public and professionals' perspectives. Design: A national population based survey, the Health Care in Canada Survey. Setting: None. Participants: One thousand Canadian adults, 101 doctors, 100 nurses, 100 pharmacists and 104 administrators, randomly selected from online panels based on multiple source recruitment. Intervention: None. Main Outcome Measure: Support for PCC, assessed using a summary score across seven items. Results: Of 1000 Canadian public adults surveyed, 51% were female, 74% were living with another person, and 62% had at least one chronic condition. Only 18% of health professionals were working in teams. Multivariable regression models showed that work in teams (0.24, 95%CI: 0.20, 0.28), use of e-technology (0.29, 95%CI: 0.17, 0.42), and patient older age (0.59, 95%CI: 0.32, 0.86) and involvement in decision-making (0.42, 95%CI: 0.30, 0.55) were significantly associated with higher support for PCC while lower adherence to medications (-0.81, 95%CI: -1.16, -0.47) was associated with a decreased support for attributes of PCC. Conclusions: The findings confirmed that perceptions of requiring health professionals to work in teams and the use of technology in healthcare are associated with support for PCC from both the public and health professionals. Programs to accelerate the implementation of healthcare teams supported by information and communication technologies are needed to deliver PCC, particularly for individuals living with chronic conditions. PMID- 30407518 TI - An efficient use of X-Ray information, Homology Modeling, Molecular Dynamics and Knowledge-based Docking techniques to predict Protein-monosaccharide complexes. AB - Unraveling the structure of lectin-carbohydrate complexes is vital for understanding key biological recognition processes and development of glycomimetic drugs. Molecular Docking application to predict them is challenging due to their low affinity, hydrophilic nature and ligand conformational diversity. In the last decade several strategies, such as the inclusion of glycan conformation specific scoring functions or our developed solvent-site biased method, have improved carbohydrate docking performance but significant challenges remain, in particular, those related to receptor conformational diversity.In the present work we have analyzed conventional and solvent-site biased autodock4 performance concerning receptor conformational diversity as derived from different crystal structures (apo and holo), Molecular Dynamics snapshots and Homology-based models, for fourteen different lectin-monosaccharide complexes. Our results show that both conventional and biased docking yield accurate lectin monosaccharide complexes, starting from either apo or homology-based structures, even when only moderate ( < 45%) sequence identity templates are available. An essential element for success is a proper combination of a middle-sized (10-100 structures) conformational ensemble, derived either from Molecular dynamics or multiple homology model building. Consistent with our previous works, results show that solvent-site biased methods improve overall performance, but that results are still highly system dependent. Finally, our results also show that docking can select the correct receptor structure within the ensemble, underscoring the relevance of joint evaluation of both ligand pose and receptor conformation. PMID- 30407520 TI - Building a livestock genetic and genomic information knowledgebase through integrative developments of Animal QTLdb and CorrDB. AB - Successful development of biological databases requires accommodation of the burgeoning amounts of data from high-throughput genomics pipelines. As the volume of curated data in Animal QTLdb (https://www.animalgenome.org/QTLdb) increases exponentially, the resulting challenges must be met with rapid infrastructure development to effectively accommodate abundant data curation and make metadata analysis more powerful. The development of Animal QTLdb and CorrDB for the past 15 years has provided valuable tools for researchers to utilize a wealth of phenotype/genotype data to study the genetic architecture of livestock traits. We have focused our efforts on data curation, improved data quality maintenance, new tool developments, and database co-developments, in order to provide convenient platforms for users to query and analyze data. The database currently has 158 499 QTL/associations, 10 482 correlations and 1977 heritability data as a result of an average 32% data increase per year. In addition, we have made >14 functional improvements or new tool implementations since our last report. Our ultimate goals of database development are to provide infrastructure for data collection, curation, and annotation, and more importantly, to support innovated data structure for new types of data mining, data reanalysis, and networked genetic analysis that lead to the generation of new knowledge. PMID- 30407519 TI - Change in Bacterial Causes of Community-Acquired Parapneumonic Effusion and Pleural Empyema in Children 6 Years After 13-Valent Pneumococcal Conjugate Vaccine Implementation. AB - We describe here changes in the bacterial causes of pleural empyema before and after implementation of the 13-valent pneumococcal conjugate vaccine (PCV13) program in France (2009-2017). For 220 (39.3%) of 560 children, a bacterial cause was found. The frequency of pneumococcal infection decreased during the study from 79.1% in 2009 to 36.4% in 2017 (P < .001). Group A streptococcus is now the leading cause of documented empyema (45.5%). PMID- 30407522 TI - Single-cell analyses identify distinct and intermediate states of zebrafish pancreatic islet development. AB - Pancreatic endocrine islets are vital for glucose homeostasis. However, the islet developmental trajectory and its regulatory network are not well understood. To define the features of these specification and differentiation processes, we isolated individual islet cells from TgBAC(neurod1:EGFP) transgenic zebrafish and analyzed islet developmental dynamics across four different embryonic stages using a single-cell RNA-seq strategy. We identified proliferative endocrine progenitors, which could be further categorized by different cell cycle phases with the G1/S sub-population displaying a distinct differentiation potential. We identified endocrine precursors, a heterogeneous intermediate-state population consisting of lineage-primed alpha, beta and delta cells that were characterized by the expression of lineage-specific transcription factors and relatively low expression of terminally differentiation markers. The terminally differentiated alpha, beta and delta cells displayed stage-dependent differentiation states, which were related to their functional maturation. Our data unveiled distinct states, events and molecular features during the islet developmental transition, and provided resources to comprehensively understand the lineage hierarchy of islet development at the single-cell level. PMID- 30407523 TI - Long title: C1q-tumor necrosis factor-related protein-3 exacerbates cardiac hypertrophy in mice. AB - Aims: C1q-tumor necrosis factor-related protein-3 (CTRP3) is an adipokine and a paralog of adiponectin. Our previous study showed that CTRP3 attenuated diabetes related cardiomyopathy. However, the precise role of CTRP3 in cardiac hypertrophy remains unclear. This study was aimed to clarify the role of CTRP3 involved in cardiac hypertrophy. Methods and results: Cardiomyocyte-specific CTRP3 overexpression was achieved using an adeno-associated virus system, and cardiac CTRP3 expression was knocked down using gene delivery of specific short hairpin RNAs in vivo. CTRP3 expression was upregulated in murine hypertrophic hearts and failing human hearts. Increased CTRP3 was mainly derived from cardiomyocytes and induced by the production of reactive oxygen species (ROS) during the hypertrophic response. CTRP3-overexpressing mice exhibited exacerbated cardiac hypertrophy and cardiac dysfunction in response to pressure overload. Conversely, Ctrp3 deficiency in the heart resulted in an alleviated hypertrophic phenotype. CTRP3 induced hypertrophy in cardiomyocytes, which could be blocked by the addition of CTRP3 antibody in the media. Detection of signaling pathways showed that pressure overload-induced activation of the transforming growth factor beta activated kinase 1 (TAK1)-c-Jun N-terminal kinase (JNK) pathway was enhanced by CTRP3 overexpression and inhibited by CTRP3 disruption. Furthermore, we found that CTRP3 lost its pro-hypertrophic effects in cardiomyocyte-specific Tak1 knockout mice. Protein kinase A (PKA) was involved in the activation of TAK1 by CTRP3. Conclusion: In conclusion, our results suggest that CTRP3 promotes pressure overload-induced cardiac hypertrophy via activation of the TAK1-JNK axis. PMID- 30407524 TI - Shades of competence? A critical analysis of the cultural competencies of the regulated-health workforce in Aotearoa New Zealand. AB - Objective: To critically examine, within the New Zealand context, the regulated health practitioners' cultural competencies, their readiness to deliver culturally responsive health services to Maori (Indigenous peoples) and identify areas for development. Design: A mixed methods critical analysis of the regulatory bodies' cultural competency standards for health practitioners from their websites. Setting: The New Zealand regulated-health workforce, legislated by the Health Practitioners' Competency Assurance Act 2003 and the Medical Practitioners Act 2007, requires practitioners to regularly demonstrate cultural competence. Participants: The information provided on the websites of the 16 professional bodies for regulated-health practitioners. Main Outcome Measure(s): These standards were analysed against indicators of the knowledge-action integration (KAI) framework for culturally responsive practice, and scored according to these being explicit, not explicit, or not evident. Results: Competency standards aligned to the 'knowledge' component were more likely to be explicit requirements. This included indicators related to understanding personal cultural values, beliefs, practices, assumptions, stereotypes and biases and the influence these have on practice. However, the 'action' and 'integration' components were less likely to be explicit. Five regulatory bodies provided no definitions of cultural competence. There was mixed engagement with te Tiriti o Waitangi or the Treaty of Waitangi. Conclusions: Variation in clarity surrounding requirements for cultural competence/responsiveness exists across most health regulatory bodies. Notably, the measurability of many standards tended to lack precision. Universal cultural competence standards could support health practitioners to deliver an improved healthcare experience for Maori, emphasizing cultural competence as a quality and safety issue. PMID- 30407525 TI - Epigenetics, DNA Organization, and Inflammatory Bowel Disease. AB - Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders affecting the gastrointestinal tract. The incidence of IBD is increasing, with more cases occurring in developed countries. Multiple factors such as genetics, environmental changes, gut microbiota, and immune abnormalities have been associated with development of IBD. In recent years, it has become increasingly apparent that epigenetic modifications of chromatin and the manner in which chromatin is organized in the nucleus are additionally important elements that can influence responses induced by the factors described above, and may therefore contribute to the onset and pathogenesis of IBD. Epigenetics and chromatin organization regulate diverse functions that include maintenance of homeostasis in the intestinal epithelium, the development and differentiation of immune cells, and modulation of responses generated by the immune system to defend against potential pathogens. Furthermore, changes in epigenetic chromatin marks and in chromatin organization have now been linked to differential gene expression in IBD patient cells. Although direct evidence for a role of histone modifications in IBD is currently very limited, in this review, we summarize the links between various epigenetic modifications, the proteins that catalyze or recognize these modifications, and the development or progression of IBD in human and experimental IBD. We also discuss how epigenetics influence the organization of DNA contacts to regulate gene expression and the implications this may have for diagnosing and treating IBD. PMID- 30407526 TI - Presence of Sergentomyia (Parrotomyia) lewisi (Diptera: Psychodidae) in Tunisia. AB - In Tunisia, 17 phlebotomine sand fly species are reported, belonging to genera Phlebotomus and Sergentomyia. However, subsequent to faunal studies and outbreaks of leishmaniasis in different regions of the country, unrecognized sand fly species could exist. Indeed, we report in this study the presence of Sergentomyia (Parrotomyia) lewisiParrot 1948. A brief collection of phlebotomine sand flies was undertaken in August 2016 in Khbina locality, in Sidi Bouzid governorate situated in Central Tunisia, which constitutes an old focus of Zoonotic Cutaneous Leishmaniasis. Sand flies were collected, using CDC light traps that were placed overnight, in different biotopes (inside habitations, outdoors, and within animal shelters). Specimens were collected and morphologically identified. Measurements were taken with an ocular micrometer. Two female specimens of the species Se. (Parrotomyia) lewisi were collected. One specimen is here described and measured. A comparison of its taxonomic characters to the holotype from Sudan and a specimen from Algeria is also presented. This species was until now only reported from Sudan, Ethiopia, Algeria, and Morocco. It is here described for the first time in Tunisia, which raises the Tunisian sand fly fauna to seven subgenera and 18 species. PMID- 30407527 TI - Erratum to Ulcerative Colitis and Atypical Hemolytic-Uremic Syndrome: An Unusual But Potentially Life-threatening Complication. PMID- 30407521 TI - Ensembl 2019. AB - The Ensembl project (https://www.ensembl.org) makes key genomic data sets available to the entire scientific community without restrictions. Ensembl seeks to be a fundamental resource driving scientific progress by creating, maintaining and updating reference genome annotation and comparative genomics resources. This year we describe our new and expanded gene, variant and comparative annotation capabilities, which led to a 50% increase in the number of vertebrate genomes we support. We have also doubled the number of available human variants and added regulatory regions for many mouse cell types and developmental stages. Our data sets and tools are available via the Ensembl website as well as a through a RESTful webservice, Perl application programming interface and as data files for download. PMID- 30407528 TI - Monitoring regression of post-orthodontic lesions with impedance spectroscopy: a pilot study. AB - Objective: To investigate if the alternating current impedance spectroscopy (ACIS) technology could be used to monitor remineralization of post-orthodontic white spot lesions (WSLs) after debonding of fixed orthodontic appliances. Material and methods: The study group consisted of 28 adolescents (aged 12-16 years) with at least two WSLs on their maxillary incisors, canines, or first premolars at debonding. Buccal surfaces (n = 194) were visually examined and scored with modified International Caries Detection and Assessment System (ICDAS) criteria and with the CarieScan Pro device by three examiners according to manufactures manual (test method). In addition, 31 surfaces with ICDAS = 0 were monitored by ACIS, serving as controls. Follow-up examinations were carried out after 8 and 16 weeks. Modified ICDAS scores, captured from digital photographs by three independent examiners, served as reference method. Four patients were lost to follow-up. Data were analysed in a mixed statistical model considering systematic effects of visit, tooth and observer, random effects of patients, and visits within patients. Results: Over 50 per cent of all surfaces had marked WSL at baseline and the corresponding values at 8 and 16 weeks were 33 per cent and 22 per cent. The ACIS readings mirrored the visual scores; the baseline estimate (56.3) was significantly decreased after 8 weeks (P < 0.05). The lateral incisors exhibited the highest values whereas the lowest were recorded for the central incisors. Limitations: ICDAS is not the same as a 'true' gold standard. The high prevalence of WSL may jeopardize the external validity. Conclusion: The ACIS technology may to some extent be used to monitor the regression of post orthodontic WSLs. PMID- 30407529 TI - BioSamples database: an updated sample metadata hub. AB - The BioSamples database at EMBL-EBI provides a central hub for sample metadata storage and linkage to other EMBL-EBI resources. BioSamples has recently undergone major changes, both in terms of data content and supporting infrastructure. The data content has more than doubled from around 2 million samples in 2014 to just over 5 million samples in 2018. Fast, reciprocal data exchange was fully established between sister Biosample databases and other INSDC partners, enabling a worldwide common representation and centralization of sample metadata. The BioSamples platform has been upgraded to accommodate anticipated increases in the number of submissions via GA4GH driver projects such as the Human Cell Atlas and the EGA, as well as from mirroring of NCBI dbGaP data. The BioSamples database is now the authoritative repository for all INSDC sample metadata, an ELIXIR Deposition Database for Biomolecular Data and the EMBL-EBI sample metadata hub. To support faster turnaround for sample submission, and to increase scalability and resilience, we have upgraded the BioSamples database backend storage, APIs and user interface. Finally, the website has been redesigned to allow search and retrieval of records based on specific filters, such as 'disease' or 'organism'. These changes are targeted at answering current use cases as well as providing functionalities for future emerging and anticipated developments. Availability: The BioSamples database is freely available at http://www.ebi.ac.uk/biosamples. Content is distributed under the EMBL-EBI Terms of Use available at https://www.ebi.ac.uk/about/terms-of-use. PMID- 30407530 TI - DeepT3: deep convolutional neural networks accurately identify Gram-Negative Bacterial Type III Secreted Effectors using the N-terminal sequence. AB - Motivation: Various bacterial pathogens can deliver their secreted substrates also called effectors through type III secretion systems (T3SSs) into host cells and cause diseases. Since T3SS secreted effectors (T3SEs) play important roles in pathogen-host interactions, identifying them is crucial to our understanding of the pathogenic mechanisms of T3SSs. However, the effectors display high level of sequence diversity, therefore making the identification a difficult process. There is a need to develop a novel and effective method to screen and select putative novel effectors from bacterial genomes that can be validated by a smaller number of key experiments. Results: We develop a deep convolution neural network to directly classify any protein sequence into T3SEs or non-T3SEs, which is useful for both effector prediction and the study of sequence-function relationship. Different from traditional machine learning based methods, our method automatically extracts T3SE-related features from a protein N-terminal sequence of 100 residues and maps it to the T3SEs space. We train and test our method on the datasets curated from 16 species, yielding an average classification accuracy of 83.7% in the 5-fold cross validation and an accuracy of 92.6% for the test set. Moreover, when comparing with known state-of-the-art prediction methods, the accuracy of our method is 6.31%-20.73% higher than previous methods on a common independent dataset. Besides, we visualize the convolutional kernels and successfully identify the key features of T3SEs, which contain important signal information for secretion. Finally, some effectors reported in the literature are used to further demonstrate the application of DeepT3. Availability: DeepT3 is freely available at: https://github.com/lje00006/DeepT3. Supplementary information: Supplementary data are available at Bioinformatics online.v. PMID- 30407531 TI - Dissecting the genomic diversification of LATE EMBRYOGENESIS ABUNDANT (LEA) protein gene families in plants. AB - Late Embryogenesis Abundant (LEA) proteins include eight multi-gene families that are expressed in response to water loss during seed maturation and in vegetative tissues of desiccation tolerant species. To elucidate LEA proteins evolution and diversification, we performed a comprehensive synteny and phylogenetic analyses of the eight gene families across 60 complete plant genomes. Our integrated comparative genomic approach revealed that synteny conservation and diversification contributed to LEA family expansion and functional diversification in plants. We provide examples that: 1) the genomic diversification of the Dehydrin family contributed to differential evolution of amino acid sequences, protein biochemical properties, and gene expression patterns, and led to the appearance of a novel functional motif in angiosperms; 2) ancient genomic diversification contributed to the evolution of distinct intrinsically disordered regions of LEA_1 proteins; 3) recurrent tandem duplications contributed to the large expansion of LEA_2; and, 4) dynamic synteny diversification played a role on the evolution of LEA_4 and its function on plant desiccation tolerance. Taken together, these results show that multiple evolutionary mechanisms have not only led to genomic diversification, but also to structural and functional plasticity among LEA proteins which have jointly contributed to the adaptation of plants to water-limiting environments. PMID- 30407533 TI - Genome-wide function of MCM-BP in Trypanosoma brucei DNA replication and transcription. AB - In Trypanosoma brucei, genes are arranged in Polycistronic Transcription Units (PTUs), which are demarcated by transcription start and stop sites. Transcription start sites are also binding sites of Origin Recognition Complex 1 (ORC1). This spatial coincidence implies that transcription and replication in trypanosomes must occur in a highly ordered and cooperative manner. Interestingly, a previously published genetic screen identified the T. brucei MCM-BP, which interacts with subunits of MCM helicase, as a protein whose downregulation results in the loss of transcriptional silencing at subtelomeric loci. Here, I show that TbMCM-BP is required for DNA replication and transcription. TbMCM-BP depletion causes a significant reduction of replicating cells in S phase and genome-wide impairments of replication origin activation. Moreover, levels of sense and antisense transcripts increase at boundaries of PTUs in the absence of TbMCM-BP. TbMCM-BP is also important for transcriptional repression of the specialized subtelomeric PTUs, the Bloodstream-form Expression-Sites (BESs), which house the major antigenic determinant (the Variant Surface Glycoprotein, VSG gene) as well as TbORC1 binding sites. Overall, this study reveals that TbMCM BP, a replication initiation protein, also guides the initiation, termination and directionality of transcription. PMID- 30407532 TI - MaizeGDB 2018: the maize multi-genome genetics and genomics database. AB - Since its 2015 update, MaizeGDB, the Maize Genetics and Genomics database, has expanded to support the sequenced genomes of many maize inbred lines in addition to the B73 reference genome assembly. Curation and development efforts have targeted high quality datasets and tools to support maize trait analysis, germplasm analysis, genetic studies, and breeding. MaizeGDB hosts a wide range of data including recent support of new data types including genome metadata, RNA seq, proteomics, synteny, and large-scale diversity. To improve access and visualization of data types several new tools have been implemented to: access large-scale maize diversity data (SNPversity), download and compare gene expression data (qTeller), visualize pedigree data (Pedigree Viewer), link genes with phenotype images (MaizeDIG), and enable flexible user-specified queries to the MaizeGDB database (MaizeMine). MaizeGDB also continues to be the community hub for maize research, coordinating activities and providing technical support to the maize research community. Here we report the changes MaizeGDB has made within the last three years to keep pace with recent software and research advances, as well as the pan-genomic landscape that cheaper and better sequencing technologies have made possible. MaizeGDB is accessible online at https://www.maizegdb.org. PMID- 30407534 TI - The UCSC Genome Browser database: 2019 update. AB - The UCSC Genome Browser (https://genome.ucsc.edu) is a graphical viewer for exploring genome annotations. For almost two decades, the Browser has provided visualization tools for genetics and molecular biology and continues to add new data and features. This year, we added a new tool that lets users interactively arrange existing graphing tracks into new groups. Other software additions include new formats for chromosome interactions, a ChIP-Seq peak display for track hubs and improved support for HGVS. On the annotation side, we have added gnomAD, TCGA expression, RefSeq Functional elements, GTEx eQTLs, CRISPR Guides, SNPpedia and created a 30-way primate alignment on the human genome. Nine assemblies now have RefSeq-mapped gene models. PMID- 30407535 TI - Associations between pancreatic lipids and beta-cell function in Black African and White European men with type 2 diabetes. AB - Context: Intrapancreatic lipid (IPL) has been linked with beta-cell dysfunction. Black populations suffer disproportionately from type 2 diabetes (T2D) and show distinctions in beta-cell function compared to Whites. Objective: We aimed to quantify IPL in White European (WE) and Black West African (BWA) men with early T2D, and to investigate relationships between IPL and beta-cell insulin secretory function (ISF). Design, Setting and Participants: We performed a cross-sectional assessment of 18 WE and 19 BWA middle-aged men with early T2D as part of the South London Diabetes and Ethnicity Phenotyping (Soul-Deep) study. Main Outcome Measures: Participants underwent Dixon magnetic resonance imaging to determine IPL in the pancreatic head, body, and tail, and subcutaneous and visceral adipose tissue volumes. Modelled first-phase and second-phase ISF were comprehensively determined using c-peptide measurements during a 3-hour meal tolerance test and a 2-hour hyperglycemic clamp test. Results: WE men had higher mean IPL than BWA men (P=0.029), mainly due to higher IPL in the pancreatic head in WE men (P=0.009). Mean IPL was inversely associated with orally stimulated first-phase ISF in WE but not BWA men (WE: r=-0.554, P=0.026; BWA: r=-0.183, P=0.468); there was no association with orally stimulated second-phase ISF in either WE or BWA men. No significant associations were found between mean IPL and intravenously stimulated ISF. Conclusions: IPL is lower in BWA than WE men with early T2D, and the lack of inverse association with orally stimulated first phase ISF in BWA men indicates that IPL may be a less important determinant of the development of T2D in BWA compared to WE men. PMID- 30407536 TI - PreMedKB: an integrated precision medicine knowledgebase for interpreting relationships between diseases, genes, variants and drugs. AB - One important aspect of precision medicine aims to deliver the right medicine to the right patient at the right dose at the right time based on the unique 'omics' features of each individual patient, thus maximizing drug efficacy and minimizing adverse drug reactions. However, fragmentation and heterogeneity of available data makes it challenging to readily obtain first-hand information regarding some particular diseases, drugs, genes and variants of interest. Therefore, we developed the Precision Medicine Knowledgebase (PreMedKB) by seamlessly integrating the four fundamental components of precision medicine: diseases, genes, variants and drugs. PreMedKB allows for search of comprehensive information within each of the four components, the relationships between any two or more components, and importantly, the interpretation of the clinical meanings of a patient's genetic variants. PreMedKB is an efficient and user-friendly tool to assist researchers, clinicians or patients in interpreting a patient's genetic profile in terms of discovering potential pathogenic variants, recommending therapeutic regimens, designing panels for genetic testing kits, and matching patients for clinical trials. PreMedKB is freely accessible and available at http://www.fudan-pgx.org/premedkb/index.html#/home. PMID- 30407538 TI - Protein Targeting to Starch 1 (PTST1) is essential for starchy endosperm development in barley. AB - Plant starch is the main energy contributor to the human diet. Its biosynthesis is catalyzed and regulated by coordinated actions of several enzymes. Recently, a factor termed Protein Targeting to Starch 1 (PTST1) was identified to be required for correct GBSS localization and demonstrated to be crucial for amylose synthesis in Arabidopsis. However, the function of its homologous protein in storage tissues (e.g. endosperm) is unknown. We identified a PTST1 homolog in barley and it was found to contain crucial coiled coil domain and carbohydrate binding module. We demonstrated the interaction between PTST1 and a granule bound starch synthase 1 (GBSS1) by fluorescence resonance energy transfer (FRET) in barley endosperm. By tagging PTST1 with the fluorophore mCherry, we observed that it is localized in the stroma of barley endosperm amyloplasts. PTST1 overexpression in endosperms increased endogenous gbss1a gene expression and amylose content. Gbss1a and ptst1 mutants were generated using CRISPR-Cas9-based targeted mutagenesis. Homozygous gbss1a mutants showed a waxy phenotype. Grains of ptst1 mutants did not accumulate any starch. These grains dried out during desiccation stage and were unable to germinate. This suggests that PTST1 is essential for development of starchy endosperm and viable grains. PMID- 30407539 TI - Synchrotron FTIR and Raman spectroscopy provide unique spectral fingerprints for Arabidopsis floral stem vascular tissues. AB - Cell walls are highly complex structures that are modified during plant growth and development. For example, the development of phloem and xylem vascular cells, which participate in the transport of sugars and water as well as support, can be influenced by cell-specific cell wall composition. Here, we used synchrotron radiation-based infrared (SR-FTIR) and Raman spectroscopy to analyze the cell wall composition of wild-type and double mutant sweet11-1sweet12-1, which impairs sugar transport, Arabidopsis floral stem vascular tissue. The SR-FTIR spectra showed that in addition to modified xylem cell wall composition, phloem cell walls in the double mutant line were characterized by modified hemicellulose composition. Moreover, combining Raman spectroscopy with a Classification and Regression Tree (CART) method identified combinations of Raman shifts that could distinguish xylem vessels and fibers. Additionally, the disruption of SWEET11 and SWEET12 genes impacts xylem cell wall composition in a cell-specific manner, with changes in hemicelluloses and cellulose observed at the xylem vessel interface. These results suggest that the facilitated transport of sugars by transporters that exist between vascular parenchyma cells and conducting cells is important to ensuring correct phloem and xylem cell wall composition. PMID- 30407537 TI - Integration of genetics and miRNA-target gene network identified disease biology implicated in tissue specificity. AB - MicroRNAs (miRNAs) modulate the post-transcriptional regulation of target genes and are related to biology of complex human traits, but genetic landscape of miRNAs remains largely unknown. Given the strikingly tissue-specific miRNA expression profiles, we here expand a previous method to quantitatively evaluate enrichment of genome-wide association study (GWAS) signals on miRNA-target gene networks (MIGWAS) to further estimate tissue-specific enrichment. Our approach integrates tissue-specific expression profiles of miRNAs (~1800 miRNAs in 179 cells) with GWAS to test whether polygenic signals enrich in miRNA-target gene networks and whether they fall within specific tissues. We applied MIGWAS to 49 GWASs (nTotal = 3 520 246), and successfully identified biologically relevant tissues. Further, MIGWAS could point miRNAs as candidate biomarkers of the trait. As an illustrative example, we performed differentially expressed miRNA analysis between rheumatoid arthritis (RA) patients and healthy controls (n = 63). We identified novel biomarker miRNAs (e.g. hsa-miR-762) by integrating differentially expressed miRNAs with MIGWAS results for RA, as well as novel associated loci with significant genetic risk (rs56656810 at MIR762 at 16q11; n = 91 482, P = 3.6 * 10-8). Our result highlighted that miRNA-target gene network contributes to human disease genetics in a cell type-specific manner, which could yield an efficient screening of miRNAs as promising biomarkers. PMID- 30407540 TI - Horizontal Gene Transfer in Five Parasite Plant Species in Orobanchaceae. AB - We sequenced genomes of five parasite species in family Orobanchaceae to explore the evolutionary role of horizontal gene transfer in plants. Orobanche minor and Aeginetia indica are obligate parasites with no photosynthetic activity, while the other three (Pedicularis keiskei, Phtheirospermum japonicum, and Melampyrum roseum) are facultative parasites. By using reference genome sequences and/or transcriptomes of 14 species from Fabaceae and Poaceae, their major host families, we detected 106 horizontally transferred genes (HGT genes), only in the genomes of the two obligate parasites (22 and 84 for O. minor and A. indica, respectively), while none in the three facultative parasites. The HGT genes, respectively, account for roughly 0.1 and 0.2% of the coding genes in the two species. We found that almost all HGT genes retained introns at the same locations as their homologs in potential host species, indicating a crucial role of DNA-mediated gene transfer, rather than mRNA mediated retro transfer. Furthermore, some of the HGT genes might have transferred simultaneously because they located very closely in the host reference genome, indicating that the length of transferred DNA could exceed 100 kb. We confirmed that almost all introns are spliced in the current genome of the parasite species, and that about half HGT genes do not have any missense mutations or frameshift-causing indels, suggesting that some HGT genes may be still functional. Evolutionary analyses revealed that the nonsynonymous-synonymous substitution ratio is on average elevated on the lineage leading to HGT genes, due to either relaxation of selection or positive selection. PMID- 30407541 TI - RNA polymerase III subunits C37/53 modulate rU:dA hybrid 3' end dynamics during transcription termination. AB - RNA polymerase (RNAP) III synthesizes tRNAs and other transcripts, and mutations to its subunits cause human disorders. The RNAP III subunit-heterodimer C37/53 functions in initiation, elongation and in termination-associated reinitiation with subunit C11. C37/53 is related to heterodimers associated with RNAPs I and II, and C11 is related to TFIIS and Rpa12.2, the active site RNA 3' cleavage factors for RNAPs II and I. Critical to termination is stability of the RNA:DNA hybrid bound in the active center, which is loose for RNAP III relative to other RNAPs. Here, we examined RNAP III lacking C37/53/C11 and various reconstituted forms during termination. First, we established a minimal terminator as 5T and 3A on the non-template and template DNA strands, respectively. We demonstrate that C11 stimulates termination, and does so independently of its RNA cleavage activity. We found that C37/53 sensitizes RNAP III termination to RNA:DNA hybrid strength and promotes RNA 3' end pairing/annealing with the template. The latter counteracts C11-insensitive arrest in the proximal part of the oligo(T)-tract, promoting oligo(rU:dA) extension toward greater hybrid instability and RNA release. The data also indicate that RNA 3' end engagement with the active site is a determinant of termination. Broader implications are also discussed. PMID- 30407542 TI - Computational sequence analysis of inversion breakpoint regions in the cactophilic Drosophila mojavensis lineage. AB - We investigated rates of chromosomal evolution in Drosophila mojavensis using whole-genome sequence information from D. mojavensis, D. buzzatii and D. virilis. D. mojavensis is a cactophilic species of the repleta group living under extreme ecological conditions in the deserts of the Southwestern USA and Northwestern Mexico. The genome of D. buzzatii, another member of the repleta group, was recently sequenced and the largest scaffolds anchored to all chromosomes using diverse procedures. Chromosome organization between D. mojavensis and D. buzzatii was compared using MUMmer and GRIMM software. Our results corroborate previous cytological analyses that indicated chromosome 2 differed between these two species by ten inversions, chromosomes X and 5 differed by one inversion each, and chromosome 4 was homosequential. In contrast, we found that chromosome 3 differed by five inversions instead of the expected two that were previously inferred by cytological analyses. Thirteen of these inversions occurred in the D. mojavensis lineage: twelve are fixed and one of them is a polymorphic inversion previously described in populations from Sonora and Baja California, Mexico. We previously investigated the breakpoints of chromosome 2 inversions fixed in D. mojavensis. Here we characterized the breakpoint regions of the five inversions found in chromosome 3 in order to infer the molecular mechanism that generated each inversion and its putative functional consequences. Overall, our results reveal a number of gene alterations at the inversion breakpoints with putative adaptive consequences that point to natural selection as the cause for fast chromosomal evolution in D. mojavensis. PMID- 30407543 TI - Impact of inflammatory marker levels one month after the first-line targeted therapy initiation on progression-free survival prediction in patients with metastatic clear cell renal cell carcinoma. AB - Objectives: Progression-free survival of first-line targeted therapy greatly influences the survival of patients with metastatic renal cell carcinoma. We evaluated whether post-treatment inflammatory markers and lactate dehydrogenase levels had impacts on progression-free survival prediction in addition to those of conventional predictors. Methods: Two hundred and fifteen patients whose tumors were clear cell type and in whom first-line targeted therapies could be continued for >1 month were evaluated. Pretreatment clinical factors, pathological factors and laboratory data 1 month after targeted therapy initiation-including inflammatory markers (neutrophil count, neutrophil-to lymphocyte ratio and C-reactive protein) and lactate dehydrogenase-were reviewed. To identify progression-free survival predictors, multivariate analyses were done. Results: The 1-year progression-free survival rate was 47%. Female gender, Karnofsky performance status <80%, time from diagnosis to systemic treatment <12 months, pretreatment C-reactive protein >3.0 mg/dl and post-treatment neutrophil to-lymphocyte ratio >3.0 were independent predictors for progression-free survival. In contrast, neither C-reactive protein increase nor neutrophil-to lymphocyte ratio increase after targeted therapy initiation were independent predictors. Pretreatment lactate dehydrogenase, post-treatment lactate dehydrogenase and lactate dehydrogenase decline were not independent predictors. When all patients were stratified by these independent factors into three groups (0 risk vs. 1 or 2 risks vs. 3 or more risks), there were significant differences in progression-free survival rates between the groups (P < 0.0001). Furthermore, there were also significant differences in overall survival rates between the groups (P < 0.0001). Conclusions: Integration of post-treatment neutrophil-to lymphocyte ratio value with pretreatment factors may lead to the establishment of effective predictive model for disease progression in patients with metastatic clear cell renal cell carcinoma who received first-line targeted therapies. PMID- 30407544 TI - The role of mesenchymal-epithelial transition in endometrial function. AB - BACKGROUND: The human uterine endometrium undergoes significant remodeling and regeneration on a rapid and repeated basis, after parturition, menstruation, and in some cases, injury. The ability of the adult endometrium to undergo cyclic regeneration and differentiation/decidualization is essential for successful human reproduction. Multiple key physiologic functions of the endometrium require the cells of this tissue to transition between mesenchymal and epithelial phenotypes, processes known as mesenchymal-epithelial transition (MET) and epithelial-mesenchymal transition (EMT). Although MET/EMT processes have been widely characterized in embryonic development and in the context of malignancy, mounting evidence demonstrates the importance of MET/EMT in allowing the endometrium the phenotypic and functional flexibility necessary for successful decidualization, regeneration/re-epithelialization and embryo implantation. OBJECTIVE AND RATIONALE: The objective of this review is to provide a comprehensive summary of the observations concerning MET and EMT and their regulation in physiologic uterine functions, specifically in the context of endometrial regeneration, decidualization and embryo implantation. SEARCH METHODS: Using variations of the search terms 'mesenchymal-epithelial transition', 'mesenchymal-epithelial transformation', 'epithelial-mesenchymal transition', 'epithelial-mesenchymal transformation', 'uterus', 'endometrial regeneration', 'endometrial decidualization', 'embryo implantation', a search of the published literature between 1970 and 2018 was conducted using the PubMed database. In addition, we searched the reference lists of all publications included in this review for additional relevant original studies. OUTCOMES: Multiple studies demonstrate that endometrial stromal cells contribute to the regeneration of both the stromal and epithelial cell compartments of the uterus, implicating a role for MET in mechanisms responsible for endometrial regeneration and re-epithelialization. During decidualization, endometrial stromal cells undergo morphologic and functional changes consistent with MET in order to accommodate embryo implantation. Under the influence of estradiol, progesterone and multiple other factors, endometrial stromal fibroblasts acquire epithelioid characteristics, such as expanded cytoplasm and rough endoplasmic reticulum required for greater secretory capacity, rounded nuclei, increased expression of junctional proteins which allow for increased cell-cell communication, and a reorganized actin cytoskeleton. During embryo implantation, in response to both maternal and embryonic-derived signals, the maternal luminal epithelium as well as the decidualized stromal cells acquire the mesenchymal characteristics of increased migration/motility, thus undergoing EMT in order to accommodate the invading trophoblast. WIDER IMPLICATIONS: Overall, the findings support important roles for MET/EMT in multiple endometrial functions required for successful reproduction. The endometrium may be considered a unique wound healing model, given its ability to repeatedly undergo repair without scarring or loss of function. Future studies to elucidate how MET/EMT mechanisms may contribute to scar-free endometrial repair will have considerable potential to advance studies of wound healing mechanisms in other tissues. PMID- 30407545 TI - The Zebrafish Information Network: new support for non-coding genes, richer Gene Ontology annotations and the Alliance of Genome Resources. AB - The Zebrafish Information Network (ZFIN) (https://zfin.org/) is the database for the model organism, zebrafish (Danio rerio). ZFIN expertly curates, organizes and provides a wide array of zebrafish genetic and genomic data, including genes, alleles, transgenic lines, gene expression, gene function, mutant phenotypes, orthology, human disease models, nomenclature and reagents. New features at ZFIN include increased support for genomic regions and for non-coding genes, and support for more expressive Gene Ontology annotations. ZFIN has recently taken over maintenance of the zebrafish reference genome sequence as part of the Genome Reference Consortium. ZFIN is also a founding member of the Alliance of Genome Resources, a collaboration of six model organism databases (MODs) and the Gene Ontology Consortium (GO). The recently launched Alliance portal (https://alliancegenome.org) provides a unified, comparative view of MOD, GO, and human data, and facilitates foundational and translational biomedical research. PMID- 30407546 TI - Monte Carlo modeling of a 60Co MRI-guided radiotherapy system on Geant4 and experimental verification of dose calculation under a magnetic field of 0.35 T. AB - Our purpose was to establish the commissioning procedure of Monte Carlo modeling on a magnetic resonance imaging-guided radiotherapy system (MRIdian, Viewray Inc.) under a magnetic field of 0.345 T through experimental measurements. To do this, we sought (i) to assess the depth-dose and lateral profiles generated by the Geant4 using either EBT3 film or the BJR-25 data; (ii) to assess the calculation accuracy under a magnetic field of 0.345 T. The radius of the electron trajectory caused by the electron return effect (ERE) in a vacuum was obtained both by the Geant4 and the theoretical methods. The surface dose on the phantom was calculated and compared with that obtained from the film measurements. The dose distribution in a phantom having two air gaps was calculated and measured with EBT 3 film. (i) The difference of depth-dose profile generated by the Geant4 from the BJR-25 data was 0.0 +/- 0.8% and 0.3 +/- 1.5% for field sizes of 4.5 and 27.3 cm2, respectively. Lateral dose profiles generated by Geant4 agreed well with those generated from the EBT3 film data. (ii) The radius of the electron trajectory generated by Geant4 agreed well with the theoretical values. A maximum of ~50% reduction of the surface dose under a magnetic field of 0.345 T was observed due to elimination of the electron contamination caused by the magnetic field, as determined by both the film measurements and the Geant4. Changes in the dose distributions in the air gaps caused by the ERE were observed on the Geant4 and in the film measurements. Gamma analysis (3%/3 mm) showed a pass rate of 95.1%. Commissioning procedures for the MRI-guided radiotherapy system on the Geant4 were established, and we concluded that the Geant4 had provided high calculation accuracy under a magnetic field of 0.345 T. PMID- 30407547 TI - Effect of in vivo post-translational modifications of the HMGB1 protein upon binding to platinated DNA: a molecular simulation study. AB - Cisplatin is one of the most widely used anticancer drugs. Its efficiency is unfortunately severely hampered by resistance. The High Mobility Group Box (HMGB) proteins may sensitize tumor cells to cisplatin by specifically binding to platinated DNA (PtDNA) lesions. In vivo, the HMGB/PtDNA binding is regulated by multisite post-translational modifications (PTMs). The impact of PTMs on the HMGB/PtDNA complex at atomistic level is here investigated by enhanced sampling molecular simulations. The PTMs turn out to affect the structure of the complex, the mobility of several regions (including the platinated site), and the nature of the protein/PtDNA non-covalent interactions. Overall, the multisite PTMs increase significantly the apparent synchrony of all the contacts between the protein and PtDNA. Consequently, the hydrophobic anchoring of the side chain of F37 between the two cross-linked guanines at the platinated site-a key element of the complexes formation - is more stable than in the complex without PTM. These differences can account for the experimentally measured greater affinity for PtDNA of the protein isoforms with PTMs. The collective behavior of multisite PTMs, as revealed here by the synchrony of contacts, may have a general significance for the modulation of intermolecular recognitions occurring in vivo. PMID- 30407548 TI - Metabolic consequences of concomitant Strongyloides stercoralis infection in Type 2 diabetes mellitus. AB - Background: Human and animal studies have demonstrated that helminth infections are associated with a decreased prevalence of Type 2 diabetes mellitus (T2DM). However, very little is known about the biochemical and immunological interactions between the two. Methods: To assess the relationship between a soil transmitted helminth, Strongyloides stercoralis (Ss) and T2DM, we examined a variety of analytes associated with glycemic control, metabolic processes and T cell driven inflammation at the time of Ss diagnosis and then 6 months after definitive anthelmintic treatment. We thus measured plasma levels of HbA1c, glucose, insulin, glucagon, adipocytokines and Th1-, Th2- and Th17- associated cytokines in those with T2DM with (INF) or without Ss infection (UN). In INF individuals, we again assessed the levels of these analytes 6 months following anthelmintic treatment. Results: INF individuals exhibited significantly diminished levels of insulin and glucagon compared to UN individuals, that increased significantly following therapy. Similarly, INF individuals exhibited significantly diminished levels of adiponectin and adipsin that reversed following therapy. INF individuals also exhibited significantly decreased levels of the Th1- and Th17- associated cytokines in comparison to UN individuals; again, anthelmintic therapy augmented the levels of these. As expected, INF individuals had elevated levels of Th2-associated and regulatory cytokines that normalized following definitive therapy. Multivariate analysis revealed that these changes were independent of age, gender, body mass index, liver and renal function. Conclusions: Thus, Ss infection is associated with a significant modulation of glycemic, hormonal and cytokine parameters in T2DM and its reversal following anthelmintic therapy. Hence, Ss infection has a protective effect on diabetes-related parameters. PMID- 30407549 TI - Lnc2Cancer v2.0: updated database of experimentally supported long non-coding RNAs in human cancers. AB - Lnc2Cancer 2.0 (http://www.bio-bigdata.net/lnc2cancer) is an updated database that provides comprehensive experimentally supported associations between lncRNAs and human cancers. In Lnc2Cancer 2.0, we have updated the database with more data and several new features, including (i) exceeding a 4-fold increase over the previous version, recruiting 4989 lncRNA-cancer associations between 1614 lncRNAs and 165 cancer subtypes. (ii) newly adding about 800 experimentally supported circulating, drug-resistant and prognostic-related lncRNAs in various cancers. (iii) appending the regulatory mechanism of lncRNA in cancer, including microRNA (miRNA), transcription factor (TF), variant and methylation regulation. (iv) increasing more than 70 high-throughput experiments (microarray and next generation sequencing) of lncRNAs in cancers. (v) Scoring the associations between lncRNA and cancer to evaluate the correlations. (vi) updating the annotation information of lncRNAs (version 28) and containing more detailed descriptions for lncRNAs and cancers. Moreover, a newly designed, user-friendly interface was also developed to provide a convenient platform for users. In particular, the functions of browsing data by cancer primary organ, biomarker type and regulatory mechanism, advanced search following several features and filtering the data by LncRNA-Cancer score were enhanced. Lnc2Cancer 2.0 will be a useful resource platform for further understanding the associations between lncRNA and human cancer. PMID- 30407550 TI - Human Disease Ontology 2018 update: classification, content and workflow expansion. AB - The Human Disease Ontology (DO) (http://www.disease-ontology.org), database has undergone significant expansion in the past three years. The DO disease classification includes specific formal semantic rules to express meaningful disease models and has expanded from a single asserted classification to include multiple-inferred mechanistic disease classifications, thus providing novel perspectives on related diseases. Expansion of disease terms, alternative anatomy, cell type and genetic disease classifications and workflow automation highlight the updates for the DO since 2015. The enhanced breadth and depth of the DO's knowledgebase has expanded the DO's utility for exploring the multi etiology of human disease, thus improving the capture and communication of health related data across biomedical databases, bioinformatics tools, genomic and cancer resources and demonstrated by a 6.6* growth in DO's user community since 2015. The DO's continual integration of human disease knowledge, evidenced by the more than 200 SVN/GitHub releases/revisions, since previously reported in our DO 2015 NAR paper, includes the addition of 2650 new disease terms, a 30% increase of textual definitions, and an expanding suite of disease classification hierarchies constructed through defined logical axioms. PMID- 30407551 TI - Posterior Cervical Decompression and Instrumented Fusion for Cervical Spondylotic Myelopathy: 2-Dimensional Operative Video. AB - Cervical spondylotic myelopathy is a common cause of progressive quadriparesis in adults. It is characterized by compression of the cervical spinal cord due to degenerative changes including intervertebral disc protrusion, ligamentum flavum hypertrophy, and osteophyte formation. Clinically, patients can present with declining motor control in the extremities, gait imbalance, spasticity, hyperreflexia, or possibly frank weakness. Surgical treatment options include ventral and dorsal approaches, whose indications vary depending on spinal alignment, number of levels requiring decompression, the dorsal/ventral/circumferential location of compression, and patient-specific anatomic constraints. Posterior cervical decompression and instrumented fusion is a mainstay of treatment for cervical spondylotic myelopathy when a dorsal approach is indicated. In this video, we present a case of a 60-yr-old female who presented with signs and symptoms of cervical myelopathy, with MRI findings of C3 on C4 anterolisthesis and circumferential central stenosis worst at C4-5 and C5 6. We demonstrate the operative steps to complete a C3 to C6 decompression and instrumented fusion with lateral mass screws. Appropriate patient consent was obtained. PMID- 30407552 TI - An educational journey in travel medicine: content analysis of CISTM conferences, 1988-2017. PMID- 30407553 TI - Structural insights into a unique preference for 3' terminal guanine of mirtron in Drosophila TUTase tailor. AB - Terminal uridylyl transferase (TUTase) is one type of enzyme that modifies RNA molecules by facilitating the post-transcriptional addition of uridyl ribonucleotides to their 3' ends. Recent researches have reported that Drosophila TUTase, Tailor, exhibits an intrinsic preference for RNA substrates ending in 3'G, distinguishing it from any other known TUTases. Through this unique feature, Tailor plays a crucial role as the repressor in the biogenesis pathway of splicing-derived mirtron pre-miRNAs. Here we describe crystal structures of core catalytic domain of Tailor and its complexes with RNA stretches 5'-AGU-3' and 5' AGUU-3'. We demonstrate that R327 and N347 are two key residues contributing cooperatively to Tailor's preference for 3'G, and R327 may play an extra role in facilitating the extension of polyuridylation chain. We also demonstrate that conformational stability of the exit of RNA-binding groove also contributes significantly to Tailor's activity. Overall, our work reveals useful insights to explain why Drosophila Tailor can preferentially select RNA substrates ending in 3'G and provides important values for further understanding the biological significances of biogenesis pathway of mirtron in flies. PMID- 30407554 TI - Microsurgical Clipping of a Ruptured Basilar Apex Aneurysm: 3-Dimensional Operative Video. AB - A 59-yr-old woman presented with a sudden onset of headache with neck pain and stiffness, Hunt and Hess grade 2. Brain computed tomography (CT) showed subarachnoid hemorrhage, Fisher Grade 2. Intra-arterial digital subtraction angiography (IADSA) showed a basilar artery apex aneurysm, dome size 9 mm and neck 3 mm, leaning towards the right, and a dominant right artery of Percheron. Endovascular treatment and microsurgical clipping were both explained to the patient, but she decided to undergo microsurgery due to the durability of treatment.She underwent a right frontotemporal craniotomy and orbital osteotomy. We performed optic nerve decompression and intradural anterior clinoidectomy to enhance the exposure. Working through the carotid-oculomotor space, the posterior communicating artery was traced back to the posterior cerebral artery. The basilar artery was temporarily occluded for aneurysm dissection after burst suppression to protect the brain. The aneurysm was irregular, multilobulated, and projecting upward. The dominant thalamoperforate artery (artery of Percheron) was arising from the right P1, and densely adherent to the sac of the aneurysm. After dissection of the artery of Percheron away from the aneurysm, it was completely occluded by a side-curved titanium clip. The patient had right oculomotor nerve paresis and headache postoperatively, but at discharge 2 wk later the headache and paresis had completely resolved. The postoperative IADSA showed total occlusion of the aneurysm with patency of the artery of Percheron.This 3 dimensional video shows the technical nuances of microsurgical clipping of a ruptured basilar apex aneurysm and intraoperative dissection of the artery of Percheron.Informed consent was obtained from the patient prior to the surgery that included videotaping of the procedure and its distribution for educational purposes. All relevant patient identifiers have also been removed from the video and accompanying radiology slides. PMID- 30407556 TI - Microtubule-associated protein IQ67 DOMAIN5 regulates morphogenesis of leaf pavement cells in Arabidopsis thaliana. AB - Plant microtubules form a highly dynamic intracellular network with important roles for regulating cell division, cell proliferation and cell morphology. Its organization and dynamics are coordinated by various microtubule-associated proteins (MAPs) that integrate environmental and developmental stimuli to fine tune and adjust cytoskeletal arrays. IQ67 DOMAIN (IQD) proteins recently emerged as a class of plant-specific MAPs with largely unknown functions. Here, using a reverse genetics approach, we characterize Arabidopsis IQD5 in terms of its expression domains, subcellular localization and biological functions. We show that IQD5 is expressed mostly in vegetative tissues, where it localizes to cortical microtubule arrays. Our phenotypic analysis of iqd5 loss-of-function lines reveals functions of IQD5 in pavement cell (PC) shape morphogenesis. Histochemical analysis of cell wall composition further suggests reduced rates of cellulose deposition in anticlinal cell walls, which correlate with reduced anisotropic expansion. Lastly, we demonstrate IQD5-dependent recruitment of calmodulin calcium sensors to cortical microtubule arrays and provide first evidence for important roles of calcium in regulation of PC morphogenesis. Our work thus identifies IQD5 as a novel player in PC shape regulation, and, for the first time, links calcium signaling to developmental processes that regulate anisotropic growth in PCs. PMID- 30407555 TI - Cigarette smoking and cervical cancer risk: an evaluation based on a systematic review and meta-analysis among Japanese women. AB - Background: There is a body of evidence to suggest that cigarette smoking increases the risk of cervical cancer in women, but no study has examined the magnitude of the association in Japanese women. Here, we evaluated the association between cigarette smoking and the risk of cervical cancer in Japanese women based on a systematic review of epidemiological evidence. Methods: Original data were obtained from a MEDLINE search using PubMed or from a search of the 'Ichushi' database, as well as by a manual search. Evaluation of associations was based on the strength of evidence and the magnitude of association, together with biological plausibility as evaluated previously by the International Agency for Research on Cancer. Meta-analysis of associations was also conducted to obtain a summarized overview of the data. Results: We identified two cohort studies and three case-control studies. All five studies had indicated strong positive associations between cigarette smoking and the risk of cervical cancer. Our summary estimate indicated that the relative risk (RR) for individuals who had ever-smoked relative to never-smokers was 2.03 (95% confidence interval: 1.49 2.57). Four studies had also demonstrated dose-response relationships between cigarette smoking and the risk of cervical cancer. Conclusion: We conclude that there is convincing evidence that cigarette smoking increases the risk of cervical cancer among Japanese women. PMID- 30407557 TI - Update of the FANTOM web resource: expansion to provide additional transcriptome atlases. AB - The FANTOM web resource (http://fantom.gsc.riken.jp/) was developed to provide easy access to the data produced by the FANTOM project. It contains the most complete and comprehensive sets of actively transcribed enhancers and promoters in the human and mouse genomes. We determined the transcription activities of these regulatory elements by CAGE (Cap Analysis of Gene Expression) for both steady and dynamic cellular states in all major and some rare cell types, consecutive stages of differentiation and responses to stimuli. We have expanded the resource by employing different assays, such as RNA-seq, short RNA-seq and a paired-end protocol for CAGE (CAGEscan), to provide new angles to study the transcriptome. That yielded additional atlases of long noncoding RNAs, miRNAs and their promoters. We have also expanded the CAGE analysis to cover rat, dog, chicken, and macaque species for a limited number of cell types. The CAGE data obtained from human and mouse were reprocessed to make them available on the latest genome assemblies. Here, we report the recent updates of both data and interfaces in the FANTOM web resource. PMID- 30407558 TI - Studying the nuts and bolts of spermatozoa. PMID- 30407560 TI - Development of a markerless tumor-tracking algorithm using prior four-dimensional cone-beam computed tomography. AB - Respiratory motion management is a huge challenge in radiation therapy. Respiratory motion induces temporal anatomic changes that distort the tumor volume and its position. In this study, a markerless tumor-tracking algorithm was investigated by performing phase recognition during stereotactic body radiation therapy (SBRT) using four-dimensional cone-beam computer tomography (4D-CBCT) obtained at patient registration, and in-treatment cone-beam projection images. The data for 20 treatment sessions (five lung cancer patients) were selected for this study. Three of the patients were treated with conventional flattening filter (FF) beams, and the other two were treated with flattening filter-free (FFF) beams. Prior to treatment, 4D-CBCT was acquired to create the template projection images for 10 phases. In-treatment images were obtained at near real time during treatment. Template-based phase recognition was performed for 4D-CBCT re-projected templates using prior 4D-CBCT based phase recognition algorithm and was compared with the results generated by the Amsterdam Shroud (AS) technique. Visual verification technique was used for the verification of the phase recognition and AS technique at certain tumor-visible angles. Offline template matching analysis using the cross-correlation indicated that phase recognition performed using the prior 4D-CBCT and visual verification matched up to 97.5% in the case of FFF, and 95% in the case of FF, whereas the AS technique matched 83.5% with visual verification for FFF and 93% for FF. Markerless tumor tracking based on phase recognition using prior 4D-CBCT has been developed successfully. This is the first study that reports on the use of prior 4D-CBCT based on normalized cross-correlation technique for phase recognition. PMID- 30407561 TI - In Reply: Overlapping Surgeries are not Associated With Worse Patient Outcomes: Retrospective Multivariate Analysis of 14 872 Neurosurgical Cases Performed at a Single Institution. PMID- 30407559 TI - Telomere shortening by transgenerational transmission of TNF-alpha-induced TERRA via ATF7. AB - Various stresses increase disease susceptibility and accelerate aging, and increasing evidence suggests that these effects can be transmitted over generation. Epidemiological studies suggest that stressors experienced by parents affect the longevity of their offspring, possibly by regulating telomere dynamics. Telomeres are elongated by telomerase and shortened by certain stresses as well as telomere repeat-containing RNA (TERRA), a telomere transcript. However, the mechanism underlying the transgenerational effects is poorly understood. Here, we show that TNF-alpha, which is induced by various psychological stresses, induces the p38-dependent phosphorylation of ATF7, a stress-responsive chromatin regulator, in mouse testicular germ cells. This caused a release of ATF7 from the TERRA gene promoter in the subtelomeric region, which disrupted heterochromatin and induced TERRA. TERRA was transgenerationally transmitted to zygotes via sperm and caused telomere shortening. These results suggest that ATF7 and TERRA play key roles in paternal stress-induced telomere shortening in the offspring. PMID- 30407562 TI - Massive diphtheria outbreak among Rohingya refugees: lessons learnt. AB - Several lessons can be learnt from the massive diphtheria outbreak faced by Rohingya (Forcibly Displaced Myanmar Nationals) refugees who fled violence in Myanmar and settled in camps and makeshift settlements in Cox's Bazar, Bangladesh, 2017-2018. PMID- 30407563 TI - In Reply: Comparative Analysis Between Lateral Orbital Rim Preservation and Osteotomy for Transorbital Endoscopic Approaches to the Cavernous Sinus: An Anatomic Study. PMID- 30407564 TI - E-learning on risk management. An opportunity for sharing knowledge and experiences in patient safety. AB - Quality problem: E-learning methodology is a good alternative to more traditional methods when economical restrictions and geographical dispersion are important. However, there is still little knowledge about its utility in the development of patient safety (PS) improvement projects. Initial assessment: Evaluation of the acceptability and utility of an e-learning risk management (RM) course for healthcare professionals to develop PS improvement projects in different clinical settings. Choice of solution: E-course offered, in Spanish and English, to facilitate the design of PS improvement projects using RM tools under the continuous support of PS experts. Implementation: The evaluation of the course was based on the reaction, learning and healthcare professional behavior. A free online database was created to disseminate and share the projects developed during the course. Evaluation: A total of 1426 professionals have completed the course (84.2%), of which 86.7% (1236) were from Spain, 8.3% (118) from Latin America and 5% (72) from other European and Eastern Mediterranean countries. More than 80% of the students were very satisfied with the e-course and 98% would recommend it to their colleagues. Learning and developing improvement projects through teamwork was highlighted as a very positive aspect. A total of 70.3% of the 387 PSIP were developed in hospitals. The most frequent topic was medication. Lesson learned: Team learning based on real cases was one of the most positive aspects of the e-course. The improvement projects developed are transferable examples of good practices that facilitate the application of RM tools in different clinical settings. PMID- 30407566 TI - Letter: Isolated Fourth Ventricle: To Shunt or Stent. PMID- 30407565 TI - Commentary: Stereotactic Radiosurgery Training for Neurosurgery Residents: Results of a Survey of Residents, Attendings, and Program Directors by the American Association of Neurological Surgeons/Congress of Neurological Surgeons Section on Tumors. PMID- 30407567 TI - Convection-Enhanced Delivery of Muscimol in Patients with Drug-Resistant Epilepsy. AB - BACKGROUND: Minimally invasive therapies for drug-resistant epilepsy (DRE) have been advocated. A study of convection-enhanced delivery (CED) of muscimol, a GABAA receptor agonist, was previously completed in non-human primates. OBJECTIVE: To investigate the safety and anti-epileptic effects of intracerebral muscimol infusion into the epileptic focus of patients with DRE. METHODS: In this phase 1 clinical trial, 3 adult patients with DRE underwent CED into the seizure focus of artificial CSF vehicle followed by muscimol for 12 to 24 h each using a crossover design. Basic pathophysiology of the epileptic focus was examined by assessing the infusions' effects on seizure frequency, electroencephalogram (EEG) spike-wave activity, and power-spectral EEG frequency. RESULTS: Inter-ictal neurological function remained normal in all patients. Pathological examination of resected specimens showed no infusion-related brain injuries. Seizure frequency decreased in 1 of 3 patients during muscimol infusion but was unchanged in all patients during vehicle infusion. Mean beta frequencies did not differ significantly before, during, or after infusion periods. Infused fluid provided insufficient MRI-signal to track infusate distribution. In the 2 yr after standard epilepsy surgery, 1 patient had temporary reduction in seizure frequency and 2 patients were seizure-free. CONCLUSION: CED of muscimol into the epileptic focus of patients with DRE did not damage adjacent brain parenchyma or adversely affect seizure surgery outcome. This study did not confirm that intracerebral muscimol infusion effectively suppressed seizures. A surrogate tracer is recommended to track infusion distribution to the epileptic focus and surrounding structures in future studies using CED to suppress the seizure focus. PMID- 30407568 TI - ICEberg 2.0: an updated database of bacterial integrative and conjugative elements. AB - ICEberg 2.0 (http://db-mml.sjtu.edu.cn/ICEberg/) is an updated database that provides comprehensive information about bacterial integrative and conjugative elements (ICEs). Compared with the previous version, three major improvements were made. First, with the aid of text mining and manual curation, it now recorded the details of 1032 ICEs, including 270 with experimental supports and 762 from bioinformatics prediction. Second, as increasing evidence has shown that ICEs frequently mobilize the so-called 'hitchhikers', such as integrative and mobilizable elements (IMEs) and cis-mobilizable elements (CIMEs), 83 known transfer interactions between 49 IMEs and 7 CIMEs with 19 ICEs taken from the literature were included and illustrated with visually intuitive directed graphs. An expanded collection of 260 chromosome-borne IMEs and 235 CIMEs was also added. At last, ICEberg 2.0 provides an online tool ICEfinder to predict ICEs or IMEs in bacterial genome sequences. It combines a similarity search for the integrase, relaxase and/or type IV secretion system and the co-localization of these corresponding homologous genes. With the recent updates, ICEberg 2.0 might provide better support for understanding the biological traits of ICEs, especially as their interaction with cognate mobilizable elements may further promote horizontal gene flow. PMID- 30407569 TI - Commentary: Regionalization of Spine Trauma Care in an Urban Trauma System in the United States: Decreased Time to Surgery and Hospital Length of Stay. PMID- 30407570 TI - Ribosomal protein eL24, involved in two intersubunit bridges, stimulates translation initiation and elongation. AB - Interactions between subunits in the Saccharomyces cerevisiae ribosome are mediated by universal and eukaryote-specific intersubunit bridges. Universal bridges are positioned close to the ribosomal functional centers, while eukaryote specific bridges are mainly located on the periphery of the ribosome. Two bridges, eB13 and B6, are formed by the ribosomal protein eL24. The eukaryotic eL24 is composed of an N-terminal domain, a linker region and a C-terminal alpha helix. Here, the functions of different domains of eL24 in the S. cerevisiae ribosome were evaluated. The C-terminal domain and the linker region of the eL24 form eukaryote-specific eB13 bridge. Phenotypic characterization of the eL24 deletion mutants indicated that the functional integrity of the eB13 bridge mainly depends on the protein-protein contacts between eL24 and eS6. Further investigation showed importance of the eB13 bridge in the subunit joining in vivo and in vitro. In vitro translation assay demonstrated the role of the eB13 bridge in both initiation and elongation steps of translation. Intriguingly, results of in vitro translation experiment suggest involvement of the N-terminal domain of eL24 in the translation initiation. Therefore, eL24 performs number of tasks required for the optimal ribosome functionality. PMID- 30407571 TI - Computational insights into the mutagenicity of two tobacco-derived carcinogenic DNA lesions. AB - 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is a potent carcinogen found in all tobacco products that leads to a variety of DNA lesions in cells, including O6-[4-oxo-4-(3-pyridyl)butyl]guanine (POB-G) and O6-[4-hydroxy-4-(3 pyridyl)butyl]guanine (PHB-G), which differ by only a single substituent in the bulky moiety. This work uses a multiscale computational approach to shed light on the intrinsic conformational and base-pairing preferences of POB-G and PHB-G, and the corresponding properties in DNA and the polymerase eta active site. Our calculations reveal that both lesions form stable pairs with C and T, with the T pairs being the least distorted relative to canonical DNA. This rationalizes the experimentally reported mutational profile for POB-G and validates our computational model. The same approach predicts that PHB-G is more mutagenic than POB-G due to a difference in the bulky moiety hydrogen-bonding pattern, which increases the stability of the PHB-G:T pair. The mutagenicity of PHB-G is likely further increased by stabilization of an intercalated DNA conformation that is associated with deletion mutations. This work thereby uncovers structural explanations for the reported mutagenicity of POB-G, provides the first clues regarding the mutagenicity of PHB-G and complements a growing body of literature highlighting that subtle chemical changes can affect the biological outcomes of DNA adducts. PMID- 30407572 TI - Dengue Epidemic in Touba, Senegal: Implications for the Grand Magal Pilgrimage for Travelers. PMID- 30407574 TI - Overexpression of ATG8 in Arabidopsis stimulates autophagic activity and increases nitrogen remobilization efficiency and grain filling. AB - Autophagy knock-out mutants in maize and in Arabidopsis are impaired for nitrogen recycling and exhibit reduced levels of nitrogen remobilization to their seeds. An important question is then to determine whether higher autophagy activity could at the reverse improve N remobilization efficiency and seed protein content, and under which circumstances.As autophagy machinery involves many genes amongst which 18 are important for the core machinery, the choice of which ATG gene to manipulate to increase autophagy was examined. We choose ATG8 overexpressions since it has been shown in yeast that it could increase autophagosome size and autophagic activity. The results we report here are original as they show for the first time that increasing ATG8 gene expression in plant increases autophagosome number and promotes autophagy activity. More importantly our data demonstrate that, when cultivated under full nitrate conditions, known to repress N remobilization due to sufficient N uptake from the soil, N remobilization efficiency can be nevertheless sharply and significantly increased by overexpressing ATG8 genomic sequences under the control of ubiquitin promoter. We show that overexpressors have improved seed N% and at the same time reduced N waste in their dry remains. In addition, we show that overexpressing ATG8 does not modify vegetative biomass nor harvest index, thus does not affect plant development. PMID- 30407573 TI - IMG/VR v.2.0: an integrated data management and analysis system for cultivated and environmental viral genomes. AB - The Integrated Microbial Genome/Virus (IMG/VR) system v.2.0 (https://img.jgi.doe.gov/vr/) is the largest publicly available data management and analysis platform dedicated to viral genomics. Since the last report published in the 2016, NAR Database Issue, the data has tripled in size and currently contains genomes of 8389 cultivated reference viruses, 12 498 previously published curated prophages derived from cultivated microbial isolates, and 735 112 viral genomic fragments computationally predicted from assembled shotgun metagenomes. Nearly 60% of the viral genomes and genome fragments are clustered into 110 384 viral Operational Taxonomic Units (vOTUs) with two or more members. To improve data quality and predictions of host specificity, IMG/VR v.2.0 now separates prokaryotic and eukaryotic viruses, utilizes known prophage sequences to improve taxonomic assignments, and provides viral genome quality scores based on the estimated genome completeness. New features also include enhanced BLAST search capabilities for external queries. Finally, geographic map visualization to locate user-selected viral genomes or genome fragments has been implemented and download options have been extended. All of these features make IMG/VR v.2.0 a key resource for the study of viruses. PMID- 30407575 TI - Structural analysis of fungal CENP-H/I/K homologs reveals a conserved assembly mechanism underlying proper chromosome alignment. AB - The kinetochore is a proteinaceous complex that is essential for proper chromosome segregation. As a core member of the inner kinetochore, defects of each subunit in the CENP-H/I/K complex cause dysfunction of kinetochore that leads to chromosome mis-segregation and cell death. However, how the CENP-H/I/K complex assembles and promotes kinetochore function are poorly understood. We here determined the crystal structures of CENP-I N-terminus alone from Chaetomium thermophilum and its complex with CENP-H/K from Thielavia terrestris, and verified the identified interactions. The structures and biochemical analyses show that CENP-H and CENP-K form a heterodimer through both N- and C-terminal interactions. CENP-I integrates into the CENP-H/K complex by binding to the C terminus of CENP-H, leading to formation of the ternary complex in which CENP-H is sandwiched between CENP-K and CENP-I. Our sequence comparisons and mutational analyses showed that this architecture of the CENP-H/I/K complex is conserved in human. Mutating the binding interfaces of CENP-H for either CENP-K or CENP-I significantly reduced their localizations at centromeres and induced massive chromosome alignment defects during mitosis, suggesting that the identified interactions are critical for CENP-H/I/K complex assembly at the centromere and kinetochore function. Altogether, our findings unveil the evolutionarily conserved assembly mechanism of the CENP-H/I/K complex that is critical for proper chromosome alignment. PMID- 30407576 TI - Letter: Overlapping Surgeries Are Not Associated With Worse Patient Outcomes: Retrospective Multivariate Analysis of 14 872 Neurosurgical Cases Performed at a Single Institution. PMID- 30407577 TI - Stemformatics: visualize and download curated stem cell data. AB - Stemformatics is an established gene expression data portal containing over 420 public gene expression datasets derived from microarray, RNA sequencing and single cell profiling technologies. Developed for the stem cell community, it has a major focus on pluripotency, tissue stem cells, and staged differentiation. Stemformatics includes curated 'collections' of data relevant to cell reprogramming, as well as hematopoiesis and leukaemia. Rather than simply rehosting datasets as they appear in public repositories, Stemformatics uses a stringent set of quality control metrics and its own pipelines to process handpicked datasets from raw files. This means that about 30% of datasets processed by Stemformatics fail the quality control metrics and never make it to the portal, ensuring that Stemformatics data are of high quality and have been processed in a consistent manner. Stemformatics provides easy-to-use and intuitive tools for biologists to visually explore the data, including interactive gene expression profiles, principal component analysis plots and hierarchical clusters, among others. The addition of tools that facilitate cross dataset comparisons provides users with snapshots of gene expression in multiple cell and tissues, assisting the identification of cell-type restricted genes, or potential housekeeping genes. Stemformatics is freely available at stemformatics.org. PMID- 30407578 TI - Bundle sheath chloroplast volume can house sufficient Rubisco to avoid limiting C4 photosynthesis during chilling. AB - C4 leaves confine Rubisco to bundle-sheath cells. Thus, the size of bundle-sheath compartments, and total volume of chloroplasts within them, limits space available for Rubisco. Rubisco activity limits photosynthesis at low temperatures. C3 plants counter this limitation by increasing leaf Rubisco content, yet few C4 species do the same. Because C3 plants usually outperform C4 plants in chilling environments, it has been suggested that there is insufficient chloroplast volume available in the bundle-sheath of C4 leaves to allow such an increase in Rubisco at low temperatures. We investigated this potential limitation by measuring bundle-sheath and mesophyll compartment volumes and chloroplast contents, as well as leaf thickness and inter-veinal distance in three C4Andropogoneae grasses: two crops (Zea mays, Saccharum officinarum) and a wild, chilling-tolerant grass (Miscanthus x giganteus). A wild C4Paniceae grass (Alloteropsis semialata) was also included. Despite significant structural differences between species, there was no evidence of increased bundle-sheath chloroplast volume per leaf area available to the chilling-tolerant species, relative to the chilling-sensitive ones. Maximal theoretical photosynthetic capacity of the leaf far exceeded the photosynthetic rates achieved even at low temperatures. C4 bundle-sheath cells therefore house more than enough chloroplasts to avoid Rubisco limitation to photosynthesis during chilling. PMID- 30407579 TI - Household Food Insecurity in Early Adolescence and Risk of Subsequent Behavior Problems: Does a Connection Persist Over Time? AB - Objective: Household food insecurity is common among U.S. families, and adolescents are almost twice as likely as school-aged children to be food insecure. However, little is known about how household food insecurity relates to adolescent behavioral outcomes over time. The purpose of this study was to examine whether food security status in early adolescence is associated with behavioral problems over a 6-year period in an ethnically diverse sample of teenagers from low-income households. Methods: The study examined longitudinal data from the Welfare, Children, and Families: A Three-City Study. A total of 1,049 primary caregivers completed measures of child/adolescent behavioral problems and household food insecurity during the past year. Data were collected across three waves, when focal children were between 10 and 14 years old, 11 and 16 years old, and 16 and 18 years old, respectively. Generalized estimating equations were used to assess initial household food insecurity as a time invariant effect on adolescent behavioral problems over time. Results: Baseline household food insecurity in pre- or early adolescence was significantly associated with greater internalizing problems and total behavioral problems over time. Conclusions: These findings indicate that household food insecurity is associated with behavioral problems throughout adolescence. This suggests the need for health providers to screen for household food insecurity during scheduled health visits and highlight the need for integration of psychosocial services into pediatric care and expansions in current federal assistance programs. PMID- 30407580 TI - Neurosurgery and Manned Spaceflight. AB - There has been a renewed interest in manned spaceflight due to endeavors by private and government agencies. Publicized goals include manned trips to or colonization of Mars. These missions will likely be of long duration, exceeding existing records for human exposure to extra-terrestrial conditions. Participants will be exposed to microgravity, temperature extremes, and radiation, all of which may adversely affect their physiology. Moreover, pathological mechanisms may differ from those of a terrestrial nature. Known central nervous system (CNS) changes occurring in space include rises in intracranial pressure and spinal unloading. Intracranial pressure increases are thought to occur due to cephalad re-distribution of body fluids secondary to microgravity exposure. Spinal unloading in microgravity results in potential degenerative changes to the bony vertebrae, intervertebral discs, and supportive musculature. These phenomena are poorly understood. Trauma is of highest concern due to its potential to seriously incapacitate crewmembers and compromise missions. Traumatic pathology may also be exacerbated in the setting of altered CNS physiology. Though there are no documented instances of CNS pathologies arising in space, existing diagnostic and treatment capabilities will be limited relative to those on Earth. In instances where neurosurgical intervention is required in space, it is not known whether open or endoscopic approaches are feasible. It is obvious that prevention of trauma and CNS pathology should be emphasized. Further research into neurosurgical pathology, its diagnosis, and treatment in space are required should exploratory or colonization missions be attempted. PMID- 30407581 TI - Pharmacological Activation of PXR and CAR Down-regulates Distinct Bile Acid metabolizing Intestinal Bacteria and Alters Bile Acid Homeostasis. AB - The gut microbiome regulates important host metabolic pathways including xenobiotic metabolism and intermediary metabolism, such as the conversion of primary bile acids (BAs) into secondary BAs. The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are well-known regulators for xenobiotic biotransformation in liver. However, little is known regarding the potential effects of PXR and CAR on the composition and function of the gut microbiome. To test our hypothesis that activation of PXR and CAR regulates gut microbiota and secondary BA synthesis, nine-week-old male conventional (CV) and germ-free (GF) mice were orally gavaged with corn oil, PXR agonist PCN (75 mg/kg), or CAR agonist TCPOBOP (3 mg/kg) once daily for four days. PCN and TCPOBOP decreased two taxa in the Bifidobacterium genus, which corresponded with decreased gene abundance of the BA-deconjugating enzyme bile salt hydrolase. In liver and small intestinal content (SIC) of GF mice, there was a TCPOBOP-mediated increase in total, primary, and conjugated BAs corresponding with increased Cyp7a1 mRNA. Bifidobacterium, Dorea, Peptociccaceae, Anaeroplasma, and Ruminococcus positively correlated with T-UDCA in LIC, but negatively correlated with T-CDCA in serum. In conclusion, PXR and CAR activation down regulates BA-metabolizing bacteria in the intestine and modulates BA homeostasis in a gut microbiota-dependent manner. PMID- 30407582 TI - Effect of different time of ultrasound treatment on physicochemical, thermal, and antioxidant properties of chicken plasma protein. AB - The aim of present study was to investigate the effect of different times (5 min (UCPP-5), 10 min (UCPP-10), 20 min (UCPP-20), and 30 min (UCPP-30)) of ultrasound treatment on physicochemical, thermal, and antioxidant properties of chicken plasma protein (CPP). UCPP-20 had the highest fluorescence intensity and the lowest particle size. However, no major changes in the subunit compositions and the secondary structure of UCPPs were presented in SDS-PAGE and circular dichroism. The surface hydrophobicity and sulfhydryl content of UCPPs increased significantly (P < 0.05) as compared to those of CPP. With the increasing time of ultrasound treatment, there were more and deeper holes on the protein surfaces. Furthermore, protein modification by ultrasound could improve the thermal properties of UCPPs. Additionally, UCPPs showed a significant increase in antioxidant properties over CPP, especially UCPP-20. These observations indicated that ultrasound treatment was necessary for modification of CPP to meet the requirements for food processing. PMID- 30407583 TI - FusionGDB: fusion gene annotation DataBase. AB - Gene fusion is one of the hallmarks of cancer genome via chromosomal rearrangement initiated by DNA double-strand breakage. To date, many fusion genes (FGs) have been established as important biomarkers and therapeutic targets in multiple cancer types. To better understand the function of FGs in cancer types and to promote the discovery of clinically relevant FGs, we built FusionGDB (Fusion Gene annotation DataBase) available at https://ccsm.uth.edu/FusionGDB. We collected 48 117 FGs across pan-cancer from three representative fusion gene resources: the improved database of chimeric transcripts and RNA-seq data (ChiTaRS 3.1), an integrative resource for cancer-associated transcript fusions (TumorFusions), and The Cancer Genome Atlas (TCGA) fusions by Gao et al. For these ~48K FGs, we performed functional annotations including gene assessment across pan-cancer fusion genes, open reading frame (ORF) assignment, and retention search of 39 protein features based on gene structures of multiple isoforms with different breakpoints. We also provided the fusion transcript and amino acid sequences according to multiple breakpoints and transcript isoforms. Our analyses identified 331, 303 and 667 in-frame FGs with retaining kinase, DNA binding, and epigenetic factor domains, respectively, as well as 976 FGs lost protein-protein interaction. FusionGDB provides six categories of annotations: FusionGeneSummary, FusionProtFeature, FusionGeneSequence, FusionGenePPI, RelatedDrug and RelatedDisease. PMID- 30407584 TI - An adaptive geometric search algorithm for macromolecular scaffold selection. AB - A wide variety of protein and peptidomimetic design tasks require matching functional 3D motifs to potential oligomeric scaffolds. For example, during enzyme design, one aims to graft active-site patterns-typically consisting of 3 15 residues-onto new protein surfaces. Identifying protein scaffolds suitable for such active-site engraftment requires costly searches for protein folds that provide the correct side chain positioning to host the desired active site. Other examples of biodesign tasks that require similar fast exact geometric searches of potential side chain positioning include mimicking binding hotspots, design of metal binding clusters and the design of modular hydrogen binding networks for specificity. In these applications, the speed and scaling of geometric searches limits the scope of downstream design to small patterns. Here, we present an adaptive algorithm capable of searching for side chain take-off angles, which is compatible with an arbitrarily specified functional pattern and which enjoys substantive performance improvements over previous methods. We demonstrate this method in both genetically encoded (protein) and synthetic (peptidomimetic) design scenarios. Examples of using this method with the Rosetta framework for protein design are provided. Our implementation is compatible with multiple protein design frameworks and is freely available as a set of python scripts (https://github.com/JiangTian/adaptive-geometric-search-for-protein-design). PMID- 30407585 TI - Structure of human telomere G-quadruplex in the presence of a model drug along the thermal unfolding pathway. AB - A multi-technique approach, combining circular dichroism spectroscopy, ultraviolet resonance Raman spectroscopy and small angle scattering techniques, has been deployed to elucidate how the structural features of the human telomeric G-quadruplex d[A(GGGTTA)3GGG] (Tel22) change upon thermal unfolding. The system is studied both in the free form and when it is bound to Actinomycin D (ActD), an anticancer ligand with remarkable conformational flexibility. We find that at room temperature binding of Tel22 with ActD involves end-stacking upon the terminal G-tetrad. Structural evidence for drug-driven dimerization of a significant fraction of the G-quadruplexes is provided. When the temperature is raised, both free and bound Tel22 undergo melting through a multi-state process. We show that in the intermediate states of Tel22 the conformational equilibrium is shifted toward the (3+1) hybrid-type, while a parallel structure is promoted in the complex. The unfolded state of the free Tel22 is consistent with a self avoiding random-coil conformation, whereas the high-temperature state of the complex is observed to assume a quite compact form. Such an unprecedented high temperature arrangement is caused by the persistent interaction between Tel22 and ActD, which stabilizes compact conformations even in the presence of large thermal structural fluctuations. PMID- 30407586 TI - Plasticity in Motion. PMID- 30407587 TI - Lack of a relationship between plasma fibroblast growth factor-23 and phosphate utilization in young chicks. AB - Fibroblast growth factor 23 (FGF-23) is proposed to be the hormone that controls phosphate (P) homeostasis in chickens. This study was initiated to investigate the effect of feeding young chicks diets that were either adequate (0.45%) or marginal (0.25%) in available P content on plasma FGF-23 levels. The dietary level of available P significantly (P <= 0.05) affected bone mineralization and bone length, but was without effect (P > 0.05) on growth rate and circulating FGF 23 concentrations. Substantial individual variation in bone mineralization and plasma FGF-23 levels was observed, and the correlation between these two variables was non-significant (P > 0.05). This suggested that there was no alteration in FGF-23 activity in response to suboptimal dietary P intake. The relationship of these observations to studies on the immunosuppression of FGF-23 activity is subsequentlydiscussed. PMID- 30407588 TI - Youth Access to Tobacco Products in the United States: Findings from Wave 1 (2013 2014) of the Population Assessment of Tobacco and Health (PATH) Study. AB - Objectives: Tobacco products in the US market are growing in diversity. Little is known about how youth access tobacco products given this current landscape. Methods: Data were drawn from 15-17 year olds from the Wave 1 youth sample of the US nationally-representative Population Assessment of Tobacco and Health (PATH) Study. Past 30-day tobacco users were asked about usual sources of access to 12 different tobacco products, and if they had been refused sale due to their age. Results: Among 15-17 year olds, social sources ("someone offered"/"asked someone") were the predominant usual source of access for each tobacco product. "Bought by self" was the usual source for users of smokeless (excluding snus; 23.2%), cigarillos (21.0%), cigarettes (13.8%), hookah (12.0%), and e-cigarettes (10.5%). Convenience stores/gas stations were the most often selected retail source for all products except hookah. Among youth who attempted purchase, 24.3% were refused sale of cigarettes; 23.9% cigarillos, and 13.8% smokeless tobacco. Conclusions: Most 15-17 year old tobacco users obtain tobacco products through social sources, however among those who purchased tobacco, the vast majority report not being refused sale due to age. At the time of survey, cigarette and cigar sales to <18y were prohibited in all 50 states, and e-cigarettes sales in 47 states and two territories. 2014 Annual Synar Reports signaled increasing trends in retail violations of state/district laws prohibiting tobacco product sales to under 18y. Monitoring illicit youth sales, conducting compliance check inspections, and penalizing violations remain important to reduce youth tobacco access at retail venues. PMID- 30407589 TI - Radiological Characteristics and Natural History of Adult IDH-Wildtype Astrocytomas with TERT Promoter Mutations. AB - BACKGROUND: Adult IDH-wildtype astrocytomas with TERT promoter mutations (TERTp) are associated with a poor prognosis. OBJECTIVE: To analyze the radiological presentation and natural history of adult IDH-wildtype astrocytomas with TERTp. METHODS: We retrospectively reviewed the characteristics of 40 IDH-wildtype TERTp mutant astrocytomas (grade II n = 19, grade III n = 21) and compared them to those of 114 IDH-mutant lower grade gliomas (LGG), of 92 IDH-wildtype TERTp mutant glioblastomas, and of 15 IDH-wildtype TERTp-wildtype astrocytomas. RESULTS: Most cases of IDH-wildtype TERTp-mutant astrocytomas occurred in patients aged >50 yr (88%) and presented as infiltrative lesions without contrast enhancement (73%) that were localized in the temporal and/or insular lobes (37.5%) or corresponded to a gliomatosis cerebri (43%). Thalamic involvement (33%) and extension to the brainstem (27%) were frequently observed, as was gyriform infiltration (33%). This radiological presentation was different from that of IDH-mutant LGG, IDH-wildtype TERTp-mutant glioblastomas, and IDH-wildtype TERTp-wildtype astrocytomas. Tumor evolution before treatment initiation was assessable in 17 cases. Ten cases demonstrated a rapid growth characterized by the apparition of a ring-like contrast enhancement and/or a median velocity of diametric expansion (VDE) >=8 mm/yr but 7 cases displayed a slow growth (VDE <8 mm/yr) that could last several years before anaplastic transformation. Median overall survival of IDH-wildtype TERTp-mutant astrocytomas was 27 mo. CONCLUSION: IDH-wildtype TERTp-mutant astrocytomas typically present as nonenhancing temporo insular infiltrative lesions or as gliomatosis cerebri in patients aged >50 yr. In the absence of treatment, although rapid tumor growth is frequent, an initial falsely reassuring, slow growth can be observed. PMID- 30407590 TI - ECO, the Evidence & Conclusion Ontology: community standard for evidence information. AB - The Evidence and Conclusion Ontology (ECO) contains terms (classes) that describe types of evidence and assertion methods. ECO terms are used in the process of biocuration to capture the evidence that supports biological assertions (e.g. gene product X has function Y as supported by evidence Z). Capture of this information allows tracking of annotation provenance, establishment of quality control measures and query of evidence. ECO contains over 1500 terms and is in use by many leading biological resources including the Gene Ontology, UniProt and several model organism databases. ECO is continually being expanded and revised based on the needs of the biocuration community. The ontology is freely available for download from GitHub (https://github.com/evidenceontology/) or the project's website (http://evidenceontology.org/). Users can request new terms or changes to existing terms through the project's GitHub site. ECO is released into the public domain under CC0 1.0 Universal. PMID- 30407591 TI - IID 2018 update: context-specific physical protein-protein interactions in human, model organisms and domesticated species. AB - Knowing the set of physical protein-protein interactions (PPIs) that occur in a particular context-a tissue, disease, or other condition-can provide valuable insights into key research questions. However, while the number of identified human PPIs is expanding rapidly, context information remains limited, and for most non-human species context-specific networks are completely unavailable. The Integrated Interactions Database (IID) provides one of the most comprehensive sets of context-specific human PPI networks, including networks for 133 tissues, 91 disease conditions, and many other contexts. Importantly, it also provides context-specific networks for 17 non-human species including model organisms and domesticated animals. These species are vitally important for drug discovery and agriculture. IID integrates interactions from multiple databases and datasets. It comprises over 4.8 million PPIs annotated with several types of context: tissues, subcellular localizations, diseases, and druggability information (the latter three are new annotations not available in the previous version). This update increases the number of species from 6 to 18, the number of PPIs from ~1.5 million to ~4.8 million, and the number of tissues from 30 to 133. IID also now supports topology and enrichment analyses of returned networks. IID is available at http://ophid.utoronto.ca/iid. PMID- 30407592 TI - The effect of nutrient restriction on the proliferation and differentiation of turkey pectoralis major satellite cells differing in age and growth rate. AB - Myogenic satellite cells are critical for posthatch muscle growth, and their activity is sensitive to nutritional regime during the immediate posthatch period. The objective of the current study was to determine if the response of satellite cells to nutrient restriction was dependent on bird age and/or growth rate. Satellite cells were isolated from the pectoralis major (p. major) muscle of 1-d, 7-wk, and 16-wk-old turkeys selected for increased body weight at 16 wk of age (F line) and the randombred control (RBC2) line from which the F line was selected. Nutrient restriction of 0, 5, 10, 20, and 40% of the standard cell culture medium was applied during proliferation with subsequent normal differentiation medium (RN) or during differentiation with preceding normal proliferation medium (NR). Satellite cell proliferation and differentiation decreased with nutrient restriction for all treatment regimens and ages, except for 1-d cell differentiation with the RN treatment, which increased with nutrient restriction. Interestingly, after 24 h of a 5% nutrient restriction during the RN treatment, proliferation increased for 1-d and 7-wk cells. Additionally, after 24 h of 5, 10, and 20% nutrient restriction during the NR treatment, differentiation increased for 1-d and 7-wk cells. The 16-wk cells did not exhibit this response to any treatment regimen. Growth rate had little effect on satellite cell response to nutrient restriction. In this study, satellite cells differentially responded to nutrient restriction depending on age, as well as duration and timing of the nutrient restriction. These data suggest that it is necessary to optimize diets throughout a bird's life to maximize satellite cell activity and p. major muscle growth. PMID- 30407593 TI - Letter: Tailored Extended Bifrontal Craniotomy for Anterior Skull Base Tumors: Anatomic Description of a Modified Surgical Technique. PMID- 30407594 TI - PANTHER version 14: more genomes, a new PANTHER GO-slim and improvements in enrichment analysis tools. AB - PANTHER (Protein Analysis Through Evolutionary Relationships, http://pantherdb.org) is a resource for the evolutionary and functional classification of genes from organisms across the tree of life. We report the improvements we have made to the resource during the past two years. For evolutionary classifications, we have added more prokaryotic and plant genomes to the phylogenetic gene trees, expanding the representation of gene evolution in these lineages. We have refined many protein family boundaries, and have aligned PANTHER with the MEROPS resource for protease and protease inhibitor families. For functional classifications, we have developed an entirely new PANTHER GO slim, containing over four times as many Gene Ontology terms as our previous GO slim, as well as curated associations of genes to these terms. Lastly, we have made substantial improvements to the enrichment analysis tools available on the PANTHER website: users can now analyze over 900 different genomes, using updated statistical tests with false discovery rate corrections for multiple testing. The overrepresentation test is also available as a web service, for easy addition to third-party sites. PMID- 30407595 TI - Seroepidemiology, modifiable risk factors and clinical symptoms of Toxocara spp. infection in northern Iran. AB - Toxocariasis is one of the most important and widespread neglected tropical infectious diseases. We designed a cross-sectional study to assess the seroepidemiological aspects of toxocariasis among the general population in northern Iran. A total of 630 rural subjects were enrolled to participate in the study. The presence of anti-Toxocara immunoglobulin G (IgG) was tested using a commercially available enzyme-linked immunosorbent assay. A structured questionnaire was also used to evaluate the potential risk factors and related clinical signs/symptoms. The presence of anti-Toxocara IgG antibodies was detected in 148 of the 630 rural subjects (23.5% [95% confidence interval {CI} 21.8 to 25.1]). By multivariate analysis, age (odds ratio [OR] 2.89 [95% CI 1 to 8.3], p=0.04), eating improperly washed vegetables (OR 4.05 [95% CI 2.47 to 6.64], p<0.001), contact with dogs (OR 3.31 [95% CI 2.13 to 5.12], p<0.001) and exposure to soil (OR 3.56 [95% CI 2.13 to 5.13], p<0.001) were significantly associated with the seroprevalence of Toxocara. The clinical study also demonstrated that the seroprevalence of Toxocara infection was significantly associated with asthma (OR 3.78 [95% CI 1.63 to 8.75], p<0.001) and ophthalmic disorder (OR 1.83 [95% CI 1.04 to 3.21], p=0.034). The findings proved that residents of rural communities in tropical regions may be heavily exposed to Toxocara spp. We highly recommend more investigations in high-risk groups. PMID- 30407596 TI - Cancer3D 2.0: interactive analysis of 3D patterns of cancer mutations in cancer subsets. AB - Our knowledge of cancer genomics exploded in last several years, providing us with detailed knowledge of genetic alterations in almost all cancer types. Analysis of this data gave us new insights into molecular aspects of cancer, most important being the amazing diversity of molecular abnormalities in individual cancers. The most important question in cancer research today is how to classify this diversity to identify subtypes that are most relevant for treatment and outcome prediction for individual patients. The Cancer3D database at http://www.cancer3d.org gives an open and user-friendly way to analyze cancer missense mutations in the context of structures of proteins they are found in and in relation to patients' clinical data. This approach allows users to find novel candidate driver regions for specific subgroups, that often cannot be found when similar analyses are done on the whole gene level and for large, diverse cohorts. Interactive interface allows user to visualize the distribution of mutations in subgroups defined by cancer type and stage, gender and age brackets, patient's ethnicity or vice versa find dominant cancer type, gender or age groups for specific three-dimensional mutation patterns. PMID- 30407597 TI - Letter: Comparative Analysis Between Lateral Orbital Rim Preservation and Osteotomy for Transorbital Endoscopic Approaches to the Cavernous Sinus: An Anatomic Study. PMID- 30407598 TI - Tenecteplase for Thrombectomy Thrombolysis. PMID- 30407599 TI - Mouse Genome Database (MGD) 2019. AB - The Mouse Genome Database (MGD; http://www.informatics.jax.org) is the community model organism genetic and genome resource for the laboratory mouse. MGD is the authoritative source for biological reference data sets related to mouse genes, gene functions, phenotypes, and mouse models of human disease. MGD is the primary outlet for official gene, allele and mouse strain nomenclature based on the guidelines set by the International Committee on Standardized Nomenclature for Mice. In this report we describe significant enhancements to MGD, including two new graphical user interfaces: (i) the Multi Genome Viewer for exploring the genomes of multiple mouse strains and (ii) the Phenotype-Gene Expression matrix which was developed in collaboration with the Gene Expression Database (GXD) and allows researchers to compare gene expression and phenotype annotations for mouse genes. Other recent improvements include enhanced efficiency of our literature curation processes and the incorporation of Transcriptional Start Site (TSS) annotations from RIKEN's FANTOM 5 initiative. PMID- 30407600 TI - Insomnia and Suicidal Ideation in Non-Affective Psychosis. AB - Study Objectives: Insomnia is a common symptom in the clinical course of schizophrenia. There is a robust association between insomnia and suicidality in other psychiatric disorders. Two previous studies found associations between insomnia and suicide attempt or completed suicide in patients with schizophrenia. We hypothesized that greater insomnia would be associated with greater levels of suicidal ideation in patients with schizophrenia and other non-affective psychoses. Method: We recruited 108 inpatients and outpatients age 18-65 between July 2010 and July 2016 with DSM-IV non-affective psychosis (schizophrenia, schizoaffective disorder, or schizophreniform disorder). We investigated relationships between current insomnia (Insomnia Severity Index [ISI]), suicidal ideation over the past week and lifetime history of suicide attempt (Beck Scale for Suicide Ideation [BSS]) in regression analyses. Results: After controlling for potential confounders, insomnia was a significant indicator of suicidal ideation (beta=0.27, p=0.032). Insomnia was also a significant indicator of a high BSS score (>=16), (OR=1.14, 95% CI 1.01-1.28, p=0.029). Furthermore, subjects with severe insomnia were almost 15 times more likely to have a lifetime history suicide attempt than subjects without current insomnia (OR=14.8, 95% CI 1.4-157, p=0.025). Insomnia was also an indicator of greater PANSS total (beta=0.33, p=0.001), positive subscale (beta=0.32, p=0.002), and general subscale (beta=0.40, p<0.001) scores. Conclusions: Insomnia is associated with suicidal ideation, lifetime suicide attempt, and greater psychopathology in patients with schizophrenia. Our findings suggest that formal assessment of insomnia may be germane to the clinical care of patients with schizophrenia as a marker of suicide risk and symptom severity. PMID- 30407601 TI - Three LcABFs are involved in the regulation of chlorophyll degradation and anthocyanin biosynthesis during fruit ripening in Litchi chinensis. AB - During litchi (Litchi chinensis Sonn.) fruits ripening, two major physiological changes, degreening (chlorophyll degradation) and pigmentation (anthocyanin biosynthesis) are visually apparent. However, the specific factor triggering this important transition is still unclear. In the present study, we found that endogenous ABA content increased sharply when chlorophyll (Chl) breakdown initiated and ABA level peaked just before the onset of anthocyanin accumulation, suggesting that ABA plays an important role during litchi fruit pigmentation. Then we characterized three ABSCISIC ACID RESPONSE ELEMENT-BINDING FACTORs (LcABF1/2/3) belonging to group A of basic leucine zipper (bZIP) transcription factors previously shown to be involved in ABA signaling under abiotic stress. LcABF1 transcripts increased at the onset of Chl degradation and the expression of LcABF3 accumulated in parallel with anthocyanin biosynthesis. In addition, dual luciferase assay and yeast one-hybrid system indicated that LcABF1/2 recognized ABA-responsive elements in the promoter region of Chl degradation related genes (PAO and SGR), while LcABF2/3 bound the promoter region of LcMYB1 and anthocyanin biosynthesis-related structural genes. Indeed, Nicotiana benthamiana leaves transiently expressed LcABF1/2 showed a senescence phenomenon with Chl degradation, and LcABF3 overexpression increased the accumulation of anthocyanin via activating LcMYB1, which is the key determinant of anthocyanin biosynthesis. These data indicate that LcABF1/2/3 are important transcriptional regulators of ABA-dependent litchi fruit ripening involving in both Chl degradation as well as anthocyanin biosynthesis. PMID- 30407602 TI - Commentary: Analysis of Wide-Neck Aneurysms in the Barrow Ruptured Aneurysm Trial. PMID- 30407603 TI - Simplified colonic dialysis with hemodialysis solutions delays the progression of chronic kidney disease. AB - Aim: To evaluate the efficacy of a simplified model of colonic dialysis with hemodialysis solutions (SCD) to delay the progression of stage 3-5 chronic kidney disease (CKD). Methods: We retrospectively analyzed 178 stage 3-5 CKD patients who did or did not receive SCD (SCD group, n = 88; control group, n = 90). The follow-up was 36 months. The outcome of CKD progression was defined as a decrease of 50% or more in estimated glomerular filtration rate, starting hemodialysis or peritoneal dialysis, or undergoing transplantation. The Kaplan-Meier analysis was used to compare CKD progression between SCD and control groups as well as between subgroups at different CKD stages. Cox proportional hazard models adjusted for patients' characteristics were used to examine the association between SCD and the outcome. Results: For all patients, the outcome was significantly better in SCD group compared to control group (p < 0.05). The results were similar in the subgroups of patients at stage 4 (p = 0.001) and stage 5 (p = 0.000), but not in the subgroup of patients at stage 3 (p = 0.121). For all patients, SCD was associated with a lower risk of CKD progression after adjusted for patients' characteristics (adjusted hazard ratio, 0.373; 95% confidence interval, 0.201 0.694; p 0.002). Conclusion: SCD is an effective supplementary therapy to delay the progression of stage 4-5 CKD. PMID- 30407604 TI - Older Adults' Lure Discrimination Difficulties on the Mnemonic Similarity Test are Significantly Correlated with their Visual Perception. AB - OBJECTIVES: Pattern separation in memory encoding entails creating and storing distinct, detailed representations to facilitate storage and retrieval. The Mnemonic Similarity Test (Stark, Yassa, Lacy, & Stark, 2013) has been used to argue that normal aging leads to pattern separation decline. We sought to replicate previous reports of age-related difficulty on this behavioral pattern separation estimate, and to examine its neuropsychological correlates, specifically long-term memory function, executive function, and visual perception. METHODS: We administered an object version of the Mnemonic Similarity Test to 31 young adults and 38 older adults. It involved a single-probe recognition memory test in which some of the originally-studied objects had been replaced with perceptually similar lures, and participants had to identify each as old, a lure, or new. RESULTS: Despite their corrected item recognition scores being superior to those of the young adults, the older adults had significantly greater difficulty than the young in discriminating the similar-looking lures from the original items. Interestingly, this lure discrimination difficulty was significantly correlated with visual perception rather than with long-term memory or executive function. DISCUSSION: These results suggest that although adult age differences on the MST are reliable, care should be taken to separate perceptual from memory discrimination difficulties as the reason. PMID- 30407605 TI - Pectin or chitosan coating fortified with eugenol reduces Campylobacter jejuni on chicken wingettes and modulates expression of critical survival genes. AB - Campylobacter jejuni infection in humans is strongly associated with the consumption of contaminated poultry products. With increasing consumer demand for minimally processed and natural product, there is a need for novel intervention strategies for controlling C. jejuni. Antimicrobial coatings are increasingly being used for preventing food contamination due to their efficacy and continuous protection of product. This study investigated the efficacy of pectin and chitosan coating fortified with eugenol to reduce C. jejuni on chicken wingettes. Pectin, chitosan, and eugenol are generally recognized as safe status compounds derived from berries, crustaceans, and cloves respectively. Each wingette was inoculated with a mixture of 4 wild-type strains of C. jejuni (approximately 107 CFU/sample) and randomly assigned to controls, pectin (3%), chitosan (2%), eugenol (0.5, 1, or 2%), or their combinations. Following 1 min of coating, wingettes were air-dried, vacuum sealed, and sampled on 0, 1, 3, 5, and 7 d of refrigerated storage for C. jejuni and aerobic counts (n = 5 wingettes/treatment/d). In addition, the effect of treatments on wingette color and expression of C. jejuni survival/virulence genes was evaluated. All 3 doses of eugenol or chitosan significantly reduced C. jejuni and aerobic bacteria from 0 d through 7 d. Incorporation of 2% eugenol in chitosan improved coating efficiency and reduced C. jejuni counts by approximately 3 Log CFU/sample at the end of 7 d of storage (P < 0.05). Similarly, the antimicrobial efficacy of pectin was improved by 2% eugenol and the coating reduced C. jejuni by approximately 2 Log CFU/sample at 7 d of storage. Chitosan coating with 2% eugenol also showed greater reductions of total aerobic counts as compared to individual treatments of eugenol and chitosan. No significant difference in the color of chicken wingettes was observed between treatments. Exposure of C. jejuni to eugenol, chitosan, or combination significantly modulated select genes encoding for motility, quorum sensing, and stress response. Results demonstrate the potential of pectin or chitosan coating fortified with eugenol as a postharvest intervention against C. jejuni contamination on poultry products. PMID- 30407607 TI - Group 2 Sigma Factors Are Central Regulators of Oxidative Stress Acclimation in Cyanobacteria. AB - Regulatory sigma factors of the RNA polymerase (RNAP) adjust gene expression according to environmental cues when the cyanobacterium Synechocystis sp. PCC 6803 acclimates to suboptimal conditions. Here we show central roles of the non essential group 2 sigma factors in oxidative stress responses. Cells missing all group 2 sigma factors fail to acclimate to chemically induced singlet oxygen, superoxide or H2O2 stresses and lose pigments in high light. The SigB and SigD are the major sigma factors in oxidative stress whereas SigC and SigE play only minor roles. The SigD factor is upregulated in high light, singlet oxygen and H2O2 stresses, and overproduction of the SigD factor in the DeltasigBCE strain leads to superior growth of DeltasigBCE cells in those stress conditions. Superoxide does not induce the production of the SigD factor but instead SigB and SigC factors are moderately induced. The SigB factor alone in DeltasigCDE can support almost as fast growth in superoxide stress as full complement of sigma factors in the control strain but an overdose of the stationary-phase-related SigC factor causes growth arrest of DeltasigBDE in superoxide stress. Drastic decrease of the functional RNA polymerase limits the transcription capacity of the cells in H2O2 stress, which explains why cyanobacteria are sensitive to H2O2. Formation of RNAP-SigB and RNAP-SigD holoenzymes is highly enhanced in H2O2 stress and cells containing only SigB (DeltasigCDE) or SigD (DeltasigBCE) show superior growth in H2O2 stress. PMID- 30407606 TI - A Meta-analysis of Immune Parameters, Variability, and Assessment of Modal Distribution in Psychosis and Test of the Immune Subgroup Hypothesis. AB - Immune parameters are elevated in psychosis, but it is unclear whether alterations are homogenous across patients or heterogeneity exists, consistent with the hypothesis that immune alterations are specific to a subgroup of patients. To address this, we examine whether antipsychotic-naive first-episode psychosis patients exhibit greater variability in blood cytokines, C-reactive protein, and white cell counts compared with controls, and if group mean differences persist after adjusting for skewed data and potential confounds. Databases were searched for studies reporting levels of peripheral immune parameters. Means and variances were extracted and analyzed using multivariate meta-analysis of mean and variability of differences. Outcomes were (1) variability in patients relative to controls, indexed by variability ratio (VR) and coefficient of variation ratio (CVR); (2) mean differences indexed by Hedges g; (3) Modal distribution of raw immune parameter data using Hartigan's unimodality dip test. Thirty-five studies reporting on 1263 patients and 1470 controls were included. Variability of interleukin-6 (IL6) (VR = 0.19), tumor necrosis factor-alpha (TNFalpha) (VR = 0.36), interleukin-1beta (VR = 0.35), interleukin-4 (VR = 0.55), and interleukin-8 (VR = 0.28) was reduced in patients. Results persisted for IL6 and IL8 after mean-scaling. Ninety-four percent and one hundred percent of raw data were unimodally distributed in psychosis and controls, respectively. Mean levels of IL6 (g = 0.62), TNFalpha (g = 0.56), interferon-gamma (IFNgamma) (g = 0.32), transforming growth factor-beta (g = 0.53), and interleukin-17 (IL17) (g = 0.48) were elevated in psychosis. Sensitivity analyses indicated this is unlikely explained by confounders for IL6, IFNgamma, and IL17. These findings show elevated cytokines in psychosis after accounting for confounds, and that the hypothesis of an immune subgroup is not supported by the variability or modal distribution. PMID- 30407608 TI - A plant proteinase inhibitor from enterolobium contortisiliquum attenuates airway hyperresponsiveness, inflammation and remodeling in a mouse model of asthma. AB - INTRODUCTION: Proteinase inhibitors have been associated with anti-inflammatory and antioxidant activities and may represent a potential therapeutic treatment for asthma. PURPOSE: The aim of the present study was to evaluate the effects of Enterolobium contortisiliquum trypsin inhibitor (EcTI) on pulmonary mechanical function, eosinophilic recruitment, inflammatory cytokines, remodeling and oxidative stress in an experimental model of chronic allergic pulmonary inflammation. METHODS: BALB/c mice were divided into 4 groups: C (saline i.p and inhalations with saline), OVA (ovalbumin i.p and inhalations with ovalbumin); C+EC (saline i.p, inhalations with s aline and treatment with EcTI); OVA+EC (ovalbumin i.p, inhalations with ovalbumin and treatment with EcTI). On day 29, we performed the following tests: resistance (Rrs) and elastance (Ers) of the respiratory system; (b) quantify eosinophils, 8-ISO-PGF2alpha, collagen and elastic fiber volume fractions; (c) IFN-gamma, IL-4, IL-5, IL-13, MMP-9, TIMP-1, TGF-beta, iNOS and p65-NFkappaB-positive cells in the airway and alveolar walls. RESULTS: In OVA+EC group, there was an attenuation of the Rrs and Ers, reduction of eosinophils, IL-4, IL-5, IL-13, IFN-gamma, iNOS and p65-NFkappaB-positive cells compared to OVA group. The 8-ISO-PGF2alpha, elastic and collagen fibers volume fractions as well as the positive cells for MMP-9, TIMP-1 and TGF-beta positive cells were decreased in OVA+EC compared to the OVA group. CONCLUSION: EcTI attenuates bronchial hyperresponsiveness, inflammation, remodeling and oxidative stress activation in this experimental mouse model of asthma. PMID- 30407609 TI - Cytokine release syndrome and neurotoxicity after CD19 chimeric antigen receptor modified (CAR-) T cell therapy. AB - Chimeric antigen receptor-modified (CAR)-T cells have demonstrated impressive results in the treatment of haematological malignancies. However, cytokine release syndrome (CRS) and neurotoxicity are common toxicities which are potentially life-threatening in severe cases. Risk factors for CRS and neurotoxicity identified so far include disease burden, lymphodepletion intensity and CAR-T cell dose administered. Risk-adapted dosing, with lower CAR-T cell doses administered to B-cell acute lymphoblastic leukaemia patients with high marrow blast counts, has been successful at decreasing severe CRS rates in this population. Intervention with therapies, such as tocilizumab and corticosteroids, have been effective at ameliorating toxicity, enabling CAR-T cells to be administered safely to many patients without significantly compromising efficacy. Deeper understanding of the pathophysiology of underlying CRS and neurotoxicity will enable the development of novel approaches to reduce toxicity and improve outcomes. PMID- 30407610 TI - Diagnosis of Hodgkin lymphoma in the modern era. AB - The Hodgkin lymphomas are a family of unique lymphoma subtypes, in which the nature of the neoplastic cell was enigmatic for many years. Much of the mystery has been solved, with all forms now considered to be of B-cell origin, in most cases of germinal centre derivation. Today we recognize Hodgkin lymphoma as an eponym that encompasses multiple entities. One of the unifying themes is the major contribution from the tumour microenvironment. Both the character of the neoplastic cells and the nature of the immune environment are critical to accurate diagnosis. Moreover, an understanding of the molecular alterations that characterize both the neoplastic cells and their microenvironment have led to therapeutic advances, targeting both neoplastic and reactive components. Other conditions may foster a similar inflammatory milieu and lead to lymphoproliferations that mimic the Hodgkin lymphomas. In this review we provide an update on the diagnostic features of the various subtypes and include additional information relevant for prognostic evaluation and investigation of potential therapeutic targets. Additionally, we also discuss those conditions that often cause confusion in diagnosis and need to be distinguished from the Hodgkin lymphomas. PMID- 30407611 TI - Auer rods in neutrophils in bone marrow and peripheral blood in mixed phenotype acute leukaemia in a child. PMID- 30407612 TI - The role of transplantation in Hodgkin lymphoma. AB - Autologous stem cell transplantation is the standard salvage strategy for young and fit patients with Hodgkin lymphoma failing induction therapy, and is effective in nearly 50% of cases. The quality of response at transplantation is the most relevant prognostic aspect, as patients in complete response can obtain better outcomes. Therefore, first-line salvage treatments applied before transplantation need to produce high quality responses without excessive myelotoxicity and without affecting peripheral blood stem cell mobilisation. In this sense, the incorporation of new agents active in Hodgkin lymphoma, such as brentuximab vedotin and anti-programmed death 1 antibodies, in conventional regimens, may help to enhance complete remission rates. Working on conditioning regimen and applying a post-autologous consolidation treatment (for example with brentuximab vedotin) are two ways for improving transplant outcomes, particularly in patients displaying high-risk features for early relapse or progression. Allogeneic transplantation maintains its curative potential also in the era of new drugs, although its most correct timing and the most suitable sequence of post-autologous salvage treatments still remain to be determined. PMID- 30407613 TI - Growth disturbances in children and adolescents receiving long-term tyrosine kinase inhibitor therapy for Chronic Myeloid Leukaemia or Philadelphia Chromosome positive Acute Lymphoblastic Leukaemia. PMID- 30407614 TI - Mutational profile and haematological response to iron chelation in myelodysplastic syndromes (MDS). PMID- 30407615 TI - The effect of age in patients with acquired aplastic anaemia treated with immunosuppressive therapy: comparison of Adolescents and Young Adults with children and older adults. AB - The incidence of acquired aplastic anaemia (AA) peaks in adolescents and young adults (AYA). Although age has been associated with response after immunosuppressive therapy (IST), few data exist about the specific outcome of AYA. We retrospectively compared the outcome of 29 children (aged <15 years), 32 AYA (15-25 years) and 23 adults (>25 years) with AA treated front-line with IST in Saint-Louis Hospital. The cumulative incidence of response was lower in adults compared with AYA (subdistribution hazard ratio [SHR] = 0.38, 95% confidence interval [CI] [0.96-1.00], P = 0.008), but no difference was observed between children and AYA (SHR = 0.84, 95% CI [0.96-1.00], P = 0.56), with a 6 months cumulative incidence of partial response of 44.8% in children, 62.5% in AYA and 21.7% in adults. The 5-year failure-free survival was 48.4%, without impact of age, with a 5-year relapse rate of 20.7%. With a median follow-up of 5.4 years, the 5-year overall survival was 86.5%, without significant difference between children and AYA overall survival (hazard ratio [HR] 1.51, 95% CI [0.25-9.02], P = 0.66), while adults displayed poorer survival than AYA (HR 4.98, 95% CI [1.00 24.73], P = 0.049). This study confirms that age is a prognostic factor in AA patients treated with IST. However, AYA patients have a similar outcome to children in terms of response rate and survival. PMID- 30407616 TI - Cannabis for the treatment of Crohn's disease. AB - BACKGROUND: Crohn's disease (CD) is a chronic immune-mediated condition of transmural inflammation in the gastrointestinal tract, associated with significant morbidity and decreased quality of life. The endocannabinoid system provides a potential therapeutic target for cannabis and cannabinoids and animal models have shown benefit in decreasing inflammation. However, there is also evidence to suggest transient adverse events such as weakness, dizziness and diarrhea, and an increased risk of surgery in people with CD who use cannabis. OBJECTIVES: The objectives were to assess the efficacy and safety of cannabis and cannabinoids for induction and maintenance of remission in people with CD. SEARCH METHODS: We searched MEDLINE, Embase, AMED, PsychINFO, the Cochrane IBD Group Specialized Register, CENTRAL, ClinicalTrials.Gov, and the European Clinical Trials Register up to 17 October 2018. We searched conference abstracts, references and we also contacted researchers in this field for upcoming publications. SELECTION CRITERIA: Randomized controlled trials comparing any form of cannabis or its cannabinoid derivatives (natural or synthetic) to placebo or an active therapy for adults with Crohn's disease were included. DATA COLLECTION AND ANALYSIS: Two authors independently screened search results, extracted data and assessed bias using the Cochrane risk of bias tool. The primary outcomes were clinical remission and relapse. Remission is commonly defined as a Crohn's disease activity index (CDAI) of < 150. Relapse is defined as a CDAI > 150. Secondary outcomes included clinical response, endoscopic remission, endoscopic improvement, histological improvement, quality of life, C-reactive protein (CRP) and fecal calprotectin measurements, adverse events (AEs), serious AEs, withdrawal due to AEs, and cannabis dependence and withdrawal effects. We calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI) for dichotomous outcomes. For continuous outcomes, we calculated the mean difference (MD) and 95% CI. Data were combined for analysis when the interventions, patient groups and outcomes were sufficiently similar (determined by consensus). Data were analyzed on an intention-to-treat basis and the overall certainty of the evidence supporting the outcomes was evaluated using the GRADE criteria. MAIN RESULTS: Three studies (93 participants) that assessed cannabis in people with active CD met the inclusion criteria. One ongoing study was also identified. Participants in two of the studies were adults with active Crohn's disease who had failed at least one medical treatment. The inclusion criteria for the third study were unclear. No studies that assessed cannabis therapy in quiescent CD were identified. The studies were not pooled due to differences in the interventional drug.One small study (N = 21) compared eight weeks of treatment with cannabis cigarettes containing 115 mg of D9-tetrahydrocannabinol (THC) to placebo cigarettes containing cannabis with the THC removed in participants with active CD. This study was rated as high risk of bias for blinding and other bias (cannabis participants were older than placebo). The effects of cannabis on clinical remission were unclear. Forty-five per cent (5/11) of the cannabis group achieved clinical remission compared with 10% (1/10) of the placebo group (RR 4.55, 95% CI 0.63 to 32.56; very low certainty evidence). A difference was observed in clinical response (decrease in CDAI score of >100 points) rates. Ninety-one per cent (10/11) of the cannabis group achieved a clinical response compared to 40% (4/10) of the placebo group (RR 2.27, 95% CI 1.04 to 4.97; very low certainty evidence). More AEs were observed in the cannabis cigarette group compared to placebo (RR 4.09, 95% CI 1.15 to 14.57; very low certainty evidence). These AEs were considered to be mild in nature and included sleepiness, nausea, difficulty with concentration, memory loss, confusion and dizziness. This study did not report on serious AEs or withdrawal due to AEs.One small study (N = 22) compared cannabis oil (5% cannabidiol) to placebo oil in people with active CD. This study was rated as high risk of bias for other bias (cannabis participants were more likely than placebo participants to be smokers). There was no difference in clinical remission rates. Forty per cent (4/10) of cannabis oil participants achieved remission at 8 weeks compared to 33% (3/9) of the placebo participants (RR 1.20, 95% CI 0.36 to 3.97; very low certainty evidence). There was no difference in the proportion of participants who had a serious adverse event. Ten per cent (1/10) of participants in the cannabis oil group had a serious adverse event compared to 11% (1/9) of placebo participants (RR 0.90, 95% CI 0.07 to 12.38, very low certainty evidence). Both serious AEs were worsening Crohn's disease that required rescue intervention. This study did not report on clinical response, CRP, quality of life or withdrawal due to AEs.One small study (N= 50) compared cannabis oil (15% cannabidiol and 4% THC) to placebo in participants with active CD. This study was rated as low risk of bias. Differences in CDAI and quality of life scores measured by the SF-36 instrument were observed. The mean quality of life score after 8 weeks of treatment was 96.3 in the cannabis oil group compared to 79.9 in the placebo group (MD 16.40, 95% CI 5.72 to 27.08, low certainty evidence). After 8 weeks of treatment, the mean CDAI score was118.6 in the cannabis oil group compared to 212.6 in the placebo group (MD -94.00, 95%CI -148.86 to -39.14, low certainty evidence). This study did not report on clinical remission, clinical response, CRP or AEs. AUTHORS' CONCLUSIONS: The effects of cannabis and cannabis oil on Crohn's disease are uncertain. Thus no firm conclusions regarding the efficacy and safety of cannabis and cannabis oil in adults with active Crohn's disease can be drawn. The effects of cannabis or cannabis oil in quiescent Crohn's disease have not been investigated. Further studies with larger numbers of participants are required to assess the potential benefits and harms of cannabis in Crohn's disease. Future studies should assess the effects of cannabis in people with active and quiescent Crohn's disease. Different doses of cannabis and delivery modalities should be investigated. PMID- 30407617 TI - High HFE mutation incidence in idiopathic erythrocytosis. PMID- 30407618 TI - Effect of body mass index on the outcome of IVF cycles among patients with poor ovarian response. AB - OBJECTIVE: To assess the effects of body mass index (BMI) on the outcome of IVF cycles among poor responders. METHODS: A prospective cohort study in Egypt enrolled 185 poor responders who underwent intracytoplasmic sperm injection via an antagonist protocol between 2012 and 2017. Participants were classified into three groups by BMI (calculated as weight in kilograms divided by the square of height in meters): 18.5-24.9 (normal, n=48); 25-29.9 (overweight, n=54); 30 or higher (obese, n=83). Outcomes were clinical pregnancy rate, implantation rate, chemical pregnancy rate, gonadotropin dose, number of oocytes and embryos, and cancellation rate. RESULTS: There was no significant difference among the three groups in gonadotropin dose; duration of stimulation; endometrial thickness on trigger day; number of oocytes retrieved, injected, or fertilized; number of embryos, transferred embryos, or frozen embryos; or day of embryo transfer. Frequency of implantation (11/81 [14%] vs 6/96 [6%] or 5/155 [3%]), chemical pregnancy (20 [42%] vs 14 [30%] or 12 [14%]) and clinical pregnancy (15 [31%] vs 12 [22%] and 9 [11%]) was significantly higher for normal than for overweight or obese women, respectively. CONCLUSION: Implantation, chemical pregnancy, and clinical pregnancy rates were inversely related to increasing BMI. CLINICALTRIALS.GOV: NCT03457233. PMID- 30407620 TI - Additive effect of sirolimus and hydroxycarbamide on fetal haemoglobin level in kidney transplant patients with sickle cell disease. PMID- 30407619 TI - Clinical outcomes in chronic lymphocytic leukaemia associated with expression of CD5, a negative regulator of B-cell receptor signalling. AB - Chronic lymphocytic leukaemia (CLL) is characterized by expression of CD5 on clonal B cells, and is partly driven by activated B-cell receptor (BCR) signalling. While CD5 is known to be a negative regulator of BCR signalling, it is unknown if variability in CD5 expression exists among patients and whether CLL cell CD5 expression affects CLL clinical outcomes. We assessed the extent to which CD5 expression is correlated with clinical outcomes, and whether this information adds to currently used prognostic markers. We evaluated CD5 expression from 1275 blood samples, established prognostic markers and time to event data from 423 CLL patients followed at the Duke University and Durham VA Medical Centers. CD5 median fluorescence intensity (MFI) was largely stable over time in individual patients, but ranged between 0.5 and 760 in the entire cohort. Lower CD5 MFI was significantly associated with a shorter time to first therapy. CD5 MFI, combined with established clinical and molecular prognostic markers, significantly improved risk-stratification. CD5 may affect disease outcomes by suppressing signalling through the BCR. Thus, a strategy to modulate CLL cell CD5 expression or function could be a therapeutic approach in CLL. PMID- 30407621 TI - Effect of testing for cancer on cancer- or venous thromboembolism (VTE)-related mortality and morbidity in people with unprovoked VTE. AB - BACKGROUND: Venous thromboembolism (VTE) is a collective term for two conditions: deep vein thrombosis (DVT) and pulmonary embolism (PE). A proportion of people with VTE have no underlying or immediately predisposing risk factors and the VTE is referred to as unprovoked. Unprovoked VTE can often be the first clinical manifestation of an underlying malignancy. This has raised the question of whether people with an unprovoked VTE should be investigated for an underlying cancer. Treatment for VTE is different in cancer and non-cancer patients and a correct diagnosis would ensure that people received the optimal treatment for VTE to prevent recurrence and further morbidity. Furthermore, an appropriate cancer diagnosis at an earlier stage could avoid the risk of cancer progression and lead to improvements in cancer-related mortality and morbidity. This is an update of a review first published in 2015. OBJECTIVES: To determine whether testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT of the lower limb or PE) is effective in reducing cancer or VTE-related mortality and morbidity and to determine which tests for cancer are best at identifying treatable cancers early. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 11 July 2018. We also undertook reference checking to identify additional studies. SELECTION CRITERIA: Randomised and quasi-randomised trials in which people with an unprovoked VTE were allocated to receive specific tests for identifying cancer or clinically indicated tests only were eligible for inclusion. Primary outcomes included all-cause mortality, cancer-related mortality and VTE-related mortality. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias and extracted data. We resolved any disagreements by discussion. MAIN RESULTS: No new studies were identified for this 2018 update. In total, four studies with 1644 participants are included. Two studies assessed the effect of extensive tests including computed tomography (CT) scanning versus tests at the physician's discretion, while the other two studies assessed the effect of standard testing plus positron emission tomography (PET)/CT scanning versus standard testing alone. For extensive tests including CT versus tests at the physician's discretion, the quality of the evidence, as assessed according to GRADE, was low due to risk of bias (early termination of the studies). When comparing standard testing plus PET/CT scanning versus standard testing alone, the quality of evidence was moderate due to a risk of detection bias. The quality of the evidence was downgraded further as detection bias was present in one study with a low number of events.When comparing extensive tests including CT versus tests at the physician's discretion, pooled analysis on two studies showed that testing for cancer was consistent with either benefit or no benefit on cancer related mortality (odds ratio (OR) 0.49, 95% confidence interval (CI) 0.15 to 1.67; 396 participants; 2 studies; P = 0.26; low-quality evidence). One study (201 participants) showed that, overall, malignancies were less advanced at diagnosis in extensively tested participants than in participants in the control group. In total, 9/13 participants diagnosed with cancer in the extensively tested group had a T1 or T2 stage malignancy compared to 2/10 participants diagnosed with cancer in the control group (OR 5.00, 95% CI 1.05 to 23.76; P = 0.04; low-quality evidence). There was no clear difference in detection of advanced stages between extensive tests versus tests at the physician's discretion: one participant in the extensively tested group had stage T3 compared with four participants in the control group (OR 0.25, 95% CI 0.03 to 2.28; P = 0.22; low-quality evidence). In addition, extensively tested participants were diagnosed earlier than control group (mean: 1 month with extensive tests versus 11.6 months with tests at physician's discretion to cancer diagnosis from the time of diagnosis of VTE). Extensive testing did not increase the frequency of an underlying cancer diagnosis (OR 1.32, 95% CI 0.59 to 2.93; 396 participants; 2 studies; P = 0.50; low-quality evidence). Neither study measured all-cause mortality, VTE-related morbidity and mortality, complications of anticoagulation, adverse effects of cancer tests, participant satisfaction or quality of life.When comparing standard testing plus PET/CT screening versus standard testing alone, standard testing plus PET/CT screening was consistent with either benefit or no benefit on all-cause mortality (OR 1.22, 95% CI 0.49 to 3.04; 1248 participants; 2 studies; P = 0.66; moderate-quality evidence), cancer-related mortality (OR 0.55, 95% CI 0.20 to 1.52; 1248 participants; 2 studies; P = 0.25; moderate quality evidence) or VTE-related morbidity (OR 1.02, 95% CI 0.48 to 2.17; 854 participants; 1 study; P = 0.96; moderate-quality evidence). Regarding stage of cancer, there was no clear difference for detection of early (OR 1.78, 95% 0.51 to 6.17; 394 participants; 1 study; P = 0.37; low-quality evidence) or advanced (OR 1.00, 95% CI 0.14 to 7.17; 394 participants; 1 study; P = 1.00; low-quality evidence) stages of cancer. There was also no clear difference in the frequency of an underlying cancer diagnosis (OR 1.71, 95% CI 0.91 to 3.20; 1248 participants; 2 studies; P = 0.09; moderate-quality evidence). Time to cancer diagnosis was 4.2 months in the standard testing group and 4.0 months in the standard testing plus PET/CT group (P = 0.88). Neither study measured VTE-related mortality, complications of anticoagulation, adverse effects of cancer tests, participant satisfaction or quality of life. AUTHORS' CONCLUSIONS: Specific testing for cancer in people with unprovoked VTE may lead to earlier diagnosis of cancer at an earlier stage of the disease. However, there is currently insufficient evidence to draw definitive conclusions concerning the effectiveness of testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT or PE) in reducing cancer- or VTE-related morbidity and mortality. The results could be consistent with either benefit or no benefit. Further good quality large-scale randomised controlled trials are required before firm conclusions can be made. PMID- 30407622 TI - A retrospective multicentre study of COCKLE, an oral chemotherapy regimen, as palliative treatment for high grade lymphoma. PMID- 30407623 TI - Natural Stimuli Calibration with Fining Direction Regularization in an Integrated Hydrologic Model. AB - The interaction between surface water and groundwater during flood events is a complex process that has traditionally been described using simplified analytical solutions, or abstracted numerical models. To make the problem tractable, it is common to idealize the flood event, simplify river channel geometry, and ignore bank soil heterogeneity, often resulting in a model that only loosely represents the site, thus limiting its applicability to any specific river cross-section. In this study, we calibrate a site-specific fully-integrated surface and subsurface HydroGeoSphere model using flood events for a cross-section along the South River near Waynesboro, VA. The calibration approach presented in this study demonstrates the incorporation of fining direction regularization with a highly parameterized inversion driven by natural stimuli, to develop several realistic realizations of hydraulic conductivity fields that reflect the depositional history of the system. Specifically, we calibrate a model with 365 unique material zones to multiple flood events recorded in a dense well network while incorporating possible fining sequences consistent with the depositional history of the riverbank. Over 25,000 individual simulations were completed using calibration software and a cloud platform specifically designed for highly parallelized computing environments. The results of this study demonstrate the use of fining direction regularization during model calibration to generate multiple calibrated model realizations that account for the depositional environment of the system. PMID- 30407624 TI - Sinonasal debridement versus no debridement for the postoperative care of patients undergoing endoscopic sinus surgery. AB - BACKGROUND: Endoscopic sinus surgery (ESS) is often recommended for symptomatic patients with recurrent acute or chronic rhinosinusitis who have failed conservative treatment. Postoperative care has been felt to be critical for both maintaining the surgical patency of the operated sinuses and improving patient symptoms. Debridement of the sinonasal cavities is one such postoperative care measure that has frequently been studied in the literature, often with conflicting conclusions. OBJECTIVES: To assess the effects of postoperative sinonasal debridement versus no debridement following endoscopic sinus surgery. SEARCH METHODS: The Cochrane ENT Information Specialist searched the ENT Trials Register; Central Register of Controlled Trials (CENTRAL, via the Cochrane Register of Studies); PubMed; EMBASE; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 21 May 2018. SELECTION CRITERIA: Randomised controlled trials comparing postoperative nasal debridement versus no debridement in adult patients with recurrent acute or chronic rhinosinusitis undergoing endoscopic sinus surgery. We included studies in which the patients acted as self-controls (i.e. one side of the nose underwent debridement and the other side did not) only for the secondary endoscopy outcomes. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. Our primary outcome measures were: health-related quality of life, disease severity (patient-reported symptom scores) and significant adverse effects (bleeding requiring intervention, severe pain, iatrogenic injury). Secondary outcomes were: postoperative endoscopic appearance of the sinonasal surgical cavities (endoscopic scores), recorded use of postoperative medical treatment and rate of revision surgery. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics. MAIN RESULTS: We included four studies (152 participants), with a follow-up duration ranging from three months to 12 months. In two studies patients acted as self-controls, i.e. one side of the nose underwent debridement and the other side did not ('split-nose' studies). The risk of bias in all studies was high, mostly due to the inability to blind the patients to the debridement procedure.Primary outcomesDisease-specific health-related quality of life scoresOnly one study (58 participants) provided data for disease-specific health-related quality of life. At six months follow-up, lower disease-specific health-related quality of life scores, measured using the Sino-Nasal Outcome Test 22 (SNOT-22, range 0 to 110), were noted in the debridement group but the difference was not statistically significant (9.7 in the debridement group versus 10.3 in the control group, P = 0.47) (low-quality evidence).Disease severity (patient-reported symptom score)Only one study (60 participants) provided data for disease severity measured by visual analogue scale (VAS) score. No significant differences in total symptom score were observed between groups postoperatively (low-quality evidence).Significant adverse effectsSignificant adverse effects related to the debridement procedure were not reported in any of the included studies, however it is not clear whether data regarding adverse effects were not collected or if none were indeed observed in any of the included studies.Secondary outcomesAll four studies assessed thepostoperative endoscopic appearance of the sinonasal cavities using the Lund-Kennedy score (range 0 to 10). A pooled analysis of endoscopic scores in the two non 'split-nose' studies revealed better endoscopic scores in the debridement group, however this was not a statistically significant difference (mean difference -0.31, 95% confidence interval (CI) -1.35 to 0.72; I2 = 0%; two studies; 118 participants) (low-quality evidence). A sub-analysis of the adhesion formation component of the endoscopic score was available for all four studies and revealed a significantly lower adhesion rate in the debridement group (risk ratio 0.43, 95% CI 0.28 to 0.68; I2 = 29%; four studies; 152 participants). Analysis of the number needed to treat to benefit revealed that for every three patients undergoing debridement, the endoscopic score would be decreased by one point in one patient. For every five patients undergoing debridement adhesion formation would be prevented in one patient.Use of postoperative medical treatment was reported in all studies, all of which recommended nasal douching. Steroids (systemic or nasal) were administered in two studies. However, the data were very limited and heterogeneous, therefore we could not analyse the impact of concomitant postoperative medical treatment.The rate of revision surgery was not reported in any of the included studies, however it is not clear whether these data were not recorded or if there were no revision surgeries in any of the included studies. AUTHORS' CONCLUSIONS: We are uncertain about the effects of postoperative sinonasal debridement due to high risk of bias in the included studies and the low quality of the evidence. Sinonasal debridement may make little or no difference to disease-specific health-related quality of life or disease severity. Low-quality evidence suggests that postoperative debridement is associated with a significantly lower risk of adhesions at three months follow up. Whether this has any impact on longer-term outcomes is unknown. PMID- 30407626 TI - The treatment of older Hodgkin lymphoma patients. AB - The outcome of patients with Hodgkin lymphoma (HL) has dramatically improved over the past decades and continues to improve with the development of novel targeted therapies, such as the immunoconjugate brentuximab vedotin and the checkpoint inhibitors nivolumab and pembrolizumab. Moreover, with the use of response adapted strategies using positron-emission-tomography (PET), the overall intensity of treatment for most patients can be reduced, resulting in less acute and late toxicity. However, these advances are mainly restricted to younger patients, as advances in patients above the age of 60 years ('older' patients) have been much less pronounced. Furthermore, about one third of all HL patients are among the older population, but only 5-10% of the patients treated in current HL clinical trials are >=60 years old. HL in older patients is characterized by aggressive disease and unfavourable prognostic features as B symptoms and predominance of advanced stages. In addition, tolerance to curative chemotherapy is drastically reduced in older patients resulting in excessive toxicity and insufficient treatment due to therapy delays and dose reductions. Therefore, there is a significant unmet medical need in older HL patients for less toxic and effective therapies, and an important gap of knowledge concerning this growing population of patients. Recent advances on epidemiology, characteristics and treatment of older HL patients will be summarized in this article. PMID- 30407627 TI - Healthcare provider interaction and other predictors of long-acting reversible contraception adoption among women in Nigeria. AB - OBJECTIVE: To test the association between healthcare provider communication and adoption of long-acting reversible contraception (LARC) among women in Nigeria. METHODS: The present cross-sectional observational secondary analysis included women aged 18-49 who were interviewed between June 1 and July 31, 2014, at selected family planning sites in Ibadan and Kaduna, Nigeria. A multivariate generalized estimating equation was utilized to assess the predictors of LARC adoption. RESULTS: 597 women were interviewed, and the study showed that each unit increase on the GATHER index-a self-reported measure of interaction with the provider-was significantly associated with a 16% increased likelihood (adjusted odds ratio [AOR] 1.16, 95% confidence interval [CI] 1.03-1.32) of adopting LARCs. Joint decision making with a partner (AOR 1.51, 95% CI 1.0-2.20), desire to have children in the next 2 years (AOR 0.36, 95% CI 0.18-0.74), whether or not a pregnancy in the next 6 months would be a problem (AOR 1.69, 95% CI 1.16-2.46), and LARC use in the past (AOR 4.15, 95% CI 1.19-14.50) were associated with LARC uptake. CONCLUSION: Improved patient-provider communication involving patient preferences, information about all methods of contraception, and planned follow up could play a central role in increasing the demand for, and uptake of, LARCs. PMID- 30407625 TI - Time to progression of mantle cell lymphoma after high-dose cytarabine-based regimens defines patients risk for death. PMID- 30407628 TI - Acquired ichthyosis as a paraneoplastic feature of ALK-negative anaplastic large cell lymphoma. PMID- 30407630 TI - Long survival in patients with Waldenstrom macroglobulinaemia diagnosed at a young age. PMID- 30407629 TI - Efficacy of bendamustine and rituximab in splenic marginal zone lymphoma: results from the phase II BRISMA/IELSG36 study. AB - Splenectomy in addition to immunotherapy with rituximab can provide quick and sometimes durable disease control in patients with splenic marginal zone lymphoma (SMZL). However, systemic chemotherapy is ultimately required in many cases. The BRISMA (Bendamustine-rituximab as first-line treatment of splenic marginal zone lymphoma)/IELSG (International Extranodal Lymphoma Study Group)36 trial is an open-label, single arm phase II study designed by the IELSG in cooperation with the Fondazione Italiana Linfomi and the lymphoma Study Association according to Simon's two-stage method. The primary endpoint was complete response rate. Fifty six patients with SMZL diagnosis confirmed on central revision were treated with bendamustine (90 mg/m2 days 1, 2) and rituximab (375 mg/m2 day 1) every 28 days for six cycles (B-R). The overall response and CR rates were 91% and 73%, respectively. Duration of response, progression-free survival and overall survival at 3 years were 93% (95% confidence interval [CI] 81-98), 90% (95% CI 77 96) and 96% (95% CI 84-98), respectively. Toxicity was mostly haematological. Neutropenia grade >=3 was recorded in 43% of patients; infections and febrile neutropenia in 5.4% and 3.6%. Overall, 14 patients (25%) experienced serious adverse events. Five patients (9%) went off-study because of toxicity and one patient died from infection. In conclusion, B-R resulted in a very effective first-line regimen for SMZL. Based on the results achieved in the BRISMA trial, B R should be considered when a chemotherapy combination with rituximab is deemed necessary for symptomatic SMZL patients. PMID- 30407631 TI - Obesity and dysregulated central and peripheral macrophage-neuron cross-talk. AB - The involvement of macrophages in the pathogenesis of obesity has been recognized since 2003. Early studies mostly focused on the role of macrophages in adipose tissue (AT) and in obesity-associated chronic low-grade inflammation. Lately, AT macrophages were shown to undergo intrinsic metabolic changes that affect their immune function (i.e., immunometabolism), corresponding to their unique properties along the range of pro- versus anti-inflammatory activity. In parallel, recent studies in mice revealed critical neuronal-macrophage interactions, both in the CNS and in peripheral tissues, including in white and brown AT. These intercellular activities impinge on energy and metabolic homeostasis, partially by also engaging adipocytes in a neuronal-macrophage adipocyte menage a trois. Finally, neuropeptides (NP), such as NPY and appetite reducing NPFF, may prove as mediators in such intercellular network. In this concise review, we highlight some of these recent insights on adipose macrophage immunometabolism, as well as central and peripheral neuronal-macrophage interactions with emphasis on their impact on adipocyte biology and whole-body metabolism. We also discuss the expanding view on the role of the NP, NPY and NPFF, in obesity. PMID- 30407632 TI - Sequential B-lymphoid and myeloid blastic transformation of Philadelphia chromosome-negative myeloproliferative neoplasm. PMID- 30407633 TI - Triacylglycerol-Lowering Effect of Docosahexaenoic Acid Is Not Influenced by Single-Nucleotide Polymorphisms Involved in Lipid Metabolism in Humans. AB - The triacylglycerol (TAG)-lowering effects of long-chain n-3 fatty acids, and in particular docosahexaenoic acid (DHA), are well documented, although these effects manifest large interindividual variability. The objective of this secondary analysis is to investigate whether common single-nucleotide polymorphisms (SNP) in genes involved in DHA synthesis and TAG metabolism are associated with the responsiveness of blood lipids, lipoprotein, and apolipoprotein concentration to dietary treatment by DHA supplied in high-oleic canola oil (HOCO). In a randomized, crossover-controlled feeding trial, 129 subjects with metabolic syndrome received high-oleic canola oil (HOCO) and high oleic canola oil supplemented with DHA (HOCO-DHA), each for 4 weeks. During the HOCO-DHA phase, the intake of DHA ranged from 1 to 2.5 g/day. The subjects were genotyped for apolipoprotein E (APOE) isoforms, and SNP including FADS1-rs174561, FADS2-rs174583, ELOVL2-rs953413, ELOVL5-rs2397142, CETP-rs5882, SCD1-rs2234970, PPARA-rs6008259, and LIPF-rs814628 were selected as important genes controlling fatty acid metabolism. Overall, consumption of HOCO-DHA oil reduced blood concentrations of TAG by 24% compared to HOCO oil. The reduction in TAG was independent of genetic variations in the studied genes. Similarly, no treatment by-gene interactions were evident in the response to other lipids, lipoproteins, or apolipoproteins to DHA supplementation. Nevertheless, a lower interindividual variation in the TAG response to DHA supplementation compared to other studies was observed in this analysis. The TAG-lowering effect of a supplemental body weight-based dose of DHA was not influenced by genetic variations in APOE, FADS1, FADS2, ELOVL2, ELOVL5, CETP, SCD1, PPARA, and LIPF. PMID- 30407634 TI - Performance analysis of a high-sensitivity multi-pinhole cardiac SPECT system with hemi-ellipsoid detectors. AB - PURPOSE: Single-photon emission computed tomography (SPECT) is a noninvasive imaging modality, used in myocardial perfusion imaging. The challenges facing the majority of clinical SPECT systems are low sensitivity, poor resolution, and the relatively high radiation dose to the patient. New generation systems (GE Discovery, DSPECT) dedicated to cardiac imaging improve sensitivity by a factor of 5-8. This improvement can be used to decrease acquisition time and/or dose. However, in the case of ultra-low dose (~3 mCi) injections, acquisition times are still significantly long, taking 10-12 min. The purpose of this work is to investigate a new gamma camera design with 21 hemi-ellipsoid detectors each with a pinhole collimator for cardiac SPECT for further improvement in sensitivity and resolution and reduced patient exposures and imaging times. METHODS: To evaluate the resolution of our hemi-ellipsoid system, GATE Monte-Carlo simulations were performed on point-sources, rod-sources, and NCAT phantoms. For average full width-half-maximum (FWHM) equivalence with base flat-detector, the pinhole diameter for the curved hemi-ellipsoid detector was found to be 8.68 mm, an operating pinhole-diameter nominally expected to be ~3 times more sensitive than state-of-the-art systems. Rod-sources equally spaced within the region of interest were acquired with a 21-detector system and reconstructed with our multi pinhole (MPH) iterative OSEM algorithm with collimator resolution recovery. The results were compared with the results of a state-of-the-art system (GE Discovery) available in the literature. The system was also evaluated using the mathematical anthropomorphic NCAT (NURBS-based Cardiac Torso; Segars et al. IEEE Trans Nucl Sci. 1999;46:503-506) phantom with a full (clinical)-dose acquisition (25 mCi) for 2 min and an ultra-low dose acquisition of 3 mCi for 5.44 min. The estimated left ventricle (LV) counts were compared with the available literature on a state-of-the-art system (DSPECT). FWHM of the LV wall on MPH-OSEM reconstructed images with collimator resolution recovery was estimated. RESULTS: On acquired rod-sources, the average resolution (FWHM) after reconstruction with resolution recovery in the entire region of interest (ROI) for cardiac imaging was on the average 4.44 mm (+/-2.84), compared to 6.9 mm (+/-1 mm) reported for GE Discovery (Kennedy et al., J Nucl Cardiol. 2014:21:443-452). For NCAT studies, improved sensitivity allowed a full-dose (25 mCi) 2-min acquisition (Ell8.68mmFD) which yielded 3.79 M LV counts. This is ~3.35 times higher compared to 1.13 M LV counts acquired in 2 min for clinical full dose for state-of-the-art DSPECT. The increased sensitivity also allowed an ultra-low dose acquisition protocol (Ell8.68 mmULD), 3 mCi (eight times less injected dose) in 5.44 min. This ultra low dose protocol yielded ~1.23 M LV counts which was comparable to the full-dose 2-min acquisition for DSPECT. The estimated NCAT average FWHM at the LV wall after 12 iterations of the OSEM reconstruction was 4.95 and 5.66 mm around the mid-short-axis slices for Ell8.68mmFD and Ell8.68mmULD, respectively. CONCLUSION: Our Monte-Carlo simulation studies and reconstruction suggest using (inverted wineglass sized) hemi-ellipsoid detectors with pinhole collimators can increase the sensitivity ~3.35 times over the new generation of dedicated cardiac SPECT systems, while also improving the reconstructed resolution for rod-sources with an average of 4.44 mm in region of interest. The extra sensitivity may be used for ultra-low dose imaging (3 mCi) at ~5.44 min for comparable clinical counts as state-of-the-art systems. PMID- 30407635 TI - The preparation and antibacterial effect of egg yolk immunoglobulin (IgY) against the outer membrane proteins of Vibrio parahaemolyticus. AB - BACKGROUND: Vibrio parahaemolyticus causes not only various diseases in aquaculture animals but also seafood-borne illness in humans. Outer membrane proteins (OMPs) are species-specific proteins found in bilayer membranes of gram negative bacteria. Egg yolk immunoglobulin (IgY) has been reported to serve as oral administration of antibodies against bacteria and virus. RESULTS: The present research extracted and identified OMPs from V. parahaemolyticus, and then the extracted OMPs were used to immunize hens to obtain specific IgY. The efficacy of IgY against V. parahaemolyticus were investigated in vitro and in vivo. The specific IgY effectively inhibited the growth of V. parahaemolyticus in liquid medium rather than Escherichia coli and Staphylococcus aureus. Specific IgY antibodies were incorporated into extruded food pellets and fed to bacteria challenged white pacific shrimp to observe the anti-bacterial effect in vivo. The bacterial loads in muscles of V. parahaemolyticus infected shrimp fed with specific IgY-included diets were significantly fewer than those fed with non specific IgY-included diets. The superoxide dismutase activities in muscles of infected shrimp fed with specific IgY-included diets were significantly higher than the control group. CONCLUSION: The results suggested that the specific IgY effectively inhibited the growth of V. parahaemolyticus and introduced passive immunity to shrimp. (c) 2018 Society of Chemical Industry. PMID- 30407636 TI - Restrictive guideline for red blood cell transfusions in preterm neonates: effect of a protocol change. AB - OBJECTIVE: To evaluate red blood cell (RBC) transfusion practices in preterm neonates before and after protocol change. METHODS: All preterm neonates (<32 weeks of gestation) admitted between 2008 and 2017 at our neonatal intensive care unit were included in this retrospective study. Since 2014, a more restrictive transfusion guideline was implemented in our unit. We compared transfusion practices before and after this guideline change. Primary outcome was the number of transfusions per neonate and the percentage of neonates receiving a blood transfusion. Secondary outcomes were neonatal morbidities and mortality during admission. RESULTS: The percentage of preterm neonates requiring a blood transfusion was 37.5% (405/1079) before and 32.7% (165/505) after the protocol change (P = 0.040). The mean number of transfusions given to each transfused neonate decreased from 2.93 (standard deviation (SD) +/- 2.26) to 2.20 (SD +/ 1.29) (P = 0.007). We observed no association between changes in transfusion practices and neonatal outcome. CONCLUSION: The use of a more restrictive transfusion guideline leads to a reduction in red blood cell transfusions in preterm neonates, without evidence of an increase in mortality or short-term morbidity. PMID- 30407637 TI - Cultural values, coping, and hope in Yup'ik communities facing rapid cultural change. AB - Historical trauma and rapid cultural change contribute to a high burden of stress in Alaska Native communities. The goal of the Yup'ik Experiences of Stress and Coping Project was to better understand stress and coping in Yup'ik communities and the role of cultural values and practices in coping. Sixty Yup'ik adults aged 18-84 years took part in semistructured interviews. They discussed how they coped with salient stressful experiences and shared the things that bought them hope and peace. Interview themes were identified and inter-relationships between themes were explored through social network analysis. Participants discussed the importance of cultural traditions in coping, including subsistence, dancing and drumming, intergenerational transmission of knowledge, and reflective awareness of interconnections with others. Participants found strength in family relationships, spirituality, helping others, and coming together as a community. Three coping clusters emerged: Ilaliurucaraq (be welcoming) involved opening one's frame of mind and building connections; Yuuyaraq (Yup'ik way of life) focused on Yup'ik traditions and values; and Assircaarturluni Yuuyaraq (try to live a better life) involved healing from historical trauma. Findings illustrate the resilience and evolving strengths of rural Yup'ik communities facing a continually changing cultural landscape and provide information for developing community-driven culturally based interventions. PMID- 30407638 TI - Perceiving time through group-based glasses: Collective temporal orientation. AB - People differ in the extent to which they focus on their personal future, past, or present. Across four studies (using both correlation and experimental designs), we explore whether people also have a temporal orientation when thinking about the social groups to which they belong (i.e., their in-group). In Studies 1-3, participants' personal temporal orientation was moderately linked with, but distinguishable from, their collective temporal orientation for their national self (i.e., 'American'). In Study 2, evidence is provided for the predictive validity of this novel concept. Specifically, greater collective past orientation was positively associated with reported collective guilt (a group based emotion that reflects the acceptance of culpability for historical harms perpetrated by the in-group), and greater collective future orientation focus on the in-group's future was positively associated with collective angst (a group based emotion that reflects concern about existential threats the in-group may face). In Study 3, collective temporal orientation was shown to differ across several groups' participants listed as self-relevant. In Study 4, participants randomly assigned to think about a past-oriented social group to which they belong reported more frequent focus on the in-group's past than participants randomly assigned to think about a future-oriented in-group (and vice versa for collective future focus). This research advances the literature on time perspective by showing that temporal cognition extends to the social self. PMID- 30407640 TI - Allergic contact dermatitis caused by glitter glue used as make-up containing methylchloroisothiazolinone. PMID- 30407639 TI - Different thermal processing effects on peanut allergenicity. AB - BACKGROUND: Peanut allergy is one of the most common food allergies worldwide. Studies have shown that the incidence of peanut allergies in Western-born Asians is higher than that in Asia-born Asians. Notably, Europeans and Americans mostly eat roasted peanuts, whereas Asians mostly eat boiled or fried peanuts. RESULTS: BALB/c mice were sensitized using purified protein from raw, roasted or boiled peanuts, then fed the same by oral gavage. The relevant allergic reactions were studied using BALB/c mice model, including a rat basophilic leukemia (RBL) cell model, simulated gastric fluid experiments, and ultraviolet (UV) and circular dichroism (CD) spectral analysis. Serological studies showed increased levels of immunoglobulin E, interleukin-4 and interleukin-5, and pathological studies showed mast cell degranulation and inflammatory changes in jejunal tissues, with an increase in thymic stromal lymphopoietin (TSLP) gene expression in all treatment groups compared with the control group (phosphate-buffered saline). Compared with the raw peanut group, sera from the roasted peanut group produced a significant increase in RBL beta-hexosaminidase A release in vitro, and roasted peanuts showed increased resistance to digestion in simulated gastric fluid experiments. Ultraviolet and CD spectral analyses showed that the roasting and boiling processes altered the structure of the major peanut allergens, which may have contributed to the differences observed in peanut allergenicity. CONCLUSION: Our findings indicate that peanut allergies are related to peanut thermal processing methods. In our mouse model, the raw, roasted and boiled peanuts elicited different degrees of allergic response. Compared with raw peanut, roasted peanuts show a higher allergenicity, whereas the boiled peanuts show a lower allergenicity. (c) 2018 Society of Chemical Industry. PMID- 30407641 TI - Dialoguing the difference: A reply to Batel and Castro's 'Re-opening the dialogue between the Theory of Social Representations and Discursive Psychology'. AB - Batel and Castro's call for reopening the dialogue between the theory of social representations and discursive psychology is to be welcomed and indeed, somewhat long overdue. Despite the case that many scholars are engaging in the kind of rapprochement being advocated for by Batel and Castro, I argue here that the intellectual trajectory discursive psychology has taken during the last thirty years makes it less amenable to the kind of reconciliation called for by Batel and Castro. Two enduring tensions between the two theories that require resolution remain: (1) how we define discursive psychology as it is practised today and (2) the epistemological and ontological status of cognition. PMID- 30407642 TI - Pharmacokinetic/pharmacodynamic integration of cefquinome against Pasteurella Multocida in a piglet tissue cage model. AB - To explore the in vivo antimicrobial activity of cefquinome against Pasteurella multocida in piglets, a piglet tissue cage infection model was used in this study. After the population of P. multocida reached 107 CFU/mL in a tissue cage, piglets received an intramuscular administration of cefquinome at 0.2, 0.4, 0.8, 1, 2, and 4 mg/kg once daily for 3 days. To assess the tissue cage pharmacokinetics (PKTCF) of cefquinome, tissue cage fluid was collected for cefquinome analysis at 1, 3, 6, 9, 12, and 24 hr after each of the 3 daily drug administrations. Bacteria were counted every 24 hr after drug administration and at 48 and 72 hr after the last administration. Evaluation of the relationship between pharmacokinetic/pharmacodynamic (PK/PD) parameters and the antibacterial effect showed that the surrogate of %T > minimum inhibitory concentration (MIC) (R2 = 0.981) was the best PK/PD index that correlated with effectiveness of cefquinome against P. multocida. The respective values of %T > MIC required for continuous 1/3-log, 1/2-log, and 1-log reductions were 14.23, 34.45, and 73.44%, respectively, during each 24-hr treatment period. In conclusion, cefquinome exhibited a potent antibacterial effect against P. multocida. When %T > MIC reached 73.44%, cefquinome exhibited a bactericidal effect against P. multocida after three successive daily administrations. PMID- 30407643 TI - NAIF1 suppresses osteosarcoma progression and is regulated by miR-128. AB - Nuclear apoptosis-inducing factor 1 (NAIF1) acts as an oncogene and involves in tumorigenesis in several cancers. However, the expression and mechanism of NAIF1 in osteosarcoma remains unclear. In this study, we demonstrated the downregulation of NAIF1 expression in both osteosarcoma tissues and cell lines. We next explored the potential role of NAIF1 in osteosarcoma cell proliferation and migration. The result showed that overexpression of NAIF1 evidently suppressed the cell proliferation and invasion of osteosarcoma. Furthermore, we investigated the potential mechanisms accounting for dysregulation of NAIF1 in osteosarcoma. The bioinformatic prediction and luciferase reporter assay revealed that miR-128 is a direct upstream regulator of NAIF1 and regulates NAIF1 expression by binding the 3'-UTR of NAIF1. Consistent with previous study, we found that miR-128 was upregulated in both osteosarcoma tissues and cell lines. Moreover, miR-128 expression levels were inversely correlated with that of NAIF1 in osteosarcoma tissues. Finally, functional assay showed that miR-128 significantly suppressed osteosarcoma progression partially mediated by inhibiting NAIF1 expression. These data indicate that the miR-128 and its target gene NAIF1 played important roles by regulating OS cell proliferation and migration phenotype. SIGNIFICANCE OF THE STUDY: Osteosarcoma (OS) is the most common malignant bone tumour and the second leading cause of cancer-related death affecting children and adolescents. Nuclear apoptosis-inducing factor 1 (NAIF1) plays an inhibitory role in the initial steps of different carcinomas. However, the expression and mechanism of NAIF1 in osteosarcoma remains unclear. The data of this study indicated that the miR-128 and its target gene NAIF1 played important roles by regulating OS cell proliferation and migration phenotype. It was demonstrated that NAIF1 would demonstrate important regulative effects and may be a promising therapeutic target of OS. PMID- 30407644 TI - A case of primary cutaneous peripheral T-cell lymphoma, not otherwise specified with cytotoxic phenotype showing multiple ulcers on the entire body. AB - Primary cutaneous peripheral T cell lymphoma, not otherwise specified (pcPTCL NOS) is a rare, aggressive, fatal type of cutaneous T-cell lymphoma. The clinical presentation of pcPTCL-NOS is characterized by generalized plaques, nodules or tumours but ulcers are uncommon. We report an atypical case of pcPTCL-NOS with cytotoxic protein expression, presenting as multiple ulcers on the entire body. A 48-year-old man first presented with pruritic papules on the trunk. The papules gradually increased in number and became ulcerated. We finally diagnosed with pcPTCL-NOS because of diffuse dermal infiltration of medium- to large-sized pleomorphic CD4 positive lymphoid cells. Ulceration suggests infiltration of lymphoid cells expressing cytotoxic proteins which can induce apoptosis in the epidermis and dermis. Our cases died of bacterial sepsis that invaded from the uncontrollable ulcers. A suspicion of pcPTCL-NOS is needed when encountering clinical pictures of refractory multiple ulcers and a biopsy should always be performed, because treatment delay may lead a very poor prognosis. This article is protected by copyright. All rights reserved. PMID- 30407645 TI - The integument of the nonamphibious goby Gobionellus oceanicus: Its functional morphology and respiratory capacity. AB - Facultative air-breathing fish can exchange respiratory gases using an air breathing organ (ABO), such as the oral cavity of the integument, during environmental hypoxia. The goby Gobionellus oceanicus inhabits areas subject to environmental hypoxia; however, its ABO is unknown. To investigate the respiratory potential of G. oceanicus, the gill and integument surface area, diffusion capacity, and their diffusion barrier thickness were measured. Our results show that although gill surface area is smaller than observed in other facultative air-breathing fish, but it has all features necessary to perform aquatic gas exchange. Additionally the integument of the palate has a short diffusion barrier thickness and a large calculated O2 -diffusion capacity suggesting that it functions as the ABO. PMID- 30407646 TI - Measuring labor and delivery unit culture and clinicians' attitudes toward birth: Revision and validation of the Labor Culture Survey. AB - BACKGROUND: Cesarean delivery rates in the United States vary widely between hospitals, which cannot be fully explained by hospital or patient factors. Cultural factors are hypothesized to play a role in cesarean overuse, yet tools to measure labor culture are lacking. The aim of this study was to revise and validate a survey tool to measure hospital culture specific to cesarean overuse. METHODS: A panel of clinicians and researchers compiled an item bank from validated surveys, added newly created items, and performed four rounds of iterative revision and consolidation. Obstetricians, family physicians, midwives, anesthesiologists, and labor nurses were recruited from 79 hospitals in California. Exploratory factor analysis was used to reduce the number of survey items and identify latent constructs to form the basis of subscales. Confirmatory factor analysis examined reliability in 31 additional hospitals. Poisson regression assessed associations between hospitals' mean score on each individual item and cesarean rates. RESULTS: A total of 1718 individuals from 70 hospitals were included in the exploratory factor analysis. The final Labor Culture Survey (LCS) consisted of 29 items and six subscales: "Best Practices to Reduce Cesarean Overuse," "Fear of Vaginal Birth," "Unit Microculture," "Physician Oversight," "Maternal Agency," and "Cesarean Safety." CONCLUSIONS: The revised LCS is a valid and reliable tool to measure constructs shown to be associated with cesarean rates. These findings support prior research that has shown that hospital culture is measurable, and that clinician attitudes are predictive of clinician behaviors. Unique to our survey is the construct of labor and delivery unit microculture. PMID- 30407647 TI - Synthesis and antimycobacterial activity of (+)-usnic acid conjugates. AB - New therapeutics are urgently needed to fight tuberculosis and mycobacteria related diseases that are a major health hazard especially in poor countries. Natural products have been the source of important antitubercular drugs in the past and still need to receive attention as a potent reservoir of chemical structures. Fifteen known and two new (+)-usnic acid (a benzofurandione formerly isolated from lichens) enamines and hydrazones are here described and tested against sensitive and multidrug-resistant strains of mycobacteria. Among several (+)-usnic acid conjugates, PS14 and PS18 showed potent activity against both susceptible and resistant Mycobacterium tuberculosis strains (MIC values of 1-32 and 2-32 mg/L, respectively) comparable with MIC of other antitubercular drugs already in use for tuberculosis treatment. PMID- 30407648 TI - Vanadium compounds and cellular death mechanisms in the A549 cell line: The relevance of the compound valence. AB - Non-small lung cell carcinoma has a high morbidity and mortality rates. The elective treatment for stage III and IV is cisplatinum that conveys serious toxic side effects. Vanadium compounds are metal molecules with proven antitumor activity that depends on its valence. Therefore, a better understanding of the mechanism of action of vanadium compounds is required. The aim of our study was to investigate the mechanisms of cell death induced by sodium metavanadate (NaVO3 [V(+5)]) and vanadyl sulfate (VOSO4 [(+4)]), both of which have reported apoptotic-inducing activity. We exposed the A549 cell line to various concentrations (0-100 MUM) and to different exposure times to each compound and determined the cell viability and expression of caspases, reactive oxygen species (ROS) production, Bcl2, Bax, FasL and NO. Our results showed that neither compounds modified the basal expression of caspases or pro- and anti-apoptotic proteins. The only change observed was the 12- and 14-fold significant increase in ROS production induced by NaVO3 and VOSO4 , respectively, at 100 MUm concentrations after 48 hours. Our results suggest that classical apoptotic mechanisms are not related to the cell death induced by the vanadium compounds evaluated here, and showed that the higher ROS production was induced by the [(+4)] valence compound. It is possible that the difference will be secondary to its higher oxidative status and thus higher ROS production, which leads to higher cell damage. In conclusion, our results suggest that the efficacy of the cell death mechanisms induced by vanadium compounds differ depending on the valence of the compound. PMID- 30407649 TI - Pelvic floor muscle training with and without supplementary KAATSU for women with stress urinary incontinence - a randomized controlled pilot study. AB - AIMS: To explore if adding occlusion training of a thigh (KAATSU) to low intensity pelvic floor muscle training (PFMT) could increase effect of PFMT in women with stress urinary incontinence (SUI). METHODS: Single-blinded randomized controlled pilot study. Women with SUI and an ICIQ-UI-SF (International Consultation on Incontinence Questionnaire-Short form) score of >=12 were randomized to a low-intensity PFMT program followed by KAATSU (KAATSU + PFMT) or to a low-intensity PFMT program without KAATSU (PFMT group), both performed four times a week for 12 weeks. PRIMARY OUTCOME: Change in the ICIQ-UI-SF score at a 12-week follow-up. SECONDARY OUTCOMES: a 3-day leakage diary, the PGI-I (Patient Global Index of Improvement scale), bother with KAATSU in a numeric rank scale and change in urethral opening pressure (UOP) measured with urethral pressure reflectometry (UPR) at rest, contraction and straining at the 12-week follow-up. RESULTS: Forty-one women with SUI and an ICIQ-UI-SF of 13 (range 12-16) were included. Fourteen in the KAATSU + PFMT and 17 in the PFMT group completed the study. Both groups had a significant and clinically relevant improvement of the ICIQ-UI-SF score and decrease in number of incontinence episodes with no significant between group differences. UOP did not increase significantly in either group. Bother with KAATSU was low but seven of 14 women expressed dislike with KAATSU. CONCLUSIONS: The added KAATSU protocol did not increase the effect of low-intensity PFMT and it was not well tolerated. While subjective effect was significant in both intervention groups this was not reflected in the UPR measures. PMID- 30407650 TI - Plasma exchange for heparin-induced thrombocytopenia in patients on extracorporeal circuits: A challenging case and a survey of the field. AB - Current management of heparin-induced thrombocytopenia (HIT) involves prompt discontinuation of all heparin products and concomitant initiation of a direct thrombin or anti-Xa inhibitor for anticoagulation. In the setting of HIT complicated by an urgent need for cardiopulmonary bypass (CPB), the safety and the efficacy of short-term heparin-based anticoagulation after therapeutic plasma exchange (TPE) have been previously demonstrated. Patients with HIT requiring TPE are frequently on extracorporeal circuits (either CPB, extracorporeal membrane oxygenation [ECMO] or external ventricular assist devices [VADs]). Performing TPE in parallel with these circuits involves additional consideration for circuit size, anticoagulant/citrate management, as well as flow rates, and risk of air embolus. We report a case of a patient with HIT on external biventricular assist device (BiVAD) requiring urgent CPB who experienced thrombotic and hemolytic complications related to anticoagulation management around apheresis line placement for TPE. We also present results from a national survey of academic apheresis services regarding specific practices in managing patients with HIT on extracorporeal circuits who require TPE. In addition, we demonstrate the utility of TPE in patients with HIT on extracorporeal circuits and the risks of this procedure and the need to develop practice guidelines. PMID- 30407651 TI - An Ambipolar Superconducting Field-Effect Transistor Operating above Liquid Helium Temperature. AB - Superconducting (SC) devices are attracting renewed attention as the demands for quantum-information processing, meteorology, and sensing become advanced. The SC field-effect transistor (FET) is one of the elements that can control the SC state, but its variety is still limited. Superconductors at the strong-coupling limit tend to require a higher carrier density when the critical temperature (TC ) becomes higher. Therefore, field-effect control of superconductivity by a solid gate dielectric has been limited only to low temperatures. However, recent efforts have resulted in achieving n-type and p-type SC FETs based on organic superconductors whose TC exceed liquid He temperature (4.2 K). Here, a novel "ambipolar" SC FET operating at normally OFF mode with TC of around 6 K is reported. Although this is the second example of an SC FET with such an operation mode, the operation temperature exceeds that of the first example, or magic-angle twisted-bilayer graphene that operates at around 1 K. Because the superconductivity in this SC FET is of unconventional type, the performance of the present device will contribute not only to fabricating SC circuits, but also to elucidating phase transitions of strongly correlated electron systems. PMID- 30407652 TI - Three-dimensional echocardiography of mechanical circulatory support devices. AB - Two-dimensional echocardiography is a crucial component for assessing the position and function of mechanical circulatory support devices, but three dimensional echocardiography provides additional information to aid in management and may improve accuracy in the assessment of these devices. In this article, we review the utility of three-dimensional echocardiography of various mechanical circulatory support devices. PMID- 30407653 TI - Expectant long-term follow-up of patients with chronic urinary retention. AB - AIMS: To describe urologic complications in patients with chronically elevated post-void residual (PVR) volumes and to evaluate other related risk factors during a long-term follow-up in patients managed conservatively. METHODS: Non neurogenic patients who refused surgical intervention of the prostate and had PVR volumes >300 mL on two or more separate occasions at least 6 months apart were included. We followed this cohort over time, recorded complications and evaluated risk factors for complications. RESULTS: Twenty-eight men with a mean age of 74 were followed for a median of 56 months (IQR: 26-101 months); 26 had benign prostatic hyperplasia with a median prostate size of 55 cc. Baseline median PVR was 468 cc (IQR: 395-828) and follow-up median PVR was 508 cc (IQR: 322-714). During follow-up, 13 patients (46%) had at least one complication with acute urinary retention being the most common occurring in 10 patients (36%) with 15 episodes. Other complications presented in less than 15%, and no patients developed permanent renal insufficiency. Patients with prostate size >= 100 cc had significantly higher total number of acute retention episodes (P-value: 0.01). CONCLUSIONS: Although the presence of CUR could commonly predispose to episodes of acute retention, severe complications are infrequent although present. Additionally, prostate size may play a role in increasing some adverse outcomes. With proper counseling about different complications, patients with retention who denied surgical treatment can be safely followed for at least 5 years without renal deterioration. PMID- 30407654 TI - Measurement tools and intensity of nipple pain among women with or without damaged nipples: A quantitative systematic review. AB - AIMS: To describe and evaluate pain scales used to measure nipple pain in breastfeeding women and to identify nipple pain intensity in women with or without nipple damage. BACKGROUND: Nipple pain is one of the most common reasons given for premature cessation of breastfeeding. However, there are no agreed tools to measure pain and no previous reviews have provided summary estimates of pain scores. DESIGN: Systematic review. DATA SOURCES: Medline, CINAHL, Scopus, Web of Science, SciELO and LILACS. REVIEW METHODS: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The guiding question was: How is nipple pain in breastfeeding women measured and how severe is it? We analysed articles published up to February 2018, excluded review articles and those that did not present the level of nipple pain or tools to estimate pain severity. RESULTS: A total of 1,023 articles were identified and 25 included in the review after applying the exclusion criteria. The Numeric Rating Scale (nine studies) and Visual Analogue Scale (seven studies) were the most prevalent tools for measuring pain. Using a pain score between 0-10, women with nipple damage reported a weighted mean of 6.2 in the first week and 5.8 after that period; women without damage reported a weighted mean of 2.7. CONCLUSION: Women with nipple damage consistently reported a higher level of pain then women without damage. To prevent premature cessation of breastfeeding, it is important to help new mothers avoid nipple damage. This article is protected by copyright. All rights reserved. PMID- 30407655 TI - Microchip gel electrophoretic analysis of perchloric acid-soluble serum proteins in systemic inflammatory disorders. AB - Perchloric acid (PCA) precipitation is a well-known method for the separation of heavily glycosylated proteins and for reducing the masking effect of major serum proteins. The aim of this study is to characterize PCA-soluble serum proteins in healthy individuals and in patients with systemic inflammatory diseases, such as Crohn's disease and sepsis. A PCA precipitation protocol was prepared and adapted to the analytical methods. After PCA treatment of the serum, the soluble proteins in the supernatant were analyzed by SDS-PAGE and by microchip gel electrophoresis (MGE). Characteristic changes of the electrophoretic patterns of the PCA-soluble fractions were observed. Four characteristic bands (at ~11, ~65, ~85, and ~120 kDa) with varying intensity were detected by MGE. The proportion of the ~65, ~85, and ~120 kDa bands were significantly higher in systemic inflammatory conditions than in healthy individuals (p < 0.001), and characteristic patterns were observed in patients with acute inflammation. The marked differences in the acid soluble protein patterns, which were observed in patients with ongoing systemic inflammation, might be a good indicator of inflammation. The MGE analysis is a fast screening and quantification method for the detection of characteristic changes among acid-soluble serum proteins. PMID- 30407656 TI - Correlates of cognitive impairment in chronic kidney failure patients on hemodialysis: Systematic review and meta-analysis. AB - AIM: To review and identify correlates of cognitive impairment in chronic kidney failure patients on hemodialysis. BACKGROUND: The literature is consistent regarding the high prevalence of cognitive impairment among chronic kidney failure patients on hemodialysis and its dependence on multidimensional risk factors. DESIGN: Systematic review and meta-analysis based on Cochrane Handbook and PRISMA. DATA SOURCES: Electronic searches of the MEDLINE, EMBASE, Cochrane Library databases and major Korean databases were used. Only original research that assessed correlates of cognitive impairment in chronic kidney failure patients on hemodialysis and published between 2004 2016 in English or Korean were included. REVIEW METHODS: Studies were selected according to the PICOS: Population (chronic kidney failure patients with cognitive impairment on hemodialysis); Intervention (not applicable); Comparison (healthy controls or chronic kidney failure patients on hemodialysis without cognitive impairment); Outcome (cognitive impairment); and Study design (primarily non-experimental correlational studies and studies with experimental, quasi-experimental, or pre post cohort designs). Q-test and I2 index were used to examine study homogeneity. RESULTS: A total of 39 studies were finally included. Age, gender, stroke history, difficulties in activities of daily life, hemoglobin levels, pain, sleep difficulties and depression were found to be significant correlates of cognitive impairment. CONCLUSIONS: Nurses should be aware that the risk of cognitive impairment in chronic kidney failure patients on hemodialysis can be significantly higher for the elderly, women and in patients with a stroke, greater difficulties in activities of daily living, lower hemoglobin concentrations, higher pain levels, sleep difficulties, or depression. This article is protected by copyright. All rights reserved. PMID- 30407657 TI - Bordetella bronchiseptica Bcr4 antagonizes the negative regulatory function of BspR by its role in the type III secretion. AB - Bordetella species, including B. pertussis, have a type III secretion system that is highly conserved among Gram-negative pathogenic bacteria. Genes encoding the component proteins of a type III secretion system are localized at the bsc locus in the Bordetella genome. Here we investigated the function of a hypothetical protein Bcr4 encoded at the bsc locus in the B. bronchiseptica genome. We created a Bcr4-deficient mutant and determined the amounts of type III secreted proteins (e.g., BopB, BopN, and Bsp22) in both the supernatant fraction and whole-cell lysates of the Bcr4-deficient mutant. The levels of these proteins were significantly lower than those of the wild-type strain. In a Bcr4-overproducing strain, the amounts of type III secreted proteins in the supernatant fraction and whole-cell lysates were greatly increased compared to those of the wild-type strain. The type III secreted protein BspR was reported to negatively regulate the type III secretion system. Here, we used a Bcr4+BspR double-knockout mutant, and we observed that this mutant did not secrete the type III secreted proteins, whereas the levels of the proteins in whole-cell lysates of this mutant were nearly equal to those in whole-cell lysates of the BspR-deficient mutant. Bcr4 thus appears to play an essential role in the extracellular secretion of type III secreted proteins. Our data also suggest that Bcr4 antagonizes the negative regulatory function of BspR. PMID- 30407658 TI - Influence of vascular access devices upon efficiency of therapeutic plasma exchange. AB - BACKGROUND: An efficient vascular access is mandatory for the proper conduction of therapeutic plasma exchanges (TPE). Peripheral and central venous catheters may be used, with respective advantages and limitations. In this study, vascular access devices (IV catheter, dialysis cannula, central venous catheter) and anatomic vein characteristics were evaluated. METHOD: From January to June 2016, 162 TPE in 29 patients were reviewed. Only TPE using centrifugation method (Spectra Optia apheresis system) were evaluated. Volume exchanged, procedure duration, mean flow rate, number of inlet, and return pressure pauses were recorded. Site, width, and depth of punctured veins were studied. RESULTS: Median exchange volume planned was 3500 mL, and 152 (94%) procedures could be completed. Peripheral venous catheter was inserted in 103 (64%) cases (IV catheter: 61, dialysis cannulae: 42). Ultrasound guidance was used in 12 (11%) cases. Median procedure duration was shorter with central venous catheter (94 minutes), rather than dialysis cannula (133 minutes) or IV catheter (133 minutes). Median numbers of inlet pressure pauses were lower with central venous catheter (0) and dialysis cannulae (6), rather than IV catheter (10). There were no complications with peripheral venous access. There were no anatomic differences between catheterized veins with IV catheter or dialysis cannula. CONCLUSION: The use of peripheral venous access is possible in most of TPE, for emergency and during maintenance therapy. Dialysis cannulae are good compromise between classic IV catheters and central venous catheters, as it allows high flow rates, are easy to insert and associated with few complications. PMID- 30407660 TI - Management of neurogenic bladder in patients with Parkinson's disease: A systematic review. AB - AIMS: To assess the different treatment methods in management of neurogenic bladder (NGB) in patients with Parkinson's disease (PD). METHODS: A systematic search was performed in Cochrane library, EMBASE, Proquest, Clinicaltrial.gov, WHO, Google Scholar, MEDLINE via PubMed, Ovid, ongoing trials registers, and conference proceedings in November 11, 2017. All randomized controlled trials (RCTs) or quasi-RCTs comparing any treatment method for management of NGB in patients with PD were included. The titles and abstracts of all identified studies were evaluated independently by two investigators. Once all of the potential related articles were retrieved, each author separately evaluated the full text of each article and the quality of the methodology of the selected studies using the Cochrane appraisal risk of bias checklist and then the data about the patient's outcomes was extracted. We registered the title in Joanna Briggs Institute (JBI) that is available in http://joannabriggs.org/research/registered_titles.aspx. RESULTS: We included 41 RCTs or quasi-RCTs or three observational study with a total of 1063 patients that evaluated pharmacological, neurosurgical, botulinum toxin, electrical neuromodulation, and behavioral therapy effects on NGB. Among the included studies only solifenacin succinate double-blind, randomized, placebo-controlled study was assessed as low risk of bias, and treatment led to an improvement in urinary incontinence. CONCLUSIONS: Although several interventions are available for treatment NGB in patients with PD, at present there is little or no evidence that treatment improves patient outcomes in this population. Additional large, well designed, randomized studies with improved methodology and reporting focused on patient-centered outcomes are needed. PMID- 30407659 TI - Physiological left ventricular segmental myocardial mechanics: Multiparametric polar mapping to determine intraventricular gradients of myocardial dynamics. AB - OBJECTIVE: We investigated physiological systolic left ventricular (LV) myocardial mechanics and gradients to provide a database for later studies of diseased hearts. METHODS: The analyses were performed in 131 heart-healthy individuals and included seven parameters of myocardial mechanics using speckle tracking echocardiography (STE). RESULTS: Basal to apical and circumferentially significant physiological intraventricular parameter gradients of myocardial activity were determined. Global mean values and segmental ranges were peak systolic longitudinal strain -21.2 +/- 3.3%, 95% confidence interval [CI] -21.8% to -20.6%), gradient (basal to apical) -16.0% to -26.7%; peak systolic longitudinal strain rate -1.24 +/- 0.31%/s, 95% CI -1.29% to -1.19%/s, gradient (basal to apical) -0.91% to -1.61%/s; post-systolic index 2.6 +/- 3.2%, 95% CI 3.15%-2.05%, gradient (basal/medial/apical) 7.0/1.2/2.4%; pre-systolic stretch index 1.3 +/- 2.7%, 95% CI 1.77%-0.83%, gradient (basal/medial/apical) 6.5/0.2/1.3%; peak longitudinal displacement 12.2 +/- 2.6 mm, 95% CI 12.6-11.8 mm, gradient (basal to apical) 21.0-3.4 mm; time-to-peak longitudinal strain 370 +/- 43 ms, 95% CI 377-363 ms, gradient (basal to apical) 396-361 ms; and time-to peak longitudinal strain rate 180 +/- 47 ms, 95% CI 188-172 ms, gradient (basal to apical) 150-200 ms. CONCLUSION: This study generated a database of seven STE derived parameters of physiological segmental and global myocardial LV mechanics. The resulting sets of three-dimensional intraventricular mappings of the entire LV provide physiological parameter gradients in baso-apical and circumferential direction by applying the 17-segment polar model. This will facilitate comparison of systolic myocardial activity of the healthy LV with diseased or otherwise altered (eg, sports) hearts. PMID- 30407661 TI - New classification of geometric patterns considering left ventricular volume in patients with chronic aortic valve regurgitation: Prevalence and association with adverse cardiovascular outcomes. AB - BACKGROUND: Left ventricular (LV) remodeling due to aortic regurgitation (AR) often leads to maladaptive responses. We assessed the prevalence and clinical implications of LV remodeling considering LV volume, mass, and relative wall thickness at the time of AR diagnosis. METHODS AND RESULTS: Between 2008 and 2017, 370 consecutive patients (mean age 67.3 +/- 16.1 years, 56.5% males), with moderate or severe AR, were retrospectively analyzed. LV geometric patterns and clinical outcomes (cardiovascular death, hospitalization for heart failure, or aortic valve replacement) were evaluated. LV dilatation (LV end-diastolic volume >75 mL/m2 ) was present in 228 patients (61.6%). Applying the new LV remodeling classification system, 40 (10.8%) patients had normal geometry, 14 (3.8%) concentric remodeling, 43 (11.6%) concentric hypertrophy (LVH), 45 (12.2%) indeterminate LVH, 38 (10.3%) mixed LVH, 93 (25.1%) dilated LVH, 54 (14.6%) eccentric LVH, and 43 (11.6%) eccentric remodeling. During a median follow-up of 3.48 years (25th-75th percentile 0.91-5.57), 97 (26.2%) had the combined endpoint. LV dilation (P < 0.001), LVH (P < 0.001), and LV remodeling patterns were significantly associated with the combined endpoint. After multivariable adjustment for age, EF, aortic stenosis, CAD history, and moderate mitral regurgitation, dilated LVH (HR 7.61, IC 95% 1.82-31.80; P = 0.005) and eccentric LVH (HR 7.91, IC 95% 1.82-34.38; P = 0.006) were associated with adverse outcome compared to eccentric remodeling, that showed the best event-free survival rate. CONCLUSIONS: In a contemporary cohort of patients with AR, applying the new LV remodeling classification system, only a minority had normal geometry. Dilated LVH and eccentric LVH showed distinct outcome penalty after adjustment for confounders. PMID- 30407662 TI - Granulomonocytapheresis as a cell-dependent treatment option for patients with inflammatory bowel disease: Concepts and clinical features for better therapeutic outcomes. AB - Ulcerative colitis (UC) and Crohn's disease (CD) are major phenotypes of the chronic inflammatory bowel disease (IBD), which afflicts millions of individuals throughout the world with debilitating symptoms. The chronic nature of IBD means that patients require life-long medications, and this may lead to drug dependency, loss of response together with adverse side effects as additional morbidity factors. The efficacy of antitumour necrosis factor (TNF)-alpha biologics has validated the role of inflammatory cytokines notably TNF-alpha in the exacerbation and perpetuation of IBD. However, cytokines are released by myeloid lineage leucocytes like the CD14+ CD16+ monocyte phenotype. Additionally in IBD, myeloid leucocytes are elevated with activation behavior, while lymphocytes are compromised. Therefore, patients' leucocytes appear logical targets of therapy. Adsorptive granulomonocytapheresis (GMA) with an Adacolumn uses carriers, which interact with the Fcgamma receptor expressing leucocytes and deplete the elevated myeloid leucocytes, while the neutrophils, which re-enter the circulation via the Adacolumn outflow (>=40%) are phagocytosed by CD19 B cells to become interleukin (IL)-10 producing Bregs or CD19high CD1Dhigh B-cells. IL-10 is an anti-inflammatory cytokine. GMA has been applied to treat patients with IBD. The efficacy outcomes have been impressive as well as disappointing, the clinical response to GMA defines the patients' disease course and severity at entry. Efficacy outcomes in patients with deep ulcers together with extensive loss of the mucosal tissue are not encouraging, while patients without these features respond well and attain a favorable long-term disease course. Accordingly, for responder patients, GMA fulfills a desire to be treated without drugs. PMID- 30407663 TI - A Capable Surgeon and a Willing Electrologist: Challenges to the Expansion of Transgender Surgical Care in the United States. AB - Since 2014, public and private insurance coverage for transgender Americans' surgical care has increased exponentially. Training clinicians and equipping institutions to meet the surge in demand has not been as rapid. Through ethnographic research at a surgical workshop focused on trans- genital reconstruction and in a U.S. hospital working to grow its transgender health program, this article shows that effects of the decades-long insurance exclusion of trans- surgery are not easily remedied through the recent event of its inclusion because patient access is not the only thing that has been restricted by coverage denial. Decades of excluding coverage for trans- genital reconstructive surgery have limited the development and circulation of technical skills required to perform these procedures, as well as the administrative processes needed to integrate them into existing clinical workflows. One surgeon estimates that turning expanded access into realized care is "a five or six-year problem." This article is protected by copyright. All rights reserved. PMID- 30407664 TI - Balancing Scattering Channels: A Panoscopic Approach toward Zero Temperature Coefficient of Resistance Using High-Entropy Alloys. AB - Designing alloys with an accurate temperature-independent electrical response over a wide temperature range, specifically a low temperature coefficient of resistance (TCR), remains a big challenge from a material design point of view. More than a century after their discovery, Constantan (Cu-Ni) and Manganin (Cu-Mn Ni) alloys remain the top choice for strain gauge applications and high-quality resistors up to 473-573 K. Here, an average TCR is demonstrated that is up to ~800 times smaller in the temperature range 5-300 K and >800 times smaller than for any of these standard materials over a wide temperature range (5 K < T < 1200 K). This is achieved for selected compositions of Alx CoCrFeNi high-entropy alloys (HEAs), for which a strong correlation of the ultralow TCR is established with the underlying microstructure and its local composition. The exceptionally low electron-phonon coupling expected in these HEAs is crucial for developing novel devices, e.g., hot-electron detectors, high-Q resonant antennas, and materials in gravitational wave detectors. PMID- 30407665 TI - Applying the latest advances in genomics and phenomics for trait discovery in polyploid wheat. AB - Improving traits in wheat has historically been challenging due to its large and polyploid genome, limited genetic diversity, and in-field phenotyping constraints. However, within recent years many of these barriers have been lowered. The availability of a chromosome-level assembly of the wheat genome now facilitates a step-change in wheat genetics and provides a common platform for resources including variation data, gene expression data, and genetic markers. The development of sequenced mutant populations and gene-editing techniques now enable the rapid assessment of gene function in wheat directly. The ability to alter gene function in a targeted manner will unmask the effects of homoeolog redundancy and allow the hidden potential of this polyploid genome to be discovered. New techniques to identify and exploit the genetic diversity within wheat wild relatives now enable wheat breeders to take advantage of these additional sources of variation to address challenges facing food production. Finally, advances in phenomics have unlocked rapid screening of populations for many traits of interest both in greenhouses and in the field. Looking forwards, integrating diverse data types, including genomic, epigenetic and phenomics data will take advantage of big data approaches including machine learning to understand trait biology in wheat in unprecedented detail. This article is protected by copyright. All rights reserved. PMID- 30407666 TI - Catalytic Generation and Chemoselective Transfer of Nucleophilic Hydrides from Dihydrogen. AB - Copper(I)/N-heterocyclic carbene (NHC) complexes enable the catalytic generation of nucleophilic hydrides from dihydrogen (H2) and their subsequent transfer to allylic chlorides. The highly chemoselective catalyst displays no concomitant hydrogenation reactivity, as the terminal double bond formed in the hydride transfer remains intact. Switching to deuterium gas (D2) allows for regioselective monodeuteration with excellent isotope incorporation. PMID- 30407667 TI - Single-Sided Competitive Axial Coordination of G-Quadruplex/Hemin as Molecular Switch for Imaging Intracellular Nitric Oxide. AB - Axial coordination is a crucial biological process to regulate biomolecules' functions in natural enzymes. However, it is a great challenge to determine the single or dual axial interaction between the metal center of enzymes and the ligand. In this work, a controllable axial coordination system was developed based on G-quadruplex/hemin complex by designing a series of fluorescent derivatives. The mechanism on axial coordination of G-quadruplex/hemin with coumarin-imidazole ligands was identified to be single-sided, and led to fluorescence quenching of ligands. Upon addition of nitric oxide, the fluorescence of ligands was recovered through competitive axial coordination, providing a "signal on" strategy for signal transduction. More significantly, the fluorescent imaging of intracellular nitric oxide was achieved after conjugating with gold nanoparticles. Also, the proposed protocol provided a smart strategy to monitor the relationship between nitric oxide and p53 protein activity in living cells. PMID- 30407668 TI - Structural and Kinetic Profiling of Allosteric Modulation of Duplex DNA Induced by DNA-Binding Polyamide Analogues. AB - A structural and quantitative biophysical profile of the DNA binding affinity, kinetics and sequence-selectivity of minor-groove binding polyamides (PAs) incorporating N-terminal 5-alkyl thiazole (Nt) and 1-alkyl imidazole (Im) units is described. DNA duplexes containing either target binding sites or mismatch sequences for a suite of hairpin PAs are immobilized on a microelectrode surface. Quantitation of the binding kinetics (i.e., kon, koff), dissociation constant (KD) and melting temperatures show that PAs exhibit picomolar to low nanomolar binding affinities for their target dsDNA sequences. NMR structural analysis of the iPr-Im-containing PA reveals the steric bulk of the isopropyl substituent induces more extensive major groove compression than the corresponding methyl-Im hairpin PA*dsDNA complex. These results show that increasing steric bulk at distal locations to the DNA binding face of the PA plays an influential role in allosteric modulation of the DNA duplex. PMID- 30407669 TI - The effect of dietary ginseng polysaccharide supplementation on porcine milk derived esRNAs involved in the host immune responses. AB - Ginseng polysaccharides (GPS) have been well known as an immune modulator. This study was conducted to investigate the effects of dietary supplemental GPS on the immune responses involved in sow's milk-derived exosomal shuttle RNAs (esRNAs) using RNA-Seq and miRNA-Seq. Of the 213 identified miRNA types, a total of 26 conserved miRNAs were differently expressed in response to GPS supplementation, including 10 up-regulated and 16 down-regulated miRNAs in GPS feeding group. In addition, exosomal transcriptome analysis identified 14,696 protein-coding genes in sow's milk exosomes, and 283 genes with 204 and 79 candidates showing up and down-regulation were significantly responded to GPS supplementation. Integrated analysis of each differently expressed miRNA with significantly expressed genes further revealed the presence of 51 highly conserved miRNA-gene interactions that were annotated to be related to immunoregulatory functions. This work provided an important advance in the functional identification of dietary GPS supplementation and more fundamental information about how GPS promoted the immune response and healthy growth of the infant from mothers at molecular levels. PMID- 30407670 TI - The Arabidopsis RRM domain protein EDM3 mediates race-specific disease resistance by controlling H3K9me2-dependent alternative polyadenylation of RPP7 immune receptor transcripts. AB - The NLR-receptor RPP7 mediates race-specific immunity in Arabidopsis. Previous screens for enhanced downy mildew (edm) mutants identified the co-chaperone SGT1b (EDM1) and the PHD-finger protein EDM2 as critical regulators of RPP7. Here, we describe a third edm mutant compromised in RPP7 immunity, edm3. EDM3 encodes a nuclear-localized protein featuring an RNA-recognition motif. Like EDM2, EDM3 promotes histone H3 lysine 9 dimethylation (H3K9me2) at RPP7. Global profiling of H3K9me2 showed EDM3 to affect this silencing mark at a large set of loci. Importantly, both, EDM3 and EDM2 co-associate in vivo with H3K9me2-marked chromatin and transcripts at a critical proximal polyadenyation site of RPP7. Our results highlight the complexity of plant NLR gene regulation and establish a functional and physical link between a histone mark and NLR-transcript processing. This article is protected by copyright. All rights reserved. PMID- 30407671 TI - Advancing consumer engagement: Supporting, developing and empowering youth leadership in cancer care. PMID- 30407672 TI - Low dose provocation and skin tests in patients with hypersensitivity to Gadolinium-based contrast agents. AB - Reported reactions rates with gadolinium-based contrast agents (GBCA) ranged from 0.07 to 2.4%, the rate of hypersensitivity reaction (HS) is around 0.1% (1) and immediate and delayed HS have been reported (1-4). The diagnosis of HS to GBCA is challenging, based on clinical history and skin tests. Although little data is available on the performances of the GBCA skin tests, its negative predictive value appears to be of interest (5). This article is protected by copyright. All rights reserved. PMID- 30407673 TI - TMSOTf-Catalyzed Koenigs-Knorr Glycosylation Reaction. AB - Presented herein is our discovery that traditional silver(I) oxide-promoted glycosidations of glycosyl bromides (Koenigs-Knorr reaction) can be greatly accelerated in the presence of catalytic TMSOTf. These reaction conditions are very mild and allow for maintaining a practically neutral pH while providing high rates and excellent glycosylation yields. In addition, unusual reactivity trends among a series of differentially protected glycosyl bromides have been documented. Also revealed is an unusual reactivity trend according to which benzoylated alpha-bromides are much more reactive than their benzylated counterparts under these con-ditions. PMID- 30407674 TI - LncRNA NEAT1 promotes the tumorigenesis of colorectal cancer by sponging miR-193a 3p. AB - OBJECTIVES: LncRNA nuclear-enriched abundant transcript 1 (NEAT1) participates in the development and progression of multiple malignancies. However, the molecular mechanism by which NEAT1 contributes to colorectal cancer (CRC) remains unclear. METHODS: The association between lncRNA NEAT1 expression and clinicopathological characteristics and prognosis in patients with CRC was analysed by TCGA RNA sequencing data. MTT, colony formation, flow cytometry, transwell assays and a xenograft tumour model were used to assess the functions of NEAT1. Bioinformatics and spearman correlation analysis were used to identify the NEAT1-specific binding with miRNAs, and luciferase gene report and RIP assays were performed to confirm the interaction between miR-193a-3p (miR-193a) and NEAT1 in CRC cells. RESULTS: Upregulation of NEAT1 expression was significantly correlated with TNM stage, poor survival and tumour recurrence in patients with CRC, and acted as an independent prognostic factor for tumour recurrence. Knockdown of NEAT1 suppressed cell proliferation, colony formation abilities and invasive potential and induced cell apoptosis, but overexpression of NEAT1 reversed these effects. Furthermore, NEAT1 was confirmed to act as a sponge of miR-193a, and knockdown of NEAT1 attenuated miR-193a inhibitor-induced tumour promoting effects and L17RD expression in CRC cells. miR-193a harboured negative correlation with NEAT1 and IL17RD expression in CRC specimens. In vivo experiment further validated the inhibitory effects of NEAT1 knockdown on xenograft tumour growth. CONCLUSION: Our findings demonstrate that lncRNA NEAT1 acts as an oncogenic role in CRC cells by sponging miR-193a and may represent a potential marker for CRC patients. PMID- 30407675 TI - Salmonella epididymo-orchitis presenting as acute scrotum in a 2-week-old infant. PMID- 30407676 TI - Clinical, Sonographic, and Electrophysiologic Longitudinal Features of Chronic Inflammatory Demyelinating Polyneuropathy. AB - BACKGROUND AND PURPOSE: Several studies have aimed to find potential biomarkers to simplify the diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) and to monitor and predict the disease course. However, reliable markers are still lacking. We aimed to investigate whether high-resolution nerve ultrasound (HRUS) is suitable for monitoring the long-term clinical course of CIDP. METHODS: Twenty patients fulfilling the definite diagnostic criteria of CIDP received clinical examination, evaluation of the INCAT (inflammatory neuropathy cause and treatment) overall disability sum score (ODSS) as well as nerve conduction studies, and HRUS every 6 months over a median follow-up time of 34 months. Patients were divided into clinically stable/regressive disease course or progressive disease course according to the development of the ODSS. RESULTS: The intranerve cross-sectional-area (CSA) variability of the nerves of the lower extremity increased with disease progression, whereas it remained unchanged in patients with a stable or remitting disease course. CONCLUSION: Nerve ultrasound can be used as a method to objectify the long-term disease course in CIDP patients. The intranerve CSA variability is suitable for monitoring the clinical course of patients with CIDP. PMID- 30407677 TI - Effectiveness of interventions to increase physical activity in individuals with intellectual disabilities: a systematic review of randomised controlled trials. AB - BACKGROUND: People with intellectual disabilities (ID) often do not meet recommended guidelines for physical activity. The aim of this study was to systematically review available evidence that evaluated the effectiveness of interventions to increase physical activity in individuals with ID. METHOD: Five electronic databases (MEDLINE, CINAHL, EMBASE, SPORTDiscus and Cochrane Central Register of Controlled Trials) were searched from inception of the database to July 2017 to identify randomised controlled trials that evaluated the effectiveness of interventions to improve physical activity among people with ID. Trials were included if they measured at least one objective measure of physical activity. Quality appraisal was completed by two independent reviewers using the Cochrane Risk of Bias Tool. The magnitude of treatment effect was estimated for each intervention by calculating the standardised mean difference (SMD) and associated 95% confidence interval. RESULTS: Nine randomised controlled trials (976 participants, 501 women, age range 9 months to 83 years) were included. Four trials evaluated unimodal interventions and five trials evaluated multimodal health promotion programmes based on using supportive environments to enable sustained behavioural changes in physical activity. None of the trials were rated as low risk of bias as all had at least one item on the Cochrane Risk of Bias Tool that was considered to be high risk. No trials were able to implement participant blinding. Three trials found statistically significant beneficial effects of interventions for increasing physical activity. Results showed that a 10-week progressive resistance training programme led to maintenance of physical activity levels at 24 weeks in adolescents with Down syndrome (SMD 0.78, 95% CI 0.17 to 1.40). Additionally, a 12- to 16-month multicomponent diet and physical activity programme produced improvement in physical activity at programme completion in adults with ID (reported effect size of 0.29). Finally, an 8-month physical activity and fitness programme increased physical activity at 8 months in adults with ID (SMD 0.91, 95% CI 0.20 to 1.60). Findings regarding other interventions were inconclusive with small effects that were not statistically significant. CONCLUSIONS: There is inconsistent evidence of the effects of interventions for improving physical activity levels in individuals with ID. A progressive resistance training programme was found to maintain physical activity levels in adolescents with Down syndrome, while a multicomponent diet and physical activity programme and a physical activity and fitness programme were found to improve physical activity levels in adults with ID. Future trials using rigorous research designs are required to confirm these findings and establish whether other interventions designed to increase physical activity in people with ID are effective. PMID- 30407678 TI - Independence of syntactic and phonological deficits in dyslexia: A study using the attraction error paradigm. AB - This paper addresses the question of whether dyslexic children suffer from syntactic deficits that are independent of limitations with phonological processing. We looked at subject-verb agreement errors after sentence subjects containing a second noun (the attractor) known to be able to attract incorrect agreement (e.g., "the owner(s) of the house(s) is/are away"). In the general population, attraction errors are not straightforwardly dependent on the presence or absence of morphophonological plural markers but on their syntactic configuration. The same would be expected for dyslexic children if their syntactic problems are not phonological in nature. We also looked at the possible effect of system overload on syntactic processing by comparing auditory and written presentation of stimuli and stimuli with high and low frequency attractors. Dyslexic children produced more agreement errors than age-matched controls, but their errors were distributed in the expected manner and did not align with the presence of morphophonological number markers in the subject overall. Furthermore, there was no effect of either presentation mode or attractor frequency on the number of agreement errors. Our results confirm the existence of syntactic difficulties in dyslexia and suggest that they are not due to a phonological deficit or to verbal working memory limitations. PMID- 30407679 TI - Microvessels may Confound the "Swallow Tail Sign" in Normal Aged Midbrains: A Postmortem 7 T SW-MRI Study. AB - BACKGROUND AND PURPOSE: Susceptibility weighted imaging (SWI) plays a role in the differential diagnosis of Parkinson's disease, but lacks widespread acceptance in clinical routine. In a descriptive pilot study, we assessed hypointense microstructures of the normal substantia nigra pars compacta at ultrahigh-field strength for interpretation of the "swallow tail sign." METHODS: Magnetic resonance imaging at 7 Tesla was performed in five postmortem samples obtained from subjects not affected by Parkinson's disease. Susceptibility weighted images, including minimum intensity projections, were created followed by consensus assessment for microvascular confound. Histological workup in this case control study included iron and myelin staining. Seven Tesla SWI images from the reference cohort of nine living subjects, all of which showed a positive "swallow tail sign" in their midbrains, were assessed visually. RESULTS: All specimens showed microvessels running through the dorsal pars compacta and along the caudolateral circumference of the red nucleus. Hypointense imaging patterns in the medial part of the "swallow tail" were due to susceptibility effects of iron deposits and microvessels. In eight out of nine control subjects, one or more microvessels were detected medial to the dorsolateral nigral hyperintensity or at least unilaterally in the medial part of the "swallow tail." One microvessel crossing nigrosome 1 was found in two in-vivo cases. CONCLUSION: Both iron deposits and microvessels contribute to the hyposignal surrounding nigrosome 1 in susceptibility weighted imaging of normal aged midbrains at ultrahigh-field strength. When assessing the substantia nigra for the presence or absence of the "swallow tail sign," intrinsic vessels may be a sporadic confounder. PMID- 30407680 TI - Ability of the Fitbit Alta HR to quantify and classify sleep in patients with suspected central disorders of hypersomnolence: A comparison against polysomnography. AB - Measuring sleep duration and early onset rapid eye movement sleep (REMS) is critical in the assessment of suspected central disorders of hypersomnolence (CDH). Current multi-sensor activity trackers that integrate accelerometry and heart rate are purported to accurately quantify sleep time and REMS; however, their utility in suspected CDH has not been established. This investigation aimed to determine the ability of a current, multi-sensor tracker, Fitbit Alta HR (FBA HR), to quantify and classify sleep in patients with suspected CDH relative to polysomnography (PSG). Forty-nine patients (46 female; mean age, 30.3 +/- 9.84 years) underwent ad libitum PSG with concurrent use of the FBA-HR. FBA-HR sleep variable quantification was assessed using Bland-Altman analysis. FBA-HR all sleep (AS), light sleep (LS; PSG N1 + N2), deep sleep (DS; PSG N3) and REMS classification was evaluated using epoch-by-epoch comparisons. FBA-HR-detected sleep-onset rapid eye movement periods (SOREMPs) were compared against PSG SOMREMPs. FBA-HR displayed significant overestimation of total sleep time (11.6 min), sleep efficiency (1.98%) and duration of deep sleep (18.2 min). FBA-HR sensitivity and specificity were as follows: AS, 0.96, 0.58; LS, 0.73, 0.72;DS, 0.67, 0.92; REMS, 0.74, 0.93. The device failed to detect any nocturnal SOREMPs. Device performance did not differ appreciably among diagnostic subgroups. These results suggest FBA-HR cannot replace EEG-based measurements of sleep and wake in the diagnostic assessment of suspected CDH, and that improvements in device performance are required prior to adoption in clinical or research settings. PMID- 30407681 TI - Proactive and reactive cognitive control rely on flexible use of the ventrolateral prefrontal cortex. AB - The role of ventral versus dorsolateral prefrontal regions in instantiating proactive and reactive cognitive control remains actively debated, with few studies parsing cue versus probe-related activity. Rapid sampling (460 ms), long cue-probe delays, and advanced analytic techniques (deconvolution) were therefore used to quantify the magnitude and variability of neural responses during the AX Continuous Performance Test (AX-CPT; N = 46) in humans. Behavioral results indicated slower reaction times during reactive cognitive control (AY trials) in conjunction with decreased accuracy and increased variability for proactive cognitive control (BX trials). The anterior insula/ventrolateral prefrontal cortex (aI/VLPFC) was commonly activated across comparisons of both proactive and reactive cognitive control. In contrast, activity within the dorsomedial and dorsolateral prefrontal cortex was limited to reactive cognitive control. The instantiation of proactive cognitive control during the probe period was also associated with sparse neural activation relative to baseline, potentially as a result of the high degree of neural and behavioral variability observed across individuals. Specifically, the variability of the hemodynamic response function (HRF) within motor circuitry increased after the presentation of B relative to A cues (i.e., late in HRF) and persisted throughout the B probe period. Finally, increased activation of right aI/VLPFC during the cue period was associated with decreased motor circuit activity during BX probes, suggesting a possible role for the aI/VLPFC in proactive suppression of neural responses. Considered collectively, current results highlight the flexible role of the VLPFC in implementing cognitive control during the AX-CPT task but suggest large individual differences in proactive cognitive control strategies. PMID- 30407682 TI - Impact of a behavior change program and health education on social interactions in survivors of head and neck cancer: Randomized controlled trial. AB - OBJECTIVE: The purpose of this study of survivors of head and neck cancer was to evaluate the effects of a behavior change program and health education on depression, fear of social interactions, avoidance of social interactions, physical function, and social-emotional function. METHODS: This was a randomized controlled trial of 100 subjects, in which changes in the scores of several psychometric scales were recorded for an experimental group (behavior change program and health education) and a control group (routine care only). Assessments were performed at baseline (T0), and at 1 month (T1), 2 months (T2), and 3 months (T3) after completing the intervention. RESULTS: After the intervention, the experimental group reported significantly less fear of social interactions, less avoidance of social interactions, and better physical function than the control group. The experimental group also had less depression at T3 than at T0, although there was no such change in the control group. Analysis of physical function indicated that both groups experienced improvements from T0 to T1, slight declines from T1 to T2, and slight declines from T2 to T3; however, both groups had significantly better physical function at T3 than at T0. CONCLUSIONS: Head and neck cancer patients who received a behavior change program and health education reported less fear of social interactions, less avoidance of social interactions, and improved physical function during the 3 months after this intervention. PMID- 30407683 TI - Reduction in grey matter volume and its correlation with clinical symptoms in Chinese boys with low functioning autism spectrum disorder. AB - BACKGROUND: Previous studies have reported changes within grey matter (GM) volume in children with autism spectrum disorder (ASD); however, little is known about GM volume changes and the relation with symptom severity in Chinese boys with low functioning autism spectrum disorder (LFASD). METHOD: GM volume was analysed using SPM 8 and compared between 16 boys with LFASD as well as 16 typically developing (TD) boys (using REST 1.8). Additionally, the correlation between GM volume and clinical symptoms was analysed, using subscales within the Autism Behaviour Checklist (ABC). RESULTS: The comparison showed a reduced volume of GM in 11 clusters in the boys with LFASD (i.e., the left inferior frontal gyrus, orbital part; right superior temporal gyrus, superior frontal gyrus, dorsolateral; precuneus and postcentral; bilateral rectus and middle temporal gyrus) and 1 area with increased GM volume (right caudate) compared to the TD group. Additionally, the GM volume of the left inferior frontal gyrus, orbital part was negatively correlated with the Social subscale score of the ABC (r = 0.765, P = 0.002), and the GM volume of the left Rectus was negatively associated with the Language, Body concept and Self-care subscale scores and the total score on the ABC(r = -0.624, P = 0.023; r = -0.657, P = 0.011; r = -0.618, P = 0.025; r = -0.625, P = 0.022). Further, the GM volume of the right Caudate was negatively correlated with the Sensory subscale on the ABC (r = -0.593, P = 0.033). CONCLUSION: In conclusion, the current study's findings display that the GM volume was widely reduced in Chinese boys with LFASD compared to TD boys and negatively correlated with the clinical symptoms, indicating a possible pathological mechanism of LFASD. PMID- 30407684 TI - Comparison of two neonatal pain assessment tools (Children and Infant's Postoperative Pain Scale and the Neonatal Facial Coding System - Revised) and their relations to clinicians' intuitive pain estimates. AB - BACKGROUND: Many neonatal observational pain assessment tools are available. Their application in clinical settings, however, has been limited. A further difficulty for decision makers may be to choose among the variety of available tools the appropriate one(s) for their patients. Aims of the present study were (1) to compare two commonly cited neonatal pain assessment tools, the Neonatal Facial Coding System - Revised (NFCS-R) and the Children and Infant's Postoperative Pain Scale (CHIPPS), with regard to their psychometric qualities and (2) to explore intuitive clinicians' ratings by relating them to the tools' items. METHODS: Three coders applied both pain assessment tools to videos of 44 neonates who were videotaped while undergoing a painful and a stressful procedure. Clinicians rated the pain neonates experienced on a numerical rating scale. Analyses of variances and regression analyses were used to investigate whether tools could discriminate between the procedures and whether tools' items were predictors of intuitive clinicians' ratings. RESULTS: Interrater reliability, internal consistency and relative convergent validity were high for both assessment tools. Both tools discriminated between painful and stressful situations equally well. Roughly one third of variance in clinicians' intuitive ratings could be explained by items of each tool, however, no single item was found to be a significant predictor. CONCLUSIONS: Both pain assessment tools performed equally well regarding psychometric comparisons. Therefore, clinical utility needs to be considered when having to choose. Possibilities of improvement for both tools were identified. Cues clinicians base their intuitive pain judgements need to be further investigated. This article is protected by copyright. All rights reserved. PMID- 30407685 TI - An In Vitro Investigation of Accuracy and Fit of Conventional and CAD/CAM Removable Partial Denture Frameworks. AB - PURPOSE: To evaluate the overall accuracy and fit of conventional versus computer aided design/computer-aided manufactured (CAD/CAM) removable partial denture (RPD) frameworks based on standard tessellation language (STL) data analysis, and to evaluate the accuracy and fit of each component of the RPD framework. MATERIALS AND METHODS: A maxillary metal framework was designed for a Kennedy class III Modification I arch. The master model was scanned and used to compare the fit and accuracy of RPD frameworks. Forty impressions (conventional and digital) of the master cast were made and divided into 4 groups based on fabrication method: group I, lost-wax technique (conventional technique), group II, CAD-printing, group III, CAD-printing from stone cast, and group IV, lost-wax technique from resin-printed model. RPD frameworks were fabricated in cobalt chromium alloy. All frameworks were scanned, and the gap distance between the framework and scanned master model was measured at 8 locations. Color mapping was conducted using comprehensive metrology software. Data were statistically analyzed using the Kruskall-Wallis test, followed by the Bonferroni method for pairwise comparisons (alpha = 0.05). RESULTS: Color mapping revealed distinct discrepancies in major connectors among the groups. When compared to 3D-printed frameworks, conventional cast frameworks fabricated using dental stone or printed resin models revealed significantly better fit (P < 0.05) particularly in the major connectors and guide plates. The biggest gap (0.33 mm +/- 0.20 mm) was observed with the anterior strap of the major connector with the printed frameworks (groups II and III). The method of fabrication did not affect the adaptation of the rests or reciprocation plates. CONCLUSIONS: Although both conventional and 3D-printing methods of framework fabrication revealed clinically acceptable adaptation, the conventional cast RPD groups revealed better overall fit and accuracy. This article is protected by copyright. All rights reserved. PMID- 30407686 TI - Paediatric new-onset seizure clinic in Australia: Experience and lessons learnt. AB - AIM: A new-onset seizure clinic (NOSC) was established at our hospital in 2011, with the aim to provide accurate diagnosis and appropriate management to children with new-onset seizures or seizure mimics. METHODS: We report on the data analysis of the first 200 children seen in NOSC. A paediatric neurologist or paediatric/neurology trainee under supervision of a neurologist reviewed all the children. A detailed history and clinical examination were undertaken. Electroencephalogram (EEGs) were undertaken prior to clinic review in most emergency departments. Children were classified as 'epilepsy positive' (EP+) or 'epilepsy negative' (EP-) after the first consultation. RESULTS: Of 200 patients, 109 were classified as EP+: generalised epilepsy in 57 of 109, focal in 36, childhood seizure susceptibility syndrome in 26 and epileptic encephalopathy in 5. EEG was available in 192: in 117, it was abnormal - 23 with background abnormalities and 109 with epileptiform activity. Of the 109 patients, 80 were commenced on anti-epileptic drugs (AEDs): 12 were able to come off medication after seizure-free period, 61 were controlled on AEDs and 7 were refractory. Children were followed up for 12-48 months. None of the children had diagnosis revised on follow-up. CONCLUSIONS: This is the first Australian study to report on a large cohort of children from a NOSC. An EEG and a paediatric neurologist assessment is a good combination to enable diagnostic accuracy: In the first 200 patients seen, there were no revisions of the initial diagnosis on follow-up. PMID- 30407687 TI - Evidence for the reliability and preliminary validity of the Adult ADHD Self Report Scale v1.1 (ASRS v1.1) Screener in an adolescent community sample. AB - OBJECTIVES: There is a need for brief and publicly-available assessments of attention deficit hyperactivity disorder (ADHD) easily administered in large scale survey efforts monitoring symptoms among adolescents. The ADHD Self-Report Scale v1.1 (ASRS; Kessler et al., 2005) Screener, a six-item measure of ADHD symptoms, is a valid and reliable screening instrument for ADHD among adults. The current study provides initial evidence for the reliability and validity of the ASRS Screener among a community sample of U.S. adolescents. METHODS: Middle and high school students in grades 6 through 12 (N = 2,472) completed the ASRS Screener, along with the Strengths and Difficulties Questionnaire (SDQ; Goodman, 2001) and several questions about school functioning. RESULTS: The ASRS Screener demonstrated good internal consistency, with items captured by a single underlying latent variable, which was invariant across subsamples differing by gender. The ASRS Screener scores were associated with the SDQ subscale measuring hyperactivity/inattention (r = 0.58) and significantly less strongly associated with other SDQ subscale scores (r = -0.15-0.41). The ASRS Screener scores were also significantly associated with student-reported school functioning. CONCLUSION: Findings suggest directions for future research and provide preliminary support for use of the ASRS Screener as a brief tool for identifying symptoms of ADHD among adolescents. PMID- 30407688 TI - Ultrasonication-Assisted Spray Ionization-based Micro-reactors for On-line Monitoring of Fast Chemical Reactions by Mass Spectrometry. AB - Microfluidics can be used to handle relatively small volumes of samples and to conduct reactions in microliter-sized volumes. Electrospray ionization (ESI) can couple microfluidics with mass spectrometry (MS) to monitor chemical reactions on line. However, fabricating microfluidic chips is time-consuming. We herein propose the use of a micro-reactor that is sustained by two capillaries and an ultrasonicator. The inlets of the capillaries were individually immersed to two different sample vials that were subjected to the ultrasonicator. The tapered outlets of the two capillaries were placed cross with an angle of ~60 degrees close to the inlet of the mass spectrometer to fuse the eluents. On the basis of capillary action and ultrasonication, the samples from the two capillaries can be continuously directed to the capillary outlets and fuse simultaneously to generate gas phase ions for MS analysis through ultrasonication-assisted spray ionization (UASI). Any electric contact applied on the capillaries is not required. Nevertheless, UASI spray derived from the eluents can readily occur in front of the mass spectrometer. That is, a micro-reactor was created from the fusing of the eluent containing different reactants from these two UASI capillaries, allowing reactions to be conducted in situ. The solvent in the fused droplets was evaporated quickly, and the product ions could be immediately observed by MS because of the extreme rise in the concentration of the reactants. For proof of concept, pyrazole synthesis reaction and cortisone derivatization by Girard T reagent were selected as the model reactions. The results demonstrated the feasibility of using UASI-based micro-reactor for on-line MS analysis to detect reaction intermediates and products. PMID- 30407689 TI - Statistical methods and reporting practices in the study of dyslexia. AB - This report presents findings from a review of the journals Dyslexia and Annals of Dyslexia over a 10-year period from 2005 to 2014. Three hundred articles were reviewed to examine statistical methodology and reporting practices. Articles were coded according to their reported covariates, effect sizes, and statistical methods. In addition, trends were examined in relation to the 2008 release of the What Works Clearinghouse Procedures and Standards Handbook from the Institute of Education Sciences in order to evaluate any potential impact of recommended practices. We found an increase in prevalence of specific statistical methods as well as increases in reporting of effect sizes following publication of the handbook. The reporting of effect sizes statistically significantly increased following publication of the manual (55% prepublication vs. 72% post publication). The use of analysis of variance increased post-publication, whereas articles using no statistical methods or descriptives only decreased. Approximately one third of articles included covariates in their analysis; inclusion of covariates was consistent from prepublication to post-publication. Findings indicate that over the past 10 years, articles are becoming increasingly rigorous in methodology and reporting practices. PMID- 30407690 TI - NEDD8 promotes the tumor progression and predicts the poor prognosis of patients with bladder cancer. AB - Neddylation has been researched in many different human carcinomas. However, the roles of neural precursor cell expressed, developmentally down-regulated 8 (NEDD8) in bladder cancer were still unknown. Our study was the first study which systematically investigated the possible functions of NEDD8 in bladder cancer (BC) progression. We performed immunohistochemistry to explore the associations between the expression of NEDD8 in tumor tissues and clinical outcomes of patients. RT-qPCR and western blot were used to detect the expressional levels of genes. The biological abilities of cell proliferation, migration and invasion were researched by in vitro and in vivo experiments. And the results were as follows: Data from TCGA database showed that NEDD8 was overexpressed in BC tissues and associated with the worse survivals of patients. The results of immunohistochemistry in our study found that NEDD8 was significantly associated with the poor clinical outcomes of BC patients. Suppression of NEDD8 could inhibit the proliferation, migration and invasion of tumor cells. Knocking down of NEDD8 could induce the apoptosis and G2 phase arrest of cell cycle progression. In vivo, suppression of NEDD8 could restrict the growth and metastasis of tumors in mice. In conclusion, NEDD8 possessed important roles in regulating the progression of BC cells and was associated with the poor prognosis of patients, which may become a potential therapeutic target of BC. This article is protected by copyright. All rights reserved. PMID- 30407691 TI - Falls resulting in health care among older people with intellectual disability in comparison with the general population. AB - BACKGROUND: Falls are common among older people with intellectual disability (ID) and are also a major contributor to injuries in this population. Yet, fall characteristics have only been sparsely studied, and the results are inconsistent. The aim of the present study was to investigate type of falls, places where they occurred and activities that caused them, as well as health outcomes and health utilisation patterns after falls, among older people with ID in comparison with their age peers in the general population. METHODS: We established an administrative cohort of people with ID aged 55 years, or more, and alive at the end of 2012 (ID cohort; n = 7936). A cohort from the general population, one-to-one matched by sex and year of birth, was used as referents. Data regarding fall-induced health care episodes in inpatient and outpatient specialist care were collected from the National Patient Register for the period 2002-2012. RESULTS: With the exception of falls from one level to another (i.e. fall on and from stairs and steps, ladder and scaffolding; fall from, out of or through building or structure; fall from tree or cliff and diving or jumping into water; or other fall from one level to another), people in the ID cohort were more likely to fall and fall more often than those in the general population cohort. Falls during a vital activity (e.g. attending to personal hygiene or eating) were twice as common among people with ID compared with the general population. When falling, people with ID were more likely to injure their head and legs but less likely to sustain injuries to the thorax and elbow/forearm. They were more likely to have superficial injuries, open wounds and fractures but less likely to have dislocations, sprain and strains. Fall-related health care visits among people with ID were more likely to be in inpatient care and be unplanned. People with ID were also more likely than those in the general population to have a readmission within 30 days. CONCLUSIONS: People with ID are more likely to require specialist care after a fall and also more likely to obtain injuries to the head, compared with the general population. This is important to consider when taking preventive measures to reduce falls and fall related injuries. PMID- 30407692 TI - Trends in the consumption of opioids for the treatment of severe pain in Europe, 1990-2016. AB - BACKGROUND: Over the last decades, consumption of opioids for the treatment of pain increased steadily in the United States, Australia, and a few European countries. To date, no study has analysed time trends in opioid consumption across Europe. METHODS: We analysed data provided by International Narcotics Control Boards on the consumption of fentanyl, oxycodone, morphine, hydromorphone and pethidine in 40 European countries over the last decade. Trends in total opioid consumption from 1990 to 2016 in 22 selected European countries, the European Union (EU) as a whole, and, for comparison purpose, the United States, were analysed using the joinpoint regression analysis. RESULTS: In 2014-2016, opioid use was >10,000 defined daily doses for statistical purposes (s-DDD) per 1,000,000 inhabitants die in Western/Northern countries, whereas it was <1000 s DDD in Southern/Eastern ones. In most European countries, opioid consumption increased to a great extent between 2004-2006 and 2014-2016; it rose from 6,477 to 8,967 s-DDD (+38.4%) in the EU, and from 14,598 to 16,491 s-DDD (+13%) in the United States. The increase in opioid use was steady since the early to mid-1990s in most European countries and it slowed down after the mid- to late 2000s. In Denmark, Finland, France, Ireland, Switzerland, Poland and the EU, opioid use levelled off or declined over most recent years. CONCLUSIONS: Consumption of opioid analgesics sharply increased in most of European countries since the early to mid-1990s. This notwithstanding, in the mid-2010s there was still a more than 10-fold difference between the highest consumption in Western/Northern countries and the lowest one in Southern/Eastern countries. SIGNIFICANCE: This study provides an updated and comprehensive analysis of time trends and geographic variations in opioid consumption use across European countries over the last three decades. PMID- 30407693 TI - Methylglyoxal as a Prognostic Factor in Patients with Chronic Kidney Disease. AB - AIM: Advanced glycation end products and their precursors cause vascular damage through oxidative stress. We investigated the hypothesis that methylglyoxal (MG), 3-deoxyglucosone (3-DG), and pentosidine influence outcomes of chronic kidney disease (CKD) patients. METHODS: We conducted a three-year prospective observational study involving 150 outpatients at CKD stages 3-5. At enrollment, MG, 3-DG, and pentosidine plasma concentrations were measured; patients were divided into tertiles according to the concentration of each substance. The primary endpoint was death, a cardiovascular event, or end-stage renal disease. Survival analysis was performed using the Cox regression model. RESULTS: The patients' mean age was 62 +/- 12 years, 97 were men, and 20 had diabetic nephropathy. The mean estimated glomerular filtration rate was 25.0 +/- 12.1 mL/min/1.73 m2 , which negatively correlated with MG but not with 3-DG and pentosidine. Forty-eight patients reached the primary endpoint. Compared with the lowest MG tertile, the hazard ratio (HR) for the primary endpoint was 7.57 (95% confidence interval [CI]: 1.71-33.54) in the middle tertile and 27.00 (CI: 6.46 112.82) in the highest tertile. When adjusted for characteristics at baseline, the corresponding HRs decreased to 2.09 (CI: 0.37-11.96) and 6.13 (CI: 0.97 38.82), but MG remained an independent risk factor for the primary endpoint. However, 3-DG and pentosidine were not related to the primary outcome. CONCLUSIONS: MG has a close clinical association with CKD. Higher MG concentrations may contribute renal function deterioration in CKD. In CKD patients, MG concentration might be useful when determining the prognosis. This article is protected by copyright. All rights reserved. PMID- 30407694 TI - Detecting the effects of a standardized meal challenge on small bowel motility with MRI in prepared and unprepared bowel. AB - OBJECTIVE: MRI is increasingly used to evaluate small bowel contractility. The objective of this study was to validate a clinically practical stimulation test (300-kcal meal) for small bowel motility. METHODS: Thirty-one healthy subjects underwent dynamic MRI to capture global small bowel motility after +/-10h fasting, of which 15 underwent bowel preparation consisting of 1 L 2.5% mannitol solution and 16 did not. Each subject underwent (1) a baseline motility scan (2) a food challenge (3) a post-challenge scan, and (4) second post-challenge scan (after +/-20 minutes). This protocol was repeated within 2 weeks. Motility was quantified using a validated motility assessment technique. KEY RESULTS: Motility in prepared subjects at baseline was significantly higher than motility in unprepared subjects (0.36 AU vs 0.18 AU, P < 0.001). In the prepared group, the food challenge produced an 8% increase in motility (P = 0.33) while in the unprepared subjects a significant increase of 30% was observed (P < 0.001). Responses to food remained insignificant (P = 0.21) and significant (P = 0.003), for the prepared and unprepared subjects, respectively, +/-20 minutes post food challenge. These results were confirmed in the repeated scan session. CONCLUSION & INFERENCES: A significant response to a 300-kcal meal was measured within 10 minutes in unprepared bowel, supporting the clinical use of this challenge to provoke and assess motility changes. A caloric challenge did not produce an observable increase in motility in mannitol prepared subjects. PMID- 30407695 TI - PODXL promotes gastric cancer progression through interacting with RUFY1 protein. AB - Podocalyxin-like protein (PODXL), a transmembrane glycoprotein with anti-adhesive properties, has been proved to associate with an aggressive tumor phenotype and poor prognosis of several cancers. To elucidate the biological significance of PODXL and its molecular mechanism in gastric cancer (GC), we investigated the expression of PODXL in GC samples, and assessed its effects on biological behaviors and the related signaling pathways in vitro and in vivo. Moreover, the possible and closely interacted partners of PODXL were identified. Our data showed that the protein or mRNA level of PODXL was significantly up-regulated in tissues or serum of GC patients, compared with normal-appearing tissues (NATs) or those of healthy volunteers. Overall survival (OS) curves showed that patients with high PODXL levels in tissues or serum had a worse 5-year OS. In vitro, restoring PODXL expression promoted tumor progression by increasing cell proliferation, colony formation, wound healing, migration and invasion as well as suppressing the apoptosis. Furthermore, the PI3K/AKT, NF-kappaB and MAPK/ERK signaling pathways were activated. Besides, there was a significant positive correlation between PODXL and RUN and FYVE domain containing 1 (RUFY1) expression in tissues or serum. Subsequent mass spectrometry analysis, Co Immunoprecipitation assays and western blot analysis identified PODXL/RUFY1 complexes in GC cells, and silencing RUFY1 expression in GC cells significantly attenuated PODXL-induced phenotypes and their underlying signaling pathways. Our results suggested that PODXL promoted GC progression via a RUFY1-dependent signaling mechanism. New GC therapeutic opportunities through PODXL and targeting the PODXL/RUFY1 complex might improve cancer therapy. This article is protected by copyright. All rights reserved. PMID- 30407696 TI - Mechanisms of spinal cord stimulation for the treatment of pain: Still in the dark after 50 years. AB - BACKGROUND AND OBJECTIVE: Despite the value of spinal cord stimulation (SCS) in treating some patients with focal neuropathic pain, technological advances in stimulator design and treatment protocols have not correlated with significant improvements in clinical outcomes. This may be because incomplete understanding of the mechanisms underlying SCS precludes improvement in clinical efficacy. In this brief review, we (a) review phenomenological effects of SCS, (b) review the literature on proposed spinal sites of action of SCS and (c) propose a novel hypothesis of mechanism of action. RESULTS: Dorsal columns, dorsal roots and dorsal horns have each been proposed as spinal sites of action of SCS. We suggest that evidence in favour of the dorsal columns or dorsal roots as the primary mediators of SCS is weak and propose that the dorsal horn is the crucial site of action. Furthermore, we hypothesize that, based on their location, and neurochemical and morphological properties, dorsal horn islet cells may mediate the effects of SCS. CONCLUSIONS: The precise spinal mechanisms of action of SCS are still unknown. Dorsal horn islet cells have properties that position them to play a key role in analgesic effects of electrical stimulation. Understanding the mechanisms responsible for positive SCS effects are needed for successful translation into clinical dividends. SIGNIFICANCE: We review possible spinal mechanisms of action of spinal cord stimulation for neuropathic pain, proposing that direct modulation of dorsal horn neurons is crucial. We suggest that mechanistic insights are needed for translation into more favourable clinical outcomes. PMID- 30407697 TI - A Ratiometric Fluorescent Probe for Cisplatin: Investigating the Intracellular Reduction of Platinum(IV) Prodrug Complexes. AB - The PtIV prodrug strategy has emerged as an excellent alternative to tackle the problems associated with conventional PtII drug therapy. However, there is a lack of tools to study how this new class of PtIV drugs are processed at the cellular level. Herein, we report the first ratiometric probe for cisplatin detection and use it to investigate PtIV anticancer complexes in biological systems. The probe was able to distinguish between cisplatin and its PtIV derivatives, allowing us to probe the intracellular reduction of PtIV prodrug complexes. The correlation between the amount of active PtII species available after intracellular reduction of PtIV complexes and their cytotoxicity and the role glutathione plays in the reduction of PtIV complexes were investigated. PMID- 30407698 TI - Providing patients visiting emergency departments with useful information using public real time data: A case study based on Italian data. AB - RATIONALE, AIMS, AND OBJECTIVES: Many hospitals provide some type of real time publicly available information about the crowding of the emergency departments (EDs). For example, at the time of writing, the number of patients waiting and in treatment is publicly available for EDs that cover more than half of the Italian population. However, usually, these data do not provide the key information that low-priority patients are seeking, which is the time they might expect to wait before being seen by a doctor. METHODS: In this paper, we reanalyze the prospectively collected public data from the two major EDs of the Friuli Venezia Giulia Italian region, which maintains a web page that provides a real time estimate of the average waiting time of current ED patients. The paper discusses the usefulness of the estimate from the patients' prospective. RESULTS: We point out a flow of the methodology used on web page of the Friuli Venezia Giulia region, and further show that the waiting time of current patients reflects poorly the expected time to treatment of new patients. DISCUSSION: The results suggest that available data should be used to develop and validate ED-specific waiting time prediction models of low-priority patients. The same data could also be used to estimate quantities that might be of interest for EDs resource management. PMID- 30407699 TI - Efficacy of ketogenic diet for pyruvate dehydrogenase complex deficiency. PMID- 30407700 TI - Tumor-derived exosomal proteins as diagnostic biomarkers in non-small cell lung cancer. AB - Accumulating evidence supports a role for exosomal protein in diagnosis. The purpose of this study was to identify the tumor-derived exosomal biomarkers in the serum that improve the diagnostic value in Chinese non-small cell lung cancer (NSCLC) patients. Serum exosomes were isolated from healthy donors (n = 46) and NSCLC patients (n = 125) by ultracentrifugation and were characterized using transmission electron microscopy, qNano, and immunoblotting. Proteomic profiles (by mass spectrometry) revealed multiple differentially expressed proteins in the healthy and NSCLC groups. The exosomal expression levels of alpha-2-HS glycoprotein (AHSG) and extracellular matrix protein 1 (ECM1) increased significantly in the NSCLC patients compared to the healthy group. Alpha-2-HS glycoprotein showed diagnostic values with a maximum area under the receiver operating characteristic curve (AUC) as 0.736 for NSCLC vs healthy individuals (P < .0001) and 0.682 for early stage NSCLC vs healthy individuals (P < .01). Extracellular matrix protein 1 showed the diagnostic capacity with AUC values of 0.683 (P < .001) and 0.656 (P < .05) in cancer and early stage NSCLC compared to healthy individuals. When AHSG was combined with ECM1, the AUCs were 0.795 and 0.739 in NSCLC and early stage patients, respectively. Taken together, the combination of AHSG, ECM1, and carcinoembryonic antigen improved the diagnostic potential of NSCLC. The diagnosis values were AUC of 0.938 for NSCLC and 0.911 for early stage NSCLC vs healthy individuals. Our results suggest that novel proteomic signatures found in serum exosomes of NSCLC patients show potential usefulness as diagnostic tools. PMID- 30407701 TI - Reassessment of clinical implication of pretransplant surgical procedures for pulmonary invasive fungal lesions. AB - Dealing with the recent series of allogeneic hematopoietic stem cell transplantation (allo-SCT) performed this decade, we reassessed the clinical impact of pretransplant surgical procedures (SP) for pulmonary lesions of invasive fungal disease (IFD) on subsequent transplant outcome. We focused on the clinical outcomes of seven patients with pulmonary IFD who underwent segmentectomy (n = 4), lobectomy (n = 2) or abscess incision with drainage only (n = 1), and compared results to those of 21 patients carrying pulmonary IFD who never underwent invasive SP before allo-SCT. The rate of exacerbation of pulmonary lesions by 180 days after allo-SCT did not differ significantly between groups (32.2% vs 42.9%, P = 0.69). Moreover, no significant differences in non relapse mortality (46.4% vs 42.3%, P = 0.93) or overall survival (53.6% vs 30.9%, P = 0.45) at 1 year were evident between groups. These results indicate that pretransplant SP for pulmonary lesions might have no survival benefit under the current antifungal prophylaxis or treatment modality. PMID- 30407702 TI - Successful long-term hematological and immunological reconstitution by autologous cord blood transplantation combined with post-transplant immunosuppression in two children with severe aplastic anemia. AB - aUCBT is a valuable curative option in pediatric patients with refractory idiopathic SAA and no available matched sibling or unrelated donors. Experience in the use of autologous cord blood units in patients with SAA is limited and private for-profit cord blood-banking programs are controversial. We report the successful treatment of two patients with SAA, aged 15 and 24 months, with autologous cord blood combined with immunosuppression. After conditioning with 200 mg/kg cyclophosphamide and ATG, 7.5 mg/kg, 32.2 * 107 /kg, and 3.8 * 107 /kg autologous cord blood nucleated cells were infused, respectively. One of our patients underwent transplantation after failure of IST. Both patients received post-transplant immunosuppression with cyclosporine for 12 months. They remain disease-free 6 years post-transplantation. PMID- 30407703 TI - Upregulation of intestinal mucosal mast cells expressing VPAC1 in close proximity to vasoactive intestinal polypeptide in inflammatory bowel disease and murine colitis. AB - BACKGROUND: Mast cells (MCs) and vasoactive intestinal polypeptide (VIP) have been proposed as regulators of the intestinal barrier and inflammation. Our aim was to map the distribution in inflammatory bowel disease (IBD) and murine colitis. METHODS: MCs, VIP, and VIP-receptors (VPACs) were quantified by immunofluorescence and enzyme-immunoassay (EIA) in ileal tissues (villus epithelium (VE) and adjacent VE, ie, VE next to the follicle-associated epithelium, (FAE)) from Crohn's disease (CD; n = 16) and non-IBD patients, and in colonic specimens of ulcerative colitis (UC; n = 12) and healthy controls (HCs). In addition, VIP levels were measured in plasma from HCs, non-IBD, and IBD in remission (CD n = 30; UC n = 30). Colon, ileum, and plasma from mice with dextran sulfate sodium (DSS)-induced colitis and control mice were analyzed likewise. KEY RESULTS: FAE-adjacent VE in ileum of CD possessed more MCs (P < 0.05) and MCs expressing VPAC1 (P < 0.05), but not VPAC2, compared to controls. Both adjacent and regular VE of CD had more MCs co-localizing/in close proximity to VIP (P < 0.05). In UC colon, more MCs (P < 0.0005), MCs close to VIP (P < 0.0005), and MCs expressing VPAC1 (P < 0.05) were found compared to controls. VIP levels were elevated in plasma from CD and UC compared to controls (P < 0.0005). Colon of DSS mice showed more MCs and MCs close to VIP (P < 0.05) compared to control mice. In vitro experiments revealed MCs expressing VPACs and internalized VIP after 120 minutes of VIP-stimulation. CONCLUSIONS AND INFERENCES: Communication between MCs and VIP is upregulated during IBD and mice colitis. In CD patients, the epithelium next to FAE seems to be more involved than the surrounding VE, suggesting increased MC-VIP-interactions in this intestinal region. PMID- 30407704 TI - What the diabetes data in FOURIER trial fail to show. AB - The FOURIER trial was set up to study the clinical outcomes of evolocumab in patients with hypercholesterolemia and a history of cardiovascular disease that use statins. Diabetes mellitus was an outcome of particular interest, because it is a known serious adverse effect of statins [1]. This article is protected by copyright. All rights reserved. PMID- 30407705 TI - Unnatural Cytosine Bases Recognized as Thymines by DNA Polymerases by the Formation of the Watson-Crick Geometry. AB - The emergence of unnatural DNA bases provides opportunities to demystify the mechanisms by which DNA polymerases faithfully decode chemical information on the template. It was previously shown that two unnatural cytosine bases (termed "M fC" and "I-fC"), which are chemical labeling adducts of the epigenetic base 5 formylcytosine, can induce C-to-T transition during DNA amplification. However, how DNA polymerases recognize such unnatural cytosine bases remains enigmatic. Herein, crystal structures of unnatural cytosine bases pairing to dA/dG in the KlenTaq polymerase-host-guest complex system and pairing to dATP in the KlenTaq polymerase active site were determined. Both M-fC and I-fC base pair with dA/dATP, but not with dG, in a Watson-Crick geometry. This study reveals that the formation of the Watson-Crick geometry, which may be enabled by the A-rule, is important for the recognition of unnatural cytosines. PMID- 30407706 TI - Neurodevelopmental disorders associated with juvenile fibromyalgia. PMID- 30407707 TI - MiR-520b promotes the progression of non-small cell lung cancer through activating Hedgehog pathway. AB - Although the non-small cell lung cancer (NSCLC) is one of the most malignant tumours worldwide, the mechanisms controlling NSCLC tumourigenesis remain unclear. Here, we find that the expression of miR-520b is up-regulated in NSCLC samples. Further studies have revealed that miR-520b promotes the proliferation and metastasis of NSCLC cells. In addition, miR-520b activates Hedgehog (Hh) pathway. Inhibitor of Hh pathway could relieve the oncogenic effect of miR-520b upon NSCLC cells. Mechanistically, we demonstrate that miR-520b directly targets SPOP 3'-UTR and decreases SPOP expression, culminating in GLI2/3 stabilization and Hh pathway hyperactivation. Collectively, our findings unveil that miR-520b promotes NSCLC tumourigenesis through SPOP-GLI2/3 axis and provide miR-520b as a potential diagnostic biomarker and therapeutic target for NSCLC. PMID- 30407708 TI - Receiver operating characteristic analysis to determine optimal fluid management during open colorectal surgery. AB - AIM: The present study aimed to analyse fluid management and to define optimal fluid-related thresholds for elective open colorectal surgery. METHOD: A retrospective analysis was made of all consecutive elective open colorectal resections performed in our tertiary centre between May 2011 and May 2017. The main outcomes were postoperative complications [overall (I-V) and severe (IIIB-V) according to the Clavien classification], respiratory complications and postoperative ileus (POI). Critical thresholds regarding perioperative fluid management and postoperative weight gain were identified by using receiver operator characteristic (ROC) analysis. Independent risk factors for overall complications were identified by multivariable logistic regression analysis. RESULTS: Of 121 patients who had open operations, 84 (69%) had some complication and 26 (21%) had severe complications. Respiratory complications and POI occurred in 15 (12%) and 46 patients (38%), respectively. The thresholds for intravenous fluids were 3.5 l at postoperative day (POD) 0 [area under ROC curve (AUROC) 0.7 for any 0.69 for respiratory complications] and 3.5 kg weight gain at POD 2 (AUROC 0.82 for respiratory complications). Multivariable analysis revealed weight gain of > 3.5 kg at POD 2 (OR 5.9; 95% CI 1.3-16.6) as a significant risk factor for overall complications. Acute kidney injury was observed in five patients (4%), three (5%) in the group with > 3.5 l at POD 0 and two (3%) in the group with < 3.5 l at POD 0 (P = 0.64). Creatinine increase was transitory and all patients regained baseline levels before discharge. CONCLUSION: A weight gain of > 3.5 kg at POD 2 has been identified as the critical threshold for overall and respiratory complications and prolonged length of stay after open elective colorectal surgery. PMID- 30407709 TI - Prevalence and progression of diabetic nephropathy in South Asians, White Europeans and Afro-Caribbeans with Type 2 diabetes; a systematic review and meta analysis. AB - INTRODUCTION: Diabetic nephropathy remains the most common cause of renal disease in patients diagnosed with type 2 diabetes. AIMS: We conducted a systematic review and meta-analysis of published observational evidence to assess the difference in the prevalence and progression of diabetic nephropathy, and the development of end-stage renal failure in three ethnicities with type 2 diabetes. METHODS: Relevant studies were identified in a literature search of MEDLINE, EMBASE, and reference lists of relevant studies to May 2018. We decided a priori that there were no differences in the prevalence and progression of diabetic nephropathy, and the development of end-stage renal failure in the three ethnicities with type 2 diabetes. Pooled relative risks of microalbuminuria by ethnicity were estimated by fitting three random effects meta-analyses models. A narrative synthesis of the nephropathy progression in the studies was done. The review was registered on PROSPERO (registration number CRD42018107350). RESULTS: Thirty-two studies with data on 153,827 unique participants were eligible. The pooled prevalence ratio of microalbuminuria in South Asian compared to White Europeans was 1.14 (95% CI: 0.99, 1.32 p=0.065). For African Caribbeans vs South Asians the pooled prevalence ration was 1.08 (95% CI: 0.93, 1.24), p=0.327. Results surrounding renal decline were inconsistent with preponderance towards a high rate of disease progression in South Asians compared to White Caucasians. The estimated pooled incident rate ratio for end stage renal disease was significantly higher in African Caribbeans vs White Europeans 2.75 (95% CI: 2.01, 3.48 p<0.001) CONCLUSION: This review did not find a significant link between ethnicity (South Asians, White Europeans and Afro-Caribbeans) and the prevalence of microalbuminuria. However, the incident rate ratio of end stage renal disease in African Caribbeans compared to White Europeans was significantly higher. Further research is needed to explore the potential non-albuminuric pathways of progression to end stage renal failure. This article is protected by copyright. All rights reserved. PMID- 30407710 TI - A Desymmetrization-Based Total Synthesis of Reserpine. AB - Reported herein is a desymmetrization-based synthetic approach to the fused polycyclic indole alkaloid reserpine. The centerpiece of the developed strategy features an internal desymmetrization process that enabled the use of a readily accessible and nonstereogenic reserpine E-ring precursor, in contrast to the synthesis-intensive and stereodefined E-ring intermediates employed in all past reserpine syntheses. Utilization of inexpensive reagents through an orchestrated sequence of carefully selected chemical transformations further highlight the overall effectiveness of the developed pathway. PMID- 30407711 TI - Association of Psychosocial Factors with Leukocyte Telomere Length among African Americans in the Jackson Heart Study. AB - Leukocyte telomere length (LTL) is a biomarker of cellular aging. African Americans report more stress than other groups; however, the association of psychosocial stressors with biological aging among African Americans remains unclear. The current study evaluated the association of psychosocial factors (negative affect and stressors) with LTL in a large sample of African American men and women (n=2,516) from the Jackson Heart Study (JHS). Using multivariable linear regression, we examined the sex-specific associations of psychosocial factors (cynical distrust, anger-in and -out, depressive symptoms, negative affect summary scores, global stress, weekly stress, and major life events-MLEs, and stress summary scores) with LTL. Model 1 adjusted for demographics and education. Model 2 adjusted for model 1, smoking, alcohol intake, physical activity, diabetes, hypertension, and high-sensitivity C-reactive protein (hsCRP). Among women, high (vs. low) cynical distrust was associated with shorter mean LTL in model 1 (b = -0.12; p=0.039). Additionally, high (vs. low) anger-out and expressed negative affect summary scores were associated with shorter LTL among women after full adjustment (b = -0.13; p=0.011; b = -0.12, p=0.031, respectively). High levels of cynical distrust, anger out and negative affect summary scores may be risk factors for shorter LTL, particularly among African American women. PMID- 30407712 TI - Ordered Mesoporous C3 N5 with a Combined Triazole and Triazine Framework and Its Graphene Hybrids for the Oxygen Reduction Reaction (ORR). AB - Mesoporous carbon nitrides (MCN) with C3 N4 stoichiometry could find applications in fields ranging from catalysis, sensing, and adsorption-separation to biotechnology. The extension of the synthesis of MCN with different nitrogen contents and chemical structures promises access to a wider range of applications. Herein we prepare mesoporous C3 N5 with a combined triazole and triazine framework via a simple self-assembly of 5-amino-1H-tetrazole (5-ATTZ). We are able to hybridize these nanostructures with graphene by using graphene mesoporous-silica hybrids as a template to tune the electronic properties. DFT calculations and spectroscopic analyses clearly demonstrate that the C3 N5 consists of 1 triazole and 2 triazine moieties. The triazole-based mesoporous C3 N5 and its graphene hybrids are found to be highly active for oxygen reduction reaction (ORR) with a higher diffusion-limiting current density and a decreased overpotential than those of bulk g-C3 N4 . PMID- 30407713 TI - Hybridisation-based target enrichment of phenology genes to dissect the genetic basis of yield and adaptation in barley. AB - Barley (Hordeum vulgare L.) is a major cereal grain widely used for livestock feed, brewing malts and human food. Grain yield is the most important breeding target for genetic improvement and largely depends on optimal timing of flowering. Little is known about the allelic diversity of genes that underlie flowering time in domesticated barley, the genetic changes that have occurred during breeding, and their impact on yield and adaptation. Here, we report a comprehensive genomic assessment of a worldwide collection of 895 barley accessions based on the targeted resequencing of phenology genes. A versatile target-capture method was used to detect genome-wide polymorphisms in a panel of 174 flowering time-related genes, chosen based on prior knowledge from barley, rice and Arabidopsis thaliana. Association studies identified novel polymorphisms that accounted for observed phenotypic variation in phenology and grain yield, and explained improvements in adaptation as a result of historical breeding of Australian barley cultivars. We found that 50% of genetic variants associated with grain yield, and 67% of the plant height variation was also associated with phenology. The precise identification of favourable alleles provides a genomic basis to improve barley yield traits and to enhance adaptation for specific production areas. PMID- 30407714 TI - Biodegradable Nerve Guidance Conduit with Microporous and Micropatterned Poly(lactic-co-glycolic acid)-Accelerated Sciatic Nerve Regeneration. AB - An innovative technique combining capillary force lithography and phase separation method in one step is applied to fabricate artificial nerve guidance conduit (NGC) for peripheral nerve regeneration. Biodegradable porous, patterned NGC (PP-NGC) using poly(lactic-co-glycolic acid) is fabricated. It has micro grooves and microporosity on the inner surface to promote axonal outgrowth and to enhance permeability for nutrient exchange. In this study, it is confirmed that the inner surface of micro-grooves can modulate neurite orientation and length of mouse neural stem cell compared to porous flat NGC (PF-NGC) in vitro. Coating with 3,4-dihydroxy-l-phenylalanine (DOPA) facilitates the hydrophilic inner surface of PF- and PP-NGCs via bioinspired catechol chemistry. For in vivo study, PF-NGC and PP-NGC coated with or without DOPA are implanted in the 10 mm sciatic nerve defect margins between proximal and distal nerves in rats. Especially, PP NGC coated with DOPA shows higher sciatic function index score, onset-to-peak amplitude, and muscle fiber diameter compared to other groups. The proposed hybrid-structured NGC not only can serve as a design for functional NGC without growth factor but also can be used in clinical application for peripheral nerve regeneration. PMID- 30407715 TI - MORC2 promotes development of an aggressive colorectal cancer phenotype through inhibition of NDRG1. AB - MORC2 (microrchidia family CW-type zinc finger 2) is a newly identified chromatin remodeling protein that functions in diverse biological processes including gene transcription. NDRG1 is a metastasis suppressor and a prognostic biomarker for colorectal cancer (CRC). However, the relationship between MORC2 and NDRG1 transcriptional regulation and the roles of MORC2 in CRC remain elusive. Here, we showed that MORC2 down-regulated NDRG1 mRNA, protein levels and promoter activity in CRC cells. We also found that MORC2 bound to the -446~-213bp region of the NDRG1 promoter. Mechanistically, histone deacetylase SIRT1 was involved in NDRG1 transcriptional regulation. MORC2 was able to interact with SIRT1 and inhibit NDRG1 promoter activity cumulatively with SIRT1. MORC2 overexpression led to a decreasement of H3Ac and H4Ac of the NDRG1 promoter. Importantly, we demonstrated that NDRG1 was essential in MORC2-mediated promotion of CRC cell migration and invasion in vitro, as well as lung metastasis of CRC cells in vivo. Moreover, MORC2 expression correlated negatively with NDRG1 expression in CRC patients. High expression of MORC2 was significantly associated with lymph node metastasis (p=0.019) and poor pTNM stage (p=0.02) and the expression of MORC2 correlated with poor prognosis in colon cancer patients. Our findings thus contribute to the knowledge of the regulatory mechanism of MORC2 in down-regulating NDRG1, and suggest MORC2 as a potential therapeutic target for CRC. This article is protected by copyright. All rights reserved. PMID- 30407716 TI - N1 lateralization and dyslexia: An event-related potential study in children with a familial risk of dyslexia. AB - The rapid automatic specialized processing of printed words is signalled by the left-lateralization of the N1 component in the visual event-related potential (ERP). In the present study, we have investigated whether differences in N1 lateralization can be observed between Dutch children with and without (a familial risk of) dyslexia around the age of 12 years using a linguistic judgement task. Forty-five participants were included in the ERP analysis, 18 in the low familial risk group without dyslexia, 15 in the high familial risk group without dyslexia, and 12 in the high familial risk group with dyslexia. The results showed that although the N1 peaked slightly earlier in the left hemisphere, the N1 amplitude was right-lateralized in all groups. Moreover, there were no group differences in N1 amplitude or latency, and there was no relationship between reading (related) test scores and N1 characteristics. The results of the present study and our previous findings in adults suggest that print-tuning lateralization is a process that is still developing in adolescence. Because other studies did find N1 lateralization in younger readers with a print versus nonprint contrast, the current results seem to indicate that differences in N1 lateralization also depend on the experimental paradigm. PMID- 30407717 TI - Resequencing of cv CRI-12 family reveals haplotype block inheritance and recombination of agronomically important genes in artificial selection. AB - Although efforts have been taken to exploit diversity for yield and quality improvements, limited progress on using beneficial alleles in domesticated and undomesticated cotton varieties is limited. Given the complexity and limited amount of genomic information since the completion of four cotton genomes, characterizing significant variations and haplotype block inheritance under artificial selection has been challenging. Here we sequenced Gossypium hirsutum L. cv CRI-12 (the cotton variety with the largest acreage in China), its parental cultivars, and progeny cultivars, which were bred by the different institutes in China. In total, 3.3 million SNPs were identified and 118, 126 and 176 genes were remarkably correlated with Verticillium wilt, salinity and drought tolerance in CRI-12, respectively. Transcriptome-wide analyses of gene expression, and functional annotations, have provided support for the identification of genes tied to these tolerances. We totally discovered 58 116 haplotype blocks, among which 23 752 may be inherited and 1029 may be recombined under artificial selection. This survey of genetic diversity identified loci that may have been subject to artificial selection and documented the haplotype block inheritance and recombination, shedding light on the genetic mechanism of artificial selection and guiding breeding efforts for the genetic improvement of cotton. PMID- 30407718 TI - Safety of catheter-based radiofrequency renal denervation on branch renal arteries in a porcine model. AB - OBJECTIVES: We aimed to investigate the safety of radiofrequency (RF)-renal denervation (RDN) on branch renal arteries (RAs) in a porcine model. BACKGROUND: The efficacy of RF-RDN was enhanced by treatment of the branch RA, in addition to the main RA. However, there are concerns regarding the safety of RF-RDN on branch RA because of their smaller diameter and proximity to the kidney. METHODS: RF was delivered to 24 RA from 12 swine. A total of 8 RA from 4 swine were untreated. Treated RA were examined by angiography and histopathology at 7, 30, and 90 days. Serum creatinine concentration, biophysical parameters during RF delivery, and renal norepinephrine concentration were also assessed. RESULTS: Angiography revealed minimal late lumen loss and diameter stenosis in the main and branch RA at any time point. There was no change in serum creatinine after RF-RDN. Histopathologically, no augmentation of medial damage or neointimal formation was found in branch RA compared with main RA. No or minimal damage to surrounding tissues including the kidneys, ureters, lymph nodes, and muscles was observed at any time point in both the main and branch RA. Equivalent electrode temperature in the main and branch RA was achieved by automatic adjustment of output power by the generator. The renal norepinephrine concentration was significantly lower in the treated group compared with the untreated group. CONCLUSIONS: RF-RDN on branch RA was safe in a porcine model, with stenosis-free healing of treated arteries and negligible kidney damage at 7, 30, and 90 days. PMID- 30407719 TI - NMR characterization of long-range contacts in intrinsically disordered proteins from paramagnetic relaxation enhancement in 13C direct-detected experiments. AB - Intrinsically disordered proteins (IDPs) carry out many biological functions. They lack a stable 3D structure and are able to adopt many different conformations in dynamic equilibrium. The interplay between local dynamics and global rearrangements is key for their function. A widely used NMR experimental approach to study long-range contacts in IDPs exploits paramagnetic effects and 1H detected experiments are generally used to determine paramagnetic relaxation enhancement (PRE) for amide protons. However, under physiological conditions exchange broadening hampers the detection of solvent exposed amide protons reducing the content of information available. Here we present an experimental approach based on direct carbon detection of PRE that provides improved resolution, reduced sensitivity to exchange broadening and complementary information deriving from the use of different starting polarization sources. PMID- 30407720 TI - A Qualitative Study of Women's Recall of Content and Skills Developed in Group Prenatal and Well-Baby Care 2 Years Later. AB - INTRODUCTION: Group prenatal and well-baby care is a system of health care visits that occur in a group setting. Each individual session lasts approximately 2 hours, allowing more time for education and support than can occur in an individual visit. Compared with individual care, research suggests that group care is associated with similar or better short-term outcomes, but no studies have yet examined potential long-term benefits beyond one year postpartum. The purpose of this qualitative descriptive study was to elicit women's recall about content covered in group prenatal and well-baby care and whether they were or were not continuing to use skills discussed during group prenatal and well-baby care 2 or more years after their group ended. METHODS: Eligible women participated in group prenatal and/or well-baby care between 2008 and 2012, were aged at least 18 years, and were English-speaking. Of the 127 eligible women, 32 were reached and 17 agreed to participate. Women were interviewed on average 3 years after group prenatal or well-baby care ended using a semistructured interview guide. Transcripts were reviewed and coded by each team member. Final codes and themes were identified using an iterative review process among the research team. RESULTS: Three themes were identified: sustained change, transferable skills, and group as a safe haven. All women were still using strategies discussed during group and had made sustained improvements in nutrition, stress management, and/or in the quality of their interactions with their children, partner, or families. The group environment was described as a safe haven: a respectful, nonjudgmental space that allowed women to share and support each other while learning new skills. DISCUSSION: This is the first study to document that group prenatal and well-baby care is associated with long-term benefits in areas not yet reported in the literature: nutrition, family communication, and parenting. PMID- 30407721 TI - How low can you go? Estimating impacts of reduced pesticide use. AB - Recent research has suggested that a high proportion of farms can dramatically reduce pesticide applications without reducing crop yields or farm profits. Yet this research has made estimation choices that may systematically bias downwards estimates of the productivity and profitability of pesticides. Fifty years of agricultural economics research provides lessons about how to avoid pitfalls in estimating pesticide productivity. Carefully done econometric studies have found evidence of overuse, underuse, and near-optimal use of pesticides in different cropping systems. There are now standard methods to test and correct for sources of biases (either upward or downward) in estimates of pesticide productivity. Ignoring these lessons and methods can seriously bias estimates of the potential for reducing pesticide use at little or no economic cost. This article is protected by copyright. All rights reserved. PMID- 30407723 TI - The behavior of polyetheretherketone healing abutments when measuring implant stability with electronic percussive testing. AB - BACKGROUND: It is unknown whether it is possible to measure implant stability with polyetheretherketone (PEEK) healing abutments using electronic percussive testing (EPT). PURPOSE: To investigate the reliability of the percussive test values (PTVs) measured with PEEK healing abutments and to compare them with the PTVs measured with titanium healing abutments. MATERIAL AND METHODS: Thirty dental implants were inserted into the fresh pelvis belonging to a cow. Titanium healing abutments (2 and 5 mm), PEEK healing abutments (5 mm), and prepable standard titanium abutments (5 mm) were screwed to the implants, respectively, and PTVs were measured by two examiners using a wireless EPT device. Differences in PTVs between different dental implant components were evaluated using Friedman's test with post hoc Wilcoxon signed-rank test and Bonferroni correction. Inter and intra-observer reliabilities were detected using interclass correlation coefficients (ICCs) RESULTS: The mean PTVs obtained using the PEEK healing abutments were significantly higher than the mean PTVs obtained using the other abutments for both examiners (P < .01). The ICCs for intra-observer reliability were detected as poor for PEEK healing abutments; and excellent for the other abutment types for both examiners. The ICCs for the inter-observer reliability between the two examiners were poor (0.25) for PEEK healing abutments, and excellent for the 2 and 5 mm titanium healing abutments and for standard abutments (0.82, 0.84 and 0.93, respectively). CONCLUSION: Within the limitations of this in vitro study, it may be concluded that EPT measurements should be avoided using PEEK healing abutments because of the poor reliability. PMID- 30407722 TI - College students' daily coping, mood, and quality of life: Benefits of problem focused engagement. AB - In this short communication, we investigated the relations of daily coping, mood, and quality of life in college students (n = 74) over seven consecutive days (n = 510). Specifically, we tested whether four types of daily coping (problem-focused engagement, problem-focused disengagement, emotion-focused engagement, and emotion-focused disengagement) were associated with three aspects of daily functioning (negative mood, positive mood, and quality of life). In a single multilevel multivariate regression model, we examined the day-to-day relations of the four coping strategies with mood and quality of life, while controlling for perceived stress. Results largely supported our hypotheses, such that problem focused engagement was linked to lower negative mood and higher positive mood and quality of daily life, whereas the three other types of coping were negatively related or unrelated to daily functioning. These findings provide support for the benefits of problem-focused engagement in coping with everyday stressors of life as a college student, and implications for psychotherapy and counselling are discussed. PMID- 30407724 TI - An evaluation of the effects of makeup on perceived age based on skin color in Korean women. AB - BACKGROUND: Makeup has been shown to increase women's attractiveness, perceived femininity, and self-confidence and reduce their perceived age. Some of these results were caused by facial contrast and visible skin color. However, they did not investigate makeup benefit by focusing skin color change. OBJECTIVES: We investigated the benefit of makeup in reducing perceived age by focusing on only skin color, based on the age-related changes in several skin color parameters (mean, standard deviation, skewness, and kurtosis), and attempted to discover the indications for youthful-looking skin color. METHODS: A total of 174 Korean women aged 20-69 years participated in this study. Their digital facial images were cropped on the cheek area, standard Red green Blue data were transformed to Quasi L*a*b*, and the statistical parameters of individual Quasi-L*a*b* data were calculated. Fourteen volunteers aged 30-45 years wore liquid-type makeup. The perceived age was assessed by 11 clinical evaluation researchers with a LCD monitor. The statistical analysis was performed using SPSS version 23.0, with a significance level of P < 0.05. RESULTS: According to a multiple regression analysis, unevenness in skin color, skin lightness, and skewness in skin yellowness significantly affected the participants' perceived age; the most important factor was the unevenness in skin yellowness in Korean women. The evaluated and calculated with the regression equation perceived age were decreased after makeup was applied. CONCLUSIONS: The makeup can reduce women's perceived age by correcting the skin's color, and it can show youthful skin properties such as a lighter and more homogenous color with less chroma. PMID- 30407725 TI - Kinase activity of SOBIR1 and BAK1 is required for immune signalling. AB - Leucine-rich repeat-receptor-like proteins (LRR-RLPs) and LRR-receptor-like kinases (LRR-RLKs) trigger immune signalling to promote plant resistance against pathogens. LRR-RLPs lack an intracellular kinase domain, and several of these receptors have been shown to constitutively interact with the LRR-RLK Suppressor Of BIR1-1/EVERSHED (SOBIR1/EVR) to form signalling-competent receptor complexes. Ligand perception by LRR-RLPs initiates recruitment of the co-receptor BRI1 Associated Kinase 1/Somatic Embryogenesis Receptor Kinase 3 (BAK1/SERK3) to the LRR-RLP/SOBIR1 complex, thereby activating LRR-RLP-mediated immunity. We employed phosphorylation analysis of in planta-produced proteins, live-cell imaging, gene silencing, and co-immunoprecipitation to investigate the roles of SOBIR1 and BAK1 in immune signalling. We show that Arabidopsis thaliana (At) SOBIR1, which constitutively activates immune responses upon its overexpression in planta, is highly phosphorylated. Moreover, in addition to kinase activity of SOBIR1 itself, kinase-active BAK1 is essential for AtSOBIR1-induced constitutive immunity and for the phosphorylation of AtSOBIR1. Furthermore, the defence response triggered upon perception of Avr4, from the extracellular pathogenic fungus Cladosporium fulvum, by the tomato LRR-RLP Cf-4, depends on kinase-active BAK1. We argue that, besides trans-autophosphorylation of SOBIR1, it is likely that SOBIR1 and BAK1 transphosphorylate, and thereby activate the receptor complex. The signalling competent cell surface receptor complex subsequently activates downstream cytoplasmic signalling partners to initiate RLP-mediated immunity. This article is protected by copyright. All rights reserved. PMID- 30407727 TI - ETP-ALL with aberrant B marker expression: Case series and a brief review of literature. PMID- 30407726 TI - Sodium-glucose cotransporter 2 inhibitors regulate ketone body metabolism via inter-organ crosstalk. AB - AIM: To investigate sodium-glucose cotransporter 2 inhibitor (SGLT2i)-induced changes in ketogenic enzymes and transporters in normal and diabetic mice models. MATERIALS AND METHODS: Normal mice were randomly assigned to receive either vehicle or SGLT2i (25 mg/kg/d by oral gavage) for 7 days. Diabetic mice were treated with vehicle, insulin (4.5 units/kg/d by subcutaneous injection) or SGLT2i (25 mg/kg/d by intra-peritoneal injection) for 5 weeks. Serum and tissues of ketogenic organs were analysed. RESULTS: In both normal and diabetic mice, SGLT2i increased beta-hydroxybutyrate (BHB) content in liver, kidney and colon tissue, as well as in serum and urine. In these organs, SGLT2i upregulated mRNA expression of ketogenic enzymes, 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 and 3-hydroxy-3-methylglutaryl-coenzyme A lyase. Similar patterns were observed in the kidney, ileum and colon for mRNA and protein expression of sodium dependent monocarboxylate transporters (SMCTs), which mediate the cellular uptake of BHB and butyrate, an important substrate for intestinal ketogenesis. In diabetic mice under euglycaemic conditions, SGLT2i increased major ketogenic enzymes and SMCTs, while insulin suppressed ketogenesis. CONCLUSIONS: SGLT2i increased systemic and tissue BHB levels by upregulating ketogenic enzymes and transporters in the liver, kidney and intestine, suggesting the integrated physiological consequences for ketone body metabolism of SGLT2i administration. PMID- 30407728 TI - gamma-secretase inhibitor DAPT mitigates cisplatin-induced acute kidney injury by suppressing Notch1 signaling. AB - Organ toxicity, including kidney injury, limits the use of cisplatin for the treatment of multiple human cancers. Hence, interventions to alleviate cisplatin induced nephropathy are of benefit to cancer patients. Recent studies have demonstrated that pharmacological inhibition of the Notch signaling pathway enhances cisplatin efficacy against several cancer cells. However, whether augmentation of the anti-cancer effect of cisplatin by Notch inhibition comes at the cost of increased kidney injury is unclear. We show here that treatment of mice with cisplatin resulted in a significant increase in Notch ligand Delta-like 1 (Dll1) and Notch1 intracellular domain (N1ICD) protein expression levels in the kidneys. N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a gamma-secretase inhibitor reversed cisplatin-induced increase in renal N1ICD expression and plasma or urinary levels of predictive biomarkers of acute kidney injury (AKI). DAPT also mitigated cisplatin-induced tubular injury and reduction in glomerular filtration rate. Real-time multiphoton microscopy revealed marked necrosis and peritubular vascular dysfunction in the kidneys of cisplatin-treated mice which were abrogated by DAPT. Cisplatin-induced Dll1/Notch1 signaling was recapitulated in a human proximal tubule epithelial cell line (HK-2). siRNA-mediated Dll1 knockdown and DAPT attenuated cisplatin induced Notch1 cleavage and cytotoxicity in HK-2 cells. These data suggest that Dll1-mediated Notch1 signaling contributes to cisplatin-induced AKI. Hence, the Notch signaling pathway could be a potential therapeutic target to alleviate renal complications associated with cisplatin chemotherapy. PMID- 30407729 TI - Radiofrequency ablation of osteoid osteoma: Aiming for excellent outcomes in an Australasian context. AB - INTRODUCTION: To report a series of patients with osteoid osteoma treated by radiofrequency ablation in whom no complications or recurrences occurred. METHODS: Over a 13-year period, 32 consecutive patients with osteoid osteoma were treated by radiofrequency ablation in an Australasian teaching centre. RESULTS: All patients had resolution of symptoms with no complication or recurrence. CONCLUSIONS: This series is further evidence for the use of radiofrequency ablation as the primary treatment for osteoid osteoma. PMID- 30407730 TI - Heterotrimeric G-protein-dependent proteome and phosphoproteome in unstimulated Arabidopsis roots. AB - The G-protein complex is a cytoplasmic on-off molecular switch that is set by plasma membrane receptors that activate upon binding of its cognate extracellular agonist. In animals, the default setting is the "off" resting state, while in plants, the default state is constitutively "on" but repressed by a plasma membrane receptor-like protein. De-repression appears to involve specific phosphorylation of key elements of the G-protein complex and possibly target proteins that are positioned downstream of this complex. To address this possibility, we quantified protein abundance and phosphorylation state in wild type and G-protein deficient Arabidopsis roots in the unstimulated resting state. A total of 3,246 phosphorylated and 8,141 non-modified protein groups were identified. We found that 428 phosphorylation sites decreased and 509 sites increased in abundance in the G-protein quadrupole mutant lacking an operable G protein-complex. Kinases with known roles in G-protein signaling including MAP KINASE 6 and FERONIA were differentially phosphorylated along with many other proteins now implicated in the control of G-protein signaling. Taken together, these datasets will enable the discovery of novel proteins and biological processes dependent on G-protein signaling. This article is protected by copyright. All rights reserved. PMID- 30407731 TI - Biofilm Induced Profiles of Immune Response Gene Expression by Oral Epithelial Cells. AB - OBJECTIVE: This study examined the oral epithelial immunotranscriptome response patterns modulated by oral bacterial planktonic or biofilm challenge METHODS: We assessed gene expression patterns when epithelial cells were challenged with a multispecies biofilm composed of S. gordonii, F. nucleatum, and P. gingivalis representing a type of periodontopathic biofilm compared to challenge with the same species of planktonic bacteria RESULTS: Of the 579 human immunology genes, a substantial signal of the epithelial cells was observed to 181 genes. Biofilm challenged stimulated significant elevations compared to planktonic bacteria for IL32, IL8, CD44, B2M, TGFBI, NFKBIA, IL1B, CD59, IL1A, CCL20 representing the top 10 signals comprising 55% of the overall signal for the epithelial cell responses. Levels of PLAU, CD9, IFITM1, PLAUR, CD24, TNFSF10, and IL1RN were all elevated by each of the planktonic bacterial challenge versus the biofilm responses. While the biofilms upregulated 123/579 genes (>2-fold), fewer genes were increased by the planktonic species [36 (S. gordonii), 30 (F. nucleatum), 44 (P. gingivalis)] CONCLUSIONS: A wide array of immune genes were regulated by oral bacterial challenge of epithelial cells that would be linked to the local activity of innate and adaptive immune response components in the gingival tissues. Incorporating bacterial species into a structured biofilm dramatically altered the number and level of genes expressed. Additionally a specific set of genes were significantly decreased with the multispecies biofilms suggesting that some epithelial cell biologic pathways are down-regulated when in contact with this type of pathogenic biofilm. This article is protected by copyright. All rights reserved. PMID- 30407732 TI - Endovascular therapy in acute basilar artery occlusion: A retrospective single centre Australian analysis. AB - INTRODUCTION: Stroke caused by basilar artery occlusion (BAO) is a rare but potentially devastating neurological condition, with poor outcomes and high mortality rates, approaching 70-90%. Success of intravenous and intra-arterial thrombolysis in BAO is variable, leading to Endovascular Therapy (EVT) being utilized to a greater degree in this clinical setting. We investigate the use of EVT in BAO with regard to success of revascularization and patient mortality/outcome. METHODS: Retrospective patient data was collected from medical records and radiology information systems. RESULTS: Twenty-eight patients underwent EVT for BAO between 2010-17, with successful revascularization in 21/28 (75%) and an inpatient mortality rate of 39%. Successful revascularization correlated with lower mortality (P = 0.0001). Better revascularization and mortality rates occurred between 2013-17 (P = 0.007, 0.04). An average time to EVT of 16.8 hours was observed between 2010-17 but this did not correlate significantly with increased mortality. Basilar stenting correlated with lower revascularization, higher mortality and basilar artery reocclusion post EVT (P = 0.021, 0.022, 0.022). EVT times over 2 and 2.5 hours respectively associated with lower revascularization rates and higher mortality (P = 0.04, 0.022). Higher mortality was seen with intra-procedural complications and symptomatic intracranial haemorrhage, non-posterior circulation infarction and basilar artery reocclusion post EVT (P = 0.016, 0.03, 0.016, 0.016). Basilar atheroma correlated with intra-procedural complications and EVT times over 2 hours (P = 0.038, 0.004). CONCLUSION: Within the limitations of an underpowered study, we observed a benefit of EVT in acute BAO. With future multicentre trials, EVT will likely become the standard of care in acute BAO. PMID- 30407733 TI - Automatic computer-aided analysis of optic disc pallor in fundus photographs. AB - PURPOSE: Assessment of optic disc pallor in fundus photographs may be frequently misinterpreted due to the subjective nature of interpretation. We developed a fully automatic computer-aided detection (CAD) system for optic disc pallor using colour fundus photographs and evaluated the accuracy of the system. METHODS: A newly proposed CAD system was developed for automated segmentation and image analysis of optic disc pallor, and a logistic regression model was developed for risk analysis. A total of 230 photographs with variable degree of optic disc pallor, and 123 normal optic discs confirmed by optical coherence tomography were tested for validation of the software. Sensitivity and specificity of the CAD system in automatic detection of optic disc pallor using colour fundus photographs were evaluated. The results of manual detection of optic disc pallor on fundus photographs by two independent ophthalmologists were compared with the efficacy of the CAD system. RESULTS: The fully automated CAD system achieved a sensitivity of 95.3% and a specificity of 96.7% for detecting optic disc pallor in colour fundus images. The overall accuracy of the CAD system was 96.1%, which was superior to the results of manual detection by individual examiners. CONCLUSIONS: We developed an automated CAD system that successfully detected optic disc pallor in fundus photographs. The proposed algorithm can assist the clinical judgement of ophthalmologists for detecting optic disc pallor in fundus photographs. PMID- 30407734 TI - Human Milk Oligosaccharides Increase Mucin Expression in Experimental Necrotizing Enterocolitis. AB - SCOPE: Necrotizing enterocolitis (NEC) is a leading cause of morbidity and death in preterm infants, occurring more often in formula-fed than breastfed infants. Studies in both rats and humans show that human milk oligosaccharides (HMOs) lower the incidence of NEC, but the mechanism underlying such protection is currently unclear. METHODS AND RESULTS: Here by extracting HMOs from pooled human breastmilk, we investigated the impact of HMOs on the intestinal mucin levels in a murine model of NEC. To confirm the results, we validated the findings by exposing human intestinal epithelial cells and intestinal organoids to HMOs and evaluated for mucin expression. HMO-gavage to pups increased Muc2 levels and decreased intestinal permeability to macromolecular dextran. HMO-treated cells have increased Muc2 expression, decreased bacterial attachment and dextran permeability during challenge by enteric pathogens. To identify the mediators involved in HMO induction of mucins, we demonstrate HMOs directly induce the expression of chaperone proteins including protein disulfide isomerase (PDI). Suppression of PDI activity removes the protective effects of HMOs on barrier function in vitro as well as NEC protection in vivo. CONCLUSIONS: Taken together, our results provide insights to the possible mechanisms by which HMOs protect the neonatal intestine through upregulation of mucins. This article is protected by copyright. All rights reserved. PMID- 30407735 TI - Efficient Delivery of Tyrosinase Related Protein-2 (TRP2) Peptides to Lymph Nodes using Serum-Derived Exosomes. AB - Exosomes (EXO) are considered to be versatile carriers for biomolecules; however, the delivery of therapeutic peptides using EXOs poses several challenges. In this study, the efficiency of serum-derived EXOs in delivering tyrosinase-related protein-2 (TRP2) peptides to lymph nodes is determined. TRP2 peptides are successfully incorporated into EXOs, which show a uniform and narrow size distribution of around 45 nm. The TRP2-incorporated exosomes (EXO-TRP2) are efficiently internalized into macrophages and dendritic cells, and are seen to display a punctate distribution. EXOs loaded with TRP2 together with MPLA, (EXO MPLA-TRP2) result in a strong release of proinflammatory cytokines (TNF-alpha and IL-6) from both RAW264.7 and DC2.4 cells. Finally, subcutaneous injection of fluorescently labeled EXO-TRP2 followed by ex vivo imaging using in vivo imaging system (IVIS) show a strong fluorescent signal in the lymph nodes after only 1 h, which is maintained until at least 4 h after injection. Taken together, the findings suggest that serum-derived EXOs can serve as promising carriers to deliver therapeutic peptides to lymph nodes for immunotherapy. PMID- 30407736 TI - Development of angiosarcoma in a mediastinal non-seminomatous germ cell tumor that exhibited growing teratoma syndrome during chemotherapy. AB - Herein, we report a case of an angiosarcoma in a mediastinal non-seminomatous germ cell tumor that exhibited growing teratoma syndrome during chemotherapy. A 26-year-old man presented with a giant anterior mediastinal mass, which was diagnosed as a non-seminomatous germ cell tumor. The patient was administered three cycles of chemotherapy (bleomycin, etoposide, and cisplatin), but the mass grew despite normalization of tumor markers. Massive bleeding during thoracic surgery resulted in incomplete resection, and the mass was clinically and pathologically diagnosed as growing teratoma syndrome (only mature teratoma). The residual mass continued to grow, and complete resection was subsequently achieved after a detailed analysis of its vascular anatomy using angiography. The final pathological findings revealed angiosarcoma, which indicated a rare somatic type of mediastinal non-seminomatous germ cell tumor. PMID- 30407737 TI - Exploring macrophage cell therapy on Diabetic Kidney Disease. AB - Alternatively activated macrophages (M2) have regenerative properties and shown promise as cell therapy in chronic kidney disease. However, M2 plasticity is one of the major hurdles to overcome. Our previous studies showed that genetically modified macrophages stabilized by neutrophil gelatinase-associated lipocalin (NGAL) were able to preserve their M2 phenotype. Nowadays, little is known about M2 macrophage effects in diabetic kidney disease (DKD). The aim of the study was to investigate the therapeutic effect of both bone marrow-derived M2 (BM-fM2) and f-NGAL macrophages in the db/db mice. Seventeen-week-old mice with established DKD were divided into five treatment groups with their controls: D+BM-fM2; D+f BM; D+f-NGAL; D+f-RAW; D+SHAM and non-diabetic (ND) (db/- and C57bl/6J) animals. We infused 1 * 106 macrophages twice, at baseline and 2 weeks thereafter. BM-fM2 did not show any therapeutic effect whereas f-NGAL significantly reduced albuminuria and renal fibrosis. The f-NGAL therapy increased the anti inflammatory IL-10 and reduced some pro-inflammatory cytokines, reduced the proportion of M1 glomerular macrophages and podocyte loss and was associated with a significant decrease of renal TGF-beta1. Overall, our study provides evidence that f-NGAL macrophage cell therapy has a therapeutic effect on DKD probably by modulation of the renal inflammatory response caused by the diabetic milieu. PMID- 30407738 TI - The effects of meteorological factors on influenza among children in Guangzhou, China. AB - BACKGROUND: Influenza seriously affects the health of children, yet little evidence is available on the association between meteorological factors and the occurrence of influenza among children in subtropical regions. The current study aimed to explore the effects of meteorological factors on influenza among children in Guangzhou, a subtropical city in China. METHODS: The distributed lag nonlinear model (DLNM) was used to assess the effects of meteorological factors on children influenza occurrence in Guangzhou, China. Daily number of influenza cases among children aged 0-17 years from 2013 to 2017 were obtained from the National Information System for Disease Control and Prevention. RESULTS: Mean temperature, relative humidity and atmospheric pressure were associated with influenza cases. The relative risks (RRs) increased as temperature fell below 20 degrees C. The relationship between relative humidity and influenza cases could be described with a U-shaped curve, and the RRs increased if relative humidity was lower than 50% or higher than 80%. The risk of influenza increased with rising atmospheric pressure with 1005 hPa as the break point. The cold effect, humid effect, dry effect, high-pressure effect and low-pressure effect showed statistical significance both in female and male. The cold effect increased with age. The humid-effect affect all age ranges of children, but dry effect mainly affected 4-14 years old. High-pressure effect mainly affected the 0-3 years old, whereas low-pressure effect protected preschool children aged 0-6 years old. CONCLUSION: Mean temperature, relative humidity and atmospheric pressure might be important predictors of the influenza occurrence among children in Guangzhou. This article is protected by copyright. All rights reserved. PMID- 30407739 TI - The spread of bovine tuberculosis in Canadian shared pastures: Data, model, and simulations. AB - Bovine tuberculosis (bTB), caused by Mycobacterium bovis, is a chronic disease typical of cattle. Nonetheless, it can affect many mammals including humans, making it one of the most widespread zoonotic diseases worldwide. In industrialized countries, the main pathways of introduction of bTB into a herd are animal trade and contact with infected wildlife. In addition, for slow spreading diseases with a long latent period such as bTB, shared seasonal pastures might be a between-herd transmission pathway, indeed farmers might unknowingly send infected animals to the pasture, since clinical signs are rarely evident in early infection. In this study, we developed a dynamic stochastic model to represent the spread of bTB in pastures. This was tailored to Canadian cow-calf herds, as we calibrated the model with data sourced from a recent bTB outbreak in Western Canada. We built a model for a herd with seasonal management, characterized by its partition into a group staying in the main facility and the remaining group(s) moving to summer pastures. We used this model to estimate the time of the first introduction of bTB into the herd. Furthermore, we expanded the model to include herds categorized as high-risk contacts with the index herd, in order to estimate the potential for disease spread on shared pastures. Finally, we explored two control scenarios to be applied to high-risk farms after the outbreak detection. Our results showed that the first introduction likely happened 3 to 5 years prior to the detection of the index herd, and the probability of bTB spreading in pastures was low, but not negligible. Nevertheless, the surveillance system currently in place was effective to detect potential outbreaks. PMID- 30407740 TI - A level-headed approach to measuring direct oral anticoagulants: A 2-year retrospective analysis of DOAC levels from a tertiary UK centre. AB - INTRODUCTION: Direct oral anticoagulants (DOAC) are commonly prescribed and measuring drug levels may be useful in a number of contexts. However, data on DOAC level measurement and their clinical utility in real-world studies are limited. METHODS: We carried out a 2-year retrospective cohort study of DOAC levels measured at our institution. RESULTS: One hundred and sixty-nine levels measured in 113 patients were included in the final analysis. Our patients had a median age of 69.9. AF was the commonest indication for anticoagulation. Median turnaround time for inpatient levels was 92 minutes. Median FXa inhibitor levels within 6 hours of last dose and following one half-life were similar to those described previously. However, the range of levels was wider than expected. Importantly, some levels remained in an on therapy range even after 3 half-lives. There was no correlation between dabigatran level and time from last dose. The reason for request varied with setting; 23 outpatient levels were to monitor drug efficacy, whereas 54 and 43 inpatient levels were collected in the context of bleeding and emergency surgery respectively. 60.3% of levels had an impact on clinical decision making. CONCLUSION: Our real-world study demonstrates that DOAC levels can be performed in a timely manner to influence clinical decision making. In addition, it suggests there is a wide variation in levels such that it can be difficult to predict in the real world. Overall, this supports the wider use of DOAC levels to help guide clinicians in managing patients taking these drugs. PMID- 30407741 TI - Catalytic upgrading of biomass-derived sugars with acidic nanoporous materials: Structural role in carbon-chain length variation. AB - Shifting from petroleum-based resources to non-edible biomass for the production of valuable chemicals and fuels is one of significant aspects in sustainable chemistry for realizing the sustainable development of our society. Various renowned biobased platform molecules, such as 5-hydroxymethylfurfrual, furfural, levulinic acid and lactic acid, are successfully accessible from the transformation of bio-based sugars. To achieve the specific reaction routes, heterogeneous nanoporous acidic materials have been served as promising catalysts for bio-sugars conversion in the past decade years. This review summarizes the advancement of various nanoporous acidic materials for bio-sugar conversion, where the number of carbon atoms is variable and controllable in the assistance of switchable structure of the nanoporous materials. The major focus of this review paper is to display the possible reaction pathways/mechanisms, and relationships of between the catalyst structure and catalytic performance. Moreover, representative examples on catalytic upgradation of bio-based platform molecules to bio-chemicals and fuels via selective C-C cleavage and coupling strategies over nanoporous acidic materials are also discussed. PMID- 30407743 TI - Computer vs human: Deep learning versus perceptual training for the detection of neck of femur fractures. AB - INTRODUCTION: To evaluate the accuracy of deep convolutional neural networks (DCNNs) for detecting neck of femur (NoF) fractures on radiographs, in comparison with perceptual training in medically-naive individuals. METHODS: This study extends a previous study that conducted perceptual training in medically-naive individuals for the detection of NoF fractures on a variety of dataset sizes. The same anteroposterior hip radiograph dataset was used to train two DCNNs (AlexNet and GoogLeNet) to detect NoF fractures. For direct comparison with perceptual training results, deep learning was completed across a variety of dataset sizes (200, 320 and 640 images) with images split into training (80%) and validation (20%). An additional 160 images were used as the final test set. Multiple pre processing and augmentation techniques were utilised. RESULTS: AlexNet and GoogLeNet DCNNs NoF fracture detection accuracy increased with larger training dataset sizes and mildly with augmentation. Accuracy increased from 81.9% and 88.1% to 89.4% and 94.4% for AlexNet and GoogLeNet respectively. Similarly, the test accuracy for the perceptual training in top-performing medically-naive individuals increased from 87.6% to 90.5% when trained on 640 images compared with 200 images. CONCLUSIONS: Single detection tasks in radiology are commonly used in DCNN research with their results often used to make broader claims about machine learning being able to perform as well as subspecialty radiologists. This study suggests that as impressive as recognising fractures is for a DCNN, similar learning can be achieved by top-performing medically-naive humans with less than 1 hour of perceptual training. PMID- 30407742 TI - Identification of a novel clade of group A rotaviruses in fatally diseased domestic pigeons in Europe. AB - Rotaviruses are well-known causative agents of enteric disorders in humans and other mammals, but little is known about their virulence and pathogenic role in pigeons and other birds. Starting in summer 2017, a series of outbreaks of an acute disease with high mortalities was reported in domestic pigeons in Germany, Belgium and Denmark. The clinical picture was characterized by diarrhoea, vomiting, hepatic necrosis and sudden fatalities. From these severe outbreaks, we discovered several previously unknown group A rotavirus (RVA) lineages of genotype G18P[17]-I4-R4-C4-M4-A4-T4-N4-E19-H4, which were closely related but not identical to an RVA variant identified in cases of fatal hepatic necrosis in Australian pigeon lofts in 2016. Retrospective analysis demonstrated that the predecessors of the highly virulent variants have circulated in Europe since at least 2010. Our data indicate that reassortment and intercontinental spread has led to the emergence of novel RVA variants, which may constitute a major threat to animal welfare and health of domestic pigeon populations worldwide. PMID- 30407744 TI - Needle-free jet versus conventional needle injection for local anesthesia in men undergoing surgical sperm retrieval. AB - BACKGROUND: Surgical sperm retrieval, requiring local anesthetic injection, is the most frequent surgical procedure in male infertility. However, needle phobia is common and may contribute to negative experiences or refusal of procedures employing needle injection. OBJECTIVES: The aim of this study was to compare the acceptability, safety, and efficacy of needle-free jet anesthetic technique (MadaJet) with conventional needle injection for surgical sperm retrievals in patients with azoospermia. MATERIALS AND METHODS: This single-blind randomized controlled trial (RCT) was included of 59 participants who underwent surgical sperm retrievals. Patients were randomly assigned to the needle-free jet (n = 29) or needle injection (n = 30) groups prior to undergoing the surgery. The primary endpoint was the pain score. RESULTS: Baseline characteristics were comparable between the two groups. The safety and adverse outcomes were also not statistically significant difference (p > 0.05). The pain score in patients using needle-free jet was significantly lower than that in patients using needle injection (p < 0.05). Patients in MadaJet group had a significantly lower discomfort score during (p < 0.001) and after (p = 0.01) injection than those in the needle injection group. However, there was no significant difference in the fear score (before, during, and after) of MadaJet and needle injection (p = 0.98, p = 0.74, and p = 0.94, respectively). The mean time to onset of anesthesia was much shorter in the MadaJet group as compared with needle injection (10 +/- 4 vs. 157.5 +/- 71 s, p < 0.001). However, the duration of anesthesia in patients using MadaJet was shorter compared with those using needle injection (44 +/- 13 vs. 63 +/- 26 min, p < 0.001). CONCLUSION: In conclusion, for local anesthesia in patients undergoing surgical sperm retrieval, MadaJet produces less pain and discomfort with quicker time to onset and offset of anesthesia compared with conventional needle injection. PMID- 30407745 TI - Myocardial Inflammation, Measured Using 18-Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography (FDG PET-CT) is Associated with Disease Activity in Rheumatoid Arthritis. AB - OBJECTIVES: To determine the prevalence and correlates of subclinical myocardial inflammation in rheumatoid arthritis (RA). METHODS: RA patients (n=119) without known cardiovascular disease (CVD) underwent cardiac 18-fluorodeoxyglucose positron emission tomography with computed tomography (FDG PET-CT). Myocardial FDG uptake was assessed visually and quantitatively by standardized uptake values (SUV). Multivariable linear regression was used to assess the associations of patient characteristics with myocardial SUV. A subset of RA patients escalating disease modifying anti-rheumatic drug (DMARD) therapy (n=8) had a second FDG PET CT scan after 6 months to assess treatment-associated changes in myocardial FDG uptake. RESULTS: Visually assessed FDG uptake was observed in 46 (37%) of RA patients, and 21 (18%) had abnormal quantitatively assessed myocardial FDG uptake [i.e. SUVmean>=3.10 units (two standard deviations above the SUVmean of a reference non-RA group (n=27)]. Average SUVmean was 31% higher for those with a clinical disease activity index (CDAI) >=10 vs. those with lower scores (p=0.005) after adjusting for potential confounders. The average adjusted SUVmean was 26% lower among those treated with non-TNF targeted biologics vs. those treated with conventional (non-biologic) DMARDs (p=0.029). In the longitudinal sub-study, myocardial SUVmean decreased from 4.50 to 2.30 units over 6 months, which paralleled the decrease in average CDAI from 23 to 12 units. CONCLUSIONS: Subclinical myocardial inflammation is frequent in RA, is associated with RA disease activity, and may decrease with RA therapy. Future longitudinal studies will be required to assess whether reduction in myocardial inflammation will reduce heart failure risk in RA. This article is protected by copyright. All rights reserved. PMID- 30407746 TI - Model informed drug development and regulation in China: challenges and opportunities. AB - Since 2016, the Center for Drug Evaluation, National Medical Product Agency has routinely received and reviewed modeling and simulation (M&S) analyses submitted at different stages of drug development. A series of related guidelines were released. The perspective identifies opportunities and challenges in applying M&S in drug regulation in China. Model informed drug development (MiDD) and regulation have played important roles in drug development worldwide. This article is protected by copyright. All rights reserved. PMID- 30407747 TI - Functional variants of the ATG7 gene promoter in acute myocardial infarction. AB - BACKGROUND: Coronary artery disease including acute myocardial infarction (AMI) is mainly caused by atherosclerosis, an inflammatory and metabolic disease. Autophagy has been demonstrated to play critical roles in lipid metabolism and inflammation. Altered autophagic activity has been reported in AMI patients. However, molecular basis for dysfunctional autophagy in AMI remains unexplained. METHODS: In this study, the promoter of the ATG7 gene, encoding a core protein for autophagy, was genetically and functionally analyzed in large cohorts of AMI patients (n = 355) and ethnic-matched healthy controls (n = 363). Related molecular mechanisms were also explored. RESULTS: A total of 19 DNA sequence variants (DSVs) including single-nucleotide polymorphisms (SNPs) were found in the ATG7 gene promoter. Two novel DSVs and five SNPs were only identified in AMI patients group. These DSVs and SNPs, except one SNP, significantly altered the transcriptional activity of the ATG7 gene promoter in both HEK-293 and H9c2 cells (p < 0.05). Further electrophoretic mobility shift assay revealed that the DSVs and SNPs evidently affected the binding of transcription factors. CONCLUSIONS: ATG7 gene DSVs and SNPs identified in AMI patients may alter the transcriptional activity of the ATG7 gene promoter and change ATG7 level, contributing to the AMI development as a rare risk factor. PMID- 30407748 TI - Gestational age-dependent gene expression profiling of ATP-binding cassette transporters in the healthy human placenta. AB - The ATP-binding cassette (ABC) transporters control placental transfer of several nutrients, steroids, immunological factors, chemicals, and drugs at the maternal fetal interface. We and others have demonstrated a gestational age-dependent expression pattern of two ABC transporters, P-glycoprotein and breast cancer resistance protein throughout pregnancy. However, no reports have comprehensively elucidated the expression pattern of all 50 ABC proteins, comparing first trimester and term human placentae. We hypothesized that placental ABC transporters are expressed in a gestational-age dependent manner in normal human pregnancy. Using the TaqMan(r) Human ABC Transporter Array, we assessed the mRNA expression of all 50 ABC transporters in first (first trimester, n = 8) and third trimester (term, n = 12) human placentae and validated the resulting expression of selected ABC transporters using qPCR, Western blot and immunohistochemistry. A distinct gene expression profile of 30 ABC transporters was observed comparing first trimester vs. term placentae. Using individual qPCR in selected genes, we validated the increased expression of ABCA1 (P < 0.01), ABCA6 (P < 0.001), ABCA9 (P < 0.001) and ABCC3 (P < 0.001), as well as the decreased expression of ABCB11 (P < 0.001) and ABCG4 (P < 0.01) with advancing gestation. One important lipid transporter, ABCA6, was selected to correlate protein abundance and characterize tissue localization. ABCA6 exhibited increased protein expression towards term and was predominantly localized to syncytiotrophoblast cells. In conclusion, expression patterns of placental ABC transporters change as a function of gestational age. These changes are likely fundamental to a healthy pregnancy given the critical role that these transporters play in the regulation of steroidogenesis, immunological responses, and placental barrier function and integrity. PMID- 30407749 TI - Shortage of energy intake rather than protein intake is associated with sarcopenia in elderly patients with type 2 diabetes: A cross-sectional study of the KAMOGAWA-DM cohort. AB - BACKGROUND: Energy intake is important for the maintenance of muscle mass. The relationship between energy intake and sarcopenia in elderly patients with type 2 diabetes (T2D) has been unclear. METHODS: Using a brief-type self-administered diet history questionnaire we assessed habitual food and nutrient intake of patients with T2D aged >=65 years, all of whom were Japanese and physically active, taking part in the KAMOGAWA-DM cohort study. Patients' body composition was evaluated by bioimpedance analysis. Sarcopenia was defined as having both a grip strength of <26 kg for men and <18 kg for women and a skeletal muscle mass index of <7.0 kg/m2 for men and <5.7 kg/m2 for women. Logistic regression analyses were used to investigate the effect of energy intake on the presence of sarcopenia in this cross-sectional study of 391 patients (205 men, 186 women). RESULTS: Fifty-five patients (14.1%) were diagnosed as having sarcopenia. Energy intake was significantly lower in patients with sarcopenia than without sarcopenia (mean +/- SD [n = 366] 1498.8 +/- 389.4 vs 1786.2 +/- 706.7 kcal/d, respectively; P = 0.016). After adjusting for age, sex, exercise, smoking status, HbA1c, and body mass index, patients' energy intake (per 100 kcal) was negatively associated with the presence of sarcopenia (odds ratio 0.86; 95% confidence interval 0.78-0.95; P = 0.001). CONCLUSION: Energy intake was negatively associated with the presence of sarcopenia in elderly patients with T2D. PMID- 30407750 TI - Discovery of Vilaprisan (BAY 1002670): A Highly Potent and Selective Progesterone Receptor Modulator Optimized for Gynecologic Therapies. AB - Progesterone plays an important role in the female reproductive system. However, there is also evidence that gynecologic disorders/diseases such as uterine fibroids and endometriosis are progesterone-dependent. Steroidal and non steroidal selective progesterone receptor modulators (SPRMs) have shown potential for the treatment of such diseases. Steroidal SPRMs, including mifepristone and ulipristal acetate, have proven effective in clinical trials. However, several steroidal SPRMs containing a dimethylamino substituent have been associated with elevated liver enzymes in patients. An earlier drug discovery program identified lonaprisan as a highly selective SPRM that did not show drug-related change in liver enzyme activity. Building on data obtained from that work, here we describe the research program that culminated in the discovery of a novel steroidal SPRM, vilaprisan, which combines an extremely high potency with very favorable drug metabolism and pharmacokinetic properties. Vilaprisan has entered clinical development and is currently undergoing phase 3 clinical trials. PMID- 30407751 TI - Quality assurance guidance for scoring and reporting for pathologists and laboratories undertaking clinical trial work. AB - While pathologists have always played a pivotal role in clinical trials ensuring accurate diagnosis and staging, pathology data from prognostic and predictive tests are increasingly being used to enrol, stratify and randomise patients to experimental treatments. The use of pathological parameters as primary and secondary outcome measures, either as standalone classifiers or in combination with clinical data, is also becoming more common. Moreover, reporting of estimates of residual disease, termed 'pathological complete response', have been incorporated into neoadjuvant clinical trials. Pathologists have the expertise to deliver this essential information and they also understand the requirements and limitations of laboratory testing. Quality assurance of pathology-derived data builds confidence around trial-specific findings and is necessarily focused on the reproducibility of pathological data, including 'estimates of uncertainty of measurement', emphasising the importance of pathologist education, training, calibration and demonstration of satisfactory inter-observer agreement. There are also opportunities to validate objective image analysis tools alongside conventional histological assessments. The ever-expanding portfolio of clinical trials will demand more pathologist engagement to deliver the reliable evidence base required for new treatments. We provide guidance for quality assurance of pathology scoring and reporting in clinical trials. PMID- 30407752 TI - Suppression of Murine Lupus by CD4+ and CD8+ T Regulatory Cells Induced by T-Cell Targeted Nanoparticles Loaded with IL-2 and TGF-beta. AB - OBJECTIVE: To develop a nanoparticle platform that can expand both CD4+ and CD8+ T regulatory cells (Tregs) in vivo for the suppression of autoimmune responses in systemic lupus erythematosus (SLE). METHODS: Poly(lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) encapsulating IL-2 and TGF-beta were coated with anti-CD2/CD4 antibodies and administered to mice with lupus-like disease induced by the transfer of DBA/2 T cells into (C57BL/6 x DBA/2)F1 (BDF1) mice. Peripheral frequency of Tregs was monitored ex vivo by flow cytometry. Disease progression was assessed by measuring serum anti-dsDNA antibodies by ELISA. Kidney disease was evaluated as proteinuria and by renal histopathology. RESULTS: Anti-CD2/4 antibody-coated, but not non-coated NPs encapsulating IL-2 and TGF-beta, induced CD4+ and CD8+ Foxp3+ Tregs in vitro. In vivo studies in non-lupus mice determined the optimal dosing regimen of NPs for expansion of CD4+ and CD8+ Tregs that was then tested in BDF1 lupus mice. The administration of anti-CD2/4 antibody-coated NPs encapsulating IL-2 and TGF-beta resulted in the expansion of CD4+ and CD8+ Tregs, a marked suppression of anti-DNA antibody production, and reduced renal disease. CONCLUSION: This study shows for the first time that T cell-targeted PLGA NPs encapsulating IL-2 and TGF-beta can expand both CD4+ and CD8+ Tregs in vivo and suppress murine lupus. This approach that enables the expansion of Tregs in vivo and inhibits pathogenic immune responses in SLE could represent a potential new therapeutic modality in autoimmune conditions characterized by impaired Tregs function associated with IL-2 deficiency. This article is protected by copyright. All rights reserved. PMID- 30407753 TI - Beyond autoantibodies: Biological roles of human autoreactive B cells in rheumatoid arthritis revealed by RNA-sequencing. AB - OBJECTIVE: To obtain the comprehensive transcriptome profile of human citrulline specific B cells from patients diagnosed with rheumatoid arthritis (RA). METHODS: Citrulline and hemagglutinin (HA) specific B cells were flow-sorted using peptide streptavidin conjugates from peripheral blood of RA patients and healthy individuals respectively. Transcriptome profile of the sorted cells was obtained by RNA-sequencing, and expression of key protein molecules was evaluated by aptamer-based SOMAscan assay and flow cytometry. The ability of these proteins to effect differentiation of osteoclasts and proliferation and migration of synoviocytes was examined by in vitro functional assays. RESULTS: Citrulline specific B cells, in comparison to citrulline-negative B cells differentially express IL15RA, and genes related to protein citrullination and cyclic AMP signaling. By analyzing an independent cohort of CCP seropositive RA patients, we demonstrate that: (1) the expression of IL15Ralpha protein is enriched in citrulline-specific B cells within RA patients, and (2) surprisingly, all B cells from RA patients were capable of producing epidermal growth factor ligand, amphiregulin (AREG). AREG directly led to increased migration and proliferation of fibroblast-like synoviocytes (FLS), and in combination with anti-citrullinated protein antibodies (ACPA) led to the increased differentiation of osteoclasts. CONCLUSION: To the best of our knowledge, this is the first study documenting the whole transcriptome profile of autoreactive B cells in any autoimmune disease. Our data identifies several genes and pathways that may be targeted by repurposing several FDA- approved drugs and can serve as the foundation for the comparative assessment of B-cell profiles in other autoimmune diseases. This article is protected by copyright. All rights reserved. PMID- 30407754 TI - Penile doppler ultrasound predicts cardiovascular events in men with erectile dysfunction. AB - BACKGROUND: Traditional risk factors used to assess cardiovascular risk miss a significant population who are indeed at risk for future cardiac events. Erectile dysfunction (ED) is an emerging marker for future cardiovascular disease (CVD) and major adverse cardiovascular events (MACE), especially in young and middle aged men with vasculogenic ED. Cavernous arteries morphological alterations at penile colour doppler ultrasound (P-CDU) are used to find a vasculogenic ED. OBJECTIVES: We investigated the possible relationship between cavernous arteries morphological alterations at P-CDU assessment and future MACE. MATERIALS AND METHODS: We conducted a retrospective cohort study involving 300 ED patients, aged 35-65 years (mean age 54.1 +/- 7.1), with a follow-up period of 10 years. Patients underwent vascular evaluation including P-CDU, colour doppler ultrasound of the carotid and lower limbs arteries. At baseline data for glucose metabolism, lipid profile, hypertension and hormonal status were collected. During the follow up period, the occurrence of MACE was evaluated. RESULTS: We found a strong association between cavernous arteries morphological alterations and CVD with a threefold increased risk of future MACE in comparison to patients with healthy cavernous arteries (RR 3.2, 95% CI 1.17-8.78). This association remained statistically significant after adjustment for CV risk factors (age, glycaemia, total cholesterol, hypertension and smoke). CONCLUSIONS: Morphological alterations of cavernous arteries are independently associated with an increased risk of future MACE. These data contribute to the formulation of the hypothesis that cavernous artery pathology at P-CDU is related to MACE. PMID- 30407755 TI - I Have Never Used Methamphetamine, But My Urinalysis Says I Do. PMID- 30407756 TI - Does Vitamin D Deficiency Cause Depression? PMID- 30407757 TI - Psychotic Features of Turner Syndrome. PMID- 30407758 TI - A Systematic Review of the Utility of Electroconvulsive Therapy in Broadly Defined Obsessive-Compulsive-Related Disorders. AB - Objective: To assess the efficacy of electroconvulsive therapy (ECT) in DSM-5 obsessive-compulsive-related disorders (OCRDs) and conditions subsumed under an "extended" OCD spectrum, including tic disorders and self-injurious behaviors. Data Sources: A systematic search of the MEDLINE, Web of Science, Scopus, and LILACS databases and other sources was performed between June 6 and July 2, 2017. Search terms included (Autis*) AND (ECT OR electroconvulsive), (Self-injur*) AND (ECT OR electroconvulsive), (Tic* OR Tourette) AND (ECT OR electroconvulsive), (Body Dysmorphic Disorder OR Dysmorphophobi*) AND (ECT OR electroconvulsive), (Hoard*) AND (ECT OR electroconvulsive), (Trichotillomani*) AND (ECT OR electroconvulsive), (Skin Picking OR Excoriation) AND (ECT OR electroconvulsive), (Grooming) AND (ECT OR electroconvulsive), (Kleptomani*) AND (ECT OR electroconvulsive), and (Pyromani*) AND (ECT OR electroconvulsive). No search restrictions (ie, date, language, or document type) were used. Study Selection: Fifty-two records that described the individual responses of OCRDs to ECT (involving 69 patients) were selected. Data Extraction: Clinical data and responses of individual cases were recorded. Data from responders were compared to nonresponders. Results: All records were case reports or case series; there were no randomized controlled trials. Of the 69 OCRD participants who had undergone ECT, a positive response was reported in 73.4% of the cases (including 44.0% of the BDD, 74.1% of the tic disorder, and 85.7% of the self-injurious behavior patients). At follow-up, the majority of responders who had abstained from further ECT had experienced relapse. However, a positive response was obtained in all participants who received a new course of ECT. Patients who responded positively to ECT were likely to report previous unsuccessful treatment with antipsychotics (P < .001) and antidepressants (P = .007). Conclusions: The finding that more than 70% of the reviewed cases showed some response to ECT should not be considered unequivocal evidence of its efficacy in OCRDs. The available evidence suggests that a randomized controlled trial of ECT in OCRDs may be warranted, particularly in severe tic disorders and self-injurious behaviors. PMID- 30407759 TI - Vagus nerve preservation during minimally invasive esophagectomy with 2-field lymphadenectomy for esophageal carcinoma: A more physiological alternative. AB - Vagal-sparing esophagectomy allows for curative tumor resection with better functional outcome and reduced postoperative morbidity, and minimally invasive esophagectomy has the advantage of avoiding the morbidities associated with big thoracoabdominal incisions. The video tutorial demonstrates our technique of preserving both vagus nerves and their celiac and hepatic branches in the abdomen during the thoracoscopic and laparoscopic phases of minimally invasive esophagectomy, with 2-field lymphadenectomy, for esophageal carcinoma. Four ports are used for thoracoscopic mobilization of the esophagus. Both vagus nerves are identified, encircled and suspended with a vascular loop and carefully separated from the esophageal wall along its whole length from above downwards beginning with the left vagus nerve then the right one. Five ports are used for laparoscopic gastric mobilization and preservation of the hepatic and celiac vagal branches. Care should be taken during ligation and division of the left gastric artery to avoid injury of the celiac branch of the vagus nerve. Resection of the common hepatic artery and left gastric artery group of lymph nodes is performed. PMID- 30407761 TI - Thoughts on 'The Clinical Significance of Relative Bradycardia'. PMID- 30407760 TI - Pleural packing, revisional surgeries, and delayed chest closure: A salvage strategy in lung transplant. AB - Coagulopathy during lung transplantation leads to 2 major problems: first, control of diffuse bleeding becomes challenging and second, massive lung edema can cause significant volume expansion. To control these potentially lethal complications, we used a combined technique of pleural packing and delayed chest wall closure with negative pressure wound therapy. We retrospectively reviewed 100 bilateral lung transplants performed in our institute over the past 30 months and identified 7 cases of coagulopathy. Five of the 7 were weaned from pleural packing and ECMO, and had a secondary chest wall closure. The combination of pleural packing and delayed wall closure is a effective management option in cases of coagulopathy and lung edema. PMID- 30407762 TI - Essential Oils: Initiating a Resident Wellness Program at a Community Hospital. PMID- 30407763 TI - Sixty Years After the Pill, Medicine Still Needs To Make Progress. PMID- 30407764 TI - Health Care Barriers to Provision of Long-Acting Reversible Contraception in Wisconsin. AB - INTRODUCTION: Long-acting reversible contraceptives (LARC), specifically implants and intrauterine devices (IUD), are highly effective, low maintenance forms of birth control. Practice guidelines from the American College of Obstetricians and Gynecologists, American Academy of Family Physicians, and American Academy of Pediatrics recommend that LARC be considered first-line birth control for most women; however, uptake remains low. In this study, we sought to understand practices and barriers to provision of LARC in routine and immediate postpartum settings as they differ between specialties. METHODS: We surveyed 3,000 Wisconsin physicians and advanced-practice providers in obstetrics-gynecology/women's health (Ob-gyn), family medicine, pediatrics, and midwifery to assess practices and barriers (56.5% response rate). This analysis is comprised of contraceptive care providers (n=992); statistical significance was tested using chi-square and 2-sample proportions tests. RESULTS: More providers working Ob-gyn (94.3%) and midwifery (78.7%) were skilled providers of LARC methods than those in family medicine (42.5%) and pediatrics (6.6%) (P < .0001). Lack of insertion skill was the most-cited barrier to routine provision among family medicine (31.1%) and pediatric (72.1%) providers. Among prenatal/delivery providers, over 50% across all specialties reported lack of device availability on-site as a barrier to immediate postpartum LARC provision; organizational practices also were commonly reported barriers. CONCLUSIONS: Gaps in routine and immediate postpartum LARC practice were strongly related to specialty, and providers' experience heightened barriers to immediate postpartum compared to routine insertion. Skills training targeting family medicine and pediatric providers would enable broader access to LARC. Organizational barriers to immediate postpartum LARC provision impact many providers. PMID- 30407765 TI - A Review of Long-Acting Reversible Contraception Methods and Barriers to Their Use. AB - Unplanned pregnancies are a serious health concern in Wisconsin. Increasing access to contraception is a proven method to reduce unplanned pregnancies while giving patients greater agency. Long-acting reversible contraception (LARC) methods, such as subdermal implants and intrauterine devices (IUD), are among the most effective contraception methods available and have high patient satisfaction. However, relatively few Wisconsin patients use these methods. Lack of provider skill in inserting and counseling about LARCs, inability to perform same-day LARC insertion, and absent hospital protocols for immediate postpartum insertion represent barriers to LARC access. Centralized efforts are required to remove these barriers so that all patients in Wisconsin can access highly effective contraception. PMID- 30407766 TI - The Legacy of the Seminal Publication by Guillain, Barre, and Strohl: The History Behind the Eponym. AB - The report, "On a syndrome of radiculoneuritis with hyperalbuminosis of the cerebrospinal fluid without a cellular reaction. Remarks on the clinical characteristics and tracings of the tendon reflexes," published in 1916, included superb longitudinal clinical observations of progressive areflexic paralysis in 2 French soldiers, unique laboratory findings from the still new at that time technique of lumbar puncture, and electrophysiological studies. The classic observation of the albumino-cytologic dissociation in the spinal fluid, even over 100 years later, is still one of the most important laboratory findings used by clinicians to confirm the suspected diagnosis of the Acute Inflammatory Demyelinating Polyneuropathy, typically eponymously referred to as Guillain Barre Syndrome (GBS). The contribution of Andre Strohl, who reported the electrophysiological abnormalities observed in their patients with novel myographic studies of tendon reflexes, led to eventual widespread use of electrodiagnostic techniques in bedside diagnosis of neuromuscular conditions. Since 1916, the clinicopathological spectrum of GBS has expanded continuously, with better understanding of the etiology, pathology, and electrodiagnostic findings. However, most of the seminal observations and conclusions presented by Guillain, Barre, and Strohl have withstood the test of time. Their landmark publication has become a standard of excellence in the history of clinical neurology. Deservedly, "GBS" is one of the most recognized medical eponyms around the world. PMID- 30407767 TI - The Effect of Understanding Issues of Personal Finance on the Well-being of Physicians in Training. AB - BACKGROUND: This study assessed trends in personal financial issues among physical medicine and rehabilitation resident physicians and their impact on resident well-being. METHODS: A 25-question cross-sectional survey was sent to 18 physical medicine and rehabilitation residents. RESULTS: A total of 17 residents completed the survey (94% response rate), with 82% (14 of 17) endorsing personal finances as a contributor to their personal health. Residents also endorsed minimal previous financial education and an interest in more formal education on related topics. DISCUSSION: This study revealed personal financial issues are a factor in resident well-being and garner high levels of interest. Despite this, residents have received little financial education. These results have motivated us to address this deficit in our education program. PMID- 30407768 TI - Diabetes Mellitus-Not Just Type 1 or Type 2 Anymore. AB - INTRODUCTION: Diabetes mellitus traditionally has been categorized as type 1 (insulin deficiency due to autoimmune destruction of islet cells) or type 2 (insulin resistance with the development of relative insulin deficiency). However, other pathophysiologic etiologies for diabetes must be considered in the evaluation of patients with new-onset diabetes. CASE PRESENTATION: We report the case of a 50-year-old man with a diagnosis of type 2 diabetes mellitus who despite appropriate pharmacotherapy-developed worsening hyperglycemia. Further investigation revealed the presence of metastatic pancreatic cancer. DISCUSSION: Although an association between pancreatic cancer and diabetes has been noted widely in the gastroenterology, oncology, and endocrine literature, a paucity of primary care literature on the topic exists. Features of predominant insulin deficiency and new onset of diabetes in a patient without family history of type 2 diabetes should raise suspicion for undetected/early-stage pancreatic cancer. CONCLUSIONS: This case highlights the importance of considering all possible pathophysiologic etiologies when a patient has a new diagnosis of diabetes. Clinicians should consider the possibility of pancreatic cancer in patients with new-onset diabetes mellitus, especially when features not characteristic of type 2 diabetes are present. Understanding the relationship between diabetes and pancreatic cancer has the potential to improve early detection of pancreatic cancer and can provide an opportunity for early treatment and improved survival. PMID- 30407769 TI - Familial Tako-tsubo Cardiomyopathy: Clinical and Echocardiographic Features Including Magnetic Resonance Imaging Findings. AB - INTRODUCTION: Tako-tsubo cardiomyopathy (TCM) is being recognized more frequently; and a familial form of this diagnosis has been suspected but is less well-established. CASE: A 75-year-old patient with a family history of TCM was admitted with suspected ST-segment elevation myocardial infarction. Transthoracic echocardiography showed apical dyskinesis with hyperdynamic basal walls and a left ventricular ejection fraction (LVEF) of 25%. Repeat echocardiography showed normal LVEF of 60% ejection fraction. Cardiac catheterization showed no significant stenosis. DISCUSSION: TCM is characterized by transient systolic left ventricular dysfunction. A few cases of familial TCM have been reported in the literature and a genetic component is suspected. CONCLUSIONS: Although there has been a paucity of data, familial cases of TCM have been reported. This case study addresses TCM and the familial occurrence of the syndrome, which may have a genetic basis. PMID- 30407770 TI - Platypnea-Orthodeoxia: A Case of Unexplained Hypoxia. AB - INTRODUCTION: Platypnea-orthodeoxia syndrome is a rare clinical syndrome defined by worsening deoxygenation and dyspnea when changing to an upright sitting or standing position. It is seen in 3 different clinical scenarios: intracardiac shunts, pulmonary arteriovenous shunts, and ventilation/perfusion mismatch in the lungs. CASE: An 82-year-old woman with a history of nonischemic cardiomyopathy with reduced ejection fraction was admitted with dyspnea and hypoxemia. She was found to have atrial septal defect with right to left shunting in the setting of normal right atrial pressures. DISCUSSION: Platypnea-orthodeoxia syndrome is a clinical syndrome where, in the setting of an interatrial communication, a right to left shunt can occur without elevated pulmonary or right atrial pressure, resulting in significant hypoxia. CONCLUSION: Platypnea-orthodeoxia syndrome is a clinical condition that is being recognized more frequently due to more accurate diagnosis, and its treatment can alleviate symptomatic hypoxemia. PMID- 30407771 TI - Shared Knowledge in Precision Cancer Care. PMID- 30407772 TI - Wisconsin Health Care Making Progress Toward CMS Quality Strategy Goals, Part II. PMID- 30407773 TI - The Safety of Consistency in a Changing World. PMID- 30407774 TI - Oral Pathology Quiz #94. Case Number 2. Fibrous dysplasia. PMID- 30407775 TI - Oral Pathology Quiz #94. Case Number 3. Epithelial dysplasia. PMID- 30407776 TI - Oral Pathology Quiz #94. Case Number 4. Fibroma. PMID- 30407780 TI - Strategic Construction of Highly Stable Metal-Organic Frameworks Combining Both Semi-Rigid Tetrapodal and Rigid Ditopic Linkers: Selective and Ultrafast Sensing of 4-Nitroaniline in Water. AB - In this work, we have designed two new 3D metal-organic frameworks (MOFs), {Zn4(TPOM)(1,4-NDC)4} n (1) and {Ni2(TPOM)(1,4-NDC)2(H2O)2} n (2), utilizing both semi-rigid tetrapodal neutral linker, tetrakis(4-pyridyloxymethylene)methane (TPOM) and rigid ditopic anionic linker, 1,4-naphthalene dicarboxylic acid (H2(1,4-NDC)). On the basis of the single-crystal X-ray diffraction, 1 has a 3D structure with star-shaped pores arising from four-fold symmetry due to the presence of a paddle-wheel core [Zn2(O2CC12H6)4(C6H4N)2] as a subunit, whereas 2 consists of a zig-zag 3D framework with strong hydrogen bonding between the coordinated water molecules and coordinated carboxylate groups. Their thermogravimetric analysis indicates an extraordinary thermal stability: 1 up to 400 degrees C and 2 up to 350 degrees C. In addition to elemental microanalysis and spectroscopic characterization (UV-vis and infra-red spectroscopy), the bulk phase purity of 1 and 2 as well as hydrolytic stability of 1 are established by powder X-ray diffraction. Exploiting the luminescence nature of 1, both solvent dependent fluorescence properties and sensing of various amines in aqueous medium are demonstrated. It exhibits good sensing ability toward 4-nitroaniline (4-NA) and 2,6-dichloro-4-nitroaniline (2,6-DCNA; a broad spectrum pesticide belonging to toxicity class III) with the lowest detection limit of 88 ppb and 0.28 ppm, respectively. The mechanism of action has been established through Stern-Volmer plots, time-resolved fluorescence studies, spectral overlap, and density functional theory calculations. The recyclability and stability of 1 after sensing experiments also reveal no change in its crystallinity. Furthermore, selectivity test and time-dependent detection for 4-NA have been successfully demonstrated. For practical applications, naked eye detection of 4-NA using test paper strips is also displayed. PMID- 30407781 TI - Correction to "Self-Adapting Hydrogel To Improve the Therapeutic Effect in Wound Healing". PMID- 30407782 TI - Tailored Colloidal Stability and Rheological Properties of Graphene Oxide Liquid Crystals with Polymer-Induced Depletion Attractions. AB - Graphene oxide liquid crystallinity (GO LC) has been widely exploited for high performance graphene-based applications. In this regard, colloidal stability of GO LC suspension is a crucial requirement, particularly while polymers are often added to the GO LC. Unfortunately, current level of knowledge on how polymers influence the structure and properties of GO LC is not sufficient to systematically guide the development of applications. Here, we investigate the microstructure and rheological properties of GO LC suspensions in the presence of polymer additives with varying molecular weights and concentrations. Similar to conventional colloidal systems, non-negligible polymer-induced interactions are found in GO LC suspensions, which can effectively modulate the interaction among GO platelets and the relevant physical properties. On the basis of extensive small-angle X-ray scattering and rheological measurements, we demonstrate that, contrary to the general perception, polymer-induced depletion attraction can increase the colloidal stability of GO, while also preventing the vitrification of GO LC. In addition, a proper level of polymer additive can reduce the viscosity of GO LC suspensions by orders of magnitude, providing an effective route to GO LC-based solution processing. After all, the colloidal stability and rheological properties of GO can significantly impact the quality of GO. Therefore, we believe that our finding will be of great interest in the field of graphene-based applications, as it presents effective strategies for improving properties. PMID- 30407783 TI - Schottky Barrier Modulation in Surface Nanoroughened Silicon Nanomembranes for High-Performance Optoelectronics. AB - Surface nanostructures of silicon nanomembranes (SiNMs) play a dominant role in modulating their energy band structures and trapping surface charges, thus strongly affecting the Schottky barrier height, the surface resistance, and the optoelectronic response of Schottky-contacted SiNMs. Here, controllable nanoroughening of SiNMs without substantial changes in thickness was realized via a metal-masked chemical-etching approach. The mechanism of surface roughness effect on the electrical characteristics and contact properties of SiNM-based diodes and thin-film transistors was investigated. Meanwhile, photodetective devices were fabricated by utilizing rough SiNMs, and significant dark current suppressions were demonstrated due to surface depletion and Schottky barrier modulations. Moreover, by introducing a three-terminal device structure (adding a gate), the photoresponse could be further enhanced with high current on/off ratio. Our work may provide guidance for creating and designing principles of SiNM-based optoelectronic devices, especially for Schottky barrier modulations. PMID- 30407784 TI - Piezoelectric Effect Tuning on ZnO Microwire Whispering-Gallery Mode Lasing. AB - We report a dynamic tuning on coherent light emission wavelengths of single ZnO microwire by using the piezoelectric effect. Owing to the dominant role occupied by the piezoelectric polarization effect in the wurtzite-structure ZnO microwire, the effective dielectric constant (or refraction index) of the gain media was modulated toward an increasing trend by applying a tensile strain, resulting in a shift of the strain-mediated whispering-gallery mode (WGM) lasing at room temperature. Also, the strain required to resolve the spectra in the two operating types of PL and lasing were systematically analyzed and compared. Because of the narrow line width in the lasing mode, the strain-dependent spectral resolution was improved by an order of magnitude, making it feasible for achieving high-precision, ultrasensitive, and noncontact stress sensing. Our results have an important impact on laser modulation, optical communication, and optical sensing technology. PMID- 30407785 TI - Tunable Luminescence Contrast in Photochromic Ceramics (1 - x)Na0.5Bi0.5TiO3- xNa0.5K0.5NbO3:0.002Er by an Electric Field Poling. AB - A binary solid solution of Er3+-doped (1 - x)Na0.5Bi0.5TiO3- xK0.5Na0.5NbO3 ( x = 0.02, 0.04, 0.06, 0.08, 0.10, 0.12) ferroelectric ceramics has been developed, and a reversible photochromic (PC) reaction and its associated luminescence modulation are realized via alternating the 405 nm light irradiation and thermal stimulation (200 degrees C). The basic crystal structure, domain structure, ferroelectricity, and dielectric behavior of the ceramics were measured. A moderate luminescence contrast Delta R t over 50% is obtained in the fresh samples. Meanwhile, a greatly enhanced luminescence contrast Delta R t is obtained via an electric poling for compositions x = 0.02, 0.04, 0.06. For example, Delta R t is promoted from 53.4 to 85.3% for x = 0.02. However, the luminescence contrast Delta R t of compositions x = 0.08, 0.10, 0.12 is depressed after poling. The mechanisms of enhanced PC reaction and luminescence contrast Delta R t are discussed and proposed. The present study may open a window for enhancing the PC reaction. PMID- 30407786 TI - Structure-Based Drug Designing Recommends HDAC6 Inhibitors To Attenuate Microtubule-Associated Tau-Pathogenesis. AB - Protein acetylation and deacetylation play vital roles in the structural and physiological behavior of target proteins. Histone deacetylase 6 (HDAC6) remains a key therapeutic target in several chronic diseases such as cancer, neurodegenerative, and hematological diseases. In tau-pathogenesis, HDAC6 tightly regulates microtubule-associated tau physiology, and its inhibition suppresses Alzheimer's phenotype. To this end, the current study has identified novel HDAC6 inhibitors by structure-based drug designing method. A pharmacophore was generated from HDAC6 in complex with trichostatin A. The selected pharmacophore had five features including two hydrogen bond donors, one hydrogen bond acceptor, and two hydrophobic features. Pharmacophore validation obtained the highest GH score of 0.80. By applying Lipinski's rule of five and ADMET Descriptors, a drug like database of 29 183 molecules was generated from the Zinc Natural Product Database. The validated pharmacophore screened 841 drug-like molecules and was subsequently subjected to molecular docking in the active site of HDAC6. Molecular docking identified 11 hits, where they showed the highest ChemPLP score (>90.00), stable conformation, and hydrogen-bond interactions with catalytic residues of HDAC6. Finally, molecular dynamics simulation identified three molecules as potent HDAC6 inhibitors with stable root-mean-square deviation and the highest number of hydrogen bonds with the catalytic residues of HDAC6. Overall, we recommend three novel inhibitors of HDAC6, capable of suppressing the microtubule-associated tau-pathogenesis. PMID- 30407787 TI - Sequentially Triggered Delivery System of Black Phosphorus Quantum Dots with Surface Charge-Switching Ability for Precise Tumor Radiosensitization. AB - Cancer radiotherapy suffers from drawbacks such as radiation resistance of hypoxic cells, excessive radiation that causes damage of adjacent healthy tissues, and concomitant side effects. Hence, radiotherapy sensitizers with improved radiotherapeutic performance and requiring a relatively small radiation dose are highly desirable. In this study, a nanosystem based on poly(lactic- co glycolic acid) (PLGA) and ultrasmall black phosphorus quantum dots (BPQDs) is designed and prepared to accomplish precise tumor radiosensitization. The PLGA nanoparticles act as carriers to package the BPQDs to avoid off-target release and rapid degradation during blood circulation. The nanosystem that targets the polypeptide peptide motif Arg-Gly-Asp-Gys actively accumulates in tumor tissues. The 2,3-dimethylmaleic anhydride shell decomposes in an acidic microenvironment, and the nanoparticles become positively charged, thereby favoring cellular uptake. Furthermore, glutathione (GSH) deoxidizes the disulfide bond of cystamine and sequentially triggers release of BPQDs, rendering tumor cells sensitive to radiotherapy. The treatment utilizing the PLGA-SS-D@BPQDs nanosystem and X-ray induces cell apoptosis triggered by overproduction of reactive oxygen species. In the in vivo study, the nanosystem shows excellent radiotherapy sensitization efficiency but negligible histological damage of the major organs. This study provides insights into the design and fabrication of surface-charge-switching and pH-responsive nanosystems as potent radiosensitizers to achieve excellent radiotherapy sensitization efficacy and negligible toxic side effects. PMID- 30407788 TI - Chirality-Induced Electron Spin Polarization and Enantiospecific Response in Solid-State Cross-Polarization Nuclear Magnetic Resonance. AB - NMR-based techniques are supposed to be incapable of distinguishing pure crystalline chemical enantiomers. However, through systematic studies of cross polarization magic angle spinning (CP-MAS) NMR in a series of amino acids, we have found a rather unexpected behavior in the intensity pattern of optical isomers in hydrogen/nitrogen nuclear polarization transfer that would allow the use of CP NMR as a nondestructive enantioselective detection technique. In all molecules considered, the d isomer yields higher intensity than the l form, while the chemical shift for all nuclei involved remains unchanged. We attribute this striking result to the onset of electron spin polarization, accompanying bond charge polarization through a chiral center, a secondary mechanism for polarization transfer that is triggered only in the CP experimental setup. Electron spin polarization is due to the chiral-induced spin selectivity effect (CISS), which creates an enantioselective response, analogous to the one involved in molecular recognition and enantiospecific separation with achiral magnetic substrates. This polarization influences the molecular magnetic environment, modifying the longitudinal relaxation time T1 of 1H, and ultimately provoking the observed asymmetry in the enantiomeric response. PMID- 30407789 TI - Functionalized Carbon Nanofibers Enabling Stable and Flexible Absorbers with Effective Microwave Response at Low Thickness. AB - Lots of work has been done to develop microwave absorbing materials (MAM) utilized as flexible electronic devices and communication instruments. Conventionally developed powder MAM are often limited in practical applications because of the bad stability and poor durability, which is out of the scope for exploiting flexible and long-term microwave absorbers. To overcome such limitations, a facile and binder-free technique from a Co-based zeolitic imidazolate framework (ZIF-67, a member of metal-organic frameworks)-coated carbon fiber precursor is developed for the in situ horizontal growth of Co3O4 nanoparticles, which embedded nitrogen-doped carbon array (triangular nanoplates) on the surface of carbon fibers in the carbon paper (NC-Co3O4/CP) as low thickness MAM. The maximum reflection loss (RL) values reaches -16.12 and -34.34 dB when the thickness is 1.1 and 1.5 mm, respectively. As the thickness increases, the absorbing performance at low frequency performs well (RL < -20 dB). The hierarchical architecture is facilely originated from a metal-organic framework precursor. In view of the simple preparation technique, NC-Co3O4/CP exhibit huge potential in large-scale production of portable microwave absorbing electronic devices with strong microwave response at low thickness. PMID- 30407790 TI - Epidermal Growth Factor Receptor-Targeting Peptide Nanoparticles Simultaneously Deliver Gemcitabine and Olaparib To Treat Pancreatic Cancer with Breast Cancer 2 ( BRCA2) Mutation. AB - Pancreatic cancer (PCa) is one of the most lethal malignancies, with a 5 year survival rate of less than 8%. Current treatment regiments have a low response rate in unselected patients. However, the subgroup of PCa patients with BRCA mutations may benefit from poly-ADP-ribose polymerase inhibitors (PARPi) due to their biological properties in DNA repair. Dose-limiting toxicity in normal tissues is frequently observed when PARPi are combined with other chemotherapies, and the co-delivery of two drugs to tumor sites at an adequate concentration is challenging. To address this issue, we have engineered an epidermal growth factor receptor (EGFR) targeting (with GE11 peptide) self-assembly amphiphilic peptide nanoparticle (GENP) to co-deliver gemcitabine and the PARPi olaparib to treat BRCA mutant PCa. The GENP was relatively stable, exhibited high encapsulation efficiency, and could coordinately release the two drugs in tumor milieu. Gemcitabine and olaparib showed strong synergistic actions in optimized conditions in vitro. The nanoparticle prolonged the half-life of both drugs and resulted in their tumor accumulation at the optimal therapeutic ratio in vivo. The drug-loaded nanoparticles were able to significantly suppress tumor growth in a murine PCa model with minimal side effects. Drug co-delivery of DNA damaging agents and PARP inhibitors via the GENP represents a promising approach for treatment of pancreatic cancers with molecular defects in the DNA repair pathway. PMID- 30407791 TI - Single Molecular Layer of Silk Nanoribbon as Potential Basic Building Block of Silk Materials. AB - In this study, nascent silk nanoribbons (SNRs) with an average thickness of 0.4 nm were extracted from natural silkworm silk by partially dissolving degummed silk (DS) in sodium hydroxide (NaOH)/urea solution at -12 degrees C. In this gentle treatment, the solvent could not destroy the nanofibrillar structure completely, but the chosen conditions would influence the dimensions of resulting SNRs. Molecular dynamics simulations of silk models indicated that the potential of mean force required to break hydrogen bonds between silk fibroin chains was 40% larger than that of van der Waals interactions between beta-sheet layers, allowing the exfoliating treatment. It was found that the resulting SNRs contained a single beta-sheet layer and amorphous silk fibroin molecules, which could be considered as the basic building block of DS consisting of hierarchical structures. The demonstrated technique for extracting ultrathin SNRs having the height of a single beta-sheet layer may provide a useful pathway for creating stronger and tougher silk-based materials and/or adding functionality and durability in materials for various applications. The hierarchical structure model based on SNRs may afford more insight into the structure and property relationship of fabricating silk-based materials. PMID- 30407793 TI - 5 S,15 S-Dihydroperoxyeicosatetraenoic Acid (5,15-diHpETE) as a Lipoxin Intermediate: Reactivity and Kinetics with Human Leukocyte 5-Lipoxygenase, Platelet 12-Lipoxygenase, and Reticulocyte 15-Lipoxygenase-1. AB - The reaction of 5 S,15 S-dihydroperoxyeicosatetraenoic acid (5,15-diHpETE) with human 5-lipoxygenase (LOX), human platelet 12-LOX, and human reticulocyte 15-LOX 1 was investigated to determine the reactivity and relative rates of producing lipoxins (LXs). 5-LOX does not react with 5,15-diHpETE, although it can produce LXA4 when 15-HpETE is the substrate. In contrast, both 12-LOX and 15-LOX-1 react with 5,15-diHpETE, forming specifically LXB4. For 12-LOX and 5,15-diHpETE, the kinetic parameters are kcat = 0.17 s-1 and kcat/ KM = 0.011 MUM-1 s-1 [106- and 1600-fold lower than those for 12-LOX oxygenation of arachidonic acid (AA), respectively]. On the other hand, for 15-LOX-1 the equivalent parameters are kcat = 4.6 s-1 and kcat/ KM = 0.21 MUM-1 s-1 (3-fold higher and similar to those for 12-HpETE formation by 15-LOX-1 from AA, respectively). This contrasts with the complete lack of reaction of 15-LOX-2 with 5,15-diHpETE [Green, A. R., et al. (2016) Biochemistry 55, 2832-2840]. Our data indicate that 12-LOX is markedly inferior to 15-LOX-1 in catalyzing the production of LXB4 from 5,15-diHpETE. Platelet aggregation was inhibited by the addition of 5,15-diHpETE, with an IC50 of 1.3 MUM; however, LXB4 did not significantly inhibit collagen-mediated platelet activation up to 10 MUM. In summary, LXB4 is the primary product of 12 LOX and 15-LOX-1 catalysis, if 5,15-diHpETE is the substrate, with 15-LOX-1 being 20-fold more efficient than 12-LOX. LXA4 is the primary product with 5-LOX but only if 15-HpETE is the substrate. Approximately equal proportions of LXA4 and LXB4 are produced by 12-LOX but only if LTA4 is the substrate, as described previously [Sheppard, K. A., et al. (1992) Biochim. Biophys. Acta 1133, 223-234]. PMID- 30407792 TI - Strategy for In Situ Imaging of Cellular Alkaline Phosphatase Activity Using Gold Nanoflower Probe and Localized Surface Plasmon Resonance Technique. AB - In this work, a simple and ultrasensitive localized surface plasmon resonance (LSPR) method that use Au nanoflowers (AuNFs) as a probe was designed for in situ monitoring of alkaline phosphatase (ALP) activity. The AuNFs were fabricated by hydrogen tetrechloroaurate-induced oxidative disruption of polydopamine-coated Au nanoparticles (AuNPs), and subsequently, growth of Au nanopetals on AuNPs occurred. The as-prepared AuNFs showed a much higher LSPR capability and stronger scattering color change than AuNPs. The strategy for in situ cellular ALP activity detection relied on the deposition of Ag on the AuNFs surface, which changed the morphology of AuNFs and led to a tremendous LSPR response and scattering color change. The deposition of Ag shell on AuNFs was related to ALP activity, where ALP catalyzed the hydrolysis of l-ascorbic acid 2-phosphate sesquimagnesium salt hydrate to form l-ascorbic acid (AA), and then AA reduced Ag+ to Ag and deposited onto AuNFs. With this concept, the ALP activity could be monitored with a detection limit of 0.03 MUU L-1. Meanwhile, the ALP activity of single HepG2 cells and HEK 293 cells was tracked with a proposed approach, which indicated the trace expression level of ALP in HEK 293T cell and overexpressed level of ALP in HepG2 cells. After treatment with drugs, the cellular ALP activity of HepG2 cells was decreased with the treating time and dose increasing. Therefore, the proposed strategy could be used for tracking the cellular ALP activity, which paved a new avenue for cell studies and held great potential for discovering novel ALP-based drugs applications. PMID- 30407794 TI - Insights into the Plasma-Assisted Fabrication and Nanoscopic Investigation of Tailored MnO2 Nanomaterials. AB - Among transition metal oxides, MnO2 is of considerable importance for various technological end-uses, from heterogeneous catalysis to gas sensing, owing to its structural flexibility and unique properties at the nanoscale. In this work, we demonstrate the successful fabrication of supported MnO2 nanomaterials by a catalyst-free, plasma-assisted process starting from a fluorinated manganese(II) molecular source in Ar/O2 plasmas. A thorough multitechnique characterization aimed at the systematic investigation of material structure, chemical composition, and morphology revealed the formation of F-doped, oxygen-deficient, MnO2-based nanomaterials, with a fluorine content tunable as a function of growth temperature ( TG). Whereas phase-pure beta-MnO2 was obtained for 100 degrees C <= TG <= 300 degrees C, the formation of mixed phase MnO2 + Mn2O3 nanosystems took place at 400 degrees C. In addition, the system nano-organization could be finely tailored, resulting in a controllable evolution from wheat-ear columnar arrays to high aspect ratio pointed-tip nanorod assemblies. Concomitantly, magnetic force microscopy analyses suggested the formation of spin domains with features dependent on material morphology. Preliminary tests in Vis-light activated photocatalytic degradation of rhodamine B aqueous solutions pave the way to possible applications of the target materials in wastewater purification. PMID- 30407795 TI - Accurate Determination of Catalyst Loading on Glassy Carbon Disk and Its Impact on Thin Film Rotating Disk Electrode for Oxygen Reduction Reaction. AB - Thin film-rotating disc electrode (TF-RDE) experiment provides a fast research platform for screening of newly developed electrocatalysts for oxygen reduction reaction (ORR) activity; however, precise estimation of their performance parameters is necessary to avoid wastage of resources in the testing of otherwise unpromising electrocatalyst in actual fuel cells. Here we show the importance of the accurate amount of catalyst (e.g., Pt) on glassy carbon (GC) disk of RDE in TF-RDE experiment by characterizing the commercial catalysts for their electrocatalysis performance (electrochemical surface area and ORR activity) values. The Pt loadings used to calculate these performance values were obtained using two schemes, namely, using the literature based (conventional) scheme and an X-ray fluorescence (XRF) based scheme. A parameter called "catalyst-density-of the-ink" is used to correlate the variations observed in performance values and the amount of Pt on GC disk of RDE obtained using both schemes. The investigation suggests that the actual Pt loading on the GC disk of RDE varies with the ink conditions, which is considered constant in the conventional scheme and might be one of the reasons of irreproducibility of the data obtained by TF-RDE experiments. The XRF-based scheme, which is simple and direct, can have the potential to replace conventional scheme for accurate catalyst loading estimation, improve experimental reproducibility, and open many other possibilities (e.g., post-mortem analysis of catalyst) in electrocatalysis studies. PMID- 30407796 TI - Rotating Magnetic Field-Assisted Adsorption Mechanism of Pollutants on Mechanically Strong Sodium Alginate/Graphene/l-Cysteine Beads in Batch and Fixed Bed Column Systems. AB - Novel, efficient bioadsorbent sodium alginate/graphene/l-cysteine (SA/GR/l-Cys) beads were prepared and used for magnetic field (MF)-assisted adsorption of pollutants. SA/GR/l-Cys has excellent mechanical properties, with a breaking stress of 3.5 MPa at 79.8%, an elastic modulus of 5.0 MPa, low swelling properties (average swelling ratio <300%), and good adsorption properties toward organic pollutants and heavy metal ions. A rotating magnetic field (RMF) was shown to have a better influence than a static magnetic field (SMF) on adsorption, with enhanced adsorption capacities 5-fold greater than those of the SMF. We investigated the different adsorption mechanisms of model contaminants through Fourier transform infrared spectroscopy, zeta potential, and X-ray photoelectrons spectroscopy. Formation of new hydrogen bonds, change in zeta potential, and acceleration in chemical reactions strongly influenced the adsorption process under the RMF. In fixed-bed column adsorption, the breakthrough time for column adsorption increased, and the adsorption capacity improved by 30.66%. The costs and practical applications of SA/GR/l-Cys under RMF were also analyzed. This work demonstrated that SA/GR/l-Cys could serve as a promising adsorbent for water pollutants under RMF exposure and could be used in practical applications. PMID- 30407797 TI - Constraints on Aerosol Nitrate Photolysis as a Potential Source of HONO and NO x. AB - The concentration of nitrogen oxides (NO x) plays a central role in controlling air quality. On a global scale, the primary sink of NO x is oxidation to form HNO3. Gas-phase HNO3 photolyses slowly with a lifetime in the troposphere of 10 days or more. However, several recent studies examining HONO chemistry have proposed that particle-phase HNO3 undergoes photolysis 10-300 times more rapidly than gas-phase HNO3. We present here constraints on the rate of particle-phase HNO3 photolysis based on observations of NO x and HNO3 collected over the Yellow Sea during the KORUS-AQ study in summer 2016. The fastest proposed photolysis rates are inconsistent with the observed NO x to HNO3 ratios. Negligible to moderate enhancements of the HNO3 photolysis rate in particles, 1-30 times faster than in the gas phase, are most consistent with the observations. Small or moderate enhancement of particle-phase HNO3 photolysis would not significantly affect the HNO3 budget but could help explain observations of HONO and NO x in highly aged air. PMID- 30407798 TI - Advanced Monoethanolamine Absorption Using Sulfolane as a Phase Splitter for CO2 Capture. AB - A novel phase splitter, namely, sulfolane, was proposed to advance the traditional monoethanolamine (MEA) absorption technology for CO2 capture by simultaneously promoting the absorption rate and lowering heat duty. The phase splitting phenomenon was observed after the CO2 loading level had exceeded 0.73 mol CO2/L, thereby generating a CO2-rich MEA upper layer and a lower layer containing sulfolane. Sulfolane facilitated CO2 absorption because of its strong affinity with acid gases, which resulted in an absorption rate 2.7 times higher than that of the conventional MEA process. The process simulation using Aspen Plus indicated that the regeneration heat with the MEA/sulfolane mixture as a solvent substantially decreased to 2.67 GJ/t-CO2, which was 31% lower than that of the conventional MEA process (3.85 GJ/t-CO2). Moreover, the sensible heat and vaporization heat of MEA/sulfolane were markedly decreased by 62.4% and 47.9%, which could be ascribed to the decreased stripping volume and relatively high CO2 partial pressure caused by liquid-liquid phase separation. The proposed system is proved to be a promising candidate for the advancement of CO2 capture techniques with high CO2 absorption capacity, rapid absorption rate, and low-energy penalty. PMID- 30407799 TI - Breaking Carbon-Chlorine Bonds with the Unconventional Lewis Acid Dodecachlorocyclohexasilane. AB - c-Si6Cl12 functions as a Lewis acid strong enough to abstract chloride ions from 2 mol of triphenylchloromethane to form the salt [Tr+]2[Si6Cl142-]. This is the first example of a Lewis acid "hole" breaking a carbon-halogen bond. PMID- 30407800 TI - A Model for Risk-Based Screening and Prioritization of Human Exposure to Chemicals from Near-Field Sources. AB - Exposure- and risk-based assessments for chemicals used indoors or applied to humans (i.e., in near-field environments) necessitate an aggregate exposure pathway framework that aligns chemical exposure information from use sources to internal dose and eventually to their potential for health effects. Such a source to-effect continuum is advocated to balance the complexity of human exposure and the insufficiency of relevant data for thousands of existing and emerging chemicals. Here, we introduce the Risk Assessment, IDentification And Ranking Indoor and Consumer Exposure (RAIDAR-ICE) model, which establishes an integrated framework to evaluate human exposure due to indoor use and direct application of chemicals to humans. As a model evaluation, RAIDAR-ICE faithfully reproduces exposure estimates inferred from biomonitoring data for 37 chemicals with direct and indirect near-field sources. RAIDAR-ICE generates different rankings for 131 chemicals based on different exposure- and risk-based assessment metrics, demonstrating its versatility for diverse chemical screening goals. When coupled with a far-field RAIDAR model, the near-field RAIDAR-ICE model enables assessment of aggregate human exposure. Overall, RAIDAR-ICE is a powerful tool for high throughput screening and prioritization of human exposure to neutral organic chemicals used indoors. PMID- 30407801 TI - DNA-Polymer Conjugates by Photoinduced RAFT Polymerization. AB - Conventional grafting-to approaches to DNA-polymer conjugates are often limited by low reaction yields due to the sterically hindered coupling of a presynthesized polymer to DNA. The grafting-from strategy, in contrast, allows one to directly graft polymers from an initiator that is covalently attached to DNA. Herein, we report blue-light-mediated reversible addition-fragmentation chain-transfer (Photo-RAFT) polymerization from two different RAFT agent terminated DNA sequences using Eosin Y as the photocatalyst in combination with ascorbic acid. Three monomer families (methacrylates, acrylates and acrylamides) were successfully polymerized from DNA employing Photo-RAFT polymerization. We demonstrate that the length of the grown polymer chain can be varied by altering the monomer to DNA-initiator ratio, while the self-assembly features of the DNA strands were maintained. In summary, we describe a convenient, light-mediated approach toward DNA-polymer conjugates via the grafting-from approach. PMID- 30407802 TI - Selective and Sensitive Sensing of Hydrogen Peroxide by a Boronic Acid Functionalized Metal-Organic Framework and Its Application in Live-Cell Imaging. AB - A new boronic acid functionalized Zr(IV) metal-organic framework having the capability of sensing H2O2 in live cells is reported. The Zr-MOF bears a UiO-66 structure and contains 2-boronobenzene-1,4-dicarboxylic acid (BDC-B(OH)2) as a framework linker. The activated Zr-UiO-66-B(OH)2 compound (called 1') is highly selective for the fluorogenic detection of H2O2 in HEPES buffer at pH 7.4, even in the presence of interfering ROS (ROS = reactive oxygen species) and other biologically relevant analytes. The fluorescent probe was found to display extraordinary sensitivity for H2O2 (detection limit 0.015 MUM) in HEPES buffer, which represents a lower value in comparison to those of the MOF probes documented so far for sensing H2O2 using other analytical methods. Taking advantage of its high selectivity and sensitivity for H2O2 in HEPES buffer, the probe was successfully employed for the imaging of intracellular H2O2. Imaging studies with MDAMB-231 cells revealed the emergence of bright blue fluorescence after loading with probe 1' and subsequent treatment with H2O2 solution. PMID- 30407803 TI - Impact of Road Salt on Drinking Water Quality and Infrastructure Corrosion in Private Wells. AB - Increased road salt use and resulting source water contamination has widespread implications for corrosion of drinking water infrastructure, including chloride acceleration of galvanic corrosion and other premature plumbing failures. In this study, we utilized citizen science sampling, bench-scale corrosion studies, and state-level spatial modeling to examine the potential extent of chloride concentrations in groundwater and the resulting impact on private wells in New York. Across the sampled community, chloride levels varied spatially, with the highest levels in private wells downgradient of a road salt storage facility followed by wells within 30 m of a major roadway. Most well users surveyed (70%) had stopped drinking their well water for aesthetic and safety reasons. In the bench-scale experiment, increasing chloride concentration in water increased galvanic corrosion and dezincification of plumbing materials, resulting in increased metal leaching and pipe wall thinning. Our simple spatial analysis suggests that 2% of private well users in New York could potentially be impacted by road salt storage facilities and 24% could potentially be impacted by road salt application. Our research underscores the need to include the damage to public and privately owned drinking water infrastructure in future discussion of road salt management. PMID- 30407804 TI - Anionic Ring-Opening Polymerization of N-(tolylsulfonyl)azetidines To Produce Linear Poly(trimethylenimine) and Closed-System Block Copolymers. AB - The anionic ring-opening copolymerization of N-( p-tolylsulfonyl)azetidine ( pTsAzet) and N-( o-tolylsulfonyl)azetidine ( oTsAzet) produces poly( pTsAzet- co- oTsAzet) as a statistical copolymer. The pTsAzet/ oTsAzet copolymerization is living and allows for the synthesis of poly(sulfonylazetidine) of target molecular weights with narrow dispersities. 1H NMR spectroscopy was used to monitor the kinetics of the polymerization and estimate the monomer reactivity ratios. It was found that the reactivity ratios for oTsAzet and pTsAzet at 180 degrees C are 1.66 and 0.60, respectively. The tosyl groups of p( pTsAzet- co- oTsAzet) were reductively removed to produce linear poly(trimethylenimine) (LPTMI). This represents the first route to LPTMI of controlled molecular weight and low dispersity. Finally, the slow kinetics of the sulfonylazetidine polymerization facilitated the synthesis of a block copolymer without requiring the sequential addition of monomer. Specifically, pTsAzet, oTsAzet, and ( N- p toluenesulfonyl-2-methylaziridine) ( pTsMAz) were combined in solution. pTsMAz selectively polymerizes to form the first block at moderate temperature. After consumption of pTsMAz, the temperature was increased to copolymerize pTsAzet and oTsAzet and produce the block copolymer p( pTsMAz)- b-p( pTsAzet- co- oTsAzet). PMID- 30407805 TI - MELD * MD Folds Nonthreadables, Giving Native Structures and Populations. AB - A current challenge is to compute the native structures of proteins from their amino acid sequences. A main approach of bioinformatics is threading, in which a protein to be predicted is computationally threaded onto protein fragments of similar sequence having an already known structure. However, ~15% of proteins cannot be folded in this way; this has been called the glass ceiling, and the proteins are called nonthreadables. For these, physical molecular dynamics (MD) modeling is promising because it does not require templates. We find that MD, when used with an accelerator called MELD, can fold many nonthreadables. For 41 nonthreadable proteins with fewer than 125 residues, MELD-accelerated MD (MELD * MD) folds 20 of them to better than 4 A error. In 10 cases, MELD * MD succeeds even when the force field does not properly encode the native state. In 11 cases, MELD * MD foretells its own success; seeing large Boltzmann populations in the simulations predicts it has converged to the correct native state. MELD * MD acceleration can be applied to a broad physical protein modeling range. PMID- 30407806 TI - Tetranuclear [MnIIIMn3IVO4] Complexes as Spectroscopic Models of the S2 State of the Oxygen Evolving Complex in Photosystem II. AB - Despite extensive biochemical, spectroscopic, and computational studies, the mechanism of biological water oxidation by the oxygen evolving complex (OEC) of Photosystem II remains a subject of significant debate. Mechanistic proposals are guided by the characterization of reaction intermediates such as the S2 state, which features two characteristic EPR signals at g = 2 and g = 4.1. Two nearly isoenergetic structural isomers have been proposed as the source of these distinct signals, but relevant structure-electronic structure studies remain rare. Herein, we report the synthesis, crystal structure, electrochemistry, XAS, magnetic susceptibility, variable temperature CW-EPR, and pulse EPR data for a series of [MnIIIMn3IVO4] cuboidal complexes as spectroscopic models of the S2 state of the OEC. Resembling the oxidation state and EPR spectra of the S2 state of the OEC, these model complexes show two EPR signals, a broad low field signal and a multiline signal, that are remarkably similar to the biological system. The effect of systematic changes in the nature of the bridging ligands on spectroscopy were studied. Results show that the electronic structure of tetranuclear Mn complexes is highly sensitive to even small geometric changes and the nature of the bridging ligands. Our model studies suggest that the spectroscopic properties of the OEC may also react very sensitively to small changes in structure; the effect of protonation state and other reorganization processes need to be carefully assessed. PMID- 30407807 TI - Turning Au Nanoclusters Catalytically Active for Visible-Light-Driven CO2 Reduction through Bridging Ligands. AB - Development of visible-light photocatalytic materials is an ultimate goal for solar-driven CO2 conversion. Au nanoclusters (NCs) may potentially serve as components for harvesting visible light but can hardly perform solar-driven CO2 reduction due to the lack of catalytic sites. Herein, we report an effective strategy for turning Au nanoclusters catalytically active for visible-light CO2 reduction, in which metal cations (Fe2+, Co2+, Ni2+, and Cu2+) are grafted to the Au NCs using l-cysteine as a bridging ligand. The metal-S bonding bridge facilitates the electron transfer from Au NCs to metal cations so that the grafted metal cations can receive photoinduced electrons and work as catalytic sites for CO2 reduction. The varied d-band centers and binding energies with CO2 for different metal cations allow tuning electron transfer efficiency and CO2 activation energy. Furthermore, the photostability of Au NCs-based catalyst can be significantly enhanced through the encapsulation with metal-organic frameworks. This work opens a new door for the photocatalyst design based on metal clusters and sheds light on the surface engineering of metal clusters toward specific applications. PMID- 30407808 TI - Degradation of Phenylurea Herbicides by a Novel Bacterial Consortium Containing Synergistically Catabolic Species and Functionally Complementary Hydrolases. AB - Phenylurea herbicides (PHs) are frequently detected as major water contaminants in areas where there is extensive use. In this study, Diaphorobacter sp. strain LR2014-1, which initially hydrolyzes linuron to 3,4-dichloroanaline, and Achromobacter sp. strain ANB-1, which further mineralizes the produced aniline derivatives, were isolated from a linuron-mineralizing consortium despite being present at low abundance in the community. The synergistic catabolism of linuron by the consortium containing these two strains resulted in more efficient catabolism of linuron and growth of both strains. Strain LR2014-1 harbors two evolutionary divergent hydrolases from the amidohydrolase superfamily Phh and the amidase superfamily TccA2, which functioned complementarily in the hydrolysis of various types of PHs, including linuron ( N-methoxy- N-methyl-substituted), diuron, chlorotoluron, fluomethuron ( N, N-dimethyl-substituted), and siduron. These findings show that a bacterial consortium can contain catabolically synergistic species for PH mineralization, and one strain could harbor functionally complementary hydrolases for a broadened substrate range. PMID- 30407809 TI - Unlocking a Diazirine Long-Lived Nuclear Singlet State via Photochemistry: NMR Detection and Lifetime of an Unstabilized Diazo-Compound. AB - Diazirines are important for photoaffinity labeling, and their photoisomerization is relatively well-known. This work shows how hyperpolarized NMR spectroscopy can be used to characterize an unstable diazo-compound formed via photoisomerization of a 15N2-labeled silyl-ether-substituted diazirine. This diazirine is prepared in a nuclear spin singlet state via catalytic transfer of spin order from para hydrogen. The active hyperpolarization catalyst is characterized to provide insight into the mechanism. The photochemical isomerization of the diazirine into the diazo-analogue allows the NMR invisible nuclear singlet state of the parent compound to be probed. The identity of the diazo-species is confirmed by trapping with N-phenyl maleimide via a cycloaddition reaction to afford bicyclic pyrazolines that also show singlet state character. The presence of singlet states in the diazirine and the diazo-compound is validated by comparison of experimental nutation behavior with theoretical simulation. The magnetic state lifetime of the diazo-compound is determined as 12 +/- 1 s in CD3OD solution at room temperature, whereas its chemical lifetime is measured as 100 +/- 5 s by related hyperpolarized NMR studies. Indirect evidence for the generation of the photoproduct para-N2 is presented. PMID- 30407810 TI - Targeted Molecular Dynamics Calculations of Free Energy Profiles Using a Nonequilibrium Friction Correction. AB - As standard unbiased molecular dynamics (MD) simulations become impractical for sampling rare events, "targeted MD" employs a moving distance constraint to enforce rare transitions along some reaction coordinate x. To calculate free energy profiles from these nonequilibrium simulations via Delta G( x) = W( x) - Wdiss( x), apart from the (readily obtained) work W( x) performed on the system, the dissipated work Wdiss( x) is also required. By employing a second-order cumulant expansion of Jarzynski's equality combined with an analysis within Langevin theory, the dissipated work can be expressed via a nonequilibrium friction coefficient GammaNEQ( x) that may be calculated on-the-fly from constraint force fluctuations. Adopting the ion dissociation of NaCl in water as a test system, this friction correction is shown to result in accurate free energy profiles, even for a modest number of simulations and at high constraint velocities. As a bonus, the analysis of GammaNEQ( x) may yield valuable insight into the microscopic mechanism of friction. PMID- 30407811 TI - Modeling of Magnetic Circular Dichroism and UV/Vis Absorption Spectra Using Fluctuating Charges or Polarizable Embedding within a Resonant-Convergent Response Theory Formalism. AB - In recent years computational methods based on embedding have become of increasing popularity when the aim is to introduce environmental effects into quantum chemistry calculations of molecular properties. This is due in particular to the efficiency of such methods while still retaining a high degree of accuracy compared to full quantum chemistry treatments. In the present paper we compare two popular embedding methods-fluctuating charges (FQ) and polarizable embedding (PE)-highlighting their similar mathematical structure. Furthermore, based on a unified formulation of the two embedding methods, we present theory and implementation of these embedding methods within resonant-convergent response theory up to the level of quadratic response. A numerical comparison between FQ and PE is presented for a set of solute-solvent systems based on calculations of UV/vis and magnetic circular dichroism spectra. Overall, we find in the cases considered the FQ and PE models to perform rather similarly, especially upon introducing effects of explicit conformational sampling into the theoretical predictions. PMID- 30407812 TI - Site-Specific Metal Chelation Facilitates the Unveiling of Hidden Coordination Sites in an FeII/FeIII-Seamed Pyrogallol[4]arene Nanocapsule. AB - Under suitable conditions, C-alkylpyrogallol[4]arenes (PgCs) arrange into spherical metal-organic nanocapsules (MONCs) upon coordination to appropriate metal ions. Herein we present the synthesis and structural characterization of a novel FeII/FeIII-seamed MONC, as well as studies related to its electrochemical and magnetic behaviors. Unlike other MONCs that are assembled through 24 metal ions, this nanocapsule comprises 32 Fe ions, uncovering 8 additional coordination sites situated between the constituent PgC subunits. The FeII ions are likely formed by the reducing ability of DMF used in the synthesis, representing a novel synthetic route toward polynuclear mixed-valence MONCs. PMID- 30407813 TI - Metabolomics-Driven Discovery of Meroterpenoids from a Mussel-Derived Penicillium ubiquetum. AB - Penicillium ubiquetum MMS330 isolated from the blue mussel Mytilus edulis collected on the Loire estuary in France was here investigated. As very few secondary metabolites have been documented for this species, its metabolome was studied following the OSMAC approach to enhance as many biosynthetic pathways as possible. Interestingly, HPLC-HRMS based hierarchical clustering analysis together with MS/MS molecular networking highlighted the selective overproduction of some structurally related compounds when the culture was performed on seawater CYA (Czapek Yeast extract Agar) medium. Mass-guided purification from large scale cultivation on this medium led to the isolation of nine meroterpenoids including two new analogues, 22-deoxyminiolutelide A (1) and 4-hydroxy-22 deoxyminiolutelide B (2), together with seven known compounds (3-9). The structures of 1 and 2 were elucidated on the basis of HR-ESIMS and NMR spectroscopic data analysis. Furthermore, NMR signals of 22-deoxyminiolutelide B (3) were reassigned. PMID- 30407814 TI - Optimizing Nonbonded Interactions of the OPLS Force Field for Aqueous Solutions of Carbohydrates: How to Capture Both Thermodynamics and Dynamics. AB - Knowledge on thermodynamic and transport properties of aqueous solutions of carbohydrates is of great interest for process and product design in the food, pharmaceutical, and biotechnological industries. Molecular simulation is a powerful tool to calculate these properties, but current classical force fields cannot provide accurate estimates for all properties of interest. The poor performance of the force fields is mainly observed for concentrated solutions, where solute-solute interactions are overestimated. In this study, we propose a method to refine force fields, such that solute-solute interactions are more accurately described. The OPLS force field combined with the SPC/Fw water model is used as a basis. We scale the nonbonded interaction parameters of sucrose, a disaccharide. The scaling factors are chosen in such a way that experimental thermodynamic and transport properties of aqueous solutions of sucrose are accurately reproduced. Using a scaling factor of 0.8 for Lennard-Jones energy parameters (epsilon) and a scaling factor of 0.95 for partial atomic charges ( q), we find excellent agreement between experiments and computed liquid densities, thermodynamic factors, shear viscosities, self-diffusion coefficients, and Fick (mutual) diffusion coefficients. The transferability of these optimum scaling factors to other carbohydrates is verified by computing thermodynamic and transport properties of aqueous solutions of d-glucose, a monosaccharide. The good agreement between computed properties and experiments suggests that the scaled interaction parameters are transferable to other carbohydrates, especially for concentrated solutions. PMID- 30407815 TI - Structure and Reactivity of a Mononuclear Nonheme Manganese(III)-Iodosylarene Complex. AB - Transition metal-iodosylarene complexes have been proposed to be key intermediates in the catalytic cycles of metal catalysts with iodosylarene. We report the first X-ray crystal structure and spectroscopic characterization of a mononuclear nonheme manganese(III)-iodosylarene complex with a tetradentate macrocyclic ligand, [MnIII(TBDAP)(OIPh)(OH)]2+ (2). The manganese(III) iodosylarene complex is capable of conducting various oxidation reactions with organic substrates, such as C-H bond activation, sulfoxidation and epoxidation. Kinetic studies including isotope labeling experiments and Hammett correlation demonstrate the electrophilic character on the Mn-iodosylarene adduct. This novel intermediate would be prominently valuable for expanding the chemistry of transition metal catalysts. PMID- 30407816 TI - Structure-Based Approach toward Identification of Inhibitory Fragments for Eleven Nineteen-Leukemia Protein (ENL). AB - Lysine acetylation is an epigenetic mark that is principally recognized by bromodomains, and recently structurally diverse YEATS domains also emerged as readers of lysine acetyl/acylations. Here we present a crystallography-based strategy and the discovery of fragments binding to the ENL YEATS domain, a potential drug target. Crystal structures combined with synthetic efforts led to the identification of a submicromolar binder, providing first starting points for the development of chemical probes for this reader domain family. PMID- 30407817 TI - Structural Correlations and Percolation in Twisted Perylene Diimides Using a Simple Anisotropic Coarse-Grained Model. AB - Large, twisted, and fused conjugated molecular architectures have begun to appear more prominently in the organic semiconductor literature. From a modeling perspective, such structures present a challenge to conventional simulation techniques; atomistic resolutions are computationally inefficient, while traditional isotropic coarse-grained models do not capture the inherent anisotropies of the molecules. In this work, we develop a simple coarse-grained model that explicitly incorporates the anisotropy of these molecular architectures, thereby providing a route toward analyzing pi-stacking, and thus qualitative electronic structure, at a computationally efficient coarse-grained resolution. Our simple coarse-grained model maintains relative orientations of conjugated rings, as well as inter-ring dihedrals, that are critical for understanding electronic and excitonic transport in bulk systems. We apply this model to understand structural correlations in several recently synthesized perylene diimide (PDI)-based organic semiconductors. Twisted and nonplanar molecular architectures are found to promote amorphous morphologies while maintaining local pi-stacking. A graph theoretical network analysis demonstrates that these twisted molecules are more likely to form percolating three dimensional pathways for charge motion than strictly planar molecules, which show connectivity in only one dimension. PMID- 30407818 TI - Brownian Dynamics Approach Including Explicit Atoms for Studying Ion Permeation and Substrate Translocation across Nanopores. AB - A Brownian dynamics (BD) approach including explicit atoms called BRODEA is presented to model ion permeation and molecule translocation across a nanopore confinement. This approach generalizes our previous hybrid molecular dynamics Brownian dynamics framework ( J. Chem. Theory Comput. 2016, 12, 2401) by incorporating a widespread and enhanced set of simulation schemes based on several boundary conditions and electrostatic models, as well as a temperature accelerated method for sampling free energy surfaces and determining substrate translocation pathways. As a test case, BRODEA was applied to study the ion diffusion as well as to ciprofloxacin and enrofloxacin transport through the outer membrane porin OmpC from E. coli. The equivalence between the different simulation schemes was demonstrated and their computational efficiency evaluated. The BRODEA results are able to reproduce the main features of the ion currents and free energy surfaces determined by all-atom molecular dynamics simulations and validated by experiments. Furthermore, the BRODEA results are able to determine the ciprofloxacin and enrofloxacin permeation pathways showing a remarkable agreement with the results obtained from a computational protocol that combines metadynamics and a zero-temperature string method ( J. Chem. Theory Comput. 2017, 13, 4553; J. Phys. Chem. B 2018, 122, 1417). To our knowledge, this is the first time such antibiotic permeation pathways have been characterized by a technique based on Brownian dynamics. PMID- 30407819 TI - Preferential Photoreaction in a Porous Crystal, Metal-Macrocycle Framework: PdII Mediated Olefin Migration over [2+2] Cycloaddition. AB - A nanosized confined space with well-defined functional surfaces has great potential to control the efficiency and selectivity of catalytic reactions. Herein we report that a 1,6-diene, which normally forms an intramolecular [2+2] cycloadduct under photoirradiation, preferentially undergoes a photoinduced olefin migration in a porous crystal, metal-macrocycle framework (MMF), and alternatively [2+2] cycloaddition is completely inhibited in the confined space. A plausible reaction mechanism for olefin migration triggered by the photoinduced dissociation of the Pd-Cl bond is suggested based on UV-vis diffuse reflectance spectroscopy, single-crystal XRD, and MS-CASPT2 calculation. The substrate scope of the photoinduced olefin migration in MMF was also examined using substituted allylbenzene derivatives. PMID- 30407820 TI - Diastereoselective alpha-Fluorination of N- tert-Butanesulfinyl Imidates. AB - A diastereoselective alpha-fluorination of N- tert-butanesulfinyl imidates was developed. Deprotonation of N- tert-butanesulfinyl imidates with lithium hexamethyldisilazide generates aza-enolates that can be intercepted, with excellent diastereocontrol, by the inexpensive electrophilic fluorinating agent NFSI. This protocol was applied to the preparation of synthetically useful trans 2-fluoro-cyclohexamine with high enantiomeric purity (99.5% ee). PMID- 30407821 TI - Discovery of small molecule splicing modulators of survival motor neuron-2 (SMN2) for the treatment of Spinal Muscular Atrophy (SMA). AB - Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a loss of function mutation of the survival motor neuron 1 (SMN1) gene. In humans, a second closely related gene SMN2 exists, however it codes for a less stable SMN protein. In recent years, significant progress has been made toward disease modifying treatments for SMA by modulating SMN2 pre-mRNA splicing. Herein, we describe the discovery of LMI070 / branaplam, a small molecule that stabilizes the interaction between the spliceosome and SMN2 pre-mRNA. Branaplam (1) originated from a high-throughput phenotypic screening hit, pyridazine 2, and evolved via multi-parameter lead optimization. In a severe mouse SMA model, branaplam treatment increased full-length SMN RNA and protein levels, and extended survival. Currently, branaplam is in clinical studies for SMA. PMID- 30407822 TI - Inter/Intramolecular Bonds in TH5+ (T = C/Si/Ge): H2 as Tetrel Bond Acceptor and the Uniqueness of Carbon Bonds. AB - Atoms in molecules (AIM), natural bond orbital (NBO), and normal coordinate analysis have been carried out at the global minimum structures of TH5+ (T = C/Si/Ge). All these analyses lead to a consistent structure for these three protonated TH4 molecules. The CH5+ has a structure with three short and two long C-H covalent bonds and no H-H bond. Hence, the popular characterization of protonated methane as a weakly bound CH3+ and H2 is inconsistent with these results. However, SiH5+ and GeH5+ are both indeed a complex formed between TH3+ and H2 stabilized by a tetrel bond, with the H2 being the tetrel bond acceptor. The three-center-two-electron bond (3c-2e) in CH5+ has an open structure, which can be characterized as a V-type 3c-2e bond and that found in SiH5+ and GeH5+ is a T-type 3c-2e bond. This difference could be understood based on the typical C H, Si-H, Ge-H, and H-H bond and the tetrel bond energies. This analysis explains the trend observed in proton affinity of TH4 which appears counterintuitive, GeH4 > SiH4 > CH4. Carbon is selective in forming a "tetrel bond" and when it does, it might be worthwhile to highlight it as a "carbon bond". PMID- 30407823 TI - Fluorescence Resonance Energy Transfer (FRET): A Powerful Tool for Probing Amphiphilic Polymer Aggregates and Supramolecular Polymers. AB - This Review Article highlights the utility of the fluorescence resonance energy transfer (FRET) to probe the dynamics and related issues in amphiphilic polymeric aggregates and supramolecular polymers. Amphiphilic polymers are more attractive compared to their small molecule analogues because they exhibit significantly lower critical aggregation concentration, relatively larger particle size (suitable for the enhanced permeation and retention effect), and a much slower dynamics of exchange between the unimer and the aggregate. Representative examples of exchange dynamics in amphiphilic polymer aggregates and their noncovalent encapsulation stability as a function of the structure of the macromolecule, cross-linking, environmental parameters, and biological conditions, as probed by FRET studies, have been included in this article. Further, related observations on the utility of FRET in studying the exchange dynamics in supramolecular polymers, particularly in aqueous medium, have been discussed at length, revealing a strong impact of chirality, side chain polarity, and other parameters. Overall, this Review Article brings out the strength of this technique to probe dynamics of aggregates and assembled systems, mostly in water medium, which has a paramount importance in designing future biomaterials. PMID- 30407824 TI - Molecular Dynamics Simulations Reveal Differentiated Context-Dependent Conformational Dynamics of Two Proteins of the Same Family. AB - The Arabidopsis pyrabactin resistant 1 (PYR1)-like family of proteins (PYLs) are receptors of abscisic acid (ABA), an essential small signaling molecule in plants. Here, we report a comparative molecular dynamics (MD) study on two PYL members, PYR1 and PYL10, which, despite their highly similar sequences and structures, have been suggested to belong to two different subclasses of PYLs, one being dimeric and relying on binding to ABA to inhibit downstream type 2C protein phosphatases (PP2Cs) and the other being monomeric and able to constitutively inhibit downstream PP2Cs without ABA. MD simulations have been carried out on these proteins in various monomeric or complexation states. Analyses of the simulations unambiguously confirm that ABA has large effects on the conformational dynamics of PYR1 but not PYL10, whereas a downstream PP2C has much larger effects on PYL10 than on PYR1. The differentiated effects are consistent with the functional differences between the two proteins. Potential of mean forces (PMFs) calculated by umbrella sampling showed that binding to ABA strengthens the PYR1-PP2C complex, increasing the PMF change for dissociation from 7.5 to 12.0 kcal mol-1. On the other hand, the same PMF change for an apo PYL10-PP2C complex was computed to be 9.5 kcal mol-1, suggesting stronger binding in apo-PYL10-PP2C than in apo-PYR1-PP2C. Several specific sequence features that may contribute to the functional differentiation between PYR1 and PYL10 are suggested based on the intersubunit residue-residue contacts occurred in the simulations. PMID- 30407826 TI - Controlling the Miscibility of X-Shaped Bolapolyphiles in Lipid Membranes by Varying the Chemical Structure and Size of the Polyphile Polar Headgroup. AB - Bolaamphiphiles are well-known naturally occurring structures that can increase the thermal and mechanical stability of the phospholipid membrane by incorporation in a transmembrane manner. Modifications of bolaamphiphiles to introduce particular structural elements such as a conjugated aromatic backbone and lateral side chains in the hydrophobic region lead to bolapolyphiles (BPs). We investigated the ability of BPs to form lyotropic phases in water. The BPs had an identical backbone and side chains, but different headgroup structures, leading to different abilities to act as hydrogen bond donors and acceptors. BPs with hydrophilic headgroups capable of acting as hydrogen bond donors as well as acceptors did not form lyotropic phases and were insoluble in water, independent of whether the polar groups were small or large. The extended lipophilic core structure and the multiple intermolecular hydrogen bonds between the headgroups prevented the formation of well-hydrated lyotropic aggregates. A BP with two large hydrophilic headgroups of several ethylene oxide moieties terminated by methyl groups formed sheet- and vesicle-like aggregates in water. These headgroups act only as hydrogen bond acceptors and cannot form hydrogen bonds in the absence of water. The miscibility of BPs with vesicles of 1,2-dipalmitoyl- sn glycero-3-phosphocholine (DPPC) in water and the resulting aggregate structures were also investigated. For BPs with headgroups acting as donors and acceptors of hydrogen bonds, macroscopic phase separation occurred in the mixed membranes, and two different membrane domains, a DPPC-rich one containing only little polyphile and a BP-rich one containing varying amounts of lipid, were formed. For headgroups without the ability to act as hydrogen bond donors, small BP aggregates were formed that were homogeneously distributed over the membrane. The lateral organization of BPs in lipid membranes can thus be controlled by the nature of the BP headgroup. PMID- 30407825 TI - Non-Native Cooperative Interactions Modulate Protein Folding Rates. AB - The energy landscape theory and the funnel description have had remarkable success in describing protein folding mechanisms and function. However, there are experimental results that are not understood using this approach. Among the puzzling examples are the alpha-spectrin results, in which the R15 domain folds 3 orders of magnitude more rapidly than the homologous R16 and R17, even though they are structurally very similar to each other. Such anomalous observations are usually attributed to the influence of internal friction on protein folding rates, but this is not a satisfactory explanation. In this study, this phenomenon is addressed by focusing on non-native interactions that could account for this effect. We carried out molecular dynamics simulations with structure-based C alpha models, in which the folding process of alpha-spectrin domains was investigated. The simulations take into account the hydrophobic and electrostatic contributions separately. The folding time results have shown qualitative agreement with the experimental data. We have also investigated mutations in R16 and R17, and the simulation folding time results correlate with the observed experimental ones. We suggest that the origin of the internal friction, at least in this case, might emerge from a cooperativity effect of these non-native interactions. PMID- 30407827 TI - Vesicle Self-Assembly of Monoalkyl Amphiphiles under the Effects of High Ionic Strength, Extreme pH, and High Temperature Environments. AB - Vesicles and other bilayered membranous structures can self-assemble from single hydrocarbon chain amphiphiles. Their formation and stability are highly dependent on experimental conditions such as ionic strength, pH, and temperature. The addition of divalent cations, for example, often results in the disruption of vesicles made of a single fatty acid species through amphiphile precipitation. However, membranes composed of amphiphile mixtures have been shown to be more resistant to low millimolar concentrations of divalent cations at room temperature. In this report, several mixtures of amphiphiles are examined for their propensity to self-assemble into membranous vesicular structures under extreme environmental conditions of low pH, high ionic strengths, and temperatures. In particular, mixtures of decylamine with polar cosurfactants were found to efficiently form membranes under these conditions far away from those normally supporting vesicle formation. We further examined decanoic acid/decylamine mixtures in detail. At pH 2 in low ionic strength solutions, the amphiphiles formed oily or crystalline structures; however, the introduction of salts or/and strong acids in conjunction with high temperature induced a stable vesiculation. Thus, extreme environments, such as volcanic or vent environments whose environmental conditions are known to support high chemical reactivity, could have harbored and most significantly promoted the formation of simple organic compartments that preceded cells. PMID- 30407828 TI - Tailoring the Core-Satellite Nanoassembly Architectures by Tuning Internanoparticle Electrostatic Interactions. AB - The use of plasmonic nanoplatforms has received increasing interest in a wide variety of fields ranging from theranostics to environmental sensing to plant biology. In particular, the development of plasmonic nanoparticles into ordered nanoclusters has been of special interest due to the new chemical functionalities and optical responses that they can introduce. However, achieving predetermined nanocluster architectures from bottom-up approaches in the colloidal solution state still remains a great challenge. Herein, we report a one-pot assembly approach that provides flexibility in precise control of core-satellite nanocluster architectures in the colloidal solution state. We found that the pH of the assembly medium plays a vital role in the hierarchy of the nanoclusters. The architecture along with the size of the satellite gold nanoparticles determines the optical responses of nanoclusters. Using electron microscopy and optical spectroscopy, we introduce a set of design rules for the synthesis of distinct architectures of silica-core gold satellites nanoclusters in the colloidal solution state. Our findings provide insight into advancing the colloidal solution state nanoclusters formation with predictable architectures and optical properties. PMID- 30407829 TI - Correction to "Divergent and Orthogonal Approach to Carbazoles and Pyridoindoles from Oxindoles via Indole Intermediates". PMID- 30407830 TI - Single-Molecule Study of Peptide Gel Dynamics Reveals States of Prestress. AB - De novo peptide surfactant (I3K) gels provide an ideal system to study the complex dynamics of lightly cross-linked semiflexible fibers because of their large contour lengths, simple chemistry, and slow dynamics. We used single molecule fluorescence microscopy to record individual fibers and Fourier decomposition of the fiber dynamics to separate thermal contributions to the persistence length from compressive states of prestress (SPS). Our results show that SPS in the network depend strongly on peptide concentration, buffer, and pH and that the fibril energies in SPS follow a Levy distribution. The presence of SPS in the network imply that collective states of self-stress are also present. Therefore, semiflexible polymer gels need to be considered as complex load bearing structures and the mean field models for polymer gel elasticity and dynamics often applied to them will not be fully representative of the behavior at the nanoscale. We quantify the impact of cross-links on reptation tube dynamics, which provides a second population of tube fluctuations in addition to those expected for uncross-linked entangled solutions. PMID- 30407831 TI - Neat Water-Vapor Interface: Proton Continuum and the Nonresonant Background. AB - Whether the surface of neat water is "acidic" or "basic" remains an active and controversial field of research. Most of the experimental evidence supporting the preferential adsorption of H3O+ ions stems from nonlinear optical spectroscopy methods typically carried out at extreme pH conditions (pH < 1). Here, we use vibrational sum frequency spectroscopy (VSFS) to target the "proton continuum", an unexplored frequency range characteristic of hydrated protons and hydroxide ions. The VSFS spectra of neat water show a broad and nonzero signal intensity between 1700 and 3000 cm-1 in the three different polarization combinations examined. By comparing the SF response of water with that from dilute HCl and NaOH aqueous solutions, we conclude the intensity does not originate from either adsorbed H3O+ or OH- ions. Contributions from the nonresonant background are then critically considered by comparing the experimental results with many-body molecular dynamics (MB-MD) simulated spectra. PMID- 30407832 TI - Synthesis of Chiral Nonracemic alpha-Difluoromethylthio Compounds with Tetrasubstituted Stereogenic Centers via a Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation. AB - The synthesis of chiral, nonracemic difluoromethylthio (SCF2H) compounds that contain a tetrasubstituted stereogenic center is reported. Racemic alpha-SCF2H beta-ketoallylesters 5 were initially prepared by an electrophilic difluoromethylthiolation of beta-ketoallylesters 6, followed by a Pd-catalyzed Tsuji decarboxylative asymmetric allylic alkylation (DAAA) to provide a wide variety of chiral, nonracemic alpha-allyl-alpha-SCF2H-ketones (4) with high enantiopurity. This strategy can be extended to the enantioselective synthesis of chiral, nonracemic alpha-allyl-alpha-trifluoromethylthio(SCF3)-ketones (7). PMID- 30407833 TI - Photocatalytic Oxyamination of Alkenes: Copper(II) Salts as Terminal Oxidants in Photoredox Catalysis. AB - A photocatalytic method for the oxyamination of alkenes using simple nucleophilic nitrogen atom sources in place of prefunctionalized electrophilic nitrogen atom donors is reported. Copper(II) is an inexpensive, practical, and uniquely effective terminal oxidant for this process. In contrast to oxygen, peroxides, and similar oxidants commonly utilized in non-photochemical oxidative methods, the use of copper(II) as a terminal oxidant in photoredox reactions avoids the formation of reactive heteroatom-centered radical intermediates that can be incompatible with electron-rich functional groups. As a demonstration of the generality of this concept, it has been shown that diamination and deoxygenation reactions can also be accomplished using similar photooxidative conditions. PMID- 30407834 TI - Ultrafast Giant Photostriction of Epitaxial Strontium Iridate Film with Superior Endurance. AB - Photostriction, optical stimulus driven mechanical deformation in materials, provides a solution toward next-generation technology. Here, the giant photostriction (~2% change of lattice) of epitaxial strontium iridate (SrIrO3) films under illumination at room temperature is revealed via power-dependent Raman scattering, which is significantly larger as compared to conventional inorganic materials. The time scale and mechanism of this giant photostriction in SrIrO3 are further studied through time-resolved transient reflectivity measurements. The main mechanism is determined to be the electron-phonon coupling. In addition, we find that such an exotic behavior happens within few picoseconds and remains up to 107 cyclic on/off operations. The observation of giant photostriction in SrIrO3 films with superior endurance promises the advance of shape responsive solids that are sensitive to environmental stimuli, which could be widely utilized for multifunctional optoelectronics and optomechanical devices. PMID- 30407835 TI - Characterization of Novel 18F-Labeled Phenoxymethylpyridine Derivatives as Amylin Imaging Probes. AB - Deposition of islet amyloid consisting of amylin constitutes one of pathological hallmarks of type 2 diabetes mellitus (T2DM), and it may be involved in the development and progression of T2DM. However, the details about the relationship between the deposition of islet amyloid and the pathology of T2DM remain unclear, since no useful imaging tracer enabling the visualization of pancreatic amylin is available. In the present study, we synthesized and evaluated six novel 18F labeled phenoxymethylpyridine (PMP) derivatives as amylin imaging probes. All 18F labeled PMP derivatives showed not only affinity for islet amyloid in the post mortem T2DM pancreatic sections but also excellent pharmacokinetics in normal mice. Furthermore, ex vivo autoradiographic studies demonstrated that [18F]FPMP-5 showed intense labeling of islet amyloids in the diabetes model mouse pancreas in vivo. The preclinical studies suggested that [18F]FPMP-5 may have potential as an imaging probe that targets amylin aggregates in the T2DM pancreas. PMID- 30407836 TI - Quantification of Loading and Laser-Assisted Release of RNA from Single Gold Nanoparticles. AB - Novel RNA-based technologies provide an avenue of possibilities to control the regulation of gene expression in cells. To realize the full potential of small interfering RNA (siRNA)-based therapy, efficient delivery vehicles and novel strategies for triggering release from carrier vehicles have to be developed. Gold nanoparticles (AuNPs) with sizes of ~50-150 nm have the ability to accumulate in tumor tissue and can be transported across the membrane by endocytosis. Therefore, a laser-controlled oligonucleotide release from such particles is of particular interest. Here, we quantify the loading of specifically attached microRNA oligonucleotides (miRNA) onto single gold nanoparticles with diameters of 80, 100, 150, and 200 nm. We show that AuNPs have a curvature-dependent density of miRNA loading: the higher the curvature, the higher the loading density. Moreover, we demonstrate how one sensing strand of an RNA duplex can be dehybridized and hence released from the AuNP by heating the AuNP by irradiation with a near-infrared (NIR) laser. Laser-induced release is also demonstrated inside living cells. Together, these findings show that plasmonic nanoparticles with high curvatures are ideal carriers of oligonucleotides into cells, and their cargo can be released in a controlled manner by a thermoplasmonic mechanism. Importantly, this remotely controlled release strategy can be applied to any cargo attached to a plasmonic nanocarrier, on either the single particle or ensemble level. PMID- 30407837 TI - Basified Human Lysozyme: A Potent Inhibitor against Amyloid beta-Protein Fibrillogenesis. AB - The aggregation of amyloid beta-proteins (Abeta) has been recognized as a key process in the pathogenesis of Alzheimer's disease (AD), so inhibiting Abeta aggregation is an important strategy to prevent the onset and treatment of AD. Our recent work indicated that decreasing the positive charges (or introducing negative charges) on human lysozyme (hLys) was unfavorable in keeping the inhibiting capability of hLys on Abeta aggregation. Therefore, we have herein proposed to basify hLys by conversion of the carboxyl groups into amino groups by modification with ethylene diamine. Basified hLys (Lys-B) preparations of three modification degrees (MDs), denoted as hLys-B1 (MD, 1.5), hLys-B2 (MD, 3.3), and hLys-B3 (MD, 4.4), were synthesized for modulating Abeta fibrillogenesis. The hLys-B preparations kept the stability and biocompatibility as native hLys did, whereas the inhibitory potency of hLys-B on Abeta fibrillogenesis increased with increasing MD. Cytotoxicity analysis showed that cell viability with 2.5 MUM hLys B3 increased from 62.5% (with 25 MUM Abeta only) to 76.1%, similar to the case with 12.5 MUM hLys (75.5%); cell viability with 6.25 MUM hLys-B3 increased to 82.0%, similar to the case with 25 MUM hLys (80.9%). The results indicate about four- to fivefold increase in the inhibition efficiency of hLys by the amino modification. Mechanistic analysis suggests that such a superior inhibitory capability of hLys-B was attributed to its more widely distributed positive charges, which promoted broad electrostatic interactions between Abeta and hLys B. Thus, hLys-B suppressed the conformational transition of Abeta to beta-sheet structures at low concentrations (e.g., 2.5 MUM hLys-B3), leading to changes in the aggregation pathway and the formation of Abeta species with less cytotoxicity. The findings provided new insights into the development of more potent protein-based inhibitors against Abeta fibrillogenesis. PMID- 30407838 TI - Balanced Crystalloid Solutions. AB - Intravenous fluid therapy is the most common intervention received by acutely ill patients. Historically, saline (0.9% sodium chloride) has been the most frequently administered intravenous fluid, especially in North America. Balanced crystalloid solutions (e.g., lactated Ringer's, Plasma-Lyte) are an increasingly used alternative to saline. Balanced crystalloids have a sodium, potassium, and chloride content closer to that of extra-cellular fluid and, when given intravenously, have fewer adverse effects on acid-base balance. Pre-clinical research has demonstrated that saline may cause hyperchloremic metabolic acidosis, inflammation, hypotension, acute kidney injury, and death. Studies of patients and healthy human volunteers suggest that even relatively small volumes of saline may exert physiological effects. Randomized trials in the operating room have demonstrated that using balanced crystalloids rather than saline prevents the development of hyperchloremic metabolic acidosis, and may reduce the need for vasopressors. Observational studies among critically ill adults have associated receipt of balanced crystalloids with lower rates of complications, including acute kidney injury and death. Most recently, large randomized trials among critically ill adults have examined whether balanced crystalloids result in less death or severe renal dysfunction than saline. Although some of these trials are still ongoing, a growing body of evidence raises fundamental concerns regarding saline as the primary intravenous crystalloid for critically ill adults and highlights fundamental, unanswered questions for future research about fluid therapy in critical illness. PMID- 30407839 TI - FDA Regulation of Tobacco Products: Time for a Course Correction. AB - The 2009 Family Smoking Prevention and Tobacco Control Act gave the U.S. Food and Drug Administration the authority to regulate all tobacco products and to adopt evidence-based tobacco product standards appropriate for the protection of the public health. Although the FDA acknowledges the importance of protecting young people from tobacco and nicotine and has taken some initial steps to do so, there is much that the FDA is charged with doing but has not done yet. This article describes the rationale and evidence base for what the FDA can do and needs to do in order to protect kids from tobacco and nicotine use initiation and addiction. PMID- 30407840 TI - Artifact-robust diffusion-weighted whole-body imaging with background suppression at 3 T using improved turbo spin-echo diffusion-weighted imaging. AB - OBJECTIVE:: To compare single-shot turbo spin-echo (TSE) diffusion-weighted whole body imaging with background suppression (DWIBS) and echo-planar imaging (EPI) DWIBS to determine the feasibility of direct-coronal TSE-DWIBS. METHODS:: All measurements were performed using a 3.0 T MRI scanner. In the phantom study, we compared the contrast ratios (CRs) of tumor-mimicking phantom (tumor) to muscle mimicking phantom (muscle) and water to muscle and the signal-to-noise ratio (SNR) between TSE-DWIBS and EPI-DWIBS. In the volunteer study, 10 healthy volunteers were whole-body scanned with direct-coronal TSE-DWIBS, direct-coronal EPI-DWIBS (corEPI-DWIBS), and transverse EPI-DWIBS (traEPI-DWIBS). Two radiologists assessed the image distortion, uniformity of fat suppression, overall artifacts, and overall image quality in maximum intensity projection (MIP) images from each DWIBS image using a 5-point scale. RESULTS:: In the phantom study, the CR of tumor to muscle was found to be lower for TSE-DWIBS (10.57 +/- 0.45) than for EPI-DWIBS (15.38 +/- 0.27), and the CR of water to muscle was higher for TSE-DWIBS (9.61 +/- 0.66) than for EPI-DWIBS (2.52 +/- 0.60). The volunteer study revealed good inter observer agreement between TSE DWIBS and EPI-DWIBS with respect to image distortion, uniformity of fat suppression, overall artifacts, and overall image quality, with weighted Cohen's kappa coefficients of 0.91, 0.74, 0.87, and 0.72, respectively. Qualitative analysis scores for image distortion, uniformity of fat suppression, overall artifacts, and overall image quality were significantly higher for TSE-DWIBS than for corEPI-DWIBS or traEPI-DWIBS (p < 0.05). CONCLUSION:: Direct-coronal TSE DWIBS is robust against magnetic field inhomogeneity. High-quality images without distortion or fat suppression inhomogeneity were obtained. ADVANCES IN KNOWLEDGE:: Many studies on DWIBS have been previously reported; however, these studies used EPI read-out. To the best of our knowledge, no studies using TSE read-out have been reported. In this study, we examined the feasibility of TSE DWIBS with lesser artifacts than EPI-DWIBS. PMID- 30407841 TI - Low contrast material dose coronary computed tomographic angiography using a dual layer spectral detector system in patients at risk for contrast-induced nephropathy. AB - OBJECTIVE:: To evaluate the effects of virtual monochromatic imaging (VMI) using dual-layer spectral detector CT on the image quality of coronary CT angiography (CCTA) acquired by using a low contrast material (CM) dose. METHODS:: We used a VMI 50keV protocol with a 50% CM dose (140 mgI kg-1) to scan 30 patients with renal insufficiency and a 120 kVp with the standard CM dose (280 mgI kg-1) to scan 30 controls without renal insufficiency. Quantitative parameters, including CT attenuation, image noise, and contrast-to-noise ratio (CNR), were measured. The visual image quality factors of contrast enhancement, image noise, beam hardening artefact, vessel sharpness, and overall image quality were scored on a 4-point scale. RESULTS:: The mean CT attenuation of the ascending aorta was significantly higher for 50 keV VMI than for 120 kVp. Image noise was significantly lower under the 50 keV VMI. CNR and the mean visual score for contrast enhancement were significantly higher for 50 keV VMI. There were no significant differences in the other visual image quality parameters between the two protocols. CONCLUSION:: Dual-layer spectral detector CT using 50 keV VMI enabled reducing the CM dose by 50 % without CCAT image quality degradation in patients with renal insufficiency. ADVANCES IN KNOWLEDGE:: The VMI 50 keV protocol using dual-layer spectral detector CT and a CM dose reduced by 50 % (140 mgI kg-1) can improve the diagnostic image quality of CCTA. PMID- 30407843 TI - New Biologics for Severe Asthma: What Patients, What Agents, What Results, at What Cost? PMID- 30407842 TI - Congenital Vertical Tracheal Septum Misdiagnosed as Laryngomalacia. PMID- 30407844 TI - Transcriptome Analysis of Sputum Cells: The "Modern Art" of Assessing Inflammation. PMID- 30407845 TI - MR imaging of spinal haematoma: a pictorial review. AB - Spinal haematoma is a rare occurrence, however has the potential to cause significant spinal injury and morbidity. MRI is the gold-standard of investigation, and urgent imaging is required for early diagnosis and treatment to ensure best patient outcomes. We present a pictorial review demonstrating the imaging features of spinal haematoma based on meningeal space assignment; epidural, subdural, subarachnoid, intramedullary and a combination of these locations. In this review, we summarise the literature and imaging findings of spinal haematoma on MRI. Particular imaging features which help to differentiate between haematoma in the different spinal meningeal compartments are discussed below. PMID- 30407846 TI - Pulmonary Function: From Genome Wide Association Studies to Genome-Wide Interaction Studies. PMID- 30407847 TI - Ward Capacity Strain: A Novel Predictor of Delays in Intensive Care Unit Survivor Throughput. PMID- 30407849 TI - Top 5 Junior Member Abstract Program Winners Announced at CAP18. PMID- 30407848 TI - Dimensional accuracy of cone beam CT with varying angulation of the jaw to the X ray beam. AB - OBJECTIVES: Cone beam CT (CBCT) machines do not always allow for patients to be scanned in the ideal position for image acquisition. This study aimed to investigate the influence of the position/angulation of the mandible relative to the X-ray beam of a CBCT machine. METHODS: Five sequential CBCT scans were captured of a human mandible at each angulation of 10 degrees , 20 degrees , 30 degrees , and 40 degrees using a coronal and sagittal positioning. Inspection software utilized a best-fit alignment to automatically calculate the three dimensional variation at 15 standardized points of interest. RESULTS: Statistically significant differences were found between the dimensional accuracy of CBCT scans taken at 10 degrees (26.3 um) of coronal angulation, as well as those taken at 20 degrees (-17.3 um) and 30 degrees (35.2 um) of sagittal angulations (p <0.001, 0.016, and <0.001, respectively). The largest deviations in accuracy included an overall maximum deviation of 490 MUm. CONCLUSIONS: The position of the mandible with respect to the X-ray beam has a clinically insignificant effect on dimensional accuracy, up to the maximum angle of 40 degrees assessed. PMID- 30407850 TI - Abstracts From the Pulmonary Pathology Society 2017 Biennial Meeting. PMID- 30407851 TI - Primary Cutaneous Follicle Center Lymphoma. AB - CONTEXT.-: Primary cutaneous follicle center lymphoma is a low-grade B-cell lymphoma that is limited to the skin at diagnosis. It has a differential diagnosis that includes systemic/nodal follicular lymphoma secondarily involving the skin; primary cutaneous diffuse large B-cell lymphoma leg type; reactive lymphoid hyperplasia; and primary cutaneous marginal zone lymphoma. OBJECTIVE.-: To review the clinical, morphologic, immunophenotypic, and genetic features of primary cutaneous follicle center lymphoma; its differential diagnosis; and the evidence that supports use of immunohistochemistry and genetic testing in the diagnosis and prognosis of this entity. DATA SOURCES.-: Pertinent literature regarding cutaneous B-cell lymphomas is summarized and University of Michigan cases are used to highlight characteristics of primary cutaneous follicle center lymphoma. CONCLUSIONS.-: Primary cutaneous follicle center lymphoma is a low grade B-cell lymphoma with distinctive features, although some cases may have elements that overlap with other lymphomas, complicating interpretation. PMID- 30407852 TI - Melanotic Neuroectodermal Tumor of Infancy. AB - CONTEXT.-: Melanotic neuroectodermal tumor of infancy, albeit rare and generally regarded as benign, is an important tumor to recognize because of its rapid growth, potential for local recurrence, and small round blue cell morphology, which can lead to misdiagnosis of a malignant neoplasm. OBJECTIVE.-: To review its clinical presentation and immunomorphologic findings, and discuss common entities in the differential diagnosis. DATA SOURCES.-: The study involved PubMed searches, including multiple review articles, case studies, retrospective studies, selected book chapters, and University of Michigan cases. CONCLUSIONS.-: Melanotic neuroectodermal tumor of infancy most commonly occurs in the bones of the head and neck region during the first year of life, but it can also present in other locations, including the central nervous system, testes, ovaries, and subcutaneous soft tissues. Histologically, it is composed of a biphasic population of cells, consisting of epithelioid melanin-producing cells and primitive neurogenic cells in a fibrocollagenous stroma. These microscopic findings, especially in small biopsies, can lead to a broad differential diagnosis that includes malignant small round blue cell tumors and malignant melanoma. Melanotic neuroectodermal tumor of infancy commonly has an infiltrative growth pattern, and anatomic constraints often lead to incomplete resection and local recurrence, requiring multiple surgical operations. Because melanotic neuroectodermal tumor of infancy can mimic a more aggressive and aggressively treated malignancy, recognition of this rare tumor is very crucial for pathologists. PMID- 30407853 TI - Use of a Web-Based Checklist to Improve Compliance With Medicare Access and CHIP Reauthorization Act of 2015 Reporting. PMID- 30407854 TI - Hyperhemolysis Syndrome in Patients With Sickle Cell Disease. AB - Sickle cell disease is a genetic disease commonly affecting people of African, Indian, and Mediterranean descent. Patients with this chronic disease often require lifelong red blood cell transfusions. Formation of alloantibodies and autoantibodies are well-known complications that can arise with multiple transfusions. Another rare, but serious complication associated with transfusion is hyperhemolysis syndrome. The acquisition of new and/or rare alloantibodies can make it more difficult to find compatible blood products for patients with sickle cell disease. Genotyping and national donor registries are useful tools for finding appropriate blood products for these patients. This review will describe the clinical and laboratory findings of sickle cell disease, including hyperhemolysis syndrome. The challenges associated with locating compatible blood for patients with various red blood cell antibodies will be reviewed. PMID- 30407855 TI - Primary Cutaneous Composite Lymphomas. AB - Composite lymphomas have been defined as 2 distinct subtypes of lymphoma occurring at a single anatomic site. Composite lymphomas limited to the skin are a rare occurrence and pose a unique challenge. Many reported cases within the skin are combined B-cell and T-cell lymphomas, typically mycosis fungoides and a low-grade B-cell lymphoma. These cases are challenging to recognize because lymphoid infiltrates within the skin often include a mixed population of B cells and T cells. In particular, reactive lymphoid proliferations (pseudolymphomas), primary cutaneous low-grade B-cell lymphomas, and primary cutaneous CD4+ T-cell lymphoproliferative disorder may show nearly equal numbers of B cells and T cells. In order to exclude these possibilities, overwhelming evidence in support of each lymphoma is helpful, including abnormal architecture, cytology, and immunophenotype, as well as molecular genetic evidence of clonality. PMID- 30407856 TI - Extraskeletal Mesenchymal Chondrosarcoma. AB - Extraskeletal mesenchymal chondrosarcoma is a rare soft tissue sarcoma arising from soft tissues, mainly of the lower extremities, meninges, and orbits. It usually presents during the second to third decades of life, and has a slight predominance in females. Histologically, it has a typical biphasic pattern comprising small cells and islands of hyaline cartilage. It can pose a diagnostic challenge in small biopsy specimens where 1 of the 2 components can be absent. The prognosis is extremely variable; survival varies depending on the location of the tumor. PMID- 30407857 TI - In Reply. PMID- 30407859 TI - Reproducibility of Malignant Pleural Mesothelioma Histopathologic Subtyping: Methodologic Issue. PMID- 30407858 TI - Histiocytic Sarcoma: Review, Discussion of Transformation From B-Cell Lymphoma, and Differential Diagnosis. AB - CONTEXT.-: Histiocytic sarcoma is a rare neoplasm of mature histiocytes with an aggressive clinical course that can arise de novo or from a low-grade B-cell lymphoma. In particular, chronic lymphocytic leukemia/small lymphocytic lymphoma is a very common malignancy in the Western hemisphere, and most cases of chronic lymphocytic leukemia/small lymphocytic lymphoma have an indolent course and behavior. However, 2% to 8% of chronic lymphocytic leukemia/small lymphocytic lymphoma cases transform. Histiocytic sarcomatous transformation is rare and portends poor prognosis. OBJECTIVE.-: To review the clinical features, morphology, and key points related to the differential diagnosis for histiocytic sarcoma. We discuss recent understanding of the biology underlying transformation. DATA SOURCES.-: University of Michigan case and review of pertinent literature about histiocytic sarcoma and morphologic differential diagnosis. CONCLUSIONS.-: Histiocytic sarcoma is a rare histiocytic neoplasm that can arise as a result of transdifferentiation from low-grade B-cell lymphomas, and has a wide differential diagnosis including other histiocytic/dendritic cell neoplasms, myeloid neoplasms, lymphomas, melanoma, and carcinoma. However, some key morphologic and immunohistochemical features allow for accurate classification. PMID- 30407860 TI - Kikuchi-Fujimoto Disease: A Review. AB - Kikuchi-Fujimoto disease (KFD) is a rare entity characterized by subacute necrotizing lymphadenopathy and frequently associated with fever. Young adults of Asian ancestry are most commonly affected, but it has been reported worldwide. Despite many studies in the literature, the cause of KFD remains uncertain. Histologically, KFD is characterized by paracortical lymph node expansion with patchy, well-circumscribed areas of necrosis showing abundant karyorrhectic nuclear debris and absence of neutrophils and eosinophils. Three evolving histologic patterns-proliferative, necrotizing, and xanthomatous-have been recognized. By immunohistochemistry, histiocytes in KFD are positive for myeloperoxidase. There is a marked predominance of T cells in the lesions (with mostly CD8-positive cells) with very few B cells. The differential diagnosis of KFD includes infectious lymphadenitis, autoimmune lymphadenopathy (primarily systemic lupus erythematosus), and lymphoma. Clinicians and pathologists are poorly familiar with this entity, which frequently causes significant diagnostic challenges. PMID- 30407861 TI - Update on Gastrointestinal Lymphomas. AB - Herein we review the following selection of gastrointestinal lymphomas: monomorphic epitheliotropic intestinal T-cell lymphoma; indolent T-cell lymphoproliferative disorder of the gastrointestinal tract; intestinal T-cell lymphoma, not otherwise specified; duodenal-type follicular lymphoma; and Epstein Barr virus-positive mucocutaneous ulcer. Definitions reflect the 2016 revision of the World Health Organization classification of lymphoid neoplasms. Clinical, morphologic, and immunophenotypic characteristics of each entity are emphasized. PMID- 30407862 TI - Sex-specific airway hyperreactivity and sex-specific transcriptome remodeling in neonatal piglets challenged with intra-airway acid. AB - Acute airway acidification is a potent stimulus of sensory nerves and occurs commonly with gastroesophageal reflux disease, cystic fibrosis and asthma. In infants and adults, airway acidification can acutely precipitate asthma-like symptoms, and treatment resistant asthma can be associated with gastroesophageal reflux disease. Airway protective behaviors, such as mucus secretion and airway smooth muscle contraction, are often exaggerated in asthma. These behaviors are manifested through activation of neural circuits. In some populations, the neural response to acid might be particularly important. For example, the immune response in infants is relatively immature compared to adults. Infants also have a high frequency of gastroesophageal reflux. Thus, in the current study, we compared the transcriptomes of an airway-nervous system circuit (e.g., tracheal epithelia, nodose ganglia, and brainstem) in neonatal piglets challenged with intra-airway acid. We hypothesized that identification of parallel changes in the transcriptomes of two neurally-connected tissues might reveal the circuit response, and hence molecules important for the manifestation of asthma-like features. Intra-airway acid induced airway hyperreactivity and airway obstruction in male piglets. In contrast, female piglets displayed airway obstruction without airway hyperreactivity. Pairwise comparisons revealed parallel changes in genes directly implicated in airway hyperreactivity (scn10a) in male acid-challenged piglets, whereas acid-challenged females exhibited parallel changes in genes associated with mild asthma (stat 1 and isg15). These findings reveal sex specific responses to acute airway acidification and highlight distinct molecules within a neural circuit that might be critical for the manifestation of asthma like symptoms in pediatric populations. PMID- 30407863 TI - Attenuation of Murine and Human Airway Contraction by a Peptide Fragment of the Cytoskeleton Regulatory Protein Gelsolin. AB - We have previously reported that mice genetically deficient in the actin binding protein gelsolin exhibit impaired airway smooth muscle (ASM) relaxation. Primary cultured ASM cells from these mice demonstrate enhanced inositol triphosphate (IP3) synthesis and increased intracellular calcium in response to Gq-coupled agonists. We hypothesized that this was due to increased intracellular availability of unbound phosphatidylinositol 4,5-bisphosphate (PIP2), based on the fact that gelsolin contains a short peptide region that binds PIP2, presumably making it a less available substrate. We now questioned whether a peptide that corresponds to the PIP2 binding region of gelsolin could modulate ASM signaling and contraction. The 10 amino acid sequence of the gelsolin peptide within the PIP2 binding region was incubated with primary cultures of human ASM cells and IP3 synthesis was measured in response to a Gq-coupled agonist. Gelsolin peptide treated cells generated less IP3 under basal and bradykinin or acetylcholine (Gq-coupled) conditions. Acetylcholine-induced contractile force measured in isolated tracheal rings from mice and human tracheal muscle strips in organ baths was attenuated in the presence of the gelsolin peptide. The gelsolin peptide also attenuated methacholine-induced airway constriction in murine precision cut lung slices. Furthermore, this peptide fragment delivered to the respiratory system of mice via nebulization attenuated subsequent methacholine induced increases in airway resistance in vivo. The current study demonstrates that introduction of this small gelsolin peptide into the airway may be a novel therapeutic option in bronchoconstrictive diseases. PMID- 30407864 TI - Could Nanotechnology Make Vitamin E Therapeutically Effective? AB - Vitamin E (VitE) has important antioxidant and anti-inflammatory effects and is necessary for normal physiological fuction. alpha-Tocopherol (alpha-T), the predominant form of VitE in human tissues, has been extensively studied, yet therapeutic trials of VitE have been uniformly negative. We postulate that a nanoparticle approach might provide effective delivery and therapeutic effect. PMID- 30407865 TI - HDAC2 attenuates airway inflammation by suppressing IL17A production in HDM challenged mice. AB - Histone deacetylase (HDAC) 2 is expressed in airway epithelium and plays a pivotal role in inflammatory cells. However, the role of HDAC2 in allergic airway inflammation remains poorly unknown. In the present study, we determined the role of HDAC2 in airway inflammation using in vivo models of HDM-induced allergic inflammation and in vitro cultures of human bronchial epithelial (HBE) cells exposed to HDM, IL17A, or both. We observed that HDM-challenged Hdac2+/- mice exhibited substantially enhanced infiltration of inflammatory cells. Higher levels of Th2 cytokines and IL17A expression were found in lung tissues of HDM challenged Hdac2+/- mice. Interestingly, IL17A deletion or anti-IL17A treatment reversed the enhanced airway inflammation induced by HDAC2 impairment. In vitro, HDM and IL17A synergistically decreased HDAC2 expression in HBE cells. HDAC2 gene silencing further enhanced HDM- and/or IL17A-induced inflammatory cytokines in HBE cells. HDAC2 overexpresion or blocking IL17A gene expression restored the enhanced inflammatory cytokines. Collectively, these results support a protective role of HDAC2 in HDM-induced airway inflammation by suppressing IL17A production and might suggest that activation of HDAC2 and/or inhibition of IL17A production could prevent the development of allergic airway inflammation. PMID- 30407866 TI - Short chain fatty acids increase TNFalpha-induced inflammation in primary human lung mesenchymal cells through the activation of p38 MAP kinase. AB - Short chain fatty acids (SCFAs), produced as by-products of dietary fibre metabolism by gut bacteria, have anti-inflammatory properties and could potentially be used for the treatment of inflammatory diseases, including asthma. The direct effects of SCFAs on inflammatory responses in primary human lung mesenchymal cells have not been assessed. We investigated whether SCFAs can protect against TNFalpha-induced inflammation in primary human lung fibroblasts (HLFs) and airway smooth muscle (ASM) cells in vitro. HLFs and ASM cells were exposed to SCFAs, acetate (C2:0), propionate (C3:0) and butyrate (C4:0) (0.01mM 25mM) with or without TNFalpha, and the release of pro-inflammatory cytokines, IL 6 and CXCL8, was measured using ELISA. We found that none of the SCFAs suppressed TNFalpha-induced cytokine release. On the contrary, challenge with supra physiological concentrations (10mM-25mM), as might be used therapeutically, of propionate or butyrate in combination with TNFalpha resulted in substantially greater IL-6 and CXCL8 release from HLFs and ASM cells than challenge with TNFalpha alone, demonstrating synergistic effects. In ASM cells challenge with acetate also enhanced TNFalpha-induced IL-6, but not CXCL8 release. Synergistic upregulation of IL-6 and CXCL8 was mediated through the activation of free fatty acid receptor (FFAR)3, but not FFAR2. The signalling pathways involved were further examined using specific inhibitors and immunoblotting, and responses were found to be mediated through p38 MAP kinase signalling. This study demonstrates that pro-inflammatory, rather than anti-inflammatory effects of SCFAs are evident in lung mesenchymal cells. PMID- 30407867 TI - High mobility group box-1 protein from CC10+ club cells promotes Type 2 response in the later stage of respiratory syncytial virus infection. AB - The type 2 immune response, induced by infection of respiratory syncytial virus (RSV), has been linked to asthma development, but it remains unclear how the response is initiated. Here, we reported that the high mobility group box-1 (HMGB1) protein promotes the type 2 response in the later stage of RSV infection. In mice, we found that type 2 cytokines were elevated in the later stages, which were strongly diminished after administration of anti-HMGB1 antibodies. Further investigation revealed that HMGB1 expression was localized to CC10+ club cells in the lung. In the clinic, levels of HMGB1 in nasopharyngeal aspirates (NPA) in hospitalized infants with RSV-bronchiolitis [median (interquartile range) 161.20 ng/ml (68.06-221.30)] were significantly higher than those without lower respiratory tract infections [21.94 ng/ml (12.12-59.82); P<0.001]. Moreover, higher levels of HMGB1 correlated with clinical severity. These results reveal a link between viral infection and the asthma-like type 2 responses that are associated with long-term consequences. PMID- 30407868 TI - Ozanimod for the treatment of relapsing remitting multiple sclerosis. AB - INTRODUCTION: Ozanimod is a selective sphingosine 1-phosphate receptor 1 and 5 modulator under development by Celgene, for the treatment of relapsing remitting multiple sclerosis. Extensive clinical experience has become available for the related compound fingolimod, favoring the sphingosine 1-phosphate therapeutic concept. Off-target effects have been attributed to its low receptor specificity and have prompted the development of next generation sphingosine 1-phosphate receptor modulators. Areas covered: The authors evaluate the literature of ozanimod, using the PubMed database as well as repositories of the European Committee for Treatment and Research in Multiple Sclerosis and the American and European Academy of Neurology. Specifically, the authors cover and discuss the preclinical data on ozanimod, pharmacokinetics and dynamics, and data on efficacy and safety from the pivotal trials. Expert opinion: Superiority of ozanimod over intramuscular interferon beta-1a with regard to reduction in annualized relapse rate and magnetic resonance imaging outcomes has been shown in two phase III trials. The beneficial effect on brain volume and gray matter loss are encouraging and in line with data on other newer immunomodulators. Ozanimod is a valuable contribution to the therapeutic armamentarium in MS, although the effect on disability progression is unclear and requires further investigations. PMID- 30407870 TI - Antitumor Action of Amygdalin on Human Breast Cancer Cells by Selective Sensitization to Oxidative Stress. AB - The treatment of MCF-7 and T47D human breast cancer cell lines with amygdalin was able to reduce the growth of both cells, in concentration and time-dependent manners. The potency of this inhibition against MCF-7 and T47D cells produced IC50 values of 39 and 45 mM, respectively. To investigate the correlation of this inhibition with oxidative stress, an amygdalin treatment of both cell lines was capable of inducing the generation of malondialdehyde (MDA) and oxidized glutathione levels. Also, this treatment caused the decrease of total glutathione and glutathione reductase activity. The proportional survival of tumor cells from this inhibition was positively correlated with the total glutathione, but it was inversely correlated with amygdalin or MDA levels (P < 0.001). In MCF-7 cells, the production of total glutathione was six times higher in the untreated than in amygdalin-treated cells, whereas this difference was reduced to 2.1 times in the T47D cells. Similarly, the production of MDA in MCF-7 cells was 2.4 times higher in the amygdalin-treated than in the untreated cultures, which were lowered to 1.3 times in the T47D cells. These data support a mechanism of amygdalin antitumor action against breast cancer cells based on the induction of oxidative stress. PMID- 30407869 TI - Prospective Assessment of the Feasibility of a Trial of Low Tidal Volume Ventilation for Patients with Acute Respiratory Failure. AB - RATIONALE: Low tidal volume ventilation (LTVV, 6 mL/kg) benefits patients with acute respiratory distress syndrome (ARDS) and may aid those with other causes of respiratory failure. Current early ventilation practices are poorly defined. OBJECTIVES: We observed patients with acute respiratory failure to assess feasibility of a pragmatic trial of LTVV and to guide experimental design. METHODS: We prospectively enrolled consecutive patients with acute respiratory failure admitted to intensive care units expected to participate in the proposed trial. We collected clinical data, initial and daily ventilator settings, and inpatient mortality. We estimated benefit of LTVV using predictive linear and non linear models. We simulated models to estimate power and feasibility of a cluster randomized trial of LTVV vs. usual care in acute respiratory failure. RESULTS: We included 2484 newly mechanically ventilated patients (31% with ARDS) from 49 hospitals. Hospital mortality was 28%. Mean initial tidal volume was 7.1 mL/kg predicted body weight (PBW) (95% CI 7.1-7.2) with 78% of patients receiving tidal volumes <= 8 mL/kg. Our models estimated a mortality benefit of 0-2% from LTVV compared to usual care. Simulation of a stepped-wedged cluster trial suggested that enrollment of 106,361 patients was necessary to achieve >90% power. CONCLUSIONS: Use of initial tidal volumes less than 8 ml/kg PBW is common at hospitals participating in the NHLBI PETAL Network. After considering the size and budgetary requirement for a cluster-randomized trial of LTVV vs. usual care in acute respiratory failure, the PETAL network deemed the proposed trial infeasible. A rapid observational study and simulations to model anticipated power may help better design trials. PMID- 30407871 TI - Cellular mechanisms promoting cachexia and how they are opposed by sirtuins. AB - Many chronic diseases are associated with unintentional loss of body weight, which is termed as cachexia. Cachexia is a complex multifactorial syndrome associated with the underlying primary disease, and characterized by loss of skeletal muscle with or without loss of fat tissue. Patients with cachexia face dire symptoms like dyspnea, fatigue, edema, exercise-intolerance and low responsiveness to medical therapy, which worsen quality of life. Since cachexia is not a stand-alone disorder, treating primary disease, such as cancer, takes precedence for the physician, and it remains mostly a neglected illness. Existing clinical trials have demonstrated limited success mostly because of their mono therapeutic approach and late detection of the syndrome. In order to conquer cachexia, it is essential to identify as many molecular targets as possible using the latest technologies we have at our disposal. In this review, we have discussed different aspects of cachexia, which include various disease settings, active molecular pathways and recent novel advances made in this field to understand consequences of this illness. We also discuss roles of the sirtuins, the NAD+-dependent lysine deacetylases, microRNAs, certain dietary options and epigenetic drugs as potential approaches, which can be used to tackle cachexia as early as possible in its course. PMID- 30407872 TI - Current and emerging medical therapeutic agents for idiopathic male infertility. AB - INTRODUCTION: Infertility is one of the great challenges of modern healthcare. It afflicts about 8-12% of reproductive-aged couples worldwide, but the prevalence is even higher in industrialized countries. In 50% of cases, a male factor of infertility underlies the problem, but in about 30% of these cases the etiology of male infertility remains unknown. This eventuality, called idiopathic infertility, requires empirical medical therapy and/or assisted reproductive techniques. Areas covered: This article reviews the literature about the medical treatments available for idiopathic male infertility. These treatments can be divided into two main categories: hormonal therapies and non-hormonal therapies. The compounds with the strongest evidence of efficacy and the most used in clinical practice for the treatment of idiopathic male infertility are follicle stimulating hormone (FSH) and estrogen receptor selective modulators (SERMs). Non hormonal treatments include a series of compounds with antioxidant and prokinetic properties, supported by variable degrees of evidence of clinical efficacy. Expert opinion: Patients with idiopathic infertility have peculiar clinical features that differentiate them from each other. Therapy must, therefore, be personalized to each patient. Furthermore, scientific research must investigate the pathophysiological mechanisms that underlie infertility; only in this way, new targeted therapies can be developed. PMID- 30407873 TI - Resistance is not futile: treatment-refractory schizophrenia - overview, evaluation and treatment. AB - INTRODUCTION: Schizophrenia is a debilitating condition with three main symptom domains: positive, negative, and cognitive. Approximately one-third of persons with schizophrenia will fail to respond to treatment. Growing evidence suggests that treatment-resistant (refractory) schizophrenia (TRS) may be a distinct condition from treatment-respondent schizophrenia. There is limited evidence on effective treatments for TRS, and a lack of standardized diagnostic criteria for TRS has hampered research. Areas covered: A literature search was conducted using Pubmed.gov and the EMBASE literature database. The authors discuss the pragmatic definitions of TRS and review treatments consisting of antipsychotic monotherapy and augmentation strategies. Expert opinion: Currently available first-line antipsychotic medications are generally effective at treating the positive symptoms of schizophrenia, leaving residual negative and cognitive symptoms. Before diagnosing TRS, rule out any pharmacodynamic or pharmacokinetic failures. Most evidence supports clozapine as having the most efficacy for TRS. If clozapine is used, it should be optimized, and serum levels should be at least 350-420 ng/ml. If clozapine is unable to be tolerated, some evidence suggests olanzapine at dosages up to 40mg/day can be useful. Augmentation strategies have weak evidence. Tailoring treatment to the specific domain is the preferred approach, and the use of a structured assessment/outcome measure is encouraged. PMID- 30407874 TI - Body Mass Index (BMI) and Infectious/Febrile Episodes in Children with Intermediate Risk Acute Lymphoblastic Leukemia (IR ALL). AB - : The incidence of treatment related mortality in children with acute lymphoblastic leukemia (ALL) is reported to be between 2% and 4% with infections being the leading cause. AIM: To establish a relationship between body mass index at diagnosis (BMI 0), after protocol I therapy completion (BMI I) and the incidence rate ratio (IRR) of infectious/febrile episodes in children with ALL intermediate risk. METHODS: Thirty one consecutive patients (2-18 years old, with a male to female ratio of 19/12) with newly diagnosed ALL that were treated uniformly according to ALL IC 2009 protocol were included in this analysis. RESULTS: A BMI decrease of at least 5% during protocol I therapy and BMI 1 under 15th percentile score corresponds significantly with higher IRR (with P-values 0.04 and 0.006 respectively) during the whole intensive therapy. CONCLUSION: Some relationships between BMI reduction and higher IRR in ALL patients were found, but their significance is limited by the size of the group analyzed. PMID- 30407875 TI - Automatic Configuration of Multi-Objective Local Search Algorithms for Permutation Problems. AB - Automatic algorithm configuration (AAC) is becoming a key ingredient in the design of high-performance solvers for challenging optimisation problems. However, most existing work on AAC deals with configuration procedures that optimise a single performance metric of a given, single-objective algorithm. Of course, these configurators can also be used to optimise the performance of multi objective algorithms, as measured by a single performance indicator. In this work, we demonstrate that better results can be obtained by using a native, multi objective algorithm configuration procedure. Specifically, we compare three AAC approaches: one considering only the hypervolume indicator, a second optimising the weighted sum of hypervolume and spread, and a third that simultaneously optimises these complementary indicators, using a genuinely multi-objective approach. We assess these approaches by applying them to a highly-parametric local search framework for two widely studied multi-objective optimisation problems, the bi-objective permutation flowshop and travelling salesman problems. Our results show that multi-objective algorithms are indeed best configured using a multi-objective configurator. PMID- 30407876 TI - Neuroevolution of a Modular Memory-Augmented Neural Network for Deep Memory Problems. AB - We present Modular Memory Units (MMUs), a new class of memory-augmented neural network. MMU builds on the gated neural architecture of Gated Recurrent Units (GRUs) and Long Short Term Memory (LSTMs), to incorporate an external memory block, similar to a Neural Turing Machine (NTM). MMU interacts with the memory block using independent read and write gates that serve to decouple the memory from the central feedforward operation. This allows for regimented memory access and update, administering our network the ability to choose when to read from memory, update it, or simply ignore it. This capacity to act in detachment allows the network to shield the memory from noise and other distractions, while simultaneously using it to effectively retain and propagate information over an extended period of time. We train MMU using both neuroevolution and gradient descent, and perform experiments on two deep memory benchmarks. Results demonstrate that MMU performs significantly faster and more accurately than traditional LSTM-based methods, and is robust to dramatic increases in the sequence depth of these memory benchmarks. PMID- 30407877 TI - Direct SUMOylation of M1 muscarinic acetylcholine receptor increases its ligand binding affinity and signal transduction. AB - SUMOylation is a significant post-translational modification (PTM) by the small ubiquitin-related modifier (SUMO). Increasing evidence shows SUMOylation regulates GPCR signaling; however, very few GPCRs have been shown to be SUMOylation targets to date. In this study, we identified M1 muscarinic acetylcholine receptor (M1 mAChR), a member of the GPCRs, as a new SUMO substrate. When the mAChR was activated by the agonist carbachol, the colocalization of the M1 mAChR and SUMO-1 protein markedly decreased in immunoprecipitation and immunofluorescence assays. SUMOylation of the M1 mAChR played an important role in increasing the ligand-binding affinity to M1 mAChR, signaling efficiencies, and receptor endocytosis. Through the site-directed mutagenesis approach, K327 was identified as the SUMOylation site of the M1 mAChR. Mutation of the consensus SUMOylation site of the M1 mAChR reduces not only the colocalization of SUMO-1, but also the ligand-binding affinity and signal transduction. The function of M1 mAChR was regulated by SUMOylation through the stabilization of active-state conformation revealed by molecular dynamics simulations. Our results provide evidence that M1 SUMOylation is an important PTM involved in regulation of the affinity for agonists and for activation of signaling pathways.-Xu, J., Tan, P., Li, H., Cui, Y., Qiu, Y., Wang, H., Zhang, X., Li, J., Zhu, L., Zhou, W., Chen, H. Direct SUMOylation of M1 muscarinic acetylcholine receptor increases its ligand-binding affinity and signal transduction. PMID- 30407878 TI - GDF11 antagonizes TNF-alpha-induced inflammation and protects against the development of inflammatory arthritis in mice. AB - Growth differentiation factor 11 (GDF11), a key member of the TGF-beta superfamily, plays critical roles in various medical conditions. Recently, GDF11 was found to suppress the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) signaling pathway and protect against inflammation. This study aimed to investigate the role of GDF11 in the development of rheumatoid arthritis (RA). We demonstrated that GDF11 treatment antagonized TNF-alpha induced inflammation in macrophages. Moreover, GDF11 inhibited the development of arthritis in the collagen-induced arthritis and collagen antibody-induced arthritis models. Local gene transfer of GDF11 via adeno-associated virus exerted therapeutic effects, while local knockdown of GDF11 exaggerated inflammation in our collagen-induced arthritis model, as detected by expression levels of inflammatory biomarkers and the destruction of joint structures. Additionally, the results from both in vitro experiments and luciferase reporter gene mouse experiments implied that the NF-kappaB pathway might play a critical role in the therapeutic effect of GDF11 in RA. This study presents GDF11 as a potential target for the treatment of inflammatory arthritis, including RA.-Li, W., Wang, W., Liu, L., Qu, R., Chen, X., Qiu, C., Li, J., Hayball, J., Liu, L., Chen, J., Wang, X., Pan, X., Zhao, Y. GDF11 antagonizes TNF-alpha-induced inflammation and protects against the development of inflammatory arthritis in mice. PMID- 30407879 TI - Response to Lange re: Calcium Oxalate Urolithiasis: A Case of Missing Microbes? PMID- 30407880 TI - Identification and Characterization of Menadione and Benzethonium Chloride as Potential Treatments of Pierce's Disease of Grapevines. AB - Xylella fastidiosa infects a wide range of plant hosts and causes Pierce's disease (PD) of grapevines. The Type 1 multidrug resistance (MDR) efflux system is essential for pathogenicity and survival of bacterial pathogens in planta. X. fastidiosa, with a single MDR system, is significantly more vulnerable to inhibition by small molecule treatments than most bacterial pathogens that typically carry redundant MDR systems. A high throughput cell viability assay using a GFP-marked strain of X. fastidiosa Temecula 1 was developed to screen two Prestwick combinatorial small molecule libraries of FDA and EMA approved drugs and phytochemicals (1600 chemicals in total) for cell growth inhibition. The screens revealed 215 chemicals that inhibited bacterial growth by greater than 50% at 50 uM concentrations. Seven chemicals proved to lyse X. fastidiosa cells at 25 uM, including four phytochemicals. Menadione (2-methyl-1,4-naphthoquinone, Vitamin K) from the phytochemical library, and benzethonium chloride (a topical disinfectant) from the chemical library both showed significant bactericidal activity against X. fastidiosa. Both menadione and benzethonium chloride foliar spray (15 mM and 5 mM, respectively) and soil drench (5 mM and 25 mM, respectively) treatments were equally effective in reducing PD symptoms by 54% - 59% and revealed that the effects of both chemical treatments became systemic. However, menadione was phytotoxic when applied as a foliar spray at effective concentrations, causing significant loss of photosynthetic capacity. PMID- 30407881 TI - System-Level Factors Associated With Use of Outpatient Specialty Palliative Care Among Patients With Advanced Cancer. AB - PURPOSE:: The proportion of patients with advanced cancer who receive outpatient specialty palliative care (OSPC) is as low as 2.0%. Improved understanding of the system-level factors influencing use of OSPC could inform adaptations to the delivery of palliative care to maximize access. We examined associations between OSPC use among patients with advanced solid tumors and oncology-OSPC clinic colocation and patient travel time to an OSPC clinic. PATIENTS AND METHODS:: We conducted a retrospective cohort study of patients with advanced solid tumors receiving oncologic treatment between January 1 and December 31, 2016, within a comprehensive cancer center network with well-established, oncology-specific OSPC clinics. Multivariable logistic regression analysis was used to evaluate the associations of clinic colocation and geographic access with OSPC use. RESULTS:: Of 9,485 patients with advanced solid tumors, 478 (5.0%) received OSPC services in 2016. After controlling for age, sex, marital status, cancer type, insurance, treatment intent, and illness severity, patients whose oncologist practices were colocated with OSPC clinics were more likely to use OSPC (odds ratio [OR], 19.2; 95% CI, 14.1 to 26.2). Compared with patients who lived > 90 minutes from an OSPC clinic, patients with travel times of < 30 minutes (OR, 3.2; 95% CI, 2.2 to 4.6) and 31 to 60 minutes (OR, 2.4; 95% CI, 1.6 to 3.6) were also more likely to use OSPC. CONCLUSION:: Among patients with advanced solid tumors, colocation of oncology and OSPC clinics and shorter patient travel time were associated with greater odds of using OSPC. Future efforts to increase OSPC use in this population should consider clinic colocation and travel burden. PMID- 30407882 TI - Factors Associated With Follow-Up Care Among Women With Early-Stage Breast Cancer. AB - PURPOSE:: Follow-up guidelines vary widely among national organizations for patients with early-stage breast cancer treated with curative intent. We sought to evaluate the patterns and predictors of provider follow-up care within the first 5 years after diagnosis. METHODS:: Using the SEER-Medicare linked data set, we evaluated patients who were diagnosed with stage I and II breast cancer who underwent breast-conserving surgery from 2002 to 2007 with follow-up until 2012. We defined discontinuation of follow-up as > 12 months from the previous physician visit without a visit claim from either a surgeon, medical oncologist, or radiation oncologist. We performed a multivariable logistic regression and Cox proportional hazards regression analysis to determine factors associated with the discontinuation of follow-up care. RESULTS:: Of the 30,053 patients enrolled in our initial cohort, 25,781 (85.8%) saw a medical oncologist and 21,612 (71.9%) saw a radiation oncologist in the first year in addition to a surgeon. Over the 5 years, 6,302 patients (21.0%) discontinued follow-up visits. Discontinuation of physician visits increased with increasing age. Women with stage II cancer ( v stage I) were less likely to discontinue follow-up visits (odds ratio, 0.78; 95% CI, 0.73 to 0.83). Time to early discontinuation was greater for patients with hormone receptor-negative tumors (hazard ratio, 1.14; 95% CI, 1.05 to 1.24). Women who were diagnosed more recently were less likely to discontinue seeing any physician. CONCLUSION:: Twenty-one percent of patients with early-stage breast cancer discontinued seeing any oncology provider over the 5 years after diagnosis. Coordination of follow-up care between oncology specialists may reduce discontinuation rates and increase clinical efficiency. PMID- 30407883 TI - Examining the effects of an obstetrics interprofessional programme on reductions to reportable events and their related costs. AB - There are many ways to account for the return on investment (ROI) in healthcare: improved communication, teamwork, culture, patient satisfaction, staff satisfaction, and clinical outcomes are but a few. Some of these are easier to quantify and associate to an intervention than others. What if the outcomes listed were not just independent results, but beget one another? In 2001, the Society of Obstetricians and Gynaecologists of Canada created the Managing Obstetrical Risk Efficiently (MOREOB) programme, to improve healthcare culture and patient outcomes in obstetrics by leveraging front-line ownership. Our study provides evidence that MOREOB lowers the frequency and cost of reportable events in maternity units. We sought to review the impact of this intervention on the frequency and cost of reportable events at the insurer level of a clinically focused, three-year interprofessional culture change intervention applied to the maternity unit. We compared the impact of reportable events both in the obstetrical and in the non-obstetrical areas of the same hospitals during the same time periods. We analysed these data using an interrupted time series (ITS) design, among 34 Ontario Canada hospitals. The ITS design assessed changes in the frequency and cost of reportable events before and after the implementation of the intervention. The method was ideally suited as the various maternity units had differing programme commencement and completion dates. The frequency of reportable events showed little change during the three-year intervention. As culture change grew, the changes in behaviour and processes that impact patient outcomes took longer to accrue. A large reduction in the frequency of reportable events occurred in the following three-year (14% reduction) and six-year (25% reduction) tranches. Our results show statistically significant reductions in the frequency and costs associated with reportable events at the level of an insurer. The results also give insight as to the investment of time required to achieve a level of sustainability. PMID- 30407884 TI - Novel germline missense DDX41 variant in a patient with an adult-onset myeloid neoplasm with excess blasts without dysplasia. PMID- 30407885 TI - Incidence and survival of T-cell acute lymphoblastic leukemia in the United States. AB - T-cell acute lymphoblastic leukemia (T-ALL) is a curable malignancy in the pediatric population. However, population-level data on its incidence and outcomes among adults is sparse. Using SEER database, we identified 1141 patients aged >=20 years with pathologically confirmed T-ALL diagnosed between the years 2001 and 2014 and actively followed. Incidence of T-ALL was 0.13 cases/100,000 population with significant variations by age, gender, race, and period. The 5 year overall survival (OS) declined significantly with increasing age (age <40, 51.9%; age 40-59, 37.3%; age 60-79, 19.2%; age >=80, 0%; p < .001) and varied by race (whites - 45.7%, blacks - 25.1%, others - 40.3%; p < .001). Over time, OS has improved significantly in patients <60 years (2001-2007, 42.8% vs 2008-2014, 53.1%; p = .005), but not in patients older than 60 years (2001-2007, 18% vs 2008 2014, 22.8%; p = .71), highlighting the need for effective and safe treatments in this population. PMID- 30407886 TI - Evaluation of the CLL-IPI in relapsed and refractory chronic lymphocytic leukemia in idelalisib phase-3 trials. AB - The CLL-IPI is a risk-weighted prognostic model for previously untreated patients with chronic lymphocytic leukemia (CLL), but has not been evaluated in patients with relapsed CLL or on novel therapies. We evaluated the CLL-IPI in 897 patients with relapsed/refractory CLL in 3 randomized trials testing idelalisib (PI3Kdelta inhibitor). The CLL-IPI identified patients as low (2.2%), intermediate (12.8%), high (48.7%), and very high (36.2%) risk and was prognostic for survival (log rank p < .0001; C-statistic 0.706). Of CLL-IPI factors, age >65, beta2 microglobulin >3.5mg/L, unmutated immunoglobulin heavy chain variable region gene, and deletion 17p/TP53 mutation were independently prognostic, but Rai I-IV or Binet B/C was not. The CLL-IPI is prognostic for survival in relapsed CLL and with idelalisib therapy. However, low/intermediate risk is uncommon, and regression parameters of individual factors in this risk-weighted model appear different in relapsed CLL. Reassessment of the weighting of the individual variables might optimize the model in this setting. PMID- 30407887 TI - School or Work? The Choice May Change Your Personality. AB - According to the social-investment principle, entering new environments is associated with new social roles that influence people's behaviors. In this study, we examined whether young adults' personality development is differentially related to their choice of either an academic or a vocational pathway (i.e., entering an academic-track school or beginning vocational training). The personality constructs of interest were Big Five personality traits and vocational-interest orientations. We used a longitudinal study design and propensity-score matching to create comparable groups before they entered one of the pathways and then tested the differences between these groups 6 years later. We expected the vocational pathway to reinforce more mature behavior and curtail investigative interest. Results indicated that choosing the vocational compared with the academic pathway was associated with higher conscientiousness and less interest in investigative, social, and enterprising activities. PMID- 30407888 TI - Alcohol use and relationship quality among South African couples. AB - OBJECTIVE: The HIV literature has largely ignored the importance of alcohol use in the quality of intimate relationships in sub-Saharan Africa (SSA), despite evidence of alcohol's role in relational behaviors that increase risk for HIV infection and other harms. The present study explored the association of alcohol use with relationship functioning among heterosexual couples from rural South Africa. METHOD: Dyadic analyses were conducted with 443 sexually active, heterosexual, South African couples (886 individuals) to examine the association between male partners' alcohol use (abstinent, nonhazardous, and hazardous), and male and female partners' reports of relationship intimacy, trust, mutually constructive communication, demand/withdraw communication, and satisfaction. Five structural equation models were fit using male partner alcohol use as a predictor of male and female reports of relationship quality. RESULTS: Women with a hazardous-drinking male partner (compared to an abstainer) reported significantly higher levels of intimacy (p <.05) and significantly more demand/withdraw communication (p <.001); men who were hazardous drinkers reported significantly less trust in their relationship compared to men who were abstainers (p < .01). CONCLUSIONS: Hazardous alcohol use among South African couples is positively correlated with women's relationship intimacy and maladaptive communication patterns, yet negatively correlated with men's perceived trust. PMID- 30407889 TI - Queering Poetics: The Impact of Poetry on LGBT+ Identity in Singaporean Adolescents. AB - This qualitative study explores identity formation in LGBT+ Singaporean adolescents, and how reading, writing, and listening to poetry shapes Singaporean adolescents' social identities as queer people. Analyzing in-depth interviews with nine LGBT+ Singaporean adolescents, four themes were found: (1) LGBT+ Singaporean adolescents interested in poetry believe that reading, writing, and/or listening to poetry has been an integral part of constructing their queer identities; (2) the poems that have impacted LGBT+ Singaporean adolescents' queer identities the most have been informed by queer sociocultural values; (3) poetry provides validation to LGBT+ Singaporean adolescents that their identities are real and that others before them have experienced the same challenges they are going through; and (4) poetry serves as a third space for LGBT+ Singaporean adolescents to safely construct their growing queer identities. Implications for teachers, counselors, and adult supporters of queer Singaporean adolescents are discussed, and recommendations for future research are provided. PMID- 30407890 TI - Brimonidine tartrate for the treatment of glaucoma. AB - INTRODUCTION: Brimonidine tartrate is a commonly used eyedrop for short- and long term lowering of intraocular pressure. Its use has been popularized due to its effects on aqueous suppression and uveoscleral outflow, as well as the suggestion of neuroprotection. Although available with alternative preservative vehicles, brimonidine is associated with high rates of local allergy and is contraindicated in breastfeeding women, neonates, young children, and the elderly due to risk of central nervous system depression. Other topical agents with differing advantages have challenged brimonidine's role in the treatment algorithm of ocular hypertension and glaucoma. Areas covered: The authors review the development of topical alpha-adrenergic agonists, with particular attention to the currently available formulations of brimonidine tartrate. Its mechanism of action, pharmacodynamics and safety, and clinical efficacy are analyzed. Expert opinion: Despite clinical familiarity with brimonidine after two decades of use, agents that offer daily dosing, nocturnal effect, and more favorable ocular and systemic side effect profiles have ultimately led to brimonidine's adjunctive use in patients with elevated intraocular pressure or high- or low-tension glaucomas. Still, brimonidine may be advantageous in patients undergoing laser trabeculoplasty or iridotomy, in certain forms of glaucoma, or in pregnant individuals prior to the last trimester, underscoring its clinical importance. PMID- 30407892 TI - 32 Shades of Neuroethics-A Review of the Routledge Handbook of Neuroethics, edited by L. Syd M Johnson and Karen S. Rommelfanger1. PMID- 30407891 TI - 'The disease isn't listening to the drug': The socio-cultural context of antibiotic use for viral respiratory infections in rural Uganda. AB - To identify factors precipitating antibiotic misuse and discuss how to promote safe antibiotics use and curb antibiotic resistance. Antibiotic misuse is a significant problem globally, leading to increased antibiotic resistance. Many socio-cultural factors facilitate antibiotic misuse: patient and provider beliefs about antibiotics, inadequate regulation, poor health literacy, inadequate healthcare provider training, and sub-optimal diagnostic capability. This study investigates the influence of such factors on antibiotic use and community health in rural Uganda. Attention was paid to patient-provider dynamics, providers' concerns, and the role of drug shops in the communities and how these situations exacerbate antibiotic misuse. Using a grounded ethnographic approach, interviews, focus groups, and observations were conducted over six weeks. Five salient themes emerged from data analysis. Based on the study results and a review of past literature on antibiotic resistance, there is need for improved health literacy and education, continued focus on efficiency and affordability in healthcare, and recognition of the role of stewardship and government in providing better healthcare. The problem of antibiotic misuse is multifactorial. Proposed solutions must target multiple contributing factors and must ultimately modify the culture and beliefs surrounding antibiotic use and encourage proper use. Such a multi-pronged approach would be most effective and would decrease rates of antibiotic resistance. PMID- 30407893 TI - Social Class for Collective Health Research: A Conceptual and Empirical Challenge. AB - Social Determination of Health (SDH)/Collective Health is a Latin American framework that sees the Marxist core concept of social class as fundamental for understanding health inequalities. In contrast to social stratification approaches, Marxist proposals seek to understand health as part of the historical transformations of capitalism's mode of production. In this article we aim to analyze the relationship between social class and health inequalities using data from the IV Oral Health National Study in Colombia. We conducted hierarchical cluster analyses to classify the population in five class positions and three living conditions clusters, which reflect how the spheres of production and social reproduction relate to social classes in Colombia. To measure oral health we use DMFT, as well as care and treatment needs indexes. Through variance analysis models we found that people from more exploited class positions and worse living conditions have more active disease and higher treatment needs. Despite technical and conceptual challenges, we conclude that a social class analytical framework can be operationalised via the interrelated spheres of production and social reproduction, which sheds light on the relationship between health inequalities and the class structure of the capitalist system. PMID- 30407894 TI - Conceptualizing De-Implementation in Cancer Care Delivery. PMID- 30407896 TI - Reply to V. Turan et al. PMID- 30407895 TI - Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial. AB - PURPOSE: Pembrolizumab is active in melanoma, but activity in patients with untreated brain metastasis is less established. We present long-term follow-up of pembrolizumab-treated patients with new or progressing brain metastases treated on a phase II clinical trial ( ClinicalTrials.gov identifier: NCT02085070). PATIENTS AND METHODS: We enrolled 23 patients with melanoma with one or more asymptomatic, untreated 5- to 20-mm brain metastasis not requiring corticosteroids; 70% of patients had prior systemic therapy. Pembrolizumab was administered for up to 24 months. Brain metastasis response, the primary end point, was assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST). Pretreatment tumors were analyzed for T-cell infiltrate and programmed death ligand 1. RESULTS: Six patients (26%) had a brain metastasis response. Eight patients (35%) did not reach a protocol evaluation scan and were unevaluable for brain metastasis response as a result of progression or need for radiation. Brain metastasis and systemic responses were concordant, with all ongoing at 24 months. The median progression-free and overall survival times were 2 and 17 months, respectively. Eleven patients (48%) were alive at 24 months. This included three unevaluable patients. One of these three patients had hemorrhaged, and two had symptoms from perilesional edema requiring radiosurgery, but all three patients remained on commercial pembrolizumab more than 24 months later. None of the 24-month survivors received subsequent BRAF inhibitors. Neurologic adverse events occurred in 65% of patients; all adverse events but one were grade 1 or 2. Three patients had seizures, which were treated with anticonvulsants. Most responders had higher pretreatment tumor CD8 cell density and programmed death ligand 1 expression, whereas all nonresponders did not. CONCLUSION: Pembrolizumab is active in melanoma brain metastases with acceptable toxicity and durable responses. Multidisciplinary care is required to optimally manage patients with brain metastases, including consideration of radiation to large or symptomatic lesions, which were excluded in this trial. Two-year survival was similar to patients without brain metastasis treated with anti programmed cell death 1 agents. Concordant brain and extracerebral responses support use of pembrolizumab to treat small, asymptomatic brain metastases. PMID- 30407897 TI - Utility of Gonadotropin-Releasing Hormone Agonists for Fertility Preservation: Lack of Biologic Basis and the Need to Prioritize Proven Methods. PMID- 30407898 TI - Reply to V. Turan et al. PMID- 30407899 TI - UV-Radiation Response Proteins Reveal Undifferentiated Cutaneous Interfollicular Melanocytes with Hyperradiosensitivity to Differentiation at 0.05 Gy Radiotherapy Dose Fractions. AB - To date, the response activated in melanocytes by repeated genotoxic insults from radiotherapy has not been explored. We hypothesized that the molecular pathways involved in the response of melanocytes to ionizing radiation and ultraviolet radiation (UVR) are similar. Skin punch biopsies, not sun-exposed, were collected from prostate cancer patients before, as well as at 1 and 6.5 weeks after daily doses of 0.05-1.1 Gy. Interfollicular melanocytes were identified by DeltaNp63- and eosin-periodic acid Schiff staining. Immunohistochemistry and immunofluorescence were performed to detect molecular markers of the melanocyte lineage. Melanocytes were negative for DeltaNp63, and the number remained unchanged over the treatment period. At radiation doses as low as 0.05 Gy, melanocytes express higher protein levels of microphthalmia-associated transcription factor (MITF) and Bcl-2. Subsets of MITF- and Bcl-2-negative melanocytes were identified among interfollicular melanocytes in unexposed skin; the cell number in both subsets was reduced after irradiation in a way that indicates low-dose hyperradiosensitivity. A corresponding increase in MITF- and Bcl-2-positive cells was observed. PAX3 and SOX10 co-localized to some extent with MITF in unexposed skin, more so than after radiotherapy. Low doses of ionizing radiation also intensified c-KIT and DCT staining. Nuclear p53 and p21 were undetectable in melanocytes. Apoptosis and proliferation could not be observed. In conclusion, undifferentiated interfollicular melanocytes were identified, and responded with differentiation in a hypersensitive manner at 0.05 Gy doses. Radioresistance regarding cell death was maintained up to fractionated doses of 1.1 Gy, applied for 7 weeks. The results suggest that the initial steps of melanin synthesis are common to ionizing radiation and UVR, and underline the importance of keratinocyte-melanocyte interaction behind hyperpigmentation and depigmentation to radiotherapy. PMID- 30407900 TI - Exposure to <=15 cGy of 600 MeV/n 56Fe Particles Impairs Rule Acquisition but not Long-Term Memory in the Attentional Set-Shifting Assay. AB - On future missions into deep space, astronauts will be required to work more autonomously than on previous missions, and thus their ability to perform executive functions could be critical to mission success. In this study, we determined the effect that <=15 cGy of 600 MeV/n 56Fe particles has on attentional set-shifting (ATSET) performance of ~10 month-old (at the time of irradiation) male Wistar rats that had been prescreened for their ability to perform the task. Exposure to 1-15 cGy of 56Fe particles leads to a significant impairment in compound discrimination (CD) performance. Should similar effects occur in astronauts, an impaired ability to execute CD would result in a decreased ability to identify and maintain focus on relevant aspects of the task being performed. The use of rats that had been prescreened for ATSET performance helped to establish that working memory of the rules for the food reward remained intact (for at least 100 days) even after 15 cGy irradiation with 600 MeV/n 56Fe particles, but that 56Fe radiation exposure affected associative cue learning/acquisition rather than an intrinsic inability to perform the CD tasks. Our data suggest that declarative memory, and the ability to transitively infer established rules, also remained intact in the irradiated rats. Thus, should similar effects occur in astronauts, 56Fe-induced CD performance deficits may only be manifested in scenarios where astronauts are required to transitively apply their knowledge to solve problems that they have not previously encountered; nevertheless, potentially one-third of astronauts may not be able to perform event-critical tasks correctly. The implication of this data, from a probabilistic risk assessment perspective, is that cognitive performance studies that use naive rodents, thus requiring task rule acquisition as well as task performance, are likely to overestimate the risk of 56Fe-induced cognitive deficits. PMID- 30407902 TI - Effects of swimming exercise on the extinction of fear memory in rats. AB - We investigated the relation between swimming exercise and fear memory extinction. Rats that performed regular swimming exercise over 6 wk underwent fear conditioning. Twenty-eight days later, they were submitted to extinction tests. Swimming rats had enhanced extinction process throughout the 5 days of the extinction test compared with sedentary rats. This suggests that the swimming exercise accelerated the process of aversive memory extinction, reducing the expression of conditioned fear behavior. These results encourage further studies addressing the anxiolytic effects of exercise, with potential implications for anxiety disorders such as posttraumatic stress disorder. NEW & NOTEWORTHY We have shown that rats that performed regular swimming exercise over 6 wk had enhanced extinction process compared with sedentary animals. The swimming exercise may accelerate the process of aversive memory extinction, reducing the expression of conditioned fear behavior. PMID- 30407903 TI - Blautia argi sp. nov., a new anaerobic bacterium isolated from dog faeces. AB - Two isolates of a Gram-positive, non-motile, coccoid or oval-shaped anaerobic bacterium, designated strains N6H1-15T and YH1_16, were isolated from faecal samples obtained from a mature dog. Analysis of 16S rRNA gene sequences indicated that the isolates belonged to the Blautia coccoidesrRNA gene group (cluster XIVa) and were closely related to Blautia hansenii KCTC 5951T, Blautia stercoris KCTC 5981T, Blautia producta producta KCTC 3695T and B. coccoides DSM 15327T, with 96.7, 94.4, 94.2 and 93.9 % sequence similarity, respectively. The two isolates contained m-diaminopimelic acid within their peptidoglycans. The major polar lipids were diphosphatidylglycerol and phosphatidylglycerol, and the major fatty acids were C16 : 0 (18.5 %), C16 : 0 (18.0 %) and C18 : 1cis 9 (16.2 %). The predominant metabolic end products of glucose fermentation were acetic and lactic acids, and the G+C content was 44.2 mol%. Thus, the polyphasic data suggest that the two new isolates represent a new species, proposed as Blautia argi sp. nov. The type strain is N6H1-15T (=KCTC 15426=JCM 31394). PMID- 30407901 TI - A New Standard DNA Damage (SDD) Data Format. AB - Our understanding of radiation-induced cellular damage has greatly improved over the past few decades. Despite this progress, there are still many obstacles to fully understand how radiation interacts with biologically relevant cellular components, such as DNA, to cause observable end points such as cell killing. Damage in DNA is identified as a major route of cell killing. One hurdle when modeling biological effects is the difficulty in directly comparing results generated by members of different research groups. Multiple Monte Carlo codes have been developed to simulate damage induction at the DNA scale, while at the same time various groups have developed models that describe DNA repair processes with varying levels of detail. These repair models are intrinsically linked to the damage model employed in their development, making it difficult to disentangle systematic effects in either part of the modeling chain. These modeling chains typically consist of track-structure Monte Carlo simulations of the physical interactions creating direct damages to DNA, followed by simulations of the production and initial reactions of chemical species causing so-called "indirect" damages. After the induction of DNA damage, DNA repair models combine the simulated damage patterns with biological models to determine the biological consequences of the damage. To date, the effect of the environment, such as molecular oxygen (normoxic vs. hypoxic), has been poorly considered. We propose a new standard DNA damage (SDD) data format to unify the interface between the simulation of damage induction in DNA and the biological modeling of DNA repair processes, and introduce the effect of the environment (molecular oxygen or other compounds) as a flexible parameter. Such a standard greatly facilitates inter model comparisons, providing an ideal environment to tease out model assumptions and identify persistent, underlying mechanisms. Through inter-model comparisons, this unified standard has the potential to greatly advance our understanding of the underlying mechanisms of radiation-induced DNA damage and the resulting observable biological effects when radiation parameters and/or environmental conditions change. PMID- 30407904 TI - Canine Influenza Virus A(H3N2) Clade with Antigenic Variation, China, 2016-2017. AB - During 2012-2017, we collected throat swabs from dogs in China to characterize canine influenza virus (CIV) A(H3N2) isolates. A new antigenically and genetically distinct CIV H3N2 clade possessing mutations associated with mammalian adaptation emerged in 2016 and replaced previously circulating strains. This clade probably poses a risk for zoonotic infection. PMID- 30407905 TI - Brain and spinal stimulation therapies for phantom limb pain: a systematic review. AB - BACKGROUND: Although many treatments exist for phantom limb pain (PLP), the evidence supporting them is limited and there are no guidelines for PLP management. Brain and spinal cord neurostimulation therapies are targeted at patients with chronic PLP but have yet to be systematically reviewed. OBJECTIVE: To determine which types of brain and spinal stimulation therapy appear to be the best for treating chronic PLP. DESIGN: Systematic reviews of effectiveness and epidemiology studies, and a survey of NHS practice. POPULATION: All patients with PLP. INTERVENTIONS: Invasive interventions - deep brain stimulation (DBS), motor cortex stimulation (MCS), spinal cord stimulation (SCS) and dorsal root ganglion (DRG) stimulation. Non-invasive interventions - repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). MAIN OUTCOME MEASURES: Phantom limb pain and quality of life. DATA SOURCES: Twelve databases (including MEDLINE and EMBASE) and clinical trial registries were searched in May 2017, with no date limits applied. REVIEW METHODS: Two reviewers screened titles and abstracts and full texts. Data extraction and quality assessments were undertaken by one reviewer and checked by another. A questionnaire was distributed to clinicians via established e-mail lists of two relevant clinical societies. All results were presented narratively with accompanying tables. RESULTS: Seven randomised controlled trials (RCTs), 30 non comparative group studies, 18 case reports and 21 epidemiology studies were included. Results from a good-quality RCT suggested short-term benefits of rTMS in reducing PLP, but not in reducing anxiety or depression. Small randomised trials of tDCS suggested the possibility of modest, short-term reductions in PLP. No RCTs of invasive therapies were identified. Results from small, non comparative group studies suggested that, although many patients benefited from short-term pain reduction, far fewer maintained their benefits. Most studies had important methodological or reporting limitations and few studies reported quality-of-life data. The evidence on prognostic factors for the development of chronic PLP from the longitudinal studies also had important limitations. The results from these studies suggested that pre-amputation pain and early PLP intensity are good predictors of chronic PLP. Results from the cross-sectional studies suggested that the proportion of patients with severe chronic PLP is between around 30% and 40% of the chronic PLP population, and that around one quarter of chronic PLP patients find their PLP to be either moderately or severely limiting or bothersome. There were 37 responses to the questionnaire distributed to clinicians. SCS and DRG stimulation are frequently used in the NHS but the prevalence of use of DBS and MCS was low. Most responders considered SCS and DRG stimulation to be at least sometimes effective. Neurosurgeons had mixed views on DBS, but most considered MCS to rarely be effective. Most clinicians thought that a randomised trial design could be successfully used to study neurostimulation therapies. LIMITATION: There was a lack of robust research studies. CONCLUSIONS: Currently available studies of the efficacy, effectiveness and safety of neurostimulation treatments do not provide robust, reliable results. Therefore, it is uncertain which treatments are best for chronic PLP. FUTURE WORK: Randomised crossover trials, randomised N-of-1 trials and prospective registry trials are viable study designs for future research. STUDY REGISTRATION: The study is registered as PROSPERO CRD42017065387. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 30407906 TI - Revisiting FDA's 1995 Guidance on Bioequivalence Establishment of Topical Dermatologic Corticosteroids: New Research Based Recommendations. AB - PURPOSE: As per the US FDA guidance issued on June 2, 1995, the establishment of bioequivalence for topical dermatologic corticosteroids is based on comparing the pharmacodynamic (PD) effects of Test and Reference products at the dose duration corresponding to the population ED50, determined either by naive pooled data or nonlinear mixed effect modeling (NLME). The guidance was introduced using a study case example where the expectation maximization (EM) NLME algorithm, as implemented in P-PHARM(r), was used. Although EM methods are relatively common, other methods such as the First-Order Conditional Estimation (FOCE) as implemented in the NONMEM(r) software are even more common. The objective of this study was to investigate the impact of using different parametric population modeling/analysis methods and distribution assumptions on population analysis results. METHODS: The dose duration-response data from 11 distinct skin blanching blinded pilot studies were fitted using FOCE (NONMEM(r)) and an EM algorithm (ADAPT5(r) (MLEM)). Three different Emax models were tested for each method. Population PD estimates and associated CV%, and the agreement between model predicted values and observed data were compared between the two methods. The impact of assuming different distributions of PD parameters was also investigated. RESULTS: The simple Emax model, as proposed in the FDA guidance, appeared to best characterize the data compared to more complex alternatives. The MLEM method in general appeared to provide better results than FOCE; lower population PD estimates with less inter-individual variability, and no variance shrinkage issues. The results also favored ln-normal versus normal distribution assumptions. CONCLUSIONS: The population ED50 estimates were influenced by both the type of population modeling methods and the distribution assumptions. We recommend updating the FDA guidance with more specific instructions related to the population approach to be used (EM-like versus FOCE-like methods) and to the normality assumptions that need to be set (ln-normal versus normal distribution). PMID- 30407907 TI - The Antioxidant Activity of Recombinant Rat Hepatic Fatty Acid Binding Protein T94A Variant. AB - PURPOSE: Liver fatty acid binding protein (FABP1) is a cytoplasmic polypeptide that transports substrates throughout the cytosol and functions as an antioxidant. A common polymorphic variant, FABP1 T94A has a minor allele frequency of 26-38%, 8.3+/-1.9% homozygous in the human population. The purpose of this study was to mutate and isolate recombinant rat FABP1 to the T94A variant to evaluate the mutant's antioxidant activity using in vitro studies. METHODS: Site-directed mutagenesis was used to generate a mutation in rat cDNA within a pGEX-6p-2 vector. This plasmid was transformed into competent cells and cultured for expression of FABP1 T94A mutant. The mutated protein was purified using GSTrap Fastflow columns within an AKTA FPLC system. A 2,7-dichlorofluorescein (DCF) assay was used to screen the T94A variant antioxidant activity. Additionally, Thiobarbituric Acid Reactive Substances (TBARS) assay was used in determining T94A mutant antioxidant activity in hydrophilic and lipophilic environments through the use of the azo compounds AAPH and MeO-AMVN, respectively and in the presence and absence of the long-chain fatty acid palmitate and alpha bromo palmitate. RESULTS: Although the FABP1 T94A (20 MUM) mutant significantly reduced DCF fluorescence compared to control (no protein; P< 0.001), there were no significant difference when compared to the wild-type (WT) FABP1. T94A was able to diminish the formation of malondialdehyde (MDA) in both lipophilic and hydrophilic systems. There were significant differences between T94A mutant and WT FABP1 at concentrations 1 and 10 MUM (P< 0.05) in the hydrophilic milieu, however, this was not seen at 20 MUM and also not seen in the lipophilic milieu at all concentrations. When T94A was pre-incubated with the long-chain fatty acids palmitate or alpha -bromo palmitate, MDA formation was decreased in both lipid peroxidation systems. There were no statistical differences between the WT FABP1 and T94A bound with fatty acids in both lipid peroxidation systems, however, there was a slight statistical difference when the T94A and WT FABP1 bound alpha-Br-PA in the AAPH lipid peroxidation system only. CONCLUSIONS: The T94A has antioxidant activity in both hydrophilic and lipophilic environments. The T94A variant of FABP1 does not have a loss of function in regard to acting as an antioxidant but the extent of function may be influenced by ligand binding. We conclude that populations having the minor T94A allele frequency would have similar ROS scavenging potential as those with nascent FABP1. PMID- 30407908 TI - Moving towards Universal Coverage of Direct-Acting Antiviral Therapies for Hepatitis C Infection in Canada: An Environmental Scan of Canadian Provinces and International Jurisdictions. AB - BACKGROUND: Direct-acting antivirals (DAAs) have become the standard treatment for patients with chronic hepatitis C infections because of their high cure rates and favourable side effect profiles; however, access to this new class of agents has been limited because of its high cost. Public payers across Canada have implemented strict criteria for drug coverage in order to contain expenditures. Efforts have been made to improve access to medication for this high-burden condition. Recent coverage criteria across national and international jurisdictions have been compared. METHODS: Coverage criteria for several DAAs were reviewed by accessing Canadian provincial drug formularies. International coverage (e.g., Europe, Australia, United States, Egypt, India) was reviewed by searching available literature. RESULTS: Coverage criteria vary across Canada. By April 2018, most Canadian jurisdictions had removed the stage 2 liver fibrosis requirement for patients to be eligible for coverage. Internationally, patients' access to DAAs differs significantly. Many jurisdictions restrict DAA prescribing authority to specialists and request documentation of chronic hepatitis C. In the US, considerable gaps of coverage are identifiable and patients might face significant financial burden to receive treatment. CONCLUSION: DAAs appear to be generally accessible through public drug plans in Canada compared to other countries. PMID- 30407910 TI - Communicating laboratory results to patients and families. AB - People are increasingly able to access their laboratory results via patient portals. The potential benefits provided by such access, such as reductions in patient burden and improvements in patient satisfaction, disease management, and medical decision making, also come with potentially valid concerns about such results causing confusion or anxiety among patients. However, it is possible to clearly convey the meaning of results and, when needed, indicate required action by designing systems to present laboratory results adapted to the people who will use them. Systems should support people in converting the potentially meaningless data of results into meaningful information and actionable knowledge. We offer 10 recommendations toward this goal: (1) whenever possible, provide a clear takeaway message for each result. (2) Signal whether differences are meaningful or not. (3) When feasible, provide thresholds for concern and action. (4) Individualize the frame of reference by allowing custom reference ranges. (5) Ensure the system is accessible. (6) Provide conversion tools along with results. (7) Design in collaboration with users. (8) Design for both new and experienced users. (9) Make it easy for people use the data as they wish. (10) Collaborate with experts from relevant fields. Using these 10 methods and strategies renders access to laboratory results into meaningful and actionable communication. In this way, laboratories and medical systems can support patients and families in understanding and using their laboratory results to manage their health. PMID- 30407911 TI - The Assessment of Reasoning Tool (ART): structuring the conversation between teachers and learners. AB - Background Excellence in clinical reasoning is one of the most important outcomes of medical education programs, but assessing learners' reasoning to inform corrective feedback is challenging and unstandardized. Methods The Society to Improve Diagnosis in Medicine formed a multi-specialty team of medical educators to develop the Assessment of Reasoning Tool (ART). This paper describes the tool development process. The tool was designed to facilitate clinical teachers' assessment of learners' oral presentation for competence in clinical reasoning and facilitate formative feedback. Reasoning frameworks (e.g. script theory), contemporary practice goals (e.g. high-value care [HVC]) and proposed error reduction strategies (e.g. metacognition) were used to guide the development of the tool. Results The ART is a behaviorally anchored, three-point scale assessing five domains of reasoning: (1) hypothesis-directed data gathering, (2) articulation of a problem representation, (3) formulation of a prioritized differential diagnosis, (4) diagnostic testing aligned with HVC principles and (5) metacognition. Instructional videos were created for faculty development for each domain, guided by principles of multimedia learning. Conclusions The ART is a theory-informed assessment tool that allows teachers to assess clinical reasoning and structure feedback conversations. PMID- 30407909 TI - CRELD1 is an evolutionarily-conserved maturational enhancer of ionotropic acetylcholine receptors. AB - The assembly of neurotransmitter receptors in the endoplasmic reticulum limits the number of receptors delivered to the plasma membrane, ultimately controlling neurotransmitter sensitivity and synaptic transfer function. In a forward genetic screen conducted in the nematode C. elegans, we identified crld-1 as a gene required for the synaptic expression of ionotropic acetylcholine receptors (AChR). We demonstrated that the CRLD-1A isoform is a membrane-associated ER resident protein disulfide isomerase (PDI). It physically interacts with AChRs and promotes the assembly of AChR subunits in the ER. Mutations of Creld1, the human ortholog of crld-1a, are responsible for developmental cardiac defects. We showed that Creld1 knockdown in mouse muscle cells decreased surface expression of AChRs and that expression of mouse Creld1 in C. elegans rescued crld-1a mutant phenotypes. Altogether these results identify a novel and evolutionarily conserved maturational enhancer of AChR biogenesis, which controls the abundance of functional receptors at the cell surface. PMID- 30407912 TI - Early adiposity rebound in patients with Prader-Willi syndrome. AB - Background Prader-Willi syndrome (PWS) is associated with marked obesity that can lead to severe complications such as diabetes mellitus. Early adiposity rebound (AR) is associated with future obesity and an increased risk of diabetes mellitus and metabolic syndrome. Previous reports have shown that the onset of AR occurred earlier in diseases that cause obesity. However, there have been no studies focusing on the timing of AR in PWS, or on the effect of growth hormone (GH) treatment on AR. The aim of this study was to explore AR in PWS patients and to analyze the effect of GH treatment on AR. Methods This retrospective study evaluated 48 patients, with 16 of the patients found to have AR prior to GH treatment. AR was constructed for each patient using Microsoft Excel, and the exact point of the nadir of body mass index (BMI) following the initial peak was determined. We additionally analyzed the relationship between GH treatment and the timing of AR onset. Results AR onset for patients found to have AR before starting GH treatment was 16.0 (13.0-21.0) months. In contrast, AR onset for patients found to have AR after starting GH treatment was 27.5 (23.8-36.3) months. The difference between the two groups was statistically significant (p=0.0001). A positive correlation was found between the GH treatment period and AR (p=0.00013). Conclusion The median age of AR onset in PWS patients was 16.0 (13.0-21.0) months, and GH treatment might delay the early AR onset. PMID- 30407913 TI - Prediction of running-induced Achilles tendinopathy with pain sensitivity - a 1 year prospective study. AB - Background and aims Achilles tendinopathy is common among runners, but the etiology remains unclear. High mechanical pain sensitivity may be a predictor of increased risk of developing Achilles tendinopathy in this group. The purpose of this study was to investigate whether local pain sensitivity could predict the development of Achilles tendinopathy in recreational male runners. The overall hypothesis was that high pain sensitivity would be related to a higher risk of developing Achilles tendinopathy among recreational male runners. Methods Ninety nine recreational male runners were recruited and followed prospectively for 1 year. At baseline and after 500 km of running the pressure pain threshold (PPT) was assessed at the infraspinatus and at the Achilles tendon (AT-PPT). Based on the AT-PPT at baseline, a median split was used to divide the runners into two groups. The high pain sensitivity groups was defined as runners displaying a pain pressure threshold below 441 kPa on the Achilles tendon, while the low pain sensitivity group was defined as runners displaying a pain pressure threshold above 441 kPa on the Achilles tendon, respectively. Subsequently, the cumulative risk difference between the two groups was assessed by using the pseudo observation method. Results High pain sensitivity runners sustained 5%-point (95% CI: -0.18 to 0.08) more Achilles tendinopathy episodes during the first 1,500 km. No significant group differences in risk were found at 100, 250, 500, 1,000 and 1,500 km of running. Conclusions No significant association was found between mechanical pain sensitivity in the Achilles tendon and the risk of developing Achilles tendinopathy. However, the risk difference indicated a association between a high mechanical pain sensitivity and an increased risk of developing Achilles tendinopathy. It is plausible that changes in pain sensitivity were masked by unmeasured covariates, such as the differences in progression/regression of training volume and running speed between the two groups. This study was limited in size, which limited the possibility to account for covariates, such as differences in progression/regression of running speed between runners. With the limitations in mind, future studies should control the training volume, speed and running shoes in the design or account for it in the analysis. Implications Pain sensitivity of the Achilles tendon seems not to be related to an increased risk of developing Achilles pain in relation to running. PMID- 30407914 TI - The utility/futility of medications for neuropathic pain - an observational study. AB - Background and aims The RELIEF (Real Life) study by AstraZeneca was designed as an observational study to validate a series of Patient Reported Outcome (PRO) questionnaires in a mixed population of subjects with neuropathic pain (NP) coming from diabetes, neurology and primary care clinics. This article is an analysis of a subset of the information to include the medications used and the effects of pharmacological treatment over 6 months. The RELIEF study was performed during 2010-2013. Methods Subjects were recruited from various specialty clinics and one general practice clinic across Canada. The subjects were followed for a total of 2 years with repeated documentation of their status using 10 PROs. A total of 210 of the recruited subjects were entered into the data base and analyzed. Of these, 123 had examination-verified painful diabetic neuropathy (PDN) and 87 had examination-verified post-traumatic neuropathy (PTN). To evaluate the responsiveness of the PROs to change, several time points were included and this study focusses primarily on the first 6 months. Subjects also maintained a diary to document all medications, both for pain and other medical conditions, including all doses, start dates and stop dates, that could be correlated to changes in the PRO parameters. Results RELIEF was successful in being able to correlate the validity of the PROs and this data was used for further AstraZeneca Phase 1, 2, and 3 clinical trials of NP. To our surprise, there was very little change in pain and low levels of patient satisfaction with treatment during the trial. Approximately 15% of the subjects reported improvement, 8% worsening of pain, the remainder reported pain unchanged despite the use of multiple medications at multiple doses, alone or in combination with frequent changes of medications and doses over the study. Those taking predominantly NSAIDs (COX-inhibitors) did no worse than those taking the standard recommended medications against NP. Conclusions Since this is a real-life study, it reflects the clinical utility of a variety of internationally recommended medications for the treatment of NP. In positive clinical trials of these medications in selected "ideal" subjects, the effects are not overwhelming - 30% are 50% improved on average. This study shows that in the real world the results are not nearly as positive and reflects information from non-published negative clinical trials. Implications We still do not have very successful medications for NP. Patients probably differ in many respects from those subjects in clinical trials. This is not to negate the use of recommended medications for NP but an indication that success rates of treatment are likely to be worse than the data coming from those trials published by the pharmaceutical industry. PMID- 30407915 TI - Opiates and the adrenal: the tip of the iceberg? AB - Opiates have been in use for millennia, and their hypogonadal effects have been readily recognised. However, their effects on the pituitary-adrenal axis have been less well described. This is especially important as there appears to be an epidemic of prescribed-opiates misuse. The present controlled study reviewed here demonstrates that at significant doses opiates administered in a Pain Clinic can often considerably suppress the hypothalamo-pituitary-adrenal axis, and such changes may be clinically important. PMID- 30407916 TI - Low PR in ER(+)/HER2(-) breast cancer: high rates of TP53 mutation and high SUV. AB - On the basis of TP53 mutations and standardized uptake values (SUVs) from 18F fluorodeoxyglucose positron emission tomography (18F-FDG-PET), we sought to enhance our knowledge of the biology underlying low progesterone receptor (PR) expression in estrogen receptor (ER)-positive/human epidermal growth factor receptor-2 (HER2)-negative tumors. This study included 272 patients surgically treated for ER-positive, HER2-negative breast cancer and who had undergone TP53 gene sequencing. Of these, 229 patients also underwent 18F-FDG PET or PET/CT. Mutational analysis of exons 5 to 9 of the TP53 gene was conducted using polymerase chain reaction amplification and direct sequencing. The SUVs were measured using 18F-FDG-PET scan images. We found that twenty-eight (10.3%) tumors had a somatic TP53 mutation. The TP53 mutation rate was significantly higher in low-PR tumors than in high-PR tumors (17.1% vs. 7.9%, P = 0.039). Low-PR tumors had significantly higher median SUVs than high-PR tumors (P = 0.046). The multivariable analysis revealed that SUV and age remained independent variables associated with low PR expression. An adverse impact of low PR expression on recurrence-free survival was observed in the multivariable Cox regression hazard model. We provide clinical evidence that genetic alteration of the TP53 gene and dysregulated glucose metabolism partly involve low PR expression in ER-positive and HER2-negative breast cancer. PMID- 30407917 TI - Kalirin/Trio Rho GDP/GTP exchange factors regulate proinsulin and insulin secretion. AB - Key features for progression to pancreatic beta-cell failure and disease are loss of glucose responsiveness and an increased ratio of secreted proinsulin to insulin. Proinsulin and insulin are stored in secretory granules (SGs) and the fine-tuning of hormone output requires signal mediated recruitment of select SG populations according to intracellular location and age. The GTPase Rac1 coordinates multiple signaling pathways that specify SG release and Rac1 activity is controlled in part by GDP/GTP exchange factors (GEFs). To explore the function of two large multidomain GEFs, Kalirin and Trio in beta-cells, we manipulated their Rac1-specific GEF1 domain activity by using small molecule inhibitors and by genetically ablating Kalirin. We examined age related secretory granule behavior employing radiolabeling protocols. Loss of Kalirin/Trio function attenuated radioactive proinsulin release by reducing constitutive-like secretion and exocytosis of 2-hour old granules. At later chase times or at steady state, Kalirin/Trio manipulations decreased glucose stimulated insulin output. Finally, use of a Rac1 FRET biosensor with cultured beta-cell lines, demonstrated that Kalirin/Trio GEF1 activity was required for normal rearrangement of Rac1 to the plasma membrane in response to glucose. Rac1 activation can be evoked by both glucose metabolism and signaling through the incretin glucagon-like peptide 1 (GLP-1) receptor. GLP-1 addition restored Rac1 localization/activity and insulin secretion in the absence of Kalirin, thereby assigning Kalirin's participation to stimulatory glucose signaling. PMID- 30407918 TI - Identification and characterization of ERV transcripts in goat embryos. AB - Endogenous retroviruses (ERVs), which are abundant in mammalian genomes, can modulate the expression of nearby genes, and their expression is dynamic and stage specific during early embryonic development in mice and humans. However, the functions and mechanisms of ERV elements in regulating embryonic development remain unclear. Here, we utilized several methods to determine the contribution of ERVs to the makeup and regulation of transcripts during embryonic genome activation (EGA). We constructed an ERV library and embryo RNA-seq library (IVF_2c and IVF_8c) of goat to serve as our research basis. The GO and KEGG analysis of nearby ERV genes revealed that some ERV elements may be associated with embryonic development. RNA-seq results were consistent with the features of EGA. To obtain the transcripts derived from the ERV sequences, we blasted the ERV sequences with embryonic transcripts and identified three lncRNAs and one mRNA that were highly expressed in IVF-8c rather than in IVF-2c (q-value < 0.05). Then, we validated the expression patterns of nine ERV-related transcripts during early developmental stages and knocked down three high-expression transcripts in EGA. The knockdown of lncRNA TCONS_00460156 or mRNA HSD17B11 significantly decreased the developmental rate of IVF embryos. Our findings suggested that some transcripts from ERVs are essential for the early embryonic development of goat, and analyzing the ERV expression profile during goat EGA may help elucidate the molecular mechanisms of ERV in regulating embryonic development. PMID- 30407919 TI - Novel mutations associated with inherited human calcium-sensing receptor disorders: a clinical genetic study. AB - OBJECTIVE: Molecular diagnosis is a useful diagnostic tool in calcium metabolism disorders. The calcium-sensing receptor (CaSR) is known to play a central role in the regulation of extracellular calcium homeostasis. We performed clinical, biochemical and genetic characterization of sequence anomalies in this receptor in a cohort of 130 individuals from 82 families with suspected alterations in the CASR gene, one of the largest series described. METHODS: The CASR gene was screened for mutations by polymerase chain reaction followed by direct Sanger sequencing. RESULTS: Presumed CaSR-inactivating mutations were found in 65 patients from 26 families. These patients had hypercalcemia (median 11.3 mg/dL) but normal or abnormally high parathyroid hormone (PTH) levels (median 52 pg/mL). On the other hand, presumed CaSR-activating mutations were detected in 17 patients from 8 families. These patients had a median serum calcium level of 7.4 mg/dL and hypoparathyroidism (median PTH 13 pg/mL). Further, common polymorphisms previously associated with high blood ionized calcium levels were found in 27 patients (median calcium 10.6 mg/dL; median PTH 65 pg/mL) with no other alterations in CASR. Overall, we found 30 different mutations, of which, 14 have not been previously reported (p.Ala26Ser, p.Cys60Arg, p.Lys119Ile, p.Leu123Met, p.Glu133Val, p.Gly222Glu, p.Phe351Ile, p.Cys542Tyr, p.Cys546Gly, p.Cys677Tyr, p.Ile816Val, p.Ala887Asp, p.Glu934*, p.Pro935_Gln945dup). CONCLUSIONS: Patients with CASR mutations may not fit the classic clinical pictures of hypercalcemia with hypocalciuria or hypocalcemia with hypercalciuria. Molecular studies are important for confirming the diagnosis and distinguishing it from other entities. Our genetic analysis confirmed CaSR disorders in 82 patients in the study cohort. PMID- 30407920 TI - Long-term complications in patients with chronic hypoparathyroidism: a cross sectional study. AB - OBJECTIVE: Chronic hypoparathyroidism and its treatment may lead to symptoms and complications affecting quality of life. We determined complications in chronic hypoparathyroid patients. DESIGN: Retrospective cross-sectional study of patients with chronic hypoparathyroidism treated with active vitamin D supplements in a tertiary care centre during the year 2015. Primary outcome parameters were history of kidney stones and seizures, and presence of renal and cerebral calcifications on imaging. Secondary outcome parameters were current symptoms of paraesthesia/cramps, hospitalization due to hyper/hypocalcaemia, and hypercalciuria. SUBJECTS: 170 patients were included: 143 (84%) with post surgical hypoparathyroidism (PSHP), 16 (9%) with non-surgical hypoparathyroidism (NSHP), 11 (7%) with pseudo-hypoparathyroidism (PHP). RESULTS: History of kidney stones and seizures was present in 15% and 9% of patients, respectively. Renal and cerebral imaging was performed in 51% and 26% of the patients, with 22% and 25% of these patients having renal and cerebral calcifications, respectively. Both history of seizures and cerebral calcifications were significantly more present in NSHP and PHP than in PSHP patients. No association was observed between seizures and cerebral calcifications. Cramps/paraesthesia were present in 16%, hospitalization related to hypocalcaemia was reported in 5% of the patients. Calciuria was screened in 47%, and in 76% of the patients during the past 5 years. In 36% of these patients calciuria was increased. CONCLUSIONS: Patients with chronic hypoparathyroidism frequently develop ectopic calcifications. Non surgical patients suffer more from seizures and cerebral calcifications than patients that developed hypoparathyroidism post-surgery. There is a need for increased screening of long-term complications, according to the guidelines. PMID- 30407921 TI - Radiofrequency ablation for benign thyroid nodules according to different US features: an Italian multicentre prospective study. AB - BACKGROUND: The purpose of this study was to confirm the generalisation of radiofrequency ablation (RFA) in the treatment of benign thyroid nodules (BTN) and to look for a correlation between final shrinkage and some US findings in a large Italian population data set. METHODS: This prospective study included 337 patients with solid cold BTN from six Italian institutions. Nodule volume, US pattern, thyroid function, symptom/cosmetic scores and complications were evaluated before and at 6 and 12 months. The primary outcome was to find a correlation between basal volume and US pattern of the nodules and final shrinkage. The secondary outcome was to confirm the efficacy and safety of RFA in a large data set. RESULTS: The median basal volume was 20.7ml which significantly decreased after RFA at 6 months (7.3ml (-63.5%), p<0.001) and at 12 months (6ml ( 70%), p vs 6 months=0.009). A significant correlation was found for US structure (a spongiform pattern showing a 76% reduction vs 67% and 66% of mix and solid patterns respectively, p<0.01) as well as for vascularity (intense peripheral and intranodal patterns showing 71% vs 68% and 67% of weak peripheral and intranodal and peripheral patterns respectively, p<0.03), but not for macrocalcifications. A slight inverse correlation was found between nodule basal volume and shrinkage (Spearman -0.23). Mean symptoms/cosmetic scores were significantly reduced. No major complications were encountered. CONCLUSIONS: This multicentre study validated the efficacy and safety of RFA for treating BTN and showed a clear correlation between final shrinkage and some common US findings. PMID- 30407922 TI - The current landscape of European registries for rare endocrine conditions. AB - OBJECTIVE: To identify cross-border international registries for rare endocrine conditions that are led from Europe and understand the extent of engagement with these registries within a network of reference centres (RC) for rare endocrine conditions. METHODS: Database search of international registries and a survey of RCs in the European Reference Network for rare endocrine conditions (Endo-ERN) with an overall response rate of 82%. RESULTS: Of the 42 conditions with orphacodes currently covered within Endo-ERN, international registries exist for 32 (76%). Of 27 registries identified in the Orphanet and RD-Connect databases, Endo-ERN RC were aware of 11 (41%). Of 21 registries identified by the RC, RD Connect and Orphanet did not have a record of 10 (48%). Of the 29 glucose RC, the awareness and participation rate in an international registry was highest for rare diabetes at 75% and 56%, respectively. Of the 37 sex development RC, the corresponding rates were highest for disorders of sex development at 70% and 52%. Of the 33 adrenal RC, the rates were highest for adrenocortical tumours at 68% and 43%. Of the 43 pituitary RC, the rates were highest for pituitary adenomas at 43% and 29%. Of the 31 genetic tumour RC, the rates were highest for MEN1 at 26% and 9%. For the remaining conditions, awareness and participation in registries was less than 25%. CONCLUSION: Although there is a need to develop new registries for rare endocrine conditions, there is a more immediate need to improve the awareness and participation in existing registries. PMID- 30407923 TI - Identification of an energy metabolism-related signature associated with clinical prognosis in diffuse glioma. AB - Now, numerous exciting findings have been yielded in the field of energy metabolism within glioma cells. In addition to aerobic glycolysis, multiple catabolic pathways are employed for energy production. However, the prognostic significance of energy metabolism in glioma remains obscure. Here, we explored the relationship between energy metabolism gene profile and outcome of diffuse glioma patients using The Cancer Genome Altas (TCGA) and Chinese Glioma Genome Altas (CGGA) datasets. Based on the gene expression profile, consensus clustering identified two robust clusters of glioma patients with distinguished prognostic and molecular features. With the Cox proportional hazards model with elastic net penalty, an energy metabolism-related signature was built to evaluate patients' prognosis. Kaplan-Meier analysis found that the acquired signature could differentiate the outcome of low and high-risk groups of patients in both cohorts. Moreover, the signature, significantly associated with the clinical and molecular features, could serve as an independent prognostic factor for glioma patients. Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) showed that gene sets correlated with high-risk group were involved in immune and inflammatory response, with the low-risk group were mainly related to glutamate receptor signaling pathway. Our results provided new insight into energy metabolism role in diffuse glioma. PMID- 30407924 TI - Non-adiabatic molecular dynamics with DeltaSCF excited states. AB - Accurate modelling of nonadiabatic transitions and electron-phonon interactions in extended systems is essential for understanding the charge and energy transfer in photovoltaic and photocatalytic materials. The extensive computational costs of the advanced excited state methods have stimulated the development of many approximations to study the nonadiabatic molecular dynamics (NA-MD) in solid state and molecular materials. In this work, we present a novel ?SCF-NA-MD methodology that aims to account for electron-hole interactions and electron phonon back-reaction critical in modelling photoinduced nuclear dynamics. The excited states dynamics is described using the delta self-consistent field (?SCF) technique within the density functional formalism and the trajectory surface hopping. The technique is implemented in the open-source Libra-X package freely available on the Internet (https://github.com/Quantum-Dynamics-Hub/Libra-X). This work illustrates the general utility of the developed ?SCF-NA-MD methodology by characterizing the excited state energies and lifetimes, reorganization energies, photoisomerization quantum yields, and by providing the mechanistic details of reactive processes in a number of organic molecules. PMID- 30407925 TI - Learning Curve of Robotic Lobectomy for Early-Stage Non-Small Cell Lung Cancer by a Thoracic Surgeon Adept in Open Lobectomy. AB - OBJECTIVE: The aim of the study was to characterize the clinical outcomes and learning curve during the adoption of a robotic platform for lobectomy for early stage non-small cell lung cancer by a thoracic surgeon experienced in open thoracotomy. METHODS: Retrospective review of 157 consecutive patients (57 open thoracotomies, 100 robotic lobectomies) treated with lobectomy for clinical stage I or II non-small cell lung cancer between 2007 and 2014. Clinical outcomes were compared between the open thoracotomy group and five consecutive groups of 20 robotic lobectomies. We used the following six metrics to evaluate learning curve: operative time, conversion to open, estimated blood loss, hospitalization duration, overall morbidity, and pathologic nodal upstaging. RESULTS: The robotic and open thoracotomy groups had equivalent preoperative characteristics, except for a higher proportion of clinical stage IA patients in the robotic cohort. The robotic group, as a whole, had lower intraoperative blood loss, less overall morbidity, shorter chest tube duration, and shorter length of hospital stay as compared with the open thoracotomy group. Operative time demonstrated a bimodal learning curve. Conversion rate diminished from 22.5% in the first two robotic groups to 6.7% in the latter three groups. The rate of pathologic nodal upstaging was statistically equivalent to the open thoracotomy group. CONCLUSIONS: Adoption of a robotic platform for lobectomy for early-stage non-small cell lung cancer by an experienced open thoracic surgeon is safe and feasible, with fewer complications, less blood loss, and equivalent nodal sampling rate even during the learning curve. The conversion to open rate significantly dropped after the first 40 robotic lobectomies, and operative time for robotic lobectomy approached open thoracotomy after 60 cases, after a bimodal curve. PMID- 30407926 TI - Nonrobotic Total Endoscopic Coronary Artery Bypass Grafting: A Proof-of-Concept Study in 20 Patients. AB - OBJECTIVE: At present, minimal invasive direct coronary artery grafting is the least invasive nonrobotic surgical approach to revascularize the left anterior descending artery with the left internal mammary artery. Total endoscopic coronary bypass grafting is performed with the help of a telemanipulator ("robot"). A prospective proof-of-concept study was initiated to investigate a nonrobotic total endoscopic coronary bypass grafting approach. METHODS: Twenty patients with significant left anterior descending artery or left main stem lesion were operated on via three or four left thoracic access ports. Under exclusive endoscopic vision, the left internal mammary artery was harvested and anastomosed to the left anterior descending artery manually. Cardiopulmonary bypass and cardioplegic arrest were planned in all cases. RESULTS: In 10 patients, the operation was completed successfully as nonrobotic total endoscopic coronary bypass grafting. Reasons for conversions to minimal invasive direct coronary artery grafting or conventional sternotomy were dense pleural adhesions (3 patients), bleeding of the anastomosis (3), diffuse bleeding during left internal mammary artery harvesting (2), identification problems of the target artery (1), or left internal mammary artery failure (1). Postoperative angiography in five primarily successful nonrobotic total endoscopic coronary bypass grafting patients showed patent anastomoses in four cases. One patient was reoperated on for early anastomotic failure in a 1.0-mm target vessel. Until now, a percutaneous coronary intervention of remaining lesions as staged hybrid procedure was performed in three patients (2 nonrobotic total endoscopic coronary bypass grafting, 1 minimal invasive direct coronary artery grafting). CONCLUSIONS: With a thoroughly surveyed learning curve, nonrobotic total endoscopic coronary bypass grafting procedure could become an alternative to other available treatment options; however, the value of the procedure has to be further investigated. PMID- 30407927 TI - Right Mini-thoracotomy Bentall Procedure. AB - OBJECTIVE: Bentall procedures are traditionally performed through a median sternotomy. The right mini-thoracotomy approach is increasingly used in aortic valve replacement. This approach has been shown to have decreased blood loss and hospital length of stay compared with sternotomy. A right mini-thoracotomy approach may also be beneficial in selected patients requiring aortic root surgery. We present our initial clinical experience of patients who have undergone a right mini-thoracotomy Bentall. METHODS: This is a single-center retrospective review of seven patients who underwent a primary elective right anterior mini-thoracotomy Bentall. A thoracoscope was used in each case. Automated suturing technology was used for annular suturing in three of the seven patients. Clinical outcomes evaluated include 30-day mortality, intensive care and hospital length of stay, time to extubation, operative times, as well as postoperative sequelae including stroke, infection, and bleeding. RESULTS: Median cardiopulmonary bypass, cross-clamp, and circulatory arrest time were 217, 153, and 28 minutes, respectively. Median time to extubation was 10 hours and median intensive care unit and hospital stay was 1 and 4 days, respectively. One patient had a wound infection and one returned to the operating room for bleeding. There were no in-hospital or 30-day mortalities. CONCLUSIONS: The Bentall procedure can be performed through a right anterior mini-thoracotomy in selected patients with excellent clinical results. PMID- 30407928 TI - Staff Nurses' Perceptions of Their Nurse Managers' Transformational Leadership Behaviors and Their Own Structural Empowerment. AB - OBJECTIVE: The aim of this study was to investigate staff nurses' perception of their nurse managers' transformational leadership behaviors and their own structural empowerment. BACKGROUND: Transformational leadership behaviors in nurse managers have been linked to increased staff nurse satisfaction and decreased turnover and burnout. Perception of nurse managers' leadership behaviors by staff nurses and the relationship to the staff nurses' structural empowerment is important to advance our understanding of the leadership role of nurse managers. METHODS: A descriptive correlational design was used to examine the relationship between staff nurses' perception of their nurse managers' transformational leadership behaviors and their own structural empowerment. Staff nurses at a conference were offered an opportunity to participate in the study. RESULTS: The transformational leadership behaviors of nurse managers were moderately correlated to staff nurses' structural empowerment. Transactional leadership behaviors were associated with staff nurses' structural empowerment to a lesser degree. CONCLUSION: Nurses who perceived their nurse managers as demonstrating transformational leadership behaviors experienced higher structural empowerment. PMID- 30407929 TI - Improving Care Transitions: An Academic Service Partnership to Achieve Coordination of Care Using Students as Health Coaches. AB - To avoid penalty through the Hospital Readmission Reduction Program, an academic practice partnership, Health Transitions Alliance, was formed with the local university, resulting in adoption of an innovative transitional care model. Key to the model was a health coach who operationalized transition care to the home setting. Health coaches, interns in their last semester of college, used motivational interviewing to help patients set disease management goals. As a result of this model, the readmission rate for program participants in the initial 7 months was reduced by 72%. PMID- 30407930 TI - The Impact of Patient and Family Advisors on Critical Care Nurses' Empathy. AB - OBJECTIVE: The objective of this study was to determine if patient and family advisors' (PFAs) collaboration in an educational program could increase the empathy levels of intensive care unit (ICU) nurses. BACKGROUND: Data suggest that nurse empathy is on the decline. Ensuring that nurses consistently empathize with patients and families helps create positive patient experiences. METHODS: Thirty nurses participated in a PFA-designed educational intervention using simulation based role playing. The Toronto Empathy Questionnaire (TEQ) was used to measure empathy before and after the intervention. RESULTS: The TEQ empathy scores increased significantly after nurses completed the PFA-designed educational program. Younger nurses (<30 years) improved on average 3.03 +/- 3.6 points compared with older nurses (>30 years), who improved, on average, only 0.43 +/- 2.06 points (t24.4 = 2.46, P = .021). For the changes in TEQ scores from preintervention to postintervention, age was significantly associated with improvements in TEQ scores. CONCLUSIONS: Patient and family advisors can positively impact empathy among ICU nurses. PMID- 30407931 TI - Effect of Medicaid Expansion on Colorectal Cancer Screening Rates. AB - BACKGROUND: Colorectal cancer screening decreases incidence and improves survival. Minorities and low-income patients have lower screening rates. The Affordable Care Act increased insurance coverage for low-income Americans by funding Medicaid expansion. Not all states expanded Medicaid. The effect of Medicaid expansion on colorectal cancer screening is unknown. OBJECTIVE: This study aimed to evaluate if Medicaid expansion improved colorectal cancer screening for minorities and low-income patients. DESIGN: We used the Behavior Risk Factor Surveillance System, a nationally representative health-related telephone survey, to compare colorectal cancer screening rates from 2012 to 2016 based on Medicaid expansion status. A difference-in-difference analysis was used to compare the trends. SETTINGS: All states were included in this survey. PATIENTS: Respondents aged 50 to 64 from the early expansion, 2014 expansion, and nonexpansion states were selected. INTERVENTIONS: Medicaid expansion was funded by the Affordable Care Act. MAIN OUTCOME MEASURES: The primary outcome measured was the screening rate based on US Preventive Services Task Force guidelines. RESULTS: Overall screening in expansion states increased (early, +4.5%, p < 0.001; 2014, +1.3%, p = 0.17) compared with nonexpansion states. Screening among low-income respondents increased in early expansion states (+5.7%; p = 0.003), whereas there was no change in 2014 expansion states compared with nonexpansion states (2014, -0.3%, p = 0.89). For blacks, there was a significant increase in early expansion states, but no change in 2014 expansion states (early, +8.1%, p = 0.045; 2014, -1.5%, p = 0.64). There was no significant change for Hispanic respondents in early or 2014 expansion states compared with nonexpansion states (early, +6.5%, p = 0.11; 2014, +1.2%, p = 0.77). LIMITATIONS: Survey data are subject to response and recall bias. Factors other than Medicaid expansion may have influenced the screening rate. CONCLUSIONS: The colorectal cancer screening rate has increased in all settings, but expansion accelerated the increases in early expansion states and among low-income and black respondents; however, there was no similar increase for Hispanic respondents. It will be important to continue to monitor the effects of Medicaid expansion on colorectal cancer care, especially the incidence by stage and mortality. See Video Abstract at http://links.lww.com/DCR/A792. PMID- 30407932 TI - Simple Electroencephalographic Treatment-Emergent Marker Can Predict Repetitive Transcranial Magnetic Stimulation Antidepressant Response-A Feasibility Study. AB - OBJECTIVES: Prefrontal repetitive transcranial magnetic stimulation (rTMS) repeated daily for 4 to 6 weeks is used to treat major depressive disorder, but more than 50% of patients do not achieve significant response. Here we test the validity of a simple electroencephalographic (EEG) marker that predicts nonresponse to rTMS. Such a marker could potentially increase rTMS effectiveness by directing nonresponders to alternative treatments or by guiding early modification of stimulation parameters. METHODS: We retrospectively analyzed 2 channel EEG data captured in the OPT-TMS National Institute of Mental Health sponsored, multicenter study. Cumulative Brain Engagement Index (cBEI), a measure derived from template matching that allows scoring EEG dynamics along treatment, was computed. RESULTS: Six hundred sixty-five EEG recordings were analyzed. In the rTMS group, the median cBEI was found to increase in the responder group but remained unchanged in the nonresponder group. The difference between the cBEI of the groups became statistically significant by the third valid EEG sample. Within 5 samples, 91% of the responders presented with a cBEI above a preset threshold. Within 9 samples, 17% of the nonresponders had a cBEI above the threshold. CONCLUSIONS: This study demonstrates the feasibility of a simple-to-capture EEG marker as a treatment-emergent marker of response to rTMS treatment of depression. In the OPT-TMS study, discontinuing treatment when the cBEI dropped below the threshold between the fifth to ninth treatment potentially could have avoided administration of 485 (63%) of 765 treatments. Because the marker can be generated online, it would be of interest to evaluate, in future studies, whether it could be used to tune treatment parameters and improve remission rates. PMID- 30407934 TI - Convulsive Adverse Event in a Nonpredisposed Individual During Single-Pulse Transcranial Magnetic Stimulation Over the Lower Extremity Motor Cortex. PMID- 30407933 TI - The Safety of Electroconvulsive Therapy in Patients With Implanted Deep Brain Stimulators: A Review of the Literature and Case Report. AB - Currently there is no consensus statement about the safety of electroconvulsive therapy in patients who have implanted electrodes for deep brain stimulation. We present a summary of the existing literature on this topic, consisting of 21 cases, and then report a case performed at the University of Maryland Medical Center. Notably, with appropriate safety precautions and careful patient selection, there were no adverse events reported in the literature that were related to the presence of the deep brain stimulation device in any of the cases. Based on our review of the literature and the case we present, we have found no evidence so far to indicate that electroconvulsive therapy in patients with an implanted deep brain stimulator is unsafe. PMID- 30407935 TI - Advances in Technique and Understanding Mechanisms of Action: Adding to the Evidence Base in Electroconvulsive Therapy (ECT). PMID- 30407936 TI - Improved anal Cytology Sampling: Tush Brush Compared With Dacron Swab. AB - OBJECTIVE: The objective of this study was to determine the performance characteristics of the Tush brush (TB) compared with a saline moistened Dacron swab (DS) as anal cytology sampling devices. MATERIALS AND METHODS: TB and DS anal cytology tests were randomly collected from 146 patients presenting for anal cytology. High-resolution anoscopy and biopsies were obtained as indicated. Sensitivity and specificity as well as rates of satisfactory specimens were determined for each method using the areas under the receiver operating characteristic curve (AUCROC) and McNemar's test, respectively. Perceived discomfort of each device was determined using a visual analog scale and compared using a paired t test. RESULTS: The adjudicated AUCROC, sensitivity, and specificity were greater, but not significantly different, for the brush (0.63, 85.5, and 40.0, respectively) compared with the swab (0.50, 79.6, and 33.3, respectively) when the anal biopsy results were considered the criterion standard. In the 1 subject diagnosed with anal cancer, the swab cytology result was normal, but the brush result was abnormal. Specimen adequacy was 95.2% for the brush and 93.2% for the swab. Mean discomfort (visual analog scale) scores were swab 28.5 mm versus brush 35.6 mm (p = .0003) with both scores within the minimal to moderate discomfort range. CONCLUSIONS: Anal cytology AUCROC, sensitivity, and specificity in detecting anal neoplasia were greater using the TB when compared with the DS. A novel anal cytology sampling device designed specifically to increase the detection of anal neoplasia would be clinically beneficial. PMID- 30407937 TI - Compensatory and Serial Processing Models for Relating Electrophysiology, Speech Understanding, and Cognition. AB - OBJECTIVES: The objective of this study was to develop a framework for investigating the roles of neural coding and cognition in speech perception. DESIGN: N1 and P3 auditory evoked potentials, QuickSIN speech understanding scores, and the Digit Symbol Coding cognitive test results were used to test the accuracy of either a compensatory processing model or serial processing model. RESULTS: The current dataset demonstrated that neither the compensatory nor the serial processing model were well supported. An additive processing model may best represent the relationships in these data. CONCLUSIONS: With the outcome measures used in this study, it is apparent that an additive processing model, where exogenous neural coding and higher order cognition contribute independently, best describes the effects of neural coding and cognition on speech perception. Further testing with additional outcome measures and a larger number of subjects is needed to confirm and further clarify the relationships between these processing domains. PMID- 30407938 TI - The Association Between Race/Ethnicity and Socioeconomic Factors and the Diagnosis and Treatment of Children with Attention-Deficit Hyperactivity Disorder. AB - OBJECTIVE: Assessing race/ethnicity and socioeconomic status (SES) relationships with Attention-Deficit/Hyperactivity Disorder (ADHD) diagnosis, treatment, and access to care has yielded inconsistent results often based only on parent report. In contrast, this study used broader ADHD diagnostic determination including case-definition to examine these relationships in a multisite elementary-school-based sample. METHOD: Secondary analysis of children with and without ADHD per parent and teacher-reported Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria evaluated SES, race/ethnicity, and other variables through simple bivariate/multivariable models within and across: parent reported diagnosis, medication treatment, and meeting ADHD study case-definition. RESULTS: The total sample included 51.9% male, 51.3% White, and 53.1% with private insurance; 10% had parent-reported ADHD diagnoses while 8.3% met ADHD study case-definition. In multivariable models, White children had higher odds of parent-reported diagnoses than Black, Hispanic, and Other Race/Ethnicity children (p < 0.05), but only Hispanic children had lower odds of being case-positive (<0.05); males and children in single-parent households had higher odds of parent reported diagnoses and being case-positive (p < 0.05); and children who were White, male, and had health insurance had higher odds of taking medication (p < 0.05). Among children who were case-positive, those with Medicaid, White, and 2 parent statuses had higher odds of parent-reported diagnoses (p < 0.05). CONCLUSION: Children with underlying ADHD appear more likely to have assessment/medication treatment access if they are White, male, have health insurance (particularly Medicaid), and live in 2-parent households. While boys and children raised by single parents may have higher rates of ADHD diagnoses, false-positive diagnostic risk also appeared higher, inviting further investigation. PMID- 30407939 TI - Assessment of Craniometric Sexual Dimorphism Using Multidetector Computed Tomographic Imaging in a Sample of Egyptian Population. AB - Sex determination is an initial and essential component of any medicolegal investigations. However, sometimes only cranial remains are available. The objective of this study was to determine sex using 12 craniofacial measurements in multidetector computed tomographic images of 150 Egyptian subjects (80 men and 70 women), with age ranging from 18 to 60 years. The results revealed a significant increase in the mean of all craniofacial measurements in men in comparison with women (P < 0.05). Bizygomatic breadth was the single most discriminant dimorphic parameter with an accuracy of 74%. Multiple discriminant functional analysis for sex prediction showed increased accuracy to 78.7% in all cases. Using multiple stepwise discriminants, functional analysis showed that the most predictive variables selected were maximal cranial breadth, minimal frontal breadth, bizygomatic breadth, orbital height, bimastoidale, and basion-prosthion length, which showed an accuracy of 80%. On the basis of this study, it is concluded that the cranial measurements obtained from multidetector computed tomographic images could be useful for forensic sex determination in Egyptians, especially in cases of skeletal remains. PMID- 30407940 TI - Copper-Beaten Skull Appearance as a Response of Chronically Increased Intracranial Pressure. AB - We present a case of 19-year-old female patient, who was injured in childhood and subsequently developed hydrocephalus, chronic elevation of intracranial pressure (ICP), and a copper-beaten skull appearance. Chronic hydrocephalus leads to an increase in intraventricular pressure, causing ventricular expansion and dislocation of adjacent cerebral structures. According to literature data, it has been hypothesized that chronically elevated ICP in persons with craniosynostosis, and other developmental structural abnormalities of the skull, may induce bone remodeling. In cases with copper-beaten skull appearance, increased ICP should be considered as a cause of death (after exclusion of all other obvious causes), and for that reason, careful examination of the skull appearance is suggested. This finding could be useful in cases with advanced postmortem changes, where it might indicate some medical conditions of the deceased or could even be considered unique feature for body identification, although this rationale should be used with great caution. PMID- 30407941 TI - ACSM Clinician Profile. PMID- 30407942 TI - Muscle Cramping in the Heat. PMID- 30407943 TI - Evaluation and Management of Grade III Acromioclavicular Joint Separations. PMID- 30407944 TI - A Marathon Runner With Vertigo After the Race. PMID- 30407945 TI - The Young Injured Gymnast: A Literature Review and Discussion. AB - Gymnastics is a sport requiring grace, strength, and flexibility, resulting in a wide variety of injuries. This article is an overview of the sport of gymnastics and associated injury trends in the artistic gymnastics population. Injury rates in gymnastics range from 1.08 to 50.3 per 1000 h of exposure. More injuries occur in competition versus practice. Fewer injuries occur in recreational gymnastics than competitive gymnastics. The most common injury in gymnastics occurs in the lower extremity, and is an ankle sprain, followed by knee internal derangement. However, in men's gymnastics the most common gymnastics injury occurs in the upper body (specifically the shoulder). The most common skills causing injury to a gymnast are front/back handsprings and saltos/flips. Unique injuries commonly seen when caring for the young gymnast include spondylolysis, ostoechondritis dissecans of the capetillium and talus, Gymnast wrist, Grip lock, Osgood Schlatter, patellofemoral syndrome, Sever's disease, and ankle sprains. Research efforts should focus on injury rates after the 2006 rule change, injury prevention, men's gymnastics injury patterns, concussions, hip injuries, and ACL injuries in gymnasts. PMID- 30407946 TI - Returning to Sport After Gymnastics Injuries. AB - Acute and overuse injuries are a common experience for artistic gymnasts; however, this population has unique needs when returning to their sport after an injury due to the technical demands imposed during gymnastics. We reviewed the current literature regarding return to play (RTP) in artistic gymnasts and developed four goals: 1) to define the guiding principles used to determine RTP in sports, 2) to identify factors that affect recovery progression among gymnasts, 3) to determine how different injury types affect RTP protocols, and 4) to create structured RTP protocols specific to gymnasts based on sex and body part injured. By establishing these guidelines, we hope to provide guidance to medical providers through a standardized approach for returning gymnasts to their sport. PMID- 30407947 TI - Competitive Endurance Activities of Middle-aged Athletes as a Risk Factor for Atrial Fibrillation. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia in athletes. Epidemiological studies have documented a greater prevalence of AF in athletes engaged in long-term endurance sports. Several mechanisms were proposed to underlie the association between exercise and AF, but the exact pathophysiology remains unclear. The studies up to now have been concentrated on the competitive middle-aged endurance athletes, but there is no evidence of AF prevalence among highly active noncompetitive athletes of the same age. Endurance athletes who do not compete might be at a lower risk for AF than their competitive peers. This hypothesis is theoretically examined, and the current evidence summarized in this article. PMID- 30407948 TI - Incidence, Diagnosis, and Management of Injury in Sport Climbing and Bouldering: A Critical Review. AB - Competition climbing will debut as an Olympic sport at the 2020 summer games in Tokyo. The aim of this article is to critically review research on the incidence of injury in sport climbing and bouldering. The pathophysiology and clinical presentation of finger and shoulder injuries is discussed. A semisystematic approach in reviewing literature on incidence was applied. Articles were identified after searches of the following electronic databases: Discover, Academic Search Complete (EBSCO), PubMed, Embase, SPORTDiscus, and ScienceDirect. Despite methodological shortcomings of the included studies, we estimated the mean +/- SD of the incidence rate of injury in sport climbing and bouldering from the eight studies to be 2.71 +/- 4.49/1000 h. Differential diagnosis and the clinical management of finger and shoulder injuries in climbers are challenging. An updated diagnostic and therapeutic algorithm for the clinical management of finger injuries in climbers is presented. PMID- 30407949 TI - A Comparison of the Mortality Risk Associated With Ventilator-Acquired Bacterial Pneumonia and Nonventilator ICU-Acquired Bacterial Pneumonia. AB - OBJECTIVES: To investigate the respective impact of ventilator-associated pneumonia and ICU-hospital-acquired pneumonia on the 30-day mortality of ICU patients. DESIGN: Longitudinal prospective studies. SETTING: French ICUs. PATIENTS: Patients at risk of ventilator-associated pneumonia and ICU-hospital acquired pneumonia. INTERVENTIONS: The first three episodes of ventilator associated pneumonia or ICU-hospital-acquired pneumonia were handled as time dependent covariates in Cox models. We adjusted using the case-mix, illness severity, Simplified Acute Physiology Score II score at admission, and procedures and therapeutics used during the first 48 hours before the risk period. Baseline characteristics of patients with regard to the adequacy of antibiotic treatment were analyzed, as well as the Sequential Organ Failure Assessment score variation in the 2 days before the occurrence of ventilator-associated pneumonia or ICU hospital-acquired pneumonia. Mortality was also analyzed for Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species(ESKAPE) and P. aeruginosa pathogens. MEASUREMENTS AND MAIN RESULTS: Of 14,212 patients who were admitted to the ICUs and who stayed for more than 48 hours, 7,735 were at risk of ventilator associated pneumonia and 9,747 were at risk of ICU-hospital-acquired pneumonia. Ventilator-associated pneumonia and ICU-hospital-acquired pneumonia occurred in 1,161 at-risk patients (15%) and 176 at-risk patients (2%), respectively. When adjusted on prognostic variables, ventilator-associated pneumonia (hazard ratio, 1.38 (1.24-1.52); p < 0.0001) and even more ICU-hospital-acquired pneumonia (hazard ratio, 1.82 [1.35-2.45]; p < 0.0001) were associated with increased 30 day mortality. The early antibiotic therapy adequacy was not associated with an improved prognosis, particularly for ICU-hospital-acquired pneumonia. The impact was similar for ventilator-associated pneumonia and ICU-hospital-acquired pneumonia mortality due to P. aeruginosa and the ESKAPE group. CONCLUSIONS: In a large cohort of patients, we found that both ICU-hospital-acquired pneumonia and ventilator-associated pneumonia were associated with an 82% and a 38% increase in the risk of 30-day mortality, respectively. This study emphasized the importance of preventing ICU-hospital-acquired pneumonia in nonventilated patients. PMID- 30407950 TI - Trends Over Time in Drug Administration During Adult In-Hospital Cardiac Arrest. AB - OBJECTIVES: Clinical providers have access to a number of pharmacologic agents during in-hospital cardiac arrest. Few studies have explored medication administration patterns during in-hospital cardiac arrest. Herein, we examine trends in use of pharmacologic interventions during in-hospital cardiac arrest both over time and with respect to the American Heart Association Advanced Cardiac Life Support guideline updates. DESIGN: Observational cohort study. SETTING: Hospitals contributing data to the American Heart Association Get With The Guidelines-Resuscitation database between 2001 and 2016. PATIENTS: Adult in hospital cardiac arrest patients. INTERVENTIONS: The percentage of patients receiving epinephrine, vasopressin, amiodarone, lidocaine, atropine, bicarbonate, calcium, magnesium, and dextrose each year were calculated in patients with shockable and nonshockable initial rhythms. Hierarchical multivariable logistic regression was used to determine the annual adjusted odds of medication administration. An interrupted time series analysis was performed to assess change in atropine use after the 2010 American Heart Association guideline update. MEASUREMENTS AND MAIN RESULTS: A total of 268,031 index in-hospital cardiac arrests were included. As compared to 2001, the adjusted odds ratio of receiving each medication in 2016 were epinephrine (adjusted odds ratio, 1.5; 95% CI, 1.3-1.8), vasopressin (adjusted odds ratio, 1.5; 95% CI, 1.1-2.1), amiodarone (adjusted odds ratio, 3.4; 95% CI, 2.9-4.0), lidocaine (adjusted odds ratio, 0.2; 95% CI, 0.2-0.2), atropine (adjusted odds ratio, 0.07; 95% CI, 0.06-0.08), bicarbonate (adjusted odds ratio, 2.0; 95% CI, 1.8-2.3), calcium (adjusted odds ratio, 2.0; 95% CI, 1.7-2.3), magnesium (adjusted odds ratio, 2.2; 95% CI, 1.9 2.7; p < 0.0001), and dextrose (adjusted odds ratio, 2.8; 95% CI, 2.3-3.4). Following the 2010 American Heart Association guideline update, there was a downward step change in the intercept and slope change in atropine use (p < 0.0001). CONCLUSIONS: Prescribing patterns during in-hospital cardiac arrest have changed significantly over time. Changes to American Heart Association Advanced Cardiac Life Support guidelines have had a rapid and substantial effect on the use of a number of commonly used in-hospital cardiac arrest medications. PMID- 30407952 TI - Reviewer Thank You. PMID- 30407951 TI - Long-Term Effects of Phased Implementation of Antimicrobial Stewardship in Academic ICUs: 2007-2015. AB - OBJECTIVES: Antimicrobial stewardship is advocated to reduce antimicrobial resistance in ICUs by reducing unnecessary antimicrobial consumption. Evidence has been limited to short, single-center studies. We evaluated whether antimicrobial stewardship in ICUs could reduce antimicrobial consumption and costs. DESIGN: We conducted a phased, multisite cohort study of a quality improvement initiative. SETTING: Antimicrobial stewardship was implemented in four academic ICUs in Toronto, Canada beginning in February 2009 and ending in July 2012. PATIENTS: All patients admitted to each ICU from January 1, 2007, to December 31, 2015, were included. INTERVENTIONS: Antimicrobial stewardship was delivered using in-person coaching by pharmacists and physicians three to five times weekly, and supplemented with unit-based performance reports. Total monthly antimicrobial consumption (measured by defined daily doses/100 patient-days) and costs (Canadian dollars/100 patient-days) before and after antimicrobial stewardship implementation were measured. MEASUREMENTS AND MAIN RESULTS: A total of 239,123 patient-days (57,195 patients) were analyzed, with 148,832 patient days following introduction of antimicrobial stewardship. Antibacterial use decreased from 120.90 to 110.50 defined daily dose/100 patient-days following introduction of antimicrobial stewardship (adjusted intervention effect -12.12 defined daily dose/100 patient-days; 95% CI, -16.75 to -7.49; p < 0.001) and total antifungal use decreased from 30.53 to 27.37 defined daily doses/100 patient-days (adjusted intervention effect -3.16 defined daily dose/100 patient days; 95% CI, -8.33 to 0.04; p = 0.05). Monthly antimicrobial costs decreased from $3195.56 to $1998.59 (adjusted intervention effect -$642.35; 95% CI, $905.85 to -$378.84; p < 0.001) and total antifungal costs were unchanged from $1771.86 to $2027.54 (adjusted intervention effect -$355.27; 95% CI, -$837.88 to $127.33; p = 0.15). Mortality remained unchanged, with no consistent effects on antimicrobial resistance and candidemia. CONCLUSIONS: Antimicrobial stewardship in ICUs with coaching plus audit and feedback is associated with sustained improvements in antimicrobial consumption and cost. ICUs with high antimicrobial consumption or expenditure should consider implementing antimicrobial stewardship programs. PMID- 30407953 TI - Tracheal Intubation Practice and Safety Across International PICUs: A Report From National Emergency Airway Registry for Children. AB - OBJECTIVES: It is unknown if variation in tracheal intubation practice and outcomes exist across PICUs in different geographical regions. We hypothesized there would be differences in the process of care and adverse outcomes for tracheal intubation across PICUs in six different geographical regions (New Zealand, Japan, Singapore, Germany, India, and North America). DESIGN: Prospective multicenter pediatric tracheal intubation database (National Emergency Airway Registry for Children) SETTING:: Six non-North American (International) and 36 North American PICUs. EVENTS: All PICU tracheal intubation encounters from July 2014 to June 2017 MEASUREMENTS AND MAIN RESULTS:: Adverse tracheal intubation-associated events and desaturation occurrence (oxygen saturation < 80%) were evaluated. A total of 1,134 and 9,376 TIs from International and North American PICUs were reported, respectively: primary tracheal intubation 9,060, endotracheal tube change 1,450. The proportion of tracheal intubations for endotracheal tube change was greater in International PICUs (37% vs 11%; p < 0.001). Median age for International tracheal intubations was younger compared with North America (0 yr [interquartile range, 0-2 yr] vs 1 yr (0-7 yr); p < 0.001). Among primary tracheal intubations, the most common indication was respiratory (International 67%, North American 63%; p = 0.049). Direct laryngoscopy was the most common device in both International (86%) and North American (74%) tracheal intubations. Occurrence of any adverse tracheal intubation-associated event was New Zealand 8%, Japan 17%, Singapore 9%, Germany 17%, and India 6%; International 11% versus North American 14%; p value equals to 0.003. Desaturation was reported less commonly in International PICUs: 13% versus North American 17%; p equals to 0.001. International PICUs used cuffed endotracheal tube less often (52% vs 95%; p < 0.001). Proportion of cuffed endotracheal tube use per PICU was inversely correlated with the rate of tube change (r = -0.67; p < 0.001). CONCLUSIONS: There were both similarities and differences in tracheal intubation practice and outcomes across international PICUs. Fewer adverse tracheal intubation-associated events were reported from International versus North American PICUs. International PICUs used cuffed endotracheal tube less often and had higher proportion of endotracheal tube change. PMID- 30407954 TI - Positive Airway Pressure Versus High-Flow Nasal Cannula for Prevention of Extubation Failure in Infants After Congenital Heart Surgery. AB - OBJECTIVES: Compare the impact of initial extubation to positive airway pressure versus high-flow nasal cannula on postoperative outcomes in neonates and infants after congenital heart surgery. DESIGN: Retrospective cohort study with propensity-matched analysis. SETTING: Cardiac ICU within a tertiary care children's hospital. PATIENTS: Patients less than 6 months old initially extubated to either high-flow nasal cannula or positive airway pressure after cardiac surgery with cardiopulmonary bypass were included (July 2012 to December 2015). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 258 encounters, propensity matching identified 49 pairings of patients extubated to high-flow nasal cannula versus positive airway pressure. Extubation failure was 12% for all screened encounters. After matching, there was no difference in extubation failure rate between groups (positive airway pressure 16% vs high-flow nasal cannula 10%; p = 0.549). However, compared with high-flow nasal cannula, patients initially extubated to positive airway pressure experienced greater resource utilization: longer time to low-flow nasal cannula (83 vs 28 hr; p = 0.006); longer time to room air (159 vs 110 hr; p = 0.013); and longer postsurgical hospital length of stay (22 vs 14 d; p = 0.015). CONCLUSIONS: In this pediatric cohort, primary extubation to positive airway pressure was not superior to high flow nasal cannula with respect to prevention of extubation failure after congenital heart surgery. Compared with high-flow nasal cannula, use of positive airway pressure was associated with increased hospital resource utilization. Prospective initiatives aimed at establishing best clinical practice for postoperative noninvasive respiratory support are needed. PMID- 30407955 TI - Interprofessional Healthcare Student Training in the Care of Sexual Assault Patients Utilizing Standardized Patient Methodology. AB - BACKGROUND: The medical assessment of sexual assault (SA) is challenging because SA patients are often hesitant to disclose their medical needs, which puts them at further physical and psychological risk, and because of provider unease in conducting SA examinations. This challenge is compounded by a lack of provider training. OBJECTIVES: The study goals were to develop an interprofessional simulation event that would foster SA interview skills, foster effective communication with SA patients, and increase learner confidence in assessing SA patients. METHODS: Participants were senior-year school of medicine (n = 165) and advanced practice registered nursing (n = 30) students (N = 195) who were enrolled in a mandatory Military Sexual Assault Assessment and Treatment course, along with data provided by trained standardized patients (SPs, n = 16) who participated in the simulation event and in assessments of learners. Measures included the Sexual Assault Interview Skills Checklist, the Essential Elements of Communication, and the Confidence in SA Assessment scale. Data were analyzed using analysis of variance and t tests at the P < 0.05 threshold. RESULTS: Postsimulation Sexual Assault Interview Skills Checklist and Essential Elements of Communication scores demonstrated an acceptable level of competence according to both students and SPs. Confidence in SA assessment rose significantly from presimulation to postsimulation. Before simulation, medical students were significantly lower than nursing students, but the simulation event closed the confidence in SA assessment gap. CONCLUSIONS: This interprofessional simulation event resulted in SA interview competence, communication skills competence, and improved confidence scores. Combined, these findings support the efficacy of simulation to train emerging healthcare providers to properly assess SA. PMID- 30407956 TI - Social Network Analysis of a Simulation Community. AB - INTRODUCTION: Graphical analysis of networking maps can be used to measure the health, connectivity, and vulnerabilities of a professional community. We aimed to capture and map the connections and relationships between individuals and organizations in the healthcare simulation community of the state of Western Australia. It was also intended that this analysis would encourage new opportunities for collaboration to advance simulation-based education. METHODS: In association with a baseline list of established simulation practitioners, an online survey instrument and propriety mapping software were used to establish links and interactions between individuals, colleagues, their own, and external organizations. RESULTS: There were 79 respondents to the survey, with 500 pairs of relationships generated for 203 nominated personnel. Two thirds of respondents were from medical, nursing, and allied health fields. The average number of collaborators for each respondent was 6.6. Collaborative patterns were presented in matrices and social network maps. These data identified leaders, important networks, and weaknesses in this community of practice. CONCLUSIONS: The study confirmed that there were a handful of simulation educators with many linkages both within and external to their own organizations. In addition, isolated groups with poor cross-organizational associations were identified. This information can be used by healthcare and educational organizations, and funding agencies, to better understand associations and collaborations across the wider simulation community and to consider appropriate improvements to strengthen the simulation network. PMID- 30407957 TI - Multiple Patient Casualty Scenarios: A Measurement Tool for Teamwork. AB - INTRODUCTION: Teamwork is a critical aspect of patient care and is especially salient in response to multiple patient casualties. Effective training and measurement improve team performance. However, the literature currently lacks a scientifically developed measure of team performance within multiple causality scenarios, making training and feedback efforts difficult. The present effort addresses this gap by integrating the input of subject matter experts and the science of multicasualty teams and training to (1) identify overarching teamwork processes and corresponding behaviors necessary for team performance and (2) develop a behavioral observation tool to optimize teamwork in multicasualty training efforts. METHOD: A search of articles including team performance frameworks associated with team training was conducted, leading to the identification of a total of 14 articles. Trained coders extracted teamwork processes and the corresponding team behaviors indicative of effective performance from these articles. Five subject matter experts were interviewed using the critical incident technique to identify additional behaviors. RESULTS: Team situation awareness, team leadership, coordination, and information exchange emerged as the four core team processes required for team performance in scenarios with multiple patient casualties. Relevant behaviors and subbehaviors within these overarching processes were identified to inform a pilot behavioral framework of team performance. CONCLUSIONS: The processes and associated behaviors identified within this effort serve as scientifically grounded behaviors of team performance in the case of multiple patient casualties simulated training scenarios. Future work can use and further refine these results to ensure that measures of team performance are grounded in specific, observable, and scientifically delineated behaviors. PMID- 30407958 TI - Comparative Analysis of Emergency Medical Service Provider Workload During Simulated Out-of-Hospital Cardiac Arrest Resuscitation Using Standard Versus Experimental Protocols and Equipment. AB - INTRODUCTION: Protocolized automation of critical, labor-intensive tasks for out of-hospital cardiac arrest (OHCA) resuscitation may decrease Emergency Medical Services (EMS) provider workload. A simulation-based assessment method incorporating objective and self-reported metrics was developed and used to quantify workloads associated with standard and experimental approaches to OHCA resuscitation. METHODS: Emergency Medical Services-Basic (EMT-B) and advanced life support (ALS) providers were randomized into two-provider mixed-level teams and fitted with heart rate (HR) monitors for continuous HR and energy expenditure (EE) monitoring. Subjects' resting salivary alpha-amylase (sAA) levels were measured along with Borg perceived exertion scores and multidimensional workload assessments (NASA-TLX). Each team engaged in the following three OHCA simulations: (1) baseline simulation in standard BLS/ALS roles; (2) repeat simulation in standard roles; and then (3) repeat simulation in reversed roles, ie, EMT-B provider performing ALS tasks. Control teams operated with standard state protocols and equipment; experimental teams used resuscitation-automating devices and accompanying goal-directed algorithmic protocol for simulations 2 and 3. Investigators video-recorded resuscitations and analyzed subjects' percent attained of maximal age-predicted HR (%mHR), EE, sAA, Borg, and NASA-TLX measurements. RESULTS: Ten control and ten experimental teams completed the study (20 EMT-Basic; 1 EMT-Intermediate, 8 EMT-Cardiac, 11 EMT-Paramedic). Median %mHR, EE, sAA, Borg, and NASA-TLX scores did not differ between groups at rest. Overall multivariate analyses of variance did not detect significant differences; univariate analyses of variance for changes in %mHR, Borg, and NASA-TLX from resting state detected significant differences across simulations (workload reductions in experimental groups for simulations 2 and 3). CONCLUSIONS: A simulation-based OHCA resuscitation performance and workload assessment method compared protocolized automation-assisted resuscitation with standard response. During exploratory application of the assessment method, subjects using the experimental approach appeared to experience reduced levels of physical exertion and perceived workload than control subjects. PMID- 30407959 TI - Using an Immersive Virtual Reality System to Assess Lay Provider Response to an Unannounced Simulated Sudden Cardiac Arrest in the Out-of-Hospital Setting. AB - BACKGROUND: A sudden cardiac arrest (SCA) occurs when the heart abruptly stops beating; because of the nature of SCA, capturing data in the out-of-hospital setting from actual bystander response is difficult. Current technologies such as virtual reality (VR) allow the creation of scenarios programmed for heightened realism. No studies have used an immersive VR system to observe lay bystander response. OBJECTIVE: We sought to characterize lay bystander response to an unannounced simulated VR SCA event during a multisensory scenario. METHODS: Using a VR wearable device combined with a cardiopulmonary resuscitation (CPR) recording manikin, we created a 3-minute multisensory SCA scenario that allowed for the observation of lay bystander response. Subjects were unaware of the nature of the emergency event but were told to respond how they would to an emergency situation. Subject's ability to proceed through the American Heart Association's Chain of Survival and their CPR quality were recorded. Frequencies and percentages were calculated using descriptive statistics. RESULTS: Between June 2016 and June 2017, 119 lay subjects were enrolled. Of those, 92% asked for 911 to be called, 81% attempted CPR, 13% requested an automated external defibrillator (AED), and 6% used the AED; 82% stated that they felt as if they were at a real SCA event. Cardiopulmonary resuscitation data were collected (n = 81), the mean CC rate was 93.5 +/- 22.4 cpm, and the mean CC depth was 38.4 +/- 13.8 mm. CONCLUSIONS: In our unannounced, immersive VR SCA observational study of lay bystanders, most subjects attempted CPR, although the majority did not use an AED. PMID- 30407960 TI - The Use of Statistical Process Control Charts to Evaluate Interprofessional Education Sessions Embedded Into a Pediatric Emergency In situ Resuscitation Program. AB - The rigorous evaluation of simulation in healthcare to improve resuscitations and team functioning can be challenging. Statistical process control (SPC) charts present a unique methodology to enable statistical rigor when evaluating simulation. This article presents a brief overview of SPC charts and its advantages over traditional before and after methodologies, followed by an exemplar using SPC to evaluate an in situ team training program with embedded interprofessional education sessions. PMID- 30407961 TI - Simulation-Based Education to Train Learners to "Speak Up" in the Clinical Environment: Results of a Randomized Trial. AB - INTRODUCTION: Assertiveness is essential for communication and/or speaking up. We performed a randomized trial to assess the effectiveness of assertiveness/advocacy/CUS/two-challenge rule (AACT) simulation-based education for labor and delivery, as well as postpartum nurses. We aimed to determine whether this training would improve labor and delivery and postpartum nurses speaking up in the clinical setting. METHODS: We conducted a randomized controlled trial among nurses on labor and delivery and postpartum units. During the intervention, participants were trained on abnormal vital signs, underwent a baseline assertiveness self-assessment, and were block-randomized (by work location: labor and delivery or postpartum) to either simulation-based AACT (intervention) or I-PASS [Illness Severity, Patient Summary, Action List, Situational Awareness and Contingency Planning, Synthesis by Receiver hand-off tool education] (control) simulation-based education. The outcome part of the study consisted of an in situ simulated clinical encounter during which each individual learner's assertive behaviors were assessed as they found out about a patient's abnormal vital signs. Two raters, different from those that participated in the intervention part of the experiment, and who were blinded to whether the learner was in the control or intervention arm, scored participants. The learner (Registered Nurse) was not aware that this was an in situ simulation and perceived this as a real clinical encounter. The degree to which the learners spoke up was measured using a validated scale (Pian-Smith). RESULTS: Seventy nurses completed the study. There were 34 learners in the intervention and 36 in the control groups. Among those in the intervention group, there were 18 labor and delivery (LDI) nurses and 16 postpartum (PPI) nurses. Among the control group, there were 14 labor and delivery (LDC) nurses and 22 postpartum (PPC) nurses. Using a five-point Pian-Smith scale, we demonstrated that there was no difference in the likelihood of speaking up between the overall intervention and control groups (2.00 +/- 1.00 and 1.65 +/- 0.82, P = 0.10). Among controls, the likelihood of speaking up was higher for labor and delivery nurses than for postpartum nurses (P < 0.006). There was a significant interaction (P = 0.02) between treatment group and work location. Although the control and intervention groups from labor and delivery showed similar higher levels of speaking up (2.29 +/- 0.89 and 2.06 +/- 0.95, respectively, P = 0.49), postpartum nurses in the intervention arm were more likely to speak up than were postpartum nurses in the control arm (1.97 +/- 1.07 vs. 1.25 +/- 0.43, P = 0.007). CONCLUSIONS: Although there was no difference in speaking up scores between intervention and control groups overall, simulation-based AACT training among postpartum nurses was associated with a statistically significant increase in the likelihood of speaking up during a challenging simulated clinical encounter. The degree of change makes the clinical significance uncertain. There was no statistically significant difference in the likelihood of speaking up among labor and delivery nurses. PMID- 30407962 TI - Risk Management in the Ambulatory Care Process in a Mutual Benefit Association Covering Work-Related Accidents and Diseases: Applying Modified Failure Mode and Effect Analysis (FMEA) Methodology. AB - AIM: To assess the impact of different forms of use of failure mode and effect analysis methodology for risk prioritization in the ambulatory care process in a mutual benefit association covering work-related accidents and diseases. METHODS: The study is based on a previously drafted and individually prioritized risk map by a multidisciplinary team made up of patient safety committee members from health care centers and clinics in a mutual benefit association covering work related accidents and diseases. The professionals mainly carry out their work in the field of management (individual manager group (IMG)). A group formed by clinicians subsequently completed 2 prioritizations: one based on the individual opinions of each of the members (individual clinical group (ICG)) and another in a consensual way (consensual clinical group (CCG)) as recommended by failure mode and effect analysis methodology. The risk prioritization was compared in the 3 groups (IMG, ICG, and CCG). RESULTS: The risk prioritization by the IMG defines 7 extreme risks (risk prioritization >= 275). When the clinical group prioritizes them in an individual way (ICG), there is no extreme risk, whereas when it does so in a consensual way (CCG), there are 21 extreme risks. With respect to the coincidences of existing causes between the 3 groups, it is noted that the "risk of falls" is rated by both the clinical and the manager group but prioritized differently. On the other hand, the ICG and CCG coincide in that pressure on health care services can contribute to carrying out incomplete anamnesis. They also both consider that internal and external waiting lists and holiday periods can cause a delay in the starting of rehabilitation. The IMG and the CCG show similarity in the risk assessment of overprescribing medication and that multiple computer sessions are initiated. Finally, the IMG and the ICG coincide in the "lack of delivery of the medication leaflet". CONCLUSIONS: The point of view of the clinicians is important in the risk prioritization of the ambulatory health care process. The difference in the risk prioritization between the clinical group at individual level and after consensus is remarkable. PMID- 30407963 TI - The Correlation Between Neonatal Intensive Care Unit Safety Culture and Quality of Care. AB - OBJECTIVES: Key validated clinical metrics are being used individually and in aggregate (Baby-MONITOR) to monitor the performance of neonatal intensive care units (NICUs). The degree to which perceptions of key components of safety culture, safety climate, and teamwork are related to aspects of NICU quality of care is poorly understood. The objective of this study was to test whether NICU performance on key clinical metrics correlates with caregiver perceptions of safety culture. STUDY DESIGN: Cross-sectional study of 6253 very low-birth-weight infants in 44 NICUs. We measured clinical quality via the Baby-MONITOR and its nine risk-adjusted and standardized subcomponents (antenatal corticosteroids, hypothermia, pneumothorax, healthcare-associated infection, chronic lung disease, retinopathy screen, discharge on any human milk, growth velocity, and mortality). A voluntary sample of 2073 of 3294 eligible professional caregivers provided ratings of safety and teamwork climate using the Safety Attitudes Questionnaire. We examined NICU-level variation across clinical and safety culture ratings and conducted correlation analysis of these dimensions. RESULTS: We found significant variation in clinical and safety culture metrics across NICUs. Neonatal intensive care unit teamwork and safety climate ratings were correlated with absence of healthcare-associated infection (r = 0.39 [P = 0.01] and r = 0.29 [P = 0.05], respectively). None of the other clinical metrics, individual or composite, were significantly correlated with teamwork or safety climate. CONCLUSIONS: Neonatal intensive care unit teamwork and safety climate were correlated with healthcare associated infections but not with other quality metrics. Linkages to clinical measures of quality require additional research.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. PMID- 30407964 TI - Vote. PMID- 30407965 TI - The Impact of Head-of-Bed Positioning and Transducer Location on Cerebral Perfusion Pressure Measurement. AB - INTRODUCTION: Head-of-bed (HOB) elevation is the standard of care for patients with intracranial pressure monitoring at risk for intracranial hypertension. Measurement of cerebral perfusion pressure (CPP) based on HOB elevation and arterial transducer position has not been adequately studied. METHODS: This is a planned secondary analysis of prospectively collected data in which paired, serial arterial blood pressure (ABP), intracranial pressure, and CPP measures were obtained once per day for 3 days, with measures leveled at the tragus (Tg) and the phlebostatic axis (PA). The HOB position was recorded for all paired readings. RESULTS: From 136 subjects, ABP and CPP values were lower when the transducer was leveled at the Tg, compared with the PA (P < .001); these differences persisted regardless of HOB position. CONCLUSION: The difference in CPP when ABP is referenced at the Tg versus PA is not consistently attributed to HOB elevation. PMID- 30407966 TI - A Pilot Primary Stroke Prevention Program for Elderly Korean Americans. AB - BACKGROUND: Stroke is a significant health issue with devastating consequences among older adults in the United States. However, it can be prevented by improving stroke knowledge and managing risk factors. Many stroke education programs have been shown to be effective. Unfortunately, a minority of older adults, such as older Korean Americans, have not benefited from the programs because of language barriers. OBJECTIVE: The purpose of this study was to examine the feasibility and preliminary impact of a primary stroke prevention program on stroke knowledge, healthy eating, and physical activity behaviors among Korean Americans. METHODS: A randomized controlled pilot trial was conducted. A total of 73 persons were randomly assigned to either an intervention group (n = 37) or a control group (n = 36). The intervention program included in-person lectures and discussions. Sociodemographic data were analyzed using descriptive statistics. Analyses of covariance and logistic regression analysis were used to evaluate the effects of the intervention program. RESULTS: The mean age of participants was 71.49 +/- 6.25 years, and most participants were female (74.0%) and married (65.8%). Upon intervention completion, the intervention group showed greater improvements than the control group in stroke knowledge and intake of sodium and total fats (F = 11.89, P = .001, etap = 0.151; F = 4.04, P = .048, etap = 0.057; and F = 4.51, P = .037,= etap = 0.062, respectively). Step counts showed marginal effects (F = 3.27, P = .075, etap = 0.049). CONCLUSION: This study demonstrated feasibility and effectiveness of the program to improve stroke knowledge and healthy behaviors in elderly Korean Americans. PMID- 30407968 TI - Pupillometry Trends in the Setting of Increased Intracranial Pressure. PMID- 30407967 TI - Pupillometry Trends in the Setting of Increased Intracranial Pressure. AB - Serial pupil examinations remain a mainstay of neurological assessments performed by neuroscience nurses. Integration of pupillometer technology has increased in recent years, because of its ability to address limitations of manual examinations and to evaluate trended data over time. Preliminary research has linked pupillometer values to intracranial pressure (ICP) values, but data on pupillary changes in the setting of increased ICP remain sparse. The purpose of this study was to determine trends in pupillometer values in the setting of increased ICP among critically ill patients with neurological injury. This is a secondary analysis of data where serial pupillometer and ICP readings were recorded hourly on adult patients with neurological injury necessitating critical care management. More than 2100 paired serial pupillometer and ICP readings were obtained from 76 subjects, with a total of 2107 paired readings for the left eye and 2175 for the right eye. There were statistically significant differences in pupillometry values in the setting of increased ICP. Time series analysis indicates that spikes in ICP values resulted in corresponding variations in pupillometer values. Use of automated pupillometry remains a value adjunct to traditional invasive therapies. Evaluation of trended data may provide insight into ICP elevations in the absence of invasive monitoring and warrants additional research. PMID- 30407969 TI - Effect of Auditory Stimulation on the Level of Consciousness in Comatose Patients Admitted to the Intensive Care Unit: A Randomized Controlled Trial. AB - BACKGROUND: Comatose patients are exposed to sensory deprivation in the intensive care units. Auditory stimulation of patients who are unconscious is a nonmedical procedure. This study examines the effect of organized voice, performed by a nurse, on the state of consciousness of comatose patients in intensive care units. METHOD: This randomized controlled trial study of 60 patients was conducted fitting between August 2017 and February 2018. For 10 days, patients received the voice of a male nurse twice a day in the morning and night shifts, recorded on MP3 and repeated at least 3 to 4 times. Glasgow Coma Scale (GCS) scores were recorded by the researcher before and after auditory stimulation. RESULTS: Patient mean age was 69.2 years; 56.7% of the experimental group and 53.3% of the control group were male. On the first day in the morning and evening after auditory stimulation, the mean GCS was 4.8 in the experimental group and 4.7 in the control group. Before and after the intervention on the 10th day after auditory stimulation, the mean GCS of patients was 9.5 in the experimental group and 7.1 in the control group in the morning and 9.6 and 7.2, respectively, in the evening. No significant differences in mean GCS by group were observed for the first 3 days (P > .05). However, the difference in mean GCS scores of the 2 groups was statistically significant after the third day (P < .05). CONCLUSIONS: Auditory stimulation is associated with higher GCS in comatose patients. PMID- 30407970 TI - Symptom Monitoring in Glioma Patients: Development of the Edmonton Symptom Assessment System Glioma Module. AB - BACKGROUND AND PURPOSE: Symptoms in glioma patients are distinctly different from symptoms in patients with other types of cancer and have a high impact on quality of life. In this study, a stepwise approach of developing a glioma module for assessment of symptoms, based on a Dutch adapted and validated version of the Edmonton Symptom Assessment System, is described. METHODS: Three phases of instrument development were conducted: a systematic literature review and a focus group interview with experts were performed (phase I) to generate relevant symptoms and construct a preliminary module (phase II). In phase III, the preliminary module was evaluated (n = 25) and pretested (n = 45) in glioma patients representing all phases of the disease. RESULTS: Our glioma module contains 11 generic and 6 neurologic symptoms. Patients completed the glioma module in a median of 5 minutes, and 56% of the patients required some assistance to complete the instrument. CONCLUSION: The glioma module has initial validity and will benefit from prospective validation in a larger cohort of patients with glioma. PMID- 30407971 TI - Unique Stroke Symptoms in Women: A Review. PMID- 30407972 TI - Facial recognition software in clinical dysmorphology. AB - PURPOSE OF REVIEW: The current review aims to discuss the incorporation of facial recognition software into the clinical practice of dysmorphology and medical genetics. RECENT FINDINGS: Facial recognition software has improved the process of generating a differential diagnosis for rare genetic syndromes, and recent publications demonstrate utility in both research and clinical applications. Software programs are freely available to verified medical providers and can be incorporated into routine clinic encounters. SUMMARY: As facial recognition software capabilities improve, two-dimensional image capture with artificial intelligence interpretation may become a useful tool within many areas of medicine. Geneticists and researchers can use such software to enhance their differential diagnoses, to study similarities and differences between patient cohorts, and to improve the interpretation of genomic data. Pediatricians and subspecialists may use tools to identify patients who may benefit from a genetic evaluation, and educators can use these tools to interest students in the study of dysmorphoplogy and genetic syndromes. PMID- 30407973 TI - Nerve blocks in paediatric and adolescent headache disorders. AB - PURPOSE OF REVIEW: Headaches in children and adolescents are common, causing debilitating symptoms in many. Treatment of headache disorders can be complex and standard lifestyle changes as well as oral medications may offer inadequate relief. The purpose of this article is to review the mechanism of action, efficacy and technique of peripheral nerve blocks (PNBs) and the role they play in treating paediatric headache disorders. RECENT FINDINGS: Evidence for the use of PNBs in youth is limited. However, available studies show evidence of benefit in both primary and secondary headache disorders. Variability exists in the type of block, medication choice, volume infused and frequency of this treatment. There are no serious side effects associated with PNBs. SUMMARY: PNBs are well tolerated and effective as adjunctive therapy for many disabling paediatric headache disorders. The technique can be easily learned by frontline and specialty practitioners. Prospective placebo-controlled studies are needed to determine how to best maximize PNBs for headache management (i.e. medication choice, timing and so on). PMID- 30407974 TI - Headache, Chiari I malformation and foramen magnum decompression. AB - PURPOSE OF REVIEW: With increasing use of MRI, more patients are being diagnosed with Chiari I malformation (CM1), many of whom are asymptomatic. When symptoms are present, headache is the most frequent presenting feature, although symptoms can be variable. The purpose of this review is to help primary care clinicians better understand the relationship between an individual's presenting symptoms and the presence of radiographic CM1, and to describe the expected outcomes for patients who undergo decompression surgery. RECENT FINDINGS: Recent literature has shown that asymptomatic patients with CM1 tend to have a benign natural history. For symptomatic Chiari malformation, headache is the most common presenting symptom and the majority of patients that present with headache will have symptom improvement after foramen magnum decompression. This improvement is most reliable for patients with classic Chiari-type headache, which are described as occipital or cervical and tussive in nature, but has also been shown in patients with atypical headaches who have undergone surgery. SUMMARY: CM1 is a common radiographic finding and associated symptoms can be variable. The relevance of this finding to a particular patient and need for intervention must be made on an individual basis. PMID- 30407975 TI - Dysregulatory syndromes: the role of signal transducers and activators of transcription. AB - PURPOSE OF REVIEW: A comparative description of dysregulatory syndromes with mutations in signal transducer and activator of transcription (STAT) genes. RECENT FINDINGS: STAT 1, 3 and 5b loss of function (LOF) and gain of function (GOF) mutations are a heterogeneous group of genetic disorders that range from immunodeficiency (ID) to autoimmune disease (AID), depending on the underlying signalling pathway defect. Between them, there are clear overlapping and differences in clinical presentation and laboratory findings. SUMMARY: Dysregulatory syndromes due to LOF and GOF mutations in STAT1, 3 and 5b are a particular group of primary immunodeficiencies (PIDs) in which AID may be the predominant finding in addition to infections susceptibility. STAT1 GOF mutations were described as the major cause of chronic mucocutaneous candidiasis, while activating STAT3 mutations result in early-onset multiorgan autoimmunity and ID. Human STAT5b deficiency is a rare disease that also involves ID and severe growth failure. In recent years, the identification of the genes involved in these disorders allowed to differentiate these overlapping syndromes in order to choose the most effective therapeutic options. PMID- 30407976 TI - The overlap between allergy and immunodeficiency. AB - PURPOSE OF REVIEW: The mechanisms underlying the overlap of, and relationship between, atopy and immunodeficiency are just beginning to be recognized, through the identification of novel genetic conditions and the reexamination of well known primary immunodeficiencies. The present review seeks both to frame the topic and to highlight the most recent literature combining allergy in the context of immunodeficiency. RECENT FINDINGS: The true prevalence of atopic disorders in the setting of primary immunodeficiency as a whole is difficult to pinpoint, however there have been recent attempts to measure prevalence. Individual immunodeficiency disorders have been more carefully dissected for atopic disease and the mechanisms underlying the atopic phenotypic, whereas several newly described immune deficiencies because of single gene mutations are highly associated with atopic phenotypes. Finally, a number of novel genetic conditions with atopy being the primary feature, even in the absence of overt immune deficiency, have been described, providing instrumental clues into the diagnostic dilemmas these syndromes create. SUMMARY: Defining and examining diseases with primary features of atopy and infection allow for a better understanding of the interplay between the two in rare disease, and hopefully sheds light on fundamental pathways involved in atopy and host defense in the general population. PMID- 30407977 TI - Economic and Outcomes Analysis of Recalcitrant Cervical Radiculopathy: Is Nonsurgical Management or Surgery More Cost-Effective? AB - INTRODUCTION: This study directly compares the economical and clinical effectiveness of the use of cervical epidural injections and continued physical therapy versus surgical management in cases of cervical radiculopathy that have failed 6 weeks of conservative management. METHODS: A theoretical cohort of patients with cervical radiculopathy resistant to 6 weeks of noninvasive conservative management were simulated to treatment with either anterior cervical diskectomy and fusion (ACDF) or cervical epidural injections and continued physical therapy and analyzed with Markov chain decision tree Monte Carlo simulation. RESULTS: The average incremental cost-effectiveness ratio associated with ACDF was $6,768 per quality-adjusted life year over the lifetime of the patient, whereas the incremental cost-effectiveness ratio associated with cervical injections ranged from $9,033 to $4,044 per quality-adjusted life year based on the success rate. DISCUSSION: Our study suggests that for the management of recalcitrant cervical radiculopathy, ACDF remains the dominant strategy compared with cervical epidural injections if the surgical avoidance rate of such injections is less than 50%. If there is a greater than 50% surgery avoidance rate with injections, then cervical epidural injections would be considered a cost-effective strategy with a role in the management of cervical radiculopathy before surgery. PMID- 30407978 TI - Thromboelastography for the Orthopaedic Surgeon. AB - Evaluation of coagulation is vital in the care of the orthopaedic patients, particularly in the subspecialties of trauma, spine, arthroplasty, and revision surgery resulting from blood loss and coagulopathies. Although conventional tests (prothrombin time/international normalized ratio, activated partial thromboplastin time, platelet count, and fibrinogen) are most commonly used, others like thromboelastography (TEG) are also available to the orthopaedic surgeons. TEG is a blood test developed in the 1950s, which provides a snapshot of a patient's coagulation profile by evaluating clot formation and lysis. Recently, TEG has been used to assess traumatic coagulopathy. The coagulation parameters measured by the TEG are reaction time (R-time), time to reach a certain clot strength (K-value), speed of fibrin build up (alpha-angle), maximum clot amplitude, and percentage decrease of clot in 30 minutes (LY30). Using these values, traumatologists have developed a better, faster, and more accurate overview of a patient's resuscitation and more successfully direct blood product use. However, many orthopaedic surgeons-despite performing surgical procedures that risk notable blood loss and postoperative clotting complications-are unaware of the existence of the TEG blood test and the critical information it provides. Increasing awareness of the TEG among orthopaedic surgeons could have a notable effect on numerous aspects of musculoskeletal care. PMID- 30407979 TI - Medial Unicompartmental Arthroplasty of the Knee. AB - Indications for medial unicompartmental knee arthroplasty (UKA) have expanded over the past two decades. Proposed advantages include faster recovery, improved kinematics, and better functional outcomes compared with total knee arthroplasty (TKA) in age-matched control subjects. A focused preoperative examination and imaging is essential to identify appropriate surgical candidates. No difference has been demonstrated between fixed- and mobile-bearing implants for implant survivorship or patient-reported outcomes. The most common reasons for conversion to a TKA are aseptic loosening and progression of osteoarthritis. Ten-year survival for UKA in cohort studies has shown to be >90% with outcomes after conversion to TKA being similar to outcomes for revision TKA. Registries have consistently shown lower implant survival for UKA compared with that for TKA, which is likely secondary to use of several different implants by surgeons of varying levels of experience. UKA has the potential to be a cost-effective alternative to TKA in certain patient populations when performed at high-volume centers with advanced surgical techniques. PMID- 30407980 TI - Course of the Femoral Artery in the Mid- and Distal Thigh and Implications for Medial Approaches to the Distal Femur: A CT Angiography Study. AB - INTRODUCTION: Unfamiliarity with the location of the femoral artery in the medial thigh has tempered surgeons' enthusiasm for medial approaches to the distal femur. The purpose of this study was to define the relationship of the femoral artery to the mid- and distal femur to assist in safely approaching the femur for fracture care. METHODS: Fifteen patients undergoing CT with angiography (CTA) of the lower extremity (CTA) were evaluated. From three-dimensional CTA images, the distance of the artery at the anterior border, midsagittal line, and posterior border of the femur from the distal femur at both the adductor tubercle and medial femoral condyle was measured. RESULTS: The average distances of the adductor tubercle to the femoral artery were 23.2 cm (+/-3.3), 18.8 cm (+/-3.4), and 14.3 cm (+/-4.1) at the level of the anterior border, midsagittal line, and posterior border of the femur, respectively. The descending genicular artery (DGA) originated 10.8 cm (+/-1.3) proximal to the adductor tubercle. DISCUSSION: A wide safe zone exists in the medial distal femur. The artery crosses the midsagittal axis of the medial femur an average of 18.8 cm proximal to the adductor tubercle. PMID- 30407981 TI - Scheuermann's Kyphosis: Diagnosis, Management, and Selecting Fusion Levels. AB - Scheuermann's kyphosis (SK) is a rigid structural deformity of the thoracic spine defined radiographically as three or more contiguous vertebrae with at least 5 degrees of wedging anteriorly. Prevalence of the disease is thought to be between 0.4% and 10%. The true cause of SK remains unclear; however, various theories include growth irregularities, mechanical factors, genetic factors, and/or poor bone quality as the causes. Patients with mild disease (less than 70 degrees ) generally have a favorable prognosis with good clinical outcomes. Most patients with SK are successfully treated nonsurgically with observation, anti inflammatory medications, and physical therapy. Surgical intervention is indicated in patients with greater than 70 degrees to 75 degrees thoracic curves, greater than 25 degrees to 30 degrees thoracolumbar curves, intractable pain, neurologic deficit, cardiopulmonary compromise, or poor cosmesis. Because of advances in posterior spinal instrumentation, surgery can typically be performed through a posterior-only approach. When surgical treatment is planned, appropriate selection of the upper- and lower-instrumented vertebrae is important to achieve a well-balanced spine, preserve motion segments, and reduce the risk of junctional kyphosis. PMID- 30407982 TI - Clinical Instructors' Experience of Managing Students' Errors: A Qualitative Study. AB - Given the importance of patient safety, this study aimed to explore clinical instructors' experience of managing students' errors. A qualitative approach was adopted to conduct semistructured interviews with 12 clinical nursing and midwifery instructors. Three main categories emerged: prevention (orienting, review of the knowledge, repeating procedure by instructor, checking steps prior to performing procedure, and reminding), action (correcting, monitoring and follow-up, and informing), and feedback (cause analysis, notifying, and affecting assessment). Patient safety and error management programs should be included in the nursing curriculum and nursing education. PMID- 30407983 TI - Reliability and Validity of NCLEX-RN(c) State Pass Rate Standards. AB - AIM: The aim of the study was to determine whether state NCLEX-RN pass rate standards for nursing education programs are valid and reliable. BACKGROUND: Nursing education programs must meet minimum NCLEX-RN pass rate standards imposed on them by state regulatory bodies. The standards suggest validity and reliability issues. METHOD: To compute descriptive statistics and reliability coefficients to evaluate state pass rate standards, the study used a database of statutes and regulations that establish pass rate standards and a database of NCLEX-RN pass rates for 2,157 nursing programs in 45 states for 2010 to 2016. RESULTS: There is substantial variation in state pass rate standards. Nursing education program pass rates are not stable over time, suggesting there may be problems with reliability and validity. CONCLUSION: State nursing boards should consider revising pass rate standards to make them more consistent and improve the reliability of pass rate violation determinations. PMID- 30407984 TI - An Appreciative Inquiry Into Nurse Educators' Exam Practices. AB - Multiple-choice examinations (MCEs) are commonly used to evaluate nursing students. Nurse educators require support to develop questions and engage in postexam analysis to ensure reliable assessment of student learning. We surveyed nurse educators and conducted focus groups to investigate current writing practices associated with MCEs. Using appreciative inquiry, participants proposed ideals to strengthen MCE practice: guidelines and expectations for faculty, faculty-developed test banks, team development, and an assessment blueprint at the curriculum level. Faculty supports are necessary to strengthen current MCE practices and best utilize the skills of educators. PMID- 30407985 TI - Successfully Incorporating Interprofessional Education in a Nonacademic Health Sciences Center. AB - Enhanced patient outcomes have led the health sciences to seek ways in which to incorporate interprofessional education in their curricula. This article presents a unique and innovative strategy for interprofessional education among nursing, medicine, and pharmacy in a nonacademic health science center setting. Nurse practitioner students from the University of Alabama in Huntsville College of Nursing, medical interns from the University of Alabama at Birmingham School of Medicine, and pharmacy students from Auburn University School of Pharmacy and their respective faculty participated in collaboratively designed simulations and skills experiences. PMID- 30407987 TI - Applying Simulation Design Criteria to Non-Manikin-Based Experiences: A Modified ShadowBox Technique. AB - Creating simulation-based learning experiences is a process. With tools such as the 2016 INACSL Standards of Best Practice: Simulation Simulation Design and theories to guide development, nurse faculty have the opportunity to create rich simulation-based learning experiences that promote student learning. The purpose of this article is to describe an innovative simulation-based experience that applies simulation design criteria in a non-manikin experience. Using a ShadowBox approach, novice nursing students were exposed to expert decision-making in a simulated environment. We describe this approach and how the simulation design criteria are applied. PMID- 30407986 TI - Developing System-Level Awareness Through Virtual Clinical Learning. AB - Lack of clinical sites and disparate experiences contribute to the challenge for RN-to-BS nursing programs to provide sufficient leadership and quality improvement opportunities. A virtual clinical learning experience using WordPress was developed as a faculty-graduate student think tank project and implemented in an RN-BS hybrid nursing leadership course. The unfolding case study created an interactive experience to portray use of systems thinking and transformational leadership. Mann-Whitney U analysis identified no significant difference in learning outcomes. The low-cost, easy-to-develop technology counteracted limited clinical sites, allowing for learning on the go with equivalent learning outcomes. PMID- 30407988 TI - Using a Low-Fidelity Simulation to Enhance Cultural Awareness and Emotional Intelligence in Nursing Students. AB - Undergraduate didactic nursing leadership courses lack experiential opportunities to address working with culturally diverse populations. The authors used Bafa Bafa(c), a cross-cultural low-fidelity simulation, to further develop critical thinking and emotional intelligence skills in prelicensure nursing students. This article describes the authors' experiences of integrating this innovative teaching strategy in the classroom to increase cultural awareness. The students' discovery of unexpected feelings, thoughts, and perceptions has the potential to extend beyond the simulated experience when coupled with faculty reinforcement of engaging in self-reflective practice as a professional nurse. PMID- 30407989 TI - High-Fidelity Simulation in an Undergraduate Ambulatory Care Nursing Course. AB - For a new ambulatory care nursing course in an undergraduate baccalaureate program, a standardized patient simulation was created to support the clinical component of the course. The goals were for students to enhance their critical thinking skills, apply the nursing process to an ambulatory setting, apply learned skills to the non-acute care setting, and increase their confidence. The simulation format included three stations: skills refresher, telehealth, and clinic. Volunteers from faculty, clinical preceptors, and nursing management acted as clients for the mock clinical settings. Feedback was positive and supported this simulation as an educational option. PMID- 30407990 TI - Which Study Strategies Are Nursing Faculty Recommending? AB - This exploratory research project examines nurse faculty preferences regarding study strategies often suggested to nursing students. Respondents were nursing faculty (n = 152) currently teaching in nursing programs in a southern state. Findings reveal that, although faculty suggest an array of "high" and "moderate" utility study methods, they also advise students to employ methods with "low" or unknown levels of utility. These findings suggest a need for faculty development with a focus on highlighting efficacious study strategies. PMID- 30407991 TI - Planning and Implementing Disaster Drills for Undergraduate Nursing Students. AB - As a component of disaster response, nurses need to understand their roles in preparing for and responding to a disaster. Limited evidence regarding educating undergraduate nursing students for disasters exists. An interdisciplinary disaster drill was developed and implemented at a university nursing program. Challenges in preparing the students without giving specific details and ways of providing a more realistic experience continue to be addressed. Continued evaluation of the simulation and making identified changes to the interdisciplinary disaster drills will improve student learning and help to prepare future nurses for disasters. PMID- 30407992 TI - The Incidence of Lacrimal Drainage Disorders Across a Tertiary Eye Care Network: Customization of an Indigenously Developed Electronic Medical Record System eyeSmart. AB - PURPOSE: To assess the incidence of lacrimal drainage disorders across a tertiary eye care network in India. METHODS: A 5-year retrospective review of all the patients who were diagnosed with lacrimal drainage disorders across the tertiary care network of L.V. Prasad Eye Institute was performed from January 2013 to December 2017. All the patient data were retrieved using all the diagnostic terms assigned to the lacrimal drainage disorders in the in-house electronic medical record system eyeSmart. The incidence of each disorder, demographic details, and clinical presentations were captured. RESULTS: A total of 20,102 patients were diagnosed with lacrimal drainage disorders in the 5-year period. The 2 most prevalent disorders were primary acquired nasolacrimal duct obstruction (n = 10,364, 51.56%) followed by congenital nasolacrimal duct obstruction (CNLDO; n = 5394, 26.83%). The most frequently encountered proximal lacrimal disorder was punctal stenosis (n = 603, 3%). More than 2/3rd of the patients presented with epiphora as their presenting complaint (n = 13,907, 69.18%) followed by a discharge (n = 4023, 20.01%). Although two-thirds of the patient with primary acquired nasolacrimal duct obstruction were females (n = 7081, 68.32%), the same was not true for the CNLDO group, where there was a near equal gender distribution (M:F = 1.06:1). Predisposition to laterality was neither noted in primary acquired nasolacrimal duct obstruction nor in CNLDO. The prevalence of complex CNLDO was 16.80% (n = 907), the rest being simple CNLDO. It was easy to capture the incidence of lacrimal disorders with the electronic medical record system; however, the same was not true for the surgical details. The reasons for this were lack of clarity with surgical codes, no separate drop downs for success/failure or complications, and variations in the documentation. CONCLUSIONS: This study depicts the incidence of various lacrimal drainage disorders in a very large cohort of patients. There is a need to modify the International Classification of Diseases (ICD) classification to incorporate all the diagnostic terminologies commonly used so as to capture the real global scenario. The present study helped to further customize the electronic medical record system that caters to the intricacies of lacrimal disorders. PMID- 30407993 TI - Novel Use of Cryopreserved Ultra-Thick Human Amniotic Membrane for Management of Anophthalmic Socket Contracture. AB - PURPOSE: To describe the use of cryopreserved ultra-thick human amniotic membrane for management of anophthalmic socket contracture. METHODS: A chart review was performed to identify patients undergoing fornix reconstruction with cryopreserved ultra-thick human amniotic membrane for management of anophthalmic socket contracture. Patient demographics, disease etiology, and data regarding postoperative prosthesis fit and complications were collected. RESULTS: The technique is described in 3 female patients with anophthalmic socket contracture who underwent fornix reconstruction using cryopreserved ultra-thick human amniotic membrane. All patients had excellent prosthesis fit at final follow up (range, 10-14 months). There were no clinically significant complications and no reoperations were performed. One pyogenic granuloma developed and was excised without affecting ocular prosthesis fit. CONCLUSIONS: Cryopreserved ultra-thick human amniotic membrane is easy to use, well tolerated, and produces good outcomes for management of anophthalmic socket contracture. PMID- 30407994 TI - Medial Orbital Wall Reconstruction to Facilitate Endoscopic Sinus Surgery for Erosive Polypoidal Sinus Disease. AB - The authors report the use of a 0.35-mm-thickness nylon implant for medial orbital wall reconstruction to facilitate functional endoscopic sinus surgery (FESS) for severe erosive polypoidal sinus disease while minimizing iatrogenic injuries to the orbital contents. A retrospective chart review identified 4 patients with extensive polypoidal sinus disease who underwent medial orbital wall reconstruction in the setting of FESS. All patients underwent successful reconstruction of bilateral eroded medial orbital walls using a 0.35-mm Supramid Foil Nylon Implant immediately followed by FESS. There were no permanent complications or iatrogenic injuries to the orbital contents due to FESS. All patients experienced improvement in sinus symptoms. Medial orbital wall reconstruction in the setting of erosive polypoidal sinus disease is a useful tool to help facilitate FESS. It allows the sinus surgeon to clear sinus disease aggressively with the orbits being protected from iatrogenic injury. PMID- 30407995 TI - Systemic Diffuse Large B-Cell Lymphoma Presenting as Bilateral Orbital Vasculopathy. AB - The authors report a case of a 58-year-old man with bilateral proptosis and signs of orbital inflammation without any associated systemic findings. MRI showed diffuse orbital infiltration. An intraconal orbital biopsy revealed polyclonal lymphoplasmacytic infiltration and non-necrotizing lymphoid small-vessel vasculopathy. The orbital symptoms resolved following a 2-week course of oral prednisone. Three months later, the patient experienced abdominal pain and weight loss. Ultrasonographic investigation showed hepatosplenomegaly, a retroperitoneal mass, and inguinal lymphadenopathy. A lymph node biopsy revealed a diffuse large B-cell lymphoma. The patient underwent chemotherapy but died 6 months later with metastatic disease. This case suggests that diffuse orbital inflammation with nonspecific vasculitis may be an early paraneoplastic finding associated with diffuse large B-cell lymphoma. PMID- 30407996 TI - Preoperative Intravenous Ketorolac Safely Reduces Postoperative Pain in Levator Advancement Surgery. AB - PURPOSE: To assess the impact of intravenous ketorolac (IVK) on self-reported pain scores, requirements for opioid analgesic and anti-emetic medications, and bleeding complications in the setting of levator advancement surgery METHODS:: A prospective randomized controlled trial was performed among adult patients undergoing levator advancement surgery. Pain scores were measured immediately after surgery, prior to discharge from the surgical facility, and on the first postoperative day. The requirements for postoperative analgesic and anti-emetic medications were recorded. Statistical comparisons were performed via a dedicated computerized software package. RESULTS: Fifty patients (20 males, 30 females, mean age = 65.7 years, standard deviation = 11.9 years) underwent levator advancement without IVK and acted as controls. An additional 50 patients received IVK (19 males, 31 females, mean age = 64.6 years, standard deviation = 12.0 years). As compared with control patients, IVK resulted in statistically significant reductions in pain score immediately after surgery (4.62 vs. 1.44, p = 0.0001) and on postoperative day 1 (3.22 vs. 1.24, p = 0.0001). Fourteen patients (28%) in the control and 4 patients (8%) in the group that received IVK required opioid analgesics (p = 0.017). Seven patients (14%) in the control group and 1 patient in the group that received IVK required anti-emetic medications (p = 0.059). No patient experienced a hemorrhagic complication. CONCLUSIONS: In the setting of levator advancement surgery, IVK results in a dramatic reduction in self-reported pain score immediately after surgery and on postoperative day 1 and the requirement for opioid analgesics. This medication may be safely utilized for ptosis repair. PMID- 30407997 TI - Acute Sterile Canaliculitis: A Case Report and Review of the Literature. AB - A 53-year-old male developed secondary canaliculitis after undergoing nasolacrimal intubation with a silicone stent. Negative cultures, symptoms refractory to antibiotics, and rapid resolution after stent removal suggest an immune reaction as the mechanism of canaliculitis. This case raises awareness of noninfectious hypersensitivity or hypersensitivity-like reactions as a potential acute or subacute complication of nasolacrimal stenting. PMID- 30407998 TI - Nasolacrimal Duct Obstruction Following Hyaluronic Acid Rejuvenation of the Tear Trough. AB - Although generally safe, hyaluronic acid rejuvenation of periorbital tissue has been reported to cause minor and major adverse events. The authors document a case of nasolacrimal duct obstruction due to hyaluronic acid rejuvenation of the tear trough. Nasolacrimal duct obstruction immediately resolved following irrigation of hyaluronidase into the affected lacrimal system. To the authors' knowledge, this is the first reported case of nasolacrimal duct obstruction due to filler injection. PMID- 30407999 TI - Phakomatous Choristoma of the Orbit With Involvement of the Inferior Oblique Muscle. AB - The authors report a case of phakomatous choristoma presenting as an orbital tumor with involvement of the inferior oblique muscle. This is the only known case of this rare tumor directly invading and incorporating the inferior oblique. This tumor should be included in the differential of eyelid tumors and orbital tumors in infants. Finally, the authors review the histopathological and embryological characteristics of this lenticular tumor. PMID- 30408000 TI - Dipylidium caninum Infection in Children: Clinical Presentation and Therapeutic Challenges. AB - Dipilidium caninum infection is a relatively uncommon parasitic infection in children. We present 10 cases treated in our tertiary care hospital during the last two years. This parasitosis has a relatively benign course, but should be considered in children with gastrointestinal symptoms and eosinophilia. Treatment can be challenging, especially in infancy. Preventative measures are necessary to avoid the spread of the disease. PMID- 30408001 TI - Evaluation of a Hexavalent-Pentavalent-Hexavalent Infant Primary Vaccination Series Followed by a Pentavalent Booster Vaccine in Healthy Infants and Toddlers. AB - BACKGROUND: This study assessed a pediatric mixed hexavalent diphtheria (D) tetanus (T)-acellular pertussis (aP)-inactivated poliovirus (IPV)-hepatitis B (HB)-Haemophilus influenzae b (PRP-T)-pentavalent (DTaP-IPV//PRP-T)-hexavalent primary series schedule followed by a pentavalent booster. METHODS: Healthy infants (N=265) who had received a prior HB vaccination received a fully liquid, hexavalent vaccine (DTaP-IPV-HB-PRP-T) at 2 and 6 months of age and a reconstituted pentavalent vaccine (DTaP-IPV//PRP-T) at 4 months of age. Coadministered vaccines were pneumococcal vaccine (PCV13) at 2 and 4 months [and optionally at 6 months of age], rotavirus (RV) vaccine at 2-4-6 months, and meningococcal serogroup C vaccine at 2 months. At 18 months, participants received DTaP-IPV//PRP-T and PCV13 boosters. Immunogenicity was assessed using validated assays and safety by parental reports. RESULTS: For the hexavalent and pentavalent vaccines, the primary series and booster immune responses in terms of seroprotection and vaccine response rates were high for all antigens (generally >99% and >95% for the primary series and booster, respectively) and pre-booster antibody persistence was good for all antigens (in particular, 92.4% of participants had pre-booster anti-HB antibody >=10 mIU/mL). The incidence of solicited reactions was lower after the booster vaccination (56.9%-73.1%) than the primary series (76.6%-97.4%); there were few vaccine-related unsolicited adverse events (1.9% and 1.5% for the primary series and booster, respectively), none led to participant discontinuation, and none was serious. CONCLUSIONS: This study provides data that allow recommending authorities to consider the use of a sequential hexavalent-pentavalent-hexavalent primary vaccination series followed by a pentavalent booster in coadministration with other common childhood vaccines. PMID- 30408002 TI - Implementing Universal Varicella Vaccination in Europe: The Path Forward. AB - Varicella is a common vaccine-preventable disease that usually presents as a mild disorder but can lead to severe complications. Before the implementation of universal varicella vaccination (UVV) in some European countries, the burden of varicella disease was broadly similar across the region. Despite this, countries adopted heterogeneous varicella vaccination strategies. UVV is currently recommended in 12 European countries. Known barriers to UVV implementation in Europe include: 1) a perceived low disease burden and low public health priority, 2) cost-effectiveness and funding availability, 3) concerns related to a shift in varicella disease and incidence of HZ, and 4) safety concerns related to MMRV associated febrile seizures after the first dose. Countries that implemented UVV experienced decreases in varicella incidence, hospitalizations, and complications, showing overall beneficial impact. Alternative strategies targeting susceptible individuals at higher risk of complications have been less effective. This paper discusses ways to overcome the barriers to move varicella forward as a truly vaccine preventable disease. PMID- 30408003 TI - Epidemiology of Serious Bacterial Infections in Infants Less Than 90 Days of Age, Presenting to a Tertiary Care Emergency Department, 2010-2016. AB - Serious infections in infants require urgent treatment. Microbiology of bacterial isolates obtained from children younger than 90 days of was reviewed. 932 infants were identified (mean age of 39 days). 74% of organisms obtained were relevent. Common pathogens identified were E. coli, S. agalactiae and S. aureus. Emergence of S. aureus (18% MRSA) and ampC producing enterobacteriaceae requires prompt attention. PMID- 30408004 TI - Viral Acute Respiratory Illnesses in Young Infants Increase the Risk of Respiratory Readmission. AB - BACKGROUND: Respiratory viruses cause acute respiratory illness (ARI) in early childhood, but their effect on subsequent ARI admissions is not fully understood. This study aimed to determine the association between initial ARI admission because of viruses including human rhinovirus (HRV), respiratory syncytial virus (RSV), human adenovirus (HAdV) and human metapneumovirus (hMPV) and the risk of ARI readmission in children. METHODS: Clinical information and nasopharyngeal swab samples were collected from children <2 years old at their initial ARI admission in Nha Trang, Vietnam, from January 2007 to April 2012. The incidence of ARI readmission during the follow-up period (initial admission to 5 years of age) was compared between children with and without 1 of 13 respiratory viruses (influenza virus A, influenza virus B, RSV, hMPV, parainfluenza virus-1, parainfluenza virus-2, parainfluenza virus-3 and parainfluenza virus-4, HRV, human coronavirus-229E, human coronavirus-OC43, HAdV and human bocavirus) at initial admission. RESULTS: A total of 1941 children were enrolled in the study. Viruses were detected in 1254 (64.6%) children at enrollment; HRV, RSV, HAdV and hMPV were detected in 499 (25.7%), 439 (22.6%), 156 (8.0%) and 47 (2.4%) children, respectively. During the follow-up period (4572.7 person-years), 277 children were readmitted with ARI. Virus-related ARI initial admission was associated with an increased risk of ARI readmission for children who were initially admitted before 6 months of age (adjusted rate ratio, 1.6; 95% confidence interval: 1.1-2.5). HAdV (4.6; 1.8-11.9), hMPV (20.4; 6.2-66.9) and HRV (1.6; 1.0-2.4) were independently associated with the outcome. These associations were not observed for children whose initial admission occurred after 6 months of age. CONCLUSIONS: HAdV-, hMPV- and HRV-related initial ARI admissions, when occurring during early infancy, increased the risk of subsequent ARI-related readmission. PMID- 30408005 TI - Performance of Tuberculin Skin Tests and Interferon-gamma Release Assays in Children Younger Than 5 Years. AB - BACKGROUND: Available data to assess the optimal diagnostic approach in infants and preschool children at risk of tuberculosis (TB) are limited. METHODS: We conducted a prospective observational study in children younger than 5 years undergoing assessment with both tuberculin skin tests (TST) and QuantiFERON-TB Gold In-Tube (QFT-GIT) assays at 2 tertiary TB units in Barcelona, Spain. RESULTS: A total of 383 children were included. One of 304 participants considered uninfected developed active TB during follow-up {median [interquartile range (IQR)]: 47 [30; 48] months}, compared with none of 40 participants with latent TB infection [follow-up since completion of anti-TB treatment: 42 (32; 45) months]. Overall test agreement between TST and QFT-GIT was moderate (kappa = 0.551), but very good in children screened after TB contact (kappa = 0.801) and in Bacillus Calmette-Guerin (BCG)-unvaccinated children (kappa = 0.816). Discordant results (16.8%, all TST+/QFT-GIT-) were mainly observed in new-entrant screening and in BCG-vaccinated children. Children with indeterminate QFT-GIT results were on average younger than those with determinate results (median age: 12 vs. 30 months; P < 0.001). The sensitivity of TSTs and QFT-GIT assays in children with confirmed active TB was 100% (95% confidence interval: 79.4%-100%) and 93.7% (95% confidence interval: 69.8%-99.8%), respectively. In patients with latent TB infection or active TB, there was no correlation between age and antigen-stimulated interferon-gamma responses (r = -0.044; P = 0.714). CONCLUSIONS: In young BCG-unvaccinated children with recent TB contact, a dual testing strategy using TST and QFT-GIT in parallel may not be necessary. However, TST+/QFT-GIT- discordance is common, and it remains uncertain if this constellation indicates TB infection or not. In active TB, QFT-GIT assays do not perform better than TSTs. PMID- 30408006 TI - Variation in Outpatient Antibiotic Dispensing for Respiratory Infections in Children by Clinician Specialty and Treatment Setting. AB - BACKGROUND: Antibiotics are commonly prescribed for children with acute respiratory infections (ARIs). This study describes the distribution of ARI diagnoses and specifically quantifies antibiotic dispensing for bronchitis and upper respiratory infection (URI) by treatment setting and specialty. METHODS: This retrospective, observational cross-sectional study used data from the HealthCore Integrated Research Environment containing claims from 14 commercial health plans for 2012 to 2014. Children (2-17 years) with first-episode ARI were identified by diagnosis of acute otitis media (AOM), sinusitis, pharyngitis, bronchitis or URI with no competing infections or chronic illnesses. Treatment setting was where diagnoses were made: primary care offices, urgent care centers (UCC), retail health clinics (RHCs) or emergency departments. Primary outcome measure was antibiotic prescription fills from pharmacies within 2 days of start of ARI episode. RESULTS: For URI, the highest proportions in antibiotic dispensing were ordered by office-based or UCC family physicians (28% and 30%, respectively) and office-based or UCC nurse practitioners/physician assistants (30% and 29%, respectively). Across all settings and specialties, there was high proportion of antibiotic dispensing for bronchitis (75%). Overall, 48% of 544,531 children diagnosed with ARI filled antibiotics. Nurse practitioners/physician assistants in RHC made the most diagnoses of AOM (24%) and streptococcal pharyngitis (22%). CONCLUSIONS: Outreach efforts to decrease antibiotic dispensing for URI can be focused on office-based and UCC family physicians and nurse practitioners/physician assistants. All specialties need widespread interventions to reduce antibiotic dispensing for bronchitis. RHC nurse practitioners/physician assistants can be targeted to reduce high proportion of AOM and streptococcal pharyngitis diagnoses. PMID- 30408007 TI - Risk Factors for Invasive Fungal Infection in Children and Adolescents With Hematologic and Malignant Diseases: A 10-year Analysis in a Single Institute in Japan. AB - Infection, especially invasive fungal infection (IFI), is an important complication of chemotherapy and stem cell transplantation. It is also a well known risk factor in pediatric hematologic malignancy, acute myelogenous leukemia, recurrent disease and allogeneic stem cell transplantation. We previously revealed that a diagnosis of acute myelogenous leukemia, recurrent disease and >10 years of age were risk factors for IFI in patients with pediatric hematologic malignancies. We examined and compared the incidence, risk factors and mortality rate from IFI between 276 patients from 2007 to 2016 and patients in our past report. The cumulative incidence of IFI was 10.5%; this comprised cases of probable and possible IFI at rates of 5.1% and 5.4%, respectively. Univariate analysis showed that age >9 years at admission, recurrent disease and acute myelogenous leukemia diagnosis were risk factors for IFI. Similar to the results of the previous study, multivariate analysis showed that each of these 3 variables was an independent predictor of IFI. The survival rate was lower in patients with IFI than in those without IFI (38.8% versus 69.9%; P < 0.001). However, IFI was a direct cause of death in only 2 patients. Although 11 patients received stem cell transplantation after IFI treatment, only 2 patients have survived, and the other 9 patients died of other complications. PMID- 30408009 TI - Simplified Treatment of Possible Severe Bacterial Infection in Young Infants When Referral Is Not Feasible. What Happened There? What Are the Implications Here? AB - Severe bacterial infections remain one of the 3 leading causes of newborn death worldwide. Most such deaths could be prevented with timely and appropriate antibiotic treatment. However, in low-income countries, there are many such cases for which, practically speaking, it is not currently feasible to offer gold standard, inpatient treatment with 7 days of parenteral antibiotics. Recent trial results, however, provide evidence for efficacy using simpler outpatient antibiotic regimens, equivalent to treatment with 7 days of procaine penicillin and gentamicin, given on an outpatient basis. Based on these findings, the World Health Organization has recently released guidelines endorsing such an approach for cases for which referral for inpatient treatment is not feasible. This brief report looks beyond the measured effect sizes in the published trials to other details on how they were implemented and what outcomes were observed for different groups of study participants. The report considers, further, the circumstances in country settings where such a strategy may be appropriate and offers issues for consideration by policy makers. PMID- 30408008 TI - Second-trimester Ultrasound and Neuropathologic Findings in Congenital Zika Virus Infection. AB - Zika virus is a mosquito-borne virus that causes congenital Zika syndrome, characterized by microcephaly and other fetal brain anomalies. This case report presents a case of Zika virus-related fetal brain anomalies including pathologic evidence of cerebral neuronal apoptosis and macrophage infiltrates and intracerebral calcification, ventriculomegaly and corpus callosum dysgenesis detected by ultrasound at 18 weeks of pregnancy. PMID- 30408011 TI - Discharge Criteria for Bronchiolitis: Does Age Matter? PMID- 30408010 TI - A Rare Complication of Giardiasis in Children: Protein-losing Enteropathy. AB - Protein-losing enteropathy may develop as a complication of a wide spectrum of diseases. Three cases of giardiasis that presented with acute onset of hypoalbuminemia were documented, and resolution of protein loss after treatment was also confirmed. Thus, chronic enteric infections should be considered as an etiology of severe intestinal protein loss, particularly in children. PMID- 30408012 TI - Re: "Discharge Criteria for Bronchiolitis: Does Age Matter?" PMID- 30408013 TI - First Otitis Media and Pneumococcal Conjugate Vaccine Serotypes in Infants. PMID- 30408014 TI - Re: "First Otitis Media and Pneumococcal Conjugate Vaccine Serotypes in Infants". PMID- 30408015 TI - Important New Resource for Clinicians Giving Expert Witness Testimony on Vaccines. PMID- 30408016 TI - Bacteriocin Isolated from Lactobacillus Rhamnosus L34 Has Antibacterial Effects in a Rabbit Model of Infection After Mandible Fracture Fixation. AB - BACKGROUND Rigid internal fixation (RIF) technology is a recently developed fracture fixation technique in which use of specific antibiotics before and after the operation and timely treatment of local infections is necessary. MATERIAL AND METHODS The bacteriocins were isolated from Lactobacillus rhamnosus L34. Twenty four New Zealand White female rabbits were divided into 2 groups: bacteriocins and control group. After mandible fracture fixation, the rabbits were infected with S. aureus and subsequently injected with either bacteriocins or saline. The biofilm samples were harvested from rabbits euthanized on the 1st, 3rd, and 5th days and observed using a fluorescence microscope. Blood samples were collected at 1 h, 12 h, 1 day, 3 days, and 5 days after the injection of either bacteriocin or saline to test the level of C-reactive protein and TNF-alpha. RESULTS Significant differences in the biofilm formation were evident between the bacteriocins and saline treatment group on days 1, 3, and 5. Moreover, the serum levels of TNF-alpha and CRP after treatment with bacteriocins were significantly lower than in controls. CONCLUSIONS Use of bacteriocins isolated from Lactobacillus rhamnosus L34 may be a promising way to control infections of mandible fracture after internal fixation in vivo. PMID- 30408017 TI - Prevalence of Arthritis Among Adults with Prediabetes and Arthritis-Specific Barriers to Important Interventions for Prediabetes - United States, 2009-2016. AB - An estimated 54.4 million U.S. adults have doctor-diagnosed arthritis (arthritis), and this number is projected to rise to 78.4 million by 2040 (1,2). Physical inactivity and obesity are two factors associated with an increased risk for developing type 2 diabetes,* and arthritis has been determined to be a barrier to physical activity among adults with obesity (3). The prevalence of arthritis among the 33.9% (estimated 84 million)? of U.S. adults with prediabetes and how these conditions are related to physical inactivity and obesity are unknown. To examine the relationships among arthritis, prediabetes, physical inactivity, and obesity, CDC analyzed combined data from the 2009-2016 National Health and Nutrition Examination Surveys (NHANES). Overall, the unadjusted prevalence of arthritis among adults with prediabetes was 32.0% (26 million). Among adults with both arthritis and prediabetes, the unadjusted prevalences of leisure-time physical inactivity and obesity were 56.5% (95% confidence intervals [CIs] = 51.3-61.5) and 50.1% (CI = 46.5-53.6), respectively. Approximately half of adults with both prediabetes and arthritis are either physically inactive or have obesity, further increasing their risk for type 2 diabetes. Health care and public health professionals can address arthritis-specific barriersS to physical activity by promoting evidence-based physical activity interventions. Furthermore, weight loss and physical activity promoted though the National Diabetes Prevention Program can reduce the risk for type 2 diabetes and reduce pain from arthritis. PMID- 30408018 TI - Notes from the Field: Cronobacter sakazakii Meningitis in a Full-Term Neonate Fed Exclusively with Breast Milk - Indiana, 2018. PMID- 30408020 TI - Notes from the Field: Increase in Coccidioidomycosis - Arizona, October 2017 March 2018. PMID- 30408019 TI - Tobacco Product Use Among Adults - United States, 2017. AB - Cigarette smoking harms nearly every organ of the body and causes adverse health consequences, including heart disease, stroke, and multiple types of cancer (1). Although cigarette smoking among U.S. adults has declined considerably, tobacco products have evolved in recent years to include various combustible, noncombustible, and electronic products (1,2). To assess recent national estimates of tobacco product use among U.S. adults aged >=18 years, CDC, the Food and Drug Administration (FDA), and the National Institutes of Health's National Cancer Institute analyzed data from the 2017 National Health Interview Survey (NHIS). In 2017, an estimated 47.4 million U.S. adults (19.3%) currently used any tobacco product, including cigarettes (14.0%; 34.3 million); cigars, cigarillos, or filtered little cigars (3.8%; 9.3 million); electronic cigarettes (e cigarettes) (2.8%; 6.9 million); smokeless tobacco (2.1%; 5.1 million); and pipes, water pipes, or hookahs (1.0%; 2.6 million). Among current tobacco product users, 86.7% (41.1 million) smoked combustible tobacco products, and 19.0% (9.0 million) used >=2 tobacco products. By univariate analyses, the prevalence of current use of any tobacco product was higher among males than among females; adults aged <65 years than among those aged >=65 years; non-Hispanic American Indian/Alaska Natives, whites, blacks, or multiracial adults than among Hispanics or non-Hispanic Asians; adults who lived in the South or Midwest than among those in the West or Northeast; adults who had a general educational development certificate (GED) than among those with other levels of education; adults who earned an annual household income of <$35,000 than among those with those with higher income; lesbian, gay, or bisexual adults than among heterosexual/straight adults; and adults who were divorced/separated/widowed or single/never married/not living with a partner than among those who were married/living with a partner. Prevalence was also higher among those who were uninsured, insured by Medicaid, or had some other public insurance than among those with private insurance or Medicare only; those who had a disability/limitation than among those who did not; and those who had serious psychological distress than among those who did not. Full implementation of evidence-based tobacco control interventions that address the diversity of tobacco products used by U.S. adults, in coordination with regulation of tobacco product manufacturing, marketing, and sales, can reduce tobacco-related disease and death in the United States (1-3). PMID- 30408022 TI - QuickStats: Percentage* of Children Having a Problem for Which Prescription Medication Has Been Taken Regularly for >=3 Months,? by Age Group and Sex - National Health Interview Survey, United States, 2017S. PMID- 30408023 TI - Erratum: Vol. 67, No. 42. PMID- 30408021 TI - Firearm Homicides and Suicides in Major Metropolitan Areas - United States, 2012 2013 and 2015-2016. AB - Firearm homicides and suicides represent a continuing public health concern in the United States. During 2015-2016, a total of 27,394 firearm homicides (including 3,224 [12%] among persons aged 10-19 years) and 44,955 firearm suicides (including 2,118 [5%] among persons aged 10-19 years) occurred among U.S. residents (1). This report updates an earlier report (2) that provided statistics on firearm homicides and suicides in major metropolitan areas during 2006-2007 and 2009-2010, and places continued emphasis on youths, in recognition of the importance of early prevention efforts. Firearm homicide and suicide rates were determined for the 50 most populous U.S. metropolitan statistical areas (MSAs)* during 2012-2013 and 2015-2016 using mortality data from the National Vital Statistics System (NVSS) and population data from the U.S. Census Bureau. In contrast to the earlier report, which indicated that firearm homicide rates among persons of all ages had been declining both nationally and in large MSAs overall, current findings show that rates have returned to levels comparable to those observed during 2006-2007. Consistent with the earlier report, these findings show that firearm suicide rates among persons aged >=10 years have continued to increase, both nationally and in large MSAs overall. Although firearm suicide rates among youths remain notably lower than those among persons of all ages, youth rates have also increased both nationally and in large MSAs collectively. These findings can inform ongoing development and monitoring of strategies directed at reducing firearm-related violence. PMID- 30408024 TI - Progress Toward Poliomyelitis Eradication - Pakistan, January 2017-September 2018. AB - Among the three wild poliovirus (WPV) serotypes, only WPV type 1 (WPV1) has been reported in polio cases or detected from environmental surveillance globally since 2012. Pakistan remains one of only three countries worldwide (the others are Afghanistan and Nigeria) that has never had interrupted WPV1 transmission. This report documents Pakistan's activities and progress toward polio eradication during January 2017-September 2018 and updates previous reports (1,2). In 2017, Pakistan reported eight WPV1 cases, a 60% decrease from 20 cases in 2016. As of September 18, 2018, four cases had been reported, compared with five cases at that time in 2017. Nonetheless, in 2018, WPV1 continues to be isolated regularly from environmental surveillance sites, primarily in the core reservoir areas of Karachi, Quetta, and Peshawar, signifying persistent transmission. Strategies to increase childhood immunity have included an intense schedule of supplemental immunization activities (SIAs), expanding and refining deployment of community based vaccination implemented by community health workers recruited from the local community in reservoir areas, and strategic placement of permanent transit points where vaccination is provided to mobile populations. Interruption of WPV1 transmission will require further programmatic improvements throughout the country with a focus on specific underperforming subdistricts in reservoir areas. PMID- 30408027 TI - Putting benchmarks in their rightful place: The heart of computational biology. AB - Research in computational biology has given rise to a vast number of methods developed to solve scientific problems. For areas in which many approaches exist, researchers have a hard time deciding which tool to select to address a scientific challenge, as essentially all publications introducing a new method will claim better performance than all others. Not all of these claims can be correct. Equally, for this same reason, developers struggle to demonstrate convincingly that they created a new and superior algorithm or implementation. Moreover, the developer community often has difficulty discerning which new approaches constitute true scientific advances for the field. The obvious answer to this conundrum is to develop benchmarks-meaning standard points of reference that facilitate evaluating the performance of different tools-allowing both users and developers to compare multiple tools in an unbiased fashion. PMID- 30408025 TI - Harnessing olfactory bulb oscillations to perform fully brain-based sleep-scoring and real-time monitoring of anaesthesia depth. AB - Real-time tracking of vigilance states related to both sleep or anaesthesia has been a goal for over a century. However, sleep scoring cannot currently be performed with brain signals alone, despite the deep neuromodulatory transformations that accompany sleep state changes. Therefore, at heart, the operational distinction between sleep and wake is that of immobility and movement, despite numerous situations in which this one-to-one mapping fails. Here we demonstrate, using local field potential (LFP) recordings in freely moving mice, that gamma (50-70 Hz) power in the olfactory bulb (OB) allows for clear classification of sleep and wake, thus providing a brain-based criterion to distinguish these two vigilance states without relying on motor activity. Coupled with hippocampal theta activity, it allows the elaboration of a sleep scoring algorithm that relies on brain activity alone. This method reaches over 90% homology with classical methods based on muscular activity (electromyography [EMG]) and video tracking. Moreover, contrary to EMG, OB gamma power allows correct discrimination between sleep and immobility in ambiguous situations such as fear-related freezing. We use the instantaneous power of hippocampal theta oscillation and OB gamma oscillation to construct a 2D phase space that is highly robust throughout time, across individual mice and mouse strains, and under classical drug treatment. Dynamic analysis of trajectories within this space yields a novel characterisation of sleep/wake transitions: whereas waking up is a fast and direct transition that can be modelled by a ballistic trajectory, falling asleep is best described as a stochastic and gradual state change. Finally, we demonstrate that OB oscillations also allow us to track other vigilance states. Non-REM (NREM) and rapid eye movement (REM) sleep can be distinguished with high accuracy based on beta (10-15 Hz) power. More importantly, we show that depth of anaesthesia can be tracked in real time using OB gamma power. Indeed, the gamma power predicts and anticipates the motor response to stimulation both in the steady state under constant anaesthetic and dynamically during the recovery period. Altogether, this methodology opens the avenue for multi-timescale characterisation of brain states and provides an unprecedented window onto levels of vigilance. PMID- 30408026 TI - TRIM59 promotes breast cancer motility by suppressing p62-selective autophagic degradation of PDCD10. AB - Cancer cells adopt various modes of migration during metastasis. How the ubiquitination machinery contributes to cancer cell motility remains underexplored. Here, we report that tripartite motif (TRIM) 59 is frequently up regulated in metastatic breast cancer, which is correlated with advanced clinical stages and reduced survival among breast cancer patients. TRIM59 knockdown (KD) promoted apoptosis and inhibited tumor growth, while TRIM59 overexpression led to the opposite effects. Importantly, we uncovered TRIM59 as a key regulator of cell contractility and adhesion to control the plasticity of metastatic tumor cells. At the molecular level, we identified programmed cell death protein 10 (PDCD10) as a target of TRIM59. TRIM59 stabilized PDCD10 by suppressing RING finger and transmembrane domain-containing protein 1 (RNFT1)-induced lysine 63 (K63) ubiquitination and subsequent phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kDa (p62)-selective autophagic degradation. TRIM59 promoted PDCD10 mediated suppression of Ras homolog family member A (RhoA)-Rho-associated coiled coil kinase (ROCK) 1 signaling to control the transition between amoeboid and mesenchymal invasiveness. PDCD10 overexpression or administration of a ROCK inhibitor reversed TRIM59 loss-induced contractile phenotypes, thereby accelerating cell migration, invasion, and tumor formation. These findings establish the rationale for targeting deregulated TRIM59/PDCD10 to treat breast cancer. PMID- 30408028 TI - The Cultural Brain Hypothesis: How culture drives brain expansion, sociality, and life history. AB - In the last few million years, the hominin brain more than tripled in size. Comparisons across evolutionary lineages suggest that this expansion may be part of a broader trend toward larger, more complex brains in many taxa. Efforts to understand the evolutionary forces driving brain expansion have focused on climatic, ecological, and social factors. Here, building on existing research on learning, we analytically and computationally model the predictions of two closely related hypotheses: The Cultural Brain Hypothesis and the Cumulative Cultural Brain Hypothesis. The Cultural Brain Hypothesis posits that brains have been selected for their ability to store and manage information, acquired through asocial or social learning. The model of the Cultural Brain Hypothesis reveals relationships between brain size, group size, innovation, social learning, mating structures, and the length of the juvenile period that are supported by the existing empirical literature. From this model, we derive a set of predictions the Cumulative Cultural Brain Hypothesis-for the conditions that favor an autocatalytic take-off characteristic of human evolution. This narrow evolutionary pathway, created by cumulative cultural evolution, may help explain the rapid expansion of human brains and other aspects of our species' life history and psychology. PMID- 30408029 TI - Hydrometeorology and flood pulse dynamics drive diarrheal disease outbreaks and increase vulnerability to climate change in surface-water-dependent populations: A retrospective analysis. AB - BACKGROUND: The impacts of climate change on surface water, waterborne disease, and human health remain a growing area of concern, particularly in Africa, where diarrheal disease is one of the most important health threats to children under 5 years of age. Little is known about the role of surface water and annual flood dynamics (flood pulse) on waterborne disease and human health nor about the expected impact of climate change on surface-water-dependent populations. METHODS AND FINDINGS: Using the Chobe River in northern Botswana, a flood pulse river floodplain system, we applied multimodel inference approaches assessing the influence of river height, water quality (bimonthly counts of Escherichia coli and total suspended solids [TSS], 2011-2017), and meteorological variability on weekly diarrheal case reports among children under 5 presenting to health facilities (n = 10 health facilities, January 2007-June 2017). We assessed diarrheal cases by clinical characteristics and season across age groups using monthly outpatient data (January 1998-June 2017). A strong seasonal pattern was identified, with 2 outbreaks occurring regularly in the wet and dry seasons. The timing of outbreaks diverged from that at the level of the country, where surface water is largely absent. Across age groups, the number of diarrheal cases was greater, on average, during the dry season. Demographic and clinical characteristics varied by season, underscoring the importance of environmental drivers. In the wet season, rainfall (8-week lag) had a significant influence on under-5 diarrhea, with a 10-mm increase in rainfall associated with an estimated 6.5% rise in the number of cases. Rainfall, minimum temperature, and river height were predictive of E. coli concentration, and increases in E. coli in the river were positively associated with diarrheal cases. In the dry season, river height (1-week lag) and maximum temperature (1- and 4-week lag) were significantly associated with diarrheal cases. During this period, a 1-meter drop in river height corresponded to an estimated 16.7% and 16.1% increase in reported diarrhea with a 1- and 4-week lag, respectively. In this region, as floodwaters receded from the surrounding floodplains, TSS levels increased and were positively associated with diarrheal cases (0- and 3-week lag). Populations living in this region utilized improved water sources, suggesting that hydrological variability and rapid water quality shifts in surface waters may compromise water treatment processes. Limitations include the potential influence of health beliefs and health seeking behaviors on data obtained through passive surveillance. CONCLUSIONS: In flood pulse river-floodplain systems, hydrology and water quality dynamics can be highly variable, potentially impacting conventional water treatment facilities and the production of safe drinking water. In Southern Africa, climate change is predicted to intensify hydrological variability and the frequency of extreme weather events, amplifying the public health threat of waterborne disease in surface-water-dependent populations. Water sector development should be prioritized with urgency, incorporating technologies that are robust to local environmental conditions and expected climate-driven impacts. In populations with high HIV burdens, expansion of diarrheal disease surveillance and intervention strategies may also be needed. As annual flood pulse processes are predominantly influenced by climate controls in distant regions, country level data may be inadequate to refine predictions of climate-health interactions in these systems. PMID- 30408030 TI - Is POC-CCA a truly reliable test for schistosomiasis diagnosis in low endemic areas? The trace results controversy. PMID- 30408031 TI - Reducing Aedes albopictus breeding sites through education: A study in urban area. AB - Aedes albopictus tends to proliferate in small, often man-made bodies of water, largely present in urban private areas. For this reason, education and community participation are considered crucial for source reduction and mosquito control. In the current study, we identify mosquito breeding habitat and evaluate the effectiveness of resident education. Since 2010 several outbreaks of West Nile virus infection occurred in Greece however urban population has no previous experience with mosquito-borne disease related to Aedes species, such as Dengue, Zika and Chikungunya. After the introduction of Ae. albopictus in Greece, urban areas have been considered to be at risk of epidemic arboviral outbreaks and identifying effective control strategies is imperative. Our study examines the relationship between mosquito breeding sources and socioeconomic or demographic characteristics of different households in a Greek municipality and evaluates efficacy of resident education. The results revealed that only a minority of residents knew where mosquitoes breed (18.6%) and only 46% felt that residents had any responsibility for managing breeding habitat. Our findings strongly suggest that only the presence of scientific staff inspecting possible habitats in their properties, could be enough to stimulate practices towards source reduction. However, educational interventions alone with printed education material cannot enhance significant community participation and source reduction. PMID- 30408033 TI - Examining the role of the surfactant family member SFTA3 in interneuron specification. AB - The transcription factor NKX2.1, expressed at high levels in the medial ganglionic eminence (MGE), is a master regulator of cortical interneuron progenitor development. To identify gene candidates with expression profiles similar to NKX2.1, previous transcriptome analysis of human embryonic stem cell (hESC)-derived MGE-like progenitors revealed SFTA3 as the strongest candidate. Quantitative real-time PCR analysis of hESC-derived NKX2.1-positive progenitors and transcriptome data available from the Allen Institute for Brain Science revealed comparable expression patterns for NKX2.1 and SFTA3 during interneuron differentiation in vitro and demonstrated high SFTA3 expression in the human MGE. Although SFTA3 has been well studied in the lung, the possible role of this surfactant protein in the MGE during embryonic development remains unexamined. To determine if SFTA3 plays a role in MGE specification, SFTA3-/- and NKX2.1 -/- hESC lines were generated using custom designed CRISPRs. We show that NKX2.1 KOs have a significantly diminished capacity to differentiate into MGE interneuron subtypes. SFTA3 KOs also demonstrated a somewhat reduced ability to differentiate down the MGE-like lineage, although not as severe relative to NKX2.1 deficiency. These results suggest NKX2.1 and SFTA3 are co-regulated genes, and that deletion of SFTA3 does not lead to a major change in the specification of MGE derivatives. PMID- 30408032 TI - A benchmark driven guide to binding site comparison: An exhaustive evaluation using tailor-made data sets (ProSPECCTs). AB - The automated comparison of protein-ligand binding sites provides useful insights into yet unexplored site similarities. Various stages of computational and chemical biology research can benefit from this knowledge. The search for putative off-targets and the establishment of polypharmacological effects by comparing binding sites led to promising results for numerous projects. Although many cavity comparison methods are available, a comprehensive analysis to guide the choice of a tool for a specific application is wanting. Moreover, the broad variety of binding site modeling approaches, comparison algorithms, and scoring metrics impedes this choice. Herein, we aim to elucidate strengths and weaknesses of binding site comparison methodologies. A detailed benchmark study is the only possibility to rationalize the selection of appropriate tools for different scenarios. Specific evaluation data sets were developed to shed light on multiple aspects of binding site comparison. An assembly of all applied benchmark sets (ProSPECCTs-Protein Site Pairs for the Evaluation of Cavity Comparison Tools) is made available for the evaluation and optimization of further and still emerging methods. The results indicate the importance of such analyses to facilitate the choice of a methodology that complies with the requirements of a specific scientific challenge. PMID- 30408034 TI - Evidence of forest restoration success and the conservation value of community owned forests in Southwest China using dung beetles as indicators. AB - Protection of the world's remaining forests and biodiversity is a matter of global concern. Yunnan, China is home to China's only mainland tropical rainforests, and 20% of China's total biodiversity. Despite restoration measures and establishment of new protected areas, this region is still experiencing biodiversity loss due to inadequate management and monitoring. We evaluate restoration success of China's tropical forests in Xishuangbanna National Nature Reserve (XSBN-NNR), Yunnan, China using dung beetles as an indicator taxon. We sampled across a land-use gradient of human alteration: protected forest, restored forest, community owned forest, and rubber plantation. We collected 3,748 dung beetles from 21 species over a 3 month period. Multivariate analyses revealed unique assemblages in each land-use category, but with restored forest most similar to protected areas, suggesting restoration success in this region. Community forests were more diverse than plantations, suggesting that community forests may be a valuable and practical conservation tool in this region. Most species were generalists, although some had dietary and habitat preferences. Furthermore, dietary niche breadths were, on average, higher in disturbed areas, suggesting that disturbance may result in dietary changes. We show that restoration of tropical forests appears to be successful for a key ecological and biological indicator group- dung beetles. Furthermore, community-owned forests appear to be valuable and practical method of maintaining ecosystem health and biodiversity in the region. Future management in this region would likely benefit from encouragement to maintain community-owned forests, economic incentives for restoring farmland to forest, and increased environmental monitoring across the land-use gradient. PMID- 30408035 TI - Phylogenetic relationships in the genus Avena based on the nuclear Pgk1 gene. AB - The phylogenetic relationships among 76 Avena taxa, representing 14 diploids, eight tetraploids, and four hexaploids were investigated by using the nuclear plastid 3-phosphoglycerate kinase gene (Pgk1). A significant deletion (131 bp) was detected in all the C genome homoeologues which reconfirmed a major structural divergence between the A and C genomes. Phylogenetic analysis indicated the Cp genome is more closely related to the polyploid species than is the Cv genome. Two haplotypes of Pgk1 gene were obtained from most of the AB genome tetraploids. Both types of the barbata group showed a close relationship with the As genome diploid species, supporting the hypothesis that both the A and B genomes are derived from an As genome. Two haplotypes were also detected in A. agadiriana, which showed close relationships with the As genome diploid and the Ac genome diploid, respectively, emphasizing the important role of the Ac genome in the evolution of A. agadiriana. Three homoeologues of the Pgk1 gene were detected in five hexaploid accessions. The homoeologues that might represent the D genome were tightly clustered with the tetraploids A. maroccana and A. murphyi, but did not show a close relationship with any extant diploid species. PMID- 30408036 TI - The use of optical coherence tomography for the detection of ocular toxicity by ethambutol. AB - OBJECTIVES: To evaluate, through (OCT), alterations in retinal thickness, secondary to use of ethambutol in the treatment of patients with tuberculosis. In addition to studying the use of simpler semiological tools, such as Amsler and Ishihara, in the screening of these cases. METHODS: Thirty patients with ethambutol were recruited from the reference service of tuberculosis treatment at the Federal University of Espirito Santo from May 2015 to July 2016. After clinical history, the following parameters were analyzed; best corrected visual acuity, biomicroscopy, tonometry, photomotor reflex testing, Ishihara test, Amsler's grid test, color digital retinography and optical coherence tomography with CIRRUS HD-OCT (Humphrey-Zeiss) every 2 months during treatment with ethambutol. They were divided into two groups according to the treatment: (1) standard group, two months of ethambutol; (2) extended group, nine to twelve months of ethambutol. RESULTS: There was a significant reduction in OCT thickness between the pre and post treatment times in ten eyes of the extended group, mean reduction of 7,8 microns and in seven eyes of the standard group, with an average of 5.57 microns. During the study, a significant reduction of retinal thickness was observed in both groups at two months of treatment, and the delta percentage was higher in those patients who presented reduction of visual acuity and / or change in the Ishihara test. CONCLUSION: There was a significant reduction in the thickness of the nerve fiber layer by OCT in the patients studied, being more pronounced in those submitted to the extended treatment regimen. This reduction was observed two months after the start of therapy, and was more significant in the cases that presented changes in the Ishihara test. PMID- 30408037 TI - Variation and diversification of the microbiome of Schlechtendalia chinensis on two alternate host plants. AB - Schlechtendalia chinensis, a gall-inducing aphid, has two host plants in its life cycle. Its wintering host is a moss (typically Plagiomnium maximoviczii) and its main host is Rhus chinensis (Sumac), on which it forms galls during the summer. This study investigated bacteria associated with S. chinensis living on the two different host plants by sequencing 16S rRNAs. A total of 183 Operational Taxonomic Units (OTUs) from 50 genera were identified from aphids living on moss, whereas 182 OTUs from 49 genera were found from aphids living in Sumac galls. The most abundant bacterial genus among identified OTUs from aphids feeding on both hosts was Buchnera. Despite similar numbers of OTUs, the composition of bacterial taxa showed significant differences between aphids living on moss and those living on R. chinensis. Specifically, there were 12 OTUs from 5 genera (family) unique to aphids living on moss, and 11 OTUs from 4 genera (family) unique to aphids feeding in galls on R. chinensis. Principal Coordinate Analysis (PCoA) also revealed that bacteria from moss-residing aphids clustered differently from aphids collected from galls. Our results provide a foundation for future analyses on the roles of symbiotic bacteria in plant-aphid interactions in general, and how gall-specific symbionts differ in this respect. PMID- 30408038 TI - Biocidal radiuses of abamectin, thiamethoxam and sulfoxaflor droplets controlling against wheat aphid (Sitobion avenae). AB - Spraying insecticide is a common practice in the control against pest insects. However, little attention has been paid to the biocidal radius of droplets. Therefore, in this study, we investigated the biocidal radiuses of abamectin, thiamethoxam and sulfoxaflor droplets controlling against wheat aphid (Sitobion avenae). The mortality of S. avenae showed a droplet density dependent process that can be described by an exponential model. Calculated mortality limit (A2) varied with the concentration of insecticides. Although similar LD50 values were observed in abamectin (13.77 ng aphid-1) and sulfoxaflor (14.52 ng aphid-1) against S. avenae, sulfoxaflor had a larger biocidal radius (r50) than abamectin due to its translocation ability at the same concentration. And sulfoxaflor had a relatively larger biocidal radius than thiamethoxam (LD50 = 68.42 ng aphid-1) because it is more toxic to S. avenae. The ratio of r50/VMD was introduced to estimate the potential of droplets. Droplets generated by the air atomizing nozzle (VMD = 43 MUm) had higher value of r50/VMD than the centrifugal atomizing nozzle (VMD = 153 MUm). Our results indicated that the mortality limit can be reached at a concentration of an insecticide. The biocidal radius of a droplet is different from its actual size. The LD50 and translocation ability of insecticides contributed to their biocidal radius. Ratio of r50/VMD is an indicator of droplets' insecticidal potential. Smaller droplets generated by the air atomizing nozzle have higher insecticidal potential. PMID- 30408040 TI - Decreased GPIHBP1 protein levels in visceral adipose tissue partly underlie the hypertriglyceridemic phenotype in insulin resistance. AB - GPIHBP1 is a protein localized at the endothelial cell surface that facilitates triglyceride (TG) lipolysis by binding lipoprotein lipase (LPL). Whether Glycosyl Phosphatidyl Inositol high density lipoprotein binding protein 1 (GPIHBP1) function is impaired and may underlie the hyperTG phenotype observed in type 2 diabetes is not yet established. To elucidate the mechanism underlying impaired TG homeostasis in insulin resistance state we studied the effect of insulin on GPIHBP1 protein expression in human microvascular endothelial cells (HMVEC) under flow conditions. Next, we assessed visceral adipose tissue GPIHBP1 protein expression in type 2 diabetes Lepr db/db mouse model as well as in subjects with ranging levels of insulin resistance. We report that insulin reduces the expression of GPIHBP1 protein in HMVECs. Furthermore, GPIHBP1 protein expression in visceral adipose tissue in Lepr db/db mice is significantly reduced as is the active monomeric form of GPIHBP1 as compared to Leprdb/m mice. A similar decrease in GPIHBP1 protein was observed in subjects with increased body weight. GPIHBP1 protein expression was negatively associated with insulin and HOMA-IR. In conclusion, our data suggest that decreased GPIHBP1 availability in insulin resistant state may hamper peripheral lipolysis capacity. PMID- 30408039 TI - Patients' perceived needs for medical services for non-specific low back pain: A systematic scoping review. AB - BACKGROUND: An improved understanding of patients' perceived needs for medical services for low back pain (LBP) will enable healthcare providers to better align service provision with patient expectations, thus improving patient and health care system outcomes. Thus, we aimed to identify the existing literature regarding patients' perceived needs for medical services for LBP. METHODS: A systematic scoping review was performed of publications identified from MEDLINE, EMBASE, CINAHL and PsycINFO (1990-2016). Descriptive data regarding each study, its design and methodology were extracted and risk of bias assessed. Aggregates of patients' perceived needs for medical services for LBP were categorised. RESULTS: 50 studies (35 qualitative, 14 quantitative and 1 mixed-methods study) from 1829 were relevant. Four areas of perceived need emerged: (1) Patients with LBP sought healthcare from medical practitioners to obtain a diagnosis, receive management options, sickness certification and legitimation for their LBP. However, there was dissatisfaction with the cursory and superficial approach of care. (2) Patients had concerns about pharmacotherapy, with few studies reporting on patients' preferences for medications. (3) Of the few studies which examined the patients' perceived need of invasive therapies, these found that patients avoided injections and surgeries (4) Patients desired spinal imaging for diagnostic purposes and legitimation of symptoms. CONCLUSIONS: Across many different patient populations with data obtained from a variety of study designs, common themes emerged which highlighted areas of patient dissatisfaction with the medical management of LBP, in particular, the superficial approach to care perceived by patients and concerns regarding pharmacotherapy. Patients perceive unmet needs from medical services, including the need to obtain a diagnosis, the desire for pain control and the preference for spinal imaging. These issues need to be considered in developing approaches for the management of LBP in order to improve patient outcomes. PMID- 30408041 TI - Systematically benchmarking peptide-MHC binding predictors: From synthetic to naturally processed epitopes. AB - A number of machine learning-based predictors have been developed for identifying immunogenic T-cell epitopes based on major histocompatibility complex (MHC) class I and II binding affinities. Rationally selecting the most appropriate tool has been complicated by the evolving training data and machine learning methods. Despite the recent advances made in generating high-quality MHC-eluted, naturally processed ligandome, the reliability of new predictors on these epitopes has yet to be evaluated. This study reports the latest benchmarking on an extensive set of MHC-binding predictors by using newly available, untested data of both synthetic and naturally processed epitopes. 32 human leukocyte antigen (HLA) class I and 24 HLA class II alleles are included in the blind test set. Artificial neural network (ANN)-based approaches demonstrated better performance than regression-based machine learning and structural modeling. Among the 18 predictors benchmarked, ANN-based mhcflurry and nn_align perform the best for MHC class I 9-mer and class II 15-mer predictions, respectively, on binding/non binding classification (Area Under Curves = 0.911). NetMHCpan4 also demonstrated comparable predictive power. Our customization of mhcflurry to a pan-HLA predictor has achieved similar accuracy to NetMHCpan. The overall accuracy of these methods are comparable between 9-mer and 10-mer testing data. However, the top methods deliver low correlations between the predicted versus the experimental affinities for strong MHC binders. When used on naturally processed MHC-ligands, tools that have been trained on elution data (NetMHCpan4 and MixMHCpred) shows better accuracy than pure binding affinity predictor. The variability of false prediction rate is considerable among HLA types and datasets. Finally, structure-based predictor of Rosetta FlexPepDock is less optimal compared to the machine learning approaches. With our benchmarking of MHC binding and MHC-elution predictors using a comprehensive metrics, a unbiased view for establishing best practice of T-cell epitope predictions is presented, facilitating future development of methods in immunogenomics. PMID- 30408042 TI - Barriers to access to visceral leishmaniasis diagnosis and care among seasonal mobile workers in Western Tigray, Northern Ethiopia: A qualitative study. AB - BACKGROUND: Ethiopia bears a high burden of visceral leishmaniasis (VL). Early access to VL diagnosis and care improves clinical prognosis and reduces transmission from infected humans; however, significant obstacles exist. The approximate 250,000 seasonal mobile workers (MW) employed annually in northwestern Ethiopia may be particularly disadvantaged and at risk of VL acquisition and death. Our study aimed to assess barriers, and recommend interventions to increase access, to VL diagnosis and care among MWs. METHODOLOGY/PRINCIPAL FINDINGS: In 2017, 50 interviews and 11 focus group discussions were conducted with MWs, mobile residents, VL patients and caretakers, community leaders and healthcare workers in Kafta Humera District, Tigray. Participants reported high vulnerability to VL among MWs and residents engaged in transitory work. Multiple visits to health facilities were consistently needed to access VL diagnosis. Inadequate healthcare worker training, diagnostic test kit unavailability at the primary healthcare level, lack of VL awareness, insufficient finances for care-seeking and prioritization of income-generating activities were significant barriers to diagnosis and care. Social (decision-making and financial) support strongly and positively influenced care-seeking; workers unable to receive salary advances, compensation for partial work, or peer assistance for contract completion were particularly disadvantaged. Participants recommended the government/stakeholders intervene to ensure: MWs access to bed-nets, food, shelter, water, and healthcare at farms or sick leave; decentralization of diagnostic tests to primary healthcare facilities; surplus medications/staff during the peak season; improved referral/feedback/reporting/training within the health system; free comprehensive healthcare for all VL-related services; and community health education. CONCLUSIONS/SIGNIFICANCE: Contrary to what health policy for VL dictates in this endemic setting, study participants reported very poor access to diagnosis and, consequently, significantly delayed access to treatment. Interventions tailored to the socio-economic and health needs of MWs (and other persons suffering from VL) are urgently needed to reduce health disparities and the VL burden. PMID- 30408043 TI - Warmer and wetter conditions will reduce offspring production of hawksbill turtles in Brazil under climate change. AB - Climate change is expected to impact animals that are heavily reliant on environmental factors, such as sea turtles, since the incubation of their eggs, hatching success and sex ratio are influenced by the environment in which eggs incubate. As climate change progresses it is therefore important to understand how climatic conditions influence their reproductive output and the ramifications to population stability. Here, we examined the influences of five climatic variables (air temperature, accumulated and average precipitation, humidity, solar radiation, and wind speed) at different temporal scales on hawksbill sea turtle (Eretmochelys imbricata) hatchling production at ten nesting beaches within two regions of Brazil (five nesting beaches in Rio Grande do Norte and five in Bahia). Air temperature and accumulated precipitation were the main climatic drivers of hawksbill hatching success (number of eggs hatched within a nest) across Brazil and in Rio Grande do Norte, while air temperature and average precipitation were the main climatic drivers of hatching success at Bahia. Solar radiation was the main climatic driver of emergence success (number of hatchlings that emerged from total hatched eggs within a nest) at both regions. Warmer temperatures and higher solar radiation had negative effects on hatchling production, while wetter conditions had a positive effect. Conservative and extreme climate scenarios show air temperatures are projected to increase at this site, while precipitation projections vary between scenarios and regions throughout the 21st century. We predicted hatching success of undisturbed nests (no recorded depredation or storm-related impacts) will decrease in Brazil by 2100 as a result of how this population is influenced by local climate. This study shows the determining effects of different climate variables and their combinations on an important and critically endangered marine species. PMID- 30408044 TI - Patient-specific modeling of right coronary circulation vulnerability post-liver transplant in Alagille's syndrome. AB - OBJECTIVES: Cardiac output (CO) response to dobutamine can identify Alagille's syndrome (ALGS) patients at higher risk of cardiovascular complications during liver transplantation. We propose a novel patient-specific computational methodology to estimate the coronary autoregulatory responses during different hemodynamic conditions, including those experienced in a post-reperfusion syndrome (PRS), to aid cardiac risk-assessment. MATERIAL AND METHODS: Data (pressure, flow, strain and ventricular volumes) from a 6-year-old ALGS patient undergoing catheter/dobutamine stress MRI (DSMRI) were used to parameterize a closed-loop coupled-multidomain (3D-0D) approach consisting of image-derived vascular models of pulmonary and systemic circulations and a series of 0D-lumped parameter networks (LPN) of the heart chambers and the distal arterial and venous circulations. A coronary microcirculation control model (CMCM) was designed to adjust the coronary resistance to match coronary blood flow (and thus oxygen delivery) with MVO2 requirements during Rest, Stress and a virtual PRS condition. RESULTS: In all three simulated conditions, diastolic dominated right coronary artery (RCA) flow was observed, due to high right ventricle (RV) afterload. Despite a measured 45% increase in CO, impaired coronary flow reserve (CFR) (~1.4) at Stress was estimated by the CMCM. During modeled PRS, a marked vasodilatory response was insufficient to match RV myocardial oxygen requirements. Such exhaustion of the RCA autoregulatory response was not anticipated by the DSMRI study. CONCLUSION: Impaired CFR undetected by DSMRI resulted in predicted myocardial ischemia in a computational model of PRS. This computational framework may identify ALGS patients at higher risk of complications during liver transplantation due to impaired coronary microvascular responses. PMID- 30408045 TI - Exploring the effect of human and animal population growth on vector-borne disease transmission with an agent-based model of Rhodesian human African trypanosomiasis in eastern province, Zambia. AB - This paper presents the development of an agent-based model (ABM) to investigate Trypanosoma brucei rhodesiense human African trypanosomiasis (rHAT) disease transmission. The ABM model, fitted at a fine spatial scale, was used to explore the impact of a growing host population on the spread of disease along a 75 km transect in the Luangwa Valley, Zambia. The model was used to gain a greater understanding of how increases in human and domestic animal population could impact the contact network between vector and host, the subsequent transmission patterns, and disease incidence outcomes in the region. Modelled incidence rates showed increases in rHAT transmission in both humans and cattle. The primary demographic attribution of infection switched dramatically from young children of both sexes attending school, to adult women performing activities with shorter but more frequent trips, such as water and firewood collection, with men more protected due to the presence of cattle in their routines. The interpretation of model output provides a plausible insight into both population development and disease transmission in the near future in the region and such techniques could aid well-targeted mitigation strategies in the future. PMID- 30408046 TI - Analysis of healthcare service utilization after transport-related injuries by a mixture of hidden Markov models. AB - BACKGROUND: Transport injuries commonly result in significant disease burden, leading to physical disability, mental health deterioration and reduced quality of life. Analyzing the patterns of healthcare service utilization after transport injuries can provide an insight into the health of the affected parties, allow improved health system resource planning, and provide a baseline against which any future system-level interventions can be evaluated. Therefore, this research aims to use time series of service utilization provided by a compensation agency to identify groups of claimants with similar utilization patterns, describe such patterns, and characterize the groups in terms of demographic, accident type and injury type. METHODS: To achieve this aim, we have proposed an analytical framework that utilizes latent variables to describe the utilization patterns over time and group the claimants into clusters based on their service utilization time series. To perform the clustering without dismissing the temporal dimension of the time series, we have used a well-established statistical approach known as the mixture of hidden Markov models (MHMM). Ensuing the clustering, we have applied multinomial logistic regression to provide a description of the clusters against demographic, injury and accident covariates. RESULTS: We have tested our model with data on psychology service utilization from one of the main compensation agencies for transport accidents in Australia, and found that three clear clusters of service utilization can be evinced from the data. These three clusters correspond to claimants who have tended to use the services 1) only briefly after the accident; 2) for an intermediate period of time and in moderate amounts; and 3) for a sustained period of time, and intensely. The size of these clusters is approximately 67%, 27% and 6% of the number of claimants, respectively. The multinomial logistic regression analysis has showed that claimants who were 30 to 60-year-old at the time of accident, were witnesses, and who suffered a soft tissue injury were more likely to be part of the intermediate cluster than the majority cluster. Conversely, claimants who suffered more severe injuries such as a brain head injury or anon-limb fracture injury and who started their service utilization later were more likely to be part of the sustained cluster. CONCLUSION: This research has showed that clustering of service utilization time series is an effective approach for identifying the main user groups and utilization patterns of a healthcare service. In addition, using logistic regression to describe the clusters in terms of demographic, injury and accident covariates has helped identify the salient attributes of the claimants in each cluster. This finding is very important for the compensation agency and potentially other authorities as it provides a baseline to improve need understanding, resource planning and service provision. PMID- 30408047 TI - Ehrlichia chaffeensis TRP47 enters the nucleus via a MYND-binding domain dependent mechanism and predominantly binds enhancers of host genes associated with signal transduction, cytoskeletal organization, and immune response. AB - Ehrlichia chaffeensis is an obligately intracellular bacterium that establishes infection in mononuclear phagocytes through largely undefined reprogramming strategies including modulation of host gene transcription. In this study, we demonstrate that the E. chaffeensis effector TRP47 enters the host cell nucleus and binds regulatory regions of host genes relevant to infection. TRP47 was observed in the nucleus of E. chaffeensis-infected host cells, and nuclear localization was dependent on a variant MYND-binding domain. An electrophoretic mobility shift assay (EMSA) demonstrated that TRP47 directly binds host DNA via its tandem repeat domain. Utilizing chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-seq) with E. chaffeensis-infected cells, TRP47 was found to bind at multiple sites in the human genome (n = 2,051 at p < 10-30). Ontology analysis identified genes involved in functions such as immune response, cytoskeletal organization, and signal transduction. TRP47-bound genes included RNA-coding genes, many of these linked to cell proliferation or apoptosis. Comparison of TRP47 binding sites with those of previously-identified E. chaffeensis nucleomodulins identified multiple genes and gene functional categories in common including intracellular transport, cell signaling, and transcriptional regulation. Further, motif analysis followed by EMSA with synthetic oligonucleotides containing discovered motifs revealed a conserved TRP47 DNA-binding motif. This study reveals that TRP47 is a nucleomodulin that enters the nucleus via a MYND-binding domain and appears to play a role in host cell reprogramming by regulation of transcription. PMID- 30408048 TI - AFLP-AFLP in silico-NGS approach reveals polymorphisms in repetitive elements in the malignant genome. AB - The increasing interest in exploring the human genome and identifying genetic risk factors contributing to the susceptibility to and outcome of diseases has supported the rapid development of genome-wide techniques. However, the large amount of obtained data requires extensive bioinformatics analysis. In this work, we established an approach combining amplified fragment length polymorphism (AFLP), AFLP in silico and next generation sequencing (NGS) methods to map the malignant genome of patients with chronic myeloid leukemia. We compared the unique DNA fingerprints of patients generated by the AFLP technique approach with those of healthy donors to identify AFLP markers associated with the disease and/or the response to treatment with imatinib, a tyrosine kinase inhibitor. Among the statistically significant AFLP markers selected for NGS analysis and virtual fingerprinting, we identified the sequences of three fragments in the region of DNA repeat element OldhAT1, LINE L1M7, LTR MER90, and satellite ALR/Alpha among repetitive elements, which may indicate a role of these non coding repetitive sequences in hematological malignancy. SNPs leading to the presence/absence of these fragments were confirmed by Sanger sequencing. When evaluating the results of AFLP analysis for some fragments, we faced the frequently discussed size homoplasy, resulting in co-migration of non-identical AFLP fragments that may originate from an insertion/deletion, SNP, somatic mutation anywhere in the genome, or combination thereof. The AFLP-AFLP in silico NGS procedure represents a smart alternative to microarrays and relatively expensive and bioinformatically challenging whole-genome sequencing to detect the association of variable regions of the human genome with diseases. PMID- 30408049 TI - Transcriptome profiling of transgenic potato plants provides insights into variability caused by plant transformation. AB - Crop genetic engineering involves transformation in which transgenic plants are regenerated through tissue culture manipulations that can elicit somaclonal variation due to mutations, translocations, and/or epigenetic alterations. Here, we report on alterations in the transcriptome in a panel of transgenic potato plants engineered to be herbicide resistant. Using an inbred diploid potato clone (DMRH S5 28-5), ten single-insert transgenic lines derived from independent Agrobacterium-mediated transformation events were selected for herbicide resistance using an allelic variant of acetolactate synthase (mALS1). Expression abundances of the single-copy mALS1 transgene varied in individual transgenic lines was correlated with the level of phenotypic herbicide resistance, suggesting the importance of transgene expression in transgenic performance. Using RNA-sequencing, differentially expressed genes were identified with the proportion of genes up-regulated significantly higher than down-regulated genes in the panel, suggesting a differential impact of the plant transformation on gene expression activation compared to repression. Not only were transcription factors among the differentially expressed genes but specific transcription factor binding sites were also enriched in promoter regions of differentially expressed genes in transgenic lines, linking transcriptomic variation with specific transcription factor activity. Collectively, these results provide an improved understanding of transcriptomic variability caused by plant transformation. PMID- 30408050 TI - Dilation of tricuspid valve annulus immediately after rupture of chordae tendineae in ex-vivo porcine hearts. AB - PURPOSE: Chordae rupture is one of the main lesions observed in traumatic heart events that might lead to severe tricuspid valve (TV) regurgitation. TV regurgitation following chordae rupture is often well tolerated with few or no symptoms for most patients. However, early repair of the TV is of great importance, as it might prevent further exacerbation of the regurgitation due to remodeling responses. To understand how TV regurgitation develops following this acute event, we investigated the changes on TV geometry, mechanics, and function of ex-vivo porcine hearts following chordae rupture. METHODS: Sonomicrometry techniques were employed in an ex-vivo heart apparatus to identify how the annulus geometry alters throughout the cardiac cycle after chordae rupture, leading to the development of TV regurgitation. RESULTS: We observed that the TV annulus significantly dilated (~9% in area) immediately after chordae rupture. The annulus area and circumference ranged from 11.4 +/- 2.8 to 13.3 +/- 2.9 cm2 and from 12.5 +/- 1.5 to 13.5 +/- 1.3 cm, respectively, during the cardiac cycle for the intact heart. After chordae rupture, the annulus area and circumference were larger and ranged from 12.3 +/- 3.0 to 14.4 +/- 2.9 cm2 and from 13.0 +/- 1.5 to 14.0 +/- 1.2 cm, respectively. CONCLUSIONS: In our ex-vivo study, we showed for the first time that the TV annulus dilates immediately after chordae rupture. Consequently, secondary TV regurgitation may be developed because of such changes in the annulus geometry. In addition, the TV leaflet and the right ventricle myocardium are subjected to a different mechanical environment, potentially causing further negative remodeling responses and exacerbating the detrimental outcomes of chordae rupture. PMID- 30408051 TI - Substrate-independent immunomodulatory characteristics of mesenchymal stem cells in three-dimensional culture. AB - Mesenchymal stem cells (MSCs) play important roles in tissue regeneration, and multi-lineage differentiation and immunomodulation are two major characteristics of MSCs that are utilized in stem cell therapy. MSCs in vivo have a markedly different three-dimensional (3D) niche compared to the traditional two dimensional (2D) culture in vitro. A 3D scaffold is predicted to provide an artificial 3D environment similar to the in vivo environment. Significant changes in MSC differentiation are shown to be occurred when under 3D culture. However, the immunomodulatory characteristics of MSCs under 3D culture remain unknown. In this study, 3D culture systems were constructed using different substrates to evaluate the common immunomodulatory characteristics of MSCs. Compared to the MSCs under 2D culture, the MSCs under 3D culture, which had higher stemness and maintained cell phenotype, showed altered immunophenotypic pattern. Gene expression profile analysis at mRNA and protein level detected by gene chip and protein chip, respectively, further revealed the difference between 3D cultured MSCs and 2D cultured MSCs, which was mainly concentrated in the immunoregulation related aspects. Moreover, the immunoregulatory role of 3D culture was confirmed by our immunosuppressive experiments. These findings demonstrated that the immunomodulatory capacities of MSCs were enhanced by the 3D geometry of substrates. PMID- 30408052 TI - Solar-powered radio tags reveal patterns of post-fledging site visitation in adult and juvenile Tree Swallows Tachycineta bicolor. AB - The availability of small, lightweight tracking devices enhances our ability to study birds during mobile phases of their lives. Tree Swallows Tachycineta bicolor, a model species of wild songbird, are well-studied during their breeding season; but our understanding of their biology at other times of the year, when they are not tied to the fixed location of a nest, is more limited. We developed a lightweight radio tag with no battery (solar nanotag) to study the movements of small animals, and we deployed it to explore the behavior of Tree Swallows after the end of their summer breeding season. We tagged 32 breeding adult swallows and 36 juveniles and monitored their presence and absence at the breeding site during the post-fledging period. Although our observations are based on very small sample sizes, the tags revealed previously unknown patterns in Tree Swallow behavior during the post-breeding season. Some Tree Swallow fledglings continued to visit the site repeatedly in the months following the nesting season, with the latest detection occurring on September 30th; by contrast, all adults had permanently departed by the end of July. These results inform future hypotheses about post-breeding movements in Tree Swallows. But, more generally, the detection of tagged swallows on their distant wintering grounds, seven months after tagging, indicates the potential of studying small passerine movements throughout their entire lifetimes, and suggests a rich array of applications for these "Life Tags" to study the movements of small animals world-wide. PMID- 30408053 TI - Temporal changes in genetic diversity and forage yield of perennial ryegrass in monoculture and in combination with red clover in swards. AB - Agricultural grasslands are often cultivated as mixtures of grasses and legumes, and an extensive body of literature is available regarding interspecific interactions, and how these relate to yield and agronomic performance. However, knowledge of the impact of intraspecific diversity on grassland functioning is scarce. We investigated these effects during a 4-year field trial established with perennial ryegrass (Lolium perenne) and red clover (Trifolium pratense). We simulated different levels of intraspecific functional diversity by sowing single cultivars or by combining cultivars with contrasting growth habits, in monospecific or bispecific settings (i.e. perennial ryegrass whether or not in combination with red clover). Replicate field plots were established for seven seed compositions. We determined yield parameters and monitored differences in genetic diversity in the ryegrass component among seed compositions, and temporal changes in the genetic composition and genetic diversity at the within plot level. The composition of cultivars of both species affected the yield and species abundance. In general, the presence of clover had a positive effect on the yield. The cultivar composition of the ryegrass component had a significant effect on the yield, both in monoculture, and in combination with clover. For the genetic analyses, we validated empirically that genotyping-by-sequencing of pooled samples (pool-GBS) is a suitable method for accurate measurement of population allele frequencies, and obtained a dataset of 22,324 SNPs with complete data. We present a method to investigate the temporal dynamics of cultivars in seed mixtures grown under field conditions, and show how cultivar abundances vary during subsequent years. We screened the SNP panel for outlier loci, putatively under selection during the cultivation period, but none were detected. PMID- 30408054 TI - Reliability, validity and responsiveness of the Chinese version of the Rotator Cuff Quality of Life Index (RC-QOL) in patients with rotator cuff disorders. AB - BACKGROUND: The Rotator Cuff Quality of Life Index (RC-QOL) is a scale designed to evaluate the impact of rotator cuff (RC) disorders on the general quality of life of patients. Our study aims to adapt the RC-QOL into Chinese and to assess its reliability, validity and responsiveness in Chinese patients with RC disorders. METHODS: First, we developed the Chinese version of RC-QOL (C-RC-QOL) through a five-step procedure. Next, the recruited patients gave three rounds of responses to the C-RC-QOL, Medical Outcomes Study Short Form 36 (SF-36) and Oxford Shoulder Score scales (OSS). Then, we calculated the Cronbach's alpha, standard error of measurement (SEM), minimally detectable change (MDC), intra class correlation coefficient (ICC), Pearson's correlation coefficient (r), effect size (ES) and standardized response mean (SRM) to evaluate the reliability, validity and responsiveness of the C-RC-QOL respectively. The unidimensionality of each subscale was assessed by principal component analysis (PCA) of the residuals. RESULTS: Overall, 124 patients with RC disorders successfully completed the first two rounds of the scales, and 108 patients completed the last round of the scales. Good or excellent internal consistency (Cronbach's alpha = 0.953) was found in the overall scale and subscales of the C RC-QOL, and good or excellent test-retest reliability (ICC = 0.854) was found as well. The SEM and MDC values of the C-RC-QOL were 4.6 and 12.8 respectively. Moderate, good or excellent correlations (r = 0.452-0.839) were obtained between the physical subscales of the C-RC-QOL and the OSS, as well as the physical subscales of the SF-36; similar results were obtained between the emotion subscale of the C-RC-QOL and the mental subscales of the SF-36 (r = 0.490-0.733), which, illustrated the good validity of the C-RC-QOL. In addition, high responsiveness was observed in the overall scale and subscales of the C-RC-QOL (ES = 1.77, SRM = 1.98). The unidimensionality of five subscales was respected according to PCA of the residuals. CONCLUSIONS: The C-RC-QOL scale is reliable, valid and responsive for the evaluation of Chinese-speaking patients with RC disorders and it would be an effective instrument. PMID- 30408055 TI - Ability to use oral fluid and fingerstick HIV self-testing (HIVST) among South African MSM. AB - BACKGROUND: HIV self-testing (HIVST) may increase HIV testing uptake, facilitating earlier treatment for key populations like MSM who experience barriers accessing clinic-based HIV testing. HIVST usability among African MSM has not been explored. METHODS: We assessed usability of oral fluid (OF) and fingerstick (FS; blood) HIVST kits during three phases among MSM with differing degrees of HIVST familiarity in Mpumalanga, South Africa. In 2015, 24 HIVST-naive MSM conducted counselor-observed OF and FS HIVST after brief demonstration. In 2016 and 2017, 45 and 64 MSM with experience using HIVST in a pilot study chose one HIVST to conduct with a counselor-observer present. In addition to written, the latter group had access to video instructions. We assessed frequency of user errors and reported test use ease, changes in error frequency by phase, and covariates associated with correct usage using log-Poisson and Gaussian generalized estimating equations. RESULTS: Among OF users (n = 57), 15-30% committed errors in each phase; however, observers consistently rated participants as able to test alone. Among FS users (n = 100), observers noted frequent errors, most commonly related to blood collection and delivery. We found suggestive evidence (not reaching statistical significance) that user errors decreased, with 37.5%, to 28.1%, and 18.2% committing errors in phases I, II, and III, respectively (p-value:0.08), however observer concerns remained constant. Ease and confidence using HIVST increased with HIV testing experience. Participants using three HIVST were more likely (RR:1.92, 95% CI:1.32, 2.80) to report ease compared to those without prior HIVST experience. Never testers (RR:0.66, 95% CI:0.44-0.99) reported less ease performing HIVST compared to participants testing in the past six months. CONCLUSIONS: MSM were able to perform the OF test. Fingerstick test performance was less consistent; however preference for fingerstick was strong and performance may improve with exposure and instructional resources. Continued efforts to provide accessible instructions are paramount. PMID- 30408056 TI - Metabolic risk factors in young adults infected with HIV since childhood compared with the general population. AB - AIM: Metabolic risk factors are poorly documented for the first generation of young adults who have lived with HIV since childhood. We compared their metabolic profile with that of adults of same age from the general population. METHODS: We conducted a cross-sectional analysis of data from two populations: (1) COVERTE (ANRS-CO19), a French national cohort of 18 to 30-year-old patients HIV-infected since childhood, and (2) ENNS, a national cross-sectional population-based household survey on nutrition. Body mass index (BMI), blood pressure, waist circumference, fasting glucose, triglycerides, and HDL-, LDL- and total cholesterol were measured in both studies. Direct standardization on overweight and education level and logistic regression were used to compare the prevalence of metabolic abnormalities between the two populations. RESULTS: Data from 268 patients from COVERTE and 245 subjects from ENNS were analyzed. Tobacco use was similar in both groups. HIV-infected patients had increased mean waist-to-hip ratio and triglycerides to HDL-cholesterol ratio and decreased mean HDL cholesterol as compared to their counterparts from the general population in both genders. In HIV-infected patients, metabolic syndrome was identified in 13.2% of men (95% confidence interval [CI]: 7.1-19.2) and 10.4% (95% CI: 5.4-15.3) of women versus 10.6% (95%CI: 1.5-19.7) and 1.7% (95%CI: 0-4.1) in subjects from the general population, respectively. CONCLUSION: Young adults infected with HIV since childhood had a higher prevalence of dyslipidemia and metabolically detrimental fat distribution than adults of same age of the general population, supporting close monitoring for cardiometabolic diseases. PMID- 30408057 TI - Factors associated with quality of life of people with Myasthenia Gravis. AB - PURPOSE: As most of patients with Myasthenia Gravis have limitations in their physical functioning, many experience changes in psychological states and often have depression. The objective of the current study was to examine the roles of communication with medical professionals, patients' loneliness, and patients' depression, in relation to their effects on the patients' quality of life. METHODS: For 120 patients with MG of 18 years and older, demographic variables, along with communication with medical professionals, loneliness, depression, and quality of life were measured. RESULTS: As a result, people suffering from MG experienced lower quality of life when their career has changed due to the illness. At the same time, depression was a significant predictor of their quality of life, both in physical and mental domains. CONCLUSIONS: The implications for clinical settings and the suggestions for future research are discussed. PMID- 30408058 TI - Variation in regional and landscape effects on occupancy of temperate bats in the southeastern U.S. AB - Habitat loss, wind energy development, and the disease white-nose syndrome are major threats contributing to declines in bat populations in North America. In the southeastern US in particular, the recent arrival of white-nose syndrome and changes in landscape composition and configuration have driven shifts in bat species populations and distributions. Effective management strategies which address these large-scale, community-level threats require landscape-scale analyses. Our objective was to model the relationship between ecoregional and landscape factors and occupancy by all bat species in South Carolina, USA, during summer. We conducted acoustic surveys from mid-May through July 2015 and 2016 and evaluated temporally dynamic occupancy models for eight bat species or species groups at the 100 km2 level. We found significant effects of landscape factors such as ecoregion and forest edge density for three species, but habitat condition effects were not statistically significant for five other species. Thus, for some species, site-use analyses may be more appropriate than larger scale occupancy analyses. However, our occupancy predictions generally matched statewide historical distributions for all species, suggesting our approach could be useful for monitoring landscape-level trends in bat species. Thus, while our scale of study was likely too coarse for assessing fine-scale habitat associations for all bat species, our findings can improve future monitoring efforts, inform conservation priorities, and guide subsequent landscape-scale studies for bat species and community-level responses to global change. PMID- 30408059 TI - News coverage, digital activism, and geographical saliency: A case study of refugee camps and volunteered geographical information. AB - The last several decades have witnessed a shift in the way in which news is delivered and consumed by users. With the growth and advancements in mobile technologies, the Internet, and Web 2.0 technologies users are not only consumers of news, but also producers of online content. This has resulted in a novel and highly participatory cyber-physical news awareness ecosystem that fosters digital activism, in which volunteers contribute content to online communities. While studies have examined the various components of this news awareness ecosystem, little is still known about how news media coverage (and in particular digital media) impacts digital activism. In order to address this challenge and develop a greater understanding of it, this paper focuses on a specific form of digital activism, that of the production of digital geographical content through crowdsourcing efforts. Using refugee camps from around the world as a case study, we examine the relationship between news coverage (via Google news), search trends (via Google trends) and user edit contribution patterns in OpenStreetMap, a prominent geospatial data crowdsourcing platform. In addition, we compare and contrast these patterns with user edit patterns in Wikipedia, a well-known non geospatial crowdsourcing platform. Using Google news and Google trends to derive a measure of thematic public awareness, our findings indicate that digital activism bursts tend to take place during periods of sustained build-up of public awareness deficit or surplus. These findings are in line with two prominent mass communication theories: agenda setting and corrective action, and suggest the emergence of a novel stimulus-awareness-activism framework in today's participatory digital age. Moreover, these findings further complement existing research examining the motivational factors that drive users to contribute to online collaborative communities. This paper brings us one step closer to understanding the underlying mechanisms that drive digital activism in particular in the geospatial domain. PMID- 30408060 TI - Body fat has stronger associations with bone mass density than body mass index in metabolically healthy obesity. AB - OBJECTIVE: The effect of obesity-induced metabolic abnormalities on bone mineral density (BMD) and osteoporosis are well established. However, the association between metabolically healthy obesity (MHO) and BMD remains unclear. Our aim was to investigate whether different obesity phenotypes in MHO were associated with BMD in a cross-sectional study. METHODS: All eligible adults receiving a health examination at the Tri-Service General Hospital from 2010 to 2016 were included. They were categorized based on body mass index (BMI) or percentage body fat (PBF). The associations between BMI or PBF and BMD were analyzed by adjusting for pertinent covariables. RESULTS: Males with normal weight and overweight and females with underweight and normal weight were associated with reduced BMD (beta = 0.221, 95%CI = -0.354, -0.088; beta = -0.155, 95%CI = -0.286, -0.023) (beta = 0.736, 95%CI = -1.043, 0.429; beta = -0.340, 95%CI = -0.567, -0.112), respectively. Females in Q1 had close to significant associations with reduced BMD (beta = -0.253, 95%CI = -0.465, -0.041). Normal weight, overweight, Q2, and Q3 had stronger prediction of low BMD with ORs of 0.402 (95%CI = 0.204-0.791), 0.539 (95%CI = 0.321-0.905), 0.694 (95%CI = 0.490-0.982), and 0.466 (95%CI = 0.342-0.636), respectively. The relationship remained significant in male population that PBF was associated with reduced BMD with ORs of 0.435 (95%CI = 0.203, 0.935), 0.494 (95%CI = 0.247, 0.991), 0.268 (95%CI = 0.120, 0.597) in Q1, Q2, Q3 respectively. CONCLUSION: Increased PBF had a significant association with low BMD in the MHO population. Obesity defined by PBF might be a useful indicator for low BMD. The association between body fat and bone health deserves further investigation regarding the potential pathophysiological mechanisms. PMID- 30408062 TI - More than just co-workers: Presence of humanoid robot co-worker influences human performance. AB - Does the presence of a robot co-worker influence the performance of humans around it? Studies of motor contagions during human-robot interactions have examined either how the observation of a robot affects a human's movement velocity, or how it affects the human's movement variance, but never both together. Performance however, has to be measured considering both task speed (or frequency) as well as task accuracy. Here we examine an empirical repetitive industrial task in which a human participant and a humanoid robot work near each other. We systematically varied the robot behavior, and observed whether and how the performance of a human participant is affected by the presence of the robot. To investigate the effect of physical form, we added conditions where the robot co-worker torso and head were covered, and only the moving arm was visible to the human participants. Finally, we compared these behaviors with a human co-worker, and examined how the observed behavioral affects scale with experience of robots. Our results show that human task frequency, but not task accuracy, is affected by the observation of a humanoid robot co-worker, provided the robot's head and torso are visible. PMID- 30408061 TI - Pneumococcal carriage among sickle cell disease patients in Accra, Ghana: Risk factors, serotypes and antibiotic resistance. AB - BACKGROUND: Pneumococcal carriage is the precursor for development of pneumococcal disease, and is also responsible for transmission of the organism from person-to-person. Individuals with Sickle Cell Disease (SCD) are more likely to develop invasive disease with S. pneumoniae compared to their healthy counterparts and the presentation of disease in the former is usually abrupt and severe. In Africa, little is known about the pneumococcus in relation to people with SCD Sickle Cell Disease (SCD). The aim of the study was to investigate the epidemiology of pneumococcal carriage among SCD patients including the carriage prevalence, risk factors, serotypes and antibiotic resistance. METHOD: This was a cross sectional study involving 402 SCD patients recruited from Korle Bu Teaching Hospital and Princess Marie Louis Hospital in Accra from October 2016 to March 2017. The study subjects included 202 children of the age groups: <=5 years (94), >5-9 years (75), >=10-13 years (33) and 200 adults of the age groups: 14-20 years (46), 21-40 years (112), 41-60 years (25), <= 61 years (17). Nasopharyngeal (NP) swabs were collected from the study participants as well as epidemiological data on demographic, household and clinical features. The NP specimens were cultured for S. pneumoniae and the isolates were serotyped by latex agglutination. Antimicrobial susceptibility tests of the isolates were done by the disc diffusion test and E-test. RESULTS: Prevalence of S. pneumoniae carriage among children and adult SCD patients enrolled in the study were 79/202 (39.1%; 95% CI: 32.3 to 46.2) and 20/200 (10.0%; 95% CI: 6.2 to 15.0) respectively. Risk factors associated with pneumococcal carriage were age (OR = 1.137; 95% CI: 1.036-1.248; p = 0.007) and runny nose (OR = 5.371; 95% CI: 1.760-16.390; p = 0.003). Overall, twenty-six pneumococcal serotypes were isolated from the study participants and the predominant serotype was 6B (10.6%), followed by 23B (8.2%). Among the children, serotype coverage of the 13-valent Pneumococcal Conjugate Vaccine, which is currently used in Ghana was 32.4%. Prevalence of penicillin resistance among the pneumococcal isolates was 37.4% (37/99) and all the penicillin resistant isolates exhibited intermediate penicillin resistance with the exception of one isolate that showed full resistance and was susceptible to ceftriaxone. Prevalence of resistance to the other antibiotics ranged from 2.5% (levofloxacin) to 85% (cotrimoxazole). Multidrug resistance occurred among 34.3% (34/99) of the pneumococcal isolates. CONCLUSION: Pneumococcal carriage was four fold higher in SCD children than adults and was characterized by predominance of non-vaccine serotypes and considerable level of multidrug resistance, though penicillin, cefotaxime and levofloxacin resistance appeared to be very low. PMID- 30408063 TI - The common truncation variant in pancreatic lipase related protein 2 (PNLIPRP2) is expressed poorly and does not alter risk for chronic pancreatitis. AB - A nonsense variant (p.W358X) of human pancreatic lipase related protein 2 (PNLIPRP2) is present in different ethnic populations with a high allele frequency. In cell culture experiments, the truncated protein mainly accumulates inside the cells and causes endoplasmic reticulum stress. Here, we tested the hypothesis that variant p.W358X might increase risk for chronic pancreatitis through acinar cell stress. We sequenced exon 11 of PNLIPRP2 in a cohort of 256 subjects with chronic pancreatitis (152 alcoholic and 104 non-alcoholic) and 200 controls of Hungarian origin. We observed no significant difference in the distribution of the truncation variant between patients and controls. We analyzed mRNA expression in human pancreatic cDNA samples and found the variant allele markedly reduced. We conclude that the p.W358X truncation variant of PNLIPRP2 is expressed poorly and has no significant effect on the risk of chronic pancreatitis. PMID- 30408064 TI - Role of variant allele fraction and rare SNP filtering to improve cellular DNA repair endpoint association. AB - BACKGROUND: Large cancer genome studies continue to reveal new players in treatment response and tumorigenesis. The discrimination of functional alterations from the abundance of passenger genetic alterations still poses challenges and determines DNA sequence variant selection procedures. Here we evaluate variant selection strategies that select homozygous variants and rare SNPs and assess its value in detecting tumor cells with DNA repair defects. METHODS: To this end we employed a panel of 29 patient-derived head and neck squamous cell carcinoma (HNSCC) cell lines, of which a subset harbors DNA repair defects. Mitomycin C (MMC) sensitivity was used as functional endpoint of DNA crosslink repair deficiency. 556 genes including the Fanconi anemia (FA) and homologous recombination (HR) genes, whose products strongly determine MMC response, were capture-sequenced. RESULTS: We show a strong association between MMC sensitivity, thus loss of DNA repair function, and the presence of homozygous and rare SNPs in the relevant FA/HR genes. Excluding such selection criteria impedes the discrimination of crosslink repair status by mutation analysis. Applied to all KEGG pathways, we find that the association with MMC sensitivity is strongest in the KEGG FA pathway, therefore also demonstrating the value of such selection strategies for exploratory analyses. Variant analyses in 56 clinical samples demonstrate that homozygous variants occur more frequently in tumor suppressor genes than oncogenes further supporting the role of a homozygosity criterion to improve gene function association or tumor suppressor gene identification studies. CONCLUSION: Together our data show that the detection of relevant genes or of repair pathway defected tumor cells can be improved by the consideration of allele zygosity and SNP allele frequencies. PMID- 30408065 TI - Real-world PD-L1 testing and distribution of PD-L1 tumor expression by immunohistochemistry assay type among patients with metastatic non-small cell lung cancer in the United States. AB - BACKGROUND: The anti-programmed death receptor-1 (anti-PD-1) pembrolizumab is approved as first-line monotherapy for metastatic non-small cell lung cancer (mNSCLC) with PD-ligand 1 (PD-L1) tumor expression >=50%. Most studies comparing PD-L1 results by immunohistochemistry (IHC) assay type have been conducted by prespecified and, in most cases, highly experienced, trained pathologists; however, knowledge is limited regarding the current use and concordance of PD-L1 assays in the real-world clinical setting. Our aim was to study the distribution of PD-L1 tumor expression by IHC assay type among patients with mNSCLC in US oncology practices. METHODS: This retrospective observational study utilized de identified, longitudinal data from a large US electronic medical record database. Eligible patients were adults (>=18 years) with histologically/cytologically confirmed initial diagnosis of metastatic or recurrent NSCLC from October 2015 through December 2017. We determined PD-L1 testing trends and distribution of PD L1 tumor expression (percentage of tumor cells staining for PD-L1) by IHC assay type. RESULTS: The 12,574 eligible patients (mean age, 69 years) included 6,620 (53%) men and 86% with positive smoking history. Of 4,868 evaluable tests, 3,799 (78%), 195 (4%), 165 (3%), and 709 (15%) used the Agilent 22C3 pharmDx, Agilent 28-8 pharmDx, Ventana PD-L1 (SP142) Assay, and laboratory-developed tests (LDTs, including SP263), respectively. The percentages of tests scoring PD-L1 tumor expression of >=50% were 33%, 32%, 10%, and 23%, respectively. Measured PD-L1 tumor expression varied across the four assay types (chi2 p < 0.001) and across three assay types excluding SP142 (p < 0.001), with no significant difference between 22C3 and 28-8 assays (p = 0.96). The PD-L1 testing rate increased from 18% in the fourth quarter of 2015 to 71% in the fourth quarter of 2017. CONCLUSIONS: In the real-world clinical setting, we observed that measured PD-L1 tumor expression is concordant using the 22C3 and 28-8 assays; however, the SP142 assay and LDTs appear discordant and could underestimate high PD-L1 positivity. Further study is needed to evaluate the association between PD-L1 tumor expression and response to therapy. PMID- 30408066 TI - Associations between three XRCC1 polymorphisms and hepatocellular carcinoma risk: A meta-analysis of case-control studies. AB - Conflicting results have been obtained regarding the association between X-ray repair cross complementation group 1 (XRCC1) and susceptibility to hepatocellular carcinoma (HCC). In this study, associations between HCC and three polymorphisms (Arg194Trp, Arg280His, and Arg399Gln) were evaluated using a meta-analysis approach. PubMed, Web of Science, Cochrane Library, the Chinese National Knowledge Infrastructure, and the Wanfang standard database were systematically searched to identify all relevant case-control studies published through March 2018. A total of 32 case-control studies, including 13 that evaluated Arg194Trp, 14 that evaluated Arg280His, and 26 that evaluated Arg399Gln, were analyzed. In the entire study population, XRCC1 Arg399Gln was significantly associated not only with overall risk of HCC (homozygous model, OR = 1.61, 95% CI: 1.40-1.85, P < 0.05; recessive model, OR = 1.40, 95% CI: 1.23-1.59, P < 0.05) but also with the risk of HCC in Chinese patients (homozygous model, OR = 1.78, 95% CI: 1.53 2.08, P < 0.05; recessive model, OR = 1.47, 95% CI: 1.27-1.70, P < 0.05). Limiting the analysis to studies demonstrating Hardy-Weinberg equilibrium (HWE), the results were consistent and robust. Similarly, a significant association between XRCC1 Arg399Gln and HCC risk was found in healthy controls in the general population but not in hospital controls. Trial sequential analysis (TSA), false positive report probabilities (FPRP), and combined genotype analysis revealed that XRCC1 Arg399Gln is mainly associated with susceptibility to liver cancer. However, there was no association between Arg194Trp or Arg280His and the risk of HCC. These results, indicating that the Arg399Gln polymorphism of XRCC1 is associated with the risk of HCC in the Chinese population, provide a basis for the development of improved detection and treatment approaches. PMID- 30408067 TI - Exploring resting-state functional connectivity invariants across the lifespan in healthy people by means of a recently proposed graph theoretical model. AB - In this paper we investigate the changes in the functional connectivity intensity, and some related properties, in healthy people, across the life span and at resting state. For the explicit computation of the functional connectivity we exploit a recently proposed model, that bases not only on the correlations data provided by the acquisition equipment, but also on different parameters, such as the anatomical distances between nodes and their degrees. The leading purpose of the paper is to show that the proposed approach is able to recover the main aspects of resting state condition known from the available literature, as well as to suggest new insights, perspectives and speculations from a neurobiological point of view. Our study involves 133 subjects, both males and females of different ages, with no evidence of neurological diseases or systemic disorders. First, we show how the model applies to the sample, where the subjects are grouped into 28 different groups (14 of males and 14 of females), according to their age. This leads to the construction of two graphs (one for males and one for females), that can be realistically interpreted as representative of the neural network during the resting state. Second, following the idea that the brain network is better understood by focusing on specific nodes having a kind of centrality, we refine the two output graphs by introducing a new metric that favours the selection of nodes having higher degrees. As a third step, we extensively comment and discuss the obtained results. In particular, it is remarkable that, despite a great overlapping exists between the outcomes concerning males and females, some intriguing differences appear. This motivates a deeper local investigation, which represents the fourth part of the paper, carried out through a thorough statistical analysis. As a result, we are enabled to support that, for two special age groups, a few links contribute in differentiating the behaviour of males and females. In addition, we performed an average-based comparison between the proposed model and the traditional statistical correlation-based approach, then discussing and commenting the main outlined discrepancies. PMID- 30408068 TI - Anti-EGFR anchored paclitaxel loaded PLGA nanoparticles for the treatment of triple negative breast cancer. In-vitro and in-vivo anticancer activities. AB - The aim of the present study is to analyze the viability of anti-EGFR anchored immunonanoparticle (INP) bearing Paclitaxel (PTX) to specifically bind the EGFR protein on the TNBC cells. The NP was prepared by nanoprecipitation and characterized the particle size, charge, entrapment of drug and release of it. The anti-EGFR anchored and the integrity was confirmed by SDS-PAGE. Cytotoxicity and NPs cellular uptake was analyzed with MDA-MB-468 type cancer cells and the EGFR expression was confirmed by PCR, qualitatively and quantitatively. The in vivo antitumor activity of INP was determined by using athymic mice model and targeting efficiency was measured by calculating the PTX accumulation in the tumor plasma. The prepared INP with the size of 336.3 nm and the charge of -3.48 mV showed sustained drug release upto 48 h. The INP showed significant reduction of cancer cell viability of 10.6% for 48 h with 93 fold higher PTX accumulation in the tumor plasma compared with NPs. Based on these reports, we recommend that anti-EGFR anchored PTX loaded NP may have the ability to target the TNBC cells and improve the therapeutic action and subsidize the side effects of PTX for the treatment of TNBC. PMID- 30408069 TI - An estimate of the effect of waiting time in the Danish asylum system on post resettlement employment among refugees: Separating the pure delay effect from the effects of the conditions under which refugees are waiting. AB - We provide an estimate of the effect of refugees' length of waiting time in the Danish asylum system on their subsequent employment using administrative data. In contrast to previous studies, we take into account that refugees' labor market integration is delayed since their labor market access is restricted during the asylum-seeking phase. We find that an additional year of waiting time decreases subsequent employment by 3.2 percentage points on average. This effect is mostly driven by the delay in the labor market engagement among refugees. Waiting time may have an effect on subsequent employment that is additional to the delay effect, and this could be either positive or negative depending on the nature of the conditions under which asylum seekers live while waiting for their cases to be processed. We find that this additional effect is positive and statistically significant until observable individual characteristics are included, at which point it becomes small in magnitude and no longer significant. PMID- 30408070 TI - HIV 2-LTR experiment design optimization. AB - Clinical trials are necessary in order to develop treatments for diseases; however, they can often be costly, time consuming, and demanding to the patients. This paper summarizes several common methods used for optimal design that can be used to address these issues. In addition, we introduce a novel method for optimizing experiment designs applied to HIV 2-LTR clinical trials. Our method employs Bayesian techniques to optimize the experiment outcome by maximizing the Expected Kullback-Leibler Divergence (EKLD) between the a priori knowledge of system parameters before the experiment and the a posteriori knowledge of the system parameters after the experiment. We show that our method is robust and performs equally well if not better than traditional optimal experiment design techniques. PMID- 30408071 TI - Impact of vitamin D and vitamin D receptor on the trophoblast survival capacity in preeclampsia. AB - BACKGROUND: Preeclampsia and intra-uterine growth restriction (IUGR) are major health problems during pregnancy affecting both mother and child. Defective placental development and failure of trophoblast differentiation during pregnancy are important aspects in the pathogenesis of both syndromes. Recent studies have shown that autophagy is involved in the trophoblast survival capacity. As vitamin D has a central role in many cellular processes, we studied the relation of vitamin D and autophagy in those processes of preeclampsia and IUGR. METHODS: Serum and placental samples from four groups of cases; normal term, IUGR, early onset and late-onset preeclampsia, were analyzed for 25(OH)D vitamin D, sFLT1, PGF, LGALS13 in serum and vitamin D receptor (VDR), MAP1LC3B and BECN1 in placental tissues. RESULTS: There was a significant difference in the sFLT1/PGF ratio in preeclamptic cases compared to controls and IUGR. There was a significant difference between these groups in the MAP1LC3B/BECN1 ratio as marker of the trophoblast survival capacity with a significantly reduced ratio in villous trophoblast of early-onset preeclampsia. Maternal vitamin D deficiency was found in all pathological pregnancies combined with significantly reduced staining levels of placental VDR in IUGR. Finally, there was a strong and significant negative correlation between the survival capacity (MAP1LC3B/BECN1) and both maternal vitamin D and placental VDR in the preeclampsia groups. CONCLUSION: Vitamin D and intracellular VDR are strongly related to the trophoblast survival capacity in preeclampsia. PMID- 30408072 TI - Test-retest reliability of task-based and resting-state blood oxygen level dependence and cerebral blood flow measures. AB - Despite their wide-spread use, only limited information is available on the comparative test-retest reliability of task-based functional and resting state magnetic resonance imaging measures of blood oxygen level dependence (tb-fMRI and rs-fMRI) and cerebral blood flow (CBF) using arterial spin labeling. This information is critical to designing properly powered longitudinal studies. Here we comprehensively quantified and compared the test-retest reliability and reproducibility performance of 8 commonly applied fMRI tasks, 6 rs-fMRI metrics and CBF in 30 healthy volunteers. We find large variability in test-retest reliability performance across the different tb-fMRI paradigms and rs-fMRI metrics, ranging from poor to excellent. A larger extent of activation in tb-fMRI is linked to higher between-subject reliability of the respective task suggesting that differences in the amount of activation may be used as a first reliability estimate of novel tb-fMRI paradigms. For rs-fMRI, a good reliability of local activity estimates is paralleled by poor performance of global connectivity metrics. Evaluated CBF measures provide in general a good to excellent test reliability matching or surpassing the best performing tb-fMRI and rs-fMRI metrics. This comprehensive effort allows for direct comparisons of test-retest reliability between the evaluated MRI domains and measures to aid the design of future tb-fMRI, rs-fMRI and CBF studies. PMID- 30408073 TI - Effect of a 20-week physical activity intervention on selective attention and academic performance in children living in disadvantaged neighborhoods: A cluster randomized control trial. AB - OBJECTIVES: To evaluate the effect of a 20-week school-based physical activity intervention program on academic performance and selective attention among disadvantaged South African primary school children. DESIGN: Cluster randomized control trial. METHODS: The study cohort included 663 children from eight primary schools, aged 8-13 years. Data assessment took place between February 2015 and May 2016 following the implementation of a 20-week school-based physical activity program. The d2 test was employed to assess selective attention, while the averaged end-of-year school results (math, life skills, home language, and additional language) were used as an indicator of academic performance. Physical fitness was assessed using the 20-m shuttle run test (VO2 max) and grip strength tests. We controlled for cluster effects, baseline scores in selective attention or academic performance, and potential confounders, such as children's age, gender, socioeconomic status, self-reported physical activity (as determined by a pre-tested questionnaire), body mass index, hemoglobin (as a proxy for anemia, as measured by blood sampling), and soil-transmitted helminth infections (as assessed by the Kato-Katz technique). RESULTS: Our multivariate analysis suggested that the physical activity intervention had a positive effect on academic performance (p = 0.032), while no effect was found on selective attention (concentration performance; p = 0.469; error percentage; p = 0.237). After controlling for potential confounders, the physical activity condition contributed to the maintenance of academic performance, whereas a decrease was observed in learners in the control condition. Furthermore, physically active and fit children tend to have better concentration performance (CP) than their less fit peers (self-reported activity; p<0.016, grip strength; p<0.009, VO2 max p>0.021). CONCLUSION: A 20-week physical activity intervention contributes to the maintenance of academic performance among socioeconomically deprived school children in South Africa. School administrators should ensure that their school staff implements physical activity lessons, which are a compulsory component of the school by the curriculum. PMID- 30408074 TI - A comparison between measured and calculated central venous oxygen saturation in critically ill patients. AB - BACKGROUND: Central venous oxygen saturation (ScvO2) is often used to help to guide resuscitation of critically ill patients. The standard gold technique for ScvO2 measurement is the co-oximetry (Co-oximetry_ScvO2), which is usually incorporated in most recent blood gas analyzers. However, in some hospitals, those machines are not available and only calculated ScvO2 (Calc_ScvO2) is provided. Therefore, we aimed to investigate the agreement between Co oximetry_ScvO2 and Calc_ScvO2 in a general population of critically ill patients and septic shock patients. METHODS: A total of 100 patients with a central venous catheter were included in the study. One hundred central venous blood samples were collected and analyzed using the same point-of-care blood gas analyzer, which provides both the calculated and measured ScvO2 values. Bland and Altman plot, intra-class correlation coefficient (ICC), and Cohen's Kappa coefficient were used to assess the agreement between Co-oximetry_ScvO2 and Calc_ScvO2. Multiple linear regression analysis was performed to investigate the independent explanatory variables of the difference between Co-oximetry_ScvO2 and Calc_ScvO2. RESULTS: In all population, Bland and Altman's analysis showed poor agreement (+4.5 [-7.1, +16.1]%) between the two techniques. The ICC was 0.754 [(95% CI: 0.393-0.880), P< 0.001], and the Cohen's Kappa coefficient, after categorizing the two variables into two groups using a cutoff value of 70%, was 0.470 (P <0.001). In septic shock patients (49%), Bland and Altman's analysis also showed poor agreement (+5.6 [-6.7 to 17.8]%). The ICC was 0.720 [95% CI: 0.222-0.881], and the Cohen's Kappa coefficient was 0.501 (P <0.001). Four independent variables (PcvO2, Co-oximetry_ScvO2, venous pH, and Hb) were found to be associated with the difference between the measured and calculated ScvO2 (adjusted R2 = 0.8, P<0.001), with PcvO2 being the main independent explanatory variable because of its highest absolute standardized coefficient. The area under the receiver operator characteristic curves (AUC) of PcvO2 to predict Co oximetry_ScvO2 >= 70% was 0.911 [95% CI: 0.837-0.959], in all patients, and 0.903 [95% CI: 0.784-0.969], in septic shock patients. The best cutoff value was >= 36 mmHg (sensitivity, 88%; specificity, 83%), in all patients, and >= 35 mmHg (sensitivity, 94%; specificity, 71%) in septic shock patients. CONCLUSIONS: The discrepancy between the measured and calculated ScvO2 is clinically not acceptable. We do not recommend the use of calculated ScvO2 to guide resuscitation in critically ill patients. In situations where the Co-oximetry technique is not available, relying on PcvO2 to predict the measured ScvO2 value above or below 70% could be an option. PMID- 30408076 TI - Temporal changes in diet quality and the associated economic burden in Canada. AB - A high-quality diet is associated with a reduced of risk of chronic disease and all-cause mortality. In this study, we assessed changes in diet quality and the associated economic burden in the Canadian population between 2004 and 2015. We used a prevalence-based cost-of-illness approach. We first calculated the diet quality using the Healthy Eating Index-Canada-2010 (HEI-C-2010) and 24-hour recall data from the Canadian Community Health Surveys (CCHS) on nutrition (CCHS 2004 cycle 2.2 and the CCHS-NU 2015). We then retrieved relative risks of HEI 2010 quintiles for chronic diseases from meta-analyses. Based on the proportions of the population following diets of varying qualities and these relative risks, we computed the population-attributable fractions and attributable costs (direct health care and indirect costs) by survey year (2004 and 2015) as well as by age and sex group. Costs were estimated in 2017 Canadian dollars for comparison purposes. We observed that on average the diet quality of Canadians improved between 2004 and 2015: the proportion of the Canadian population that did not eat a diet of high quality decreased from 83% to 76%. This improvement in diet quality translated in a decrease in economic burden of $133 million, down from $13.21 billion in 2004 to $13.08 billion in 2015. The economic burden decreased by $219 million among males but increased by $86 million among females. It also decreased among people under the age of 65 years ($333 million) but increased among those over 65 years ($ 200 million). Our findings suggest that, despite some temporal improvements, the diet of the majority of Canadians is of poor quality resulting in a high attributable economic burden. Policy and decision makers are encouraged to expand nutrition programs and policies and to specifically target the elderly in order to prevent chronic diseases and reduce health care costs. PMID- 30408075 TI - Molecular characterisation of atypical BSE prions by mass spectrometry and changes following transmission to sheep and transgenic mouse models. AB - The prion hypothesis proposes a causal relationship between the misfolded prion protein (PrPSc) molecular entity and the disease transmissible spongiform encephalopathy (TSE). Variations in the conformation of PrPSc are associated with different forms of TSE and different risks to animal and human health. Since the discovery of atypical forms of bovine spongiform encephalopathy (BSE) in 2003, scientists have progressed the molecular characterisation of the associated PrPSc in order to better understand these risks, both in cattle as the natural host and following experimental transmission to other species. Here we report the development of a mass spectrometry based assay for molecular characterisation of bovine proteinase K (PK) treated PrPSc (PrPres) by quantitative identification of its N-terminal amino acid profiles (N-TAAPs) and tryptic peptides. We have applied the assay to classical, H-type and L-type BSE prions purified from cattle, transgenic (Tg) mice expressing the bovine (Tg110 and Tg1896) or ovine (TgEM16) prion protein gene, and sheep brain. We determined that, for classical BSE in cattle, the G96 N-terminal cleavage site dominated, while the range of cleavage sites was wider following transmission to Tg mice and sheep. For L-BSE in cattle and Tg bovinised mice, a C-terminal shift was identified in the N-TAAP distribution compared to classical BSE, consistent with observations by Western blot (WB). For L-BSE transmitted to sheep, both N-TAAP and tryptic peptide profiles were found to be changed compared to cattle, but less so following transmission to Tg ovinised mice. Relative abundances of aglycosyl peptides were found to be significantly different between the atypical BSE forms in cattle as well as in other hosts. The enhanced resolution provided by molecular analysis of PrPres using mass spectrometry has improved insight into the molecular changes following transmission of atypical BSE to other species. PMID- 30408078 TI - Moral licensing, instrumental apology and insincerity aversion: Taking Immanuel Kant to the lab. AB - Moral licensing, equivalently called "self-licensing", is the instrumental use of a Good Act to cover up a Bad Act. This paper's thesis is that "instrumental apology" i.e., bad-faith apology, is a case of moral licensing. A decision maker may issue an apology (Good Act) after committing a Bad Act, but if the decision maker uses the apology instrumentally, he or she is using the apology to justify the Bad Act. Hence, the apology is insincere. Sincerity is the fine line between a good-faith apology or, more generally, a Good Act, on one hand, and an instrumental apology or, more generally, moral licensing, on the other. In this light, moral licensing should be separated from genuine apology that attains moral equilibrium, which is called in the literature moral "self-regulation' and "conscience accounting." According to Kantian ethics, not just the consequences of an act matter, but also the sincerity with which the act was conducted. This pits Kant against the utilitarian view, which downplays intentions and focuses on consequences. We take Kant to the lab. Participants play a modified ultimatum game, where proposers in some treatments have the option of issuing apology messages and responders have both costly and costless options for rewarding or punishing proposers. We introduce different treatments of the apology message to allow responders to form doubts about the sincerity of the apology messages. Our results support the Kantian position: responders, once they become suspicious of the sincerity of the proposers' apology, exhibit "insincerity aversion" and punish proposers. PMID- 30408077 TI - Space and time in episodic memory: Effects of linearity and directionality on memory for spatial location and temporal order in children and adults. AB - Episodic memory is a critical capacity that involves remembering past events along with their spatial and temporal contexts. Relatively little is known about the relations between spatial and temporal information in long-term memory in children or adults. The present research examined the influence of the mental timeline (linear horizontal display extending from the left to right direction for English speakers) on memory for events and their spatial and temporal features in 7-year-olds, 9-year-olds, 11-year-olds and young adults (N = 146). During encoding, participants studied triplets of objects, varying on two dimensions of the mental timeline: linearity (whether objects were presented in linear succession or not) and direction (whether objects were presented from left to-right or right-to-left). After a delay, during retrieval, participants were tested on their memory for individual objects, and either the spatial location or temporal order of the objects. We found that overall accuracy for spatial location was higher than accuracy for temporal order, and there was a parallel developmental trajectory for both these aspects of memory. Across age groups we found that memory for temporal order, but not spatial location, was influenced by linearity and direction (i.e., match to mental timeline). Thus, in both children and adults the spatiotemporal mental timeline supported memory for temporal order, converging with predictions generated within domains of language and thought and enhancing our understanding of how space and time are represented in the mind. PMID- 30408079 TI - Cost-effectiveness of screening for chronic hepatitis B and C among migrant populations in a low endemic country. AB - BACKGROUND: Chronic infection with hepatitis B or C virus (HBV/HCV) can progress to cirrhosis, liver cancer, and even death. In a low endemic country as the Netherlands, migrants are a key risk group and could benefit from early diagnosis and antiviral treatment. We assessed the cost-effectiveness of screening foreign born migrants for chronic HBV and/or HCV using a societal perspective. METHODS: The cost-effectiveness was evaluated using a Markov model. Estimates on prevalence, screening programme costs, participation and treatment uptake, transition probabilities, healthcare costs, productivity losses and utilities were derived from the literature. The cost per Quality Adjusted Life Year (QALY) gained was estimated and sensitivity analyses were performed. RESULTS: For most migrant groups with an expected high number of chronically infected cases in the Netherlands combined screening is cost-effective, with incremental cost effectiveness ratios (ICERs) ranging from ?4,962/QALY gained for migrants originating from the Former Soviet Union and Vietnam to ?9,375/QALY gained for Polish migrants. HBV and HCV screening proved to be cost-effective for migrants from countries with chronic HBV or HCV prevalence of >=0.41% and >=0.22%, with ICERs below the Dutch cost-effectiveness reference value of ?20,000/QALY gained. Sensitivity analysis showed that treatment costs influenced the ICER for both infections. CONCLUSIONS: For most migrant populations in a low-endemic country offering combined HBV and HCV screening is cost-effective. Implementation of targeted HBV and HCV screening programmes to increase early diagnosis and treatment is important to reduce the burden of chronic hepatitis B and C among migrants. PMID- 30408080 TI - Anemia and its association with coffee consumption and hookworm infection among pregnant women attending antenatal care at Debre Markos Referral Hospital, Northwest Ethiopia. AB - BACKGROUND: Anemia in pregnancy is a major public health concern worldwide, especially in developing countries. Thus, there is a need of having current information and local data on the prevalence of anemia and associated factors during pregnancy to help inform preventive programmes. The aim of this study was to assess the prevalence of anemia and associated factors among pregnant women attending antenatal care at Debre Markos Referral Hospital, Northwest Ethiopia. METHODS: An institution based cross-sectional study was conducted at Debre Markos Referral Hospital in July and August 2016. A total of 234 randomly-selected pregnant women took part in the study. Data on sociodemographic factors, environmental and sanitation factors, reproductive factors, and nutrition related characteristics were collected using a structured questionnaire. Hemoglobin level was determined using hematological analyzer (Cell Dyn 1800) machine. The stool sample was collected to identify intestinal parasitic infections. Statistical analysis was done using logistic regression. The p value of less than 0.05 at 95% confidence interval was considered statistically significant. RESULTS: The overall prevalence of anemia among pregnant women was 11.5% (95% CI: 8.2%- 14.9%). The result of multivariable analysis revealed that, coffee consumption [AOR = 2.91; 95% CI (1.63, 8.78)], and hookworm infection [AOR = 2.65; 95% CI (1.48, 4.72)] were factors significantly associated with anemia among pregnant women. CONCLUSION: Anemia is of public health concern among pregnant women in the study area. All pregnant women coming to antenatal clinics should be screened and treated routinely for intestinal parasitic infection. Pregnant women should limit coffee consumption, and avoid drinking coffee with meals. PMID- 30408081 TI - Prognostic function to estimate the probability of meaningful clinical improvement after surgery - Results of a prospective multicenter observational cohort study on patients with lumbar spinal stenosis. AB - BACKGROUND: Approximately two thirds of patients with lumbar spinal stenosis (LSS) who undergo surgical treatment benefit from the surgery. The objective of this study was to derive a prognostic probability function (PPF) to identify patients with a high probability of post-surgical improvement because there is currently no method available. METHODS: In this multicenter, prospective, observational study, we collected data from eight medical centers in Switzerland in which patients underwent surgery for LSS. The endpoints were meaningful clinically important differences (MCID) in pain and disability one year after baseline. We developed a PPF named PROCESS (PostopeRative OutComE Spinal Stenosis), based on a large set of prognostic indicators extracted from the literature. The PPF was derived using data from a random subset of two thirds of the patients and validated in the remaining third. We addressed overfitting by shrinking the regression coefficients. The area under the ROC curve (AUC) and calibration determined the accuracy of the PPF. RESULTS: In this study, 452 LSS patients received surgery. 73% of the 300 patients in the derivation subset reached an MCID in pain and 68% reached an MCID in disability. The corresponding values were 70% and 63% in the validation subset, respectively. In the derivation subsample, the AUC was 0.64 (95% CI 0.57 to 0.71) for of the PPF predicting MCID in pain and 0.71 (0.64 to 0.77) for MCID in disability, after shrinkage. The corresponding numbers were 0.62 (0.52 to 0.72) and 0.70 (0.60 to 0.79) in the validation subsample, and the PPF showed good calibration. CONCLUSIONS: Surgical treatment for patients with lumbar spinal stenosis is being performed with increasing frequency. PROCESS is conditional on the individual pattern of preoperatively available prognostic indicators, and may be helpful for clinicians in counselling patients and in guiding the discussion on individual treatment decision in the era of personalized medicine. PMID- 30408083 TI - A hybrid approach based on the analytic hierarchy process and 2-tuple hybrid ordered weighted averaging for location selection of distribution centers. AB - Distribution centers (DCs) are an important part of the modern logistics system. The selection of a location for a DC is significant for saving costs and reducing externalities caused by distribution. In this paper, we propose a new hybrid method based on the analytic hierarchy process (AHP) and 2-tuple hybrid ordered weighted averaging (THOWA) to select the location of a DC in a megacity. First, we propose a new set of evaluation criteria integrating economic, political, social and ecological information based on the characteristics of Chinese megacities. Second, subjective criteria weights are calculated by AHP combining the evaluation of logistics experts. Third, experts from academia, enterprise and government assess the performance of alternatives. In addition, the overall evaluation values are aggregated by an improved THOWA operator to rank the alternatives. Finally, we conduct a sensitivity analysis to investigate the influence of criteria weights on the decision-making process. The proposed method is novel and addresses the uncertainty under limited quantitative information, which has the advantages of avoiding information loss and distortion problems in the integrating process and operating linguistic evaluation information effectively. The proposed method can be practically applied by municipal planning departments in deciding on the location of new DCs. A numerical application of the proposed method is provided. PMID- 30408082 TI - Characterization of sensory neuronal subtypes innervating mouse tongue. AB - The tongue is uniquely exposed to water-soluble environmental chemicals that may lead to injury or tumorigenesis. However, comparatively little research has focused on the molecular and functional organization of trigeminal ganglia (TG) afferent neurons innervating the tongue. The current study identified and characterized lingual sensory neurons based on a neuronal subtype classification previously characterized in the dorsal root ganglion (DRG) neurons. We employed immunohistochemistry on transgenic reporter mouse lines as well as single-cell PCR of known markers of neuronal subtypes to characterize neuronal subtypes innervating the tongue. Markers expressed in retrogradely labeled TG neurons were evaluated for the proportion of neurons expressing each marker, intensity of expression, and overlapping genes. We found that tongue-innervating sensory neurons primarily expressed CGRP, TRPV1, TrkC, 5HT3A and Parvalbumin. These markers correspond to peptidergic and a subgroup of non-peptidergic C nociceptors, peptidergic A nociceptors, proprioceptors and myelinated low threshold mechanoreceptors (LTMRs). Interestingly, as reported previously, we also found several differences between TG and DRG neurons indicating the need for single-cell sequencing of neuronal types based on tissue type within all TG as well as DRG neurons. PMID- 30408086 TI - First U-Pb zircon ages for late Miocene Ashfall Konservat-Lagerstatte and Grove Lake ashes from eastern Great Plains, USA. AB - This paper documents the first U-Pb zircon ages for Ashfall Fossil Beds (Nebraska, USA), a terrestrial Konservat-Lagerstatte mass-death assemblage that is arguably the most diverse of its type and age. The Ashfall tephra was correlated with ignimbrites from the Bruneau-Jarbidge volcanic field (12.7-10.5 Ma) in southwest Idaho based on geochemical analysis. The methods and geochemical data supporting the original age assessment of the ash bed, however, were never published, and there has been a persistent misconception that dateable heavy minerals (e.g., zircon) are absent. Notwithstanding, we recovered abundant zircons from Ashfall Fossil Beds, and from an ash bed ~6 km to the southeast at Grove Lake, Nebraska, and analyzed them through LA-ICP-MS. Our new zircon U-Pb age of 11.86 +/- 0.13 Ma substantiates correlation of the Ashfall Fossil Beds deposit to tuffs originating from the Bruneau-Jarbidge caldera (~12.7-10.5 Ma). Our U-Pb zircon age of 6.42 +/- 0.06 Ma for the Grove Lake ash bed coincides with supervolcanic activity in the Heise volcanic field (6.6-4.3 Ma) in eastern Idaho. These new dates improve age constraints of strata comprising the Ogallala Group and the important paleontological site. Moreover, we find that detrital and airfall zircons are unevenly distributed in the stratified ash beds we describe herein and presumably in similar deposits worldwide. Therefore, a higher resolution sampling scheme is necessary in such cases. PMID- 30408085 TI - Correlation of Vascular Endothelial Growth Factor subtypes and their receptors with melanoma progression: A next-generation Tissue Microarray (ngTMA) automated analysis. AB - INTRODUCTION: Finding new markers to assess prognosis of melanoma without the necessity to perform a surgical interventions is an important goal in melanoma research. The current study aimed to assess the correlation of clinical course and prognosis of primary and metastatic melanoma with expression of VEGF family and their receptors. METHODS: A ngTMA block was made from the randomly selected paraffin tissue blocks of the patients with melanocytic nevi, primary and metastatic melanoma. Then sections cut from ngTMA-block were immunohistochemically stained with proper antibodies. Expression of these proteins was investigated using automated image analysis and compared among the study groups. RESULTS: We analyzed the tissue of 238 patients with following diagnoses: 101 (42.4%) with a diagnosis of nevus, 86 (36.1%) Malignant melanoma and 51 (21.4%) metastasis. Median follow-up time for the malignant lesions was 5.71 years. Among the tested antigen, VEGF-C (p = 0.016), VEGF-R2 (p<0.001) and VEGF-R3 (p = 0.002) were significantly higher expressed in the metastatic tissues. When these scores were assessed in multiple regression models, the only independent factor linked to patient's diagnosis was VEGF-R2 (p<0.001). In addition, groups of highly correlated variables (VEGF-C and VEGF-R3, VEGF-A and VEGF-R1) were found to form separate sub-clusters. On the other side, high values of VEGF-C were associated with both overall and disease-free survival with a statically significant HR of 2.76 (95% CI: 1.27, 5.98; p = 0.01) and 2.82 (95%CI: 1.62, 4.91; p<0.001), respectively. CONCLUSIONS: This study shows that VEGF-C and VEGF-R2 might represent new prognostic marker in MM. However, further prospective studies are warranted to test their real efficacy as a prognostic marker. PMID- 30408084 TI - Probabilistic approach for assessing cancer risk due to benzo[a]pyrene in barbecued meat: Informing advice for population groups. AB - BACKGROUND: Consumption of meat prepared by barbecuing is associated with risk of cancer due to formation of carcinogenic compounds including benzo[a]pyrene (BaP). Assessment of a population's risk of disease and people's individual probability of disease given specific consumer attributes may direct food safety strategies to where impact on public health is largest. The aim of this study was to propose a model that estimates the risk of cancer caused by exposure to BaP from barbecued meat in Denmark, and to estimate the probability of developing cancer in subgroups of the population given different barbecuing frequencies. METHODS: We developed probabilistic models applying two dimensional Monte Carlo simulation to take into account the variation in exposure given age and sex and in the individuals' sensitivity to develop cancer after exposure to BaP, and the uncertainty in the dose response model. We used the Danish dietary consumption survey, monitoring data of chemical concentrations, data on consumer behavior of frequency of barbecuing, and animal dose response data. FINDINGS: We estimated an average extra lifetime risk of cancer due to BaP from barbecued meat of 6.8 * 10 5 (95% uncertainty interval 2.6 * 10-7 - 7.0 * 10-4) in the Danish population. This corresponds to approximately one to 4,074 extra cancer cases over a lifetime, reflecting wide uncertainty. The impact per barbecuing event on the risk of cancer for men and women of low body weight was higher compared to higher bodyweight. However, the difference due to sex and bodyweight between subgroups are dwarfed by the uncertainty. INTERPRETATION: This study proposes a model that can be applied to other substances and routes of exposure, and allows for deriving the change in risk following a specific change in behaviour. The presented methodology can serve as a valuable tool for risk management, allowing for the formulation of behaviour advice targeted to specific sub-groups in the population. PMID- 30408087 TI - A comparative venomic fingerprinting approach reveals that galling and non galling fig wasp species have different venom profiles. AB - The galling habit represents a complex type of interaction between insects and plants, ranging from antagonism to mutualism. The obligate pollination mutualism between Ficus and fig wasps relies strongly on the induction of galls in Ficus flowers, where wasps' offspring develop. Even though gall induction plays an important role in many insect-plant interactions, the mechanisms that trigger gall formation are still not completely known. Using a fingerprinting approach, we show here that venom protein profiles from galling fig wasps differ from the venom profiles of non-galling species, suggesting the secretion plays different roles according to the type of interaction it is involved in. Each studied cleptoparasitic species had a distinct venom profile, suggesting that cleptoparasitism in fig wasps covers a vast diversity of molecular interactions. Fig wasp venoms are mainly composed of peptides. No low molecular weight compounds were detected by UPLC-DAD-MS, suggesting that such compounds (e.g., IAA and cytokinines) are not involved in gall induction. The differences in venom composition observed between galling and non-galling fig wasp species bring new perspectives to the study of gall induction processes and the role of insect secretions. PMID- 30408088 TI - The beginning of the end: A qualitative study of falls among HIV+ individuals. AB - Falls are an important concern for individuals living with HIV (HIV+). The purpose of this study was to understand perceptions of HIV+ individuals who had fallen regarding what caused their falls, prevention strategies that they used, and the impact of falls on their lives. Qualitative Description was the approach best suited to our study. We conducted in-depth interviews with 21 HIV+ individuals aged 47 to 71 years who had fallen within the past two years and who received care in a primary care/HIV clinic. Participants identified causes of falls as intrinsic (HIV, opportunistic infections, antiretroviral therapy, substance use, polypharmacy) or extrinsic (icy sidewalks, wet floors). Among those who felt that their falls could be prevented, prevention strategies included physical therapy and avoiding extrinsic fall risk factors. Some participants, however, felt that their falls could not be prevented. While some participants responded adaptively to falls, for many, the experience of falling was connected with deep feelings of loss and suffering. For these individuals, falls were understood to be "the beginning of the end" and a source of social isolation, changing family roles, diminished sense of self, and stigma. PMID- 30408089 TI - Measuring radiation-induced DNA damage in Cryptococcus neoformans and Saccharomyces cerevisiae using long range quantitative PCR. AB - DNA damage has been considered to be the universal critical lesion in cells after exposure to ionizing radiation. Measuring radiation-induced DNA damage is important to understand the mechanisms of radiation-induced toxicity and monitor DNA damage repairs. Currently the most widely used methods to measure DNA damage are pulsed-field gel electrophoresis (PFGF) and single-cell gel electrophoresis (also known as the comet assay), both of which are technically challenging and time consuming. Long range quantitative polymerase chain reaction (LR-QPCR) has been used successfully to measure nuclear and mitochondrial DNA damage in mammalian and several model organism cells. The principle of this assay is that DNA lesions will slow down or block the progression of DNA polymerase. Therefore, the amplification efficiency of DNA with fewer lesions will be higher than DNA with more lesions under the same reaction condition. Here, we developed the LR QPCR assay primers and reaction conditions to quantify DNA damage in Cryptococcus neoformans (C. neoformans) and Saccharomyces cerevisiae (S. cerevisiae) after gamma ray exposure. Under these conditions, long DNA targets of C. neoformans H99 and S. cerevisiae BY4741 (17.6 and 16.4 kb for nuclear DNA and 15.3 and 14.6 kb for mitochondrial DNA) were quantitatively amplified using extracted DNA templates, respectively. Two short mitochondrial DNA targets of these two species (207 bp and 154 bp) were also quantitatively amplified and used to monitor the number of mitochondria. Using the LR-QPCR method, we showed that the frequency of radiation-induced mitochondrial and nuclear DNA lesions had a significant linear correlation with the radiation doses (from 500 Gy to 3000 Gy) in both species. Furthermore, the faster disappearance of DNA damage detected in C. neoformans H99S strain compared to H99 strain may help to explain the different radiation sensitivity of these two strains. In summary, we developed a simple, sensitive method to measure radiation-induced DNA damage, which can greatly facilitate the study of radiation-induced toxicity and can be widely used as a dosimetry in radiation-induced cell damage. PMID- 30408091 TI - Correlation and the time interval over which the variables are measured - A non parametric approach. AB - It is known that when one (or both) variable is multiplicative, the choice of differencing intervals (n) (for example, differencing interval of n = 7 means a weekly datum which is the product of seven daily data) affects the Pearson correlation coefficient (rho) between variables (often asset returns) and that rho converges to zero as n increases. This fact can cause the resulting correlation to be arbitrary, hence unreliable. We suggest using Spearman correlation (r) and prove that as n increases Spearman correlation tends to a limit which only depends on Pearson correlation based on the original data (i.e., the value for a single period). In addition, we show, via simulation, that the relative variability (CV) of the estimator of rho increases with n and that r does not share this disadvantage. Therefore, we suggest using Spearman when one (or both) variable is multiplicative. PMID- 30408090 TI - Recovery planning towards doubling wild tiger Panthera tigris numbers: Detailing 18 recovery sites from across the range. AB - With less than 3200 wild tigers in 2010, the heads of 13 tiger-range countries committed to doubling the global population of wild tigers by 2022. This goal represents the highest level of ambition and commitment required to turn the tide for tigers in the wild. Yet, ensuring efficient and targeted implementation of conservation actions alongside systematic monitoring of progress towards this goal requires that we set site-specific recovery targets and timelines that are ecologically realistic. In this study, we assess the recovery potential of 18 sites identified under WWF's Tigers Alive Initiative. We delineated recovery systems comprising a source, recovery site, and support region, which need to be managed synergistically to meet these targets. By using the best available data on tiger and prey numbers, and adapting existing species recovery frameworks, we show that these sites, which currently support 165 (118-277) tigers, have the potential to harbour 585 (454-739) individuals. This would constitute a 15% increase in the global population and represent over a three-fold increase within these specific sites, on an average. However, it may not be realistic to achieve this target by 2022, since tiger recovery in 15 of these 18 sites is contingent on the initial recovery of prey populations, which is a slow process. We conclude that while sustained conservation efforts can yield significant recoveries, it is critical that we commit our resources to achieving the biologically realistic targets for these sites even if the timelines are extended. PMID- 30408092 TI - Effects of pepsin and pepstatin on reflux tonsil hypertrophy in vitro. AB - There is evidence that pepsin can aggravate tonsil hypertrophy. Pepstatin is a potent inhibitor of pepsin activity and could protect patients against reflux tonsil hypertrophy by inhibiting pepsin. We examined the effects of pepstatin on the development of tonsil hypertrophy to investigate pepsin's role in the pathogenesis of tonsil lesions. We investigated whether pepstatin suppresses pepsin-mediated lymphocyte proliferation in tonsil hypertrophy. Forty-nine children with tonsil hypertrophy and twenty-two adults with tonsillitis were recruited to the study prior to surgery. Tonsil tissue from each patient was harvested and assessed for changes in the number of lymphocytes and macrophages in the presence of pepsin and pepstatin. We found that the proportions of CD4- and CD14-positive cells were significantly lower (p < 0.05), but that the proportions of CD19- and CD68-positive cells were significantly higher (p < 0.05), in children than in adults. There were significantly more CD4-positive cells after pepsin treatment, but these numbers were reduced by pepstatin. The levels of both interleukin-2 (IL-2) and interferon gamma (IFN-gamma) increased significantly in response to pepsin, but were reduced when pepsin was inhibited by pepstatin. The level of IL-10 is reduced in pepsin-treated CD4 cells and the level is restored by pepstatin. IL-2 blocking reduced the increased CD4 cell number by pepsin. But, an additive or a synergic effect is not founded in combined with IL-2 blocking and pepstatin. Pepsin-positive cells did not co localize with CD20 and CD45 cells, but they were found surrounding CD20- and CD45 positive hypertrophic tonsil cells. Pepsin-positive cells co-localized with CD68 positive cells. It is probable that pepsin from extraesophageal reflux aggravates tonsil hypertrophy and pepstatin exerts a protective effect by inhibiting pepsin activity. PMID- 30408093 TI - Influence of hypoxic stimulation on angiogenesis and satellite cells in mouse skeletal muscle. AB - We clarified in our previous study that hypoxic training promotes angiogenesis in skeletal muscle, but the mechanism of angiogenesis in skeletal muscle remains unknown. In this study, we investigated the influence of differences in hypoxia exposure on angiogenesis in skeletal muscles at differing ages and metabolic characteristics at which the production of reactive oxygen species and nitric oxide may differ. Ten-week-old (young) and 20-month-old (old) mice were separated into control (N), continuous hypoxia (H), and intermittent hypoxia (IH) groups. The H group was exposed to 16% O2 hypoxia for 5 days and the IH group was exposed to 16% O2 hypoxia at one-hour intervals during the light period for 5 days. After completion of hypoxia exposure, the soleus and gastrocnemius muscles were immediately excised, and mRNA expression of angiogenesis- and satellite cell related genes was investigated using real-time RT-PCR. In addition, muscle fiber type composition, muscle fiber area, number of satellite cells, and capillary density were measured immunohistochemically. In the young soleus muscle, the muscle fiber area was decreased in the H group, and mRNA expression of satellite cell activation-related MyoD, MHCe, and BDNF was significantly increased. On the other hand, in the old soleus muscle, nNOS and VEGF-A mRNA expression, and the capillary density were significantly increased in the H group. In the superficial portion of the gastrocnemius, mRNA expression of FGF2, an angiogenic factor secreted by satellite cells, was significantly increased in the young IH group. In addition, a positive correlation between VEGF-A mRNA expression and nNOS mRNA expression in the soleus muscle and eNOS mRNA expression in the superficial portion of the gastrocnemius was noted. These data demonstrated that age, hypoxia exposure method and muscle metabolic characteristics are related, which results in significant differences in angiogenesis. PMID- 30408094 TI - Whole brain and deep gray matter atrophy detection over 5 years with 3T MRI in multiple sclerosis using a variety of automated segmentation pipelines. AB - BACKGROUND: Cerebral atrophy is common in multiple sclerosis (MS) and selectively involves gray matter (GM). Several fully automated methods are available to measure whole brain and regional deep GM (DGM) atrophy from MRI. OBJECTIVE: To assess the sensitivity of fully automated MRI segmentation pipelines in detecting brain atrophy in patients with relapsing-remitting (RR) MS and normal controls (NC) over five years. METHODS: Consistent 3D T1-weighted sequences were performed on a 3T GE unit in 16 mildly disabled patients with RRMS and 16 age-matched NC at baseline and five years. All patients received disease-modifying immunotherapy on study. Images were applied to two pipelines to assess whole brain atrophy [brain parenchymal fraction (BPF) from SPM12; percentage brain volume change (PBVC) from SIENA] and two other pipelines (FSL-FIRST; FreeSurfer) to assess DGM atrophy (thalamus, caudate, globus pallidus, putamen). MRI change was compared by two sample t-tests. Expanded Disability Status Scale (EDSS) and timed 25-foot walk (T25FW) change was compared by repeated measures proportional odds models. RESULTS: Using FreeSurfer, the MS group had a ~10-fold acceleration in on-study volume loss than NC in the caudate (mean decrease 0.51 vs. 0.05 ml, p = 0.022). In contrast, caudate atrophy was not detected by FSL-FIRST (mean decrease 0.21 vs. 0.12 ml, p = 0.53). None of the other pipelines showed any difference in volume loss between groups, for whole brain or regional DGM atrophy (all p>0.38). The MS group showed on-study stability on EDSS (p = 0.47) but slight worsening of T25FW (p = 0.054). CONCLUSIONS: In this real-world cohort of mildly disabled treated patients with RRMS, we identified ongoing atrophy of the caudate nucleus over five years, despite the lack of any significant whole brain atrophy, compared to healthy controls. The detectability of caudate atrophy was dependent on the MRI segmentation pipeline employed. These findings underscore the increased sensitivity gained when assessing DGM atrophy in monitoring MS. PMID- 30408095 TI - Radiobiological effects and proton RBE determined by wildtype zebrafish embryos. AB - The increasing use of proton radiotherapy during the last decade and the rising number of long-term survivors has given rise to a vital discussion on potential effects on normal tissue. So far, deviations from clinically applied generic RBE (relative biological effectiveness) of 1.1 were only obtained by in vitro studies, whereas indications from in vivo trials and clinical studies are rare. In the present work, wildtype zebrafish embryos (Danio rerio) were used to characterize the effects of plateau and mid-SOBP (spread-out Bragg peak) proton radiation relative to that induced by clinical MV photon beam reference. Based on embryonic survival data, RBE values of 1.13 +/- 0.08 and of 1.20 +/- 0.04 were determined four days after irradiations with 20 Gy plateau and SOBP protons relative to 6 MV photon beams. These RBE values were confirmed by relating the rates of embryos with morphological abnormalities for the respective radiation qualities and doses. Besides survival, the rate of spine bending, as one type of developmental abnormality, and of pericardial edema, as an example for acute radiation effects, were assessed. The results revealed that independent on radiation quality both rates increased with time approaching almost 100% at the 4th day post irradiation with doses higher than 15 Gy. To sum up, the applicability of the zebrafish embryo as a robust and simple alternative model for in vivo characterization of radiobiological effects in normal tissue was validated and the obtained RBE values are comparable to previous finding in animal trials. PMID- 30408097 TI - Barriers to clinical research in children with inflammatory bowel disease: The patients' perspective. AB - BACKGROUND: The aim of this study was to determine the proportion of patients' caregivers willing to participate in clinical research and examine the possible barriers against recruitment to clinical research in children with inflammatory bowel disease. METHODS: In a cross-sectional study, caregivers and children with inflammatory bowel disease were surveyed via a questionnaire that addressed parents' willingness to participate in clinical studies and factors influencing their willingness to participate. RESULTS: A total of 118 caregivers to children with inflammatory bowel disease [median age 14.5, IQR: 12.0-15.8 years, 60 boys, 61 (52%) with Crohn's disease] who were followed for a median duration of 1.73 years (IQR 0.4-3.6 years) completed the survey. One hundred and four (88.2%) caregivers answered "Definitely" or "Probably" to participate in clinical research while 14 (11.8%) were "Neutral" or "Probably" unwilling to participate (P<0.001). Patients were less likely to participate in clinical research if they had longer disease duration (P = 0.019), or were in clinical relapse (P = 0.03). Parents' education, income, age of children at diagnosis, money incentive, disease relapse and medications at the time of the survey did not have any significant effect on willingness to participate. CONCLUSIONS: The majority of children with inflammatory bowel disease and their caregivers are willing to participate in clinical research. PMID- 30408096 TI - miR-483-5p associates with obesity and insulin resistance and independently associates with new onset diabetes mellitus and cardiovascular disease. AB - Our aim was to identify serum microRNAs (miRNAs) in healthy humans which associate with future onset of both diabetes mellitus and cardiovascular disease. We performed global profiling of 753 mature human miRNAs in serum of 12 pilot subjects followed by measurement of 47 consistently expressed miRNAs in fasting serum of 553 healthy subjects from the baseline exam (1991-1994) of the population based Malmo Diet and Cancer Study Cardiovascular Cohort (MDC-CC), of whom 140 developed diabetes, and 169 cardiovascular diseases during follow-up. We used multivariate logistic regression to test individual miRNAs for association with incident diabetes and cardiovascular disease as compared to control subjects (n = 259). After Bonferroni correction and adjustment for age and sex, each SD increment of log-transformed miR-483-5p was significantly associated with both incident diabetes (OR = 1.48; 95% CI 1.18-1.84, P = 0.001) and cardiovascular disease (OR = 1.40; 95% CI 1.15, 1.72, P = 0.001). In cross sectional analysis, miR-483-5p was correlated with BMI (r = 0.162, P = 0.0001), fasting insulin (r = 0.156, P = 0.0002), HDL (r = -0.099, P = 0.02) and triglycerides (r = 0.11, P = 0.01). Adjustment for these metabolic risk factors, as well as traditional risk factors attenuated the miR-483-5p association with incident diabetes (OR = 1.28 95% CI 1.00-1.64, P = 0.049) whereas its association with incident cardiovascular disease remained virtually unchanged (OR = 1.46 95% CI, 1.18-1.81, P = 0.0005). In conclusion, miR-483-5p associates with both diabetes and cardiovascular disease. The association with diabetes seems partly mediated by obesity and insulin resistance, whereas the association with incident cardiovascular disease is independent of these metabolic factors and traditional cardiovascular disease risk factors. PMID- 30408098 TI - Aphid parasitism and parasitoid diversity in cotton fields in Xinjiang, China. AB - Aphids are major pests of cotton crops in the Xinjiang Uygur Autonomous Region in China, and parasitoids are considered as important natural enemies in regulating aphid populations. However, information on aphid parasitoids in the Xinjiang cotton fields is limited, which hinders the study of aphid-parasitoid interactions and the application of conservation biological control against cotton aphids. In this study, a 3-year survey was conducted in a large geographical range that included three primary cotton planting areas in southern and northern Xinjiang. The population dynamics and the parasitism levels of an assemblage of aphids in the cotton fields were investigated along with the composition of the parasitoid community associated with these aphids. Aphid parasitization varied significantly within both years and seasons, with parasitism levels ranging from 0 to 26%, indicating that there is less effective biological control of parasitoids on aphids under field conditions. Among the primary parasitoids described, Binodoxys communis (Gahan) constituted 95.19% of the parasitoid species, followed by Praon barbatum Mackauer (3.15%), Trioxys asiaticus Telenga (1.01%) and Lysiphlebus fabarum Marshall (0.65%). Significant differences were found in the composition of the primary parasitoid species between the cotton seedling period (June) and the flowering period (July-August), and two more primary aphid parasitoids were found in the seedling period. Twelve hyperparasitoid species belonging to six genera were found in our study, of which Pachyneuron aphidis (Bouche), Syrphophagus species and Dendrocerus laticeps (Hedicke) were the dominant species. The composition of the hyperparasitoid community also differed significantly between the seedling and the flowering periods. The description of this parasitoid community-associated assemblage of aphids in cotton fields will facilitate the study of aphid-parasitoid interactions and promote the development of effective cotton aphid management strategies in Xinjiang. PMID- 30408099 TI - Context-sensitive attention is socialized via a verbal route in the parent-child interaction. AB - The way humans perceive and attend to visual scenes differs profoundly between individuals. This is most compellingly demonstrated for context-sensitivity, the relative attentional focus on focal objects and background elements of a scene, in cross-cultural comparisons. Differences in context-sensitivity have been reported in verbal accounts (e.g. picture descriptions) and in visual attention (e.g., eye-tracking paradigms). The present study investigates (1) if the way parents verbally guide the attention of their children in visual scenes is associated with differences in children's context-sensitivity and (2) if verbal descriptions of scenes are related to early visual attention (i.e., gaze behavior) in 5-year-old children and their parents. Importantly, the way parents verbally described visual scenes to their children was related to children's context-sensitivity, when describing these scenes themselves. This is, we found a correlation in the number of references made to the object versus the background as well as the number of relations made between different elements of a scene. Furthermore, verbal descriptions were closely related to visual attention in adults, but not in children. These findings support our hypotheses that context sensitivity is socialized via a verbal route and that visual attention processes align with acquired narrative structures only later in development, after the preschool years. PMID- 30408100 TI - Eustachian tube dysfunction: A diagnostic accuracy study and proposed diagnostic pathway. AB - BACKGROUND AND AIMS: Eustachian tube dysfunction (ETD) is a commonly diagnosed disorder of Eustachian tube opening and closure, which may be associated with severe symptoms and middle ear disease. Currently the diagnosis of obstructive and patulous forms of ETD is primarily based on non-specific symptoms or examination findings, rather than measurement of the underlying function of the Eustachian tube. This has proved problematic when selecting patients for treatment, and when designing trial inclusion criteria and outcomes. This study aims to determine the correlation and diagnostic value of various tests of ET opening and patient reported outcome measures (PROMs), in order to generate a recommended diagnostic pathway for ETD. METHODS: Index tests included two PROMs and 14 tests of ET opening (nine for obstructive, five for patulous ETD). In the absence of an accepted reference standard two methods were adopted to establish index test accuracy: expert panel diagnosis and latent class analysis. Index test results were assessed with Pearson correlation and principle component analysis, and test accuracy was determined. Logistic regression models assessed the predictive value of grouped test results. RESULTS: The expert panel diagnosis and PROMs results correlated with each other, but not with ET function measured by tests of ET opening. All index tests were found to be feasible in clinic, and acceptable to patients. PROMs had very poor specificity, and no diagnostic value. Combining the results of tests of ET function appeared beneficial. The latent class model suggested tympanometry, sonotubometry and tubomanometry have the best diagnostic performance for obstructive ETD, and these are included in a proposed diagnostic pathway. CONCLUSIONS: ETD should be diagnosed on the basis of clinical assessment and tests of ET opening, as PROMs have no diagnostic value. Currently diagnostic uncertainty exists for some patients who appear to have intermittent ETD clinically, but have negative index test results. PMID- 30408101 TI - In-hospital mortality is associated with high NT-proBNP level. AB - OBJECTIVE: To compare in-hospital mortality in unselected adult patients according to N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. METHOD: Retrospective study including 3833 adult patients (median age 72 years, 45% women) hospitalized between January 2013 and April 2015 in a Swiss university hospital, with at least one NT-proBNP level measurement during hospitalization. Patients were categorized in quintiles regarding their highest NT-proBNP level. In-hospital mortality and length of stay (LOS) were compared between the highest and the other quintiles. RESULTS: In-hospital mortality rate and LOS (average+/ standard deviation) were higher in the fifth quintile than in the others (6.5% vs 20.3%, and 20.8+/-24.0 vs. 14.9+/-26.5 days respectively, both p<0.001). After multivariate adjustment on age, gender, principal diagnoses, stage 5 renal failure and type of management, patients in the fifth quintile had a hazard ratio [95% confidence interval] of 1.97 [1.57-2.46] for in-hospital mortality and an adjusted LOS (average+/-standard error) of 20.4+/-1.0 vs. 14.9+/-0.5 days for the other quintiles (p<0.001). Further stratification on the main diagnosis at discharge led to similar findings. CONCLUSION: Patients with high levels of NT proBNP are at higher risk of in-hospital mortality and longer LOS, regardless of their clinical characteristics. NT-proBNP level can be a helpful tool for predicting in-hospital patient outcome in unselected adult patients. PMID- 30408102 TI - Low birth weight of institutional births in Cambodia: Analysis of the Demographic and Health Surveys 2010-2014. AB - BACKGROUND: Low birth weight (LBW), an important risk factor for early childhood mortality and morbidity, is a major public health concern in developing countries including Cambodia. This study examined the prevalence of LBW across provinces in Cambodia and changes over time, and identified the factors associated with such condition. METHODS: We used children datasets from Cambodia Demographic and Health Survey (CDHS) 2010 and 2014. There were 3,522 children and 4,991 children in both surveys. Maps illustrating provincial variation in LBW prevalence were constructed. Then, multivariate analyses were conducted to assess factors independently associated with LBW in CDHS 2014. RESULTS: LBW prevalence remained stable between 2010 and 2014, at around 7.0% 95% CI: 5.8-8.1). all institutional births, but within significant variation across provinces. Factors independently associated with LBW included mother's no education compared with those whose mothers had secondary or higher education (AOR = 1.6, 95% CI: 1.0-2.6), babies born to mothers with < 4 antenatal care (ANC) visits during the pregnancy compared with those whose mothers had at least 4 ANC visits (AOR = 2.0, 95% CI: 1.5-2.8). Also, first-born babies were at greater risk of LBW compared with second-born babies (AOR = 1.4, 95% CI: 1.0-2.0). CONCLUSION: The study points to key sub-populations at greater risk and regions where LBW is particularly prevalent. Programs should target provinces where LBW prevalence remains high. Illiterate women, especially those pregnant for the first time should be the program priority. The current national program policy, which recommends that pregnant women have >= 4 ANC visits during pregnancy should be further reinforced and implemented. Program design should consider ways to communicate the importance of making the recommended number of ANC visits among women with no formal education. PMID- 30408103 TI - Loss of CXCL12/CXCR4 signalling impacts several aspects of cardiovascular development but does not exacerbate Tbx1 haploinsufficiency. AB - The CXCL12-CXCR4 pathway has crucial roles in stem cell homing and maintenance, neuronal guidance, cancer progression, inflammation, remote-conditioning, cell migration and development. Recently, work in chick suggested that signalling via CXCR4 in neural crest cells (NCCs) has a role in the 22q11.2 deletion syndrome (22q11.2DS), a disorder where haploinsufficiency of the transcription factor TBX1 is responsible for the major structural defects. We tested this idea in mouse models. Our analysis of genes with altered expression in Tbx1 mutant mouse models showed down-regulation of Cxcl12 in pharyngeal surface ectoderm and rostral mesoderm, both tissues with the potential to signal to migrating NCCs. Conditional mutagenesis of Tbx1 in the pharyngeal surface ectoderm is associated with hypo/aplasia of the 4th pharyngeal arch artery (PAA) and interruption of the aortic arch type B (IAA-B), the cardiovascular defect most typical of 22q11.2DS. We therefore analysed constitutive mouse mutants of the ligand (CXCL12) and receptor (CXCR4) components of the pathway, in addition to ectodermal conditionals of Cxcl12 and NCC conditionals of Cxcr4. However, none of these typical 22q11.2DS features were detected in constitutively or conditionally mutant embryos. Instead, duplicated carotid arteries were observed, a phenotype recapitulated in Tie-2Cre (endothelial) conditional knock outs of Cxcr4. Previous studies have demonstrated genetic interaction between signalling pathways and Tbx1 haploinsufficiency e.g. FGF, WNT, SMAD-dependent. We therefore tested for possible epistasis between Tbx1 and the CXCL12 signalling axis by examining Tbx1 and Cxcl12 double heterozygotes as well as Tbx1/Cxcl12/Cxcr4 triple heterozygotes, but failed to identify any exacerbation of the Tbx1 haploinsufficient arch artery phenotype. We conclude that CXCL12 signalling via NCC/CXCR4 has no major role in the genesis of the Tbx1 loss of function phenotype. Instead, the pathway has a distinct effect on remodelling of head vessels and interventricular septation mediated via CXCL12 signalling from the pharyngeal surface ectoderm and second heart field to endothelial cells. PMID- 30408104 TI - Effects of fructose-containing sweeteners on fructose intestinal, hepatic, and oral bioavailability in dual-catheterized rats. AB - OBJECTIVE: Fructose is commonplace in Western diets and is consumed primarily through added sugars as sucrose or high fructose corn syrup. High consumption of fructose has been linked to the development of metabolic disorders, such as cardiovascular diseases. The majority of the harmful effects of fructose can be traced to its uncontrolled and rapid metabolism, primarily within the liver. It has been speculated that the formulation of fructose-containing sweeteners can have varying impacts on its adverse effects. Unfortunately, there is limited data supporting this hypothesis. The objective of this study was to examine the impact of different fructose-containing sweeteners on the intestinal, hepatic, and oral bioavailability of fructose. METHODS: Portal and femoral vein catheters were surgically implanted in male Wistar rats. Animals were gavaged with a 1 g/kg carbohydrate solution consisting of fructose, 45% glucose/55% fructose, sucrose, glucose, or water. Blood samples were then collected from the portal and systemic circulation. Fructose levels were measured and pharmacokinetic parameters were calculated. RESULTS: Compared to animals that were gavaged with 45% glucose/55% fructose or sucrose, fructose-gavaged animals had a 40% greater fructose area under the curve and a 15% greater change in maximum fructose concentration in the portal circulation. In the systemic circulation of fructose-gavaged animals, the fructose area under the curve was 17% and 24% higher and the change in the maximum fructose concentration was 15% and 30% higher than the animals that received 45% glucose/55% fructose or sucrose, respectively. After the oral administration of fructose, 45% glucose/55% fructose, and sucrose, the bioavailability of fructose was as follows: intestinal availability was 0.62, 0.53 and 0.57; hepatic availability was 0.33, 0.45 and 0.45; and oral bioavailability was 0.19, 0.23 and 0.24, respectively. CONCLUSIONS: Our studies show that the co-ingestion of glucose did not enhance fructose absorption, rather, it decreased fructose metabolism in the liver. The intestinal, hepatic, and oral bioavailability of fructose was similar between 45% glucose/55% fructose and sucrose. PMID- 30408105 TI - Low mucosal-associated invariant T-cell number in peripheral blood of patients with immune thrombocytopenia and their response to prednisolone. AB - Mucosal-associated invariant T (MAIT) cells help protect against certain infections and are related to some autoimmune diseases. Immune thrombocytopenia (ITP) is a relatively rare hematological autoimmune disease associated with low platelet count. We designed a cross-sectional study wherein we examined peripheral blood samples of patients with ITP for the number of MAIT cells (CD3+TCR-Valpha7.2+CD161+IL-18Ralpha+ lymphocytes) and their CD4/8 subsets (by flow cytometry) and levels of cytokines (by multiplex assays). The study cohort included 18 patients with ITP and 20 healthy controls (HCs). We first compared the number of MAIT cells between HCs and patients with ITP and then performed subgroup analysis in patients with ITP. The number of total MAIT cells in patients with ITP was significantly lower than that in HCs (p < 0.0001), and the CD4-CD8+ subset of MAIT cells showed the same trend. Moreover, patients with ITP refractory to prednisolone exhibited a significantly lower number of total MAIT and CD4-CD8+ MAIT cells than patients sensitive to prednisolone. The number of total MAIT and CD4-CD8+ MAIT cells was not correlated with the response to thrombopoietin receptor agonist treatment or with Helicobacter pylori infection. We found no relation between cytokine levels and response to prednisolone treatment, although the levels of IP-10 and RANTES showed a correlation with the number of total MAIT and CD4-CD8+ MAIT cells. In conclusion, total MAIT and CD4 CD8+ MAIT cells in peripheral blood were decreased in patients with ITP, correlating with their response to prednisolone. PMID- 30408106 TI - Regorafenib treatment for patients with hepatocellular carcinoma who progressed on sorafenib-A cost-effectiveness analysis. AB - BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related deaths. Patients with advanced HCC are treated with sorafenib. A recent randomized controlled trial demonstrated a survival benefit for regorafenib treatment in patients with advanced HCC who had progressed on sorafenib. We aimed to evaluate the cost-effectiveness of this approach. METHODS: To evaluate the cost effectiveness of regorafenib, we used a Markov model that incorporates health outcomes, measured by life-years and quality-adjusted life years (QALYs). Drug costs were based on 2017 discounted prices. Model robustness was validated by probabilistic sensitivity analyses using Monte Carlo simulations. RESULTS: The use of regorafenib results in a gain of 19.76 weeks of life (0.38 Life Years) as compared to placebo. When adjusted for quality of life, using regorafenib produced a gain of 0.25 quality adjusted life years (QALYs). The incremental cost-effectiveness ratio for regorafenib compared with best supportive care was between $201,797 and $268,506 per QALY. CONCLUSION: The modest incremental benefit at a relatively high incremental cost of regorafenib treatment suggests that it is not cost-effective at commonly accepted willingness to pay thresholds. PMID- 30408107 TI - Retraction: Protein Isoaspartate Methyltransferase Prevents Apoptosis Induced by Oxidative Stress in Endothelial Cells: Role of Bcl-Xl Deamidation and Methylation. PMID- 30408108 TI - Vulnerable combinations of functional dopaminergic polymorphisms to late-onset treatment resistant schizophrenia. AB - BACKGROUND: A significant portion of patients with schizophrenia who respond to initial antipsychotic treatment acquire treatment resistance. One of the possible pathogeneses of treatment-resistant schizophrenia (TRS) is antipsychotic-induced dopamine supersensitivity psychosis (Ai-DSP). Patients with this disease progression might share some genetic vulnerabilities, and thus determining individuals with higher risks of developing Ai-DSP could contribute to preventing iatrogenic development of TRS. Therefore, we decided to examine whether combinations of functional single nucleotide polymorphisms (SNPs) known to affect dopaminergic functions are related to Ai-DSP development. METHODS: In this case control study, 357 Japanese participants diagnosed with schizophrenia or schizoaffective disorder were recruited and divided into two groups, those with and without Ai-DSP. As functional SNPs, we examined rs10770141 of the tyrosine hydroxylase gene, rs4680 of the catechol-O-methyltransferase gene, and rs1799732 and rs1800497 of the DRD2 genes, which are known to possess strong directional ties to dopamine synthesis, dopamine degradation and post-synaptic DRD2 prevalence, respectively. RESULTS: Among the 357 Japanese patients with schizophrenia or schizoaffective disorder, 130 were classified as Ai-DSP(+) and the other 227 as Ai-DSP(-). Significantly higher proportions of Ai-DSP(+) patients were found to have the SNP combinations of rs10770141/rs4680 (57.9%, OR2.654, 95%CI1.036-6.787, P = 0.048) and rs10770141/rs4680/ rs1800497 (64.3%, OR4.230, 95%CI1.306-13.619, P = 0.029). However, no single SNP was associated with Ai-DSP. CONCLUSIONS: We preliminarily found that carrying particular combinations of functional SNPs, which are related to relatively higher dopamine synthesis and dopamine degradation and lower naive DRD2, might indicate vulnerability to development of Ai-DSP. However, further studies are needed to validate the present results. PMID- 30408109 TI - Risk of adverse treatment outcomes among new pulmonary TB patients co-infected with diabetes in Pakistan: A prospective cohort study. AB - PURPOSE: The escalating burden of diabetes in countries tackling high burden of tuberculosis (TB) has adverse implications for co-infected individuals and National TB control efforts. We aimed to study whether there was a difference in treatment outcome among diabetic and non-diabetic pulmonary TB patients and identify the determinants of treatment outcome among the two groups. MATERIALS AND METHODS: This prospective cohort study recruited new patients of pulmonary tuberculosis (PTB) aged 15 years and above who were diagnosed at and registered with Gulab Devi Chest Hospital, Lahore, Pakistan for anti-tuberculosis treatment (ATT). PTB patients were screened for diabetes using random and fasting blood glucose tests. Diabetic and non-diabetic PTB patients were followed up at second, fifth and sixth month of ATT and 6 months after ATT completion to determine treatment outcome. Multivariate logistic regression analysis was conducted to assess association between various factors and treatment outcome. RESULTS: Of 614 PTB patients, (n = 113 [18%]) were diabetic and (n = 501 [82%]) non-diabetic. Final model showed that diabetics were more likely to experience an unfavorable outcome as compared to non-diabetics (adjusted odds ratio [aOR] = 2.70, 95% Confidence Interval [CI] = 1.30 to 5.59). Other predictors of unfavorable outcome included rural residence (aOR = 1.98, 95% CI = 1.14 to 3.47), body mass index less than 18.50 (aOR = 1.89, 95% CI = 1.03 to 3.47) and being a smoker (aOR = 2.03, 95%CI = 1.04 to 3.94). CONCLUSION: Our study shows unfavorable treatment outcome among diabetic PTB patients. Integrated models of care with screening/testing and management for diabetes and TB could improve TB treatment outcomes. PMID- 30408110 TI - Correction: Quadriceps neuromuscular function in women with patellofemoral pain: Influences of the type of the task and the level of pain. AB - [This corrects the article DOI: 10.1371/journal.pone.0205553.]. PMID- 30408111 TI - Age-related changes in trunk muscle activity and spinal and lower limb kinematics during gait. AB - The influence of age on spinal muscle activation patterns and its relation to kinematics is poorly understood. We aimed at understanding age-related changes to spine and trunk muscle activity in addition to spinal and lower limb kinematics during treadmill walking under various conditions. An observational study was conducted evaluating asymptomatic young (n = 10; 3F, 7M; 26.3+/-2.5yrs) and older (n = 9; 3F, 6M; 67.1+/-4.2yrs) adults' treadmill walking at 2km/h and 4km/h, each at 0, 1, 5, and 10% inclination. Unilateral (right side) electromyography (EMG) was recorded from deep and superficial multifidus (intramuscular) and erector spinae and abdominal obliques (surface); trunk and leg kinematics were also measured. Muscle activity was characterised by peak amplitude and duration of activity, and the time-point of peak amplitude in the gait cycle (0-100%). Peak activation in older adults was lower for the superficial multifidus (p<0.0001) and higher for the thoracolumbar (p<0.001) and lumbar erector spinae (p<0.01). The duration of activation was longer in older adults for all muscles (p<0.05) except the superficial multifidus, and longer during faster walking for all participants. The time-point of peak amplitude in the gait cycle was earlier in older participants for the external obliques (p<0.05). Walking speed appeared to influence muscle activity more than inclination. Older adults used less spine, trunk and lower limb motion, except at the ankle. Age-related differences within multifidus and between paravertebral and trunk muscles were inconsistent. Walking at 4km/h at 5-10% inclination may specifically target the lumbar paravertebral muscles. PMID- 30408112 TI - Lysophosphatidic acid is associated with neuropathic pain intensity in humans: An exploratory study. AB - The underlying mechanisms of neuropathic pain remain to be elucidated. Basic animal research has suggested that lysophosphatidic acids, which are bioactive lipids produced by autotaxin from lysophosphatidylcholine, may play key roles in the initiation and maintenance of neuropathic pain. Here, we investigated the clinical relevance of lysophosphatidic acids signaling on neuropathic pain in humans. Eighteen patients who had been diagnosed with neuropathic pain with varied etiologies participated in the study. Cerebrospinal fluid samples were obtained by lumbar puncture and the concentrations of 12 species of lysophosphatidic acids and lysophosphatidylcholine, autotaxin, and the phosphorylated neurofilament heavy subunit were measured. Pain symptoms were assessed using an 11-point numeric rating scale and the Neuropathic Pain Symptom Inventory regarding intensity and descriptive dimensions of neuropathic pain. The total lysophosphatidic acids were significantly associated with both pain intensity and symptoms. 18:1 and 20:4 lysophosphatidic acids in particular demonstrated the most correlations with dimensions of pain symptoms. Autotaxin and the phosphorylated neurofilament heavy subunit showed no association with pain symptoms. In conclusions, lysophosphatidic acids were significantly associated with pain symptoms in neuropathic pain patients. These results suggest that lysophosphatidic acids signaling might be a potential therapeutic target for neuropathic pain. PMID- 30408113 TI - Retinal blood flow reduction after panretinal photocoagulation in Type 2 diabetes mellitus: Doppler optical coherence tomography flowmeter pilot study. AB - To use a Doppler optical coherence tomography (DOCT) flowmeter to investigate segmental retinal blood flow (RBF) and sum of the segmental RBFs (SRBF) changes after panretinal photocoagulation (PRP) was used to treat type 2 diabetes mellitus with severe diabetic retinopathy (DR). Data from five patients with proliferative DR (PDR) (mean age 51.9 +/- 10.5 years) was analyzed. The vessel diameter (D), average velocity (V), and retinal blood flow (RBF) in veins were measured using a DOCT flowmeter before and four weeks after PRP. Segmental RBF from inferotemporal (IT), superotemporal (ST), inferonasal (IN), and superonasal (SN) veins were measured, and SRBF was defined as the sum of these measurements. All data were analyzed by Wilcoxson test. After PRP, there were statistically significant decreases in the every segmental D, V, RBF (P<0.03) and SRBF (P = 0.002). The other parameters showed no statistically significant differences (P>0.05). The DOCT flowmeter has the potential to be a clinically useful tool to noninvasively evaluate the changes in retinal circulation during PRP in patients with PDR. PMID- 30408114 TI - The calendar of epidemics: Seasonal cycles of infectious diseases. PMID- 30408115 TI - Safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected individuals: HPTN 077, a phase 2a randomized controlled trial. AB - BACKGROUND: Cabotegravir (CAB) is a novel strand-transfer integrase inhibitor being developed for HIV treatment and prevention. CAB is formulated both as an immediate-release oral tablet for daily administration and as a long-acting injectable suspension (long-acting CAB [CAB LA]) for intramuscular (IM) administration, which delivers prolonged plasma exposure to the drug after IM injection. HIV Prevention Trials Network study 077 (HPTN 077) evaluated the safety, tolerability, and pharmacokinetics of CAB LA in HIV-uninfected males and females at 8 sites in Brazil, Malawi, South Africa, and the United States. METHODS AND FINDINGS: HPTN 077 was a double-blind, placebo-controlled phase 2a trial. Healthy individuals age 18-65 years at low HIV risk were randomized (3:1) to receive CAB or placebo (PBO). In the initial oral phase, participants received 1 daily oral tablet (CAB or PBO) for 4 weeks. Those without safety concerns in the oral phase continued and received injections in the injection phase (Cohort 1: 3 injections of CAB LA 800 mg or 0.9% saline as PBO IM every 12 weeks for 3 injection cycles; Cohort 2: CAB LA 600 mg or PBO IM for 5 injection cycles; the first 2 injections in Cohort 2 were separated by 4 weeks, the rest by 8 weeks). The primary analysis included weeks 5 to 41 of study participation, encompassing the injection phase. The cohorts were enrolled sequentially. Primary outcomes were safety and tolerability. Secondary outcomes included pharmacokinetics and events occurring during the oral and injection phases. Between February 9, 2015, and May 27, 2016, the study screened 443 individuals and enrolled 110 participants in Cohort 1 and 89 eligible participants in Cohort 2. Participant population characteristics were as follows: 66% female at birth; median age 31 years; 27% non-Hispanic white, 41% non-Hispanic black, 24% Hispanic/Latino, 3% Asian, and 6% mixed/other; and 6 transgender men and 1 transgender woman. Twenty two (11%) participants discontinued the oral study product; 6 of these were for clinical or laboratory adverse events (AEs). Of those who received at least 1 CAB LA injection, 80% of Cohort 1 and 92% of Cohort 2 participants completed all injections; injection course completion rates were not different from those in the PBO arm. Injection site reactions (ISRs) were common (92% of Cohort 1 and 88% of Cohort 2 participants who received CAB LA reported any ISR). ISRs were mostly Grade 1 (mild) to Grade 2 (moderate), and 1 ISR event (Cohort 1) led to product discontinuation. Grade 2 or higher ISRs were the only AEs reported more commonly among CAB LA recipients than PBO recipients. Two Grade 3 (severe) ISRs occurred in CAB recipients, 1 in each cohort, but did not lead to product discontinuation in either case. Seven incident sexually transmitted infections were diagnosed in 6 participants. One HIV infection occurred in a participant 48 weeks after last injection of CAB LA: CAB was not detectable in plasma both at the time of first reactive HIV test and at the study visit 12 weeks prior to the first reactive test. Participants in Cohort 2 (unlike Cohort 1) consistently met prespecified pharmacokinetic targets of at least 95% of participants maintaining CAB trough concentrations above PA-IC90, and 80% maintaining trough concentrations above 4* PA-IC90. Study limitations include a modest sample size, a short course of injections, and a low-risk study population. CONCLUSIONS: In this study, CAB LA was well tolerated at the doses and dosing intervals used. ISRs were common, but infrequently led to product discontinuation. CAB LA 600 mg every 8 weeks met pharmacokinetic targets for both male and female study participants. The safety and pharmacokinetic results observed support the further development of CAB LA, and efficacy studies of CAB LA for HIV treatment and prevention are in progress. TRIAL REGISTRATION: ClinicalTrials.gov Registry: ClinicalTrials.gov Trial number: NCT02178800. PMID- 30408117 TI - Correction: High level expression of A2ARs is required for the enhancing function, but not for the inhibiting function, of gammadelta T cells in the autoimmune responses of EAU. AB - [This corrects the article DOI: 10.1371/journal.pone.0199601.]. PMID- 30408116 TI - Waist, neck circumferences, waist-to-hip ratio: Which is the best cardiometabolic risk marker in women with severe obesity? The SOON cohort. AB - METHODS: Data from women (n = 305, aged 43 [34; 53] years-old, BMI 44.2 [40.8; 48.2] kg/m2) included in the Severe Obesity Outcome Network (SOON) cohort were analyzed (i) to evaluate collinearity between the different anthropometric markers, (ii) to compare the association of markers with hypertension, type 2 diabetes, obstructive sleep apnea syndrome (OSAS) and other cardiometabolic risks. RESULTS: Hip, waist and neck circumferences correlated with BMI with respectively less collinearity (r = 0.70, r = 0.59 and r = 0.37, respectively, p<0.001) whereas waist-to-hip ratio was not correlated (r = 0.11, p = 0.072). Waist and neck circumferences were significantly associated with hypertension, type 2 diabetes and OSAS in univariate logistic regressions, waist-to-hip ratio with hypertension and type 2 diabetes. Hip circumference was inversely correlated with type 2 diabetes (OR 0.970 (95CI: 0.948; 0.991) p = 0.006). BMI was only linked to OSAS (OR 1.092 (95CI: 1.043; 1.143) p<0.001). Neck circumference was the only marker significantly associated with all cardiometabolic risk markers (HOMA-IR, apnea-hypopnea index, Log Triglycerides/HDL-c, alanin-aminotransferase, aspartate-aminotransferase, gammaglutamyl transpeptidase). CONCLUSIONS: Neck circumference appears the most appropriate anthropometric marker to identify the fat distribution associated with high cardiometabolic risk in women with severe obesity. PMID- 30408120 TI - Correction: Functional abnormalities in induced Pluripotent Stem Cell-derived cardiomyocytes generated from titin-mutated patients with dilated cardiomyopathy. AB - [This corrects the article DOI: 10.1371/journal.pone.0205719.]. PMID- 30408118 TI - Risk factors associated with prolonged hospital length-of-stay: 18-year retrospective study of hospitalizations in a tertiary healthcare center in Mexico. AB - BACKGROUND: Hospital length-of-Stay has been traditionally used as a surrogate to evaluate healthcare efficiency, as well as hospital resource utilization. Prolonged Length-of-stay (PLOS) is associated with increased mortality and other poor outcomes. Additionally, these patients represent a significant economic problem on public health systems and their families. We sought to describe and compare characteristics of patients with Normal hospital Length-of-Stay (NLOS) and PLOS to identify sociodemographic and disease-specific factors associated with PLOS in a tertiary care institution that attends adults with complicated diseases from all over Mexico. MATERIALS AND METHODS: We conducted a retrospective analysis of hospital discharges from January 2000-December 2017 using institutional databases of medical records. We compared NLOS and PLOS using descriptive and inferential statistics. PLOS were defined as those above the 95th percentile of length of hospitalization. RESULTS: We analyzed 85,904 hospitalizations (1,069,875 bed-days), of which 4,427 (5.1%) were PLOS (247,428 bed-days, 23.1% of total bed-days). Hematological neoplasms were the most common discharge diagnosis and surgery of the small bowel was the most common type of surgery. Younger age, male gender, a lower physician-to-patient ratio, emergency and weekend admissions, surgery, the number of comorbidities, residence outside Mexico City and lower socioeconomic status were associated with PLOS. Bone marrow transplant (OR 18.39 [95% CI 12.50-27.05, p<0.001), complex infectious diseases such as systemic mycoses and parasitoses (OR 4.65 [95% CI 3.40-6.63, p<0.001), and complex abdominal diseases such as intestinal fistula (OR 2.57 [95% CI 1.98 3.32) had the greatest risk for PLOS. Risk of mortality in patients with PLOS increased more than threefold (3.7% vs 13.3%, p<0.001). CONCLUSIONS: We report some key sociodemographic and disease-specific differences in patients with PLOS. These could serve to develop a specific model of directed hospital healthcare for patients identified as in risk of PLOS. PMID- 30408119 TI - Prediction of prodromal symptoms and schizophrenia-spectrum personality disorder traits by positive and negative schizotypy: A 3-year prospective study. AB - The present study extends previous cross-sectional findings by examining the predictive validity of positive and negative schizotypy in a young adult sample at a three-year follow-up. Schizotypy and schizophrenia share a comparable multidimensional structure with positive and negative dimensions being the most strongly supported factors. Previous cross-sectional and longitudinal studies employing the psychometric high-risk strategy indicated that schizotypy is a useful method for identifying risk and resilience factors for the development of schizophrenia-spectrum psychopathology. In the present study, 103 participants (77% of 134 candidate participants) were reassessed at a three-year follow-up. As hypothesized, positive schizotypy predicted psychotic-like symptoms, depression, low self-esteem, and general psychopathology. Negative schizotypy predicted emotional disturbances, schizoid personality traits, and mental health treatment during the past year. As expected, both schizotypy dimensions predicted schizotypal, paranoid, and avoidant personality traits, and impaired functioning. These longitudinal findings provide additional evidence supporting the multidimensional model of schizotypy as a valid framework for studying etiological mechanisms and trajectories of psychosis. PMID- 30408121 TI - Seasonal dynamics and changing sea level as determinants of the community and trophic structure of oribatid mites in a salt marsh of the Wadden Sea. AB - Global change processes affect seasonal dynamics of salt marshes and thereby their plant and animal communities. However, these changes have been little investigated for microarthropod communities. We studied the effect of seasonality and changes in sea level on oribatid mites in the natural salt marsh and on artificial islands in the back-barrier environment of the island Spiekeroog (Wadden Sea, Germany). Three zones of the artificial islands were filled with transplanted sods from the lower salt marsh zone and thereby exposed to three different inundation frequencies. We hypothesized that oribatid mite communities will differ along the natural salt marsh vegetation zones [upper salt marsh (USM), lower salt marsh (LSM), pioneer zone (PZ)], which are influenced by different tidal regimes. Accordingly, total oribatid mite densities declined from the USM and LSM to the PZ. Similarly, oribatid mite species compositions changed along the salt marsh transect and also responded to variations in inundation frequency in LSM on artificial islands with typical species of the USM, LSM and PZ being Multioppia neglecta (USM), Hermannia pulchella (LSM), Zachvatkinibates quadrivertex (LSM, PZ) and Ameronothrus schneideri (LSM, PZ). Oribatid mite density in the salt marsh and on the artificial islands was at a maximum in winter and spring; this was due in part to high density of juveniles, pointing to two reproductive periods. We hypothesized that oribatid mite trophic structure changes due to variations in abiotic (e.g., tidal dynamics, temperature) and biotic conditions (e.g., resource availability). Stable isotope (15N, 13C) and neutral lipid fatty acid analyses indicated that oribatid mite species have different diets with e.g., Z. quadrivertex feeding on macroalgae and fungi, A. schneideri feeding on microalgae and bacteria, and Scheloribates laevigatus and M. neglecta feeding on dead organic matter, bacteria and fungi. Overall, the results indicate that oribatid mite species in salt marshes are affected by changes in environmental factors such as inundation intensity, with the effects being most pronounced in species with narrow trophic niches and limited niche plasticity. The results also indicate that oribatid mite communities of the LSM respond little to short-term (one year) changes in inundation frequency. PMID- 30408122 TI - A Tuba/Cdc42/Par6A complex is required to ensure singularity in apical domain formation during enterocyte polarization. AB - Apico-basal polarity establishment is a seminal process in tissue morphogenesis. To function properly it is often imperative that epithelial cells limit apical membrane formation to a single domain. We previously demonstrated that signaling by the small GTPase Cdc42, together with its guanine nucleotide exchange factor (GEF) Tuba, is required to prevent the formation of multiple apical domains in polarized Ls174T:W4 cells, a single cell model for enterocyte polarization. To further chart the molecular signaling mechanisms that safeguard singularity during enterocyte polarization we generated knockout cells for the Cdc42 effector protein Par6A. Par6A loss results in the formation of multiple apical domains, similar to loss of Cdc42. In Par6A knockout cells, we find that active Cdc42 is more mobile at the apical membrane compared to control cells and that wild type Cdc42 is more diffusely localized throughout the cell, indicating that Par6A is required to restrict Cdc42 signaling. Par6A, Cdc42 and its GEF Tuba bind in a co immunoprecipitation experiment and they partially colocalize at the apical membrane in polarized Ls174T:W4 cells, suggesting the formation of a trimeric complex. Indeed, in a rescue experiment using Par6A mutants, we show that the ability to establish this trimeric complex correlates with the ability to restore singularity in Par6A knockout cells. Together, these experiments therefore indicate that a Tuba/Cdc42/Par6A complex is required to ensure the formation of a single apical domain during enterocyte polarization. PMID- 30408124 TI - Correction: Seasonal changes in morphology govern wettability of Katsura leaves. AB - [This corrects the article DOI: 10.1371/journal.pone.0202900.]. PMID- 30408123 TI - Changes in aortic reactivity associated with the loss of equilibrative nucleoside transporter 1 (ENT1) in mice. AB - Slc29a1 encodes for equilibrative nucleoside transporter subtype 1 (ENT1), the primary mechanism of adenosine transfer across cell membranes. Previous studies showed that tissues isolated from Slc29a1-null mice are relatively resistant to injury caused by vascular ischemia-reperfusion. To determine if there are similar changes in the microvasculature, and investigate underlying mechanism, we examined aortas isolated from wildtype and Slc29a1-null mice. Aorta macrostructure and gene expression were examined histologically and by qPCR, respectively. Wire myography was used to assess the contractile properties of isolated thoracic aortic rings and their response to adenosine under both normoxic and hypoxic conditions. In vivo haemodynamic parameters were assessed using the tail-cuff method. Slc29a1-null mice had significantly (P<0.05) increased plasma adenosine (2.75-fold) and lower blood pressure (~15% ?) than wild-type mice. Aortas from Slc29a1-null mice were stiffer with a smaller circumference (11% ?), and had an enhanced contractile response to KCl and receptor-mediated stimuli. Blockade of ENT1 with nitrobenzylthioinosine significantly enhanced (by ~3.5-fold) the response of aorta from wild-type mice to phenylephrine, but had minimal effect on aortas from Slc29a1-null mice. Adenosine enhanced phenylephrine-mediated constriction in the wild-type tissue under both normoxic (11.7-fold) and hypoxic (3.6-fold) conditions, but had no effect on the Slc29a1-null aortic aorta. In conclusion, aortas from Slc29a1-null mice respond to hypoxic insult in a manner comparable to wild-type tissues that have been pharmacologically preconditioned with adenosine. These data also support a role for ENT1 in the regulation of the protective effects of adenosine on contractile function in elastic conduit arteries such as thoracic aorta. PMID- 30408125 TI - Vitamin D deficiency is associated with hepatic decompensation and inflammation in patients with liver cirrhosis: A prospective cohort study. AB - BACKGROUND: Vitamin D is required to maintain the integrity of the intestinal barrier and inhibits inflammatory signaling pathways. OBJECTIVE: Vitamin D deficiency might be involved in cirrhosis-associated systemic inflammation and risk of hepatic decompensation in patients with liver cirrhosis. METHODS: Outpatients of the Hepatology Unit of the University Hospital Frankfurt with advanced liver fibrosis and cirrhosis were prospectively enrolled. 25 hydroxyvitamin D (25(OH)D3) serum concentrations were quantified and associated with markers of systemic inflammation / intestinal bacterial translocation and hepatic decompensation. RESULTS: A total of 338 patients with advanced liver fibrosis or cirrhosis were included. Of those, 51 patients (15%) were hospitalized due to hepatic decompensation during follow-up. Overall, 72 patients (21%) had severe vitamin D deficiency. However, patients receiving vitamin D supplements had significantly higher 25(OH)D3 serum levels compared to patients without supplements (37 ng/mL vs. 16 ng/ml, P<0.0001). Uni- and multivariate analyses revealed an independent association of severe vitamin D deficiency with the risk of hepatic decompensation during follow-up (multivariate P = 0.012; OR = 3.25, 95% CI = 1.30-8.2), together with MELD score, low hemoglobin concentration, low coffee consumption, and presence of diabetes. Of note, serum levels of C reactive protein, IL-6 and soluble CD14 were significantly higher in patients with versus without severe vitamin D deficiency, and serum levels of soluble CD14 levels declined in patients with de novo supplementation of vitamin D (median 2.15 vs. 1.87 ng/mL, P = 0.002). CONCLUSIONS: In this prospective cohort study, baseline vitamin D levels were inversely associated with liver-cirrhosis related systemic inflammation and the risk of hepatic decompensation. PMID- 30408127 TI - Radial shape discrimination testing for new-onset neovascular age-related macular degeneration in at-risk eyes. AB - We investigated the performance of the handheld radial shape discrimination (hRSD) test in detecting the development of neovascular AMD (nAMD) in a prospective, longitudinal, observational study. Patients diagnosed with unilateral nAMD, with no nAMD in the other eye (the study eye, SE), completed the hRSD test on consecutive, routine clinic visits up to a maximum of 12, or until they were diagnosed with nAMD in the SE based on slit-lamp biomicroscopy and spectral-domain OCT assessment, with fluorescein angiography confirmation. Masked grading was carried out to confirm the diagnosis of nAMD, and to ensure no cases of nAMD were missed. Receiver operating characteristics (ROC) analysis was used to explore the diagnostic performance of the hRSD test relative to clinical diagnosis. Data were available from 179 patients of whom 19 (10.6%; "converters") developed nAMD in the SE. The mean hRSD threshold at conversion was -0.47 (95% CI -0.38 to -0.55) logMAR compared to -0.53 (-0.50 to -0.57) logMAR in 160 non converters. hRSD threshold in the converters began to decline 190 days before diagnosis of nAMD. The ROC curve demonstrated that at an hRSD cut-off of -0.60 logMAR, sensitivity was 0.79 (0.54-0.94) with a specificity of 0.54 (0.46-0.62); positive and negative predictive values were 0.16 and 0.96 respectively. We conclude that the hRSD test has moderate sensitivity for detecting the earliest stages of nAMD in the at-risk fellow eyes of patients with unilateral nAMD, compared to clinical diagnosis. Given its relative inexpensiveness, ease of use and the inherent connectivity of the platforms it can be presented on, it may have a role in early detection of nAMD in the population at large. PMID- 30408126 TI - Influence of warming and reanimation conditions on seminiferous tubule morphology, mitochondrial activity, and cell composition of vitrified testicular tissues in the domestic cat model. AB - Understanding critical roles of warming and reanimation is critical to improve the survival of vitrified testicular tissue in domestic cats. The objective was to study structural and functional properties of testicular tissues from prepubertal domestic cats after standard vitrification followed by two warming protocols (directly at 37 degrees C or with a 5-second pre-exposure to 50 degrees C) and three reanimation time points (immediately, 24 h and 5 days post-warming). In Experiment 1, tissues were evaluated for histo-morphology and mitochondrial activity immediately or 24 h after warming protocols. In Experiment 2, cell viability, DNA fragmentation, and germ cell composition were assessed immediately, 24 h, or 5 days after optimal warming. Preservation of seminiferous tubule structure was better using warming at 50 degrees C for five seconds, and survival of somatic as well as germinal cells was higher compared to direct warming at 37 degrees C for one minute. Short term in vitro culture (for reanimation) also proved that cellular composition and functionality were better preserved when warmed for a short time at 50 degrees C. Collective data showed that short warming at 50 degrees C led to better quality of seminiferous tubule structure and cell composition after vitrification and short-term culture. In addition, data suggest clear directions to further understand and optimize testicular tissue survival after fertility preservation procedures. PMID- 30408128 TI - A comparative analysis of EGFR-targeting antibodies for gold nanoparticle CT imaging of lung cancer. AB - Computed tomography (CT) is the standard imaging test used for the screening and assessment of suspected lung cancer, but distinguishing malignant from benign nodules by CT is an ongoing challenge. Consequently, a large number of avoidable invasive procedures are performed on patients with benign nodules in order to exclude malignancy. Improving cancer discrimination by non-invasive imaging could reduce the need for invasive diagnostics. In this work we focus on developing a gold nanoparticle contrast agent that targets the epidermal growth factor receptor (EGFR), which is expressed on the cell surface of most lung adenocarcinomas. Three different contrast agents were compared for their tumor targeting effectiveness: non-targeted nanoparticles, nanoparticles conjugated with full-sized anti-EGFR antibodies (cetuximab), and nanoparticles conjugated with a single-domain llama-derived anti-EGFR antibody, which is smaller than the cetuximab, but has a lower binding affinity. Nanoparticle targeting effectiveness was evaluated in vitro by EGFR-binding assays and in cell culture with A431 cells, which highly express EGFR. In vivo CT imaging performance was evaluated in both C57BL/6 mice and in nude mice with A431 subcutaneous tumors. The cetuximab nanoparticles had a significantly shorter blood residence time than either the non-targeted or the single-domain antibody nanoparticles. All of the nanoparticle contrast agents demonstrated tumor accumulation; however, the cetuximab-targeted group had significantly higher tumor gold accumulation than the other two groups, which were statistically indistinguishable from one another. In this study we found that the relative binding affinity of the targeting ligands had more of an effect on tumor accumulation than the circulation half life of the nanoparticles. This study provides useful insight into targeted nanoparticle design and demonstrates that nanoparticle contrast agents can be used to detect tumor receptor overexpression. Combining receptor status data with traditional imaging characteristics has the potential for better differentiation of malignant lung tumors from benign lesions. PMID- 30408129 TI - Impact of fee subsidy policy on perinatal health in a low-resource setting: A quasi-experimental study. AB - BACKGROUND: A national subsidy policy was introduced in 2007 in Burkina Faso to improve financial accessibility to facility-based delivery. In this article, we estimated the effects of reducing user fees on institutional delivery and neonatal mortality, immediately and three years after the introduction of the policy. METHODS: The study was based on a quasi-experimental design. We used data obtained from the 2010 Demographic and Health Survey, including survival information for 32,102 live-born infants born to 12,474 women. We used a multilevel Poisson regression model with robust variances to control for secular trends in outcomes between the period before the introduction of the policy (1 January, 2007) and the period after. In sensitivity analyses, we used two different models according to the different definitions of the period "before" and the period "after". RESULTS: Immediately following its introduction, the subsidy policy was associated with increases in institutional deliveries by 4% (RR = 1.04, 95% CI: 0.98-1.10) in urban areas and by 12% (RR = 1.12, 95% CI: 1.04 1.20) in rural areas. The results showed similar patterns in sensitivity analyses. This effect was particularly marked among rural clusters with low institutional delivery rates at baseline (RR = 1.44, 95% CI: 1.33-1.55). It was persistent for 42 months after the introduction of the policy but these increases were not statistically significant. At 42 months, the delivery rates had increased by 26% in rural areas (RR = 1.26; 95% CI: 0.86-1.86) and 13% (RR = 1.13; 95% CI: 0.88-1.46) in urban areas. There was no evidence of a significant decrease in neonatal mortality rates. CONCLUSION: The delivery subsidy implemented in Burkina Faso is associated with short-term increases in health facility deliveries. This policy has been particularly beneficial for rural households. PMID- 30408131 TI - What happens to migrant tuberculosis patients who are transferred out using a web based system in China? AB - BACKGROUND: In China, internal migrants constitute one-fifth of tuberculosis (TB) patients registered for treatment in web-based TB information management system (TBIMS). Though China added a specific module in the web-based TBIMS in 2009, web based transfer-out is not specifically recommended in the national guidelines. OBJECTIVE: In this country wide study among all registered migrant TB patients (2014-2015) that were transferred out using web-based TBIMS in China, to determine the i) timing of transfer-out in relation to period of treatment; ii) delay and attrition during transfer interval (between transfer-out and transfer in); and iii) extent and risk factors for 'not evaluated' as the treatment outcome. METHODS: This was a cohort study involving review of web-based TBIMS data. Modified Poisson regression was used to build a predictive model for risk factors of 'not evaluated' as the treatment outcome. RESULTS: Among 7 284 patients, 5 900 (81.0%) were transferred out during the first two months after initiation of treatment or before treatment initiation and 7 088 (97.3%) patients had arrived at transfer-in unit. The median transfer interval was three (interquartile range: 0-14) days. Sixteen percent (1 176/7 284) patients had 'not evaluated' as their treatment outcome. 'Not evaluated' contributed to 66% of the unfavourable outcomes. Patients transferred from referral hospitals, migrated from out of prefecture, transferred out of prefecture, with sputum smear negative pulmonary TB, with TB pleurisy and with long delay between symptom onset and treatment initiation had significantly higher risk of 'not evaluated' as the outcome. CONCLUSION: Web-based transfer helped as the delay and attrition during the transfer interval was quite short and treatment outcomes of more than four fifths of transferred out migrant TB patients were available with transfer-out BMU. Once strategies to address the independent predictors of 'not evaluated' treatment outcome are devised, China may consider mandatory use of web-based TBIMS for transferring out migrant TB patients. PMID- 30408130 TI - Anhedonia in cocaine use disorder is associated with inflammatory gene expression. AB - Treatments for Cocaine Use Disorder (CUD) are variably effective, and there are no FDA-approved medications. One approach to developing new treatments for CUD may be to investigate and target poor prognostic signs. One such sign is anhedonia (i.e. a loss of pleasure or interest in non-drug rewards), which predicts worse outcomes in existing CUD treatments. Inflammation is thought to underlie anhedonia in many other disorders, but the relationship between anhedonia and inflammation has not been investigated in CUD. Therefore, we assessed peripheral genome-wide gene expression in n = 48 individuals with CUD with high (n = 24) vs. low (n = 24) levels of anhedonia, defined by a median split of self-reported anhedonia. Our hypothesis was that individuals with high anhedonia would show differential gene expression in inflammatory pathways. No individual genes were significantly different between the low and high anhedonia groups when using t-tests with a stringent false discovery rate correction (FDR corrected p < 0.05). However, an exploratory analysis identified 166 loci where t tests suggested group differences at a nominal p < 0.05. We used DAVID, a bioinformatics tool that provides functional interpretations of complex lists of genes, to examine representation of this gene list in known pathways. It confirmed that mechanisms related to immunity were the top significant associations with anhedonia in the sample. Further, the two top differentially expressed genes in our sample, IRF1 and GBP5, both have primary inflammation and immune functions, and were significantly negatively correlated with total scores on our self-report of anhedonia across all 48 subjects. These results suggest that prioritizing development of anti-inflammatory medications for CUD may pay dividends, particularly in combination with treatment-matching strategies using either phenotypic measures of anhedonia or biomarkers of inflammatory gene expression to individualize treatment. PMID- 30408133 TI - Abortion care in Haiti: A secondary analysis of demographic and health data. AB - BACKGROUND: Abortion-related mortality accounts for 8% of all global maternal deaths and 97% of the estimated 25 million unsafe abortions performed each year occur in low- and middle-income countries. Haiti has the highest rate of maternal mortality in the western hemisphere and to further understand the circumstances of induced abortion in Haiti, the current work uses data from the 2012 Demographic and Health Survey (DHS) to describe the methods of induced abortion in Haiti between 2007-2012 and to identify potential factors associated with use of different abortion methods. METHODS: This is a secondary analysis of nationally representative cross-sectional data from the 2012 Haitian DHS, a two stage cluster randomized household survey. Analysis included descriptive statistics on participant demographics, methods of abortion, and location of / assistant for the abortion. Multivariate regression was conducted to determine if demographic characteristics were associated with: 1) increased or decreased odds of having an abortion; or 2) increased or decreased odds of reporting an evidence based or non-evidence based method of abortion. RESULTS: Among the 14,287 women of childbearing age who completed the 2012 Haiti DHS survey, 289 women reported having an induced abortion in the previous five years. Recommended methods, manual vacuum aspiration (MVA) or misoprostol alone, were used in 26.6% of the abortions (n = 77). Additionally, 13.8% (n = 40) of abortions used these recommended methods in combination with a non-evidenced based method such as injections, plants or tablets. A total of 92 women had a dilation and curettage (D&C) abortion, either alone (n = 77) or in combination with another method (n = 15) and over a quarter (n = 80) of reported abortions were conducted by non evidence based methods (n = 80). A majority of abortions using a recommended method were assisted by a relative/friend (n = 28) or were unassisted (n = 34). Most abortions occurred in private homes (n = 174) with hospitals/clinics being the second most common location (n = 84). Women in the middle (OR = 3.3, 95% CI = 2.0-5.6) and highest (OR = 7.4, 95% CI = 4.4-12.3) wealth brackets were more likely to have had an abortion in comparison to women in the lowest wealth bracket. Women who had ever been in a marital union were more likely to have had an abortion than those who had not. The only demographic factor predictive of aborting using a recommended method was living in an urban area, with urban dwelling women being less likely to use a recommended abortion method (OR = 0.4, 95% CI = 0.2-0.9) in comparison with women living in rural settings. CONCLUSION: In a nationally representative survey in Haiti, 2% of women of childbearing age reported having an abortion in the five years prior to the survey. A large proportion of these abortions were carried out using non-evidence based methods and over half occurred outside of the formal health care system. Understanding women's attitudes, knowledge and barriers around abortion is paramount to improving knowledge and access to evidence-based abortion care in an effort to decrease maternal morbidity and mortality in Haiti. PMID- 30408132 TI - The prognosis of heart failure patients: Does sodium level play a significant role? AB - INTRODUCTION: Heart failure (HF), a major cardiovascular disorder, remains a grievous clinical condition regardless of advances in medical care. Hyponatremia is classified as a serum sodium concentration of <135 mEq/L, and the prevalence, clinical impact and prognostic factor of hyponatremia in heart failure patients varies widely. The current study was conducted with the aim of assessing the prevalence of hyponatremia in patients hospitalized with a diagnosis of HF and comparing baseline clinical characteristic of HF patients based on their sodium status. Survival difference between patients with hyponatremia and normonatremia was also assessed and the clinical prognostic indicators of overall mortality in HF patients were evaluated. METHOD: A retrospective cohort study was conducted to assess medical records of heart failure patients who were admitted to Gondar University Referral Hospital. Patients were categorized based on their sodium level status at their first admission to the internal medicine department. Each patient was assigned to either of the following groups: hyponatremia if sodium < 135 mmol/L, or normonatremia if sodium >= 135 mmol/L. RESULT: Among 388 participants, the prevalence of hyponatremia in the study cohorts was 51.03%. Kaplan-Meier survival curves showed that there was a significant difference in survival status of HF patients among the two cohorts (Log-Rank test, P <0.0001). Hence, patients with normal sodium levels had a higher chance of survival over hyponatremic patients. Multivariate Cox regression has revealed a statistically significant association of mortality with the following variables: advanced age (AHR = 1.035 (1.012-1.058), P = 0.003), hyponatremia (AHR = 4.003 (1.778-9.009), P = 0.001), higher creatinine level (AHR = 1.929 (1.523-2.443), P = <0.0001) and, prescription of angiotensin-converting enzyme inhibitors (AHR = 0.410 (0.199 0.842), P = 0.015) and spironolactone (AHR = 0.511 (0.275-0.949), P = 0.033. CONCLUSION: In conclusion, hyponatremia is one of the crucial factors in the clinical prognosis of heart failure patients. However, as other prognostic factors (i.e. medication, creatine level, and age) also played vital roles in overall survival, well-controlled clinical trials (complete with medication dosing, laboratory outputs and long-term prospective follow up) are required to further study the impact of hyponatremia in HF patient's prognosis in low income nations. PMID- 30408134 TI - Dietary fiber sources and non-starch polysaccharide-degrading enzymes modify mucin expression and the immune profile of the swine ileum. AB - Due to their complex chemical and physical properties, the effects and mechanisms of action of natural sources of dietary fiber on the intestine are unclear. Pigs are commonly fed high-fiber diets to reduce production costs and non-starch polysaccharide (NSP)-degrading enzymes have been used to increase fiber digestibility. We evaluated the expression of mucin 2 (MUC2), presence of goblet cells, and ileal immune profile of pigs housed individually for 28 days and fed either a low fiber diet based on corn-soybean meal (CSB, n = 9), or two high fiber diets formulated adding 40% corn distillers' dried grains with solubles (DDGS, n = 9) or 30% wheat middlings (WM, n = 9) to CSB-based diet. Pigs were also fed those diets supplemented with a NSP enzymes mix (E) of xylanase, beta glucanase, mannanase, and galactosidase (n = 8, 10, and 9 for CSB+E, DDGS+E and WM+E, respectively). Feeding DDGS and WM diets increased ileal MUC2 expression compared with CSB diet, and this effect was reversed by the addition of enzymes. There were no differences in abundance of goblet cells among treatments. In general, enzyme supplementation increased gene expression and concentrations of IL-1beta, and reduced the concentrations of IL-4, IL-17A and IL-11. The effects of diet-induced cytokines on modulating intestinal MUC2 were assessed in vitro by treating mouse and swine enteroids with 1 ng/ml of IL-4 and IL-1beta. In accordance with previous studies, treatment with Il-4 induced Muc2 and expansion of goblet cells in mouse enteroids. However, swine enteroids did not change MUC2 expression or number of goblet cells when treated with IL-4 or IL-1beta. Our results suggest that mucin and immune profile are regulated by diet in the swine intestine, but by mechanisms different to mouse, emphasizing the need for using appropriate models to study responses to dietary fiber in swine. PMID- 30408136 TI - Implant Survival in the Edentulous Jaw: 30 Years of Experience. Part II: A Retro Prospective Multivariate Regression Analysis Related to Treated Arch and Implant Surface Roughness. AB - PURPOSE: To report retro-prospective, long-term data on the prevalence of implant failures related to maxillary and mandibular arches and to different implant surfaces in a large number of edentulous patients. MATERIALS AND METHODS: Altogether, 3,493 and 1,092 edentulous arches were consecutively treated with implants with turned (1986-2002) or moderately rough (2003-2015) surfaces, respectively, during two time periods at one referral clinic. All implant failures were consecutively identified during routine follow-up, and a multivariate logistic regression analysis was performed to analyze implant failure related to arch and implant surface. RESULTS: Overall cumulative survival rates (CSR) for arches treated with turned surface implants were 75.7% and 94.6% for the maxilla and mandible, respectively. The corresponding 10-year CSRs for arches treated with implants with a moderately rough surface were 91.9% and 96.1%, respectively. The strongest significant association (P < .05) with risk for implant failure was the maxilla, and this was more pronounced for implants with a turned surface. Age at surgery, implant surgeon, calendar year of surgery, and time of follow-up also had significant associations with risk of implant failure (P < .05). CONCLUSION: Risk for implant failure was significantly higher for treatment in the maxilla, but this risk was decreased significantly when using implants with a moderately rough surface. The impact of surface was not so obvious for treatment in the mandible. Risk for late implant failures after the first year was lower for implants with a moderately rough surface in the maxilla, but this risk seemed to be comparable for the different surfaces in the mandible. PMID- 30408135 TI - Venous thromboembolic events during warm autoimmune hemolytic anemia. AB - Thrombotic manifestations are a hallmark of many auto-immune diseases (AID), specially of warm autoimmune hemolytic anemia (wAIHA), as 15 to 33% of adults with wAIHA experience venous thromboembolic events (VTE). However, beyond the presence of positive antiphospholipid antibodies and splenectomy, risk factors for developing a VTE during wAIHA have not been clearly identified. The aim of this retrospective study was to characterize VTEs during wAIHA and to identify risk factors for VTE. Forty-eight patients with wAIHA were included, among whom 26 (54%) had secondary wAIHA. Eleven (23%) patients presented at least one VTE, that occurred during an active phase of the disease for 10/11 patients (90%). The frequency of VTE was not different between primary and secondary AIHA (23.7 vs. 19.2%; p = 0.5). The Padua prediction score based on traditional risk factors was not different between patients with and without VTE. On multivariate analysis, total bilirubin >= 40 MUmol/L [odds ratio (OR) = 7.4; p = 0.02] and leucocyte count above 7x109/L (OR = 15.7; p = 0.02) were significantly associated with a higher risk of thrombosis. Antiphospholipid antibodies were screened in 9 out the 11 patients who presented a VTE and were negative. Thus, the frequency of VTE is high (23%) during wAIHA and VTE preferentially occur within the first weeks of diagnosis. As no clinically relevant predictive factors of VTE could be identified, the systematic use of a prophylactic anticoagulation should be recommended in case of active hemolysis and its maintenance after hospital discharge should be considered. The benefit of a systematic screening for VTE and its procedure remain to be determined. PMID- 30408137 TI - The Geniohyoid Muscle Directly Affects Masticatory Function: Evaluation with Decision-Tree Analysis. AB - PURPOSE: To clarify the effect of geniohyoid (GH) muscle morphology and related function on masticatory ability using a decision-tree analysis. MATERIALS AND METHODS: A total of 103 participants were enrolled. A cross-sectional area (CSA) of the GH muscle, neck circumference, body mass index, tongue pressure, jaw opening strength, and masticatory ability score were measured. The CSA of the GH muscle was selected as an independent variable for the first layer of the decision tree, with masticatory score as the dependent variable. RESULTS AND CONCLUSION: These data suggest that the CSA of the GH muscle may have a large impact on the masticatory ability score when evaluating masticatory ability. PMID- 30408138 TI - Digital vs Conventional Workflow for Screw-Retained Single-Implant Crowns: A Comparison of Key Considerations. AB - PURPOSE: To evaluate patient perception and operating time of digital (DW) and conventional (CW) workflows for the rehabilitation of a screw-retained, single implant crown. MATERIALS AND METHODS: A convenience sample of 10 patients with single implants in posterior sites was recruited for treatment with screw retained single crowns, fabricated with either a DW or a CW protocol. Operating time and clinical adjusting time were recorded with a stopwatch, and patient preference and self-perception of the esthetic outcome were evaluated with a visual analog scale. RESULTS: The mean operating time for the DW crowns was 16:21 minutes and for the CW crowns was 28:28 minutes. The mean total adjustment times were 118.1 seconds for the DW protocol and 181.5 seconds for the CW protocol. The mean score regarding self-perception of the esthetic outcome was 73 for DW crowns and 69 for CW crowns; for discomfort, the mean score was 15.5 for DW and 62 for CW. CONCLUSION: The DW approach resulted in a time reduction for both the impression phase and operative time. PMID- 30408139 TI - Survival Rate and Bone Resorption in Immediate Loading of Atrophic Maxillary Arches Using Normal and Long Implants: A Pilot Observational Study. AB - PURPOSE: To estimate implant survival and peri-implant bone resorption around long vs normal-length implants in full-arch immediate loading rehabilitation of maxillary arches of low bone quality (D4). MATERIALS AND METHODS: A total of 45 patients received two mesial normal-length (10 to 15 mm) or longer (18 to 20 mm) implants and two long (18 to 20 mm) distally tilted implants. Differences in bone resorption at 24 months were assessed using the Mann-Whitney U Test. RESULTS: At the 24-month follow-up, no significant differences were found in survival (global cumulative survival rate: 98.9%) or bone resorption (mean: 1.1 mm) between long and normal implants (P = .053). CONCLUSION: At 24 months, the use of long implants provides favorable survival and bone maintenance results in the immediate loading rehabilitation of low-quality maxillary arches. PMID- 30408140 TI - A New Membrane Obturator Prosthesis Concept for Soft Palate Defects. AB - When soft palate defects lead to palatal insufficiency, the patient's quality of life is affected by difficulties swallowing, hypernasality, and poor intelligibility of speech. If immediate surgical reconstruction is not an option, the patient may benefit from the placement of a rigid obturator prosthesis. Unfortunately, the residual muscle stumps are often unable to adequately move this stiff and inert obturator to properly restore the velopharyngeal valve function. In the present case history report, a new membrane obturator concept is described: Using a dental dam to compensate for the soft palate defect, swallowing and speech were significantly improved. PMID- 30408141 TI - Biomechanical Behavior of Implants with a Sloped Marginal Configuration. AB - PURPOSE: To evaluate the biomechanical behavior of implants with different neck designs. MATERIALS AND METHODS: Finite element models of implants with two different neck designs (OsseoSpeed EV and OsseoSpeed Profile EV) were generated. Implants and abutments were subjected to buccally and lingually directed 30 degree oblique loads of 200 N. RESULTS: Under buccally angulated load, the Profile implant model showed lower minimum principal stress when compared to the standard implant model (-63.4 vs -91.9 MPa), whereas the von Mises stress value of the Profile implant model was higher (342 MPa). CONCLUSION: This preliminary study showed that Profile implants placed in alveolar ridges with buccolingual bone height discrepancy showed similar stress distribution and stress value outcomes when compared to standard implants. PMID- 30408142 TI - Comparison of Mechanical Properties of CAD/CAM-Milled and Selective Laser-Melted Ti-6Al-4V for Dental Superstructures. AB - PURPOSE: To determine whether selective laser melting (SLM) is suitable for the fabrication of dental superstructures. MATERIALS AND METHODS: Mechanical properties of Ti-6Al-4V, manufactured with SLM or numerically controlled milling, were evaluated and compared. RESULTS AND CONCLUSION: Both groups showed a mechanical strength greater than 500 MPa and an elongation greater than 2%, as required by the International Organization for Standardization 22674 standard. However, a reduced ductility was observed for SLM samples. PMID- 30408143 TI - Intraspecific variation in semicircular canal morphology-A missing element in adaptive scenarios? AB - OBJECTIVES: Recent evidence suggests that the amount of intraspecific variation in semicircular canal morphology may, itself, be evidence for varying levels of selection related to locomotor demands. To determine the extent of this phenomenon across taxa, we expand upon previous work by examining intraspecific variation in canal radii and canal orthogonality in a broad sample of strepsirrhine and platyrrhine primates. Patterns of interspecific variation are re-examined in light of intraspecific variation to better understand the resolution at which locomotion can be reconstructed from single individuals. MATERIALS AND METHODS: Data was collected from high-resolution CT scans of 14 size-matched, related species. Six of these taxa have existing data on rotational head speeds. RESULTS: The level of intraspecific variation was found to differ in strepsirrhine and in platyrrhine species pairs, with larger ranges of variation generally observed for the slower moving taxon than the faster moving one. Taxa that are classified as relatively agile can to some extent be separated from those who are slower-moving, but only when comparing similarly sized, closely related species with more extreme forms of locomotion. DISCUSSION: Our findings agree with previous research showing that canal intraspecific variation can fluctuate according to species-specific locomotor behavior and extends this further by identifying behaviors that may be under unusual selective pressure. It also demonstrates the complexity of interpreting inner ear morphology in the context of broadly applicable locomotor "categories" of the kind commonly used in behavioral studies. We suspect that simplified models predicting vestibular sensitivity may be unable to differentiate behaviors when only a single specimen is available. PMID- 30408144 TI - A rare complication of bone marrow aspiration and trephine biopsy: Staphylococcus aureus osteomyelitis and septicaemia. PMID- 30408145 TI - The incidence of symptomatic osteonecrosis after allogeneic haematopoietic stem cell transplantation in children with acute lymphoblastic leukaemia - controversy on dexamethasone as a risk factor. PMID- 30408146 TI - Educational assortative mating: a micro-educational approach. AB - This article presents a new way of analysing educational assortative mating patterns, using a detailed 'micro-educational' classification capturing both hierarchical and horizontal forms of educational differentiation. Taking advantage of rich Danish population data, we apply log-linear models that include four ways of measuring educational homogamy patterns: (a) by returns to education, (b) by macro-education (five aggregated levels), (c) by field of study (16 categories), and (d) by a disaggregated micro-educational classification, combining levels and fields of study (54 groups). Our results show declines in educational homogamy from 1984 to 2013, but the odds ratios of being educationally homogamous at the university college and university levels remain of substantial magnitude, by both the macro- and micro-educational measures. The micro-educational classification outperforms all other measures in explaining the associations in the homogamy tables. The income measure ('returns to education') does a particularly poor job of explaining homogamy patterns from 1984 to 2013. PMID- 30408147 TI - CXCR4 mutations in lymphoplasmacytic lymphoma lead to altered CXCR4 expression. PMID- 30408148 TI - Cell-of-origin in diffuse large B-cell lymphoma: findings from the UK's population-based Haematological Malignancy Research Network. PMID- 30408149 TI - Granular B-lineage acute lymphoblastic leukaemia mimicking acute myeloid leukaemia. PMID- 30408150 TI - Functional and developmental influences on intraspecific variation in catarrhine vertebrae. AB - OBJECTIVES: We tested whether patterns of intraspecific variation in catarrhine vertebral shape are consistent with developmental or functional predictions. Intraspecific variation was compared across column regions, morphological features, and species. Transitional regions and later ossifying morphological features were predicted to exhibit increased variation. The lumbosacral region, biomechanically important morphological features, and species with high locomotor demand and/or dedicated pronogrady were predicted to exhibit decreased variation. MATERIALS AND METHODS: We used a modified Levene's test to compare intraspecific variation in dimensions of the neural canal, vertebral bodies, and spinous and transverse processes in lower thoracic to proximal sacral vertebrae. The sample included all hominoid genera and one cercopithecoid (Chlorocebus). RESULTS: We found little difference in variation across regions of the vertebral column. In hominoids, vertebral body dimensions were the least variable, neural canal dimensions the most variable, with spinous and transverse processes generally intermediate. Among species, there was a general though not always significant pattern for Chlorocebus to exhibit the least variation, followed by Homo or Hylobates. DISCUSSION: Patterns of variation across morphological features may reflect the complex interaction of functional constraints, developmental timing, and/or variable biomechanical forces. Pongo's elevated variation in spinous process length suggests a release from functional constraint, consistent with its suspensory locomotion and reduced spinous processes. Interspecific differences in vertebral variation based on locomotor demand or posture are generally consistent with patterns previously reported for vertebral formula and other aspects of morphology. Future research would benefit from an expanded taxonomic sample and more detailed analyses of vertebral modularity and developmental timing. PMID- 30408152 TI - Role of the Embodied Cognition Process in Perspective-Taking Ability During Childhood. AB - This study examined developmental changes in Level-2 visual perspective taking (VPT2) in 90 children aged 4-12 years and tested the role of their ability to mentally simulate changes to their bodily locations (self-motion imagery; SMI). Performance of a mental toy rotation task and a self-motion (SM) task (changing location of children) was superior to that of VPT2 and SMI tasks. Task performance of SMI was better than that of VPT2 before 10;0 (years;months). Furthermore, egocentric responses in VPT2 and SMI tasks were significantly more frequent than those in the mental rotation and SM tasks before 10;3. These findings suggest the involvement of embodied cognitive processes in perspective taking and the advantage of utilizing bodily information by age 10. PMID- 30408153 TI - MYD88 p.(L265P) detection on cell-free DNA in liquid biopsies of patients with primary central nervous system lymphoma. PMID- 30408151 TI - Spatial phylogenetics reveals evolutionary constraints on the assembly of a large regional flora. AB - PREMISE OF THE STUDY: We used spatial phylogenetics to analyze the assembly of the Wisconsin flora, linking processes of dispersal and niche evolution to spatial patterns of floristic and phylogenetic diversity and testing whether phylogenetic niche conservatism can account for these patterns. METHODS: We used digitized records and a new molecular phylogeny for 93% of vascular plants in Wisconsin to estimate spatial variation in species richness and phylogenetic alpha and beta diversity in a native flora shaped mainly by postglacial dispersal and response to environmental gradients. We developed distribution models for all species and used these to infer fine-scale variation in potential diversity, phylogenetic distance, and interspecific range overlaps. We identified 11 bioregions based on floristic composition, mapped areas of neo- and paleo endemism to establish new conservation priorities and predict how community assembly patterns should shift with climatic change. KEY RESULTS: Spatial phylogenetic turnover most strongly reflects differences in temperature and spatial distance. For all vascular plants, assemblages shift from phylogenetically clustered to overdispersed northward, contrary to most other studies. This pattern is lost for angiosperms alone, illustrating the importance of phylogenetic scale. CONCLUSIONS: Species ranges and assemblage composition appear driven primarily by phylogenetic niche conservatism. Closely related species are ecologically similar and occupy similar territories. The average level and geographic structure of plant phylogenetic diversity within Wisconsin are expected to greatly decline over the next half century, while potential species richness will increase throughout the state. Our methods can be applied to allochthonous communities throughout the world. PMID- 30408154 TI - Shades of complexity: New perspectives on the evolution and genetic architecture of human skin. AB - Like many highly variable human traits, more than a dozen genes are known to contribute to the full range of skin color. However, the historical bias in favor of genetic studies in European and European-derived populations has blinded us to the magnitude of pigmentation's complexity. As deliberate efforts are being made to better characterize diverse global populations and new sequencing technologies, better measurement tools, functional assessments, predictive modeling, and ancient DNA analyses become more widely accessible, we are beginning to appreciate how limited our understanding of the genetic bases of human skin color have been. Novel variants in genes not previously linked to pigmentation have been identified and evidence is mounting that there are hundreds more variants yet to be found. Even for genes that have been exhaustively characterized in European populations like MC1R, OCA2, and SLC24A5, research in previously understudied groups is leading to a new appreciation of the degree to which genetic diversity, epistatic interactions, pleiotropy, admixture, global and local adaptation, and cultural practices operate in population-specific ways to shape the genetic architecture of skin color. Furthermore, we are coming to terms with how factors like tanning response and barrier function may also have influenced selection on skin throughout human history. By examining how our knowledge of pigmentation genetics has shifted in the last decade, we can better appreciate how far we have come in understanding human diversity and the still long road ahead for understanding many complex human traits. PMID- 30408155 TI - Mesenchymal stem cells gene signature in high-risk myeloma bone marrow linked to suppression of distinct IGFBP2-expressing small adipocytes. AB - Recent studies suggest that multiple myeloma (MM) induces proliferation and expansion of bone marrow (BM) mesenchymal stem cells (MSCs), but others showed that MM cells induce MSC senescence. To clarify the interaction between MM and MSCs, we exploited our established MSC gene signature to identify gene expression changes in myeloma MSCs and associated functional differences. Single MSCs from patients with MM had changes in expression of genes associated with cellular proliferation and senescence and a higher proportion of senescent cells and lower proliferative potential than those from age-matched healthy donors. Single MSCs from both sources heterogeneously express MSC genes associated with adipogenesis and osteoblastogenesis. We identified the gene encoding insulin-like growth factor-binding protein 2 (IGFBP2), an MSC gene commonly altered in high risk MM, as under-expressed. Morphologically, IGFBP2+ cells are underrepresented in MM BM compared to smouldering MM. Strong IGFBP2 and adiponectin co-expression was detected in a subset of small adipocytes. Co-culturing normal MSCs with myeloma cells suppressed MSC differentiation to adipocytes and osteoblasts, and reduced expression of IGFBP2 and adiponectin. Recombinant IGFBP2 blocked IGF1-mediated myeloma cell growth. Our data demonstrate that myeloma MSCs are less proliferative and that IGFBP2+ small adipocytes are a distinct mesenchymal cell population suppressed by myeloma. PMID- 30408156 TI - Current treatment paradigms for advanced stage Hodgkin lymphoma. AB - The treatment of advanced classical Hodgkin Lymphoma (cHL) has evolved over the last 50 years with a progressive improvement in long term cure rates in patients up to the age of 60 years. However, a minority of these survivors experience severe morbidity and mortality resulting from intensive chemotherapy and radiotherapy, leading to a drive to de-escalate treatment without compromising survival. The early identification of patients with chemoresistant disease by functional imaging allows the modulation of therapy and an efficient means to test new agents in those most in need of more effective therapy. The outcomes of treatment for older patients have not improved at the same rate, and this group requires a different approach, incorporating specialist geriatric support to personalise therapy. Clinical trials that focus on quality of life, comorbidity and survival are needed to improve survival rates for this expanding population with complex needs. PMID- 30408157 TI - Understanding how older age drives decision-making and outcome in Immune Thrombocytopenia. A single centre study on 465 adult patients. AB - We analysed the impact of older age on the management of immune thrombocytopenia (ITP) in 465 adult patients diagnosed between 1995 and 2017 and followed at our institution for a minimum of 12 months. Over a follow-up of 4248 patient-years, front-line corticosteroids therapy was required in 334 patients (71.8%), mainly (85.3%) within 1 year from diagnosis. Need for first-, second- and third-line therapy was comparable in younger and older (age >=65 years, n = 154) patients. Older patients presented more frequently with severe haemorrhages, started therapy with a higher platelet count and received lower dose front-line corticosteroids; thereafter, they were preferentially treated with mild immunosuppressive therapies/thrombopoietin-receptor agonists. Conversely, younger patients were more frequently treated with rituximab and splenectomy, achieving higher rates of complete responses. Incidence rates of >=grade 2 complications were: 2.87 (haemorrhages), 1.55 (infections) and 0.66 (thromboses) per 100 patient-years. Older age (P = 0.01) and active haemorrhages at diagnosis (P = 0.01) significantly predicted grade >=2 haemorrhages during follow-up. Older age (P = 0.01), male gender (P = 0.01), and thrombopoietin receptor agonist use (P = 0.02) were significantly associated with a higher probability of thrombosis over time. Older age is a significant driver of diagnostic/therapeutic strategy in ITP resulting in different responses and complications rates. PMID- 30408158 TI - Group formation, styles, and grammars of commonality in local activism. AB - This article argues that in order to analyse democracy as a pattern constantly processed in a given society, it is useful to look at activist groups' agenda setting and recruitment principles, group bonds and boundaries, and how these actions direct and influence ways of creating the common. Based on an ethnographic study on bicycle activism in Helsinki, Finland, it describes a local critical mass movement that was successful in promoting a bicycle friendly and sustainable city, yet dissolved due to lack of people involved, and the bicycle demonstrations stopped at a moment of high public interest. This empirical puzzle is addressed by combining three theoretical perspectives: Kathleen Blee's work on path dependencies in nascent activist groups; Nina Eliasoph and Paul Lichterman's work on group styles, and Laurent Thevenot's work on the grammars of commonality. These theoretical tools help understand the sense of what is deemed possible, desirable and feasible in activist groups, and the consequences thereof to social movement 'success' and 'failure'. The article claims that everyday practices and interaction are crucial in understanding the 'democratic effects' of social movements. It concludes that following specific processes of politicization and their conditionings in activist groups provides keys to understanding contextual differences in democracies without resorting to methodological nationalism or to exaggerated global isomorphism, and thus may contribute to figuring out how to succeed global action plans over wicked, pressing problems like global warming. PMID- 30408159 TI - The collective/affective practice of cancer survivorship. AB - Whether within an atmosphere of hope, or amidst relations of fear, the emotions of cancer are unavoidably collectively produced. Yet persistent individualistic paradigms continue to obscure how the emotions of cancer operate relationally - between bodies, subjects, discourses, and practices - and are intertwined with circulating beliefs, cultural desires, and various forms of normativity. Drawing on interviews with 80 people living with cancer in Australia, this paper illustrates why recognition of the collective enterprise of survivorship - and the collective production of emotion, more generally - is important in light of persistent, culturally dominant conceptions of the individual patient as the primary 'afflicted', 'feeling', and 'treated' subject. Building on previous work on affective relations and moral framings, we posit that the collective affects of survivorship inflect what people living with cancer can, and should, feel. We highlight how such things as hope, resignation, optimism, and dread are 'products' of the collective affects of cancer, with implications for how survivorship is lived, felt, and done. PMID- 30408160 TI - The effect on lymphocyte subsets of decreasing/stopping tyrosine kinase inhibitor therapy in chronic myeloid leukaemia: data from the DESTINY trial. PMID- 30408161 TI - Postnatal developmental trajectory of dopamine receptor 1 and 2 expression in cortical and striatal brain regions. AB - Healthy brain function requires a balance between the activity of dopamine receptor 1 (D1) and dopamine receptor 2 (D2). Alterations in this balance increase the risk for numerous developmental brain disorders. Indeed, D1 and D2 expression fluctuates throughout maturation, although there is conflicting evidence regarding the precise changes that occur. Here, we used stereology to investigate the developmental changes in the number of D1- or D2-expressing neurons in the prelimbic cortex, infralimbic cortex (IL), insula cortex, dorsal striatum, and ventral striatum of female and male mice with green fluorescent protein-tagged D1 or D2. Postnatal day 17, 25, 35, 49, and 70 were examined to cover juvenility to adulthood. In all regions, analysis of D1 density compared to D2 density within each sex seldom detected effects or interactions involving age. However, D1:D2 density ratio changed across age depending on sex. In the IL, D1:D2 density ratio increased in females from adolescence, whereas it was stable in males. In the insula cortex, D1:D2 ratio initially increased in males but decreased in females from juvenility to pre-adolescence. The ratio then increased in males and females from adolescence to adulthood, with males showing a more dramatic increase. In both the dorsal and ventral striatum, the ratio increased from adolescence. In all regions, females had a higher ratio compared to males throughout development, except in the insula cortex at P25. These comprehensive observations are novel, and highlight how the maturational changes in the expression of these receptors may contribute to developmental disorders. This article is protected by copyright. All rights reserved. PMID- 30408162 TI - Perioperative alcohol cessation intervention for postoperative complications. AB - BACKGROUND: Risky consumption of alcohol is a global problem. More than 3.3 million deaths annually are associated with risky use of alcohol, and global alcohol consumption continues to increase. People who have high alcohol consumption often require planned and emergency surgical procedures.Risky drinking is associated with increased postoperative complications such as infections, cardiopulmonary complications, and bleeding episodes. Alcohol causes disorders of the liver, pancreas, and nervous system. Stopping consumption of alcohol can normalize these organ systems to some degree and may reduce the occurrence of complications after surgery.This review was first published in 2012 and was updated in 2018. OBJECTIVES: To assess the effects of perioperative alcohol cessation interventions on rates of postoperative complications and alcohol consumption. SEARCH METHODS: We searched the following databases up until 21 September 2018: Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; MEDLINE; Embase; CINAHL via EBSCOhost; and two trials registers. We scanned the reference lists and citations of included trials and any identified relevant systematic reviews for further references to additional trials. When necessary, we contacted trial authors to ask for additional information. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) that evaluated the effects of perioperative alcohol cessation interventions on postoperative complications and alcohol consumption. We included participants with risky consumption of alcohol who were undergoing all types of elective or acute surgical procedures under general or regional anaesthesia or sedation, who were offered a perioperative alcohol cessation intervention or no intervention.We defined 'risky drinking' as alcohol consumption equivalent to more than 3 alcoholic units (AU)/d or 21 AU/week (with 1 AU containing 12 grams of ethanol) with or without symptoms of alcohol abuse or dependency. This corresponds to the amount of alcohol associated with increased postoperative complication rates in most clinical studies. DATA COLLECTION AND ANALYSIS: We used guidance provided in the Cochrane Handbook for Systematic Reviews of Interventions. We presented main outcomes as dichotomous variables in a meta analysis. When data were available, we conducted subgroup and sensitivity analyses to explore the risk of bias. Primary outcome measures were postoperative complications and in-hospital and 30-day mortality. Secondary outcomes were successful quitting at the end of the programme, postoperative alcohol use, and length of hospital stay. We assessed the quality of evidence using the GRADE approach. MAIN RESULTS: We included in this updated review one new study (70 participants), resulting in a total of three RCTs (140 participants who drank 3 to 40 AU/d). All three studies were of moderate to good quality. All studies evaluated the effects of intensive alcohol cessation interventions, including pharmacological strategies for alcohol withdrawal symptoms, patient education, and relapse prophylaxis. We identified one ongoing study.Overall, 53 of the 122 participants from three studies who underwent surgery developed any type of postoperative complication that required treatment. Of 61 participants in the intervention groups, 20 had complications, compared with 33 of 61 participants in the control groups (risk ratio (RR) 0.62, 95% confidence interval (CI) 0.40 to 0.96). Results show differences between the three clinical studies regarding outcome measurement and intensity of the interventions. However, all alcohol cessation programmes were intensive and included pharmacological therapy. The overall quality of evidence for this outcome is moderate.In-hospital and 30-day postoperative mortality rates were low in the three studies. Researchers reported one death among 61 participants in the intervention groups, and three deaths among 61 participants in the control groups (RR 0.47, 95% CI 0.07 to 2.96). The quality of evidence for this outcome is low.Investigators describe more successful quitters at the end of the intervention programme than among controls. Forty-one out of 70 participants in the intervention groups successfully quit drinking compared with only five out of 70 participants in the control groups (RR 8.22, 95% CI 1.67 to 40.44). The quality of evidence for this outcome is moderate.All three studies reported postoperative alcohol consumption (grams of alcohol/week) at the end of the programme as median and range values; therefore it was not possible to estimate the mean and the standard deviation (SD). We performed no meta-analysis. All three studies reported length of stay, and none of these studies described a significant difference in length of stay. Data were insufficient for review authors to perform a meta-analysis. No studies reported on the prevalence of participants without risky drinking in the longer term. AUTHORS' CONCLUSIONS: This systematic review assessed the efficacy of perioperative alcohol cessation interventions for postoperative complications and alcohol consumption. All three studies showed a significant reduction in the number of participants who quit drinking alcohol during the intervention period. Intensive alcohol cessation interventions offered for four to eight weeks to participants undergoing all types of surgical procedures to achieve complete alcohol cessation before surgery probably reduced the number of postoperative complications. Data were insufficient for review authors to assess their effects on postoperative mortality. No studies reported an effect on length of stay, and no studies addressed the prevalence of risky drinking in the longer term.Included studies were few and reported small sample sizes; therefore one should be careful about drawing firm conclusions based on these study results. All three studies were conducted in Denmark, and most participants were men. The included participants may represent a selective group, as they could have been more motivated and/or more interested in participating in clinical research or otherwise different, and effects may have been overestimated for both intervention and control groups in these studies. Trial results indicate that these studies are difficult to perform, that strong research competencies are necessary for future studies, and that further evaluation of perioperative alcohol cessation interventions in high-quality randomized controlled trials is needed. Once published and assessed, the one 'ongoing' study identified may alter the conclusions of this review. PMID- 30408163 TI - Maternal breast volume in pregnancy and lactation capacity. AB - OBJECTIVES: Successful breastfeeding, crucial for a child's development, depends on a woman's ability to initiate lactation, milk yield, and composition. Those traits differ among women, but the cause and physiological mechanisms responsible for this variation are not fully understood yet. Growing evidence shows that lactation and milk composition vary among women and depend on maternal traits. The aim of this study was to test whether breast volume and its changes during pregnancy are related to the nutritional quality of breastmilk and to breastfeeding dynamics. MATERIAL AND METHODS: Almost 93 pregnant women (mean age: 29.67 +/- 3.65), participated in the longitudinal study. Breast measurement was performed at each pregnancy trimester using 3D scanning. Milk samples were collected in the beginning of the second month of lactation from 69 women. Milk macronutrient and calorie content were measured. Women were also interviewed on breastfeeding time and frequency. RESULTS: Breast volume changes during pregnancy were not related to the probability of establishing successful lactation, milk calorie, fat and protein content. We found a negative correlation between milk lactose content and breast volume in the second and third trimester but not with breast volume change. Maternal breast volume in pregnancy was also positively related to the total breastfeeding time (per 24 hr). CONCLUSIONS: The results are in line with the notion that milk macronutrient content tends to be weakly associated with various maternal factors and adverse conditions. However, maternal breast volume and its changes during pregnancy are related with time spent breastfeeding per day, what suggests a positive correlation between breast volume in pregnancy and milk yield. PMID- 30408164 TI - Dose-limiting stomatitis associated with ibrutinib therapy: a case series. PMID- 30408165 TI - Distribution of endogenous normal tau in the mouse brain. AB - Tau is a microtubule-associated protein (MAP) that is localized to the axon. In Alzheimer's disease (AD), the distribution of tau undergoes a remarkable alteration, leading to the formation of tau inclusions in the somatodendritic compartment. While the abnormal aggregated tau has been extensively studied in human patient tissues and animal models of AD, how normal tau localizes to the axon, which would be the foundation to understand how the mis-localization occurs, has not been well studied due to the poor detectability of normal unaggregated tau in vivo. Therefore, we developed immunohistochemical techniques that can detect normal mouse and human tau in brain tissues with high sensitivity. Using these techniques, we demonstrate the global distribution of tau in the mouse brain and confirmed that normal tau is exclusively localized to the axonal compartment in vivo. Interestingly, tau antibodies strongly labeled nonmyelinated axons such as hippocampal mossy fibers, while white matters generally exhibited low levels of immunoreactivity. Furthermore, mouse tau is highly expressed not only in neurons but also in oligodendrocytes. With super resolution imaging using the stimulated-depletion microscopy, axonal tau appeared punctate rather than fibrous, indicating that tau decorates microtubules sparsely. Co-labeling with presynaptic and postsynaptic markers revealed that normal tau is not localized to synapses but sparsely distributes in the axon. Taken together, this study reports novel antibodies to investigate the localization and mis-localization of tau in vivo and novel findings of normal tau localization in the mouse brain. PMID- 30408166 TI - Indirect pathway to pectoral fin motor neurons from nucleus ruber in the Nile tilapia Oreochromis niloticus. AB - Supraspinal motor control systems of pectoral fins remain unclear in teleosts. Nucleus ruber of Goldstein (1905; NRg), which has been identified as the probable homologue of nucleus ruber of tetrapods, is a candidate structure serving for such functions. In the present study, we investigated possible involvement of the NRg in the control of pectoral fin movement by tract-tracing experiments in the Nile tilapia Oreochromis niloticus. Tracer injections into the NRg revealed the fiber course of rubrospinal tract. Rubrospinal fibers crossed the midline at the level of midbrain, descended through the tegmentum, and terminated in a region ventrally adjacent to the dorsal horn at the spinomedullary junction, without reaching the ventral horn where pectoral fin motor neurons are present. Tracer injection experiments into the dorsal horn region resulted in labeled terminals in proximities of presumed pectoral fin motor neurons in the ventral horn. Tracer injection experiments into the ventral horn resulted in retrogradely labeled neurons ventrally adjacent to the dorsal horn, where labeled terminals were detected following rubral injections. These anatomical analyses suggest that the NRg of actinopterygians is involved in the control of pectoral fin motor neurons through an indirect pathway via interneurons in the dorsal horn. This article is protected by copyright. All rights reserved. PMID- 30408167 TI - Distribution and density of mixed-input ON bipolar cells of the goldfish (Carassius auratus) during growth. AB - Neurons are continuously produced at different rates and locations in the teleost retina. Goldfish rods are homogeneously distributed and maintain a stable density throughout growth, whereas little is known about their post-synaptic partners. We examined the distribution and density of mixed-input ON bipolar cells (ON mBCs) in 57 goldfish of various sizes by immunolabeling their retinas with an antibody against PKCalpha and counting PKCalpha-positive neurons in wholemounts. Cell densities were correlated with morphometric data for the same animals, and the spatial resolution of the ON mBC mosaic was calculated in each case. The distribution of ON mBCs is homogeneous throughout growth. For a 10-fold change in body size (i.e., from 20 to 200 mm), the total number of ON mBCs increases 2.8 times, while retinal area expands around 10 times. As a consequence, the density of ON mBCs in large fish falls to ~1/3 of that of small animals, and intercellular spacing doubles. The eye and the lens become around 3 times larger from small to large fish. This causes the retinal magnification factor (and thereby the image projected onto retina) to augment by the same amount. Because the retinal magnification factor rises more than the intercellular spacing in the same animals, the spatial resolution of the ON mBC mosaic improves from 0.8 to 1.4 cycles/degree as the body size increases from 20 to 200 mm. Since ON mBCs are mostly rod-driven, our results suggest that the scotopic acuity of the goldfish may improve as the animal grows. This article is protected by copyright. All rights reserved. PMID- 30408168 TI - PRBAM: a new tool to analyze the MHC class I and HLA-DR anchor motifs. AB - MHC genes are highly polymorphic, what makes each MHC molecule different regarding the peptide repertoire they can bind and present to T lymphocytes. The increasing importance of immunopeptidomics and its use in personalized medicine in different fields as oncology or autoimmunity demands the correct analysis of the peptide repertoires bound to HLA-I and -II molecules. Purification of the peptide pool by affinity chromatography and individual peptide sequencing using mass spectrometry techniques is the standard protocol to define the binding motifs of the different MHC-I and MHC-II molecules. The identification of MHC-I binding motifs is relatively simple, but it is much more complicated for MHC-II. There are some programs which identify the anchor motifs of MHC-II molecules. However, these programs do not identify the anchor motif correctly for some HLA II molecules and some anchor motifs have been deduced using subjective interpretation of the data. Here, we present a new software, called PRBAM (Peptide Repertoire-Based Anchor Motif) that uses a new algorithm based on the peptide-MHC interactions and, using peptide lists obtained by MS sequencing, identifies the binding motif of MHC-I and HLA-DR molecules. PRBAM has an interface easy to use, and the results are presented in graphics, tables and peptide lists. Finally, the fact that PRBAM uses a new algorithm makes it complementary to other existing programs. This article is protected by copyright. All rights reserved. PMID- 30408169 TI - Synaptic distributions of pS214-tau in rhesus monkey prefrontal cortex are associated with spine density, but not with cognitive decline. AB - Female rhesus monkeys and women are subject to age- and menopause-related deficits in working memory, an executive function mediated by the dorsolateral prefrontal cortex (dlPFC). Long-term cyclic administration of 17beta-estradiol improves working memory, and restores highly plastic axospinous synapses within layer III dlPFC of aged ovariectomized monkeys. In this study, we tested the hypothesis that synaptic distributions of tau protein phosphorylated at serine 214 (pS214-tau) are altered with age or estradiol treatment, and couple to working memory performance. First, ovariectormized young and aged monkeys received vehicle or estradiol treatment, and were tested on the delayed response (DR) test of working memory. Serial section electron microscopic immunocytochemistry was then performed to quantitatively assess the subcellular synaptic distributions of pS214-tau. Overall, the majority of synapses contained pS214-tau immunogold particles, which were predominantly localized to the cytoplasm of axon terminals. pS214-tau was also abundant within synaptic and cytoplasmic domains of dendritic spines. The density of pS214-tau immunogold within the active zone, cytoplasmic, and plasmalemmal domains of axon terminals, and subjacent to the postsynaptic density within the subsynaptic domains of dendritic spines, were each reduced with age. None of the variables examined were directly linked to cognitive status, but a high density of pS214-tau immunogold particles within presynaptic cytoplasmic and plasmalemmal domains, and within postsynaptic subsynaptic and plasmalemmal domains, accompanied high synapse density. Together, these data support a possible physiological, rather than pathological, role for pS214-tau in the modulation of synaptic morphology in monkey dlPFC. PMID- 30408170 TI - Subglottic stenosis: An evaluation of an elderly treatment-seeking population. AB - OBJECTIVES/HYPOTHESIS: To evaluate the demographics, etiology, intraoperative findings, and treatment outcomes of patients with subglottic stenosis (SGS), comparing those patients aged <65 years to an elderly population aged >=65 years. STUDY DESIGN: Retrospective cohort study. METHODS: Nine-year retrospective review of patients with SGS. Forty-eight adults presented for evaluation and treatment of SGS between January 2008 and December 2016. At the time of presentation, 41 were aged <65 years and seven were aged >=65 years. RESULTS: Comparing the aged <65 years group to the aged >=65 years group, the etiology was idiopathic SGS in 50.0% versus 42.8%, intubation-related SGS in 22.5% versus 28.6%, and granulomatosis with polyangiitis in 27.5% versus 28.6%, respectively. No statistically significant difference was noted in the two groups when comparing the demographics, etiology, treatment, intraoperative findings, or intertreatment interval (ITI). CONCLUSIONS: We sought to analyze an older patient population with SGS and found no statistically significant differences compared to a younger population. ITI trended toward older patients requiring surgery more frequently but was not significant. LEVEL OF EVIDENCE: 4 Laryngoscope, 2018. PMID- 30408171 TI - Modified endoscopic endonasal approach with a minimally invasive transoral approach-an adjunct to infrapetrous approaches. AB - OBJECTIVES/HYPOTHESIS: To evaluate the potential of a minimally invasive transoral-transpalatal approach (MITA) to the retrocarotid petrous apex, as an adjunct to endoscopic endonasal approaches (EEAs). STUDY DESIGN: Cadaver study. METHODS: Five cadaveric specimens were dissected raising an inverted U-shaped palatal mucoperiosteal flap, and drilling a rectangular palatotomy (between the greater palatine foramens, and just anterior to the palatine aponeurosis). This allowed a transpterygoid EEA with cross-court access (contralateral line of sight), followed by an extradural clivectomy that exposed the petroclival junction bilaterally. Surgical targets were marked on the posterior and medial surface of the petrous internal carotid artery (ICA), at its anterior genu, midhorizontal portion, and posterior genu. For each target and approach, the surgical freedom and angles of approach (in the horizontal and vertical planes) were calculated and statistically compared. RESULTS: Compared to EEA, the MITA resulted in greater surgical freedom for all targets, with the highest values at the anterior genu (1,661.37 mm2 vs. 312.76 mm2 , P <.001), and maintaining superiority in this regard all the way to the posterior genu (847.84 mm3 vs. 138.91 mm3 , P < .005). MITA also offered greater angles of approach for all targets. CONCLUSIONS: This study suggests that the MITA may be indicated to supplement the exposure provided by a transpterygoid EEA. This technique, associated with low potential morbidity, offers an alternative to internal carotid lateralization while managing extradural lesions that are adjacent to the petrous ICA. LEVEL OF EVIDENCE: NA Laryngoscope, 2018. PMID- 30408172 TI - Impact of pretreatment growth on Tumor control for vestibular schwannomas following gamma knife. AB - OBJECTIVES/HYPOTHESIS: To determine if volumetric growth prior to gamma knife (GK) radiosurgery predicts long-term tumor control. STUDY DESIGN: Retrospective cohort study. METHODS: Sporadic vestibular schwannomas (VS) treated with GK between 2002 and 2014 at a single tertiary care center were identified. Patients were included if they had over 6 months of pretreatment observation and over 1.5 years of posttreatment follow-up. Volumetric tumor analysis was performed on T1 postcontrast imaging. Pretreatment and posttreatment volume change was calculated. Tumors with over 20% volume increase were classified as growing. RESULTS: There were 62 patients included in this study; 48 had pretreatment growth and 14 had no pretreatment growth. Median tumor volume was 0.58 +/- 1.8 cm3 and median follow-up was 3.3 +/- 2.0 years. For tumors with and without pretreatment growth, salvage treatment rates were 2% and 7% (P = .35), and posttreatment radiologic stability rates were 73% and 86%, respectively (P = .33). Median pretreatment growth was 27 +/- 33% per year for tumors with posttreatment radiographic growth and 18 +/- 26% per year for tumors without posttreatment radiographic growth (P = .99). CONCLUSIONS: Pretreatment growth was not associated with increased salvage treatment or posttreatment radiographic progression rates in VS following GK. LEVEL OF EVIDENCE: 4 Laryngoscope, 2018. PMID- 30408173 TI - Measurement reliability of phonation threshold pressure in pediatric subjects. AB - OBJECTIVES/HYPOTHESIS: Phonation threshold pressure (PTP), the minimum subglottal pressure (Ps ) required for phonation, is sensitive to changes in laryngeal biomechanics and is often elevated with pathology. Little is reported on PTP in children; challenges with task performance and measurement reliability represent barriers to routine clinical assessment. STUDY DESIGN: Pilot study evaluating PTP and Ps measurement reliability in children using labial and mechanical interruption. METHODS: Twenty-two subjects aged 4 to 17 years (10.7 +/- 3.9 years) participated. Ten trials were performed for each method; task order was randomized. For labial interruption, subjects produced /palpha/ five times at softest (onset PTP) and comfortable amplitude. For mechanical interruption, subjects produced a sustained /alpha/ while a balloon valve interrupted phonation five times for 250 ms each; mechanical interruption was performed with a mouthpiece and mask. PTP was recorded as the difference between Ps and supraglottal pressure at phonation cessation (offset PTP). Mean PTP and Ps and intrasubject coefficients of variation were compared. Correlations with age were evaluated. RESULTS: Mean PTP (P < .001) and Ps (P = .005) were higher for labial interruption. Intrasubject coefficients of variation for PTP (P = .554) and Ps (P = .305) were similar across methods. Coefficient of variation was related to age for mechanical-mask trials only (r = -0.628, P = .00175). CONCLUSIONS: Differences in means are likely related to differences in task and PTP hysteresis effect. Reliability is comparable with all methods; using a mouthpiece may be preferable to a mask for mechanical interruption. Measurement of PTP is noninvasive, reliable, and may be a useful adjunct in pediatric voice assessment. LEVEL OF EVIDENCE: 3b Laryngoscope, 2018. PMID- 30408174 TI - Sex bias in basic science and translational otolaryngology research. AB - OBJECTIVES/HYPOTHESIS: Recent studies revealed sex bias in surgical research. Although many diseases exhibit sex-based clinically relevant differences, otolaryngology research has not been evaluated for sex reporting and sex-based analysis. We postulate that a similar bias is prevalent in otolaryngology literature. STUDY DESIGN: Literature review. METHODS: Articles published from 2016 to 2017 in The Laryngoscope, Otolaryngology-Head and Neck Surgery, and JAMA Otolaryngology-Head and Neck Surgery were reviewed. Articles with animal subjects, human subject cells, or commercial cell lines were included. Data collected included study type, cell/animal sex, and sex-based data analysis. RESULTS: One hundred forty-four basic/translational research articles were identified. Sixty-nine (47.9%) of those lacked sex reporting. Of 75 studies that reported sex, 22 (29.3%) included both sexes, and 11 (14.7%) analyzed data by sex. One hundred five (72.9%) used animal subjects, of which 54 (51.9%) lacked sex breakdown. Among animal studies, 48/105 included only one sex, and three articles analyzed data by sex. Fifty-four studies used commercial cell lines (N = 23) or human/animal subject cells (N = 31). Among cell groups, 28/54 (51.9%) were of unknown sex, and seven were single sex. Eight (14.8%) studies included data analysis by sex. Domestic studies exhibited a lower rate of sex reporting in both animal and cell studies, and a lower rate of sex-based analysis in cell studies. CONCLUSIONS: Sex may influence outcomes significantly but is underreported and underanalyzed in basic/translational otolaryngology research. Because this research frequently lays the groundwork for clinical trials and standards of care, future research must address these sex-based discrepancies. LEVEL OF EVIDENCE: NA Laryngoscope, 2018. PMID- 30408175 TI - Automated Indentation Mapping of Vocal Fold Structure and Cover Properties Across Species. AB - OBJECTIVES/HYPOTHESIS: Various animal models have been employed to investigate vocal fold (VF) and phonatory function. However, biomechanical testing techniques to characterize vocal fold structural properties vary and have not compared critical properties across species. We adapted a nondestructive, automated indentation mapping technique to simultaneously quantify VF structural properties (VF cover layer and intact VF) in commonly used species based on the hypothesis that VF biomechanical properties are largely preserved across species. STUDY DESIGN: Ex vivo animal model. METHODS: Canine, leporine, and swine larynges (n = 4 each) were sagittally bisected, measured, and subjected to normal indentation mapping (indentation at 0.3 mm; 1.2 mm/s) with a 2-mm spherical indenter to quantify normal force along the VF cover layer, structural stiffness, and displacement at 0.8 mN; two-dimensional maps of the free VF edge through the conus elasticus were created for these characterizations. RESULTS: Structural stiffness was 7.79 gf/mm (0.15-74.55) for leporine, 2.48 gf/mm (0.20-41.75) for canine, and 1.45 gf (0.56-4.56) for swine. For each species, the lowest values were along the free VF edge (mean +/- standard deviation; leporine: 0.40 +/- 0.21 gf/mm, canine: 1.14 +/- 0.49 gf/mm, swine: 0.89 +/- 0.28 gf/mm). Similar results were obtained for the cover layer normal force at 0.3 mm. On the free VF edge, mean (standard deviation) displacement at 0.08 gf was 0.14 mm (0.05) in leporine, 0.11 mm (0.03) in canine, and 0.10 mm (0.02) in swine. CONCLUSIONS: Automated indentation mapping yielded reproducible biomechanical property measurement of the VF cover and intact VF. Divergent VF structural properties across canine, swine, and leporine species were observed. LEVEL OF EVIDENCE: NA. Laryngoscope, 2018. PMID- 30408176 TI - The Prevalence of Cricopharyngeal Webs in Elderly Cadavers. AB - OBJECTIVE: Cricopharyngeal webs (CPW) are a frequent cause of solid food dysphagia. They are difficult to diagnose and are often missed on swallowing fluoroscopy. The prevalence of CPWs is uncertain. The purpose of this study was to determine the prevalence of CPWs in elderly cadavers. METHODS: Direct laryngoscopy and cervical esophagoscopy were performed in 19 embalmed cadavers by independent two-clinician consensus. Cadaver demographics and the presence and laterality of a CPW were recorded. The prevalence of CPW was calculated, and the size of the cricopharyngeus muscle (CPM) was quantified. RESULTS: The mean age of the cohort was 83 ( +/- 12) years. Fifty-three percent were female, and the mean body mass index was 19.7 ( +/- 3). The causes of death were cardiovascular disease (10 of 19), cancer (5 of 19), and respiratory failure (4 of 19). A CPW was present in 68% (13 of 19) of cadavers. Forty-seven percent (9 of 19) had a unilateral web, and 21% (4 of 19) had a bilateral web. There was no laterality predominance (P > 0.05). Forty-two percent (8 of 19) had no CPM prominence; 32% (6 of 19) had a small/moderate CPM prominence; and 26% (5 of 19) had a significant CPM prominence. CONCLUSION: The prevalence of cricopharyngeal webs in elderly cadavers is high (68%). The clinician should maintain a high index of suspicion for CPWs in patients with no other identifiable etiology of solid food dysphagia. LEVEL OF EVIDENCE: 3b. Laryngoscope, 2018. PMID- 30408177 TI - Structural mechanisms for defective CFTR gating caused by the Q1412X mutation, a severe Class VI pathogenic mutation in cystic fibrosis. AB - KEY POINTS: Electrophysiological characterization of Q1412X-CFTR, a C-terminal truncation mutation of cystic fibrosis transmembrane conductance regulator (CFTR) associated with the severe form of cystic fibrosis (CF), reveals a gating defect that has not been reported previously. Mechanistic investigations of the gating deficit in Q1412X-CFTR suggest that the reduced open probability in Q1412X-CFTR is the result of a disruption of the function of the second ATP binding site (or site 2) in the nucleotide binding domains (NBDs). Detailed comparisons of several mutations with different degrees of truncation in the C-terminal region of NBD2 reveal the importance of the last two beta-strands in NBD2 for maintaining proper gating functions. The results of the present study also show that the application of clinically-approved drugs (VX-770 and VX-809) can greatly enhance the function of Q1412X, providing in vitro evidence for a therapeutic strategy employing both reagents for patients bearing Q1412X or similar truncation mutations. ABSTRACT: Cystic fibrosis (CF) is caused by loss-of-function mutations of cystic fibrosis transmembrane conductance regulator (CFTR), a phosphorylation-activated but ATP gated chloride channel. Based on the molecular mechanism of CF pathogenesis, disease-associated mutations are categorized into six classes. Among them, Class VI, whose members include some of the C-terminal truncation mutations such as Q1412X, is defined as decreased membrane expression because of a faster turnover rate. In the present study, we characterized the functional properties of Q1412X CFTR, a severe-form premature stop codon mutation. We confirmed previous findings of a ~90% decrease in membrane expression but found a ~95% reduction in the open probability (Po ). Detailed kinetic studies support the idea that the gating defect is the result of a dysfunctional ATP-binding site 2 in the nucleotide binding domains (NBDs). Because the Q1412X mutation results in a deletion of the last two beta-strands in NBD2 and the whole C-terminal region, we further characterized truncation mutations with different degrees of deletion in this segment. Mutations that completely or partially remove the C-terminus of CFTR at the same time as keeping an intact NBD2 (i.e. D1425X and S1455X) assume gating function almost identical to that of wild-type channels. However, the deletion of the last beta-strand in the NBD2 (i.e. N1419X) causes gating dysfunction that is milder than that of Q1412X. Thus, normal CFTR gating requires structural integrity of NBD2. Moreover, our observation that clinically-approved VX-809 (Lumacaftor, Vertex Pharmaceuticals, Boston, MA, USA) and VX-770 (Ivacaftor, Vertex Pharmaceuticals, Boston, MA, USA) significantly enhance the overall function of Q1412X-CFTR provides the conceptual basis for the treatment of patients carrying this mutation. PMID- 30408178 TI - Topical Application of 5-Aminolevulinic Acid Is Sufficient for Photodynamic Therapy on Vocal Folds. AB - OBJECTIVES: To evaluate the feasibility of topical photodynamic therapy (PDT) using 5-aminolevulinic acid (5-ALA) for vocal fold leukoplakia. STUDY DESIGN: Ex vivo and in vivo. METHODS: 5-ALA was applied topically as a 20% solution to ex vivo canine vocal folds. The penetration depth and concentrations of 5-ALA in tissue were quantified using frozen sectioning and fluorescamine derivatization after 5-ALA contact incubation or topical spraying. Then, 5-ALA solution was sprayed on leporine vocal folds once, twice, or given systemically in vivo. Protoporphyrin IX (PPIX) location was visualized using fluorescence microscopy, and PPIX concentrations were measured using a fluorescent quantitative method. Hematoxylin and eosin (H&E) staining was performed to visualize the histological changes of vocal folds after PDT for each group. RESULTS: Topical incubation of 15 minutes with 5-ALA achieved a penetration depth of over 2 mm and similar concentrations within the superficial 500 MUm of epithelium, compared with longer incubation times. Topical spraying of 5-ALA produced sufficient concentrations in vocal folds, but the retention time is short. An in vivo leporine model showed that laryngeal spraying of 20% 5-ALA induced similar penetration depth and concentrations of PPIX compared to systemic administration of 5-ALA. Two sprays of 20% 5-ALA solution with an interval of 30 minutes are needed to produce complete exfoliation of vocal fold epithelium. CONCLUSION: Topical PDT with laryngeal spraying of 20% 5-ALA solution achieves sufficient therapeutic effects and is potentially applicable for the treatment of vocal fold leukoplakia. LEVEL OF EVIDENCE: NA. Laryngoscope, 2018. PMID- 30408179 TI - Real steak knives of cincinnati: Repeated foreign body ingestion with novel endoscopic removal. AB - Repeated ingestion of foreign objects presents a multidisciplinary endoscopic dilemma. We report a 32-year-old female patient with history of multiple previous foreign body ingestions requiring several past exploratory laparotomies, who presents with a knife blade in the esophagus. We present a novel method of using a rigid cervical esophagoscope with a salivary bypass tube. The tip of the knife was isolated into the cervical esophagoscope, and the salivary bypass tube advanced off the cervical esophagoscope over the knife, shielding the serrated edge during removal preventing laceration to the esophagus. PMID- 30408180 TI - Glottic exposure for transoral laser microsurgery: Proposal of a mini-version of the laryngoscore. AB - OBJECTIVES: Good laryngeal exposure (GLE) is typically regarded as an essential prerequisite for transoral laser microsurgery (TLM). The Laryngoscore is a preoperative scoring system aimed at predicting glottic visualization through the laryngoscope using easy patient-derived parameters. However, the presence of subjective variables may hamper its reliability and reproducibility. The aim of the present study was to provide a validation of the Laryngoscore and to develop a revised mini-version of the same, called mini-Laryngoscore (mLS), which could allow even quicker, yet sufficiently accurate, preoperative prediction of GLE. STUDY DESIGN: Prospective cohort study. METHODS: We prospectively evaluated 310 consecutive patients submitted to TLM between 2014 and 2017, grading each patient according to the variables considered in the Laryngoscore. RESULTS: Among the 11 variables of the previous Laryngoscore, three were confirmed as statistically significant at validation: interincisors gap, thyromental distance, and upper jaw dental status. We chose these three variables as part of the revised mLS (ranging from 0 to 4). In our cohort, 30% of the patients obtained a score of 0, 57% a score of 1, 11% a score of 2, and 2% a score of >=3. GLE was achieved in 97%, 85%, 65%, and 20% of cases, respectively. CONCLUSION: Our validation confirmed the predictive ability of the Laryngoscore. Furthermore, although composed of only three clinical parameters, the mLS was still able to convey useful information regarding the possibility of obtaining GLE. LEVEL OF EVIDENCE: 2. Laryngoscope, 2018. PMID- 30408181 TI - The therapeutic potential of the insect metalloproteinase inhibitor against infections caused by Pseudomonas aeruginosa. AB - OBJECTIVES: The objective of this study was to investigate the therapeutic potential of the insect metalloproteinase inhibitor (IMPI) from Galleria mellonella, the only known specific inhibitor of M4 metalloproteinases. METHODS: The fusion protein IMPI-GST (glutathione-S-transferase) was produced by fermentation in Escherichia coli and was tested for its ability to inhibit the proteolytic activity of the M4 metalloproteinases thermolysin and Pseudomonas elastase (PE), the latter a key virulence factor of the wound-associated and antibiotic-resistant pathogen Pseudomonas aeruginosa. We also tested the ability of IMPI to inhibit the secretome (Sec) of a P. aeruginosa strain obtained from a wound. KEY FINDINGS: We found that IMPI-GST inhibited thermolysin and PE in vitro and increased the viability of human keratinocytes exposed to Sec by inhibiting detachment caused by changes in cytoskeletal morphology. IMPI-GST also improved the cell migration rate in an in vitro wound assay and reduced the severity of necrosis caused by Sec in an ex vivo porcine wound model. CONCLUSIONS: The inhibition of virulence factors is a novel therapeutic approach against antibiotic resistant bacteria. Our results indicate that IMPI is a promising drug candidate for the treatment of P. aeruginosa infections. PMID- 30408182 TI - Does anatomic subsite influence oral cavity cancer mortality? A SEER database analysis. AB - OBJECTIVE: To determine if there are differences in mortality from oral cavity squamous cell carcinoma (OCSCC) based on oral cavity (OC) subsites. METHODS: Using the Surveillance, Epidemiology, and End Results Program (SEER) 9 database, patients with sequence number 0 or 1 squamous cell OCSCC were analyzed by OC subsite for 5-year cause-specific mortality (CSM) from OCSCC. Proportional hazards regression determined the association between 5-year CSM and OC subsites while controlling for treatment modality, stage, and demographic characteristics using hazard ratios. Significance was set at alpha = 0.05. RESULTS: 20,647 OC patients were included in the regression analysis. The most commonly diagnosed sites were floor of mouth (34.4%) and oral tongue (34.3%). Floor of mouth, upper gum, and retromolar trigone were associated with lower CSM compared to oral tongue. Not receiving surgery and receiving radiation were associated with increased CSM, and CSM increased with cancer staging when distant or regional disease was compared to localized disease. Also, patients diagnosed at 60 years or older and black patients had increased CSM. CONCLUSION: Among OCSCC patients, those with oral tongue cancer are more likely to experience CSM than patients with floor of mouth, upper gum, and retromolar trigone cancer. It is important to understand these mortality related differences in the management of OCSCC patients. Understanding subsite-specific mortality may benefit prognosis counseling of OCSCC patients and elicit subsite-directed research as a means to improve outcomes. LEVEL OF EVIDENCE: NA. Laryngoscope, 2018. PMID- 30408183 TI - Primary tumor location in stage III colon cancer has prognostic impact on subsequent liver metastasis. AB - BACKGROUND AND OBJECTIVES: We aim to investigate whether a difference exists between right-sided and left-sided colon cancer at the same disease stage and subsequent liver metastasis and identify whether tumor location can independently influence survival. METHODS: Right-sided colon cancer was defined as malignancy arising from the cecum to the transverse colon; left-sided colon cancer was defined as malignancy arising from the splenic flexure to the sigmoid colon. Clinicopathological features and survival data were collected for analysis. RESULTS: Overall, 1442 patients were included for analysis. The median follow-up time was 58.2 months. Patients with left-sided colon cancer had better 5-year overall survival (75.2% vs 61.7%, P = 0.005), 5-year cancer-specific survival (81.6% vs 73.4%, P = 0.001), and 5-year recurrence-free survival (70.9% vs 66.5%, P = 0.033) compared with patients having right-sided colon cancer. After the presentation of subsequent liver metastasis, patients with primary left-sided colon cancer had better 3-year cancer-specific survival ( P < 0.001). In the multivariate analysis, cancer location was an independent prognostic factor for cancer-specific survival (right vs left, HR: 1.276, 95% CI: 1.002-1.625). CONCLUSIONS: The primary tumor location can serve as a prognostic factor for treatment outcomes either in primary stage III colon cancer or subsequent liver metastasis. PMID- 30408184 TI - Optimal resection margin for head and neck cutaneous melanoma. AB - OBJECTIVES/HYPOTHESIS: The objective of this study was to examine the difference between a narrow (between 1 and 2 cm) and a wide (>2 cm) margin in the surgical resection of head and neck cutaneous melanoma. STUDY DESIGN: Population-based cohort analysis. METHODS: The Surveillance, Epidemiology, and End Results database was employed to identify patients who had cutaneous melanoma of the head and neck from 2004 to 2014. Outcome measures were overall survival (OS) and disease-specific survival (DSS). RESULTS: Among the total of 3,583 cases of cutaneous melanoma of the head and neck with known resection margins, 2,641 individuals had narrow resection margins, and 942 patients had wide margins. Most of the tumors presented in the skin of the scalp and neck, followed by the face, external ear, and other areas. The 5-year and 10-year Kaplan-Meier OS probabilities for narrow and wide margins were 65% and 66%, respectively, compared with 49% and 48%, respectively. The DSS probabilities exhibited similar trends between the two groups at these time points. In the Cox regression model, the patients who received narrow margins had similar OS (95% confidence interval [CI]: 0.918-1.217) and DSS (95% CI: 0.856-1.352) compared with the wide resection margin group, even when controlled for age, sex, T stage, and histology. CONCLUSIONS: The survival of patients with cutaneous melanoma of the head and neck depends on age, depth of tumor invasion, and histology. Within the head and neck, a wider resection margin of >2 cm does not confer any additional survival benefit compared with a narrower margin. Future studies should examine whether wider surgical margins would confer survival benefit in local or recurrent melanoma. LEVEL OF EVIDENCE: 4 Laryngoscope, 2018. PMID- 30408185 TI - Is a schirmer's test necessary before blepharoplasty? PMID- 30408186 TI - Aspiration in children with unilateral vocal fold paralysis. AB - OBJECTIVES/HYPOTHESIS: To describe the prevalence of aspiration in children with unilateral vocal fold paralysis who underwent objective assessment of swallow function. STUDY DESIGN: Retrospective chart review. METHODS: A study of patients presenting to our institution with unilateral vocal fold paralysis in 2015 was conducted. All patients were diagnosed using flexible laryngoscopy. Patients were included if they underwent at least one modified barium swallow (MBS) study for evaluation of their swallowing function due to recurrent respiratory issues and/or feeding difficulty. RESULTS: Twenty-eight patients diagnosed with unilateral vocal fold paralysis underwent an MBS study at our institution in 2015. Median age at the time of MBS study was 1.7 years (interquartile range: 0.4 4.3). Twenty-six patients (92.9%) had dysphagia. Sixteen patients were found to aspirate on MBS study. All patients who aspirated did so without overt signs (silent aspiration). Eighteen patients had congenital heart disease (64.3%) and nine had a history of prematurity (32.1%). Eight patients (28.6%) presented with developmental delays. CONCLUSIONS: Patients who present with unilateral vocal fold paralysis and recurrent respiratory and/or feeding issues may be affected by prominent issues such as swallowing dysfunction and silent aspiration. Clinicians should be aware of this risk and evaluate patients for any signs of feeding or swallowing difficulties. LEVEL OF EVIDENCE: 4 Laryngoscope, 2018. PMID- 30408187 TI - What defines asymmetric sensorineural hearing loss? PMID- 30408188 TI - Interesting case of late Gore-Tex extrusion following medialization laryngoplasty. AB - A 65-year-old female presented with a foreign body sensation following an asthmatic attack associated with severe coughing. Six years earlier, the patient underwent medialization laryngoplasty (ML), which was complicated by a small tear (2 mm) in the right ventricle. One year following this, the patient developed Gore-Tex extrusion but elected only for partial removal. Healing was complete until 5 years later; on examination, the patient had evidence of Gore-Tex extrusion through the right ventricle. Implant extrusion is a recognized complication of ML. This case demonstrates several important surgical steps that can benefit otolaryngologists at all stages of their surgical career. Laryngoscope, 2018. PMID- 30408189 TI - The epidemiology of autologous tissue grafting in primary and revision rhinoplasty. AB - OBJECTIVES/HYPOTHESIS: To determine the percentage of primary versus revision rhinoplasty cases that require an extranasal source of grafting, as well as age and gender-specific trends. STUDY DESIGN: Cross-sectional analysis of multistate ambulatory surgery and hospital databases. METHODS: Ambulatory rhinoplasty procedures were extracted from the State Ambulatory Surgery Databases for New York, Kentucky, North Carolina, Michigan, and Florida for 2014 to 2015. Cases were examined for simultaneous use of extranasal grafts. RESULTS: A total of 8,510 rhinoplasties were extracted (65.3% female, mean age = 35.6 years), and 11.9% were revision cases (95% confidence interval [CI]: 11.2-12.6). An extranasal, autologous source of grafting was required in 12.7% of cases (5.3% auricular, 95% CI: 4%-6.6%; 1.8% costal, 95% CI: 1%-2.6%). Revision cases were more likely to require a secondary source of grafting (24.4%, 95% CI: 21.8%-27.1% vs. 11.1%, 95% CI: 10.3%-11.8%). In revision cases, the most common graft was auricular cartilage (14.4%, 95% CI: 12.2%-16.6%) followed by costal (7.1%, 95% CI: 5.52%-8.69%). Only 1.1% of primary cases required costal cartilage (95% CI: 0.88%-1.36%) compared to 7.1% of revision cases (95% CI: 5.52%-8.69%). Of the primary cases, 4.1% required auricular cartilage grafting (95% CI: 3.67%-4.57%) compared to 14.4% of revision cases (95% CI: 12.2%-16.6%). Patients who required a graft were older. Significantly more males required autologous grafting than females (P = .047). CONCLUSIONS: Cartilaginous or bony grafting is a critical surgical technique in both primary and secondary rhinoplasties. This is the first study to examine percentages of site-specific autologous grafting from auricular and costal donor sites for primary and revision cases. Gender and age-specific trends associated with specific grafting sites are also identified. These data are important to help guide preoperative counseling and informed consent for all rhinoplasty surgeries. LEVEL OF EVIDENCE: NA Laryngoscope, 2018. PMID- 30408190 TI - Do preoperative corticosteroids benefit patients with chronic rhinosinusitis with nasal polyposis? PMID- 30408191 TI - Decision aid prototype for treatment of pediatric sleep disordered breathing: A randomized pilot study. AB - OBJECTIVES: 1) To examine the feasibility and usability of a decision aid prototype (DA) for pediatric obstructive sleep apnea (OSA). 2) to estimate parameters for a future randomized controlled trial. STUDY DESIGN: Multicenter randomized pilot trial. METHODS: Ninety-nine parents of children ( < 6 years of age) undergoing consultation for adenotonsillectomy for sleep-disordered breathing were prospectively enrolled. Families were randomly assigned to receive the DA or to follow standard care procedures. All consultations were video recorded and coded with the observing patient involvement in decision making (OPTION) instrument. Following the consultation, parents completed the Decisional Conflict Scale (DCS) and Shared Decision-Making Questionnaire (SDM-Q-9), whereas otolaryngologists completed the physician version (SDM-Q-Doc). A subset of parents and surgeons were interviewed to assess the usability of the DA. RESULTS: Overall, a significantly negative correlation between DCS and SDM-Q-9 was observed (P < 0.001). Interviews showed that parents found the DA helpful but wanted more time to read and contemplate the information. Both parents and surgeons indicated that instructions on how to use the DA would be beneficial. For parents receiving the DA, the mean total OPTION score was 13.83 out of 40 (standard deviation 5.24), compared to 11.95 (standard deviation 5.21) in those not receiving the DA (P = 0.11). There were no significant differences in the decisional conflict or shared decision making when using the DA. CONCLUSION: The DA was feasible but used differently among surgeons. The need to improve SDM techniques was suggested by both surgeons and parents. Future studies training otolaryngologists on effective SDM techniques and how to appropriately utilize decision aids may improve SDM for pediatric OSA. LEVEL OF EVIDENCE: 1B. Laryngoscope, 2018. PMID- 30408192 TI - I dream of Gini: Quantifying inequality in otolaryngology residency interviews. AB - OBJECTIVES: Otolaryngology applicants routinely decry conflicting interview dates because this limits the number of interviews that one can attend, despite being offered an interview. Conversely, applicants also perceive that a large number of interviews are offered to a minority of applicants. We sought to verify and quantify the inequality in distribution of interviews attended. STUDY DESIGN: Retrospective analysis of the National Resident Matching Program (NRMP) 2016 Charting Outcomes in the Match and Electronic Residency Application Service (ERAS) historic specialty data. METHODS: The Gini coefficient, a commonly used indicator of economic inequality, was calculated using data from the 2016 Charting Outcomes in the Match to estimate the distribution of interviews attended. This data was compared to nine other specialties, comprising a wide range of competitiveness and specialty size. RESULTS: 26% (110 of 416) of otolaryngology applicants accounted for half (1,721 of 3,426) of all possible interview positions. The Gini coefficient ranged from 0.43 to 0.84 across 10 specialties, with a higher coefficient indicating higher inequality. The Gini coefficient among otolaryngology applicants was 0.43, indicating lower inequality than most other specialties. When including only applicants who interviewed, the Gini coefficient was 0.23. CONCLUSION: There is an unequal distribution of interview invitations, which likely reflects the reality of asymmetry in applicant competitiveness. Otolaryngology demonstrates the greatest equality in distribution, which may stem from a greater burden of hoarding. The specialty's perceived competitiveness mitigates factors such as cost and time, essentially encouraging more people to take as many interviews as they can. LEVEL OF EVIDENCE: NA. Laryngoscope, 2018. PMID- 30408193 TI - Activity of swallowing-related neurons in the medulla in the perfused brainstem preparation in rats. AB - OBJECTIVES/HYPOTHESIS: We aimed to investigate and validate the cellular activity patterns and the potential topographical organization of neurons of the medullary swallowing pattern generator (Sw-CPG). We used the perfused brainstem preparation as an innovative experimental model that allows for stable neuronal recording in the brainstem. STUDY DESIGN: Animal model. METHODS: Experiments were conducted in 14 juvenile Wistar rats. The activities of the phrenic, vagus, and hypoglossal nerves were recorded at baseline, and fictive swallowing was elicited by stimulation of the superior laryngeal nerve. Extracellular action potentials of 72 swallowing-related neurons were recorded in the Sw-CPG of the dorsal medulla oblongata. RESULTS: Neurons could be classified into three types: sensory relay, and neurons that were excited or inhibited during fictive swallowing. Approximately one-third of the neurons likely received monosynaptic input from the laryngeal afferents. One-third of neurons recorded showed respiratory-related activity, most of which exhibited inspiratory modulation. The neurons were widely distributed in the nucleus tractus solitarius and reticular formation. CONCLUSIONS: The perfused brainstem preparation of rat fully preserves the Sw CPG. The recorded cellular activities and general topographical organization of swallowing neurons are in accordance with previous in vivo studies. Thus, the perfused brainstem preparation is an ideal experimental model to advance the understanding of neuronal mechanisms underlying swallowing. LEVEL OF EVIDENCE: NA Laryngoscope, 2018. PMID- 30408194 TI - Potential cellular and energetic mechanisms for age-related differences in skeletal muscle fatigue. AB - Skeletal muscle fatigue is defined as the contraction-induced decline in maximal force- or power-generating capacity and can be caused by failure at any site along the pathway of force production. Several studies have observed greater skeletal muscle fatigue in older compared with young adults during high-velocity contractions, but the cause of this difference remains unclear. Because activities of daily living, such as climbing stairs or walking, require repeated dynamic contractions, the ability to resist muscle fatigue may be important for maintaining physical function into old age. This article is protected by copyright. All rights reserved. PMID- 30408195 TI - Trace Evidence Potential in Postmortem Skin Microbiomes: From Death Scene to Morgue. AB - Microbes can be used effectively as trace evidence, at least in research settings. However, it is unknown whether skin microbiomes change prior to autopsy and, if so, whether these changes interfere with linking objects to decedents. The current study included microbiomes from 16 scenes of death in the City and County of Honolulu and tested whether objects at the scenes can be linked to individual decedents. Postmortem skin microbiomes were stable during repeated sampling up to 60 h postmortem and were similar to microbiomes of an antemortem population. Objects could be traced to decedents approximately 75% of the time, with smoking pipes and medical devices being especially accurate (100% match), house and car keys being poor (0%), and other objects like phones intermediate (~80%). These results show that microbes from objects at death scenes can be matched to individual decedents, opening up a new method of establishing associations and identifications. PMID- 30408196 TI - Evaluation of early oral cavity cancer treatment quality at a single institution. AB - OBJECTIVE: To evaluate the adherence to oral cavity quality guidelines endorsed by the American Head and Neck Society (AHNS) at a large tertiary care hospital. METHODS: This retrospective study identified patients treated for early-stage oral tongue squamous cell carcinoma at a tertiary care hospital from 1992 to 2013. Patient charts were reviewed for 26 process quality measures and four key indicator process quality measures as endorsed by the AHNS. Patients were then grouped by diagnosis date either before (historical group, 1992-2007) or after (current treatment group, 2008-2013) the published process quality measures from the AHNS. Descriptive statistics were used to evaluate the rates of adherence for each process quality measure within the 2 groups. RESULTS: Of the 57 patients identified, 29 were female (51%). The mean age was 62.3 years. A majority of the oral cavity cancers were stage I (59.6%), followed by stage II (35.1%) and stage III (5.3%). Compliance with the process quality measures was in the acceptable range in both cohorts. However, several areas demonstrated lower adherence in both cohorts. Statistically significant improvements were noted between the two cohorts, which showed a measurable improvement in adherence to process quality measures in several key areas over time. CONCLUSION: Using the process quality measures proposed by the AHNS, adherence to the process quality measures for early-stage oral cavity cancer care at a tertiary care center was successfully evaluated. In general, good compliance with the proposed process quality measures was found and several areas for improvement were identified. LEVEL OF EVIDENCE: 2c. Laryngoscope, 2018. PMID- 30408197 TI - Canal wall up surgery with mastoid and epitympanic obliteration in acquired cholesteatoma. AB - OBJECTIVES/HYPOTHESIS: The objective of this study was to evaluate surgical outcome and residual and recurrence rates of canal wall up (CWU) surgery with obliteration of the mastoid and epitympanum. STUDY DESIGN: Retrospective cohort study in a tertiary referral center. METHODS: Patients with (sequelae of) acquired cholesteatoma treated with primary or revision CWU surgery with obliteration of the epitympanum and mastoid were identified retrospectively from 2010 to 2014. Obliteration was performed with cartilage chips or a periosteal midtemporal flap in combination with bone pate and/or hydroxyapatite. Patients were followed up with micro-otoscopy and magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI). RESULTS: Ninety-nine ears in 96 patients were managed with obliteration of the epitympanum and mastoid following CWU surgery. Mean postoperative follow-up was 39.6 (standard deviation [SD] = 16.3). Mean follow-up until the last MRI-DWI was 29.7 months (SD = 16.0). In total, 74 ears in 72 adult patients (mean age = 46.8 years) were operated and 25 ears in 24 pediatric patients (mean age = 12.8 years). The overall recurrence rate was 7.1%, and the residual rate was 7.1%. In comparison, before the introduction of obliteration, the residual rate in our clinic was 24.4% and the recurrence rate 39.7%. After CWU surgery with obliteration, recurrence in pediatric patients (16.0%) was more frequent than in adults (4.1%). Although this difference was not statistically significant, a trend was observed (P = .066). CONCLUSIONS: Obliteration of the epitympanum and mastoid is a reliable and safe technique following CWU surgery for cholesteatoma, resulting in low residual and recurrence rates. LEVEL OF EVIDENCE: 4 Laryngoscope, 2018. PMID- 30408198 TI - Preclinical assessment of resorbable silk splints for the treatment of pediatric tracheomalacia. AB - OBJECTIVE: Tracheomalacia is characterized by weakness of the tracheal wall resulting in dynamic airway collapse during respiration; severe cases often require surgical intervention. Off-label external splinting with degradable implants has been reported in humans; however, there remains a need to develop splints with tunable mechanical properties and degradation profiles for the pediatric population. The objective of this pilot study is to assess the safety and efficacy of silk fibroin-based splints in a clinically relevant preclinical model of tracheomalacia. METHODS: Silk splints were evaluated in a surgically induced model of severe tracheomalacia in N = 3 New Zealand white rabbits for 17, 24, and 31 days. An image-based assay was developed to quantify the dynamic change in airway area during spontaneous respiration, and histopathology was used to study the surrounding tissue response. RESULTS: The average change in area in the native trachea was 23% during spontaneous respiration; surgically induced tracheomalacia resulted in a significant increase to 86% (P < 0.001). The average change in airway area after splint placement was reduced at all terminal time points (17, 24, and 31 days postimplantation), indicating a clinical improvement, and was not statistically different than the native trachea. Histopathology showed a localized inflammatory reaction characterized by neutrophils, eosinophils, and mononuclear cells, with early signs suggestive of fibrosis at the splint and tissue interface. CONCLUSION: This pilot study indicates that silk fibroin splints are well tolerated and efficacious in a rabbit model of severe tracheomalacia, with marked reduction in airway collapse following implantation and good tolerability over the studied time course. LEVEL OF EVIDENCE: NA. Laryngoscope, 2018. PMID- 30408199 TI - Donor incentives improve cardiovascular disease risk profile and donation rates. AB - BACKGROUND: Blood centers may offer point-based reward systems or cardiovascular disease (CVD) screening to incentivize donors. However, combining these incentives to improve CVD risk and blood donation rates has not been studied. STUDY DESIGN AND METHODS: Study was a three-arm prospective controlled trial: Group 1, control (routine points, no CVD screening); Group 2, CVD screening with routine points; and Group 3, CVD screening plus incentive double points. The primary objective was to determine if double versus routine incentive points led to improvement or maintenance of CVD risk profile assessed using self-reported changes in 1) reading food labels for calorie and fat content, 2) exercising daily, 3) reduced fat intake, and 4) increase in eating fruits and vegetables. Outcomes were compared at first and final (2-year) follow-up visits. As secondary outcome, median blood donation rates before enrollment and during study were compared. RESULTS: A total of 570 donors (290 in Group 1, 134 in Group 2, 146 Group 3) were selected. At first follow-up visit, 71.4% in Group 3 versus 62.0% in Group 2 subjects reported at least one of four positive behavioral changes (p < 0.001). Increase in reading food labels for calorie and fat content was the most common change and higher in Group 3 (Group 3 from 60.9% to 79.1%; Group 2 from 67.6% to 77.5%; p < 0.001). Final evaluation showed significant increase in self-reported exercise in Group 3 only (from baseline 52.9% to 68.3%; p < 0.05). Group 3 reported higher increase in median number of donations/year during study enrollment (6.8 [IQR, 4.3-12] vs. baseline 4.6 [IQR, 3.2-7.1] donations/year) than Group 2 (5.6 [IQR, 4.2-10.5] vs. baseline 4.9 [IQR, 3.5-10.2]) and Group 1 (4.4 [IQR, 2.7-8.0] vs. baseline 4.4 [IQR, 2.5-6.0] donations/year; p < 0.001). CONCLUSION: Positive donor reinforcement (double vs. routine points) resulted in better self-reported health maintenance behavior and increased donation rates. PMID- 30408200 TI - Risk Information Seeking and Processing About Particulate Air Pollution in South Korea: The Roles of Cultural Worldview. AB - This study integrates cultural theory of risk into the risk information seeking and processing model in the context of particulate air pollution in South Korea. Specifically, it examines how cultural worldviews (hierarchy, individualism, egalitarianism, and fatalism) influence the way people interpret risk about an environmental risk, which may in turn promote or deter their information seeking and processing about the risk. An online survey (N = 645) showed that egalitarianism was positively associated with perceptions of societal and personal risks, affective responses toward the risk, and informational subjective norms. Perceived societal risk, in particular, mediated the effect of egalitarianism on information insufficiency. Moreover, cultural worldview was a significant moderator of the relationships between information insufficiency and risk information seeking and processing. The positive relationship between information insufficiency and information seeking grew stronger with increasing egalitarianism. In contrast, the negative relationship between information insufficiency and heuristic processing was strengthened with increasing hierarchy. This study extends prior theories and models in risk communication by addressing the roles of cultural worldview, an important individual difference factor in interpreting environmental risks. PMID- 30408201 TI - Rethinking Social Amplification of Risk: Social Media and Zika in Three Languages. AB - Using the Zika outbreak as a context of inquiry, this study examines how assigning blame on social media relates to the social amplification of risk framework (SARF). Past research has discussed the relationship between the SARF and traditional mass media, but the role of social media platforms in amplification or attenuation of risk perceptions remains understudied. Moreover, the communication and perceptions of Zika-related risk are not limited to discussions in English. To capture conversations in languages spoken by affected countries, this study combines data in English, Spanish, and Portuguese. To better understand the assignment of blame and perceptions of risk in new media environments, we looked at three different facets of conversations surrounding Zika on Facebook and Twitter: the prominence of blame in each language, how specific groups were discussed throughout the Zika outbreak, and the sentiment expressed about genetically engineered (GE) mosquitoes. We combined machine learning with human coding to analyze public discourse in all three languages. We found differences between languages and platforms in the amount of blame assigned to different groups. We also found more negative sentiments expressed about GE mosquitoes on Facebook than on Twitter. These meaningful differences only emerge from analyses across the three different languages and platforms, pointing to the importance of multilingual approaches for risk communication research. Specific recommendations for outbreak and risk communication practitioners are also discussed. PMID- 30408202 TI - Effect of photopolymerized glaze application on bacterial adhesion on ocular acrylic resin surfaces submitted to accelerated ageing. AB - Conditions of the acrylic resin (AR) surface, such as roughness, can promote a favourable environment for the adhesion of micro-organisms, even on the surface of ocular prostheses. This study evaluated the influence of photopolymerized glaze application on the roughness of ARs and adhesion of Staphylococcus aureus and Staphylococcus epidermidis on ocular AR surfaces submitted to accelerated ageing. Two hundred and eighty-eight samples of white colour (N1) and colourless ARs were distributed in eight groups (n = 9), based on surface treatments (glaze or ARs submitted to only a final polishing), accelerated ageing (before and after) and periods of microbial growth (24- and 48-h). The roughness average (Ra) and total height of roughness profile (Rt) values were greater for the groups with glaze and increased for all groups after ageing. The microbial adhesion among the groups with and without glaze did not present a statistically significant difference. The ageing did not statistically affect the adhesion of Staph. epidermidis, but affected the adhesion of Staph. aureus, which presented an increase after 24 h of growth on only N1 AR with glaze. These results demonstrate that the glaze did not contribute to adhesion of Staph. aureus and Staph. epidermidis, which are responsible for most ocular prosthetic infections. SIGNIFICANCE AND IMPACT OF THE STUDY: Some recent evidence suggested that the surface finish of ocular prostheses influences the accumulation of deposits that can affect the interaction with pathogenic bacteria, increasing the probability of infections. In addition, surface deterioration over time can increase the roughness and, consequently, biofilm formation. Thus, a better understanding of the influence of surface finish on bacterial adhesion becomes extremely important. In this study, we tested a glaze for surface polishing compared to mechanical polishing, before and after ageing. The results suggest that the glaze did not contribute to microbial adhesion and might be useful in preventing possible prosthetic infections. PMID- 30408203 TI - Energy-based treatment for gynecologic conditions including genitourinary syndrome of menopause: Consensus, controversies, recommendations, and FDA clearance. PMID- 30408204 TI - Histopathological diagnosis of persistent pruritic eruptions associated with adult-onset Still's disease. AB - AIMS: Persistent pruritic eruptions (PPEs), presenting with dyskeratotic keratinocytes histologically, are common in patients with adult-onset Still's disease (AOSD). The lesions may be histologically similar to other entities that present with dyskeratosis. METHODS AND RESULTS: To investigate whether histopathological findings can be used to discriminate among PPEs and other entities presenting with dyskeratotic keratinocytes, cutaneous histopathological changes of PPEs associated with AOSD (n=26) were compared with those of systemic lupus erythematosus (SLE) (n=16), dermatomyositis (n=19), and drug eruption (n=16). Dyskeratosis was observed in the upper 1/3 of the epidermal layer in all 26 PPE cases. The rate of dyskeratosis for PPEs was higher than that for SLE (18.8%) and dermatomyositis (15.8%). In drug eruptions, the dyskeratotic cells were distributed in all levels of the epidermis. Variable densities of neutrophils were found in the dermis in all PPE cases. CONCLUSIONS: Although this was a retrospective study conducted at a single centre, presentation of dyskeratotic keratinocytes in the upper 1/3 of the epidermal layer is a distinctive histopathological reactive pattern of PPEs. This pattern may be a useful histopathological marker for early diagnosis of AOSD. This article is protected by copyright. All rights reserved. PMID- 30408205 TI - THE INITIAL ASSESSMENT OF A COMMUNITY-BASED INTERVENTION WITH MEXICAN-HERITAGE PARENTS IN BOOSTING THE EFFECTS OF A SUBSTANCE USE PREVENTION INTERVENTION WITH YOUTH. AB - Drawing from an ecodevelopmental framework, this article examines if adding a parenting component, Families Preparing the New Generation (Familias Preparando la Nueva Generacion), to an efficacious classroom-based drug abuse prevention intervention, keepin'it REAL, will boost the effects of the youth intervention in preventing substance use for middle school Mexican-heritage students. Youth attending schools in a large urban area in the Southwestern U.S. (N = 462) were randomly assigned to 1 of 3 conditions: parent and youth, youth only, or control. Using ordinary least squares regression, changes in youth substance use outcomes were examined. Results indicate that youth whose parents also participated in prevention programming exhibited significantly lower use of alcohol, cigarettes, marijuana, and inhalants compared to youth who received only keepin'it REAL. These initial effects indicate that involving parents in prevention efforts can strengthen the overall efficacy of a youth prevention intervention. This article discusses specific implications for the design of prevention interventions, policy, and future research. PMID- 30408206 TI - Pharmacokinetics of R-(-)ondansetron compared with that of S-(-)ondansetron in rats using a LC-MS/MS method. AB - AIM: To study pharmacokinetics of R-(-)ondansetron (R-ond) compared with that of S-(-)ondansetron (S-ond) in rats. METHODS: After R-ond and S-ond were injected intravenously into rats at a dose of 2.0 mg/kg, respectively. Stability of ondansetron enantiomers in rat were determined by chiral HPLC, and the concentrations of R-ond and S-ond in plasma were determined by an LC/MS/MS method. The pharmacokinetic parameters were calculated and analyzed statistically using the t test. RESULTS: The enantiomers inversions of between R-ond and S-ond didn't occurred in rat. The pharmacokinetic parameters (t1/2 , AUC, MRT, CL) of R ond and S-ond differed significantly. The concentration in plasma of R/S enantiomeric ratio reached a maximum value of 9.5 at 4.0 h postdose. CONCLUSION: The pharmacokinetics of R-ond and S-ond are stereoselective in rat, which indicate substantial stereoselectivity in the disposition of ondansetron enantiomers in rat. R-ond is more potential than S-ond to be developed as a single enantiomer drug. PMID- 30408208 TI - Cultivating Metacognition in Each of Us: Thinking About "Thinking" in Interdisciplinary Disaster Research. AB - Although there is an emerging literature on interdisciplinary disaster research (IDR), one of the overlooked aspects relates to our thinking itself: how to actively think about our thinking-metacognition-while embarking on our interdisciplinary journeys. This article argues that metacognition has an instrumental value both for IDR projects and for individual researchers involved in IDR. For IDR projects, metacognition can help: (1)overcome disciplinary barriers in IDR by revealing cognitive abilities and inabilities for each team member through identifying what is hindering or enabling individuals and the group to transcend disciplinary boundaries toward true integration across the disciplines; (2)deal with "wicked" problems that characterize disaster contexts in a more effective and creative manner; (3)oversee team functioning; and (4)monitor and evaluate progress toward meeting project goals and objectives. For individual researchers, metacognition can help them grow intellectually, and understand the fallacies and limitations in their thinking. It can also encourage them to live an authentic and unified life as an individual. The article concludes with guidance on how individual researchers, principal investigators of IDR projects, and institutions such as universities and funding agencies can cultivate metacognition. To our knowledge, this is the first article that introduces metacognition as a tool for enhancing our thinking on IDR. PMID- 30408207 TI - Intradonor reproducibility and changes in hemolytic variables during red blood cell storage: results of recall phase of the REDS-III RBC-Omics study. AB - BACKGROUND: Genetic determinants may underlie the susceptibility of red blood cells (RBCs) to hemolyze in vivo and during routine storage. This study characterized the reproducibility and dynamics of in vitro hemolysis variables from a subset of the 13,403 blood donors enrolled in the RBC-Omics study. STUDY DESIGN AND METHODS: RBC-Omics donors with either low or high hemolysis results on 4 degrees C-stored leukoreduced (LR)-RBC samples from enrollment donations stored for 39 to 42 days were recalled 2 to 12 months later to donate LR-RBCs. Samples of stored LR-RBCs from the unit and from transfer bags were evaluated for spontaneous and stress-induced hemolysis at selected storage time points. Intradonor reproducibility of hemolysis variables was evaluated in transfer bags over two donations. Hemolysis data at serial storage time points were generated on LR-RBCs from parent bags and analyzed by site, sex, race/ethnicity, and donation frequency. RESULTS: A total of 664 donors were successfully recalled. Analysis of intradonor reproducibility revealed that osmotic and oxidative hemolysis demonstrated good and moderate reproducibility (Pearson's r = 0.85 and r = 0.53, respectively), while spontaneous hemolysis reproducibility was poor (r = 0.40). Longitudinal hemolysis in parent bags showed large increases over time in spontaneous (508.6%) and oxidative hemolysis (399.8%) and smaller increases in osmotic (9.4%) and mechanical fragility (3.4%; all p < 0.0001). CONCLUSION: Spontaneous hemolysis is poorly reproducible in donors over time and may depend on site processing methods, while oxidative and osmotic hemolysis were reproducible in donors and hence could reflect consistent heritable phenotypes attributable to genetic traits. Spontaneous and oxidative hemolysis increased over time of storage, whereas osmotic and mechanical hemolysis remained relatively stable. PMID- 30408209 TI - Cigarette use among individuals with alcohol use disorders in the United States, 2002-2016: Trends overall and by race/ethnicity. AB - BACKGROUND: Individuals with alcohol use disorders (AUDs) who smoke cigarettes experience greater health risks than those using either substance alone. Further, disparities exist in AUDs and smoking by race/ethnicity. Although smoking has declined in the general population, it is not known whether the smoking prevalence has changed over time for individuals with AUDs. The current study used representative US data to estimate the prevalence of current cigarette use from 2002 to 2016 by AUD status and severity overall and by race/ethnicity. METHODS: Data were drawn from the National Survey on Drug Use and Health, an annual cross-sectional study of US individuals, from 2002 to 2016 (total analytic sample n=837,326). Cigarette smoking prevalence was calculated annually among those with and without past-year AUD and by AUD severity level (mild, moderate, severe AUD). Time trends in smoking prevalence by AUD status and severity were tested using logistic regression for the overall sample and significant interactions were subsequently stratified by race/ethnicity (non-Hispanic (NH) White, NH Black, Hispanic, NH Other). RESULTS: Cigarette use was persistently over twice as common among those with AUDs compared to without AUDs (2016: 37.84% versus 16.29%). Cigarette use was also more common among those at each level of AUD severity criteria (2016: mild AUD 34.59%; moderate AUD 35.35%; severe AUD 52.23%). Approximately half of NH Black respondents with AUDs, and three-quarters of NH Black respondents with severe AUDs, reported smoking in 2016. The prevalence of smoking decreased significantly over time among respondents with and without AUDs; however, there were differences by race. There was no decline in smoking prevalence among NH Black respondents with AUDs over time in contrast to a significant decrease for every other racial/ethnic group with and without AUDs. CONCLUSIONS: Individuals with AUDs may need additional resources and interventions to quit smoking, especially NH Black individuals. This article is protected by copyright. All rights reserved. PMID- 30408210 TI - Changes in dental anxiety among 15- to 21-year-olds. A 2-year longitudinal analysis based on the Tromso study: Fit futures. AB - OBJECTIVE: Identify predictive variables related to the development and continuation of high dental anxiety among young people over 2 years and assess differences between youth experiencing increased, decreased or unchanged dental anxiety scores over time. METHODS: An observational panel study of 15- to 21-year old people in Tromso and Balsfjord region followed students from their first to their last year of upper secondary school (2010/11-2012/13). Logistic regression was used to estimate odds ratios and their 95% confidence intervals (CI) of possible predictive variables assessed at baseline when using dental anxiety score from the second wave as a dichotomous dependent variable. Variables measured at baseline: Sex, Dental Caries Experiences (DMFS index), Dental Anxiety (Corah's Dental Anxiety Scale/DAS), Psychological Distress (Hopkins Symptom Checklist/HSCL-10), Avoidance of dental treatment, Pain Estimation at the dentist and motivational questions related to tooth brushing and caries (Self and Social Motivation). Wilcoxon signed-rank tests and Kruskal-Wallis tests were used to test whether changes in DAS score between waves were associated with changes in Pain Estimation between waves and HSCL-10 scores at baseline. RESULTS: Hopkins Symptom Checklist, DMFS and DAS scores at baseline predicted high dental anxiety scores after 2 years. Sex, motivation related to oral hygiene and avoidance due to fear at baseline did not contribute significantly to our model. DMFS and HSCL 10 were higher among young people who reported a substantial change in DAS score (2.0 > Interquartile range/IQR), irrespective of the direction of change. Pain Estimation changed consistently with a change in DAS score. CONCLUSION: Mental health symptoms, pre-existing dental anxiety and dental health status are important contributors to the development of dental anxiety in youth. Estimations of pain at the dentist are central when it comes to changes in dental anxiety over time in this study. PMID- 30408211 TI - A Risk Assessment Framework for the Socioeconomic Impacts of Electricity Transmission Infrastructure Failure Due to Space Weather: An Application to the United Kingdom. AB - Space weather phenomena have been studied in detail in the peer-reviewed scientific literature. However, there has arguably been scant analysis of the potential socioeconomic impacts of space weather, despite a growing gray literature from different national studies, of varying degrees of methodological rigor. In this analysis, we therefore provide a general framework for assessing the potential socioeconomic impacts of critical infrastructure failure resulting from geomagnetic disturbances, applying it to the British high-voltage electricity transmission network. Socioeconomic analysis of this threat has hitherto failed to address the general geophysical risk, asset vulnerability, and the network structure of critical infrastructure systems. We overcome this by using a three-part method that includes (i) estimating the probability of intense magnetospheric substorms, (ii) exploring the vulnerability of electricity transmission assets to geomagnetically induced currents, and (iii) testing the socioeconomic impacts under different levels of space weather forecasting. This has required a multidisciplinary approach, providing a step toward the standardization of space weather risk assessment. We find that for a Carrington sized 1-in-100-year event with no space weather forecasting capability, the gross domestic product loss to the United Kingdom could be as high as L15.9 billion, with this figure dropping to L2.9 billion based on current forecasting capability. However, with existing satellites nearing the end of their life, current forecasting capability will decrease in coming years. Therefore, if no further investment takes place, critical infrastructure will become more vulnerable to space weather. Additional investment could provide enhanced forecasting, reducing the economic loss for a Carrington-sized 1-in-100-year event to L0.9 billion. PMID- 30408212 TI - Simultaneous determination of fifteen multiclass organic pollutants in human saliva and serum by liquid chromatography-tandem ultraviolet/fluorescence detection: A validated method. AB - A quick and inexpensive validated method, based on sample treatment by liquid liquid microextraction followed by liquid chromatography (LC) coupled with ultraviolet tandem fluorescence detection is proposed for the determination of 15 multiclass pollutants both in serum and in saliva, as a simple and easy to draw matrix. The method was set up and validated according to European guidelines. The compounds of interest include some endocrine-disrupting chemicals (i.e. bisphenol A, bisphenol B, bisphenol E, bisphenol F, bisphenol AF, bisphenol A diglycidyl ether, bisphenol M, diethylhexyl phthalate, monoethylhexyl phthalate, triclosan and 4-nonylphenol), as well as other pollutants belonging to the class of volatile organic compounds (2-chlorophenol, 1,2 dichlorobenzene, 1,2,4,5 tetrachlorobenzene). The limits of quantifications ranged from 2.28 * 10-3 MUg mL-1 (bisphenol A diglycidyl ether) to 6.29 MUg mL-1 (diethylhexyl phthalate), while those of detection ranged from 0.068 * 10-3 MUg mL-1 (bisphenol A diglycidyl ether) to 1.031 MUg mL-1 (diethylhexyl phthalate). To test method suitability, it was applied to real saliva and serum samples of healthy human volunteers and was found to meet the demands of the laboratories handling simple and relatively inexpensive equipment for screening oriented at rapid and reliable contamination assessment of a population. PMID- 30408213 TI - Ex vivo cadaveric study of a laterally placed Leipzig stifle distractor for arthroscopic evaluation of the lateral meniscus in dogs. AB - OBJECTIVE: To evaluate safety and accuracy of lateral pin placement for the use of a Leipzig stifle distractor (LSD) and to assess improvements in visualization and treatment of the lateral meniscus in the canine stifle. STUDY DESIGN: Ex vivo cadaveric study. SAMPLE POPULATION: Paired canine cadaveric hind limbs (n = 10). METHODS: Pins for the LSD were placed from lateral to medial in the distal femur and proximal tibia. Safety and accuracy of lateral pin placement were evaluated via anatomical dissection, computed tomography (CT), and arthroscopy. In every case, distraction of the lateral compartment of the femorotibial joint space was evaluated arthroscopically, and the meniscus was probed. Afterward, the limbs were assigned to 1 of 2 groups, and a partial meniscectomy was attempted with or without distraction. Stifles were disarticulated to evaluate the meniscectomy and iatrogenic cartilage damage. RESULTS: Computed tomography revealed some variation in pin placement, although sufficient distraction was achieved for all stifle joints. No damage to the surrounding structures was observed during anatomical dissection, CT, or arthroscopy. Disarticulation provided evidence that using an LSD allowed for complete caudal horn meniscectomies and less articular cartilage damage than when meniscectomy was attempted with manual distraction. CONCLUSION: Lateral placement of an LSD proved to be safe and effective for the distraction of the lateral femorotibial joint space and the examination and treatment of the lateral meniscus in dogs weighing 18-42 kg. CLINICAL SIGNIFICANCE: Canine lateral meniscus pathology, although rare, leads to severe pain. A laterally placed LSD improves arthroscopic evaluation and treatment of this pathology. PMID- 30408214 TI - The histologic diagnosis of IgG4-related disease on small biopsies: Challenges and pitfalls. AB - INTRODUCTION: The pathologic diagnosis of IgG4-related disease (IgG4-RD) relies on histology, IgG4 positive cells and increased IgG4:IgG. Small biopsies from patients with a presumptive diagnosis of IgG4-RD often fail to meet consensus histologic guidelines. We evaluate consecutive small biopsies from patients with a presumptive diagnosis of IgG4-RD and assess the significance of the pathologic findings. METHODS: We evaluated 55 small biopsies from patients with a presumptive diagnosis of IgG4-RD. The retrospective cohort comprised of 71 patients with IgG4-RD and 57 mimics. We performed immunohistochemistry (IHC) and in situ hybridization (ISH) for IgG4 and IgG. RESULTS: 26 patients from the prospective cohort met histologic criteria for IgG4-RD (definite); twenty-nine patients lacked one or more pathologic features (borderline). Twenty biopsies (36%) lacked both storiform fibrosis and obliterative phlebitis, nine (16%) lacked increase in IgG4 positive plasma cells. 93% of patients showed IgG4: total IgG of >40% (>30% by ISH). There was no difference in the incidence of multi organ disease (p=0.9), serum IgG4 (p=0.6) and response to therapy between the definite and borderline groups. A strong correlation (Pearson 0.77) between the IHC and ISH platforms was noted with regard to IgG4:total IgG. CONCLUSION: Patients with a presumptive diagnosis of IgG4-RD but lacking characteristic pathologic features of this disease appear clinically similar to those that meet current pathologic guidelines. An elevated IgG4:total IgG is the most sensitive pathologic feature and ISH provides a robust quantitation platform. We recommend evaluating tumefactive lymphoplasmacytic infiltrates with increased IgG4:IgG, regardless of histological features, for IgG4-RD. This article is protected by copyright. All rights reserved. PMID- 30408215 TI - Paola Bonfante. PMID- 30408216 TI - Eltonian niche width determines range expansion success in ectomycorrhizal conifers. PMID- 30408217 TI - Disentangling the factors shaping arbuscular mycorrhizal fungal communities across multiple spatial scales. PMID- 30408218 TI - Passengers and drivers of arbuscular mycorrhizal fungal communities at different scales. PMID- 30408219 TI - Cross-scale integration of mycorrhizal function. PMID- 30408220 TI - Alastair H. Fitter. PMID- 30408221 TI - Water, water everywhere ... but how does it affect the functional diversity of ectomycorrhizal fungi? PMID- 30408222 TI - Allergen-specific IgE over time in women before, during and after pregnancy. PMID- 30408223 TI - Estrogen modulates ethanol-induced memory deficit in postpubertal adolescent rats. AB - BACKGROUND: Our laboratory and others have reported that ethanol impairs hippocampus-associated memory formation in prepubertal adolescent rats. Acute alcohol exposure in humans produces a syndrome of memory loss ("blackouts") that is similar to impairments caused by hippocampal damage. The ability to form new long-term explicit memories is affected but not short-term memory storage or recall of information from long-term storage. Alcohol-induced memory impairment, similar to teenage alcohol blackouts, has been shown in prepubertal adolescent rodents. In the present study, ethanol's effect on contextual fear memory was examined in postpubertal rats. METHODS: In Experiment 1, intact male and female postpubertal rats were treated with an acute intraperitoneal injection of ethanol or vehicle. Thirty minutes later, rats were trained in the fear conditioning paradigm, and 24h after training all rats were tested for contextual fear conditioning. In Experiment 2, groups of intact postpubertal female rats were treated with a single injection of ethanol, or vehicle, during different phases of the estrus cycle, and tested for fear conditioning. In Experiment 3, groups of postpubertal female rats were ovariectomized (OVX) and were given hormonal supplementation (estrogen with or without progesterone) and tested for ethanol induced memory formation. Additional controls included sham-operated, oil-treated postpubertal female rats. In Experiment 4, intact postpubertal male rats were administered exogenous estrogen alone or together with progesterone, and tested for ethanol-induced contextual memory formation. RESULTS: Following an acute ethanol exposure, intact postpubertal female rats exhibited significant impairments in contextual fear conditioning. But acute ethanol had little effect on contextual fear conditioning in intact postpubertal males. Ethanol impaired memory formation during all phases of the estrus cycle except during estrus phase when blood levels of estrogen are low. OVX rats did not show any ethanol-induced impairment in contextual freezing compared to vehicle-treated OVX rats. In female rats bilateral ovariectomy eliminated ethanol-induced memory deficit and estrogen replacement reintroduced ethanol-induced memory impairment. Although postpubertal male rats were insensitive to ethanol's effect on contextual fear conditioning when treated with exogenous estrogen, they performed poorly in the contextual memory task. CONCLUSION: Together, these data suggest that the female gonadal hormone estrogen is an important modulator of ethanol-induced cognitive behavior in postpubertal female and male rats, and that it may play an important role in teenage alcohol blackout. This article is protected by copyright. All rights reserved. PMID- 30408224 TI - Construction of confidence intervals for the maximum of the Youden index and the corresponding cutoff point of a continuous biomarker. AB - Evaluation of the overall accuracy of biomarkers might be based on average measures of the sensitivity for all possible specificities -and vice versa- or equivalently the area under the receiver operating characteristic (ROC) curve that is typically used in such settings. In practice clinicians are in need of a cutoff point to determine whether intervention is required after establishing the utility of a continuous biomarker. The Youden index can serve both purposes as an overall index of a biomarker's accuracy, that also corresponds to an optimal, in terms of maximizing the Youden index, cutoff point that in turn can be utilized for decision making. In this paper, we provide new methods for constructing confidence intervals for both the Youden index and its corresponding cutoff point. We explore approaches based on the delta approximation under the normality assumption, as well as power transformations to normality and nonparametric kernel- and spline-based approaches. We compare our methods to existing techniques through simulations in terms of coverage and width. We then apply the proposed methods to serum-based markers of a prospective observational study involving diagnosis of late-onset sepsis in neonates. PMID- 30408225 TI - High PTGS2 expression in post neoadjuvant chemotherapy treated oesophageal adenocarcinoma is associated with improved survival: a population-based cohort study. AB - AIMS: High prostaglandin endoperoxide synthase-2 (PTGS2) enzyme expression in oesophageal adenocarcinoma has been shown to independently predict poor prognosis, however evidence is inconsistent. We investigated the association between PTGS2 expression and prognosis in patients with oesophageal adenocarcinoma. METHODS AND RESULTS: A cohort of 135 patients with oesophageal adenocarcinoma who received neoadjuvant chemotherapy and surgery from 2004 to 2012 was identified in the Northern Ireland Cancer Centre. Tissue microarrays were created in the Northern Ireland Biobank, sampling triplicate cores from each tumour. Immunohistochemical PTGS2 expression was scored by two independent assessors with intensity and proportion of tumour staining used to calculate H scores for each patient. Cox regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (95% CIs) for overall and cancer specific survival, and recurrence-free survival by PTGS2 expression, adjusting for potential confounders. Patients were followed up for a mean of 3.0 (SD 1.8) years. The PTGS2 expression cut-off value was determined using the median H-score of the cohort (270/300). High (n=79), compared to low (n=56), PTGS2 expression was associated with improved cancer-specific survival (adjusted HR 0.56, 95% CI 0.33-0.94; p=0.03). PTGS2 expression was not significantly associated with recurrence-free survival (adjusted HR 0.85, 95% CI 0.52-1.38; p=0.51). CONCLUSIONS: High PTGS2 expression in oesophageal adenocarcinoma tissue was associated with improved overall and cancer-specific survival, contrasting previous evidence. As this is the first study of its kind to include patients who had undergone neoadjuvant chemotherapy further studies are needed to clarify these associations. This article is protected by copyright. All rights reserved. PMID- 30408226 TI - A Bayesian decision analysis approach to assess voice disorder risks by using acoustic features. AB - Vocal fold nodules are recognized as an occupational disease for all collective of workers performing activities for which maintained and continued use of voice is required. Computer-aided systems based on features extracted from voice recordings have been considered as potential noninvasive and low cost tools to diagnose some voice-related diseases. A Bayesian decision analysis approach has been proposed to classify university lectures in three levels of risk: low, medium, and high, based on the information provided by acoustic features extracted from healthy controls and people suffering from vocal fold nodules. The proposed risk groups are associated with different treatments. The approach is based on the calculation of posterior probabilities of developing vocal fold nodules and considers utility functions that include the financial cost and the probability of recovery for the corresponding treatment. Maximization of the expected utilities is considered. By using this approach, the risk of having vocal fold nodules is identified for each university lecturer, so he/she can be properly assigned to the right treatment. The approach has been applied to university lecturers according to the Disease Prevention Program of the University of Extremadura. However, it can also be applied to other voice professionals (singers, speakers, coaches, actors...). PMID- 30408227 TI - Brain-State Dependent Stimulation boosts functional recovery following stroke. AB - OBJECTIVE: Adjuvant protocols devised to enhance motor recovery in subacute stroke patients have failed to show benefits with respect to classic therapeutic interventions. Here we evaluate the efficacy of a novel brain-state dependent intervention based on known mechanisms of memory and learning, that is integrated as part of the weekly rehabilitation program in subacute stroke patients. METHODS: Twenty-four hospitalized subacute stroke patients were randomly assigned to two intervention groups; 1. The associative group received thirty pairings of a peripheral electrical nerve stimulus (ES) such that the generated afferent volley arrived precisely during the most active phase of the motor cortex as patients attempted to perform a movement; 2. In the control group the ES intensity was too low to generate a stimulation of the nerve. Functional (including the lower extremity Fugl-Meyer assessment (LE-FM; primary outcome measure)) and neurophysiological (changes in motor evoked potentials (MEPs)) assessments were performed prior to and following the intervention period. RESULTS: The associative group significantly improved functional recovery with respect to the control group (median (interquartile range) LE-FM improvement: 6.5 (3.5-8.25) and 3 (0.75-3), respectively; p=0.029). Significant increases in MEP amplitude were seen following all sessions in the associative group only (p's<=0.006). INTERPRETATION: This is the first evidence of a clinical effect of a neuromodulatory intervention in the subacute phase of stroke. This was evident with relatively few repetitions in comparison to available techniques, making it a clinically-viable approach. The results indicate the potential of the proposed neuromodulation system in daily clinical routine for stroke rehabilitation. This article is protected by copyright. All rights reserved. PMID- 30408228 TI - Politics and health outcomes: A path analytic approach. AB - Social and health policies and political participation are associated with each political tradition related to public health outcomes. However, there is a lack of evidence for the relationship between policy and outcomes. This study seeks to determine the relationship between politics, labour and welfare state indicators, economic inequality, and health outcome indicators. Data to test the model was obtained from the Turkish Statistical Institute (TurkStat) that belongs to the 81 provinces of Turkey. Path analysis was used to model the associations between policy, labour and welfare states, economic inequality, and health outcomes. To test the goodness of fit of the model, multiple criteria of model fit indices were utilised. The fit of the respecified path analytic model data is good (normed fit index [NFI] is 0.91, comparative fit index [CFI] is 0.92, goodness of fit index [GFI] is 0.91, and adjusted goodness of fit index [AGFI] is 0.93). Study results illustrate a strong relationship between voter partisanship, employment rate, satisfaction from both social security and health services, and life expectancy at birth and mortality. These results represent an important step towards understanding the elusive relationship between policy and health outcomes. Designing socially inclusive policies, considering labour market opportunities, and enhancing the population's well-being are advisable strategies for policymakers who wish to optimise public health outcomes. PMID- 30408229 TI - Helicobacter pylori increases the risk of low-dose aspirin ulcers: A meta analysis. AB - BACKGROUND AND AIM: Owing to wide-spread use, low-dose aspirin (LDA) produces a substantial amount of peptic ulcer disease. Current guidelines are ambivalent about the need for Helicobacter pylori eradication to protect against LDA ulcers. This study aimed to determine, through meta-analysis, if (and by how much) infection alters the baseline risk of peptic ulcers during LDA therapy. METHODS: Literature screening was performed in MEDLINE and EMBASE from inception to May 2018. Original studies reporting prevalence or incidence of uncomplicated ulcers in LDA users were included. Ulcer endpoints needed to be specified separately, according to Helicobacter pylori infection status. Meta-analysis was performed in MIX 2.0 Pro. RESULTS: Ten cross-sectional studies and seven randomized controlled trials were included (n = 5964). The pooled odds ratios (OR) with 95% confidence intervals (CI) for the risk of LDA ulcers in Helicobacter pylori-positive vs. negative individuals were 1.68 (95%CI 1.40-2.02) and 1.65 (95%CI 1.29-2.08) under fixed- and random-effects models, respectively. Heterogeneity among studies was minimal (I2 = 26.9%). After adjusting for the protective effects of antisecretory drugs, the OR increased to 1.94 (95%CI 1.54-2.46). CONCLUSION: This analysis suggests Helicobacter pylori increases the risk of LDA ulcers by almost 70% in a population where some were taking proton pump inhibitors and/or other acid suppressants. Without antisecretory drugs, the risk almost doubles. Clinically, these findings may support the use of a test-and-treat approach to Helicobacter pylori in LDA users, particularly those at higher risk of developing for peptic ulcers. PMID- 30408230 TI - Magnetic resonance T1w/T2w ratio: A parsimonious marker for Parkinson's disease. AB - OBJECTIVE: Newer MRI techniques have shown promise in capturing early Parkinson's disease (PD)-related changes in the substantia nigra pars compacta (SNc), the key pathological loci. Their translational value, however, is hindered by technical complexity and inconsistent results. METHODS: A novel yet simple MRI contrast, the T1w/T2w ratio, was used to study 76 PD patients and 70 controls. The T1w/T2w ratio maps were analyzed using both voxel-based and region-of-interest approaches in normalized space. The sensitivity and specificity of the SN T1w/T2w ratio in discriminating between PD and controls also were assessed. In addition, its diagnostic performance was tested in a subgroup of PD patients with disease duration <=2 years (PDE). A second independent cohort of 73 PD and 49 controls was used for validation. RESULTS: Compared to controls, PD patients showed a higher T1w/T2w ratio in both the right (cluster size=164 mm3 , p<0.0001) and left (cluster size=213 mm3 , p<0.0001) midbrain that was located ventrolateral to the red nucleus and corresponded to the SNc. The region-of-interest approach confirmed the group difference in the SNc T1w/T2w ratio between PD and controls (p<0.0001). The SNc T1w/T2w ratio had high sensitivity (0.908) and specificity (0.80) to separate PD and controls (AUC=0.926), even for PDE patients (AUC=0.901, sensitivity=0.857, specificity=0.857). These results were validated in the second cohort. INTERPRETATION: The T1w/T2w ratio can detect PD-related changes in the SN and may be used as a novel, parsimonious in vivo biomarker for the disease, particularly early stage patients, with high translational value for clinical practice and research. This article is protected by copyright. All rights reserved. PMID- 30408231 TI - Use of DNA sequencing for noncommunicable diseases in low-income and middle income countries' primary care settings: A narrative synthesis. AB - OBJECTIVE: To present a systematic narrative review, informed by international experience, on the use of genomic analysis technologies in the primary care of noncommunicable chronic diseases (NCDs) during the last 20 years. METHODS: We used the methodology for conducting systematic reviews proposed by the Center for Coordination and Information on Evidence for Policies and Practices. The selected articles were organized by time, place, study design, and type of DNA sequencing. Finally, we analyzed the implications of our findings for health systems in middle-income and low-income countries focusing on a NCD high prevalence country such as Mexico. RESULTS: Evidence concerning the use of DNA sequencing in primary care for NCDs was scarce and geographically concentrated in high-income countries. Use was limited by costs, insufficient knowledge among health care personnel, and a lack of confidence on the part of users. CONCLUSIONS: The use of DNA sequencing for primary care of NCDs is a challenge for low- and middle-income countries. More evidence is needed on cost effectiveness, public funding mechanisms, and the training of health care personnel for its implementation. PMID- 30408232 TI - Impact of pharmacists' counseling on caregiver's knowledge in the management of pediatric atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is a common skin condition in childhood. AD management can be complex, and caregivers may have inadequate information on the disease, aggravating factors, and management. Comprehensive therapeutic education has been closely associated with increased compliance and is recommended for all patients. There are, as yet, no studies on the impact of a pharmacist-led eczema counseling service. OBJECTIVES: The primary objective was to assess the impact of a pharmacist-led eczema counseling service on improving caregivers' knowledge. The secondary objective was to evaluate caregivers' satisfaction of the service and their confidence in handling the patient's condition after counseling. METHODS: This was a prospective, questionnaire-based observational study. After obtaining informed consent, caregivers were required to complete questionnaire A, containing items on demographics and knowledge assessment. Caregivers then underwent a counseling session by a dermatology-trained pharmacist. After counseling, caregivers were required to complete questionnaire B containing items on satisfaction and confidence level. A follow-up phone call was conducted after initial counseling session, during which knowledge-based questionnaire C would be completed. RESULTS: Data from 32 participants were included in the analysis. There was a significant improvement in caregivers' knowledge score after receiving counseling, with mean precounseling score of 8.38 +/- 3.92 and mean postcounseling score of 13.88 +/- 3.65 (P < 0.001). Majority was satisfied with the service and was confident in handling their child's condition. CONCLUSION: Pharmacist-led eczema counseling has a positive impact on caregiver's knowledge and can lead to improved compliance. The service was well received, although more time could be spent during the counseling. PMID- 30408233 TI - Tocilizumab treatment for new onset refractory status epilepticus. AB - We investigated the therapeutic potential of the interleukin-6 receptor inhibitor tocilizumab in 7 patients with new onset refractory status epilepticus (NORSE) who remained refractory to conventional immunotherapy with rituximab (n = 5) or without rituximab (n = 2). Status epilepticus (SE) was terminated after 1 or 2 doses of tocilizumab in 6 patients with a median interval of 3 days from the initiation. They had no recurrence of SE during the observation. However, 2 patients experienced severe adverse events related to infection during the tocilizumab therapy. Further prospective controlled studies are warranted to validate the efficacy and safety of tocilizumab in patients with NORSE. Ann Neurol 2018. PMID- 30408234 TI - Circulating miR-26a and miR-21 as biomarkers for glioblastoma multiform. AB - Glioblastoma multiform is the most common and lethal primary central nervous system tumor. Circulating microRNAs (miRNAs), present in cell-free bodily fluids, have been gaining importance as cancer biomarkers. The primary aim of this study was to assess whether circulating miRNA-128, -21, and -26a in glioblastoma patients can be used as diagnostic biomarkers. Venous blood samples were collected from 11 noncancerous volunteers and 15 glioblastoma patients pre- and post operation. Also, tissue tumor samples were obtained intra-operationally to assay consistency of miRNA levels in serum and tissue samples. Serum and tissue levels of miRNAs were determined by quantitative reverse transcription PCR. miR 21 and miR-26a were both significantly upregulated in pre- and postoperation serum samples of glioblastoma patients compared with the serum samples of noncancerous controls. We found that all three miR-128, -21, and -26a expression levels were reduced in postoperative serum samples compared with pre-operative serum samples, though this decrease was only significant for miR-26a. The serum miR-26a and miR-21 upregulation in glioblastoma patients compared to noncancerous controls and their downregulation in postoperative serum from glioblastoma patients suggest that these miRNAs could be used as serum-derived miRNA biomarkers for glioblastoma. PMID- 30408235 TI - Challenges of implementation: Strategic purchasing in Iran Health Insurance Organization. AB - BACKGROUND: Strategic purchasing has been introduced as a key strategy for solving the problems faced by insurance companies. In Iran, the government has mandated the Iran Health Insurance Organization (IHIO) to implement this strategy. However, there are serious challenges to achieving that. The present study aims to identify these challenges. METHODS: In this qualitative study, a semi-structured interview was conducted on 27 health managers and experts at the national level. The dimensions of the A. Preker model were used to analyze the data. RESULTS: Challenges of strategic purchasing in the IHIO were categorized into five concepts-political economy, policy design, organizational structure, organizational environment, and management capacity; within these concepts, 22 challenges were identified. CONCLUSIONS: Improving strategic purchasing in Iran requires adopting a coherent approach and taking into account all the affecting factors. By revising some policies, and modifying and defining the rules needed to solve the infrastructural problems, the success of strategic purchasing can be obtained. PMID- 30408236 TI - The ethnographer as health service leader: An insider's view of organisational change. AB - PURPOSE: The conceptual presentation of a detailed case study of structural reorganisation in the English NHS illustrates what factors lead to productive or unproductive organisational change. FINDINGS: This autoethnography of a NHS Trust chair provides an account of two reorganisations over an 8-year period. The paper is based on diaries that allow for the presentation of examples that highlight different processes and outcomes. The various actors in the two reorganisations gave complex and multilayered meanings to structural changes and their impact. Two theoretical frameworks helped to analyse the dynamics of productive and unproductive changes. CONCLUSION: It is argued that structural change rarely delivers and that working through people and paying due attention to their motivations and moral imperatives will more likely produce benefits to organisations, staff, and patients. PMID- 30408237 TI - Cytome Micronucleus Assays with a Metabolically Competent Human Derived Liver Cell Line (Huh6): A Promising Approach for Routine Testing of Chemicals? AB - One of the main problems of in vitro genotoxicity tests is the inadequate representation of drug metabolizing enzymes in most indicator cell lines which are currently used. We identified recently a human derived liver cell line (Huh6) which detected induction of DNA damage by representatives of different groups of promutagens without enzyme mix and showed that these cells are more suitable in terms of reproducibility and sensitivity as other currently used liver derived lines. We developed a protocol for micronucleus (MN) cytome assays with these cells and validated the procedure in experiments with representatives of different groups of directly and indirectly acting genotoxic carcinogens (MMS, cisplatin, PhIP, IQ, NDMA, B(a)P, AFB1, etoposide, and H2 O2 ). The optimal cytochalasin B concentration in combination with 48 hr treatment was found to be 1.5 MUg/mL and leads to a cytokinesis block proliferation index in the range between 1.7 and 2.0. The morphological characteristics of different nuclear anomalies which reflect DNA damage (MN, nuclear bridges, and buds) and their baseline frequencies in untreated cells were characterized, and the rates which are required to cause significant effects were calculated. All compounds caused dose dependent induction of MN when the cells were treated for 24 hr, longer and shorter exposure times were less effective. Experiments with different serum levels (fetal bovine serum [FBS]) showed that 10% FBS in the medium (instead of 4%) causes a substantial increase of the sensitivity of the cells. Our results indicate that the new protocol is a promising approach for routine testing of chemicals. Environ. Mol. Mutagen. 2018. (c) 2018 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society. PMID- 30408238 TI - High resolution in-vivo DT-CMR using an interleaved variable density spiral STEAM sequence. AB - PURPOSE: Diffusion tensor cardiovascular magnetic resonance (DT-CMR) has a limited spatial resolution. The purpose of this study was to demonstrate high resolution DT-CMR using a segmented variable density spiral sequence with correction for motion, off-resonance, and T2*-related blurring. METHODS: A single shot stimulated echo acquisition mode (STEAM) echo-planar-imaging (EPI) DT-CMR sequence at 2.8 * 2.8 * 8 mm3 and 1.8 * 1.8 * 8 mm3 was compared to a single-shot spiral at 2.8 * 2.8 * 8 mm3 and an interleaved spiral sequence at 1.8 * 1.8 * 8 mm3 resolution in 10 healthy volunteers at peak systole and diastasis. Motion induced phase was corrected using the densely sampled central k-space data of the spirals. STEAM field maps and T2* measures were obtained using a pair of stimulated echoes each with a double spiral readout, the first used to correct the motion-induced phase of the second. RESULTS: The high-resolution spiral sequence produced similar DT-CMR results and quality measures to the standard resolution sequence in both cardiac phases. Residual differences in fractional anisotropy and helix angle gradient between the resolutions could be attributed to spatial resolution and/or signal-to-noise ratio. Data quality increased after both motion-induced phase correction and off-resonance correction, and sharpness increased after T2* correction. The high-resolution EPI sequence failed to provide sufficient data quality for DT-CMR reconstruction. CONCLUSION: In this study, an in vivo DT-CMR acquisition at 1.8 * 1.8 mm2 in-plane resolution was demonstrated using a segmented spiral STEAM sequence. Motion-induced phase and off-resonance corrections are essential for high-resolution spiral DT-CMR. Segmented variable density spiral STEAM was found to be the optimal method for acquiring high-resolution DT-CMR data. PMID- 30408239 TI - A study of nurse-based Injury Units in Ireland: An emergency care development for consideration worldwide. AB - The aim of this 2018 research study was to determine why nurse-based Injury Units were developed in Ireland and how they function in the Irish healthcare system, including what they contribute in relation to addressing the healthcare needs of Irish citizens. A document review was completed and interviews of nurse practitioners and physicians working in Irish Emergency Rooms (ERs) and Injury Units, as well as nurse managers with responsibility for Injury Units and health service executives who helped design Injury Units. A new model of emergency care was needed 20 years ago when two issues were apparent. The first was concern over unsafe care in small ERs as a result of low patient volumes and staff not having ER expertise. The second issue was long waits for ER care. Considerable opportunity for change was present, including financial imperatives and nurse, physician, and political leaders who were together ready to design and move a new to-Ireland ER services model and nurse practitioner education forward. The Injury Unit model is based on nurse practitioners providing a defined set of services to nonurgent patients in daytime hours. This model was pilot tested and is being implemented across Ireland after it was determined that quality services were being rapidly and safely provided. Nurse practitioner education was also initiated and is now in expansion mode to gain 700 more nurse practitioners by the year 2021 over the current 240. PMID- 30408240 TI - Stable and Persistent Acyclic Diaminocarbenes with Cycloalkyl Substituents and Their Transformation to beta-Lactams by Uncatalysed Carbonylation with CO. AB - Four new acyclic diaminocarbenes (ADACs), viz. [(cyclo-CnH2n - 1)2N]2C (n = 5 - 7) and iPr2N-C-N(cyclo-C6H11)2, were synthesised by reacting the corresponding formamidinium hexafluorophosphates with NaN(SiMe3)2. Their nucleophilicities and electrophilicities were respectively judged from the 1JCH values determined for the N2CH unit of the corresponding formamidinium cations and from the 77Se NMR chemical shifts of the selenourea derivatives obtained from the reaction of elemental selenium with the corresponding ADACs. An ambiphilic profile essentially identical to that of the "Alder carbene" (iPr2N)2C was found in each case. Similar to the latter carbene, the new ADACs undergo a well-defined thermal decomposition by beta-fragmentation, affording an alkene and a formamidine. The stabilities of [(cyclo-CnH2n - 1)2N]2C depend strongly on the value of n, following the order 6 > 5 > 7, with the latter congener being too unstable for isolation. [(cyclo-C6H11)2N]2C shows no thermal decomposition at room temperature in solution and is thus significantly more stable than (iPr2N)2C. The stability of iPr2N-C-N(cyclo-C6H11)2 is intermediate between that of (iPr2N)2C and [(cyclo C6H11)2N]2C, its beta-fragmentation selectively affording propene and iPrN=CH N(cyclo-C6H11)2. [(cyclo-CnH2n - 1)2N]2C (n = 5 - 7) react readily with CO under mild conditions, selectively affording trisubstituted spirocyclic beta-lactam derivatives with an antimicrobial activity spectrum similar to that of penicillin G. PMID- 30408241 TI - The Majority of Piriformis Muscles are Innervated by the Superior Gluteal Nerve. AB - INTRODUCTION: The piriformis muscle is clinically implicated in pain disorders, posterior approaches for total hip arthroplasty, and iatrogenic injury to the muscle and the surrounding nerves. The piriformis muscle has been said to receive innervation from L5 to S3 ventral rami with most sources using S1 and S2 ventral rami as the most common innervation this muscle. However, descriptions of the nerve in the literature are vague. Therefore, the aim of this study was to clarify the anatomy of the nerve supply to the piriformis muscle. MATERIALS AND METHODS: Twenty sides from ten fresh-frozen cadavers were studied. Specifically, via anterior dissection of the sacral plexus, branches to the piriformis were identified. Once identified, the nerves to the piriformis muscle were traced proximally to clarify their origin. RESULTS: Nerves supplying the piriformis muscle existed on all sides. On 80% of sides, the piriformis was innervated by two to three nerves. The origin of these nerves was from the superior gluteal nerve on 14 sides (70%), inferior gluteal nerve on one side (5%), L5 ventral ramus on one side (5%), S1 ventral ramus on 17 sides (85%), and S2 ventral ramus on 14 sides (70%), respectively. CONCLUSIONS: The most common nerve branches to the piriformis are from the superior gluteal nerve, and the ventral rami of S1 and S2. Based on our study, a single 'nerve to piriformis' does not exist in the majority of specimens thus this term should be abandoned. This article is protected by copyright. All rights reserved. PMID- 30408242 TI - Mitochondrial dysfunction and oxidative stress in induced pluripotent stem cell models of Parkinson's disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disease. Two percent of the population above the age of 60 is affected by the disease. The pathological hallmarks of PD include loss of dopaminergic neurons and the presence of Lewy bodies. Mitochondrial dysfunction and oxidative stress are thought to play a pivotal role in both sporadic and familial forms of the disease. In this review we focus on the role of mitochondrial dysfunction and oxidative stress in induced pluripotent stem cell (IPSC) models of PD.We also provide an overview of therapeutics that have been tested and some possible new therapeutics that can be tested in IPSC models of PD. PMID- 30408243 TI - Deterministic fate assignment of Muller glia cells in the zebrafish retina suggests a clonal backbone during development. AB - The optic cup houses multipotent retinal progenitor cells that proliferate and differentiate to form the mature retina, containing five main types of neurons and a single glial cell type, the Muller cell. Progenitors of the zebrafish optic cup generate clones that vary regarding the number and types of neurons, a process we previously showed could be described by stochastic models. Here, we present data indicating that each retinal progenitor cell, in the 24 hrs post fertilization optic cup, is predestined to form a single Muller cell. This striking fate assignment of Muller cells reveals a dual nature of retinal lineages where stochastic mechanisms produce variable numbers of neurons while there is a strong deterministic component governing the formation of glia cells. A possible mechanism for this stereotypic fate assignment could be the maintenance of a clonal backbone during retina development, which would be similar to invertebrate and rodent cortical neurogenesis. PMID- 30408244 TI - Fatigue, treatment satisfaction and health-related quality of life among patients receiving novel drugs suppressing androgen signalling for the treatment of metastatic castrate-resistant prostate cancer. AB - Clinical studies have demonstrated the benefits of abiraterone acetate + prednisone (AAP) and enzalutamide (ENZ) in significantly improving survival among metastatic castration-resistant prostate cancer (mCRPC) patients. However, evidence regarding patient's real-world experience, particularly with respect to fatigue, treatment satisfaction and health-related quality of life (HRQoL) is limited. Interviews were initially conducted with patients (n = 38) and carers (n = 12) to elicit qualitative data regarding their experiences. Findings informed the design of a quantitative, multinational online survey of mCRPC patients (n = 152) receiving AAP or ENZ. Participants completed validated questionnaires assessing fatigue (Brief Fatigue Inventory), treatment satisfaction (Cancer Therapy Satisfaction Questionnaire) and HRQoL (EuroQol-5-Dimensions). Results indicated that patients were generally satisfied with these therapies, more specifically with reductions in prostate-specific antigen levels and extended survival. Fatigue was commonly linked to poor HRQoL and responses indicated that significantly fewer patients in the AAP group reported feeling usually tired or fatigued in the last week compared to the ENZ group (33% vs. 55%, p = 0.006 respectively). Findings highlight the benefit of AAP and ENZ in promoting the "quality" of extended survival. That fatigue was lower among patients receiving AAP may be important for informing treatment decisions. Further research is needed to gain deeper insights. PMID- 30408245 TI - The FTO polymorphism influences the risk of rejection in heart transplant patients. AB - Heart transplantation is a relatively common treatment for end-stage heart failure. The major complication of heart transplantation is organ rejection. Epigenetic could play a role in the pathogenesis of organ rejection, and the FTO gene is a mediator of DNA methylation. We analysed a tagging FTO SNP rs17817449 in both donor and recipient DNA obtained through 370 heart transplantations. Recipient FTO genotypes were not associated with either type of rejection or with the general increase in the risk of rejection. When compared with patients without a history of rejection, carriers of transplanted hearts with the FTO TT genotype exhibited a significantly increased risk (P = .02) of suffering from both types of rejection in comparison to carriers of hearts with at least one G allele (OR; 95% CI = 2.56; 1.15-5.69). Our results suggest that the donor, but not the recipient, FTO genotype could be a significant predictor of acute rejection in heart transplant patients. This article is protected by copyright. All rights reserved. PMID- 30408246 TI - Cost-of-illness of Melanoma in Europe - a systematic review of the published literature. AB - Malignant melanoma accounts for the vast majority of skin cancer deaths. Primary prevention is used to increase knowledge about skin cancer and set incentives for a change in behaviour, which leads to a decrease in cases. Primary prevention may be cost-effective or even cost saving. Cost-of-illness studies provide information on such potential savings. The purpose of this study is to give an overview on cost-of-illness studies in European countries and to compare the cost of-illness in total and by cost categories. The results can be used to model potential cost savings from prevention. We conducted a systematic literature research in PubMed using the PRISMA checklist. All costs were converted into Euro and adjusted for the reference year 2012. For the ranking of countries according to their cost-of-illness, all costs were adjusted for the purchasing power parity. Studies focusing on stage III-IV melanoma all include information on hospital, hospice, and outpatient treatment. Costs for the treatment of advanced melanoma range between ? 2,972 in Italy and ? 17,408 in Sweden after adjusting for PPP. Most studies on stage I-IV melanoma include costs of hospitalisation, outpatient treatment and GP consultation. Direct costs range from ? 923 in Sweden to ? 9,829 in Denmark. Three articles also include information on indirect costs. Mortality costs vary between ? 3,511 in Sweden and ? 20,408 in England, morbidity costs between ? 103 in Sweden and ? 4,550 in England. We showed that costs for the treatment of skin cancer are moderately high in the included countries. Since after publication of the articles new costly drugs were approved in Europe, treatment costs of melanoma in Europe may be expected to have risen in the last few years, which means that there is a high expectable potential for prevention programmes to become cost-effective or even cost saving. This article is protected by copyright. All rights reserved. PMID- 30408247 TI - Mannosylerythritol lipids inhibit melanogenesis via suppressing ERK-CREB-MiTF tyrosinase signaling in normal human melanocytes and a three-dimensional human skin equivalent. AB - Hyperpigmentation is caused by excessive production of melanin in melanocytes. Mannosylerythritol lipids (MELs) are glycolipid biosurfactants that are abundantly produced by yeasts and used commercially in cosmetics. However, the potential depigmenting efficacy of MELs has not been evaluated. In this study, the depigmentary effect of MELs was tested in primary normal human melanocytes (NHMs), alpha-melanocyte-stimulating hormone (MSH)-stimulated B16 cells (murine melanoma cells) and a human skin equivalent (MelanoDerm) using photography, Fontana-Masson (F&M) staining, and two-photon microscopy. MELs significantly decreased the melanin contents in NHMs and alpha-MSH-stimulated B16 cells. Consistent with these findings, MELs treatment had a clear whitening effect in a human skin equivalent, brightening the tissue color and reducing the melanin content. The molecular mechanism underlying the anti-melanogenic effect of MELs treatment was examined by real-time PCR and Western blotting. Mechanistically, MELs clearly suppressed the gene expression levels of representative melanogenic enzymes, including tyrosinase, Tyrp-1, and Tyrp-2, by inhibiting the ERK/CREB/MiTF signaling pathway in NHMs. This work demonstrates for the first time that MELs exert whitening effects on human melanocytes and skin equivalent. Thus, we suggest that MELs could be developed as a potent anti-melanogenic agent for effective whitening, beyond their use as a biosurfactant in cosmetics. This article is protected by copyright. All rights reserved. PMID- 30408248 TI - A high-pressure praseodymium fluoride borate linking multiple structural features of apatite-type compounds. AB - Pr5(BO4)3-x(BO3)x(F,OH)2.67O0.28 (x ~ 1.6), a boron-containing fluoride oxoapatite-like compound, was obtained by the application of high-pressure/high temperature synthesis. It exhibits a superstructure of the fluorite type with a tripled c lattice parameter (space group P63/m) and shows complex anion disorder along the 63 screw axis and occupation of distorted octahedral as well as almost trigonal planar sites by oxygen and fluorine atoms. Furthermore, a distinct BO4 / (BO3 + F) group disorder is found, 46% of the sites being occupied by BO4 groups and 54% by BO3 groups with a fluoride ion located near the missing oxygen atom. The rare earth cations in the 4f sites exhibit a specific distorted tricapped trigonal prismatic coordination with a mean metaprism angle of 21.3 degrees . The crystal structure of Pr5(BO4)3-x(BO3)x(F,OH)2.67O0.28 (x ~ 1.6) shows much "flexibility" resulting in split and off-site positions of all other rare earth cations. The title compound therefore combines many structural features of apatite-like compounds, for example biologically highly important carbonated apatites, shading more light onto the complex structural chemistry of apatites. PMID- 30408249 TI - Behavioral, neuroendocrine and physiological indicators of the circadian biology of male and female rabbits. AB - locomotion, body temperature, blood and intraocular pressure, corticosteroid secretion, and sleep. Control of several circadian rhythms involves a light entrained circadian clock and a food-entrained oscillator. Nursing periodicity, however, relies on a suckling stimulation threshold. Brain structures regulating this activity include the paraventricular nucleus and preoptic area, as determined by lesions and quantification of cFOS- and PER1 clock gene immunoreactive proteins. Melatonin synthesis in the rabbit pineal gland shows a diurnal rhythm, with highest values at night and lowest ones during the day. In kits the main zeitgeber is milk intake, which synchronizes locomotor activity, body temperature, and corticosterone secretion. Brain regions involved in these effects include the median preoptic nucleus and several olfactory structures. As models for particular human illnesses rabbits have been valuable for studying glaucoma and cardiovascular disease. Circadian variations in intraocular pressure (main risk factor for glaucoma) have been found, with highest values at night, which depend on sympathetic innervation. Rabbits fed a high fat diet develop cholesterol plaques and high blood pressure, as do humans, and such increased fat intake directly modulates cardiovascular homeostasis and circadian patterns, independently of white adipose tissue accumulation. Rabbits have also been useful to investigate the characteristics of sleep across the day and its modulation by infections, cytokines and other endogenous humoral factors. Rabbit circadian biology warrants deeper investigation of the role of the suprachiasmatic nucleus in regulating most behavioral and physiological rhythms described above. This article is protected by copyright. All rights reserved. PMID- 30408250 TI - Ce(IO3)2F2.H2O: The First Rare Earth Iodate Fluoride with Large Second Harmonic Generation Response. AB - The first rare earth iodate fluoride, Ce(IO3)2F2.H2O, has been synthesized via hydrothermal method. In the structure, the CeO5F4 polyhedra connect with isolated IO3 groups to form one-dimensional infinite 1infinity[Ce(IO3)2F2] chains, which interconnect with each other by weak hydrogen bond to construct the whole structure. Ce(IO3)2F2.H2O produces a large second harmonic generation response, which is 3 times that of KDP. Theoretical calculations using density functional theory and dipole moments were executed to illustrate the relationships between the structure and the properties. The results show that Ce(IO3)2F2.H2O is a new iodate fluoride with novel structure and has potential applications in the field of nonlinear optics. PMID- 30408251 TI - Cluster secondary ion emission of silicon: an influence of the samples' dimensional features. AB - Time-of-flight secondary ion mass spectrometry was used to study cluster emission of three kind of Si samples with different dimensional features - massive single crystal wafer, pressed pellet made of 60 nm in diameter particles and holographical grating consisted of the columns of 200 nm in height and 160 nm in diameter. It was shown that under 25 keV Bi3 + ion-beam bombardment both nanosized samples exhibited more intense negative cluster secondary ion emission as compared with massive Si sample. The nanoscale effect of sputtering was found to be more pronounced for large Sin - clusters with n > 7 and for the pressed nanopowder pellet, in which individual particles are more isolated than in the columns formed holographic grating. PMID- 30408252 TI - Nano-Sized Lipidated Dendrimers as Potent and Broad-Spectrum Antibacterial Agents. AB - There is considerable interest in the development of antimicrobial polymers including dendrimers due to the ease of synthesis and low manufacturing cost compared to host defense peptides (HDPs). Herein, a new class of nanomaterials lipidated amphiphilic dendrimers-is presented that mimic the antibacterial mechanism of HDPs by compromising bacterial cell membranes. Unlike conventional dendrimers that are prepared generation by generation symmetrically with molecular weight distribution, these lipidated dendrimers are prepared on the solid phase with a hanging lipid tail and precisely controlled structure. It is shown through rational design that these lipidated dendrimers display potent and selective antimicrobial activity against both Gram-positive and Gram-negative bacteria, including multidrug-resistant strains. In addition to antibacterial activity against planktonic bacteria, these dendrimers are also shown to inhibit bacterial biofilms effectively. This class of dendrimers as a new class of biomaterials may lead to a useful generation of antibiotic agents with practical applications. PMID- 30408253 TI - Pushing attention to one side: Force field adaptation alters neural correlates of orienting and disengagement of spatial attention. AB - Sensorimotor adaptation to wedge prisms can alter the balance of attention between left and right space in healthy adults, and improve symptoms of spatial neglect after stroke. Here we asked whether the orienting of spatial attention to visual stimuli is affected by a different form of sensorimotor adaptation that involves physical perturbations of arm movement, rather than distortion of visual feedback. Healthy participants performed a cued discrimination task before and after they made reaching movements to a central target. A velocity-dependent force field pushed the hand aside during each reach, and required participants to apply compensatory forces toward the opposite side. We used event-related potentials (ERPs) to determine whether electroencephalography (EEG) responses reflecting orienting (cue-locked N1) and disengagement (target-locked P1) of spatial attention are affected by adaptation to force fields. After adaptation, the cue-locked N1 was relatively larger for stimuli presented in the hemispace corresponding to the direction of compensatory hand force. P1 amplitudes evoked by invalidly cued targets presented on the opposite side were reduced. This suggests that force field adaptation boosted attentional orienting responses toward the side of hand forces, and impeded attentional disengagement from that side, mimicking previously reported effects of prism adaptation. Thus, remapping between motor commands and intended movement direction is sufficient to bias ERPs, reflecting changes in the orienting of spatial attention in the absence of visuo-spatial distortion or visuo-proprioceptive mismatch. Findings are relevant to theories of how sensorimotor adaptation can modulate attention, and may open new avenues for treatment of spatial neglect. PMID- 30408254 TI - Decreasing sunbed use in the German population between 2001-2015: survey in 155,679 working persons. AB - BACKGROUND: UV radiation is a proven cause of skin cancer. Use of sunbeds has been shown to provide an attributable risk. OBJECTIVE: To evaluate the proportion of regular sunbed use in Germany based on large-scale population-based surveys over 15 years. METHODS: Skin cancer screenings by dermatologists were conducted between 2001 and 2015 in more than 500 German companies, including a clinical examination and interviews on the risk behavior related to sunburns and sunbeds. RESULTS: Among 155,679 persons included regular sunbed use significantly declined from 11.0% in 2001 to 1.6% in 2015 (p < 0.001). There were significantly higher rates of sunbed use in women (12.5% / 2.0%) versus men (7.3% / 1.3%; p < 0.001), in younger persons and in participants with darker skin (type II and III) versus fair skin (type I). Individuals with sunburns in childhood were significantly more often sunbed users (5.1% vs. 4.6%; p = 0.002). A remarkable decline of sunbed use was observed after 2009 (7.0% in 2001-2008 and 2.2% in 2009-2015). This reduction occurred in the time of a legal ban of sunbed use for minors but also with the start of the national skin cancer screening program. CONCLUSION: Use of sunbeds in the German adult population has dropped by more than 85% in the past decade. Primary prevention, including the large public awareness following the legal ban of sunbed use for young people and the effects of the statutory skin cancer screening program may have contributed to this. This article is protected by copyright. All rights reserved. PMID- 30408255 TI - The Basophil Activation Test reduces the need for a food challenge test in children suspected of IgE-mediated cow's milk allergy. AB - BACKGROUND: The gold standard for the diagnosis of cow's milk allergy is the Double-Blind Placebo-Controlled Food Challenge (DBPCFC) test. However, disadvantages of the DBPCFC are the potential risk of anaphylactic reactions, the time consuming procedure and high costs. OBJECTIVE: The aim of this study is to determine the reliability of the Basophil Activation Test (BAT) both for the initial diagnosis of cow's milk allergy in children and for determination of tolerance in children with cow's milk allergy. METHODS: 97 BATs and cow's milk specific IgE (sIgE) tests were performed in 86 infants/young children, suspected of (persistent) cow's milk allergy, who were qualified for an in-hospital DBPCFC. The BAT was performed with cow's milk extract and the purified major allergens casein, alpha-lactalbumin, beta-lactoglubulin. Basophil activation was determined by CD63 up-regulation measured by flow cytometry. The BAT results were compared to the DBPCFC outcomes. RESULTS: Based on unequivocal DBPCFC and BAT result combinations (80%), the BAT had a sensitivity and specificity of 100% (CI 86-100% and 68-100%, respectively) in IgE sensitized children (41% of the tested children). All non-IgE sensitized children (59%) had a negative DBPCFC and BAT, except for five patients. These latter showed delayed and relatively mild symptoms in the DBPCFC with a negative BAT, supporting a non-IgE mediated allergy in these children. CONCLUSIONS AND CLINICAL RELEVANCE: The BAT seems reliable and cost-effective to diagnose patients with an IgE-mediated cow's milk allergy. In IgE sensitized patients a BAT might replace a DBPCFC. For non-IgE sensitized patients presenting with mild symptoms we propose to consider a (double-blind) extended (time) challenge test at home. This article is protected by copyright. All rights reserved. PMID- 30408256 TI - Evidence for neurogenic inflammation in lichen planopilaris and frontal fibrosing alopecia pathogenic mechanism. AB - Lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) are lymphocytic scarring alopecias affecting primarily the scalp. Although both diseases may share some clinical and histopathological features, in the last decade, FFA has become an "epidemic" particularly in Europe, North and South America with unique clinical manifestations compared to LPP, thus, raising the idea that this disease may have a different pathogenesis. Symptoms such as scalp burning, pruritus, or pain are usually present in both diseases, suggesting a possible role for nerves and neuropeptides in the pathogenesis of both diseases. Based on some previous studies, neuropeptides, such as substance P (SP) and calcitonin gene-related peptide (CGRP), have been associated with lipid metabolism and many chronic inflammatory disorders. In this study we asked if these neuropeptides are associated with LPP and FFA scalp lesions. Alteration in the expression of SP and CGRP in affected and unaffected scalp skin from patients with both diseases was found with examination of sections using immunohistochemical techniques and confocal microscopy. We then quantitatively assessed and compared SP and CGRP expression from control, LPP and FFA scalp biopsies. Although LPP and FFA share similar histopathologic findings, opposite results were found in affected and unaffected scalp in the ELISA tests, suggesting that these diseases may have different pathogenic mechanisms. We also found presence of histopathological inflammation irrespective of evident clinical lesions, which raises the possibility that both diseases may be more generalized processes affecting the scalp. This article is protected by copyright. All rights reserved. PMID- 30408257 TI - Role of induction therapy in low immune risk kidney transplant recipients: A mate kidney analysis. AB - We aimed to evaluate the impact of induction on outcomes in low-immunological risk kidney transplant recipients (KTRs) using a mate-kidney model. Using OPTN/UNOS database, we identified three groups of low-immune risk KTRs (first transplant, panel reactive antibody <20%, human leukocyte antigen mismatches <=3) with each group containing recipients of mate-kidneys from same donor and differed by induction received: group1: no induction vs. interleukin-2 receptor antibody (IL2RA) induction; group2: no induction vs. depleting antibody induction; group3: IL2RA vs. depleting antibody induction. Outcomes were compared between mate-kidney recipients in each group in an adjusted model. Total of 1034 mate-kidney recipients were identified: group1, n=192; group2, n=362 and group3, n=480. Adjusted risk for DGF was higher (OR 1.89, 95% CI 1.09-3.25, .p=0.02) and one-year acute rejection trended lower (OR 0.53, 95% CI 0.25-1.11, p=0.09) among depleting antibody induced patients in group2. Adjusted five-year graft survivals were similar between mate-kidney recipients in all three groups. Adjusted patient death risk was significantly lower in depleting antibody induced patients in group2 (HR 0.48, 95% CI 0.26-0.88, p=0.02), and trended lower in IL2RA induced patient in group1 (HR 0.32, 95% CI 0.10-1.01, p=0.05). Perioperative antibody induction was associated with lower patient death risk in low-immune risk KTRs. This article is protected by copyright. All rights reserved. PMID- 30408258 TI - Photoresponsive, Water-Soluble Supramolecular Dendronized Polymer with Specific Lysosome-Targetable Bioimaging Application in Living Cells. AB - A novel photoresponsive, water-soluble supramolecular dendronized polymer (SDP) is prepared through a gamma -cyclodextrin (gamma -CD)-coumarin host-guest interaction. The supramolecular formation, photoresponsive process, and fluorescence properties are investigated by nuclear magnetic resonance (NMR) techniques and spectrometric measurements. Upon different-wavelength light irradiation, this supramolecular polymer undergoes noncovalent polymer and covalent polymer conversion due to coumarin cycloaddition and cleavage reactions. In addition, SDP for bioimaging in Michigan Cancer Foundation-7 (MCF-7) cells is performed and results show that the obtained SDP has good biocompatibility and is lysosome-targetable. This research enriches the field of supramolecular dendrimers and the photo-stimulation response material may have application prospects in organelle-targeting applications. PMID- 30408259 TI - Impact of hepatic artery size mismatch between donor and recipient on outcomes after living-donor liver transplantation using the right lobe. AB - INTRODUCTION: The aim of this study was to evaluate the effect of hepatic artery (HA) size mismatch anastomosis on outcomes after living-donor liver transplantation (LDLT). MATERIALS AND METHODS: After excluding 128 patients with the exclusion criteria among 233 LDLTs using the right lobe, 104 LDLT patients were divided into two groups: donor HA diameter that was greater than or equal to the recipient HA diameter (D >= R group; n = 79), and donor HA diameter that was smaller than the recipient HA diameter (D < R group; n = 25). RESULTS: Hepatic artery-related complications occurred in only one patient (HA thrombosis; 1.0%) who was in the D < R group. The reconstructed HA flow in the D >= R group was significantly greater than that in the D < R group (P = 0.015). There was a higher incidence of anastomotic biliary stricture in the D < R group (32.0%) compared with the D >= R group (13.9%, P = 0.022) after LDLT. A multivariate analysis with Cox regression revealed that the HA anastomosis of the D < R group and hepaticojejunostomy were significant independent risk factors for postoperative anastomotic biliary stenosis. CONCLUSIONS: Hepatic artery anastomosis with a donor HA diameter smaller than that of the recipient HA might be an independent risk factor for postoperative biliary stenosis after LDLT using the right lobe. PMID- 30408260 TI - How quantitative is metabarcoding: a meta-analytical approach. AB - Metabarcoding has been used in a range of ecological applications such as taxonomic assignment, dietary analysis, and the analysis of environmental DNA. However, after a decade of use in these applications there is little consensus on the extent to which proportions of reads generated corresponds to the original proportions of species in a community. To quantify our current understanding we conducted a structured review and meta-analysis. The analysis suggests that a weak quantitative relationship may exist between the biomass and sequences produced (slope = 0.52 +/-0.34, p<0.01), albeit it with a large degree of uncertainty. None of the tested moderators: sequencing platform type, the number of species used in a trial, or the source of DNA were able to explain the variance. Our current understanding of the factors affecting the quantitative performance of metabarcoding is still limited: additional research is required before metabarcoding can be confidently utilised for quantitative applications. Until then, we advocate the inclusion of mock communities when metabarcoding as this facilitates direct assessment of the quantitative ability of any given study. This article is protected by copyright. All rights reserved. PMID- 30408261 TI - Transdiagnostic neural correlates of volitional emotion regulation in anxiety and depression. AB - BACKGROUND: Individuals who suffer from anxiety and/or depression face difficulty in adaptively managing emotional responses, while accumulating evidence suggests impaired emotion regulation is a transdiagnostic feature of psychopathology. Effectual regulation in the context of negative stimuli is characterized by engagement of the prefrontal cortex (PFC) coupled with reduced amygdala reactivity. In anxiety disorders and major depression, PFC underengagement and atypical PFC-amygdala connectivity has been observed, although patient findings based on case-control studies have been mixed with regard to magnitude, locality, and extent of dysfunction. As anxiety disorders and major depression are heterogeneous disorders and frequently comorbid with one another, delineating relationships between reappraise-related substrates and symptoms may advance our understanding of emotion dysregulation in these populations. METHODS: We examined PFC activation and its functional connectivity (FC) to the amygdala using functional magnetic resonance imaging in a large sample of patients (N = 174) with primary generalized anxiety disorder (n = 47), social anxiety disorder (n = 78), or major depressive disorder (n = 49) during a reappraisal-based emotion regulation task. Comorbidity was permitted and the majority of participants had a concurrent psychiatric illnesses. RESULTS: Across participants, whole-brain results showed that (1) greater anxiety and depression symptom severity was related to less engagement of the dorsal anterior cingulate cortex (ACC) and (2) less FC between the amygdala and ventrolateral PFC. Results were driven by anxiety, while depression symptoms were not significant. CONCLUSION: These findings demonstrate that individual differences in anxiety and depression may help explain ACC and PFC dysfunction during emotion regulation observed across anxiety and depressive disorders. PMID- 30408262 TI - Siberian genetic diversity reveals complex origins of the Samoyedic-speaking populations. AB - OBJECTIVES: We examined autosomal genome-wide SNPs and Y-chromosome data from 15 Siberian and 12 reference populations to study the affinities of Siberian populations, and to address hypotheses about the origin of the Samoyed peoples. METHODS: Samples were genotyped for 567 096 autosomal SNPs and 147 Y-chromosome polymorphic sites. For several analyses, we used 281 093 SNPs from the intersection of our data with publicly available ancient Siberian samples. To examine genetic relatedness among populations, we applied PCA, FST , TreeMix, and ADMIXTURE analyses. To explore the potential effect of demography and evolutionary processes, the distribution of ROH and IBD sharing within population were studied. RESULTS: Analyses of autosomal and Y-chromosome data reveal high differentiation of the Siberian groups. The Siberian populations have a large proportion of their genome in ROH and IBD segments. Several populations (ie, Nganasans, Evenks, Yukagirs, and Koryaks) do not appear to have experienced admixture with other Siberian populations (ie, producing only positive f3), while for the other tested populations the composition of mixing sources always included Nganasans or Evenks. The Nganasans from the Taymyr Peninsula demonstrate the greatest level of shared shorter ROH and IBD with nearly all other Siberian populations. CONCLUSIONS: Autosomal SNP and Y-chromosome data demonstrate that Samoyedic populations differ significantly in their genetic composition. Genetic relationship is observed only between Forest and Tundra Nentsi. Selkups are affiliated with the Kets from the Yenisey River, while the Nganasans are separated from their linguistic neighbors, showing closer affinities with the Evenks and Yukagirs. PMID- 30408263 TI - Respiratory adjuncts to NIV in neuromuscular disease. AB - Muscle weakness is an intrinsic feature of neuromuscular diseases (NMD). When the respiratory muscles are involved, the ability to take a deep breath is compromised, leading to reduced lung volumes and a restrictive ventilatory impairment. Inspiratory, expiratory and bulbar muscle weakness can also impair cough, which may impede secretion clearance. Non-invasive ventilation (NIV) is an established and indispensable therapy to manage hypoventilation and respiratory failure. The role of other therapies that support respiratory health is less clearly defined, and the evidence of efficacy is also harder to summarize as the underlying data are of a lesser quality. This narrative review appraises the evidence for respiratory therapies in adults with NMD and respiratory system involvement. Techniques that assist lung inflation and augment cough, such as lung volume recruitment (LVR) and mechanical insufflation-exsufflation (MI-E), are a particular focus of this review. The evidence suggests that LVR, MI-E and various combinations thereof have clinical utility generally, but important methodological limitations limit the strength of clinical recommendations and hamper the integration of evidence into practice. Future trials should prospectively assess the long-term impact of LVR and cough augmentation on clinical outcomes and burden of care in addition to lung mechanics, as well as determine clear predictors of benefit from these techniques. PMID- 30408264 TI - Stand basal area and solar radiation amplify white spruce climate sensitivity in interior Alaska: Evidence from carbon isotopes and tree rings. AB - The negative growth response of North American boreal forest trees to warm summers is well documented and the constraint of competition on tree growth widely reported, but the potential interaction between climate and competition in the boreal forest is not well studied. Because competition may amplify or mute tree climate-growth responses, understanding the role current forest structure plays in tree growth responses to climate is critical in assessing and managing future forest productivity in a warming climate. Using white spruce tree ring and carbon isotope data from a long-term vegetation monitoring program in Denali National Park and Preserve, we investigated the hypotheses that (a) competition and site moisture characteristics mediate white spruce radial growth response to climate and (b) moisture limitation is the mechanism for reduced growth. We further examined the impact of large reproductive events (mast years) on white spruce radial growth and stomatal regulation. We found that competition and site moisture characteristics mediated white spruce climate-growth response. The negative radial growth response to warm and dry early- to mid-summer and dry late summer conditions intensified in high competition stands and in areas receiving high potential solar radiation. Discrimination against 13 C was reduced in warm, dry summers and further diminished on south-facing hillslopes and in high competition stands, but was unaffected by climate in open floodplain stands, supporting the hypothesis that competition for moisture limits growth. Finally, during mast years, we found a shift in current year's carbon resources from radial growth to reproduction, reduced 13 C discrimination, and increased intrinsic water-use efficiency. Our findings highlight the importance of temporally variable and confounded factors, such as forest structure and climate, on the observed climate-growth response of white spruce. Thus, white spruce growth trends and productivity in a warming climate will likely depend on landscape position and current forest structure. PMID- 30408266 TI - Climate Change and Health: An Urgent Call to Academic Emergency Medicine. AB - There is consensus among 97% of scientists that anthropogenic climate change is occurring and international agreement of the grave threat it poses.1,2 A Lancet Commission declared climate change "the biggest global health threat of the 21st century" with "potentially catastrophic risk to human health."3,4 Emergency medicine (EM) is already on the frontlines as climate change directly affects our patients, clinical practice, and emergency departments (EDs). This presents EM with a profound leadership opportunity to join our colleagues in the house of medicine to improve health and save lives. This article is protected by copyright. All rights reserved. PMID- 30408265 TI - Real time monitoring and quantification of uptake carbon nanodots in eukaryotic cells. AB - The real time monitoring and quantification of the concentration of highly fluorescent nitrogen-doped carbon nanodots (C-dots) in eukaryotic Tobacco bright yellow-2 (BY-2) plant cells was investigated by fluorescence and confocal microscopy. The quantitative measurement of their fluorescent emission intensity was possible because of the high photo-resistance, good water solubility and the absence of fading effect of the nanoparticles, which is frequent occurred problem of the conventional organic dyes. The microscopic analysis revealed that C-dots entered generally into the cells through endocytosis and caused negligible cytotoxicity. The multicolor cellular imaging of labeled Tobacco BY-2 demonstrates that the cells were in good health conditions and any blinking artifacts were not observed. The quantification of fluorescence emission intensity was carried out in the intracellular regions where the relationship between the C-dots concentration and relative emission was linear. Based on a control experiment with fluorescence liposomes with known dependence between C dots concentration and emission, we were able to determine the amount of accumulated nanoparticles in the inner compartments of the eukaryotic cell through subsequent digital image analysis. The reported microscopic approach may be used for accurate testing and direct examination of the drug internalization mechanisms by C-dots as sensitive probes in single cells or tissues. PMID- 30408267 TI - Saponins enriched in the epidermal layer of Holothuria leucospilota body wall. AB - Saponins are secondary metabolites that provide medicinal benefits in controlling body homeostasis and metabolic functions. Sea cucumber has been consumed in many Asian countries due to their health benefits. Active chemicals found in sea cucumber include natural source of saponins which are enriched in their tissues, including the Cuvierian tubules and the body wall. Tissue origin of the saponin biosynthesis and accumulation is limitedly known. The present study is to indicate major compositions and distributions of saponins in the body wall of Holothuria leucospilota. Structurally, their body wall consisted of the pigmented layer of the epidermis, the dermal connective tissues, and inner muscular layers. Interestingly, release of the pigmented granules from the epidermis was related to detection of epidermal saponins. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) revealed identical mass spectra in the saponin extracts and compared to the known compounds of holothurians. To investigate the release of epidermal saponins, the epidermis dissolved in either butanol or distilled water were analyzed and presented the saponin masses with two prominent masses of m/z 1,243.3 (holothurin A and scabraside B) and 1,259.3 (holothurin A3). MALDI-IMS also demonstrated strong signals of the known saponins which were only localized in the epidermis of the body wall. Taken together, this study shows that granule release from epidermal pigmented cells is somehow related to the amount of epidermal saponins released to surrounding seawater. Hence, the future research in the sea cucumber better focuses on epidermal cells that are the enriched site of saponins, although several active compounds require further investigation. PMID- 30408268 TI - Quantitative radiomic biomarkers for discrimination between neuromyelitis optica spectrum disorder and multiple sclerosis. AB - BACKGROUND: Precise diagnosis and early appropriate treatment are of importance to reduce neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) morbidity. Distinguishing NMOSD from MS based on clinical manifestations and neuroimaging remains challenging. PURPOSE: To investigate radiomic signatures as potential imaging biomarkers for distinguishing NMOSD from MS, and to develop and validate a diagnostic radiomic-signature-based nomogram for individualized disease discrimination. STUDY TYPE: Retrospective, cross-sectional study. SUBJECTS: Seventy-seven NMOSD patients and 73 MS patients. FIELD STRENGTH/SEQUENCE: 3T/T2 -weighted imaging. ASSESSMENT: Eighty-eight patients and 62 patients were respectively enrolled in the primary and validation cohorts. Quantitative radiomic features were automatically extracted from lesioned regions on T2 -weighted imaging. A least absolute shrinkage and selection operator analysis was used to reduce the dimensionality of features. Finally, we constructed a radiomic nomogram for disease discrimination. STATISTICAL TESTS: Features were compared using the Mann-Whitney U-test with a nonnormal distribution. We depicted the nomogram on the basis of the results of the logistic regression using the rms package in R. The Hmisc package was used to investigate the performance of the nomogram via Harrell's C-index. RESULTS: A total of 273 quantitative radiomic features were extracted from lesions. A multivariable analysis selected 11 radiomic features and five clinical features to be included in the model. The radiomic signature (P < 0.001 for both the primary and validation cohorts) showed good potential for building a classification model for disease discrimination. The area under the receiver operating characteristic curve was 0.9880 for the training cohort and 0.9363 for the validation cohort. The nomogram exhibited good discrimination, a concordance index of 0.9363, and good calibration in the primary cohort. The nomogram showed similar discrimination, concordance (0.9940), and calibration in the validation cohort. DATA CONCLUSION: The diagnostic radiomic-signature-based nomogram has potential utility for individualized disease discrimination of NMOSD from MS in clinical practice. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 30408269 TI - Single Maintenance and Reliever Therapy (SMART) Regimen for Management of Persistent Asthma. AB - Asthma is a chronic respiratory disease affecting 235 million people worldwide,1 burdening both patients, their families, and society in terms of lost work and school, lessened quality-of-life, avoidable emergency department (ED) visits, hospitalizations, and deaths. Data from the Centers for Disease Control and Prevention report that asthma affects roughly 8% of the U.S. population (approximately 26 million people), accounting for 2 million ED visits, 480,000 hospitalizations, and 3,400 deaths annually with an economic burden of about $82 billion. This article is protected by copyright. All rights reserved. PMID- 30408270 TI - In silico and in vivo models for Qatari-specific classical homocystinuria as basis for development of novel therapies. AB - Homocystinuria is a rare inborn error of methionine metabolism caused by cystathionine beta-synthase (CBS) deficiency. The prevalence of homocystinuria in Qatar is 1:1,800 births, mainly due to a founder Qatari missense mutation, c.1006C>T; p.R336C (p.Arg336Cys). We characterized the structure-function relationship of the p.R336C-mutant protein and investigated the effect of different chemical chaperones to restore p.R336C-CBS activity using three models: in silico, DeltaCBS yeast, and CRISPR/Cas9 p.R336C knock-in HEK293T and HepG2 cell lines. Protein modeling suggested that the p.R336C induces severe conformational and structural changes, perhaps influencing CBS activity. Wild type CBS, but not the p.R336C mutant, was able to restore the yeast growth in DeltaCBS-deficient yeast in a complementation assay. The p.R336C knock-in HEK293T and HepG2 cells decreased the level of CBS expression and reduced its structural stability; however, treatment of the p.R336C knock-in HEK293T cells with betaine, a chemical chaperone, restored the stability and tetrameric conformation of CBS, but not its activity. Collectively, these results indicate that the p.R336C mutation has a deleterious effect on CBS structure, stability, and activity, and using the chemical chaperones approach for treatment could be ineffective in restoring p.R336C CBS activity. PMID- 30408271 TI - A neuromarker of clinical outcome in attention bias modification therapy for social anxiety disorder. AB - BACKGROUND: Attention bias modification (ABM) therapy aims to modify threat related attention patterns via computerized tasks. Despite showing medium clinical effect sizes for anxiety disorders, underlying neural-cognitive mechanisms of change remain unclear. We used visual mismatch negativity (vMMN), an event-related potential sensitive to violations of learned statistical contingencies, to assess therapy-related contingency extraction processes in healthy participants and in patients with social anxiety disorder (SAD). We then assessed whether vMMN amplitude predicts ABM treatment outcome. METHODS: A modified version of the dot-probe task was used to elicit vMMN, in which 80% of trials were standard and 20% were deviant. In study 1, 30 healthy adults were randomly assigned to one of two ABM conditions: one in which threat-congruent targets were deviant trials and threat-incongruent targets were standard trials, and another in which the contingency was reversed. Electroencephalography (EEG) was continuously measured and vMMN analyzed. In study 2, 38 patients with SAD underwent six sessions of ABM therapy. We tested whether rule extraction in the ABM task, indicated by vMMN amplitude, predicts treatment outcome. RESULTS: vMMN clearly emerged over prespecified scalp locations indicating contingency extraction during ABM (study 1). vMMN amplitude predicted clinical improvement after ABM therapy, uniquely accounting for 7% and 14.4% of the variance in clinician-rated and self-reported posttreatment SAD symptoms, respectively. CONCLUSIONS: vMMN emerges as a neural marker for contingency learning in ABM, suggesting a significant role for contingency extraction processes in the clinical efficacy of this therapy. PMID- 30408272 TI - Effect of three semi-occluded vocal tract therapy programmes on the phonation of patients with dysphonia: lip trill, water-resistance therapy and straw phonation. AB - BACKGROUND: To date, the immediate effects of a semi-occluded vocal tract (SOVT) configuration have been thoroughly demonstrated. However, it is not yet sufficiently confirmed whether a therapy programme (i.e. longer than one session) using SOVT exercises leads to an enhanced phonation and improved vocal quality. AIMS: The aim of this study was to investigate the effect of three SOVT therapy programmes: lip trill, water-resistance therapy (WRT) and straw phonation, on the vocal quality, vocal capacities, psychosocial impact and vocal tract discomfort of patients with dysphonia. METHODS & PROCEDURES: A blocked-randomized sham controlled trial was used. Thirty-five patients with dysphonia (mean age = 21 years; 33 women, two men) were assigned to either a lip trill group, a WRT group, a straw phonation group or a control group using blocked randomization. The lip trill, WRT and straw phonation groups practised their respective SOVT exercise across 3 weeks, whereas the control group received a sham treatment across the same time span. A multidimensional voice assessment consisting of both objective (multiparametric indices: Dysphonia Severity Index (DSI), Acoustic Voice Quality Index (AVQI)) and subjective (subject's self-report, auditory-perceptual evaluation) vocal outcomes was performed by a blinded assessor pre- and post therapy. OUTCOMES & RESULTS: Lip trill and straw phonation therapy led to a significant improvement in DSI. Auditory-perceptual grade and roughness significantly decreased after straw phonation. Lip trill and WRT both led to a significant decrease in Voice Handicap Index. Subjects reported a better self perceived vocal quality and a more comfortable voice production after WRT. No changes were found after the sham treatment in the control group. CONCLUSIONS & IMPLICATIONS: Results suggest that SOVT therapy programmes including lip trill or straw phonation can improve the objective vocal quality in patients with dysphonia. Auditory-perceptual improvements were found after straw phonation therapy, whereas psychosocial improvements were found after lip trill and WRT. Patients seem to experience more comfort and a better self-perceived vocal quality after WRT. This study supports the use of the three SOVT therapy programmes in clinical practice. They all had a positive impact on one or more outcomes of the multidimensional voice assessment. Strikingly, vocal quality outcomes were not in line with the subject's opinion. Larger-scale investigation is needed to support these preliminary findings. PMID- 30408273 TI - Disease-causing variants of the conserved +2T of 5' splice sites can be rescued by engineered U1snRNAs. AB - The ability of variants of the spliceosomal U1snRNA to rescue splicing has been proven in several human disease models, but not for nucleotide changes at the conserved GT nucleotide of 5' splice sites (5'ss), frequent and associated with severe phenotypes. Here, we focused on variants at the 5'ss of F9 intron 3, leading to factor IX (FIX) deficiency (hemophilia B). Through minigene expression, we demonstrated that all changes induce complete exon 3 skipping, which explains the associated hemophilia B phenotype. Interestingly, engineered U1snRNAs remarkably increased the proportion of correct transcripts in the presence of the c.277+4A>G (~60%) and also c.277+2T>C mutation (~20%). Expression of splicing-competent cDNA constructs indicated that the splicing rescue produces an appreciable increase of secreted FIX protein levels. These data provide the first experimental evidence that even part of variants at the conserved 5'ss +2T nucleotide can be rescued, thus expanding the applicability of this U1snRNA-based approach. PMID- 30408274 TI - Twenty-first-century climate change impacts on marine animal biomass and ecosystem structure across ocean basins. AB - Climate change effects on marine ecosystems include impacts on primary production, ocean temperature, species distributions, and abundance at local to global scales. These changes will significantly alter marine ecosystem structure and function with associated socio-economic impacts on ecosystem services, marine fisheries, and fishery-dependent societies. Yet how these changes may play out among ocean basins over the 21st century remains unclear, with most projections coming from single ecosystem models that do not adequately capture the range of model uncertainty. We address this by using six marine ecosystem models within the Fisheries and Marine Ecosystem Model Intercomparison Project (Fish-MIP) to analyze responses of marine animal biomass in all major ocean basins to contrasting climate change scenarios. Under a high emissions scenario (RCP8.5), total marine animal biomass declined by an ensemble mean of 15%-30% (+/-12%-17%) in the North and South Atlantic and Pacific, and the Indian Ocean by 2100, whereas polar ocean basins experienced a 20%-80% (+/-35%-200%) increase. Uncertainty and model disagreement were greatest in the Arctic and smallest in the South Pacific Ocean. Projected changes were reduced under a low (RCP2.6) emissions scenario. Under RCP2.6 and RCP8.5, biomass projections were highly correlated with changes in net primary production and negatively correlated with projected sea surface temperature increases across all ocean basins except the polar oceans. Ecosystem structure was projected to shift as animal biomass concentrated in different size-classes across ocean basins and emissions scenarios. We highlight that climate change mitigation measures could moderate the impacts on marine animal biomass by reducing biomass declines in the Pacific, Atlantic, and Indian Ocean basins. The range of individual model projections emphasizes the importance of using an ensemble approach in assessing uncertainty of future change. PMID- 30408275 TI - Structural and chemical characterization of rice and potato starch granules using microscopy and spectroscopy. AB - Starch is a polysaccharide that plays an important role in our diet and aids in determining the blood glucose levels and is the main source of energy to humans and plants. Starch is broken down by hydrolases which are present in our digestive system. We have used alpha-amylase for investigating the rate of hydrolysis of rice and potato starch granules. It is found that the hydrolysis depends on the morphology and composition of the starch granules by means of the action of alpha-amylase. The micro-scale structure of starch granules was observed under an optical microscope and their average sizes were in the range, 1 100 MUm. The surface topological structures of starches with micro holes due to the effect of alpha- amylase were also visualized under scanning electron microscope (SEM). The chemical and structural composition of rice and potato starches before and after hydrolysis is characterized using Fourier-transform infrared (FTIR) and X-ray diffraction (XRD) spectroscopy, respectively. The potato starch is more resistant to alpha-amylase than rice starch. The XRD spectra of native and hydrolyzed starch granules remain same which suggests that the degradation occurs mostly in amorphous regions but not in crystalline. Compactly bound water in starch was attributed to the sharp band at 1,458 cm-1 in FTIR spectra. Bands at 920-980 cm-1 associated to alpha-(1-4) glycosidic linkage (C-O-C) and skeletal mode vibrations in both potato and rice starches. PMID- 30408276 TI - Image segmentation by graph cut for radiation images of small animal blood vessels. AB - Synchrotron radiation (SR) based X-ray imaging is an attractive method for analyzing biomedical structure. However, despite its many advantages, there are few gold standards in image processing methods, especially in segmentation. Image segmentation is an essential step in medical imaging for image analysis and three dimensional reconstruction. Although there are many algorithms for image segmentation, a decisive method does not exist in SR X-ray imagery, because of a lack of data. This study focused on finding a suitable algorithm for image segmentation in high-resolution medical imaging. In this study, we used following four algorithms to segment blood vessel of mouse; interactive graph cuts algorithm, which segments an image using fast min-cut/max-flow algorithm to solve global solution, binary partition tree algorithm, which uses an interactive method creating tree nodes to segment an image by using splitting and merging an image, seeded region growing algorithm, which performs segmentation by connecting similar pixel value, simple interactive object extraction, which generates color signature for segmentation based on color model of an image. PMID- 30408277 TI - Silibinin attenuates Streptococcus suis serotype 2 virulence by targeting suilysin. AB - AIMS: To determine the antivirulence properties of silibinin against suilysin (SLY), a virulence factor of Streptococcus suis serotype 2 (SS2) that plays an important role in the pathogenesis of S. suis infection and its protective effect against SS2 infection in a mouse model. METHODS AND RESULTS: Susceptibility testing, haemolysis assay and Western blot assays were employed to evaluate the performance of silibinin on SLY pore-forming activity. Cytotoxicity assays and mouse infection tests were also performed to determine the efficacy of silibinin against SS2 infection. The results showed that silibinin, a flavonoid with little anti-S. suis activity, was identified to be a potent antagonist of SLY-mediated haemolysis through the inhibition of its oligomerization. Treatment with silibinin reduced S. suis-induced cytotoxicity in macrophages (J774 cells). In addition, S. suis-infected mice that received silibinin showed a lower bacterial burden. CONCLUSIONS: Our results demonstrated that silibinin is a promising candidate for the development of antivirulence therapeutic agents to treat S. suis infections. SIGNIFICANCE AND IMPACT OF THE STUDY: The antivirulent property of silibinin against SS2 by targeting SLY provides the possibility for the future pharmaceutical application of silibinin to prevent and treat S. suis infection. PMID- 30408278 TI - Effects of selenium on oxidative damage and antioxidant enzymes of eukaryotic cells: wine Saccharomyces cerevisiae. AB - AIM: To clarify the effects of selenium (Se), parameters related to oxidative issues, as well as the antioxidant response were investigated on an autochthonous wine yeast strain. METHODS AND RESULTS: Antioxidant enzyme activity, gel electrophoresis, Western blot and MDA level were used to investigate the effects of different concentration of Se in wine yeast. We found that Se is able to affect the enzymatic activities of catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD). An increase in lipid peroxidation was observed in a dose-dependent manner of (Se), thus, indicating the occurrence of cell membrane damage. Additionally, Se induced post-translational oxidative modifications of proteins, especially oxidation of thiol groups (both reversible and irreversible) and protein carbonylation (irreversible oxidation). CONCLUSION: These results obtained could further the understanding the effect of different concentration of Se in wine yeast strain with which Se affect the enzymatic activities and induces some post-translational modifications of proteins. SIGNIFICANCE AND IMPACT OF THE STUDY: The understanding of mechanisms regulating the response of wine yeast to Se is important for future work using selenized yeast as enriched Se supplements in human nutrition. PMID- 30408279 TI - Construction of cloning-friendly minigenes for mammalian expression of full length human NF1 isoforms. AB - The neurofibromatosis type 1 (NF1) tumor suppressor gene is one of the most frequently mutated genes in human tumors. Research on the NF1 proteins has been partially hindered by the difficulties in cloning and propagating the full-length coding cDNAs. We have now established a condition for propagating the natural open reading frames (ORFs) and have assembled the ORFs for human NF1 type 1 and 2 isoforms. Furthermore, we were able to eliminate the cDNA cloning toxicity by introducing a mini-intron. These NF1 minigenes were expressed similarly to the intronless version and could be used to purify full-length NF1 proteins. The NF1 isoforms expressed from the minigenes showed Ras-GAP activity in vivo and in vitro, while the type 1 was more potent. Our constructs expand currently available full-length NF1 constructs and should be valuable tools in expediting the understanding of NF1, particularly the isoform-specific functions and regulation. PMID- 30408280 TI - Influenza vaccine: Where are we and where do we go? AB - The alarming rise of morbidity and mortality caused by influenza pandemics and epidemics has drawn attention worldwide since the last few decades. This life threatening problem necessitates the development of a safe and effective vaccine to protect against incoming pandemics. The currently available flu vaccines rely on inactivated viral particles, M2e-based vaccine, live attenuated influenza vaccine (LAIV) and virus like particle (VLP). While inactivated vaccines can only induce systemic humoral responses, LAIV and VLP vaccines stimulate both humoral and cellular immune responses. Yet, these vaccines have limited protection against newly emerging viral strains. These strains, however, can be targeted by universal vaccines consisting of conserved viral proteins such as M2e and capable of inducing cross-reactive immune response. The lack of viral genome in VLP and M2e-based vaccines addresses safety concern associated with existing attenuated vaccines. With the emergence of new recombinant viral strains each year, additional effort towards developing improved universal vaccine is warranted. Besides various types of vaccines, microRNA and exosome-based vaccines have been emerged as new types of influenza vaccines which are associated with new and effective properties. Hence, development of a new generation of vaccines could contribute to better treatment of influenza. PMID- 30408282 TI - Early rehabilitation of cancer patients-An individual randomized stepped-care stress-management intervention. AB - OBJECTIVE: To evaluate the effects of an individual stepped-care stress management intervention for cancer patients on cancer-related stress reactions (intrusion/avoidance), and secondarily on psychological distress (anxiety/depression) and emotional reactivity (impatience/hostility). METHODS: Consecutively 291 cancer patients were included in a randomized controlled intervention study. Patients randomized to the intervention who did not report clinically significant stress levels (n = 72) after the first counseling session participated in only one counseling session and a follow-up (Step 1). The remaining patients (n = 66) received an additional three to eight sessions, depending on individual needs (Step 2). The intervention used techniques derived from cognitive behavioral therapy (CBT) such as daily registration of events and behaviors as well as scheduled behavioral and physical activity, along with short relaxation exercises. The intervention was completed within 26 weeks of inclusion. The Impact of Event Scale, Hospital Anxiety and Depression Scale, and Everyday Life Stress Scale were used to evaluate effects for 2 years. RESULTS: The linear mixed effects model analysis showed a difference between the randomization groups in favor of the intervention for avoidance and intrusion after the first 6 weeks (P = 0.001 and P = 0.003) and for emotional reactivity after 17 weeks (P = 0.007). There were no differences in psychological distress. Decreases in cancer-related stress reactions and depression were noted for the Step 2 intervention. CONCLUSIONS: An individual stepped-care stress-management intervention for cancer patients, performed by specially educated health professionals using techniques derived from CBT, seems beneficial for cancer patients and may therefore be a realistic complement to routine cancer care. PMID- 30408281 TI - Compare the microscopic characteristics of stems of the 24 Dendrobium species utilized in the traditional Chinese medicine "Shihu". AB - Shihu is a famous Chinese Materia Medica derived from species of the Dendrobium. In order to differentiate 24 Dendrobium species, microscopic features of the 24 Dendrobium species were systemically observed, including the trend of vascular bundle number with different internodes and the transverse section characteristics of stem. The results indicate that the thickness of cuticle, the level of thickening of epidermal cells and cell types, the number of vascular bundles, the shape of vascular bundle sheath, the type and distribution of calcium oxalate crystals, the presence or absence of silica masses can be used to authenticate the 24 Dendrobium species. In addition, the number of vascular bundles in stems of 24 Dendrobium species also have changed at different internodes, and showed a trend of first increasing and then decreasing. For some specific species, the vascular bundle numbers had typical differences, which can provide some support for the identification of Dendrobium plants. Thus, using the multiple microscopic characteristics of stems can identify the Dendrobium plants effectively and quickly. PMID- 30408283 TI - Ecological modeling over seven years to describe the number of host-seeking Amblyomma americanum in each life stage in northeast Missouri. AB - Amblyomma americanum (L.), the lone star tick, is a vector of pathogens in humans and other animals throughout the United States. Our objective was to characterize how environmental factors influence patterns of A. americanum activity throughout its life cycle by creating statistical models that describe the number of active off-host larvae, nymphs, and adults in northeast Missouri from 2007 to 2013. Ticks were collected every other week from a permanent sampling grid in a second growth forest and in an old field habitat. Each of the three life stage models considered six meteorological variables and one biotic variable. Regression modeling was used to make candidate models which were evaluated with eight selection criteria. Best-selected models were useful in describing seasonality and magnitude of A. americanum activity for larvae, nymphs, and adults. While distinct subsets of environmental variables were optimal in each life stage, all three models incorporated cumulative degree days, habitat, and number of ticks in the previous life stage. These models further elucidate how environmental and demographic factors influence patterns of host-seeking activity throughout the A. americanum life cycle, providing insight into how changing climate may impact risk of tick-borne pathogen transmission. PMID- 30408284 TI - Temperature effects on the activity of vectors for Leishmania tropica along rocky habitat gradients in the Eastern Mediterranean. AB - Cutaneous leishmaniasis caused by Leishmania tropica, transmitted by Phlebotomus sergenti and Phlebotomus arabicus, has been detected in Israel. This research strives to identify the complexity of temperature effects on vectors of L. tropica and to analyze seasonality and distribution across altitudinal levels. Sand fly trappings were conducted monthly during 2015-2016 in an endemic region for L. tropica in the eastern Galilee. Trappings were conducted in hyrax den sites across a broad topographic and climatic gradient. Using N-mixture models, we investigated the activity levels of sand flies as related to temporary and periodic climatic variables. We tested generality of climate-driven models using Root-Mean-Square Error (RMSE) values by comparing the 2015-2016 data with trapping data from 2013. P. sergenti activity was found to be positively and exponentially correlated with early night temperatures and more strongly correlated with average early-night temperatures for two weeks. P. arabicus exhibited a linear correlation with temperature. Climate-driven models for both species yielded lower RMSE values for the 2013 data, which validate the generality of the models. Considerable differences were found in slope coefficients of temperature effect on sand fly activity among sites related to elevation levels, implying differential local responses of sand flies to temperature. PMID- 30408285 TI - Susceptibility of Musca domestica larvae and adults to entomopathogenic nematodes (Rhabditida: Heterorhabditidae, Steinernematidae) native to Mexico. AB - We evaluated the pathogenicity of the entomopathogenic nematodes native to Mexico, Heterorhabditis indica, Heterorhabditis sp. and Steinernema sp., towards M. domestica under controlled conditions. For adults, concentrations of 1,600 (A) and 1,200 (B) nematodes/ml were considered. For larvae, only the first concentration applied to filter paper, wheat bran, and peat moss as substrates was evaluated. An analysis of variance showed that the differences in adult mortality were only significant (p = 0.0001) among nematode species but not among concentrations within species. However, differences were significant (p = 0.0001) when data were analyzed when 50% of the individuals died (LT50 ). For H. indica, the LT50 were 46.5 h and 65.8 h for the concentrations A and B, respectively. Females were more susceptible than males. H. indica recorded the highest mortality, with 79.2% and 35.5% for females and males, respectively. Significant differences (p <= 0.05) were recorded in larval mortality. H. indica induced the highest mortality (53.3%) when applied on peat moss. The results are a fundamental basis for future management studies of M. domestica by entomopathogenic nematodes. PMID- 30408286 TI - A comparative analysis of the metaphase karyotypes of Aedes excrucians, Ae. behningi, and Ae. euedes (Diptera: Culicidae) imaginal disss. AB - Karyotypes of Aedes (Culicidae) mosquitoes (Ae. excrucians, Ae. behningi, and Ae. euedes) have been analyzed using the metaphase chromosomes of imaginal discs. Lacto-aceto-orcein, C-banding, and DAPI staining have detected species-specific features in the morphology and lengths of these chromosomes in the examined species. Species-specific features of chromosome 1 in the location of heterochromatin blocks have been shown. Thus, the metaphase chromosomes in the imaginal discs of Ae. excrucians, Ae. behningi, and Ae. euedes are a characteristic for species identification of mosquito species. PMID- 30408287 TI - First record of Triatoma barberi Usinger, 1939 (Hemiptera: Reduviidae) in northern State of Mexico, Mexico. PMID- 30408288 TI - Potential of essential oils to prevent fly strike and their effects on the longevity of adult Lucilia sericata. AB - Lucilia sericata is a facultative ectoparasite causing fly strike or myiasis in warm-blooded vertebrates. It is controlled by traps or insecticides, but both have drawbacks and alternative ways of control are urgently needed. Essential oils (EOs) of vetiver (Chrysopogon zizanioides), cinnamon (Cinnamomum zeylanicum), and lavender (Lavandula angustifolia) and their blends (OBs); OB1 (2 ml of each EO plus 4 ml of sunflower oil as a carrier) and OB2 (2 ml of each EO) were tested. Oils were tested at 5% for deterrence assays, and a dose response assay 0.01-0.6%, was conducted to determine forced-contact toxicity. We evaluated the efficacy of oils as oviposition deterrents, repellents/attractants, and their effects on mortality and longevity of adult L. sericata. Our data indicated that 0.2% EOs killed all flies by 5 min post-treatment and that vetiver oil greatly deterred flies from the oviposition medium and reduced adult longevity. Sunflower oil repelled all flies from ovipositing and greatly reduced the lifespan of treated adults. The blend of the four oils (OB1) had the greatest repellent effect on the flies. EOs have insecticidal, repellent, and oviposition-deterrent activities against L. sericata that could be used for suppression of blow fly populations. PMID- 30408289 TI - Molecular identification of Aedes phoeniciae (Diptera: Culicidae) in rockpools along the northern Israeli coast. PMID- 30408290 TI - Horse flies and their seasonal abundance in El Tarf Province of northeastern Algeria. AB - The horse flies of El Tarf Province, northeastern Algeria comprise 15 species within two subfamilies (Chrysopsinae and Tabaninae) belonging to five genera (Atylotus, Chrysops, Dasyrhamphis, Haematopota, and Tabanus). The genera Chrysops, Dasyrhamphis, and Haematopota are represented by two species for each, while the genera Atylotus and Tabanus are represented by four and five species, respectively. Seasonal abundance was assessed from mid-March until the end of September, 2017 for the trapped species. Haematopota pluvialis and Tabanus autumnalis appeared in April and lasted until September with a peak in May. Atylotus agrestis appeared in May with the highest density and lasted until September. Atylotus fulvus, Atylotus kroberi, and Haematopota italica emerged in April with peaks in May, while Chrysops flavipes appeared in March, reaching its peak in May and June, declining in July, and disappearing thereafter. Atylotus flavoguttatus, Chrysops mauritanicus, and Dasyrhamphis tomentosus appeared in April with a peak in June, then disappearing in August. Tabanus nemoralis started to appear in April with a peak in May and disappearance after July. Dasyrhamphis algirus, Tabanus bromius, and Tabanus eggeri started to appear in May. Both Tabanus eggeri and Dasyrhamphis algirus peaked in June and July, whereas T. eggeri lasted until the end of September. Tabanus tinctus was observed in June with a peak in August and lasted until September. PMID- 30408291 TI - Diversity of Anopheles mosquitoes from four landscapes in the highest endemic region of malaria transmission in Brazil. AB - Malaria transmission in South America is overwhelmingly located in the Amazon region with limited cases outside that biome. A key factor in the mitigation of malaria transmission is the determination of vector diversity and bionomics in endemic areas. Anopheles mosquitoes were collected in four different landscapes of Cruzeiro do Sul-Acre, the current area with highest malaria transmission in Brazil. We performed adult mosquito collections every three months over two years and associated vector occurrence with local abiotic factors. A total of 1,754 Anopheles belonging to nine species were collected, but only four of them (An. albitarsis s.l. Lynch-Arribalzaga, An. braziliensis Chagas, An. peryassui Dyar and Knab, and An. triannulatus Neiva and Pinto) represented 77.1% of the total. Vector density and diversity was uneven across field sites and collection periods. Higher Anopheles abundance (54.8%) and richness were observed in a deforested palm tree area (IFC), with An. braziliensis the most frequent mosquito (40.5%). Only 7.3% of mosquitoes were collected in the SAB village, but 66.4% of them were An. darlingi and An. oswaldoi, species often regarded as primary and secondary vectors of malaria in the Amazon region. A distinct biting preference was observed between 18:00-19:40. The distance from the nearest breeding site and minimum temperature explained 41.6% of the Anopheles community composition. Our data show that the Anopheles species composition may present great variation on a microgeographic scale. PMID- 30408292 TI - Dye another day: the predatory impact of cyclopoid copepods on larval mosquito Culex pipiens is unaffected by dyed environments. PMID- 30408293 TI - First detection of Mansonia titillans (Diptera: Culicidae) infected with St. Louis encephalitis virus (Flaviviridae: Flavivirus) and Bunyamwera serogroup (Peribunyaviridae: Orthobunyavirus) in Argentina. PMID- 30408294 TI - Diversity patterns of hematophagous insects in Atlantic forest fragments and human-modified areas of southern Bahia, Brazil. AB - There have been several important outbreaks of mosquito-borne diseases in the Neotropics in recent years, particularly in Brazil. Some taxa are also considered to be indicators of environmental health. Despite the importance of understanding insect abundance and distribution to the understanding of disease dynamics and design strategies to manage them, very little is known about their ecology in many tropical regions. We studied the abundance and diversity of mosquitoes and sand flies in the Bahia State of Brazil, a point of origin for arbovirus outbreaks, including Zika and Chikungunya fever. During 2009-2014, 51 mosquito taxa were identified, belonging to three dipteran families, Ceratopogonidae, Culicidae, and Psychodidae. The family Culicidae, including the Sabethini tribe, were the most abundant (81.5%) and most taxa-rich (n=45). While season (winter and summer) was a strong factor determinant of the occurrence of the most abundant taxa, the stratification level in the forest (ground or tree level) had a strong effect and the dominant taxa at ground level were completely different from the dominant species collected at tree level. We suggest that sites with a mix of forest and agroforestry systems support the highest biodiversity of hematophagous insects as compared to highly disturbed landscapes. PMID- 30408295 TI - Focal amplification and suppression of West Nile virus transmission associated with communal bird roosts in northern Colorado. AB - To explain the patchy distribution of West Nile virus (WNV), we propose that avian immunity encountered by Culex vectors regulates WNV transmission, particularly at communal bird roosts. To test this hypothesis, we selected two test sites with communally roosting American robins (Turdus migratorius) and two control sites that lacked communal roosts. The density of vector-vertebrate contacts, represented by engorged Culex pipiens, was 23-fold greater at test sites compared to control sites, and the density of blood-engorged Cx. pipiens measured in resting mosquito traps correlated positively with the presence of robins and negatively with the presence of other birds, confirming an attraction to robins for blood feeding. WNV transmission was alternately up-regulated (amplification) and down-regulated (suppression) at both test sites. At one test site, infection in resting Cx. pipiens surged from zero to 37.2 per thousand within four weeks, and robin immunity rose from 8.4% to 64% before reducing to 33%. At this site, ten potentially infectious contacts between vector and vertebrates (including nine robins and a mourning dove [Zenaida macroura]) were documented. Infectious vector-vertebrate contacts were absent from control sites. The use of infectious vector-vertebrate contacts, rather than infected mosquitoes, to evaluate a transmission focus is novel. PMID- 30408296 TI - Establishing and maintaining colonies of Forcipomyia taiwana in the laboratory. AB - Successful colonies of the biting midge Forcipomyia taiwana (Shiraki) were established and maintained in the laboratory by feeding blood with an artificial blood-feeding apparatus, rearing larvae on a soil substrate employing algae liquid, and setting suitable mating cages. The feeding rates of F. taiwana fed on pig blood (69.9%) and artificial blood (72.7%) were not significantly different from those fed on human blood (67.0%). The mean numbers of adults produced by females fed on the artificial blood and the human blood were 32.0 and 33.0, respectively. The algae liquid, Chlorella vulgaris, was suitable for rearing larvae, with larval hatching rate, pupation rate, and emergence rate of midges fed with artificial blood and human blood meal cohorts observed as 76.0%-88.8%, 98.2%-96.4%, and 98.0-94.3%, respectively. Swarming and copulation occurred 1 h before and 2 h after the lights were turned on (07:00-10:00). The average female mating rates were approximately 50-60%, and males were observed to mate with multiple females. PMID- 30408297 TI - Short-term movement of Phlebotomus argentipes (Diptera: Psychodidae) in a visceral leishmaniasis-endemic village in Bihar, India. AB - Visceral leishmaniasis (VL), transmitted by the sand fly, Phlebotomus argentipes, is frequently reported on the Indian subcontinent where its basic ecology is largely unknown. Our objective was to evaluate the effectiveness of sugar solution (10%), containing colored food dye (0.5%) applied to peridomestic vegetation, to mark P. argentipes and subsequently estimate horizontal movement by capturing dye-marked specimens in CDC light traps in a village in Bihar, India. From September 30 to November 27, 2016, a total of 667 captured sand flies were successfully marked using sugar baits, of which 608 were P. argentipes (~91.2%). Although the majority of P. argentipes were captured <100 m from the respective marking sites, a significantly greater proportion of females (15.7%) was captured >100 m from marking sites when compared to males (3.1%). Sand flies that ingested sugar bait were only collected from areas containing >eight vegetation types and mature banana plants. The average number of marked P. argentipes captured per trap-night (+/-SD) <100 m from respective marking sites was greatest in peridomestic vegetation (Males: 0.9 +/- 1.97; Females: 0.63 +/- 1.44), followed by areas with livestock (Males: 0.66 +/- 2.75; Females: 0.24 +/- 0.69), and areas with humans only (Males: 0.1 +/- 0.36; Females: 0.11 +/- 0.31). To our knowledge, this is the only study in Bihar in which sand flies have been marked with food dyes, and the results demonstrate the potential usefulness of food dyes in estimating short-term movement of P. argentipes. Limitations of this experiment are that the number of each trap location type, vegetation composition at marking sites, and distance of all trap sites from marking sites were not homogenous, and the total number of marked sand flies collected were relatively low. In spite of the above limitations, these data should prove useful in developing a large-scale study addressing the caveats. Results of such a study could provide important information regarding the dynamics of VL transmission and inspire managers to pursue alternative means of sand fly control on the Indian subcontinent. PMID- 30408299 TI - Transmission cycle analysis in a Leishmania infantum focus: Infection rates and blood meal origins in sand flies (Diptera: Psychodidae). AB - An entomological study was conducted in a Leishmania infantum focus, including the identification of the sand fly species, the detection and the characterization of Leishmania DNA in female sand flies, and blood meal origins in engorged sand flies. A total of 643 sand flies (31% female, 69% male) was identified based on their morphological features or molecular markers. Ten different species were identified, with Phlebotomus perniciosus, the confirmed vector of L. infantum, being the most abundant (56%), P. papatasi in 25% of sand flies, the unique vector species of L. major, and P. longicuspis in 7% of cases, the suspected second vector of L. infantum. Moreover, the infection rate was 3.4% in P. perniciousus, P. papatasi, P. longicuspis, and Sergentomya minuta. Also, L. infantum was identified in five unfed P. perniciosus and two P. longicuspis. Our results suggest the vector role of P. perniciosus and P. longicuspis in the transmission cycle of L. infantum. The DNA of four mammalian species (human, rabbit, horse, and cow) was identified in the blood meals of sand flies, suggesting that these species are potential reservoirs of leishmaniasis, though it is not yet fully elucidated (especially for MON-24 and MON-80). We suggest the existence of different transmission cycles of L. infantum involving different species of sand flies and hosts. PMID- 30408298 TI - Bromeliad targeted foliar treatments with Aqualuer(r) 20-20 for hot spot mitigation using three hand sprayers against Aedes albopictus (Diptera: Culicidae). AB - Bromeliads serve as a key environmental resource for Aedes albopictus (Skuse) in some peridomestic landscapes and are not addressed through conventional source reduction. As an alternative, three handheld sprayers were evaluated in point source applications of permethrin to bromeliads in Saint Augustine, FL. Each machine was screened for its utility in point-source harborage treatments, while we simultaneously evaluated bromeliad-focused treatments for reducing Ae. albopictus egg abundance in bromeliad plants. Semi-field tests against caged Ae. albopictus produced 100% mortality at 24 h with each sprayer. Three field sites were assigned to each machine and a control, and bromeliad residual applications of Aqualuer 20-20(r) were assessed through egg surveillance using ovitraps both within and beyond 30 m of the treated bromeliad harborage. The treatment decreased Ae. albopictus egg abundance across the field sites for three weeks post-treatment with no significant differences among the equipment. Functional differences among machines, such as automated pressure control or leak guards on the nozzle, depend on the accessories that offer the greatest logistical benefit to the user. The field results suggest bromeliads are a viable target for harborage treatments. Selective treatments to bromeliads could offer a possible solution to containers that homeowners refuse to eliminate. PMID- 30408300 TI - Behavioral responses of gravid Culex quinquefasciatus, Aedes aegypti, and Anopheles quadrimaculatus mosquitoes to aquatic macrophyte volatiles. AB - Mosquitoes use many cues to assess whether a habitat is conducive for reproduction, possibly including the presence of stimuli from aquatic macrophytes. The effect of water infusions of water hyacinth (Eichhornia crassipes), water lettuce (Pista stratioles), parrotfeather (Myriophyllum aquaticum), and water pennywort (Hydrocotyle umbellata) on mosquito oviposition and attraction was investigated. Gravid Culex quinquefasciatus deposited significantly more egg rafts in water hyacinth, water lettuce, or Bermuda hay (positive control) infusions compared to water, while water pennywort and parrotfeather infusions did not differ from water. In-flight attraction responses of Cx. quinquefasciatus, Aedes aegypti, and Anopheles quadrimaculatus were evaluated. The strongest attraction of gravid Cx. quinquefasciatus and Ae. aegypti occurred in the presence of volatiles from infusions of water hyacinth and water lettuce, which were equal in attractiveness to hay infusion. Water pennywort and parrotfeather infusions were not attractive. Gravid An. quadrimaculatus were not attracted to aquatic plant volatiles. The results suggest that water hyacinth and water lettuce emit volatile chemicals that attract two of three mosquito species tested and stimulate oviposition by Cx. quinquefasciatus, demonstrating that the level of attraction of aquatic plant volatiles varies among species in ways that may have relevance to bait-based detection and control methods. PMID- 30408303 TI - Malcolm McIntosh Prize: J. K. Clegg / Tetrahedron Prize for Creativity: S. L. Buchwald and J. F. Hartwig. PMID- 30408301 TI - Formation of Multicomponent Size-Sorted Assembly Patterns by Tunable Templated Dewetting. AB - Selective and deterministic assembly of particles is fundamentally significant for manufacturing functional devices. However, it is still a challenge to precisely and facilely manipulate particles of different sizes into different assembly patterns. Herein, a method is presented to achieve precise control over the formation of binary or ternary particle size-sorted assemblies. We investigate the assembly process of particles by capillary confinement and show that different size-sorted assemblies of multiple components can be realized by tuning the templated dewetting. By controlling the dewetting direction, receding contact angle, and pillar height of the template, assembly of dual-ring patterns, "comet" structures, and patterns with component separation are regulated. These structures can be further diversified by tuning the composition of the particles. This approach is general for particle assemblies of different sizes and materials, which will be significant for the fabrication of printed micro/nanohybrid devices. PMID- 30408302 TI - Isovalent Cation Ordering in the Polar Rhombohedral Perovskite Bi2 FeAlO6. AB - Ordering of cations in different structural types occurs when there is a significant difference in the oxidation states and ionic radii of the ions involved. Herein we report an unusual ordering of isovalent cations Fe3+ and Al3+ in the polar rhombohedral R3 double perovskite structure of Bi2 FeAlO6 synthesized at high-pressure (6 GPa) and high-temperature (1000 degrees C). This ordered structure is derived from the 1:1 combination of the polar oxides BiFeO3 (R3c) and BiAlO3 (R3c), which results in reduction of symmetry to an R3 structure where the Fe3+ and Al3+ ions are ordered in a rock salt manner. However, these ions remain disordered in BiFe1-x Alx O3 (x=0.2, 0.3, 0.4) perovskites with R3c structure. The ordered compound undergoes antiferromagnetic ordering at TN ~280 K. The butterfly nature of piezoelectric displacement loop further confirms the polar nature of the cation-ordered Bi2 FeAlO6 . PMID- 30408304 TI - Malignant peripheral nerve sheath tumor: Transformation in a patient with neurofibromatosis type 2. AB - Malignant peripheral nerve sheath tumor (MPNST) is a rare soft-tissue sarcoma with an unfavorable prognosis and limited therapeutic options. MPNSTs can be sporadic, but are often associated with neurofibromatosis (NF) 1 and usually arise from preexisting neurofibromas. MPNSTs in patients with NF2 have been reported in only exceedingly rare cases, and the mechanisms underlying transformation into an MPNST have not been fully elucidated. Here, we describe the clinicopathological and genomic features of a peripheral nerve sheath tumor (PNST), with a primary diagnosis of a neurofibroma, as it transforms into a high grade MPNST in the context of NF2. PMID- 30408305 TI - A Mass-Spectrometry-Based Modelling Workflow for Accurate Prediction of IgG Antibody Conformations in the Gas Phase. AB - Immunoglobulins are biomolecules involved in defence against foreign substances. Flexibility is key to their functional properties in relation to antigen binding and receptor interactions. We have developed an integrative strategy combining ion mobility mass spectrometry (IM-MS) with molecular modelling to study the conformational dynamics of human IgG antibodies. Predictive models of all four human IgG subclasses were assembled and their dynamics sampled in the transition from extended to collapsed state during IM-MS. Our data imply that this collapse of IgG antibodies is related to their intrinsic structural features, including Fab arm flexibility, collapse towards the Fc region, and the length of their hinge regions. The workflow presented here provides an accurate structural representation in good agreement with the observed collision cross section for these flexible IgG molecules. These results have implications for studying other nonglobular flexible proteins. PMID- 30408306 TI - Adolescent survivors' information needs for transitions to postsecondary education and employment. AB - BACKGROUND: Adolescent and young adult (AYA) survivors of cancer and central nervous system (CNS) tumors endure major life disruptions with their diagnosis, treatment, and the burden of emerging learning difficulties. Survivors and their parents often struggle to obtain more academic support as survivors transition through school. This study explored the knowledge and experience survivors and their parents need as they progress through school to college. METHODS: This cross-sectional study examined childhood cancer and CNS tumor survivors, aged 11 to 21 years, with a known learning difficulty (Individual Education Plan, 504 Plan) and their parents. We assessed participants' knowledge of and experience with transition planning for postsecondary education and independent living. RESULTS: Ninety-two AYA survivors and parents (45 survivors, 47 parents) completed the survey. High school-aged survivors described their learning difficulties better than middle school-aged survivors. Survivors estimated their abilities higher than did their parents. Despite a majority of survivors expecting to attend college, 68.5% of survivors and 57.9% of parents were not certain how to get special accommodations for standardized college entrance exams. Only 20.8% of survivors were aware of what a transition plan includes. Parents understood the transition planning process and when it should begin better than the students (P = 0.001), but many parents (40.0%) were still unsure. CONCLUSIONS: AYA survivors and parents lack knowledge necessary to successfully transition to their goals after high school. Greater education is needed. PMID- 30408307 TI - Physician perspectives on compassionate use in pediatric oncology. AB - BACKGROUND: Targeted cancer treatments are almost always first studied in adults, even when there is a biologically plausible potential for efficacy in children. Through compassionate use programs, children who are not eligible for a clinical trial and for whom there are no known effective therapies may obtain access to investigational agents, including drugs under development for adults. However, little is known about pediatric oncologists' experiences with applying for and obtaining compassionate use agents. METHODS: This study surveyed 132 pediatric oncologists to assess awareness and utilization of compassionate use programs, to identify barriers to their use, and to evaluate available institutional support and resources. RESULTS: We found that the process of applying for access to drugs in development is poorly understood, which presents a barrier to obtaining investigational drugs. Fifty-seven percent of the pediatric oncologists applied for compassionate use. Providers from larger institutions or with more than 15 years of clinical experience were more likely to complete an application and obtain investigational agents for their patients. CONCLUSION: Identified perceived and actual barriers to compassionate use application submission suggest pediatric oncologists may benefit from educational resources and support to ensure children with cancer equal access to investigational agents and care. PMID- 30408308 TI - Monte Carlo and analytic modeling of an Elekta Infinity linac with Agility MLC: Investigating the significance of accurate model parameters for small radiation fields. AB - PURPOSE: To explain the deviation observed between measured and Monaco calculated dose profiles for a small field (i.e., alternating open-closed MLC pattern). A Monte Carlo (MC) model of an Elekta Infinity linac with Agility MLC was created and validated against measurements. In addition, an analytic model which predicts the fluence at the isocenter plane was used to study the impact of multiple beam parameters on the accuracy of dose calculations for small fields. METHODS: A detailed MC model of a 6 MV Elekta Infinity linac with Agility MLC was created in EGSnrc/BEAMnrc and validated against measurements. An analytic model using primary and secondary virtual photon sources was created and benchmarked against the MC simulations and the impact of multiple beam parameters on the accuracy of the model for a small field was investigated. Both models were used to explain discrepancies observed between measured/EGSnrc simulated and Monaco calculated dose profiles for alternating open-closed MLC leaves. RESULTS: MC-simulated dose profiles (PDDs, cross- and in-line profiles, etc.) were found to be in very good agreements with measurements. The best fit for the leaf bank rotation was found to be 9 mrad to model the defocusing of Agility MLC. Moreover, a very good agreement was observed between results from the analytic model and MC simulations for a small field. Modifying the radial size of the incident electron beam in the BEAMnrc model improved the agreement between Monaco and EGSnrc calculated dose profiles by approximately 16% and 30% in the position of maxima and minima, respectively. CONCLUSION: Accurate modeling of the full-width-half-maximum (FWHM) of the primary photon source as well as the MLC leaf design (leaf bank rotation, etc.) is essential for accurate calculations of dose delivered by small radiation fields when using virtual source or MC models of the beam. PMID- 30408309 TI - In-hospital outcomes of transcatheter versus surgical aortic valve replacement in non-teaching hospitals. AB - OBJECTIVES: To assess the in-hospital outcomes of transcatheter aortic valve replacement (TAVR) vs. surgical aortic valve replacement (SAVR) in non-teaching hospitals. BACKGROUND: TAVR has become widely available in the United States. However, the comparative outcomes of TAVR vs. SAVR in non-teaching hospitals are largely under explored. METHODS: We queried the Nationwide Inpatient Sample database from 2011 to September 2015 to identify those who were 50 years or above and underwent either trans-arterial TAVR or SAVR at non-teaching hospital. In hospital clinical outcomes were compared with odds ratio (OR) in propensity matched cohorts. RESULTS: We identified un-weighted 957 and 7,465 SAVR admissions. In propensity-matched model, 596 admissions in each arm were included for final analysis. In-patient mortality (3.9 vs. 2.5%, OR 1.54, P = 0.34), acute kidney injury requiring dialysis (2.2 vs. 2.7%, OR 0.80, P = 0.57), stroke (2.0 vs. 3.2%, OR 0.61, P = 0.20), and pacemaker placement (8.9 vs. 6.4%, OR 1.47, P = 0.09) was similar between TAVR and SAVR. Sub-group analysis showed that female and those with prior coronary artery bypass surgery had higher risk of in-patient morality in TAVR admission. Cost was higher (59,103 vs. 53,411 dollars, P = 0.006) but length of stay was shorter in TAVR (6.9 vs. 10.2 days, P < 0.001). CONCLUSIONS: TAVR conferred similar in-hospital mortality and major peri procedural complications compared with SAVR in non-teaching hospitals. For those with limited access to teaching hospitals, non-teaching hospitals appear to be a reasonable option for candidates of aortic valve replacement for severe aortic stenosis. PMID- 30408310 TI - Corrosion behavior and biocompatibility evaluation of a novel zinc-based alloy stent in rabbit carotid artery model. AB - Zinc (Zn) and its alloys have been proved to be promising candidate materials for biodegradable cardiovascular stents. In this study, a novel extruded Zn-0.02 Mg 0.02Cu alloy was prepared. Compared with pure Zn, the Zn-based alloy showed higher mechanical properties, and the Zn-based alloy could significantly accelerate Zn2+ release, reaching 0.61 +/- 0.11 MUg/mL at 15 days of immersion. In vitro biocompatibility studies demonstrated that the Zn-based alloy had excellent cytocompatibility and hemocompatibility, including low hemolysis rate (0.63 +/- 0.12%) and strong inhibitory effect on platelet adhesion. Subsequently, the Zn-based alloy stent was implanted into the left carotid arteries of New Zealand white rabbits for 12 months. All the rabbits survived without any adverse clinical events, and all the stented arteries were patent during the study period. Rapid endothelialization at 1 week of implantation was observed, suggesting a low cytotoxicity and thrombosis risk. The stent corroded slowly and no obvious intimal hyperplasia was observed for 6 months, after which corrosion accelerated at 12 months. In addition, no obvious thrombosis and systemic toxicity during implantation period were observed, indicating its potential as the backbone of biodegradable cardiovascular stents. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: 00B: 000-000, 2018. PMID- 30408311 TI - Design of Single Gold Atoms on Nitrogen-Doped Carbon for Molecular Recognition in Alkyne Semi-Hydrogenation. AB - Single-atom heterogeneous catalysts with well-defined architectures are promising for deriving structure-performance relationships, but the challenge lies in finely tuning the structural and electronic properties of the metal. To tackle this point, a new approach based on the surface diffusion of gold atoms on different cavities of N-doped carbon is presented. By controlling the activation temperature, the coordination neighbors (Cl, O, N) and the oxidation state of the metal can be tailored. Semi-hydrogenation of various alkynes on the single-atom gold catalysts displays substrate-dependent catalytic responses; structure insensitive for alkynols with gamma-OH and unfunctionalized alkynes, and sensitive for alkynols with alpha-OH. Density functional theory links the sensitivity for alkynols to the strong interaction between the substrate and specific gold-cavity ensembles, mimicking a molecular recognition pattern that allows to identify the cavity site and to enhance the catalytic activity. PMID- 30408312 TI - Voices for gender equity in medical physics. PMID- 30408313 TI - The utility of routine surveillance screening with magnetic resonance imaging to detect tumor recurrence/progression in children with high-grade central nervous system tumors: a systematic review. AB - BACKGROUND: Surveillance magnetic resonance imaging (MRI) is routinely used to detect recurrence in children with high-grade central nervous system (CNS) tumors, although no consensus has been reached regarding its effectiveness and whether earlier detection is associated with improved patient outcomes. This review aimed to evaluate this practice and any associated benefits and harms. METHODS: Systematic searches for relevant studies were undertaken in a number of databases, including MEDLINE and EMBASE, from 1985 to August 2018. Study selection and data extraction was undertaken independently by two reviewers. Due to heterogeneity between studies, no pooling of data was undertaken. Reporting followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: No comparative studies were identified. Three retrospective observational studies involving 306 patients were reviewed. All had high risk of bias by virtue of study design. Two studies reported outcomes by symptomatic status-both recurrence rates and overall survival for asymptomatic patients were comparable with those for clinically symptomatic patients. No quality-of-life outcomes were reported. CONCLUSION: There is a paucity of evidence to guide clinical practice as to the effectiveness of MRI surveillance in pediatric patients with high-grade CNS tumors. These studies do not clearly demonstrate benefit or harm for the practice. With more research needed, there is a role for researchers to build into future trials data collection on surveillance imaging to give more information for the assessment of imaging frequency and duration in asymptomatic patients. This is an important question not only to clinicians and patients and their families but also from a health service resource perspective. PMID- 30408314 TI - Influence of chemically modified Luffa on the preparation of nanofiber and its biological evaluation for biomedical applications. AB - In the present investigation, the natural cellulose was extracted from Luffa cylindrica vegetable sponge by chemical modification. Both chemically modified and unmodified Luffa was characterized by Fourier-transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRD), scanning electron microscopy (SEM), and energy-dispersive X-ray spectroscopy. The chemically modified cellulose was used for the preparation of a nanofibrous scaffold using the electrospinning method. In order to achieve the uniform and bead free fibers with desired fiber diameter the parameters such as applied voltage, tip to collector distance, solution concentration were optimized. Different ratio of hydroxyapatite (HAP): polylactic acid (PLA) such as 40:60, 50:50, 60:40, and 70:30 have been selected for the current evaluation and was compared with HAP-treated cellulose (TC)-PLA. With the increase in the concentration of HAP in the polymeric network, the diameter of the fiber was found to be thin with the high electric field. The functional group, phase formation and dielectric and mechanical properties of the developed nanofiber have been characterized by FTIR, XRD, mechanical property measurements, and SEM. From the results, we observed that the polymer composite developed with the ratio of 70:30 produces a bead free product with enhanced mechanical and bioactivity property by the formation of hydroxy carbonated apatite layer on the surface. All the nanofibrous scaffold fabricated with and without modification have shown good Cyto compatibility on MG-63 Osteoblast cell lines at 48 hr. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 00A: 000-000, 2018. PMID- 30408315 TI - Clarifying the Difference between Iterative Saturation Mutagenesis as a Rational Guide in Directed Evolution and OmniChange as a Gene Mutagenesis Technique. AB - Oil and water, apples and pears: Mixing things that should not be mixed can result in scientifically unsound conclusions. A recent directed-evolution study compared iterative saturation mutagenesis (ISM) with the OmniChange version of saturation mutagenesis (SM). ISM is a semirational strategy in directed evolution that is independent of the particular type of SM, thus the two should not be compared. PMID- 30408316 TI - Mild Methylenetetrahydrofolate Reductase Deficiency Alters Inflammatory and Lipid Pathways in Liver. AB - SCOPE: Dietary and genetic folate disturbances can lead to nonalcoholic fatty liver disease (NAFLD). A common variant in methylenetetrahydrofolate reductase (MTHFR 677C->T) causes mild MTHFR deficiency with lower 5-methyltetrahydrofolate for methylation reactions. The goal is to determine whether mild murine MTHFR deficiency contributes to NAFLD-related effects. METHODS AND RESULTS: Wild-type and Mthfr+/- mice, a model for the human variant, are fed control (CD) or high fat (HFAT) diets for 8 weeks. On both diets, MTHFR deficiency results in decreased S-adenosylmethionine, increased S-adenosylhomocysteine, and decreased betaine with reduced methylation capacity, and changes in expression of several inflammatory or anti-inflammatory mediators (Saa1, Apoa1, and Pon1). On CD, MTHFR deficiency leads to microvesicular steatosis with expression changes in lipid regulators Xbp1s and Cyp7a1. The combination of MTHFR deficiency and HFAT exacerbates changes in inflammatory mediators and introduces additional effects on inflammation (Saa2) and lipid metabolism (Nr1h4, Srebf1c, Ppara, and Crot). These effects are consistent with increased expression of pro-inflammatory HDL precursors and greater lipid accumulation. MTHFR deficiency may enhance liver injury through alterations in methylation capacity, inflammatory response, and lipid metabolism. CONCLUSION: Individuals with the MTHFR variant may be at increased risk for liver disease and related complications, particularly when consuming high-fat diets. PMID- 30408318 TI - Urgent transcatheter aortic valve replacement for severe acute aortic regurgitation following open mitral valve surgery. AB - Transcatheter aortic valve replacement (TAVR) is not currently approved for pure native valve aortic incompetence, and is typically performed on a compassionate basis in selected patients who are at high risk for conventional surgery. We describe the first use of TAVR to treat iatrogenic severe acute pure aortic incompetence following mitral valve surgery. A 71-year-old gentleman developed life-threatening acute aortic regurgitation (AR) within hours of a very challenging fifth open heart mitral valve replacement. Careful inspection of echocardiographic and computed tomographic imaging identified the cause as a disrupted left coronary cusp at the commissure caused by the surgical mitral annular reconstruction. Medical management with afterload reduction failed with recurrent pulmonary edema, and a sixth open heart surgery was deemed prohibitively high risk. The lack of aortic annular calcium onto which anchors a transcatheter valve was a concern for TAVR. However, we postulated that the struts of the mitral valve bioprosthesis would offer some support to the TAVR valve. We opted for a self-expanding system because of concerns about potential unfavorable interaction between the balloon onto which balloon-expandable bioprosthesis is mounted and the struts of the mitral bioprosthesis, and because the Evolut R system has additional anchoring points at the crown which might enhance transcatheter valve stability in the non-calcified annulus, compared with the Edwards Sapien system. Transfemoral TAVR, performed with a Medtronic Evolut R 34 mm system under general anesthesia and using moderately rapid ventricular pacing, was successful with minimal residual AR. On follow-up 1 month later the patient was asymptomatic, and the aortic and mitral bioprostheses were functioning normally on echocardiogram. PMID- 30408317 TI - Modified delivery of SAPIEN 3 valve in the pulmonary position: Evolution of technique or dire need? AB - Transcatheter pulmonary valve replacement (TPVR) is now common practice in patients with significant pulmonary regurgitation (PR), stenosis (PS), or mixed pulmonary valve disease. While the Melody valve (Medtronic, Inc.) and its delivery system were specifically designed for use in the right ventricular outflow tract (RVOT), Sapien valves (XT and S3, Edwards Lifesciences, Inc.) and their delivery systems (Novaflex and Commander) were not. As a result, placement of Sapien valves in the RVOT can be challenging secondary to the stiffness of the current delivery system. Manipulating a stiff delivery system within the RV also introduces risk to the tricuspid valve and its chordal attachments. We report a novel delivery technique for the Sapien S3 valve which has greatly simplified valve delivery into the RVOT and may potentially reduce the risk of tricuspid valve injury. PMID- 30408319 TI - The effect of preoperative chemotherapy on histological subtyping and staging of Wilms tumors: The United Kingdom Children's Cancer Study Group (UKCCSG) Wilms tumor trial 3 (UKW3) experience. AB - BACKGROUND: Two principal approaches to Wilms tumor (WT) treatment are immediate surgery (IS) and preoperative chemotherapy (PCT), and both treatments use the risk-adapted approach that includes histological subclassification of the tumor, combined with additional prognostic factors. In the UKW3 trial, these two approaches were compared. The aim of the present study was to compare histological features between the two groups, to assess the impact of PCT on distribution of histological subtyping and staging and to evaluate whether PCT resulted in more staging discrepancies between local and central pathology review (CPR). MATERIALS AND METHODS: The cases were identified from the UKW3 trial database. The criteria for inclusion in the study were unilateral, nonmetastatic, nonanaplastic WTs, and submitted for CPR with an adequate number of slides. They were subclassified according to the NWTS and later the SIOP 9301 criteria. RESULTS: There were 244 WTs in the IS and 182 in the PCT group subclassified as follows: blastemal 86 (35%) vs 9 (5%), epithelial 34 (14%) vs 12 (7%), stromal 12 (5%) vs 25 (14%), mixed 112 (46%) vs 45 (25%), respectively, plus 40% regressive and 10% completely necrotic WTs in the PCT group. The differences between the two groups for blastemal and mixed types were statistically significant. In the PCT group, there was a significant decrease in stage III tumors. The discrepancies in staging between local and CPR were not significant. CONCLUSION: PCT significantly altered histological features and typing of WTs. It resulted in fewer stage III tumors, and staging discrepancies were equally represented in both groups. PMID- 30408320 TI - Preparation, characterization and application of a protein hydrogel with rapid self-healing and unique autofluoresent multi-functionalities. AB - A smart hydrogel with dual self-healing and autofluoresent functionalities is presented. The protein hydrogel is fabricated by denaturing bovine serum albumin in a basic environment. Upon gelation, autofluorescence is induced and the protein hydrogel can be excited by a wide range of spectrum, ranging from 320 to 520 nm. It was also found that the as-prepared autofluorescent protein hydrogel possessed rapid and repetitive self-healing capability. Without any external stimulus, more than 90% recovery of the mechanical strength can be obtained within 10 min after destruction. Moreover, the as-prepared hydrogel exhibits excellent biocompatibility and cell attachment property after its pH adjustment to neutral pH, while both autofluorescence and self-healing properties were still retained. This study suggests a promising means to prepare multi-functional protein hydrogel with dual physicochemical functionalities, which holds great potential in biomedical related applications. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 81-91, 2019. PMID- 30408321 TI - Enhanced chondrogenic differentiation of bone marrow mesenchymal stem cells on gelatin/glycosaminoglycan electrospun nanofibers with different amount of glycosaminoglycan. AB - Tissue engineering is a new technique to help damaged cartilage treatment using cells and scaffolds. In this study we tried to evaluate electrospun scaffolds composed of gelatin/glycosaminoglycan (G/GAG) blend nanofibers in chondrogenesis of bone marrow-derived mesenchymal stem cells (BMMSCs). Scaffolds were fabricated by electrospinning technique with different concentration of glycosaminoglycan (0%, 5%, 10%, and 15%) in gelatin matrix. BMMSCs were cultured on the scaffolds for chondrogenesis process. MTT assay was done for scaffold's biocompatibility and cells viability evaluation. Alcian blue staining was carried out to determine the release of GAG and reverse transcription polymerase chain reaction (RT-PCR) was done for expression of COL2A1 and also immunocytochemistry assay were used to confirm expression of type II collagen. Scaffold with 15% GAG showed better result for biocompatibility (p =0.02). Scanning electron microscopy (SEM) micrographs showed that MSCs have good attachment to the scaffolds. Alcian blue staining result confirmed that cells produce GAG during differentiation time different from GAG in the scaffolds. Also the results for RT-PCR showed the expression of COL2A1 marker. Immunocytochemistry assay for type II collagen confirm that this protein expressed. Scaffold comprising 15% GAG is better results for chondrogenesis and it can be a good applicant for cartilage tissue engineering. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 38 48, 2019. PMID- 30408322 TI - Bad Language. AB - Bad Language in stereochemistry - and elsewhere - can lead to sloppy thinking. In this essay I review the history of stereochemical concepts and vocabulary in the hope that it may contribute a little to better thinking and communication. PMID- 30408323 TI - Identification and Directed Development of Non-Organic Catalysts with Apparent Pan-Enzymatic Mimicry into Nanozymes for Efficient Prodrug Conversion. AB - Nanozymes, nanoparticles that mimic the natural activity of enzymes, are intriguing academically and are important in the context of the Origin of Life. However, current nanozymes offer mimicry of a narrow range of mammalian enzymes, near-exclusively performing redox reactions. We present an unexpected discovery of non-proteinaceous enzymes based on metals, metal oxides, 1D/2D-materials, and non-metallic nanomaterials. The specific novelty of these findings lies in the identification of nanozymes with apparent mimicry of diverse mammalian enzymes, including unique pan-glycosidases. Further novelty lies in the identification of the substrate scope for the lead candidates, specifically in the context of bioconversion of glucuronides, that is, human metabolites and privileged prodrugs in the field of enzyme-prodrug therapies. Lastly, nanozymes are employed for conversion of glucuronide prodrugs into marketed anti-inflammatory and antibacterial agents, as well as "nanozyme prodrug therapy" to mediate antibacterial measures. PMID- 30408324 TI - Introducing robotic radical hysterectomy for stage 1bi cervical cancer-A prospective evaluation of clinical and economic outcomes in a single UK institution. AB - BACKGROUND: We have assessed the impact of introducing robotics for a stage 1b cervical cancer service on laparotomy rates, complications, and costs. METHODS: Data were collected prospectively from 90 consecutive patients who had a radical hysterectomy between 1 April 2010 and 31 December 2017. RESULTS: There were 37 women before the first robotic procedure and 53 after. The laparotomy rate reduced from 75% (9/12) in 2010 to 0% (0/18) in 2017. The length of stay reduced from 6 days (range 3-39) to 3 days (range 1-15) (P < 0.0001). The complication rate before robotics was 68% (25/37) compared with 45% (24/53) afterwards (P = 0.0493). The blood transfusion rate reduced from 43% (16/37) to 11% (6/53) (P = 0.0007). There were no differences between the total costs before and after the introduction of robotics or between each route. CONCLUSIONS: In this series, introducing robotics for cervical carcinoma reduced hospital stay and complications. No cost differences were demonstrated. PMID- 30408326 TI - Academie des Sciences Prizes 2018. PMID- 30408325 TI - Evaluation of 2-Thiothiazolidine-4-Carboxylic Acid, a Common Metabolite of Isothiocyanates, as a Potential Biomarker of Cruciferous Vegetable Intake. AB - SCOPE: Cruciferous vegetable consumption is associated with favorable health outcomes. Bioactive compounds arising in these, especially isothiocyanates, exert effects that contribute to prevention of disease, in large part through the attenuation of inflammation and oxidative stress. However, much about isothiocyanate metabolites and their role as biomarkers of crucifer intake remain unknown. METHODS AND RESULTS: The utility and limitations of 2-thiothiazolidine-4 carboxylic acid (TTCA) as a urinary biomarker of broccoli beverage intake are tested in a randomized crossover clinical trial where 50 participants consumed either a glucoraphanin-rich (GRR) or sulforaphane-rich (SFR) beverage. Compared to run-in and wash-out periods, significantly higher urinary TTCA is observed after broccoli beverage consumption. Measurements also show that TTCA is present in beverage powders and in all tested cruciferous vegetables. GRR results in excretion of ~87% of the ingested TTCA while SFR results in excretion of ~176%. Elevated urinary TTCA is observed in rats administered 100 umol kg-1 SFN. Unlike SFN, TTCA does not activate Nrf2-mediated cytoprotective signaling. CONCLUSION: Collectively, TTCA appears to be a common isothiocyanate-derived metabolite that has the capacity to be utilized as a biomarker of cruciferous vegetables that would be beneficial for objective and quantitative tracking of intake in studies. PMID- 30408327 TI - Clinical utility of intraprocedural three-dimensional integrated image guided transcatheter aortic valve implantation using novel automated computed tomography software: A single-center preliminary experience. AB - OBJECTIVES: Novel automated computed tomography (CT) software (Valve ASSIST 2) has been developed for transcatheter aortic valve implantation (TAVI), which not only provides three-dimensional (3D) reconstruction of multidetector (MD) CT images, but also enables intraprocedural real-time fusion of fluoroscopic and MDCT images. We aimed to clarify the reproducibility and accuracy of this software in the aortic annulus assessment and verify the potential of intraprocedural integrated MDCT imaging for TAVI. METHODS AND RESULTS: We examined 50 patients with severe aortic stenosis undergoing transfemoral TAVI. Aortic annulus measurements were performed using 3mensio and the novel planning software. For intraprocedural imaging, preoperative CT dataset was overlaid onto fluoroscopy with the fusion software. The two images were aligned using the aortic root anatomy visible on both modalities. Novel planning software provided excellent reproducibility for the measurement of aortic annulus area (intraobserver intraclass correlation coefficients [ICC] 0.959, interobserver ICC 0.941), and perimeter (intraobserver ICC 0.915, interobserver ICC 0.912). Excellent correlation was found between novel planning software and 3mensio (ICC 0.952 for aortic annulus area, and 0.923 for perimeter). Intraprocedural fusion image of CT aortography and fluoroscopic aortic root aortography generated by this novel software identified coronary orifices and the distribution of aortic valve calcification during the device positioning. Fusion image displayed coronary orifices after device implantation. CONCLUSIONS: Novel planning software showed excellent reproducibility and accuracy in the assessment of aortic root anatomy. Furthermore, the integrated 3D fusion image might have a potential as an intraprocedural imaging modality to contribute to the development of a safer TAVI procedure. PMID- 30408328 TI - Nickel as a Lewis Base in a T-Shaped Nickel(0) Germylene Complex Incorporating a Flexible Bis(NHC) Ligand. AB - Flexible, chelating bis(NHC) ligand 2, able to accommodate both cis- and trans coordination modes, was used to synthesize (2)Ni(eta2 -cod), 3. In reaction with GeCl2 , it produced (2)NiGeCl2 , 4, featuring a T-shaped Ni0 and a pyramidal Ge center. Complex 4 could also be prepared from [(2)GeCl]Cl, 5, and Ni(cod)2 , in a reaction that formally involved Ni-Ge transmetalation, followed by coordination of the extruded GeCl2 moiety to Ni. A computational analysis showed that 4 possesses considerable multiconfigurational character and the Ni->Ge bond is formed through sigma-donation from the Ni 4s, 4p, and 3d orbitals to Ge. (NHC)2 Ni(cod) complexes 9 and 10, as well as (NHC)2 GeCl2 derivative 11, incorporating ligands that cannot accommodate a wide bite angle, failed to produce isolable Ni Ge complexes. The isolation of (2)Ni(eta2 -Py), 12, provides further evidence for the reluctance of the (2)Ni0 fragment to act as a sigma-Lewis acid. PMID- 30408330 TI - The Initial Impact of the Anatomical Society Gross Anatomy Core Syllabus for Medicine in the United Kingdom: Student and Teacher Perspectives. AB - "What do students studying medicine need to know" is an important question for curriculum planners, anatomy educators and students. The Core Regional Anatomy Syllabus (CRAS), published by the Anatomical Society in 2016, contains 156 learning outcomes (LOs) and has informed "what needs to be known." This project explored how CRAS had impacted undergraduate anatomy and anatomists in the United Kingdom. A cross-sectional study was designed in two phases. Phase 1, involved a survey of students in clinical years (N = 164). Phase 2 included a survey of anatomist's views (n = 50) and focus groups of anatomy educators (N = 16). The students' perspective showed that specific regions of CRAS are deemed less relevant. These were also the body areas where students perceived their anatomical knowledge to be more deficient. Only 46% (n = 75) of students estimated that they knew over 50% (n = 78) of the LOs. Phase two revealed that all anatomists were aware of the syllabus and 48% (n = 24) had checked the CRAS against their own institutional LOs. Anatomists had shared CRAS with colleagues 64% (n = 32) and students at 34% (n = 17), respectively. Forty-six percent (n = 23) of anatomists reported having changed their teaching in some way because of CRAS. The focus groups generated four key themes: "support for CRAS," "standardization and validation," "professional identity," and "limitations and leverage." Overall CRAS has been well received and is establishing itself within the anatomical community as the new standard for anatomy teaching for medical students. PMID- 30408329 TI - Mitochondrial membrane potential and delayed graft function following kidney transplantation. AB - Delayed graft function (DGF) complicates 20%-40% of deceased-donor kidney transplants and is associated with increased length of stay and subsequent allograft failure. Accurate prediction of DGF risk for a particular allograft could influence organ allocation, patient counseling, and postoperative planning. Mitochondrial dysfunction, a reported surrogate of tissue health in ischemia perfusion injury, might also be a surrogate for tissue health after organ transplantation. To understand the potential of mitochondrial membrane potential (MMP) in clinical decision-making, we analyzed whether lower MMP, a measure of mitochondrial dysfunction, was associated with DGF. In a prospective, single center proof-of-concept study, we measured pretransplant MMP in 28 deceased donor kidneys and analyzed the association between MMP and DGF. We used hybrid registry augmented regression to adjust for donor and recipient characteristics, minimizing overfitting by leveraging Scientific Registry of Transplant Recipients data. The range of MMP levels was 964-28 333 units. Low-MMP kidneys (MMP<4000) were more likely from female donors (75% vs 10%, P = .002) and donation after cardiac death donors (75% vs 12%, P = .004). For every 10% decrease in MMP levels, there were 38% higher odds of DGF (adjusted odds ratio = 1.08 1.381.78 , P = .01). In summary, MMP might be a promising pretransplant surrogate for tissue health in kidney transplantation and, after further validation, could improve clinical decision-making through its independent association with DGF. PMID- 30408331 TI - CD38 is not expressed in pediatric ALK-positive anaplastic large cell lymphoma. PMID- 30408332 TI - Antibacterial Polymeric Films Fabricated by [2+2] Cycloaddition Retroelectrocyclization and Ag+ Ion Coordination. AB - The [2+2] cycloaddition-retroelectrocyclization (CA-RE) between N,N dialkylaniline-substituted alkynes and 7,7,8,8-tetracyanoquinodimethane (TCNQ) is employed to fabricate functional cross-linked polymer films containing the intramolecular charge-transfer (CT) chromophores at the cross-linking points. Polystyrene bearing N,N-dialkylaniline-substituted alkynes (P1) and TCNQ polyester (P2) are mixed in tetrahydrofuran (THF), then this solution is spray coated onto an indium tin oxide or glass plate. Heating to 100 degrees C initiates the [2+2] CA-RE reaction, resulting in the formation of cross-linked polymer films. The reaction progress and completion are evaluated by monitoring the CT absorption band and cyano vibration peaks. The resulting cross-linked polymer films show reversible cathodic electrochromism between the neutral and anion radical states. In addition, they also display the visual detection behavior of protic acids and Lewis acids, such as Ag+ ions. Accordingly, the Ag+ ion-loaded polymer films are prepared, and their antibacterial activities are studied. As more Ag+ ions are loaded, the CT band more bathochromically shifts and more potent antibacterial activities are obtained. Therefore, the antibacterial activity of the polymer films can be visually recognized by the film colors. Furthermore, the loaded Ag+ ions can be released from the polymer films by application of an electrochemical potential. PMID- 30408333 TI - A High-Throughput Absolute-Level Quantification of Protein-Bound Amino Acids in Seeds. AB - In this unit, we describe a high-throughput absolute quantification protocol for 16 protein-bound amino acids (PBAAs) that combines a microscale protein hydrolysis step and an absolute quantification step using multiple reaction monitoring-based liquid chromatography-tandem mass spectrometry detection. The approach facilitates analysis of a few hundred samples per week by using a 96 well-plate extraction setup and avoiding use of additives. Importantly, the method uses only ~3 mg of tissue per sample and includes 12 heavy-amino-acid internal standards to enable quantification of the absolute levels of PBAAs with high precision, accuracy, and reproducibility. The protocol described herein has been optimized for seed samples but is applicable to other plant tissues. (c) 2018 by John Wiley & Sons, Inc. PMID- 30408334 TI - Disparate growth strategies within Aetosauria: Novel Histologic Data from the Aetosaur Coahomasuchus chathamensis. AB - Aetosaurs comprise a clade of quadrupedal, armored, omnivores to herbivores that lived across much of the supercontinent of Pangea during the Late Triassic. Their relative abundance in many units, and the rarity of other Triassic herbivores, points to them as key components of Late Triassic ecosystems. Debate persists about whether they were growing more or less slowly when compared to extant crocodylians, and bone histology is sparsely sampled within the group. We undertook a histological examination of Coahomasuchus chathamensis to address its ontogenetic trajectory and characterize its histology. We sampled a paramedian osteoderm from the holotype specimen, as well as five osteoderms (two paramedian, one lateral, and two of uncertain position) and two incomplete limb bones (radius and fibula), from referred specimens discovered at the type locality. Using these we estimated specimen ages with lines of arrested growth (LAGs) to determine that the study individuals reached from 2 to 7 years old. All of the sampled elements contained woven-fibered bone with extensive vasculature within the internal cortex. In some specimens, more poorly vascularized, parallel-fibered bone is evident externally. The holotype of C. chathamensis represents a juvenile individual, and raises the possibility that the holotype of C. kahleorum is a juvenile as well, complicating aetosaur systematics and diversity. When compared to aetosaurs of similar size, it is clear that C. chathamensis was growing comparatively rapidly, about 3 times the rate of similarly sized specimens of Aetosauroides scagliai from Argentina. This discovery reveals the presence of disparate growth strategies within Aetosauria. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30408335 TI - Malformations in the murine kidney caused by loss of CENP-F function. AB - Centromere-binding protein F (CENP-F) is a large and complex protein shown to play critical roles in mitosis and various other interphase functions. Previous studies have shown that the disruption of CENP-F function leads to detrimental effects on human development. Still, it is important to note the lack of studies focusing on the effects that the loss of this essential protein may have on specific adult organs. In the current study, we used a novel global knockout murine model to analyze the potential consequences deletion of CENP-F has on adult kidney structure and function. We discovered several structural abnormalities including loss of ciliary structure, tubule dilation, and disruption of the glomerulus. Along with these structural irregularities, renal dysfunction was also detected suggesting hydronephrosis and acute kidney injury (AKI) in these knockout organs. Importantly, this is the first study linking CENP F to kidney disease and hopefully these data will serve as a platform to further investigate the molecular mechanisms disrupted in the kidney by the loss of CENP F. This article is protected by copyright. All rights reserved. PMID- 30408336 TI - Cost-Efficient Graphitic Carbon Nitride as an Effective Photocatalyst for Antibiotic Degradation: An Insight into the Effects of Different Precursors and Coexisting Ions, and Photocatalytic Mechanism. AB - In this study, the photocatalytic activity of graphitic carbon nitride (g-C3 N4 ) synthesized via different precursors (urea, thiourea, and dicyandiamide) is investigated in the degradation process of tetracycline. Owing to the efficient charge separation and transfer, prolonged radiative lifetime of charge, large surface area, and nanosheet morphology, the urea-derived g-C3 N4 exhibits superior photocatalytic activity for tetracycline degradation under visible-light irradiation. This performance can compare with that of most reported g-C3 N4 based composite photocatalysts. Through the time-circle degradation experiment, the urea-derived g-C3 N4 is found to have an excellent photocatalytic stability. The presence of NO3 - , CH3 COO- , Cl- and SO4 2- ions with the concentration of 10 mm inhibits the photocatalytic activity of urea-derived g-C3 N4 , where this inhibitory effect is more obvious for Cl- and SO4 2- ions. For the coexisting Cu2+ , Ca2+ , and Zn2+ ions, the Cu2+ ion exhibits a significantly higher inhibitory effect than Ca2+ and Zn2+ ions for tetracycline degradation. However, both the inhibitory and facilitating effects are observed in the presence of Fe3+ ion with different concentration. The h+ , . OH and . O2 - radicals are confirmed as major oxidation species and a possible photocatalytic mechanism is proposed in a urea-derived g-C3 N4 reaction system. This study is of important significance to promote the large-scale application of g-C3 N4 photocatalysts in antibiotic wastewater purification. PMID- 30408337 TI - Silk-Based Antimicrobial Polymers as a New Platform to Design Drug-Free Materials to Impede Microbial Infections. AB - Surgical site infections (SSI) represent a serious health problem that occur after invasive surgery, thus new antimicrobial biomaterials able to prevent SSI are needed. Silks are natural biopolymers with excellent biocompatibility, low immunogenicity and controllable biodegradability. Spider silk-based materials can be bioengineered and functionalized with specific peptides, such as antimicrobial peptides, creating innovative polymers. Herein, we explored new drug-free multifunctional silk films with antimicrobial properties, specifically tailored to hamper microbial infections. Different spider silk domains derived from the dragline sequence of the spider Nephila clavipes (6mer and 15mer, 27 and 41 kDa proteins, respectively) were fused with the two antimicrobial peptides, Hepcidin (Hep) and Human Neutrophil peptide 1 (HNP1). The self-assembly features of the spider silk domains (beta-sheets) were maintained after functionalization. The bioengineered 6mer-HNP1 protein demonstrated inhibitory effects against microbial pathogens. Silk-based films with 6mer-HNP1 and different contents of silk fibroin (SF) significantly reduced bacterial adhesion and biofilm formation, whereas higher bacterial counts were found on the films prepared with 6mer or SF alone. The silk-based films showed no cytotoxic effects on human foreskin fibroblasts. The positive cellular response, together with structural and antimicrobial properties, highlight the potential of these multifunctional silk-based films as new materials for preventing SSI. PMID- 30408338 TI - Magnesium(I) Halide versus Magnesium Metal: Differences in Reaction Energy and Reactivity Monitored in Reduction Processes of P-Cl Bonds. AB - Magnesium(I) halides (MgI X; X=Cl, Br, I), as high temperature molecules, are trapped and finally stored at -80 degrees C in toluene/donor solutions. These solutions provide insights into the fundamental mechanism of reduction reactions using activated magnesium metal as a prototype for every base metal. The most important example of such a reaction is the preparation of Grignard reagents (RMgX). The details of this highly complex mechanism especially of intermediates between Mg metal and MgII (RMgX) remain unknown until today. The same is true for the reaction of bulk magnesium with Group 15 halide compounds that give biradicaloid species. We investigate the reduction of P-Cl bonds with solutions of [MgI Br(Nn Bu3 )]2 (1). The phosphanes [ClP(MU-NTer)]2 (2) and (Me3 Si)2 N PCl2 (3), were chosen as they had successfully been reduced by Mg metal before. Furthermore, reactions of both 1 and Mg metal are compared with an MgI chelate complex L1 Mg-MgL1 containing a strong Mg-Mg sigma-bond. PMID- 30408339 TI - A Photocrosslinking-Based RNA Chemical Proteomics Approach to Profile m6 A Regulated Protein-RNA Interactions. AB - Post-transcriptional modifications play an important role in RNA biology. In particular, the addition of small chemical groups to the nucleobases of mRNA can affect how modified transcripts are processed in the cell, thereby impacting gene expression programs. In order to study the molecular mechanisms underlying these modifications, it is necessary to characterize their 'readers', that is, proteins that directly bind to these modifications to mediate their functional consequences; this is a major challenge because we lack approaches to precisely manipulate RNA chemistry in the cell and because protein-modified RNA interactions can be low affinity. In this unit, we describe in detail a photocrosslinking-based RNA chemical proteomics approach to profile the protein modified RNA interactome modulated by N6 -methyladenosine (m6 A), the most abundant internal modification in eukaryotic mRNA. First, we present protocols for the synthesis and characterization of short, diazirine-containing synthetic RNA probes, followed by a description of their use in mass spectrometry-based proteomics with HeLa cell lysate and a short commentary on data analysis and result interpretation. (c) 2018 by John Wiley & Sons, Inc. PMID- 30408340 TI - Remodeling of the Embryonic Interventricular Communication in Regard to the Description and Classification of Ventricular Septal Defects. AB - Ventricular septal defects are the commonest congenital cardiac malformations. Appropriate knowledge of the steps involved in completion of ventricular septation should provide clues as to the morphology of the different phenotypes. Currently, however, consensus is lacking regarding the components of the developing ventricular septum, and how best to describe the different phenotypes seen in postnatal life. We have reassessed the previous investigations devoted to closure of the embryonic interventricular communication. On this basis, we discuss how studies in the early part of the 20th century correctly identified the steps involved in the remodeling of the embryonic interventricular foramen subsequent to the stage at which the outflow tract arises entirely above the cavity of the developing right ventricle. There has, however, already been remodeling of the foramen from the stage at which the atrioventricular canal is supported exclusively by the developing left ventricle. We show how these temporal changes in morphology can provide explanations for the different ventricular septal defects seen in the clinical setting. Thus, muscular defects represent inappropriate coalescence of muscular ventricular septum. The channels that are perimembranous are due to failure of closure of the persisting embryonic interventricular foramen. Those that are doubly committed and juxta-arterial reflect failure of formation of the free-standing subpulmonary muscular infundibular sleeve. The findings also point to the importance of appropriate alignment, during development, between the developing atrial and ventricular septums, and between the apical component of the ventricular septum and the ventricular outlet components. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30408341 TI - Hospitalization following Outpatient Medical Care for Influenza: US Influenza Vaccine Effectiveness Network, 2011-12-2015-16. AB - Over five seasons, we determined the proportion of outpatients with laboratory confirmed, influenza-associated illness who were hospitalized within 30 days following the outpatient visit. Overall, 136 (1.7%) of 7,813 influenza-positive patients were hospitalized a median of 4 days after an outpatient visit. Patients aged >=65 years and those with high-risk conditions were at increased risk of hospitalization. After controlling for age and high-risk conditions, vaccination status and infecting influenza virus type were not associated with hospitalization risk among adults. This article is protected by copyright. All rights reserved. PMID- 30408342 TI - Exercise training remodels human skeletal muscle mitochondrial fission and fusion machinery towards a pro-elongation phenotype. AB - AIMS: Mitochondria exist as a morphologically plastic network driven by cellular bioenergetic demand. Induction of fusion and fission machinery allows the organelle to regulate quality control and substrate flux. Physiological stressors promote fragmentation of the mitochondrial network, a process implicated in the onset of metabolic disease, including type 2 diabetes and obesity. It is well known that exercise training improves skeletal muscle mitochondrial volume, number, and density. However, the effect of exercise training on muscle mitochondrial dynamics remains unclear. METHODS: Ten sedentary adults (65.8 +/- 4.6 years; 34.3 +/- 2.4 kg/m2 ) underwent 12 weeks of supervised aerobic exercise training (5 day/wk, 85% of HRMAX ). Body composition, cardio-metabolic testing, hyperinsulinaemic-euglycaemic clamps, and skeletal muscle biopsies were performed before and after training. MFN1, MFN2, OPA1, OMA1, FIS1, Parkin, PGC-1alpha, and HSC70 protein expression was assessed via Western blot. RESULTS: Exercise training led to improvements in insulin sensitivity, aerobic capacity, and fat oxidation (all P < 0.01), as well as reductions in body weight, BMI, fat mass and fasting glucose (all P < 0.001). When normalized for changes in mitochondrial content, exercise reduced skeletal muscle FIS1 and Parkin (P < 0.05), while having no significant effect on MFN1, MFN2, OPA1, and OMA1 expression. Exercise also improved the ratio of fusion to fission proteins (P < 0.05), which positively correlated with improvements in glucose disposal (r2 = 0.59, P < 0.05). CONCLUSIONS: Exercise training alters the expression of mitochondrial fusion and fission proteins, promoting a more fused, tubular network. These changes may contribute to the improvements in insulin sensitivity and substrate utilization that are observed after exercise training. PMID- 30408343 TI - Site-to-Site Reproducibility and Spatial Resolution in MALDI-MSI of Peptides from Formalin-Fixed Paraffin-Embedded Samples. AB - PURPOSE: To facilitate the transition of MALDI-MS Imaging (MALDI-MSI) from basic science to clinical application, it is necessary to analyze formalin-fixed paraffin-embedded (FFPE) tissues. Our aim was to improve in-situ tryptic digestion for MALDI-MSI of FFPE samples and determine if similar results would be reproducible if obtained from different sites. EXPERIMENTAL DESIGN: FFPE tissues (mouse intestine, human ovarian teratoma, tissue microarray of tumor entities sampled from three different sites) were prepared for MALDI-MSI. Samples were coated with trypsin using an automated sprayer then incubated using deliquescence to maintain a stable humid environment. After digestion, samples were sprayed with CHCA using the same spraying device and analyzed with a rapifleX MALDI Tissuetyper at 50MUm spatial resolution. Data were analyzed using flexImaging, SCiLS and R. RESULTS: Trypsin application and digestion were identified as sources of variation and loss of spatial resolution in the MALDI-MSI of FFPE samples. Using the described workflow, it is possible to discriminate discrete histological features in different tissues and enabled different sites to generate images of similar quality when assessed by spatial segmentation and PCA. CONCLUSIONS AND CLINICAL RELEVANCE: Spatial resolution and site-to-site reproducibility can be maintained by adhering to a standardized MALDI-MSI workflow. This article is protected by copyright. All rights reserved. PMID- 30408344 TI - Monodisperse Sequence-Controlled alpha-l-Fucosylated Glycooligomers and Their Multivalent Inhibitory Effects on LecB. AB - The opportunistic bacterium Pseudomonas aeruginosa, often exhibiting multiresistance against conventional antibiotics, expresses the lectin LecB that is suspected to be an important factor during biofilm formation via interactions with cell-surface presented carbohydrate ligands such as the blood group antigens. Therefore, carbohydrate-based ligands interfering with LecB binding have the potential to lead to new anti-biofilm and anti-adhesion therapies. This study explores in vitro binding potencies of glycomimetic ligands containing up to six alpha-l-fucose ligands on a monodisperse, sequence-controlled oligoamide scaffold interacting with LecB. Surface plasmon resonance (SPR) and a modified enzyme-linked lectin assay (mELLA) revealed an increasing affinity to LecB with increasing fucose valency. Furthermore, fucosylated glycooligomers were shown to inhibit the formation of P. aeruginosa biofilm up to 20%. Overall these results show the potential of fucosylated oligoamides to be further developed as inhibitors of LecB binding and biofilm formation. PMID- 30408345 TI - The use of video-laryngoscopy in head and neck surgery. AB - Direct visualisation of the upper aerodigestive tract is a fundamental skill for ENT surgeons. Rigid endoscopes themselves have seen little transformation since they were first developed for gastroscopy by Kussmaul in 18681 . In an era of ultra high definition and 3D technology, a straight, rigid metal tube with adjoining light source carrier to inspect mucosal surfaces up to 40cm from the surgeon's eye could benefit from updating. In our department, we favour the use of the video-laryngoscope, specifically the C-MAC system from Karl Storz. This article is protected by copyright. All rights reserved. PMID- 30408346 TI - Kinetic Resolution of Acylsilane Cyanohydrins via Organocatalytic Cycloetherification. AB - An asymmetric cyanation of acylsilanes involving the in-situ formation of chiral acylsilane cyanohydrins followed by their kinetic resolution via organocatalytic cycloetherification is described. The highly enantio- and diastereoselective cycloetherification was crucial for achieving a high efficiency in the kinetic resolution. Consequently, acylsilane cyanohydrins containing a tetrasubstituted chiral carbon atom bearing silyl, cyano, and hydroxy groups were obtained in an enantioenriched form. This protocol therefore offers an efficient catalytic approach to optically active acylsilane cyanohydrins, which exhibit potential as chiral building blocks for the synthesis of pharmaceutically relevant chiral organosilanes. PMID- 30408347 TI - Graphene Oxide Immobilized PLGA-polydopamine Nanofibrous Scaffolds for Growth Inhibition of Colon Cancer Cells. AB - Graphene oxide (GO)/poly (lactide-co-glycolic acid) (PLGA) scaffolds have promising applications in the biomedical field. However, greater attention is focused on the incorporated system and its applications in normal cells. In this work, a novel GO immobilized PLGA nanofibrous scaffold assisted by polydopamine (PLGA-PDA-GO) is developed for growth inhibition of HT-29 colon cancer cells. The interactions between GO and PDA are attributed to a pi-pi conjugate interaction and electrostatic attraction. In addition to the enhancement of thermal stability and mechanical strength, the surface roughness, hydrophilicity, and electro activity of the scaffolds are significantly improved by immobilization of GO. The scaffolds show good inhibition of HT-29, and immobilized GO is observed to be in contact with but not internalized in HT-29 cells. The cytotoxicity mechanism of scaffolds toward HT-29 is attributed to intracellular activated reactive oxygen species that result from the physical interaction of the sharp GO edges and electrical signals of pi-pi stacking between PDA and GO. PMID- 30408348 TI - Guided Hands-On Activities Can Improve Student Learning in a Lecture-Based Qualitative Biomechanics Course. AB - A qualitative biomechanics (functional anatomy) course is a typical course in kinesiology curriculum. Most evidence suggests that biomechanics learning could be improved with the inclusion of laboratory experiences. However, implementing laboratories into biomechanics curriculum is difficult due to cost and time constraints. This study was conducted to evaluate whether hands-on activities in lecture improve qualitative biomechanics learning. A lecture format was compared to the same course with guided and unguided hands-on activities included during lecture. Test performance and student evaluations were compared between lecture formats to determine if hands-on experiences improve learning. The hands-on group performed better on the same test questions and they evaluated their overall course activities as beneficial to their learning. The findings suggest that guided hands-on experiences may improve learning compared to unguided activities. The hands-on experiences seem to provide an embodied cognitive learning experience, facilitating retention of learned material through three-dimensional and tactile mental representations. Findings from this research are currently shaping how biomechanics is taught to students at this university and could at other universities as well. PMID- 30408349 TI - Nanoimprinted Anisotropic Topography Preferentially Guides Axons and Enhances Nerve Regeneration. AB - Surface topography has a profound effect on the development of the nervous system, such as neuronal differentiation and morphogenesis. While the interaction of neurons and the surface topography of their local environment is well characterized, the neuron-topography interaction during the regeneration process remains largely unknown. To address this question, an anisotropic surface topography resembling linear grooves made from poly(ethylene-vinyl acetate) (EVA), a soft and biocompatible polymer, using nanoimprinting, is established. It is found that neurons from both the central and peripheral nervous system can survive and grow on this grooved surface. Additionally, it is observed that axons but not dendrites specifically align with these grooves. Furthermore, it is demonstrated that neurons on the grooved surface are capable of regeneration after an on-site injury. More importantly, these injured neurons have an accelerated and enhanced regeneration. Together, the data demonstrate that this anisotropic topography guides axon growth and improves axon regeneration. This opens up the possibility to study the effect of surface topography on regenerating axons and has the potential to be developed into a medical device for treating peripheral nerve injuries. PMID- 30408350 TI - Investigation of RNA-RNA Interactions Using the RISE Database. AB - RNA-RNA interactions (RRIs) are essential to understanding the regulatory mechanisms of RNAs. Mapping RRIs in vivo in a transcriptome-wide manner remained challenging until the recent development of several sequencing-based technologies. However, RRIs generated from large-scale studies had not been systematically collected and analyzed before. This article introduces RISE, a database of the RNA Interactome from Sequencing Experiments. RISE provides a comprehensive collection of RRIs in human, mouse, and yeast, derived from transcriptome-wide sequencing experiments, as well as targeted sequencing studies and other public databases/datasets. To facilitate better understanding of the biological roles of these RRIs, RISE also offers rich functional annotations involving RNAs, and an interactive interface to explore the analysis results. Here, we provide a brief description of the RISE website and a step-by-step protocol for using RISE to study RRIs. (c) 2018 by John Wiley & Sons, Inc. PMID- 30408351 TI - One Month of Cannabis Abstinence in Adolescents and Young Adults Is Associated With Improved Memory. AB - OBJECTIVE: Associations between adolescent cannabis use and poor neurocognitive functioning have been reported from cross-sectional studies that cannot determine causality. Prospective designs can assess whether extended cannabis abstinence has a beneficial effect on cognition. METHODS: Eighty-eight adolescents and young adults (aged 16-25 years) who used cannabis regularly were recruited from the community and a local high school between July 2015 and December 2016. Participants were randomly assigned to 4 weeks of cannabis abstinence, verified by decreasing 11-nor-9-carboxy-?9-tetrahydrocannabinol urine concentration (MJ Abst; n = 62), or a monitoring control condition with no abstinence requirement (MJ-Mon; n = 26). Attention and memory were assessed at baseline and weekly for 4 weeks with the Cambridge Neuropsychological Test Automated Battery. RESULTS: Among MJ-Abst participants, 55 (88.7%) met a priori criteria for biochemically confirmed 30-day continuous abstinence. There was an effect of abstinence on verbal memory (P = .002) that was consistent across 4 weeks of abstinence, with no time-by-abstinence interaction, and was driven by improved verbal learning in the first week of abstinence. MJ-Abst participants had better memory overall and at weeks 1, 2, 3 than MJ-Mon participants, and only MJ-Abst participants improved in memory from baseline to week 1. There was no effect of abstinence on attention: both groups improved similarly, consistent with a practice effect. CONCLUSIONS: This study suggests that cannabis abstinence is associated with improvements in verbal learning that appear to occur largely in the first week following last use. Future studies are needed to determine whether the improvement in cognition with abstinence is associated with improvement in academic and other functional outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03276221. PMID- 30408352 TI - When Further Pharmacotherapy Seems Futile. PMID- 30408354 TI - Innovation, technology focus at RRI meeting. PMID- 30408353 TI - What we learned at Kidney Week. PMID- 30408355 TI - Physician assistants and nurse practitioners: The future is now. PMID- 30408356 TI - A PROPOSAL: Relieving the kidney donor shortage. PMID- 30408357 TI - True Love: A kidney donor for the long haul. PMID- 30408359 TI - Can Republicans compromise with each other to pass ACA repeal bill?. AB - House conservatives want to scale back the bill's coverage while Senate Republicans want to improve it, which would raise the bill's price tag. PMID- 30408358 TI - PART 2. NEPHROLOGY SOCIAL WORK: LOOKING BACK, LOOKING FORWARD. AB - The field of nephrology social work has undergone considerable change since the release of the 1976 federal regulations requiring a master's level social worker to be part of the renal team. Moderated by veteran nephrology social worker Stephanie Johnstone, LCSW, those who have served patients in the front lines of kidney care speak here about the past-"What has nephrology social work contributed in the last three decades, and what it has struggled to accomplish?" and about the future: "How can nephrology social workers best serve patients in the years ahead? Where is their greatest potential to advance the industry?" Ms. Johnstone, an NN&I Editorial Advisory Board member, has worked for Fresenius Kidney Care for over 33 years. She is currently the Field Support Liaison, Clinical Innovations Team and Lead Social Worker, So Cal Region for FKC, and is based in San Diego. PMID- 30408360 TI - What did the media miss in the CBO report?. AB - Everyone reported the top-line numbers from the analysis of the House Republicans' American Health Care Act, a bill to repeal and replace the Affordable Care Act. The nonpartisan Congressional Budget Office and the Joint Committee on Taxation estimated the bill would drive up the number of uninsured Americans by 24 million over the next decade and reduce the federal deficit by $337 billion. PMID- 30408361 TI - Missouri opioid Rx-monitoring fight ignites debate over national program. AB - The debate over a national prescription-drug-monitoring database has gone on so long that the concept may no longer be viable. PMID- 30408362 TI - Cherry-picking patients? Mayo Clinic aims to'prioritize' privately insured. AB - The Mayo Clinic health system operates in five states, including campuses in Arizona and Florida. In 2016, it reported $11 billion in revenue and $475 million in income. PMID- 30408363 TI - Tapping telehealth for complex cases. AB - Telehealth is moving beyond easier access for low-acuity patients. Leading health systems are using the technology for more-complex cases in remote locations. PMID- 30408364 TI - Consumers fueling outpatient construction. AB - Construction leaders continue to see their biggest opportunities in outpatient care, but providers still face challenges delivering levels of customer service that patients have come to expect. PMID- 30408365 TI - The AHCA's hidden costs will hurt everyone. AB - It's time to start calling the American Health Care Act by its true name-the Force Older and Poorer Americans to Postpone Health Care Act. PMID- 30408368 TI - 'My position is, when it comes to the risk side, you've got to partner'. AB - Anthony Tersigni, the CEO of Ascension, oversees a sprawling empire of 141 Catholic hospitals in 24 states and the District of Columbia with 150,000 employees over 2,500 care sites. At a time of potentially far-reaching political changes, the $21 billion organization is going through its own transition, having recently tapped Chief Operating Officer Patricia Maryland to succeed Robert Henkel as CEO of Ascension Health, the holding company's largest operating division. During January's J.P. Morgan Healthcare Conference in San Francisco, Modern Healthcare finance reporter Dave Barkholz spoke with Tersigni about the drama in Washington over repealing and replacing the Affordable Care Act, what the nation's largest not-for-profit healthcare group has planned regarding mergers and acquisitions and the transition underway at Ascension. The following is an edited transcript. PMID- 30408367 TI - Sharing Lean ideas to improve quality. PMID- 30408366 TI - Changes needed in our healthcare system, but we can't revert to life before the ACA. AB - Everything changed for healthcare in 2010 with the signing of the Affordable Care Act. While admittedly flawed and laden with complexities, the ACA eliminated some of the worst practices in the insurance industry. PMID- 30408369 TI - Finding the brightest star... PMID- 30408370 TI - A closer look at the Dialysis PATIENTS Act. PMID- 30408371 TI - Health care gets Trumped, but a busy year for kidney care. PMID- 30408372 TI - Transportation requirements and dialysis care. PMID- 30408373 TI - Leadership changes take place as ESRD Network awards are finalized. PMID- 30408374 TI - RIDING A WAVE OF RENAL RESEARCH. 30 YEARS INTO THE FUTURE. PMID- 30408375 TI - PART 1. NEPHROLOGY SOCIAL WORK: LOOKING BACK, LOOKING FORWARD. PMID- 30408376 TI - Comparison of the Trends in Risk Factors and Management of Severe Postpartum Hemorrhage Years 2000-2004 Versus 2005-2008. AB - OBJECTIVE: To compare trends in the etiology and management of severe postpartum hemorrhage (PPH) during 2 time periods: 2000-2004 (Period 1) versus 2005-2008 (Period 2). STUDY DESIGN: Medical records with a diagnosis of PPH were identified by ICD-9 codes for immediate, third-stage, delayed, and secondary. PPH and post- partum coagulation defect. Subjects having a PPH within 24 hours of delivery who also received blood component therapy (defined as severe PPH) during Period 1 were compared with those from Period 2. RESULTS: There were 109 and 119 cases identified from Periods 1 and 2, respectively. Uterine atony was the most common cause of severe PPH during both time periods. In the second time period women with severe PPH had a lower mean hematocrit (p<0.05), a greater mean BMI (p<0.05), and more induced labor (p<0.01) as compared to the first time period. A greater proportion of the women in the second time period received misoprostol (p<0.0001) and platelets (p<0.05). The proportions of other therapies and surgical interventions remained unchanged, as did the ultimate outcomes. CONCLUSION: At a single large institution over the course of a 9-year period the management of severe PPH changed to include a greater utilization of misoprostol and platelet therapy. PMID- 30408377 TI - Fertility Outcomes After Hysteroscopic Morcellation of Intrauterine Leiomyomas and Polyps. AB - OBJECTIVE: To assess fertility outcomes in infertile women after hysteroscopic morcellation of intrauterine lesions. STUDY DESIGN: Retrospective case series from 2 U.S. fertility clinics. Women with intrauterine pathology and infertility (>=6 months' duration if age >=35, or >=12 months' duration if age <35) or recurrent pregnancy loss underwent hysteroscopic morcellation of intrauterine lesions. Main outcome mea- sures were postoperative pregnancies, live births, and procedure-related adverse events through 6 months. RESULTS: Of 101 women screened, 62 satisfied inclusion criteria and 44 (71%) conceived, resulting in 39 live births. Women who conceived were 37.1+/-4.6 years old (range, 28.0-46.8) at intervention; mean treatment-to-pregnancy interval was 8.4? 7.0 months (range, 1 32). Body mass index was lower in women who conceived (24.94.4 kg/M2 versus women who remained infertile (28.9+/-04 kg/IM2, p=0.0362). Of 67 lesions in women who conceived, fibroids, polyps, and adhesions comprised 21%, 70%, and 9%, respectively. Mean respective fibroid and polyp sizes in women who conceived were 2.1+/-1.3 and 1.4+/-0.8 cm, respectively, similar to those in women who did not conceive. Fibroids were 74% type 0 and 26% type 1. Lesion area eradication was 95.8+/-9.9% for fibroids and 100% for polyps. No serious/severe adverse events occurred. CONCLUSION: Morcellation of intrauterine pathologies in subfertile women undergoing fertility therapy safely supports postopera- tive pregnancy and live birth. PMID- 30408378 TI - Day 3 Biopsy and Blastulation Rates. AB - OBJECTIVE: To determine if blastomere biopsy affects the rate of blastulation as compared to intact embryos. STUDY DESIGN: Retrospective age-matched cohort study. RESULTS: Forty-one patients with 41 in vitro fertilization (IVF) cycles and 329 embryos who under- went cleavage-stage biopsy with preimplantation genet- ic screening using array com- parative genomic hybridiza- tion were compared to 41 IVF cycles with 352 embryos eligible for biopsy but who did not undergo biopsy January 2011-July 2013. The proportion of embryos that developed to the blastocyst stage was significantly lower in the case group than in the control group (46.5% vs. 59.9%; p=0.0134). This was most evident in the age group >35 years old (43.2% vs. 58.8%; p=0.035). No significant difference was detected in proportions that developed to fully expanded' or hatching blastulation between cases and controls (28.0% vs. 24.4%, p=0.56). There was a statistically .significant difference in the proportion of euploid embryos available for transfer when comparing day 3 vs. day 5 biopsy (20.9% vs. 13.1%, p=0.0003). CONCLUSION: Cleavage stage biopsy for genetic testing lowers the overall proportion of embryos that develop to the blastocyst stage by 25% (from 59.9% to 46.5%). When compared to trophectoderm biopsy, cleavage stage biopsy allows for a larger cohort of euploid embryos to be available for selection and transfer. PMID- 30408379 TI - Management and Outcomes of Patients with Stage I and IlIl Low-Risk Gestational Trophoblastic Neoplasia Treated in Sheffield, UK, from 1997-2006. AB - OBJECTIVE: To review the outcome of patients treated for low-risk gestational trophoblastic neoplasia (GTN) over a 10-year period with the particular aim of assessing response to treatment in Stages I and III disease. Approximately 90% of women requiring treatment for GTN have low-risk disease. Methotrexate is the treat- ment of choice in the UK and achieves complete response rates of 50% and 90%. STUDY DESIGN: A retro- spective review of management and outcomes of patients treated for low-risk GTN at the Trophoblastic Disease Centre, Sheffield, UK, from 1997 to 2006. RESULTS: Overall 280 patients were treated for low- risk GTN during this time; 8.6% had stage III disease. Single-agent methotrexate was used as first-line therapy in 99% of cases, with a remission rate of 56%. There was no significant difference (p=0.67) in the complete response rate after first line methotrexate between those with stage I and those with stage III disease. CONCLUSION: The overall cure rate for women with low-risk GTN was high (99.6%), and the complete response rate after first-line management was not sig- nificantly different between stages I and III disease. PMID- 30408380 TI - Education of Providers Crucial in Ensuring that Patients Receive Desired Postpartum Sterilization Procedures. AB - OBJECTIVE: In July 2012 the American College of Obstetricians and Gynecologists (ACOG) published Committee Opinion No. 530, stating that postpartum sterilization should be considered an urgent surgical procedure. The purpose of this study was to determine whether active dissemination of the ACOG Committee Opinion and education of staff (our intervention) would result in higher rates of postpartum sterilizations. STUDY DESIGN: Two separate studies were conducted: (1) a retrospective chart review that examined postpartum sterilization rates prior to our intervention and (2) a prospective study that examined postpartum sterilization rates after the intervention. RESULTS: In the 3 months prior to the ACOG publication, 14 of 23 (61%) intended postpartum sterilization procedures were performed. During the 4 months after publication, 29 of 52 (55%) were completed (x2 p=0.619). In the 5 months after education efforts, 69 of 79 (87%) were completed, showing a statistically significant improvement frot both prior time periods (x2 p<0.001). CONCLUSION: Patients who desired postpartum sterilization during the prospective study were 5 times less likely to have their procedure canceled than were patients in the retrospective study. The Committee Opinion had. no significant effect on. com- pletion rates. Education of staff and the ongoing study were instrumental in facilitating desired tubal sterilizations. PMID- 30408381 TI - Placental Site Trophoblastic Tumor: A Distinct Entity of Gestational Trophoblastic Disease Experience from a Tertiary Referral Center in Hong Kong. AB - OBJECTIVE: To review the clinical and pathological characteristics of patients with placental site trophoblastic tumor (PS TT) managed in a tertiary referral center in Hong Kong. STUDY DESIGN: Patients with a diagnosis of PSTT from 1995 to 2012 were identified from a computer database. Clinical and patho- logical data were obtained from medical records and the electronic database. RESULTS: Ten patients with PSTT were identified. Only 4 patients (40%) had disease confined to the uterus at presentation (Stage I). The most common site of metastasis was the lung. Four patients had pretreatment serum hCG levels <1,000 IU/L, and all of them had disease 'confined to the uterus. Of the 4 patients with Stage I disease 3 had hysterectomy only and 1 had both hysterectomy and chemotherapy. All 4 patients achieved complete remission; although 1 of them had a recurrence successfully treated with che- motherapy. For patients with Stage III/IV disease most of them had both hysterectomy and chemotherapy. Only 1 patient (20%) was alive without evidence of disease. CONCLUSION: Patients with Stage I disease have excellent prognosis after hysterectomy, and adjuvant treatment is not recommended. A low pretreatment serum hCG level (<1,000 IU/L) was a good predictor of early stage disease. The prognosis for patients with metastatic disease was poor despite surgery and com- bination chemotherapy. PMID- 30408382 TI - Unintended Live Births Following Second Trimester Pregnancy Termination by Labor Induction. AB - OBJECTIVE: To determine the incidence of live births following labor induction for pregnancy termination in 16-22-week pregnancies. This information is important in order to be able to adequately counsel a pregnant woman regarding the options for pregnancy termination. STUDY DESIGN: We con- ducted a retrospective study over a 10-year period of all pregnancies that underwent labor induction for pregnan- cy termination between 16 and 22 gestational weeks. The indications for pregnancy termination included fetal anomalies and pregnancy complications. RESULTS: Over the 10-year period 94 patients under- went labor induction for pregnancy termination and were included in the study. There were 14 unintended live births. The gestational age at termination was significantly higher in the unintended live births as com- pared to stillbirths, 21.03+/-0.65 weeks vs. 20.28+/-1.15 weeks (p<0.05). In fetuses with trisomy 21 the unintended live births were more common. CONCLUSION: Unintended live birth following labor induction between 16 and 22 weeks' gestation occurs in about 15% of cases; however, the duration of heart beat is <2 hours in the majority of cases. The incidence of live birth was more common in more advanced pregnancies but did not differ by the method of induction or duration of labor. PMID- 30408384 TI - Does Anti-Mllerian Hormone Predict Outcome of Pregnancy in Women with Recurrent Miscarriage?. AB - OBJECTIVE: To evaluate the prognostic value of anti- Millerian hormone (AAMH) on the outcome of pregnancy in women with recurrent miscarriage (RM). STUDY DESIGN: Retrospective cohort study; data from 98 women with unexplained RM were analyzed. The serum AMH and follicle-stimulating hormone (FSH) concentrations prior to and within 6 months of conception were determined with enzyme-linked immu-" nosorbent assay (ELISA) on day 2-6 of a cycle. RESULTS: There was no difference in AMH or FSH results between those who had live birth or miscarriage. Neither AMH nor FSH results had any significant prognostic value on the outcome of the pregnancy. CONCLUSION: AMH and FSH on their own do not seem to predict the outcome of pregnancy in women with unexplained recurrent miscarriage. PMID- 30408383 TI - Gonadotropin-Releasing Hormone Analog Combined with Depot Medroxyprogesterone Acetate in the Management of Endometrial Hyperplasia A Prospective Randomized Clinical Study. AB - OBJECTIVE: To compare the effectiveness of combined treatment of depot medroxyprogesterone acetate (MPA) with gonadotropin-releasing hormone (GnRH) analog and depot MPA alone in the management of simple endometrial hyperplasia without atypia among heavy bleeders. STUDY DESIGN: Thirty- four patients with endo- metrial hyperplasia with- out atypia were selected in this prospective randomized study. Group I consisted of 15 patients who were treated with depot MPA combined with GnRH analog. Group 2 consisted of 19 patients who were treated with depot MPA alone. Injections were applied at the beginning of the study and at the end of the 3rd month. Endometrial biopsies were performed at the end of the 6th month. Main outcome measures were endometrial response and reduction of duration and amount of menstrual bleeding. RESULTS: Total and mean duration of menstruation and total number of standardized pads used were signifi- cantly decreased in both groups. These parameters were also significantly lower in group 1 than in group 2 at the end of both the 3rd and 6th months of the study (p<0.01). Endometrial response rates were significant- ly higher in group I than in group 2 (100% vs. 44.4%, respectively, p <0.05). CONCLUSION: Management of endometrial hyper- plasia with GnRH analog in addition to depot MPA provides prompt endometrial response and rapid menstru- al cycle control. PMID- 30408385 TI - Gestational Trophoblastic Neoplasia and Pregnancy Outcome After Routine Second Curettage for Hydatidiform Mole A Retrospective Observational Study. AB - OBJECTIVE: To investigate gestational trophoblastic neoplasia (GTN), fertility, and pregnancy outcome in molar patients who underwent routine second curettage. STUDY DESIGN: Eighty-two patients who visited our hospital for hydatidi- form mole between 2002 and 2011 were registered in this study. All patients had sec- ond curettage around the 7th day after first evacuation. We performed retrospective analysis on several factors between a remission group and a GTN group. RESULTS: Fourteen patients (17.1%) had chemotherapy after being diagnosed with GTN. Multivariate analysis revealed that the hCG value before first evac- uation was only one independent prognostic factor for GTN. The median follow-up period was 45.5 months, and 41 patients had 62 pregnancies after remission of hydatidiform mole and GTN. The fertility rate was 80% in 45 patients with desire for a baby, and 39 pregnancies (62.9%) ended in live births without congenital malformation. CONCLUSION: The incidence of GTN was not lower in hydatidiform mole with routine second curettage. An independent prognostic factor for GTN- was the hCG value before the first evac- uation in molar patients. Our results suggest that rou- tine second curettage does not affect the fertility rate or increase a risk of adverse outcomes in subsequent prej- nancies. PMID- 30408386 TI - Efficacy and Safety of Perioperative Use of Epinephrine for Laparoscopic Myomectomy in Infertile Women with Symptomatic Solitary Intramural Uterine Fibroids A Randomized Clinical Trial. AB - OBJECTIVE: To determine the efficacy and safety of intramyometrial application of epinephrine during a laparoscopic myomectomy in women of reproductive age desiring pregnancy and with clinically symptomatic uter- ine fibroids, in comparison with a placebo-based patient control group. STUDY DESIGN: The study group (n=96, 53.3%) underwent an application of 12 MUg epinephrine hydro- chloride diluted in 20 mL of NaCl solution, while the control group (n=84, 46.7%) received 20 mL of NaCl only. Perioperative blood loss, duration of surgery, length of hospital stay, and incidence of perioperative and postoperative complications were evaluated. RESULTS: A significantly lower blood loss (mean +/ SD: 57+/- 23 mL) was observed in the group with local appli- cation of epinephrine as compared to the control group (143+/-106 mL) (p<0.001), along with a significantly shortened duration of surgery (53 +/-16 min) vs. control group (72+/-26 min) (p=0.006), and a significantly shortened hospital stay (3.0+/- 1.2 days) vs. the control group (4.3 +/-1.4 days) (p= 0.003). No serious perioper- ative complications were observed in either group, and no statistically significant difference in the incidence of postoperative complica- tions was recorded with our study group when compared to the control group (2.1% vs. 7.1%) (p=0.143). CONCLUSION: Epineph- rine use during a laparo- scopic myomectomy is both effective and safe. PMID- 30408387 TI - Prevalence and Risk Factors of Ejaculation Failure on the Day of Operation Among Chinese Males Undergoing Assisted Reproductive Technique Treatments. AB - OBJECTIVE: To describe the prevalence and risk factors for ejaculation failure on the day of operation in Chinese men undergoing assisted reproductive technique (ART) treatments. STUDY DESIGN: A pro- spective study of 843 men undergoing ART treatments at Zhongnan Hospital of Wuhan University . and Tongji Hospital of Huazhong - University of Science and Technology, Wuhan, China. Surveys included age, BMI, education, duration of marriage, duration of infertility, smoking, type of infertility, infertility causes, history of ejaculation failure, financial burden of the treatment, anxiety, and whether ejaculation failure happened during obtainment of sperm samples by masturbation on the day of oocyte retrieval or operation for intrauterine insemination. Their anxiety statuses were assessed using the State-Trait Anxiety Inventory. Logistic regression models were used to identify risk factors for ejaculation failure. RESULTS: On the day of operation 70 (8.3%) men undergoing ART treatments had ejaculation failure (OR= 12.29, 95% CI 6.98-21.64) and state of anxiety (OR=1.90, 95% CI 1.13-3.20). CONCLUSION: History of ejaculation failure and state of anxiety are associated with an increased risk for ejacu- lation failure on the day of operation. PMID- 30408388 TI - Live Birth from Electively Cryopreserved Oocytes: A Feasible Option for Couples Opposed to Embryo Cryopreservation A Case Report. AB - BACKGROUND: This case report describes a relatively novel indication for oocyte cryopreservation. CASE: A couple undergoing infertility treatment at our institution was opposed to embryo cryopreservation for religious reasons. After multiple unsuccessful infer- tility treatment cycles in- cluding ovulation induction combined with' artificial insemination as well as cycles of therapy with in vitro maturation, we were able to offer them fertilization of a limited number of oocytes followed by oocyte cryopreservation. Since our initial fresh embryo transfer was unsuccessful, the thawing of a limited number of these oocytes prevented a second oocyte retrieval. The couple had 3 oocytes thawed and fertilized and had a successful term birth. CONCLUSION: Elective oocyte cryopreservation is a feasible option for successful pregnancy in patients opposed to embryo cryopreservation. PMID- 30408389 TI - Isolated Recurrent Hematotrachelos After Abdominal Myomectomy A Case Report. AB - BACKGROUND: Isolated hematotrachelos is an ex- tremely rare condition. More commonly it is associated with hematometra and/or hematocolpos. It may devel- op secondary to congenital anomalies of the reproductive tract or may be an acquired condition following cervical surgery or manipulation. No case has been reported fol- lowing abdominal myomec- tomy. CASE: A 40-year-old, nul- ligravid woman was diag- nosed with isolated hemato- trachelos when she presented with severe abdominal pain following ovulation induction with clomiphene citrate. After the diagnosis was obtained, she recounted 2 similar presentations occurring months earlier. Both episodes had been attributed to gastroenteritis, but each had re- solved with "explosive" onset of menses. All 3 episodes plus 1 later recurrence happened within a 36-month period following an abdominal myomectomy. CONCLUSION: Acquired hematotrachelos is a rare condition, and the diagnosis is often missed. To our knowledge, this is the first reported case of isolated, recurrent hematotrachelos following the use of a uterine manipulator cannula in association with an abdominal myomectomy. PMID- 30408391 TI - Republican governors may determine fate of ACA repeal. PMID- 30408390 TI - Choriocarcinoma in Situ in a Partial Hydatidiform Mole A: Case Report. AB - BACKGROUND: Choriocarcinoma most frequently arises in a complete hydatidiform mole. Less common are cases following a normal pregnancy or a nonmolar abortion. Its occurrence after a partial hydatidiform mole is extremely rare. CASE REPORT: Here we report a choriocarcinoma in situ diagnosed after dilation and curettage for a first tri- mester partial hydatidiform mole. The diagnosis was con- firmed by immunohistochemistry, fluorescent in situ hybridization, and microsatellite instability genotyping of the products of conception and blood of the mother and father. We demonstrated a diandric triploidy. At the time of diagnosis CT scan showed lung metastasis. The pa- tient was classified as high-risk gestational trophoblas- tic neoplasia and treated with high-dose methotrexate- etoposide. CONCLUSION: This is the first reported case of a cho- riocarcinoma arising in a first trimester partial mol. PMID- 30408393 TI - Price champions controversial ACA replacement ideas to Senate. AB - Written responses to lawmakers' questions reveal Price wants to give states more authority and give patients more choices. PMID- 30408392 TI - GOP Medicaid overhaul will hit insurers where it hurts. AB - Insurers stand to lose millions of Medicaid members and take a big hit to the bottom line if the GOP's healthcare bill is passed. PMID- 30408394 TI - Trump's immigration ban puts a damper on Match Day. AB - There's little information on how hospitals, doctors and patients make delivery decisions, which could help drop related healthcare costs and our nation's high C section rate. PMID- 30408396 TI - Quelling a Storm of Violence. AB - Despite unanimous agreement that healthcare workers need to be protected from violence at work, there's little consensus over how to address the problem. PMID- 30408397 TI - Changing how doctors get paid. AB - While many hospital systems and large physician practices are moving their employed physicians to bonus plans that reward quality and patient satisfaction as well as productivity, some are doing away with bonuses altogether. PMID- 30408395 TI - Why wildly varying C-section rates persist. AB - There's little information on how hospitals, doctors and patients make delivery decisions, which could help drop related healthcare costs and our nation's high C section rate. PMID- 30408398 TI - Trump and Ryan are playing the long game. AB - Last week, the nation's hospital and physician groups joined patient, consumer and senior advocates in condemning the newly introduced American Health Care Act, which guts Medicaid and provides inadequate subsidies for buying individual health insurance plans. PMID- 30408399 TI - Coordinated, systemwide efforts necessary to accelerate progress against preventable harm. AB - Preventable harm in healthcare is a leading cause of death in America and should be tackled as a public health crisis with its own coordinated response. PMID- 30408400 TI - Startups learn from hospital investors. AB - Benefits of hospitals investing their venture capital in health startups: The startups get more than funds. They get instant feedback on products. Startups can roll out products across a health system rather than marketing door-to-door. Hospitals and systems get first crack at technologies that they have nurtured. Hospitals diversify their investments beyond bonds, stocks and other traditional instruments. PMID- 30408402 TI - In charges of steering, patients lose out. PMID- 30408401 TI - 'The software should be a joy to use'. AB - Since its founding in 1979, Epic Systems Corp. of Verona, Wis., has grown to become the nation's No. 1 healthcare software firm, with $2.5 billion in annual sales and 9,700 employees. Founder Judith Faulkner, one of Modern Healthcare's Top 25 Women In Healthcare, still plays a major role in setting strategy at the firm. At last month's Healthcare Information and Management Systems Society's annual conference in Orlando, Fla., Modern Healthcare Editor Merrill Goozner sat down with Faulkner for an interview. The following is an edited transcript. PMID- 30408403 TI - An open letter to CMS. How we can improve patient care. PMID- 30408404 TI - The CMO Initiative. Peritoneal dialysis growth in the U.S. encounters unexpected hurdles. PMID- 30408405 TI - Finding your way (home) at Kidney Week. PMID- 30408406 TI - Nursing home care. Daily HHD vs conventional dialysis: A survival comparison. AB - Patients that dialyze in the nursing home setting are known to be an especially at-risk vulnerable population compared to the overall ESRD population. This is likely due to the nursing home dialysis patients' advanced age, multiple co morbidities, and frailty, requiring skilled nursing support. These challenges often result in worse outcomes compared to the overall end-stage renal disease (ESRD) population but few studies have investigated interventions to improve health outcomes in this population. Previously, we reported results from a study using a large epidemiological database of patients from an independent nursing home dialysis provider, showing that patients treated with daily home hemodialysis had improved outcomes compared to patients treated with conventional dialysis. One limitation of the previous study was that the timeframe for the two comparison groups was different; therefore, the results could have been due to over-all improvements in care over time unrelated to the modality of dialysis: To address this as well as expand on the previous analysis, the objective of the present study was to compare outcomes in ESRD patients in the nursing home setting treated with daily home hemodialysis versus con- ventional three-day-a week (TIW) hemodialysis using an updated database, specifically assessing patients treated during a concurrent time: frame. Health status was evaluated for 6,314 patients (n=4,778 conventional, n=1,902 daily home hemodialysis; 2006 to November 2015 for conventional; 2011 to November 2015 for daily home hemodialysis). Analyses included monthly mortality rates, Kaplan-Meier survival analysis, and laboratory values. In the "Compared to the conventional dialysis population, daily HHD patients had similar or lower incident mortality rates." analysis of patients treated during the concurrent timeframe, median overall survival was 36 months with daily home hemodialysis versus 21 months with conventional dialysis (P=0.0025). These results were similar to the analysis of all patients regardless of timeframe. Compared to the conventional dialysis population, daily home hemodialysis patients had similar or lower incident mortality rates. Survival rates were higher at 3 months (89% vs 82%), 6 months (84% vs 73%), and 12 months (74% vs 62%) in the daily home hemodialy- sis population compared to conventional dialysis population. Monthly mean albumin was consistent over time in the daily home hemodialysis population but gradually increased in the conventional dialysis population. Hemoglobin values were consistently lower over the follow-up period in the daily home hemodialysis population and ferritin values were similar in both populations. These results confirm and extend previous findings that daily home hemodialysis is associated with improved patient outcomes compared to conventional hemodialysis. Although difficult to conduct practically, a prospective randomized outcomes study evaluating daily home hemodialysis versus conventional TIW dialysis would be valuable in informing the standard of dialysis care in this population. PMID- 30408407 TI - AKI moves into the outpatient dialysis setting. What the new law means for patients, staff. PMID- 30408408 TI - Olig2-expressing Mesenchymal Stem Cells Enhance Functional Recovery after Contusive Spinal Cord Injury. AB - Background and Objectives: Glial scarring and inflammation after spinal cord injury (SCI) interfere with neural regeneration and functional recovery due to the inhibitory microenvironment of the injured spinal cord. Stem cell transplantation can improve functional recovery in experimental models of SCI, but many obstacles to clinical application remain due to concerns regarding the effectiveness and safety of stem cell transplantation for SCI patients. In this study, we investigated the effects of transplantation of human mesenchymal stem cells (hMSCs) that were genetically modified to express Olig2 in a rat model of SCI. Methods: Bone marrow-derived hMSCs were genetically modified to express Olig2 and transplanted one week after the induction of contusive SCI in a rat model. Spinal cords were harvested 7 weeks after transplantation. Results: Transplantation of Olig2-expressing hMSCs significantly improved functional recovery in a rat model of contusive SCI model compared to the control hMSC transplanted group. Transplantation of Olig2-expressing hMSCs also attenuated glial scar formation in spinal cord lesions. Immunohistochemical analysis showed that transplanted Olig2-expressing hMSCs were partially differentiated into Olig1 positive oligodendrocyte-like cells in spinal cords. Furthermore, NF-M-positive axons were more abundant in the Olig2-expressing hMSC-transplanted group than in the control hMSC-transplanted group. Conclusions: We suggest that Olig2 expressing hMSCs are a safe and optimal cell source for treating SCI. PMID- 30408409 TI - A Genetic Circuit Compiler: Generating Combinatorial Genetic Circuits with Web Semantics and Inference. AB - A central strategy of synthetic biology is to understand the basic processes of living creatures through engineering organisms using the same building blocks. Biological machines described in terms of parts can be studied by computer simulation in any of several languages or robotically assembled in vitro. In this paper we present a language, the Genetic Circuit Description Language (GCDL) and a compiler, the Genetic Circuit Compiler (GCC). This language describes genetic circuits at a level of granularity appropriate both for automated assembly in the laboratory and deriving simulation code. The GCDL follows Semantic Web practice, and the compiler makes novel use of the logical inference facilities that are therefore available. We present the GCDL and compiler structure as a study of a tool for generating kappa-language simulations from semantic descriptions of genetic circuits. PMID- 30408410 TI - Perpendicular Optical Reversal of the Linear Dichroism and Polarized Photodetection in 2D GeAs. AB - The ability to detect linearly polarized light is central to practical applications in polarized optical and optoelectronic fields and has been successfully demonstrated with polarized photodetection of in-plane anisotropic two-dimensional (2D) materials. Here, we report the anisotropic optical characterization of a group IV-V compound-2D germanium arsenic (GeAs) with anisotropic monoclinic structures. High-quality 2D GeAs crystals show the representative angle-resolved Raman property. The in-plane anisotropic optical nature of the GeAs crystal is further investigated by polarization-resolved absorption spectra (400-2000 nm) and polarization-sensitive photodetectors. From the visible to the near-infrared range, 2D GeAs nanoflakes demonstrate the distinct perpendicular optical reversal with a 75-80 degrees angle on both the linear dichroism and polarization-sensitive photodetection. Obvious anisotropic features and the high dichroic ratio of Ipmax /Ipmin ~ 1.49 at 520 nm and Ipmax /Ipmin ~ 4.4 at 830 nm are achieved by the polarization-sensitive photodetection. The polarization-dependent photocurrent mapping implied that the polarized photocurrent mainly occurred at the Schottky photodiodes between electrode/GeAs interface. These experimental results are consistent with the theoretical calculation of band structure and band realignment. Besides the excellent polarization-sensitive photoresponse properties, GeAs-based photodetectors also exhibit rapid on/off response. These results demonstrate that the 2D GeAs crystals have promising potential for polarization optical applications. PMID- 30408411 TI - Ultra-Stiff Graphene Foams as Three-Dimensional Conductive Fillers for Epoxy Resin. AB - Conductive epoxy composites are of great interest due to their applications in electronics. They are usually made by mixing powdered conductive fillers with epoxy. However, the conductivity of the composite is limited by the low filler content because increasing filler content causes processing difficulties and reduces the mechanical properties of the epoxy host. We describe here the use of ultra-stiff graphene foams (uGFs) as three-dimensional (3D) continuous conductive fillers for epoxy resins. The powder metallurgy method was used to produce the dense uGFs monoliths that resulted in a very high filler content of 32 wt % in the uGF-epoxy composite, while the density of epoxy was only increased by 0.09 g/cm3. The composite had an electrical conductivity of 41.0 +/- 6.3 S/cm, which is among the highest of all of the polymer-based composites with non-conductive polymer matrices and comparable with the conductive polymer matrices reported to date. The compressive modulus of the composite showed a remarkable improvement of >1700% compared to pure epoxy. We have demonstrated that the 3D uGF filler substantially improves the conductivity and reinforces the polymer matrix with a high filler content while retaining a density similar to that of the epoxy alone. PMID- 30408412 TI - Sigma Factor-Mediated Tuning of Bacterial Cell-Free Synthetic Genetic Oscillators. AB - Cell-free transcription-translation provides a simplified prototyping environment to rapidly design and study synthetic networks. Despite the presence of a well characterized toolbox of genetic elements, examples of genetic networks that exhibit complex temporal behavior are scarce. Here, we present a genetic oscillator implemented in an E. coli-based cell-free system under steady-state conditions using microfluidic flow reactors. The oscillator has an activator repressor motif that utilizes the native transcriptional machinery of E. coli: the RNAP and its associated sigma factors. We optimized a kinetic model with experimental data using an evolutionary algorithm to quantify the key regulatory model parameters. The functional modulation of the RNAP was investigated by coupling two oscillators driven by competing sigma factors, allowing the modification of network properties by means of passive transcriptional regulation. PMID- 30408413 TI - Combination-Responsive MoO3- x-Hybridized Hyaluronic Acid Hollow Nanospheres for Cancer Phototheranostics. AB - It is of extreme importance to reduce side effects resulting from the nonspecific uptake of phototherapeutic agents by normal tissues. Currently, the single responsive strategy still cannot entirely satisfy the requirements of practical applications. In this study, we developed one kind of combination-responsive phototherapeutic nanoplatforms, where oxygen-deficient molybdenum oxide (MoO3- x) hybridized hyaluronic acid (HA) hollow nanospheres, namely, MoO3- x@HA HNSs, were constructed via a facile one-step method. In MoO3- x@HA HNSs, the reasonable combination of actively targeted specificity endowed by the HA component and tumor microenvironment-responsive phototherapy activity induced by the MoO3- x component can effectively improve the precision of phototherapy. The in vitro and in vivo experimental results confirm that MoO3- x@HA HNSs can selectively kill CD44-overexpressing cancer cells and inhibit tumor growth under an 808 nm laser irradiation, revealing their remarkable synergistic photothermal therapy/photodynamic therapy effect with CD44 receptor-targeted specificity and pH responsiveness in treating cancer. We also prove that MoO3- x@HA HNSs can serve as one kind of contrast agent to achieve the computed tomography/photoacoustic imaging. Encouraged by these results, it is anticipated that the reasonable combination of active targeting and tumor microenvironment responsiveness can be a promising strategy to develop phototherapeutic nanoplatforms for precise multimodality cancer theranostics. PMID- 30408414 TI - Experimental Evidence for a Triplet Biradical Excited-State Mechanism in the Photoreactivity of N,C-Chelate Organoboron Compounds. AB - N,C-chelate organoborates represent an emerging class of photoresponsive materials due to their photochromic switching at a boron center. Despite the promising applicability of such systems, little is known about the excited-state processes that lead to their unique photoreactivity, which is detrimental to the design of next-generation smart materials based on boron. As part of our ongoing effort to understand and improve the utility of these organoboron compounds, we report some of the first experimental evidence to support an excited-state mechanism for N,C-chelate organoborates. Femtosecond transient absorption spectroscopy combined with steady-state UV/vis and fluorescence measurements gives direct insight into their underlying photochemical processes, such as the formation of a common triplet charge-transfer state which either relaxes radiatively or undergoes the desired photoisomerization through a biradical intermediate. With this information, a complete mechanistic picture of the excited-state reactivity of N,C-chelate organoborates has been established, which is anticipated to lead to new smart materials with improved performance. PMID- 30408415 TI - Discovery of Neuroregenerative Peptoid from Amphibian Neuropeptide That Inhibits Amyloid-beta Toxicity and Crosses Blood-Brain Barrier. AB - Development of potential therapeutics for Alzheimer's disease (AD) requires a multifaceted strategy considering the high levels of complexity of the human brain and its mode of function. Here, we adopted an advanced strategy targeting two key pathological hallmarks of AD: senile plaques and neurofibrillary tangles. We derived a lead short tetrapeptide, Ser-Leu-Lys-Pro (SLKP), from a dodeca neuropeptide of amphibian (frog) brain. Results suggested that the SLKP peptide had a superior effect compared to the dodecapeptide in neuroprotection. This result encouraged us to adopt peptidomimetic approach to synthesize an SLKP peptoid. Remarkably, we found that the SLKP peptoid is more potent than its peptide analogue, which significantly inhibits Abeta fibrillization, moderately binds with tubulin, and promotes tubulin polymerization as well as stabilization of microtubule networks. Further, we found that SLKP peptoid is stable in serum, shows significant neuroprotection against Abeta mediated toxicity, promotes significant neurite outgrowth, maintains healthy morphology of rat primary cortical neurons and crosses the blood-brain barrier (BBB). To the best of our knowledge, our SLKP peptoid is the first and shortest peptoid to show significant neuroprotection and neuroregeneration against Abeta toxicity, as well as to cross the BBB offering a potential lead for AD therapeutics. PMID- 30408416 TI - Novel Isotope-Coded Derivatization Method for Aldehydes Using 14N/15N-Ammonium Acetate and 9,10-Phenanthrenequinone. AB - Isotope-coded derivatization (ICD) is used as a promising alternative approach to isotope internal standards in order to overcome matrix effects caused by coexisting substances that often occur while analyzing metabolites by LC-MS/MS. ICD introduces two different mass tags to every analyte via the use of heavy and light forms of the derivatization reagents. Herein, we report the first ICD approach for aldehydes that uses commercially available reagents avoiding the need for expensive and tedious multisteps synthetic procedures. The method is based on the reaction of the safe and stable derivatizing agent, 9,10 phenanthrenequinone, and the cheap and commercially available ICD reagent, 14N/15N-ammonium acetate, with aldehydes followed by LC/ESI+-MS/MS. Multiple reaction monitoring is done at the transitions m/ z [M + H]+ -> m/ z [Product ion A] and m/ z [M + 2 + H]+ -> m/ z [Product ion A + 2] for 14N- and 15N-labeled analytes, respectively. Among lipid peroxidation products, 4-hydroxy-2-nonenal (HNE) and 4-hydroxy-2-hexenal (HHE) are considered the most toxic produced aldehydes as they contain additional two reactive functional groups, the unsaturated bond and the hydroxyl group, besides the aldehyde one. Thus, they were chosen as representative analytes in this study. The developed method was able to detect HHE and HNE in human serum with very high sensitivity down to LOQ of 0.2 and 0.05 nM, respectively, employing an expedient salting out liquid liquid extraction method. The developed method was able to differentiate between the levels of HHE and HNE in serum samples of healthy subjects and diabetic, rheumatic, and cardiac disorder patients. PMID- 30408417 TI - Molecular Design for Electron-Driven Double-Proton Transfer: A New Scenario for Excited-State Proton-Coupled Electron Transfer. AB - Proton-coupled electron transfer (PCET) reactions play important roles in solar energy conversion processes. Designing efficient artificial photosystems with PCET mechanisms is a promising solution for the growing demands of energy resources. Compared to ground states, inducing the PCET reactions directly from electronically excited states, named excited-state PCET (ES-PCET) reactions, is a more direct and efficient avenue to the formation of solar fuels. Here, based on benzimidazole phenolic derivatives, we have designed and studied some molecular structures that can undergo the electron-driven double-proton transfer (EDDPT) reactions within the ES-PCET framework. According to our DFT/TDDFT calculation results, the two protons transfer in a stepwise manner in the EDDPT process, and compared to the common way of electron-driven single-proton transfer (EDSPT) reactions, the proton transfer in the EDDPT process not only has a smaller energy barrier but also experiences a longer transferring distance, which has beneficial effects on producing solar fuels. The study of ES-PCET reactions under the mechanism of EDDPT may cast light on the regulation of proton transfer at defined distances and time scales, which is important in energy conversion processes. PMID- 30408418 TI - Coarse-Grained Model for Zippering of SNARE from Partially Assembled States. AB - Neuronal transmitters are released from nerve terminals via the fusion of synaptic vesicles with the presynaptic membrane. Vesicles are attached to the membrane via the SNARE complex, comprising the vesicle associated protein synaptobrevin (Syb), the membrane associated protein syntaxin (Syx), and the cytosolic protein SNAP25, that together form a four-helical bundle. The full assembly of Syb onto the core SNARE bundle promotes vesicle fusion. We investigated SNARE assembly using a coarse-grained model of the SNARE complex that retains chemical specificity. Steered force-control simulations of SNARE unzippering were used to set up initial disassembled states of the SNARE complex. From these states, the assembly process was simulated. We find that if Syb is in helical form and proximal to the other helices, then the SNARE complex assembles rapidly, on a microsecond time-scale, which is well within in vivo synaptic vesicle fusion time scales. Assembly times grow exponentially with a separation distance between Syb and Syx C-termini. Our results indicate that for biologically relevant rapid assembly of the SNARE complex, Syb should be in helical form, and the SNARE constituent helices brought into proximity, possibly by an agent, such as a chaperone. PMID- 30408419 TI - Structural Quantification for Graphene and Related Two-Dimensional Materials by Raman Spectroscopy. PMID- 30408420 TI - An in Vivo Binding Assay for RNA-Binding Proteins Based on Repression of a Reporter Gene. AB - We study translation repression in bacteria by engineering a regulatory circuit that functions as a binding assay for RNA binding proteins (RBP) in vivo. We do so by inducing expression of a fluorescent protein-RBP chimera, together with encoding its binding site at various positions within the ribosomal initiation region (+11-13 nt from the AUG) of a reporter module. We show that when bound by their cognate RBPs, the phage coat proteins for PP7 (PCP) and Qbeta (QCP), strong repression is observed for all hairpin positions within the initiation region. Yet, a sharp transition to no-effect is observed when positioned in the elongation region, at a single-nucleotide resolution. Employing in vivo Selective 2'-hydroxyl acylation analyzed by primer extension followed by sequencing (SHAPE seq) for a representative construct, established that in the translationally active state the mRNA molecule is nonstructured, while in the repressed state a structured signature was detected. We then utilize this regulatory phenomena to quantify the binding affinity of the coat proteins of phages MS2, PP7, GA, and Qbeta to 14 cognate and noncognate binding sites in vivo. Using our circuit, we demonstrate qualitative differences between in vitro to in vivo binding characteristics for various variants when comparing to past studies. Furthermore, by introducing a simple mutation to the loop region for the Qbeta-wt site, MCP binding is abolished, creating the first high-affinity QCP site that is completely orthogonal to MCP. Consequently, we demonstrate that our hybrid transcriptional-post-transcriptional circuit can be utilized as a binding assay to quantify RNA-RBP interactions in vivo. PMID- 30408421 TI - A randomized comparison of bone-cement K-wire fixation vs. plate fixation of shaft fractures of proximal phalanges. AB - BACKGROUND: The objective of this study (ClinicalTrials.gov ID: NCT03031015) is to compare the treatments of hand proximal phalanx shaft fractures with external fixation technique using the combination of K-wires and bone-cement vs. open reduction and internal fixation technique using a miniature plate-and-screw system. METHODS: A total of 107 patients (134 cases) were randomly allocated to group A (67 cases in 56 patients) and B (64 cases in 51 patients). Fingers in group A were treated with bone-cement K-wire fixation, and fingers in group B were treated using a plate-and-screw system. RESULTS: Follow-ups lasted 2 years. In group A, active range of motion of proximal interphalangeal joint reached 93% +/- 6.7% of the opposite fingers. In group B, the data reached 86% +/- 14.4% of the opposite fingers. Based on total active motion scoring system, we obtained 21 excellent and 46 good results in group A; and 9 excellent, 50 good, and 5 fair results in group B. There was a significant difference with regards to the function of the fingers (p < 0.05). CONCLUSIONS: The bone-cement K-wire fixation may be another option for the treatment of shaft fractures of proximal phalanges. The minimally invasive technique allows early joint motion, resulting in minimal complications and good functional recovery. PMID- 30408422 TI - Diabetic retinopathy: a complex pathophysiology requiring novel therapeutic strategies. AB - INTRODUCTION: Diabetic retinopathy (DR) is the leading cause of vision loss in the working age population of the developed world. DR encompasses a complex pathology, and one that is reflected in the variety of currently available treatments, which include laser photocoagulation, glucocorticoids, vitrectomy and agents which neutralize vascular endothelial growth factor (VEGF). Whilst these options demonstrate modest clinical benefits, none is yet to fully attenuate clinical progression or reverse damage to the retina. This has led to an interest in developing novel therapies for the condition, such as mediators of angiopoietin signaling axes, immunosuppressants, nonsteroidal anti-inflammatory drugs (NSAIDs), oxidative stress inhibitors and vitriol viscosity inhibitors. Further, preclinical research suggests that gene therapy treatment for DR could provide significant benefits over existing treatments options. Areas covered: Here we review the pathophysiology of DR and provide an overview of currently available treatments. We then outline recent advances made towards improved patient outcomes and highlight the potential of the gene therapy paradigm to revolutionize DR management. Expert opinion: Whilst significant progress has been made towards our understanding of DR, further research is required to enable the development of a detailed spatiotemporal model of the disease. In addition, we hope that improvements in our knowledge of the condition facilitate therapeutic innovations that continue to address unmet medical need and improve patient outcomes, with a focus on the development of targeted medicines. PMID- 30408423 TI - Learning spinal manipulation: Gender and expertise differences in biomechanical parameters, accuracy, and variability. AB - OBJECTIVE:: The purpose of this study was to investigate gender differences and expertise effects on biomechanical parameters as well as force accuracy and variability for students learning spinal manipulation. METHODS:: A total of 137 fourth- and fifth-year students were recruited for the study. Biomechanical parameters (preload, time to peak force, peak force, rate of force), as well as accuracy and variability of thoracic spine manipulation performance, were evaluated during 5 consecutive trials using a force-sensing table and a target force of 450 N. Gender, expertise differences on biomechanical parameters, as well as constant, variable, and absolute error were assessed using 2-way analysis of variance. RESULTS:: Analyses showed significant gender differences for several biomechanical parameters, as well as significant gender differences in accuracy and variability. Although women showed lower time to peak force and rate of force values, they were more precise and showed less variability than men when performing thoracic spine manipulations. Students with clinical expertise (fifth year students) used less force and were more precise. CONCLUSION:: Our results showed that gender differences in spinal manipulation performance exist and that these differences seem to be mainly explained by alternative motor strategies. To develop gender-specific teaching methods, future studies should explore why men and women approach spinal manipulation tasks differently. PMID- 30408424 TI - Safety and performance of current abuse deterrent formulations. AB - INTRODUCTION: Prescription opioid abuse is now an epidemic that has forced the government and industries to take initiatives. These include developing abuse deterrent formulations (ADFs), issuing regulatory guidances, and allocating massive budgets to ensure the of safety and effectiveness of these medications. Areas covered: This review covers the regulatory guidance on evaluation and labeling of the branded and generic ADFs. It also includes the relevant patents and technologies, the in-vitro, in-vivo, the post-marketing data, the FDA reviews, and the products' labeling of the FDA-approved products with abuse deterrent features. Expert opinion: Despite the development of a dozen products with abuse-deterrent features, most of these technologies rely on the same deterrent agent, making it easier for abusers to focus their manipulation efforts and share their experience to defeat the technology. Further advancement in the field requires developing more robust, more diverse, safer, and affordable deterrent technologies for the extended- and immediate-release opioid products. Moreover, advances in the reporting of the post-market results, issuance of policies in support of the ADFs, and concurrent monitoring of the illicit opioid market are other considerations that can further help in confronting the epidemic. PMID- 30408425 TI - Oral health among Dutch elite athletes prior to Rio 2016. AB - OBJECTIVES: Elite athletes are at high risk for poor oral health. A screening program to assess oral health and create dental awareness can improve oral health among elite athletes but has not been performed in the Netherlands before. We summarize the first results from such a screening conducted in Dutch elite athletes of the Nederlands Olympisch Committee*Nederlandse Sport Federatie (NOC*NSF, Dutch Olympic Committee). METHODS: In this cross-sectional study, 800 Dutch athletes eligible for the Olympic and Paralympic Games in Rio de Janeiro 2016 were invited to a costless and voluntary oral examination. The decayed, missing, and filled teeth-index (DMFT), the basic erosive wear examination (BEWE) and the Dutch Periodontal Screening-index (DPSI) were used to evaluate athlete's oral health. Information on sociodemographic variables and sport performance were collected in questionnaires. RESULTS: In total, 116 Dutch elite athletes were included in the study. The median (90%-range) DMFT-score was 3.0 (0.0-16.0), the median BEWE-score was 2.0 (0.0-10.0), and the mean+/- SD DPSI-score was 2.0 +/- 0.73. Oral health-related quality of life was generally high, although only 28.2% of the athletes reported never having problems with their dentition or mouth. In 43% of the athlete's clinical findings were reported which needed a direct referral to the general dentist. CONCLUSION: Oral health in this subsample of Dutch elite athletes was surprisingly affected as almost half of them needed dental treatment. Further research is needed to allow conclusions about oral health in Dutch elite athletes more broadly. However, regular screening of oral health incorporated into the general preventive health care of elite athletes is necessary to ensure athletes are fully healthy during competitions like the Olympic and Paralympic Games. PMID- 30408426 TI - Modifications of the Dmax method in comparison to the maximal lactate steady state in young male athletes. AB - OBJECTIVE: To investigate the influence of different approaches for first-rise determination on the accuracy of Dmax as an estimate of the maximal lactate steady state (MLSS). METHODS: Seventeen male cyclists and 18 male runners with different levels of endurance performance completed graded exercise tests either on a cycle ergometer or treadmill to determine Dmax, calculated by the final data point and five modifications of the first rise in blood lactate concentration. Two or more constant load tests over 30 min were performed to determine MLSS. Differences between the modifications of the first rise in blood lactate concentration as well as the corresponding Dmax variants and MLSS were tested, using one-way repeated measure ANOVA with Bonferroni post-hoc tests, and illustrated, using the Bland-Altman method. The absolute agreement was observed, using intra-class correlation coefficients, based on a single measure, absolute agreement, 2-way mixed effects model. RESULTS: The peak power output/running velocity of the groups averaged 275 +/- 43 W and 4.3 +/- 0.4 m . s-1, respectively. The mean power output/running velocity at MLSS was 229 +/- 38 W and 3.77 +/- 0.38 m . s-1. For both running and cycling the original Dmax described by Cheng et al. was significantly lower than MLSS (p < 0.01). All modifications showed good agreement with MLSS (ICC >=0.75). According to the Bland-Altman method the mean differences of the modifications compared to MLSS in cycling ranged from -7 (43) to 2 (41) W. In running the mean differences ranged from 0.12 (0.34) to -0.08 (0.35) m. s-1. CONCLUSION: We suggest using the first rise in blood lactate concentration for calculating Dmax instead of the first data point of a lactate curve as originally described. The approach of first rise determination has no substantial influence on the accuracy of Dmax compared to MLSS in cycling and running. PMID- 30408427 TI - Lost in the crowd: identifying targetable MHC class I neoepitopes for cancer immunotherapy. AB - INTRODUCTION: The recent development of checkpoint blockade immunotherapy for cancer has led to impressive clinical results across multiple tumor types. There is mounting evidence that immune recognition of tumor derived MHC class I (MHC-I) restricted epitopes bearing cancer specific mutations and alterations is a crucial mechanism in successfully triggering immune-mediated tumor rejection. Therapeutic targeting of these cancer specific epitopes (neoepitopes) is emerging as a promising opportunity for the generation of personalized cancer vaccines and adoptive T cell therapies. However, one major obstacle limiting the broader application of neoepitope based therapies is the difficulty of selecting highly immunogenic neoepitopes among the wide array of presented non-immunogenic HLA ligands derived from self-proteins. Areas covered: In this review, we present an overview of the MHC-I processing and presentation pathway, as well as highlight key areas that contribute to the complexity of the associated MHC-I peptidome. We cover recent technological advances that simplify and optimize the identification of targetable neoepitopes for cancer immunotherapeutic applications. Expert commentary: Recent advances in computational modeling, bioinformatics, and mass spectrometry are unlocking the underlying mechanisms governing antigen processing and presentation of tumor-derived neoepitopes. PMID- 30408428 TI - Investigational small molecules in phase II clinical trials for the treatment of epilepsy. AB - INTRODUCTION: Epilepsy is a neurological disorder that significantly impacts the quality of life of affected persons. Despite advances in research, nearly a third of patients have refractory or pharmacoresistant epilepsy. Even though numerous antiepileptic drugs (AEDs) have been approved over the past decade, there are no agents that halt the development of epilepsy. Thus, new and improved AEDs to prevent these conditions are necessary. Areas covered: We highlight recent advances in new and innovative drugs for epilepsy disorders. We review three small molecule drugs in phase II clinical trials: Cannabidivarin, BGG492 (Selurampanel) and Ganaloxone. Expert opinion: The full potential of Cannabidivarin will be realized by testing in other types of treatment-resistant seizures; if they are beneficial, larger phase III clinical trials would probably be undertaken in the same patient population. About BGG492, the challenge will be to find 'superselective' AMPAR antagonists targeting only calcium-permeable receptors, with specific mechanisms, that may be attractive partners for drugs in polytherapy. Moreover, there is anew interest surrounding Ganaloxone because of a new submicron formulation that improves its absorption and pharmacokinetic profile, but new studies are necessary before progressing. Further clinical innovations will define the future for these small molecule-type drugs in epilepsy therapeutics. PMID- 30408430 TI - PrEP Communications Accelerator: a digital demand creation tool for sub-Saharan Africa. AB - : Background Strategic communications are critical for successful market introduction of oral pre-exposure prophylaxis (PrEP). This paper focuses on the OPTIONS Consortium's approach to developing the PrEP Communications Accelerator, a digital tool that provides communication strategies and tools for generating demand for PrEP across sub-Saharan Africa. METHODS: The PrEP Communications Accelerator was developed through needs assessment, communications landscape and gap analysis, market research and content development and testing. Stakeholder consultations across multiple African countries and audiences were conducted to validate and refine findings at each step. RESULTS: The PrEP Communications Accelerator provides customised communications plans that vary by target audience (adolescent girls and young women, female sex workers, serodiscordant couples, men who have sex with men, people who inject drugs and the general population) and by setting (clinic, community, subnational or national level). Users of the interactive tool receive custom-built demand creation strategy guidance, including suggested media channels and communication tactics based on available evidence about the population and setting. DISCUSSION: The PrEP Communications Accelerator is a digital demand creation tool intended to equip those who work in resource- and time-constrained environments with the evidence-based guidance needed to jump-start local demand creation efforts. The tool provides guidance on strategic PrEP communications for target audiences most at risk of HIV infection, as well as a broad profile of the general population to cultivate support for PrEP as a new public health product. PMID- 30408429 TI - Musculoskeletal and head injuries in the Ultimate Fighting Championship (UFC). AB - OBJECTIVES: Mixed martial arts (MMA) has witnessed a surge in popularity worldwide. This study explores the musculoskeletal and head injuries sustained in the professional fights of the Ultimate Fighting Championship (UFC), and establishes associations between injury profiles and impactful contributory factors. METHODS: The Nevada State Athletic Commission database was screened for ringside physician reports of UFC fights between January 2016 and July 2018. Information on the fighter's gender, weight, injury, way of finish, and match result were collected. Injury rates were calculated and statistical analyses were conducted to determine significant associations among variables. P-values <0.05 were considered significant (95% CI). RESULTS: A total of 291 injuries were recorded in 285 fights from nine weight divisions. The overall injury rate was 51 per 100 athletic exposures (AE). Males predominantly partook in 249 matches (87%) and had higher injury rates (54 injuries per 100 AE) than females (30 injuries per 100 AE). Decision was the most common way a match ended. Knockouts (KOs) were significantly higher in males (36%) than in females (14%, P = 0.0007). Submissions were significantly higher in females (36%) than in males (16%, P = 0.001). Head injuries (67%) were the most common injuries reported with a rate of 34 per 100 AE. Upper limb injuries were significantly higher in females (40%) than in males (14%, P = 0.0003). Lower limb injuries were significantly higher in males (19%) than in females (5%, P = 0.01). Head injuries were significantly associated with KOs (P < 0.0001). Upper limb injuries (P = 0.032) and lower limb injuries (P = 0.034) were significantly associated with matches that ended with Decision. Trend-line analyses showed that as weight division increases, overall injury rates, head injuries, lower limb injuries, and KOs' frequency increase, whereas upper limb injuries, Submission frequency, and Decision frequency decrease. CONCLUSION: MMA has a high injury rate. Gender, way of finish, and weight play an important role in predicting fight outcomes and injury profiles. Injury prevention policies must be entertained to limit injury risk in MMA. PMID- 30408431 TI - Understanding and measuring uptake and coverage of oral pre-exposure prophylaxis delivery among adolescent girls and young women in sub-Saharan Africa. AB - In response to World Health Organization (WHO) guidance recommending oral pre exposure prophylaxis (PrEP) for all individuals at substantial risk for HIV infection, significant investments are being made to expand access to oral PrEP globally, particularly in sub-Saharan Africa. Some have interpreted early monitoring reports from new programs delivering oral PrEP to adolescent girls and young women (AGYW) as suggestive of low uptake. However, a lack of common definitions complicates interpretation of oral PrEP uptake and coverage measures, because various indicators with different meanings and uses are used interchangeably. Furthermore, operationalising these measures in real-world settings is challenged by the difficulties in defining the denominator for measuring uptake and coverage among AGYW, due to the lack of data and experience required to identify the subset of AGYW at substantial risk of HIV infection. This paper proposes an intervention-centric cascade as a framework for developing a common lexicon of metrics for uptake and coverage of oral PrEP among AGYW. In codifying these indicators, approaches to clearly define metrics for uptake and coverage are outlined, and the discussion on 'low' uptake is reframed to focus on achieving the highest possible proportion of AGYW using oral PrEP when they need and want it Recommendations are also provided for making increased investments in implementation research to better quantify the sub-group of AGYW in potential need of oral PrEP.and for improving monitoring systems to more efficiently address bottlenecks in the service delivery of oral PrEP to AGYW so that implementation can be taken to scale. PMID- 30408432 TI - Pre-exposure prophylaxis rollout in a national public sector program: the Kenyan case study. AB - : Background While advances have been made in HIV prevention and treatment, new HIV infections continue to occur. The introduction of pre-exposure prophylaxis (PrEP) as an additional HIV prevention option for those at high risk of HIV may change the landscape of the HIV epidemic, especially in sub-Saharan Africa, which bears the greatest HIV burden. METHODS: This paper details Kenya's experience of PrEP rollout as a national public sector program. The process of a national rollout of PrEP guidance, partnerships, challenges, lessons learnt and progress related to national scale up of PrEP in Kenya, as of 2018, is described. National rollout of PrEP was strongly lead by the government, and work was executed through a multidisciplinary, multi-organisation dedicated team. This required reviewing available evidence, providing guidance to health providers, integration into existing logistic and health information systems, robust communication and community engagement. Mapping of the response showed that subnational levels had existing infrastructure but required targeted resources to catalyse PrEP provision. Rollout scenarios were developed and adopted, with prioritisation of 19 counties focusing on high incidence area and high potential PrEP users to maximise impact and minimise costs. RESULTS: PrEP is now offered in over 900 facilities countrywide. There are currently over 14000 PrEP users 1 year after launching PrEP. CONCLUSIONS: Kenya becomes the first African country to rollout PrEP as a national program, in the public sector. This case study will provide guidance for low- and middle-income countries planning the rollout of PrEP in response to both generalised and concentrated epidemics. PMID- 30408433 TI - 6-gingerol ameliorates age-related hepatic steatosis: Association with regulating lipogenesis, fatty acid oxidation, oxidative stress and mitochondrial dysfunction. AB - The prevalence of NAFLD increases with age. As the main active ingredient of ginger, 6-gingerol significantly improves lipid metabolism abnormalities in adult rodents. However, few studies have reported its effect on age-related NAFLD. This study was to investigate the effects of 6-gingerol on age-related hepatic steatosis and its potential targets. As expected, 6-gingerol dramatically normalized the hepatic triglyceride content, plasma insulin and HOMA-IR index of ageing rats. Mechanistically, 6-gingerol affected lipid metabolism by increasing beta-oxidation and decreasing lipogenesis through activation of PPARalpha and CPT1alpha and inhibition of DGAT-2. Furthermore, 6-gingerol reversed the decreases in citrate, Cs and ATP, lessened the damage caused by ROS, and upregulated mitochondrial marker enzymes NOX, SDH, and SIRT3 in the ageing liver, indicating its ability to strengthen mitochondrial function. Our results showed 6 gingerol exerted a positive effect on insulin sensitivity by regulating Akt. In conclusion, the hepatic anti-steatotic effect of 6-gingerol is associated with inhibition of de novo lipogenesis, upregulation of fatty acid oxidation, reduction in oxidative stress and synergistic enhancement of mitochondrial function. PMID- 30408434 TI - Psychophysical evaluation of individual low-level feature influences on visual attention. AB - In this study we provide the analysis of eye movement behavior elicited by low level feature distinctiveness with a dataset of synthetically-generated image patterns. Design of visual stimuli was inspired by the ones used in previous psychophysical experiments, namely in free-viewing and visual searching tasks, to provide a total of 15 types of stimuli, divided according to the task and feature to be analyzed. Our interest is to analyze the influences of low-level feature contrast between a salient region and the rest of distractors, providing fixation localization characteristics and reaction time of landing inside the salient region. Eye-tracking data was collected from 34 participants during the viewing of a 230 images dataset. Results show that saliency is predominantly and distinctively influenced by: 1. feature type, 2. feature contrast, 3. temporality of fixations, 4. task difficulty and 5. center bias. This experimentation proposes a new psychophysical basis for saliency model evaluation using synthetic images. PMID- 30408435 TI - Inflamed Astrocytes: A Path to Depression Led by Menin. AB - Increasing evidence supports a role for inflammation in the development of mood disorders. In this issue of Neuron, Leng et al. (2018) show that reduction of menin expression in astrocytes of stress-related brain regions exacerbates neuroinflammation, promoting the establishment of depression-like behaviors in mice. PMID- 30408436 TI - Circadian and Sleep Circuits Ring Together. AB - Prolonged wakefulness stimulates the homeostatic need to sleep, but transition to sleep also depends on the circadian time of day. However, links between circadian and homeostatic influences are not well understood. Guo et al. (2018) identify a Drosophila circuit connecting circadian clock neurons to sleep-promoting ring neurons in the ellipsoid body. PMID- 30408437 TI - Dendritic Inhibition in Layer 1 Cortex Gates Associative Memory. AB - Learning-related plasticity is critical for emotional memory. In this issue of Neuron,Abs et al., (2018) describe novel dynamics mediated by neurogliaform cells in layer 1 neocortex of mouse that are associated with aversive memory. PMID- 30408438 TI - Seeing Order and Disorder in the Behaving Brain. AB - The medial prefrontal cortex (mPFC) is important for control of social behavior and is commonly studied in disorders of social dysfunction. Here, Liang et al. (2018) perform calcium imaging in the mPFC of freely behaving mice, elucidating the complex dynamics of mPFC neurons during social behavior and changes in activity after pharmacological disruption. PMID- 30408439 TI - The Thalamostriatal Pathway and the Hierarchical Control of Action. AB - Sequential ordering of motor commands is required for the simplest of our daily activities. In this issue of Neuron, Diaz-Hernandez et al. (2018) show that distinct thalamic inputs to different regions of the dorsal striatum critically modulate the initiation and execution of action sequences. PMID- 30408440 TI - Unlocking the Potential for Endogenous Repair to Restore Sight. AB - The eye often leads the way in the development of novel strategies for treating neurodegenerative disorders. Here, we highlight an exciting new study examining the potential for reactivating endogenous repair mechanisms and enabling the mammalian retina to repair itself. PMID- 30408441 TI - Spike Time Synchrony in the Absence of Continuous Oscillations. AB - Eliav et al., (2018) recently reported hippocampal-entorhinal spiking in bats occurring preferentially at specific phases of nonrhythmic extracellular voltage fluctuations. This disentanglement of phase coding from continuous oscillations raises new questions about the importance of rhythms for neuronal coordination. PMID- 30408442 TI - The Calyx of Held: A Hypothesis on the Need for Reliable Timing in an Intensity Difference Encoder. AB - The calyx of Held is the preeminent model for the study of synaptic function in the mammalian CNS. Despite much work on the synapse and associated circuit, its role in hearing remains enigmatic. We propose that the calyx is one of the key adaptations that enables an animal to lateralize transient sounds. The calyx is part of a binaural circuit that is biased toward high sound frequencies and is sensitive to intensity differences between the ears. This circuit also shows marked sensitivity to interaural time differences, but only for brief sound transients ("clicks"). In a natural environment, such transients are rare except as adventitious sounds generated by other animals moving at close range. We argue that the calyx, and associated temporal specializations, evolved to enable spatial localization of sound transients, through a neural code congruent with the circuit's sensitivity to interaural intensity differences, thereby conferring a key benefit to survival. PMID- 30408445 TI - Vascular and Neurogenic Rejuvenation in Aging Mice by Modulation of ASM. PMID- 30408443 TI - Global and Multiplexed Dendritic Computations under In Vivo-like Conditions. AB - Dendrites integrate inputs nonlinearly, but it is unclear how these nonlinearities contribute to the overall input-output transformation of single neurons. We developed statistically principled methods using a hierarchical cascade of linear-nonlinear subunits (hLN) to model the dynamically evolving somatic response of neurons receiving complex, in vivo-like spatiotemporal synaptic input patterns. We used the hLN to predict the somatic membrane potential of an in vivo-validated detailed biophysical model of a L2/3 pyramidal cell. Linear input integration with a single global dendritic nonlinearity achieved above 90% prediction accuracy. A novel hLN motif, input multiplexing into parallel processing channels, could improve predictions as much as conventionally used additional layers of local nonlinearities. We obtained similar results in two other cell types. This approach provides a data-driven characterization of a key component of cortical circuit computations: the input output transformation of neurons during in vivo-like conditions. PMID- 30408446 TI - Firearm legislation and firearm use in female intimate partner homicide using National Violent Death Reporting System data. AB - Firearms account for over half of female intimate partner homicides (IPH) in the National Violent Death Reporting System (NVDRS). Although firearm-related IPH is directly associated with state-level firearm prevalence and inversely associated with specific firearm legislation targeting intimate partner violence perpetrators, these associations may be due to the underlying nature of the perpetrator population rather than the legislation or policy. We explored the impact of firearm legislation on weapon use in IPH in a cross-sectional analysis using NVDRS data via the WISQARS online interactional system, through examination of firearm (F) and non-firearm (NF) age-adjusted mortality rates and firearm: non firearm (F:NF) rate ratios across victim gender and in states with varying levels of firearm restrictions. Overall, for 2015 (27 states aggregated), the impact of gender was substantial: the F:NF ratio for male victims was 0.92, indicating a small lead for NF mechanisms, but for female victims, it was 1.5, with greater firearm use apparent. When looking only at female IPH, jurisdictions with high firearm restrictions show a pronounced trend for a F:NF ratio <1.0 whereas states with few of these restrictions demonstrate ratios >1.0. Numerous limitations apply, including: the cross sectional nature of the data, varying years for available state data; and lack of control for multiple demographic variables. Despite its limitations, this analysis extends prior research by comparing rates of NF use across jurisdictions, and suggests that availability of firearms by itself plays an important role in driving IPH rates higher in areas with fewer firearm restrictions. PMID- 30408444 TI - Noninvasive Ultrasonic Drug Uncaging Maps Whole-Brain Functional Networks. AB - Being able to noninvasively modulate brain activity, where and when an experimenter desires, with an immediate path toward human translation is a long standing goal for neuroscience. To enable robust perturbation of brain activity while leveraging the ability of focused ultrasound to deliver energy to any point of the brain noninvasively, we have developed biocompatible and clinically translatable nanoparticles that allow ultrasound-induced uncaging of neuromodulatory drugs. Utilizing the anesthetic propofol, together with electrophysiological and imaging assays, we show that the neuromodulatory effect of ultrasonic drug uncaging is limited spatially and temporally by the size of the ultrasound focus, the sonication timing, and the pharmacokinetics of the uncaged drug. Moreover, we see secondary effects in brain regions anatomically distinct from and functionally connected to the sonicated region, indicating that ultrasonic drug uncaging could noninvasively map the changes in functional network connectivity associated with pharmacologic action at a particular brain target. PMID- 30408447 TI - Television viewing time, walking time, and risk of type 2 diabetes in Japanese men and women: The Japan Collaborative Cohort Study. AB - We examined the effect of television viewing and walking on the risk of type 2 diabetes among an Asian population. A total of 25,240 participants (9786 men and 15,454 women) aged 40-79 years, with no history of diabetes, stroke, coronary heart disease, or cancer at the baseline (1988-1990) and who have completed the 5 year follow-up questionnaire were included. During the 5-year follow-up, 778 new cases of type 2 diabetes were reported (397 men and 381 women). Television viewing time was positively associated with risk of type 2 diabetes (p for trend = 0.01). The multivariable OR (95% CI) for >=5 h/day versus <2 h/day television viewing was 1.51 (1.03-2.19) in women and 1.06 (0.71-1.59) in men (p for interaction = 0.82). Walking time was inversely associated with type 2 diabetes risk in a fully adjusted model (p for trend = 0.02). The multivariable OR for type 2 diabetes of >=1 h/day walking time was 0.87 (0.71-1.06) compared with 0.5 h/day walking time. The inverse association was found in men (p for trend = 0.02), but not in women (p for trend = 0.38) (p for interaction = 0.36). The multivariable OR for type 2 diabetes of <5 h/day television viewing and >=1 h/day walking times was 0.72 (0.55-0.94) in fully adjusted model compared with >=5 h/day television viewing and <1 h/day walking times. Limiting television viewing time and increasing walking time may reduce risk of type 2 diabetes among Japanese. PMID- 30408448 TI - Examining quit attempts and successful quitting after recent cigarette tax increases. AB - As cigarette smoking rates decline, an important policy question is whether increasing cigarette taxes will continue to encourage smoking cessation. We tested this question following recent tobacco tax increases. Data were from the Minnesota Adult Tobacco Survey, a serial cross-sectional telephone survey conducted statewide, and was limited to past-year cigarette smokers in 2010 (n = 1029) and 2014 (n = 1382). Weighted estimates were calculated of the prevalence of past year smokers, smokers who attempted to quit smoking, and those who successfully quit by demographics, tobacco use, use of evidence-based cessation assistance to quit, and smoker perceptions of the tax increases. Among past year smokers, almost 60% reported a quit attempt in both years, 12.8% successfully quit in 2010 and 15.6% in 2014. Although older age, daily smoking, mean cigarettes per day, and more days of e-cigarette use, were associated with quit attempts in unadjusted models, only the perceived tax increase effect (AOR = 8.9; 95% CI 6.3-12.5) and low nicotine dependence (AOR = 1.9, 95% CI 1.3-2.7) were associated with making a quit attempt in adjusted models. Successful 12-month quits were predicted by college education (AOR = 3.2, 95% CI 1.3-7.8), the use of cessation support (AOR = 2.1, 95% CI 1.3-3.6), and reporting the tax increase helped maintain a quit (AOR = 12.3, 95% CI 7.5-20.1). These findings suggest that a large tax increase is effective in promoting quitting even in the presence of strong tobacco control measures such as indoor smoking bans and other smoking restrictions, mass media campaigns, and universal access to cessation support. PMID- 30408449 TI - Catalytic activity, structure and stability of proteinase K in the presence of biosynthesized CuO nanoparticles. AB - Here, CuO nanoparticles were synthesized using Sambucus nigra (elderberry) fruit extract. Further, the binding of proteinase K, as a model enzyme with green synthesized nanoparticles was investigated. The results demonstrated that the structural changes in enzyme were induced by the binding of nanoparticles. These changes were accompanied by the decrease in the Michaelis-Menten constant at 298 K. This means that the enzyme affinity for the substrate was increased. Thermodynamic parameters of protein stability and protein-ligand binding were estimated from the spectroscopic measurements at 298-333 K. Depending on the temperature, CuO nanoparticles showed a dual effect on the thermodynamic stability and binding affinity of enzyme. Nanoparticles increase the stability of the native state of enzyme at room temperature. On the other hand, nanoparticles stabilize the unfolded state of enzyme at 310-333 K. An overall favorable Gibbs energy change was observed for the binding process at 298-333 K. The enzyme nanoparticle binding is enthalpically driven at room temperature. It was concluded that hydrogen bonding plays a key role in the interaction of enzyme with nanoparticles at 298-310 K. At higher temperatures, the protein-ligand binding is entropically driven. This means that hydrophobic association plays a major role in the proteinase K-CuO binding at 310-333 K. PMID- 30408450 TI - Intelligent and active furcellaran-gelatin films containing green or pu-erh tea extracts: Characterization, antioxidant and antimicrobial potential. AB - Biodegradable films from furcellaran and gelatin (FUR/GEL) with pu-erh (RTE) and green tea (GTE) water extracts (TEs) were obtained by a casting method. The films were examined in terms of physical properties (thickness, density, water solubility, water content, degree of swelling, color), antioxidant properties (DPPH, ABTS, TPC), antimicrobial properties (Escherichia coli, Staphylococcus aureus, Candida albicans and Henseniaspora uvarum) and mechanical properties (tensile strength, elongation at break). The values of tensile strength (TS) increased from 9.62 to 24.14 or 13.59 MPa after GTE or RTE incorporation, respectively. Parameters of elongation at break were not changed. Higher color parameters: a*, b* and ?E were observed in biocomposite films with RTE. The FUR/GEL films with GTE and RTE can be used for intelligent food packaging, due to their sensibility of pH changes. Possible interaction between the film matrix and TEs was confirmed using FTIR. The antioxidant properties were significantly enhanced with increasing GTE and RTE concentration reaching 43.92 and 48.94% of DPPH and 15.76 and 14.98% of ABTS radical inhibition, respectively. The microbiological analysis confirmed antimicrobial properties of FUR/GEL with GTE against E.coli and S. aureus (inhibition zones of 16 and 22.5 mm, respectively). PMID- 30408451 TI - The first two mitochondrial genomes of wood wasps (Hymenoptera: Symphyta): Novel gene rearrangements and higher-level phylogeny of the basal hymenopterans. AB - The Symphyta has long been recognized as a paraphyletic grade forming the base of the remaining Hymenopteran, and the superfamily relationships within Symphyta remain controversial. Here, the first two representative mitochondrial genomes from the superfamily Siricoidea and Xiphydrioidea (Hymenoptera: Symphyta) are obtained using next-generation sequencing. The complete mitochondrial genome of Xiphydria sp. is 16,482 bp long with an A + T content of 84.18% while the incomplete one of Tremex columba is 16,847 bp long and A + T content is 81.69%. All 37 typical mitochondrial genes are possessed in both species. The secondary structure of tRNAs and rRNAs for both species are successfully predicted. Compared with the ancestral organization, seven and five tRNA genes are rearranged in mitochondrial genomes of Tremex and Xiphydria, respectively, which are the most rearrangement events within Symphyta. The rearrangement patterns in Tremex and Xiphydria present in this study are all novel to the Symphyta. Phylogenetic relationships among the major lineages of Symphyta are reconstructed using mitochondrial genomes. Both maximum likelihood and Bayesian inference analyses highly support Symphyta is a paraphyletic grade, Xyeloidea + (Tenthredinoidea + (Pamphilioidea + (Xiphydrioidea + (Cephoidea + (Orussoidea + Apocrita))))). PMID- 30408452 TI - Therapeutic effects of polysaccharides from Anoectochilus roxburghii on type II collagen-induced arthritis in rats. AB - Anoectochilus roxburghii, a famous Chinese herbal medicine, has been commonly used for the treatment of liver disease, diabetes, and rheumatoid arthritis. Our study aimed to investigate the anti-rheumatoid arthritis effects of A. roxburghii polysaccharides (ARP), using the rat's model of type II collagen-induced arthritis (CIA). ARP was prepared by alcohol sedimentation and structurally characterized based on combined chemical, chromatographic and spectroscopic methods. High Performance Size Exclusion Chromatography-Multiangle Laser Light Scattering-Refrative Index (HPSEC-MALLS-RI) analysis revealed that ARP includes two peaks, and the weight-average molecular weight (Mw) of the principal one was estimated as 5.90 kDa with a relative content of 98.2%. Pharmacological results exhibited that ARP significantly decreased the arthritis index and ameliorated the inflammatory cell infiltration and the synovial tissue destruction in CIA rats. Additionally, ARP possessed significant NO production inhibitory effects and antioxidant activity. Further anti-inflammatory mechanism investigations indicated that ARP significantly inhibited the activation of nuclear factor kappaB (NF-kappaB) pathway by suppressing the phosphorylation of IkappaB and p65, which subsequently down-regulated the mRNA expressions of IL-1beta and IL-6 in LPS-stimulated RAW 264.7 cells. These findings suggested that ARP has great potential in the development of functional foods and dietary supplements for the treatment of rheumatoid arthritis. PMID- 30408453 TI - Pullulan modification via poly(N-vinylimidazole) grafting. AB - A new cationic pullulan derivative was obtained via graft copolymerization of N vinylimidazole (NVI). Grafting of poly(N-vinylimidazole) (PNVI) onto pullulan has been achieved in aqueous medium using ammonium persulphate (APS) as the initiator. The effect of monomer concentration, pullulan concentration, initiator concentration, time and temperature on the grafting yield has been investigated. The highest grafting yield (513%) of pullulan-graft-PNVI was obtained using 0.016 M pullulan, 0.66 M NVI, 0.18 M APS at 40 degrees C in aqueous solution for 3 h under nitrogen atmosphere. Water-soluble products were obtained which were further characterized by FTIR, elemental, TGA, SEC and H-1 NMR analyses. Pullulan graft-PNVI gave soluble and insoluble complexes in aqueous acidic medium with tripolyphosphate and citrate ions due to its cationic nature. PMID- 30408454 TI - Role of Musa paradisiaca ascorbate peroxidase in the transformation of methyl phenyl sulfide to its sulfoxide. AB - An ascorbate peroxidase from a new source Musa paradisiaca leaf juice has been purified to homogeneity using a simple procedure involving concentration by ultra filtration and anion exchange chromatography on diethyl amino ethyl [DEAE] cellulose column. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis [SDS PAGE] analysis of the purified enzyme has shown a single protein band of molecular mass 208.9 kDa which has been confirmed by native-PAGE and intact mass analysis by mass spectrometry. The Km and kcat values of the enzyme using ascorbate and H2O2 as the variable substrates were 0.13 m mol L-1, 40.42 s-1 and 0.23 m mol L-1, 27.24 s-1, respectively. The pH and temperature optima of the enzyme were 7.0 and 298 K, respectively. The enzyme transformed approximately 97% methyl phenyl sulfide to its sulfoxide. The product was racemic mixture. PMID- 30408455 TI - Anti-glycation and anti-hardening effects of microencapsulated mulberry polyphenols in high-protein-sugar ball models through binding with some glycation sites of whey proteins. AB - Assembling between polyphenols and proteins has been freshly spotlighted. We studied the antiglycation and anti-hardening effects of microencapsulated mulberry polyphenols (MMPs) in a high-protein-sugar ball (HPSB) model during storage using multi-dimensional approaches, including UPLC-ESI-MS/MS, SDS-PAGE, MALDI-TOF-MS, FTIR, and a molecular docking study. It was found that MMPs significantly relegated the browning development, AGEs, and/or CML levels of HPSB after 45 d of storage at 45 degrees C. MMPs also downgraded the protein insolubility, aggregation, oligomerization, and glycoxidation during late storage. A molecular docking scrutiny proved that cyanidin 3-O-rutinoside and quercetin 3-O-rutinoside interacted with whey proteins subunits via H-bonding and pi-pi interactions. This binding blocked some glycation residues of whey proteins especially lysyl residues, namely Lys5, 16, 60, 69, 93, 94, and 122. Our data disclosed that MMPs could be valorized as promising antiglycative ingredients to mitigate AGEs-generation and other subsequent unwanted changes in protein-rich food matrices. PMID- 30408456 TI - The effect of immediate postpartum levonorgestrel contraceptive implant use on breastfeeding and infant growth: a randomized controlled trial. AB - OBJECTIVE: This study assessed whether immediate postpartum insertion of levonorgestrel contraceptive implants is associated with a difference in infant growth from birth to 6 months, onset of lactogenesis, or breastfeeding continuation at 3 and 6 months postpartum compared to delayed insertion at 6 to 8 weeks postpartum. STUDY DESIGN: We conducted a randomized trial of women in Uganda who desired contraceptive implants postpartum. We randomly assigned participants to receive either immediate (within 5 days of delivery) or delayed (6 to 8 weeks postpartum) insertion of a two-rod levonorgestrel contraceptive implant system. This is a prespecified secondary analysis evaluating breastfeeding outcomes. The primary outcome of this secondary analysis was change in infant weight; infants were weighed and measured at birth and 6 months. We used a validated questionnaire to assess onset of lactogenesis daily in person while participants were in the hospital, and then daily by phone after they left the hospital, until lactogenesis was documented. We used interviewer-administered questionnaires to assess breastfeeding continuation and concerns at 3 months and 6 months postpartum. RESULTS: Among the 96 women randomized to the immediate group and the 87 women to the delayed group, the mean change in infant weight from birth to 6 months was similar between groups: 4632 g in the immediate group and 4407 g in the delayed group (p=.26). Among the 97 women who had not experienced lactogenesis prior to randomization, the median time to onset of lactogenesis did not differ significantly between the immediate and delayed groups (65 h versus 63 h; p=.84). Similar proportions of women in the immediate and delayed groups reported exclusive breastfeeding at 3 months (74% versus 71%; p=.74) and 6 months (48% versus 52%; p=.58). CONCLUSION: We found no association between the timing of postpartum initiation of levonorgestrel contraceptive implants and change in infant growth from birth to 6 months, onset of lactogenesis, or breastfeeding continuation at 3 or 6 months postpartum. IMPLICATIONS: This study provides evidence that immediate postpartum initiation of contraception implants does not have a deleterious effect on infant growth or initiation or continuation of breastfeeding. PMID- 30408457 TI - Development of a quantification method for adenosine in tumors by LC-MS/MS with dansyl chloride derivatization. AB - Adenosine is known to be an important signaling molecule in many physiological processes and has recently been shown to be an important molecule in oncology. A fit for purpose method has been developed for the quantification of adenosine in murine tumor samples using pre-column derivatization and liquid chromatography mass spectrometry (LC-MS/MS). To overcome adenosine quantification challenges, derivatization with dansyl chloride was employed. This derivatization technique, following protein precipitation and liquid-liquid extraction, improved the sensitivity and selectivity of adenosine in tumor samples through the reduction of endogenous interference and matrix effects. This method utilizes a mouse plasma calibration curve, qualified over a range of 0.019 MUM-37 MUM. The 15 min derivatization incubation time and 1 min chromatographic run time allow for higher throughput. The following established method overcomes challenges associated with the quantification of low molecular weight, polar, endogenous molecules, such as adenosine, using derivatization and LC-MS/MS. With the additional analysis of murine tumors, this method will contribute to the understanding of the impact adenosine plays in the tumor microenvironment and the bearing it has on targeted cancer therapies. PMID- 30408458 TI - A modified method for plasmid extraction from Lactobacillus plantarum contained lysozyme removal step. AB - Plasmids of Lactobacillus plantarum PC518 cannot be effectively extracted by existing methods. It was studied that the effect of lysozyme treatment and removal on plasmid extraction by 7 protocols. The modified method was compared with a commercial kit using L. plantarum PC518, 410, 9L15, and JS193 and Weissella cibaria M2 as the tested strains. The results suggested that the step of lysozyme removal is the key to improve the efficiency of plasmid extraction. The concentrations of plasmid DNA isolated from the 5 tested strains were increased by 10.6, 9.5, 6, 5.6 and 1.5 times respectively compared with the commercial kit. PMID- 30408459 TI - The possible ameliorative effect of simvastatin versus sulfasalazine on acetic acid induced ulcerative colitis in adult rats. AB - OBJECTIVE: Inflammatory bowel diseases (IBD) are chronic and recurrent disorders of the gastrointestinal tract with unknown etiology and have two major forms, ulcerative colitis (UC) and Crohn diseases. In view of the adverse effects and incomplete efficacy of currently administered drugs, it is essential to investigate new and harmless drugs with more desirable beneficial effects. Statins have many additional pleiotropic effects other than their lipid-lowering effect. This study aims to investigate the role of simvastatin (SIM) at different doses against induced UC in rats. METHODS: SIM (10, 20 mg/kg), and sulfasalazine as a standard therapy (100 mg/kg) were given from five days before and seven days after induction of UC by acetic acid (AA). Colonic mucosal inflammation was evaluated macroscopically and microscopically. Furthermore, the colonic tissue tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL 1B), nod-like receptor family pyrin domain-1 containing 3 (NLRP3), malondialdehyde (MDA), reduced glutathione (GSH) and super oxide dismutase (SOD) were assayed in addition to immunohistochemistry of caspase-1 and cyclooxygenase-2 (COX2). RESULTS: SIM in a dose dependant manner significantly improved macroscopic and histological scores, diminished colonic levels of IL 1B, TNF-alpha, NLRP3, MDA, caspase-1 and COX2 and elevated GSH and SOD. CONCLUSION: SIM has anti inflammatory, cytoprotective and antioxidants effects that are not directly related to its cholesterol lowering activity against AA induced colitis this makes it a new therapeutic target for UC. PMID- 30408460 TI - A synthetic chalcone derivative, 2-hydroxy-3',5,5'-trimethoxychalcone (DK-139), triggers reactive oxygen species-induced apoptosis independently of p53 in A549 lung cancer cells. AB - 2-Hydroxy-3',5,5'-trimethoxychalcone (named DK-139) is a synthetic chalcone derivative that has anti-inflammatory, anti-tumor, and endoplasmic reticulum mediated apoptosis activities. However, the mode of action of DK-139 on reactive oxygen species (ROS)-induced apoptosis remains unknown. In this study, we found that DK-139 activated DNA damage responses, as was revealed by the accumulation of the tumor suppressor p53 and the phosphorylation of histone H2AX at Ser139 (called gamma-H2AX), which are hallmarks of DNA damage responses. The occurrence of DK-139-induced DNA damage was confirmed through single-cell gel electrophoresis (comet tail assay). Interestingly, using p53-null HCT116 cells revealed that p53 was not involved in DK-139-induced apoptosis. Instead, we found that DK-139 increased the production of ROS, which led to the processing of caspase-2, BH3 interacting-domain death agonist (BID), caspase-9, and caspase-7. Pretreatment with the ROS scavenger N-acetyl cysteine reduced the frequency of DK 139-induced gamma-H2AX formation, demonstrating that DK-139 triggered DNA damage through ROS production. In addition, NAC pretreatment prevented DK-139-induced processing of caspase-2, BID, caspase-9, caspase-7, and poly(ADP-ribose) polymerase. These results suggest that DK-139 triggers apoptosis through ROS mediated DNA damage and activation of the caspase-2 cascade in A549 human lung cancer cells. PMID- 30408461 TI - First report of Neospora caninum seroprevalence in farmed raccoon dogs in China. AB - Neospora caninum is an intracellular protozoan parasite with a worldwide distribution, which can cause abortion and stillbirth in ruminants. However, little is known of N. caninum infection in raccoon dogs in China. Thus, a total of 1181 serum samples of farmed raccoon dogs were collected from the major production areas of Jilin, Changchun in Jilin province, and Rizhao, Weihai and Yantai in Shandong province in China. The antibodies to N. caninum were examined by a competitive-inhibition enzyme-linked immunoassay (cELISA). While the N. caninum seroprevalence in farmed raccoon dogs from different regions (cities) were not statistically significant, farmed raccoon dogs in Shandong province had a significantly higher N. caninum seroprevalence (8.99%, 95% CI 7.13-10.85) than those in Jilin province (4.46%, 95% CI 1.99-6.93) (P < 0.05). N. caninum seroprevalence in male and female raccoon dogs were 7.91% (95% CI 5.99-9.83) and 8.06% (95% CI 5.46-10.66), respectively. In addition, the seroprevalence of N. caninum infection in infancy, youth and adult raccoon dogs was 7.32% (95% CI 4.31 10.33), 7.93% (95% CI 5.44-10.42) and 8.41% (95% CI 5.82-11.00), respectively. This is the first report of N. caninum seroprevalence in farmed raccoon dogs in China, which provided baseline data for the prevention of N. caninum infection in raccoon dogs in China. PMID- 30408462 TI - Molecular characterisation of antibiotic-resistant Salmonella enterica isolates recovered from meat in South Africa. AB - Salmonella enterica is a leading cause of human gastroenteritis in both developed and developing countries, causing significant economic losses on humans and animals worldwide. There are several routes for contracting salmonellosis, but the consumption of contaminated foods is by far the most frequent cause of human infections. This study aimed to assess the prevalence and resistance determinants of S. enterica isolates obtained from meat. Swab samples from meat were cultured for the identification of Salmonella spp., and 239 presumptive S. enterica isolates were recovered, purified and kept in glycerol stocks. The S. enterica. confirmed by polymerase chain reaction (PCR) were further tested against 15 antimicrobials using the disc-diffusion method on Muller-Hinton agar and the genotypic antimicrobial resistance determinants by PCR. Resistance among tetracyclines, beta-lactams, and 3rd generation cephalosporins was found to be most frequent with a noticeable rise in the number of multi-drug resistance ranging from two to seven antimicrobials. A total of 20 resistance determinants were assessed with their prevalence and distributions obtained as follows; [aminoglycosides: aadA (89%), aacC2 (100%), aphA1 (38%), aphA2 (0%) and strA (7%)], [beta-lactams: (ampC 100%), blaTEM, (33%), blaZ (17%) and blaOXA (10%)], [Chloramphenicol: catI (9%), catII (7%), and cmIA1 (10%)] and [tetracyclines: tetA (57%), tetB (30%), tetC (11%), tetD (73%), tetK (20%) and tetM, (43%)], and [sulfonamides: sulI (82%), sulII (7%)]. The findings signify a high prevalence of multidrug-resistant (MDR) S. enterica isolates and resistance determinants indicating increased public health risks associated with the consumption of contaminated meat. PMID- 30408463 TI - Neural correlates of visual awareness at stimulus low vs. high-levels of processing. AB - A crucial view in the graded vs. dichotomous debate on visual awareness proposes that its graded or dichotomous nature may depend on the depth of stimulus processing (or level of processing) associated to the experimental task. In the present study, we explored the behavioral patterns and neural correlates of different degrees of awareness associated to different depths (i.e. low vs. high) of stimulus processing. The low-level stimulus condition consisted of detecting the location of the target based on its brightness characteristics, whereas the high-level stimulus condition consisted of identifying which of four possible targets (numbers/letters) had appeared. Behavioral results showed that both subjective ratings of awareness and accuracy levels increased linearly as a function of awareness and independently of the level of stimulus processing. Additionally, the electrophysiological recordings revealed two correlates of visual awareness: enhanced posterior negativity in the N200 time window (VAN, visual awareness negativity) and enhanced positivity in the P3 time window (LP, late positivity). Interestingly, we found evidence of awareness levels modulating N200/VAN amplitudes in a graded manner only for the low-level task, whereas P3/LP amplitudes were modulated in a graded manner for both low and high-level tasks. The finding that the early posterior correlate of visual awareness (VAN at 150 250 ms) was sensitive to level of processing is consistent with task effects occurring in the visual cortex and supports the view that it is mediated by attention to task-relevant features. The amplitudes of P3/LP in both tasks correlate more directly with graded awareness and behavioral accuracy. PMID- 30408464 TI - FAPP2 promotes tumor cell growth in human colon cancer through activation of Wnt signaling. AB - Human phosphatidylinositol-4-phosphate adaptor protein-2 (FAPP2) is well-known to function as a cytoplasmic lipid transfer protein during vesicle maturation. However, the expression and role of FAPP2 in tumor remain elusive. In this study, data from immunohistochemical assays displayed that FAPP2 was remarkably upregulated (57.8%) in 90 cases of colon cancer samples in contrast to their corresponding adjacent tissues. Disruption of FAPP2 by CRISPR/Cas9 technique in colon cancer cells led to an attenuated effect on cell growth analyzed by CCK8 and colony formation assays. Meanwhile, the tumorigenicity of FAPP2 downregulated cells also decreased in nude mice model. Accordantly, CCK8 assays also indicated that FAPP2 overexpression could promote colon cancer cell growth. In addition, dual luciferase reporter assays and western blot analyses revealed that Wnt/beta catenin signaling was involved in the FAPP2-regulated tumor cell growth. These findings suggest that FAPP2 could act as an oncogene in the regulation of tumor growth and may provide a new therapeutic target for human colon cancer. PMID- 30408465 TI - Vitronectin from brain pericytes promotes adult forebrain neurogenesis by stimulating CNTF. AB - Vitronectin (VTN) is a glycoprotein in the blood and affects hemostasis. VTN is also present in the extracellular matrix of various organs but little is known about its function in healthy adult tissues. We show, in adult mice, that VTN is uniquely expressed by approximately half of the pericytes of subventricular zone (SVZ) where neurogenesis continues throughout life. Intracerebral VTN antibody injection or VTN knockout reduced neurogenesis as well as expression of pro neurogenic CNTF, and anti-neurogenic LIF and IL-6. Conversely, injections of VTN, or plasma from VTN+/+, but not VTN-/- mice, increased these cytokines. VTN promoted SVZ neurogenesis when LIF and IL-6 were suppressed by co-administration of a gp130 inhibitor. Unexpectedly, VTN inhibited FAK signaling and VTN-/- mice had increased FAK signaling in the SVZ. Further, an FAK inhibitor or VTN increased CNTF expression, but not in conditional astrocytic FAK knockout mice, suggesting that VTN increases CNTF through FAK inhibition in astrocytes. These results identify a novel role of pericyte-derived VTN in the brain, where it regulates SVZ neurogenesis through co-expression of CNTF, LIF and IL-6. VTN integrin-FAK and gp130 signaling may provide novel targets to induce neurogenesis for cell replacement therapies. PMID- 30408466 TI - Endogenous muscle atrophy F-box is involved in the development of cardiac rupture after myocardial infarction. AB - Muscle atrophy F-box (MAFbx/atrogin-1), an E3 ubiquitin ligase, is a crucial mediator of skeletal muscle atrophy and cardiac hypertrophy in response to pressure overload and exercise. The role of MAFbx in the regulation of cardiac remodeling after myocardial infarction (MI) remains unclear. Permanent coronary ligation of the left coronary artery was performed on MAFbx knockout (KO) and wild-type (WT) mice and MAFbx expression in the WT mice was shown to be significantly increased in the left ventricles after MI. The mortality rate due to post-MI cardiac rupture was significantly decreased in MAFbx KO mice compared to that in the WT mice. DNA microarray and mRNA expression analyses revealed that the upregulation of genes involved in inflammatory processes and cell motility of leukocytes and neutrophils, including Mmp9, Il1b, Cxcl2, and Nlrp3, was significantly attenuated in MAFbx KO mice 1 day after MI. MAFbx downregulation inhibited nuclear factor-kappaB (Nfkb) activation after MI. Flow cytometry results demonstrated that the myocardial infiltration of neutrophils was suppressed in MAFbx KO mice 1 day after MI. Nlrp3 and Il1b protein levels were decreased in MAFbx KO mice compared with those in the WT mice. MAFbx downregulation significantly attenuated Tnfa-induced Cxcl2, Il1b, and Nlrp3 expression in cardiomyocytes. We conclude that MAFbx plays an important role in the mediation of excessive inflammation, including neutrophil infiltration, inflammasome formation, and production of proinflammatory cytokines through the activation of Nfkb, promoting cardiac rupture after MI. PMID- 30408467 TI - The Bicuspid Aortic Valve Condition: The Critical Role of Echocardiography and the Case for a Standard Nomenclature Consensus. AB - The bicuspid aortic valve (BAV) condition is characterized by prominent heterogeneity of its valvular phenotypic expression, of its associated disorders, its complications and its prognosis. Echocardiography serves as the first-line imaging modality in 5 major capacities: (1) BAV diagnosis, (2) valvular phenotyping, (3) assessment of valvular function, (4) measurement of the thoracic aorta and exclusion of aortic coarctation, and (5) assessment of uncommon but serious complications such as infective endocarditis and aortic dissection. This article presents a nosological perspective on the BAV condition, discusses the critical role of echocardiography as it relates to these 5 aforementioned capacities; and makes the case for a unified standard nomenclature for the BAV condition. PMID- 30408468 TI - Is Speckle Tracking Imaging Ready for Prime Time in Current Echo Clinical Practice? AB - Accurate assessment of left and right ventricular systolic function plays a fundamental role in the prognostication and management of patients with known or suspected cardiovascular disease. Traditional echocardiographic parameters, including left ventricular ejection fraction, may lack the sensitivity to detect subclinical left ventricular systolic dysfunction. The advent of speckle tracking echocardiography for left and right ventricular systolic function assessment provides a further tool in this evaluation. Speckle tracking echocardiography has been demonstrated to provide incremental prognostic value beyond traditional echocardiographic parameters. This review discusses the clinical application of speckle tracking echocardiography in the evaluation of cardiovascular disease and its implementation within the clinical echocardiography laboratory. PMID- 30408469 TI - Prognostic Implications of Left Ventricular Hypertrophy. AB - Left ventricular hypertrophy (LVH) was one of the earliest studied echocardiographic characteristics of the left ventricle. As the myriad of measurable metrics has multiplied over recent years, this reliable and relevant variable can often be overlooked. In this paper, we discuss appropriate techniques for accurate analysis, underlying pathophysiology, and the contributions from various risk factors. The prognostic implications of LVH on stroke, serious arrhythmias, and sudden cardiac death are reviewed. Finally, we examine the effect of therapy to reduce LVH and the resultant clinical outcomes. PMID- 30408470 TI - Neuroticism is associated with reduced oxygenation levels in the lateral prefrontal cortex following exposure to unpleasant images. AB - The aim of this study was to explore the prefrontal cortex response to emotional salient stimuli in subjects with high scores in Neuroticism (and low in Sensation Seeking) or high scores in Sensation Seeking (and low in Neuroticism) personality traits, -called now Neuroticism and Sensation Seeking groups-. For this purpose, we selected 24 females (mean age: 20; SD: 1.74 years) and assigned them to two different groups according to their extreme score in personality dimensions. Ten pleasant and ten unpleasant pictures from the International Affective Picture System were presented. Neuroticism group showed significant effects for valence at the lateral prefrontal cortex in both brain hemispheres. They showed higher Oxygenation for pleasant pictures, more significantly in the left (Z = 2.49, p = 0.01) than in the right hemisphere (Z = 2.19, p = 0.03). The highest differences were registered in ventral optodes. In contrast, Sensation Seeking group did not show significant differences in hemodynamic variables as depending on the valence of the pictures. These data suggest a differential functioning of the lateral prefrontal cortex, mainly the left ventrolateral cortex, in Neuroticism group to pleasant and unpleasant visual stimuli. We hypothesize that if the lateral prefrontal activity is low, it could be the result of an over-activation of the amygdala in response to unpleasant pictures in subjects with Neuroticism or negative emotionality. These activation patterns could be related to vulnerability to emotional disorders. PMID- 30408471 TI - Predator odor exposure in early adolescence influences the effects of the bacterial product, propionic acid, on anxiety, sensorimotor gating, and acoustic startle response in male rats in later adolescence and adulthood. AB - It is becoming evident than the adolescent period is a sensitive period in stress response programming. Stressors during this time may alter signaling from the gut microbiome, which has been shown to increase the risk for psychiatric disorders. It was hypothesized that adolescent stressors may potentiate the symptoms of anxiety and sensory abnormalities induced by a gut bacterial product, the short chain fatty acid, propionic acid (PPA). The present study investigated the effects of repeated predator odor exposure during early adolescence on male rats administered PPA in late adolescence and adulthood on a behavioral test battery. Male adolescent Long-Evans rats were repeatedly exposed to a worn or unworn cat collar stimulus in early adolescence on postnatal days (P) 28, P30, P32, and P34. They were administered either PPA (500 mg/kg i.p.), or its vehicle in late adolescence on P40 and P43, and were subsequently tested on the light-dark anxiety task and acoustic startle task, respectively. In adulthood, the rats were again injected with PPA or its vehicle on P74 and P77, and subsequently tested on the light-dark apparatus and acoustic startle task, respectively. The repeated predator odor exposure was aversive and produced long-term anxiogenic effects as measured by the light-dark apparatus. PPA decreased activity and percent prepulse inhibition of the acoustic startle response, with its effects on vertical activity, a putative measure of escape behavior, being potentiated by prior predator stress. PPA's effects in adulthood were diminished in comparison to adolescence. These results suggest the importance of evaluating the effects of early adolescent stress on subsequent environmental insults on the development of behavioral abnormalities. PMID- 30408472 TI - Tracking acetate through a journey of living world: Evolution as alternative cellular fuel with potential for application in cancer therapeutics. AB - Acetate is a short chain fatty acid, comprising carbon, hydrogen and oxygen (C2H3O2-), which has emerged as a key alternative fuel for cellular metabolism. Beginning its voyage from the abiotic atmosphere, acetate has contributed to the physiology of both prokaryotes and eukaryotes. The main role of acetate includes its contribution to the global carbon cycle, bioenergetic and biosynthetic metabolic processes. Based on the ability to produce and consume acetate, organisms are categorized as acetogenic, acetate-consumers or both depending on their genetic make-up of the metabolizing enzymes' repertoire. The key molecules implicated in utilization and production of acetate include, but not limited to, monocarboxylate transporters, enzymes regulating acetate utilization like AMP forming Acetyl CoA synthetase (ACS-AMP), Acyl-CoA short chain synthetase 1, 2 (ACSS1, 2), and production like Acetate kinase (ACK)/Phosphotransacetylase (PTA), ADP-forming acetyl CoA synthetase (ACS-ADP), Pyruvate:ferredoxin oxidoreductase, histone deacetylase and acetyl CoA hydrolase. These enzymes are utilized by the acetate homeostasis machinery in a variable manner. As malignant cells also display highly upregulated metabolic processes for rapid energy generation, they display an immense need for alternative carbon sources to fuel their metabolism. Tumor cells display over expression of transporters and enzymes implicated in their acetate utility machinery. This review also highlights mechanisms of the pro and antitumor potential of acetate depending on the genetic and metabolic makeup of neoplastic cells. The present review is a comprehensive compilation of the available literature with respect to the role of acetate in the biology of living organisms and its potential for being maneuvered in anticancer therapeutics. PMID- 30408473 TI - Development and characterization of late-stage diabetes mellitus and -associated vascular complications. AB - Preclinical investigation is the key mark of medical research, as the major breakthroughs including treatment of devastating diseases in biomedical research have been led by animal studies. Type 2 diabetes mellitus (T2DM) is a predominant metabolic disorder having high prevalence of morbidity worldwide which create an urgent need to understand the pathogenesis, complication and other possible influences by development of appropriate animal model. High-fat diet (HFD) fed animals (21 days) were treated with single cycle of repetitive dose (SCRD) of streptozotocin (STZ; 40, 30 and 20 mg/kg/per day in three respective group at 1st, 3rd, and 5th day) and double cycle of repetitive dose (DCRD) of streptozocin (STZ) (20, 10 and 5 mg/kg/per day in three respective group at 1st, 3rd, and 5th day in one cycle and 21st, 23rd, 25th day in second cycle of treatment) to induce late-stage diabetic complications. Induction of hyperglycemia was assessed by fasting and postprandial blood glucose, HbA1c, insulin, C-peptide, pancreatic beta-cells and dyslipidaemia up to 12 weeks. Combined treatment of HFD and STZ (20 mg/kg) in the DCRD manner were significantly induced late-stage diabetic complication with sustained hyperglycaemia, no mortality, increased HbA1c and dyslipidaemia, reduced insulin, C-peptide and beta cells. Moreover, biochemical and histological assessment of micro and macrovascular tissues confirmed the significant cardio-renal injury, endothelial and hepatic damage. The study confirmed the development of chronic diabetic model in rat mimicked to clinical pathology with associated micro and macrovascular abnormalities which can further explore the molecular aspects of diseases. PMID- 30408474 TI - Loss of HCN1 subunits causes absence epilepsy in rats. AB - Hyperpolarized-activated cyclic nucleotide-gated (HCN) channels underlie hyperpolarization-activated current (Ih) and are involved in controlling the excitability and electrical responsiveness of neurons. Absence epilepsy is clinically defined by a sudden, brief impairment of consciousness and behavioral arrest. Spike-and-wave discharges (SWDs) on electroencephalograms (EEG) are a diagnostic hallmark of absence epilepsy. In rat models of absence epilepsy, impaired function or expression of HCN1, a subtype of HCN channels, has been found. Here, to evaluate whether HCN1 deficiency causes absence epilepsy in rats, we developed Hcn1-knockout rats by transcription activator-like effector nuclease mutagenesis. The cortical and hippocampal pyramidal neurons of these rats displayed a significant reduction of Ih, a pronounced hyperpolarizing shift of the resting membrane potential, and increased input resistance, which indicated that the Hcn1-knockout rats were deficient in HCN1 function. The Hcn1-knockout rats were also more vulnerable to pentylenetetrazol-induced acute convulsions. More importantly, they exhibited spontaneous SWDs, which were accompanied by behavioral arrest, both of which were suppressed by ethosuximide. These results confirm the involvement of the HCN1 subunit in the regulation of input resistance and provide direct evidence that a deficiency of HCN1 caused absence epilepsy in rats. PMID- 30408475 TI - Detection and localization of interictal ripples with magnetoencephalography in the presurgical evaluation of drug-resistant insular epilepsy. AB - Precise noninvasive presurgical localization of insular epilepsy is important. The objective of the present study was to detect and localize interictal high frequency oscillations (HFOs) in patients with insular epilepsy at the source levels using magnetoencephalography (MEG). We investigated whether HFOs can delineate epileptogenic areas. We analysed MEG data with new accumulated source imaging (HFOs, 80-250 Hz ripples during spikes) and conventional dipole modelling (spikes) methods for localizing epileptic foci. We evaluated the relationship of the resection of focal brain regions containing interictal HFOs and the spikes with the postsurgical seizure outcome. Interictal HFOs were localized in the insular epileptogenic zone (EZ) in 18 out of 21 patients undergoing surgical treatment for clinically diagnosed insular epilepsy. While dipole clusters of spikes were involved in the insular EZ in 15 patients. Both the HFOs and the dipole cluster were localized in the insula in 14 patients. The seizure-free percentage was 87% for the resection of brain regions generating HFOs, whereas 80% for the resection of brain regions generating spikes. There was a much higher chance of freedom from seizures with complete resection of the HFO-generating regions than with partial resection or no resection (P=0.031). No such difference was seen for spike-generating regions. Our results suggest that HFOs from insular epilepsy could be noninvasively detected and quantitatively assessed with MEG technology. MEG HFOs (ripples during spikes) may be valuable for the localization of the epileptogenic zone in insular epilepsy. PMID- 30408476 TI - Abnormal Golgi morphology and decreased COPI function in cells with low levels of SMN. AB - We report here the finding of abnormal Golgi apparatus morphology in motor neuron like cells depleted of SMN as well as Golgi apparatus morphology in SMA patient fibroblasts. Rescue experiments demonstrate that this abnormality is dependent on SMN, but can also be rescued by expression of the COPI coatomer subunit alpha COP. A motor neuron-like cell line containing an inducible alpha-COP shRNA was created to generate a parallel system to study knockdown of SMN or alpha-COP. Multiple assays of COPI-dependent intracellular trafficking in cells depleted of SMN demonstrate that alpha-COP function is suboptimal, including failed sequestration of plasma membrane proteins, altered binding of mRNA, and defective targeting and transport of Golgi-resident proteins. PMID- 30408477 TI - Presynaptic increase in IP3 receptor type 1 concentration in the early phase of hippocampal synaptic plasticity. AB - The inositol 1,4,5-trisphosphate receptor (IP3R) subtype IP3R1 is highly enriched in the brain, including hippocampal neurons. It plays an important function in regulating intracellular calcium concentrations. Residing on the smooth endoplasmic reticulum (sER), the IP3R1 mobilizes calcium into the cytosol upon binding the intracellular signaling molecule IP3, whose concentration is increased by stimulating certain metabotropic glutamate receptors. Increased calcium may mediate synaptic changes occurring during long-term plasticity, which includes molecular mechanisms underlying memory encoding. The exact synaptic localization of IP3R1 in the central nervous system (CNS) remains unclear. We hypothesized that IP3R1, in addition to its known expression in soma and dendritic shafts of hippocampal CA1 pyramidal neurons, also may be present in postsynaptic spines. Moreover, we hypothesized that IP3R1 may be present in presynaptic terminals as well, given the importance of calcium in regulating presynaptic neurotransmitter exocytosis. To test these two hypotheses, we used IP3R1 immunocytochemistry at the light and electron microscopical levels in the CA1 area of the hippocampus. Furthermore, we hypothesized that induction of long term potentiation (LTP) would be accompanied by an increase in synaptic IP3R1 concentrations, thereby facilitating synaptic mechanisms of long term plasticity. To investigate this, we used quantitative immunogold electron microscopy to determine possible changes in IP3R1 concentration in sub-synaptic compartments before and five minutes after high frequency tetanizations. Firstly, our data confirm localization of IP3R1 in both presynaptic terminals and postsynaptic spines. Secondly, the concentration of IP3R1 after tetanization was significantly increased in the presynaptic compartment, suggesting a presynaptic role of IP3R1 in early phases of synaptic plasticity. It is therefore possible that IP3R1 is involved in modulating neurotransmitter release by regulating calcium homeostasis presynaptically. PMID- 30408478 TI - LncRNA NEAT1 facilitates survival and angiogenesis in oxygen-glucose deprivation (OGD)-induced brain microvascular endothelial cells (BMECs) via targeting miR-377 and upregulating SIRT1, VEGFA, and BCL-XL. AB - OBJECTIVE: The present study was designed to investigate the mechanism by which lncRNA NEAT1 regulates survival and angiogenesis in oxygen-glucose deprivation (OGD)-induced brain microvascular endothelial cells (BMECs). METHODS: OGD-treated BMECs were used to mimic cerebral ischaemia in vitro. The expression of lncRNA NEAT1 and miR-377 and proteins including VEGFA, SIRT1, and BCL-XL were measured by real-time quantitative PCR (qRT-PCR) and western blot, respectively. Cell viability and caspase 3 activity of BMECs under different conditions were determined using MTT and caspase activity assays, respectively. Matrigel-based angiogenesis assays were employed to evaluate the effect of lncRNA NEAT1 on angiogenesis. A dual-luciferase reporter assay was used to validate direct binding of miR-377 to putative targets. RESULTS: OGD exposure reduced the cell viability of BMECs. Upregulation of lncRNA NEAT1 and downregulation of miR-377 were also observed under OGD conditions. Knockdown of lncRNA NEAT1 inhibited angiogenesis and aggravated apoptosis in OGD-induced BMECs. Meanwhile, the expression level of miR-377 was upregulated while its downstream targets (VEGFA, SIRT1, and BCL-XL) were downregulated after lncRNA NEAT1 knockdown. Furthermore, miR-377 inhibited the angiogenesis and survival of OGD-induced BMECs. The expression of VEGFA, SIRT1, and BCL-XL were all attenuated by miR-377 overexpression. The dual-luciferase reporter assay proved miR-377 targeted the 3' UTR sequences of lncRNA NEAT1, VEGFA, SIRT1, and BCL-XL. CONCLUSION: lncRNA NEAT1 facilitated the survival and angiogenesis of OGD-induced BMECs via targeting miR 377 and promoting the expression of VEGFA, SIRT1, and BCL-XL, suggesting that lncRNA NEAT1 could be a promising target for cerebral ischaemia treatment. PMID- 30408479 TI - Exendin-4 Improves Behaviorial Deficits via GLP-1/GLP-1R Signaling following Partial Hepatectomy. AB - Recent studies indicate that glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonists exhibit neurotrophic and neuroprotective effects. The aim of this study was to explore whether the GLP-1R agonist exendin-4 can alter surgery-induced behavioral deficits and exert neuroprotective effects via the activation of the hippocampal GLP-1/GLP-1R pathway. 120 male Sprague-Dawley rats (aged 18-20 months old) were randomly divided into four groups: control group, exendin-4 group, surgery group, and surgery + exendin-4 group. The animals received either exendin 4 (5 ug/kg/day) or saline intra-peritoneally for 14 days, and then were subjected to partial hepatectomy 24 h after the last injection. Behavioral changes were evaluated with Morris Water Maze and Open field testing on postoperative days 7 and 14. The levels of IL-1beta, NF-kappaB, Iba-1, Synaptophysin, GLP-1/GLP-1R, GSK-3beta, p-GSK-3beta (Ser9), p-Tau (Ser396), and p-Tau (Ser202/199) in the hippocampus were measured at the same time point. Surgical trauma induced an exacerbated spatial learning and memory impairment, increased the levels of depressive performance, and enhanced hippocampal NF-kappaB and IL-1beta expression in the aged rats on postoperative day 7. A corresponding decline in GLP-1R was also found following surgical challenge on postoperative day 7. Exendin-4 treatment partly reversed surgery-induced postoperative behavioral impairment, downregulated the levels of NF-kappaB and IL-1beta, ameliorated tau hyperphosphorylation and enhanced the activity of p-GSK-3beta (Ser9). Together, the downregulation of GLP-1R exacerbated surgery-induced behavior deficits. Exendin-4 treatment attenuated these effects by inhibiting neuroinflammation and tau hyperphosphorylation. These findings suggest that pretreatment with exendin-4 is a potential adjuvant for preventing surgery-induced behavioral deficits. PMID- 30408480 TI - Novel mutations in BMP1 induce a rare type of osteogenesis imperfecta. AB - BACKGROUND: Osteogenesis imperfecta (OI) is a group of hereditary disorders characterized by low bone mass and recurrent fractures. OI patients of autosomal recessive inheritance are extremely rare, of which OI type XIII is attributable to mutation in BMP1 gene. CASE REPORT: Here, we detect the pathogenic mutations and analyze their relation to the phenotypes in a Chinese family with OI using next-generation sequencing (NGS) and Sanger sequencing. We also evaluate the efficacy of alendronate treatment in the patient with OI type XIII. The clinical phenotypes of the patient included recurrent fractures, muscle weakness, bone deformity, macrocephaly and elbow contractures, but no blue sclera or dentinogenesis imperfecta. High-resolution peripheral quantitative computed tomography revealed high bone mineral density and bone volume, but reduced trabecular numbers, increased porosity and comprised strength in this patient. Novel heterozygous mutations of c.1324G > T (p.Asp442Tyr) and c.148 + 1G > A in BMP1 gene were found in the proband, which would affect the CUB2 domain and the prodomain of mutant proteins. The parents were heterozygous carriers for the two mutations respectively, but with normal phenotype. CONCLUSIONS: We report for the first time that the novel pathogenic mutations in BMP1 can lead to the extremely rare OI type XIII, which exhibit unique characters of high bone mass, but with impaired bone microstructure and comprised bone strength. Alendronate is beneficial in increasing bone mineral density and decreasing bone resorption biomarkers, but concerns still remain whether it can reduce fracture incidence in this rare type of OI. PMID- 30408481 TI - Multi-centre validation of a flow cytometry method to identify optimal responders to interferon-beta in multiple sclerosis. AB - BACKGROUND AND OBJECTIVES: Percentages of blood CD19+CD5+ B cells and CD8+perforin+ T lymphocytes can predict response to Interferon (IFN)-beta treatment in relapsing-remitting multiple sclerosis (RRMS) patients. We aimed to standardize their detection in a multicenter study, prior to their implementation in clinical practice. METHODS: Fourteen hospitals participated in the study. A reference centre was established for comparison studies. Peripheral blood cells of 105 untreated RRMS patients were studied. Every sample was analyzed in duplicate in the participating centre and in the reference one by flow cytometry. When needed, participating centres corrected fluorescence compensations and negative cut-off position following reference centre suggestions. Concordance between results obtained by participating centres and by reference one was evaluated by intraclass correlation coefficients (ICC) and Spearman correlation test. Centre performance was measured by using z-scores values. RESULTS: After results review and corrective actions implementation, overall ICC was 0.86 (CI: 0.81-0.91) for CD19+CD5+ B cell and 0.89 (CI: 0.85-0.93) for CD8+ perforin+ T cell quantification; Spearman r was 0.92 (0.89-0.95; p <0.0001) and 0.92 (0.88 0.95; p <0.0001) respectively. All centres obtained z-scores<=0.5 for both biomarkers. CONCLUSION: Homogenous percentages of CD19+CD5+ B cells and CD8 perforin+ T lymphocytes can be obtained if suitable compensation values and negative cut-off are pre-established. PMID- 30408482 TI - Development of specific chemiluminescent immunoassays for three subtypes of vitellogenin in grey mullet (Mugil cephalus). AB - Chemiluminescent immunoassays (CLIAs) were developed for each of three subtypes of vitellogenin (VtgAa, VtgAb and VtgC) in grey mullet, primarily for use in monitoring estrogenic pollution of the environment. The working range of VtgAa CLIA and VtgAb-CLIA was from 0.975 to 1,000 ng/ml, while that of VtgC-CLIA was from 0.487 to 1,000 ng/ml. Each CLIA appeared to be specific to the targeted Vtg subtype. Intra- and inter-assay coefficients of variation in the developed CLIAs were lower than 10%. In male serum, VtgAa, VtgAb and VtgC were detected in ranges from 0.01 to 0.38, 0.02 to 1.01, and 0.01 to 3.12 MUg/ml, respectively, during various sampling periods. In vitellogenic females (October), serum VtgAb levels (1,192.05 +/- 237.81 MUg/ml) were significantly higher than levels of the other two Vtg subtypes (120.82 +/- 30.42 and 119.23 +/- 16.95 MUg/ml for VtgAa and VtgC, respectively). When immature mullet were fed diets containing 17alpha ethinylestradiol (EE2) at three different doses (0.4, 40 and 4,000 ng/g body weight), all Vtg subtypes were induced by 40 ng/g and 4,000 ng/g EE2. The VtgC (610.30 +/- 150.18 MUg/ml) was most highly expressed among the three Vtgs in fish fed 40 ng/g EE2, while VtgAb (33.25 +/- 13.58 mg/ml) was highest in expression in fish fed 4,000 ng/g EE2. The present study provided practical subtype-specific Vtg assays for the first time in grey mullet, providing the necessary means to evaluate estrogenic activities in aquatic environments. PMID- 30408483 TI - The case for thyroid disruption in early life stage exposures to thiram in zebrafish (Danio rerio). AB - Thiram, a pesticide in the dithiocarbamate chemical family, is widely used to prevent fungal disease in seeds and crops. Its off-site movement to surface waters occurs and may place aquatic organisms at potential harm. Zebrafish embryos were used for investigation of acute (1 h) thiram exposure (0.001-10 uM) at various developmental stages. Survival decreased at 1 uM and 10 uM and hatching was delayed at 0.1 uM and 1 uM. Notochord curvatures were seen at 0.1 and 1 MUM thiram when exposure was initiated at 2 and at 10 hpf. Similar notochord curvatures followed exposure to the known TPO inhibitor, methimazole (MMI). Changes were absent in embryos exposed at later stages, i.e., 12 hpf. In embryos exposed to 0.1 or 1 MUM at 10 hpf, levels of the thyroid enzyme, Deiodinase 3, increased by 12 hpf. Thyroid peroxide (TPO), important in T4 synthesis, decreased by 48 hpf in embryos exposed to 1 uM at 10 hpf. Thiram toxicity was stage-dependent and early life stage exposure may be responsible for adverse effects seen later. These effects may be due to impacts on the thyroid via regulation of specific thyroid genes including TPO and Deiodinase 3. PMID- 30408484 TI - Assessing impacts of precocious steroid exposure on thyroid physiology and gene expression patterns in the American alligator (Alligator mississippiensis). AB - The thyroid gland is sensitive to steroid hormone signaling, and many thyroid disrupting contaminants also disrupt steroid hormone homeostasis, presenting the possibility that thyroid disruption may occur through altered steroid hormone signaling. To examine this possibility, we studied short-term and persistent impacts of embryonic sex steroid exposure on thyroid physiology in the American alligator. Alligators from a lake contaminated with endocrine disrupting contaminants (Lake Apopka, FL, USA) have been shown to display characteristics of thyroid and steroid hormone disruption. Previous studies suggest these alterations arise during development and raise the possibility that exposure to maternally deposited contaminants might underlie persistent organizational changes in both thyroidal and reproductive function. Thus, this population provides a system to investigate contaminant-mediated organizational thyroid disruption in an environmentally-relevant context. We assess the developmental expression of genetic pathways involved in thyroid hormone biosynthesis and find that expression of these genes increases prior to hatching. Further, we show that nuclear steroid hormone receptors are also expressed during this period, indicating the developing thyroid is potentially responsive to steroid hormone signaling. We then explore functional roles of steroid signaling during development on subsequent thyroid function in juvenile alligators. We exposed alligator eggs collected from both Lake Apopka and a reference site to 17beta estradiol and a non-aromatizable androgen during embryonic development, and investigated effects of exposure on hatchling morphometrics and thyroidal gene expression profiles at 5 months of age. Steroid hormone treatment did not impact the timing of hatching or hatchling size. Furthermore, treatment with steroid hormones did not result in detectable impacts on thyroid transcriptional programs, suggesting that precocious or excess estrogen and androgen exposure does not influence immediate or long-term thyroidal physiology. PMID- 30408485 TI - Therapeutic impacts of environmental enrichment: Neurobiological mechanisms informing molecular targets for enviromimetics. PMID- 30408486 TI - Neuroprotective action of diazepam at very low and moderate doses in Alzheimer's disease model rats. AB - Early manifestations of Alzheimer's disease (AD) include neuroinflammation, disrupted neurotransmission and cognitive deficits. Impairment of the GABAergic system is essentially involved in the pathogenesis of AD. Traditionally, agonists of GABAA receptors at doses above 1 mg/kg are known to possess memory impairing effects. However, we have previously found that GABAA receptor GABA site ligand muscimol at very low doses acted contrary - enhanced spatial learning/memory, as well as prevented neuroinflammation and augmented neurotransmission in AD model rats. Therefore, in the present study we focused on the assessment of the effects of non-sedative - very low (0.05 mg/kg) and moderate (1 mg/kg) - doses of diazepam, a positive allosteric modulator of benzodiazepine site of GABAA receptors. Its effects on spatial learning/memory and brain proteins related to neuroinflammation (GFAP and Iba-1), synaptic plasticity (SYP1), as well as acetylcholine breakdown and GABA biosynthesis were studied. Non-transgenic AD model rats (intracerebroventricular streptozocin injection) were used with the aim to mimic the pre-dementia stage of AD in humans. The obtained data showed that diazepam at both doses protected against streptozocin induced detrimental effects by enhancing spatial learning/memory, preventing neuroinflammation, preserving synaptic plasticity, as well as normalizing the hippocampal and cortical protein expression related to acetylcholine breakdown and GABA biosynthesis. One may suggest that at low and moderate doses diazepam is targeting non-specific, probably allosteric GABAA receptor sites, thus leading to stimulatory effects that can be beneficial for diazepam use in early pre-dementia stages of AD. PMID- 30408487 TI - Enhancement of synaptic plasticity and reversal of impairments in motor and cognitive functions in a mouse model of Angelman Syndrome by a small neurogenic molecule, NSI-189. AB - NSI-189 Phosphate, (4-benzylpiperazin-1-yl)-[2-(3-methyl-butylamino)pyridin-3-yl] methanone is a new chemical entity under development for the treatment of MDD, based upon preclinical data demonstrating stimulation of neurogenesis of human hippocampus-derived neural stem cells in vitro and in mouse hippocampus in vivo. Previous studies have examined the tolerability and efficacy of NSI-189 for treating major depressive disorder (MDD). NSI-189 has shown significant potential as a treatment for MDD, with concurrent improvement of a cognition scale in a small double-blind, placebo-controlled study. The current study evaluated its possible application for the treatment of Angelman Syndrome. Incubation of acute hippocampal slices from wild-type mice with NSI-189 resulted in a time- and dose dependent increase in the magnitude of long-term potentiation (LTP) elicited by theta burst stimulation (TBS). The same protocol enhanced TBS-induced LTP in acute hippocampal slices from AS mice. A short treatment with daily injections of NSI-189 in AS mice reversed impairments in cognitive and motor functions, while it slightly enhanced performance of WT mice. The effects of NSI-189 on synaptic plasticity and cognitive functions were associated with activation of the TrkB and Akt pathways. These results suggest that NSI-189 could represent a potential treatment for AS patients. PMID- 30408488 TI - Heterosynaptic modulation in the paraventricular nucleus of the hypothalamus. AB - The stress response-originally described by Hans Selye as "the nonspecific response of the body to any demand made upon it"-is chiefly mediated by the hypothalamic-pituitary-adrenal (HPA) axis and is activated by diverse sensory stimuli that inform threats to homeostasis. The diversity of signals regulating the HPA axis is partly achieved by the complexity of afferent inputs that converge at the apex of the HPA axis: this apex is formed by a group of neurosecretory neurons that synthesize corticotropin-releasing hormone (CRH) in the paraventricular nucleus of the hypothalamus (PVN). The afferent synaptic inputs onto these PVN-CRH neurons originate from a number of brain areas, and PVN CRH neurons respond to a long list of neurotransmitters/neuropeptides. Considering this complexity, an important question is how these diverse afferent signals independently and/or in concert influence the excitability of PVN-CRH neurons. While many of these inputs directly act on the postsynaptic PVN-CRH neurons for the summation of signals, accumulating data indicates that they also modulate each other's transmission in the PVN. This mode of transmission, termed heterosynaptic modulation, points to mechanisms through which the activity of a specific modulatory input (conveying a specific sensory signal) can up- or down regulate the efficacy of other afferent synapses (mediating other stress modalities) depending on receptor expression for and spatial proximity to the heterosynaptic signals. Here, we review examples of heterosynaptic modulation in the PVN and discuss its potential role in the regulation of PVN-CRH neurons' excitability and resulting HPA axis activity. PMID- 30408489 TI - Ethanol->Nicotine & Nicotine ->Ethanol Drug-Sequence Discriminations: Conditional Stimulus Control with Two Interoceptive Drug Elements in Rats. AB - Self-administration of Ethanol (E) and nicotine (N) occurs frequently in tandem orders (i.e., N->E vs. E->N) and thereby produce differing interoceptive profiles of subjective effects in humans. If the interoceptive stimulus characteristics of N->E differ from E->N, it is possible that such differences contribute to their co-dependence. The rationale for the present investigation was to determine if E when preceded or followed by N produces different discriminative stimulus effects in rats. In two experiments, using a one manipulanda operant drug discrimination procedure, rats were trained to discriminate temporal sequential administrations of ethanol (1.0 g/kg) that was followed or preceded by nicotine (0.3 mg/kg). Sessions alternated between food-reinforcement sessions on a variable interval 30 s schedule (i.e., SD) and non-reinforcement sessions (i.e., SDelta). In Exp 1, administrations of E were followed or preceded by a 10 min interval of N. Training sessions took place 10 min following the second drug injection. Four groups of rats were trained to discriminate only one sequence from sequential administrations of saline, and each drug sequence was counterbalanced across groups for their roles as SD or SDelta. There was robust stimulus control. N->E and E->N functioned equally well as SD or SDelta. Exp 2 used two groups of rats. For one group, the E->N sequence functioned as the SD and the N->E sequence functioned as the SDelta. The drug sequences were counterbalanced for the other group. Brief non-reinforcement tests revealed significantly greater responding during the SD sequence compared to the SDelta sequence for both groups. These results suggest that different drug sequences of ethanol followed, or preceded, by nicotine established reliable discriminative stimulus control over operant responding potentially because of characteristic differences in the overlapping pharmacokinetic profiles of the NE compound. The results are discussed in terms of: 1) conditional stimulus control among two interoceptive drug states; and 2) the clinical modulation of human alcohol consumption and tobacco smoking. PMID- 30408490 TI - Isolation and characterization of a broad-spectrum phage of multiple drug resistant Salmonella and its therapeutic utility in mice. AB - Salmonella are causes of livestock, poultry, and other animal diseases but they also have the potential to infect people. Currently, antibiotics are the first choice for treatment of Salmonella infections. Thus, the utility of phage has become the research focus for scientists for several reasons. There are efficient, non-toxic, ubiquitous, easy to prepare and can result in the lysis of host bacteria. In this study, a broad spectrum bacteriophage of Salmonella was isolated from the fecal samples of a poultryfarm and we studied the morphological aspects, thermal stability, pH stability, optimal multiplicity of infection (MOI), and one-step growth curve of this phage. This phage was named Salmonella phage SaFB14 and lysed 54.12%(105/194)Salmonella spp. SaFB14 belongs to the Siphoviridae and has a polyhedron head with a diameter approximating 60 * 60 nm and a tail approximating 140 nm. The optimum growth temperature was 37 degrees C and maintained high activity over a widepH range(pH3-10) with an optimum of pH 7.0. The optimal MOI was 0.1. A one-step growth curve showed that its latency time was 10 min, burst time was 70 min, and burst was 23 particles. In order to study the therapeutic effect of phage SaFB14 in infected mice, mice were challenged with 2 * 109 CFU/mouse Salmonella (cs20130523-001-1). Each mouse was injected to 2 * 1010 PFU SaFB14 1 h later. SaFB14 protected 40% of mice from infection. Then, the same dose of phage was given to mice for 3 days continuously. After 3 days treatment, the survival rate increased to 60%.In conclusion, phage SaFB14 showed wide host range and good activity in vivo, it is promising against diseases caused by Salmonella. PMID- 30408491 TI - Recombinant outer membrane protein T (OmpT) of Vibrio ichthyoenteri, a potential vaccine candidate for flounder (Paralichthys olivaceus). AB - Vibrio ichthyoenteri is a marine pathogen that primarily causes bacterial enteritis of flatfish. In order to screen out the effective vaccine candidate proteins, five outer membrane proteins (OMPs) of V. ichthyoenteri, including OmpV, OmpU, OmpT, Omp1 and Omp2, were selected and recombinantly expressed in Escherichia coli. The result of western blotting showed that all of these recombinant proteins could be recognized by flounder anti-V. ichthyoenteri antibodies. The immune protective effect of the five rOMPs were also investigated, and the relative percent survival (RPS) of rOmpV, rOmpU, rOmpT, rOmp1 and rOmp2 was 69.2%, 46.2%, 76.9%, 65.4% and 30.8%, respectively. The RPS of rOmpT was significantly higher than inactivated V. ichthyoenteri (57.7%) and other rOMPs, so the immune responses of flounder induced by rOmpT were further investigated. The results showed that both the production of specific serum antibodies and the proliferation of sIg + lymphocytes could be significantly induced by rOmpT. Meanwhile, the MHCIIalpha, INF-gamma, CD4-1, and IL-1beta genes were significantly up-regulated after immunization with rOmpT. These results demonstrated that rOmpT could induce strong innate and humoral immune response in flounder and provided effective immune protection against V. ichthyoenteri challenge, which indicated that OmpT is a promising vaccine candidate against V. ichthyoenteri infection. PMID- 30408493 TI - Impact of a poorly performing point-of-care test during the 2017-2018 influenza season. PMID- 30408492 TI - A low-density lipoprotein receptor (LDLR) class A domain-containing C-type lectin from Litopenaeus vannamei plays opposite roles in antibacterial and antiviral responses. AB - C-type lectins (CTLs) are a group of pattern recognition receptors (PRRs) that contain carbohydrate recognition domains and play important roles in innate immunity. CTLs that contain an additional low-density lipoprotein receptor (LDLR) class A domain (LdlrCTL) have been identified in many crustaceans, but their functions in immune responses are mostly unknown. In this study, a novel LdlrCTL was identified from pacific white shrimp Litopenaeus vannamei (LvLdlrCTL), which showed high homology with previously reported crustacean LdlrCTLs. LvLdlrCTL was highly expressed in hemocytes and its expression was up-regulated after immune stimulations. Silencing of LdlrCTL significantly promoted infection of shrimp by Vibrio parahaemolyticus but inhibited infection by white spot syndrome virus (WSSV), suggesting that LdlrCTL could play opposite roles in antibacterial and antiviral responses. LdlrCTL exhibited agglutination activity against bacteria and fungi and could potentiate the phagocytosis of hemocytes. Moreover, the expression of many immune effector genes and signalling pathway components was significantly changed in LdlrCTL-silenced shrimp, indicating that LdlrCTL could be involved in immune regulation. PMID- 30408494 TI - Unusual Neisseria species as a cause of infection in patients taking eculizumab. AB - BACKGROUND: Non-meningococcal, non-gonococcal Neisseria spp. are typically commensal and rarely cause invasive disease. Eculizumab is a terminal complement inhibitor that increases susceptibility to meningococcal disease, but data on disease caused by typically-commensal Neisseria spp. are lacking. This series describes postmarketing reports of typically-commensal Neisseria spp. disease in patients receiving eculizumab. METHODS: We searched the FDA Adverse Event Reporting System (FAERS) and medical literature for reports of commensal Neisseria spp. disease in patients receiving eculizumab, from eculizumab U.S. approval (2007) through January 31, 2018. RESULTS: We identified seven FAERS reports (including one case also reported in the literature) of non meningococcal, non-gonococcal Neisseria disease, including N. sicca (mucosa)/subflava (n = 2), N. cinerea (n = 2), N. sicca (mucosa) (n = 1), N. mucosa (n = 1, with concurrent alpha-hemolytic Streptococcus bacteremia), and N. flavescens (subflava) (n = 1). Four cases had sources of patient immunosuppression in addition to eculizumab. Three patients had sepsis (n = 2) or septic shock (n = 1). Five patients were bacteremic. All patients were hospitalized; the infections resolved with antibiotics. CONCLUSIONS: Our search identified seven cases of disease from typically commensal Neisseria spp. in eculizumab recipients. These findings suggest that any Neisseria spp. identified from a normally sterile site in an eculizumab recipient could represent true infection warranting prompt treatment. PMID- 30408495 TI - The NLRP3 inflammasome is involved in the neuroprotective mechanism of neural stem cells against microglia-mediated toxicity in SH-SY5Y cells via the attenuation of tau hyperphosphorylation and amyloidogenesis. AB - The cognitive impairment caused by Alzheimer's disease (AD) is associated with beta-amyloid (Abeta) and tau proteins, and is accompanied by inflammation. Recently, a novel inflammasome signaling pathway has been uncovered. Inflammasomes are implicated in the execution of inflammatory responses and pyroptotic death leading to neurodegeneration. Thus, the inflammasome signaling pathway could be a potential therapeutic target for AD. Neural stem cells (NSCs) are multipotent cells that can self-renew and differentiate into distinct neural cells. NSC therapy has been considered to be a promising therapeutic approach in protecting the central nervous system and restoring it following damage. However, the mechanisms involved remain unclear. The aims of this study were to investigate the protective effects of NE4C neural stem cells against microglia mediated neurotoxicity and to explore molecular mechanisms mediating their actions. NE4C decreased the levels of caspase-1 and IL-1beta, and attenuated the level of the NLRP3 inflammasome and its associated protein adapter, apoptosis associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) in LPS-stimulated BV2 microglial cells, possibly by regulating the phosphorylation of p38alpha MAPK. The conditioned media obtained from co-culture of LPS-stimulated BV2 and NE4C cells exhibited protective effects on SH-SY5Y cells against microglia-mediated neurotoxicity; this was associated with an attenuation of tau phosphorylation and amyloidogenesis and accompanied by down regulation of GSK-3beta and p38alpha MAPK signalling pathways. In conclusion, the present study suggested that NSC therapy could be a potential strategy against microglia-mediated neurotoxicity. NSCs regulate NLRP3 activation and IL-1beta secretion, which are critical in the initiation of the inflammatory responses, hence preventing the release of neurotoxic pro-inflammatory factors by microglia. This eventually reduces tau hyperphosphylation and amyloidogenesis, possibly through the regulation of GSK-3beta and p38alpha MAPK signalling pathways, and thus protects SH-SY5Y cells against microglia-mediated neurotoxicity. PMID- 30408496 TI - Development and Pilot Testing of a Simulation to Study How Physicians Facilitate Surrogate Decision-Making Based on Critically Ill Patients' Values and Preferences. AB - CONTEXT: There are no evidence-based programs to train physicians to facilitate shared decision-making based on incapacitated intensive care unit (ICU) patients' values and preferences. OBJECTIVES: To develop a high-fidelity simulation to fill this gap. METHODS: Case development involved 6 steps: 1) drafting a case about an elderly patient receiving prolonged mechanical ventilation; 2) engaging an expert advisory board to optimize case content; 3) revising the case based on advisory board input; 4) training actors to portray the case patient's daughter; 5) obtaining physician feedback on the simulation; 6) revising the case based on their feedback. We conducted a cross-sectional pilot study with 50 physicians to assess feasibility and acceptability, defined a priori as an enrollment rate > 40 physicians/year, study procedures <75 minutes/participant, >95% actor adherence to standardization rules, and high physician ratings of realism and acceptability. RESULTS: Advisory panel feedback yielded two modifications: 1) refocusing the case on decision-making about tracheostomy and percutaneous gastrostomy; 2) making the patient's values more authentic. Physician feedback yielded two additional modifications: 1) reducing how readily the actor divulged the patient's values; 2) making her more emotional. All 50 physicians enrolled in the pilot study over 11 months completed study procedures in <75 minutes. Actor adherence to standardization rules was 95.8%. Physicians' mean ratings of realism and acceptability were 8.4 and 9.1 respectively on a 10-point scale. CONCLUSION: Simulation is feasible, acceptable, and can be adequately standardized to study physicians' skills for facilitating surrogate decision-making based on an incapacitated ICU patient's values and preferences. PMID- 30408497 TI - Histamine-4 receptor antagonist JNJ7777120 inhibits pro-inflammatory microglia and prevents the progression of Parkinson-like pathology and behaviour in a rat model. AB - The activation of microglial cells is presumed to play a key role in the pathogenesis of Parkinson's disease (PD). The activity of microglia is regulated by the histamine-4 receptor (H4R), thus providing a novel target that may prevent the progression of PD. However, this putative mechanism has so far not been validated. In our previous study, we found that mRNA expression of H4R was upregulated in PD patients. In the present study, we validated this possible mechanism using the rotenone-induced PD rat model, in which mRNA expression levels of H4R-, and microglial markers were significantly increased in the ventral midbrain. Inhibition of H4R in rotenone-induced PD rat model by infusion of the specific H4R antagonist JNJ7777120 into the lateral ventricle resulted in blockade of microglial activation. In addition, pharmacological targeting of H4R in rotenone-lesioned rats resulted in reduced apomorphine-induced rotational behaviour, prevention of dopaminergic neuron degeneration and associated decreases in striatal dopamine levels. These changes were accompanied by a reduction of Lewy body-like neuropathology. Our results provide first proof of the efficacy of an H4R antagonist in a commonly used PD rat model, and proposes the H4R as a promising target to clinically tackle microglial activation and thereby the progression of PD. PMID- 30408498 TI - A challenge of predicting seizure frequency in temporal lobe epilepsy using neuroanatomical features. AB - The pathological and clinical characteristics of temporal lobe epilepsy (TLE) tend to be affected by epileptic seizures, specifically represented by seizure lateralization and frequency. Although the lateralization of the epileptogenic zone can be clarified in terms of neuroanatomical damage, there have been conflicting findings on the relationship between seizure frequency and neuroanatomical damage. In this study we sought to examine the relationship in the framework of machine learning-based predictive modeling. We acquired 60 grey matter (GM) anatomical features from structural MRI data and 46 white matter (WM) anatomical features from diffusion-weighted MRI data for 42 TLE patients and 45 healthy controls and applied the random forests method to the neuroanatomical features. We demonstrated that, whereas the neuroanatomical features were promising markers for the discrimination of the TLE patients from the healthy controls, the separation between the TLE patients with low and high seizure frequency on the basis of the neuroanatomical features was challenging. When we applied feature selection techniques for the construction of the predictive models, a greater number of features were selected as being relevant to the distinction of the TLE patients from the healthy controls than to the classification of the TLE patients according to seizure frequency. Furthermore, we adopted model-based clustering analysis and showed that seizure frequency based subgroups were not matched well with neuroanatomy-based subgroups in the TLE patients. We propose that the challenge of predicting seizure frequency using neuroanatomical features could be attributable to considerable inter-individual variability in neuroanatomical damage among seizure frequency-based subgroups. PMID- 30408499 TI - Seneca Valley Virus 3C protease negatively regulates the type I interferon pathway by acting as a viral deubiquitinase. AB - The mechanisms that enable Seneca Valley Virus (SVV) to escape the host innate immune response are not well known. Previous studies demonstrated that SVV 3Cpro suppresses innate immune responses by cleavage of host proteins and degradation of IRF3 and IRF7 protein expression. Here, we showed that SVV 3C protease (3Cpro) has deubiquitinating activity. Overexpressed 3Cpro inhibits the ubiquitination of cellular substrates, acting on both lysine-48- and lysine-63-linked polyubiquitin chains. SVV infection also possessed deubiquitinating activity. The ubiquitin proteasome system was significantly involved in SVV replication. Furthermore, 3Cpro inhibited the ubiquitination of retinoic acid-inducible gene I (RIG-I), TANK-binding kinase 1 (TBK1), and TNF receptor-associated factor 3 (TRAF3), thereby blocking the expression of interferon (IFN)-beta and IFN stimulated gene 54 (ISG54) mRNAs. A detailed analysis revealed that mutations (H48A, C160A, or H48A/C160A) that ablate the Cys and His residues of 3Cpro abrogated its deubiquitinating activity and the ability of 3Cpro to block IFN-beta induction. Together, our results demonstrate a novel mechanism developed by SVV 3Cpro to promote viral replication, and may also provide a novel strategy for improving ubiquitination-based therapy. PMID- 30408500 TI - Novel amplification targets for rapid detection and differentiation of Xylella fastidiosa subspecies fastidiosa and multiplex in plant and insect tissues. AB - Xylella fastidiosa is an insect-transmitted bacterial plant pathogen which causes a variety of economically important diseases worldwide. Molecular identification of X. fastidiosa is used for quarantine screening, surveillance, and research applications; many of which require subspecies level differentiation of pathogen isolates. This study describes quantitative PCR (qPCR) and isothermal amplification assays which can rapidly identify X. fastidiosa isolates belonging to the fastidiosa and multiplex subspecies. The TaqMan qPCR primers described here are used to differentiate X. fastidiosa strains by subspecies in plant and insect tissue in a single reaction, with the inclusion of a general amplification control probe to identify potential false negative samples. This TaqMan qPCR protocol can identify between 103 and 104 cfu/ml concentrations of X. fastidiosa at the subspecies level in a variety of sample types. Additionally, loop-mediated isothermal amplification (LAMP) targets were designed for faster detection of X. fastidiosa subspecies fastidiosa and multiplex, applicable to a field setting. These assays are effective for strain differentiation in artificially and naturally inoculated plant material, and in field collected insect vectors. PMID- 30408501 TI - Function of local circuits in the hippocampal dentate gyrus-CA3 system. AB - Anatomical observations, theoretical work and lesioning experiments have supported the idea that the CA3 in the hippocampus is important for encoding, storage and retrieval of memory while the dentate gyrus (DG) is important for the pattern separation of the incoming inputs from the entorhinal cortex. Study of the presumed function of the dentate gyrus in pattern separation has been hampered by the lack of reliable methods to identify different excitatory cell types in the DG. Recent papers have identified different cell types in the DG, in awake behaving animals, with more reliable methods. These studies have revealed each cell type's spatial representation as well as their involvement in pattern separation. Moreover, chronic electrophysiological recording from sleeping and waking animals also provided more insights into the operation of the DG-CA3 system for memory encoding and retrieval. This article will review the local circuit architectures and physiological properties of the DG-CA3 system and discuss how the local circuit in the DG-CA3 may function, incorporating recent physiological findings in the DG-CA3 system. PMID- 30408502 TI - Virus-like nanoparticles as a novel delivery tool in gene therapy. AB - Viruses are considered as natural nanomaterials as they are in the size range of 20-500 nm with a genetical material either DNA or RNA, which is surrounded by a protein coat capsid. Recently, the field of virus nanotechnology is gaining significant attention from researchers. Attention is given to the utilization of viruses as nanomaterials for medical, biotechnology and energy applications. Removal of genetic material from the viral capsid creates empty capsid for drug incorporation and coating the capsid protein crystals with antibodies, enzymes or aptamers will enhance their targeted drug deliver efficiency. Studies reported that these virus-like nanoparticles have been used in delivering drugs for cancer. It is also used in imaging and sensory applications for various diseases. However, there is reservation among researchers to utilize virus-like nanoparticles in targeted delivery of genes in gene therapy, as there is a possibility of using virus-like nanoparticles for targeted gene delivery. In addition, other biomedical applications that are explored using virus-like nanoparticles and the probable mechanism of delivering genes. PMID- 30408503 TI - The role of 17betaHSDs in breast tissue and breast cancers. AB - The family of seventeen beta hydroxysteroid dehydrogenase enzymes has a long and diverse history in breast and breast cancer research. Given the known dependence of the breast on steroid signalling and intracrine steroid metabolism these enzymes are considered to be essential local fine tuners of overall steroid balance in the tissue. This review will cover the current state of knowledge regarding the expression, clinical effect and biological regulation of enzymes in both cancerous and normal states. In addition we will also cover the current state of knowledge regarding 17betaHSD actions in the often neglected adipose and stromal components of tumours. PMID- 30408504 TI - Reduction of Nosocomial Blood Stream infections and Nosocomial Vancomycin Resistant Enterococcus faecium on an Intensive Care Unit After Introduction of Antiseptic Octenidine-based Bathing. AB - BACKGROUND: Vancomycin-resistant Enterococcus faecium (VRE) is emerging in German intensive care units (ICUs). On a 32 bed surgical ICU at a university hospital increasing numbers of nosocomial cases occurred despite enforcement of hand hygiene and environmental disinfection. AIM: Introduction of universal octenidine based bathing in order to reduce the burden of VRE. METHODS: Between 1/2012 and 3/2014 patients were screened for VRE on admission and twice weekly. Active surveillance for VRE infection and colonisation, and for blood stream infections (BSI) with any pathogen was performed. Intervention in this before-after study comprised of standardised octenidine-based bathing. Distinct subgroups of VRE colonisation or infection were defined and used for statistical analysis of frequency, prevalence and incidence density (ID). FINDINGS: In the pre intervention period (1/2012 to 4/2013) the admission prevalence of VRE was 4/100 patients and the mean ID of nosocomial cases was 7.55/1000 patient days (PD). Pulsed-field gel electrophoresis analysis revealed prevalence of three vanA and two vanB clusters. Post-interventionally (8/2013 to 3/2014), the admission prevalence was 2.41/100 patients and the ID 2.61/1000 PDs (p = 0.001 (pre vs post intervention)). Nosocomial VRE infections were 10 in the pre- and one in the post intervention period. Incidence densities of BSI pre- and post-intervention were 2.98 and 2.06/1000 PDs (p = 0.15), respectively. CONCLUSION: The epidemiology of emerging VRE appeared as a complex mix of admitted cases and transmissions in small clusters, challenging infection control measures. The implementation of universal octenidine-based bathing combined with a standardised washing regime led to a significant reduction of nosocomial VRE. PMID- 30408505 TI - In-house validation of the cobas Liat Influenza A/B & RSV assay for use with gargles, sputa and endotracheal secretions. PMID- 30408506 TI - Individual differences in appeal of energy dense foods predicts lower body mass change during adolescence. AB - Highly energy dense foods are often synonymous with high palatability, excess intake and weight gain. However, food preferences show individual differences. Food preferences are closely related to food intake, which can impact weight change over time. We examined whether the energy density of food images rated as appetizing and unappetizing foods related to baseline BMI and change in BMI over 3-year follow-up (n = 117; 45% Male, Baseline BMI: 21.1 +/- 1.9. Participants completed hedonic visual analog scales (-100 to 100) ratings of 103 food images, and reported dietary intake at baseline, and had their height and weight directly measured over 3-year follow-up. Energy density (ED) of the food depicted in each image was calculated. For each participant, food images (kcal/g) were categorized into appetizing (32 images) and unappetizing foods (32 images) based on each individual's hedonic ratings. We observed significant interaction between energy density and hedonic value driven by an inverse relation between unappetizing food energy density and BMI change (p = 0.008). Specifically, participants who rated higher energy dense foods as unappetizing showed less weight gain (beta= -0.83; p = 0.00052). There was no significant relation between the energy density of appetizing foods and weight change (p = 0.67), suggesting that dislike of highly energy dense foods more strongly associates with lower weight gain than preference for low energy dense foods. Post-hoc analyses revealed that individuals with a higher preference for low energy density foods showed less weight gain over 3-years (beta = - 0.007, p = 0.02). Results support the idea that individual hedonic ratings for foods varying in energy density is a determinant of weight change in adolescents and may represent an important intervention target for obesity prevention programs. PMID- 30408507 TI - Myocardial ischemia suppresses ketone body utilization. PMID- 30408508 TI - Perfluoroalkane sulfonyl fluorides non-covalently bind to human serum albumin at Sudlow's sites. AB - Perfluorooctane sulfonyl fluoride (PFOSF) has been defined as persistent organic pollutant in the Stockholm Convention in 2009. Currently PFOSF and its substitutes (structural analogues in which octyl group is substituted for other aliphatic chains) are still scarcely studied. HSA is a main carrier for drugs in blood, and the influence of exogenous compounds including pollutants on HSA is of particular interest. In this work, the binding sites of HSA to Perfluoroalkane sulfonyl fluoride (PFASFs) were determined by fluorescence technique. The results demonstrated that PFASFs competitively bind to HSA at Sudlow's site I against warfarin and at Sudlow's site II against dansyl-proline and the related association constants were determined. The association constants of PFOSF, perfluorohexane sulfonyl fluoride (PFHSF) and perfluorobutane sulfonyl fluoride (PFBSF) were determined to be 2.59 * 10-3 MUM-1, 4.65 * 10-3 MUM-1 and 2.85 * 10 3 MUM-1 at Sudlow's site I and 8.68 * 10-4 MUM-1, 3.43 * 10-2 MUM-1 and 1.92 * 10-2 MUM-1 at Sudlow's site II, respectively. The results showed that PFASFs can bind tightly to HSA and thus migrate to all parts of the body through vascular system. Non-covalent interaction between HSA and PFASFs was confirmed with tryptic digestion experiment. The mass spectra results indicated that other binding sites of HSA are also involved in the binding of PFHSF and PFBSF. The total binding numbers of PFOSF, PFHSF and PFBSF on HSA are 2, 6 and 3, respectively. PMID- 30408509 TI - Optimization of chemico-physical transformation methods for various bacterial species using diverse chemical compounds and nanomaterials. AB - Bacterial transformation is a fundamental technology to deliver engineered plasmids into bacterial cells, which is essential in industrial protein production, chemical production, etc. Previously, we developed a simple chemico physical transformation method that can be applied to various bacterial species. Here, to accelerate the advance of bacteria biotechnology we optimize our method by combinatorially evaluating chemical compounds (rubidium chloride, lithium acetate, cesium chloride, dimethyl sulfoxide, and magnesium chloride) for increasing membrane permeability and nanomaterials (sepiolite, gold(III) chloride, multiwalled carbon nanotube, and chitosan) for piercing the membranes. The best transformation efficiencies were achieved as follows; 2.84 * 104 CFU/MUg DNA in Lactococcus lactis subsp. lactics (0.1 M CsCl and gold(III) chloride), 3.60 * 104 CFU/MUg DNA in Enterococcus faecalis (1 M Li-acetate and MWCNT), 2.41 * 104 CFU/MUg DNA in Bacillus sp. (0.01 M RbCl and sepiolite), 3.49 * 104 CFU/MUg DNA (0.1 M RbCl and gold(III) chloride) in Ralstonia eutropha (also known as Cupriavidus necator) and 8.78 * 104 CFU/MUg DNA (1 M RbCl and chitosan) in Methylomonas sp. DH-1. The efficiencies are up to 100-fold higher than those without optimization. Accordingly, our fast and simple chemico-physical transformation with chemical-nanomaterial optimization allows for the efficient DNA entry into various bacterial cells with high efficiency. PMID- 30408510 TI - Three decades of nucleic acid aptamer technologies: Lessons learned, progress and opportunities on aptamer development. AB - Aptamers are short single-stranded nucleic acid sequences capable of binding to target molecules in a way similar to antibodies. Due to various advantages such as prolonged shelf life, low batch to batch variation, low/no immunogenicity, freedom to incorporate chemical modification for enhanced stability and targeting capacity, aptamers quickly found their potential in diverse applications ranging from therapy, drug delivery, diagnosis, and functional genomics to bio-sensing. Aptamers are generated by a process called SELEX. However, the current overall success rate of SELEX is far from being satisfactory, and still presents a major obstacle for aptamer-based research and application. The need for an efficient selection strategy consisting of defined procedures to deal with a wide variety of targets is significantly important. In this work, by analyzing key aspects of SELEX including initial library design, target preparation, PCR optimization, and single strand DNA separation, we provide a comprehensive analysis of individual steps to facilitate researchers intending to develop personalized protocols to address many of the obstacles in SELEX. In addition, this review provides suggestions and opinions for future aptamer development procedures to address the concerns on key SELEX steps, and post-SELEX modifications. PMID- 30408511 TI - Physically active life style is associated with increased grey matter brain volume in a medial parieto-frontal network. AB - To examine the association between the amount of sports activity performed during leisure time and gray matter volume (GMV) of the brain we investigated differences in GMV in a large cohort study of community-dwelling older adults. 967 individuals indicated their average weekly sports activity via a questionnaire, and underwent high resolution T1-weighted structural imaging of the brain. We used voxel based morphometry (CAT 12) in a region of interest approach for (1) comparing participants with higher versus lower sports activity (median split) and (2) calculating a linear regression on GMV and sports activity. We carefully corrected for other factors known to have an impact on GMV (sex, age, total brain volume, education, cigarettes and alcohol consumption, body mass index) and excluded pathology (history of psychiatric or neurological disease; visual inspection of brain scans). Those participants who spend more time performing sports activity per week (median split with > 1 h/week) showed higher GMV in the dorsomedial frontal lobe, the superior parietal lobe, and the precuneus/cuneus area. When splitting participants by their median (55.5 years) into two groups we found a stronger protective effect of sports against age related GMV decline for the older part of the cohort. Overall, a more active lifestyle was associated with increased GMV in areas associated with self awareness and working memory. These cohort data support data on the protective role of sports activity for the GMV. PMID- 30408512 TI - Neural bases underlying the association between balanced time perspective and trait anxiety. AB - The aims of present study were to investigate the association between balanced time perspective (BTP) and trait anxiety, and the neural substrates underlying this association using voxel-based morphometry (VBM) and resting-state functional connectivity (RSFC) methods. 140 college students (83 females) ranging in age from 17 to 25 years were assessed on deviation from the balanced time perspective (DBTP) and trait anxiety. Behavioral analyses found BTP could significantly predict trait anxiety after controlling age and gender. Whole-brain VBM analyses found that DBTP was positively correlated with gray matter volume (GMV) in the parahippocampal gyrus (PHG) and precuneus, while trait anxiety positively correlated with GMV in the PHG. Considering the overlapping region in the PHG, we further defined the overlapping region as the seed, and calculated seed-to-voxel based functional connectivity in resting-state. RSFC results showed that DBTP was positively associated with the RSFC between the PHG and medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC), and precuneus, whereas negatively correlated with the RSFC between the PHG and cuneus. Trait anxiety was also positively correlated with the RSFC between the PHG and PCC while negatively correlated with the RSFC between the PHG and cuneus. Mediation analysis further found GMV in the overlapping PHG and PHG-PCC, PHG-cuneus functional connectivity played significantly mediating roles in the relation between DBTP and trait anxiety. In sum, our research suggests the structural features of the PHG and its connectivity with PCC and cuneus may be the neural bases underlying the association between BTP and trait anxiety. PMID- 30408513 TI - Modeling human RNA spliceosome mutations in the mouse: not all mice were created equal. AB - Myelodysplastic syndromes (MDS) and related myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) are clonal stem cell disorders, primarily affecting patients over 65 years of age. Mapping of the MDS and MDS/MPN genome identified recurrent heterozygous mutations in the RNA splicing machinery, with the SF3B1, SRSF2, and U2AF1 genes being frequently mutated. To better understand how spliceosomal mutations contribute to MDS pathogenesis in vivo, numerous groups have sought to establish conditional murine models of SF3B1, SRSF2, and U2AF1 mutations. The high degree of conservation of hematopoiesis between mice and human and the well established phenotyping and genetic modification approaches make murine models an effective tool with which to study how a gene mutation contributes to disease pathogenesis. The murine models of spliceosomal mutations described to date recapitulate human MDS or MDS/MPN to varying extents. Reasons for the differences in phenotypes reported between alleles of the same mutation are varied, but the nature of the genetic modification itself and subsequent analysis methods are important to consider. In this review, we summarize recently reported murine models of SF3B1, SRSF2, and U2AF1 mutations, with a particular focus on the genetically engineered modifications underlying the models and the experimental approaches applied. PMID- 30408514 TI - Evaluation of Fowler-Stephens orchiopexy for high-level intra-abdominal cryptorchidism: A systematic review and meta-analysis. AB - BACKGROUND AND OBJECTIVE: There has been no consensus regarding the best surgical strategy for patients with cryptorchidism involving high-level intra-abdominal testes. This systematic review and meta-analysis compared the outcomes of Fowler Stephens orchiopexy (FSO) conducted as 1-stage or 2-stage, open or laparoscopic. METHODS: The databases PubMed, Cochrane Library, Web of Science Database, Russian Science Citation Index, SciELO Citation Index, China National Knowledge Infrastructure, WanFang Data, and China Biology Medical disc were systematically searched for relevant articles. RESULTS: Sixty studies involving 1991 operated testes were included in the final analysis. The overall success rates for 1- and 2-stage FSOs were 85% and 87%, respectively; overall atrophy rates for both were 10%. The success rates of 1-stage FSOs, open and laparoscopic, were 83% and 87%; with atrophy rates of 12% and 8%. The corresponding success rates of 2-stage FSOs were 81% and 89%; with atrophy rates of 17% and 8%. The odds ratios indicated that 2-stage FSO was significantly superior to 1-stage, and laparoscopic superior to open. Evaluating laparoscopic FSO over time, the success rates prior to year 2000, 2000 through 2010, and after 2010 were 85%, 89%, and 88%, and atrophy rates were 15%, 9%, and 6%, with no heterogeneity in the reports, and the funnel plot showed no publication bias. CONCLUSION: Each surgical technique for correcting high-level intra-abdominal testes (IATs) had an acceptable success rate, from 81% to 89%. However, in terms of highest success rate and lowest atrophy rate, 2 stage laparoscopic FSO is the first choice for treating high intra-abdominal cryptorchidism. PMID- 30408515 TI - Nitric oxide mediated redox regulation of protein homeostasis. AB - Nitric oxide is a versatile diffusible signaling molecule, whose biosynthesis by three NO synthases (NOS) is tightly regulated at transcriptional and posttranslational levels, availability of co-factors, and calcium binding. Above normal levels of NO have beneficial protective effects for example in the cardiovascular system, but also contribute to the pathophysiology in the context of inflammatory diseases, and to aging and neurodegeneration in the nervous system. The effect specificity relies on the functional and spatial specificity of the NOS isoenzymes, and on the duality of two major signaling mechanisms (i) activation of soluble guanylycylase (sGC)-dependent cGMP production and (ii) direct S-nitrosylation of redox sensitive cysteines of susceptible proteins. The present review summarizes the functional implications of S-nitrosylation in the context of proteostasis, and focuses on two NO target proteins, heat shock cognate of 70 kDa (Hsc70/HSPA8) and the ubiquitin 2 ligase (UBE2D), because both are modified on functionally critical cysteines and are key regulators of chaperone mediated and assisted autophagy and proteasomal protein degradation. SNO modifications of these candidates are associated with protein accumulations and adoption of a senescent phenotype of neuronal cells suggesting that S nitrosylations of protein homeostatic machineries contribute to aging phenomena. PMID- 30408516 TI - Does acupuncture help patients with spasticity? A narrative review. AB - Spasticity is a motor disorder encountered after upper motor neuron lesions. It adversely affects quality of life in most patients and causes long-term burden of care and has significant financial implications. The effect of conventional therapies for spasticity including physical therapy, surgery, and pharmacotherapy are not always satisfying because of the short-term effects or side effects in some patients. Acupuncture is a part of traditional medicine originating from China. It has been used to resolve functional recovery problems after central nervous system injury for many years in Asian countries and is increasingly popular in western countries. Some researches suggest that acupuncture has therapeutic potential to help improve limb movement function and decrease the severity of spasticity. This review synthesizes studies involving stroke, brain injury, spinal cord injury, cerebral palsy, and multiple sclerosis to give an overall picture of the effect and potential mechanisms of acupuncture on spasticity occurring after upper motor neuron lesions. Moderate-quality evidence suggests that electroacupuncture combined with conventional routine care (pharmacological/rehabilitation) could reduce spasticity and improve motor function and activities in daily living after stroke. However, there is not enough evidence to conclude that acupuncture (including electroacupuncture) could reduce spasticity with other central nervous system diseases. PMID- 30408517 TI - Spasticity: To treat or not to treat? PMID- 30408518 TI - Comparative evaluation of dimeric and monomeric forms of ADAPT scaffold protein for targeting of HER2-expressing tumours. AB - ADAPTs are small engineered non-immunoglobulin scaffold proteins, which have demonstrated very promising features as vectors for radionuclide tumour targeting. Radionuclide imaging of human epidermal growth factor 2 (HER2) expression in vivo might be used for stratification of patients for HER2 targeting therapies. ADAPT6, which specifically binds to HER2, has earlier been shown to have very promising features for in vivo targeting of HER2 expressing tumours. In this study we tested the hypothesis that dimerization of ADAPT6 would increase the apparent affinity to HER2 and accordingly improve tumour targeting. To find an optimal molecular design of dimers, a series of ADAPT dimers with different linkers, -SSSG- (DiADAPT6L1), -(SSSG)2- (DiADAPT6L2), and -(SSSG)3- (DiADAPT6L3) was evaluated. Dimers in combination with optimal linker lengths demonstrated increased apparent affinity to HER2. The best variants, DiADAPT6L2 and DiADAPT6L3 were site-specifically labelled with 111In and 125I, and compared with a monomeric ADAPT6 in mice bearing HER2-expressing tumours. Despite higher affinity, both dimers had lower tumour uptake and lower tumour-to-organ ratios compared to the monomer. We conclude that improved affinity of a dimeric form of ADAPT does not compensate the disadvantage of increased size. Therefore, increase of affinity should be obtained by affinity maturation and not by dimerization. PMID- 30408519 TI - Robust mucosal and systemic responses against HTLV-1 by delivery of multi-epitope vaccine in PLGA nanoparticles. AB - In this investigation, the immunogenicity of HTLV-1 fusion epitope-loaded PLGA nanoparticles (NPs) was assessed in the absence or presence of co-encapsulated CpG ODN adjuvant, in a mice model. For this purpose, the multi-epitope chimera including Tax, env, and gag immunodominant HTLV-1 epitopes was encapsulated in biodegradable PLGA NPs with or without CpG adjuvant. PLGA nanospheres produced by a double emulsion method had a size of <200 nm, and encapsulation efficiency of chimera antigen was 85%. The release profile of radiolabeled chimera indicated that only 17.4% and 20.1% of chimera were released from PLGA NPs without or with co-encapsulated CPG ODN during one month, respectively. The PLGA formulations significantly elevated titers of IgG1, IgG2a, and sIgA antibodies, as well as IL 10, and IFN-gamma cytokines and also reduced the amount of TGF-beta1 production relative to the other vaccines. Additionally, co-delivery of chimera and CpG ODN in PLGA NPs significantly promoted cellular and mucosal responses compared to the incorporation of CpG and chimera antigen. In summary, these results revealed that the sustained release of chimera from PLGA as an efficient polymeric system elicited potent cell-mediated and mucosal immunity without inflammatory responses against HTLV-1. Therefore, the proper design of vaccine formulation and immunization strategy are crucial factors to construct an efficient vaccine. PMID- 30408520 TI - Integrating data on bone modeling and morphological ontogenetic changes of the maxilla in modern humans. AB - The aim of this work is to assess the association between the patterns of bone modeling and the changes in shape and size of the maxilla along ontogeny in modern humans. The sample analyzed includes an ontogenetic series of 30 individuals from an archeological site from Pampa Grande, northwest of Argentina. The areas of bone resorption and formation were described by histological analysis of bone surfaces and then quantified using spatial statistics. Morphological changes were analyzed by geometric morphometric methods using landmarks and semilandmarks digitized on 3D surfaces obtained from CT-scans. The regression of bone modeling maps on the centroid size shows no significant association between both variables neither in subadult nor adult individuals. On the contrary, the results of the partial least squares analysis shows a strong association between the shape changes in the maxilla with changes in the pattern of bone modeling in both groups of age, subadults and adults. Overall, this study contributes to the understanding of the mechanisms and processes that model maxillary morphology during growth. PMID- 30408521 TI - A proposal for a new classification of the fibular (lateral) collateral ligament based on morphological variations. AB - BACKGROUND: The fibular collateral ligament (FCL) is subject to varus forces at all knee flexion angles and is also resistant to external rotation near extension. It originates on the lateral epicondyle of the femur and inserts on the lateral surface of the head of the fibula. However, its anatomical characteristics are inconsistent. Recent publications have focused on morphological variations concerning mainly femoral and fibular attachments, as well as morphometric measurements. Less attention has been paid to the morphology of the FCL and its relationship to the antero-lateral ligament (ALL). QUESTION/PURPOSES: The aim of this paper is therefore to introduce the first complete classification of the FCL that includes all important aspects of morphological variability. METHODS: Classical anatomical dissection was performed on 111 lower limbs (25 isolated and 86 paired) fixed in 10% formalin solution. The lateral compartment of the knee was investigated in detail. RESULTS: The fibular collateral ligament was present in all specimens. The FCL originated most commonly (72.1% of cases) from the lateral femoral epicondyle, and the inserted on the lateral surface of the head of the fibula (Type I). In addition, bifurcated (Type IIa - 12.6%) and trifurcated (Type IIb - 0.9%) ligaments were also found with two and three distal bands, respectively. A double FCL was also found (Type III - 6.3%), as was fusion of the FCL and ALL (Type IV - 8.1%). CONCLUSION: The FCL is characterized by high morphological variability. Knowledge of these variants is essential for surgeries performed in this region concerning the FCL and the ALL. CLINICAL RELEVANCE: Distinguishing FCL from the FCL-ALL Complex is necessary when planning surgical procedures. PMID- 30408522 TI - A dynamic in vitro permeation study on solid mono- and diacyl-phospholipid dispersions of celecoxib. AB - The current study documents enhanced apparent solubility of the BCS class II drug celecoxib (CXB) when formulated as solid phospholipid dispersion (SPD) with either mono- or diacyl-phospholipids by freeze drying from hydro-alcoholic solvent. The enhanced solubility upon dispersion in buffer or fasted state simulated intestinal fluid (FaSSIF) is interpreted to be due to two effects: (1) amorphization of CXB, inducing supersaturation, which is also observed when CXB is freeze dried in the absence of phospholipids and (2) association of CXB with spontaneously forming colloidal structures, such as vesicles and/or micelles, promoting solubilization. The latter effect depended on the CXB-to-phospholipid ratio, where monoacyl-phospholipid was a more efficient solubilizer than diacyl phospholipid. In the case of diacyl-phospholipid, solubilization also depended strongly on the dispersion medium, where FaSSIF induced a more pronounced solubilization effect than buffer. In contrast, a significantly enhanced in-vitro permeability of CXB across a biomimetic barrier (Permeapad(r)) was found only with low lipid contents up to a CXB to phospholipid mass-ratio of 1:10 or in the absence of phospholipid; above this critical ratio, permeability was not enhanced, i.e. comparable to that observed with a suspension of non-processed (crystalline) drug. This non-linear dissolution-/permeation-behavior was observed independently of (1) the type of phospholipid (monoacyl- or diacyl-) employed and (2) the dispersion medium (buffer or FaSSIF), despite the fact that different patterns of co-existing colloidal states were observed from mono-/diacyl phospholipid formulations in buffer/FaSSIF (small bile salt micelles, intermediate size mixed micelles and large vesicular structures), assessed by asymmetric flow field-flow fractionation/multi angle laser light scattering. A uniform mechanistic hypothesis is presented to describe the impact of phospholipids on CXB permeation behavior: Obviously, the critical drug-to phospholipid ratio represents a compromise between optimal stabilization of the amorphous state-induced supersaturation and reduced thermodynamic activity of CXB due to association with colloidal states, where the type of colloidal state (vesicle or micelle) appears to be of minor importance. PMID- 30408523 TI - iPLA2beta and its role in male fertility, neurological disorders, metabolic disorders, and inflammation. AB - The Ca2+-independent phospholipases, designated as group VI iPLA2s, also referred to as PNPLAs due to their shared homology with patatin, include the beta, gamma, delta, epsilon, zeta, and eta forms of the enzyme. The iPLA2s are ubiquitously expressed, share a consensus GXSXG catalytic motif, and exhibit organelle/cell specific localization. Among the iPLA2s, iPLA2beta has received wide attention as it is recognized to be involved in membrane remodeling, cell proliferation, cell death, and signal transduction. Ongoing studies implicate participation of iPLA2beta in a variety of disease processes including cancer, cardiovascular abnormalities, glaucoma, and peridonditis. This review will focus on iPLA2beta and its links to male fertility, neurological disorders, metabolic disorders, and inflammation. PMID- 30408524 TI - The Grand Magal of Touba in the time of a dengue outbreak in Senegal. PMID- 30408525 TI - Chemogenetic inactivation of the dorsal hippocampus and medial prefrontal cortex, individually and concurrently, impairs object recognition and spatial memory consolidation in female mice. AB - The dorsal hippocampus (DH) and medial prefrontal cortex (mPFC) are brain regions essential for processing and storing episodic memory. In rodents, the DH has a well-established role in supporting the consolidation of episodic-like memory in tasks such as object recognition and object placement. However, the role of the mPFC in the consolidation of episodic-like memory tasks remains controversial. Therefore, the present study examined involvement of the DH and mPFC, alone and in combination, in object and spatial recognition memory consolidation in ovariectomized female mice. To this end, we utilized two types of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to inactivate the DH alone, the mPFC alone, or both brain regions concurrently immediately after object training to assess the role of each region in the consolidation of object recognition and spatial memories. Our results using single and multiplexed DREADDS suggest that excitatory activity in the DH and mPFC, alone or in combination, is required for the successful consolidation of object recognition and spatial memories. Together, these studies provide critical insight into how the DH and mPFC work in concert to facilitate memory consolidation in female mice. PMID- 30408526 TI - Interaction of nectin-2alpha with the auxiliary protein of the voltage-gated A type K+ channel Kv4.2 dipeptidyl aminopeptidase-like protein at the boundary between the adjacent somata of clustered cholinergic neurons in the medial habenula. AB - The medial habenula (MHb) receives septal inputs and sends efferents to the interpeduncular nucleus and is implicated in stress, depression, memory, and nicotine withdrawal syndrome. We previously showed by immunofluorescence microscopy that the cell adhesion molecule nectin-2alpha is expressed in the cholinergic neurons in the developing and adult mouse MHbs and localized at the boundary between the adjacent somata of clustered cholinergic neurons where the voltage-gated A-type K+ channel Kv4.2 is localized. We further showed by immunoelectron microscopy that Kv4.2 is localized at the membrane specializations (MSs) whereas nectin-2alpha is localized mostly outside of these MSs. In addition, we showed that genetic ablation of nectin-2 delays the localization of Kv4.2 at the MSs in the developing MHb. We investigated here how nectin-2alpha regulates this localization of Kv4.2 at the MSs. In vitro biochemical analysis revealed that nectin-2alpha interacted with the auxiliary protein of Kv4.2 dipeptidyl aminopeptidase-like protein 6 (DPP6), but not with Kv4.2 or another auxiliary protein Kv channel-interacting protein 1 (KChIP1). Immunofluorescence microscopy analysis showed that DPP6 was colocalized with nectin-2alpha at the boundary between the adjacent somata of the clustered cholinergic neurons in the developing and adult MHbs. Immunoelectron microscopy analysis on this boundary revealed that DPP6 was localized both at the inside and the outside of the MSs. Genetic ablation of nectin-2 did not affect the localization of DPP6 at the boundary between the adjacent somata of the clustered cholinergic neurons in the developing and adult MHbs. These results indicate that nectin-2alpha interacts with DPP6 but regulates the localization of Kv4.2 at the MSs in a DPP6 independent manner. PMID- 30408527 TI - Growing synergy of nanodiamonds in neurodegenerative interventions. AB - Neurodegenerative diseases are complex in both their nature and prognosis. The difficulties associated with penetrating the blood-brain barrier (BBB), achieving site-specific targeting to the brain, and identifying the genetic etiologies responsible make treating neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and stroke, challenging. The aim to treat disease at the molecular level has galvanized nanotechnology research. Among the forms of nanoparticles (NPs) explored thus far, nanodiamonds (NDs) have shown great potential. Their unique physicochemical properties, such as a nanometer size range, stable and inert core, tunable surface, intrinsic fluorescence without photobleaching, negligible toxicity, and the ability to form complexes with drugs, highlight their theranostic potential. The ability of NDs to penetrate the BBB and target specific affected areas of the brain could take research one step closer to understanding the underlying disease etiology and unlocking more efficient methods of delivering neuromedicine to specific areas of the brain. Here, we explore interactions between NDs and the neuronal circuitry with a focus on the therapeutic potential of NDs as treatments for neurodegenerative diseases. PMID- 30408528 TI - Interplay between hereditary and environmental factors to establish an in vitro disease model of keratoconus. AB - Keratoconus (KC) is a bilateral corneal dystrophy and a multifactorial, multigenic disorder with an etiology involving a strong environmental component and complex inheritance patterns. The underlying pathophysiology of KC is poorly understood because of potential crosstalk between genetic-epigenetic variants possibly triggered by the environmental factors. Here, we decode the etiopathological basis of KC using genomic, transcriptomic, proteomic and metabolic approaches. The lack of relevant models that accurately imitate this condition has been particularly limiting in terms of the effective management of KC. Tissue-engineered in vitro models of KC could address this need and generate valuable insights into its etiopathology for the establishment of disease models to accelerate drug discovery. PMID- 30408529 TI - Therapeutic potential of endogenous stem cells and cellular factors for scar-free skin regeneration. AB - Injured human skin fails to regenerate, resulting in scar formation. Annually, 100 million new skin-scarring incidents, occurring as a result of surgery, disease, burns, or sports-related damage, remain untreated. Here, we review knowledge gained from scar-free experimental animal models that have natural regenerative mechanisms for scar-free skin recovery. We also focus on the unique role of endogenous stem cells and other cellular and molecular factors, including the balance of the transforming growth factor-beta (TGF-beta) pathway in the context of human skin regeneration. This new strategy opens a new window in drug development for scar-free skin regeneration treatments in both the clinical and cosmetic practice settings. PMID- 30408530 TI - Development and in vitro evaluation of a self-emulsifying drug delivery system (SEDDS) for oral vancomycin administration. AB - The aim of this study was to develop a self-emulsifying drug delivery system (SEDDS) containing the glycopeptide antibiotic vancomycin (VAN) with improved intestinal mucosa permeating properties in order to increase oral drug absorption. VAN was effectively incorporated into SEDDS increasing the lipophilicity of the drug via hydrophobic ion pairing (HIP) with cetyltrimethylammonium bromid (CTAB). Newly developed SEDDS formulations containing VAN/CTAB complex were characterized with respect to droplet size, polydispersity index and zeta potential. Furthermore, permeating properties were investigated in porcine intestinal mucus using Transwell setup and on freshly excised porcine intestinal mucosa utilizing Ussing-type chamber. In addition, minimum inhibitory concentration (MIC) of VAN/CTAB-SEDDS against Staphylococcus aureus was evaluated. The developed formulations F1 (25% Capmul 808G EP/NF, 37.5% Cremophor RH 40, 37.5%), F2 (26.5% Capmul 808G EP/NF, 33.2% Cremophor RH 40, 13.8% Transcutol, 26.5% DMSO) and F3 (28.8% Captex 8000, 35% Cremophor EL, 20% Transcutol, 16.2% DMSO) with a mean droplet size of 14 nm, 15 nm and 153 nm, respectively, exhibited improved ability to permeate porcine intestinal mucosal barrier. F1-VAN/CTAB showed 219-fold, F2-VAN/CTAB 46-fold and F3-VAN/CTAB 63-fold higher permeation of VAN through the mucus layer after 4 h in comparison to free VAN. Moreover, all formulations demonstrated a 4-8-fold improvement in permeation of intestinal mucosa compared to free VAN solution. Additionally, F2-VAN/CTAB with a MIC of 0.313 mg/L showed higher effectivity against S. aureus (ATCC(r) 29213) compared to free VAN. According to these results, HIP combined with SEDDS should be taken into consideration as promising tool for oral antibiotic delivery. PMID- 30408531 TI - Modified gelatin nanoparticles for gene delivery. AB - Gelatin nanoparticles (GNPs) are one of the most extensively used natural polymers for gene therapy. With advantages of being biodegradable, biocompatible, low cost and easily modified, gelatin holds great promise as a non-viral system for gene delivery. This review examines various methods of preparation of modified gelatin nanoparticles and considers how these modifications apply to gene delivery. The article discusses cationic gelatin, PEGylated gelatin, thiolated gelatin, alendronate gelatin, and EGFR gelatin nanoparticles. This article also considers several advantages of these modifications and their contribution to the improvement in the efficiency of these systems, resulting in superior transfection and enhanced gene delivery in general. PMID- 30408532 TI - Nanoparticle eluting-angioplasty balloons to treat cardiovascular diseases. AB - Nanoparticles (NPs) can be used to locally deliver anti-restenosis drugs when they are infused directly to the injured arteries after intervention procedures such as angioplasty. However, the efficacy of transferring NPs via infusion to the arterial wall is limited, at least partially, due to poor NP retention on the inner artery wall. To improve NP retention, angioplasty balloons coated with drug loaded NPs were fabricated via either layer-by-layer (LbL) electrostatic coating or acrylic-based hydrogel (AAH) coating techniques. Three types of NPs, namely poly (lactide-co-glycolide) (PLGA), biodegradable photo-luminescent PLGA and urethane doped polyester were studied. The transfer efficacy of NPs from various coatings to the arterial wall were further evaluated to find the optimal coating conditions. The ex vivo NP transfer studies showed significantly more NPs being transferred to the rat arterial wall after the angioplasty procedure by the AAH coating (95% transfer efficiency) compared to that of the LbL technique (60%) and dip coating (20%) under flow conditions (10 dyn/cm2). Our results suggest that the AAH coating of drug-loaded NPs on the angioplasty balloon could potentially provide superior retention of drug-loaded NPs onto the arterial wall for a better local delivery of drug-loaded NPs to effectively treat arterial diseases. PMID- 30408533 TI - Effect of apigenin isolated from Aster yomena against Candida albicans: apigenin triggered apoptotic pathway regulated by mitochondrial calcium signaling. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Aster yomena, a perennial herb that grows mainly in South Korea, has been employed in the traditional temple food for antibiotic efficacy. Recently, it was reported that apigenin isolated from A. yomena has a physical antifungal mechanism targeting membrane against Candida albicans. AIM OF THE STUDY: Our study aimed to investigate the biochemical responses underlying the antifungal activity of apigenin isolated from A. yomena due to lack studies reporting the investigation of intracellular responses of apigenin in C. albicans. MATERIALS AND METHODS: Apigenin was isolated from the aerial parts of A. yomena. To evaluate apigenin-induced inhibitory effects and membrane damages, the measurement of the cell viability assay and the flux of cytosolic components were performed with at various concentrations. Intracellular external potassium and calcium levels were assayed by an ion-selective electrode meter, Fura2-AM and Rhod2-AM, respectively. Mitochondrial dysfunctions were analyzed by using JC-1, Mitotracker Green FM, and MitoSOX Red dye. H2DCFDA, glutathione, and MDA assay were used to detect oxidative damage. Also, flow cytometry was carried out to detect apoptotic hallmarks using Annexin V-PI, TUNEL, and FITC-VAD-FMK staining. Tetraethylammoniumchloride (TEA), Ruthenium red (RR), and N-acetylcysteine (NAC) were used as a potassium channel blocker, mitochondrial calcium uptake inhibitor, and reactive oxygen species (ROS) scavenger, respectively. RESULTS: We confirmed that there was no decrease of cell survival percentages in crude extracts of A. yomena treatment, however, only isolated apigenin has the antifungal effect in C. albicans. Apigenin triggered a dose-dependent mitochondrial calcium uptake followed by mitochondrial dysfunction, loss of the membrane potential and an increase in the mitochondrial mass and ROS. Apigenin also induced intracellular redox imbalance as indicated by the ROS accumulation, glutathione oxidation, and lipid peroxidation. Interestingly, NAC failed the restore the mitochondrial calcium levels and thus alleviate the mitochondrial damages, however, RR reduced the apigenin-induced redox imbalance. Furthermore, apigenin induced apoptosis activation marked by the phosphatidylserine exposure, DNA fragmentation, and caspase activation. The pro-apoptotic effect of apigenin was counteracted by RR and NAC pretreatment. In particular, RR significantly reduced the pro-apoptotic responses. CONCLUSIONS: Apigenin isolated from A. yomena induced mitochondrial mediated apoptotic pathway, and mitochondrial calcium signaling is main factor in its pathway in C. albicans. PMID- 30408535 TI - Anticancer activity of saponin isolated from Albizia lebbeck using various in vitro models. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Albizia lebbeck (L.) Benth. (Family: Mimosaceae) is commonly known as Sirisha in Sanskrit. The leaves and pods of A. lebbeck were claimed to be used against cancer in traditional medicine. Previous studies using bark, leaves, seeds and pods of A. lebbeck showed cytotoxic activity against hepatic, colon, larynx, cervical and breast cancer cell lines. AIM OF THE STUDY: To evaluate the anticancer activity of saponin rich fraction of Albizia lebbeck by using various in vitro models. MATERIALS AND METHODS: Albiziasaponins (A-E) are oleanene triterpene presents in Albizia lebbeck were used for in silico studies. In silico testing of albiziasaponins for structure based pharmacological activity prediction using PASS Online software and docking with Autodock tool and Autodock Vina revels it's anticancer and apoptogenic potential. Antiproliferative activity of saponin rich fraction of A. lebbeck was performed using MCF-7 human breast cancer cells by MTT assay methods. Anti-angiogenic property of saponin rich fraction of A. lebbeck was evaluated in in vitro shell less chick embryo cultures with different concentrations (0.1ug/ml, 0.5ug/ml, and 1ug/ml) by using ImageJ software. In vitro cultured lymphocytes chromosomal aberration assay was performed to determine the physical integrity of chromosomes in cells and effect of saponin rich fraction of A. lebbeck on cell cycle. Apoptogenic potential was evaluated using Caspases-3 and Caspase-8 ELISA assay in MCF-7 cells. RESULTS: Result of MTT assay showed IC50 of saponin rich fraction of A. lebbeck at 1MUg/mL in MCF-7 cells. Treatment with saponin rich fraction of A. lebbeck significantly (p<0.05) reduced angiogenic parameters. Significant chromosomal aberrations (hypodiploid, hyperdiploid, ring, premature separation, Dicentric fragments, Acentric fragment, chromatid break, and chromosomal gap) were observed in saponin rich fraction of A. lebbeck treated groups. Treatment with saponin rich fraction of A. lebbeck increased levels of Caspases-3 (optical density of 0.24 at 450nm) and Caspase-8 (optical density of 0.31 at 450nm) as compared to staurosporine (optical density of 2.47 and 2.65 for caspases-3 and -8 respectively at 450nm). CONCLUSION: In our study, saponin rich fraction of A. lebbeck showed antiproliferative, antiangiogenic and apoptogenic potential using various in vitro models. It also found to increase chromosomal aberration and thereby may affect cell cycle. PMID- 30408534 TI - The ethnopharmacology, phytochemistry and pharmacology of Angelica biserrata - A review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Angelica biserrata (R.H. Shan & C.Q. Yuan) C.Q. Yuan & R.H. Shan (Angelica pubescens Maxim. f. biserrata Shan et Yuan) (A.biserrata) is a widely used traditional Chinese medicine; its roots known as 'Duhuo' in China. The herb is used for expelling wind, eliminating dampness, and terminating pain. Moreover, it is used for treating the onset of anemofrigid-damp arthralgia, pain of the waist and knee and headache caused by latent wind pathogenic factor or damp-cold pathogenic factor. A.biserrata is slightly warm, bitter and pungent in taste, and it is well distributed in regions such as Sichuan and Hubei Provinces. AIM OF THE STUDY: This review aims to provide critical summary of the current evidence on A.biserrata. In particular, the progress of studies in the fields of botany, ethnopharmacology, phytochemistry, pharmacology and toxicity are discussed. Possible directions for future research are also briefly proposed. MATERIALS AND METHODS: Information on A.biserrata was collected from the internet database PubMed, Elsevier, China Knowledge Resource Integrated databases, ResearchGate, Web of Science, Wiley Online Library and Europe PMC using a combination of various relevant keywords. Other published books providing an overview of extant literature studies were considered for reference if they are related to the taxonomy, traditional knowledge, phytochemistry, pharmacology and toxicity of the plant. RESULTS: A substantial proportion of the isolated and identified compounds of the herb were reported to be coumarins and volatile oils. Biological effects, such as neuroprotective, anti tumor, anti-arthritis, anti-inflammatory, and sedative, were also validated in In vitro and in vivo studies. Therapeutic effects are attributed to the bioactivities of the naturally occurring compounds in this herb. CONCLUSIONS: A.biserrata has been proven as a valuable medicinal sources from traditional herb. Some conventional uses has been evaluated by pharmacological investigation. Although the crude extracts of A.biserrata has been emerged to possess more pharmacological activities, it is now time to isolate and identify more active chemical constituents by Bioactivity-Guided and elucidate their structure activity relationship. More designed investigations are need to focus on understanding the multi-target network pharmacology, clarity the molecular mechanism of action and efficacy as well as identifying the effective doses of A.biserrata. In addition, A.biserrata is not fully assessed regarding its safety. Further studies are essential to investigate its toxicity on human. It's useful to provide identify its underlying therapeutic remedy and economic value of developing new medicine in the future. PMID- 30408537 TI - Evaluation of Rubus grandifolius L. (wild blackberries) activities targeting management of type-2 diabetes and obesity using in vitro models. AB - Rubus grandifolius Lowe (wild blackberries) is an endemic species from Madeira Archipelago (Portugal) used in folk medicine for alleviating diabetic complications. In this work, R. grandifolius methanolic extracts were analysed for in vitro inhibitory effect on digestive enzymes linked to type-2 diabetes, as well as aldose reductase activity and protein glycation. The phenolic composition, antioxidant and cytotoxic activities were also determined. Methanolic extracts exhibited strong inhibition of glucosidases (alpha- and beta), but were less potent for alpha-amylase and pancreatic lipase when compared to current pharmaceutical drugs. The total phenolic content determined by HPLC DAD varied between 92.96 - 97.47 and 118.01-137.41 mg g-1 of dry extract for berries and leaves, respectively. Fifty polyphenols were quantified, anthocyanins and ellagitannins being the main compounds. Cyanidin-3-glucoside was identified as one of the main hypoglycaemic and hypolipidemic agents in all extracts. R. grandifolius also prevented glycation of bovine-serum albumin (BSA) and showed strong radical scavenging activity against tested free radicals. At low concentration, the extracts were not cytotoxic against Caco-2 cells. Based on the results of this study, wild blackberry extracts demonstrated a potential beneficial effect on the control/management of type-2 diabetes mellitus, validating their use in folk medicine. PMID- 30408536 TI - RIFM fragrance ingredient safety assessment, pentyl benzoate, CAS Registry Number 2049-96-9. PMID- 30408538 TI - RIFM fragrance ingredient safety assessment, 1-oxaspiro[4.5]decan-2-one, 8-ethyl , trans-, CAS Registry Number 91069-40-8. PMID- 30408539 TI - The functional role of Bax/Bak in palmitate-induced lipoapoptosis. AB - Induction of programmed cell death, mainly apoptosis (lipoapoptosis) is a major cellular consequence of the lipotoxicity, a harmful effect resulting from the overload of lipids. Both Endoplasmic reticulum (ER) stress and autophagy have been suggested to play important role in the regulation of lipoapoptosis. However, the exact mechanisms underlying lipoapoptosis remain unclear. In the present study, we aimed to investigate the functional role of Bax/Bak in lipoapoptosis using mouse embryonic fibroblasts (MEFs) cell culture model. Results showed that palmitate induced caspase-dependent apoptosis in wild-type Bax/Bak MEF cells, whereas a caspase-independent cell death was induced by palmitate in Bax/Bak knockout MEF cells, suggesting requirement of Bax/Bak in palmitate-induced caspase activation. More importantly, we found that the status of Bax/Bak is a determinant that governs the decision between the pro-survival or pro-death function of autophagy in response to palmitate exposure, and Bax/Bak is required for palmitate-induced activation of endoplasmic reticulum (ER) stress and subsequently ER stress-mediated apoptosis. The findings of the present study provided novel insights into understanding the mechanisms involved in the regulation of palmitate-induced lipoapoptosis. PMID- 30408540 TI - 3-NOP: Mutagenicity and genotoxicity assessment. AB - 3-NOP (3-nitroxy-propanol) is a new development compound which reduces methane emission from ruminating animals. For registration purposes with emphasis on EU and North America data requirements, mutagenic and genotoxic potential was assessed following OECD protocols and respective guidance documents. 3-NOP mutagenicity and genotoxicity testing raised no flags with regard to these endpoints. In silico assessment of 3-NOP and its major plasma metabolite NOPA (3 nitroxy-propionic acid) were predicted negative with regard to the bacterial reverse mutation (Ames) test. Ames test, mouse lymphoma assay, in vitro micronucleus test, and the oral in vivo micronucleus test using rat bone marrow were all negative. Exposure of the rat bone marrow was verified by the presence of 3-NOP and its metabolites NOPA and HPA (3-hydroxy-propionic acid) a naturally occurring substance in mammals) in plasma following oral dosing. It is therefore concluded that 3-NOP and its metabolites pose no mutagenic and genotoxic potential. PMID- 30408541 TI - RIFM fragrance ingredient safety assessment, 2(10)-pinen-3-ol, CAS Registry Number 5947-36-4. PMID- 30408542 TI - RIFM fragrance ingredient safety assessment, 4-methylnonanoic acid, CAS Registry Number 45019-28-1. PMID- 30408543 TI - An overview of epigenetic agents and natural nutrition products targeting DNA methyltransferase, histone deacetylases and microRNAs. AB - Several humans' diseases such as; cancer, heart disease, diabetes retain an etiology of epigenetic, and a new therapeutic option termed as "epigenetic therapy" can offer a potential way to treat these diseases. A numbers of epigenetic agents such as; inhibitors of DNA methyltransferase (DNMT) and histone deacetylases (HDACs) have grew an intensive investigation, and many of these agents are currently being tested in a clinical trial, while some of them have been approved for the use by the authorities. Since miRNAs can act as tumor suppressors or oncogenes, the miRNA mimics and molecules targeted at miRNAs (antimiRs) have been designed to treat some of the diseases. Much naturally occurring nutrition were discovered to alter the epigenetic states of cells. The nutrition, including polyphenol, flavonoid compounds, and cruciferous vegetables possess multiple beneficial effects, and some can simultaneously change the DNA methylation, histone modifications and expression of microRNA (miRNA). This review mainly summarizes the information of epigenetic agents of DNMTs and HDACs inhibitors, miRNA mimics and antimiRs, as well as the natural nutrition. In addition, some future perspectives related to the epigenetic therapy are also included. PMID- 30408544 TI - Mining of Ebola virus entry inhibitors identifies approved drugs as two-pore channel pore blockers. AB - Two-pore channels (TPCs) are Ca2+-permeable ion channels localised to the endo lysosomal system where they regulate trafficking of various cargoes including viruses. As a result, TPCs are emerging as important drug targets. However, their pharmacology is ill-defined. There are no approved drugs to target them. And their mechanism of ligand activation is largely unknown. Here, we identify a number of FDA-approved drugs as TPC pore blockers. Using a model of the pore of human TPC2 based on recent structures of mammalian TPCs, we virtually screened a database of ~1500 approved drugs. Because TPCs have recently emerged as novel host factors for Ebola virus entry, we reasoned that Ebola virus entry inhibitors may exert their effects through inhibition of TPCs. Cross-referencing hits from the TPC virtual screen with two recent high throughput anti-Ebola screens yielded approved drugs targeting dopamine and estrogen receptors as common hits. These compounds inhibited endogenous NAADP-evoked Ca2+ release from sea urchin egg homogenates, NAADP-mediated channel activity of TPC2 re-routed to the plasma membrane, and PI(3,5)P2-mediated channel activity of TPC2 expressed in enlarged lysosomes. Mechanistically, single channel analyses showed that the drugs reduced mean open time consistent with a direct action on the pore. Functionally, drug potency in blocking TPC2 activity correlated with inhibition of Ebola virus-like particle entry. Our results expand TPC pharmacology through the identification of approved drugs as novel blockers, support a role for TPCs in Ebola virus entry, and provide insight into the mechanisms underlying channel regulation. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech. PMID- 30408545 TI - The deubiquitination of the PTS1-import receptor Pex5p is required for peroxisomal matrix protein import. AB - Peroxisomal biogenesis depends on the correct import of matrix proteins into the lumen of the organelle. Most peroxisomal matrix proteins harbor the peroxisomal targeting-type 1 (PTS1), which is recognized by the soluble PTS1-receptor Pex5p in the cytosol. Pex5p ferries the PTS1-proteins to the peroxisomal membrane and releases them into the lumen. Finally, the PTS1-receptor is monoubiquitinated on the conserved cysteine 6 in Saccharomyces cerevisiae. The monoubiquitinated Pex5p is recognized by the peroxisomal export machinery and is retrotranslocated into the cytosol for further rounds of protein import. However, the functional relevance of deubiquitination has not yet been addressed. In this study, we have analyzed a Pex5p-truncation lacking Cys6 [(Delta6)Pex5p], a construct with a ubiquitin-moiety genetically fused to the truncation [Ub-(Delta6)Pex5p], as well as a construct with a reduced susceptibility to deubiquitination [Ub(G75/76A) (Delta6)Pex5p]. While the (Delta6)Pex5p-truncation is not functional, the Ub (Delta6)Pex5p chimeric protein can facilitate matrix protein import. In contrast, the Ub(G75/76A)-(Delta6)Pex5p chimera exhibits a complete PTS1-import defect. The data show for the first time that not only ubiquitination but also deubiquitination rates are tightly regulated and that efficient deubiquitination of Pex5p is essential for peroxisomal biogenesis. PMID- 30408546 TI - STIM1 and Orai1 regulate Ca2+ microdomains for activation of transcription. AB - Since calcium (Ca2+) regulates a large variety of cellular signaling processes in a cell's life, precise control of Ca2+ concentrations within the cell is essential. This enables the transduction of information via Ca2+ changes in a time-dependent and spatially defined manner. Here, we review molecular and functional aspects of how the store-operated Ca2+ channel Orai1 creates spatiotemporal Ca2+ microdomains. The architecture of this channel is unique, with a long helical pore and a six-fold symmetry. Energetic barriers within the Ca2+ channel pathway limit permeation to allow an extensive local Ca2+ increase in close proximity to the channel. The precise timing of the Orai1 channel function is controlled by direct binding to STIM proteins upon Ca2+ depletion in the endoplasmic reticulum. These induced Ca2+ microdomains are tailored to, and sufficient for, triggering long-term activation processes, such as transcription factor activation and subsequent gene regulation. We describe the principles of spatiotemporal activation of the transcription factor NFAT and compare its signaling characteristics to those of the autophagy regulating transcription factors, MITF and TFEB. PMID- 30408547 TI - One 16 bp insertion/deletion (indel) within the KDM6A gene revealing strong associations with growth traits in goat. AB - Lysine demethylase 6A (KDM6A), as a candidate gene associated with skeletal dysplasia and the differentiation of osteogenesis, might affect the growth traits in animals. In the previous study (Cui et al., 2018), one 16 bp intronic insertion/deletion (NW_017189516.1: g.138, 431_138,446delAATGTATAGCTTAAAA) within the KDM6A gene significantly influenced KDM6A gene expression. The objective of this work was to investigate the association between this 16 bp indel and growth related traits in Shaanbei White Cashmere goat (SWCG). Association analyses showed the 16 bp indel was related to growth traits strongly (body height, chest depth, height across the hip, body length and chest circumference) in SWCG population (n = 1953, P < 0.05). Insertion/insertion (II) genotype individuals (n = 1502) had the best growth traits, by comparison of those of insertion/deletion (ID) (n = 410) and the deletion/deletion (DD) genotypes (n = 41). Particularly, the body weight of II genotype individuals were significantly higher than ID and DD genotypes (P < 0.01). Besides, the remarkable influence of this indel on traits might cause by the change of MEF2 binding site. These findings hinted that the 16 bp deletion mutation in KDM6A gene, which was significantly associated with growth-related traits, could be assigned to an effective molecular marker for growth traits in goat breeding. PMID- 30408548 TI - Mining of aminotransferase gene ota3 from Bacillus pumilus W3 via genome analysis, gene cloning and expressing for compound bioamination. AB - Aminotransferases are widely employed as biocatalysts to produce chiral amines and biologically active pharmaceuticals via asymmetric synthesis. In this study, transaminase genes in the Bacillus pumilus W3 genome were analysed, and gene ota3 encoding a putative (R)-selective transaminase was identified. The sequence of ota3 shares highest sequence identity (24.7%) with the first (R)-selective aminotransferase from Arthrobacter sp. KNK 168. Amino acid sequence and conserved domains analyses indicated that omega-BPAT encoded by ota3 belonged to the pyridoxal 5'-phosphate-dependent class IV (PLPDE_IV) superfamily. Both native and codon-optimised omega-BPAT genes were recombinantly expressed, and the purified proteins had a molecular mass of ~33.4 kDa. Furthermore, enantioselectivity tests with (S)- and (R)-alpha-phenethylamine revealed its (R)-selectivity. The optimal conditions for catalytic reaction were 45 degrees C and pH 7.0, and omega-BPAT retained stability at 20 degrees C and pH 7.0. Thus, omega-BPAT is a novel (R) selective aminotransferase with great potential as a universal biocatalyst. PMID- 30408549 TI - WITHDRAWN: Spleen tyrosine kinase (SYK) protects renal tubular epithelial cell against hypoxia injury in children with acute kidney injury. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 30408550 TI - miR-509-3p enhances platinum drug sensitivity in ovarian cancer. AB - Drug-resistance of platinum remains a big challenge for effective treatment of patients with ovarian cancer. MicroRNAs (miRNAs) act as post-transcriptional regulators of gene expression and are associated with multi-drug resistance. Our study aims on identifying role of miRNAs in drug-resistance of platinum in ovarian cancer. In present study, we compared the expression profiles of miRNAs between three pairs of platinum-resistant and platinum-sensitive ovarian tissues and found that miR-509-3p was significantly down-regulated in cisplatin-resistant ovarian cancer tissues. The different expression of miR-509-3p was further determined by RT-qPCR analyses of tissue samples from groups of 20 patients with cisplatin-sensitive ovarian cancer and 7 patients with cisplatin-resistant ovarian cancer. Functional studies demonstrated that miR-509-3p inhibitor decreased cell response to cisplatin (CDDP) and promoted cell survival in SKOV3 ovarian cancer cells. Furthermore, we found gene expression level of Golgi phosphoprotein-3 (GOLPH3) and wntless Wnt ligand secretion mediator (WLS) were regulated by miR-509-3p. The direct bindings of miR-509-3p to GOLPH3 and WLS genes were confirmed by dual-luciferase reporter assay. And the negative correlation between their expression levels in SKOV3 cells was further verified with RT-qPCR. Altogether, our data provide preliminary evidence, supporting that targeting miR-509-3p might be a potential therapeutic strategy for patients with platinum-resistant ovarian cancer. PMID- 30408551 TI - EZH2-mediated epigenetic suppression of EphB3 inhibits gastric cancer proliferation and metastasis by affecting E-cadherin and vimentin expression. AB - EphB3 is a member of the EPH family of receptors and has been found to play a role in the carcinogenesis of some human cancers. However, its expression and clinical significance in gastric cancer (GC) have not been well documented. In the present study, we detected the expression of EphB3 in GC and adjacent noncancerous tissues and explored its relationships with the clinicopathological features and prognosis of GC patients. It was found that EphB3 silenced GC cells epigenetically by direct transcriptional repression of GC cells via polycomb group protein EZH2 mediation. EphB3 was downregulated in GC cells and tissues, and EphB3 depletion promoted GC cell growth and invasion, while ectopic overexpression of EphB3 produced a significant anti-tumor effect. EphB3 was found to be involved in epithelial-mesenchymal transition by regulating E-cadherin and vimentin expression. In addition, patients with reduced EphB3 expression had shorter disease-free survival (DFS), indicating that EphB3 may prove to be a biomarker for prognosis of GC. These results demonstrated that EphB3 functioned as a tumor-suppressor and prognostic biomarker in GC. PMID- 30408552 TI - The origin of neural stem cells impacts their interactions with targeted-lipid nanocapsules: Potential role of plasma membrane lipid composition and fluidity. AB - The adsorption of a peptide (NFL-TBS.40-63 peptide (NFL)) known to induce neural stem cells (NSC) differentiation in vitro, at the surface of lipid nanocapsules (LNC) provides a targeting drug delivery system (NFL-LNC) that penetrates subventricular zone-neural stem cells (SVZ-NSC) but not central canal-NSC (CC NSC). We hypothesized preferential interactions could explaine, at least partially, the different properties of SVZ- and CC-NSC plasma membranes. The objective of this work was to compare SVZ- and CC-NSC plasma membrane lipid composition, fluidity and permeability. Plasma membranes of SVZ- and CC-NSC were isolated and analyzed by LC-MS for their lipid content. Membrane fluidity was evaluated by measuring the generalized polarization (GP) of Laurdan and membrane permeability by fluorescent dextran penetration. Liposomes with different lipid compositions and steady state fluidities were prepared. DeltaGP was measured after incubation with NFL-LNC. A significantly higher proportion of cholesterol, ceramides, sphingomyelins, phosphatidylethanolamines and a lower proportion of phosphatidylcholines and sulfatides were observed in SVZ- compared to CC-NSC. Fluidity, probably more than lipid composition, drove NFL-LNC and NSC interactions, and SVZ-NSC were more sensitive to NFL permeabilization than CC NSC. We demonstrated that NSC membrane lipid composition and fluidity depended of NSC origin and that these features could play a role in the specific interactions with NFL-LNC. PMID- 30408553 TI - Relationship between amorphous solid dispersion in vivo absorption and in vitro dissolution: phase behavior during dissolution, speciation, and membrane mass transport. AB - Enzalutamide is a fast crystallizing, hydrophobic compound that has solubility limited absorption in vivo. Given the low aqueous solubility of this compound, it was of interest to evaluate amorphous formulations in vitro and in vivo. Amorphous solid dispersions (ASD) of enzalutamide were prepared with the hydrophilic polymers, hydroxypropyl methylcellulose acetate succinate (HPMCAS) and copovidone (PVPVA). A side-by-side diffusion cell was developed as an in vitro characterization tool to discriminate enzalutamide ASDs based upon the solute thermodynamic activity achieved during dissolution and its impact on the subsequent membrane transport rates, phase behavior, and drug speciation. The same formulations were then tested in vivo in rats using oral dosing of ASD suspensions. Different levels of plasma exposure were observed between the ASDs, which could be correlated to the phase behaviors of the ASDs following dissolution. Unsurprisingly, ASDs that underwent crystallization show lower plasma exposures. However, differences were also observed between ASDs that dissolved to form nanosized amorphous drug aggregates versus those that dissolved to yield only supersaturated solutions, with the former outperforming the latter in terms of the plasma exposure. These observations highlight the importance of thoroughly understanding the phase behavior of an amorphous formulation following dissolution and the need to discriminate between different types of precipitation, specifically crystallization versus glass liquid phase separation to form nanosized amorphous aggregates. PMID- 30408554 TI - Peptide-based targeted therapeutics: Focus on cancer treatment. AB - Therapeutic peptides are attracting increasing attention for biomedical applications. Peptides present promising opportunities in targeted drug delivery due to their high specificity, selectivity, small dimensions, ease of modification, and high biocompatibility. During the last decade, the potential of peptides as therapeutics or targeting ligands has been boomed in nanotechnology and cancer research. This review summarizes various peptides as therapeutics and targeting ligands in cancer therapy. At first, two categories of tumor homing and cell penetrating peptides (CPPs) are introduced and then we will discuss the modification of CPPs. Then various types of tumor targeting peptides and their applications in cancer research are represented. PMID- 30408555 TI - Boosting RNAi therapy for orthotopic glioblastoma with nontoxic brain-targeting chimaeric polymersomes. AB - Glioblastoma with intracranial infiltrative growth remains an incurable disease mainly owing to existence of blood brain barrier (BBB) and off-target drug toxicity. RNA interference (RNAi) with a high specificity and low toxicity emerges as a new treatment modality for glioblastoma. The clinical application of RNAi technology is, however, hampered by the absence of safe and brain-targeting transfection agents. Here, we report on angiopep-2 peptide-decorated chimaeric polymersomes (ANG-CP) as a nontoxic and brain-targeting non-viral vector to boost the RNAi therapy for human glioblastoma in vivo. ANG-CP shows excellent packaging and protection of anti-PLK1 siRNA (siPLK1) in its lumen while quickly releasing payloads in a cytoplasmic reductive environment. Notably, in vitro experiments demonstrate that ANG-CP can effectively permeate the bEnd.3 monolayer, transport siRNA into the cytosol of U-87 MG glioblastoma cells via the LRP-1-mediated pathway, and significantly silence PLK1 mRNA and corresponding oncoprotein in U 87 MG cells. ANG-CP greatly prolongs the siPLK1 circulation time and enhances its accumulation in glioblastoma. RNAi with siPLK1 induces a strong anti-glioblastoma effect and significantly improves the survival time of glioblastoma carrying mice. PMID- 30408556 TI - Mapping ventricular fibrillation ... another piece from the jigsaw. PMID- 30408558 TI - Cross-subject network investigation of the EEG microstructure: A sleep spindles study. AB - BACKGROUND: The microstructural EEG elements and their functional networks relate to many neurophysiological functions of the brain and can reveal abnormalities. Despite the blooming variety of methods for estimating connectivity in the EEG of a single subject, a common pitfall is seen in relevant studies; grand averaging is used for estimating the characteristic connectivity patterns of a group of subjects. This averaging may distort results and fail to account for the internal variability of connectivity results across the subjects of a group. NEW METHOD: In this study, we propose a novel methodology for the cross-subject network investigation of EEG graphoelements. We used dimensionality reduction techniques in order to reveal internal connectivity properties and to examine how consistent these are across a number of subjects. In addition, graph theoretical measures were utilized to prioritize regions according to their network attributes. RESULTS: As proof of concept, we applied this method on fast sleep spindles across 10 healthy subjects. Neurophysiological findings revealed subnetworks of the spindle events across subjects, highlighting a predominance for occipito parietal areas and their connectivity with frontal regions. COMPARISON WITH EXISTING METHODS: This is a new approach for the examination of within-group connectivities in EEG research. The results accounted for more than 85% of the overall data variance and the detected subnetworks were found to be meaningful down-projections of the grand average of the group, suggesting sufficient performance for the proposed methodology. CONCLUSION: We conclude that the proposed methodology can serve as an observatory tool for the EEG connectivity patterns across subjects, providing a supplementary analysis of the existing topography techniques. PMID- 30408557 TI - In vitro assessment of radiobiology of meningioma: A pilot study. AB - BACKGROUND: Meningioma are the second most common brain tumors in adults and can cause significant morbidity and mortality. The scarcity of in vitro and in vivo models represents the major obstacle to understand the molecular basis of meningioma tumorigenesis. The main aim of this study was to assess a method for radiobiology of meningioma cells colture by means of well-known meningioma lines. NEW METHOD: We carried out a protocol of cells culture for irradiation of meningioma cells. We used the immortalized cell lines IOMM-Lee and CH-157 to study their radiation-reponse by means of clonogenic assays and to evaluate their proliferation and apoptosis. We irradiated the cells with different total doses using two different linear accelerators. RESULTS: We observed a more radiation resistance of the IOMM-Lee than the CH-157. Indeed, the cellular death of CH-157 was obtained at a very low dose irradiation. Moreover, we showed a dose-response effect due to the early and late apoptosis, in fact the rate of apoptotic cells is greater than that of the necrotic cells at any dose of irradiation and at any time of analysis. COMPARISON WITH EXISTING METHODS: There is not a standardized method for radiobiology of meningioma experiments. CONCLUSIONS: Our method of cells culture appears suitable for radiosensitivity studies on meningioma. We can confirm that the response to radiotherapy depends not only on irradiation features, but also on tumor radiosensitivity. PMID- 30408559 TI - A new polymer-based approach for in vivo transfection in postnatal brain. AB - BACKGROUND: Gene delivery within the central nervous system at postnatal age is one of the most challenging tasks in neuroscience and currently only a few effective methods are available. COMPARISON WITH EXISTING METHODS: For postnatal central nervous system cells, viral approaches are commonly used for genetic engineering but they face several biosafety requirements for production and use making them less accessible to the community. Conversely, lipid-based methods are widely used in cell culture but face limitation in vivo mainly due to the inflammatory responses they induce. To this aspect, the use of a transgenic mouse line can represent a credible answer to the community working on rat models still requires an effective and successful solution to circumvent these difficulties. NEW METHOD: We describe a new polymer-based gene delivery system allowing persistent and robust in vivo transfection with low DNA amount, reduced inflammation and high diffusion. The expression profile along the brain, the stability, the diffusion of the DNA together with the quantity of cells transfected were evaluated through in vivo approaches. RESULTS: With a single low volume injection, we targeted different cell types within the rat brain. We measured the diffusion rate ranging from 1 to 5 mm based on the injected volume, in the three-dimensions axis. Finally, we modified brain susceptibility to epileptic seizures using a specific knock-down of the neuronal specific potassium chloride transporter 2. CONCLUSIONS: This safe and easy system opens perspectives for non viral gene delivery in the rat brain with perspectives to study brain function in vivo. PMID- 30408560 TI - Mineralization in micropores of calcium phosphate scaffolds. AB - With the increasing demand for novel bone repair solutions that overcome the drawbacks of current grafting techniques, the design of artificial bone scaffolds is a central focus in bone regeneration research. Calcium phosphate scaffolds are interesting given their compositional similarity with bone mineral. The majority of studies focus on bone growth in the macropores (>100 um) of implanted calcium phosphate scaffolds where bone structures such as osteons and trabeculae can form. However, a growing body of research shows that micropores (<50 um) play an important role not only in improving bone growth in the macropores, but also in providing additional space for bone growth. Bone growth in the micropores of calcium phosphate scaffolds offers major mechanical advantages as it improves the mechanical properties of the otherwise brittle materials, further stabilizes the implant, improves load transfer, and generally enhances osteointegration. In this paper, we review evidence in the literature of bone growth into micropores, emphasizing on identification techniques and conditions under which bone components are observed in the micropores. We also review theories on mineralization and propose mechanisms, mediated by cells or not, by which mineralization may occur in the confined micropore space of calcium phosphate scaffolds. Understanding and validating these mechanisms will allow to better control and enhance mineralization in micropores to improve the design and efficiency of bone implants. STATEMENT OF SIGNIFICANCE: The design of synthetic bone scaffolds remains a major focus for engineering solutions to repair damaged and diseased bone. Most studies focus on the design of and growth in macropores (>100 um), however research increasingly shows the importance of microporosity (<50 um). Micropores provide an additional space for bone growth, which provides multiple mechanical advantages to the scaffold/bone composite. Here, we review evidence of bone growth into micropores in calcium phosphate scaffolds and conditions under which growth occurs in micropores, and we propose mechanisms that enable or facilitate growth in these pores. Understanding these mechanisms will allow researchers to exploit them and improve the design and efficiency of bone implants. PMID- 30408561 TI - Backside wear in acetabular hip joint replacement. AB - INTRODUCTION: Besides head-insert articulation in hip joint replacements, micro motions between the backside of assembled polyethylene acetabular liners and the metal cup may cause additional wear. Pelvic osteolysis frequently occurs in the region of screw holes, and cup loosening hints to clinically relevant amounts of polyethylene backside wear. It has yet to be confirmed whether backside wear particles differ in size and morphology compared to articulating wear. Previous methods have been limited to subjective assessment of backside surface damages without consideration of wear debris. The aim of this study was to develop and validate a method for quantitative in vitro measurements of polyethylene backside wear in artificial hip cups and to characterize these wear particles for the first time. METHODS: Titanium cup-systems (Plasmafit(r)Plus7, Aesculap, UHMWPE liner) were sinusoidally loaded (2.5 kN) and a torque of 5 Nm was simultaneously applied. The front and rear side of the cup were separated to isolate backside wear. After 2 * 106 cycles the surrounding fluid was filtered and a particle analysis was performed. RESULTS: Backside wear had a particles size of 64.1 +/- 1.9 nm and was verified as round and oval particles with partly rough outlines. An estimated total number of particles of 1.26 * 109 +/- 1.67 * 108 per 106 cycles was determined. CONCLUSION: Backside wear was estimated to be several times lower than published values of articulating wear. However, polyethylene backside wear particles represented significantly smaller particles with partly roughened outlines than articulating wear particles and may therefore cause higher biological response in macrophage-mediated bone resorption compared to articulated particles. STATEMENT OF SIGNIFICANCE: Within this study, an analytical method for quantitative measuring polyethylene backside wear of artificial hip cups was successfully developed and validated for the first time. It could be shown that backside wear is still present, even in modern cup systems. These findings can be further used for investigations of the osteolytic potential of polyethylene particles, for evaluating and improving new implant systems and to evaluate the effectiveness of screw hole plugs to prevent the particle migration to the acetabulum. PMID- 30408562 TI - Determination of food allergens by LC-MS: Impacts of sample preparation, food matrix, and thermal processing on peptide detectability and quantification. AB - Food allergies are a growing worldwide concern and the contamination of products with food allergens represents a significant health risk to allergic consumers. With the introduction of reference doses, quantitative methods are needed for the monitoring of allergen levels, and the potential of LC-MS/MS is of hugely growing interest. In this study, we demonstrate that relevant food matrices (bakery products and chocolates) and thermal food processing substantially influence the quantification of 18 marker peptides from various nut and peanut allergens via targeted proteomics. In addition, we characterize the individual release kinetics of marker peptides and provide examples for metastable marker peptide candidates. Matrix recovery rates overall ranged between 15 and 250% with the observed variation being linked to the individual peptide structure as well as to specific matrix interferences. In contrast, thermal processing considerably influences the detectability of allergens on the protein level as different marker peptides from the identical parent allergen are similarly affected, leading to a loss in signal of up to 83% in extreme cases after a 45-min simulated baking. Provided data are finally used for evaluation of different calibrators as well as the overall potential and challenges of LC-MS for the absolute quantification of food allergens. SIGNIFICANCE: With the scientific discussion moving towards a risk based management of food allergens, including the establishment of threshold doses, robust methods for the absolute quantification of allergens in food samples are urgently needed. Because the currently used antibody- and DNA-based technologies show severe limitations in terms of specificity and reproducibility, LC-MS has emerged as a promising alternative. Its application to absolute quantification, however, first requires an understanding of the various impacts that affect quantification results, including different food matrices, sample preparation, and thermal processing of foodstuffs. Knowledge of these factors, which are assessed as part of a comprehensive survey in this study, is also an important prerequisite to evaluate means of calibration for an LC-MS-based quantification of food allergens. PMID- 30408563 TI - Toward characterizing germination and early growth in the non-orthodox forest tree species Quercus ilex through complementary gel and gel-free proteomic analysis of embryo and seedlings. AB - By using two complementary proteomics, gel-based and gel-free (shotgun) approaches, the protein profiles of the non-orthodox forest tree species Quercus ilex seeds during germination and early seedling growth have been compared. Proteins were extracted from embryo axis, radicle and shoot tissues at different developmental stages. Proteins were subjected to one- and two-dimensional gel electrophoresis. A multivariate analysis (PCA) revealed that SDS-PAGE clearly separated germination (0-24 h post-imbibition), postgermination (72-216 h post imbibition) and early seedling growth stages (2 weeks post-imbibition). Image analysis of the two-dimensional gels revealed a total of 732 spots, 103 of which were significantly variable among developmental stages. After MALDI-TOF/TOF MS analysis, 90 spots were identified, belonging to six main functional categories: carbohydrate, amino acids, energy, and protein metabolism, biosynthesis of secondary metabolites, and redox processes. The gel-based approach disclosed important metabolic changes that occurred in the holm oak seed after the germination. However, few proteins were significantly altered during the germination period (from 0 h to 24 h post imbibition) and, because of that, a further shotgun analysis was therefore used to analyse changes in the protein profile during seed germination. Up to 1250 proteins could be confidently identified, with 153 being variable. They belonged to the main functional categories of carbohydrate, amino acids and secondary metabolism, protein degradation, and responses to abiotic stress. The accumulation of proteases and amino acids metabolism proteins in mature seeds can be reflecting the production of energy from the mobilization of storage proteins to start germination. These results, therefore, corroborate the hypothesis that the mature non-orthodox seeds of Q. ilex have all the machinery necessary for rapidly resuming metabolic activities and starting the germination process, in contrast to that occurs in orthodox seeds, which metabolic activity ceases in mature dry seeds. The use of a genus-specific database combined with the public Viridiplantae database improved the quality and quantity of protein identification in this orphan species. In addition, both proteomics approaches (gel-based and shotgun) were complementary, with shotgun increasing by over two-fold the coverage of the proteome analysed. Both approaches provided similar results and supported the same conclusions on the metabolic switch experienced by the seed upon germination. SIGNIFICANCE: The optimal seed germination is a prerequisite for successful seedling establishment and plant vigour, being of great relevance in the case of crops and commercial woody plants. By using a complementary gel-based and gel-free proteomic strategy we have study the protein profiles of the non-orthodox forest tree species Quercus ilex seeds during germination and early seedling growth. The contribution of this work is of great importance, due to the complemented proteomic approaches giving similar clues to the metabolic state of the mature Q. ilex seed before the germination starts, and the metabolic switch experienced by the imbibed acorn until the seedling is established. PMID- 30408565 TI - Fecal Microbiota Transplantation: Restoring the Injured Microbiome after Allogeneic Hematopoietic Cell Transplantation. AB - Disruption of the intestinal microbiome early after allogeneic hematopoietic cell transplantation (allo-HCT) has been linked to adverse outcomes in transplant recipients. To date, whether microbiome-directed interventions will be able to impact important clinical endpoints remains unknown. Fecal microbiota transplantation (FMT) is a compelling intervention to restore healthy diversity to the intestinal microenvironment after allo-HCT, but currently has no established role in transplant recipients. In this review, we examine the use of FMT as treatment for Clostridium difficile infection and acute graft-versus-host disease, and also as a restorative intervention early after allo-HCT. Ongoing and planned studies will help determine the ultimate role of FMT in allo-HCT recipients. PMID- 30408564 TI - Family Mismatched Allogeneic Stem Cell Transplantation for Myelofibrosis: Report from the Chronic Malignancies Working Party of European Society for Blood and Marrow Transplantation. AB - This analysis included 56 myelofibrosis (MF) patients transplanted from family mismatched donor between 2009 and 2015 enrolled in the European Society for Blood and Marrow Transplantation database. The median age was 57 years (range, 38 to 72); 75% had primary MF and 25% had secondary MF. JAK2 V617F was mutated in 61%. Donors were HLA mismatched at 2 or more loci. Stem cells were sourced from bone marrow in 66% and peripheral blood in 34%. The median CD34+ cell dose was 4.8 * 106/kg (range, 1.7 to 22.9; n = 43). Conditioning was predominantly myeloablative in 70% and reduced intensity in the remainder. Regimens were heterogeneous with thiotepa, busulfan, fludarabine, and post-transplant cyclophosphamide used in 59%. The incidence of neutrophil engraftment by 28 days was 82% (range, 70% to 93%), at a median of 21 days (range, 19 to 23). At 2 years the cumulative incidence of primary graft failure was 9% (1% to 16%) and secondary graft failure was 13% (4% to 22%). The cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and III to IV was 28% (16% to 40%) and 9% (2% to 17%) at 100 days. The cumulative incidence of chronic GVHD at 1 year was 45% (32% to 58%), but the cumulative incidence of death without chronic GVHD by 1 year was 20% (10% to 31%). With a median follow-up of 32 months, the 1- and 2-year overall survival was 61% (48% to 74%) and 56% (41% to 70%), respectively. The 1- and 2- year progression-free survival was 58% (45% to 71%) and 43% (28% to 58%), respectively, with a 2-year cumulative incidence of relapse of 19% (7% to 31%). The 2-year nonrelapse mortality was 38% (24% to 51%). This retrospective study of MF allo-SCT using family mismatched donors demonstrated feasibility of the approach, timely neutrophil engraftment in over 80% of cases, and acceptable overall and progression-free survival rates with relapse rates not dissimilar to the unrelated donor setting. However, strategies to minimize the risk of graft failure and the relatively high nonrelapse mortality need to be used, ideally in a multicenter prospective fashion. PMID- 30408566 TI - Summary of the Second Annual BMT CTN Myeloma Intergroup Workshop on Minimal Residual Disease and Immune Profiling. AB - The second annual Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Myeloma Intergroup Workshop on Minimal Residual Disease and Immune Profiling was convened on December 7, 2017, at the American Society of Hematology (ASH) meeting. During this workshop, investigators from around the world presented their latest research involving assessment of minimal residual disease (MRD) and immune profiling (IP) in myeloma. This document summarizes the workshop presentations as well as relevant ASH abstracts and focuses on the regulatory issues involved in the integration of MRD and IP assessment in clinical trial design and practice. PMID- 30408567 TI - Peripheral blood DNA methylation as potential biomarker of Malignant Pleural Mesothelioma in asbestos-exposed subjects. AB - INTRODUCTION: Malignant pleural mesothelioma (MPM) is an aggressive tumour strongly associated with asbestos exposure. Patients are usually diagnosed when current treatments have limited benefits, highlighting the need for non-invasive early diagnosis tests to monitor asbestos-exposed people. METHODS: We used a genome-wide methylation array to identify, in asbestos-exposed subjects, novel blood DNA methylation markers of MPM in 163 MPM cases and 137 cancer-free controls (82/68 Training Set; replication in 81/69, Test Set) sampled from the same areas. RESULTS: Evidence of differential methylation between MPM cases and controls was found (>800 CpG sites, Pfdr<0.05), mainly in immune system related genes. Considering the "top" differentially methylated signals, 7 single-CpGs and 5 genomic regions of coordinated methylation replicated with similar effect size in the Test Set (pfdr<0.05). The top hypomethylated single-CpG (cases vs controls effect size<-0.15, pfdr <0.05 in both Training and Test sets) was detected in FOXK1 (Forkhead-box K1) gene, an interactor of BAP1 which was found mutated in MPM tissue and as germline mutation in familial MPM. In the Test set, comparison of receiver operating characteristic (ROC) curves and the area under the curve (AUC) of two models, including/excluding methylation, showed a significant increase in case/control discrimination when considering DNA methylation together with asbestos exposure (AUC=0.81 vs AUC=0.89, DeLong's test p=0.0013). CONCLUSIONS: We identified signatures of differential methylation in DNA from whole blood between asbestos exposed MPM cases and controls. Our results provide the rationale to further investigate, in prospective studies, the potential use of blood DNA methylation profiles for the identification of early changes related to MPM carcinogenic process. PMID- 30408568 TI - A population-based study of outcomes in surgically resected T3N0 non-small cell lung cancer in the Netherlands, defined using TNM-7 and TNM-8; justification of changes and an argument to incorporate histology in the staging algorithm? AB - PURPOSE: To study outcomes in patients surgically staged as pT3N0 non-small cell lung cancer (NSCLC) in a population registry, comparing TNM-7 and TNM-8 staging classifications. MATERIALS AND METHODS: Details of patients who underwent surgery for a pT3N0M0 NSCLC from 2010 to 2013, based on the TNM-7 classification, were retrieved from the Netherlands Comprehensive Cancer Organization (IKNL). These were next matched with corresponding pathology data from a nationwide registry. Patients were categorized into 4 major pT3 subgroups: '> 7cm' tumor diameter, 'separate tumor nodules in the same lobe' (2nd+ nodule), 'parietal pleural invasion' and a 'mixed group' (mainly '> 7 cm' combined with 'parietal pleural invasion'). RESULTS: 683 patients were eligible for analysis. The 3- and 5-years overall survival (OS) for the subtype '> 7 cm' were 59.9% and 47.2%, respectively, and comparable to the subtype with pleural invasion were 50.4% and 45.3%, respectively. The 'mixed group' had a worse 3- and 5-year OS probability of 37.5% and 28.7%, which were comparable to outcomes for TNM-8 staged IIIB and pT4 cases in the IASLC database. For the subtype 2nd+ nodule, 3- and 5-year OS were 70.6% and 62.8%, respectively, with patients with adenocarcinoma showing a significantly better OS compared to squamous cell carcinoma: 5-years OS of 65.1% versus 47.2%, respectively (p<0.001), suggesting that prognosis for the adenocarcinoma subgroup may be comparable to the pT2 category, whereas squamous cell carcinoma nodules can remain pT3. CONCLUSION: This population analysis of overall survivals in pT3N0 subcategories for NSCLC suggests that histology is a relevant descriptor in the 2nd+ nodule category. The findings do not support migration of the '>7 cm' group to the pT4 category in TNM-8, and suggest that a combination of two pT3 descriptors ('mixed group') merits migration to pT4. PMID- 30408569 TI - Co-expression analysis reveals mechanisms underlying the varied roles of NOTCH1 in non-small cell lung cancer. AB - INTRODUCTION: Notch receptor family dysregulation can be tumor promoting or suppressing depending on cellular context. Our studies shed light on the mechanistic differences that are responsible for NOTCH1's opposing roles in lung adenocarcinoma and lung squamous cell carcinoma. METHODS: We integrated transcriptional patient-derived datasets with gene co-expression analyses to elucidate mechanisms behind NOTCH1 function in subsets of non-small cell lung cancer. Differential co-expression was examined using hierarchical clustering and principal component analysis. Enrichment analyses was used to examine pathways associated with the underlying transcriptional networks. These pathways were validated in vitro and in vivo. Endogenously epitope-tagged NOTCH1 was used to identify novel interacting proteins. RESULTS: NOTCH1 co-expressed genes in lung adenocarcinoma and squamous carcinoma were distinct, and associated with either angiogenesis and immune system pathways or cell cycle control and mitosis pathways, respectively. Tissue culture and xenograft studies of lung adenocarcinoma and lung squamous models with NOTCH1 knockdown demonstrated growth differences and opposing effects on these pathways. Differential NOTCH1 interacting proteins were identified as potential mediators of these differences. CONCLUSIONS: Recognition of the opposing role of NOTCH1 in lung cancer, downstream pathways, and interacting proteins in each context may help direct the development of rational NOTCH1 pathway-dependent targeted therapies for specific tumor subsets of non-small cell lung cancer. PMID- 30408570 TI - Neoadjuvant Crizotinib in Resectable Locally Advanced Non-Small-Cell Lung Cancer with ALK-rearrangement: A Brief Report. AB - BACKGROUND: Locally advanced non-small-cell lung cancer (NSCLC) is one of the most heterogeneous condition with multidimensional treatments involved. Neoadjuvant therapy was commonly considered as an optimal management for operable locally advanced patients. However, as targeted therapy has been widely applied in advanced NSCLC, neoadjuvant targeted therapy remains poorly explored in locally advanced disease. METHODS: We described 11 ALK (anaplastic lymphoma kinase)-positive patients with pathologically confirmed N2 NSCLC who were treated with neoadjuvant crizotinib. All patients were treatment naive and received crizotinib at a starting dose of 250mg twice daily. Case 3 was provided dynamic monitoring before and after neo-adjuvant therapy through next generation sequencing (NGS) of plasma and tissue. Case 4 was performed NGS for preoperative tissue. RESULTS: 10 patients were partial response and one was stable disease after neoadjuvant crizotinib with one suffered from grade 4 hepatic damage. 10/11 (91.0%) patients received R0 resection and 2 patients achieved pathological complete response (pCR) to neoadjuvant crizotinib. 6 patients had disease recurrence and 5 of them receiving crizotinib as first line treatment achieved long duration of response. Dynamic monitoring with both plasma and tissue indicated simultaneously decrease of sensitive ALK-signaling in the patient with partial response (-50%) and no ALK-dependent resistant variants were captured. CONCLUSION: Neoadjuvant crizotinib may be feasible and well-tolerated in locally advanced disease for complete resection. crizotinib prior to surgery may provide thorough elimination of circulating molecular residual disease and not influence the reusing of first-line crizotinib, but ongoing prospective trials are warranted to prove its efficacy in neoadjuvant setting. PMID- 30408571 TI - Danhong injection in cardiovascular and cerebrovascular diseases: Pharmacological actions, molecular mechanisms, and therapeutic potential. AB - Cardiovascular and cerebrovascular diseases are the main cause of mortality worldwide, currently with less than optimum therapeutic options. Danhong injection (DHI) is a medicinal preparation based on two eminent Chinese herbal medicines, Salviae Miltiorrhizae (Dan Shen; family: Lamiaceae) and Flos Carthami (Hong Hua; family: Compositae/Asteraceae). DHI has been mainly used in the clinical therapy of cardiovascular (such as acute coronary syndrome and angina pectoris) and cerebrovascular diseases (such as stroke) in China for many years. The pharmacological properties of DHI include anti-inflammatory, anti-oxidant, anti-coagulatory, hypolipidemic, anti-apoptotic, vasodilatory, and angiogenesis promoting actions. DHI offers a safe and effective therapeutic agent against cardiovascular and cerebrovascular diseases by modulating multiple disease relevant signaling pathways and molecular targets. Herein, we provide a comprehensive review of the phytochemistry, therapeutic effects, molecular mechanisms, and adverse reactions of DHI in cardiovascular and cerebrovascular diseases. We also highlight the latest pharmacological advances and therapeutic potential of this promising herb-derived cardiovascular drug preparation. PMID- 30408572 TI - Long-term effectiveness of bisoprolol in patients with angina: A real-world evidence study. AB - A cohort analysis using UK Clinical Practice Research Datalink (CPRD) was performed to compare the effects of bisoprolol, other beta-blockers, and drugs other than beta-blockers on the long-term risk of mortality and cardiovascular events in patients with angina. Adult patients first diagnosed with angina from 2000 to 2014, with >=365 days of registration to first angina diagnosis and initiating monotherapies of bisoprolol, other beta-blockers, or drugs other than beta-blockers within 6 months of angina diagnosis were included. Incidence rates for each treatment cohort were compared using adjusted hazard ratio (HR) and 95% confidence intervals (CI) obtained from Cox regression analyses. Overall, 987 patients were treated with bisoprolol, 1348 with other beta-blockers and 5272 with drugs other than beta-blockers. Over the total follow-up (<=14 years), the HR of bisoprolol versus other beta-blockers and drugs other than beta-blockers for mortality was 0.45 (95% CI: 0.34-0.61) and 0.50 (95% CI: 0.38-0.66), respectively. The HR of bisoprolol versus other beta-blockers for angina was 0.58 (95% CI: 0.50-0.68) and versus drugs other than beta-blockers was 0.77 (95% CI: 0.68-0.88), respectively. For myocardial infarction, the HR of bisoprolol versus drugs other than beta-blockers up to 14 years was 0.34 (95% CI: 0.23-0.52) and versus other beta-blockers up to 5 years was 0.45 (95% CI: 0.27-0.75). At 5 years, the HR of bisoprolol versus other beta-blockers, and drugs other than beta blockers, for arrhythmia was 0.60 (95% CI: 0.35-1.0) and 0.61 (95% CI: 0.40 0.93), respectively. In conclusion, long-term significant reduction in the risk of mortality and various cardiovascular events with bisoprolol versus other beta blockers, and drugs other than beta-blockers, confirm treatment guidelines recommendation that bisoprolol is particularly well suited as the first-line treatment of angina in primary care. PMID- 30408574 TI - Identification of factors associated with first-cycle drug approval rates and regulatory outcomes for new drug applications. AB - The aims of this study were to identify types of deficiencies resulting in delay of approvals for drugs eventually approved by the US FDA and to search for factors associated with higher first-cycle approval rates. Review documents of New Drug Applications approved between 2008 and 2017 were retrieved from the Drugs@FDA database. Basic characteristics of the applications, regulatory actions, and reasons for non-approvals and/or major amendments after first review cycle were investigated. Of 825 applications studied, 446 (54.1%) applications received first-cycle approvals without a review extension resulting from a major amendment. Non-approvals (240, 29.1%) were based primarily on chemistry/manufacturing/controls and safety reasons. A higher first-cycle approval rate was associated with factors related to unmet medical needs or innovative development. The association between higher first-cycle approval rates and innovative drugs or those addressing unmet needs reveals the FDA's commitment in advancing innovation and protecting public health. PMID- 30408573 TI - The effect of polypharmacy on prefrontal cortex activation during single and dual task walking in community dwelling older adults. AB - INTRODUCTION: Polypharmacy, defined as the use of 5 or more medications is associated with multiple adverse outcomes in older adults, including falls and slow gait velocity. However, the relationship between polypharmacy and cortical control of locomotion has not been reported. The purpose of this study was to examine the relationship between polypharmacy and activation patterns in the prefrontal cortex (PFC), a brain region involved in higher order control of locomotion during attention-demanding conditions. METHODS: Using Functional Near Infrared Spectroscopy (fNIRS) to quantify PFC oxygenated hemoglobin (HbO2) levels, we performed a cross sectional analysis of 325 community dwelling adults age >=65 years, and examined HbO2 levels during single tasks (Single-Task-Walk (STW), (talking, cognitive interference (Alpha)) and Dual-Task Walk (DTW)). RESULTS: The prevalence of polypharmacy was 33% (n = 104) amongst the 325 participants (mean age 76.4 +/- 6.7 years, 56% women). Among the 221 participants with no polypharmacy there was an increase in HbO2 levels from STW to DTW (estimate = -0.625; p = <0.001) and from Alpha to DTW (estimate=-0.079; p = 0.031). Polypharmacy status, however, moderated the change in HbO2 levels comparing the two single tasks to the dual-task walking condition. Specifically, the presence of polypharmacy was associated with an attenuated increase in HbO2 levels from STW to DTW (estimate = 0.149; p = 0.027) and with a decline in HbO2 levels from Alpha to DTW (estimate = 0.169; p = 0.009) after adjustments for potential confounders including medical comorbidities and the use of high-risk medications. CONCLUSION: The results of this study further support the need for clinicians to reduce polypharmacy in older adults, given its significant association with the PFC hemodynamic response during attention-demanding locomotion. PMID- 30408575 TI - Curcumin in Combination with Anti-Cancer Drugs: A Nanomedicine Review. AB - A huge surge of research is being conducted on combination therapy with anticancer compounds formulated in the form of nanoparticles (NPs). Numerous advantages like dose minimalization and synergism, reversal of multi drug resistance (MDRs), enhanced efficacy have emerged with nanoencapsulation of chemotherapeutic agents with chemo-sensitizing agent like curcumin. Within last couple of years various nano-sized formulations have been designed and tested both in vitro with cell lines for different types of cancers and in vivo with cancer types and drug resistance models. Despite the combinatorial models being advanced, translation to human trials has not been as smooth as one would have hoped, with as few as twenty ongoing clinical trials with curcumin combination, with less than 1/10th being nano-particulate formulations. Mass production of nano-formulation based on their physico-chemical and pharmacokinetics deficits poses as major hurdle up the ladder. Combination of these nano-sized dosage with poorly bioavailable drugs, unspecific target binding ability and naturally unstable curcumin further complicates the formulation aspects. Emphasis is now therefore being laid on altering natural forms of curcumin and usage of formulations like prodrug or coating of curcumin to overcome stability issues and focus more on enhancing the pharmaceutical and therapeutic ability of the nano composites. Current studies and futuristic outlook in this direction are discussed in the review, which can serve as the basis for upcoming research which could boost commercial translational of improved nano-sized curcumin combination chemotherapy. PMID- 30408576 TI - Type C botulism outbreak in feedlot cattle fed contaminated corn silage. AB - A large outbreak of botulism in feedlot steers fed corn silage contaminated with Clostridium botulinum neurotoxin type C (BoNT/C) is reported occurring in Midwestern Brazil in August 2017. The onset of the outbreak occurred 15 days after 1700 steers started to be fed the contaminated corn silage. Affected steers were alert and afebrile with varying degrees of flaccid paralysis in various muscle groups. A total of 1100 steers were affected, 1090 of which died within four days. Ten steers recovered after treatment with antitoxin. No gross or microscopic lesions were found in affected steers. The diagnosis was based on epidemiological data, characteristic clinical signs, and positive mouse bioassay results. This outbreak is interesting due to the high number of fatally affected cattle and the on-site diagnostic approach. This case report demonstrates the difficulties in diagnosing and treating botulism in cattle. PMID- 30408577 TI - RECEPTOR-LIKE KINASE 902 Associates with and Phosphorylates BRASSINOSTEROID SIGNALING KINASE1 to Regulate Plant Immunity. AB - Plants employ receptor-like kinases (RLKs) and receptor-like proteins for rapid recognition of invading pathogens, and RLKs then transmit signals to receptor like cytoplasmic kinases (RLCKs) to activate immune responses. RLKs are under fine regulation mediated by subcellular trafficking, which contributes to proper activation of plant immunity. In this study, we show that Arabidopsis thaliana RECEPTOR-LIKE KINASE 902 (RLK902) plays important roles in resistance to the bacterial pathogen Pseudomonas syringae, but not to the fungal powdery mildew pathogen Golovinomyces cichoracearum. RLK902 localizes at the plasma membrane and associates with ENHANCED DISEASE RESISTANCE 4 (EDR4), a protein involved in clathrin-mediated trafficking pathways. EDR4 and CLATHRIN HEAVY CHAIN 2 (CHC2) regulate the subcellular trafficking and accumulation of RLK902 protein. Furthermore, we found that RLK902 directly associates with the RLCK BRASSINOSTEROID-SIGNALING KINASE1 (BSK1), a key component of plant immunity, but not with other members of the FLAGELLIN SENSING 2 immune complex. RLK902 phosphorylates BSK1, and its Ser-230 is a key phosphorylation site critical for RLK902-mediated defense signaling. Taken together, our data indicate that EDR4 regulates plant immunity by modulating the subcellular trafficking and protein accumulation of RLK902, and that RLK902 transmits immune signals by phosphorylating BSK1. PMID- 30408578 TI - Dampness and mold hypersensitivity syndrome and vaccination as risk factors for chronic fatigue syndrome. PMID- 30408579 TI - Target Therapy in SLE. AB - The intention of this paper is to review actual developments in target therapy in SLE. Target therapy includes both the objective of intervention and the aim of treatment. The objective should be linked to the pathophysiologic process of SLE; the aim has to be in any case an improved outcome. The current therapeutic in SLE is guided mostly by secondary prevention. In SLE, besides a BASIC concept with antimalarials, bone and sun protection, vaccination and cardiovascular risk minimising, treatment waits for new manifestations to be started to prevent secondarily damage. With the new treatment target remission, treatment should aim at ensuring long-term survival, preventing organ damage and optimizing health related quality-of-life by controlling disease activity and minimising comorbidities and drug toxicity. First examples show that some patients are in remission and that those patients have a better outcome. But for treat-to-target a strategy needs to be developed that needs to be evaluated. PMID- 30408580 TI - Adrenal insufficiency in systematic lupus erythematosus (SLE) and antiphospholipid syndrome (APS): A systematic review. AB - BACKGROUND: Adrenal insufficiency (AI) is associated with high morbidity and mortality. The aim of this systematic review was to enhance diagnostic approaches and summarize therapeutic strategies in the management of AI in patients with systematic lupus erythematosus (SLE) or antiphospholipid syndrome (APS). METHODS: A literature search of PubMed and Medline databases was performed and 91 publications containing 105 cases were included for the final analysis. RESULTS: The following frequency of clinical signs and symptoms was noted: abdominal pain (39.04%) was the leading symptom, followed by fever (33.33%), vomiting (23.81%), and nausea (19.05%). APS was present in 73%, SLE in 17% of the patients, while 2% had a diagnosis of both, SLE and APS. ACTH stimulation test (ACTHst) was performed in 18% of cases and 76.6% of them were unresponsive towards stimulation. Variable treatment approaches were used: hydrocortisone was most commonly used (38.09%), followed by fludrocortisone (26.67%), prednisolone (20.00%) and volume replacement treatment (11.43%), respectively. CONCLUSIONS: This analysis highlights the importance of an early diagnosis and initiation of therapeutic management when AI is suspected. In line, signs and symptoms related to autoimmune diseases in patients with AI should be reviewed crtitically. PMID- 30408581 TI - Immunogenicity, safety and tolerability of anti-pneumococcal vaccination in systemic lupus erythematosus patients: An evidence-informed and PRISMA compliant systematic review and meta-analysis. AB - The immunological perturbations associated with systemic lupus erythematosus (SLE) puts many patients at higher risk of infections including pneumococcal pneumonia. However, the uptake and utility of anti-pneumococcal vaccines in SLE patient is both controversial and not completely agreed on. Indeed, several epidemiological studies of anti-pneumococcal vaccine safety and efficacy in SLE have reported short term immunogenicity with elevated anti-pneumococcal antibody titres but inconsistent long term findings with some studies finding poor responses, mainly for long-term immune protection. Moreover, the safety and efficacy of the pneumococcal vaccine in SLE patients remains controversial due to the different types of anti-pneumococcal vaccines, and the heterogeneity of SLE patients. Several reviews addressing anti-pneumococcal vaccination in SLE patients exist, however, to the best of our knowledge, the present is the first systematic review and meta-analysis. To better understand the efficacy and safety of pneumococcal vaccination in SLE, a comprehensive literature search was performed identifying 18 studies in the present systematic reviews and meta analysis. All studies were designed as longitudinal investigations, two, in particular, were of high quality, being randomized, double-blind trials (RCTs). Four studies had control groups. Sample size ranged from 12 to 204 participants. Vaccine immunogenicity in terms of subjects with protective antibody titers ranged from 36.0% to 97.6%. According to our metanalysis high erythrocyte sedimentation rate (ESR), older earlier SLE, high disease activity, and immunosuppressive therapy were predictors of poor immunogenicity, although belimumab was found to have no significant impact. With regard to safety, no serious adverse events were found, with up to third of cases reporting mild/low grade and complaints. In conclusion, due to the high risk of pneumococcal infection in SLE patients and given the safety and, at least partial, effectiveness according our study in such patients, preventive strategies mainly by immunization are required in all age groups and in those needing immunosuppressive therapy, immunization should be given prior the initiation of the treatment. PROSPERO registration code 103605. PMID- 30408583 TI - Autoimmune diseases in myelodysplastic syndrome favors patients survival: A case control study and literature review. AB - BACKGROUND: We conducted a monocentric retrospective study of patients with myelodysplastic syndromes (MDS) and autoimmune or inflammatory disorders (AIMs) and a literature review. We analyzed the association with subgroups of the WHO 2016 MDS classification and patient's survival in a case control study. Risk factors associated with survival were analyzed by uni- and multivariate analysis. RESULTS: From all MDS patients 11% presented with AIMs. These were heterogeneous and the most frequent where polyarthritis (25%) and autoimmune cytopenias (17%). No difference for frequency and type of AIMs was observed for the WHO 2016 MDS subgroups (p = .3). In the case control study WHO classification, karyotype abnormalities, IPSS-R and IPSS were similar in both groups. The overall survival from MDS diagnosis was better in the group with AIMs [10.3 +/- 0.6 (IC95% 6.2 12.9) versus 4.8 +/- 1.1 years (IC95% 4.2-8.7), p = .04]. The better survival was restricted to MDS with low or intermediate-1 IPSS [11.1 +/- 1.5 (IC95% 9.9-NR) versus 8.7 +/- 1.3 years (IC95% 4.8-10.3), p = .006]. The better survival was only observed when AIMs diagnosis was timely associated or appeared after MDS diagnosis (p = .04). Factors associated with a better overall survival and survival without AML were steroid dependence [respectively HR = 0.042, p = .003, (IC95% 0.005-0.33) and HR = 0.07, p = .002, (IC95% 0.013-0.39)], a diagnosis of AIMs and MDS timely associated [respectively HR = 0.05, p = .009, (IC95% 0.006 0.478) and HR = 0.1, p = .008, (IC95% 0.018-0.54)] or a diagnosis of AIMs after MDS [respectively HR = 0.024, p = .009, (IC95% 0.001-0.39) and HR = 0.04, p = .008, (IC95% 0.003-0.43)]. CONCLUSION: Autoimmune and inflammatory diseases associated to MDS are heterogeneous. AIMs diagnosed after or concomitantly to MDS seems associated with a better survival. Prospective studies are necessary to demonstrate that autoimmunity is associated to a better control of the MDS clone. PMID- 30408582 TI - Guidelines for biomarkers in autoimmune rheumatic diseases - evidence based analysis. AB - Autoimmune rheumatic diseases are characterised by an abnormal immune system response, complement activation, cytokines dysregulation and inflammation. In last years, despite many progresses in managing these patients, it has been shown that clinical remission is reached in less than 50% of patients and a personalised and tailored therapeutic approach is still lacking resulting in a significant gap between guidelines and real-world practice. In this context, the need for biomarkers facilitating early diagnosis and profiling those individuals at the highest risk for a poor outcome has become of crucial interest. A biomarker generally refers to a measured characteristic which may be used as an indicator of some biological state or condition. Three different types of medical biomarkers has been suggested: i. mechanistic markers; ii. clinical disease markers; iii. therapeutic markers. A combination of biomarkers from these different groups could be used for an ideal more accurate diagnosis and treatment. However, although a growing body of evidence is focused on improving biomarkers, a significant amount of this information is not integrated on standard clinical care. The overarching aim of this work was to clarify the meaning of specific biomarkers during autoimmune diseases; their possible role in confirming diagnosis, predicting outcome and suggesting specific treatments. PMID- 30408584 TI - The characteristics and pivotal roles of triggering receptor expressed on myeloid cells-1 in autoimmune diseases. AB - Triggering receptor expressed on myeloid cells-1 (TREM-1) engagement can directly trigger inflammation or amplify an inflammatory response by synergizing with TLRs or NLRs. Autoimmune diseases are a family of chronic systemic inflammatory disorders. The pivotal role of TREM-1 in inflammation makes it important to explore its immunological effects in autoimmune diseases. In this review, we summarize the structural and functional characteristics of TREM-1. Particularly, we discuss recent findings on TREM-1 pathway regulation in various autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), type 1 diabetes (T1D), and psoriasis. This receptor may potentially be manipulated to alter the inflammatory response to chronic inflammation and possible therapies are explored in this review. PMID- 30408587 TI - Liver-associated immune abnormalities. AB - In recent years, the cross talk between the liver and the immune system is being uncovered, in part by studying liver involvement in primary immune deficiencies (PID) and in part by investigating the alterations of the immune system following orthotopic liver transplantation (OLT). Here we review some of the reciprocal interactions between the liver and the immune system. Patients with PID, particularly those involving inherited defects in T and B cells or innate immunity are prone to infections and inflammatory responses that often involve the liver. Omenn's syndrome, familial hemophagocytic lymphohistiocytosis, AIRE, FOXP3 and CD25 deficiencies, common variable immunodeficiency, CD40 ligand deficiency, chronic granulomatous disease and autoimmune lymphoproliferative syndrome are some of the notable PID associated with typical hepatobiliary abnormalities. Knowledge gained from studying these PID together with laboratory and histological evaluations can assist in managing PID-associated liver dysfunction. The liver itself also has important effects on the immune system, as evident from the growing experience with patients surviving OLT. Up to 40% of pediatric patients who receive OLT suffer from post transplantation allergy, autoimmunity, and immune-mediated disorders (PTAA). PTAA is more common after liver and heart transplantations than kidney transplantations. Potential contributing factors for the increased frequency of PTAA after OLT include the age of the patients, the prolonged use of tacrolimus and the reduced regulatory immune function with a shift towards a TH2 immune response. Better understanding of the mechanisms leading to the development of PTAA after OLT will also improve the management of these conditions. PMID- 30408585 TI - Arthritis in primary Sjogren's syndrome: Characteristics, outcome and treatment from French multicenter retrospective study. AB - OBJECTIVE: To describe the characteristics and the outcome of primary Sjogren Syndrome (pSS) associated arthritis and to compare the efficacy of different therapeutic regimen. METHODS: We conducted a retrospective study using Club Rhumatisme and Inflammation (CRI) and French Internal Medicine Society (SNFMI) networks. All patients with a diagnosis of pSS and at least one episode of clinical and/or echographic synovitis were included. Patients with synovitis (cases) were compared to pSS patients without synovitis (controls). RESULTS: 57 patients (93% women) were included with a median age of 54 years [45-63]. Patients with synovitis had more frequently lymph node enlargement (12.3% vs. 1.8%, p = .007) and a higher ESSDAI score (8 [6-12] vs. 2 [1-4], p < .0001). There was no difference concerning CRP levels, rheumatoid factor and cyclic citrullinated peptide (CCP)-antibodies positivity. Among 57 patients with synovitis, 101 various treatment courses have been used during the follow-up of 40 [22.5-77] months. First treatment course consisted in steroids alone (3.5%), steroids in association (79%) with hydroxychloroquine (HCQ) (49%), methotrexate (MTX) (35%), rituximab (RTX) (5.3%) or other immunosuppressive drugs (7%). HCQ, MTX, and RTX were associated with a significant reduction of tender and swollen joint count, and a significant steroids-sparing effect. No difference could be shown for the joint response between these treatment regimens. CONCLUSION: pSS articular manifestations may include synovitis which could mimic rheumatoid arthritis but differ by the absence of structural damage. Even if the use of HCQ, MTX, and RTX seem to be effective for joint involvement, the best regimen remains to be determined. PMID- 30408586 TI - Validation and meta-analysis of kappa index biomarker in multiple sclerosis diagnosis. AB - The importance of studying the cerebrospinal fluid (CSF) in Multiple Sclerosis (MS) is included in the last McDonald criteria (2018). The study of oligoclonal IgG bands (OCGB) assay is strongly recommended in some situations in which MS diagnosis is uncertain. New biomarkers are developed during the last years. Kappa free light chains (FLC) can predict conversion to MS in patients with Clinically Isolated Syndrome (CIS). The aim of this work is to validate the clinical usefulness of the kappa index, and to establish the actual state of knowledge for kappa index as a biomarker of conversion in CIS patients by a meta-analysis. Kappa index seems more relevant than the mere concentration of kappa FLC in CSF. In the validation study, 334 patients were included; in which 100 were CIS patients. Patients were divided in two groups according kappa index cut-off of 10.62: group 1 (kappa index>10.62); group 2 (kappa index<10.62). In group 1 more patients had positive OCGB, IgG index>0.56 and fulfilled magnetic resonance imaging (MRI) criteria. In contrast, in group 2, more patients showed negative OCGB, IgG index<0.56 and did not fulfilled MRI criteria. While 67.6% of patients from group 1 converted to MS, only 12.5% of patients from group 2 converted to MS. An HR of 6.02 was obtained in the Kaplan-Meier analysis. In the meta analysis, 8 studies were finally included. The SROC curve revealed a high diagnostic performance for the kappa index as a MS diagnostic biomarker. Despite heterogeneity found between studies, the global OR revealed a good discriminatory capacity of kappa index. In conclusion, kappa index has a great clinical sensitivity and specificity as a support in MS diagnosis. High kappa index increase the probability of CIS to MS conversion. A correct sample processing in the preanalytical stage is key to obtain right results and to allow establishing comparison between laboratories. PMID- 30408588 TI - Diagnostic performance of temporal artery ultrasound for the diagnosis of giant cell arteritis: a systematic review and meta-analysis of the literature. AB - Despite major recent advances in the therapeutic management of Giant cell arteritis (GCA), the diagnosis accuracy of temporal artery ultrasound remains controversial in this disease. We performed a systematic review to determine the sensitivity, specificity, and summary positive (LR+) and negative (LR-) likelihood ratios of temporal artery ultrasound for the diagnosis of GCA. For this, we searched EMBASE, MEDLINE and the Cochrane Database of Systematic Reviews without language restriction. Original articles reporting on diagnostic accuracy of temporal artery ultrasound compared to temporal artery biopsy, for the diagnosis of GCA, were selected. Sensitivity and specificity from each study were used to fit a bivariate diagnosis accuracy model. Of 1280 articles identified, 48 underwent full-text review, and 25 were included. Based on a total of 20 studies, the sensitivity and specificity of hypoechoic halo compared to positive temporal artery biopsy were respectively of 68% (95% CI: 57-78) and 81% (95%CI: 75-86). The summary mean positive and negative likelihood ratios were respectively of 3.64 (95%CI: 2.76-4.73) and 0.40 (0.28-0.52). Taking into account 11 studies reporting on the presence of any abnormal sign on temporal artery ultrasound yielded similar results with largely overlapping 95% confidence interval regions. This study provides the summary estimates of the diagnostic properties of temporal artery ultrasound compared to temporal artery biopsy, for the diagnosis of GCA. Those parameters allow the calculation of the post-test probability of GCA in a given patient, based on the results of temporal artery ultrasound and will help improving the diagnosis strategy for this common disease. PMID- 30408589 TI - X chromosome and female bias in systemic lupus erythematosus: Focus on population based evidence. PMID- 30408590 TI - Astrocytic expression of the chaperone DNAJB6 results in non-cell autonomous protection in Huntington's disease. AB - Several neurodegenerative diseases like Huntington's, a polyglutamine (PolyQ) disease, are initiated by protein aggregation in neurons. Furthermore, these diseases are also associated with a multitude of responses in non-neuronal cells in the brain, in particular glial cells, like astrocytes. These non-neuronal responses have repeatedly been suggested to play a disease-modulating role, but how these may be exploited to delay the progression of neurodegeneration has remained unclear. Interestingly, one of the molecular changes that astrocytes undergo includes the upregulation of certain Heat Shock Proteins (HSPs) that are classically considered to maintain protein homeostasis, thus resulting in cell autonomous protection. Previously, we discovered DNAJB6, a member of the human DNAJ family, as potent cell autonomous suppressor of PolyQ aggregation and related neurodegeneration. Using cell type specific expression systems in D. melanogaster, we show that exclusive expression of DNAJB6 in astrocytes (that do not express PolyQ protein) can delay neurodegeneration and expands lifespan when the PolyQ protein is exclusively expressed in neurons (that do not co-express DNAJB6 themselves). This provides direct evidence for a non-cell autonomous protective role of astrocytes in PolyQ diseases. PMID- 30408591 TI - Portrait of blood-derived extracellular vesicles in patients with Parkinson's disease. AB - The production of extracellular vesicles (EV) is a ubiquitous feature of eukaryotic cells but pathological events can affect their formation and constituents. We sought to characterize the nature, profile and protein signature of EV in the plasma of Parkinson's disease (PD) patients and how they correlate to clinical measures of the disease. EV were initially collected from cohorts of PD (n = 60; Controls, n = 37) and Huntington's disease (HD) patients (Pre manifest, n = 11; manifest, n = 52; Controls, n = 55) - for comparative purposes in individuals with another chronic neurodegenerative condition - and exhaustively analyzed using flow cytometry, electron microscopy and proteomics. We then collected 42 samples from an additional independent cohort of PD patients to confirm our initial results. Through a series of iterative steps, we optimized an approach for defining the EV signature in PD. We found that the number of EV derived specifically from erythrocytes segregated with UPDRS scores corresponding to different disease stages. Proteomic analysis further revealed that there is a specific signature of proteins that could reliably differentiate control subjects from mild and moderate PD patients. Taken together, we have developed/identified an EV blood-based assay that has the potential to be used as a biomarker for PD. PMID- 30408592 TI - Dopaminergic degeneration induces early posterior cortical thinning in Parkinson's disease. AB - BACKGROUND: Cognitive decline in Parkinson's disease (PD) is a highly prevalent condition with no effective treatment. Cortical atrophy is thought to promote its development but to design optimal therapeutic approaches in this clinical setting we need to understand the physiopathological mechanisms leading to this disorder. OBJECTIVE: To characterize the impact of dopaminergic degeneration on cortical integrity in early PD. METHODS: We studied 87 recently-diagnosed PD patients and 38 healthy controls from the Parkinson's Progression Marker Initiative who underwent I123-ioflupane SPECT (DATSCAN) and T1-MRI imaging. Using Freesurfer 6.0, we characterized baseline and longitudinal (one-year) correlations between striatal DAT uptake and cortical thickness. We also addressed the association between these imaging biomarkers and cognitive measures. RESULTS: Reduced DAT uptake in PD patients was associated with cross-sectional and longitudinal cortical thinning in frontal and posterior-cortical brain regions. Imaging parameters correlated with cognitive indicators in multiple domains that extend beyond frontal-executive tasks. Dopaminergic medication attenuated the longitudinal loss of cortical integrity in frontal and a subset of parietal regions, but not in other key regions such as the precuneus. DISCUSSION: To date, posterior cortical alterations in PD, known to play a major role in the development of PD-dementia, have mainly been attributed to a cholinergic degeneration occurring in later stages of the disease. Our results suggest that dopamine loss also promotes posterior-cortical atrophy from the very early stages of Parkinson's disease, which may have potential clinical and therapeutic implications. PMID- 30408593 TI - Mito-nuclear interactions modify Drosophila exercise performance. AB - Endurance exercise has received increasing attention as a broadly preventative measure against age-related disease and dysfunction. Improvement of mitochondrial quality by enhancement of mitochondrial turnover is thought to be among the important molecular mechanisms underpinning the benefits of exercise. Interactions between the mitochondrial and nuclear genomes are important components of the genetic basis for variation in longevity, fitness and the incidence of disease. Here, we examine the effects of replacing the mitochondrial genome (mtDNA) of several Drosophila strains with mtDNA from other strains, or from closely related species, on exercise performance. We find that mitochondria from flies selected for longevity increase the performance of flies from a parental strain. We also find evidence that mitochondria from other strains or species alter exercise performance, with examples of both beneficial and deleterious effects. These findings suggest that both the mitochondrial and nuclear genomes, as well as interactions between the two, contribute significantly to exercise capacity. PMID- 30408594 TI - Mitochondrial dynamics, a key executioner in neurodegenerative diseases. AB - Neurodegenerative diseases (NDs) are the group of disorder that includes brain, peripheral nerves, spinal cord and results in sensory and motor neuron dysfunction. Several studies have shown that mitochondrial dynamics and their axonal transport play a central role in most common NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS) etc. In normal physiological condition, there is a balance between mitochondrial fission and fusion process while any alteration to these processes cause defect in ATP (Adenosine Triphosphate) biogenesis that lead to the onset of several NDs. Also, mitochondria mediated ROS may induce lipid and protein peroxidation, energy deficiency environment in the neurons and results in cell death and defective neurotransmission. Though, mitochondria is a well studied cell organelle regulating the cellular energy demands but still, its detail role or association in NDs is under observation. In this review, we have summarized an updated mitochondria and their possible role in different NDs with the therapeutic strategy to improve the mitochondrial functions. PMID- 30408595 TI - Mitochondrial dysfunction and gut microbiota imbalance: An intriguing relationship in chronic kidney disease. PMID- 30408596 TI - Volitional limbic neuromodulation has a multifaceted clinical benefit in Fibromyalgia patients. AB - Volitional neural modulation using neurofeedback has been indicated as a potential treatment for chronic conditions that involve peripheral and central neural dysregulation. Here we utilized neurofeedback in patients suffering from Fibromyalgia - a chronic pain syndrome that involves sleep disturbance and emotion dysregulation. These ancillary symptoms, which have an amplification effect on pain, are known to be mediated by heightened limbic activity. In order to reliably probe limbic activity in a scalable manner fit for EEG-neurofeedback training, we utilized an Electrical Finger Print (EFP) model of amygdala-BOLD signal (termed Amyg-EFP), that has been successfully validated in our lab in the context of volitional neuromodulation. We anticipated that Amyg-EFP-neurofeedback training aimed at limbic down modulation should improve chronic pain in patients suffering from Fibromyalgia, by balancing disturbed indices for sleep and affect. We further expected that improved clinical status would correspond to successful training as indicated by improved down modulation of the Amygdala-EFP signal. Thirty-Four Fibromyalgia patients (31F; age 35.6 +/- 11.82) participated in a randomized placebo-controlled trial with biweekly Amyg-EFP-neurofeedback sessions and placebo of sham neurofeedback (n = 9) for a total duration of five consecutive weeks. Following training, participants in the Real-neurofeedback group were divided into good (n = 13) or poor (n = 12) modulators according to their success in the neurofeedback training. Before and after treatment, self reports on pain, depression, anxiety, fatigue and sleep quality were obtained, as well as objective sleep Indices. Long-term clinical follow-up was made available, within up to three years of the neurofeedback training completion. REM latency and objective sleep quality index were robustly improved following the treatment course only in the Real-neurofeedback group (both time * group p < 0.05) and to a greater extent among good modulators (both time*sub-group p < 0.05). In contrast, self-report measures did not reveal a treatment-specific response at the end of the treatment. However, the follow-up assessment revealed a delayed improvement in chronic pain and subjective sleep experience, evident only in the Real neurofeedback group (both time * group p < 0.05). Moderation analysis showed that the enduring clinical effects on pain evident in the follow-up assessment were predicted by the immediate improvements following training in objective sleep and subjective affect measures. Our findings suggest that Amyg-EFP- neurofeedback that specifically targets limbic activity down modulation offers a successful principled approach for volitional EEG based neuromodulation training in Fibromyalgia patients. Importantly, it seems that via its immediate sleep improving effect, the neurofeedback training induced a delayed reduction in the target subjective symptom of chronic pain, far and beyond the immediate placebo effect. This indirect approach to chronic pain management reflects the necessary link between somatic and affective dysregulation that can be successfully targeted using neurofeedback. PMID- 30408597 TI - Modular architecture of metabolic brain network and its effects on the spread of perturbation impact. AB - : Metabolic brain network, which is based on functional correlation patterns of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) images, has been widely applied in both basic and clinical neuroscience. Exploring the properties of the metabolic brain network can provide valuable insight to the physiologic and pathologic processes of the brain. Based on the network theory, modular architecture has the ability to limit the spread of local perturbation impact and therefore modular networks are more robust against external damage. However, whether the metabolic brain network has modular architecture remains unknown. METHODS: 77 rats performed 18F-FDG PET brain imaging. The metabolic brain network was then constructed by measuring interregional metabolic correlation in inter subject manner. Afterwards, modular architecture of the network was detected by a greedy algorithm. Further, we perturbed the metabolic brain network by inducing focal photothrombotic ischemia in the bilateral motor cortex and then measured the glucose metabolic change of each brain region using FDG-PET. RESULTS: A significant modular architecture was found in the metabolic brain network. The network could be divided into four modules which corresponding approximately to executive, learning/memory, visual/auditory and sensorimotor processing functional domains. After inducing the focal ischemia on the bilateral motor cortex, most of the significantly changed brain regions (13 of 17) belong to the sensorimotor module. CONCLUSION: Our results revealed an inherent modular architecture in the metabolic brain network and gave an experimental evidence that the modularity of the metabolism brain network could limit the spread of local perturbation impact. PMID- 30408598 TI - Decentralized temporal independent component analysis: Leveraging fMRI data in collaborative settings. AB - The field of neuroimaging has recently witnessed a strong shift towards data sharing; however, current collaborative research projects may be unable to leverage institutional architectures that collect and store data in local, centralized data centers. Additionally, though research groups are willing to grant access for collaborations, they often wish to maintain control of their data locally. These concerns may stem from research culture as well as privacy and accountability concerns. In order to leverage the potential of these aggregated larger data sets, we require tools that perform joint analyses without transmitting the data. Ideally, these tools would have similar performance and ease of use as their current centralized counterparts. In this paper, we propose and evaluate a new Algorithm, decentralized joint independent component analysis (djICA), which meets these technical requirements. djICA shares only intermediate statistics about the data, plausibly retaining privacy of the raw information to local sites, thus making it amenable to further privacy protections, for example via differential privacy. We validate our method on real functional magnetic resonance imaging (fMRI) data and show that it enables collaborative large-scale temporal ICA of fMRI, a rich vein of analysis as of yet largely unexplored, and which can benefit from the larger-N studies enabled by a decentralized approach. We show that djICA is robust to different distributions of data over sites, and that the temporal components estimated with djICA show activations similar to the temporal functional modes analyzed in previous work, thus solidifying djICA as a new, decentralized method oriented toward the frontiers of temporal independent component analysis. PMID- 30408599 TI - Analysis of Brassica napus dehydrins and their Co-Expression regulatory networks in relation to cold stress. AB - Dehydrins (DHNs) are plant specific cold and drought stress-responsive proteins that belong to late embryogenesis abundant (LEA) protein families. B. napus DHNs (BnDHNs) were computationally analyzed to establish gene regulatory- and protein protein interaction networks. Promoter analyses suggested functionality of phytohormones in BnDHNs gene network. The relative expressions of some BnDHNs were analyzed using qRT-PCR in seedling leaves of both cold-tolerant (Zarfam) and -sensitive (Sari Gul) canola treated/untreated by cold. Our expression data were indicative of the importance of BnDHNs in cold tolerance in Zarfam. BnDHNs were classified into three classes according to the expression pattern. Moreover, expression of three BnDHN types, SKn (BnLEA10 and BnLEA18), YnKn (BnLEA90) and YnSKn (BnLEA104) were significantly high in the tolerant cultivar at 12 h of cold treatment. Our findings put forward the possibility of considering these genes as screening biomarker to determine cold-tolerant breeding lines; something that needs to be further corroborated. Furthermore, these genes may have some implications in developing such tolerant lines via transgenesis. PMID- 30408600 TI - Transcriptomic responses to low temperature stress in the Nile tilapia, Oreochromis niloticus. AB - The Nile tilapia, Oreochromis niloticus, is a species of high economic value and extensively cultured. The limited stress tolerance of this species to a low temperature usually leads to mass mortality and great loss. Nevertheless, there is limited information on the molecular mechanisms underlying the susceptibility to low temperature in the tilapia. In this study, tilapia was treated at 28 degrees C to a lethal temperature of 8 degrees C by a gradual decrement. Transcriptomic response of the immune organ, kidney, in tilapia was characterized using RNA-seq. In total, 2191 genes were annotated for significant expression, which were mainly associated with metabolism and immunity. Pathway analysis showed that immune-related pathways of phagosome and cell adhesion molecules (CAMs) pathway were significantly down-regulated under low temperature. Moreover, ferroptosis, a significantly changed pathway involved in tissue damage and acute renal failure, is reported here for the first time. The levels of serum parameters associated with kidney damage such as urea and uric acid (UA) increased significantly under low temperature. The immunofluorescence staining of the kidney showed that cell apoptosis occurred at low temperature. The results of the present study indicate that exposure to low temperature can cause kidney disfunction and down-regulate the immune-related pathway in the kidney of tilapia. This study provides new insight into the mechanism of kidney damage in fish under low temperature. PMID- 30408601 TI - Characterisation of amphioxus protein kinase C-delta/theta reveals a unique proto V3 domain suggesting an evolutionary mechanism for PKC-theta unique V3. AB - A primitive adaptive immune system has recently been suggested to be present in a basal chordate amphioxus (Branchiostoma belcheri, Bb), making it an ideal model for studying the origin of adaptive immune. The novel protein kinase C isoform PKC-theta, but not its closest isoform PKC-delta, plays a critical role for mammalian T-cell activation via translocation to immunological synapse (IS) mediated by a unique PKC-theta V3 domain containing one PxxP motif. To understand the evolution of this unique PKC-theta V3 domain and the primitive adaptive immune system in amphioxus, we comparatively studied the orthologs of PKC-delta and -theta from amphioxus and other species. Phylogenetic analysis showed BbPKC delta/theta to be the common ancestor of vertebrate PKC-delta and PKC-theta, with a V3 domain containing two PxxP motifs. One motif is conserved in both zebrafish and mammalian PKC-theta but is absent in PKC-delta V3 domain of these species, and has already emerged in drosophila PKC-delta. The other non-conserved motif emerged in BbPKC-delta/theta, and only retained in Danio rerio PKC-delta (DrPKC delta) but lost in mammalian PKC-delta and -theta. Comparative analyses of the sequence and function of BbPKC-delta/theta, DrPKC-delta, DrPKC-theta and Homo sapiens PKC-theta (HsPKC-theta) in IS translocation and T-cell receptor (TCR) induced NF-kappaB activation revealed that retention of the conserved PxxP motif and loss of the non-conserved PxxP motif in mammalian PKC-theta and loss of both PxxP motifs in mammalian PKC-delta accomplish the unique function of PKC-theta in T cells. Together, this study suggests an evolutionary mechanism for PKC-theta unique V3 and reveals BbPKC-delta/theta is the common ancestor of PKC-delta and theta with a functional proto-V3 domain, supplying new evidence for the existence of primitive adaptive immune system in amphioxus. PMID- 30408602 TI - Eye contact reduces lying. AB - The perception of watching eyes has been found to reduce dishonest behavior. This effect, however, has only been shown in situations where it can be explained by increased adherence to rules and norms, and thus a watching-eyes effect on dishonesty per se has not been demonstrated. Moreover, the effect has been investigated only with images of watching eyes, not in an interactive situation with a live person, which may arguably have different effects on behavior. In the present study, the effect of watching eyes on dishonesty was investigated with an interactive computer game of lying. Participants played the game against a confederate, whom they believed to be another participant. On each trial, they were briefly presented with a view of the confederate, after which they chose whether to lie in the game. The confederate alternated between the use of direct and downward gaze. The results showed that another individual's direct gaze reduced lying in the game. The findings have implications for both everyday and professional situations, such as clinical conversations and police interrogations. PMID- 30408603 TI - How pervasive is mind wandering, really? AB - Recent claims that people spend 30-50% of their waking lives mind wandering (Killingsworth & Gilbert, 2010; Kane et al., 2007) have become widely accepted and frequently cited. While acknowledging attention to be inconstant and wavering, and mind wandering to be ubiquitous, we argue and present evidence that such simple quantitative estimates are misleading and potentially meaningless without serious qualification. Mind-wandering estimates requiring dichotomous judgments of inner experience rely on questionable assumptions about how such judgments are made, and the resulting data do not permit straightforward interpretation. We present evidence that estimates of daily-life mind wandering vary dramatically depending on the response options provided. Offering participants a range of options in estimating task engagement yielded variable mind-wandering estimates, from approximately 60% to 10%, depending on assumptions made about how observers make introspective judgments about their mind-wandering experiences and how they understand what it means to be on- or off-task. PMID- 30408604 TI - Narrative abilities of bilingual children with and without Developmental Language Disorder (SLI): Differentiation and the role of age and input factors. AB - PURPOSE: The narrative abilities of bilinguals with TD and with DLD/SLI in their English L2 were examined in order to 1) identify the narrative components that differentiate these two groups and 2) determine the role of age and input factors in predicting L2 narrative abilities in each group. METHOD: Participants were 24 English L2 children with DLD and 63 English L2 children with TD, matched on age (mean = 5; 8) and length of exposure to the L2 (mean = 24 months). Narrative samples were elicited using a story generation task and a parent questionnaire provided age and input variables. RESULTS: Bilinguals with DLD had significantly lower scores for story grammar than their TD peers, but showed similar scores for narrative microstructure components. Length of L2 exposure in school and richness of the L2 environment predicted better narrative abilities for the group with TD but not with DLD. Older age predicted better narrative abilities for the group with DLD but not with TD. Quantity of L2 input/output at home did not predict story grammar or microstructure abilities in either group. CONCLUSION: Story grammar might differentiate between children with TD and DLD better than microstructure among bilinguals with less exposure to the L2 and when a story generation task is used. Bilinguals with TD make more efficient use of L2 input than bilinguals with DLD. PMID- 30408605 TI - European paediatric non-alcoholic fatty liver disease registry (EU-PNAFLD): Design and rationale. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in children and has the potential to progress to advanced fibrosis/cirrhosis, end stage liver disease and hepatocellular carcinoma. However, the natural history of the condition is poorly understood and there are no approved treatments. The European Paediatric Non-Alcoholic Fatty Liver Disease Registry (EU-PNAFLD) is a multi-centre registry of paediatric NAFLD that will serve as a prospective, observational, natural history study and provide a tractable back-bone to support recruitment into subsequent interventional trials. Collection of samples into a bio-repository will facilitate translational studies, including genome sequencing and metabolomics. EU-PNAFLD will work closely alongside the existing adult European NAFLD Registry to obtain data on clinical outcomes after 20-30 years. Through an international, well-characterised large-scale cohort, EU-PNAFLD will address the key questions in paediatric NAFLD and benefit patients with the condition. PMID- 30408606 TI - Design of the Rural LEAP randomized trial: An evaluation of extended-care programs for weight management delivered via group or individual telephone counseling. AB - Obesity is a major contributor to the greater prevalence of chronic disease morbidity and mortality observed in rural versus nonrural areas of the U.S. Nonetheless, little research attention has been given to modifying this important driver of rural/urban disparities in health outcomes. Although lifestyle treatments produce weight reductions of sufficient magnitude to improve health, the existing research is limited with respect to the long-term maintenance of treatment effects and the dissemination of services to underserved populations. Recent studies have demonstrated the feasibility of delivering lifestyle programs through the infrastructure of the U.S. Cooperative Extension Service (CES), which has >2900 offices nationwide and whose mission includes nutrition education and health promotion. In addition, several randomized trials have shown that supplementing lifestyle treatment with extended-care programs consisting of either face-to-face sessions or individual telephone counseling can improve the maintenance of weight loss. However, both options entail relatively high costs that inhibit adoption in rural communities. The delivery of extended care via group-based telephone intervention may represent a promising, cost-effective alternative that is well suited to rural residents who tend to be isolated, have heightened concerns about privacy, and report lower quality of life. The Rural Lifestyle Eating and Activity Program (Rural LEAP) is a randomized trial, conducted via CES offices in rural communities, targeted to adults with obesity (n = 528), and designed to evaluate the effectiveness and cost-effectiveness of extended-care programs delivered via group or individual telephone counseling compared to an education control condition on long-term changes in body weight. PMID- 30408607 TI - Effects of Pre-Existing Comorbidities on Outcomes in Patients with Chronic Subdural Hematoma. AB - OBJECTIVE: The number of patients with chronic subdural hematoma (CSDH) showing comorbidities and/or impaired activities of daily living (ADL) before the onset of CSDH has increased with the recent aging of society. The purposes of this study were to evaluate ADL worsening by comparing premorbid ADL and ADL at discharge and to investigate the effects of pre-existing comorbidity-related clinical factors on the outcomes. METHODS: A total of 570 patients with CSDH admitted from 2006 to 2016 were studied retrospectively. Clinical factors, including pre-existing comorbidities, related to outcomes were identified by multivariate analysis. A variation of the modified Rankin Scale (mRS) using 5 united categories of mRS scores 0/1, 2, 3/4, 5, and dead was used for evaluation of ADL. RESULTS: Of 570 patients, 390 (68.4%) had pre-existing comorbidities and 120 (21.1%) showed premorbid impaired ADL (mRS scores 2 and worse). Considering pre-existing impaired ADL, ADL deteriorated after CSDH in 92 patients (16.1%), whereas ADL impairment at discharge was found in 173 patients (30.4%). Comorbidities related to ADL deterioration on multivariate analysis were hemodialysis and chronic heart failure. Antithrombotic use for cardiovascular diseases was a predictor of acute-on-chronic subdural hematoma, which was the sole common predictor for ADL deterioration and the occurrence of surgical complications. CONCLUSIONS: In patients with CSDH, pre-existing comorbidity linked factors related to outcomes were hemodialysis, chronic heart failure, and antithrombotic use. Patients with acute-on-chronic subdural hematoma with these factors should be regarded as a high-risk group. PMID- 30408608 TI - Monitoring Corticocortical Evoked Potentials During Intracranial Vascular Surgery. AB - BACKGROUND: Monitoring of corticocortical evoked potentials (CCEPs) during brain tumor surgery of patients under anesthesia was recently reported to be effective in assisting in preservation of speech function. The aim of this study was to investigate whether CCEPs can be reproducibly measured between the frontal and temporal lobes during standard intracranial vascular surgery under general anesthesia; whether dynamic changes in CCEPs caused by reduced focal cerebral blood flow can be measured; and whether CCEPs can be used to monitor speech function, particularly associated with the left side of the brain. METHODS: We monitored CCEPs during 58 vascular surgeries (42 clipping procedures; 15 bypasses, 1 of which overlapped with clipping; and 2 hematoma removals from the left frontal and temporal lobe) at Kashiwaba Neurosurgical Hospital from October 2016 to January 2018. RESULTS: CCEPs could be reproducibly and routinely monitored in bilateral vascular surgeries. None of the patients experienced any postoperative symptoms or showed any ischemic lesions on postoperative magnetic resonance imaging; however, 5 patients temporarily demonstrated reduced CCEPs intraoperatively that were caused by transient obstructions of blood flow. Motor evoked potentials and somatosensory evoked potentials were simultaneously monitored intraoperatively and did not show any changes. CONCLUSIONS: The results of our pilot study show that CCEPs can be routinely monitored during bilateral intracranial vascular surgery and that they are sensitive to ischemia. CCEPs on the left side could serve as unique intraoperative monitoring of speech function under anesthesia. PMID- 30408609 TI - Determining degradation intermediates and the pathway of 3' to 5' degradation of histone mRNA using high-throughput sequencing. AB - The half-life of an mRNA is an important parameter contributing to the steady state level of the mRNA. Rapid changes in mRNA levels can result from decreasing the half-life of an mRNA. Establishing the detailed pathway of mRNA degradation for a particular class of mRNAs requires the ability to isolate mRNA degradation intermediates. High-throughput sequencing provides a method for detecting these intermediates. Here we describe a method for determining the intermediates in 3' to 5' degradation. Characterizing these intermediates requires not only determining the precise 3' end of the molecule to a single nucleotide resolution, but also the ability to detect and characterize any untemplated nucleotides present on the intermediates. We achieve this by ligating a known sequence to all the 3' termini in the cell, and then sequence the 3' termini and the ligated linker to identify any alterations to the genomic reference sequence. We have applied this method to characterize the intermediates in histone mRNA metabolism, allowing us to deduce the pathway of 3' to 5' degradation. This method can potentially be applied to any RNA, and we discuss possible strategies for extending the method to include simultaneous determination of the 3' and 5' end of the same RNA molecule. PMID- 30408610 TI - Phenotyping and genotyping of skeletal dysplasias: Evolution of a center and a decade of experience in India. AB - Genetic heterogeneity, high burden and the paucity of genetic testing for rare diseases challenge genomic healthcare for these disorders in India. Here we report our experience over the past decade, of establishing the genomic evaluation of skeletal dysplasia at a tertiary university hospital in India. Research or clinical genomic testing was carried out by Sanger sequencing and next-generation sequencing. Close national and international collaborations aided phenotyping and genotyping. We report 508 families (557 affected individuals) with the definitive molecular diagnosis of skeletal dysplasia. Dysostoses multiplex (n = 196), genetic inflammatory/rheumatoid-like osteoarthropathies (n = 114) and osteogenesis imperfecta and decreased bone density (n = 58) were the most common diagnoses. We enumerate the processes, clinical diagnoses and causal variants in the cohort with 48 novel variants in 21 genes. We summarize scientific contributions of the center to the description of clinical and mutation profiles and discovery of new phenotypes and genetic etiology. Our study illustrates the establishment and application of genomic testing tools for genetic disorders of skeleton in a large cohort. We believe this could be a model to emulate for other developing genetic centers. PMID- 30408611 TI - Use it or lose it to age: A review of bone and muscle communication. AB - Until recently, it was assumed that the only interaction between muscle and bone is mechanical, that the muscle acts as a pulley and the bone as a lever to move the organism. A relatively new concept is that muscle, especially contracted muscle, acts as a secretory organ, regulating metabolism. An even newer concept is that bone, especially the osteocytes in bone, act as endocrine cells targeting other organs such as kidney and more recently, muscle. These two new concepts logically led to the third concept: that muscle and bone communicate via soluble factors. Crosstalk occurs through muscle factors such as myostatin, irisin, and a muscle metabolite, beta-aminoisobutyric acid, BAIBA, and through bone factors such as osteocalcin, transforming growth factor beta, TGFbeta, Prostaglandin E2, PGE2 and Wnts. Some of these factors have positive and some negative effects on the opposing tissue. One feature both bone and muscle have in common is that their tissues are mechanically loaded and many of their secreted factors are regulated by load. This mechanical loading, also known as exercise, has beneficial effects on many systems leading to the hypothesis that muscle and bone factors can be responsible for the beneficial effects of exercise. Many of the characteristics of aging and diseases associated with aging such as sarcopenia and osteoporosis and neurological conditions such as Alzheimer's disease and dementia, are delayed by exercise. This beneficial effect has been ascribed to increased blood flow increasing oxygen and nutrients, but could also be due to the secretome of the musculoskeletal system as outlined in this review. PMID- 30408612 TI - Bone and muscle specific circulating microRNAs in postmenopausal women based on osteoporosis and sarcopenia status. AB - MicroRNAs (miRNAs) are short, non-coding RNA molecules that fine tune posttranscriptional protein expression. Aging is accompanied by progressive declines in muscle mass and strength, and in bone mineral density (BMD). Although miRNAs in pathology have been extensively studied, the role of circulating miRNAs (c-miRNAs) in osteoporosis and sarcopenia has to date not been well understood. The purpose of this study was to examine the difference in bone and muscle specific c-miRNAs in postmenopausal women based on their bone and muscle status, and to determine the associations between these specific c-miRNAs and muscle and bone variables. Seventy-five postmenopausal women aged 60 to 85 years old participated in this study. Body composition and BMD, functional performance tests (grip strength, gait speed, and countermovement jumps) were assessed. Levels of c-miRNAs (miR-1-3p, -21-5p, -23a-3p, -24-3p, -100-5p, -125b-5p, -133a 3p, -206) and bone turnover markers were analyzed. Statistically, there were no significant differences in specific c-miRNAs based on sarcopenia and osteoporosis status. However, fold changes of miR-21-5p (FC = 2.59) and -23a-3p (FC = 2.09) indicated upregulation and miR-125b-5p (FC = 0.46) indicated downregulation in the osteoporotic group compared to the non-osteoporotic group. The relative expression level of miR-125b-5p was significantly positively correlated with age (p < 0.05). The relative expression level of miR-21-5p was significantly negatively correlated with trochanter BMC (p < 0.05). Furthermore, the relative expression level of miR-23a-3p was significantly positively correlated with TRAP5b levels (p < 0.05). Although no statistical differences were found in target c-miRNAs based on muscle and bone status, our results indicate that there are biological differential expressions in some c-miRNAs between osteoporotic and non-osteoporotic individuals. Other circulating miRNAs need to be studied in the future. PMID- 30408613 TI - Aberrantly elevated Wnt signaling is responsible for cementum overgrowth and dental ankylosis. AB - Vertebrate teeth are attached to the jawbones using a variety of methods but in mammals, a fibrous connection is the norm. This fibrous periodontal ligament (PDL) allows teeth to move in the jawbones in response to natural eruptive forces, mastication, and orthodontic tooth movement. In some disease states the PDL either calcifies or is replaced by a mineralized tissue and the result is ankylosis, where the tooth is fused to the alveolar bone. To understand how the PDL maintains this fibrous state we examined a strain of mice in which tooth movement is arrested. DabetacatOt mice express a stabilized form of beta-catenin in DMP1-positive alveolar bone osteocytes and cementocytes, which results in elevated Wnt signaling throughout the periodontium. As a consequence, there is an accrual of massive amounts of cellular cementum and alveolar bone, the PDL itself calcifies and teeth become ankylosed. These data suggest that to maintain its fibrous nature, Wnt signaling must normally be repressed in the PDL space. PMID- 30408614 TI - Turning distractors into targets increases the congruency sequence effect. AB - The congruency effect in distractor-interference tasks is typically smaller after incongruent trials than after congruent trials. Current views posit that this congruency sequence effect (CSE) reflects control processes that come into play when an irrelevant distractor cues a different response than a relevant target. However, the CSE is counterintuitively larger in the prime-probe task when the prime is occasionally a second target than when the prime is more frequently a distractor. In the present study, we investigated whether this effect occurs because the appearance of an occasional prime target (a) constitutes a rare, unexpected event that triggers heightened control or (b) allows participants to use the same task set (i.e., stimulus-response mapping) for the prime and probe in each trial. Consistent with the latter hypothesis, we observed this effect in Experiment 1 even when the critical trial types appeared equally often. Further, in Experiment 2, we extended this finding while ruling out perceptual differences between conditions as an alternative account. These findings provide novel support for the task set hypothesis and reveal that the CSE reflects control processes that do more than minimize distraction from irrelevant stimuli. PMID- 30408615 TI - Relationship between anaphylaxis and use of beta-blockers and angiotensin converting enzyme inhibitors: a systematic review and meta-analysis of observational studies. AB - BACKGROUND: Beta-blockers (BBs) and angiotensin-converting enzyme inhibitors (ACEIs) have been associated with an increased risk and severity of anaphylaxis. However, the evidence supporting these findings is contradictory. OBJECTIVE: We carried out a systematic review and meta-analysis of studies that assess the influence of BBs and ACEIs on anaphylaxis. METHODS: We searched PubMed/MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, and the Web of Science for relevant observational studies. We searched for studies where the presence and severity of anaphylaxis were compared between patients taking BBs, ACEIs, both types of drug, or neither type of drug. We performed a meta-analysis using a random-effects model. RESULTS: A total of 21 studies met the study criteria. Of these, 15 assessed the severity and 9 the incidence of anaphylaxis. The studies brought together 22,313 anaphylaxis episodes for the severity studies and 18,101 anaphylaxis episodes for the studies of new cases of anaphylaxis. BBs and ACEIs increased the severity of anaphylaxis (BBs, OR 2.19, 95% CI 1.25-3.84; ACEIs, OR 1.56, 95% CI 1.12-2.16), but not the presence of new cases of anaphylaxis (BBs, OR 1.40, 95% CI 0.91-2.14; ACEIs, OR 1.38, 95% CI 0.39-4.86). It was not possible to perform an analysis adjusted for cardiovascular diseases, since only 1 study each for BBs and ACEIs, respectively, had adjusted data. CONCLUSION: The quality of evidence showing that use of BBs and ACEI increases the severity of anaphylaxis is low owing to differences in the control of confounders arising from the concomitant presence of cardiovascular diseases. PMID- 30408616 TI - Efficacy of rituximab as a single-agent therapy for the treatment of granulomatous and lymphocytic interstitial lung disease in patients with common variable immunodeficiency. PMID- 30408617 TI - Integrin binding site within the gC1q domain orchestrates EMILIN-1-induced lymphangiogenesis. AB - Lymphatic vessels (LVs) play a pivotal role in the control of tissue homeostasis and also have emerged as important regulators of immunity, inflammation and tumor metastasis. EMILIN-1 is the first ECM protein identified as a structural modulator of the growth and maintenance of LV; accordingly, Emilin1-/- mice display lymphatic morphological alterations leading to functional defects as mild lymphedema, leakage and compromised lymph drainage. Many EMILIN-1 functions are exerted by the binding of its gC1q domain with the E933 residue of alpha4 and alpha9beta1 integrins. To investigate the specific regulatory role of this domain on lymphangiogenesis, we generated a transgenic mouse model expressing an E933A mutated EMILIN-1 (E1-E933A), unable to interact with alpha4 or alpha9 integrin. The mutant resulted in abnormal LV architecture with dense, tortuous and irregular networks; moreover, the number of anchoring filaments was reduced and collector valves had aberrant narrowed structures. E933A mutation also affected lymphatic function in lymphangiography assays and made the transgenic mice more prone to lymph node metastases. The finding that the gC1q/integrin interaction is crucial for a correct lymphangiogenesis response was confirmed and reinforced by functional in vitro tubulogenesis assays. In addition, ex vivo thoracic-duct ring assays revealed that E1-E933A-derived lymphatic endothelial cells had a severe reduction in sprouting capacity and were unable to organize into capillary-like structures. All these data provide evidence that the novel "regulatory structural" role of EMILIN-1 in the lymphangiogenic process is played by the integrin binding site within its gC1q domain. PMID- 30408618 TI - Cardiorespiratory morbidity and mortality of opioid overdose during admission to safety-net hospitals. AB - STUDY OBJECTIVE: Safety-net hospitals disproportionately care for high-risk patients. Prior work has shown safety-net hospitals to have inferior postoperative outcomes with higher cost and worse patient ratings. We aim to examine the association of hospital safety-net burden with morbidity and mortality in patients with opioid overdose hospital admission. DESIGN: Retrospective cross-sectional analysis using the National Inpatient Sample registry from 2010 to 2014. SETTING: Multi-institutional. PATIENTS: We included 547, 399 patients admitted to a United States hospital with an International Classification of Disease, Ninth Revision, code of opioid overdose. To study the association of hospital safety-net burden on mortality and morbidity, we calculated hospital safety-net burden defined as the percent of Medicaid or uninsured among all admitted patients. Hospitals were categorized into one of three categories: low burden hospitals, medium burden hospitals, and high burden hospitals (i.e., safety-net hospitals). We performed a mixed effects multivariable logistic regression analysis to assess the association of hospital safety-net burden with short-term inpatient outcomes. INTERVENTION: None. MEASUREMENTS: The primary outcomes were inpatient mortality and morbidity. MAIN RESULTS: Compared to MBHs and LBHs, HBHs had a greater proportion of minority patients (i.e., Black, Hispanic, and Native American) and patients with median household income in the lowest quartile (p < 0.001). Among prescription opioid overdose admissions, the odds of inpatient mortality and pulmonary and cardiac morbidity were also not significantly higher between HBHs versus LBHs (p > 0.05). CONCLUSIONS: Safety-net hospital disproportionately care for vulnerable populations, however the odds of poor outcomes were no different in opioid overdose. Safety-net hospitals should have equal access to the funding and resources that allows them to deliver the same standard of care as their counterparts. PMID- 30408619 TI - Airway management in a case of Morbihan syndrome; A rare clinical entity. PMID- 30408620 TI - Aksu approach for lumbar erector spinae plane block for pediatric surgeries. PMID- 30408621 TI - System-integrated technology-enabled model of care to improve the health of stroke patients in rural China: protocol for SINEMA-a cluster-randomized controlled trial. AB - BACKGROUND: Despite the significant burden of stroke in rural China, secondary prevention of stroke is suboptimal. This study aims to develop a SINEMA for the secondary prevention of stroke in rural China and to evaluate the effectiveness of the model compared with usual care. METHODS: The SINEMA model is being implemented and evaluated through a 1-year cluster-randomized controlled trial in Nanhe County, Hebei Province in China. Fifty villages from 5 townships are randomized in a 1:1 ratio to either the intervention or the control arm (usual care) with a target to enroll 25 stroke survivors per village. Village doctors in the intervention arm (1) receive systematic cascade training by stroke specialists on clinical guidelines, essential medicines and behavior change; (2) conduct monthly follow-up visits with the support of a mobile phone application designed for this study; (3) participate in virtual group activities with other village doctors; 4) receive performance feedback and payment. Stroke survivors participate in a health education and project briefing session, receive monthly follow-up visits by village doctors and receive a voice message call daily as reminders for medication use and physical activities. Baseline and 1-year follow up survey will be conducted in all villages by trained staff who are blinded of the randomized allocation of villages. The primary outcome will be systolic blood pressure and the secondary outcomes will include diastolic blood pressure, medication adherence, mobility, physical activity level and quality of life. Process and economic evaluation will also be conducted. DISCUSSION: This study is one of very few that aim to promote secondary prevention of stroke in resource constrained settings and the first to incorporate mobile technologies for both healthcare providers and patients in China. The SINEMA model is innovative as it builds the capacity of primary healthcare workers in the rural area, uses mobile health technologies at the point of care, and addresses critical health needs for a vulnerable community-dwelling patient group. The findings of the study will provide translational evidence for other resource-constrained settings in developing strategies for the secondary prevention of stroke. PMID- 30408623 TI - Dual functionality of lamprey VLRB C-terminus (LC) for multimerization and cell surface display. AB - Lamprey, one of the living representatives of jawless vertebrates, uses variable lymphocyte receptors B (VLRB) for antigen recognition, rather than immunoglobulin (Ig) based receptors as used by higher vertebrates. The C-terminus of lamprey VLRB (LC) possess a glycosylphosphatidylinositol (GPI) signal sequence and seven cysteine residues providing dual functionality of the VLRB antibody in the form of a humoral agglutinin and cell membrane receptors. Here, we show that the LC can be either secreted or be membrane anchored as a heterologous fused protein in a multimeric form comprising of eight or ten monomeric units. Using serially truncated LC variants, we showed that the LC, in which the last three amino acid "RKR" were deleted, referred to as LC7, was the most suitable domain for multimeric construction, whereas, the intact LC is more tailored for applications involving membrane anchorage. We show that an antibody specific for viral hemorrhagic septicemia virus (VHSV) (VLR43), displayed on HEK-293F cells using a PiggyBac (PB) transposase system, exhibited a dose-dependent reaction with its antigen, verifying that the LC can be applied in antibody display technology. Therefore, the present report provides valuable insight into the structure of the lamprey VLRB and highlights its potential use as a novel fusion partner for multimerization and membrane anchorage of chimeric proteins. PMID- 30408622 TI - Acidic pH promotes oxidation-induced dissociation of C-reactive protein. AB - BACKGROUND: Circulating levels of the systemic inflammation marker C-reactive protein (CRP) have been associated with increased risk and poor outcomes of many diseases, such as cardiovascular events and cancer. Accumulating evidence has indicated that the conformational rearrangement of human pentameric CRP (pCRP) to monomeric CRP (mCRP) is a prerequisite for participation in the pathogenesis. Therefore, determining the mechanism of the dissociation of pCRP into pro inflammatory mCRP under physiological/pathological circumstances has been intriguing. METHODS: The effects of oxidative and acidic stress occurring in inflammation on pCRP were examined by electrophoresis, electron microscopy, protein fluorescence, neoepitope expression and endothelial cell responses. RESULTS: Reactive oxygen species (ROS) generated by the copper-hydrogen peroxide system could rapidly induce the dissociation of CRP at mild acidic pH within four hours, but not at physiological pH of 7.4. Meanwhile, mannitol, a ROS scavenger, could not protect against dissociation, which implied that local ROS from accessible histidine residues may be crucially beneficial to the formation of mCRP in a redox-balanced microenvironment. Furthermore, mCRP generated by ROS could be reduced by DTT, which indicated the exposure of functional motif aa35 47, and showed potent proinflammatory actions on endothelial cells, comparable to mCRP generated by urea. CONCLUSION: dissociation of pCRP to mCRP could be rapidly induced by ROS from copper- hydrogen peroxide system in dependence on mildly acidic stress regardless of a redox-balanced microenvironment. PMID- 30408624 TI - Concept of sample-specific correction of immunoassay results for precise and accurate IgG quantification in horse plasma. AB - The hyperimmune horse plasma (HHP), prepared through active immunisation of horses with an antigen of interest, is the most common starting material for antitoxin (animal antibody-based therapeutics) production. Precise IgG quantification in plasma is a prerequisite for accurate estimation of the purification process efficiency. Although immunoglobulins from HHP have been purified for over a century, there is still no in vitro method for precise and accurate determination of IgG content in HHP. For this reason, the purification process efficiency has been assessed by antibody activity measurements, mostly performed in vivo. Here we describe the development of a precise and accurate in vitro immunoassay for IgG quantification in HHP. We showed and highlighted that any difference in composition of IgG population between the standard and the sample, with respect to both IgG subclass distribution and antigen-specific IgG content, leads to inaccurate IgG quantification. We demonstrated that caprylic acid precipitation as the method for IgG isolation from horse plasma renders the composition of IgG population unchanged. This very efficient, fast, simple and inexpensive method was used to prepare internal, sample-specific reference IgG for each plasma sample, which was tested simultaneously to a respective plasma sample. Deviation of IgG quantity determined by ELISA for each sample-specific reference from its nominal value was used for correction of the results of respective plasma sample, which led to accurate and precise IgG quantification as shown by method validation. The here presented novel concept of sample-specific correction of immunoassay results could be widely applicable and easily introduced in different immunoassays for more accurate and precise plasma IgG quantification. PMID- 30408625 TI - Optimal pulmonary valve annulus diameter for annulus preservation in tetralogy of Fallot may be far smaller than normal annulus size. AB - OBJECTIVES: We hypothesized that optimal pulmonary valve annulus (PVA) diameter upon annulus preservation (AP) in tetralogy of Fallot (ToF) may be far smaller than the normal diameter. METHODS: Retrospective review of the 61 consecutive patients who underwent ToF repair between January 2016 and September 2017 was performed. Median age, body weight, and median PVA (Z) at repair were 166 days (Interquartile range, IQR, 141-182 days), 7.4 kg (IQR, 6.6-8.0 kg), and -1.83 (IQR, -2.56--0.90), respectively. Upon AP, subvalvar and supravalvar obstruction were completely eliminated, leaving a pressure gradient only at the valve level. RESULTS: AP was achieved in 58 patients (95.1%). Pulmonary valve intervention comprised commissurotomy in 35 patients, commissurotomy with bougination in 8 patients, and transannular patching (TAP) in 3 patients. For 15 patients, the pulmonary valve was left intact. Median PVA diameter measured by Hegar dilator after PV intervention was 8 mm (IQR, 7 to 9 mm), which was 3.9 mm (IQR, 2.3 to 4.3 mm) smaller than normal dimension and translated to a PVA (Z) of -1.85 (IQR, 2.40 to -0.78). Post-repair right and left ventricular pressure ratio was 0.47 +/ 0.12. During the median follow-up duration of 353 days (IQR, 191 to 482 days), 4 patients (including three who underwent TAP) developed significant pulmonary regurgitation. Freedom from reintervention for PS, significant PS and PR at 1 year was 92.4%, 83.2% and 90.6%, respectively. CONCLUSIONS: Optimal PVA for AP may be far smaller than the normal diameter. Minimizing PV intervention upon AP can prevent superfluous postoperative PR. PMID- 30408627 TI - A novel systemic inflammation response index (SIRI) for predicting postoperative survival of patients with esophageal squamous cell carcinoma. AB - BACKGROUND: Inflammation is closely associated with the initiation and development of tumors. Based on the counts of peripheral neutrophils, monocytes and lymphocytes, we established a new systemic inflammation response index (SIRI) to predict postoperative survival of patients with esophageal squamous cell carcinoma (ESCC). METHODS: A total of 916 ESCC patients treated with radical esophagectomy were enrolled in the present study. RESULTS: Survival analysis indicated that the median overall survival (OS) in patients with SIRI<=1.2 was significantly higher than that in patients with SIRI>1.2. The nomogram including SIRI could more accurately predict OS compared with the TNM staging system. In addition, the changes of SIRI from baseline to 8 weeks after the operation were correlated with patient survival. The patients with an increase in SIRI >75% had worse OS compared with those with no change, while the patients with a decrease in SIRI >75% or in the scope of 25% ~75% exhibited better OS. CONCLUSIONS: SIRI was an independent prognostic index of ESCC patients after the radical resection. The nomogram integrating the SIRI could help clinicians to screen the high-risk patients and formulate the individualized treatment schemes. PMID- 30408628 TI - Liposomes encapsulated dimethyl curcumin regulates dipeptidyl peptidase I activity, gelatinase release and cell cycle of spleen lymphocytes in-vivo to attenuate collagen induced arthritis in rats. AB - Rheumatoid arthritis (RA) is an autoimmune disease and characterized by the excessive cell proliferation, abnormal cell cycle of lymphocytes and synovial cells. The therapeutic effects of curcumin in active RA patients were reported, but limited by its insolubility and rapid systemic elimination. Dimethyl curcumin (DiMC) is a metabolically stable analogue of curcum with anti-inflammatory property. In this study, liposomes encapsulated dimethyl curcumin (Lipo-DiMC) was prepared to improve the bioavailability and metabolic-stability; collagen induced arthritis (CIA) rat model was employed to investigate the effects of Lipo-DiMC treatments during CIA progress. Physical assessments and routine-blood-test were performed. Fresh spleen lymphocytes were isolated from normal, CIA and Lipo-DiMC treated CIA rats; flow-cytometry for cell-cycle analysis, western-blotting for intracellular signal pathway protein expressions, gelatin-zymography for matrix metalloproteases 2/9 (MMP-2/9) and GF-AFC for dipeptidyl-peptidase I (DPPI) activity assay. Compared with untreated CIA rats, Lipo-DiMC treatments relieved paw-swellings, suppressed the increments of immunocytes numbers and inhibited DPPI and MMP-2/9 over-activity in blood. Lipo-DiMC adjusted CIA-induced cell cycle dysfunction at G0/G1-phase and S-phase of spleen lymphocytes for CIA rats. The intracellular expression-trends of P38, P21, Bcl-2, JNK-1 and DPPI of spleen lymphocytes were observed during CIA progress with and without Lipo-DiMC administrations. Lipo-DiMC exhibited its therapeutic functions by attenuating CIA development in rats, associated with down-regulating CIA-induced lymphocytes numbers, inhibiting over-expressed of DPPI and MMP-2/9, and adjusting cell cycles. These findings provide a new insight into the mechanism of Lipo-DiMC treatment in CIA rat model and suggest that Lipo-DiMC could be considered as a potential drug for RA treatment. PMID- 30408626 TI - Neuroanatomical abnormalities in fragile X syndrome during the adolescent and young adult years. AB - Abnormal brain development and cognitive dysfunction have been reported both in children and in adults with fragile X syndrome (FXS). However, few studies have examined neuroanatomical abnormalities in FXS during adolescence. In this study we focus on adolescent subjects with FXS (N = 54) as compared to age- and sex matched subjects with idiopathic intellectual disability (Comparison Group) (N = 32), to examine neuroanatomical differences during this developmental period. Brain structure was assessed with voxel-based morphometry and independent groups t-test in SPM8 software. Results showed that the FXS group, relative to the comparison group, had significantly larger gray matter volume (GMV) in only one region: the bilateral caudate nucleus, but have smaller GMV in several regions including bilateral medial frontal, pregenual cingulate, gyrus rectus, insula, and superior temporal gyrus. Group differences also were noted in white matter regions. Within the FXS group, lower FMRP levels were associated with less GMV in several regions including cerebellum and gyrus rectus, and less white matter volume (WMV) in pregenual cingulate, middle frontal gyrus, and other regions. Lower full scale IQ within the FXS group was associated with larger right caudate nucleus GMV. In conclusion, adolescents and young adults with FXS demonstrate neuroanatomical abnormalities consistent with those previously reported in children and adults with FXS. These brain variations likely result from reduced FMRP during early neurodevelopment and mediate downstream deleterious effects on cognitive function. PMID- 30408629 TI - B-cell-specific mammalian target of rapamycin complex 1 activation results in severe osteoarthritis in mice. AB - This study aims to investigate the effect of enriched plasma cells on the production of inflammatory cytokines and development of osteoarthritis (OA) in mice with B-cell-specific conditional deletion of the tuberous sclerosis 1 gene (TSC1). OA was induced by destabilization of the medial meniscus (DMM) in mice with TSC1 disruption in B cells (CD19-TSC1) and in littermate control mice (CON). The effects of DMM and incidence of OA were evaluated histologically, mRNA levels of inflammatory cytokines were detected by polymerase chain reaction, and serum cytokine levels were detected by enzyme-linked immunosorbent assay. Deletion of TSC1 caused constitutive activation of mechanistic target of rapamycin complex 1 mTORC1 in B cells. CON mice subjected to DMM exhibited a severe OA phenotype with increased inflammatory cytokines in B cells, serum, and the synovial membrane. Importantly, inflammatory cytokine production was also increased in B cells from the spleen of CD19-TSC1 conditional KO mice, but the OA phenotype was significantly elevated in conditional KO mice after DMM surgery compared with CON mice, as indicated by more severe articular cartilage destruction, increased protein expression of matrix metalloproteinase-13 and mRNA of type X collagen in the articular cartilage, decreased mRNA expression of type II collagen in the articular cartilage, and increased inflammatory cytokines in serum and the synovial membrane. The results demonstrate that inflammatory cytokine synthesis by B cells was enriched in CD19-TSC1 conditional KO mice, and this enhanced synthesis of inflammatory cytokines accelerated the incidence of OA. PMID- 30408631 TI - Factors and mechanisms that influence the reactivity of trivalent copper: A novel oxidant for selective degradation of antibiotics. AB - Trivalent copper complexes are active intermediates in aquatic redox reactions that involve copper ions or structural copper, but their reactivity and selectivity toward pollutants remain unknown. We characterized copper(III) periodate, a representative trivalent copper compound, with phenol and several antibiotics as model contaminants. The results show that Cu(III) is highly reactive to phenol degradation; near-complete degradation was achieved after 10 min at a molar ratio of 3:1 (Cu[III]: phenol). Common alcohols, including methanol and 2-propanol, showed pH-dependent reactivity for Cu(III). In contrast to aquo trivalent copper ions that react rapidly with tert-butanol, Cu(III) showed limited reactivity toward tert-butanol. A mechanistic investigation showed that the degradation was caused by direct oxidation by Cu(III) and that no hydroxyl radicals were involved. Common water components such as chloride ions did not influence the reaction, which suggests that the use of Cu(III) may help mitigate the generation of chlorinated products. As a one-electron oxidant, Cu(III) showed high reactivity to degrade electron-rich compounds; the concentrations of sulfamethazine, sulfamethoxazole, and sulfadiazine (100 MUg/L) were reduced to 1.8, 7.5, and 42.5 ng/L, respectively, after 2 min of reaction with 10 MUM Cu(III). These results demonstrate a novel and highly efficient oxidant for selective removal of ubiquitous micropollutants from water bodies. PMID- 30408630 TI - Apigenin reverses lung injury and immunotoxicity in paraquat-treated mice. AB - Paraquat (PQ) induces acute lung injury (ALI) and immunotoxicity. Apigenin exerts anti-oxidant and anti-inflammatory properties. The purpose of this study was to investigate the possible protective effects of apigenin on PQ-induced ALI and immunotoxicity in mice. Female C57BL/6 mice received a single injection of PQ (50 mg/kg). Apigenin was given for 7 consecutive days starting 5 days before PQ exposure. The toxicity markers were evaluated in terms of weight loss, lung histopathology, oxidative stress, inflammation, and T cell functions after PQ exposure. Poisoned mice exhibited severe lung tissue lesions, inflammatory cell infiltration and the release of pro-inflammatory cytokines IL-6 and TNF-alpha. PQ administration increased the lung wet/dry ratios and lipid peroxidation by the increase of MDA levels and decreased anti-oxidase activity including SOD, GSH-PX, and CAT. While such effect on lung was reversed by apigenin. Importantly, PQ induced immunotoxicity was also observed in a decrease of spleen weight, inhibition of T cell proliferation and T-cell secreting IL-2 from splenocytes. Further mechanism analysis found that PQ administration could decrease total splenocytes, CD4+ and CD8+ T cells, SOD, GSH-PX, and CAT activity, and increased the levels of MDA and the concentrations of pro-inflammatory cytokines IL-6 and TNF-alpha compared to control mice. However, apigenin treatment reversed PQ induced immunotoxicity. In summary, all results suggest that apigenin has beneficial effects on PQ-induced ALI and immunotoxicity possibly, and it could be related, at least in part, to its ability in modulating inflammation and oxidative stress, although in-depth studies might be needed to fully understand the mechanism of action. PMID- 30408632 TI - To sense or not to sense-new insights from GPCR-based and arrestin-based biosensors. AB - Advances in resolving crystal structures of GPCRs and their binding partners as well as improvements in live-cell microscopy and the fluorescent proteins pallet has greatly driven new ideas for designing optical sensors for the same. Sensors have been developed to monitor ligand binding as well as the ensuing ligand induced conformational changes in GPCRs, G-proteins and arrestins. In this review we will highlight the functionality of such sensor designs starting from monitoring ligand binding to receptor activation and interaction with arrestins. Furthermore, we will highlight the importance of sensor designs to monitor receptor-dependent arrestin conformations and give an idea about the various detected arrestin conformations and their possible implications. PMID- 30408633 TI - Evaluation of ions and metals in the blood of GRMD dogs submitted to hASCs therapy by NAA and XRF techniques. AB - The elements Br, Ca, Cl, Cr, Fe, K, Mg, Na, P, Rb, S, and Zn were investigated in the whole blood samples of Golden Retriever dogs submitted to cell therapy (hASCs). These analyses were performed over 2 years using Neutron Activation Analysis and X-Ray Fluorescence techniques. The results were compared with control and untreated dog's. A significant increase was observed in K blood levels. There was also variation in blood levels of Br, Cr, Fe, Rb, S, and Zn. PMID- 30408634 TI - Evaluation of 72Se/72As generator and production of 72Se for supplying 72As as a potential PET imaging radionuclide. AB - Positron-emitting 72As is the PET imaging counterpart for beta-emitting 77As. Its parent, no carrier added (n.c.a.) 72Se, was produced for a 72Se/72As generator by irradiating an enriched 7 degrees Ge metal-graphite target via the 70Ge(alpha, 2 n)72Se reaction. Target dissolution used a fast, environmentally friendly method with 93% radioactivity recovery. Chromatographic parameters of the 72Se/72As generator were evaluated, the eluted n.c.a. 72As was characterized with a phantom imaging study, and the previously reported trithiol and aryl-dithiol ligand systems were radiolabeled with the separated n.c.a. 72As in high yield. PMID- 30408635 TI - Elevated coagulation factor levels affect the tissue factor-threshold in thrombin generation. AB - INTRODUCTION: Altered levels of factor (F)VIII, prothrombin, or antithrombin have been associated with an increased risk for venous thromboembolism (VTE). However, the exact molecular mechanism by which these altered factor levels modulate the risk is incompletely understood. Here we hypothesize that elevated factor levels affect the pro- and anticoagulant balance in coagulation such that even minute amounts of tissue factor (TF) will initiate thrombin formation, thereby contributing to the VTE risk. MATERIALS AND METHODS: To test this so-called TF threshold hypothesis, we monitored thrombin generation initiated by very low TF concentrations in FXII-deficient plasma, to avoid any contact pathway-mediated thrombin formation. Furthermore, similar experiments were performed in the presence of increasing concentrations of pro- and anticoagulant proteins. RESULTS: A TF-threshold was established in the FXII-deficient plasma, which is subject to inter-individual variation. Elevated plasma levels of procoagulant factors, such as FVIII or prothrombin, enhanced thrombin generation and reduced the amount of TF required for the initiation of thrombin formation. Conversely, elevated levels of the coagulation inhibitor antithrombin increased the TF threshold. CONCLUSIONS: Our findings support a mediating role for the TF threshold in the association between high procoagulant factor levels and the risk for VTE. Furthermore, elevated levels of anticoagulants may have a protective effect on the development of VTE. PMID- 30408636 TI - A dichotomy in platelet activation: Evidence of different functional platelet responses to inflammatory versus haemostatic stimuli. AB - INTRODUCTION: Platelets participate in inflammatory disorders through a variety of different functional responses, including chemotaxis, platelet-leukocyte complex formation and facilitation of leukocyte recruitment that are thought to be distinct from platelet aggregation. This may account for why classical anti platelet drugs have failed to ameliorate inflammatory disorders where platelets are known to participate, suggesting that distinct pathways may control inflammatory and haemostatic functions of platelets. In the present study, we have therefore investigated the effect of different stimuli on several different functions of platelets preferentially involved either in haemostasis or in inflammation. MATERIALS AND METHODS: Human platelets were stimulated with either inflammatory (fMLP, histamine, IL-1beta, LPS, MDC/CCL22, SDF-1alpha/CXCL12 and 5 HT) or haemostatic (ADP, collagen, convulxin, epinephrine, TRAP-6 and U46619) stimuli. Aggregation, platelet-leukocyte complex formation, platelet migration and platelet protein phosphorylation were assessed. RESULTS: Haemostatic stimuli induced platelet aggregation, whilst inflammatory agonists induced platelet migration. The haemostatic stimuli, with the exception of epinephrine, and some of the inflammatory stimuli induced platelet-leukocyte complex formation, even if to a different extent. Furthermore, inflammatory stimuli induced a shorter lasting profile of platelet protein phosphorylation compared with haemostatic stimuli. CONCLUSIONS: Stimulation of platelets with inflammatory stimuli triggers the activation of non haemostatic functions different from those induced by haemostatic stimuli, supporting the existence of alternative platelet responses depending on the stimulus (haemostatic or inflammatory). A deeper understanding of the biochemical pathways behind these functional differences may lead to the development of novel therapeutic options targeting the inflammatory actions of platelets, without affecting their critical role in haemostasis. PMID- 30408637 TI - Heparin-induced thrombocytopenia and sepsis. PMID- 30408638 TI - Increased expression of a novel miRNA in peripheral blood is negatively correlated with hippocampal volume in patients with major depressive disorder. AB - BACKGROUND: Major depressive disorder (MDD) is a serious psychiatric illness with unclear pathophysiology. As one of the post-transcriptional regulators, prior research has indicated that miRNAs are involved in the pathophysiology of MDD. The aim of this study was to screen the MDD-related miRNAs in the peripheral blood and investigate the target genes of the differentially expressed miRNAs and their potential functions in MDD pathophysiology. METHODS: miRNA sequencing was performed using the peripheral blood of patients with MDD and matched controls (cohort A, 10 vs 10). The nominal significant results were validated in an independent sample (cohort B, 72 vs 75) by real-time quantitative polymerase chain reaction (PCR). The target genes of verified miRNAs were predicted using Miranda software. Luciferase assay was used to verify one of the predicted target genes. Furthermore, we analyzed the correlations between the expression of pmiR chr11 and hippocampal volume. RESULTS: Ten miRNAs were nominally significantly dysregulated in patients with MDD in cohort A. One of the 10 miRNAs, pmiR-chr11, was significantly dysregulated in cohort B. The pmiR-chr11 could regulate one of the target genes, BRPF1 (bromodomain and PHD finger containing 1), via binding its 3' untranslated region (UTR). The expression of pmiR-chr11 was negatively correlated with hippocampal volume in patients with MDD. LIMITATIONS: The expression of the miRNAs and mRNAs detected in the peripheral blood may not reflect the expression in the brain. CONCLUSIONS: Our findings suggested that the pmiR-chr11 may influence hippocampal volume by regulating BRPF1 in MDD. PMID- 30408639 TI - Food allergy is associated with depression and psychological distress: A web based study in 11,876 Japanese. AB - BACKGROUND: Although some studies suggest a possible association between food allergy (FA) and depression/psychological distress, empirical data are still scarce. We aimed to examine whether this association exists in a large sample of the Japanese population. METHODS: This web-based cross-sectional survey included 1000 individuals with self-reported lifetime history of clinical depression (mean age: 41.4 years, 501 men), and the remaining 10,876 subjects served as controls (mean age: 45.1 years, 5691 men). A six-item Kessler scale (K6) test was used to evaluate severe psychological distress. Information on FA was obtained by a self report checking for 27 specific allergens. RESULTS: Participants with FA, 2 or more, 3 or more, and 4 or more allergens were more common in the depression group than in the control group (odds ratio [OR] = 1.64, 1.75, 2.02, and 2.27, respectively; p < 0.001). In the allergen analyses, allergies for shrimp, egg, mackerel, crab, kiwi fruit, milk, banana, and squid (nominal, p < 0.05) were more common in the depression group than in the controls. The proportion of individuals who had a K6 test cut-off score >= 13 was higher in the FA group than in the non-FA group, in the total sample (OR = 1.32, 1.62, 2.04 and 2.51; 1, 2, 3, and 4 or more allergens, respectively; p < 0.001). LIMITATIONS: The identification of FA and depression was based on self-reports. CONCLUSIONS: Our data suggest that FA is a risk factor for depression and severe psychological distress, which depends on the number of allergens. PMID- 30408640 TI - Naturally occurring nanotube with surface modification as biocompatible, target specific nanocarrier for cancer phototherapy. AB - Phototherapy has drawn increasing attention including the use of nanocarriers with high drug loading capacity and delivery efficacy for target-specific therapy. We have made use of naturally-occurring halloysite nanotubes (HNTs) to build a biomimetic nanocarrier platform for target-specific delivery of phototherapeutic agents. The HNTs were decorated with poly(sodium-p styrenesulfonate) (PSS) to enhance the biocompatibility, and were further functionalized by lumen loading the type-II photosensitizer indocyanine green (ICG). The HNT-PSS-ICG nanocarrier, without further tethering targeting groups, was shown to associate with the membrane of giant unilamellar vesicles (GUVs) via Pickering effects. Application of HNT-PSS-ICG nanocarrier to human breast cancer cells gave rise to a cell mortality as high as 95%. The HNT-PSS-ICG nanocarrier was further coated with MDA-MB-436 cell membranes to endow it with targeting therapy performance against breast cancer, which was confirmed by in vivo experiments using breast cancer tumors in mice. The membrane-coated and biocompatible nanocarrier preferentially concentrated in the tumor tissue, and efficiently decreased the tumor volume by a combination of photodynamic and photothermal effects upon near-infrared light exposure. Our results demonstrate that the HNT-based nanocarrier by virtue of facial preparation and high loading capacity can be a promising candidate for membrane-targeting nanocarriers. PMID- 30408641 TI - Endometrial expression of the acute phase molecule SAA is more significant than HP in reflecting the severity of endometritis. AB - This study investigated the correlation between endometrial local expressions of serum amyloid A (SAA) and haptoglobin (Hp) and severity of endometritis in 20 Chinese Holstein dairy cows at 40-60 days postpertum, aged 3-6, and 2-5 parities. Endometrial biopsies were collected and categorized into normal, mild endometritis, and severe endometritis based on clinical signs and histopathology. The protein and mRNA expression of SAA and Hp in endometrial tissue were measured using western blot and real-time PCR, respectively. Furthermore, bovine endometrial epithelial cells were isolated and cultured in vitro. The protein and mRNA expression of SAA and Hp were also determined in the cells treated with increasing concentrations of lipopolysaccharide (LPS; 0, 1, 5, 10 MUg/ml). The results showed that both of protein and mRNA of SAA was increased in endometritis or in LPS-stimulated cells, and the increases were positively correlated with severity of endometritis in vivo or LPS stimulation strength in vitro. Meanwhile, protein expression of Hp were also increased in endometritis or in LPS-stimulated cells, but the increases were negatively correlative with severity of inflammation as well as mRNA expression of Hp in vivo or in vitro. Therefore, our results suggest that endometrial local expression of SAA is more significant than Hp as a potential biomarker to assess severity of endometritis in cows. PMID- 30408642 TI - Primary motor cortex crucial for action prediction: A tDCS study. AB - The neural network underlying action observation - i.e., the action observation network - forms an anticipatory representation of observed actions. Although correlational studies suggest that the motor cortex (M1) might be involved in this anticipatory coding, it is unclear whether M1 is also causally essential for making accurate predictions about observed actions. To test the functional relevance of M1 to action prediction, we used offline monopolar transcranial direct current stimulation (tDCS). In four tDCS groups of healthy participants, we administered 15 min of anodal or cathodal constant currents of 1 or 2 mA over the left M1 before participants performed two tasks requiring them to make predictions about the outcomes of reaching-grasping human actions (Action Prediction - AP) or non-human movements (Non-human Prediction - NP). In each group, participants received sham and active tDCS in two separate sessions. We found that 2 mA cathodal tDCS (c-tDCS2mA) selectively impaired accuracy in the AP task, but not in the NP task. No change in performance was found following anodal or 1-mA tDCS protocols. Additionally, no change was found following c-tDCS2mA administered over a control site. These findings show task-, polarity-, intensity and site-specific disruption of AP abilities following c-tDCS2mA over M1. Thus, our study establishes specific tDCS parameters for effective M1 stimulation in AP and highlights the functional relevance of the motor system to making accurate predictions about the outcomes of human actions. PMID- 30408643 TI - Biodegradation of metal complex Naphthol Green B and formation of iron-sulfur nanoparticles by marine bacterium Pseudoalteromonas sp CF10-13. AB - Treatment of metal complex dye wastewater has attracted growing attention due to the degradation-resistant, high cost and potential hazards of current techniques. This study reported a marine bacterium (Pseudoalteromonas sp CF10-13) with potential performance in decolorization and degradation of a metal complex dye Naphthol Green B (NGB) at wide ranges of salinity, dye concentration and alkalinity under anaerobic conditions. It was inferred that the secretion of electron mediators in soluble extracellular metabolites by P. sp CF10-13 played important roles in NGB decolorization and degradation through extracellular electron transfer. Naphthalenesulfonate, the major structure in NGB molecule, was further degraded into low-toxic benzamide. Black stable iron-sulfur nanoparticles were formed endogenously avoiding H2S releasing, exogenous sulfur addition and metal sludge in accumulation. Accordingly, this study provided a cost-effective and eco-friendly biodegradation method to refractory NGB, further promoting the understanding of dye resources recovery. PMID- 30408644 TI - Effect of hydroxypropyl-beta-cyclodextrin on the cometabolism of phenol and phenanthrene by a novel Chryseobacterium sp. AB - Cometabolic degradation is an effective method to remove the polycyclic aromatic hydrocarbons (PAHs) with phenol as growth substrate from coal chemical wastewater (CCW). Unfortunately, the toxicity and low solubility of PAHs always restrict their degradation. In this study, Chryseobacterium sp. H202 was firstly isolated from the aerobic segment of CCW. Then, to improve the cometabolic degradation of PAHs, the effects of hydroxypropyl-beta-cyclodextrin (HPCD) were investigated. Phenanthrene removal was accelerated in the presence of phenol; however, the degradation of phenol was inhibited because of the toxicity of phenanthrene. Addition of 50 mg/L HPCD accelerated the degradation of phenol and effectively improved the phenanthrene removal rate by about 55%. Inclusion of HPCD appeared to increase the apparent solubility and reduce the toxicity of phenanthrene, thereby improving the cometabolic degradation of phenol and phenanthrene. Therefore, HPCD can enhance the degradation of phenanthrene with phenol as the growth substrate during CCW treatment. PMID- 30408645 TI - Characteristics of ultra-fine bubble water and its trials on enhanced methane production from waste activated sludge. AB - In this study biogas production efficiency was evaluated by adding ultra-fine bubble water (UFBW) into waste activated sludge (WAS) through anaerobic digestion (AD). Four kinds of gases, i.e. Air, N2, CO2 and H2 were introduced into tap water (TW) to prepare the UFBW with their properties being first investigated. Results show that hundreds of millions of nanoscale bubbles with the negative zeta potential could be stable in the UFBW for longer than two weeks whereas almost no nanometer bubbles could be detected in the raw TW. As for their impact on subsequent AD of WAS, the cumulative methane production with the addition of UFBW was 14-21% higher than that from the raw TW addition group. Interestingly, the Air-UFBW also could promote the biogas production in this study, which is different from the common understanding of AD, an obligate anaerobic process. PMID- 30408646 TI - Gender and onset age related-differences of non-motor symptoms and quality of life in drug-naive Parkinson's disease. AB - OBJECTIVE: This study aims to explore the gender and onset age-related differences of non-motor symptoms (NMS) and the determinants of quality of life (QoL) in a large cohort of Chinese drug-naive Parkinson's disease (PD) patients. PATIENTS AND METHODS: A cross-sectional analysis of 569 drug-naive PD patients was conducted. The frequency and severity of each NMS was evaluated by Non-Motor Symptom Scale (NMSS), which consists of 9 subdomains. PD Questionnaire-39 (PDQ 39) was used to assess the QoL of PD patients. A stepwise multiple regression model was used to explore the determinants of QoL. RESULTS: A total of 552 patients (97.0%) exhibited at least one NMS. The three most common NMS were sleep/fatigue (74%), attention/memory (62.7%) and miscellaneous (62%). The frequencies of sleep/fatigue and mood/apathy were more prevalent in women and the frequencies of urinary and sexual dysfunction were more prevalent in men (P < 0.05). Patients with late-onset PD showed higher frequencies of perceptual problems/hallucinations, attention/memory, gastrointestinal, urinary, sexual dysfunction, and miscellaneous compared to patients with early-onset PD (P < 0.05). The multiple regression analysis model indicated that female, disease duration, UPDRS III score, depression, and NMSS subcores including sleep/fatigue, mood/apathy, attention/memory, and gastrointestinal were the determinants of QoL in patients with drug-naive PD. CONCLUSIONS: NMS was common in untreated PD patients. They are heterogeneous in patients with drug-naive PD, which are dramatic determinants on decreased QoL in PD. Our results are beneficial for clinical management of NMS in drug-naive PD. PMID- 30408647 TI - Screening of lactic acid bacteria and yeast strains to select adapted anti-fungal co-cultures for cocoa bean fermentation. AB - Contamination with filamentous fungi during cocoa bean fermentation and drying reduces the quality of cocoa beans and poses a health risk for consumers due to the potential accumulation of mycotoxins. The aim of this study was to develop anti-fungal lactic acid bacteria (LAB)-yeast co-cultures by selecting anti-fungal strains best adapted to the cocoa bean fermentation process from 362 LAB and 384 yeast strains isolated from cocoa bean post-harvest processes. The applied multiphasic screening approach included anti-fungal activity tests in vitro and in vivo and assessment of the carbon metabolism and stress tolerance of the anti fungal strains in a cocoa pulp simulation medium. The anti-fungal strains, Lactobacillus fermentum M017, Lb. fermentum 223, Hanseniaspora opuntiae H17, and Saccharomyces cerevisiae H290, were selected based on their high fungal growth inhibition capacity and their well-adapted metabolism. Up to seven filamentous fungal strains of the genera Aspergillus, Penicillium, and Gibberella were inhibited on average by 63 and 75% of the maximal inhibition zone by M017 and 223, respectively, and by 25 and 31% by the strains H17 and H290, respectively. Both Lb. fermentum strains converted the medium's glucose, fructose, and citric acid into 20.4-23.0 g/l of mannitol, 3.9-6.2 g/l acetic acid, and 8.6-10.3 g/l lactic acid, whereas the two yeast strains metabolized glucose and fructose to produce 7.4-18.4 g/l of ethanol. The Lb. fermentum strains were further characterized as particularly tolerant towards ethanol, acetic acid, and heat stress and both yeast strains tolerated high amounts of ethanol and lactic acid in the medium. Finally, the anti-fungal in vivo assays revealed that the two Lb. fermentum strains completely inhibited growth of the citrinin-producing strain, P. citrinum S005, and the potentially fumonisin-producing strain, G. moniliformis S003, on the surface of cocoa beans. Furthermore, growth of the aflatoxin producer A. flavus S075 was inhibited after 10-14 days by all four selected anti fungal strains, i.e. Lb. fermentum M017, Lb. fermentum 223, H. opuntiae H17, and Sacc. cerevisiae H290, at 51-95% when applied as single cultures and at 100% when the strains were combined into four co-cultures, each composed of a Lb. fermentum and one of the two yeast strains. As a conclusion, these four LAB-yeast co cultures are recommended for future applications to limit the growth of filamentous fungi and the concomitant mycotoxin production during the fermentation of cocoa beans. PMID- 30408648 TI - Design, synthesis and pharmacological evaluation of some substituted dihydropyrimidines with L-/T-type calcium channel blocking activities. AB - New dihydropyrimidines bearing various lipophilic pharmacophores and functionalities at position 3 were designed and synthesized. The basic framework of the new compounds was designed to maintain the main structural requirements for calcium channel blocking activity of the known dihydropyridines and dihydropyrimidines calcium channel blockers. The newly synthesized compounds were evaluated as antagonists for CaV1.2 and CaV3.2 using the whole-cell patch clamp technique. Seven compounds (4b, 4c, 6c, 9, 13c, 13e and 17b) showed promising dual calcium channel blocking activity and three compounds (13b, 14b and 17a) were selective against Cav3.2. Their drug-likeness has been assessed using Molinspiration and Molsoft softwares. Their physicochemical properties and pharmacokinetic profiles recommend that they can be considered as drug-like candidates. PMID- 30408649 TI - Novel 4-(3-phenylpropionamido), 4-(2-phenoxyacetamido) and 4-(cinnamamido) substituted benzamides bearing the pyrazole or indazole nucleus: synthesis, biological evaluation and mechanism of action. AB - Based on some common structural features of known compounds interfering with p53 pathways and our previously synthesized benzamides, we synthesized new ethyl 5-(4 substituted benzamido)-1-phenyl-1H-pyrazole-4-carboxylates 26a-c, ethyl 5-(4 substituted benzamido)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylates 27a-c and N (1H-indazol-6-yl)-4-substituted benzamides 31a,b bearing in the 4 position of the benzamido moiety the 2-phenylpropanamido or 2-phenoxyacetamido or cinnamamido groups. A preliminary test to evaluate the antiproliferative activity against human lung carcinoma H292 cells highlighted how compound 26c showed the best activity. This last was therefore selected for further studies with the aim to find the mechanism of action. Compound 26c induces intrinsic apoptotic pathway by activating p53 and is also able to activate TRAIL-inducing death pathway by promoting increase of DR4 and DR5 death receptors, downregulation of c-FLIPL and caspase-8 activation. PMID- 30408650 TI - Discovery of novel quinazolines as potential anti-tubulin agents occupying three zones of colchicine domain. AB - A series of novel quinazolines as tubulin inhibitors occupying three zones of colchicine domain have been designed and synthesized inspired by the recently disclosed crystal structure of verubulin analogue 6 with tubulin. Among the newly synthesized compounds, 19c showed noteworthy potency against K562, HepG2, KB, HCT 8 and MDB-MB-231 cancer cells. In vitro microtubule polymerization assays identified 19c as a potent tubulin assembly inhibitor, the binding mode of which with tubulin was confirmed by molecular modeling studies to occupy three zones of tubulin domain. Furthermore, 19c disrupted the intracellular microtubule network, caused G2/M phase arrest, induced cell apoptosis and depolarized mitochondria of K562 cells. 19c also reduced the cell migration and disrupted the capillary-like tube formation of human umbilical vein endothelial cells (HUVECs). Importantly, 19c significantly and dose dependently inhibited tumor growth in H22 liver cancer xenograft mouse model. All these results suggested that 19c deserves further research as a novel and potential anti-tubulin agent for the treatment of cancers. PMID- 30408651 TI - Effect of polybrominated diphenyl ethers on the formation of disinfection byproducts in the water system. AB - Disinfection byproducts (DBPs) can be formed from many different kinds of carbon- and nitrogen-based organic materials. This study investigated DBP formation in the presence of two types of polybrominated diphenyl ethers (PBDEs), 2,2',4,4' tetrabromodiphenyl ether (BDE 47) and 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (BDE 209). The effects of PBDEs on the formation of DBPs upon the chlorination (or chloramination) of Suwannee River humic acid (SRHA) were also evaluated. Results indicated that the chlorination of BDE 47 and BDE 209 resulted in the formation of DBPs, with 1,1,1-trichloro-2-propanone (1,1,1-TCP) being the major DBP type formed. When PBDEs were present in the SRHA solution, a lower amount of CHCl3 was formed, and more 1,1,1-TCP was produced. However, the effects of PBDEs on the formation of DBPs in the real surface water were insignificant because of the complicated water chemistry. PMID- 30408652 TI - Evidence of accumulation and elimination of inorganic contaminants from the lachrymal salt glands of leatherback sea turtles (Dermochelys coriacea). AB - Plasma osmolalities of marine vertebrates are generally lower than the surrounding medium; therefore, marine organisms must cope with the osmoregulatory challenges of life in a salty environment. The salt glands serve to maintain osmotic and ionic homeostasis in a number of lower marine vertebrates. One marine reptile, the leatherback sea turtle (Dermochelys coriacea), ingests excessive amounts of salts due to their diet of gelatinous zooplankton. Outside of the normal osmoregulatory function of the salt gland, little research has been conducted on contaminant accumulation and excretion in this organ. Here, we established arsenic, cadmium, lead, mercury, and selenium concentrations in red blood cells (RBCs) and salt gland secretions (SGSs) of nesting leatherbacks. We also collected salt glands from different life stage classes of dead stranded leatherbacks from the western Atlantic Ocean to determine if inorganic contaminants accumulate in this organ. Using non-metric multidimensional scaling and regression analyses, we determined that RBC and SGS inorganic contaminant concentrations were not correlated. Additionally, RBCs showed significantly higher concentrations of these contaminants in comparison to SGSs, likely due to the affinity of inorganic contaminants for the heme group of RBCs. Lastly, we found that salt gland cadmium and mercury concentrations tended to increase with increasing curved carapace length (CCL) in stranded leatherbacks. Our results indicate that different physiological mechanisms determine the distribution of inorganic contaminants in blood and SGSs. Increases in salt gland contaminant concentrations with increasing CCL suggest this organ as a potential target for accumulation. PMID- 30408653 TI - Disinfection byproduct formation and toxicity of graphene oxide in water treatment system. AB - Graphene oxide (GO) is a structural analog of graphene and contains numerous O containing functional groups. As rapidly increasing production and usage of GO, it is inevitable to flow into the water and wastewater treatment system and finally oxidized by disinfectants to form DBPs. Meanwhile, as GO is a nano sized carbon material, it may also break the human digestion system when it was absorbed by human body. This study explored the DBP formation when only GO was present. Effects of Br- were also considered during the DBP formation. Both trihalomethanes (THMs) and haloacetic acids (HAAs) were formed during the chlorination and chloramination procedure, but the total concentration of THMs was at least three times higher than that of HAAs. Irradiation can significantly enhance the DBP formation via the formation of radicals. The wrinkled appearance and decomposition of aromatic ring may both be effective on the DBP formation via chlorination or bromination. The findings of this study advance knowledge on the DBP formation of GO in water treatment systems and provide insight on the toxic effects of the transformation products of GO. PMID- 30408654 TI - Corrigendum to 'Ketamine in electroconvulsive therapy for depressive disorder: A systematic review and meta-analysis' [Journal of Psychiatric Research 104 (2018) 144-156]. PMID- 30408656 TI - Neuromuscular characterisation in Cerebral Palsy using hybrid Hill-type models on isometric contractions. AB - BACKGROUND: Muscles of individuals with Cerebral Palsy (CP) undergo structural changes over their lifespan including an increase in muscle stiffness, decreased strength and coordination. Being able to identify these changes non-invasively would be beneficial to improve understanding of CP and assess therapy effectiveness over time. This study aims to adapt an existing EMG-driven Hill type muscle model for neuromuscular characterisation during isometric contractions of the elbow joint. METHODS: Participants with (n = 2) and without CP (n = 8) performed isometric force ramps with contraction levels ranging between 15 and 70% of their maximum torque. During these contractions, high density EMG data were collected from the M. Biceps and Triceps brachii with 64 electrodes on each muscle. The EMG-driven Hill-type muscle model was used to predict torques around the elbow joint, and muscle characterisation was performed by applying a genetic algorithm that tuned individuals' parameters to reduce the RMS error between observed and predicted torque data. RESULTS: Observed torques could be predicted accurately with an overall mean error of 1.24Nm +/- 0.53Nm when modelling individual force ramps. The first four parameters of the model could be identified relatively reliably across different experimental protocols with a full-scale variation of below 20%. CONCLUSION: An HD-EMG muscle modelling approach to evaluating neuromuscular properties in participants with and without CP has been presented. This pilot study confirms the feasibility of the experimental protocol and demonstrates some parameters can be identified robustly using the isometric contraction force ramps. PMID- 30408657 TI - Joint segmentation and characterization of the dermis in 50 MHz ultrasound 2D and 3D images of the skin. AB - We propose a novel joint segmentation and characterization algorithm for the assessment of skin aging using 50 MHz high-frequency ultrasound images. The proposed segmentation method allows a fine determination of the envelope signal's statistics in the dermis as a function of depth. The sequence of statistical estimates obtained is then combined into a single aging score. The segmentation is based on tailored recursive non-linear filters. The epidermis and the dermis are jointly segmented with a non-parametric active contour combining a texture criterion, an epidermis indicator map and the geometric constraint of horizontal continuity. The algorithm is designed to apply to 2D and 3D images as well. We evaluated skin photo-aging on ultrasound images with an experimental study on a cohort of 76 women separated into 2 groups of different ages. Two aging scores are computed from the images: local dermal contrast and skin roughness. We show that these scores are much better at identifying the two groups (p-value ~10-6) than the previously used MGVR indicator (p-value 0.046). Moreover, we find that a combined score more reliably evaluates skin photo-aging, with 84% success, than a scoring of the ultrasound images by 4 experts. PMID- 30408655 TI - Characterization of brain acetylcholinesterase of bentonic fish Hoplosternum littorale: Perspectives of application in pesticides and metal ions biomonitoring. AB - Acetylcholinesterase (AChE; EC 3.1.1.7) is a serine hydrolase, whose main function is to modulate neurotransmission at cholinergic synapses. It is, therefore, the primary target of some pesticides and heavy metals. Its inhibition in aquatic organisms has been used as an indicator of the presence of these pollutants in water bodies. The present study aimed to characterize physicochemical and kinetic parameters of brain AChE in the benthic fish Hoplosternum littorale and to analyze the in vitro effects of pesticides (dichlorvos, diazinon, chlorpyrifos, parathion-methyl, temephos, carbaryl, carbofuran, aldicarb, diflubenzuron, novaluron and pyriproxyfen) and metal ions (As3+, Cd2+, Cu2+, Fe2+, Mn2+, Mg2+, K+, Pb2+, Hg2+, Zn2+) investigating the potential of this enzyme as environmental biomarker based on current regulations. Specific substrates and inhibitors have indicated AChE to be the predominant cholinesterase (ChE) in the brain of H. littorale. Peak activity was observed at pH 8.0 and 30 degrees C. The enzymatic activity is otherwise moderately thermostable (~ 50% activity at 45 degrees C). The enzyme can reduce the activation energy of acetylthiocholine hydrolysis reaction to 8.34 kcal mol-1 while reaching a rate enhancement of 106. Among the pesticides under study, dichlorvos presented an IC50 value below the maximum concentrations allowed by legislation. This study presents the first report on the inhibition of brain AChE activity from Siluriformes by the pesticides novaluron and pyriproxyfen. Mercury ion also exerted a strong inhibitory effect on its enzymatic activity. The H. littorale enzyme thus has the potential to function as an in vitro biomarker for the presence of the pesticide dichlorvos as well as mercury in areas of mining and industrial discharge. PMID- 30408658 TI - A global paucity of wild bird feeding policy. AB - Feeding wild birds is a common and popular human-wildlife interaction throughout the world. However, controversy exists over the benefits and costs to the birds and humans involved. This bibliometric study documents wild bird feeding policies around the globe and examines environmental and socio-cultural factors which may influence the position adopted by these policies. We located 412 policies from 237 different countries, territories or dependencies (jurisdictions); 58.7% of jurisdictions had no information available online regarding wild bird feeding policy. Generalized Linear Modelling revealed that colder minimum ambient temperatures were associated with more pro-feeding policy settings. An index of controversy was calculated for each jurisdiction; most (77.6%) had no controversy. This study highlights the significant variation in policy settings for wild bird feeding across jurisdictions and controversy in almost a quarter of jurisdictions. Recommendations are made for the development of clear, consistent and readily available policy advice on this globally popular human-wildlife interaction. PMID- 30408659 TI - Removal of antibiotic resistance genes in four full-scale membrane bioreactors. AB - Antibiotic resistance genes (ARGs) discharged through wastewater treatment plants (WWTPs) has aroused growing public concern for its risk to human health and ecological safety. Membrane bioreactor (MBR) has been recognized as an effective approach to remove ARGs in full-scale WWTPs, but its advantage over traditional processes was not clearly quantified. To address this, we investigated four full scale WWTPs containing parallel MBR and traditional processes (oxidation ditch or sequencing batch reactor) to compare the reduction of eight types of ARGs (blaTEM, ermB, tetW, tetO, sul1, sul2, addD, and qnrS) and int1. In general, MBRs reduced the ARGs (1.1-7.3 log removal) better than parallel processes (0.4-4.2 log removal). Notably, the dominant ARGs in the influent, such as ermB, sul1 and int1 (106.39-107.79 copies/mL), were more effectively reduced by MBRs (1.5-7.3 log removal) than traditional processes (0.8-3.4 log removal). Meanwhile, the distribution of those ARGs in activated sludge was not significantly different between aforementioned processes (p > 0.05). The separation coefficient (Ksw) was proposed to represent the contribution of solid separation on ARG removal, subsequent analysis revealed surprisingly strong correlation between Ksw values of dominant ARGs (ermB, sul1 and int1) and their log removal by MBR (R = 0.79 0.96, p < 0.05), while such correlation was much weaker in traditional process (R = 0.33-0.37), indicating solid separation was the major pathway for removal of dominant ARGs and int1. According to the canonical correlation analysis between process operation and ARG removal in MBR, sludge retention time (SRT) seemed to be the major factor affecting removal of dominant ARGs and int1. This comparative study can be helpful for further understanding and operating MBR process to reduce the ARGs in effluent. PMID- 30408660 TI - Land pavement depresses photosynthesis in urban trees especially under drought stress. AB - Investigations into the photosynthetic response of urban trees on paved land under drought stress would help to improve the management of trees under rapid urbanization and climate change. An experiment was designed to grow two common greening tree saplings, ash (Fraxinus chinensis Roxb.) and ginkgo (Ginkgo biloba L.), in environments of both land pavement and drought. The results showed that (1) land pavement increased surface and air temperatures and decreased air humidity as well as net photosynthetic rate (Pn) and photosynthetic capacity (Amax) of ginkgo significantly; (2) drought significantly decreased Pn, Amax and maximum net photosynthetic rate (Pnmax) as well as other photosynthetic parameters of both ash and ginkgo; (3) the negative effects of the combination of land pavement and drought on photosynthetic parameters were more significant than the effects of drought treatment for both ash and ginkgo. This implies that urban trees, especially those growing on land pavements, will confront harsher environments and a greater decline of photosynthesis under the severe and more frequent droughts predicted in the future. Overall, ash showed more tolerance to land pavement and drought than ginkgo, indicating that the selection of tolerant tree species is important for urban planting. PMID- 30408661 TI - Dietary metal bioavailability in razor clam Sinonovacula constricta under fluctuating seston environments. AB - To understand the potential risks of dietary metals to marine bivalves, it is important to study the interaction between dietary metal bioaccumulation and bivalve feeding behavior. Key processes in affecting the dietary metal influx are the selection of different particles during the ingestion process as well as the differential assimilation of metals during the digestion process. In this study, we quantified the influences of seston quality and quantity on the dietary assimilation of Cd and Zn as well as pre-ingestion particle selectivity in a razor clam Sinonovacula constricta following feeding on radiolabeled diatoms and sediments with different mixtures at four food concentrations. Bioavailability of 109Cd and 65Zn from seston was measured by assimilation efficiency (AE) using a pulse-chase feeding technique. The AEs of Cd and Zn were significantly affected by the seston quantity and quality (higher for Zn than they were for Cd and higher for diatoms than for suspended sediments), but were independent of the presence of other particles during the feeding process. Dual gamma radiotracer technique was further employed to study pre-ingestion particle selectivity. Particle selectivity was weak during pre-ingestion in razor clams, although there was evidence that clams might be able to differentiate particles during the process of pseudofeces production. Our study demonstrated that seston composition and quantity substantially affected the bioavailability of Cd and Zn to the razor clams. The results are important to understand the bioaccumulation of metals in clams living in dynamic food environments of estuary. PMID- 30408662 TI - Explainable extreme gradient boosting tree-based prediction of toluene, ethylbenzene and xylene wet deposition. AB - Current research suggests that, apart from photochemical reactions, toluene, ethylbenzene and xylene (TEX) removal from ambient air might be affected by atmospheric precipitation, depending on the concentrations and water solubility of the compounds, Henry's law, physico-chemical properties of the water, as well as the frequency and intensity of precipitation events. Nevertheless, existing knowledge of the role that wet deposition plays in biogeochemical cycles of volatile species remains insufficient, and this topic requires more scientific effort to be explored and understood. In this study, we employed the eXtreme Gradient Boosting tree ensemble for revealing TEX transfer from ambient air to rainwater, and applied a novel SHapley Additive exPlanations feature attribution framework to examine the relevance of the monitored parameters and identify key factors that govern wet deposition of TEX. According to the results, main impacts, including ambient air TEX concentrations, and rainwater and air temperatures, and occasional, but less important impacts, including wind speed, air pressure, turbidity, and total organic carbon, NO3-, Cl- and K+ rainwater concentration, shaped TEX partition between gaseous and aqueous phases during rain events. PMID- 30408663 TI - Use of convertible flow cells to simulate the impacts of anthropogenic activities on river biofilm bacterial communities. AB - Bacterial attachment to surfaces and the development of biofilms are crucial processes during the self-purification of polluted rivers. Biofilm bacterial communities also are a potential indicator of the human impact on an aquatic system. Here, we used indoor reactors with 7.7 cm3 transparent convertible flow cells to observe the formation of biofilms in river water from different land-use areas (i.e., an undisturbed mountainous area, a wastewater-discharge urban area, and a pesticide-fertilizer applied agricultural area). We then compared the bacterial biomass, composition, and function among the formed biofilms and explored whether the biofilm bacterial communities formed in polluted river water (urban area) could shift to those formed in unpolluted water (mountainous area) after simulating water-body remediation. After 60 d of indoor biofilm cultivation, the biofilms formed with the three types of influent were markedly different. Anthropogenic activities (e.g., wastewater discharge and pesticide fertilizer use) facilitated biofilm bacterial production and the metabolic rate and altered the composition and metabolic patterns of the biofilm bacterial communities. After switching from an urban water to mountainous water influent in the same reactor, the biofilm bacterial communities that initially formed in the polluted discharge did not shift to that formed in unpolluted water. This result indicated that even after water remediation, the composition of the river biofilm bacterial community would not recover to a community like that observed under non polluted conditions. Our study highlights possible issues related to current pollution-remediation routines and emphasizes the importance of sustainable anthropogenic activities within river basins. PMID- 30408664 TI - The effect of natural and anthropogenic factors on PM2.5: Empirical evidence from Chinese cities with different income levels. AB - The aim of this paper is to estimate the effects of natural conditions and anthropogenic factors on PM2.5 concentrations, taking into consideration differences in the income levels, and thus the development stages, of the cities studied. To achieve this goal, a balanced dataset of 287 Chinese cities was divided into different income-based panels for the period 1998-2015. The empirical estimation results indicated that meteorological conditions exerted varied effects on PM2.5 concentrations across different income-based panels. The results show that the coefficients of temperature were positive and significant in all panels, with the exception of upper-middle-income cities. Whilst wind speed and precipitation were found to be conducive to reducing PM2.5 concentrations, no such significant correlation was found in relation to relative humidity (except in high-income cities). In terms of the anthropogenic factors addressed in the study, we found an inverted U-shaped relationship between economic development and PM2.5 concentrations, confirming the Environmental Kuznets Curve hypothesis. In addition, the industrial structure and road density were observed to exert significant positive impacts on PM2.5 concentrations. The empirical analysis of the effects of FDI on PM2.5 concentrations indicate that FDI aggravated PM2.5 pollutions in the total cities and lower-middle-income cities panels, supporting the Pollution Haven Hypothesis. The empirical results for population density suggested that it does not significantly influence PM2.5 concentrations. Moreover, we found that built-up area exerts mixed effects on PM2.5 concentrations. These results cast a new light on the issue of PM2.5 pollution for government policy makers tasked with formulating measures to mitigate the concentration of such pollutants, encouraging that consideration be given to the differences between cities with different income levels. PMID- 30408665 TI - Species-specific accumulation and temporal trends of bisphenols and benzophenones in mollusks from the Chinese Bohai Sea during 2006-2015. AB - Information on the occurrence and bioaccumulation of bisphenols and benzophenones in coastal marine invertebrates is limited. In this study, concentrations of eight bisphenol and five benzophenone analogues were determined in 186 mollusks collected from coastal areas of the Chinese Bohai Sea during the period 2006 2015. Total concentrations of bisphenols and benzophenones were in range of not detected (nd)-58 (geometric mean: 13.0 ng/g) and nd-59.1 (2.06 ng/g) on a dry weight basis, respectively. BPA and BPF were the major bisphenols, collectively accounting for >90% of the total concentrations. BP-3 was the predominant benzophenone, representing 74% of the total concentrations. The mollusk species, Meretrix meretrix, accumulated high concentrations of both bisphenols and benzophenones. A steady increase in bisphenol concentrations in mollusks was observed in recent years, whereas no obvious temporal trend was found for benzophenones. The estimated daily intakes of bisphenols through consumption of mollusks were lower than the current reference dose. This study establishes a baseline concentration for bisphenols and benzophenones in mollusks in Chinese coastal waters. PMID- 30408666 TI - Transcriptomic analysis reveals dose-dependent modes of action of benzo(a)pyrene in polar cod (Boreogadus saida). AB - Polar cod (Boreogadus saida) has been used as a model Arctic species for hazard assessment of environmental stressors such as polycyclic aromatic hydrocarbons (PAHs). However, most of the PAH studies using polar cod rely on targeted biomarker-based analysis thus may not adequately address the complexity of the toxic mechanisms of the stressors. The present study was performed to develop a broad-content transcriptomic platform for polar cod and apply it for understanding the toxic mechanisms of a model PAH, benzo(a)pyrene (BaP). Hepatic transcriptional analysis using a combination of high-density polar cod oligonucleotide microarray and quantitative real-time RT-PCR was conducted to characterize the stress responses in polar cod after 14d repeated dietary exposure to 0.4 (Low) and 20.3 MUg/g fish/feeding (High) BaP doses. Bile metabolic analysis was performed to identify the storage of a key BaP hepatic biotransformation product, 3-hydroxybenzo(a)pyrene (3-OH-BaP). The results clearly showed that 3-OH-BaP was detected in the bile of polar cod after both Low and High BaP exposure. Dose-dependent hepatic stress responses were identified, with Low BaP suppressing genes involved in the defense mechanisms and High BaP inducing genes associated with these pathways. The results suggested that activation of the aryl hydrocarbon receptor signaling, induction of oxidative stress, DNA damage and apoptosis were the common modes of action (MoA) of BaP between polar cod or other vertebrates, whereas induction of protein degradation and disturbance of mitochondrial functions were proposed as novel MoAs. Furthermore, conceptual toxicity pathways were proposed for BaP-mediated effects in Arctic fish. The present study has for the first time reported a transcriptome wide analysis using a polar cod-specific microarray and suggested novel MoAs of BaP. The analytical tools, bioinformatics solutions and mechanistic knowledge generated by this study may facilitate mechanistically-based hazard assessment of environmental stressors in the Arctic using this important fish as a model species. PMID- 30408667 TI - Human exposure to airborne pollen and relationships with symptoms and immune responses: Indoors versus outdoors, circadian patterns and meteorological effects in alpine and urban environments. AB - Pollen exposure is a major cause of respiratory allergies worldwide. However, it is unclear how everyday exposure is related to symptoms and how allergic patients may be affected spatially and temporally. Hence, we investigated the relationship of pollen, symptoms and immune responses under a controlled regime of 'high-low moderate' pollen exposure in urban versus alpine environment. The research was conducted in 2016 in two locations in Germany: urban Augsburg (494 m) and Schneefernerhaus (UFS) on Zugspitze mountain (2656 m). Monitoring of airborne pollen took place using Hirst-type volumetric traps. On UFS, both indoor and outdoor samples were taken. Grass pollen allergic human volunteers were monitored daily during the peak of the grass pollen season, in Augsburg, on UFS, then again in Augsburg. Nasal biosamples were obtained throughout the study to investigate immune responses. All symptoms decreased significantly during the stay on UFS and remained low even after the return to Augsburg. The same was observed for nasal total IgE and IgM levels and for nasal type 2 cytokines and chemokines. Augsburg showed higher pollen concentrations than those on UFS. At all sites, pollen were present throughout each day, but were more abundant in Augsburg during morning. On UFS, outdoor pollen levels were up to 6-fold higher than those indoors. Nasal, ocular and pulmonary symptoms correlated with current and previous days' pollen concentrations and relative humidity. Stays in low-exposure environments during the peak pollen season can be an efficient means of reducing allergic symptoms and immune responses. However, in alpine environments, even occasional pollen exposure during short intervals may still trigger symptoms because of the additional environmental stress posed onto allergics. This highlights the need for the consideration of additional environmental factors, apart from symptom diaries and immune responses, so as to efficiently predict high-risk allergy periods. PMID- 30408668 TI - Empirical assessing cement CO2 emissions based on China's economic and social development during 2001-2030. AB - Cement industry is a large emitter of carbon dioxide (CO2), taking up 5-8% of anthropogenic CO2 emissions. China is the largest developing country in the world. With the fast urbanization rate, economic growth and rapid development of industry, China's cement production is soaring year by year. Also, cement CO2 emissions increased year by year and aroused the rising attention. However, the historical province- and nation-level cement production situations, driving forces of cement output and/or demand based on rapid economic growth and urbanization rate, the peak of cement consumption and China's cement demand projection and CO2 emissions through 2030 when China should fulfill the international commitments were not clear. The present study summarized the characteristics of China's cement production and CO2 emissions during 2001-2015, projected cement CO2 emission scenarios based on diffusion of alternative materials and technical innovation toward 2030. The following results were summarized, clinker- and cement- CO2 emission factors (EFs) were declining year by year with the technical innovation. CO2 emissions increased with the increase of cement output year by year. The discrepancies of CO2 emissions from different researches were becoming large year by year, and the biggest difference of CO2 emissions reached 49% in 2015. Accordingly, we recommended active EFs for the calculation of cement CO2 emissions. Cement production situation varies greatly with province, as manifested in unbalanced NSP technology and clinker-to-cement ratio, and energy consumption, which was primarily attributed to the unbalanced resource reserves and economic development. There is still sufficient room for CO2 reduction in China's cement industry, and the use of alternative material was better than technical innovation in such reduction. The optimal emissions in 2030 will be 1490 Mt CO2. And China's cement consumption will be stable in 2030, cumulative cement consumption per capita will be peaked at 23394 kg, and UR will reach 70.1%. PMID- 30408669 TI - Phthalic acid esters disturbed the genetic information processing and improved the carbon metabolism in black soils. AB - Phthalic acid esters (PAEs), such as dimethyl phthalate (DMP) and dibutyl phthalate (DBP), are widely distributed as environmental pollutants. In this study, the effects of these chemicals were investigated in black soils using a metagenomics approach. The results clearly showed that DMP or DBP increased the abundance of genes involved in transcription, replication and repair in black soils. In addition, the abundances of genes associated with metabolic functions was improved following treatment with DMP or DBP, including those involved in lipid transport and metabolism, carbohydrate transport and metabolism, and energy production and conversion. There could be many reasons for these observed changes. First, the DMP or DBP treatments increased the abundances of genes associated with the LuxR family, the UvrABC repair system, DNA replication pathways, the RNA polymerase complex and base excision repair. Second, the abundances of genes associated with isocitrate lyase regulator (IclR) family transcriptional regulators, lipid metabolism and carbohydrate active enzymes (CAZys) were altered by the DMP or DBP treatments. Finally, the DMP or DBP treatments also increased the emission load of CO2 and altered the fluorescence intensity of humic acid. Therefore, the results of this study suggested that DMP and DBP contamination altered the abundances of genes associated with genetic information processing and improved the carbon metabolism in black soils. PMID- 30408670 TI - Roles of gender and obesity in defining correlations between perfluoroalkyl substances and lipid/lipoproteins. AB - Data from National Health and Nutrition Examination Survey (NHANES) for 2005-2014 for those aged >=20 years fasting for >=8 h (N = 3629) were analyzed to evaluate the role that gender and obesity play in defining correlations between selected perfluoroalkyl substances (PFAS) and total cholesterol (TC), low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL), and triglycerides. PFAS considered for analyses were: perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorodecanoic acid (PFDA), perfluorononanoic acid (PFNA), perfluorohexane sulfonate (PFHxS), perfluoroundecanoic acid (PFUnDA), and 2-(N-methyl-perfluorooctane sulfonamido) acetic acid (Me-FOSAA). Gender and obesity stratified regression models were fitted to estimate associations between PFAS and lipid/lipoproteins with adjustments made for confounders. For obese males, but not for nonobese males, positive associations were found between TC and LDL with PFOA (beta = 0.0519, p = 0.01 for TC and beta = 0.0822, p = 0.03 for LDL), and PFNA (beta = 0.0328, p = 0.03 for TC and beta = 0.0679, p = 0.04 for LDL). For obese females, adjusted concentrations of TC increased with increase in the concentrations of PFDA (beta = 0.0247, p = 0.048), PFNA (beta = 0.0286, p = 0.04), and Me-PFOSAA (beta = 0.0274, p = 0.02), and there was a positive association of LDL with PFOS (beta = 0.0375, p = 0.04), PFDA (beta = 0.0397, p = 0.047), and PFNA (beta = 0.0593, p = 0.02). The findings, concerning the relationship of longer chain PFAS to serum lipids, suggest greater susceptibility to elevated TC and LDL cholesterol in the obese participants, with some differences between men and women. The key contributing modifiable risk for nonalcoholic steatosis is obesity, and, the development of nonalcoholic steatosis is recognized to be sexually dimorphic. The epidemiologic observation of a susceptible obese subgroup in our data is consistent with toxicology literature findings of disrupted cholesterol metabolism via induced steatosis following PFAS exposure. Gender differences affect serum concentration of PFAS during the reproductive years, and our data add a secondary question concerning whether they also affect the interaction between PFAS exposure and lipid handling in males and females. PMID- 30408671 TI - Forward osmosis remediation of high salinity Permian Basin produced water from unconventional oil and gas development. AB - Unconventional oil and gas operations are on the rise, and they are an integral component to meeting the nation's energy needs. Produced water is the primary by product of oil and gas operations, and it has proven challenging to treat to date. The aim of this study was to evaluate the feasibility of using forward osmosis with thin-film composite hollow fiber membranes as a remediation option for produced water with high total dissolved solids levels from the Permian Basin. Trials consisted of a series of 5 experiments in order to evaluate the performance of the membrane. Three PW samples, each from different locations, were used to conduct the series of experiments and compare the performance of the membranes on samples with TDS levels ranging from 16,000 to 210,000 mg/L. It was concluded that forward osmosis can be used to extract water from high salinity oil field brines and PW. Flux decreased over the course of the trials due to a combination of membrane fouling, concentration polarization, and temperature fluctuations. The flux of the PW was similar to the flux measured for the PW mimic with small difference due to the influence of activity on the osmotic pressure. The flux was also influenced by temperature and the linear velocity of the feed solution and draw solution. PMID- 30408672 TI - Exploring miRNAs for developing climate-resilient crops: A perspective review. AB - Climate changes and environmental stresses have significant implications on global crop production and necessitate developing crops that can withstand an array of climate changes and environmental perturbations such as irregular water supplies leading to drought or water-logging, hyper soil-salinity, extreme and variable temperatures, ultraviolet radiations and metal stress. Plants have intricate molecular mechanisms to cope with these dynamic environmental changes, one of the most common and effective being the reprogramming of expression of stress-responsive genes. Plant microRNAs (miRNAs) have emerged as key post transcriptional and translational regulators of gene-expression for modulation of stress implications. Recent reports are establishing their key roles in epigenetic regulations of stress/adaptive responses as well as in providing plants genome-stability. Several stress responsive miRNAs are being identified from different crop plants and miRNA-driven RNA-interference (RNAi) is turning into a technology of choice for improving crop traits and providing phenotypic plasticity in challenging environments. Here we presents a perspective review on exploration of miRNAs as potent targets for engineering crops that can withstand multi-stress environments via loss-/gain-of-function approaches. This review also shed a light on potential roles plant miRNAs play in genome-stability and their emergence as potent target for genome-editing. Current knowledge on plant miRNAs, their biogenesis, function, their targets, and latest developments in bioinformatics approaches for plant miRNAs are discussed. Though there are recent reviews discussing primarily the individual miRNAs responsive to single stress factors, however, considering practical limitation of this approach, special emphasis is given in this review on miRNAs involved in responses and adaptation of plants to multi-stress environments including at epigenetic and/or epigenomic levels. PMID- 30408673 TI - Corrigendum to "Effects of carbamazepine on the P-gp and CYP3A expression correlated with PXR or NF-kappaB activity in the bEnd.3 cells" [Neurosci. Lett. 690, 18 (January) (2019) 48-55]. PMID- 30408674 TI - Reversing multi-drug tumor resistance to Paclitaxel by well-defined pH-sensitive amphiphilic polypeptide block copolymers via induction of lysosomal membrane permeabilization. AB - A series of hybrid di-block copolymers of poly(l- glutamic acid-b-l- leucine) (PGA-PLeu), methoxy poly (ethylene glycol)-b-poly(l-leucine) (PEG-PLeu), methoxy poly(ethylene glycol)-b-poly(gamma-benzyl-l-glutamic acid) (PEG-PBLG) and tri block copolymers of poly(ethylene glycol)-b-poly(l-glutamic acid-co-null-leucine) (PEG-PGA-PLeu) were synthesized through sequential HMDS-mediated ring-opening polymerization (ROP). Chemical structure of copolymers was studied by FTIR and 1H NMR and their molecular weight was determined by 1H-NMR and gel permeation chromatography (GPC). Copolymers self-assembled into nanomicelles with particle size (PS) of 65 to 139 nm. Higher fraction of polyleucine (% fPLeu) led to significantly larger PS, lower critical aggregation concentration (CAC) and higher drug loading content (DLC%). In addition, introducing PEG segment led to significant decrease in PS, increase of CAC and DLC%. Apart from copolymer composition, DLC% changed by the method with significantly higher loading for solid dispersion. Remarkably, the release of PTX from PEG-PGA-PLeu tri-block copolymers was highly dependent on pH, revealing a relatively two-fold faster release at pH 5 than pH 7.4. CD spectroscopy showed transition to alpha-helix secondary structure at acidic pH. Hemocompatibility assay confirmed that copolymers were absolutely hemocompatible at physiological pH. MTT assays demonstrated that unlike MCF7 and 4T1 cells that PTX-loaded nanoparticles (PTX NPs) exhibited similar antitumor activity, ten-fold higher toxicity was recognized in multidrug-resistant uterine sarcoma cells (MES-SA/DX5). Fluorescent imaging and flow cytometric analysis of cellular uptake showed that nanoparticles' uptake was time-dependent. It was also revealed that higher toxicity of the PTX-NPs could be due to ability of copolymer to inhibit P-gp pumps and induce lysosomal membrane permeabilization (LMP). PMID- 30408675 TI - The effect of strontium incorporation into sol-gel biomaterials on their protein adsorption and cell interactions. AB - It is known strontium can both inhibit the osteoclast formation and stimulate the osteoblast maturation, so biomaterials containing this element can favour bone structure stabilisation. The addition of Sr to biomaterials could affect their interactions with proteins and cells. Here, a silica-hybrid sol-gel network doped with different amounts of SrCl2 and applied as coatings on titanium discs was examined. in vitro analysis was performed to determine the potential effect of Sr in the coatings, showing enhanced gene expression of osteogenic markers (alkaline phosphatase and transforming growth factor-beta) in MC3T3-E1 incubated with Sr doped biomaterials. The examination of inflammatory markers (tumour necrosis factor-alpha and interleukin 10) in RAW 264.7 macrophages revealed an anti inflammatory potential of these materials. Proteins adsorbed onto the coatings incubated with human serum (3 h at 37 degrees C) were also analysed; mass spectrometry was used to characterise the proteins adhering to materials with different Sr content. Adding Sr to the coatings increased their affinity to APOE and VTNC proteins (associated with anti-inflammatory and osteogenic functions). Moreover, the proteins involved in coagulation processes, such as prothrombin, were more abundant on the coatings containing Sr than on the base sol-gel surfaces. Correlations between gene expression and proteomic results were also examined. PMID- 30408676 TI - Assessment of the impact of PS3-induced resistance to downy mildew on grapevine physiology. AB - Elicitor-induced resistance against diseases is an attractive strategy that could contribute to reduce the use of fungicides for plant protection. However, activation of defenses has an energetic cost that plants have to fuel by a mobilization of their primary metabolism with possible adverse effect on their physiology. In this context, this study was performed to determine whether elicitor-induced resistance of grapevine leaves against downy mildew impacted its development and metabolism. The elicitor PS3 (sulfated beta-glucan laminarin) was sprayed on grapevine herbaceous cuttings grown in greenhouses once or three times, and its impact was studied on young and older grapevine leaves, prior to, and after Plasmopara viticola inoculation. PS3 did not affect grapevine development during the time course of the experiment. A metabolomic analysis, mainly focused on primary metabolites, highlighted a leaf age dependent effect of PS3 treatment. Nitrogen compounds, and sugars to a lesser extent, were impacted. The results obtained complete the current knowledge of the impact of elicitor induced resistance on plant physiology. They will be helpful to guide further experiments required to better determine the costs and benefits of elicitor induced resistance in plants. PMID- 30408677 TI - Integration of small RNAs and mRNAs by high-throughput sequencing reveals a complex regulatory network in Chinese sea cucumber, Russian sea cucumber and their hybrids. AB - The body wall of the sea cucumber is an important tissue with high nutritional value. In this study, the parents of Apostichopus japonicus were derived from Russia (R) and China (C). We examined the transcriptional profiles in the body wall from F1 hybrids (CR and RC) and purebreds (CC and RR) at 9 months. In total, 34.07 G clean data were obtained from the transcriptome, 100,870 unigenes were identified, and 26,483 unigenes were annotated. Based on edgeR, 1097 4,587differentially expressed genes (DEGs) were identified. In total, 50.72 M clean data were obtained from the small RNA libraries, and 202 miRNAs were identified, including 7 known miRNAs and 195 novel miRNAs. In total, 175 miRNAs were identified as significantly differentially expressed miRNAs (diffmRNAs). Additionally, 3538 target genes were predicted, and 2243 genes were annotated in NR, COG, GO and KEGG. Furthermore, the relationships between the small RNAs and transcripts were identified, and the novel miRNA functions were predicted by integrating the small RNAs and transcriptome. According to the saponins content, RR was lower than other lines. DEGs involved in the biosynthesis of saponins were identified, including 23 DEGs involved in glycosyl, 21 DEGs involved in P450s, 5 DEGs involved in transferases and 15 DEGs involved in OSCs, from these, gdp-l fucose, fucTcpa2 and cyp17A1 may affect the differences in the saponins development of the body wall in RR purebreds. In addition, miRNA_11347 and miRNA_32095 was associated in saponins. Our study provides fundamental information regarding the molecular mechanism of the heterosis of the sea cucumber and may suggest strategies for the selection of rapidly growing and highly nutritive strains of sea cucumber in aquaculture. PMID- 30408678 TI - Coding/non-coding cross-talk in intestinal epithelium transcriptome gives insights on how fish respond to stocking density. AB - Fish respond to increasing stocking density as a stressor, adjusting physiological functions to increase energy supply for coping with deleterious effects and adapting. These responses are complex and systemic, and the molecular mechanisms involved remain undetermined. One of the most sensitive organs to environmental and homeostatic disruptions is the intestine, and since it plays several vital functions, understanding the molecular underpinnings of this organ under deleterious conditions is imperative for health improvement in aquaculture systems. This study aimed to understand how different stocking densities of rainbow trout (Oncorhynchus mykiss) modulates the coding and non-coding RNAs profiling, that in turn, play key roles to maintain the fish homeostasis. For this, the intestine tissue of juvenile trout stocked for 30 days either at low (LD: 3 kg m-3) or high density (HD: 40 kg m-3) were sampled to isolate total RNA and then construct cDNA libraries for an illumina sequencing platform. Differential gene expression analysis revealed a generalized downregulation of transcripts, including coding and long non-coding RNAs (lncRNAs). Notably, significant differences in transcripts involved in metabolic pathways, as well as immune and epithelium integrity and stability related pathways were found. A high number of downregulated transcripts enriched these pathways, and a strong correlation was observed between the most differentially expressed transcripts and the highly expressed lncRNAs. This study suggests a cross-talk between coding and non-coding RNAs in the intestine of fish exposed to suboptimal conditions, providing new insights into the regulatory role of the lncRNAs on fish response to stressors. PMID- 30408679 TI - Phononic crystal as a neutron detector. AB - A perfect phononic crystal model composed of concrete and epoxy, and another defect model of Aluminum/Concrete/Epoxy were proposed. The two models were analyzed computationally and theoretically based on the transfer matrix method. The proposed models were capable of detecting and sensing neutrons irradiations over a wide fluence range based on the effects of neutrons fluence on the Young's modulus of the concrete. The neutrons fluence significantly changed the transmission spectra of the phononic crystal models whether the neutrons-induced temperature was considered or not as the phononic band gaps and the local resonant peaks were shifted. Also, neutrons irradiations made a strong dispersion in the conventional parameters of the proposed phononic crystal models. The results presented in this work might pave the way for designing an effective detector that works over a wide range of neutron fluence. PMID- 30408680 TI - A combined linear and nonlinear ultrasound time-domain approach for impact damage detection in composite structures using a constructive nonlinear array technique. AB - Discovery and evaluation concerns of barely visible impact damage in composite materials is a well-known issue in industries using these materials. This work proposes a frequency sweep method where damage assessment is conducted with respect to the time domain. Firstly, a combined linear and nonlinear ultrasound imaging technique is proposed, which focuses on the excitation of damage/defect regions using a frequency sweep methodology from multiple transducer locations. Secondly, the method deconstructs time domain signals, which allows for the visualisation of linear and nonlinear ultrasound components independently. While, a filtering and frequency band separation method was used to exploit defect responses over different frequency ranges and provide time domain visualisation at the damage region. Finally, image segmentation was employed to automate the damage sizing procedure, while a binary imaging method was used to remove false positive damage regions produced by material vibration mode excitation (fundamental frequency responses) by using the nonlinear responses as a baseline free tool. The results showed that the combined linear and nonlinear results provided more accurate results than a purely linear or nonlinear approach, furthermore the results were shown to be equivalent to those of a standard phased array system. The ability of the method to visualise nonlinear outputs in time can improve the understanding of nonlinear ultrasound mechanisms while provides a clear argument that a complete approach, incorporating both linear and nonlinear methods should be regarded as the future of NDT/E systems. PMID- 30408681 TI - Ultrasound attenuation and phase velocity of moderately concentrated silica suspensions. AB - Ultrasound attenuation coefficient and phase velocity of moderately concentrated suspensions of charged silica particles were measured as a function of frequency. The attenuation coefficients were found to be significantly smaller than the theoretical prediction, and such a difference did not appear in the neutral particle suspensions under the corresponding concentrations. In this study, we have investigated the acoustic spectra of silica particles with different particle sizes, concentrations as well as salt concentrations. It was revealed that the noticeable deviation from the theoretical estimation only appeared in the case of large particle sizes close to the wavelength of ultrasound, and could be circumvented by addition of small amount of salt to suppress the electrostatic interactions of the charged silica particles. PMID- 30408682 TI - Behavior of 36Cl in agricultural soil-plant systems: A review of transfer processes and modelling approaches. AB - This article aims to review up-to-date knowledge and data acquired on 36Cl transfers to terrestrial soil-plant systems, evaluate the existing modelling approaches and identify priorities for future model improvements. This update has revealed the existence of fairly recent studies, whose results could be used for improving the modelling approaches which have been developed over the last decade. The priority areas include the consideration of the dry deposition process and the transfer of both gaseous and aerosol 36Cl to plants. The consideration of secondary processes such as the synthesis/mineralization of organochlorines and plant biomass litterfall is not recognized as a priority issue when assessing the impact of gaseous discharges. It was also identified that additional experimental studies had to be conducted to improve the understanding of the processes governing stable Cl and 36Cl dynamics in other terrestrial ecosystems (field crops, vegetables, grass) than forest environments on which most of the reported knowledge and data are reviewed. PMID- 30408683 TI - Nursing students' perceptions of faculty trustworthiness: Thematic analysis of a longitudinal study. AB - BACKGROUND: Although trust and perceived trustworthiness have been studied for decades, few studies have examined nursing students' perceptions of faculty trustworthiness. OBJECTIVES: To uncover the characteristics and behaviors of faculty members that lead nursing students to trust them. DESIGN: A longitudinal, qualitative study using focus group data. SETTING: A baccalaureate nursing school at a state university in the southeastern United States. PARTICIPANTS: Two cohorts of nursing students (starting in the Fall of 2015 or Spring of 2016) during the beginning, middle, and end of their advancement through the nursing school curriculum. METHODS: Eleven focus groups were held with a total of 77 participants from a purposeful sample of two cohorts. Thematic analysis was conducted on the focus group data. RESULTS: Three core themes emerged regarding the characteristics and behaviors of faculty members that lead nursing students to trust them: Giving of Oneself, Being Competent, and Having Integrity. The study findings provide guidance to nursing faculty regarding how to be perceived as trustworthy by students and how to avoid being perceived as untrustworthy. CONCLUSIONS: Upon examining their personal traits, words and behaviors, nursing educators may choose to change aspects of their demeanor to foster a student faculty relationship built on trust. PMID- 30408684 TI - France's citizen consultation on vaccination and the challenges of participatory democracy in health. AB - BACKGROUND: Confronted with a rise in vaccine hesitancy, public health officials increasingly try to involve the public in the policy decision-making process to foster consensus and public acceptability. In public debates and citizen consultations tensions can arise between the principles of science and of democracy. To illustrate this, we analyzed the 2016 citizen consultation on vaccination organized in France. This consultation led to the decision to extend mandatory vaccination. METHODS: The analysis combines qualitative and quantitative methods. We analyze the organization of the consultation and its reception using the documents provided by its organizing committee, articles of newsmedia and the contents of 299 vaccine-critical websites. Using methods from computational linguistics, we investigate the 10435 public comments posted to the consultation's official website. RESULTS: The combination of a narrow framing of debates (how to restore trust in vaccination and raise vaccination coverages) and a specific organization (latitude was given to the orientation committee with a strong presence of medical experts) was successful in avoiding legitimizing vaccine critical arguments. But these choices have been at the expense of a real reflection on the acceptability of mandatory vaccination and it did not quell vaccine-critical mobilizations. CONCLUSIONS: Public health officials must be aware that when trying to increase democratic participation into their decision making process, how they balance inputs from the various actors and how they frame the discussion determine whether this initiative will provide meaningful information and democratic legitimacy. PMID- 30408685 TI - Removal kinetics of sulfamethazine and its transformation products formed during treatment using a horizontal flow-anaerobic immobilized biomass bioreactor. AB - Sulfamethazine (SMZ) is an antibiotic from sulfonamides class widely used in veterinary medicine and reported in wastewater and sewage. Thus, it is essential to study technologies to reduce SMZ present in the aquatic environment. Anaerobic bioreactors are a low-cost technology applied for wastewater treatment. The objective of this paper is to study kinetics parameters related to SMZ removal using a horizontal flow-anaerobic immobilized biomass reactor (HAIB) and to evaluate its transformation products formed during this treatment. The bioreactor was operated at mesophilic condition with a hydraulic retention time of 12 h. The removal of SMZ was evaluated at three different concentrations: 200 ng L-1 (phase I), 400 ng l-1 (phase II) and 600 ng L-1 (phase III). The apparent first-order removal constant obtained for chemical oxygen demand was 0.885 +/- 0.094 h-1 while SMZ showed a removal constant of 0.356 h-1. SMZ was removed with an efficiency of 56.0 +/- 13.0 % (phase I); 62.0 +/- 12.0 % (phase II) and 62.0 +/- 6.00 % (phase III). Seven transformation products were detected and one of these with m/z 233 is reported for the first-time. The HAIB bioreactor has a potential to assist in wastewater treatment to remove contaminants at ng L-1 concentration level. PMID- 30408686 TI - Performance of anaerobic treatment of blackwater collected from different toilet flushing systems: Can we achieve both energy recovery and water conservation? AB - Source-diverted blackwater (toilet wastewater) contains most of the organic energy in domestic wastewater and can be treated anaerobically to maximize energy recovery. Blackwater collected from toilets of different water saving options (e.g., conventional, dual and vacuum toilets) represents different characteristics, but their digestibility has not been discussed. In the present study, blackwater collected from different toilet flushing systems were characterized and compared in terms of chemical composition, digestibility and microbial population development during biochemical methane potential (BMP) tests. Interestingly, the highest BMP (48%) was achieved for conventional/dual flush toilet (5-9 L water/flush) blackwaters, whereas vacuum toilet (0.5-1.2 L water/flush) blackwater BMP was only 34%. Elevated free ammonia (FA) concentration (>205 mg L-1) appeared to contribute to the reduced digestibility of high-water saving toilet (< 1.5 L water/flush) blackwaters. Methanogenesis was the major FA inhibition step in anaerobic digestion as evident by batch kinetics studies; where Methanosarcina methanogens predominate in all blackwater, but ammonia-tolerance methanogens Methanoculleus and Methanomicrobiales were also predominant in blackwater collected from vacuum toilets. This work underlines that overall measures of sustainability also need to consider blackwater characteristics when designing resource recovery based source-diverted sanitary treatment systems. PMID- 30408687 TI - Selective removal of nicotine from the main stream smoke by using a surface imprinted polymer monolith as adsorbent. AB - Using molecularly imprinted polymer as a selective adsorbent for gaseous toxicants is a novel attempt. In present work, a nicotine surface-imprinted monolith (MIM) was used for the selective removal of nicotine from smoke. First, the retention capacity and selectivity for this MIM was tested by using it as the stationary phase in gas chromatography and chromatographic conditions optimized. Then, the gas phase adsorption isotherms of MIM were constructed and the adsorption thermodynamics explored. At last, the applicability for MIM in the removal of nicotine in smoke was explored. Results indicated a stronger retention capacity and a higher selectivity of MIM toward the template vapor, with a capacity factor (87.88) and a selectivity factor (10.15) under the optimized conditions. A higher standard adsorption enthalpy change for this MIM toward the template (DeltaHa0 = 65.53 kJ mol-1) than that for the non-imprinted monolith (NIM) column (DeltaHa0 = 47.46 kJ mol-1) was observed. The adsorption isotherm for MIM appears the BET type II shape, while that for the NIM was approximately linear. When this MIM was used as the adsorbent, it exhibited a high performance in the selective removal of nicotine from the main stream smoke, with an adsorption percentage of 99.43%. PMID- 30408688 TI - Efficient removal of zinc from water and wastewater effluents by hydroxylated and carboxylated carbon nanotube membranes: Behaviors and mechanisms of dynamic filtration. AB - In this work, a bench scale study was designed to investigate the removal of zinc (Zn2+) and regeneration efficiencies of functionalized-MWCNT (f-MWCNT) membranes. The f-MWCNTs were incorporated into polyvinylchloride (PVC) hollow fiber membranes (HFMs), which acted as a substrate and a barrier for MWCNTs leaching to water. The results revealed that the removal capacity of Zn2+ through f-CNT membranes were above 98% for the synthetic water and over 70% for real wastewater effluents; predominantly involved surface complexation reaction. The acquired removal efficiency of CNT membrane is attributed to high absolute zeta potential followed by the hydrophilicity of the nanotubes coated the inside surface of HFMs and high concentration of oxygen functional groups on CNT surfaces. Later on, different regenerating solutions were used to desorb Zn2+ ions repeatedly from the inner surface of membranes and to recycle the CNT membranes for continuous removal of Zn2+ from water. The XPS analysis revealed that, Zn2+ ions were completely recovered owing to the ion exchange interactions. The results further confirmed that f-CNT membranes retained their original removal capacity after several successive cycles. Therefore, we recommend that, f-CNTs-based membranes have the potential to be used for large-scale removal and recovery of heavy metal ions from water or wastewater. PMID- 30408690 TI - Directed assembly of nanoparticles into continuous microstructures by standing surface acoustic waves. AB - Directed-assembly by standing surface acoustic waves (SSAWs) only requires an acoustic contrast between particles and their surrounding medium. It is therefore highly attractive as this requirement is fulfilled by almost all dispersed systems. Previous studies utilizing SSAWs demonstrated mainly reversible microstructure arrangements from nanoparticles. The surface chemistry of colloids dramatically influences their tendency to aggregate and sinter; therefore, it should be possible to form permanent microstructures with intimate contact between nanoparticles by controlling this property. Dispersed silver nanoparticles in a microfluidic channel were exposed to SSAWs and reversibly accumulated at the pressure nodes. We show that addition of chloride ions that remove the polyacrylic capping of the nanoparticles trigger their sintering and the formation of stable conducting silver microstructures. Moreover, if the destabilizing ions are added prior to nanoparticle assembly while continuously streaming the dispersion through the acoustic aperture, the induced aggregation leads to formation of significantly thinner microstructures, which are (for the first time) unlimited in length by the acoustic apparatus. This new approach overcomes the discrepancy between the need for organic dispersants to prevent unwanted aggregation in the dispersion, and the end product's requirement for intimate contact between the colloidal particles. PMID- 30408689 TI - Room temperature synthesis of CdS/SrTiO3 nanodots-on-nanocubes for efficient photocatalytic H2 evolution from water. AB - Spontaneous solar-driven water splitting to generate H2 with no pollution discharge is an ideal H2 generation approach. However, its efficiency remains far from real application owing to the poor light-harvesting and ultrafast charge recombination of photocatalysts. To address these issues, herein, we employed a novel but simple chemical bath deposition (CBD) method to construct CdS/SrTiO3 nanodots-on-nanocubes at room temperature (ca. 25 degrees C). The as-synthesized nanohybrids not only expand light absorption from ultraviolet (UV) to visible light but also significantly retard charge recombination owing to the well defined heterostructure formation. As a result, the CdS/SrTiO3 exhibits high photocatalytic performance with H2 evolution rate of 1322 MUmol g-1 h-1, which is 2.8 and 12.2 times higher than that of pristine CdS and SrTiO3, respectively. This work provides a universal approach for the heterostructure construction, and inspired by this, higher efficient photocatalysts for H2 evolution may be developed in the near future. PMID- 30408691 TI - In situ-generated yttrium-based nanoparticle/polyethersulfone composite adsorptive membranes: Development, characterization, and membrane formation mechanism. AB - In this study, a series of in situ-generated yttrium-based nanoparticle (NP)/polyethersulfone (PES) composite adsorptive membranes were prepared by the phase inversion method for the first time. The Y(NO3)3.6H2O as precursor, uniformly dispersed at the molecular level in casting solution, reacted with OH- in a coagulation bath and ambient CO2 during the phase inversion process. The Y(CO3)0.5(OH)2 NPs were formed in situ and distributed homogeneously in a PES matrix, which was confirmed by X-ray photoelectron spectroscopy (XPS) and Energy Dispersive X-Ray Spectroscopy (EDS) results. The compatibility of the nanocomposite membranes was improved by an in situ preparation method. With the increase in content of Y-based NPs in composite membranes, the surface hydrophilicity and water permeability first increased from M1 to M2, and then slightly decreased from M3 to M5, which was mainly related to membrane structure. From M1 to M5, the demixing way changed from instantaneous demixing to delayed demixing process as a result of thermodynamic enhancement and viscosity hindrance in the phase inversion process. A higher demixing rate led to a structure with large finger-like macro-voids, i.e., M1, whereas a lower demixing rate caused the suppression of finger-like macro-voids, i.e., M5. More importantly, the adsorption study indicated that the nanocomposite adsorptive membranes were stable in the treatment of fluoride-containing water, with no leakage of Y-based NPs from membrane matrix to solution. It is expected that the in situ preparation technique could be used to produce next-generation nanocomposite adsorptive membranes with improved comprehensive properties for application in water treatment. PMID- 30408692 TI - Implicit incremental natural actor critic algorithm. AB - Natural policy gradient (NPG) methods are promising approaches to finding locally optimal policy parameters. The NPG approach works well in optimizing complex policies with high-dimensional parameters, and the effectiveness of NPG methods has been demonstrated in many fields. However, the incremental estimation of the NPG is computationally unstable owing to its high sensitivity to the step-sizes values, especially to the one used to update the estimate of NPG. In this study, we propose a new incremental and stable algorithm for the NPG estimation. We call the proposed algorithm the implicit incremental natural actor critic (I2NAC), and it is based on the idea of the implicit update. The convergence analysis for I2NAC is provided. Theoretical analysis results indicate the stability of I2NAC and the instability of conventional incremental NPG methods. Numerical experiments were performed, and the results show that I2NAC is less sensitive to the values of the meta-parameters, including the step-size for the NPG update, compared to the existing incremental NPG method. PMID- 30408693 TI - Variational inference with Gaussian mixture model and householder flow. AB - The variational auto-encoder (VAE) is a powerful and scalable deep generative model. Under the architecture of VAE, the choice of the approximate posterior distribution is one of the crucial issues, and it has a significant impact on tractability and flexibility of the VAE. Generally, latent variables are assumed to be normally distributed with a diagonal covariance matrix, however, it is not flexible enough to match the true complex posterior distribution. We introduce a novel approach to design a flexible and arbitrarily complex approximate posterior distribution. Unlike VAE, firstly, an initial density is constructed by a Gaussian mixture model, and each component has a diagonal covariance matrix. Then this relatively simple distribution is transformed into a more flexible one by applying a sequence of invertible Householder transformations until the desired complexity has been achieved. Additionally, we also give a detailed theoretical and geometric interpretation of Householder transformations. Lastly, due to this change of approximate posterior distribution, the Kullback-Leibler distance between two mixture densities is required to be calculated, but it has no closed form solution. Therefore, we redefine a new variational lower bound by virtue of its upper bound. Compared with other generative models based on similar VAE architecture, our method achieves new state-of-the-art results on benchmark datasets including MNIST, Fashion-MNIST, Omniglot and Histopathology data a more challenging medical images dataset, the experimental results show that our method can improve the flexibility of posterior distribution more effectively. PMID- 30408694 TI - Unsupervised feature extraction by low-rank and sparsity preserving embedding. AB - Manifold based feature extraction has been proved to be an effective technique in dealing with the unsupervised classification tasks. However, most of the existing works cannot guarantee the global optimum of the learned projection, and they are sensitive to different noises. In addition, many methods cannot catch the discriminative information as much as possible since they only exploit the local structure of data while ignoring the global structure. To address the above problems, this paper proposes a novel graph based feature extraction method named low-rank and sparsity preserving embedding (LRSPE) for unsupervised learning. LRSPE attempts to simultaneously learn the graph and projection in a framework so that the global optimal projection can be obtained. Moreover, LRSPE exploits both global and local information of data for projection learning by imposing the low rank and sparse constraints on the graph, which promotes the method to obtain a better performance. Importantly, LRSPE is more robust to noise by imposing the l2,1 sparsity norm on the reconstruction errors. Experimental results on both clean and noisy datasets prove that the proposed method can significantly improve classification accuracy and it is robust to different noises in comparison with the state-of-the-art methods. PMID- 30408696 TI - Fixed-time synchronization of inertial memristor-based neural networks with discrete delay. AB - This paper is concerned with the fixed-time synchronization control of inertial memristor-based neural networks with discrete delay. We design four different kinds of feedback controllers, under which the considered inertial memristor based neural networks can realize fixed-time synchronization perfectly. Moreover, the obtained fixed-time synchronization criteria can be verified by algebraic operations. For any initial synchronization error, the settling time of fixed time synchronization is bounded by a fixed constant, which can be calculated beforehand based on system parameters and controller parameters. Numerical simulations are given to illustrate the effectiveness of our theoretical results. PMID- 30408695 TI - Intrinsic motivation and mental replay enable efficient online adaptation in stochastic recurrent networks. AB - Autonomous robots need to interact with unknown, unstructured and changing environments, constantly facing novel challenges. Therefore, continuous online adaptation for lifelong-learning and the need of sample-efficient mechanisms to adapt to changes in the environment, the constraints, the tasks, or the robot itself are crucial. In this work, we propose a novel framework for probabilistic online motion planning with online adaptation based on a bio-inspired stochastic recurrent neural network. By using learning signals which mimic the intrinsic motivation signal cognitive dissonance in addition with a mental replay strategy to intensify experiences, the stochastic recurrent network can learn from few physical interactions and adapts to novel environments in seconds. We evaluate our online planning and adaptation framework on an anthropomorphic KUKA LWR arm. The rapid online adaptation is shown by learning unknown workspace constraints sample-efficiently from few physical interactions while following given way points. PMID- 30408697 TI - Evaluating performance of neural codes in model neural communication networks. AB - Information needs to be appropriately encoded to be reliably transmitted over physical media. Similarly, neurons have their own codes to convey information in the brain. Even though it is well-known that neurons exchange information using a pool of several protocols of spatio-temporal encodings, the suitability of each code and their performance as a function of network parameters and external stimuli is still one of the great mysteries in neuroscience. This paper sheds light on this by modeling small-size networks of chemically and electrically coupled Hindmarsh-Rose spiking neurons. We focus on a class of temporal and firing-rate codes that result from neurons' membrane-potentials and phases, and quantify numerically their performance estimating the Mutual Information Rate, aka the rate of information exchange. Our results suggest that the firing-rate and interspike-intervals codes are more robust to additive Gaussian white noise. In a network of four interconnected neurons and in the absence of such noise, pairs of neurons that have the largest rate of information exchange using the interspike-intervals and firing-rate codes are not adjacent in the network, whereas spike-timings and phase codes (temporal) promote large rate of information exchange for adjacent neurons. If that result would have been possible to extend to larger neural networks, it would suggest that small microcircuits would preferably exchange information using temporal codes (spike timings and phase codes), whereas on the macroscopic scale, where there would be typically pairs of neurons not directly connected due to the brain's sparsity, firing-rate and interspike-intervals codes would be the most efficient codes. PMID- 30408698 TI - Joint effect of less than 1 h of daytime napping and seven to 8 h of night sleep on the risk of stroke. AB - BACKGROUND: The joint effect of daytime naps and night sleep on the risk of stroke has not been clarified. Our research aimed to verify this relationship based on data from a large sample-sized cross-sectional study and a cohort study. METHODS: The cross-sectional study included 7887 subjects, aged 20-74 years. Using stratified random sampling, 1928 individuals were selected for the cohort study. We then followed up with these individuals for an average of 4.94 years and collected detailed sleep information with the Pittsburgh Sleep Quality Index (PSQI). Serum fasting blood glucose, triglyceride, cholesterol and high density lipoprotein were analyzed, and anthropometric measurements were taken. Interaction and joint analyses were performed. RESULTS: Consistent with the results in the cross-sectional study, hazard ratios (HRs) (95% CI) of stroke were 1.94 (1.21-3.13) and 2.24 (1.05-4.79) for daytime napping >=1 h and nighttime sleeping >=9 h in the cohort study. For no naps combined with <7 h of nighttime sleeping, the HR (95%CI) was 2.61 (1.17-5.82). For >=1 h of naps combined with <7 h, 7-8 h, 8-9 h, and >=9 h of nighttime sleeping, HRs (95% CI) were 2.16 (1.03 4.51), 2.36 (1.07-5.20), 2.41 (1.11-5.20) and 3.37 (1.05-10.81), respectively. CONCLUSIONS: Individuals with 7-8 h of night sleep combined with no daytime naps or less than 1 h of daytime napping were at low risk of stroke; nighttime sleeping >=9 h combined with daytime napping >=1 h and night sleep <7 h combined with 0 or >1 h daytime napping was associated with high risk of stroke. CLINICAL TRIAL REGISTRY: http://www.chictr.org. TRAIL NUMBER: ChiCTR-ECH-1200272, ChiCTR ECH-12002938. PMID- 30408699 TI - Distress tolerance and cessation-related cannabis processes: The role of cannabis use coping motives. AB - Robust evidence implicates perceived distress tolerance as a risk factor for maladaptive cannabis use and poorer cannabis cessation outcomes. Past work suggests that perceived distress tolerance may be related to an array of clinically-relevant cannabis processes and outcomes via cannabis coping motives. Although promising, the generalizability of this work to racially/ethnically diverse samples of adult cannabis users is unknown. Additionally, investigation into alternative cannabis processes has been limited and has not controlled for the effects of other cannabis motives. Thus, the present study investigated cannabis coping motives as an explanatory variable for the relation between perceived distress tolerance and cannabis use processes that may impede cessation (e.g., cannabis use cravings, perceived barriers to cannabis cessation, and withdrawal symptoms) among an ethnically diverse sample of current cannabis using adults. Participants included 131 adult cannabis users (Mage = 36.67 years; 29.8% female; 59.2% Black, 26.2% White, 16.0% Hispanic). Results indicated that perceived distress tolerance was indirectly associated with all criterion variables through cannabis coping motives after controlling for the variance attributable to four other motives. The current study builds upon previous theoretically-supported work by examining these models among an ethnically diverse sample of current cannabis using adults and testing alternative cessation related cannabis processes while controlling for the independent effects of four other cannabis motives. PMID- 30408700 TI - Changes in posttraumatic stress symptoms, cognitions, and depression during treatment of traumatized youth. AB - OBJECTIVE: Although there is compelling evidence that trauma-focused cognitive behavioral therapy (TF-CBT) is an effective treatment for traumatized youth, we know less about the mechanisms contributing to symptom reduction. To improve the understanding of change mechanisms in TF-CBT, this paper investigates the possible bi-directional longitudinal relationship between changes in posttraumatic stress symptoms (PTSS), cognitions and depression in a clinical sample of traumatized youth. METHODS: The study includes 79 youth (M age = 15.0 years, SD = 2.2, 74.7% girls) who received TF-CBT. The youth were assessed for PTSS, posttraumatic cognitions, and depressive symptoms at baseline, mid treatment, post-treatment, 12 months after baseline, and 18 months after post treatment. RESULTS: Growth curve analyses showed that PTSS, posttraumatic cognitions and depressive symptoms decreased over time. Cross-lagged mediation analyses demonstrated that reduction in posttraumatic cognitions predicted reduction in both PTSS and depression at the subsequent measurement wave, but we did not find a clear pattern in the longitudinal relationship between PTSS and depression. CONCLUSIONS: Changes in posttraumatic cognitions mediate the therapeutic effects of TF-CBT on symptoms of posttraumatic stress and depression. Future studies should seek to tease out how clinicians can best proceed to help youth reduce their posttraumatic cognitions and thereby improve treatment outcome. PMID- 30408701 TI - TEMUC3, a computer program for unit-cell determination of crystalline phases in TEM experiments. AB - A new computer program, TEMUC3, has been developed for unit-cell determination of crystal phases using electron diffraction data. A graphic user-friendly interface was designed for the following operations, (i) a reciprocal lattice is reconstructed from a tilt series of electron diffraction patterns; (ii) a Niggli cell is generated from the two electron diffraction patterns in a tilt series; iii) a Niggli cell is generated from three electron diffraction patterns, in which each pair shares a common reflection vector; (iv) a conventional unit-cell is converted from a Niggli cell; (v) a unit-cell is refined from a set of reflections. The application of TEMUC3 is further elucidated in three examples. A brief discussion on the generation of a primitive cell from electron diffraction data and the cell reduction in reciprocal and direct space is presented. PMID- 30408702 TI - Extender osmolality, glycerol and egg yolk on the cryopreservation of epididymal spermatozoa for gamete banking of the Cantabric Chamois (Rupicapra pyrenaica parva). AB - Germplasm banking is a key technology enabling the ex-situ conservation of wild species. However, cryopreservation protocols must be tested to assure the applicability of the banked material. The objective of this study was defining a range of parameters for the composition of a semen extender for Cantabrian chamois epididymal spermatozoa (post-mortem collection). The freezing extender was based in a TES-Tris-fructose buffer, modifying its composition in three experiments: Osmolality of the buffer (320, 380 or 430 mOsm/kg, 8% glycerol, 15% egg yolk), glycerol (4 or 8%, 430 mOsm/kg, 15% egg yolk), egg yolk (10 or 15%, 430 mOsm/kg, 4% glycerol). Sperm was extended at 100 mill. spermatozoa/ml, cooled at 5 degrees C and frozen at -20 degrees C/min. Sperm quality was assessed pre and post-thawing (CASA, HOS test, abnormal forms, cytoplasmic droplets, and viability and acrosomal damage by flow cytometry). Freezability was good overall, with total motility of 65.5% +/- 2.4 initial and 55.8% +/- 2.4 post-thawing. The extenders affected the post-thaw sperm quality marginally. Whereas osmolalities and glycerol concentrations seemed not to differ, 430 mOsm/kg and 4% glycerol might be preferred. Egg yolk concentrations only differed on sperm velocity (VCL: 84.0 +/- 6.7 MUm/s in 10% vs. 70.7 +/- 6.2 MUm/s in 15%, P < 0.05). Our results suggest a good cryotolerance of chamois epididymal spermatozoa, with a preferred extender composition of hyperosmotic buffer, glycerol in the 4% range and lower egg yolk (10% range) than other ruminants. PMID- 30408703 TI - Epidemiology of injury in English Professional Football players: A cohort study. AB - OBJECTIVE: To estimate the current incidence and location of injury in English professional football. DESIGN: Prospective cohort study conducted over one competitive season (2015/16). SETTING: Professional football players competing in the English Football League and National Conference. PARTICIPANTS: 243 players from 10 squads (24.3 +/- 4.21 per squad). MAIN OUTCOME MEASURE: Injury incidence, training and match exposure were collected in accordance with the international consensus statement on football injury epidemiology. RESULTS: 473 injuries were reported. The estimated incidence of injury was, 9.11 injuries/1000 h of football related activity. There was a higher incidence of injury during match play (24.29/1000 h) compared to training (6.84/1000 h). The thigh was the most common site of injury (31.7%), muscle strains accounted for 41.2% of all injuries. The hamstrings were the most frequently strained muscle group, accounting for 39.5% of all muscle strains and 16.3% of all injuries. Moderate severity injuries (8-28 days) were the most common (44.2%). CONCLUSIONS: Incidence of injury has increased over the last 16 years with muscle strains remaining the most prevalent injury. The hamstrings remain the most commonly injured muscle group. PMID- 30408704 TI - Cancer frequency detected by positron emission tomography-computed tomography in limbic encephalitis. AB - OBJECTIVE: Paraneoplastic limbic encephalitis (LE) occurs frequently with considerable variability according to literature reports. We thus determined the cancer frequency in mixed LE subtypes sharing the diagnosis of temporal lobe epilepsy (TLE). METHODS: All patients underwent magnetic resonance imaging (MRI) of the brain, electroencephalography (EEG) recordings, neuropsychological testing, immunohistochemistry, and clinical examination together with whole body 2-fluor-2-desoxy-d-glucose (FDG)-positron emission tomography (PET)/computed tomography (CT) to detect cancer in this observatory study. RESULTS: Ninety-three patients (median: 52 years) with TLE due to autoimmune LE were investigated. Cancer was detected in the FDG-PET/CTs of 3 out of 93 (3.2%) patients with LE. Cancer was diagnosed upon, 5 years earlier and 5 years after FDG-PET/CT in 7 of 93 (7.5%) of all patients with LE. The cancer frequency in those patients was significantly lower than that reported in the largest series of patients with LE associated with and without different antibodies (7.5% vs. 23.5%, Bootstrap test, p < 0.05), but was indistinguishable from the estimated age-dependent cancer frequency in the German regional North-Rhine-Westfalian population without LE in 2014 (Chi-square test: p = 0.2). CONCLUSIONS: Our findings reveal that the cancer frequency in patients with TLE with LE detected by FDG-PET/CT is low and not different from the age-dependent natural cancer occurrence in a regional population. PMID- 30408705 TI - The cognitive phenotype of idiopathic generalized epilepsy. AB - OBJECTIVE: Dysexecutive traits have been described in idiopathic generalized epilepsy (IGE), but studies mainly focused on juvenile myoclonic epilepsy (JME). To better understand the neuropsychology of IGE, more research is needed on syndromes other than JME, controlling potential confounding factors as the cognitive effects of valproate and epileptic discharges (ED). We describe the neuropsychological profile of a group of patients with different syndromes of IGE including simultaneous video electroencephalography (EEG). METHODS: We performed a comprehensive cognitive and neuropsychiatric evaluation with video-EEG on 61 adults with IGE (JME 19; IGE with generalized tonic-clonic seizures [GTCS] alone [IGE-GTCS] 22; childhood absence epilepsy [CAE] or juvenile absences epilepsy [JAE] persisting in adulthood 20). We compared results between patients (globally and by syndrome) and a control group of 21 individuals (similar age, educational level); p-values were adjusted for multiple testing according to a 0.05 false discovery rate. RESULTS: Patients obtained significantly lower results than controls on visuospatial working memory, processing speed, cognitive flexibility and strategy, abstract visuospatial reasoning, arithmetic, and acquired knowledge. While CAE/JAE showed the lowest scores on cognitive assessment and highest anxiety index, IGE-GTCS showed the most favorable scores. Most tests were not influenced by valproate intake, and the dose did not correlate with cognitive performance in the test that yielded differences between patients and controls. Epileptic discharges during assessment were not frequent (10 patients, 1-4 tests). SIGNIFICANCE: Our findings suggest that patients with IGE have significantly lower abilities in various executive functions and acquired knowledge, compared to population of same age and education. The low frequency of ED on simultaneous video-EEG and absence of correlation of scores with valproate dose reinforce that the obtained results are due to a cognitive phenotype in IGE. This phenotype may be influenced by syndrome, and patients with CAE/JAE persisting in the adult may have a wider neuropsychiatric impairment. PMID- 30408706 TI - The psychological wellbeing outcomes of nonpharmacological interventions for older persons with insomnia symptoms: A systematic review and meta-analysis. AB - Nonpharmacological treatment of insomnia in older persons has been associated with reduced insomnia symptoms and increased psychological wellbeing. This systematic review and meta-analysis examined whether nonpharmacological interventions can promote wellbeing indicators in older persons who experience insomnia symptoms and investigated the components of these interventions. Twenty studies met inclusion criteria. Psychological wellbeing outcomes included symptoms of depression, anxiety, mental health-related quality of life, and fatigue. Interventions significantly reduced depression and fatigue symptoms in most of the studies that included these outcomes. Findings of our qualitative analysis suggest that mindfulness-based interventions in particular can potentially reduce depression symptoms in older persons with insomnia symptoms. Meta-analyses of studies that included psychological wellbeing outcomes showed small-medium weighted mean effects indicating reductions in symptoms of depression, anxiety, and fatigue. The results suggest that nonpharmacological interventions for older persons with insomnia symptoms can potentially reduce depression and fatigue symptoms and highlight interventions that may be particularly valuable for this purpose. PMID- 30408707 TI - Unfolding meaning in context: The dynamics of conceptual similarity. AB - How are relationships between concepts affected by the interplay between short term contextual constraints and long-term conceptual knowledge? Across two studies we investigate the consequence of changes in visual context for the dynamics of conceptual processing. Participants' eye movements were tracked as they viewed a visual depiction of e.g. a canary in a birdcage (Experiment 1), or a canary and three unrelated objects, each in its own quadrant (Experiment 2). In both studies participants heard either a semantically and contextually similar "robin" (a bird; similar size), an equally semantically similar but not contextually similar "stork" (a bird; bigger than a canary, incompatible with the birdcage), or unrelated "tent". The changing patterns of fixations across time indicated first, that the visual context strongly influenced the eye movements such that, in the context of a birdcage, early on (by word offset) hearing "robin" engendered more looks to the canary than hearing "stork" or "tent" (which engendered the same number of looks), unlike in the context of unrelated objects (in which case "robin" and "stork" engendered equivalent looks to the canary, and more than did "tent"). Second, within the 500 ms post-word-offset eye movements in both experiments converged onto a common pattern (more looks to the canary after "robin" than after "stork", and for both more than after "tent"). We interpret these findings as indicative of the dynamics of activation within semantic memory accessed via pictures and via words, and reflecting the complex interaction between systems representing context-independent and context dependent conceptual knowledge driven by predictive processing. PMID- 30408708 TI - Increased expression of the membrane-bound CD40 ligand on peripheral CD4+ T cells in the acute phase of AQP4-IgG-seropositive neuromyelitis optica spectrum disorders. AB - Currently, no data are available regarding the expression levels of CD40L on CD4+ T cells in patients with neuromyelitis optica spectrum disorders (NMOSD). The percentage of circulating CD40L+CD4+ T cells was measured by flow cytometry in 23 NMOSD patients and 10 healthy controls. The ratio of CD40L+CD4+ to CD4+ T cells in patients at acute phase (18.28 +/- 15.56%) was significantly higher than that in healthy controls (7.23 +/- 5.94%, P = .032) and was positively correlated with disease severity (r = 0.532, P = .041). Thus, our results suggest an important role of this molecule in acute attacks of NMOSD. PMID- 30408709 TI - Kinesiophobia, but not strength is associated with altered movement in women with patellofemoral pain. AB - BACKGROUND: Evidence indicates the presence of both kinesiophobia and knee extension strength deficits in women with patellofemoral pain (PFP). Both impairments may contribute to apparent compensatory gait patterns including reduced cadence and peak knee flexion during stair negotiation. RESEARCH QUESTION: Is kinesiophobia or knee extension strength associated with movement pattern in women with patellofemoral pain? METHODS: Forty women with PFP were assessed with three-dimensional kinematic analyses during stair descent; isokinetic dynamometry of the knee extensors (isometric, concentric and eccentric); and the Tampa scale for kinesiophobia. Pearson coefficients were calculated to determine relationship among variables. RESULTS: Kinesiophobia correlated significantly with cadence (r = -0.62, p < 0.001), and peak knee flexion (r = -0.76, p < 0.001). No significant correlations were found between any knee extensor strength variables and kinematics (cadence or peak knee flexion); or kinesiophobia (p > 0.05). SIGNIFICANCE: Findings of this study could suggest addressing strength impairments alone may not adequately address kinesiophobia and movement pattern impairments in women with PFP. However, high quality randomised controlled trials are needed to test this assumption. Further value may be added if currently evidence-based knee strengthening exercise is combined with education and/or graded exposure to address kinesiophobia, and consideration to gait retraining to address altered movement patterns at the knee. PMID- 30408710 TI - Paretic propulsion as a measure of walking performance and functional motor recovery post-stroke: A review. AB - BACKGROUND: Although walking speed is the most common measure of gait performance post-stroke, improved walking speed following rehabilitation does not always indicate the recovery of paretic limb function. Over the last decade, the measure paretic propulsion (Pp, defined as the propulsive impulse generated by the paretic leg divided by the sum of the propulsive impulses of both legs) has been established as a measure of paretic limb output and recently targeted in post stroke rehabilitation paradigms. However, the literature lacks a detailed synthesis of how paretic propulsion, walking speed, and other biomechanical and neuromuscular measures collectively relate to post-stroke walking performance and motor recovery. OBJECTIVE: The aim of this review was to assess factors associated with the ability to generate Pp and identify rehabilitation targets aimed at improving Pp and paretic limb function. METHODS: Relevant literature was collected in which paretic propulsion was used to quantify and assess propulsion symmetry and function in hemiparetic gait. RESULTS: Paretic leg extension during terminal stance is strongly associated with Pp. Both paretic leg extension and propulsion are related to step length asymmetry, revealing an interaction between spatiotemporal, kinematic and kinetic metrics that underlies hemiparetic walking performance. The importance of plantarflexor function in producing propulsion is highlighted by the association of an independent plantarflexor excitation module with increased Pp. Furthermore, the literature suggests that although current rehabilitation techniques can improve Pp, these improvements depend on the patient's baseline plantarflexor function. SIGNIFICANCE: Pp provides a quantitative measure of propulsion symmetry and should be a primary target of post-stroke gait rehabilitation. The current literature suggests rehabilitation techniques that target both plantarflexor function and leg extension may restore paretic limb function and improve gait asymmetries in individuals post stroke. PMID- 30408711 TI - Neighbourhood influences and its association with the mental health of adolescents in Kuala Lumpur, Malaysia. AB - BACKGROUND: Mental health problems are affecting more children and adolescents worldwide. Individual, family and school factors are often linked with mental health problems among adolescents. AIM: To determine the neighbourhood factors influencing the prevalence of abnormal mental health status among adolescents in an urban population. METHOD: A cross-sectional study was conducted among adolescents aged 13, 14 and 16 years old from thirteen secondary schools in Kuala Lumpur using validated questionnaires. A total of 567 adolescents participated in this study. RESULTS: The prevalence of abnormal mental health status in this study was 4.4%. In multivariable analysis, female (OR = 1.79, 95%CI: 1.11-2.89), having divorced parents (OR = 3.53, 95%CI: 1.96-6.36), high educational stress (OR = 8.18, 95%CI: 4.25-15.75), medium educational stress (OR = 2.99, 95%CI: 1.53 5.83), whose house has been broken in before (OR = 2.02, 95%CI: 1.11-3.68) and living in a neighbourhood with low socioeconomic status (OR = 2.09, 95%CI: 1.23 3.56) were more likely to have abnormal mental health status. CONCLUSIONS: Neighbourhood factors were found to be significant in determining adolescents' mental health status. The findings emphasize the importance of those in the public health sector to highlight these significant neighbourhood factors to the Ministry of Housing and Local Government. Swift action needs to be taken by the Ministry to provide solutions related to the neighbourhood factors and this can contribute to improvement in the adolescents' mental health. PMID- 30408712 TI - A life with seizures: Argentine patients' perspectives about the impact of drug resistant epilepsy on their lives. AB - PURPOSE: To understand the experience of drug-resistant epilepsy in patients from Argentina, a developing nation. METHOD: A qualitative approach using semi structured interviews was used to gain an in-depth and contextual understanding of the perspectives of 20 patients with DRE. Data collection and analysis were followed by an inductive and interpretive approach informed by the principles of thematic analysis. RESULTS: Six main themes emerged: 1) Characteristics of the illness, including seizure features -unpredictability, presence of auras, physical and cognitive consequences- and how patients relate with the use of antiepileptic drugs; 2) interactions with health system, regarding the features of the Argentine's health system, and patient's health-seeking behaviours; 3) beliefs about the illness, including psychosocial, biological and folk explanatory models; 4) beliefs about how other people perceive them, which included prejudice, responsibility and overprotection; 5) self-perception, and 6) impact of the illness on their activities. CONCLUSIONS: This information might be useful to help in the development of a conceptual model of the impact epilepsy on patients' lives. Many of the topics mentioned as relevant in Argentina coincide with those highlighted in studies that were carried out in first-world countries. However, additional topics were also reported including the role of traditional healing in health-seeking behaviour and explanatory models of illness. It is important to understand these perspectives to develop appropriate psychosocial interventions for this specific population. PMID- 30408714 TI - Circulating renin-angiotensin system-regulating specific aminopeptidase activities in pre- and post- menopausal women with breast cancer treated or not with neoadyuvant chemotherapy. A two years follow up study. AB - We have previously described changes in several circulating renin-angiotensin system (RAS)-regulating aminopeptidase activities in pre- and postmenopausal women with breast cancer treated or not with neoadjuvant chemotherapy. Women with breast cancer presented a reduced catabolism of angiotensin II (AngII) when compared to healthy individuals, although specific enzyme activities were different between pre- and post- menopausal women. In addition, neoadjuvant chemotherapy in breast cancer patients caused changes in aminopeptidase activities leading to increased AngII catabolism independently of hormonal status. Here we extend the aminopeptidase analysis to three time points of the patient follow-up (6, 12, and 24 months). No changes occur in enzyme activities during this time period and the effects of therapy remain unaltered overtime both in pre- and in postmenopausal women. PMID- 30408713 TI - Visual field defects after radiosurgery versus temporal lobectomy for mesial temporal lobe epilepsy: Findings of the ROSE trial. AB - PURPOSE: Stereotactic radiosurgery (SRS) may be an alternative to anterior temporal lobectomy (ATL) for mesial temporal lobe epilepsy (MTLE). Visual field defects (VFD) occur in 9-100% of patients following open surgery for MTLE. Postoperative VFD after minimally invasive versus open surgery may differ. METHODS: This prospective trial randomized patients with unilateral hippocampal sclerosis and concordant video-EEG findings to SRS versus ATL. Humphries perimetry was obtained at 24 m after surgery. VFD ratios (VFDR = proportion of missing homonymous hemifield with 0 = no VFD, 0.5 = complete superior quadrantanopsia) quantified VFD. Regressions of VFDR were evaluated against treatment arm and covariates. MRI evaluated effects of volume changes on VFDR. The relationships of VFDR with seizure remission and driving status 3 years after surgery were evaluated. RESULTS: No patients reported visual changes or had abnormal bedside examinations, but 49 of 54 (91%) of patients experienced VFD on formal perimetry. Neither incidence nor severity of VFDR differed significantly by treatment arm. VFDR severity was not associated with seizure remission or driving status. CONCLUSION: The nature of VFD was consistent with lesions of the optic radiations. Effective surgery (defined by seizure remission) of the mesial temporal lobe results in about a 90% incidence of typical VFD regardless of method. PMID- 30408715 TI - Development and validation of modified risk prediction models for cardiovascular disease and its subtypes: The Hisayama Study. AB - BACKGROUND AND AIMS: Predicting cardiovascular events is of practical benefit for disease prevention. The aim of this study was to develop and evaluate an updated risk prediction model for cardiovascular diseases and its subtypes. METHODS: A total of 2462 community residents aged 40-84 years were followed up for 24 years. A Cox proportional hazards regression model was used to develop risk prediction models for cardiovascular diseases, and separately for stroke and coronary heart diseases. The risk assessment ability of the developed model was evaluated, and a bootstrapping method was used for internal validation. The predicted risk was translated into a simplified scoring system. A decision curve analysis was used to evaluate clinical usefulness. RESULTS: The multivariable model for cardiovascular diseases included age, sex, systolic blood pressure, hemoglobin A1c, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, smoking habits, and regular exercise as predictors. The models for stroke and coronary heart diseases incorporated both shared and unique variables. The developed models showed good discrimination with little evidence of overfitting (optimism-corrected Harrell's C statistics 0.726-0.777) and calibrations (Hosmer Lemeshow test, p = 0.44-0.90). The decision curve analysis revealed that the predicted risk-based decision-making would have higher net benefit than either a CVD intervention strategy for all individuals or no individuals. CONCLUSIONS: The developed risk prediction models showed a good performance and satisfactory internal validity, which may help understand individual risk and setting personalized goals, and promote risk stratification in public health strategies for CVD prevention. PMID- 30408716 TI - Early onset ACS: An age based clinico-epidemiologic and angiographic comparison. AB - BACKGROUND AND AIMS: Acute coronary syndrome (ACS) in the very young is a rare entity, with limited data. We aimed to study patterns and profile of ACS in patients aged 20-30 years in comparison with those above 30 years. METHODS: In this retrospective record-based study, the demographic and clinical profile of all patients with ACS in the last 12 years (n = 35259) was analysed: group I (20 30 years) and group II (above 30 years). Patients in group II were selected by systematic sampling. Age, gender, domicile, body mass index (BMI), serum cholesterol, smoking, alcohol use, drug abuse, diabetes, hypertension, family history, type of ACS, angiographic findings and management strategies were recorded. Chi-square test and Fischer's exact test were used for data analysis. RESULTS: Of 35,259 patients, 0.32% (n = 114) were from the younger age group, with a rising trend of prevalence over 12 years. Obesity, overweight, urban living, smoking, alcohol and drug abuse were significantly higher in group I (p < 0.05). Diabetes mellitus and hypertension were more prevalent in group II (p = 0.001). STEMI in group I (76.3%) and NSTEMI in group II (47.1%) were the common modes of presentation (p = 0.001). 42.1% of group I patients had recanalized coronaries with conservative management in comparison to 3% in group II (p = 0.001). CONCLUSIONS: There is a rising trend in prevalence of ACS in very young patients. Overweight, obesity, urbanization and drug abuse are potential risk factors. The younger subset of ACS patients is different from the older population due to their thrombotic milieu, which could be more amenable to intensive pharmacologic management. PMID- 30408717 TI - Effect of low carbohydrate high fat diet on LDL cholesterol and gene expression in normal-weight, young adults: A randomized controlled study. AB - BACKGROUND AND AIMS: The effects of a low carbohydrate/high fat (LCHF) diet on health are debated. This study aims to explore the effects of a diet with less than 20 g carbohydrates per day (LCHF) on plasma low density lipoprotein cholesterol (LDL-C) in young and healthy adults. The secondary aim is the assessment of lipid profile and peripheral blood mononuclear cells (PBMC) gene expression. METHODS: This was a randomized controlled parallel-designed intervention study. Participants were either assigned to a three-week LCHF diet or a control group continuing habitual diet ad libitum, in both groups. RESULTS: In total, 30 healthy normal weight participants completed the study. Nine subjects did not complete it due to adverse events or withdrawn consent. In the LCHF diet group (n = 15), plasma LDL-C increased from (mean +/- SD) 2.2 +/- 0.4 mmol/l before intervention to 3.1 +/- 0.8 after, while in the control group (n = 15), LDL-C remained unchanged: 2.5 +/- 0.8 mmol/l (p < 0.001 between groups). There was a significant increase in apolipoprotein B, total cholesterol, high density lipoprotein cholesterol, free fatty acids, uric acid and urea in the LCHF group versus controls. Plasma levels of triglycerides, lipoprotein (a), glucose, C-peptide or C-reactive protein (CRP), blood pressure, body weight or body composition did not differ between the groups. PBMC gene expression of sterol regulator element binding protein 1 (SREBP-1) was increased in the LCHF group versus controls (p <= 0.01). The individual increase in LDL-C from baseline varied between 5 and 107% in the LCHF group. CONCLUSIONS: An LCHF diet for three weeks increased LDL-C with 44% versus controls. The individual response on LCHF varied profoundly. PMID- 30408718 TI - Structural determination of ananatoside A: An unprecedented 15-membered macrodilactone-containing glycolipid from Pantoea ananatis. AB - The bacterium Pantoea ananatis was reported to produce glycolipid biosurfactants of unknown structures. Herein, we present the isolation and structural determination of ananatoside A, the main congener of a new family of 15-membered macrodilactone-containing glucolipids. The structure of ananatoside A was elucidated via chemical degradation and spectroscopic methods including 1D/2D NMR analysis, tandem MS/MS, GC-MS, HR-ESI-TOF-MS, MALDI-TOF-MS, and polarimetry. Computational methods were used to predict the most abundant conformers of ananatoside A. PMID- 30408719 TI - Functional signature of conversion of patients with mild cognitive impairment. AB - The entorhinal-hippocampal circuit is a strategic hub for cognition and the first site affected by Alzheimer's disease (AD). We investigated magnetic resonance imaging patterns of brain atrophy and functional connectivity in an Alzheimer's Disease Neuroimaging Initiative data set that included healthy controls, mild cognitive impairment (MCI), and patients with AD. Individuals with MCI were clinically evaluated 24 months after the first magnetic resonance imaging scan, and the cohort subdivided into sets of individuals who either did or did not convert to AD. The MCI group was also divided into patients who did show or not the presence of AD-related alterations in the cerebrospinal fluid. Patients with AD exhibited the collapse of the long-range hippocampal/entorhinal connectivity, pronounced cortical/subcortical atrophy, and a dramatic decline in cognitive performances. Patients with MCI who converted to AD or patients with MCI who showed the presence of AD-related alterations in the cerebrospinal fluid showed memory deficits, entorhinal/hippocampal hypoconnectivity, and concomitant atrophy of the two regions. Patients with MCI who did not convert to AD or patients with MCI who did not show the presence of AD-related alterations in the cerebrospinal fluid had no atrophy but showed hippocampal/entorhinal hyperconnectivity with selected neocortical/subcortical regions involved in memory processing and brain metastability. This hyperconnectivity may represent a compensatory strategy against the progression of cognitive impairment. PMID- 30408720 TI - Effects of androsterone on the protective action of various antiepileptic drugs against maximal electroshock-induced seizures in mice. AB - This study evaluated the effect of androsterone (AND), a metabolite of testosterone, on the ability of selected classical and novel antiepileptic drugs to prevent seizures caused by maximal electroshock (MES), which may serve as an experimental model of human generalized tonic-clonic seizures in mice. Single intraperitoneal (i.p.) administration of AND (80 mg kg-1) significantly raised the threshold for convulsions in the MES seizure threshold test. Lower doses of AND (5, 10, 20, and 40 mg kg-1) failed to change the threshold. AND at a subthreshold dose of 40 mg kg-1 significantly enhanced the protective activity of carbamazepine, gabapentin, and phenobarbital against MES-induced seizures decreasing their median effective doses (ED50) values +/- SEM from 8.59 +/- 0.76 to 6.05 +/- 0.81 mg kg-1 (p = 0.0308) for carbamazepine, from 419.9 +/- 120.6 to 111.5 +/- 41.1 mg kg-1 (p = 0.0405) for gabapentin, and from 20.86 +/- 1.64 to 10.0 +/- 1.21 mg kg-1 (p = 0.0007) for phenobarbital. There were no significant changes in total brain concentrations of carbamazepine, gabapentin, and phenobarbital following AND administration. This suggests that the enhancing effects of AND on the protective activity of these antiepileptic drugs are not related to pharmacokinetic factors. A lower dose of AND (20 mg kg-1) had no effect on the protective activity of carbamazepine, gabapentin, and phenobarbital. AND administered at a dose of 40 mg kg-1 failed to change the anticonvulsant activity of lamotrigine, oxcarbazepine, phenytoin, topiramate, and valproate in the MES test. In the chimney test, AND given at a dose enhancing the protective activity of carbamazepine, gabapentin, and phenobarbital (which alone was without effect on motor performance of mice) did not affect impairment of motor coordination produced by the antiepileptics. Our findings recommend further preclinical and clinical research on AND in respect of its use as adjuvant therapy in the management of epilepsy in men with deficiency of androgens. PMID- 30408721 TI - Salivary cortisone, as a biomarker for psychosocial stress, is associated with state anxiety and heart rate. AB - BACKGROUND: Stress activates the central nervous, the autonomic nervous, and the endocrine system. This study aimed to (1) test the usability of salivary cortisone in a standardized psychosocial stressor, (2) create a comprehensive profile of hormonal responses to determine laboratory parameters with high discriminatory power, and (3) analyze their association with psychometric and autonomic stress measures. METHODS: Healthy young men (18-35 years) completed either the Trier Social Stress Test (TSST) (n = 33) or a Placebo-TSST (n = 34). Blood and saliva were collected at 14 time points along with state-anxiety (STAI) and heart rate. Serum steroids (cortisol*, cortisone*, dehydroepiandrosterone sulfate, androstenedione*, progesterone*, 17-hydroxyprogesterone*, testosterone, estradiol*, aldosterone*), salivary cortisol* and cortisone*, copeptin*, adrenocorticoptropic hormone*, corticosteroid-binding globulin, and salivary alpha-amylase* were analyzed. We used mixed-design ANOVAs to test group differences, receiver operator characteristic (ROC) curve analyses to assess the discriminatory power of each measure, and Spearman correlation analyses to probe the association between measures. RESULTS: The largest area under the ROC curve was observed in salivary cortisone at 20 min after the end of the TSST (AUC = 0.909 +/- 0.044, p < 0.0001). Significant time-by-group interactions were found in the parameters marked with * above, indicating stress-induced increases. The peak response of salivary cortisone was significantly associated with those of STAI (rho = 0.477, p = 0.016) and heart rate (rho = 0.699, p < 0.0001) in the TSST group. CONCLUSION: Our study found salivary cortisone to be a stress biomarker with high discriminatory power and significant correlations with subjective and autonomic stress measures. Our results can inform future stress studies of sampling time for different laboratory parameters. PMID- 30408723 TI - Women's fertility cues affect cooperative behavior: Evidence for the role of the human putative chemosignal estratetraenol. AB - Previous studies demonstrating that women's body odor during ovulation is perceived as more attractive suggest that exposure to women's chemosignals of high fertility increases mating motivation. Building on previous evidence showing that cooperative behaviors are perceived as attractive, in the current study we investigated whether chemosignals of women's fertility affect men's tendency to behave cooperatively. In the first experiment we found that in the presence of women's body odor during ovulation, men increase their tendency to apply a cooperative strategy, while their tendency to apply an individualistic strategy decreases. To examine the mechanism underlying this effect, we tested a different sample of men exposed to the putative human pheromone estratetraenol (estra 1,3,5(10),16-tetraen-3-ol) or to a control solution. Exposure toestratetraenol compared with control yielded strikingly similar effects of increased cooperation. The results indicate that women's chemosignals of high fertility increase mating motivation among man, encouraging them to act in a cooperative manner toward others, a response that may highlight their attractive qualities and thus attract mates. We further conclude that estratetraenol may serve as one of the biological agents that mediate the behavioral effects of women's chemosignals of fertility on social behavior. PMID- 30408722 TI - Methylation of the glucocorticoid receptor gene associated with depression in patients with acute coronary syndrome. AB - OBJECTIVE: The present study investigated the longitudinal effects of NR3C1 1 F exon methylation on the risk of depression following ACS and treatment outcomes. METHODS: In total, 969 patients admitted for recent ACS were recruited within 2 weeks of ACS; 711 of these patients were followed up at 1 year. Depressive disorder was diagnosed according to DSM-IV criteria and included prevalent depressive disorder at baseline and incident or persistent depressive disorder at follow-up based on depression status at the two examinations. Of the 378 baseline participants who were diagnosed with depression, 255 participated in a randomized double-blind placebo-controlled trial of escitalopram, while the remaining 123 were managed with the usual medical treatment for ACS.NR3C1 1 F exon methylation was measured using peripheral blood samples, and various demographic and clinical characteristics were assessed as covariates. RESULTS: Higher NR3C1 1 F exon methylation levels were independently associated with prevalent depressive disorder at baseline but not with incident or persistent depressive disorder at follow-up based on logistic regression analyses adjusted for covariates. The effects of escitalopram on the remission of depressive symptoms was not influenced by NR3C1 1 F exon methylation status in ACS patients, but a placebo effect on the remission of depressive symptoms was observed, particularly in patients with lower methylation levels. CONCLUSIONS: ACS patients with higher NR3C1 1 F exon methylation levels were at higher risk of developing depressive disorder within 2 weeks of ACS. Additionally, adequate antidepressant treatment may be effective for the remission of depressive symptoms regardless of NR3C1 1 F exon methylation status. PMID- 30408724 TI - Preparation and characterization of zirconium silico188W-tungstate as a base material for 188W/188Re generator. AB - Zr:W:Si. The optimum gel was prepared using the molar ratio 1:1:7 at pH 8. The ZrSiW gel was investigated by FTIR, XRD, thermal analysis (TGA and DTA), FESEM, XRF, and NAA. Then, XRF and NAA techniques were used to estimate the proportion of the constituents of the gel according to the molecular formula [ZrO2(Si(WO4)2)16H2O]. 188W/188Re generator was prepared based on the selected ZrSi188W gel, which gives the highest tungsten content (393.3 mg W/g gel) with 75 +/- 3% elution yield of 188Re. Quality control was studied on the 188Re to make sure its validity for clinical applications. PMID- 30408725 TI - Amplitude degradation of thin layer in neutron logging. AB - The paper presents an analysis and discussion of the problem of underestimation of neutron signal amplitude in profiling of the thin-layers rock media. The corresponding neutron profiles were modeled using the Monte Carlo method, and the formalism of the general neutron parameter GNP was used to analyze the results. We show that the degradation of the thin layer signal amplitude depends on the layer thickness, and on the difference in the neutron properties of the layer and its surrounding medium. PMID- 30408727 TI - BRCA-analyzer: Automatic workflow for processing NGS reads of BRCA1 and BRCA2 genes. AB - The use of targeted next-generation sequencing (NGS) provides great new opportunities for molecular and medical genetics. However, in order to take advantage of these opportunities, we need to have reliable tools for extracting the necessary information from the huge amount of data generated by NGS. Here we present our automatic multithreaded workflow for processing NGS data of BRCA1 and BRCA2 genes obtained with NGS technology named BRCA-analyzer. Optimizing it on the sequencing data of 899 samples from 693 patients, we were able to find the most reliable tools and adjust their parameters in such a way that all pathogenic variants found were confirmed by Sanger's sequencing. For 82 and 24 DNA samples from blood and formalin-fixed paraffin-embedded blocks, NGS libraries were prepared with GeneRead BRCA panel v2 (Qiagen). The reads obtained were processed with BRCA-analyzer and Qiagen GeneRead Data analysis workflow. In total 27 pathogenic variants were found and confirmed by Sanger's sequencing, with all of them determined with BRCA-analyzer. Qiagen GeneRead Data analysis discarded 5 true pathogenic variants due to their location in homopolymeric sequence stretches. For other 793 samples, libraries were prepared by the in-house method, and NGS data were analyzed by BRCA-analyzer in comparison to another free automatic amplicon NGS workflow Canary. From total 137 pathogenic variations, BRCA-analyzer found 135 and Canary 123. Mutations were missed by BRCA-analyzer due to the trimming primer sequences from reads before mapping to be fixed in the next version. On the freely available NGS data, we showed that BRCA-analyzer could also be used for hybrid capture gene panels, although it needs more extensive testing on such library preparation methods. Thus, BRCA-analyzer is an automatic workflow for processing NGS data of BRCA1/2 genes with variant filters adapted to amplicon-based targeted NGS data. BRCA-analyzer can be used to identify germline as well as somatic mutations. BRCA-analyzer is freely available at https://github.com/aakechin/BRCA-analyzer. PMID- 30408726 TI - Validation of diagnostic gene sets to identify critically ill patients with sepsis. AB - PURPOSE: Gene expression diagnostics have been proposed to identify critically ill patients with sepsis. Three expression-based scores have been developed, but have not been compared in a prospective validation. We sought to validate these scores using an independent dataset and analysis. METHODS: We generated gene expression profiles from 61 critically ill patients. We validated the performance of 3 expression-based sepsis scores including 1) the Sepsis MetaScore (SMS); 2) the SeptiCyteTM Lab; and 3) the FAIM3:PLAC8 ratio. Sepsis was identified as the presence of definite, probable, or possible infection in the setting of organ dysfunction (SOFA score >= 2). RESULTS: For all 3 models, scores were significantly different between patients with and without sepsis. Discrimination was highest for the SMS (area under the receiver operating characteristics curve [AUROC 0.80 [95% CI 0.67-0.92]), with greater confidence in the presence of infection resulting in better model performance (max AUROC 0.93 [0.87-1.0]). CONCLUSIONS: All three scores distinguished septic from non-septic ICU patients, with the SMS showing the best performance overall in our cohort. Our results suggest that models developed from the co-analysis of multiple cohorts are more generalizable. Further work is needed to identify expression-based biomarkers of response to specific therapies. PMID- 30408728 TI - Acyl atractyligenin and carboxyatractyligenin glycosides from Antennaria rosea subsp. confinis. AB - Eight previously undescribed acyl atractyligenin and carboxyatractyligenin glycosides were isolated from whole Antennaria rosea subsp. confinis (Greene) R. J. Bayer (Compositae) [syn. Leontopodium leontopodioides (Willd.) Beauv. (Asteraceae)] plants and their structures were determined by spectroscopic and chemical methods. The compounds were trivially named leontopodiosides F-M. Seven of the compounds showed potent in vitro inhibitory activity toward pancreatic lipase with IC50 values ranging from 3.4 to 52.5 MUM, suggesting that they participate in the previously observed effect this plant has in reducing triglyceride absorption in rats. PMID- 30408729 TI - Inoculation of Rhizoglomus irregulare or Trichoderma atroviride differentially modulates metabolite profiling of wheat root exudates. AB - Root exudation patterns are linked to, among other things, plant growth, plant microbe interaction and the priming effect. In this work, two complementary metabolomic approaches (both liquid and gas chromatography coupled to mass spectrometry) were applied to investigate the modulation of root exudation imposed by two beneficial fungi (substrate treatment of Trichoderma atroviride AT10, substrate application of Rhizoglomus irregulare BEG72 and seed treatment with T. atroviride AT10) on wheat (Triticum aestivum L.). The inoculation with R. irregulare elicited significant increases (by 18%, 39% and 20%) in the shoot, root dry biomass and root-to-shoot ratio compared to untreated plants, whereas inoculation with T. atroviride, as a substrate drench or as a seed coating, exhibited intermediate values for these parameters. The metabolomic approach demonstrated a broad chemical diversity, with more than 2900 compounds annotated in the root exudates. Overall, the Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) supervised modelling highlighted a distinctive modulation of the metabolic profile in the root exudates as a function of both fungal inoculation and means of application. Most of the differences could be ascribed to lipids (sterols and membrane lipids), phenolic compounds and terpenoids, siderophores and chelating acids, derivatives of amino acids and phytohormones, and as such, the interaction between the wheat roots and beneficial fungi resulted in a complex response in terms of root exudates, likely involving a cascade of processes. Nonetheless, the changes imposed by plant microbe interactions can contribute to the support of the biostimulant effects of both T. atroviride and R. irregulare. PMID- 30408730 TI - Evaluating a chemical source-tracing suite for septic system nitrate in household wells. AB - Reducing human and ecological risks of groundwater nitrate contamination requires understanding the source of nitrate. Land use practices, such as agriculture and residential development, can increase groundwater nitrate concentrations. This study evaluated a chemical source-tracing suite that paired analysis of agricultural herbicide metabolites and human wastewater constituents. The source tracing suite was tested in an area subject to nitrate from both agriculture and on-site waste ("septic") systems. Monitoring wells showed that agricultural contamination was deeper (>5 m) in the aquifer consistent with its origin a greater distance from wells and that on-site waste ("septic system") contamination was shallower in the aquifer (<3 m). Repeated sampling of seventeen household wells showed evidence of both agricultural and on-site waste contamination in wells with higher nitrate concentrations. The artificial sweeteners sucralose and acesulfame and the antibiotic sulfamethoxazole were the only septic system indicators consistently detected. Less persistent compounds, such as caffeine and acetaminophen, were never detected in the household wells indicating they were attenuated over the distance between septic system and well and reducing their utility as a tracer of septic system nitrate. Overall, there was a positive relationship between sucralose, acesulfame and nitrate in wells with low levels of agricultural contamination although the relationship varied between wells. PMID- 30408731 TI - Temporal variability of parasites, bacterial indicators, and wastewater micropollutants in a water resource recovery facility under various weather conditions. AB - Wastewater discharges lead to the deterioration of receiving waters through treated effluents and by-passes, combined and sanitary sewer overflows, and cross connections to storm sewers. The influence of weather conditions on fecal indicator bacteria, pathogens and wastewater micropollutants on raw and treated sewage concentrations has not been extensively characterized. However, such data are needed to understand the effects of by-pass discharges and incomplete treatment on receiving waters. A water resource recovery facility was monitored for pathogenic parasites (Cryptosporidium oocysts, Giardia cysts), fecal indicator bacteria (Escherichia coli, Clostridium perfringens), and wastewater micropollutants (caffeine, carbamazepine, 2-hydroxycarbamazepine, acesulfame, sucralose, and aspartame) during 6 events under different weather conditions (snowmelt and trace to 32 mm 2-day cumulative precipitation). Greater intra- and inter-event variability was observed for Giardia, E. coli and C. perfringens than for studied WWMPs. Even with the addition of inflow and infiltration, daily variations dominated concentration trends. Thus, afternoon and early evening were identified as critical times with regards to high concentrations and flows for potential by-pass discharges. Peak concentrations of Giardia were observed during the June wet weather event (1010 cysts/L), with the highest flowrates relative to the mean monthly flowrate. Overall, Giardia, E. coli and C. perfringens concentrations were positively correlated with flowrate (R > 0.32, p < 0.05). In raw sewage samples collected under high precipitation conditions, caffeine, carbamazepine and its metabolite 2-OH-carbamazepine were significantly correlated (p < 0.05) with Giardia, E. coli, and C. perfringens demonstrating that they are useful markers for untreated sewage discharges. Data from the study are needed for estimating peak concentrations discharged from wastewater sources in relation to precipitation or snowmelt events. PMID- 30408732 TI - In situ biodegradation, photooxidation and dissolution of petroleum compounds in Arctic seawater and sea ice. AB - In pristine sea ice-covered Arctic waters the potential of natural attenuation of oil spills has yet to be uncovered, but increasing shipping and oil exploitation may bring along unprecedented risks of oil spills. We deployed adsorbents coated with thin oil films for up to 2.5 month in ice-covered seawater and sea ice in Godthaab Fjord, SW Greenland, to simulate and investigate in situ biodegradation and photooxidation of dispersed oil. GC-MS-based chemometric methods for oil fingerprinting were used to identify characteristic signatures for dissolution, biodegradation and photooxidation. In sub-zero temperature seawater, fast degradation of n-alkanes was observed with estimated half-life times of ~7 days. PCR amplicon sequencing and qPCR quantification of bacterial genes showed that a biofilm with a diverse microbial community colonised the oil films, yet a population related to the psychrophilic hydrocarbonoclastic gammaproteobacterium Oleispira antarctica seemed to play a key role in n-alkane degradation. Although Oleispira populations were also present in sea ice, we found that biofilms in sea ice had 25 to 100 times lower bacterial densities than in seawater, which explained the non-detectable n-alkane degradation in sea ice. Fingerprinting revealed that photooxidation, but not biodegradation, transformed polycyclic aromatic compounds through 50 cm-thick sea ice and in the upper water column with removal rates up to ~1% per day. Overall, our results showed a fast biodegradation of n-alkanes in sea ice-covered seawater, but suggested that oils spills will expose the Arctic ecosystem to bio-recalcitrant PACs over prolonged periods of time. PMID- 30408733 TI - Cotransport of nanoplastics (NPs) with fullerene (C60) in saturated sand: Effect of NPs/C60 ratio and seawater salinity. AB - Nanoplastics (NPs) have been identified as newly emerging particulate contaminants. In marine environments, the interaction between NPs and other engineered nanoparticles remains unknown. This study investigated the cotransport of NPs with fullerene (C60) in seawater-saturated columns packed with natural sand as affected by the mass concentration ratio of NPs/C60 and the hydrochemical characteristics. In seawater with 35 practical salinity units (PSU), NPs could remarkably enhance C60 dispersion with a NPs/C60 ratio of 1. NPs behaved as a vehicle to facilitate C60 transport by decreasing colloidal zeta-potential and forming stable primary heteroaggregates. As the NPs/C60 ratio decreased to 1/3, NPs mobility was progressively restrained because of the formation of large secondary aggregates. When the ratio continuously decreased to 1/10, the stability and transport of colloids were governed by C60 rather than NPs. Under this condition, the transport trend of binary suspensions was similar to that of single C60 suspension, which was characterized by a ripening phenomenon. Seawater salinity is another key factor affecting the stability and associated transport of NPs and C60. In seawater with 3.5 PSU, NPs and C60 (1:1) in binary suspension exhibited colloidal dispersion, which was driven by a high-energy barrier. Thus, the profiles of the cotransport and retention of NPs/C60 resembled those of single NPs suspension. This work demonstrated that the cotransport of NPs/C60 strongly depended on their mass concentration ratios and seawater salinity. PMID- 30408734 TI - Stratification of nitrifier guilds in granular sludge in relation to nitritation. AB - A lab-scale partial nitritation granular sludge air-lift reactor was operated in continuous mode treating low strength synthetic medium (influent ca. 50 mg-N NH4+/L). Granules were initially stratified with AOB in the external shell and NOB in the inner core at 20 degrees C. Once temperature was decreased progressively from 20 degrees C to 15 degrees C, nitrate production was initially observed during several weeks. However, by maintaining relatively high ammonium concentrations in the liquid (ca. 28 mg-N-NH4+/L), effluent nitrate concentrations in the reactor decreased in time and process performance was recovered. Batch tests were performed in the reactor at different conditions. To understand the experimental results an existing one-dimensional biofilm model was used to simulate batch tests and theoretically assess the impact of stratification, dissolved oxygen (DO) and short-term effects of temperature on time course concentrations of ammonium, nitrite and nitrate. This theoretical assessment served to develop an experimental methodology for the evaluation of in situ batch tests in the partial nitritation reactor. These batch tests proved to be a powerful tool to easily monitor the extent of stratification of nitrifier guilds in granular sludge and to determine the required bulk ammonium concentration to minimize nitrite oxidation. When nitrifier guilds were stratified in the granular sludge, a higher bulk ammonium concentration was required to efficiently repress NOB at lower temperature (ca. 19 versus 7 mg-N NH4+/L at 15 and 20 degrees C, respectively). PMID- 30408735 TI - Performance comparison of hematite (alpha-Fe2O3)-polymer composite and core-shell nanofibers as point-of-use filtration platforms for metal sequestration. AB - Point-of-use water treatment technologies can help mitigate risks from drinking water contamination, particularly for metals (and metalloids) that originate in distribution systems (e.g., chromium, lead, copper) or are naturally occurring in private groundwater wells (e.g., arsenic). Here, composite nanofibers of polyacrylonitrile (PAN) with embedded hematite (alpha-Fe2O3) nanoparticles were synthesized via a single-pot electrospinning synthesis. A core-shell nanofiber composite was also prepared through the subsequent hydrothermal growth of alpha Fe2O3 nanostructures on embedded hematite composites. Properties of embedded hematite composites were controlled using electrospinning synthesis variables (e.g., size and loading of embedded alpha-Fe2O3 nanoparticles), whereas core shell composites were also tailored via hydrothermal treatment conditions (e.g., soluble iron concentration and duration). Although uptake of Cu(II), Pb(II), Cr(VI), and As(V) was largely independent of the core-shell variables explored, metal uptake on embedded nanofibers increased with alpha-Fe2O3 loading. Both materials exhibited maximum surface-area-normalized sorption capacities that were comparable to alpha-Fe2O3 nanoparticle dispersions and exceeded that of a commercial iron oxide based sorbent. Further, both types of composite exhibited strong performance across a range of environmentally relevant pH values (6.0 8.0). Notably, core-shell structures, with a majority of surface accessible alpha Fe2O3, performed far better than embedded composites in kinetically limited flow through systems than was anticipated from their relative performance in equilibrium batch systems. Core-shell nanofiber filters also retained much of the durability and flexibility exhibited by embedded nanofibers. Additional tests with authentic groundwater samples demonstrated the ability of the core-shell nanofiber filters to remove simultaneously both As and suspended solids, illustrating their promise as a nano-enabled technology for point-of-use water treatment. PMID- 30408736 TI - Capping with activated carbon reduces nutrient fluxes, denitrification and meiofauna in contaminated sediments. AB - Sediment capping with activated carbon (AC) is an effective technique used in remediation of contaminated sediments, but the ecological effects on benthic microbial activity and meiofauna communities have been largely neglected. This study presents results from a 4-week experiment investigating the influence of two powdered AC materials (bituminous coal-based and coconut shell-derived) and one control material (clay) on biogeochemical processes and meiofauna in contaminated sediments. Capping with AC induced a 62-63% decrease in denitrification and a 66-87% decrease in dissimilatory nitrate reduction to ammonium (DNRA). Sediment porewater pH increased from 7.1 to 9.0 and 9.7 after addition of bituminous AC and biomass-derived AC, respectively. High pH (>8) persisted for at least two weeks in the bituminous AC and for at least 24 days in the coconut based AC, while capping with clay had no effect on pH. We observed a strong impact (nitrate fluxes being halved in presence of AC) on nitrification activity as nitrifiers are sensitive to high pH. This partly explains the significant decrease in nitrate reduction rates since denitrification was almost entirely coupled to nitrification. Total benthic metabolism estimated by sediment oxygen uptake was reduced by 30 and 43% in presence of bituminous coal-based AC and coconut shell-derived AC, respectively. Meiofauna abundances decreased by 60 62% in the AC treatments. Taken together, these observations suggest that AC amendments deplete natural organic carbon, intended as food, to heterotrophic benthic communities. Phosphate efflux was 91% lower in presence of bituminous AC compared to untreated sediment probably due to its content of aluminum (Al) oxides, which have high affinity for phosphate. This study demonstrates that capping with powdered AC produces significant effects on benthic biogeochemical fluxes, microbial processes and meiofauna abundances, which are likely due to an increase in porewater pH and to the sequestration of natural, sedimentary organic matter by AC particles. PMID- 30408737 TI - Blockade of peripheral endothelin receptors abolishes heat hyperalgesia and spontaneous nociceptive behavior in a rat model of facial cancer. AB - OBJECTIVE: To improve understanding of the pathophysiology of cancer-induced facial nociception, by evaluating the contribution of peripheral endothelin receptors in tumor-induced facial heat hyperalgesia, increased spontaneous grooming, as well as ongoing nociception in a rat model of facial cancer. DESIGN: The study was conducted using 396 rats. Facial cancer was induced by inoculating a suspension of Walker-256 cells into the rats' right vibrissal pad. Facial heat hyperalgesia and spontaneous grooming were assessed on day 6, while the conditioned place preference (CPP) test was performed on days 3-6 after tumor cells inoculation. Rats received local injections of the non-peptidic dual ETA/ETB endothelin receptors antagonist, bosentan (10 and 30 MUg/50 MUL), single or combined injections of peptidic ETA and ETB endothelin receptors antagonists (BQ-123 and BQ-788, at 20 ug/50 MUL, each), or of lidocaine (1 mg/50 MUl) and morphine (30 MUg/50 MUL). RESULTS: Bosentan, lidocaine and morphine local treatment all attenuated tumor-induced heat hyperalgesia (p < 0.05) and spontaneous facial grooming (p < 0.05). However, BQ-123 and BQ-788 did not modify tumor-induced heat hyperalgesia or the spontaneous facial grooming (p > 0.05). Whether this difference in effectiveness is due to receptor affinity or to pharmacokinetic factors still needs to be explored. Local injection of bosentan, lidocaine or morphine failed to control ongoing nociception, as evidenced by the absence of CPP in tumor-bearing rats (p > 0.05). CONCLUSION: Endothelins, acting through peripheral ETA and ETB receptors, may play a significant role on the development of heat hyperalgesia and increased spontaneous grooming associated to facial cancer in rats. PMID- 30408738 TI - Case report of surgical treatment of scoliosis caused by neurofibroma located posterior mediastinum. AB - BACKGROUND: Neurofibromatosis type 1 (NF-1) is often associated with various orthopedic disorders, especially scoliosis. Spinal deformity in patients with NF 1 can be induced by localized neurofibromas. CASE PRESENTATION: Scoliosis can be induced by a localized neurofibroma. A 12-year-old boy diagnosed with neurofibromatosis type 1 had severe scoliosis caused by a neurofibroma located in the posterior mediastinum. We performed two-stage procedure involving the extirpation of the neurofibroma in the lateral position, and posterior spinal fusion with segmental spinal instrumentation for the scoliosis in the prone position. DISCUSSION: The optimum surgical approach for the extirpation of neurofibroma located in the posterior mediastinal remains to be established. It may be difficult to extirpate a tumor in this position via a posterior approach alone, as the tumor is surrounded by several tissue, e.g. azygos vein, trachea and esophagus. In our case, we first extirpated the tumor located in the posterior mediastinum via a posterolateral incision in the right lateral position. With this approach, it may be easy to confirm the safe relationship between the tumor and surrounding tissue. CONCLUSIONS: We safely performed a two stage procedure involving the extirpation of a neurofibroma in the lateral position, and posterior spinal fusion with segmental spinal instrumentation for scoliosis in the prone position. PMID- 30408739 TI - A case report of a rare and challenging gangrenous splenic flexure volvulus in a pregnant patient. AB - INTRODUCTION: Splenic flexure volvulus is a rare cause of intestinal obstruction and is uncommonly encountered in young patients from developed countries. PRESENTATION OF CASE: This report details a challenging case of a gangrenous large bowel volvulus in a 25 year old woman 20 weeks pregnant, highlighting the diagnostic and operative challenges that this rare clinical situation presents. After urgent MRI confirming a splenic flexure volvulus, an emergency open left hemicolectomy and end colostomy was performed. Following uneventful recovery and successful delivery of her baby at full term, she was reversed 6 months later. DISCUSSION: Splenic flexure volvulus is a rare cause of large bowel obstruction, and as such can result in a delay in diagnosis, particularly in the setting of pregnancy. In this case, the patient was not diagnosed until day 3 of her admission when she decompensated with a rising white cell count. CONCLUSION: Splenic flexure volvulus is a rare occurrence. This case report of a young pregnant woman presenting with a large bowel obstruction due to splenic flexure volvulus highlights the importance of considering and investigating for this diagnosis. PMID- 30408740 TI - A proliferating trichilemmal cyst in the perianal region: A case report. AB - INTRODUCTION: Proliferating trichilemmal cysts (PTCs) are rare benign neoplasms originating from the follicular isthmus. They can undergo trichilemmal keratinization and malignant degeneration to form epidermoid carcinoma. They occur on the scalp in more than 90% of patients and are more common in elderly women. PRESENTATION OF CASE: A 56-year-old woman complained of perianal discomfort upon sitting. She presented with a perianal nodule of approximately 3 cm in diameter that had exhibited slow and progressive growth over 8 years. After surgical excision of the lesion with safety margins, histopathological examination showed that it was a proliferating trichilemmal cyst in the perianal region. DISCUSSION: There are no reports in the literature on PTC in the perianal region. The location with the highest prevalence is the scalp; other sites of occurrence are the neck, trunk, underarms, pubis, vulva, lower and upper limbs, upper lip, and gluteal region. CONCLUSION: The development of PTC in the perianal region is an exceptional occurrence, and when it does occur, surgical treatment should always be indicated because of the risk of malignant degeneration to form epidermoid carcinoma. PMID- 30408741 TI - A rare case of primary thyroid amyloidosis. AB - INTRODUCTION: Amyloid goiter is due to the deposition of amyloid in the thyroid, resulting with enlargement of the gland and compressive symptoms. CASE: We herein present a case of a 45-year-old male patient who complained of a big swelling in the neck. Ultrasound showed an enlarged thyroid gland with mediastinal involvement. The multinodular appearance was consistent with the diagnosis of multinodular goiter. He had a history of multiple myeloma but no sign of systemic amyloidosis. DISCUSSION: Thyroid gland was removed and the histopathological examination revealed a diffuse deposition of amyloid associated with metaplastic lipomatosis of the stroma. CONCLUSIONS: The treatment of choice in patients with amyloid goiter is total thyroidectomy to solve compression symptoms. PMID- 30408742 TI - Intestinal occlusion by stenotic neuroendocrine tumours of left colon and concomitant association with small bowel gastrointestinal stromal tumours: A case report. AB - INTRODUCTION: The association between Gastrointestinal Stromal Tumours (GIST) and Neuroendocrine Tumours (NET) is very rare. These tumours have various clinical expressions and sometimes are asymptomatic. Synchronous NETs and GISTs have been already described in literature in few case reports. On the other hand, there is no mention of concomitant presence of discending colon NEC-G3 and small intestinal GIST. PRESENTATION OF CASE: we presented a case of a patient with clinical evidence of intestinal occlusion and radiological and intraoperative aspects of an adenocarcinoma of the left colon with a single metastasis on small bowel. The pathology analysis of the tumour showed a stenotic left colon NEC-G3 and a small bowel GIST. DISCUSSION: In this case report GIST was surgically treated as a small bowel ripetitive lesion and NET as a left colon adenocarcinoma. These tumours may have a similar presentation in terms of symptoms, endoscopic findings and imaging results. CONCLUSION: Concomitant NEC and GIST is rare but it is important to investigate patients before surgery in order to distinguish these from other tumours because of the different prognosis. PMID- 30408743 TI - A case report of Villar's nodule in a woman without surgical history. AB - INTRODUCTION: Villar's nodule is an umbilical endometriosis without anterior or ongoing pelvic endometriosis. The primitive location of this nodule at the umbilical level is rare. Its etiopathogenesis remains unclear. PRESENTATION OF CASE: We report a case of umbilical endometriosis with unusual clinical expression in a woman in the reproductive years with no surgical history and no known history of endometriosis. Endometriosis manifested as progressive transformation of the normal umbilicus into several small nodules, with bleeding coinciding with the menstrual cycle. The diagnosis was confirmed by histology and surgical treatment consisted of omphalectomy. DISCUSSION: Umbilical endometriosis is a rare disease that occurs naturally in patients with pelvic endometriosis. Etiopathogenesis of the disease is still unclear. In our patient, the appearance of the nodule was impressively, by a gradual transformation of the normal aspect of the umbilicus, into several small, slightly pigmented, firm, painful and concomitantly bleeding nodules during periods of menstruation. In the literature, this multinodular or budding form would be of exceptional observation. CONCLUSION: The characteristics of the umbilical tumor, associated with the cyclical nature of tumor bleeding in a patient without previous history of endometriosis, strongly suggest the diagnosis of Villar's nodule, but the confirmation is still histological. The treatment is always surgical and recurrence is very rare. PMID- 30408744 TI - Generation of two induced pluripotent stem cells lines from a Mucopolysaccharydosis IIIB (MPSIIIB) patient. AB - Mucopolysaccharydosis IIIB is the second most frequent form of Sanfilippo syndrome, a degenerative, pediatric lysosomal storage disease (LSD) characterized by severe neurological disorders and death. We have generated two iPSCs lines derived from dermal fibroblast from a MPSIIIB homozygous (P358L) donor. Cells were reprogrammed with OriP/EBNA1-based episomal plasmids containing: OCT3/4, SOX2, KLF4, L-MYC, LIN28, BCL-xL and shp53. Both cell lines are homozygous for the P358L mutation of the alpha-N-acetylglucosaminidase (NAGLU) gene, have normal karyotype, are free of plasmid integration, express high levels of pluripotency associated markers and can differentiate into the three germ layers. RESOURCE TABLE: RESOURCE UTILITY: Although the generation of iPSCs has been reported for some lysosomal storage diseases (LSD) in general, and from other mutations of the NAGLU gene in particular (Lemonnier et al., 2011), this is the first time that NAGLU Pro358Leu MPSIIIB-iPSCs lines have been generated and fully characterized demonstrating their quality as iPS cells. RESOURCE DETAILS: Mucopolysaccharidosis IIIB (MPSIII, Sanfilippo syndrome type B) is a pediatric neurodegenerative disorder caused by a deficiency in NAGLU, an enzyme required for lysosomal degradation of heparin sulphate (HS). When the enzyme is absent or malfunctioning, HS accumulates in the cells of several tissues, with devastating effects in the brain and central nervous system. MPSIIIB is inherited in an autosomal recessive manner and presents an incidence between 0.03 and 0.78 cases per 1 * 105 live births (Fedele, 2015) depending on the country. Currently there is no therapy available. The NAGLU gene was identified in 1996, is located on chromosome 17q21.1 and contains 6 exons. More than 150 NAGLU mutations have been reported, being most of them missense (Valstar et al., 2010). All of them lead to MPSIIIB but, unlike MPSIIIA, none is predominant. The two iPSCs lines described in this report, IMEDEAi005-A and IMEDEAi005-B, (See Table 1) were generated from skin fibroblast obtained from a clinically affected homozygous donor. The mutant allele consists on a C > T transversion at nucleotide 1073 (1073 > T) resulting in a substitution of leucine for proline at codon 358 (Pro358Leu). Skin fibroblasts were reprogrammed to iPSCs by nucleofection with four OriP/EBNA1 (Epstein-Barr nuclear antigen-1) based episomal plasmids encoding 5 reprogramming genes (OCT3/4, SOX2, KLF4, L-Myc, LIN28 and BCL-xL), in addition to a short hairpin RNA against p53. The iPSCs lines showed morphology (Fig. 1A) and growth behaviour typical of human Embryonic Stem Cells (hESC), as well as normal female karyotype (46, XX) (Fig. 1B). After 12 passages, PCR analysis confirmed that both iPSCs lines had completely lost the episomal vectors (Fig. 1C). The identity of iPS cells and their parental fibroblasts was confirmed by STR analysis (Table 2, data not shown) in addition to the identification of the disease-associated mutation in the NAGLU gene by DNA sequencing (Fig. 1D). Regarding the iPSC phenotype, both lines expressed the pluripotency-associated markers: OCT3/4, NANOG, SOX2 and TRA-1-60 (Fig. 1E), and TRA-1-81 quantified by flow cytometry (Fig. 1G), resulting in 88.17% and 83.4% of TRA-1-81 positive cells in IMEDEAi005 A and IMEDEAi005-B respectively. Finally, the differentiation capacity of iPSCs lines was analyzed by embryoid body (EBs) formation. Expression of markers specific of the three germ layers was observed after at least 10 days of spontaneous differentiation (Fig. 1F). Mycoplasma analysis was negative for both iPSCs lines (Supplementary Fig. S1). Skin fibroblasts were reprogrammed to iPSCs by nucleofection with four OriP/EBNA1 (Epstein-Barr nuclear antigen-1) based episomal plasmids encoding 5 reprogramming genes (OCT3/4, SOX2, KLF4, L-Myc, LIN28 and BCL-xL), in addition to a short hairpin RNA against p53. The iPSCs lines showed morphology (Fig. 1A) and growth behaviour typical of human Embryonic Stem Cells (hESC), as well as normal female karyotype (46, XX) (Fig. 1B). After 12 passages, PCR analysis confirmed that both iPSCs lines had completely lost the episomal vectors (Fig. 1C). The identity of iPS cells and their parental fibroblasts was confirmed by STR analysis (Table 2, data not shown) in addition to the identification of the disease-associated mutation in the NAGLU gene by DNA sequencing (Fig. 1D). Regarding the iPSC phenotype, both lines expressed the pluripotency-associated markers: OCT3/4, NANOG, SOX2 and TRA-1-60 (Fig. 1E), and TRA-1-81 quantified by flow cytometry (Fig. 1G), resulting in 88.17% and 83.4% of TRA-1-81 positive cells in IMEDEAi005-A and IMEDEAi005-B respectively. Finally, the differentiation capacity of iPSCs lines was analyzed by embryoid body (EBs) formation. Expression of markers specific of the three germ layers was observed after at least 10 days of spontaneous differentiation (Fig. 1F). Mycoplasma analysis was negative for both iPSCs lines (Supplementary Fig. S1). In conclusion, we have successfully generated and characterized, for the first time to our knowledge, two human iPSCs lines from a MPSIIIB donor homozygous for the P358L NAGLU mutation. The new lines will complement the existing murine MPS IIIB model, with their potential to be used in a development of a purely human in vitro model of the disease. PMID- 30408745 TI - Kinetic analysis and degradation mechanism for natural attenuation of xylenes under simulated marine conditions. AB - Microcosm experiments were conducted to examine the attenuation of selected chemicals, i.e. m-xylene (MX), o-xylene (OX) and p-xylene (PX), under simulated marine conditions. Natural attenuation and the contribution of oxidation, photodegradation, biodegradation and volatilization to total attenuation were evaluated. The development of attenuation was in agreement with pseudo-first order kinetics for all xylenes. The half-lives of MX, OX, and PX under optimal conditions were 0.76, 0.74 and 0.88 days, respectively. Attenuation kinetics were proposed to analyze the natural attenuation of xylenes. The leading attenuation type of MX, OX, and PX was volatilization, and the attenuation rate constants (KV) were 0.5587, 0.6733, and 0.4821 d-1, respectively. Biodegradation of OX (Kb: 0.0003 d-1) was extremely inhibited. The attenuation kinetics presented the attenuation of xylenes in microcosm. The reaction kinetics could be applied to analyze the natural attenuation of chemicals. MX and OX can be converted to one another under certain conditions. Toluene and ethylbenzene were detected for OX in the OP (oxidation and photodegradation) experiment under simulated marine conditions. 4-Methylbenzyl alcohol, p-methyl benzaldehyde and p-toluic acid, as the major intermediates, were identified during the natural attenuation of PX using GC/MS. PMID- 30408746 TI - Antileishmanial activity of new hybrid tetrahydroquinoline and quinoline derivatives with phosphorus substituents. AB - Heterocyclic compounds, such as hybrid tetrahydroquinoline and quinoline derivatives with phosphorated groups, have been prepared by multicomponent cycloaddition reaction between phosphorus-substituted anilines, aldehydes and styrenes. The antileishmanial activity of these compounds has been evaluated on both promastigotes and intramacrophagic amastigotes of Leishmania infantum. Good antileishmanial activity of functionalized tetrahydroquinolines 4a, 5a, 6b and quinoline 8b has been observed with similar activity than the standard drug amphotericin B and close selective index (SI between 43 and 57) towards L. infantum amastigotes to amphotericin B. Special interest shows tetrahydroquinolylphosphine sulfide 5a with an EC50 value (0.61 +/- 0.18 MUM) similar to the standard drug amphotericin B (0.32 +/- 0.05 MUM) and selective index (SI = 56.87). In addition, compound 4c shows remarkable inhibition on Leishmania topoisomerase IB. Parallel theoretical study of stereoelectronic properties, application of docking-based virtual screening methods, along with molecular electrostatic potential and predictive druggability analyses are also reported. PMID- 30408747 TI - Second generation of diazachrysenes: Protection of Ebola virus infected mice and mechanism of action. AB - Ebola virus (EBOV) causes a deadly hemorrhagic fever in humans and non-human primates. There is currently no FDA-approved vaccine or medication to counter this disease. Here, we report on the design, synthesis and anti-viral activities of two classes of compounds which show high potency against EBOV in both in vitro cell culture assays and in vivo mouse models Ebola viral disease. These compounds incorporate the structural features of cationic amphiphilic drugs (CAD), i.e they possess both a hydrophobic domain and a hydrophilic domain consisting of an ionizable amine functional group. These structural features enable easily diffusion into cells but once inside an acidic compartment their amine groups became protonated, ionized and remain trapped inside the acidic compartments such as late endosomes and lysosomes. These compounds, by virtue of their lysomotrophic functions, blocked EBOV entry. However, unlike other drugs containing a CAD moiety including chloroquine and amodiaquine, compounds reported in this study display faster kinetics of accumulation in the lysosomes, robust expansion of late endosome/lysosomes, relatively more potent suppression of lysosome fusion with other vesicular compartments and inhibition of cathepsins activities, all of which play a vital role in anti-EBOV activity. Furthermore, the diazachrysene 2 (ZSML08) that showed most potent activity against EBOV in in vitro cell culture assays also showed significant survival benefit with 100% protection in mouse models of Ebola virus disease, at a low dose of 10 mg/kg/day. Lastly, toxicity studies in vivo using zebrafish models suggest no developmental defects or toxicity associated with these compounds. Overall, these studies describe two new pharmacophores that by virtue of being potent lysosomotrophs, display potent anti-EBOV activities both in vitro and in vivo animal models of EBOV disease. PMID- 30408748 TI - Synthesis and antibacterial profiles of targeted triclosan derivatives. AB - There is an ongoing urgent need for new targeted antibacterial compounds with novel mechanisms of action for the treatment of infections caused by bacteria that are resistant to currently available materials. Since the expression of glycosidase enzymes within bacteria is unequally distributed, glycoside derivatives of antibacterial agents offer potential as targeted prodrugs for bacterial infections. Herein we report the synthesis and characterisation of four alpha-D-glycopyranosides and three beta-D-glycopyranosides of the broad antibacterial agent triclosan, in generally good synthetic yields, and with excellent purities. Each glycoside was analysed to determine its ability to inhibit the growth of a wide range of Gram-negative and Gram-positive organisms, including many of clinical significance. All of the triclosan glycosides that were synthesized demonstrated antibacterial activity against many of the organisms that were examined. For example, beta-galactoside (3a) and alpha arabinoside (3c) had MIC values of 0.5 MUg/ml for several strains of S. aureus and S. haemolyticus. The triclosan glycosides were also generally found to be more water soluble and much more selective than the underivatized triclosan, making them ideal both for the targeted inhibition of bacterial growth and as agents for the selective recovery of bacteria from mixed cultures. In the latter case, two Bacillus strains could be identified from various strains of Bacillus and Staphylococcus after inoculation onto Nutrient Agar No. 2 with 0.25 MUg/ml triclosan-alpha-D-glucopyranoside (3e). This glucoside may, therefore, be of use for the isolation and identification of the food-poisoning organism Bacillus cereus. PMID- 30408749 TI - Synthesis and biological evaluation of bifendate derivatives bearing acrylamide moiety as novel antioxidant agents. AB - Oxidative stress plays a significant role in the pathogenesis of various human diseases. In this study, a series of bifendate derivatives bearing acrylamide moiety were synthesized and evaluated as anti-oxidant agents. Biological evaluation indicated that compounds 6a and 6e displayed more potent cytoprotective effect against H2O2-induced HBZY-1 mesangial cells death than lead compound bifendate and positive control resveratrol and sulforaphane. Preliminary anti-oxidant mechanism studies showed that compound 6e could diminish the ROS accumulation by dose- and time-dependently activating Nrf2 and increasing the expression of downstream detoxification enzymes NQO-1, HO-1, GCLM and GCLC at protein and mRNA levels, thus displaying potent anti-oxidant activity. Interestingly, the Nrf2 activating effect of 6e is achieved, at least partly, in Michael acceptor and Keap1-dependent manners. These results, together with the low intrinsic cytotoxicity, suggested that compound 6e might be a promising lead for the development of novel anti-oxidant agents to prevent diseases induced by oxidative stress. PMID- 30408750 TI - Phthalate exposure during pregnancy and long-term weight gain in women. AB - BACKGROUND: Phthalates are known endocrine disruptors and peroxisome proliferator activated receptor (PPAR) activators, potentially capable of promoting an obesogenic effect. Pregnant women are especially vulnerable to phthalate exposure due to physiological and metabolic changes during pregnancy, including those related to the metabolism of xenobiotics. Phthalate exposure during pregnancy has been associated with early gestational weight gain, however, its effect on long term weight gain remains unclear. The aim of the present study was to evaluate the association between phthalate exposure during pregnancy and long-term changes in weight among women. METHODS: Urinary phthalate concentrations, socioeconomic, anthropometry and information on diet and socioeconomic status were collected during pregnancy from 178 women from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) birth cohort. Maternal body weight and diet information was also collected up to 5 times in the first year postpartum and twice during follow-up visits 5.2-10.7 years later. A path analysis was performed to assess associations between urinary phthalate metabolite levels during pregnancy and change in weight (kg) per year after delivery, including age, education, living with/without partner, parity, daily energy intake and breastfeeding duration. RESULTS: The mean age at pregnancy was 27.3 +/- 5.9 years and mean body mass index during the first postpartum year was 27.07 +/- 4.22 kg/m2. On average, women gained 3.48 kg (0.52 +/- 0.84 kg/year). A unit increase in log-transformed mono-3-carboxypropyl phthalate (MCPP) was associated with 0.33 kg (95% CI: 0.09, 0.56) higher weight gain per year, and mono-benzyl phthalate (MBzP) with 0.21 kg (95% CI: -0.38, -0.03) lower weight gain per year. CONCLUSION: Exposure to certain phthalates during pregnancy may be associated with long-term weight change in women. More studies on the effects of phthalate exposure during pregnancy on women's long-term health are required. PMID- 30408751 TI - Prenatal exposure to organophosphate esters and cognitive development in young children in the Pregnancy, Infection, and Nutrition Study. AB - Organophosphate esters (OPEs) are a class of chemicals commonly used as flame retardants and plasticizers. OPEs are applied to a wide variety of consumer products and have a propensity to leach from these products. Consequently, OPEs are ubiquitous contaminants in many human environments and human exposure is pervasive. Accumulating evidence suggests that OPEs are capable of interfering with childhood cognitive development through both neurologic- and endocrine mediated mechanisms. However, observational evidence of cognitive effects is limited. We used data collected in the third phase of the Pregnancy, Infection, and Nutrition Study to investigate cognitive effects of prenatal exposure to OPEs. In a spot prenatal maternal urine sample, we measured the following OPE metabolites: diphenyl phosphate (DPHP), bis(1,3-dichloro-2-propyl phosphate) (BDCIPP), isopropyl-phenyl phenyl phosphate (ip-PPP), and 1-hydroxyl-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP). We assessed children's language and multi-faceted and overall cognitive development between two and three years of age using the MacArthur-Bates Communicative Development Inventories (MB-CDI) and the Mullen Scales of Early Learning (MSEL). We used linear regression to estimate the change in children's scores on these developmental assessments per interquartile range (IQR) increase in log-transformed, specific-gravity-corrected prenatal OPE metabolite concentrations, adjusted for maternal age, education, income, race/ethnicity, BMI, and child's sex. A total of 149 children had both OPE metabolite measurements and MB-CDI scores, and 227 children had both OPE metabolite measurements and MSEL scores. We observed that higher concentrations of ip-PPP (ng/ml) were associated with lower scores on the MSEL Cognitive Composite Score (beta = -2.61; 95% CI: -5.69, 0.46), and separately on two of the four MSEL Scales that comprise the Cognitive Composite, specifically the Fine Motor Scale (beta = -3.08; 95% CI: -5.26, -0.91) and the Expressive Language Scale (beta = -1.21; 95% CI: -2.91, 0.49). We similarly observed that prenatal ip PPP concentrations were inversely associated with age-standardized scores on the MB-CDI Vocabulary assessment (beta = -1.19; 95% CI: -2.53, 0.16). Other OPE metabolites were not strongly associated with performance on either assessment. Our results suggest that isopropylated triarylphosphate isomers, the presumed parent compounds of ip-PPP, may adversely impact cognitive development, including fine motor skills and early language abilities. Our study contributes to the growing body of observational evidence that suggests prenatal exposure to OPEs may adversely affect cognitive development. PMID- 30408752 TI - The manganese(III) porphyrin MnTnHex-2-PyP5+ modulates intracellular ROS and breast cancer cell migration: Impact on doxorubicin-treated cells. AB - Manganese(III) porphyrins (MnPs) are superoxide dismutase (SOD) mimics with demonstrated beneficial effects in cancer treatment in combination with chemo- and radiotherapy regimens. Despite the ongoing clinical trials, little is known about the effect of MnPs on metastasis, being therefore essential to understand how MnPs affect this process. In the present work, the impact of the MnP MnTnHex 2-PyP5+ in metastasis-related processes was assessed in breast cancer cells (MCF 7 and MDA-MB-231), alone or in combination with doxorubicin (dox). The co treatment of cells with non-cytotoxic concentrations of MnP and dox altered intracellular ROS, increasing H2O2. While MnP alone did not modify cell migration, the co-exposure led to a reduction in collective cell migration and chemotaxis. In addition, the MnP reduced the dox-induced increase in random migration of MDA-MB-231 cells. Treatment with either MnP or dox decreased the proteolytic invasion of MDA-MB-231 cells, although the effect was more pronounced upon co-exposure with both compounds. Moreover, to explore the cellular mechanisms underlying the observed effects, cell adhesion, spreading, focal adhesions, and NF-kappaB activation were also studied. Although differential effects were observed according to the endpoints analysed, overall, the alterations induced by MnP in dox-treated cells were consistent with a therapeutically favorable outcome. PMID- 30408754 TI - Y TXT N DRIVE? Predictors of texting while driving among a sample of Ontario youth and young adults. AB - BACKGROUND: Distracted driving is of particular concern among young drivers. According to the 2012 National Highway Traffic Safety Administration (NHTSA) survey, the greatest proportion of distraction prone drivers is within the 16-19 and 20-24 age groups. One relatively new distraction is texting while driving behaviour (TWD). TWD increases the amount of time drivers spend looking away from the road, slows reaction times and increases the risk of collisions by two-fold. To deter this behaviour many distracted driving campaigns focus on highlighting the risks and dangers of distracted driving; however, evidence suggests that youth and young adults continue to engage in TWD despite awareness of the related risks. Previous studies have examined constructs from the theory of planned behaviour as predictors of TWD (e.g., attitudes, intentions). Understanding the full range of factors that may influence this behaviour can inform the development of evidence-based public awareness campaigns and related interventions. PURPOSE: The purpose of this paper was to examine predictors of TWD behaviour among youth and young adults. We examined constructs from the theory of planned behaviour in addition to the role played by perceived TWD driving skills, experience with collisions due to TWD, descriptive norms (i.e., an individual's beliefs about a behaviour that are gained as a result of observing the actions of others) and risk perceptions. METHODS: An online survey was administered to 2001 Ontario youth and young adults examining potential predictors of TWD behaviour. Regression models were used to examine which key variables were associated with TWD (both reading and sending behaviour) among participants. RESULTS: Overall, regression models had good predictability for reading and sending behaviours. Perceived TWD driving skills and 'almost getting in a collision due to TWD' were positively associated with TWD behaviour in the past week (both reading and sending behaviours). Descriptive norms were positively associated with sending text messages while driving in the past week, but were not significant for reading. In contrast, risk perceptions were positively associated with reading text messages in the past week but not sending. DISCUSSION AND CONCLUSION: The results from this study highlight constructs that can be used to design interventions to deter young drivers from engaging in TWD. Interventions targeting perceived TWD driving skills and descriptive norms have the potential to be more effective than interventions emphasizing risk perceptions. Future studies are needed to better understand the relationships between these predictors and TWD behaviour among this population. PMID- 30408755 TI - Identifying street design elements associated with vehicle-to-pedestrian collision reduction at intersections in New York City. AB - OBJECTIVE: We evaluated associations between the installation of eleven street design elements, between 2007 and 2015, and subsequent changes in vehicle-to pedestrian collisions in New York City. METHODS: Collision data were from Accident Location Information System in the New York State Department of Transportation. Safety improvement projects at 118 intersections were reviewed and their implemented street design elements were identified. First, we assessed potential regression-to-the-mean effects using historic trends of pedestrian collision count at the intersection project locations. Second, we used a two group pretest-posttest design to assess individual element's associations with pedestrian collision reduction after installations. Pedestrian collision count and pedestrian- and vehicle-based pedestrian collision rates were examined. Third, regression trees were used to classify the intersections with design elements as independent variables for the target variables of collision outcomes, to identify street design element combinations associated with pedestrian collision reductions. RESULTS: Treatments with pedestrian refuge island or pedestrian plaza had reductions in pedestrian collision count and pedestrian based collision rate while their comparisons had no changes. Treatments with pedestrian refuge island had a larger reduction in pedestrian collision when combined with lane removal or narrowing. Treatment with curb extension or pedestrian plaza had reductions in vehicle-based pedestrian collision rate while their comparisons had no changes. Other studied elements showed no, small, or insignificant associations with post-project pedestrian collision reductions. PMID- 30408753 TI - A high-throughput real-time in vitro assay using mitochondrial targeted roGFP for screening of drugs targeting mitochondria. AB - Most toxic compounds including cancer drugs target mitochondria culminating in its permeabilization. Cancer drug-screening and toxicological testing of compounds require cost-effective and sensitive high-throughput methods to detect mitochondrial damage. Real-time methods for detection of mitochondrial damage are less toxic, allow kinetic measurements with good spatial resolution and are preferred over end-stage assays. Cancer cell lines stably expressing genetically encoded mitochondrial-targeted redox-GFP2 (mt-roGFP) were developed and validated for its suitability as a mitochondrial damage sensor. Diverse imaging platforms and flow-cytometry were utilized for ratiometric analysis of redox changes with known toxic and cancer drugs. Key events of cell death and mitochondrial damage were studied at single-cell level coupled with mt-roGFP. Cells stably expressing mt-roGFP and H2B-mCherry were developed for high-throughput screening (HTS) application. Most cancer drugs while inducing mitochondrial permeabilization trigger mitochondrial-oxidation that can be detected at single-cell level with mt roGFP. The image-based assay using mt-roGFP outperformed other quantitative methods of apoptosis in ease of screening. Incorporation of H2B-mCherry ensures accurate and complete automated segmentation with excellent Z value. The results substantiate that most cancer drugs and known plant-derived antioxidants trigger cell-death through mitochondrial redox alterations with pronounced ratio change in the mt-roGFP probe. Real-time analysis of mitochondrial oxidation and mitochondrial permeabilization reveal a biphasic ratio change in dying cells, with an initial redox surge before mitochondrial permeabilization followed by a drastic increase in ratio after complete mitochondrial permeabilization. Overall, the results prove that mitochondrial oxidation is a reliable indicator of mitochondrial damage, which can be readily determined in live cells using mt roGFP employing diverse imaging techniques. The assay described is highly sensitive, easy to adapt to HTS platforms and is a valuable resource for identifying cytotoxic agents that target mitochondria and also for dissecting cell signaling events relevant to redox biology. PMID- 30408756 TI - Dentin pretreatment with 45S5 and niobophosphate bioactive glass: Effects on pH, antibacterial, mechanical properties of the interface and microtensile bond strength. AB - OBJECTIVES: The aim of the study was to evaluate the effect of bioactive glass (45S5 and NbG) suspensions on bond strength (uTBS), hardness, modulus of elasticity, pH and antibacterial activity of the resin-dentin interfaces after 3 months. METHODS: Groups with different concentrations (5% and 20%) of two types of glass (45S5 and NbG), and a control group (distilled water) were studied. Twenty-five extracted human third molars were etched with phosphoric acid. The data from uTBS, hardness and modulus of elasticity data were submitted to two-way ANOVA (suspension vs. time) and Holm-Sidak tests (=0.05). The antimicrobial activity data were analyzed by the Kruskal-Wallis test (alpha = 5%). RESULTS: The interactions were significant among groups for uTBS (p = 0.033). Significant reductions in uTBS were observed after 3 months storage in PBS for the Control and 5% NbG Groups. Suspensions with 5% and 20% 45S5 glass and 20% NbG resulted in stable uTBS values and increased hardness after 3 months. Both 20% suspensions (45S5 and NbG) increased the elastic modulus. A significant greater reduction in bacterial growth was observed with the use of 20% 45S5. CONCLUSION: Rewetting dentin with the suspension of 20% 45S5 glass prevented the reduction in bond strength; increased hardness; modulus of elasticity of the resin-dentin interface, and demonstrated antibacterial activity against Streptococcus mutans. PMID- 30408757 TI - Color Doppler imaging evaluation of blood flow parameters in ophthalmic and posterior ciliary arteries and optic nerve diameter in chronic optic neuritis in multiple sclerosis patients. AB - BACKGROUND AND PURPOSE: Optic neuritis (ON) is a common clinical manifestation of Multiple Sclerosis (MS), which is associated with reduced visual acuity, blurred vision, blindness and retro-bulbar pain. In several studies, specific relations between optic nerve diameter and hemodynamics of the eye bulb arteries with ON have been reported. However, no consensus has been reached in this regard. We aim at determining the alterations in optic nerve diameter and eye bulb arteries hemodynamics in ON in MS patients. METHODS: This case-control study includes 40 patients, who at least had experienced one phase of ON, in one of their eyes. To measure hemodynamics of arteries in the affected eyes, a color Doppler imaging was performed and end diastolic velocity (EDV), peak systolic velocity (PSV), peripheral resistance indices i.e. resistance index (RI) and pulsatile index (PI) were measured in posterior ciliary artery (PCA) and ophthalmic artery (OA). Also, optic nerve diameter was measured using sonography. Non-affected eyes of these patients were considered as control group. RESULTS: There were no significant differences in EDV, PSV, RI and PI in PCA and OA. The mean optic nerve diameter in the affected eyes was 4.73 mm, whereas, it was 4.31 mm in unaffected eyes, which was significantly different (P = .02). CONCLUSION: These results indicate that there is a significant relation between eye involvement and increased optic nerve diameter in MS patients with chronic ON. While, there were no significant relations in EDV, PSV, RI and PI in PCA and OA comparing two groups. PMID- 30408758 TI - Paraneoplastic neuromyelitis optica associated with fever of unknown origin as an early manifestation: A case report. AB - Tumors have been frequently reported to be associated with neuromyelitis optica (NMO). Here we review a case of a 34-year-old woman who presented with complaint of one-sided visual loss. All Lab tests exhibited negative results which decreased the possibility of Auto-immune or neuro-inflammatory disorders. Magnetic resonance imaging (MRI) of the brain and spinal cord was done as a part of work up, which showed Meningioma in anterior fossa without any other findings supporting neuro-demyelinating disorders. After complete surgical removal of the meningioma, patient's visual loss was completely resolved. 4 weeks later, she was admitted to the hospital for the second time with fever fulfilling the Fever of Unknown Origin (FUO) criteria. One week after she was discharged, she came back with paraplegia. MRI with Gadolinium showed an enhancing lesion involving T6-T9 segments of the thoracic spine. In order to rule in NMO, we checked for antibody to aquaporin-4 (AQP4-Ab) and the result was positive. This is the first report showing a probable association between FUO and NMO. Our case also demonstrates how variable the clinical presentations of NMO can be. We suggest that the diagnosis of NMO should be considered in the appropriate clinical setting despite of the presence of unconventional manifestations. PMID- 30408759 TI - Which treatment strategies for polyrefractory Neuro-Behcet disease? PMID- 30408760 TI - A biomechanical breast model evaluated with respect to MRI data collected in three different positions. AB - BACKGROUND: Mammography is a specific type of breast imaging that uses low-dose X rays to detect cancer in early stage. During the exam, the women breast is compressed between two plates in order to even out the breast thickness and to spread out the soft tissues. This technique improves exam quality but can be uncomfortable for the patient. The perceived discomfort can be assessed by the means of a breast biomechanical model. Alternative breast compression techniques may be computationally investigated trough finite elements simulations. METHODS: The aim of this work is to develop and evaluate a new biomechanical Finite Element (FE) breast model. The complex breast anatomy is considered including adipose and glandular tissues, muscle, skin, suspensory ligaments and pectoral fascias. Material hyper-elasticity is modeled using the Neo-Hookean material models. The stress-free breast geometry and subject-specific constitutive models are derived using tissues deformations measurements from MR images. FINDINGS: The breast geometry in three breast configurations were computed using the breast stress-free geometry together with the estimated set of equivalent Young's modulus (Ebreastr = 0.3 kPa, Ebreastl = 0.2 kPa, Eskin = 4 kPa, Efascia = 120 kPa). The Hausdorff distance between estimated and measured breast geometries for prone, supine and supine tilted configurations is equal to 2.17 mm, 1.72 mm and 5.90 mm respectively. INTERPRETATION: A subject-specific breast model allows a better characterization of breast mechanics. However, the model presents some limitations when estimating the supine tilted breast configuration. The results show clearly the difficulties to characterize soft tissues mechanics at large strain ranges with Neo-Hookean material models. PMID- 30408761 TI - Comparison of secondary organic aerosol (SOA) formation during o-, m-, and p xylene photooxidation. AB - Despite extensive effort to characterize xylene-isomer-derived secondary organic aerosols (SOAs) over the past decade, differences in SOA composition among xylene isomers, and their relative contributions to SOA formation remain poorly understood. Herein, we reinvestigated the photooxidation of o-, m-, and p-xylene under two limiting NO conditions. Dicarbonyls, TBM (the acronym of C3-trione, 2,3 butanedione, and 3-methyl-2-oxiranecarbaldehyde with the same [M+H]+m/z value of 87), and highly oxidized species (HOS), based on the m/z 61 fragment, were determined to be the predominant SOA components arising from xylene photooxidation; however, their relative contributions to SOA formation appear to depend on the xylene substitution pattern. In the initial stages of the reaction, dicarbonyls present in the SOA from m- and p-xylene, and TBM in the SOA from o xylene, were the main contributors to new particle formation (NPF). Based on their significant levels of formation, HOS and TBM were characterized to be critical components that enhance SOA growth. High NO levels were noted to inhibit the formation of C3-trione and 2,3-butanedione in the SOA from m- and o-xylene, whereas the formation of 3-methyl-2-oxiranecarbaldehyde during p-xylene photooxidation was significantly promoted. These results reveal that the substitution pattern of the xylene isomer is a significant factor that determines these differences. In addition, decreases in the levels of dicarbonyls and TBM during NPF and the formation of HOS in the presence of high levels of NO may be important factors that lead to lower SOA yields compared to those obtained under low-NO conditions. This work contributes to a better understanding of the formation mechanism of xylene-derived SOAs. PMID- 30408762 TI - Understanding long-term variations of meteorological influences on ground ozone concentrations in Beijing During 2006-2016. AB - Recently, ground ozone has become one major airborne pollutant and the frequency of ozone-induced pollution episodes has increased rapidly across China. However, due to the lack of long-term observation data, relevant research on the characteristics and influencing factors of urban ozone concentrations remains limited. Based on ground ozone observation data during 2006-2016, we quantified the causality influence of individual meteorological factors on ozone concentrations in Beijing using a convergent cross mapping (CCM) method. The result indicated that the influence of each meteorological factor on ozone concentrations varied significantly across seasons and years. At the inter-annual scale, all-year meteorological influences on ozone concentrations were much more stable than seasonal meteorological influences. At the seasonal scale, meteorological influences on ozone concentrations were stronger in spring and autumn. Amongst multiple individual factors, temperature was the key meteorological influencing factor for ozone concentrations in all seasons except winter, when wind, humidity and SSD exerted major influences on ozone concentrations. In addition to temperature, air pressure was another meteorological factor that exerted strong influences on ozone concentrations. At both the inter-annual and seasonal scale, the influence of temperature and humidity on ozone concentrations was generally stable whilst that of other factors experienced large variations. Different from PM2.5, meteorological influences on ozone concentrations were relatively weak in summer, when ozone concentrations were the highest in Beijing. Given the generally stable meteorological influences on ozone concentrations and human-induced emissions of VOCs and NOx across seasons, warming induced notable increase in summertime biogenic emissions of VOCs and NOx can be a major driver for the increasing ozone pollution episodes. This research provides useful references for understanding long-term meteorological influences on ozone concentrations in mega cities in China. PMID- 30408763 TI - Real-time combustion rate of wood charcoal in the heating fire basin: Direct measurement and its correlation to CO emissions. AB - Previous studies of solid fuel emissions in household stoves focused more on emission measurements of the overall combustion process instead of the dynamic burning rate and its connection to the emissions. This study put forward a measurement system to monitor the dynamic fuel burning rate and emission rate directly, and explored their relationships during different combustion phases. Experiments were conducted using two types of wood charcoal consumed in a small open pan (i.e. fire basin) used commonly for space heating in rural China. The measured real-time CO emission rate (ERCO), fuel burning rate (BRF), and calculated carbon burning rate (BRC) all rose and then subsided as the combustion progressed. The relationships between ERCO and BRF and between ERCO and BRC were different for the two charcoals during a phase with rising carbon content in the combusted fuel (Phase I), likely because moisture evaporation and volatile matter release were the dominant processes and the reaction was complex during this phase. ERCO and BRF or BRC had linear relationships during a phase with stable carbon content in the combusted fuel (Phase II) for the two charcoals, which may be generalized to other solid fuels, because this phase is associated to fixed carbon dominating phase which usually exist during solid fuel combustion. The study presented a novel measurement approach to the combustion properties of solid fuels. The results implied that a complex relationship between the combustion and pollutant emissions existed in Phase I, and presented the possibility of estimating the fuel burning rate based on emission measurements in Phase II, or vice versa. PMID- 30408764 TI - Enhanced distribution of humic acid-modified nanoscale magnesia for in situ reactive zone removal of Cd from simulated groundwater. AB - Efficient injection and distribution of nanoparticles in porous media are considered a formidable technical hurdle for injection-based in situ remediation. One approach to enhance the mobility of nanoparticles in an aquifer is to use surface modifiers. In this study, nanoscale magnesia (NMgOs), an innovative and effective remedial material for cadmium (Cd) removal from groundwater, was modified with the negatively charged and eco-friendly humic acid to enhance its mobility in aquifers. A two-dimensional reactor (60 * 50 * 10 cm), with 2 injection wells and 30 monitoring wells was designed, constructed, and sand packed in the laboratory to simulate a saturated aquifer. The simulated aquifer was pre-contaminated with Cd to simulate a plume in groundwater. The distribution of injected unmodified NMgOs and humic acid-modified NMgOs slurry were evaluated in the reactor. The radius of influence (ROI) of humic acid-modified NMgOs was estimated to be approximately 5 cm based on visual observation, while no ROI was apparent for the unmodified NMgOs because of their aggregation at the bottom of the injection wells. The concentrations of Cd and magnesium (Mg) were monitored in all 30 monitoring wells at different time intervals to evaluate the effectiveness of Cd removal. The breakthrough curve analysis revealed that humic acid enhances the transport of NMgOs in the saturated porous media. Furthermore, the results of scanning electron microscopy-energy dispersive x-ray (SEM-EDX) characterization of silica sand before and after injection of NMgOs verified the presence of 5.78% of Mg from humic acid-modified NMgOs and 0.19% from unmodified NMgOs at 35 cm downgradient of the injection wells, which are consistent with the conclusion drawn from the breakthrough curves. PMID- 30408765 TI - Understanding the impact of mental health placements on student nurses' attitudes towards mental illness. AB - Student nurses maintain unfavorable views of people with mental health issues. Many continue to perpetuate common stereotypes, are fearful and believe people with mental health problems are in some way dangerous. The impact of placements greatly affects these views. A pre-post survey of 85 student nurses was conducted to establish the opinions and attitudes of student nurses regarding mental health. Groups were allocated to either community or hospital placements. Each group received the same educational preparation prior to placement. Both community and hospital placed students had improved clinical confidence when working with people experiencing mental health problems. Community placed students demonstrated greater positive attitudes towards people experiencing mental health issues across a number of domains. Students in hospital settings demonstrated more confidence when working with people with mental health issues yet had less attitudinal change about mental health. The approach taken by clinical facilitators also influenced student attitudes. It is suggested that offering community opportunities along with exposure to positive instructor beliefs about mental illness will both improve student attitudes prior to the completion of their nursing studies and may encourage entry into mental health as a nursing option post-education. PMID- 30408766 TI - Adsorption of Sr(II) from water by mercerized bacterial cellulose membrane modified with EDTA. AB - The treatment of low-level radioactive wastewater is a critical and considerable challenge. Bacterial cellulose membrane (BCM) modified with ethylenediaminetetraacetic acid (EDTA) using (3-aminopropyl) triethoxysilane (APTES) as a crosslinker were used to remove Sr2+ in this work. SEM, XPS, and FTIR were used to characterize the morphology, structure, chemical shift, and functional groups of the as-prepared adsorbent. The synthesized BCM@APTES-EDTA presented a three-layer structure of membrane-net-membrane with nano-sized fibers (<100 nm). The adsorption of Sr2+ onto BCM@APTES-EDTA was investigated as a function of contact time and initial concentration of Sr2+. Results showed that the adsorption of Sr2+ followed the pseudo second-order kinetic model (R2 = 0.999), and fitted well with the Langmuir isotherm model (R2 = 0.996). The maximum adsorption capacity was calculated to be 44.86 mg g-1, which was comparable to other adsorbents. Additionally, the mechanism of Sr2+ adsorbed by the as-prepared adsorbent was studied through FTIR and XPS analysis, which indicated that the tertiary amines and carboxylate from grafted EDTA participated in the adsorption of Sr2+. PMID- 30408767 TI - Synthesis and applications of biogenic nanomaterials in drinking and wastewater treatment. AB - The continuous increase in water pollution by various organic & inorganic contaminants has become a major issue of concern worldwide. Furthermore, the anthropogenic activities for the manufacturing of various products have boosted this problem manifold. To overcome this serious issue, nanotechnology has initiated to explore various proficient strategies to treat waste water in a more precise and accurate way with the support of various nanomaterials. In recent times, nanosized materials have proved their applicability to provide clean and affordable water treatment technologies. The exclusive features such as high surface area and mechanical properties, greater chemical reactivity, lower cost and energy, efficient regeneration for reuse allow the nanomaterials perfect for water remediation. But the conventional routes of synthesis of nanomaterials encompass the involvement of hazardous and volatile chemicals; therefore the use of nanomaterials further creates the secondary pollution. This issue has intrigued the scientists to develop biogenic pathways and procedures which are environmentally safer and inexpensive. It has led to the new trends that involve developing bio-inspired nano-scale adsorbents and catalysts for the removal and degradation of a wide range of water pollutants. Carbohydrates, proteins, polymers, flavonoids, alkaloids and several antioxidants obtained from plants, bacteria, fungi, and algae have proven their effectiveness as capping and stabilizing agents during manufacture of nanomaterials. Application of biogenic nanomaterials for waste water treatment is relatively newer but rapidly escalating area of research. In the present review, promises and challenges for the synthesis of various biogenic nanomaterials and their potential applications in waste water treatment and/or water purification have been discussed. PMID- 30408768 TI - Selective synthesis of zeolites A and X from two industrial wastes: Crushed stone powder and aluminum ash. AB - Crushed stone powder and aluminum ash are industrial wastes, and effective utilization of these wastes has been highly expected. Since the main components of the two wastes are Si, Al and O, those wastes can be used as starting materials for synthesis of zeolites of which some types have been commercialized as catalysts and ion-exchangers. In this study, zeolites A and X well-known as practical materials were successfully synthesized with high purity using the two industrial wastes by a mild process based on two hydrothermal treatments with intermediate acid treatment. In the first hydrothermal treatment at 150 degrees C, quartz in the crushed stone powder was dissolved and acid-soluble hydroxysodalite (Na8(AlSiO4)6(H2O)2(OH)2) with Si/Al = 1 and sodium aluminosilicate (Na6(AlSiO4)6) were formed. Those compounds were dissolved with HCl aq. solution. The zeolites were successfully synthesized from the second hydrothermal treatment of the yellow dried filtrates at 80 degrees C in NaOH aq. solution. In the process proposed, removal of Ca from the crushed stone powder was effective to formation of zeolites A and/or X. Selective synthesis of zeolites A and X was achieved by controlling the acid treatment conditions. Furthermore, the effect of the drying condition of the filtrate obtained after the acid treatment was also investigated on the differences in the product phase. PMID- 30408769 TI - Crustacean shell-based biosorption water remediation platforms: Status and perspectives. AB - The importance of water pollutants on human health has been the subject of intense study and constitutes perhaps the most significant grand challenge for the future of human society. Water remediation faces many challenges in effectively combating pollution, especially for low income populations where poor water sanitation and little to no access to technically competent and cost effective remediation are nearly insurmountable issues. In an effort to provide low-cost adsorbents, research over the last few years has focused on biological residual materials from plants and animal biomass to not only to add value, but to remediate water at a lower cost with the same or improved efficiency as commercially available option. Crustacean shells are among a class of biological residues that are commonly treated as a waste product of the sea food industry. However, potential valorization by remediation of heavy metal ions, organic matter, and anionic species is a topic of high interest in the current eco friendly environment. The aim of this review is to provide insight on the state of the art of crustacean shells for addressing water remediation and to offer some perspective regarding challenges and the future of this type of biomass. PMID- 30408770 TI - Overexpression of CBS and CSE genes affects lifespan, stress resistance and locomotor activity in Drosophila melanogaster. AB - Recent experimental studies highlighted the role of hydrogen sulfide (H2S) in aging and longevity. The cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE) are the key enzymes responsible for H2S production. Here we investigated the geroprotective effects of CSE and CBS overexpression in Drosophila. Overexpression of CSE did not affect a lifespan and decrease (mitochondrial form of CSE) or increase (cytoplasmic form of CSE) age dynamics of locomotor activity, while overexpression of CBS increase median (by 12.5%) and maximum (by 6.9%) lifespan and locomotor activity. Increasing of both CSE and CBS expression levels resulted in thermotolerance, but the resistance to combination of arid and food-free conditions decreased. The resistance to oxidative stress (paraquat) was not affected in flies with overexpression of CBS and cytoplasmic CSE, but decreased in flies overexpressing mitochondrial form of CSE. Thus, transgene overexpression of the CSE and CBS in Drosophila induce similar effects on stress-resistance and locomotor activity, however lifespan extending effect was revealed for CBS overexpression only. PMID- 30408771 TI - Spindle pole body component 25 regulates stemness of prostate cancer cells. AB - Spindle pole body component 25 (SPC25) is a component of NDC80 complex that controls spindle assembly checkpoint in the microtubule-binding domain of kinetochores. We recently showed that SPC25 is required for prostate cancer (PrC) cell proliferation and cell cycle progression, and here we investigated whether SPC25 may be a Cancer stem cell (CSC) marker in PrC. We found that the levels of SPC25 were higher in PrC samples than paired normal prostate tissue. The overall survival of PrC patients with high SPC25 was poorer than those with low SPC25. PrC cell lines were transduced with two vectors carrying a luciferase reporter and a mCherry fluorescent reporter under a cytomegalovirus promoter and a nuclear green fluorescent protein reporter under the control of a SPC25 promoter, respectively, to allow differentiating SPC25+ from SPC25- PrC cells by flow cytometry. Compared to SPC25- cells, SPC25+ cells formed significantly more tumor spheres in culture, appeared to be more resistant towards docetaxel-induced cell apoptosis, and generated larger tumors with higher frequency after serial adoptive transplantation. Thus, our data suggest that SPC25 may be highly expressed in the CSC-like cells in PrC and could be a promising target for effective treatment of PrC. PMID- 30408772 TI - The Arboranan Frogs: Preface. PMID- 30408773 TI - The Arboranan Frogs: Foreword. PMID- 30408774 TI - The Arboranan Frogs: Introduction. PMID- 30408775 TI - Primary Tracheal Mucosa-Associated Lymphoid Tissue Lymphoma Treated with a Water Jet Hybrid Knife: A Case Report. AB - Primary mucosa-associated lymphoid tissue (MALT) lymphoma of the trachea is very rare and is easily misdiagnosed as a bronchogenic carcinoma or benign tracheal tumor. Here, we report a clinical case where a new clinical approach involving a water-jet hybrid knife was employed in the diagnosis and treatment of primary tracheal MALT lymphoma. PMID- 30408776 TI - Joint Mobility and Physical Function of Danish Hemophilia Patients: A Three-Wave Panel Study Spanning 24 Years. AB - BACKGROUND: The positive effects of factor treatment of hemophilia are well established, but the long-term outcomes are not well documented. This panel study evaluated changes in bleeding frequency, joint mobility, physical function, and symptoms in Danish patients with moderate to severe hemophilia A or B over 24 years. METHODS: Three anonymous surveys were conducted in 1988, 2001, and 2012 targeting Danish patients with moderate to severe hemophilia, and the study participants, respectively, were 128, 156, and 164 male patients with hemophilia (PWH). The number of bleeding episodes, the use of factor concentrate, comorbidities, joint mobility, physical function, and symptoms were evaluated by means of self-reporting. Trends over time were analyzed using ordinal and multinomial logistic-regression models controlling for age group. RESULTS: The proportion of PWH in the oldest age group (55-88 years) increased from 4% in 1988 to 18% in 2012. In 1988, a high risk of bleeding episodes was primarily found in the age group of 16-34 years. In 2012, a high risk was primarily found in the age group of 35-54 years. Joint mobility and physical function increased significantly from 1988 to 2012 but showed a noticeable decrement in the older age groups, even in 2012. Pain in the extremities, anxiety, and depression decreased significantly, but back pain increased. No significant changes were found for 7 other symptoms. CONCLUSIONS: Significant improvements in joint mobility and physical function have occurred over the last 24 years, but PWH > 35 years still experience a decline in these areas with age. This decline underscores the importance of life-long treatment and continuous rehabilitation of PWH. PMID- 30408777 TI - TLR Activation Alters Bone Marrow-Derived Macrophage Differentiation. AB - Early exposure to inflammatory signals may have a lasting impact on immune function. Present throughout embryogenesis, macrophages are key cells providing innate immune protection to the developing fetus and newborn. Here, we have used an established model of macrophage development to test how early inflammatory signals can impact cellular differentiation and function. Bone marrow-derived macrophages were treated with Escherichia coli lipopolysaccharide (LPS) 2 days after initial isolation and culture. LPS treatment during this early stage of differentiation decreased the expression of CSF1R and increased that of the mature macrophage marker F4/80. These early changes in macrophage differentiation were also measured in cells from mice lacking IKKbeta, but the change in CSF1R expression after LPS treatment was blocked with MAPK inhibition. LPS-induced changes in macrophage marker expression persisted following LPS removal, suggesting that early inflammatory activation could induce a lasting developmental impact. Early LPS exposure inhibited macrophage phagocytosis of labeled E. coli while LPS had no effect on fully differentiated macrophages. Our data demonstrate that early inflammatory exposure to a microbial stimulus induce lasting phenotypic changes in macrophages. PMID- 30408778 TI - Exosomes from Thymic Stromal Lymphopoietin-Activated Dendritic Cells Promote Th2 Differentiation through the OX40 Ligand. AB - OBJECTIVES: Exosomes are extracellular vesicles released from various inflammatory cells, such as T cells, B cells, dendritic cells (DCs), and mast cells, which have been implicated in the modulation of immune response in asthma. This study aimed to investigate whether exosomes from DCs activated by thymic stromal lymphopoietin (TSLP) play a role in T-helper cell differentiation through the OX40 ligand (OX40L). METHODS: Serum samples from patients with asthma were collected to measure the levels of OX40L, T-helper type 1 (Th1) cytokine interferon (IFN)-gamma, and T-helper type 2 (Th2) cytokine interleukin (IL)-4 by enzyme-linked immunosorbent assay (ELISA). Exosomes were isolated from TSLP activated DCs and co-cultured with CD4+ T cells. Western blot and ELISA assays were used to measure the levels of OX40L, IFN-gamma, and IL-4 in DCs and CD4+ T cells. Flow cytometry was applied to detect Th1 and Th2 cells. RESULTS: OX40L and IL-4 were increased and IFN-gamma was decreased in serum from asthmatic patients compared with healthy controls. TSLP induced DCs to express OX40L in released exosomes, which could promote proliferation of CD4+ T cells, elevate the level of IL-4, and promote Th2 differentiation. CONCLUSION: Blockade of OX40L in DC derived exosomes could inhibit exosome-mediated CD4+ T proliferation and Th2 differentiation. PMID- 30408779 TI - Hepatitis B Reactivation Rate Is Higher Undergoing Some Cytotoxic Chemotherapy in Patients with Solid Tumors: A Large Retrospective Study. AB - OBJECTIVE: The reactivation rate of chronic hepatitis B virus infection in cancer patients and chemotherapy regimens thought to be associated with hepatitis reactivation were investigated. PATIENTS AND METHODS: In all, 3,890 cancer patients were included in this study. Mortality rates, chemotherapy regimens, cancer types, number of positive hepatitis serology and reactivation rates were obtained. RESULTS: Only 354 patients had positive hepatitis serology results (HBsAg+). Twenty-four patients (6.7%) with HBsAg positive serology had reactivation. In patients with hepatitis reactivation, the rates of usage of 5 fluorouracil (5-FU), cisplatin, cyclophosphamide, doxorubicin, steroid, rituximab, and vincristine were found to be significantly higher than corresponding rates in patients with positive hepatitis serology results but without hepatitis reactivation (p < 0.05 for all). CONCLUSION: Increased reactivation rates were detected with usage of 5-FU, cisplatin, cyclophosphamide, doxorubicin, steroid, rituximab, and vincristine. PMID- 30408780 TI - Pulse Waveform Analysis in Ocular Microcirculation by Laser Speckle Flowgraphy in Patients with Left Ventricular Systolic and Diastolic Dysfunction. AB - PURPOSE: To determine: (1) whether variables of a pulse wave form analysis of ocular microcirculation shown by laser speckle flowgraphy (LSFG) correlate with left ventricular (LV) systolic dysfunction and (2) whether these variables correlate with LV diastolic dysfunction in subjects without LV systolic dysfunction as assessed by echocardiography. METHODS: We studied 200 consecutive subjects. LV systolic dysfunction has been determined to be present when the LV ejection fraction was < 50%. LV diastolic dysfunction was diagnosed when subjects had an E/e' ratio >=15 and an e' velocity < 10 cm/s. We evaluated the pulse waveform analysis variables "rising rate" and the blowout score (BOS) using LSFG in the optic nerve head (ONH) and choroid. RESULTS: The brain natriuretic peptide (BNP) level, the rising rate in the choroid area (rising rate-choroid), and heart rate were revealed as independent factors for LV systolic dysfunction, and BOS choroid was identified as an independent factor for LV diastolic dysfunction. The areas under the curve (AUC) of BNP and rising rate-choroid for LV systolic dysfunction were 0.83 and 0.81, respectively. The AUC of BOS-choroid for LV diastolic dysfunction was 0.73. CONCLUSION: Pulse waveform analysis in the choroid has a significant correlation with LV systolic and LV diastolic function. PMID- 30408781 TI - Derived Subendocardial Viability Ratio and Cardiovascular Events in Patients with Chronic Kidney Disease. AB - BACKGROUND: Chronic kidney disease (CKD) is a well-known mortality risk factor. The subendocardial viability ratio (SEVR) is one of the pulse wave analysis parameters that constitutes a non-invasive measure of coronary perfusion. We aimed to assess the prognostic value of the SEVR for cardiovascular outcome in non-dialysis CKD patients. METHODS: A total of 98 CKD patients (mean age 60 years) were prospectively followed up from the date of the SEVR measurement until their death or the start of dialysis/transplantation, maximally up to 7.1 years (mean 5 years). According to the manufacturer's instructions regarding normal SEVR values, the patients were divided into a low SEVR group (SEVR <=130%, n = 26) and a normal SEVR group (SEVR > 130%, n = 72). RESULTS: During the follow-up period, 13 patients (13.3%) suffered fatal and 23 patients (23.5%) suffered combined (non-fatal and fatal) cardiovascular events. In the patients who died of cardiovascular causes, the SEVR values were statistically significantly lower (130 vs. 154%; p = 0.017) than in those who survived. A Kaplan-Meier survival analysis showed that the cardiovascular survival rate in the low SEVR group of patients was statistically significantly lower (log-rank test: p < 0.001). Using an unadjusted Cox regression analysis, the patients in the low SEVR group had a 5.6-fold higher risk (95% CI: 1.8-17.3; p = 0.002) of fatal cardiovascular events and a 2.7-fold higher risk (95% CI: 1.1-6.3; p = 0.024) of combined fatal and non fatal cardiovascular events. In the adjusted Cox regression model, the patients in the low SEVR group had a 16-fold higher risk (95% CI: 1.2-9.7; p = 0.004) of fatal cardiovascular events and a 7-fold higher risk (95% CI: 1-9.7; p = 0.009) of combined fatal and non-fatal cardiovascular events. CONCLUSIONS: An SEVR < 130% predicts fatal and non-fatal cardiovascular events in non-dialysis CKD patients. PMID- 30408782 TI - The Arboranan Frogs: Materials and Methods. PMID- 30408783 TI - Hospital Volume and Mortality following Diagnostic Bronchoscopy in Lung Cancer Patients: Data from a National Inpatient Database in Japan. AB - BACKGROUND: Recent advances in bronchoscopy utilizing endobronchial ultrasound (EBUS) as well as lung cancer therapy may have driven physicians to perform diagnostic bronchoscopy (DB) for high-risk patients. OBJECTIVES: The aim of this study was to clarify the relationship between hospital volume (HV) and outcomes of DB. METHODS: We collected data on inpatients with lung cancer who underwent DB from July 2010 to March 31, 2014. The annual HV of DB was classified as "very low" (<=50 cases/year), "low" (51-100 cases/year), "high" (101-300 cases/year), or "very high" (> 300 cases/year). The primary outcome was all-cause 7-day mortality after DB. Multivariable logistic regression fitted with a generalized estimation equation was performed to evaluate the association between HV and all cause 7-day mortality after DB, adjusted for patient background factors. RESULTS: We identified a total of 77,755 eligible patients in 954 hospitals. All-cause 7 day mortality was 0.5%. Compared with the low-volume group, 7-day mortality was significantly lower in the high-volume group (odds ratio [OR] = 0.69, 95% confidence interval [CI]: 0.52-0.92, p = 0.010), and a similar trend was shown in the very-high-volume group (OR = 0.67; 95% CI: 0.43-1.05, p = 0.080). Radial EBUS with the guide sheath method and EBUS-guided transbronchial needle aspiration showed a significantly lower 7-day mortality. CONCLUSIONS: All-cause 7-day mortality was inversely associated with HV. The risk of DB in patients with lung cancer should be recognized, and the exploitation of EBUS may help reduce mortality after DB. PMID- 30408784 TI - Implementation of a Carrier Screening Program in a High-Risk Undergraduate Student Population Using Digital Marketing, Online Education, and Telehealth. AB - BACKGROUND/AIMS: Access to preconception carrier screening, which provides at risk couples with more reproductive options, is critically important. To address this need in the Jewish community, genetic counselors at Emory University launched JScreen (www.jscreen.org), a national online genetic disease education and carrier screening program. To reach the preconception demographic, JScreen initiated a study evaluating the impact of marketing and education on knowledge and screening activity on college campuses. METHODS: Students at 10 universities were targeted with a marketing campaign designed for this initiative. Those who elected screening were provided pre-test video education designed for the study. Success was assessed through enrollment in testing, comparison of pre- and post education knowledge quizzes, and patient satisfaction surveys evaluating genetic counseling and the JScreen process. RESULTS: A total of 1,794 participants were enrolled. Over 99% of those screened were not pregnant. Knowledge quiz scores improved significantly post-education, and patient satisfaction was over 98%. CONCLUSIONS: Findings suggested that the use of targeted marketing helped promote preconception screening in this population. The study demonstrated that video education was effective in educating participants about benefits and limitations of testing. Also, the use of telehealth technology facilitated access to professional genetic counseling services. This study serves as a model for future public health initiatives. PMID- 30408785 TI - Health-Related Quality of Life and Depression in Women following Intrauterine Interventions in Complicated Monochorionic Twin Pregnancies. AB - INTRODUCTION: The aim of this study was to explore maternal health-related quality of life (HRQoL) and depression following intrauterine interventions in complicated monochorionic twin pregnancies at the Medical University Graz. MATERIAL AND METHODS: In a cross-sectional questionnaire survey, women with at least one liveborn infant following intrauterine intervention during 2011 and 2015 were matched with uncomplicated monochorionic and dichorionic pregnancies. All completed the 12-Item Short Form Health Survey to measure HRQoL and the Patient Health Questionnaire-9 to measure depression. Results were compared with local normative values. RESULTS: There were no differences in physical and mental HRQoL as compared to those with uncomplicated pregnancy. However, the whole study population had significantly lower HRQoL scores (p < 0.001) than the normative sample. Additionally, 11% of the whole study population experienced moderate (6.2%) or moderately severe (4.6%) depression. Women following uncomplicated dichorionic pregnancy revealed more depressive symptoms compared to women with intervention. DISCUSSION: Women with at least one surviving infant following intervention in complicated monochorionic twin pregnancy do not seem to have an impaired HRQoL as compared to women following uncomplicated monochorionic or dichorionic pregnancies. However, twin pregnancy itself appears to impair HRQoL, at least in the first 4 postnatal years. PMID- 30408787 TI - The Arboranan Frogs: Dedication. PMID- 30408786 TI - Depression Symptoms Predict Worse Clinical Response to Etanercept Treatment in Psoriasis Patients. AB - BACKGROUND/AIMS: This study aimed to investigate the predicting values of depression and anxiety symptoms for clinical response to etanercept treatment in psoriasis patients. METHODS: A total of 85 psoriasis patients who received 6 months of etanercept treatment were consecutively enrolled in this prospective cohort study. The Psoriasis Area and Severity Index (PASI) score was evaluated at month 0 (M0), M1, M3, and M6, and the corresponding PASI 75/90 response at each visit was assessed. Also, anxiety and depression symptoms were assessed by the Hospital Anxiety and Depression Scale (HADS) at M0, M1, M3, and M6. RESULTS: Depression symptoms were observed to correlate with female gender (p = 0.004), longer disease duration (p = 0.018), and higher PASI score (p < 0.001), and anxiety symptoms were seen to be associated with female gender (p = 0.017), larger psoriasis-affected body surface area (p = 0.049), and higher PASI score (p = 0.017) in psoriasis patients. After etanercept treatment, HADS-Depression (HADS D) and HADS-Anxiety (HADS-A) scores were both decreased at M1, M3, and M6 (all p < 0.001) compared with M0. Most importantly, baseline depressed patients presented with a lower PASI 75 response rate at M3 (p = 0.014) and M6 (p = 0.005), and a reduced PASI 90 response rate at M6 (p = 0.045) compared with baseline non-depressed patients. Furthermore, multivariate logistic regression analyses revealed that depression symptoms at baseline were an independent predictive factor for the lower possibility of both PASI 75 response (p = 0.048) and PASI 90 response (p = 0.048) achievements at M6 in psoriasis patients. However, no correlation of baseline anxiety symptoms with PASI 75/90 responses was observed. CONCLUSION: Depression symptoms at baseline independently predict a worse clinical response to etanercept treatment in psoriasis patients. PMID- 30408788 TI - Effects of L-Carnitine on Mineral Metabolism in the Multicentre, Randomized, Double Blind, Placebo-Controlled CARNIDIAL Trial. AB - BACKGROUND: The use of L-carnitine has been proposed in haemodialysis (HD) when deficiency is present to improve anaemia resistant to erythropoietin stimulating agent, intradialytic hypotension or cardiac failure. We tested the effects of L carnitine supplementation on parameters of chronic kidney disease-mineral bone disorder. METHODS: CARNIDIAL was a randomized, double-blinded trial having included 92 incident HD subjects for a 1-year period to receive L-carnitine versus placebo. Determinant factors of C-terminal fibroblast growth factor 23 (cFGF23) and intact FGF23 were studied including Klotho level. The L-carnitine effect on mineral metabolism was analyzed between groups by mixed linear models for repeated measurements. RESULTS: Klotho was below the lower limit of quantification (LLOQ) in 55% of the 163 samples. In multivariate analysis, cFGF23 was positively correlated with calcium and phosphate and was higher in subjects having Klotho > LLOQ. No correlation existed between Klotho and phosphate and phosphate was even higher in subjects having Klotho > LLOQ (p < 0.001). Both forms of FGF23 were not related to iron markers nor to IV iron dose. No L carnitine effect was detected on parathyroid hormone (PTH) or FGF23 during the study period where PTH slightly decreased over time, whereas FGF23 increased. But calcium and phosphate increased more in the L-carnitine group. CONCLUSION: L carnitine supplementation increased calcium and phosphate plasma concentrations with no detected downregulation effect on PTH and FGF23. (Clinical Trial 00322322, May 5, 2006). PMID- 30408789 TI - Genistein modifies hamster behavioral and expression of inflammatory factors following sub-chronic unpredictable mild stress. AB - INTRODUCTION: Previous studies have pointed to the protective role of genistein against stress adaptations despite neuromolecular mechanisms are not yet fully known. With this work, we evaluated the influence of such a phytoestrogen on hamster behavioral and molecular activities following exposure to sub-chronic unpredictable mild stress (sCUMS).

Methods: Motor behaviors of hamsters (n = 28) were analyzed using elevated plus-maze (EPM), hole board test (HB) and forced swim test (FST). In addition, neurodegeneration events were assessed with amino cupric silver stain (ACS) while expression variations of tropomyosin receptor-B kinase (TrkB), nuclear factor kappa- light-chain-enhancer of activated B1 cells (NF-kB1), and heat shock protein 70 (Hsp70) mRNAs were highlighted in limbic neuronal fields via in situ hybridization (ISH).

Conclusion: Genistein accounted for increased motor performances in EPM and HB, but reduced immobility during FST, which were correlated with diminished argyrophilic signals in some limbic neuronal fields. Contextually, up-regulated Hsp70 and TrkB mRNAs occurred in hippocampal and hypothalamic neuronal fields. Conversely, diminished NF-kB1 levels were mainly obtained in the hippocampus. Hormonal neuroprotective properties of genistein corroborating anxiolytic and antidepressant role(s) through elevated expression levels of stress proteins and trophic factors, may constitute novel therapeutic measures against emotional and stressful-related motor performances. PMID- 30408790 TI - Neoadjuvant Treatment for Borderline Resectable Pancreatic Ductal Adenocarcinoma. AB - One of the main reasons for the dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is its late diagnosis. At the time of presentation, only approximately 15-20% of all patients with PDAC are considered resectable and around 30% are considered borderline resectable. A surgical approach, which is the only curative option, is limited in borderline resectable patients by local involvement of surrounding structures. In borderline resectable pancreatic cancer (BRPC), neoadjuvant treatment regimens have been introduced with the rationale to downstage and downsize the tumor in order to enable resection and eliminate microscopic distant metastases. However, there are no official guidelines for the preoperative treatment of BRPC. In the majority of cases, patients are administered -Gemcitabine-based or FOLFIRINOX-based chemotherapy regimens with or without radiation. Radiologic restaging after neoadjuvant therapy has to be judged with caution when it comes to predict tumor response and resectability, since inflammation induced by neoadjuvant therapy may mimic solid tumor. Patients who do not show any disease progression during neoadjuvant therapy should be offered surgical exploration, since a high percentage is likely to undergo resection with negative margins (R0) and, thus, achieve improved overall survival although imaging judged it unlikely. Despite the promising new approaches of neoadjuvant treatment regimens during the last 2 decades, surgery remains the first choice if the tumor appears to be primary resectable at the time of diagnosis. At present, there are no international guidelines regarding the preoperative treatment of BRPC. Therefore, in order to standardize and adjust neoadjuvant treatment in the future, new guidelines have to be determined on the basis of upcoming prospective randomized studies. PMID- 30408791 TI - Risk Factors for Recurrence of Right Colonic Diverticulitis. AB - BACKGROUND: Right colonic diverticulitis (RCD) is more common in Asian countries than in Western countries, and the risk factors for recurrence of RCD are not fully understood. The objective of this study was to assess the risk factors for recurrence of RCD. METHODS: We analyzed 296 patients admitted for treatment of RCD in the Gachon University Gil Medical Center from December 2001 to October 2014. Gender, age, BMI, obesity, hypertension, diabetes mellitus, alcohol consumption, smoking, Hinchey classification, and hospital stay were investigated as risk factors for recurrence. RESULTS: Of the 296 patients with RCD, 31 patients recurred after conservative treatment. The median time interval between the initial episode and recurrence of diverticulitis was 10.4 months. In the univariate analysis, a high recurrence rate was observed in patients with a history of alcohol consumption, smoking, and long hospital stay. In the multivariate analysis, the recurrence rate was much higher (p < 0.001) in patients who stayed in the hospital for more than 10 days after the first attack. Smoking also elevated the recurrence rate (p = 0.011). CONCLUSION: Factors associated with recurrence of RCD may include smoking and the long hospital stay due to complexity when first diverticulitis occurs. Further prospective large scale studies are needed to draw a definite conclusion. PMID- 30408792 TI - Optimal Biopsy Protocol to Evaluate Histological Effectiveness of Proton Pump Inhibitor Therapy in Patients with Eosinophilic Esophagitis. AB - OBJECTIVE: Recent guidelines propose that both proton pump inhibitor (PPI) responders and nonresponders are included in eosinophilic esophagitis (EoE). Although multiple biopsies should be required to diagnose EoE because of patchy distribution of esophageal eosinophils, it is unclear whether multiple biopsies are required to evaluate histological effectiveness of PPI therapy. This study aimed to determine the optimal biopsy protocol after PPI therapy in patients with EoE. METHODS: Of 110 EoE patients, 22 PPI nonresponders were enrolled. Intraepithelial eosinophils were counted in areas of high density in multiple biopsy specimens after PPI therapy. The prevalence of esophageal eosinophilia and peak eosinophil counts after PPI therapy was analyzed according to the biopsy sites and endoscopic findings. Positive predictive value (PPV) was calculated according to the number of biopsies. RESULTS: Of 124 biopsies, 59 (47.6%) specimens showed esophageal eosinophilia (>=15 per high-power field). Eosinophil counts were significantly higher in specimens from the lower esophagus than in those from the upper esophagus but not in those from the middle esophagus. Prevalence of esophageal eosinophilia was 76.2, 40.9, and 24.3% in the lower, middle, and upper esophagus respectively. PPI nonresponders were diagnosed in all cases with 4 biopsy specimens obtained from the lower and middle esophagus, showing that PPV for non-effectiveness of PPI therapy was 0.910 (95% CI 0.773 1.000). The prevalence of esophageal eosinophilia and peak eosinophil counts was higher in cases with white plaques and linear furrows. CONCLUSION: Multiple biopsies should be required to evaluate histological effectiveness of PPI therapy in patients with EoE. Four biopsies from the lower and middle esophagus may be sufficient. PMID- 30408794 TI - The Arboranan Frogs: Results and Discussion. PMID- 30408793 TI - Effective Fetal Epigenetic Biomarkers for Noninvasive Fetal Trisomy 21 Detections. AB - INTRODUCTION: Recently, we identified three novel fetal-specific epigenetic DNA regions (FSERs) on chromosome 21 for detection of noninvasive fetal trisomy 21 (T21). In this study, the diagnostic accuracies of the three FSERs were assessed on a larger panel of the first-trimester pregnant women. MATERIAL AND METHODS: This study was conducted with maternal plasma collected from 167 pregnant women carrying 155 chromosomally normal and 12 T21 fetuses (10-13 gestational weeks). Accuracies of FSERs for noninvasive prenatal test of fetal T21 were estimated by the area under the receiver operator characteristic curve (AUC). RESULTS: The levels of all FSERs increased in pregnant women with T21 fetuses when compared with controls (p < 0.001 for all). The levels of the three FSERs did not differ according to maternal age, body mass index, and fetal sex at maternal blood sampling (p > 0.05 for all). In noninvasive fetal T21 detection, the AUC of FSER1, FSER2, and FSER3 were 0.859 (95% CI: 0.746-0.972), 0.919 (95% CI: 0.856 0.982), and 0.868 (95% CI: 0.746-0.990), respectively. DISCUSSION: The findings of this study suggest that all FSERs may be useful for noninvasive fetal T21 detection, regardless of maternal age, body mass index, and fetal sex. PMID- 30408795 TI - Unusual Clinical Presentation and Association of Cranial Dermoid Tumor and Tethered Cord Syndrome. AB - Tethered cord syndrome (TCS), a neurological disorder characterized by the lower settlement of the conus medullaris, is a congenital spinal disease which is caused by split cord syndrome, meningomyelocele, and spinal tumors. Cranial dermoid tumor (CDT) is a congenital benign tumor which is generally located on the midline of the cranium. Even though TCS is highly associated with spinal dermoid tumor, the relationship of CDT and TCS is unusual. We pre-sent a case with an unusual symptom of CDT, motion-dependent pain, and an uncommon togetherness with TCS. PMID- 30408796 TI - Relation between Early Over- and Undertreatment and Behavioural Problems in Preadolescent Children with Congenital Hypothyroidism. AB - OBJECTIVE: Congenital hypothyroidism (CH) per se, when not treated or undertreated, may lead to severe behavioural problems (cretinism), whereas overtreatment of CH seems associated with attention problems. DESIGN AND METHODS: For 55 CH patients, prospectively followed from birth until 11 years, parents rated the Child Behaviour Checklist and teachers the Teacher's Report Form at children's ages 6 and 11 years. We related scores regarding Attention, Delinquency, and Aggression (ADA scores, indicative for attention deficit hyperactivity syndrome, ADHD), and scores regarding Withdrawn, Anxious, Social, and Thought problems (WAST scores, indicative for autism) to the occurrence of over- and undertreatment in five age periods. Over- and undertreatment were defined as free thyroxine (fT4) concentrations above/below the range of the patient's individual fT4 steady state concentration. RESULTS: ADA scores at 6 and 11 years for patients overtreated in the period 1-3 months postnatally were higher than those for patients who were not overtreated. Patients with severe CH undertreated in the period 3-6 months postnatally had higher WAST scores at 6 and 11 years than all other patients. CONCLUSIONS: This is the first study suggesting that permanent ADHD as well as autism in CH patients at ages 6 and 11 years are the result of early overtreatment and undertreatment, respectively. PMID- 30408797 TI - A Case of Stent Under-Expansion due to Calcified Plaque Treated with Shockwave Lithoplasty. AB - We report the case of a stent under-expansion due to heavily calcified plaque treated with the shockwave lithoplasty system. A 77-year-old woman underwent coronary angiography, and intravascular ultrasound revealed stent under-expansion due to calcified plaque. Shockwave lithoplasty balloon was used to disrupt calcium deposits around the stent, thereby allowing a correct stent expansion with an excellent angiographic and intravascular ultrasound result. PMID- 30408798 TI - The Arboranan Frogs: Acknowledgements. PMID- 30408799 TI - Neutrophil, Platelets, and Eosinophil to Lymphocyte Ratios Predict Gleason Score Upgrading in Low-Risk Prostate Cancer Patients. AB - BACKGROUND: Several biochemical and clinical markers have been proposed for selecting patients for active surveillance (AS). However, some of these are expensive and not easily accessible. Moreover, currently about 30% of patients on AS harbor aggressive disease. Hence, there is an urgent need for other tools to accurately identify patients with low-risk prostate cancer (PCa). PATIENTS: We retrospectively reviewed the medical records of 260 patients who underwent radical prostatectomy and were eligible for AS according to the following criteria: clinical stage T2a or less, prostate-specific antigen level < 10 ng/mL, 2 or fewer cores involved with cancer, Gleason score (GS) <=6 grade, and prostate specific antigen density < 0.2 ng/mL/cc. METHODS: Univariate and multivariate analyses were performed to evaluate the association of patient and tumor characteristics with reclassification, defined as upstaged (pathological stage >pT2) and upgraded (GS >=7) disease. A base model (age, prostate-specific antigen, prostate volume, and clinical stage) was compared with models considering neutrophil to lymphocyte ratio (NLR) or platelets to lymphocyte ratio (PLR), monocyte to lymphocyte (MLR), and eosinophil to lymphocyte ratio (ELR). OR and 95% CI were calculated. Finally, a decision curve analysis was performed. RESULTS: Univariate and multivariate analyses showed that NLR, PLR, and ELR upgrading were significantly associated with upgrading (ORs ranging from 2.13 to 4.13), but not with upstaging except for MLR in multivariate analysis, showing a protective effect. CONCLUSION: Our results showed that NLR, PLR, and ELR are predictors of Gleason upgrading. Therefore, these inexpensive and easily available tests might be useful in the assessment of low-risk PCa, when considering patients for AS. PMID- 30408800 TI - The Impact of Cerebral Atherosclerosis According to Location on Prognosis after Coronary Artery Bypass Grafting. AB - BACKGROUND: In the previous prospective observational study, we found that cerebral atherosclerosis is an independent predictor of acute stroke after coronary artery bypass grafting (CABG). However, it is unknown whether intracranial cerebral atherosclerosis (ICAS) is important as much as extracranial cerebral atherosclerosis (ECAS) in estimating the risk of post-CABG adverse events. Extending the previous study, we aimed to investigate the immediate and long-term prognostic value of the location of cerebral atherosclerosis in CABG patients. METHODS: This follow-up study of previously reported prospective cohort included 1,367 consecutive patients who received CABG between 2004 and 2007. All patients underwent preoperative magnetic resonance angiography (MRA) to assess intracranial and ECAS, both defined by significant steno-occlusion (>=50%). Participants were classified into 4 groups according to the location of cerebral atherosclerosis: no cerebral atherosclerosis, ECAS only, ICAS only, and ECAS + ICAS. Post-CABG stroke within 14 days (immediate outcome) and mortality (long term outcome) following CABG were compared between the groups. Survival data for all participants through June 2016 were obtained from the Korean National Registry of Vital Statistics. The Cox proportional hazards model was used to estimate the hazard ratio (HR) of post-CABG stroke and mortality; patients lacking cerebral atherosclerosis were defined as the reference group. RESULTS: The median follow-up duration after CABG was 9.2 years (interquartile range 8.4 10.2 years). Of the participants, 278 (20.3%) patients had ICAS only, while 269 (19.7%) and 347 (25.4%) showed ECAS only and ECAS + ICAS, respectively, in their preoperative MRA. Having ICAS only (HR 5.07; 95% CI 1.37-18.75; p = 0.015) and having ECAS + ICAS (HR 8.43; 95% CI, 2.48-28.61; p = 0.001) independently predicted the immediate stroke, whereas being with ECAS only did not (HR 1.71; 95% CI 0.35-8.50; p = 0.509). Conversely, ICAS-only status was not independently associated with long-term mortality (HR 1.22; 95% CI 0.90-1.65; p = 0.207), whereas ECAS-only status (HR 1.42; 95% CI 1.05-1.90; p = 0.021) and ECAS + ICAS status (HR 1.58; 95% CI 1.20-2.07; p = 0.001) showed independent associations. CONCLUSIONS: Over 10 years of follow-up, cerebral atherosclerosis significantly associated with the development of adverse outcomes after CABG. The prognostic value of ICAS might be different from that of ECAS; immediate post-CABG stroke was more closely associated with ICAS, whereas there was a closer association between long-term post-CABG mortality and ECAS. PMID- 30408802 TI - The Arboranan Frogs: Remarks. PMID- 30408801 TI - Effectiveness and Safety of Intravitreal Dexamethasone Implant (Ozurdex) in Patients with Diabetic Macular Edema: A Real-World Experience. AB - INTRODUCTION: There are few real-life studies on the intravitreal 0.7-mg dexamethasone implant for the treatment of diabetic macular edema (DME) conducted in Latin America. We aimed to assess the effectiveness and safety of this implant in clinical practice. METHODS: Twenty-seven centers from Brazil and one from Argentina provided information on patients with DME treated with Ozurdex. The efficacy outcome variables were best-corrected visual acuity (BCVA) in Snellen and central retinal thickness (CRT). Safety was assessed by the elevation in intraocular pressure (IOP), occurrence of cataracts, and adverse events. RESULTS: A total of 329 eyes (both treated cases and naive eyes) from 282 patients underwent treatment. The time since diagnosis of DME ranged from 1 to 156 months. The median BCVA was 0.7 logMAR/50 letters at baseline and 0.3 logMAR/70 letters after treatment (both p < 0.001). Median CRT values decreased from 425 um at baseline to 270 um after treatment (p < 0.001). Increases in IOP of at least 10 mm Hg were observed in 7.4% of eyes, and 4% of eyes had cataract evolution. No cases of endophthalmitis were reported. CONCLUSION: These real-life results suggest that the intravitreal dexamethasone implant is effective and safe for eyes with DME. PMID- 30408805 TI - The Arboranan Frogs: Species Index. PMID- 30408804 TI - A Non-Lethal Osteogenesis Imperfecta Type II Mutation. AB - BACKGROUND: We discuss the ethical decision points in a case report that describes a novel COL1A1 mutation associated to Osteogenesis Imperfecta type II, but with a non-lethal outcome. CASE: A 33-year-old female underwent a 21-week ultrasound that revealed short bowed femurs and humeri with old fractures and bowed tibias and fibulas. Amniotic fluid testing revealed a novel COL1A1 mutation (c.1840G>A; p.Gly614Arg). OI Type II diagnosis was made. A previously reported mutation of the same gene but different locus (c.1840G>C; p.Gly614Arg) led to a lethal form of OI type II. The newborn was delivered via a cesarean delivery and intravenous bisphosphonates (Zaledronic acid) was administered every 3 months. Currently the infant is 22 months old, is growing, with mild bilateral conductive hearing loss. CONCLUSION: The unexpected clinical outcome should serve as a reminder that phenotypic variability can occur with genetic mutations. Our case shows that the diagnosis of the type of OI should be based not only on clinical findings and genetic investigations but also on the clinical course over time. PMID- 30408806 TI - MiR-202-5p Promotes M2 Polarization in Allergic Rhinitis by Targeting MATN2. AB - BACKGROUND: The aim of this study was to investigate the effect of MiR-202-5p on macrophages involved in allergic rhinitis. METHODS: Thirty allergic rhinitis patients and 10 healthy controls were recruited. Nasal lavage was utilized to collect mucosal tissues and mucus-derived macrophages. Flow cytometry was used to detect and sort type 2 macrophages, and qRT-PCR and Western blot were adopted to determine the expression of miR-202-5p and MATN2. Luciferase reporter assay and biotin-RNA pulldown were performed to testify the direct binding of miR-202-5p with MATN2. MATN2 was further overexpressed to test its effect on M2 polarization. RESULTS: miR-202-5p, which can promote M2 polarization, was highly expressed in allergic rhinitis mucosal tissues and macrophages compared with the healthy controls. MATN2 could be directly targeted by miR-202-5p and can reverse miR-202-5p-mediated M2 phenotype polarization in allergic rhinitis. CONCLUSIONS: miR-202-5p could target MATN2 to induce M2 polarization involved in allergic rhinitis. PMID- 30408803 TI - The Effects of Direct Oral Anticoagulants, Warfarin, Aspirin and Thienopyridine on the Performance of Immunochemical, Faecal, Occult Blood Tests. AB - AIM: To clarify whether antithrombotic drugs affect diagnosis using the immunochemical faecal occult blood test -(iFOBT) of colorectal neoplasia. METHODS: Using the Japan Endoscopy Database from 8 centres between 2015 and 2017, we analyzed data about patients who were iFOBT positive and had received direct oral anticoagulants (DOAC), warfarin, aspirin or thienopyridine. One-to-one matching-analogue propensity score weighted analyses were performed to compare the positive predictive value (PPV) of all neoplasms, invasive and non-invasive colorectal cancers and adenomas between drug users and non-users. All neoplasms included invasive and non-invasive colorectal cancer, and adenomas. RESULTS: We analyzed 197 DOAC users and 196 non-users, 153 warfarin users and 153 non-users, 408 aspirin users and 415 non-users, and 97 thienopyridine users and 97 non users. No significant differences were observed in the PPV for all neoplasms (56.67 vs. 50.43%), invasive cancer (4.32 vs. 3.53%), non-invasive cancer (15.58 vs. 15.56%) or adenoma (53.13 vs. 48.09%) between the DOAC user and non-user groups. No significant differences were observed in the PPV for all neoplasia, invasive and non-invasive cancer, or adenoma between warfarin, aspirin and thienopyridine use and non-users. CONCLUSIONS: DOAC, warfarin, aspirin and thienopyridine use did not decrease the PPVs of the iFOBT used to evaluate all colorectal neoplasia. PMID- 30408807 TI - The Arboranan Frogs: Appendices. PMID- 30408808 TI - Comparison of Nocturnal Cough Analysis in Healthy Subjects and in Patients with Cystic Fibrosis and Primary Ciliary Dyskinesia: A Prospective Observational Study. AB - BACKGROUND: Cough is a key symptom in patients with cystic fibrosis (CF) and primary ciliary dyskinesia (PCD). OBJECTIVE: The study objectives were to test whether cough is related to parameters reflecting their disease severity and whether CF and PCD differ in cough frequency. METHODS: In this prospective observational study, we used a microphone-based monitoring system (LEOSound(r) Monitor) to count the coughs in healthy subjects (HS) and in stable patients with CF and PCD (25 subjects per group) on 2 consecutive nights. RESULTS: The median number of coughs/h in the HS, CF, and PCD groups was 0.0, 1.3, and 0.5 on the first night and 0.0, 2.3, and 0.2 on the second night, respectively. Patients with CF and PCD coughed more than HS (p < 0.001 and p = 0.009, respectively) and CF patients coughed more than PCD patients (p = 0.023). A multivariable mixed model analysis revealed forced expiratory volume in 1 s as an independent risk factor for increased cough frequency in patients. The reliability for repeated measurements was higher for cough epochs/h than for coughs/h (intraclass correlation coefficient: 0.75 and 0.49, respectively). CONCLUSIONS: Patients with CF cough more than patients with PCD. The cough frequency in CF and PCD is associated with parameters reflecting disease severity. Cough frequency is a possible endpoint in clinical trials and cough epochs/h may be more useful than coughs/h. PMID- 30408809 TI - Effect of Cellulose Powder on Human Nasal Epithelial Cell Activity and Ciliary Beat Frequency. AB - BACKGROUND: Cellulose powder (CP) has been reported as a safe and effective complementary treatment for allergic rhinitis (AR). Currently, CP has gained increasing application for clinical management worldwide, particularly in China. However, studies focusing on the effect of CP on normal human nasal epithelial cells (hNECs) and ciliary function are lacking. Here, we aimed to explore the adverse effects of CP on the activity and ciliary function of hNECs. METHODS: We biopsied ethmoid sinus or middle turbinate tissues during surgical resection from control subjects who underwent endoscopic sinus surgery for diseases other than AR. Cells were isolated and passaged, followed by differentiation in an air liquid interface (ALI). Flow cytometry and cell viability test (cell counting kit 8) were performed to detect the cytotoxicity of CP (effects on cell proliferation) on normal hNECs. By using the ALI culture model, we investigated the effects of CP on ciliary beat frequency (CBF). RESULTS: There was a significant reduction in hNEC count at high concentrations of CP (2.5 mg/mL) at days 3 and 7 (both p < 0.05). As the concentration increased, cell death increased progressively from day 3 to day 7. However, these effects were not evident at low concentrations (0.25 mg/mL, p > 0.05). High-dose CP (2.5 mg) significantly reduced the CBF (p < 0.05). At lower concentrations (0.25-2.5 mg/mL), CP initially increased but subsequently reduced the CBF of hNECs compared with control group. CONCLUSIONS: Cytotoxicity and the suppression of ciliary beat at high concentrations justify more prudent use of CP for the management of AR. PMID- 30408810 TI - Effect of Salt Intake on the Serum Cardiotrophin-1 Levels in Chinese Adults. AB - BACKGROUND: Dietary sodium affects fluctuations in blood pressure (BP) and vascular function. Cardiotrophin-1 (CT-1), a stress-induced cytokine that belongs to the interleukin 6 family, is released by cells in response to potentially harmful stresses and plays a pivotal role in congestive heart failure, hypertension and arterial stiffness. In this study, we performed a randomized trial to confirm the effects of altered salt intake on the serum CT-1 levels in humans. METHODS: Forty-four subjects (18-65 years of age) were selected from a rural community in northern China. All subjects initially maintained a baseline period for 3 days, transitioned to a low-salt (LS) diet for 7 days (3.0 g/day of NaCl) and then a high-salt (HS) diet for an additional 7 days (18.0 g/day of NaCl). RESULTS: For the whole group, the serum CT-1 concentrations were significantly increased in the HS period compared to those of the LS period (293.50 +/- 137.70 vs. 360.40 +/- 162.83 pg/mL, p = 0.040). The serum CT-1 concentrations significantly decreased from the baseline period to the LS diet (419.91 +/- 123.50 to 256.49 +/- 109.75 pg/mL, p < 0.01) and significantly increased from the LS to HS diet (256.49 +/- 109.75 to 414.39 +/- 191.21 pg/mL, p < 0.01). These changes were observed in salt-sensitive (SS) individuals but not in salt-resistant (SR) individuals. In addition, a significant positive relationship was observed between the changes in the CT-1 concentrations and systolic BP as well as the changes in the mean arterial pressure from the LS period to the HS period (r = 0.376, p = 0.012; r = 0.311, p = 0.040). The serum CT-1 concentrations were positively correlated with the 24-h urinary sodium-to potassium (Na/K) excretion ratios during both of the LS and HS diet intervention periods in SS subjects (r = 0.621, p < 0.01), but this correlation was not evident in SR subjects (r = 0.208, p = 0.107). CONCLUSIONS: Our study indicates that variations in dietary salt intake affect the serum CT-1 levels in Chinese adults. PMID- 30408811 TI - Neonatal Glycaemia and Neurodevelopmental Outcomes: A Systematic Review and Meta Analysis. AB - BACKGROUND: Hypoglycaemia is the most common metabolic problem in neonates but there is no universally accepted threshold for safe blood glucose concentrations due to uncertainty regarding effects on neurodevelopment. OBJECTIVE: To systematically assess the association between neonatal hypoglycaemia on neurodevelopment outcomes in childhood and adolescence. METHODS: We searched MEDLINE, EMBASE, CINAHL, and PsycINFO from inception until February 2018. We included studies that reported one or more prespecified outcomes and compared children exposed to neonatal hypoglycaemia with children not exposed. Studies of neonates with congenital malformations, inherited metabolic disorders and congenital hyperinsulinism were excluded. Two authors independently extracted data using a customized form. We used ROBINS-I to assess risk of bias, GRADE for quality of evidence, and REVMAN for meta-analysis (inverse variance, fixed effects). RESULTS: 1,665 studies were screened, 61 reviewed in full, and 11 included (12 publications). In early childhood, exposure to neonatal hypoglycaemia was not associated with neurodevelopmental impairment (n = 1,657 infants; OR = 1.16, 95% CI = 0.86-1.57) but was associated with visual-motor impairment (n = 508; OR = 3.46, 95% CI = 1.13-10.57) and executive dysfunction (n = 463; OR = 2.50, 95% CI = 1.20-5.22). In mid-childhood, neonatal hypoglycaemia was associated with neurodevelopmental impairment (n = 54; OR = 3.62, 95% CI = 1.05-12.42) and low literacy (n = 1,395; OR = 2.04, 95% CI = 1.20-3.47) and numeracy (n = 1,395; OR = 2.04, 95% CI = 1.21-3.44). No data were available for adolescents. CONCLUSIONS: Neonatal hypoglycaemia may have important long-lasting adverse effects on neurodevelopment that may become apparent at later ages. Carefully designed randomized trials are required to determine the optimal management of neonates at risk of hypoglycaemia with long-term follow-up at least to school age. PMID- 30408813 TI - Gout in Aotearoa New Zealand: the equity crisis continues in plain sight. PMID- 30408812 TI - Rural matters. PMID- 30408814 TI - A prospective audit of the 10-year outcomes from low dose-rate brachytherapy for early stage prostate cancer. AB - AIM: New Zealand men diagnosed with early stage prostate cancer need to know what outcomes to expect from management options. METHODS: Between 2001 and 2016, 951 men were treated with low dose-rate brachytherapy (permanent iodine-125 seed implantation) by the Wellington Prostate Brachytherapy Group based at Southern Cross Hospital, Wellington. At follow up after treatment, men had their PSA measured and were scored for urinary, bowel and sexual side effects. RESULTS: Median follow-up of men was 7.9 years (range 2.0-16.3 years). Ten-year PSA control was 95% for the 551 men with low-risk prostate cancer and 82% for the 400 men with intermediate-risk prostate cancer. Adverse effects were generally minor and short-term only. Temporary urinary obstruction developed soon after the implant in 2.6% men, and the 10-year cumulative risk of urethral stricture was 2.6%. Erectile dysfunction developed in 29% men, two-thirds of whom had a good response to a PDE5 inhibitor. Most men returned to a normal routine within four days of the implant. CONCLUSION: LDR brachytherapy is a highly effective low impact treatment option for New Zealand men with early stage prostate cancer. PMID- 30408815 TI - Privacy protection for health information research in New Zealand district health boards. AB - AIM: To examine the practices used by New Zealand's 20 district health boards (DHBs) to protect patient privacy when patient information is used for research, and particularly practices for de-identifying information. METHOD: An e-mailed questionnaire survey, using New Zealand's Official Information Act to request information on the policies and practices of each DHB. RESULTS: 19/20 DHBs (95%) responded to the survey, one of which reported that it did not provide patient information for research. 18/18 (100%) of the DHBs that reported providing patient information for research required the project to have ethics approval. 18/18 (100%) of the DHBs that offered patient data for research also required individual patient consent and/or de-identification of the information before it was used for research. 14/18 DHBs (78%) deidentified data before releasing it for research, 8/18 DHBs (48%) sought individual patient consent before releasing data for research, and 5/18 (28%) used both methods. Other measures to protect privacy included confidentiality agreements, encryption and cybersecurity procedures. CONCLUSION: Our findings show DHBs self-report that they have sufficient measures in place to protect privacy when patient information is used for research. However, these measures need to be continuously evaluated against rapidly evolving international practices and technological developments. PMID- 30408816 TI - Te Wero tonu-the challenge continues: Maori access to medicines 2006/07-2012/13 update. AB - AIM: Analysis of dispensings of prescription medicines in New Zealand in 2006/07 reported large inequities between Maori and non-Maori. This present study has now updated the earlier work by describing variations in disease burden-adjusted medicines access by ethnicity in 2012/13, and changes over time. METHOD: The update has linked prescription medicine data with burden of disease estimates by ethnicity for 2012/13 and comparing with 2006/07. This has re-examined the shortfall in prescriptions for Maori vs non-Maori adjusting for age, population and burden of disease (ie, health loss, in disability-adjusted life years (DALYs)). RESULTS: After adjusting for age, population and burden of disease, large inequalities still existed for Maori compared with non-Maori, with generally no improvement over the six years. In 2012/13, Maori had 41% lower dispensings overall than non-Maori; this was nominally worse compared with the 37% relative gap in 2006/07, but the trend was not statistically significant. Many complexities and limitations hamper valid interpretation, but large inequities in access and persistence, across many therapeutic groups, remain. The full University of Auckland report details these inequities. CONCLUSION: Large inequities in medicines access for Maori continue. Inequities in access are unacceptable, their causes likely complex and entrenched; we believe they need deeper understanding of systems and barriers, pragmatic ways to monitor outcomes, and an all-of-sector approach and beyond. PHARMAC has committed to strategic action to eliminate inequities in access to medicines by 2025, recognising it needs partners to drive the necessary change. Kei a tatou tonu katoa te wero kia mahikaha, kia mahi tino mohio, me te mahitahi (The challenge continues for us to work harder, work smarter, and work together); everyone in the health sector has a role. PMID- 30408817 TI - Incidence of motor neurone disease within MidCentral Region, New Zealand. AB - AIM: The aims of this observational study were firstly to calculate annual incidence of motor neurone disease (MND) within the midcentral region of New Zealand and secondly to characterise the demographics of this patient group, including age, sex, ethnicity and geographical distribution within the region. METHOD: Patients with a new diagnosis of MND over a five-year period (1 February 2013-31 January 2018) were identified via a clinical coding search of all outpatient and inpatient encounters. Records were then individually screened to confirm a new diagnosis of MND via both clinical (confirmation by a neurologist) and neurophysiological (needle electromyography) criteria. RESULTS: Twenty-five new diagnoses of MND were identified. The incidence was 2.9 per 100,000/year. Mean and median age at diagnosis were 69 and 72 respectively (range 38-84), and the male:female ratio was 13:12. Of the 25 identified cases, 21 (84%) were of European descent, two (8%) of Maori descent, and two of undetermined ethnicity. DISCUSSION: The findings from this study (incidence of 2.9/100,000) are in concordance with the higher incidence of MND found in other regions of New Zealand compared with other areas of the world. Further studies are warranted to investigate incidence in other regions, thereby building the foundations for the study of genetic and environmental factors. PMID- 30408818 TI - Antidepressant prescribing in New Zealand between 2008 and 2015. AB - AIM: To examine antidepressant prescribing trends in New Zealand adults from 2008 2015. METHODS: Antidepressant prescribing data was sourced via the Ministry of Health. Data were examined by year, type of drug, ethnicity, gender, age and location of district health board. RESULTS: All individuals dispensed an antidepressant in New Zealand were included. In 2015, 12.6% of all New Zealanders were prescribed an antidepressant (16% of females and 9% of males) an increase of 21% from 2008. The largest increase in drug classes were venlafaxine and tetracyclic antidepressants. The largest class of drugs prescribed were SSRIs, which made up 57% of the total. Europeans were the most likely to receive antidepressants at 15.7%, but increases were seen across all ethnic categories. The highest users were older European females at 22.8%. CONCLUSIONS: Antidepressant prescribing rates continue to increase in New Zealand although this rate of increase is slowing. The highest users were European women, particularly those age 65 and older. PMID- 30408819 TI - Distress in informal carers of the elderly in New Zealand. AB - AIMS: Informal care, which is unpaid and often provided by family and friends, is the primary source of aged care in New Zealand. In addition to financial costs there are known psychological costs of being a carer, including poor mental health. METHODS: This research aimed to interview a group of New Zealand carers and describe their rates of depression and anxiety, their motivations for providing care, costs of care and their experience of aggression. Interviews used standardised questions and were conducted over the phone. RESULTS: Results are reported from interviews of 48 carers and suggest this group have elevated symptoms of depression and anxiety. Most of the carers are partners or children of the carees and likely do the caring out of love. Unpaid family carers experience low levels of aggression. Carers reported personal and social restriction, and physical and emotional health the most burdensome aspect of being a carer. CONCLUSIONS: Carers of the elderly in New Zealand show elevated levels of distress. Higher levels of emotional support are needed for New Zealand carers. If the health system continues to rely on unpaid carers more should be done to support them. PMID- 30408820 TI - Proposal for a National Interprofessional School of Rural Health. AB - Shortages of health professionals persist in much of rural New Zealand despite a range of targeted university and professional college initiatives. In response to this a collective of universities, professional colleges and sector groups have put a proposal to Government for a National Interprofessional School of Rural Health. If adopted, this proposal would embed rural health professional education and research in rural communities around New Zealand, empowering them to organise the education that occurs in their community, in a coherent and coordinated way. What is being proposed is not a new or separate education provider but rather an 'enabling body' that would lever off the expertise and resources of the existing tertiary institutions, colleges and rural communities. It calls for an 'all of systems' approach that encompasses all the health professions that practise in rural areas, undergraduate education and postgraduate training, and rural health research. Although modelled on successful Australian rural clinical schools, it is a uniquely New Zealand solution that is cognisant of the New Zealand context and resources. PMID- 30408821 TI - Mana Tu: a whanau ora approach to type 2 diabetes. AB - In 2017, the National Hauora Coalition, a Maori-led Primary Health Organisation (PHO), was awarded a Long-Term Conditions Partnership Research grant to test the effectiveness of Mana Tu: a whanau ora approach to type 2 diabetes. With moves to replicate aspects of it in programmes around New Zealand, it is timely to describe the rationale for Mana Tu and the key components of its unique model of care. Mana Tu was developed in response to current ethnic and social inequities in type 2 diabetes rates, outcomes and wider determinants. It attempts to address various system, service and patient factors that impact on the whanau's ability to 'mana tu' or 'stand with authority' when living with a long-term condition. Results, including clinical, implementation and cost-effectiveness data, will be collected and analysed over the next two years. PMID- 30408822 TI - Surgical management of self-inflicted facial gunshot wounds. PMID- 30408823 TI - A population-based study of the diabetes paradox in stress cardiomyopathy. PMID- 30408824 TI - Do interns publish findings of their scholarly research projects? PMID- 30408825 TI - Development of a single-tube nested PCR-lateral flow biosensor assay for rapid and accurate detection of Alternaria panax Whetz. AB - Alternaria panax Whetz causes one of the most commonly occurring and serious diseases in ginseng cultivation, and may cause significant production and economic losses in the ginseng industry. Rapid, early, and accurate identification of Alternaria panax Whetz is an essential prerequisite for the effective prevention and control of further infection spread. In this work, a rapid and accurate molecular diagnostic method, a single-tube nested PCR-lateral flow biosensor assay (STNPCR-LFBA), was developed for rapid identification of Alternaria panax Whetz. The STNPCR-LFBA was 100 times more sensitive than the traditional PCR-LFBA. Besides that, the PCR product was checked by a lateral flow biosensor assay, which provided a basis for the migration of the detection technology to a point-of-care test (POCT) format. STNPCR-LFBA was specific to Alternaria panax Whetz, and no cross-reactions were observed in other non-target samples; the limit of detection was up to 0.01 pg of Alternaria panax Whetz genomic DNA. STNPCR-LFBA could also be used for specific identification of Alternaria panax Whetz in real samples. STNPCR-LFBA is useful for identifying Alternaria panax Whetz due to its rapidity, accuracy, and simple manipulation. PMID- 30408826 TI - Phylogenetic, ecological and biomechanical constraints on larval form: A comparative morphological analysis of barnacle nauplii. AB - Barnacle naupliar larvae are differentiated from other zooplankton by their unique pair of frontal lateral horns, frontal filaments, and a pear-shaped cephalic shield. Their morphology impose constraints on their ecological functions and reflect their evolutionary history. To explore the potential functional basis underlying the similarities and differences in barnacle larval form, we conducted a meta-analysis on the shape of the barnacle nauplii's cephalic shield and examined its relation to larval size, trophic mode, pelagic larval duration and habitat. Nauplii cephalic shield morphology of 102 species were quantified with normalized elliptic Fourier analysis. Most of the species were distributed around the center of the morphospace but a few extreme groups occupied the periphery: nauplii that were large and lecithotrophic. Subsequent principal component regression analyses showed that larval size was a good predictor of the first shape variations axis (aspect ratio). After allometry adjustment, nauplii from different trophic modes differentiated along the second axis of the major shape variations (relative frontal horn length). Habitat was a poor predictor of variations in naupliar body form, but it could be used to differentiate extreme morphology groups from other nauplii. Our result suggests that size-related biomechanical or developmental constraints and feeding requirements are important in shaping the evolution of the naupliar body form. Within the limitations of these functional constraints, habitat drives the divergence of extreme morphology groups from the majority of species. Our comparative morphometrics analysis demonstrated how variations in larval body form can be quantitatively linked to the functional needs that constrain or drive their diversity, and inform further empirical experiments on larval functional morphology. PMID- 30408827 TI - Increasing proportions of HIV-1 non-B subtypes and of NNRTI resistance between 2013 and 2016 in Germany: Results from the national molecular surveillance of new HIV-diagnoses. AB - BACKGROUND: Molecular surveillance of newly diagnosed HIV-infections is important for tracking trends in circulating HIV-variants, including those with transmitted drug resistances (TDR) to sustain ART efficacy. METHODS: Dried serum spots (DSS) are received together with the statutory notification of a new diagnosis. 'Recent infections' (<155 days) classified by a 'recent infection test algorithm' (BED CEIA and clinical data) are genotyped in HIV-protease (PR), reverse transcriptase (RT) and integrase (INT) to determine the HIV-1 subtype, to calculate prevalence and trends of TDR, to predict baseline susceptibility and to identify potential transmission clusters for resistant variants. RESULTS: Between January 2013 and December 2016, 1,885 recent infections were analysed regarding the PR/RT genomic region, with 43.5% of these also being subjected to the analysis of INT. The proportion of HIV-1 non-B viruses (31.3%; 591/1,885) increased from 21.6% to 36.0%, particularly the subtypes A (5.0% to 8.3%) and C (3.2% to 7.7%; all ptrends < 0.01). The subtype A increment is mainly due to transmissions within men who have sex with men (MSM) while subtype C transmissions are associated with heterosexuals and people who inject drugs. The prevalence of TDR was stable at 11.0% (208/1,885) over the study period. Resistances to nucleotide RT inhibitors (NRTI) and PR inhibitors (PI) were 4.5% and 3.2%, respectively, without identifiable trends. In contrast, resistances to non-NRTIs (NNRTI, 4.7%) doubled between 2014 and 2016 from 3.2% to 6.4% (ptrend = 0.02) mainly due to the K103N mutation (from 1.7% to 4.1%; ptrend = 0.03) predominantly detected in recently infected German MSM not linked to transmission clusters. Transmitted INSTI mutations were present in only one case (T66I) and resistance to dolutegravir was not identified at all. Reduced susceptibility to recommended first-line therapies was low with 1.0% for PIs, 1.3% for NRTIs and 0.7% for INSTIs, but high for the NNRTIs efavirence (4.9%) and rilpivirine (6.0%) due to the K103N mutation and the polymorphic mutation E138A. These trends in therapy-naive individuals impact current first-line regimens and require awareness and vigilant surveillance. PMID- 30408829 TI - [Test Your Knowledge]. PMID- 30408828 TI - Lethal and behavioral effects of synthetic and organic insecticides on Spodoptera exigua and its predator Podisus maculiventris. AB - BACKGROUND: The beet armyworm, Spodoptera exigua (Lepidoptera: Noctuidae), is a key insect pest of edible vegetables around the world and it is resistant to insecticide of different classes. Insecticides that are effective to this pest and selective to predator stinkbugs are required for the integrated management of S. exigua. METHODS: The toxicity of four commercial insecticide formulations azadirachtin + pyrethrin, spinosad, pyrethrin and chlorantraniliprole was tested on the target pest and their side effect were evaluated on the spined soldier bug, Podisus maculiventris (Heteroptera: Pentatomidae) through different bioassays. RESULTS: Spinosad and chlorantraniliprole were more toxic to S. exigua than to the predator P. maculiventris but opposite results were obtained for pyrethrin and azadirachtin + pyrethrin in contact toxicity bioassay. Chlorantraniliprole was the most toxic to S. exigua in oral toxicity bioassay, followed by spinosad, pyrethrin and azadirachtin + pyrethrin. Spinosad in oral toxicity bioassay was the most toxic to P. maculiventris, followed by pyrethrin, azadirachtin + pyrethrin and chlorantraniliprole. Spinosad caused irritability to the predator while pyrethrin to the pest. The insecticide repellency was not observed over the tested insect species. The synthetic insecticide chlorantraniliprole was less toxic than the natural pyrethrin, azadirachtin + pyrethrin and spinosad to the predator. CONCLUSIONS: This work provides useful information on the combination of commercial insecticides with the predator P. maculiventris to controlling S. exigua in integrated pest management (IPM) programs. PMID- 30408830 TI - [Strategies to Overcome Acquired Resistance to EGFR-TKI Therapy Based on T790M Specific Substances using Osimertinib as an Example]. AB - Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) are widely used in non-small cell lung cancer patients harboring activating EGFR mutations. However, resistance mechanisms, particularly the T790 M mutation, hamper longer-term therapeutic success of first and second generation EGFR-TKIs. To address this unmet medical need, EGFR-TKIs of the third generation are under clinical development. Relevant clinical efficacy with mainly mild to moderate class-specific side effects has been shown for third-generation EGFR-TKIs. Molecular testing is of major importance in deciding for treatment with third generation EGFR-TKIs. This article elucidates the developmental state of third generation EGFR-TKIs with its focus on Osimertinib, the first and currently the only compound in this class which is approved in Germany. Additionally, the medical importance of molecular diagnosis using tumor tissue and circulating tumor DNA is discussed. PMID- 30408831 TI - [Are Small Airways the Key to Understanding Pathophysiology and Treatment Efficacy in Chronic Obstructive Pulmonary Diseases?] AB - This review presents updated information on small airways in the pathogenesis of chronic obstructive respiratory diseases. The lungs have a branching structure, segmentally divided from trachea down to the alveoli (generations 1 - 23). Airways can be divided into a conducting (generations 1 - 16) and a respiratory zone (generations 17 - 23). Conducting zone is mainly for air transportation, respiratory zone for gas exchange. Increasing attention has been directed to the role of small airways in chronic obstructive respiratory diseases. The small conducting airways < 2 mm in diameter are the major site of airway inflammation and obstruction in COPD. It has been shown that the last generation of small conducting airways, the terminal bronchioles, are significantly destroyed in patients with very severe COPD. At what stage in the development of COPD the loss of small airways occurs is not exactly known. The small airways represent the most important target for deposition of inhaled therapeutic particles. Currently there is no gold standard for detecting small airway dysfunction. Techniques such as spirometry and body plethysmography can provide information on air trapping. High-resolution CT enables the diagnosis of pulmonary emphysema and diseases of the large airways. Only micro-CT imaging offers the option to describe microstructure of terminal bronchioles. Impulse oscillometry, gas washout techniques and analysis of exhaled nitric oxide are diagnostic tools which have to be validated for diagnosis and treatment response of small airway diseases. PMID- 30408832 TI - Serum Vitamin D Binding Protein Level Associated with Metabolic Cardiovascular Risk Factors in Women with the Polycystic Ovary Syndrome. AB - The objective of the study was to measure the levels of 25-hydroxyvitamin D [25(OH)D] and vitamin D binding protein (VDBP) and assess their relationships with cardiovascular risk factors in women with the polycystic ovary syndrome (PCOS). A group of 267 women, aged 20-35 years (24.7 +/- 4.9): 167 with PCOS and 100 healthy women were divided according to body mass index. Biochemical and hormonal parameters were measured. Free and bioavailable 25(OH)D were calculated using the mathematical equations. The percentage of body fat and visceral fat deposit were assessed by DXA. In the normal weight control group total, free, bioavailable 25(OH)D (p<0.001 for all) were significantly higher than in its overweight/obese counterpart, while VDBP levels were comparable. In PCOS women total 25(OH)D (p<0.001), and VDBP (p -0.006) were lower in the overweight/obese subgroups than in the normal weight ones. In both groups serum VDBP levels correlated negatively with serum insulin and positively with sex hormone binding globulin. In PCOS group, in contrast to control group, VDPB was negatively correlated with abdominal fat deposit, BMI, fasting glucose and positively with HDL. Despite lower total 25(OH)D in obese PCOS women, all women with PCOS (lean and obese) had comparable free and bioavailable 25(OH)D, which might be a result of concomitantly lowered serum VDBP levels in obese PCOS women. VDBP might play important role in the regulation of availability of active fractions of 25(OH)D in PCOS women. VDBP seems to be associated with cardiovascular risk factors such as BMI, waist circumference, visceral fat, and fasting serum insulin in women with PCOS. PMID- 30408833 TI - [A rare differential diagnosis of tonsillopharyngitis]. PMID- 30408834 TI - [Sexual Abuse of Minors: Development in Light Field Statistics and Dark Field Research Since 1953 and Implications For The Health Care System]. AB - Data on sexual abuse of minors can be obtained from official Police Crime Statistics and from dark field surveys. This article deals with the longitudinal development of the offense in the last 63 years in Germany. The criminal offenses of sexual abuse of children according to S 176 StGB (German Criminal Code) in the Police Crime Statistics show a decrease of frequency in the reporting period (1953-2016). The empirical results of the dark field research are inconsistent, but partially show a decline in frequency. In this study, the importance of these findings for prevention and health policy is discussed. PMID- 30408835 TI - Treatment regimens and outcomes in severe and moderate haemophilia A in the UK: The THUNDER study. AB - INTRODUCTION: The THUNDER study provides an analysis of treatment patterns and outcomes in UK patients with severe or moderate haemophilia A (SHA/MHA) in 2015. METHODS: Patients with SHA or MHA registered with the UK National Haemophilia Database (NHD) were segregated by severity, inhibitor status and age. Haemophilia joint health score (HJHS) was derived from NHD records and treatment regimen and annualized bleed/joint-bleed rate (ABR/AJBR) from Haemtrack (HT) in HT-compliant patients. RESULTS: We report 1810 patients with SHA and 864 with MHA. Prophylaxis was used in 94.9% (n = 130/137) of HT-compliant children <12 years with SHA, falling to 74.1% (n = 123/166) aged >=40 years. Median ABR increased with age (1.0, IQR 0.0-5.0, <12 years; 3.0 IQR, 1.0-8.0, >=40 years). Inhibitors were present in 159 (8.8%) SHA and 34 (3.9%) MHA. Median ABR increased from 2.0 (<12 years) to 21.0 (>=40 years) in SHA inhibitor patients using prophylaxis. Prophylaxis was used by 68.8% of HT-compliant MHA patients (n = 106) (median FVIII baseline 0.01 IU/mL) associated with a median (IQR) ABR of 3.0 (1.0-7.0). Median HJHS (n = 453) increased with age in SHA and MHA. Median (IQR) HJHS was higher in SHA inhibitor (17.0, 0.0-64.5) than non- or past inhibitor patients (7.0, 0.0-23.0). CONCLUSIONS: Increasing ABR with age persists despite current prophylaxis regimens. SHA and MHA had similar ABR/AJBR and HJHS, leading to a suspicion that a subgroup of MHA may be relatively undertreated. More intensive prophylaxis may improve outcomes, but this requires further study. PMID- 30408836 TI - Evaluation of endogenous urinary biomarkers for indirect detection of urine adulteration attempts by five different chemical adulterants in mass spectrometry methods. AB - Reliable detection of urine adulteration attempts to circumvent positive drug testing represents a critical step for laboratories in abstinence control settings. An ideal workflow for high-throughput testing would involve simultaneous detection of adulteration attempts in the same run with drug detection. Monitoring of degraded or oxidized endogenous urinary compounds as indirect markers has been previously evaluated for that purpose exemplified for the adulterant potassium nitrite (KNO2 ). Fifteen, previously identified endogenous markers should now be evaluated for their general applicability to detect adulteration attempts for the adulterants hypochlorite-based bleach (NaOCl), peroxidase and peroxide (H2 O2 ), pyridinium chlorochromate (PCC), and iodine (I2 ). Initial experiments revealed similar results for the tested adulterants regarding degradation of indolylacryloylglycine (IAG), uric acid (UA), or UA derivatives. 5-Hydroxyisourate (HIU), the oxidation product of UA, was however only formed by KNO2 , PCC, and H2 O2 . Amino acids showed larger adulterant-dependent differences. All reactions were shown to be influenced by the adulterant concentration and the urinary pH with large variances depending on compound and adulterant. Except for HIU/PCC, all markers were stable within +/- 30% variation for all adulterants at -20 degrees C. Receiver operating characteristics indicated best sensitivity and specificity over all adulterants for IAG (specificity 0.9, sensitivity 1.0) and UA (specificity 1.0, sensitivity 0.9). HIU gave best results for KNO2 , PCC, and H2 O2 and N-acetylneuraminic acid for PCC and H2 O2 , respectively. When integrating a limited number of targets into existing screening methods, monitoring of UA, IAG, N-acetylneuraminic acid, and HIU is recommended. PMID- 30408838 TI - Analytical considerations for (un)-targeted metabolomic studies with special focus on forensic applications. AB - Over the past few years, the interest in metabolomics has increased in various fields including forensic toxicology. Forensic analysis typically requires a high degree of accuracy, which is often a problem in metabolomics applications. We aimed for a systematic evaluation of different analytical considerations of a metabolomics workflow allowing a targeted approach within an untargeted setup. Samples with 69 metabolites from different chemical classes were qualitatively and quantitatively analyzed on a high resolution quadrupole time of flight mass spectrometer coupled to liquid chromatography (UHPLC-QTOF). Three issues were addressed: (a) Two different approaches on "blind matrix" a simulated body fluid (SBF) and plasma-filtrate, were tested for calibration samples; (b) comparison of two different HPLC columns, reverse-phase (RP) and hydrophilic interaction chromatography (HILIC); and (c) comparison of three different acquisition modes (TOF-MS, information dependent data acquisition (IDA), and sequential window acquisition of all theoretical fragment-ion spectra (SWATH). Samples were measured repeatedly for method comparison based on sensitivity, accuracy, precision, and detection robustness. The blind matrices showed similar accuracy for most analytes, while SBF provided an easier preparation with satisfying results. To cover a wide part of the human metabolome, a combination of RP and HILIC showed the best results. The different scan modes performed equally regarding metabolite quantification while TOF-MS was more sensitive but lacked MS/MS spectra generation. IDA and SWATH files were aligned to various databases where IDA showed good MS/MS spectra matches. SWATH seemed to be beneficial in detection rate but was incompatible with many important software tools in metabolomics. PMID- 30408839 TI - Information is the key to successful participation for patients receiving surgery for upper gastrointestinal cancer. AB - Fast-track programmes are aimed at improving perioperative care. The purpose of this study was to identify and explore patient participation among patients who had surgery for liver, bile duct or pancreatic cancer and followed a fast-track programme. A total of 116 questionnaires to investigate patient participation were analysed. Information was important for the patients, as was having the opportunity to ask questions and express personal views. The results showed differences by sex; men responded to a greater extent that they did not want to make decisions as a patient (p = 0.044) and that they had been motivated to take more responsibility for their future health (p = 0.011). Patients with pancreatic cancer discussed treatment goals with doctors to a greater extent than did patients with liver cancer (p = 0.041). Half of the patients perceived that they had not been involved in their care planning after discharge but had a desired to be involved. This seems to be an important point to improve in future care, and also that professionals should be aware of patients' needs for information and participation, especially at discharge. PMID- 30408840 TI - Severe acquired von Willebrand syndrome secondary to systemic lupus erythematosus. PMID- 30408841 TI - Discharge from hospital - a national survey of transition to out-patient care. AB - INTRODUCTION: Despite a generally decreased length of stay in Swedish hospitals, an increasing delay of discharge has been observed among patients with long-term care need. AIM: Identify challenges and opportunities in the transition of patients between hospitals and out-patient care. METHOD: Data were obtained from national registers on patients discharged from hospitals in 2014, interviews with public care authorities, and a systematic literature review. RESULTS: A total of 1 121 823 persons were discharged from Swedish hospitals in 2014. Of all discharged patients, 334 420 (30%) was in need of further out-patient medical care while 221 221 (20%) needed social services. Among these discharged patients, 53 763 (5%) needed both medical care and social services. In this group of frail persons (primarily females 80 years or older), 25 760 (48%) were readmitted to hospital within 30 days from the discharge. Main reported challenges in the transition were as follows: a decreasing number of beds in hospitals and nursing homes, lack of staff with proper education, and problems in transfer of information between caregivers. To solve these problems, respondents reported some new approaches: extensive initial home services after discharge, out-patient care organised by both municipalities and county councils, local follow-up of patient data as well as an emphasis on collaboration between caregivers. The literature reported ambiguous results about effects of single interventions at discharge. However, evidence suggests that the number of readmissions to hospital may be reduced by combining several interventions before discharge (individual planning, geriatric assessment, and patient education) with follow-up after discharge. CONCLUSION: Since many frail patients are readmitted to hospital within 30 days after discharge, Swedish out-patient care may need new working methods in order to promote a coherent care. Further, multi-component interventions at discharge, including follow-up after discharge, may prevent unintended readmissions. PMID- 30408842 TI - Incubation optimizes the promoting effects of rewards on creativity. AB - We tested the incubation effect on promoting problem-solving insight in a "test incubation-retest" procedure in different groups receiving a reward notification (RN) before or after the incubation phase, or no RN. Only RN given before incubation significantly promoted creative performance, implying that incubation may help optimize the promoting effects of reward on creativity. PMID- 30408843 TI - The impact of the peer review of literature search strategies in support of rapid review reports. AB - OBJECTIVE: The objective of this study was to investigate the impact of the peer review of literature search strategies prepared in support of rapid reviews. METHODS: A sample of 200 CADTH rapid reviews was selected. For each rapid review meeting the inclusion criteria, the pre-peer-reviewed and corresponding post-peer reviewed search strategies were run, and the search results were compared. Bibliographic records retrieved solely by the post-peer-reviewed search strategy and included in the rapid review report were identified as representing "included studies." The publication type of each included study was determined, and the attributes of the corresponding record were analyzed to determine the reason for its retrieval by the post-peer-reviewed search. RESULTS: The peer review of search strategies resulted in the retrieval of one or more additional records for 75% of the searches investigated, but only a small proportion of these records (4%) represented included studies. The main publication types of the included studies were nonrandomized studies (60%) and narrative reviews (20%). The principal changes to search strategies that resulted in the retrieval of additional included studies were the inclusion of more keywords or subject headings or a change in the way concepts were combined. CONCLUSIONS: The peer review of literature search strategies aids in the retrieval of relevant records particularly those representing nonrandomized studies. The scrutiny of keywords, subject headings, and the relation between search concepts are key components of the peer review process. PMID- 30408844 TI - Green tea intake and risk of incident kidney stones: Prospective cohort studies in middle-aged and elderly Chinese individuals. AB - OBJECTIVES: To investigate the association between green tea intake and incident stones in two large prospective cohorts. METHODS: We examined self-reported incident kidney stone risk in the Shanghai Men's Health Study (n = 58 054; baseline age 40-74 years) and the Shanghai Women's Health Study (n = 69 166; baseline age 40-70 years). Information on the stone history and tea intake was collected by in-person surveys. Multivariable Cox proportional hazards models were adjusted for baseline demographic variables, medical history and dietary intakes including non-tea oxalate from a validated food frequency questionnaire. RESULTS: During 319 211 and 696 950 person-years of follow up, respectively, 1202 men and 1451 women reported incident stones. Approximately two-thirds of men and one-quarter of women were tea drinkers at baseline, of whom green tea was the primary type consumed (95% in men, 88% in women). Tea drinkers (men: hazard ratio 0.78, 95% confidence interval 0.69-0.88; women: hazard ratio 0.8, 95% confidence interval 0.77-0.98) and specifically green tea drinkers (men: hazard ratio 0.78, 95% confidence interval 0.69-0.88; women: hazard ratio 0.84, 95% confidence interval 0.74-0.95) had lower incident risk than never/former drinkers. Compared with never/former drinkers, a stronger dose-response trend was observed for the amount of dried tea leaf consumed/month by men (hazard ratiohighest category 0.67, 95% confidence interval 0.56-0.80, Ptrend < 0.001) than by women (hazard ratiohighest category 0.87, 95% confidence interval 0.70-1.08, Ptrend = 0.041). CONCLUSIONS: Green tea intake is associated with a lower risk of incident kidney stones, and the benefit is observed more strongly among men. PMID- 30408845 TI - Phytochemical analysis of Ononis arvensis L. by liquid chromatography coupled with mass spectrometry. AB - Ononis arvensis L. can be found overall in Europe and is used to treat infections of the urinary tract and skin diseases in ethnopharmacology. Flavonoids, hydroxycinnamic acids, oxycoumarin scopoletin and scopolin, phytosterols, lectins and some selected isoflavonoids were identified in O. arvensis till date; however, there is a lack of the detailed investigation of the isoflavonoid profile of the plant. With the application of high-resolution tandem mass spectrometry, the fragmentation patterns of isoflavonoid derivatives found in O. arvensis roots and aerial parts were investigated and discussed. Isoflavonoid glucosides, glucoside malonates, aglycones and beta amino acid derivatives were characterized, among which homoproline isoflavonoid glucoside esters were described for the first time. Besides the known isoflavonoid aglycones described earlier in other Ononis species, two 2'-methoxy isoflavonoid derivatives were detected. The presence of licoagroside B was verified and its structure was also corroborated by NMR experiments. Altogether, the high-resolution fragmentation pattern of 47 isoflavonoids and glycosides are presented and their relative quantity in the roots and the aerial parts can be evaluated. Based on this information, the chemotaxonomic relation of Ononis species and the biosynthesis of their compounds could be comprehended to a greater depth. PMID- 30408846 TI - In search of a good fit: CPAP therapy mask selection for obstructive sleep apnoea. PMID- 30408847 TI - Editorial Comment to Hypertension and diabetes mellitus are not associated with worse renal functional outcome after partial nephrectomy in patients with normal baseline kidney function. PMID- 30408848 TI - Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data. AB - INTRODUCTION: Concizumab enhances thrombin generation (TG) potential in haemophilia patients by inhibiting tissue factor pathway inhibitor (TFPI). In EXPLORER3 (phase 1b), a dose-dependent pharmacokinetic/pharmacodynamic (PK/PD) relationship was confirmed between concizumab dose, free TFPI and TG potential. AIM: Determine the association between concizumab exposure, PD markers (free TFPI; peak TG) and bleeding episodes to establish the minimum concizumab concentration for achieving sufficient efficacy. METHODS: Free TFPI predictions were generated using an estimated concizumab-free TFPI exposure-response (Emax ) model based on concizumab phase 1/1b data for which simultaneously collected concizumab and free TFPI samples were available. Concizumab concentration at the time of a bleed was predicted using a PK model, based on available data for concizumab doses >50 MUg/kg to <=9 mg/kg. Peak TG vs concizumab concentration analyses and an Emax model were constructed based on EXPLORER3 observations. RESULTS: The Emax model showed a tight PK/PD relationship between concizumab exposure and free TFPI; free TFPI decreased with increasing concizumab concentration. A strong correlation between concizumab concentration and peak TG was observed; concizumab >100 ng/mL re-established TG potential to within the normal reference range. Estimated EC50 values for the identified concizumab-free TFPI and concizumab-TG potential models were very similar, supporting free TFPI as an important biomarker. A correlation between bleeding episode frequency and concizumab concentration was indicated; patients with a concizumab concentration >100 ng/mL experienced less frequent bleeding. The PK model predicted that once daily dosing would minimize within-patient concizumab PK variability. CONCLUSION: Concizumab phase 2 trials will target an exposure >=100 ng/mL, with a once-daily regimen. PMID- 30408850 TI - It all looks so different now ... PMID- 30408849 TI - Curing Medicare's hospital readmissions penalties. PMID- 30408851 TI - The Great Disruption: What's next for healthcare policy? PMID- 30408852 TI - Daughter, student, caregiver, nurse. Helping healthcare's hidden labor force. PMID- 30408853 TI - Words of wisdom for 2017. AB - Probably the best thing that can be said about 2016 is that it's finally over. Alas, 2017 doesn't hold much promise, either. The healthcare industry is headed for turbulent times. PMID- 30408854 TI - Repeal of ACA without adequate replacement will drive severe disruptions beyond insurance. AB - It seems that any post-election discussion of healthcare in the U.S. inevitably leads to the certainty that President Donald Trump will ask Congress to quickly repeal and replace the Affordable Care Act, better known as Obamacare. Some in Congress have suggested repealing first and then passing a replacement bill at a future date. PMID- 30408856 TI - VA hospitals with the lowest and highest congestive heart failure readmission rates Ranked by 30-day readmission rates for VA Medicare patients in 2015. PMID- 30408855 TI - Addressing neonatal abstinence syndrome before birth. PMID- 30408857 TI - Anaerobic digestion as an alternative disposal for phytoremediated biomass from heavy metal contaminated sites. AB - It is desirable to establish an environmentally benign platform for disposing biomass from the phytoremediation process while recovering energy is of importance. To this end, the biochemical methane potential (BMP) tests were conducted using four different biomass samples (i.e., sunflower: Helianthus annuus) that were obtained from the different remediation sites. In particular, this study laid great emphasis on evaluating the inhibition for the anaerobic digestion (AD) process induced by endogenous heavy metal (Cd, Cu, Ni, Pb, and Zn) content in biomass. Despite the high levels of heavy metal contents (Cd: 58.4, Cu: 23.0, Ni: 2.01, Pb: 9.88, and Zn: 146 mg kg-1) in the substrate for the AD process, the overall performance was comparable relative to the case of the references. Therefore, this study signified that the inhibition derived from heavy metals was nearly negligible, which suggested that biomass from the phytoremediation site could be used as a substrate for the AD process. PMID- 30408858 TI - Estimation of PM2.5 mortality burden in China with new exposure estimation and local concentration-response function. AB - The estimation of PM2.5-related mortality is becoming increasingly important. The accuracy of results is largely dependent on the selection of methods for PM2.5 exposure assessment and Concentration-Response (C-R) function. In this study, PM2.5 observed data from the China National Environmental Monitoring Center, satellite-derived estimation, widely collected geographic and socioeconomic information variables were applied to develop a national satellite-based Land Use Regression model and evaluate PM2.5 exposure concentrations within 2013-2015 with the resolution of 1 km * 1 km. Population weighted concentration declined from 72.52 MUg/m3 in 2013 to 57.18 MUg/m3 in 2015. C-R function is another important section of health effect assessment, but most previous studies used the Integrated Exposure Regression (IER) function which may currently underestimate the excess relative risk of exceeding the exposure range in China. A new Shape Constrained Health Impact Function (SCHIF) method, which was developed from a national cohort of 189,793 Chinese men, was adopted to estimate the PM2.5-related premature deaths in China. Results showed that 2.19 million (2013), 1.94 million (2014), 1.65 million (2015) premature deaths were attributed to PM2.5 long-term exposure, different from previous understanding around 1.1-1.7 million. The top three provinces of the highest premature deaths were Henan, Shandong, Sichuan, while the least ones were Tibet, Hainan, Qinghai. The proportions of premature deaths caused by specific diseases were 53.2% for stroke, 20.5% for ischemic heart disease, 16.8% for chronic obstructive pulmonary disease and 9.5% for lung cancer. IER function was also used to calculate PM2.5-related premature deaths with the same exposed level used in SCHIF method, and the comparison of results indicated that IER had made a much lower estimation with less annual amounts around 0.15-0.5 million premature deaths within 2013-2015. PMID- 30408859 TI - Association of urinary concentrations of bisphenols with type 2 diabetes mellitus: A case-control study. AB - Bisphenols, as synthetic chemicals, have been widely detected in environmental and human samples. Epidemiological studies have reported relationships between bisphenol A (BPA) and type 2 diabetes mellitus (T2DM), but results are inconsistent. Additionally, the associations between other bisphenols (i.e., the substitutes of BPA) with T2DM have been scarcely reported. A case-control study was conducted to examine the associations of urinary bisphenols with T2DM by investigating 8 bisphenols in urine samples of 251 T2DM cases and 251 controls and using different statistic models. Urinary bisphenol AF (BPAF) and bisphenol S (BPS) concentrations were significantly positively associated with T2DM in the log-transformed statistical models and adjusted odd ratios (ORs) were separately 4.95 [95% confidence interval (CI): 3.15, 7.79] and 1.73 (95% CI: 1.37, 2.18), which was consistent with the results in categorical models (OR = 2.03; 95% CI: 1.31, 3.15; p = 0.001 for BPAF; OR = 3.83; 95% CI: 2.37, 6.20; p < 0.001 for BPS). In addition, in the categorical models, elevated odds of T2DM were observed in the second BPA quartile (OR = 2.58; 95% CI: 1.38, 4.80) and the third quartile (OR = 1.89; 95% CI: 1.03, 3.46), but not in the fourth quartile, which reflected a nonlinear association between urinary BPA and T2DM. Similarly, only significant positive association with T2DM was found in the second quartile of the sum of bisphenols (OR = 2.07; 95% CI: 1.12, 3.82). In the sensitivity analyses, the associations of bisphenols with T2DM remained consistent except for BPAF in the categorical model. Our study suggested that several urinary bisphenols were positively associated with T2DM. PMID- 30408860 TI - Neonicotinoid insecticide mixtures: Evaluation of laboratory-based toxicity predictions under semi-controlled field conditions. AB - Neonicotinoid insecticide mixtures are frequently detected in aquatic environments in agricultural regions. Recent laboratory studies have indicated that neonicotinoid mixtures can elicit greater-than-additive toxicity in sensitive aquatic insects (e.g. Chironomus dilutus). However, this has yet to be validated under field conditions. In this study, we compared the chronic (28- and 56-day) toxicity of three neonicotinoids (imidacloprid, clothianidin, and thiamethoxam) and their mixtures to natural aquatic insect communities. Using experimental in-situ enclosures (limnocorrals), we exposed wetland insects to single-compounds and binary mixtures at equitoxic concentrations (1 toxic unit under the principle of Concentration Addition). We assessed the composition of all emerged insect taxa and the cumulative Chironomidae emergence and biomass over time. In treated limnocorrals, there were subtle shifts in community composition, with greater mean proportions of emergent Trichoptera and Odonata. Cumulative emergence and biomass increased over time and there was a significant interaction between time and treatment. At 28 days, cumulative Chironomidae emergence and biomass were not significantly different between neonicotinoid treatments and controls. However, cumulative emergence in the imidacloprid, clothianidin, and clothianidin-thiamethoxam treatments were 42%, 20%, and 44% lower than predicted from applied doses. At 56 days, effects on cumulative emergence and biomass were significant for imidacloprid, clothianidin, and the clothianidin-thiamethoxam mixture. Contrary to laboratory predictions, mixtures were not more toxic than single compounds under semi-controlled field settings. Furthermore, only clothianidin significantly shifted sex-ratios towards female dominated populations. Results showed that the responses of natural Chironomidae populations to neonicotinoids and their mixtures cannot be adequately predicted from laboratory-derived single-species models, and although occasional overdosing may have influenced the magnitude of effects, reductions in Chironomidae emergence and biomass can occur at average neonicotinoid concentrations below some current water quality guidelines. Therefore, neonicotinoid guidelines should be revised to ensure that Chironomidae and other sensitive aquatic insects inhabiting agricultural wetlands are adequately protected. PMID- 30408861 TI - Water-soluble ions in PM2.5 during spring haze and dust periods in Chengdu, China: Variations, nitrate formation and potential source areas. AB - Hourly concentrations of water-soluble inorganic ions (Na+, NH4+, K+, Mg2+, Ca2+, Cl-, NO3- and SO42-) in PM2.5 and related reactive gases were measured with a Gas and Aerosol Collector combined with Ion Chromatography (GAC-IC) in urban Chengdu from April 17 to May 27, 2017, during which both haze and dust episodes occurred frequently. Nitrate was the most abundant ion in PM2.5 and substantially increased during haze pollution with the NO3-/SO42- mass ratio increasing from 0.78 during clean period to 1.1 during haze period. Aerosols in Chengdu were generally ammonium-rich, wherein ammonium nitrate was primarily formed through homogeneous gas-phase reactions and limited by the availability of HNO3, indicating that preferentially reducing the emissions of NOx could make for mitigating spring haze pollution in Chengdu. Backward trajectory clustering coupled with measured species and a potential source contribution function (PSCF) for PM2.5, PM10/PM2.5, sulfate, nitrate, ammonium, and Ca2+ indicated that regionally transported pollutants from the southern and southeastern Sichuan Basin strongly contributed to springtime PM2.5 pollution in Chengdu, but long distance transport from northwestern China also contributed to dust pollution. Moreover, the treatment of urban fugitive dust in southern Sichuan is also important for reducing coarse particles in Chengdu. Therefore, the improvement of air quality in Chengdu, even in the Sichuan Basin, requires the regional joint emission reduction of particles and gaseous precursors across the entire Sichuan Basin, especially for cities located in southeastern Sichuan Basin. PMID- 30408862 TI - Seabird plastic ingestion differs among collection methods: Examples from the short-tailed shearwater. AB - Despite the increase of literature on seabird plastic ingestion in recent years, few studies have assessed how plastic loads vary according to different sampling methods. Most studies use necropsies of seabirds with a natural cause of death, e.g. beached or predated, to determine plastic loads and monitor marine debris. Sampling naturally dead seabirds may be biased as they have perished because of their intrinsic factors, e.g. poor body condition, high parasite loads, sickness or predation, affecting estimates of plastic loads. However, seabirds killed accidentally may be more representative of the population. Here, we used the short-tailed shearwater Ardenna tenuirostris to test different sampling methods: naturally beached fledglings and accidentally road-killed fledglings after being attracted and grounded by artificial lights. We compared plastic load, body condition, and feeding strategies (through using feathers' delta13C and delta15N isotope niche) between beached and road-killed fledglings. Beached birds showed higher plastic loads, poorer body condition and reduced isotopic variability, suggesting that this group is not a representative subsample of the whole cohort of the fledgling population. Our results might have implications for long-term monitoring programs of seabird plastic ingestion. Monitoring plastic debris through beached birds could overestimate plastic ingestion by the entire population. We encourage the establishment of refined monitoring programs using fledglings grounded by light pollution if available. These samples focus on known cohorts from the same population. The fledgling plastic loads are transferred from parents during parental feeding, accumulating during the chick-rearing period. Thus, these fledglings provide a higher and valuable temporal resolution, which is more useful and informative than unknown life history of beached birds. PMID- 30408863 TI - A review on sorbent devices for oil-spill control. AB - Multiple research areas have emerged in view of the deleterious impacts of oil spills on the environment and the relative intractability of the problem per se. The dimensions mostly explored thus far, relate to the prediction of the fate of oil-spill and development of effective counter-measures. Among the counter measures, development of effective sorbents for oil-spill remediation has sustained interest for quite long, in spite of the numerous challenges associated with it. Most importantly, the sorbent materials need to be assembled in such a structure or form that they can survive the oceanic currents and other prevailing environmental conditions without themselves becoming a source of secondary pollution. This review paper focuses on the chronological development of such assemblies or devices over the past century and a critical appraisal of the same. Relevant major factors affecting the performance of sorbent assemblies can be identified as: structural features and modes of sorption, effect of weathering on oil-sorption capacity, mode of distribution and harvesting of such absorbent units, and the final disposal after feasible cycles of sorption and release. This review paper incorporates a detailed discussion on the major inventions and the extant open literature in this field. PMID- 30408864 TI - Theoretical study on gas-phase reactions of nitrate radicals with methoxyphenols: Mechanism, kinetic and toxicity assessment. AB - Creosol and 4-ethylguaiacol are two important methoxyphenols, lignin pyrolysis products, which are discharge into the atmosphere in large quantities. In this work, theoretical calculations of the reaction mechanism towards the two compounds with NO3 radicals was performed using DFT method. The rate constants and toxicity assessment were also investigated. The atmospheric lifetime for creosol and 4-ethylguaiacol were 0.82 and 0.19 h, respectively. A new reaction pathway was proposed for the transformation of methoxyl into hydroxyl, which has not yet been clarified in previous studies. The toxicity of methoxyphenols and their degradation products is closely related to their hydrophobicity. Although most degradation products are less toxic, they also should be pay more attention, especially for nitro-substituents. A new reaction pathway was proposed for the transformation of methoxyl into hydroxyl. The toxicity is closely related to their hydrophobicity. PMID- 30408865 TI - A systematic risk characterization related to the dietary exposure of the population to potentially toxic elements through the ingestion of fruit and vegetables from a potentially contaminated area. A case study: The issue of the "Land of Fires" area in Campania region, Italy. AB - Potentially toxic elements are widespread soil contaminants, whose occurrence could entail a concern for human health upon ingestion of fruit and vegetables harvested in a polluted area. This work set out to evaluate the concentrations of lead and cadmium as well as the levels of thirteen heavy metals for which a limit value is yet to be established by the food safety authorities, in order to perform a risk characterization related to the dietary intake of these metals and to provide a scientific opinion with wider relevance in the light of current worldwide regulatory issues. The sampling consisted of fruit and vegetables grown in a potentially contaminated area of southern Italy due to the illegal dump of hazardous wastes. An evaluation of the dietary exposure through the calculation of the Hazard Index (HI), the Maximum Cumulative Ratio (MCR) and the Target Cancer Risk (TCR) was adopted to this end. The results revealed that about the 30% of samples showed quantifiable levels of chemicals and no significant difference emerged between the potentially polluted area and the nearby cities that were selected as a control landfill site. The overall risk characterization for non-carcinogenic endpoints showed that the HI did not reach unsafe values, except for a small number of samples mainly because of aberrant occurrences and, in any case, the cumulative toxicity was mainly driven by thallium and vanadium. As far as the carcinogenic effects of arsenic are concerned, the distribution of TCR values broadly lay below the safety threshold; a certain percentage of data, however, exceeded this limit and should be taken into account for the enforcement of future regulatory thresholds. PMID- 30408866 TI - Ambient air quality in the holy city of Makkah: A source apportionment with elemental enrichment factors (EFs) and factor analysis (PMF). AB - Air pollution remains a major global public health and environmental issue. We assessed the levels of PM2.5 and delineated the major sources in Makkah, Saudi Arabia. Fine particulate matter (PM2.5) sampling was performed from February 26, 2014-January 27, 2015 in four cycles/seasons. Samples were analyzed for black carbon (BC) and trace elements (TEs). PM2.5 source apportionment was performed by computing enrichment factors (EFs) and positive matrix factorization (PMF). Backward-in time trajectories were used to assess the long-range transport. Significant seasonal variations in PM2.5 were observed, Spring: 113 +/- 67.1, Summer: 88.3 +/- 36.4, Fall: 67.8 +/- 24, and Winter: 67.6 +/- 36.9 MUg m-3. The 24-h PM2.5 exceeded the WHO (25 MUg m-3) and Saudi Arabia's (35 MUg m-3) guidelines, with an air quality index (AQI) of "unhealthy to hazardous" to human health. Most delta-C computations were below zero, indicating minor contributions from bio-mass burning. TEs were primarily Si, Ca, Fe, Al, S, K and Mg, suggesting major contributions from soil (Si, Ca, Fe, Al, Mg), and industrial and vehicular emissions (S, Ca, Al, Fe, K). EF defined two broad categories of TEs as: anthropogenic (Cu, Zn, Eu, Cl, Pb, S, Br and Lu), and earth-crust derived (Al, Si, Na, Mg, Rb, K, Zr, Ti, Fe, Mn, Sr, Y, Cr, Ga, Ca, Ni and Ce). Notably, all the anthropogenic TEs can be linked to industrial and vehicular emissions. PMF analysis defined four major sources as: vehicular emissions, 30.1%; industrial mixed dust, 28.9%; soil/earth-crust, 24.7%; and fossil-fuels/oil combustion, 16.3%. Plots of wind trajectories indicated wind direction and regional transport as major influences on air pollution levels in Makkah. In collusion, anthropogenic emissions contributed >75% of the observed air pollution in Makkah. Developing strategies for reducing anthropogenic emissions are paramount to controlling particulate air pollution in this region. PMID- 30408867 TI - Interaction between Al2O3 and different sizes of GO in aqueous environment. AB - Although the aggregation of graphene oxide (GO) has been widely researched, the influence of the GO size on the homoaggregation behavior and its interaction with environmental media are still unexplored. In this work, critical coagulation concentration (CCC) values for GO with different sizes, from micro to nanosheet, were measured with NaCl and CaCl2 electrolytes, and the results indicated that GO with the largest size presented the smallest CCC value. Aluminum oxide (Al2O3) was selected as a natural solid particle representative to mimic the interaction between GO and environmental media. Batch experiments were conducted in solution with different pH and ionic strength. Results indicated that the attachment capacity of large GO onto Al2O3 particles was greater than that of small GO. The experimental data were well fitted with Freundlich model. The electrostatic attraction and hydrogen-bonding interaction dominated the interaction process between GO and Al2O3. These findings are important for better understanding in the environmental fate and transport of GO. PMID- 30408868 TI - Facile fabrication of crumpled graphene oxide nanosheets and its Platinum nanohybrids for high efficient catalytic activity. AB - Crumpled graphene oxide nanosheets have drawn large attentions due to its compressibility and self-avoiding stacking as flat graphene sheets trend to aggregate and restack. Up to now, most of the synthesis approaches were relied on external substrates, such as elastic substrates or ultrasonic atomizer, and the crumpled structures were obtained in a solid state directly. Here we report a facile method to produce crumpled dispersive nanosheets in solution through general base-washing treatment by taking advantage of the amphipathy of GO nanosheets. With the dissociation of oxygen-functional groups on nanosheets in alkaline environment, highly water-soluble oxidative debris (OD) would fall off from the nanosheets due to the increase of electrostatic repulsions, and resulted in the crumple of the flat sheets, while the covalent oxygen-functional groups on the nanosheets were reserved. As a result, the nanosheets remained dispersible in solution, and could be used directly for surface modifications. Pt nanoparticles could be directly deposited onto both sides of the sheets through common nucleation and growth from precursor ions process. Compared with flat graphene based hybrid, the catalytic performance of crumpled-graphene-Pt (CG-Pt) is more excellent and attractive, and corresponding apparent kinetic rate constant (kapp) of CG-Pt toward 4-nitrophenol reduction is enhanced by 2.7-4.6-fold. This study provides a new and facile way to fabricate crumpled nanosheets and demonstrates to be easy modified for various purpose. PMID- 30408869 TI - Nitrogen deposition increases N2O emission from an N-saturated subtropical forest in southwest China. AB - Nitrous oxide (N2O) is a major greenhouse gas, with elevated emission being reported from subtropical forests that receive high nitrogen (N) deposition. After 10 years of monthly addition of ammonium nitrate (NH4NO3) or sodium nitrate (NaNO3) to a Mason pine forest at Tieshanping, near Chongqing city in Southwest China, the simulated N deposition was stopped in October 2014. The results of soil N2O emissions monitoring in different seasons during the nitrogen application period showed that nitrogen addition significantly increased soil N2O emission. In general, the N2O emission fluxes were positively correlated to nitrate (NO3-) concentrations in soil solution, supporting the important role of denitrification in N2O production, which was also modified by environmental factors such as soil temperature and moisture. After stopping the application of nitrogen, the soil N2O emissions from the treatment plots were no longer significantly higher than those from the reference plots, implying that a decrease in nitrogen deposition in the future would cause a decrease in N2O emission. Although the major forms of N deposition, NH4+ and NO3-, had not shown significantly different effects on soil N2O emission, the reduction in NH4+ deposition may decrease the NO3- concentrations in soil solution faster than the reduction in NO3- deposition, and thus be more effective in reducing N2O emission from N-saturated forest soil in the future. PMID- 30408870 TI - Enantioselective toxic effects of cyproconazole enantiomers against Rana nigromaculata. AB - The environmental contaminant, especially pesticides, threatened the amphibian population. In this assay, the enantioselective behavior of cyproconazole on Rana nigromaculata was studied. We found LC50 (lethal concentration causing 50% mortality) of 4-enantiomers was nearly twice as 3-enantiomers in 96 h acute toxicity test. Besides, the significant considerable variation of oxidative stress and LDH (lactic dehydrogenase) induced by the four enantiomers indicated that cyproconazole could enantioselectively affect enzymes in tadpoles. Bioaccumulation experiments showed the order of cyproconazole in the tadpoles was 4-enantiomers>3- enantiomers>2- enantiomers>1- enantiomers during the exposure for 28d. In tissue distribution test, cyproconazole was formed and accumulated in order of 4-enantiomers>2-enantiomers>3- enantiomers>1- enantiomers, except that in the gut. During the elimination experiment, cyproconazole was rapidly eliminated by 95% within the only 24 h. These results suggested that the influence of enantioselective behavior should consider when assessing ecological risk of chiral pesticides to amphibians. PMID- 30408871 TI - Solid-phase distribution and mobility of thallium in mining-metallurgical residues: Environmental hazard implications. AB - Thallium (Tl) and its compounds are non-essential and highly toxic for living organisms, even at low concentrations. In this paper, we analyzed the presence and geochemical distribution of Tl in different mining-metallurgical and sediment samples collected from several mining zones of Mexico. A modified BCR sequential extraction procedure was also applied to the samples to investigate the geochemical behavior and potential environmental risk of Tl according to types of ore deposit and mineral processing method applied. Results revealed the presence of Tl in the majority of the mining-metallurgical samples, with labile concentrations reaching up to values of 184.4 mg kg-1, well above the environmental standards. A comparison of Tl partitioning in different samples showed that Tl was usually found associated with labile fractions instead of entrapped in the environmentally-passive residual fraction. Specifically, high levels of Tl were extracted from the exchangeable/acid-extractable and poorly crystalline reducible fractions, suggesting its association with both soluble and amorphous Fe-Mn oxyhydroxides, respectively. Besides, Tl was also frequently found associated with the crystalline reducible fraction, presumably bonded to manganese oxides and jarosite-like minerals. Lastly, little amounts of Tl were extracted from the oxidizable fraction. Considering the fractionation of Tl in these mining-metallurgical samples, they may pose a significant environmental hazard. This study provides useful insights into the potential sources of Tl pollution in Mexico and emphasizes the need for further research to determine the extent of its impact and to develop effective remediation protocols to protect the environment from Tl toxicity. PMID- 30408872 TI - Influence of rhamnolipid biosurfactant and Brij-35 synthetic surfactant on 14C Pyrene mineralization in soil. AB - Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous contaminants in soil and are considered priority pollutants due to their carcinogenicity. Bioremediation of PAH-contaminated soils is often limited by the low solubility and strong sorption of PAHs in soil. Synthetic surfactants and biosurfactants have been used to enhance the bioavailability of PAHs and to accelerate microbial degradation. However, few studies have compared synthetic and biosurfactants in their efficiency in promoting PAH biodegradation in either native or bioaugmented soils. In this study, we evaluated mineralization of 14C-pyrene in soils with or without the augmentation of Mycobacterium vanbaalenii PYR-1, and characterized the effect of Brij-35 (synthetic) and rhamnolipid biosurfactant at different amendment rates. Treatment of rhamnolipid biosurfactant at 140 or 1400 MUg surfactant g-dry soil-1 rates resulted in a significantly longer lag period in 14C-pyrene mineralization in both native and bioaugmented soils. In contrast, amendment of Brij-35 generally increased 14C-pyrene degradation, and the greatest enhancement occurred at 21.6 or 216 MUg surfactant g-dry soil-1 rates, which may be attributed to increased bioavailability. Brij-35 and rhamnolipid biosurfactant were found to be non-toxic to M. vanbaalenii PYR-1 at 10X CMC, thus indicating rhamnolipid biosurfactant likely served as a preferential carbon source to the degrading bacteria in place of 14C-pyrene, leading to delayed and inhibited 14C pyrene degradation. Mineralization of 14C-pyrene by M. vanbaalenii PYR-1 was rapid in the unamended soils, and up to 60% of pyrene was mineralized to 14CO2 after 10 d in the unamended or Brij-35 surfactant-amended soils. Findings of this study suggest that application of surfactants may not always lead to enhanced PAH biodegradation or removal. If the surfactant is preferentially used as an easier carbon substrate than PAHs for soil microorganisms, it may actually inhibit PAH biodegradation. Selection of surfactant types is therefore crucial for the effectiveness of surfactant-aided bioremediation of PAH-contaminated soils. PMID- 30408873 TI - Glyphosate is lethal and Cry toxins alter the development of the stingless bee Melipona quadrifasciata. AB - Brazil is the second largest producer of genetically modified plants in the world. This agricultural practice exposes native pollinators to contact and ingestion of Bacillus thuringiensis proteins (e.g. Cry toxins) from transgenic plants. Furthermore, native bees are also exposed to various herbicides applied to crops, including glyphosate. Little is known about the possible effects of glyphosate and Cry proteins on stingless bees, especially regarding exposure at an immature stage. Here, we show for the first time that glyphosate is lethal, and that Cry toxins (Cry1F, Cry2Aa) alter the development of the stingless bee Melipona quadrifasciata upon contamination of larval food. Glyphosate was very toxic to the bee larvae, killing all of them within only a few days of exposure. Bees treated with Cry2Aa proteins had a higher survival rate and were delayed in their development, compared to the negative controls. Those treated with the Cry1F protein also suffered delays in their development, compared to the negative controls. In conclusion, the proteins Cry1F, Cry2Aa, and the herbicide glyphosate were highly toxic to the stingless bee M. quadrifasciata, causing lethal or sublethal effects which can severely impair colony growth and viability, and reduce pollination ability. PMID- 30408874 TI - Enzyme activity indicates soil functionality affectation with low levels of trace elements. AB - The use of the soil can alter its functionality and influence the (bio)availability of any contaminants present. Our study considers two types of agricultural soils, rainfed and olive soils, managed according to conventional practices that apply contaminants directly to the soil (fertilizers, pesticides, fungicides, etc.) and receive contaminants from the atmosphere (traffic, industry, etc.); and a forest soil that is not subject to these agricultural practices. In this scenario, we consider a mixture of 16 trace elements (As, Ba, Be, Cd, Co, Cr, Cu, Hg, Mo, Ni, Pb, Se, Sb, Sn, V and Zn), since their interactions with the soil can produce synergistic and/or antagonistic effects that are not considered in most studies. We studied whether the content and (bio)availability of low concentrations of a mixture of trace elements affect the soil functionality in terms of the activity of some key enzymes We analysed the total, potentially and immediately available fractions, the soil parameters and soil enzyme activity. The results show that the functionality of the soils studied was affected despite the low concentrations of trace elements. The highest concentrations of total trace elements and available fractions were found in forest soils compared to the other two uses. Soil enzyme activity is best explained by the potentially available fraction of a mixture of trace elements and physico-chemical soil variables. In our study, pH, total nitrogen, organic carbon and fine mineral particles (silt and clay) had an influence on soil enzyme activity and the (bio)available fractions of trace elements. PMID- 30408875 TI - DNA methylation and gene expression alterations in zebrafish early-life stages exposed to the antibacterial agent triclosan. AB - There is increasing evidence that toxicant exposure can alter DNA methylation profile, one of the main epigenetic mechanisms, particularly during embryogenesis when DNA methylation patterns are being established. In order to investigate the effects of the antibacterial agent Triclosan on DNA methylation and its correlation with gene expression, zebrafish embryos were exposed during 7 days post-fertilization (starting at maximum 8-cells stage) to 50 and 100 MUg/l, two conditions for which increased sensitivity and acclimation have been respectively reported. Although global DNA methylation was not significantly affected, a total of 171 differentially methylated fragments were identified by Reduced Representation Bisulfite Sequencing. The majority of these fragments were found between the two exposed groups, reflecting dose-dependant specific responses. Gene ontology analysis revealed that pathways involved in TGF-beta signaling were enriched in larvae exposed to 50 MUg/l, while de novo pyrimidine biosynthesis functions were overrepresented in fish exposed to 100 MUg/l. In addition, gene expression analysis revealed a positive correlation between mRNA levels and DNA methylation patterns in introns, together with significant alterations of the transcription of genes involved in nervous system development, transcriptional factors and histone methyltransferases. Overall this work provides evidence that Triclosan alters DNA methylation in zebrafish exposed during embryogenesis as well as related genes expression and proposes concentration specific modes of action. Further studies will investigate the possible long-term consequences of these alterations, i.e. latent defects associated with developmental exposure and transgenerational effects, and the possible implications in terms of fitness and adaptation to environmental pollutants. PMID- 30408876 TI - Associations of urinary polycyclic aromatic hydrocarbons with age at natural menopause in U.S. women aged 35-65, NHANES 2003-2012. AB - Polycyclic aromatic hydrocarbons (PAHs) mediated ovarian toxicity has been demonstrated in animal experiments. However, this issue has not been assessed in humans. Based on the National Health and Nutrition Examination Survey (NHANES) 2003-2012, data analysis was restricted to 1221 general U.S. women aged 35-65 years with complete data of interest. Levels of nine PAH metabolites in spot urine specimens were measured by isotope dilution gas chromatography/tandem mass spectrometry (GC-MS/MS). Self-reported information on the menopause status and age at menopause were obtained during interview. Cox proportional hazards regression was employed to assess the associations between PAH levels and natural menopause. Compared with women in the first quartile, subjects in the highest quartile of 1-Hydroxynapthalene [hazard ratio (HR) = 1.46, 95% confidence interval (CI) = 1.06 to 2.01], 2-Hydroxynapthalene (HR = 1.51, 95% CI = 1.12 to 2.05) and 3-Hydroxyfluorene (HR = 1.51, 95% CI = 1.06 to 2.16), or in the second quartile of 9-Hydroxyfluorene (HR = 1.53, 95% CI = 1.05 to 2.22), had elevated risks of earlier onset of natural menopause. Our findings suggested positive associations between urinary PAH levels and earlier age at natural menopause in the general U.S. women. Prospective studies are warranted to confirm the causality in the future. PMID- 30408877 TI - Formation of disinfection by-products during chlorination of organic matter from phoenix tree leaves and Chlorella vulgaris. AB - To better understand the precursor of disinfection by-products (DBPs) and provide useful information for water utilities to manage the drinking water, a study of DBP formation was conducted through chlorination of leaf organic matter (OM) from phoenix tree and algal OM from Chlorella vulgaris. DBPs investigated include trichloromethane (TCM), trichloroacetic acid (TCAA), dichloroacetic acid (DCAA), chloroacetic acid (CAA), dichloroacetonitrile (DCAN) and trichloroacetonitrile (TCNM). Results show that the specific yields (MUg/mg C) of C-DBPs (TCM, CAA, DCAA and TCAA) from leaf OM were higher but the specific yields of N-DBPs (DCAN and TCNM) were lower than those from algal OM. Correlation analysis revealed that C-DBPs yields (MUg/L) were significantly (p < 0.01) interrelated with each other (r = 0.937-0.996), and for each C-DBP, the hydrophobic OM contributed more to their formation (61-90% of total yields) as compared with hydrophilic OM. In spite of these characteristics, an in-depth examination was conducted revealing that the hydrophobicity and aromaticity of C-DBPs precursors were in the order of TCAA > DCAA & TCM > CAA. DCAN precursors were highly variable: they were dominated by hydrophobic OM (leaf OM: 86%) or hydrophilic OM (algal OM: 61%). Hydrophilic OM was the most important precursor for TCNM (76-79% of total yields), followed by hydrophobic neutral and base substances (29-45% of total yields), but the hydrophobic acids exhibited an inhibition role in TCNM formation. PMID- 30408878 TI - Characteristics of perfluoroalkyl acids in atmospheric PM10 from the coastal cities of the Bohai and Yellow Seas, Northern China. AB - The concentration distributions, compositional profiles and seasonal variations of 17 perfluoroalkyl acids (PFAAs) in PM10 (particles with aerodynamic diameters < 10 MUm) were determined in seven coastal cities of the Bohai and Yellow Seas. The detection rates of perfluorooctanoic acid (PFOA) and short-chain components (perfluoroalkyl carboxylic acids (PFCAs) with <=7 carbon atoms and perfluoroalkane sulfonic acids (PFSAs) with <=5 carbon atoms) were much higher than those of other long-chain PFAA species. The annual average concentration of total PFAAs in PM10 ranged from 23.6 pg/m3 to 94.5 pg/m3 for the sampling cities. The monthly mean concentrations of PFAAs in PM10 in some sampling cities reached a peak value in winter, while no significant seasonal differences presented in other cities. High concentrations of PFAAs in the northern cities generally occurred during the local heating period (from November to March). Generally, the dominant components of PFAAs were PFOA and perfluorobutyric acid (PFBA). Some significantly positive correlations (p < 0.01) between the 10 dominant components were revealed in the sampling cities, which implied similar sources and fate behaviors. Based on the simulated 72-hr backward trajectory tracking of air masses, the clustering results demonstrated the sampling cities were affected mainly by the atmospheric transport in sequence from the northwest, the southwest and the open seas, and many transport trajectories of air masses passed by the local fluorine chemical manufacturers in Liaoning, Shandong, Jiangsu, and Hubei Provinces. The estimated average daily intake (ADI) corresponding to the residents in different age groups indicated insignificant contributions to PFOA and perfluorooctane sulfonate (PFOS) exposures by inhalation of PM10 compared to ingestion by daily diet, while the higher ADI of PFOA than the reported levels for adults should be a concern. The calculated hazard ratios (HR) exhibited low noncancer risks by inhalation exposure to PFOA and PFOS in PM10. PMID- 30408879 TI - Crosstalk of oxidative damage, apoptosis, and autophagy under endoplasmic reticulum (ER) stress involved in thifluzamide-induced liver damage in zebrafish (Danio rerio). AB - Although the hepatotoxicity of thifluzamide in zebrafish has been characterized, its toxic mechanisms have not been fully explored. The present study demonstrated that thifluzamide damaged the zebrafish liver and endoplasmic reticulum (ER). In addition, thifluzamide significantly changed the expression of genes encoding antioxidant proteins and increased the malondialdehyde (MDA) content, leading to oxidative damage in zebrafish liver. Additionally, the autophagic ultrastructure was observed by transmission electron microscopy (TEM), and LC3-I/LC3-II conversion was obviously upregulated under western blotting (WB) measurements, verifying that autophagy was induced by thifluzamide. Moreover, the activities of Caspase-3 and Caspase-9 were obviously decreased, indicating that apoptosis was inhibited in adult zebrafish exposed to a higher concentration of thifluzamide. In summary, oxidative damage and autophagy but not apoptosis under ER injury might lead to the hepatotoxicity of thifluzamide in zebrafish. Our findings provide a new mechanistic insight into the toxicity of thifluzamide in zebrafish. PMID- 30408880 TI - Vegetation reflectance spectroscopy for biomonitoring of heavy metal pollution in urban soils. AB - Heavy metals in urban soils may impose a threat to public health and may negatively affect urban tree viability. Vegetation spectroscopy techniques applied to bio-indicators bring new opportunities to characterize heavy metal contamination, without being constrained by laborious soil sampling and lab-based sample processing. Here we used Tilia tomentosa trees, sampled across three European cities, as bio-indicators i) to investigate the impacts of elevated concentrations of cadmium (Cd) and lead (Pb) on leaf mass per area (LMA), total chlorophyll content (Chl), chlorophyll a to b ratio (Chla:Chlb) and the maximal PSII photochemical efficiency (Fv/Fm); and ii) to evaluate the feasibility of detecting Cd and Pb contamination using leaf reflectance spectra. For the latter, we used a partial-least-squares discriminant analysis (PLS-DA) to train spectral based models for the classification of Cd and/or Pb contamination. We show that elevated soil Pb concentrations induced a significant decrease in the LMA and Chla:Chlb, with no decrease in Chl. We did not observe pronounced reductions of Fv/Fm due to Cd and Pb contamination. Elevated Cd and Pb concentrations induced contrasting spectral changes in the red-edge (690-740 nm) region, which might be associated with the proportional changes in leaf pigments. PLS-DA models allowed for the classifications of Cd and Pb contamination, with a classification accuracy of 86% (Kappa = 0.48) and 83% (Kappa = 0.66), respectively. PLS-DA models also allowed for the detection of a collective elevation of soil Cd and Pb, with an accuracy of 66% (Kappa = 0.49). This study demonstrates the potential of using reflectance spectroscopy for biomonitoring of heavy metal contamination in urban soils. PMID- 30408881 TI - Effects of broadband sound exposure on the interaction between foraging crab and shrimp - A field study. AB - Aquatic animals live in an acoustic world in which they often rely on sound detection and recognition for various aspects of life that may affect survival and reproduction. Human exploitation of marine resources leads to increasing amounts of anthropogenic sound underwater, which may affect marine life negatively. Marine mammals and fishes are known to use sounds and to be affected by anthropogenic noise, but relatively little is known about invertebrates such as decapod crustaceans. We conducted experimental trials in the natural conditions of a quiet cove. We attracted shore crabs (Carcinus maenas) and common shrimps (Crangon crangon) with an experimentally fixed food item and compared trials in which we started playback of a broadband artificial sound to trials without exposure. During trials with sound exposure, the cumulative count of crabs that aggregated at the food item was lower, while variation in cumulative shrimp count could be explained by a negative correlation with crabs. These results suggest that crabs may be negatively affected by artificially elevated noise levels, but that shrimps may indirectly benefit by competitive release. Eating activity for the animals present was not affected by the sound treatment in either species. Our results show that moderate changes in acoustic conditions due to human activities can affect foraging interactions at the base of the marine food chain. PMID- 30408882 TI - Long-term monitoring of waste-rock weathering at the Antamina mine, Peru. AB - The weathering of mine waste rock can cause release of metal-laden and acidic drainage that requires long-term and costly environmental management. To identify and quantify the geochemical processes and physical transport mechanisms controlling drainage quality, we monitored the weathering of five large-scale (20,000 t) instrumented waste-rock piles of variable and mixed-composition at the Antamina mine, Peru, in a decade-long monitoring program. Fine-grained, sulfidic waste rock with low-carbonate content exhibited high sulfide oxidation rates (>1 g S kg-1 waste rock yr-1) and within 7 years produced acidic (pH < 3) drainage with high Cu and Zn concentrations in the g L-1 range. In contrast, drainage from coarse, carbonate-rich waste rock remained neutral for >10 years and had significantly lower metal loads. Efficient metal retention (>99%) caused by sorption and secondary mineral formation of e.g., gypsum, Fe-(oxy)hydroxides, and Cu/Zn-hydroxysulfates enforced strong (temporary) controls on drainage quality. Furthermore, reactive waste-rock fractions, as small as 10% of total mass, dominated the overall drainage chemistry from the waste-rock piles through internal mixing. This study demonstrates that a reliable prediction of the timing and quality of waste-rock drainage on practice-relevant spatiotemporal scales requires a quantitative understanding of the prevailing in-situ porewater conditions, secondary mineralogy, and spatial distribution of reactive waste-rock fractions in composite piles. PMID- 30408883 TI - Endocrine activities and adipogenic effects of bisphenol AF and its main metabolite. AB - Bisphenol AF (BPAF) is a fluorinated analog of bisphenol A (BPA), and it is a more potent estrogen receptor (ER) agonist. BPAF is mainly metabolized to BPAF glucuronide (BPAF-G), which has been reported to lack ER agonist activity and is believed to be biologically inactive. The main goal of the current study was to examine the influence of the metabolism of BPAF via glucuronidation on its ER activity and adipogenesis. Also, as metabolites can have different biological activities, the effects of BPAF-G on other nuclear receptors were evaluated. First, in-vitro BPAF glucuronidation was investigated using recombinant human enzymes. Specific reporter-gene assays were used to determine BPAF and BPAF-G effects on estrogen, androgen, glucocorticoid, and thyroid receptor pathways, and on PXR, FXR, and PPARgamma pathways. Their effects on lipid accumulation and differentiation were determined in murine 3T3L1 preadipocytes using Nile Red, with mRNA expression analysis of the adipogenic markers adiponectin, Fabp4, Cebpalpha, and PPARgamma. BPAF showed strong agonistic activity for hERalpha and moderate antagonistic activities for androgen and thyroid receptors, and for PXR. BPAF-G was antagonistic for PXR and PPARgamma. BPAF (0.1 MUM) and BPAF-G (1.0 MUM) induced lipid accumulation and increased expression of key adipogenic markers in murine preadipocytes. BPAF-G is therefore not an inactive metabolite of BPAF. Further toxicological and epidemiological investigations of BPAF effects on human health are warranted, to provide better understanding of the metabolic end-elimination of BPAF. PMID- 30408884 TI - First detection of tetrodotoxin and high levels of paralytic shellfish poisoning toxins in shellfish from Sicily (Italy) by three different analytical methods. AB - Paralytic shellfish toxins (PST) and tetrodotoxin (TTX) are naturally-occurring toxins that may contaminate the food chain, inducing similar neurological symptoms in humans. They are co-extracted under the same conditions and thus their combined detection is desirable. Whilst PST are regulated and officially monitored in Europe, more data on TTX occurrence in bivalves and gastropods are needed before meaningful regulations can be established. In this study, we used three separate analytical methods - pre-column oxidation with liquid chromatography and fluorescence detection, ultrahigh performance hydrophilic interaction liquid chromatography (HILIC) tandem mass spectrometry (MS/MS) and HILIC high resolution (HR) MS/MS - to investigate the presence of PST and TTX in seawater and shellfish (mussels, clams) collected in spring summer 2015 to 2017 in the Mediterranean Sea. Samples were collected at 10 sites in the Syracuse Bay (Sicily, Italy) in concomitance with a mixed bloom of Alexandrium minutum and A. pacificum. A very high PST contamination in mussels emerged, unprecedentedly found in Italy, with maximum total concentration of 10851 MUg saxitoxin equivalents per kg of shellfish tissue measured in 2016. In addition, for the first time TTX was detected in Italy in most of the analysed samples in the range 0.8-6.4 MUg TTX eq/kg. The recurring blooms of PST-producing species over the 3 year period, the high PST levels and the first finding of TTX in mussels from the Syracuse bay, suggest that monitoring programmes of PST and TTX in seafood should be activated in this geographical area. PMID- 30408885 TI - Wastewater treatment and microbial community dynamics in a sequencing batch reactor operating under photosynthetic aeration. AB - A sequencing batch bioreactor (SBR) treating municipal wastewater was photosynthetically aerated using microalgae cultivated in a photobioreactor (PBR). Symbiotic interactions and CO2/O2 exchange were established between activated sludge in the SBR and microalgae in the PBR through hydrophobic hollow fiber membranes. Photosynthetic aeration enhanced COD removal in the SBR from 52.2% (without external aeration) to 90.3%, whereas N-NH4+ and P-PO43- removal increased by 63.5% and 90.4%, respectively. The SBR performance under photosynthetic aeration was comparable to that under mechanical aeration. However, no nitrification was observed in the SBR, indicating oxygen limitation and poor growth condition for nitrifiers. In the PBR, there was a rapid increase in biomass concentration and it stabilized at 3.0 g/L after 22 days of operation. High nitrogen demand in the PBR indicated the steady flow of inorganic carbon from the SBR through the membranes. Prolonged oxygen limitation and massive sludge attachment on the membranes resulted in low suspended sludge concentration in the SBR. Microbial community analysis indicated gradual enrichment of facultative and strictly anaerobic microorganisms in the SBR. These results highlight the potential of microalgae in lowering the cost of wastewater aeration and underline the challenges in sustaining symbiotic gas exchange during long term. PMID- 30408886 TI - Toxicological effects of transition metal-doped titanium dioxide nanoparticles on goldfish (Carassius auratus) and common carp (Cyprinus carpio). AB - The aim of present study was to assess the toxicological effects of transition metal-doped titanium dioxide nanoparticles (TiO2 NPs) on histopathological changes, behavioral patterns, and antioxidant responses of goldfish (Carassius auratus) and common carp (Cyprinus carpio). The synthesized nanoparticles were confirmed by Transmission Electron Microscopy, Field Emission Scanning Electron Microscopy, X-ray diffraction, UV-visible, and Vibration Sample Magnetometer. Fish in four experimental groups exposed to sub-lethal concentrations of pure TiO2 NPs (10 mg L-1), chromium (Cr), iron (Fe), and nickel (Ni) doped TiO2 NPs for seven days. Statistical analysis of oxidative stress responses in gills showed significant differences in superoxide dismutase, total antioxidant capacity, and malondialdehyde parameters between two species and in all parameters than glutathione peroxidase between experimental groups and control group. In intestine, no significant difference was observed among groups, but oxidative responses were markedly different in all parameters among fish species. The histopathological analysis showed hyperplasia, fusion, and aneurism in the gills as well as degeneration, integration of villi, necrosis and erosion of the intestine. Our findings indicated that compare to pure TiO2 NPs, exposure to transition metals-doped TiO2 NPs induced oxidative stress and histopathological changes in both fish species. PMID- 30408887 TI - Uptake, translocation, and accumulation of Cd and its interaction with mineral nutrients (Fe, Zn, Ni, Ca, Mg) in upland rice. AB - An analysis of the Cd and mineral nutrients accumulation of upland rice was performed in an experimental field with hard-ridged plots containing three soils with exogenous Cd addition at rates of 0, 0.25, 0.5, 1, 2, 4, 8, 16 mg kg-1 five years prior to commence this experiment. Aims of this investigation were to study uptake, translocation, and accumulation of Cd by an upland rice (Huyou2) and effects of Cd addition on the accumulation of Fe, Zn, Ni, Ca, and Mg. The results demonstrate the mean Cd content in the plant parts, from highest to lowest, were as follows: root, stem, leaf, and brown rice. The Cd content in the brown rice of the upland rice was below the limit of Cd in rice (0.2 mg kg-1) from China (GB 2762-2017) when the amount of Cd added was <= 1 mg kg-1. This observation can be attributed to lower TFsoil-grain of Cd in upland rice. Significant differences were observed between Cd concentrations present in brown rice from the three soils which can be mainly attributed to the differences in DTPA-extractable soil Cd because of different soil pH. Addition of high concentrations of Cd to soil was found to reduce Fe, Zn, Mg, and increased Ni uptake by the roots and their accumulation in brown rice. Altogether, results of this study suggest that it may be possible to cultivate upland rice in slightly Cd-polluted soils and Cd toxicity and accumulation in upland rice can be minimized by optimizing the macro and micronutrient composition of the soil. PMID- 30408888 TI - Role of pigment epithelium-derived factor (PEDF) on arsenic-induced neuronal apoptosis. AB - Chronic exposure to high levels of arsenic is closely associated with nervous system disorders that harm learning, memory, and intelligence. Studies have shown that the primary characteristic of brain damage is neuronal apoptosis. Arsenic induces apoptosis in a variety of nerve cells. Therefore, substance that inhibit apoptosis promise to mitigate arsenic toxicity. Pigment epithelium-derived factor (PEDF) is widely distributed in brain tissues and has various effects on neurons, including induction of apoptosis. Our previous study suggested that PEDF might augment arsenic-induced apoptosis in rat brains. In this study of 151 adults with normal, mild, moderate, and high exposure to arsenic, the measured serum PEDF levels were 15.46 +/- 5.87 ng/mL, 17.33 +/- 8.22 ng/mL, 19.43 +/- 9.51 ng/mL and 21.65 +/- 14.46 ng/mL, respectively. Multiple linear regression analysis revealed an independent positive correlation between serum PEDF levels and arsenic exposure in drinking water. To study the underlying mechanism of arsenic-induced apoptosis, we exposed PEDF-transfected PC12 cells to NaAsO2. We discovered that NaAsO2--induced mitochondrial apoptosis was enhanced in cells that over expressed PEDF. Moreover, p53 up regulated modulator of apoptosis (PUMA) gene and B-cell lymphoma 2 (Bcl-2) protein were primary factors in the progression of arsenic induced apoptosis. Taken together, our results suggest that PEDF inhibition might mitigate arsenic toxicity to nerve cells. PMID- 30408889 TI - Adverse impact of nocturnal transportation noise on glucose regulation in healthy young adults: Effect of different noise scenarios. AB - BACKGROUND: Epidemiological evidence indicates an association between transportation noise exposure and a higher risk of developing type 2 diabetes. Sleep disturbances are thought to be one of the mechanisms as it is well established that a few nights of short or poor sleep impair glucose tolerance and insulin sensitivity in healthy good sleepers. OBJECTIVES: The present study aimed to determine the extent to which exposure to nocturnal transportation noise affects glucose metabolism, and whether it is related to noise-induced sleep alterations. METHODS: Twenty-one young healthy volunteers (nine women) participated in a six-day laboratory study starting with a noise-free baseline night, then four nights sleeping with randomly-presented transportation noise scenarios (three road and one railway noise scenario) with identical average sound level of 45dB but differing in eventfulness and ending with a noise-free recovery night. Sleep was measured by polysomnography. Glucose tolerance and insulin sensitivity were measured after the baseline, the last noise night and the recovery nights with an oral glucose tolerance test using Matsuda and Stumvoll insulin sensitivity indexes. Eleven participants were assigned a less eventful noise scenario during the last noise night (LE-group), while the other ten had a more eventful noise scenario (ME-group). Baseline metabolic and sleep variables between the two intervention groups were compared using a non parametric Mann-Whitney U test while mixed models were used for repeated measure analysis. RESULTS: All participants had increased glucoseAUC (mean+/-SE, 14+/-2%, p<0.0001) and insulinAUC (55+/-10%, p<0.0001) after the last noise night compared to the baseline night. 2h-glucose level tended to increase only in the ME-group between baseline (5.1+/-0.22mmol.L-1) and the last noise night (6.1+/-0.39mmol.L 1, condition: p=0.001, interaction: p=0.08). Insulin sensitivity assessed with Matsuda and Stumvoll indexes respectively decreased by 7+/-8% (p=0.001) and 9+/ 2% (p<0.0001) after four nights with transportation noise. Only participants in the LE-group showed beneficial effects of the noise-free recovery night on glucose regulation (relative change to baseline: glucoseAUC: 1+/-2%, p=1.0 for LE group and 18+/-4%, p<0.0001 for ME-group; Stumvoll index: 3.2+/-2.6%, p=1.0 for LE-group and 11+/-2.5%, p=0.002 for ME-group). Sleep was mildly impaired with increased sleep latency of 8+/-2min (<0.0001) and more cortical arousals per hour of sleep (1.8+/-0.6arousals/h, p=0.01) during the last noise night compared to baseline. No significant associations between sleep measures and glucose tolerance and insulin sensitivity were found. CONCLUSION: In line with epidemiological findings, sleeping four nights with transportation noise impaired glucose tolerance and insulin sensitivity. Based on the presented sound exposure, the eventfulness of the noise scenarios seems to play an important role for noise induced alterations in glucose regulation. However, we could not confirm our hypothesis that transportation noise impairs glucose regulation via deterioration in sleep quality and quantity. Therefore, other factors, such as stress-related pathways, may need to be considered as potential triggers for noise-evoked glucose intolerance in future research. PMID- 30408891 TI - Aspergillus and aspergillosis-Progress on many fronts. PMID- 30408890 TI - Assessment of impact of traffic-related air pollution on morbidity and mortality in Copenhagen Municipality and the health gain of reduced exposure. AB - BACKGROUND: Health impact assessment (HIA) of exposure to air pollution is commonly based on city level (fine) particle concentration and may underestimate health consequences of changing local traffic. Exposure to traffic-related air pollution can be assessed at a high resolution by modelling levels of nitrogen dioxide (NO2), which together with ultrafine particles mainly originate from diesel-powered vehicles in urban areas. The purpose of this study was to estimate the health benefits of reduced exposure to vehicle emissions assessed as NO2 at the residence among the citizens of Copenhagen Municipality, Denmark. METHODS: We utilized residential NO2 concentrations modelled by use of chemistry transport models to calculate contributions from emission sources to air pollution. The DYNAMO-HIA model was applied to the population of Copenhagen Municipality by using NO2 concentration estimates combined with demographic data and data from nationwide registers on incidence and prevalence of selected diseases, cause specific mortality, and total mortality of the population of Copenhagen. We used exposure-response functions linking NO2 concentration estimates at the residential address with the risk of diabetes, cardiovascular diseases, and respiratory diseases derived from a large Danish cohort study with the majority of subjects residing in Copenhagen between 1971 and 2010. Different scenarios were modelled to estimate the dynamic impact of NO2 exposure on related diseases and the potential health benefits of lowering the NO2 level in the Copenhagen Municipality. RESULTS: The annual mean NO2 concentration was 19.6 MUg/m3 and for 70% of the population the range of exposure was between 15 and 21 MUg/m3. If NO2 exposure was reduced to the annual mean rural level of 6 MUg/m3, life expectancy in 2040 would increase by one year. The greatest gain in disease-free life expectancy would be lifetime without ischemic heart disease (1.4 years), chronic obstructive pulmonary disease (1.5 years for men and 1.6 years for women), and asthma (1.3 years for men and 1.5 years for women). Lowering NO2 exposure by 20% would increase disease-free life expectancy for the different diseases by 0.3-0.5 years. Using gender specific relative risks affected the results. CONCLUSIONS: Reducing the NO2 exposure by controlling traffic-related air pollution reduces the occurrence of some of the most prevalent chronic diseases and increases life expectancy. Such health benefits can be quantified by DYNAMO-HIA in a high resolution exposure modelling. This paper demonstrates how traffic planners can assess health benefits from reduced levels of traffic-related air pollution. PMID- 30408892 TI - Fungal responses to reactive oxygen species. AB - Reactive oxygen species (ROS) such as hydrogen peroxide, produced externally or during normal metabolism, can damage different cell components and usually trigger a counteracting antioxidant response. The fact that animals and humans utilize ROS and related nitrogen reactive species to prevent fungal infection has generated great interest in defining the components of the antioxidant response and studying their role as virulence determinants in fungi. Here we review the role of specific enzyme and non-enzyme mediated antioxidant mechanisms in virulence, as well as the signal transduction mechanisms that fungal cells use to perceive high ROS levels and induce gene expression. We focus on Schizosaccharomyces pombe antioxidant responses, which involve a prokaryotic-type multistep phosphorelay coupled to a stress-response MAP kinase pathway and an AP 1 type transcription factor, in relation to homologous mechanisms in Aspergillus nidulans and the human pathogen A. fumigatus. Compared to S. pombe and other unicellular fungi, filamentous fungi have additional mechanisms to handle ROS, such as the presence of a larger number of phosphorelay sensor kinases, antioxidant enzymes and secondary metabolites with antioxidant functions. In addition, filamentous fungi have enzymes like the NADPH oxidases, which regulate multicellular development through ROS production and therefore, offer a unique opportunity to study the interplay between ROS production, perception and detoxification, and the role of these processes in cell differentiation and pathogenesis. PMID- 30408893 TI - Programmed cell death in the aspergilli and other filamentous fungi. AB - Programmed cell death (PCD), in which cells actively participate in their own death through the activation of defined pathways, has long been established as an important developmental pathway in metazoan systems but it is only recently that evidence for a primitive form of PCD in the fungi has come to light. While much of the evidence for this comes from studies in the yeast Saccharomyces cerevisiae, recent evidence strongly suggests the presence of a metacaspase (primitive orthologues of the mammalian caspases) independent and dependent pathways in the Aspergilli which can be activated by deleterious environmental stimuli such as starvation, oxidative stress and antifungal agents as well as developmentally during sporulation. Bioinformatic evidence for these pathways suggests that the PCD pathway(s) is more complex in the Aspergilli compared to yeasts. PMID- 30408894 TI - Animal models of Aspergillus infection in preclinical trials, diagnostics and pharmacodynamics: What can we learn from them? AB - Animal models of aspergillosis, particularly those studied in rodents, are an integral part of antifungal drug development. The capacity to control different variables is beneficial, allowing a well defined model system to be used to address various issues of efficacy with monotherapy, combinations, or immunotherapy. One beneficial aspect of the use of animal models is that they enable us to investigate novel indications of drugs prior to a clinical trial or where a clinical trial is impractical. Included in these types of studies is the testing of potentially preventative vaccines. Animal models also are useful for studying diagnostic assays, as well as pharmacology and toxicity. Thus, because of the ability of the best models to mimic human diseases, and our ability to infect genetically identical cohorts of the same age, sex, co-morbidities and risk factors, with an identical challenge inoculum at the same time, we are able to address issues in vivo that cannot be answered by in vitro tests. We also can have sufficient numbers of subjects for statistical analyses, can vary the severity of infection at will and can choose to terminate the experiments to enable using survival or clearance of residual infection as the efficacy end point. Are these animal models predictive of clinical efficacy, pharmacology and toxicity of an antifungal drug? No single model should be relied upon, as different models of aspergillosis in mice or other animals sometimes show somewhat different results. However, the accumulated wealth of experience has demonstrated the utility of these models in predicting clinical efficacy, pharmacology and toxicity. PMID- 30408895 TI - Identification of clinically relevant aspergilli. AB - As the number of cases of aspergillosis grows, the number of species reported to cause the disease is increasing. Historically, classification and identification of aspergilli was accomplished using morphological characteristics. A number of molecular, immunological and biochemical methods are now available. For the most part, the results of the various approaches concur, yielding similar results in identifying aspergilli, so the 'best' method for identification is the method that best suits the needs of the researcher or clinician. Each identification method has advantages and disadvantages which will be discussed herein. The paper contains a listing of some of the available identification systems from those that address the whole genus to those capable of separating intraspecific strains. PMID- 30408896 TI - Gene regulation in Aspergillus: From genetics to genomics. AB - A fundamental aspect of any organism's success is the ability to monitor and respond effectively to its environment, a process which is largely achieved through the appropriate regulation of gene expression. There are few better examples than fungi, which inhabit diverse and often hostile environments, ranging from leaf litter to the human body. Regulation can occur at many levels, and as we investigate specific genes in detail, the paradigm is one of increasing complexity. We will briefly review the different levels at which regulation is known to occur in Aspergillus and the insights gained from the available genome sequences. PMID- 30408897 TI - Old and new concepts of species differentiation in Aspergillus. AB - The classification of the genus Aspergillus has been studied by many taxonomists. The most important monograph on which most taxonomies are derived from is strictly based on phenotypical characters. Later revisions of certain Aspergillus sections have been predominantly nomenclatural changes and primarily used morphological criteria. Many new taxa were added particularly in the genera Emericella and Neosartorya. Identification of the most common and often important species remains problematic due to the variability in the phenotypic characters. This has caused errors in the literature, especially concerning the links to mycotoxin formation. The new taxonomies are based on a polyphasic approach using phenotypical characters together with multigene DNA sequences. In a polyphasic approach micro- and macromorphology, physiology, metabolites produced and molecular data are all important, and in principle no particular method should be overemphasized. In particular extrolite profiles have proven to be specific for the taxa and this has contributed to a stable species concept, but DNA sequence data have also been very valuable in critical revisions of species and their taxonomy and phylogeny. Examples of new classifications for species in section Circumdati, Flavi,Fumigati and Nigri are presented. Although the polyphasic approach might reveal clear cut species, problems may arise for some species if they are to be separated based only on their microscopic features and few physiological features. Suggestions for new methods in order to carry out more fast and precise identifications will be discussed. Full genome sequencing and DNA arrays offers exciting new bases for identifying the Aspergilli, but recent methods based on image analysis of accurately fingerprinted phenotypes are also very promising. However both methods require a stable and well resolved taxonomy and nomenclature. Validated careful phenotypic classification (taxonomy) together with phylogenetic treatment of DNA sequence data is a prerequisite for reliable rapid identification methods and database formation. Concerning identification, DNA bar coding will be possible in the future, either based on molecular methods or certain phenotypic features. PMID- 30408898 TI - Molecular typing of aspergilli: Recent developments and outcomes. AB - Aspergillus spp. have been the subject of numerous epidemiological studies. The most useful typing techniques are DNA based methods including the random amplified polymorphic DNA technique, microsatellite length polymorphisms, restriction fragment length polymorphism (RFLP) analysis using retrotransposon like sequences as probes, and multilocus sequence typing. The results of typing clinical isolates indicate that most of the invasive aspergillosis (IA) patients were infected by a single strain. Genetic analysis could not discriminate between clinical and environmental isolates of Aspergillus. fumigatus, indicating that every strain present in the environment is a potential pathogen if it encounters the appropriate host. The source of infection can also be monitored by typing. Typing studies led to the discovery of a new pathogenic species, A. lentulus, and to the identification of several species not known previously to be pathogenic. Typing studies revealed the existence of two genetically isolated groups within a global A. fumigatus population. Aspergillus fumigatus was found to be the first example of a true cosmopolitan fungus. Additionally, the results obtained in several studies support the premise that recombination played an important role in A. fumigatus populations. The discovery of functional mating type genes in A. fumigatus indicates that past or recent sexual processes could be responsible for the observed recombining population structure. PMID- 30408899 TI - Defining the diagnosis of invasive aspergillosis. AB - Invasive aspergillosis (IA) is a leading cause of death in severely immunocompromised patients. Delayed diagnosis remains a major impediment to successful treatment of IA. Conventional diagnostic methods based on use of histology and culture remain the cornerstone of diagnosis of IA. However, they have a low yield, and performance of them is frequently precluded in patients with cytopenia and/or underlying comorbidities. In recent years, efforts have been directed toward identifying non-culture-based markers for early, reliable diagnosis of IA by detection of Aspergillus components such as galactomannan (GM), 1,3-beta-D-glucan, and DNA. Studies of profoundly neutropenic hematopoietic stem cell transplant recipients on fluconazole prophylaxis have shown high sensitivity (67-100%) and specificity (86-99%) rates for the GM assay. However, the performance of the GM assay in other settings, including pediatric patients, patients receiving mould-active antifungal prophylaxis, patients with GvHD and recipients of solid organ transplants, is suboptimal. Other factors, such as the pretest probability of infection, sequestration of Aspergillus lesions, the patient's immune status, the presence of anti-GM antibodies, antibacterial therapy, and diet, may also affect both the performance and interpretation of the GM assay. A colorimetric assay for the detection of 1,3-beta-D-glucan, an integral cell-wall component of most pathogenic fungi, has shown promising sensitivity (55-100%) and specificity (52-100%) in limited studies. Polymerase chain reaction (PCR) analysis of Aspergillus DNA is also a promising method for early detection of IA and other opportunistic fungal infections. The sensitivity of PCR is excellent, but its low level of specificity for invasive infections can be problematic. Multiple unresolved issues accompany the use of PCR for diagnosis of IA, including the sample type, amplification strategy, protocol, and primer selection, and account for the lack of a standardized, commercially available assay. Comparative prospective evaluation of non-culture-based assays would facilitate their incorporation into pre-emptive strategies for the optimal management of IA. Combinations of non-culture-based assays could enhance their performance and broaden the spectrum of detectable fungi. Clearly, there is a need for innovation in this area. Preclinical studies suggest that detection of secondary metabolites for Aspergillus and use of novel immunolabeling approaches to positron emission tomography are potentially new avenues for the development of novel diagnostics. In view of the evolving epidemiology of opportunistic mould infections, developing diagnostic strategies to distinguish between pulmonary aspergillosis and other lung mycoses is another important future research direction. PMID- 30408900 TI - Defining a case of invasive aspergillosis by serum galactomannan. AB - The timely diagnosis of invasive aspergillosis (IA) remains difficult. In recent years, increased experience has been gained with the PlateliaTM Aspergillus enzyme immunoassay. However, the excellent sensitivity and high positive predictive value that has been reported in earlier studies cannot consistently be reproduced in some of the more recent studies. As expected, this stems from major methodological and clinical heterogeneities between studies. This article reviews these between-study heterogeneities and concludes that the detection of serum galactomannan can be used to define a case of IA in a well-defined population of at-risk patients. PMID- 30408901 TI - Issues with galactomannan testing. AB - Within the past decade detection of the aspergillus antigen galactomannan has become an important and reliable tool for the early diagnosis of invasive aspergillosis. The galactomannan molecule, that is detected by the commercial sandwich ELISA (Platelia Aspergillus, Biorad), was found not to be a single molecule, but a family of molecules that have the epitope that reacts with the monoclonal antibody. Also the cut off level is now world-wide lowered to 0.5 which will help to further standardize and compare this diagnostic tool. Despite the advantages of galactomannan detection, there are several issues that have impact on its use in clinical practice. Both false negative and false positive reactivity is encountered and although the causes of false reactivity are not fully understood, new insights have become available which help us to optimize the use of the assay. This review discusses present issues with galactomannan testing with a view to future research and management. PMID- 30408902 TI - Usefulness of determination of beta-D-glucan in the diagnosis of deep mycosis - experience in Japan. AB - The G-test was developed in 1992 by Obayashi et al. as a serological diagnostic test for the measurement of beta-D-glucan (BDG). A multicenter clinical study demonstrated the utility of the G-test for the diagnosis of deep mycosis with a sensitivity of 90% and specificity of 100%. Determination of BDG has found wide application in Japan, particularly in the fields of hematological diseases and hematopoietic stem cell transplants. A case of invasive pulmonary aspergillosis in which BDG determination was useful for diagnosis was presented. BDG was expected to serve as an extremely useful method of screening of deep mycosis. The possibility of BDG as a surrogate marker for a presumptive therapy of patients with fever not responding to broad-spectrum antibiotics was discussed. PMID- 30408903 TI - Aspergillus PCR - Platforms, strengths and weaknesses. AB - PCR is a useful tool to aid in the diagnosis of invasive aspergillosis. However, it is essential that an optimal method be agreed to allow inclusion in future consensus diagnosis criteria. It should be used in conjunction with other methods (e.g., galatomannan (GM) ELISA and high resolution computed tomography (HRCT)) to enhance the opportunity for detection of this devastating infection. This manuscript will try to highlight the benefits but mainly the limitations occurring throughout the process of molecular testing. It will focus on real-time methods although many of the points will be relevant to block-based amplification. PMID- 30408904 TI - Early diagnosis of invasive aspergillosis in infants and children. AB - Effective management of invasive aspergillosis (IA) requires early and accurate diagnosis. Microscopy and culture of appropriate specimens remain the gold standard of mycological diagnosis. High-resolution computed tomography serially performed constitutes a sensitive mode of diagnosis of pulmonary IA in hematological patients, but similar data is lacking for children. While early diagnosis of IA has been improved with galactomannan assay in adults, its use is problematic in young infants due to specificity inferiority. Galactomannan testing also is characterized by low sensitivity in pediatric patients with primary immunodeficiencies including chronic granulomatous disease and Job's syndrome. Beta-D glucan assay has been studied in adult patients with fungal infections including IA. The high negative predictive value of the assay allows its use for excluding IA; no specific data, however, exist for children. Polymerase chain reaction (PCR) may be a powerful tool for early diagnosis of IA but has not been standardized for routine use yet. No studies address the issue in neonates, whereas in children PCR has not been specifically studied but is probably as good as in adults. A high degree of suspicion in immunodeficient pediatric hosts, suggestive clinical and radiological findings, as well as mycological data by application of multiple diagnostic methods including serology and molecular biology, are expected to enhance the capacity to diagnose IA in young patients. PMID- 30408905 TI - Fungal pneumonia, chronic respiratory diseases and glucocorticoids. AB - Invasive pulmonary aspergillosis (IPA) usually occurs in severely immunocompromised patients. The expanded use of glucocorticoids (GC) in clinical practice accounts for the increasing number of fungal infections reported in mildly or non-immunocompromised hosts. We report a series of 8 patients with fungal pneumonia in whom long term high dose GC treatment was the only risk factor for opportunistic infections. All patients except one had chronic underlying disorders (asthma, idiopathic fibrosis, chronic obstructive pulmonary disease, COPD). Seven patients were diagnosed with pulmonary aspergillosis. Etiological suspicion of fungal infection was obtained during lifetime in six cases and in one case was confirmed only in the post-mortem examination. In most cases bronchoscopic techniques allowed identification of the microorganism. However, delay in establishing the diagnosis (mean 20 days) precluded a prompt initiation of a specific treatment. The course of the fungal infection was ominous. All but one patient experienced progressive respiratory failure requiring ICU admission and mechanical ventilation support. Despite this, all of them died. The only survivor was a patient receiving early empirical antifungal treatment due to a high clinical suspicion of fungal infection. Based on the present and previous findings, antifungal treatment should be considered in chronic respiratory patients requiring high or repetitive doses of GC when there is clinical evidence of pneumonia and isolation of Aspergillus spp. from respiratory secretions. PMID- 30408906 TI - Interaction of Aspergillus fumigatus with the alveolar macrophage. AB - Aspergillus fumigatus is a human pathogen, able to cause invasive aspergillosis in immunosuppressed patients. In the immunocompetent situation inhaled conidia are easily cleared by the immune system. Knowledge of the cellular pathways involved in the innate immunity against A. fumigatus is poorly represented. Therefore, we aimed to investigate the immune response against A. fumigatus in murine alveolar macrophages in terms of MAP kinases, NF-kappaB and cytokine signalling. Our investigations revealed that in murine alveolar macrophages, MAP kinases, ERK and p38 are activated under in vitro conditions, following addition of A. fumigatus conidia. In vivo experiments, however, showed that only ERK is directly involved, because activation of p38 was negligible. Immunosuppression with corticosteroids inhibited phosphorylation of ERK and was directly accompanied with a strongly decreased level of TNF-alpha and additional cytokines. In addition, killing of A. fumigatus conidia is reduced using the ERK inhibitor. Therefore, ERK appears to be an essential MAP kinase in the defence against A. fumigatus. Activation of the transcription factor NFkappaB appeared only at late times after infection suggesting an association with the intracellular swelling of conidia. PMID- 30408907 TI - Toll-like receptors: Recent advances, open questions and implications for aspergillosis control. AB - Aspergillus fumigatus is a pathogenic mould that can cause severe and life threatening infections in immunocompromised patients. Apart from novel and improved antifungals, additional strategies are required to protect patients at risk from developing invasive aspergillosis. Given the problems in diagnosis of this disease, important perspectives lie in attempts to elicit and strengthen a protective immunity. The innate immune system is the first line of defence against A. fumigatus. Phagocytes engulf and kill inhaled conidia, but also closely communicate with the adaptive immune system. Recognition of invading microbes is mediated by pattern recognition receptors (PRRs), and Toll-like receptors (TLR) 2 and TLR4 have been implicated in the immune response to A. fumigatus. The analysis of this process is hampered by the fact that A. fumigatus infections are inevitably coupled to germination resulting in the appearance of different fungal morphotypes, like conidia and hyphae. While conflicting data still exist on the relative importance of TLR2 and 4 in recognition of distinct A. fumigatus morphotypes, recent evidence suggests that certain TLR agonists can be used to divert the immune response towards an optimal fungicidal activity in the absence of detrimental inflammatory consequences. PMID- 30408908 TI - Th1/Th2 in aspergillosis. AB - The outcome of the Th1/Th2 balance is a critical determinant of the outcome in invasive aspergillosis. The innate immune system encounters the pathogen first. Dendritic cells (DC) appear to be the critical fulcrum at the intersection of the innate immune system, and which receptors are engaged, particularly which Toll like receptors are triggered by the pathogen, likely determines which co stimulatory molecules are expressed during the DC maturation process, and thus which cytokine pathway will eventually dominate. Some proinflammatory cytokines initially produced by naive phagocytes may also direct dendritic cell direction. Thus DC are the main connections of the innate and adaptive immune systems. The cytokine pathway may be affected by the antigen load, whether and what type of immunosuppressive drug or immunosuppressive co-morbidity is present, the pathogen's success in converting from conidia to hyphae, the pathogen's production of toxins, and later whether appropriate antimicrobial chemotherapy is given. Chemokines triggered by cellular interaction with the pathogen call different host cell populations to the site of infection, collectins affect the phagocyte-fungus interaction, and the cytokines produced by the adaptive immune system then regulate the antifungal power of mononuclear phagocytes and polymorphonuclear neutrophils. In these ways the innate and adaptive immune systems work together in host defense. The key cytokines associated with a successful outcome of Aspergillus infection are upregulation of Th1 and proinflammatory cytokines IFNgamma, TNFalpha, IL-12, GM-CSF, IL-1, IL-6 and IL 18, and down-regulation of IL-4 and IL-10. The converse is associated with progressive disease. The most data about favorable cytokine effects on phagocytes vs. Aspergillus concerns IFNgamma, GM-CSF and G-CSF, and for unfavorable effects, IL-10 and IL-4. GM-CSF and IFNgamma have also been shown to possess the ability to reverse the down-regulating effects of immunosuppressants on anti-Aspergillus phagocyte function. Neutralization of several Th1 cytokines in vivo has been shown directly to result in a bad outcome of infection, whereas administering Th1 or proinflammatory cytokines or neutralizing Th2 cytokines has been shown to produce a favorable outcome. Antifungal chemotherapy is associated with a switch to a Th1 profile, and antifungal chemotherapy combined with Th1 cytokine immunotherapy acts synergistically. Thus improved definition of the Th1/Th2 balance is essential for future prospects for immunotherapy, antimicrobial chemotherapy, and vaccination. PMID- 30408909 TI - Relative reactivity of Aspergillus allergens used in serological tests. AB - Aspergillus is a common disease-causing agent, both as an allergen causing ABPA and severe asthma with fungal sensitization (SAFS) and as a pathogen causing invasive aspergillosis in immunocompromised individuals and chronic cavitating disease (CCPA) in apparently immune competent individuals. Currently detection of Aspergillus is problematic and some of the most useful tests rely on detection of antibody response to Aspergillus allergens. Here we examine the IgE antibody response to crude and recombinant allergen tests (Asp f 1, Asp f 2, Asp f 4 and Asp f 6) in individuals with allergic conditions ABPA, SAFS and in individuals with CCPA. Additionally we use recently obtained genomic information to examine the possibility of cross reaction to these allergens and show that possible cross reactive epitopes occur in several species of Aspergillus. PMID- 30408911 TI - Asthma and mould allergy - Does it matter? PMID- 30408910 TI - Manipulating immunity against Aspergillus fumigatus. AB - Efficient response to Aspergillusfumigatus requires different mechanisms. Polymorphonuclear neutrophils (PMNs) are the predominant immune cells in the acute stage of most fungal infections and play a crucial role in determining the type of pathology associated with fungal infections in different clinical settings. Dendritic cells (DC) are able to decode the fungus-associated information and translate it into different T helper (Th) and regulatory (Treg) cell responses. Functionally distinct Treg cells are activated after exposure to Aspergillus conidia. Early in infection, inflammation/Th1 reactivity is controlled by Treg cells suppressing PMNs and the immunogenic program of DC. The levels of IFN-gamma produced in this phase set the subsequent adaptive stage by conditioning the indoleamine 2, 3-dioxygenase (IDO)-dependent tolerogenic program of DC and the subsequent activation of tolerogenic Treg cells, which inhibit Th2 cells and prevent allergy to the fungus. Knowledge of the immunopathogenesis of Aspergillus infections may pave the way to promising strategies for immunotherapy. PMID- 30408912 TI - Structural aspects and clinical relevance of Aspergillus fumigatus antigens/allergens. AB - Robotics-based high throughput screening of Aspergillus fumigatus cDNA libraries displayed on phage surfaces revealed at last 81 different structures able to bind IgE from serum of patients sensitized to this fungus. Among these, species specific as well as phylogenetically highly conserved structures and such with unknown function have been detected. A subset of cDNAs have been used to produce and characterize the corresponding recombinant allergens which have proven to be useful diagnostic reagents allowing specific detection of A. fumigatus sensitization and differential diagnosis of allergic bronchopulmonary aspergillosis. Phylogenetically highly conserved structures like manganese dependent superoxide dismutase, P2 acidic ribosomal protein, cyclophilins and thioredoxins induce, beyond sensitization, IgE antibodies able to cross-react with the corresponding homologous self antigens. These reactions, likely to contribute to the exacerbation and perpetuation of allergic bronchopulmonary aspergillosis, can be traced back to shared conformational B-cell epitopes build up from conserved amino acid residues scattered over the surface of the molecules as shown by detailed analyses of the crystal structures. PMID- 30408913 TI - Critique of trials in allergic bronchopulmonary aspergillosis and fungal allergy. AB - Treatment of allergic bronchopulmonary aspergillosis (ABPA) emerged from uncontrolled published series of patients on prolonged oral glucocorticosteroids. Oral steroids remain the mainstay of treatment, but dose regime and duration have never been standardized. Oral steroids are problematic due to frequency of relapse, lack of steroid action on airway fungal burden and toxicities. Prospective randomized double-blind placebo-controlled trials of inhaled corticosteroids (n=1) or oral itraconazole (n=2) in patients with asthma and ABPA have shown efficacy for the latter drug only. Itraconazole is an effective steroid-sparing agent with anti-inflammatory aspects. Use of inhaled budesonide with itraconazole can lead to adrenal suppression due to inhibition of hepatic cytochrome P450. Despite combined use of oral steroids and itraconazole in ABPA, relapses and steroid dependence or toxicity have led to examination of alternative agents in uncontrolled case reports and series. Reports of nebulized amphotericin B in several patients with cystic fibrosis (CF) and ABPA suggest a potential benefit. Voriconazole has also been used with some success but also some toxicity. Both itraconazole and voriconazole have also been used in some CF ABPA patients as monotherapy with mixed results. A recent report described treatment of refractory CF-ABPA with monthly high-dose intravenous (IV) methylprednisolone, also with mixed results. No controlled trials of voriconazole, inhaled amphotericin, or IV pulse steroids have been published. Future studies should focus on controlled trials of antifungal and immunomodulatory agents since conventional steroid therapy remains problematic. PMID- 30408914 TI - Risk factors for allergic Aspergillus sinusitis. AB - Allergic Aspergillus sinusitis is a type of allergic fungal sinusitis (AFS), a form of chronic rhinosinusitis with pathological findings similar to those seen in allergic bronchopulmonary aspergillosis (ABPA). There are no evidence-based criteria for diagnosis or management, and the pathogenesis is unknown. Known risk factors are underlying chronic rhinitis, exposure to Aspergillus fumigatus, and the ability to make an IgE-mediated allergic response to that organism. While many individuals meet these conditions, it is not known why only some go on to develop allergic Aspergillus sinusitis. Speculative risk factors are unknown conditions permitting fungal growth, concomitant superantigen responses, and HLA associations. PMID- 30408915 TI - Allergic fungal rhinosinusitis: A review of clinical manifestations and current treatment strategies. AB - Allergic fungal rhinosinusitis is a relatively newly characterized disease entity that commands a great deal of interest. Large amounts of information are being generated addressing the underlying etiology of the disease, its clinical presentation, and forms of treatment. Although controversy still exists, recent evidence supports the theory that AFRS represents an immunologic, rather than infectious, disease process. An improved understanding of this underlying disease process has led to an evolution in the treatment of AFRS. PMID- 30408916 TI - Consensus definitions for invasive fungal disease: Strengths, limitations, and revisions. AB - The European Organization for Research and Treatment of Cancer (EORTC)/ Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (MSG) consensus definitions for opportunistic invasive fungal infections have achieved their objective in fostering better communication between researchers but their limitations necessitated revision. In the last two years a group of experts drawn from both sides of the Atlantic have agreed a proposal for a new set of definitions that attempt to rectify omissions and problems arising from the original set whilst preserving their basic principles. PMID- 30408917 TI - Clinical antifungal efficacy trials in invasive aspergillosis: Consensus standards for trial design and room for improvement. AB - Despite recent improvements in outcome of invasive aspergillosis there are still high failure and fatality rates. The trial comparing voriconazole to amphotericin B deoxycholate has become a reference for clinical trials in invasive aspergillosis due to the large number of patients included, the use of definition criteria close to the international consensus criteria, the inclusion of the halo sign on chest computed tomography for the definition of probable cases, the extensive review of the data by a panel of experts including radiologists, and most important, the successful efficacy results. Similar strict methodology for eligibility and assessment of outcome has been applied in the recently completed liposomal amphotericin B trial. This study compared a standard daily dose of liposomal amphotericin B (3 mg/kg) versus a high loading dose (10 mg/kg/d). The option to include possible cases in this trial and to give the investigators a few days to upgrade the diagnosis to a probable or definite level proved to be an effective strategy, saving four months in the duration of the recruitment period. Additional progress can be expected in future trials with the use of a standardized cutoff for the galactomannan detection test and a stratification at randomization on the most critical prognostic factor such as progressive underlying malignancy or allogeneic stem cell transplantation. PMID- 30408918 TI - Challenges associated with indoor moulds: Health effects, immune response and exposure assessment. AB - Assessment of the health effects of indoor moulds is complicated by the diversity of mould species found in homes and the limitations of current methods to determine exposure. Thus it is difficult to establish whether there is a relationship between mould exposure and disease. Allergic respiratory diseases are commonly caused by Alternaria, Aspergillus, Cladosporium and Penicillium spp. IgE-mediated sensitization to these moulds is a strong risk factor for asthma: IgG and IgE antibody responses to Aspergillus fumigatus are common in patients with other respiratory diseases, including allergic bronchopulmonary aspergillosis and cystic fibrosis. Several important mould allergens have been cloned with different biologic functions. These allergens can also serve as immunologic markers which may be associated with disease activity. Evidence for health effects associated with exposure to mould toxins e.g. from Stachybotrys spp. is less compelling. Recently, several new technolgies have been introduced which could be applied to mould exposure assessment. Ion-charging devices can silently sample air within homes and have been successfully used to monitor animal allergens. Fluorescent multiplex array technology is being used to make quantitative measurements of five to ten allergens simultaneously on dust samples. The development of monospecific (monoclonal or polyclonal) antibodies to specific fungal antigens or allergens will facilitate more accurate assessments of the mould burden in homes, schools and commercial buildings. The application of these techniques in well-designed clinical studies will enable better understanding of the health effects of moulds. PMID- 30408919 TI - Challenges of patient recruitment for invasive aspergillosis trials. AB - The main challenge in patient recruitment for invasive aspergillosis (IA) trials is to include a maximum number of patients for a minimum length of time, bearing in mind that the final objective is to improve the prognosis of patients with IA. Theoretically, all that is needed is a good drug and a good strategy. The analysis of patient recruitment rates in the most recent important trials of fist line and salvage therapy of IA shows that they are quite low, ranging from two to 18 patients per month, despite high numbers of participating countries and investigators. Several difficulties are encountered: IA is not a frequent disease and inclusion criteria may well exclude patients with true aspergillosis. Competing IA trials and concomitant non IA protocols are often conducted at the same center. Conversely, large numbers of patients (hundreds) are mandatory in the frequently chosen 'non-inferiority' trials. Considering the fact that a significant number of IA cases are not diagnosed premortem, new diagnostic methods should be developed to allow an early diagnosis and thus increase the number of treatable patients. Furthermore, the choice of other endpoints for assessing antifungal activity could decrease the duration of studies and, hopefully, the number of needed patients. PMID- 30408920 TI - Dose finding in aspergillosis. AB - Invasive aspergillosis (IA) continues to represent a significant challenge for physicians in charge of immunocompromised patients. Voriconazole, caspofungin, itraconazole, and the different formulations of amphotericin B (AmB) are all approved for therapy of IA. To collect information on the effect of high dose of antifungals in the treatment of IA, data from the available medical literature were reviewed. For AmB there are no data demonstrating any better clinical activity of doses higher than standard. For liposomal-AmB preliminary data seem to show that high doses are not more efficacious than the standard dose, and it is probably more toxic. Anecdotal data of itraconazole suggest that high dosages might be feasible and it has been associated with good clinical results. Unpublished data about voriconazole suggest the absence of any better activity of high plasma concentrations. For caspofungin the efficacy of higher dosage did not seem to be better than that obtained with the traditional dosage. Prospective studies are required, because many confounding factors may obscure the effects of the higher dosages when data are retrieved retrospectively. PMID- 30408921 TI - Whole genome comparison of the A. fumigatus family. AB - The availability of the genome sequences of multiple Aspergillus spp. presents the research community with an unprecedented opportunity for discovery. The genomes of Neosartorya fischeri and Aspergillus clavatus have been sequenced in order to extend our knowledge of Aspergillus fumigatus, the primary cause of invasive aspergillosis. Through comparative genomic analysis, we hope to elucidate both obvious and subtle differences between genomes, developing new hypotheses that can be tested in the laboratory. A preliminary examination of the genomes and their predicted proteomes reveals extensive conservation between protein sequences and significant synteny, or conserved gene order. Comparative genomic analysis at the level of these closely related aspergilli should provide important insight into the evolutionary forces at play and their effect on gene content, regulation and expression. PMID- 30408922 TI - The debate: The trials have told us very little. AB - The original trials of empiric intravenous amphotericin-B in the 1980s failed to prove conclusively its efficacy in the treatment of febrile neutropenia. Despite that, all subsequent studies of the therapy of presumed, possible, probable and proven invasive aspergillosis have assumed that this drug, either as deoxycholate or in lipid-based form, is the gold standard treatment against which all newcomers should be compared. This has led to a series of further inconclusive randomized controlled trials of empiric therapy as a result of which the most we can say is that nearly all new drugs are less toxic but also no more effective than amphotericin-B deoxycholate. The toxicity of the non-lipid formulation of this drug should have led us to withdraw it from both RCTs and routine clinical practice some years ago in view of the increasing evidence of equivalent efficacy and lower toxicity of other agents including lipid amphotericin formulations.Recent studies of the use of newer diagnostic techniques (i.e., CT and serology) reinforce the need to abandon the empiric trial approach in which we have repeatedly shown lack of superiority in the treatment of an infection which most patients do not have. Even in the small number of trials of the therapy of proven or probable invasive aspergillosis, results have been inconclusive or at best confusing in trying to find a better option than amphotericin-B. The trial of voriconazole versus amphotericin-B deoxycholate for this indication is a model for study for all those interested in the difficulties of designing trials which lead to convincing results.Effective prophylaxis trials and their analyses began by following a more rational pathway, first showing convincingly that fluconazole reduced the risk of C. albicans systemic infection in transplant patients. Unfortunately the widespread faith in the ability of this drug to prevent a wider range of systemic fungal infections in a wider range of patients is simply not supported by the data from many subsequent single trials and meta-analyses. This attachment to fluconazole has been mirrored by unwillingness to accept the evidence that itraconazole is superior in prophylaxis to fluconazole which is inactive against Aspergillus spp. In this case the trials have not told us enough because we have not believed the results. Results of trials of extended range azoles such as posaconazole are interesting but there are insufficient data to claim that posaconazole is superior to itraconazole.The progress in therapy and prophylaxis of systemic fungal infection has been unsatisfactory and slow. A new approach is needed for the design of clinical trials for these indications. There is good evidence that supportive investigations should now be used routinely in clinical practice and trials to increase certainty about the presence of invasive infection, to limit unnecessary use of expensive and toxic drugs and to improve analysis of efficacy of old and new antifungal agents. PMID- 30408923 TI - Defining clinical failure for salvage studies. AB - In patients with invasive aspergillosis (IA), there are numerous clinical settings where stable disease or progression of findings or deterioration of the patient's condition does not indicate failure, and subsequent response to a 'salvage' antifungal is not necessarily attributable to this drug. Many patients, in whom pulmonary aspergillosis emerges during profound neutropenia, show enlargement of their lesions on computer tomography (CT) scans, eventually accompanied by clinical deterioration, during hematopoietic recovery. This may in fact represent the recruitment of neutrophils and monocytes to the pulmonary 'battlefield', resulting in a favorable clinical outcome also without changing antifungal treatment. Infarcted tissue may contain vital filamentous fungi, because it is poorly penetrated by the antifungal, not indicating a lack of efficacy of this drug against the respective fungal pathogen. In patients treated with an echinocandin, serum galactomannan levels may increase despite successful treatment. Piperacillin-tazobactam or other semi-synthetic beta-lactam antibiotics may cause false positive serum Aspergillus galactomannan levels. Patients primarily treated with a lipid formulation of AmB (LF-AmB), who are switched to a 'salvage' antifungal, will unequivocally receive a combination therapy due to the persistence of high LF-AmB concentrations in tissue. Criteria to define 'clinical refractoriness', 'resistance', 'non-response' or 'failure' respectively should be re-defined. One option to establish a more valid definition would be to use a composite score including clinical as well as radiological and microbiological or mycological criteria. The latter may include non-culture based methods such as serum galactomannan. Assessment should not be made earlier than after seven days of full-dose systemic antifungal treatment. However, in individual cases, e.g. a patient with hematopoietic recovery, who shows an increasing volume of pulmonary aspergillosis and clinical deterioration, it may be recommended to refrain from switching the patient to another regimen and continue the current antifungal treatment for another seven days before failure is stated. Clinical studies on second-line antifungal treatment for IA should be randomized and blinded, patients should be evaluated separately with respect to their reason for 'failure' of primary antifungal treatment, and stratified according to their previous antifungal treatment. Ideally, the first line regimen would be standardized. Host criteria such as neutropenia or graft versus-host disease (GVHD) should be clearly defined and documented with respect to their course over time, and patients should be stratified according to these criteria. A three-arm study (continuation of primary antifungal vs. combination of primary antifungal with a 'salvage' drug vs. the 'salvage' drug alone) would be ideal. PMID- 30408924 TI - Antifungal susceptibility testing in Aspergillus spp. according to EUCAST methodology. AB - The availability of new antifungal agents has multiplied the demand for in vitro antifungal susceptibility testing for Aspergillus spp. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) has charged its Antifungal Susceptibility Testing Subcommittee (AFST-EUCAST) with the preparation of new guidelines for in vitro susceptibility testing of antifungals against Aspergillus spp (EUCAST-AST-ASPERGILLUS). This committee has modified the reference method for broth dilution antifungal susceptibility testing of filamentous fungi (M38-A) as follows: (i) RPMI 1640 supplemented with 2% glucose (RPMI 2%G) as assay medium, (ii) inoculum preparation by conidium counting in a haemocytometer and (iii) an inoculum size of 2*105-5*105 CFU/ml. The incubation time is about 48 h at 35 degrees C and MIC is read visually. The MIC value is a no-growth visual endpoint. The standard method described herein is intended to provide a valid and economic method for testing the susceptibility to antifungal agents of Aspergillus spp., to identify resistance, and to facilitate an acceptable degree of conformity, e.g. agreement within specified ranges and between laboratories in measuring the susceptibility. PMID- 30408925 TI - Novel preventative strategies against invasive aspergillosis. AB - Invasive fungal infections, such as invasive aspergillosis (IA) represent a major threat to immunocompromised patients, especially patients with hematological malignancies or who receive hematopoietic stem cell transplantation. Hence, prevention of IA is a critical strategy that requires a clear understanding of the mould's environmental sources and how it is transmitted to immunocompromised patients. Knowledge of the exposure, mechanisms of transmission, and host susceptibility to IA are vital in selecting appropriate preventive strategies to those settings where infection is more likely to occur. Among the strategies to reduce the incidence of IA is the maintenance of high quality air, i.e. air with low spore counts in hospital areas visited by patients at risk. Housing patients in laminar airflow facilities with high-energy particulate air-filtered rooms helps prevent IA, but it is only realistic and cost-effective for the highest risk groups and for limited time periods. Air filtration is a costly preventive strategy of questionable value when done with portable filtration units. Moreover, air control measures outside the hospital are extremely difficult to implement and this is important since the majority of cases of IA after allogeneic stem cell transplantation occurs during the post-engraftment period. For these reasons, targeted antifungal prophylaxis remains the most promising of the potential prevention strategies against IA. Many older and newer antifungal agents have been used for this purpose. Amphotericin B, being the oldest and most widely used antifungal, has been used prophylactically in various doses and schedules, but has largely been replaced by its lipid and liposomal formulations that have improved safety profile. Although prophylactic fluconazole prevents candidiasis, this drug has no activity against moulds, including Aspergillus spp. On the other hand itraconazole appears to prevent IA in those patients who can tolerate the drug, since its poor tolerability limits its use. The newer extended spectrum triazole posaconazole has been used in prophylactic trials with encouraging results in selected populations of patients at risk. Voriconazole, another extended spectrum triazole that has emerged as the treatment of choice for IA has been used as secondary prophylaxis in immunocompromised patients with history of IA. Echinocandins, such as caspofungin and micafungin appear to be extremely safe and effective for primary and secondary prophylaxis of IA. Patients undergoing transplantation for hematological malignancies from mismatched or unrelated donors are clearly at higher risk of IA compared to patients undergoing autologous transplantation, since among other risk factors they frequently receive moderate doses of corticosteroids for extended periods for Graft vs. Host Disease (GvHD), a well-known risk factor for IA. Hence, results of studies in specific populations should be analyzed with caution and prophylaxis should be applied to similar patients, because antifungals are not devoid of side effects and overuse selects for resistant fungi. In conclusion, more studies are clearly needed to better define patient populations who will clearly benefit from prophylactic antifungal therapy against IA. PMID- 30408926 TI - Managing building-related Aspergillus exposure. AB - Aspergillus exposure is difficult to avoid. Indoor dust contains spores and thermotolerant molds may colonize damp or water-damaged building materials or components. Dust control should be part of diligent maintenance since disturbing dusts, especially during building renovation, can expose occupants to spores. Colonization of HVAC systems can shed spores into a building and expose occupants. Mold colonization warrants prompt and effective remediation, including removal of the colonization with associated debris and dusts without unduly exposing remediation workers, and while controlling fugitive dusts. Cleaning may suffice for non-porous surfaces, but colonized porous materials typically must be removed. Determining successful remediation can be challenging; the objective is not to sanitize, but a building in a 'normal and typical' state, a state that is often poorly defined. This is even more troublesome for colonized HVAC components and for health care facilities. Practical remediation assessment emphasizes inspection and then environmental monitoring. Air sampling may prove useful after inspection and monitoring, assuming prior consensus on the purposeof sampling and interpretation of results. Thoughtful design, careful construction and renovation, and diligent operation and maintenance of a building are all needed to minimize the exposure of building occupants to mold. PMID- 30408927 TI - Antifungal strategies for managing invasive aspergillosis: The prospects for a pre-emptive treatment strategy. AB - Invasive Aspergillosis (IA) is now the leading infectious cause of mortality in patients with haematological malignancies. Studies have identified those patient groups and the time-periods associated with high-risk for IA. The current management strategies for IA include prophylaxis and empiric antifungal therapy (EAFT). The rationale for prophylaxis in high-risk patients exists. However toxicities, drug interactions and breakthrough infections limit the benefits and the optimal duration for prophylaxis remains unknown. In recent EAFT studies in high-risk patients, <10% of persistent febrile neutropenic episodes were due to IA, suggesting that a disproportionate number of patients are treated with EAFT resulting in unnecessary drug-related costs. An increasing proportion of IA occurs in the absence of fevers and neutropenia, thus use of febrile neutropenia as the trigger to administer antifungal therapy will fail a significant proportion of patients. Recent research efforts have focused on the development of sensitive, specific and rapid diagnostic tests for IA, such as Aspergillus polymerase chain reaction (PCR) and antigen testing, which may be of value in guiding pre-emptive treatment strategies. However, studies evaluating the impact of pre-emptive therapy on patient outcomes and health-care costs have yet to be completed. Practical issues such as the combination of tests used and frequency of testing need to be resolved. PMID- 30408928 TI - Managing drug interactions in the patient with aspergillosis. AB - Drug interactions are a common and recurring problem in immunocompromised patients with aspergillosis. While the introduction of new antifungals has expanded opportunities for lowering drug toxicity, virtually all antifungal regimens still carry the risk for pharmacokinetic and pharmacodynamic interactions. Drug interactions affecting the pharmacokinetics of antifungals used in the treatment of aspergillosis, or interactions that decrease the metabolism/elimination of a drug with a narrow index for efficacy (e.g. anti retroviral therapy) or safety (e.g. immunosuppressants, chemotherapy) have the greatest potential to cause serious harm. Additionally, azole-based treatment regimens for aspergillosis carry a risk for uncommon, but potentially life threatening, interactions that affect cardiac conduction leading to severe tachyarrythmias such as Torsades des Pointes. Clinical diagnosis of antifungal drug interactions in immunocompromised patients remains a challenge, as adverse sequelae are often masked by infection or other drug therapies (especially chemotherapy). Therefore, a high index of suspicion and a proactive, multidisciplinary approach is essential for preventing drug interactions in patients with aspergillosis. Improvements in laboratory support (i.e. patient pharmacogenetic profiling, expanded use of serum drug level monitoring) will become increasingly important for managing drug interactions patients on complex treatment regimens. PMID- 30408929 TI - Treatment of invasive aspergillosis: Polyenes, echinocandins, or azoles? AB - Three classes of antifungals - the polyenes, the echinocandins, and the extended spectrum azoles - are now availabel for treating invasive aspergillosis (IA). New agents and formulations in these classes offer the possibility of decreased toxicity and improved outcomes. With the availability of newer antifungals, clinicians are challenged to understand the advantages and limitations of these new choices. Standard amphotericin B deoxycholate is associated with poor outcomes in addition to unacceptable toxicity and is no longer recommended as primary therapy for most patients. Lipid formulations of amphotericin reduce toxicity, but because of cost and toxicity concerns, they may not be used at optimal doses. Interestingly, a recent trial showed that initial use of higher doses of liposomal amphotericin at 10 mg kg-1 d-1 did not improve efficacy and was associated with more toxicity. Due to lack of complete killing or inhibition of Aspergillus, the echinocandins are not frequently used as primary therapy for aspergillosis, although their minimal toxicity and potential for combination therapy remains attractive. The newer triazoles, including voriconazole and posaconazole, offer fungicidal activity against Aspergillus and, for voriconazole, both intravenous as well as oral therapy. Voriconazole was compared with amphotericin B followed by other licensed therapy in a global trial that showed better outcomes and improved survival so that voriconazole is recommended as primary therapy for most patients with this disease. These studies also show that early, effective therapy is a key factor for a successful outcome. Consideration of risk for IA and early initiation of therapy may improve outcomes in this often lethal infection. PMID- 30408930 TI - Clinical efficacy of caspofungin in the treatment of invasive aspergillosis. AB - Caspofungin, the main representative of the echinocandin family has undergone a clinical experience that covers gradually the whole spectrum of the standard care of invasive aspergillosis (IA). Caspofungin salvage therapy in cases of previous therapy refractoriness or intolerance resulted in a 45% response rate. Empiric therapy with caspofungin compared with L-AMB in neutropenic patients with persisting fever showed an overall response rate of approximately 34%, with less toxicity for caspofungin. Combination therapy of caspofungin with other antifungal drugs has been studied mainly retrospectively in open non randomized trials and in one prospective non comparative small study showing an encouraging response rate of 55% as salvage combined treatment. The clinical experience with caspofungin as first-line therapy in IA is limited to 32 patients with an overall response rate of 56%. Caspofungin is well tolerated with very few histamine release reactions and a good toxicity profile. PMID- 30408931 TI - New resistance mechanisms to azole drugs in Aspergillus fumigatus and emergence of antifungal drugs-resistant A. fumigatus atypical strains. AB - Azole drug resistance in Aspergillus fumigatus is an uncommon but well-known phenomenon. The analysis of resistance mechanisms at molecular level has identified the bases for A. fumigatus azole resistance. To date, the most prevalent mechanism of azole resistance appears to be the modification of Cyp51, specifically mutations in cyp51A gene. These mutations have been associated with three different antifungal susceptibility profiles: (i) cross-resistance to itraconazole and posaconazole that has been associated with amino acid substitutions at glycine 54 (G54), (ii) elevated MICs to all azole drugs associated with amino acid substitutions at methionine M220, and (iii) cross resistance to all azole drugs related to the presence of Cyp51A substitutions at leucine 98 for histidine (L98H) linked to a duplication in tandem of a 34 bp repeat in the cyp51A promoter region, which seem to be responsible for increased cyp51A gene expression. Another matter of concern is the increasing reports of isolation of genetic variants of A. fumigatus, originally misidentified as poorly sporulating strains of A. fumigauts, as a causative agents of invasive infection. Many of these isolates belonging to the Aspergillus section Fumigati have been found to be resistant in vitro to multiple antifungal drugs. Current data show that susceptibility profile of these variants could be predictable depending on the species. Resistance among clinical strains of filamentous fungi may become more common in the future associated with the spread of prophylaxis, pre-emptive treatments and specific therapies with antifungal agents. PMID- 30408932 TI - Combination antifungal therapy for invasive aspergillosis - Is it indicated? AB - The optimal therapy for invasive aspergillosis (IA) is unknown, and there is little agreement on the exact antifungal management of IA. The previously stagnant landscape of antifungal choices for IA is rapidly changing with newer antifungals and newer targets. While amphotericin B had historically been the preferred therapy, recent studies support voriconazole as primary therapy or caspofungin as salvage therapy. However, in vitro studies, animal models, and limited clinical reports suggest that combination antifungal therapy might offer improved outcome. While treatment of malignancy or HIV has advanced after years of clinical trials investigating optimal combinations, therapy for IA is comparatively decades behind. Until very recently, combination antifungal therapy for IA was of little consequence since there were a limited number of possible permutations available. There have been a great deal of new data published exploring the possibilities of combination therapy, but clinicians need to be aware of the potential advantages and disadvantages of combination antifungal therapy for IA as well as the difficulties in interpreting the available data. PMID- 30408933 TI - Granulocyte transfusion therapy 2006: The comeback kid? AB - There has been an increased interest in the use of therapeutic granulocyte transfusion in recent years because premedication of donors with granulocyte colony stimulating factors produces much higher doses of granulocytes for transfusion. Other factors which influence the outcome of transfusion include the types of infection being treated, the likelihood of recipient marrow recovery and recipient alloimmunization. This review provides a historical perspective on these issues. PMID- 30408934 TI - Medical mycology development and epidemiology in the USA, UK and Japan. AB - Medical mycology is a relatively young sub-discipline of medicine, institutionalized principally after the Second World War. In this paper, I will trace the process leading to the establishment of medical mycology in the United States, United Kingdom and Japan, three of the most important players in the International Society for Human and Animal Mycology (ISHAM) today. Throughout the paper, I will highlight both common features and the unique trajectory found in each country. The latter point resulted from the relative emphasis placed upon certain phenomena in each country. In the US, it was environmental conditions, tradition of soil sciences and particular settings of public health, which all created a stage for medical mycology. In Britain, among many medical specialists involved in building a society for medical mycology, contributions of those in tropical medicine and veterinary science stood out, and after the war, studies of allergy and bronchopulmonary aspergillosis and participation of the MRC were decisive. In Japan, concrete reports on visceral candidiasis and the so-called Bikini Incident were critical determinants. It appears that, although medical mycology emerged almost concomitantly in the three countries, the paths taken were different, thus seemingly the origins and pathways of modern medical mycology in each country ought to be understood in terms of broader historical themes. PMID- 30408935 TI - Host genetics affect susceptibility to invasive aspergillosis. AB - Invasive aspergillosis is a common and life-threatening infection in immunocompromised individuals. Epidemiologic risk factors do not fully explain susceptibility to disease amongst at-risk persons. Recently, the contribution of host genetics and genetic polymorphisms to disease susceptibility has begun to be explored. This paper highlights methodologies for evaluating the role of host genetics in aspergillosis susceptibility. PMID- 30408936 TI - Genetic and respiratory tract risk factors for aspergillosis: ABPA and asthma with fungal sensitization. AB - Allergic bronchopulmonary aspergillosis (ABPA) is a Th2 allergic hypersensitivity lung disease due to bronchial colonization of Aspergillus fumigatus that affects 1-2% of asthmatic and 7-9% of cystic fibrosis (CF) patients. We hypothesize that genetic risk factors predispose these patients to develop ABPA. We previously reported HLA-DR2 and DR5 restriction as a risk factor for the development of ABPA. We further propose that HLA-DR restriction is necessary but not sufficient for the development of ABPA. Recently, we reported that IL-4Ralpha single nucleotide polymorphisms (SNP) and in particular the ile75val SNP in the IL-4 binding region is another risk factor and is associated with increased sensitivity to IL-4 stimulation. It has been reported that the combination of IL 4Ralpha and IL-13 SNP, ile75val/arg110gln, is associated with more severe asthma. In preliminary studies, we have observed increased frequency of this combination in ABPA asthmatic and CF patients. Another genetic risk factor reported by Brouard et al. is the -1082 GG genotype in the IL-10 promoter in CF patients for the colonization of A. fumigatus and development of ABPA. This genotype was associated with increased plasma IL-10 levels, and perhaps may be associated with increased skewing of Th2 Aspergillus responses rather than down-regulation of inflammatory responses. We hypothesize that increased sensitivity of IL-4 mediated activities secondary to polymorphisms IL-4R in conjunction of other polymorphisms such as IL-13 and IL-10 in conjunction with HLA-DR2/DR5 restriction to Aspergillus antigens in ABPA patients result in increased B-cell activity, monocyte/dendritic cell phenotype that skews Th2 responses, and skewing of Aspergillus-specific Th2 cells. This model system may be applicable to other fungi such as Alternaria and Cladosporium which is associated with increased asthma severity. PMID- 30408937 TI - Aspergillosis in the ICU - The new 21st century problem? AB - Invasive pulmonary aspergillosis (IPA) is a serious opportunistic infection mainly affecting seriously immunocompromised patients. The major risk factor is prolonged granulocytopenia. Most literature on the epidemiology and clinical impact of Aspergillus spp. infections concern patients with hematological malignancies, cancer, stem cell transplantation and solid organ transplant patients. However, evidence from recent literature indicates that Aspergillus spp. may cause invasive disease in other categories of patients without apparent immunodeficiency, including patients in intensive care units (ICUs). Clinical diagnosis of IPA in non-immunocompromised patients is difficult. Standardized diagnostic definitions, developed by the European Organization for the Research and Treatment of Cancer/Mycosis Study Group for research purposes in patients with cancer and in recipients of haematopoietic stem cell transplants, are not feasible for patient categories with an intermediate to low probability for acquiring IPA. In routine clinical practice, most Aspergillus isolates from non sterile body sites do not represent disease. Invasive diagnostic procedures are often not feasible in patients with severe respiratory insufficiency and critical illness. The presence of systemic risk factors, or underlying predisposing lung disease or general debilitation, may enhance the clinical relevance of a positive culture. The finding of an Aspergillus spp. positive respiratory specimen in an ICU patient should not be discarded; pre-emptive antifungal treatment should be considered, while attempting to substantiate the diagnosis. PMID- 30408938 TI - LaeA, a global regulator of Aspergillus toxins. AB - Several toxins have been implicated in Aspergillus fumigatus pathogenicity. Among these are gliotoxin, fumagillin, fumagatin, and helvolic acid. Recently we have identified a nuclear protein, LaeA, that regulates the production of all of these metabolites. Several criteria support the role of LaeA as a potent A. fumigatus virulence factor. Among these are a decreased ability of the laeA deletion strain (DeltalaeA) to cause fatal infections in the murine model, increased macrophage phagocytosis of DeltalaeA conidia and decreased ability of DeltalaeA to kill polymorphonuclear neutrophils [1]. Here we present our current knowledge of LaeA function and future directions of study of LaeA mechanism. PMID- 30408939 TI - Gene essentiality in Aspergillus fumigatus. AB - Products of essential genes of Aspergillus fumigatus are seen as potential targets for antifungal drugs, and both functional screens and bioinformatics approaches have been used to help identify such genes. The random screening approach makes use of the deletion of one copy of a gene in a diploid, and failure to recover the deletant during haploidization. In order to investigate the function of putative essential genes identified by both screening and bioinformatics approaches, the conditional promoter of the alcA gene of Aspergillus nidulans has been used. In some cases, the genes identified are not absolutely essential, but their deletion leads to slow growth. Such deletants can be recovered and cultivated for phenotypic characterization following transformation of haploid strains. PMID- 30408940 TI - Whole genome comparison of Aspergillus flavus and A. oryzae. AB - Aspergillus flavus is a plant and animal pathogen that also produces the potent carcinogen aflatoxin. Aspergillus oryzae is a closely related species that has been used for centuries in the food fermentation industry and is Generally Regarded As Safe (GRAS). Whole genome sequences for these two fungi are now complete, providing us with the opportunity to examine any genomic differences that may explain the different ecological niches of these two fungi, and perhaps to identify pathogenicity factors in A. flavus. These two fungi are very similar in genome size and number of predicted genes. The estimated genome size (36.8 Mb) and predicted number of genes (12 197) for A. flavus is similar to that of A. oryzae (36.7 Mb and 12 079, respectively). These two fungi have significantly larger genomes than Aspergillus nidulans (30.1) and Aspergillus fumigatus (29.4). The A. flavus and A. oryzae genomes are enriched in genes for secondary metabolism, but do not differ greatly from one another in the predicted number of polyketide synthases, nonribosomal peptide synthases or the number of genes coding for cytochrome P450 enzymes. A micro-scale analysis of the two fungi did show differences in DNA correspondence between the two species and in the number of transposable elements. Each species has approximately 350 unique genes. The high degree of sequence similarity between the two fungi suggests that they may be ecotypes of the same species and that A. oryzae has resulted from the domestication of A. flavus. PMID- 30408941 TI - Amino acid acquisition, cross-pathway control, and virulence in Aspergillus. AB - Supply of all amino acids required for translation is crucial for the synthesis of new proteins. Fungal amino acid biosynthesis has to be coordinated with amino acid uptake as well as protein degradation. A global regulator that connects amino acid biosynthesis and developmental programs is the transcription factor CpcA/Gcn4p. This transcriptional activator is conserved within the fungal kingdom and the cellular levels of this protein are carefully regulated. Deletion of the encoding cpcA gene in the opportunistic pathogen Aspergillus fumigatus results in impaired virulence in immuno-compromised mice, suggesting a role of the cross pathway control system in fungal pathogenicity. PMID- 30408942 TI - Understanding the microbiology of the Aspergillus cell wall and the efficacy of caspofungin. AB - The efficacy of echinocandins against Aspergillus species has been established through in vitro assays, in animal models of infection, and in clinical practice. Caspofungin is an inhibitor of 1,3-beta-D glucan synthesis (GS) that produces dramatic morphological changes, but incomplete clearing, in cultures of growing hyphae. Despite the apparent fungistatic in vitro activity against Aspergillus species, compounds in this class have strong efficacy in vivo. For example, caspofungin prolonged survival in chronically immunosuppressed mice with induced disseminated aspergillosis, even when neutropenia was maintained for weeks after a short dosing regimen. Kidneys of these mice showed no evidence of recrudescent Aspergilluis fumigatus burden after the infection had been treated. One possible explanation for echinocandin-mediated clearance of A. fumigatus in vivo stems from the newly-discovered role of beta-glucan in the inflammatory response. Binding of cell wall beta-glucan to the dectin-1 receptor of macrophages leads to production of proinflammatory cytokines, which augment the innate immune response to swollen conidia and germlings. Changes in A. fumigatus cell wall structure, such as those produced by exposure to an echinocandin like caspofungin, may increase the opportunity for interactions between 1,3-beta-D glucan and dectin-1, and lead to a heightened response to 'wounded' hyphae. PMID- 30408943 TI - Endoscopic treatment or balloon-occluded retrograde transvenous obliteration is safe for patients with esophageal/gastric varices in Child-Pugh class C end-stage liver cirrhosis. AB - Background/Aims: There is a controversy about the availability of invasive treatment for esophageal/gastric varices in patients with Child-Pugh class C (CP C) end-stage liver cirrhosis (LC). We have evaluated the validity of invasive treatment with CP-C end-stage LC patients. Methods: The study enrolled 51 patients with CP-C end-stage LC who had undergone invasive treatment. The treatment modalities included endoscopic variceal ligation in 22 patients, endoscopic injection sclerotherapy in 17 patients, and balloon-occluded retrograde transvenous obliteration (BRTO) in 12 patients. We have investigated the overall survival (OS) rates and risk factors that contributed to death within one year after treatment. Results: The OS rate in all patients at one, three, and five years was 72.6%, 30.2%, and 15.1%, respectively. The OS rate in patients who received endoscopic treatment and the BRTO group at one, three, and five years was 67.6%, 28.2% and 14.1% and 90.0%, 36.0% and 18.0%, respectively. The average of Child-Pugh scores (CPS) from before treatment to one month after variceal treatment significantly improved from 10.53 to 10.02 (P=0.003). Three significant factors that contributed to death within one year after treatment included the presence of bleeding varices, high CPS (>=11), and high serum total bilirubin levels (>=4.0 mg/dL). Conclusions: The study demonstrated that patients with a CPS of up to 10 and less than 4.0 mg/dL of serum total bilirubin levels may not have a negative impact on prognosis after invasive treatment for esophageal/gastric varices despite their CP-C end-stage LC. PMID- 30408944 TI - Is it Possible to Successfully Treat Locally Advanced Colon Cancer Using Pre Operative Chemoradiotherapy? AB - Pre-operative chemoradiotherapy (CRT) is a preferable treatment option for patients with locally advanced rectal cancer. However, few data are available regarding pre-operative CRT for locally advanced colon cancer. Here, we describe two cases of successful treatment with pre-operative CRT and establish evidence supporting this treatment option in patients with locally advanced colon cancer. In the first case, a 65-year-old woman was diagnosed with ascending colon cancer with duodenal invasion. In the second case, a 63-year-old man was diagnosed with a colonic-duodenal fistula due to transverse colon cancer invasion. These case reports will help to establish a treatment consensus for pre-operative CRT in patients with locally advanced colon cancer. PMID- 30408945 TI - Technical Feasibility of a Guidetube for Various Endoscopic Procedures in Human Gastrointestinal Simulators. AB - Background/Aims: Many gastrointestinal (GI) endoscopic procedures are difficult and cumbersome owing to the limitation of currently available endoscopic devices. This study aimed to develop an endoscopic guidetube for multipurpose endoscopic procedures and assess its use in a realistic GI endoscopic simulator. Methods: The guidetube used is a soft overtube composed of neoprene and is designed to assist various endoscopic procedures on demand. In total, 15 types of procedures were performed in GI simulators. Four procedures were performed in the stomach model and 11 in the colon model. The procedures include repeated endoscopic insertion and foreign body removal in various positions. The mean insertion and procedure time were assessed in each session. All procedures were performed by 5 expert endoscopists. Results: Endoscopic procedures with the new guidetube were faster and more effective than the conventional endoscopic techniques. The mean insertion time of the endoscope with the guidetube was significantly shorter than that without the guidetube. The guidetube was safely inserted without scratch using low pushing force. Objects of various sizes larger than the endoscopic channel were easily removed by the guidetube-assisted endoscopic procedures. Conclusions: This preliminary study shows that guidetube-assisted endoscopic procedures are faster, easier, safer and cheaper than conventional endoscopic procedures. PMID- 30408946 TI - Endoscopic Ultrasound in the Diagnosis of Pancreatoduodenal Groove Pathology: Report of Three Cases and Brief Review of the Literature. AB - The pancreatoduodenal groove is a small area where pathologic processes involving the distal bile duct, duodenum, pancreatic head, ampulla of Vater, and retroperitoneum converge. Despite great advances in imaging techniques, a definitive preoperative diagnosis is challenging because of the complex anatomy of this area. Therefore, surgical intervention is frequently required because of the inability to completely exclude malignancy. We report 3 cases of patients with different groove pathologies but similar clinical and imaging presentation, and show the essential role of endoscopic ultrasound (EUS) in making a specific preoperative diagnosis, excluding malignancy in the first case, changing diagnosis in the second case, and confirming malignancy in the third case. EUS was a fundamental tool in this cohort of patients, not only because of its ability to provide superior visualization of a difficult anatomical region, but because of the ability to guide precise, realtime procedures, such as fine-needle aspiration. PMID- 30408947 TI - Refractory Irritable Bowel Syndrome and Functional Abdominal Pain Syndrome: Should Small Bowel Endoscopy Be Performed? PMID- 30408948 TI - Visiting the dentist during pregnancy AB - In pregnancy, it is necessary to pay particu-lar attention to oral health, as inflammatory periodontal changes can occur due to the ex-ceptional hormonal situation. The popular be-lief, still existing today, that "each pregnancy costs the woman a tooth" is no longer valid considering conventional oral hygiene mea sures and the fact that most pregnant women are very conscious of their nutrition (diet). PMID- 30408949 TI - Visualization of the Delivery and Release of Small RNAs Using Genetic Code Expansion and Unnatural RNA-Binding Proteins. AB - Endogenously expressed noncoding RNAs are regulators of mRNA translation and affect diverse biological pathways spanning embryogenesis to cholesterol and fatty acid metabolism. Recently, microRNAs have become an important therapeutic target with strategies that employ oligonucleotides as both mimics and inhibitors of target microRNAs, successfully altering gene expression and cellular pathways in relevant contexts. However, delivery of these exogenous effectors remains a major challenge. Here, we present a method for evaluating noncoding RNA delivery using the viral suppressor of RNA silencing (VSRS) protein p19, optimized for cellular delivery of small RNAs. Using genetic code expansion technology, p azidophenylalanine (AzF) was incorporated into a recombinant p19 protein and used to develop a fluorescence resonance energy transfer (FRET) sensor. AzF was used to attach FRET acceptor moieties using bioorthogonal chemistry. We show that this strategy not only gives rise to FRET signals that report on small RNA binding, but also allows for fluorescence quenching as well, convenient for measuring RNA release. We demonstrate the successful use of a modified version of the probe to track the delivery and release of small RNAs into mammalian cells. The results provide a basis for a further development of vehicles for small RNA delivery and release for intervening in noncoding RNA biology. PMID- 30408950 TI - Porous Silicon-Based Photonic Biosensors: Current Status and Emerging Applications. PMID- 30408951 TI - Self-Assembled Ferroelectric Nanoarray. AB - Self-assembled heteroepitaxial nanostructures have played an important role for miniaturization of electronic devices, e.g., the ultrahigh density ferroelectric memories, and cause for great concern. Our first principle calculations predict that the materials with low formation energy of the interface ( Ef) tend to form matrix structure in self-assembled heteroepitaxial nanostructures, whereas those with high Ef form nanopillars. Under the guidance of the theoretical modeling, perovskite BiFeO3 (BFO) nanopillars are swimmingly grown into CeO2 matrix on single-crystal (001)-SrTiO3 (STO) substrates by pulsed laser deposition, where CeO2 has a lower formation energy of the interface ( Ef) than BFO. This work provides a good paradigm for controlling self-assembled nanostructures as well as the application of self-assembled ferroelectric nanoscale memory. PMID- 30408952 TI - Fast and Simultaneous Determination of Gas Diffusivities and Solubilities in Liquids Employing a Thin-Layer Cell Coupled to a Mass Spectrometer, Part II: Proof of Concept and Experimental Results. AB - A new method for simultaneously determining gas diffusivities and solubilities in liquids was presented and discussed in detail in Part I of this series. In this part of the series, the new measurement cell was employed to determine oxygen solubilities and diffusivities in 20 different dimethyl sulfoxide-based electrolytes. In addition, a comparison to values available in literature was made. From the temperature dependence of the diffusivity between 20 and 40 degrees C an activation barrier of 19 kJ mol-1 for the diffusion of oxygen in pure dimethyl sulfoxide was found. Moreover, qualitative agreement between Jones Dole viscosity coefficients and the dependence of the diffusivity on the electrolyte concentration was confirmed. The temperature-dependent solubility measurements revealed an unexpected increase of the oxygen solubility for temperatures above 30 degrees C. While the oxygen solubility in the case of the alkali-perchlorates decreases with increasing electrolyte concentration, a pronounced salting-in effect for lithium bis(trifluoromethane)sulfonimide was observed. PMID- 30408954 TI - Tunable Expression Systems for Orthogonal DNA Replication. AB - We recently developed an orthogonal DNA replication (OrthoRep) system capable of driving the rapid continuous evolution of genes in vivo. However, OrthoRep uses a special transcription system, the components of which (e.g., promoters) have previously limited the strength with which OrthoRep-encoded genes can be expressed. Here, we report a collection of synthetic and evolved OrthoRep expression parts that allow OrthoRep-encoded genes to span expression levels matching those of endogenous Saccharomyces cerevisiae genes. Specifically, we found that various promoter mutations as well as a genetically encoded poly(A) tail enable us to tune the expression level of OrthoRep-encoded genes over a large range and up to levels 43-fold higher than were previously attained, reaching at least ~40% of the strength of the genomic TDH3 promoter. We further show that expression level gains using our new parts are stable over passaging and consistent across multiple genes and OrthoRep systems of different mutation rates. This new set of expression parts further expands OrthoRep's applicability to the continuous in vivo evolution of proteins and pathways. PMID- 30408953 TI - Engineering Mannitol Biosynthesis in Escherichia coli and Synechococcus sp. PCC 7002 Using a Green Algal Fusion Protein. AB - The genetic engineering of microbial cell factories is a sustainable alternative to the chemical synthesis of organic compounds. Successful metabolic engineering often depends on manipulating several enzymes, requiring multiple transformation steps and selection markers, as well as protein assembly and efficient substrate channeling. Naturally occurring fusion genes encoding two or more enzymatic functions may offer an opportunity to simplify the engineering process and to generate ready-made protein modules, but their functionality in heterologous systems remains to be tested. Here we show that heterologous expression of a fusion enzyme from the marine alga Micromonas pusilla, comprising a mannitol-1 phosphate dehydrogenase and a mannitol-1-phosphatase, leads to synthesis of mannitol by Escherichia coli and by the cyanobacterium Synechococcus sp. PCC 7002. Neither of the heterologous systems naturally produce this sugar alcohol, which is widely used in food, pharmaceutical, medical, and chemical industries. While the mannitol production rates obtained by single-gene manipulation were lower than those previously achieved after pathway optimization with multiple genes, our findings show that naturally occurring fusion proteins can offer simple building blocks for the assembly and optimization of recombinant metabolic pathways. PMID- 30408955 TI - Fast and Simultaneous Determination of Gas Diffusivities and Solubilities in Liquids Employing a Thin-Layer Cell Coupled to a Mass Spectrometer, Part I: Setup and Methodology. AB - Transport properties and solubilities of volatile species in liquid solutions are of high interest in different chemical, biological, and physical systems. In this work, a new approach for determining the diffusivity and solubility of gases in liquids simultaneously is presented. The method presented relies on the diffusion of a volatile species through a thin, liquid layer and the subsequent detection of the species using a mass spectrometer. Evaluation of the time development of the resulting transient yields the diffusion coefficient, while the concentration of the species in the liquid layer can be calculated from the steady-state value of the flux into the mass spectrometer. Apart from the geometry of the thin layer and the calibration constant of the mass spectrometer no additional or external data are required. Experimental results of the temperature-dependent solubility and diffusivity of oxygen in dimethyl sulfoxide are presented in our companion paper Part II and serve as a proof of concept. PMID- 30408956 TI - Evaluated Site-Specific Rate Constants for Reaction of Isobutane with H and CH3: Shock Tube Experiments Combined with Bayesian Model Optimization. AB - Evaluated site-specific rate constants for the reactions of isobutane with CH3 and H were determined in a combined analysis of new shock tube experiments and existing literature data. In our shock tube experiments, CH3 radicals, produced from the pyrolysis of di- tert-butylperoxide, and H atoms, produced from the pyrolysis of C2H5I, were reacted with dilute mixtures of isobutane in argon at 870-1130 K and 140-360 kPa, usually with a radical chain inhibitor. Propene and isobutene, measured with GC/FID and MS, were quantified as characteristic of H abstraction from the primary and tertiary carbons, respectively. Using the method of uncertainty minimization using polynomial chaos expansions (MUM-PCE), a comprehensive Cantera kinetics model based on JetSurF 2.0 was optimized to our experiments and available literature data spanning ambient temperatures to 1327 K. Based on Bayes' theorem, MUM-PCE constrains the kinetics model to the experimental data. The isobutane literature data used for optimization included both raw experimental data and reported branching and total rate measurements. Data for ethane were also included to better define the absolute rate constant for abstraction of H from primary carbons. For both H and CH3, the optimization increased the relative rate of tertiary to primary H-abstraction compared with existing estimates, especially at higher temperatures. We combine the present data for primary and tertiary sites with previous results from our group on 1 butane to derive site-specific rate constants for the reaction of H and CH3 with generic primary, secondary, and tertiary carbons suitable for a wide range of temperatures. PMID- 30408957 TI - Hepatitis B Virus Therapeutic Agent ARB-1740 Has Inhibitory Effect on Hepatitis Delta Virus in a New Dually-Infected Humanized Mouse Model. AB - Hepatitis delta virus (HDV) infects 10-20 million individuals worldwide and causes severe fulminant hepatitis with high likelihood of cirrhosis and hepatocellular carcinoma. HDV infection cannot occur in the absence of the surface antigen (HBsAg) of the hepatitis B virus. RNA interference is an effective mechanism by which to inhibit viral transcripts, and siRNA therapeutics sharing this mechanism have begun to demonstrate clinical efficacy. Here we assessed the outcome of HBV-targeting siRNA intervention against HDV and compared it to a direct anti-HDV siRNA approach in dually infected humanized mice. Treatment with ARB-1740, a clinical stage HBV-targeting siRNA agent delivered using lipid nanoparticle (LNP) technology, effectively reduced HBV viremia by 2.3 log10 and serum HBsAg by 2.6 log10, leading to 1.6 log10 reduction of HDV viremia. In contrast, HDV-targeting siRNA inhibited HDV in both blood and liver compartments without affecting HBV and PEGylated interferon-alpha reduced HBV viremia by 2.0 log10 but had no effect on HDV viremia under these study conditions. These results illustrate the inhibitory effects of siRNAs against these two viral infections and suggest that ARB-1740 may be of therapeutic benefit for hepatitis delta patients, a subpopulation with high unmet medical need. PMID- 30408958 TI - MitoTarget Modeling Using ANN-Classification Models Based on Fractal SEM Nano Descriptors: Carbon Nanotubes as Mitochondrial F0F1-ATPase Inhibitors. AB - Recently, it has been suggested that the mitochondrial oligomycin A-sensitive F0 ATPase subunit is an uncoupling channel linked to apoptotic cell death, and as such, the toxicological inhibition of mitochondrial F0-ATP hydrolase can be an interesting mitotoxicity-based therapy under pathological conditions. In addition, carbon nanotubes (CNTs) have been shown to offer higher selectivity like mitotoxic-targeting nanoparticles. In this work, linear and nonlinear classification algorithms on structure-toxicity relationships with artificial neural network (ANN) models were set up using the fractal dimensions calculated from CNTs as a source of supramolecular chemical information. The potential ability of CNT-family members to induce mitochondrial toxicity-based inhibition of the mitochondrial H+-F0F1-ATPase from in vitro assays was predicted. The attained experimental data suggest that CNTs have a strong ability to inhibit the F0-ATPase active-binding site following the order oxidized-CNT (CNT-COOH > CNT OH) > pristine-CNT and mimicking the oligomycin A mitotoxicity behavior. Meanwhile, the performance of the ANN models was found to be improved by including different nonlinear combinations of the calculated fractal scanning electron microscopy (SEM) nanodescriptors, leading to models with excellent internal accuracy and predictivity on external data to classify correctly CNT mitotoxic and nonmitotoxic with specificity (Sp > 98.9%) and sensitivity (Sn > 99.0%) from ANN models compared with linear approaches (LNN) with Sp ~ Sn > 95.5%. Finally, the present study can contribute toward the rational design of carbon nanomaterials and opens new opportunities toward mitochondrial nanotoxicology-based in silico models. PMID- 30408959 TI - Application of Bioactivity Profile-Based Fingerprints for Building Machine Learning Models. AB - The volume of high throughput screening data has considerably increased since the beginning of the automated biochemical and cell-based assays era. This information-rich data source provides tremendous repurposing opportunities for data mining. It was recently shown that biochemical or cell-based assay results can be compiled into so-called high-throughput fingerprints (HTSFPs) as a new type of descriptor describing molecular bioactivity profiles which can be applied in virtual screening, iterative screening, and target deconvolution. However, so far, studies around HTSFPs and machine learning have mainly focused on predicting the outcome of molecules in single high-throughput assays, and no one has reported the modeling of compounds' biochemical assay activities toward a panel of target proteins. In this article, we aim at comparing how our in-house HTSFPs perform at this when combined with multitask deep learning versus the single task support vector machine method both in terms of hit identification and of scaffold hopping potential. Performances obtained from the two HTSFP models were reported with respect to the performances of multitask deep learning and support vector machine models built with the structural descriptors ECFP. Moreover, we investigated the effect of high throughput screening false positives and negatives on the performance of the generated models. Our results showed that the two fingerprints yielded in similar performances and diverse hits with very little overlap, thus demonstrating the orthogonality of bioactivity profile-based descriptors with structural descriptors. Therefore, modeling compound activity data using ECFPs together with HTSFPs increases the scaffold hopping potential of the predictive models. PMID- 30408960 TI - Stacking-Dependent Magnetism in Bilayer CrI3. AB - We report the connection between the stacking order and magnetic properties of bilayer CrI3 using first-principles calculations. We show that the stacking order defines the magnetic ground state. By changing the interlayer stacking order, one can tune the interlayer exchange interaction between antiferromagnetic and ferromagnetic. To measure the predicted stacking-dependent magnetism, we propose using linear magnetoelectric effect. Our results not only gives a possible explanation for the observed antiferromagnetism in bilayer CrI3 but also have direct implications in heterostructures made of two-dimensional magnets. PMID- 30408961 TI - Current-Induced Crossover of Flux Periodicity from h/2 e to h/e in a Superconducting Nb Nano-Ring. AB - Magnetoresistance measurements in a granular Nb nanoring reveal current-induced crossover between two distinct quantum coherence effects. At low bias currents, Cooper-pair coherence is manifested by Little-Parks oscillations with flux periodicity of h/2 e. At high bias currents, magnetoresistance oscillations with flux periods of h/ e are observed and interpreted as Aharonov-Bohm oscillations, reflecting the phase coherence of individual quasi-particles. The model explaining these data views the ring as a chain of superconducting grains weakly coupled by tunnel junctions. Low bias currents allow coherent tunneling of Cooper pairs between the grains. Increasing the current above the critical current of all the junctions creates a quasi-particles conduction channel along the ring, allowing for quantum interference of quasi-particles. PMID- 30408962 TI - Multiplex Assay for Quantification of Acute Phase Proteins and Immunoglobulin A in Dried Blood Spots. AB - Inflammation is the first line defense mechanism against infection, tissue damage, or cancer development. However, inappropriate inflammatory response may also trigger diseases. The quantification of inflammatory proteins is essential to distinguish between harmful and beneficial immune response. Currently used immunoanalytical assays may suffer specificity issues due to antigen-antibody interaction and possible cross-reactivity of antibody with other protein species. In addition, immunoanalytical assays typically require invasive blood sampling and additional logistics; they are relatively costly and highly challenging to multiplex. We present a multiplex assay based on selected reaction monitoring (SRM) for quantification of seven acute-phase proteins (i.e., SAA1, SAA2 isoform1, SAA4, CRP, A1AT-isoform1, A1AG1, A1AG2) and the adaptive immunity effector IGHA1 in dried blood spots. This type of sample is readily available from all human subjects including newborns. The study utilizes proteotypic isotopically labeled peptides with trypsin-cleavable tag and presents optimized and reproducible workflow and several important practical remarks regarding quantitative SRM assays development. The panel of inflammatory proteins was quantified with sequence specificity capable to differentiate protein isoforms with intra- and interday precision (<16.4% coefficient of variation (CV) and <14.3% CV, respectively). Quantitative results were correlated with immuno nephelometric assay (typically greater than 0.9 Pearson's R). PMID- 30408963 TI - Nonradiative Decay Channels for a Structurally-Distorted, Monostrapped BODIPY Derivative. AB - A boron dipyrromethene (BODIPY) derivative has been synthesized whereby a phenoxyl ring attached at the 3-position is bound through the oxygen atom to the boron center. This compound is structurally distorted, with the molecular surface being curved, and undergoes further geometrical perturbation at the excited singlet state level. Fluorescence is readily observed in solution at ambient temperature, with the quantum yield rising with increasing viscosity of the surrounding solvent. Dual-exponential decay kinetics are observed, corresponding to E-type delayed fluorescence. In solution, the emission yield falls with increasing temperature, but the opposite situation is found for the same compound dispersed in an amorphous sugar. These results are considered in terms of two radiationless decay channels. A viscosity-dependent avenue allows the fluorophore to function as a conventional fluorescent rotor for tracking changes in local rheology. A temperature-dependent channel leads to trapping within a new conformation, which is weakly coupled to the ground state but is able to repopulate the emitting state on a relatively slow time scale. Analysis of the experimental data allows estimation of some of the key kinetic parameters as a function of temperature. PMID- 30408964 TI - Complex formation equilibria between cholesterol and diosgenin analogues in monolayers determined by the Langmuir method. AB - The purpose of this study was to investigate the interaction between diosgenin analogues [DioA: diosgenin acetate (DAc) and (25R)-5alpha,6beta dihydroxyspirostan-3beta-ol acetate (DSol)] and cholesterol (Ch) monolayers at the air/water interface. The surface tension of pure and mixed lipid monolayers at 22 degrees C was measured by using the Langmuir method with a Teflon trough and a Nima 9002 tensiometer. The surface tension values were used to calculate the pi-A isotherms and to determine the molecular surface areas. The interactions between Ch and each DioA resulted in significant deviations from the additivity rule. The theory described in this work was used to determine the stability constants, the areas occupied by one molecule of Ch-DAc or Ch-DSol, and the complex formation energy (Gibbs free energy) values. PMID- 30408965 TI - Controllable functionalization of hydroxyl-terminated self-assembled monolayers via catalytic oxa-Michael reaction. AB - Traditional strategies for the functionalization of materials displaying hydroxyl groups either require active esterification reagents or involve the nucleophilic attack of the hydroxyl group toward electrophilic groups. The former tends to hydrolyze in aqueous solutions while the latter occurs under harsh conditions. Herein, the authors reported a new method for the functionalization of hydroxyl groups on the surface via catalytic oxa-Michael addition with vinyl sulfones. Using hydroxyl group terminated self-assembled monolayers as a model surface, a series of organocatalysts were screened and triphenylphosphine stood out for the best catalytic activity. The catalytic reaction on the surface was characterized by x-ray photoelectron spectroscopy. The information of reaction kinetics was obtained using static water contact angle measurements. Once conjugated with ligands onto the functionalized surfaces, the multivalence binding of proteins was investigated by quartz crystal microbalance experiments. By varying the reaction conditions, e.g., catalyst types and reaction times, ligands can be anchored with a controllable density, which would be helpful to establish the relationships between ligand density and bioactivity. PMID- 30408966 TI - Switching of binding site from nonpolar to polar ligands toward cationic benzonitrile revealed by infrared spectroscopy. AB - Noncovalent interactions of aromatic molecules in their various charge states with their surrounding environment are of fundamental importance in chemistry and biology. Herein, we analyze the infrared photodissociation spectra of mass selected cationic clusters of benzonitrile (BN, cyanobenzene, C6H5CN) with L = Ar, N2, and H2O (W), in the CH and OH stretch range (2950-3800 cm-1) with the aid of density functional theory calculations at the dispersion-corrected B3LYP D3/aug-cc-pVTZ level to probe the interaction of this fundamental aromatic cation in its 2B1 ground electronic state with nonpolar, quadrupolar, and dipolar solvent molecules. While Ar and N2 prefer pi-stacking to the aromatic ring of BN+ strongly supported by dispersion forces, W forms a bifurcated CH?O ionic hydrogen bond to two adjacent CH groups stabilized by electrostatic forces. Comparison of the BN+-L dimers with related aromatic clusters reveals the effect of ionization, protonation, and substitution of functional groups on the type and strengths of the competing ligand binding motifs. PMID- 30408967 TI - Abnormal subsurface hydrogen diffusion behaviors in heterogeneous hydrogenation reactions. AB - Hydrogen adsorption and diffusion behaviors on noble metal model catalyst surfaces and into the subsurfaces are of paramount significance in the exploration of novel heterogenous catalytic hydrogenation reactions. We present an in-depth study of hydrogen adsorption on and diffusion into the subsurfaces of three typical 5d noble metals from three-dimensional electronically adiabatic potential energy surfaces (PESs) by interpolating plenty of ab initio density functional theory (DFT) configuration-energy points. The surfaces and subsurfaces regions of the relaxed Ir(100) and (111), Pt(100) and (111), and Au(100) and (111) surfaces, are, respectively, taken into account. For hydrogen adsorption on the (100) surfaces, the lowest adsorption energy site is the Bridge site, instead of the traditional Hollow site. Hydrogen prefers to follow the indirect pathway with a lower diffusion barrier, in the competition with the direct pathway with much higher diffusion barrier. For hydrogen diffusion on the (111) surfaces, hydrogen follows the pathway from Top site to fcc site on the surface and prefers an up-down direct pathway into the subsurface. Importantly, the nudged elastic band (NEB) based on the PESs can reproduce those results calculated from the NEB(DFT) very well. The developed highly-accurate and efficient approach based on the PESs helps us to further investigate the more complex reactant diffusion dynamics at surfaces. PMID- 30408968 TI - Bond dissociation energy and electronic spectroscopy of Cr+(NH3) and its isotopomers. AB - The electronic spectra of Cr+(NH3), Cr+(ND3), and Cr+(15NH3) have been measured from 14 200 to 17 400 cm-1 using photodissociation spectroscopy. Transitions are predominantly observed from the 6A1 ground state, in which the Cr+ has a 3d 5 electronic configuration, to the B 6E (Pi) state (3d 44s). There is extensive vibronic structure in the spectrum due to a long progression in the Cr-N stretch and transitions to all six spin-orbit levels in the upper state. The spin-orbit splitting in the excited state is observed to be Aso' = 39 cm-1. For the lowest spin-orbit level, the Cr-N stretching frequency in the excited state is 343 cm-1, with an anharmonicity of 4.2 cm-1. The 6E (Pi) origin is predicted to lie at T0 = 14 697 cm-1. The first peak observed is due to v' = 1, so the observed photodissociation onset is thermodynamic rather than spectroscopic, giving D0(Cr+ NH3) = 14 830 +/- 100 cm-1 (177.4 +/- 1.2 kJ/mol) and D0(Cr+-ND3) = 15 040 +/- 30 cm-1 (179.9 +/- 0.4 kJ/mol). The 6E (Pi) state of Cr+(NH3) is ~2740 cm-1 less strongly bound than the ground state, and the Cr-N bond length increases by 0.23 +/- 0.03 A upon electronic excitation. Calculations at the time-dependent density functional theory (M06) and equations of motion coupled cluster, with single and double excitations (EOM-CCSD) level fairly accurately predict the energy and vibrational frequency of the excited state. Multi-reference configuration interaction calculations show how the spin-orbit states of Cr+(NH3) evolve into those of Cr+ + NH3. PMID- 30408969 TI - Probing the predissociated levels of the S1 state of acetylene via H-atom fluorescence and photofragment fluorescence action spectroscopy. AB - We report two new experimental schemes to obtain rotationally resolved high resolution spectra of predissociated S1 acetylene levels in the 47 000-47 300 cm 1 energy region (~1200 cm-1 above the predissociation threshold). The two new detection schemes are compared to several other detection schemes (employed at similar laser power, molecular beam temperature, and number of signal averages) that have been used in our laboratory to study predissociated S1 acetylene levels, both in terms of the signal-to-noise ratio (S/N) of the resultant spectra and experimental simplicity. In the first method, H-atoms from the predissociated S1 acetylene levels are probed by two-photon laser-induced fluorescence (LIF). The H-atoms are pumped to the 3d level by the two-photon resonance transition at 205.14 nm. The resulting 3d-2p fluorescence (654.5 nm) is collected by a photomultiplier. The S/N of the H-atom fluorescence action spectrum is consistently better by ~3* than that of the more widely used H-atom resonance enhanced multiphoton ionization (REMPI) detection. Laser alignment is also considerably easier in H-atom fluorescence detection than H-atom REMPI detection due to the larger number-density of molecules that can be used in fluorescence vs. REMPI detection schemes. In the second method, fluorescence from electronically excited C2 and C2H photofragments of S1 acetylene is detected. In contrast to the H-atom detection schemes, the detected C2 and C2H photofragments are produced by the same UV laser as is used for the A-X acetylene excitation. As a result, laser alignment is greatly simplified for the photofragment fluorescence detection scheme, compared to both H-atom detection schemes. Using the photofragment fluorescence detection method, we are able to obtain action spectra of predissociated S1 acetylene levels with S/N ~2* better than the HCCH REMPI detection and ~10* better than H-atom and HCCH LIF detection schemes. PMID- 30408970 TI - First vibrational investigations of N2O-H2O, N2O-(H2O)2, and (N2O)2-H2O complexes from the far to the near-infrared spectral region by neon matrix isolation and ab initio calculations. AB - We present for the first time the investigation of water molecules complexed with dinitrogen monoxide, two abundant molecules in atmosphere, in solid neon using Fourier transform infrared (IR) spectroscopy. We identify at least three complexes from concentration effects, N2O-H2O, N2O-(H2O)2, and (N2O)2-H2O, by observation of new absorption bands close to the monomer fundamental modes from the far to the near IR region. We highlight the presence of isomers for the N2O H2O complex with the help of theoretical calculations at second order Moller Plesset (MP2) and coupled-cluster single double triple-F12a/aug-cc-pVTZ levels. The observed frequencies for the N2O-(H2O)2 and (N2O)2-H2O complexes are compared with MP2/aug-cc-pVTZ harmonic data. Anharmonic coupling constants have been derived from the observations of overtones and combination bands. PMID- 30408971 TI - Orientational dynamics of a heated Janus particle. AB - Using large scale molecular dynamics simulations, we study the orientational dynamics of a heated Janus particle which exhibits self-propulsion. The asymmetry in the microscopic interaction of the colloid with the solvent is implemented by choosing different wetting parameters for the two halves of the sphere. This choice leads to a different microscopic Kapitza resistance across the solid-fluid boundary of the two halves of the sphere, and consequently a gradient in temperature is created across the poles of the sphere. It is this self-created temperature gradient which leads to a self-propulsion along the direction of the symmetry axis. In this article, we look at the orientational dynamics of such a system, as well as the subsequent enhancement of the translational diffusivity of the heated Janus colloid at late times. The orientational correlation of the symmetry axis is measured from the simulation and provides a direct access to the rotational diffusion constant. The heating leads to an increase in the rotational diffusivity of the colloid. We quantify this increase in rotational diffusion D r against the temperature difference deltaT = T(R, 0) - T(R, pi) across the poles of the Janus sphere as well as the average surface temperature difference DeltaT = T(R) - T(infinity) from the ambient fluid. Since the rotational diffusion is determined by the complete flow field in the solvent, we illustrate that comparing D r against deltaT is misleading and is better quantified when compared against DeltaT. The later quantification results in a data collapse for different choices of the microscopic interaction. The average propulsion velocity is also measured for different choices of the wetting parameter. The directionality of self-propulsion changes depending on the microscopic interaction. We show that whenever the attractive interaction of the colloid with the solvent is switched off, the phoretic mobility changes sign. Furthermore, the propulsion velocity is zero for heating below a certain threshold value. This is also corroborated by the probability distribution of the angle between the displacement vector Deltar(t) = r(t) - r(0) and the symmetry axis. Finally, we combine the measured propulsion velocity and the rotational diffusion time tau r = 1/2D r to estimate the enhancement in the long time diffusion coefficient of the particle. PMID- 30408973 TI - Perspective: Dynamics of confined liquids. AB - Liquids confined on nanometer lengthscales are ubiquitous in chemistry, occurring in systems ranging from mesoporous catalysts to the crowded interior of a cell. Understanding how the properties of the liquid in these environments differs from that in the corresponding bulk is key to interpreting measurements, developing methods for theoretical predictions, and controlling chemical pathways. This area has received significant attention in recent years, resulting in notable progress. In this perspective, we discuss the advances in understanding the dynamics of confined liquids as well as the nontrivial remaining challenges. PMID- 30408972 TI - Water access and ligand dissociation at the binding site of proteins. AB - Although water is undoubtedly an essential mediator of protein-ligand interactions, whether or not such water molecules are critical for the progress of ligand dissociation remains unclear. To gain a more complete understanding, molecular dynamics simulations are performed with two molecular systems, rigid model binding sites and trypsin-benzamidine. Free-energy landscapes are calculated with a suitably chosen solvent coordinate, which well describes water access to the ligand binding site. The results of free energy provided clear description of water-ligand exchange process, where two different mechanisms appear depending on whether the binding site is buried or not. As the site is more buried, water access is more difficult. When water does not access the site, ligand dissociation produces a large energy barrier, i.e., slow dissociation kinetics. This indicates that control of ligand dissociation kinetics becomes possible with burying the binding site. However, the results also showed that appropriate burying is important because burying reduces not only water access but also ligand binding. The role of the protein structural change is also discussed; it likely plays a similar role to water access because during ligand dissociation, it can make new coordination with the ligand binding site like water. These results contribute to the future pharmaceutical drug design and will be useful for fundamental exploration of various molecular events. PMID- 30408974 TI - Performance evaluation of the symmetrical quasi-classical dynamics method based on Meyer-Miller mapping Hamiltonian in the treatment of site-exciton models. AB - The symmetrical quasi-classical dynamics method based on the Meyer-Miller mapping Hamiltonian (MM-SQC) shows the great potential in the treatment of the nonadiabatic dynamics of complex systems. We performed the comprehensive benchmark calculations to evaluate the performance of the MM-SQC method in various site-exciton models with respect to the accurate results of quantum dynamics method multilayer multiconfigurational time-dependent Hartree (ML MCTDH). The parameters of the site-exciton models are chosen to represent a few of prototypes used in the description of photoinduced excitonic dynamics processes in photoharvesting systems and organic solar cells, which include the rather broad situations with the fast or slow bath and different system-bath couplings. When the characteristic frequency of the bath is low, the MM-SQC method performs extremely well, and it gives almost the identical results to those of ML-MCTDH. When the fast bath is considered, the deviations exist between the MM-SQC and ML-MCTDH results if the high-frequency bath modes are improperly treated by the classical manner. When the so-called adiabatic renormalization was employed to construct the reduced Hamiltonian by freezing high-frequency modes, the MM-SQC dynamics can give the results comparable to the ML-MCTDH ones. Thus, the MM-SQC method itself provides reasonable results in all test site-exciton models, while the proper treatments of the bath modes must be employed. The possible dependence of the MM-SQC dynamics on the different initial sampling methods for the nuclear degrees of freedom is also discussed. PMID- 30408975 TI - A topological order parameter for describing folding free energy landscapes of proteins. AB - We studied the refolding free energy landscape of 26 proteins using the Go-like model. The distance between the denaturated state and the transition state, X F, was calculated using the Bell theory and the nonlinear Dudko-Hummer-Szabo theory, and its relation to the geometrical properties of the native state was considered in detail. We showed that none of the structural parameters, such as the contact order, protein length, and radius of cross section, correlate with X F for all classes of proteins. To overcome this problem, we have introduced the nematic order parameter P 02, which describes the ordering of the structured elements of the native state. Due to its topologically global nature, P 02 is better than other structural parameters in describing the folding free energy landscape. In particular, P 02 displays a good correlation with X F extracted from the nonlinear theory for all three classes of proteins. Therefore, this parameter can be used to predict X F for any protein, if its native structure is known. PMID- 30408976 TI - Inducing wetting morphologies and increased reactivities of small Au clusters on doped oxide supports. AB - Au nanoparticles are promising catalysts for industrially important reactions. Their catalytic activity is known to depend on their charge state and morphology. Using density functional theory calculations, we have studied how the induced charge and dimensionality of small Au clusters can be tuned by doping the oxide support that they are deposited on. We have investigated Au n clusters of sizes n = 1, 2, 3, and 20 on Al-doped MgO and Mo-doped CaO. We show that substitutionally doping the oxide support with an electron donor changes the cluster morphology from an upright and/or three-dimensional geometry to a flat geometry. This structural wetting transition results in an increase in the negative charge induced on the cluster and a consequent lowering in the dissociation barrier for the O2 atoms adsorbed on the cluster. We find that the nature of Mo and Al dopants differs: only for the former is it true that the charge state of the dopant atoms depends on the presence or absence of Au nanoparticles and their size. PMID- 30408977 TI - Electronic interactions do not affect electronic decoherence in the pure dephasing limit. AB - The relationship between electronic interactions and electronic decoherence is a fundamental problem in chemistry. Here we show that varying the electron-electron interactions does not affect the electronic decoherence in the pure-dephasing limit. In this limit, the effect of varying the electronic interactions is to rigidly shift in energy the diabatic potential energy surfaces without changing their shape, thus keeping the nuclear dynamics in these surfaces that leads to the electronic decoherence intact. This analysis offers a simple and intuitive understanding of previous theoretical and computational efforts to characterize the influence of electronic interactions on the decoherence and opens opportunities to study exact electronic decoherence with approximate electronic structure theories. PMID- 30408978 TI - Anomalous packing and dynamics of a polymer chain confined in a static porous environment. AB - Polymers in confined porous environments are ubiquitous throughout biology, physics, materials science, and engineering. Several experiments have suggested that in some porous environments, chain dynamics can become extremely slow. While phenomenological explanations exist, the exact mechanisms for these slow dynamics have not been fully characterized. In this work, we initiate a joint simulation theory study to investigate chain packing and dynamics in a static porous environment. The main theoretical concept is the free energy of the chain partitioning into several chambers of the porous environment. Both the theoretical results and Langevin dynamics simulations show that chain packing in each of the chambers is predominantly independent of chain length; it is determined by the maximal packing of segments in each chamber. Dynamically, short chains (compared to the chamber size) become trapped in a single chamber and dynamics become extremely slow, characteristic of an Ogston sieving-like behavior. For longer chains, on the other hand, a hierarchy of slow dynamics is observed due to entropic trapping, characterized by sub-diffusive behavior and a temporary plateau in the mean square displacement. Due to the slow nature of the dynamics, the inevitable long-time diffusive behavior of the chains is not captured by our simulations. Theoretically, the slow dynamics are understood in terms of a free energy barrier required to thread the chain from one chamber to the next. There is overall qualitative and quantitative agreement between simulations and theory. This work provides foundations for a better understanding of how chain dynamics are affected by porous environments. PMID- 30408979 TI - Coupling of state-resolved rovibrational coarse-grain model for nitrogen to stochastic particle method for simulating internal energy excitation and dissociation. AB - We propose to couple a state-resolved rovibrational coarse-grain model to a stochastic particle method for simulating internal energy excitation and dissociation of a molecular gas. A coarse-grained model for a rovibrational reaction mechanism of an ab initio database developed at the NASA Ames Research Center for the N2-N system is modified based on variably spaced energy bins. The thermodynamic properties of the modified coarse-grained model allow us to closely match those obtained with the full set of rovibrational levels over a wide temperature range, while using a number of bins significantly smaller than the complete mechanism. The chemical-kinetic behavior of equally and variably spaced bin formulations is compared by simulating internal energy excitation and dissociation of nitrogen in an adiabatic, isochoric reactor. We find that the variably spaced formulation is better suited for reproducing the dynamics of the full database at conditions of interest in the Earth atmospheric entry. Also in this paper, we discuss the details of our particle method implementation for the uniform rovibrational collisional bin model and describe changes to the Direct Simulation Monte Carlo (DSMC) collision algorithm, which become necessary to accommodate our state-resolved reaction mechanism for excitation and dissociation reactions. The DSMC code is then verified against equivalent master equation calculations. In these simulations, state-resolved cross sections are used in analytical form. These cross sections verify micro-reversibility relations for the rovibrational bins and allow for fast execution of the DSMC code. In our verification calculations, we obtain very close agreement for the concentrations profiles of N and N2, as well as the translational and rovibrational mode temperatures obtained independently through both methods. In addition to macroscopic moments, we compare discrete internal energy populations predicted at selected time steps via DSMC and the master equations. We observe good agreement between the two sets of results within the limits imposed by statistical scatter, which is inherent to particle-based DSMC solutions. As future work, the rovibrational coarse-grain model coupled to the particle method will allow us to study 3D reentry flow configurations. PMID- 30408980 TI - Structural evolution and bonding properties of BSin-/0 (n = 4-12) clusters: Size selected anion photoelectron spectroscopy and theoretical calculations. AB - Size-selected anion photoelectron spectroscopy and theoretical calculations were used to investigate the structural evolution and bonding properties of BSin -/0 (n = 4-12) clusters. The results showed that the B atom in BSi4-12 -/0 prefers to occupy the high coordination sites to form more B-Si bonds. The lowest-lying isomers of BSi4-7 -/0 primarily adopt bowl-shaped based geometries, while those of BSi8-12 -/0 are mainly dominated by prismatic based geometries. For anionic clusters, BSi11 - is the critical size of the endohedral structure, whereas BSin neutrals form the B-endohedral structure at n = 9. Interestingly, both anionic and neutral BSi11 have a D 3h symmetric tricapped tetragonal antiprism structure with the B atom at the center and exhibit 3D aromaticity. The BSi11 - anion possesses sigma plus pi doubly delocalized bonding characters. The natural population analysis charge distributions on the B atom are related with the structural evolution of BSin - and the B-Si interactions. PMID- 30408981 TI - A magnetic guide to purify radical beams. AB - Generating a controllable and pure source of molecular free-radicals or open shell atoms has been one of the primary barriers hindering the detailed study of radical processes in the laboratory. Here, we introduce a novel magnetic guide for the generation of a pure beam of velocity-selected radicals-a tuneable source that will enable the study of radical interactions with exceptional control over the properties of the radical species. Only radicals with a selected velocity are transmitted through the guide; all other components of the incoming beam (radical species traveling at other velocities, precursor molecules, and seed gas) are removed. The guide is composed of four Halbach arrays-hexapolar focusing elements and two skimming blades. The relative positions of these components can be adjusted to tune the properties of the resulting beam and to optimise transmission for a given velocity. Experimental measurements of Zeeman decelerated H atoms transmitted through the guide, combined with extensive simulations, show that the magnetic guide removes 99% of H-atoms traveling outside the narrow target velocity range. PMID- 30408982 TI - Broadband models and their consequences on line shape analysis in vibrational sum frequency spectroscopy. AB - Vibrational sum-frequency generation (SFG) spectroscopy can provide valuable qualitative and quantitative information about molecular species at surface and buried interfaces. For example, the resonance frequency of a particular chemical function group is revealing of the surface environment, especially when compared to what is observed in bulk IR absorption or Raman scattering spectra. Furthermore, the amplitude of the mode can be related to the molecular orientation, providing a detailed quantitative account of the surface structure. Each of these attributes, however, requires fitting the spectra to some vibrationally resonant line shape. This is particularly challenging when the modes of interest co-exist with broad resonance features, such as water O-H stretching. In this perspective, we examine the merits and consequences of different approaches to fitting homodyne SFG data. We illustrate that, while any model can provide a useful description of the data, no model can accurately and consistently provide even the relative phase deeply encoded in homodyne data without the use of additional information. PMID- 30408983 TI - Active microrheology in corrugated channels. AB - We analyze the dynamics of a tracer particle embedded in a bath of hard spheres confined in a channel of varying section. By means of Brownian dynamics simulations, we apply a constant force on the tracer particle and discuss the dependence of its mobility on the relative magnitude of the external force with respect to the entropic force induced by the confinement. A simple theoretical one-dimensional model is also derived, where the contribution from particle particle and particle-wall interactions is taken from simulations with no external force. Our results show that the mobility of the tracer is strongly affected by the confinement. The tracer velocity in the force direction has a maximum close to the neck of the channel, in agreement with the theory for small forces. Upon increasing the external force, the tracer is effectively confined to the central part of the channel and the velocity modulation decreases, which cannot be reproduced by the theory. This deviation marks the regime of validity of linear response. Surprisingly, when the channel section is not constant, the effective friction coefficient is reduced as compared to the case of a plane channel. The transversal velocity, which cannot be studied with our model, follows qualitatively the derivative of the channel section, in agreement with previous theoretical calculations for the tracer diffusivity in equilibrium. PMID- 30408984 TI - Nematic order in solutions of semiflexible polymers: Hairpins, elastic constants, and the nematic-smectic transition. AB - Coarse-grained models of lyotropic solutions of semiflexible polymers are studied by both molecular dynamics simulations and density functional theory calculations, using an implicit solvent bead-spring model with a bond-angle potential. We systematically vary the monomer density, persistence length, and contour length over a wide range and explore the full range from the isotropic nematic transition to the nematic-smectic transition. In the nematic regime, we span the entire regime from rigid-rod like polymers to thin wormlike chains, confined in effective straight tubes caused by the collective nematic effective ordering field. We show that the distribution of bond angles relative to the director is well described by a Gaussian, irrespective of whether the chains are rod-like or rather flexible. However, the related concept of "deflection length" is shown to make sense only in the latter case for rather dilute solutions since otherwise the deflection length is of the order of about two bond lengths only. When the solution is semi-dilute, a substantial renormalization of the persistence length occurs, while this effect is absent in the isotropic phase even at rather high monomer densities. The effective radii of the "tubes" confining the chains in the related description of orientational ordering are significantly larger than the distances between neighboring chains, providing evidence for a pronounced collective character of orientational fluctuations. Hairpins can be identified close to the isotropic-nematic transition, and their probability of occurrence agrees qualitatively with the Vroege-Odijk theory. The corresponding theoretical predictions for the elastic constants, however, are not in good agreement with the simulations. We attribute the shortcomings of the theories to their neglect of the coupling between local density and orientational fluctuations. Finally, we detected for this model a transition to a smectic phase for reduced monomer densities near 0.7. PMID- 30408985 TI - Phase diagrams of multicomponent lipid vesicles: Effects of finite size and spherical geometry. AB - We study the phase behavior of multicomponent lipid bilayer vesicles that can exhibit intriguing morphological patterns and lateral phase separation. We use a modified Landau-Ginzburg model capable of describing spatially uniform phases, microemulsions, and modulated phases on a spherical surface. We calculate its phase diagram for multiple vesicle sizes using analytical and numerical techniques as well as Monte Carlo simulations. Consistent with previous studies on planar systems, we find that thermal fluctuations move phase boundaries, stabilizing phases of higher disorder. We also show that the phase diagram is sensitive to the size of the system at small vesicle radii. Such finite size effects are likely relevant in experiments on small, unilamellar vesicles and should be considered in their comparison to theoretical and simulation results. PMID- 30408987 TI - Active learning in Gaussian process interpolation of potential energy surfaces. AB - Three active learning schemes are used to generate training data for Gaussian process interpolation of intermolecular potential energy surfaces. These schemes aim to achieve the lowest predictive error using the fewest points and therefore act as an alternative to the status quo methods involving grid-based sampling or space-filling designs like Latin hypercubes (LHC). Results are presented for three molecular systems: CO2-Ne, CO2-H2, and Ar3. For each system, two of the active learning schemes proposed notably outperform LHC designs of comparable size, and in two of the systems, produce an error value an order of magnitude lower than the one produced by the LHC method. The procedures can be used to select a subset of points from a large pre-existing data set, to select points to generate data de novo, or to supplement an existing data set to improve accuracy. PMID- 30408986 TI - An ab initio investigation for elastic and electronically inelastic electron scattering from para-benzoquinone. AB - We report the results of ab initio calculations for elastic scattering and also for excitation of individual electronic states of para-benzoquinone (pBQ) by the impact of low-energy electrons. The calculations for elastic scattering were performed with the Schwinger multichannel method implemented with pseudopotentials (SMCPP) in the static-exchange (SE) plus polarization (SEP) approximation for energies up to 50 eV. The assignments for the resonance spectrum obtained in this study are, in general, in good agreement with previous results available in the literature. For electronic excitation by electron impact, the SMCPP method with N energetically open electronic states (N open ), at either the static-exchange (N open ch-SE) or the static-exchange-plus polarisation (N open ch-SEP) approximation, was employed to calculate the scattering amplitudes using a channel coupling scheme that ranges from the 1ch SEP up to the 89ch-SE level of approximation, depending on the energy of interest. Integral cross sections (ICSs) and differential cross sections (DCSs) were obtained for incident electron energies lying between 15 eV and 50 eV. The study focuses on the influence of multichannel coupling effects for electronically inelastic processes, more specifically, on how the number of excited states included in the open-channel space impacts upon the convergence of the cross sections at intermediate and higher energies. In particular, we found that the magnitude of DCS and ICS results for electronic excitation decreases as more channels are included in the calculations. To the best of our knowledge, there are no other experimental or theoretical ICS or DCS results for excitation into individual electronic states of pBQ available in the literature between 15 and 50 eV against which we might compare the present calculations. PMID- 30408988 TI - Ratchet-induced variations in bulk states of an active ideal gas. AB - We study the distribution of active, noninteracting particles over two bulk states separated by a ratchet potential. By solving the steady-state Smoluchowski equations in a flux-free setting, we show that the ratchet potential affects the distribution of particles over the bulks and thus exerts an influence of infinitely long range. As we show, an external potential that is nonlinear is crucial for having such a long-range influence. We characterize how the difference in bulk densities depends on activity and on the ratchet potential, and we identify power law dependencies on system parameters in several limiting cases. While weakly active systems are often understood in terms of an effective temperature, we present an analytical solution that explicitly shows that this is not possible in the current setting. Instead, we rationalize our results by a simple transition state model that presumes particles to cross the potential barrier by Arrhenius rates modified for activity. While this model does not quantitatively describe the difference in bulk densities for feasible parameter values, it does reproduce-in its regime of applicability-the complete power law behavior correctly. PMID- 30408989 TI - Effects of ensembles, ligand, and strain on adsorbate binding to alloy surfaces. AB - Alloying elements with strong and weak adsorption properties can produce a catalyst with optimally tuned adsorbate binding. A full understanding of this alloying effect, however, is not well-established. Here, we use density functional theory to study the ensemble, ligand, and strain effects of close packed surfaces alloyed by transition metals with a combination of strong and weak adsorption of H and O. Specifically, we consider PdAu, RhAu, and PtAu bimetallics as ordered and randomly alloyed (111) surfaces, as well as randomly alloyed 140-atom clusters. In these alloys, Au is the weak-binding component and Pd, Rh, and Pt are characteristic strong-binding metals. In order to separate the different effects of alloying on binding, we calculate the tunability of H- and O binding energies as a function of lattice constant (strain effect), number of alloy-substituted sublayers (ligand effect), and randomly alloyed geometries (ensemble effect). We find that on these alloyed surfaces, the ensemble effect more significantly tunes the adsorbate binding as compared to the ligand and strain effects, with the binding energies predominantly determined by the local adsorption environment provided by the specific triatomic ensemble on the (111) surface. However, we also find that tuning of adsorbate binding from the ligand and strain effects cannot be neglected in a quantitative description. Extending our studies to other bimetallics (PdAg, RhAg, PtAg, PdCu, RhCu, and PtCu), we find similar conclusions that the tunability of adsorbate binding on random alloys is predominately described by the ensemble effect. PMID- 30408990 TI - Four-component relativistic range-separated density-functional theory: Short range exchange local-density approximation. AB - We lay out the extension of range-separated density-functional theory to a four component relativistic framework using a Dirac-Coulomb-Breit Hamiltonian in the no-pair approximation. This formalism combines a wave-function method for the long-range part of the electron-electron interaction with a density(-current) functional for the short-range part of the interaction. We construct for this formalism a short-range exchange local-density approximation based on calculations on a relativistic homogeneous electron gas with a modified Coulomb Breit electron-electron interaction. More specifically, we provide the relativistic short-range Coulomb and Breit exchange energies per particle of the relativistic homogeneous electron gas in the form of Pade approximants which are systematically improvable to arbitrary accuracy. These quantities, as well as the associated effective Coulomb-Breit exchange hole, show the important impact of relativity on short-range exchange effects for high densities. PMID- 30408991 TI - Importance of corners in fracture of highly crosslinked polymeric adhesives. AB - Very large molecular dynamics simulations with open ends between two solid adherends have been performed treating tensile deformation of coarse-grained, highly crosslinked polymer networks modeling epoxy systems. The open boundary and the presence of corners dramatically alter the fracture behavior. In contrast to systems with periodic boundaries, the failure strain decreases with increasing system size until a critical size is reached. This decrease greatly reduces the difference in the crack initiation strains between simulation and experiment. In the open geometry, the sides of the polymer network contract inward forming wedge shaped corners. The stress and strain are concentrated in the corners where the shear component is present and large. The nonuniformity of the strain results in accumulation of bond breaking in the corners and crack initiation there. Moreover, the corner strain is system size dependent, which results in a system size dependence of the failure strain. PMID- 30408992 TI - Communication: Inside the water wheel: Intrinsic differences between hydrated tetraphenylphosphonium and tetraphenylborate ions. AB - Tetraphenylphosphonium tetraphenylborate (TPTB) is a common reference electrolyte in physical chemistry of solutions allowing for a convenient partitioning of thermodynamic properties into single-ion contributions. Here, we compute on the basis of ab initio molecular dynamics simulations the infrared (IR) spectra for hydrated constituent ions of the TPTB assumption. Using spectral decomposition techniques, we extract important information pertaining to the state of the hydration water from the IR spectra. Within their physical radii, the ions manage to capture about a dozen H2O molecules, several of which penetrate deep into the grooves between the tetrahedrally oriented "sails" of the rotating ions. In accordance with previous IR and Raman experiments, we find a considerable blue shift of the nu OH stretching band of liquid water by 240 cm-1 for TB, due to the extensive O-H?pi hydrogen bonding, which is much weaker for TP. On the other hand, both ions show a second prominent band in the nu OH vibration range, only mildly blue shifted with respect to bulk water and attributable to the general distortion of the hydrogen bond network of the neighboring solvent. Finally, spatially resolved IR spectra allow us to pinpoint the exact location around the solutes, from which different IR resonances of the solvent originate. PMID- 30408993 TI - Gaussian-based multiconfiguration time-dependent Hartree: A two-layer approach. II. Application to vibrational energy transport in a molecular chain. AB - We report on first applications of the Two-Layer Gaussian-based Multi Configuration Time-Dependent Hartree (2L-GMCTDH) method [Romer et al., J. Chem. Phys. 138, 064106 (2013)] for high-dimensional quantum propagation using variational Gaussian basis sets. This method circumvents the limitations of conventional variational Gaussian wavepacket (GWP) methods by introducing a hierarchical wavefunction representation with a fully flexible first layer composed of orthogonal single-particle functions, which are in turn expressed as superpositions of GWPs of fixed width. The method is applied to a model Hamiltonian describing vibrational energy transport through a molecular chain. The model combines bilinear site-to-site couplings with site-local couplings induced by cubic anharmonicities. We report on simulation results for realizations comprising 5 sites with 35 vibrational modes and 18 sites with 90 vibrational modes, which are shown to be in excellent agreement with reference calculations by the Multi-Layer MCTDH method. PMID- 30408994 TI - A sequential nanopore-channel device for polymer separation. AB - In this work, we investigated whether a series of nanopores connected by channels can be used to separate polymer mixtures by molecular size. We conducted multiscale coarse-grained simulations of semiflexible polymers driven through such a device. Polymers were modelled as chains of beads near the nanopores and as single particles in the bulk of the channels. Since polymers rarely escape back into the bulk of the channels after coming sufficiently close to the nanopores, the more computationally expensive simulations near the pores were decoupled from those in the bulk. The distribution of polymer positions after many translocations was deduced mathematically from simulations across a single nanopore-channel pair, under the reasonable assumption of identical and independent dynamics in each channel and each nanopore. Our results reveal rich polymer dynamics in the nanopore-channel device and suggest that it can indeed produce polymer separation. As expected, the mean time to translocate across a single nanopore increases with the chain length. Conversely, the mean time to cross the channels from one nanopore to the next decreases with the chain length, as smaller chains explore more of the channel volume between translocations. As such, the time between translocations is a function of the length and width of the channels. Depending on the channel dimensions, polymers are sorted by increasing length, decreasing length, or non-monotonically by length such that polymers of an intermediate size emerge first. PMID- 30408995 TI - Unified theory of plasmon-induced resonance energy transfer and hot electron injection processes for enhanced photocurrent efficiency. AB - Plasmons in metal nanoparticles (MNPs) promise to enhance solar energy conversion in semiconductors. Two essential mechanisms of enhancement in the near-field regime are hot electron injection (HEI) and plasmon-induced resonance energy transfer (PIRET). Individual studies of both mechanisms indicate that the PIRET efficiency is limited by the short lifetime of the plasmon, whereas the hot electrons result from the plasmon decay. The development of a unified theory of the coupled HEI and PIRET processes is fundamentally interesting and necessary for making reliable predictions but is complicated by the multiple interactions between various components that participate in the enhancement process. In this paper, we use the model-Hamiltonian approach to develop a combined theoretical framework including both PIRET and HEI. The coupled dynamics as well as the time evolution of hot electron energy distribution are studied. The theory further predicts an interference-induced asymmetry in the spectral dependence of PIRET, which can be used to distinguish it from HEI. As the relative contributions of PIRET and HEI strongly depend on the size of the MNPs, this presents itself as a simple route to control the strength of their contributions. The results presented here can further guide future applications of plasmonic solar energy harvesting. PMID- 30408996 TI - Conformationally averaged iterative Brownian dynamics simulations of semidilute polymer solutions. AB - The dynamics of semidilute polymer solutions are important to many polymer solution processing techniques such as fiber spinning and solution printing. The out-of-equilibrium molecular conformations resulting from processing flows directly impact material properties. Brownian dynamics (BD) simulations are a standard technique for studying this connection between polymer conformations in solution and processing flows because they can capture molecular-level polymer dynamics. However, BD simulations of semidilute polymer solutions are computationally limited by the calculation of hydrodynamic interactions (HIs) via an Ewald summed diffusion tensor and stochastic Brownian displacements via the decomposition of the diffusion tensor. Techniques based on the Cholesky decomposition scale with the number of particles N as O(N 3) and approximations in the literature have reduced this scaling to as low as O(N). These methods still require continuous updating of the diffusion tensor and Brownian displacements, resulting in a significant constant per-time step cost. Previously, we introduced a method that avoids this cost for dilute polymer solutions by iterative conformational averaging (CA) of intramolecular HIs. In this work, we extend the CA method to semidilute solutions by introducing a grid space average of intermolecular HIs and a pairwise approximation to the Brownian displacements based on the truncated expansion ansatz of Geyer and Winter. We evaluate our method by first comparing the computational cost with that of other simulation techniques. We verify our approximations by comparison with expected results for static and dynamic properties at equilibrium and use our method to demonstrate the concentration dependence of HI screening. PMID- 30408997 TI - Quantum dynamics study of rotational transitions of NCCN induced by He collision. AB - Quantum dynamics of the molecule cyanogen (NCCN) and its collision with helium taking place in the interstellar medium has been studied. An ab initio potential energy surface of NCCN-He, a van der Waals complex, is generated using the high level single reference coupled-cluster with single and double and perturbative triple excitation method and aug-cc-pVQZ basis sets. Using the multipole expansion, Legendre coefficients have been calculated and utilized in determining collisional cross sections. Close-coupling calculations have been performed to study rotational excitations for He collision with NCCN. Due to nuclear spin statistics, collision induced transitions have even Deltaj, while odd Deltaj transitions are forbidden. The presence of resonances arising from rapid oscillation of cross sections in the low energy region is the result of quasi bound states in the NCCN-He van der Waals complex. Among all the transitions, Deltaj = 2 are found to be predominant for excitation. Thereafter, for each transition, the rate coefficients have been calculated which decrease with increasing values of j and Deltaj. The result of this work will be helpful to accurately model the abundance of cyanogen in stellar atmospheres and interstellar gas. PMID- 30408998 TI - Temperature dependence of the solid-liquid interface free energy of Ni and Al from molecular dynamics simulation of nucleation. AB - The temperature dependence of the solid-liquid interfacial free energy, gamma, is investigated for Al and Ni at the undercooled temperature regime based on a recently developed persistent-embryo method. The atomistic description of the nucleus shape is obtained from molecular dynamics simulations. The computed gamma shows a linear dependence on the temperature. The values of gamma extrapolated to the melting temperature agree well with previous data obtained by the capillary fluctuation method. Using the temperature dependence of gamma, we estimate the nucleation free energy barrier in a wide temperature range from the classical nucleation theory. The obtained data agree very well with the results from the brute-force molecular dynamics simulations. PMID- 30408999 TI - Optical saturation effects in intracavity Faraday modulation spectroscopy (INFAMOS). AB - We report on the observation of saturation effects in Intracavity Faraday Modulation Spectroscopy (INFAMOS). A quantum cascade laser operating at ~5.3 MUm is used to probe the 2Pi3/2 and 2Pi1/2 R(3.5) transitions in the fundamental band of nitric oxide. With average intracavity intensities up to 450 W cm-2, the saturation of these molecular transitions is observed up to a total pressure of ~240 Torr. The experimental data are interpreted by incorporating saturation into a model for the INFAMOS line shape in the homogeneously broadened limit. PMID- 30409000 TI - Dynamics of polar polarizable rotors acted upon by unipolar electromagnetic pulses: From the sudden to the adiabatic regime. AB - We study, analytically as well as numerically, the dynamics that arises from the interaction of a polar polarizable rigid rotor with single unipolar electromagnetic pulses of varying length, Deltatau, with respect to the rotational period of the rotor, tau r . In the sudden, non-adiabatic limit, Deltatau ? tau r , we derive analytic expressions for the rotor's wavefunctions, kinetic energies, and field-free evolution of orientation and alignment. We verify the analytic results by solving the corresponding time-dependent Schrodinger equation numerically and extend the temporal range of the interactions considered all the way to the adiabatic limit, Deltatau > tau r , where general analytic solutions beyond the field-free case are no longer available. The effects of the orienting and aligning interactions as well as of their combination on the post-pulse populations of the rotational states are visualized as functions of the orienting and aligning kick strengths in terms of population quilts. Quantum carpets that encapsulate the evolution of the rotational wavepackets provide the space-time portraits of the resulting dynamics. The population quilts and quantum carpets reveal that purely orienting, purely aligning, or even-break combined interactions each exhibit sui generis dynamics. In the intermediate temporal regime, we find that the wavepackets as functions of the orienting and aligning kick strengths show resonances that correspond to diminished kinetic energies at particular values of the pulse duration. PMID- 30409001 TI - Isotopic and symmetry breaking effects on phosphine spectra under H -> D substitutions from ab initio variational calculations. AB - Variationally computed infrared spectra in the range [0-5000] cm-1 are reported for the deuterated PH2D and PHD2 molecules from accurate potential energy and dipole moment surfaces initially derived for the major isotopologue PH3( C3v ). Energy level and line intensity calculations were performed by using a normal mode model combined with isotopic and symmetry transformations for the H -> D substitutions. Theoretical spectra were computed at 296 K up to J max = 30 and will be made available through the TheoReTS information system (http://theorets.univ-reims.fr, http://theorets.tsu.ru). For the very first time, ab initio intensity predictions of PH2D/PHD2 are in good qualitative agreement with the literature. This work will be useful for spectral intensity analysis for which accurate spectral intensity data are still missing. PMID- 30409002 TI - Rotation and translation dynamics of coumarin 153 in choline chloride-based deep eutectic solvents. AB - The equilibrium and dynamic solvation responses of coumarin 153 (C153) in a range of deep eutectic solvents (DESs) based on choline chloride with either urea (molar ratio 1:2, ChCl:U), glycerol (1:2, ChCl:G), ethylene glycol (1:2, ChCl:E), or malonic acid (1:1, ChCl:Mal) were investigated using both steady-state and time-resolved fluorescence emission spectroscopy at room temperature (298 K). From steady-state fluorescence data, "red-edge effects" were observed in all the DESs studied, attributed to spatial heterogeneity of the DES matrix. Time resolved Stokes shifts were used to quantify dynamic solvation with the solvation response function in DES found to be a biexponential function of time, which were used to obtain average solvation times (?tau s ?) which are generally faster in DES than in ionic liquids of comparable viscosity. Average solvation times showed a partial correlation with viscosity between different DESs. The choline chloride glycerol DES showed deviation from the viscosity trend observed in the other DES for both dynamic and steady-state results. Rotational reorientation times obtained from dynamic anisotropy (r(t)) measured for these DESs showed a partial correlation with viscosity between different DESs. Determination of the DES rotational coupling with C153 showed more "slip"-like behavior than the previously reported ionic liquids and dipolar solvents. PMID- 30409003 TI - Transport of particles driven by the traveling obstacle arrays. AB - Transport of three types of particles (passive particles, active particles without polar interaction, and active particles with polar interaction) is numerically investigated in the presence of traveling obstacle arrays. The transport behaviors are different for different types of particles. For passive particles, there exists an optimal traveling speed (or the translational diffusion) at which the average velocity of particles takes its maximum value. For active particles without polar interaction, the average velocity of particles is a peaked function of the obstacle traveling speed. The average velocity decreases monotonically with increase of the rotational diffusion for large driving speed, while it is a peaked function of the rotational diffusion for small driving speed. For active particles with polar interaction, interestingly, within particular parameter regimes, active particles can move in the opposite direction to the obstacles. The average velocity of particles can change its direction by changing the system parameters (the obstacles driving speed, the polar interaction strength, and the rotational diffusion). PMID- 30409004 TI - Six-dimensional quantum dynamics for the dissociative chemisorption of HCl on rigid Ag(111) on three potential energy surfaces with different density functionals. AB - We carried out six-dimensional quantum dynamics calculations for the dissociative chemisorption of HCl on a rigid Ag(111) surface, employing three potential energy surfaces (PESs) which were recently constructed using the neural network approach based on extensive density functional theory calculations with Perdew-Burke Ernzerhof, Perdew-Wang91, and revised Perdew-Burke-Ernzerhof functionals, respectively. The vibrational excitation of HCl enhances the reactivity substantially, and the dissociation is most favored for HCl molecules colliding with rotation in a plane parallel to the Ag(111) surface (helicopter alignment). The influence of rotational excitation on the dissociation probability is much more complicated, with different trends at high and at low kinetic energies. The usage of three different PESs does not change the effects of vibrational excitation, rotational excitation, and rotational-alignment qualitatively, but it does change the magnitude of dissociation probabilities quantitatively due to the different barrier heights. PMID- 30409005 TI - Surface free energy of a hard-sphere fluid at curved walls: Deviations from morphometric thermodynamics. AB - We report molecular-dynamics (MD) simulation results for the surface free energy of a hard-sphere fluid at cylindrical and spherical hard walls of different radii. The precision of the results is much higher than that in our previous study [B. B. Laird et al., Phys. Rev. E 86, 060602 (2012)], allowing us to estimate the size of deviations from the predictions of Morphometric Thermodynamics (MT). We compare our results to the analytical expressions for the surface energy as a function of wall radius R and fluid density derived from the White Bear II variant of the density functional theory, as well as to the leading terms of the virial expansion. For the cylindrical wall, we observe deviations from MT proportional to R -2 and R -3, which are consistent with the available virial expressions. For the spherical wall, while the precision is not sufficient to detect statistically significant deviations from MT, the MD results indicate the range of densities for which the truncated virial expansions are applicable. PMID- 30409006 TI - Quantum wavepacket method for state-to-state reactive cross sections in hyperspherical coordinates. AB - We present theory for calculating state-to-state differential cross sections (DCS) of triatomic reactive scattering in hyperspherical coordinates using a quantum wavepacket method. The adiabatically adjusting, principal axes hyperspherical coordinates proposed by Pack and Parker [J. Chem. Phys. 87, 3888 (1987)] are applied, which deal with all arrangement channels equivalently, allowing the analysis of the products in all three arrangement channels with one main propagation. The propagated wavepacket is analyzed by projecting it onto the product ro-vibrational states at a fixed, asymptotic radius, R, of the corresponding Jacobi coordinates; thus, the channel-specified S-matrix elements can be calculated by matching the projections with the boundary conditions in the Jacobi coordinates. For numerical demonstrations, state-to-state DCS of the H + HD ( v 0 = 0, j 0 = 0) reaction and state-to-state reaction probabilities of the O + O2 ( v 0 = 0, j 0 = 0) reaction and the F + HCl ( v 0 = 0, j 0 = 0) -> HF + Cl reaction for zero total angular momentum are presented. The second order split operator method and the Chebyshev polynomial expansion method were applied to propagate the wavefunction. The relative numerical efficiencies for calculating the state-to-state information of triatomic reactive scattering using the hyperspherical coordinate and the reactant Jacobi coordinate are discussed. PMID- 30409007 TI - Efficient calculation of (resonance) Raman spectra and excitation profiles with real-time propagation. AB - We investigate approaches for the calculation of (resonance) Raman spectra in a real-time time-dependent density functional theory (RT-TDDFT) framework. Several short time approximations to the Kramers, Heisenberg, and Dirac polarizability tensor are examined with regard to the calculation of resonance Raman spectra: One relies on a Placzek type expansion of the electronic polarizability and the other one relies on the excited state gradient method. The first one is shown to be in agreement with an approach based on perturbation theory in the case of a weak delta-pulse perturbation. The latter is newly applied in a real time propagation framework, enabled by the use of Pade approximants to the Fourier transform which allow for a sufficient resolution in the frequency domain. An analysis of the performance of Pade approximants is given. All approaches were found to be in good agreement for uracil and R-methyloxirane. Moreover it is shown how RT-TDDFT can be used to calculate Raman excitation profiles efficiently. PMID- 30409008 TI - The quantum mechanics-based polarizable force field for water simulations. AB - We report here a new force field for water based solely on quantum mechanics (QM) calculations with no empirical data. The QM was at a high level, coupled cluster single double triple, for all orientations and distances for water dimer plus X3LYP density functional theory (DFT) on 19 larger water clusters. In addition, we included charge and polarization based on the polarizable charge equilibration method and nonbond interactions from DFT-D3 calculations on the H2 and O2 crystal. This model, denoted as RexPoN, provides quite excellent agreement with experimental (expr) data for the solid and liquid phase of water: T melt = 273.3 K (expr = 273.15 K) and properties at 298 K: DeltaH vap = 10.36 kcal/mol (expr = 10.52), density = 0.9965 gr/cm3 (expr = 0.9965), entropy = 68.4 (J/mol)/K (expr = 69.9), dielectric constant = 76.1 (expr = 78.4), and ln D s (self-diffusion coef) = -10.08 (expr = -11.24). Such an accurate force field for water will, we believe, be useful for full solvent calculations of electrocatalysis, where we can restrict QM water to just the first one or two layers involving reactions, using RexPoN to provide the polarization for a more distant solvent. Also, RexPoN may provide a better description of the solvent for proteins, DNA, polymers, and inorganic systems for applications to biomolecular, pharma, electrocatalysis (fuel cells and water splitting), and batteries where interaction with explicit water molecules plays a significant role. PMID- 30409009 TI - Hierarchical visualization of materials space with graph convolutional neural networks. AB - The combination of high throughput computation and machine learning has led to a new paradigm in materials design by allowing for the direct screening of vast portions of structural, chemical, and property spaces. The use of these powerful techniques leads to the generation of enormous amounts of data, which in turn calls for new techniques to efficiently explore and visualize the materials space to help identify underlying patterns. In this work, we develop a unified framework to hierarchically visualize the compositional and structural similarities between materials in an arbitrary material space with representations learned from different layers of graph convolutional neural networks. We demonstrate the potential for such a visualization approach by showing that patterns emerge automatically that reflect similarities at different scales in three representative classes of materials: perovskites, elemental boron, and general inorganic crystals, covering material spaces of different compositions, structures, and both. For perovskites, elemental similarities are learned that reflects multiple aspects of atom properties. For elemental boron, structural motifs emerge automatically showing characteristic boron local environments. For inorganic crystals, the similarity and stability of local coordination environments are shown combining different center and neighbor atoms. The method could help transition to a data-centered exploration of materials space in automated materials design. PMID- 30409010 TI - Rate coefficients of the H + H2O2 -> H2 + HO2 reaction on an accurate fundamental invariant-neural network potential energy surface. AB - The rate coefficients of the H + H2O2 -> H2 + HO2 reaction are calculated using the ring polymer molecular dynamics (RPMD), quasi-classical trajectory (QCT), and canonical variational transition state theory (CVT) with small curvature tunneling (SCT) correction, in conjunction with the recently constructed fundamental invariant-neural network (FI-NN) potential energy surface (PES) [X. Lu et al., Phys. Chem. Chem. Phys. 20, 23095 (2018)]. In RPMD calculations, 32, 16, and 8 beads are used for computing the rate coefficients at 200 K <= T <= 400 K, 500 K <= T <= 700 K, and 700 K < T <= 1000 K, respectively. Given that the previous experimental rate coefficients vary widely, in particular, at low temperatures, the present RPMD rate coefficients agree well with most of the experimental results. In addition, comparing with some experimental values, the present QCT and CVT/SCT calculations on the FI-NN PES also predict accurate results at some temperatures. These results strongly support the accuracy of the present dynamics calculations as well as the full-dimensional FI-NN PES. PMID- 30409011 TI - Equation-of-motion coupled-cluster theory based on the 4-component Dirac-Coulomb( Gaunt) Hamiltonian. Energies for single electron detachment, attachment, and electronically excited states. AB - We report in this paper an implementation of a 4-component relativistic Hamiltonian based Equation-of-Motion Coupled-Cluster with singles and doubles (EOM-CCSD) theory for the calculation of ionization potential, electron affinity, and excitation energy. In this work, we utilize the previously developed double group symmetry-based generalized tensor contraction scheme and also extend it in order to carry out tensor contractions involving non-totally symmetric and odd ranked tensors. Several approximated spin-free and two-component Hamiltonians can also be accessed in this implementation. We have applied this method to the halogen monoxide (XO, X = Cl, Br, I, At, Ts) species, in order to assess the quality of a few other recent EOM-CCSD implementations, where spin-orbit coupling contribution has been approximated in different degrees. Besides, we have also studied various excited states of CH2IBr, CH2I2, and I3- (as well as single electron attachment and detachment electronic states of the same species) where comparison has been made with a closely related multi-reference coupled-cluster method, namely, Intermediate Hamiltonian Fock Space Coupled-Cluster singles and doubles theory. PMID- 30409012 TI - Conformer-specific photoionization and conformational stabilities of isobutanal revealed by one-photon mass-analyzed threshold ionization (MATI) spectroscopy. AB - Isobutanal is an aliphatic aldehyde which has been extensively studied as an important intermediate in isomerization reactions as well as in astrochemically relevant models in the interstellar medium. Herein, we report on the conformer specific photoionization and conformational stabilities of isobutanal utilizing one-photon mass-analyzed threshold ionization (MATI) spectroscopy with vacuum ultraviolet (VUV) pulses. The conformational population of isobutanal under different supersonic expansion conditions was explored to identify the conformers, from which their intrinsic photoionizations can be directly elucidated by measuring the VUV-MATI spectrum corresponding to each conformer. The observed MATI spectra could be analyzed through Franck-Condon simulations at the B3LYP/cc-pVTZ level for the isobutanal conformers, trans and gauche, for which the adiabatic ionization energies were precisely determined to be 78 133 +/ 3 cm-1 (9.6873 +/- 0.0004 eV) and 78 557 +/- 3 cm-1 (9.7398 +/- 0.0004 eV), respectively. Notably, only the gauche conformer undergoes a unique geometrical change upon ionization, resulting in the progression of the CHO torsional mode in the MATI spectra. Consequently, we determined the conformational stabilities of isobutanal by conformer-specific photoionization, given that the gauche is more stable than the trans by 162 +/- 50 cm-1 in the neutral ground state, while the cationic gauche is less stable than the cationic trans by 262 +/- 50 cm-1. PMID- 30409013 TI - Bond dissociation energies of FeSi, RuSi, OsSi, CoSi, RhSi, IrSi, NiSi, and PtSi. AB - Resonant two-photon ionization spectroscopy has been used to investigate the spectra of the diatomic late transition metal silicides, MSi, M = Fe, Ru, Os, Co, Rh, Ir, Ni, and Pt, in the vicinity of the bond dissociation energy. In these molecules, the density of vibronic states is so large that the spectra appear quasicontinuous in this energy range. When the excitation energy exceeds the ground separated atom limit, however, a new decay process becomes available molecular dissociation. This occurs so rapidly that the molecule falls apart before it can absorb another photon and be ionized. The result is a sharp drop to the baseline in the ion signal, which we identify as occurring at the thermochemical 0 K bond dissociation energy, D0. On this basis, the measured predissociation thresholds provide D0 = 2.402(3), 4.132(3), 4.516(3), 2.862(3), 4.169(3), 4.952(3), 3.324(3), and 5.325(9) eV for FeSi, RuSi, OsSi, CoSi, RhSi, IrSi, NiSi, and PtSi, respectively. Using thermochemical cycles, the enthalpies of formation of the gaseous MSi molecules are derived as 627(8), 700(10), 799(10), 595(8), 599(8), 636(10), 553(12), and 497(8) kJ/mol for FeSi, RuSi, OsSi, CoSi, RhSi, IrSi, NiSi, and PtSi, respectively. Likewise, combining these results with other data provides the ionization energies of CoSi and NiSi as 7.49(7) and 7.62(7) eV, respectively. Chemical bonding trends among the diatomic transition metal silicides are discussed. PMID- 30409014 TI - Power-law decay in the nonadiabatic photodissociation dynamics of alkali halides due to quantum wavepacket interference. AB - The nonadiabatic photodissociation dynamics of alkali halide molecules excited by a femtosecond laser pulse in the gas phase are investigated theoretically, and it is shown that the population of the photoexcited molecules exhibits power-law decay with exponent -1/2, in contrast to exponential decay, which is often assumed in femtosecond spectroscopy and unimolecular reaction theory. To elucidate the mechanism of the power-law decay, a diagrammatic method that visualizes the structure of the nonadiabatic reaction dynamics as a pattern of occurrence of dynamical events, such as wavepacket bifurcation, turning, and dissociation, is developed. Using this diagrammatic method, an analytical formula for the power-law decay is derived, and the theoretical decay curve is compared with the corresponding numerical decay curve computed by a wavepacket dynamics simulation in the case of lithium fluoride. This study reveals that the cause of the power-law decay is the quantum interference arising from the wavepacket bifurcation and merging due to nonadiabatic transitions. PMID- 30409016 TI - Molecular search with conformational change: One-dimensional discrete-state stochastic model. AB - Molecular search phenomena are observed in a variety of chemical and biological systems. During the search, the participating particles frequently move in complex inhomogeneous environments with random transitions between different dynamic modes. To understand the mechanisms of molecular search with alternating dynamics, we investigate the search dynamics with stochastic transitions between two conformations in a one-dimensional discrete-state stochastic model. It is explicitly analyzed using the first-passage time probability method to obtain a full dynamic description of the search process. A general dynamic phase diagram is developed. It is found that there are several dynamic regimes in the molecular search with conformational transitions, and they are determined by the relative values of the relevant length scales in the system. Theoretical predictions are fully supported by Monte Carlo computer simulations. PMID- 30409015 TI - Low frequency vibrational anharmonicity and nuclear spin effects of Cl-(H2) and Cl-(D2). AB - Low frequency combination bands of 35Cl-(H2) and 35Cl-(D2) have been measured in the region between 600 and 1100 cm-1 by infrared predissociation spectroscopy in a cryogenic 22-pole ion trap using a free electron laser at the FELIX Laboratory as a tunable light source. The 35Cl-(H2) (35Cl-(D2)) spectrum contains three bands at 773 cm-1 (620 cm-1), 889 cm-1 (692 cm-1), and 978 cm-1 (750 cm-1) with decreasing intensity toward higher photon energies. Comparison of the experimentally determined transition frequencies with anharmonic vibrational self consistent field and vibrational configuration interaction calculations suggests the assignment of the combination bands v1 + v2, 2v1 + v2, and 3v1 + v2 for 35Cl (H2) and 2v1 + v2, 3v1 + v2, and 4v1 + v2 for 35Cl-(D2), where v1 is the 35Cl-?H2 stretching fundamental and v2 is the Cl-(H2) bend. The observed asymmetric temperature dependent line shape of the v1 + v2 transition can be modeled by a series of ?+-? ro-vibrational transitions, when substantially decreasing the rotational constant in the vibrationally excited state by 35%. The spectrum of 35Cl-(D2) shows a splitting of 7 cm-1 for the strongest band which can be attributed to the tunneling of the ortho/para states of D2. PMID- 30409017 TI - Monte Carlo explicitly correlated many-body Green's function theory. AB - A highly scalable stochastic algorithm is proposed and implemented for computing the basis-set-incompleteness correction to the diagonal, frequency-independent self-energy of the second-order many-body Green's function (GF2) theory within the explicitly correlated (F12) formalism. The 6-, 9-, 12-, and 15-dimensional integrals comprising the F12 correction are directly evaluated by the Monte Carlo method using appropriate weight functions for importance sampling. The method is naturally and easily parallelized, involves minimal memory space and no disk I/O, and can use virtually any mathematical form of a correlation factor. Its computational cost to correct all ionization energies (IEs) is observed to increase as the fourth power of system size, as opposed to the fifth power in the case of the deterministic counterparts. The GF2 calculations and their F12 corrections for the first IEs of C60 and C70 were executed on 128 graphical processing units (GF2) and 896 central processing units (F12), respectively, to reach the results with statistical errors of 0.04 eV or less. They showed that the basis-set-incompleteness (from aug-cc-pVDZ) accounts for only 50%-60% of the deviations from experiments, suggesting the significance of higher-order perturbation corrections. PMID- 30409018 TI - Gaussian-based multiconfiguration time-dependent Hartree: A two-layer approach. III. Application to nonadiabatic dynamics in a charge transfer complex. AB - In this paper, we report on first applications of the Two-Layer Gaussian-based Multi-Configuration Time-Dependent Hartree (2L-GMCTDH) method to nonadiabatic dynamics. Simulations of ultrafast, coherent charge transfer dynamics are performed for a two-state linear vibronic coupling model describing an oligothiophene-fullerene charge transfer complex, for system dimensions ranging from 20 to 100 modes. Different variants of the state-dependent 2L-GMCTDH propagation are assessed, notably single-set and multi-set versions, along with a third hybrid variant. It is shown that the method is suitable to perform accurate and efficient nonadiabatic dynamics simulations in many dimensions. PMID- 30409020 TI - Simple eigenvalue-self-consistent Delta-GW0. AB - We show that a rigid scissors-like GW self-consistency approach, labeled here Delta-GW0 , can be trivially implemented at zero additional cost for large scale one-shot G 0 W 0 calculations. The method significantly improves one-shot G 0 W 0 and for large systems is very accurate. Delta-GW0 is similar in spirit to evGW 0 where the self-consistency is only applied on the eigenvalues entering Green's function, while both W and the eigenvectors of Green's function are held fixed. Delta-GW0 further assumes that the shift of the eigenvalues is rigid scissors like so that all occupied states are shifted by the same amount and analogously for all the unoccupied states. We show that this results in a trivial modification of the time-dependent G 0 W 0 self-energy, enabling an a posteriori self-consistency cycle. The method is applicable for our recent stochastic-GW approach, thereby enabling self-consistent calculations for giant systems with thousands of electrons. The accuracy of Delta-GW0 increases with the system size. For molecules, it is up to 0.4-0.5 eV away from coupled-cluster single double triple (CCSD(T)), but for tetracene and hexacene, it matches the ionization energies from both CCSD(T) and evGW 0 to better than 0.05 eV. For solids, as exemplified here by periodic supercells of semiconductors and insulators with 6192 valence electrons, the method matches evGW 0 quite well and both methods are in good agreement with the experiment. PMID- 30409019 TI - Slow photoelectron velocity-map imaging of cold C7- and C9-. AB - High-resolution anion photoelectron spectra of cryogenically cooled C7 - and C9 - clusters obtained using slow photoelectron velocity-map imaging are presented, providing insight into the vibronic structure of neutral C7 and C9. These spectra yield accurate measurements of vibrational frequencies for the neutral clusters as well as electron affinities of 3.3517(4) and 3.6766(14) eV for C7 and C9, respectively. In the C7 - spectrum, transitions involving the previously unreported v 1 and v 2 symmetric stretching modes, as well as the v 9, v 10, and v 11 asymmetric bending modes, are assigned. Spin-orbit splitting is observed for several transitions in this spectrum, giving an energy difference of 28(6) cm-1 between the Pi1/2g2 and Pi3/2g2 spin-orbit levels of the C7 - anion. In the spectrum of C9 -, transitions involving the previously unreported symmetric stretch v 1 and the asymmetric bend v 11 are observed. In both spectra, several features are assigned to Franck-Condon forbidden transitions involving the doubly degenerate v 10 and v 11 modes of C7 and the v 13 and v 14 modes of C9. The appearance of these transitions is attributed to Herzberg-Teller coupling between the electronic states of the neutral clusters. Additional FC-forbidden transitions to states previously observed in gas-phase infrared experiments are observed and attributed to vibronic coupling between the electronic states of the anion, resulting in non-totally symmetric character in the anion's full vibrational ground state. Finally, consideration of the energy dependence of detachment cross sections and Dyson orbital analyses reveal that addition of more carbon atoms to the linear chain results in photodetachment from delocalized molecular orbitals with increasing nodal structure, leading to threshold photodetachment cross sections that differ considerably from simple symmetry considerations. PMID- 30409021 TI - Primary Care 2.0: Design of a Transformational Team-Based Practice Model to Meet the Quadruple Aim. AB - A new transformational model of primary care is needed to address patient care complexity and provider burnout. An 18-month design effort (2015-2016) included the following: (1) Needs Finding, (2) Integrated Facility Design, (3) Design Process Assessment, and (4) Development of Evaluation. Initial outcome metrics were assessed. The design team successfully applied Integrated Facility Design to primary care transformation design; qualitative survey results suggest that design consensus was facilitated by team-building activities. Initial implementation of Quadruple Aim-related outcome metrics showed positive trends. Redesign processes may benefit from emphasis on team building to facilitate consensus and increased patient involvement to incorporate patient voices successfully. PMID- 30409022 TI - Relationship of care staff attitudes with social well-being and challenging behavior of nursing home residents with dementia: a cross sectional study. AB - OBJECTIVES: This study investigates the relationship between attitudes of care staff and social well-being and challenging behavior of residents in long-term dementia care. METHODS: The study was based on a cross-sectional design using questionnaires. Care staff members (N = 291) of 15 long-term care facilities in the Netherlands completed the Approaches to Dementia Questionnaire. Additionally, the primary professional caregiver of each participating resident (N = 239) completed an observational questionnaire regarding that resident's behavior, which contained the scale for Social Wellbeing Of Nursing home residents and the Cohen-Mansfield Agitation Inventory. Data were analyzed using multilevel analyses, taking characteristics of residents into account. RESULTS: Attitudes of care staff towards residents with dementia differed between facilities. Further, residents experienced more social well-being and displayed less challenging behavior in facilities where care staff had more hopeful attitudes. CONCLUSION: This study demonstrates a relationship between attitudes of care staff and resident well-being. The results indicate that it is important to address attitudes towards residents with dementia in the education of (future) care staff. Care processes may also be improved by focusing on the attitudes of care staff. In this way, the well-being of residents with dementia can potentially be improved as well. PMID- 30409024 TI - Considerations When Designing a Microbiome Study: Implications for Nursing Science. AB - Nurse scientists play an important role in studying complex relationships among human genetics, environmental factors, and the microbiome, all of which can contribute to human health and disease. Therefore, it is essential that they have the tools necessary to execute a successful microbiome research study. The purpose of this article is to highlight important methodological factors for nurse scientists to consider when designing a microbiome study. In addition to considering factors that influence host-associated microbiomes (i.e., microorganisms associated with organisms such as humans, mice, and rats), this manuscript highlights study designs and methods for microbiome analysis. Exemplars are presented from nurse scientists who have incorporated microbiome methods into their program of research. This review is intended to be a resource to guide nursing-focused microbiome research and highlights how study of the microbiome can be incorporated to answer research questions. PMID- 30409023 TI - Preventive Inhalation of Hypertonic Saline in Infants with Cystic Fibrosis (PRESIS): A Randomized, Double-Blind, Controlled Study. AB - RATIONALE: Cystic fibrosis (CF) lung disease starts in early infancy suggesting that preventive treatment may be most beneficial. Lung clearance index (LCI) and chest magnetic resonance imaging (MRI) have emerged as promising endpoints of early CF lung disease, however, randomized controlled trials testing the safety and efficacy of preventive therapies in infants with CF are lacking. OBJECTIVES: To determine feasibility, safety and efficacy of preventive inhalation with hypertonic saline (HS) compared to isotonic saline (IS) in infants with CF including LCI and MRI as outcome measures. METHODS AND MAIN RESULTS: In this randomized, double-blind, controlled trial 42 infants with CF less than 4 months of age were randomized across 5 sites to twice daily inhalation of 6% HS (n=21) or 0.9% IS (n=21) for 52 weeks. Inhalation of HS and IS was generally well tolerated by CF infants and the number of adverse events did not differ between groups (P=0.49). The change in LCI from baseline to week 52 was larger in CF infants treated with HS (-0.6) compared to IS (-0.1, P<0.05). In addition, weight gain was improved in CF infants treated with HS (P<0.05), whereas pulmonary exacerbations and chest MRI scores did not differ in the HS vs. IS group. CONCLUSIONS: Preventive inhalation with HS initiated in the first months of life was safe and well tolerated, and resulted in improvements in LCI and weight gain in infants with CF. Our results support feasibility of LCI as endpoint in randomized controlled trials in infants with CF. Clinical trial registration available at www.clinicaltrials.gov, ID NCT01619657. PMID- 30409025 TI - Are women's experiences of emotional and economic intimate partner violence associated with HIV-risk behaviour? A cross-sectional analysis of young women in informal settlements in South Africa. AB - Women's experiences of emotional intimate partner violence (IPV) and economic IPV are rarely considered in research on women's HIV-risk. Using cross-sectional data of young women (18-30) in Durban, South Africa, we assessed whether women's experiences of emotional IPV and economic IPV were independently associated with six HIV-risk behaviours. Amongst 680 women enrolled between September 2015 and September 2016, past year emotional IPV (78.1%) and economic IPV (52.2%) were common. In adjusted logistic regressions, women reporting past year emotional IPV were less likely to report condom use at last sex, and those reporting past year economic IPV were more likely to report transactional sex with a main partner, or casual partner. Overlaps between economic IPV and transactional sex, suggests economic IPV may be part of male economic coercion of women. Association between emotional IPV and condom use suggests complex inter-personal and psychodynamic relationships shape condom use. PMID- 30409026 TI - Mitochondrial DNA haplogroups influence the risk of aortic stenosis. AB - AIM: The underlying pathophysiologic mechanisms of aortic stenosis are not clear. Mitochondrial dysfunction plays a role in many pathological conditions including cardiac diseases. We aimed to analyze the mitochondrial DNA haplogroups in a group of patients undergoing valve replacement surgery due to severe aortic stenosis. METHODS: Mitochondrial DNA haplogroups were assessed in 176 patients with severe aortic stenosis and 308 control subjects. Cardiovascular risk factors and demographics were similar in both groups. RESULTS: Patients carrying haplogroup Uk had a lower risk of developing aortic stenosis, especially compared to patients carrying haplogroup H (odds ratio = 0.507; 95% confidence interval: 0.270-0.952, p = 0.035). CONCLUSIONS: Mitochondrial DNA haplogroups could be involved in the development of severe aortic stenosis. Specifically, haplogroup H could be a risk factor and Uk a protective factor for severe aortic stenosis in a population from Spain. PMID- 30409027 TI - U6 as a microRNA normalizer in serum of patients with hepatocellular carcinoma. PMID- 30409028 TI - EXPRESS: Application of Different Fourier Transform Infrared (FT-IR) Methods in the Characterization of Lime-Based Mortars with Oxblood. PMID- 30409029 TI - Syllogistic reasoning reveals reduced bias in people with higher autistic-like traits from the general population. AB - Recent theories of autism have emphasised the cognitive strengths and weaknesses in those with autism, which are also seen to some degree in non-clinical samples with higher autistic-like traits. The dual process theory of autism proposes that people with autism and non-clinical people with a higher degree of autistic-like traits have a propensity to show reduced intuitive processing (automatic and typically faster) alongside enhanced propensity towards deliberative processing (dependent on general cognitive ability and typically slower). This study aimed to further test the dual process theory of autism by investigating syllogistic reasoning (whether a conclusion can be logically deduced from two propositions) in addition to the cognitive reflection test (correct responses to which reflect deliberative processing over-riding intuitive processing) with respect to the degree of autistic-like traits and general cognitive ability in a non-clinical sample of 189 adults. Results showed that higher levels of autistic-like traits were related to lower levels of intuitive processing and higher levels of deliberative processing, which was found across both the syllogistic reasoning and cognitive reflection test measures - over and above the effect of general cognitive ability. The findings are consistent with the dual process theory of autism, and implications for autism are discussed. PMID- 30409030 TI - EXPRESS: Bulk Protein and Oil Prediction in Soybean Using Transmission Raman Spectroscopy: A Comparison of Approaches to Optimize Accuracy. PMID- 30409031 TI - Feasibility of a trauma-informed parent-teacher cooperative training program for Syrian refugee children with autism. AB - Although the number of Syrians affected by the civil war rises, little work has been done to address the needs of Syrian refugee children with autism spectrum disorder. This research aimed to test the feasibility and acceptability of a culturally sensitive intervention developed specifically for children with autism spectrum disorder affected by trauma. Local partners advised the program team on cultural norms. Nine parents and 11 teachers were recruited to participate in 12 week parent-teacher cooperatives in a large Turkish city. We used qualitative methods to analyze interviews with each participant after intervention completion. A total of 14 participants completed the program (70%). All interviewees were women and Syrian refugees. Local political events, transportation costs and safety, and illnesses impacted attrition and attendance. All participants were satisfied with program content, including gains in autism knowledge, behavior management skills, and social support. Program-related challenges included applying skills to nonverbal children. The majority of participants made recommendations for program improvement, including a need for services outside urban areas. Flexible program delivery methods, including online options, might better accommodate participants unable to travel due to distance, political unrest, or safety. More research is needed to rigorously test program outcomes and to evaluate efforts to train local program leaders. PMID- 30409032 TI - EXPRESS: An Optimizing Dynamic Spectrum Differential Extraction Method for Noninvasive Blood Component Analysis. PMID- 30409033 TI - Wound healing effects of methanol extract of Laurocerasus officinalis roem. AB - Laurocerasus officinalis Roem. (syn: Prunus laurocerasus L.) is a member of Rosaceae family. We investigated the antimicrobial and antioxidant activity of L. officinalis Roem in wound healing both in vivo and in vitro using an excisional wound model model in mice. We used four groups of eight mice as follows: untreated (control), empty gel, extract + gel (L. officinalis + gel), and Madecassol(r) groups. All treatments were applied topically once daily. The scar area, percentage wound closure and epithelization time were measured. L. officinalis promoted wound healing and increased granulation tissue, epidermal regeneration and angiogenesis. L. officinalis extract, which is known for its antioxidant and antimicrobial activities, may be useful for promoting wound healing. PMID- 30409034 TI - French validation of the Arthritis Self-Efficacy Scale and further psychometric properties exploration among 168 people with osteoarthritis. AB - OBJECTIVE:: To validate the Arthritis Self-Efficacy Scale-French version (ASES-F) of the ASES questionnaire designed to evaluate self-efficacy in arthritis population and to confirm its psychometric properties. DESIGN:: The translation/back-translation procedure was done in line with cross-cultural adaptation international guidelines. Prospective multicenter validation was performed on 168 patients with osteoarthritis who filled out the ASES-F. Function subscale of the Western Ontario and McMaster Universities Arthritis Index, Hospital Anxiety and Depression (HAD), Knee Osteoarthritis Fears and Beliefs Questionnaire, and pain on visual analog scale were collected. Acceptability, internal consistency, reproducibility, internal and external structure validity, and sensitivity following a self-management program focused on physical activity were analyzed. The retest was performed 15 days later. RESULTS:: A culturally adapted version was obtained following the validation procedure. The final translated questionnaire is available within the full article. Cronbach's alpha coefficient was at 0.95 for the overall ASES-F. Regarding the test-retest reproducibility, Lin's concordance coefficient was at 0.84. The internal and external validity was also explored with correlations at -0.50 between ASES-F and (WOMAC), and significant correlations between ASES-F and HAD. Sensitivity shown significant improvement at three months for the subscale function only (+2.65, P < 0.01). CONCLUSION:: The ASES-F, French version of the ASES, available in supplementary data, was validated in knee osteoarthritis patients and could be used in clinical practice and research for French-speaking patients. Sensitivity needs to be more explored. PMID- 30409035 TI - Hypoplastic thrombocytopenia and platelet transfusion: therapeutic goals. AB - Platelet transfusions consist a major part of the management of hypoplastic thrombocytopenia, the latter occurring mainly among patients with hematological malignancies. Platelet transfusions have led to a reduction of deaths attributable to thrombocytopenia-induced bleeding, despite their possible complications; nonetheless, prophylactic administration of platelets to patients with severe thrombocytopenia or before invasive procedures should be based on specific criteria, as well as therapeutic administration during active bleeding. Recently developed ex-vivo procedures have resulted in producing safer blood products, yet it remains unclear whether these pathogen-inactivated products have sufficient efficacy. What is more, another significant problem that remains to be more effectively addressed is the developing refractoriness to platelet transfusions. PMID- 30409036 TI - Early and Late Protective Effect of Bone Marrow Mononuclear Cell Transplantation on Radiation-Induced Vascular Dysfunction and Skin Lesions. AB - Skin lesions caused by accidental exposure to radiation or by radiotherapy are a major clinical challenge. We evaluated the effect of bone marrow mononuclear cells (BMMNC) on collagen remodeling and vascular function in radiation-induced skin lesions in the acute and late phases in mice. We studied the effect of BMMNC transplantation in a mouse model of cutaneous radiation injury combining local skin gamma-irradiation and biopsy punch wound. Mice were first irradiated, punched and then BMMNC were intramuscularly administered. Seven days after injury, BMMNC promoted wound healing by (i) increasing re-epithelialization, tissue collagen density and mRNA levels of collagens 1A1, 1A2, and 3A1, and (ii) inhibiting the radiation-induced vascular activation and limiting interactions between leukocytes and the vascular endothelium compared with control. Importantly, BMMNC did not amplify the inflammatory response despite the infiltration of neutrophils and macrophages associated with the expression of IL 6 and MCP-1 mRNAs in the tissue. Remarkably, the beneficial effects of BMMNC therapy on matrix remodeling were maintained for 2 months. Furthermore, BMMNC injection restored vascular function in skin tissue by increasing vascular density and vascular permeability. This therapeutic strategy based on BMMNC injection protects against radiation-induced skin lesions by preventing vascular dysfunction and unfavorable remodeling in the acute and late phases. PMID- 30409037 TI - Type-2 diabetes mellitus and cardiovascular disease. AB - The global prevalence of diabetes has risen in adults from 4.7% in 1980 to 8.5% in 2014. 90-95% of adults with diabetes have Type 2 diabetes (T2D). This paper focuses on the diagnosis and treatment of T2D patients who have or are at risk for cardiovascular disease. Hyperglycemia, insulin resistance and excess fatty acids increase oxidative stress, disrupt protein kinase C signaling and increase advanced glycation end-products that result in vascular inflammation, vasoconstriction, thrombosis and atherogenesis. Intensive T2D treatment produces a >=10% risk reduction in major macrovascular and microvascular events. Glucose lowering therapies must be individualized. Metformin is an optimal drug for monotherapy. If hemoglobin A1c is not at goal, a sodium-glucose cotransporter-2 inhibitor or a dipeptidyl peptidase-4 inhibitor should be considered for therapy with metformin. Coronary angioplasty/stenting is recommended for diabetic patients with acute myocardial infarctions. Coronary artery bypass grafting is recommended for symptomatic diabetic patients with multivessel disease. PMID- 30409038 TI - Cost-effectiveness of novel regimens for Chinese patients with chronic hepatitis C. AB - OBJECTIVE: Direct-acting antiviral agents (DAAs) have been approved for treating hepatitis C virus (HCV) infection in China. However, they are substantially more expensive. The current analysis will investigate the cost-effectiveness of novel regimens compared with pegylated interferon and ribavirin (PR) therapies for informing Chinese decision makers. METHODS: A Markov model was developed to measure economic and health outcomes of novel regimens for genotype 1b, 2, 3 and 6 HCV infections compared with PR treatment. Clinical, cost and utility inputs were gathered from published sources. Discounted quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs) are shown. The uncertainty was facilitated by one-way and probabilistic sensitivity analyses. RESULTS: For genotype 1b HCV infection, the combination of paritaprevir, ritonavir, ombitasvir and dasabuvir was cost-saving compared with four competing alternatives. The ICERs of sofosbuvir plus ribavirin for genotypes 2 and 3 were lower than the threshold ($18,234/QALY). Among available strategies for patients with genotype 6, sofosbuvir in combination with ribavirin was the cost-saving alternative compared with PR. The results were robust to sensitivity analyses. CONCLUSIONS: For both genotype 1b and 6 HCV infections in the context of Chinese patients, there were combinations of DAAs that were cost-saving compared with the usual PR treatment and cost-effective for genotypes 2 and 3. PMID- 30409039 TI - Post traumatic headache (PTH) in a cohort of UK compensation claimants. AB - AIM: To explore post traumatic headache characteristics and risk factors in compensation claimants by observational retrospective cohort analysis. CASE RESULTS: Medicolegal reports on 116 consecutive compensation claimants aged 41.9 +/- 15.0 years were reviewed 21 +/- 14 months after injury. Eighty eight had suffered head and neck injuries, 21 reported only neck injury and seven had "other injuries". Ninety four percent of the head injuries were "mild". The incidence of post traumatic headache following neck injury did not differ from that following head and neck injury, and none of the "other injuries" cases developed post traumatic headache. We anticipated that all head and neck injury claimants would seek compensation for post traumatic headache, but 25% denied developing headache. Post traumatic headache was very strongly correlated with a past history of primary headache ( p < 0.0001) but no other risk factors were identified. Post traumatic headache semiology was consistent with "migraine" or "probable migraine" in 90% of cases. Headache resolved in 30% of claimants between 3 and 24 months after injury but 70% continued to suffer headaches at the time of assessment. Forty one percent of claimants had received no treatment for post traumatic headache in primary care. CONCLUSIONS: Our data suggest that post traumatic headache is essentially "migraine" provoked by head or neck concussion. It is not clear why so many post traumatic headache sufferers receive poor or inadequate treatment for this condition. PMID- 30409040 TI - Short sleep and late bedtimes are detrimental to educational learning and knowledge transfer: An investigation of individual differences in susceptibility. AB - Good sleep hygiene practices, including consistent bedtimes and 7-9 h of sleep/night, are theorized to benefit educational learning. However, individuals differ in how much sleep they need, as well as in their chronotype preference. Therefore, some students may be more vulnerable to the cognitive effects of sleep loss, later bedtimes and nonpreferred times of learning than others. One prominent example is the debate regarding whether sleep loss and later bedtimes affect classroom learning more in female or male students. To inform this gender and-sleep-loss debate, we developed a virtual college-level lecture to use in a controlled, laboratory setting. During Session 1, 78 undergraduate students were randomly assigned to take the lecture at 12:00 (noon condition) or 19:30 (evening condition). Then participants wore wristband actigraphy for 1 week to monitor average and intraindividual variability in sleep duration, bedtime and midpoint of sleep. During Session 2, participants completed a test at the same time of day as Session 1. The test included basic questions that were similar to trained concepts during the lecture (trained items) as well as integration questions that required application of learned concepts (knowledge-transfer items). Bayesian analyses supported the null hypothesis that time of learning did not affect test performance. Collapsed across time of testing, regression analyses showed that shorter sleep durations and later bedtimes explained 13% of the variance in test performance. Longer sleep durations and earlier bedtimes predicted better test performance primarily in females, younger students and morning-types. Interestingly, students with above-median fluid intelligence scores were resilient to short sleep and late bedtimes. Our findings indicate that both sleep and circadian factors should be addressed to optimize educational learning, particularly in the students who are most susceptible to sleep loss. PMID- 30409041 TI - Design of a resilient ring for middle ear's chamber stapes prosthesis. AB - This paper presents the process of designing a new elastic element replacing a membrane in the chamber stapes prosthesis (ChSP). The results of the study are volume displacement characteristics obtained for the prosthesis and physiological stapes. Simulation tests on a 3D CAD model have confirmed that a properly designed ring can stimulate perilymph with the same or greater efficacy as the physiological stapes footplate placed on the elastic annular ligament. The ChSP with a new elastic element creates a good chance of improving hearing in patients suffering from otosclerosis. PMID- 30409042 TI - Effect of microalbuminuria on macular thickness in patients with type-2 diabetes mellitus. AB - PURPOSE:: To investigate the effect of microalbuminuria on macular thickness in patients with type-2 diabetes mellitus with no or mild diabetic retinopathy and to investigate the relationship between macular thickness and metabolic parameters. MATERIALS AND METHODS:: Fifty eight eyes of 58 patients without diabetic retinopathy (group 1) in microalbuminuria stage, 42 eyes of 42 patients with mild diabetic retinopathy (group 2) in microalbuminuria stage, and 50 eyes of 50 patients without diabetic retinopathy and microalbuminuria (group 3) were included in this study. After detailed ophthalmologic examination, all patients underwent spectral domain-optical coherence tomography measurements. Macular thickness was noted from nine different areas (fovea, four parafoveal, and four perifoveal areas) and compared between groups. The correlations between macular thickness and age, duration of diabetes mellitus, microalbuminuria, serum urea, creatinine, glycosylated hemoglobin (HbAIc), albumin, sodium (Na), and urinary Na were evaluated. RESULTS:: The mean age was 53.29 +/- 6.49 in group 1, 55.86 +/- 6.97 in group 2, and 52.98 +/- 5.66 years in group 3 (p = 0.06). The macular thickness values of superior, inferior, and nasal parafoveal areas were significantly different between groups (p = 0.001, p = 0.006, and p = 0.03, respectively). Bonferroni post test revealed that this difference originated from the difference between group 2 and 3 (p < 0.05 for all values). There were significant negative correlations between the macular thickness values of parafoveal areas and serum urea, HbA1c, albumin, microalbuminuria levels (p < 0.05 for all values). CONCLUSION:: In this study, a significantly decreased parafoveal macular thickness was measured in patients with mild diabetic retinopathy and microalbuminuria compared to patients without diabetic retinopathy and microalbuminuria. PMID- 30409043 TI - Multimodal imaging in a young male with osteogenesis imperfecta complicated with choroidal neovascularization. AB - PURPOSE:: To evaluate the role of multimodal imaging in the diagnosis and monitoring of patients with osteogenesis imperfecta complicated with choroidal neovascularization. CASE REPORT:: A 28-year-old man, diagnosed with osteogenesis imperfecta, was referred 2 months after the appearance of central scotoma and metamorphopsia in the right eye. The patient underwent a complete ophthalmological evaluation including visual acuity examination as well as ophthalmoscopy, spectral-domain optical coherence tomography, optical coherence tomography angiography, fundus autofluorescence imaging, fluorescein angiography and microperimetry. Complete examination revealed macular lacquer crack with subretinal haemorrhage. A further investigation with spectral-domain optical coherence tomography and fluorescein angiography revealed the presence of choroidal neovascularization without clear activity associated to the lacquer crack. After a 1-month follow-up, both visual acuity and retinal sensitivity improved spontaneously. CONCLUSION:: Collagen deficiency of osteogenesis imperfecta leads to fragility of the Bruch's membrane; tension forces probably act at this level determining ruptures with bleeding and choroidal neovascularization formation. Multimodal imaging and functional evaluation are needed to assess retinal alterations in patients with osteogenesis imperfecta, whereas treatment of choroidal neovascularization should be reserved only for active lesion to prevent evolution and visual acuity decrement. PMID- 30409044 TI - Impact of electromagnetic fields on in vitro toxicity of silver and graphene nanoparticles. AB - The correlation between shape and concentration of silver nanoparticles (AgNPs), their cytotoxicity and formation of reactive oxygen species (ROS) in the presence of electromagnetic fields (EMFs) has been investigated. In addition, the bio effects caused by the combination of EMFs and graphene nanoparticles (GrNPs) have been also assessed. The AgNPs of three shapes (triangular, spherical and colloidal) and GrNPs were added in high concentrations to the culture of human fibroblasts and exposed to EMF of three different frequencies: 900, 2400 and 7500 MHz. The results demonstrated the dependence of the EMF-induced cytotoxicity on the shape and concentration of AgNPs. The maximal cell killing effect was observed at 900 MHz frequency for NPs of all shapes and concentrations. The highest temperature elevation was observed for GrNPs solution irradiated by EMF of 900 MHz frequency. The exposure to EMF led to significant increase of ROS formation in triangular and colloidal AgNPs solutions. However, no impact of EMF on ROS production was detected for spherical AgNPs. GrNPs demonstrated ROS protective activity that was dependent on their concentration. Our findings indicate the feasibility to control cytotoxicity of AgNPs by means of EMFs. The effect EMF on the biological activity of AgNPs and GrNPs is reported here for the first time. PMID- 30409045 TI - Assessing the relative contribution of social exclusion, income-poverty, and financial strain on depressive symptoms among older people in Hong Kong. AB - OBJECTIVES: The role of social exclusion in depressive symptoms in older people has not been examined systematically. This study examines the associations of social exclusion, income poverty, and financial strain with depressive symptoms and evaluates the moderating effect of social support in the link between social exclusion and depressive symptoms. METHOD: Our sample consisted of 850 older people (65 years old or above) in Hong Kong randomly selected through a household survey. We used a logistic regression to evaluate the associations of social exclusion, income poverty, and financial strain with depressive symptoms, controlling for social support and social network variables, health indicators, and socio-demographic variables. RESULTS: We found that social exclusion, income poverty, and financial strain are positively associated with depressive symptoms, but only social exclusion (OR: 2.13, 95% CI: 1.51-2.99, p < 0.001) and financial strain (OR: 1.54, 95% CI: 1.16-2.03, p < 0.01) maintain their significance after all other covariates are adjusted. Moreover, perceived social support negatively moderates the relationship between social exclusion and depressive symptoms. CONCLUSION: Social exclusion is significantly associated with depressive symptoms in older people, but this association can be moderated by social support. PMID- 30409046 TI - Seasonal variation of novel arterial stiffness indexes in Japanese hypertensive patients. AB - BACKGROUND AND OBJECTIVE: Seasonal variation of blood pressure (BP) is well known, and a relationship between increases in BP and the incidence of cardiovascular accidents (CVAs) in the winter has been reported. Parameters of arterial stiffness may exhibit seasonal variation; however, available data are currently limited. Novel arterial stiffness indexes, namely the arterial velocity pulse index (AVI) and arterial pressure-volume index (API), can be determined through usual maneuver for BP measurement during the regular examination in the outpatient clinic.The present study assessed the seasonal variation of AVI and API in 59 hypertensive patients undergoing stable treatment and regularly visiting our outpatient clinic over a period of 30 months. METHODS: BP, pulse rate (PR), AVI, and API were measured using the AVE-1500 (Pasesa) in the sitting position. Six time frames of assessment were established. All measurements (average: 17.9 measurements per person) were sorted using these six time frames, and their averages were used for analysis. RESULTS: Significant seasonal variations in PR (P < 0.001) and AVI (P < 0.001), along with weak variation in systolic BP (SBP) (P = 0.047) and marginal variation in API (P = 0.055), were confirmed by repeated analysis of variance. SBP, API, and PR were decreased, whereas AVI was increased in the summer. Coefficient variations were SBP 5.1%, PR 4.9%, AVI 12.6%, and API 10.6%. CONCLUSION: AVI was associated with reflected wave like as augmentation index. Thus, a high AVI may suggest increased central wave reflection. Although the significance of seasonal variation of AVI remains unknown, AVI may influence seasonal variations in the incidence of CVA. PMID- 30409047 TI - The impact of proactive rounding on rapid response team calls: an observational study. AB - BACKGROUND: Rapid response teams (RRTs) improve mortality by intervening in the hours preceding arrest. Implementation of these teams varies across institutions. SETTING AND DESIGN: Our health-care system has two different RRT models at two hospitals: Hospital A does not utilize a proactive rounder while Hospital B does. We studied the patterns of RRT calls at each hospital focusing on the differences between night and day and during nursing shift transitions. RESULTS: The presence of proactive surveillance appeared to be associated with an increased total number of RRT calls with more than twice as many calls made at the smaller Hospital B than Hospital A. Hospital B had more calls in the daytime compared to the nighttime. Both hospitals showed a surge in the night-to-day shift transition (7-8am) compared to the preceding nighttime. Hospital A additionally showed a surge in calls during the day-to-night shift transition (7-8pm) compared to the preceding daytime. CONCLUSIONS: Differences in the diurnal patterns of RRT activation exist between hospitals even within the same system. As a continuously learning system, each hospital should consider tracking these patterns to identify their unique vulnerabilities. More calls are noted between 7-8am compared to the overnight hours. This may represent the reestablishment of the 'afferent' arm of the RRT as the hospital returns to daytime staffing and activity. Factors that influence the impact of proactive rounding on RRT performance may deserve further study. PMID- 30409048 TI - What's the Risk in Seeking Help for Depression? Assessing the Nature and Pleasantness of Outcome Perceptions Among Individuals With Depressive Symptomatology. AB - Despite a growing mental health crisis in the United States, empirical indicators of what could make a depression help-seeking message effective and why are currently not available. Even worse, some depression help-seeking messages can activate negative beliefs among depressed individuals that may make help-seeking even less likely than before. The current study is based on the premise that normative theoretical frameworks used for health promotion purposes might not work in populations affected by depression. Addressing a primary driver for health behavior change in gain-and-loss framing, the present research examines the nature of risk perceptions regarding help-seeking among those with depressive symptomatology who have not yet sought help ( N = 738) to inform more effective suicide prevention efforts. Previously, quantitative analyses revealed that the effectiveness of gain-and-loss framing, particularly on attitudes toward help seeking, depends on the severity of depressive symptomatology. Whereas a persuasive gain-frame advantage was found for those with mild and severe depression symptoms, both framing strategies appeared to backfire and worsen attitudes among those with moderately severe depression symptoms. The present study enriches those results by conducting an in-depth analysis of risk perceptions regarding help-seeking to inform more effective depression help seeking messages. Risk perceptions were primarily indicative of stigma and the related resistance to seeking help. Judgment and mistreatment were expected not only from the general public but also from the mental health professionals from whom help should be sought. Theoretical and practical implications are discussed. PMID- 30409049 TI - Five-year follow-up of a cluster-randomized controlled trial of a client-centred activities of daily living intervention for people with stroke. AB - OBJECTIVE:: To compare five-year outcomes and changes over time of a client centred activities of daily living (ADL) intervention versus usual ADL interventions for people with stroke and their significant others. DESIGN:: Five year follow-up of a cluster-randomized controlled trial where a client-centred ADL intervention ( n = 129) or usual ADL interventions ( n = 151) were delivered to people with stroke. SETTING:: Multicentre study including 16 inpatient or home based rehabilitation units. PARTICIPANTS:: People with stroke and significant others. INTERVENTION:: The client-centred ADL intervention aimed at enabling agency in daily activities and participation in everyday life and at reducing caregiver burden. MAIN MEASURES:: For people with stroke, perceived participation (Stroke Impact Scale), independence in ADL, life satisfaction, and use of formal/informal care were measured. For significant others, caregiver burden, life satisfaction, and mood (Hospital Anxiety and Depression Scale) were assessed. RESULTS:: Five years post-intervention, data were collected from 145 people with stroke (intervention group: n = 71/control group: n = 74) and 75 significant others (intervention group: n = 36/control group: n = 39). For those with stroke, the Participation domain of the Stroke Impact Scale showed no group differences at year five (68.9 vs 75.4, P = 0.062) or in changes over time. At year five, the control group had better outcomes regarding Other help/supervision. Significant others in the control group were more likely to show signs of depression at year five (odds ratio = 22.3; P < 0.001). CONCLUSION:: The client-centred ADL intervention appears to render similar long term effects as usual ADL interventions for people with stroke, but for significant others signs of depression might be reduced. PMID- 30409050 TI - An intron variant in the FLT1 gene increases the risk of preeclampsia in Iranian women. AB - BACKGROUND: Preeclampsia is a hypertensive disorder that affects pregnancy, mother, and fetus. Pathogenesis of preeclampsia could be associated with the angiogenesis pathways. The vascular endothelial growth factor (VEGF) family is one of the important factors for normal pregnancy and angiogenesis. Genetic variations in the gene family members may play a role in the etiology of preeclampsia. We investigated the possible association between VEGFA gene rs3025039, and VEGFR1 (FLT1) gene rs722503 polymorphisms and preeclampsia in a sample of Iranian patients. METHODS: Genotyping was performed in 395 women, including, 204 pre-eclamptic pregnant women and 191 healthy normotensive pregnant women by using the PCR-RFLP method. RESULTS: The rs722503 polymorphism was associated with preeclampsia under the dominant model (P = 0.04, OR = 1.53, 95% CI: 1.03-2.27). No significant difference was observed for the rs3025039 alleles and genotypes in the studied groups. CONCLUSIONS: Based on our study, rs722503 polymorphism in the FLT1 gene may play an important role in susceptibility to preeclampsia. PMID- 30409051 TI - Complete resolution of a cervical spine aneurysmal bone cyst after single session of endovascular embolization: Case report. AB - Treatment options for aneurysmal bone cysts include intralesional curettage, segmental excision, en bloc resection and endovascular embolization. The most commonly used treatment is intralesional curettage and selective arterial embolization is normally an adjunctive therapy, not a definitive treatment. We report a case of a C1 lateral mass aneurysmal bone cyst treated with a single session of endovascular embolization. Long-term follow up demonstrated complete resolution of the cyst. A study of aneurysmal bone cyst embolization was conducted and the key points for obtaining maximal devascularization of the cyst along with embolic material and technique are discussed. PMID- 30409052 TI - Psychosocial and organizational determinants of safe food handling at retail and food service establishments: a systematic review and meta-analysis. AB - Various psychosocial and organizational factors have been investigated as determinants of food handlers' food safety behaviours. A systematic review and meta-analysis of studies in this area was conducted to identify and synthesize the key behavioural determinants. Standard systematic review steps were followed: comprehensive search strategy; relevance screening; article characterization; risk of bias assessment; data extraction; and random-effects meta-analysis. Sixty two relevant studies were identified, and knowledge was the most commonly investigated behavioural determinant (n = 51). Increased knowledge was consistently associated with safe food handing behaviours across both correlation (r = 0.30; 95% confidence interval [CI]: 0.12, 0.46; n = 24 studies; I2 = 98%) and odds ratio (OR) measures (adjusted OR = 1.85; 95% CI: 1.27, 2.70; n = 3; I2 = 0%). Seven other behavioural determinant categories were also consistently associated with various food safety behaviour outcomes. In contrast, no association was found between food handler experience and behaviour. The findings can inform the development of targeted training initiatives for food handlers. PMID- 30409053 TI - Beyond health and economy: resource interactions in retirement adjustment. AB - OBJECTIVES: The retirement transition is a multidimensional and dynamic process of adjustment to new life circumstances. Research has shown that individual differences in resource capability accounts for a substantial amount of the previously observed heterogeneity in retirement adjustment. The aim of the present study was to investigate interaction effects of self-esteem, autonomy, social support, self-rated physical health, self-rated cognitive ability, and basic financial resources on levels and changes in life satisfaction in the retirement transition. METHOD: Our sample included 1924 older adults from the longitudinal population-based HEalth, Ageing, and Retirement Transitions in Sweden (HEARTS) study. The participants were assessed annually over a three-year period, covering the transition from work to retirement (n = 614). Participants continuously working (n = 1310) were included as a reference group. RESULTS: Results from latent growth curve models showed that the relationship between a particular resource and levels and changes in life satisfaction varied depending on other available resources, but also that these effects varied between retirees and workers. Autonomy moderated the effect of physical resources, and social support and perceived cognitive ability moderated the effect of financial resources. DISCUSSION: Our findings add to the current knowledge on retirement adjustment and suggest that negative effects of poor health and lack of basic financial resources on retirees life satisfaction may be compensated for by higher levels of autonomy, social support, and perceived cognitive ability. PMID- 30409054 TI - Association between handgrip strength and vascular function in patients with hypertension. AB - BACKGROUND: Increased handgrip strength has been associated with lower cardiovascular and non-cardiovascular mortality in different populations. In patients with hypertension, arterial stiffness relates to cardiovascular mortality. However, whether muscle strength is associated with arterial stiffness in hypertensives is unknown. Thus, the objective of this study was to analyze the association between handgrip strength and arterial stiffness parameters in hypertensive patients. METHODS: Seventy-two hypertensive patients completed all evaluations and were included in the analysis. The ambulatory arterial stiffness index (AASI) was obtained based on 24-h ambulatory blood pressure monitoring. Carotid-femoral pulse wave velocity (cfPWV), and reflected wave indicator (AIx and AIx@75) were estimated using applanation tonometry technique, whereas handgrip strength test was performed using a digital dynamometer. Crude and adjusted linear regression models were performed. RESULTS: The crude analysis revealed a negative association between handgrip strength and AASI (b = -0.41, p = 0.002) and AIx (b = -0.49, p < 0.001), and AIx@75 (b = -0.54, p < 0.001) which remained significant after adjustments for age, sex, and body mass index, mean blood pressure, and heart rate only for AASI (b = -0.46, p = 0.028) and AIx@75 (b = -0.24, p- = 0.040). Handgrip strength was not associated with cfPWV (p > 0.05). CONCLUSION: Handgrip strength is negatively associated with AASI and AIx@75, but not with AIx and cfPWV in hypertensive patients. PMID- 30409055 TI - Perceived victimization risk, avoidance behavior, and health of community dwelling older adults in urban China. AB - OBJECTIVES: This study examined the associations between perceived crime-specific victimization risk, avoidance behavior, and their relationships with health of older adults. METHOD: A representative sample of 453 Chinese aged 60 and older from Kunming provided information on their socio-demographic characteristics, perceived crime victimization risk, avoidance behavior, physical and mental health. RESULTS: Avoidance behavior was common among participants, with 61.4% avoiding unsafe areas and 42.2% avoiding social activities. Path analyses showed that perceived risk of vandalism was associated with avoiding participating in social activities, while perceived risk of attack was related to avoiding unsafe areas during the day. Meanwhile, avoiding social activities and perceived risk of vandalism were significant predictors of poor mental health, and avoiding unsafe areas was a salient predictor of poor physical health. Perceived risk of attack had an indirect effect on physical health through avoiding unsafe areas during the day. CONCLUSION: Study findings highlight the importance of addressing perceived victimization risk in encouraging social participation and mobility among older adults. PMID- 30409056 TI - In memoriam of Lois Jovanovic, MD, MACE. PMID- 30409057 TI - Automatic prediction of intelligible speaking rate for individuals with ALS from speech acoustic and articulatory samples. AB - PURPOSE: This research aimed to automatically predict intelligible speaking rate for individuals with Amyotrophic Lateral Sclerosis (ALS) based on speech acoustic and articulatory samples. METHOD: Twelve participants with ALS and two normal subjects produced a total of 1831 phrases. NDI Wave system was used to collect tongue and lip movement and acoustic data synchronously. A machine learning algorithm (i.e. support vector machine) was used to predict intelligible speaking rate (speech intelligibility * speaking rate) from acoustic and articulatory features of the recorded samples. RESULT: Acoustic, lip movement, and tongue movement information separately, yielded a R2 of 0.652, 0.660, and 0.678 and a Root Mean Squared Error (RMSE) of 41.096, 41.166, and 39.855 words per minute (WPM) between the predicted and actual values, respectively. Combining acoustic, lip and tongue information we obtained the highest R2 (0.712) and the lowest RMSE (37.562 WPM). CONCLUSION: The results revealed that our proposed analyses predicted the intelligible speaking rate of the participant with reasonably high accuracy by extracting the acoustic and/or articulatory features from one short speech sample. With further development, the analyses may be well-suited for clinical applications that require automatic speech severity prediction. PMID- 30409058 TI - Assessment of the potential allergenicity of genetically-engineered food crops. AB - An extensive safety assessment process exists for genetically-engineered (GE) crops. The assessment includes an evaluation of the introduced protein as well as the crop containing the protein with the goal of demonstrating the GE crop is "as safe-as" non-GE crops in the food supply. One of the evaluations for GE crops is to assess the expressed protein for allergenic potential. Currently, no single factor is recognized as a predictor for protein allergenicity. Therefore, a weight-of-the-evidence approach, which accounts for a variety of factors and approaches for an overall assessment of allergenic potential, is conducted. This assessment includes an evaluation of the history of exposure and safety of the gene(s) source; protein structure (e.g. amino acid sequence identity to human allergens); stability of the protein to pepsin digestion in vitro; heat stability of the protein; glycosylation status; and when appropriate, specific IgE binding studies with sera from relevant clinically allergic subjects. Since GE crops were first commercialized over 20 years ago, there is no proof that the introduced novel protein(s) in any commercialized GE food crop has caused food allergy. PMID- 30409059 TI - Neuromechanical Modelling of Articulatory Movements from Surface Electromyography and Speech Formants. AB - Speech articulation is produced by the movements of muscles in the larynx, pharynx, mouth and face. Therefore speech shows acoustic features as formants which are directly related with neuromotor actions of these muscles. The first two formants are strongly related with jaw and tongue muscular activity. Speech can be used as a simple and ubiquitous signal, easy to record and process, either locally or on e-Health platforms. This fact may open a wide set of applications in the study of functional grading and monitoring neurodegenerative diseases. A relevant question, in this sense, is how far speech correlates and neuromotor actions are related. This preliminary study is intended to find answers to this question by using surface electromyographic recordings on the masseter and the acoustic kinematics related with the first formant. It is shown in the study that relevant correlations can be found among the surface electromyographic activity (dynamic muscle behavior) and the positions and first derivatives of the first formant (kinematic variables related to vertical velocity and acceleration of the joint jaw and tongue biomechanical system). As an application example, it is shown that the probability density function associated to these kinematic variables is more sensitive than classical features as Vowel Space Area (VSA) or Formant Centralization Ratio (FCR) in characterizing neuromotor degeneration in Parkinson's Disease. PMID- 30409060 TI - Prevalence and Correlates of Electronic Cigarette Use Among a Clinical Sample of Polysubstance Users in Kentucky: Long Live the Cigarette? AB - BACKGROUND: E-cigarette use has increased in the US, yet, in some regions rates of cigarette use remain high. PURPOSE: To describe the prevalence and features of lifetime and past-year e-cigarette use among a clinical sample of polysubstance users in Kentucky, and to determine significant associations of past-year e cigarette use. RESULTS: Of the final sample (N = 497), 83.5% reported having ever used e-cigarettes and 97.2% reported having ever used cigarettes. These rates surpass those found among Kentucky's general population. Compared to those who did not report e-cigarette use, e-cigarette users were more likely to be younger ([Formula: see text] = 33.4 vs. 43.6, p<.001) and White (88.2.1% vs. 62.5%, p = .001). E-cigarette users showed higher rates for lifetime incarceration (91.1% vs. 72.8%, p = .001) and past-year arrest (75.0% vs. 47.5%, p = .001). This group also presented with more severe substance use history and lower mean age for illicit drug use initiation ([Formula: see text] = 13.8 vs. 16.4, p = .001). Approximately 65% of the sample reported past-year e-cigarette use and 96.6% reported past-year cigarette use. Logistic regression indicated that being younger (AOR = .973, p = .030), White (AOR = 1.92, .046), having a past-year arrest (AOR = 1.73, p = .047) and having used cigarettes (AOR = 8.93, p = .001) or kratom (AOR = 3.04, p = .025) within the past year were significantly associated with past-year e-cigarette use. CONCLUSIONS: E-cigarette use was related to more severe drug-using patterns. Rates of dual tobacco use among this sample are high, particularly among younger individuals. In ecological contexts where cigarette use remains normative, it is likely that dual use will persist for nicotine-dependent, polysubstance-using individuals. PMID- 30409061 TI - Mindfulness-Based Relapse Prevention in a Jail Drug Treatment Program. AB - BACKGROUND: More than half of prisoners in the United States are estimated to suffer from a substance use disorder. Mindfulness involves attention to the present moment, and nonjudgmental acceptance of sensations, thoughts, and emotional states. Mindfulness-based relapse prevention (MBRP) following substance use disorder treatment has been shown to reduce substance use. OBJECTIVE: We sought to adapt and test MBRP for a jail substance use disorder treatment setting. METHODS: We enrolled successive cohorts of incarcerated men participating in a drug treatment program in a large urban jail (n = 189) into six weekly sessions of either MBRP or an comparison communication skills intervention, between 2013 and 2015. MBRP was delivered by a culturally competent African-American trainer. Pre- and post-test measures included mindfulness, anxiety, posttraumatic stress disorder (PTSD), and drug craving. RESULTS: At baseline, measures of mindfulness were significantly inversely correlated with anxiety, PTSD symptoms and drug cravings. Anxiety, PTSD symptoms and cravings declined significantly in both treatment arms, and mindfulness increased. Comparison of the two study arms using maximum likelihood estimation suggested a small but significantly greater increase in mindfulness in the treatment arm. Conclusions/Importance. An attention control trial of a mindfulness intervention, delivered by a culturally competent trainer, is feasible in a jail setting. PMID- 30409062 TI - Knockdown of FOXP1 promotes the development of lung adenocarcinoma. AB - Lung cancer is one of the most common cancers in the world, which accounts for about 27% of all cancer deaths. However, the mechanisms underlying the pathogenesis of lung cancer cells remain largely elusive. In this study, we examined the role of the Forkhead box protein P1 (FOXP1) in lung cancer development. Our Oncomine analysis shows that FOXP1 is downregulated in lung adenocarcinoma compared with normal lung tissue. Knockdown of FOXP1 promotes the growth and invasion of PC9 and A549 cells by regulating genes of chemokine signaling molecules, including CCR1, ADCY5, GNG7, VAV3, and PLCB1. Simultaneous knockdown of CCR1 and FOXP1 attenuated FOXP1 knockdown-induced increase of lung cancer cell growth. Finally, knockdown of FOXP1 in PC9 cells promotes the tumorigenesis via CCR1 signaling in xenograft mouse model. Taken together, our data suggest that FOXP1 plays important roles in preventing lung adenocarcinoma development via suppressing chemokine signaling pathways. PMID- 30409063 TI - Reply: The true clinical utility of quantitative fetal fibronectin. PMID- 30409064 TI - The Adapted Self-Report Delinquency Scale for Adolescents: Validity and Reliability Among Portuguese Youths. AB - Self-report delinquency scales have contributed greatly to the contemporary basis of our understanding of juvenile delinquency. Nevertheless, they have not been immune to criticism and further improvement and extensive measurement research is still necessary. The present study examined the psychometric properties of one such measure of self-reported delinquency, the Adapted Self-Report Delinquency Scale (ASRDS). The ASRDS was administered to a Portuguese sample of male youths ( N = 470, 12-20 years of age), subdivided into a forensic sample ( n = 217) and a school sample ( n = 253). The Portuguese version of the ASRDS demonstrated satisfactory psychometric properties, in terms of its factor structure, internal consistency, convergent validity, discriminant validity, criterion-related validity, and known-groups validity, thereby justifying its use among this population. PMID- 30409065 TI - Adaptations from the prosthetic and intact limb during standing on a sway referenced support surface for transtibial prosthesis users. AB - PURPOSE: To investigate the bilateral postural adaptations as a result of standing on an increasingly unstable sway-referenced support surface with both the intact and prosthetic limb for transtibial prosthesis users (TPUs). METHOD: TPUs (n = 14) and matched controls (n = 14) stood quietly in multiple foot placement conditions (intact foot, prosthetic foot and both feet) on a sway referenced support surface which matched surface rotation to the movement of the centre of pressure (CoP). Force and motion data were collected and used to analyse CoP mean position, displacement integral and force components under intact and prosthetic limbs. RESULTS: Significant differences were found between prosthesis users and controls in CoP mean position in anteroposterior (1.5 (95% CI, 1.2-1.8) cm) and mediolateral directions (3.1 (95% CI, 0.5-5.7) cm. CoP displacement integrals were significantly different greater for prosthesis user group in the anteroposterior direction. Force components differences were found in all planes (anteroposterior: 0.6 (95% CI, 0.4-0.8 N); mediolateral: 0.1 (95% CI, 0.0-0.2 N & 0.3 (95% CI, 0.2-0.4) N, inferosuperior: 2.2 (95% CI, 1.4-3.0) N). CONCLUSIONS: TPUs have bilateral static and dynamic postural adaptations when standing on a sway-referenced support surface that is different to controls, and between prosthetic and intact sides. Results further support evidence highlighting importance of the intact limb in maintenance of postural control in prosthesis users. Differences indicate clinical treatment should be directed towards improving outcomes on the intact side. Implications for rehabilitation Prosthesis users have bilateral adaptations when standing on a sway referenced support surface These adaptations are different to controls, and between prosthetic and intact sides. The intact limb is the major contributor to maintenance of postural control in prosthesis users. Clinical treatment should account for this when interventions are designed. PMID- 30409066 TI - The relation of SF3B1 mutation and intracellular iron in myelodysplastic syndrome with less than 5% bone marrow blasts. AB - According to 2008 WHO classification RARS is regarded as less than 5% blasts and more than 15% ring sideroblasts in the bone marrow. In 2016 WHO classification MDS-RS is revised as more than 15% ring sideroblasts or more than 5% ring sideroblasts in the presence of the SF3B1 mutation. In our study, we classified intracellular iron in bone marrow into four types according to the size and quantity of iron granules. We found that there was a significant difference between SF3B1-mutant and SF3B1-wild-type MDS patients in intracellular iron III, intracellular iron IV and ring sideroblasts. We defined intracellular iron (III + IV + RS)%*100 as 'Iron score'. We suggest that the patients carrying SF3B1 mutation with Iron score >=10 will extend the subtype of MDS-RS, in addition to the current WHO classification criteria. This study gives us a new insight into the relation of SF3B1 mutation and intracellular iron in lower-risk MDS. PMID- 30409067 TI - Bradykinin receptor in immune-mediated renal tubular injury in trichloroethylene sensitized mice: Impact on NF-kappaB signaling pathway. AB - Trichloroethylene (TCE) is known to induce skin disorders and multi-system dysfunction, but the mechanism of this multi-organ injury is not entirely clear. It was shown in a previous study that levels of pivotal end-products of the kallikrein-kinin system (KKS), i.e. bradykinin (BK) and BK receptors B1R/B2R, in the kidneys were increased by TCE exposure. Unfortunately, how BK and its receptors acted in the etiology of the induced renal injury is not clear. Thus, this study explored any correlation between BK receptors and immune renal injury in TCE-sensitized mice by blocking the BK receptors B1R/B2R. BALB/c mice were sensitized (via skin) by TCE, with or without pre-treatment with a B1R or B2R antagonist. Renal lesions, increased expressions of B1R, B2R, Kim-1, Lipocalin-2, and NF-kappaB p65 subunit on tubular epithelial cells were all observed in TCE sensitized mice. Serum levels of creatinine (Cr), microglobulin alpha1 and beta2, along with mRNA levels for inflammatory cytokines and NF- kappaB p65 in kidneys, were all increased by 72 h after a final challenge. Highly selective antagonist pre-treatment blocked B2R and significantly attenuated TCE-induced changes. Blocking B1R or B2R attenuated release of pro-inflammatory cytokines and activation of NF-kappaB signaling pathway (as reflected in lower up-regulation of pIkappaB and nuclear NF-kappaB p65 subunit, and down-regulation of IkappaB in the kidneys. These results provided evidence that TCE-sensitization caused KKS activation and enhanced the expression of B1R and B2R on tubular epithelial cells. This, in turn, accelerated NF-kappaB signaling pathway activation and amplified inflammatory cytokine release, which all likely contributed to TCE induced immune renal injury. PMID- 30409068 TI - The true clinical utility of quantitative fetal fibronectin. AB - Faron et al.'s dismissal of fFN in screening asymptomatic women is based on a flawed assumption that positive likelihood ratios (PLR) < 10 and negative likelihood ratios (NLR) > 0.1 are not valuable, and on evaluation of qualitative fFN only. We would argue that there is ample evidence to support its use in asymptomatic high-risk women and in threatened preterm labour when used in its quantitative form, not analysed in this meta-analysis. PMID- 30409069 TI - Extended dynamometry: reference values. AB - Grip strength is used as a measure of capacity in disability and personal injury claims. Although seemingly an objective measure, it is widely recognized that it is fallible to the effects of sub-maximal effort. We have developed an extended test protocol that uses the five positions of a Jamar dynamometer. The protocol mitigates the effect of inconsistency while retaining the ability to detect sub maximal effort. Dynamometry was undertaken in 242 volunteers (male:female, 124:118) with a median age of 39 years (range 18-89, interquartile range 29-52). Normative values for consistency, curve deviation and variation from the expected curve pattern are provided. None of these measures were significantly affected by laterality, hand dominance, sex or age despite the effects of these variables on grip strength. The study defines the methodology and reference values to allow assessment of both the capacity of a patient and the reliability of the test for use in medicolegal practice. Level of evidence: II. PMID- 30409070 TI - Effects of environmental modification on activities of daily living, social participation and quality of life in the older adults: a meta-analysis of randomized controlled trials. AB - PURPOSE: This study aims to provide evidence of the benefits and effects of environmental modification intervention on activities of daily living, quality of life and social participation in older adults. METHODS: This study searched and used randomized controlled trial research studies from the databases of MEDLINE, CINAHL and the Cochrane Library. A systematic review and meta-analysis were conducted using the Jadad scale, risk of bias and the patient, intervention, comparison, outcome (PICO) process. The domains of impact considered in this meta analysis were activities of daily living, quality of life and social participation. The analysis was completed with the Review Manager software 5.3. RESULTS: Jadad scores of collected studies were 3-4 in seven studies and 2 in one study, which means that most studies had high levels of quality. This study comprised of 733 subjects in the experimental group and 672 subjects in the control group. The effect size of environmental interventions on basic activities of daily living, instrumental activities of daily living and overall activities of daily living were 0.37, 0.65 and 0.47, respectively. Meanwhile, the environmental intervention was neither effective on quality of life nor social participation. CONCLUSIONS: Environmental modifications are effective in facilitating the daily life activities of older adults. This kind of intervention is shown to be useful for enhancing life performance. In order to confirm intervention effects on the quality of life and social participation of older adults, studies should conduct environmental modifications interventions that take into account contexts such as individual characteristics, lifestyle and physical activities. Implications for rehabilitation Environmental modifications are effective in improving older adults' performance of daily activities (ADL). Appropriate environmental modification interventions should be considered before the quality of life (QoL) and levels of social participation of older adults decline. PMID- 30409071 TI - Oligoclonal selection of nanobodies targeting vascular endothelial growth factor. AB - While monoclonal antibodies are efficient therapeutics for cancer treatment, nanobodies or variable heavy domain - due to their small size, high stability, and solubility - have many advantages in comparison. Oligoclonal nanobodies are a mixture of nanobodies against different epitopes of an antigen. Specific nanobodies against vascular endothelial growth factor (VEGF, which has an important role in cancer angiogenesis) were selected from an immune camel library using biopanning. Specific binding of the nanobodies to VEGF antigen was assessed by periplasmic extract enzyme-linked immunosorbent assay (ELISA). Bioinformatics analysis and molecular docking were performed on selected nanobodies against VEGF. The in vitro inhibitory effects of each single nanobody, as well as a pool of selected nanobodies (oligoclonal nanobodies), on proliferation and tube formation by/in human umbilical vein endothelial cells (HUVEC) cells was evaluated using MTT and Tube formation assays, respectively. Four nanobodies showed the highest signal intensity in the periplasmic extract ELISA. Sequencing revealed that four unique nanobodies with different CDR3 rejoin were selected. Oligoclonal nanobodies inhibited proliferation and tube formation of the HUVEC cells more potently than did each individual nanobody. Taken together, this data from this study suggests that in vitro use of nanobodies (in an oligoclonal mode) that target distinct epitopes on VEGF could be promising as a novel therapy to treat VEGF-dependent pathologies. However, this needs to be further tested in in vivo studies. PMID- 30409072 TI - Changes in mechanical properties of sprinting during repeated sprint in elite rugby sevens athletes. AB - This study aimed to analyse fatigue-induced changes in mechanical sprinting properties during a specific repeated-sprint test in elite rugby sevens athletes. Twenty elite rugby sevens players performed ten 40 m sprints on a 30 s cycle with participant's running back and forth in a marked lane. Radar was used to assess maximal overground sprint performance over each 40 m. Macroscopic mechanical properties (maximal horizontal force (F0), maximal horizontal power (Pmax), maximal ratio of horizontal force (RFpeak), decrease in the ratio of horizontal to-total force (DRF), total force and maximal sprinting velocity (v0)) were drawn from horizontal force velocity relationships, using a validated method applied to the speed-time data. Fatigue-induced changes were analysed comparing the first sprint to an average of 2nd-4th, 5th-7th and 8th-10th. Repeated-sprint ability (RSA) testing induced substantial changes in the maximal velocity component, with a decrease (-15%) in v0 (effect size (ES) = -2.46 to -4.98), and to a lower extent (-5.9%) in the maximal force component F0 (ES = -0.59). DRF moderately decreased (14%; ES=-0.76-1.11), and RFpeak largely decreased in the later sprints (ES = -0.32 to -1.27). Fatigue observed in this RSA test appeared to have a greater effect on the technical ability to produce horizontal force at high velocities, likely due to an alteration in the ability to maintain horizontally oriented force application when velocity increases rather than during the initial acceleration phase, but also the overall force production capacity. The ability to maintain forward-oriented force at high velocities is of central importance for identifying fatigue and monitoring load. PMID- 30409073 TI - Unpacking Adultification: Institutional Experiences and Misconduct of Adult Court and Juvenile Court Youth Living Under the Same Roof. AB - The present study explores the ability of juvenile waiver policy and the resulting adult court status to impact the experiences and behavior of male youth originating from differing jurisdictions but incarcerated together within state level juvenile correctional facilities. Using official agency data and youth survey data, this research examines how "adult" status influences behavior for waived youth compared with their juvenile court counterparts. Structural equation modeling and multiple group analysis is used to determine the extent to which adult status moderates the measurement structure of models related to individual characteristics, institutional experiences, and institutional misconduct. Results reveal an improvement in model fit to occur when estimated across the two groups of juvenile court and adult court youth, beyond that which occurs when parameters are constrained to be equal for these two groups. This work reveals adult status to be powerful enough to moderate the effects of who a youth is and what that youth experiences, on how that youth behaves during a term of juvenile incarceration. PMID- 30409074 TI - Anesthetic management of a patient with an unusual broken tracheostomy tube: a case report. AB - OBJECTIVE: This study was performed to investigate the management of general anesthesia in an unusual case involving a patient with a broken tracheostomy tube presenting as an airway foreign body. METHODS: We herein describe the anesthetic management of a patient with a broken tracheostomy tube. A 77-year-old Chinese man who had been involved in a car accident underwent a tracheostomy. One year later, he presented with cough and bleeding at the tracheostomy site. Preoperative evaluation revealed that the metal tracheostomy tube was lodged in his left main bronchus. General anesthesia was induced to maintain spontaneous breathing, and adequate topical anesthesia of the airway was administered. RESULTS: The metal tracheostomy tube was successful removed, and a new tracheal tube was put in place. CONCLUSIONS: General anesthesia to maintain spontaneous breathing and adequate topical anesthesia of the airway can be safely used when removing broken tracheostomy tubes. PMID- 30409075 TI - Improving survival in end-stage renal disease: A case study. AB - BACKGROUND: With the increase of life expectancy, *On behalf of the REIN registry. end-stage renal disease (ESRD) is affecting a growing number of people. Simultaneously, renal replacement therapies (RRTs) have considerably improved patient survival. We investigated the way current RRT practices would affect patients' survival. METHODS: We used a multi-state model to represent the transitions between RRTs and the transition to death. The concept of "crude probability of death" combined with this model allowed estimating the proportions of ESRD-related and ESRD-unrelated deaths. Estimating the ESRD-related death rate requires comparing the mortality rate between ESRD patients and the general population. Predicting patients' courses through RRTs and Death states could be obtained by solving a system of Kolmogorov differential equations. The impact of practice on patient survival was quantified using the restricted mean survival time (RMST) which was compared with that of healthy subjects with same characteristics. RESULTS: The crude probability of ESRD-unrelated death was nearly zero in the youngest patients (18-45 years) but was a sizeable part of deaths in the oldest (>=70 years). Moreover, in the oldest patients, the proportion of expected death was higher in patient without vs. with diabetes because the former live older. In men aged 75 years at first RRT, the predicted RMSTs in patients with and without diabetes were, respectively, 61% and 69% those of comparable healthy men. CONCLUSION: Using the concept of "crude probability of death" with multi-state models is feasible and useful to assess the relative benefits of various treatments in ESRD and help patient long-term management. PMID- 30409076 TI - Vitamin D Receptor Deletion Leads to the Destruction of Tight and Adherens Junctions in Lungs. AB - Vitamin D deficiency has been linked to various inflammatory diseases in lungs, including pneumonia, asthma and chronic obstructive pulmonary disease. However, the mechanisms by which vitamin D and vitamin D receptor reduce inflammation in lung diseases remain poorly understood. In this study, we investigated the expression and cell-specific distribution of tight and adherens junctions in the lungs of vitamin D receptor-deficient (VDR-/-) mice. Our results demonstrated that mRNA and protein levels of claudin-2, claudin-4 and claudin-12 were significantly decreased in the lungs of VDR-/- mice. Other tight and adherens junction proteins, such as ZO-1, occludin, claudin-10, beta-catenin, and VE cadherin, showed significant differences in expression in the lungs of VDR-/- and wild-type mice. These data suggest that altered expression of tight and adherens junction molecules, especially of claudin-2, -4, -10, -12, and -18, after chronic pneumonia caused by VDR deletion could increase lung permeability.Therefore, VDR may play an important role in maintaining pulmonary barrier integrity. Further studies should confirm whether vitamin D/VDR is beneficial for the prevention or treatment of lung diseases. PMID- 30409077 TI - Potential benefits of near critical and supercritical pre-treatment of lignocellulosic biomass towards anaerobic digestion. AB - Vegetable crop residues, such as sugarcane bagasse (SCB), despite their limited biodegradability, are potential materials for anaerobic processes because of their low cost, high availability, and sugar content. The difficulty of biodegrading this type of material is primarily related to its chemical composition and to the complex interactions between its compounds (cellulose, hemicelluloses, and lignin). Thus, the following supercritical and near critical carbon dioxide (CO2) pre-treatments were evaluated with and without the addition of sodium hydroxide (NaOH): (i) 40 degrees C/70 kgf.cm-2; (ii) 60 degrees C/200 kgf.cm-2; and (iii) 80 degrees C/200 kgf.cm-2, aiming to enhance the anaerobic biodegradability of SCB. The methanogenic production of SCB increased in all cases in which the material was pre-treated, except the case in which NaOH was used together with a high temperature. The condition using CO2 at 60 degrees C/200 kgf.cm-2 was highlighted with a lignin removal of 8.07% and an accumulated methane production of 0.6498 +/- 0.014 LN (273.15K, 1.01325 * 105 Pa), 23.4% higher than the value obtained with the untreated material. This condition also showed the highest net energy at the energy balance that was calculated for comparison with the tested conditions. The results showed that pre-treatments with near critical and supercritical fluids have the potential to reduce structural obstacles of lignocellulosic materials and to enhance their anaerobic biodegradability. PMID- 30409078 TI - Development of methodology to document and code farm-related injuries and fatalities involving manure storage, handling and transport - with summary of 2017 incidents. AB - As part of ongoing surveillance of fatalities and injuries involving agricultural confined spaces by Purdue University's Agricultural Safety and Health Program, nearly 300 cases involving manure storage, handling, and transport equipment and facilities have been documented over the past 30 years. With the exception of a summary of 77 fatalities published by Beaver and Field1, these cases have not been previously analysed or published due to a lack of resources and the limitations of the Purdue Agricultural Confined Spaces Incident Database (PACSID) which was designed primarily for analysis of grain-related cases. These limitations included differences in terminology used to code case information in the PACSID and dissimilar causative and contributing factors. To develop a consistent and more useful approach to process and analyze data, 28 U.S. manure related incidents involving 39 victims documented as having occurred in 2017 were examined for type of incident, victim characteristics, primary contributing factors, and nature of injuries. A review of literature was conducted to identify previously reported contributing factors, and a coding rubric was developed and reviewed by a panel of experts. It was determined that the rubric provided a consistent way to code and analyze descriptive information available on each case. A pilot analysis was completed of the 39 cases using the new tool, and results were summarized. The final methodology will be used to analyze all historically documented incidents, as well as future incidents. Findings presented include a review of relevant literature, discussion of the methods used in case documentation, classifications developed from sample data, and a summary of incidents in 2017. Anticipated outcomes include: 1) consistent strategy to document, code, and summarize manure-related incidents; 2) means of classification of key contributing factors; 3) identification of new or emerging trends; and 4) completion of previously documented incidents. PMID- 30409079 TI - "It is never okay to talk about suicide": Patients' reasons for concealing suicidal ideation in psychotherapy. AB - OBJECTIVE: To identify psychotherapy clients' motives for concealing suicidal ideation from their therapist, and their perceptions of how their therapists could better elicit honest disclosure. METHOD: A sample of 66 psychotherapy clients who reported concealing suicidal ideation from their therapist provided short essay responses explaining their motives for doing so and what their therapist could do to help them be more honest. Content analysis was used to identify major motives and themes in these responses. RESULTS: Seventy percent of suicidal ideation concealers cited fear of unwanted practical impacts outside therapy as the reason they did not disclose. Chief among these unwanted impacts was involuntary hospitalization, a perceived outcome of disclosing even mild suicidal thoughts. Less concrete motives for concealment, such as shame or embarrassment, were significant but secondary concerns. Nearly half of suicide concealing clients said they would be more honest only if the threat of hospitalization was somehow reduced or controlled. CONCLUSION: Fostering disclosure of suicidal ideation in therapy may require renewed attention to providing transparent, comprehensive, and easy-to-understand psychoeducation about the triggers for hospitalization and other interventions. Clients make risk benefit calculations about whether to disclose suicidal ideation, but may operate with exaggerated or inaccurate ideas about the consequences of disclosure. PMID- 30409080 TI - A quick and accurate method for the estimation of covariate effects based on empirical Bayes estimates in mixed-effects modeling: Correction of bias due to shrinkage. AB - Nonlinear mixed-effects modeling is a popular approach to describe the temporal trajectory of repeated measurements of clinical endpoints collected over time in clinical trials, to distinguish the within-subject and the between-subject variabilities, and to investigate clinically important risk factors (covariates) that may partly explain the between-subject variability. Due to the complex computing algorithms involved in nonlinear mixed-effects modeling, estimation of covariate effects is often time-consuming and error-prone owing to local convergence. We develop a fast and accurate estimation method based on empirical Bayes estimates from the base mixed-effects model without covariates, and simple regressions outside of the nonlinear mixed-effect modeling framework. Application of the method is illustrated using a pharmacokinetic dataset from an anticoagulation drug for the prevention of major cardiovascular events in patients with acute coronary syndrome. Both the application and extensive simulations demonstrated that the performance of this high-throughput method is comparable to the commonly used maximum likelihood estimation in nonlinear mixed effects modeling. PMID- 30409081 TI - Adolescents need more sleep: Rethinking the preventive options of school environments. AB - Sleep problems in adolescence have both somatic and psychological consequences for health. Most adolescents spend a considerable amount of time in school, but there is little published research on how the school environment affects adolescent health and well-being. This commentary explores whether using a nap room in the middle of the school day can reduce perceived stress and fatigue in high school students and improve their sleep quality. We show that a short nap of 10 minutes can prevent stress-related problems. A method of improving adolescent health might be the reorganization of the school environment. PMID- 30409082 TI - Decoding emotions in expressive music performances: A multi-lab replication and extension study. AB - With over 560 citations reported on Google Scholar by April 2018, a publication by Juslin and Gabrielsson (1996) presented evidence supporting performers' abilities to communicate, with high accuracy, their intended emotional expressions in music to listeners. Though there have been related studies published on this topic, there has yet to be a direct replication of this paper. A replication is warranted given the paper's influence in the field and the implications of its results. The present experiment joins the recent replication effort by producing a five-lab replication using the original methodology. Expressive performances of seven emotions (e.g. happy, sad, angry, etc.) by professional musicians were recorded using the same three melodies from the original study. Participants (N = 319) were presented with recordings and rated how well each emotion matched the emotional quality using a 0-10 scale. The same instruments from the original study (i.e. violin, voice, and flute) were used, with the addition of piano. In an effort to increase the accessibility of the experiment and allow for a more ecologically-valid environment, the recordings were presented using an internet-based survey platform. As an extension to the original study, this experiment investigated how musicality, emotional intelligence, and emotional contagion might explain individual differences in the decoding process. Results found overall high decoding accuracy (57%) when using emotion ratings aggregated for the sample of participants, similar to the method of analysis from the original study. However, when decoding accuracy was scored for each participant individually the average accuracy was much lower (31%). Unlike in the original study, the voice was found to be the most expressive instrument. Generalised Linear Mixed Effects Regression modelling revealed that musical training and emotional engagement with music positively influences emotion decoding accuracy. PMID- 30409083 TI - Therapeutic targeting of transcriptional cyclin-dependent kinases. AB - The fact that many cancer types display transcriptional addiction driven by dysregulation of oncogenic enhancers and transcription factors has led to increased interest in a group of protein kinases, known as transcriptional cyclin dependent kinases (tCDKs), as potential therapeutic targets. Despite early reservations about targeting a process that is essential to healthy cell types, there is now evidence that targeting tCDKs could provide enough therapeutic window to be effective in the clinic. Here, we discuss recent developments in this field, with an emphasis on highly-selective inhibitors and the challenges to be addressed before these inhibitors could be used for therapeutic purposes. Abbreviations: CAK: CDK-activating kinase;CDK: cyclin-dependent kinase;CMGC group: CDK-, MAPK-, GSK3-, and CLK-like;CTD: C-terminal repeat domain of the RPB1 subunit of RNA polymerase II;DRB: 5,6-dichloro-1-beta-D ribofuranosylbenzimidazole;mCRPC: metastatic castration-resistant prostate cancer;NSCLC: non-small cell lung cancer;P-TEFb: positive elongation factor b;RNAPII: RNA polymerase II;S2: serine-2 of CTD repeats;S5: serine-5 of CTD repeats;S7: serine-7 of CTD repeats;SEC: super elongation complex;tCDK: transcriptional cyclin-dependent kinase;TNBC: triple-negative breast cancer. PMID- 30409084 TI - Child marriage and relationship quality in Ethiopia. AB - Child marriage is prevalent in Africa, with almost 40% of girls being married before age 18. Although child marriage is linked to a range of adverse outcomes, including intimate partner violence, little is known about the quality of these marriages in terms of the levels of communication, trust, equality, intimacy, conflict, marital satisfaction or happiness. We used both quantitative and qualitative data to examine how exact age at first marriage influenced multiple domains of relationship quality in Ethiopia. Our analysis was based on household survey data from 3396 currently married or recently divorced women aged 18-45, 32 in-depth interviews and 8 participatory focus groups in two regions. The regression results show a strong negative effect of marriage at or before age 12 on relationship quality across multiple domains. The qualitative data suggest a more pervasive effect on marital quality, with the lack of ability to choose whom they married and reduced agency emerging as particularly important factors influencing marital quality. This relationship may be direct or indirect, potentially mediated by factors such as intimate partner violence. Interventions intending to mitigate the effects of child marriage should include components that aim to improve the quality of spousal relationships, particularly in terms of communication and negotiation skills. PMID- 30409085 TI - A Mediterranean diet supplemented with dairy foods improves mood and processing speed in an Australian sample: results from the MedDairy randomized controlled trial. AB - BACKGROUND: The Mediterranean diet has been linked to improved cognitive function and reduced risk of dementia. However, a traditional Mediterranean diet may not meet calcium requirements for older non-Mediterranean populations, which could limit long-term sustainability in Western countries. The current study therefore aimed to determine the cognitive and psychological effects of a Mediterranean diet with adequate calcium for an ageing Australian population. METHOD: A randomized controlled cross-over design trial compared a Mediterranean diet with 3-4 daily serves of dairy food (MedDairy) with a low-fat (LF) control diet. Forty one participants aged >=45 years with systolic blood pressure >=120 mm Hg and at least two other risk factors for cardiovascular disease completed each dietary intervention for 8 weeks, with an 8-week washout period separating interventions. Attention, processing speed, memory and planning were assessed at the start and end of each intervention using the Cambridge Automated Neuropsychological Test Battery. Mood and health-related quality of life were evaluated using the Profile of Mood States (POMS) and Short-Form Health Survey (SF-36). Dementia risk was also measured using the Framingham Vascular Risk and CAIDE scores. RESULTS: Significant improvements were observed for processing speed (P = .04), Total Mood Disturbance (P = .01), Tension (P = .03), Depression (P = .03), Anger (P = .02), and Confusion (P = .004) following the MedDairy intervention. No significant effects were found for attention, memory and planning, or measures of dementia risk. CONCLUSION: Our study provides evidence that a Mediterranean diet supplemented with dairy foods may benefit cognitive function and psychological well-being in an ageing population at risk of dementia. PMID- 30409086 TI - Development of Competencies for Respiratory Protection for Health Care Workers. AB - According to the Bureau of Labor Statistics, more than 18 million health care workers in the United States are currently employed in the health care field and at risk of infectious respiratory exposure. With the emergence of global infectious diseases such as Ebola and Severe Acute Respiratory Syndrome (SARS), there is a need for increased and more clinically competent use of respiratory protection among healthcare workers. In an effort to improve knowledge about the practice of respiratory protection against respiratory infectious agents, a NIOSH funded project that included an educational program, observations of HCWs, and focus groups was conducted. This study aimed to develop, implement, and evaluate respiratory protection educational program for HCWs and hospital management. This study identified respiratory protection practice issues among HCWs and strategies for integration of respiratory protection standards and procedures into practice. Findings from these efforts were used to develop respiratory protection competencies. Any worker who has the potential for respiratory exposure to infectious agents should be protected and should be able to demonstrate these specific competencies to achieve a standard level of respiratory protection. PMID- 30409087 TI - An autopsied case of MM1-type sporadic Creutzfeldt-Jakob disease with pathology of Wernicke encephalopathy. AB - An 83-year-old Japanese man presented with gait disturbance followed by rapidly progressive cognitive impairment. Magnetic resonance diffusion-weighted images showed extensive hyperintense regions in the cerebral cortex. Four weeks after symptom onset, myoclonus appeared, and the patient developed difficulty swallowing; intravenous peripheral continuous infusions without vitamin supplementation were administered during the last two months of the patient's life. The patient reached the akinetic mutism state and died 12 weeks after symptom onset due to sepsis. The brain weighed 940 g and showed general cerebral atrophy. Extensive spongiform change were observed in the cerebral cortex, striatum, thalamus, and cerebellar cortex, but gliosis was generally mild. Numerous newly-developed hemorrhage foci were observed in the mammillary body, the areas adjacent to the third and fourth ventricles, and the periaqueduct of the midbrain; however, proliferation of capillaries and endothelium and collections of macrophages were relatively inconspicuous. These findings suggested comorbidity with the acute stage of Wernicke encephalopathy (WE). Immunostaining showed extensive diffuse synaptic-type prion protein deposition in the gray matter. According to the neuropathological, genetic, and molecular findings, the present case was finally diagnosed as MM1-type sporadic Creutzfeldt Jakob disease (CJD) with WE. We should remain alert to the diagnosis of WE when CJD is suspected, and it is necessary to consider the complications of both diseases. This report emphasizes the importance of pathological investigations for the diagnosis of CJD, WE, and the coexistence of both. PMID- 30409088 TI - Objectively measured absolute and relative physical activity intensity levels in postmenopausal women. AB - OBJECTIVES: To investigate how objectively measured physical activity (PA) levels differ according to absolute moderate intensity recommendation (3-6 METs) and relative to individual lactate thresholds (LT1 and LT2), and to verify if high fit women record higher PA levels compared to women with lower aerobic fitness. METHODS: Seventy-five postmenopausal women performed an incremental exercise test and several constant-velocity tests wearing an accelerometer to identify the activity counts (ct min-1) corresponding to LT1 and LT2. Individual linear regression determined activity counts cut-points for each intensity: (1) sedentary (<200 ct min-1), (2) light (from 200 ct min-1 to ct min-1 at LT1), (3) moderate (ct min-1 between LT1 and LT2) and (4) vigorous (ct min-1 > LT2). Participants then wore an accelerometer during a week to measure the time spent at each PA intensity level. RESULTS: According to absolute intensity categorisation, high-fit postmenopausal women recorded twice as much time at moderate-to-vigorous PA (MVPA) (P < 0.01) than low-fit women. However, when PA intensity was calculated relative to individual lactate thresholds, MVPA was significantly reduced by half (P < 0.01) and the data revealed no differences (P = 0.62) between groups (~20 min day-1 at MVPA). CONCLUSIONS: Accelerometer cut points derived from absolute moderate-intensity recommendations overestimated MVPA. Similar time at MVPA was recorded by high- and low-fit postmenopausal women when the cut-points were tailored to individual lactate thresholds. A more accurate estimation of PA behaviour could be provided with the use of individually tailored accelerometer cut-points. PMID- 30409089 TI - Synergistic effect of phosphodiesterase 4 inhibitor and serum on migration of endotoxin-stimulated macrophages. AB - Macrophage migration is an essential step in host defense against infection and wound healing. Elevation of cAMP by inhibiting phosphodiesterase 4 (PDE4), enzymes that specifically degrade cAMP, is known to suppress various inflammatory responses in activated macrophages, but the role of PDE4 in macrophage migration is poorly understood. Here we show that the migration of Raw 264.7 macrophages stimulated with LPS was markedly and dose-dependently induced by the PDE4 inhibitor rolipram as assessed by scratch wound healing assay. Additionally, this response required the involvement of serum in the culture medium as serum starvation abrogated the effect. Further analysis revealed that rolipram and serum exhibited synergistic effect on the migration, and the influence of serum was independent of PDE4 mRNA expression in LPS-stimulated macrophages. Moreover, the enhanced migration by rolipram was mediated by activating cAMP/exchange proteins directly activated by cAMP (Epac) signaling, presumably via interaction with LPS/TLR4 signaling with the participation of unknown serum components. These results suggest that PDE4 inhibitors, together with serum components, may serve as positive regulators of macrophage recruitment for more efficient pathogen clearance and wound repair. PMID- 30409091 TI - Whatever happened to the Shwartzman phenomenon? AB - Ninety years ago, Gregory Shwartzman first reported an unusual discovery following the intradermal injection of sterile culture filtrates from principally Gram-negative strains from bacteria into normal rabbits. If this priming dose was followed in 24 h by a second intravenous challenge (the provocative dose) from same culture filtrate, dermal necrosis at the first injection site would regularly occur. This peculiar, but highly reproducible, event fascinated the microbiologists, hematologists, and immunologists of the time, who set out to determine the mechanisms that underlie the pathogenesis of this reaction. The speed of this reaction seemed to rule out an adaptive, humoral, immune response as its cause. Histopathologic material from within the necrotic center revealed fibrinoid, thrombo-hemorrhagic necrosis within small arterioles and capillaries in the micro-circulation. These pathologic features bore a striking resemblance to a more generalized coagulopathic phenomenon following two repeated endotoxin injections described 4 yr earlier by Sanarelli. This reaction came to be known as the generalized Shwartzman phenomenon, while the dermal reaction was named the localized or dermal Shwartzman reaction. A third category was later added, called the single organ or mono-visceral form of the Shwartzman phenomenon. The occasional occurrence of typical pathological features of the generalized Shwartzman reaction limited to a single organ is notable in many well-known clinical events (e.g., hyper-acute kidney transplant rejection, fulminant hepatic necrosis, or adrenal apoplexy in Waterhouse-Fredrickson syndrome). We will briefly review the history and the significant insights gained from understanding this phenomenon regarding the circuitry and control mechanisms responsible for disseminated intravascular coagulation, the vasculopathy and the immunopathy of sepsis. PMID- 30409092 TI - Carbon monoxide (CO) and nitric dioxide (NO2) exposure during fetal life: impact on neonatal and placental weight, a prospective study. AB - OBJECTIVE: This prospective study aims to analyze how CO and NO2 exposure during pregnancy affects birth and placental weight as well as umbilical arterial pH. STUDY DESIGN: The population in study includes 3614 women born in Italy, living in Lombardia Region, consecutively admitted to the Clinica Mangiagalli for an elective cesarean section from January 2004 to December 2006. Outdoor air quality data was provided by the Department of the Regional Environmental Protection Agency and obtained by a network of fixed monitoring stations distributed in eight geographical areas across the region. RESULTS: A positive association was found between birth weight and the concentration of CO to whom women were exposed during the last 10 days of pregnancy (mean change g + 28, 95% CI +1-+55, p 0,04). Conversely, placental weight was not influenced by exposure to CO while a statistically significant weight reduction was related to an increase in NO2 exposure during the last trimester of pregnancy. CONCLUSION: Fetal weight was positively associated with an increased exposure to CO during the last 10 days of pregnancy. NO2 exposure was associated to a placental weight reduction. These findings underline the existence of a complex biological role of such pollutants, especially of CO, in cell oxygenation at a placental level. PMID- 30409093 TI - Editor's presentation. PMID- 30409094 TI - ? PMID- 30409096 TI - [14 years in the editorial offi ce of the German Journal of Child and Adolescent Psychiatry and Psychotherapy - a glimpse into the future]. PMID- 30409095 TI - ? PMID- 30409097 TI - ? PMID- 30409098 TI - [Farewell and thank-you to Beate Herpertz-Dahlmann]. PMID- 30409099 TI - Can the National Call to Prevent Gun Violence Reduce Suicides? PMID- 30409100 TI - Redirecting the Mental Health and Gun Violence Conversation From Mass Shootings to Suicide. PMID- 30409101 TI - False diagnosis of and needless therapy for presumed gestational trophoblastic disease in women with an unusual site of residual pregnancy. AB - OBJECTIVE: This study aimed to determine the diagnostic value of magnetic resonance imaging (MRI), hysteroscopy, and laparoscopy to avoid unnecessary treatment when patients present with clinical manifestations that are close to those of gestational trophoblastic neoplasia (GTN). METHODS: Three patients who were falsely diagnosed with presumed GTN and received needless chemotherapy in our hospital from July 2011 to March 2012 were studied. We also reviewed data of patients with similar clinical features who were diagnosed as having residual pregnancy in recent years. Clinical manifestations were evaluated. RESULTS: All three patients had persistently high serum beta-human chorionic gonadotrophin levels and a mass with abundant blood supply in the uterus after termination of pregnancy. The patients were diagnosed with GTN and underwent chemotherapy. They responded poorly to chemotherapy and underwent surgery. The pathological diagnosis in all patients was residual pregnancy. In recent years, no patients were misdiagnosed because pelvic MRI, hysteroscopy, or laparoscopy was used when residual pregnancy could not be excluded. CONCLUSION: Gynecologists should diagnose carefully when patients present with clinical manifestations that are close to those of GTN to avoid unnecessary treatment. MRI, hysteroscopy, and laparoscopy could be important examinations for excluding residual pregnancy. PMID- 30409102 TI - James P. Lovegren, MPH (1932-2018). PMID- 30409103 TI - Different Error Size During Locomotor Adaptation Affects Transfer to Overground Walking Poststroke. AB - BACKGROUND: Studies in neurologically intact subjects suggest that the gradual presentation of small perturbations (errors) during learning results in better transfer of a newly learned walking pattern to overground walking. Whether the same result would be true after stroke is not known. OBJECTIVE: To determine whether introducing gradual perturbations, during locomotor learning using a split-belt treadmill influences learning the novel walking pattern or transfer to overground walking poststroke. METHODS: Twenty-six chronic stroke survivors participated and completed the following walking testing paradigm: baseline overground walking; baseline treadmill walking; split-belt treadmill/adaptation period (belts moving at different speeds); catch trial (belts at same speed); post overground walking. Subjects were randomly assigned to the Gradual group (gradual changes in treadmill belts speed during adaptation) or the Abrupt group (a single, large, abrupt change during adaptation). Step length asymmetry adaptation response on the treadmill and transfer of learning to overground walking was assessed. RESULTS: Step length asymmetry during the catch trial was the same between groups ( P = .195) confirming that both groups learned a similar amount. The magnitude of transfer to overground walking was greater in the Gradual than in the Abrupt group ( P = .041). CONCLUSIONS: The introduction of gradual perturbations (small errors), compared with abrupt (larger errors), during a locomotor adaptation task seems to improve transfer of the newly learned walking pattern to overground walking poststroke. However, given the limited magnitude of transfer, future studies should examine other factors that could impact locomotor learning and transfer poststroke. PMID- 30409104 TI - Caprine herpesvirus 1 (CpHV-1) as a potential candidate for oncolytic virotherapy. AB - Caprine Herpesvirus type 1 (CpHV-1) is a species-specific herpes virus able to induce apoptosis in several biological systems. In the present study we aimed to investigate the ability of CpHV-1 to reduce cells viability, to replicate and to cause cell death also in human cancer cell lines. We tested the CpHV-1 effects on HEL-299, Vero, MDA-MB-468, HeLa, U2OS, PC3, A549 and K562 neoplastic cell lines and on MDBK cells. Firstly, we evaluated the effect of CpHV-1 infection on cell viability by MTT assay and our data showed that CpHV-1 can induce a marked cytopathic effect (CPE) in most of cell lines tested, except for HEL-299, Vero and K562 cells. The reduction of cell viability was associated with a significant increase of viral production. We next investigated if CpHV-1 was able to induce cell death and so through western blotting analysis we evaluated cleaved caspase 3, LC3II and p62 protein levels after infection. Caspase 3 activation was detected in MDBK cells and, even if at different times p.i., also in MDA-MB-468, U2OS, and PC3 cell lines, while LC3II increase and concomitant p62 protein reduction were observed only in U2OS, and A549 cells, no significant alteration of these proteins was observed in the other cell lines tested. Finally, to confirm virus ability to trigger apoptosis we performed an Annexin-V apoptosis test after 24 h p.i. Although we need to further explore mechanisms underlying CpHV-1 treatment, this study could serve as the basis for the development of new treatment options aiming to fight several cancer types. PMID- 30409105 TI - Lactobacillus plantarum bacteriocin is associated with intestinal and systemic improvements in diet-induced obese mice and maintains epithelial barrier integrity in vitro. AB - We investigated the Lactobacillus plantarum bacteriocin plantaricin EF (PlnEF) system for its contributions to L. plantarum mediated benefits in a mouse model of diet-induced obesity. C57BL/6J mice on a high-fat diet (HFD) were administered a rifampicin resistant mutant of L. plantarum NCMIB8826 (NICMB8826-R) or an isogenic DeltaplnEFI mutant strain, LM0419, every 48 h for nine weeks. Mice fed wild-type L. plantarum, but not LM0419, reduced their consumption of the HFD starting three weeks into the study and exhibited an overall 10% reduction in weight gain. The responses were independent of glucose homeostasis, as both NCMIB8826-R and LM0419 fed mice had improved oral glucose tolerance compared to sham controls. Although bacteriocins have antibacterial properties, the ileal, cecal, and fecal microbiota and cecocolic metabolomes were unchanged between mice fed either wild-type L. plantarum or the DeltaplnEFI mutant. Instead, only mice fed NCMIB8826-R showed an increased production of ZO-1 in ileal tissues. To verify a potential role for the plantaricin EF system in supporting intestinal epithelial function, synthesized PlnEF peptides were applied to Caco-2 cell monolayers challenged with TNF-alpha and IFN-gamma. The combination of PlnE and PlnF were required to prevent sustained cytokine-induced losses to Caco-2 cell para- and transcellular permeability and elevated IL-8 levels. In conclusion, this study shows that probiotic L. plantarum ameliorates the effects of obesogenic diets through a mechanism that involves the plantaricin EF system and likely includes L. plantarum - induced fortification of the intestinal epithelium. PMID- 30409106 TI - Navigating double marginalisation: migrant Chinese sexual and gender minority young people's views on mental health challenges and supports. AB - Sexual and/or gender minority young people who are also members of an ethnic minority can experience unique challenges. Limited research draws directly on the mental health experiences of these 'double minority' youth. This study focused on Chinese sexual/gender minority youth in New Zealand. It sought to explore features they found challenging for, or supportive of, their mental health and wellbeing. Semi-structured interviews were conducted with 11 Chinese sexual/gender minority participants aged between 19 and 29 years old and residing in Auckland, New Zealand. An inductive approach to qualitative data analysis was used. Two major domains of findings emerged. Firstly, participants described mental health challenges linked to racism, sexism, cis-heteronormativity and challenges in relation to intersecting identities. Secondly, Chinese culture and community connections, family and peer support and role models seemed to facilitate resiliency. However, the fear of 'losing face', unwillingness to disclose distress when unwell and mental health service providers' lack of cultural and linguistic competency were described as barriers to effective mental health support. In conclusion, Chinese and sexual/gender minority identities were integral parts of participants' sense of self, and this was associated with their mental health and wellbeing. Further research is required to explore ways to reduce barriers and promote resiliency. PMID- 30409107 TI - Dopamine Replacement Medication Does Not Influence Implicit Learning of a Stepping Task in People With Parkinson's Disease. AB - INTRODUCTION: Treatment of Parkinson's disease (PD) with exogenous dopamine (ie, levodopa) may positively affect motor symptoms, but may negatively affect other functions such as the learning of motor skills necessary for rehabilitation. This study aimed to determine whether levodopa medication affects general and sequence specific learning of a stepping task and the transfer of movement skill to untrained balance tasks in people with PD. METHODS: Participants with PD were randomized to practice "on" (n = 14) or "off" (n = 13) levodopa medication. Participants practiced 6 blocks of 6 trials of 24 steps of a stepping task over an acquisition period of 3 consecutive days, followed by single retention blocks of 6 trials 2 and 9 days later. Participants were also assessed on untrained balance (ie, transfer) tasks "on" levodopa before practice and following late retention. RESULTS: There were no between-group differences in general learning, sequence-specific learning, or transfer of skill to untrained balance tasks ( P > .05). Both groups demonstrated general and sequence-specific learning ( P < .001) and trends for improvement in untrained tasks ( P < .001 to P = .26) following practice. Detailed analysis of early acquisition revealed no difference between medication groups. CONCLUSION: People with PD improved performance on the stepping task with practice. The between-group effect sizes were small, suggesting that levodopa medication status ("on" versus "off") during practice did not significantly affect general or sequence-specific learning of the task or components of early acquisition. The practice dose required to optimally result in functional improvements in untrained balance tasks, including reductions in falls, remains to be determined. PMID- 30409108 TI - Effects of topical vs injection treatment of cervical myofascial trigger points on headache symptoms in migraine patients: a retrospective analysis. AB - BACKGROUND: In migraine patients with cervical myofascial trigger points whose target areas coincide with migraine sites (M + cTrPs), TrP anesthetic injection reduces migraine symptoms, but the procedure often causes discomfort. This study evaluated if a topical TrP treatment with 3% nimesulide gel has similar efficacy as the injection but produces lesser discomfort with higher acceptability by the patients. METHODS: Retrospective analysis of medical charts of M + cTrPs patients in the period January 2012-December 2016 at a single Headache Center. Three groups of 25 patients each were included, all receiving migraine prophylaxis (flunarizine 5 mg/day) for 3 months and symptomatic treatment on demand. Group 1 received no TrP treatment, group 2 received TrP injections (bupivacaine 5 mg/ml at basis, 3rd, 10th, 30th and 60th day), group 3 received daily TrP topical treatment with 1.5 g of 3% nimesulide gel for 15 consecutive days, 15 days interruption and again 15 consecutive days. The following were evaluated: monthly number of migraine attacks and rescue medications, migraine intensity; pain thresholds to skin electrical stimulation (EPTs) and muscle pressure stimulation (PPTs) in TrP and target (basis, 30th, 60th and 180th days); discomfort from, acceptability of and willingness to repeat treatment (end of study). ANOVA for repeated measures and 1-way ANOVA were used to assess temporal trends in each group and comparisons among groups, respectively. Significance level was set at p < 0.05. RESULTS: Migraine improved over time in all groups, but significantly more and earlier in those receiving TrP treatment vs no TrP treatment (0.02 < p < 0.0001, 30-180 days for intensity and rescue medication, 60-180 days for number). All thresholds in the non-TrP-treated group did not change over time, while significantly improving in both the injection and nimesulide gel groups (0.01 < p < 0.0001, 30-180 days). Improvement of migraine and thresholds did not differ in the two TrP-treated groups. Discomfort was significantly lower, acceptability and willingness to repeat treatment significantly higher (0.05 < p < 0.0001) with gel than injection. CONCLUSION: In migraine patients, topical treatment of cervical TrPs with 5% nimesulide gel proves equally effective as TrP injection with local anesthetics but more acceptable by the patients. This treatment could be effectively associated to standard migraine prophylaxis to improve therapeutic outcomes. PMID- 30409109 TI - Migraine induction with calcitonin gene-related peptide in patients from erenumab trials. AB - BACKGROUND: Migraine prevention with erenumab and migraine induction by calcitonin gene-related peptide (CGRP) both carry notable individual variance. We wanted to explore a possible association between individual efficacy of anti-CGRP treatment and susceptibility to migraine induction by CGRP. METHODS: Thirteen migraine patients, previously enrolled in erenumab anti-CGRP receptor monoclonal antibody trials, received CGRP in a double-blind, placebo-controlled, randomized cross-over design to investigate their susceptibility to migraine induction. A standardized questionnaire was used to assess the efficacy of previous antibody treatment. The patients were stratified into groups of high responders and poor responders. Primary outcomes were incidence of migraine-like attacks and area under the curve of headache intensity after infusion of CGRP and placebo. All interviews and experiments were performed in laboratories at the Danish Headache Center, Copenhagen, Denmark. RESULTS: Ten high responders and three poor responders were included. CGRP induced migraine-like attacks in ten (77%) patients, whereof two were poor responders, compared to none after placebo (p = 0.002). The area under the curve for headache intensity was greater after CGRP, compared to placebo, at 0-90 min (p = 0.009), and 2-12 h (p = 0.014). The median peak headache intensity score was 5 (5-9) after CGRP, compared to 2 (0-4) after placebo (p = 0.004). CONCLUSIONS: Patients with an excellent effect of erenumab are highly susceptible to CGRP provocation. If an association is evident, CGRP provocation could prove a biomarker for predicting antibody treatment efficacy. TRIAL REGISTRATION: Retrospectively registered at clinicaltrials.gov with identifier: NCT03481400 . PMID- 30409110 TI - Identification of transcription factor genes involved in anthocyanin biosynthesis in carrot (Daucus carota L.) using RNA-Seq. AB - BACKGROUND: Anthocyanins are water-soluble colored flavonoids present in multiple organs of various plant species including flowers, fruits, leaves, stems and roots. DNA-binding R2R3-MYB transcription factors, basic helix-loop-helix (bHLH) transcription factors, and WD40 repeat proteins are known to form MYB-bHLH-WD repeat (MBW) complexes, which activates the transcription of structural genes in the anthocyanin pathway. Although black cultivars of carrots (Daucus carota L.) can accumulate large quantities of anthocyanin in their storage roots, the regulatory genes responsible for their biosynthesis are not well characterized. The current study aimed to analyze global transcription profiles based on RNA sequencing (RNA-Seq), and mine MYB, bHLH and WD40 genes that may function as positive or negative regulators in the carrot anthocyanin biosynthesis pathways. RESULTS: RNA was isolated from differently colored calli, as well as tissue samples from taproots of various black carrot cultivars across the course of development, and gene expression levels of colored and non-colored tissue and callus samples were compared. The expression of 32 MYB, bHLH and WD40 genes were significantly correlated with anthocyanin content in black carrot taproot. Of those, 11 genes were consistently up- or downregulated in a purple color-specific manner across various calli and cultivar comparisons. The expression of 10 out of these 11 genes was validated using real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). CONCLUSIONS: The results of this study provide insights into regulatory genes that may be responsible for carrot anthocyanin biosynthesis, and suggest that future focus on them may help improve our overall understanding of the anthocyanin synthesis pathway. PMID- 30409111 TI - Case report: dual primary AIDS-defining cancers in an HIV-infected patient receiving antiretroviral therapy: Burkitt's lymphoma and Kaposi's sarcoma. AB - BACKGROUND: The incidence of AIDS-defining cancers (ADCs) has decreased markedly in the era of highly active antiretroviral therapy (HAART). The occurrence of two ADCs is rare in people living with HIV or AIDS (PWHA) who are severely immunosuppressed or have incomplete virologic suppression. CASE PRESENTATION: We report a case of dual primary ADCs, especially NHL followed by KS, in a 70-year old HIV-infected man who was on antiretroviral therapy and had successful virologic suppression. During HAART, he presented with generalized myalgia and abdominal pain. Multiple liver masses were detected and a biopsy revealed Burkitt's lymphoma. After three cycles of anticancer chemotherapy with a favorable response, he was diagnosed with cytomegalovirus retinitis and the anti cancer chemotherapy was discontinued. Despite successful virologic suppression with HAART, human herpes virus-8 associated Kaposi's sarcoma was diagnosed in his right thigh. He underwent radiation therapy. CONCLUSION: These findings suggest that multiple ADCs can occur in PWHA who are receiving HAART and have successful virologic suppression. Healthcare providers caring for PWHA should maintain vigilance for the development of a broad spectrum of cancers. PMID- 30409112 TI - Nephrotic syndrome associated with Kimura's disease: a case report and literature review. AB - BACKGROUND: Kimura's disease (KD) is a rare chronic inflammatory disorder with a high incidence of renal involvement. In this report, we present a case study of KD-associated nephrotic syndrome combined with minimal change disease (MCD) and acute renal tubular injury. Meanwhile, the clinical and histopathological characteristics of 26 patients with KD presenting with renal involvement were retrospectively evaluated. CASE PRESENTATION: Here, we report a case study of a 59-year-old male patient with KD confirmed by a lymph node biopsy. He developed widespread edema and decreased urine output. A palpable swollen mobile and non tender lymph node behind the left ear was observed upon admission. A renal biopsy revealed minimal-change lesions and acute renal tubular injury. The patient received hemodialysis because of the oliguria and renal insufficiency, and an initial dose of 40 mg/d methylprednisolone and then continued treatment with 40 mg/d prednisolone. He exhibited a good clinical response to the steroid after 6 weeks of treatment. Of the other 26 patients included in the review, 13 patients presented with mesangial proliferative glomerulonephritis, 4 with membranous nephropathy, 3 with MCD, 3 with focal segmental glomerulosclerosis, 2 with IgA nephropathy and 1 with acute tubular injury. With the exception of 2 patients who progressed to end-stage renal disease and received hemodialysis, the majority of patients responded well to treatment with corticosteroids alone. CONCLUSIONS: MCD combined with acute renal tubular injury is rare in patients with KD presenting with renal involvement. Corticosteroids may be a beneficial treatment for renal injury in patients with KD. PMID- 30409114 TI - Pancreatic acinar cell carcinoma-case report and literature review. AB - BACKGROUND: Pancreatic acinar cell carcinoma (ACC) is a rare tumor that constitutes 1% of all pancreatic neoplasms. Pancreatic ACC has unique characteristics in terms of biological behavior, imaging and prognosis. CASE PRESENTATION: The present study reported two cases of pancreatic ACC confirmed by postoperative pathology and both cases exhibited several different imaging features and laboratory test results. Both cases had approximately 4 cm mass located in uncinate process of pancreas. Dilated intra- and extra-hepatic bile ducts was observed in one case, along with calcification. Heterogeneous enhancement of the tumor was exhibited in both patients with different intensities. Obstructive jaundice, elevated alpha-fetoprotein and CA 19-9 was found in one case, while the other case had normal liver function and tumor markers. CONCLUSIONS: It was difficult to accurately diagnose pancreatic ACC before the operation despite its unique characteristics. Radical resection was the best treatment modality for resectable pancreatic ACC. PMID- 30409113 TI - Relevance of vitamin D deficiency in patients with chronic autoimmune atrophic gastritis: a prospective study. AB - BACKGROUND: Chronic autoimmune atrophic gastritis (CAAG) is an autoimmune disease characterized by hypo/achlorhydria. A role of CAAG in the pathogenesis of nutritional deficiencies has been reported, therefore we hypothesized a possible association between CAAG and 25-OH-Vitamin D [25(OH)D] deficiency. Aim of the present study is to evaluate the prevalence of 25(OH)D deficiency in CAAG patients. METHODS: 87 CAAG patients (71 females; mean age 63.5 +/- 12.8 years) followed at our Centre from January 2012 to July 2015 were consecutively evaluated. 25(OH)D, vitamin B12, parathormone, and calcium were measured in all the CAAG patients. The results were compared with a control group of 1232 healthy subjects. RESULTS: In the CAAG group the mean 25(OH)D levels were significantly lower than in the control group (18.8 vs. 27.0 ng/ml, p < 0.0001). 25(OH)D levels < 20 ng/ml was observed in 57 patients, while levels < 12.5 ng/ml in 27 patients. A significant correlation between vitamin B12 values at diagnosis and 25(OH)D levels was observed (rs = 0.25, p = 0.01). Interestingly, the CAAG patients with moderate/severe gastric atrophy had lower 25(OH)D values as compared to those with mild atrophy (11.8 vs. 20 ng/ml; p = 0.0047). Moreover, the 25(OH)D levels were significantly lower in CAAG patients with gastric carcinoid as compared to those without gastric carcinoid (11.8 vs. 19.8 ng/ml; p = 0,0041). CONCLUSION: Data from the present study showed a significant reduction of 25(OH)D levels in CAAG patients and a possible impairment of vitamin D absorption in CAAG may be postulated. Any implication to the genesis of gastric carcinoids remains to be elucidated. PMID- 30409116 TI - Disease severity-based evaluation of utility weights for lung cancer-related health states in Korea. AB - BACKGROUND: Utility weight, a measure of health-related quality of life, is used in disease burden measurements and economic evaluations. In this study, we used the visual analogue scale (VAS) and standard gamble (SG) method to determine the utility weights of lung cancer health states in South Korea from a societal perspective. METHODS: Six hypothetical health states for lung cancer or a related health state reflective of disease severity were developed: 1) Stage I, 2) Stage II, 3) Stage IIIa, 4) Stage IIIB, 5) Stage IV, and 6) Pulmonary nodule. The description of each health state description was divided into four parts: diagnosis, symptoms, treatment, and progression and prognosis. A total of 515 representative adult Korean participants used a VAS and SG to evaluate these six health states via face-to-face computer-assisted interviews. The means, standard deviations, and median utility weights of the six health states were estimated by valuation method. RESULTS: The two valuation methods of the scenarios yielded the same mean utility rankings. Pulmonary nodule received the highest rank (VAS, 0.66 and SG, 0.83), whereas Stage 4 was assigned the lowest rank (VAS, 0.09 and SG, 0.31). For all health states, the mean utility weights calculated using the SG were greater than those calculated using the VAS. The differences between the utility weights obtained using the two valuation methods ranged from 0.14 (Stage I) to 0.22 (Stage IV). The two approaches tended to yield larger differences for more severe stages. CONCLUSIONS: This study determined utilities for squamous cell lung cancer that will be useful for estimating the burden of lung cancer and for conducting economic evaluations of lung cancer interventions. PMID- 30409115 TI - Comparative transcriptome analysis of roots, stems and leaves of Isodon amethystoides reveals candidate genes involved in Wangzaozins biosynthesis. AB - BACKGROUND: Isodon amethystoides (Ben-th) Cy Wu et Hsuan is an important traditional medicinal plant endowed with pharmacological properties effective in the treatment of various diseases, including pulmonary tuberculosis. The tetracyclic diterpenoids, Wangzaozins (Wangzaozin A, glaucocalyxin A, glaucocalyxin B), are the major bioactive compounds of I. amethystoides. However, the molecular information about the biosynthesis of these compounds still remains unclear. RESULTS: An examination of the accumulated levels of Wangzaozins in I. amethystoides revealed considerable variations in the root, stem, and leaf tissues of this plant, indicating possible differences in metabolite biosynthesis and accumulation among various tissues. To better elucidate the tetracyclic diterpenoid biosynthesis pathway, we generated transcriptome sequences from the root, stem, and leaf tissues, and performed de novo sequence assembly, yielding 230,974 transcripts and 114,488 unigenes, with average N50 lengths of 1914 and 1241 bp, respectively. Putative functions could be assigned to 73,693 transcripts (31.9%) based on BLAST searches against annotation databases, including GO, KEGG, Swiss-Prot, NR, and Pfam. Moreover, the candidate genes involving in the diterpenoid biosynthesis, such as CPS, KSL, were also analyzed. The expression profiles of eight transcripts, involving the tetracyclic diterpenoid biosynthesis, were validated in different I. amethystoides tissues by qRT-PCR, unraveling the gene expression profile of the pathway. The differential expressions of ISPD, ISPF and ISPH (MEP pathway), and IaCPS and IaKSL (diterpenoid pathway) candidate genes in leaves and roots, may contribute to the high accumulation of Wangzaozins in I. amethystoides leaves. CONCLUSION: The genomic dataset and analyses reported here lay the foundations for further research on this important medicinal plant. PMID- 30409117 TI - Rapidly progressive renal failure due to tubulointerstitial infiltration of peripheral T-cell lymphoma, not otherwise specified accompanied by uveitis: a case report. AB - BACKGROUND: Rapid decline in renal dysfunction due to primary renal lymphoma, or secondary renal lymphoma by infiltration from a primary origin, is extremely rare. There are notably few reports indicating infiltration of T-cell lymphoma into the kidney. CASE PRESENTATION: A 61-year-old woman with a sudden body rash and liver dysfunction was brought to our hospital presenting with a dull headache and blurred vision. Laboratory tests revealed rapidly progressive renal failure. Histological examination of the kidney and skin indicated infiltration of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). Infiltration of PTCL-NOS to the liver and spleen, and presence of Uveitis masquerade syndrome were suspected. Imaging showed that the lesion was limited to extralymphatic organs. Renal function was improved with administration of steroids, including pulse steroid therapy, before administering cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) therapy. CONCLUSIONS: This is the first reported case of rapidly progressive renal failure caused by perivascular tubulointerstitial nephritis with the direct invasion of PTCL-NOS. In our case, a single steroid dose showed dramatic results with respect to renal symptoms. PMID- 30409118 TI - Cultural adaptation and harmonization of four Nordic translations of the revised Premature Infant Pain Profile (PIPP-R). AB - BACKGROUND: Preterm infants are especially vulnerable to pain. The intensive treatment often necessary for their survival unfortunately includes many painful interventions and procedures. Untreated pain can lead to both short- and long term negative effects. The challenge of accurately detecting pain has been cited as a major reason for lack of pain management in these non-verbal patients. The Premature Infant Pain Profile (PIPP) is one of the most extensively validated measures for assessing procedural pain in premature infants. A revised version, PIPP-R, was recently published and is reported to be more user-friendly and precise than the original version. The aims of the study were to develop translated versions of the PIPP-R in Finnish, Icelandic, Norwegian, and Swedish languages, and to establish their content validity through a cultural adaptation process using cognitive interviews. METHODS: PIPP-R was translated using the recommendations from the International Society for Pharmacoeconomics and Outcomes Research and enhanced with cognitive interviews. The respondent nurse was given a copy of the translated, national version of the measure and used this together with a text describing the infant in the film to assess the pain of an infant in a short film. During the assessment the nurse was asked to verbalize her thought process (thinking aloud) and upon completion the interviewer administered probing questions (verbal probing) from a structured interview guide. The interviews were recorded, transcribed, and analyzed using a structured matrix approach. RESULTS: The systematic approach resulted in translated and culturally adapted versions of PIPP-R in the Finnish, Icelandic, Norwegian and Swedish languages. During the cultural adaptation process several problems were discovered regarding how the respondent understood and utilized the measure. The problems were either measure problems or other problems. Measure problems were solved by a change in the translated versions of the measure, while for other problems different solutions such as education or training were suggested. CONCLUSIONS: This study have resulted in translations of the PIPP-R that have content validity, high degree of clinical utility and displayed beginning equivalence with each other and the original version of the measure. PMID- 30409119 TI - Spatially varying effects of predictors for the survival prediction of nonmetastatic colorectal Cancer. AB - BACKGROUND: An increasing number of studies have identified spatial differences in colorectal cancer survival. However, little is known about the spatially varying effects of predictors in survival prediction modeling studies of colorectal cancer that have focused on estimating the absolute survival risk for patients from a wide range of populations. This study aimed to demonstrate the spatially varying effects of predictors of survival for nonmetastatic colorectal cancer patients. METHODS: Patients diagnosed with nonmetastatic colorectal cancer from 2004 to 2013 who were followed up through the end of 2013 were extracted from the Surveillance Epidemiology End Results registry (Patients: 128061). The log-rank test and the restricted mean survival time were used to evaluate survival outcome differences among spatial clusters corresponding to a widely used clinical predictor: stage determined by AJCC 7th edition staging system. The heterogeneity test, which is used in meta-analyses, revealed the spatially varying effects of single predictors. Then, considering the above predictors in a standard survival prediction model based on spatially clustered data, the spatially varying coefficients of these models revealed that some covariate effects may not be constant across the geographic regions of the study. Then, two types of survival prediction models (a statistical model and a machine learning model) were built; these models considered the predictors and enabled survival prediction for patients from a wide range of geographic regions. RESULTS: Based on univariate and multivariate analysis, some prognostic factors, such as "TNM stage", "tumor size" and "age at diagnosis," have significant spatially varying effects among different regions. When considering these spatially varying effects, machine learning models have fewer assumption constraints (such as proportional hazard assumptions) and better predictive performance compared with statistical models. Upon comparing the concordance indexes of these two models, the machine learning model was found to be more accurate (0.898[0.895,0.902]) than the statistical model (0.732 [0.726, 0.738]). CONCLUSIONS: Based on this study, it's recommended that the spatially varying effect of predictors should be considered when building survival prediction models involving large-scale and multicenter research data. Machine learning models that are not limited by the requirement of a statistical hypothesis are promising alternative models. PMID- 30409120 TI - The effect of body mass index, lower extremity performance, and use of a private car on incident life-space restriction: a two-year follow-up study. AB - BACKGROUND: The purpose of the study was to explore the single and combined contributions of body mass index (BMI) and lower extremity performance as modifiable physical factors, and the influence of use of a private car as an environmental factor on prevalent and incident life-space restriction in community-dwelling older people. METHODS: Community-dwelling people aged 75-90 years (n = 823) participated in the Life-Space Mobility in Old Age (LISPE) two year follow-up study. Participants who reported that the largest life-space area they had attained, without aid from any device or another person, was the neighborhood or less were considered to have life-space restriction. Incident life-space restriction was the endpoint of Cox's proportional hazard model. BMI, lower extremity performance (Short Physical Performance Battery, SPPB), and use of a private car were predictors. RESULTS: At baseline, people who had both obesity (BMI >=30.0) and impaired lower extremity performance (SPPB 0-9) had a higher prevalence of life-space restriction (prevalence ratio 3.6, 95% confidence interval, CI, 2.0-6.3) compared to those with normal weight (BMI 23.0-24.9) and intact physical performance (SPPB 10-12). The 581 people without life-space restriction at the baseline contributed 1033 person-years during the two-year follow-up. Incident life-space restrictions were reported by 28.3% participants. A higher hazard ratio (HR) for incident life-space restriction was observed in subjects having both obesity and impaired lower extremity performance (HR 3.6, 95% CI, 1.7-7.4), impaired lower extremity performance only (HR 1.9, 95% CI 0.9 4.1), and obesity only (HR 1.8, 95% CI, 0.9-3.5) compared to those with normal weight and intact performance. Private car passengers (HR 2.0, 95% CI, 1.3-3.0) compared to car drivers had a higher risk of life-space restriction. All models were adjusted for age, sex, chronic diseases, and education. CONCLUSIONS: Older people with impaired lower extremity performance have an increased risk of incident life-space restriction especially if combined with obesity. Also, not driving a car renders older people vulnerable to life-space restriction. PMID- 30409121 TI - Multilevel analysis of factors associated with assistance during delivery in rural Nigeria: implications for reducing rural-urban inequity in skilled care at delivery. AB - BACKGROUND: Studies have observed rural-urban inequity in the use of skilled delivery in Nigeria. A number of studies have explicitly examined associated factors of assistance during delivery in rural areas. However, the studies so far conducted in rural Nigeria have investigated mainly individual-level characteristics with near exclusion of community-level characteristics. Also, most of the studies that have investigated community-level influence on use of maternal healthcare services in Nigeria did not isolate rural areas for specific research attention. The objective of this study was to investigate the individual level and community-level characteristics associated with assistance during delivery in rural Nigeria. METHODS: The study analysed women data of 2013 Nigeria Demographic and Health Survey. A weighted sample size of 12,665 rural women was analysed. The outcome variable was assistance during delivery, dichotomised into 'skilled assistance' and 'unskilled assistance'. The explanatory variables are selected individual-level characteristics (maternal education, parity, age at first birth, religion, healthcare decision, employment status, access to mass media, and means of transportation); and selected community-level characteristics (community literacy level, community childcare burden, proportion of women employed outside agriculture, proportion of women who perceived distance to facility as a big problem, community poverty level, and geographical region). The mixed-effects logistic regression was applied. RESULTS: During the most recent deliveries, 23.0% of rural women utilised skilled assistance compared with 77.0% who utilised unskilled assistance. Maternal education, parity, religion, healthcare decision, access to mass media, and means of transportation were the individual-level characteristics that revealed significant effects on the likelihood of utilising skilled assistance during delivery, while community literacy level, community poverty level, community perception of distance to health facility, and geographic region were the community-level characteristics that revealed significant effects on the odds of using skilled assistance during delivery. Results of Intra-Class Correlation (ICC) supported significant community-level effects on the likelihood of using skilled assistance during delivery. CONCLUSIONS: Assistance during delivery is influenced by individual level and community-level characteristics. Health policies and programmes seeking to reduce rural-urban inequity in skilled delivery should endeavour to identify and address important factors at both the individual and community levels of the social environment. PMID- 30409122 TI - Immune activation and regulatory T cells in Mycobacterium tuberculosis infected lymph nodes. AB - BACKGROUND: Lymph node tuberculosis (LNTB) is the most frequent extrapulmonary form of tuberculosis (TB). Studies of human tuberculosis at sites of disease are limited. LNTB provides a unique opportunity to compare local in situ and peripheral blood immune response in active Mycobacterium tuberculosis (Mtb) disease. The present study analysed T regulatory cells (Treg) frequency and activation along with CD4+ T cell function in lymph nodes from LNTB patients. RESULTS: Lymph node mononuclear cells (LNMC) were compared to autologous peripheral blood mononuclear cells (PBMC). LNMC were enriched for CD4+ T cells with a late differentiated effector memory phenotype. No differences were noted in the frequency and mutifunctional profile of memory CD4+ T cells specific for Mtb. The proportion of activated CD4+ and Tregs in LNMC was increased compared to PBMC. The correlation between Tregs and activated CD4+ T cells was stronger in LNMC than PBMC. Tregs in LNMC showed a strong positive correlation with Th1 cytokine production (IL2, IFNgamma and TNFalpha) as well as MIP-1alpha after Mtb antigen stimulation. A subset of Tregs in LNMC co-expressed HLA-DR and CD38, markers of activation. CONCLUSION: Further research will determine the functional relationship between Treg and activated CD4+ T cells at lymph node sites of Mtb infection. PMID- 30409124 TI - Pain score, desire for pain treatment and effect on pain satisfaction in the emergency department: a prospective, observational study. AB - BACKGROUND: Pain management in the Emergency Department has often been described as inadequate, despite proven benefits of pain treatment protocols. The aim of this study was to investigate the effectiveness of our current pain protocol on pain score and patient satisfaction whilst taking the patients' wishes for analgesia into account. METHODS: We conducted a 10-day prospective observational study in the Emergency Department. Demographics, pain characteristics, Numeric Rating Scale pain scores and the desire for analgesics were noted upon arrival at the Emergency Department. A second Numeric Rating Scale pain score and the level of patient satisfaction were noted 75-90 min after receiving analgesics. Student T-tests, Mann-Whitney U tests and Kruskall-Wallis tests were used to compare outcomes between patients desiring vs. not desiring analgesics or patients receiving vs. not receiving analgesics. Univariate and multivariate logistic regression models were used to investigate associations between potential predictors and outcomes. RESULTS: In this study 334 patients in pain were enrolled, of which 43.7% desired analgesics. Initial pain score was the only significant predictive factor for desiring analgesia, and differed between patients desiring (7.01) and not desiring analgesics (5.14). Patients receiving analgesics (52.1%) had a greater decrease in pain score than patients who did not receive analgesics (2.41 vs. 0.94). Within the group that did not receive analgesics there was no difference in satisfaction score between patients desiring and not desiring analgesics (7.48 vs. 7.54). Patients receiving analgesics expressed a higher satisfaction score than patients not receiving analgesics (8.10 vs. 7.53). CONCLUSIONS: This study pointed out that more than half of the patients in pain entering the Emergency Department did not desire analgesics. In patients receiving analgesics, our pain protocol has shown to adequately treat pain, leading to a higher satisfaction for emergency health-care at discharge. This study emphasizes the importance of questioning pain score and desire for analgesics to prevent incorrect conclusions of inadequate pain management, as described in previous studies. PMID- 30409123 TI - Evaluating gut microbiota profiles from archived fecal samples. AB - BACKGROUND: Associations between colorectal cancer and microbiota have been identified. Archived fecal samples might be valuable sample sources for investigating causality in carcinogenesis and biomarkers discovery due to the potential of performing longitudinal studies. However, the quality, quantity and stability of the gut microbiota in these fecal samples must be assessed prior to such studies. We evaluated i) cross-contamination during analysis for fecal blood and ii) evaporation in stored perforated fecal immunochemical tests (iFOBT) samples, iii) temperature stability as well as iv) comparison of the gut microbiota diversity and composition in archived, iFOBT and fresh fecal samples in order to assess feasibility of large scale microbiota studies. METHODS: The microbiota profiles were obtained by sequencing the V3-V4 region of 16S rDNA gene. RESULTS: The iFOBT does not introduce any cross-sample contamination detectable by qPCR. Neither could we detect evaporation during freeze-thaw cycle of perforated iFOBT samples. Our results confirm room temperature stability of the gut microbiome. Diverse microbial profiles were achieved in 100% of fresh, 81% of long-term archived and 96% of iFOBT samples. Microbial diversity and composition were comparable between fresh and iFOBT samples, however, diversity differed significantly between long-term archived, fresh and iFOBT samples. CONCLUSION: Our data showed that it is feasible to exploit archived fecal sample sets originally collected for testing of fecal blood. The advantages of using these sample sets for microbial biomarker discovery and longitudinal observational studies are the availability of high-quality diagnostic and follow up data. However, care must be taken when microbiota are profiled in long-term archived fecal samples. PMID- 30409125 TI - Is excess weight a burden for older adults who suffer chronic pain? AB - BACKGROUND: Obesity and chronic pain are common comorbidities and adversely influence each other. Advanced age is associated with more comorbidities and multi-morbidities. In this study, we investigated the burden of overweight/obesity and its comorbidities and their associations with chronic pain in a random population sample of Swedish older adults. METHODS: The cross sectional analysis involved a random sample of a population >= 65 years in south eastern Sweden (N = 6243). Data were collected from a postal questionnaire that addressed pain aspects, body mass index (BMI), and health experiences. Chronic pain was defined as pain during the previous three months. According to the 0-10 Numeric Rating Scale, pain scored >=7 corresponds to severe pain. Binary logistic regression was used to determine the variables associated to pain aspects. RESULTS: A total of 2633 (42%) reported chronic pain. More obese older adults (BMI >=30 kg/m2) experienced chronic pain (58%) than those who were low-normal weight (BMI < 25 kg/m2, 39%) or overweight (25 <= BMI < 30 kg/m2, 41%). Obese elderly more frequently had pain in extremities and lower back than their peers. In the multivariate model, obesity (Odds Ratio (OR) 1.59, 95% Confidence Interval (CI) 1.33-1.91) but not overweight (OR 1.08, 95% CI 0.95-1.22) was associated with chronic pain. Obesity (OR 1.53, 95% CI 1.16-2.01) was also significantly related to severe pain. We also found other comorbidities - i.e., traumatic history (OR 2.52, 95% CI 1.99-3.19), rheumatic diseases (OR 5.21, 95% CI 4.54 5.97), age >= 85 years (OR 1.66, 95% CI 1.22-2.25), and depression or anxiety diagnosis (OR 1.83, 95% CI 1.32-2.53) - showed stronger associations with pain aspects than weight status. CONCLUSION: In older adults, excess weight (BMI 30 or above) is a potentially modifiable factor but not the only risk factor that is associated with chronic pain and severe pain. Future studies should investigate the effectiveness of interventions that treat comorbid pain and obesity in older adults. PMID- 30409127 TI - Nomogram for predicting preoperative lymph node involvement in patients with invasive micropapillary carcinoma of breast: a SEER population-based study. AB - BACKGROUND: Invasive micropapillary carcinoma (IMPC) is an unusual and distinct subtype of invasive breast tumor with high propensity for regional lymph node metastases. This study was to identify risk factors accounting for IMPC of the breast and to develop a nomogram to preoperatively predict the probability of lymph node involvement. METHODS: A retrospective review of the clinical and pathology records was performed in patients diagnosed with IMPC between 2003 and 2014 from Surveillance, Epidemiology, and End Results (SEER) database. The cohort was divided into training and validation sets. Training set comprised patients diagnosed between 2003 and 2009, while validation set included patients diagnosed thereafter. A logistic regression model was used to construct the nomogram in the training set and then varified in the validation set. Nomogram performance was quantified with respect to discrimination and calibration using R 3.4.1 software. RESULTS: Overall, 1407 patients diagnosed with IMPC were enrolled, of which 527 in training set and 880 in validation set. Logistic regression analysis indicated larger lesions, younger age at diagnosis, black ethnic and lack of hormone receptor expression were significantly related to regional nodes involvement. The AUC of the nomogram was 0.735 (95% confidential interval (CI) 0.692 to 0.777), demonstrating a good prediction performance. Calibration curve for the nomogram was plotted and the slope was close to 1, which demonstrated excellent calibration of the nomogram. The performance of the nomogram was further validated in the validation set, with AUC of 0.748 (95% CI 0.701 to 0.767). CONCLUSIONS: The striking difference between IMPC and IDC remains the increased lymph node involvement in IMPC and therefore merits aggressive treatment. The nomogram based on the clinicalpathologic parameters was established, which could accurately preoperatively predict regional lymph node status. This nomogram would facilitate evaluating lymph node state preoperatively and thus treatment decision making of individual patients. PMID- 30409126 TI - Immunotherapy for non-small cell lung cancers: biomarkers for predicting responses and strategies to overcome resistance. AB - Recent breakthroughs in targeted therapy and immunotherapy have revolutionized the treatment of lung cancer, the leading cause of cancer-related deaths in the United States and worldwide. Here we provide an overview of recent progress in immune checkpoint blockade therapy for treatment of non-small cell lung cancer (NSCLC), and discuss biomarkers associated with the treatment responses, mechanisms underlying resistance and strategies to overcome resistance. The success of immune checkpoint blockade therapies is driven by immunogenicity of tumor cells, which is associated with mutation burden and neoantigen burden in cancers. Lymphocyte infiltration in cancer tissues and interferon-gamma-induced PD-L1 expression in tumor microenvironments may serve as surrogate biomarkers for adaptive immune resistance and likelihood of responses to immune checkpoint blockade therapy. In contrast, weak immunogenicity of, and/or impaired antigen presentation in, tumor cells are primary causes of resistance to these therapies. Thus, approaches that increase immunogenicity of cancer cells and/or enhance immune cell recruitment to cancer sites will likely overcome resistance to immunotherapy. PMID- 30409128 TI - Lung-infiltrating T helper 17 cells as the major source of interleukin-17A production during pulmonary Cryptococcus neoformans infection. AB - BACKGROUND: IL-17A has emerged as a key player in the pathologies of inflammation, autoimmune disease, and immunity to microbes since its discovery two decades ago. In this study, we aim to elucidate the activity of IL-17A in the protection against Cryptococcus neoformans, an opportunistic fungus that causes fatal meningoencephalitis among AIDS patients. For this purpose, we examined if C. neoformans infection triggers IL-17A secretion in vivo using wildtype C57BL/6 mice. In addition, an enhanced green fluorescence protein (EGFP) reporter and a knockout (KO) mouse models were used to track the source of IL-17A secretion and explore the protective function of IL-17A, respectively. RESULTS: Our findings showed that in vivo model of C. neoformans infection demonstrated induction of abundant IL-17A secretion. By examining the lung bronchoalveolar lavage fluid (BALF), mediastinal lymph node (mLN) and spleen of the IL-17A-EGFP reporter mice, we showed that intranasal inoculation with C. neoformans promoted leukocytes lung infiltration. A large proportion (~ 50%) of the infiltrated CD4+ helper T cell population secreted EGFP, indicating vigorous TH17 activity in the C. neoformans infected lung. The infection study in IL-17A-KO mice, on the other hand, revealed that absence of IL-17A marginally boosted fungal burden in the lung and accelerated the mouse death. CONCLUSION: Therefore, our data suggest that IL-17A is released predominantly from TH17 cells in vivo, which plays a supporting role in the protective immunity against C. neoformans infection. PMID- 30409129 TI - Performance of a feature-based algorithm for 3D-3D registration of CT angiography to cone-beam CT for endovascular repair of complex abdominal aortic aneurysms. AB - BACKGROUND: A crucial step in image fusion for intraoperative guidance during endovascular procedures is the registration of preoperative computed tomography angiography (CTA) with intraoperative Cone Beam CT (CBCT). Automatic tools for image registration facilitate the 3D image guidance workflow. However their performance is not always satisfactory. The aim of this study is to assess the accuracy of a new fully automatic, feature-based algorithm for 3D3D registration of CTA to CBCT. METHODS: The feature-based algorithm was tested on clinical image datasets from 14 patients undergoing complex endovascular aortic repair. Deviations in Euclidian distances between vascular as well as bony landmarks were measured and compared to an intensity-based, normalized mutual information algorithm. RESULTS: The results for the feature-based algorithm showed that the median 3D registration error between the anatomical landmarks of CBCT and CT images was less than 3 mm. The feature-based algorithm showed significantly better accuracy compared to the intensity-based algorithm (p < 0.001). CONCLUSION: A feature-based algorithm for 3D image registration is presented. PMID- 30409130 TI - Regional differences and determinants of self-rated health in a lower middle income rural Society of China. AB - OBJECTIVE: Self-rated health represents a reliable and important health measure related to general health and quality of life. This study aimed to identify the differences of health states of rural residents in a lower middle income setting in China and its associated factors. METHODS: A descriptive study of a stratified random sample of 3870 individuals was conducted in rural Anhui during 2015. We investigated the influence of five independent variables: individual demographic characteristics, family factors, social capital traits, physical health conditions and healthy lifestyle habits of participants who self-related their health as good. A chi-square test and ordinal logistic regression analyses were used to identify the relationship of these variables and self-rated health. RESULTS: The study found that respondents who negatively rated their health often were female, elderly, poor, lived alone, had low levels of education, inadequate social support, poor physical health, used healthcare services and lived in the lower economic regions. We found no significant correlations between self-rated health and employment, marital status, medical insurance, or exercise frequency. Surprisingly, smoking and drinking also seemed to be unrelated to poor self reported health. CONCLUSION: Health differences based on region were apparent in rural China. We highlighted the possible impacts of income, age, physical health, education, advanced age, and social support on health. The results from this study could inform the delivery of appropriate health and social healthcare interventions to promote rural residents' health and quality of life. PMID- 30409131 TI - Immunomodulatory effects of intraoperative dexmedetomidine on T helper 1, T helper 2, T helper 17 and regulatory T cells cytokine levels and their balance: a prospective, randomised, double-blind, dose-response clinical study. AB - BACKGROUND: The ratio of T helper 1 (Th1) to T helper 2 (Th2) as well as T helper 17 (Th17) to regulatory T cells (Treg) represents the state and direction of immune response. Recent studies demonstrated that dexmedetomidine reduced the secretion of inflammatory cytokines. We performed this study to investigate the effect of different doses of intraoperative dexmedetomidine on the expression of Th1, Th2, T17 and Treg cytokines and their ratios. METHODS: Seventy-five patients undergoing laparoscopic cholecystectomy were randomly separated into one of three groups: the full dose group (n = 25), in which dexmedetomidine was infused with a 1.0 MUg/kg loading followed by an infusion of 0.5 MUg/kg/min after anaesthetic induction, or the half dose group (n = 26), in which the dose was half of that of full dose group, or the saline group (n = 24) which was control. T cell cytokines were quantified by sandwich enzyme-linked immunoassay for blood samples taken after anaesthetic induction (T0), at the end of surgery (T1), and 60 min after surgery (T2). IFN-gamma/IL-4 and IL-17/IL-10, which represent the ratio of Th1/Th2 and Th17/Treg cytokines, respectively, were calculated as indices of immune cell levels based upon serum cytokines levels in place of direct measurements. C-reactive protein (CRP) concentrations were measured on the next day following surgery. RESULTS: The full dose group was associated with higher ratios of IFN-gamma/IL-4 than those of half dose group and control [10.1 vs. 1.9 at T1 (P = 0.041) compared with half dose group, and 10.1 vs. 0.2 at T1 (P = 0.031), 7.4 vs. 0.1 at T2 (P = 0.025) compared with control]. IL-17/IL-10 ratios were higher in the full dose group than those in control [4.2 vs. 0.6 at T1 (P = 0.013), 3.0 vs. 0.3 at T2 (P = 0.011)]. The CRP levels were lower in the dexmedetomidine-treated groups in a dose-dependent manner. CONCLUSIONS: Dexmedetomidine exhibits immunomodulatory effects, shifting the Th1/Th2 and T17/Treg cytokine balance toward Th1 and T17, respectively, in a dose-dependent pattern in patients with surgical and anaesthetic stress. TRIAL REGISTRATION: Clinical Research Information Service, Republic of Korea (CRIS); KCT0000503 ; Registration date: Aug 13, 2012. PMID- 30409133 TI - Lavandula stoechas essential oils protect against Malathion-induces reproductive disruptions in male mice. AB - BACKGROUND: The current study was conducted to evaluate the protective effect of Lavandula stoechas essential oils (LSEO) against malathion (M) exposure-caused reprotoxicity in male mice as well as the possible mechanisms implicated in such protection. METHODS: Six-eight-week-old male mice weighting 25-30 g were used and divided into four groups: normal-control, LSEO (50 mg/kg, b.w.), malathion (200 mg/kg, b.w.) and malathion + LSEO treated mice. Malathion was emulsioned in corn oil and per orally administered for 30 days. LSEO was daily administrated during the same period. LSEO chemical identification was done by Gas chromatography-mass spectrometry (GC-MS). Reproduction-damages and LSEO-benefits were assessed using histopathological, biochemical and steroidogenesis gene expression disruptions and improvements. RESULTS: The GC-MS analysis, allowed to the identification of 25 bioactive compounds in MCEO. In vivo, we firstly found that malathion exposure induced a clear reprotoxicity as assessed by a significant-decrease (P < 0.05) of testis/epididymis relative weights, serum testosterone level and reproductive performance. Malathion also produced lipoperoxidation, thiol (-SH) groups decrease as well as a significant-depletion (P < 0.05) of antioxidant enzyme activities such as catalase (CAT) and glutathione peroxidase (GPx), total superoxide dismutase (SOD), Cu/Zn-SOD and Mn-SOD in testis and epididymis. The histopathological examination showed marked change in both studied tissues. All these biochemical and structural changes were significantly (P < 0.05) corrected by LSEO co-administration. More importantly, malathion exposure remarkably (P < 0.05) down-regulated the expression of StAR gene as well as, the mRNA levels of P450scc, 3betaHSD and 17beta-HSD, while LSEO-administration strangely protected against steroidogenesis disruption. CONCLUSIONS: The potential protective effects of LSEO against malathion-induced reprotoxicity and oxidative stress might be partially to its antioxidant properties as well as its opposite effect against some gene expression involved in the steroidogenesis. PMID- 30409132 TI - Female sex reduces the risk of hospital-associated acute kidney injury: a meta analysis. AB - BACKGROUND: Female sex has been included as a risk factor in models developed to predict the development of AKI. In addition, the commentary to the Kidney Disease Improving Global Outcomes Clinical Practice Guideline for AKI concludes that female sex is a risk factor for hospital-acquired AKI. In contrast, a protective effect of female sex has been demonstrated in animal models of ischemic AKI. METHODS: To further explore this issue, we performed a meta-analysis of AKI studies published between January, 1978 and April, 2018 and identified 83 studies reporting sex-stratified data on the incidence of hospital-associated AKI among nearly 240,000,000 patients. RESULTS: Twenty-eight studies (6,758,124 patients) utilized multivariate analysis to assess risk factors for hospital-associated AKI and provided sex-stratified ORs. Meta-analysis of this cohort showed that the risk of developing hospital-associated AKI was significantly greater in men than in women (OR 1.23 (1.11,1.36). Since AKI is not a single disease but instead represents a heterogeneous group of disorders characterized by an acute reduction in renal function, we performed subgroup meta-analyses. The association of male sex with AKI was strongest among studies of patients who underwent non-cardiac surgery. Male sex was also associated with AKI in studies which included unselected hospitalized patients and in studies of critically ill patients who received care in an intensive care unit. In contrast, cardiac surgery-associated AKI and radiocontrast-induced AKI showed no sexual dimorphism. CONCLUSIONS: Our meta-analysis contradicts the established belief that female sex confers a greater risk of AKI and instead suggests a protective role. PMID- 30409134 TI - Risk factors for the presence of Fasciola hepatica antibodies in bulk-milk samples and their association with milk production decreases, in Cuban dairy cattle. AB - BACKGROUND: Worldwide, Fasciola hepatica infection causes high production losses in the livestock industry. Recently, studies have analyzed the association between measurements of F. hepatica infection intensity and herd management practices. The aim of the present study, the first of its kind in a subtropical region, was to evaluate associations between F. hepatica bulk-tank milk ELISA results with herd management factors and milk yield in dairy herds, in Camaguey, Cuba. The SVANOVIR(r) F. hepatica-AB ELISA was used to measure F. hepatica antibody levels in a random sample of 516 dairy herds during the period of May July of 2014. Farm management practice data were collected using a questionnaire. RESULTS: With 82% of the herds testing positive, the results indicate that F. hepatica is very widespread in this area. Reductions in milk production of 18 and 32% were observed in herds with Optical Density Ratios (ODR) of 0.3-0.6 and > 0.6, respectively, when compared to herds with ODR < 0.3. Overall, the longer the milking cows were put out to pasture, the higher the levels of anti-parasite antibodies. Co-grazing with sheep and goats also significantly increased the risk of high ODR. CONCLUSIONS: Our data show a widespread occurrence of the parasite as well as a major potential impact of the infection on the Cuban development goal of becoming self-sufficient in milk production. Our risk factor analysis suggests that the prevention of infection around water sources, and the separation of cattle from small ruminants could be useful control measures. This is the first epidemiological survey of F. hepatica abundance, and associated reductions in milk yield, in dairy herds in Cuba. PMID- 30409136 TI - G6PD deficiency, primaquine treatment, and risk of haemolysis in malaria-infected patients. AB - BACKGROUND: The incidence of malaria in the Americas has decreased markedly in recent years. Honduras and the other countries of Mesoamerica and the island of Hispaniola have set the goal of eliminating native malaria by the year 2020. To achieve this goal, Honduras has recently approved national regulations to expand the possibilities of a shortened double dose primaquine (PQ) treatment for vivax malaria. Considering this new shortened anti-malarial treatment, the high frequency of G6PDd genotypes in Honduras, and the lack of routinely assessment of the G6PD deficiency status, this study aimed at investigating the potential association between the intake of PQ and haemolysis in malaria-infected G6PDd subjects. METHODS: This was a prospective cohort and open-label study. Participants with malaria were recruited. Plasmodium vivax infection was treated with 0.25 mg/kg of PQ daily for 14 days. Safety and signs of haemolysis were evaluated by clinical criteria and laboratory values before and during the 3rd and 7th day of PQ treatment. G6PD status was assessed by a rapid test (CareStartTM) and two molecular approaches. RESULTS: Overall 55 participants were enrolled. The frequency of G6PD deficient genotypes was 7/55 (12.7%), where 5/7 (71.4%) were hemizygous A- males and 2/7 (28.6%) heterozygous A- females. Haemoglobin concentrations were compared between G6PD wild type (B) and G6PDd A- subjects, showing a significant difference between the means of both groups in the 3rd and 7th days. Furthermore, a statistically significant difference was evident in the change in haemoglobin concentration between the 3rd day and the 1st day for both genotypes, but there was no statistical difference for the change in haemoglobin concentration between the 7th day and the 1st day. Besides these changes in the haemoglobin concentrations, none of the patients showed signs or symptoms associated with severe haemolysis, and none needed to be admitted to a hospital for further medical attention. CONCLUSIONS: The findings support that the intake of PQ during 14 days of treatment against vivax malaria is safe in patients with a class III variant of G6PDd. In view of the new national regulations in the shortened treatment of vivax malaria for 7 days, it is advisable to be alert of potential cases of severe haemolysis that could occur among G6PD deficient hemizygous males with a class II mutation such as the Santamaria variant, previously reported in the country. PMID- 30409135 TI - RNA-seq analysis reveals considerable genetic diversity and provides genetic markers saturating all chromosomes in the diploid wild wheat relative Aegilops umbellulata. AB - BACKGROUND: Aegilops umbellulata Zhuk. (2n = 14), a wild diploid wheat relative, has been the source of trait improvement in wheat breeding. Intraspecific genetic variation of Ae. umbellulata, however, has not been well studied and the genomic information in this species is limited. RESULTS: To develop novel genetic markers distributed over all chromosomes of Ae. umbellulata and to evaluate its genetic diversity, we performed RNA sequencing of 12 representative accessions and reconstructed transcripts by de novo assembly of reads for each accession. A large number of single nucleotide polymorphisms (SNPs) and insertions/deletions (indels) were obtained and anchored to the pseudomolecules of Ae. tauschii and barley (Hordeum vulgare L.), which were regarded as virtual chromosomes of Ae. umbellulata. Interestingly, genetic diversity in Ae. umbellulata was higher than in Ae. tauschii, despite the narrow habitat of Ae. umbellulata. Comparative analyses of nucleotide polymorphisms between Ae. umbellulata and Ae. tauschii revealed no clear lineage differentiation and existence of alleles with rarer frequencies predominantly in Ae. umbellulata, with patterns clearly distinct from those in Ae. tauschii. CONCLUSIONS: The anchored SNPs, covering all chromosomes, provide sufficient genetic markers between Ae. umbellulata accessions. The alleles with rarer frequencies might be the main source of the high genetic diversity in Ae. umbellulata. PMID- 30409137 TI - EQ-5D-5L norms for the urban Chinese population in China. AB - BACKGROUND: To generate Chinese population norms for the EQ-5D-5L dimensions, EQ VAS (Visual Analogue Scale) scores and EQ-5D-5L index scores, stratified by gender and age. The EQ-5D is a widely used generic health-related quality of life instrument to describe population health and health outcomes in clinical trials and health economic evaluations. Currently, there are no EQ-5D-5L population norms for China. METHODS: This norm study utilized the data collected in an EQ-5D 5L valuation study in China between December 2012 and January 2013. In the valuation study, respondents were asked to report their own health states using the EQ-5D-5L descriptive system and the EQ-VAS. Respondents' demographic information was also collected. The EQ index score was calculated using the EQ-5D 5L value set based on the Chinese urban population. Norm scores were reported by important demographic variables. RESULTS: The mean EQ-VAS scores ranged between 88.3 for males of < 19 years and 82.9 for females of 60-69 years. Contrary to other population studies, females reported higher EQ-VAS scores than males in every age group except for 20-29 years. The mean EQ-5D-5L index values ranged from 0.912 for females of > 70 years to 0.971 for females of 30-39 years. Respondents reported more problems in the dimensions 'pain/discomfort' and 'anxiety/depression' than in the dimensions 'mobility', 'self-care' and 'usual activities' in all age groups. CONCLUSIONS: The population norm scores for the EQ 5D can be used as reference values for comparative purposes in future Chinese studies. Further research into rural and/or a more representative population is warranted. PMID- 30409138 TI - Assessment of drug resistance associated genetic diversity in Mauritanian isolates of Plasmodium vivax reveals limited polymorphism. AB - BACKGROUND: Plasmodium vivax is the predominant malaria species in northern Mauritania. Molecular data on P. vivax isolates circulating in West Africa are scarce. The present study analysed molecular markers associated with resistance to antifolates (Pvdhfr and Pvdhps), chloroquine (Pvmdr1), and artemisinin (Pvk12) in P. vivax isolates collected in two cities located in the Saharan zone of Mauritania. METHODS: Blood samples were obtained from P. vivax-infected patients recruited for chloroquine therapeutic efficacy study in 2013 and febrile patients spontaneously consulting health facilities in Nouakchott and Atar in 2015-2016. Fragments of Pvdhfr (codons 13, 33, 57, 58, 61, 117, and 174), Pvdhps (codons 382, 383, 512, 553, and 585), Pvmdr1 (codons 976 and 1076) and Pvk12 (codon 552) genes were amplified by PCR and sequenced. RESULTS: Most of the isolates in Nouakchott (126/154, 81.8%) and Atar (44/45, 97.8%) carried the wild-type Pvdhfr allelic variant (IPFSTSI). In Nouakchott, all mutants (28/154; 18.2%) had double Pvdhfr mutations in positions 58 and 61 (allelic variant IPFRMSI), whereas in Atar only 1 isolate was mutant (S117N, allelic variant IPFSTNI). The wild-type Pvdhps allelic variant (SAKAV) was found in all tested isolates (Nouakchott, n = 93; Atar, n = 37). Few isolates in Nouakchott (5/115, 4.3%) and Atar (3/79, 3.8%) had the mutant Pvmdr1 allele 976F or 1076L, but not both, including in pre treatment isolates obtained from patients treated successfully with chloroquine. All isolates (59 in Nouakchott and 48 in Atar) carried the wild-type V552 allele in Pvk12. CONCLUSIONS: Polymorphisms in Pvdhfr, Pvdhps, Pvmdr1, and Pvk12 were limited in P. vivax isolates collected recently in Nouakchott and Atar. Compared to the isolates collected in Nouakchott in 2007-2009, there was no evidence for selection of mutants. The presence of one, but not both, of the two potential markers of chloroquine resistance in Pvmdr1 in pre-treatment isolates did not influence the clinical outcome, putting into question the role of Pvmdr1 mutant alleles 976F and 1076L in treatment failure. Molecular surveillance is an important component of P. vivax malaria control programme in the Saharan zone of Mauritania to predict possible emergence of drug-resistant parasites. PMID- 30409139 TI - Correction to: Semivariogram and Semimadogram functions as descriptors for AMD diagnosis on SD-OCT topographic maps using Support Vector Machine. AB - After publication, it was highlighted that the original publication [1] contained a spelling mistake in the first name of Marcelo Gattas. This was incorrectly captured as Marelo Gattass in the original article which has since been updated. PMID- 30409141 TI - A step forward for an attenuated blood-stage malaria vaccine. AB - Efforts to develop an effective malaria vaccine have encountered multiple challenges, and have had limited success to date. As the need remains urgent, novel approaches must be explored. One concept that has gained attention uses whole malaria parasites. Building on preclinical studies in animal models, Stanisic et al. describe the development of a vaccine based on chemically attenuated Plasmodium falciparum blood-stage parasites, with an evaluation of safety and immunogenicity in malaria-naive human subjects. The vaccine was shown to be safe, well tolerated, and capable of priming antigen-specific T cells. This work, and the completion of an initial clinical trial in human subjects, represents a significant advance. While the path forward for this attenuated vaccine remains challenging, these initial findings are encouraging. Importantly, the results provide the foundation and framework for testing modified immunization protocols, and designing subsequent clinical trials to further evaluate safety, test for enhanced immunogenicity, and ultimately measure protective efficacy.Please see related article: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-018-1173-9. PMID- 30409140 TI - Characterization and monitoring of deltamethrin-resistance in Anopheles culicifacies in the presence of a long-lasting insecticide-treated net intervention. AB - BACKGROUND: Deltamethrin-impregnated, long-lasting insecticidal nets (LLINs) were distributed in the study area from November 2014 to January 2015 to evaluate their impact on malaria transmission in the presence of insecticide-resistant vectors. Studies were carried out in 16 selected clusters in Keshkal sub district, Chhattisgarh State, India to monitor and characterize deltamethrin resistance in Anopheles culicifacies sensu lato. RESULTS: Deltamethrin susceptibility of An. culicifacies decreased in a post-LLIN survey compared to a pre-LLIN survey and was not significant (p > 0.05) while, the knockdown values showed significant increase (p < 0.05). Pre-exposure to piperonyl butoxide, triphenyl phosphate showed synergism against deltamethrin (p < 0.001). Biochemical assays showed significantly (p < 0.05) elevated monooxygenases in 3 of 5 clusters in post-LLIN survey-I that increased to 10 of 11 clusters in post LLIN survey-II, while esterases were found significantly elevated in all clusters and both enzymes were involved in conferring pyrethroid resistance, not discounting the involvement of kdr (L1014L/S) gene that was heterozygous and at low frequency (4-5%). CONCLUSION: This field study, in a tribal district of India, after distribution of deltamethrin-impregnated LLINs showed decrease in deltamethrin susceptibility in An. culicifacies, a major vector of malaria in this study area and in India. Results indicated development of resistance as imminent with the increase in insecticide selection pressure. There is an urgent need to develop new vector control tools, with insecticide classes having novel mechanisms of resistance, to avoid or delay the onset of resistance. Regular insecticide resistance monitoring and mechanistic studies should be the priority for the malaria control programmes to suggest strategies for insecticide resistance management. The global commitment to eliminate malaria by 2030 needs various efforts that include development of combination vector control products and interventions and few are becoming available. PMID- 30409142 TI - Circulating serotonin levels in COPD patients: a pilot study. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major and increasing global health problem. Serotonin is a neurotransmitter that participates in several pulmonary functions and it has been involved in oxidative stress, which plays essential roles in the pathogenesis of COPD. The current study aimed at establishing the levels of circulating serotonin in COPD, and investigating eventual relations between serotonin and oxidative stress markers. METHODS: Whole blood serotonin was assessed in 43 consecutive patients with stable COPD and in 43 age and sex-matched healthy controls. RESULTS: Serotonin blood levels were significantly higher in COPD patients than in controls (median 0.81 MUmol/L, IQR: 0.61-4.02 vs 0.65 MUmol/L, IQR: 0.53-1.39, p = 0.02). The univariate logistic regression analysis evidenced that serotonin levels are independently associated with presence of COPD (crude OR = 7.29, 95% CI: 1.296 41.05, p = 0.003) and such an association was confirmed also after adjusting for several confounders (OR 21.92, 95% CI 2.02-237.83; p = 0.011). CONCLUSIONS: Our study showed higher levels of circulating serotonin in COPD and an inverse correlation with the worsening of airway obstruction. Future studies are necessary to investigate the clinical utility of this finding. PMID- 30409144 TI - How social and geographical backgrounds affect hospital admission with a serious condition: a comparison of 11 immigrant groups with native-born Norwegians. AB - BACKGROUND: The foreign-born population in Norway displays considerable diversity in terms of source country, socioeconomic status and settlement experience. This study assessed the consequences of this diversity for the risk of being admitted to hospital with a serious condition. To what extent could variations between immigrant and native-born hospitalisation patterns be accounted for by variations in income, education and residential area characteristics? METHODS: The study linked information on socioeconomic and geographical level-of-living factors involving 2,820,283 individuals between 20 and 69 years old to hospital admissions recorded in Norway's National Patient Registry. Immigrants from 11 of the most frequently represented countries were included. The outcome variable consisted of a selection of relatively serious diagnoses (neoplasms and endocrine, circulatory and respiratory diseases), totalling 548,140 admissions from 2008 to 2011. Age- and gender-adjusted admission rates were analysed using a Poisson regression. RESULTS: The adjustments for income and education reduced the hospitalisation rates of almost all immigrant groups. The groups whose previous rates were above native-born rates moved towards the Norwegian reference, whereas groups that initially had lower age- and gender-adjusted rates compared with the Norwegian-born population increased the distance to the Norwegian reference. The risk of hospitalisation among most immigrant groups decreased compared with the Norwegian-born population when their income and educational levels were accounted for. Particularly, immigrants with lower levels of income or education tended to have relatively low hospitalisation rates, indicating the possibility of a healthy immigrant effect. While many immigrant groups used less somatic healthcare than the native-born population did, higher educational or income levels did not prevent hospitalisation to the same extent as they did for the native-born population. CONCLUSIONS: Although adjustments for socioeconomic factors tended towards lower hospitalisation rates for most immigrant groups, the adjustments did not reduce the considerable variations among individual countries. PMID- 30409146 TI - Larvivorous potentiality of Puntius tetrazona and Hyphessobrycon rosaceus against Culex vishnui subgroup in laboratory and field based bioassay. AB - OBJECTIVES: This study assessed the predatory potentiality of two unexplored fishes, Puntius tetrazona and Hyphessobrycon rosaceus on Culex vishnui subgroup larvae in order to utilize natural resources to diminish mosquito population. Larval feeding rate was evaluated in laboratory under varying prey density and volume of water. The experiment was extended to semi field condition. RESULTS: Puntius tetrazona and H. rosaceus consumed from 66 to 600 and from 87 to 718 Cx. vishnui larvae respectively in laboratory condition at 10 prey density levels (100-1000 larvae) at an increment of 100 larvae at 2 l water volume. In semi field condition, a 78% reduction in larval density was observed at day 30 post introduction of P. tetrazona, whereas 91% reduction was noted on day 21 for H. rosaceus and in the subsequent samples no mosquito larvae were found in ditches. Withdrawal of predators from the ditches resulted gradual increase in larval density. Laboratory and semi field bioassay of both the species indicated their potentiality as efficient mosquito larval predator though H. rosaceus exhibited better performance than P. tetrazona. It is recommended to utilize these natural resources to diminish mosquito population in the countries of their native range. PMID- 30409145 TI - Right heart size and function significantly correlate in patients with pulmonary arterial hypertension - a cross-sectional study. AB - BACKGROUND: The objective of this study was to assess, whether right atrial (RA) and ventricular (RV) size is related to RV pump function at rest and during exercise in patients with pulmonary arterial hypertension (PAH). METHODS: We included 54 patients with invasively diagnosed PAH that had been stable on targeted medication. All patients underwent clinical assessments including right heart catheterization and echocardiography at rest and during exercise. RV output reserve was defined as increase of cardiac index (CI) from rest to peak exercise (?CIexercise). Patients were classified according to the median of RA and RV area. RV pump function and further clinical parameters were compared between groups by student's t-test. Uni- and multivariate Pearson correlation analyses were performed. RESULTS: Patients with larger RA and/or RV-areas (above a median of 16 and 20cm2, respectively) showed significantly lower ?CIexercise, higher mean pulmonary arterial pressure, pulmonary vascular resistance at rest and NT proBNP levels. Furthermore, patients with higher RV-areas presented with a significantly lower RV stroke volume and pulmonary arterial compliance at peak exercise than patients with smaller RV-size. RV area was identified as the only independent predictor of RV output reserve. CONCLUSION: RV and RA areas represent valuable and easily accessible indicators of RV pump function at rest and during exercise. Cardiac output reserve should be considered as an important clinical parameter. Prospective studies are needed for further evaluation. PMID- 30409143 TI - Helicobacter pylori outer membrane vesicles involvement in the infection development and Helicobacter pylori-related diseases. AB - Helicobacter pylori - (H. pylori) play a role in the pathogenesis of gastritis, gastric and duodenal ulcers as well as gastric cancer. A possible involvement of outer membrane vesicles (OMVs) produced by H. pylori in the distribution of bacterial antigens through the gastric epithelial barrier and their role in the development of local and systemic host inflammatory and immune responses has been suggested. OMVs contain various biologically active compounds, which internalize into host cells affecting signaling pathways and promoting apoptosis of gastric epithelial and immunocompetent cells. OMVs-associated H. pylori virulence factors may strengthen or downregulate the immune responses leading to disease development. This review describes the biological importance of H. pylori OMVs and their role in the course of H. pylori infections, as well as H. pylori related local and systemic effects. PMID- 30409148 TI - Self-care practices and associated factors among diabetes patients attending the outpatient department in Bahir Dar, Northwest Ethiopia. AB - OBJECTIVE: The aim of this study was to assess diabetes self-care practice and associated factors among diabetes patients attending Felege-Hiwot Referral Hospital, Bahir Dar, Northwest Ethiopia. RESULT: Prevalence of desirable self care behaviors toward Diabetes Mellitus was 28.4% (95% CI 24.0-32.7%). There were significant association between the combined treatment modality of tablet with insulin (AOR: 2.72; 95% CI 1.01, 7.40), primary and secondary education level (AOR: 4.82; 95% CI 1.88, 12.35 and AOR: 3.08; 95% CI 1.26, 7.53, respectively). A considerable number of the patients had poor self-care practice, especially lack of social support and treatment modality, which have critical roles in controlling diabetes. Therefore, attention should be given to improve self-care practice. PMID- 30409147 TI - Exposure to mild blast forces induces neuropathological effects, neurophysiological deficits and biochemical changes. AB - Direct or indirect exposure to an explosion can induce traumatic brain injury (TBI) of various severity levels. Primary TBI from blast exposure is commonly characterized by internal injuries, such as vascular damage, neuronal injury, and contusion, without external injuries. Current animal models of blast-induced TBI (bTBI) have helped to understand the deleterious effects of moderate to severe blast forces. However, the neurological effects of mild blast forces remain poorly characterized. Here, we investigated the effects caused by mild blast forces combining neuropathological, histological, biochemical and neurophysiological analysis. For this purpose, we employed a rodent blast TBI model with blast forces below the level that causes macroscopic neuropathological changes. We found that mild blast forces induced neuroinflammation in cerebral cortex, striatum and hippocampus. Moreover, mild blast triggered microvascular damage and axonal injury. Furthermore, mild blast caused deficits in hippocampal short-term plasticity and synaptic excitability, but no impairments in long-term potentiation. Finally, mild blast exposure induced proteolytic cleavage of spectrin and the cyclin-dependent kinase 5 activator, p35 in hippocampus. Together, these findings show that mild blast forces can cause aberrant neurological changes that critically impact neuronal functions. These results are consistent with the idea that mild blast forces may induce subclinical pathophysiological changes that may contribute to neurological and psychiatric disorders. PMID- 30409149 TI - The roll-out of a health insurance program and its impact on the supply of healthcare services: a new method to evaluate time-varying continuous interventions. AB - BACKGROUND: We analyze the effects of the Mexican universal health insurance program, Seguro Popular, on key variables associated with the provision of healthcare services. Given that the program was introduced gradually over a period that lasted more than a decade, the dynamics of the roll-out of the program and its reaction to the expansion of healthcare services it caused should be accounted for when evaluating the program. METHODS: We present a new semiparametric procedure to analyze time-varying continuous interventions. This is accomplished by bringing together the literatures on continuous and on dynamic treatments. Our approach allows the researcher to estimate mean and quantile dose response functions by applying local regression methods to appropriately weighted samples that control for time-dependent confounding. RESULTS: Using administrative data, we show compelling evidence that Seguro Popular has incremented the human and physical resources available for healthcare services over the period 2001-2013. Moreover, we show that these effects have been heterogeneously distributed. CONCLUSIONS: The program has proven most helpful in less vulnerable territories, leaving behind those in greater need. PMID- 30409150 TI - Multiparametric ultrasound: evaluation of greyscale, shear wave elastography and contrast-enhanced ultrasound for prostate cancer detection and localization in correlation to radical prostatectomy specimens. AB - BACKGROUND: The diagnostic pathway for prostate cancer (PCa) is advancing towards an imaging-driven approach. Multiparametric magnetic resonance imaging, although increasingly used, has not shown sufficient accuracy to replace biopsy for now. The introduction of new ultrasound (US) modalities, such as quantitative contrast enhanced US (CEUS) and shear wave elastography (SWE), shows promise but is not evidenced by sufficient high quality studies, especially for the combination of different US modalities. The primary objective of this study is to determine the individual and complementary diagnostic performance of greyscale US (GS), SWE, CEUS and their combination, multiparametric ultrasound (mpUS), for the detection and localization of PCa by comparison with corresponding histopathology. METHODS/DESIGN: In this prospective clinical trial, US imaging consisting of GS, SWE and CEUS with quantitative mapping on 3 prostate imaging planes (base, mid and apex) will be performed in 50 patients with biopsy-proven PCa before planned radical prostatectomy using a clinical ultrasound scanner. All US imaging will be evaluated by US readers, scoring the four quadrants of each imaging plane for the likelihood of significant PCa based on a 1 to 5 Likert Scale. Following resection, PCa tumour foci will be identified, graded and attributed to the imaging-derived quadrants in each prostate plane for all prostatectomy specimens. Primary outcome measure will be the sensitivity, specificity, negative predictive value and positive predictive value of each US modality and mpUS to detect and localize significant PCa evaluated for different Likert Scale thresholds using receiver operating characteristics curve analyses. DISCUSSION: In the evaluation of new PCa imaging modalities, a structured comparison with gold standard radical prostatectomy specimens is essential as first step. This trial is the first to combine the most promising ultrasound modalities into mpUS. It complies with the IDEAL stage 2b recommendations and will be an important step towards the evaluation of mpUS as a possible option for accurate detection and localization of PCa. TRIAL REGISTRATION: The study protocol for multiparametric ultrasound was prospectively registered on Clinicaltrials.gov on 14 March 2017 with the registry name 'Multiparametric Ultrasound-Study for the Detection of Prostate Cancer' and trial registration number NCT03091231. PMID- 30409151 TI - The negative effect of ANGPTL8 on HDL-mediated cholesterol efflux capacity. AB - BACKGROUND: It is well known that angiopoietin-like protein 8 (ANGPTL8) exerts its effects on lipid metabolism through the inhibition of lipoprotein lipase and subsequent elevation of plasma triglyceride. However, it is not clear whether ANGPTL8 could affect lipid metabolism via other pathways. The study was aimed to investigate the effects of ANGPTL8 on the function of high-density lipoprotein (HDL), which plays a protective role in atherosclerosis progression. METHODS: Two hundred and ten subjects were recruited. Plasma ANGPTL8 was measured by enzyme linked immunosorbent assays. Cholesterol efflux capacity was chosen as the biomarker of HDL function and measured via H3-cholesterol loading THP-1 cell models. RESULTS: ANGPTL8 exhibited no significant difference between CAD group and nonCAD group, but ANGPTL8 in DM group was significantly higher than that in the nonDM group [568.3 (406.2-836.8) vs 458.2 (356.8-755.6), P = 0.023]. Compared to controls, subjects in CAD group and DM group exhibited significantly lower cholesterol efflux capacity [CAD: 14.58 +/- 2.06 vs 12.51 +/- 2.83%, P < 0.0001; DM: 13.62 +/- 2.57 vs 12.34 +/- 3.16%, P = 0.0099]. ANGPTL8 was inversely correlated with cholesterol efflux capacity (r = - 0.188, P < 0.01). Regression analysis revealed that plasma ANGPTL8 was an independent contributor to cholesterol efflux capacity (standardized beta = - 0.143, P = 0.023). CONCLUSION: ANGPTL8 presents a negative effect on HDL-mediated cholesterol efflux capacity. PMID- 30409152 TI - MAPLE-PD trial (Mesenteric Approach vs. Conventional Approach for Pancreatic Cancer during Pancreaticoduodenectomy): study protocol for a multicenter randomized controlled trial of 354 patients with pancreatic ductal adenocarcinoma. AB - BACKGROUND: The mesenteric approach is an artery-first approach to pancreaticoduodenectomy for pancreatic cancer, which starts with the dissection of connective tissues around the superior mesenteric artery. The procedure aims for early confirmation of resectability by checking the surgical margin around the superior mesenteric artery first during the operation. It also aims to decrease intraoperative blood loss by early ligation of the inferior pancreaticoduodenal artery and to increase R0 rate by complete clearance of the lymph nodes around the superior mesenteric artery and pancreatic head plexus II, the most favorable positive margin site for pancreatic ductal adenocarcinoma. Furthermore, it aims to avoid the spread of cancer cells during operation (nontouch isolation technique). The MAPLE-PD (Mesenteric Approach vs. Conventional Approach for Pancreatic Cancer during Pancreaticoduodenectomy) trial investigates whether the mesenteric approach can prolong the survival of patients with pancreatic ductal adenocarcinoma who undergo pancreaticoduodenectomy compared with the conventional approach. METHODS/DESIGN: The MAPLE-PD trial is a Japanese multicenter randomized controlled trial that compares the surgical outcomes between the mesenteric and conventional approaches to pancreaticoduodenectomy. Patients with pancreatic ductal adenocarcinoma scheduled to undergo pancreaticoduodenectomy are randomized before operation to either a conventional approach (arm A) or a mesenteric approach (arm B). In arm A, the operation starts with Kocher's maneuver. At the final step of the removal procedure, the connective tissues around the superior mesenteric artery are dissected. In arm B, the operation starts with dissection of the connective tissues around the superior mesenteric artery and ends with Kocher's maneuver. In total, 354 patients from 15 Japanese high-volume centers will be randomized. The primary endpoint is overall survival by intention-to-treat analysis. Secondary endpoints include intraoperative blood loss, R0 rate, and recurrence-free survival. DISCUSSION: If the MAPLE-PD trial shows the oncological benefits of the mesenteric approach for patients with pancreatic ductal adenocarcinoma, this procedure may become a standard approach to pancreaticoduodenectomy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03317886 . Registered on 23 October 2017. University Hospital Medical Information Network Clinical Trials Registry, UMIN000029615 . Registered on 15 January 2018. PMID- 30409153 TI - The actual conditions of traditional Japanese Kampo education in all the pharmacy schools in Japan: a questionnaire survey after the enforcement of the new national 2015 core curriculum. AB - BACKGROUND: To investigate the present status of Kampo education, which has still not been elucidated, after the introduction of the new core national curriculum of 2015 into nationwide pharmacy education, in all 74 pharmacy schools in Japan. METHODS: A postal questionnaire survey was conducted from August 2015 to January 2016. The completed questionnaires were returned by mail. Web-based syllabi were also investigated to ascertain the detailed lecture curricula in each school. Descriptive analyses were conducted without statistics. RESULTS: A total of 74 questionnaires were collected (response rate, 100%). In 2015, the numbers of clinical Kampo classes as required subjects during the 6 years of regular pharmacy school education ranged from 0 to 36 (median, 13; mean, 11.8 +/- 7.6). Of the 74 schools, 49 schools (66%) provided Kampo education from a clinical standpoint. Pharmacists employed in pharmacies and physicians taught most of these classes. The major problems to be solved first are: selecting and retaining teachers to teach clinical Kampo medicine (43 of 74 schools, 58%), preparing standard textbooks (37 schools, 50%), and improving the environment for practical Kampo training (30 schools, 41%). CONCLUSIONS: Curricula for teaching Kampo medicine significantly differ at each of the 74 Japanese pharmacy schools. In addition to selecting teachers who can adequately teach clinical Kampo medicine, improving training environments, and nationwide standardization of the curricula and textbooks are critical. PMID- 30409154 TI - Live imaging and tracking of genome regions in CRISPR/dCas9 knock-in mice. AB - CRISPR/dCas9 is a versatile tool that can be used to recruit various effectors and fluorescent molecules to defined genome regions where it can modulate genetic and epigenetic markers, or track the chromatin dynamics in live cells. In vivo applications of CRISPR/dCas9 in animals have been challenged by delivery issues. We generate and characterize a mouse strain with dCas9-EGFP ubiquitously expressed in various tissues. Studying telomere dynamics in these animals reveals surprising results different from those observed in cultured cell lines. The CRISPR/dCas9 knock-in mice provide an important and versatile tool to mechanistically study genome functions in live animals. PMID- 30409155 TI - RIVET: comprehensive graphic user interface for analysis and exploration of genome-wide translatomics data. AB - BACKGROUND: Translatomics data, particularly genome-wide ribosome profiling and polysome profiling, provide multiple levels of gene regulatory information that can be used to assess general transcription and translation, as well translational efficiency. The increasing popularity of these techniques has resulted in multiple algorithms to detect translational regulation, typically distributed in the form of command line tools that require a basic level of programming ability. Additionally, due to the static nature of current software, dynamic transcriptional and translational comparative analysis cannot be adequately achieved. In order to streamline hypothesis generation, investigators must have the ability to manipulate and interact with their data in real-time. RESULTS: To address the lack of integration in current software, we introduce RIVET, Ribosomal Investigation and Visualization to Evaluate Translation, an R shiny based graphical user interface for translatomics data exploration and differential analysis. RIVET can analyze either microarray or RNA sequencing data from polysome profiling and ribosome profiling experiments. RIVET provides multiple choices for statistical analysis as well as integration of transcription, translation, and translational efficiency data analytics and the ability to visualize all results dynamically. CONCLUSIONS: RIVET is a user friendly tool designed for bench scientists with little to no programming background. RIVET facilitates the data analysis of translatomics data allowing for dynamic generation of results based on user-defined inputs and publication ready visualization. We expect RIVET will allow for scientists to efficiently make more comprehensive data observations that will lead to more robust hypothesis regarding translational regulation. PMID- 30409157 TI - Complicated Gitelman syndrome and autoimmune thyroid disease: a case report with a new homozygous mutation in the SLC12A3 gene and literature review. AB - BACKGROUND: Gitelman syndrome (GS) is an inherited autosomal recessive renal tubular disorder characterized by low levels of potassium and magnesium in the blood, decreased excretion of calcium in the urine, and elevated blood pH. GS is caused by an inactivating mutation in the SLC12A3 gene, which is located on the long arm of chromosome 16 (16q13) and encodes a thiazide-sensitive sodium chloride cotransporter (NCCT). CASE PRESENTATION: A 45-year-old man with Graves' disease complicated by paroxysmal limb paralysis had a diagnosis of thyrotoxic periodic paralysis for 12 years. However, his serum potassium level remained low despite sufficiently large doses of potassium supplementation. Finally, gene analysis revealed a homozygous mutation in the SLC12A3 gene. After his thyroid function gradually returned to normal, his serum potassium level remained low, but his paroxysmal limb paralysis resolved. CONCLUSIONS: GS combined with hyperthyroidism can manifest as frequent episodes of periodic paralysis; to date, this comorbidity has been reported only in eastern Asian populations. This case prompted us to more seriously consider the possibility of GS associated with thyroid dysfunction. PMID- 30409156 TI - Influence of confluent marine currents in an ecotonal region of the South-West Atlantic on the distribution of larval anisakids (Nematoda: Anisakidae). AB - BACKGROUND: In the marine environment, transitional zones between major water masses harbour high biodiversity, mostly due to their productivity and by containing representatives of species characteristic of adjacent communities. With the aim of assessing the value of larval Anisakis as zoogeographical indicators in a transitional zone between subtropical and sub-Antarctic marine currents, larvae obtained from Zenopsis conchifer were genetically identified. Larvae from Pagrus pagrus and Merluccius hubbsi from two adjacent zoogeographical provinces were also sequenced. RESULTS: Four species were genetically identified in the whole sample, including Anisakis typica, A. pegreffii, A. berlandi and a probably new species related to A. paggiae. Anisakis typica and A. pegreffii were identified as indicators of tropical/subtropical and sub-Antarctic waters, respectively, and their presence evidenced the transitional conditions of the region. Multivariate analyses on prevalence and mean abundance of Anisakis spp. of 18 samples represented by 9 fish species caught south of 35 degrees S determined that host trophic level and locality of capture were the main drivers of the distribution of parasites across zoogeographical units in the South-West Atlantic. CONCLUSIONS: Most samples followed a clear zoogeographical pattern, but the sample of Z. conchifer, composed mostly of A. typica, was an exception. This finding suggests that population parameters of A. typica and A. pegreffii could differ enough to be considered as a surrogates of the identity of larvae parasitizing a given host population and, therefore, a step forward the validation of the use of larval Anisakis as biological indicators for studies on host zoogeography. PMID- 30409158 TI - Sero-prevalence and associated risk factors of Brucellosis among Malaria negative febrile out-patients in Wakiso district, Central Uganda. AB - OBJECTIVE: Brucellosis is a zoonotic disease usually acquired through direct contact with the infected animals and consumption of contaminated milk and meat products. In humans Brucellosis presents similar signs with other febrile diseases like Malaria, typhoid and other febrile conditions. This study was carried out to determine the prevalence of Brucella abortus among patients with fever but were negative for Malaria. RESULTS: A cross-sectional study was carried out in Namayumba Health Centre IV, Wakiso district involving 200 participants. Blood samples was screened for B. abortus using Serum Agglutination Test and confirmed with Tube Agglutination test. A questionnaire was used to collect data on socio-demographic characteristics and human Brucellosis related risk factors. Human B. abortus sero-prevalence was at 7.5% (n = 200). The prevalence was high among participants aged 18-35 years (13.3%), muslims 12 (14.0%), those with no formal education (33.3%) and divorced 2 (14.3%). Consuming of raw milk (OR 2.162, 95% CI 0.021-1.379) and being a Muslim (OR 6.101, 95% CI 1.601-23.248) were associated with increased risk of Brucella abortus. It was concluded that human Brucella infection due to Brucella abortus is commonly associated with consumers of raw milk products and muslims in Wakiso district. PMID- 30409160 TI - GRam stain-guided Antibiotics ChoicE for Ventilator-Associated Pneumonia (GRACE VAP) trial: rationale and study protocol for a randomised controlled trial. AB - BACKGROUND: Optimising the use of antibiotic agents is a pressing challenge to overcoming the rapid emergence and spread of multidrug-resistant pathogens in intensive care units (ICUs). Although Gram staining may possibly provide immediate information for predicting pathogenic bacteria, Gram stain-guided initial antibiotic treatment is not well established in the ICU setting. We planned the GRam stain-guided Antibiotics ChoicE for Ventilator-Associated Pneumonia (GRACE-VAP) trial to investigate whether Gram staining can safely restrict the use of broad-spectrum antibiotics in patients with ventilator associated pneumonia (VAP), which is one of the most common hospital-acquired infections in ICUs. METHODS/DESIGN: The GRACE-VAP trial is a multicentre, randomised, open-label parallel-group trial to assess the non-inferiority of Gram stain-guided initial antibiotic treatment to guidelines-based initial antibiotic treatment for the primary endpoint of clinical response rate in patients with VAP. Secondary endpoints include the coverage rates of initial antibiotic therapies, the selected rates of anti-pseudomonal agents and anti-methicillin resistant Staphylococcus aureus (anti-MRSA) agents as initial antibiotic therapies, 28-day all-cause mortality, ICU-free days, ventilator-free days and adverse events. Patients are randomly assigned to receive Gram stain-guided treatment or guidelines-based treatment at a ratio of 1:1. In the Gram stain group, results of Gram staining of endotracheal aspirate are used to guide the selection of antibiotics. In the guidelines group, the combination of an anti pseudomonal agent and an anti-MRSA agent is administered. A total sample size of 200 was estimated to provide a power of 80% with a one-sided alpha level of 2.5% and a non-inferiority margin of 20%, considering 10% non-evaluable patients. DISCUSSION: The GRACE-VAP trial is expected to reveal whether Gram staining can reduce the use of broad-spectrum antibiotics without impairing patient outcomes and thereby provide evidence for an antibiotic selection strategy in patients with VAP. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03506113 . Registered on 29 March 2018. University Hospital Medical Information Network, UMIN000031933. Registered on 26 March 2018. PMID- 30409161 TI - Abdominal aortic calcification score can predict future coronary artery disease in hemodialysis patients: a 5-year prospective cohort study. AB - BACKGROUND: Abdominal aortic calcification (AAC) has been known to be associated with cardiovascular mortality in hemodialysis. However, the association between AAC and future coronary artery disease (CAD) occurrence is not clear. We aimed to clarify the association of AAC severity and the occurrence of future CAD events in hemodialysis patients. METHODS: Hemodialysis (HD) patients were recruited in this prospective cohort study. AAC severity was quantified by AAC score, which was measured by lateral lumbar radiography. We used receiver operation curve (ROC) analysis to find the cutoff AAC value for CAD prediction. CAD-free survival was analyzed by Kaplan-Meier study. RESULTS: There were 303 patients recruited for study with a median (interquartile range) follow-up of 95 (65-146) months. The AAC score in patients with occurrence of new CAD [9 (3-15.25), n = 114] was higher than in patients without new CAD occurrence [5 (1-9) n = 189], p < 0.001. Multivariate hazard ratio of AAC score for CAD was 1.039 (p = 0.016). ROC study showed that an AAC score of 5.5 had a sensitivity of 0.658 and a specificity of 0.587 in the prediction of new CAD occurrence. Patients with AAC score above 5.5 had significantly higher cumulative incidence of CAD than patients with AAC score below 5.5. Age, diabetes, prior history of CAD, and longer dialysis vintage were major factors associated with higher AAC score. CONCLUSIONS: AAC score can predict the occurrence of future CAD events in HD patients. The best cut-off value of AAC score is 5.5. AAC score greater than 5.5 is a reliable abdominal aortic calcification marker, and can predict future CAD in ESRD patients. Major contributive factors for higher AAC score were age, presence of diabetes, prior history of CAD, and longer dialysis vintage. PMID- 30409159 TI - Complete genome sequencing of three human clinical isolates of Staphylococcus caprae reveals virulence factors similar to those of S. epidermidis and S. capitis. AB - BACKGROUND: Staphylococcus caprae is an animal-associated bacterium regarded as part of goats' microflora. Recently, S. caprae has been reported to cause human nosocomial infections such as bacteremia and bone and joint infections. However, the mechanisms responsible for the development of nosocomial infections remain largely unknown. Moreover, the complete genome sequence of S. caprae has not been determined. RESULTS: We determined the complete genome sequences of three methicillin-resistant S. caprae strains isolated from humans and compared these sequences with the genomes of S. epidermidis and S. capitis, both of which are closely related to S. caprae and are inhabitants of human skin capable of causing opportunistic infections. The genomes showed that S. caprae JMUB145, JMUB590, and JMUB898 strains contained circular chromosomes of 2,618,380, 2,629,173, and 2,598,513 bp, respectively. JMUB145 carried type V SCCmec, while JMUB590 and JMUB898 had type IVa SCCmec. A genome-wide phylogenetic SNP tree constructed using 83 complete genome sequences of 24 Staphylococcus species and 2 S. caprae draft genome sequences confirmed that S. caprae is most closely related to S. epidermidis and S. capitis. Comparative complete genome analysis of eight S. epidermidis, three S. capitis and three S. caprae strains revealed that they shared similar virulence factors represented by biofilm formation genes. These factors include wall teichoic acid synthesis genes, poly-gamma-DL-glutamic acid capsule synthesis genes, and other genes encoding nonproteinaceous adhesins. The 17 proteinases/adhesins and extracellular proteins known to be associated with biofilm formation in S. epidermidis were also conserved in these three species, and their biofilm formation could be detected in vitro. Moreover, two virulence associated gene clusters, the type VII secretion system and capsular polysaccharide biosynthesis gene clusters, identified in S. aureus were present in S. caprae but not in S. epidermidis and S. capitis genomes. CONCLUSION: The complete genome sequences of three methicillin-resistant S. caprae isolates from humans were determined for the first time. Comparative genome analysis revealed that S. caprae is closely related to S. epidermidis and S. capitis at the species level, especially in the ability to form biofilms, which may lead to increased virulence during the development of S. caprae infections. PMID- 30409162 TI - Serotonin induced hepatic steatosis is associated with modulation of autophagy and notch signaling pathway. AB - BACKGROUND: Besides its neurotransmitter and vasoconstriction functions, serotonin is an important mediator of numerous biological processes in peripheral tissues including cell proliferation, steatosis, and fibrogenesis. Recent reports indicate that serotonin may promote tumor growth in liver cancer, however, the molecular mechanisms remain elusive. n this study, we investigated the role and molecular signaling mechanisms mediated by serotonin in liver cancer cell survival, drug resistance, and steatosis. METHODS: Effect of serotonin on modulation of cell survival/proliferation was determined by MTT/WST1 assay. Effect of serotonin on the regulation of autophagy biomarkers and lipid/fatty acid proteins expression, AKT/mTOR and Notch signaling was evaluated by immunoblotting. The role of serotonin in normal human hepatocytes and liver cancer cell steatosis was analyzed by Oil Red O staining. The mRNA expression levels of lipid/fatty acid proteins and serotonin receptors were validated by qRT PCR. The important roles of autophagy, Notch signaling, serotonin receptors and serotonin re-uptake proteins on serotonin-mediated cell steatosis were investigated by using selective inhibitors or antagonists. The association of peripheral serotonin, autophagy, and hepatic steatosis was also investigated using chronic EtOH fed mouse model. RESULTS: Exposure of liver cancer cells to serotonin induced Notch signaling and autophagy, independent of AKT/mTOR pathway. Also, serotonin enhanced cancer cell proliferation/survival and drug resistance. Furthermore, serotonin treatment up-regulated the expression of lipogenic proteins and increased steatosis in liver cancer cells. Inhibition of autophagy or Notch signaling reduced serotonin-mediated cell steatosis. Treatment with serotonin receptor antagonists 5-HTr1B and 5-HTr2B reduced serotonin-mediated cell steatosis; in contrast, treatment with selective serotonin reuptake inhibitors (SSRIs) increased steatosis. In addition, mice fed with chronic EtOH resulted in increased serum serotonin levels which were associated with the induction of hepatic steatosis and autophagy. CONCLUSIONS: Serotonin regulates liver cancer cell steatosis, cells survival, and may promote liver carcinogenesis by activation of Notch signaling and autophagy. PMID- 30409163 TI - Impact of antagonistic muscle co-contraction on in vivo knee contact forces. AB - BACKGROUND: The onset and progression of osteoarthritis, but also the wear and loosening of the components of an artificial joint, are commonly associated with mechanical overloading of the structures. Knowledge of the mechanical forces acting at the joints, together with an understanding of the key factors that can alter them, are critical to develop effective treatments for restoring joint function. While static anatomy is usually the clinical focus, less is known about the impact of dynamic factors, such as individual muscle recruitment, on joint contact forces. METHODS: In this study, instrumented knee implants provided accurate in vivo tibio-femoral contact forces in a unique cohort of 9 patients, which were used as input for subject specific musculoskeletal models, to quantify the individual muscle forces during walking and stair negotiation. RESULTS: Even between patients with a very similar self-selected gait speed, the total tibio femoral peak forces varied 1.7-fold, but had only weak correlation with static alignment (varus/valgus). In some patients, muscle co-contraction of quadriceps and gastrocnemii during walking added up to 1 bodyweight (~ 50%) to the peak tibio-femoral contact force during late stance. The greatest impact of co contraction was observed in the late stance phase of stair ascent, with an increase of the peak tibio-femoral contact force by up to 1.7 bodyweight (66%). CONCLUSIONS: Treatment of diseased and failed joints should therefore not only be restricted to anatomical reconstruction of static limb axes alignment. The dynamic activation of muscles, as a key modifier of lower limb biomechanics, should also be taken into account and thus also represents a promising target for restoring function, patient mobility, and preventing future joint failure. TRIAL REGISTRATION: German Clinical Trials Register: ID: DRKS00000606 , date: 05.11.2010. PMID- 30409164 TI - Putting family into family-based obesity prevention: enhancing participant engagement through a novel integrated knowledge translation strategy. AB - BACKGROUND: With 1 in 4 Canadian preschoolers considered overweight or obese, identifying risk factors for excess weight gain and developing effective interventions aimed at promoting healthy weights and related behaviours among young children have become key public health priorities. Despite the need for this research, engaging and maintaining participation is a critical challenge for long-term, family-based studies. The aim of this study is to describe the implementation and evaluation of a parent-only advisory council designed to engage participants in the implementation and evaluation of a longitudinal, family-based obesity prevention intervention. METHODS: A Family Advisory Council (n = 14 parents, 70% mothers, 64% white), was established to engage participant stakeholders in decisions related to research protocols and strategies to engage and sustain family participation. Using a mixed methods approach, including a participant survey and focus group, we examined the council members' perceptions of their role and the impact this novel integrated Knowledge Translation (iKT) strategy had on the Guelph Family Health Study (GFHS), a longitudinal family based study. RESULTS: All members of the Family Advisory Council felt the topics discussed were appropriate, felt that their opinions were valued and that their suggestions have had an impact and direct benefit on the GFHS. The addition of the Family Advisory Council led to changes in study protocol (i.e. creation of more detailed intervention emails, creation of kid-friendly accelerometer bands) that may have contributed to the high retention rate of the GFHS (95% at 6-month follow-up). CONCLUSIONS: Engaging parents as research partners in family-based research studies may be an effective way to increase participant engagement and study retention. PMID- 30409166 TI - Breeders' knowledge on cattle fodder species preference in rangelands of Benin. AB - BACKGROUND: We undertook ethnobotanical and ecological studies on fodder plants grazed by cattle across Benin national area. The study aims to ascertain the top priority fodder plants in order to catalogue the indigenous knowledge regarding their use. METHODS: Data were collected through semi-structured interviews and covered 690 breeders and 40 days of pasture walk. These were analysed using similarity index of Jaccard (IS), relative frequency citation (RFC) and fodder value during pasture walk (FVPW). RESULTS: We documented a total of 257 fodder plant species, of which 116 recorded during ethnobotanical investigations and 195 during pasture walk. These species belong to 181 genera and 54 families. Both methods shared 52 species. Leaves (58%) and leafy stem (28%) were the most grazed parts of plant. The most common species used as fodder included Andropogon gayanus, Panicum maximum, Pterocarpus erinaceus and Flueggea virosa. The top species with a highest FVPW were Panicum maximum and Pterocarpus erinaceus. A total of 16 species were considered as top fodder plants in Benin. CONCLUSIONS: The wide diversity of plants reported indicates that there is a number of promising fodder species in the flora of Benin. The insight gained in this study relating to bovine feeds could guide in the selection and introduction of feed innovations that could improve livestock production. PMID- 30409165 TI - Antagonistic interaction between Nodal and insulin modulates pancreatic beta-cell proliferation and survival. AB - BACKGROUND: Insulin signaling pathway in beta-cell is essential to promote beta cells proliferation and survival, while Nodal-ALK7-Smad3 signaling involves beta cells apoptosis. We attempted to address inter-relationship between Nodal and insulin in modulating beta-cell proliferation and apoptosis. METHODS: Using INS-1 beta-cells and isolated rat islets, we examined the effects of Nodal, insulin, or the two combined on beta-cell proliferation and/or apoptosis. RESULTS: The beta cells under high-glucose or palmitate conditions showed significant up-regulation of Nodal expression and activation of its downstream signaling pathway resulted in increased cleaved caspase-3. Insulin treatment led to significantly attenuated Nodal-induced cell apoptotic pathway. Similar results were found in directly Nodal-treated beta-cell that insulin could partially block Nodal-induced up regulation of ALK7-Smad3-caspase-3 signaling pathways with significantly attenuated beta-cell apoptosis. Interestingly, we found that insulin-induced Akt activation and downstream molecules including GSK-3beta, beta-catenin and ERK1/2 was significantly attenuated by the co-treatment with Nodal, resulted in decreased cell proliferation. Furthermore, Nodal decreased glucose-evoked calcium influx and played a negative role during glucose-stimulated insulin secretion in the beta-cells. Immunocytochemistry studies showed that Nodal treatment translocated Smad3 from cytosol mostly to the nucleus; however, co-treatment with insulin significantly decreased Smad3 nuclear localization. Co immunoprecipitation experiments showed a directly interaction between Smad3 and Akt, and this interaction was enhanced by co-treatment with insulin. CONCLUSIONS: Our data suggest that the antagonistic interaction between Nodal and insulin has a role in the regulation of beta-cell mass and secretion. PMID- 30409167 TI - Additive effect of bFGF and selenium on expansion and paracrine action of human amniotic fluid-derived mesenchymal stem cells. AB - BACKGROUND: Mesenchymal stem cell-derived conditioned medium (MSC-CM) has emerged as a promising cell-free tool for restoring degenerative diseases and treating traumatic injuries. The present study describes the effect of selenium as a reactive oxygen species (ROS) scavenger and its additive effect with basic fibroblast growth factor (bFGF) on in vitro expansion of amniotic fluid (AF)-MSCs and the paracrine actions of AF-MSC-CM as well as the associated cellular and molecular mechanisms. METHODS: In this study, we obtained CM from human AF-MSCs cultured with selenium. The stemness of selenium-treated AF-MSCs was evaluated by cell growth and differentiation potential. Human fibroblasts were treated with AF MSC-CM and analyzed for cell signaling changes. For in vivo wound healing assay, ICR mice with a full-thickness skin wound were used. RESULTS: Selenium played a critical role in in vitro expansion of AF-MSCs through activation of the AKT ERK1/2, Smad2, and Stat3 signaling pathways along with inactivation of GSK3beta. When administered together with bFGF, it showed remarkable effect in inhibiting ROS accumulation and preserving their multipotency. Proliferation and migration of human dermal fibroblasts and in vivo wound healing were improved in the CMs derived from AF-MSCs exposed to selenium and bFGF, which was caused by the Smad2, AKT-MEK1/2-ERK, and NFkappaB signaling triggered by the paracrine factors of AF MSCs, such as TGF-beta, VEGF, and IL-6. Our results suggest the following: (a) supplementation of selenium in AF-MSC culture contributes to in vitro expansion and preservation of multipotency, (b) ROS accumulation causes progressive losses in proliferative and differentiation potential, (c) the separate activities of bFGF and selenium in MSCs exert an additive effect when used together, and (d) the additive combination improves the therapeutic effects of AF-MSC-derived CMs on tissue repair and regeneration. CONCLUSION: Antioxidants, such as selenium, should be considered as an essential supplement for eliciting the paracrine effects of MSC-CMs. PMID- 30409168 TI - Amputee perception of prosthetic ankle stiffness during locomotion. AB - BACKGROUND: Prosthetic feet are spring-like, and their stiffness critically affects the wearer's stability, comfort, and energetic cost of walking. Despite the importance of stiffness in ambulation, the prescription process often entails testing a limited number of prostheses, which may result in patients receiving a foot with suboptimal mechanics. To understand the resolution with which prostheses should be individually optimized, we sought to characterize below-knee prosthesis users' psychophysical sensitivity to prosthesis stiffness. METHODS: We used a novel variable-stiffness ankle prosthesis to measure the repeatability of user-selected preferred stiffness, and implemented a psychophysical experiment to characterize the just noticeable difference of stiffness during locomotion. RESULTS: All eight subjects with below-knee amputation exhibited high repeatability in selecting their Preferred Stiffness (mean coefficient of variation: 14.2 +/- 1.7%) and were able to correctly identify a 7.7 +/- 1.3% change in ankle stiffness (with 75% accuracy). CONCLUSIONS: This high sensitivity suggests prosthetic foot stiffness should be tuned with a high degree of precision on an individual basis. These results also highlight the need for a pairing of new robotic prescription tools and mechanical characterizations of prosthetic feet. PMID- 30409169 TI - Cow-to-mouse fecal transplantations suggest intestinal microbiome as one cause of mastitis. AB - BACKGROUND: Mastitis, which affects nearly all lactating mammals including human, is generally thought to be caused by local infection of the mammary glands. For treatment, antibiotics are commonly prescribed, which however are of concern in both treatment efficacy and neonate safety. Here, using bovine mastitis which is the most costly disease in the dairy industry as a model, we showed that intestinal microbiota alone can lead to mastitis. RESULTS: Fecal microbiota transplantation (FMT) from mastitis, but not healthy cows, to germ-free (GF) mice resulted in mastitis symptoms in mammary gland and inflammations in serum, spleen, and colon. Probiotic intake in parallel with FMT from diseased cows led to relieved mastitis symptoms in mice, by shifting the murine intestinal microbiota to a state that is functionally distinct from either healthy or diseased microbiota yet structurally similar to the latter. Despite conservation in mastitis symptoms, diseased cows and mice shared few mastitis-associated bacterial organismal or functional markers, suggesting striking divergence in mastitis-associated intestinal microbiota among lactating mammals. Moreover, an "amplification effect" of disease-health distinction in both microbiota structure and function was apparent during the cow-to-mouse FMT. CONCLUSIONS: Hence, dysbiosis of intestinal microbiota may be one cause of mastitis, and probiotics that restore intestinal microbiota function are an effective and safe strategy to treat mastitis. PMID- 30409170 TI - Early mobilisation by head-up tilt with stepping versus standard care after severe traumatic brain injury - Protocol for a randomised clinical feasibility trial. AB - BACKGROUND: Intensive rehabilitation of patients with severe traumatic brain injury is generally applied in the subacute stages of the hospital stay. Few studies have assessed the association between early and intensive physical rehabilitation and functional outcomes. The aim of this trial is to assess the feasibility of an intensive physical rehabilitation intervention focusing on mobilisation to the upright position, starting as early as clinically possible versus standard care in the intensive care unit. The feasibility study is intended to inform a subsequent randomised clinical trial that will investigate benefits and harms of the intervention. METHODS: This randomised clinical feasibility trial with a follow-up period of 1 year will use blinded outcome assessors for the Coma Recovery Scale-Revised. A maximum of 60 patients admitted to the neurointensive care unit at Rigshospitalet, Denmark, with traumatic brain injury (age of at least 18 years), a low level of consciousness, and stable intracranial pressure will be included in the trial. Patients will be randomly assigned to experimental intervention versus standard care (1:1) stratified according to their Glasgow Coma Score. The intervention group will receive daily mobilisation in a tilt table with an integrated stepping device (ERIGO(r)). Feasibility is declared if more than 60% (the lower 95% confidence interval of the proportion) of eligible patients are included in the trial and more than 52% (the lower 95% confidence interval of the proportion) of patients in the intervention group receive more than 60% of the planned interventions. Safety is assessed by the occurrence of adverse events and adverse reactions. Exploratory clinical outcomes consist of cerebral haemodynamics (blood flow velocity and pressure autoregulation) and baroreceptor sensitivity in the early phase as well as functional outcomes (Coma Recovery Scale-Revised, Early Functional Ability scale, and Functional Independence Measure). DISCUSSION: Our findings will inform a future, larger-scale randomised clinical trial on early mobilisation using a tilt table early after severe traumatic brain injury. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02924649 . Registered on 3 October 2016. PMID- 30409171 TI - Protocol for evaluating the impact of a national school policy on physical activity levels in Danish children and adolescents: the PHASAR study - a natural experiment. AB - BACKGROUND: In 2014 the Danish Government introduced a wide-ranging school reform that applies to all public schools in Denmark. The reform involves changes in several aspects of the school structure and content. In a physical activity promotion perspective, a distinctive feature of the school reform is that it has become mandatory to integrate an average of 45 min of daily physical activity in the regular school day. The overarching objective of the PHASAR study is to evaluate the implementation and effect of this ambitious policy-driven physical activity promotion initiative on physical activity and overweight. This paper describes in detail the study protocol. METHODS: The evaluation is divided into a quantitative effect evaluation and a combined quantitative and qualitative process evaluation. A total of 31 schools are enrolled in the PHASAR study including more than 2,000 school-aged children. Objectively measured physical activity data are obtained in the PHASAR study in 2017/18 and compared to repeated cross sectional data collected in four historical school-based studies from 1998 to 2012. Body mass index data from 2012 to 2018 will be collected from The Child Database, which includes repeated cross-sectional assessments on approximately 100,000 children annually. In the absence of a control group, interrupted time-series analysis will be used to evaluate pre- and post-reform physical activity and body mass index levels and trends. A characterization of the school environment for physical activity promotion on a political, environmental, organizational and individual level and school implementation processes will be conducted to evaluate the implementation process. Data will be collected using interviews, surveys, document analyses and observations. DISCUSSION: The PHASAR study is a rare opportunity to evaluate the effectiveness of a nation-wide policy-driven school-based physical activity promotion initiative. The use of objectively measured pre- and post-reform physical activity and body mass index data combined with a characterization of the school implementation processes for physical activity promotion will provide a comprehensive source to evaluate the school reform. The study findings have the potential to influence national and international policy makers, health professionals and school staff. PMID- 30409174 TI - Anaesthesia for a biopsy of corpus callosum in patient with a recent intra operative anaphylaxis to an unknown anaesthetic allergen: a case report. AB - BACKGROUND: Anaphylaxis in general anaesthesia occurs with a frequency of 1:5000 1:20000. This clinical summary reports on the use of an effective risk management strategy employing second line anaesthesia agents and alternative endotracheal intubation tools in a patient with a recent history of an intra-operative anaphylaxis to an unknown anaesthetic agent. CASE PRESENTATION: A 71-year-old male presented for a repeat biopsy of corpus callosum 4 days following the cancellation of the procedure for a presumed anaphylactic reaction to an unknown anaesthetic agent. During the repeat care episode, the decision was made to proceed based on the urgent need for tissue diagnosis to facilitate further treatment and lack of feasibility for more definitive identification of the causative agent(s). A consideration was made of the optimum ways to manage and mitigate risk in this setting. The airway was managed using flexible endoscopic intubation in a spontaneously ventilating awake patient. Continuous remifentanil infusion was maintained throughout the case. Anaesthesia was maintained with sevoflurane at less than one MAC, with an uneventful completion of the biopsy of corpus callosum. All of the anaesthetic agents used during the prior care episode, with the exception of remifentanil, were avoided. CONCLUSION: In cases of an anaphylaxis to an unknown anaesthetic allergen, anaesthetic strategy consists of careful risk mitigation and deployment of second agent approaches. Awake flexible endoscopic intubation and remifentanil infusion are viable alternatives to standard induction techniques. PMID- 30409173 TI - Omega-3 polyunsaturated fatty acid attenuates traumatic brain injury-induced neuronal apoptosis by inducing autophagy through the upregulation of SIRT1 mediated deacetylation of Beclin-1. AB - BACKGROUND: Enhancing autophagy after traumatic brain injury (TBI) may decrease the expression of neuronal apoptosis-related molecules. Autophagy-mediated neuronal survival is regulated by the sirtuin family of proteins (SIRT). Omega-3 polyunsaturated fatty acids (omega-3 PUFA) are known to have antioxidative and anti-inflammatory effects. We previously demonstrated that omega-3 PUFA supplementation attenuated neuronal apoptosis by modulating the neuroinflammatory response through SIRT1-mediated deacetylation of the HMGB1/NF-kappaB pathway, leading to neuroprotective effects following experimental traumatic brain injury (TBI). However, no studies have elucidated if the neuroprotective effects of omega-3 PUFAs against TBI-induced neuronal apoptosis are modulated by SIRT1 mediated deacetylation of the autophagy pathway. METHODS: The Feeney DM TBI model was adopted to induce TBI rats. Modified neurological severity scores, the rotarod test, brain water content, and Nissl staining were employed to determine the neuroprotective effects of omega-3 PUFA supplementation. Immunofluorescent staining and western blot analysis were used to detect Beclin-1 nuclear translocation and autophagy pathway activation. The impact of SIRT1 deacetylase activity on Beclin-1 acetylation and the interaction between cytoplasmic Beclin-1 and Bcl-2 were assessed to evaluate the neuroprotective effects of omega-3 PUFAs and to determine if these effects were dependent on SIRT1-mediated deacetylation of the autophagy pathway in order to gain further insight into the mechanisms underlying the development of neuroprotection after TBI. RESULTS: omega-3 PUFA supplementation protected neurons against TBI-induced neuronal apoptosis via enhancement of the autophagy pathway. We also found that treatment with omega-3 PUFA significantly increased the NAD+/NADH ratio and SIRT1 activity following TBI. In addition, omega-3 PUFA supplementation increased Beclin-1 deacetylation and its nuclear export and induced direct interactions between cytoplasmic Beclin 1 and Bcl-2 by increasing SIRT1 activity following TBI. These events led to the inhibition of neuronal apoptosis and to neuroprotective effects through enhancing autophagy after TBI, possibly due to elevated SIRT1. CONCLUSIONS: omega-3 PUFA supplementation attenuated TBI-induced neuronal apoptosis by inducing the autophagy pathway through the upregulation of SIRT1-mediated deacetylation of Beclin-1. PMID- 30409172 TI - Decoding the synaptic dysfunction of bioactive human AD brain soluble Abeta to inspire novel therapeutic avenues for Alzheimer's disease. AB - Pathologic, biochemical and genetic evidence indicates that accumulation and aggregation of amyloid beta-proteins (Abeta) is a critical factor in the pathogenesis of Alzheimer's disease (AD). Several therapeutic interventions attempting to lower Abeta have failed to ameliorate cognitive decline in patients with clinical AD significantly, but most such approaches target only one or two facets of Abeta production/clearance/toxicity and do not consider the heterogeneity of human Abeta species. As synaptic dysfunction may be among the earliest deficits in AD, we used hippocampal long-term potentiation (LTP) as a sensitive indicator of the early neurotoxic effects of Abeta species. Here we confirmed prior findings that soluble Abeta oligomers, much more than fibrillar amyloid plaque cores or Abeta monomers, disrupt synaptic function. Interestingly, not all (84%) human AD brain extracts are able to inhibit LTP and the degree of LTP impairment by AD brain extracts does not correlate with Abeta levels detected by standard ELISAs. Bioactive AD brain extracts also induce neurotoxicity in iPSC derived human neurons. Shorter forms of Abeta (including Abeta1-37, Abeta1-38, Abeta1-39), pre-Abeta APP fragments (- 30 to - 1) and N-terminally extended Abetas (- 30 to + 40) each showed much less synaptotoxicity than longer Abetas (Abeta1-42 - Abeta1-46). We found that antibodies which target the N-terminus, not the C-terminus, efficiently rescued Abeta oligomer-impaired LTP and oligomer facilitated LTD. Our data suggest that preventing soluble Abeta oligomer formation and targeting their N-terminal residues with antibodies could be an attractive combined therapeutic approach. PMID- 30409175 TI - Evaluation of pancreatic tumor development in KPC mice using multi-parametric MRI. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is a fatal disease with very poor prognosis. Development of sensitive and noninvasive methods to monitor tumor progression in PDA is a critical and unmet need. Magnetic resonance imaging (MRI) can noninvasively provide information regarding underlying pathophysiological processes such as necrosis, inflammatory changes and fibrotic tissue deposition. METHODS: A genetically engineered KPC mouse model that recapitulates human PDA was used to characterize disease progression. MR measures of T1 and T2 relaxation times, magnetization transfer ratio (MTR), diffusion and chemical exchange saturation transfer were compared in two separate phases i.e. slow and rapid growth phase of tumor. Fibrotic tissue accumulation was assessed histologically using Masson's trichrome staining. Pearson correlation coefficient (r) was computed to assess the relationship between the fibrotic tissue accumulation and different MR parameters. RESULTS: There was a negative correlation between amide proton transfer signal intensity and tumor volume (r = - 0.63, p = 0.003) in the slow growth phase of the tumor development. In the terminal stage of rapid growth phase of the tumor development MTR was strongly correlated with tumor volume (r = 0.62, p = 0.008). Finally, MTR was significantly correlated with % fibrosis (r = 0.87; p < 0.01), followed by moderate correlation between tumor volume (r = 0.42); T1 (r = - 0.61), T2 (r = - 0.61) and accumulation of fibrotic tissue. CONCLUSIONS: Here we demonstrated, using multi-parametric MRI (mp-MRI), that MRI parameters changed with tumor progression in a mouse model of PDA. Use of mp-MRI may have the potential to monitor the dynamic changes of tumor microenvironment with increase in tumor size in the transgenic KPC mouse model of pancreatic tumor. PMID- 30409176 TI - Mapping health care of rare diseases: the example of epidermolysis bullosa in Germany. AB - BACKGROUND: Rare diseases affect approximately 30 million people in the European Union and present a major health issue. Over 1000 rare skin diseases are known, many of which are of genetic origin and manifest in childhood. One of these diseases is epidermolysis bullosa (EB), a genodermatosis presenting with skin fragility and blistering. With an estimate of up to 2000 affected individuals in Germany, many of these children, but only two specialist centres, the question arose where and how health care for this rare disease is provided. This question was addressed by an online survey of all paediatric and dermatological departments in Germany. RESULTS: The response rate was 40.5% (203/501), and 39 departments confirmed treating EB (7.8% of the units addressed). Health care for individuals with EB was provided both by dermatological and paediatric departments (19.8 and 4.2% respectively). The geographic distribution of EB health care was uneven. The two EB centres in Hanover and Freiburg treated 70 and 113 patients, two other departments saw 11 to 20 patients, while the majority saw less than 10 patients annually. There existed large variations between 1. the consultation setting, time frame and frequency, 2. the recommended examinations and check-ups and 3. the diagnostics used to establish the diagnosis. Over 50% of participating physicians were dissatisfied with health care outside of hospitals and more than 20% with their patients' supply with bandages or medications. CONCLUSIONS: The survey results show that health care for individuals with EB in Germany is provided multidisciplinarily. Approaches to diagnostics and follow-up recommendations are heterogeneous and national guidelines are lacking. Functioning and innovative political structures are needed to improve networking and strengthening specialised centres to meet the special needs of individuals with EB and other rare diseases. PMID- 30409178 TI - Resection versus preservation of the middle turbinate in surgery for chronic rhinosinusitis with nasal polyposis: a randomized controlled trial. AB - BACKGROUND: Chronic rhinosinusitis (CRS) affects up to 16% of the population. When medical treatment fails, endoscopic sinus surgery (ESS) is considered. The value of resecting the middle turbinate to optimize surgical outcomes has been hypothesized but remains controversial and unproven. Whether the middle turbinate should be left in place or resected is controversial. Our objective is to determine if middle turbinectomy improves objective surgical outcomes after ESS. METHODS: Sixteen patients (15 men, 15 primary surgery) undergoing bilateral complete ESS for CRS with nasal polyposis were recruited. Nasal cavities were randomized so that middle turbinectomy was performed on one side while the middle turbinate was preserved on the other. Each participant acted as their own control. Nasal cavities were compared using Perioperative Sinus Endoscopy (POSE) and Lund-Kennedy (LKES) scores pre-operatively, and at 1, 3 and 6 months after ESS. Results were analyzed using Wilcoxon signed-rank test. RESULTS: Pre operatively, the POSE (12.4 +/- 2.9 vs 12.8 +/- 2.6, p = 0.33, for the preserved side and the resected side, respectively) and LKES (5.0 +/- 1.0 vs 4.8 +/- 1.2, p = 0.33) scores were similar between sides. During follow up, resection was associated with more crusting at 1 month following ESS (1.0 +/- 0.7 vs 0.4 +/- 0.6, p = 0.02). There was a small, but statistically significant, difference between the nasal cavities at 3 months, where the resected side showed better endoscopic appearance (2.0 +/- 2.2 vs 3.4 +/- 2.8, p = 0.01). No difference was found at 6 months. Frontal sinus scores were similar between sides at 6 months (0.7 +/- 0.5 vs 0.7 +/- 0.5, p = 1.00). CONCLUSION: Our results show no sustained objective endoscopic benefit of routine middle turbinectomy, at least within the first six postoperative months, in patients undergoing primary ESS for CRS with polyposis. TRIAL REGISTRATION: NCT, NCT02855931 . Registered 16 August 2016. PMID- 30409177 TI - Visualization-assisted binning of metagenome assemblies reveals potential new pathogenic profiles in idiopathic travelers' diarrhea. AB - BACKGROUND: Travelers' diarrhea (TD) is often caused by enterotoxigenic Escherichia coli, enteroaggregative E. coli, other bacterial pathogens, Norovirus, and occasionally parasites. Nevertheless, standard diagnostic methods fail to identify pathogens in more than 40% of TD patients. It is predicted that new pathogens may be causative agents of the disease. RESULTS: We performed a comprehensive amplicon and whole genome shotgun (WGS) metagenomic study of the fecal microbiomes from 23 TD patients and seven healthy travelers, all of which were negative for the known etiologic agents of TD based on standard microbiological and immunological assays. Abnormal and diverse taxonomic profiles in TD samples were revealed. WGS reads were assembled and the resulting contigs were visualized using multiple query types. A semi-manual workflow was applied to isolate independent genomes from metagenomic pools. A total of 565 genome bins were extracted, 320 of which were complete enough to be characterized as cellular genomes; 160 were viral genomes. We made predictions of the etiology of disease for many of the individual subjects based on the properties and features of the recovered genomes. Multiple patients with low-diversity metagenomes were predominated by one to several E. coli strains. Functional annotation allowed prediction of pathogenic type in many cases. Five patients were co-infected with E. coli and other members of Enterobacteriaceae, including Enterobacter, Klebsiella, and Citrobacter; these may represent blooms of organisms that appear following secretory diarrhea. New "dark matter" microbes were observed in multiple samples. In one, we identified a novel TM7 genome that phylogenetically clustered with a sludge isolate; it carries genes encoding potential virulence factors. In multiple samples, we observed high proportions of putative novel viral genomes, some of which form clusters with the ubiquitous gut virus, crAssphage. The total relative abundance of viruses was significantly higher in healthy travelers versus TD patients. CONCLUSION: Our study highlights the strength of assembly-based metagenomics, especially the manually curated, visualization-assisted binning of contigs, in resolving unusual and under characterized pathogenic profiles of human-associated microbiomes. Results show that TD may be polymicrobial, with multiple novel cellular and viral strains as potential players in the diarrheal disease. PMID- 30409180 TI - USP17 is required for trafficking and oncogenic signaling of mutant EGFR in NSCLC cells. AB - BACKGROUND: The deubiquitinase USP17 is overexpressed in NSCLC and has been shown to be required for the growth and motility of EGFR wild-type (WT) NSCLC cells. USP17 is also required for clathrin-mediated endocytosis of EGFR. Here, we examine the impact of USP17 depletion on the growth, as well as EGFR endocytosis and signaling, of EGFR mutant (MT) NSCLC cells. In particular, we examine NSCLC cells harboring an EGFR activating exon 19 deletion (HCC827), or both the L858R activating mutation and the T790M resistance gatekeeper mutation (H1975) which renders them resistant to EGFR tyrosine kinase inhibitors (TKIs). METHODS: MTT, trypan blue and clonogenic assays, confocal microscopy, Western blotting and cell cycle analysis were performed. RESULTS: USP17 depletion blocks the growth of EGFRMT NSCLC cells carrying either the EGFR exon 19 deletion, or L858R/T790M double mutation. In contrast to EGFRWT cells, USP17 depletion also triggers apoptosis of EGFRMT NSCLC cells. USP17 is required for clathrin-mediated endocytosis in these EGFRMT NSCLC cells, but it is not required for the internalization of the mutated EGFR receptors. Instead, USP17 depletion alters the localization of these receptors within the cell, and although it does not decrease basal EGFR activation, it potently reduces activation of Src, a key kinase in mutant EGFR-dependent tumorigenicity. Finally, we demonstrate that USP17 depletion can trigger apoptosis in EGFRWT NSCLC cells, when combined with the EGFR tyrosine kinase inhibitor (TKI) gefitinib. CONCLUSIONS: Our data reveals that USP17 facilitates trafficking and oncogenic signaling of mutant EGFR and indicates targeting USP17 could represent a viable therapeutic strategy in NSCLC tumours carrying either an EGFR activating mutation, or a resistance gatekeeper mutation. PMID- 30409179 TI - Sex and sexual orientation in relation to tobacco use among young adult college students in the US: a cross-sectional study. AB - BACKGROUND: Sexual minority young adults represent a high-risk population for tobacco use. This study examined cigarette and alternative tobacco product (ATP) use prevalence across sexual orientation (heterosexual, gay/lesbian, and bisexual) among college-attending young adult men and women, respectively. METHODS: Baseline data from a two-year longitudinal study of 3386 young adult college students aged 18-25 in Georgia were analyzed. Correlates examined included sociodemographics (age, sex, sexual orientation, race/ethnicity, college type, and parental education). Outcomes included past 30-day use of tobacco (cigarette, little cigars/cigarillos [LCCs], e-cigarettes, hookah, any tobacco product used, and number of tobacco products used, respectively). Two-group, multivariate multiple regression models were used to examine predictors of tobacco use among men and women, respectively. RESULTS: Among men (N = 1207), 34.7% used any tobacco product; 18.6% cigarettes; 12.3% LCCs; 16.8% e-cigarettes; and 14.7% hookah. Controlling for sociodemographics, gay sexual orientation (OR = 1.62, p = 0.012) was associated with higher odds of cigarette use; no other significant associations were found between sexual orientation and tobacco use. Among women (N = 2179), 25.3% used any tobacco product; 10.4% cigarettes; 10.6% LCCs; 7.6% e-cigarettes; and 10.8% hookah. Being bisexual was associated with cigarette (p < 0.001), LCC (p < 0.001), and e-cigarette use (p = 0.006). Lesbian sexual orientation was associated with cigarette (p = 0.032) and LCC use (p < 0.001). Being bisexual predicted any tobacco product used (p = 0.002), as well as number of tobacco products used (p = 0.004). Group comparisons showed that the effect of sexual minority status on LCC use was significantly different for men versus women. CONCLUSION: Sexual minority women, especially bisexual women, are at higher risk for using specific tobacco products compared to heterosexual women; homosexual men are at increased risk of cigarette use compared to heterosexual men. These nuances in tobacco use should inform interventions targeting sexual minorities. PMID- 30409181 TI - Investigation on the processing and improving the cleavage efficiency of furin cleavage sites in Pichia pastoris. AB - BACKGROUND: Proprotein convertase furin is responsible for the processing of a wide variety of precursors consisted of signal peptide, propeptide and mature peptide in mammal. Many precursors processed by furin have important physiological functions and can be recombinantly expressed in Pichia pastoris expression system for research, pharmaceutical and vaccine applications. However, it is not clear whether the furin cleavage sites between the propeptide and mature peptide can be properly processed in P. pastoris, bringing uncertainty for proper expression of the coding DNA sequences of furin precursors containing the propeptides and mature peptides. RESULTS: In this study, we evaluated the ability of P. pastoris to process furin cleavage sites and how to improve the cleavage efficiencies of furin cleavage sites in P. pastoris. The results showed that P. pastoris can process furin cleavage sites but the cleavage efficiencies are not high. Arg residue at position P1 or P4 in furin cleavage sites significantly affect cleavage efficiency in P. pastoris. Kex2 protease, but not YPS1, in P. pastoris is responsible for processing furin cleavage sites. Heterologous expression of furin or overexpression of Kex2 in P. pastoris effectively increased cleavage efficiencies of furin cleavage sites. CONCLUSIONS: Our investigation on the processing of furin cleavage sites provides important information for recombinant expression of furin precursors in P. pastoris. Furin or Kex2 overexpressing strains may be good choices for expressing precursors processed by furin in P. pastoris. PMID- 30409182 TI - The polyphenol quercetin induces cell death in leukemia by targeting epigenetic regulators of pro-apoptotic genes. AB - BACKGROUND: In the present study, we investigated the molecular mechanisms underlying the pro-apoptotic effects of quercetin (Qu) by evaluating the effect of Qu treatment on DNA methylation and posttranslational histone modifications of genes related to the apoptosis pathway. This study was performed in vivo in two human xenograft acute myeloid leukemia (AML) models and in vitro using HL60 and U937 cell lines. RESULTS: Qu treatment almost eliminates DNMT1 and DNMT3a expression, and this regulation was in part STAT-3 dependent. The treatment also downregulated class I HDACs. Furthermore, treatment of the cell lines with the proteasome inhibitor, MG132, together with Qu prevented degradation of class I HDACs compared to cells treated with Qu alone, indicating increased proteasome degradation of class I HDACS by Qu. Qu induced demethylation of the pro-apoptotic BCL2L11, DAPK1 genes, in a dose- and time-dependent manner. Moreover, Qu (50 MUmol/L) treatment of cell lines for 48 h caused accumulation of acetylated histone 3 and histone 4, resulting in three- to ten fold increases in the promoter region of DAPK1, BCL2L11, BAX, APAF1, BNIP3, and BNIP3L. In addition, Qu treatment significantly increased the mRNA levels of all these genes, when compared to cells treated with vehicle only (control cells) (*p < 0.05). CONCLUSIONS: In summary, our results showed that enhanced apoptosis, induced by Qu, might be caused in part by its DNA demethylating activity, by HDAC inhibition, and by the enrichment of H3ac and H4ac in the promoter regions of genes involved in the apoptosis pathway, leading to their transcription activation. PMID- 30409183 TI - Dissection of the molecular bases of genotype x environment interactions: a study of phenotypic plasticity of Saccharomyces cerevisiae in grape juices. AB - BACKGROUND: The ability of a genotype to produce different phenotypes according to its surrounding environment is known as phenotypic plasticity. Within different individuals of the same species, phenotypic plasticity can vary greatly. This contrasting response is caused by gene-by-environment interactions (GxE). Understanding GxE interactions is particularly important in agronomy, since selected breeds and varieties may have divergent phenotypes according to their growing environment. Industrial microbes such as Saccharomyces cerevisiae are also faced with a large range of fermentation conditions that affect their technological properties. Finding the molecular determinism of such variations is a critical task for better understanding the genetic bases of phenotypic plasticity and can also be helpful in order to improve breeding methods. RESULTS: In this study we implemented a QTL mapping program using two independent cross (~ 100 progeny) in order to investigate the molecular basis of yeast phenotypic response in a wine fermentation context. Thanks to whole genome sequencing approaches, both crosses were genotyped, providing saturated genetic maps of thousands of markers. Linkage analyses allowed the detection of 78 QTLs including 21 with significant interaction with the environmental conditions. Molecular dissection of a major QTL demonstrated that the sulfite pump Ssu1p has a pleiotropic effect and impacts the phenotypic plasticity of several traits. CONCLUSIONS: The detection of QTLs and their interactions with environment emphasizes the complexity of yeast industrial traits. The validation of the interaction of SSU1 allelic variants with the nature of the fermented juice increases knowledge about the impact of the sulfite pump during fermentation. All together these results pave the way for exploiting and deciphering the genetic determinism of phenotypic plasticity. PMID- 30409184 TI - Fructose increases risk for kidney stones: potential role in metabolic syndrome and heat stress. AB - BACKGROUND: Fructose intake, mainly as table sugar or high fructose corn syrup, has increased in recent decades and is associated with increased risk for kidney stones. We hypothesized that fructose intake alters serum and urinary components involved in stone formation. METHODS: We analyzed a previously published randomized controlled study that included 33 healthy male adults (40-65 years of age) who ingested 200 g of fructose (supplied in a 2-L volume of 10% fructose in water) daily for 2 weeks. Participants were evaluated at the Unit of Nephrology of the Mateo Orfila Hospital in Menorca. Changes in serum levels of magnesium, calcium, uric acid, phosphorus, vitamin D, and intact PTH levels were evaluated. Urine magnesium, calcium, uric acid, phosphorus, citrate, oxalate, sodium, potassium, as well as urinary pH, were measured. RESULTS: Ingestion of fructose was associated with an increased serum level of uric acid (p < 0.001), a decrease in serum ionized calcium (p = 0.003) with a mild increase in PTH (p < 0.05) and a drop in urinary pH (p = 0.02), an increase in urine oxalate (p = 0.016) and decrease in urinary magnesium (p = 0.003). CONCLUSIONS: Fructose appears to increase urinary stone formation in part via effects on urate metabolism and urinary pH, and also via effects on oxalate. Fructose may be a contributing factor for the development of kidney stones in subjects with metabolic syndrome and those suffering from heat stress. TRIAL REGISTRATION: ClinicalTrials.gov NCT00639756 March 20, 2008. PMID- 30409185 TI - Pamidronate decreases bilirubin-impaired cell death and improves dentinogenic dysfunction of stem cells from human deciduous teeth. AB - BACKGROUND: Hyperbilirubinemia that occurs in pediatric liver diseases such as biliary atresia can result in the development of not only jaundice in the brain, eyes, and skin, but also tooth abnormalities including green pigmentation and dentin hypoplasia in the developing teeth. However, hyperbilirubinemia-induced tooth impairments remain after liver transplantation. No effective dental management to prevent hyperbilirubinemia-induced tooth impairments has been established. METHODS: In this study, we focused on pamidronate, which is used to treat pediatric osteopenia, and investigated its effects on hyperbilirubinemia induced tooth impairments. We cultured stem cells from human exfoliated deciduous teeth (SHED) under high and low concentrations of unconjugated bilirubin in the presence or absence of pamidronate. We then analyzed the effects of pamidronate on the cell death, associated signal pathways, and dentinogenic function in SHED. RESULTS: We demonstrated that a high concentration of unconjugated bilirubin induced cell death in SHED via the mitochondrial pathway, and this was associated with the suppression of AKT and extracellular signal-related kinase 1 and 2 (ERK1/2) signal pathways and activation of the nuclear factor kappa B (NF-kappaB) signal pathway. The high concentration of unconjugated bilirubin impaired the in vitro and in vivo dentinogenic capacity of SHED, but not the low concentration. We then demonstrated that pamidronate decreased the bilirubin-induced cell death in SHED via the altered AKT, ERK1/2, and NF-kappaB signal pathways and recovered the bilirubin-impaired dentinogenic function of SHED. CONCLUSIONS: Our findings suggest that pamidronate may prevent tooth abnormalities in pediatric patients with hyperbilirubinemia. PMID- 30409186 TI - Propofol vs. inhalational agents to maintain general anaesthesia in ambulatory and in-patient surgery: a systematic review and meta-analysis. AB - BACKGROUND: It is unclear if anaesthesia maintenance with propofol is advantageous or beneficial over inhalational agents. This study is intended to compare the effects of propofol vs. inhalational agents in maintaining general anaesthesia on patient-relevant outcomes and patient satisfaction. METHODS: Studies were identified by electronic database searches in PubMedTM, EMBASETM and the CochraneTM library between 01/01/1985 and 01/08/2016. Randomized controlled trials (RCTs) of peer-reviewed journals were studied. Of 6688 studies identified, 229 RCTs were included with a total of 20,991 patients. Quality control, assessment of risk of bias, meta-bias, meta-regression and certainty in evidence were performed according to Cochrane. Common estimates were derived from fixed or random-effects models depending on the presence of heterogeneity. Post-operative nausea and vomiting (PONV) was the primary outcome. Post-operative pain, emergence agitation, time to recovery, hospital length of stay, post-anaesthetic shivering and haemodynamic instability were considered key secondary outcomes. RESULTS: The risk for PONV was lower with propofol than with inhalational agents (relative risk (RR) 0.61 [0.53, 0.69], p < 0.00001). Additionally, pain score after extubation and time in the post-operative anaesthesia care unit (PACU) were reduced with propofol (mean difference (MD) - 0.51 [- 0.81, - 0.20], p = 0.001; MD - 2.91 min [- 5.47, - 0.35], p = 0.03). In turn, time to respiratory recovery and tracheal extubation were longer with propofol than with inhalational agents (MD 0.82 min [0.20, 1.45], p = 0.01; MD 0.70 min [0.03, 1.38], p = 0.04, respectively). Notably, patient satisfaction, as reported by the number of satisfied patients and scores, was higher with propofol (RR 1.06 [1.01, 1.10], p = 0.02; MD 0.13 [0.00, 0.26], p = 0.05). Secondary analyses supported the primary results. CONCLUSIONS: Based on the present meta-analysis there are several advantages of anaesthesia maintenance with propofol over inhalational agents. While these benefits result in an increased patient satisfaction, the clinical and economic relevance of these findings still need to be addressed in adequately powered prospective clinical trials. PMID- 30409187 TI - Nicotine promotes neuron survival and partially protects from Parkinson's disease by suppressing SIRT6. AB - Parkinson's disease is characterized by progressive death of dopaminergic neurons, leading to motor and cognitive dysfunction. Epidemiological studies consistently show that the use of tobacco reduces the risk of Parkinson's. We report that nicotine reduces the abundance of SIRT6 in neuronal culture and brain tissue. We find that reduction of SIRT6 is partly responsible for neuroprotection afforded by nicotine. Additionally, SIRT6 abundance is greater in Parkinson's patient brains, and decreased in the brains of tobacco users. We also identify SNPs that promote SIRT6 expression and simultaneously associate with an increased risk of Parkinson's. Furthermore, brain-specific SIRT6 knockout mice are protected from MPTP-induced Parkinson's, while SIRT6 overexpressing mice develop more severe pathology. Our data suggest that SIRT6 plays a pathogenic and pro inflammatory role in Parkinson's and that nicotine can provide neuroprotection by accelerating its degradation. Inhibition of SIRT6 may be a promising strategy to ameliorate Parkinson's and neurodegeneration. PMID- 30409188 TI - Urothelium with barrier function differentiated from human urine-derived stem cells for potential use in urinary tract reconstruction. AB - BACKGROUND: Autologous urothelial cells are often obtained via bladder biopsy to generate the bio-engineered urethra or bladder, while urine-derived stem cells (USC) can be obtained by a non-invasive approach. The objective of this study is to develop an optimal strategy for urothelium with permeability barrier properties using human USC which could be used for tissue repair in the urinary tract system. METHODS: USC were harvested from six healthy adult individuals. To optimize urothelial differentiation, five different differentiation methods were studied. The induced cells were assessed for gene and protein expression markers of urothelial cells via RT-PCR, Western blotting, and immunofluorescent staining. Barrier function and ultrastructure of the tight junction were assessed with permeability assays and transmission electron microscopy (TEM). Induced cells were both cultured on trans-well membranes and small intestinal submucosa, then investigated under histology analysis. RESULTS: Differentiated USC expressed significantly higher levels of urothelial-specific transcripts and proteins (Uroplakin III and Ia), epithelial cell markers (CK20 and AE1/AE3), and tight junction markers (ZO-1, ZO-2, E-cadherin, and Cingulin) in a time-dependent manner, compared to non-induced USC. In vitro assays using fluorescent dye demonstrated a significant reduction in permeability of differentiated USC. In addition, transmission electron microscopy confirmed appropriate ultrastructure of urothelium differentiated from USC, including tight junction formation between neighboring cells, which was similar to positive controls. Furthermore, multilayered urothelial tissues formed 2 weeks after USC were differentiated on intestine submucosal matrix. CONCLUSION: The present study illustrates an optimal strategy for the generation of differentiated urothelium from stem cells isolated from the urine. The induced urothelium is phenotypically and functionally like native urothelium and has proposed uses in in vivo urological tissue repair or in vitro urethra or bladder modeling. PMID- 30409189 TI - Factors contributing to motivation of volunteer community health workers in Ethiopia: the case of four woredas (districts) in Oromia and Tigray regions. AB - BACKGROUND: The use of community health workers (CHWs) has been considered as one of the strategies to address the growing shortage of health workers, predominantly in low-income countries. They are playing a pivotal role in lessening health disparities through improving health outcomes for underserved populations. Yet, little is known about what factors motivate and drive them to continue working as CHWs. In this study, we aimed to examine factors contributing to the motivation of volunteer CHWs (vCHWs) in Ethiopia currently known as one-to five network leaders (1to5NLs) and explore variations between attributes of social and work-related determinants. METHOD: We conducted a cross-sectional study in four selected woredas (the second lowest administrative structure in Ethiopia, and similar to a district) of Oromia and Tigray regions and interviewed 786 1to5NLs. The effects of each motivational factor were explored using percentage of respondents who agreed and strongly agreed to each of them and Mann Whitney U test. RESULTS: Individual, community, and health system factors contributed to the motivation of 1to5NLs in this study. Intrinsic desire to have a good status in the community as a result of their volunteer service (81.86%) followed by a commitment to serve the community (81.61%) and to gain satisfaction by accomplishing something worthwhile to the community (81.61%) were some of the factors motivating 1to5NLs in our study. Despite these motivational items, factors such as lack of career development (51.47%), unclear health development army guideline (59.26%), limited supervision and support (62.32%), and lack of recognition and appreciation of accomplishments (63.22%) were the factors negatively affecting motivation of 1to5NLs. Lack of career development, limited supervision and support, and lack of recognition and appreciation of accomplishments were significantly varied between attributes of educational level, marital status, service year as 1to5NLs, and previous volunteer engagement (at P < 0.05). CONCLUSION: Findings of our study indicated that non-financial incentives such as the creation of career development models is the key to motivating and retaining CHWs where they are not receiving stipends. Sustainability of CHW program should consider exploring enhanced innovations to strengthen supportive supervision, development of better mechanisms to publicize the role of CHWs, and improvement of recognition and appreciation schemes for CHWs' efforts and accomplishments. PMID- 30409190 TI - Fat extract promotes angiogenesis in a murine model of limb ischemia: a novel cell-free therapeutic strategy. AB - BACKGROUND: The proangiogenic capacity of adipose tissue and its derivatives has been demonstrated in a variety of studies. The paracrine mechanism of the cellular component is considered to play a critical role in the regenerative properties of these tissues. However, cell-based therapy for clinical application has been hindered by limitations such as safety, immunogenicity issues, and difficulties in cell preservation, transportation, and phenotype control. In the current study, we aimed to produce a cell-free extract directly from human fat tissue and evaluate its potential therapeutic efficacy. METHODS: We developed a novel physical approach to produce a cell-free aqueous extract from human fat tissue (fat extract (FE)). The therapeutic potential of FE was investigated in the ischemic hindlimb model of nude mice. After establishment of hindlimb ischemia with ligation of the left femoral artery and intramuscular injection of FE, blood perfusion was monitored at days 0, 7, 14, 21, and 28. Tissue necrosis and capillary density were evaluated. Enzyme-linked immunosorbent assay was used to analyze the growth factors contained in FE. Moreover, the proliferation, migration, and tube formation ability were tested on human umbilical vein endothelial cells (HUVECs) in vitro when treated with FE. The proangiogenic ability of FE was further assessed in an in-vivo Matrigel plug assay. RESULTS: FE was prepared and characterized. The intramuscular injection of FE into the ischemic hindlimb of mice attenuated severe limb loss and increased blood flow and capillary density of the ischemic tissue. Enzyme-linked immunosorbent assay showed that FE contained high levels of various growth factors. When added as a cell culture supplement, FE promoted HUVEC proliferation, migration, and tube formation ability in a dose-dependent manner. The subcutaneous injection of Matrigel infused with FE enhanced vascular formation. CONCLUSIONS: We developed a novel cell-free therapeutic agent, FE, produced from human adipose tissue. FE was able to attenuate ischemic injury and stimulate angiogenesis in ischemic tissues. This study indicates that FE may represent a novel cell-free therapeutic agent in the treatment of ischemic disorders. PMID- 30409191 TI - Mutant UBQLN2P497H in motor neurons leads to ALS-like phenotypes and defective autophagy in rats. AB - Mutations in ubiquilin2 (UBQLN2) have been linked to abnormal protein aggregation in amyotrophic lateral sclerosis (ALS). The mechanisms underlying UBQLN2-related neurodegenerative diseases remain unclear. Using a tetracycline-regulated gene expression system, the ALS-linked UBQLN2P497H mutant was selectively expressed in either the spinal motor neurons or astrocytes in rats. We found that selectively expressing mutant UBQLN2P497H in the spinal motor neurons caused several core features of ALS, including the progressive degeneration of motor neurons, the denervation atrophy of skeletal muscles, and the abnormal protein accumulation. Furthermore, mutant UBQLN2P497H accumulation was associated with an age-dependent decrease in several core autophagy-related proteins. ALS-like phenotypes were not observed when mutant UBQLN2P497H was overexpressed in the astrocytes, however, even though the expression of the mutant UBQLN2P497H protein was higher in these rats. Our results suggest that selectively expressing mutant UBQLN2P497H in motor neurons is sufficient to trigger the development of ALS in rats. Our results further indicate that the compromised autophagy-lysosomal pathway plays a critical role in the pathogenesis of UBQLN2-related neurodegenerative diseases. PMID- 30409192 TI - Overcoming barriers to facilitate the regulation of multi-centre regenerative medicine clinical trials. AB - In the context of regenerative medicine and cellular therapies, the treatment under study often targets a less common disease or condition for which recruitment of a large number of research participants at any given site is challenging, if not impossible. One way to overcome this challenge is with a multi-centre clinical trial. This manuscript first aims to briefly outline the existing ethical, legal and social implications as well as the regulatory frameworks associated with multi-centre regenerative medicine clinical trials. Second, it considers the regulatory limitations and barriers surrounding the initiation of such trials in Canada, the USA and Europe. Third, it concludes with a set of recommendations for facilitating multi-centre clinical trials, at both national and international levels. PMID- 30409194 TI - Costs incurred by outpatients at a university hospital in northwestern Ethiopia: a cross-sectional study. AB - BACKGROUND: Out-of-pocket expenditure constitutes high proportion of healthcare spending in low-income countries. It can affect patients' adherence to treatments leading to serious health consequences. The objective of this study was to document costs incurred by patients visiting Gondar University Referral Hospital, in Gondar, northwestern Ethiopia. METHODS: An institution-based cross-sectional study was conducted among 346 outpatients at the hospital from 2nd to 20th of May 2016. Data collection took place through interviews with patients coming to the outpatient pharmacy after finishing their visits at the different departments in the hospital. Data were collected on socio-demographic information, cost incurred before and during hospital visit as well as ownership of household items. RESULTS: Among the 342 interviews included in the final analysis, a median total cost of 22.25 USD was incurred by patients. This constituted spending on solutions tried before hospital visit, direct medical, nonmedical and indirect costs. Among these, direct nonmedical and indirect costs constituted a large share. Medicine, transportation and waiting time during visit were major components of direct medical, nonmedical and indirect costs respectively. Total median cost was found to be predicted by residence, marital status and payment scheme used to pay for hospital services. CONCLUSIONS: Outpatients visiting the hospital incurred significant costs for illnesses/conditions associated with their visit to the hospital, the main components being nonmedical and indirect costs. Residence, marital status and payment scheme, predicted median total cost. Direct nonmedical costs and indirect costs were found to be significant components associated to the spending and loss of earning by patients and their families in their trip to and from the hospital. PMID- 30409193 TI - Metformin induces apoptosis in mesenchymal stromal cells and dampens their therapeutic efficacy in infarcted myocardium. AB - BACKGROUND: Cardiovascular complications, especially myocardial infarctions (MIs), are the leading mortality cause in diabetic patients. The transplantation of stem cells into damaged hearts has had considerable success as a treatment for MI, although whether antidiabetic drugs affect the therapeutic efficacy of stem cell transplantation is still unknown. This study aims to understand whether and how metformin, one of the first-line drugs used to treat type 2 diabetes mellitus (T2DM), induces mesenchymal stromal cell (MSC) apoptosis and dampens their cardioprotective effect after transplantation into infarcted hearts. METHODS: A mouse MI model was generated via permanent ligation of the left anterior descending (LAD) coronary artery. MSCs with or without metformin treatment were transplanted after MI in diabetic mice. Echocardiography was used to assess cardiac function and determine cardiac remodeling, and TTC staining was performed to evaluate infarction size. A mouse gavage model was performed to evaluate bone marrow MSCs for flow cytometry assay. RESULTS: Metformin dampened MSC therapeutic efficacy, which increased infarct size and restricted functional cardiac recovery. Specifically, metformin induced the activation of AMP-activated protein kinase (AMPK)-mediated apoptosis through the inhibition of S6K1-Bad-Bcl-xL cell survival signaling, resulting in the upregulated expression of apoptosis associated proteins and increased MSC apoptosis. Accordingly, counteracting AMPK attenuated metformin-induced apoptosis in MSCs and partially restored their cardioprotective effects in diabetic mice with MI. Furthermore, a decrease in peripheral blood MSCs was found in patients with T2DM who had a metformin medication history. CONCLUSIONS: Our results highlight an unexpected adverse effect of metformin-induced MSC apoptosis through AMPK-mediated mTOR suppression, which is attenuated by an AMPK inhibitor. Moreover, AMPK inhibition may be a novel strategy for enhancing the effectiveness of stem cell therapy after MI in diabetes. PMID- 30409196 TI - Association of facial ageing with DNA methylation and epigenetic age predictions. AB - Evaluation of biological age, as opposed to chronological age, is of high relevance for interventions to increase healthy ageing. Highly reproducible age associated DNA methylation (DNAm) changes can be integrated into algorithms for epigenetic age predictions. These predictors have mostly been trained to correlate with chronological age, but they are also indicative for biological ageing. For example, accelerated epigenetic age of blood is associated with higher risk of all-cause mortality in later life. The perceived age of facial images (face-age) is also associated with all-cause mortality and other ageing associated traits. In this study, we therefore tested the hypothesis that an epigenetic predictor for biological age might be trained on face-age as a surrogate for biological age rather than on chronological age. Our data demonstrate that facial ageing does not correlate with either the epigenetic clock or blood-based DNAm measures. PMID- 30409195 TI - Feasibility and acceptability of a proposed trial of acupuncture as an adjunct to lifestyle interventions for weight loss in Polycystic Ovary Syndrome: a qualitative study. AB - BACKGROUND: Polycystic Ovary Syndrome (PCOS) is a common female reproductive disorder with multiple manifestations. Weight management is a key therapeutic goal. Acupuncture is a potential adjunctive weight loss treatment in non-PCOS populations. We aimed to engage patients in co-design and assess the feasibility and acceptability of methods for a randomised controlled trial (RCT) on acupuncture and telephone-based health coaching for weight management in overweight or obese women with PCOS using qualitative methods. METHODS: We recruited women who had PCOS and were aged 18-45 years and with a body mass index of 25 kg/m2 and over, using social media. Two face-to-face focus group meetings and three semi-structured telephone interviews were conducted (n = 10). We analysed data using thematic analysis and aimed to compare and contrast motivations for joining the trial between women who were actively trying to conceive (n = 7) and not trying to conceive (n = 3). Attitudes to, knowledge and experiences of acupuncture; perceptions and attitudes towards the interventions in the RCT (real acupuncture, sham acupuncture and telephone-based health coaching); the outcomes of importance; and barriers and facilitators to successful trial recruitment and retention were collected. RESULTS: Women were both acupuncture-naive and acupuncture-experienced. Overall, attitudes towards acupuncture were positive, and the trial design was acceptable with appointment flexibility requested. Ideal enrolment time, if women were trying to conceive, was six months prior to conception. Women supported three-month intervention and the use of sham acupuncture as a control. Financial incentives were not believed to be necessary, and women spoke of altruistic intentions in enrolling for such a trial. Women who were trying to conceive voiced a need for support from their family, health coaches, and peers. The telephone-based health coaching offered welcome support and accountability, noted as possible facilitators of weight loss. CONCLUSIONS: Our findings show that acupuncture is a likely acceptable adjunct to lifestyle interventions for weight loss in PCOS, and that a sham controlled trial is feasible and acceptable to PCOS women. Further research is required in order to evaluate the efficacy of acupuncture together with lifestyle for weight management in PCOS. PMID- 30409197 TI - Ultrasound-guided vessel puncture: calling for Pythagoras' help. PMID- 30409198 TI - Perspective on nanochannels as cellular mediators in different disease conditions. AB - Tunnelling nanotubes (TNTs), also known as membrane nanochannels, are actin-based structures that facilitate cytoplasmic connections for rapid intercellular transfer of signals, organelles and membrane components. These dynamic TNTs can form de novo in animal cells and establish complex intercellular networks between distant cells up to 150 MUm apart. Within the last decade, TNTs have been discovered in different cell types including tumor cells, macrophages, monocytes, endothelial cells and T cells. It has also been further elucidated that these nanotubes play a vital role in diseased conditions such as cancer, where TNT formation occurs at a higher pace and is used for rapid intercellular modulation of chemo-resistance. Viruses such as HIV, HSV and prions also hijack the existing TNT connections between host cells for rapid transmission and evasion of the host immune responses. The following review aims to describe the heterogeneity of TNTs, their role in different tissues and disease conditions in order to enhance our understanding on how these nanotubes can be used as a target for therapies. PMID- 30409199 TI - Synovial sarcoma of the brachial plexus - a rare tumor in a rare area: a case report. AB - BACKGROUND: Synovial cell sarcomas are usually seen in a juxta-articular location. However, they occur rarely in the head and neck region. CASE PRESENTATION: We report a rare case of brachial plexus synovial sarcoma in a 24 year old South Asian man treated successfully with surgical excision followed by radiotherapy. CONCLUSIONS: Synovial sarcoma arising from the brachial plexus is rare. The treatment is multimodal with complete excision (often challenging owing to the proximity of the neurovascular structures) and adjuvant therapy. PMID- 30409201 TI - Impact of seasons on stroke-related depression, mediated by vitamin D status. AB - BACKGROUND: This study aimed to describe the seasonal variation of depression prevalence among stroke patients at 1 month and to explore whether vitamin D plays a role in the association between seasons and post-stroke depression (PSD). METHODS: Data were collected from 402 acute stroke patients. Seasons were stratified by summertime (June to November) and wintertime (December to May) based on vitamin D status. The impact of seasons on PSD was assessed via binary logistic regression, with summertime considered the referent category. The mediating effect was used to evaluate whether vitamin D plays a role in the association between seasons and PSD. RESULTS: The prevalence of PSD was significantly higher in the wintertime group than in the summertime group (P = 0.003). The serum vitamin D level was lower in wintertime than in summertime (P < 0.001). Lower vitamin D levels were associated with higher HAMD scores (P < 0.001). In the multivariate analysis, patients in the wintertime group had a higher prevalence of PSD compared with those in the summertime group across all binary logistic regression models after adjusting for potential confounders. When serum vitamin D was added to the above model, there was no association between seasons and PSD (P = 0.056). Vitamin D was independently associated with PSD (OR 0.95, 95% CI 0.935-0.966, P < 0.001). CONCLUSION: There was a clear seasonal variation in depression prevalence among stroke patients. Vitamin D status plays a critical mediating role in the relationship between season and post-stroke depression. PMID- 30409200 TI - Postoperative pain and short-term complications after two elective sterilization techniques: ovariohysterectomy or ovariectomy in cats. AB - BACKGROUND: Surgical sterilization of cats is one of the most commonly performed procedures in veterinary practice and it can be accomplished by two different techniques: ovariohysterectomy (OVH) or ovariectomy (OVE). Although there is an apparent preference for OVH in United States and Canada, OVE seems to be the standard of care in many European countries due to its advantages, such as a smaller surgical incision and potentially less complications associated with surgical manipulation of the uterus. The aim of this randomized, blind, prospective study was to compare postoperative pain and short-term complications in cats undergoing ovariohysterectomy or ovariectomy. METHODS: Twenty female cats were randomly assigned into two groups (OVH, n = 10 and OVE, n = 10). Pain was assessed prior to surgery (baseline) and 1, 2, 4, 8 12 and 24 h after the procedure using pain and sedation scales, physiologic parameters and blood glucose levels. Short-term complications were evaluated in the early postoperative period and reassessed at day 7 and day 10. RESULTS: Changes in cardiovascular parameters were not clinically relevant, however cats in OVH group had higher heart rates at T1 h compared with baseline (p = 0.0184). Blood glucose levels in OVH group were also higher at T1 h compared with baseline (p = 0.0135) and with OVE group (p = 0.0218). Surgical time was higher in OVH group (p = 0.0115). Even though no significant differences in pain scores were observed between groups or time points, cats in OVH group had greater need for rescue analgesia compared with OVE (2/10 and 0/10, respectively). Complications were not observed in any cat during surgery, at days 7 and 10 postoperatively or at discharge. CONCLUSIONS: Both surgical techniques promoted similar intensity of postoperative pain in cats and there were no short-term complications throughout the study's evaluation period. Therefore, both techniques may be indicated for surgical sterilization of cats, according to the surgeon's preference and expertise. Cats that underwent ovariectomy did not require rescue analgesia and surgical time was shorter in that group. PMID- 30409202 TI - Time course of changes in motor-cognitive exergame performances during task specific training in patients with dementia: identification and predictors of early training response. AB - BACKGROUND: Some studies have already suggested that exergame interventions can be effective to improve physical, cognitive, motor-cognitive, and psychological outcomes in patients with dementia (PwD). However, little is known about the training volume required to induce such positive effects and the inter-individual differences in training response among PwD. The aim of the study was to analyze the time course of changes in motor-cognitive exergame performances during a task specific training program and to identify predictors of early training response in PwD. METHODS: Secondary analyses of data from the intervention group (IG) of a randomized, placebo-controlled trial to improve motor-cognitive performances in PwD. Fifty-six geriatric patients with mild-to-moderate dementia randomized to the IG underwent a 10-week, task-specific training program (2*/week) on an exergame-based balance training system (Physiomat(r)), combining postural control tasks with cognitive tasks of an established neuropsychological test (Trail Making Test). Main outcome was the time required to complete different Physiomat(r)-Tasks (PTs) assessed at baseline (T1), training session 7 (TS7) and 14 (TS14), and post-intervention after 20 training sessions (T2). Reliable change indices were used to identify early responders from T1 to TS7. A multivariate logistic regression analysis was performed to determine independent predictors of early training response. RESULTS: Completion time significantly improved already from T1 to TS7 in all PTs (p <= .001-.006), with moderate to very large effect sizes (r = .38-.52; Cohen's d = .85-1.45). For most PTs, significant progressive improvements from TS7 to TS14 and TS14 to T2 were not observed. Thirty-one (59.6%) participants were classified as early responders and 21 (40.4%) as non early responders. Lower baseline exergame performance and lower visuospatial and divided attention abilities were independently associated with early training response. CONCLUSIONS: Substantial task-specific improvements in complex motor cognitive exergame performances can be obtained within a surprisingly short intervention period in PwD. Our results confirm that not only an excellent training response can be achieved in this patient population, but also that more vulnerable patients with greater deficits in domain-specific cognitive functions associated with fall risk may even reap the most and fastest benefit from motor cognitive exergame interventions. TRIAL REGISTRATION: ISRCTN registry, ISRCTN37232817 (retrospectively registered on 04/02/2012). PMID- 30409203 TI - Serum AGE/RAGEs as potential biomarker in idiopathic pulmonary fibrosis. AB - BACKGROUND: The soluble receptor for advanced glycation end-products (sRAGE) has been suggested that it acts as a decoy for capturing advanced glycation end products (AGEs) and inhibits the activation of the oxidative stress and apoptotic pathways. Lung AGEs/sRAGE is increased in idiopathic pulmonary fibrosis (IPF). The objective of the study was to evaluate the AGEs and sRAGE levels in serum as a potential biomarker in IPF. METHODS: Serum samples were collected from adult patients: 62 IPF, 22 chronic hypersensitivity pneumonitis (cHP), 20 fibrotic non specific interstitial pneumonia (fNSIP); and 12 healthy controls. In addition, 23 IPF patients were re-evaluated after 3-year follow-up period. Epidemiological and clinical features were recorded: age, sex, smoking habits, and lung function. AGEs and sRAGE were evaluated by ELISA, and the results were correlated with pulmonary functional test values. RESULTS: IPF and cHP groups presented a significant increase of AGE/sRAGE serum concentration compared with fNSIP patients. Moreover, an inverse correlation between AGEs and sRAGE levels were found in IPF, and serum sRAGE at diagnosis correlated with FVC and DLCO values. Additionally, changes in serum AGEs and sRAGE correlated with % change of FVC, DLCO and TLC during the follow-up. sRAGE levels below 428.25 pg/ml evolved poor survival rates. CONCLUSIONS: These findings demonstrate that the increase of AGE/sRAGE ratio is higher in IPF, although the levels were close to cHP. AGE/sRAGE increase correlates with respiratory functional progression. Furthermore, the concentration of sRAGE in blood stream at diagnosis and follow up could be considered as a potential prognostic biomarker. PMID- 30409204 TI - Experiences of Dutch general practitioners and district nurses with involving care services and facilities in palliative care: a mixed methods study. AB - BACKGROUND: Generals practitioners (GPs) and district nurses (DNs) play a leading role in providing palliative care at home. Many services and facilities are available to support them in providing this complex care. This study aimed to examine the extent to which GPs and DNs involve these services, what their experiences are, and how involvement of these services and facilities can be improved. METHODS: Sequential mixed methods consisting of an online questionnaire with structured and open questions completed by 108 GPs and 258 DNs, followed by three homogenous online focus groups with 8 GPs and 19 DNs, analyzed through open coding. RESULTS: Most GPs reported that they sometimes or often involved palliative home care teams (99%), hospices (94%), and palliative care consultation services (93%). Most DNs reported sometimes or often involving volunteers (90%), hospices (88%), and spiritual caregivers (80%). The least involved services and facilities were psychologists and psychiatrists (51% and 50%) and social welfare (44% and 57%). Main reason for not involving services and facilities was 'not needing' them. If they had used them, most GPs and DNs (68 93%) reported solely positive experiences. Hardly anyone (0-3%) reported solely negative experiences with any of the services and the facilities. GPs and DNs suggested improvements in three areas: (1) establishment of local centers giving information on available services and facilities, (2) presentation of services and facilities in local multidisciplinary meetings, and (3) support organizations to proactively offer their facilities and services. CONCLUSION: Psychological, social, and spiritual services are involved less often, suggesting that the classic care model, which focuses strongly on somatic issues, is still well entrenched. More familiarity with services that can provide additional care in these areas, regarding their availability and their added value, could improve the quality of life for patients and relatives at the end of life. PMID- 30409205 TI - Histone acetyl transferase TIP60 inhibits the replication of influenza a virus by activation the TBK1-IRF3 pathway. AB - Influenza A virus (IAV) is an important pathogen that poses a severe threat to the health of humans. Nucleoprotein (NP) of IAV plays crucial roles in the viral life cycle by interacting with various cellular factors. Histone Acetyl Transferase TIP60 is a key target of several viral proteins during infection, including HIV-1 Tat, HPV E6, HTLV-1 p30II and HCMV UL27 proteins. However, Whether the interaction between the IAV NP and TIP60, and the role of TIP60 in IAV life cycle are largely unknown. Here, we showed that IAV infection up regulated TIP60 protein and RNA expression. Overexpression of TIP60 inhibited viral protein and RNA expression and reduced the progeny viral titer. Further study revealed that TIP60 inhibited viral replication through activation of TBK1 IRF3 signaling pathway. Furthermore, we demonstrated that the NP protein of IAV interacted with TIP60. Together, these results indicate that TIP60 play a repressor in IAV infection, and it may be a possible target for antiviral drugs. PMID- 30409206 TI - Bacterial profile, antibiotic susceptibility pattern and associated factors among pregnant women with Urinary Tract Infection in Goba and Sinana Woredas, Bale Zone, Southeast Ethiopia. AB - OBJECTIVE: Urinary tract infection (UTI) is one of the commonest infections affecting millions worldwide, especially pregnant women. It can lead to poor maternal and perinatal outcomes. Untreated UTI can be associated with serious obstetric complications. So the objective of present study was to determine the bacterial profile, antibiotic susceptibility pattern and associated factors of UTI among pregnant women in Goba and Sinana Woredas, Bale Zone, Southeast Ethiopia. RESULTS: The overall prevalence of UTI was 44/169 (26%) with 18/51 (35.3%) in symptomatic and 26/118 (22%) in asymptomatic pregnant women, respectively. Of the 44 bacterial isolates, E. coli 12/44 (27.3%), K. pneumonia 9/44 (20.5%) and S. marcescens 4/44 (9.1%) were the commonest bacterial pathogens. C. freundii 3/44 (6.8%), M. morganii 3/44 (6.8%), P. aeruginosa 3/44 (6.8%) and S. enteritidis 3/44 (6.8%) isolates were the moderately identified bacterial species. K. oxytoca 1/44 (2.3%) was the least common bacterium to be detected. The antibiotic susceptibility pattern showed that 90.9%, 88.6% and 86.3% of the isolates were sensitive to amoxicillin/clavulanic acid, gentamycin and norfloxacin, respectively. Significant bacteriuria was associated with low educational status (p = 0.024; AOR = 6.617; CI = 1.87-9.94) and kidney problems (p = 0.018; AOR = 0.286; CI = 1.19-2.81). PMID- 30409208 TI - Correction to: Prevalence, antimicrobial susceptibility profile and predictors of asymptomatic bacteriuria among pregnant women in Adigrat General Hospital, Northern Ethiopia. AB - Following publication of the original article [1], the authors reported that one of the authors' names was spelled incorrectly. In this Correction the incorrect and correct author name are shown. The original publication of this article has been corrected. PMID- 30409207 TI - An adult autosomal recessive chronic granulomatous disease patient with pulmonary Aspergillus terreus infection. AB - BACKGROUND: Genetic mutations that reduce intracellular superoxide production by granulocytes causes chronic granulomatous disease (CGD). These patients suffer from frequent and severe bacterial and fungal infections throughout their early life. Diagnosis is usually made in the first 2 years of life but is sometimes only diagnosed when the patient is an adult although they may have suffered from symptoms since childhood. CASE PRESENTATION: A 26-year-old man was referred with weight loss, fever, hepatosplenomegaly and coughing. He had previously been diagnosed with lymphadenopathy in the neck at age 8 and prescribed anti tuberculosis treatment. A chest radiograph revealed extensive right-sided consolidation along with smaller foci of consolidation in the left lung. On admission to hospital he had respiratory problems with fever. Laboratory investigations including dihydrorhodamine-123 (DHR) tests and mutational analysis indicated CGD. Stimulation of his isolated peripheral blood neutrophils (PMN) with phorbol 12-myristate 13-acetate (PMA) produced low, subnormal levels of reactive oxygen species (ROS). Aspergillus terreus was isolated from bronchoalveolar lavage (BAL) fluid and sequenced. CONCLUSIONS: We describe, for the first time, the presence of pulmonary A. terreus infection in an adult autosomal CGD patient on long-term corticosteroid treatment. The combination of the molecular characterization of the inherited CGD and the sequencing of fungal DNA has allowed the identification of the disease-causing agent and the optimal treatment to be given as a consequence. PMID- 30409209 TI - Self-management needs of Irish adolescents with Juvenile Idiopathic Arthritis (JIA): how can a Canadian web-based programme meet these needs? AB - BACKGROUND: Juvenile Idiopathic Arthritis (JIA) affects over 1000 children and adolescents in Ireland, potentially impacting health-related quality-of-life. Accessible self-management strategies, including Internet-based interventions, can support adolescents in Ireland where specialist rheumatology care is geographically-centralised within the capital city. This study interviewed adolescents with JIA, their parents, and healthcare professionals to (i) explore the self-management needs of Irish adolescents; and (ii) evaluate the acceptability of an adapted version of a Canadian JIA self-management programme (Teens Taking Charge: Managing Arthritis Online, or TTC) for Irish users. METHODS: Focus groups and interviews were conducted with Irish adolescents with JIA (N = 16), their parents (N = 13), and Irish paediatric healthcare professionals (HCPs; N = 22). Adolescents were aged 12-18 (Mage = 14.19 years), and predominantly female (62.5%). Participants identified the needs of adolescents with JIA and evaluated the usefulness of the TTC programme. Data were analysed using a thematic analysis approach. RESULTS: Five themes emerged: independent self-management; acquiring skills and knowledge to manage JIA; unique challenges of JIA in Ireland; views on web-based interventions; and understanding through social support. Adolescents acknowledged the need for independent self management and gradually took additional responsibilities to achieve this goal. However, they felt they lacked information to manage their condition independently. Parents and adolescents emphasised the need for social support and felt a peer-support scheme could provide additional benefit to adolescents if integrated within the TTC programme. All participants endorsed the TTC programme to gain knowledge about JIA and offered suggestions to make the programme relevant to Irish users. CONCLUSIONS: There is scope for providing easily accessible, accurate information to Irish families with JIA. The acceptability of adapting an existing JIA self-management intervention for Irish users was confirmed. PMID- 30409211 TI - In vitro MSC function is related to clinical reaction in vivo. AB - BACKGROUND: We recently demonstrated that intracellular xenogen-contaminated autologous MSCs (FBS) and non-xenogen-contaminated allogeneic (ALLO) MSCs caused an adverse clinical response after repeated intra-articular injection in horses, whereas autologous (AUTO) MSCs did not. Our current objective was to use clinical data from the previous study to compare MSC stemness against adverse response indicated by synovial total nucleated cell count (TNCC) following intra-articular MSC injection. METHODS: Stemness, quantified by a trilineage differentiation (TLD) score; immunomodulation, quantified by mixed lymphocyte reactions (MLRs); and degree of MHCI expression, quantified by mean fluorescent intensity (MFI); were correlated to the synovial TNCC 24 h after naive and primed injection. RESULTS: There was a trend of a negative correlation (p = 0.21, r = - 0.44) between TLD score and TNCC after primed injection in the ALLO group. Within the ALLO group only, there was a significant positive correlation (p = 0.05, r = 0.77) between MHCI MFI and TNCC after naive injection and a trend (p = 0.16, r = 0.49) of a positive association of MHCI MFI to TNCC after primed injection. Within the FBS group only, there was a positive correlation (p = 0.04, r = 1) between TNCC and lymphocyte proliferation after both injections. CONCLUSIONS: The trend of a negative correlation of TLD score and TNCC in the ALLO, but not the FBS group, together with the association of MHCI expression and TNCC in the ALLO group, indicates that improved stemness is associated with reduced MSC immunogenicity. When inflammation was incited by xenogen, there was a strong correlation of lymphocyte activation in vitro to adverse response in vivo, confirming that MLRs in vitro reflect MSC immunomodulatory activity in vivo. The relationship of stemness in vitro, suppression of lymphocyte activation in vitro, MHCI expression in vitro, and clinical response in vivo should be further investigated. PMID- 30409210 TI - Reduction of the survival time of pig xenotransplants by porcine cytomegalovirus. AB - BACKGROUND: Xenotransplantation using pig cells, tissues and organs may help to overcome the shortage of human tissues and organs for the treatment of tissue and organ failure. Progress in the prevention of immunological rejection using genetically modified pigs and new, more effective, immunosuppression regimens will allow clinical application of xenotransplantation in near future. However, xenotransplantation may be associated with the transmission of potentially zoonotic porcine microorganisms. Until now the only xenotransplantation associated transmission was the transmission of the porcine cytomegalovirus (PCMV) into non-human primates. PCMV caused a significant reduction of the survival time of the pig transplant. Here the available publications were analysed in order to establish the mechanism how PCMV shortened the survival time of xenotransplants. PCMV is a herpesvirus related to the human cytomegalovirus and the human herpesviruses 6 and 7. These three human herpesviruses can cause serious disease among immunocompromised human individuals, including transplant recipients. It was shown that PCMV predominantly contributes to the reduction of transplant survival in non-human primates by disruption of the coagulation system and by suppression and exhaustion of the immune system. CONCLUSION: Although it is still unknown whether PCMV infects primate cells including human cells, indirect mechanism of the virus infection may cause reduction of the xenotransplant survival in future clinical trials and therefore PCMV has to be eliminated from donor pigs. PMID- 30409212 TI - Results of a randomized controlled trial of level IIb preserving neck dissection in clinically node-negative squamous carcinoma of the oral cavity. AB - BACKGROUND: The lymphatic spread from the cancers of the oral cavity follows an orderly progression and involvement of lower nodes without involvement of upper nodes and skip metastasis is rare. Selective neck dissections are increasingly being performed for node-positive patients; however, in node-negative patients the options of wait and watch, prophylactic radiotherapy, and prophylactic elective node dissections are debated. Quality of life and shoulder functions are important to choose the appropriate therapeutic modality. PATIENTS AND METHODS: Patients with oral squamous carcinoma with clinically and radiologically negative neck were randomized to IIb preserving superselective neck dissection or conventional supraomohyoid neck dissection. The primary end point of the study was recurrence of disease (clinical or radiological) and shoulder function as demonstrated by the clinical examination and electromyography. The secondary end point was quality of life as measured by the FACT-HN version 4 questionnaire at the end of 1 year follow-up. RESULTS: The mean number of lymph node harvested per patient was 25.6 (range 8-85). Of the 32 patients, 3 had histologically positive node in level Ib, one of these patients had single positive node while the remaining two had three positive nodes in level Ib. At median follow-up of 36 months disease-free survival in IIb, sparing group was 83% compared to 91% in control arm, the difference in survival between two groups was statistically not significant (p = 0.694). EMG of the shoulder showed denervation pattern in 45% patients undergoing IIb preserving surgery at 1 month follow-up compared to 95% in conventional surgery group, this recovered in all patients but one at 3 months and 100% recovery was seen at 6 months. CONCLUSIONS: The results of the present study indicate that superselective IIb preserving neck dissections are technically feasible and appear to be oncologically safe procedures when performed as elective prophylactic procedures in highly select group of patients. A significant number of occult metastasis seen in the present study suggests prophylactic dissection to be better than wait and watch policy. Results also show initial higher shoulder morbidity at 1 month in patients undergoing IIb preserving dissections; however, at the end of 1 year recovery is complete and both procedures are comparable. TRIAL REGISTRATION: The trial is registered at clinicaltrials.gov with registration no NCT00847717 ; registered on February 19, 2009. PMID- 30409214 TI - What is the place for philosophy within the field of medicine? A review of contemporary issues in medical ethics. AB - This extended essay seeks to unpack some of the key aspects of philosophy which are applicable to medical thought and practice. It proceeds via an analytical discussion of the contemporary debate in three key areas of medical ethics: euthanasia, concepts of health & disease and psychiatry.The main claims are as follows: 1. The case for legalising euthanasia is strong on philosophical grounds but there are numerous practical obstacles. 2. Elements from the normative and naturalistic definitions of disease are necessary for a thorough definition that dodges common objections to either. 3. Mental health cannot be subsumed under a purely physicalist model of health rendering it distinctly different from other fields in Medicine. Through a detailed discussion of three salient issues in the philosophy of medicine, it is argued that the application of profound philosophical thought to medicine and its practices reveals a depth that necessitates exploration before simply following the aims of curing all. Philosophical rigour matched with modern medicine has the potential to engage patients and help them make independent, informed decisions and assist physicians to think more clearly, analytically and empathetically. PMID- 30409215 TI - Characterization of minority HIV-1 drug resistant variants in the United Kingdom following the verification of a deep sequencing-based HIV-1 genotyping and tropism assay. AB - BACKGROUND: The widespread global access to antiretroviral drugs has led to considerable reductions in morbidity and mortality but, unfortunately, the risk of virologic failure increases with the emergence, and potential transmission, of drug resistant viruses. Detecting and quantifying HIV-1 drug resistance has therefore become the standard of care when designing new antiretroviral regimens. The sensitivity of Sanger sequencing-based HIV-1 genotypic assays is limited by its inability to identify minority members of the quasispecies, i.e., it only detects variants present above ~ 20% of the viral population, thus, failing to detect minority variants below this threshold. It is clear that deep sequencing based HIV-1 genotyping assays are an important step change towards accurately monitoring HIV-infected individuals. METHODS: We implemented and verified a clinically validated HIV-1 genotyping assay based on deep sequencing (DEEPGENTM) in two clinical laboratories in the United Kingdom: St. George's University Hospitals Healthcare NHS Foundation Trust (London) and at NHS Lothian (Edinburgh), to characterize minority HIV-1 variants in 109 plasma samples from ART-naive or -experienced individuals. RESULTS: Although subtype B HIV-1 strains were highly prevalent (44%, 48/109), most individuals were infected with non-B subtype viruses (i.e., A1, A2, C, D, F1, G, CRF02_AG, and CRF01_AE). DEEPGENTM was able to accurately detect drug resistance-associated mutations not identified using standard Sanger sequencing-based tests, which correlated significantly with patient's antiretroviral treatment histories. A higher proportion of minority PI , NRTI-, and NNRTI-resistance mutations was detected in NHS Lothian patients compared to individuals from St. George's, mainly M46I/L and I50 V (associated with PIs), D67 N, K65R, L74I, M184 V/I, and K219Q (NRTIs), and L100I (NNRTIs). Interestingly, we observed an inverse correlation between intra-patient HIV-1 diversity and CD4+ T cell counts in the NHS Lothian patients. CONCLUSIONS: This is the first study evaluating the transition, training, and implementation of DEEPGENTM between three clinical laboratories in two different countries. More importantly, we were able to characterize the HIV-1 drug resistance profile (including minority variants), coreceptor tropism, subtyping, and intra-patient viral diversity in patients from the United Kingdom, providing a rigorous foundation for basing clinical decisions on highly sensitive and cost-effective deep sequencing-based HIV-1 genotyping assays in the country. PMID- 30409216 TI - Impact of one versus two doses of mesenchymal stromal cells on lung and cardiovascular repair in experimental emphysema. AB - BACKGROUND: A single administration of mesenchymal stromal cells (MSCs) has been shown to reduce lung inflammation in experimental elastase-induced emphysema; however, effects were limited in terms of lung-tissue repair and cardiac function improvement. We hypothesized that two doses of MSCs could induce further lung and cardiovascular repair by mitigating inflammation and remodeling in a model of emphysema induced by multiple elastase instillations. We aimed to comparatively investigate the effects of one versus two doses of MSCs, administered 1 week apart, in a murine model of elastase-induced emphysema. METHODS: C57BL/6 mice were randomly divided into control (CTRL) and emphysema (E) groups. Mice in the E group received porcine pancreatic elastase (0.2 IU, 50 MUL) intratracheally once weekly for four consecutive weeks; the CTRL animals received sterile saline (50 MUL) using the same protocol. Three hours after the last instillation, the E group was further randomized to receive either saline (SAL) or murine MSCs (105 cells) intratracheally, in one or two doses (1 week apart). Fourteen days later, mice were euthanized, and all data analyzed. RESULTS: Both one and two doses of MSCs improved lung mechanics, reducing keratinocyte-derived chemokine and transforming growth factor-beta levels in lung homogenates, total cell and macrophage counts in bronchoalveolar lavage fluid (BALF), and collagen fiber content in airways and blood vessels, as well as increasing vascular endothelial growth factor in lung homogenates and elastic fiber content in lung parenchyma. However, only the two-dose group exhibited reductions in tumor necrosis factor alpha in lung tissue, BALF neutrophil and lymphocyte count, thymus weight, and total cellularity, as well as CD8+ cell counts and cervical lymph node CD4+ and CD8+ T cell counts, as well as further increased elastic fiber content in the lung parenchyma and reduced severity of pulmonary arterial hypertension. CONCLUSIONS: Two doses of MSCs enhanced lung repair and improvement in cardiac function, while inducing T cell immunosuppression, mainly of CD8+ cells, in elastase-induced emphysema. PMID- 30409213 TI - Distinct role of autophagy on angiogenesis: highlights on the effect of autophagy in endothelial lineage and progenitor cells. AB - Autophagy plays a critical role in the dynamic growth of each cell through different conditions. It seems that this intracellular mechanism acts as a two edged sword against the numerous cell insults. Previously, autophagy was described in the context of cell activity and behavior, but little knowledge exists related to the role of autophagy in endothelial cells, progenitors, and stem cells biology from different tissues. Angiogenic behavior of endothelial lineage and various stem cells are touted as an inevitable feature in the restoration of different damaged tissues and organs. This capacity was found to be dictated by autophagy signaling pathway. This review article highlights the fundamental role of cell autophagic response in endothelial cells function, stem cells dynamic, and differentiation rate. It seems that elucidation of the mechanisms related to pro- and/or anti-angiogenic potential of autophagy inside endothelial cells and stem cells could help us to modulate stem cell therapeutic feature post-transplantation. PMID- 30409218 TI - A review: therapeutic potential of adipose-derived stem cells in cutaneous wound healing and regeneration. AB - As the most important barrier for the human body, the skin often suffers from acute and chronic injuries, especially refractory wounds, which seriously affect the quality of life of patients. For these refractory wounds that cannot be cured by various surgical methods, stem cell transplantation becomes an effective research direction. As one of the adult stem cells, adipose-derived stem cells play an indispensable role in the repair of skin wounds more than other stem cells because of their advantages such as immune compatibility and freedom from ethical constraints. Here, we actively explore the role of adipose-derived stem cells in the repair of cutaneous wound and conclude that it can significantly promote cutaneous wound healing and regeneration. Based on a large number of animal and clinical trials, we believe that adipose-derived stem cells will have a greater breakthrough in the field of skin wound repair in the future, especially in chronic refractory wounds. PMID- 30409217 TI - The monocyte-macrophage-mast cell axis in dengue pathogenesis. AB - Dengue virus, the causative agent of dengue disease which may have hemorrhagic complications, poses a global health threat. Among the numerous target cells for dengue virus in humans are monocytes, macrophages and mast cells which are important regulators of vascular integrity and which undergo dramatic cellular responses after infection by dengue virus. The strategic locations of these three cell types, inside blood vessels (monocytes) or outside blood vessels (macrophages and mast cells) allow them to respond to dengue virus infection with the production of both intracellular and secretory factors which affect virus replication, vascular permeability and/or leukocyte extravasation. Moreover, the expression of Fc receptors on the surface of monocytes, macrophages and mast cells makes them important target cells for antibody-enhanced dengue virus infection which is a major risk factor for severe dengue disease, involving hemorrhage. Collectively, these features of monocytes, macrophages and mast cells contribute to both beneficial and harmful responses of importance to understanding and controlling dengue infection and disease. PMID- 30409219 TI - Mesenchymal stem cell transplantation ameliorates Sjogren's syndrome via suppressing IL-12 production by dendritic cells. AB - BACKGROUND: Mesenchymal stem cells (MSCs) have been demonstrated to be effective in treating autoimmune diseases including Sjogren's syndrome (SS). We aim to compare the effects of MSC transplantation (MSCT) and the role of serum interleukin-12 (IL-12) in SS. METHODS: IL-12 levels were measured by ELISA. IL-12 mRNA transcripts in dendritic cells (DCs) were determined by RT-PCR. After co culturing with MSCs, IL-12 mRNA transcripts in mouse and human DCs were detected. Non-obese diabetic (NOD) mice received MSCT, recombinant IL-12, or anti-IL-12 mAb treatment, respectively. Then, salivary flow rates, histopathology of salivary glands, and splenic lymphocyte subsets were examined in these mice. RESULTS: IL 12 levels in the serum were significantly increased in SS patients and positively correlated with the EULAR 2010 Sjogren's syndrome disease activity index. DCs from SS patients produced more IL-12 than those from the control. Likewise, IL-12 treatment in NOD mice significantly decreased salivary flow rates and promoted lymphocyte infiltration in salivary glands. IL-12 antibodies downregulated Th1, Th17, and Tfh cell. MSCT enhanced salivary flow rates and decreased lymphocyte infiltrations in salivary glands of NOD mice. MSCT downregulated Th17 and Tfh cells but upregulated regulatory T cells. MSCT reduced IL-12 productions in both SS patients and mice. CONCLUSION: Our results indicate that MSCs ameliorate SS possibly via suppressing IL-12 production in DCs and that IL-12 could be a potential therapeutic target of SS. TRIAL REGISTRATION: NTC00953485 . Registered June 2009. PMID- 30409220 TI - Detection of an amplification bias associated to Leuconostocaceae family with a universal primer routinely used for monitoring microbial community structures within food products. AB - OBJECTIVES: Sequencing of 16S rDNA V3-V4 region is widely applied for food community profiling. However, two different universal forward primers (named here MUYZER-primer1 and KLINDWORTH-primer2) targeting an identical conservative sequence upstream of the V3 region of 16S rRNA gene, and only distinguished by a single mismatch are both used. This study was carried out to compare whether the accuracy of food microbiota analysis would depend on the choice of one of these two primers. RESULTS: Alignment of both primers with common food-borne bacteria 16S sequences revealed that the mismatch between both primers might specifically affect the amplification of Leuconostoc, Oenococcus and Fructobacillus species but not Weissella species. Food products containing either Leuconostoc and/or Weissella were selected for a detection test. As expected from our in silico analysis, our study showed that this mismatch induced a strong biased amplification specifically associated to the OTUs belonging to the genus Leuconostoc but not to the genus Weissella. In presence of Muyzer-primer1, none of the sequences expected for Leuconostoc genus was detected whereas those sequences were correctly amplified with Klindworth-primer2. Since Leuconostoc is an important genus in food, agro-environments and in digestive tract of animals, we recommend that Muyzer-primer1 should thus be abandoned for the bacterial characterization of their associated microbiota. PMID- 30409221 TI - Global output of research on the health of international migrant workers from 2000 to 2017. AB - BACKGROUND: Approximately 150 million international migrant workers work under conditions that increase their risk of illness and injuries. The current study aimed to assess and analyze the global output of research on the health of international migrant workers to promote national and international policies that could help improve the health of international migrant workers. METHODS: A bibliometric methodology was implemented using Scopus database after retrieving documents relevant to the health of migrant workers during the study period from 2000 to 2017. RESULTS: In total, 955 documents were retrieved. The mean number of authors per document was 4.5 while the mean number of citation per document was 10.2. The retrieved documents were mainly in health policy and systems (n = 452; 47.3%), infectious diseases (n = 252; 26.4%), and mental and psychosocial health (n = 239; 25.0%). The health of Latino migrant farmworkers represented the largest cluster of keywords. The USA led (n = 389; 40.7%) with regard to the number of publications followed by China (n = 86; 9.0%) and the UK (n = 66; 6.9%). Researchers from the USA and Spain dominated the field. There were limited international research collaboration and a limited number and size of research networks. The American Journal of Industrial Medicine was most active (7.1%; n = 68) in publishing documents on health of migrant workers while the Wake Forest University was the most active (10.9%; n = 104) institution in this topic. CONCLUSION: The volume of global research output on the health of migrant workers was low. There was inadequate research on non-communicable diseases and maternal health of migrant workers. International research collaboration and the number of research networks were limited. Role of several world regions, particularly Arab region with 11% of international migrant workforce was also limited. There is an urgent need to prioritize research on migrant workers, especially female migrant workers in regions with low research contribution. PMID- 30409222 TI - Circulating healing (CH) cells expressing BST2 are functionally activated by the injury-regulated systemic factor HGFA. AB - BACKGROUND: Restoration of damaged tissues through the activation of endogenous progenitors is an attractive therapeutic option. A deep evaluation of the intrinsic stem/progenitor cell properties as well as the reciprocal interactions with injured environments is of critical importance. METHODS: Here, we show that bone marrow stromal cell antigen 2 (BST2) allows the isolation of a population of circulating progenitors, the circulating healing (CH) cells, characterized by a distinctive core signature. The bone marrow (BM) origin of BST2pos CH cells has been strengthened by the co-expression of leptin receptor, the hallmark of a subpopulation of BM-skeletal stem cells. RESULTS: BST2pos CH cells retained the capacity to (i) respond to injury signals generated by a bone fracture, (ii) modify the expression of cell motility genes following damage, and (iii) react to hepatocyte growth factor-activator (HGFA), an injury-related stimulus sufficient to induce their transition into GALERT, a state in which cells are functionally activated and participate in tissue repair. CONCLUSIONS: Taken together, these results could pave the way for the identification of new strategies to enhance and potentiate endogenous regenerative mechanisms for future therapies. PMID- 30409223 TI - Research trends on human trafficking: a bibliometric analysis using Scopus database. AB - BACKGROUND: Human trafficking is a crime against humanity. It is also a serious threat to global health and security. Globalization has made human trafficking an easier task for the criminal organizations. No data are available on the volume, research trends, and key players in this field. Therefore, the aim of this study was to assess the research activity and research trends on human trafficking. METHODS: A bibliometric method was adopted. Literature published in academic journals indexed in Scopus database was retrieved. The study period was set from 2000 to 2017. RESULTS: Two thousand forty-four documents were retrieved. The average number of authors per document was 1.9. Over one third (n = 771; 37.7%) of the retrieved documents were about sex trafficking, 616 (30.1%) were about labor trafficking/forced labor, 199 (9.7%) were about child trafficking, and 138 (6.8%) were about organ trafficking. One third (n = 707; 34.6%) of the documents were in health-related fields while 1526 (74.7%) were in social sciences and humanities. The USA ranked first (n = 735; 36.0%) regarding the number of published documents. Geographic distribution of the retrieved document showed that world regions with a high prevalence of human trafficking had the least research contribution. International research collaboration has a limited contribution to the retrieved literature. The Harvard University (USA) was the most active institution (n = 39; 1.9%). International Migration (n = 35; 1.7%) was the most active journal in publishing documents on HT. Documents published in Transplantation journal received the highest number of citations per document (25.5) and two of the most cited documents were about organ trafficking. CONCLUSION: There was an under-representation of health-related literature on human trafficking. Literature on sex trafficking dominated the field of human trafficking. Research networks and research collaboration between the source and destination countries is important. Future research plans need to focus on health issues and on exploited/trafficked laborers. PMID- 30409224 TI - The expression of TRIAD1 and DISC1 after traumatic brain injury and its influence on NSCs. AB - BACKGROUND: After cerebral injury, the proliferation and differentiation of neural stem cells are important for neural regeneration. METHODS: We used the SD rat to establish the traumatic brain injury model. Then, we verified molecular expression, interaction through Western blot, immunoprecipitation (IP), immunofluorescence, and other methods. All data were analyzed with Stata 8.0 statistical software. RESULTS: We showed for the first time that the interaction of TRIAD1 and DISC1 plays an important role in neural stem cell proliferation and differentiation after traumatic brain injury. In a rat model of traumatic brain injury, we found that the expression of TRIAD1 increased progressively, reached a peak at 3 to 5 days, and then decreased gradually. While the expression level of DISC1 was correlated with TRIAD1, its expression level at 3 days was significantly lower than at other time points. Immunofluorescence on frozen brain sections showed that TRIAD1 and DISC1 are co-localized in neural stem cells. Immunoprecipitation data suggested that TRIAD1 may interact with DISC1. We transfected 293T tool cells with plasmids containing truncated fragments of TRIAD1 and DISC1 and used additional IPs to reveal that these two proteins interact via specific fragments. Finally, we found that overexpressing TRIAD1 and DISC1 in primary neural stem cells, via lentiviral transfection, significantly affected the proliferation and differentiation of those neural stem cells. CONCLUSIONS: Taken together, these data show that the expression of TRIAD1 and DISC1 change after traumatic brain injury and that their interaction may affect the proliferation and differentiation of neural stem cells. Our research may provide a sufficient experimental basis for finding molecular targets for neural stem cell proliferation and differentiation. TRIAL REGISTRATION: We did not report the results of a health care intervention on human participants. PMID- 30409225 TI - Key genes and integrated modules in hematopoietic differentiation of human embryonic stem cells: a comprehensive bioinformatic analysis. AB - BACKGROUND: The generation of hematopoietic stem cells (HSCs) and blood cells from human embryonic stem cells (hESCs) is a major goal for regenerative medicine; however, the differentiation mechanisms are largely undefined. Here, we aimed to identify the regulated genes and functional modules related to the early differentiation of the endothelial-to-hematopoietic transition (EHT) using comprehensive bioinformatics analyses. METHODS: Undifferentiated hESCs (hESC-H9), CD34+ cells from 10-day differentiated hESC-H9 cells, and CD34+ cells from umbilical cord cells were isolated and collected. Cells from these three groups were subjected to RNA extraction and microarray analysis by which differentially expressed genes (DEGs) and time-series profiles were analyzed by significance analysis of microarray (SAM) and short time-series expression miner (STEM) algorithms. Gene enrichment analysis was performed by ClusterProfiler Package in Rstudio, while a protein-protein interaction (PPI) network was constructed by search tool for the retrieval of interacting genes (STRING) and visualized in Cytoscape. Hub genes were further identified with the MCODE algorithm in Cytoscape. RESULTS: In the present study, we identified 11,262 DEGs and 16 time series profiles that were enriched in biological processes of chromosome segregation, cell cycle, and leukocyte activation and differentiation, as well as hematopoiesis. Analysis using the MCODE algorithm further identified six integrated modules that might play an important role in the EHT process, including mitosis/cell cycle, mitochondrial process, splicing, ubiquitination, ribosome, and apoptosis. CONCLUSIONS: The study identified potential genes and integrated functional modules associated with the hematopoietic and endothelial differentiation of human ESCs. PMID- 30409226 TI - Otologic, audiometric and speech findings in patients undergoing surgery for cleft palate. AB - BACKGROUND: Although considerable progress has been made in the last 30 years in the treatment of cleft palate (CP), a multidisciplinary approach combining examinations by a paediatrician, maxillofacial surgeon, otolaryngologist and speech and language pathologist followed by surgical operation is still required. In this work, we performed an observational cross-sectional study to determine whether the CP grade or number of ventilation tubes received was associated with tympanic membrane abnormalities, hearing loss or speech outcomes. METHODS: Otologic, audiometric, tympanometric and speech evaluations were performed in a cohort of 121 patients (children > 6 years) who underwent an operation for CP at the Vall d'Hebron Hospital, Barcelona from 2000 to 2014. RESULTS: The most and least frequent CP types evaluated according to the Veau grade were type III (55.37%) and I (8.26%), respectively. A normal appearance of the membrane was observed in 58% individuals, of whom 55% never underwent ventilation ear tube insertion. No statistically significant associations were identified between the CP type and number of surgeries for insertion of tubes (p = 0.820). The degree of hearing loss (p = 0.616), maximum impedance (p = 0.800) and tympanic membrane abnormalities indicative of chronic otitis media (COM) (p = 0.505) among examined patients revealed no statistically significant association with the grade of CP. However, an association was identified between hypernasality and the grade of CP (p = 0.053), COM (p = 0.000), hearing loss (p = 0.000) and number of inserted ventilation tubes. CONCLUSION: Although the placement of tympanic ventilation tubes has been accompanied by an increased rate of COM, it is still important to assess whether this is a result of the number of ventilation tubes inserted or it is intrinsic to the natural history of middle ear inflammatory disease of such patients. Our results do not support improvements in speech, hearing, or tympanic membrane abnormalities with more aggressive management of COM with tympanostomy tubes. PMID- 30409227 TI - Long-term effectiveness of local BM-MSCs for skeletal muscle regeneration: a proof of concept obtained on a pig model of severe radiation burn. AB - BACKGROUND: Medical management of the severe musculocutaneous radiation syndrome involves surgical intervention with debridement of necrotic tissue. Even when skin excision is replaced by specific plastic surgery, treatment of the muscle radiation injury nonetheless remains difficult, for it involves a massive muscle defect in an unpredictable environment, subject to inflammatory waves weeks to months after irradiation, which delay healing and predispose the patient to the development of fibrous scar tissue. In this study, we investigated the long-term effect of local injections of bone marrow-derived mesenchymal stromal cells (BM MSCs), combined with plastic surgery, to treat muscle necrosis in a large animal model. METHODS: Three months after irradiation to the rump, minipigs were treated by excision of necrotic muscle tissue, vascularized flap surgery, and four injections with or without local autologous BM-MSCs, performed weekly. The quality of the muscle wound healing was examined 1 year post-surgery. RESULTS: The skeletal muscle surgery without MSC treatment led to permanent deposition of collagen 1 and 3, decreased myofiber diameter, failed muscle fiber regeneration, a reduced number of capillaries, and the accumulation of high calcium and fat. In animals treated by surgery and MSC injections, these indicators were substantially better and demonstrated established regeneration. MSC therapy acts at several levels by stimulating growth factors such as VEGF, which is involved in angiogenesis and satellite cell pool maintenance, and creating a macrophage M1/M2 balance. CONCLUSION: Thus, cell therapy using BM-MSCs is an effective and safe way to improve recovery of irradiation-induced skeletal muscle damage without signs of long-term degeneration. PMID- 30409228 TI - Validation of the shortened Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS). AB - BACKGROUND: The rare disease, Hunter Syndrome (mucopolysaccharidosis type II; MPS II), characterized by iduronate-2-sulfatase deficiency, has heterogeneous symptoms often including cognitive impairment (CI). To evaluate physical functioning and daily activity limitations of patients with MPS II, the multidomain shortened Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS) questionnaire was previously developed and preliminarily validated. Here we gather data in a dedicated prospective longitudinal observational study using direct responses to the shortened instrument and assess its psychometric properties further. METHODS: Interview data were collected from eligible self-reporting patients (>= 12 years of age) or caregivers of patients using respective versions of the instrument at baseline and 2-4 weeks later. Internal consistency, test-retest reliability, convergent and discriminant validity, and validity of known groups were assessed. Participants also completed Child Health Questionnaire (CHQ), Health Utilities Index Mark 3, and Global Impression of Severity (GIS) questionnaires. RESULTS: All patients were male, consisting of 31 caregiver-reported patients (aged 3-26 years) and 20 self-reported patients (aged 12-58 years). Most (77.4%) caregiver reported patients had CI. Both questionnaire versions demonstrated good internal consistency and test-retest reliability; Cronbach's alpha and intra-class correlation coefficients were > 0.70. Spearman's correlations demonstrated good convergent validity with moderate (> 0.3) to high (> 0.6) correlations of the HS FOCUS total score with physical functioning, role/social-physical, and bodily pain domains of CHQ. The tool also differentiated between MPS II severity levels based on GIS scores. CONCLUSIONS: The shortened HS-FOCUS questionnaire was found to be a valid and reliable tool to assess the physical functioning impact of MPS II. PMID- 30409229 TI - Vitamin D levels in a pediatric population of a primary care centre: a public health problem? AB - OBJECTIVE: Vitamin D deficiency is a public health problem that occurs more frequently than expected. The aim of this study is to evaluate the vitamin D levels of children attending the paediatrics unit of the Bertamirans primary care centre (A Coruna NW Spain). This is an observational study carried out during 1 year on a random sample of the pediatric population aged between 5 and 15 years. The levels of vitamin D (25(OH)D) were determined by immunoassay (ADVIA Centaur Vitamin D(r)). The results were classified as sufficient (> 20 ng/ml), insufficient (10-20 ng/ml) and deficient (< 10 ng/ml). RESULTS: 153 analyses of vitamin D were carried out (58.2% in girls and 41.8% in boys), distributed in two age groups: 5-10 (62) and 10-15 (91). 66% of the total of the sample presented some degree of vitamin D deficit (60.1% insufficient (92) and 5.9% (11) deficient). In Galicia, there is a high prevalence of vitamin D deficiency/insufficiency in the healthy population, which increases if the patients present some kind of chronic pathology, thus leading to a public health problem. It is advisable to increase the consumption of fortified foods and/or to reconsider the administration of vitamin supplements. PMID- 30409231 TI - Effect of dietary interventions in mild cognitive impairment: a systematic review. AB - Diet has been investigated in relation to its ability to promote cognitive function. However, evidence is currently limited and has rarely been systematically reviewed, particularly in a mild cognitive impairment (MCI) population. This review examined the effect of diet on cognitive outcomes in MCI patients. A total of five databases were searched to find randomised controlled trial (RCT) studies, with diet as the main focus, in MCI participants. The primary outcome was incident dementia and/or Alzheimer's disease (AD) and secondary outcomes included cognitive function across different domains using validated neuropsychological tests. Sixteen studies met the inclusion criteria. There was a high degree of heterogeneity relating to the nature of the dietary intervention and cognitive outcomes measured, thus making study comparisons difficult. Supplementation with vitamin E (one study, n 516), ginkgo biloba (one study, n 482) or Fortasyn Connect (one study, n 311) had no significant effect on progression from MCI to dementia and/or AD. For cognitive function, the findings showed some improvements in performance, particularly in memory, with the most consistent results shown by B vitamins, including folic acid (one study, n 266), folic acid alone (one study, n 180), DHA and EPA (two studies, n 36 and n 86), DHA (one study, n 240) and flavonol supplementation (one study, n 90). The findings indicate that dietary factors may have a potential benefit for cognitive function in MCI patients. Further well-designed trials are needed, with standardised and robust measures of cognition to investigate the influence of diet on cognitive status. PMID- 30409230 TI - Human tissue-specific MSCs demonstrate differential mitochondria transfer abilities that may determine their regenerative abilities. AB - BACKGROUND: Recent studies have demonstrated mesenchymal stem cells (MSCs) as effective mitochondrial donors with therapeutic success in multiple experimental models of human disease. MSCs obtained from different tissue sources such as bone marrow (BM), adipose (AD), dental pulp (DP), and Wharton's jelly (WJ) are routinely used in clinical trials with no known study of their mitochondrial donor capacity. Here, we show for the first time that MSCs derived from different tissue sources have different mitochondrial donor properties and that this is correlated with their intrinsic respiratory states. METHODS: MitoTracker(r) labeled MSCs were co-cultured with Cell Trace-labeled U87-MG cells or rat cardiomyocytes. Mitochondrial transfer abilities of MSCs were assessed by using flow cytometry analysis and fluorescence imaging. Mitochondrial reactive oxygen species (mtROS) levels were analyzed by using MitoSOX red-based staining, and mitochondrial respiration parameters were analyzed by using a Seahorse XF Analyzer. RESULTS: AD-MSCs and BM-MSCs displayed higher mitochondrial transfer than DP-MSCs and WJ-MSCs. Counterintuitively, DP-MSCs and WJ-MSCs were more effective in suppressing mtROS levels in stressed recipient cells than AD-MSCs or BM-MSCs. Interestingly, the oxygen consumption rates and intrinsic mitochondrial respiration parameters like ATP levels, basal and maximal respiration, and mitochondrial DNA copy number in donor MSCs showed a highly significant inverse correlation with their mitochondrial donation. CONCLUSIONS: We find that there are intrinsic differences in the mitochondrial respiration, donation capacity, and therapeutic efficacy among MSCs of different tissue origin. MSCs with high mitochondrial respiration capacities are associated with lower mitochondrial transfer but more effective suppression of mtROS in stressed recipient cells. This is most compatible with a model where recipient cells optimally regulate mitochondrial transfer such that they take more mitochondria from MSCs with lower mitochondrial function. Furthermore, it appears to be advantageous to use MSCs such as DP-MSCs or WJ-MSCs with higher mitochondrial respiratory abilities that achieved better therapeutic effect with lower mitochondrial transfer in our study. This opens up a new direction in stem cell therapeutics. PMID- 30409232 TI - Insights into the metabolism and behaviour of Varroa destructor mites from analysis of their waste excretions. AB - Varroa destructor mites (Acari: Varroidae) are harmful ectoparasites of Apis mellifera honey bees. Female foundresses of wax-capped pupal host cells and their daughters feed on host fluids from open wounds on the host's integument. Details of V. destructor mite nutrition are forthcoming, and little is known about the potential physical effects on hosts from mite feeding. Chemical analysis of waste excretions can infer details of animals' nutrition. Here, chemical analysis by high-performance liquid chromatography/mass spectrometry (HPLC-MS/MS) of mite excretions showed that the purine content of V. destructor waste consists of guanine with traces of hypoxanthine. Traces of uric acid and caffeine were also detected. Concentrations of guanine attenuated over time and excretions collected from senescing mites did not contain detectable guanine. Non-reproducing individual female mites maintained in vitro, housed in gelatin capsules and provided a honey bee pupa, deposited an average of nearly 18 excretions daily, mostly on the host's integument rather than on the capsule wall. The weight and volume of excretions suggest mites can consume nearly a microlitre of host fluids each day. Compounded over 10 days, this together with open wounds, could lead to substantial water loss and stress to developing pupae. PMID- 30409233 TI - Variability in antimicrobial use in pediatric ventilator-associated events. AB - OBJECTIVE: To assess variability in antimicrobial use and associations with infection testing in pediatric ventilator-associated events (VAEs). DESIGN: Descriptive retrospective cohort with nested case-control study. SETTING: Pediatric intensive care units (PICUs), cardiac intensive care units (CICUs), and neonatal intensive care units (NICUs) in 6 US hospitals.PatientsChildren<=18 years ventilated for>=1 calendar day. METHODS: We identified patients with pediatric ventilator-associated conditions (VACs), pediatric VACs with antimicrobial use for>=4 days (AVACs), and possible ventilator-associated pneumonia (PVAP, defined as pediatric AVAC with a positive respiratory diagnostic test) according to previously proposed criteria. RESULTS: Among 9,025 ventilated children, we identified 192 VAC cases, 43 in CICUs, 70 in PICUs, and 79 in NICUs. AVAC criteria were met in 79 VAC cases (41%) (58% CICU; 51% PICU; and 23% NICU), and varied by hospital (CICU, 20-67%; PICU, 0-70%; and NICU, 0-43%). Type and duration of AVAC antimicrobials varied by ICU type. AVAC cases in CICUs and PICUs received broad-spectrum antimicrobials more often than those in NICUs. Among AVAC cases, 39% had respiratory infection diagnostic testing performed; PVAP was identified in 15 VAC cases. Also, among AVAC cases, 73% had no associated positive respiratory or nonrespiratory diagnostic test. CONCLUSIONS: Antimicrobial use is common in pediatric VAC, with variability in spectrum and duration of antimicrobials within hospitals and across ICU types, while PVAP is uncommon. Prolonged antimicrobial use despite low rates of PVAP or positive laboratory testing for infection suggests that AVAC may provide a lever for antimicrobial stewardship programs to improve utilization. PMID- 30409234 TI - Field Expedient Vasopressors During Aeromedical Evacuation: A Case Series from the Puerto Rico Disaster Response. AB - IntroductionEmergency physicians are using bolus-dose vasopressors to temporize hypotensive patients until more definitive blood pressure support can be established. Despite a paucity of clinical outcome data, emergency department applications are expanding into the prehospital setting. This series presents two cases of field expedient vasopressor use by emergency medicine providers for preflight stabilization during aeromedical evacuation to a hospital ship as part of the United States Navy disaster response in Puerto Rico. A critical approach and review of the literature are discussed.Case ReportTwo critically ill patients were managed in an austere environment as a result of the devastation from Hurricane Maria (Yabucoa, Puerto Rico; 2017). They both exhibited signs of respiratory distress, hemodynamic instability, and distributive shock requiring definitive airway management and hemodynamic support prior to aeromedical evacuation.DiscussionThe novel use of field expedient vasopressors prior to induction for rapid sequence intubation was successfully and safely employed in both cases. Both patients had multiple risk factors for peri-induction cardiac arrest given their presenting hemodynamics. Despite their illness severity, both patients were induced, transported, and ultimately admitted to the intensive care unit (ICU) in stable condition following administration of the field expedient vasopressors. CONCLUSION: Field expedient vasopressors were safely and effectively employed in an austere field environment during a disaster response. This case series contributes to the growing body of literature of safe bolus-dose vasopressor use by emergency physicians to temporize hypotensive patients in resource-constrained situations.Hardwick JM, Murnan SD, Morrison-Ponce DP, Devlin JJ. Field expedient vasopressors during aeromedical evacuation: a case series from the Puerto Rico disaster response. PMID- 30409235 TI - Antibiotic prescribing upon discharge from the hospital to long-term care facilities: Implications for antimicrobial stewardship requirements in post-acute settings. AB - OBJECTIVE: To quantify the frequency and outcomes of receiving an antibiotic prescription upon discharge from the hospital to long-term care facilities (LTCFs). DESIGN: Retrospective cohort study. SETTING: A 576-bed, academic hospital in Portland, Oregon.PatientsAdult inpatients (>=18 years of age) discharged to an LTCF between January 1, 2012, and June 30, 2016. METHODS: Our primary outcome was receiving a systemic antibiotic prescription upon discharge to an LTCF. We also quantified the association between receiving an antibiotic prescription and 30-day hospital readmission, 30-day emergency department (ED) visit, and Clostridium difficile infection (CDI) on a readmission or ED visit at the index facility within 60 days of discharge. RESULTS: Among 6,701 discharges to an LTCF, 22.9% were prescribed antibiotics upon discharge. The most prevalent antibiotic classes prescribed were cephalosporins (20.4%), fluoroquinolones (19.1%), and penicillins (16.7%). The medical records of ~82% of patients included a diagnosis code for a bacterial infection on the index admission. Among patients prescribed an antibiotic upon discharge, the incidence of 30-day hospital readmission to the index facility was 15.9%, the incidence of 30-day ED visit at the index facility was 11.0%, and the incidence of CDI on a readmission or ED visit within 60 days of discharge was 1.6%. Receiving an antibiotic prescription upon discharge was significantly associated with 30-day ED visits (adjusted odds ratio [aOR], 1.2; 95% confidence interval [CI], 1.02-1.5) and with CDI within 60 days (aOR, 1.7; 95% CI, 1.02-2.8) but not with 30-day readmissions (aOR, 1.01; 95% CI, 0.9-1.2). CONCLUSIONS: Antibiotics were frequently prescribed upon discharge to LTCFs, which may be associated with increased risk of poor outcomes post discharge. PMID- 30409236 TI - Neural circuitry and precision medicines for mental disorders: are they compatible? AB - Given the failure of psychiatry to develop clinically useful biomarkers for psychiatric disorders, and the concomitant failure to develop significant advances in diagnosis and treatment, the National Institute of Mental Health (NIMH) in 2010 launched the Research Domain Criteria (RDoC), a framework for research based on the assumption that mental disorders are disorders of identifiable brain neural circuits, with neural circuitry at the center of units of analysis ranging from genes, molecules, and cells to behavior, self-reports, and paradigms. These were to be integrated with five validated dimensional psychological constructs such as negative and positive valence systems. Four years later, the NIMH stated that the ultimate goal of RDoC is precision medicine for psychiatry, with the assumption that precision medications will normalize dysfunctional neural circuits. How this could be accomplished is not obvious, given that neural circuits are widely distributed, have unclear boundaries, and exhibit a significant degree of neuroplasticity, with multiple circuits present in any given disorder. Moreover, the early focus on neural circuitry has been criticized for its reductionism and neglect of the more recent RDoC emphasis on the integration and equivalence of biological and psychological phenomena. Yet this seems inconsistent with the priorities of the NIMH director, an advocate of the central role of neural circuitry and projects such as the Brain Initiative and the Human Connectome Project. Will such projects, at a cost of at least $10 billion, lead to precision medications for mental disorders, or further diminish funding for clinical care and research? PMID- 30409237 TI - Pre-loss personal factors and prolonged grief disorder in bereaved mothers. AB - BACKGROUND: Identifying characteristics of individuals at greatest risk for prolonged grief disorder (PGD) can improve its detection and elucidate the etiology of the disorder. The Safe Passage Study, a study of women at high risk for sudden infant death syndrome (SIDS), prospectively examined the psychosocial functioning of women while monitoring their healthy pregnancies. Mothers whose infants died of SIDS were followed in bereavement. METHODS: Pre-loss data were collected from 12 000 pregnant mothers and analyzed for their associations with grief symptoms and PGD in 50 mothers whose infants died from SIDS, from 2 to 48 months after their infant's death, focusing on pre-loss risk factors of anxiety, depression, alcohol use, maternal age, the presence of other living children in the home, and previous child loss. RESULTS: The presence of any four risk factors significantly predicted PGD for 24 months post-loss (p < 0.003); 2-3 risk factors predicted PGD for 12 months (p = 0.02). PGD rates increased in the second post loss year, converging in all groups to approximately 40% by 3 years. Pre-loss depressive symptoms were significantly associated with PGD. Higher alcohol intake and older maternal age were consistently positively associated with PGD. Predicted risk scores showed good discrimination between PGD and no PGD 6-24 months after loss (C-statistic = 0.83). CONCLUSIONS: A combination of personal risk factors predicted PGD in 2 years of bereavement. There is a convergence of risk groups to high rates at 2-3 years, marked by increased PGD rates in mothers at low risk. The risk factors showed different effects on PGD. PMID- 30409238 TI - Lifestyle intervention strategies in early life to improve pregnancy outcomes and long-term health of offspring: a narrative review. AB - Adverse exposures during fetal life and the postnatal period influence physical, cognitive and emotional development, and predispose to an increased risk of various chronic diseases throughout the life course. Findings from large observational studies in various populations and experimental animal studies have identified different modifiable risk factors in early life. Adverse maternal lifestyle factors, including overweight, unhealthy diet, sedentary behavior, smoking, alcohol consumption and stress in the preconception period and during pregnancy, are the most common modifiable risk factors leading to a suboptimal in utero environment for fetal development. In the postnatal period, breastfeeding, infant growth and infant dietary intake are important modifiable factors influencing long-term offspring health outcomes. Despite the large amount of findings from observational studies, translation to lifestyle interventions seems to be challenging. Currently, randomized controlled trials focused on the influence of lifestyle interventions in these critical periods on short-term and long-term maternal and offspring health outcomes are scarce, have major limitations and do not show strong effects on maternal and offspring outcomes. New and innovative approaches are needed to move from describing these causes of ill-health to start tackling them using intervention approaches. Future randomized controlled lifestyle intervention studies and innovative observational studies, using quasi-experimental designs, are needed focused on the effects of an integrated lifestyle advice from preconception onwards on pregnancy outcomes and long-term health outcomes in offspring on a population level. PMID- 30409239 TI - Parasite-specific proliferative responses of chicken spleen cells upon in vitro stimulation with Eimeria tenella antigen. AB - This study aimed to set up methodology to monitor parasite-specific T-cell activation in vitro using Eimeria tenella-infected chickens. A sonicated E. tenella sporozoite protein preparation was used for the activation of chicken spleen cell cultures. Proliferation assessed by 3H-thymidin incorporation or blast transformation of T-cells assessed by immunofluorescence labelling and flow cytometry were used as read-outs for activation. Results showed that E. tenella specific proliferation was detected in cultures of spleen cells collected in a 'window' between 8 and 14 days after primary infection. However, due to high variation in proliferative responses between individuals and to high background proliferation, large numbers of observations were needed to obtain significant results. Moreover, the outcome was not improved by increasing the infection dose to chickens or by depletion of T-cell receptor (TCR) gamma/delta expressing cells from cultures. An E. tenella-specific blast transformation response was observed for TCRalpha/beta expressing cells within the same 'window', confirming the identity of the responding cells as classic T-cells. Thus, it is possible to study the kinetics of E. tenella-specific T-cell responses in vitro. However, more in-depth phenotypic identification of the responding T-cells could improve the methodology. PMID- 30409240 TI - Clostridium difficile infection increases acute and chronic morbidity and mortality. AB - OBJECTIVE: In this study, we aimed to quantify short- and long-term outcomes of Clostridium difficile infection (CDI) in the elderly, including all-cause mortality, transfer to a facility, and hospitalizations. DESIGN: Retrospective study using 2011 Medicare claims data, including all elderly persons coded for CDI and a sample of uninfected persons. Analysis of propensity score-matched pairs and the entire population stratified by the propensity score was used to determine the risk of all-cause mortality, new transfer to a long-term care facility (LTCF), and short-term skilled nursing facility (SNF), and subsequent hospitalizations within 30, 90, and 365 days. RESULTS: The claims records of 174,903 patients coded for CDI were compared with those of 1,318,538 control patients. CDI was associated with increased risk of death (odds ratio [OR], 1.77; 95% confidence interval [CI], 1.74-1.81; attributable mortality, 10.9%), new LTCF transfer (OR, 1.74; 95% CI, 1.67-1.82), and new SNF transfer (OR, 2.52; 95% CI, 2.46-2.58) within 30 days in matched-pairs analyses. In a stratified analysis, CDI was associated with greatest risk of 30-day all-cause mortality in persons with lowest baseline probability of CDI (hazard ratio [HR], 3.04; 95% CI, 2.83 3.26); the risk progressively decreased as the baseline probability of CDI increased. CDI was also associated with increased risk of subsequent 30-day, 90 day, and 1-year hospitalization. CONCLUSIONS: CDI was associated with increased risk of short- and long-term adverse outcomes, including transfer to short- and long-term care facilities, hospitalization, and all-cause mortality. The magnitude of mortality risk varied depending on baseline probability of CDI, suggesting that even lower-risk patients may benefit from interventions to prevent CDI. PMID- 30409241 TI - Determinants of hearing loss severity in tympanic membrane perforations in a sub Saharan African setting. AB - BACKGROUND: Factors specific to sub-Saharan Africa could have an impact on tympanic membrane perforation characteristics. Obtaining precise information on these characteristics and determinants of hearing loss severity would enable better management. OBJECTIVE: To determine the relationship between characteristics of tympanic membrane perforation and subsequent hearing impairment. METHODS: A cross-sectional study of consenting patients presenting with tympanic membrane perforation was conducted. They were examined using otoendoscopy with a digital camera to obtain precise measurements, followed by pure tone audiometry. RESULTS: Eighty-six cases of tympanic membrane perforation were included. Mean tympanic membrane perforation proportion was 34.1 +/- 18.4 per cent. Medium-sized tympanic membrane perforations were predominant (47.7 per cent). Median tympanic membrane perforation duration was 20 years. Tympanic membrane perforation size was found to be a predictor of hearing loss severity (odds ratio = 2.5, 95 per cent confidence interval = 1.02-6.13, p = 0.04). CONCLUSION: Tympanic membrane perforation size was a predictor of hearing loss severity in our setting. Site, duration and aetiology seem to have no impact on hearing loss severity. PMID- 30409242 TI - Trends in incidence and mortality of tuberculosis in Japan: a population-based study, 1997-2016. AB - Japan is still a medium-burden tuberculosis (TB) country. We aimed to examine trends in newly notified active TB incidence and TB-related mortality in the last two decades in Japan. This is a population-based study using Japanese Vital Statistics and Japan Tuberculosis Surveillance from 1997 to 2016. We determined active TB incidence and mortality rates (per 100 000 population) by sex, age and disease categories. Joinpoint regression was applied to calculate the annual percentage change (APC) in age-adjusted mortality rates and to identify the years showing significant trend changes. Crude and age-adjusted incidence rates reduced from 33.9 to 13.9 and 37.3 to 11.3 per 100 000 population, respectively. Also, crude and age-adjusted mortality rates reduced from 2.2 to 1.5 and 2.8 to 1.0 per 100 000 population, respectively. Average APC in the incidence and mortality rates showed significant decline both in men (-6.2% and -5.4%, respectively) and women (-5.7% and -4.6%, respectively). Age-specific analysis demonstrated decreases in incidence and mortality rates for every age category, except for the incidence trend in the younger population. Although trends in active TB incidence and mortality rates in Japan have favourably decreased, the rate of decline is far from achieving TB elimination by 2035. PMID- 30409243 TI - A systematic review of the geospatial barriers to antiretroviral initiation, adherence and viral suppression among people living with HIV. AB - Background: With the emergence of antiretroviral therapy (ART), Treatment as Prevention (TasP) has become the cornerstone of both HIV clinical care and HIV prevention. However, despite the efficacy of treatment-based programs and policies, structural barriers to ART initiation, adherence and viral suppression have the potential to reduce TasP effectiveness. These barriers have been studied using Geographic Information Systems (GIS). While previous reviews have examined the use of GIS for HIV testing - an essential antecedent to clinical care - to date, no reviews have summarised the research with respect to other ART-related outcomes. Methods: Therefore, the present review leveraged the PubMed database to identify studies that leveraged GIS to examine the barriers to ART initiation, adherence and viral suppression, with the overall goal of understanding how GIS has been used (and might continue to be used) to better study TasP outcomes. Joanna Briggs Institute criteria were used for the critical appraisal of included studies. Results: In total, 33 relevant studies were identified, excluding those not utilising explicit GIS methodology or not examining TasP-related outcomes. Conclusions: Findings highlight geospatial variation in ART success and inequitable distribution of HIV care in racially segregated, economically disadvantaged, and, by some accounts, increasingly rural areas - particularly in the United States. Furthermore, this review highlights the utility and current limitations of using GIS to monitor health outcomes related to ART and the need for careful planning of resources with respect to the geospatial movement and location of people living with HIV (PLWH). PMID- 30409244 TI - Gonorrhoea gone wild: rising incidence of gonorrhoea and associated risk factors among gay and bisexual men attending Australian sexual health clinics. AB - Background: Gonorrhoea notifications continue to rise among gay and bisexual men in Australia and around the world. More information is needed on infection trends, accounting for testing and complimented by demographics and risk practices. Methods: A retrospective cohort analysis was undertaken using repeat gonorrhoea testing data among gay and bisexual men from 2010 to 2017, which was extracted from a network of 47 sexual health clinics across Australia. Poisson and Cox regression analyses were used to determine temporal trends in gonorrhoea incidence rates, as well as associated demographic and behavioural factors. Results: The present analysis included 46904 gay and bisexual men. Gonorrhoea incidence at any anatomical site increased from 14.1/100 person years (PY) in 2010 to 24.6/100 PY in 2017 (P<0.001), with the greatest increase in infections of the pharynx (5.6-15.9/100 PY, P<0.001) and rectum (6.6-14.8/100 PY, P<0.001). After adjusting for symptomatic and contact-driven presentations, the strongest predictors of infection were having more than 20 sexual partners in a year (hazard ratio (HR)=1.9, 95% confidence interval (CI): 1.7-2.2), using injecting drugs (HR=1.7, 95%CI: 1.4-2.0), being HIV positive (HR=1.4, 95%CI: 1.2-1.6) and being aged less than 30 years old (HR=1.4, 95%CI: 1.2-1.6). Conclusions: Gonorrhoea has increased dramatically among gay and bisexual men in Australia. Enhanced prevention efforts, as well as more detailed, network-driven research are required to combat gonorrhoea among young men, those with HIV and those who use injecting drugs. PMID- 30409245 TI - Community pharmacists and their role in pharmacogenomics testing: an Australian perspective drawing on international evidence. AB - Patients obtaining a prescription from a pharmacy expect that the drug will be effective and have minimal side-effects. Unfortunately, drugs exhibit the desired effect in ~25-60% of people prescribed any medication. Adverse effects occur at a rate of 10% in patients taking a medication, and this rate increases during and after hospitalisation, with the transition of care back to the ambulatory setting posing a particular risk. Pharmacogenomics testing has been shown to optimise pharmacotherapy by increasing medication effectiveness and reducing drug-related toxicity, thus curtailing overall healthcare costs. Evidence from international studies have shown that community pharmacists would be able to offer this highly relevant professional service to their clients, given suitable training. This specific training complements pharmacists' existing skills and expertise by educating them in an emerging scientific area of pharmacogenomics. However, in an increasingly tight financial climate, the provision of pharmacogenomics testing by Australian community pharmacists will only be viable with an appropriate reimbursement through the Medicare Benefits Schedule, currently accessible by other allied health practitioners but not by pharmacists. PMID- 30409246 TI - 3D-Bioprinting and Micro-/Nano-Technology: Emerging Technologies in Biomedical Sciences. PMID- 30409247 TI - Itch: From mechanism to (novel) therapeutic approaches. AB - Itch is a common sensory experience that is prevalent in patients with inflammatory skin diseases, as well as in those with systemic and neuropathic conditions. In patients with these conditions, itch is often severe and significantly affects quality of life. Itch is encoded by 2 major neuronal pathways: histaminergic (in acute itch) and nonhistaminergic (in chronic itch). In the majority of cases, crosstalk existing between keratinocytes, the immune system, and nonhistaminergic sensory nerves is responsible for the pathophysiology of chronic itch. This review provides an overview of the current understanding of the molecular, neural, and immune mechanisms of itch: beginning in the skin, proceeding to the spinal cord, and eventually ascending to the brain, where itch is processed. A growing understanding of the mechanisms of chronic itch is expanding, as is our pipeline of more targeted topical and systemic therapies. Our therapeutic armamentarium for treating chronic itch has expanded in the last 5 years, with developments of topical and systemic treatments targeting the neural and immune systems. PMID- 30409248 TI - Translational review: Neuroimmune mechanisms in cough and emerging therapeutic targets. AB - Cough is an essential defensive behavior for maintaining airway patency and to protect the lungs from potentially harmful agents. However, inflammatory pathologies can sensitize and activate the neural pathways regulating cough, leading to excessive and nonproductive coughing that serves little protective utility. Problematic cough continues to be one of the most common reasons for seeking medical advice, yet for many patients, it can be refractory to disease specific treatments and currently available antitussive therapies. The effect of inflammation on cough neural processing occurs not only at the level of the bronchopulmonary sensory nerve terminals but also within the nervous system at multiple peripheral and central sites. Sensory nerves also actively regulate inflammation, and it is therefore a complex interplay between the immune and nervous systems that contributes to chronic cough and the associated sensory hypersensitivities. In this review we provide a brief overview of cough neurobiology in health and disease and then explore the peripheral and central nervous system sites at which neuroimmune interactions can occur. We present advancements in the development of effective antitussive therapies and suggest novel targets for future consideration. PMID- 30409249 TI - New aspects of neuroinflammation and neuroimmune crosstalk in the airways. AB - Neuroimmune interaction has long been discussed in the pathogenesis of allergic airway diseases, such as allergic asthma. Mediators released during inflammation can alter the function of both sensory and parasympathetic neurons innervating the airways. Evidence has been provided that the inflammatory response can be altered by various mediators that are released by sensory and parasympathetic neurons and vice versa. Our aim is to demonstrate recent developments in the reciprocal neuroimmune interaction and to include, if available, data from in vivo and clinical studies. PMID- 30409251 TI - Correction. PMID- 30409252 TI - Functional MRI in Atypical Parkinsonisms. AB - The present chapter reports the current knowledge on the use of functional MRI (fMRI) in patients with atypical parkinsonisms, including Multiple System Atrophy, Corticobasal Syndrome and Progressive Supranuclear Palsy syndrome. Both resting state functional connectivity and task-based brain activity abnormalities are reported in atypical parkinsonisms relative to healthy controls and Parkinson's disease patients. Functional alterations were observed earlier than structural damage and may help to make early diagnosis. The chapter also examines the few longitudinal evidence on fMRI changes in patients with these conditions. The potential use of fMRI techniques in aiding the differential diagnosis, accurately measuring disease progression and assessing the effectiveness of therapeutic interventions is discussed. PMID- 30409253 TI - PET Molecular Imaging in Familial Parkinson's Disease. AB - Most cases of Parkinson's disease (PD) are idiopathic, but some characteristics, such as early onset or a positive family history, raise suspicions of an inherited form of the disease. In the last decades several genes have been linked to parkinsonism, with different patterns of inheritance and different clinical phenotypes. Positron emission tomography (PET) imaging has helped to characterize genetic-linked parkinsonism, thanks to the availability of dopaminergic and nondopaminergic tracers. On the other hand, investigation of molecular changes in mutation carriers, even at preclinical stages, has provided a deeper comprehension of the pathogenesis of PD and of the compensatory mechanisms that take place in the very early stages of the disease. PMID- 30409254 TI - SPECT Molecular Imaging in Familial Parkinson's Disease. AB - Dopamine transporter (DAT) imaging with single-photon emission computed tomography (SPECT) is a diagnostic tool to study the integrity of the dopaminergic system in patients with parkinsonism and uncertain diagnosis. DAT SPECT enables to detect the presence of nigrostriatal deficit even in the early or pre-symptomatic stages of the disease and to quantify the DAT loss with the progression of nigrostriatal degeneration. For these reasons, DAT SPECT has been also used as a tool to study genetic conditions that are associated with parkinsonism in order to examine the degree and patterns of dopaminergic deficits that are present in at risk subjects and in affected patients carrying the mutations. Studies included subjects with sporadic mutations of common genes associated with Parkinson's disease (PD) and families with both affected patients and asymptomatic carriers. For obvious reasons, the majority of the studies have included a limited number of subjects. Therefore, because of the heterogeneity and the size of the cohorts examined, in many cases the findings can be merely descriptive and general conclusions on the patterns of dopaminergic deficit in different genetic conditions need to take into account some exceptions. PMID- 30409255 TI - Structural and Functional MRI in Familial Parkinson's Disease. AB - Between 10 and 15% of Parkinson disease (PD) cases can be traced to a genetically identified causative mutation which currently number over 40. This enables the study of both "at risk" populations for future development of PD and a unique sub group of genetically determined patient population. Structural and functional magnetic imaging has the potential of assisting diagnosis, early detection and disease progression as it is relatively cheap and easy to implement. However, the large variety of imaging options and different analytical approaches hamper the pursuit of a unified imaging biomarker. This chapter details the current imaging options and summarizes the findings among both genetically determined patients with PD and their non-manifesting first degree relatives, speculating on possible compensational mechanisms while mapping future directions in order to better utilize MRI in the research of genetic PD. PMID- 30409256 TI - Molecular Imaging in Huntington's Disease. AB - Huntington's disease (HD) is a rare monogenic neurodegenerative disorder caused by a trinucleotide CAG repeat expansion in the huntingtin gene resulting in the formation of intranuclear inclusions of mutated huntingtin. The accumulation of mutated huntingtin leads to loss of GABAergic medium spiny neurons (MSNs); subsequently resulting in the development of chorea, cognitive dysfunction and psychiatric symptoms. Premanifest HD gene expansion carriers, provide a unique cohort to examine very early molecular changes, occurring before the development of overt symptoms, to elucidate disease pathophysiology and identify reliable biomarkers of HD progression. Positron emission tomography (PET) is a non invasive molecular imaging technique allowing the evaluation of specific molecular targets in vivo. Selective PET radioligands provide invaluable tools to investigate the role of the dopaminergic system, brain metabolism, microglial activation, phosphodiesterase 10A, and cannabinoid, GABA, adenosine and opioid receptors in HD. PET has been employed to monitor disease progression aiming to identify a reliable biomarker to predict phenoconversion from premanifest to manifest HD. PMID- 30409257 TI - PET Molecular Imaging in Atypical Parkinsonism. AB - Multiple System Atrophy, Progressive Supranuclear Palsy, and Corticobasal Degeneration are three neurodegenerative disorders characterized by parkinsonism along with involvement of other brain cortical and subcortical regions. The ante mortem diagnosis of these disorders is extremely challenging with up to a quarter of these patients being misdiagnosed, particularly in the early stages of disease. While highly specific and sensitive imaging biomarkers of individual atypical parkinsonisms have not been identified yet, molecular PET and SPECT imaging have improved our knowledge of the physiopathology and neuropathology of these disorders and are often used as supportive criteria for the differential diagnosis of these conditions. This chapter will provide a state-of-the-art overview of the use of PET in atypical parkinsonisms. PMID- 30409258 TI - Structural Magnetic Resonance Imaging in Huntington's Disease. AB - Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder, caused by expansion of the CAG repeat in the huntingtin gene. HD is characterized clinically by progressive motor, cognitive and neuropsychiatric symptoms. There are currently no disease modifying treatments available for HD, and there is a great need for biomarkers to monitor disease progression and identify new targets for therapeutic intervention. Neuroimaging techniques provide a powerful tool for assessing disease pathology and progression in premanifest stages, before the onset of overt motor symptoms. Structural magnetic resonance imaging (MRI) is non invasive imaging techniques which have been employed to study structural and microstructural changes in premanifest and manifest HD gene carriers. This chapter described structural imaging techniques and analysis methods employed across HD MRI studies. Current evidence for structural MRI abnormalities in HD, and associations between atrophy, structural white matter changes, iron deposition and clinical performance are discussed; together with the use of structural MRI measures as a diagnostic tool, to assess longitudinal changes, and as potential biomarkers and endpoints for clinical trials. PMID- 30409259 TI - SPECT Molecular Imaging in Atypical Parkinsonism. AB - Atypical parkinsonism is the second most common diagnosis for patients with hypokinetic movement disorders. Beside common parkinsonian symptoms (i.e. bradykinesia and muscular rigidity) patients may also present a variety of additional motor and non-motor symptoms, such as oculomotor abnormalities, postural instability, ataxia, limb apraxia, autonomic dysfunctions, etc. Clinical heterogeneity and gradual manifestation during the disease course often hamper the diagnosis and adequate treatment. This chapter provides an overview of the contribution of single photon emission computed tomography (SPECT) in the differential diagnosis of atypical parkinsonism. PMID- 30409260 TI - Functional Magnetic Resonance Imaging in Huntington's Disease. AB - Huntington's disease is an inherited neurodegenerative condition characterized by motor dysfunction, cognitive impairment and neuropsychiatric disturbance. The effects of the underlying pathology on brain morphology are relatively well understood. Numerous structural Magnetic Resonance Imaging (MRI) studies have demonstrated macrostructural change with widespread striatal and cortical atrophy and microstructural white matter loss in premanifest and manifest HD gene carriers. However, disease effects on brain function are less well characterized. Functional MRI provides an opportunity to examine differences in brain activity either in response to a particular task or in the brain at rest. There is increasing evidence that HD gene carriers exhibit altered activation patterns and functional connectivity between brain regions in response to the neurodegenerative process. Here we review the growing literature in this area and critically evaluate the utility of this imaging modality. PMID- 30409262 TI - Preface. PMID- 30409261 TI - Structural Imaging in Atypical Parkinsonism. AB - Qualitative and quantitative structural magnetic resonance imaging offer objective measures of the underlying neurodegeneration in atypical parkinsonism. Regional changes in tissue volume, signal changes and increased deposition of iron as assessed with different structural MRI techniques are surrogate markers of underlying neurodegeneration and may reflect cell loss, microglial proliferation and astroglial activation. Structural MRI has been explored as a tool to enhance diagnostic accuracy in differentiating atypical parkinsonian disorders (APDs). Moreover, the longitudinal assessment of serial structural MRI derived parameters offers the opportunity for robust inferences regarding the progression of APDs. This review summarizes recent research findings as (1) a diagnostic tool for APDs as well as (2) as a tool to assess longitudinal changes of serial MRI-derived parameters in the different APDs. PMID- 30409263 TI - Current and Emerging Inhaled Therapies of Repositioned Drugs. PMID- 30409264 TI - Analysis of Bulk Tissue Transcriptome Data Reveals Convergence of Cell Types Altered in Schizophrenia and Bipolar Disorder. PMID- 30409265 TI - Clock Genes and Light Signaling Alterations in Bipolar Disorder: When the Biological Clock Is Off. PMID- 30409266 TI - Erratum. PMID- 30409267 TI - Erratum. PMID- 30409268 TI - Erratum. PMID- 30409269 TI - Reshaping the Depressed Brain: A Focus on Synaptic Health. PMID- 30409270 TI - Reduction in the Creatine Kinase Forward Reaction Rate as a Potential Trait Biomarker of Bipolar Disorder: Implications for Mitochondrial and Energy Metabolism Models. PMID- 30409271 TI - Intracardiac Echocardiography in Structural Heart Disease Interventions. AB - Intracardiac echocardiography has historically been used to guide a limited number of transcatheter cardiac interventions. However, the tremendous advances in structural heart disease interventions in the last decade led to a growing interest in intracardiac echocardiography as a potential alternative to transesophageal echocardiography that mitigates the need for endotracheal intubation. Nonetheless, the scarcity of data, the imperfection of the current probes, and the limited experience among operators prevented a wider adoption of this technology. This review summarizes the contemporary relevant evidence and provides the structural interventionalist with an illustrative guide on the use of intracardiac echocardiography to guide various structural heart interventions. PMID- 30409273 TI - Transcatheter Aortic Valve Replacement Without On-Site Cardiac Surgery: A Disappointing Step Backward! PMID- 30409272 TI - Impact of On-Site Cardiac Surgery on Clinical Outcomes After Transfemoral Transcatheter Aortic Valve Replacement. AB - OBJECTIVES: This study sought to investigate the outcome of high-risk and inoperable patients with severe symptomatic aortic stenosis undergoing transfemoral transcatheter aortic valve replacement (TAVR) in hospitals with (iOSCS) versus without institutional on-site cardiac surgery (no-iOSCS). BACKGROUND: Current guidelines recommend the use of TAVR only in institutions with a department for cardiac surgery on site. METHODS: In this analysis of the prospective multicenter Austrian TAVI registry, 1,822 consecutive high-risk patients with severe symptomatic aortic stenosis undergoing transfemoral TAVR were evaluated. A total of 290 (15.9%) underwent TAVR at no-iOSCS centers (no iOSCS group), whereas the remaining 1,532 patients (84.1%) were treated in iOSCS centers (iOSCS group). RESULTS: Patients of the no-iOSCS group had a higher perioperative risk defined by the logistic EuroSCORE (20.9% vs. 14.2%; p < 0.001) compared with patients treated in hospitals with iOSCS. Procedural survival was 96.9% in no-iOSCS centers and 98.6% in iOSCS centers (p = 0.034), whereas 30-day survival was 93.1% versus 96.0% (p = 0.039) and 1-year survival was 80.9% versus 86.1% (p = 0.017), respectively. After propensity score matching for confounders procedural survival was 96.9% versus 98.6% (p = 0.162), 93.1% versus 93.8% (p = 0.719) at 30 days, and 80.9% versus 83.4% (p = 0.402) at 1 year. CONCLUSIONS: Patients undergoing transfemoral TAVR in hospitals without iOSCS had a significantly higher baseline risk profile. After propensity score matching short and long-term mortality was similar between centers with and without iOSCS. PMID- 30409275 TI - A Stitch in Time: Biomarker-Guided Timing of Aortic Valve Replacement for Severe Aortic Stenosis? PMID- 30409274 TI - Multimarker Approach to Identify Patients With Higher Mortality and Rehospitalization Rate After Surgical Aortic Valve Replacement for Aortic Stenosis. AB - OBJECTIVES: This study sought to evaluate whether a multimarker approach might identify patients with higher mortality and hospitalization rates after aortic valve replacement (AVR) for aortic stenosis (AS). BACKGROUND: The society valve guidelines include accepted triggers for AVR in patients with severe asymptomatic AS, but circulating biomarkers do not have a clear role. METHOD: From a prospective registry of patients undergoing cardiac surgery between 2000 and 2012, 665 treated with surgical AVR (441 isolated) were evaluated. Seven biomarkers were measured on blood samples obtained before AVR. Biomarker levels were adjusted to account for the influence of age, sex, body mass index, and renal function; the median was used to determine an elevated value. Endpoints included all-cause mortality and all-cause and cardiovascular hospitalizations. Mean follow-up was 10.7 years and 299 (45%) died. RESULTS: Patients with 0 to 1, 2 to 3, 4 to 6, and 7 biomarkers elevated had 5-year mortality of 10%, 12%, 24%, and 33%, respectively, and 10-year mortality of 24%, 35%, 58%, and 71%, respectively (log-rank p < 0.001). The association between an increasing number of elevated biomarkers and increased all-cause mortality was observed among those with minimal symptoms (New York Heart Association functional class I or II) and those with a low N-terminal pro-B-type natriuretic peptide (p < 0.01 for both). Compared with those with 0 to 1 biomarkers elevated, patients with 4 to 6 or 7 biomarkers elevated had an increased hazard of mortality after adjustment for clinical risk scores (p < 0.01) and a 2- to 3-fold higher rate of all-cause and cardiovascular rehospitalization after AVR. Similar findings were obtained when evaluating cardiovascular mortality. Among patients with no or minimal symptoms, 42% had >=4 biomarkers elevated. CONCLUSIONS: Among patients with severe AS treated with surgical AVR, an increasing number of elevated biomarkers of cardiovascular stress was associated with higher all-cause and cardiovascular mortality and a higher rate of repeat hospitalization. A multimarker approach may be useful in the surveillance of asymptomatic patients with severe AS to optimize surgical timing. PMID- 30409277 TI - Hybrid Operating Rooms for Transcatheter Aortic Valve Replacement: A Must-Have or Nice to Have? PMID- 30409276 TI - Transcatheter Aortic Valve Replacement in the Catheterization Laboratory Versus Hybrid Operating Room: Insights From the FRANCE TAVI Registry. AB - OBJECTIVES: This study sought to compare outcomes of patients undergoing transcatheter aortic valve replacement (TAVR) in a catheterization laboratory (cath lab) to those undergoing TAVR in a hybrid operating room (OR). BACKGROUND: TAVR can be performed in a cath lab or in a hybrid OR. Comparisons between these locations are scarce. METHODS: All TAVRs performed in 48 centers across France between January 2013 and December 2015 were prospectively included in the FRANCE TAVI (French Transcatheter Aortic Valve Implantation) registry. The primary endpoint of this study was all-cause mortality at 1 year. Secondary endpoints consisted of 30-day complications and 3-year mortality. All analyses were adjusted for baseline and procedural characteristics. RESULTS: A total of 12,121 patients were included in this study, 62% of which underwent TAVR in a cath lab versus 38% in a hybrid OR. Mean age was 82.9 +/- 7.2 years, 48.9% of patients were men, and mean Logistic EuroScore was 17.9% +/- 12.3%. Both procedure locations showed similar, below 2% rates of intraprocedural complications. After adjusting for baseline and procedural characteristics, major bleeding and infections were significantly higher in the hybrid OR group (bleeding, 6.3% vs. 4.8%; infection, 6.1% vs. 3.5%; p < 0.05). Adjusted mortality rates at 1 and 3 years did not differ significantly between groups (for cath lab vs. hybrid OR, respectively: 1 year: 16.2% vs. 15.8%; p = 0.91; 3 years: 38.4% vs. 36.4%; p = 0.49). CONCLUSIONS: Midterm mortality after TAVR was similar between the cath lab and the hybrid OR. These findings support the performance of TAVR in either location, which has important implications on health care organization and costs. PMID- 30409279 TI - Transcatheter Aortic Valve Replacement Versus Surgical Aortic Valve Replacement: A Prior Sternotomy Is Not the Problem. PMID- 30409278 TI - Transcatheter Versus Surgical Aortic Valve Replacement in Patients With Prior Cardiac Surgery in the Randomized PARTNER 2A Trial. AB - OBJECTIVES: The aim of this study was to further evaluate clinical outcomes in patients with and without PCS. BACKGROUND: Prior cardiac surgery (PCS) is associated with increased surgical risk and post-operative complications following surgical aortic valve replacement (SAVR), but whether this risk is similar in transcatheter aortic valve replacement (TAVR) is unclear. METHODS: In the PARTNER 2A (Placement of Aortic Transcatheter Valve) trial, 2,032 patients with severe aortic stenosis at intermediate surgical risk were randomized to TAVR with the SAPIEN XT valve or SAVR. Adverse clinical outcomes at 30 days and 2 years were compared using Kaplan-Meier event rates and multivariate Cox proportional hazards regression models. The primary endpoint of the PARTNER 2 trial was all-cause death and disabling stroke. RESULTS: Five hundred nine patients (25.1%) had PCS, mostly (98.2%) coronary artery bypass grafting. There were no significant differences between TAVR and SAVR in patients with or without PCS in the rates of the primary endpoint at 30 days or 2 years. Nevertheless, an interaction was observed between PCS and treatment arm; whereas no-PCS patients treated with TAVR had higher rates of 30-day major vascular complications than patients treated with SAVR (adjusted hazard ratio: 2.66; 95% confidence interval: 1.68 to 4.22), the opposite was true for patients with PCS (adjusted hazard ratio: 0.27; 95% confidence interval: 0.11 to 0.66) (pinteraction <0.0001). A similar interaction was observed for life-threatening or disabling bleeding. CONCLUSIONS: In the PARTNER 2A trial of intermediate-risk patients with severe aortic stenosis undergoing SAVR versus TAVR, the relative risk for 2-year adverse clinical outcomes was similar between TAVR and SAVR in patients with or without PCS. PMID- 30409281 TI - The Power of Imaging: The Default Question Should Become When Should Intravascular Imaging Be Avoided? PMID- 30409280 TI - The 21st Century Cures Act and Early Feasibility Studies for Cardiovascular Devices: What Have We Learned, Where Do We Need to Go? AB - Performance of early feasibility studies in the United States can advance the goal of evaluating the safety and effectiveness of new devices aimed at unmet clinical needs and facilitating earlier access for U.S. patients to new technology. Early feasibility studies are an important component of the 21st Century Cures Act, enacted by Congress in 2016. Although regulatory processes have improved since the introduction of the Early Feasibility Studies Program, impediments at the hospital and clinical site level remain. In this paper, the authors review these issues and outline the structure and function of a clinical site consortium designed to address the problems and improve the U.S. clinical trial ecosystem. PMID- 30409282 TI - Reply: The Power of Imaging: The Default Question Should Become When Should Intravascular Imaging Be Avoided? PMID- 30409283 TI - Multiple Overlapping Stents Might Be a Promising Therapeutic Target for Coronary Artery Aneurysms. PMID- 30409284 TI - What Is the Value of Continuous Monitoring Post-Transcatheter Aortic Valve Replacement? PMID- 30409285 TI - Reply: What Is the Value of Continuous Monitoring Post-Transcatheter Aortic Valve Replacement? PMID- 30409286 TI - BI-SILICA During Transcatheter Aortic Valve Replacement for Noncalcific Aortic Insufficiency: Initial Human Experience. PMID- 30409287 TI - First Evaluation of Acute Left Ventricular Response to Off-Pump Transcatheter Mitral Valve Replacement in High-Risk Patients. PMID- 30409288 TI - Post-operative radiation effects on lymphopenia, neutrophil to lymphocyte ratio, and clinical outcomes in palatine tonsil cancers. AB - OBJECTIVE: To evaluate radiation-induced lymphopenia associated with unilateral vs. bilateral neck radiation and to test post-treatment neutrophil to lymphocyte ratio (NLR) as a prognostic clinical biomarker. METHODS: This was a single academic center retrospective review of palatine tonsil squamous cell cancer patients treated with post-operative intensity modulated radiation therapy (IMRT) from 1997 to 2013. Absolute lymphocyte count (ALC) and NLR were evaluated during and after radiation for up to a year. Correlations of lab values with loco regional control (LRC), freedom from distant metastases (FFDM), and overall survival (OS) were assessed. RESULTS: Ninety-nine patients with median follow up 5.8 years had ALC recorded at least at baseline and within one year of starting RT. Acute grade 3-4 lymphopenia (<10 weeks from RT start) occurred in 79% of bilateral neck RT patients (n = 70) and 58% of unilateral neck RT patients (n = 29), p = 0.03. There was no significant difference in late grade 3-4 (p = 0.12) lymphopenia. In a multivariable Cox regression model, acute NLR > 11.875 correlated with worse OS (HR = 4.4, 95% CI 1.2-16). Late NLR > 6.875 independently correlated with significantly worse FFDM (HR = 16, 95% CI 1.9-137) and OS (HR = 12, 95% CI 3.0-48). CONCLUSIONS: Unilateral neck radiation may prevent acute iatrogenic immunosuppression. In exploratory analyses, elevated post-treatment NLR was associated with risk for distant metastases and death. PMID- 30409289 TI - Comparison of hospital based and home based exercise on quality of life, and neck and shoulder function in patients with spinal accessary nerve injury after head and neck cancer surgery. AB - OBJECTIVES: The purpose of this study was to compare the effects of hospital based and home-based exercise programs on quality of life (QOL) and neck and shoulder function of patients who underwent head and neck cancer (HNC) surgery. METHODS: This clinical trial included 40 patients with neck and shoulder dysfunction after HNC. The exercise program included range of motion (ROM) exercises, massage, stretching, and strengthening exercises. Twenty patients who were assigned to the hospital-based exercise group performed physical therapy for 40 min three times a week for four weeks, and the remaining 20 patients were assigned to the home-based group. The European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30), the EORTC Head and Neck Questionnaire (EORTC QLQ-H&N), the Neck and Shoulder Disability Index (NDI), ROM, and numeric rating scale (NRS) were assessed before and after the exercise program. The program consisted of a 10-minute ROM to the neck and shoulder, a 10-minute massage, and 15 min of progressive resistance exercises, followed by a five-minute stretching exercise. RESULTS: There were statistically significant differences in the changes of neck and shoulder disability index (p < .05). Additionally, there were significant differences in neck extension and rotation ROM and NRS in the hospital-based group compared with the home-based group (p < .05). QOL was not significantly different between the two groups. CONCLUSIONS: Home-based exercise was effective for improving QOL, shoulder function, and pain relief. Hospital-based exercise had better effects on physical function of the neck and shoulder and reduced pain. PMID- 30409290 TI - Aurora kinases are a novel therapeutic target for HPV-positive head and neck cancers. AB - OBJECTIVES: Human papilloma virus (HPV) is the main culprit in cancers of the cervix, penis, anus, skin, eye and head and neck. Current treatments for HPV cancers have not altered survival outcomes for 30 years and there is a significant lack of targeted therapeutic agents in the management of advanced HPV related HNSCC. Here we show that survival and maintenance of HPV-positive HNC cells relies on the continuous expression of the major HPV oncogene, E7, and that Aurora kinases are critical for survival of high-risk HPV-positive HNC cells. MATERIALS AND METHODS: To assess the role of HPV E7 on HNC cell survival, RNA interference (RNAi) of the E7 gene was initially performed. Using an Aurora kinase inhibitor, Alisertib, the role of Aurora kinases in the carcinogenesis of HPV E7 positive HNC tumour lines was then investigated. An in vivo HNC xenograft model was also utilised to assess loss of tumour volume in response to RNAi E7 gene silencing and Alisertib treatment. RESULTS: RNAi silencing of the HPV E7 gene inhibited the growth of HPV-positive HNC cells and in vivo tumour load. We show that HPV E7 oncogene expression confers sensitivity to Alisertib on HNC cells where Alisertib-mediated loss in in vitro cell viability and in vivo tumour load is dependent on E7 expression. Moreover, Aurora kinase inhibition induced degradation of MCL-1 in HPV E7-expressing HNC cells. CONCLUSION: Overall, we show that Aurora kinases are a novel therapeutic target for HPV-positive HNCs. It might be feasible to combine Aurora kinase and MCL-1 inhibitors for future HNC therapies. PMID- 30409291 TI - Non-smoking, non-drinking elderly females, a 5 year follow-up of a clinically distinct cohort of oral squamous cell carcinoma patients. AB - To examine differences in survival and clinical outcomes of elderly patients without traditional risk factors presenting with oral squamous cell carcinoma. Retrospective review of 287 consecutive patients divided into 2 treatment period cohorts treated for oral SCC between the 1st Jan 2007 and 31st Dec 2012. Patients were classified as either smoker-drinkers (SD) or non-smoking, non-drinking (NSND). Only patients with oral sub-site primaries according to ICD-10 were included. Carcinomas of the lip, tonsil, base of tongue and oro-pharyngeal subsites were excluded. Of the study population (N = 287), 24.4% were NSND and 9.75% were NSND elderly (older than 70 years) females. >50% of tumours arose from the oral tongue in NSND patients (p = 0.022) and there was a higher rate of recurrent and persistent disease (42.9% vs 27.6%, p = 0.005). Disease specific survival at 5 years was significantly reduced when NSND elderly females were compared to all other patients (p < 0.001) as well as age matched controls (p = 0.006). This effect was verified independently in each cohort.The results of this study suggest that NSND elderly females are a distinct patient population with poorer disease specific survival outcomes. PMID- 30409292 TI - Survival for HPV-positive oropharyngeal squamous cell carcinoma with surgical versus non-surgical treatment approach: A systematic review and meta-analysis. AB - The optimal management of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) with primary surgical versus non-surgical treatment is unclear. The objective of this systematic review was to evaluate the literature and compare survival for primary surgical versus non-surgical treatment of HPV-positive OPSCC. We performed a comprehensive literature search of multiple electronic databases for relevant articles up to February, 2017. Studies reporting mortality or hazard ratio (HR) for overall survival (OS) in primary HPV-positive OPSCC patients were eligible. Seventy-three articles were eligible, of which 66 included single-modality (19 surgical, 47 non-surgical), and 7 included both surgical and non-surgical modalities. There were no randomized studies comparing outcomes between both modalities. In a meta-analysis of both-modality studies, OS with surgical treatment was not significantly different from non-surgical treatment (pooled HR 1.12; 95% CI: 0.35, 3.57). There was significant heterogeneity between studies (I2 = 82.4%). Among single-modality studies, the mortality rate was lower with surgical [pooled proportion 0.15 (95% CI: 0.09, 0.21)] versus non-surgical treatment [0.20 (95% CI:0.15, 0.24)]. In a subgroup analysis, OS was higher for HPV-positive versus HPV-negative OPSCC, irrespective of the treatment modality. We conclude that there is an absence of high-quality studies that compare survival for HPV-positive OPSCC treated with primary surgical versus non-surgical approach. The available data suggest no statistical or clinically meaningful difference in survival between the two approaches. HPV-positivity was a key prognostic factor irrespective of treatment modality. Further high-quality studies with consistent data reporting are needed to inform the choice for optimal treatment modality for HPV-positive OPSCC. PMID- 30409293 TI - Definitive radiation with concurrent cetuximab vs. radiation with or without concurrent cytotoxic chemotherapy in older patients with squamous cell carcinoma of the head and neck: Analysis of the SEER-medicare linked database. AB - OBJECTIVE: To evaluate OS and toxicity after definitive radiation with concurrent cetuximab (CTX-RT) compared to radiation with concurrent cytotoxic chemotherapy (CRT) in older HNSCC patients via the SEER-Medicare linked database. MATERIALS AND METHODS: We used the SEER-Medicare linked database to evaluate OS in HNSCC patients (Oropharynx, Larynx, Hypopharynx, Nasopharynx) diagnosed over 2005-2011, following FDA approval of cetuximab in combination with radiation therapy (RT) in March 2006. RESULTS: 2135 beneficiaries were identified. Median age was 73 (66 104) years. Primary was oropharynx (61%), hypopharynx (15%), nasopharynx (5%), and larynx (19%). CRT was platinum based in 82% of patients. CTX-RT was associated with worse OS compared to CRT (P < 0.005), and similar OS to RT (P = 0.21); 5-year OS was 46% for CRT, 35% for CTX-RT, 32% for RT. Patients were more likely to receive CTX-RT vs. CRT if they had oropharyngeal vs nasopharyngeal primary, Charlson comorbidity index 2 vs 0, older age at diagnosis. Multivariable Cox regression showed that CTX-RT was associated with a higher risk of death compared to CRT (hazard ratio = 1.23, 1.07-1.42; p = 0.005), after stratifying by stage and primary site, and adjusting for gender, race, age, income, Charlson comorbidity index, marital status, hospital type, and year of diagnosis. There were no differences in dysphagia, gastrostomy tube placement, pneumonia, and weight loss over the first 12 months after diagnosis. CONCLUSION: Despite the limitations to comparative effectiveness evaluation in population-based registries, our data suggest that cytotoxic chemotherapy should be used with RT for eligible older HNSCC patients. PMID- 30409294 TI - Triggering TLR3 pathway promotes tumor growth and cisplatin resistance in head and neck cancer cells. AB - Over the last decades, significant advances in targeted therapies have helped provide more effective treatment for head and neck cancer patients. However, chemo-resistance to cisplatin significantly contributes to treatment failure in the clinical management of patients. In response to chemotherapeutic agents, certain molecules inside the cell are released or secreted from damaged or dead/dying cells, named damage-associated molecular patterns (DAMPs), thereby initiating an immune response through interaction with pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs). In present study, we investigated the link between cisplatin-induced DAMPs and TLR3 signaling. We found that cisplatin could be a potential activator of TLR3 and cisplatin treatment results in activation of PRRs' signaling and down-stream associated cytokine/chemokine, IFNbeta, and CCL5 in TLR3High OC2 cells, but not in TLR3Low FaDu cells. Furthermore, knockdown of the TLR3 gene attenuates the expression of IFNbeta and CCL5 mRNA and enhances the cytotoxicity of cisplatin in TLR3High OC2 cells. To determine whether TLR3 status affects the stress response of OC2 cells to cisplatin, we generated TLR3 knockdown OC2 cells (psi-TLR3 cells) with a psiRNA-hTLR3 plasmid containing shRNA to TLR3 and control OC2 cells (psi-NT cells) expressing non-silencing shRNA. OC2 cells were more sensitive to cisplatin treatment after TLR3 knockdown. In our animal model, OC2 psi-NT cells were more tumorigenic than were OC2 psi-TLR3 cells. Together, our in vitro and in vivo data imply TLR3 may contribute to tumor development and protect cisplatin-induced DNA damage response leading to cisplatin resistance in head and neck cancer cells. PMID- 30409295 TI - Performance of different imaging techniques in the diagnosis of head and neck cancer mandibular invasion: A systematic review and meta-analysis. AB - BACKGROUND: To assess diagnostic efficacy of imaging techniques for mandibular invasion by head and neck cancer. METHODS: Thirteen databases were searched. Study inclusion, data-extraction and quality assessment were performed independently. STATA 14.0 were mainly used for meta-analysis. RESULTS: Forty-nine studies were included. For mandibular invasion (cortex and marrow), CBCT, SPECT, CT, MRI, orthopantomography, PET-CT and bone-scintigraphy showed pooled sensitivities of 90%, 97%, 73%, 88%, 75%, 90%, 92%, specificities of 85%, 69% 91%, 90%, 83%, 89%, 79%, AUC of 0.9461, 0.9434, 0.8995, 0.9296, 0.8761, 0.9290, 0.9207, respectively. The combined SROC curves indicated CBCT and SPECT were superior to other techniques. For mandibular medullary invasion (marrow), CT and MRI showed pooled sensitivities of 85% and 93%, specificities of 86% and 84%. CONCLUSIONS: CBCT was top-priority choice for bone invasion diagnosis. SPECT was recommended for exclusion, CT and MRI were suitable for conformation. Further investigations are needed for mandibular medullary involvement. PMID- 30409296 TI - Oncological and functional outcomes of trans-oral robotic surgery for pyriform sinus carcinoma: A French GETTEC group study. AB - BACKGROUND: Pyriform sinus carcinomas (SCC) present specific functional and oncological issues. The recent advent of trans-oral robotic surgery (TORS), as a conservative procedure, has opened up new perspectives. OBJECTIVES: To present the oncological and functional outcomes of TORS for pyriform sinus SCC. MATERIALS AND METHODS: We included, retrospectively, all TORS procedures for pyriform sinus SCC performed between 2009 and 2017 in eight French tertiary referral centers. We excluded lesions involving the pyriform sinus that had developed from the oropharynx, larynx, or other anatomic sub-sites of the hypopharynx. RESULTS: We included 57 TORS procedures. Median hospital stay was 10 days. A preventive tracheotomy was performed in seven cases (12%), and all were successfully decannulated. Oral re-feeding was possible for 93%, after a median of 5 days. The main surgical complications were hemorrhages (three cases), all successfully handled, although 2 patients with heavy comorbidities died from blood loss in the days after. Adjuvant therapy was proposed in 31 cases (54%), including two cases of salvage surgery (total pharyngolaryngectomy). After a median follow-up of 23 months, overall and disease-free survival were, respectively, 84% and 74% at 24 months, and 66% and 50% at 48 months. At the end of follow-up, organ preservation rate was 96%. None of the surviving patients needed a tracheotomy and oral diet was possible for 96%. CONCLUSION: The functional and oncological outcomes of TORS for pyriform sinus cancer are encouraging, and this procedure can be considered safe for selected early or moderately advanced cases as a conservative treatment. PMID- 30409297 TI - The interplay of IMRT and transoral surgery in HPV-mediated oropharyngeal cancer: Getting the balance right. AB - Transoral surgery (TOS) and IMRT represent two primary local ablative treatment modalities for oropharyngeal cancer (OPC). The choice of one over the other represents an interplay between the chance of cure vs risk of late sequelae. HPV mediated (HPV+) OPC patients generally have excellent outcomes, especially in TNM 8 stage I disease. Controversies exist over which treatment has a more favorable toxicity profile and equal efficacy in the management of this population. Non randomized retrospective data show comparable oncological and functional outcomes between TOS-based vs IMRT-based treatment for this disease. Several de intensification concepts have been explored in this subset in both primary surgery-based vs primary radiotherapy-based trials. However, no robust mature trial data are available to convincingly guide treatment selection. TOS is often presented as one of the de-intensification options although the majority of series also describe the use of adjuvant treatments which inevitably result in non-negligible toxicities. Patient selection and surgeons' training are paramount. Understanding tumor biology and the prognostic value of traditional 'adverse' features will further guide trial design for refinement of risk tailored approach. In conclusion, comparative data suggests TOS and IMRT are both effective treatment for TNM-8 stage I HPV+ OPC with similar oncological and functional outcomes. TOS as a single modality has potential advantages in mitigating radiation included toxicities. TOS should be avoided in the presence of clinically overt extranodal extension or when negative margins are unlikely to be achieved. TOS is also less ideal for cases with radiological features predicting a high risk of distant metastasis. PMID- 30409298 TI - Invasion of the mandible in gingivobuccal complex cancers: Histopathological analysis of routes of tumour entry and correlation with preoperative assessment. AB - OBJECTIVES: To determine the most accurate imaging modality predicting mandibular invasion in gingivobuccal (GB) complex cancers. To determine patterns of invasion and routes of tumour entry into the mandible by detailed histopathologic analysis. MATERIAL AND METHODS: Prospective observational study of GB Complex cancers juxtaposed with the mandible clinically necessitating some form of mandibular resection. Orthopantomogram (OPG), Multi Detector Computed Tomography (MDCT), DENTA scan and Single Photon Emission Computed Tomography scan (SPECT) were performed after which the patient was subjected to surgery. Histopathological assessment was systematically performed with serial cuts of the mandibular segment. RESULTS: Of 70 patients, MDCT was the most accurate with area under curve (AUC) of 0.833. OPG, DENTA and SPECT had AUC of 0.714, 0.786 and 0.738 respectively. Mean calculated difference of involved height was -0.025 cm by MDCT (p value 0.87), -0.2 cm by OPG (p value 0.09) and 0.12 by DENTA scan (p value 0.41). Mean difference of involved length was -0.51 cm (p value 0.08) and 1.02 cm (p value 0.04) for MDCT and OPG respectively. 50% of tumour invasion was through the occlusal route while large tumours demonstrated multiple routes of entry. CONCLUSION: -Gingivobuccal complex cancers are homogenous with respect to mandibular invasion, preferred route of tumour entry being the occlusal surface. Multidetector CT scan is fairly accurate in detecting mandibular involvement and predicting extent of involvement. -Oncological safety can be achieved by positioning the bone cuts corresponding to the adjacent soft tissue margins in segmental mandibulectomy. PMID- 30409299 TI - Pathological risk factors stratification in pN3b oral cavity squamous cell carcinoma: Focus on the number of positive nodes and extranodal extension. AB - OBJECTIVE: According to the AJCC 2017 Staging Manual, oral cavity squamous cell carcinoma (OCSCC) with pN2 disease (based on the AJCC 2010 criteria) and extra nodal extension (ENE) should be classified as pN3b. We performed a detailed outcome analyses in this patient subgroup. MATERIAL AND METHODS: We retrospectively reviewed the clinical records of consecutive OCSCC patients who underwent radical surgery between 1996 and 2017. Patients with pN3b disease (n = 365) were divided into a pN+ >=8/ENE >=5 subgroup (defined by the presence of pN+ >=8 nodes or ENE >=5 nodes, n = 77) and a pN+ <=7/ENE <=4 subgroup (defined by the presence of pN+ <=7 nodes and ENE <=4 nodes, n = 288). Patients with pN0/pN1/pN2 (n = 1192/179/197) disease were included for comparison purposes. RESULTS: Patients in the pN+ >=8/ENE >=5 subgroup had less favorable 5-year outcomes than those in the pN+ <=7/ENE <=4/pN2/pN1/pN0 groups (local control, 64%/79%/86%/83%/88%, p < 0.001; neck control, 55%/75%/80%/86%/93%, p < 0.001; distant metastases, 67%/28%/20%/12%/3%, p < 0.001; disease-free survival, 21%/51%/64%/72%/82%, p < 0.001; disease-specific survival, 25%/55%/71%/82%/92%, p < 0.001; overall survival, 19%/40%/54%/64%/82%, p < 0.001; respectively). Among patients with pN3b disease, multivariable analysis identified the pN+ >=8/ENE >=5 subgroup, lower neck (level IV/V) metastases, and depth of invasion >=25 mm as independent adverse prognostic factors for 5-year distant metastases and survival rates. CONCLUSIONS: Patients in the pN+ >=8/ENE >=5 subgroup have an unfavorable prognosis and their classification as pN3b is advisable. In contrast, patients in the pN+ <=7/ENE <=4 subgroup should be classified as pN3a. PMID- 30409300 TI - Adaptive radiotherapy for head and neck cancer: Are we ready to put it into routine clinical practice? AB - Patients with head and neck cancer who are treated with radiotherapy often have significant weight loss or tumor regression during treatment. Adaptive radiotherapy refers to acquiring new imaging during treatment and changing the parameters of the radiation plan based on the new imaging findings. There is accumulating evidence that adaptive radiotherapy can reduce toxicity and improve tumor control, though it is not yet known which patients benefit most. For patients with profound tumor regression, there is also uncertainty about how much to shrink the region receiving high radiation dose. Another form of adaptive radiotherapy uses advanced imaging such as positron emission tomography to visualize changes in tumor biology during treatment. Tumor regions that are thought to be more radioresistant can then be treated to a higher radiation dose, and vice-versa. Studies employing this strategy to boost radiation dose have shown a high rate of late toxicity, specifically the development of persistent mucosal ulcers. Therefore, this sort of adaptive radiotherapy is currently confined to the research setting. PMID- 30409301 TI - Decision making in advanced larynx cancer: An evidenced based review. AB - Organ preservation versus total laryngectomy for advanced laryngeal cancer continues to be hotly debated. This review presents evidence-based decision making points for these patents. PMID- 30409302 TI - From VA Larynx to the future of chemoselection: Defining the role of induction chemotherapy in larynx cancer. AB - Organ preservation protocols utilizing induction chemotherapy as a selection agent have played a critical role in the treatment of advanced laryngeal squamous cell carcinoma (LSCC). The selection of patients who will have a good response to chemoradiation allows for organ preservation in a significant group of patients and minimizes the rate of surgical salvage. While there remains debate regarding its utility when compared to surgery or other organ preservation regimens, the data does suggest an important role for induction chemotherapy in LSCC. In addition, there are continued opportunities to identify pretreatment biomarkers for induction chemotherapy, whether genetic, epigenetic or cellular, that could predict response to treatment and select patients to therapy (whether organ preservation or surgery). As our understanding of the biology of larynx cancer advances, induction paradigms have utility for the development and adoption of novel agents and therapeutics. The background of induction chemotherapy as a selection agent and future directions of this approach are discussed. PMID- 30409303 TI - Label-free tissue proteomics can classify oral squamous cell carcinoma from healthy tissue in a stage-specific manner. AB - OBJECTIVES: No prognostic or predictive biomarkers for oral squamous cell carcinoma (OSCC) exist. We aimed to discover novel proteins, altered in OSCC, to be further investigated as potential biomarkers, and to improve understanding about pathways involved in OSCC. MATERIALS AND METHODS: Proteomic signatures of seven paired healthy and OSCC tissue samples were identified using ultra definition quantitative mass spectrometry, then analysed and compared using Anova, principal component analysis, hierarchical clustering and OPLS-DA modelling. A selection of significant proteins that were also altered in the serum from a previous study (PMID: 28632724) were validated immunohistochemically on an independent cohort (n = 66) to confirm immunopositivity and location within tumour tissue. Ingenuity Pathways Analysis was employed to identify altered pathways. RESULTS: Of 829 proteins quantified, 257 were significant and 72 were able to classify healthy vs OSCC using OPLS-DA modelling. We identified 19 proteins not previously known to be upregulated in OSCC, including prosaposin and alpha-taxilin. KIAA1217 and NDRG1 were upregulated in stage IVa compared with stage I tumours. Altered pathways included calcium signalling, cellular movement, haematological system development and function, and immune cell trafficking, and involved NF-kB and MAPK networks. CONCLUSIONS: We found a set of proteins reliably separating OSCC tumour from healthy tissue, and multiple proteins differing between stage I and stage IVa OSCC. These potential biomarkers can be studied and validated in larger cohorts. PMID- 30409304 TI - Shared genetic and epigenetic mechanisms between chronic periodontitis and oral squamous cell carcinoma. AB - OBJECTIVES: To analyze bioinformatic datasets for detecting genetic and epigenetic mechanisms shared by chronic periodontitis (CP) and oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Datasets from GEO and TCGA databases reporting mRNAs, miRNAs or methylation expression in human CP and OSCC tissues were analyzed. Differential expression, functional enrichment and protein-protein interaction (PPI) network analyses were performed. Differentially expressed miRNAs (DEmiRNAs) and genes (DEG) in CP and OSCC were determined. DEmiRNA-target and DEmiRNA-DEG networks were constructed. Directly and indirectly interacting cross-talk genes were screened, and their prediction accuracy and association with OSCC prognosis was determined. RESULTS: 3 DE-miRNAs (miR-375, miR-3609 and miR-3652) expressed in both CP and OSCC critically regulated most DEGs. Among 12 directly interacting cross-talk genes, NCAPH was significantly related with the prognosis of OSCC. NR2F2 had highest differential expression in CP and OSCC. Among 4 cross-talk genes (FN1, MPPED1, NDEL1, and NR2F2) differentially expressed in CP, 3 (FN1, MPPED1, NDEL1) were also expressed in OSCC. Among 12 indirectly interacting cross-talk genes differentially expressed in OSCC, 3 genes (CDCA8, HIST1H3J, and RAD51) were significantly related to its prognosis. Significant pathways involved in CP and OSCC included: chemokine receptors, class I PI3K signaling events, epithelial-to-mesenchymal transition and signaling events by VEGFR1 and VEGFR2, EGF receptor (ErbB1). CONCLUSION: Bioinformatic analysis of available datasets implicated 1 directly interacting cross-talk gene (NCAPH), 4 indirectly interacting cross-talk genes (NCAPH, NR2F2, FN1, and MPPED1) and 3 DE miRNAs (hsa-miR-375, miR-3609 and miR-3652) as shared genetic and epigenetic expression patterns between CP and OSCC. PMID- 30409305 TI - Patterns of failure, treatment outcomes and late toxicities of head and neck cancer in the current era of IMRT. AB - Intensity modulated radiotherapy (IMRT) in head and neck cancer allows sculpting of radiation dose to conform closely to target volumes and spare organs at risk. However, this may be offset by an increased risk of a geographical miss and reduction in survival outcomes. We reviewed the data from 5 prospective randomized controlled trials, one prospective phase II trial and 10 retrospective comparative series in terms of patterns of failure, treatment outcomes and late toxicities to determine any compromise in survival outcomes in favour of reduced late toxicity. Whilst there was some variablility in target volume delineation, radiation dose and technique, the published data consistently show reduced long term xerostomia (ranging from 0.5 to 87%) with IMRT compared to older radiation techniques. Some studies showed reduced incidence of >10% weight loss and grade >=2 dysphagia with IMRT, and 2 studies reported higher rates of dysphagia with IMRT. Most studies demonstrated better, though non-significant, locoregional, disease-free and overall survival. The 4 studies that did demonstrate significantly better overall survival with IMRT were the largest cohorts with around 250 patients or greater. Standardization of target volume delineation, treatment verification protocols and outcome reporting will reduce heterogeneity and allow data to be pooled in order to be adequately powered for survival analyses. PMID- 30409306 TI - Crosstalk between Raf-MEK-ERK and PI3K-Akt-GSK3beta signaling networks promotes chemoresistance, invasion/migration and stemness via expression of CD44 variants (v4 and v6) in oral cancer. AB - BACKGROUND: The cell-surface glycoprotein CD44 is an important oral cancer stem cell (OCSC) marker and plays significant role in oral squamous cell carcinoma (OSCC) aggressiveness, however, the regulation of CD44 is incompletely understood. METHODS: In the present study, 145 fresh human OSCC tissue specimens, including 18 adjacent normal, 42 noninvasive (N0), 53 invasive tumor samples (N1 3) and 32 chemo-radiation resistant samples (RCRT), were included. The expression of CD44 standard (CD44s) and variants (CD44v4, CD44v6); the activation of pERK1/2, GSK3beta, NICD (Notch) pathways; the cell viability; and the MMP-9/-2 activity were assessed using RT-PCR, immunohistochemistry, Western blotting, MTT assay and gelatin zymography. OSCC cell lines, including parental (SCC9/SCC4) and Cisplatin-resistant (CisR-SCC9/-SCC4) cells, were used. Knock down of CD44v4/CD44v6 (by siRNA) or inactivation of MAPK/PI3K pathways using specific PD98059/LY294002 was achieved for in vitro analysis of chemoresistance and invasion/migration. RESULTS: Elevated CD44 variants were associated with overall OSCC progression, chemoresistance and invasion. Positive correlations were observed, mainly between the expression of CD44v4 and the activation of ERK1/2 causing chemoresistance, whereas CD44v6 expression and inactivation of GSK3beta caused invasiveness of OSCC. Cisplatin resistant, CisR-SCC9/SCC4 cell lines showed OCSC properties. Inhibition of MEK/ERK1/2 by SMI or knock down (KD) of CD44v4 by siRNA reversed cisplatin-resistance, whereas blocking the PI3K/Akt/GSK3beta pathway by SMI or KD of CD44v6 isoforms by respective siRNA diminished invasion/metastasis potential. CONCLUSION: Collectively, our results demonstrated that CD44v4 expression is more linked with ERK1/2 activation and promote cisplatin resistance, whereas CD44v6 expression is associated primarily with PI3K/Akt/GSK3beta activation and driving tumor invasion/migration. PMID- 30409307 TI - Hypopharyngeal cancer: A state of the art review. AB - Cancer of the hypopharynx is relatively rare and accounts for roughly 3% of all head and neck cancers. Unfortunately, hypopharyngeal carcinoma has one of the worst prognosis of all head and neck cancers with a reported 5-year overall survival rate of approximately 30-35%. Toxicity related to therapy, and the need for surgical salvage continue to dominate the landscape in this disease. In this article, we set out to discuss a comprehensive overview of the current management principles, recent literature and evidence based therapeutic options surrounding treatment for hypopharyngeal squamous cell carcinoma, with a special focus on the evolution of an organ sparing paradigm. PMID- 30409308 TI - The transcriptional co-activator YAP: A new player in head and neck cancer. AB - The Hippo-YAP (Yes-associated protein) pathway is a key regulator of tissue growth, organ size and stem cell function. More recently, a fundamental role for this pathway has emerged in stem cell function and tumorigenesis. Activation of the transcriptional co-activator YAP promotes cell-contact independent proliferation, epithelial to mesenchymal transition (EMT), cancer stem cell features and drug resistance. In this review, we describe the main components of the pathway, the microenvironment and the cell-intrinsic cues governing its activation, the downstream players of the pathway and the biological implications of their activation in the context of cancer. We will focus on the existing knowledge of this pathway in head and neck squamous carcinoma (HNSCC), its clinical value in this type of cancer as a marker of poor prognosis and resistance to therapy, as well as the most encouraging therapeutic strategies targeting the pathway. PMID- 30409310 TI - A novel scoring model to predict benefit of additional induction chemotherapy to concurrent chemoradiotherapy in stage II-IVa nasopharyngeal carcinoma. AB - OBJECTIVES: Induction chemotherapy (IC) is gaining recognition for the treatment of nasopharyngeal carcinoma (NPC). We aimed to develop a model to predict benefit from additional IC to concurrent chemoradiotherapy (CCRT). MATERIALS AND METHODS: From an NPC-specific database, 7413 patients with stage II-IVa disease who received CCRT with or without IC were included. Distant metastasis-free survival (DMFS) was the primary outcome and benefit from IC was evaluated by adjusted hazard ratio. Interaction terms between IC and other prognostic factors were identified in multivariate Cox model, and IC benefit score (ICBS) was calculated based on beta coefficients from the Cox model. RESULTS: Nodal category, overall stage, and pre-treatment plasma Epstein-Barr virus DNA (log transformed as continuous variable) interacted with IC and determined ICBS. ICBS could discriminate patients who benefited differently from IC in terms of DMFS well, especially for patients with high and low ICBS. As for patients with medium ICBS, predictive performance of ICBS seemed reduced. CONCLUSIONS: Based on the ICBS model, we proposed a decision-making process to help in clinical practice. Multi institutional and prospective studies are warranted to further validate our findings. PMID- 30409309 TI - Carcinogenic epithelial-mesenchymal transition initiated by oral cancer exosomes is inhibited by anti-EGFR antibody cetuximab. AB - Overexpression and increased signaling from the epidermal growth factor receptor (EGFR) often changes oral squamous cell carcinoma (OSCC) and thus EGFR is frequently targeted molecularly by the therapeutic antibody cetuximab. We assessed the roles of OSCC-derived extracellular vesicles (EVs), including exosomes in the trafficking of cetuximab and in epithelial-mesenchymal transition (EMT) of epithelial cells. OSCC cells abundantly expressed EGFR, which was secreted from cells with OSCC-EVs upon EGF stimulations. The OSCC-EGFR-EVs were then able to enter into and transform epithelial cells leading to increased mesenchymal traits with increased vimentin and spindle-like shapes. EGF priming of OSCC cells further increased this EMT-initiating effect of the OSCC-EVs. The internalization and pro-EMT effects of the OSCC-EVs were largely blocked by cetuximab. Thus, OSCC-derived EVs transform normal epithelial cells into a mesenchymal phenotype and anti-EGFR therapeutic antibody cetuximab inhibits such a carcinogenic effect of the OSCC-EVs. PMID- 30409311 TI - Multivariable model for predicting acute oral mucositis during combined IMRT and chemotherapy for locally advanced nasopharyngeal cancer patients. AB - INTRODUCTION/OBJECTIVE: Oral and oropharyngeal mucositis (OM) represents amultifactorialand complexinterplayof patient-, tumor-, and treatment-related factors. We aimed to build a predictive model for acute OM for locally advanced nasopharyngeal carcinoma (NPC) patients by combining clinical and dosimetric factors. MATERIALS/METHODS: A series of consecutive NPC patients treated curatively with IMRT/VMAT + chemotherapy at 70 Gy (2-2.12 Gy/fr) was considered. For each patient, clinical- tumor- and treatment-related data were retrospectively collected. oral cavity (OC) and parotid glands (PG, considered as a single organ) were selected as organs-at-risk (OARs). Acute OM was assessed according to CTCAE v4.0 at baseline and weekly during RT. Two endpoints were considered: grade >=3 and mean grade >=1.5. DVHs were reduced to Equivalent Uniform Dose (EUD). Dosimetric and clinical/treatment features selected via LASSO were inserted into a multivariable logistic model. Goodness of fit was evaluated through Hosmer-Lemeshow test and calibration plot. RESULTS: Data were collected for 132 patients. G >= 3 and mean G >= 1.5 OM were reported in 40 patients (30%). Analyses resulted in a 3-variables model for G >= 3 OM, including OC EUD with n = 0.05 (OR = 1.02), PG EUD with n = 1 (OR = 1.06), BMI >= 30 (OR = 3.8, for obese patients), and a single variable model for mean G >= 1.5 OM, i.e. OC EUD with n = 1 (mean dose) (OR = 1.07). Calibration was good in both cases. CONCLUSION: OC mean dose was found to impact most on OM duration (mean G >= 1.5), while G >= 3 OM was associated to a synergic effect between PG mean dose and high dose received by small OC volumes, with BMI acting as a dose-modifying factor. PMID- 30409312 TI - Routine surveillance scanning in HNSCC: Lung screening CT scans have value but head and neck scans do not. AB - OBJECTIVES: To examine the utility of computed tomography (CT) imaging during routine surveillance for the detection of recurrent head and neck squamous cell carcinoma (HNSCC). MATERIALS/METHODS: Clinical characteristics of HNSCC patients treated between 2008 and 2017 with radiation therapy or concurrent chemoradiation were abstracted from medical records. In patients who achieved a complete response to treatment by positron emission tomography scan, surveillance CT scans were conducted to the maxillofacial area, neck, and chest every 3 months in year 1, every 6 months in year 2, and every 12 months in years 3 and beyond. RESULTS: Within the entire cohort (n = 534), complete response was achieved in 446 patients (83.5%); of these, 84 (15.7%) patients had a recurrence. Among the 84 patients with disease recurrence, 25 (30%) patients remained alive, of which 15 (18%) underwent successful salvage treatment and became free of disease. Lung screening CT scans detected failure in 8 of these successfully salvaged patients. Among the 8 patients successfully salvaged for locoregional recurrence, 3 failures were asymptomatic at onset and detected by laryngoscope or dental exam. The remaining 5 failures were symptomatic and detected upon work up prompted by symptoms. Maxillofacial and neck surveillance CT imaging failed to detect any successfully salvaged patients. CONCLUSIONS: Routine surveillance for HNSCC patients with lung CT imaging had value but routine head and neck CT scans failed to identify any successfully salvaged patients. Given this finding, routine CT imaging surveillance in HNSCC patients should be restricted to annual lung screening with low-dose chest CT. PMID- 30409314 TI - Target delineation for postoperative treatment of head and neck cancer. AB - Patients who undergo primary surgical resection for a Head and Neck Squamous Cell Carcinoma (HNSCC) are stratified post-operatively, based on the presence or absence of pathological risk factors for recurrence, to estimate their risk of treatment failure. Post-operative radiotherapy, with or without concurrent chemotherapy, is offered if there is a significant risk of recurrence, in order to eradicate potential microscopic residual cancer cells and ultimately improve loco-regional control and survival. This review will offer practical guidelines for delineation of the post-operative primary and nodal Clinical Target Volumes (CTVs) based on a geometric expansion of the pre-operative primary and nodal Gross Tumour Volumes (GTVs), as already implemented in the definitive radiotherapy setting. Nodal levels requiring elective treatment are defined for inclusion in the prophylactic CTV. Optimising patient selection for post operative treatment is discussed as well as areas of controversy, relating to the dose prescription and extent of nodal volumes to be included in the CTV. Finally, clinical trials exploring the prospect of adjuvant treatment de-intensification after transoral surgery for HPV-positive oropharyngeal cancer are outlined. The aim is to improve consensus amongst clinicians and contribute towards improving outcomes for surgically treated patients with HNSCC. PMID- 30409313 TI - Utility of CD8 score by automated quantitative image analysis in head and neck squamous cell carcinoma. AB - INTRODUCTION: In head and neck squamous cell carcinoma (HNSCC) high numbers of tumor infiltrating CD8 T cells in the tumor microenvironment are associated with better outcome. However, no investigators have employed automated image analysis on whole slide images to permit CD8 scores for use in clinical practice. The aim of this study was to develop and validate an image analysis algorithm to automatically quantify CD8 T cells in patients with oropharyngeal HNSCC. MATERIALS AND METHODS: Using brightfield image analysis results were cross validated with fluorescence based quantification (AQUATM). A nuclear image algorithm designed to run on whole slide images was optimized to manual count. The algorithm was locked down and used on a cohort of whole tissue sections from HNSCC patients. Multivariate clinicopathologic parameters and outcomes were statistically correlated with image analysis results. RESULTS: Linear correlation between manual counts and the customized CD8 algorithm was 0.943. A total of 74 oropharyngeal HNSCC cases were analyzed for CD8 immune cell infiltrate using this image analysis algorithm. A CD8 immune cell density above 136 cells/mm2 was associated with median survival of 18 years compared to 5 years. When multivariate modeling was performed, HPV infection was the only predictor of survival; however, when HPV was excluded only CD8 cell density predicts survival. CONCLUSIONS: We report the successful technical development and clinical validation of an image algorithm to automate CD8 immune cell density for oropharyngeal HNSCC. Employing brightfield image analysis on entire tumor sections instead of tumor subcompartments permits this strategy to be widely implemented. PMID- 30409315 TI - Patterns of cervical node positivity, regional failure rates, and fistula rates for HPV+ oropharyngeal squamous cell carcinoma treated with transoral robotic surgery (TORS). AB - OBJECTIVES: (1) Report the patterns of cervical node positivity for HPV + oropharyngeal squamous cell carcinoma (OPSCC) treated with transoral robotic surgery (TORS) and a unilateral level II-IV node dissection. (2) Investigate the regional failure rate following this operation. (3) Report the rate of pharyngocutaneous fistula (PCF) formation intraoperatively and postoperatively following TORS/neck dissection. METHODS: Retrospective case series of 88 patients with HPV+ OPSCC treated with TORS and simultaneous neck dissection levels II-IV at the University of Washington from 2010 to 2016. Primary endpoints were PCF, regional recurrence, disease-free survival (DFS), and overall survival (OS). RESULTS: The overall frequency of cervical node positivity was 93%, with 84% in level IIa, 7% in IIb, 23% in III, and 13% in IV. Two patients developed PCF intraoperatively, repaired with a local digastric flap, and no postoperative PCF occurred. Sixteen patients (18%) received surgery alone, 49 patients (56%) received adjuvant radiation, and 23 patients (26%) underwent adjuvant chemoradiation. DFS at 2 years was 95% and OS at 2 years was 100%. No concerning level Ib nodes were identified preoperatively or during surgery, and no regional failures occurred in this location. CONCLUSION: Our data suggests, in TORS for HPV+ OPSCC, neck dissection of levels II-IV accurately stages the neck pathologically and prevents regional recurrences, with adjuvant therapy when indicated, and survival outcomes are excellent. Single-staged operations did not result in any postoperative PCF. Avoiding dissection of level Ib with TORS oropharyngectomy limits morbidity to the marginal mandibular nerve and salivary function, and resulted in no postoperative fistulas with minimal reconstruction interventions. PMID- 30409316 TI - Organ preservation for advanced larynx cancer: A review of chemotherapy and radiation combination strategies. AB - The larynx is an organ of the upper aerodigestive tract that is involved in many critical functions such as breathing, speaking, and swallowing. As a result, both larynx cancer and its treatment may significantly affect quality of life. The management of laryngeal cancer has focused on improving survival while preserving the function of the organ. This manuscript focuses on the use of chemotherapy and radiation therapy as a non-surgical approach and potential organ preservation strategy for patients with advanced larynx cancer. We review the key clinical data on the following treatment courses: (1) induction chemotherapy followed by definitive radiation therapy, (2) concurrent chemotherapy and radiation, and (3) induction chemotherapy followed by concurrent chemo-radiation. We also review the clinical data on organ preservation for patients with hypopharynx cancers. Results from phase III studies suggest that patients with advanced T4 cancers have better outcomes with a primary surgical approach, while for patients with T2N+ and T3 tumors, definitive concurrent chemotherapy and radiation or induction chemotherapy followed by definitive radiation therapy are acceptable options. Choosing the optimal treatment strategy depends on patients' desires, tumor extent, and adequate follow-up to detect early recurrences in cases of larynx preservation treatments. To proceed with an organ preservation strategy, the patient should have a good pre-treatment larynx function, and there must be a high level of skill and cooperation among various disciplines. PMID- 30409317 TI - Concurrent HPV-related oropharyngeal carcinoma in four couples. AB - OBJECTIVES: Typically, HPV-related cancers are sexually transmitted, however, the natural history of HPV-related oropharyngeal squamous cell carcinoma (OPSCC) is unclear. HPV16 transmission has been reported previously between five couples with OPSCC. We report the clinico-pathological features of a further four couples with HPV-related OPSCC and compare them with the published cases. PATIENTS AND METHODS: We identified four couples in long-term heterosexual relationships that all had HPV-related OPSCC. The couples were treated at three UK hospitals and presented between 2009 and 2015. HPV tests included p16 immunohistochemistry, high-risk HPV DNA in-situ hybridisation and Roche Cobas HPV test. DNA sequencing was used to determine the HPV variant. RESULTS: The four couples represented < 2% of patients with HPV-related OPSCC at the three contributing hospitals (8 of 457 consecutive patients). The couples' tumours all contained HPV16. The mean age was 63 years old (range 52-72 years). The interval between the index cancer and the partner's cancer was 16, 24, 26 and 64 months respectively. The majority of patients had Stage I disease (UICC TNM8). Six of eight patients are disease free, one patient is alive with disease and there was one death from loco-regional recurrence. CONCLUSION: This report highlights the occurrence of HPV-related OPSCC in heterosexual couples and raises the possibility of transmission of HPV16. Despite increasing prevalence of HPV-related OPSCC and increased awareness of the disease, there is a paucity of couples with the disease, suggesting either under-reporting or that the development of OPSCC following HPV transmission between couples is a rare event. PMID- 30409318 TI - State of the art: Rehabilitation of speech and swallowing after total laryngectomy. AB - Despite the development and expansion of non-surgical organ preservation therapy, total laryngectomy continues to be the optimal therapy for far-advanced local disease and the only curative option for radiotherapy failures not amenable to partial laryngeal procedures. Laryngectomy, however, remains a life-altering operation with profound effects on swallowing and speech. In the nearly 150 years since the first total laryngectomy was performed, few ablative aspects have changed, but reconstructive techniques have undergone radical evolution. This review will trace the origins of laryngeal rehabilitation for voice and swallowing, the current state of the art with attention to pre-treatment considerations and post-operative management, current surgical management techniques, and the future of functional laryngeal reconstruction. PMID- 30409319 TI - Modification of the eight-edition tumor-node-metastasis staging system with N1b for papillary thyroid carcinoma: A multi-institutional cohort study. AB - OBJECTIVES: Based on the tumor-node-metastasis staging system, eighth edition (TNM-8), N1b is no longer used as a variable to determine final stage in papillary thyroid carcinoma (PTC). We aimed to evaluate the predictability of a simple modification of the TNM staging with N1b classification in a large multicenter thyroid cancer cohort. MATERIALS AND METHODS: This study included 7717 patients with PTC who underwent thyroid surgery between 1996 and 2005 from six tertiary hospitals. We classified patients with stage II into stage IIA and IIB with modified-TNM: older patients with N1b disease were classified as stage IIB, while remaining patients were classified as stage IIA. RESULTS: The mean age was 46.2 years, and 24% were aged >=55 years. In older patients, the 10-year disease-specific survival (DSS) rate of N1b disease (86.3%) was approximately 10% lower than that of N1a disease, and patients with N1b had significantly poorer DSS than those with N1a (HR = 3.3, p < 0.001). When the modified-TNM was applied, DSS curves between stage groups significantly differed (p < 0.001), and the relative risk of DSS in stage IIB patients was 2.3 times higher than in stage IIA patients (p < 0.001). The proportion of variation explained value of the modified TNM was 4.9% and that of the TNM-8 was 4.7%. CONCLUSION: This multicenter study reveals that the presence of lateral lymph node metastasis affects disease mortality in PTC, especially in older patients. The sub-classification of stage II in older patients improves DSS predictability. This simple modification of TNM 8 provides better prognostic information for patients with PTC. PMID- 30409320 TI - A gene expression profile associated with perineural invasion identifies a subset of HNSCC at risk of post-surgical recurrence. AB - OBJECTIVES: Perineural invasion (PNI) is a common histopathological finding in head and neck squamous cell carcinoma (HNSCC). We aimed to explore the molecular mechanisms involved in PNI and the role of PNI as an aggressive pathological feature. MATERIALS AND METHODS: We used data from The Cancer Genome Atlas (TCGA) to relate the histological presentation of 528 HNSCC tumours to clinical, whole genome expression and proteomic data. RESULTS: We identified a specific gene expression profile highly enriched in genes related to muscle differentiation/function and associated with PNI in HNSCC. We explored the clinical significance of this profile in three groups of HNSCC tumours stratified according to their low, intermediate or high risk of post-surgical recurrence. In the "low-risk" group, defined as tumours indicated for surgery without adjuvant radiotherapy (n = 51), the PNI gene expression profile identified a subset of HNSCC with a higher rate of tumour recurrence, decreased Disease Free Survival (DFS) and Overall Survival (OS) (p < 0.0001 and p = 0.0064, respectively). Comparable results were observed in "intermediate risk" tumours (n = 112), but not in "high risk" tumours (n = 147), whose prognosis was driven by the presence of lymph node extracapsular spread. Finally, we found that tumours with histological PNI had increased activation levels of the Akt/PKB and mTOR (mammalian Target Of Rapamycin) kinases. CONCLUSION: PNI is characterised by a specific gene expression profile and distinct biological characteristics. Analysing the PNI gene expression profile holds potential for therapeutic stratification of HNSCC and identification of a subset of tumours with a higher risk of recurrence. PMID- 30409321 TI - Intensity-modulated radiotherapy for paranasal sinuses and base of skull tumors. AB - Paranasal sinus and skull base tumors are rare aggressive head and neck cancers, and typically present in the locally advanced stages. As a result, achieving wide surgical resection with clear margins is a challenge for these tumors, and radiotherapy is thus usually indicated as an adjuvant modality following surgery to optimize local control. Given the integral role of radiotherapy in the management of this subgroup of head and neck tumors, the advent of intensity modulated radiotherapy (IMRT) has led to substantial improvement of clinical outcomes for these patients. This is primarily driven by the improvement in radiation dosimetry with IMRT compared to conventional two dimensional (2D)- and 3D-techniques, in terms of ensuring dose intensity to the tumor target coupled with minimizing dose exposure to critical organs. Consequently, the evident clinical benefits of IMRT have been in reduction of normal tissue toxicities, ranging from critical neurological symptoms to less debilitating but bothersome symptoms of eye infections and radiation-induced skin changes. Another domain where IMRT has potential clinical utility is in the management of a subset of non resectable T4 paranasal sinus and skull base tumors. For these inoperable lesions, the steep dose-gradient between tumor and normal tissue is even more advantageous, given the crucial need to maintain dose intensity to the tumor. Innovative strategies in this space also include the use of induction chemotherapy for patient selection. In this review, we summarized the data for the aforementioned topics, including specific discussions on the different histologic subtypes of paranasal sinus and skull base tumors. PMID- 30409322 TI - HPV status predicts for improved survival following chemotherapy in metastatic squamous cell carcinoma of the oropharynx. AB - OBJECTIVE: We sought to further define prognostic and predictive value of human papillomavirus (HPV) status in metastatic squamous cell carcinoma of the oropharynx (OPC). MATERIALS AND METHODS: A Surveillance, Epidemiology, and End Results custom database identified 5940 adult patients, >18-years-old, with primary SCCHN and known HPV status, diagnosed from 2013 to 2014. Wilcoxon rank sum and Mantel-Haenszel chi2 tests compared distributions of continuous and categorical covariates. Fine-Gray competing risks regressions estimated hazard ratios by HPV status, and predictive analyses were performed including the interaction term HPV status * Receipt of Chemotherapy. RESULTS: 182 of 5940 patients (4.0%) had metastatic OPC at diagnosis (106/3925 [2.7%] HPV+ and 76/1894 [4.0%] HPV-). HPV+ disease was prognostic for improved 20-month cancer-specific mortality (CSM) (47.1% vs 72.5%, HR 0.43, 95% CI 0.26-0.74, p = 0.002) on univariable analysis. HPV status was predictive of response to chemotherapy adjusted HRs for receipt of chemotherapy were 0.11 (95% CI 0.03-0.37) and 0.34 (95% CI 0.18-0.64) for HPV+ versus HPV- disease, respectively (PHPV status*Chemotherapy = 0.036). CONCLUSION: HPV status has known prognostic value in locally advanced OPC, but data on metastatic OPC are sparse. In this work, we demonstrate that HPV status is strongly prognostic for CSM in metastatic OPC and show for the first time that HPV status predicts for response to chemotherapy. PMID- 30409323 TI - Utilization of Transoral Robotic Surgery (TORS) in patients with Oropharyngeal Squamous Cell Carcinoma and its impact on survival and use of chemotherapy. AB - OBJECTIVE: To determine whether patients with Oropharyngeal Squamous Cell Carcinoma (OPSCC) treated with Transoral Robotic Surgery (TORS) have similar survival to patients treated with definitive RT. MATERIALS AND METHODS: Using the National Cancer Database (NCDB) registry, we identified patients with newly diagnosed clinical T1-T2, N0-N2b OPSCC between 2010 and 2014. A multivariable logistic regression was utilized to determine the association between chemotherapy use and primary treatment modality (TORS vs definitive RT). Kaplan Meier survival analysis was used to estimate overall survival. Propensity score matching was utilized to address selection bias. RESULTS: We identified 17,150 patients, of which 14,470 (84.4%) received primary RT and 2,680 (15.6%) underwent TORS. The median follow-up for the cohort was 31.4 months. Propensity score matching demonstrated similar 5-year OS for patients treated with either definitive RT or TORS (81% vs 84%, log rank p = 0.10). There was no difference in survival outcomes by treatment selection (TORS or definitive RT) in either HPV positive or HPV negative subtypes. Patients treated with TORS were less likely to receive chemotherapy compared to patients treated with definitive RT and this was also demonstrated in a propensity matched analysis (OR: 0.09, 95%CI 0.078-0.12, p < 0.001). Only 68.4% of TORS treated patients underwent adjuvant RT, compared to 100% of patients in the primary RT cohort (p < 0.001). CONCLUSIONS AND RELEVANCE: For patients with OPSCC, TORS results in similar OS outcomes and is associated with decreased chemotherapy and RT use compared to definitive RT. Our results demonstrate the feasibility of TORS in a select subgroup of OPSCC patients. PMID- 30409324 TI - Revisiting the dose constraints for head and neck OARs in the current era of IMRT. AB - Head and neck cancer poses a particular challenge in radiation therapy, whilst being an effective treatment modality it requires very high doses of radiation to provide effective therapy. This is further complicated by the fact that the head and neck region contains a large number of radiosensitive tissues, often resulting in patients experiencing debilitating normal tissue complications. In the era of intensity-modulated radiation therapy (IMRT) treatments can be delivered using non-uniform dose distributions selectively aimed at reducing the dose to critical organs-at-risk while still adequately covering the tumor target. Dose-volume constraints for the different risk organs play a vital role in one's ability to devise the best IMRT treatment plan for a head and neck cancer patient. To this end, it is pivotal to have access to the latest and most relevant dose constraints available and as such the goal of this review is to provide a summary of suggested dose-volume constraints for head and neck cancer RT that have been published after the QUANTEC reports were made available in early 2010. PMID- 30409326 TI - IMRT - Biomarkers for dose escalation, dose de-escalation and personalized medicine in radiotherapy for head and neck cancer. AB - Radiotherapy (RT) is an integral component in the management of head and neck cancer. Despite progress in several respects, a noteworthy proportion of the treated patients do not achieve complete response after RT. Regardless of novel dose delivery technologies, RT for head and neck cancer is still associated with acute as well as late toxicity. These challenges could potentially be addressed by means of personalized treatment. In this paper, we discuss the possibilities for dose escalation, dose de-escalation and allocation to systemic concomitant treatment based on prognostic and predictive markers for tumor control as well as predictive markers for normal tissue radiosensitivity. PMID- 30409325 TI - The prognostic role of PD-L1 expression for survival in head and neck squamous cell carcinoma: A systematic review and meta-analysis. AB - BACKGROUND: Programmed death-ligand 1 (PD-L1) is an immune checkpoint that is primarily located on the surface of tumor cells. PD-L1 expression detected by immunohistochemistry (IHC) assays has been widely studied to predict survival outcomes in head and neck squamous cell carcinoma (HNSCC) recently. We aimed to review comprehensively the prognostic role of PD-L1 expression for survival in HNSCC. METHODS: We systematically searched PubMed, Embase, Web of Science, Cochrane Library and Scopus to identify studies investigating the prognostic role of PD-L1 expression in HNSCC. All studies published before March 31, 2018 were screened. Included studies were assessed using the Quality in Prognosis Studies (QUIPS) tool. Data were extracted and overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), disease-specific survival (DSS) were combined and presented as hazard ratios (HR) with 95% confidence interval (CI) using the generic inverse-variance method. RESULTS: Twenty-three studies with 3105 patients were analysed. The overall positive rate of PD-L1 in HNSCC was 0.42 (95% CI: 0.36-0.48). There was no significant difference between PD-L1 positive and -negative HNSCC patients in OS (HR: 0.98; 95% CI: 0.71-1.37; p = 0.93), DFS (HR: 1.07; 95% CI: 0.68-1.70; p = 0.76), and DSS (HR: 0.90; 95% CI: 0.63-1.29; p = 0.56). An improved PFS was observed in patients with positive PD L1 expression (HR: 0.71; 95% CI: 0.55-0.93; p = 0.01). In patients with low CD8+ tumor-infiltrating T cells, a poorer OS was detected in patients with positive PD L1 expression (HR: 1.90; 95% CI: 1.07-3.36; p = 0.03). Patients with HPV-positive HNSCC were associated with increased PD-L1 expression (OR: 1.99; 95% CI: 1.50 2.64; p < 0.001). However, PD-L1 expression showed no significant benefit on OS in HPV-positive HNSCC (HR: 1.04; 95% CI: 0.65-1.65; p = 0.88). CONCLUSIONS: PD-L1 expression detected by IHC was not recommended to predict survival in HNSCC patients. However, the positive PD-L1 expression might predict better PFS in patients with advanced HNSCC. The combined effects of PD-L1 expression and CD8+ tumor-infiltrating T cells should be further elucidated. PMID- 30409327 TI - Noninvasive Assessment of Coronary Anatomy and its Hemodynamic Consequences During a Single Test: Are We There Yet? PMID- 30409328 TI - FFRCT Versus SPECT to Diagnose Coronary Artery Disease: Toward a Tailored Approach. PMID- 30409329 TI - Merits of FDG PET/CT and Functional Molecular Imaging Over Anatomic Imaging With Echocardiography and CT Angiography for the Diagnosis of Cardiac Device Infections. AB - The diagnosis of cardiac device infections, particularly device-related endocarditis, is challenging. Fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is based on in vivo FDG targeting of the pre-existing inflammatory cells at an infectious site. Hence, it is able to identify cardiac device infection early, before the development of morphological damages from the infectious process. Transesophageal echocardiography (TEE) and electrocardiographically gated computed tomographic angiography (CTA) are currently the first-line imaging studies for device-related endocarditis, but their application to evaluate the extracardiac components or sources of primary infection and/or emboli is limited. Functional FDG PET/CT may have unique advantages over the anatomically based TEE and CT or CTA in the following settings: 1) diagnosing infection earlier than TEE and CTA, before morphological damage ensues; 2) identifying prosthetic endocarditis when findings on TEE and CTA are inconclusive; 3) evaluating infection in the extracardiac components of devices; 4) detecting unexpected source of the primary infection; and 5) discovering embolic consequences of endocarditis in the body. All of these findings may ultimately affect patient management. Although the nonspecific nature of FDG is a concern in differentiating infection from inflammation, accurate diagnosis of infection can be reasonably achieved on the basis of FDG distribution pattern and clinical history or by adding radiolabeled white blood cell scan to improve specificity. Recent publications support the judicious use of FDG PET/CT, particularly in patients with inconclusive or negative results on initial echocardiography and CT. PMID- 30409330 TI - Lung Ultrasound for the Cardiologist. AB - For a cardiologist, lung ultrasound is an add-on to transthoracic echocardiography, just as lung auscultation is part of a cardiac physical examination. A cardiac 3.5- to 5.0-MHz transducer is generally suitable because the small footprint makes it ideal for scanning intercostal spaces. The image quality is often adequate, and the lung acoustic window is always patent. The cumulative increase in imaging time is <1 min for the 2 main applications targeted on pleural water (pleural effusion) and lung water (pulmonary congestion as multiple B-lines). In these settings, lung ultrasound outperforms the diagnostic accuracy of the chest radiograph, with a low-cost, portable, real time, radiation-free method. A "wet lung" detected by lung ultrasound predicts impending acute heart failure decompensation and may trigger lung decongestion therapy. The doctors of tomorrow may still listen with a stethoscope to their patient's lung, but they will certainly be seeing it with ultrasound. PMID- 30409331 TI - Building Bridges in Cardiology and Radiology: Why Collaboration Is the Future of Cardiovascular Imaging. PMID- 30409332 TI - RESPONSE: Collaboration and Collegiality: The Dual Pillars of Cardiovascular Imaging Now and in the Future. PMID- 30409333 TI - Cardiac Computed Tomography 2.0: Adding Physiology to Anatomy. PMID- 30409334 TI - Identifying heart failure using EMR-based algorithms. AB - BACKGROUND: Heart failure (HF) is a major clinical and public health problem, the management of which will benefit from large-scale pragmatic research that leverages electronic medical records (EMR). Requisite to using EMRs for HF research is the development of reliable algorithms to identify HF patients. We aimed to develop and validate computable phenotype algorithms to identify patients with HF using standardized data elements defined by the Patient Centered Outcomes Research Network (PCORnet) Common Data Model (CDM). METHODS: We built HF computable phenotypes utilizing the data domains of HF diagnosis codes, prescribed HF-related medications and N-terminal B-type natriuretic peptide (NT proBNP). Algorithms were validated in a cohort (n = 76,254) drawn from Olmsted County, MN between 2010-2012 a sample of whose records were manually reviewed to confirm HF according to Framingham criteria. RESULTS: The different algorithms we tested provided different tradeoffs between sensitivity and positive predictive value (PPV). The highest sensitivity (78.7%) algorithm utilized one HF diagnosis code and had the lowest PPV (68.5%). The addition of more algorithm components, such as additional HF diagnosis codes, HF medications or elevated NT-proBNP, improved the PPV while reducing sensitivity. When added to a diagnostic code, the addition of NT-proBNP (>450 pg/mL) had a similar impact compared to additional HF medication criteria, increasing PPV by ~3-4% and decreasing sensitivity by ~7 10%. CONCLUSIONS: Algorithms derived from PCORnet CDM elements can be used to identify patients with HF without manual adjudication with reasonable sensitivity and PPV. Algorithm choice should be driven by the goal of the research. PMID- 30409336 TI - Exchanging personal health data with electronic health records: A standardized information model for patient generated health data and observations of daily living. AB - OBJECTIVE: The development of a middleware information model to facilitate better interoperability between Personal and Electronic Health Record systems in order to allow exchange of Patient Generated Health Data and Observations of Daily Leaving between patients and providers in order to encourage patient self management. MATERIALS AND METHODS: An information model based on HL7 standards for interoperability has been extended to support PGHD and ODL data types. The new information models uses HL7 CDA to represent data, is instantiated as a Protege ontology and uses a set of mapping rules to transfer data between Personal and Electronic Health Record systems. RESULTS: The information model was evaluated by executing a set of use case scenarios containing data exported from three consumer health apps, transformed to CDA according to developed mapping rules and validated against a CDA schema. This allowed various challenges to emerge as well as revealed gaps in current standards in use and the information model has been refined accordingly. DISCUSSION AND CONCLUSION: Our proposed middleware solution offers a number of advantages. When modifications are made to either a Personal or Health Electronic Health Record system or any integrated consumer app, they can be incorporated by altering only the instantiation of the information model. Our proposition uses current standards in use such as CDA. The solution is applicable to any EHR system with HL7 CDA support. PMID- 30409335 TI - Authenticity and credibility aware detection of adverse drug events from social media. AB - OBJECTIVES: Adverse drug events (ADEs) are among the top causes of hospitalization and death. Social media is a promising open data source for the timely detection of potential ADEs. In this paper, we study the problem of detecting signals of ADEs from social media. METHODS: Detecting ADEs whose drug and AE may be reported in different posts of a user leads to major concerns regarding the content authenticity and user credibility, which have not been addressed in previous studies. Content authenticity concerns whether a post mentions drugs or adverse events that are actually consumed or experienced by the writer. User credibility indicates the degree to which chronological evidence from a user's sequence of posts should be trusted in the ADE detection. We propose AC-SPASM, a Bayesian model for the authenticity and credibility aware detection of ADEs from social media. The model exploits the interaction between content authenticity, user credibility and ADE signal quality. In particular, we argue that the credibility of a user correlates with the user's consistency in reporting authentic content. RESULTS: We conduct experiments on a real-world Twitter dataset containing 1.2 million posts from 13,178 users. Our benchmark set contains 22 drugs and 8089 AEs. AC-SPASM recognizes authentic posts with F1 - the harmonic mean of precision and recall of 80%, and estimates user credibility with precision@10 = 90% and NDCG@10 - a measure for top-10 ranking quality of 96%. Upon validation against known ADEs, AC-SPASM achieves F1 = 91%, outperforming state-of-the-art baseline models by 32% (p < 0.05). Also, AC-SPASM obtains precision@456 = 73% and NDCG@456 = 94% in detecting and prioritizing unknown potential ADE signals for further investigation. Furthermore, the results show that AC-SPASM is scalable to large datasets. CONCLUSIONS: Our study demonstrates that taking into account the content authenticity and user credibility improves the detection of ADEs from social media. Our work generates hypotheses to reduce experts' guesswork in identifying unknown potential ADEs. PMID- 30409337 TI - Communication matters: Exploring older adults' current use of patient portals. AB - OBJECTIVES: Patient portals have the potential to increase patient engagement. Older patients are of particular interest as they are likely to suffer from multiple chronic conditions. Yet, questions remain about how patient portals are perceived and deemed useful by older adults. This study explored attitudes toward, perceived utility of, and requirements of a patient portal from the perspective of older adults. METHODS: We used a mixed-method approach integrating online surveys, a review of existing portals, and participatory design workshops with 17 people who were 65 years old and over. RESULTS: The findings demonstrate that the participants used a patient portal primarily as one of the communication channels to interact with their providers, rather than as a tool for accessing and managing personal health information. Consequently, the perception of whether or not a provider would use the patient portal was a primary factor that older adults considered in determining the adoption and use of a portal. CONCLUSIONS: It is important to understand that older adults would perceive a patient portal as one part of a larger communication system to interact with a provider. This finding will help researchers and practitioners to advance the design and use of a patient portal to effectively incorporate it into older adults' health care and better serve the unique needs of the ageing population. PMID- 30409338 TI - SCREEN-DR: Collaborative platform for diabetic retinopathy. AB - BACKGROUND AND OBJECTIVE: Diabetic retinopathy (DR) is the most prevalent microvascular complication of diabetes mellitus and can lead to irreversible visual loss. Screening programs, based on retinal imaging techniques, are fundamental to detect the disease since the initial stages are asymptomatic. Most of these examinations reflect negative cases and many have poor image quality, representing an important inefficiency factor. The SCREEN-DR project aims to tackle this limitation, by researching and developing computer-aided methods for diabetic retinopathy detection. This article presents a multidisciplinary collaborative platform that was created to meet the needs of physicians and researchers, aiming at the creation of machine learning algorithms to facilitate the screening process. METHODS: Our proposal is a collaborative platform for textual and visual annotation of image datasets. The architecture and layout were optimized for annotating DR images by gathering feedback from several physicians during the design and conceptualization of the platform. It allows the aggregation and indexing of imagiology studies from diverse sources, and supports the creation and annotation of phenotype-specific datasets to feed artificial intelligence algorithms. The platform makes use of an anonymization pipeline and role-based access control for securing personal data. RESULTS: The SCREEN-DR platform has been deployed in the production environment of the SCREEN-DR project at http://demo.dicoogle.com/screen-dr, and the source code of the project is publicly available. We provide a description of the platform's interface and use cases it supports. At the time of publication, four physicians have created a total of 1826 annotations for 701 distinct images, and the annotated data has been used for training classification models. PMID- 30409339 TI - Challenges optimizing the after visit summary. AB - BACKGROUND: The after visit summary (AVS) is a paper or electronic document given to patients after a medical appointment, which is intended to summarize patients' health and guide future care, including self-management tasks. OBJECTIVE: To describe experiences of health systems implementing a redesigned outpatient AVS in commercially available electronic health record (EHR) systems to inform future optimization. MATERIALS AND METHODS: We conducted semi-structured interviews with information technology and clinical leaders at 12 hospital and community-based healthcare institutions across the continental United States focusing on the process of AVS redesign and implementation. We also report our experience implementing a redesigned AVS in the Epic EHR at the Mount Sinai Hospital in New York City, NY. RESULTS: Health systems experienced many challenges implementing the redesigned AVS. While many IT leaders noted that the redesigned AVS is easier to understand and the document is better organized, they claim the effort is time consuming, Epic system upgrades render AVS modifications non-functional, and primary care and specialty practices have different needs in regards to content and formatting. Our team was able to modify the document by changing the order of print groups, modifying the font size, bolding section headers, and inserting page breaks. Similar to other health systems, our team found that it is difficult to achieve some desired features due to limitations in the EHR platform. CONCLUSION: Health IT leaders view the AVS as a valuable source of information for patients. However, limitations to AVS modifications in EHR systems present challenges to optimizing the tool. EHR vendors should incorporate learning from healthcare systems innovation efforts and consider building more flexibility into their product development. PMID- 30409340 TI - OpenEHR modeling for genomics in clinical practice. AB - PURPOSE: The increasing usage of high throughput sequencing in personalized medicine brings new challenges to the realm of healthcare informatics. Patient records need to accommodate data of unprecedented size and complexity as well as keep track of their production process. In this work we present a solution for integrating genomic data into electronic health records via openEHR archetypes. METHODS: We use the popular Variant Call Format as the base format to represent genetic test results within openEHR. We evaluate existing openEHR archetypes to determine what can be extended or specialized and what needs to be developed ex novo. RESULTS: Eleven new archetypes have been developed, while an existing one has been specialized to represent genomic data. We show their applicability to rare genetic diseases and compare our approach to HL7 FHIR. CONCLUSION: The proposed model allows to represent genetic test results in health records in a structured format. It supports different levels of abstraction, allowing both automated processing and clinical decision support. It is extensible via external references, allowing to keep track of data provenance and adapt to future domain changes. PMID- 30409341 TI - Authenticity and credibility aware detection of adverse drug events from social media. AB - OBJECTIVES: Adverse drug events (ADEs) are among the top causes of hospitalization and death. Social media is a promising open data source for the timely detection of potential ADEs. In this paper, we study the problem of detecting signals of ADEs from social media. METHODS: Detecting ADEs whose drug and AE may be reported in different posts of a user leads to major concerns regarding the content authenticity and user credibility, which have not been addressed in previous studies. Content authenticity concerns whether a post mentions drugs or adverse events that are actually consumed or experienced by the writer. User credibility indicates the degree to which chronological evidence from a user's sequence of posts should be trusted in the ADE detection. We propose AC-SPASM, a Bayesian model for the authenticity and credibility aware detection of ADEs from social media. The model exploits the interaction between content authenticity, user credibility and ADE signal quality. In particular, we argue that the credibility of a user correlates with the user's consistency in reporting authentic content. RESULTS: We conduct experiments on a real-world Twitter dataset containing 1.2 million posts from 13,178 users. Our benchmark set contains 22 drugs and 8089 AEs. AC-SPASM recognizes authentic posts with F1 - the harmonic mean of precision and recall of 80%, and estimates user credibility with precision@10 = 90% and NDCG@10 - a measure for top-10 ranking quality of 96%. Upon validation against known ADEs, AC-SPASM achieves F1 = 91%, outperforming state-of-the-art baseline models by 32% (p < 0.05). Also, AC-SPASM obtains precision@456 = 73% and NDCG@456 = 94% in detecting and prioritizing unknown potential ADE signals for further investigation. Furthermore, the results show that AC-SPASM is scalable to large datasets. CONCLUSIONS: Our study demonstrates that taking into account the content authenticity and user credibility improves the detection of ADEs from social media. Our work generates hypotheses to reduce experts' guesswork in identifying unknown potential ADEs. PMID- 30409343 TI - Internet-based self-monitoring interventions for overweight and obese adolescents: A systematic review and meta-analysis. AB - BACKGROUND: Internet-based self-monitoring intervention offers accessibleand convenient weight management. This review aimed to systematically review the evidence on the effectiveness of internet-based self-monitoring intervention for overweight and obese adolescents. METHOD: PubMed, CINAHL, Cochrane Library, EMBASE, ProQuest, PsycINFO and SCOPUS were systematically searched for randomised controlled trials (RCTs) from inception until December 13, 2017. The risk of bias and strength of evidence was assessed using the Cochrane Collaboration Risk of Bias Tool and the Grading of Recommendations, Assessment, Development and Evaluations criteria. Meta-analysis was performed on the RevMan software using a random effects model. The overall effect was assessed using effect size (Cohen'sd)and heterogeneity was evaluated using Cochrane Q and I2 values. PROSPERO database #CRD42016050089. RESULTS: A total of 6841 records were identified. Six RCTs in 10 articles were selected amongst 505 adolescents across three countries who were overweight and obese. The meta-analysis revealed a small effect on the reduction of body mass index (BMI) and BMI z-scores (d = 0.30, 95% CI: -0.48 to -0.12). Subgroup analyses suggest the use of daily multicomponent self-monitoring, specified goal setting, face-to-face counselling and parental involvement. The overall quality of evidence was low due to the risk of bias and imprecision. CONCLUSION: Internet-based self-monitoring intervention is a possible approach for overweight and obese adolescents to reduce their BMI. Further well-designed RCTs with follow-up data and large sample sizes are needed to ensure the robustness of the evidence. PMID- 30409342 TI - Feasibility of representing adherence to blood glucose monitoring through visualizations: A pilot survey study among healthcare workers. AB - BACKGROUND: Measuring adherence to processes is one of the established ways to quantify the quality of healthcare. Providing timely feedback to healthcare workers on the level of adherence can improve process measures. However, it is challenging to present data on adherence to repetitive time-sensitive tasks in a clear manner. OBJECTIVES: We used inpatient glucose monitoring as a test case to explore the feasibility of using visualizations to communicate adherence to repetitive scheduled tasks to healthcare workers. METHODS: We selected four candidate plots that represented distribution across time: histogram, probability density function plot (pdf plot), violin plot and cumulative density function plot (cdf plot). Doctors and nurses involved in inpatient diabetes care in a tertiary hospital were invited to complete a self-administered questionnaire that measured self-reported baseline knowledge, performance, and perception towards the visualizations. Performance was assessed by determining if a participant was able to correctly identify visualizations representing protocol adherence. We also assessed the perception of usability of these visualizations for monitoring protocol adherence. Binomial regression models were used to identify factors associated with overall performance and perception. Logistic regression models with generalized estimating equation were used to compare performance and perception between visualizations, and identify effect modifiers. RESULTS: A total of 57 doctors and nurses completed the questionnaire. Participants were most familiar with histogram (87.7%), followed by cdf plot (61.4%), pdf plot (40.4%), and violin plot (7%). However, the percentages of participants who identified non-adherence using these plots were generally lower, ranging from 29.8% to 40.4%. Participants' perception of usability ranged from 14% to 17.5% across these visualizations. More favorable perceptions were found among participants with baseline knowledge for two or more visualizations (adjusted odds ratio: 3.21; 95%CI: 1.29, 7.96; p-value: 0.012) and having identified two or more non-adherent visualizations (adjusted odds ratio: 4.23; 95%CI: 1.95, 9.16; p value: < 0.001). CONCLUSIONS: Adherence to repetitive time-sensitive tasks can be presented in the form of visualizations. However, nurses' and doctors' knowledge and understanding of these visualizations are generally poor. This may influence their perception of usability of these plots. Therefore, these visualizations need to be implemented in tandem with training on their interpretation, to enhance the usefulness of these plots in motivating quality improvement. PMID- 30409344 TI - Health information management practices in informal caregiving: An artifacts analysis and implications for IT design. AB - INTRODUCTION: Unpaid informal caregivers of adult care recipients, including persons with dementia, experience multiple unmet information needs and information management challenges. OBJECTIVES: To understand the current personal health information management (PHIM) practices in informal caregiving for adults with and without dementia. METHODS: Semi-structured interviews were performed with ten informal caregivers-half of whom were caring for persons with dementia and four formal caregivers at an adult day service. Interviews centered on a paper-based tool distributed by the day service, the CARE Kit, permitting an artifacts analysis of the tools used by participants for PHIM. Qualitative thematic analysis was applied to interview data. RESULTS: Caregivers' PHIM practices aimed to support daily care management and decision-making on behalf of care recipients, through: 1) information acquisition and integration across multiple sources and records; 2) information maintenance, updating, and use over time; and 3) information sharing and communication with healthcare professionals and other family caregivers. Participants reported advantages and challenges of their PHIM practices and tools, including fitting PHIM into their daily lives, managing PHIM-related cognitive workload, the functionality of PHIM tools, and the dynamic, longitudinal nature of PHIM. CONCLUSION: The study produced a number of implications for caregiver health information management information technology (CHIM IT), based on findings about the nature of caregivers' practices for managing information for adult care recipients. We present CHIM IT requirements related to privacy and security, customization and flexibility, ease of use, credibility and sensitivity, situation awareness, information integration, delegation and shared use, updating and maintenance, archiving and versioning, communication, agency and information access, and validation. PMID- 30409345 TI - Validation of the accuracy of postpartum haemorrhage data in the ObstetriX database: A retrospective cohort study. AB - BACKGROUND: Data related to postpartum haemorrhage (PPH) are important clinical parameters which can be applied to all places of birth, and their recording can be missed by busy clinicians providing critical care to women. We compared the accuracy of electronic ObstetriX records to the paper-based medical records of the women who sustained PPH. METHODS: In this retrospective cohort study over a period of one month, 363 electronic records were compared to the paper-based medical records. The volume of blood loss for each patient and interventions for PPH were compared across birth unit, operating theatre and postpartum ward. The kappa statistic for agreement between the two types of recording methods was calculated. RESULTS: There was substantial agreement between the ObstetriX records and medical records for the volume of blood loss at birth (kappa = 0.74), but poor agreement between records for the cumulative total volume of blood loss (kappa = 0.18). More women who experienced PPH and delivered in the operating theatre had errors in their ObstetriX records compared to women who had PPH with births in the birth unit (50% vs 16%; n = 73, P = 0.005). Interventions for PPH were found to be poorly recorded in ObstetriX, with 84% (n = 64/76) of women who experienced PPH having none of the interventions they received recorded. CONCLUSIONS: The ObstetriX database was not a generally reliable source of data relating to PPH. However, some data were recorded reliably, in particular, the volume of blood loss at birth. PMID- 30409346 TI - Towards automated clinical coding. AB - BACKGROUND: Patients' encounters with healthcare services must undergo clinical coding. These codes are typically derived from free-text notes. Manual clinical coding is expensive, time-consuming and prone to error. Automated clinical coding systems have great potential to save resources, and realtime availability of codes would improve oversight of patient care and accelerate research. Automated coding is made challenging by the idiosyncrasies of clinical text, the large number of disease codes and their unbalanced distribution. METHODS: We explore methods for representing clinical text and the labels in hierarchical clinical coding ontologies. Text is represented as term frequency-inverse document frequency counts and then as word embeddings, which we use as input to recurrent neural networks. Labels are represented atomically, and then by learning representations of each node in a coding ontology and composing a representation for each label from its respective node path. We consider different strategies for initialisation of the node representations. We evaluate our methods using the publicly-available Medical Information Mart for Intensive Care III dataset: we extract the history of presenting illness section from each discharge summary in the dataset, then predicting the International Classification of Diseases, ninth revision, Clinical Modification codes associated with these. RESULTS: Composing the label representations from the clinical-coding-ontology nodes increased weighted F1 for prediction of the 17,561 disease labels to 0.264-0.281 from 0.232 0.249 for atomic representations. Recurrent neural network text representation improved weighted F1 for prediction of the 19 disease-category labels to 0.682 0.701 from 0.662-0.682 using term frequency-inverse document frequency. However, term frequency-inverse document frequency outperformed recurrent neural networks for prediction of the 17,561 disease labels. CONCLUSIONS: This study demonstrates that hierarchically-structured medical knowledge can be incorporated into statistical models, and produces improved performance during automated clinical coding. This performance improvement results primarily from improved representation of rarer diseases. We also show that recurrent neural networks improve representation of medical text in some settings. Learning good representations of the very rare diseases in clinical coding ontologies from data alone remains challenging, and alternative means of representing these diseases will form a major focus of future work on automated clinical coding. PMID- 30409347 TI - Development of a techno-humanist model for e-health adoption of innovative technology. AB - BACKGROUND AND PURPOSE: After investing billions of dollars in an integrated Electronic Medical Records (physicians) and Personal Health Records (patients) system to allow both parties to manage and communicate through e-health innovative technologies, Canada is still making slow adoption progress. In an attempt to bridge the human and technological perspectives by developing and testing a holistic model, this study purports to predict patients' behavioral intentions to use e-health applications. METHODS: An interdisciplinary approach labelled as a techno-humanism model (THM) is testing twelve constructs identified from the technological, sociological, psychological, and organizational research literature and deemed to have a significant effect upon and positive relationship with patients' e-health applications adoption. Subjects were Canadians recruited in a mall-intercept mode from a region representing a demographically diverse population, including rural and urban residents. The SmartPLS measurement tool was used to evaluate the reliability and validity of study constructs. The twelve constructs were separately tested with quantitative data such as factor analysis, single, multiple, and hierarchical multiple regression. RESULTS: The hierarchical multiple regression analysis process led us to formulate four models, each hinged on a combination of interdisciplinary variables. Model 1 consisted of the technological predictors and explained 62.3% (p < .001) of variance in the behavioral intention to use e-health. Model 2 added the sociological predictors to the equation and explained 72.3% (p < .001) of variance. Model 3 added the psychological predictors to Model 2 and explained 72.8% (p < .001). Finally, Model 4 included all twelve predictors and explained 73% (p < .001) of variance in the behavioral intention to use e-health applications. CONCLUSIONS: One of the greatest barriers to applying e-health records in Canada resides in the lack of coordination among stakeholders. The present study implies that healthcare policy makers must consider the twelve variables with their findings and implications as a whole. The techno-humanist model (THM) we are proposing is a more holistic and continuous approach. It pushes back to a breakdown of the various technological, sociological, psychological, and managerial factors and stakeholders that are at the root cause of behavioral intentions to use e-health, as opposed to merely observing behavioral outcomes at the end of the "assembly line". Active participation and coordination of all stakeholders is a key feature. PMID- 30409348 TI - The use of social media in nutrition interventions for adolescents and young adults-A systematic review. AB - OBJECTIVE: Social media is a potentially engaging way to support adolescents and young adults in maintaining healthy diets and learning about nutrition. This review identifies interventions that use social media to promote nutrition, examines their content and features, and evaluates the evidence for the use of such platforms among these groups. MATERIAL AND METHODS: We conducted a systematic search of 5 databases (PubMed, CINAHL, EMBASE, PsycINFO, and ACM Digital Library) for studies that included: 1) adolescents and/or young adults (ages 10-19; ages 18-25); 2) a nutrition education or behavior change intervention component, or outcomes related to nutrition knowledge or dietary changes; and 3) a social media component that allowed users to communicate or share information with peers. RESULTS: 16 articles were identified that included a social media component in a nutrition-related intervention for adolescents or young adults. Interventions included features in 7 categories: social media; communication; tracking health; education; tailoring; social support; and gamification. 11 out of the 16 studies had at least one significant nutrition related clinical or behavioral outcome. CONCLUSION: Social media is a promising feature for nutrition interventions for adolescents and young adults. A limited number of studies were identified that included social media. A majority of the identified studies had positive outcomes. We found that most studies utilized only basic social media features, did not evaluate the efficacy of social media components, and did not differentiate between the efficacy of social media compared to other delivery mechanisms. PMID- 30409349 TI - Functional requirements of critical care information systems (CCIS) from the users' perspective. AB - INTRODUCTION: Critical care information systems (CCIS) are computer software systems specialized for supporting the data processing tasks of clinical staff in intensive care units (ICUs). Reports on the impact of CCIS vary strongly from large benefits to harmful impact. One factor causing these inconsistent results is a large functional heterogeneity of the currently available systems, as no standards exist. Therefore, the aim of this study was to derive recommendations for a minimum range of functions that CCIS should incorporate from the perspective of clinical users. MATERIALS AND METHODS: We performed a web-based survey targeting clinical ICU staff in Germany. Participants rated the usefulness of pre-defined CCIS functions (36 for physicians / 31 for nurses) between 0-5. To capture confounders that might influence the ratings, we recorded 18 individual and workplace characteristics. RESULTS: The 912 participants rated all but three of the investigated functions as useful with median scores of 4-5. A multivariable analysis showed that the ratings were influenced by whether CCIS were used on the participants' wards, by the rating of the function quality of the used CCIS, the years of work experience and whether the participant was a physician or a nurse. CONCLUSIONS: Clinical ICU staff considers all but three of the here investigated CCIS functions as useful. Even though we identified a variety of factors influencing the usefulness ratings, their influence is rather small and thus does not limit the validity of our findings. Accordingly, we commend the functions identified as useful to be incorporated in CCIS. PMID- 30409350 TI - Utilizing Twitter data for analysis of chemotherapy. AB - OBJECTIVE: Twitter has become one of the most popular social media platforms that offers real-world insights to healthy behaviors. The purpose of this study was to assess and compare perceptions about chemotherapy of patients and health-care providers through analysis of chemo-related tweets. MATERIALS AND METHODS: Cancer related Twitter accounts and their tweets were obtained through using Tweepy (Python library). Multiple text classification algorithms were tested to identify the models with best performance in classifying the accounts into individual and organization. Chemotherapy-specific tweets were extracted from historical tweetset, and the content of these tweets was analyzed using topic model, sentiment analysis and word co-occurrence network. RESULTS: Using the description in Twitter users' profiles, the accounts related with cancer were collected and coded as individual or organization. We employed Long Short Term Memory (LSTM) network with GloVe word embeddings to identify the user into individuals and organizations with accuracy of 85.2%. 13, 273 and 14,051 publicly available chemotherapy-related tweets were retrieved from individuals and organizations, respectively. The content of the chemo-related tweets was analyzed by text mining approaches. The tweets from individual accounts pertained to personal chemotherapy experience and emotions. In contrast with the personal users, professional accounts had a higher proportion of neutral tweets about side effects. The information about the assessment of response to chemotherapy was deficient from organizations on Twitter. DISCUSSION: Examining chemotherapy discussions on Twitter provide new lens into content and behavioral patterns associated with treatments for cancer patients. The methodology described herein allowed us to collect relatively large number of health-related tweets over a greater time period and exploit the potential power of social media, which provide comprehensive view on patients' perceptions of chemotherapy. CONCLUSION: This study sheds light on using Twitter data as a valuable healthcare data source for helping oncologists (organizations) in understanding patients' experiences while undergoing chemotherapy, in developing personalize therapy plans, and a supplement to the clinical electronic medical records (EMRs). PMID- 30409351 TI - Poor agreement in the calculation of venoarterial PCO2 to arteriovenous O2 content difference ratio using central and mixed venous blood samples in septic patients. AB - PURPOSE: Central venous minus arterial PCO2 to arterial minus central venous O2 content difference ratio (Pcv-aCO2/Ca-cvO2) has been proposed as a clinical surrogate for respiratory quotient. Our goal was to assess its interchangeability with mixed venous minus arterial PCO2 to arterial minus mixed venous O2 content difference ratio (Pmv-aCO2/Ca-mvO2). MATERIALS AND METHODS: This is a subanalysis of a previously published study. We studied 23 septic patients who had an indwelling Swan-Ganz catheter. The agreement between Pcv-aCO2/Ca-cvO2 and Pmv aCO2/Ca-mvO2 was evaluated by Bland and Altman analysis. We also performed linear regression analysis with Pmv-aCO2/Ca-mvO2 as the dependent variable. RESULTS: 95% limits of agreement between Pcv-aCO2/Ca-cvO2 and Pmv-aCO2/Ca-mvO2 were 1.48. Pmv aCO2/Ca-mvO2 was significantly correlated with hemoglobin and lactate (R2 = 0.48 and 0.31, respectively, P < 0.01 for both). CONCLUSIONS: In this study, Pcv aCO2/Ca-cvO2 and Pmv-aCO2/Ca-mvO2 were not interchangeable. In addition, Pmv aCO2/Ca-mvO2 is a composite variable, which depends on several determinants. Values of Pcv-aCO2/Ca-cvO2 should be cautiously interpreted in the assessment of critically ill patients. PMID- 30409353 TI - Burying Our Heads in the Sand: Cross-Contamination During Bronchoscopy. PMID- 30409352 TI - Obesity survival paradox in pneumonia supported with extracorporeal membrane oxygenation: Analysis of the national registry. AB - PURPOSE: To investigate whether the obesity survival paradox, where obesity is associated with improved survival, exists for pneumonia supported with extracorporeal membrane oxygenation (ECMO). MATERIALS AND METHODS: Between January 2014 and December 2015, 223 patients with acute respiratory failure who underwent ECMO in 11 hospitals in South Korea were enrolled retrospectively, and data relating to pneumonia cases were analyzed. Patients were divided into groups according to their pre-treatment body mass index (BMI): obese (BMI >= 25 kg/m2) and non-obese (BMI < 25 kg/m2). The BMI cut-off was adopted from the World Health Organization for Asian populations. RESULTS: In total, 84 patients had pneumonia: obese group, 26; non-obese group, 58 (mean BMI, 27.8 vs. 21.4, p < 0.001). Pre ECMO parameters and rescue therapy did not differ between the groups. The rate of successful weaning from ECMO was not different between the groups (76.9% vs. 72.4%, p = 0.753), but survival-to-discharge (73.1% vs. 36.2%, p = 0.002) and 6 month survival (69.2% vs. 36.2%, p = 0.005) rates were higher in the obese group. After adjusting for age and the pre-treatment PaO2/FiO2 ratio, low BMI was significantly associated with 6-month mortality (odds ratio 3.28, 95% confidence interval: 1.06-11.03, p = 0.044). CONCLUSIONS: An obesity survival paradox exists in pneumonia supported with ECMO. PMID- 30409354 TI - Is It Time to Rethink Blood Glucose Targets in Critically Ill Patients? PMID- 30409355 TI - The Diagnosis of Sarcoidosis: Attempting to Apply Rigor to Arbitrary and Circular Reasoning. PMID- 30409356 TI - POINT: Should All Patients With Atrial Fibrillation Who Are About to Undergo Pulmonary Vein Ablation Be Evaluated for OSA? Yes. PMID- 30409357 TI - COUNTERPOINT: Should All Patients With Atrial Fibrillation Who Are About to Undergo Pulmonary Vein Ablation Be Evaluated for OSA? No. PMID- 30409358 TI - Rebuttal From Drs Mehra and Wazni. PMID- 30409359 TI - Rebuttal From Drs Mansukhani, Somers, and Caples. PMID- 30409360 TI - Specimen Room (The National Museum of Health and Medicine). PMID- 30409361 TI - Like a lantern long unlit. PMID- 30409362 TI - Response. PMID- 30409363 TI - Untangling BNP and BMI: Does Obesity Limit the Predictive Capability of BNP in PAH? PMID- 30409364 TI - A Young Man With Abdominal Pain, Shock, and Respiratory Distress. PMID- 30409365 TI - A 54-Year-Old Woman With Chest Pain and Shortness of Breath. PMID- 30409366 TI - A 67-Year-Old Man With Psoriatic Arthritis and New-Onset Dyspnea. AB - A 67-year-old retired air force officer presented with a 6-month history of nonproductive cough, progressive exertional dyspnea, and weight loss. He was unable to walk beyond 100 m compared with his baseline of unlimited walking distance. He denied fever, hemoptysis, myalgia, or chest pain. He had a 30-year history of chronic plaque psoriasis with arthritis, which was managed by his dermatologist with emollients and vitamin D analogues. Joint involvement had previously been controlled with methotrexate, which was discontinued 15 years ago after resolution of his symptoms. He developed a polyarthritis flare a year ago, and adalimumab was initiated with good response. PMID- 30409367 TI - An 80-Year-Old Man With Hemoptysis and Unilateral Patchy Opacities. AB - CASE PRESENTATION: An 80-year-old man presented with a 5-day history of hemoptysis, mild shortness of breath on exertion, fatigue, and malaise. He denied chest pain or fever. He had a history of hypertension, congestive heart failure, and left nephrectomy for renal cancer 10 years earlier; he was a former cigarette smoker with a 50 pack-year history, having quit 5 years prior to presentation. The patient did not report any recent travel history or occupational or animal exposures, and he did not have gastroesophageal reflux. Medications included diltiazem hydrochloride, irbesartan, hydrochlorothiazide, and ranitidine. PMID- 30409368 TI - A 48-Year-Old Athletic Man With Bradycardia During Sleep. AB - CASE PRESENTATION: A 48-year-old athletic man with history of dyslipidemia and second-degree atrioventricular block (Mobitz type I 2:1 atrioventricular block) endorses sleep-related difficulties at his annual physical examination. Mobitz type I block was diagnosed 11 years earlier when the patient presented to his primary care physician with left-sided chest pain for 2 months. He was evaluated by cardiology, with a normal stress echocardiogram. The impression was that the chest pain was nonanginal. He describes sleeping for only a few hours at a time and has nighttime awakenings. He does not wake up feeling refreshed. He experiences passive daytime sleepiness and evening somnolence. He is very active, runs every day, and has participated in several half-marathons. He currently undergoes high-intensity interval training, including running and lifting. Per his wife, the patient snores loudly and has apneic episodes during sleep. One of his siblings has OSA. He denies excessive sleepiness, with an Epworth Sleepiness Scale score of 2. PMID- 30409369 TI - A 40-Year-Old Man With Albinism and Progressive Dyspnea. AB - CASE PRESENTATION: A 40-year-old male subject employed as a grocery store manager presented to a pulmonary clinic with a dry cough and progressive dyspnea of 1 year duration. The patient was previously an avid cyclist and first noted his dyspnea when he was unable to bike as far as before. Bilateral interstitial lung infiltrates were recently noted on chest radiography. At the time of presentation, he could no longer cycle due to dyspnea. The patient's medical history was significant for albinism and severe visual impairment. He had no family history of albinism or pulmonary disorders. He had never smoked, drank alcohol only occasionally, and had no significant environmental exposures. PMID- 30409370 TI - A 32-Year-Old Man With HIV Infection, Pleural Effusions, and Lymphadenopathy. AB - CASE PRESENTATION: A 32-year-old man presented with fever, nonproductive cough, diffuse lymphadenopathy, and polyarticular pain for 2 weeks. His medical history included HIV diagnosed 10 years ago, anal intraepithelial neoplasia, Kaposi sarcoma, and herpes simplex virus-2 infection. The patient was not receiving antiretroviral therapy or antibiotic prophylaxis, and his last known CD4 count a month before was 45 cells/mm3. He was prescribed a course of doxycycline by his primary care physician, which did not improve his symptoms. PMID- 30409371 TI - Pure spatial and space-time clusters of self-harm in Kwai Tsing 2004 to 2012. PMID- 30409372 TI - Detecting spatiotemporal clusters of dementia mortality in the United States, 2000-2010. AB - Based on national death certificate data during 2000 and 2010, we employed the space-time scan statistic to identify spatiotemporal clusters of dementia mortality in the contiguous United States. Results revealed that, for both Alzheimer's disease and all-cause dementia mortality in the total population, the most likely clusters occurred in the Northeast region, with lower than average relative risk. The most likely excess mortality clusters were in the Pacific Northwest and Ohio River Valley and Carolinas. Temporal information of clusters suggested reduction in the relative risk of Alzheimer's disease and all-cause dementia mortality in most of the highly likely clusters. The results should propel public health agencies to evaluate the capacity of local health and social care to meet dementia patients' needs before death in the high-risk cluster areas. Further investigation of causal factors of these clusters is needed. PMID- 30409373 TI - Longitudinal impacts of two causal drivers of alcohol demand on outlet concentrations within community settings: Population size and income effects. AB - We analyzed counts of licensed bars, restaurants and off-premise alcohol outlets within 53 California cities from 2000-2013. Poisson models were used to assess overall space-time associations between outlet numbers and population size and median household income in local and spatially adjacent block groups. We then separated covariate effects into distinct spatial and temporal components ("decomposed" models). Overall models showed that densities of all outlet types were generally greatest within block groups that had lower income, were adjacent to block groups with lower income, had greater populations, and were adjacent to block groups that had greater populations. Decomposed models demonstrate that over time greater income was associated with increased counts of bars, and greater population was associated with greater numbers of restaurants and off premise outlets. Acknowledging the many negative consequences for populations living in areas of high outlet density, these effects are a predictable and powerful social determinant of health. PMID- 30409374 TI - Distance to HIV care and treatment adherence: Adjusting for socio-demographic and geographical heterogeneity. AB - Distance to health services plays an important role in determining access to care and an individual's health. This study aims to examine the relationship between distance to antiretroviral therapy (ART) prescribing physician and adherence to HIV treatment in British Columbia, Canada. Only participants who provided highly accurate locational data for both place of residence and their physician were used in the analysis. Using logistic regression, a multivariable confounder model was created to assess the association between distance and adherence. A geographically weighted logistic regression was also performed to adjust for spatial dependency. There were 1528 participants in the analysis, for a median distance of 17.85km. The final model showed further away from ART prescribing physician had a higher chance of incomplete adherence to ART (adjusted odds ratio 1.31; 95% Confidence Interval 1.04-1.65). Mobile services could potentially increase adherence rates for population residing further away from their ART prescribing physician. PMID- 30409375 TI - Using spatiotemporal models to generate synthetic data for public use. AB - When agencies release public-use data, they must be cognizant of the potential risk of disclosure associated with making their data publicly available. This issue is particularly pertinent in disease mapping, where small counts pose both inferential challenges and potential disclosure risks. While the small area estimation, disease mapping, and statistical disclosure limitation literatures are individually robust, there have been few intersections between them. Here, we formally propose the use of spatiotemporal data analysis methods to generate synthetic data for public use. Specifically, we analyze ten years of county-level heart disease death counts for multiple age-groups using a Bayesian model that accounts for dependence spatially, temporally, and between age-groups; generating synthetic data from the resulting posterior predictive distribution will preserve these dependencies. After demonstrating the synthetic data's privacy-preserving features, we illustrate their utility by comparing estimates of urban/rural disparities from the synthetic data to those from data with small counts suppressed. PMID- 30409376 TI - Risk maps for cities: Incorporating streets into geostatistical models. AB - Vector-borne diseases commonly emerge in urban landscapes, and Gaussian field models can be used to create risk maps of vector presence across a large environment. However, these models do not account for the possibility that streets function as permeable barriers for insect vectors. We describe a methodology to transform spatial point data to incorporate permeable barriers, by distorting the map to widen streets, with one additional parameter. We use Gaussian field models to estimate this additional parameter, and develop risk maps incorporating streets as permeable barriers. We demonstrate our method on simulated datasets and apply it to data on Triatoma infestans, a vector of Chagas disease in Arequipa, Peru. We found that the transformed landscape that best fit the observed pattern of Triatoma infestans infestation, approximately doubled the true Euclidean distance between neighboring houses on different city blocks. Our findings may better guide control of re-emergent insect populations. PMID- 30409377 TI - A spatial analysis of giardiasis and cryptosporidiosis in relation to public water supply distribution in North West England. AB - Giardia and Cryptosporidium are both waterborne parasites and leading causes of gastroenteritis. Although specimens from diarrhoeic patients are routinely examined for Cryptosporidium, they are often not examined for Giardia so many cases go undiagnosed. Since 2002, all faecal specimens in Central Lancashire have been tested for infection with Giardia and Cryptosporidium. The aim of this paper is to gain insight into the factors contributing to giardiasis and cryptosporidiosis, including evidence of transmission via drinking water. Our analysis found a higher risk of both conditions for young children and a second peak in risk of giardiasis in adults. There was a significantly higher risk of giardiasis for males and a higher risk of cryptosporidiosis for females. The geographical location was significant, with an increased risk in the north. Residence in an area with increased supply from one water treatment works was a significant predictor for cryptosporidiosis. PMID- 30409378 TI - Spatial analysis of the relative risk of suicide for Virginia counties incorporating uncertainty of variable estimates. AB - PURPOSE: This research aimed to identify significantly elevated areas of risk for suicide in Virginia adjusting for risk factors and risk factor uncertainty. METHODS: We fit three Bayesian hierarchical spatial models for relative risk of suicide adjusting for risk factors and considering different random effects. We compared models with and without incorporating parameter estimates' margin of error (MOE) from the American Community Survey and identified counties with significantly elevated risk and highly significantly elevated risk for suicide. RESULTS: Incorporating MOEs and using a mixing parameter between unstructured and spatially structured random effects achieved the best model fit. Fifty-two counties had significantly elevated risk and 18 had highly significantly elevated risk of suicide. Models without MOEs underestimated relative risk and over identified counties with elevated risk. CONCLUSIONS: Accounting for uncertainty in parameter estimates achieved better model fit. Efficient allocation of resources for suicide prevention can be attained by targeting clusters of counties with elevated risk. PMID- 30409379 TI - Porokeratosis-Like Grover Disease: More Than an Acantholytic Pattern. PMID- 30409380 TI - Leiomyosarcoma and Pleomorphic Dermal Sarcoma: Guidelines for Diagnosis and Treatment. AB - There are 3 types of leiomyosarcoma of the skin: dermal, subcutaneous, and metastatic cutaneous. Dermal leiomyosarcoma arises from smooth muscle fibers in arrector pili muscles, genital dartos muscles, and the nipple-areola complex. It is an intermediate-grade tumor associated with a tendency for local recurrence (24%) and low metastatic potential (4%). Subcutaneous leiomyosarcoma originates from smooth muscle in blood vessel walls and has higher rates of local recurrence (37%) and metastasis (43%). Plemorphic dermal sarcoma typically affects elderly patients and arises in sun-exposed areas (e.g., the scalp). Its histologic and immunohistochemical characteristics are similar to those of atypical fibroxanthoma, but it is more aggressive (metastasis rate of 10-20%). Histologically, it can be distinguished from atypical fibroxanthoma by the observation of subcutaneous tissue invasion, perineural invasion, and foci of necrosis. PMID- 30409381 TI - Carotid Artery Stiffness and Incident Depressive Symptoms: The Paris Prospective Study III. AB - BACKGROUND: Arterial stiffness may contribute to late-life depression via cerebral microvascular damage, but evidence is scarce. No longitudinal study has evaluated the association between arterial stiffness and risk of depressive symptoms. Therefore, we investigated the association between carotid artery stiffness and incident depressive symptoms in a large community-based cohort study. METHODS: This longitudinal study included 7013 participants (mean age 59.7 +/- 6.3 years; 35.8% women) free of depressive symptoms at baseline. Carotid artery stiffness (high-resolution echo tracking) was determined at baseline. Presence of depressive symptoms was determined at baseline and at 4 and 6 years of follow-up, and was defined as a score >=7 on the validated Questionnaire of Depression, Second Version, Abridged and/or new use of antidepressant medication. Logistic regression and generalized estimating equations were used. RESULTS: In total, 6.9% (n = 484) of the participants had incident depressive symptoms. Individuals in the lowest tertile of carotid distensibility coefficient (indicating greater carotid artery stiffness) compared with those in the highest tertile had a higher risk of incident depressive symptoms (odds ratio: 1.43; 95% confidence interval: 1.10-1.87), after adjustment for age, sex, living alone, education, lifestyle, cardiovascular risk factors, and baseline Questionnaire of Depression, Second Version, Abridged scores. Results were qualitatively similar when we used carotid Young's elastic modulus as a measure of carotid stiffness instead of carotid distensibility coefficient, and when we used generalized estimating equations instead of logistic regression. CONCLUSIONS: Greater carotid stiffness is associated with a higher incidence of depressive symptoms. This supports the hypothesis that carotid stiffness may contribute to the development of late-life depression. PMID- 30409382 TI - Vascular dementia encoding in the French nationwide discharge summary database (PMSI): Variability over the 2007-2017 period. AB - OBJECTIVE: Vascular dementia (VaD) is the second leading cause of dementia. Diagnostic criteria have evolved from the concept of multiple infarctions to different subtypes: acute onset VaD, subcortical VaD, mixed cortical and subcortical VaD. Our aim was to analyze the evolution in the coding of these different subtypes of VaD in the French nationwide exhaustive hospital discharge database (PMSI) between 2007 and 2017. METHOD: We included all principal diagnoses of VaD in the PMSI hospital stays from 2007 to 2017. RESULTS: Between 2007 and 2017, we show a relative decrease in the number of hospital stays for VaD compared to all hospital stays (0.0437% to 0.0404%). The 11,654 hospital stays for VaD in 2017 represent 13.5% of mental organic disorders. Subtype analysis shows a decrease in hospital stays for multiple infarctions between 2007 and 2017 (-50%), an increase for subcortical or mixed VaD (+20%), acute onset VaD (+184%) and an increase in "other VaD" (+85%). CONCLUSION: These data suggest a slight decrease in hospital stays for VaD, possibly related to better control of cardiovascular risk factors. They also suggest that the coding should be consistent with the evolution of diagnostic criteria. PMID- 30409383 TI - Towards the development of a high throughput screening approach for Mytilus edulis hemocytes: A case study on silicon-based nanomaterials. AB - To have an understanding of potential mechanistic effects, sublethal endpoints able to discriminate between nanomaterials with similar physical and chemical features need to be used. In this sense, quantitative PCR was used to measure a battery of genes linked to a wide array of different cellular processes. Gene expression was measured in Mytilus edulis hemocytes following an in vitro and in vivo exposure to pure silicon (40 nm) and carbon-coated silicon (40 and 75 nm) after 24 h. Partial least squares discriminant analysis and correlation analysis were used to develop an integrative model, describing the relationship between genes, to identify which genes were important in describing responses to engineered nanomaterial exposure. The results suggested that some discriminations could be made based on the presence of a carbon coating or the alteration of size which could inform industrial patterns on ways to reduce the ecotoxicological impact of their product. The results also indicate that HTS on Mytilus hemocytes may be integrated into a safer-by-design approach but additional characterization of nanomaterial behavior in media is required to determine if it is a suitable alternative to in vivo testing. PMID- 30409384 TI - Sessile macrobenthos (Ochrophyta) drives seasonal change of meiofaunal community structure on temperate rocky reefs. AB - Unlike the soft bottom meiofauna, meiofauna associated to hard substrata is poorly studied, despite its ecological relevance. Since communities of hard substrata are usually characterized by species with different life cycles and strategies from those of soft bottom assemblages, information on hard substrata meiofauna is still needed. In this study, sessile macrobenthos and the associated meiofaunal assemblages of two sites of Portofino (NW Mediterranean) were investigated in two seasons at three different depths on both sub-vertical and inclined reefs. The study aimed to assess the abundance, diversity and composition of the meiofauna and the factors structuring its assemblages. Moreover, as meiofauna is known to be dependent upon the substrate characteristics, the study investigated whether the meiofaunal patterns could be related to the sessile macrobenthos structure and composition, and to which extent. Macroalgae dominated the sessile macrobenthic assemblages, while Nematoda and Copepoda were the main meiofaunal groups. Meiofaunal higher-taxa richness and diversity resulted very high, due to the large number of different microhabitats offered by macroalgae. Macrobenthic assemblages were dominated by Rodophyta and Ochrophyta in summer, the latter dramatically collapsing in winter. The meiofaunal abundance and composition changed significantly with the season, consistently with the sessile macrobenthic assemblages, and resulted strongly correlated with Ochrophyta. Shaping the meiofaunal assemblages, macroalgae appeared to act as ecosystem engineer for the meiofauna. PMID- 30409385 TI - Memories of and influenced by the Trier Social Stress Test. AB - Psychosocial stress influences cognition, affect and behavior. This current review summarizes the impact of acute stress on human long-term memory taking a neuroendocrine perspective. In this respect the stress associated increase in activity of the sympathetic nervous system (SNS) and the hypothalamus-pituitary adrenal (HPA) axis are key. A special focus will be placed on findings obtained with the Trier Social Stress Test (TSST). This paradigm can be used to induce stress before or after a memory task. It was shown repeatedly that stress enhances long-term consolidation but impairs long term memory retrieval. However the TSST can also be used to assess memories of this stressful episode itself. The latter requires a standardized presentation of relevant stimuli during the TSST as well as a carefully designed control condition. Moreover special care has to be taken to control potential influences on visual exploration and working memory in order to correctly interpret observed effects on memory. The results obtained so far fit to the idea of enhanced encoding of salient information under stress. These findings are of relevance for educational, organizational and clinical applications. PMID- 30409386 TI - Take This Cognitive Training Efficacy Bar Fight Outside (to a Regulatory Agency). PMID- 30409387 TI - How to Resolve Controversies in Cognitive Training: Let the Data Speak! PMID- 30409388 TI - Dispositional Neural Signatures: When Group Main Effects on Functional Magnetic Resonance Imaging Tasks Can Still Be Interesting. PMID- 30409389 TI - Ventral Striatal Function Interacts With Positive and Negative Life Events to Predict Concurrent Youth Depressive Symptoms. AB - BACKGROUND: Life events and reward-system functioning contribute to resilience and risk for depression. However, interactions between life events and neural responses to reward and loss have not been previously investigated in relation to depression symptoms in child and adolescent populations. METHODS: An unselected sample (N = 130) of 8- to 14-year-old girls (mean = 12.6 years) completed the Child Depression Inventory and a functional magnetic resonance imaging guessing task in which they won or lost money on each trial. Parents completed a measure of life events experienced by the child. Life events were separated by positive versus negative and whether they were likely related or unrelated to the daughter's behavior (i.e., dependent vs. independent, respectively). Multiple regressions tested whether the interaction between ventral striatal (VS) response to wins or losses and recent life events were associated with child-reported depressive symptoms. RESULTS: A greater number of dependent positive life events related to decreased total depression symptoms when VS response to wins was robust. Conversely, a greater number of independent negative life events related to increased negative mood depression symptoms when VS response to losses was robust; this relationship was in the opposite direction when VS response to loss was low. CONCLUSIONS: VS response to reward and loss were independent moderators of the relationship between recent life events (positive and negative, respectively) and depressive symptoms. Findings suggest that targeting neural responses (i.e., increasing responses to winning or decreasing responses to losing) may be important for both improving resilience and reducing risk in different environmental contexts. PMID- 30409392 TI - An analysis of within-treatment change trajectories in valued activity in relation to treatment outcomes following interdisciplinary Acceptance and Commitment Therapy for adults with chronic pain. AB - A key issue in chronic pain treatment concerns changes necessary for reduced pain related distress and disability. Acceptance and Commitment Therapy (ACT), a behavior change approach, theorizes several important treatment processes. Increased engagement in valued activities appears highly relevant as previous work has indicated it is related to current and future functioning and to treatment outcomes. This study sought to examine change trajectory in valued activity over the course of an interdisciplinary program of ACT and its relation to outcomes at treatment conclusion and three-month follow-up (N = 242). Latent change trajectories of valued activity were assessed weekly over four weeks of treatment and analyzed via latent growth curve and growth mixture modeling. A single latent trajectory with an increasing linear slope was indicated. Overall, slope of change in valued activity was predictive of improvement in psychosocial outcomes at post-treatment, including psychosocial disability, depression, pain anxiety, and discrepancy between values importance and success. Slope was not related to change in pain intensity or physical disability at post-treatment, nor was it related to change in any variable at follow-up. Findings are discussed in relation to the ACT model, in that support was provided in relation to post treatment improvements for psychosocial variables. PMID- 30409393 TI - One portal endoscopic release of the first extensor compartment in de Quervain's disease. AB - OBJECTIVES: We aimed to present preliminary result of one portal endoscopic assisted release of first dorsal compartment at wrist in a case series with de Quervain disease as a minimal invasive surgical method. MATERIALS AND METHODS: The patients, who underwent an endoscopic-assisted release of the first extensor compartment for de Quervain's disease by same hand surgeon between 2015 and 2017, were retrospectively analyzed. Operative treatment was considered if the patients did not respond to non-operative treatment including oral anti-inflammatory medications, splinting, and steroid injection. Surgical release was recommended after minimum four months of unsuccesful non-operative treatment, including a steroid injection. 10 wrists were treated with one portal endoscopic assisted release. All patients were evaluated at an average of 16.1 months follow-up using visual analog scale (VAS) pain ratings and the Disabilities of Arm, Shoulder and Hand (DASH) score. RESULTS: The mean operating time was 13.9 min (range, 10 21min). The mean VAS and DASH scores were improved from 8.2 to 1.9 and 70.51 to 2.81 respectively. No significant difference was found between operated and non operated arms in postoperative pinch and strengths. Transient superficial radial nerve paresthesia (two wrists) and significant scar tenderness (one) were identified in three cases. There was no patient that complain of unsightly scar and tendon subluxation. CONCLUSIONS: One portal endoscopic assisted release of the extensor compartment is an effective and safe minimal invasive procedure with similar complication rates reported previously in open and endoscopic procedures in patients with de Quervain's disease who are unresponsive to non-operative treatments. LEVEL OF EVIDENCE: Level IV Therapeutic Study. PMID- 30409391 TI - Relationship of Hippocampal Volumes and Posttraumatic Stress Disorder Symptoms Over Early Posttrauma Periods. AB - BACKGROUND: Smaller hippocampal volume is associated with more severe posttraumatic stress disorder (PTSD) symptoms years after traumatic experiences. Posttraumatic stress symptoms appear early following trauma, but the relationship between hippocampal volume and PTSD symptom severity during early posttrauma periods is not well understood. It is possible that the inverse relationship between hippocampal volume and PTSD symptom severity is already present soon after trauma. To test this possibility, we prospectively examined the association between hippocampal volumes and severity of PTSD symptoms within weeks to months after trauma due to a motor vehicle collision. METHODS: Structural magnetic resonance imaging scans of 44 survivors were collected about 2 weeks and again at 3 months after a motor vehicle collision to measure hippocampal volumes. The PTSD Checklist was used to evaluate PTSD symptoms at each scan time. Full (n = 5) or partial (n = 6) PTSD was evaluated using the Clinician-Administered PTSD Scale at 3 months. RESULTS: Left hippocampal volumes at both time points negatively correlated with PTSD Checklist scores, and with subscores for re-experiencing symptoms at 3 months. Left hippocampal volumes at 3 months also negatively correlated with hyperarousal symptoms at 3 months. Finally, neither left nor right hippocampal volumes significantly changed between 2 weeks and 3 months posttrauma. CONCLUSIONS: The results suggest that small hippocampal volume at early posttrauma weeks is associated with increased risk for PTSD development. Furthermore, the inverse relationship between hippocampal volume and PTSD symptoms at 3 months did not arise from posttrauma shifts in hippocampal volume between 2 weeks and 3 months after trauma. PMID- 30409394 TI - Preface: AIME 2017. PMID- 30409390 TI - Anhedonia in Trauma-Exposed Individuals: Functional Connectivity and Decision Making Correlates. AB - BACKGROUND: Reward processing deficits have been increasingly associated with trauma exposure and are a core feature of posttraumatic stress disorder (PTSD). While altered resting-state functional connectivity (rsFC) of ventral striatal regions, including the nucleus accumbens (NAcc), has been associated with anhedonia in some stress-related disorders, relationships between NAcc rsFC and anhedonia have not previously been investigated in trauma-exposed individuals. Additionally, relationships between anhedonia and reward-related decision making remain unexplored in relation to trauma exposure. We hypothesized that elevated anhedonia would be associated with altered rsFC between NAcc and default mode network regions and with increased delay discounting. METHODS: The sample included 51 participants exposed to a DSM-IV PTSD Criterion A event related to community trauma. Participants completed the Clinician Administered PTSD Scale, the Snaith-Hamilton Pleasure Scale, the Beck Depression Inventory, a computerized delay discounting paradigm, and resting-state functional magnetic resonance imaging. rsFC data were analyzed in SPM12 and CONN. RESULTS: Higher levels of anhedonia were associated with increased rsFC between seed regions of bilateral NAcc and areas of right dorsomedial prefrontal cortex. This relationship remained significant after accounting for Clinician Administered PTSD Scale total scores, Beck Depression Inventory total scores, or diagnostic group in the regression. Additionally, anhedonia was associated with elevated (increased) delay discounting. CONCLUSIONS: Greater anhedonia was related to higher positive connectivity between NAcc and right dorsomedial prefrontal cortex and to increased delay discounting, i.e., greater preference for smaller immediate versus larger delayed rewards. These findings contribute to a growing body of literature emphasizing the importance of anhedonia in trauma-exposed individuals. PMID- 30409395 TI - Illuminating the processes of microevolution: A bioarchaeological analysis of dental non-metric traits from Armenian Highland. AB - Non-metric dental traits provide useful information for assessing temporal changes as well as for assessing biological relationships among living and ancient populations. Dental morphological traits were employed in this study as direct indicators of biological affinities among the populations that inhabited the Armenian Highland from the Late Chalcolithic-Early Bronze Age to Modern times. Sixteen morphological features in 2643 permanent adult teeth from 41 samples coming from 5 areas within the Armenian Highland were scored. Both Zubov's standard protocol and Turner's ASUDAS were employed. Given the paucity of odontological data for this area, this study contributes to the dental non-metric traits' history of Armenian Highland and is a summary compilation and comparison of previously conducted work where non-metric traits were used in relation to dental reductions within the ancient Caucasus and Near East. The chronological sequence is considerable and spans from the Late Chalcolithic-Bronze Age to the Modern Age. It is suggested that offspring of ancient inhabitants of Armenian Highland continued to inhabit this area during the Late Iron Age, Classical/Late Antiquity, Middle Age and Modern period. This scenario indicates genetic continuity and gene flow between populations. Such a perspective is supported by the archaeological and molecular findings. PMID- 30409396 TI - Public health and the workplace: a new era dawns. PMID- 30409397 TI - Does lifestyle matter for sickness absence? PMID- 30409398 TI - Wellness programmes in the workplace in India. PMID- 30409400 TI - Dietary carbohydrate intake and mortality: reflections and reactions. PMID- 30409399 TI - Dietary carbohydrate intake and mortality: reflections and reactions. PMID- 30409401 TI - Dietary carbohydrate intake and mortality: reflections and reactions. PMID- 30409402 TI - Dietary carbohydrate intake and mortality: reflections and reactions. PMID- 30409403 TI - Dietary carbohydrate intake and mortality: reflections and reactions. PMID- 30409404 TI - Dietary carbohydrate intake and mortality: reflections and reactions - Authors' reply. PMID- 30409405 TI - Correction to Lancet Public Health 2018; 3: e365-73. PMID- 30409406 TI - Lifestyle factors and risk of sickness absence from work: a multicohort study. AB - BACKGROUND: Lifestyle factors influence the risk of morbidity and mortality, but the extent to which they are associated with employees' absence from work due to illness is unclear. We examined the relative contributions of smoking, alcohol consumption, high body-mass index, and low physical activity to diagnosis specific sickness absence. METHODS: We did a multicohort study with individual level data of participants of four cohorts from the UK, France, and Finland. Participants' responses to a lifestyle survey were linked to records of sickness absence episodes, typically lasting longer than 9 days; for each diagnostic category, the outcome was the total number of sickness absence days per year. We estimated the associations between lifestyle factors and sickness absence by calculating rate ratios for the number of sickness absence days per year and combining cohort-specific estimates with meta-analysis. The criteria for assessing the evidence included the strength of association, consistency across cohorts, robustness to adjustments and multiple testing, and impact assessment by use of population attributable fractions (PAF), with both internal lifestyle factor prevalence estimates and those obtained from European populations (PAFexternal). FINDINGS: For 74 296 participants, during 446 478 person-years at risk, the most common diagnoses for sickness absence were musculoskeletal diseases (70.9 days per 10 person-years), depressive disorders (26.5 days per 10 person-years), and external causes (such as injuries and poisonings; 12.8 days per 10 person-years). Being overweight (rate ratio [adjusted for age, sex, socioeconomic status, and chronic disease at baseline] 1.30, 95% CI 1.21-1.40; PAFexternal 8.9%) and low physical activity (1.23, 1.14-1.34; 7.8%) were associated with absences due to musculoskeletal diseases; heavy episodic drinking (1.90, 1.41-2.56; 15.2%), smoking (1.70, 1.42-2.03; 11.8%), low physical activity (1.67, 1.42-1.96; 19.8%), and obesity (1.38, 1.11-1.71; 5.6%) were associated with absences due to depressive disorders; heavy episodic drinking (1.64, 1.33 2.03; 11.3%), obesity (1.48, 1.27-1.72; 6.6%), smoking (1.35, 1.20-1.53; 6.3%), and being overweight (1.20, 1.08-1.33; 6.2%) were associated with absences due to external causes; obesity (1.82, 1.40-2.36; 11.0%) and smoking (1.60, 1.30-1.98; 10.3%) were associated with absences due to circulatory diseases; low physical activity (1.37, 1.25-1.49; 12.0%) and smoking (1.27, 1.16-1.40; 4.9%) were associated with absences due to respiratory diseases; and obesity (1.67, 1.34 2.07; 9.7%) was associated with absences due to digestive diseases. INTERPRETATION: Lifestyle factors are associated with sickness absence due to several diseases, but observational data cannot determine the nature of these associations. Future studies should investigate the cost-effectiveness of lifestyle interventions aimed at reducing sickness absence and the use of information on lifestyle for identifying groups at risk. FUNDING: NordForsk, British Medical Research Council, Academy of Finland, Helsinki Institute of Life Sciences, and Economic and Social Research Council. PMID- 30409407 TI - Regarding: A clinical prediction model to estimate the metastatic potential of pheochromocytoma/paraganglioma: ASES score. PMID- 30409408 TI - [Effects of intraarticular tramadol, magnesium and ketamine on postoperative pain in arthroscopic meniscectomy]. AB - OBJECTIVE: Postoperative pain control is important in terms of early recovery and rehabilitation in arthroscopic meniscectomy. For this purpose, we aimed to compare the effects of intraarticular tramadol, magnesium, and ketamine with combinations of pericapsular bupivacaine on postoperative pain and recovery in arthroscopic meniscectomy. METHODS: Ninety patients who underwent arthroscopic meniscectomy were enrolled in the study. Group T was given tramadol, Group K was given ketamine, and Group M was given magnesium reconstituted intraarticularly, and all groups received periarticular bupivacaine. Comparisons were made in terms of the patients' postoperative Visual Analogue Scale scores with and without movement, need for additional analgesics, first analgesic time, mobilization times, adverse effects, and satisfaction with the analgesics. RESULTS: The Visual Analogue Scale scores were lowest in Group T at 0 minutes, and were higher in the 15th and 30th minutes and 1st, 2nd, and 6th hours. Visual Analogue Scale values with movement were found to be high in Group M at 0 and 15 minutes, but they were found to be higher in group T in the 30th minute, 1st, 2nd and 6th hour. The groups were similar in terms of postoperative additional analgesic use, number of analgesic use, and satisfaction with analgesics; however, the first analgesic time was earlier in Group M, and the first mobilization time was earlier in Group K. CONCLUSION: Intraarticular ketamine enables early mobilization and less need for additional analgesics, it also provides a better analgesic effect in comparison with intraarticular tramadol and magnesium. PMID- 30409409 TI - [Effect of magnesium sulphate and milrinone on cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a randomized study]. AB - BACKGROUND: Aneurysmal subarachnoid hemorrhage is an important cause of premature death and disability worldwide. Magnesium sulphate is shown to have a neuroprotective effect and it reverses cerebral vasospasm. Milrinone is also used in the treatment of cerebral vasospasm. The aim of the present study was to compare the effect of prophylactic magnesium sulphate and milrinone on the incidence of cerebral vasospasm after subarachnoid hemorrhage. METHODS: The study included 90 patients with aneurysmal subarachnoid hemorrhage classified randomly (by simple randomization) into two groups: magnesium sulphate was given as an infusion of 500mg.day-1 without loading dose for 21 days. Group B: milrinone was given as an infusion of 0.5MUg.kg-1.min-1 without loading dose for 21 days. The cerebral vasospasm was diagnosed by mean cerebral blood flow velocity in the involved cerebral artery (mean flow velocity>=120cm.s-1), neurological deterioration by Glasgow coma scale, or angiography (the decrease in diameter of the involved cerebral artery >25%). RESULTS: The mean cerebral blood flow velocity decreased significantly in the magnesium group compared to milrinone group through Day 7, Day 14 and Day 21 (p<0.001). The incidence of cerebral vasospasm decreased significantly with magnesium compared to milrinone (p=0.007). The Glasgow coma scale significantly improved in the magnesium group compared to milrinone group through Day 7, Day 14 and Day 21 (p=0.036, p=0.012, p=0.016, respectively). The incidence of hypotension was higher with milrinone than magnesium (p=0.012). CONCLUSIONS: The incidence of cerebral vasospasm after aneurysmal subarachnoid hemorrhage was significantly lower and Glasgow coma scale significantly better with magnesium when compared to milrinone. Milrinone was associated with a higher incidence of hypotension and requirement for dopamine and norepinephrine when compared to magnesium. PMID- 30409410 TI - [Lung isolation for emergent thoracotomy in the bleeding airway patient: the choice of bronchial blocker may make a difference]. PMID- 30409411 TI - Decade Long Trends (2001-2011) in the Incidence Rates of Initial Acute Myocardial Infarction. AB - Despite the magnitude and impact of acute coronary disease, there are limited population-based data in the United States describing relatively recent trends in the incidence rates of acute myocardial infarction (AMI). The objectives of this study were to describe decade long (2001-2011) trends in the incidence rates of initial hospitalized episodes of AMI, with further stratification of these rates by age, sex, and type of AMI, in residents of central Massachusetts hospitalized at 11 area medical centers. The study population consisted of 3,737 adults hospitalized with a first AMI at 11 medical centers in central Massachusetts on a biennial basis between 2001 and 2011. The median age of this study population was 70 years, 57% were men, and 90% were white. Patients hospitalized during the most recent study years (2009/11) were younger, more likely to be men, have more co morbidities, and less in-hospital complications as compared with those in the earliest study years (2001/03). The overall age-adjusted hospital incidence rates (per 100,000 persons) of initial AMI declined (from 319 to 163), for men (from 422 to 219), women (from 232 to 120), for patients with a ST segment elevation (129 to 56), and for those with an non-ST segment elevation (190 to 107) between 2001 and 2011, respectively. In conclusion, the incidence rates of initial AMI declined appreciably in residents of central Massachusetts who were hospitalized with AMI during the years under study. PMID- 30409412 TI - Predictors of Patient Participation and Completion of Home-Based Cardiac Rehabilitation in the Veterans Health Administration for Patients With Coronary Heart Disease. AB - Traditional, facility-based cardiac rehabilitation (CR) is vastly underutilized in the United States. The Veterans Health Administration (VA) has developed new home-based cardiac rehabilitation (HBCR) programs to address this issue. However, the characteristics of patients who choose HBCR are unknown. We sought to determine predictors of participation and completion of HBCR at the San Francisco VA (SFVA). We evaluated patients hospitalized for ischemic heart disease between 2013 and 2016 at SFVA. Logistic regression models were used to identify predictors of participation and completion of HBCR. In 724 patients with ischemic heart disease who were eligible for CR between 2013 and 2016, 314 (43%) enrolled in HBCR. Older age was associated with lower odds of participation in HBCR (odds ratio [OR] 0.84; p <0.01). Additionally, patients with coronary artery bypass grafting (CABG) were twice as likely as those with percutaneous coronary intervention to participate in HBCR (OR 2.03; 95% confidence interval 1.40, 2.97). In HBCR participants, 48% (150/314) completed >=9 sessions. Patients with CABG were twice as likely as those with percutaneous coronary intervention to complete the HBCR program (OR 2.02; 95% confidence interval 1.18, 3.44). There were no differences in participation or completion rates by gender, race, ethnicity, or rurality. Our study showed that the SFVAMC HCBR program achieved a 43% participation rate, well above the VA average of 13%. There were no disparities by gender, race, or rurality in terms of participation and adherence. CABG as the indication for CR was the most significant predictor of participation and completion of HBCR. PMID- 30409413 TI - Usefulness of Antithrombotic Therapy in Patients With Atrial Fibrillation and Acute Myocardial Infarction. AB - To examine patterns of preadmission and discharge antithrombotic therapies in coronary artery disease (CAD) and atrial fibrillation (AF) patients admitted for acute myocardial infarction (AMI), we performed a retrospective analysis of the Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines (ACTION Registry-GWTG), which captures consecutive AMI patients treated at participating US hospitals. We included patients with CAD, AF, and CHA2DS2-VASc score >=2 admitted for AMI (07/01/2013-09/30/2016). In the 15,034 AMI patients with previous AF and CAD, median age was 75; 32% were female. Preadmission, 32% of patients were on P2Y12 inhibitors, 36% were anticoagulated, 72% were on aspirin, and 5% were on triple therapy. At discharge post-AMI, 73% were prescribed P2Y12 inhibitors and 41% anticoagulation. Discharge anticoagulation use did not vary directly with CHA2DS2-VASc score; 16% of previously anticoagulated patients had discontinued anticoagulation at discharge. In patients receiving anticoagulants at discharge, 27% used nonvitamin K antagonist oral anticoagulants. Triple therapy was prescribed in 23% at discharge; 27% of these were with nonvitamin K antagonist oral anticoagulants and 14% with prasugrel or ticagrelor. P2Y12 inhibitors and anticoagulants without aspirin were used in 2%. In conclusion, patients with previous CAD and AF are undertreated for both recurrent ischemic events and stroke prevention. After AMI hospitalization, P2Y12 inhibition was preferentially selected over oral anticoagulation. PMID- 30409414 TI - Impact of Prolonged Sitting on Peripheral and Central Vascular Health. AB - Prolonged, uninterrupted sitting negatively impacts markers of peripheral vascular health, particularly, vasodilatory function of leg arteries. Whether sitting can similarly impact measures of central vascular health, as well as overall leg vasoreactivity (i.e., vasodilatory and vasoconstrictor function) remains unknown. To address this, measurements were made in relatively healthy participants (i.e., free of overt disease; n = 20, age = 26 +/- 7; body mass index = 30 +/- 7 kg/m2; 7 female) pre, during and post 3 hours of uninterrupted sitting. Measures of central vascular health included arterial wave reflection (augmentation index and Reflection Magnitude-RM%) and aortic vascular stiffness (aortic pulse wave velocity). Local vasoreactivity of the distal, posterior tibial artery was measured using flow-mediated dilation-FMD, coupled with low flow mediated constriction, and microvascular function was assessed through the total hyperemic blood velocity (area-under-curve) response during FMD. After sitting, there was a significant increase in aortic pulse wave velocity (pre sit = 5.7 +/- 0.3 vs post sit = 6.1 +/- 0.3 m/s; p = 0.009, d = 0.36), whereas, augmentation index decreased (pre sit = 13 +/- 3 vs post sit = 3 +/- 1%; p < 0.001, d = 0.71). Albeit a moderate effect for decrease, RM% was not significantly altered during sitting (p = 0.13, d = 0.3). Vasodilatory (i.e., FMD pre sit = 0.5 +/- 0.04 vs post sit = 0.3 +/- 0.04 mm; p = 0.014, d = 0.29) and microvascular function (i.e., Microvascular area-under-curve: pre sit = 2,196 +/- 333 vs 1,157+/-172 AU; p = 0.003, d = 0.31) decreased, but vasoconstrictor function (low-flow mediated constriction; p = 0.85, d = 0.005) was unaffected by sitting. In conclusion, these data demonstrate that a prolonged bout of uninterrupted sitting negatively impacts markers of peripheral and central vascular health in relatively healthy adults. PMID- 30409415 TI - Musculoskeletal rheumatic complications of immune checkpoint inhibitor therapy: A single center experience. AB - BACKGROUND: The use of immune checkpoint inhibition (ICI) has revolutionized cancer treatment. However, these medications are associated with significant and potentially debilitating immune-related adverse events (irAEs). While certain toxicities have been well studied, rheumatic complications have been less widely recognized and characterized. METHODS: We report our experience of patients who were evaluated by rheumatology after the development of a suspected rheumatic irAE following ICI treatment. Cases of rheumatic irAEs were included if active rheumatic signs or symptoms developed during or after ICI treatment and were confirmed by a treating rheumatologist. RESULTS: Twenty-nine patients were evaluated by rheumatology for suspected rheumatic irAEs. Eighteen patients had confirmed toxicity including inflammatory arthritis (n = 12) and PMR (n = 6). Twelve patients had de novo toxicity and six had a flare of a pre-existing rheumatic condition. The onset of de novo toxicity occurred late into treatment (median 38 weeks), while patients with pre-existing rheumatic disease flared soon after initiation of ICI treatment (median 4.6 weeks). Management often required systemic or intra-articular steroids, with initiation of disease modifying anti rheumatic drug (DMARD) therapy in those unable to wean off steroids. CONCLUSION: De novo rheumatic irAEs are generally delayed in onset after ICI initiation, while flares of pre-existing rheumatic conditions occur shortly after ICI initiation. Effective management often requires systemic corticosteroids as well as DMARDs in a subset of patients. Future prospective studies are needed to accurately describe the incidence and spectrum of rheumatic irAEs and to identify the most effective management strategies. PMID- 30409416 TI - Combined pulmonary fibrosis and emphysema in systemic sclerosis: A syndrome associated with heavy morbidity and mortality. AB - BACKGROUND: The syndrome of combined pulmonary fibrosis and emphysema (CPFE) primarily due to tobacco smoking has been reported in connective tissue disease, but little is known about its characteristics in systemic sclerosis (SSc). METHODS: In this retrospective multi-center case-control study, we identified 36 SSc patients with CPFE, and compared them with 72 SSc controls with interstitial lung disease (ILD) without emphysema. RESULTS: Rate of CPFE in SSc patients with CT scan was 3.6%, and 7.6% among SSc patients with ILD. CPFE-SSc patients were more likely to be male (75 % vs 18%, p < 0.0001), smokers (83 % vs 33%, p < 0.0001), and to have limited cutaneous SSc (53 % vs 24% p < 0.01) than ILD-SSc controls. No specific autoantibody was significantly associated with CPFE. At diagnosis, CPFE-SSc patients had a greater decrease in carbon monoxide diffusing capacity (DLCO 39 +/- 13 % vs 51 +/- 12% of predicted value, p < 0.0001) when compared to SSc-ILD controls, whereas lung volumes (total lung capacity and forced vital capacity) were similar. During follow-up, CPFE-SSc patients more frequently developed precapillary pulmonary hypertension (PH) (44 % vs 11%, p < 10-4), experienced more frequent unscheduled hospitalizations (50 % vs 25%, p < 0.01), and had decreased survival (p < 0.02 by Kaplan-Meier survival analysis) as compared to ILD-SSc controls. CONCLUSIONS: The CPFE syndrome is a distinct pulmonary manifestation in SSc, with higher morbidity and mortality. Early diagnosis of CPFE by chest CT in SSc patients (especially smokers) may result in earlier smoking cessation, screening for PH, and appropriate management. PMID- 30409417 TI - Regulatory B cells: New players in inflammatory and autoimmune rheumatic diseases. AB - OBJECTIVE: Regulatory B cells (Bregs) are a new subset of B cells with immunoregulatory functions, mainly through IL-10 production. Bregs suppress inflammatory Th1 and Th17 differentiation and induce Tregs suppressing autoimmune diseases. The aim of the study was to review the literature related to Bregs in autoimmune rheumatic diseases (ARDs). METHODS: A literature review of publications in PUBMED published in English was performed using the relevant combinations of terms. RESULTS: All relevant publications are discussed. Overall, recent studies in rheumatic diseases found Bregs to be decreased in ANCA associated vasculitides (AAV) and in systemic sclerosis (SSc), particularly in SSc-associated lung fibrosis. In AAV Bregs levels are negatively correlated with autoantibody levels whereas in SSc this association is less clear but there is an inverse association with Th1 and Th17 cells. In rheumatoid arthritis (RA), Bregs were decreased, particularly in RA-associated lung fibrosis. In psoriatic arthritis IL-10 + Bregs are decreased and inversely associated with Th1 and Th17 cells. In systemic lupus erythematosus (SLE), the role of Bregs is unclear. In experimental diseases, when Bregs were expanded ex-vivo, they ameliorated established disease. CONCLUSION: Bregs appear to be a new player in the pathogenesis of ARDs, and may offer a new strategy for therapeutic intervention. PMID- 30409418 TI - Alkylamine ion-pairing reagents and the chromatographic separation of oligonucleotides. AB - Alkylamines are commonly used to improve both chromatographic and mass spectral performance of electrospray ionization liquid chromatography mass spectrometry based methods for the analysis of oligonucleotides. Recently several new alkylamines have been introduced to enhance the electrospray mass spectral response for oligonucleotides; however, the chromatographic properties of these new alkylamines have not been rigorously assessed. We have investigated the retention, peak width, resolution and general chromatographic performance of fifteen different alkylamines for the separation of a model DNA, RNA and an antisense therapeutic oligonucleotide. Eleven of the fifteen alkylamines were shown to provide similar chromatographic performance across all three classes of oligonucleotides. Based on these findings, a model for the mechanism of retention of oligonucleotides using alkylamines and hexafluoroisopropanol mobile phases is proposed. Depending on the concentrations of alkylamines and pH adjustment, oligonucleotides can be retained by micellar chromatography and not the generally held ion-pairing mechanism. This conclusion is supported by light scattering, transmission electron microscopy and ion mobility experiments detecting three micron aggregates in the mobile phase at concentrations that are routinely used for LC-MS analysis of oligonucleotides. These aggregates are not detected at lower alkylamine concentrations where the retention mechanism follows an ion pairing mechanism. The formation of these aggregates appears to be dependent on the pH of the mobile phase. PMID- 30409419 TI - Giant cell tumor of the superior maxilla. PMID- 30409420 TI - Corrigendum to 'Antitumor effects of seleno-beta-lactoglobulin (Se-beta-Lg) against human gastric cancer MGC-803 cells' [Eur. J. Pharmacol. 833 (2018) 109 115]. PMID- 30409421 TI - Promoting hepatogenic differentiation of human mesenchymal stem cells using a novel laminin-containing gelatin cryogel scaffold. AB - Liver transplantation is the only definitive treatment currently available for acute and chronic liver failure. However, this approach has been restricted by complications including rejection and infection. Tissue engineering approaches using stem cell-derived functional hepatic cells offer a potential alternative. Using biologically compatible scaffolds is an important complementary key to achieve optimal construct for hepatic replacement. In the present study, to optimize the differentiation of human adipose-derived mesenchymal stem cells (ADMSCs) toward hepatocyte-like cells, a previously described gelatin cryogel was optimized and improved by laminin, the major component of basal lamina. The ADMSCs seeded on the scaffold displayed increased attachment in the presence of laminin and the MTT assay showed good compatibility for cell proliferation. The differentiation of stem cells were evaluated using glycogen staining, urea secretion measurement, hepatocyte specific cell surface analysis and gene expression analysis. The results of tests indicated that laminin protein and gelatin cryogel 3D scaffold, each on its own, enhanced hepatogenic differentiation of ADMSCs. However, when laminin immobilized on the gelatin cryogel surface, the differentiation was promoted significantly and the resulting cells showed striking similarity to HepG2 in terms of expressing studied hepatocyte markers. PMID- 30409422 TI - Mesenchymal stem cells induced CD4+ T cell apoptosis in treatment of lupus mice. AB - Umbilical cord-derived mesenchymal stem cell transplantation (UCMSCT) has been used to treat human autoimmune diseases like lupus for example, but little is known about its effect on cell apoptosis. Here we evaluated the efficacy of UCMSCT for lupus treatment and explored the mechanism by which mesenchymal stem cells (MSCs) modulate T cell apoptosis in lupus mice. 1 * 106 human umbilical cord-derived mesenchymal stem cells (UC-MSCs) were injected into B6.MRL-Faslpr (B6.lpr) mice via tail vein. 6 h, 24 h or 4 weeks later, the mice were sacrificed and the apoptosis of lymphocytes in peripheral blood and spleen were detected by flow cytometry. The immune cell subpopulations in spleen were also measured at 6 h and 24 h, respectively. The therapeutic effects were assessed after 4 weeks. The frequency of peripheral blood CD4+ T cell apoptosis was reduced in lupus prone B6.lpr mice. UCMSCT alleviated the disease phenotypes in B6.lpr mice, decreased the ratio of Th1 as well as Th2 cells, and increased percentages of apoptotic CD4+ T cells in vivo and vitro. Collectively, our findings unravel that UCMSCT alleviate lupus disease and reverse immune imbalance possibly by promoting T cell apoptosis in B6.lpr mice. PMID- 30409423 TI - A novel morphometry system automatically assessing the growth and regeneration of intestinal organoids. AB - As compared with 2D cell line cultures, 3D intestinal organoids are better at maximally recapitulating the physiological features of stem cells in vivo. However, the complex 3D structure is an obstacle which must be objectively and automatically evaluated to assess colony growth and regeneration. Meanwhile, no internal standard currently exists for evaluating the size of heterogeneities in organoids or defining those regenerating colonies. Herein, we developed a simple morphometry system to image MTT-stained organoids. The growth curve of organoids can be automatically generated based upon analyzing the integrated optical density using software. Referencing the definition standards of in vivo regenerating crypts, the perimeters of crypts cultured 24 h after seeding were selected as an "Organoid Unit" to further evaluate colony survival rate and colony size heterogeneities after exposure to varying doses of irradiation. Moreover, the morphometry-based quantification data collected confirmed other findings associated with radiation sensitizing effects of ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related protein (ATR) inhibitor and the radiation protective effect of IL-22. In summary, the novel organoid morphometry system combined with a new internal reference is a practical means for standardizing assessment of growth, survival and regeneration of intestinal organoid colonies. This method has promise to facilitate drug screens in intestinal and other organoid systems. PMID- 30409424 TI - Generation of regulable EGFRvIII targeted chimeric antigen receptor T cells for adoptive cell therapy of glioblastoma. AB - Adoptive immunotherapy using chimeric antigen receptors-modified T cells (CAR-T) is a promising approach for cancer treatment. However, CARs currently applied in the clinics cannot be effectively regulated and the safety of CAR-T cell therapies remains a major concern. To improve the safety of CAR-T cells, we designed a synthetic splitting CAR (ssCAR) that can regulate T cell functions exogenously. Epidermal growth factor receptor variant III (EGFRvIII) was used as a molecular target for ssCAR. Our results indicate that both EGFRvIII and small molecule are needed for the activation of the ssCAR-T cells. AP21967 dose dependently increased the expression of T cell activation, production of cytokines and extent of cell lysis. In conclusion, the gene switch designed in this study allows for temporal and spatial control over engineered T cells in a dose-and time-dependent manner by AP21967. Our work demonstrates the feasibility and improved safety profile of this novel treatment approach. PMID- 30409425 TI - Compound D159687, a phosphodiesterase 4D inhibitor, induces weight and fat mass loss in aged mice without changing lean mass, physical and cognitive function. AB - AIMS: Therapies that recapitulate the health benefits of caloric restriction in older adults are needed. Phosphodiesterase 4 inhibitors demonstrate such promise. We examined their effects on body weight and composition, physical and cognitive function in aged mice using Compound D159687 (D159687). METHODS: Nineteen 18 months old mice were randomized to receive either control (DMSO) or D159687 for seven weeks. We assessed food intake, body weight and body composition over time and performed once the following tests: treadmill, inverted grip strength, rotarod, spontaneous Y maze tests and skeletal muscle mitochondrial biogenesis. RESULTS: Four of the D159687 treated mice died in the first week. Necropsy suggests acute lung injury. D159687 treated mice weighed more than control mice at baseline. After controlling for baseline weight, D159687 treated mice lost 4.2 grams(g) more weight than control mice, mainly from fat mass loss (p value < 0.001). Muscle mass was unchanged between the two mice groups. D159587 mice ate significantly more food than the control mice. We found no difference between the two groups in the results of treadmill, rotarod and spontaneous Y maze tests and in mitochondrial biogenesis. CONCLUSION: Compound D159687 induced weight loss, predominantly fat mass loss and increased food intake in aged mice. The caloric restriction and lean mass preservation potential of PDE4D inhibitors deserve further verification. Findings may have major therapeutic implications when translated to the older adult population. Although physical and cognitive parameters were unchanged in this study, further studies would be needed to verify these results. The high death rate in the D159687 treated mice may have been due to the technical aspects of oral gavage. PMID- 30409426 TI - Developing a circularly permuted variant of Renilla luciferase as a bioluminescent sensor for measuring Caspase-9 activity in the cell-free and cell based systems. AB - Biosensors and whole cell biosensors consisting of biological molecules and living cells can sense a special stimulus on a living system and convert it to a measurable signal. A major group of them are the bioluminescent sensors derived from luciferases. This type of biosensors has a broad application in molecular biology and imaging systems. In this project, a luciferase-based biosensor for detecting and measuring caspase-9 activity is designed and constructed using the circular permutation strategy. The spectroscopic method results reveal changes in the biosensor structure. Additionally, its activity is examined in a cell-free coupled assay system. Afterward, the biosensor is utilized for measuring the cellular caspase-9 activity upon apoptosis induction in a cancer cell line. In following the gene of biosensor is sub-cloned into a eukaryotic vector and transfected to HEK293T cell line and then its activity is measured upon apoptosis induction in the presence and absence of a caspase-9 inhibitor. The obtained results show that the designed biosensor detects the caspase-9 activity in the cell-free and cell-based systems. PMID- 30409427 TI - Codium fragile F2 sensitize colorectal cancer cells to TRAIL-induced apoptosis via c-FLIP ubiquitination. AB - This study demonstrates that combined treatment with subtoxic doses of Codium extracts (CE), a flavonoid found in many fruits and vegetables, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), induces apoptosis in TRAIL-resistant colorectal cancer (CRC) cells. Effective induction of apoptosis by combined treatment with CE and TRAIL was not blocked by Bcl-xL overexpression, which is known to confer resistance to various chemotherapeutic agents. While TRAIL-mediated proteolytic processing of procaspase-3 was partially blocked in various CRC cells treated with TRAIL alone, co-treatment with CE efficiently recovered TRAIL-induced caspase activation. We observed that CE treatment of CRC cells did not change the expression of anti-apoptotic proteins and pro-apoptotic proteins, including death receptors (DR4 and DR5). However, CE treatment markedly reduced the protein level of the short form of the cellular FLICE-inhibitory protein (c-FLIPS), an inhibitor of caspase-8, via proteasome-mediated degradation. Collectively, these observations show that CE recovers TRAIL sensitivity in various CRC cells via down-regulation of c-FLIPS. PMID- 30409428 TI - Teniposide regulates the phenotype switching of vascular smooth muscle cells in a miR-21-dependent manner. AB - The switch of vascular smooth muscle cells (SMCs) from the contractile phenotype to proliferative one can make contributions to atherosclerosis and neointima formation. MiR-21 can prevent the rupture of advanced lesion plaques. We previously reported the protection of DNA topoisomerase II (Topo II) inhibitors against atherosclerosis and vascular calcification. However, it remains unknown if Topo II inhibitors can change SMC phenotypes. Herein, we show that teniposide protected SMC phenotype switching during atherosclerosis by enhancing expression of smooth muscle alpha-actin (SMA) while reducing osteopontin (OPN) expression in aortic lesion plaques. In vitro, teniposide induced expression of smooth muscle protein 22-alpha and calponin 1, but inhibited expression of OPN and epiregulin in human aortic SMCs (HASMCs). Moreover, teniposide attenuated platelet derived growth factor-BB-induced HASMC proliferation and migration. Mechanistically, the effect of teniposide on SMC phenotypes was completed, at least in part, by activating miR-21 expression. In addition, teniposide ameliorated ligation induced carotid artery remodeling in C57BL/6J mice by regulating SMA and OPN expression. Taken together, our study demonstrates that teniposide regulates SMC phenotype switching by upregulating expression of contractile genes in a miR-21 dependent manner, and this function is an important anti-atherogenic mechanism of teniposide. PMID- 30409429 TI - Down-regulation of arginine decarboxylase gene-expression results in reactive oxygen species accumulation in Arabidopsis. AB - Arabidopsis amiR:ADC-L2 is a non-lethal line with several developmental defects, it is characterized by a drastic reduction in free polyamine content. Herein, we found that catalase application had growth-promoting effects in amiR:ADC-L2 and parental Ws seedlings. Differences in ROS content between amiR:ADC-L2 and Ws seedlings were detected. Increased H2O2 levels were found in the amiR:ADC-L2, as well as low AtCAT2 gene expression and reduced catalase activity. Estimation of polyamine oxidase activity in amiR:ADC-L2 line indicated that the over accumulation of H2O2 is independent of polyamine catabolism. However, increments in NADPH oxidase activity and O2*- content could be associated to the higher H2O2 levels in the amiR:ADC-L2 line. Our data suggest that low polyamine levels in Arabidopsis seedlings are responsible for the accumulation of ROS, by altering the activities of enzymes involved in ROS production and detoxification. PMID- 30409430 TI - Identification of small molecule compounds active against Staphylococcus aureus and Proteus mirabilis. AB - Staphylococcus aureus is a human pathogen rapidly becoming a serious health problem due to ease of acquiring antibiotic resistance. To help identify potential new drug candidates effective against the pathogen, a small focused library was screened for inhibition of bacterial growth against several pathogens, including S. aureus. At least one of the compounds, Compound 10, was capable of blocking bacterial growth of S. aureus in a test tube with IC50 = 140 +/- 30 MUM. Another inhibitor, Compound 7, was bacteriostatic against S. aureus with IC50 ranging from 33 to 150 MUM against 3 different strains. However, only Compound 7 was bactericidal against P. mirabilis as examined by electron microscopy. Human cell line toxicity studies suggested that both compounds had small effect on cell growth at 100 MUM concentration as examined by MTT assay. Analysis of compounds' structures showed lack of similarity to any known antibiotics and bacteriostatics, potentially offering the inhibitors as an alternative to existing solutions in controlling bacterial infections for selected pathogens. PMID- 30409431 TI - Defective rapid cell shape and transendothelial migration by calpain-1 null neutrophils. AB - It has been proposed that Ca2+ activation of calpain-1 is an important trigger for rapid cell spreading by neutrophils. In this paper, we have investigated this by assessing the ex vivo functioning of neutrophils from calpain-1 null mice, Calpain-1 null neutrophils failed to migrate through TNF-activated endothelial monolayers. The failure to transmigrate through endothelial monolayers was therefore unlikely to be due to a failure of chemotaxis as chemotaxis by adherent calpain-1 null neutrophils towards fMLP was unpaired. In contrast, the capacity of calpian-1 neutrophils to spontaneously spread was limited to smaller diameters than for wild type cells. Photolytic uncaging of IP3 with Individual wild type neutrophils resulted in a large Ca2+ signal and rapid cell spreading. In contrast, calpain-1 neutrophils failed to spread in response to the IP3-induced Ca2+ signal. This work has therefore demonstrated that the presence of calpain-1 was required for effective rapid cell spreading by neutrophils. PMID- 30409432 TI - Targeted cancer cell ablation in mice by an alpha-particle-emitting astatine-211 labeled antibody against major histocompatibility complex class I chain-related protein A and B. AB - Major histocompatibility complex class I chain-related protein A and B (MICA/B) are ligands of the immune receptor, natural-killer group 2 member D. MICA/B expression is often found in several types of cancer but is restricted in normal tissues. Here, we show that an alpha-particle emitting astatine-211 (211At) labeled antibody targeting MICA/B (211At-anti MICA/B Ab) efficiently ablates cancer cells in vitro and in vivo. We generated 211At-anti MICA/B Ab, an anti MICA/B antibody conjugated with a highly cytotoxic alpha-particle emitting radionuclide 211At. 211At-anti MICA/B Ab binds to human osteosarcoma SaOS2 and U2OS cells that exhibit high levels of MICA/B expression and efficiently kills those cells in vitro. Biodistribution analysis using xenograft mouse models of HCT116 p53-/- positive for MICA/B expression, showed increased 211At in the xenografts for up to 22 h after injection as time proceeded. A single dose of 211At-anti MICA/B Ab (1 MBq) showed significant reduction in the tumor growth rate of HCT116 p53-/- xenografts compared to 211At-labeled mouse IgG (1 MBq) at 21 days after injection. No body weight loss and erythrocytopenia was evident in mice that received 211At-anti MICA/B. Leukocytopenia and thrombocytopenia were observed within a week after 211At-anti MICA/B injection, but counts of red blood cells and platelets were recovered to control levels at about 3-4 weeks after injection. Taken together, these data strongly demonstrate that targeted alpha particle therapy using 211At-anti-MICA/B Ab emitting highly cytotoxic alpha particles is a potential new therapeutic option for several types of cancer. PMID- 30409434 TI - ? AB - Xeroderma pigmentosum (XP) is a form of general dermatosis characterised by photo induced cutaneous-ocular impairment and by skin cancers. In addition to these signs, there may also be neurological involvement. This disease is related to a defect in genes within the nucleotide excision repair system for the first seven genetic groups (A-G), and to an abnormality in transcription groups for the eighth group (xeroderma pigmentosum variant - XPV). Cutaneous carcinomas are the most common types of cancer seen. They may begin in childhood. Multiple melanoma commonly occurs during the course of XP but given the frequency of spontaneous regression, the incidence is underestimated. The clinical appearance is characterised by polymorphous lesions with characteristic dyschromia and in most cases it is sufficient to establish the diagnosis. Investigation of unscheduled DNA synthesis (UDS) and cell survival following ultraviolet (UV) radiation were formerly considered the reference examination for laboratory diagnosis. However, these tests are now being replaced by new molecular biology techniques to screen for the genetic mutations characteristic of the disease. These techniques have proved extremely useful in identifying heterozygous patients and in antenatal diagnosis. Photoprotection is the key preventive measure: patients must avoid all exposure to the sun and to artificial sources of UV radiation. The therapeutic arsenal has recently been enriched by several modern therapeutic methods used to destroy cutaneous tumours such as imiquimod and photodynamic therapy (PDT). These approaches are valuable since they eliminate incipient tumours while sparing healthy skin. Surgery and cryosurgery are the most suitable methods for treating cutaneous tumours in children. Chemotherapy may be considered an alternative for the treatment of keratoacanthomas and squamous cell carcinomas (SCC). Cryosurgery may be combined with other therapeutic approaches to eliminate SCC of the lip. Management of these patients in reference centres, coupled with assistance from associations providing support for patients' families, has resulted in improved quality of therapy while slowing down disease progression. PMID- 30409433 TI - 2018 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations Summary. AB - The International Liaison Committee on Resuscitation has initiated a continuous review of new, peer-reviewed, published cardiopulmonary resuscitation science. This is the second annual summary of International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations that includes the most recent cardiopulmonary resuscitation science reviewed by the International Liaison Committee on Resuscitation. This summary addresses the role of antiarrhythmic drugs in adults and children and includes the Advanced Life Support Task Force and Pediatric Task Force consensus statements, which summarize the most recent published evidence and an assessment of the quality of the evidence based on Grading of Recommendations, Assessment, Development, and Evaluation criteria. The statements include consensus treatment recommendations approved by members of the relevant task forces. Insights into the deliberations of each task force are provided in the Values and Preferences and Task Force Insights sections. Finally, the task force members have listed the top knowledge gaps for further research. PMID- 30409435 TI - [Impact of climate change and ozone layer evolution on surface ultraviolet radiation]. PMID- 30409436 TI - [Ascher's syndrome]. PMID- 30409437 TI - Multi-year CO2 efflux measurements for assessing natural source zone depletion at a large hydrocarbon-impacted site. AB - The changing landscape of fuel consumption related, in part, to increased engine efficiency and the inexpensive supply of natural gas, has led to the closure of multiple refineries. As the operational lifetime of many refineries exceeds 100 years, historical releases of oil and refined products is common. To evaluate remediation and rehabilitation options, there is a need to understand the rate and distribution of natural hydrocarbon mass losses across these large properties. Here, surficial CO2 flux measurements were used to evaluate naturally occurring hydrocarbon mass losses at a large-scale former refinery that has been closed since 1982. Natural source zone depletion (NSZD) rates over a five-year period (2012-2016) were derived from surficial CO2 efflux measurements on a high resolution grid (N > 80). Results demonstrate substantial variations of mass loss rates across the site. Average site-wide mass loss rates ranged from 1.1-5.4 g TPH m-2 d-1 as C10H22 with a multi-year average of 4.0 g TPH m-2 d-1 as decane (C10H22), consistent with observations at other sites. Statistical analysis demonstrated that the same average mass loss rates would have been obtained with fewer measurement locations (N = 20-30). Comparing NSZD rates to site metadata show CO2 fluxes to be a reasonably good proxy for zones of subsurface hydrocarbon contamination - particularly with respect to vadose zone impacts. It is hypothesized that the observed decline of NSZD rates over the study period is related to rise of groundwater levels, leading to increased submergence of the smear zone. Overall, mass loss rates calculated from CO2 fluxes show NSZD can result in substantial contaminant removal, which may rival that obtained from engineered remediation, under some conditions. PMID- 30409438 TI - Corrigendum to "Immune modulatory properties of 6-gingerol and resveratrol in Atlantic salmon macrophages" [Mol. Immunol. 95 (2018) 10-19]. PMID- 30409439 TI - Delay-tolerant distributed voltage control for multiple smart loads in AC microgrids. AB - With increasing penetration of variable loads and intermittent distributed energy resources (DERs) with uncertainty and variability in distribution systems, the power system gradually inherits some features (e.g., lack of rotating inertia), which leads to the voltage instability in microgrids. As a means to provide stability support for smart grid against high penetration of intermittent DERs, inverter-based smart loads across the distribution grid has been suggested recently. Accordingly, this paper presents a delay-tolerant distributed voltage control scheme based on consensus protocol for multiple-cooperative smart loads through effective demand-side management in ac microgrids, in which the time delay effect on transmission communication occurred in information exchanges is considered. The proposed distributed voltage control scheme always enables the output voltage of each smart load to be synchronized to their reference value, which improves the robustness of system stability against transmission communication delays. The Lyapunov-Krasovskii functions are employed to analyze the stability of our proposed distributed control scheme, then the delay independent stability conditions are derived, which allows some large communication delays. Moreover, the sensitivity analysis is developed to show how the time delay affects system dynamics in order to validate the robustness of proposed delay-independent stability conditions. Furthermore, a sparse communication network is employed to implement the proposed distributed control protocols, which thus satisfies the plug-and-play requirement of smart microgrids. Finally, the simulation results of an ac microgrid in MATLAB/SimPowerSystems are presented to demonstrate the effectiveness of the proposed control methodology. PMID- 30409440 TI - Lobectomy vs. segmentectomy. A propensity score matched comparison of outcomes. AB - BACKGROUND: Segmentectomy has emerged as a lung parenchymal sparring alternative to the gold standard lobectomy in non-small cell lung cancer (NSCLC) patients. We hypothesized that there is parity between functional, local recurrence and survival outcomes. PATIENTS AND METHODS: Parenchymal sparring procedures including anatomical segmentectomies were propensity score matched 1:1 with lobectomies (n = 64). The primary outcomes included survival, functional and oncological outcomes. The oncological outcomes were: post-operative histology, clear margins and local recurrence rates. Kaplan Meier survival curves were used to compare the survival. Oncological and functional variables were assessed by Fischer exact test and t-test. RESULTS: The pre-operative performance status, ASA grade, lung function, risk factors, surgical approach and tumour histology were similar between the groups. The tumour size was significantly higher for lobectomies (32.4 +/- 17 vs. 24.6 +/- 12 mm, p = 0.01). The tumour staging in the segmentectomy group was similar to the lobectomy group (Ia; 50 vs. 34%; Ib: 29 vs. 37%; IIa 11 vs. 9.3%; IIb 5 vs. 14%; IIIa 5 vs. 4.6%, p = 0.83). The loco regional recurrence was lower in the segmentectomy group (1.5 vs. 3.1%, p = 0.69). The up-staging and down-staging post-surgery was similar in both groups, while neo-adjuvant therapy was used in 5 lobectomy and 3 segmentectomy cases. The survival was similar at 1 year between the groups (88 vs. 92%, p = 0.65). Between 4 and 5 years, the survival reduced in the parenchymal sparing group to 39% vs. 68% in the lobectomy group (p = 0.04). CONCLUSION: Surgical selection bias could be an important confounder in the selection of patients undergoing segmentectomy. Similar up and down staging were demonstrated in the two groups. This is one of the first studies to investigate the results of segmentectomy versus lobectomy in stage II/IIIa NSCLC tumours. No significant differences were found in functional outcomes, but the survival decreased after 4 years in the segmentectomy group, which could be explained by lower survival in the stage II/IIIa tumours treated with segmentectomy. PMID- 30409441 TI - Short-term complications in elderly patients undergoing CRS and HIPEC: A single center's initial experience. AB - INTRODUCTION: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a well-established curative treatment for patients with peritoneal carcinomatosis (PC) from colorectal cancer (CRC) and pseudomyxoma peritonei (PMP). The study's aim was to present a single center's initial experience with CRS and HIPEC and report the postoperative morbidity in elderly patients. METHODS: A retrospective observational study was conducted of all patients with peritoneally disseminated colorectal cancer or pseudomyxoma peritonei undergoing CRS and HIPEC between March 2014 and March 2017. Patient characteristics and the peri- and postoperative course were reviewed. Elderly patients were defined as those aged >= 65 years. Postoperative complications were classified according to the Serious Adverse Event (SAE) grading system. RESULTS: 122 patients undergoing CRS and HIPEC were split into two groups based on age (< 65 years versus >= 65 years) at the time of surgery. Both groups were comparable for ASA score, Peritoneal Cancer Index (PCI), procedure time and blood loss. Serious Adverse Event (SAE) grade > 3 morbidity was 26.7% in the elderly group as opposed to 10.4% in the younger group (p = 0.034). Both univariate and multivariate logistic regression analysis demonstrated that age was a significant risk factor (OR = 3.2, 95% CI 1.1-9.4, p = 0.033) for severe postoperative morbidity (SAE > 3). CONCLUSION: This retrospective study showed advanced age to be a significant risk factor for SAE > 3, after undergoing CRS and HIPEC. The initial institutional experience resembles previously published literature in terms of severe postoperative morbidity in elderly patients. PMID- 30409442 TI - Mucoactive agents for adults with acute lung conditions: A systematic review. AB - BACKGROUND AND OBJECTIVES: Inhaled mucoactive agents are used to enhance airway clearance, however efficacy and safety are unclear in adults with acute respiratory conditions. METHODS: We systematically reviewed randomized controlled trials assessing respiratory function; safety; length of stay (LOS); mucus; radiology; and oxygenation. RESULTS: No adverse events were reported for dornase alfa (n = 63), N-acetylcysteine (NAC, n = 50), ambroxol (n = 140), hypertonic saline (n = 33), heparin (n = 384), mannitol (n = 20) or isotonic saline. During invasive ventilation, NAC, dornase alfa and saline had no effect on mucus. Postoperatively, mucus characteristics improved with NAC (n = 10). Ambroxol lowered LOS (mean difference 4 days) and halved complications following lung carcinoma resection (n = 140). Heparin improved ventilator-free days (n = 130, mean difference 3.9-4.6) and intensive care LOS (n = 223, 3.2 days), but not ventilator-acquired pneumonia. CONCLUSION: Dornase alfa, hypertonic saline and NAC were ineffective for atelectasis/mucus plugging while intubated. More data are required to support using NAC, ambroxol and heparin during acute illness. PMID- 30409443 TI - Immunogenicity, safety, and tolerability of the measles-vectored chikungunya virus vaccine MV-CHIK: a double-blind, randomised, placebo-controlled and active controlled phase 2 trial. AB - BACKGROUND: Chikungunya fever is an emerging viral disease and substantial threat to public health. We aimed to assess the safety, tolerability, and immunogenicity of a live-attenuated, measles-vectored chikungunya vaccine (MV-CHIK). METHODS: In this double-blind, randomised, placebo-controlled and active-controlled phase 2 trial, we enrolled healthy volunteers aged 18-55 years at four study sites in Austria and Germany. Participants were randomly assigned to receive intramuscular injections with MV-CHIK (5 * 104 or 5 * 105 50% tissue culture infectious dose), control vaccine, or measles prime and MV-CHIK, in two different administration regimens. Randomisation was done by use of three-digit randomisation codes in envelopes provided by a data management service. The participants and investigators were masked to treatment assignment, which was maintained by use of sterile saline as a placebo injection. The primary endpoint was immunogenicity, defined as the presence of neutralising antibodies against chikungunya virus, at day 56, which is 28 days after one or two immunisations. The primary endpoint was assessed in all participants who completed the study without major protocol deviations (per-protocol population) and in all randomised participants who received at least one study treatment (modified intention-to-treat population). The safety analysis included all participants who received at least one study treatment. This trial is registered with ClinicalTrials.gov (NCT02861586) and EudraCT (2015-004037-26) and is completed. FINDINGS: Between Aug 17, 2016, and May 31, 2017, we randomly assigned 263 participants to receive control vaccine (n=34), MV-CHIK (n=195), or measles prime and MV-CHIK (n=34). 247 participants were included in the per-protocol population. Neutralising antibodies against chikungunya virus were detected in all MV-CHIK treatment groups after one or two immunisations, with geometric mean titres ranging from 12.87 (95% CI 8.75-18.93) to 174.80 (119.10-256.50) and seroconversion rates ranging from 50.0% to 95.9% depending on the dose and administration schedule. Adverse events were similar between groups, with solicited adverse events reported in 168 (73%) of 229 participants assigned to MV-CHIK and 24 (71%) of 34 assigned to control vaccine (p=0.84) and unsolicited adverse events in 116 (51%) participants assigned to MV CHIK and 17 (50%) assigned to control vaccine (p=1.00). No serious adverse events related to the vaccine were reported. INTERPRETATION: MV-CHIK showed excellent safety and tolerability and good immunogenicity, independent of pre-existing immunity against the vector. MV-CHIK is a promising candidate vaccine for the prevention of chikungunya fever, an emerging disease of global concern. FUNDING: Themis. PMID- 30409444 TI - Licensed chikungunya virus vaccine: a possibility? PMID- 30409445 TI - Charcot Marie Tooth disease type 2S with late onset diaphragmatic weakness: An atypical case. AB - Immunoglobulin-helicase-MU-binding protein 2 (IGHMBP2) mutations are associated with partial continuum between two extremes of rapidly lethal disorder of spinal muscular atrophy with respiratory distress type 1 (SMARD1), with infantile axonal neuropathy, diaphragmatic weakness and commonly death before 1 year of age, and Charcot-Marie-Tooth disease (CMT) type 2S with slowly progressive weakness and sensory loss but no significant respiratory compromise. We present an atypical case of CMT2S. A 9 month old boy presented with bilateral feet deformities and axonal neuropathy. Genetic testing revealed two heterozygous variants in the IGHMBP2 gene: c.1156 T > C p.(Trp386Arg) in exon 8 and c.2747G > A p.(Cys916Tyr) in exon 14, that were inherited from his father and mother respectively. At 9 years, he developed diaphragmatic weakness, following which he was established on non-invasive ventilation. Our case emphasizes the importance of life long respiratory surveillance for patients with CMT2S and expands the phenotype of this condition. PMID- 30409446 TI - Cone-beam Computed Tomography Compared with Intraoral Radiographic Lesions in Endodontic Outcome Studies: A Systematic Review. AB - INTRODUCTION: The purpose of this systematic review was to compare and quantify endodontic outcome using cone-beam computed tomographic (CBCT) imaging with intraoral periapical radiography. METHODS: Two reviewers independently conducted a comprehensive literature search. The MEDLINE, Embase, Cochrane, and PubMed databases were searched. Additionally, bibliographies, gray literature of all relevant articles, and textbooks were manually searched. There was no disagreement between the 2 reviewers. RESULTS: Six articles met the inclusion criteria with low to moderate risk of bias (good/fair quality). The certainty of evidence was moderate, indicating that the authors are moderately confident that the true effect lies close to that of the estimate of the effect as determined by Grading of Recommendations Assessment Development and Evaluation criteria. The odds ratio of CBCT imaging versus traditional imaging to detect a periapical lesion was 2.04 (95% confidence interval, 1.52-2.73). CONCLUSIONS: Although intraoral radiographs are the imaging modality of choice, when 2-dimensional intraoral radiography is inconclusive, CBCT imaging was reported in this investigation to have twice the odds of detecting a periapical lesion than traditional periapical radiography in endodontic outcome studies. PMID- 30409447 TI - A Comparison of 3 Quantitative Radiographic Measurement Methods for Root Development Measurement in Regenerative Endodontic Procedures. AB - INTRODUCTION: The outcomes of an immature tooth with necrotic pulp treated with regenerative endodontic procedures (REPs) were assessed clinically and radiographically. Root maturation is an important outcome of REPs, and several radiographic measurement methods have been used to measure this. The aim of this study was to compare radiographic measurement methods, measuring root maturation in immature teeth with necrotic pulp treated with REPs. METHODS: Seventy-one radiographic images of REP cases were measured and compared using 3 radiographic measurement methods described by Bose et al (2009), Alobaid et al (2014), and Flake et al (2014). The intraclass correlation coefficient values were evaluated using the intra- and interobserver reliability test and the effect of the stage of root development. RESULTS: The intra- and interobserver reliability for Alobaid et al's method and Flake et al's method were slightly higher than Bose et al's method as quantified by the intraclass correlation coefficient without a significant difference (P > .05). The stage of root development did not affect the reliability of the measurement methods. A high level of agreement was found among the 3 stages of root development for all 3 quantitative radiographic measurement methods. CONCLUSIONS: All 3 quantitative radiographic measurement methods exhibited high agreement regarding reliability. The stage of root development did not have an impact on the reliability of the measurement methods. PMID- 30409448 TI - Apical Papilla Cells Are Capable of Forming a Pulplike Tissue with Odontoblastlike Cells without the Use of Exogenous Growth Factors. AB - INTRODUCTION: Dental pulp is a complex tissue with highly differentiated cells, which makes its reconstruction a challenging task. The apical papilla is an undifferentiated tissue considered as the remnant of the dental papilla that forms the dentin-pulp complex. Aiming to analyze morphologic features of the tissue formed in an in vivo pulp model, we used human apical papilla as a cell source without the use of exogenous growth factors. METHODS: A construct was built using newborn mice molar crowns treated with TrypLE (Fisher Scientific, Loughborough, UK) and EDTA. The crowns were filled with PuraMatrix (Corning Inc, Corning, NY) and a pool population of human apical papilla cells. As a control, we used crowns filled only with PuraMatrix and empty crowns. The constructs were transplanted under severe combined immunodeficient mice kidney capsules. Immunohistochemistry for lamin A, dentin sialophosphoprotein, and dentin matrix protein 1 was performed. RESULTS: Morphologic analysis of all transplanted crowns showed the formation of a loose connective tissue of variable cellularity with the presence of well-formed functional vessels. In the study group, lamin A positive cells represented the majority of cells within the pulp chamber and a few cells in the vessel lining. We also found positivity for dentin sialophosphoprotein and dentin matrix protein 1, an indicator of odontoblast differentiation. CONCLUSIONS: In our study model, human transplanted apical papilla cells mixed with the host cells and formed a vascularized viable tissue, and these cells were able to differentiate into odontoblastlike cells without the use of exogenous growth factors. PMID- 30409449 TI - Enhanced Capability of Bone Morphogenetic Protein 2-loaded Mesoporous Calcium Silicate Scaffolds to Induce Odontogenic Differentiation of Human Dental Pulp Cells. AB - INTRODUCTION: Calcium silicate bioceramics have been broadly used as reparative or grafting materials with good bioactivity and biocompatibility in dental application. It has been shown that applying a mesoporous process to calcium silicate gives it great potential as a controlled drug delivery system. METHODS: The aim of this study was to investigate a novel osteoinductive scaffold by loading bone morphogenetic protein 2 (BMP-2) to mesoporous calcium silicate (MesoCS) and fabricating it as 3-dimensional scaffolds using fused deposition modeling combined with polycaprolactone. RESULTS: The MesoCS/BMP-2 scaffold showed similar patterns to that of a calcium silicate scaffold in releasing calcium and silicon ions in a simulated body fluid (SBF) immersion test for 7 days, but BMP-2 continued releasing from the MesoCS/BMP-2 scaffold significantly more than the CS scaffold from 48 hours to 7 days. Adhesion and proliferation of human dental pulp cells cultured on a MesoCS/BMP-2 scaffold were also more significant than scaffolds without BMP-2 or mesoporous as well as the results of the test on alkaline phosphatase activity. CONCLUSIONS: The results support that the novel 3-dimensional-printed MesoCS scaffold performed well as BMP-2 delivery system and would be an ideal odontoinductive biomaterial in regenerative endodontics. PMID- 30409450 TI - Cyclic Fatigue Resistance of One Curve, 2Shape, ProFile Vortex, Vortex Blue, and RaCe Nickel-Titanium Rotary Instruments in Single and Double Curvature Canals. AB - INTRODUCTION: The aim of this study was to evaluate and compare the resistance to cyclic fatigue of the new One Curve (OC) instrument in double (S-shaped) and single curvature canals compared with other nickel-titanium rotary instruments. METHODS: Size 25/.06 of OC, 2Shape (TS), Vortex Blue (VB), ProFile Vortex (PV), and RaCe (RC) instruments were tested inside artificial canals with a single curvature (60 degrees curvature, 5 mm radius) and double curvature (coronal curve, 60 degrees curvature, 5 mm radius; and apical curve, 70 degrees curvature and 2 mm radius) while immersed in saline at 37 degrees C +/- 1 degrees C. The number of cycles to failure (NCF) was calculated, and the fracture surface was examined by using a scanning electron microscope. The data of NCF and fragment length were analyzed by using one-way analysis of variance and Tukey post hoc tests. The t test was performed between the data of fragment length in different curvatures. The level of significance was set at P < .05. RESULTS: The VB instrument had a significantly higher NCF compared with the other instruments in double (S-shaped) and single curvature canals (P < .05). There was no significant difference between OC and TS in the NCF in single, apical, and coronal double curvature canals (P > .05). The lowest NCF values were recorded for RC instrument in all curvatures (P < .05). CONCLUSIONS: The fatigue resistance of VB was greater than that of other instruments. OC and TS instruments displayed superior cyclic fatigue resistance than PV and RC instruments. PMID- 30409451 TI - Early life exposure to particulate matter air pollution (PM1, PM2.5 and PM10) and autism in Shanghai, China: A case-control study. AB - BACKGROUND: The evidence for adverse effects of ambient particulate matter (PM) pollution on mental health is limited. Studies in Western countries suggested higher risk of autism spectrum disorder (ASD) associated with PM air pollution, but no such study has been done in developing countries. METHODS: A case-control study was performed in Shanghai with a multi-stage random sampling design. Children's exposures to PM1, PM2.5 and PM10 (particulate matter with aerodynamic diameter < 1 MUm, < 2.5 MUm and < 10 MUm, respectively) during the first three years after birth were estimated with satellite remote sensing data. Conditional logistic regression was used to examine the PM-ASD association. RESULTS: In total, 124 ASD cases and 1240 healthy controls were included in this study. The median levels of PM1, PM2.5 and PM10 exposures during the first three years of life were 48.8 MUg/m3, 66.2 MUg/m3 and 95.4 MUg/m3, respectively, and the interquartile range (IQR) for these three pollutants were 4.8 MUg/m3, 3.4 MUg/m3 and 4.9 MUg/m3, respectively. The adjusted odds ratios (and 95% confidence intervals) of ASD associated with an IQR increase for PM1, PM2.5 and PM10 were 1.86 (1.09, 3.17), 1.78 (1.14, 2.76) and 1.68 (1.09, 2.59), respectively. Higher ORs of ASD associated with PM pollution were observed in the second and the third year after birth. CONCLUSIONS: Exposures to PM1, PM2.5 and PM10 during the first three years of life were associated with the increased risk of ASD and there appeared to be stronger effects of ambient PM pollution on ASD in the second and the third years after birth. PMID- 30409452 TI - Ultrastructural immunolocalization of telomerase and hyaluronate in migrating keratinocytes in a case of oro-pharyngeal squamous cancer. AB - The ultrastructural immunolocalization of telomerase and hyaluronate has been studied in a case of oropharyngeal squamous carcinoma. Immunofluorescence shows that telomerase immunolabeling is present in the cytoplasm and in nuclei of some keratinocytes during their migration into the underlying connective tissue. The electron microscope shows that the nuclear localization of telomerase mainly occurs in the large nucleoli and in likely Cajal bodies, the sites of assembling and maturation of proteins forming the telomerase complex. Aside ribosomes, the nucleolus has a role in the biosynthesis of this reverse transcriptase during cell proliferation in normal tissues and in tumors. The cytoplasmic labeling for telomerase is frequently associated with an irregular network of keratin bundles but the significance of this observation is unclear. Hyaluronate, detected through ultrastructural immunolocalization of a hyaluronate binding protein, is abundant mostly along the cell membrane of the detaching basal keratinocytes during epithelial mesenchymal transition. A coat of hyaluronate surrounds the free keratinocytes of the squamous epithelium and is present around the connective cells present underneath. The study supports the hypothesis that hyaluronate forms a pathway along which epithelial cells can migrate during epidermal mesenchymal transition and may also shield cancer cells from immune cells. PMID- 30409453 TI - Experimental peri-implant mucositis around titanium and zirconia implants in comparison to a natural tooth: part 1-host-derived immunological parameters. AB - The purpose of this study was to assess host-derived parameters around dental zirconia and titanium implants and natural teeth during the occurrence of mucositis. After 4 weeks of perfect oral hygiene, 16 clinically profiled patients were asked to refrain from oral hygiene for 2 weeks, resulting in experimental plaque accumulation. This was followed by 4 weeks of perfect oral hygiene to reverse the inflammation. Immunological samples were analyzed for interleukin 6 (IL-6), tumour necrosis factor alpha (TNF-alpha), and interleukin 1beta (IL 1beta). Immunological parameters were measured each week, starting at week 4 (session 2) and ending at week 10 (session 8). There were significant differences in IL-6 between the groups (zirconia vs. tooth and titanium vs. tooth), with unfavourable values for the tooth unit (P<0.05). After reinstitution of oral hygiene, there was a significant increase in TNF-alpha values for the tooth but not for the zirconia and titanium implants. There were significant differences in IL-1beta between the groups (zirconia vs. titanium and titanium vs. tooth), with higher IL-1beta levels around titanium implants (P<0.05). The soft tissue around titanium implants developed a stronger inflammatory response to experimental plaque accumulation in terms of IL-1beta values, whereas the teeth presented an increase in IL-6 and TNF-alpha values. PMID- 30409454 TI - An assessment and comparison of nasolabial aesthetics in bilateral clefts using the anatomical subunit-based scale: a nasoalveolar moulding versus non nasoalveolar moulding study. AB - Nasoalveolar moulding is a presurgical orthopaedic technique used to improve the outcomes of bilateral clefts. However, the lack of a validated scale tailored to bilateral clefts makes it difficult to quantify the merits of nasoalveolar moulding and compare it to other techniques. In this study, a recently published anatomical subunit scale was used to evaluate and compare the early effects of nasoalveolar moulding. Two groups of similarly treated bilateral cleft patients were included: one in which patients underwent presurgical nasoalveolar moulding and one in which they did not. The nasolabial aesthetics were evaluated on two dimensional photographs at 6 months post cheiloplasty. Cupid's bow, vermilion symmetry, vermilion notching, premaxillary show at rest, scar aesthetics, columella height, columella height, and bialar width were all significantly better in the nasoalveolar moulding group. Using the new scale, it was found that nasolabial aesthetics at 6 months post cheiloplasty were significantly better in patients who had undergone nasoalveolar moulding in infancy. PMID- 30409455 TI - Acoustic Comparison of Lower and Higher Belt Ranges in Professional Broadway Actresses. AB - PURPOSE: Current research on the female belt voice has generally been limited to the range of C5, which is not representative of the current requirements on Broadway. Additionally, much belt research uses voice teachers or college students. The goal of this study was to acoustically examine both higher and lower belt ranges in 10 women who have performed belt roles on Broadway during the last decade. METHOD: We analyzed the long-term average spectrum of the middle stable portion of three belted pitches, one from a lower, more traditional belt song and two from a higher, more contemporary belt song. The dB levels of the first three peaks in the long-term average spectrum corresponding to the first three harmonics were extracted and compared across tasks. Age, professional roles played on Broadway, and self-perceived belt strategy were obtained via interview to find potential unifying factors in resonance strategies. RESULTS: Overall, the dB level of the peaks closest to the second and third harmonics were higher than the peak close to the fundamental frequency. The difference between peaks was statistically greater in the lower belt compared to both higher belt tasks, indicating these singers relied more on a single harmonic in the lower belt range than the higher belt range. In the higher belt range, there was less variability between peaks. No patterns emerged between resonance strategies and demographic information. CONCLUSIONS: Elite female belters use varying resonance strategies to create commercially viable belt sounds in different belt ranges. PMID- 30409456 TI - Tenascin-C protects against acute kidney injury by recruiting Wnt ligands. AB - The development of acute kidney injury (AKI) is a complex process involving tubular, inflammatory, and vascular components, but less is known about the role of the interstitial microenvironment. We have previously shown that the extracellular matrix glycoprotein tenascin-C (TNC) is induced in fibrotic kidneys. In mouse models of AKI induced by ischemia-reperfusion injury (IRI) or cisplatin, TNC was induced de novo in the injured sites and localized to the renal interstitium. The circulating level of TNC protein was also elevated in AKI patients after cardiac surgery. Knockdown of TNC by shRNA in vivo aggravated AKI after ischemic or toxic injury. This effect was associated with reduced renal beta-catenin expression, suggesting an impact on Wnt signaling. In vitro, TNC protected tubular epithelial cells against apoptosis and augmented Wnt1-mediated beta-catenin activation. Co-immunoprecipitation revealed that TNC physically interacts with Wnt ligands. Furthermore, a TNC-enriched kidney tissue scaffold prepared from IRI mice was able to recruit and concentrate Wnt ligands from the surrounding milieu ex vivo. The ability to recruit Wnt ligands in this ex vivo model diminished after TNC depletion. These studies indicate that TNC is specifically induced at sites of injury and recruits Wnt ligands, thereby creating a favorable microenvironment for tubular repair and regeneration after AKI. PMID- 30409457 TI - Factors Related to Long Term Motor, Behavioral, and Scholastic Outcome in Children with Acute Disseminated Encephalomyelitis. AB - OBJECTIVE: To study the long-term outcome of Acute disseminated encephalomyelitis (ADEM). METHODS: A retrospective cohort study was done among children diagnosed with ADEM (fulfilling IPMSSG criteria). Major outcome variables were motor deficit, scholastic underperformance and behavioral abnormality. RESULTS: The inclusion criteria were fulfilled by 102 children. Three died in hospital. The follow up ranged from 1-10 years (median 4 years). Motor deficit was seen in 17(17.2%), attention deficit in 25(25.3%), behavioral abnormality in 13(13.1%), persistent seizures in 7(7%) and poor learning skills in 22(22.2%). Recurrence of demyelination was seen in 7 (7.1%). Two of them had a recurrent demyelinating disorder (a chronic relapsing demyelinating disorder) that could not be classified as Multiple sclerosis (MS), two had ADEM with sequential optic neuritis and 3 had multiphasic ADEM. At follow-up, mean (SD) modified Rankin Scale (mRS) score was 0.556 (1.36) and Expanded disability status scale score was 1.71(2.22). On multivariate analysis, mRS score at discharge (p<0.01) and thalamic lesions (MRI) (p<0.01) were associated with motor sequelae; poor learning skills with ADEM with concomitant polyneuropathy (p<0.02) and behavioral abnormality with tumefactive demyelination (p<0.02). CONCLUSIONS: Children who had ADEM may have motor or cognitive sequelae, seizures or recurrent demyelinating events on follow-up. We have identified a few risk factors for these sequelae. Factors that affected outcome on discharge from hospital did not affect chances of having long-term sequelae. On follow-up, none of the children fulfilled the diagnostic criteria for MS, suggesting that the chance of conversion of ADEM to MS is less likely. PMID- 30409458 TI - Incidence of Epilepsy and Associated Risk Factors in Perinatal Ischemic Stroke Survivors. AB - INTRODUCTION: Epilepsy is a serious and often lifelong consequence of perinatal arterial ischemic stroke (PAIS). Variable incidences and risk factors for long term epilepsy in PAIS have been reported. To determine the incidence of epilepsy in PAIS survivors and report factors associated with the risk of developing epilepsy, a meta-analysis and systematic review of prior publications was performed. METHODS: We examined studies on perinatal or neonatal patients (<=28 days of life) with arterial ischemic strokes in which the development of epilepsy was reported. EMBASE and MEDLINE/PubMed databases were systematically searched in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses. RESULTS: A meta-analysis of 10 studies revealed a summary incidence of epilepsy in PAIS patients of 27.2% (95% confidence interval 16.6% to 41.4%) over a mean study duration of 10.4 years (range 1.5 to 17). More recent studies generally reported a lower epilepsy incidence. A systematic review identified seven possible risk factors for epilepsy in PAIS patients: hippocampal volume reduction, infarct on prenatal ultrasound, a modified Alberta Stroke Program Early Computed Tomography score >=9, family history of seizures, cerebral palsy, and initial presentation with cognitive impairment or seizures. CONCLUSIONS: About a third of children with PAIS will develop epilepsy. While seven possible risk factors have been reported, further research is warranted to confirm the strength of their association with the development of epilepsy. PMID- 30409459 TI - Diagnostic histochemistry in hepatic pathology. AB - Histochemistry has an important, continuing role in the current assessment of hepatic biopsies and resection specimens. The evaluation of connective tissue elements in the liver can be accomplished with such methods as the Masson trichrome, Snook reticulin, Vierhoff van Gieson, orcein, and Victoria blue stains. The results contribute to the diagnosis of acute and chronic hepatitis, submassive necrosis, venous outflow obstruction, steatohepatitis, and cirrhosis. Fat stains done on frozen sections of liver tissue are routinely performed in the evaluation of donor liver allograft biopsies. Iron stains such as Perls' method and the Prussian blue technique contribute to the recognition of hemochromatosis and hemosiderosis. The rhodanine, orcein, and Timm stains for copper are used in the characterization of chronic cholestatic liver disease and Wilson's disease. Labeling of carbohydrate-based moieties in various disorders is accomplished with the digested and undigested periodic acid-Schiff method, and Congo red or crystal violet stains can be employed to detect amyloid deposition. Lastly, evaluations of the thickness of the cell plates and continuity of the reticulin framework, as seen with the Snook reticulin stain, can contribute to the diagnostic separation of benign from malignant hepatocellular neoplasms. PMID- 30409461 TI - Coagulopathic hemorrhage with use of synthetic cannabinoids. AB - Synthetic cannabinoids contain many different chemicals and compounds, which pose new health risks to the population using these drugs. In May of 2018 the Center for Disease Control issued a health alert providing information on a multistate outbreak of coagulopathy from exposure to synthetic cannabinoid products containing a Vitamin K-dependent antagonistic agent such as brodifacoum. Recognizing signs, symptoms and imaging findings related to this outbreak is essential for clinicians caring for patients with a history or suspicion of using synthetic cannabinoids. To our knowledge, there are no studies that report the imaging findings demonstrating the coagulopathic complications associated with these synthetic compounds. PMID- 30409460 TI - Vitamin D status in children with epilepsy treated with levetiracetam monotherapy. PMID- 30409462 TI - Scan the lung: Point-of-care ultrasound of a pulmonary consolidation with loculated pleural effusion. AB - Thoracic ultrasound has become an increasingly valuable tool in the evaluation of critically ill patients in the emergency department (ED). The utility of point-of care ultrasound (POCUS) to identify suspected pneumothorax, pulmonary edema, pleural effusion and pneumonia has been well established (Pagano et al.; Brogi et al.; Cortellaro et al.; Irwin and Cook [1-4]). The 2014 American College of Emergency Physicians (ACEP) Ultrasound Imaging Compendium included lung and pleural ultrasound with the primary indication of identifying pneumothorax and pleural effusion as part of the core POCUS indications for all emergency physicians [5]. We present a unique case in which a patient presented to the ED in respiratory distress. Portable chest X-ray demonstrated near complete opacification of his right hemithorax. POCUS demonstrated a large right sided loculated pleural effusion with associated septations and surrounding consolidation suggestive of a parapneumonic effusion. PMID- 30409463 TI - Advanced liver fibrosis and care continuum in emergency department patients with chronic hepatitis C. AB - BACKGROUND: FIB-4, a non-invasive serum fibrosis index (which includes age, ALT, AST, and platelet count), is frequently available during ED visits. Our objective was to define 1-year HCV-related care outcomes of ED patients with known HCV, for the overall group, and both those with and without advanced fibrosis. METHODS: As part of an ongoing HCV linkage-to-care (LTC) program, HCV-infected ED patients were identified retrospectively via medical record review. Components of FIB-4 were abstracted, and patients with an FIB-4 > 3.25 were classified with advanced fibrosis and characterized with regards to downstream HCV care continuum outcomes at one-year after enrollment. RESULTS: Of the 113 patients with known HCV, 38 (33.6%) had advanced fibrosis. One-year outcomes along the HCV care continuum after ED encounter for 'all' 113, 75 'without advanced fibrosis', and 38 'advanced fibrosis' patients, respectively, were as follows: agreeing to be linked to care [106 (93.8%), 72 (96.0%), 34 (89.5%)]; LTC [38 (33.6%), 21 (28.0%), 17 (44.7%)]; treatment initiation among those linked [16 (42.1%), 9 (42.9%), 7 (41.2%)]; sustained virologic response 4 weeks post-treatment among those treated [15 (93.8%), 9 (100.0%), 6 (85.7%)]; documented all-cause mortality [10 (8.8%), 3 (4.0%), 7 (18.4%)]. Notably, 70% of those who died had advanced fibrosis. For those with advanced liver fibrosis, all-cause mortality was significantly higher, than those without (18.4% versus 4.0%, p = 0.030). CONCLUSIONS: Over one-third of HCV-infected ED patients have advanced liver fibrosis, incomplete LTC, and higher mortality, suggesting this readily-available FIB-4 might be used to prioritize LTC services for those with advanced fibrosis. PMID- 30409464 TI - Ex situ machine perfusion strategies in liver transplantation. PMID- 30409465 TI - Anti-sperm antibodies detection by a modified MAR test: Towards a better definition of its indications. AB - RESEARCH QUESTION: Anti-sperm antibodies (ASA) have been shown to reduce male fertility but consensus about the precise situations in which tests should be carried out are lacking. In infertility investigations, should the mixed antiglobulin reaction (MAR) test be a first-line test? Should it be carried out systematically before assisted reproductive technology (ART)? What are the risk factors for ASA? DESIGN: All infertile patients (n = 1364) were tested with SpermMar (modified MAR test) between July 2013 and June 2017. Intra-patient variability of the MAR test was also assesed by comparing two tests within the same year in selected patients (n = 101). RESULTS: The main factor that influenced the percentage of ASA was the presence or absence of sperm agglutination. In the presence of agglutinations, 27 out of 72 (37.5%) patients were positive for ASA compared with 33 out of 1292 (2.6%) in the absence of agglutinations (P < 0.0001). When one risk factor was present (spontaneous sperm agglutination, history of scrotal trauma or inguinal surgery), 33 out of 179 (18.44%) tests were positive for ASA (>=50% coated spermatozoa), whereas only 27 out of 1242 (2.2%) were positive when no risk factor was present (P < 0.0001). CONCLUSIONS: ASA detection should not be systematically recommended in investigations of fertility status and before ART but reserved for when sperm agglutination is found during conventional sperm examination, or if the patient has a history of scrotal trauma or has undergone inguinal surgery. PMID- 30409466 TI - [Second allogeneic hematopoietic stem cell transplant: Guidelines from the francophone Society of bone marrow transplantation and cellular therapy (SFGM TC)]. AB - Disease recurrence and graft dysfunction after allogeneic hematopoietic stem cell transplantation (allo-HSCT) currently remain among the major causes of treatment failure in malignant and non-malignant hematological diseases. A second allo-HSCT is a valuable therapeutic option to salvage those situations. During the 8th annual harmonization workshops of the french Society of bone marrow transplantation and cellular therapy (SFGM-TC), a designated working group reviewed the literature in order to elaborate unified guidelines on feasibility, indications, donor choice and conditioning in the case of a second allo-HSCT. In case of relapse, a second allo-HSCT with reduced intensity or non-myeloablative conditioning is a reasonable option, particularly in patients with a good performance status (Karnofsky/Lansky>80%), low co-morbidity score (EBMT score<=3), a longer remission duration after the first allo-HSCT (>6 months), and who present low disease burden at the time of second allo-HSCT. Matched related donors tend to be associated with better outcomes. In the presence of graft dysfunction (primary and secondary graft rejection), an immunoablative conditioning regimen is recommended. A donor change remains a valid option, especially in the absence of graft-versus-host disease after the first allo-HSCT. PMID- 30409467 TI - [Epidemiology of microsatellite instability across solid neoplasms]. AB - Microsatellite instability (MSI) is a predictive biomarker for the efficacy of immune checkpoint inhibitors, regardless of the tumor type. While clinical characteristics of MSI cancer patients have been largely described in tumor localizations frequently associated with this genetic phenotype (i.e. colorectal cancer, endometrial cancer), it remains poorly characterized in other neoplasms. Pan-tumor high-throughput genome sequence analyses have contributed to the broadening of knowledge about the landscape of MSI. This review aims at synthetizing the literature concerning the frequency of MSI status in solid cancers, according to the cancer stage and the hereditary or sporadic origin of the mismatch repair deficiency. We then check for other cancers frequently associated with MSI and describe the clinical and pathological characteristics that should suggest a MSI phenotype. PMID- 30409468 TI - Effect of inspiratory rise time on sputum movement during ventilator hyperinflation in a test lung model. AB - OBJECTIVES: Physiotherapists may use ventilator hyperinflation to enhance secretion clearance for intubated patients. This study investigated the effects of altering percentage inspiratory rise time (IRT) on sputum movement, ratio of peak inspiratory to expiratory flow rate (PIF:PEF ratio) and net peak expiratory flow (PEF) during ventilator hyperinflation in a test lung model. DESIGN: Laboratory-based bench study. INTERVENTIONS: Simulated sputum (two viscosities) was inserted into clean, clear tubing and connected between a ventilator and a resuscitation bag. Thirty-six ventilator hyperinflation breaths were applied for each 5% incremental increase in IRT between 0% and 20%. MAIN OUTCOME MEASURES: The primary outcome was sputum displacement (cm). Secondary outcomes included PIF:PEF ratio and net PEF. RESULTS: Significant cephalad sputum movement of 2.42cm (1.59 to 3.94) occurred with IRT between 5% and 20%, compared with caudad movement of 0.53 cm (0.31 to 1.53) at 0% IRT (median sputum movement difference 3.7cm, 95% confidence interval 2.2 to 4.8, P<0.001). Incremental increases in IRT percentage produced linear enhancements in PIF:PEF ratio and net PEF for both sputum concentrations (P<0.001). However, once the critical threshold for PIF:PEF ratio of 0.9 was achieved, the distance of sputum movement remained consistent for all IRT values exceeding 5%. CONCLUSIONS: Significant increases in sputum movement occurred when IRT percentage was lengthened to achieve the optimal PIF:PEF ratio, irrespective of sputum viscosity. This provides a theoretical rationale for therapists to consider this technique when treating mechanically ventilated patients. As no additional sputum movement was seen beyond the critical PIF:PEF ratio threshold, a low IRT percentage may potentially be used to achieve effective sputum movement. PMID- 30409469 TI - Coeliac disease under a microscope: Histological diagnostic features and confounding factors. AB - Coeliac disease (CD) and gluten-related disorders represent an important cornerstone of the daily practice of gastroenterologists, endoscopists and dedicated histopathologists. Despite the knowledge of clinical, serological and histological typical lesions, there are some conditions to consider for differential diagnosis. From the first description of histology of CD, several studies were conducted to define similar findings suggestive for microscopic enteritis. Considering the establishment of early precursor lesions, the imbalance of gut microbiota is another point still requiring a detailed definition. This review assesses the importance of a right overview in case of suspected gluten-related disorders and the several conditions mimicking a similar histology. PMID- 30409470 TI - Medical Ultrasound Disinfection and Hygiene Practices: WFUMB Global Survey Results. AB - As ultrasound technology rapidly evolves and is used more frequently in every area of medical diagnosis and treatment, it may be overlooked as a potential vector in the transmission of a health care-associated infection. A survey on disinfection and hygiene practice in medical ultrasound was disseminated via the World Federation for Ultrasound in Medicine and Biology (WFUMB) to its six member federations and associated ultrasound societies globally. One thousand twenty nine responses were obtained across a broad range of ultrasound practitioners. A total of 76% of respondents used transducer covers every time to scan open wounds and 71% when blood and bodily fluids were present or for an interventional procedure. Approved high-level disinfectants are not always used, even when blood comes into contact with the transducer or after endocavity scans. Alcohol-based wipes were used by many respondents to clean both external transducers and endocavity transducers. Open-ended responses indicated that a large caseload hindered the time required for cleaning and that access to clear guidelines would be beneficial. Global survey results indicate that some users do not comply with disinfection practice, and there is a gap in knowledge on basic infection prevention and control education within the ultrasound unit. As the infectious status of a patient is not often disclosed prior to an ultrasound examination, training in suitable protocols for the cleaning and disinfection of ultrasound equipment is imperative to mitigate the risk of potential infection. PMID- 30409472 TI - Operative treatment of geriatric ankle fractures with conventional or locking plates. A retrospective case-control study. AB - BACKGROUND: The incidence of geriatric ankle fractures continues to rise due to demographic changes. While locking plates have become standard implants for injuries of other body regions, clinical studies on their use for geriatric ankle fractures are rare. METHODS: Therefore, a retrospective case-control study, including 333 patients with a mean age of 73.5 years was performed. 263 patients underwent operative fixation with one- third tubular plates and 70 were treated with locking plates. Early outcomes and complication rates of locking plates as compared with conventional one- third tubular plates are described. RESULTS: In the present study, patients treated with locking plates were older and suffered from more severe fracture patterns. In addition, these patients had more severe comorbidities. Treatment with conventional or locking plate fixation resulted in a comparable complication and revision rate. A matched pair analysis showed significantly more complications and required revision surgeries and a trend towards more implant failures in the group that underwent conventional plating. CONCLUSIONS: Therefore, we conclude that precontoured locking plates represent an appropriate treatment option for severe ankle fractures in patients suffering from relevant co-morbidities. Prospective randomized trials are warranted to prove superiority of locking plates for treatment of geriatric ankle fractures. Level 3: Retrospective case- control study. PMID- 30409471 TI - Primary Application of Micro-Flow Imaging Technology in the Diagnosis of Hepatic Tumors. AB - The purpose of the study was to evaluate the vascular architecture of focal liver lesions with the newly released non-contrast micro-flow imaging (MFI) technique. Eighty patients with 80 hepatic tumors were enrolled in this study. The richness of displayed blood flow was first compared with color Doppler flow imaging using grades according to Adler's method. The results indicated that MFI outperformed color Doppler flow imaging with a statistically significant difference (p <0.0001). With the enhanced position in arterial phase of contrast-enhanced ultrasound imaging as the ground truth, the displayed blood flow distribution within tumors in MFI was further evaluated. The coincidence rate between MFI and contrast-enhanced ultrasound was 73.75% (59/80), which was higher than that of color Doppler flow imaging (52.5%, 42/80) (p < 0.0001). Moreover, for the five cases of focal nodular hyperplasia, MFI clearly revealed the spoke-wheel or radiating intra-tumoral vasculature, a finding specific to the diagnosis of focal nodular hyperplasia. PMID- 30409473 TI - Quantitative assessment of 4D hemodynamics in cerebral aneurysms using proper orthogonal decomposition. AB - BACKGROUND AND PURPOSE: The comparison of different time-varying three dimensional hemodynamic data (4D) is a formidable task. The purpose of this study is to investigate the potential of the proper orthogonal decomposition (POD) for a quantitative assessment. METHODS: The complex spatial-temporal flow information was analyzed using proper orthogonal decomposition to reduce the complexity of the system. PC-MRI blood flow measurements and computational fluid dynamic simulations of two subject-specific IAs were used to compare the different flow modalities. The concept of Modal Assurance Criterion (MAC) provided a further detailed objective characterization of the most energetic individual modes. RESULTS: The most energetic flow modes were qualitatively compared by visual inspection. The distribution of the kinetic energy on the modes was used to quantitatively compare pulsatile flow data, where the most energetic mode was associated to approximately 90% of the total kinetic energy. This distribution was incorporated in a single measure, termed spectral entropy, showing good agreement especially for Case 1. CONCLUSION: The proposed quantitative POD-based technique could be a valuable tool to reduce the complexity of the time-dependent hemodynamic data and to facilitate an easy comparison of 4D flows, e.g., for validation purposes. PMID- 30409474 TI - Opioid-Sparing Analgesia for Sternotomy: Do Surgical Site Continuous Local Anesthetics Actually Work? PMID- 30409475 TI - Transvenous Biopsy in the Diagnosis of Intravascular or Perivascular Neoplasm: A Single-Center Retrospective Analysis of 36 Patients. AB - Between September 2008 and August 2017, 36 patients (mean age 56 y; range, 30-89 y) underwent transvenous biopsy of suspected tumor thrombus or perivascular tumor. Intravascular biopsy was pursued because of inaccessible percutaneous access in 9 patients (25%) and as part of a planned revascularization procedure in 27 patients (75%). Histopathologic results showed malignancy in 26 patients (72%) and benign etiologies in 10 patients (28%). No patients required repeat biopsy. There were no complications related to the biopsy procedure. The present series suggests that transvenous biopsy is a safe and accurate method of intravascular and perivascular mass tissue sampling. PMID- 30409476 TI - Transverse testicular ectopia discovered following reduction of an inguinal hernia. AB - Transverse testicular ectopia is a rare condition in which both testicles occupy a single hemiscrotum. The aberrant positioning may lead to vascular compromise or impaired temperature regulation, which elevate the risks for torsion, infertility and testicular cancer. Definitive therapy consists of orchiectomy or orchiopexy. We report a case of a 10-month-old boy with an incarcerated inguinal hernia who was discovered to have transverse testicular ectopia following hernia reduction. The patient was treated with herniorrhaphy and open transseptal orchiopexy. PMID- 30409478 TI - Rubber tourniquet technique: A simple, safe, and cost-effective method of hepatic resection in neonates and infants. AB - BACKGROUND: Despite the improvements in patient care, understanding of surgical anatomy of liver and surgical techniques, liver resection is a high-risk procedure specifically in infants and neonates; whose blood volume is limited (80 ml/kg). This report shares the experience of hepatic resection with "Rubber tourniquet technique" in patients less than 6-months of age. METHODS: Hepatic resection in a 4-month-old pair of Conjoined twins with shared liver and a 3-day old baby with large Congenital Hepatoblastoma was performed using Penrose rubber drain as a tourniquet around the liver parenchyma to reduce blood loss. RESULTS: Blood loss was minimal (<20CC) and all the three babies survived the procedure without complications. CONCLUSION: Rubber tourniquet technique is simple, safe and cost-effective for liver resections in neonates and infants with hepatic lesions and separation of conjoined twins with shared liver and it can easily be employed in resource constraint settings. PMID- 30409477 TI - Primary placement of a skin-level Cecostomy Tube for Antegrade Colonic Enema Administration Using a Modification of the Laparoscopic-Assisted Percutaneous Endoscopic Cecostomy (LAPEC). AB - PURPOSE: Children failing medical management for severe constipation and/or fecal incontinence may undergo surgical intervention for antegrade enema administration. We present a modification of the laparoscopic-assisted percutaneous endoscopic cecostomy (LAPEC) procedure that allows primary placement of a skin-level device. METHODS: A single-institution retrospective review was performed from 2009 to 2015. In the modified technique the colonoscope is advanced to the cecum, cecal suspension sutures are placed under laparoscopic visualization, and percutaneous needle puncture of the cecum is performed under direct laparoscopic and endoscopic visualization. A skin-level cecostomy tube is then placed over a guide wire. Patient characteristics and 30-day results were analyzed by Fisher's exact test. RESULTS: Fifty-two patients underwent attempted LAPEC. Successful LAPEC using both laparoscopic and endoscopic guidance was achieved in 46 (88.5%). A MIC-KEY device was placed in 38. Corflo PEG tube placement was necessary in 14 due to high BMI (mean 28.4). Colonoscopy failed to reach the cecum in 6 and laparoscopy alone was utilized to achieve successful tube placement. Cecostomy site infections occurred in 3 (5.8%), only in those undergoing PEG placement using a pull technique (p < 0.05). CONCLUSION: Primary placement of a skin-level device was successful in the majority of patients undergoing cecostomy tube placement for bowel management utilizing antegrade colonic enemas. This technique avoids a second anesthesia for tube conversion. Visualization via colonoscopy with the use of cecal suspension sutures is recommended. High BMI necessitates initial placement of a PEG tube and complications exclusively occurred in this group. TYPE OF STUDY: Clinical. LEVEL OF EVIDENCE: IV Case series study. PMID- 30409479 TI - Digestive side-effects with teriflunomide: Thoughts on lactose. AB - INTRODUCTION: Teriflunomide, a novel, orally bioavailable, active metabolite of leflunomide, has anti-inflammatory activity. It is prescribed as a first-line treatment for relapsing-remitting multiple sclerosis (RRMS) at a dose of one 14mg tablet per day. Common adverse reactions observed in placebo-controlled trials with a frequency>=10% and a rate twofold or more than reported with placebo, include digestive disorders. As teriflunomide tablets also contain lactose, the official recommendations are clear about not prescribing this drug to patients with known lactose intolerance and those with rare hereditary problems due to galactose intolerance. METHODS: Our study systematically collected, from our MS clinical practice, all adverse events presenting in the first 100 patients treated with teriflunomide. All of these patients were systematically asked if they were known to have lactose intolerance. RESULTS: None of these 100 patients declared having known, documented lactose intolerance. Yet, after starting teriflunomide, 14 reported mild-to-moderate diarrhea, which resolved within a month, but four of these patients continued to have daily diarrhea (grade 2 WHO classification), prompting us to perform a lactose breath test (LBT) for malabsorption. All four tested positive and were therefore diagnosed with lactose intolerance. Digestive symptoms were resolved with probiotics, and teriflunomide was maintained in three cases; the fourth patient decided, despite the adverse event being resolved, to stop taking teriflunomide. CONCLUSION: In cases of prolonged digestive side-effects after the introduction of teriflunomide, a lactose-malabsorption breath test should be proposed to confirm the culpability or not of an enzymatic defect in the occurrence of adverse events. PMID- 30409480 TI - O'Sullivan-McLeod syndrome: Unmasking a rare atypical motor neuron disease. AB - Atypical motor neuron disease represents a rare heterogeneous group of neurodegenerative disorders with clinical, genetic and neuroimaging features distinct from those of the classic spinal or bulbar-onset amyotrophic lateral sclerosis (ALS). O'Sullivan-McLeod syndrome represents an extremely rare lower motor neuronopathy with early adult-onset distal amyotrophy and weakness in the upper limbs with asymmetrical involvement. To add to the few case series and epidemiological and genetic studies describing this variant syndrome, our team here presents a series of seven unrelated Brazilian patients with O'Sullivan McLeod syndrome in a detailed review of their clinical, neuroimaging, laboratory and neurophysiological findings. A male-to-female ratio of 2.5 to 1 and a mean age at onset of 34.3years was observed, with a mean time delay of 6.6years between symptom-onset and a definitive diagnosis. A positive family history was observed in one case, yet whole-exome sequencing results were negative. Neuroimaging studies were unremarkable. All cases presented with chronic denervation restricted to cervical myotomes and normal sensory nerve conduction studies. This case series, one of the largest groups of patients with O'Sullivan McLeod syndrome reported in the literature, confirms the sporadic nature of the condition and the difficulties faced in arriving at a definite diagnosis, and also expands the age limit in late adult-onset cases. PMID- 30409481 TI - Aging, Sarcopenia, and Frailty in Chronic Respiratory Diseases. PMID- 30409482 TI - An Unusual Combination of Diffuse Pulmonary Cysts and a Nodule. PMID- 30409483 TI - Changes in the Melting Point of Hybridization Probes Used for Genotyping in Alpha 1 Antitrypsin Deficiency Do Not Always Imply Errors. PMID- 30409484 TI - Calcified Pulmonary Nodules in an Oncological Patient. PMID- 30409485 TI - Overnight Change in Urinary Prostacyclin and Thromboxane in Obstructive Sleep Apnea. PMID- 30409486 TI - Influenza A: New Therapeutic Targets for a Deadly Disease. PMID- 30409487 TI - Chest Wall Seroma Following Surgery for Malignant Pleural Effusion. PMID- 30409488 TI - Alternate Venous Supply and Superior Vena Cava Occlusion in a Patient with Behcet's Disease. PMID- 30409489 TI - Novel treatment options in platinum-sensitive recurrent ovarian cancer: A review. AB - Epithelial ovarian cancer (EOC) is the leading cause of death due to gynecologic malignancy. The majority of advanced stage EOC patients, even those who respond well to frontline therapy, will ultimately recur and succumb to their disease. In platinum-sensitive EOC patients, or those who recur >=6 months from initial diagnosis, treatment of recurrent disease has traditionally consisted of repeat platinum-based chemotherapy. Secondary cytoreduction remains controversial. Due to recent advances in molecularly targeted treatment options, outcomes for advanced stage EOC patients are significantly improving and hold great promise. This review discusses pivotal trials establishing platinum-based combination chemotherapy as the standard of care and addresses the utility of increasing a patient's platinum-free interval. It then discusses the role of anti-angiogenesis therapeutics, specifically bevacizumab, cediranib, and trebananib and their side effects. Lastly, it reviews key trials for the three poly-adenosine diphosphate [ADP]-ribose polymerases (PARP) inhibitors that have been FDA-approved for maintenance therapy in platinum-sensitive recurrent EOC: olaparib, rucaparib, and niraparib. This review concludes with a discussion regarding ongoing and future clinical trials. PMID- 30409491 TI - Association Between the Discrepancy in Self-Reported and Performance-Based Physical Functioning Levels and Risk of Future Falls Among Community-Dwelling Older Adults: The Locomotive Syndrome and Health Outcomes in Aizu Cohort Study (LOHAS). AB - OBJECTIVES: A discrepancy in self-reported and performance-based physical functioning levels is often observed among older adults. We investigated the association of discrepancy in self-reported and performance-based physical functioning levels with risk of future falls among community-dwelling older adults. DESIGN: Prospective cohort study. SETTING: Two communities in Fukushima Prefecture, Japan. PARTICIPANTS: 1379 older adults who took part in the yearly health checkup in both 2009 and 2010. MEASURES: The performance-based and self reported physical functioning levels were evaluated by the Timed Up and Go test and the Short-Form 12 Health Survey (Japanese version) physical functioning subscale, respectively. We divided the participants into 4 groups based on the combinations of low or high performance-based and self-reported physical functioning groups, which were classified by age- and sex-specific reference values. The main outcome was the occurrence of any falls within the 1-year follow up period, assessed using a self-reported questionnaire. RESULTS: A total of 22% of the participants reported the occurrence of a fall during the follow-up period. In multivariable logistic regression analysis, the adjusted odds ratios of the high self-reported and low performance-based, low self-reported and high performance-based, and low self-reported and low performance-based physical functioning groups were 1.10 (95% confidence interval [CI], 0.67-1.82), 1.76 (95% CI, 1.17-2.66), and 1.80 (95% CI, 1.11-2.90), respectively, compared with the high self-reported and high performance-based physical functioning group. CONCLUSIONS: Our findings suggest that the discrepancy as high performance-based but low self-reported physical functioning level is associated with an increased risk of future falls in older adults aged 65-89 years. Clinicians should carefully assess older adults whose subjective perception of their physical functioning capacity is lower than those in similar age and sex groups, even if their actual physical functioning appears to be objectively high. PMID- 30409492 TI - Depression is Associated With Sarcopenia Due to Low Muscle Strength: Results From the ELSA-Brasil Study. AB - OBJECTIVES: To investigate the association of sarcopenia and its defining components with depression in Brazilian middle-aged and older adults. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: This analysis included 5927 participants from the ELSA-Brasil Study second data collection, aged 55 years and older, with complete data for exposure, outcome, and covariates. MEASURES: Muscle mass was evaluated by bioelectrical impedance analysis and muscle strength by hand-grip strength. Sarcopenia was defined according to the Foundation for the National Institutes of Health (FNIH) criteria. Depression was assessed using the Clinical Interview Scheduled Revised (CIS-R). Information on sociodemographic characteristics, lifestyle, and clinical comorbidities were also obtained. RESULTS: The frequencies of sarcopenia, presarcopenia, low muscle mass, low muscle strength, and low muscle strength without loss of muscle mass was 1.9%, 18.8%, 20.7%, 4.8%, and 2.9%, respectively. After adjustment for sociodemographic characteristics, clinical conditions, and lifestyle factors, depression was associated with sarcopenia (odds ratio [OR] = 2.23, 95% confidence interval [CI] = 1.11-4.48, P = .024) and low muscle strength (OR = 1.94, 95% CI = 1.20-3.15, P = .007), but it was not associated with presarcopenia, low muscle mass, and low muscle strength without loss of muscle mass. CONCLUSIONS: Depression is associated with sarcopenia defined by the FNIH criteria mainly because of its association with weakness. Future studies are needed to clarify the temporal relationship between both conditions. PMID- 30409490 TI - Real-world effectiveness of bevacizumab based on AURELIA in platinum-resistant recurrent ovarian cancer (REBECA): A Korean Gynecologic Oncology Group study (KGOG 3041). AB - PURPOSE: To evaluate the effectiveness of bevacizumab with single-agent chemotherapy for platinum-resistant ovarian cancer in a real-world setting. PATIENTS AND METHODS: We enrolled recurrent platinum-resistant ovarian cancer patients from 27 institutions. All had received bevacizumab with single-agent chemotherapy (weekly paclitaxel, pegylated liposomal doxorubicin (PLD), topotecan) between 2015 and 2017 for second- or third-line chemotherapy in routine clinical practice. The primary endpoint was progression-free survival (PFS) and safety. Secondary endpoints included the objective response rate (ORR), PFS2, overall survival, duration of chemotherapy, and reasons for discontinuing chemotherapy. RESULTS: Of 391 patients, 259 (66.2%) received bevacizumab with PLD, 94 (24.0%) with topotecan, and 38 (9.7%) with weekly paclitaxel. The median PFS was 6.1 months with all forms of bevacizumab-containing therapy. Although the cohort with weekly paclitaxel had a better PFS than the PLD cohort (P = 0.028), this finding was not found in patients with a previous platinum-free interval of less than three months. The median duration of therapy was five cycles (range, one to 20 cycles), and 29 patients (7.4%) discontinued treatment because of adverse events from bevacizumab-containing regimens. The PLD cohort had fewer grade >= 3 adverse events than the other regimens (PLD, 35.8%; weekly paclitaxel, 52.6%; topotecan, 51.1%; P = 0.012), especially events of hematologic toxicities. CONCLUSION: In Korean ovarian cancer patients, the safety and effectiveness of chemotherapy with bevacizumab in a real-world setting was consistent with the results from a randomized controlled study. The effectiveness and toxicity profiles varied among the chemotherapy regimens, and this finding should be considered in practice. CLINICAL TRIALS REGISTRATION: NCT03367182. PMID- 30409493 TI - Aggressive Behaviors Among Nursing Home Residents: Association With Dementia and Behavioral Health Disorders. AB - OBJECTIVES: We measured the prevalence and severity of aggressive behaviors (ABs) among nursing home (NH) residents and examined whether individuals with behavioral health disorders were more likely to exhibit aggressive behaviors than others. SETTING AND PARTICIPANTS: The analytical sample included 3,270,713 first Minimum Data Set (MDS) assessments for residents in 15,706 NHs in 2015. MEASURES: Individuals were identified as having (1) behavioral health disorders only (hierarchically categorized as schizophrenia/psychosis, bipolar disorder, personality disorder, substance abuse, depression/anxiety); (2) dementia only; (3) behavioral health disorders and dementia; or (4) neither. The Aggressive Behavior Scale (ABS) measured the degree of aggressive behaviors exhibited, based on 4 MDS items (verbal, physical, other behavioral symptoms, and rejection of care). The ABS scores ranged from 0 to 12 reflecting symptom severity as none (ABS score = 0), mild (ABS score = 1-2), moderate (ABS score = 3-5), and severe (ABS score = 6-12). Bivariate comparisons and multinomial logistic regressions were performed. RESULTS: Residents with behavioral health disorders and dementia had the highest prevalence of ABs (23.1%), followed by dementia only (15.3%), behavioral health disorders only (9.3%), and neither (5.3%). After controlling for individual risk factors and facility covariates, the relative risk of exhibiting severe ABs was 2.47, 5.50, and 9.42 for residents with behavioral health disorders only, dementia only, and behavioral health disorders and dementia, respectively, with a similar pattern for moderate or mild ABs. CONCLUSIONS: Residents with behavioral health disorders were less likely than residents with dementia to exhibit aggressive behaviors in nursing homes. Thus, anecdotally reported concerns that aggressive behaviors are primarily an issue for residents with behavioral health disorders, rather than those with dementia, were not empirically justified. PMID- 30409494 TI - Prevalence and Associated Factors of Sarcopenia in Nursing Home Residents: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To review the prevalence and associated factors of sarcopenia in nursing homes. DESIGN: A systematic review and meta-analysis of published studies in MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials. SETTING: Nursing homes. PARTICIPANTS: Older adults aged >=60 years. MEASUREMENTS: Sarcopenia was defined according to various validated diagnostic criteria, such as the European Working Group on Sarcopenia in Older People (EWGSOP) criteria and skeletal muscle index (SMI). We performed meta-analyses with random effects models to calculate the pooled prevalence of sarcopenia. The risk of bias of the included studies was evaluated using a 10-item tool explicitly designed for prevalence studies. RESULTS: We included 16 studies with a total of 3585 participants from 129 nursing homes. The included studies were of low to moderate risk of bias. The pooled prevalences of EWGSOP-defined sarcopenia and SMI-defined sarcopenia were 41% [95% confidence interval (CI) 32%-51%, 12 studies, 2685 cases] and 59% (95% CI 24%-93%, 3 studies, 643 cases), respectively. The pooled prevalences of EWGSOP-defined sarcopenia in women and men were 46% (8 studies, 1332 cases) and 43% (8 studies, 739 cases), respectively. The pooled data showed that malnutrition was an independent associated factor of EWGSOP-defined sarcopenia (odds ratio [OR] 1.74, 95% CI 1.36-2.24; 3 studies, 718 cases), but malnutrition risk (OR 1.01, 95% CI 0.53-1.94; 2 studies, 379 cases) and female gender were not (OR 1.14, 95% CI 0.11-11.66; 3 studies, 827 cases). The association between age and body mass index with sarcopenia was inconsistent across studies. Limited evidence indicated that smoking might be related to sarcopenia. CONCLUSIONS/IMPLICATIONS: Sarcopenia is highly prevalent in older nursing home residents. Malnutrition may be an associated factor of sarcopenia. More prospective studies are needed to clarify the association between age, gender, malnutrition, and smoking with sarcopenia. PMID- 30409495 TI - Taiwan National Newborn Screening Program by Tandem Mass Spectrometry for Mucopolysaccharidoses Types I, II, and VI. AB - OBJECTIVE: To evaluate the initial cutoff values, rates of screen positives, and genotypes for the large-scale newborn screening program for multiple mucopolysaccharidoses (MPS) in Taiwan. STUDY DESIGN: More than 100 000 dried blood spots were collected consecutively as part of the national Taiwan newborn screening programs. Enzyme activities were measured by tandem mass spectrometry from dried blood spot punches. Genotypes were obtained when a second newborn screening specimen again had a decreased enzyme activity. Additional clinical evaluation was then initiated based on enzyme activity and/or genotype. RESULTS: Molecular genetic analysis for cases with low enzyme activity revealed 5 newborns with pathogenic alpha-L-iduronidase mutations, 3 newborns with pathogenic iduronate-2-sulfatase mutations, and 1 newborn was a carrier of an arylsulfatase B mutation. Several variants of unknown pathogenic significance were also identified, most likely causing pseudodeficiency. CONCLUSIONS: The highly robust tandem mass spectrometry-based enzyme assays for MPS-I, MPS-II, and MPS-VI allow for high-throughput newborn screening for these lysosomal storage disorders. Optimized cutoff values combined with second tier testing could largely eliminate false-positive results. Accordingly, newborn screening for these lysosomal storage disorders is possible. PMID- 30409496 TI - The role of meniscal tears and meniscectomy in the mechanical stability of the anterior cruciate ligament deficient knee. AB - BACKGROUND: The role of an intact meniscus in providing mechanical stability to the knee of anterior cruciate ligament (ACL) deficient and ACL reconstructed patients has not been well studied. METHODS: This was a prospective cohort study. A total of 205 patients undergoing ACL reconstruction were enrolled, of which 61 had normal menisci, 49 had a tear in the posterior horn of the medial meniscus (PHMM) (tear <40% of width = 19; >40% of width = 30), 35 had a tear in the lateral meniscus (<40% of width = 15; >40% = 20), 13 had a tear in the body and/or anterior horn of the medial meniscus (<40% of width = 6; >40% = 7) and 47 patients had a tear in both menisci. Patients with a tear in both menisci were excluded. The anterior translation of the tibia (ATT) was calculated preoperatively and postoperatively at three months and six months using KT-1000. Partial meniscectomy was performed in all unstable meniscal tears. RESULTS: The mean age at the time of surgery was 25.2 +/- 5.1 years. Patients with a normal meniscus showed side to side difference in KT-1000 of 4.8 +/- 2.5 mm whereas those with a <40% tear and >40% tear in PHMM had a difference of 5.36 +/- 3.07 mm (P = 0.46) and 7.08 +/- 2.78 mm (P = 0.0002), respectively. Patients with a lateral meniscus <40% and >40% tear had a mean difference of 5.68 +/- 2.96 mm (P = 0.22) and 5.95 +/- 2.39 mm (P = 0.09), respectively. Patients with body and/or anterior horn of medial meniscus <40% and >40% had a difference of 5.41 +/- 1.11 mm (P = 0.59) and 5.78 +/- 2.38 mm (P = 0.35), respectively. At three months and six months KT-1000 differences of 2.3 +/- 1.2 mm and 2.1 +/- 1.2 mm were seen in patients with normal meniscus; 2.26 +/- 1.51 mm and 2.16 +/- 0.9 mm with partial meniscectomy of the PHMM <40%; 2.65 +/- 1.53 mm and 2.4 +/- 1.35 mm with partial meniscectomy of the PHMM >40%; 2.27 +/- 1.19 mm and 2.07 +/- 1.52 mm with partial meniscectomy of the lateral meniscus <40%; and 2.27 +/- 1.44 mm and 2.07 +/- 1.14 mm with partial meniscectomy of the lateral meniscus >40%; 2.55 +/- 1.56 mm and 1.91 +/- 1.09 mm with partial meniscectomy in body and/or anterior horn of medial meniscus <40% and 2.07 +/- 1.81 and 2.14 +/- 1.10 mm with partial meniscectomy in body and/or anterior horn of medial meniscus >40% (P > 0.05). CONCLUSION: PHMM acts as a secondary stabilizer of the knee joint in the absence of functional ACL. There is no effect of partial meniscectomy on mechanical stability of the knee in ACL reconstructed patients. Medial or lateral partial meniscectomy performed at the time of ACL reconstruction does not affect the stability of ACL reconstructed knee. However, the presence of a concomitant tear in PHMM is associated with increased instability in ACL deficient knee. PMID- 30409497 TI - Evaluation of the patellofemoral joint in total knee arthroplasty: Validation of the weight bearing merchant radiographic view. AB - BACKGROUND: Standard radiographic views for patellofemoral joint assessment do not reflect loading at which TKA patients may describe post-operative anterior symptoms. A novel weight bearing (WB) Merchant view has been described and demonstrated a number of tracking changes that correlated with clinical outcomes. In this study, we aim to validate the WB Merchant view and assess relationships with patient outcome scores. METHODS: Patients were randomly allocated to receive one of the three commonly used patellar implants with a single TKA prosthesis. Patients were evaluated at six months post-operatively using both NWB and WB Merchant views. Indicators of patellar tracking were correlated with improvement in KOOS, WOMAC and Kujala scores. For reliability assessment, radiographs were assessed twice by two readers. RESULTS: The WB Merchant view showed a reduction in the percentage of outliers of tracking indices in comparison to the NWB view (Congruence angle: NWB = 37%, WB = 24%; Displacement: NWB = 2%, WB = 0%; Tilt angle: NWB = 60%, WB = 56%). There was an increase in the lateral contact state with the WB Merchant view (Type I: NWB = 19%, WB = 28%; Type II: NWB = 3%, WB = 4%). The state of lateral contact had a consistent and statistically significant correlation with the improvement in KOOS, WOMAC and Kujala scores (p value = 0.01, 0.01 and 0.03, respectively). All radiographic indices had good reliability with accepted variability. CONCLUSION: The WB Merchant radiograph is an easy to perform and reliable view for the evaluation of patellar tracking and may provide additional information to the routinely used NWB view. PMID- 30409498 TI - A Review of the Efficacy and Safety Profiles of the Novel Oral Anticoagulants in the Treatment and Prevention of Venous Thromboembolism. AB - PURPOSE: This study aims to review the published literature concerning the use of novel oral anticoagulants (NOACs) in the treatment and prevention of venous thromboembolism (VTE) and to identify the appropriate niche for each NOAC by comparing their behaviors in Phase III and Phase IV clinical trial settings. METHODS: The ClinicalTrials.gov database was used to identify Phase III and postmarketing (Phase IV) randomized controlled trials concerning the efficacy and safety profiles of the oral NOACs (apixaban, dabigatran etexilate, exodaban, and rivaroxaban) for the treatment or prevention of VTE. Studies of special interest included those that compared the administration of a NOAC versus standard anticoagulation therapy with low-molecular-weight heparin and/or a vitamin K antagonist. FINDINGS: Overall, the NOACs offer a simplified anticoagulation regimen that has noninferiority and similar rates of bleeding when compared with standard therapy throughout multiple studies. This finding held true across several VTE conditions that required anticoagulation, such as the treatment and prophylaxis of acute VTE, including both deep vein thrombosis and pulmonary embolism. Absence of dietary restrictions and fixed oral dosing that does not require monitoring makes NOACs ideal for the outpatient setting. Apparent niches for each individual NOAC are discussed in detail; however, the paucity of trials comparing NOAC performance in specific clinical settings makes precise definition of these niches problematic. IMPLICATIONS: It now seems reasonable for clinicians to consider NOACs as first-line agents for both the treatment and prophylaxis of VTE and to attempt to tailor their particular medication choices for each patient scenario. More trials comparing NOAC performance in specific clinical settings are essential to ensure these medications are being used to their full potential. (Clin Ther. 2012;34:XXX-XXX) (c) 2012 Elsevier HS Journals, Inc. PMID- 30409499 TI - Diet quality is lower among adults with a BMI >=40kgm-2 or a history of weight loss surgery. AB - BACKGROUND: Poor diet is a major public health issue requiring strategies to support improvements. Nutrition knowledge influences eating behaviours, yet few studies have examined relationships with diet quality. The current study aimed to explore relationships between demographic characteristics, nutrition knowledge, and diet quality using the Australian Recommended Food Score (measuring diet variety). METHODS: Adults 18-60 years completed a 210-item survey including questions on demographics, health, nutrition knowledge, and diet. Statistical analysis used chi-square tests, linear and multiple regression, adjusted for covariates. RESULTS: 480 respondents with a mean (SD) age 39.1+/-11.6 years (18% male) completed all questions. Overall diet quality scores were high (ARFS 39.5+/ 9 points). Nutrition knowledge (p<0.001) and BMI (p<0.001) were positively associated with ARFS. ARFS scores were higher for those with higher nutrition knowledge scores (ARFS 42+/-8 points) and of lower BMI (ARFS 40+/-8 points) compared to those with lower knowledge (ARFS 37+/-11) and higher BMI (ARFS 35+/ 10 points). Those with BMI>=40kg.m-2 and weight loss surgery reported the lowest diet quality (ARFS 31+/-10 points). CONCLUSION: Diet quality was highest among those with high nutrition knowledge and lower BMI. Those with a BMI >=40kg.m-2, particularly those with past weight loss surgery reported the lowest diet quality, despite comparable levels of nutrition knowledge. It remains unclear which factors explain the variation in diet quality in the weight loss surgery group and this deserves further attention given the growing popularity of weight loss surgery. PMID- 30409500 TI - Combined rotational atherectomy and intravascular lithotripsy for the treatment of severely calcified in-stent neoatherosclerosis: A mini-review. AB - Coronary calcifications remain associated to increased rate of complications and worse clinical outcomes, particularly in the setting of in-stent restenosis. We present the first reported case of combined rotational atherectomy and intravascular lithotripsy for the treatment of heavily calcified neoatherosclerosis. PMID- 30409501 TI - Associations between initial opioid exposure and the likelihood for long-term use. AB - OBJECTIVES: This study examined the association between initial opioid exposure and subsequent long-term use in 2 national Veterans Administration (VA) cohorts from 2011 and 2016, a period during which opioid prescribing declined. DESIGN: Two methodologies were used to determine the relationship between initial exposure and subsequent long-term use. SETTING AND PARTICIPANTS: Incident opioid users during 2016 were identified using national VA administrative data. OUTCOME MEASURES: Furthermore, relationships between days' supply, daily dose, and number of fills within the first 30 days and subsequent long-term opioid use were also examined. All analyses were repeated for an identically derived cohort during 2011. RESULTS: In 2016, 6.2% (method 1: Deyo replication) or 16.8% (method 2: Shah replication) of incident opioid users progressed to long-term opioid use. In 2011, 14.3% (method 1) or 29.2% (method 2) of incident users progressed to long term use. Cumulative days' supply emerged as the strongest predictor in a multivariable model of long-term opioid use, which occurred in 1.5% of patients dispensed 7 days' supply or less and in 27.7% of patients dispensed greater than 30 days' supply. Results were similar in the 2011 cohort. Although the relationship between days' supply of incident opioid exposure and long-term opioid use remained consistent over time (in both 2011 and 2016), the overall rate of becoming a long-term opioid user decreased over time across levels of initial exposure. CONCLUSION: The findings confirm existing literature demonstrating a strong relationship between initial opioid exposure and future likelihood for long-term use. This valuable prognostic information could potentially be leveraged for intervention, including pharmacist-based approaches to prevent progression to long-term opioid use when it is unintended or clinically inappropriate. PMID- 30409502 TI - Comparisons of immunization records between a community pharmacy, a regional registry, and a health system. AB - OBJECTIVES: To compare the completeness of immunization records for 6 vaccines between a community pharmacy database, a regional immunization information system (IIS), and a health system's electronic health record (EHR). METHODS: In a community pharmacy immunization program, 2 pharmacists and a community pharmacy resident performed a needs assessment for 6 vaccines (tetanus-diphtheria acellular pertussis vaccine for adults or diphtheria-tetanus-acellular pertussis vaccine for children and adolescents, zoster vaccine live, 13-valent pneumococcal conjugate vaccine, 23-valent pneumococcal polysaccharide vaccine, hepatitis B vaccine series, and human papillomavirus vaccine) for more than 2400 patients from August 2016 to March 2017. This was a retrospective study to review immunization records for 243 patients. Inclusion criteria included patients from the community pharmacy immunization program who also had at least 1 medication prescribed by an academic health system provider. Immunization records for 6 vaccines were collected from the community pharmacy database, the regional IIS, and the EHR. RESULTS: A total of 186 of 243 patients (77%) had additional immunization records in the regional IIS or EHR that were not found in the community pharmacy database. Among those 186 patients, 108 (58%) had additional immunization records for 2 or more unique vaccines. In total, 378 additional immunization records were identified for the 6 vaccines. For all 6 vaccines, the regional IIS and EHR possessed more complete immunization records than the community pharmacy database (P < 0.05 for HPV and P < 0.001 for the remaining 5 vaccines). CONCLUSION: Our study showed that immunization records were more complete in a regional IIS and health system EHR compared with a community pharmacy database. If all 3 sources were used by the pharmacist during the needs assessment, the community pharmacy team would have made fewer vaccine recommendations, which would have reduced the potential for duplicate or inappropriate vaccines. PMID- 30409503 TI - Geniposide and Gentiopicroside Suppress Hepatic Gluconeogenesis via Regulation of AKT-FOXO1 Pathway. AB - BACKGROUND: Hepatic gluconeogenesis plays an important role in regulating fasting plasma glucose levels and is a target of anti-diabetic drugs. Several kinds of iridoid glucosides exhibit hypoglycemic effect, whereas the mechanism was not clear. AIM OF THE STUDY: In this study, the effects of geniposide and gentiopicroside, two natural iridoid glucosides, on hepatic gluconeogenesis were investigated. METHODS: Glucose uptake assay, MTT assay, q-PCR, luciferase assay and western blot assay were performed to investigate the pharmacological effect of geniposide and gentiopicroside on human liver cell line L02. Thereby the fast blood glucose and intraperitoneal glucose tolerance were measured in high fat diet induced hyperglycemic mice after geniposide or gentiopicroside administration. RESULTS: The results showed that geniposide and gentiopicroside inhibited the transcription of G6PC and PEPCK in L02 cells and in mice. Additional experimental data indicated that these two compounds were able to inhibit the transcriptional activity of FOXO1 by inducing phosphorylation of AKT at Ser473. Furthermore, we found that these two compounds alleviated high fat diet induced hyperglycemia in mice. CONCLUSIONS: Geniposide and gentiopicroside might reduce blood glucose and suppress hepatic gluconeogenesis by regulating the AKT-FOXO1 pathway, and the potential use of these two iridoid glucosides as anti diabetic agents merits further in-depth exploration. PMID- 30409505 TI - Supplemental Method for Reduction of Irreducible Mallet Finger Fractures by the 2 Extension Block Technique: The Dorsal Counterforce Technique. AB - PURPOSE: We suggest a method to achieve anatomical reduction in mallet finger fractures that are insufficiently treated by the 2-extension block wire technique. METHODS: We performed a retrospective review of 18 patients who were found to have an irreducible dorsal fragment and distal interphalangeal joint incongruence owing to rotation of the dorsal fragment in the sagittal plane. In these cases, we additionally employed a dorsal counterforce technique to supplement the 2-extension block technique. An additional K-wire was used to apply counterforce against the distal part of the dorsal fragment and control rotation in the sagittal plane. RESULTS: All 18 fractures united. Congruent joint surfaces and anatomical reduction were seen in all cases. The mean active flexion of the distal interphalangeal joints was 83.8 degrees (range, 79 degrees -88 degrees ) and the mean extension loss was 0.4 degrees (range, 0 degrees -4 degrees ). CONCLUSIONS: We believe that the dorsal counterforce technique effectively supplements the 2-extension block K-wire technique and aids control of dorsal fragment rotation in the sagittal plane. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 30409504 TI - [Public, private or third sector management? Differences in the results in Primary Care in Catalonia]. AB - GOAL: Compare the performance of primary health centers managed by the public sector (ICS), the third sector (Hospitals) or by small private organizations known as EBAs. DESIGN: Multidimensional comparative analysis. We follow a quasi experimental logic comparing primary health centers managed by EBAs with other centers managed by the public sector (ICS) o by the third sector (hospitals). LOCALIZATION: Barcelona, Catalonia, Spain. PARTICIPANTS: We have 368 observations (primary health centers) and 18 indicators measured in 2015. INTERVENTION: Different management models (public, third sector, private). MAIN MEASURES: We compare activity measures, measures of effectiveness in the process of medical assistance, and efficiency. We compare before and after controlling for the socio economic level corresponding to the basic health area and the characteristics of the population and health region. We conduct a test of significant differences between the indicators corresponding to centers managed differently, after a process of matching using key variables and Propensity Score Matching. RESULTS: Significant differences in the measure of work load for family doctors, in five measures of effectiveness in the process of assistance and in the cost per user. CONCLUSIONS: The diversity in the management model through EBAs shows results that can be interpreted in favor of the maintenance or the expansion of this model of management. The majority of EBAs have been implanted in areas of a medium or high level, but their results are still significantly positive once the socio economic level of the area is controlled. PMID- 30409506 TI - Relationship of Carpal Tunnel Release and New Onset Trigger Finger. AB - PURPOSE: Carpal tunnel syndrome and trigger finger (TF) frequently present concomitantly; some studies suggest that carpal tunnel release (CTR) is a risk factor for the development of ipsilateral TF in the postoperative period. The primary objective of this study was to elucidate the relationship between CTR and the subsequent development of TF. METHODS: A retrospective study was conducted of 1,386 hands in 1,140 patients who underwent primary CTR at a tertiary referral center from July 2008 to June 2013. After exclusion of cases in which contralateral CTR was performed within the first postoperative year after ipsilateral CTR, conditional logistic regression was performed in 906 hands in 890 patients to determine the association between CTR and TF in the first postoperative year in the operative hand compared with the contralateral hand. Conditional logistic regression and Poisson regression were performed in 1,386 hands in 1,140 patients to examine the association between CTR and TF in the year before surgery compared with the year after surgery. Multivariable regression analysis was used to determine associated risk factors. RESULTS: Of 1,386 hands, a new TF was seen in 147 (10.6%) within 1 year before CTR and 81 (5.8%) within 1 year after CTR. The occurrence of postoperative TF was associated with 2.5 times higher odds in the operative hand compared with the contralateral hand in the conditional logistic regression model of 906 cases. However, the incidence of TF was associated with 0.5 times lower odds during the year after CTR compared with the year before CTR in both conditional logistic regression and Poisson regression models of 1,386 cases. Increased body mass index is statistically associated with TF after CTR, but the attributable risk is negligible. CONCLUSIONS: There is a predisposition for these 2 common hand pathologies to present in the same hand; however, patients can be counseled that CTR does not cause new incidence of TF in the operative hand. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV. PMID- 30409507 TI - Tumor deposit versus extra nodal extension: a differential evaluation of prognostic relevance. PMID- 30409509 TI - From CLSI to EUCAST, a necessary step in Spanish laboratories. AB - The Spanish Antibiogram Committee (Comite Espanol del Antibiograma, COESANT) presents in this document a simple "roadmap" or decalogue of recommendations, with a view to facilitating the transition from the Clinical and Laboratory Standards Institute (CLSI) to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) antimicrobial susceptibility testing regulations to the Clinical Microbiology Spanish laboratories that still use the CLSI guidelines. The objectives are to adapt the closer European regulations to the Spanish clinical and epidemiological reality and to fully implement the EUCAST recommendations in all microbiology laboratories in Spain. PMID- 30409508 TI - Human Induced Pluripotent Stem Cell-Derived Astrocytes Are Differentially Activated by Multiple Sclerosis-Associated Cytokines. AB - Recent studies highlighted the importance of astrocytes in neuroinflammatory diseases, interacting closely with other CNS cells but also with the immune system. However, due to the difficulty in obtaining human astrocytes, their role in these pathologies is still poorly characterized. Here, we develop a serum-free protocol to differentiate human induced pluripotent stem cells (hiPSCs) into astrocytes. Gene expression and functional assays show that our protocol consistently yields a highly enriched population of resting mature astrocytes across the 13 hiPSC lines differentiated. Using this model, we first highlight the importance of serum-free media for astrocyte culture to generate resting astrocytes. Second, we assess the astrocytic response to IL-1beta, TNF-alpha, and IL-6, all cytokines important in neuroinflammation, such as multiple sclerosis. Our study reveals very specific profiles of reactive astrocytes depending on the triggering stimulus. This model provides ideal conditions for in-depth and unbiased characterization of astrocyte reactivity in neuroinflammatory conditions. PMID- 30409510 TI - High frequency transient-evoked otoacoustic emission measurements using chirp and click stimuli. AB - Transient-evoked otoacoustic emissions (TEOAEs) at high frequencies are a non invasive physiological test of basilar membrane mechanics at the basal end, and have clinical potential to detect risk of hearing loss related to outer-hair-cell dysfunction. Using stimuli with constant incident pressure across frequency, TEOAEs were measured in experiment 1 at low frequencies (0.7-8 kHz) and high frequencies (7.1-14.7 kHz) in adults with normal hearing up to 8 kHz and varying hearing levels from 9 to 16 kHz. In combination with click stimuli, chirp stimuli were used with slow, medium and fast sweep rates for which the local frequency increased or decreased with time. Chirp TEOAEs were transformed into equivalent click TEOAEs by inverse filtering out chirp stimulus phase, and analyzed similarly to click TEOAEs. To improve detection above 8 kHz, TEOAEs were measured in experiment 2 with higher-level stimuli and longer averaging times. These changes increased the TEOAE signal-to-noise ratio (SNR) by 10 dB. Slower sweep rates were investigated but the elicited TEOAEs were detected in fewer ears compared to faster rates. Data were acquired in adults and children (age 11-17 y), including children with cystic fibrosis (CF) treated with ototoxic antibiotics. Test-retest measurements revealed satisfactory repeatability of high frequency TEOAE SNR (median of 1.3 dB) and coherence synchrony measure, despite small test-retest differences related to changes in forward and reverse transmission in the ear canal. The results suggest the potential use of such tests to screen for sensorineural hearing loss, including ototoxic loss. Experiment 2 was a feasibility study to explore TEOAE test parameters that might be used in a full-scale study to screen CF patients for risk of ototoxic hearing loss. PMID- 30409511 TI - Biophysical characterization and antitumor activity of synthetic Pantinin peptides from scorpion's venom. AB - Antimicrobial peptides have been extensively described as bioactive agents, mainly considering their selective toxicity towards bacteria but not to healthy mammalian cells. In past years, this class of compounds has been classified as an attractive and novel family of anticancer agents. Pantinin peptides isolated from scorpion Pandinus imperator presented antimicrobial activity. In this study, we have explored the in vitro antitumor activity of antimicrobial pantinin peptides against the tumor cell lines MDA-MB-231 (breast adenocarcinoma) and DU - 145 (prostate adenocarcinoma) and healthy fibroblasts HGF - 1. To further improve our mechanistic understanding for this class of compounds, we have also performed a biophysical characterization of these peptides in lipid model membranes. Cell viability assays revealed that all peptides were more effective on tumor cells when compared to fibroblasts, indicating selectivity towards cancer cells. Furthermore, flow cytometry analysis revealed that all peptides induced apoptosis in cancer cells in a different way from fibroblasts. Circular dichroism spectroscopy showed that all peptides adopted an alpha-helical structure and an evaluation of the binding constant indicates a higher affinity of the peptides to negatively charged phospholipids. Additionally, permeabilization assays showed that POPG and POPS anionic vesicles were more susceptible to peptide-induced lysis than POPC:Chol and POPC:POPE vesicles. Moreover, we have observed that increasing concentrations of cholesterol inhibits peptide binding process. Therefore, our findings suggest that Pantinin peptides may have chemotherapeutic potential for cancer treatment. PMID- 30409512 TI - Effect of polyols on the DMPC lipid monolayers and bilayers. AB - In this study, the effect of polyols, erythritol, xylitol, mannitol, on a model membrane systems composed of DMPC was investigated using differential scanning calorimetry and Fourier transform infrared spectroscopy. Generally, it is considered that polyols possess strong hydrophilic properties, and either does not interact with the hydrophobic environment at all, or these interactions are very weak. To better understand the mutual interactions between polyols and the lipid system, the Langmuir technique was used to examine the molecular organization of monolayers and to calculate their thickness in the presence of polyols at the subphase. The detailed description of the interactions between polyols and DMPC molecules was complemented by the analysis of the morphology of monolayers with the application of Brewster angle microscopy. From ATR FTIR, the significant spectral shift is observed only for the PO2- stretching band, which correlates strongly with the polyol chain-length. The longer the polyol chain, the weaker the observed interactions with lipid molecules. The most important findings, obtained from thickness measurements, reveal that short-chain polyols may prevent the formation of bilayers by the DMPC molecules under high surface pressure. The changes in the organization of DMPC monolayers on the surface, as visualized by Brewster angle microscopy, showed that the domains observed for phospholipid film spread on pure water differ substantially from those containing polyols in the subphase. PMID- 30409513 TI - Expression of voltage-gated calcium channels augments cell susceptibility to membrane disruption by nanosecond pulsed electric field. AB - We compared membrane permeabilization by nanosecond pulsed electric field (nsPEF) in HEK293 cells with and without assembled CaV1.3 L-type voltage-gated calcium channel (VGCC). Individual cells were subjected to one 300-ns pulse at 0 (sham exposure); 1.4; 1.8; or 2.3 kV/cm, and membrane permeabilization was evaluated by measuring whole-cell currents and by optical monitoring of cytosolic Ca2+. nsPEF had either no effect (0 and 1.4 kV/cm), or caused a lasting (>80 s) increase in the membrane conductance in about 50% of cells (1.8 kV/cm), or in all cells (2.3 kV/cm). The conductance pathway opened by nsPEF showed strong inward rectification, with maximum conductance increase for the inward current at the most negative membrane potentials. Although these potentials were below the depolarization threshold for VGCC activation, the increase in conductance in cells which expressed VGCC (VGCC+ cells) was about twofold greater than in cells which did not (VGCC- cells). Among VGCC+ cells, the nsPEF-induced increase in membrane conductance showed a positive correlation with the amplitude of VGCC current measured in the same cells prior to nsPEF exposure. These findings demonstrate that the expression of VGCC makes cells more susceptible to membrane permeabilization by nsPEF. Time-lapse imaging of nsPEF-induced Ca2+ transients confirmed permeabilization by a single 300-ns pulse at 1.8 or 2.3 kV/cm, but not at 1.4 kV/cm, and the transients were expectedly larger in VGCC+ cells. However, it remains to be established whether larger transients reflected additional Ca2+ entry through VGCC, or were a result of more severe electropermeabilization of VGCC+ cells. PMID- 30409514 TI - The homologous Arabidopsis MRS2/MGT/CorA-type Mg2+ channels, AtMRS2-10 and AtMRS2 1 exhibit different aluminum transport activity. AB - Magnesium (Mg2+) plays a critical role in many physiological processes. The AtMRS2/MGT family, which consists of nine Arabidopsis genes (and two pseudo genes) belongs to a eukaryotic subset of the CorA superfamily of divalent cation transporters. AtMRS2-10 and AtMRS2-1 possess the signature GlyMetAsn sequence conserved in the CorA superfamily; however, they have low sequence conservation with CorA. Direct measurement using the fluorescent dye mag-fura-2 revealed that reconstituted AtMRS2-10 and AtMRS2-1 mediated rapid Mg2+ uptake into proteoliposomes. The rapid Mg2+ uptake through AtMRS2-10 was inhibited by aluminum. An assay using the Al-sensitive dye morin indicated Al uptake into the proteoliposomes through AtMRS2-10. AtMRS2-10 also exhibited Ni2+ transport activity but almost no Co2+ transport activity. The rapid Mg2+ uptake through AtMRS2-1 was not inhibited by aluminum. Al uptake into the proteoliposomes through AtMRS2-1 was not observed. The functional complementation assay in Escherichia coli strain TM2 showed that AtMRS2-1 was capable of mediating Mg2+ uptake. Heterologous expression using the E. coli mutant cells also showed that the E. coli cells expressing AtMRS2-1 was more resistant to aluminum than the E. coli cells expressing AtMRS2-10. The results suggested that AtMRS2-10 transported Al into the E. coli cells, and then the transported Al inhibited the growth of E. coli. AtMRS2-1 has been localized to the Arabidopsis tonoplast, indicating that AtMRS2-1 is exposed to much higher concentration of aluminum than AtMRS2-10. Under the conditions, it may be required that the Mg2+ transport of AtMRS2-1 is insensitive to Al inhibition, and AtMRS2-1 is impermeable to Al. PMID- 30409515 TI - Effect of late endosomal DOBMP lipid and traditional model lipids of electrophysiology on the anthrax toxin channel activity. AB - Anthrax toxin action requires triggering of natural endocytic transport mechanisms whereby the binding component of the toxin forms channels (PA63) within endosomal limiting and intraluminal vesicle membranes to deliver the toxin's enzymatic components into the cytosol. Membrane lipid composition varies at different stages of anthrax toxin internalization, with intraluminal vesicle membranes containing ~70% of anionic bis(monoacylglycero)phosphate lipid. Using model bilayer measurements, we show that membrane lipids can have a strong effect on the anthrax toxin channel properties, including the channel-forming activity, voltage-gating, conductance, selectivity, and enzymatic factor binding. Interestingly, the highest PA63 insertion rate was observed in bis(monoacylglycero)phosphate membranes. The molecular dynamics simulation data show that the conformational properties of the channel are different in bis(monoacylglycero)phosphate compared to PC, PE, and PS lipids. The anthrax toxin protein/lipid bilayer system can be advanced as a novel robust model to directly investigate lipid influence on membrane protein properties and protein/protein interactions. PMID- 30409516 TI - Cell surface proteoglycan-mediated uptake and accumulation of the Alzheimer's disease peptide Abeta(1-42). AB - Proteoglycans (PGs) have been found in Alzheimer's disease amyloid-beta (Abeta) plaques and their glycosaminoglycan chains reportedly influence Abeta aggregation, neurotoxicity and intracellular accumulation in cell and animal models, but their exact pathophysiological role(s) remain unclear. We have studied the cellular uptake of fluorescently labelled Abeta(1-42) and Abeta(1-40) peptides in normal CHO cells (K1) and the mutant cell line (pgsA-745) which lacks all protein-attached heparan and chondroitin sulfate chains. After 24 h of incubation, CHO-K1 accumulates more Abeta(1-42) and Abeta(1-40) compared with CHO pgsA-745, consistent with the suggested role of PGs in Abeta uptake. However, after short incubation times (<=3 h) there was no difference; moreover, the time evolution of Abeta(1-42) accumulation in CHO-K1 followed an unusual sigmoidal like trend, indicating a possible involvement of PG-mediated peptide aggregation in Abeta endocytosis. Neither Abeta(1-42) nor Abeta(1-40) could stimulate uptake of a 10 kDa dextran (a general endocytosis marker) suggesting that Abeta-induced upregulation of endocytosis does not occur. CHO-K1 cells contained a higher number of Abeta(1-42)-positive vesicles, but the intensity difference per vesicle was only marginal suggesting that the superior accumulation of Abeta(1-42) stems from a higher number of endocytic events. FRET imaging support that intracellular Abeta(1-42) is aggregated in both cell types. We also report that CHO-pgsA-745 cells perform less endocytosis than CHO-K1 and, albeit this does not explain their difference in Abeta internalisation, we discuss a general method for data compensation. Altogether, this study contributes new insights into the mechanisms of PG-mediated Abeta uptake that may be relevant for our understanding of their role in AD pathology. PMID- 30409517 TI - Cholesterol and phosphatidylserine are engaged in adenoviral dodecahedron endocytosis. AB - Adenoviral dodecahedron is a virus-like particle composed of twelve penton base proteins, derived from the capsid of human adenovirus type 3. Due to the high cell penetration capacity, it was used as a vector for protein, peptide and drug delivery. Two receptors are known to be involved in the endocytic dodecahedron uptake, namely alphav integrins and heparan sulfate proteoglycans. Since it has been observed, that dodecahedron efficiently penetrates a wide range of cancer cells, it suggests that other cellular compounds may play a role in the particle endocytosis. To shed some light onto the interactions with membrane lipids and their potential role in dodecahedron entry, we performed a series of experiments including biochemical assays, fluorescence confocal imaging of giant unilamellar vesicles and surface plasmon resonance, which indicated specific preference of the particle to anionic phosphatidylserine. Experiments performed on cholesterol depleted epithelial cells showed that cholesterol is essential in the endocytic uptake, however a direct interaction was not observed. We believe that the results will allow to better understand the role of lipids in dodecahedron entry and to design more specific dodecahedron-based vectors for drug delivery to cancer cells. PMID- 30409518 TI - Lipid bilayer position and orientation of novel carprofens, modulators of gamma secretase in Alzheimer's disease. AB - gamma-Secretase is an integral membrane protein complex and is involved in the cleavage of the amyloid precursor protein APP to produce amyloid-beta peptides. Amyloid-beta peptides are considered causative agents for Alzheimer's disease and drugs targeted at gamma-secretase are investigated as therapeutic treatments. We synthesized new carprofen derivatives, which showed gamma-secretase modulating activity and determined their precise position, orientation, and dynamics in lipid membranes by combining neutron diffraction, solid-state NMR spectroscopy, and molecular dynamics simulations. Our data indicate that the carprofen derivatives are inserted into the membrane interface, where the exact position and orientation depends on the lipid phase. This knowledge will help to understand the docking of carprofen derivatives to gamma-secretase and in the design of new potent drugs. The approach presented here promises to serve as a general guideline how drug/target interactions in membranes can be analyzed in a comprehensive manner. PMID- 30409519 TI - Molecular details on the intermediate states of melittin action on a cell membrane. AB - Antimicrobial peptides (AMPs) provide a promising solution to the serious threat of multidrug-resistant bacteria or superbugs to public healthcare, due to their unique disruption to bacterial membrane such as perforation. Unfortunately, the underlying action mechanism of AMPs, especially the possible transition between the membrane binding and perforation states of peptides (i.e., the classical two state model), is still largely unknown. Herein, by combining experimental techniques with pertinent membrane models and molecular dynamic (MD) simulations, new insights into the intermediate states of the AMP melittin-membrane interaction process are obtained. Specifically, it is demonstrated that, after the initial binding, the accumulated melittin on the bilayer triggers vigorous fluctuation of the membrane and even extracts some lipid molecules exclusively from the deformed outer leaflet of the bilayer. Such a distinctive mass removal manner and the resultant local asymmetry in lipid number between the two leaflets change the mechanical status of the membrane and in turn reduce the free energy barrier for the melittin insertion. Finally, the formation of the transmembrane pores is facilitated significantly. These findings provide new insights into the complicated antimicrobial mechanisms of AMPs. PMID- 30409520 TI - Short arginine-rich lipopeptides: From self-assembly to antimicrobial activity. AB - In this paper, we examine antimicrobial and cytotoxic activities, self-assembly and interactions with anionic and zwitterionic membranes of short arginine-rich lipopeptides: C16-RRRR-NH2, C14-RRRR-NH2, C12-RRRR-NH2, and C16-PRRR-NH2. They show a tendency to self-assembly into micelles, but it is not required for antimicrobial activity. The membrane binding of the lipopeptides can be accompanied by other factors such as: peptide aggregation, pore formation or micellization of phospholipid bilayer. The shortening of the acyl chain results in compounds with a lower haemolytic activity and a slightly improved antimicrobial activity against Gram-positive bacteria, what indicates enhanced cell specificity. Results of coarse-grained molecular dynamics simulations indicate different organization of membrane lipids upon binding of arginine-based lipopeptides and the previously studied lysine-based ones. PMID- 30409521 TI - Trypanosoma brucei aquaglyceroporins mediate the transport of metabolic end products: Methylglyoxal, D-lactate, L-lactate and acetate. AB - Bloodstream forms of Trypanosoma (T.) brucei, the causative agent of African sleeping sickness, possess a highly active glycolysis, which generates as main end-products: pyruvate under aerobic conditions, and pyruvate and glycerol under anaerobic conditions. To secrete them into the extracellular milieu, the parasites have at least two main specific membrane proteins, the pyruvate transporter and the aquaglyceroporins However, there are several other minor products from the glycolysis that must be excreted by the parasites and whose exit pathway until now remained elusive. As aquaglyceroporins from T. brucei (TbAQP1, 2, and 3) show a wide permeability profile for small solutes, we decided to evaluate if these proteins allow the passage of methylglyoxal, L-lactate, D lactate and acetate molecules. We expressed heterologously TbAQP1, 2, and 3 in aquaglyceroporin-null yeast cells or in Xenopus laevis oocytes and demonstrated that these channels are permeable for methylglyoxal, L-lactate, D-lactate and acetate. We further demonstrate that methylglyoxal is highly toxic for bloodstream forms of T. brucei, while L-lactate and D-lactate appear almost harmless. Additionally, we discuss all our findings in the light of the novel metabolic discoveries, putting in context the participation of TbAQP1, 2, 3, and other proteins in the excretion of unwanted metabolic end-products. PMID- 30409522 TI - Elementary processes of antimicrobial peptide PGLa-induced pore formation in lipid bilayers. AB - Antimicrobial peptide PGLa induces the leakage of intracellular content, leading to its bactericidal activity. However, the elementary process of PGLa-induced leakage remains poorly understood. Here, we examined the interaction of PGLa with lipid bilayers using the single giant unilamellar vesicle (GUV) method. We found that PGLa induced membrane permeation of calcein from GUVs comprised of dioleoylphosphatidylcholine (DOPC) and dioleoylphosphatidylglycerol (DOPG) and its rate increased with time to reach a steady value, indicating that PGLa induced pores in the bilayer. The binding of PGLa to the GUV membrane raised its fractional area change, delta. At high PGLa concentrations, the time course of delta showed a two-step increase; delta increased to a value, delta1, which was constant for an extended period before increasing to another constant value, delta2, that persisted until aspiration of the GUV. To reveal the distribution of PGLa, we investigated the interaction of a mixture of PGLa and carboxyfluorescein (CF) -labeled PGLa (CF-PGLa) with single GUVs. The change of the fluorescence intensity of the GUV rim, I, over time showed a two-step increase from a steady value, I1, to another, I2, concomitant with the entering of CF-PGLa into the lumen of the GUV prior to AF647 leakage. The simultaneous measurement of delta and I indicated that their time courses were virtually the same and the ratios (delta2/delta1 and I2/I1) were almost 2. These results indicated that CF-PGLa translocated across the bilayer before membrane permeation. Based on these results, the elementary processes of the PGLa-induced pore formation were discussed. PMID- 30409523 TI - A DIE responsive NIR-fluorescent cell membrane probe. AB - It is challenging to achieve selective off to on modulation of the emissive state of a fluorophore within a complex and heterogeneous cellular environment. Herein we show that the dis-assembly of a non-fluorescent aggregate to produce individual fluorescent molecules, termed disaggregation induced emission (DIE), can be utilised to achieve this goal with an amphiphilic BF2-azadipyrromethene (NIR-AZA) probe. Optical near-infrared properties of the NIR-AZA probe used in this study include absorption and emission maxima at 700 and 726 nm respectively when in the emissive non-aggregated state. Key to the success of the probe is the bis-sulfonic acid substitution of the NIR-AZA fluorophore, which is atypical for membrane probes as it does not contain zwitterionic lipid substituents. The aggregation/disaggregation properties of the NIR-fluorophore have been investigated in model surfactant and synthetic liposomal systems and shown to be emissive responsive to both. Real-time live cell imaging experiments in HeLa Kyoto and MC3T3 cells showed a rapid switch on of emission specific to the plasma membrane of viable and apoptotic cells attributable to a disaggregation-induced emission of the probe. Image analysis software confirmed localisation of fluorescence to the plasma membrane. Cell membrane staining was also effective for formaldehyde fixed cells, with staining possible either before or after fixation. This study adds new and important findings to recent developments of DIE responsive probes and further applications of this controllable emission switching event are anticipated. PMID- 30409524 TI - Multiple facial angiofibromas in severe atopic dermatitis. Study of two patients. PMID- 30409525 TI - Prevalence of influenza B Yamagata lineage in adults in the 2017-2018 flu season. PMID- 30409526 TI - Congenital glucose-galactose malabsorption: A rare and severe cause of infant diarrhea. PMID- 30409527 TI - Unusual features of ependymoma in a patient with Parkinson's disease. AB - The diagnosis and management of ependymoma may be challenging when there is a comorbidity of ependymoma and Parkinson's disease (PD). We report the first case to demonstrate unusual clinical and pathological features of an ependymoma associated with PD. A 77-year-old male with a history of PD had brain magnetic resonance imaging (MRI) that showed signal abnormalities in the right temporal lobe, most consistent with a low-grade glioma. He underwent an imaging-guided resection of that lesion, which pathological examination revealed mild hypercellularity with gliosis but no neoplasm, as well as Lewy bodies (LBs) and alpha-synucleinopathy in the temporal cortex compatible with advanced PD. Follow up MRI exhibited tumor-like progression of signal abnormalities in that brain region. Twenty-nine months after the first resection, a head computerized tomography scan disclosed an obvious mass centered in the right temporal lobe. A second resection was performed for the mass, which pathological examination revealed an ependymoma with focal anaplasia and additional unusual features including an infiltrative growth pattern and intermixed alpha-synuclein positivity with electron microscopy finding of LB-like inclusions. Our observation suggests that an ependymoma in the patient with PD may present with unusual features possibly due to altered tumorigenesis and disease progression associated with alpha-synucleinopathy. PMID- 30409529 TI - The same old things: Ancient CHA2DS2-VASC score. PMID- 30409528 TI - Pathogenesis of idiopathic Normal Pressure Hydrocephalus: A review of knowledge. AB - Idiopathic Normal Pressure Hydrocephalus (iNPH) is a frequent neuropsychiatric entity. Clinically it is characterised by Hakim's triad: Dementia, gait disturbance and urinary incontinence. While its symptomatology is typical, the etiology and thereby physiopathology of iNPH still remain enigmatic. This review summarizes and synthesizes different etiologic conceptions and physiopathologic aspects of iNPH. A research of literature via the PubMed/MEDLINE and the Cochrane database was conducted. Only English language articles clearly outlining a reasonable concept of physiopathology were included. Most authors advocate that iNPH is a result of chronically altered cerebrospinal fluid (CSF) dynamics, i.e. deranged CSF production, kinetics and reabsorption. In addition, there are vascular, metabolo-neurodegenerative and hereditary factors. Neuroinflammation does not seem to play a significant role in the etiology of iNPH. All in all, iNPH seems to combine several pathogenetic factors leading to a self-reinforcing vicious circle. The majority of studies hint at CSF disturbances on grounds of altered hemodynamics. PMID- 30409530 TI - Extreme lateral interbody fusion (XLIF) as a treatment for acute spondylodiscitis: Leeds spinal unit experience. AB - Extreme lateral interbody fusion (XLIF) is a minimally invasive lateral trans psoas approach to the thoraco-lumbar spine that enables surgical debridement of the disc space and facilitates fusion. Previous reports are limited to case series, which have no outcomes measuring improvement. We aim to determine the effectiveness of XLIF in the treatment of patients with spondylodiscitis. We performed a cohort study over four years (2008-2011). Patients were treated with XLIF if they met our selection criteria - symptoms suggestive of discitis with consistent imaging and intractable back pain making patients bedbound. Patients were excluded if medically unfit for surgery. Pre and post-operative VAS and ODI scores were used as formal outcome measures. 14 patients were included and at 12 months, median VAS and ODI scores had improved 4.0 (95% CI, 1.9-6.5) (p = 0.005) and 37.0% (95% CI, 10.7-53.7) (p = 0.015) respectively. All patients with available imaging showed evidence of fusion. Patients typically received 6-8 weeks of antibiotics and all showed normalisation of inflammatory markers. At 5 year follow-up, median VAS and ODI were still improved at 3.0 (95% CI, 1.7-4.4) (p = 0.01) and 40% (95% CI, 10-52) (p = 0.028) respectively. The median length of inpatient stay was 10 days (range 4-40 days). This is the first study to demonstrate that the XLIF technique can significantly improve pain in discitis patients using validated formal outcome measurements. This technique could therefore potentially be used to reduce pain in patients with discitis, help them to mobilise earlier and reduce the duration of their hospital stay. PMID- 30409531 TI - Postoperative lower limb compensation in patient with adult spinal deformity. AB - The objective of this study was to determine whether inadequate decompensation of spine and pelvis would lead to persistent compensatory action of lower extremity. Patients who underwent adult spinal deformity from January 2014 to December 2016 were included. Postoperatively, patients who showed persistent lower extremity compensation (femur obliquity angle/FOA >= 5 degrees ) were classified into compensated lower extremity (CLE) group and decompensated lower extremity (DLE) group with FOA < 5 degrees . Sagittal vertical axis (SVA), T1 spinopelvic inclination, TPA (T1 pelvic angle), thoracic kyphosis, lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt, sacral slope and FOA were measured and compared between two groups. The lack of lumbar lordosis was assessed by PI-LL mismatch and multivariate analysis were used to investigate correlation in changes of parameters. 115 patients were classified into CLE group (23 patients) and DLE group (92 patients). Thoracic compensations were more prevalent in the CLE group while pelvic compensation was more prominent in the DLE group. Both postoperative TPA and PI-LL in the CLE group were greater than those in the DLE group while postoperative SVA was similar. At 1 year postoperatively, SVA was increased in the CB group with persistent lower extremity compensation. Changes in FOA had moderate correlation with changes in SVA and strong correlation with changes in TPA. In conclusion, postoperative persistent lower limb compensation can be interpreted into surgical undercorrection. TPA rather than SVA is a useful parameter to assess global alignment and compensatory action of the lower extremity. PMID- 30409532 TI - A novel surgical approach for intraorbital optic nerve tumors. AB - Although orbital tumors involving the optic nerve are rare, it is well-known that they are very likely to cause serious visual impairment in a patient. Unfortunately, at present, there are no effective interventions that can reliably preserve visual function while controlling tumor growth into intracranial spaces. To ensure visual function of the non-affected side, transection of the optic nerve together with the tumors involved is necessary in some cases. For this procedure large craniotomy and orbital unroofing are commonly utilized. As an alternative, we propose a novel surgical intervention for transection of the optic nerve having optic nerve tumors, which utilizes a lateral orbitotomy approach. To evaluate the invasiveness of different surgical approaches, we compared the days of hospitalization after surgery across patients who underwent the transcranial, lateral, and anterior approaches, respectively. We successfully removed 2 optic nerve tumors using the lateral approach, which required significantly shorter hospitalization than the transcranial approach. The transection of the optic nerve together with tumor removal by the lateral approach may be one of the novel surgical interventions for optic nerve tumors as this method is considerably less invasive than the transcranial removal method. PMID- 30409534 TI - Renal Angina: A New Paradigm for the Prevention of Acute Kidney Injury After Cardiac Surgery. PMID- 30409533 TI - "In Safe Hands" - A costly integrated care program with limited benefits in stroke unit care. AB - Given reported favourable outcomes of accountable care unit models of health care delivery (Taylor et al., 2017; Stein et al., 2015; Kara et al., 2015), the Clinical Excellence Commission of NSW has embraced "In Safe Hands" (ISH) to enhance coordination of care. ISH embraces the structured interdisciplinary bedside round (SIBR) component, for which reported outcomes include reduced length of stay (Taylor et al., 2017; Stein et al., 2015; Kara et al., 2015), possible reduction in overall costs of care (Kara et al., 2015), and enhanced patient and staff satisfaction (O'Leary et al., 2011). It is not yet clear whether the benefits of such a model are translatable to the Australian Health Care System (Hunyh et al., 2016) and/or established units with an already strong multi-disciplinary approach to patient care. The purpose of this prospective cohort study of 200 participants was to assess the effect(s) of implementation of ISH in a stroke unit of a tertiary hospital in Sydney, Australia. Data on length of stay, re-admission rates, adverse events, as well as patient and nursing satisfaction, were collected pre and post implementation. There was no significant difference in length of stay in median days (5 (IQR 2-7) versus 4 (IQR 2-6), P = 0.55) or incidence of adverse events (10% versus 12%, P = 0.82). Stroke outcome disability scores were not affected by the intervention. There were no significant differences overall in reported patient and nursing satisfaction. Implementation of the ISH program cost approximately AUD$ 1805/week (USD$ 1365) in wages. The ISH program was a costly intervention of limited benefit in a well-established acute stroke unit. We here discuss potential reasons for the failure of this intervention to achieve its primary aim in this setting. PMID- 30409535 TI - An update on sphingosine-1-phosphate receptor 1 modulators. AB - Sphingolipids represent an essential class of lipids found in all eukaryotes, and strongly influence cellular signal transduction. Autoimmune diseases like asthma and multiple sclerosis (MS) are mediated by the sphingosine-1-phosphate receptor 1 (S1P1) to express a variety of symptoms and disease patterns. Inspired by its natural substrate, an array of artificial sphingolipid derivatives has been developed to target this specific G protein-coupled receptor (GPCR) in an attempt to suppress autoimmune disorders. FTY720, also known as fingolimod, is the first oral disease-modifying therapy for MS on the market. In pursuit of improved stability, bioavailability, and efficiency, structural analogues of this initial prodrug have emerged over time. This review covers a brief introduction to the sphingolipid metabolism, the mechanism of action on S1P1, and an updated overview of synthetic sphingosine S1P1 agonists. PMID- 30409536 TI - Structure-based design and discovery of potent and selective lysine-specific demethylase 1 (LSD1) inhibitors. AB - The histone demethylase LSD1 is a key enzyme in the epigenetic regulation of gene transcription. Here we present our efforts to discover small molecule reversible inhibitors of LSD1 as an attractive approach to treat hematologic malignancies and certain solid tumors. Using structure-based drug design, we designed and synthesized a novel series of heteroaromatic imidazole inhibitors that demonstrate potent inhibition of the demethylase activity and low nanomolar cell based activity. This novel LSD1 inhibitor series was further optimized by attenuating the hERG inhibition and improving oral bioavailability. PMID- 30409537 TI - The effect of body mass index on glucagon-like peptide receptor gene expression in the post mortem brain from individuals with mood and psychotic disorders. AB - There is an increasing interest in the putative role of glucagon-like peptide 1 receptor (GLP-1R) agonists as novel therapeutic agents for mental disorders. Herein, we investigated the expressions of GLP-1R and GLP-2R genes, and its relationship with body mass index (BMI), in the post-mortem brain tissue of patients with mood (MD) and psychotic disorders. Brain samples were localized to the dorsolateral prefrontal cortex (dlPFC) (n = 459) and hippocampus (n = 378). After adjustment for age, sex, ethnicity, post-mortem interval (PMI) and BMI, we observed significant differences, between healthy controls and MD subjects, in GLP-1R and GLP-2R gene expression in the dlPFC (beta = 1.504, p = 0.004; and beta = 1.305, p = 0.011, respectively); whereas in the hippocampus, only GLP-1R expression was significantly associated with MD (beta = -1.28, p = 0.029). No significant differences were found in relation to schizophrenia. In addition, we observed a moderating effect of MD diagnosis on the associations between BMI, GLP 1R and GLP-2R expression values in the dlPFC (beta = -0.05, p = 0.003; and beta = -0.04, p = 0.004, respectively). There was a similar moderating effect for GLP-1R in the hippocampus (beta = 0.043, 95% CI 0.003; 0.08 p = 0.03), but in an opposite direction than observed in the dlPFC. This is the first evidence of abnormal gene expression of GLP-1R and GLP-2R in postmortem brain of individuals with MD, providing a rationale for further inquiry and proof of principle interventional studies. PMID- 30409538 TI - Aging, inflammation and cancer. AB - Aging is a key aspect of neoplasia at the level of cells, individuals and populations. Unrestrained expression and production of inflammatory mediators is a key feature of aging at the cellular and organism level. Inflammatory cells and mediators are a key component of the tumor microenvironment and drive tumor progression. Non-resolving smoldering inflammation increases the risk of cancer (the extrinsic pathway connecting inflammation and cancer). In the intrinsic pathway, genetic events that cause neoplasia (oncogenes and oncosupressor genes) orchestrate the construction of cancer-related inflammation. We argue that uncontrolled smoldering inflammation drives carcinogenesis in aging and acts as a common denominator linking aging and cancer. PMID- 30409540 TI - Donor sites for radial forearm flaps: a direct comparison of closure with a local "hatchet" flap and split thickness skin grafts in a single patient. PMID- 30409539 TI - Surgical management of recurrent dislocation of the temporomandibular joint: a new treatment protocol. AB - Recurrent dislocation of the temporomandibular joint (TMJ) is rare. It is distinct from acute or chronic dislocation and is associated with considerable morbidity and deterioration in quality of life. To formulate a practical surgical treatment algorithm, we retrospectively reviewed the management and long-term outcomes of 14 patients who presented to a single hospital department over a period of six years (2010-2016), and collected data on demographics, clinical features, operation, and outcome. Patients were followed up for a minimum of 12 months and a maximum of seven years. Results showed effective long-term resolution of symptoms after a combination of eminectomy and disc plication (meniscopexy). Patients whose symptoms had resulted from dystonia of the lateral pterygoid muscle also benefitted from additional lateral pterygoid myotomy. A combination of eminectomy and disc plication (meniscopexy) effectively provides successful long-term outcomes in this group of patients. PMID- 30409541 TI - Which antiretrovirals should be prescribed as first-line treatments? Changes over the past 10 years in France. AB - OBJECTIVE: To describe the changes in first-line antiretroviral (ART) regimens in France between 2005 and 2015 and patients' characteristics related to the use of protease inhibitors in 2015. METHODS: We extracted all patients starting ART between 2005 and 2015 from a large prospective cohort. Regimens were classified as three nucleoside reverse transcriptase inhibitors (NRTI), or two NRTIs with a boosted protease inhibitor (bPI), with a non-nucleoside reverse transcriptase inhibitor (NNRTI), or with an INSTI. Patients' characteristics at the time of initiation were collected. A multinomial logit model was fitted to analyze characteristics related to the choice of regimen in 2015. RESULTS: We analyzed data from 15,897 patients. The proportion of patients starting with (i) a bPI decreased from 60% before 2014 to 38.1% in 2015; (ii) an NNRTI decreased from 30% to 17.8% in 2015; (iii) an INSTI gradually increased to 39.4% in 2015. In 2015, patients with an initial viral load ?5 log copies/mL were less likely to receive NNRTI (OR=0.08) or INSTI regimens (OR=0.69) than bPIs. Patients with initial CD4+ T cell count ?200/mm3 were less likely to receive an NNRTI (OR=0.28) or an INSTI regimen (OR=0.52) than a bPI. Women were less likely to receive an NNRTI (OR=0.79) or an INSTI regimen (OR=0.71) than a bPI; although this depended on age. CONCLUSION: The use of bPI as first-line ART declined sharply in France from 2005 to 2015. bPI remained of preferential use in patients with high viral load, low CD4+ T cell count, and in women. PMID- 30409542 TI - Impact of mandatory vaccination extension on infant vaccine coverages: Promising preliminary results. AB - OBJECTIVE: In France infant vaccines protecting against 11 diseases have changed from a recommended to a mandatory status for all children born on or after January 1, 2018. Using the Vaccinoscopie survey, we measured the impact of this new vaccination policy on vaccine coverage rates (VCRs) and on mothers' perception of vaccination. METHODS: Online survey with 1000 mothers of 0- to 11 month-old infants. RESULTS: VCRs for at least one dose at the age of 6 months strongly progressed for diseases that previously did not meet Public Health objectives (+8 points for Hepatitis B and +31 points for meningococcal C vaccines). Mothers were more favorable to mandatory vaccination and better informed in 2018 than in 2017. CONCLUSION: These first results showed a positive impact of the extension of mandatory vaccination on mothers' opinion regarding vaccination and on infant VCRs. PMID- 30409543 TI - [Knowledge and preferences on end-of-life resources in a sample of professionals of the Community of Madrid]. AB - OBJECTIVE: The Law (4/2017) on rights and guarantees of persons in the process of dying in Community of Madrid regulates the exercise of the rights of the person during this process. The main objective of this study was to determine the knowledge and preferences about palliative sedation (PS), euthanasia, physician assisted suicide (PAS), and adequacy of the therapeutic effort (ATE). MATERIALS AND METHODS: A questionnaire was designed to collect knowledge about definition and legality of detailed resources, and disposition for themselves or for a relative. The questionnaire was completed by a total of 192 palliative care Conference attendees (October 2017). RESULTS: Of those that completed the questionnaire, 160 (83.3%) were women, and the mean age was of 39 years (SD=15.8). More than two-thirds (131; 68.2%) did not know that the law existed. The definition with the highest rate of knowledge was on PS (89.1%; 171) and the lowest was ATE (50.5%; 97). On legality, the most successful was euthanasia (94.8%; 182) and the lowest was ATE (63.5%; 122). PS was considered the most appropriate resource (93.2%; 179), and the greater willingness of use in both relatives (91.7%; 176) as well as by themselves (90.6%; 174). PAS was the least suitable (34.4%; 66), and that less might resort in case of end-of-life of a relative (29.7%; 57), and themselves (33.3%; 64). CONCLUSIONS: There is a greater awareness of the condition of legality or illegality of each resource than of the definition of the terms. The use of the PAS and euthanasia is disapproved. It is important to clarify the meaning of ATE, and clarify its confusion with other measures such as PS and PAS. PMID- 30409544 TI - [Characteristics of the sexual sphere in elderly patients]. AB - OBJECTIVE: Sexuality plays a fundamental role in our lives, but there is little research on this subject with representative samples. This study aims to analyse the knowledge and characteristics of sexual function in people over 60 years of age. MATERIAL AND METHODS: An observational cross-sectional study was carried out. The sample consisted of people over 60 years of age who voluntarily attended health education talks on sexuality held in urban centres for the elderly. Before the talk, they were given a questionnaire to assess their sexual habits and practices. The talk on sexuality was given, and a questionnaire related to the concepts mentioned while the talk was delivered. The data from the questionnaires were collected on spreadsheets in Microsoft Office Excel for Windows, and the statistical analysis was performed with the statistical package SPSS. RESULTS: The results show that sexual activity is important in those over sixty years, with 52.53% of respondents having relationships. More than 70% of adults over 60 refer to being sexually attractive for their age. There were concepts about sexuality that were not clear after the talk. CONCLUSION: Our society is experiencing progressive aging involving the elderly groups in sex education, emphasising the changes at the sexual level implied by age. It is important to start training sessions on health education with content on sexuality and body image reinforcement in the elderly population. PMID- 30409545 TI - [Elevation of prolactin in patients with intellectual disability on psychopharmacological treatment]. PMID- 30409546 TI - [Treatment options for functional dyspepsia in 2018]. PMID- 30409547 TI - Prescription and Nonprescription Sleep Product Use Among Older Adults in the United States. AB - OBJECTIVE: Older adults commonly use products that may be used to promote sleep, such as benzodiazepines and over-the-counter medications, but the current extent of use of both prescription and nonprescription products specifically for sleep in the United States is unknown. METHODS: Respondents in this cross-sectional, nationally representative survey (the National Poll on Healthy Aging) of community-dwelling older adults aged 65-80 (n = 1,065) reported difficulty initiating sleep or early awakening ("sleep symptoms") and use of prescription medication or nonprescription aids to promote sleep ("sleep product"), including prescription sleep medication, over-the-counter (OTC) sleep aids, prescription pain medication, and herbal/natural sleep aids. Logistic regression was used to determine the association of respondent sociodemographic and clinical characteristics with the use of sleep products. RESULTS: Sleep symptoms were endorsed by 67.7% of respondents (95% confidence interval [CI] 64.7%-70.7%). Use of a sleep product was reported by 35.4% (95% CI 32.4%-38.6%), with 21.9% (95% CI 19.4%-24.7%) using OTC sleep aids, 12.5% using herbal/natural aids (95% CI 10.6% 14.8%), 8.3% using prescription sleep medication (95% CI 6.7%-10.3%), and 5.0% using prescription pain medication (95% CI 3.8%-6.7%). Self-reported fair/poor mental health (relative to excellent/very good) was associated with increased odds of sleep product use (adjusted odds ratio 2.28, 95% CI 1.10-4.72, p = 0.03). CONCLUSION: More than a third of older adults use medications or aids to help with sleep-most commonly OTC aids. Clinicians should routinely ask older patients about sleep-related difficulties and the use of nonprescription sleep aids. PMID- 30409548 TI - Advanced Research Institute (ARI): An Effective Model for Career Development and Transition to Independence. AB - The vitality of geriatric mental health research requires an ongoing infusion of new investigators into the career pipeline. This report examines outcomes of the NIMH-funded, Advanced Research Institute (ARI) in Geriatric Mental Health, a national mentoring program supporting the transition of early career researchers to independent investigators. Outcome data for 119 ARI Scholars were obtained from the NIH Reporter database, CVs, and PubMed: 95.0% continue in research, 80.7% had obtained federal grants, and 45.4% had achieved an NIH R01. Among all NIMH mentored K awardees initially funded 2002-2014 (n=901), 60.4% (32/53) of ARI participants vs. 42.0% (356/848) of nonparticipants obtained an R01. Controlling for funding year, ARI participants were 1.9 times more likely to achieve R01 funding than nonparticipants. These data suggest that ARI has helped new generations of researchers to achieve independent funding, become scientific leaders, and conduct high impact research contributing to public health and patient care. PMID- 30409549 TI - Mental Health Integration in Geriatric Patient-Aligned Care Teams in the Department of Veterans Affairs. AB - OBJECTIVES: To inform geriatric mental health policy by describing the role of behavioral healthcare providers within a geriatric patient-aligned care team (GeriPACT), a patient-centered medical home model of care within the Veterans Health Administration (VHA), serving older veterans with chronic disease, functional dependency, cognitive decline, and psychosocial challenges, and/or those who have elder abuse, risk of long-term care placement, or impending disability. METHODS: The authors used mixed methods, consisting of a national survey and site visits between July 2016 and February 2017, at VHA outpatient clinics. The participants, 101 GeriPACTs at 44 sites, completed surveys, and 24 medical providers were interviewed. A standardized survey and semi-structured interview guide were developed based on the program handbook, with input from experts in the VHA Office of Geriatrics and Extended Care Services, guided by the Consolidated Framework for Implementation Science Research. RESULTS: Of surveyed GeriPACTs, 42.6% had a mental health provider on the team-a psychiatrist (28.7%) and/or psychologist (23.8%). Of these, the mean was 0.27 full-time equivalent psychiatrists and 0.44 full-time equivalent psychologists per team (suggested panel = 800 patients). In surveys, teams with behavioral health providers were more likely to manage psychosocial chi2 = 8.87, cognitive chi2 = 8.68, and depressive chi2 = 11.85 conditions in their panel than those without behavioral health providers. CONCLUSION: GeriPACT mental health integration is less than 50%. Population differences between general primary care and geriatric primary care may require different care approaches and provider competencies and need further study. PMID- 30409550 TI - BrainWorks: A Comparative Effectiveness Trial to Examine Alzheimer's Disease Education for Community-Dwelling African Americans. AB - OBJECTIVES: To test a culturally tailored intervention to improve Alzheimer's disease (AD) literacy among African Americans. DESIGN: A 3-arm randomized comparative effectiveness trial. SETTING: Community sites in Los Angeles, CA. PARTICIPANTS: 193 African American community-dwelling adults, ages 45 to 95 years old. INTERVENTION: All groups attended BrainWorks Live, a culturally tailored, 60 minute talk show and received standard printed educational materials on AD. From there: a) the BrainWorks Live group received no further contact until the post test; b) one intervention group received a 1-month, culturally tailored, unidirectional, daily text-message program; and c) a second intervention group received daily text messages based on the printed educational materials that the general public would receive. AD literacy was measured at baseline and one month post intervention. MEASUREMENTS: Alzheimer's disease literacy and demographic and health covariates. RESULTS: At one month, participants who received culturally tailored text messages had the highest increase in AD literacy levels, followed by those in the BrainWorks Live arm. Participants who received general text messages had a lower overall increase in AD literacy levels compared to the other arms, but had higher mean AD literacy levels than the BrainWorks Live arm. There was a significantly greater increase in AD literacy levels among participants who received culturally tailored text messages compared with those who attended BrainWorks Live only. There were no other statistically significant differences between arms. CONCLUSIONS: AD literacy among African Americans can be improved after only one month through culturally competent, economically feasible educational formats. PMID- 30409551 TI - Anxiety as a Risk Factor for Cognitive Decline: A 12-Year Follow-Up Cohort Study. AB - OBJECTIVE: Anxiety might be a risk factor for cognitive decline, but previous studies had short follow-up or small sample sizes or studied general or single cognitive domain functioning. METHODS: Anxiety symptoms were assessed with the Symptom Checklist-90 in 918 participants of the Maastricht Aging Study aged 50 years or older. Anxiety was analyzed both dichotomously (highest versus lower quartiles as a group) and continuously. Neuropsychological tests measured executive function, memory, speed of information processing, and verbal fluency. Linear mixed models were conducted with anxiety symptoms as predictor and change in cognitive scores as outcome. Differences of associations by age and gender were studied with three-way interactions. RESULTS: Higher anxiety symptoms were significantly associated with more decline in verbal memory in those aged 65 years and older (delayed recall: chi2 = 9.30, df = 2, p = 0.01; immediate recall: chi2 = 11.81, df = 2, p = 0.003). There were sex differences in executive function (chi2 = 6.63, df = 2, p = 0.036), fluency (chi2 = 6.89, df = 2, p = 0.032), and processing speed (chi2 = 8.83, df = 2, p = 0.012), with lower performance in women over time. CONCLUSION: In participants without cognitive impairments at baseline, anxiety symptoms were associated with a decline in verbal memory in older adults and with poorer performance in nonamnestic domains in women. Adequate treatment of anxiety symptoms could have a beneficial influence on the risk of developing neurodegenerative diseases. Further research is needed to elucidate whether this association is causal. PMID- 30409552 TI - Toward Precision Medicine: Promising Areas of Research in Glioma. AB - OBJECTIVE: To present and describe three emerging areas of glioma research: volumetric imaging analysis, molecular profiling, and the use of liquid biopsies. DATA SOURCES: Published manuscripts and textbook chapters. CONCLUSION: As new imaging and molecular technologies for the patient with glioma become main stream, precise care can be individualized and personalized. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses caring for patients with gliomas can gain knowledge of emerging research and help increase accessibility to this technology by referring patients to clinical trials that apply this technology. PMID- 30409553 TI - Surgery and Evidence-based Treatments in Patients with Newly Diagnosed High-grade Glioma. AB - OBJECTIVE: To describe the currently accepted standard-of-care practice for surgical and medical management of newly diagnosed high-grade glioma. DATA SOURCES: Peer-reviewed journals, nationally accepted guidelines, and personal experience of the authors. CONCLUSION: There is a widely accepted standard-of care treatment protocol for patients with newly diagnosed high-grade glioma that includes maximal safe resection followed by radiation therapy with concurrent and adjuvant temozolomide. The regimen is well-tolerated and side effects are manageable. IMPLICATIONS FOR NURSING PRACTICE: Nurses who are involved in the care of patients with newly diagnosed high-grade glioma should be familiar with the regimen and its side effects to provide crucial patient and caregiver education in an accurate and beneficial manner. PMID- 30409554 TI - Pilot Study to Describe the Trajectory of Symptoms and Adaptive Strategies of Adults Living with Low-grade Glioma. AB - OBJECTIVES: To describe the adaptability to the patterns in symptoms and quality of life (QoL) during 6 months post low-grade glioma diagnosis by valid and reliable tools; to identify through qualitative interviews patient/provider adaptive techniques and strategies; and to assess associations among patient characteristics, symptoms and QoL, and adaptive techniques or strategies. DATA SOURCES: Demographic, clinical and pathologic data from medical records. Validated instruments that assess QoL, fatigue, depression, and distress were completed at 2, 4, and 6 months post diagnosis. Qualitative interviews identifying the symptoms, challenges, adaptive techniques and strategies were conducted at 4 and 6 months. CONCLUSION: The most frequently used adaptive strategies included: obtaining community support (87%), managing expectations (73%) and support systems (67%), and seeking out knowledge about physical (67%) and behavioral symptoms (53%). Seizures were reported with IDH1mut (11%) but not IDH1wildtype. Patients with either IDH1mut or TERTmut consistently reported lower QoL and higher distress, depression, and fatigue scores. IDH1/TERTmut may be related to lower QoL because of IDH1mut-related seizures. IMPLICATIONS FOR NURSING PRACTICE: Findings provide a list of adaptive strategies and characteristics to address the problems and symptoms that may improve overall QoL in patients with low-grade glioma. PMID- 30409555 TI - Tissue is the Issue: Biomarkers of Prognosis and Classification in Adult Gliomas. AB - OBJECTIVE: To explain several biomarkers used in primary adult brain tumor diagnosis and the methodologies for their application. DATA SOURCES: Peer reviewed literature. CONCLUSION: In the past few years, several biomarkers have been touted as providing reliable and objective assays of histogenesis, prognosis, and therapeutic sensitivity. A number of these markers have failed the test of time and rigorous practice applications. More recently, assays with diagnostic applications have been reported and validated from multiple laboratories using large numbers of patients in routine clinical practices. IMPLICATIONS FOR NURSING PRACTICE: This article provides a reference for biomarker tests for gliomas. There is a greater need for nurses to understand the translational interface between basic science and clinical medicine to determine the applications of these biomarkers for the best interests of their patients. PMID- 30409556 TI - 2D Flow CMR for Risk Assessment in Coronary Artery Disease: An Alternative to PET? PMID- 30409557 TI - Prognostic Implications of Mitral Annular Plane Systolic Excursion in Patients with Hypertension and a Clinical Indication for Cardiac Magnetic Resonance Imaging: A Multicenter Study. AB - OBJECTIVES: This study sought to evaluate the prognostic value of cardiac magnetic resonance (CMR)-derived mitral annular plane systolic excursion (MAPSE) in a large multicenter population of patients with hypertension. BACKGROUND: In patients with hypertension, cardiac abnormalities are powerful predictors of adverse outcomes. Long-axis mitral annular movement plays a fundamental role in cardiac mechanics and is an early marker for a number of pathological processes. Given the adverse consequences of cardiac involvement in hypertension, the authors hypothesized that lateral MAPSE may provide incremental prognostic information in these patients. METHODS: Consecutive patients with hypertension and a clinical indication for CMR at 4 U.S. medical centers were included in this study (n = 1,735). Lateral MAPSE was measured in the 4-chamber cine view. The primary endpoint was all-cause death. Cox proportional hazards regression modeling was used to examine the association between lateral MAPSE and death. The incremental prognostic value of lateral MAPSE was assessed in nested models. RESULTS: Over a median follow-up period of 5.1 years, 235 patients died. By Kaplan-Meier analysis, risk of death was significantly higher in patients with a lateral MAPSE < median (10 mm) (log-rank; p < 0.0001). Lateral MAPSE was associated with risk of death after adjustment for clinical and imaging risk factors (hazard ratio [HR]: 1.402-per-millimeter decrease; p < 0.001). Addition of lateral MAPSE in this model resulted in significant improvement in the C statistic (0.735 to 0.815; p < 0.0001). Continuous net reclassification improvement was 0.739 (95% confidence interval: 0.601 to 0.902). Lateral MAPSE remained significantly associated with death even after adjustment for feature tracking global longitudinal strain (HR: 1.192-per-millimeter decrease; p < 0.001). Lateral MAPSE was independently associated with death among the subgroups of patients with preserved ejection fraction (HR = 1.339; p < 0.001) and in those without history of myocardial infarction (HR: 1.390; p < 0.001). CONCLUSIONS: CMR derived lateral MAPSE is a powerful, independent predictor of mortality in patients with hypertension and a clinical indication for CMR, incremental to common clinical and CMR risk factors. These findings may suggest a role for CMR derived lateral MAPSE in identifying hypertensive patients at highest risk of death. PMID- 30409558 TI - Global Coronary Flow Reserve Measured During Stress Cardiac Magnetic Resonance Imaging Is an Independent Predictor of Adverse Cardiovascular Events. AB - OBJECTIVES: The aim of this study was to evaluate the incremental prognostic value of global coronary flow reserve (CFR) in patients with known or suspected coronary artery disease who were undergoing stress cardiac magnetic resonance (CMR) imaging. BACKGROUND: Coronary microvascular dysfunction results in impaired global CFR and is implicated in the development of both atherosclerosis and heart failure. Although noninvasive assessment of CFR with positron emission tomography provides independent prognostic information, the incremental prognostic value of CMR-derived CFR remains unclear. METHODS: Consecutive patients undergoing stress perfusion CMR were prospectively enrolled (n = 507). Coronary sinus flow was measured using phase-contrast imaging at baseline (pre) and immediately after stress (peak) perfusion. CFR was calculated as the ratio of peak to pre-flow. Patients were followed for major adverse cardiac events (MACE): death, nonfatal myocardial infarction, heart failure hospitalization, sustained ventricular tachycardia, and late revascularization. Cox proportional hazards regression modeling was used to examine the association between CFR and MACE. The incremental prognostic value of CFR was assessed in nested models. RESULTS: Over a median follow-up of 2.1 years, 80 patients experienced MACE. By Kaplan-Meier analysis, the risk of MACE was significantly higher in patients with CFR lower than the median (2.2) (log-rank p < 0.001); this remained significant after adjustment for the presence of ischemia and late gadolinium enhancement (LGE) (log-rank p < 0.001). CFR was significantly associated with the risk of MACE after adjustment for clinical and imaging risk factors, including ischemia extent, ejection fraction, and LGE size (hazard ratio: 1.238; p = 0.018). Addition of CFR in this model resulted in significant improvement in the C-index (from 0.70 to 0.75; p = 0.0087) and a continuous net reclassification improvement of 0.198 (95% confidence interval: 0.120 to 0.288). CONCLUSIONS: CMR-derived CFR is an independent predictor of MACE in patients with known or suspected coronary artery disease, incremental to common clinical and CMR risk factors. These findings suggest a role for CMR-derived CFR in identifying patients at risk of adverse events following stress CMR, even in the absence of ischemia and LGE. PMID- 30409559 TI - The Aryl Hydrocarbon Receptor: Connecting Immunity to the Microenvironment. AB - The aryl hydrocarbon receptor (AhR) is a cytoplasmic receptor and transcription factor activated through cognate ligand binding. It is an important factor in immunity and tissue homeostasis, and structurally diverse compounds from the environment, diet, microbiome, and host metabolism can induce AhR activity. Emerging evidence suggests that AhR is a key sensor allowing immune cells to adapt to environmental conditions and changes in AhR activity have been associated with autoimmune disorders and cancer. Furthermore, AhR agonists or antagonists can impact immune disease outcomes identifying AhR as a potentially actionable target for immunotherapy. In this review, we describe known ligands stimulating AhR activity, downstream proinflammatory and suppressive mechanisms potentiated by AhR, and how this understanding is being applied to immunopathology to help control disease outcomes. PMID- 30409560 TI - Red flags phenotyping: A systematic review on clinical features in atypical parkinsonian disorders. AB - To establish a clinical diagnosis of a parkinsonian disorder, physicians rely on their ability to identify relevant red flags, in addition to cardinal features, to support or refute their working diagnosis in an individual patient. The term 'red flag', was originally coined in 1989 to define the presence of non-cardinal features that may raise a suspicion of multiple system atrophy (MSA), or at least suggest alternative diagnosis to Parkinson's disease (PD). Since then, the term 'red flag', has been consistently used in the literature to denote the clinical history or signs that may signal to physicians the possibility of an atypical parkinsonian disorder (APD). While most red flags were originally based on expert opinion, many have gained acceptance and are now included in validated clinical diagnostic criteria of PD and APDs. The clinical appreciation of red flags, in conjunction with standard criteria, may result in a more accurate and earlier diagnosis compared to standard criteria alone. However, red flags can be clinical signs that are non-neurological, making the systematic assessment for them a real challenge in clinical practice. Here, we have conducted a systematic review to identify red flags and their clinical evidence in the differential diagnosis of common degenerative parkinsonism, including PD, MSA, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and dementia with Lewy body (DLB). Increasing awareness and appropriate use of red flags in clinical practice may benefit physicians in the diagnosis and management of their patients with parkinsonism. PMID- 30409561 TI - Use of Novel Anthropomorphic Breast Ultrasound Phantoms for Radiology Resident Education. AB - PURPOSE: This study evaluated the training and assessment role of anthropomorphic breast ultrasound phantoms that simulated both the morphological and sonographic characteristics of breast tissue, including lesions, in a group of radiology residents at a large academic medical center. METHODS: This was a prospective study involving nine residents across second to fourth years of a radiology residency program. Two devices (phantom 1 and phantom 2) were designed and constructed to produce similar realistic sonographic images of breast morphology with a range of embedded pathologies to provide a realistic training experience. Baseline assessments of all residents' ability to detect and characterize lesions in phantom 1 were carried out, followed by a 2-hour teaching session on the same phantom. All residents underwent a posttraining, final assessment on phantom 2 to evaluate changes in their lesion detection rate and ability to correctly characterize the lesions. RESULTS: The results demonstrated there was a significant increase in both the pooled detection and correct characterization score for all residents pre- and posttraining of 26% +/- 14% and 17% +/- 8%, P < .0003, respectively. Posttraining assessment surveys revealed that residents rated the training experience highly. CONCLUSIONS: This study suggests that there is a benefit in including a simulation training workshop with a novel anthropomorphic breast ultrasound training device to a radiology resident education program. Finally, the phantoms used in this study are useful for training and assessment purposes because they provide a lifelike simulation of breast tissue to practice ultrasound imaging without direct exposure to patients, in an environment with no pressure. PMID- 30409562 TI - A Bright Future for Nuclear Medicine. PMID- 30409563 TI - Cross-Sectional Study of Temozolomide-Induced Chemotherapy-Induced Nausea and Vomiting in Patients with Glioma. PMID- 30409564 TI - Antibiotic Prophylaxis and Incidence of Endocarditis Before and After the 2007 AHA Recommendations. AB - BACKGROUND: The American Heart Association updated its recommendations for antibiotic prophylaxis (AP) to prevent infective endocarditis (IE) in 2007, advising that AP cease for those at moderate risk of IE, but continue for those at high risk. OBJECTIVES: The authors sought to quantify any change in AP prescribing and IE incidence. METHODS: High-risk, moderate-risk, and unknown/low risk individuals with linked prescription and Medicare or commercial health care data were identified in the Truven Health MarketScan databases from May 2003 through August 2015 (198,522,665 enrollee-years of data). AP prescribing and IE incidence were evaluated by Poisson model analysis. RESULTS: By August 2015, the 2007 recommendation change was associated with a significant 64% (95% confidence interval [CI]: 59% to 68%) estimated fall in AP prescribing for moderate-risk individuals and a 20% (95% CI: 4% to 32%) estimated fall for those at high risk. Over the same period, there was a barely significant 75% (95% CI: 3% to 200%) estimated increase in IE incidence among moderate-risk individuals and a significant 177% estimated increase (95% CI: 66% to 361%) among those at high risk. In unknown/low-risk individuals, there was a significant 52% (95% CI: 46% to 58%) estimated fall in AP prescribing, but no significant increase in IE incidence. CONCLUSIONS: AP prescribing fell among all IE risk groups, particularly those at moderate risk. Concurrently, there was a significant increase in IE incidence among high-risk individuals, a borderline significant increase in moderate-risk individuals, and no change for those at low/unknown risk. Although these data do not establish a cause-effect relationship between AP reduction and IE increase, the fall in AP prescribing in those at high risk is of concern and, coupled with the borderline increase in IE incidence among those at moderate risk, warrants further investigation. PMID- 30409565 TI - Preventing Endocarditis: No Rest for the Worrier. PMID- 30409566 TI - Prescriber Patterns of SGLT2i After Expansions of U.S. Food and Drug Administration Labeling. PMID- 30409567 TI - Impact of Statins on Cardiovascular Outcomes Following Coronary Artery Calcium Scoring. AB - BACKGROUND: Compared with traditional risk factors, coronary artery calcium (CAC) scores improve prognostic accuracy for atherosclerotic cardiovascular disease (ASCVD) outcomes. However, the relative impact of statins on ASCVD outcomes stratified by CAC scores is unknown. OBJECTIVES: The authors sought to determine whether CAC can identify patients most likely to benefit from statin treatment. METHODS: The authors identified consecutive subjects without pre-existing ASCVD or malignancy who underwent CAC scoring from 2002 to 2009 at Walter Reed Army Medical Center. The primary outcome was first major adverse cardiovascular event (MACE), a composite of acute myocardial infarction, stroke, and cardiovascular death. The effect of statin therapy on outcomes was analyzed stratified by CAC presence and severity, after adjusting for baseline comorbidities with inverse probability of treatment weights based on propensity scores. RESULTS: A total of 13,644 patients (mean age 50 years; 71% men) were followed for a median of 9.4 years. Comparing patients with and without statin exposure, statin therapy was associated with reduced risk of MACE in patients with CAC (adjusted subhazard ratio: 0.76, 95% confidence interval: 0.60 to 0.95; p = 0.015), but not in patients without CAC (adjusted subhazard ratio: 1.00, 95% confidence interval: 0.79 to 1.27; p = 0.99). The effect of statin use on MACE was significantly related to the severity of CAC (p < 0.0001 for interaction), with the number needed to treat to prevent 1 initial MACE outcome over 10 years ranging from 100 (CAC 1 to 100) to 12 (CAC >100). CONCLUSIONS: In a largescale cohort without baseline ASCVD, the presence and severity of CAC identified patients most likely to benefit from statins for the primary prevention of cardiovascular diseases. PMID- 30409568 TI - Message for 2018 Cholesterol Management Guidelines Update: Time to Accept the Power of Zero. PMID- 30409570 TI - Alpha-Methylacetoacetic Aciduria in an Rh-Negative Pregnant Omani Woman With Breech Presentation Delivered With Favourable Outcome. AB - BACKGROUND: Alpha-methylacetoacetic aciduria, an autosomal recessive disorder of isoleucine and ketone body metabolism, is caused by a mutation in the acetyl coenzyme A acetyltransferase-1 gene (ACAT1; 607809) on chromosome 11q22. Ketoacidotic episodes in such patients are triggered by stress situations with increased energy demands. Pregnancy, surgical procedures, and prolonged fasting are potential triggers for metabolic crisis in such cases. CASE: A young Rh negative Omani woman with alpha-methylacetoacetic aciduria is described here during her second pregnancy. Her metabolic condition was detected at the age of 18 months. She was successfully delivered of a clinically healthy baby through emergency CS for breech presentation. CONCLUSION: Prompt management by a multidisciplinary team is vital to avoid metabolic crisis and to promote a favourable outcome in these cases. PMID- 30409569 TI - Vaccination Against Influenza in Pregnancy: A Survey of Canadian Maternity Care Providers. AB - OBJECTIVE: Influenza vaccine uptake among Canadian pregnant individuals is suboptimal. Failure to incorporate vaccination into routine prenatal care and a lack of recommendations from healthcare providers are recognized as barriers to vaccination. The aim of this study was to assess Canadian maternity care providers' knowledge, attitudes, and practices regarding influenza vaccination in pregnancy. METHODS: A cross-sectional Web-based questionnaire was sent during July and August 2017 to family physicians, obstetricians-gynaecologists, midwives, pharmacists, and nurses who care for pregnant individuals. A multivariable logistic regression model was used to determine variables independently associated with providers' recommendation of the influenza vaccine in pregnancy. RESULTS: The analysis included 1061 providers. Most participants (85%) reported being vaccinated against influenza themselves, and 72% reported recommending the influenza vaccine to all of their pregnant patients during the previous influenza season. Participants' attitudes regarding influenza vaccination during pregnancy were generally positive: 64% strongly agreed that pregnant individuals are at an increased risk of complications from influenza, and 69% strongly agreed that it is safe to vaccinate pregnant individuals against influenza. The main determinants of participants' recommendations for influenza vaccination to all pregnant patients were following official recommendations on influenza vaccination, discussing vaccines with most or all pregnant individuals seen in their practice, and being vaccinated themselves during the previous influenza season. CONCLUSION: Enhancing influenza vaccine uptake in pregnancy is largely dependent on maternity care providers' recommendations. This study provides valuable insight on providers' knowledge, attitudes, and practices. PMID- 30409571 TI - Quantification of polyglutamyl 5-methyltetrahydrofolate, monoglutamyl folate vitamers, and total folates in different berries and berry juice by UHPLC-MS/MS. AB - Edible berries are good sources of several phytochemicals. However, the native folate levels in berries are not well known. The structure of native folates contains polyglutamyl chains, which reportedly jeopardize the bioavailability of native folates; further gamma-glutamyl hydrolase (GGH) can deglutamylate polyglutamyl chains. In this study we use a validated ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method to determine the distribution of polyglutamyl 5-methyltetrahydrofolate (5-CH3THF-Glun), folate vitamers, and total folates in different berries and to monitor changes in their concentration during processing of berries into juice. The pre-boiling treatment was optimized during extraction to stabilize the native polyglutamyl folates profile and facilitate folate extraction, which can replace the traditional di enzyme treatment process. Additionally, the efficiency of commercially available human recombinant GGH was tested and it was found that a 10 ug GGH/mL extract at a pH of 6 could completely deconjugate polyglutamyl folates into monoglutamyl folates when incubated for 30 min. Pure human recombinant GGH with a higher catalytic efficiency and stable enzymatic properties was better than traditional folate conjugase for this purpose. From experimental analysis, it could be inferred that strawberries and blackberries contained the highest amount of total folates (93-118 ug/100 g), while the total folate contents in blueberries were the lowest. Most of the investigated berries are good to excellent folate sources. This study is the first time that 5-CH3THF-Glun and distribution of folate vitamers in various berries are quantitated. Further, this is the first study to show the application of recombinant pure GGH for the deconjugation of polyglutamyl folates for folate vitamers and total folates analysis. PMID- 30409572 TI - Formation of aqueous and alcoholic adducts of curcumin during its extraction. AB - Curcumin is a phenolic compound produced by some plants, among which Curcuma longa is the reachest in this principal curcuminoid. Curcumin is known from its lability, however, the structural curcumin transformations and the formation of hydroxy and alkoxy adducts has not been reported yet. The formation of the mentioned derivatives is favoured by an alkaline environment. The presented results are important both from the analytical and food processing point of view as curcumin transformation products can be mistakenly treated as new components naturally present in turmeric, while in fact they may be formed during food products preparation, causing consumer misinformation about their bioactivity. In this context, an attempt has been made to investigate this problem. The present paper shows that curcumin easily transforms into ketonic/enolic structural isomers and forms adducts with water and alcohols. All structures of these compounds were confirmed by MSn, HRMS and partly also by NMR data. PMID- 30409573 TI - Physical and oxidative stability of high fat fish oil-in-water emulsions stabilized with sodium caseinate and phosphatidylcholine as emulsifiers. AB - The physical and oxidative stability of high-fat omega-3 delivery systems such as fish oil-in-water emulsions stabilized with combinations of sodium caseinate (CAS) and phosphatidylcholine (PC) was optimized. The influence of fish oil content (50, 60 and 70%, w/w), amount of total emulsifier CAS + PC (1.4, 2.1 and 2.8%, w/w) and ratio between CAS and PC (0.4, 1.2 and 2) on physical and oxidative parameters was investigated. Creaming and droplet size significantly decreased when the amount of fish oil, total emulsifier and ratio of CAS to PC were increased. Viscosity decreased significantly with decreasing fish oil content, whereas the ratio of CAS to PC did not have a significant influence. Decreasing the ratio of CAS to PC led to emulsions with a significantly lower concentration of 1-penten-3-ol, while no significant effect was found for other volatiles such as (E)-2-pentenal, (E)-2-hexenal and (E,E)-2,4-heptadienal. PMID- 30409574 TI - Industrial scale preparation of pea flour fractions with enhanced nutritive composition by dry fractionation. AB - This study determined influence of industrial scale milling and air classification on separation of pea flours into fine and coarse fractions. Three commercial field pea flours were chosen from field peas grown in Manitoba, Canada, - whole green pea flour (WGPF), split green pea flour (SGPF), and organic split yellow pea flour (OSYPF). The ranges of 85-87% protein, 74-95% fat, and 66 76% minerals were enriched in the pea fine fractions. A range of 78-91% starch was enriched in the coarse fractions. Scanning electron microscopy and proximate analysis confirmed compositional shift between the fine and coarse fractions. The particle size analysis demonstrated that the milling in this study was sufficient and effective in reducing the flour particle size to smaller than 22 um, which was considered to be the cut-point. The yield of the fine fraction was as high as 44% and acceptable for an industrial manufacture. PMID- 30409575 TI - Structural and interfacial characteristics of oil bodies in coconuts (Cocos nucifera L.). AB - This study investigated the structural characteristics of oil bodies from mature coconut (Cocos nucifera L.) fruit. The ultrastructure and the distribution of oil bodies in coconut endosperm were investigated using cryo-scanning electron microscopy. The interfacial characteristics of the oil bodies in suspensions isolated using two different protocols were studied using confocal laser scanning microscopy (CLSM), and the oleosins stabilizing the oil bodies were characterized using sodium dodecyl sulfate polyacrylamide electrophoresis. The oil bodies were found to be preferentially accumulated in endosperm tissues away from the inner endosperm and had a polydisperse size distribution, both intracellularly and in suspensions. The CLSM of oil bodies revealed uniform distribution of proteins and phospholipids at the interface along with glycolipids. Six different proteins were found to be associated with oil bodies some of which were disulfide-linked. This work provides new insights into the structure of coconut oil bodies and mechanisms for their stabilization. PMID- 30409576 TI - Evaluation of cleanup procedures in pesticide multi-residue analysis with QuEChERS in cinnamon bark. AB - Cinnamon bark is a very complex spices matrix for pesticide residue analysis. In this study, two cleanup procedures, dispersive solid-phase extraction (d-SPE) and repetitive d-SPE, combined with Quick, Easy, Cheap, Effective, Rugged and Safe (QuEChERS) extraction were both investigated and applied for the determination of 60 pesticide residues in cinnamon bark by liquid chromatography - tandem mass spectrometry (LC-MS/MS) detection. The extraction solvents, phase partition salts, and cleanup sorbents were optimized. The results showed that 150 mg MgSO4 + 50 mg C18 showed the best performance in d-SPE. The repetitive d-SPE achieved less matrix effects than d-SPE, but several high water-solubility analytes were lost during the cleanup, and also the 10 fold dilution compromised the sensitivities of analytes. With the validated QuEChERS-d-SPE method, 44 of 60 pesticides obtained satisfactory recoveries (71%-118%) and RSDs (2%-27%) at three to five spiking levels. The method was applied to monitor 15 market cinnamon samples. PMID- 30409577 TI - Effects of atmospheric pressure plasma jet on the conformation and physicochemical properties of myofibrillar proteins from king prawn (Litopenaeus vannamei). AB - The aim of this study was to ascertain the impact of atmospheric pressure plasma jet treatment (APPJ) as a function of treatment times (0, 2, 4, 6, 8 and 10 min) on the conformation and physicochemical properties of myofibrillar proteins (MPs) extracted from king prawn (Litopenaeus vannamei). The results showed that the pH and protein solubility were decreased after 10 min treatment of APPJ. These results were also confirmed by dynamic light scattering, which indicated an increase in mean particle diameter of MPs from 654 to 2297 nm. Complementary methodologies used to characterize the structural changes confirmed the exposure of hydrophobic groups and promotion of protein-protein interactions. These occurrences were particularly more intense at the longest treatment duration. The high energetic and oxidizing species contained in the plasma gas may have considerable implications on the physical and structural characteristics of MPs from king prawn. PMID- 30409578 TI - Physicochemical properties and mineral content of honey samples from Vojvodina (Republic of Serbia). AB - Forty-five honey samples of three honey types - two monofloral (acacia and sunflower) and one polyfloral (meadow) were collected from the Autonomous Province of Vojvodina (Republic of Serbia) and analysed for their physicochemical parameters (moisture, acidity, pH, ash, electrical conductivity, glucose, fructose, hydroxymethylfurfural (HMF), CIE L*a*b* colour and mineral content). All tested physicochemical parameters were in agreement with the EU regulation except for moisture (4 samples) and HMF content (1 sample). Principal component analysis (PCA) was used for assessing the effects of three honey types on all investigated physicochemical parameters. According to PCA, acacia honey samples can be clearly isolated and form a cluster, while, regarding other honey types, PCA can offer the possibility to distinguish sunflower and meadow honey samples regarding examined physicochemical parameters and mineral content. PMID- 30409579 TI - Rapid and sensitive detection of acrylamide in fried food using dispersive solid phase extraction combined with surface-enhanced Raman spectroscopy. AB - A rapid, reliable, and quantitative method to determine acrylamide content in fried food based on surface-enhanced Raman spectroscopy (SERS) by re-oxidized graphene oxide/Au nanoparticle composites and dispersive solid-phase extraction has been proposed. The peak at ?v = 1478 cm-1 was selected as the characteristic peak of acrylamide for quantitation. Sufficient linearity was obtained in the concentration range of 5-100 MUg.kg-1 (R2 = 0.983). The limits of detection and quantification in fried food were 2 and 5 MUg.kg-1, respectively. The recovery rates for acrylamide were 73.4-92.8% with coefficients of variation less than 4.2%, and the long-term stability of the substrates was approximately 180 days at 4 degrees C. The results of detection using the proposed method were consistent with those obtained by LC-MS/MS, while the measurement time was reduced to 9.5 min per sample. The study also demonstrates that this method can potentially be used for acrylamide detection in the field. PMID- 30409580 TI - Pulsed electric fields treatment at different pH enhances the antioxidant and anti-inflammatory activity of ovomucin-depleted egg white. AB - This research investigated the effects of pulsed electric fields (PEF) (1.4-1.7 kV/cm, 653-695 kJ/kg) and heating (60 and 80 degrees C for 10 min) at different pH (4, 5, 7, and 9) on the antioxidant and anti-inflammatory activity of ovomucin depleted egg white (OdEW) after in vitro gastrointestinal hydrolysis. PEF and heating (80 degrees C for 10 min) at pH 4 enhanced the antioxidant activity of the whole hydrolysates, chemically determined using DPPH and ORAC assays. Furthermore, the anti-inflammatory activity of protein hydrolysates was assessed in lipopolysaccharide-stimulated HT-29 cells using ELISA assay. PEF and heating at pH 4 enhanced the anti-inflammatory activity of the whole hydrolysates dose dependently. Hydrolysates at 1 mg/ml showed similar inhibition (35.5% and 35.9%) of interleukin-8 production, due to PEF treatment and heating (80 degrees C for 10 min), respectively. Results indicated that prior PEF treatment can analogously enhance both antioxidant and anti-inflammatory activity of OdEW hydrolysates to heating, with potentially reduced thermal input. PMID- 30409581 TI - Preconcentrations and determinations of copper, nickel and lead in baby food samples employing Coprinus silvaticus immobilized multi-walled carbon nanotube as solid phase sorbent. AB - Preconcentrations of Cu(II), Ni(II) and Pb(II) ions by using Coprinus silvaticus immobilized multiwalled carbon nanotube (MWCNT) were investigated. Effects of important parameters on preconcentration procedure were examined. The best pH values of for Cu(II), Ni(II) and Pb(II) were found to be 6.0, 6.0 and 4.0, respectively. Flow rate of sample solution was 2.0 mL min-1, while desorption was achieved at 1.0 mL min-1 flow rate. Preconcentration factors were achieved as 60 for Cu(II), Ni(II) and 70 for Pb(II) (by dividing initial sample volume to final volume). LODs were calculated as 0.014, 0.016 and 0.093 ng mL-1, respectively for Cu(II), Ni(II) and Pb(II). Accuracy of the method was checked by applying to certified reference samples. Inductively coupled plasma optical emission spectrometer (ICP OES) was employed for measurements of Cu(II), Ni(II) and Pb(II) in digested baby food samples. PMID- 30409582 TI - Antimicrobial and antioxidant activity of unencapsulated and encapsulated clove (Syzygium aromaticum, L.) essential oil. AB - Clove (Syzygium aromaticum, L.) essential oil is known for its antimicrobial activity against several pathogenic bacteria. Encapsulation of clove oil was proposed as a mean to disguise its strong odor that limits its uses in food industry. Thus, the aim of this study was extraction, encapsulation and assessment of the antimicrobial and antioxidant potential of clove essential oil. The essential oil showed high DPPH scavenging capacity and low hydroxyl radical inhibition. Clove essential oil showed in vitro inhibitory and bactericidal effect against S. aureus, E. coli, L. monocytogenes and S. Typhimurium. In addition, in situ antimicrobial activity of clove oil against S. aureus was superior to nitrite. The essential oil particles encapsulated with sodium alginate and emulsifiers, showed high encapsulation efficiency, low antioxidant activity and strong antimicrobial inhibition. Similar bacterial growth was observed in meat-like products after addition of either particles or nitrite. PMID- 30409583 TI - Effect of the winemaking process on the volatile composition and aromatic profile of Tempranillo Blanco wines. AB - The effects of the carbonic maceration and conventional winemaking on the volatile composition and aromatic sensory characteristics of Tempranillo Blanco wines were studied for the first time, during three consecutive vintages. Relationships between instrumental (volatiles) and sensory variables were analyzed applying partial least squares regression (PLS). Carbonic macerated wines had higher contents of alcohols and carbonyl compounds, yet lower concentrations of C6 alcohols and volatile acids than wines conventionally produced. The Odor Activity Values (OAV) exhibited an increase in wines when carbonic maceration was applied. According to the geometric mean (% GM) obtained from aroma descriptors the effect of the winemaking process was significant for seed fruit, ripe fruit and floral notes. When subjected to PLS the data from the instrumental analysis yielded a satisfactory model for the prediction of aroma descriptors in this set of wines. PMID- 30409584 TI - Effects of smoking or baking procedures during sausage processing on the formation of heterocyclic amines measured using UPLC-MS/MS. AB - We used an UPLC-MS/MS method to investigate the effects of smoking or baking on the formation of heterocyclic amines (HAs) in sausage processing. We used principal component analysis (PCA) to differentiate the chemical composition, pH and colour of the processed sausages. We detected and quantified eight types of HAs (PhIP, DMIP, Phe-P-1, IQ[4,5-b], 7,8-DiMeIQx, AalphaC, harman and norharman) in sausages, finding total HA concentrations as high as 422 +/- 17.5 ng/g. Higher smoking temperatures led to higher concentrations of total HA in smoked sausages (330 +/- 8.19 to 422 +/- 17.5 ng/g). On the contrary, higher baking temperatures created lower total HA concentrations in baked sausages (ranging from 139 +/- 9.83 to 306 +/- 0.92 ng/g). Our results demonstrated that HAs are produced even at low temperatures, which means that HAs should be controlled during sausage processing to minimise their formation. PMID- 30409585 TI - Simultaneous determination of 131 pesticides in tea by on-line GPC-GC-MS/MS using graphitized multi-walled carbon nanotubes as dispersive solid phase extraction sorbent. AB - A rapid and sensitive method was developed to determine 131 pesticides in tea by on-line gel permeation chromatography-gas chromatography tandem mass spectrometer (on-line GPC-GC-MS/MS) using graphitized multi-walled carbon nanotubes (MWCNTs) as dispersive solid phase extraction (DSPE) sorbent in sample pretreatment. Sample clean-up performance of various functionalized MWCNTs and their influences to recoveries were investigated. In the method validation, good linearity correlation coefficients (R2) were obtained, which were higher than 0.99 for all pesticides. The percent recoveries were 78.2%-113.9% at the spiked concentration levels of 20, 50 and 200 ug/kg with relative standard deviations (RSDs, n = 6) lower than 15.8%. Limits of detections (LODs) were in the range of 0.5-5.0 ug/kg. This method is simple and fast with relatively high sensitivity and can achieve the requirements of pesticides analysis. PMID- 30409586 TI - Preparation of camellia oil-based W/O emulsions stabilized by tea polyphenol palmitate: Structuring camellia oil as a potential solid fat replacer. AB - Water-in-oil (W/O) emulsions with a discontinuous aqueous phase dispersed in a continuous camellia oil phase were prepared by using tea polyphenol palmitate (Tp palmitate) particle as effective stabilizers and their properties were characterized by droplet size, slip melting point (SMP), stability, microstructure and rheology. The d(4,3) and d(3,2) decreased from 7.96 MUm to 4.67 MUm and from 5.98 MUm to 3.07 MUm, respectively, and the SMP rose from 33.73 degrees C to 38.60 degrees C when the Tp-palmitate concentration increased from 1.0% to 2.5% (m/v). The storage stability, freeze/thaw stability and thermal stability significantly enhanced and the droplets aggregation progressively increased with the increasing of Tp-palmitate concentration. The liquid camellia oil was transformed into solid-like viscoelastic emulsion gels with a SMP of 38.6 degrees C when using 2.5% Tp-palmitate as particle stabilizers. This study provides a promising method for production of edible gel-like W/O emulsions using polyphenol-lipid complexes to potentially replace solid fats. PMID- 30409587 TI - An update to the fatty acid profiles of bovine retail milk in the United Kingdom: Implications for nutrition in different age and gender groups. AB - This study investigated the effect of UK dairy production system, month, and their interaction, on retail milk fatty acid (FA) profile throughout the year. Milk samples (n = 120) from four conventional (CON), four organic (ORG) and two free-range (FR) brands were collected monthly. ORG milk had more nutritionally desirable polyunsaturated FA, including rumenic acid and the omega-3 PUFA alpha linolenic, eicosapentaenoic and docosapentaenoic acids, and less of the nutritionally-undesirable palmitic acid. Milk FA profile was similar between FR and CON systems, but FR milk had less saturated FA (SFA) and/or palmitic acid, and/or greater alpha-linolenic and rumenic acids in certain months within the peak-grazing season. According to the measured milk FA profiles and UK milk fat intakes, milk and dairy products contribute around one-third of the maximum recommended SFA intake. A small increased intake of beneficial PUFA may be expected by consuming ORG milk but human health implications from such differences are unknown. PMID- 30409588 TI - Effect of extrusion on the physicochemical and antioxidant properties of value added snacks from whole wheat (Triticum aestivum L.) flour. AB - Nutritional quality of snacks prepared from cereals can be improved by the addition of crude lycopene (CL), tomato powder (TP) and saffron extracts (SE) which are known for their high photochemical content. The study was undertaken to prepare extruded snacks from whole wheat flour enriched with CL, TP and SE. Effect of extrusion on physicochemical, antioxidant and sensory properties of snacks was also investigated. Hardness of snacks containing CL and TP was higher than the control. Pasting properties of the formulations were significantly (p < 0.05) reduced upon addition of CL and TP. Total phenolic content (TPC) of the formulations with added TP increased significantly (p < 0.05). Antioxidant properties of snacks enhanced after enrichment. Extrusion significantly (p < 0.05) reduced the TPC, DPPH scavenging activity and pasting properties of snacks while, reducing power and inhibition of lipid peroxidation increased. Storage period lowered the hardness and antioxidant properties of snacks. PMID- 30409589 TI - Ancient olive trees as a source of olive oils rich in phenolic compounds. AB - Olive oil phenolic compounds are receiving increased attention due to its influence on sensory characteristics and to scientific evidences of positive health effects. In this work, 28 ancient olive trees were selected and, during four consecutive seasons (2014-2017), oils were extracted and their phenolic fraction characterized. Hydroxytyrosol and tyrosol secoiridoids were the predominant groups, with contents between 32 and 496 mg of tyrosol equivalents/kg. Based on principal component analysis it could be concluded that the individual phenolic contents enabled the unsupervised grouping of olive oils by crop year. Furthermore, linear discriminant analysis allowed achieving sensitivities greater than 90%. It was shown that some specimens consistently allowed obtaining oils with high phenolic contents (>=500 mg tyrosol equivalents/kg). The identification of centenarian specimens for breeding based on their potential to produce oils with high levels of healthy compounds is of utmost interest, contributing to preserve the genetic heritage. PMID- 30409590 TI - Effects of low power ultrasonic treatment on the transformation of cyanidin-3-O glucoside to methylpyranocyanidin-3-O-glucoside and its stability evaluation. AB - Pyranoanthocyanins are anthocyanin derivatives that are formed during fermentation and oxygenation processes in aged wine. They play a critical role in assessing the aging of wine based on its colour quality. Naturally, the formation process of pyranoanthocyanins is fairly slow. In this respect, the present work studies the role and efficiency of ultrasonic treatment in accelerating the formation of methylpyranocyanidin-3-O-glucoside and investigates the spectral characteristics as well as the stability of this derivative toward heat, bisulfite bleaching and pH variation in a simulation system. Our results showed that the yield of methylpyranocyanidin-3-O-glucoside can be increased by 32.5% by ultrasonic treatment at 100 W for 40 min, and excessive treatment (>=60 min) does not have a positive effect on the yield. Moreover, this derivative exhibits a better stability toward heat, pH variation and bisulfite bleaching than its precursor cyanidin-3-O-glucoside. PMID- 30409591 TI - Characterization of molecular biomarkers of mercury exposure to muscle tissue of Plagioscion squamosissimus and Colossoma macropomum from the Amazon region. AB - Mercury has the ability to bind to a variety of biomolecules, which can compromise its structure and functionality and thus promote its toxic effects. The aim of this study is to identify possible mercury biomarkers in muscle samples of Plagioscion squamosissimus (carnivorous fish) and Colossoma macropomum (omnivorous fish), from the Amazon region. The muscle proteome of fish species was separated by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), and the total mercury concentrations in protein spots were determined by graphite furnace atomic absorption spectrometry (GFAAS). The protein spots containing mercury were characterized by electrospray ionization tandem mass spectrometry (ESI-MS/MS). The mercury concentrations in the protein spots were in the range of 1.10 +/- 0.02-23.90 +/- 0.33 MUg g-1. The proteins phosphoglycerate mutase 2 (P. squamosissimus), hemoglobin beta and cytochrome P450scc (C. macropomum), identified by ESI-MS/MS and showing the highest values of mercury concentration, may be considered possible mercury biomarkers. PMID- 30409592 TI - Electrostatically in situ binding of zwitterionic glycine on the surface of MGO for determination of nitrite in various real samples. AB - Zwitterionic dispersive magnetic solid phase extraction (ZI-DMSPE) was developed through in situ binding of glycine on the magnetic graphene oxide, electrostatically. This highly selective sorbent was applied for the determination and preconcentration of trace levels of nitrite in soil, sausage, water samples (tap, mineral, and rain), and vegetables (potato, onion, spinach, radish, and lettuce) prior to its determination by UV-Vis spectrophotometry. The major advantage of the method is the analyte adsorption in both acidic and basic media. The sorbent was characterized by SEM, XRD, EDS, and FT-IR. Several parameters affecting ZI-DMSPE were optimized. Under the optimal conditions, LOD and RSD were obtained 17 ng L-1 and 1.3% respectively. Preconcentration factor and sorption capacity of the proposed method were 666 and 238 mg g-1 respectively. Accuracy was assessed by comparing results with those obtained by direct determination using ion chromatography and spiked real samples. PMID- 30409593 TI - Novel biologically active principles from spinach, goji and quinoa. AB - Spinach leaves, goji berries and quinoa seeds are claimed to have a great nutraceutical potential due to their high content of compounds providing benefits for human health, such as amino acids, polyunsaturated fatty acids, carotenoids, betaine, vitamins, fibre, minerals and polyphenols. Samples of these plants were extracted with different solvent mixtures (e.g. EtOH, H2O/EtOH 3:7 and H2O/EtOH 7:3) and extractions were accomplished using a microwave apparatus. Subsequent UHPLC analysis and photodiode array detection were employed for the quantification of biologically active compounds like 7-isopentenyloxycoumarin, auraptene, umbelliprenin, boropinic acid and 4'-geranyloxyferulic acid. EtOH was found to be the best solvent in terms of extractive yields and the above mentioned phytochemicals were recorded in the concentration range 2.01-49.22 ug/g dry extract. The findings depicted herein revealed that spinach, goji and quinoa are good sources of oxyprenylated umbelliferone and ferulic acid derivatives. PMID- 30409594 TI - Characterization and comparison of whey N-glycoproteomes from human and bovine colostrum and mature milk. AB - Milk glycoproteins are crucial nutrients with a variety of functions. However, whey N-glycoproteomes in human and bovine milks have not been characterized during lactation. Herein, using lectin enrichment and liquid chromatography tandem mass spectrometry, 68, 58, 100, and 98 N-glycoproteins were identified in human colostrum and mature milk as well as bovine colostrum and mature milk whey. Gene Ontology and KEGG pathway analyses were used to elucidate the biological functions of whey N-glycoproteins in human and bovine colostrum and mature milks. Whey N-glycoproteomes differed dramatically between human and bovine milks and across lactation stages. The conserved and specific whey N-glycoproteins in all four sample types were also determined. Our results improve understanding of the properties and biological functions of whey N-glycoproteins in human and bovine milk and colostra, and provide insight into the potential application of some N glycoproteins in infant formulae at different stages of development. PMID- 30409595 TI - Influence of oven and microwave cooking with the addition of herbs on the exposure to multi-mycotoxins from chicken breast muscle. AB - Mycotoxins can contaminate poultry production via fungal infection of feeds. The impact of different cooking methods on mycotoxins stability and bioaccessibility is scarcely studied. Recent cooking practices such as the use of roasting bags along with some seasonings to cook chicken have become a trend to maintain the tenderness of the meat. This study evaluated the impact of oven roasting and microwaving of chicken breast muscles, with/without roasting bags and/or herbs addition on the stability and bioaccessibility of the 10 prevalent mycotoxins. Cooking itself reduced mycotoxins content, while using bags did not confer any advantage; adding herbs reduced mycotoxins content by up to 60%, but also appeared to increase their bioaccessibility. Thus, strategies to reduce their increased bioaccessibility should be the subject of future research. Notwithstanding, adding herbs prior to cooking could be used as a mitigation strategy to reduce mycotoxins in meat. PMID- 30409596 TI - Annual ryegrass (Lolium rigidum Gaud) competition altered wheat grain quality: A study under elevated atmospheric CO2 levels and drought conditions. AB - Annual ryegrass is one of the most serious, costly weeds of winter cropping systems in Australia. To determine whether its competition-mediated plant defence mechanisms effect on wheat grain quality, wheat (cv. Yitpi) and annual ryegrass were grown under two levels of CO2 (400 ppm; (a[CO2]) vs 700 ppm; (e[CO2]), two levels of water (well-watered vs drought) and two types of competition (wheat only; (W), and wheat * annual ryegrass; (W * R) with four replicates. The competition * [CO2] interaction had a significant effect on wheat grain protein content, where it was increased in W * R under both e[CO2] (+17%) and a[CO2] (+21%). Grain yield, total grain reducing power and phenolic content were significantly affected by [CO2] * drought * competition. In a summary, annual ryegrass competition significantly altered the wheat grain quality under both [CO2] levels (depending on the soil water level), while also decreasing the grain yield. PMID- 30409597 TI - Preparation of conducting polyaniline/protoporphyrin composites and their application for sensing VOCs. AB - Polyaniline/protoporphyrin nanocomposites were prepared via a simple chemical method in the acidic suspension of protoporphyrin. The scanning electron microscope images revealed that the polyaniline/protoporphyrin composites exhibited an interesting nanosheet structure decorated with nanoparticles, which is rather different with the usual nanofiber morphology of polyaniline. The formation of the nanosheet structure is because protoporphyrin molecules may exist as a bilayer form at low pH, which is similar with the phospholipid bilayer in membranes of cells. To demonstrate the application potential of the composites, the sensing performance of the composites was tested when exposed to four volatile organic compounds, including trimethylamine, triethylamine, ethanol, and ethyl acetate. The composites exhibited highest response value (S) of 39.482 toward trimethylamine, and fast response time of 2-4 s toward trimethylamine and triethylamine. The outstanding sensing performance showed that the prepared composites had great application potential in electronic noses system in further work. PMID- 30409598 TI - Stability of vitamin B12 with the protection of whey proteins and their effects on the gut microbiome. AB - Cobalamin degrades in the presence of light and heat, which causes spectral changes and loss of coenzyme activity. In the presence of beta-lactoglobulin or alpha-lactalbumin, the thermal- and photostabilities of adenosylcobalamin (ADCBL) and cyanocobalamin (CNCBL) are increased by 10-30%. Similarly, the stabilities of ADCBL and CNCBL are increased in the presence of whey proteins by 19.7% and 2.2%, respectively, when tested in gastric juice for 2 h. Due to the limited absorption of cobalamin during digestion, excess cobalamin can enter the colon and modulate the gut microbiome. In a colonic model in vitro, supplementation with cobalamin and whey enhanced the proportions of Firmicutes and Bacteroidetes spp. and reduced those of Proteobacteria spp., which includes pathogens such as Escherichia and Shigella spp., and Pseudomonas spp. Thus, while complex formation could improve the stability and bioavailability of cobalamin, these complexes might also mediate gut microecology to influence human nutrition and health. PMID- 30409599 TI - Formation of soy protein isolate-carrageenan complex coacervates for improved viability of Bifidobacterium longum during pasteurization and in vitro digestion. AB - Soy protein isolate (SPI) and carrageenan (IC) complex coacervates were formed through electrostatic attractions for encapsulating Bifidobacterium longum. The effects of pH (2.0-5.0) and SPI:IC mass ratios (10:1, 15:1, 20:1) on coacervate yield, entrapment efficiency and viability of the probiotic bacteria were investigated. The coacervates produced at pH 3 had higher yields and entrapment efficiency, and a SPI:IC mass ratio of 10:1 produced a complex coacervate with more compact microstructure. Compared to the native ones, the bacteria encapsulated in the coacervates had significantly improved viability during storage (4 degrees C), pasteurization (85 degrees C for 5, 10 and 30 min) and in vitro dynamic gastric and intestinal digestion. The findings also suggested that the coacervate with a SPI:IC ratio of 10:1 was more capable to protect the bacteria from loss against different stresses. This study provides a novel approach for designing efficient microcapsules containing probiotic bacteria with enhanced functional properties. PMID- 30409600 TI - Electron spin resonance (ESR) spectroscopy study of cheese treated with accelerated electrons. AB - The generation, accumulation and decay of free radicals in six varieties of cheese, irradiated (0-4 kGy) in an electron accelerator, have been studied by electron spin resonance (ESR) spectroscopy. Remarkably, the ESR spectra of all untreated cheeses showed only one singlet signal with a g-factor of 2.0064 +/- 0.0005. Surprisingly, the ESR spectra of irradiated samples presented a new signal with g-factor of 2.0037 +/- 0.0003 which was independent of the type of cheese, and which might be due to free radicals from the radiolysis of proteins. Surface regression models (P < 0.0001) established the relationship among signal intensity, absorbed dose (0, 1, 2 and 4 kGy) and storage time (0-180 days) for the different types of cheese. Results suggested that the analysis by ESR (or electron paramagnetic resonance, EPR) is suitable to evaluate, either qualitatively or quantitatively, the irradiation treatment of different types of cheese. PMID- 30409601 TI - Zein-hyaluronic acid binary complex as a delivery vehicle of quercetagetin: Fabrication, structural characterization, physicochemical stability and in vitro release property. AB - The antisolvent coprecipitation method was utilized for fabricating the zein and hyaluronic acid complex at different mass ratios (100:5, 100:10, 100:15, 100:20, 100:25 and 100:30). Results showed that negatively charged zein-hyaluronic acid complex with small size (181.5 nm) was formed through the driving force of electrostatic attraction, followed by hydrogen bonding and hydrophobic effects. The incorporation of hyaluronic acid led to conformational change of zein, and improved its physical and thermal stability. Native hyaluronic acid showed a three-dimensional network structure, while zein-hyaluronic acid binary complex exhibited two different microstructures, including nanoparticles (zein: hyaluronic acid, above 100:20) and particle-filled-microgel (zein: hyaluronic acid, below 100:20). In addition, zein-hyaluronic acid complex was designed as a new delivery vehicle to anti- thermal degradation and control release of quercetagetin. These findings indicated that zein-hyaluronic acid complex would be a useful and promising delivery vehicle for embedding and protecting bioactive compounds. PMID- 30409602 TI - Effect of malvidin-3-glucoside and epicatechin interaction on their ability to interact with salivary proline-rich proteins. AB - At red wine pH, malvidin-3-glucoside (mv-3-glc), the major anthocyanin of red wine, is expected to be present mainly in its non-colored hemiketal form. However, due to copigmentation with flavanols (e.g. epicatechin), the stabilization of the colored forms of mv-3-glc occurs. Some flavanols have been linked to astringency, due to their ability to interact/precipitate salivary proteins, namely proline-rich proteins (PRPs). So, a major question is if this copigmentation interaction could affect the ability of flavanols to interact with SP. To answer this, the effect of the interaction between mv-3-glc and epicatechin with basic and acidic PRPs, was investigated by saturation-tranfer difference (STD)-NMR and isothermal titration calorimetry (ITC). The most relevant result was that epicatechin:mv-3-glc mixture presents a synergic effect toward the interaction with both PRPs when compared to individual polyphenols. Furthermore, was observed that epicatechin interaction was driven by hydrophobic and hydrophilic interactions while mv-3-glc interaction was driven by electrostatic interactions. PMID- 30409603 TI - A novel method based on fluorescent magnetic nanobeads for rapid detection of Escherichia coli O157:H7. AB - Fluorescent lateral flow immunoassay (FLFIA) based on immunomagnetic separation (IMS) has the advantage of sensitivity. However, its complex operation includes IMS, elution, incubation, and FLFIA steps. Here, we prepared a core@shell@satellite structure fluorescent magnetic nanobeads (FMNBs) and firstly introduced them into the novel method that integrated IMS with FLFIA (I-IMS FLFIA) for the detection of Escherichia coli O157:H7. The FMNBs exhibited excellent magnetic and fluorescent properties for applications in IMS and FLFIA. However, the inner filter effect (IFE) of FMNBs may disturb the detection of I IMS-FLFIA. Systematical studies showed that the amount of immuno-FMNBs and the concentration of monoclonal antibody can be controlled to obtain maximum photoluminescence intensity and effectively weaken or solve IFE. Under optimum conditions, this method allows for the quantified detection of 2.39 * 102 CFU/mL and qualified detection of 2.50 * 103 CFU/mL. The method is simple, safe, efficient, and sensitive for the detection of foodborne pathogens. PMID- 30409605 TI - Electrochemical detection of monosodium glutamate in foodstuffs based on Au@MoS2/chitosan modified glassy carbon electrode. AB - We report an amperometric immunosensor for the detection of monosodium glutamate (MSG) using a glassy carbon electrode modified with gold nanoparticle decorated on a molybdenum disulfide/chitosan (Au@MoS2/Ch) nanocomposite. In the present detection technique, Au@MoS2/Ch was used as a conductive matrix and anti glutamate antibody was immobilized on to its surface via carbodiimide coupling method. Chemical and morphological attributes of the various components of the immunosensor were confirmed by UV-vis spectroscopy, SEM, TEM and XRD analysis. Electrochemical characterizations were carried out by CV, DPV and EIS. Overall results showed the effective fabrication of highly conductive Au@MoS2/Ch nanocomposite for sensitive electrochemical detection of MSG. A linear relationship was perceived between the change in current and concentration of MSG. The relationship was found to be consistent in the detection range of 0.05 200 uM. Statistical validation of the assay showed limit of detection and limit of quantification values as 0.03 and 0.1 uM, respectively (R2 = 0.99). PMID- 30409604 TI - Bioaccessibility and antimicrobial properties of a shrimp demineralization extract blended with chitosan as wrapping material in ready-to-eat raw salmon. AB - A shrimp extract (SME) obtained from the mild-acid demineralization treatment of shrimp shells to produce chitosan was collected. It was mainly composed of fat (~73%), protein (~19%), and ash (~9%) and contained considerable amounts of calcium (~1.9 g/100 g), astaxanthin (~30 mg/100 g) and unsaturated fatty acids (~27% MUFA, ~39% PUFA). The SME was used in combination with chitosan for wrapping raw salmon to produce a ready-to-eat product enriched in calcium. No significant changes in hardness were found, as compared to the unwrapped salmon. Estimated intakes of bioaccessible calcium increased significantly by 3.6-fold, whereas intake of bioaccessible fat was reduced by 15%. SFA were the main fatty acid group reduced (~80%), whereas MUFA and PUFA were only reduced by ~20% each. Total viable counts, pseudomonads, enterobacteria, and specific fish spoilers were reduced by 2-4 log CFU/g in wrapped sample during the chilled storage period (19 days). PMID- 30409606 TI - Development of a method for the quantification of fish major allergen parvalbumin in food matrix via liquid chromatography-tandem mass spectrometry with multiple reaction monitoring. AB - The availability of analytical methods for quantification of allergens is crucial for the correct assessment and labeling of products in order to protect allergic consumers. For this purpose, a simple, sensitive and accurate technique was developed based on liquid chromatography-tandem mass spectrometry and multiple reaction monitoring mass spectrometry (LC-MRM-MS/MS). The proposed method uses a simple purification with heat and a completely optimized tryptic digestion. This method has been validated according to the requirements defined by ICH (Q2 [R1]), having a linear range from 0.10 to 1179.36 nM with r > 0.999. The parvalbumin beta in flounder (Paralichthys olivaceus) has been quantified at a low level down to 0.10 ug/g with satisfactory precision (RSD < 18.35%) and accuracy (<13.3%). The new approach was successfully applied for the determination of parvalbumin beta in the other food matrices. PMID- 30409607 TI - Rapid determination of atrazine in apple juice using molecularly imprinted polymers coupled with gold nanoparticles-colorimetric/SERS dual chemosensor. AB - Rapid and reliable determination of atrazine, a common chemical contaminant, in agri-foods is highly necessary. We reported a novel dual-chemosensor coupling, a separation [molecularly imprinted polymers (MIPs)], an instrumental-free detection [gold nanoparticles (AuNPs)-based colorimetric assay] and an instrument based quantification [surface enhanced Raman spectroscopy (SERS)] method for high throughput and sensitive determination of atrazine in apple juice. Used as the selective sorbent for the solid phase extraction, MIPs effectively extracted atrazine from apple juice with high recoveries (~93%). AuNPs of different sizes (large; medium; and small) performed differently in the two analytical methods. Large-AuNPs provided the highest sensitivity in colorimetric analysis (<0.01 mg L 1), while medium-AuNPs achieved the lowest limit of detection (0.0012 mg L-1) and quantification (0.0040 mg L-1) in SERS analysis. With minor modifications, protocols for both analytical methods can rapidly detect and/or quantify atrazine in different food products complying with the Health Canada regulation (0.005 mg L-1). PMID- 30409608 TI - Antihypertensive effects of orally administered eggplant (Solanum melongena) rich in acetylcholine on spontaneously hypertensive rats. AB - Our previous results (Nakamura et al., 2013, 2016) indicated that acetylcholine (ACh) in orally administered foods exerts antihypertensive effects. Eggplants (Solanum melongena) contain abundant ACh (Horiuchi et al., 2003), and their food functionality was discovered, using spontaneously hypertensive rats, by measuring blood pressure after oral administration of a suspension of lyophilized eggplant powder. We found that lyophilized eggplant powder induced significantly lowered acute and chronic blood pressure levels at very low doses of 0.0650 mg/kg body weight (b.w.) and 0.821 mg/(kg b.w..day), respectively. Chronic administration suppressed adrenaline and noradrenaline excretion in the urine, and aorta assays showed that eggplant acted on the M3 muscarinic ACh receptor (M3 mAChR). ACh was conclusively shown to function as the main component of eggplant contributing to antihypertensive activity by suppressing sympathetic nervous activity via M3 mAChR. This report reveals a new food functionality of eggplant and its potential as a novel antihypertensive food. PMID- 30409609 TI - Identifying an isoflavone from the root of Pueraria lobata as a potent tyrosinase inhibitor. AB - Traditionally, the root of Pueraria lobata are widely used as a functional food. It was observed that a 70% ethanol extract showed a dose-dependent inhibition towards mushroom tyrosinase. Among the different isolated compounds, calycosin demonstrated potent inhibitory activity against substrates l-tyrosine and l-DOPA, with IC50 of 1.45 +/- 0.03 and 7.02 +/- 0.46 uM, respectively. Conversely, formononetin and daidzein exhibit weak inhibition. Moreover, kinetic studies revealed calycosin to be a competitive inhibitor for both substrates. Additionally, molecular docking simulation showed that the hydroxyl groups at C 3' and C-7 positions interacted with the catalytic site and peripheral residues, demonstrating a higher affinity toward mushroom tyrosinase. Accordingly, our results suggest that, rather than a mono-substituted hydroxyl or methoxyl group, the presence of a hydroxyl group at C-3' and a methoxyl group at C-4' position of the isoflavone skeleton plays an essential role in the manifestation of anti browning activity in food products. PMID- 30409610 TI - Simultaneous determination of sodium iron chlorophyllin and sodium copper chlorophyllin in food using high-performance liquid chromatography and ultra performance liquid chromatography-mass spectrometry. AB - A simultaneous method for analyzing sodium iron chlorophyllin (SIC) and sodium copper chlorophyllin (SCC) using high-performance liquid chromatography was developed. This method employed an Inertsil ODS-2 column and diode array detection at 395 nm, using methanol-water (97:3 and 80:20, v/v) containing 1% acetic acid as the mobile phase. Liquid chromatography-tandem mass spectrometry was used to identify the main components of SIC and SCC as Fe-isochlorine e4 and Cu-isochlorine e4, respectively. The limits of detection and quantitation of SIC were 1.2 and 4.1 mg/kg, respectively, while those of SCC were 1.4 and 4.8 mg/kg, respectively. For intraday and interday tests, the SIC recoveries from candy ranged from 81% to 101%, while SCC recoveries ranged from 100% to 109%. The developed method can be applied to the rapid determination of SIC and SCC in candy. PMID- 30409611 TI - Factors that affect polychlorinated naphthalenes formation and distribution during the heating of sucralose. PMID- 30409612 TI - Interferences of anthocyanins with the uptake of lycopene in Caco-2 cells, and their interactive effects on anti-oxidation and anti-inflammation in vitro and ex vivo. AB - Lycopene was combined with the glucosides of each of the six common anthocyanidins at 3 different ratios to investigate their interactions on antioxidant and anti-inflammatory activities, and cellular uptake. The bioactivity interaction between lycopene and anthocyanins was studied in both chemical and cellular models. Anti-oxidative synergy was not seen in any of the tested lycopene-anthocyanin mixtures, nor in the models studied. When lycopene was paired with the methoxylated anthocyanins, the anti-inflammatory effect on the inhibition of the cytokine IL-8, which is a pro-inflammatory biomarker, was increased by 15-69% of the expected additive activity, indicating synergistic interaction between the compounds. The cellular uptake of lycopene was significantly impaired by the presence of the anthocyanins: reduced by 50-80% at the lycopene: anthocyanin combinatory ratios of 2.5:7.5 MUM (1:3) or 5:5 MUM (1:1). The reduced intracellular lycopene content might be partly responsible for the antagonistic cellular antioxidant property seen in some of the tested mixtures. PMID- 30409613 TI - Comparison of the in vitro gastrointestinal bioavailability of acylated and non acylated anthocyanins: Purple-fleshed sweet potato vs red wine. AB - Acylated anthocyanins from purple-fleshed sweet potato (PFSP) have been reported to have multiple benefits to human health. Although, the bioavailability of these anthocyanins remains unknown. In the present study, a characterization of the gastrointestinal bioavailability of PFSP anthocyanins was assayed and compared with the bioavailability of Red Wine anthocyanins. Acylated anthocyanins showed higher resistance to overall simulated digestions when compared to less complex anthocyanins from Red wine, with degradation at the intestinal level of about 30% and 45%, respectively. Transport rates of absorption of acylated anthocyanins were not dependent on the cell type. However, a higher transport efficiency was observed in gastric cells (8%) when compared to the intestinal cells (5%). Glucose and proteins, but not starch, decreased the transport efficiency of anthocyanins in about 3-7% in gastric cells and 2-3% in intestinal cells. These results bring new insights and lay the groundwork for further research on acylated anthocyanins bioavailability. PMID- 30409614 TI - Development of a modified QuEChERS method based on magnetic multiwalled carbon nanotubes for the simultaneous determination of veterinary drugs, pesticides and mycotoxins in eggs by UPLC-MS/MS. AB - A modified QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) method was developed for the simultaneous determination of veterinary drugs, pesticides and mycotoxins in eggs by ultrahigh-pressure liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Several extraction conditions were tested and optimized, and the obtained extraction efficiency of all the targeted compounds (particularly macrolides) could fulfill the requirements. In the purification procedure, magnetic multiwalled carbon nanotubes (Fe3O4-MWCNTs) were used as adsorbents, and an external magnet was utilized to achieve a faster adsorbent separation, compared to the traditional centrifugation process. The recoveries of all analytes were in the range of 60.5%-114.6% at three fortified levels with relative standard deviations (RSDs) of less than 20%, and the LOQs ranged from 0.1 MUg.kg-1 to 17.3 MUg.kg-1. This method was successfully applied to the analysis of egg samples, demonstrating its applicability and suitability for the routine analysis of multiclass residues in egg samples. PMID- 30409615 TI - Influence of Saccharomyces cerevisiae and Lachancea thermotolerans co-inoculation on volatile profile in fermentations of a must with a high sugar content. AB - The aim of this work was to evaluate how the use of mixed cultures of Saccharomyces cerevisiae and Lachancea thermotolerans indigenous yeast strains influences the volatile composition of wine. Multivariate curve resolution (MCR) method has been applied to data analysis. Five fermentation trials were carried out: three co-inoculated with L. thermotolerans:S. cerevisiae, at the ratio of 50:1, 20:1 and 5:1 respectively, and two with a pure culture of each strain. A must from sun-dried Pedro Ximenez grapes was employed. Volatile composition was determined by dual sequential stir bar sorptive extraction, followed by GC-MS analysis. MCR provided 171 peaks. Results in co-inoculation fermentations revealed that the majority compounds obtained in each case followed the same trend as that observed for the pure culture of the strain that was present in a higher proportion. Finally, 50:1 and 20:1 seemed to be the best proportions to obtain a wine with a quality volatile profile. PMID- 30409616 TI - Dekkera bruxellensis, a beer yeast that specifically bioconverts mogroside extracts into the intense natural sweetener siamenoside I. AB - In response to growing concerns about the consumption of artificial sweeteners, the demand for natural sweeteners has recently increased. Mogroside V is a common natural sweetener extracted from the fruit of Siraitia grosvenorii, but its taste should be improved for marketability. Here, we screened various microbes for the ability to perform selective hydrolysis of glycosidic bonds in mogroside V, converting it to siamenoside I, which has a higher sweetening power and better taste than other mogrosides. Dekkera bruxellensis showed the most promising results in the screen, and the Exg1 gene (coding for a beta-glucosidase) of D. bruxellensis was cloned and purified. We then used HPLC-MS/MS to assess the beta glucosidase activity of purified enzymes on p-nitrophenyl beta-glucoside and mogroside V. The results demonstrated that D. bruxellensis had a unique enzyme that can selectively hydrolyze mogrol glycosides and promote the conversion of the natural sweetener mogroside V to siamenoside I. PMID- 30409617 TI - Biodegradation of deoxynivalenol and its derivatives by Devosia insulae A16. AB - Deoxynivalenol (DON), a notorious mycotoxin mainly found in Fusarium-contaminated crops, causes great loss in livestock farming and severe safety risks to human health. Here we report the isolation of a Gram-negative bacterial strain with effective biodegrading abilities on DON and its derivatives including 3-acetyl DON and 15-acetyl-DON. The strain was identified as Devosia insulae A16 on the basis of morphological and physiological characteristics and 16S rRNA-based phylogenetic analysis. D. insulae A16 was able to degrade 88% of 20 mg/l DON within 48 h under aerobic conditions at 35 degrees C and neutral pH. The major degradation product of DON and its derivatives was 3-keto-DON by the oxidation of the hydroxyl group at C-3. Both 3-acetyl-DON and 15-acetyl-DON underwent a deacetylation reaction to generate DON prior to the degradation to 3-keto-DON. The results provide the potential use of D. insulae A16 as a biodegradation agent to control DON contamination in cereals. PMID- 30409618 TI - Antioxidant capacity of Maillard reaction products in the digestive tract: An in vitro and in vivo study. AB - The release of biscuit Maillard reaction products (MRP) with antioxidant capacity was compared by in vitro and in vivo studies. Antioxidant determinations were performed by DPPH, FRAP and ICRED. Results indicated that an intense heat treatment on biscuits increases the amount of MRP with antioxidant capacity (p < 0.05). Besides, a low amount of antioxidant compounds was obtained after enzymatic digestion, whereas the highest proportion was released by colonic bacteria. Moreover, a high amount of non-released antioxidant compounds remained in faeces of Wistar rats; this was only predicted by in vitro ICRED determination. In addition, an increase in the stool amount and in the cecum weight/body weight ratio was observed in animals fed with a diet enriched in MRP (p < 0.05), which indicated a possible prebiotic activity. In conclusion, the in vitro digestion/fermentation procedure combined with ICRED determination would be a useful methodology to predict the release of antioxidant MRP in vivo. PMID- 30409619 TI - Evaluation of the composition of Chinese bayberry wine and its effects on the color changes during storage. AB - The color changes of Chinese bayberry wines during storage is a wide and urgent problem and its mechanism is still not clear. The changes of composition and color parameters of Chinese bayberry wines were studied during 70 days of storage in the dark at three different temperatures (4, 25 and 37 degrees C). The L*, a*, b*, anthocyanins, total phenols, and total flavonoids decreased along with the increase of polymeric pigments at all temperatures while 5 Hydroxymethylfurfural and browning index increased only at 37 degrees C. The degradation of anthocyanins followed a first-order kinetic model. No furfurals and ascorbic acid were detected at all temperatures during storage. Wines stored at higher temperature showed higher polymeric pigments. The result probably indicated phenols especially anthocyanins and polymeric pigments seem to be main factors than Maillard reaction in the color changes of Chinese bayberry wines during storage. PMID- 30409620 TI - Thiol-functionalized magnetic carbon nanotubes for magnetic micro-solid phase extraction of sulfonamide antibiotics from milks and commercial chicken meat products. AB - Thiol-functionalized magnetic carbon nanotubes (TMCNTs) were employed as the sorbent in the magnetic micro-solid phase extraction (M-u-SPE) of sulfonamide antibiotics (SAs) in water, milks and chicken meat products prior to high performance liquid chromatography-diode array detector (HPLC-DAD) analysis. The synthesized sorbent was characterized by several spectroscopic techniques. Optimum conditions were: 20 mg of TMCNTs at pH 4, 2 min extraction time, 10% addition of salt and 30 mL of sample volume. Under the optimized TMCNTs-M-u-SPE and HPLC-DAD conditions, the method showed good linearity in the range of 0.1-500 ug L-1 (r2 >= 0.9950), low limits of detection (0.02-1.5 ug L-1), good analytes recovery (80.7-116.2%) and acceptable RSDs (0.3-7.7%, n = 15). The method was applied to tap water (1), milks (15) and commercial chicken meat products (35), SAs were detected in five chicken meat samples (3.0-25.7 ug L-1). The method is critically compared to those reported in the literature. PMID- 30409621 TI - Electrospraying as a suitable method for nanoencapsulation of the hydrophilic bioactive dihydrochalcone, aspalathin. AB - The bioactive hydrophilic dihydrochalcone, aspalathin, has poor stability and bioavailability hampering its use in functional food ingredients with standardised aspalathin content. The aim of the study was to produce nanoparticles with controlled release to overcome these obstacles. Nanoencapsulation was investigated using both natural (chitosan and lecithin) and synthetic (poly(lactide-co-glycolide) and Eudragit S100(r) (ES100)) polymers by suitable conventional methods and electrospraying for all polymers. All polymer method combinations produced particles smaller than 1.1 um. Electrospraying produced more favourable results than conventional methods for the synthetic polymers, resulting in spherical particles with higher (p < 0.05) encapsulation efficiencies (>50%) and loading capacities (>10%). Opposite trends were observed for natural polymers. An in vitro release study revealed biphasic aspalathin release profiles at pH 7.4 with ES100 electrosprayed nanoparticles having the slowest (p < 0.05) release rate (1.67 h-1). Overall, ES100 electrosprayed nanoparticles showed the most favourable combination of parameters. PMID- 30409622 TI - Is it possible to obtain nanodispersions with jaboticaba peel's extract using low energy methods and absence of any high cost equipment? AB - Jaboticaba (Myrciaria cauliflora) is considered a "super fruit" due to its remarkable phenolic content and antioxidant capacity. Despite the great potential of its peels, to our knowledge the investigation of novel nanostructured systems with this natural raw material, still considered an industrial residue, is scarce. The present study aimed to obtain nanodispersions with its peel's extract through a low energy method. Antioxidant assays were performed, showing positive results for DPPH (IC50 = 0.89 MUg/mL) and FRAP (225.53 MUmol equivalent ferrous sulphate/g). The chemical characterization in terms of flavonoids (2.56%) and total monomeric anthocyanins (0.80%) contents were also performed. Overall, the nanodispersion prepared with the non-ionic surfactant polysorbate 85 and the hydroalcoholic extract standardized in ellagic acid (129 ug/mL) presented the best properties regarding particle size distribution and zeta potential. Thus, it opens perspectives for the generation of novel food-grade nanodispersions through an ecofriendly approach that is in accordance to sustainable concepts. PMID- 30409623 TI - Oenological potential of extracts from winery and cooperage by-products in combination with colloidal silver as natural substitutes to sulphur dioxide. AB - The aim of this study was to evaluate the oenological potential of natural extracts from winery and cooperage by-products, either alone or with a colloidal silver complex (CSC), on the quality of red wines, as possible substitutes to SO2. Natural extracts were obtained from grape seeds and American oak wood by accelerated extraction with subcritical water. The prefermentative addition of grape seed or oak wood extracts was an useful tool to control acetic acid bacteria development, without affecting the alcoholic and malolactic fermentations. Both extracts protected the wines against oxidation, without negatively modifying their phenolic and volatile composition. They did not cause organoleptic defects in wines, which presented greater aromatic complexity and were positively evaluated by the tasters. Therefore, the use of grape seed or oak wood extracts in red vinification could be a good alternative to replace or reduce the doses of SO2. PMID- 30409624 TI - Optimization of thermosonication conditions for cloudy strawberry nectar with using of critical quality parameters. AB - The optimum thermosonication parameters, temperature and ultrasound energy density (UED), determined by using response surface methodology to inactivate polyphenol oxidase (PPO) and protecting the quality parameters, especially color of strawberry nectar. The PPO inactivation was successfully achieved by thermosonication treatment. Increasing of temperature resulted with decreasing of browning index and increasing of hydroxymethyl furfural. High temperature-low UED combination can be applied to obtain minimum change in DeltaE* and maximum protection of ascorbic acid. Thermosonication at mild temperature (~50 degrees C) and UED (~230 J/g) ensured the maximum levels of total monomeric anthocyanin and total phenolic content. The combination of 59 degrees C and 455 J/g was the conditions of optimum thermosonication to minimize quality parameters which cause undesirable changes like color degradation in nectar and maximize desirable ones which have beneficial effects on characteristics of nectar or on human health like phenolic content of nectar. PMID- 30409625 TI - Rapid quantification of trace chloramphenicol in honey under ambient conditions using direct analysis via real-time QTRAP mass spectrometry. AB - In this paper, we employed a direct analysis in real time (DART) ion source coupled to QTRAP mass spectrometry for the analysis of chloramphenicol (CAP) in honey. The accuracy of the DART-MS/MS method for the analysis of CAP in honey was evaluated by comparison with data generated by a validated HPLC-MS/MS method. The sample preparation procedure was optimized to obtain sensitive and accurate determination of trace CAP residue in honey at concentrations less than 1.0 ug/kg. The DART-MS/MS method offers faster analysis time, lower cost per analysis, and reduced matrix effects and simplicity compared to HPLC-MS/MS method. Fifty-two honey samples collected from a Chinese market were analyzed using two methods. The results of the two methods are in good agreement, suggesting DART-MS/MS as a potential technique for the direct detection of trace amounts of veterinary drugs in complex matrixes. PMID- 30409626 TI - Identification and characterization of a thermostable pectate lyase from Aspergillus luchuensis var. saitoi. AB - Pectinolytic enzymes are used in diverse industrial applications. We sought to isolate a pectate lyase from Aspergillus luchuensis var. saitoi, a filamentous fungus used in traditional food and beverage preparation in Japan. The identified enzyme, named AsPelA, is orthologous to PelA from A. luchuensis mut. kawachii (AkPelA); the enzymes exhibit 99% amino acid sequence identity, with Ile140 and Val197 of AsPelA being replaced by Val and Asp in AkPelA, respectively. AsPelA activity decreased to 71%, 61%, and 46% of maximal activity after 60-min incubation at 60 degrees C, 70 degrees C, and 80 degrees C, whereas AkPelA activity dropped to 16%, 10%, and 8.5%, respectively, indicating that AsPelA is more thermostable than AkPelA. Furthermore, AsPelA was stable within a neutral-to alkaline pH range, as well as in the presence of organic solvents, detergents, and metal ions. Our findings suggest that AsPelA represents a candidate pectate lyase for applications in food, paper, and textile industries. PMID- 30409627 TI - Formation of heterocyclic aromatic amines in relation to pork quality and heat treatment parameters. AB - The aim of the research was to analyze the influence of chemical composition, technological and sensory pork quality on the formation of heterocyclic aromatic amines (HAAs) after heat treatment. Material for analysis was taken from 36 samples of pork with different ultimate pH. The results showed that the studied meat was characterized by variation in chemical composition, especially in precursors of HAAs. The formation of HAAs in meat was significantly related to ultimate pH (r = -0.80), glucose concentration (r = 0.60) and color parameters (r = 0.61-0.80). These studies also demonstrated the increased amount of HAAs in meat with higher temperature of grilling. Raising the grill temperature from 180 degrees C to 220 degrees C resulted in a two-fold increase in the 4,8-DiMeIQx content and nine-fold 7,8-DiMeIQx. In the case of grilling at 220 degrees C, the increase in 7,8-DiMeIQx content was accompanied by a decrease in tenderness and juiciness (r = -0.60) and deterioration of overall quality (r = 0.70). PMID- 30409628 TI - Conformation, allergenicity and human cell allergy sensitization of tropomyosin from Exopalaemon modestus: Effects of deglycosylation and Maillard reaction. AB - Tropomyosin (TM) from Exopalaemon modestus was glycoprotein, the effects of deglycosylation (enzyme and chemical regents) and Maillard reaction on the conformation, allergenicity and human cell sensitization of TM were investigated. TM had both N-glycan and O-glycan. After deglycosylation and glycation, the alpha helix of TM reduced, while other secondary structures promoted. Deglycosylation enhanced TM allergenicity and digestibility, contributed to digests with lower allergenicity, glucose glycation weakened the allergenicity and digestibility of TM, led to digests with weaker allergenicity. Gastric digestion partly reduced allergenicity of digests, intestinal digestion highly reduced digests' allergenicity, gastrointestinal digestion most efficiently weakened the allergenicity of digests. After deglycosylation, the deglycosylated TM exerted stronger activation of basophil (KU812), while glucose glycated TM weakened KU812 activation. Deglycosylation exerted inhibition on colon cell (Caco-2) proliferation and increase of IL-8 release, while glucose glycated TM suppressed Caco-2 proliferation and IL-8 release. PMID- 30409629 TI - A statistical exploration of data to identify the role of cultivar and origin in the concentration and composition of yeast assimilable nitrogen. AB - The study was undertaken to gain insight into the nitrogen status of grape juices currently used to make commercial wines in South Africa. This was done as yeast assimilable nitrogen (YAN) is most often suspected as the cause for problematic fermentations and has major implications for the organoleptic qualities of the final product. Using exploratory statistical methods, this study explored the possibility of identifying the role of cultivar and grape-growing district in the determination of the concentration and composition of YAN. However, as the dataset was found to be non-parametric and heteroscedastic, paired with unequal sample sizes, data analysis was approached with caution. Through the use of various suitable statistical analyses, cultivar was shown to play the more important role in determining the concentration and composition of YAN. PMID- 30409630 TI - Determination of phenolic acid profiles by HPLC-MS in vegetables commonly consumed in China. AB - This study aimed to establish a precise HPLC-MS approach to determine the concentrations and distribution of major phenolic acids in six categories of vegetables that are commonly consumed in China. We detected 17 phenolic acids within 15 min under optimized conditions. The method showed detection limits varying from 0.008 mg/L to 0.042 mg/L, average recoveries ranging from 71.0% to 110.7%, and a RSD of <=9.98%. The average concentrations of total phenolic acids followed the order of flower > root > leafy > stem > bean > fruit vegetables. The phenolic acids were more abundant in the leafy, root, and stem vegetables than in the other vegetable samples. Furthermore, the levels of isoferulic acid, p coumaric acid, and ferulic acid were greater than those of other phenolic acids in the vegetables. Free soluble phenolic acids were the dominant species in all vegetables (P < 0.001), except in the stem vegetables (P < 0.027). PMID- 30409631 TI - Effect of selected strains on physical and organoleptic properties of breads. AB - The use of selected Saccharomyces cerevisiae PS7314, Lactobacillus rossiae NOS7307, Lactobacillus brevis NOS7311, and Lactobacillus plantarum NOS7315 as mono-culture or co-culture for production of sourdoughs, their breads showed different physical and organoleptic properties. The pH of breads fermented with sourdoughs incubated with mono-culture or co-culture all decreased. An opposite trend was found for TTA. The use of single lactobacillus for the dough fermentation decreased the specific volume of bread, which was 4.15-19.10% lower than that of control bread (CB). However, the synergetic fermentation helped the improvement of bread quality. Compared to CB, the mixed culture 4 sourdough remarkably decreased the hardness by 52.08%, increased the specific volume by 5.29%, improved porosity of final product by 24.90%, and gave a preferable sensory characteristic to bread. Thus, the MC4 could be recommended for replacing spontaneous sourdough for improving the quality of bread. PMID- 30409632 TI - Heat treatment of sunflower protein isolates near isoelectric point: Effect on rheological and structural properties. AB - In the present study sunflower protein isolates were subjected to heat treatment (80 degrees C for 5 min, 15 min and 25 min) at three pH values (3.5, 4.5 and 5.5). The strength of gel prepared from treated protein isolates was lower than the gels from native protein isolates and gel strength increased with increase in temperature treatment. Higher denaturation temperatures were observed in treated protein isolates than native protein isolates and increased with increase in thermal treatment time. Treated protein isolates showed more resistance against thermal degradation than native protein isolates as was evident from thermal gravimetric analysis. Secondary and tertiary structure determined by circular dichroism and intrinsic fluorescence respectively were significantly altered after thermal treatment. Lower crystal size along with reduced crystallinity was observed in treated protein isolates than native protein isolates and was further reduced with increase in heating time as was determined by X-ray diffraction. PMID- 30409633 TI - Use of density sorting for the selection of aromatic grape berries with different volatile profile. AB - The aim of the study was to investigate the application of berry density sorting as a tool for the selection of grapes with different volatile and precursor profiles. The study was carried out on Moscato giallo, Malvasia di Schierano, Malvasia nera lunga, and Brachetto aromatic grape varieties. Free and glycosidically-bound terpene compounds including linalool, geraniol, nerol, citronellol, and terpineol, as well as lipoxygenases activity-derived compounds, were evaluated using head space-solid phase microextraction-gas chromatography mass spectrometry (HS-SPME-GC-MS) in density sorted berries (1075-1119 kg m-3). Total free terpenes changed with the berry density, while no significant changes were found in total glycosylated compounds, except for Malvasia nera lunga grapes where nerol, linalool, and geraniol contributed strongly to the increase of total contents with increasing berry density. Given that these variations were strongly variety-dependent, the possible use of density sorting equipment in winery for this aim may be less effective. PMID- 30409634 TI - Changes on the phytochemicals profile of instant corn flours obtained by traditional nixtamalization and ohmic heating process. AB - We studied the changes in the phytochemicals profile of two instant corn flours produced by different process: traditional nixtamalization process (TN) and by ohmic heating process (OH). The highest total phenolics content was found in the OH flours (OHF), which showed predominance of bound phenolics and free flavonoids compared with the TN flours (TNF). Ferulic acid measured by HPLC-DAD was the most abundant compound in its bound form in the OHF, but decreased by 57% in TNF. The insoluble fiber content was preserved by the OHF (17.49%) and the soluble fiber increased ~65% compared with TNF. These data suggest that instant corn flours processed by OH preserves the phenolic profile and antioxidant profile similarly than flours processed by TN; furthermore, water waste was reduced significantly, and no effluents were produced in the ohmic heating process. PMID- 30409635 TI - Effect of milling and long-term storage on volatiles of black rice (Oryza sativa L.) determined by headspace solid-phase microextraction with gas chromatography mass spectrometry. AB - Although black rice has gained popularity, the changes in volatiles produced during black rice storage remain unclear. Herein, the volatile composition of unmilled and milled black rice stored at 25 degrees C or 35 degrees C for 0-12 months was investigated by headspace solid-phase microextraction with gas chromatography-mass spectrometry. Fifty-four volatiles were identified, 15 of which were not previously identified in black rice, including 4 propylbenzaldehyde, methyl 2-hydroxybenzoate, methyl 2-methylpentanoate, 2,5 dimethylnonane, 5-methyldecane, and 2-methylundecane. In this study, octanal increased at a high rate during early storage compared with hexanal, a traditional oxidation marker; thus, octanal may be an early oxidation marker in black rice. The results suggested that high temperature is not appropriate for storage of unmilled or milled black rice because it promotes lipid oxidation, producing volatile compounds. At 25 degrees C, black rice stored for short times such as 3 months should be milled, whereas for 6 months, black rice should be stored without milling. PMID- 30409636 TI - Enzymatic hydrolysis of native granular starches by a new beta-amylase from peanut (Arachis hypogaea). AB - The present work describes efficient hydrolysis of native starch by a novel beta amylase from peanut (Arachis hypogaea). The Dextrose Equivalent value, which is a measure of starch hydrolysis, for potato and corn starch increased significantly by 40% and 10%, respectively, releasing maltose. Scanning electron microscopy revealed that enzymatic corrosion occurred mainly at the surface of starch granules, leaving broken granules to smaller particles at later stage of digestion. Further, X-ray analysis and Fourier transform infrared spectroscopy displayed the loss of ordered structure in the enzyme degraded starches. These results described the pattern of hydrolysis. Since the action of already known plant beta-amylases (sweet potato and soybean) on native starch granule is not very effective and requires gelatinization for maltose production, beta-amylase from peanut could be a useful alternative in the present endeavor. It would potentially save time and money arising from gelatinization and lead to improvements in industrial maltose production. PMID- 30409637 TI - Optimisation of steam blanching on enzymatic activity, color and protein degradation of alfalfa (Medicago sativa) to improve some quality characteristics of its edible protein. AB - The use of alfalfa protein in human food is limited by its low quality. Response Surface Methodology was employed to optimise the combined effects of different steam blanching conditions on the enzymatic activity, browning and protein degrading which cause undesirable characteristics. The optimum conditions were: steaming time 4.36 min, particle size 23 mm, time from harvesting to steaming 2 h leading to a residual activity of polyphenol oxidase of 1.31% and a completely inactivation of peroxidase. The Browning Index value was 108.3 and the non protein nitrogen 170.2 (g kg-1 TN). The browning and protein degradation rates of alfalfa treated under the optimum conditions were much lower than the control alfalfa after 60 days ensiling. This suggests that blanching of fresh whole alfalfa leaves under the optimum conditions was helpful for avoiding the appearance of the dark color and degradation of the extracted protein, improving its quality for human consumption. PMID- 30409638 TI - Characteristics of pea, lentil and faba bean starches isolated from air classified flours in comparison with commercial starches. AB - This study aimed to isolate starches of a high purity from starch-rich pea, lentil and faba bean flours and to characterize and compare the isolated starches with important commercial starches. Isolated pulse starches had a purity of 94.8 97.9% and contained only 0.9-1.1% damaged starch. The isolated pulse starches showed amylose contents and amylopectin branch-chain-length distributions similar to those of commercial pea starch. Therefore, the granular morphologies, crystalline structure, thermal properties, pasting properties, gelling ability and in vitro digestibility of the isolated pulse starches were comparable to those of commercial pea starch but different from those of commercial maize and tapioca starches. The desirable functionality of the pulse starches (e.g., strong gelling ability) renders them suitable for some specific industrial applications, and further modifications can be utilized to enhance their functionality for broader use. This research provided the fundamental knowledge required for future efforts to promote value-added utilization of pulse starches. PMID- 30409639 TI - A review of arsenic in crops, vegetables, animals and food products. AB - Arsenic (As) is a carcinogenic element threatening the health of millions of people around the world. The sources for human exposure include drinking water, crops, processed food items, vegetables, mushrooms, animal products etc. The people at most risk are those living in hotspots of As contamination viz., Bangladesh and West Bengal, India. However, it has been found that rice growing in other uncontaminated regions like Australia can also contain high As levels. Further, rice import/export among various countries make the problem of global concern. The emergence of several reports of As in rice based food products including baby food from different parts of the world demonstrates that even the infants and toddlers are not spared. The variation in the levels of inorganic and organic As species in different food items influence the associated As toxicity. This review tries to present the available data on As levels in various dietary sources. PMID- 30409640 TI - Gastric digestion of cow and goat milk: Peptides derived from simulated conditions of infant digestion. AB - Infant formula products are predominantly manufactured using cow milk protein; goat milk also provides a suitable protein source. In this study, we directly compared cow and goat milk protein digestion using pH and enzyme conditions to simulate infant gastric conditions. Generated peptides, identified using liquid chromatography coupled to a mass spectrometer, show both similarities and differences in cow and goat milk post-digestion profiles. The majority of peptides were from casein proteins, 50% representing beta-casein, with many peptides unique to each species. Low or no peptides for beta-Lactoglobulin and alpha-Lactalbumin, respectively, suggest these proteins were highly resistant to infant gastric digestion, as reported by others. Minor milk proteins, comprising 5% of peptides, were represented by different proteins from cow and goat. Peptides with known bioactivities were also observed, both in common and unique to each species. Together these data may explain reported differences in digestion characteristics of cow and goat milk. PMID- 30409641 TI - Bitter profiling of phenolic fractions of green Cyclopia genistoides herbal tea. AB - The bitter taste of Cyclopia genistoides infusions is unacceptable to consumers, who are used to the slightly sweet taste of the herbal teas produced from other Cyclopia species. Bitter taste intensities of crude phenolic fractions of a bitter hot water extract of C. genistoides were determined by a trained panel to identify the fraction contributing most to the bitter taste. Fractions, enriched in benzophenones (B), xanthones (X) and flavanones (F), and each tested at their infusion equivalent concentration (IEC) scored 5, 31 and 13 (on a 100-point scale), respectively. Fraction B, containing mostly iriflophenone glucosides, was perceived as not bitter. The major xanthone in fraction X, mangiferin, was significantly (p < 0.05) more bitter than its regio-isomer, isomangiferin, at equal concentration. A mixture of isomangiferin and mangiferin at their IECs was significantly (p < 0.05) less bitter than the mangiferin solution alone, indicating bitter suppression by isomangiferin. PMID- 30409642 TI - Effect of nitric oxide on myofibrillar proteins and the susceptibility to calpain 1 proteolysis. AB - This study was designed to investigate the nature of modification of myofibrillar proteins by nitric oxide (NO) and the extent to which S-nitrosylation alters their susceptibility to calpain-1 proteolysis. Isolated myofibrils from porcine semimembranosus muscle were incubated with the NO donor S-nitrosoglutathione (GSNO) at 0, 20, 50, 250, 1000 uM for 30 min at 37 degrees C and then incubated with purified calpain-1. GSNO treatment decreased the thiol content of myofibrillar proteins and increased their intensity and amount of S nitrosylation. GSNO caused the formation of proteins cross-linkage through intermolecular disulfide. More desmin and titin (T2, the degraded fragment of original titin) were degraded by calpain-1 when myofibrils were incubated with 1000 uM GSNO. Incubation with 250 and 1000 uM GSNO suppressed calpain-1-catalyzed cleavage of troponin-T. The data suggest that NO could change the redox state of myofibrillar proteins and subsequently affect the extent of proteolysis by calpain-1 in a protein-dependent manner. PMID- 30409643 TI - Kinetics of conversion of dihydroxyacetone to methylglyoxal in New Zealand manuka honey: Part V - The rate determining step. AB - Monomer formation from dimeric DHA has previously been suggested as the rate determining step in formation of methylglyoxal, the bioactive component in manuka honey. This step was studied by 1H NMR in DMSO-d6. First order reaction rate was 3.31 * 10-3 +/- 9.1 * 10-4 min-1. Upon titration with D2O, little change was observed until ~15 mass% whereupon an exponential increase in rate occurred until indistinguishable from the rate observed in water. Acid or base caused rate accelerations. Theoretical modelling confirmed the existence of acid and base catalysed mechanisms for dimer decomposition and the structures of two intermediates observed. In honey it is likely the base-catalysed decomposition predominates with water as catalyst but there is little rate acceleration at the levels of water present normally in honey however a small increase in the mass% of water in the honey could cause significant rate acceleration of dimer decomposition and hence formation of methylglyoxal. PMID- 30409644 TI - Effect of stressful malolactic fermentation conditions on the operational and chemical stability of silica-alginate encapsulated Oenococcus oeni. AB - Oenococcus oeni was encapsulated into inter-penetrated polymer networks of silica alginate (SiO2-ALG). Fourier transform infrared spectroscopy analysis proved the presence and the polycondensation of the siliceous material used in SiO2-ALG capsules. Environmental scanning electron microscopy showed that the structure of SiO2-ALG biocapsules was rougher than in alginate (ALG) biocapsules. The behaviour of SiO2-ALG biocapsules was evaluated at pH 3.0-3.6 and alcohol degrees of 12-15%. Repeated-batch malolactic fermentations (MLF) demonstrated that SiO2 ALG biocapsules can be reused efficiently for five times in either low-pH or high ethanol wines, while free bacteria only can be used once under the most favourable MLF conditions. The inclusion of siliceous materials into ALG hydrogel improved the stability of the biocapsules, reducing their shrinking and achieving an excellent integrity under winemaking conditions. These results proved the possibility of industrial application of SiO2-ALG biocapsules in winemaking. PMID- 30409645 TI - Maillard induced aggregation of individual milk proteins and interactions involved. AB - The aggregation of alpha-lactalbumin, beta-lactoglobulin and beta-casein after heating in dry state was studied in absence and presence of saccharides. In absence of saccharides, differences were observed in the extent of aggregation. Differences between the proteins were mostly due to differences in covalent aggregation. The presence of glucose during the heat treatment of milk proteins significantly increased the extent of aggregation, and decreased differences between proteins. alpha-Lactalbumin was selected as a model protein for the study of cross-links formed after heat treatment. In the presence of saccharides, these cross-links were found to consist of 36% of disulphide bridges (compared to >75% in the absence of glucose), followed by other cross-links such as lanthionine. Larger saccharides led to a decrease in Maillard induced aggregation; maltotriose actually even inhibited the formation of alpha-lactalbumin aggregates. PMID- 30409646 TI - Enhanced extraction of hydroxytyrosol, maslinic acid and oleanolic acid from olive pomace: Process parameters, kinetics and thermodynamics, and greenness assessment. AB - Three techniques of ultrasound-assisted extraction (UAE), microwave-assisted extraction (MAE) and solvent extraction (SE) were used for enhancing the hydroxytyrosol (HT), maslinic acid (MA) and oleanolic acid (OA) extraction from olive pomace, being evaluated and compared through process parameters, kinetics and thermodynamics, plus greenness assessment analysis. Results showed that UAE yielded the maximum compounds due to a strong cavitation effect and the strongest mass and heat transfer efficiency involving the kinetic constants (h, Ce and K) and thermodynamic parameters (?H, ?S and ?G). Additionally, the optimal extraction conditions were acquired: ethanol concentration of 90%, extraction temperature of 50 degrees C, extraction time of 5 min, liquid to solid ratio of 30 mL/g, ultrasound intensity of 135.6 W/cm2, and ultrasound frequency of 60 kHz. UAE was confirmed as an effective and greener technique with the lowest E factor, energy consumption and carbon emission during the extraction process of bioactive compounds from olive pomace. PMID- 30409647 TI - Stability of resveratrol esters with caprylic acid during simulated in vitro gastrointestinal digestion. AB - Lipophenols, esterified phenols with fatty acids, have attracted increasing attention because of their better protective effects in lipid-based food matrices from oxidation. However, little is known about their digestion. In this study, the digestive stability of resveratrol (RSV) esters with caprylic acid (RCAPs) in a model gastrointestinal digestion system was evaluated. The results demonstrated that RCAPs were relatively stable without hydrolysis in mouth and gastric phases. However, in the intestinal phase, pancreatic lipase rather than phospholipase A2 could hydrolyze monoester and diesters to free RSV. After 120 min of incubation at 37 degrees C, 53.68% of monoester and 11.36% of diesters were hydrolyzed. However, no hydrolysis of the triester was noticed. Obviously, the level of hydrolysis of RCAPs was negatively correlated with the degree of substitution. Therefore, it was speculated that RSV in fatty acid ester forms could partially be absorbed by intestinal lumen in the form of free RSV. PMID- 30409648 TI - An overview of organosulfur compounds from Allium spp.: From processing and preservation to evaluation of their bioavailability, antimicrobial, and anti inflammatory properties. AB - The use of Allium species and their extracts has been known since immemorial times due to their health beneficial properties. It is known that functional properties of Allium genus come from the high content of bioactive compounds. The biological activity of Allium extracts will be conditioned by the type of Allium variety, agricultural conditions, and specific extraction process used since all these factors affect the content and the profile of bioactive compounds. Innovative extraction techniques in comparison to conventional processes could be considered as a promising tool to recover bioactive compounds from Allium spp. with antimicrobial and anti-inflammatory properties. Trying to fill the gap in the literature, this paper reviews the chemical composition, the effects of processing on the nutritional and bioactive composition of Allium species and their extracts. Moreover, the antimicrobial and anti-inflammatory effects, as well as the bioavailability of bioactive compounds of edible members from the Allium genus is discussed. PMID- 30409649 TI - In vitro metabolism of elderberry juice polyphenols by lactic acid bacteria. AB - In this study, ten strains of Lactobacillus were used to assess the in vitro metabolism of elderberry juice polyphenols. Total polyphenolic compounds increased after starter addition, especially with three L. rhamnosus and one L. plantarum strains, of dairy origin: quercetin-3-O-rutinoside was the most abundant compound (from 39.02 +/- 5.28 to 127.56 +/- 11.34 ug/mL) and hydroxycinnamic acids, flavonols and anthocyanins reached the highest amounts. When L. plantarum were used phenyllactic acids presented a value of 7.05 +/- 2.38 ug/mL, while in the other samples it was around 5.56 +/- 1.65 ug/mL. Hydroxycinnamic and hydroxybenzoic acids were subjected to lactic acid bacteria metabolism: caffeic and protocatechuic acids were consumed during fermentation while dihydrocaffeic acid and catechol were produced. Anthocyanins increased in a strain-specific way. So, by this study we highlighted that dairy strains can produced (phenyllactic acids), modified (hydroxycinnamic acids) or increased (flavonols glycosides and anthocyanins) phenolic compounds. PMID- 30409650 TI - The phytochemical variability of fatty acids in basil seeds (Ocimum basilicum L.) affected by genotype and geographical differences. AB - Basil (Ocimum basilicum) from the Lamiaceae family is among the most important medicinal plants, and its seed fatty acid (FA) composition and quantity affects its nutritional and health values. It was hypothesized basil species and geographical properties significantly affect seed FA composition and quantity, which has not been previously investigated, to our knowledge. The collected seeds of the 18 basil populations were planted in a farmer's field, and the seed saturated (palmitic and stearic) and unsaturated (oleic, linoleic, and linolenic) FA were determined. Shiraz1 (14.7%) and Mobarakeh (5.1%) had the highest and the least rates of total FA, respectively. The populations were significantly different in terms of saturated FA ranging from 10.73% (Ardestan) to 13.51% (Bid Zard). However, the seed unsaturated FA (expect linoleic acid) were not significantly different from each other (average = 87.27%). Basil species and geographical properties significantly affected basil saturated FA and just unsaturated linoleic acid. PMID- 30409651 TI - A colorimetric paper-based sensor for toltrazuril and its metabolites in feed, chicken, and egg samples. AB - In this study, a sensitive monoclonal antibody (mAb) against toltrazuril (Tol) was developed based on a novel hapten. The 50% inhibitory concentrations (IC50) of toltrazuril and its metabolites ranged from 2.19 ng/mL to 4.21 ng/mL. Based on this mAb, a colorimetric paper-based sensor was developed for the rapid screening of Tol and its metabolites in samples. The proposed assay has cutoff values of <20 MUg/kg for Tol and 50 MUg/kg for Tol sulfone when evaluated with the naked eye, and the results could be obtained in 15 min. Quantitative results were obtained with a strip scan reader, with limits of detection <2.60 MUg/kg for Tol and its metabolites in real samples. The sensitivity of both qualitative and quantitative detection meets the European Union requirements. Therefore, this strip assay provides a useful tool for the on-site detection and rapid initial screening of Tol and its derivatives in feed, egg, and chicken samples. PMID- 30409652 TI - Predicting calcium in grape must and base wine by FT-NIR spectroscopy. AB - Calcium content in sparkling wines may not exceed 80 mg/L due to the risk of aggregation with alginate capsules. The high calcium content usually found in wine and must emphasizes the need to develop alternative and appropriate techniques faster and cleaner than atomic absorption spectrometry (AAS). To obtain a robust model to predict calcium content, FT-NIR spectroscopy was used in 98 base white wine samples and 60 must samples from an Alentejo winery. The reference method for calcium determination was AAS technique, with a dry ashing sample procedure, as a prior treatment. Results confirmed the ability of FT-NIR as an alternative technique to AAS, to predict calcium content in grape must and base wine. Advance knowledge of the calcium content in the grape must will help avoid obtaining a mixture of musts with a high calcium content in the same container. PMID- 30409653 TI - Limited cross reactivity among arginine kinase allergens from mealworm and cricket edible insects. AB - Insects are seen as a solution to the increasing demand for protein sources for food. However, entomophagy has unfortunately been linked to allergic reactions in Europe with people with professional contacts. As mealworms (Tenebrio molitor) and crickets (Acheta domesticus) have recently become commercially available (both whole or in food formulation) in several European countries, this research assessed the cross allergenicity of arginine kinase (AK). Based on the collection of sera from a entomology laboratory staff, oven cooked insects but also purified AK fractions were tested. Immunoblotting against the protein extracts revealed different Immunoglobulin E reactivity of sera according to the insect target species: two bands (40 and 14 kDa) for crickets and a pattern including light responses at 17, 25 and 37 kDa for mealworms. Focusing on AK, low specific allergenicity was here illustrated and discussed in relation to the development of a safe edible insect consumption by humans. PMID- 30409654 TI - Evaluation of total polyphenol content of wines by means of voltammetric techniques: Cyclic voltammetry vs differential pulse voltammetry. AB - Taking advantage of the low oxidation potential of polyphenolic compounds, voltammetric techniques, such as cyclic voltammetry (CV) and differential pulse voltammetry (DPV) are used rather indiscriminately. In this work, we report Total Polyphenols results (TPP) obtained by these two techniques from a set of nine samples of red and Tawny Port wine. The CV and DPV voltammograms display significant correlations with the physical-chemical parameters used to characterize red and Tawny Port wines, particularly with polyphenols. Although data obtained from CV and DPV for a single polyphenol are directly proportional, important deviations are found between voltammetric results from wines. Results from CV tend to be larger than those from DPV. This difference, that can reach 50% of the TPP value, was related to the presence of total sulphur dioxide. In view of the present study, the polyphenol quantification in wines should be performed by DPV to minimize the interference of SO2. PMID- 30409655 TI - Food fraud in oregano: Pesticide residues as adulteration markers. AB - Oregano, a widely used and popular herb, is particularly vulnerable to fraud. Less valued plants, adulterants that are often used for dilution, may introduce into this commodity additional contaminants such as pesticide residues. In this study, more than 400 pesticides were screened in a representative set of 42 genuine and 34 adulterated dried oregano samples collected from various locations across Europe. The results obtained by advanced mass spectrometry-based methods, showed, that some pesticide residues could be detected in virtually all tested samples, nevertheless, on average, higher contamination was found in the adulterated oregano samples. Increased incidence of insecticides such as cyfluthrin, permethrin and cyhalothrin was typical for these samples, moreover, pyriproxyfen was detected exclusively in adulterated samples. Thus, based on a critical assessment of pesticide profiles, suspected adulterated oregano samples can be selected for follow up authenticity testing. PMID- 30409656 TI - In silico food allergenic risk evaluation of proteins extracted from macroalgae Ulva sp. with pulsed electric fields. AB - Extraction of protein from macroalgae, currently defined as "novel food", is challenging and limited information about the health impacts of these proteins is available. Here, we report on a non-thermal, chemical-free green macroalgae Ulva sp. protein extraction by osmotic shock combined with pulsed electric fields (PEF) followed by hydraulic pressure. The extracted proteins were identified and annotated to allergens using sequence similarity. The allergenicity potential of PEF extracted proteins was compared to osmotic shock extracts and complete Ulva sp. proteome, extracted with the thermochemical method. The PEF extracts contained 'superoxide dismutase' (SOD), a known food allergen, osmotic shock extract contained 'troponin C', and thermochemical extract contained two additional potential food allergens 'aldolase A' and 'thioredoxin h'. This study shows an importance and the need for deep investigation of algal proteins and protein extraction technology health impacts prior to large-scale release to the market of "novel food" derived proteins. PMID- 30409657 TI - Monitoring of the dopamine D2 receptor agonists hordenine and N-methyltyramine during the brewing process and in commercial beer samples. AB - The phenethylamine alkaloid hordenine, present in germinated barley, was identified recently as a functionally selective dopamine D2 receptor agonist contributing potentially to the rewarding effects of drinking beer. Here, it was shown that the hordenine precursor N-methyltyramine binds with a similar affinity to the dopamine D2 receptor as hordenine (Ki 31.3 uM) showing also selectivity towards the G protein-mediated pathway over the beta-arrestin pathway. Using a newly developed UHPLC-ESI-MS/MS method to monitor beer production, we demonstrated that hordenine and N-methyltyramine were released continuously from barley malt during mashing and were stable during fermentation and conditioning. The amounts released from different base malt types were in a similar range but tended to be higher from caramel malts. Hordenine and N-methyltyramine concentrations in 24 types of beer varied between 1.05-6.32 and 0.59-4.61 mg/L, respectively. Thus, the human uptake of the alkaloids during beer consumption is in the low milligram range. PMID- 30409658 TI - Extraction and characterization of starch granule-associated proteins from rice that affect in vitro starch digestibility. AB - Starch granule-associated proteins (SGAPs) including granule-surface proteins and granule-channel proteins in waxy, low- and high-amylose rice starch were extracted and identified. The in vitro digestibility of starch was investigated before and after the extraction of granule-channel proteins or total SGAPs. The results showed that 10 types of major differentially expressed proteins (DEPs) including 14-3-3-like protein and ribosomal protein were found among starches. In addition, the lack of only granule-channel proteins or total SGAPs led to significant and different changes in the levels of rapidly digestible starch, slowly digestible starch and resistant starch. Possible mechanisms are related to the accessibility of amylase into starch granules and structural properties of SGAPs. This study provides more information about DEPs in rice starch with different amylose content and supports further study on the relationship between SGAPs and in vitro starch digestibility. PMID- 30409659 TI - Analysis of the distribution of rice allergens in brown rice grains and of the allergenicity of products containing rice bran. AB - To understand the allergenicity of rice bran, the distribution of rice allergens in brown rice grains was analysed and the allergenicity of cosmetics and health foods containing rice bran determined. RAG2 and a 19-kDa globulin were localized in polished rice, while a 52-kDa globulin was localized in rice bran. The 52-kDa globulin was also identified as the most likely causative allergen of rice bran allergy. Several products containing intact rice bran were found to contain the 52-kDa globulin. Our study provides the first data regarding cosmetics and health foods containing potential rice bran allergens. Western blot analysis using a rice-bran-allergic patient's plasma showed that 52-kDa globulin was detected as an IgE-binding protein of rice bran and some rice bran-containing cosmetics and health foods. Our results indicate that patients with rice bran allergy need to be careful about using products containing intact rice bran as a constituent. PMID- 30409660 TI - Determination of sinapine in rapeseed pomace extract: Its antioxidant and acetylcholinesterase inhibition properties. AB - Sinapine is the main secondary metabolite present in rapeseed pomace (RSP) with its concentration being dependent on rapeseed processing, growing conditions, extraction parameters and the country of origin. Here we report, the concentration of sinapine from an extract of defatted RSP harvested in the North East of Scotland. Using liquid chromatography tandem mass spectrometry, the most abundant phenolic compound in the RSP extract was, as expected, sinapine (109.1 mg/g RSP extract). Additionally, sinapic, caffeic, ferulic and syringic acids were identified (0.159-3.91 mg/g RSP extract). Sinapine together with the phenolics at the concentration present in the RSP extract, exhibited >=50% activity relative to the extract in antioxidant assays. Furthermore, sinapine provided plasmid DNA (pBR322) protection, from 2,2'-azobis(2-amidinopropane) dihydrochloride and inhibited acetylcholinesterase activity by 85%. Molecular docking was utilised to explain the inhibitory activity. RSP can be an excellent source of bioactive compounds for pharmaceuticals, food additive and nutraceutical applications. PMID- 30409661 TI - Effects of different dephytinisation methods on chemical properties of commercial and traditional breads prepared from composite flour. AB - The influence of different dephytinisation methods such as malt flour addition, phytase enzyme application and citric acid addition on some properties of commercial bread and traditional flat bread containing 25% of cereal-legume (rye, barley, oat, chickpea, soy and lupin) flours was investigated. Ash, protein, crude fat, antioxidant activity, total phenolic content and mineral matters of both breads increased with the usage of cereal-legume flour blend. Cereal-legume flour blend also resulted in increments on phytic acid content of commercial bread (330 mg/100 g) and traditional flat bread (422 mg/100 g) compared to its controls (98 and 152 mg/100 g, respectively). Phytase enzyme application provided the highest loss of phytic acid for commercial bread (54%) and traditional flat bread (52%). Dephytinisation methods had no significant effect on weight, specific volume and hardness (24 h) of commercial bread containing 25% cereal legume flour blend. Compared to other dephytinisation methods citric acid addition provided higher diameter, spread ratio and hardness (72 h) values in traditional flat bread. Taste and odour parameters of breads were not affected by the dephytinisation methods. PMID- 30409662 TI - Interaction mechanism of flavonoids and zein in ethanol-water solution based on 3D-QSAR and spectrofluorimetry. AB - Zein has the potential application of establishing the delivery systems for flavonoids. But there are few reports about the effect of the molecular structures of flavonoids on their interaction with zein. In this study, the binding behaviour of 21 flavonoids and zein was investigated by spectrofluorimetry. The corresponding 3D-QSAR model was also established by Topomer CoMFA method, whose steric and electrostatic field analysis could explain the binding performance of the tested flavonoids with zein. The fluorescence analysis suggested that the flavonoids could interact with zein by forming the complex at the molar ratio of 1. The flavonoids with glucosyl groups at ring A exhibited the outstanding binding capacity with zein, and their binding process with zein was driven by hydrophobic force. The synchronous and 3D fluorescence spectra showed that there was no apparent change in the microenvironment surrounding the tyrosine residues of zein during the interaction. PMID- 30409664 TI - Effect of nanocomposite-based packaging on microstructure and energy metabolism of Agaricus bisporus. AB - Rapid deterioration of postharvest Agaricus bisporus is a serious problem. Measures to improve the shelf-life are of great importance. Therefore, we used a nanocomposite-based packaging material (Nano-PM) containing nano-TiO2, nano-SiO2, nano-Ag and attapulgite to study its effect on microstructure and energy metabolism of A. bisporus. Nano-PM reduced the oxidation of lipids and proteins by activating antioxidant enzyme activities and inhibiting the accumulation of ROS, thereby maintained high level of energy status. Meanwhile, ATP content and energy charge of A. bisporus in Nano-PM increased through the energy metabolism system. This was attributed to the lower respiration rate and higher mitochondrial respiratory enzyme activities. These results indicated that Nano-PM could maintain the dense and intact microstructure of A. bisporus thus improve its shelf-life. PMID- 30409663 TI - Characterisation and attempted differentiation of European and extra-European olive oils using stable isotope ratio analysis. AB - European law requires a designation of origin for virgin and extra virgin olive oils (at least in terms of EU/non-EU provenance). Stable isotope ratios have been successfully applied to determine the geographical origin of olive oils, but never to distinguish EU and non-EU oils. In this study 2H/1H, 13C/12C and 18O/16O ratios were analysed in bulk olive oils using Isotope Ratio Mass Spectrometry (IRMS) as well as 13C/12C and 2H/1H in the four main fatty acids (linoleic, oleic, palmitic and stearic acids) using IRMS coupled with GC. The isotopic composition of olive oils was successfully used to distinguish samples originating in the two areas. Specifically, when bulk data were combined with fatty acid isotopic data the differentiation power of the method improved clearly. This separation is due to the specific isotopic fingerprint of the individual countries making up the EU and non-EU samples. PMID- 30409665 TI - Self-aggregation of oxidized procyanidins contributes to the formation of heat reversible haze in apple-based liqueur wine. AB - The ability of tannins to self-associate or form complexes with other macromolecules has important nutritional implications but can also result in defects in beverages. In addition, oxidation may be involved in the aggregation properties of tannins. In order to assess the impact of tannin oxidation on their self-association, oligomeric procyanidins were oxidized in a model solution and their aggregation kinetics were studied using light scattering. Under the conditions tested, only oxidized procyanidins were involved in haze formation. An increase in the level of oxidation and the degree of polymerization of procyanidins enhanced aggregation. Procyanidin oxidation products were depolymerized and the evolution of their markers was monitored throughout the aggregation process using liquid chromatography coupled with mass spectrometry. This revealed the involvement of intramolecular coupling in reversible haze formation. The haze formed in a model solution was partially reversible at high temperature. This property was similar in pommeau, an apple-based beverage. This work highlighted the involvement of oxidized tannins in reversible haze. PMID- 30409666 TI - Effect of phosphorus application rate on Mentha spicata L. grown in deep flow technique (DFT). AB - The present study evaluated the impact of phosphorus application rate on plant growth and physiological parameters, antioxidant activity, chemical composition, and essential oil yield and composition of hydroponically grown spearmint plants. Increased P levels resulted in high dry matter content of the aerial part. Antioxidant activity of spearmint leaves was significantly higher at the highest P levels. Although essential oil yield was not affected, essential oil composition varied among the studied P levels, especially carvone content. Total and individual organic acids content was higher when 50 mg/L P were added in the nutrient solution. Rosmarinic acid was the main detected phenolic compound, while the highest total phenolic compounds and rosmarinic acid content was observed at 50 and 70 mg/L of P, respectively. In conclusion, phosphorus application rate may affect spearmint growth and development, as well as chemical composition and essential oil composition. PMID- 30409667 TI - Elucidation of rheological, microstructural, water mobility, and noodle-making properties of rice flour affected by turanose. AB - The effects of turanose on the physicochemical properties of rice flour systems (aqueous suspension, dough, and noodles) were investigated in terms of rheology, microstructure, and water mobility. Inclusion of turanose increased the pasting viscosities of rice flour by maintaining a closely-packed structure at high temperatures that was confirmed by the real-time microscopic measurements during heating. The elevated probability of intergranular interactions by turanose apparently raised both storage (G') and loss (G") moduli of the rice flour pastes as well as their respective viscosities. NMR spin-spin relaxation times showed two distinct water populations in the turanose-rice flour samples. The Mixolab experiments demonstrated that the rice doughs with higher levels of turanose exhibited greater dough stability as well as higher degrees of starch gelatinization and retrogradation. Furthermore, the extruded rice noodles containing turanose exhibited a higher expansion ratio and a firmer texture that contributed to lowering the cooking loss by 24.5%. PMID- 30409668 TI - Differential accumulation of specialized metabolite l-theanine in green and albino-induced yellow tea (Camellia sinensis) leaves. AB - l-Theanine is a specialized metabolite in tea (Camellia sinensis) leaves that contributes to tea function and quality. Yellow tea leaves (albino) generally have higher l-theanine contents than green tea leaves (normal), but the reason is unknown. The objective of this study was to investigate why l-theanine is accumulated in yellow tea leaves. We compared original normal leaves (green) and light-sensitive albino leaves (yellow) of cv. Yinghong No. 9. The l-theanine content was significantly higher in yellow leaves than in green leaves (p <= 0.01). After supplementation with [2H5]-l-theanine, yellow leaves catabolized less [2H5]-l-theanine than green leaves (p <= 0.05). Furthermore, most plants contained the enzyme catalyzing l-theanine conversion to ethylamine and l glutamic acid. In conclusion, l-theanine accumulation in albino-induced yellow tea leaves was due to weak l-theanine catabolism. The differential accumulation mechanism differed from the l-theanine accumulation mechanism in tea and other plants. PMID- 30409670 TI - Deciphering phenotypic variance in different models of DNA-PKcs deficiency. AB - DNA-PKcs deficiency has been studied in numerous animal models and cell culture systems. In previous studies of kinase inactivating mutations in cell culture systems, ablation of DNA-PK's catalytic activity results in a cell phenotype that is virtually indistinguishable from that ascribed to complete loss of the enzyme. However, a recent compelling study demonstrates a remarkably more severe phenotype in mice harboring a targeted disruption of DNA-PK's ATP binding site as compared to DNA-PKcs deficient mice. Here we investigate the mechanism for these divergent results. We find that kinase inactivating DNA-PKcs mutants markedly radiosensitize immortalized DNA-PKcs deficient cells, but have no substantial effects on transformed DNA-PKcs deficient cells. Since the non-homologous end joining mechanism likely functions similarly in all of these cell strains, it seems unlikely that kinase inactive DNA-PK could impair the end joining mechanism in some cell types, but not in others. In fact, we observed no significant differences in either episomal or chromosomal end joining assays in cells expressing kinase inactivated DNA-PKcs versus no DNA-PKcs. Several potential explanations could explain these data including a non-catalytic role for DNA-PKcs in promoting cell death, or alteration of gene expression by loss of DNA-PKcs as opposed to inhibition of its catalytic activity. Finally, controversy exists as to whether DNA-PKcs autophosphorylates or is the target of other PIKKs; we present data demonstrating that DNA-PK primarily autophosphorylates. PMID- 30409669 TI - Efficacy of a self-management education programme on patients with type 2 diabetes in primary care: A randomised controlled trial. AB - AIM: The purpose of this study was to assess the efficacy of the Spanish Diabetes Self-Management Program (SDSMP) versus usual care in adults with type 2 diabetes mellitus (T2DM) residing in a Spanish region. METHODS: A two-year follow-up randomised controlled trial. The intervention consisted of 6 weekly structured peer-to-peer workshops. The primary outcome was change in HbA1c levels. Secondary outcomes included other clinical measures, quality of life, self-efficacy, life style changes, medication and use of healthcare services. Mixed effect models were fitted. RESULTS: n=297 patients were recruited in each study arm. Baseline HbA1c levels were comparable in both groups with an overall mean 7.1 (SD=1.2). The intervention did not significantly modify HbA1c, or other cardiovascular variables. Significant improvements were seen in self-efficacy, and in particularly its disease control component. Certain differences were also observed in the use of healthcare resources and medication consumption. High workshop participation and satisfaction rates were achieved. CONCLUSION: HbA1c reductions are difficult to obtain in adequately controlled patients. On the other hand, raising awareness on one's disease can increase disease control self efficacy. This finding, accompanied by reduced medication consumption and healthcare use rates, highlights that usual care would be benefited by incorporating certain SDSMP aspects. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01642394. PMID- 30409671 TI - Health status and life satisfaction among people with disabilities: Evidence from Taiwan. AB - BACKGROUND: Two important dimensions of subjective well-being are self-reported 'health status' and 'life satisfaction', both of which are generally perceived as being lower among people with disabilities. Although the factors associated with health status and life satisfaction have been well documented among the general population, relevant research relating to disabled people remains limited, indeed, almost non-existent in Taiwan. OBJECTIVE: Our aim in the present study is to explore the levels of, and the factors associated with, self-reported health status and life satisfaction among people with disabilities in Taiwan. METHODS: The dataset used in this study was drawn from a representative population-based survey carried out in a municipal city in Taiwan involving 983 disabled people aged between 15 and 64. Descriptive statistics were applied to provide both a profile of the respondents and the distribution of the related variables, with ordinal logistic regression models being employed to identify the factors associated with health status and life satisfaction. RESULTS: As compared to the findings reported on western societies, health status and life satisfaction levels among disabled people in Taiwan were found to be similar. Age, incidences of chronic conditions, and medical barriers encountered were found to have negative associations with health status, whilst better household finances, living environment, and social support were positively associated with life satisfaction. CONCLUSIONS: Since both individual and contextual factors may be related to the subjective well-being of disabled people, policy interventions should target specific aspects so as to improve the lives of people with disabilities. PMID- 30409672 TI - Social Media and Radiology Education: Are We #Ready? AB - Social media has become integrated into the lives of millions of people, but it has only recently been explored as a potential teaching tool. There is a body of literature to suggest that today's learners desire use of these interactive platforms for learning and that they result in higher degrees of student satisfaction, although it is not yet clear that a greater degree of knowledge transfer or retention is achieved. There are barriers to implementation in a curriculum, but as we learn to overcome these barriers and find new and creative ways to leverage social media we as educators will meet our students needs in the era of "web 2.0" and the digital native generation. PMID- 30409673 TI - "What program directors think IV": Results of the 2017 Annual Survey of the Association of Program Directors in Radiology. AB - RATIONALE AND OBJECTIVES: The Association of Program Directors in Radiology (APDR) regularly surveys its members to gather information regarding a broad range of topics related to radiology residency. The survey results provide insight into the opinions of residency program leadership across the country. MATERIALS AND METHODS: This is an observational cross-sectional study using a web based survey posed to the APDR membership in the fall of 2017. The final survey consisted of 53 items, 48 multiple choice questions and five write-in comments. An invitation to complete the survey was sent to all 319 active APDR members. RESULTS: Deidentified responses were collected electronically, tallied utilizing Qualtrics software, and aggregated for the purposes of analysis and reporting at the 66th annual meeting of the Association of University Radiologists. The response rate was 36%. CONCLUSION: Over the past 16 years, more PDs have assistant and APDs to administer growing residency programs, but the time allocation for these APDs has come from the PD's protected time. An overwhelming majority of PDs consider independent call beneficial to residents and most think a call assistant is desirable. The vast majority of PDs support a unified fellowship match and allow resident moonlighting. Most fourth year residents are actively or moderately involved in clinical work and teaching. The majority of PDs have lost or expect to lose DR training positions to the new IR/DR programs. In a competitive match, PDs do not rely on residency interviews in their selection process. PMID- 30409674 TI - Molecular basis for increased 2-acetyl-1-pyrroline contents under alternate wetting and drying (AWD) conditions in fragrant rice. AB - Factors affecting rice aroma biosynthesis have been well documented previously, however the molecular mechanism lies behind the regulations in grain 2-acetyl-1 pyrroline (2AP) biosynthesis under alternate wetting and drying (AWD) remained largely unexplored. Present study investigated the effects of three irrigation regimes i.e., conventional irrigation (CI), alternate wetting and moderate drying (WMD), and alternate wetting and severe drying (WSD) on the yield, quality traits, intermediates, enzyme activities and genes involved in 2-acetyl-1 pyrroline biosynthesis in two fragrant rice cultivars viz, Meixiangzhan2 and Xiangyaxiangzhan. Results revealed that the levels of intermediates such as Delta1-pyrroline-5-carboxylate (P5C) and Delta1-pyrroline, and the activity of enzymes such as proline dehydrogenase (PRODH), Delta1-pyrroline-5-carboxylate synthetase (P5CS), diamine oxidase (DAO), and gene expressions of PRODH, P5CS2 and DAO were comparatively higher under AWD than CI in both aromatic rice cultivars. The levels of gamma-aminobutyric acid (GABA), betaine aldehyde dehydrogenase 2 (BADH2) and BADH2 gene were lower that together led to enhanced 2 AP contents in rice grains. Moreover, WMD irrigation improved yield and yield characters, while WSD irrigation reduced yield and quality traits of rice. Overall, up-regulation of P5C and Delta1-pyrroline and down-regulation of GABA under AWD treatments resulted in enhanced 2AP biosynthesis in both rice cultivars. Evaluation and adoption of AWD (within safe limits) at field level could be an alternative option to conventional flooded rice to get better yield and quality. PMID- 30409675 TI - Corrigendum re "Neoadjuvant Short-term Intensive Intravesical Mitomycin C Regimen Compared with Weekly Schedule for Low-grade Recurrent Non-muscle-invasive Bladder Cancer: Preliminary Results of a Randomised Phase 2 Study" [Eur Urol 2012;62:797 802]. PMID- 30409676 TI - Which Patients with Clinically Node-positive Prostate Cancer Should Be Considered for Radical Prostatectomy as Part of Multimodal Treatment? The Impact of Nodal Burden on Long-term Outcomes. AB - BACKGROUND: A role for local therapies including radical prostatectomy (RP) in prostate cancer (PCa) patients with clinical lymphadenopathies has been proposed. However, no data are available to identify men who would benefit from RP in this setting. OBJECTIVE: To identify predictors of clinical recurrence (CR) in surgically managed PCa patients with clinical lymphadenopathies. DESIGN, SETTING, AND PARTICIPANTS: We identified 162 patients with lymphadenopathies treated with RP and lymph node dissection at three referral centers. OUTCOME MEASURES AND STATISTICAL ANALYSES: CR was defined as the onset of metastases detected by conventional imaging. Kaplan-Maier analyses assessed time to CR after stratifying patients according to the site of lymphadenopathies and nodal burden. Regression tree analysis stratified patients into risk groups on the basis of their preoperative characteristics. RESULTS AND LIMITATIONS: Overall, 80% of patients had lymphadenopathies in the pelvis alone and 20% in the retroperitoneum+/ pelvis. The median size of positive nodes was 13mm. A total of 84 patients (52%) received neoadjuvant androgen deprivation therapy and 127 (78%) had pathological lymph node invasion. The median follow-up for survivors was 64 mo. The 8-yr CR free and CSM-free survival rates were 59% and 80%, respectively. Biopsy grade group and preoperative nodal burden should identify patients more likely to experience CR. While <10% of men with biopsy grade group 1-3 and two or fewer clinical lymphadenopathies developed CR, up to 60% of patients with biopsy grade group 4-5 and retroperitoneal node involvement ultimately experienced CR at 8 yr after RP. The discrimination of the regression tree was 76% according to the area under the receiver operating characteristic curve. Our study is limited by potential unmeasured confounders and the relatively small sample size. CONCLUSIONS: Surgery in a multimodal setting might play a role in PCa patients with biopsy grade group 1-3 and/or enlarged nodes in the pelvis. Conversely, grade group 4-5 PCa and lymphadenopathies in the retroperitoneum are associated with worse oncologic outcomes. PATIENT SUMMARY: Approximately half of prostate cancer patients with clinical lymphadenopathies treated with radical prostatectomy are free from metastases at 8-yr follow-up. Radical prostatectomy with or without systemic therapies might play a role in selected patients with biopsy grade group 1-3 disease and/or enlarged nodes in the pelvis. Conversely, a higher grade group and the presence of lymphadenopathies in the retroperitoneum should identify candidates for systemic therapies upfront. PMID- 30409677 TI - Stress, strain and mechanical power: Is material science the answer to prevent ventilator induced lung injury? PMID- 30409678 TI - Preoperative skin antisepsis. AB - Surgical wound infection is one of the main complications of patients undergoing surgery and has significant clinical and economical consequences, especially when it affects prosthetic implants or is caused by multidrug resistant bacteria. Cutaneous preparation is one of the main preventive measures. Clinical practice guidelines recommend not to remove the hair from the surgery site unless it interferes with the operation, and that if removal proves necessary, it should be done with a single-use cutter, as close as possible to the time of surgery. With regard to preoperative showering, the current recommendation is to perform it with a soap (whether antimicrobial or otherwise) or an antiseptic product, at least the night before surgery. Regarding preparation of the incision area and surrounding zone, the use of an alcohol-based antiseptic is generally advised, preferably alcoholic chlorhexidine, due to its high antibacterial activity and prolonged residual effect, respecting the evaporation drying time. PMID- 30409679 TI - Attitudes of healthcare professionals towards cardiopulmonary resuscitation: Results of a survey. PMID- 30409680 TI - Lymphopenic hospital acquired sepsis (L-HAS): An immunological phenotype conferring higher risk of mortality. PMID- 30409681 TI - Antiseptic measures during the insertion and manipulation of vascular catheters. AB - Several measures related to asepsis for preventing catheter-related bloodstream infection have been proposed. The aseptic measures recommended by scientific societies include hand hygiene of the person who is inserting or manipulating the catheter; maximum sterile barrier precautions during catheter insertion; disinfection of catheter hubs; the use of needle-less connectors and injection ports; the avoidance of antibiotic ointments (except in hemodialysis catheters); change the dressing if it is soiled, loose or damp; and aseptic technique during dressing changes. Other measures only recommended by the most recently published guides (possibly due to the publication of recent studies reporting their beneficial effects) are the use of antimicrobial-impregnated dressings, changing transparent dressings every 7 days, and bathing of the patient with chlorhexidine. PMID- 30409682 TI - Public health burden of antimicrobial resistance in Europe. PMID- 30409683 TI - Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis. AB - BACKGROUND: Infections due to antibiotic-resistant bacteria are threatening modern health care. However, estimating their incidence, complications, and attributable mortality is challenging. We aimed to estimate the burden of infections caused by antibiotic-resistant bacteria of public health concern in countries of the EU and European Economic Area (EEA) in 2015, measured in number of cases, attributable deaths, and disability-adjusted life-years (DALYs). METHODS: We estimated the incidence of infections with 16 antibiotic resistance bacterium combinations from European Antimicrobial Resistance Surveillance Network (EARS-Net) 2015 data that was country-corrected for population coverage. We multiplied the number of bloodstream infections (BSIs) by a conversion factor derived from the European Centre for Disease Prevention and Control point prevalence survey of health-care-associated infections in European acute care hospitals in 2011-12 to estimate the number of non-BSIs. We developed disease outcome models for five types of infection on the basis of systematic reviews of the literature. FINDINGS: From EARS-Net data collected between Jan 1, 2015, and Dec 31, 2015, we estimated 671 689 (95% uncertainty interval [UI] 583 148-763 966) infections with antibiotic-resistant bacteria, of which 63.5% (426 277 of 671 689) were associated with health care. These infections accounted for an estimated 33 110 (28 480-38 430) attributable deaths and 874 541 (768 837-989 068) DALYs. The burden for the EU and EEA was highest in infants (aged <1 year) and people aged 65 years or older, had increased since 2007, and was highest in Italy and Greece. INTERPRETATION: Our results present the health burden of five types of infection with antibiotic-resistant bacteria expressed, for the first time, in DALYs. The estimated burden of infections with antibiotic-resistant bacteria in the EU and EEA is substantial compared with that of other infectious diseases, and has increased since 2007. Our burden estimates provide useful information for public health decision-makers prioritising interventions for infectious diseases. FUNDING: European Centre for Disease Prevention and Control. PMID- 30409684 TI - Focus on Internal Urethrotomy as Primary Treatment for Untreated Bulbar Urethral Strictures: Results from a Multivariable Analysis. AB - BACKGROUND: The use of internal urethrotomy for treatment of urethral stricture remains a controversial topic in urology. OBJECTIVE: To investigate outcomes and predictors of failure for internal urethrotomy as primary treatment for untreated bulbar urethral strictures. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective analysis of patients who underwent internal urethrotomy. Patients with bulbar urethral stricture who did not receive any previous treatment were included. Patients with traumatic, penile or posterior urethral strictures, lichen sclerosus, failed hypospadias repair, or stricture length >4cm were excluded. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was treatment failure. Kaplan-Meyer plots were used to depict treatment failure-free survival. Univariate and multivariable Cox regression analyses were used to test the association between predictors (age, body mass index, diabetes, history of smoking, etiology, stenosis type and length, preoperative maximum flow [pQmax]) and treatment failure. RESULTS AND LIMITATIONS: Overall, 136 patients were included. The median stricture length was 2cm. Median follow-up was 55 mo. At 5 yr follow-up the failure-free survival rate was 57%. On univariate analysis, diabetes, nonidiopathic etiology, stricture length of 3-4cm, and pQmax were significantly associated with treatment failure. These predictors were included in a multivariable analysis, in which pQmax was the only significant predictor of treatment failure. CONCLUSIONS: Failure of internal urethrotomy for untreated bulbar urethral strictures greatly depends on pQmax flow at uroflowmetry. Patients with pQmax >8ml/s have a high probability of success, while patients with pQmax <5ml/s have a low probability of success. PATIENT SUMMARY: The use of internal urethrotomy in patients with an untreated bulbar urethral stricture should only be considered in selected cases. PMID- 30409685 TI - How a New Conservation Action Concept Has Accelerated Plant Conservation in China. AB - Since 2005, a new conservation action concept has been implemented to address the most threatened plant species requiring priority conservation in China. The concept is now widely recognized at different levels of governmental departments and by the general public, and is leading to great achievements for plant conservation in China. PMID- 30409686 TI - The Strawberry Tales: Size Matters. AB - The history of the strawberry is one of ambitious kings and cunning spies, overseas adventures, and religious symbolism. Here, we will tell these stories, illustrated by relevant paintings and drawings, to give insight into the domestication of the strawberry. Furthermore, we will briefly discuss the complex strawberry genomes and aroma. PMID- 30409687 TI - A Resurrected Scenario: Single Gain and Massive Loss of Nitrogen-Fixing Nodulation. AB - Root nodule endosymbiosis with nitrogen-fixing bacteria provides plants with unlimited access to fixed nitrogen, but at a significant energetic cost. Nodulation is generally considered to have originated in parallel in different lineages, but this hypothesis downplays the genetic complexity of nodulation and requires independent recruitment of many common features across lineages. Recent phylogenomic studies revealed that genes that function in establishing or maintaining nitrogen-fixing nodules are independently lost in non-nodulating relatives of nitrogen-fixing plants. In our opinion, these data are best explained by a scenario of a single gain followed by massively parallel loss of nitrogen-fixing root nodules triggered by events at geological scale. PMID- 30409689 TI - The Evolution of Mammography Controversy in the News Media: A Content Analysis of Four Publicized Screening Recommendations, 2009 to 2016. AB - BACKGROUND: There is longstanding expert disagreement about the age at and frequency with which women should be screened for breast cancer. These debates are reflected in the conflicting recommendations about mammography issued by major professional organizations, such the U.S. Preventive Services Task Force and the American Cancer Society. Previous research has shown that these recommendations garner substantial media attention-and therefore might affect women's screening perceptions and behaviors-but to date analyses of such media coverage have focused on single publicized announcements. METHODS: To assess whether media coverage of mammography screening recommendations has evolved, we conducted a content analysis of televised news from four discrete media events from 2009 to 2016, all of which focused on publicized screening recommendations from the U.S. Preventive Services Task Force and American Cancer Society (N = 364 stories). RESULTS: Media coverage of mammography screening recommendations has featured persistent messages of conflict and/or controversy over time. The evolution of controversy was also reflected in shifts in the relative attention given to mammography screening's risks and benefits, with consistent and, in some cases, heightened attention to screening's risks during more recent media events. Overall, the accuracy of media coverage improved over time. CONCLUSIONS: Results underscore the continued prevalence of conflicting and/or controversial information about mammography screening in the public information environment. Cumulative exposure to such messages could influence women's decision making around screening and trust in cancer prevention recommendations. Strategies are needed to better equip all women (and particularly underserved women) to negotiate mammography controversy and weigh the benefits and risks of screening. PMID- 30409688 TI - Next generation of radiotracers for sentinel lymph node biopsy: What is still necessary to establish new imaging paradigms? AB - Sentinel lymph node (SLN) biopsy is now the standard of care for regional staging in several solid tumors. The interstitial administration of a radiotracer around the primary tumor provide the possibility to sequentially obtain images with a gamma camera and visualize lymphatic mapping and the SLN. There is, however, a large geographical variability in those radiotracers and nanocolloids ranging from 15-100nm which are most widely employed in Europe, while filtered and unfiltered 99mTc-sulfur colloid (range 20-1000nm) is usually used in the USA with different drawbacks in its use. The new radiotracer 99mTc-Tilmanocept, designed specifically for the identification of SLNs and recently becoming commercially available in USA and Europe, appears to have the potency to overcome the shortcomings described for the conventional radiotracers used until now for SLN biopsy and at the same time to transform current imaging paradigms. After delineating the challenges for the next generation of radiotracers, this paper discusses the properties of 99mTc-Tilmanocept, its validation process for SLN biopsy and its emerging clinical applications in various malignancies. PMID- 30409690 TI - Type 1 diabetes: new and fellow travellers. PMID- 30409691 TI - Co-occurrence of early diabetes-related complications in adolescents and young adults with type 1 diabetes: an observational cohort study. AB - BACKGROUND: One in three adolescents and young adults with type 1 diabetes have at least one early diabetes-related complication or comorbidity. We aimed to examine the prevalence and pattern of co-occurring complications in this population, as well as the related risk factors. METHODS: This observational cohort study includes data from individuals diagnosed with type 1 diabetes before age 20 years who participated in the SEARCH for Diabetes in Youth Study across five sites in the USA. We assessed sociodemographic and metabolic risk factors at baseline and at follow-up, and diabetes complications at follow-up. A frequency analysis was done to examine the difference in observed versus expected prevalence (calculated using a contingency table assuming independence across cells) of co-occurring complications or comorbidities. A cluster analysis was done to identify unique clusters of participants based on demographic characteristics and metabolic risk factors. FINDINGS: 1327 participants who completed the follow-up visit were included in the frequency analysis. The mean age was 10.1 (SD 3.9) years at the time of type 1 diabetes diagnosis and 18.0 (4.1) years at follow-up. At a mean diabetes duration of 7.8 [SD 1.9] years, co occurrence of any two or more complications was observed in 78 (5.9%) participants, more frequently than expected by chance alone (58 [4.4%], p=0.015). Specifically, the complications that co-occurred more frequently than expected were retinopathy and diabetic kidney disease (11 [0.8%] vs three [0.2%]; p=0.0007), retinopathy and arterial stiffness (13 [1.0%] vs four [0.3%]; p=0.0016), and arterial stiffness and cardiovascular autonomic neuropathy (24 [1.8%] vs 13 [1.0%]; p=0.015). We identified four unique clusters characterised by progressively worsening metabolic risk factor profiles (longer duration of diabetes and higher glycated haemoglobin, non-HDL cholesterol, and waist-to height ratio). The prevalence of at least two complications increased across the clusters (six [2.3%] of 261 in the low-risk cluster, 32 [6.3%] of 509 in the moderate-risk cluster, 28 [8%] of 348 in the high-risk cluster, and five [20.8%] of 24 in the highest-risk cluster). Compared with the low-risk and moderate-risk clusters, the high-risk and highest-risk clusters were characterised by a lower proportion of participants who were non-Hispanic white, and a higher proportion of participants who had a household income below US$50 000 and did not have private health insurance. INTERPRETATION: Early complications co-occur in adolescents and young adults with type 1 diabetes more frequently than expected. Identification of individuals with adverse risk factors could enable targeted behavioural or medical interventions that reduce the likelihood of early development of lifelong diabetes-related morbidity. FUNDING: US Centers for Disease Control and Prevention, US National Institutes of Health. PMID- 30409692 TI - Translation and initial validation of the Medication Adherence Report Scale (MARS) in Italian patients with Crohn's Disease. AB - The MARS-5 (Medication Adherence Report Scale) was developed in English. The aim of this project was to analyse the MARS-5I ((c) Prof Rob Horne) psychometric properties and to identify whether its Italian translation is suitable for assessing medication adherence in Crohn Disease (CD) Italian patients. The MARS was translated and linguistically validated in Italian. The MARS-5I was used for evaluating medication adherence in the SOLE study, conducted in Italy on 552 subjects with CD. In order to un-bias the questionnaire results from the effects of treatment change and/or effectiveness, the analyses were performed on the 277 patients whose disease activity remained stable, selected among the 371 patients who maintained the same treatment between two consecutive visits. Internal consistency was high (Cronbach's alpha of 0.86). Pearson's correlation coefficient was 0.50 (p < 0.001) and 0.86 (p < 0.001- outliers removed), indicating satisfactory test-retest. MARS 5I scores were not correlated with Treatment Satisfaction Questionnaire for Medication but a small and statistically significant correlation was shown with physician-evaluated medication adherence, indicating convergent validity. MARS-5I, the Italian translation of the English MARS, showed satisfactory internal consistency and test-retest, and a low but statistically significant convergent validity. We confirmed the utility of this tool in patients with CD. PMID- 30409693 TI - Cardiac involvement in patients with end-stage liver disease, beyond the hepatopulmonary syndrome. PMID- 30409694 TI - Traditional Food Practices, Attitudes, and Beliefs in Urban Alaska Native Women Receiving WIC Assistance. AB - OBJECTIVE: To identify practices, attitudes, and beliefs associated with intake of traditional foods among Alaska Native women. DESIGN: Cross-sectional study that measured traditional food intake; participation in food-sharing networks; presence of a hunter or fisherman in the home; the preference, healthfulness, and economic value of traditional foods; and financial barriers to obtaining these foods. PARTICIPANTS: Purposive sample of 71 low-income Alaska Native women receiving Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) assistance in Anchorage, AK. ANALYSIS: Bivariate and multivariate regression analyses. RESULTS: Traditional foods contributed 4% of total daily calories. Given a choice, 63% of participants indicated that they would prefer half or more of the foods they ate to be traditional (ie, not store-bought). The majority of participants (64%) believed that traditional foods were healthier than store-bought foods. Of all participants, 72% relied on food-sharing networks for traditional foods; only 21% acquired traditional foods themselves. Participants who ate more traditional foods preferred traditional foods (B = .011 P = .02). IMPLICATIONS FOR RESEARCH AND PRACTICE: Traditional food intake was low and findings suggested that Alaska Native women living in an urban setting prefer to consume more but are unable to do so. Future research might examine the effect of enhancing social networks and implementing policies that support traditional food intake. PMID- 30409695 TI - Preliminary data indicating a connection between stress-induced prefrontal dopamine release and hippocampal TSPO expression in the psychosis spectrum. AB - Prolonged stress can cause neuronal loss in the hippocampus resulting in disinhibition of glutamatergic neurons proposed to enhance dopaminergic firing in subcortical regions including striatal areas. Supporting this, imaging studies show increased striatal dopamine release in response to psychosocial stress in healthy individuals with low childhood maternal care, individuals at clinical high risk for psychosis (CHR) and patients with schizophrenia. The prefrontal cortex (PFC) is connected to the hippocampus and a key region to control neurochemical responses to stressful stimuli. We recently reported a disrupted PFC dopamine-stress regulation in schizophrenia, which was intact in CHR. Given the available evidence on the link between psychosocial stress, PFC dopamine release and hippocampal immune activation in psychosis, we explored, for the first time in vivo, whether stress-induced PFC dopamine release is associated with hippocampal TSPO expression (a neuroimmune marker) in the psychosis spectrum. We used an overlapping sample of antipsychotic-naive subjects with CHR (n = 6) and antipsychotic-free schizophrenia patients (n = 9) from our previously published studies, measuring PFC dopamine release induced by a psychosocial stress task with [11C]FLB457 positron emission tomography (PET) and TSPO expression with [18F]FEPPA PET. We observed that participants on the psychosis spectrum with lower stress-induced dopamine release in PFC had significantly higher TSPO expression in hippocampus (beta = -2.39, SE = 0.96, F(1,11) = 6.17, p = 0.030). Additionally, we report a positive association between stress-induced PFC dopamine release, controlled for hippocampal TSPO expression, and Global Assessment of Functioning. This is the first exploration of the relationship between PFC dopamine release and hippocampal TSPO expression in vivo in humans. PMID- 30409696 TI - Motor cortical plasticity in schizophrenia: A meta-analysis of Transcranial Magnetic Stimulation - Electromyography studies. AB - BACKGROUND: Several lines of investigations converge upon aberrant synaptic plasticity as a potential pathophysiological characteristic of schizophrenia. In vivo experiments using neuromodulatory perturbation techniques like Transcranial Magnetic and Direct Current Stimulation (TMS & tDCS) have been increasingly used to measure 'motor cortical plasticity' in schizophrenia. A systematic quantification of cortical plasticity and its moderators in schizophrenia is however lacking. METHOD: The PubMed/MEDLINE database was searched for studies up to December 31st, 2017 that examined case-control experiments comparing neuromodulation following single-session of TMS or tDCS. The primary outcome was the standardized mean difference for differential changes in motor evoked potential (MEP) amplitudes measured with single-pulse TMS (MEP Delta) between patients and healthy subjects following TMS or tDCS. After examining heterogeneity, meta-analyses were performed using fixed effects models. RESULTS: A total of 16 datasets comparing cortical plasticity (MEP Delta) between 189 schizophrenia patients and 187 healthy controls were included in the meta analysis. Patients demonstrated diminished MEP Delta with effect sizes (Cohen's d) ranging from 0.66 (LTP-like plasticity) to 0.68 (LTD-like plasticity). Heterosynaptic plasticity studies demonstrated a greater effect size (0.79) compared to homosynaptic plasticity studies (0.62), though not significant (P = 0.43). Clinical, perturbation protocol- and measurement-related factors, and study quality did not significantly moderate the aberrant plasticity demonstrated in schizophrenia. CONCLUSIONS: Schizophrenia patients demonstrate diminished LTP- and LTD-like motor cortical plasticity, which is not influenced by the various clinical and experimental protocol related confounders. These consistent findings should encourage the use of perturbation-based biomarkers to characterize illness trajectories and treatment response. PMID- 30409697 TI - Altered functional connectivity between sub-regions in the thalamus and cortex in schizophrenia patients measured by resting state BOLD fMRI at 7T. AB - The thalamus is a small brain structure that relays neuronal signals between subcortical and cortical regions. Abnormal thalamocortical connectivity in schizophrenia has been reported in previous studies using blood-oxygenation-level dependent (BOLD) functional MRI (fMRI) performed at 3T. However, anatomically the thalamus is not a single entity, but is subdivided into multiple distinct nuclei with different connections to various cortical regions. We sought to determine the potential benefit of using the enhanced sensitivity of BOLD fMRI at ultra high magnetic field (7T) in exploring thalamo-cortical connectivity in schizophrenia based on subregions in the thalamus. Seeds placed in thalamic subregions of 14 patients and 14 matched controls were used to calculate whole brain functional connectivity. Our results demonstrate impaired thalamic connectivity to the prefrontal cortex and the cerebellum, but enhanced thalamic connectivity to the motor/sensory cortex in schizophrenia. This altered functional connectivity significantly correlated with disease duration in the patients. Remarkably, comparable effect sizes observed in previous 3T studies were detected in the current 7T study with a heterogeneous and much smaller cohort, providing evidence that ultra-high field fMRI may be a powerful tool for measuring functional connectivity abnormalities in schizophrenia. Further investigation with a larger cohort is merited to validate the current findings. PMID- 30409698 TI - Autologous bone marrow-derived CD133 cells with core decompression as a novel treatment method for femoral head osteonecrosis: a pilot study. AB - BACKGROUND: Avascular necrosis (AVN) of femoral head is a progressive bone disease due to ischemia of femoral head; patients experience pain and they can not do normal activity. There is not an effective way to treat the cause of this disease. In recent studies, treatment of this disease using pluripotent stem cell derived mesenchyme is safe and effective, but this method needs more investigation. In this study, the safety and efficacy of CD133+ cells were evaluated as a novel method of stem cell therapy to treat AVN. METHODS: In this prospective quasi-experimental study, the participants were selected among patients with AVN who were referred to the Royan Cell Therapy Center. Autologous bone marrow-derived CD133+ cells were injected into the necrotic site of the femoral head during core decompression (CD). The Visual Analogue Scale (VAS), Harris Hip Score (HHS), Western Ontario and McMaster Universities Arthritis Index (WOMAC) and walking distance (WD) were measured before and 2, 6 and 12 months after CD. RESULTS: Overall, nine patients (six men and three women) were investigated in this study. Their mean age was 26 years old. All of them significantly improved in VAS, HHS, WOMAC and WD scores and they could do more activity without pain. Also, imaging findings demonstrated significant reductions in joint injuries. Significant complications were not seen in patients. DISCUSSION: This prospective quasi-experimental study demonstrated that, in patients with AVN, a single bone marrow-derived CD133+ cell injection into the necrotic site of the femoral head during CD is safe and effective in providing significant, clinically relevant pain relief and patients could do more activity over 2, 6 and 12 months. This pilot study suggested further clinical trials over an extended assessment period to approve bone marrow-derived CD133+ cell injection to treat AVN. PMID- 30409699 TI - Evaluation of different routes of administration and biodistribution of human amnion epithelial cells in mice. AB - Placenta is a non-controversial and promising source of cells for the treatment of several liver diseases. We previously reported that transplanted human amnion epithelial cells (hAECs) differentiate into hepatocyte-like cells, resulting in correction of mouse models of metabolic liver disease or acute hepatic failure. As part of preclinical safety studies, we investigated the distribution of hAECs using two routes of administration to efficiently deliver hAECs to the liver. Optical imaging is commonly used because it can provide fast, high-throughput, whole-body imaging, thus DiR-labeled hAECs were injected into immunodeficient mice, via the spleen or the tail vein. The cell distribution was monitored using an in vivo imaging system over the next 24 h. After splenic injection, the DiR signal was detected in liver and spleen at 1, 3 and 24 h post-transplant. The distribution was confirmed by analysis of human DNA content at 24 h post transplant and human-specific cytokeratin 8/18 staining. Tail vein infusion resulted in cell engraftment mainly in the lungs, with minimal detection in the liver. Delivery of cells to the portal vein, via the spleen, resulted in efficient delivery of hAECs to the liver, with minimal, off-target distribution to lungs or other organs. PMID- 30409700 TI - Exosome-transmitted LINC00461 promotes multiple myeloma cell proliferation and suppresses apoptosis by modulating microRNA/BCL-2 expression. AB - BACKGROUND: Multiple myeloma (MM) is a hematologic cancer caused by the abnormal expansion of plasma cells, but the exact mechanism underlying MM development is not completely known. Recently, multiple long noncoding RNAs (lncRNAs) were implicated in the regulation of MM development. METHODS: Samples from patients with MM were collected and detected for LINC00461 expression using real-time polymerase chain reaction (PCR). LINC00461 was knocked down in MM cell lines by short hairpin RNAs (shRNAs) to measure its effect on MM cell proliferation and apoptosis. The function of mesenchymal stromal cell (MSC)-derived exosomes was analyzed using chamber assays. RESULTS: LINC00461 was highly expressed in MM. Knockdown of LINC00461 dramatically reduced MM cell proliferation and induced cell apoptosis. Further study showed that LINC00461 relieved the inhibitory effect of microRNA (miR)-15a/miR-16 on BCL-2. In addition, we observed that MSC derived exosomes promoted MM cell proliferation through LINC00461. CONCLUSION: Our findings demonstrate that LINC00461, a sponge for miR-15a/16, is highly expressed in MSC-derived exosomes, and enhances MM cell proliferation, which may become an excellent candidate for therapeutic applications. PMID- 30409701 TI - Comparison of successful percutaneous coronary intervention versus optimal medical therapy in patients with coronary chronic total occlusion. AB - BACKGROUND: Chronic total occlusion (CTO) is a challenging entity in coronary interventions. With improvements in technology and techniques, success rates for percutaneous coronary intervention (PCI) of CTO continue to improve. However, the clinical benefits of PCI remain unclear. The aim of the study was to determine the effectiveness of successful PCI on clinical outcomes using drug-eluting stents in patients with CTO. METHODS: From 2004 to 2010, we analyzed 898 patients with at least one CTO who underwent successful PCI (n=424, 448 lesions) or only medical treatment (n=474, 519 lesions) from a multicenter registry. The primary outcome was all-cause death. RESULTS: During a median of 2.2 years, incidence rate of all-cause death after successful PCI was lower than that after medical treatment (10.6% and 17.5%, p=0.004). However, the multivariate Cox proportional hazards model showed that successful PCI was not associated with improvement in mortality compared to medical treatment [adjusted hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.57-1.24, p=0.38]. Comparable results were obtained after propensity-score matching. Subgroup analysis of propensity-score matched population demonstrated that patients with age under 65 years benefited from successful PCI (HR 0.25, 95% CI 0.08-0.75, p for interaction=0.005). CONCLUSIONS: In patients considered for CTO intervention, medical treatment appears to be associated with a similar mortality compared to successful PCI. Successful CTO PCI might be associated with survival benefit in younger patients compared to medical treatment. PMID- 30409702 TI - Design, synthesis, and ex vivo evaluation of a selective inhibitor for retinaldehyde dehydrogenase enzymes. AB - The retinaldehyde dehydrogenase (RALDH) enzymes, RALDH1, RALDH2, and RALDH3, catalyze the irreversible oxidation of retinaldehyde to all-trans-retinoic acid (ATRA). Despite the importance of the RALDH enzymes in embryonic development, postnatal growth and differentiation, and in several disease states, there are no commercially available inhibitors that specifically target these isozymes. We report here the development and characterization of a small molecule inhibitor dichloro-all-trans-retinone (DAR) (Summers et al., 2017) that is an irreversible inhibitor of RALDH1, 2, and 3 that effectively inhibits RALDH1, 2, and 3 in the nanomolar range but has no inhibitory activity against mitochondrial ALDH2. These results provide support for the development of DAR as a specific ATRA synthesis inhibitor for a variety of experimental and clinical applications. PMID- 30409703 TI - Diet-dependent function of the extracellular matrix proteoglycan Lumican in obesity and glucose homeostasis. AB - OBJECTIVE: Extracellular matrix remodeling is required for adipose expansion under increased caloric intake. In turn, inhibited expandability due to aberrant collagen deposition promotes insulin resistance and progression towards the metabolic syndrome. An emerging role for the small leucine-rich proteoglycan Lumican in metabolically driven nonalcoholic fatty liver disease sparks an interest in further understanding its role in diet-induced obesity and metabolic complications. METHODS: Whole body ablation of Lumican (Lum-/-) gene and adeno associated virus-mediated over-expression were used in combination with control or high fat diet to assess energy balance, glucose homeostasis as well as adipose tissue health and remodeling. RESULTS: Lumican was found to be particularly enriched in the stromal cells isolated from murine gonadal white adipose tissue. Likewise murine and human visceral fat showed a robust increase in Lumican as compared to fat from the subcutaneous depot. Lumican null female mice exhibited moderately increased fat mass, decreased insulin sensitivity and increased liver triglycerides in a diet-dependent manner. These changes coincided with inflammation in adipose tissue and no overt effects in adipose expandability, i.e. adipocyte formation and hypertrophy. Lumican over-expression in visceral fat and liver resulted in improved insulin sensitivity and glucose clearance. CONCLUSIONS: These data indicate that Lumican may represent a functional link between the extracellular matrix, glucose homeostasis, and features of the metabolic syndrome. PMID- 30409704 TI - Iodine-supported titanium implants have good antimicrobial attachment effects. AB - BACKGROUND: We have developed iodine-supported titanium implants, which were shown to have good anti-bacterial effects for Methicillin-sensitive Staphylococcus aureus (MSSA) in our past basic research. However, PJI can be caused by various bacteria including MRSA, Pseudomonas aeruginosa, MSSE, and fungus. The purpose of this study was to investigate whether these implants also have good antibacterial attachment effects for MRSA, P. aeruginosa, MSSE, and fungus. METHODS: Ti-6Al-4V titanium plates were either left untreated (Ti), treated with oxide film on the Ti surface by anodization (Ti-O), or treated with an iodine coating on oxidation film (Ti-I). The antibacterial activity of the TiI was measured by experimental methods according to Japanese Industrial Standard (JIS) protocols. Implants in this study were exposed to MRSA (ATCC43300), P. aeruginosa (ATCC27853), MSSE (ATCC35984), and Candida Albicans (ATCC10231). Colonies were counted immediately after the bacteria attached to the metal surface and again after 24 h incubation. The difference in the number of bacteria on each metal plate was statistically investigated and an antibacterial activity value was calculated. An effective antibacterial active value of more than 2.0 was judged to be effective according to JIS protocol. RESULTS: No countable viable bacteria were observed on the Ti-I surface. For all bacteria there was a significant difference in the mean number of viable bacteria between Ti-I and Ti or Ti-O. Antibacterial activity value in Ti-I and Ti-O was more than 5.9 and 3.6 respectively for MRSA, more than 2.8 and zero for P. aeruginosa, more than 4.3 and zero for MSSE, and more than 4.7 and zero for C. Albicans. CONCLUSIONS: This study showed that iodine-supported titanium implants have good antimicrobial attachment effects for MRSA, P. aeruginosa, MSSE, and C. Albicans. Iodine supported titanium implants could have great potential as innovative antibacterial implants that can prevent early onset periprosthetic joint infection. PMID- 30409706 TI - Tailored Text Message-Based Self-Management Program May Improve Glycemic Control in Patients with Poorly Controlled Diabetes. PMID- 30409705 TI - Myocardial Ischemia Amelioration Reducing Venous Outflow. PMID- 30409707 TI - History of Atrial Fibrillation and Trajectory of Decongestion in Acute Heart Failure. AB - OBJECTIVES: This study sought to characterize the course of decongestion among patients hospitalized for acute heart failure (AHF) by history of atrial fibrillation (AF) and/or atrial flutter (AFL). BACKGROUND: AF/AFL and chronic heart failure (HF) commonly coexist. Little is known regarding impact of AF/AFL on relief of congestion among patients who develop AHF. METHODS: We pooled patients from 3 randomized trials of AHF conducted within the Heart Failure Network, the DOSE (Diuretic Optimization Strategies) trial, the ROSE (Renal Optimization Strategies) trial, and the CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) trial. The association between history of AF/AFL and in-hospital changes in various metrics of congestion was assessed using covariate-adjusted linear and ordinal logistic regression models. RESULTS: Of 750 unique patients, 418 (56%) had a history of AF/AFL. Left ventricular ejection fraction was higher (35% vs. 27%, respectively; p < 0.001), and N terminal pro-brain natriuretic peptide (NT-proBNP) levels were nonsignificantly lower at baseline (4,210 pg/ml vs. 5,037 pg/ml, respectively; p = 0.27) in patients with AF/AFL. After adjustment of covariates, history of AF/AFL was associated with less substantial loss of weight (-5.7% vs. -6.5%, respectively; p = 0.02) and decrease in NT-proBNP levels (-18.7% vs. -31.3%, respectively; p = 0.003) by 72 or 96 h. History of AF/AFL was also associated with a blunted increase in global sense of well being at 72 or 96 h (p = 0.04). There was no association between history of AF/AFL and change in orthodema congestion score (p = 0.67) or 60-day composite clinical endpoint (all-cause mortality or any rehospitalization; hazard ratio: 1.21; 95% confidence interval: 0.92 to 1.59; p = 0.17). CONCLUSIONS: More than half of the patients admitted with AHF had a history of AF/AFL. History of AF/AFL was independently associated with a blunted course of in-hospital decongestion. Further research is required to understand the utility of specific therapies targeting AF/AFL during hospitalization for AHF. PMID- 30409708 TI - Global burden of motor neuron diseases: mind the gaps. PMID- 30409710 TI - Corrigendum to "Probing the radical chemistry and the reaction zone during the sono-degradation of endocrine disruptor 2-phenoxyethanol in water" [Ultrason. Sonochem. 41 (2018) 521-526]. PMID- 30409711 TI - Mechanism of improving the rate of sono-oxidation of a KI solution by introduction of CO2 into an Ar atmosphere. AB - The rate of sono-oxidation of KI increased in a CO2-Ar system compared to Ar alone. Higher values were obtained at 200 kHz with a maximum ratio of about forty. To determine the role of additional CO2 in the system, the effect of the pH of the reactant solution, the additional effect of NaHCO3, sonoluminescence, and an analysis of products were examined. It appeared that the pH was not a significant contributor to the acceleration of sono-oxidation activity although the rate depended on the pH. On the other hand, in spite of the alkaline solution, the reaction rate in NaHCO3-KI solution was higher than that in the solution without NaHCO3. This behavior was similar to the case of introduction of CO2, implying the possible evolution of CO2 from NaHCO3. Our data suggested that CO2 reacted with H radicals, which were produced together with OH radicals during sonication and a considerable amount of OH radicals remained. Because OH radicals have strong oxidative power, the level of sono-oxidation activity increases. PMID- 30409709 TI - Global, regional, and national burden of motor neuron diseases 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. AB - BACKGROUND: Understanding how prevalence, incidence, and mortality of motor neuron diseases change over time and by location is crucial for understanding the causes of these disorders and for health-care planning. Our aim was to produce estimates of incidence, prevalence, and disability-adjusted life-years (DALYs) for motor neuron diseases for 195 countries and territories from 1990 to 2016 as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016. METHODS: The motor neuron diseases included in this study were amyotrophic lateral sclerosis, spinal muscular atrophy, hereditary spastic paraplegia, primary lateral sclerosis, progressive muscular atrophy, and pseudobulbar palsy. Incidence, prevalence, and DALYs were estimated using a Bayesian meta-regression model. We analysed 14 165 site-years of vital registration cause of death data using the GBD 2016 cause of death ensemble model. The 84 risk factors quantified in GBD 2016 were tested for an association with incidence or death from motor neuron diseases. We also explored the relationship between Socio-demographic Index (SDI; a compound measure of income per capita, education, and fertility) and age-standardised DALYs of motor neuron diseases. FINDINGS: In 2016, globally, 330 918 (95% uncertainty interval [UI] 299 522-367 254) individuals had a motor neuron disease. Motor neuron diseases have caused 926 090 (881 566-961 758) DALYs and 34 325 (33 051-35 364) deaths in 2016. The worldwide all-age prevalence was 4.5 (4.1-5.0) per 100 000 people, with an increase in age-standardised prevalence of 4.5% (3.4-5.7) over the study period. The all-age incidence was 0.78 (95% UI 0.71-0.86) per 100 000 person-years. No risk factor analysed in GBD showed an association with motor neuron disease incidence. The largest age-standardised prevalence was in high SDI regions: high-income North America (16.8, 95% UI 15.8 16.9), Australasia (14.7, 13.5-16.1), and western Europe (12.9, 11.7-14.1). However, the prevalence and incidence were lower than expected based on SDI in high-income Asia Pacific. INTERPRETATION: Motor neuron diseases have low prevalence and incidence, but cause severe disability with a high fatality rate. Incidence of motor neuron diseases has geographical heterogeneity, which is not explained by any risk factors quantified in GBD, suggesting other unmeasured risk factors might have a role. Between 1990 and 2016, the burden of motor neuron diseases has increased substantially. The estimates presented here, as well as future estimates based on data from a greater number of countries, will be important in the planning of services for people with motor neuron diseases worldwide. FUNDING: Bill & Melinda Gates Foundation. PMID- 30409712 TI - Vagus nerve stimulation intensity influences motor cortex plasticity. AB - BACKGROUND: Vagus nerve stimulation (VNS) paired with forelimb motor training enhances reorganization of movement representations in the motor cortex. Previous studies have shown an inverted-U relationship between VNS intensity and plasticity in other brain areas, such that moderate intensity VNS yields greater cortical plasticity than low or high intensity VNS. However, the relationship between VNS intensity and plasticity in the motor cortex is unknown. OBJECTIVE: In this study we sought to test the hypothesis that VNS intensity exhibits an inverted-U relationship with the degree of motor cortex plasticity in rats. METHODS: Rats were taught to perform a lever pressing task emphasizing use of the proximal forelimb musculature. Once proficient, rats underwent five additional days of behavioral training in which low intensity VNS (0.4 mA), moderate intensity VNS (0.8 mA), high intensity VNS (1.6 mA), or sham stimulation was paired with forelimb movement. 24 h after the completion of behavioral training, intracortical microstimulation (ICMS) was used to document movement representations in the motor cortex. RESULTS: VNS delivered at 0.8 mA caused a significant increase in motor cortex proximal forelimb representation compared to training alone. VNS delivered at 0.4 mA and 1.6 mA failed to cause a significant expansion of proximal forelimb representation. CONCLUSION: Moderate intensity 0.8 mA VNS optimally enhances motor cortex plasticity while low intensity 0.4 mA and high intensity 1.6 mA VNS fail to enhance plasticity. Plasticity in the motor cortex exhibits an inverted-U function of VNS intensity similar to previous findings in auditory cortex. PMID- 30409713 TI - Anti-angiogenic effects of valproic acid in a mouse model of oxygen-induced retinopathy. AB - Pathological retinal angiogenesis contributes to the pathogenesis of several ocular diseases. Valproic acid, a widely used antiepileptic drug, exerts anti angiogenic effects by inhibiting histone deacetylase (HDAC). Herein, we investigated the effects of valproic acid and vorinostat, a HDAC inhibitor, on pathological retinal angiogenesis in mice with oxygen-induced retinopathy (OIR). OIR was induced in neonatal mice by exposure to 80% oxygen from postnatal day (P) 7 to P10 and to atmospheric oxygen from P10 to P15. Mice were subcutaneously injected with valproic acid, vorinostat, or vehicle once a day from P10 to P14. At P15, retinal neovascular tufts and vascular growth in the central avascular zone were observed in mice with OIR. Additionally, immunoreactivity for phosphorylated ribosomal protein S6 (pS6), an indicator of mammalian target of rapamycin (mTOR) activity, was detected in the neovascular tufts. Both valproic acid and vorinostat reduced the formation of retinal neovascular tuft without affecting vascular growth in the central avascular zone. Valproic acid reduced the pS6 immunoreactivity in neovascular tufts. Given that vascular endothelial growth factor (VEGF) activates mTOR-dependent pathways in proliferating endothelial cells of the neonatal mouse retina, these results suggest that valproic acid suppresses pathological retinal angiogenesis by interrupting VEGF mTOR pathways. PMID- 30409714 TI - Riluzole prevents oxaliplatin-induced cold allodynia via inhibition of overexpression of transient receptor potential melastatin 8 in rats. AB - Oxaliplatin causes acute cold hypersensitivity in most patients. We previously reported oxalate derived from oxaliplatin induced cold allodynia via overexpression of transient receptor potential melastatin 8 (TRPM8) in the dorsal root ganglion (DRG) in rats. In this study, we examined the effect of riluzole on oxaliplatin-induced cold allodynia. In cultured DRG neurons, riluzole suppressed oxalate-induced increase of the number of menthol (TRPM8 agonist)-sensitive cells. Moreover, riluzole prevented cold allodynia and increase in levels of TRPM8 mRNA in oxaliplatin-treated rats. These results suggest that riluzole prevents oxaliplatin-induced cold allodynia via inhibition of TRPM8 overexpression in the DRG. PMID- 30409715 TI - Order in The Court? The Association Between Substance Use, Exposure to Violence, Risky Sexual Behaviors & Observed Court Behaviors Among Women Involved in the Criminal Justice System. AB - Drug courts, therapeutic justice programs for individuals charged with drug offenses, have sub-optimal completion rates. The Courtroom Behavior Checklist (CRBCL), an assessment that quantifies readiness for drug court and drug court behaviors, was developed to predict female offenders who may be at-risk for non compliance and termination. Data derived from 264 mainly urban women recruited from a Municipal Drug Court System in St. Louis, MO, were used to evaluate the association between substance use, victimization, HIV/AIDS risk behaviors, and observed drug court behaviors. Results showed that women who reported recent substance use or were categorized as at risk for HIV/AIDS were significantly more likely to have scores indicative of unfavorable drug court behaviors, while women who experienced victimization had scores indicative of favorable drug court behaviors. Other factors significantly associated with unfavorable drug court behaviors included greater lifetime arrests, lower education, and being less religious or spiritual. Our findings suggest that the CRBCL may have added utility in identifying women in drug court with recent substance use and risky sexual behaviors. However, further studies on other samples of offenders are needed to support these findings. PMID- 30409716 TI - A Contemporary Analysis of Outcomes and Modifiable Risk Factors of Ethnic Disparities in Kidney Transplantation. AB - OBJECTIVE: The aim of this study was to provide a contemporary analysis of longitudinal kidney transplant outcomes and to evaluate potential causes of ethnic disparities among African American (AA) and Caucasian American (CA) patients undergoing kidney transplantation at our institution. PATIENTS AND METHODS: 1400 patients were identified who underwent kidney transplantation from 2003 to 2013 from a large, academic institution in Cleveland, OH. Relevant recipient and donor demographic and clinical covariates were obtained from an institutional transplant database. Simple descriptive statistics and comparative survival analyses were performed to assess overall survival and graft survival. RESULTS: The final cohort was comprised of 341 AA and 1059 CA patients. AAs were less likely to receive a living donor transplant (27.6% vs. 57.2%, p < 0.001) compared to CAs. Overall patient survival did not significantly differ between the two groups even when stratified by ethnicity. However, AAs had a significantly lower rate of graft survival (p < 0.001). On stratified analysis, there was no difference in the rate of graft survival among AAs and CAs who received living donor grafts. On univariate analysis, AAs demonstrated higher rates of immunosuppression non-compliance and chronic rejection (both p < 0.05). On multivariate analysis, AA recipient ethnicity (HR 1.56, p = 0.047), recipient history of diabetes (HR 1.67, p < 0.001), and AA donor ethnicity (HR 1.56, p = 0.047) were significantly associated with graft failure. CONCLUSION: AAs undergoing deceased donor renal transplantation demonstrated lower graft survival compared to CAs. Conversely, this disparity did not exist among AAs undergoing living donor transplantation. AAs had higher rates of deceased donor transplantation, immunosuppression non-compliance, chronic rejection, and diabetes. Opportunities exist to use patient education, alternative immunosuppression regimens, and living transplantation to close the ethnic disparity in renal allograft survival. PMID- 30409717 TI - Prostate Cancer Screening Guidelines for African American Veterans: A New Perspective. AB - BACKGROUND: Prostate cancer is the most common form of cancer, other than skin cancers, in American men and the second leading cause of cancer deaths. In 2012, the US Preventative Task Force recommended against the prostate specific antigen based screening for prostate cancer, regardless of race or age, due to overtreatment of low-risk disease and lack of impact on disease outcomes. In African-American men, however, the incidence of prostate cancer is almost 60% higher and the mortality rate is two- to three-times greater than that of Caucasian men. In the subpopulation of African-American veterans, many have been exposed to chemicals that increase incidence of high-risk prostate cancer. The yearly total number of veterans with prostate cancer based on quantification is 3471.9, and the total number of annual prostate cancer deaths is 556. Considering these facts, we examine whether or not it is appropriate to screen African American veteran males for prostate cancer. Previously, we reviewed data on African-Americans in the general population. We concluded that new guidelines needed to be implemented for screening African-Americans. Here we review the pertinent issues related to African-American veterans. METHODS: We performed a PubMed and Google Scholar search using the keywords: African-American veteran, prostate cancer, mortality, PSA density, molecular markers, and Agent Orange. The articles that were relevant to the clinical, molecular, social, and health policy aspects of the diagnosis and treatment of prostate cancer in African-American veterans were analyzed. The data was then summarized. RESULTS: After surveying the literature, we found several areas where the African-American veteran population differed from their Caucasian counterparts. These areas were incidence, clinical course, social differences, PSA levels, mortality rate, and molecular markers. A subset of the veteran population was also exposed to Agent Orange, which has been shown to increase the incidence of aggressive forms of prostate cancer. Lastly, the current USPTF guidelines recommending against prostate cancer screening were based on patient cohorts containing disproportionately low numbers of African-Americans, limiting their extension to the African-American veteran population. CONCLUSION: After reviewing and summarizing the literature, we contend that a need exists to develop and implement more targeted prostate cancer screening guidelines for African-American veterans. PMID- 30409719 TI - Modified VR-CAP, Alternating With Rituximab and High-dose Cytarabine: An Effective Pre-transplant Induction Regimen for Mantle Cell Lymphoma. AB - BACKGROUND: Initial treatment of mantle cell lymphoma (MCL) incorporating autologous stem cell transplantation affords long-term remissions, but relapses still occur. Optimal pretransplant therapy will afford high complete response rates and not impair stem cell collection. Incorporation of bortezomib represents a natural evolution of pretransplant therapy, given its proven first-line efficacy and minimal impact on stem cell collection. PATIENTS AND METHODS: At the University of Washington/Seattle Cancer Care Alliance and the Cleveland Clinic Foundation, we developed modified VR-CAP/R+ara-C (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone, alternating with rituximab and high-dose cytarabine), for transplant-eligible patients with MCL. This regimen was administered as standard-of-care, pretransplant therapy to consecutive patients with MCL from April 2015 to the present. RESULTS: A total of 37 patients were treated with this regimen, including 18 at the University of Washington/Seattle Cancer Care Alliance and 19 at the Cleveland Clinic Foundation. Most patients had intermediate- or high-risk disease by both (mantle cell lymphoma international prognostic index (MIPI)-B and MIPI-C category. Complete response to induction was achieved in 32 (86%) of 37 evaluable patients; 2 achieved partial response, and 3 had primary refractory disease. Stem cell collection was successful in 1 attempt in 30 of 32 patients. The median follow-up of survivors measured from start of treatment is 17.4 months. Five patients have progressed, and 4 have died (2 owing to lymphoma, 2 from toxicity). CONCLUSION: Modified VR-CAP/R+ara-C is feasible pretransplant therapy for patients with MCL and is associated with a high rate of complete response and eligibility for autologous stem cell transplantation. PMID- 30409718 TI - Ibrutinib Dose Adherence and Therapeutic Efficacy in Non-Hodgkin Lymphoma: A Single-Center Experience. AB - BACKGROUND: As oral targeted agents, such as ibrutinib, become more widely used, understanding the impact of suboptimal dosing on overall survival (OS) and progression-free survival (PFS) outside of clinical trials is imperative. PATIENTS AND METHODS: Data on ibrutinib discontinuation, dose reductions, and treatment interruptions were collected on 170 non-Hodgkin lymphoma and chronic lymphocytic leukemia (CLL; n = 115, 64%) patients treated with ibrutinib at a single institution. Ibrutinib dose adherence was calculated as the proportion of days in which ibrutinib was administered out of the total number of days ibrutinib was prescribed in the first 8 weeks. Kaplan-Meier curves and log-rank tests were used to compare conditional survival outcomes beyond 8 weeks in patients with >= 80% dose adherence and patients with < 80% dose adherence. RESULTS: Median OS among those who discontinued therapy for progression was poor (n = 51, 1.7 months; 95% confidence interval, 0.3-3.7). Lower dose adherence (< 80%) was associated with significantly worse PFS (P = .002) and OS (P = .021). However, among CLL patients, lower dose adherence was only associated with worse PFS (P = .043). Patients with early dose reductions had significantly worse PFS (P = .004) and OS (P = .014). Patients with dose interruptions lasting > 1 week had worse PFS (P = .047) but not OS (P = .577). CONCLUSION: In this observational study, non-Hodgkin lymphoma and CLL patients experienced poor outcomes after discontinuing ibrutinib for disease progression. The inferior survival related to suboptimal dose adherence of ibrutinib was predominantly due to early dose reduction. These data confirm poor survival in CLL and lymphoma patients alike after ibrutinib discontinuation, and support recommendations for full dose at treatment initiation. PMID- 30409720 TI - Safety recommendations of winter terrain park jumps into airbags. AB - OBJECTIVES: In winter terrain parks special airbags are used for skiers and snowboarders to practice jumps and achieve safe landings. However, in 2010 two skiers landed at the end of oval airbags. One suffered fatal, the other severe, injuries. The aim of this study was to identify parameters that lead to jumping over the airbag and to suggest preventive measures. DESIGN: Simulation study. METHODS: For the calculation of the flight distance the equation of motion was solved for the jumper's approach and flight phase. Measured data of five jumps into an airbag employed in a similar geometry and conditions as in the second accident case were used to validate the simulation and to measure typical takeoff velocities. The effect of approach and takeoff parameters on the flight distance for oval and flat airbags was analyzed with the simulations. RESULTS: In both accident cases a too long approach led to a too high takeoff speed, which was the cause for landing at the end of the oval airbags. The effect of flight distance is considerably more sensitive to approach and takeoff parameters with oval versus flat airbags. CONCLUSIONS: Three measures are recommended to prevent jumping over an airbag. An approach corridor with top and lateral fences has to be set up and the approach should be steep. Flat airbags are preferable to oval airbags. Airbags should be equipped with a heightening at the end. PMID- 30409722 TI - Computer-based implant planning involving a prefabricated custom tray with alumina landmark structures. AB - The purpose of this technical report was to describe a method for the fabrication of a custom tray with landmark structures to coordinate cone beam computed tomography and scan data for use in guided implant surgery in patients with numerous artifact-causing metal prostheses. The fabricated custom tray can be used to coordinate cone beam computed tomography data and scan data from the dentition, as well as to fabricate the prostheses. PMID- 30409721 TI - Effect of different times of nonthermal argon plasma treatment on the microtensile bond strength of self-adhesive resin cement to yttria-stabilized tetragonal zirconia polycrystal ceramic. AB - STATEMENT OF PROBLEM: Nonthermal argon plasma may increase the surface energy of yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) dental ceramics. However, studies that evaluated the effect of increased plasma treatment times on the bond strength of resin cements to Y-TZP ceramics are lacking. PURPOSE: The purpose of this in vitro study was to evaluate the effect of different nonthermal argon plasma (NTAP) treatment times on the surface energy and bond strength of a self-adhesive resin cement to Y-TZP ceramic. MATERIAL AND METHODS: Forty-eighty Y TZP plates were divided into 2 groups (n=24): as-sintered (AS) and airborne particle abrasion (APA) with 50-MUm Al2O3, which were subdivided into 4 groups (n=6) according to the time of NTAP treatment: 0, 20, 60, and 120 seconds. The surface energy was evaluated with a goniometer. Forty Y-TZP blocks submitted to the same surface treatments (8 groups; n=5) were cemented to composite resin blocks, using a self-adhesive resin cement. After storage in distilled water at 37 degrees C for 24 hours, the Y-TZP-composite resin blocks were cut into beams and submitted to a microtensile bond strength (MUTBS) test. Data were analyzed using 2-way ANOVA and the Tukey honestly significant differences test (alpha=.05). RESULTS: Treatment with NTAP increased the surface energy for AS and APA groups (P<.05). For both groups, the MUTBS was as follows: 0 seconds < 20 seconds < 60 seconds = 120 seconds (P<.05). Only after 120 seconds of NTAP treatment was the MUTBS of APA higher than that of AS (P<.05). CONCLUSIONS: Treatment with NTAP improved the surface energy and increased the MUTBS of self adhesive resin cement to Y-TZP ceramic, with higher times of plasma treatment resulting in higher bond strength. PMID- 30409723 TI - Biological activation of bone grafts using injectable platelet-rich fibrin. AB - Platelet-rich fibrin (PRF) is gaining acceptance as a bioactive surgical additive in regenerative dentistry. However, PRF has only been available in gel or membrane form and is not suitable for injection. Recently, however, a liquid, injectable PRF has been introduced. This paper introduces the concept of injectable PRF and discusses its applications for biologic activation of bone grafts. PMID- 30409724 TI - Repair bond strength and nanoleakage of artificially aged CAD-CAM composite resin. AB - STATEMENT OF PROBLEM: The polymerization of computer-aided design and computer aided manufacturing (CAD-CAM) composite resins during their manufacture enhances their physical properties and biocompatibility but might compromise their reparability. PURPOSE: The purpose of this in vitro study was to determine the microtensile bond strength and nanoleakage (NL) of aged LAVA Ultimate (LU) CAD CAM composite resin after different repair protocols. MATERIAL AND METHODS: Fifty eight LU miniblocks were prepared, thermocycled (10000 cycles, 5 degrees C to 55 degrees C), and assigned to 10 surface pretreatment and bonding protocols: (1) tribochemical silica coating (CoJet, CoJet Sand; 3M ESPE)+Scotchbond Universal Adhesive (SBU; 3M ESPE); (2) CoJet+silane (SI, ESPE Sil; 3M ESPE)+Adper Scotchbond 1 XT Adhesive (XT; 3M ESPE); (3) CoJet+10-methacryloyloxydecyl dihydrogen phosphate-based silane (MO; Monobond Plus; Ivoclar Vivadent)+XT; (4) CoJet+XT; (5) 30-MUm alumina airborne-particle abrasion (AL)+SBU; (6) AL+SI+XT; (7) AL+MO+XT; (8) AL+XT; (9) no pretreatment+SBU; and (10) no pretreatment+XT. All blocks were repaired using the Filtek Supreme XTE (3M ESPE) composite resin. Stick-shaped specimens (0.9*0.9 mm) were obtained and submitted to microtensile bond strength (MUTBS) and %NL testing after 24 hours. MUTBS data were analyzed with 1-way ANOVA, followed by the Tukey post hoc test, and NL data with nonparametric Kruskal-Wallis and Dunn tests (alpha=.05). RESULTS: For MUTBS, CoJet, and AL pretreatments showed significantly higher mean MUTBS, especially when used together with SBU. No pretreatment+XT yielded the lowest mean MUTBS. For NL, marginal sealing improved significantly after the use of SBU regardless of the surface treatment. This improvement was only statistically different after tribochemical silica coating. CONCLUSIONS: Airborne-particle abrasion with alumina particles, silica coated or not, together with the application of SBU resulted in the highest mean MUTBS. The lowest %NL was recorded when aged LU blocks were repaired using SBU. PMID- 30409725 TI - Transcriptomic response of the Crassostrea virginica gonad after exposure to a water-accommodation fraction of hydrocarbons and the potential implications in reproduction. AB - The Crassostrea virginica oyster has biological and economic importance in the Gulf of Mexico, an area with a high extraction and production of hydrocarbons. Exposure to hydrocarbons affects the reproductive processes in bivalves. In C. virginica, the effect of hydrocarbons on the gonad of the undifferentiated organism has not been evaluated to determine the possible damage during the maturation process. To evaluate this effect, RNA-seq data was generated from C. virginica gonads exposed to a 200 MUg/L of hydrocarbons at different exposure times (7, 14 and 21 days) and a control treatment (without hydrocarbons). The analysis of the gonad transcriptome showed the negative effect of hydrocarbons on maturation, with a sub-expression of 22 genes involved in different stages of this process. Additionally, genes in the immune system were down-regulated, which may indicate that exposure to hydrocarbons causes immunosuppression in bivalves. A group of oxidative stress genes was also reduced. These data contribute to a better understanding of the effect of hydrocarbons on the reproductive process in bivalves and, at the same time, allow us to identify possible biomarkers associated with hydrocarbon contamination in the gonad of C. virginica. PMID- 30409726 TI - Communication apprehension mediates the effects of past experience discussing substance use on child and adolescent psychiatrists' self-efficacy. AB - Objective Child and Adolescent Psychiatrists (CAPs) treat patients who are at an increased risk of developing a substance use disorder in their lifetime. However, CAPs often experience apprehension when it comes to discussing substance use with their patients, and this apprehension may come from past experiences when these discussions have gone poorly. This study seeks to understand whether or not apprehension moderates the relationship between past experiences and self efficacy for CAPs when discussing substance use with their patients. Methods This study used a national online survey of CAPs (n = 170) to test the extent to which apprehension mediated the relationship between past experiences discussing substance use and self-efficacy to do so. Results The results showed that past experience affects self-efficacy and apprehension serves as a mediator of this relationship. Conclusion This study helps to shed light on the determinants that influence providers' perceptions of self-efficacy. Understanding what factors affect self-efficacy is important because these factors can then be targeted through training. Practice implications Patient-provider communication skills training for CAPs should happen early in their education so that they are less likely to become apprehensive about discussing substance use with their patients. PMID- 30409727 TI - A healthy dose of realism: The role of optimistic and pessimistic expectations when facing a downward spiral in health. AB - RATIONALE AND OBJECTIVES: Whether expectations about future health are adaptive or maladaptive in late life likely depends on the extent to which they conform to or defy a future reality of declining health. Our premise was that, when adults face a downward spiral in health, it can be adaptive to realistically expect poorer future health and maladaptive to unrealistically expect good health. METHOD: This 18-year-long study of community-dwelling older Canadians (n = 132, 72-98 years) involved a baseline interview to identify those who anticipated heath would decline (pessimistic expectation) or improve/remain stable (optimistic expectation). We determined initial (baseline) health status by assessing the severity of chronic conditions. An objective within-person measure of actual health change was derived by documenting hospital admissions (HAs) over time to capture a continuum that ranged from no declines (HAs remained stable) to greater declines in health (increasing numbers of HAs). Our a priori hypotheses examined the effects of health expectations (pessimistic, optimistic) and actual health change on the outcomes of depressive symptoms and mortality. RESULTS: Support was found for our premise that it is adaptive to be realistic when forecasting future health, at least at low levels of initial chronic condition severity. Regression analyses showed that realistically pessimistic (vs. unrealistically optimistic) expectations predicted significantly fewer depressive symptoms and a lower risk of death. The results also supported our premise that it is maladaptive to be unrealistically optimistic when health subsequently declines in reality: The risk of death was 313% higher for those with optimistic expectations that were unrealistic (vs. realistic). CONCLUSION: These findings provide insights for health care professionals regarding the messages they communicate to their patients. Together, they imply that, when good health is slipping away, it seems optimal to encourage a healthy dose of realism. PMID- 30409728 TI - Stem cells derived from burned skin - The future of burn care. AB - BACKGROUND: Thermal injuries affect millions of adults and children worldwide and are associated with high morbidity and mortality. The key determinant for the survival of burns is rapid wound healing. Large wounds exceed intrinsic wound healing capacities, and the currently available coverage materials are insufficient due to lack of cellularity, availability or immunological rejection. METHODS: Using the surgically debrided tissue, we isolated viable cells from burned skin. The isolated cells cultured in tissue culture dishes and characterized. FINDINGS: We report here that debrided burned skin, which is routinely excised from patients and otherwise considered medical waste and unconsciously discarded, contains viable, undamaged cells which show characteristics of mesenchymal skin stem cells. Those cells can be extracted, characterized, expanded, and incorporated into created epidermal-dermal substitutes to promote wound healing in immune-compromised mice and Yorkshire pigs without adverse side effects. INTERPRETATION: These findings are of paramount importance and provide an ideal cell source for autologous skin regeneration. Furthermore, this study highlights that skin contains progenitor cells resistant to thermal stress. FUND: Canadian Institutes of Health Research # 123336. CFI Leader's Opportunity Fund: Project # 25407 National Institutes of Health 2R01GM087285-05A1. EMHSeed: Fund: 500463, A generous donation from Toronto Hydro. Integra(c) Life Science Company provided the meshed bilayer Integra(c) for porcine experiments. PMID- 30409729 TI - Dose-guided patient positioning in proton radiotherapy using multicriteria optimization. AB - Proton radiotherapy (PT) requires accurate target alignment before each treatment fraction, ideally utilizing 3D in-room X-ray computed tomography (CT) imaging. Typically, the optimal patient position is determined based on anatomical landmarks or implanted markers. In the presence of non-rigid anatomical changes, however, the planning scenario cannot be exactly reproduced and positioning should rather aim at finding the optimal position in terms of the actually applied dose. In this work, dose-guided patient alignment, implemented as multicriterial optimization (MCO) problem, was investigated in the scope of intensity-modulated and double-scattered PT (IMPT and DSPT) for the first time. A method for automatically determining the optimal patient position with respect to pre-defined clinical goals was implemented. Linear dose interpolation was used to access a continuous space of potential patient shifts. Fourteen head and neck (H&N) and eight prostate cancer patients with up to five repeated CTs were included. Dose interpolation accuracy was evaluated and the potential dosimetric advantages of dose-guided over bony-anatomy-based patient alignment investigated by comparison of clinically relevant target and organ-at-risk (OAR) dose-volume histogram (DVH) parameters. Dose interpolation was found sufficiently accurate with average pass-rates of 90% and 99% for an exemplary H&N and prostate patient, respectively, using a 2% dose-difference criterion. Compared to bony-anatomy based alignment, the main impact of automated MCO-based dose-guided positioning was a reduced dose to the serial OARs (spinal cord and brain stem) for the H&N cohort. For the prostate cohort, under-dosage of the target structures could be efficiently diminished. Limitations of dose-guided positioning were mainly found in reducing target over-dosage due to weight loss for H&N patients, which might require adaptation of the treatment plan. Since labor-intense online quality assurance is not required for dose-guided patient positioning, it might, nevertheless, be considered an interesting alternative to full online re-planning for initially mitigating the effects of anatomical changes. PMID- 30409730 TI - Incidence and strategies for preventing sustained hypothermia of crash victims during prolonged vehicle extrication. AB - BACKGROUND: Vehicle extrication of crash victims is a highly-demanding challenge, due to the frequently life-threatening injuries of entrapped occupants. In this phase, crash victims are often exposed to the outdoor-temperature, with the risk of sustained hypothermia. Hypothermia can significantly raise the morbidity and mortality rates of crash victims. Therefore, we have correlated the incidence of severe car accidents with entrapped patients, the outdoor conditions, and expenditure of time for extrication. Furthermore, different warming strategies have been evaluated regarding their integrability within the rescue procedure. METHODS: To estimate the incidence of severe car accidents with entrapped patients, we performed retrospective data mining for the cold season of a three year period in a rural district in Germany. We evaluated the integrability of a chemical heated blanket, its combined application with a forced-air warmer, or with an infrared radiator for patient warming. Therefore, we analysed the time tracking of extrication reference points during extrication exercises undertaken by the rescue services, simulating a severe vehicle accident and evaluated questionnaires administered to rescue personnel and subjects. Furthermore, we monitored subjects' physiologic parameters to estimate the warming effect. RESULTS: Incidence analysis resulted in extrication times of up to 80 min, representing two severely-entrapped patients per month in the cold seasons, corresponding to about four entrapments per 100.000 inhabitants every year. Of the different warming strategies analysed, the chemical blanket and the combination infrared radiator/chemical blanket were favoured regarding the items 'operator convenience', 'weight/size/handling', 'stability in positioning', 'time needed for installation', 'manpower requirement', 'hindrance during extrication operation', 'versality during extrication process', and 'robustness' by the rescue personnel; the forced-air warmer and the infrared radiator were preferred with regard to 'warming effect', the forced-air warmer and the chemical blanket was advantageous with regard to 'physical protection'. CONCLUSIONS: Vehicle extrication procedures are time consuming, a relevant finding that provides a rationale for discussing and optimising the rescue procedure to prevent sustained hypothermia. We determined that combined application of an infrared radiator and a chemical blanket is advantageous in terms of integration into the rescue process. However, a more detailed investigation, focussing on warming efficacy, must be performed. PMID- 30409731 TI - Does external fixator pin site distance from definitive implant affect infection rate in pilon fractures? AB - INTRODUCTION: Tibial pilon fractures are often treated with initial external fixation followed by delayed definitive fixation. It has been postulated that the external fixator pin site may correlate with infection risk. The purpose of this study was to determine whether external fixator pin-site distance from definitive implants impacts the risk of deep infection in pilon fractures. MATERIALS AND METHODS: A retrospective cohort study was completed at a single level 1 trauma center. All patients ages 15-65 who underwent open reduction and internal fixation (ORIF) of a distal tibial fracture (AO/OTA Classification 43) from 2007 to 2013 were included. The final study population was 133 patients. The impact of external fixation pin location (relative to the definitive implant location) on postoperative infection was measured. RESULTS: As a continuous variable, the distance between the closest pin site and plate was 62.1 +/- 44.1 mm in the infected cohort and 62.2 +/- 49.7 mm in the non-infected cohort (p = 0.991). Further analysis was performed by grouping the distances into less than 0 mm (i.e. overlapping), >0.0 - 25.0 mm, >25.0 - 50.0 mm, >50.0 - 75.0 mm, >75.0 - 100.0 mm, and >100.0 mm of separation. No significant differences were noted with regards to the risk for infection. CONCLUSIONS: Staged care has been shown to be an effective treatment strategy for AO/OTA type 43 fractures. There are many variables to consider when placing an external fixator construct. In this cohort, pin site distance from definitive implant location was not associated with an increase in deep infections. LEVEL OF EVIDENCE: Level III. PMID- 30409732 TI - [Antenatal management in case of preterm premature rupture of membranes before fetal viability: CNGOF Preterm Premature Rupture of Membranes Guidelines]. AB - OBJECTIVES: To evaluate the maternal, perinatal and long-term prognosis in the event of previable premature rupture of the membranes (PROM) and to specify the interventions likely to reduce the risks and improve the prognosis. METHODS: The PubMed database, the Cochrane Library and the recommendations from the French and foreign obstetrical societies or colleges have been consulted. RESULTS: Previable PROM is a rare event whose frequency varies from 0.3 to 1% according to estimates (NP4). When occurring as a complication of amniocentesis, the prognosis is generally better than when spontaneous (NP3). Between 23 and 39% of women will deliver in the week following PROM and nearly 40% of women will not have given birth 2 weeks after (NP3). The frequency of medical termination of pregnancy varies greatly according to the studies (NP4), as does that of fetal death (NP4). Hospital survival and survival rates without major morbidity as a proportion of conservatively treated patients range from 17-55% and 26-63%, respectively (NP4). Neonatal prognosis is largely dominated by prematurity and its complications (NP3). The frequency of maternal sepsis varies from 0.8 to 4.8% in the most recent studies (NP4). Only one case of maternal death is reported, although 3 cases were identified in France between 2007 and 2012 (NP3). Information is a major component of the care to be provided to women and their partners (Professional consensus). An initial period of hospitalization may be proposed after previable PROM (Professional consensus). Thereafter, there is no argument to recommend hospital management rather than extra-hospital management when there is no argument in favour of intrauterine infection (Professional consensus). An evaluation of the amount of amniotic fluid by ultrasound may be proposed at the initial consultation and after a period of 7 to 14 days if pregnancy continues (Professional consensus). Prophylactic antibiotic treatment is recommended as soon as PROM is diagnosed (Professional consensus). The gestational age at which corticosteroid therapy may be proposed will depend on the thresholds selected for neonatal resuscitation care. In particular, it will take into account parental positioning (Professional consensus). From the time of the decision to perform neonatal resuscitation until the gestational age of 32 weeks, it is recommended to administer MgSO4 to the woman whose delivery is imminent (Grade A). Tocolysis is not recommended in this context (Professional consensus). In certain situations, meeting strictly the conditions mentioned by the CSP article L. 2213 1, a maternal request for medical interruption of pregnancy may be discussed. CONCLUSION: The levels of evidence of scientific work on the management of previable PROM are low, therefore, most of the recommendations proposed here are based on professional agreement by "reasonable" extension of recommendations valid for later gestational ages. PMID- 30409733 TI - Cardiac contractility modulation treatment in patients with symptomatic heart failure despite optimal medical therapy and cardiac resynchronization therapy (CRT). AB - BACKGROUND: A significant proportion of patients receiving CRT are non responders. We evaluated the efficacy of Cardiac Contractility Modulation in subjects with reduced LVEF who, despite cardiac resynchronization therapy (CRT), continued to experience clinically significant symptoms. METHODS: This was a multi-center, open label, treatment-only, feasibility study of 17 CRT non responders who received CCM therapy. Changes in NYHA class, ejection fraction (EF), Minnesota Living with Heart Failure Questionnaire (MLWHFQ) score, and exercise tolerance (6 minute walk test; 6MWT and peak VO2) were analyzed over 6 months. Mortality and hospitalization rates were determined. RESULTS: Patients (82% male) were 69.4 +/- 9.6 years of age with baseline EF = 22.8 +/- 6.5%. Among primary endpoints, peak VO2 increased 1.1 +/- 1.6 ml/kg/min (p = 0.03) and MLWHFQ improved (-16 +/- 16 points; p < 0.01). Mean NYHA class improved (-0.33 +/- 0.49; p = 0.02), 6MWT increased (52 +/- 60 m; p < 0.01), while EF trended up (2.9 +/- 5.8%; p = 0.08) at 6 months. During the 6-month follow-up period, there were 18 hospitalizations in 9 subjects and 2 patients died. CONCLUSIONS: Patients with heart failure and reduced ejection fraction who remain moderately to severely symptomatic despite use of CRT, may benefit from CCM therapy with improvement in quality of life and exercise tolerance. A larger prospective study in this population is warranted. PMID- 30409735 TI - Balloon pulmonary angioplasty for the treatment of residual or recurrent pulmonary hypertension after pulmonary endarterectomy. AB - BACKGROUND: Pulmonary endarterectomy (PEA) is the treatment of choice for chronic thromboembolic pulmonary hypertension (CTEPH). However, persistent pulmonary hypertension continues in 5-35% of patients after PEA. Recently, balloon pulmonary angioplasty (BPA) showed promise as a strategy for patients with non operable CTEPH. Therefore, we investigated the usefulness of BPA for residual pulmonary hypertension after PEA. METHODS: Fifteen patients with residual pulmonary hypertension after PEA received 71 BPA sessions (4.7 +/- 1.4 sessions/patient). The mean time between the PEA and the first BPA session was 28.1 +/- 25.8 months. All patients underwent a comprehensive diagnostic work-up, including right heart catheterization, functional and laboratory tests, before, and 6-4 weeks after the BPA sessions. RESULTS: After BPA, the mean pulmonary arterial pressure decreased from 44.7 +/- 6.4 to 30.8 +/- 7.5 mm Hg (31% decline; p < 0.001). Pulmonary vascular resistance decreased from 551.9 +/- 185.2 to 343.8 +/- 123.8 dyn*s/cm-5 (38% decline; p < 0.001). The 6-min walking distance increased from 383 +/- 104 to 476 +/- 107 m (mean change +93 m; p < 0.001). In two sessions (2.8%), serious periprocedural complications occurred. During a mean follow-up of 18 +/- 14.3 months, one patient died two months after the last BPA session. Fourteen patients survived. CONCLUSIONS: BPA could be a promising therapeutic strategy for persistent pulmonary hypertension after PEA in patients with CTEPH. PMID- 30409734 TI - The Erasmus Frailty Score is associated with delirium and 1-year mortality after Transcatheter Aortic Valve Implantation in older patients. The TAVI Care & Cure program. AB - BACKGROUND: Frailty in patients undergoing Transcatheter Aortic Valve Implantation (TAVI) has been associated with an increased 1-year mortality rate but the relation of frailty and short term outcomes yields conflicting results. This study investigated the association of a novel and self-developed Erasmus Frailty Score with both short and long term outcomes after TAVI. METHODS: TAVI Care & Cure is an observational ongoing study, which includes consecutive patients undergoing TAVI at the Erasmus University Medical Centre. Prior to the TAVI, frailty status was assessed. The Erasmus Frailty Score (EFS) was defined as follows: 1 point assigned if: MMSE was <27 points, MUST >=2 points, grip strength <20 kg for females, <30 kg for males, KATZ index >=1 limited activity, Lawton and Brody index >=2 limited activity. The maximum score was 5. Patients were classified as frail when the score was >=3. Presence of delirium was evaluated by daily clinical assessment by a geriatrician pre- and post-TAVI. Mortality data were obtained from the Dutch Civil Registry. The impact of frailty on short and long term outcomes was evaluated. RESULTS: 213 patients were included for analysis. Frailty was present in 28.6% (n = 61), (EFS >= 3). Baseline frailty was associated with patients developing a delirium [OR 3.3 (95% CI 1,55-7,10), p = 0.002] and with increased risk of 1-year mortality [HR 2.1 (95% CI 1.01-4.52), p = 0.047]. CONCLUSION: The Erasmus Frailty Score is associated with delirium and 1 year mortality in older patients after TAVI and can be used as a complement to traditional risk factors. PMID- 30409736 TI - Single and persistent elevation of C-reactive protein levels and the risk of atrial fibrillation in a general population: The Ansan-Ansung Cohort of the Korean Genome and Epidemiology Study. AB - BACKGROUND: Inflammation has been reported to cause atrial fibrillation (AF). However, it remains unclear whether C-reactive protein (CRP) levels predict AF. We investigated whether there was an association between serum CRP levels and the development of AF. METHODS: A total of 10,030 subjects aged between 40 and 69 years were enrolled and followed biennially over a 12-year period in the Ansan Ansung cohort study. Serum CRP levels were measured at baseline and high sensitivity CRP (hsCRP) levels were measured at every revisit. AF was identified using 12-lead standard electrocardiography. Inverse probability of treatment weighting was applied to balance the confounders of AF development between groups. RESULTS: Serum CRP levels were higher in subjects with AF at baseline and those with new-onset AF than in those without AF. Cox-regression analysis showed that high CRP levels (>3 mg/L) and intermediate CRP levels (1-3 mg/L) at baseline were not associated with a higher risk of new-onset AF compared with low CRP levels (<1 mg/L) after adjustments for covariates. The weighted incidences of AF also did not differ according to the CRP levels. In contrast, persistent elevation of CRP or hsCRP levels (>=1 mg/L at all visits) was associated with a higher risk of AF compared with nonpersistent elevation of CRP or hsCRP levels after adjustment for covariates in both unweighted and weighted cohorts. CONCLUSION: A high CRP level at a single measurement was not associated with the risk of AF, whereas persistently elevated CRP levels independently predicted the development of AF. PMID- 30409737 TI - Prevalence of 18F-fluorodeoxyglucose positron emission tomography abnormalities in patients with arrhythmogenic right ventricular cardiomyopathy. AB - BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable heart muscle disease that causes sudden cardiac death in the young. Inflammatory myocardial infiltrates have been described at autopsy and on biopsy, but there are few data on the presence of myocarditis in living patients with ARVC using non-invasive imaging techniques. FDG-PET is a validated technique for detecting myocardial inflammation in clinically suspected myocarditis. We aimed to determine the prevalence of myocardial inflammation in patients with ARVC using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). METHODS AND RESULTS: We performed a retrospective analysis of a single centre cohort of patients with ARVC referred for FDG-PET scans between 2012 and 2017 for investigation of symptoms or suspected device infection. Sixteen patients (12 male; age 42 +/- 13 years) with a definite diagnosis of ARVC were identified. Seven had positive FDG-PET scans, two of whom had cardiac sarcoidosis on endomyocardial biopsy. Of the remaining five, two carried pathogenic desmoplakin mutations. FDG uptake was found in the left ventricular myocardium in all cases. One patient also had right ventricular uptake. CONCLUSION: In this exploratory study, we show that some patients with ARVC have evidence for myocardial inflammation on FDG-PET, suggesting that myocarditis plays a role in disease pathogenesis. PMID- 30409738 TI - Clinical outcome of the 2nd generation cryoballoon for pulmonary vein isolation in patients with persistent atrial fibrillation - A sub-study of the randomized trial evaluating single versus dual cryoballoon applications. AB - AIMS: To assess the efficacy of the 2nd generation Cryoballoon for pulmonary vein isolation (PVI) in patients with persistent atrial fibrillation (PersAF), and to compare it to patients with paroxysmal atrial fibrillation (PAF). METHODS: The outcome (arrhythmia recurrence at 12 months) was prospectively assessed in patients with PersAF(n = 77) and compared to that in patients with PAF(n = 62), who underwent PVI within a randomized trial evaluating single versus dual applications with the 2nd generation cryoballoon. Other endpoints included symptoms of AF, quality of life, procedure related characteristics, redo ablation rates and adverse events. Variables predicting recurrences were studied including all patients. RESULTS: Freedom from arrhythmia recurrence was 64.9% after a single ablation and 68.8% after one or more procedures, which was significantly lower compared to PAF patients; 82.2% (p = 0.029) and 83.9% (p = 0.048) respectively, at 12 months. The improvements in EHRA score (-1.3 +/- 0.8, p < 0.0001), symptom severity score (SSQ) (-5.0 +/- 4.2, p < 0.0001) and EQ5D-5 L global score (+10.4 +/- 20.3, p = 0.0002) after ablation was significant compared to baseline. The re-ablation rate was 7/77 (9.1%) which did not differ from that in PAF patients, 9/62 (14.5%), p = 0.42. Procedure duration, 104.8 +/- 37.4 versus 113 +/- 31.2 min (p = 0.129), application time, 1605 +/- 659 versus 1521 +/- 557 s (p = 0.103) and total adverse events after 12 months, 8/77 (10.4%) versus 5/62 (8.1%) (p = 0.77) did not differ in PersAF versus PAF patients. CONCLUSION: Both symptoms and QoL improved significantly in patients with PersAF after ablation. Freedom from AF was clinically significant but lower than in PAF patients. The cryoballoon seems an effective technique also in patients with persistent AF. PMID- 30409739 TI - Reduced levels of vasopressin, an independent mechanism in the obesity paradox in patients with chronic heart failure: Insights from the DAMOCLES study. AB - BACKGROUND: An "obesity paradox" has been described in patients with chronic heart failure (CHF), obese patients having a better survival. Vasopressin is elevated in patients with CHF, and higher levels are associated with worsening severity of the disease. We aimed at evaluating the relationship between body mass index (BMI), obesity (BMI >=30 kg/m2), and vasopressin in patients with CHF, as well as the prognostic implications of vasopressin across the full spectrum of BMI values. METHODS: We included 1132 consecutive CHF patients referred to a multidisciplinary CHF unit. BMI and vasopressin levels were measured at baseline, and their association was evaluated using multivariable linear and logistic regression models. Death was evaluated after a median follow-up of 2.93 years and using Cox regression analyses. RESULTS: Mean age was 73 years, 43% women, mean BMI 28 kg/m2. Vasopressin levels were independently associated with all-cause death across the whole spectrum of BMI values, and were significantly lower in obese as compared to non-obese patients (median adjusted estimated levels of log vasopressin in obese patients 2.57 [95% CI 1.5-3.67], in non-obese patients 3.16 [95% CI 2.11-4.23]; p < 0.001). Also, the higher the BMI, the lower the vasopressin levels, at least for patients with BMI <35 kg/m2. Subgroup analyses stratifying by left ventricle ejection fraction and sensitivity analyses further adjusting for norepinephrin levels yielded similar findings. CONCLUSIONS: Reduced levels of vasopressin may represent an independent mechanism in the survival paradox in obese patients with CHF. Studies including larger samples of patients BMI >=35 kg/m2 are needed. PMID- 30409740 TI - Sex-related differences in cardiomyopathies. AB - Cardiomyopathies (CMPs) are a heterogeneous group of heart muscle diseases with several different phenotypes defined as myocardial disorders in which the heart muscle is structurally and functionally abnormal in the absence of coronary artery disease, hypertension, valvular heart disease and congenital heart disease sufficient to explain the observed myocardial abnormality. CMPs can be classified into one of the following, i.e. hypertrophic CMP (HCM), dilated CMP (DCM), arrhythmogenic right ventricular CMP (ARVC), restrictive CMP (RCM), and unclassified CMPs. Although an increasing number of CMPs are now recognized to have a genetic basis, single mutations are associated with phenotypic variability and may cause not only a specific CMP, but also several different CMPs. Recently, it has become evident that, along with environmental interactions, age and sex may affect the penetrance of disease genes thus determining the phenotypic expression of CMPs. Noteworthy, an increasing body of data indicates that sex plays an important role in various forms of CMPs. The mode of inheritance may affect the sex-related occurrence of CMPs. Also, sex is a relevant determinant of the clinical manifestation of CMPs, and sex-related characteristics can be found in all forms. Sex-specific aspects of clinical disease expression as well as potential modes of inheritance should be therefore taken into proper consideration in order to improve the diagnostic work-up and treatment strategy of CMPs in both sexes. PMID- 30409741 TI - Association of initial mucogingival status with clinical outcome of non-surgical periodontal therapy: A retrospective analysis of 204 patients. AB - BACKGROUND/PURPOSE: This study was conducted to evaluate the influence of mucogingival parameters, including keratinized mucosa (KM) and attached gingiva (AG), on the outcome of non-surgical periodontal therapy (NSPT). METHODS: A total of 204 non-smoking patients with generalized chronic periodontitis who received NSPT between 2012 and 2014 were included. The Mantel-Haenszel chi-square test was used to assess the associations between initial mucogingival parameters and initial clinical parameters on the buccal aspect, and the associations between initial mucogingival parameters and outcome clinical parameters on the buccal aspect of the sites with severe periodontal destruction. The generalized liner model was used to evaluate the contribution of initial clinical parameters to the outcome of NSPT. RESULTS: KM >= 3 mm was associated with greater probing pocket depth (PD), less gingival recession (REC), and less clinical attachment level (CAL), and AG < 1 mm was associated with greater PD, REC, and CAL before NSPT. At the sites with severe periodontal destruction, KM >= 3 mm was associated with greater PD reduction (0.25 +/- 0.08 mm) and CAL gain (0.25 +/- 0.09 mm), and AG < 1 mm was associated with greater CAL gain (0.15 +/- 0.08 mm) after NSPT. Initial PD >= 7 mm and non-molar teeth showed greater contribution to the outcome of NSPT. CONCLUSION: Less AG (<1 mm) was associated with greater periodontal destruction at baseline. At the sites with severe periodontal destruction, greater KM (>=3 mm) and less AG (<1 mm) resulted in better outcomes of NSPT. PMID- 30409742 TI - Special issue on new technologies for alcohol research and treatment. PMID- 30409743 TI - The Impact of Covert Lacunar Infarcts and White Matter Hyperintensities on Cognitive and Motor Outcomes After Stroke. AB - BACKGROUND AND AIMS: In addition to overt stroke lesions, co-occurring covert lesions, including white matter hyperintensities (WMH) and covert lacunar infarcts (CLI), contribute to poststroke outcome. The purpose of this study was to examine the relationship between covert lesions, and motor and cognitive outcomes in individuals with chronic stroke. METHODS: Volumetric quantification of clinically overt strokes, covert lesions (periventricular and deep: pWMH, dWMH, pCLI, dCLI), ventricular and sulcal CSF (vCSF, sCSF), and normal appearing white (NAWM) and gray matter (NAGM) was performed using structural magnetic resonance imaging. We assessed motor impairment and function, and global cognition, memory, and other cognitive domains. When correlation analysis identified more than one MR parameter relating to stroke outcomes, we used regression modeling to identify which factor had the strongest impact. RESULTS: Neuropsychological and brain imaging data were collected from 30 participants at least 6 months following a clinically diagnosed stroke. Memory performance related to vCSF (r = -0.52, P = .004). The strongest predictor of nonmemory domains was pCLI (r2 = 0.28, P = .004). Motor impairment and function were most strongly predicted by the volume of stroke and NAWM (r2 = 0.36; P = .001), and dWMH (r2 = 0.39; P = .001) respectively. CONCLUSIONS: Covert lesion type and location have important consequences for post-stroke cognitive and motor outcome. Limiting the progression of covert lesions in aging populations may enhance the degree of recovery post-stroke. PMID- 30409744 TI - Angiotensinogen M235T Gene Polymorphism is a Genetic Determinant of Cerebrovascular and Cardiopulmonary Morbidity in Adolescents with Sickle Cell Disease. AB - BACKGROUND: Cerebrovascular stroke is a common critical complication of sickle cell disease (SCD). Angiotensinogen (AGT) M235T gene polymorphism is associated with risk of ischemic stroke and cardiovascular disease. AIM: We investigated the potential association between angiotensinogen M235T gene polymorphism and susceptibility to cerebrovascular and cardiopulmonary complications in adolescents with SCD. METHODS: Forty-six patients with SCD in steady state were studied stressing on history of stroke, hydroxyurea/chelation therapy, hematological profile, and echocardiographic findings. Polymerase chain reaction based restriction fragment length polymorphism analysis was used to detect AGT M235T gene polymorphism. Fifty sex- and age-matched healthy controls were enrolled for assessment of M235T gene polymorphism pattern. RESULTS: The distribution of AGT M235T gene polymorphism was similar between SCD patients and healthy controls. The frequency of T allele of AGT M235T gene polymorphism (TT and MT genotypes) was significantly higher among patients with history of manifest stroke (P < .001). Patients with TT and MT genotypes had higher incidence of cardiopulmonary complications (P = .041) as well as higher percentage of HbS (P < .001) and lower hemoglobin level (P = .008) compared with those with MM genotype. Serum ferritin, liver iron concentration, and cardiac T2* were not related to T alleles or genotypes. Logistic regression analysis revealed that M235T genotype was a significant independent factor related to the occurrence of stroke among patients with SCD (Odds Ratio 14.05, 95% confidence interval 3.82-28.91; P = .001). CONCLUSION: AGT M235T gene polymorphism may represent a genetic modifier to vascular morbidities in Egyptian patients with SCD. PMID- 30409745 TI - Subcutaneous Heparin Therapy for Patients with Cancer-Associated Stroke. AB - BACKGROUND: Anticoagulation therapy, particularly subcutaneous heparin therapy, is recommended for cancer-associated thrombosis. However, not starting or discontinuing anticoagulation was not rare. The aim of the present study was to examine the practical issues related to anticoagulation therapy and effects of subcutaneous heparin therapy for cancer-associated stroke. METHODS: Patients with cancer-associated stroke in our stroke center between October 2014 and August 2017 who were diagnosed as having acute ischemic stroke based on diffusion weighted imaging were retrospectively enrolled. Baseline clinical characteristics, heparin injection, reasons for no subcutaneous heparin therapy, and clinical outcomes were collected. RESULTS: A total of 59 patients with cancer associated stroke (75 +/- 10 years old, male 42%) were enrolled. Lung cancer was the most frequently observed cancer (n = 17, 29%), followed by gastric cancer (n = 8, 14%) and pancreatic cancer (n = 8, 14%). Of the 19 patients (32%) who underwent subcutaneous heparin therapy, it was discontinued in 9 (47%), mainly because of patients' medical conditions (deterioration of cancer or hemorrhagic complication). Ten patients with long-term subcutaneous heparin therapy did not have stroke recurrence. In contrast, among nine patients who discontinued subcutaneous heparin therapy, three (33%) had recurrence of ischemic stroke. Of the 40 patients without subcutaneous heparin therapy, the main reasons for no subcutaneous heparin therapy were the patients' medical conditions (n = 22, 55%). CONCLUSIONS: Although subcutaneous heparin therapy was given to only one third of cancer-associated stroke patients, long-term subcutaneous heparin therapy might prevent recurrence of cancer-associated stroke. PMID- 30409746 TI - Persistent Primitive Olfactory Artery as Novel Collateral Channel to the Anterior Cerebral Artery in Moyamoya Disease. AB - BACKGROUND: There are a variety of collateral routes to compensate persistent cerebral ischemia in moyamoya disease. However, there is no report presenting the persistent primitive olfactory artery (POA) as a spontaneous collateral route to the anterior cerebral artery (ACA) in moyamoya disease. METHODS: We precisely examined cerebral angiography in 84 patients with moyamoya disease to identify the collateral channel through the persistent POA. Its anatomy was evaluated on pre- and postoperative angiography. RESULTS: Of 84 patients, four (4.8%) had spontaneous collateral channel through the persistent POA. All of these four hemispheres were categorized into Stage 5. In all four patients, the collateral blood flow arose from the ophthalmic artery and run to the persistent POA through the ethmoidal moyamoya. The persistent POA provided collateral blood flow from the ophthalmic artery to the ACA in all four patients. Superficial temporal artery to middle cerebral artery anastomosis and encephalo-duro-myo-arterio pericranial synangiosis was performed in three of four patients. After surgery, the collateral channel through the persistent POA completely disappeared or markedly regressed, suggesting a significant improvement of cerebral hemodynamics in the territory of not only the MCA but also the ACA. CONCLUSION: The persistent POA can potentially provide collateral blood flow to the ACA in about 5% of patients with moyamoya disease, and should be recognized as a novel collateral channel in moyamoya disease. The persistent POA may be useful to evaluate therapeutic effects of surgical revascularization on the ACA territory. PMID- 30409748 TI - [Use of time of a nurse involved in breaking the diagnosis of lung cancer and navigating patients in the healthcare system: Experience of an academic thoracic oncology ward]. AB - The Plans cancer 1 and 2 created new nursing posts to improve the way that news about cancer was given to patients and to coordinate their care, helping them to navigate the system. We describe the way a nurse, assuming the role of assisting the doctor when a diagnosis of cancer is revealed and coordinating the care of patients in a teaching hospital, uses her time. One thousand and forty-one patients were supported by the nurse during 6515 procedures over 4.27 years. The median (interquartile range) number of interventions per patient was 3 (7). Helping to break news of cancer and the coordination of care represented approximately 20 and 80% of the working time of the nurse, respectively. The nurse spent 43% of her time without the doctor and more than half of this duration was dedicated to meetings with patients. The nurse timetable analysis shows that her role is very similar to a Canadian 'Pivot' nurse in oncology. In our experience, this combination of the announcement of cancer diagnosis and the coordination of subsequent care seems relevant, but the nurse is not replaced in the case of absence. PMID- 30409749 TI - MERRF syndrome (Myoclonic Epilepsy with Ragged Red Fibres) presenting with cervicothoracic lipomatosis. AB - INTRODUCTION: Patients with MERRF syndrome (Myoclonic Epilepsy with Ragged Red Fibres) usually present with encephalomyopathy. However, progressive, recurrent cervicothoracic lipomatosis may be rarely observed. CASE REPORT: The authors report 4 cases of MERRF syndrome associated with lipomatosis. In 3 patients, the diagnosis of MERRF syndrome was established on the basis of the clinical features of the lipomas and clinical interview revealing a personal or family history of lipomas and myopathy. DISCUSSION: In the presence of extensive spinal lipomatosis, the presence of other clinical signs of MERRF syndrome in the patient or the patient's family must be investigated. A diagnosis of MERRF syndrome can guide appropriate genetic counselling. PMID- 30409747 TI - Patients with Acute Lacunar Infarction Have Benefit from Intravenous Thrombolysis. AB - INTRODUCTION: Usefulness of intravenous thrombolysis in patients with acute lacunar cerebral infarction is questionable. The aim of this study was to evaluate the efficacy and safety of intravenous thrombolysis in patients with lacunar infarction in comparison with patients with nonlacunar infarction as well as with patients with lacunar infarction who were not treated with intravenous thrombolysis. MATERIALS AND METHODS: In the first part of the study, among patients with acute ischemic stroke treated with intravenous thrombolysis, characteristics and outcomes of 46 patients with lacunar and 221 patients with nonlacunar infarction were compared. In the second part, 46 patients with lacunar infarction treated with intravenous thrombolysis were compared with 45 lacunar infarction patients who were not treated with intravenous thrombolysis. RESULTS: Patients with lacunar infarction had a lower National Institutes of Health Stroke Scale score (9.2 versus 13.9, P < .001), a greater Alberta Stroke Program Early computed tomography (CT) score (9.7 versus 9.2, P = .002), a lower prevalence of atrial fibrillation (6.5% versus 41.2%, P < .001), and significantly more frequently an excellent outcome after 3 months (76.1% versus 36.2%, P < .001) compared with patients with nonlacunar infarction. Among patients with lacunar infarction, an excellent outcome at discharge was significantly more frequent in the intravenous thrombolysis group (41.3% versus 15.6%, P = .01), and the length of hospitalization was significantly shorter (9.5 days versus 14.3 days, P = .002). There was no hemorrhagic transformation among patients with lacunar infarction treated with intravenous thrombolysis. CONCLUSION: Intravenous thrombolysis has proven to be effective and safe in patients with lacunar infarction and should always be applied if there are no absolute contraindications. PMID- 30409750 TI - Co-delivery of siRNA and etoposide to cancer cells using an MDEA esterquat based drug delivery system. AB - Cancer has become the leading cause of death in many countries. Chemotherapy is a key component in the treatment of most cancers but has limited efficacy if the cancer develops resistance to the treatment over time and recur. RNA interference may be used to reduce the production of the proteins responsible for chemotherapeutic resistance. Small interfering RNAs (siRNA) may be used to induce RNA interference but the application of these to cancer cells is hampered by poor serum stability and delivery to their cytoplasmic site of activity. This work introduces a novel nanoparticle delivery system for siRNA and hydrophobic anticancer drugs. The system is based on a cationic MDEA esterquat, which is widely and safely used in personal care products but has never been assessed for drug delivery applications. We show that MDEA forms spherical compact nanoparticles when combined with siRNA that delivers the siRNA to cancer cells where it induces gene silencing. By combining DOPE and MDEA in ratios of 2:1 and 3:1, even higher gene silencing levels (>90%) may be achieved. The system is capable of combinational therapy by co-delivering siRNA and the chemotherapeutic drug etoposide to cancer cells and these particles both induce gene silencing and chemotherapy induced cell death. We believe the present system may be used for intra-tumoral injection of chemotherapy in solid chemotherapy resistant tumors and for systemic delivery with further development. PMID- 30409751 TI - Smartphone-Based Healthy Weight Management Intervention for Chinese American Adolescents: Short-Term Efficacy and Factors Associated With Decreased Weight. AB - PURPOSE: This study aimed to examine the short-term efficacy of a smartphone based intervention for Chinese American adolescents who are overweight or obese and to explore factors associated with decreased body mass index (BMI). METHODS: A randomized controlled study design was used. Intervention group received culturally appropriate and tailored educational program for weight management while control group received general health information. Anthropometrics, blood pressure, levels of physical and sedentary activity, diet, self-efficacy, and quality of life were assessed at baseline, 3 months, and 6 months. Linear mixed effects models and regression models were used to analyze outcomes. RESULTS: The study included 40 adolescent participants. Adolescents in the intervention reduced their BMI (z = -4.89, p < .001), BMI z score (z = -4.72, p < .001), sugary beverage (z = -.44, P = .001), and TV and computer time (z = -.51, p < .001) and increasing in self-efficacy in nutrition and physical activity significantly more than those in the control group. BMI reduction was significantly correlated with decreased fast food consumption and increased physical activity (F = 6.99, p = .007, r2 = .40). Being female and decreased sugary beverage consumption were related to decreased BMI z score (F = 8.38, p = .003, r2 = .511). CONCLUSIONS: A culturally appropriate smartphone-based intervention has great potential to reduce obesity and improve adherence to a healthy lifestyle. Reducing sugary beverages and fast food intake and decreasing sedentary time are associated with decreased BMI among adolescents who are overweight or obese. PMID- 30409752 TI - Racial Discrimination and Acute Physiological Responses Among Black Young Adults: The Role of Racial Identity. AB - PURPOSE: Racial discrimination has long-term consequences for cardiovascular health, potentially by dysregulating acute physiological responses. However, the role of psychological factors that may be protective or increase vulnerability for dysregulated responses, such as racial identity, remains unclear. This study examines the association between racial discrimination and acute parasympathetic responses, and the role of racial centrality, private regard, and public regard in this association. METHODS: Black young adults (N = 119, Mage = 19.45) recruited from a predominantly White institution in the southeastern United States completed an online survey (in which racial discrimination, racial identity, and control variables were reported) and a laboratory visit, during which they were exposed to a vignette of racial discrimination while their parasympathetic activity (indexed by respiratory sinus arrhythmia) was recorded. RESULTS: While racial discrimination was not associated with respiratory sinus arrhythmia reactivity or recovery, centrality moderated this association such that more frequent racial discrimination was associated with greater parasympathetic reactivity and recovery only among participants low in racial centrality. Neither private regard nor public regard emerged as significant moderators. CONCLUSIONS: This study is the first to show that lower levels of racial centrality can mitigate the association between discrimination and acute parasympathetic responses, which has important implications for initiatives aimed at reducing cardiovascular risk for Black young adults. PMID- 30409753 TI - Trends in Physical Fitness Among 12-Year-Old Children in Urban and Rural Areas During the Social Transformation Period in China. AB - AIMS: To investigate the 29-year (1985-2014) trends in body dimensions and physical fitness test performances among 12-year-old Chinese children living in urban and rural areas. METHODS: The data were from the findings of seven cross sectional surveys from the Chinese National Survey on Students' Constitution and Health. In the seven surveys, there were 34,238; 11,664; 17,485; 18,057; 19,254; 17,962; and 17,906 children, respectively. Anthropometric measurements and physical fitness performances of 12-year-old Chinese children living in rural and urban areas were analyzed. Polynomial models were used to analyze trends in test performances. Analysis of variance was used to assess the urban-rural differentials. RESULTS: The height and weight of both urban and rural children substantially increased from 1985 to 2014. Urban children were taller and heavier than rural children. A slight narrowing of the urban-rural differential in height was observed. The disparity in weight increased from 1985 to 2000 and decreased thereafter. Urban children performed better in most of the physical fitness tests examined, such as standing long jump, 50-m run, and sit-ups. The urban-rural disparity decreased from 1985 to 2014 in 50-m run, standing long jump, and sit-up score; the largest difference in 10 * 50 m run and pull-up score was observed in 2000 and 2005, respectively. CONCLUSIONS: There was a general decline in physical fitness in both urban and rural children after 2000. Urgent, targeted actions need to be taken by public health policy officials and parents to maintain or improve the physical fitness of children. PMID- 30409754 TI - Health Effects Reported by Adolescent Water Pipe and/or Cigarette Smokers Compared to Nonsmokers. AB - PURPOSE: The purpose of this study was to determine the prevalence of respiratory and/or physical fitness health problems in adolescent (ages 18-21) water pipe (WP) smokers (with or without cigarette smoking), cigarette-only smokers, and nonsmokers. METHODS: A comparative four-group study design was used to recruit a non-probability sample of 153 WP smokers only, 103 cigarette smokers only, and 102 cigarette+WP smokers along with 296 nonsmokers. Our hypothesis was that youth who smoked WPs and/or cigarettes would report more respiratory problems and/or poorer physical fitness than those who did not smoke. RESULTS: The results showed that coughs were significantly associated with smoking in all three of the smoking groups (p < .05). Cigarette-only smokers reported the most adverse outcomes with more wheezing, difficulty breathing, and less ability to exercise without shortness of breath. A dose-response analysis showed similar patterns of adverse health effects for both WP and cigarette smokers. The combined use of both products was not appreciably worse than smoking one product alone. This could be due to cigarette+WP smokers' reporting using less of the respective products when only one product was smoked. CONCLUSIONS: Even during the adolescent years, WP and/or cigarette smoking youth experienced reportable negative health effects. PMID- 30409755 TI - Lifetime Prevalence of Self-Reported Concussion Among Adolescents Involved in Competitive Sports: A National U.S. Study. AB - PURPOSE: Examine lifetime prevalence of diagnosed concussion in US-national samples of 8th, 10th, and 12th graders involved in 16 different competitive sports; examine associations between concussion and individual sports, controlling for demographic characteristics and multiple sports involvement. METHODS: Analysis of nationally representative Monitoring the Future data from 2 cohorts (2016-2017; n = 25,408). RESULTS: Adolescents who participated in baseball, basketball, football, gymnastics, ice hockey, lacrosse, soccer, track, weightlifting, and 'other sports' had greater odds of reporting multiple diagnosed concussions compared with peers not participating in these sports. Adolescents who participated in tennis had lower odds of reporting any diagnosed concussion or multiple concussions. Females who participated in gymnastics, soccer, and swimming showed a stronger association in reporting a diagnosed concussion when compared with males who participated in these same types of sports. CONCLUSIONS: The study provides needed epidemiological information on prevalence of reported diagnosed concussion among teens participating in popular school and community sports. Certain high contact (e.g., football) and high volume (e.g., basketball) sports need increased efforts to manage adolescent athletes who already have a history of concussion or repeated concussions. PMID- 30409756 TI - In silico analysis of plasmodium falciparum CDPK5 protein through molecular modeling, docking and dynamics. AB - Calcium-Dependent Protein Kinase 5 (CDPK5) protein is one of the family members of a calcium-dependent protein kinase that is found in plants and some species of protozoa which includes Plasmodium falciparum (Pf), the pathogen responsible for malaria. CDPKs regulate many biological processes in Apicomplexans such as Plasmodium, Toxoplasma or Cryptosporidium. The study addresses the similarity in sequences and evolutionary relationship of CDPK5 across Apicomplexans. Further, the three-dimensional structural conformation of PfCDPK5 is generated through homology modeling. Molecular dynamics simulation of the homology model for a time interval of 40 ns resulted in a stable conformation of the PfCDPK5 protein. Inhibitor identification was carried out from computational screening of known anti-malarial compounds. The reliability of the binding mode for the best inhibitor compound MMV687246 was validated through a complex molecular dynamics study. This findings advocates that MMV687246 from Pathogen Box as the best inhibitor against PfCDPK5 protein and can be considered for experimental validation study in future. PMID- 30409757 TI - Induction of Lrp5 HBM-causing mutations in Cathepsin-K expressing cells alters bone metabolism. AB - High-bone-mass (HBM)-causing missense mutations in the low density lipoprotein receptor-related protein-5 (Lrp5) are associated with increased osteoanabolic action and protection from disuse- and ovariectomy-induced osteopenia. These mutations (e.g., A214V and G171V) confer resistance to endogenous secreted Lrp5/6 inhibitors, such as sclerostin (SOST) and Dickkopf homolog-1 (DKK1). Cells in the osteoblast lineage are responsive to canonical Wnt stimulation, but recent work has indicated that osteoclasts exhibit both indirect and direct responsiveness to canonical Wnt. Whether Lrp5-HBM receptors, expressed in osteoclasts, might alter osteoclast differentiation, activity, and consequent net bone balance in the skeleton, is not known. To address this, we bred mice harboring heterozygous Lrp5 HBM-causing conditional knock-in alleles to Ctsk-Cre transgenic mice and studied the phenotype using DXA, MUCT, histomorphometry, serum assays, and primary cell culture. Mice with HBM alleles induced in Ctsk-expressing cells (TG) exhibited higher bone mass and architectural properties compared to non-transgenic (NTG) counterparts. In vivo and in vitro measurements of osteoclast activity, population density, and differentiation yielded significant reductions in osteoclast-related parameters in female but not male TG mice. Droplet digital PCR performed on osteocyte enriched cortical bone tubes from TG and NTG mice revealed that ~8-17% of the osteocyte population (depending on sex) underwent recombination of the conditional Lrp5 allele in the presence of Ctsk-Cre. Further, bone formation parameters in the midshaft femur cortex show a small but significant increase in anabolic action on the endocortical but not periosteal surface. These findings suggest that Wnt/Lrp5 signaling in osteoclasts affects osteoclastogenesis and activity in female mice, but also that some of the changes in bone mass in TG mice might be due to Cre expression in the osteocyte population. PMID- 30409758 TI - Diffusion tensor imaging shows mechanism-specific differences in injury pattern and progression in rat models of acute spinal cord injury. AB - We investigate the ability of diffusion tensor imaging (DTI) to distinguish between three experimental rat models of spinal cord injury mechanism - contusion, dislocation, and distraction. Ex vivo DTI scans were performed on cord specimens that were preserved at different time points of the acute injury (3 hr, 24 hr, and 7 days post-injury) across all three injury mechanisms. White matter was classified as abnormal if their DTI metric was substantially different from regional values measured from a set of uninjured controls, thus allowing generation of binary "white matter damage maps" which categorizes each pixel in the DTI image as "normal" or "damaged". Damage classification was most robust using thresholds in the longitudinal diffusivity, which supports previous studies that show that longitudinal diffusivity is the most robust DTI metric in depicting damage in SCI. Furthermore, the spatial damage patterns from all subjects in the same group were consolidated into a "damage occurrence ratio map", which illustrates an average damage shape that characterizes the injury mechanism. Our analysis has yielded a dataset which highlights the differences in injury pattern due to the initial mode of mechanical injury. For example, contusion produced an initial injury that emanated radially outward from the central canal, with subsequent damage along the caudal corticospinal tract and rostral gracile fasciculus; dislocation injuries showed a high level of involvement in the lateral and ventral white matter which became less apparent by 7 days post-injury, and distraction injuries were found to be less focal and more distributed rostrocaudally. This work represents a first step in adopting the use of the primary injury mechanism as a clinical prognostic factor in SCI, which may help to inform the trialing of existing neuroprotective treatment candidates, the development of new therapies as well as personalize the management of SCI for the individual patient. PMID- 30409760 TI - Treatment of allergic rhinitis reduces acute asthma exacerbation risk among asthmatic children aged 2-18 years. AB - BACKGROUND/PURPOSE: Asthma and allergic rhinitis (AR) frequently coexist in the same individuals in childhood and adolescence. We evaluated whether AR had an impact on acute exacerbation (AE) and whether intranasal corticosteroid (INCS) and second-generation antihistamines (SGH) for AR modified the association of AR with AE in asthmatics aged 2-6 years and 7-18 years. METHODS: Using the National Health Research Institutes (NHRI) Database 2005 of Taiwan, we investigated patients who had been diagnosed with asthma in the years 2000 through 2012 and who had then been followed-up with for at least one year. The risk factors of AE were evaluated using multiple Cox proportional hazards regression analysis. RESULTS: The incidence of AE was higher in the preschool group than the older group (adj. HR: 1.68, 95% CI: 1.44-1.95). The AR with INCS and/or SGH group was found to have a lower risk of AE than the non-AR group (adj. HR: 0.32, 0.44 and 0.30), but the AR without treatment group did not have a significant difference with the non-AR group. After propensity score matching, the use of INCS and/or SGH was associated with a significant reduction in the occurrence of AE among AR patients aged 2-6 years old (adj. HR: 0.38, 0.57 and 0.45) and 7-18 years old (adj. HR: 0.50, 0.52 and 0.35). CONCLUSION: The preschool patients had a higher incidence of AE than the older patients in general. Adequate treatment with INCS and/or SGH in asthma with AR patients is important for reducing the incidence of AE of asthma. PMID- 30409759 TI - Angiography-Derived Fractional Flow Reserve in the SYNTAX II Trial: Feasibility, Diagnostic Performance of Quantitative Flow Ratio and Clinical Prognostic Value of Functional SYNTAX Score Derived From Quantitative Flow Ratio in Patients With Three-Vessel Disease. AB - OBJECTIVES: The aims of the present study were to investigate the applicability of quantitative flow ratio (QFR) in patients with 3-vessel disease and to demonstrate the impact of functional SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score derived from QFR (fSSQFR) on clinical outcomes. BACKGROUND: The applicability of QFR in patients with 3-vessel disease and the feasibility of fSSQFR have not yet been investigated. METHODS: All lesions interrogated using instantaneous wave-free ratio and/or fractional flow reserve in the SYNTAX II trial were retrospectively screened and analyzed for QFR. The diagnostic performance of QFR was investigated using hybrid wire-derived pressure assessment (instantaneous wave-free ratio and fractional flow reserve), used in the trial as a reference. Patients with analyzable QFR in 3 vessels were stratified according to fSSQFR to evaluate its clinical prognostic value on the basis of 2-year patient-oriented composite endpoint. RESULTS: QFRs were analyzable in 71.0% of lesions (836 lesions). The diagnostic performance of QFR to predict binary wire-based ischemia was substantial (area under the curve 0.81, accuracy 73.8%), with a positive predictive value of 85.9%. Independent predictors of diagnostic discordance were lesions in side branches, involvement of bifurcation or trifurcation, and small vessel. According to the 2-year patient-oriented composite endpoint, fSSQFR reclassified 26.1% of the patients (36 of 138) in the high- to intermediate-risk group into the low-risk group appropriately (net reclassification improvement 0.32, p < 0.001). The area under the curve for fSSQFR to predict the 2-year patient-oriented composite endpoint was higher than that of the classic anatomic SYNTAX score (0.68 vs 0.56, p = 0.002). CONCLUSIONS: QFR demonstrated substantial applicability in patients with 3-vessel disease. The fSSQFR has the potential to further refine prognostic risk estimation compared with the classic anatomic SYNTAX score. PMID- 30409761 TI - Analysis of glucose-derived amino acids involved in one-carbon and cancer metabolism by stable-isotope tracing gas chromatography mass spectrometry. AB - A major hallmark of cancer is a perturbed metabolism resulting in high demand for various metabolites, glucose being the most well studied. While glucose can be converted into pyruvate for ATP production, the serine synthesis pathway (SSP) can divert glucose to generate serine, glycine, and methionine. In the process, the carbon unit from serine is incorporated into the one-carbon pool which makes methionine and maintains S-adenosylmethionine levels, which are needed to maintain the epigenetic landscape and ultimately controlling what genes are available for transcription. Alternatively, the carbon unit can be used for purine and thymidylate synthesis. We present here an approach to follow the flux through this pathway in cultured human cells using stable isotope enriched glucose and gas chromatography mass spectrometry analysis of serine, glycine, and methionine. We demonstrate that in three different cell lines this pathway contributes only 1-2% of total intracellular methionine. This suggests under high extracellular methionine conditions, the predominance of carbon units from this pathway are used to synthesize nucleic acids. PMID- 30409762 TI - HER2-mediated GLI2 stabilization promotes anoikis resistance and metastasis of breast cancer cells. AB - Breast cancer metastasis is a multi-step process and requires cells to overcome anoikis. Anoikis is defined as cell-death that occurs due to loss of cell adhesion. During the course of cancer progression, tumor cells acquire resistance to anoikis. However, mechanisms of anoikis resistance are not clear. Human epidermal growth receptor 2 (HER2) overexpressing breast tumors are known to be highly aggressive and metastatic. The mechanisms correlating HER2 with metastasis are poorly understood. We observed increased anoikis resistance in HER2 overexpressing breast cancer cells. In addition, we identified that HER2 overexpression was also associated with increased sonic hedgehog (SHH) signaling especially GLI2, and that inhibition of SHH pathway suppressed anoikis resistance. GSK3beta is known to facilitate proteasome-mediated degradation of GLI2. Moreover, we observed that silencing of GLI2 resulted in reduced migration and invasion of HER2 overexpressing cells. Anoikis resistant HER2 overexpressing cells also showed increased rate and extent of metastasis in vivo, as compared to wild type anoikis resistant cells. Taken together, this study indicates a novel role of HER2/GSK3beta/GLI2 axis in anoikis resistance and metastasis, and that GLI2 could be a potential target for anti-cancer therapies. PMID- 30409763 TI - Activity and expression of E-NTPDase is altered in peripheral lymphocytes of systemic lupus erythematosus patients. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease, where there is irreversible breakdown of immunological self-tolerance. Extracellular adenosine triphosphate (ATP) and adenosine are signaling molecules that play an important part in the immune response. During inflammation and the immune response, a group of enzymes control these molecules, including ectonucleoside triphosphate diphosphohydrolase (E-NTPDase), E-5'-nucleotidase, and ecto-adenosine deaminase (E-ADA). We determined the activity and expression of E-NTPDase, the expression of E-5'-nucleotidase, the activity of E-ADA in lymphocytes and serum of SLE patients. METHODS: This study involved 35 patients with SLE and 30 healthy subjects as a control group. E-NTPDase activity and expression were increased in lymphocytes from SLE patients (31% and 37% for activity and expression, respectively) compared with the control group. RESULTS: An approximately 42% increase in E-ADA activity in lymphocytes was observed in SLE patients compared with the control group, in serum the ADA activity was decreased by 57% in SLE patients. Expression of E-5'-nucleotidase was not changed in SLE patients. CONCLUSIONS: E-NTPDase and E-ADA perform key functions in the modulation of the immune and inflammatory response in SLE. PMID- 30409764 TI - Acrylamide induces adipocyte differentiation and obesity in mice. AB - Obesity is a critical risk factor for various diseases including type II diabetes, cerebral infarction, cardiovascular diseases, and various cancers. Acrylamide (ACR) is present in wide range of foods, including fried potato products, root vegetables, bakery products, chips, cakes, cereals, and coffee. In this study, ACR treatment dramatically increased the accumulation of lipid droplets. We also examined expression levels of peroxisome proliferator-activated receptors gamma (PPARgamma), CCAAT enhancer binding protein alpha (c/EBPalpha), and CCAAT enhancer binding protein beta (c/EBPbeta) as adipogenic transcription factors for adipocyte differentiation. They were dose-dependently increased by treatment of ACR. Moreover, effects of ACR on mitogen-activated protein kinases (MAPKs) and 5' AMP-activated protein kinase (AMPK)-Acetyl-CoA carboxylase (ACC) activation were investigated. Results also showed that ACR induced phosphorylation of MAPKs and AMPK-ACC. ACR also induced expression of adipocyte fatty acid-binding protein (aP2), lipoprotein lipase (LPL), sterol regulatory element-binding protein (SREBP)-1c, and fatty acid synthase (FAS). Exposure of ACR to high fat diet (HFD)-fed mice significantly increased body weight, organ weight, and fat mass of mice. Collectively, these result showed that ACR can act as an enhancer of adipocyte. Therefore, we suggest that up-regulation of the adipogenesis by ACR may be related to the regulation of the MAPKs and AMPK-ACC pathway. PMID- 30409765 TI - Using Facebook for Large-Scale Online Randomized Clinical Trial Recruitment: Effective Advertising Strategies. AB - Targeted Facebook advertising can be an effective strategy to recruit participants for a large-scale online study. Facebook advertising is useful for reaching people in a wide geographic area, matching a specific demographic profile. It can also target people who would be unlikely to search for the information and would thus not be accessible via Google AdWords. It is especially useful when it is desirable not to raise awareness of the study in a demographic group that would be ineligible for the study. This paper describes the use of Facebook advertising to recruit and enroll 1145 women over a 15-month period for a randomized clinical trial to teach support skills to female partners of male smokeless tobacco users. This tutorial shares our study team's experiences, lessons learned, and recommendations to help researchers design Facebook advertising campaigns. Topics covered include designing the study infrastructure to optimize recruitment and enrollment tracking, creating a Facebook presence via a fan page, designing ads that attract potential participants while meeting Facebook's strict requirements, and planning and managing an advertising campaign that accommodates the rapid rate of diminishing returns for each ad. PMID- 30409766 TI - Evaluating the Use of Smart Home Technology by People With Brain Impairment: Protocol for a Single-Case Experimental Design. AB - BACKGROUND: Smart home technologies are emerging as a useful component of support delivery for people with brain impairment. To promote their successful uptake and sustained use, focus on technology support services, including training, is required. OBJECTIVE: The objective of this paper is to present a systematic smart home technology training approach for people with brain impairment. In addition, the paper outlines a multiple-baseline, single-case experimental design methodology to evaluate training effectiveness. METHODS: Adult participants experiencing acquired brain impairment who can provide consent to participate and who live in housing where smart home technology is available will be recruited. Target behaviors will be identified in consultation with each participant based on his or her personal goals for technology use. Target behaviors may include participant knowledge of the number and type of technology functions available, frequency of smart home technology use, and number of function types used. Usage data will be gathered via log-on smart home technology servers. A smart technology digital training package will also be developed and left on a nominated device (smartphone, tablet) with each participant to use during the trial and posttrial, as desired. Measures of the target behavior will be taken throughout the baseline, intervention, and postintervention phases to provide the evidence of impact of the training on the target behaviors and ascertain whether utilization rates are sustained over time. In addition, trial results will be analyzed using structured visual analysis, supplemented with statistical analysis appropriate to single-case methodology. RESULTS: While ascertaining the effectiveness of this training protocol, study results will offer new insights into technology-related training approaches for people with brain impairment. Preliminary data collection has been commenced at one supported housing site, with further scoping work continuing to recruit participants from additional sites. CONCLUSIONS: Evaluation evidence will assist in planning for the smart technology set-up as well as training and support services necessary to accompany the provision of new devices and systems. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/10451. PMID- 30409768 TI - Correlations Between Hospitals' Social Media Presence and Reputation Score and Ranking: Cross-Sectional Analysis. AB - BACKGROUND: The US News and World Report reputation score correlates strongly with overall rank in adult and pediatric hospital rankings. Social media affects how information is disseminated to physicians and is used by hospitals as a marketing tool to recruit patients. It is unclear whether the reputation score for adult and children's hospitals relates to social media presence. OBJECTIVE: The objective of our study was to analyze the association between a hospital's social media metrics and the US News 2017-2018 Best Hospital Rankings for adult and children's hospitals. METHODS: We conducted a cross-sectional analysis of the reputation score, total score, and social media metrics (Twitter, Facebook, and Instagram) of hospitals who received at least one subspecialty ranking in the 2017-2018 US News publicly available annual rankings. Regression analysis was employed to analyze the partial correlation coefficients between social media metrics and a hospital's total points (ie, rank) and reputation score for both adult and children's hospitals while controlling for the bed size and time on Twitter. RESULTS: We observed significant correlations for children's hospitals' reputation score and total points with the number of Twitter followers (total points: r=.465, P<.001; reputation: r=.524, P<.001) and Facebook followers (total points: r=.392, P=.002; reputation: r=.518, P<.001). Significant correlations for the adult hospitals reputation score were found with the number of Twitter followers (r=.848, P<.001), number of tweets (r=.535, P<.001), Klout score (r=.242, P=.02), and Facebook followers (r=.743, P<.001). In addition, significant correlations for adult hospitals total points were found with Twitter followers (r=.548, P<.001), number of tweets (r=.358, P<.001), Klout score (r=.203, P=.05), Facebook followers (r=.500, P<.001), and Instagram followers (r=.692, P<.001). CONCLUSIONS: A statistically significant correlation exists between multiple social media metrics and both a hospital's reputation score and total points (ie, overall rank). This association may indicate that a hospital's reputation may be influenced by its social media presence or that the reputation or rank of a hospital drives social media followers. PMID- 30409767 TI - Usability Study of Mainstream Wearable Fitness Devices: Feature Analysis and System Usability Scale Evaluation. AB - BACKGROUND: Wearable devices have the potential to promote a healthy lifestyle because of their real-time data monitoring capabilities. However, device usability is a critical factor that determines whether they will be adopted on a large scale. Usability studies on wearable devices are still scarce. OBJECTIVE: This study aims to compare the functions and attributes of seven mainstream wearable devices and to evaluate their usability. METHODS: The wearable devices selected were the Apple Watch, Samsung Gear S, Fitbit Surge, Jawbone Up3, Mi Band, Huawei Honor B2, and Misfit Shine. A mixed method of feature comparison and a System Usability Scale (SUS) evaluation based on 388 participants was applied; the higher the SUS score, the better the usability of the product. RESULTS: For features, all devices had step counting, an activity timer, and distance recording functions. The Samsung Gear S had a unique sports track recording feature and the Huawei Honor B2 had a unique wireless earphone. The Apple Watch, Samsung Gear S, Jawbone Up3, and Fitbit Surge could measure heart rate. All the devices were able to monitor sleep, except the Apple Watch. For product characteristics, including attributes such as weight, battery life, price, and 22 functions such as step counting, activity time, activity type identification, sleep monitoring, and expandable new features, we found a very weak negative correlation between the SUS scores and price (r=-.10, P=.03) and devices that support expandable new features (r=-.11, P=.02), and a very weak positive correlation between the SUS scores and devices that support the activity type identification function (r=.11, P=.02). The Huawei Honor B2 received the highest score of mean 67.6 (SD 16.1); the lowest Apple Watch score was only 61.4 (SD 14.7). No significant difference was observed among brands. The SUS score had a moderate positive correlation with the user's experience (length of time the device was used) (r=.32, P<.001); participants in the medical and health care industries gave a significantly higher score (mean 61.1, SD 17.9 vs mean 68.7, SD 14.5, P=.03). CONCLUSIONS: The functions of wearable devices tend to be homogeneous and usability is similar across various brands. Overall, Mi Band had the lowest price and the lightest weight. Misfit Shine had the longest battery life and most functions, and participants in the medical and health care industries had the best evaluation of wearable devices. The perceived usability of mainstream wearable devices is unsatisfactory and customer loyalty is not high. A consumer's SUS rating for a wearable device is related to their personal situation instead of the device brand. Device manufacturers should put more effort into developing innovative functions and improving the usability of their products by integrating more cognitive behavior change techniques. PMID- 30409769 TI - Pediatric Inpatient-Status Volume and Cost at Children's and Nonchildren's Hospitals in the United States: 2000-2009. AB - OBJECTIVES: The evolving role of children's hospitals (CHs) in the setting of rising health care costs has not been fully explored. We compared pediatric inpatient discharge volumes and costs by hospital type and examined the impact of care complexity and hospital-level factors on costs. METHODS: A retrospective, cross-sectional study of care between 2000 and 2009 was performed by using the Kids' Inpatient Database. Weighted discharge data were used to generate national estimates for a comparison of inpatient volume, cost, and complexity at CHs and nonchildren's hospitals (NCHs). Linear regression was used to assess how complexity, payer mix, and hospital-level characteristics affected inflation adjusted costs. RESULTS: Between 2000 and 2009, the number of discharges per 1000 children increased from 6.3 to 7.7 at CHs and dropped from 55.4 to 53.3 at NCHs. The proportion of discharges at CHs grew by 6.8% between 2006 and 2009 alone. In 2009, CHs were responsible for 12.6% (95% confidence interval: 10.4%-14.9%) of pediatric discharges and 14.7% of major therapeutic procedures, yet they accounted for 23.0% of inpatient costs. Costs per discharge were significantly higher at CHs than at NCHs for all years (P < .001); however, the increase in costs seen over time was not significant. Care complexity increased during the study period at both CHs and NCH, but it could not be used to fully account for the difference in costs. CONCLUSIONS: National trends reveal a small rise in both the proportion of inpatient discharges and the hospital costs at CHs, with costs being significantly higher at CHs than at NCHs. Research into factors influencing costs and the role of CHs is needed to inform policy and contain costs. PMID- 30409770 TI - HD-Marker: a highly multiplexed and flexible approach for targeted genotyping of more than 10,000 genes in a single-tube assay. AB - Targeted genotyping of transcriptome-scale genetic markers is highly attractive for genetic, ecological, and evolutionary studies, but achieving this goal in a cost-effective manner remains a major challenge, especially for laboratories working on nonmodel organisms. Here, we develop a high-throughput, sequencing based GoldenGate approach (called HD-Marker), which addresses the array-related issues of original GoldenGate methodology and allows for highly multiplexed and flexible targeted genotyping of more than 12,000 loci in a single-tube assay (in contrast to fewer than 3100 in the original GoldenGate assay). We perform extensive analyses to demonstrate the power and performance of HD-Marker on various multiplex levels (296, 795, 1293, and 12,472 genic SNPs) across two sequencing platforms in two nonmodel species (the scallops Chlamys farreri and Patinopecten yessoensis), with extremely high capture rate (98%-99%) and genotyping accuracy (97%-99%). We also demonstrate the potential of HD-Marker for high-throughput targeted genotyping of alternative marker types (e.g., microsatellites and indels). With its remarkable cost-effectiveness (as low as $0.002 per genotype) and high flexibility in choice of multiplex levels and marker types, HD-Marker provides a highly attractive tool over array-based platforms for fulfilling genome/transcriptome-wide targeted genotyping applications, especially in nonmodel organisms. PMID- 30409771 TI - A physical and genetic map of Cannabis sativa identifies extensive rearrangements at the THC/CBD acid synthase loci. AB - Cannabis sativa is widely cultivated for medicinal, food, industrial, and recreational use, but much remains unknown regarding its genetics, including the molecular determinants of cannabinoid content. Here, we describe a combined physical and genetic map derived from a cross between the drug-type strain Purple Kush and the hemp variety "Finola." The map reveals that cannabinoid biosynthesis genes are generally unlinked but that aromatic prenyltransferase (AP), which produces the substrate for THCA and CBDA synthases (THCAS and CBDAS), is tightly linked to a known marker for total cannabinoid content. We further identify the gene encoding CBCA synthase (CBCAS) and characterize its catalytic activity, providing insight into how cannabinoid diversity arises in cannabis. THCAS and CBDAS (which determine the drug vs. hemp chemotype) are contained within large (>250 kb) retrotransposon-rich regions that are highly nonhomologous between drug and hemp-type alleles and are furthermore embedded within ~40 Mb of minimally recombining repetitive DNA. The chromosome structures are similar to those in grains such as wheat, with recombination focused in gene-rich, repeat-depleted regions near chromosome ends. The physical and genetic map should facilitate further dissection of genetic and molecular mechanisms in this commercially and medically important plant. PMID- 30409772 TI - Defining TP53 pioneering capabilities with competitive nucleosome binding assays. AB - Accurate gene expression requires the targeting of transcription factors (TFs) to regulatory sequences often occluded within nucleosomes. The ability to target a transcription factor binding site (TFBS) within a nucleosome has been the defining characteristic for a special class of TFs known as pioneer factors. Recent studies suggest TP53 functions as a pioneer factor that can target its TFBS within nucleosomes, but it remains unclear how TP53 binds to nucleosomal DNA. To comprehensively examine TP53 nucleosome binding we competitively bound TP53 to multiple in vitro formed nucleosomes containing a high or low-affinity TP53 TFBS located at differing translational and rotational positions within the nucleosome. Stable TP53-nucleosome complexes were isolated and quantified using next generation sequencing. Our results demonstrate TP53 binding is limited to nucleosome edges with significant binding inhibition occurring within 50-bp of the nucleosome dyad. Binding site affinity only affects TP53 binding for TFBS located at the same nucleosomal positions, otherwise nucleosome position takes precedence. Furthermore, TP53 has strong non-specific nucleosome binding facilitating its interaction with chromatin. Our in vitro findings were confirmed by examining TP53 induced binding in a cell line model, showing induced binding at nucleosome edges flanked by a nucleosome free region. Overall, our results suggest that the pioneering capabilities of TP53 are driven by non-specific nucleosome binding with specific binding at nucleosome edges. PMID- 30409773 TI - Managing antithrombotic therapy in immune thrombocytopenia: development of the TH2 risk assessment score. PMID- 30409775 TI - Variations in hospital inpatient palliative care service use: a retrospective cohort study. AB - OBJECTIVE: Use of palliative care in hospitals for people at end of life varies. We examined rate and time of in-hospital palliative care use and associated interhospital variations. METHODS: We used admissions from all hospitals in New South Wales, Australia, within a 12-month period, for a cohort of adults who died in 73 public acute care hospitals between July 2010 and June 2014. Receiving palliative care and its timing were based on recorded use. RESULTS: Among 90 696 adults who died, 27% received palliative care, and the care was initiated 7.6 days (mean; SD: 3.3 days) before death. Over the 5-year period, the palliative care rate rose by 58%, varying extent across chronic conditions. The duration of palliative care before death declined by 7%. Patient (demographics, morbidities and service use) and hospital factors (size, location and availability of palliative care unit) explained half of the interhospital variation in outcomes: adjusted IQR in rate and duration of palliative care among hospitals were 23%-39% and 5.2-8.7 days, respectively. Hospitals with higher rates often initiated palliative care earlier (correlation: 0.39; p<0.01). CONCLUSION: Despite an increase over time in the palliative care rate, its initiation was late and of brief duration. Palliative care use was associated with patient and hospital characteristics; however, half of the between hospital variation remained unexplained. The observed suboptimal practices and variability indicate the need for expanded and standardised use of palliative care supported by assessment tools, service enhancement and protocols. PMID- 30409774 TI - Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis. AB - OBJECTIVE: To provide a complete toxicity profile, toxicity spectrum, and a safety ranking of immune checkpoint inhibitor (ICI) drugs for treatment of cancer. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Electronic databases (PubMed, Embase, Cochrane Library, and Web of Science) were systematically searched to include relevant studies published in English between January 2007 and February 2018. REVIEW METHODS: Only head-to-head phase II and III randomised controlled trials comparing any two or three of the following treatments or different doses of the same ICI drug were included: nivolumab, pembrolizumab, ipilimumab, tremelimumab, atezolizumab, conventional therapy (chemotherapy, targeted therapy, and their combinations), two ICI drugs, or one ICI drug with conventional therapy. Eligible studies must have reported site, organ, or system level data on treatment related adverse events. High quality, single arm trials and placebo controlled trials on ICI drugs were selected to establish a validation group. RESULTS: 36 head-to-head phase II and III randomised trials (n=15 370) were included. The general safety of ICI drugs ranked from high to low for all adverse events was as follows: atezolizumab (probability 76%, pooled incidence 66.4%), nivolumab (56%, 71.8%), pembrolizumab (55%, 75.1%), ipilimumab (55%, 86.8%), and tremelimumab (54%, not applicable). The general safety of ICI drugs ranked from high to low for severe or life threatening adverse events was as follows: atezolizumab (49%, 15.1%), nivolumab (46%, 14.1%), pembrolizumab (72%, 19.8%), ipilimumab (51%, 28.6%), and tremelimumab (28%, not applicable). Compared with conventional therapy, treatment related adverse events for ICI drugs occurred mainly in the skin, endocrine, hepatic, and pulmonary systems. Taking one ICI drug was generally safer than taking two ICI drugs or one ICI drug with conventional therapy. Among the five ICI drugs, atezolizumab had the highest risk of hypothyroidism, nausea, and vomiting. The predominant treatment-related adverse events for pembrolizumab were arthralgia, pneumonitis, and hepatic toxicities. The main treatment-related adverse events for ipilimumab were skin, gastrointestinal, and renal toxicities. Nivolumab had a narrow and mild toxicity spectrum, mainly causing endocrine toxicities. Integrated evidence from the pooled incidences, subgroup, and sensitivity analyses implied that nivolumab is the best option in terms of safety, especially for the treatment of lung cancer. CONCLUSIONS: Compared with other ICI drugs used to treat cancer, atezolizumab had the best safety profile in general, and nivolumab had the best safety profile in lung cancer when taking an integrated approach. The safety ranking of treatments based on ICI drugs is modulated by specific treatment-related adverse events. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017082553. PMID- 30409777 TI - New Classification for Myeloproliferative Neoplasms. AB - Myeloproliferative neoplasms have traditionally been split into three categories, but a new study that analyzed mutations in more than 2,000 patients suggests dividing the illness into eight subtypes. Using statistical models that incorporated clinical and genomic data, researchers accurately predicted overall survival and the likelihood of disease progression. PMID- 30409776 TI - Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Non-randomized, Open-label, Phase 2 Study. AB - BACKGROUND: Preclinical models showed that blocking PD-1/PD-L1 pathways enhanced anti-leukemic responses. Azacitidine up-regulates PD-1 and interferon-gamma signaling. METHODS: In this single arm trial, patients with relapsed/refractory (R/R) AML were treated with azacitidine 75mg/m2 Days 1-7 intravenously/subcutaneously with nivolumab 3mg/kg intravenously on Day 1 and 14, every 4-6 weeks. FINDINGS: Seventy-patients were treated. The median age was 70 years (range,22-90). The median number of prior therapies was 2 (range,1-7). The overall response rate (ORR) was 33% including 15 (22%) complete remission (CR)/complete remission with insufficient recovery of counts (CRi), 1 partial response, and 7 patients with hematologic improvement (HI) maintained >6 months. Six-patients (9%) had stable disease >6 months. The ORR was 58% and 22%, in HMA naive (n=25) and HMA pre-treated (n=45) patients, respectively. Grade 3-4 immune related adverse events occurred in 8 (11%) patients. Pretherapy bone marrow and peripheral blood CD3 and CD8 were significantly predictive for response on flow cytometry. CTLA-4 was significantly up-regulated on CD4+Teff in non-responders after 2 and 4 doses of nivolumab. INTERPRETATION: Azacitidine-nivolumab therapy produced an encouraging response rate and overall survival in patients with R/R AML, particularly in HMA-naive and Salvage-1 patients. Pretherapy bone marrow aspirate and peripheral blood CD3 percentage may be biomarkers for patient selection. PMID- 30409778 TI - Pembro Ups Survival in PD-L1-positive HNSCC. AB - In a phase III trial, first-line treatment with single-agent pembrolizumab led to deep and durable responses among patients with head and neck tumors that expressed high levels of PD-L1. PMID- 30409779 TI - Doctors' wellbeing-is anybody listening? PMID- 30409780 TI - Sex Differences in Coronary Microvascular Function in Individuals with Type 2 Diabetes Mellitus. AB - Cardiovascular (CV) disease fatality rates are higher for women compared to men with diabetes despite lower rates of obstructive coronary artery disease (CAD). Impaired coronary flow reserve (CFR), the ratio of adenosine-stimulated to rest myocardial blood flow (MBF), is an indicator of coronary microvascular dysfunction and predicts major adverse CV events. We performed a post-hoc analysis to determine if there was a sex disparity in coronary microvascular dysfunction among 46 men and 27 women with well-controlled Type 2 DM and without clinical evidence of obstructive CAD. We found that women had a higher rest MBF, lower CFR, and worse diastolic function compared to men. Additionally, rest MBF was positively correlated with worse diastolic function in women. We previously showed mineralocorticoid blockade improved CFR in men and women with Type 2 DM, implicating aldosterone in the pathophysiology of coronary microvascular dysfunction. We therefore examined aldosterone levels and found that women had larger increases in aldosterone in response to an angiotensin-II infusion than did men. In conclusion, among individuals with Type 2 DM and good cardiometabolic control, women had worse myocardial perfusion and diastolic function compared to men. The greater aldosterone responsivity in women may be a mechanism for this sex effect. PMID- 30409781 TI - Risk Factor Modeling for Cardiovascular Disease in Type I Diabetes in the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study: A Comparison to the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study. AB - In a recent Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) report, mean HbA1c was the strongest predictor of cardiovascular disease (CVD) after age. In DCCT/EDIC, mean diabetes duration was 6 (median 4) years at baseline and those with high blood pressure or cholesterol were excluded. We now replicate these analyses in the Pittsburgh Epidemiology of Diabetes Complications (EDC) prospective cohort study of childhood-onset (<17 years) type 1 diabetes, with similar age (mean 27 years in both studies) but longer diabetes duration (mean 19, median 18 years) and no CVD risk factor exclusion at baseline. CVD incidence (CVD death, myocardial infarction, stroke, revascularization, angina, or ischemic ECG) was associated with diabetes duration, most recent albumin excretion rate (AER), updated mean triglycerides, baseline hypertension, baseline LDLc, and most recent HbA1c. Major atherosclerotic cardiovascular events (MACE) (CVD death, myocardial infarction, or stroke) were associated with diabetes duration, most recent AER, baseline SBP, baseline smoking, and updated mean HbA1c. Compared to DCCT/EDIC, traditional risk factors similarly predict CVD, however AER predominates in EDC and HbA1c in DCCT/EDIC. Thus, the relative impact of HbA1c and kidney disease in type 1 diabetes varies according to diabetes duration. PMID- 30409782 TI - TGR5 Activation Promotes Stimulus-Secretion Coupling of Pancreatic Beta-Cells via a PKA-Dependent Pathway. AB - The Takeda-G-protein-receptor-5 (TGR5) mediates physiological actions of bile acids. Since it was shown that TGR5 is expressed in pancreatic tissue, a direct TGR5 activation in beta-cells is currently postulated and discussed. The present study reveals that oleanolic acid (OLA) affects murine beta-cell function by TGR5 activation. Both, a Galphas inhibitor and an inhibitor of adenylyl cyclase (AC) prevented stimulating effects of OLA. Accordingly, OLA augmented the intracellular cAMP concentration. OLA and two well-established TGR5 agonists, RG239 and tauroursodeoxycholic acid (TUDCA), acutely promoted stimulus-secretion coupling (SSC). OLA reduced ATP-dependent K+ (KATP) current and elevated current through Ca2+ channels. Accordingly, in mouse and human beta-cells TGR5 ligands increased the cytosolic Ca2+ concentration by stimulating Ca2+ influx. Higher OLA concentrations evoked a dual reaction, probably due to activation of a counter regulating pathway. Protein kinase A (PKA) was identified as a downstream target of TGR5 activation. In contrast, inhibition of phospholipase C and phosphoinositide-3-kinase did not prevent stimulating effects of OLA. Involvement of exchange-protein-directly-activated-by-cAMP 2 (Epac2) or farnesoid-X-receptor (FXR) was ruled out by experiments with knockout mice. The proposed pathway was not influenced by local GLP-1 secretion from alpha-cells, shown by experiments with MIN6 cells, and a GLP-1 receptor antagonist. In summary, these data clearly demonstrate that activation of TGR5 in beta-cells stimulates insulin secretion via an AC/cAMP/PKA-dependent pathway which is supposed to interfere with SSC by affecting KATP and Ca2+ currents and thus membrane potential. PMID- 30409783 TI - A Network Analysis of Biomarkers for Type 2 Diabetes. AB - Numerous studies have investigated individual biomarkers in relation to risk of type 2 diabetes. However, few have considered the interconnectivity of these biomarkers in the etiology of diabetes as well as the potential changes in the biomarker correlation network during diabetes development. We conducted a secondary analysis of 27 plasma biomarkers representing glucose metabolism, inflammation, adipokines, endothelial dysfunction, insulin-like growth factor axis and iron store plus age and BMI at blood collection from an existing case control study nested in the Nurses' Health Study, including 1,303 incident diabetes cases and 1,627 healthy women. A correlation network was constructed based on pairwise Spearman correlations of the above factors that were statistically different between cases and non-cases using permutation tests (p<0.0005). We further evaluated the network structure separately among diabetes cases diagnosed <5 years, 5-10 years, and >10 years after blood collection versus non-cases. Although pairwise biomarker correlations tended to have similar directions comparing diabetes cases to non-cases, most correlations were stronger in non-cases than in cases, with the largest differences observed for the insulin/HbA1c and leptin/adiponectin correlations. Leptin and soluble leptin receptor were two hubs of the network, with large numbers of different correlations with other biomarkers in cases versus non-cases. When examining the correlation network by timing of diabetes onset, there were more perturbations in the network for cases diagnosed >10 years versus <5 years after blood collection, with consistent differential correlations of insulin and HbA1c. C-peptide was the most highly connected node in the early-stage network, whereas leptin was the hub for mid- or late-stage networks. Our results suggest that perturbations of the diabetes-related biomarker network may occur decades prior to clinical recognition. In addition to the persistent dysregulation between insulin and HbA1c, our results highlight the central role of the leptin system in diabetes development. PMID- 30409786 TI - CT scan shortage endangers angina patients, say radiologists. PMID- 30409784 TI - Epidermal gammadelta T cells originate from yolk sac hematopoiesis and clonally self-renew in the adult. AB - The murine epidermis harbors two immune cell lineages, Langerhans cells (LCs) and gammadelta T cells known as dendritic epidermal T cells (DETCs). LCs develop from both early yolk sac (YS) progenitors and fetal liver monocytes before locally self-renewing in the adult. For DETCs, the mechanisms of homeostatic maintenance and their hematopoietic origin are largely unknown. Here, we exploited multicolor fate mapping systems to reveal that DETCs slowly turn over at steady state. Like for LCs, homeostatic maintenance of DETCs is achieved by clonal expansion of tissue-resident cells assembled in proliferative units. The same mechanism, albeit accelerated, facilitates DETC replenishment upon injury. Hematopoietic lineage tracing uncovered that DETCs are established independently of definitive hematopoietic stem cells and instead originate from YS hematopoiesis, again reminiscent of LCs. DETCs thus resemble LCs concerning their maintenance, replenishment mechanisms, and hematopoietic development, suggesting that the epidermal microenvironment exerts a lineage-independent influence on the initial seeding and homeostatic maintenance of its resident immune cells. PMID- 30409785 TI - Nucleobase carbonyl groups are poor Mg2+ inner-sphere binders but excellent monovalent ion binders - A critical PDB survey. AB - Precise knowledge of Mg2+ inner-sphere binding site characteristics is vital for understanding the structure and function of nucleic acid systems. Unfortunately, the PDB, that represents the main source of Mg2+ binding sites, contains a significant number of ion assignment issues that significantly blur our understanding of the functions of these ions. Here, following a preceding study devoted to Mg2+ binding to nucleobase nitrogens, we surveyed PDB nucleic acid crystallographic structures with resolutions < 2.9 A to classify the Mg2+ inner sphere binding patterns to nucleotide carbonyl, ribose hydroxyl, cyclic ether and phosphodiester oxygen atoms to derive a set of "prior-knowledge" nucleobase Mg2+ binding sites. We report that crystallographic examples of trustworthy nucleobase Mg2+ binding sites are fewer than expected given that many of those bind misidentified Na+ or K+ We also emphasize that binding of Na+ and K+ to nucleic acids is much more frequent than anticipated. Overall, we provide crystallographic evidence that nucleobases are poor inner-sphere Mg2+ binders but good binders for monovalent ions. Based on strict stereochemical criteria, we propose an extended set of guidelines designed to help in the assignment and validation of ions directly contacting nucleobase and ribose atoms. These guidelines should help in the interpretation of X-ray and cryo-EM solvent density maps. When borderline metal ion stereochemistry is observed, alternative placement of Na+, K+, or Ca2+ should be considered. We also critically examine the use of lanthanides (Yb3+, Tb3+) as Mg2+ substitutes in crystallography experiments. PMID- 30409789 TI - Epithelial Shaping by Diverse Apical Extracellular Matrices Requires the Nidogen Domain Protein DEX-1 in Caenorhabditis elegans. AB - The body's external surfaces and the insides of biological tubes, like the vascular system, are lined by a lipid, glycoprotein-, and glycosaminoglycan-rich apical extracellular matrix (aECM). aECMs are the body's first line of defense against infectious agents and promote tissue integrity and morphogenesis, but are poorly described relative to basement membranes and stromal ECMs. While some aECM components, such as zona pellucida domain (ZP) proteins, have been identified, little is known regarding the overall composition of the aECM or the mechanisms by which different aECM components work together to shape epithelial tissues. In Caenorhabditis elegans, external epithelia develop in the context of an ill defined ZP-containing aECM that precedes secretion of the collagenous cuticle. C. elegans has 43 genes that encode at least 65 unique ZP proteins, and we show that some of these comprise distinct pre-cuticle aECMs in the embryo. Previously, the nidogen- and EGF-domain protein DEX-1 was shown to anchor dendrites to the C. elegans nose tip in concert with the ZP protein DYF-7. Here, we identified a new, strong loss-of-function allele of dex-1, cs201 dex-1 mutants die as L1 larvae and have a variety of tissue distortion phenotypes, including excretory defects, pharyngeal ingression, alae defects, and a short and fat body shape, that strongly resemble those of genes encoding ZP proteins. DEX-1 localizes to ZP containing aECMs in the tissues that show defects in dex-1 mutants. Our studies suggest that DEX-1 is a component of multiple distinct embryonic aECMs that shape developing epithelia, and a potential partner of multiple ZP proteins. PMID- 30409788 TI - Epidermal Remodeling in Caenorhabditis elegans Dauers Requires the Nidogen Domain Protein DEX-1. AB - Phenotypic plasticity is a critical component of an organism's ability to thrive in a changing environment. The free-living nematode, Caenorhabditis elegans, adapts to unfavorable environmental conditions by pausing reproductive development and entering a stress-resistant larval stage known as dauer. The transition into dauer is marked by vast morphological changes - including remodeling of epidermis, neurons and muscle. Though many of these dauer-specific traits have been described, the molecular basis of dauer-specific remodeling is still poorly understood. Here we show that the nidogen-domain containing protein DEX-1 facilitates stage-specific tissue remodeling during dauer morphogenesis. DEX-1 was previously shown to regulate sensory dendrite formation during embryogenesis. We find that DEX-1 is also required for proper remodeling of the stem cell-like epidermal seam cells. dex-1 mutant dauers lack distinct lateral cuticular alae during dauer and have increased sensitivity to sodium dodecyl sulfate (SDS). Furthermore, we find that DEX-1 is required for proper dauer mobility. We show that DEX-1 is secreted from the seam cells during dauer, but acts locally in a cell autonomous manner. We find that dex-1 expression during dauer is regulated through DAF-16/FOXO-mediated transcriptional activation. Finally, we show that dex-1 acts with a family of zona pellucida domain-encoding genes to regulate dauer-specific epidermal remodeling. Taken together, our data indicate that DEX-1 is an extracellular matrix component that plays a central role in C. elegans epidermal remodeling during dauer. PMID- 30409787 TI - Different agonists induce distinct single-channel conductance states in TRPV1 channels. AB - The TRPV1 ion channel is a membrane protein that is expressed in primary afferent nociceptors, where it is activated by a diverse array of stimuli. Our prior work has shown that this channel is activated by lysophosphatidic acid (LPA), an unsaturated lysophospholipid that is produced endogenously and released under certain pathophysiological conditions, resulting in the sensation of pain. Macroscopic currents activated by saturating concentrations of LPA applied to excised membrane patches are larger in magnitude than those activated by saturating concentrations of capsaicin, which causes near-maximal TRPV1 open probability. Here we show that activation of TRPV1 by LPA is associated with a higher single-channel conductance than activation by capsaicin. We also observe that the effects of LPA on TRPV1 are not caused by an increase in the surface charge nor are they mimicked by a structurally similar lipid, ruling out the contribution of change in membrane properties. Finally, we demonstrate that the effects of LPA on the unitary conductance of TRPV1 depend upon the presence of a positively charged residue in the C terminus of the channel, suggesting that LPA induces a distinct conformational change. PMID- 30409790 TI - Lysosome Membrane Permeabilization and Disruption of the Molecular Target of Rapamycin (mTOR)-Lysosome Interaction Are Associated with the Inhibition of Lung Cancer Cell Proliferation by a Chloroquinoline Analog. AB - Lysosomes degrade cellular proteins and organelles and regulate cell signaling by providing a surface for the formation of critical protein complexes, notably molecular target of rapamycin (mTOR) complex 1 (mTORC1). Striking differences in the lysosomes of cancer versus normal cells suggest that they could be targets for drug development. Although the lysomotropic drugs chloroquine (CQ) and hydroxychloroquine (HCQ) have been widely investigated, studies have focused on their ability to inhibit autophagy. We synthesized a novel compound, called EAD1, which is structurally related to CQ but is a 14-fold more potent inhibitor of cell proliferation. Here we find that EAD1 causes rapid relocation, membrane permeabilization (LMP), and deacidification of lysosomes, and it induces apoptosis and irreversibly blocks proliferation of human lung cancer H460, H520, H1299, HCC827, and H1703 cells. EAD1 causes dissociation of mTOR from lysosomes and increases mTOR's perinuclear versus cytoplasmic localization, changes previously shown to inactivate mTORC1. The effect on mTOR was not seen with HCQ, even at >10-fold greater concentrations. Phosphorylation of a downstream target of mTORC1, ribosomal protein S6, was inhibited by EAD1. Although EAD1 also inhibited autophagy, it retained full antiproliferative activity in autophagy deficient H1650 lung cancer cells, which have a biallelic deletion of Atg7, and in H460 Atg7-knockout cells. As Atg7 is critical for the canonical autophagy pathway, it is likely that inhibition of autophagy is not how EAD1 inhibits cell proliferation. Further studies are needed to determine the relationship of LMP to mTORC1 disruption and their relative contributions to drug-induced cell death. These studies support the lysosome as an underexplored target for new drug development. PMID- 30409791 TI - Rat Organic Cation Transporter 1 Contains Three Binding Sites for Substrate 1 Methyl-4-phenylpyridinium per Monomer. AB - Organic cation transporters OCT1 (SLC22A1) and OCT2 (SLC22A2) are critically involved in absorption and excretion of diverse cationic drugs. Because drug-drug interactions at these transporters may induce adverse drug effects in patients, in vitro testing for interaction with the human transporters during drug development is mandatory. Recent data performed with rat OCT1 (rOCT1) suggest that currently performed in vitro tests assuming one polyspecific binding site are insufficient. Here we measured binding and transport of model substrate 1 methyl-4-phenylpyridinium+ (MPP+) by cell-free-expressed fusion proteins of rOCT1 and various rOCT1 mutants with green fluorescent protein that were reconstituted into nanodiscs or proteoliposomes. The nanodiscs were formed with major scaffold protein MSP and different phospholipids whereas the proteoliposomes were formed with a mixture of cholesterol, phosphatidylserine and phosphatidylcholine. In nanodiscs formed with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine or cholesterol, phosphatidylserine and phosphatidylcholine two low-affinity MPP+ binding sites and one high-affinity MPP+ binding site per transporter monomer were determined. Mutagenesis revealed that tryptophan 218 and aspartate 475 in neighboring positions in the modeled outward-open cleft contribute to one low affinity binding site whereas arginine 440 located distantly in the cleft is critical for MPP+ binding to another low-affinity site. Comparing MPP+ binding with MPP+ transport suggests that the low-affinity sites are involved in MPP+ transport whereas high-affinity MPP+ binding influences transport allosterically. The data provide a rationale for future reliable, more sophisticated in vitro testing and for the generation of pharmacophore models with high predictive power. They will be helpful to interprete future crystal structures. PMID- 30409792 TI - Age and the Risk of Paclitaxel-Induced Neuropathy in Women with Early-Stage Breast Cancer (Alliance A151411): Results from 1,881 Patients from Cancer and Leukemia Group B (CALGB) 40101. AB - PURPOSE: A few previous studies report a direct relationship between older age and chemotherapy-induced neuropathy. This study further evaluated this adverse event's age-based risk. METHODS: CALGB 40101 investigated adjuvant paclitaxel (80 mg/m2 once per week or 175 mg/m2 every 2 weeks) in patients with breast cancer and served as a platform for the current study that investigated age-based differences in neuropathy. Grade 2 or worse neuropathy, as per Common Terminology Criteria for Adverse Events version 4, was the primary endpoint; patients were assessed at baseline, every 6 months for 2 years, and then annually for 15 years. RESULTS: Among these 1,881 patients, 230 were 65 years of age or older, 556 were 55-64 years, and 1,095 were younger than 55; 1,226 neuropathy events (commonly grade 1 or 2) were reported in 65% of the cohort. The number of grade 2 or worse events was 63 (27%), 155 (28%), and 266 (24%) within respective age groups (p = .14). In univariate analysis, only motor neuropathy had a higher age-based incidence: 19 (8%), 43 (8%), and 60 (5%), respectively (p = .04); in multivariate analyses, this association was no longer statistically significant. Other endpoints, such as time to onset of neuropathy (time from trial enrollment to neuropathy development) and time to improvement (time from maximal grade sensory neuropathy to a one-category improvement), showed no statistically significant age-based differences. In contrast, obesity was associated with neuropathy, and every 2-week paclitaxel was associated with trends toward neuropathy. CONCLUSION: Although paclitaxel-induced neuropathy is common, older age is not an independent risk factor. Clinical trial identification number. NCT00041119 (CALGB 40101). IMPLICATIONS FOR PRACTICE: Age alone is not an independent risk factor for paclitaxel-induced neuropathy. PMID- 30409794 TI - Detection and characterization of homozygosity of mutated CALR by copy neutral loss of heterozygosity in myeloproliferative neoplasms among cases with high CALR mutation loads or with progressive disease. PMID- 30409793 TI - Relevance of Reference Centers in Sarcoma Care and Quality Item Evaluation: Results from the Prospective Registry of the Spanish Group for Research in Sarcoma (GEIS). AB - BACKGROUND: Reference centers (RCs) are a key point for improving the survival of patients with soft-tissue sarcomas (STS). The aim of this study was to evaluate selected items in the management of patients with STS, comparing results between RC and local hospitals (LHs). MATERIALS AND METHODS: Diagnostic and therapeutic data from patients diagnosed between January 2004 and December 2011 were collected. Correlation with outcome was performed. RESULTS: A total of 622 sarcomas were analyzed, with a median follow-up of 40 months. Imaging of primary tumor preoperatively (yes vs. no) correlated with a higher probability of free surgical margins (77.4% versus 53.7%; p = .006). The provenance of the biopsy (RC vs. LH) significantly affected relapse-free survival (RFS; 3-year RFS 66% vs. 46%, respectively; p = .019). Likewise, 3-year RFS was significantly worse in cases with infiltrated (55.6%) or unknown (43.4%) microscopic surgical margins compared with free margins (63.6%; p < .001). Patients managed by RCs had a better 3-year overall survival compared with those managed by LHs (82% vs. 70.4%, respectively; p = .003). Perioperative chemotherapy in high-risk STS, more frequently administered in RCs than in LHs, resulted in significantly better 3 year RFS (66% vs. 44%; p = .011). In addition, patients with stage IV disease treated in RCs survived significantly longer compared with those in LHs (30.4 months vs. 18.5 months; p = .036). CONCLUSION: Our series indicate that selected quality-of-care items were accomplished better by RCs over LHs, all with significant prognostic value in patients with STS. Early referral to an RC should be mandatory if the aim is to improve the survival of patients with STS. IMPLICATIONS FOR PRACTICE: This prospective study in patients diagnosed with soft tissue sarcoma shows the prognostic impact of reference centers in the management of these patients. The magnitude of this impact encompasses all steps of the process, from the initial management (performing diagnostic biopsy) to the advanced disease setting. This is the first prospective evidence showing improvement in outcomes of patients with metastatic disease when they are managed in centers with expertise. This study provides extra data supporting referral of patients with sarcoma to reference centers. PMID- 30409795 TI - Gastrointestinal iron excretion and reversal of iron excess in a mouse model of inherited iron excess. AB - The current paradigm in the field of mammalian iron biology states that body iron levels are determined by dietary iron absorption, not by iron excretion. Iron absorption is a highly regulated process influenced by iron levels and other factors. Iron excretion is believed to occur at a basal rate irrespective of iron levels and is associated with processes such as turnover of intestinal epithelium, blood loss, and exfoliation of dead skin. Here we explore iron excretion in a mouse model of iron excess due to inherited transferrin deficiency. Iron excess in this model is attributed to impaired regulation of iron absorption leading to excessive dietary iron uptake. Pharmacologic correction of transferrin deficiency not only normalized iron absorption rates and halted progression of iron excess but also reversed body iron excess. Transferrin treatment did not alter the half-life of 59Fe in mutant mice. 59Fe based studies indicated that most iron was excreted via the gastrointestinal tract and suggested that iron-loaded mutant mice had increased rates of iron excretion. Direct measurement of urinary iron levels agreed with 59Fe-based predictions that urinary iron levels were increased in untreated mutant mice. Fecal ferritin levels were also increased in mutant mice relative to wild-type mice. Overall, these data suggest that mice have a significant capacity for iron excretion. We propose that further investigation into iron excretion is warranted in this and other models of perturbed iron homeostasis, as pharmacologic targeting of iron excretion may represent a novel means of treatment for diseases of iron excess. PMID- 30409796 TI - The sympathomimetic agonist mirabegron did not lower JAK2-V617F allele burden, but restored nestin-positive cells and reduced reticulin fibrosis in patients with myeloproliferative neoplasms: results of phase 2 study SAKK 33/14. AB - The beta-3 sympathomimetic agonist BRL37344 restored nestin-positive cells within the stem cell niche, and thereby normalized blood counts and improved myelofibrosis in a mouse model of JAK2-V617F positive myeloproliferative neoplasms. We therefore tested the effectiveness of mirabegron, a beta-3 sympathomimetic agonist, in a phase II trial including 39 JAK2-V617F positive MPN with a mutant allele burden >20%. Treatment consisted of mirabegron 50 mg daily for 24 weeks. The primary endpoint, reduction of the JAK2-V617F allele burden >=50%, was not reached in any of the patients. One patient achieved a 25% reduction in JAK2-V617F allele burden by 24 weeks. A small subgroup of patients showed hematological improvement. As a side study, bone marrow biopsies were evaluated in 20 patients.We found an increase in the nestin+ cells from a median of 1.09 (interquartile range 0.38-3.27)/mm2 to 3.95 (interquartile range 1.98 8.79)/mm2 (p<0.0001) and a slight decrease of reticulin fibrosis from a median grade of 1.0 (interquartile range 0-3) to 0.5 (interquartile range 0-2) (p=0.01) between start and end of mirabegron treatment. Despite the fact that the primary endpoint of reducing JAK2-V617F allele burden was not reached, the observed effects on nestin+ MSCs and reticulin fibrosis is encouraging and shows that mirabegron can modify the microenvironment where the JAK2-mutant stem cells are maintained. PMID- 30409797 TI - A new BCR-ABL1 Drosophila model as a powerful tool to elucidate pathogenesis and progression of chronic myeloid leukemia. AB - The oncoprotein BCR-ABL1 triggers Chronic Myeloid Leukemia. It is clear that the disease relies on the constitutive BCR-ABL1 kinase activity, but not all the interactors and regulators of the oncoprotein are known. We describe and validate a Drosophila leukemia model based on inducible human BCR-ABL1 expression controlled by tissue specific promoters and thought as a versatile tool to perform genetic screens. BCR-ABL1 expression in the developing eye interferes with ommatidia differentiation and expression in the hematopoietic precursors increases the number of circulating blood cells. We show that BCR-ABL1 interferes with the pathway of endogenous dAbl with which it shares the target protein Ena. Loss of function of ena or Dab, an upstream regulator of dAbl, respectively suppresses or enhances both the BCR-ABL1 dependent phenotypes. Importantly, in patients with leukemia decrease of human Dab1 and Dab2 expression correlates with a more severe disease and Dab1 expression reduces the proliferation of leukemia cells. Globally, these observations validate our Drosophila model that promises to be an excellent system to perform unbiased genetic screens aimed at identifying new BCR-ABL1 interactors and regulators to better elucidate the mechanism of leukemia onset and progression. PMID- 30409798 TI - Phase 1/2 trial of cladribine, high-dose cytarabine, mitoxantrone, and G-CSF with dose-escalated mitoxantrone for relapsed/refractory acute myeloid leukemia or other high-grade myeloid neoplasms. PMID- 30409799 TI - miRNAs involvement in the pathogenesis of Richter's syndrome. AB - Richter syndrome represents the transformation of the most frequent type of leukemia, chronic lymphocytic leukemia into an aggressive lymphoma. Patients with Richter syndrome have limited response to therapies and dismal survival. The underlying mechanisms of transformation are insufficiently understood and there is a major lack of knowledge regarding the roles of microRNAs that have already proved to be causative for most cases of chronic lymphocytic leukemia. Here, by using four types of genomic platforms and independent sets of patients from three institutions, we identified microRNAs involved in the transformation of chronic lymphocytic leukemia to Richter syndrome. The expression signature is composed of miR-21, miR-150, miR-146b and miR-181b, with confirmed targets significantly enriched in pathways involved in cancer, immunity and inflammation. In addition, we demonstrated that genomic alterations may account for microRNA deregulation in a subset of Richter syndrome cases. Furthermore, network analysis showed that Richter transformation leads to a complete rearrangement, resulting in a highly connected microRNA network. Functionally, ectopic overexpression of miR-21 increased proliferation of malignant B-cells in multiple assays, while miR-150 and miR-26a are downregulated in a chronic lymphocytic leukemia xenogeneic mouse transplantation model. Together, our results suggest that Richter transformation is associated with significant expression and genomic loci alterations of microRNAs involved in both malignancy and immunity. PMID- 30409800 TI - Emergence of phytoplankton patchiness at small scales in mild turbulence. AB - Phytoplankton often encounter turbulence in their habitat. As most toxic phytoplankton species are motile, resolving the interplay of motility and turbulence has fundamental repercussions on our understanding of their own ecology and of the entire ecosystems they inhabit. The spatial distribution of motile phytoplankton cells exhibits patchiness at distances of decimeter to millimeter scales for numerous species with different motility strategies. The explanation of this general phenomenon remains challenging. Furthermore, hydrodynamic cell-cell interactions, which grow more relevant as the density in the patches increases, have been so far ignored. Here, we combine particle simulations and continuum theory to study the emergence of patchiness in motile microorganisms in three dimensions. By addressing the combined effects of motility, cell-cell interaction, and turbulent flow conditions, we uncover a general mechanism: The coupling of cell-cell interactions to the turbulent dynamics favors the formation of dense patches. Identification of the important length and time scales, independent from the motility mode, allows us to elucidate a general physical mechanism underpinning the emergence of patchiness. Our results shed light on the dynamical characteristics necessary for the formation of patchiness and complement current efforts to unravel planktonic ecological interactions. PMID- 30409802 TI - Comparative genomics reveals the molecular determinants of rapid growth of the cyanobacterium Synechococcus elongatus UTEX 2973. AB - Cyanobacteria are emerging as attractive organisms for sustainable bioproduction. We previously described Synechococcus elongatus UTEX 2973 as the fastest growing cyanobacterium known. Synechococcus 2973 exhibits high light tolerance and an increased photosynthetic rate and produces biomass at three times the rate of its close relative, the model strain Synechococcus elongatus 7942. The two strains differ at 55 genetic loci, and some of these loci must contain the genetic determinants of rapid photoautotrophic growth and improved photosynthetic rate. Using CRISPR/Cpf1, we performed a comprehensive mutational analysis of Synechococcus 2973 and identified three specific genes, atpA, ppnK, and rpaA, with SNPs that confer rapid growth. The fast-growth-associated allele of each gene was then used to replace the wild-type alleles in Synechococcus 7942. Upon incorporation, each allele successively increased the growth rate of Synechococcus 7942; remarkably, inclusion of all three alleles drastically reduced the doubling time from 6.8 to 2.3 hours. Further analysis revealed that our engineering effort doubled the photosynthetic productivity of Synechococcus 7942. We also determined that the fast-growth-associated allele of atpA yielded an ATP synthase with higher specific activity, while that of ppnK encoded a NAD+ kinase with significantly improved kinetics. The rpaA SNPs cause broad changes in the transcriptional profile, as this gene is the master output regulator of the circadian clock. This pioneering study has revealed the molecular basis for rapid growth, demonstrating that limited genetic changes can dramatically improve the growth rate of a microbe by as much as threefold. PMID- 30409801 TI - Cell size control driven by the circadian clock and environment in cyanobacteria. AB - How cells maintain their size has been extensively studied under constant conditions. In the wild, however, cells rarely experience constant environments. Here, we examine how the 24-h circadian clock and environmental cycles modulate cell size control and division timings in the cyanobacterium Synechococcus elongatus using single-cell time-lapse microscopy. Under constant light, wild type cells follow an apparent sizer-like principle. Closer inspection reveals that the clock generates two subpopulations, with cells born in the subjective day following different division rules from cells born in subjective night. A stochastic model explains how this behavior emerges from the interaction of cell size control with the clock. We demonstrate that the clock continuously modulates the probability of cell division throughout day and night, rather than solely applying an on-off gate to division, as previously proposed. Iterating between modeling and experiments, we go on to identify an effective coupling of the division rate to time of day through the combined effects of the environment and the clock on cell division. Under naturally graded light-dark cycles, this coupling narrows the time window of cell divisions and shifts divisions away from when light levels are low and cell growth is reduced. Our analysis allows us to disentangle, and predict the effects of, the complex interactions between the environment, clock, and cell size control. PMID- 30409804 TI - Quantifying reputation and success in art. AB - In areas of human activity where performance is difficult to quantify in an objective fashion, reputation and networks of influence play a key role in determining access to resources and rewards. To understand the role of these factors, we reconstructed the exhibition history of half a million artists, mapping out the coexhibition network that captures the movement of art between institutions. Centrality within this network captured institutional prestige, allowing us to explore the career trajectory of individual artists in terms of access to coveted institutions. Early access to prestigious central institutions offered life-long access to high-prestige venues and reduced dropout rate. By contrast, starting at the network periphery resulted in a high dropout rate, limiting access to central institutions. A Markov model predicts the career trajectory of individual artists and documents the strong path and history dependence of valuation in art. PMID- 30409803 TI - A small single-domain protein folds through the same pathway on and off the ribosome. AB - In vivo, proteins fold and function in a complex environment subject to many stresses that can modulate a protein's energy landscape. One aspect of the environment pertinent to protein folding is the ribosome, since proteins have the opportunity to fold while still bound to the ribosome during translation. We use a combination of force and chemical denaturant (chemomechanical unfolding), as well as point mutations, to characterize the folding mechanism of the src SH3 domain both as a stalled ribosome nascent chain and free in solution. Our results indicate that src SH3 folds through the same pathway on and off the ribosome. Molecular simulations also indicate that the ribosome does not affect the folding pathway for this small protein. Taken together, we conclude that the ribosome does not alter the folding mechanism of this small protein. These results, if general, suggest the ribosome may exert a bigger influence on the folding of multidomain proteins or protein domains that can partially fold before the entire domain sequence is outside the ribosome exit tunnel. PMID- 30409805 TI - E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator. AB - Junctophilin-2 (JP2) is a structural protein required for normal excitation contraction (E-C) coupling. Following cardiac stress, JP2 is cleaved by Ca2+ dependent protease calpain, which disrupts the E-C coupling ultrastructural machinery and drives heart failure progression. Here we demonstrate that stress induced proteolysis of JP2 liberates an N-terminal fragment (JP2NT) that translocates to the nucleus, binds to genomic DNA and controls expression of a spectrum of genes in cardiomyocytes. Transgenic overexpression of JP2NT in mice modifies the transcriptional profile resulting in attenuated pathological remodeling in response to cardiac stress. Conversely, loss of JP2NT function accelerates stress-induced development of hypertrophy and heart failure in mutant mice. These data reveal a self-protective mechanism in failing cardiomyocytes that transduce mechanical information (E-C uncoupling) into salutary transcriptional reprogramming in the stressed heart. PMID- 30409806 TI - Quantifying the contribution of recessive coding variation to developmental disorders. AB - We estimated the genome-wide contribution of recessive coding variation in 6040 families from the Deciphering Developmental Disorders study. The proportion of cases attributable to recessive coding variants was 3.6% in patients of European ancestry, compared with 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, owing to elevated autozygosity. Half of this recessive burden is attributable to known genes. We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models. Our results suggest that recessive coding variants account for a small fraction of currently undiagnosed nonconsanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration. PMID- 30409808 TI - Formyl-methionine as an N-degron of a eukaryotic N-end rule pathway. AB - In bacteria, nascent proteins bear the pretranslationally generated N-terminal (Nt) formyl-methionine (fMet) residue. Nt-fMet of bacterial proteins is a degradation signal, termed fMet/N-degron. By contrast, proteins synthesized by cytosolic ribosomes of eukaryotes were presumed to bear unformylated Nt-Met. Here we found that the yeast formyltransferase Fmt1, although imported into mitochondria, could also produce Nt-formylated proteins in the cytosol. Nt formylated proteins were strongly up-regulated in stationary phase or upon starvation for specific amino acids. This up-regulation strictly required the Gcn2 kinase, which phosphorylates Fmt1 and mediates its retention in the cytosol. We also found that the Nt-fMet residues of Nt-formylated proteins act as fMet/N degrons and identified the Psh1 ubiquitin ligase as the recognition component of the eukaryotic fMet/N-end rule pathway, which destroys Nt-formylated proteins. PMID- 30409809 TI - Ultralow-loading platinum-cobalt fuel cell catalysts derived from imidazolate frameworks. AB - Achieving high catalytic performance with the lowest amount of platinum is critical in fuel cell cost reduction. We describe a method of preparing highly active yet stable electrocatalysts containing ultralow Pt content using Co or Co/Zn zeolitic imidazolate frameworks as precursors. Synergistic catalysis between strained Pt-Co core-shell nanoparticles over a platinum-group-metal-free (PGM-free) catalytic substrate led to excellent fuel cell performance under 1 atmosphere of O2 or air at both high voltage and high current domains. Two catalysts achieved the oxygen reduction reaction (ORR) mass activities of 1.08 A mgPt -1/1.77 A mgPt -1 and retained 64%/15% of initial values after 30,000 voltage cycles in fuel cell. Computational modeling reveals that the interaction between Pt-Co and PGM-free sites improves ORR activity and durability. PMID- 30409810 TI - Zinc Transporter 8 Autoantibodies (ZnT8A) and a Type 1 Diabetes Genetic Risk Score Can Exclude Individuals With Type 1 Diabetes From Inappropriate Genetic Testing for Monogenic Diabetes. PMID- 30409807 TI - Early human dispersals within the Americas. AB - Studies of the peopling of the Americas have focused on the timing and number of initial migrations. Less attention has been paid to the subsequent spread of people within the Americas. We sequenced 15 ancient human genomes spanning from Alaska to Patagonia; six are >=10,000 years old (up to ~18* coverage). All are most closely related to Native Americans, including those from an Ancient Beringian individual and two morphologically distinct "Paleoamericans." We found evidence of rapid dispersal and early diversification that included previously unknown groups as people moved south. This resulted in multiple independent, geographically uneven migrations, including one that provides clues of a Late Pleistocene Australasian genetic signal, as well as a later Mesoamerican-related expansion. These led to complex and dynamic population histories from North to South America. PMID- 30409811 TI - Resurgence of Diabetes-Related Nontraumatic Lower Extremity Amputation in the Young and Middle-Aged Adult U.S. Population. AB - OBJECTIVES: To determine whether declining trends in lower extremity amputations have continued into the current decade. RESEARCH DESIGN AND METHODS: We calculated hospitalization rates for nontraumatic lower extremity amputation (NLEA) for the years 2000-2015 using nationally representative, serial cross sectional data from the Nationwide Inpatient Sample on NLEA procedures and from the National Health Interview Survey for estimates of the populations with and without diabetes. RESULTS: Age-adjusted NLEA rates per 1,000 adults with diabetes decreased 43% between 2000 (5.38 [95% CI 4.93-5.84]) and 2009 (3.07 [95% CI 2.79 3.34]) (P < 0.001) and then rebounded by 50% between 2009 and 2015 (4.62 [95% CI 4.25-5.00]) (P < 0.001). In contrast, age-adjusted NLEA rates per 1,000 adults without diabetes decreased 22%, from 0.23 per 1,000 (95% CI 0.22-0.25) in 2000 to 0.18 per 1,000 (95% CI 0.17-0.18) in 2015 (P < 0.001). The increase in diabetes related NLEA rates between 2009 and 2015 was driven by a 62% increase in the rate of minor amputations (from 2.03 [95% CI 1.83-2.22] to 3.29 [95% CI 3.01-3.57], P < 0.001) and a smaller, but also statistically significant, 29% increase in major NLEAs (from 1.04 [95% CI 0.94-1.13] to 1.34 [95% CI 1.22-1.45]). The increases in rates of total, major, and minor amputations were most pronounced in young (age 18-44 years) and middle-aged (age 45-64 years) adults and more pronounced in men than women. CONCLUSIONS: After a two-decade decline in lower extremity amputations, the U.S. may now be experiencing a reversal in the progress particularly in young and middle-aged adults. PMID- 30409812 TI - Plain tobacco packaging, increased graphic health warnings and adolescents' perceptions and initiation of smoking: DePICT, a French nationwide study. AB - BACKGROUND: Plain packaging (PP) of tobacco products and increased graphic warnings may contribute to lower attractiveness of smoking, particularly among youths. In France, this policy was introduced on 1 January 2017. We examined changes in smoking-related perceptions and behaviours among a nationwide sample of French adolescents before (2016) and 1 year post (2017) implementation. METHODS: DePICT is a two-wave cross-sectional national telephone survey of adolescents aged 12-17 years per study wave (2016: n=2046 2017: n=1999). All participants reported smoking-related perceptions, as well as ever and current tobacco use. Smokers were also asked about their perceptions of tobacco brands. Data were weighted to be representative of youths in the French population: adjusted prevalence ratios (PRs, 95% CI) estimating changes between the two study waves were calculated using multivariate log-binomial regression models. RESULTS: In 2017, as compared with 2016, French adolescents were more likely to report fear of the consequences of smoking (PR=1.06, 95% CI 1.02 to 1.09) and that smoking is dangerous (PR=1.08, 95% CI 1.05 to 1.11). They were also less likely to report that their friends (PR=0.61, 95% CI 0.54 to 0.70) and family (PR=0.51, 95% CI 0.44 to 0.60) accept smoking. Additionally, smoking initiation significantly decreased (PR=0.96, 95% CI 0.93 to 0.98) and a non-statistically significant drop in current tobacco use was observed (PR=0.93, 95% CI 0.78 to 1.11). Smokers' attachment to their tobacco brand also decreased (PR=0.47, 95% CI 0.30 to 0.73). CONCLUSION: Our findings suggest that PP and increased graphic warnings could contribute to changes in smoking norms and rates among adolescents. PMID- 30409813 TI - Retailers' perspectives on selling tobacco in a low-income San Francisco neighbourhood after California's $2 tobacco tax increase. AB - BACKGROUND: California's tobacco tax increased by $2.00 per pack in 2017. Although such increases are among the most effective tobacco control strategies, little is known about their impact from the perspective of corner store owners in low-income neighbourhoods with high concentrations of tobacco outlets. METHODS: We interviewed 38 corner store owners and managers in San Francisco's Tenderloin, the district with the city's highest tobacco outlet density, 60-90 days following implementation of the tax increase. Questions focused on perceptions of the impact of the higher tobacco tax on their revenues, customers and tobacco company promotions. We used qualitative content analysis to identify, compare and reconcile key themes. RESULTS: Most retailers reported a decline in cigarette sales, with customers buying fewer cigarettes, switching to cheaper brands or other products like marijuana, or trying to quit smoking. Retailers described challenges associated with running a small business and selling tobacco and concerns about selling a product that is 'bad' for customers' health. Contrary to expectation, tobacco companies appeared to be offering few product promotions in this neighbourhood. CONCLUSIONS: Small, independent retailers' concerns, about selling tobacco and about the health and well-being of customers, suggest that such retailers may be important allies in tobacco control efforts,particularly those focused on the point-of-sale. PMID- 30409814 TI - Establishment of a murine culture system for modeling the temporal progression of cranial and trunk neural crest cell differentiation. AB - The neural crest (NC) is a transient population of embryonic progenitors that are implicated in a diverse range of congenital birth defects and pediatric syndromes. The broad spectrum of NC-related disorders can be attributed to the wide variety of differentiated cell types arising from the NC. In vitro models of NC development provide a powerful platform for testing the relative contributions of intrinsic and extrinsic factors mediating NC differentiation under normal and pathogenic conditions. Although differentiation is a dynamic process that unfolds over time, currently, there is no well-defined chronology that characterizes the in vitro progression of NC differentiation towards specific cell fates. In this study, we have optimized culture conditions for expansion of primary murine NC cells that give rise to both ectodermal and mesoectodermal derivatives, even after multiple passages. Significantly, we have delineated highly reproducible timelines that include distinct intermediate stages for lineage-specific NC differentiation in vitro In addition, isolating both cranial and trunk NC cells from the same embryos enabled us to make direct comparisons between the two cell populations over the course of differentiation. Our results define characteristic changes in cell morphology and behavior that track the temporal progression of NC cells as they differentiate along the neuronal, glial, and chondrogenic lineages in vitro These benchmarks constitute a chronological baseline for assessing how genetic or environmental disruptions may facilitate or impede NC differentiation. Introducing a temporal dimension substantially increases the power of this platform for screening drugs or chemicals for developmental toxicity or therapeutic potential. PMID- 30409815 TI - Hospital suspends chemotherapy because of nurse shortage. PMID- 30409816 TI - NHS outpatient model is no longer fit for purpose, says RCP. PMID- 30409817 TI - Variable radiologic lung nodule evaluation leads to divergent management recommendations. AB - Radiologic evaluation of incidentally-detected lung nodules on computed tomography (CT) influences management. We assessed international radiologic variation in (1) pulmonary nodule characterisation; (2) hypothetical guideline derived management, and (3) radiologists' management recommendations.107 radiologists from 25 countries evaluated 69 CT-detected nodules, recording: i) first-choice composition (solid, part-solid [PSN] or ground-glass [GGN], with percentage confidence), ii) morphologic features, iii) dimensions, iv) recommended management and (v) decision-influencing factors. We modelled hypothetical management decisions on: (1) the 2005 and (2) updated 2017 Fleischner Society, and (3) liberal and (4) parsimonious interpretations of the British Thoracic Society 2015 guidelines.Overall agreement for first-choice nodule composition was good (Fleiss' k=0.65), but poorest for PSNs (weighted Kappa, Kw=0.62; IQR=0.50-0.71). Morphologic variables, including spiculation (k=0.35), showed poor-to-moderate agreement (k=0.23-0.53). Diameter variation was greatest at key thresholds (5 mm and 6 mm). Agreement for radiologists' recommendations was poor (k=0.30); 21% disagreed with the majority. Although agreement within the four guideline-modelled management strategies was good (k=0.63-0.73), 5-10% of radiologists would disagree with majority decisions if they strictly applied guidelines.Agreement was lowest for part-solid nodules, while significant measurement variation exists at important size thresholds. These variations resulted in generally good agreement for guideline-modelled management, but poor agreement for radiologists' actual recommendations. PMID- 30409818 TI - Limitations of resting haemodynamics in chronic thromboembolic disease without pulmonary hypertension. PMID- 30409819 TI - Digital technologies and adherence in respiratory diseases: the road ahead. AB - Outcomes for patients with chronic respiratory diseases remain poor despite the development of novel therapies. In part, this reflects the fact that adherence to therapy is low and clinicians lack accurate methods to assess this issue. Digital technologies hold promise to overcome these barriers to care. For example, algorithmic analysis of large amounts of information collected on health status and treatment use, along with other disease relevant information such as environmental data, can be used to help guide personalised interventions that may have a positive health impact, such as establishing habitual and correct inhaler use. Novel approaches to data analysis also offer the possibility of statistical algorithms that are better able to predict exacerbations, thereby creating opportunities for preventive interventions that may adapt therapy as disease activity changes. To realise these possibilities, digital approaches to disease management should be supported by strong evidence, have a solid infrastructure, be designed collaboratively as clinically effective and cost-effective systems, and reflect the needs of patients and healthcare providers. Regulatory standards for digital interventions and strategies to handle the large amounts of data generated are also needed. This review highlights the opportunities provided by digital technologies for managing patients with respiratory diseases. PMID- 30409821 TI - Treatment of latent tuberculosis with 12-weeks isoniazid/rifapentine in clinical practice. PMID- 30409820 TI - Determinants of diagnostic delay in chronic thromboembolic pulmonary hypertension: results from the European CTEPH Registry. PMID- 30409822 TI - Predictors of One Year Compliance with Adaptive Servo-Ventilation in Patients with Heart Failure and Sleep- Disordered Breathing: Preliminary Data from the ADVENT-HF Trial. AB - Peak flow-targeted adaptive servo ventilation (ASVpf) suppresses both obstructive (OSA) and central sleep apnoea (CSA). Although high hours of positive airway pressure (PAP) use improves quality of life, long-term compliance is problematic. We evaluated ASVpf use in patients with heart failure and reduced ejection fraction with either OSA or CSA to determine the short and long-term predictors of ASV pf compliance.Of 177 patients randomised to ASVpf, compliance data were available at one and 12 months post-randomisation in 91 with OSA and 45 with CSA. Among patients with OSA, ASVpf use was 4.6 [2.9] h per day at one month but decreased to 4.1 [4.7] h at 12 months (p=0.04). Among patients with CSA, median ASVpf use was 5.2 [4.0] h per day at one month and 5.2 [3.5] h per day at 12 months (p=0.52). The only predictor of ASVpf use at 12 months was hours of use at one month (OR 2.02: CI 1.58-2.60, p<0.01).These data indicate better compliance with ASVpf than previously reported for other PAP devices in patients with cardiovascular diseases. Hours of daily use at one month predicted compliance at 12 months, indicating that if good short-term compliance is achieved, this effect can be sustained long-term. PMID- 30409824 TI - Circulating cytokines predict immune-related toxicity in melanoma patients receiving anti-PD-1-based immunotherapy. AB - PURPOSE: Combination PD-1 and CTLA-4 inhibitor therapy has dramatically improved the survival of patients with advanced melanoma but is also associated with significant immune-related toxicities. This study sought to identify circulating cytokine biomarkers of treatment response and immune-related toxicity. EXPERIMENTAL DESIGN: The expression of 65 cytokines was profiled longitudinally in 98 melanoma patients treated with PD-1 inhibitors, alone or in combination with anti-CTLA-4, and in an independent validation cohort of 49 patients treated with combination anti-PD-1 and anti-CTLA-4. Cytokine expression was correlated with RECIST response and immune-related toxicity, defined as toxicity that warranted permanent discontinuation of treatment and administration of high dose steroids. RESULTS: Eleven cytokines were significantly upregulated in patients with severe immune-related toxicities at baseline and early during treatment. The expression of these eleven cytokines was integrated into a single toxicity score, the CYTOX score, and the predictive utility of this score was confirmed in the discovery and validation cohorts. The area under the curve for the CYTOX score in the validation cohort was 0.68 at PRE (95% CI, 0.51-0.84, p=0.037) and 0.70 at EDT (95% CI, 0.55-0.85, p=0.017) using receiver operating characteristic (ROC) analysis. CONCLUSIONS: The CYTOX score is predictive of severe immune-related toxicity in melanoma patients treated with combination anti-CTLA-4 and anti-PD-1 immunotherapy. This score, which includes pro-inflammatory cytokines such as IL 1a, IL-2 and IFNa2, may help in the early management of severe, potentially life threatening immune-related toxicity. PMID- 30409825 TI - Identification of Active Site Residues Implies a Two-step Catalytic Mechanism for Acyl-ACP Thioesterase. AB - In plants and bacteria that use a Type II fatty acid synthase (FAS), isozymes of acyl-acyl carrier protein (ACP) thioesterase (TEs) hydrolyze the thioester bond of acyl-ACPs, terminating the process of fatty acid biosynthesis. These TEs are therefore critical in determining the fatty acid profiles produced by these organisms. Past characterizations of a limited number of plant-sourced acyl-ACP TEs have suggested a thiol-based, papain-like catalytic mechanism, involving a triad of Cys, His, and Asn residues. In this study, sequence alignment of 1019 plant and bacterial acyl-ACP TEs revealed that the previously proposed Cys catalytic residue is not universally conserved and therefore may not be a catalytic residue. Systematic mutagenesis of this residue to either Ser or Ala in three plant acyl-ACP TEs, CvFatB1 and CvFatB2 from Cuphea viscosissima and CnFatB2 from Cocos nucifera , resulted in enzymatically active variants, demonstrating that this Cys residue (Cys348 in CvFatB2) is not catalytic. In contrast, the multiple sequence alignment, together with the structure modeling of CvFatB2 suggest that the highly conserved Asp309 and Glu347, in addition to previously proposed Asn311 and His313, may be involved in catalysis. The substantial loss of catalytic competence associated with site-directed mutants at these positions confirmed the involvement of these residues in catalysis. By comparing the structures of acyl-ACP TE and the Pseudomonas 4-hydroxybenzoyl-CoA TE, both of which fold in the same hot-dog tertiary structure and catalyze the hydrolysis reaction of thioester bond, we have proposed a two-step catalytic mechanism for acyl-ACP TE that involves an enzyme-bound anhydride intermediate. PMID- 30409823 TI - IND-enabling studies for a clinical trial to genetically program a persistent cancer-targeted immune system. AB - PURPOSE: To improve persistence of adoptively transferred T cell receptor (TCR) engineered T cells and durable clinical responses, we designed a clinical trial to transplant genetically-modified hematopoietic stem cells (HSCs) together with adoptive cell transfer (ACT) of T cells both engineered to express an NY-ESO-1 TCR. Here, we report the preclinical studies performed to enable an investigational new drug (IND) application. EXPERIMENTAL DESIGN: HSCs transduced with a lentiviral vector expressing NY-ESO-1 TCR and the PET reporter/suicide gene HSV1-sr39TK and T cells transduced with a retroviral vector expressing NY ESO-1 TCR were co-administered to myelodepleted HLA-A2/Kb mice within a formal GLP-compliant study to demonstrate safety, persistence and HSC differentiation into all blood lineages. Non-GLP experiments included assessment of transgene immunogenicity and in vitro viral insertion safety studies. Furthermore, GMP compliant cell production qualification runs were performed to establish the manufacturing protocols for clinical use. RESULTS: TCR genetically-modified and ex vivo cultured HSCs differentiated into all blood subsets in vivo after HSC transplantation, and co-administration of TCR-transduced T cells did not result in increased toxicity. The expression of NY-ESO-1 TCR and sr39TK transgenes did not have a detrimental effect on gene-modified HSCs differentiation to all blood cell lineages. There was no evidence of genotoxicity induced by the lentiviral vector. GMP batches of clinical-grade transgenic cells produced during qualification runs had adequate stability and functionality. CONCLUSION: Co administration of HSCs and T cells expressing an NY-ESO-1 TCR is safe in preclinical models. The results presented in this manuscript led to the U.S. FDA approval of IND 17471. PMID- 30409828 TI - Seven days in medicine: 31 October to 6 November 2018. PMID- 30409826 TI - GPCR structure and function relationship: identification of a biased apelin receptor mutant. AB - Biased ligands of G protein-coupled receptors (GPCRs) may have improved therapeutic benefits and safety profiles. However, the molecular mechanism of GPCR biased signaling remains largely unknown. Using apelin receptor (APJ) as a model, we systematically investigated the potential effects of amino acid residues around the orthosteric binding site on biased signaling. We discovered that a single residue mutation I109A (I1093.32) in the transmembrane domain 3 (TM3) located in the deep ligand-binding pocket was sufficient to convert a balanced APJ into a G protein signaling biased receptor. APJ I109A mutant receptor retained full capabilities in ligand binding and G protein activation, but was defective in GRK recruitment, beta-arrestin recruitment, and downstream receptor-mediated ERK activation. Based on molecular dynamics simulations, we proposed a molecular mechanism for biased signaling of I109A mutant receptor. We postulate that due to the extra space created by I109A mutation, the phenyl group of the last residue (Phe-13) of apelin rotates down and initiates a cascade of conformational changes in TM3. Phe-13 formed a new cluster of hydrophobic interactions with the sidechains of residues in TM3, including F1103.33 and M1133.36, which stabilizes the mutant receptor in a conformation favoring biased signaling. Interruption of these stabilizing interactions by double mutation F110A/I109A or M113A/I109A largely restored the beta-arrestin-mediated signaling. Taken together, we describe herein the discovery of a biased APJ mutant receptor and provide detailed molecular insights into APJ signaling selectivity, facilitating the discovery of novel therapeutics targeting APJ. PMID- 30409829 TI - Role of linoleic acid in autoimmune disorders: a Mendelian randomisation study. PMID- 30409827 TI - Rational engineering of a malate dehydrogenase for microbial production of 2,4 dihydroxybutyric acid via homoserine pathway. AB - A synthetic pathway for the production of 2,4-dihydroxybutyric acid from homoserine, composed of two consecutive enzymatic reaction steps has been recently reported. An important step in this pathway consists in the reduction of 2-keto-4-hydroxybutyrate (OHB) into (L)-dihydroxybutyrate (DHB), by an enzyme with OHB reductase activity. In this study, we used a rational approach to engineer an OHB reductase by using the cytosolic (L)-malate dehydrogenase from Escherichia coli (Ec-Mdh) as the template enzyme. Structural analysis of (L) malate dehydrogenase and (L)-lactate dehydrogenase enzymes acting on sterically cognate substrates revealed key residues in the substrate and co-substrate binding sites responsible for substrate discrimination. Accordingly, amino acid changes were introduced in a step-wise manner into these regions of the protein. This rational engineering led to the production of a Ec-Mdh-5E variant (I12V/R81A/M85E/G179D/D86S) with a turnover number (kcat) on OHB that was increased by more than 2,000 fold (from 0.03 up to 65.0 s-1), which turned out to be 7 fold higher than that on its natural substrate oxaloacetate. Further kinetic analysis revealed the engineered enzyme to possess comparable catalytic efficiencies (kcat/Km) between natural and synthetic OHB substrates (84 and 31 s 1 mM-1, respectively). Shake-flask cultivation of an homoserine-overproducing E. coli strain expressing this improved OHB reductase together with a transaminase encoded by aspC able to convert homoserine to OHB resulted in 89 % increased DHB production as compared to our previous report using a E. coli host strain expressing an OHB reductase derived from the lactate dehydrogenase A of Lactococcus lactis. PMID- 30409831 TI - Metering the METEOR in methotrexate failure: is propensity score a falling star? PMID- 30409832 TI - Prostanoid EP4 receptor-mediated augmentation of Ih currents in Abeta dorsal root ganglion neurons underlies neuropathic pain. AB - An injury of the somatosensory system causes neuropathic pain, which is usually refractory to conventional analgesics, thus warranting the development of novel drugs against this kind of pain. The mechanism of neuropathic pain in rats that had undergone left L5 spinal nerve transection was analyzed. After 10 days of the surgery, these rats acquired neuropathic pain. The patch-clamp technique was used on the isolated bilateral L5 dorsal root ganglion neurons. The current-clamped neurons on the ipsilateral side exhibited significantly higher excitability than those on the contralateral side. However, only neurons with diameters of 40-50 MUm on the ipsilateral side exhibited significantly larger voltage sags in response to hyperpolarizing current pulses than those on the contralateral side. Under the voltage clamp, only these neurons on the ipsilateral side showed a significantly larger density of an inward current at <-80 mV (Ih current) with a rightward-shifted activation curve than that on the contralateral side. Ivabradine--an Ih current inhibitor--inhibited Ih currents in these neurons on both the sides in a similar concentration-dependent manner, with an IC50 of ~3 MUM. Moreover, the oral administration of ivabradine significantly alleviated the neuropathic pain on the ipsilateral side. An inhibitor of adenylyl cyclase or an antagonist of prostanoid EP4 receptors (CJ-023423) inhibited ipsilateral, but not contralateral Ih currents in these neurons. Furthermore, the intrathecal administration of CJ-023423 significantly attenuated neuropathic pain on the ipsilateral side. Thus, ivabradine and/or CJ-023423 may be a lead compound for the development of novel therapeutics against neuropathic pain. PMID- 30409833 TI - Vaccination reduces fentanyl distribution to the brain and fentanyl-induced toxicity in mice and rats: a potential role for a prophylactic vaccine against fentanyl-induced overdose. AB - Fentanyl is an extremely potent synthetic opioid that has been increasingly used to adulterate heroin, cocaine and counterfeit prescription pills leading to an increase in opioid-induced fatal overdoses in the US, Canada, and Europe. A vaccine targeting fentanyl could offer protection against fatal overdoses in both recreational drug users and others in professions at risk of accidental exposure. This study focuses on the development of a vaccine consisting of a fentanyl hapten (F) conjugated to keyhole limpet hemocyanin (KLH) carrier protein or to GMP-grade subunit KLH (sKLH). Immunization with F-KLH in mice and rats reduced fentanyl-induced hotplate antinociception and in rats reduced fentanyl distribution to brain compared to controls. F-KLH did not reduce antinociceptive effects of equianalgesic doses of heroin or oxycodone in rats. To assess vaccine effect on fentanyl toxicity, rats immunized with F-sKLH or unconjugated sKLH were exposed to increasing s.c. doses of fentanyl. Vaccination with F-sKLH shifted the dose-response curves to the right for both fentanyl-induced antinociception and respiratory depression. Naloxone reversed fentanyl effects in both groups, showing that its activity for reversing opioid overdose was preserved. These data demonstrate pre-clinical selectivity and efficacy of a fentanyl vaccine and suggest that vaccines may offer a therapeutic option in reducing fentanyl-induced overdoses. PMID- 30409835 TI - Wellbeing support for general practitioners. PMID- 30409834 TI - Influence of Stereochemistry on the Bioactivation and Glucuronidation of 4 Ipomeanol. AB - A potential CYP4B1 suicide gene application in engineered T-cell treatment of blood cancers has revived interest in the use of 4-Ipomeanol (IPO) in gene directed enzyme prodrug therapy, where disposition of the administered compound may be critical. IPO contains one chiral center at the carbon bearing a secondary alcohol group; it was of interest to determine the effect of stereochemistry on (i) CYP4B1-mediated bioactivation and (ii) UGT-mediated glucuronidation. (R)-IPO and (S)-IPO were synthesized and utilized, firstly, to assess cytotoxicity in HepG2 cells expressing rabbit CYP4B1 and re-engineered human CYP4B1, where the enantiomers were found to be equipotent. Next, a sensitive UPLC-MS/MS assay was developed to measure the IPO glucuronide diastereomers and product stereoselectivity in human tissue microsomes. Human liver and kidney microsomes generated (R)- and (S)-IPO-glucuronide diastereomers in ratios of 57:43 and 79:21, respectively. In a panel of thirteen recombinantly expressed UGTs, UGT1A9 and UGT2B7 were the major isoforms responsible for IPO glucuronidation. (R)-IPO glucuronide diastereoselectivity was apparent with each rUGT, except UGT2B15 and UGT2B17, which favored the formation of (S)-IPO-glucuronide. Incubations with IPO and the UGT1A9 specific chemical inhibitor niflumic acid significantly decreased glucuronidation in human kidney, but only marginally in human liver microsomes, consistent with known tissue expression patterns of UGTs. We conclude that IPO glucuronidation in human kidney is mediated by UGT1A9 and UGT2B7, and in human liver, primarily by UGT2B7 and to a lesser extent UGT1A9 and UGT2B15. Overall, the lack of pronounced stereoselectivity for IPO's bioactivation in CYP4B1 transfected HepG2 cells, or for hepatic glucuronidation, suggests the racemate is an appropriate choice for use in suicide gene therapies. PMID- 30409836 TI - Role model: Carolyn Chew-Graham. PMID- 30409830 TI - Short-term progression of interstitial lung disease in systemic sclerosis predicts long-term survival in two independent clinical trial cohorts. AB - OBJECTIVE: To assess survival and identify predictors of survival in patients with systemic sclerosis-interstitial lung disease (SSc-ILD) who participated in the Scleroderma Lung Studies (SLS) I and II. METHODS: SLS I randomised 158 patients with SSc-ILD to 1 year of oral cyclophosphamide (CYC) vs placebo. SLS II randomised 142 patients to 1 year of oral CYC followed by 1 year of placebo vs 2 years of mycophenolate mofetil. Counting process Cox proportional hazard modelling identified variables associated with long-term mortality in SLS I and II. Internal validation was performed using joint modelling. RESULTS: After a median follow-up of 8 years, 42% of SLS I patients died, and when known the cause of death was most often attributable to SSc. There was no significant difference in the time to death between treatment arms in SLS I or II. Higher baseline skin score, older age, and a decline in the forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLCO) over 2 years were independently associated with an increased risk of mortality in SLS I. The Cox model identified the same mortality predictor variables using the SLS II data. CONCLUSION: In addition to identifying traditional mortality risk factors in SSc (skin score, age), this study demonstrated that a decline in FVC and DLCO over 2 years was a better predictor of mortality than baseline FVC and DLCO. These findings suggest that short-term changes in surrogate measures of SSc-ILD progression may have important effects on long-term outcomes. PMID- 30409837 TI - Quantitation of lysosomal trapping of basic lipophilic compounds using in vitro assays and in silico predictions based on the determination of the full pH profile of the endo-/lysosomal system in rat hepatocytes. AB - Lysosomal sequestration may affect the pharmacokinetics, efficacy and safety of new basic lipophilic drug candidates potentially impacting their intracellular concentrations and tissue distribution. It may also be involved in drug-drug interactions, drug resistance or phospholipidosis. Currently, however, there are no assays to evaluate the lysosomotropic behaviour of compounds in a setting fully meeting the needs of drug discovery. We have therefore integrated a set of methods to reliably rank order, quantify and calculate the extent of lysosomal sequestration in rat hepatocytes. An indirect fluorescence-based assay monitors the displacement of the fluorescence probe LysoTrackerTM Red by test compounds. Using a lysosomal specific evaluation algorithm allows to generate IC50 values at lower than previously reported concentrations. The concentration range directly agrees with the concentration dependency of the lysosomal drug content itself directly quantified by LC-MS/MS and thus permits a quantitative link between the indirect and the direct trapping assay. Furthermore, we have determined the full pH profile and corresponding volume fractions of the endo-/lysosomal system in plated rat hepatocytes, enabling a more accurate in silico prediction of the extent of lysosomal trapping based only on pKa values as input allowing early predictions even prior to chemical synthesis. The concentration dependency, i.e. the saturability of the trapping can then be determined by the IC50 values generated in vitro. Thereby, a more quantitative assessment of the susceptibility of basic lipophilic compounds for lysosomal trapping is possible. PMID- 30409838 TI - Berberine Directly Impacts the Gut Microbiota to Promote Intestinal Farnesoid X Receptor Activation. AB - Intestinal bacteria play an important role in bile acid metabolism and in the regulation of multiple host metabolic pathways (e.g., lipid and glucose homeostasis) through modulation of intestinal farnesoid X receptor (FXR) activity. Here, we examined the effect of berberine (BBR), a natural plant alkaloid, on intestinal bacteria using in vitro and in vivo models. In vivo, the metabolomic response and changes in mouse intestinal bacterial communities treated with BBR (100 mg/kg) for 5 days were assessed using NMR- and mass spectrometry-based metabolomics coupled with multivariate data analysis. Short term BBR exposure altered intestinal bacteria by reducing the Clostridium cluster XIVa and IV and their bile salt hydrolase (BSH) activity, which resulted in the accumulation of taurocholic acid (TCA). The accumulation of TCA was associated with activation of intestinal FXR, which can mediate bile acid, lipid, and glucose metabolism. In vitro, isolated mouse cecal bacteria were incubated with three doses of BBR (0.1, 1, and 10 mg/ml) for 4 h in an anaerobic chamber. NMR based metabolomics combined with flow cytometry was used to evaluate the direct physiologic and metabolic impact of BBR on the bacteria. In vitro, BBR exposure not only altered bacterial physiology, but also changed the bacterial community composition and function, especially reducing BSH expressing bacteria like Clostridium spp. These data suggest that BBR directly impacts bacteria to alter bile acid metabolism and activate FXR signaling. These data provide new insights into the link between intestinal bacteria, nuclear receptor signaling, and xenobiotics. PMID- 30409839 TI - Tumour heterogeneity in triplet-paired metastatic tumour tissues in metastatic renal cell carcinoma: concordance analysis of target gene sequencing data. AB - AIMS: The aim of the present study was to determine the concordant correlation in the expression of 88 target genes from triple-paired metastatic tissues in individual patients with metastatic renal carcinoma (mRCC) using a target gene sequencing (TGS) approach. METHODS: Between 2002 and 2017, a total of 350 triple paired metastatic tissue samples from 262 patients with mRCC obtained from either nephrectomy or metastasectomy were used for TGS of 88 candidate genes. After quality check, 243 tissue samples from 81 patients were finally applied to TGS. The concordance of triple-paired tissues was analysed with the 88 TGS panels using bioinformatics tools. RESULTS: Among 81 patients, alterations were observed in 42 (51.9%) for any of the 88 mRCC panel genes; however, no pathogenic gene was detected in 38 (39.5%) . Concordance >95% for altered gene expression among the three tissues was reported in 12 (28.6%) patients, while concordance >95% within two tissues was reported in 30 (71.4%); concordance <50% was reported in the remaining eight patients. Considering several types of genetic alterations, including deletions, insertions, missense and nonsense mutations, and splice variants, genes most frequently detected with genetic alterations in the patients with mRCC were PTEN loss, followed by FLCN, BCR, SMARCA2, AKAP9, MLH1, MYH11, APC and TP53. CONCLUSIONS: The study provides reference information on the genetic alterations at various organ sites and the multi-heterogeneity of mRCC tissues. The concordance of pathogenic gene alterations within tissues was not high, and approximately half of the patients showed no pathogenic gene alterations at all. PMID- 30409840 TI - Apocrine lesions of the breast: part 1 of a two-part review: benign, atypical and in situ apocrine proliferations of the breast. AB - Apocrine morphology is a common phenomenon encountered in everyday breast pathology practice, and is defined as cuboidal or columnar cells exhibiting abundant eosinophilic granular cytoplasm, prominent apical granules, a low nuclear-cytoplasmic ratio, and round nuclei with pale chromatin and prominent nucleoli. Apocrine morphology is recognised in benign, atypical and malignant lesions of the breast. The morphology of apocrine atypia and non-high-grade apocrine ductal carcinoma in situ (DCIS) is less well defined due to the relative rarity of these lesions. In part 1 of this two-part review, we focus on the morphological characteristics of benign, atypical and in situ apocrine lesions of the breast, summarise the available data to date regarding distinction of atypical apocrine proliferations from non-high-grade apocrine DCIS and the biological significance of apocrine atypia, and provide practical guidance on handling these difficult lesions. Part 2 of this review will focus on the concept of pure apocrine carcinoma with emphasis on its definition and molecular data, including the current understanding of the molecular apocrine signature in breast carcinoma. We complete the review with a synopsis on the utility of immunohistochemistry in the diagnosis of apocrine lesions of the breast. PMID- 30409842 TI - Child Abuse, Incarceration, and Decisions About Life-sustaining Treatment. AB - Most critical care interventions for children occur in the framework of a supportive environment with loving parents that are present at the bedside to help to guide medical interventions through shared decision-making. What happens, however, if the parents are precluded from being at the bedside because of legal entanglements? How should clinical decisions progress in those cases? In this Ethics Rounds, we present the case of an infant with severe hypoxic-ischemic encephalopathy at birth whose mother was incarcerated shortly after delivery. We explore clinical and legal challenges that the medical team faces in determining best interests for the infant in this context and difficulties in deciding what therapies to provide and for how long. PMID- 30409843 TI - Making doctors better: change doctors' beliefs rather than provide special services. PMID- 30409841 TI - Child BMI Over Time and Parent-Perceived Overweight. AB - BACKGROUND AND OBJECTIVES: Parents often do not accurately perceive overweight and/or obesity in their children. Changing this is widely considered an essential first step to reducing child overweight, but recent research suggests that, in fact, this could promote greater weight gain. We aimed to determine the directionality over time between higher child adiposity and parental perception of child overweight. METHODS: Participants were from 2 cohorts of the population based Longitudinal Study of Australian Children followed biennially since 2004. Repeated measures of BMI z scores and parental perceptions of overweight were available for the kindergarten cohort at 6 waves (ages 4-5, 6-7, 8-9, 10-11, 12 13, and 14-15 years; n = 4632) and for the birth cohort at 4 waves (ages 2-3, 4 5, 8-9, and 10-11 years; n = 4445). Bidirectionality between overweight perception and BMI z score was examined by using cross-lagged regression models. RESULTS: In both cohorts, wave-on-wave lagged effects were strong (all: P < .001) but much larger from BMI z score to parent perception. For every unit increase in the BMI z score, the odds of a child being perceived as overweight in the next wave ranged from 2.9 (birth cohort: age 2-3 years) to 10.4 (kindergarten cohort: age 6-7 years). These effects were ~3 to 12 times larger than the reverse, whereby the perception of overweight predicted 0.2 to 0.5 higher BMI z score in the next wave. CONCLUSIONS: Higher child BMI z scores strikingly predicted a subsequent parental perception of child overweight. Parent-perceived overweight preceded rising (not falling) BMI, but these effects were small. Clinician efforts to make parents aware of overweight may not be harmful but seem unlikely to improve children's BMI status. PMID- 30409845 TI - Antibiotic resistant bacteria cause nearly one in five infections in wealthy countries, report warns. PMID- 30409844 TI - Chiral lipidomics of monoepoxy and monohydroxy metabolites derived from long chain polyunsaturated fatty acids. AB - A chiral lipidomics approach was established for comprehensive profiling of regio and stereoisomeric monoepoxy and monohydroxy metabolites of long-chain polyunsaturated fatty acids as generated enzymatically by cytochromes P450, lipoxygenases, and cyclooxygenases and, in part, also unspecific oxidations. The method relies on reversed-phase chiral liquid chromatography coupled with electrospray ionization/tandem mass spectrometry. Applications revealed partially opposing enantioselectivities of soluble and microsomal epoxide hydrolases. Ablation of the soluble epoxide hydrolase gene resulted in specific alterations in the enantiomeric composition of endogenous monoepoxy metabolites. For example, the (R,S)/(S,R)-ratio of circulating 14,15-EET changed from 2.1:1 in wild-type to 9.7:1 in the sEH knockout mice. Studies with liver microsomes suggested that cytochrome P450/microsomal epoxide hydrolase interactions play a primary role in determining the enantiomeric composition of monoepoxy metabolites during their generation and release from the endoplasmic reticulum. Analysis of human plasma showed significant enantiomeric excess with several monoepoxy metabolites. Monohydroxy metabolites were generally present as racemates; however, Ca2+ ionophore stimulation of whole blood samples resulted in enantioselective increases of lipoxygenase (12S-HETE and 17S-HDHA) and cyclooxygenase (11R-HETE) derived metabolites. Our chiral approach may provide novel opportunities for investigating the role of bioactive lipid mediators that generally exert their physiological functions in a highly regio- and stereospecific manner. PMID- 30409846 TI - Imaging of Surgical Free Flaps in Head and Neck Reconstruction. AB - Head and neck surgical reconstruction is complex, and postoperative imaging interpretation is challenging. Surgeons now use microvascular free tissue transfer, also known as free flaps, more frequently in head and neck reconstruction than ever before. Thus, an understanding of free flaps, their expected appearance on cross-sectional imaging, and their associated complications (including tumor recurrence) is crucial for the interpreting radiologist. Despite the complexity and increasing frequency of free flap reconstruction, there is no comprehensive head and neck resource intended for the radiologist. We hope that this image-rich review will fill that void and serve as a go to reference for radiologists interpreting imaging of surgical free flaps in head and neck reconstruction. PMID- 30409847 TI - Parapharyngeal Space Venous Malformation: An Imaging Mimic of Pleomorphic Adenoma. AB - Venous malformations in the parapharyngeal space are rare and may be challenging to diagnose with imaging secondary to multiple overlapping features with pleomorphic adenoma, which is much more commonly found in this region. While both lesions are T1 isointense and T2 hyperintense relative to skeletal muscle and demonstrate contrast enhancement, more uniform T2 hyperintensity and progressive contrast pooling on delayed postcontrast T1WI may allow the radiologist to include venous malformation in the differential diagnosis. This is important because it has the potential to alter management from surgical resection to observation. The primary aim of this study was to review the imaging appearance of parapharyngeal venous malformations through a retrospective case series. PMID- 30409848 TI - Transdural Blood Supply in Cerebral Arteriovenous Malformations: A Systematic Evaluation of Angioarchitecture. AB - BACKGROUND AND PURPOSE: Arterial transdural blood supply is a rare angiographic phenomenon in cerebral AVMs. This study aimed to evaluate angiographic transdural blood supply characteristics and to describe the clinical peculiarities of these lesions. MATERIALS AND METHODS: A prospective AVM data base of 535 patients, enrolled from 1990 to 2016, was analyzed retrospectively. Clinical information was reviewed through patients' medical charts and radiologic studies. Patients with previous AVM treatment were excluded (n = 28). RESULTS: Patients with (n = 32, male/female ratio = 10:22; mean age, 46 +/- 15 years; range, 13-75 years) and without transdural blood supply (n = 475, male/female ratio = 260:215; mean age, 40 +/- 18 years; range, 2-87 years) did not show significant differences in clinical presentation (age, hemorrhage, seizures, chronic headache). The predominant nidus size in patients with transdural blood supply was >=30 mm, with significantly more patients with large AVMs (>60 mm, P = .001). To describe the transdural blood supply, we used 3 grades based on the angiographic transdural blood supply proportion and intensity of AVM nidus perfusion (I-III). Fifty-seven percent of patients with chronic headache had a strong and substantial transdural nidus perfusion (III) and a high-flow transdural blood supply. CONCLUSIONS: Cerebral AVMs with transdural blood supply represent a rare and heterogeneous subgroup. Lesions can be graded by quantifying the transdural blood supply of the nidus and by capturing hemodynamic characteristics. The broad spread of angiographic features and comparable clinical patterns of patients with or without transdural blood supply raises questions about the relevance of the transdural blood supply to the natural history risk of an AVM and the intention for treatment. PMID- 30409849 TI - Functional MRI as an Objective Measure of Olfaction Deficit in Patients with Traumatic Anosmia. AB - BACKGROUND AND PURPOSE: While posttraumatic anosmia is not uncommon, the olfactory function evaluation has strongly relied on subjective responses given by patients. We aimed to examine the utility of fMRI as an objective tool for diagnosing traumatic anosmia. MATERIALS AND METHODS: Sixteen patients (11 men and 5 women; mean age, 42.2 +/- 10.4 years) with clinically diagnosed traumatic anosmia and 19 healthy control subjects (11 men and 8 women; mean age, 29.3 +/- 8.5 years) underwent fMRI during olfactory stimulation with citral (a pleasant odor) or beta-mercaptoethanol (an unpleasant odor). All patients were subjected to a clinical olfactory functional assessment and nasal endoscopic exploration. Two-sample t tests were conducted with age as a covariate to examine group differences in brain activation responses to olfactory stimulation (false discovery rate-corrected P < .05). RESULTS: Compared with healthy control subjects, patients with traumatic anosmia had reduced activation in the bilateral primary and secondary olfactory cortices and the limbic system in response to beta-mercaptoethanol stimulation, whereas reduced activation was observed only in the left frontal subgyral region in response to citral stimulation. CONCLUSIONS: Brain activation was decreased in the bilateral primary and secondary olfactory cortices as well as the limbic system in response to olfactory stimulation in patients with traumatic anosmia compared with healthy control subjects. These preliminary results may shed light on the potential of fMRI for the diagnosis of traumatic anosmia. PMID- 30409850 TI - Differentiation of Hemorrhage from Iodine Using Spectral Detector CT: A Phantom Study. AB - BACKGROUND AND PURPOSE: Conventional CT often cannot distinguish hemorrhage from iodine extravasation following reperfusion therapy for acute ischemic stroke. We investigated the potential of spectral detector CT in differentiating these lesions. MATERIALS AND METHODS: Centrifuged blood with increasing hematocrit (5% 85%) was used to model hemorrhage. Pure blood, blood-iodine mixtures (75/25, 50/50, and 25/75 ratios), and iodine solutions (0-14 mg I/mL) were scanned in a phantom with attenuation ranging from 12 to 75 HU on conventional imaging. Conventional and virtual noncontrast attenuation was compared and investigated for correlation with calculation of relative virtual noncontrast attenuation. Values for all investigated categories were compared using the Mann-Whitney U test. Sensitivity and specificity of virtual noncontrast, relative virtual noncontrast, conventional CT attenuation, and iodine quantification for hemorrhage detection were determined with receiver operating characteristic analysis. RESULTS: Conventional image attenuation was not significantly different among all samples containing blood (P > .05), while virtual noncontrast attenuation showed a significant decrease with a decreasing blood component (P < .01) in all blood-iodine mixtures. Relative virtual noncontrast values were significantly different among all investigated categories (P < .01), with correct hemorrhagic component size estimation for all categories within a 95% confidence interval. Areas under the curve for hemorrhage detection were 0.97, 0.87, 0.29, and 0.16 for virtual noncontrast, relative virtual noncontrast, conventional CT attenuation, and iodine quantification, respectively. A >=10-HU virtual noncontrast, >=20-HU virtual noncontrast, >=40% relative virtual noncontrast, and combined >=10-HU virtual noncontrast and >=40% relative virtual noncontrast attenuation threshold had a sensitivity/specificity for detecting hemorrhage of 100%/23%, 89%/95%, 100%/82%, and 100%/100%, respectively. CONCLUSIONS: Spectral detector CT can accurately differentiate blood from iodinated contrast in a phantom setting. PMID- 30409851 TI - How to Size Intracranial Aneurysms: A Phantom Study of Invasive and Noninvasive Methods. AB - BACKGROUND AND PURPOSE: Endovascular treatment of intracranial aneurysms has relevantly changed over the past decades. Multiple new devices such as intrasaccular flow diverters have broadened the treatment spectrum but require very exact aneurysm sizing. In this study, we investigated multidetector and flat panel angiographic CT and digital subtraction imaging as well as different postprocessing methods (multiplanar reconstruction, volume-rendering technique, 3D DSA, and conventional 2D angiography) for their ability to exactly size 2 aneurysm models. MATERIALS AND METHODS: Two aneurysm models with known aneurysm sizes were placed inside a human skull. After injection of iodine contrast media, imaging was performed using a 128-slice CT scanner or an Artis Q biplane angiosuite, respectively. Aneurysms were measured for width, neck, and height, and the mean difference from the known sizes was calculated for each technique. The technique with the most exact measurement was defined as the criterion standard. We performed Bland-Altman plots comparing all techniques against the criterion standard. RESULTS: Angiograms adjusted according a previous 3D run with a short object-to-detector distance resulted in the most exact aneurysm measurement: -0.07 +/- 0.61 mm for aneurysm 1 and 0.17 +/- 0.39 mm for aneurysm 2. Measurements of conventional DSA images were similar, and CT-based images were significantly inferior to the criterion standard. CONCLUSIONS: 2D DSA with a short objective-to-detector distance adjusted according to a previous 3D run resulted in the most exact aneurysm measurement and should therefore be performed before all endovascular aneurysm treatments. PMID- 30409852 TI - Initial and Long-Term Outcomes of Complex Bifurcation Aneurysms Treated by Y Stent-Assisted Coiling with Low-Profile Braided Stents. AB - BACKGROUND AND PURPOSE: Coiling complex intracranial bifurcation aneurysms often necessitates the implantation of double stents in various configurations, such as Y-stent placement. Low-profile braided stents have been introduced recently to facilitate the endovascular treatment of wide-neck aneurysms. We aimed to investigate the feasibility, safety, efficacy, and durability of Y-stent-assisted coiling with double low-profile braided stents for the treatment of complex bifurcation aneurysms. MATERIALS AND METHODS: A retrospective review was performed to identify patients who were treated using Y-stent-assisted coiling with low-profile braided stents. Technical success was assessed, as were initial and follow-up clinical and angiographic outcomes. Periprocedural and delayed complications were reviewed. Preprocedural and follow-up clinical statuses were assessed using the modified Rankin Scale. RESULTS: Forty patients with 40 intracranial aneurysms were included in the study. Y-stent placement was successfully performed in all cases. Immediate postprocedural digital subtraction angiography images revealed total aneurysm occlusion in 72.5% of cases. The mean angiographic follow-up time was 24.8 months. The last follow-up angiograms showed complete occlusion in 85% of patients. During follow-up, only 1 patient showed an increase in the filling status of the aneurysm and that patient did not require retreatment. There was no mortality in this study. The overall procedure-related complication rate, including asymptomatic complications, was 17.5%. A permanent morbidity developed in 1 patient (2.5%). CONCLUSIONS: The long-term angiographic and clinical outcomes of this retrospective study demonstrate that Y-stent assisted coiling using low-profile braided stents is an effective, relatively safe, and durable endovascular treatment for wide-neck and complex bifurcation aneurysms. PMID- 30409853 TI - Depiction of the Superior Petrosal Vein Complex by 3D Contrast-Enhanced MR Angiography. AB - BACKGROUND AND PURPOSE: Intraoperative obliteration of the superior petrosal vein complex has a relevant risk of postoperative complications. A large venous diameter and the absence of anastomoses have been previously suggested as possible risk factors. 3D contrast-enhanced MRA was evaluated for the identification of superior petrosal vein anatomy. MATERIALS AND METHODS: Twenty five patients (10 men; age, 20-77 years) with a 3D-MRA (voxel size, 0.4 * 0.4 * 0.5 mm3) at 3T, including the posterior fossa, were retrospectively identified. Image evaluation was performed independently by 2 neuroradiologists with respect to overall image quality and the presence, location, size, tributaries, and anastomotic veins of the superior petrosal vein complex. Additionally, 8 neurosurgical cases with intraoperative validation of the venous anatomy were examined. RESULTS: All studies were of diagnostic image quality. Interobserver agreement was excellent for image-quality measurements (r = 0.751-0.982) and good for measured vessel size (r = 0.563-0.828). A total of 83 superior petrosal veins were identified. The distribution of drainage locations and identification of tributaries and anastomotic veins were consistent with previous anatomic studies. The results showed that 4.8% of superior petrosal veins had a diameter of >2 mm and lacked a visible anastomosis. All surgical cases showed excellent agreement between the MRA and the intraoperative observations. CONCLUSIONS: 3D-MRA with high resolution is appropriate for analyzing the size, course, tributaries, and anastomoses of the superior petrosal vein. A total of 4.8% of the identified superior petrosal veins had to be classified as potential high-risk veins. The measurements correlated with the intraoperative findings. PMID- 30409854 TI - Synthesizing a Contrast-Enhancement Map in Patients with High-Grade Gliomas Based on a Postcontrast MR Imaging Quantification Only. AB - BACKGROUND AND PURPOSE: Administration of a gadolinium-based contrast agent is an important diagnostic biomarker for blood-brain barrier damage. In clinical use, detection is based on subjective comparison of native and postgadolinium-based contrast agent T1-weighted images. Quantitative MR imaging studies have suggested a relation between the longitudinal relaxation rate and proton-density in the brain parenchyma, which is disturbed by gadolinium-based contrast agents. This discrepancy can be used to synthesize a contrast-enhancement map based solely on the postgadolinium-based contrast agent acquisition. The aim of this study was to compare synthetic enhancement maps with subtraction maps of native and postgadolinium-based contrast agent images. MATERIALS AND METHODS: For 14 patients with high-grade gliomas, quantitative MR imaging was performed before and after gadolinium-based contrast agent administration. The quantification sequence was multidynamic and multiecho, with a scan time of 6 minutes. The 2 image stacks were coregistered using in-plane transformation. The longitudinal relaxation maps were subtracted and correlated with the synthetic longitudinal relaxation enhancement maps on the basis of the postgadolinium-based contrast agent images only. ROIs were drawn for tumor delineation. RESULTS: Linear regression of the subtraction and synthetic longitudinal relaxation enhancement maps showed a slope of 1.02 +/- 0.19 and an intercept of 0.05 +/- 0.12. The Pearson correlation coefficient was 0.861 +/- 0.059, and the coefficient of variation was 0.18 +/- 0.04. On average, a volume of 1.71 +/- 1.28 mL of low intensity enhancement was detected in the synthetic enhancement maps outside the borders of the drawn ROI. CONCLUSIONS: The study shows that there was a good correlation between subtraction longitudinal relaxation enhancement maps and synthetic longitudinal relaxation enhancement maps in patients with high-grade gliomas. The method may improve the sensitivity and objectivity for the detection of gadolinium-based contrast agent enhancement. PMID- 30409855 TI - Brain MR Imaging Findings in Woodhouse-Sakati Syndrome. AB - BACKGROUND AND PURPOSE: Woodhouse-Sakati syndrome is a rare autosomal recessive disorder characterized by hypogonadism, alopecia, diabetes mellitus, and progressive extrapyramidal signs. The disease is caused by biallelic pathogenic variants in the DCAF17 gene. The purpose of this study was to describe the spectrum of brain MR imaging abnormalities in Woodhouse-Sakati syndrome. MATERIALS AND METHODS: We reviewed brain MR images of 26 patients with a clinical and genetic diagnosis of Woodhouse-Sakati syndrome (12 males, 14 females; age range, 16-45 years; mean age, 26.6 years). Follow-up studies were conducted for 6 patients. RESULTS: All patients had abnormal MR imaging findings. The most common abnormalities were a small pituitary gland (76.9%), pronounced basal ganglia iron deposition (73%), and white matter lesions in 69.2%. White matter lesions showed frontoparietal and periventricular predominance. All white matter lesions spared subcortical U-fibers and were nonenhanced. Prominent perivascular spaces (15.3%) and restricted diffusion in the splenium of the corpus callosum (7.6%) were less frequent findings. Follow-up studies showed expansion of white matter lesions with iron deposition further involving the red nucleus and substantia nigra. Older age was associated with a more severe degree of white matter lesions (P < .001). CONCLUSIONS: Small pituitary gland, accentuated iron deposition in the globus pallidus, and nonenhancing frontoparietal/periventricular white matter lesions were the most noted abnormalities seen in our cohort. The pattern and extent of these findings were observed to correlate with older age, reflecting a possible progressive myelin destruction and/or axonal loss. The presence of pituitary hypoplasia and white matter lesions can further distinguish Woodhouse Sakati syndrome from other neurodegenerative diseases with brain iron accumulation subtypes. PMID- 30409856 TI - PUMPKIN, the sole Plastid UMP Kinase, Associates with Group II Introns and Alters Their Metabolism. AB - The chloroplast hosts photosynthesis and a variety of metabolic pathways that are essential for plant viability and acclimation processes. In this study, we show that PUMPKIN, the sole plastid UMP kinase in Arabidopsis (Arabidopsis thaliana), associates specifically with the introns of the plastid transcripts trnG-UCC, trnV-UAC, petB, petD, and ndhA in vivo, as revealed by RNA immunoprecipitation coupled with deep sequencing (RIP-Seq), and can bind RNA efficiently in vitro. Analyses of the target transcripts showed that PUMPKIN affects their metabolism. Null alleles and knockdowns of pumpkin were viable but clearly affected in growth, plastid translation, and photosynthetic performance. In pumpkin mutants, the levels of many plastid transcripts were reduced, while the amounts of others were increased, as revealed by RNA-Seq analysis. PUMPKIN is a homomultimeric plastid-localized protein that forms in vivo RNA-containing megadalton-sized complexes and catalyzes the ATP-dependent conversion of UMP to UDP in vitro with properties characteristic of known essential eubacterial UMP kinases. A moonlighting function of PUMPKIN combining RNA and pyrimidine metabolism is discussed. PMID- 30409857 TI - EPFL signals in the boundary region of the SAM restrict its size and promote leaf initiation. AB - The shoot apical meristem (SAM) enables the formation of new organs throughout the life of a plant. ERECTA family (ERf) receptors restrict SAM size and promote initiation of leaves while simultaneously supporting establishment of correct phyllotaxy. In the epidermis and during organ elongation ERf activity is regulated by a family of Epidermal Patterning Factor-Like (EPFL) secreted cysteine-rich small proteins. Here we show that ERfs play a critical role in communication between the SAM leaf boundary and the central zone. Ectopic expression of ERECTA in the central zone using CLAVATA3 promoter is sufficient to restrict meristem size and promote leaf initiation. Genetic analysis demonstrated that four putative ligands: EPFL1, EPFL2, EPFL4, and EPFL6 function redundantly in the SAM. These genes are expressed at the SAM-leaf boundary and in the peripheral zone. Previously EPFL4 and EPFL6 have been linked with elongation of aboveground organs. Here we demonstrate that EPFL1 and EPFL2 promote organ elongation as well. In addition, we show that expression of ERECTA in the central zone of the SAM has a strong impact on elongation of internodes and pedicels and growth of leaves. These results suggest that ERfs can stimulate organ growth cell non-autonomously. PMID- 30409858 TI - Characterization of proteome variation during modern maize breeding. AB - The success of modern maize breeding has been demonstrated by remarkable increases in productivity with tremendous modification of agricultural phenotypes over the last century. Although the underlying genetic changes of the maize adaptation from tropical to temperate regions have been extensively studied, our knowledge is limited regarding the accordance of protein and mRNA expression levels accompanying such adaptation. Here we conducted an integrative analysis of proteomic and transcriptomic changes in a maize association panel. The minimum extent of correlation between protein and RNA levels suggests that variation in mRNA expression is often not indicative of protein expression at a population scale. This is corroborated by the observation that mRNA- and protein-based co expression networks are relatively independent of each other, and many pQTLs arise without the presence of corresponding eQTLs. Importantly, compared to transcriptome, the subtypes categorized by the proteome show a markedly high accuracy to resemble the genomic subpopulation. These findings suggest that proteome evolved under a greater evolutionary constraint than transcriptome during maize adaptation from tropical to temperate regions. Overall, the integrated multi-omics analysis provides a functional context to interpret gene expression variation during modern maize breeding. PMID- 30409859 TI - Perivascular dendritic cells elicit anaphylaxis by relaying allergens to mast cells via microvesicles. AB - Anaphylactic reactions are triggered when allergens enter the blood circulation and activate immunoglobulin E (IgE)-sensitized mast cells (MCs), causing systemic discharge of prestored proinflammatory mediators. As MCs are extravascular, how they perceive circulating allergens remains a conundrum. Here, we describe the existence of a CD301b+ perivascular dendritic cell (DC) subset that continuously samples blood and relays antigens to neighboring MCs, which vigorously degranulate and trigger anaphylaxis. DC antigen transfer involves the active discharge of surface-associated antigens on 0.5- to 1.0-micrometer microvesicles (MVs) generated by vacuolar protein sorting 4 (VPS4). Antigen sharing by DCs is not limited to MCs, as neighboring DCs also acquire antigen-bearing MVs. This capacity of DCs to distribute antigen-bearing MVs to various immune cells in the perivascular space potentiates inflammatory and immune responses to blood-borne antigens. PMID- 30409860 TI - Contingency and determinism in evolution: Replaying life's tape. AB - Historical processes display some degree of "contingency," meaning their outcomes are sensitive to seemingly inconsequential events that can fundamentally change the future. Contingency is what makes historical outcomes unpredictable. Unlike many other natural phenomena, evolution is a historical process. Evolutionary change is often driven by the deterministic force of natural selection, but natural selection works upon variation that arises unpredictably through time by random mutation, and even beneficial mutations can be lost by chance through genetic drift. Moreover, evolution has taken place within a planetary environment with a particular history of its own. This tension between determinism and contingency makes evolutionary biology a kind of hybrid between science and history. While philosophers of science examine the nuances of contingency, biologists have performed many empirical studies of evolutionary repeatability and contingency. Here, we review the experimental and comparative evidence from these studies. Replicate populations in evolutionary "replay" experiments often show parallel changes, especially in overall performance, although idiosyncratic outcomes show that the particulars of a lineage's history can affect which of several evolutionary paths is taken. Comparative biologists have found many notable examples of convergent adaptation to similar conditions, but quantification of how frequently such convergence occurs is difficult. On balance, the evidence indicates that evolution tends to be surprisingly repeatable among closely related lineages, but disparate outcomes become more likely as the footprint of history grows deeper. Ongoing research on the structure of adaptive landscapes is providing additional insight into the interplay of fate and chance in the evolutionary process. PMID- 30409861 TI - Navigating cognition: Spatial codes for human thinking. AB - The hippocampal formation has long been suggested to underlie both memory formation and spatial navigation. We discuss how neural mechanisms identified in spatial navigation research operate across information domains to support a wide spectrum of cognitive functions. In our framework, place and grid cell population codes provide a representational format to map variable dimensions of cognitive spaces. This highly dynamic mapping system enables rapid reorganization of codes through remapping between orthogonal representations across behavioral contexts, yielding a multitude of stable cognitive spaces at different resolutions and hierarchical levels. Action sequences result in trajectories through cognitive space, which can be simulated via sequential coding in the hippocampus. In this way, the spatial representational format of the hippocampal formation has the capacity to support flexible cognition and behavior. PMID- 30409863 TI - News at a glance. PMID- 30409862 TI - Facing hatred. PMID- 30409864 TI - World poised to adopt new metric units. PMID- 30409866 TI - Ancient DNA tracks migrations around Americas. PMID- 30409865 TI - Early Mongolians ate dairy, but lacked the gene to digest it. PMID- 30409867 TI - Indonesian fatwa causes immunization rates to drop. PMID- 30409869 TI - Stopping the sting. PMID- 30409868 TI - U.S. labs using a record number of monkeys. PMID- 30409870 TI - Whose science? A new era in regulatory "science wars". PMID- 30409871 TI - Dangerous liaisons in anaphylaxis. PMID- 30409872 TI - A key ingredient for priming killer T cells. PMID- 30409873 TI - Pesticide affects social behavior of bees. PMID- 30409874 TI - Recruiting more proteins to the RNA world. PMID- 30409875 TI - Scaling up solid-state quantum photonics. PMID- 30409876 TI - Denuclearizing North Korea requires trust. PMID- 30409877 TI - Neutrino physics for Korean diplomacy. PMID- 30409878 TI - Improve traffic death statistics in China. PMID- 30409879 TI - Suppressing corrosion in primary aluminum-air batteries via oil displacement. AB - Primary aluminum-air batteries boast high theoretical energy densities, but negative electrode corrosion irreversibly limits their shelf life. Most corrosion mitigation methods are insufficient or compromise power and energy density. We suppressed open-circuit corrosion by displacing electrolyte from the electrode surface with a nonconducting oil during battery standby. High power and energy density are enabled by displacing the oil with electrolyte for battery discharge. The underwater-oleophobic wetting properties of the designed cell surfaces allow for reversible oil displacement. We demonstrate this method in an aluminum-air cell that achieves a 420% increase in usable energy density and 99.99% reduction in corrosion, which lowers self-discharge to a rate of 0.02% a month and enables system energy densities of 700 watt-hours per liter and 900 watt-hours per kilogram. PMID- 30409880 TI - Nested sequences of hippocampal assemblies during behavior support subsequent sleep replay. AB - Consolidation of spatial and episodic memories is thought to rely on replay of neuronal activity sequences during sleep. However, the network dynamics underlying the initial storage of memories during wakefulness have never been tested. Although slow, behavioral time scale sequences have been claimed to sustain sequential memory formation, fast ("theta") time scale sequences, nested within slow sequences, could be instrumental. We found that in rats traveling passively on a model train, place cells formed behavioral time scale sequences but theta sequences were degraded, resulting in impaired subsequent sleep replay. In contrast, when the rats actively ran on a treadmill while being transported on the train, place cells generated clear theta sequences and accurate trajectory replay during sleep. Our results support the view that nested sequences underlie the initial formation of memory traces subsequently consolidated during sleep. PMID- 30409881 TI - Global pattern of nest predation is disrupted by climate change in shorebirds. AB - Ongoing climate change is thought to disrupt trophic relationships, with consequences for complex interspecific interactions, yet the effects of climate change on species interactions are poorly understood, and such effects have not been documented at a global scale. Using a single database of 38,191 nests from 237 populations, we found that shorebirds have experienced a worldwide increase in nest predation over the past 70 years. Historically, there existed a latitudinal gradient in nest predation, with the highest rates in the tropics; however, this pattern has been recently reversed in the Northern Hemisphere, most notably in the Arctic. This increased nest predation is consistent with climate induced shifts in predator-prey relationships. PMID- 30409882 TI - Neonicotinoid exposure disrupts bumblebee nest behavior, social networks, and thermoregulation. AB - Neonicotinoid pesticides can negatively affect bee colonies, but the behavioral mechanisms by which these compounds impair colony growth remain unclear. Here, we investigate imidacloprid's effects on bumblebee worker behavior within the nest, using an automated, robotic platform for continuous, multicolony monitoring of uniquely identified workers. We find that exposure to field-realistic levels of imidacloprid impairs nursing and alters social and spatial dynamics within nests, but that these effects vary substantially with time of day. In the field, imidacloprid impairs colony thermoregulation, including the construction of an insulating wax canopy. Our results show that neonicotinoids induce widespread disruption of within-nest worker behavior that may contribute to impaired growth, highlighting the potential of automated techniques for characterizing the multifaceted, dynamic impacts of stressors on behavior in bee colonies. PMID- 30409883 TI - Heterogeneity in efflux pump expression predisposes antibiotic-resistant cells to mutation. AB - Antibiotic resistance is often the result of mutations that block drug activity; however, bacteria also evade antibiotics by transiently expressing genes such as multidrug efflux pumps. A crucial question is whether transient resistance can promote permanent genetic changes. Previous studies have established that antibiotic treatment can select tolerant cells that then mutate to achieve permanent resistance. Whether these mutations result from antibiotic stress or preexist within the population is unclear. To address this question, we focused on the multidrug pump AcrAB-TolC. Using time-lapse microscopy, we found that cells with higher acrAB expression have lower expression of the DNA mismatch repair gene mutS, lower growth rates, and higher mutation frequencies. Thus, transient antibiotic resistance from elevated acrAB expression can promote spontaneous mutations within single cells. PMID- 30409886 TI - Finding peace with pencil. PMID- 30409887 TI - Stress and functional neurological disorders: mechanistic insights. AB - At the interface between mind and body, psychiatry and neurology, functional neurological disorder (FND) remains poorly understood. Formerly dominant stress related aetiological models have been increasingly challenged, in part due to cases without any history of past or recent trauma. In this perspective article, we review current evidence for such models, and how research into the role of traumatic stress in other disorders and the neurobiology of the stress response can inform our mechanistic understanding of FND. First, we discuss the association between stress and the onset or exacerbation of a variety of physical and mental health problems. Second, we review the role of hypothalamic-pituitary adrenal axis dysfunction in the neurobiology of ill-health, alongside evidence for similar mechanisms in FND. Third, we advocate a stress-diathesis model, in which biological susceptibility interacts with early life adversity, where FND can be precipitated by traumatic events later in life and maintained by psychological responses. We hypothesise that greater biological susceptibility to FND is associated with less severe remote and recent stress, and that FND precipitated by more severe stress is associated with lower biological vulnerability. This would explain clinical experience of variable exposure to historical and recent traumatic stress among people with FND and requires empirical investigation. A testable, evidence-based stress-diathesis model can inform nuanced understanding of how biological and psychological factors interact at the individual level, with potential to inform personalised treatment pathways. Much-needed research to establish the aetiology of FND will enhance clinical care and communication, facilitate effective treatment and inform prevention strategies. PMID- 30409884 TI - WDFY4 is required for cross-presentation in response to viral and tumor antigens. AB - During the process of cross-presentation, viral or tumor-derived antigens are presented to CD8+ T cells by Batf3-dependent CD8alpha+/XCR1+ classical dendritic cells (cDC1s). We designed a functional CRISPR screen for previously unknown regulators of cross-presentation, and identified the BEACH domain-containing protein WDFY4 as essential for cross-presentation of cell-associated antigens by cDC1s in mice. However, WDFY4 was not required for major histocompatibility complex class II presentation, nor for cross-presentation by monocyte-derived dendritic cells. In contrast to Batf3 -/- mice, Wdfy4 -/- mice displayed normal lymphoid and nonlymphoid cDC1 populations that produce interleukin-12 and protect against Toxoplasma gondii infection. However, similar to Batf3 -/- mice, Wdfy4 -/ mice failed to prime virus-specific CD8+ T cells in vivo or induce tumor rejection, revealing a critical role for cross-presentation in antiviral and antitumor immunity. PMID- 30409885 TI - De novo design of self-assembling helical protein filaments. AB - We describe a general computational approach to designing self-assembling helical filaments from monomeric proteins and use this approach to design proteins that assemble into micrometer-scale filaments with a wide range of geometries in vivo and in vitro. Cryo-electron microscopy structures of six designs are close to the computational design models. The filament building blocks are idealized repeat proteins, and thus the diameter of the filaments can be systematically tuned by varying the number of repeat units. The assembly and disassembly of the filaments can be controlled by engineered anchor and capping units built from monomers lacking one of the interaction surfaces. The ability to generate dynamic, highly ordered structures that span micrometers from protein monomers opens up possibilities for the fabrication of new multiscale metamaterials. PMID- 30409888 TI - Evidence for increased completed suicide in first-degree relatives of LRRK2 G2019S mutation Parkinson's disease. PMID- 30409889 TI - Soft signs in movement disorders: friends or foes? PMID- 30409891 TI - Chemotherapy-free induction in MCL: ready for prime time? PMID- 30409890 TI - Epidemiology of ALS in Korea using nationwide big data. AB - OBJECTIVE: This study aimed to determine the incidence, prevalence and survival time of Korean patients with amyotrophic lateral sclerosis (ALS) using National Health Insurance Service (NHIS) data. METHODS: Using NHIS data, the Korean nationwide health dataset, we identified patients with motor neuron diseases who were first diagnosed with a KCD-6 code (G12.20-G12.28; modified from ICD-10 codes) between 2011 and 2015. ALS (G12.21 code) epidemiological characteristics, including annual incidence, prevalence, mortality rates and survival time, were analysed and compared with sociodemographic variables. RESULTS: New patients with ALS (n=3049) were enrolled over 5 years. The mean annual incidence was 1.20/100 000, and the sex ratio was 1.60 (male:female). The mean age at the time of diagnosis was 61.4 years. The prevalence rate was 3.43/100 000 in 2015. In this period, riluzole was prescribed to 53.6% of patients with ALS. Furthermore, 20.3% of patients with ALS underwent tracheostomy. When analysed for age and socioeconomic status, ALS prevalence rate was 10.71 in the aged group (>=60) in 2015 and was lowest in the middle-income group compared with that in the high income and low-income groups. The estimated mean survival time in this population was 50.0 months, and the 3-year and 5-year mortality rates were 52.1% and 63.7%, respectively. CONCLUSIONS: This study is the first nationwide survey for epidemiological characteristics of ALS in Korea using national data. The use of these data substantially advances the understanding of Korean and Asian ALS epidemiology and its relationship with socioeconomic status, age and sex. PMID- 30409893 TI - Erythrocytes and erythroblasts give up iron. PMID- 30409892 TI - EPHB2 regulates platelet activation. PMID- 30409894 TI - HLH: watch and wait, or act and cure? PMID- 30409895 TI - One over PAR or one under PAR: vive la difference. PMID- 30409896 TI - B & B: basophils and bleeding, an atypical case of acute promyelocytic leukemia. PMID- 30409897 TI - Gynaecologist whose erasure was quashed in High Court is fit to practise. PMID- 30409898 TI - Hypercalcaemia with undetectable parathormone levels. PMID- 30409899 TI - Prevalence of Opioid, Gabapentinoid, and NSAID Use in Patients with CKD. PMID- 30409900 TI - Hyperactivity of the transcription factor Nrf2 causes metabolic reprogramming in mouse esophagus. AB - Mutations in the genes encoding nuclear factor (erythroid-derived 2)-like 2 (NRF2), Kelch-like ECH-associated protein 1 (KEAP1), and cullin 3 (CUL3) are commonly observed in human esophageal squamous cell carcinoma (ESCC) and result in activation of the NRF2 signaling pathway. Moreover, hyperactivity of the transcription factor Nrf2 has been found to cause esophageal hyperproliferation and hyperkeratosis in mice. However, the underlying mechanism is unclear. In this study, we aimed to understand the molecular mechanisms of esophageal hyperproliferation in mice due to hyperactive Nrf2. Esophageal tissues were obtained from genetically modified mice that differed in the status of the Nrf2 gene and genes in the same pathway (Nrf2-/-, Keap1-/-, K5Cre;Pkm2fl/fl;Keap1-/-, and wild-type) and analyzed for metabolomic profiles, Nrf2 ChIP-Seq, and gene expression. We found that hyperactive Nrf2 causes metabolic reprogramming and up regulation of metabolic genes in the mouse esophagus. One of the glycolysis genes encoding pyruvate kinase M2 (Pkm2) was not only differentially up-regulated, but also glycosylated and oligomerized, resulting in increased ATP biosynthesis. However, constitutive knockout of Pkm2 failed to inhibit this esophageal phenotype in vivo, and this failure may have been due to compensation by Pkm1 up regulation. Transient inhibition of NRF2 or glycolysis inhibited the growth of human ESCC cells in which NRF2 is hyperactive in vitro In summary, hyperactive Nrf2 causes metabolic reprogramming in the mouse esophagus through its transcriptional regulation of metabolic genes. Blocking glycolysis transiently inhibits cell proliferation and may therefore have therapeutically beneficial effects on NRF2high ESCC in humans. PMID- 30409901 TI - The ribosomal maturation factor P from Mycobacterium smegmatis facilitates the ribosomal biogenesis by binding to the small ribosomal protein S12. AB - The ribosomal maturation factor P RimP is a highly conserved protein in bacteria and has been shown to be important in ribosomal assembly in Escherichia coli (E coli). Because of its central importance in bacterial metabolism, RimP represents a good potential target for drug design to combat human pathogens such as Mycobacterium tuberculosis (Mtb). However, to date the only RimP structure available is the NMR structure of the ortholog in another bacterial pathogen Streptococcus pneumoniae Here, we report a 2.2 A resolution crystal structure of MSMEG_2624, the RimP ortholog in the close Mtb relative Mycobacterium smegmatis, and using in vitro binding assays, we show that MSMEG_2624 interacts with the small ribosomal protein S12, also known as RpsL. Further analyses revealed that the conserved residues in the linker region between the N- and C-terminal domains of MSMEG_2624 are essential for binding to RpsL. However, neither of the two domains alone was sufficient to form strong interactions with RpsL. More importantly, the linker region was essential for in vivo ribosomal biogenesis. Our study provides critical mechanistic insights into the role of RimP in ribosome biogenesis. We anticipate that the MSMEG_2624 crystal structure has the potential to beused for drug design to manage Mtb infections. PMID- 30409902 TI - Prostaglandin E2down-regulates sirtuin 1 (SIRT1) leading to elevated levels of aromatase, providing insights into the obesity-breast cancer connection. AB - Obesity increases the risk of hormone receptor-positive breast cancer in postmenopausal women. Levels of aromatase, the rate-limiting enzyme in estrogen biosynthesis, are increased in the breast tissue of obese women. Both prostaglandin E2(PGE2) and hypoxia-inducible factor 1alpha (HIF-1alpha) contribute to the induction of aromatase in adipose stromal cells (ASCs). Sirtuin 1 (SIRT1) binds, deacetylates and thereby inactivates HIF-1alpha. Here, we sought to determine whether SIRT1 also plays a role in regulating aromatase expression. We demonstrate that reduced SIRT1 levels are associated with elevated levels of acetyl-HIF-1alpha, HIF-1alpha and aromatase in breast tissue of obese compared with lean women. To determine whether these changes were functionally linked, ASCs were utilized. In ASCs, treatment with PGE2, which is increased in obese individuals, down regulated SIRT1 levels, leading to elevated acetyl-HIF-1alpha and HIF-1alpha levels and enhanced aromatasegene transcription. Chemical SIRT1 activators (SIRT1720, resveratrol) suppressed the PGE2-mediated induction of acetyl-HIF-1alpha, HIF-1alpha and aromatase. Silencing of p300/CBP-associated factor (PCAF), which acetylates HIF-1alpha, blocked PGE2-mediated increases in acetyl-HIF-1alpha, HIF-1alpha and aromatase. SIRT1 overexpression or PCAF silencing inhibited the interaction between HIF-1alpha and p300, a coactivator of aromatase expression, and suppressed p300 binding to the aromatasepromoter. PGE2 acted via prostaglandin E2 receptor 2 (EP2) and EP4 to induce activating transcription factor 3 (ATF3), a repressive transcription factor, which bound to a CREB site within the SIRT1promoter and reduced SIRT1 levels. These findings suggest that reduced SIRT1-mediated deacetylation of HIF-1alpha contributes to the elevated levels of aromatase in breast tissues of obese women. PMID- 30409903 TI - The nucleosome remodeling and deacetylase complex protein CHD4 regulates neural differentiation of mouse embryonic stem cells by down-regulating p53. AB - Lineage specification of the three germ layers occurs during early embryogenesis and is critical for normal development. The nucleosome remodeling and deacetylase (NuRD) complex is a repressive chromatin modifier that plays a role in lineage commitment. However, the role of chromodomain helicase DNA-binding protein 4 (CHD4), one of the core subunits of the NuRD complex, in neural lineage commitment is poorly understood. Here, we report that the CHD4/NuRD complex plays a critical role in neural differentiation of mouse embryonic stem cells (ESCs). We found that RNAi-mediated Chd4 knockdown suppresses neural differentiation, as did knockdown of methyl-CpG binding domain protein Mbd3, another NuRD subunit. Chd4 and Mbd3 knockdowns similarly affected changes in global gene expression during neural differentiation and up-regulated several mesendodermal genes. However, inhibition of mesendodermal genes by knocking out the master regulators of mesendodemal lineages, Brachyury and Eomes, through a CRISPR/Cas9 approach could not restore the impaired neural differentiation caused by the Chd4 knockdown, suggesting that CHD4 controls neural differentiation not by repressing other lineage differentiation processes. Notably, Chd4 knockdown increased the acetylation levels of p53, resulted in increased protein levels of p53. Double knockdown of Chd4 and p53 restored the neural differentiation rate. Furthermore, overexpression of BCL2, a downstream factor of p53, partially rescued the impaired neural differentiation caused by the Chd4 knockdown. Our findings reveal that the CHD4/NuRD complex regulates neural differentiation of ESCs by down regulating p53. PMID- 30409904 TI - Reciprocal negative regulation between the tumor suppressor protein p53 and B cell CLL/lymphoma 6 (BCL6) via control of caspase-1 expression. AB - Even in the face of physiological DNA damage or expression of the tumor suppressor protein p53, B cell CLL/lymphoma 6 (BCL6) increases proliferation and antagonizes apoptotic responses in B cells. BCL6 represses TP53 transcription and also appears to inactivate p53 at the protein level, and additional findings have suggested negative mutual regulation between BCL6 and p53. Here, using Bcl6-/- knockout mice, HEK293A and HCT116 p53 -/- cells, and site-directed mutagenesis, we found that BCL6 interacts with p53 and thereby inhibits acetylation of Lys-132 in p53 by E1A binding protein p300 (p300), a modification that normally occurs upon DNA damage-induced cellular stress and whose abrogation by BCL6 diminished transcriptional activation of p53 target genes, including that encoding caspase 1. Conversely, we also found that BCL6 protein is degraded via p53-induced, caspase-mediated proteolytic cleavage and the formation of a BCL6-p53-caspase-1 complex. Our results suggest that p53 may block oncogenic transformation by decreasing BCL6 stability via caspase-1 up-regulation, whereas aberrant BCL6 expression inactivates transactivation of p53 target genes, either by inhibiting p53 acetylation by p300 or repressing TP53 gene transcription. These findings have implications for B cell development and lymphomagenesis. PMID- 30409905 TI - Up-regulation of collagen proteins in colorectal liver metastasis compared with normal liver tissue. AB - Changes to extracellular matrix (ECM) structures are linked to tumor cell proliferation and metastasis. We previously reported that naturally occurring peptides of collagen type I are elevated in urine of patients with colorectal liver metastasis (CRLM). In the present study, we took an MS-based proteomic approach to identify specific collagen types that are up-regulated in CRLM tissues compared with healthy, adjacent liver tissues from the same patients. We found that 19 of 22 collagen alpha chains are significantly up-regulated (P < 0.05) in CRLM tissues compared with the healthy tissues. At least four collagen alpha chains were absent or had low expression in healthy colon and adjacent tissues, but were highly abundant in both colorectal cancer (CRC) and CRLM tissues. This expression pattern was also observed for six non-collagen colon specific proteins, two of which (CDH17 and PPP1R1B/DARP-32) had not previously been linked to CRLM. Furthermore, we observed CRLM-associated up-regulation of 16 proteins (out of 20 associated proteins identified) known to be required for collagen synthesis, indicating increased collagen production in CRLM. Immunohistochemistry validated that collagen type XII is significantly up regulated in CRLM. The results of this study indicate that most collagen isoforms are up-regulated in CRLM compared with healthy tissues, most likely as a result of an increased collagen production in the metastatic cells. Our findings provide further insight into morphological changes in the ECM in CRLM and help explain the finding of tumor metastasis-associated proteins and peptides in urine, suggesting their utility as metastasis biomarkers. PMID- 30409906 TI - Coagulation factor XIIIa crosslinks amyloid b into dimers and oligomers and to blood proteins. AB - In cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD), the amyloid beta(Abeta) peptide deposits along the vascular lumen, leading to degeneration and dysfunction of surrounding tissues. Activated coagulation factor XIIIa (FXIIIa) covalently crosslinks proteins in blood and vasculature, such as in blood clots and on the extracellular matrix. Although FXIIIa co-localizes with Abeta in CAA, the ability of FXIIIa to crosslink Abeta has not been demonstrated. Using Western blotting, kinetic assays and microfluidic analyses, we show that FXIIIa covalently crosslinks Abeta40 into dimers and oligomers (kcat/Km = 1.5 X 105 M -1s-1), as well as to fibrin, platelet proteins, and to blood clots under flow in vitro Abeta40 also increased the stiffness of platelet-rich plasma clots in the presence of FXIIIa. These results suggest that FXIIIa-mediated crosslinking may contribute to the formation of Abeta deposits in CAA and AD. PMID- 30409907 TI - Functional consequences of the CAPOS mutation E818K of Na+,K+-ATPase. AB - The CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) syndrome is caused by the single mutation E818K of the alpha3-isoform of Na+,K+-ATPase. Here, using biochemical and electrophysiological approaches, we examined the functional characteristics of E818K as well as of E818Q and E818A mutants. We found that these amino acid substitutions reduce the apparent Na+ affinity at the cytoplasmic-facing sites of the pump protein and that this effect is more pronounced for the lysine and glutamine substitutions (3- to 4-fold) than for the alanine substitution. The electrophysiological measurements indicated a more conspicuous, ~30-fold reduction of apparent Na+ affinity for the extracellular-facing sites in the CAPOS mutant, which was related to an accelerated transition between the phosphoenzyme intermediates E1P and E2P. The apparent affinity for K+ activation of the ATPase activity was unaffected by these substitutions, suggesting that primarily the Na+-specific site III is affected. Furthermore, the apparent affinities for ATP and vanadate were wild type-like in E818K, indicating a normal E1-E2 equilibrium of the dephosphoenzyme. Proton-leak currents were not increased in E818K. However, the CAPOS mutation caused a weaker voltage dependence of the pumping rate and a stronger inhibition by cytoplasmic K+ than the wild type enzyme, which together with the reduced Na+ affinity of the cytoplasmic-facing sites precluded proper pump activation under physiological conditions. The functional deficiencies could be traced to the participation of Glu-818 in an intricate hydrogen bonding/salt bridge network connecting it to key residues involved in Na+ interaction at site III. PMID- 30409908 TI - Chaperome heterogeneity and its implications for cancer study and treatment. AB - The chaperome is the collection of proteins in the cell that carry out molecular chaperoning functions. Changes in the interaction strength between chaperome proteins lead to an assembly that is functionally and structurally distinct from each constituent member. In this review, we discuss the epichaperome, the cellular network that forms when the chaperome components of distinct chaperome machineries come together as stable, functionally integrated, multimeric complexes. In tumors, maintenance of the epichaperome network is vital for tumor survival, rendering them vulnerable to therapeutic interventions that target critical epichaperome network components. We discuss how the epichaperome empowers an approach for precision medicine cancer trials where a new target, biomarker, and relevant drug candidates can be correlated and integrated. We introduce chemical biology methods to investigate the heterogeneity of the chaperome in a given cellular context. Lastly, we discuss how ligand-protein binding kinetics are more appropriate than equilibrium binding parameters to characterize and unravel chaperome targeting in cancer and to gauge the selectivity of ligands for specific tumor-associated chaperome pools. PMID- 30409909 TI - Carboxypeptidase in prolyl oligopeptidase family: Unique enzyme activation and substrate-screening mechanisms. AB - Serine peptidases of the prolyl oligopeptidase (POP) family are of substantial therapeutic importance because of their involvement in diseases such as diabetes, cancer, neurological diseases, and autoimmune disorders. Proper annotation and knowledge of substrate specificity mechanisms in this family are highly valuable. Although endopeptidase, dipeptidyl peptidase, tripeptidyl peptidase, and acylaminoacyl peptidase activities have been reported previously, here we report the first instance of carboxypeptidase activity in a POP family member. We determined the crystal structures of this carboxypeptidase, a S9C subfamily member from Deinococcus radiodurans, in its active and inactive states at 2.3 A resolution, providing an unprecedented view of assembly and disassembly of the active site mediated by an arginine residue. We observed that this residue is poised to bind substrate in the active structure and disrupts the catalytic triad in the inactive structure. The assembly of the active site is accompanied by the ordering of gating loops, which reduces the effective size of the oligomeric pore. This prevents the entry of larger peptides and constitutes a novel mechanism for substrate screening. Further, we observed structural adaptations that enable its carboxypeptidase activity, with a unique loop and two arginine residues in the active site cavity orienting the peptide substrate for catalysis. Using these structural features, we identified homologs of this enzyme in the POP family and confirmed the presence of carboxypeptidase activity in one of them. In conclusion, we have identified a new type within POP enzymes that exhibits not only unique activity, but also a novel substrate-screening mechanism. PMID- 30409910 TI - Blocking the proteolytic activity of zymogen matriptase with antibody-based inhibitors. AB - Matriptase is a member of the type-II transmembrane serine protease (TTSP) 1 family and plays a crucial role in the development and maintenance of epithelial tissues. As all chymotrypsin-like serine proteases, matriptase is synthesized as a zymogen (proform), requiring a cleavage event for full activity. Recent studies suggest that the zymogen of matriptase possesses enough catalytic activity to not only facilitate autoactivation, but also carry out its in vivo functions, which include activating several proteolytic and signaling cascades. Inhibition of zymogen matriptase may therefore be a highly effective approach for limiting matriptase activity. To this end, here we sought to characterize the catalytic activity of human zymogen matriptase and to develop monoclonal antibody inhibitors against this enzyme form. Using a mutated variant of matriptase in which the serine protease domain is locked in the zymogen conformation, we confirmed that the zymogen form of human matriptase has catalytic activity. Moreover, the crystal structure of the catalytic domain of zymogen matriptase was solved to 2.5 A resolution to characterize specific antibody-based matriptase inhibitors and to further structure-based studies. Finally, we describe the first antibody-based competitive inhibitors that target both the zymogen and activated forms of matriptase. We propose that these antibodies provide a more efficient way to regulate matriptase activity by targeting the protease both before and after its activation and may be of value for both research and pre-clinical applications. PMID- 30409911 TI - Replacement of Lys-300 with a glutamine in the NhaA Na+/H+ antiporter of Escherichia coli yields a functional electrogenic transporter. AB - Much of the research on Na+/H+ exchange has been done in prokaryotic models, mainly on the NhaA Na+/H+ exchanger from Escherichia coli (EcNhaA). Two conserved aspartate residues, Asp-163 and Asp-164, are essential for transport and are candidates for possible binding sites for the two H+ that are exchanged for one Na+ to make the overall transport process electrogenic. More recently, a proposed mechanism of transport for EcNhaA has suggested direct binding of one of the transported H+ to the conserved Lys-300 residue, a salt bridge partner of Asp 163. This contention is supported by a study reporting that substitution of the equivalent residue, Lys-305, of a related Na+/H+ antiporter, NapA from Thermus thermophilus, renders the transporter electroneutral. In this work, we sought to establish whether the Lys-300 residue and its partner Asp-163 are essential for the electrogenicity of EcNhaA. To that end, we replaced Lys-300 with Gln, either alone or together with the simultaneous substitution of Asp-163 with Asn, and characterized these transporter variants in electrophysiological experiments combined with H+ transport measurements and stability analysis. We found that K300Q EcNhaA can still support electrogenic Na+/H+ antiport in EcNhaA, but has reduced thermal stability. A parallel electrophysiological investigation of the K305Q variant of TtNapA revealed that it is also electrogenic. Furthermore, replacement of both salt bridge partners in the ion-binding site of EcNhaA produced an electrogenic variant (D163N-K300Q). Our findings indicate that alternative mechanisms sustain EcNhaA activity in the absence of canonical ion binding residues and that the conserved lysines confer structural stability. PMID- 30409913 TI - Correction: Systemic inflammation and suicide risk: cohort study of 419 527 Korean men and women. PMID- 30409912 TI - Dynamic acetylation of the kinetochore-associated protein HEC1 ensures accurate microtubule-kinetochore attachment. AB - Faithful chromosome segregation during mitosis is critical for maintaining genome integrity in cell progeny and relies on accurate and robust kinetochore microtubule attachments. The NDC80 complex, a tetramer comprising kinetochore protein HEC1 (HEC1), NDC80 kinetochore complex component NUF2 (NUF2), NDC80 kinetochore complex component SPC24 (SPC24), and SPC25, plays a critical role in kinetochore-microtubule attachment. Mounting evidence indicates that phosphorylation of HEC1 is important for regulating the binding of the NDC80 complex to microtubules. However, it remains unclear whether other post translational modifications, such as acetylation, regulate NDC80-microtubule attachment during mitosis. Here, using pulldown assays with Hela cell lysates and site-directed mutagenesis, we show that HEC1 is a bona fide substrate of the lysine acetyltransferase Tat-interacting protein, 60KD(TIP60) and that TIP60 mediated acetylation of HEC1 is essential for accurate chromosome segregation in mitosis. We demonstrate that TIP60 regulates the dynamic interactions between NDC80 and spindle microtubules during mitosis and observed that TIP60 acetylates HEC1 at two evolutionarily conserved residues Lys-53 and Lys-59. Importantly, this acetylation weakened the phosphorylation of the N-terminal HEC11-80 region at Ser-55 and Ser-62, which is governed by Aurora B and regulates NDC80 microtubule dynamics, indicating functional cross-talk between these two post translational modifications of HEC1. Moreover, the TIP60-mediated acetylation was specifically reversed by sirtuin1 (SIRT1). Taken together, our results define a conserved signaling hierarchy, involving HEC1, TIP60, Aurora B, and SIRT1, which integrates dynamic HEC1 acetylation and phosphorylation for accurate kinetochore- microtubule attachment in the maintenance of genomic stability during mitosis. PMID- 30409915 TI - Comparative effectiveness and harms of intravitreal antivascular endothelial growth factor agents for three retinal conditions: a systematic review and meta analysis. AB - Intravitreal antivascular endothelial growth factor (VEGF) agents are widely used to treat ocular conditions but the benefits and harms of these treatments are uncertain. We conducted a systematic review to compare the effects of aflibercept, bevacizumab and ranibizumab on best-corrected visual acuity (BCVA) changes, quality of life and ocular or systemic adverse events in patients with neovascular age-related macular degeneration (NVAMD), diabetic macular oedema (DME) and central or branch retinal vein occlusion (RVO). We searched published and unpublished literature sources to February 2017 for randomised controlled trials and cohort or modelling studies reporting comparative costs in the USA. Two reviewers extracted data and graded the strength of the evidence using established methods. Of 17 included trials, none reported a clinically important difference (>= 5 letters) in visual acuity gains between agents. Nine trials provide high-strength evidence of no difference between bevacizumab and ranibizumab for NVAMD. Three trials provide moderate-strength evidence of no difference between bevacizumab and ranibizumab for DME. There was low-strength evidence of similar effects between aflibercept and ranibizumab for NVAMD, aflibercept and bevacizumab for RVO and all three agents for DME. There was insufficient evidence to compare bevacizumab and ranibizumab for RVO. Rates of ocular adverse events were low, and systemic harms were generally similar between groups, although 1 DME trial reported more arterial thrombotic events with ranibizumab versus aflibercept. Overall, no agent had a clear advantage over another for effectiveness or safety. Aflibercept and ranibizumab were significantly less cost-effective than repackaged bevacizumab in two trials. Systematic review registration number: CRD42016034076. PMID- 30409916 TI - Quantitative analysis of structure-function relationship between ocular motility and superior oblique muscle hypoplasia in unilateral superior oblique palsy. AB - AIMS: To determine the structure-function relationship between the degree of superior oblique (SO) hypoplasia and ocular motility in unilateral SO palsy. METHODS: A total of 166 patients with unilateral SO palsy were divided into three groups based on their aetiology and high-resolution MRI findings by an in-plane resolution of 0.25 mm: (1) congenital SO palsy and unilateral trochlear nerve agenesis (absent group, n=79), (2) congenital SO palsy and symmetric trochlear nerves on both sides (present group, n=40) and (3) acquired SO palsy (acquired group, n=47) who all had symmetric trochlear nerves on both sides. The degree of SO hypoplasia was defined as the ratio of SO area between the paretic and nonparetic sides (SOP/N) at the optic nerve-globe junction on MR images. Multivariate analysis was performed to investigate the relationship between SO hypoplasia and ocular motility parameters. RESULTS: The degree of SO hypoplasia (SOP/N) showed a weak negative correlation with bilateral head tilt differences in all groups (beta=-0.009, p<0.001 in the absent group; beta=-0.003, p=0.034 in the present group; beta=-0.007, p=0.002 in the acquired group). There was only a weak positive correlation with SOP/N and hypertropia differences between both gazes in the absent group (beta=0.009, p<0.001) and the acquired group (beta=0.007, p=0.001). In addition, none of the other ocular motility parameters were related to the degree of SO hypoplasia in all groups. CONCLUSION: Regardless of the aetiology of unilateral SO palsy, the structure-function relationship of the paretic SO size and ocular motility examination was weak and almost negligible. PMID- 30409917 TI - Human papillomavirus vaccine uptake among young gay and bisexual men who have sex with men with a time-limited targeted vaccination programme through sexual health clinics in Melbourne in 2017. AB - OBJECTIVE: In mid-2017, the Victorian Government funded a free time-limited human papillomavirus (HPV) vaccination catch-up programme for gay and bisexual men who have sex with men (MSM) aged up to 26 years through sexual health clinics or other immunisation centres. We aimed to examine the uptake of the HPV vaccine among young MSM attending the Melbourne Sexual Health Centre (MSHC). METHODS: MSM aged <=26 attending MSHC between 27 April 2017 and 31 December 2017 were included in the analysis. HPV vaccine uptake was calculated based on the first consultation of each patient during the period. Multivariable logistic regression was performed to examine the association between vaccine uptake and patient factors. RESULTS: There were 2108 MSM aged <=26 who attended MSHC over the study period, with 7.6% (n=161) reporting previous HPV vaccination. Of the 1947 eligible men, 1134 (58.2%, 95% CI 56.0% to 60.4%) were offered the vaccine by the clinicians, and 830 men received it on the day. The vaccine coverage among all eligible MSM was 42.6% (95% CI 40.4% to 44.9%; 830 of 1947) and among MSM who were offered the vaccine by the clinicians was 73.2% (95% CI 70.5% to 75.8%; 830 of 1134). Men with a history of genital warts (adjusted OR (aOR)=3.11, 95%CI 1.39 to 6.99) and those who had >4male partners in the last 12 months (aOR=1.38, 95% CI 1.04 to 1.85) were more likely to receive the HPV vaccine on the day. 304 men declined the vaccine; most men did not specify the reason (31.3%, n=95), while 27.3% (n=83) needed time to think. CONCLUSION: Although vaccine uptake was 73.2% among those offered, the actual coverage of those eligible remained unsatisfactory (42.6%) in a sexual health clinic. This highlights a clinic-based targeted MSM programme may not reach sufficiently high vaccine coverage to provide MSM with the same vaccine benefits as heterosexuals. PMID- 30409918 TI - Inconsistent condom use with known HIV-positive partners among newly diagnosed HIV-positive men who have sex with men interviewed for partner services in New York City, 2014. AB - OBJECTIVES: Condomless anal intercourse contributes significantly to the spread of HIV among men who have sex with men (MSM). Factors related to condomless anal intercourse with known HIV-positive partners among MSM are not well understood. The authors describe factors associated with inconsistent condom use with known HIV-positive partners prior to participants' diagnosis with HIV. METHODS: New York City health department disease intervention specialists interviewed newly HIV-diagnosed MSM ages >=13 years reporting knowingly having anal sex with HIV positive partners between June 2013 and October 2014. Univariate and bivariate statistics were calculated, in addition to logistic regression analysis. RESULTS: Among 95 MSM interviewed, 56% were >30 years and 74% had higher than a high school education. Respondents reported a median of 2 known HIV-positive sex partners. Drug or alcohol use during last sex with their last known HIV-positive partner was reported by 53% of participants. Sixty-five per cent of participants reported inconsistent condom use with last known HIV-positive partner. Inconsistent condom use with all HIV-positive partners was higher among individuals reporting two or more known HIV-positive partners since sexual debut than among those with one (90% vs 59%, p<0.01) and among those reporting feelings of love/emotional attachment as a reason for having sex (85% vs 63%, p=0.02). In the bivariate logistic regression models for inconsistent condom use, feelings of love or emotional attachment were the only significant predictor of inconsistent condom use (OR 3.43, 95% CI 1.23 to 9.58). After adjusting for confounding, the relationship feelings of love or emotional attachment continued to be the only significant predictor of inconsistent condom use (OR 3.69, 95% CI 1.06 to 12.82). CONCLUSIONS: Surveyed MSM engaged in high-risk behaviours, including condomless anal sex and drug or alcohol use during sex with persons known to be HIV-positive. These findings can inform interventions with MSM in serodiscordant partnerships. PMID- 30409914 TI - Prevalence and causes of blindness and vision impairment: magnitude, temporal trends and projections in South and Central Asia. AB - BACKGROUND: To assess prevalence and causes of vision loss in Central and South Asia. METHODS: A systematic review of medical literature assessed the prevalence of blindness (presenting visual acuity<3/60 in the better eye), moderate and severe vision impairment (MSVI; presenting visual acuity <6/18 but >=3/60) and mild vision impairment (MVI; presenting visual acuity <6/12 and >=6/18) in Central and South Asia for 1990, 2010, 2015 and 2020. RESULTS: In Central and South Asia combined, age-standardised prevalences of blindness, MSVI and MVI in 2015 were for men and women aged 50+years, 3.72% (80% uncertainty interval (UI): 1.39-6.75) and 4.00% (80% UI: 1.41-7.39), 16.33% (80% UI: 8.55-25.47) and 17.65% (80% UI: 9.00-27.62), 11.70% (80% UI: 4.70-20.32) and 12.25% (80% UI:4.86-21.30), respectively, with a significant decrease in the study period for both gender. In South Asia in 2015, 11.76 million individuals (32.65% of the global blindness figure) were blind and 61.19 million individuals (28.3% of the global total) had MSVI. From 1990 to 2015, cataract (accounting for 36.58% of all cases with blindness in 2015) was the most common cause of blindness, followed by undercorrected refractive error (36.43%), glaucoma (5.81%), age-related macular degeneration (2.44%), corneal diseases (2.43%), diabetic retinopathy (0.16%) and trachoma (0.04%). For MSVI in South Asia 2015, most common causes were undercorrected refractive error (accounting for 66.39% of all cases with MSVI), followed by cataract (23.62%), age-related macular degeneration (1.31%) and glaucoma (1.09%). CONCLUSIONS: One-third of the global blind resided in South Asia in 2015, although the age-standardised prevalence of blindness and MSVI decreased significantly between 1990 and 2015. PMID- 30409919 TI - Modulation of mutant KrasG12D-driven lung tumorigenesis in vivo by gain or loss of PCDH7 function. AB - PROTOCADHERIN 7 (PCDH7), a transmembrane receptor and member of the Cadherin superfamily, is frequently overexpressed in lung adenocarcinoma and is associated with poor clinical outcome. While PCDH7 was recently shown to promote transformation and facilitate brain metastasis in lung and breast cancers, decreased PCDH7 expression has also been documented in colorectal, gastric, and invasive bladder cancers. These data suggest context-dependent functions for PCDH7 in distinct tumor types. Given that PCDH7 is a potentially targetable molecule on the surface of cancer cells, further investigation of its role in tumorigenesis in vivo is needed to evaluate the therapeutic potential of its inhibition. Here we report the analysis of novel PCDH7 gain- and loss-of-function mouse models and provide compelling evidence that this cell-surface protein acts as a potent lung cancer driver. Employing a Cre-inducible transgenic allele, we demonstrated that enforced PCDH7 expression significantly accelerates KrasG12D driven lung tumorigenesis and potentiates MAPK pathway activation. Furthermore, we performed in vivo somatic genome editing with CRISPR/Cas9 in KrasLSL-G12D; Tp53fl/fl (KP) mice to assess the consequences of PCDH7 loss of function. Inactivation of PCDH7 in KP mice significantly reduced lung tumor development, prolonged survival, and diminished phospho-activation of ERK1/2. Together, these findings establish a critical oncogenic function for PCDH7 in vivo and highlight the therapeutic potential of PCDH7 inhibition for lung cancer. Moreover, given recent reports of elevated or reduced PCDH7 in distinct tumor types, the new inducible transgenic model described here provides a robust experimental system for broadly elucidating the effects of PCDH7 overexpression in vivo. Implications: In this study, we establish a critical oncogenic function for PCDH7 in vivo using novel mouse models and CRISPR/Cas9 genome editing, and we validate the therapeutic potential of PCDH7 inhibition for lung cancer. PMID- 30409920 TI - Are inequalities in cancer diagnosis through emergency presentation narrowing, widening or remaining unchanged? Longitudinal analysis of English population based data 2006-2013. AB - BACKGROUND: Diagnosis of cancer through emergency presentation is associated with poorer prognosis. While reductions in emergency presentations have been described, whether known sociodemographic inequalities are changing is uncertain. METHODS: We analysed 'Routes to Diagnosis' data on patients aged >=25 years diagnosed in England during 2006-2013 with any of 33 common or rarer cancers. Using binary logistic regression we determined time-trends in diagnosis through emergency presentation by age, deprivation and cancer site. RESULTS: Overall adjusted proportions of emergency presentations decreased during the study period (2006: 23%, 2013: 20%). Substantial baseline (2006) inequalities in emergency presentation risk by age and deprivation remained largely unchanged. There was evidence (p<0.05) of reductions in the risk of emergency presentations for most (28/33) cancer sites, without apparent associations between the size of reduction and baseline risk (p=0.26). If there had been modest reductions in age inequalities (ie, patients in each age group acquiring the same percentage of emergency presentations as the adjacent group with lower risk), in the last study year we could have expected around 11 000 fewer diagnoses through emergency presentation (ie, a nationwide percentage of 16% rather than the observed 20%). For similarly modest reductions in deprivation inequalities, we could have expected around 3000 fewer (ie, 19%). CONCLUSION: The proportion of cancer diagnoses through emergency presentation is decreasing but age and deprivation inequalities prevail, indicating untapped opportunities for further improvements by reducing these inequalities. The observed reductions in proportions across nearly all cancer sites are likely to reflect both earlier help-seeking and improvements in diagnostic healthcare pathways, across both easier-to-suspect and harder-to-suspect cancers. PMID- 30409921 TI - Patterns of BMI development between 10 and 42 years of age and their determinants in the 1970 British Cohort Study. AB - BACKGROUND: Mixture modelling is a useful approach to identify subgroups in a population who share similar trajectories. We aimed to identify distinct body mass index (BMI) trajectories between 10 and 42 years and investigate how known early-life risk factors are related to trajectories. METHODS: Sample: 9187 participants in the 1970 British Birth Cohort Study, with BMI observations between 10 and 42 years and data on birth weight, parental BMI, socioeconomic status, breast feeding and puberty. Latent growth mixture modelling in Mplus was used to model age-related BMI trajectories and test associations of risk factors with trajectory membership. RESULTS: A three latent class model was most credible: (1) normative: 92%: started normal weight but gradually increased BMI to become overweight in adulthood; (2) childhood onset persistent obesity (COP): 4%: persistently high BMI from childhood; (3) adolescent and young adulthood onset obesity (AYAO): 4%: normal weight in childhood but had a steep ascending trajectory. Higher maternal and paternal BMI and early puberty increased the probability of being in either the COP or the AYAO classes compared with the normative class. CONCLUSION: Most individuals gradually increased BMI and became overweight in mid-adulthood. Only 8% demonstrated more severe BMI trajectories. Further research is needed to understand the underlying body composition changes and health risks in the COP and AYAO classes. PMID- 30409922 TI - Age-related inequalities in colon cancer treatment persist over time: a population-based analysis. AB - BACKGROUND: Older people experience poorer outcomes from colon cancer. We examined if treatment for colon cancer was related to age and if inequalities changed over time. METHODS: Data from the UK population-based Northern and Yorkshire Cancer Registry on 31 910 incident colon cancers (ICD10 C18) diagnosed between 1999-2010 were obtained. Likelihood of receipt of: (1) cancer-directed surgery, (2) chemotherapy in surgical patients, (3) chemotherapy in non-surgical patients by age, adjusting for sex, area deprivation, cancer stage, comorbidity and period of diagnosis, was examined. RESULTS: Age-related inequalities in treatment exist after adjustment for confounding factors. Patients aged 60- 69, 70-79 and 80+ years were significantly less likely to receive surgery than those aged <60 years (multivariable ORs (95% CI) 0.84(0.74 to 0.95), 0.54(0.48 to 0.61) and 0.19(0.17 to 0.21), respectively). Age-related differences in receipt of surgery and adjuvant chemotherapy (but not chemotherapy in non-surgical patients) narrowed over time for the 'younger old' (aged <80 years) but did not diminish for the oldest patients. CONCLUSIONS: Age inequality in treatment of colon cancer remains after adjustment for confounders, suggesting age remains a major factor in treatment decisions. Research is needed to better understand the cancer treatment decision-making process, and how to influence this, for older patients. PMID- 30409924 TI - A historical note on the evolution of "Ringworm". PMID- 30409923 TI - Prevalence of skin diseases among Omani population attending dermatology clinics in North Batinah Governorate, Oman - retrospective study of 2,32,362 cases. PMID- 30409925 TI - Does using a high sun protection factor sunscreen on face, along with physical photoprotection advice, in patients with melasma, change serum vitamin D concentration in Indian conditions? A pragmatic pretest-posttest study. AB - Background: Use of sunscreens on the face is becoming popular, and patients with melasma are prescribed sunscreen for use on the face. Results of a few Western studies on the effect of sunscreen use on serum vitamin D concentration are not applicable to Indian conditions. Aims: To examine the effect of use of a high sun protection factor (SPF 50+, PA++++) sunscreen on face in patients with melasma on serum concentration of 25-hydroxyvitamin D. Methods: Forty-five Indian patients (Fitzpatrick skin types III and IV) with melasma were advised to use a sunscreen with SPF 50 + for 3 months, 43 (33 female, 10 male; age 32.9 +/- 8 years) completed the study. Patients staying outdoor for <4 hours applied sunscreen once daily after bath. Patients staying outdoors for >4 hours reapplied sunscreen 4 hours after first application. Patients were provided a container to measure the amount of sunscreen for use, which was approximately equal to recommended thickness. Compliance was tested by weighing the used tubes and tubes in use during monthly visits. Serum concentration of 25-hydroxyvitamin D was tested before and after the study period. Results: Amount of sunscreen advised (100.5 +/ 29.2 ml) and the actual amount used (96.6 +/- 27.9 ml) were similar (P = 0.53, t test). The difference between serum concentrations of 25-hydroxyvitamin D at the baseline (19.20 +/- 9.06 ng/ml) and at 3 months (18.91 +/- 8.39 ng/ml) was not significant (P = 0.87, paired t-test, 95% confidence interval of difference -3.33 to 3.92). No correlation was found between the amount of sunscreen used and the percentage change in serum 25-hydroxyvitamin D concentration at 3 months (rho = 0.099, P = 0.528, Spearman's rank correlation). Limitations: Longer duration of application and a larger sample size may detect minor differences in vitamin D concentration. Conclusion: Using a high SPF sunscreen on the face, along with physical photoprotection advice, in patients with melasma for 3 months does not influence serum 25-hydroxyvitamin D concentration in Indian conditions. PMID- 30409927 TI - EUS-directed transgastric access to the excluded stomach to facilitate pancreaticobiliary interventions in patients with Roux-en-Y gastric bypass anatomy. PMID- 30409926 TI - A randomized, double-blind trial of amorolfine 0.25% cream and sertaconazole 2% cream in limited dermatophytosis. AB - Background: Dermatophytosis is becoming increasingly unresponsive to conventional antifungals. Newer topical antifungals may be more effective in these patients. Aims: To evaluate and compare the efficacy and safety of amorolfine 0.25% cream and sertaconazole 2% cream in limited tinea cruris/corporis. Methods: A single center, randomized (1:1), double-blind, parallel group, active-controlled trial (CTRI/2014/12/005246) was performed. Sixty-six untreated adults with acutely symptomatic tinea cruris/corporis were included in the study. All patients had limited cutaneous involvement and were KOH mount positive. Group A received amorolfine 0.25% cream, and group B received sertaconazole 2% cream twice daily application to the lesions for 4 weeks. After the baseline visit, four follow-up visits were carried out. The outcome measures for effectiveness were clinical and mycological cure. Safety parameters studied were treatment-emergent adverse events and changes in routine laboratory parameters. Results: Both sertaconazole and amorolfine significantly reduced symptoms (P < 0.001) in both groups. However, improvement in symptoms (pruritus, burning sensation, erythema, scaling and crusting) was significantly greater in the sertaconazole group at every follow-up visit. Sertaconazole cream was also more effective than amorolfine cream in reducing the number of lesions (P = 0.002 at 12 weeks) and improving the Dermatology Life Quality Index (P < 0.001) at all the follow-up visits. Adverse events were similar in the two groups (P = 0.117). Fungal cultures became negative in 92.3% of the sertaconazole group as compared to 80% in the amorolfine group (P = 0.010). Limitations: Antifungal susceptibility testing could not be done. Conclusion: Sertaconazole 2% is superior to amorolfine 0.25%, both in terms of effectiveness and tolerability. Improvement can be appreciated from second week onwards. PMID- 30409928 TI - The difficulties in continuing education in geriatric dentistry; analysis. PMID- 30409929 TI - Role of research evidence in clinical decision-making: Intuition versus clinical experience versus scientific evidence. PMID- 30409930 TI - Habit-breaking methods employed by mothers of children with nonnutritive sucking habits resident in suburban Nigeria. AB - Context: Parents are often concerned about their children's nonnutritive sucking (NNS) habits and may institute mechanisms to try to break them. Aim: The study identified various methods instituted by mothers resident in a suburban Nigeria to break NNS habits of children, reasons for wanting to break the habit, and the association between instituted methods and sociodemographic profile of the mothers. Materials and Methods: The data of 129 mothers of children aged 4 years to 12 years who had NNS habits at the time of conducting a household survey were analyzed. Statistical Analysis: Tests of associations were conducted to determine the association between maternal age and level of education and methods employed to break child's NNS habits. Results: Eighty-four mothers (65.1%) made efforts to break the habit. Habit persisting to older age was the main concern. The most common method employed for breaking habits was punishing the child (54.8%).Only 7 (20.0%) mothers who were concerned about NNS habit(s) sought professional advice. A greater though insignificant percentage of mothers in the 25-34 years age group (57.2%; P = 0.48) and those with secondary school level of education (56.0%; P = 0.12) made efforts to break their children's NNS habits. Conclusions: The majority of mothers were concerned about their children's NNS habits. However, very few concerned mothers sought professional advice. Efforts need to be made to improve the public awareness about the availability of professional services for managing NNS habits and potential impact of employing nonprofessional methods to break habits. PMID- 30409931 TI - Knowledge and attitude of general dentists regarding common emergencies in dental offices: A cross-sectional study in Shiraz, Iran. AB - Background: Medical emergencies are likely to occur in dental offices due to the use of anesthetics, anxiety, and systemic complications of the patient. Since such emergencies are life threatening in many cases, preparedness of the dentist is highly required. Aims: This study was carried out to evaluate the dentists' knowledge and attitude regarding diagnosis and treatment of medical emergencies in dental offices in Shiraz, Iran. Methods: This cross-sectional study was performed on 150 general dentists in Shiraz with at least 5 years since graduation in 2015. They were asked to complete a validated questionnaire including the dentists' demographic information and inquiries about their performance and knowledge in emergency situations. Statistical Analysis Used: Independent t-test, one-way ANOVA, and Pearson's correlation coefficient were used in this study. Results: According to the inclusion criteria, 105 dentists participated in the study. The mean knowledge and attitude of the dentists was estimated 4.98 (+/-1.50) out of 10. No significant correlation was detected between age, sex, number of patients per day, and working hours with the knowledge of managing an emergency situation (P > 0.05). Out of the number of studied dentists, 49% had attended training workshops and 90% called for re attending a workshop. The knowledge score of those who had participated in workshops was significantly higher than those who had not (P = 0.016). Conclusion: The results of this study revealed that the dentists' knowledge about emergency situations was average while the knowledge was higher in those who had attended emergency workshops. Thus, retraining courses and workshops must be considered more often for graduated dentists. PMID- 30409932 TI - Effectiveness of crystallization test in screening of potentially malignant oral disorders and oral cancer. AB - Aim: This study aims to determine the effectiveness of crystallization test in screening of oral potentially malignant disorders (PMDs) and oral cancer. Materials and Methods: Thirty patients of oral PMD, 30 patients of oral cancer and 40 normal healthy people were selected. One drop of blood was collected and added to 1 cc of double-distilled water at room temperature to get a final dilution of 6% hemolyzed blood. 0.1-0.2 cc of this blood sample is added to 10 cc of 20% cupric chloride solution and further is subjected to crystallization test. Results: In the normal healthy group, the pattern was typical with an eccentrically placed center of gravity with needles arranged in radiating fashion. Whereas in oral PMD and cancer groups, there was "transverse form" formation. This test had sensitivity and specificity of about 83.33% and 86.84% for PMDs group and 96.30% and 86.84% for oral cancer group respectively. Conclusion: Crystallization test was found to be sensitive, reliable, economical and less-invasive procedure for screening of oral PMDs and oral cancer. PMID- 30409933 TI - Evaluation of relationship between nutritional status and oral health related quality of life in complete denture wearers. AB - Introduction: The prevalence of malnutrition increases with old age, especially in developing countries like India, and it is the most common cause of morbidity and mortality, because of many factors out of which dentate status is one. Aim and Objective: The aim of this study is to evaluate and determine the effect of nutritional status and dietary intake on the oral health-related quality of life (OHRQOL) of elderly edentulous complete denture-wearing patients and to know whether elderly complete denture wearers have a higher risk of malnutrition. The objective was to assess the need to include dietary and nutritional counseling during prosthodontic rehabilitation of elderly edentulous patients. Materials and Methods: A cross-sectional study was conducted among 200 elderly denture-wearing patients above 60 years of age from Nagpur, Maharashtra. Mini-Nutritional Assessment (MNA) questionnaire was used to assess nutritional status, and Geriatric Oral Health Assessment Index (GOHAI) questionnaire was used to determine the OHRQOL of these patients. Descriptive statistics were used to analyze data using SPSS version 21 (SPSS Inc., Chicago, IL, USA). Results: Among the assessed participants, nearly 95% of them had total scores of GOHAI between 12 and 57 which require "needed dental care." As per MNA, 10.5% had adequate nutrition, 70% were at risk of malnutrition, and remaining 19.5% of participants were malnourished. There was a significant correlation between GOHAI and MNA scores. Conclusion: Low nutritional status was associated with the poor OHRQOL among the elderly. A strong association was found between mean GOHAI and MNA scores and thereby nutritional status and OHRQOL. The use of conventional dentures increases the risk of malnutrition in the elderly due to inability to eat and chew food properly. Dietary analysis and counseling should be strictly incorporated into geriatric treatment planning during prosthetic rehabilitation. PMID- 30409934 TI - Sociodemographic and behavioral factors associated with early childhood caries among preschool children of Western Maharashtra. AB - Introduction: Early childhood caries is a preventable disease of multifactorial etiology and is a public health problem affecting majority of the preschool-age children of the country. If left untreated, it has many social, economic, and nutritional implications and affects the quality of life of the affected child. Methods: This cross-sectional study was conducted among 200 preschool children of Karad city, western Maharashtra, to assess the prevalence of dental caries among the preschool children and to assess the factors affecting the development of dental caries. Various child-level, parent-level, attitudinal- and family-level factors, and clinical variables were evaluated. Results: High prevalence of caries of 87.5% was observed in the study sample. Bivariate analysis showed a significant association of age of child (P < 0.001), age of mother at birth (P = 0.041), feeding during 1st year (P = 0.034), snacking habits (P = 0.001), and brushing frequency (P = 0.03) with dental caries. On multivariate analysis, the factors of snacking habits (P = 0.003) and age of child (P = 0.002) remained significantly correlated with dental caries. Conclusion: There was a strong and consistent relation of the snacking habits with the prevalence of dental caries among the preschool children of Karad city. There is a need to sensitize the caregivers regarding the role of frequent snacking in dental caries. PMID- 30409935 TI - Knowledge, attitude, and practice of dental implants among dental postgraduates and practitioners in Davangere City, Karnataka: A cross-sectional study. AB - Background: Implant therapy has become an important part of treatment to restore function and esthetics in partially/completely edentulous patients. Inspite of the progress made in implant dentistry since its inception, there have been some loopholes in scientific based knowledge and established clinical experience amongst dental professionals and postgraduates.So,an analysis was performed of the real picture. Objectives: A study was conducted to assess and compare the knowledge, attitude and practice of dental implants among dental postgraduate students and dental practitioners (General and institutional)in Davangere City, Karnataka and to identify the variations in their knowledge, attitude and practice with respect to dentist's factors (years of experience, implant training and their specialization). Materials and Methods: A cross sectional questionnaire based survey was conducted using census approach with informed consent. A pretested, self administered questionnaire containing demographic details and knowledge ,attitude and practice based questions was distributed and collected back from the respondents. Responses were coded before and decoded after the analysis. Statistical analysis was performed using SPSS SoftwareV17.0. Results: The results were determined after the statistically analyzed and concluded that the knowledge was widespread among postgraduates and dental practitioners and variations existed amongst the subjects with respect to age, gender, years of experience, practice type, implant training and their specialization. It was also found that the attitude and practice towards implants and their evidence based knowledge about the same was variable. PMID- 30409936 TI - Role of anxiety and depression in association with migraine and myofascial pain temporomandibular disorder. AB - Background: Previous studies have demonstrated a strong association between primary headaches (HAs) and temporomandibular disorders (TMDs), specifically the myofascial pain subtype of TMD (MP TMD). The role of anxiety and depression in presentation and maintenance of MP TMD and migraine is previously demonstrated. Therefore, the objective of the current study was to evaluate the modification effect of anxiety and depression on the possible association of MP TMD and migraine. Methods: In this retrospective case-control study, individuals between 15 and 45 years old who were diagnosed with migraine HA according to the international classification of headache disorder-II (ICHD-II) were selected as case subjects (n = 65). Non-HA control subjects were matched by sex and age (n = 63). Research diagnostic criteria (RDC/TMD) (Axis I) was used to diagnose patients with MP TMD; other subtypes of RDC/TMD Axis I were excluded from the study. Subjects' anxiety and depression were screened using Persian version of Hospital Anxiety and Depression Scale-14. Chi-square and Mantel-Haenszel tests were used to analyze the data. P < 0.05 was considered statistically significant. Results: A significant association was found between migraine and MP TMD so that subjects with MP TMD had a five times chance of developing HA (P < 0.001). Further analysis using stratification method revealed that anxiety and depression have a modification effect in the association of MP TMD and HA and MP TMD patients with anxiety or depression had more chance of developing migraine HA (P = 0.003). Conclusion: Association between HA and TMD was observed in this study. Besides, we depicted that anxiety and depression interact in this association so that patients who did not have anxiety or depression did not demonstrate an association between TMD and HA. We suggest further studies to confirm the modifying effects of anxiety and depression. PMID- 30409938 TI - Reverse rotary instrumentation in the apical third of the root canal system: An scanning electron microscope analysis. AB - Aims: The aim of the present study was to evaluate the efficacy of reverse rotary instrumentation in disinfection of the root canal at the apical third and qualitative confirmatory analysis using the scanning electron microscope (SEM). Subjects and Methods: Sixty single-rooted mandibular premolars were instrumented up to Protaper rotary file size F2 and contaminated with a known species of Enterococcus faecalis (ATCC 29212). The samples were then divided into three groups; Group 1: Experimental group-irrigation by agitation of 1% NaOCl with reverse rotary instrumentation; Group 2: Negative control-no irrigation; and Group 3 positive control-irrigation with 1% NaOCl using a 30-gauge needle. The colony forming units of all the groups were checked. SEM analysis of the samples was focused on the apical third to confirm the absence of E. faecalis biofilms. The data obtained were statistically analyzed by the Fisher's exact test and Pearson's Chi-square test. Results: Group I and III showed significant reduction in the growth of E. faecalis (P <= 0.001). SEM confirmed dense bacterial colonies in the Group II consistent with biofilm formation and reduction in bacterial colonies in Group I and II. Conclusion: Agitation with reverse rotary instrumentation in the apical third of the root canal along with 1% sodium hypochlorite proved effective in disinfection of the apical third of the root canal, which was further confirmed by scanning electron microscopic analysis. Hence, it can be used as an adjunct during rotary instrumentation in efficient cleansing of the root canal system in the apical third of the root canal system. PMID- 30409937 TI - Comparative evaluation of cathepsin K levels in gingival crevicular fluid among smoking and nonsmoking patients with chronic periodontitis. AB - Background: The aim of the study is to comparatively evaluate the levels of cathepsin K (CSTK) in gingival crevicular fluid (GCF) among smoking and nonsmoking patients with chronic periodontitis (CP). Materials and Methods: A total of 160 systemically healthy male patients were included in the study. Based on probing pocket depth, clinical attachment level, plaque index, and modified sulcular bleeding index, the patients were allotted into four groups: Group I - with forty subjects who were smokers with healthy periodontium, Group II - with forty nonsmoking subjects with healthy periodontium, Group III - forty patients who were smokers with CP, and Group IV - with forty nonsmoking CP patients. Those who claimed to have never smoked were recruited into the nonsmoker group, whereas subjects who reported smoking >=10 cigarettes per day for more than 5 years were recruited into the smoker group. The GCF samples were collected using microcapillary pipettes and analyzed for levels of CSTK using enzyme-linked immunosorbent assay. Results: The GCF concentration of CSTK was expressed in pg/MUl. The mean CSTK levels in the groups were Group I - 0.158 +/- 0.043 pg/MUl, Group II - 0.145 +/- 0.026 pg/MUl, Group III - 15.768 +/- 12.40 pg/MUl, and for Group IV - 11.59 +/- 12.15 pg/MUl, respectively. The levels of CSTK were statistically higher in Group III when compared with Group IV (P = 0.037) (P < 0.05). Conclusion: CSTK levels were significantly increased in smokers with CP than nonsmokers, suggesting a positive influence of smoking on CSTK which could possibly play a role in the increased susceptibility for osteoclastic bone destruction in smoker subjects. PMID- 30409939 TI - Root coverage by modified coronally advanced flap with and without platelet-rich fibrin: A clinical study. AB - Background: Marginal gingival recession can cause major functional and esthetic problems. Advanced flaps are the simplest, yet unpredictable procedures for managing these conditions. The predictability of root coverage can be increased by combining coronally advanced flap (CAF) or its modified approach with other regenerative techniques. Objective: To ascertain the potential benefits of platelet-rich fibrin (PRF) on modified CAF for the treatment of gingival recession. Materials and Methods: Study comprised of 12 patients with Millers' class I and class II gingival recession in two non-adjacent anterior teeth having a minimum 3 mm width of attached gingiva. Following split-mouth design, one tooth with gingival recession was subjected to modified CAF, while another was treated by CAF with PRF. The clinical parameters, i.e., plaque index, modified sulcular bleeding index, vertical gingival recession depth (VGRD), gingival recession width (GRW), clinical attachment level (CAL), and gingival thickness (GT) were recorded at baseline, 1 month, 3 months, and 6 months. Results: VGRD, GRW, CAL, and GT improved significantly from baseline to 1 month in both test and control groups. However, change in these parameters from 1 month to 3 months and 3 months to 6 months were statistically nonsignificant in both groups. On intergroup comparison, only the change in GT was found to be statistically significant (P < 0.05) at all three post-treatment visits. Conclusion: Benefits of the combined technique in terms of increased GT appear to justify the use of PRF along with modified CAF for the treatment of mild to moderate gingival recessions. PMID- 30409940 TI - Impacted mandibular third molar: Comparison of coronectomy with odontectomy. AB - Aim: Damage to the inferior alveolar nerve (IAN) while extracting lower third molars is often caused by the intimate relationship between the nerve and the roots of the teeth. The aim of this study was to compare the sequelae of coronectomy with odontectomy in impacted mandibular third molars. Patients and Methods: This study included thirty patients which were divided into two groups, Group-I (test group) including 15 patients undergoing coronectomy and Group-2 (control group) of 15 patients undergoing odontectomy. Investigations included digital orthopantomogram. The parameters for this study included pain, swelling, nerve paresthesia, trismus, postoperative infection, postoperative wound dehiscence, postoperative pocket depth, and migration. Results: In Group-1 (coronectomy group), the patients underwent follow-up for 6 months to evaluate migration of the retained mandibular third molar root which was in proximity with the IAN. There was a mean increase in migration when the distance from the inferior border of IAN until the apex of the retained mandibular third molar root was measured which was by 3.43 mm after 6 months of follow up. Conclusion: On statistical analysis, the result in this study showed no statistical difference in both the groups in all the parameters that were taken. PMID- 30409942 TI - Effectiveness of casein phosphopeptide-amorphous calcium phosphate and xylitol chewing gums on salivary pH, buffer capacity, and Streptococcus mutans levels: An interventional study. AB - Aim: The aim of the study is to compare the anticariogenic effectiveness of Casein phosphopeptide- Amorphous Calcium phosphate (CPP-ACP) and xylitol chewing gums based on salivary pH, buffer capacity, and Streptococcus mutans levels. Materials and Methods: A group of twenty individuals in the age group of 18-25 years were randomly divided into two Groups A and B. Test arm A received xylitol gums and test arm B received CPP-ACP gums and they were instructed to use the gums thrice daily for 2 weeks. Unstimulated salivary samples were collected before they began the use of the gums for baseline values, 24 h after beginning the usage of chewing gums and at the end of 14 days. The samples were analyzed for pH, buffer capacity, and S. mutans levels. Results: A statistically significant reduction of salivary S. mutans levels, improvement in salivary pH, and buffer capacity were displayed in both groups 24 h and 14 days after the intervention when compared with baseline. Group B showed more statistically significant improvement in pH than group A after 24 h (P = 0.028) and at the end of 2 weeks (P = 0.041). Conclusion: CPP-ACP has better ability than xylitol in improving the pH of saliva. Both CPP-ACP and xylitol gums individually have remarkable ability in bringing down S. mutans levels while simultaneously improving the pH and buffer of saliva. PMID- 30409941 TI - Comparison of efficacy of 0.75% ropivacaine and 2% lidocaine with 1:200,000 adrenaline in pain control in extraction of mandibular posterior teeth: A double blind study. AB - Background: Two percent lidocaine hydrochloride is the gold standard for dental anesthesia against which newer local anesthetic agents may be compared. 0.75% ropivacaine is a newer, long-acting amide local anesthetic agent with inherent vasoconstriction property. Aim: This study aims to compare the efficacy of 0.75% ropivacaine and 2% lidocaine hydrochloride with 1:200,000 adrenaline in pain control in extraction of mandibular posterior teeth. Settings and Design: This is a prospective, double-blind, and split-mouth study. Subjects and Methods: Twenty patients were divided into two groups according to the right and left sides of patient - side A and side B. The side, where 0.75% ropivacaine was to be administered, was randomly selected by flip coin method. Then, the pterygomandibular and long buccal nerve blocks were administered with 0.75% ropivacaine and necessary dental extraction was performed. After 1 week, the same procedure was repeated using 2% lidocaine hydrochloride with 1:200,000 adrenaline. The parameters assessed were pain on injection, onset of anesthesia, pain during the extraction, and duration of anesthesia. Statistical Analysis Used: The nonparametric data were assessed by Mann Whitney "U" test. Results: The mean onset of action for solution A was 7.15 +/- 4.934 min and for solution B was 9.75+/-5.128 min. This was statistically significant. The mean duration of action, pain on injection, and pain during extraction were not significant. Conclusion: This study clearly states that there is no clear advantage of using 0.75% ropivacaine in pterygomandibular nerve block over the gold standard. However, more clinical studies with larger sample size are necessary. PMID- 30409943 TI - Gaps in oral health-care service provision systems for children in Nigeria: A case study of a tertiary health institution. AB - Background: The study investigated the common dental conditions of children seen in a Nigerian tertiary hospital. The referral patterns were also determined to know how many of the patients had sought care at the lower levels of health before visiting a tertiary hospital. Methods: All the children aged 0-15 years seen at the Dental hospital, Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria over a 4-year period were included in the study. Information retrieved from their case notes including patterns of referral, presenting complaints, diagnosis, and treatment were extracted from the case records of the patients. Treatment plans for patients seen at this tertiary hospital were categorized into primary, secondary, and tertiary health-care services. Results: A total of 1,866 children sought treatment over a 4-year period at this tertiary hospital of which 1715 (91.9%) sought treatment without referral from lower levels of care. Only 102 (5.4%) children were referred from primary health care (PHC) centers. Six hundred and seventy-five (36.2%) children presented with pain while 502 (26.9%) attended for a "check-up." Furthermore, 779 (41.8%) children were diagnosed with periodontal disease (including gingivitis) and 539 (28.9%) with dental caries. Scaling and polishing with oral hygiene instruction was the most common treatment recommended. Only 5% of children seen at this tertiary health facility required specialized oral health-care services provided by tertiary health institutions. Conclusions: The range of oral health care needed and service provided by and for patients who visited this tertiary health-care institution can be effectively provided in a primary or secondary oral health-care delivery center. The poor integration of oral health care into PHC services in Osun State burdens the tertiary health-care institutions to provide nonspecialized oral health-care services. PMID- 30409944 TI - Evaluation of incidence of mental nerve loop in Central India population using cone beam computed tomography. AB - Context: Anatomical literature has described the anterior loop being an extension of the mental nerve which is present anterior to the mental foramen while the caudal loop has been described as the distance between the lower border of the mental foramen and the lowest point of the mandibular canal. The knowledge and identification of the anterior and caudal loop of the mental nerve are important in surgical procedures performed around the mental foramen to avoid inadvertent damage to these vital structures resulting in postoperative complications. Aim: The present study was conducted to determine the incidence and measurement of mental nerve loop in the mandibular arches using cone beam computed tomography (CBCT). Settings and Design: A total of 200 CBCT images were retrieved and inspected for the presence of the mental nerve loop. The length of the anterior loop was measured by counting the number of consecutive contiguous vertical cross sections displaying two round hypodense images. This number was multiplied by the thickness of the slices. The caudal loop was measured as the distance between the lower border of the mental foramen and the lowest point of mandibular canal. Statistical Analysis Used: Shapiro-Wilk test and Mann-Whitney U-test were used. P < 0.05 was considered statistically significant. Results: 57.5% (n = 200 scans) presented with the anterior loop of the mental nerve with a mean length of 0.50 mm and 0.37 mm on the right side and left side, respectively. All the samples of CBCT scans taken were having caudal loop extension with a mean length of 3.53 mm. Conclusion: A considerable number of individuals (57.5%) in the present study presented with the anterior loop of the mental nerve. CBCT was found to be an effective imaging modality for the detection of anterior loop of the mental nerve. PMID- 30409945 TI - A three-dimensional finite element analysis to evaluate stress distribution tooth in tooth implant-supported prosthesis with variations in non-rigid connector design and location. AB - Background: The physiologically mobile natural tooth and rigidly fixed dental implant causes different distribution of stress when connected in prosthesis and nonrigid connector compensates this. Understanding of biomechanical behavior is necessary for an adequate choice and construction of this type of rehabilitation. However, there has been insufficient research focusing on different location and type of the nonrigid connector related with the prognosis of both implant and the tooth. Aim of the Study: The purpose of this finite element (FE) analysis was to evaluate the stress distribution around bone, implant, and tooth in tooth implant fixed prosthesis under static load with variations in design and location of nonrigid connectors under simulated functional loads. Materials and Method: Three, 3-dimensional FE models connecting tooth and implant were constructed with different location and type of nonrigid connector. Simulated occlusal load was applied on the restorations and stresses developed in the supporting structures were monitored. Results: The highest stresses were found around the implant in model with nonrigid connector placed between the tooth and implant and model with modified nonrigid connector. On the other hand, less stress was noted around the implant where nonrigid connector was placed between the implant and pontic. Conclusion: It is advisable to place the nonrigid connector between the implant and the pontic to protect the implant from torque effects in a tooth implant fixed prosthesis. PMID- 30409946 TI - Antimicrobial Efficacy of Acacia nilotica, Murraya koenigii L. Sprengel, Eucalyptus hybrid, Psidium guajava extracts and their combinations on Fusobacterium nucleatum and Porphyromonas gingivalis. AB - Background: The herbal extracts have been effectively tried in the treatment and prevention of many oral diseases. Aim: The aim is to assess the antimicrobial efficacy of Acacia nilotica, Murraya koenigii L. Sprengel, Eucalyptus hybrid, Psidium guajava extracts and their combinations on Fusobacterium nucleatum (Fn) and Porphyromonas gingivalis (Pg). Materials and Methods: The extraction process was carried out by Soxhlet apparatus using ethanol as solvent. The combinations of the four plant extracts were prepared by combining an equal quantity of 10% solution of each of the four plant extracts. The antimicrobial efficacy testing of the plant extracts and their combinations on Fn and Pg was performed using agar well diffusion method. Columbia 5% of sheep blood agar plates were used for antimicrobial efficacy testing under anaerobic conditions. The qualitative assay was carried out to identify the various phytochemical constituents. Dimethyl sulfoxide and 0.2% chlorhexidine acted as negative and positive controls, respectively. The mean diameter of inhibition zone between different categories was compared using one-way analysis of variance. Results: All the individual plant extracts and their double, triple, and quadruple combinations were effective in inhibiting the growth of these bacteria. However, 0.2% chlorhexidine produced the highest mean diameter of inhibition zone. Conclusion: The plant extracts in combinations offer enhanced antimicrobial efficacy due to their synergistic action besides slowing the development of bacterial resistance. Hence, these extracts in combinations could be used tried as effective alternates to chlorhexidine. PMID- 30409948 TI - Micro-shear bond strength of composite resin to glass ionomer cement using an alternative method to build up test specimens. AB - Context: Despite the relevance of the sandwich technique, there are still doubts about the best adhesive strategy and surface treatment for glass ionomer cements (GICs). Aim: The aim of this study is to evaluate the best surface treatment for GIC to ensure an effective and durable adhesion to resin, through micro-shear test, using an alternative method to build up test specimens. Subjects and Methods: Eighty GIC samples were divided into eight groups (n = 10) according to five surface treatments (none, etching, air drying, grinding, and grinding plus etching) and according to the adhesive system (conventional or self-etch). Five starch tubes were positioned on each sample, and a flowable composite was inserted generating 50 resin test bodies per group and a total of 400 tested areas. All specimens were submitted to the micro-shear test: half immediately and half after thermal cycling (10,000 cycles of 20 s each/5 degrees and 55 degrees C). All samples were analyzed to evaluate fracture. Representative samples were also analyzed by scanning electron microscopy and energy dispersive spectroscopy. Data were analyzed with two-way ANOVA and Tukey's honest significant difference post hoc test (P <.05). Results: The bond strengths in the thermal cycled specimens were lower and showed a statistically significant difference (P = 0). The "grinding" groups showed the highest bond strength. Conclusions: The alternative method to build up test specimens was effective and easy to execute. Grinding of the GIC surface, which is not normally performed before the use of the adhesive system, represented the best option of surface treatment. PMID- 30409947 TI - Effect of antioxidant on orthodontic bracket bond strength after vital bleaching. AB - Objectives: : The objective of this study is to compare the neutralization effect of various antioxidant agents on the bond strength of composite resins on stainless steel and ceramic brackets immediately bonded to previously bleached teeth. Materials and Methods: One hundred and sixty human maxillary premolars were used for the study. Teeth were divided into four groups (n = 40): Group 1 (control), Group 2 (bleached), Group 3 (sodium ascorbate), and Group 4 (tocopherol acetate). Each group was divided into two subgroups, one was bonded with stainless steel and other with ceramic brackets using 3M Transbond XT. Universal testing machine was used to determine the shear bond strength (SBS). Results: Among the metal brackets, Group 1A had the highest SBS (12.18 + 1.41 MPa) and Group 2A had the least SBS (6.18 + 1.49 MPa). Weibull analysis indicated that bond strength for a 90% probability of failure was highest for Group 1A (13.99 MPa) and lowest for Group 2A (8.49 MPa). For ceramic brackets, Group 1B had the highest SBS (13.80 + 1.69 MPa) and Group 2B had the least SBS (8.05 + 1.85 MPa). Weibull analysis indicated that bond strength for a 90% probability of failure was highest for Group 1B (14.61 MPa) and lowest for Group 2B (8.85MPa). Conclusion: The in vitro study showed that bleaching reduced the SBS significantly, and this could be effectively reversed by the application of antioxidants in both metal and ceramic brackets. PMID- 30409949 TI - Evaluation of the effect of denture cleansers on the surface roughness of hard denture base material: An In vitro study. AB - Background: Maintaining the oral hygiene of denture wearers is a challenge faced in modern dentistry. Biofilm formed on dentures has been associated with denture stomatitis, malodor, aspiration pneumonia, infectious endocarditis, gastrointestinal infection, and chronic obstructive pulmonary disease. Objective: The purpose of this study was to evaluate the effect of denture cleansers on the surface roughness of hard denture base material. Materials and Methods: A total of 100 heat-cure acrylic resin specimens were fabricated with dimensions 30 mm * 15 mm * 3 mm in length, width, and thickness, respectively. All specimens were distributed into four groups randomly. Three commonly prescribed denture cleansers were used for immersion in this study. Regular tap water was used for immersion in the control group. Surface roughness was determined before immersion and after immersion in denture cleansing solutions using contact profilometer. The data were subjected to statistical analysis using paired t-test, one-way analysis of variance, and Tukey's multiple post hoc test. Results: The change in surface roughness of acrylic samples immersed in Clanden group was statistically significant (P < 0.05) at individual group level. However, the change in surface roughness of acrylic samples after immersion, when compared between the groups, namely, control, Clinsodent, Clanden, and Fittydent, was not statistically significant (P > 0.05). Conclusion: Within the limitation of this study, the three denture cleansing materials, namely, Clinsodent powder, Clanden tablet, and Fittydent tablet, are safe to be prescribed as denture cleansers. PMID- 30409950 TI - A comparison of the effect of application of sodium ascorbate and amla (Indian gooseberry) extract on the bond strength of brackets bonded to bleached human enamel: An In vitro study. AB - Introduction: Whitening of teeth is a popular choice among dental clinicians and patients. However, the changes in enamel structure and composition induced by the bleaching agents cause a decrease in the shear bond strength of brackets leading to premature bracket debonding. Among several methods to overcome this, the most common is delaying bonding by 2-4 weeks. This waiting period can be eliminated by applying an antioxidant (sodium ascorbate) which causes a reversal in the reduction of bond strength. Aim: This study aims to compare the efficacy of a naturally occurring antioxidant (gooseberry) and sodium ascorbate in normalizing the bond strength of enamel to prebleached levels. Materials and Methods: Seventy two extracted premolars were divided into 4 equal groups; 1st group - control group - unbleached teeth, bonded directly, 2nd group - bleached with 16% carbamide peroxide (8 h for 1 week), then bonded. 3rd and 4th group - similarly bleached, followed by application of 10% sodium ascorbate and gooseberry extract (3 h respectively), then bonded. Bond strength was checked using Instron Universal Testing Machine. Results: The bond strength of the control group was the highest and that of the carbamide group was drastically reduced. Considerable increase in the bond strength was seen after treatment with sodium ascorbate with negligible difference between sodium ascorbate and control group (P > 0.05). Conclusion: Treatment with gooseberry extract did improve the bond strength but was not as effective as sodium ascorbate postbleaching. PMID- 30409951 TI - Ectopic teeth in the maxillary sinus: A case report and literature review. AB - Ectopic eruption of teeth is a rare phenomenon although there have been reports of teeth in the nasal septum, mandibular condyle, and maxillary sinus. This impaction can present itself in a variety of ways such as chronic or recurrent sinusitis, sepsis, and facial numbness and can also be asymptomatic. The aim of this study was to describe, by means of research literature and by a case report, the characteristics and occurrence of ectopic eruption in the maxillary sinus. We have analyzed and compared clinical cases of ectopic teeth in the maxillary sinus with a search on PubMed utilizing keywords such as "ectopic," "teeth," "sinus," "maxillary," and Boolean operators "or" and "and" up until 2016. Fifty-one cases were found, of which 53% were female. The age ranged between 3 and 72 years, with an average age of 28.36 years. The higher prevalence of ectopic teeth is the 3rd molars. Ten of these teeth are associated with a dentigerous cyst, 1 by an osteoma, and 2 by soft tissue. Standard treatment for an ectopic tooth is extraction, but for other patients, treatment of choice in asymptomatic ectopic tooth cases is continued observation. Ectopic teeth tend to form a cyst or tumor if not managed. PMID- 30409952 TI - Sodium bicarbonate: A review and its uses in dentistry. AB - Denture stomatitis, periodontitis, and peri-implantitis are the growing problems in restorative dentistry. Chemicals play an important role as an adjuvant to mechanical cleaning of teeth, implants, surrounding tissues, and prostheses. Current mouth rinses are reported to affect the tissues and prostheses if used on a long-term basis. Sodium bicarbonate, the common baking soda, has been reported to be versatile. A search of the resources through Medline and Google Scholar was made to understand the current status of the mouth rinses and the use of sodium bicarbonate. Different MeSH and search criteria were used for the different search engines. Baking soda, being a common household item, with its ready availability, safety, minimal abrasivity, and bactericidal property makes it a patient-friendly mouthwash, component in the dentifrice, or chewing gum, which can be used on a long-term basis as an adjunct virtually free of any side effects. PMID- 30409953 TI - Peripheral giant cell granuloma manifestation in pregnancy. AB - The peripheral giant cell granuloma (PGCG) is a benign oral lesion occurring on the gingiva and alveolar ridge. It is the most common oral lesion and occurs at an average age of 30 years. The upsurge in the levels of estrogen and progesterone in pregnancy leads to a plethora of changes in various parts of human body, including the oral cavity. In the oral cavity, changes are commonly seen on the gingiva. These include pyogenic granuloma, PGCG and also peripheral ossifying fibroma, etc., The etiology of PGCG in our case might be related to hormonal alterations during the gestation period. PMID- 30409955 TI - Rare granular cell tumor affecting a 13-year-old boy. AB - Granular cell tumor (GCT) is a rare soft-tissue neoplasm, first described in 1926. GCT often manifests as a single, painless nodule that shows a slow enlargement in the cutaneous, subcutaneous, or submucosal tissues. It is commonly reported in adults in the third to sixth decade of life. This case report is of an incidental finding in a young boy, who was radiologically examined for orthodontic treatment purpose and found to have a radiolucent lesion in the mandible. The lesion was later diagnosed as GCT. Central GCT is rare, and the presentation in a child is even rare. Although GCT is reported to be benign, it can turn malignant in 2% of the cases and possibly metastasize too. The local recurrence within a year is characteristic for malignant GCT. The 1-year follow up of the present case indicated no local recurrence. The case stresses the need for the frequent dental examination, specialist reference. GCT should be included in the differential diagnosis of head and neck masses, even when inside jaws. It shall be remembered that such tumors may arise in any atypical locations and there is a possibility of malignancy. PMID- 30409954 TI - Management of maxillary first molar with six canals using operating microscope. AB - The purpose of this article was to highlight the importance of having a thorough knowledge about the root canal morphology. This case report highlights the unusual anatomy of a maxillary first molar with three mesiobuccal (MB) canals, two palatal canals, and one distobuccal canal which is extremely rare. The use of operating microscope was crucial, both for the detection and for the management of the additional canals. The use of surgical operating microscope and digital radiograph showed that MB root had Type 3-1 of Gulabivala classification and palatal canal showed Vertucci's Type II canal morphology This report describes and discusses the identification of variation in canal morphology of maxillary first molar and the use of latest adjuncts in successfully diagnosing and negotiating them. PMID- 30409956 TI - Comparison of shear bond strength of orthodontic color change adhesive with traditional adhesive. AB - Introduction: The purpose of this study was to compare the shear bond strength of color-change adhesive with a conventional light-cure adhesive at different debonding times. Materials and Methods: Seventy-two intact extracted human permanent premolar teeth were used in this research. The brackets were bonded with Transbond XT (Group I) and Transbond Plus color change adhesive (Group II). Each of the two adhesive groups were then further divided into three subgroups of 12 specimens each, for a total of six subgroups. The subgroups represented the three different time points to be tested, 15 min, 24 h, and 1 week. Then, the shear bond strength (SBS) of the brackets was tested with a Universal Testing Machine. Adhesive remnant index (ARI) scores were calculated for each debonded teeth. Results: Although Transbond XT yielded the lowest SBS values at 1 week, there was no significant difference between samples regarding shear bond at different times and ARI. Conclusion: The application of these adhesives did not affect bond strength. Both adhesives demonstrated acceptable bond strength to withstand orthodontic forces throughout the experiment. PMID- 30409957 TI - Parental awareness, knowledge, and attitude toward conscious sedation in North Indian children population: A questionnaire-based study. AB - Aim: The purpose of this study is to find the opinion, attitude, beliefs, and the existing knowledge of parents of Himachal Pradesh suburban city about conscious sedation. Objective: To know the effect of education of parent and prior sedation experience of the child on opinion, attitude, and knowledge of parent about conscious sedation. Methodology: A questionnaire in Hindi/English was provided to parents who accompanied their child for the treatment in the Paedodontics Department of HPGDC College Shimla. Information regarding demography, existing knowledge gained through television, the internet, opinion about the safety of the procedure, knowledge of nothing by mouth guidelines, restraints usage, and knowing their preferences of staying with the child during treatment was explored. Questions were straight yes or no type and multiple choice type. Some questions were statements and wanted the respondents to strongly agree, agree, disagree, or strongly disagree. Results and Conclusion: A total of 350 questionnaires were collected. Parents feel sedation is safe in the dental office as an adjunct to dental treatment. Education played a role in existing knowledge about sedation and perception about the safety of conscious sedation. PMID- 30409958 TI - Novel noninvasive quantification of penile corpus cavernosum lesions in hyperlipidemia-induced erectile dysfunction in rabbits by two-dimensional shear wave elastography. AB - Structural alterations in fibroelastic components of the penile corpus cavernousum (CC) may impair its compliance, resulting in venous leakage and erectile dysfunction (ED). Our study evaluated the effectiveness of noninvasive two-dimensional shear-wave elastography (2-D SWE) in quantifying penile CC lesions in rabbits with hyperlipidemia-induced ED. A total of 12 New Zealand white rabbits were randomly divided into two groups. Six were fed a high cholesterol diet containing 2% cholesterol and 8.5% lard for 10 weeks and the other six were fed normal diet as controls. We measured the shear-wave elastic quantitative (SWQ) value of penile CC by 2-D SWE. Erectile function was investigated by intracavernous injection of papaverine, and immunohistochemical (IHC) staining and the western blot analysis to determine the penile CC lesions. After 10 weeks, the SWQ values obtained from penile CC were remarkably higher in the high-cholesterol-fed compared with the control group, and the DeltaICP (ICP plateau minus ICP baseline)/MAP (ICP: intracavernous pressure, MAP: mean arterial pressure) was markedly decreased. The IHC staining and western blot revealed extracellular matrix (ECM) accumulation in penile cavernous tissues, and the smooth muscle cell (SMC) phenotypic transition was affected, as indicated by reduced alpha-smooth muscle actin and calponin-1 expression and increased phospho myosin light chain20 (p-MLC20)/MLC20 and osteopontin expression. Hyperlipidemia resulted in ECM accumulation accompanied with SMC phenotypic transition in penile CC and impaired the erectile function eventually. These might, in turn, lead to variations in the SWQ values. It suggests that 2-D SWE may be a novel, noninvasive and effective approach that distinguishes penile CC lesions secondary to hyperlipidemia from normal. PMID- 30409959 TI - The therapeutic effect of pelvic floor muscle exercise on urinary incontinence after radical prostatectomy: a meta-analysis. AB - Pelvic floor muscle exercise (PFME) is the most common conservative management for urinary incontinence (UI) after radical prostatectomy (RP). However, whether the PFME guided by a therapist (G-PFME) can contribute to the recovery of urinary continence for patients after RP is still controversial. We performed this meta analysis to investigate the effectiveness of G-PFME on UI after RP and to explore whether the additional preoperative G-PFME is superior to postoperative G-PFME alone. Literature search was conducted on Cochrane Library, Embase, Web of Science, and PubMed, to obtain all relevant randomized controlled trials published before March 1, 2018. Outcome data were pooled and analyzed with Review Manager 5.3 to compare the continence rates of G-PFME with control and to compare additional preoperative G-PFME with postoperative G-PFME. Twenty-two articles with 2647 patients were included. The continence rates of G-PFME were all superior to control at different follow-up time points, with the odds ratio (OR) (95% confidence interval [CI]) of 2.79 (1.53-5.07), 2.80 (1.87-4.19), 2.93 (1.19 7.22), 4.11 (2.24-7.55), and 2.41 (1.33-4.36) at 1 month, 3 months, 4 months, 6 months, and 12 months after surgery, respectively. However, there was no difference between additional preoperative G-PFME and postoperative G-PFME, with the OR (95% CI) of 1.70 (0.56-5.11) and 1.35 (0.41-4.40) at 1 month and 3 months after RP, respectively. G-PFME could improve the recovery of urinary continence at both early and long-term stages. Starting the PFME preoperatively might not produce extra benefits for patients at early stage, compared with postoperative PFME. PMID- 30409960 TI - Living Donor Liver Transplant as Rescue Surgery for a Patient with Hepatocellular Carcinoma Who Underwent Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS). AB - BACKGROUND The associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is an important tool to induce fast liver hypertrophy. The degree of hepatic fibrosis/cirrhosis in patients with HCC negatively impacts their health, and the risk of liver failure is always present. In these cases, liver transplantation may be necessary as a rescue procedure. We present the case of a patient with HCC who underwent ALPPS and developed liver failure. A living donor liver transplant was performed as a rescue procedure. CASE REPORT A 49-year old man with chronic hepatitis B without cirrhosis underwent computed tomography, which revealed an expansive lesion in the right lobe of his liver that was diagnosed as hepatocellular carcinoma. Liver resection was indicated and liver cirrhosis was observed with high portal pressure after transection. The treatment strategy was switched from right hepatectomy to ALPPS. The patient developed severe liver dysfunction and liver transplantation was indicated. His postoperative course was uneventful and 3 months after the procedure the patient was without complications. CONCLUSIONS Living donor liver transplantation may be necessary as a rescue procedure for patients who underwent ALPPS and develop liver dysfunction. PMID- 30409962 TI - Silencing of Xeroderma Pigmentosum Group D Gene Promotes Hepatoma Cell Growth by Reducing P53 Expression. AB - BACKGROUND This study investigated the effect of xeroderma pigmentosum group D (XPD) silencing on the growth of hepatoma cells and assessed the mechanisms. MATERIAL AND METHODS XPD gene was silenced by siRNA in hepatoma cells. The experiments were randomly divided into a control group, a liposome control group, a negative control (NC) group, an XPD siRNA group, and an XPD siRNA + P53 inhibitor group. 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) was used to detect cell viability 24 h after gene silencing and treatments. Terminal deoxynucleotidyl transferases (TdT)-mediated dUTP nick-end labeling (TUNEL) and flow cytometry were used to detect apoptosis. Invasive ability was detected by Transwell assay. Additionally, the expression of mouse double-minute 2 homolog (Mdm2), mouse double-minute 4 homolog (Mdm4), CyclinD1, P21, Bax, P53, C-sis, and Bcl-2 was detected by real-time polymerase chain reaction and Western blotting. RESULTS Compared with the NC group, XPD siRNA significantly reduced XPD expression at both mRNA and protein levels. XPD siRNA significantly promoted cell proliferation, reduced apoptosis, and promoted cell invasive ability. Expression of CyclinD1, Bcl-2, and C-sis increased significantly after XPD silencing, while the expression of P21, Mdm2, Mdm4, Bax, and P53 significantly decreased (vs. NC, P<0.05). Importantly, P53 inhibitor (1 MUM bpV) further enhanced the effect of XPD silencing (vs. XPD silencing, P<0.05). CONCLUSIONS Our data revealed that XPD silencing promoted growth of hepatoma cells by reducing P53 expression. PMID- 30409963 TI - Bortezomib, lenalidomide, and dexamethasone (VRd) followed by autologous stem cell transplant for multiple myeloma. AB - We retrospectively reviewed all patients (n = 243) receiving bortezomib, lenalidomide, and dexamethasone (VRd) induction followed by autologous stem cell transplantation (ASCT) for multiple myeloma at the Mayo Clinic between January 2010 and April of 2017. Median age was 61 (interquartile range, 55-67) with 62% of patients being male. High-risk cytogenetic abnormalities (HRA) were present in 34% of patients. A total of 166 (68%) patients received some form of maintenance/other therapy post transplant (no maintenance (NM, n = 77), lenalidomide maintenance (LM, n = 108), bortezomib maintenance (BM, n = 39), and other therapy (OT, n = 19)). Overall response rate at day 100 post ASCT was 99% (CR 42%) with CR rate increasing to 62% at time of best response post transplant. Two year and 5 year overall survival rates were 90% and 67%, respectively, with an estimated median overall survival (OS) and progression-free survival (PFS) of 96 and 28 months, respectively. HRA was associated with a worse OS but not PFS (median OS: not reached for standard risk vs 60 months for HRA, P = 0.0006; median PFS: 27 months for standard risk vs 22 months for HRA, P = 0.70). The combination of VRd followed by ASCT is a highly effective regimen producing deep and durable responses in many patients. PMID- 30409961 TI - Colonoscopy as Part of Pre-Transplant Work-Up in Successful Kidney Transplant Candidates: Single-Center Experience and Review of Literature. AB - BACKGROUND Screening colonoscopy is not obligatory in kidney pre-transplant work up guidelines. According to recommendations, only transplant recipients over age 50 years should be screened. The aim of this study was to characterize endoscopic findings revealed as part of pre-transplant work-up. MATERIAL AND METHODS We retrospectively reviewed pre-transplant work-up charts of 434 adult patients who received a cadaveric donor kidney transplantation (KT) from 2012 to 2015. Endoscopic findings analysis with age subgroup (<50 and 350) analysis were performed. RESULTS Out of 434 of patients that underwent KT, 29% have had a colonoscopy. In 75.6% of those, pathologies were found. Hemorrhoids were found in 33% and polyps in 30.7% of patients. Adenoma detection rate (ADR) was 18.1% (67.5% distal predominance). Advanced ADR was 10.2% (distal predominance). Diverticulosis was found in 28.3% of patients and ulcerative colitis was found in 2.4%. In age subgroup analysis, ADR was higher in patients 350 years compared to those <50 years (21.6% vs. 4%; p=0.041). CONCLUSIONS Colonoscopy as part of pre transplant work-up enables removal of precancerous lesions and management of benign findings. All candidates meeting criteria for the general population should be screened. Patients under age 50 years could also benefit from colonoscopy as part of the pre-transplant work-up. Therefore, we suggest that baseline colonoscopy should be included in pre-transplant work-up guidelines for all patients, regardless of age. However, further studies are needed to confirm this recommendation. PMID- 30409964 TI - miR-146b promotes cell proliferation and increases chemosensitivity, but attenuates cell migration and invasion via FBXL10 in ovarian cancer. AB - Epithelial ovarian carcinoma (EOC) is the most lethal gynecologic malignancy. However, the molecular mechanisms remain unclear. In this study, we found that miR-146b was downregulated in EOC and its expression level was negatively correlated with the pathological staging. Follow-up functional experiments illustrated that overexpression of miR-146b significantly inhibited cell migration and invasion, and increased cell proliferation, but it also improved the response to chemotherapeutic agents. Mechanistically, we demonstrated that miR-146b exerted its function mainly through inhibiting F-box and leucine-rich repeat protein 10 (FBXL10), and upregulated the Cyclin D1, vimentin (VIM), and zona-occludens-1 (ZO-1) expression in EOC. These findings indicate that miR-146b FBXL10 axis is an important epigenetic regulation pathway in EOC. Low miR-146b may contribute to cancer progression from primary stage to advanced stage, and may be the promising therapeutic target of EOC. PMID- 30409966 TI - Publisher Correction: Unravelling the structure of glycosyl cations via cold-ion infrared spectroscopy. AB - The original version of this Article contained an error in Fig. 1, in which an oxygen atom was missing from the 'Acetoxonium type' structure. This has been corrected in both the PDF and HTML versions of the Article. PMID- 30409965 TI - Adaptation to sub-optimal hosts is a driver of viral diversification in the ocean. AB - Cyanophages of the Myoviridae family include generalist viruses capable of infecting a wide range of hosts including those from different cyanobacterial genera. While the influence of phages on host evolution has been studied previously, it is not known how the infection of distinct hosts influences the evolution of cyanophage populations. Here, using an experimental evolution approach, we investigated the adaptation of multiple cyanophage populations to distinct cyanobacterial hosts. We show that when infecting an "optimal" host, whose infection is the most efficient, phage populations accumulated only a few mutations. However, when infecting "sub-optimal" hosts, different mutations spread in the phage populations, leading to rapid diversification into distinct subpopulations. Based on our results, we propose a model demonstrating how shifts in microbial abundance, which lead to infection of "sub-optimal" hosts, act as a driver for rapid diversification of viral populations. PMID- 30409968 TI - Electrochemically-mediated selective capture of heavy metal chromium and arsenic oxyanions from water. AB - The removal of highly toxic, ultra-dilute contaminants of concern has been a primary challenge for clean water technologies. Chromium and arsenic are among the most prevalent heavy metal pollutants in urban and agricultural waters, with current separation processes having severe limitations due to lack of molecular selectivity. Here, we report redox-active metallopolymer electrodes for the selective electrochemical removal of chromium and arsenic. An uptake greater than 100 mg Cr/g adsorbent can be achieved electrochemically, with a 99% reversible working capacity, with the bound chromium ions released in the less harmful trivalent form. Furthermore, we study the metallopolymer response during electrochemical modulation by in situ transmission electron microscopy. The underlying mechanisms for molecular selectivity are investigated through electronic structure calculations, indicating a strong charge transfer to the heavy metal oxyanions. Finally, chromium and arsenic are remediated efficiently at concentrations as low as 100 ppb, in the presence of over 200-fold excess competing salts. PMID- 30409967 TI - Overexpression of the vascular brassinosteroid receptor BRL3 confers drought resistance without penalizing plant growth. AB - Drought represents a major threat to food security. Mechanistic data describing plant responses to drought have been studied extensively and genes conferring drought resistance have been introduced into crop plants. However, plants with enhanced drought resistance usually display lower growth, highlighting the need for strategies to uncouple drought resistance from growth. Here, we show that overexpression of BRL3, a vascular-enriched member of the brassinosteroid receptor family, can confer drought stress tolerance in Arabidopsis. Whereas loss of-function mutations in the ubiquitously expressed BRI1 receptor leads to drought resistance at the expense of growth, overexpression of BRL3 receptor confers drought tolerance without penalizing overall growth. Systematic analyses reveal that upon drought stress, increased BRL3 triggers the accumulation of osmoprotectant metabolites including proline and sugars. Transcriptomic analysis suggests that this results from differential expression of genes in the vascular tissues. Altogether, this data suggests that manipulating BRL3 expression could be used to engineer drought tolerant crops. PMID- 30409969 TI - Combined effusive-explosive silicic volcanism straddles the multiphase viscous-to brittle transition. AB - Magma is a viscoelastic fluid that can support fracture propagation when local shear stresses are high, or relax and flow when shear stresses are low. Here we present experiments to confirm this using synthetic and natural magmatic liquids across eruptive conditions and use Maxwell's linear viscoelasticity to parameterize our results and predict the maximum stresses that can be supported during flow. This model proves universal across a large range of liquid compositions, temperatures, crystallinity and rates of strain relevant to shallow crustal magma ascent. Our results predict that the 2008 Volcan Chaiten eruption resided in the viscous field at the onset of magma ascent, but transitioned to a mixed viscous-brittle regime during degassing, coincident with the observed combined effusive-explosive behaviour during dome extrusion. Taking a realistic maximum effusive ascent rate, we propose that silicic eruptions on Earth may straddle the viscous-to-brittle transition by the time they reach the surface. PMID- 30409970 TI - TAp73-induced phosphofructokinase-1 transcription promotes the Warburg effect and enhances cell proliferation. AB - The Warburg effect is a prominent metabolic feature associated with neoplastic diseases; however, the underlying mechanism remains incompletely understood. TAp73, a structural homolog of the tumor suppressor p53, is frequently overexpressed in human tumors, indicating a proliferative advantage that it can confer to tumor cells. Here we show that TAp73 stimulates the expression of phosphofructokinase-1, liver type (PFKL), which catalyzes the committed step in glycolysis. Through this regulation, TAp73 enhances glucose consumption and lactate excretion, promoting the Warburg effect. By activating PFKL, TAp73 also increases ATP production and bolsters anti-oxidant defense. TAp73 deficiency results in a pronounced reduction in tumorigenic potential, which can be rescued by forced PFKL expression. These findings establish TAp73 as a critical regulator of glycolysis and reveal a mechanism by which tumor cells achieve the Warburg effect to enable oncogenic growth. PMID- 30409971 TI - Electrically induced and detected Neel vector reversal in a collinear antiferromagnet. AB - Antiferromagnets are enriching spintronics research by many favorable properties that include insensitivity to magnetic fields, neuromorphic memory characteristics, and ultra-fast spin dynamics. Designing memory devices with electrical writing and reading is one of the central topics of antiferromagnetic spintronics. So far, such a combined functionality has been demonstrated via 90 degrees reorientations of the Neel vector generated by the current-induced spin orbit torque and sensed by the linear-response anisotropic magnetoresistance. Here we show that in the same antiferromagnetic CuMnAs films as used in these earlier experiments we can also control 180 degrees Neel vector reversals by switching the polarity of the writing current. Moreover, the two stable states with opposite Neel vector orientations in this collinear antiferromagnet can be electrically distinguished by measuring a second-order magnetoresistance effect. We discuss the general magnetic point group symmetries allowing for this electrical readout effect and its specific microscopic origin in CuMnAs. PMID- 30409972 TI - Membrane association and remodeling by intraflagellar transport protein IFT172. AB - The cilium is an organelle used for motility and cellular signaling. Intraflagellar transport (IFT) is a process to move ciliary building blocks and signaling components into the cilium. How IFT controls the movement of ciliary components is currently poorly understood. IFT172 is the largest IFT subunit essential for ciliogenesis. Due to its large size, the characterization of IFT172 has been challenging. Using giant unilamellar vesicles (GUVs), we show that IFT172 is a membrane-interacting protein with the ability to remodel large membranes into small vesicles. Purified IFT172 has an architecture of two globular domains with a long rod-like protrusion, resembling the domain organization of coatomer proteins such as COPI-II or clathrin. IFT172 adopts two different conformations that can be manipulated by lipids or detergents: 1) an extended elongated conformation and 2) a globular closed architecture. Interestingly, the association of IFT172 with membranes is mutually exclusive with IFT57, implicating multiple functions for IFT172 within IFT. PMID- 30409973 TI - Divergent trends in functional and phylogenetic structure in reptile communities across Africa. AB - Despite extensive research on ecological community compositions, general patterns across large-scale environmental gradients have remained unclear. A widely used explanatory model is the stress dominance hypothesis (SDH), predicting that the relative influence of environmental filtering is greater in stressful habitats while competition is more important in benign environments. Here, we test the SDH using African squamates as a model system to facilitate general predictions on community structures amidst changing global environments. For the first time we investigate changes in functional, phylogenetic and species diversity across continental, environmental gradients within a multidimensional, phylogenetically informed approach. Results suggest that phylogenetic patterns of African squamates were likely shaped by clade-specific biogeographic histories, whereas functional structure reflects SDH predictions. We further detected significant structuring at both local and regional spatial scales, emphasizing the impact of regional-historical processes on local assemblages, and the need for broad conceptual frameworks to detect general patterns of community composition. PMID- 30409974 TI - Vibrational fingerprint of localized excitons in a two-dimensional metal-organic crystal. AB - Long-lived excitons formed upon visible light absorption play an essential role in photovoltaics, photocatalysis, and even in high-density information storage. Here, we describe a self-assembled two-dimensional metal-organic crystal, composed of graphene-supported macrocycles, each hosting a single FeN4 center, where a single carbon monoxide molecule can adsorb. In this heme-like biomimetic model system, excitons are generated by visible laser light upon a spin transition associated with the layer 2D crystallinity, and are simultaneously detected via the carbon monoxide ligand stretching mode at room temperature and near-ambient pressure. The proposed mechanism is supported by the results of infrared and time-resolved pump-probe spectroscopies, and by ab initio theoretical methods, opening a path towards the handling of exciton dynamics on 2D biomimetic crystals. PMID- 30409976 TI - Probing molecule-like isolated octahedra via-phase stabilization of zero dimensional cesium lead halide nanocrystals. AB - Zero-dimensional (0D) inorganic perovskites have recently emerged as an interesting class of material owing to their intrinsic Pb2+ emission, polaron formation, and large exciton binding energy. They have a unique quantum-confined structure, originating from the complete isolation of octahedra exhibiting single molecule behavior. Herein, we probe the optical behavior of single-molecule-like isolated octahedra in 0D Cesium lead halide (Cs4PbX6, X = Cl, Br/Cl, Br) nanocrystals through isovalent manganese doping at lead sites. The incorporation of manganese induced phase stabilization of 0D Cs4PbX6 over CsPbX3 by lowering the symmetry of PbX6 via enhanced octahedral distortion. This approach enables the synthesis of CsPbX3 free Cs4PbX6 nanocrystals. A high photoluminescence quantum yield for manganese emission was obtained in colloidal (29%) and solid (21%, powder) forms. These performances can be attributed to structure-induced confinement effects, which enhance the energy transfer from localized host exciton states to Mn2+ dopant within the isolated octahedra. PMID- 30409975 TI - A structural mechanism for directing corepressor-selective inverse agonism of PPARgamma. AB - Small chemical modifications can have significant effects on ligand efficacy and receptor activity, but the underlying structural mechanisms can be difficult to predict from static crystal structures alone. Here we show how a simple phenyl-to pyridyl substitution between two common covalent orthosteric ligands targeting peroxisome proliferator-activated receptor (PPAR) gamma converts a transcriptionally neutral antagonist (GW9662) into a repressive inverse agonist (T0070907) relative to basal cellular activity. X-ray crystallography, molecular dynamics simulations, and mutagenesis coupled to activity assays reveal a water mediated hydrogen bond network linking the T0070907 pyridyl group to Arg288 that is essential for corepressor-selective inverse agonism. NMR spectroscopy reveals that PPARgamma exchanges between two long-lived conformations when bound to T0070907 but not GW9662, including a conformation that prepopulates a corepressor bound state, priming PPARgamma for high affinity corepressor binding. Our findings demonstrate that ligand engagement of Arg288 may provide routes for developing corepressor-selective repressive PPARgamma ligands. PMID- 30409977 TI - Long term but not short term exposure to obesity related microbiota promotes host insulin resistance. AB - The intestinal microbiota and insulin sensitivity are rapidly altered after ingestion of obesogenic diets. We find that changes in the composition of the fecal microbiota precede changes in glucose tolerance when mice are fed obesogenic, low fiber, high fat diets (HFDs). Antibiotics alter glycemia during the first week of certain HFDs, but antibiotics show a more robust improvement in glycemic control in mice with protracted obesity caused by long-term feeding of multiple HFDs. Microbiota transmissible dysglycemia and glucose intolerance only occur when germ-free mice are exposed to obesity-related microbes for more than 45 days. We find that sufficient host exposure time to microbiota derived from HFD-fed mice allows microbial factors to contribute to insulin resistance, independently from increased adiposity in mice. Our results are consistent with intestinal microbiota contributing to chronic insulin resistance and dysglycemia during prolonged obesity, despite rapid diet-induced changes in the taxonomic composition of the fecal microbiota. PMID- 30409978 TI - Voxel-Based Morphometry Correlates of an Agitated-Aggressive Syndrome in the At Risk Mental State for Psychosis and First Episode Psychosis. AB - There are mixed reports on structural neuroimaging correlates of aggression in schizophrenia with weak evidence due to cohort overlaps and lack of replications. To our knowledge, no study examined volumetric neuroimaging correlates of aggression in early stages of psychosis. An agitated-aggressive syndrome is present in at-risk mental state (ARMS) and in first-episode psychosis (FEP) - it is unclear whether this syndrome is associated with structural brain abnormalities in early stages of psychosis. Using three-dimensional magnetic resonance imaging and a whole brain voxel-based morphometry approach, we examined 56 ARMS patients, 55 FEP patients and 25 healthy controls. We operationalized aggression using the Excited Component of the Brief Psychiatric Rating Scale (BPRS-EC) and dichotomized our patient group by median split into "BPRS-EC high" (n = 49) and "BPRS-EC low" groups (n = 62). The "BPRS-EC high" group had significantly smaller left lingual gyrus volume than HC. This finding was not present in the "BPRS-EC low" group. In addition, grey matter volume in the left lingual gyrus showed a negative linear correlation with BPRS-EC over all subjects (rho = -0.318; p = 0.0001) and in the patient group (rho = -0.202; p = 0.033). These findings provide first hints on structural brain abnormalities associated with an agitated-aggressive syndrome in ARMS and FEP patients. PMID- 30409979 TI - Author Correction: Socio-ecological dynamics of Caribbean coral reef ecosystems and conservation opinion propagation. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30409981 TI - Proportion of neuropathic pain in the back region in chronic low back pain patients -a multicenter investigation. AB - Neuropathy can contribute to low back pain (LBP) in the region of the back. Our study investigated the proportion of neuropathic pain (NP) in low back region in chronic LBP patients from multicenter and clinics in China and identified associated factors. Assessment was made using a questionnaire and the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS, only tested in low back region), as well as Quantitative Sensory Testing (QST, merely applied to the low back region), the Hospital Anxiety and Depression Scale (HADS) and the Oswestry Disability Index (ODI). Our questionnaire collected demographic information, behavioral habits and medical records. 2116 outpatients over 18 years old complaining of LBP lasting more than 3 months were enrolled in this study. The NP proportion in low back region in chronic LBP patients was 2.8%. Multivariable logistic regression analysis showed that histories of lumbar surgery, abdominal or pelvic surgery, and drinking alcohol were independent positive predictors for LBP of predominantly neuropathic origin (LBNPO), while history of low back sprain and frequently carrying weight as independent negative predictor. Using these parameters may help the identification of patients with chronic LBP likely to develop NP leading to improved treatment outcomes. PMID- 30409982 TI - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) shows adaptation of grass pollen composition. AB - MALDI time-of-flight mass spectrometry (MALDI-TOF MS) has become a widely used tool for the classification of biological samples. The complex chemical composition of pollen grains leads to highly specific, fingerprint-like mass spectra, with respect to the pollen species. Beyond the species-specific composition, the variances in pollen chemistry can be hierarchically structured, including the level of different populations, of environmental conditions or different genotypes. We demonstrate here the sensitivity of MALDI-TOF MS regarding the adaption of the chemical composition of three Poaceae (grass) pollen for different populations of parent plants by analyzing the mass spectra with partial least squares discriminant analysis (PLS-DA) and principal component analysis (PCA). Thereby, variances in species, population and specific growth conditions of the plants were observed simultaneously. In particular, the chemical pattern revealed by the MALDI spectra enabled discrimination of the different populations of one species. Specifically, the role of environmental changes and their effect on the pollen chemistry of three different grass species is discussed. Analysis of the group formation within the respective populations showed a varying influence of plant genotype on the classification, depending on the species, and permits conclusions regarding the respective rigidity or plasticity towards environmental changes. PMID- 30409980 TI - FXR agonist obeticholic acid induces liver growth but exacerbates biliary injury in rats with obstructive cholestasis. AB - Cholestasis impairs liver regeneration following partial liver resection (PHx). Bile acid receptor farnesoid X-receptor (FXR) is a key mediator of liver regeneration. The effects of FXR agonist obeticholic acid (OCA) on liver (re)growth were therefore studied in cholestatic rats. Animals underwent sham surgery or reversible bile duct ligation (rBDL). PHx with concurrent internal biliary drainage was performed 7 days after rBDL. Animals were untreated or received OCA (10 mg/kg/day) per oral gavage from rBDL until sacrifice. After 7 days of OCA treatment, dry liver weight increased in the rBDL + OCA group, indicating OCA-mediated liver growth. Enhanced proliferation in the rBDL + OCA group prior to PHx concurred with a rise in Ki67-positive hepatocytes, elevated hepatic Ccnd1 and Cdc25b expression, and an induction of intestinal fibroblast growth factor 15 expression. Liver regrowth after PHx was initially stagnant in the rBDL + OCA group, possibly due to hepatomegaly prior to PHx. OCA increased hepatobiliary injury markers during BDL, which was accompanied by upregulation of the bile salt export pump. There were no differences in histological liver injury. In conclusion, OCA induces liver growth in cholestatic rats prior to PHx but exacerbates biliary injury during cholestasis, likely by forced pumping of bile acids into an obstructed biliary tree. PMID- 30409983 TI - The conserved mosaic prophage protein paratox inhibits the natural competence regulator ComR in Streptococcus. AB - Horizontal gene transfer is an important means of bacterial evolution. This includes natural genetic transformation, where bacterial cells become "competent" and DNA is acquired from the extracellular environment. Natural competence in many species of Streptococcus, is regulated by quorum sensing via the ComRS receptor-signal pair. The ComR-XIP (mature ComS peptide) complex induces expression of the alternative sigma factor SigX, which targets RNA polymerase to CIN-box promoters to activate genes involved in DNA uptake and recombination. In addition, the widely distributed Streptococcus prophage gene paratox (prx) also contains a CIN-box, and here we demonstrate it to be transcriptionally activated by XIP. In vitro experiments demonstrate that Prx binds ComR directly and prevents the ComR-XIP complex from interacting with DNA. Mutations of prx in vivo caused increased expression of the late competence gene ssb when induced with XIP as compared to wild-type, and Prx orthologues are able to inhibit ComR activation by XIP in a reporter strain which lacks an endogenous prx. Additionally, an X-ray crystal structure of Prx reveals a unique fold that implies a novel molecular mechanism to inhibit ComR. Overall, our results suggest Prx functions to inhibit the acquisition of new DNA by Streptococcus. PMID- 30409985 TI - Effect of Early Calf-Hood Nutrition on the Transcriptional Regulation of the Hypothalamic-Pituitary-Testicular axis in Holstein-Friesian Bull Calves. AB - The aim of this study was to investigate the effect of early calf-hood nutrition on the transcriptomic profile of the arcuate nucleus of the hypothalamus, anterior pituitary and testes in Holstein-Friesian bulls. Holstein-Friesian bull calves with a mean (+/-S.D.) age and bodyweight of 19 (+/-8.2) days and 47.5 (+/ 5.3) kg, respectively, were offered a high (n = 10) or low (n = 10) plane of nutrition in order to achieve an overall growth rate of 1.2 and 0.5 kg/day. At 126 (+/-3) days of age, calves were euthanized, hypothalamus (arcuate region), anterior pituitary and testicular parenchyma samples were harvested and RNAseq analysis was performed. There were 0, 49 and 1,346 genes differentially expressed in the arcuate nucleus, anterior pituitary and testicular tissue of bull calves on the low relative to the high plane of nutrition, respectively (P < 0.05; False Discovery Rate <0.05). Cell cycle processes in the anterior pituitary were down regulated in the low relative to the high plane of nutrition; there was no differential expression of genes related to reproductive processes. Gene expression involved in cholesterol and androgen biosynthesis in the testes were down regulated in animals on the low plane of nutrition. This study provides insight into the effect of early life plane of nutrition on the regulation of the HPT axis. PMID- 30409986 TI - Positional Patterns Among the Auriculotemporal Nerve, Superficial Temporal Artery, and Superficial Temporal Vein for use in Decompression Treatments for Migraine. AB - This study aimed to clarify intersection patterns and points among the superficial temporal artery (STA), superficial temporal vein (STV), and auriculotemporal nerve (ATN) based on surface anatomical landmarks to provide useful anatomical information for surgical decompression treatments of migraine headaches in Asians. Thirty-eight hemifaces were dissected. The positional patterns among the ATN, STA, and STV were divided into three morphological types. In type I, the ATN ran toward the temporal region and superficially intersected the STA and STV (n = 32, 84.2%). In type II, the ATN ran toward the temporal region and deeply intersected the STA and STV (n = 4, 10.5%). In type III, the ATN ran toward the temporal region and deeply intersected the STV alone (n = 2, 5.3%). The intersection points of types II and III were 10.3 +/- 5.6 mm (mean +/- SD) and 10.4 +/- 6.1 mm anterior and 42.1 +/- 21.6 mm and 41.4 +/- 18.7 mm superior to the tragus, respectively. The ATN superficially intersected the STA and STV in all the Korean cadaver, while the ATN deeply intersected the STA and STV in 15% of the Thai cadavers. The pattern of the ATN deeply intersecting the STA and STV was less common in present Asian populations than in previously reported Caucasian populations, implying that migraine headaches (resulting from the STA and STV compressing the ATN) are less common in Asians. PMID- 30409984 TI - Assessment of coding region variants in Kuwaiti population: implications for medical genetics and population genomics. AB - Consanguineous populations of the Arabian Peninsula have been underrepresented in global efforts that catalogue human exome variability. We sequenced 291 whole exomes of unrelated, healthy native Arab individuals from Kuwait to a median coverage of 45X and characterised 170,508 single-nucleotide variants (SNVs), of which 21.7% were 'personal'. Up to 12% of the SNVs were novel and 36% were population-specific. Half of the SNVs were rare and 54% were missense variants. The study complemented the Greater Middle East Variome by way of reporting many additional Arabian exome variants. The study corroborated Kuwaiti population genetic substructures previously derived using genome-wide genotype data and illustrated the genetic relatedness among Kuwaiti population subgroups, Middle Eastern, European and Ashkenazi Jewish populations. The study mapped 112 rare and frequent functional variants relating to pharmacogenomics and disorders (recessive and common) to the phenotypic characteristics of Arab population. Comparative allele frequency data and carrier distributions of known Arab mutations for 23 disorders seen among Arabs, of putative OMIM-listed causal mutations for 12 disorders observed among Arabs but not yet characterized for genetic basis in Arabs, and of 17 additional putative mutations for disorders characterized for genetic basis in Arab populations are presented for testing in future Arab studies. PMID- 30409987 TI - Improving genetic transformation rates in honeybees. AB - Functional genetic studies in honeybees have been limited by transformation tools that lead to a high rate of transposon integration into the germline of the queens. A high transformation rate is required to reduce screening efforts because each treated queen needs to be maintained in a separate honeybee colony. Here, we report on further improvement of the transformation rate in honeybees by using a combination of different procedures. We employed a hyperactive transposase protein (hyPBaseapis), we tripled the amount of injected transposase mRNAs and we injected embryos into the first third (anterior part) of the embryo. These three improvements together doubled the transformation rate from 19% to 44%. We propose that the hyperactive transposase (hyPBaseapis) and the other steps used may also help to improve the transformation rates in other species in which screening and crossing procedures are laborious. PMID- 30409988 TI - Embryonic origin and genetic basis of cave associated phenotypes in the isopod crustacean Asellus aquaticus. AB - Characteristics common to animals living in subterranean environments include the reduction or absence of eyes, lessened pigmentation and enhanced sensory systems. How these characteristics have evolved is poorly understood for the majority of cave dwelling species. In order to understand the evolution of these changes, this study uses an invertebrate model system, the freshwater isopod crustacean, Asellus aquaticus, to examine whether adult differences between cave and surface dwelling individuals first appear during embryonic development. We hypothesized that antennal elaboration, as well as eye reduction and pigment loss, would be apparent during embryonic development. We found that differences in pigmentation, eye formation, and number of segments of antenna II were all present by the end of embryonic development. In addition, we found that cave and surface hatchlings do not significantly differ in the relative size of antenna II and the duration of embryonic development. To investigate whether the regions responsible for eye and pigment differences could be genetically linked to differences in article number, we genotyped F2 hybrids for the four previously mapped genomic regions associated with eye and pigment differences and phenotyped these F2 hybrids for antenna II article number. We found that the region previously known to be responsible for both presence versus absence of pigment and eye size also was significantly associated with article number. Future experiments will address whether pleiotropy and/or genetic linkage play a role in the evolution of cave characteristics in Asellus aquaticus. PMID- 30409989 TI - A complete Leishmania donovani reference genome identifies novel genetic variations associated with virulence. AB - Leishmania donovani is responsible for visceral leishmaniasis, a neglected and lethal parasitic disease with limited treatment options and no vaccine. The study of L. donovani has been hindered by the lack of a high-quality reference genome and this can impact experimental outcomes including the identification of virulence genes, drug targets and vaccine development. We therefore generated a complete genome assembly by deep sequencing using a combination of second generation (Illumina) and third generation (PacBio) sequencing technologies. Compared to the current L. donovani assembly, the genome assembly reported within resulted in the closure over 2,000 gaps, the extension of several chromosomes up to telomeric repeats and the re-annotation of close to 15% of protein coding genes and the annotation of hundreds of non-coding RNA genes. It was possible to correctly assemble the highly repetitive A2 and Amastin virulence gene clusters. A comparative sequence analysis using the improved reference genome confirmed 70 published and identified 15 novel genomic differences between closely related visceral and atypical cutaneous disease-causing L. donovani strains providing a more complete map of genes associated with virulence and visceral organ tropism. Bioinformatic tools including protein variation effect analyzer and basic local alignment search tool were used to prioritize a list of potential virulence genes based on mutation severity, gene conservation and function. This complete genome assembly and novel information on virulence factors will support the identification of new drug targets and the development of a vaccine for L. donovani. PMID- 30409990 TI - Gradient Relationship between Increased Mean Corpuscular Volume and Mortality Associated with Cerebral Ischemic Stroke and Ischemic Heart Disease: A Longitudinal Study on 66,294 Taiwanese. AB - The gradient relationship between mean corpuscular volume (MCV) and mortality due to ischemic vascular disease has not been researched using a large-scale population-based study. This study evaluated the association between MCV and death attributable to cerebrovascular disease (CVD) and cardiovascular disease (CAD) in a large population- and community-based Taiwanese cohort. A longitudinal study with a 9-year follow-up was conducted to evaluate individuals aged 20 years or older who had participated in the Keelung (the northernmost city in Taiwan) community-based integrated screening (abbreviated as KCIS) program since September 1999. The mortality rates associated with CVD and CAD were classified across a range of different MCV levels. Increased MCV levels were associated with an increased risk of CVD/CAD-related death (adjusted hazard ratio [aHR] = 1.42, trend test P = 0.0119). Marginally statistically significant associations were noted for specific deaths from ischemic heart disease (aHR = 1.44, trend test P = 0.0992) and cerebral ischemic stroke (aHR = 1.66, trend test P = 0.0667), respectively, but no significant gradient relationship was noted for death from cerebral hemorrhage stroke (aHR = 1.23, trend test, P = 0.6278). A gradient relationship between baseline MCV level and CVD/CAD-related death was noted, but whether such gradient relationships existed for two specific deaths and how these relationships may be confounded by extraneous factors that were not considered here should be investigated in the future. PMID- 30409991 TI - Structural basis for the recognition of sulfur in phosphorothioated DNA. AB - There have been very few reports on protein domains that specifically recognize sulfur. Here we present the crystal structure of the sulfur-binding domain (SBD) from the DNA phosphorothioation (PT)-dependent restriction endonuclease ScoMcrA. SBD contains a hydrophobic surface cavity that is formed by the aromatic ring of Y164, the pyrolidine ring of P165, and the non-polar side chains of four other residues that serve as lid, base, and wall of the cavity. The SBD and PT-DNA undergo conformational changes upon binding. The S187RGRR191 loop inserts into the DNA major groove to make contacts with the bases of the GPSGCC core sequence. Mutating key residues of SBD impairs PT-DNA association. More than 1000 sequenced microbial species from fourteen phyla contain SBD homologs. We show that three of these homologs bind PT-DNA in vitro and restrict PT-DNA gene transfer in vivo. These results show that SBD-like PT-DNA readers exist widely in prokaryotes. PMID- 30409993 TI - Dramatic cropland expansion in Myanmar following political reforms threatens biodiversity. AB - Effective conservation planning needs to consider the threats of cropland expansion to biodiversity. We used Myanmar as a case study to devise a modeling framework to identify which Key Biodiversity Areas (KBAs) are most vulnerable to cropland expansion in a context of increasingly resolved armed conflict. We studied 13 major crops with the potential to expand into KBAs. We used mixed effects models and an agricultural versus forest rent framework to model current land use and conversion of forests to cropland for each crop. We found that the current cropland distribution is explained by higher agricultural value, lower transportation costs and lower elevation. We also found that protected areas and socio-political instability are effective in slowing down deforestation with conflicts in Myanmar damaging farmland and displacing farmers elsewhere. Under plausible economic development and socio-political stability scenarios, the models forecast 48.5% of land to be converted. We identified export crops such as maize, and pigeon pea as key deforestation drivers. This cropland expansion would pose a major threat to Myanmar's freshwater KBAs. We highlight the importance of considering rapid land-use transitions in the tropics to devise robust conservation plans. PMID- 30409992 TI - Altered Placental Chorionic Arterial Biomechanical Properties During Intrauterine Growth Restriction. AB - Intrauterine growth restriction (IUGR) is a pregnancy complication due to placental dysfunction that prevents the fetus from obtaining enough oxygen and nutrients, leading to serious mortality and morbidity risks. There is no treatment for IUGR despite having a prevalence of 3% in developed countries, giving rise to an urgency to improve our understanding of the disease. Applying biomechanics investigation on IUGR placental tissues can give important new insights. We performed pressure-diameter mechanical testing of placental chorionic arteries and found that in severe IUGR cases (RI > 90th centile) but not in IUGR cases (RI < 90th centile), vascular distensibility was significantly increased from normal. Constitutive modeling demonstrated that a simplified Fung type hyperelastic model was able to describe the mechanical properties well, and histology showed that severe IUGR had the lowest collagen to elastin ratio. To demonstrate that the increased distensibility in the severe IUGR group was related to their elevated umbilical resistance and pulsatility indices, we modelled the placental circulation using a Windkessel model, and demonstrated that vascular compliance (and not just vascular resistance) directly affected blood flow pulsatility, suggesting that it is an important parameter for the disease. Our study showed that biomechanics study on placenta could extend our understanding on placenta physiology. PMID- 30409994 TI - Manipulating azobenzene photoisomerization through strong light-molecule coupling. AB - The formation of hybrid light-molecule states (polaritons) offers a new strategy to manipulate the photochemistry of molecules. To fully exploit its potential, one needs to build a toolbox of polaritonic phenomenologies that supplement those of standard photochemistry. By means of a state-of-the-art computational photochemistry approach extended to the strong-coupling regime, here we disclose various mechanisms peculiar of polaritonic chemistry: coherent population oscillations between polaritons, quenching by trapping in dead-end polaritonic states and the alteration of the photochemical reaction pathway and quantum yields. We focus on azobenzene photoisomerization, that encompasses the essential features of complex photochemical reactions such as the presence of conical intersections and reaction coordinates involving multiple internal modes. In the strong coupling regime, a polaritonic conical intersection arises and we characterize its role in the photochemical process. Our chemically detailed simulations provide a framework to rationalize how the strong coupling impacts the photochemistry of realistic molecules. PMID- 30409995 TI - Exosomes play a role in multiple myeloma bone disease and tumor development by targeting osteoclasts and osteoblasts. AB - Progression of multiple myeloma (MM) is largely dependent on the bone marrow (BM) microenvironment wherein communication through different factors including extracellular vesicles takes place. This cross-talk not only leads to drug resistance but also to the development of osteolysis. Targeting vesicle secretion could therefore simultaneously ameliorate drug response and bone disease. In this paper, we examined the effects of MM exosomes on different aspects of osteolysis using the 5TGM1 murine model. We found that 5TGM1 sEVs, or 'exosomes', not only enhanced osteoclast activity, they also blocked osteoblast differentiation and functionality in vitro. Mechanistically, we could demonstrate that transfer of DKK-1 led to a reduction in Runx2, Osterix, and Collagen 1A1 in osteoblasts. In vivo, we uncovered that 5TGM1 exosomes could induce osteolysis in a similar pattern as the MM cells themselves. Blocking exosome secretion using the sphingomyelinase inhibitor GW4869 not only increased cortical bone volume, but also it sensitized the myeloma cells to bortezomib, leading to a strong anti tumor response when GW4869 and bortezomib were combined. Altogether, our results indicate an important role for exosomes in the BM microenvironment and suggest a novel therapeutic target for anti-myeloma therapy. PMID- 30409997 TI - Massive Stokes shift in 12-coordinate Ce(NO2)63-: crystal structure, vibrational and electronic spectra. AB - The Ce3+ ion in Cs2NaCe(NO2)6 (I), which comprises the unusual Th site symmetry of the Ce(NO2)63- ion, demonstrates the largest Ce-O Stokes shift of 8715 cm-1 and the low emission quenching temperature of 53 K. The activation energy for quenching changes with temperature, attributed to relative shifts of the two potential energy curves involved. The splitting of the Ce3+ 5d1 state into two levels separated by 4925 cm-1 is accounted for by a first principles calculation using the crystal structure data of I. The NO2- energy levels and spectra were investigated also in Cs2NaLa(NO2)6 and modelled by hybrid DFT. The vibrational and electronic spectral properties have been thoroughly investigated and rationalized at temperatures down to 10 K. A comparison of Stokes shifts with other Ce-O systems emphasizes the dependence upon the coordination number of Ce3+. PMID- 30409996 TI - Inducing controlled cell cycle arrest and re-entry during asexual proliferation of Plasmodium falciparum malaria parasites. AB - The life cycle of the malaria parasite Plasmodium falciparum is tightly regulated, oscillating between stages of intense proliferation and quiescence. Cyclic 48-hour asexual replication of Plasmodium is markedly different from cell division in higher eukaryotes, and mechanistically poorly understood. Here, we report tight synchronisation of malaria parasites during the early phases of the cell cycle by exposure to DL-alpha-difluoromethylornithine (DFMO), which results in the depletion of polyamines. This induces an inescapable cell cycle arrest in G1 (~15 hours post-invasion) by blocking G1/S transition. Cell cycle-arrested parasites enter a quiescent G0-like state but, upon addition of exogenous polyamines, re-initiate their cell cycle. This ability to halt malaria parasites at a specific point in their cell cycle, and to subsequently trigger re-entry into the cell cycle, provides a valuable framework to investigate cell cycle regulation in these parasites. We subsequently used gene expression analyses to show that re-entry into the cell cycle involves expression of Ca2+-sensitive (cdpk4 and pk2) and mitotic kinases (nima and ark2), with deregulation of the pre replicative complex associated with expression of pk2. Changes in gene expression could be driven through transcription factors MYB1 and two ApiAP2 family members. This new approach to parasite synchronisation therefore expands our currently limited toolkit to investigate cell cycle regulation in malaria parasites. PMID- 30409999 TI - The dissolution of temporal distance increases risk-taking: experimental evidence. AB - Earlier research shows that delaying the realization of a lottery (temporal distance) increases risk tolerance. Presumably, this happens because temporal distance protects one from encountering the negative emotions produced when facing risk. However, no study has tested whether people that made a choice in the presence of temporal distance would actually change their decision later on (in the absence of temporal distance), towards the safer choice. To test this, 137 participants were subject to actual temporal distance, consisting of a four week waiting period. To explore how each participant behaved "in the heat of the moment" (in the absence of temporal distance), we assessed their electrodermal activity and analysed self-description measures of susceptibility to affect. Participants had to choose between 40 lottery pairs (they could win up to the equivalent of about $400 US; the expected payout for each participant was about $12). Results showed that, contrary to expectations, participants tended to choose riskier lotteries after the waiting period. The results of an additional experiment suggest that this is not the result of prior exposure to the same set of lotteries, however, interestingly, an exploratory analysis showed that the main effect was driven by the behaviour of male participants. We discuss possible explanations for our surprising main finding and its implications for studies on temporal distance. PMID- 30409998 TI - The prebiotic inulin modulates gut microbiota but does not ameliorate atherosclerosis in hypercholesterolemic APOE*3-Leiden.CETP mice. AB - Gut microbiota have been implicated in the development of atherosclerosis and cardiovascular disease. Since the prebiotic inulin is thought to beneficially affect gut microbiota, we aimed to determine the effect of inulin supplementation on atherosclerosis development in APOE*3-Leiden.CETP (E3L.CETP) mice. Female E3L.CETP mice were fed a western-type diet containing 0.1% or 0.5% cholesterol with or without 10% inulin. The effects of inulin were determined on: microbiota composition, cecal short-chain fatty acid (SCFA) levels, plasma lipid levels, atherosclerosis development, hepatic morphology and hepatic inflammation. Inulin with 0.5% dietary cholesterol increased specific bacterial genera and elevated levels of cecal SCFAs, but did not affect plasma cholesterol levels or atherosclerosis development. Surprisingly, inulin resulted in mild hepatic inflammation as shown by increased expression of inflammation markers. However, these effects were not accompanied by increased hepatic macrophage number. Analogously, inulin induced mild steatosis and increased hepatocyte size, but did not affect hepatic triglyceride content. Inulin with 0.1% dietary cholesterol did not affect hepatic morphology, nor hepatic expression of inflammation markers. Overall, inulin did not reduce hypercholesterolemia or atherosclerosis development in E3L.CETP mice despite showing clear prebiotic activity, but resulted in manifestations of hepatic inflammation when combined with a high percentage of dietary cholesterol. PMID- 30410000 TI - Differential responses of heterotrophic and autotrophic respiration to nitrogen addition and precipitation changes in a Tibetan alpine steppe. AB - Soil respiration (Rs) is an important source of atmospheric CO2 flux and is sensitive to changes in soil nutrient and water contents. Despite extensive studies on the effects of enhanced atmospheric nitrogen (N) deposition and changes in precipitation (P) on Rs, few studies have taken into account the effects of interactions between these factors on Rs of alpine grasslands. To address these questions, we investigated the effects of N addition (10 g N m-2 yr 1), changes in precipitation (+/-50% precipitation), and their interaction on soil respiration and its components, including heterotrophic respiration (Rh) and autotrophic respiration (Ra),in a Tibetan alpine steppe during three consecutive growing seasons. We found that Rs differed in its response to N addition and precipitation regimes. Specifically, decreased precipitation led to a significant reduction in Rs during the last two years, whereas N addition minimally impacted Rs. Another important finding was that soil respiration components differed in their response to N addition and precipitation regimes. Nitrogen addition significantly enhanced Ra, whereas Rh was not altered in response to N addition. By contrast, the precipitation regime led to marked changes in Rh, but exhibited marginally significant effects on Ra. Therefore, our findings highlighted that soil respiration differed in its response to N addition and precipitation regimes mainly due to the different responses of soil respiration components to these factors. Therefore, carbon dynamics should take soil respiration components into account under global change scenarios. PMID- 30410001 TI - Quantitative morphometric analysis of adult teleost fish by X-ray computed tomography. AB - Vertebrate models provide indispensable paradigms to study development and disease. Their analysis requires a quantitative morphometric study of the body, organs and tissues. This is often impeded by pigmentation and sample size. X-ray micro-computed tomography (micro-CT) allows high-resolution volumetric tissue analysis, largely independent of sample size and transparency to visual light. Importantly, micro-CT data are inherently quantitative. We report a complete pipeline of high-throughput 3D data acquisition and image analysis, including tissue preparation and contrast enhancement for micro-CT imaging down to cellular resolution, automated data processing and organ or tissue segmentation that is applicable to comparative 3D morphometrics of small vertebrates. Applied to medaka fish, we first create an annotated anatomical atlas of the entire body, including inner organs as a quantitative morphological description of an adult individual. This atlas serves as a reference model for comparative studies. Using isogenic medaka strains we show that comparative 3D morphometrics of individuals permits identification of quantitative strain-specific traits. Thus, our pipeline enables high resolution morphological analysis as a basis for genotype-phenotype association studies of complex genetic traits in vertebrates. PMID- 30410002 TI - Localising functionalised gold-nanoparticles in murine spinal cords by X-ray fluorescence imaging and background-reduction through spatial filtering for human sized objects. AB - Accurate in vivo localisation of minimal amounts of functionalised gold nanoparticles, enabling e.g. early-tumour diagnostics and pharmacokinetic tracking studies, requires a precision imaging system offering very high sensitivity, temporal and spatial resolution, large depth penetration, and arbitrarily long serial measurements. X-ray fluorescence imaging could offer such capabilities; however, its utilisation for human-sized scales is hampered by a high intrinsic background level. Here we measure and model this anisotropic background and present a spatial filtering scheme for background reduction enabling the localisation of nanoparticle-amounts as reported from small-animal tumour models. As a basic application study towards precision pharmacokinetics, we demonstrate specific localisation to sites of disease by adapting gold nanoparticles with small targeting ligands in murine spinal cord injury models, at record sensitivity levels using sub-mm resolution. Both studies contribute to the future use of molecularly-targeted gold-nanoparticles as next-generation clinical diagnostic and pharmacokinetic tools. PMID- 30410003 TI - Enhancing Humoral Responses Against HIV Envelope Trimers via Nanoparticle Delivery with Stabilized Synthetic Liposomes. AB - An HIV vaccine capable of eliciting durable neutralizing antibody responses continues to be an important unmet need. Multivalent nanoparticles displaying a high density of envelope trimers may be promising immunogen forms to elicit strong and durable humoral responses to HIV, but critical particle design criteria remain to be fully defined. To this end, we developed strategies to covalently anchor a stabilized gp140 trimer, BG505 MD39, on the surfaces of synthetic liposomes to study the effects of trimer density and vesicle stability on vaccine-elicited humoral responses in mice. CryoEM imaging revealed homogeneously distributed and oriented MD39 on the surface of liposomes irrespective of particle size, lipid composition, and conjugation strategy. Immunization with covalent MD39-coupled liposomes led to increased germinal center and antigen-specific T follicular helper cell responses and significantly higher avidity serum MD39-specific IgG responses compared to immunization with soluble MD39 trimers. A priming immunization with liposomal-MD39 was important for elicitation of high avidity antibody responses, regardless of whether booster immunizations were administered with either soluble or particulate trimers. The stability of trimer anchoring to liposomes was critical for these effects, as germinal center and output antibody responses were further increased by liposome compositions incorporating sphingomyelin that exhibited high in vitro stability in the presence of serum. Together these data highlight key liposome design features for optimizing humoral immunity to lipid nanoparticle immunogens. PMID- 30410004 TI - Different responses of colorectal cancer cells to alternative sequences of cetuximab and oxaliplatin. AB - Therapeutic protocols including EGFR antibodies in the context of oxaliplatin based regimens have variable clinical effect in colorectal cancer. Here, we tested the effect of the EGFR antibody cetuximab in different sequential combinations with oxaliplatin on the growth of colorectal cancer cells in vitro and in vivo. Cetuximab reduced the efficacy of oxaliplatin when administered before oxaliplatin but provided additive effect when administered after oxaliplatin regardless of the KRAS or BRAF mutation status of the cells. Systemic gene expression and protein phosphorylation screens revealed alternatively activated pathways regulating apoptosis, cell cycle and DNA damage response. Functional assays indicated that cetuximab-induced arrest of the cells into the G1 phase of the cell cycle was associated with reduced responsiveness of the cells to subsequent treatment with oxaliplatin. In contrast, oxaliplatin-enhanced responsiveness to subsequent treatment with cetuximab was associated with increased apoptosis, inhibition of STAT3 activity and increased EGFR down regulation. This preclinical study indicates that optimizing the sequence of administration may enhance the antitumor effect of combination therapy with EGFR antibodies and oxaliplatin. PMID- 30410006 TI - Variation of mechanical and thermal properties in sustainable graphene oxide/epoxy composites. AB - In this work, the functional graphene oxide (bGO) was facilely synthesized through a grafted reaction between graphene oxide (GO) and bio-based bis-furan di epoxide (BFDE). The structure of bGO was confirmed by FTIR spectra and Raman spectra. The properties of polymer composite materials depend on the distribution of the nanofiller in the matrix and due to the presence of polymer chains our bGO sheets exhibit a better dispersibility in solvents and polymer matrix, which provides a potential opportunity for the preparation of BFDE composites with excellent performance. Bio-based BFDE composites containing 0.05-0.5 wt.% of bGO exhibit superior mechanical and thermal properties. The addition of just 0.5 wt% such bGO to an BFDE causes 80%, 49%, 21%, 69% and 97% enhancement in tensile strength, flexural strength, flexural modulus, critical stress intensity factor and critical strain energy release rate, respectively. The thermal decomposition temperature Td of bGO/BFDE composites was increased about ~17 degrees C compared to blank BFDE sample. In addition, we found that introducing unmodified GO to epoxy matrix lead to an insignificant increase of the thermal property of the resulting GO/BFDE composites. The enhanced mechanical properties and thermal properties of bGO/BFDE composites could be attributed to strong interfacial interactions and high affinity between bGO and epoxy matrix. PMID- 30410005 TI - Syncytial germline architecture is actively maintained by contraction of an internal actomyosin corset. AB - Syncytial architecture is an evolutionarily-conserved feature of the germline of many species and plays a crucial role in their fertility. However, the mechanism supporting syncytial organization is largely unknown. Here, we identify a corset like actomyosin structure within the syncytial germline of Caenorhabditis elegans, surrounding the common rachis. Using laser microsurgery, we demonstrate that actomyosin contractility within this structure generates tension both in the plane of the rachis surface and perpendicular to it, opposing membrane tension. Genetic and pharmacological perturbations, as well as mathematical modeling, reveal a balance of forces within the gonad and show how changing the tension within the actomyosin corset impinges on syncytial germline structure, leading, in extreme cases, to sterility. Thus, our work highlights a unique tissue-level cytoskeletal structure, and explains the critical role of actomyosin contractility in the preservation of a functional germline. PMID- 30410007 TI - Southern Hemisphere forcing of South Asian monsoon precipitation over the past ~1 million years. AB - The orbital-scale timing of South Asian monsoon (SAM) precipitation is poorly understood. Here we present new SST and seawater delta18O (delta18Osw) records from the Bay of Bengal, the core convective region of the South Asian monsoon, over the past 1 million years. Our records reveal that SAM precipitation peaked in the precession band ~9 kyrs after Northern Hemisphere summer insolation maxima, in phase with records of SAM winds in the Arabian Sea and eastern Indian Ocean. Precession-band variance, however, accounts for ~30% of the total variance of SAM precipitation while it was either absent or dominant in records of the East Asian monsoon (EAM). This and the observation that SAM precipitation was phase locked with obliquity minima and was sensitive to Southern Hemisphere warming provides clear evidence that SAM and EAM precipitation responded differently to orbital forcing and highlights the importance of internal processes forcing monsoon variability. PMID- 30410008 TI - Antimicrobial agent isolated from Coptidis rhizome extract incubated with Rhodococcus sp. strain BD7100. AB - Coptidis rhizome (CR) is a widely used herbal medicine that contains protoberberine-type alkaloids. CR extract exhibits various pharmacologic activities. A previous study reported the isolation of Rhodococcus sp. strain BD7100 as a berberine (BBR)-utilizing bacterium, and the BBR-degradation pathway has been investigated. When we incubated strain BD7100 cells with CR extract, the number of viable cells declined with the degradation of components in the CR extract, and the culture broth exhibited antibacterial activity against strain BD7100. These results suggest that CR extract cultured in the presence of strain BD7100 contains one or more antibacterial agents. In this study, we isolated coptirhoquinone A (1) from CR extract incubated with strain BD7100 in Luria Bertani (LB) medium, and the structure was elucidated using NMR and MS analysis. We also report the total synthesis and antimicrobial activities of 1 against bacteria, fungi, and Pythium sp. PMID- 30410009 TI - AtHKT1 gene regulating K+ state in whole plant improves salt tolerance in transgenic tobacco plants. AB - The status of K+ is important for plant health. However, little is known about if high-affinity potassium transporter HKTs may help K+ retention under salt stress. Here, we determined the effect of Arabidopsis thaliana transporter gene (AtHKT1) on the K+ status, Na+-induced toxicity, and salt tolerance in tobacco (Nicotiana tabacum L.). Six AtHKT1 transformed tobacco lines (T1, T2, ... T6) were contrasted with a non-transgenic plantlet at the whole-plant and molecule levels. AtHKT1 gene was expressed in the xylems of stem, root and leaf vein in the transgenic tobacco, with the line T3 having highest expression. At Day 15, in the 200 mmol L-1 NaCl stress treatment, the transgenic plants remained a healthy K+ status, while the control plants decreased K+ content by 70% and Na+ contents in leaves and stems were 1.7 times that in the transgenic line. The AtHKT1 expression enhanced the activities of SOD, CAT and POD, raised chlorophyll and soluble sugar contents and root activity, and decreased MDA and proline contents and electrolyte leakage destruction. The constitutive over-expression of AtHKT1 that helps maintain a healthy K+ status while reducing Na+ toxicity may serve as a possible mechanism in maximizing productivity of tobacco under salt stress. PMID- 30410010 TI - Novel approach on reduction in GHG emissions from sludge lime stabilization as an emergent and regional treatment in China. AB - As a typical organic solid waste, sludge plays an important role in contributing to greenhouse gas (GHG) emissions resulted by its treatment and disposal. As a temporary and emergent treatment measurement, sludge lime stabilization is regionally adopted in most sludge generated units in China. In present case, sludge lime stabilization system in China was productive of total GHG emissions, including indirect and direct emissions during lime stabilization and carbon reduction owing to lime synthesis and consumption, were first quantified respectively. The results indicated that electricity consumption was main component of indirect emissions, including mixing and transportation related mechanical equipment use. Direct emission was attributed to CO2 absorption during the second step in hydration reaction of lime stabilization. Meanwhile, a carbon credit portion of lime synthesis was also taken to the consideration of carbon budget. In brief, reduction in total replaceable carbon emission resulted by sludge lime treatment in comparison to landfill was calculated to be 0.8092 tCO2e.t-1. As treated production, lime-stabilized sludge is suggested to amend acidic soil for its revegetation. It is concluded that lime stabilization of sludge shows a significant GHG reduction effect despite of its temporary and emergent nature. PMID- 30410011 TI - K-variant BCHE and pesticide exposure: Gene-environment interactions in a case control study of Parkinson's disease in Egypt. AB - Pesticide exposure is associated with increased risk of Parkinson's disease (PD). We investigated in Egypt whether common variants in genes involved in pesticide detoxification or transport might modify the risk of PD evoked by pesticide exposure. We recruited 416 PD patients and 445 controls. Information on environmental factors was collected by questionnaire-based structured interviews. Candidate single-nucleotide polymorphisms (SNPs) in 15 pesticide-related genes were genotyped. We analyzed the influence of environmental factors and SNPs as well as the interaction of pesticide exposure and SNPs on the risk of PD. The risk of PD was reduced by coffee consumption [OR = 0.63, 95% CI: 0.43-0.90, P = 0.013] and increased by pesticide exposure [OR = 7.09, 95% CI: 1.12-44.01, P = 0.036]. The SNP rs1126680 in the butyrylcholinesterase gene BCHE reduced the risk of PD irrespective of pesticide exposure [OR = 0.38, 95% CI: 0.20-0.70, P = 0.002]. The SNP rs1803274, defining K-variant BCHE, interacted significantly with pesticide exposure (P = 0.007) and increased the risk of PD only in pesticide exposed individuals [OR = 2.49, 95% CI: 1.50-4.19, P = 0.0005]. The K-variant BCHE reduces serum activity of butyrylcholinesterase, a known bioscavenger for pesticides. Individuals with K-variant BCHE appear to have an increased risk for PD when exposed to pesticides. PMID- 30410012 TI - Retinal micro-vascular and aortic macro-vascular changes in postmenopausal women with primary hyperparathyroidism. AB - Aim of the study was to evaluate the micro and macro-vascular changes in patients with primary hyperparathyroidism (PHPT) compared to controls. 30 postmenopausal PHPT women (15 hypertensive and 15 normotensive) and 30 normotensive controls underwent biochemical evaluation of mineral metabolism and measurements of arterial stiffness by 24 hour ambulatory blood pressure monitoring. Retinal microcirculation was imaged by a Retinal Vessel Analyzer. PHPT patients also underwent bone mineral density measurements and kidney ultrasound. PHPT patients had higher mean calcium and parathyroid hormone values compared to controls. Evaluating macro-vascular compartment, we found higher values of 24 hours systolic, diastolic blood pressure, aortic pulse wave velocity (aPWV) and aortic augmentation index (Aix) in hypertensive PHPT, but not in normotensive PHPT compared to controls. The eye examination showed narrowing arterial and venular diameters of retinal vessels in both hypertensive and normotensive PHPT compared to controls. In hypertensive PHPT, 24 hours systolic blood pressure was associated only with parathyroid hormone (PTH) levels (beta = 0.36, p = 0.04). aPWV was associated with retinal diameter (beta = -0.69, p = 0.003), but not with PTH. Retinal artery diameter was associated with PTH (beta = -0.6, p = 0.008). In the normotensive PHPT, only PTH was associated with retinal artery diameter (beta = -0.60, p = 0.01) and aortic AIx (beta = 0.65, p = 0.02). In conclusion, we found macro-vascular impairment in PHPT and that micro-vascular impairment is negatively associated with PTH, regardless of hypertension in PHPT. PMID- 30410013 TI - Automatic Verification of the Gradient Table in Diffusion-Weighted MRI Based on Fiber Continuity. AB - In diffusion-weighted magnetic resonance imaging (dMRI), the coordinate systems where the image and the diffusion gradients are represented may be inconsistent, thus impacting the quality of subsequent fiber tracking and connectivity analysis. Empirical verification of the reconstructed fiber orientations and subsequent correction of the gradient table (by permutation and flipping), both time-consuming tasks, are therefore often necessary. To save manual labor in studies involving dMRI, we introduce a new automatic gradient-table verification approach, which we propose to include in the dMRI processing pipeline. To that end, we exploit the concept of fiber continuity - the assumption that, in the fibrous tissue (such as the brain white matter), fiber bundles vary smoothly along their own orientations. Our tractography-free method tries all possible permutation and flip configurations of the gradient table, and in each case, assesses the consistency of the reconstructed fiber orientations with fiber continuity. Our algorithm then suggests the correct gradient table by choosing the configuration with the most consistent fiber orientations. We validated our method in 185 experiments on human brain dMRI data form three public data sources. The proposed algorithm identified the correct permutation and flip configuration for the gradient table in all the experiments. PMID- 30410015 TI - Prognostic role of the systemic immune-inflammation index in brain metastases from lung adenocarcinoma with different EGFR mutations. AB - The prognostic value of the systemic immune-inflammation index (SII) has been shown in various types of cancers. We aimed to evaluate the predictive values in brain metastases from lung adenocarcinoma with status of EGFR mutations. We, retrospectively, examined 310 patients with brain metastases from lung adenocarcinoma with status of EGFR mutations. SII was calculated using P * N/L, where P, N, and L, respectively refer to peripheral blood lymphocyte, neutrophil, and platelet counts. The cut-off value of SII was assessed by area under the curve (AUC). The log-rank test and Cox proportional hazard model were used to confirm the impact of SII and other variables on survival. The SII value <= 1218.81 was associated with prolonged survival in patients with brain metastases from lung adenocarcinoma in both variable and multivariable analysis In patients with EGFR mutations, the SII had statistical effect on OS only in invariable test. While, for patients with wild-type EGFR, SII achieved statistically significant differences both in variable and multivariable analyses. SII is an independent prognostic factor in brain metastases from lung adenocarcinoma. SII may have varying prognostic effects on patients with and without EGFR mutations and is a promising variable for the future prognostic systems. PMID- 30410014 TI - Intrinsic functional connectivity correlates of person-level risk for bipolar disorder in offspring of affected parents. AB - Offspring of parents with bipolar disorder (OBP) are at increased risk to develop bipolar disorder (BD). Alterations in resting-state functional connectivity (rsFC) have been identified in OBP; however, replication has been limited and correlation with person-level risk is unknown. A recent study found reduced rsFC between left inferior frontal gyrus (IFG) and clusters in the left insula (LINS), lentiform nucleus (LENT), and midcingulate cortex (MCING) in OBP (Roberts et al. 2017); here, we aim to extend these findings to at-risk youth. We scanned a subset of the Pittsburgh Bipolar Offspring Study, a longitudinal study of OBP and community controls. Twenty-four OBP, 20 offspring of control parents with non bipolar psychopathology (OCP), and 27 healthy controls (HC) had acceptable rsFC data. After preprocessing steps, we assessed group differences in seed-based rsFC between the IFG and target clusters (LINS, LENT, MCING) using multivariate regression. Next, we tested whether rsFC correlated with person-level risk score and with other dimensional measures. We did not find group differences in rsFC between IFG and target regions. Within OBP, risk score negatively correlated with IFG-LINS rsFC (p = 0.002). Across groups, mood lability correlated negatively with rsFC between IFG and target regions (p = 0.0002), due to negative correlation with IFG-LINS (p = 0.0003) and IFG-MCING (p = 0.001) rsFC. While group-level differences were not replicated, IFG-LINS rsFC was negatively correlated with a person-level risk score in OBP and with mood lability (a predictor of BD) across the sample. Thus, IFG-LINS rsFC might constitute a risk marker, within OBP, for the development of BD. PMID- 30410016 TI - Impact of lower urinary tract symptoms on mortality: a 21-year follow-up among middle-aged and elderly Finnish men. AB - BACKGROUND: The usefulness of lower urinary tract symptoms (LUTS) as mortality risk factors remains unclear. Repeated assessments are required to take into account symptom fluctuation and de novo symptom appearance. The study objective was to evaluate mortality in relation to three urinary storage symptoms-urgency, daytime frequency, and nocturia-in middle-aged and elderly men, considering also other time-varying factors during follow-up. METHODS: A mail survey of a population-based cohort of men initially aged 50, 60, and 70 years was conducted in Finland in 1994, 1999, 2004, and 2009. The questionnaire included assessments of LUTS based on the Danish Prostatic Symptom Score and comorbidities. The men were followed up for mortality through the population registry through 2014. LUTS related hazard ratios (HR) were analyzed with time-dependent Cox regression adjusted for the year of birth and comorbidities using variable values updated every 5 years. Sensitivity analyses were conducted using values of all variables fixed to the baseline assessment of 1994. RESULTS: Of the 1332 eligible men with data on LUTS from each preceding survey, 514 (38.6%) died during the 21-year follow-up. In time-dependent analyses, daytime frequency, and nocturia were significantly associated with increased mortality: the adjusted HR was 1.42 (95% CI 1.11-1.83) for daytime frequency, 1.38 (1.07-1.79) for nocturia and 1.19 (0.94 1.50) for urgency. In sensitivity analyses with fixed baseline characteristics, only nocturia was suggestively associated with an increased risk of death: the adjusted HR was 1.09 (0.84-1.42) for daytime frequency, 1.41 (0.99-2.02) for nocturia and 0.94 (0.52-1.68) for urgency. CONCLUSIONS: Among aging men, LUTS are more accurate predictors of short-term than longer-term mortality risk. Repeated assessments are needed to detect clinically relevant and persistent symptoms, often associated with ill health. Accordingly, men with daytime frequency or nocturia exhibit a 1.4-fold risk of death and therefore, should be evaluated for underlying comorbidity. PMID- 30410017 TI - Structure of the 4-1BB/4-1BBL complex and distinct binding and functional properties of utomilumab and urelumab. AB - 4-1BB (CD137, TNFRSF9) is an inducible costimulatory receptor expressed on activated T cells. Clinical trials of two agonist antibodies, utomilumab (PF 05082566) and urelumab (BMS-663513), are ongoing in multiple cancer indications, and both antibodies demonstrate distinct activities in the clinic. To understand these differences, we solved structures of the human 4-1BB/4-1BBL complex, the 4 1BBL trimer alone, and 4-1BB bound to utomilumab or urelumab. The 4-1BB/4-1BBL complex displays a unique interaction between receptor and ligand when compared with other TNF family members. Furthermore, our ligand-only structure differs from previously published data. Utomilumab, a ligand-blocking antibody, binds 4 1BB between CRDs 3 and 4. In contrast, urelumab binds 4-1BB CRD-1, away from the ligand binding site. Finally, cell-based assays demonstrate utomilumab is a milder agonist than urelumab. Collectively, our data provide a deeper understanding of the 4-1BB signaling complex, providing a template for future development of next generation 4-1BB targeted biologics. PMID- 30410019 TI - An interpretable approach for social network formation among heterogeneous agents. AB - Understanding the mechanisms of network formation is central in social network analysis. Network formation has been studied in many research fields with their different focuses; for example, network embedding algorithms in machine learning literature consider broad heterogeneity among agents while the social sciences emphasize the interpretability of link formation mechanisms. Here we propose a social network formation model that integrates methods in multiple disciplines and retain both heterogeneity and interpretability. We represent each agent by an "endowment vector" that encapsulates their features and use game-theoretical methods to model the utility of link formation. After applying machine learning methods, we further analyze our model by examining micro- and macro- level properties of social networks as most agent-based models do. Our work contributes to the literature on network formation by combining the methods in game theory, agent-based modeling, machine learning, and computational sociology. PMID- 30410018 TI - A rice Serine/Threonine receptor-like kinase regulates arbuscular mycorrhizal symbiosis at the peri-arbuscular membrane. AB - In terrestrial ecosystems most plant species live in mutualistic symbioses with nutrient-delivering arbuscular mycorrhizal (AM) fungi. Establishment of AM symbioses includes transient, intracellular formation of fungal feeding structures, the arbuscules. A plant-derived peri-arbuscular membrane (PAM) surrounds the arbuscules, mediating reciprocal nutrient exchange. Signaling at the PAM must be well coordinated to achieve this dynamic cellular intimacy. Here, we identify the PAM-specific Arbuscular Receptor-like Kinase 1 (ARK1) from maize and rice to condition sustained AM symbiosis. Mutation of rice ARK1 causes a significant reduction in vesicles, the fungal storage structures, and a concomitant reduction in overall root colonization by the AM fungus Rhizophagus irregularis. Arbuscules, although less frequent in the ark1 mutant, are morphologically normal. Co-cultivation with wild-type plants restores vesicle and spore formation, suggesting ARK1 function is required for the completion of the fungal life-cycle, thereby defining a functional stage, post arbuscule development. PMID- 30410022 TI - Evolutionary puppets. PMID- 30410020 TI - Src-transformed cells hijack mitosis to extrude from the epithelium. AB - At the initial stage of carcinogenesis single mutated cells appear within an epithelium. Mammalian in vitro experiments show that potentially cancerous cells undergo live apical extrusion from normal monolayers. However, the mechanism underlying this process in vivo remains poorly understood. Mosaic expression of the oncogene vSrc in a simple epithelium of the early zebrafish embryo results in extrusion of transformed cells. Here we find that during extrusion components of the cytokinetic ring are recruited to adherens junctions of transformed cells, forming a misoriented pseudo-cytokinetic ring. As the ring constricts, it separates the basal from the apical part of the cell releasing both from the epithelium. This process requires cell cycle progression and occurs immediately after vSrc-transformed cell enters mitosis. To achieve extrusion, vSrc coordinates cell cycle progression, junctional integrity, cell survival and apicobasal polarity. Without vSrc, modulating these cellular processes reconstitutes vSrc-like extrusion, confirming their sufficiency for this process. PMID- 30410021 TI - Serum Amyloid A3 is required for normal lung development and survival following influenza infection. AB - Serum amyloid A (SAA) proteins are a family of acute phase apolipoproteins implicated to directly modulate innate and adaptive immune responses. However, new studies comparing endogenous SAAs and recombinant forms of these proteins have questioned the function of SAA in inflammation and immunity. We generated SAA3 knockout mice to evaluate the contribution of SAA3 to lung development and immune-mediated lung disease. While SAA3 deficiency does not affect the generation of house dust mite-induced allergic asthma, mice lacking SAA3 develop adult-onset obesity, intrinsic airway hyperresponsiveness, increased inflammatory and fibrotic gene expression in the lung, and elevated levels of lung citrullinated proteins. Polyclonally stimulated CD4+ T cells from SAA3-/- mice exhibit impaired glycolytic activity, decreased TH2 and TH1 cytokine secretion, and elevated IL-17A production compared to wild type cells. Polyclonally stimulated CD8+ T cells from SAA3-/- mice also exhibit impaired glycolytic activity as well as a diminished capacity to produce IL-2 and IFNgamma. Finally, SAA3-/- mice demonstrate increased mortality in response to H1N1 influenza infection, along with higher copy number of viral RNAs in the lung, a lack of CD8+ T cell IFNgamma secretion, and decreased flu-specific antibodies. Our findings indicate that endogenous SAA3 regulates lung development and homeostasis, and is required for protection against H1N1 influenza infection. PMID- 30410023 TI - Transient hydrodynamic effects influence organic carbon signatures in marine sediments. AB - Ocean dynamics served an important role during past dramatic climate changes via impacts on deep-ocean carbon storage. Such changes are recorded in sedimentary proxies of hydrographic change on continental margins, which lie at the ocean atmosphere-earth interface. However, interpretations of these records are challenging, given complex interplays among processes delivering particulate material to and from ocean margins. Here we report radiocarbon (14C) signatures measured for organic carbon in differing grain-size sediment fractions and foraminifera in a sediment core retrieved from the southwest Iberian margin, spanning the last ~25,000 yr. Variable differences of 0-5000 yr in radiocarbon age are apparent between organic carbon in differing grain-sizes and foraminifera of the same sediment layer. The magnitude of 14C differences co-varies with key paleoceanographic indices (e.g., proximal bottom-current density gradients), which we interpret as evidence of Atlantic-Mediterranean seawater exchange influencing grain-size specific carbon accumulation and translocation. These findings underscore an important link between regional hydrodynamics and interpretations of down-core sedimentary proxies. PMID- 30410024 TI - Author Correction: From alkylarenes to anilines via site-directed carbon-carbon amination. AB - The version of this Article originally published online did not include a caution statement relating to safety concerns over some of the reagents used. All versions of the Article now have the following text included at the start of the Methods section "Caution: Sodium azide (NaN3) is highly toxic and also a potential explosion hazard; it can also react with organohalides to form explosive organic azides. Under acidic conditions, sodium azide can form hydrazoic acid (HN3) which is highly toxic. Considering these hazards, appropriate safety precautions should be taken when undertaking the C-C amination reactions reported in this Article." Furthermore, in Fig. 2a, in the reaction conditions on the first equation it should have read DDQ not DDG; this has also been amended. PMID- 30410025 TI - Nonsense-mediated RNA decay in the brain: emerging modulator of neural development and disease. AB - Steady-state RNA levels are controlled by the balance between RNA synthesis and RNA turnover. A selective RNA turnover mechanism that has received recent attention in neurons is nonsense-mediated RNA decay (NMD). NMD has been shown to influence neural development, neural stem cell differentiation decisions, axon guidance and synaptic plasticity. In humans, NMD factor gene mutations cause some forms of intellectual disability and are associated with neurodevelopmental disorders, including schizophrenia and autism spectrum disorder. Impairments in NMD are linked to neurodegenerative disorders, including amyotrophic lateral sclerosis. We discuss these findings, their clinical implications and challenges for the future. PMID- 30410028 TI - Bottle beam generation from a frequency-doubled Nd:YVO4 laser. AB - We demonstrate, for the first time, the direct generation of a bottle beam with a well-isolated three-dimensional zero-intensity dark core (high potential barrier) from a compact intracavity frequency-doubled Nd:YVO4 laser with a nearly hemispherical cavity. We also numerically calculate the physical properties of the generated bottle beam using a coherent superposition of a series of frequency locked Laguerre-Gaussian modes. PMID- 30410026 TI - HLA-B57 micropolymorphism defines the sequence and conformational breadth of the immunopeptidome. AB - Immunophenotypic differences between closely related human leukocyte antigen (HLA) alleles have been associated with divergent clinical outcomes in infection, autoimmunity, transplantation and drug hypersensitivity. Here we explore the impact of micropolymorphism on peptide antigen presentation by three closely related HLA molecules, HLA-B*57:01, HLA-B*57:03 and HLA-B*58:01, that are differentially associated with the HIV elite controller phenotype and adverse drug reactions. For each allotype, we mine HLA ligand data sets derived from the same parental cell proteome to define qualitative differences in peptide presentation using classical peptide binding motifs and an unbiased statistical approach. The peptide repertoires show marked qualitative overlap, with 982 peptides presented by all allomorphs. However, differences in peptide abundance, HLA-peptide stability, and HLA-bound conformation demonstrate that HLA micropolymorphism impacts more than simply the range of peptide ligands. These differences provide grounds for distinct immune reactivity and insights into the capacity of micropolymorphism to diversify immune outcomes. PMID- 30410029 TI - Long-term combined application of manure and chemical fertilizer sustained higher nutrient status and rhizospheric bacterial diversity in reddish paddy soil of Central South China. AB - Bacteria, as the key component of soil ecosystems, participate in nutrient cycling and organic matter decomposition. However, how fertilization regime affects the rhizospheric bacterial community of reddish paddy soil remains unclear. Here, a long-term fertilization experiment initiated in 1982 was employed to explore the impacts of different fertilization regimes on physicochemical properties and bacterial communities of reddish paddy rhizospheric soil in Central South China by sequencing the 16S rRNA gene. The results showed that long-term fertilization improved the soil nutrient status and shaped the distinct rhizospheric bacterial communities. Particularly, chemical NPK fertilizers application significantly declined the richness of the bacterial community by 7.32%, whereas the application of manure alone or combined with chemical NPK fertilizers significantly increased the biodiversity of the bacterial community by 1.45%, 1.87% compared with no fertilization, respectively. Moreover, LEfSe indicated that application of chemical NPK fertilizers significantly enhanced the abundances of Verrucomicrobia and Nitrospiraceae, while manure significantly increased the abundances of Deltaproteobacteria and Myxococcales, but the most abundant Actinobacteria and Planctomycetes were detected in the treatment that combined application of manure and chemical NPK fertilizers. Furthermore, canonical correspondence analysis (CCA) and the Mantel test clarified that exchangeable Mg2+ (E-Mg2+), soil organic carbon (SOC) and alkali-hydrolyzable nitrogen (AN) are the key driving factors for shaping bacterial communities in the rhizosphere. Our results suggested that long-term balanced using of manure and chemical fertilizers not only increased organic material pools and nutrient availability but also enhanced the biodiversity of the rhizospheric bacterial community and the abundance of Actinobacteria, which contribute to the sustainable development of agro-ecosystems. PMID- 30410027 TI - Genome-wide associations for benign prostatic hyperplasia reveal a genetic correlation with serum levels of PSA. AB - Benign prostatic hyperplasia and associated lower urinary tract symptoms (BPH/LUTS) are common conditions affecting the majority of elderly males. Here we report the results of a genome-wide association study of symptomatic BPH/LUTS in 20,621 patients and 280,541 controls of European ancestry, from Iceland and the UK. We discovered 23 genome-wide significant variants, located at 14 loci. There is little or no overlap between the BPH/LUTS variants and published prostate cancer risk variants. However, 15 of the variants reported here also associate with serum levels of prostate specific antigen (PSA) (at a Bonferroni corrected P < 0.0022). Furthermore, there is a strong genetic correlation, rg = 0.77 (P = 2.6 * 10-11), between PSA and BPH/LUTS, and one standard deviation increase in a polygenic risk score (PRS) for BPH/LUTS increases PSA levels by 12.9% (P = 1.6*10 55). These results shed a light on the genetic background of BPH/LUTS and its substantial influence on PSA levels. PMID- 30410031 TI - Distinct patterns of variation in the distribution of knee pain. AB - The patient's expression of pain using digital-body maps expands analytic opportunities for exploring the spatial variation of bodily pain. A common knee pain condition in adolescents and adults is patellofemoral pain (PFP) and recently PFP was shown to be characterized by a heterogeneous distribution of pain. Whether there are important patterns in these distributions remains unclear. This pioneering study assesses the spatial variation of pain using principal component analysis and a clustering approach. Detailed digital-body maps of knee pain were drawn by 299 PFP patients of mixed sex, age, and pain severity. Three pain distribution patterns emerged resembling an Anchor, Hook, and an Ovate shape on and around the patella. The variations in pain distribution were independent of sex, age, and pain intensity. Bilateral pain associated with a longer duration of pain and the majority characterized by the Hook and Ovate pain distributions. Bilateral and/or symmetrical pain between the left and right knees may represent symptoms associated with longstanding PFP. The distinct patterns of pain location and area suggest specific underlying structures cannot be ruled out as important drivers, although central neuronal mechanisms possibly exemplified by the symmetrical representation of pain may play a role in individuals with longstanding symptoms. PMID- 30410030 TI - Convergence of independent DISC1 mutations on impaired neurite growth via decreased UNC5D expression. AB - The identification of convergent phenotypes in different models of psychiatric illness highlights robust phenotypes that are more likely to be implicated in disease pathophysiology. Here, we utilize human iPSCs harboring distinct mutations in DISC1 that have been found in families with major mental illness. One mutation was engineered to mimic the consequences on DISC1 protein of a balanced translocation linked to mental illness in a Scottish pedigree; the other mutation was identified in an American pedigree with a high incidence of mental illness. Directed differentiation of these iPSCs using NGN2 expression shows rapid conversion to a homogenous population of mature excitatory neurons. Both DISC1 mutations result in reduced DISC1 protein expression, and show subtle effects on certain presynaptic proteins. In addition, RNA sequencing and qPCR showed decreased expression of UNC5D, DPP10, PCDHA6, and ZNF506 in neurons with both DISC1 mutations. Longitudinal analysis of neurite outgrowth revealed decreased neurite outgrowth in neurons with each DISC1 mutation, which was mimicked by UNC5D knockdown and rescued by transient upregulation of endogenous UNC5D. This study shows a narrow range of convergent phenotypes of two mutations found in families with major mental illness, and implicates dysregulated netrin signaling in DISC1 biology. PMID- 30410032 TI - Serum Gamma-Glutamyltransferase Levels are Associated with Cardiovascular Risk Factors in China: A Nationwide Population-Based Study. AB - Serum gamma-glutamyltransferase (GGT), which is mainly derived from the liver, is a sensitive marker of liver cell damage and oxidative stress. More recently, it has been found that increased GGT plasma activity is also associated with cardiovascular disease (CVD). However, data on the relationship between GGT and cardiovascular risk factors (CRFs) are lacking in nationally representative samples of the Chinese population. Here, we aim to investigate both the association between GGT and CRFs and CRF clustering. A cross-sectional survey was conducted in a representative sample of 22897 adults aged 18 years and older from 2007 to 2011 nationally, which included a plurality of ethnic minorities. The participants were then divided into quartiles of sex-specific serum GGT. From the low to high GGT quartiles, the incidence of each CRF and clustered risk factors increased after adjusting for age, uric acid (UA), ethnicity, drinking, and all other risk factors. Individuals in the upper stratum (>75th percentile) had higher prevalence rates of CRFs than did those in the lower stratum (all P < 0.05). Furthermore, the subjects with clustering of 1, 2, or >=3 CRFs were still more likely to belong to the upper GGT quartiles (75th percentiles) than were those without risk factors (all P < 0.05). In conclusion, our data highlight that there is an association between higher serum GGT levels and prevalence of CRFs, which tend to cluster with the increase in GGT activity in Chinese adults. PMID- 30410033 TI - Multiple sclerosis. AB - Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system in young adults. This disorder is a heterogeneous, multifactorial, immune-mediated disease that is influenced by both genetic and environmental factors. In most patients, reversible episodes of neurological dysfunction lasting several days or weeks characterize the initial stages of the disease (that is, clinically isolated syndrome and relapsing-remitting MS). Over time, irreversible clinical and cognitive deficits develop. A minority of patients have a progressive disease course from the onset. The pathological hallmark of MS is the formation of demyelinating lesions in the brain and spinal cord, which can be associated with neuro-axonal damage. Focal lesions are thought to be caused by the infiltration of immune cells, including T cells, B cells and myeloid cells, into the central nervous system parenchyma, with associated injury. MS is associated with a substantial burden on society owing to the high cost of the available treatments and poorer employment prospects and job retention for patients and their caregivers. PMID- 30410034 TI - Real-time coherent diffraction inversion using deep generative networks. AB - Phase retrieval, or the process of recovering phase information in reciprocal space to reconstruct images from measured intensity alone, is the underlying basis to a variety of imaging applications including coherent diffraction imaging (CDI). Typical phase retrieval algorithms are iterative in nature, and hence, are time-consuming and computationally expensive, making real-time imaging a challenge. Furthermore, iterative phase retrieval algorithms struggle to converge to the correct solution especially in the presence of strong phase structures. In this work, we demonstrate the training and testing of CDI NN, a pair of deep deconvolutional networks trained to predict structure and phase in real space of a 2D object from its corresponding far-field diffraction intensities alone. Once trained, CDI NN can invert a diffraction pattern to an image within a few milliseconds of compute time on a standard desktop machine, opening the door to real-time imaging. PMID- 30410037 TI - ACG Clinical Guideline on Crohn's Disease: A Point of View from Europe. PMID- 30410036 TI - Primary Intestinal Lymphangiectasia (Waldmann's disease). PMID- 30410035 TI - Lenalidomide plus R-CHOP21 in newly diagnosed diffuse large B-cell lymphoma (DLBCL): long-term follow-up results from a combined analysis from two phase 2 trials. AB - Lenalidomide-RCHOP (R2-CHOP21) has been shown to be safe and effective in patients with untreated diffuse large B-cell lymphoma (DLBCL). The aim of this analysis is to report long-term outcome and toxicities in newly diagnosed DLBCL patients who received R2-CHOP21 in two independent phase 2 trials, conducted by Mayo Clinic (MC) and Fondazione Italiana Linfomi (FIL). All patients received R CHOP21 plus lenalidomide. Long-term progression-free survival (PFS), time to progression (TTP), overall survival (OS) and late toxicities and second tumors were analyzed. Hundred and twelve patients (63 MC, 49 FIL) were included. Median age was 69 years, 88% were stage III-IV. At a median follow-up of 5.1 years, 5y PFS was 63.5%, 5y-TTP 70.1% and 5y-OS 75.4%; according to cell of origin (COO): 5y-PFS 52.8% vs 64.5%, 5y-TTP 61.6% vs 69.6% and 5y-OS 68.6% vs 74.1% in germinal center (GCB) vs non-GCB respectively. Four patients experienced grade 4-5 late toxicities. Grade <= 3 toxicities were infections (N = 4), thrombosis (N = 1) and neuropathy (N = 3). Seven seconds tumors were observed. Long-term follow-up demonstrates that R2-CHOP21 efficacy was maintained with high rates of PFS, TTP, and OS. Lenalidomide appears to mitigate the negative prognosis of non-GCB phenotype. Incidence of therapy-related secondary malignancies and late toxicities were low. PMID- 30410038 TI - Prevalence of Chronic Constipation and Chronic Diarrhea in Diabetic Individuals in the United States. AB - INTRODUCTION: Diabetic individuals commonly report disordered bowel habits. This study aims to report the prevalence and associated factors of chronic diarrhea (CD) and chronic constipation (CC) in diabetics using a nationally representative sample of US adults. METHODS: Analyses were performed using data from subjects in the 2009-2010 National Health and Nutrition Examination Survey (NHANES) dataset who completed the Bowel Health Questionnaire. The NHANES dataset provides medical comorbidities, demographics, and dietary habits of a nationally representative group of adult survey participants in the United States. CC and CD were defined by Bristol Stool Form Scale (BSFS) Types 1 & 2 and BSFS Types 6 & 7 as the "usual or most common stool type," respectively, and frequent laxative users were also defined as having CC. Co-variables for all subjects included demographic and lifestyle factors, and co-variables evaluated only in diabetics included treatment and severity markers for diabetes. RESULTS: We identified 661 diabetic subjects and 4488 non-diabetic subjects. Diabetic subjects (25.8%) reported disordered bowel habits. In unadjusted analysis, CD was more prevalent in diabetics than in non-diabetics (11.2% vs. 6.0%; p < 0.0001); however, the prevalence of CC was not significantly different between groups (14.6% vs. 11.2%; p = 0.126). When adjusting for covariates (e.g., BMI, gender, age, race/ethnicity, education level, etc.), diabetes itself remained associated with CD. Diabetic individuals with CD more frequently used drugs to lower blood sugar, and diabetic subjects with CC more frequently had poor kidney function. CONCLUSION: CD is significantly more prevalent in diabetics than in non diabetics, whereas CC is not, and the association between CD and diabetes remains significant when adjusting for covariates. Use of medications that lower blood sugar is associated with CD in diabetic individuals, whereas poor kidney function is associated with CC in diabetics. PMID- 30410039 TI - Sofosbuvir-Based Therapy in Hepatitis C Virus-infected Cancer Patients: A Prospective Observational Study. AB - BACKGROUND: Data are sparse on treatment of chronic hepatitis C virus (HCV) in cancer patients. We evaluated the efficacy and safety of sofosbuvir-based therapy (SOFBT) in cancer patients. METHODS: Patients treated with SOFBT at our center during 2014-2017 were included in a prospective observational study. Efficacy [sustained virologic response at 12 weeks after the end of treatment (SVR12)], cancer-related outcomes and adverse events (AEs) were assessed. RESULTS: We included 153 patients. Most were men (109; 71%), white (92; 60%), non-cirrhotic (105; 69%), and with HCV genotype 1 (110; 72%). The most common cancers were hepatocellular carcinoma (HCC) (27; 18%) and multiple myeloma (14; 9%). The overall SVR12 rate was 91% (128/141). SVR12 was 100% in patients treated with ledipasvir/sofosbuvir for 8 weeks. Of the 32 patients initially excluded from cancer clinical trials because of HCV, 27 (84%) were granted cancer therapy access after starting SOFBT. Six patients with indolent non-Hodgkin's lymphoma (NHL) received SOFBT without cancer treatment. Two achieved complete remission, one had partial remission, and two had stable cancer. Within 6 months after SOFBT, 5% (6/121) of patients in remission or with stable cancer, had progression or recurrence (two with HCC and one each with esophageal cancer, cholangiocarcinoma, NHL, and tonsillar cancer). No de novo HCCs occurred. AEs were most commonly grade 1-2 (90%). DISCUSSION: SOFBT in HCV-infected cancer patients is effective and safe, may permit access to investigational cancer therapy expanding treatment options, may induce remission of NHL, and may be used for 8 weeks. PMID- 30410040 TI - Spectrum of Liver Disease in Hepatitis B Virus (HBV) Patients Co-infected with Human Immunodeficiency Virus (HIV): Results of the HBV-HIV Cohort Study. AB - BACKGROUND/AIMS: Because most HBV/HIV co-infected patients on combination antiretroviral therapy (cART) have suppressed HBV DNA and normal liver enzymes, the histologic spectrum of liver disease in HBV/HIV coinfection is poorly defined. To address this gap in knowledge, we conducted a prospective study to comprehensively characterize liver disease severity assessed by liver biopsy in a well-defined cohort of HBV/HIV patients in North America receiving cART. METHODS: Adult HIV/HBsAg positive patients on stable cART were recruited. Demographic, clinical, serological, and virological data were collected. Liver histology was assessed by a central pathology committee. The association of demographic, clinical, serologic, and virologic characteristics with liver histology was assessed using logistic regression. RESULTS: In this cross-sectional analysis, the mean age of the cohort (N = 139) was 49 years; 92% were male, 51% were non Hispanic black, 7% had at-risk alcohol use with a median duration of infections of 14 years. The median ALT was 28 IU/L and CD4 count was 568 cells/mm3. Almost all (99%) were on cART. Three-fourths (75%) had undetectable HIV RNA (<20 copies/mL). HBeAg was positive in 62%, HBV DNA was below the limit of quantification (<20 IU/mL) in 57% and <1000 IU/mL in 80%; 7% had incomplete viral suppression (HBV DNA >=1000 IU/mL and HIV RNA <20 copies/mL). Liver histology (available in n = 114) showed significant periportal, lobular, and portal inflammation (scores >=2) in 14%, 31%, and 22% respectively. Over a third (37%) had significant fibrosis (Ishak stage >=2); 24% had advanced fibrosis (Ishak stage >=3). Higher ALT (adjusted OR 1.19 per 10 IU/L; 95% CI [1.01, 1.41]; p = 0.03) and lower platelet count (adjusted OR 0.81 per 20,000 mm3; 95% CI [0.67 0.97]; p = 0.02) but not HBV DNA were independently associated with advanced fibrosis. CONCLUSIONS: In this cohort of patients with HBV/HIV coinfection receiving long-term cART with viral suppression, we observed significant fibrosis in more than one-third of patients. PMID- 30410041 TI - A Randomized Controlled Trial of TELEmedicine for Patients with Inflammatory Bowel Disease (TELE-IBD). AB - INTRODUCTION: Telemedicine has shown promise in inflammatory bowel disease (IBD). The objective of this study was to compare disease activity and quality of life (QoL) in a 1 year randomized trial of IBD patients receiving telemedicine versus standard care. METHODS: Patients with worsening symptoms in the prior 2 years were eligible for randomization to telemedicine (monitoring via texts EOW or weekly) or standard care. The primary outcomes were the differences in change in disease activity and QoL between the groups; change in health care utilization among groups was a secondary aim. RESULTS: 348 participants were enrolled (117 control group, 115 TELE-IBD EOW, and 116 TELE-IBD weekly). 259 (74.4%) completed the study. Age was 38.9 +/- 12.3 years, 56.6% were women, 91.9% were Caucasian, 67.9% had Crohn's disease (CD) and 42.5% had active disease at baseline. In CD, all groups experienced a decrease in disease activity (control -5.2 +/- 5.0 to 3.7 +/- 3.6, TELE-IBD EOW 4.7 +/- 4.1 to 4.2 +/- 3.9, and TELE-IBD weekly 4.2 +/- 4.2 to 3.2 +/- 3.4, p < 0.0001 for each of the groups) In UC, only controls had a significant decrease in disease activity (control 2.9 +/-;3.1 to 1.4 +/- 1.4, p = 0.01, TELE-IBD EOW 2.7 +/- 3.1 to 1.7 +/- 1.9, p = 0.35, and TELE-IBD Weekly 2.5 +/- 2.5 to 2.0 +/- 1.8, p = 0.31). QoL increased in all groups; the increase was significant only in TELE-IBD EOW (control 168.1 +/- 34.0 to 179.3 +/- 28.2, p = 0.06, TELE-IBD EOW 172.3 +/- 33.1 to 181.5 +/- 28.2, p = 0.03, and TELE-IBD Weekly 172.3 +/- 34.5 to 179.2 +/- 32.8, p = 0.10). Unadjusted and adjusted changes in disease activity and QoL were not significantly different among groups. Health care utilization increased in all groups. TELE-IBD weekly were less likely to have IBD-related hospitalizations and more likely to have non invasive diagnostic tests and electronic encounters compared to controls; both TELE-IBD groups had decreased non-IBD related hospitalizations and increased telephone calls compared to controls. DISCUSSION: Disease activity and QoL, although improved in all participants, were not improved further through use of the TELE-IBD system. TELE-IBD participants experienced a decrease in hospitalizations with an associated increase in non-invasive diagnostic tests, telephone calls and electronic encounters. Research is needed to determine if TELE-IBD can be improved through patient engagement and whether it can decrease healthcare utilization by replacing standard care. PMID- 30410042 TI - Author Correction: Spinocerebellar ataxias: prospects and challenges for therapy development. AB - In Table 3 of this article as originally published, a sentence within the column "Comments" in the row "SCA6" contains an error. The text incorrectly reads "Needs rigorous preclinical studies in SCA3 animal models". This sentence has been corrected to "Needs rigorous preclinical studies in SCA6 animal models" in the PDF and HTML versions of the article. PMID- 30410043 TI - Extensions to Michaelis-Menten Kinetics for Single Parameters. AB - Biochemical transformation kinetics is based on the formation of enzyme-substrate complexes. We developed a robust scheme based on unit productions of enzymes and reactants in cyclic events to comply with mass action law to form enzyme substrate complexes. The developed formalism supports a successful application of Michaelis-Menten kinetics in all biochemical transformations of single parameters. It is an essential tool to overcome some challenging healthcare and environmental issues. In developing the formalism, we defined the substrate [S]= [Product]3/4 and rate of reaction based on rate and time perspectives. It allowed us to develop two quadratic equations. The first, represents a body entity that gave a useful relationship of enzyme E = 2S0.33, and the second nutrients/feed, each giving [Enzymes] and [Enzyme-substrate complexes], simulating rate of reaction, [substrate], and their differentials. By combining [Enzymes] and [Enzyme-substrate complexes] values, this quadratic equation derives a Michaelis Menten hyperbolic function. Interestingly, we can derive the proportionate rate of reaction and [Enzymes] values of the quadratics resulting in another Michaelis Menten hyperbolic. What is clear from these results is that between these two hyperbolic functions, in-competitive inhibitions exist, indicating metabolic activities and growth in terms of energy levels. We validated these biochemical transformations with examples applicable to day to day life. PMID- 30410045 TI - Critical Drip Size and Blue Flame Shedding of Dripping Ignition in Fire. AB - Dripping of molten fuels is a widely observed fire phenomenon, and, by igniting other fuels, it can promote fire spread and increase fire hazards. In this work, dripping phenomena from fires of horizontally oriented wires, coated with polyethylene (PE), are investigated in the laboratory. It is found that as long as a flame is attached to the drip, thin tissue paper can be ignited by a single drip. Below a minimum diameter (Dmin = 0.63 mm), the drip floats up. Above a critical diameter (Dcrt = 2.3 mm), a flame can remain attached to the drip and ignite tissue paper as it falls through a distance of at least 2.6 m, thereby posing a significant fire hazard. A falling burning drip appears to the eye to be a blue chain of flame as a result of persistence of vision. Photographic evidence identifies a flame-shedding process, most likely associated with continual sequential ignition of fuel vapor within a von Karman vortex street generated behind the falling burning drip. The frequency of flame shedding agrees with both the frequency of modeled vortex shedding and the frequency of the unexpected sound that is heard during the process. This is the first time that combustion characteristics of dripping fire phenomena have been studied in detail, and this helps to better evaluate the risk and hazards of wire and facade fires. PMID- 30410044 TI - Exosomes exert cardioprotection in dystrophin-deficient cardiomyocytes via ERK1/2 p38/MAPK signaling. AB - As mediators of intercellular communication, exosomes containing molecular cargo are secreted by cells and taken up by recipient cells to influence cellular phenotype and function. Here we have investigated the effects of exosomes in dystrophin-deficient (Dys) induced pluripotent stem cell derived cardiomyocytes (iCMs). Our data demonstrate that exosomes secreted from either wild type (WT) or Dys-iCMs protect the Dys-iCM from stress-induced injury by decreasing reactive oxygen species and delaying mitochondrial permeability transition pore opening to maintain the mitochondrial membrane potential and decrease cell death. The protective effects of exosomes were dependent on the presence of exosomal surface proteins and activation of ERK1/2 and p38 MAPK signaling. Based on our findings, the acute effects of exosomes on recipient cells can be initiated from exosome membrane proteins and not necessarily their internal cargo. PMID- 30410046 TI - Structural basis for the second step of group II intron splicing. AB - The group II intron and the spliceosome share a common active site architecture and are thought to be evolutionarily related. Here we report the 3.7 A crystal structure of a eukaryotic group II intron in the lariat-3' exon form, immediately preceding the second step of splicing, analogous to the spliceosomal P complex. This structure reveals the location of the intact 3' splice site within the catalytic core of the group II intron. The 3'-OH of the 5' exon is positioned in close proximity to the 3' splice site for nucleophilic attack and exon ligation. The active site undergoes conformational rearrangements with the catalytic triplex having different configurations before and after the second step of splicing. We describe a complete model for the second step of group II intron splicing that incorporates a dynamic catalytic triplex being responsible for creating the binding pocket for 3' splice site capture. PMID- 30410047 TI - Systemic neurotransmitter responses to clinically approved and experimental neuropsychiatric drugs. AB - Neuropsychiatric disorders are the third leading cause of global disease burden. Current pharmacological treatment for these disorders is inadequate, with often insufficient efficacy and undesirable side effects. One reason for this is that the links between molecular drug action and neurobehavioral drug effects are elusive. We use a big data approach from the neurotransmitter response patterns of 258 different neuropsychiatric drugs in rats to address this question. Data from experiments comprising 110,674 rats are presented in the Syphad database [ www.syphad.org ]. Chemoinformatics analyses of the neurotransmitter responses suggest a mismatch between the current classification of neuropsychiatric drugs and spatiotemporal neurostransmitter response patterns at the systems level. In contrast, predicted drug-target interactions reflect more appropriately brain region related neurotransmitter response. In conclusion the neurobiological mechanism of neuropsychiatric drugs are not well reflected by their current classification or their chemical similarity, but can be better captured by molecular drug-target interactions. PMID- 30410048 TI - Structural Studies based on two Lysine Dioxygenases with Distinct Regioselectivity Brings Insights Into Enzyme Specificity within the Clavaminate Synthase-Like Family. AB - Iron(II)/alpha-ketoacid-dependent oxygenases (alphaKAOs) are enzymes that catalyze the oxidation of unactivated C-H bonds, mainly through hydroxylation. Among these, those that are active towards amino-acids and their derivatives are grouped in the Clavaminate Synthase Like (CSL) family. CSL enzymes exhibit high regio- and stereoselectivities with strict substrate specificity. This study reports the structural elucidation of two new regiodivergent members, KDO1 and KDO5, active towards lysine, and the structural and computational analysis of the whole family through modelling and classification of active sites. The structures of KDO1 and KDO5 in complex with their ligands show that one exact position in the active site controls the regioselectivity of the reaction. Our results suggest that the substrate specificity and high stereoselectivity typical of this family is linked to a lid that closes up in order to form a sub-pocket around the side chain of the substrate. This dynamic lid is found throughout the family with varying sequence and length and is associated with a conserved stable dimeric interface. Results from this study could be a starting-point for exploring the functional diversity of the CSL family and direct in vitro screening in the search for new enzymatic activities. PMID- 30410049 TI - Homotaurine, a safe blood-brain barrier permeable GABAA-R-specific agonist, ameliorates disease in mouse models of multiple sclerosis. AB - There is a need for treatments that can safely promote regulatory lymphocyte responses. T cells express GABA receptors (GABAA-Rs) and GABA administration can inhibit Th1-mediated processes such as type 1 diabetes and rheumatoid arthritis in mouse models. Whether GABAA-R agonists can also inhibit Th17-driven processes such as experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), is an open question. GABA does not pass through the blood-brain barrier (BBB) making it ill-suited to inhibit the spreading of autoreactivity within the CNS. Homotaurine is a BBB-permeable amino acid that antagonizes amyloid fibril formation and was found to be safe but ineffective in long-term Alzheimer's disease clinical trials. Homotaurine also acts as GABAA-R agonist with better pharmacokinetics than that of GABA. Working with both monophasic and relapsing-remitting mouse models of EAE, we show that oral administration of homotaurine can (1) enhance CD8+CD122+PD-1+ and CD4+Foxp3+ Treg, but not Breg, responses, (2) inhibit autoreactive Th17 and Th1 responses, and (3) effectively ameliorate ongoing disease. These observations demonstrate the potential of BBB permeable GABAA-R agonists as a new class of treatment to enhance CD8+ and CD4+ Treg responses and limit Th17 and Th1-medaited inflammation in the CNS. PMID- 30410050 TI - Three-dimensional localization spectroscopy of individual nuclear spins with sub Angstrom resolution. AB - Nuclear magnetic resonance (NMR) spectroscopy is a powerful method for analyzing the chemical composition and molecular structure of materials. At the nanometer scale, NMR has the prospect of mapping the atomic-scale structure of individual molecules, provided a method that can sensitively detect single nuclei and measure inter-atomic distances. Here, we report on precise localization spectroscopy experiments of individual 13C nuclear spins near the central electronic sensor spin of a nitrogen-vacancy (NV) center in a diamond chip. By detecting the nuclear free precession signals in rapidly switchable external magnetic fields, we retrieve the three-dimensional spatial coordinates of the nuclear spins with sub-Angstrom resolution and for distances beyond 10 A. We further show that the Fermi contact contribution can be constrained by measuring the nuclear g-factor enhancement. The presented method will be useful for mapping atomic positions in single molecules, an ambitious yet important goal of nanoscale nuclear magnetic resonance spectroscopy. PMID- 30410051 TI - Hierarchical Flowerlike 3D nanostructure of Co3O4@MnO2/N-doped Graphene oxide (NGO) hybrid composite for a high-performance supercapacitor. AB - The present study investigates the fabrication of hierarchical 3D nanostructures with multi-component metal oxides in the presence of highly-porous graphene and characterized for its applications in high-performance supercapacitors. A hierarchical flowers like 3D nanostructure of Co3O4 @MnO2 on nitrogen-doped graphene oxide (NGO) hybrid composite was synthesized by thermal reduction process at 650 degrees C in the presence of ammonia and urea. The synthesized Co3O4@MnO2/NGO hybrid composites were studied via Raman, XRD, X-ray XPS, FE-SEM, FE-SEM with EDX, FE-TEM and BET analyses. The electrochemical analysis of Co3O4@MnO2/NGO hybrid composite electrode was investigated using cyclic voltammetry, chronopotentiometry and electrochemical impedance measurements. The hybrid composite electrode showed significant specific capacitance results of up to 347 F/g at 0.5 A/g and a corresponding energy density of 34.83 Wh kg-1 with better rate performance and excellent long-term cycling stability were achieved for 10,000 cycles. The obtained electrochemical results paved a way to utilize Co3O4@MnO2/NGO composite electrode as a promising electrode material in high performance supercapacitors. PMID- 30410052 TI - The HamE scaffold positively regulates MpkB phosphorylation to promote development and secondary metabolism in Aspergillus nidulans. AB - Mitogen-activated protein kinase (MAPK) pathways are conserved signalling cascades in eukaryotes which regulate a myriad of processes in fungi from sexual reproduction to stress responses. These pathways rely on recruitment of three kinases on a scaffold protein to facilitate efficient kinase phosphorylation and subsequent downstream signalling to the nucleus. The model filamentous fungus Aspergillus nidulans utilises a MAPK pathway termed the pheromone module to regulate both development and secondary metabolism. This complex consists of the MAP3K (SteC), MAP2K (MkkB), MAPK (MpkB) and adaptor protein SteD. To date, there has been no scaffold protein identified for this MAPK pathway. In this study, we characterised a protein termed HamE, which we propose as a scaffold that regulates kinase phosphorylation and signalling in the pheromone module. Mass spectrometry analysis and BIFC experiments revealed that HamE physically interacts with both MkkB and MpkB and transiently interacts with SteC. Deletion of hamE or any of the pheromone module kinases results in reduced sporulation and complete abolishment of cleistothecia production. Mutants also exhibited reductions in expression of secondary metabolite gene clusters, including the velvet complex and sterigmatocystin genes. HamE acts as a positive regulator of MpkB phosphorylation, allowing for HamE to subsequently regulate development and secondary metabolism. PMID- 30410054 TI - Effects of rotation on temperature fluctuations in turbulent thermal convection on a hemisphere. AB - Rotation is present in many physical and geophysical systems and its role in determining flow properties and modifying turbulent fluctuations is of crucial importance. Here we focus on the role of rotation on temperature fluctuations in turbulent thermal convection. The system used consists of a rotating half soap bubble heated from below. This system has features, curvature and a quasi two dimensional character, which are reminiscent of atmospheric and planetary systems. Our experiments and numerical simulations show that rotation changes the nature of turbulent fluctuations and a new scaling regime is obtained for the temperature field. This change in the scaling behavior of temperature fluctuations, due to rotation, is put forth by studying the so called second moment of temperature differences across different scales. For high enough rotation rates, these temperature differences display a transition from Bolgiano Obukhov scaling to a new scaling regime. This scaling is at odds with expectations from theory, numerics, and experiments in three dimensions, suggesting that the effects of rotation on turbulent flows depend strongly on geometry and spatial dimension. PMID- 30410053 TI - Higher primate-like direct corticomotoneuronal connections are transiently formed in a juvenile subprimate mammal. AB - The corticospinal (CS) tract emerged and evolved in mammals, and is essentially involved in voluntary movement. Over its phylogenesis, CS innervation gradually invaded to the ventral spinal cord, eventually making direct connections with spinal motoneurons (MNs) in higher primates. Despite its importance, our knowledge of the origin of the direct CS-MN connections is limited; in fact, there is controversy as to whether these connections occur in subprimate mammals, such as rodents. Here we studied the retrograde transsynaptic connection between cortical neurons and MNs in mice by labeling the cells with recombinant rabies virus. On postnatal day 14 (P14), we found that CS neurons make direct connections with cervical MNs innervating the forearm muscles. Direct connections were also detected electrophysiologically in whole cell recordings from identified MNs retrogradely-labeled from their target muscles and optogenetic CS stimulation. In contrast, few, if any, lumbar MNs innervating hindlimbs showed direct connections on P18. Moreover, the direct CS-MN connections observed on P14 were later eliminated. The transient CS-MN cells were distributed predominantly in the M1 and S1 areas. These findings provide insight into the ontogeny and phylogeny of the CS projection and appear to settle the controversy about direct CS-MN connections in subprimate mammals. PMID- 30410055 TI - Heterogeneous Fenton Reaction Enabled Selective Colon Cancerous Cell Treatment. AB - A selective colon cancer cell therapy was effectively achieved with catalase mediated intra-cellular heterogeneous Fenton reactions triggered by cellular uptake of SnFe2O4 nanocrystals. The treatment was proven effective for eradicating colon cancer cells, whereas was benign to normal colon cells, thus effectively realizing the selective colon cancer cell therapeutics. Cancer cells possess much higher innate hydrogen peroxide (H2O2) but much lower catalase levels than normal cells. Catalase, an effective H2O2 scavenger, prevented attacks on cells by reactive oxygen species induced from H2O2. The above intrinsic difference between cancer and normal cells was utilized to achieve selective colon cancer cell eradication through endocytosing efficient heterogeneous Fenton catalysts to trigger the formation of highly reactive oxygen species from H2O2. In this paper, SnFe2O4 nanocrystals, a newly noted outstanding paramagnetic heterogeneous Fenton catalyst, have been verified an effective selective colon cancerous cell treatment reagent of satisfactory blood compatibility. PMID- 30410057 TI - Comment on 'Addition of ultrasound to mammography in the case of dense breast tissue: systematic review and meta-analysis'. PMID- 30410056 TI - Modifying the cancer-immune set point using vaccinia virus expressing re-designed interleukin-2. AB - The complex immune tumour microenvironment requires an equally complex immunotherapy approach, especially when the cancer-immune set point is non inflamed. Oncolytic viruses expressing immune activating cytokines might optimally modify the immune microenvironment and improve the antitumour effects. In this study, we have explored a variety of IL-2 constructs expressed by a tumour-selective oncolytic vaccinia virus, designed to maintain IL-2 in the tumour microenvironment to reduce systemic toxicity. An IL-2 construct combining a glycosylphosphatidylinositol (GPI) anchor with a rigid peptide linker leads to functional IL-2 expression on the tumour cell surface and in the tumour microenvironment. This virus construct effectively modifies the cancer-immune set point and treats a variety of murine tumour models with no toxic side effects. In combination with PD-1/PD-L1 blockade this virus cures most of the mice with a high tumour burden. This combination represents a treatment for cancers which are to date unresponsive to immunotherapy. PMID- 30410058 TI - Reply to 'Comment on 'Addition of ultrasound to mammography in the case of dense breast tissue: systematic review and meta-analysis". PMID- 30410059 TI - Improving clinical diagnosis of early-stage cutaneous melanoma based on Raman spectroscopy. AB - BACKGROUND: Clinical diagnosis of early melanoma (Breslow thickness less than 0.8 mm) is crucial to disease-free survival. However, it is subjective and can be exceedingly difficult, leading to missed melanomas, or unnecessary excision of benign pigmented skin lesions. An objective technique is needed to improve the diagnosis of early melanoma. METHODS: We have developed a method to improve diagnosis of (thin) melanoma, based on Raman spectroscopy. In an ex vivo study in a tertiary referral (pigmented lesions) centre, high-wavenumber Raman spectra were collected from 174 freshly excised melanocytic lesions suspicious for melanoma. Measurements were performed on multiple locations within the lesions. A diagnostic model was developed and validated on an independent data set of 96 lesions. RESULTS: Approximately 60% of the melanomas included in this study were melanomas in situ. The invasive melanomas had an average Breslow thickness of 0.89 mm. The diagnostic model correctly classified all melanomas (including in situ) with a specificity of 43.8%, and showed a potential improvement of the number needed to treat from 6.0 to 2.7, at a sensitivity of 100%. CONCLUSION: This work signifies an important step towards accurate and objective clinical diagnosis of melanoma and in particular melanoma with Breslow thickness <0.8 mm. PMID- 30410060 TI - Prolyl-4-hydroxylase Alpha subunit 2 (P4HA2) expression is a predictor of poor outcome in breast ductal carcinoma in situ (DCIS). AB - BACKGROUND: Extracellular matrix (ECM) plays a crucial role in tumour behaviour. Prolyl-4-hydroxlase-A2 (P4HA2) is a key enzyme in ECM remodelling. This study aims to evaluate the prognostic significance of P4HA2 in breast ductal carcinoma in situ (DCIS). METHODS: P4HA2 expression was assessed immunohistochemically in malignant cells and surrounding stroma of a large DCIS cohort comprising 481 pure DCIS and 196 mixed DCIS and invasive carcinomas. Outcome analysis was evaluated using local recurrence free interval (LRFI). RESULTS: High P4HA2 expression was detected in malignant cells of half of pure DCIS whereas its expression in stroma was seen in 25% of cases. Higher P4HA2 expression was observed in mixed DCIS cases compared to pure DCIS both in tumour cells and in stroma. High P4HA2 was associated with features of high risk DCIS including younger age, higher grade, comedo necrosis, triple negative and HER2-positive phenotypes. Interaction between P4HA2 and radiotherapy was also observed regarding the outcome. High P4HA2 expression was an independent prognostic factor in predicting shorter LRFI. CONCLUSION: P4HA2 plays a role in DCIS progression and can potentially be used to predict DCIS outcome. Incorporation of P4HA2 with other clinicopathological parameters could refine DCIS risk stratification that can potentially guide management decisions. PMID- 30410061 TI - Improved relapse-free survival on aromatase inhibitors in breast cancer is associated with interaction between oestrogen receptor-alpha and progesterone receptor-b. AB - BACKGROUND: Recent pre-clinical studies indicate that activated progesterone receptor (PR) (particularly the PR-B isoform) binds to oestrogen receptor-alpha (ER) and reprogrammes transcription toward better breast cancer outcomes. We investigated whether ER and PR-B interactions were present in breast tumours and associated with clinical parameters including response to aromatase inhibitors. METHODS: We developed a proximity ligation assay to detect ER and PR-B (ER:PR-B) interactions in formalin-fixed paraffin-embedded tissues. The assay was validated in a cell line and patient-derived breast cancer explants and applied to a cohort of 229 patients with ER-positive and HER2-negative breast cancer with axillary nodal disease. RESULTS: Higher frequency of ER:PR-B interaction correlated with increasing patient age, lower tumour grade and mitotic index. A low frequency of ER:PR-B interaction was associated with higher risk of relapse. In multivariate analysis, ER:PR-B interaction frequency was an independent predictive factor for relapse, whereas PR expression was not. In subset analysis, low frequency of ER:PR-B interaction was predictive of relapse on adjuvant aromatase inhibitor (HR 4.831, p = 0.001), but not on tamoxifen (HR 1.043, p = 0.939). CONCLUSIONS: This study demonstrates that ER:PR-B interactions have utility in predicting patient response to adjuvant AI therapy. PMID- 30410062 TI - Bi-directional signaling by membrane-bound KitL induces proliferation and coordinates thymic endothelial cell and thymocyte expansion. AB - The ligand for the c-Kit receptor, KitL, exists as a membrane-associated (mKitL) and a soluble form (sKitL). KitL functions outside c-Kit activation have not been identified. We show that co-culture of c-Kit- and mKitL-expressing NIH3T3 cells results in signaling through mKitL: c-Kit-bound mKitL recruits calcium-modulating cyclophilin ligand (CAML) to selectively activate Akt, leading to CREB phosphorylation, mTOR pathway activation, and increased cell proliferation. Activation of mKitL in thymic vascular endothelial cells (VECs) induces mKitL- and Akt-dependent proliferation, and genetic ablation of mKitL in thymic VECs blocks their c-Kit responsiveness and proliferation during neonatal thymic expansion. Therefore, mKitL-c-Kit form a bi-directional signaling complex that acts in the developing thymus to coordinate thymic VEC and early thymic progenitor (ETP) expansion by simultaneously promoting ETP survival and VEC proliferation. This mechanism may be relevant to both normal tissues and malignant tumors that depend on KitL-c-Kit signaling for their proliferation. PMID- 30410063 TI - Experiment of GBR for repair of peri-implant alveolar defects in beagle dogs. AB - To guide barrier membrane choice in the treatment of peri-implant alveolar bone defects, we evaluated guided bone regeneration (GBR) using titanium (Ti) mesh or Bio-Gide membrane, independently or in combination, for repair of alveolar bone defects in Beagle dogs. Six months after extraction of the mandibular premolars and first molars from three beagle dogs, we inserted implants assigned into 3 groups and covered with the following membrane combinations: Group A: Implant + Bio-Oss + Ti-mesh, Group B: Implant + Bio-Oss + Bio-Gide, and Group C: Implant + Bio-Oss + Ti-mesh + Bio-Gide. At 6 months, micro-CT revealed that bone volume/total volume (BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th) was significantly greater in Group C than the other two groups, while trabecular separation (Tb.Sp) was significantly lower, suggesting improved bone regeneration. The distance between bands of three fluorescent tracking dyes was significantly greater in Group C, indicating faster deposition of new bone. The Bio-Oss particles were ideally integrated with newly deposited bone and bone thickness was significantly larger in Group C. These findings suggest that combination of Bio-Gide membrane and titanium mesh can effectively repair peri implant alveolar bone defects, achieving enhanced bone regeneration compared to titanium mesh or Bio-Gide alone, and therefore providing a novel treatment concept for clinical implant surgery. PMID- 30410064 TI - Functional connectome organization predicts conversion to psychosis in clinical high-risk youth from the SHARP program. AB - The emergence of prodromal symptoms of schizophrenia and their evolution into overt psychosis may stem from an aberrant functional reorganization of the brain during adolescence. To examine whether abnormalities in connectome organization precede psychosis onset, we performed a functional connectome analysis in a large cohort of medication-naive youth at risk for psychosis from the Shanghai At Risk for Psychosis (SHARP) study. The SHARP program is a longitudinal study of adolescents and young adults at Clinical High Risk (CHR) for psychosis, conducted at the Shanghai Mental Health Center in collaboration with neuroimaging laboratories at Harvard and MIT. Our study involved a total of 251 subjects, including 158 CHRs and 93 age-, sex-, and education-matched healthy controls. During 1-year follow-up, 23 CHRs developed psychosis. CHRs who would go on to develop psychosis were found to show abnormal modular connectome organization at baseline, while CHR non-converters did not. In all CHRs, abnormal modular connectome organization at baseline was associated with a threefold conversion rate. A region-specific analysis showed that brain regions implicated in early course schizophrenia, including superior temporal gyrus and anterior cingulate cortex, were most abnormal in terms of modular assignment. Our results show that functional changes in brain network organization precede the onset of psychosis and may drive psychosis development in at-risk youth. PMID- 30410065 TI - Genetics of response to cognitive behavior therapy in adults with major depression: a preliminary report. PMID- 30410066 TI - Evolving changes in M-protein and hemoglobin as predictors for progression of smoldering multiple myeloma. PMID- 30410067 TI - Space lidar observations constrain longwave cloud feedback. AB - Some of the most challenging questions in atmospheric science relate to how clouds will respond as the climate warms. On centennial scales, the response of clouds could either weaken or enhance the warming due to greenhouse gas emissions. Here we use space lidar observations to quantify changes in cloud altitude, cover, and opacity over the oceans between 2008 and 2014, together with a climate model with a lidar simulator to also simulate these changes in the present-day climate and in a future, warmer climate. We find that the longwave cloud altitude feedback, found to be robustly positive in simulations since the early climate models and backed up by physical explanations, is not the dominant longwave feedback term in the observations, although it is in the model we have used. These results suggest that the enhanced longwave warming due to clouds might be overestimated in climate models. These results highlight the importance of developing a long-term active sensor satellite record to reduce uncertainties in cloud feedbacks and prediction of future climate. PMID- 30410069 TI - Author Correction: Multiple Approaches Detect the Presence of Fungi in Human Breastmilk Samples from Healthy Mothers. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30410068 TI - Induction of OTUD4 by viral infection promotes antiviral responses through deubiquitinating and stabilizing MAVS. AB - The activity and stability of the adapter protein MAVS (also known as VISA, Cardif and IPS-1), which critically mediates cellular antiviral responses, are extensively regulated by ubiquitination. However, the process whereby MAVS is deubiquitinated is unclear. Here, we report that the ovarian tumor family deubiquitinase 4 (OTUD4) targets MAVS for deubiquitination. Viral infection leads to the IRF3/7-dependent upregulation of OTUD4 which interacts with MAVS to remove K48-linked polyubiquitin chains, thereby maintaining MAVS stability and promoting innate antiviral signaling. Knockout or knockdown of OTUD4 impairs RNA virus triggered activation of IRF3 and NF-kappaB, expression of their downstream target genes, and potentiates VSV replication in vitro and in vivo. Consistently, Cre-ER Otud4fl/fl or Lyz2-Cre Otud4fl/fl mice produce decreased levels of type I interferons and proinflammatory cytokines and exhibit increased sensitivity to VSV infection compared to their control littermates. In addition, reconstitution of MAVS into OTUD4-deficient cells restores virus-induced expression of downstream genes and cellular antiviral responses. Together, our findings uncover an essential role of OTUD4 in virus-triggered signaling and contribute to the understanding of deubiquitination-mediated regulation of innate antiviral responses. PMID- 30410070 TI - Diverse light responses of cyanobacteria mediated by phytochrome superfamily photoreceptors. AB - Cyanobacteria are an evolutionarily and ecologically important group of prokaryotes. They exist in diverse habitats, ranging from hot springs and deserts to glaciers and the open ocean. The range of environments that they inhabit can be attributed in part to their ability to sense and respond to changing environmental conditions. As photosynthetic organisms, one of the most crucial parameters for cyanobacteria to monitor is light. Cyanobacteria can sense various wavelengths of light and many possess a range of bilin-binding photoreceptors belonging to the phytochrome superfamily. Vital cellular processes including growth, phototaxis, cell aggregation and photosynthesis are tuned to environmental light conditions by these photoreceptors. In this Review, we examine the physiological responses that are controlled by members of this diverse family of photoreceptors and discuss the signal transduction pathways through which these photoreceptors operate. We highlight specific examples where the activities of multiple photoreceptors function together to fine-tune light responses. We also discuss the potential application of these photosensing systems in optogenetics and synthetic biology. PMID- 30410071 TI - Bleomycin-induced genome structural variations in normal, non-tumor cells. AB - Many anticancer drugs are genotoxic agents inducing DNA breaks in actively proliferating cancer cells. However, these same drugs also induce mutations, mostly genome structural variations (GSVs). The detection of GSVs in normal cells and tissues is a major challenge due to the very low abundance of these mutations, which are essentially only detectable in clonal outgrowths, such as tumors. Previously we developed Structural Variant Search (SVS) - an NGS-based assay for the quantitative detection of somatic GSVs in normal cells. Using an improved version of SVS we now demonstrate that the same dose of the anti-cancer drug bleomycin induces about 5 times more somatic GSVs in quiescent primary human fibroblasts than in proliferating cells. GVS induction in non-dividing, normal cells was subsequently confirmed in vivo by demonstrating that a single dose of bleomycin leads to a significant increase of GSV frequency in mouse liver and heart, two postmitotic tissues. Our findings suggest that normal non-cycling differentiated cells may serve as a reservoir of iatrogenically induced mutations. These results provide more insight into the possible molecular mechanisms that underlie late-life morbidities in cancer survivors exposed to chemotherapy. PMID- 30410072 TI - Induction of intracellular ferritin expression in embryo-derived Ixodes scapularis cell line (ISE6). AB - Iron is a very important nutrient for cells; however, it could also cause fatal effects because of its capability to trigger oxidative stress. Due to high exposure to iron from their blood diet, ticks make use of several mechanisms to cope up with oxidative stress. One mechanism is iron sequestration by ferritin and its control protein (IRP). Since the IRP activity is dependent on the ferrous iron concentration, we tried to induce intracellular ferritin (FER1) protein expression by exposing Ixodes scapularis embryo-derived cell line (ISE6) to different concentrations of ferrous sulphate at different time points. We were able to induce FER1 protein after exposure to 2 mM of ferrous sulphate for 48 h, as observed in both Western blotting and indirect immunofluorescent antibody tests. This could indicate that the FER1 produced could be a product of the release of IRPs from the FER1 mRNA leading to its translation. The RNA interference of FER1, through the transfection of dsRNA, led to an increase in mortality and decrease in the cellular proliferation of ISE6 cells. Overall, ISE6 cells could be a good tool in further understanding the mechanism of FER1 action, not just in Ixodes ticks but in other tick species as well. PMID- 30410073 TI - Changes in long non-coding RNA expression profiles related to the antagonistic effects of Escherichia coli F17 on lamb spleens. AB - Sheep colibacillosis is one of the most common bacterial diseases found at large scale sheep farms. The aim of this study was to employ RNA-seq to screen differentially expressed (DE) long non-coding RNAs (lncRNAs) that impart antagonistic or sensitive effects on Escherichia coli F17. In this study, individuals who had antagonistic or sensitive responses to E. coli F17 were identified by feeding E. coli F17 strains to Hu lambs. The sensitive group had higher levels of intestinal bacteria than that in the antagonistic group (P < 0.05), the jejunum showed various levels of mucosal tissue damage and had a dark colour, and disintegration of part of the small intestinal villi was observed. Totals of 34 DE lncRNAs and 703 DE mRNAs in two groups were identified. qRT-PCR results for 12 randomly selected DE lncRNAs and DE mRNAs were consistent with the RNA-seq data. Gene Ontology (GO), KEGG Pathway enrichment and lncRNA-mRNA interaction analyses identified 6 co-expressed genes, namely, MYO1G, TIMM29, CARM1, ADGRB1, SEPT4, and DESI2. This is the first study that has performed expression profiling of lncRNAs in the spleen of antagonistic and sensitive lambs. The identification of DE lncRNAs can facilitate investigations into the molecular mechanism underlying resistance to diarrhoea in sheep. PMID- 30410074 TI - Sirtuin 1 genetic variation, energy balance and colorectal cancer risk by sex and subsite in the Netherlands Cohort Study. AB - Sirtuin 1 (SIRT1) is an energy-sensing protein, which may affect tumorigenesis. We used SIRT1 variants as time-independent indicators of SIRT1 involvement in carcinogenesis and we studied two tagging SIRT1 variants in relation to colorectal cancer (CRC) risk. We also evaluated known energy balance-related CRC risk factors within SIRT1 genotype strata. The Netherlands Cohort Study includes 120,852 individuals and has 20.3 years follow-up (case-cohort: nsubcohort = 5000; nCRC cases = 4667). At baseline, participants self-reported weight, weight at age 20, height, trouser/skirt size reflecting waist circumference, physical activity, and early life energy restriction. SIRT1 rs12778366 and rs10997870 were genotyped in toenail DNA available for ~75% of the cohort. Sex- and subsite-specific Cox hazard ratios (HRs) showed that the rs12778366 CC versus TT genotype decreased CRC and colon cancer risks in women (HRCRC = 0.53, 95% confidence interval: 0.30 0.94) but not men. Multiplicative interactions were observed between SIRT1 variants and energy balance-related factors in relation to CRC endpoints, but the direction of associations was not always conform expectation nor specific to one genotype stratum. In conclusion, these results support SIRT1 involvement in colon cancer development in women. No conclusions could be made regarding a modifying effect of SIRT1 variants on associations between energy balance-related factors and CRC risk. PMID- 30410075 TI - Amino acid modified [70] fullerene derivatives with high radical scavenging activity as promising bodyguards for chemotherapy protection. AB - Despite the great efforts for tumor therapy in the last decades, currently chemotherapy induced toxicity remains a formidable problem for cancer patients, and it usually prohibits the cancer therapy from successful completion due to severe side effects. In general, the main side effects of chemotherapeutic agents are from the as-produced reactive oxygen species (ROS) that not only harm the tumor cells but also damage the patients' organs. Here we report the application of amino acid derivatives of fullerene (AADF) in the chemotherapy which strongly scavenge the excess ROS to protect the tested mice against the chemotherapy induced hepatotoxicity and cardiotoxicity. Two amino acids, i.e., L-lysine and beta-alanine were separately employed to chemically modify C70 fullerene, and L lysine derivative of fullerene (C70-Lys) exhibits superior radical scavenging activity to beta-alanine derivative of C70 (C70-Ala). As expected, C70-Lys show much better protective effect than C70-Ala against the chemotherapy injuries in vivo, which is verified by various histopathological, haematological examinations and antioxidative enzyme studies. Moreover, the L-glutathione level is increased and the cytochrome P-450 2E1 expression is inhibited. They are potentially developed as promising bodyguards for chemotherapy protection. PMID- 30410076 TI - Multifractality and cross-correlation analysis of streamflow and sediment fluctuation at the apex of the Pearl River Delta. AB - The fluctuation and distribution of hydrological signals are highly related to the fluvial and geophysical regime at estuarine regions. Based on the long daily streamflow and sediment data of Makou (MK) and Sanshui (SS) stations at the apex of the Pearl River Delta, the scaling behavior of the streamflow and sediment is explored by multifractal detrended fluctuation analysis (MF-DFA). The results indicated that there was significant multifractal structure present in the fluctuations of streamflow and sediment. Meanwhile, the multifractal degree and complexity of sediment were much stronger than streamflow. Although the scaling exponents of streamflow were larger than sediment at both MK and SS, no evident differences have been found on the scaling properties of streamflow and sediment for the ratios MK/SS. Moreover, the cross-correlation between streamflow and sediment is further detected by Multifractal Detrended Cross-Correlation Analysis (MF-DXA). The multifractal response between streamflow and sediment at small timescale is characterized by long-range correlations whereas it exhibits random behavior at large timescale. The interaction of the broadness of probability density function and the long-range correlations should be responsible for the multifractal properties of hydrological time series as the multifractal degree of surrogate and shuffled data was significantly undermined. PMID- 30410077 TI - TGF-beta-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure. AB - The extracellular matrix (ECM) is a key determinant of cancer progression and prognosis. Here we report findings from one of the largest pan-cancer analyses of ECM gene dysregulation in cancer. We define a distinct set of ECM genes upregulated in cancer (C-ECM) and linked to worse prognosis. We found that the C ECM transcriptional programme dysregulation is correlated with the activation of TGF-beta signalling in cancer-associated fibroblasts and is linked to immunosuppression in otherwise immunologically active tumours. Cancers that activate this programme carry distinct genomic profiles, such as BRAF, SMAD4 and TP53 mutations and MYC amplification. Finally, we show that this signature is a predictor of the failure of PD-1 blockade and outperforms previously-proposed biomarkers. Thus, our findings identify a distinct transcriptional pattern of ECM genes in operation across cancers that may be potentially targeted, pending preclinical validation, using TGF-beta blockade to enhance responses to immune checkpoint blockade. PMID- 30410078 TI - Fundamental of swapping phenomena in naturally occurring gas hydrates. AB - Amount of natural gas contained in the gas hydrate accumulations is twice that of all fossil fuel reserves currently available worldwide. The conventional oil and gas recovery technologies are not really suitable to gas hydrates because of their serious repercussions on geo-mechanical stability and seabed ecosystem. To address this challenge, the concept of methane-carbon dioxide (CH4-CO2) swapping has appeared. It has the potential in achieving safe and efficient recovery of natural gas, and sequestration of CO2. By this way, the energy generation from gas hydrates can become carbon neutral. This swapping phenomenon has not yet been elucidated at fundamental level. This work proposes a theoretical formulation to understand the physical insight into the transient swapping between natural gas and CO2 occurred under deep seabed and in permafrost. Addressing several practical concerns makes the model formulation novel and generalized enough in explaining the swapping phenomena at diverse geological conditions. PMID- 30410080 TI - Olaparib maintenance moves to first line. PMID- 30410079 TI - New window of opportunity with ICIs in melanoma. PMID- 30410081 TI - Method and rationale for recalculating dilution spaces to a single, common time point in doubly labeled water studies. AB - BACKGROUND: The doubly labeled water (DLW) method has become widely used in studies of energy expenditure and body composition. Researchers differ in the analytical methods used to calculate the dilution spaces for deuterium and oxygen 18. Some determine dilution spaces using isotope enrichments extrapolated to the instant of dosing with DLW (slope-intercept method), but others use measured enrichments from body water samples obtained 3-10 h after dosing (plateau method). These differences limit the comparability of analyses across labs. METHODS: I derive a simple mathematical approach for recalculating reported dilution spaces to any time point post dosing, using reported dilution spaces and rates of isotope depletion. Simulated data are used to examine the effects of different dilution space protocols. RESULTS: Recalculating dilution spaces enables researchers to determine outcome variables of interest (e.g., total body water, energy expenditure, and water throughput) from different labs under a unified protocol for determining dilution spaces, and improves comparisons among studies. CONCLUSIONS: Differences between dilution space protocols can lead to substantial differences in outcome variables of interest in DLW studies. When comparing results of DLW studies that employ different dilution space protocols, dilution spaces should be recalculated for a common time point, and outcome variables recalculated as needed, prior to comparison across studies. PMID- 30410082 TI - Post-transplant immunotherapy with WT1-specific CTLs for high-risk acute myelogenous leukemia: a prospective clinical phase I/II trial. PMID- 30410083 TI - BEAC (carmustine, etoposide, cytarabine, and cyclophosphamide) in autologous hematopoietic cell transplantation: a safe and effective alternative conditioning regimen for Hodgkin and non-Hodgkin lymphoma. PMID- 30410084 TI - Origin and age of the causative mutations in KLC2, IMPA1, MED25 and WNT7A unravelled through Brazilian admixed populations. AB - The mutation age and local ancestry of chromosomal segments harbouring mutations associated with autosomal recessive (AR) disorders in Brazilian admixed populations remain unknown; additionally, inbreeding levels for these affected individuals continue to be estimated based on genealogical information. Here, we calculated inbreeding levels using a runs of homozygosity approach, mutation age and local ancestry to infer the origin of each chromosomal segments containing disorder-causing mutations in KLC2, IMPA1, MED25 and WNT7A. Genotyped data were generated from 18 patients affected by AR diseases and combined to the 1000 genome project (1KGP) and Simons genome diversity project (SGDP) databases to infer local ancestry. We found a major European contribution for mutated haplotypes with recent mutation age and inbreeding values found only in Native American and Middle East individuals. These results contribute to identifying the origin of and to understanding how these diseases are maintained and spread in Brazilian and world populations. PMID- 30410085 TI - Structural, electronic and magnetic properties of MnxGa/Co2MnSi (x = 1, 3) bilayers. AB - Directly coupled hard and soft ferromagnets were popularly used as the hybridized electrodes to enhance tunnel magnetoresistance (TMR) ratio in the perpendicular magnetic tunnel junction (pMTJ). In this paper, we employ the density functional theory (DFT) with general gradient approximation (GGA) to investigate the interfacial structure and magnetic behavior of tetragonal Heusler-type MnGa (MG)/L21-Co2MnSi (CMS) Heusler alloy bilayers with the MnGa being D022-MnGa alloy (Mn3Ga) and L10-MnGa alloy (MnGa). The MM-MS_B interface with the bridge (B) connection of MnMn termination (MM) of D022- and L10-MnGa layers to MnSi termination (MS) of CMS layers is found to be most stable in the energy point of view. Also, a strong antiferromagnetic coupling and relatively higher spin polarization can be observed in the MM-MS_B interface. Further, a remarkable potential difference to derive electrons to transfer from MG layer to CMS layer appears at the interface. These theoretical results indicate that the MG/CMS bilayers are promising candidates as coupled composites, and moreover, the D022 MG/CMS bilayer is better than L10-MG/CMS bilayer due to its larger spin polarization and built-in field at the interface. PMID- 30410086 TI - Generation of brilliant green fluorescent petunia plants by using a new and potent fluorescent protein transgene. AB - The application of fluorescent proteins in ornamental plants has lagged behind despite the recent development of powerful genetic tools. Although we previously generated transgenic torenia plants expressing green fluorescent protein from marine plankton (CpYGFP), in which bright fluorescence was easily visible at the whole plant level, the maximum excitation of this protein within the visible light spectrum required the use of a coloured emission filter to eliminate exciting light. Here, to overcome this limitation, we generated transgenic petunia plants expressing eYGFPuv, a CpYGFP derivative exhibiting bright fluorescence under invisible ultraviolet (UV) light excitation, with a novel combination of transcriptional terminator plus translational enhancer. As expected, all transgenic plants exhibited brilliant green fluorescence easily visible to the naked eye without an emission filter. In addition, fluorescence expressed in transgenic petunia flowers was stable during long-term vegetative propagation. Finally, we visually and quantitatively confirmed that transgenic petunia flowers resist to long-term exposure of UV without any damages such as fluorescence decay and withering. Thus, our whole-plant fluorescence imaging tool, that does not require high sensitive imaging equipment or special imaging conditions for observation, might be useful not only for basic plant research but also for ornamental purposes as a novel flower property. PMID- 30410087 TI - Random Neuronal Networks show homeostatic regulation of global activity while showing persistent changes in specific connectivity paths to theta burst stimuli. AB - Learning in neuronal networks based on Hebbian principle has been shown to lead to destabilizing effects. Mechanisms have been identified that maintain homeostasis in such networks. However, the way in which these two opposing forces operate to support learning while maintaining stability is an active area of research. In this study, using neuronal networks grown on multi electrode arrays, we show that theta burst stimuli lead to persistent changes in functional connectivity along specific paths while the network maintains a global homeostasis. Simultaneous observations of spontaneous activity and stimulus evoked responses over several hours with theta burst training stimuli shows that global activity of the network quantified from spontaneous activity, which is disturbed due to theta burst stimuli is restored by homeostatic mechanisms while stimulus evoked changes in specific connectivity paths retain a memory trace of the training. PMID- 30410088 TI - Multiple sclerosis. PMID- 30410089 TI - Author Correction: The discovery of Bombali virus adds further support for bats as hosts of ebolaviruses. AB - In the version of this Article originally published, the bat species for 12 individuals were incorrectly identified in Supplementary Table 1 and 2. After resequencing the MT-CytB and MT-CO1 segments and reviewing the data, the authors have corrected the errors for these 12 animals. In the amended version of the Supplementary Information, Supplementary Tables 1 and 2 have been replaced to include the corrected host species information. None of the 12 bats affected were positive for the Bombali virus, and the conclusions of the study are therefore unchanged. PMID- 30410090 TI - Viscosity measurement of Xanthan-Poly(vinyl alcohol) mixture and its effect on the mechanical properties of the hydrogel for 3D modeling. AB - Biomodels made of poly(vinyl alcohol) (PVA) are demanded because they can represent the geometries and mechanical properties of human tissues realistically. Injecting and molding, commonly used in three-dimensional (3D) modeling, help to represent the blood vessels accurately. However, these techniques sometimes require higher pressures than the upper pressure limit of the dispensers for pouring in high viscosity materials; the material viscosity should therefore be lower. Moreover, the mechanical properties of the biomodels should be reproduced. This study proposes a PVA solution through the addition of xanthan gum (XG) for 3D modeling, which lowers liquid viscosity while maintaining the mechanical properties of biomodels. XG is known to facilitate the achievement of non-Newtonian fluidity; however, the effects of XG on a PVA solution and PVA hydrogel (PVA-H) are not confirmed. The viscosity measurement using 15 wt% PVA with XG solution (PVA/XG) shows that it will provide easier pouring than 17 wt% PVA solution. The tensile test using the PVA-H of PVA(15 wt%)/XG(0.2 wt%) reveals that the gel is comparable in Young's modulus to 17 wt% PVA-H. X-ray diffraction shows the crystalline structures of the PVA/XG gel and PVA-H are identical. Thus, this PVA/XG would be useful for fabricating biomodels using injection molding techniques. PMID- 30410091 TI - LIP formation and protracted lower mantle upwelling induced by rifting and delamination. AB - Large Igneous Provinces (LIPs) are commonly attributed to mantle plumes, hot upwellings from the deep lower mantle, apparently unrelated to plate motions. However, LIPs often form in association with rifting and breakup. Using numerical modelling, we introduce a novel idea that explains plume-like mantle upwelling by plate tectonic processes. Our model indicates that rifting-induced delamination of orogenic lithosphere can perturb the thermochemical mantle stratification and induce lower mantle upwelling which causes syn-rift LIP formation followed by protracted and enhanced mid ocean ridge basalt (MORB) generation. Our model provides an explanation for the geographical correlation between the Caledonian suture, the North Atlantic Igneous Province (NAIP) and present-day Icelandic magmatism. PMID- 30410092 TI - Relationship between aqueous humor cytokine level changes and retinal vascular changes after intravitreal aflibercept for diabetic macular edema. AB - The aim of this work was to investigate the changes in aqueous humor cytokine levels after intravitreal injection of aflibercept in diabetic macular edema (DME) and to evaluate the relationship between cytokines modifications and central macular thickness (CMT) and retinal/choroidal vascular changes using structural and functional optical coherence tomography (OCT). Aqueous concentrations of 38 cytokines were measured via multiplex bead assay. In addition, spectral domain OCT and OCT angiography with SSADA software (XR Avanti(r) AngioVue) were performed at baseline and after intravitreal injections. VEGF, IL-6, IL-5, IL-1beta, Eotaxin, GRO, IL-12p40, IL-12p70, IL-1RA, Flt-3L and IP-10 showed a statistically significant decrease through the follow-up (p < 0.05; p < 0.001), while Fraktalkine and GM-CSF significantly increased (p < 0.05). Best corrected visual acuity significantly increased and CMT significantly decreased during follow-up (p < 0.001 and p = 0.013). Superficial capillary plexus and deep capillary plexus density significantly increased (p < 0.001 and p = 0.014). A positive relation was found between GRO, VEGF, Fraktalkine, IP-10, IL 12p70 aqueous humor levels and CMT (p < 0.05; p < 0.001). Aflibercept is a primary anti-VEGF treatment producing a decrease of DME due to the reduction of vascular permeability, nevertheless other inflammatory cytokines showed modification after aflibercept intravitreal injections probably related to edema modification or to an interaction of aflibercept with other inflammatory cytokines. PMID- 30410093 TI - Causal Evidence for the Dependence of the Magnitude Effect on Dorsolateral Prefrontal Cortex. AB - Impulsivity refers to the tendency to insufficiently consider alternatives or to overvalue rewards that are available immediately. Impulsivity is a hallmark of human decision making with well documented health and financial ramifications. Numerous contextual changes and framing manipulations powerfully influence impulsivity. One of the most robust such phenomenon is the finding that people are more patient as the values of choice options are increased. This magnitude effect has been related to cognitive control mechanisms in the dorsal lateral prefrontal cortex (dlPFC). We used repetitive transcranial magnetic stimulation (rTMS) to transiently disrupt dlPFC neural activity. This manipulation dramatically reduced the magnitude effect, establishing causal evidence that the magnitude effect depends on dlPFC. PMID- 30410094 TI - The ALS-inducing factors, TDP43A315T and SOD1G93A, directly affect and sensitize sensory neurons to stress. AB - There is increased recognition that sensory neurons located in dorsal root ganglia (DRG) are affected in amyotrophic lateral sclerosis (ALS). However, it remains unknown whether ALS-inducing factors, other than mutant superoxide dismutase 1 (SOD1G93A), directly affect sensory neurons. Here, we examined the effect of mutant TAR DNA-binding protein 1 (TDP43A315T) on sensory neurons in culture and in vivo. In parallel, we reevaluated sensory neurons expressing SOD1G93A. We found that cultured sensory neurons harboring either TDP43A315T or SOD1G93A grow neurites at a slower rate and elaborate fewer neuritic branches compared to control neurons. The presence of either ALS-causing mutant gene also sensitizes sensory neurons to vincristine, a microtubule inhibitor that causes axonal degeneration. Interestingly, these experiments revealed that cultured sensory neurons harboring TDP43A315T elaborate shorter and less complex neurites, and are more sensitive to vincristine compared to controls and to SOD1G93A expressing sensory neurons. Additionally, levels of two molecules involved in stress responses, ATF3 and PERK are significantly different between sensory neurons harboring TDP43A315T to those with SOD1G93A in vitro and in vivo. These findings demonstrate that sensory neurons are directly affected by two ALS inducing factors, suggesting important roles for this neuronal subpopulation in ALS-related pathogenesis. PMID- 30410096 TI - Derivation and Numerical analysis of an Attenuation Operator for non-relativistic waves. AB - Quantum mechanical models for particles are strictly dependent on the Schrodinger equation, where the solutions and the Hermitian polynomials form a mathematical foundation to derive expectation values for observables. As for all quantum systems, the solutions are derived in discrete energy levels, and yield probability density, the kinetic energy and average momentum. In this study however, an attenuation Hamiltonian is derived by the algebraic relation of the momentum and position operators, and the derived equation, where the attenuation of kinetic energy is the eigenvalue, is studied numerically. The numerical solutions suggest that the change in kinetic energy from one transition to the next proceeds in an undular fashion, and not in a definite manner. This suggests that any sub-atomic particle which experiences a transition from one level to the next, does so by both gaining and losing energy in an undular manner before reaching an equilibrium with a new and stabilized kinetic energy. The results show also that the phase of the change in kinetic energy between transitions differs between high and low momenta and that higher levels of momentum attenuate more smoothly than transitions between lower energy levels. The investigated attenuation operator may be important for future pinning and quasipinning approaches and play a role in future quantum information processing. Future research is required on the spectrum of the operator and on its potential analytical solutions. PMID- 30410095 TI - Nonimmune hydrops fetalis: identifying the underlying genetic etiology. AB - PURPOSE: Numerous etiologies may lead to nonimmune hydrops fetalis (NIHF), and the underlying cause often remains unclear. We aimed to determine the proportion of NIHF cases in which the etiology was clearly determined in a large, contemporary, and diverse cohort, as well as to describe the etiologies with a focus on genetic causes. METHODS: Retrospective review of NIHF cases between 2015 and 2017 from the five University of California Fetal-Maternal Consortium sites. Singleton pregnancies with prenatally diagnosed NIHF were included, and cases with maternal alloimmunization were excluded. Cases were categorized as being of confirmed, suspected, or unknown etiology. RESULTS: Sixty-five NIHF cases were identified. Forty-six percent (30/65) remained of unknown etiology, while 9.2% (6/65) had a suspected etiology and 44.6% (29/65) were of confirmed etiology. Among confirmed cases, 11 resulted from aneuploidy; 7 from fetal structural anomalies; 2 each from fetal arrhythmia, Noonan syndrome, and generalized lymphatic dysplasia; and 1 each from arthrogryposis, parvovirus, neonatal alloimmune thrombocytopenia, fetal goiter, and Kasabach-Merritt syndrome. CONCLUSION: In this contemporary, multicenter study, the cause of prenatally diagnosed NIHF was confirmed in only 44% of cases, and a genetic etiology was found in only 25% of those that received standard of care genetic testing. PMID- 30410097 TI - Breakdown-induced conductive channel for III-nitride light-emitting devices. AB - III-nitride semiconductor-based light-emitting diodes (LEDs) have superior physical properties, such as high thermal stability and brightness, for application to solid-state lighting sources. With the commercialization of GaN based LEDs, improving LED reliability is important because they can be affected by electrostatic discharge, reverse leakage, and breakdown. However, research on the reverse bias characteristics of GaN-based LEDs is insufficient. We studied the reverse breakdown mechanism and demonstrated that a local breakdown can form a conductive channel in GaN-based LEDs, which can be expanded to a novel planar type LED structure without an n-contact electrode. Furthermore, we found that this approach can be applied to AC-controllable light-emitting devices without any AC-DC converter. PMID- 30410098 TI - Correction: PLA2G6-associated neurodegeneration presenting as a complicated form of hereditary spastic paraplegia. AB - The originally published version of this article contained an error in Fig. 1 and Table 2. The correct figure and table of this article should have read as below. This has now been corrected in the PDF and HTML versions of the article. The authors apologize for any inconvenience caused. PMID- 30410100 TI - Microbial metabolite linked to T2DM. PMID- 30410099 TI - Surgical and Functional Outcome after Endoprosthetic Reconstruction in Patients with Osteosarcoma of the Humerus. AB - Endoprosthetic reconstruction (EPR) is the most widely used reconstruction technique after humeral osteosarcoma (OSA). Complications are common and function is often compromised due to the premise of wide resection. In the current study we evaluated (1) the risk of complications after resection and EPR; (2) the functional outcome and how it is influenced by the preservation/resection of deltoid muscle (DM), rotator cuff (RC), axillary nerve or the type of resection (intra-/extraarticular) and (3) if the preservation/resection of DM, RC, axillary nerve or the type of resection has a negative influence on the oncological outcome. We retrospectively evaluated data of 49 patients with humeral OSA. All patients underwent resection and EPR. Complication-free survival according to the ISOLS classification was estimated by a competing risk model. Functional outcome was evaluated by range of motion (ROM) in abduction and the MSTS score. Eleven patients (22%) had at least one complication. The estimated cumulative incidence for the first complication was 18% at one year, 23% at five years, and 28% at ten years, respectively. Soft tissue failure was the most common complication. ROM and MSTS scores were significantly higher in patients where DM and RC (p = 0.043/p = 0.046) and axillary nerve (p = 0.014/p = 0.021) could be preserved. Preservation of these structures had no negative influence on the surgical margins. In conclusion, EPR is a good treatment method with an acceptable complication rate. Preservation of the abductor mechanism, when possible in the setting of obtaining negative margins, provides superior functional outcome. PMID- 30410102 TI - Ancient cities rescued from rubble, bit by bit. PMID- 30410101 TI - Current and future perspectives of liquid biopsies in genomics-driven oncology. AB - Precision oncology seeks to leverage molecular information about cancer to improve patient outcomes. Tissue biopsy samples are widely used to characterize tumours but are limited by constraints on sampling frequency and their incomplete representation of the entire tumour bulk. Now, attention is turning to minimally invasive liquid biopsies, which enable analysis of tumour components (including circulating tumour cells and circulating tumour DNA) in bodily fluids such as blood. The potential of liquid biopsies is highlighted by studies that show they can track the evolutionary dynamics and heterogeneity of tumours and can detect very early emergence of therapy resistance, residual disease and recurrence. However, the analytical validity and clinical utility of liquid biopsies must be rigorously demonstrated before this potential can be realized. PMID- 30410103 TI - The forgotten quantum pioneer who turned wartime spy. PMID- 30410104 TI - Kuen Charles Kao (1933-2018). PMID- 30410105 TI - Dietary metabolism, the gut microbiome, and heart failure. AB - Advances in our understanding of how the gut microbiota contributes to human health and diseases have expanded our insight into how microbial composition and function affect the human host. Heart failure is associated with splanchnic circulation congestion, leading to bowel wall oedema and impaired intestinal barrier function. This situation is thought to heighten the overall inflammatory state via increased bacterial translocation and the presence of bacterial products in the systemic blood circulation. Several metabolites produced by gut microorganisms from dietary metabolism have been linked to pathologies such as atherosclerosis, hypertension, heart failure, chronic kidney disease, obesity, and type 2 diabetes mellitus. These findings suggest that the gut microbiome functions like an endocrine organ by generating bioactive metabolites that can directly or indirectly affect host physiology. In this Review, we discuss several newly discovered gut microbial metabolic pathways, including the production of trimethylamine and trimethylamine N-oxide, short-chain fatty acids, and secondary bile acids, that seem to participate in the development and progression of cardiovascular diseases, including heart failure. We also discuss the gut microbiome as a novel therapeutic target for the treatment of cardiovascular disease, and potential strategies for targeting intestinal microbial processes. PMID- 30410106 TI - Short sleep duration and cardiometabolic risk: from pathophysiology to clinical evidence. AB - Short sleep duration has a substantial influence on the overall health of an individual. Short sleep time can be a consequence of lifestyle habits, environmental factors, or the presence of a sleep disorder, such as insomnia or sleep-disordered breathing. Short sleep time is associated with increased morbidity and mortality, mainly from cardiovascular disorders (including coronary artery disease, arrhythmias, and hypertension). Several biological mechanisms have been proposed as a possible link between short sleep duration and these diseases, such as involvement of the autonomic nervous system, endothelial function, metabolic regulation, inflammation, and the coagulation system. In this Review, we provide an overview on the effects of short sleep duration on cardiovascular health and diseases and discuss the main pathophysiological mechanisms involved, taking into account both experimental data and clinical evidence. PMID- 30410107 TI - The role of B cells in atherosclerosis. AB - The cardiovascular system is subject to hyperlipidaemic, inflammatory, and pro oxidant stressors. Over time, these factors drive prevalent chronic diseases, of which atherosclerosis is most prominent and accounts for the majority of deaths globally. Antibody-producing B cells perform a unique role in responses to stress, injury, and infection. The power, inducibility, and adaptability of the antibody repertoire require an equally complex range of control measures. Defects and chronic perturbations in these checkpoints lead to inappropriate antibody responses, which might have important roles in shaping the development and outcome of atherosclerotic disease. A unique aspect related to atherosclerosis is the prominent role of natural antibodies, specifically those binding to the oxidized epitopes that are abundant on modified lipoproteins and cellular debris. B cells control cellular immune responses through cell-cell contact, antigen presentation, and cytokine production, and thereby participate in systemic and local immune responses in atherosclerotic arteries. To date, both proatherogenic and antiatherogenic properties have been assigned to B cells, depending on subsets and how they are functionally targeted. For these reasons, a deeper understanding of how B cells influence atherosclerotic plaque development is being pursued with the hope of providing novel B cell-targeted interventions to prevent inflammation-driven cardiovascular events. PMID- 30410108 TI - Immune cells inhibit the tumor metastasis in the 4D cellular lung model by reducing the number of live circulating tumor cells. AB - The immune system and tumor microenvironment play a decisive role in tumor progression. We developed a novel model to better understand tumor progression and interaction with immune cells and the cellular components. We grew 393 P non metastatic and 344SQ metastatic murine cells in an acellular metastatic lung cancer model, where both cell lines formed circulating tumor cells (CTC) and metastatic lesions. When the CTC from this model were placed in the tail vein of nu/nu mice, both cell lines formed metastatic lesions. However, in syngeneic immune-competent mice, the CTC from the non-metastatic cell line did not metastasize while the CTC from the metastatic cell line metastasized. When we placed the activated immune cells in the cellular lung model, it decreased CTC and metastatic lesion formation for the non-metastatic cell line while it had no impact on metastatic cell line. The metastatic cell line had a significant increase in expression of programmed death-ligand 1 (PDL-1) compared to the non metastatic cell line in the model. Overall, the immune cells showed an impact on viability of CTC for cell lines with a decreased expression of PDL-1 that leads to decreased metastatic lesion formation. Further studies are needed to understand the subtype of immune cells and mechanism of decreased CTC viability and metastasis inhibition. PMID- 30410109 TI - Pili mediated intercellular forces shape heterogeneous bacterial microcolonies prior to multicellular differentiation. AB - Microcolonies are aggregates of a few dozen to a few thousand cells exhibited by many bacteria. The formation of microcolonies is a crucial step towards the formation of more mature bacterial communities known as biofilms, but also marks a significant change in bacterial physiology. Within a microcolony, bacteria forgo a single cell lifestyle for a communal lifestyle hallmarked by high cell density and physical interactions between cells potentially altering their behaviour. It is thus crucial to understand how initially identical single cells start to behave differently while assembling in these tight communities. Here we show that cells in the microcolonies formed by the human pathogen Neisseria gonorrhoeae (Ng) present differential motility behaviors within an hour upon colony formation. Observation of merging microcolonies and tracking of single cells within microcolonies reveal a heterogeneous motility behavior: cells close to the surface of the microcolony exhibit a much higher motility compared to cells towards the center. Numerical simulations of a biophysical model for the microcolonies at the single cell level suggest that the emergence of differential behavior within a multicellular microcolony of otherwise identical cells is of mechanical origin. It could suggest a route toward further bacterial differentiation and ultimately mature biofilms. PMID- 30410110 TI - Tetanus toxin C-fragment protects against excitotoxic spinal motoneuron degeneration in vivo. AB - The tetanus toxin C-fragment is a non-toxic peptide that can be transported from peripheral axons into spinal motoneurons. In in vitro experiments it has been shown that this peptide activates signaling pathways associated with Trk receptors, leading to cellular survival. Because motoneuron degeneration is the main pathological hallmark in motoneuron diseases, and excitotoxicity is an important mechanism of neuronal death in this type of disorders, in this work we tested whether the tetanus toxin C-fragment is able to protect MN in the spinal cord in vivo. For this purpose, we administered the peptide to rats subjected to excitotoxic motoneuron degeneration induced by the chronic infusion of AMPA in the rat lumbar spinal cord, a well-established model developed in our laboratory. Because the intraspinal infusion of the fragment was only weakly effective, whereas the i.m. administration was remarkably neuroprotective, and because the i.m. injection of an inhibitor of Trk receptors diminished the protection, we conclude that such effects require a retrograde signaling from the neuromuscular junction to the spinal motoneurons. The protection after a simple peripheral route of administration of the fragment suggests a potential therapeutic use of this peptide to target spinal MNs exposed to excitotoxic conditions in vivo. PMID- 30410111 TI - Spontaneous innovation of hook-bending and unbending in orangutans (Pongo abelii). AB - Betty the crow astonished the scientific world as she spontaneously crafted hook tools from straight wire in order to lift a basket out of vertical tubes. Recently it was suggested that this species' solution was strongly influenced by predispositions from behavioural routines from habitual hook-tool manufacture. Nevertheless, the task became a paradigm to investigate tool innovation. Considering that young humans had surprising difficulties with the task, it was yet unclear whether the innovation of a hooked tool would be feasible to primates that lacked habitual hook making. We thus tested five captive orangutans in a hook bending and unbending task. Orangutans are habitually tool-using primates that have been reported to use but not craft hooked tools for locomotion in the wild. Two orangutans spontaneously innovated hook tools and four unbent the wire from their first trial on. Pre-experience with ready-made hooks had some effect but did not lead to continuous success. Further subjects improved the hook-design feature when the task required the subjects to bent the hook at a steeper angle. Our results indicate that the ability to represent and manufacture tools according to a current need does not require stereotyped behavioural routines, but can indeed arise innovatively. Furthermore, the present study shows that the capacity for hook tool innovation is not limited to large brained birds within non-human animals. PMID- 30410112 TI - CD200 facilitates the isolation of corneal epithelial cells derived from human pluripotent stem cells. AB - The in vitro induction of corneal epithelial cells (CECs) from human induced pluripotent stem cells (iPSCs) represents a new strategy for obtaining CE stem/progenitor cells for the surgical reconstruction of a diseased or injured ocular surface. The clinical promise of this strategy is considerable, but if the approaches' potential is to be realised, robust methods for the purification of iPSC-derived CE lineage cells need to be developed to avoid contamination with other cells that may carry the risk of unwanted side effects, such as tumorigenesis. Experiments conducted here revealed that during CEC isolation, CD200-negative selection using a cell sorter considerably reduced the contamination of the cell population with various non-CECs compared with what could be achieved using TRA-1-60, a conventional negative marker for CECs. Furthermore, CD200-negative sorting did not affect the yield of CECs nor that of their stem/progenitor cells. Single-cell gene expression analysis for CEC sheets obtained using CD200-negative sorting showed that all analysed cells were CE lineage cells, expressing PAX6, delta-N p63, and E-cadherin. Non-CECs, on the other hand, expressed non-CEC genes such as FGFR1 and RPE65. CD200, thus, represents a robust negative marker for purification of induced CE lineage cells, which is expressed by undifferentiated iPSCs and non-CECs, including iPSC-derived neural and retinal cells. PMID- 30410114 TI - High carnivore population density highlights the conservation value of industrialised sites. AB - As the environment becomes increasingly altered by human development, the importance of understanding the ways in which wildlife interact with modified landscapes is becoming clear. Areas such as industrial sites are sometimes presumed to have little conservation value, but many of these sites have areas of less disturbed habitats around their core infrastructure, which could provide ideal conditions to support some species, such as mesocarnivores. We conducted the first assessments of the density of serval (Leptailurus serval) at the Secunda Synfuels Operations plant, South Africa, using camera trap surveys analysed within a spatially explicit capture recapture framework. We show that servals occurred at densities of 76.20-101.21 animals per 100 km2, which are higher than previously recorded densities for this species, presumably due to high abundance of prey and the absence of persecution and/or competitor species. Our findings highlight the significant conservation potential of industrialised sites, and we suggest that such sites could help contribute towards meeting conservation goals. PMID- 30410113 TI - Dietary calcium status during maternal pregnancy and lactation affects lipid metabolism in mouse offspring. AB - Calcium plays important roles in lipid metabolism and adipogenesis, but whether its status in early life affects later lipid profiles needs to be clarified. Three to four-week old C57BL/6J female mice were fed with three different reproductive diets containing normal, low (insufficient) and high (excessive) calcium concentrations respectively throughout pregnancy and lactation. At postnatal 21 days, the weaning male and female pups from each group were sacrificed for experiments and the remaining were fed with the normal chow diet for 16 weeks. Meanwhile, some of the weaning female pups from maternal low calcium diet group were fed with the normal calcium, low calcium and high calcium mature diets respectively for 8 weeks. Maternal insufficient or excessive calcium status during pregnancy and lactation programmed an abnormal expression of hepatic and adipose genes (PPAR-gamma, C/EBP-alpha, FABP4, Fasn, UCP2, PPAR alpha, HMG-Red1, Acc1, and SREBP-1c) in the offspring and this may lead to dyslipidemia and accumulation of hepatic triglyceride (TG) and total cholesterol (TC) in later life. The effects of maternal calcium status on lipid metabolism were found only in the female adult offspring, but were similar between offspring males and females at postnatal 21 days. Additionally, the dyslipidemia and hepatic lipid accumulation caused by insufficient calcium status in early life may be reversed to some extent by dietary calcium supplementation in later life. PMID- 30410115 TI - Affinity to cellulose is a shared property among coiled-coil domains of intermediate filaments and prokaryotic intermediate filament-like proteins. AB - Coiled-coil domains of intermediate filaments (IF) and prokaryotic IF-like proteins enable oligomerisation and filamentation, and no additional function is ascribed to these coiled-coil domains. However, an IF-like protein from Streptomyces reticuli was reported to display cellulose affinity. We demonstrate that cellulose affinity is an intrinsic property of the IF-like proteins FilP and Scy and the coiled-coil protein DivIVA from the genus Streptomyces. Furthermore, IF-like proteins and DivIVA from other prokaryotic species and metazoan IF display cellulose affinity despite having little sequence homology. Cellulose affinity-based purification is utilised to isolate native FilP protein from the whole cell lysate of S. coelicolor. Moreover, cellulose affinity allowed for the isolation of IF and IF-like protein from the whole cell lysate of C. crescentus and a mouse macrophage cell line. The binding to cellulose is mediated by certain combinations of coiled-coil domains, as demornstrated for FilP and lamin. Fusions of target proteins to cellulose-binding coiled-coil domains allowed for cellulose based protein purification. The data presented show that cellulose affinity is a novel function of certain coiled-coil domains of IF and IF-like proteins from evolutionary diverse species. PMID- 30410116 TI - The swimming plus-maze test: a novel high-throughput model for assessment of anxiety-related behaviour in larval and juvenile zebrafish (Danio rerio). AB - Larval zebrafish (Danio rerio) has the potential to supplement rodent models due to the availability of resource-efficient, high-throughput screening and high resolution imaging techniques. Although behavioural models are available in larvae, only a few can be employed to assess anxiety. Here we present the swimming plus-maze (SPM) test paradigm, a tool to assess anxiety-related avoidance of shallow water bodies in early developmental stages. The "+" shaped apparatus consists of arms of different depth, representing different levels of aversiveness similarly to the rodent elevated plus-maze. The paradigm was validated (i) in larval and juvenile zebrafish, (ii) after administration of compounds affecting anxiety and (iii) in differentially aversive experimental conditions. Furthermore, we compared the SPM with conventional "anxiety tests" of zebrafish to identify their shared characteristics. We have clarified that the preference of deeper arms is ontogenetically conserved and can be abolished by anxiolytic or enhanced by anxiogenic agents, respectively. The behavioural readout is insensitive to environmental aversiveness and is unrelated to behaviours assessed by conventional tests involving young zebrafish. Taken together, we have developed a sensitive high-throughput test allowing the assessment of anxiety-related responses of zebrafish regardless of developmental stage, granting the opportunity to combine larva-based state-of-the-art methods with detailed behavioral analysis. PMID- 30410117 TI - A rapamycin derivative, biolimus, preferentially activates autophagy in vascular smooth muscle cells. AB - Although rapamycin is a well-known conformational inhibitor of mTORC1, it is now widely used for treating arterial restenosis. Various rapamycin analogues (rapalogue) have been made for applying to drug-eluting stents. Here we show that two major rapalogues, everolimus and biolimus, exert a differential effect on the mTORC1-mediated signaling pathways in vascular smooth muscle cells. In balloon injured carotid arteries, both rapalogues strongly inhibit neointimal hyperplasia. Signaling pathway analyses reveal that everolimus exert cytotoxicity by increasing cellular reactive oxygen species and consequently reduce energy metabolism. By contrast, biolimus confers a preferential induction of autophagy by more strongly activating major autophagy regulator, ULK1, in vascular smooth muscle cells than everolimus does. As a consequence, the implantation of biolimus eluting stent reduces endothelial loss, which in turn reduces inflammation, in porcine coronary arteries. Thus, this study reveals that a chemical derivatization can cause a change among mTORC1-dependent signaling pathways in vascular smooth muscle cells, thereby enabling to elicit a differential efficacy on arterial restenosis. PMID- 30410118 TI - The Antiarrhythmic Drug, Dronedarone, Demonstrates Cytotoxic Effects in Breast Cancer Independent of Thyroid Hormone Receptor Alpha 1 (THRalpha1) Antagonism. AB - Previous research has suggested that thyroid hormone receptor alpha 1 (THRalpha1), a hormone responsive splice variant, may play a role in breast cancer progression. Whether THRalpha1 can be exploited for anti-cancer therapy is unknown. The antiproliferative and antitumor effects of dronedarone, an FDA approved anti-arrhythmic drug which has been shown to antagonize THRalpha1, was evaluated in breast cancer cell lines in vitro and in vivo. The THRalpha1 splice variant and the entire receptor, THRalpha, were also independently targeted using siRNA to determine the effect of target knockdown in vitro. In our study, dronedarone demonstrates cytotoxic effects in vitro and in vivo in breast cancer cell lines at doses and concentrations that may be clinically relevant. However, knockdown of either THRalpha1 or THRalpha did not cause substantial anti proliferative or cytotoxic effects in vitro, nor did it alter the sensitivity to dronedarone. Thus, we conclude that dronedarone's cytotoxic effect in breast cancer cell lines are independent of THRalpha or THRalpha1 antagonism. Further, the depletion of THRalpha or THRalpha1 does not affect cell viability or proliferation. Characterizing the mechanism of dronedarone's anti-tumor action may facilitate drug repurposing or the development of new anti-cancer agents. PMID- 30410120 TI - Tunable Magnetocaloric Effect in Ni-Mn-Ga Microwires. AB - Magnetic refrigeration is of great interest due to its high energy efficiency, environmental friendliness and low cost. However, undesired hysteresis losses, concentrated working temperature interval (WTI) and poor mechanical stability are vital drawbacks that hinder its practical application. Off-stoichiometric Ni-Mn Ga Heusler alloys are capable of giant magnetocaloric effect (MCE) and tunable transformation temperatures. Here, by creating Ni-Mn-Ga microwires with diameter of 35-80 MUm using a melt-extraction technique, negligible hysteresis and relatively good mechanical stability are found due to the high specific surface area (SSA) that reduces incompatibility between neighboring grains. The high SSA also favors the element evaporation at high temperatures so that the transformation temperatures can be feasibly adjusted. Tunable magnetocaloric effect owing to different magneto-structural coupling states is realized by (i) composition design and subsequent tuning, which adjusts the temperature difference between the martensite transformation (MT) and the magnetic transition, and (ii) creation of gradient composition distribution state, which manipulates the MT range. Magnetic entropy change DeltaSm ~-18.5 J kg-1 K-1 with relatively concentrated WTI and WTI up to ~60 K with net refrigeration capacity ~240 J kg-1 at 50 kOe are demonstrated in the present Ni-Mn-Ga microwires. This criterion is also applicable for other small-sized materials. PMID- 30410119 TI - Depletion of regulatory T cells in ongoing paracoccidioidomycosis rescues protective Th1/Th17 immunity and prevents fatal disease outcome. AB - In human paracoccidioidomycosis (PCM), a primary fungal infection typically diagnosed when the disease is already established, regulatory T cells (Treg) cells are associated with disease severity. Experimental studies in pulmonary PCM confirmed the detrimental role of these cells, but in most studies, Tregs were depleted prior to or early during infection. These facts led us to study the effects of Treg cell depletion using a model of ongoing PCM. Therefore, Treg cell depletion was achieved by treatment of transgenic C57BL/6DTR/eGFP (DEREG) mice with diphtheria toxin (DT) after 3 weeks of intratracheal infection with 1 * 106 Paracoccidioides brasiliensis yeasts. At weeks 6 and 10 post-infection, DT treated DEREG mice showed a reduced number of Treg cells associated with decreased fungal burdens in the lungs, liver and spleen, reduced tissue pathology and mortality. Additionally, an increased influx of activated CD4+ and CD8+ T cells into the lungs and elevated production of Th1/Th17 cytokines was observed in DT-treated mice. Altogether, our data demonstrate for the first time that Treg cell depletion in ongoing PCM rescues infected hosts from progressive and potentially fatal PCM; furthermore, our data indicate that controlling Treg cells could be explored as a novel immunotherapeutic procedure. PMID- 30410121 TI - GPCR drug discovery: integrating solution NMR data with crystal and cryo-EM structures. AB - The 826 G protein-coupled receptors (GPCRs) in the human proteome regulate key physiological processes and thus have long been attractive drug targets. With the crystal structures of more than 50 different human GPCRs determined over the past decade, an initial platform for structure-based rational design has been established for drugs that target GPCRs, which is currently being augmented with cryo-electron microscopy (cryo-EM) structures of higher-order GPCR complexes. Nuclear magnetic resonance (NMR) spectroscopy in solution is one of the key approaches for expanding this platform with dynamic features, which can be accessed at physiological temperature and with minimal modification of the wild type GPCR covalent structures. Here, we review strategies for the use of advanced biochemistry and NMR techniques with GPCRs, survey projects in which crystal or cryo-EM structures have been complemented with NMR investigations and discuss the impact of this integrative approach on GPCR biology and drug discovery. PMID- 30410122 TI - A practical protocol for measurements of spinal cord functional connectivity. AB - Resting state functional magnetic resonance imaging (fMRI) has been used to study human brain function for over two decades, but only recently has this technique been successfully translated to the human spinal cord. The spinal cord is structurally and functionally unique, so resting state fMRI methods developed and optimized for the brain may not be appropriate when applied to the cord. This report therefore investigates the relative impact of different acquisition and processing choices (including run length, echo time, and bandpass filter width) on the detectability of resting state spinal cord networks at 3T. Our results suggest that frequencies beyond 0.08 Hz should be included in resting state analyses, a run length of ~8-12 mins is appropriate for reliable detection of the ventral (motor) network, and longer echo times - yet still shorter than values typically used for fMRI in the brain - may increase the detectability of the dorsal (sensory) network. Further studies are required to more fully understand and interpret the nature of resting state spinal cord networks in health and in disease, and the protocols described in this report are designed to assist such studies. PMID- 30410123 TI - Impact of Non-alcoholic Fatty Liver Disease on long-term cardiovascular events and death in Chronic Obstructive Pulmonary Disease. AB - Chronic Obstructive Pulmonary Disease (COPD) and Non-Alcoholic Fatty Liver Disease (NAFLD) both independently increase cardiovascular risk. We hypothesized that NAFLD might increase the incidence of cardiovascular disease and death in COPD patients. The relationship between NAFLD, incident cardiovascular events, and death was assessed in a prospective cohort of COPD patients with 5-year follow-up. Noninvasive algorithms combining biological parameters (FibroMax(r)) were used to evaluate steatosis, non-alcoholic steatohepatitis (NASH) and liver fibrosis. Univariate and multivariate Cox regression models were used to assess the hazard for composite outcome at the endpoint (death or cardiovascular event) for each liver pathology. In 111 COPD patients, 75% exhibited liver damage with a prevalence of steatosis, NASH and fibrosis of 41%, 37% and 61%, respectively. During 5-year follow-up, 31 experienced at least one cardiovascular event and 7 died. In univariate analysis, patients with liver fibrosis had more cardiovascular events and higher mortality (Hazard ratio [95% CI]: 2.75 [1.26; 6.03]) than those with no fibrosis; this remained significant in multivariate analysis (Hazard ratio [95% CI]: 2.94 [1.18; 7.33]). We also found that steatosis and NASH were not associated with increased cardiovascular events or mortality. To conclude, early assessment of liver damage might participate to improve cardiovascular outcomes in COPD patients. PMID- 30410124 TI - Author Correction: Necroptosis microenvironment directs lineage commitment in liver cancer. AB - In this Article, the pCaMIN construct consisted of 'mouse MYC and mouse NrasG12V' instead of 'mouse Myc and human NRASG12V; and the pCAMIA construct consisted of 'mouse Myc and human AKT1' instead of 'mouse Myc and Akt1' this has been corrected online. PMID- 30410125 TI - Author Correction: A global slowdown of tropical-cyclone translation speed. AB - In this Letter, two errors in the methodology are corrected, leading to changes in Figs. 1-3 and Extended Data Figs. 1 and 2, although the essential results are not affected. The original Letter has been corrected online. PMID- 30410126 TI - Functional cure of HIV: the scale of the challenge. AB - A variety of interventions to induce a functional cure of HIV are being explored, with the aim being to allow patients to cease antiretroviral therapy (ART) for prolonged periods of time or for life. These interventions share the goal of inducing ART-free remission from HIV pathogenesis and disease progression but achieve this in quite different ways, by reducing the size of the latent reservoir (for example, small-molecule stimulation of latently infected cells), reducing the number of target cells available for the virus (for example, gene therapy) or improving immune responses (for example, active or passive immunotherapy). Here, we consider a number of these alternative strategies for inducing post-treatment control of HIV and use mathematical modelling to predict the scale of the challenge inherent in these different approaches. For many approaches, over 99.9% efficacy will likely be required to induce durable ART free remissions. The efficacy of individual approaches is currently far below what we predict will be necessary, and new technologies to achieve lifelong functional cure are needed. PMID- 30410127 TI - Role modelling: A missing link in medical education1554. PMID- 30410128 TI - Effectiveness of intralesional steroid injections with dilatation in corrosive oesophageal strictures - A Randomized Control Trial AB - OBJECTIVE: To compare the improvement of dilatation among patients receiving intralesional steroid injection with dilatation versus dilatation alone for the management of corrosive ooesophageal strictures. METHODS: The randomized controlled trial was conducted at Mayo Hospital, Lahore, Pakistan, from November 10, 2014, to November 10, 2015, and comprised patients of either gender aged 15 50years who had corrosive ooesophageal stricture. They were randomised into 2 groups by using the lottery method. In the dilatation group, only endoscopic dilation was done, while in the combination group, intralesional triamcinolone injection was injected followed by dilatation. Follow-up endoscopic dilatation was done every two weeks. Data was analysed using SPSS 21. RESULTS: There were 60 patients randomised into two groups of 30(50%) each. The overall mean age was 32.58+/-10.58 years and the male-to-female ratio was 1.7:1. At baseline, in dilatation group, the mean stricture length was 23.30+/-2.28cm while in combination group, it was 24.23+/-3.06cm. In dilatation group, the mean stricture length was 11.20+/-3.09cm while in combination group, it was 5.33+/-3.09cm (p=0.0001).. CONCLUSIONS: oesophageal Combination group was more effective than the dilatation-alone group. PMID- 30410130 TI - Plantation is an effective measure in addressing the health issues. AB - OBJECTIVE: To highlight the influence of environmental hazards and geographical degradation on population health status. METHODS: The ecological study was conducted at the Institute of Health Management, Dow University of Health Sciences, Karachi, and incorporated facts and figures gathered from primary and secondary data sources between November and December 2016. Employing proportionate quota sampling, data from both developed and developing countries was included. Parameters analysed included life expectancy, health expenditure characterising health profile, urbanisation, forest, agriculture land area proportions characterising geographic profile, and air, noise pollution index characterizing environmental profile. Data was analysed on Microsoft Excel 2016. RESULTS: Of the 20 countries, 4(20%) were developed and 16(80%) were developing. Overall, 5(25%) countries, either considerably or modestly-forested were likely to be less polluted, while the opposite was true for 7(35%) others. Besides, 7(44%) agrarian states -- 2(50%) developed and 5(31%) developing-- correlated sustenance proportionately with healthy prolonged life expectancy. Overall, 15(75%) countries validated healthy life expectancy proportionate with health expenditure. The only exceptions were 5(31%) developing countries. Also, 14(70%) states associated urbanisation with health expense. CONCLUSIONS: Growing urbanisation is the biggest threat to ecological resources. Plantation is an effective measure to address these challenges. PMID- 30410129 TI - The relationship between placental transfusion, and thymic size and neonatal morbidities in premature infants - A Randomized Control Trial AB - OBJECTIVE: To compare the effect of umbilical cord milking and early cord clamping on thymic size, and neonatal mortality and morbidity in preterm infants. METHODS: This single-center, prospective, double-blind, randomised controlled study was conducted at Baskent University, Konya Education and Research Centre, Konya, Turkey, between October 2015 and April 2016. Pregnant women who delivered before 32 weeks of gestation were randomised to receive umbilical cord milking (group 1) or early cord clamping (group 2). Ultrasonographic evaluation was performed in each newborn by an experienced radiologist within the first 24 hours of life. Thymic si ze was estimated in l ine with literatu re. SPSS 15 was u sed for a ll data analyses. RESULTS: There were 38 subjects in group 1 and 37 in group 2. There were as many infants in the two groups (p>0.05) The haemoglobin levels was higher in group 1, but not significantly (p=0.213). The absolute neutrophil count in group 1 was significantly lower (p= 0.017) than group 2. In terms of neonatal mortaility and morbidity, there were no significant differences between the groups (p>0.05). CONCLUSIONS: Umbilical cord milking was not associated with thymic size during the the first 24h of life. PMID- 30410131 TI - Interferon alpha receptors and STAT1 as therapy predictors of a sustained virological response in hepatitis C/B co-infection. AB - OBJECTIVE: : To determine the expression of interferon alpha receptors 1 and 2 along with signal transducer and activator of transcription-1 in peripheral blood mononuclear cells of both hepatitis C mono-infected and hepatitis C and B co infected patients, and to assess whether these targeted genes predict sustained virological response to interferon therapy. METHODS: This cross-sectional study was carried out at the Army Medical College, Rawalpindi, Pakistan, from January 2012 to December 2015, and comprised hepatitis C mono-infected and hepatitis C and B co-infected patients. The patients were divided into groups 1 and 2. Group 1a and group-2a consisted of mono-infected and co-infected sustained responders, while group-1b and group-2b had mono-infected and co-infected non sustained responders. Peripheral blood mononuclear cells from healthy controls were also quantified for these subunits. Target gene expressions were studied by retro transcription of respective messenger ribonuclieic acid extracted from the cells followed by polymerase chain reaction amplification. RESULTS: Of the 191 subjects, there were 20(10.5%) in group-1a, 35(18.3%) in group-2a, 65(34%) in group-1b and 51(26.7%) in group-2b. The remaining 20(10.5%) were controls. Overall, 106 (55.5%) were males and 85 (44.5%) were females. Interferon alpha receptor 1 expression in groups 1a and 2a was significantly higher compared to groups 1b (p=0.018) and 2b (p 0.031). Signal transducer and activator of transcription-1 protein expression showed no significant difference (p=0.062 and p=0.519). No difference in expression was measured between the two sets of groups with regard to interferon alpha receptor 2 expression (p=0.278 and p=0.590). CONCLUSIONS: Our results show that levels of IFNAR-1 mRNA expression may be a good predictor for IFN-related anti-viral activity in both HCV mono infected and HCV/HBV co-infected patients. PMID- 30410132 TI - Investigation of factors affecting postpartum maternal weight retention: A cross sectional study. AB - OBJECTIVE: To examine weight retention and affecting factors among 12-18 months postpartum women.. METHODS: The descriptive cross-sectional study was conducted from January 1 to June 30, 2012 at Gazikent 3rd Primary Health Care Centre, Izmir, Turkey, and comprised pregnant women registered with the centre in their 12-18 months postpartum phase. Data was collected using Mother Introduction Form and International Physical Activity Questionnaire-Short Form. SPSS 15 was used for data analysis. RESULTS: There were 239 women with a mean age of 30.81+/-4.59 years. Of the total, 182(76.2%) subjects had weight retention; 106(44.4%) having 0.5-5kg, and 49(20.6%) with 5.5-10 kg. Overall mean weight retention rate was 4.09+/-4.90kg (range: -9-27kg). Weight retention had significant correlations with chronic illness (p=0.037), having been educated about physical exercise during pregnancy (p=0.001), skipping meals (p=0.036), average pre-pregnancy weights (p=0.019), average pre-pregnancy body mass index (p=0.049), average weight gained during pregnancy (p=0.009), achieving weight gain during pregnancy as recommended by the Institute of Medicine guidelines (p=0.002), and mean physical activity score (p=0.006). CONCLUSIONS: Women should be monitored for their body mass index and weight in the postpartum period and during pregnancy. PMID- 30410133 TI - Association of RETN C-420G single nucleotide polymorphism with type 2 diabetes mellitus in Pakistani Punjabi Rajput population. AB - OBJECTIVE: To determine the association of human resistin gene RETN C-420G single nucleotide polymorphism with type 2 diabetes mellitus in a specific ethnic population.. METHODS: The controlled study was conducted from June 2012 to January 2015 at Military Hospital, Rawalpindi, Army Medical College, Rawalpindi, and the Institute of Biomedical and Genetic Engineering, Islamabad, Pakistan. Patients with type 2 diabetes and healthy controls belonging to Pakistani Punjabi Rajput ethnic group were genotyped for human resistin gene RETNC-420G single nucleotide polymorphism. Serum resistin, serum insulin, fasting blood sugar, lipid profile, body mass index and insulin resistance was determined and correlated with genotypes. SPSS 18 was used for data analysis. RESULTS: Of the 789 subjects, 539(68%) were diabetics and 250(32%) were controls. Serum resistin levels were significantly higher in diabetics than controls (p<0.05). The frequency of GG, GC and CC was 15(2.8%), 322(59.75%) and 202(37.5%) in diabtics. This single nucleotide polymorphism was associated with diabetes (p<0.02).Human resistin gene RETN C-420G single nucleotide polymorphism was not associated with serum resistin, insulin, body mass index, insulin resistance and dyslipidaemia in both groups (p<0.05 each). CONCLUSIONS: Human resistin gene RETN C-420G single nucleotide polymorphism was found to be a risk factor for type 2 diabetes in Pakistani Punjabi Rajput population.. PMID- 30410134 TI - The ADRIFT study - Assessing Diabetes Distress and its associated factors in the Pakistani population. AB - OBJECTIVE: To assess diabetes distress and its associated factors in Pakistani population.. METHODS: The cross-sectional study was conducted at Pakistan Institute of Medical Sciences, Islamabad, Pakistan, from July to December 2017, and comprised patients of diabetes type 2. After noting down demographic and clinical parameters, diabetes distress of the subjects was measured by applying the 17-item diabetes distress scale which also assesses sub domains like emotional burden, physicianrelated distress, regimen-related distress and interpersonal distress. SPSS 20 was used to analyse data. RESULTS: There were 349 subjects with a mean age of 53.14+/-11.77 years, mean diabetes duration of 8.36+/ 6.64 years and a mean glycated haemoglobin value of 9.05+/-1.93%. Mean overall diabetes distress score was 2.55+/-0.75, signifying moderate distress. Overall, prevalence of diabetes distress was found among 266(76.2%) subjects;164(47%) moderate and 102(29.2%) high level distress. Emotional burden was most substantially elevated, with 296(84.8%) patients reporting moderate to high levels. Total diabetes distress was significantly related to demographic background (p<0.0001), education level (p=0.015), monthly income, frequency of administration of medication, adherence to medical treatment (p<0.05), number of complications (p<0.05) and overall glycaemic control (p<0.001). CONCLUSIONS: Modifiable factors, such as frequency of medication and compliance to treatment, should be addressed with the aim of decreasing diabetes distress and improve glycaemic control.. PMID- 30410135 TI - Assessment of dental maturation on orthopantomograms among children with various dental malocclusions at a tertiary care hospital. AB - OBJECTIVE: To determine and compare the median dental age among males and females and in subjects with dental Class I, II and III malocclusions. METHODS: The retrospective study was conducted at Aga Khan University Hospital and comprised dental records of patients from July to December 2016 who were aged 9-16 years and had complete dentition excluding third molars. The sample was divided according to dental malocclusion which was further categorised according to chronological age groups. SPSS 21 was used for data analysis. RESULTS: Of the 270 sbjects whose radiographs were studied, 135(50%) each were males and females. Children aged 11-12 years showed a statistically significant difference (p=0.03) in the median dental age among genders. There was a strong positive correlation in the dental and chronological ages in the males (p<0.001) and females (p<0.001) sample. Median time of eruption of mandibular second permanent molar in different malocclusions was 11 years and 2 months. CONCLUSIONS: There was a strong positive correlation between chronological and dental ages for males and females. Females subjects were dentally advanced compared to the male subjects aged 11-12 years. .. PMID- 30410136 TI - Psychological distress in students appearing for the medical school entrance examination in Peshawar. AB - OBJECTIVE: To explore psychological distress in terms of depression, anxiety, social dysfunction, depressive and somatic symptoms among students appearing for medical school entrance examination. METHODS: The cross-sectional study was conducted at Peshawar Medical College, Peshawar, Pakistan, from August 2015 to May 2016, and comprised all students who appeared in the written test. The subjects were asked to fill the General Health Questionnaire for the evaluation of psychological distress. Those who scored 24 and more and were called for the entrance interview were further assessed on Hamilton R ating Scale for Depression. SPSS 20 was used for data analysis.. RESULTS: Of the 1334 subjects, 745(55.8%) were males and 589(44.2%) were females. The mean age was 18.9+/-1.41 years and 182(13.6%) subjects had psychological distress. On the four subscales of the questionnaire, 472 (35.4%) students had somatic symptoms, 560 (42%) had anxiety/insomnia, 819 (61.4%) had social dysfunction and 323 (24.2%) had depressive symptoms. Amongst the 322(24%) students who were called for interviews, 73(22.7%) had psychological distress based on the questionnaire and 9 (2.8%) had depression on the Hamilton scale. There was a significant correlation between female gender and psychological distress based on the questionnaire scores (p<0.05). Among those who had both the assessments, there was no significant gender-based correlation (p>0.05). No significant correlation was found between academic performance and either of the assessment tools (p>0.05 each). CONCLUSIONS: A significant proportion of students at the medical school entrance examination level had psychological distress. PMID- 30410137 TI - Coping mechanisms as predictors of suicidal ideation among the medical students of Pakistan. AB - OBJECTIVE: To identify the coping mechanisms as positive and negative predictors of suicidal ideation among medical students. METHODS: This cross-sectional analytical study was conducted from January to October 2017, and comprised students aged 19-25 years selected from 3 public-sector medical colleges located in Gujrat and Lahore, both in the Punjab province of Pakistan. Multilevel mixed methods sampling was used. Two standardised scales were used to assess the suicidal ideation and coping mechanisms of the participants. RESULTS: Of the 1200 subjects, 640(53%) were males and 560(47%) were females. Besides, 390(32%) subjects hailed from Gujrat and 810(68%) from Lahore. Self-distraction (p<0.05)), active coping (p<0.0001), use of emotional support (p<0.05), use of instrumental support (p<0.001) positive reframing (p<0.0001), planning (p<0.001), humour (p>0.05), acceptance (p<0.001) and religion (p<0.0001) were negative predictors of suicidal ideation whereas denial (p<0.0001), substance use (p<0.05), venting (p>0.05) and self-blame (p<0.0001) were positive predictors of suicidal ideation. CONCLUSIONS: A psycho-educational programme must be introduced for medical students to enable them to adopt the right coping strategies in order to handle stressful situations. PMID- 30410138 TI - Granulocyte-colony stimulating factor in neonatal sepsis with leukopenia: A prospective cohort study. AB - OBJECTIVE: To observe the duration for normalization of the Total Leucocyte Count (TLC) with adjuvant Granulocyte-Colony Stimulating Factor (G-CSF) treatment in leukopenic neonatal sepsis, and to compare the neutrophilic response to G-CSF in neutropenic vs non-neutropenic subgroups. METHODS: This prospective cohort study was carried out at the Neonatal Intensive Care Unit at Military Hospital Rawalpindi (NICU) from 1st August 2015 to 25th January 2017. Fifty one newborns with sepsis and leucopenia were sampled judgmentally from a population of 5666 admitted to NICU during the study period. The sample was then divided into neutropenic (exposed) and non-neutropenic (non-exposed) subgroups on basis of the absolute neutrophil count (ANC). Adjuvant G-CSF was given to all subjects and stopped once TLC normalized. SPSS v22 was used to calculate mean G-CSF treatment duration and rise in ANC. A Pearson correlation coefficient and simple linear regression were computed to assess the relationship between pre-GCSF ANC and the duration of treatment with GCSF. Comparison of subgroups with respect to rise in ANC was done using independent samples T-test. RESULTS: The mean duration of G CSF treatment was 1.82+/-0.81 days (1.0 - 4.0). Neutropenic neonates constituted 49% (n=25). The Pearson correlation coefficient showed a positive but negligible and non-significant correlation between the two variables, r = 0.070, n = 51, p = 0.625. A non-significant regression equation was found (F(1,49) = 0.242,p=0.625) with an R2 of 0.005. There was a 7.06+/-4.5 fold rise in ANC in the neutropenic subgroup compared to the 4.5+/-3.1 fold rise in the non-neutropenic subgroup (p=0.04). CONCLUSIONS: The mean duration for recovery from leukopenia with G-CSF treatment in neonatal sepsis was less than 2 days and had no significant relationship with pre-GCSF absolute neutrophil count. The neutrophilic response was significantly higher in neutropenic compared to non-neutropenic neonates. As GCSF made no difference to the outcome in terms of mortality, its routine use is not recommended in leukopenic neonatal sepsis. . PMID- 30410139 TI - Tumour Lysis Syndrome in children with haematological cancers: Experience at a tertiary care hospital in Karachi. AB - OBJECTIVE: To determine the incidence of tumour lysis syndrome and to identify associated factors and mortality rate in paediatric haematological patients. METHODS: The prospective study was conducted from April to September 2016 at Indus Children Cancer Hospital, Karachi, and collected data for all new paediatric oncology patients registered with diagnosis of haematological malignancies. Each patient was monitored for a period of three days before and seven days after the start of the treatment. SPSS 21 was used for data analysis. RESULTS: of the 232 patients, 86(37.1%) developed laboratory tumour lysis syndrome and 35(40.7%) of these patients developed the spontaneous variety. Overall, 24 (10.3%) patients progressed to clinical syndrome with 12(50%) of them developing spontaneous clinical syndrome. Mortality occurred in 17 (7.3%) patients. CONCLUSIONS: Despite preventive measures, tumour lysis syndrome remains an oncological emergency in children with haematological malignancies. PMID- 30410140 TI - Thiol disulphide homeostasis in patients with acute myocardial infarction (AMI). AB - OBJECTIVE: To investigate novel oxidative stress marker thiol disulphide homeostasis in patients with acute myocardial infarction.. METHODS: The case control study was conducted at Yildirim Beyazit University, Ankara, Turkey, between October 26, 2015 and January 26, 2016. It comprised patients of ST elevation myocardial infarction, and healthy individuals. Troponin levels, native thiol, total thiol, and disulphide were compared among the groups. Results: Of the 128 subjects, 98(76.5%) were patients and 30(23.43%) were controls. Disulphide levels were lower in the patients compared to the controls (p<0.001).As troponin levels increased, native thiol, total thiol and disulphide levels in patients decreased (p<0.05). RESULTS: Of the 128 subjects, 98(76.5%) were patients and 30(23.43%) were controls. Disulphide levels were lower in the patients compared to the controls (p<0.001).As troponin levels increased, native thiol, total thiol and disulphide levels in patients decreased (p<0.05). CONCLUSIONS: Native thiol and total thiol levels may be used as a novel oxidative stres marker in patients with acute myocardial infarction. PMID- 30410141 TI - The effect of theoretical and simulation training on medical errors of nurse students in Karadeniz Technical University, Turkey. AB - OBJECTIVE: To assess the efficacy of theoretical training related to medical errors and patient safety and practical simulation training on students' knowledge and skill levels.. METHODS: This experimental study was conducted from March 28 to May 18, 2016, at nursing department of a university and comprised of students attending the third grade of the nursing school. The subjects were divided into two equal experimental and control groups. The experimental group, among other things, received simulation training that involved a demonstration and subsequent one-to-one practice. Data was collected on a proforma that included demographic information, pretest and post-test scores, checklists for pre-assessments and final assessments related to nursing practices. RESULTS: There were 62 nurses divided into two groups of 31(50%) each. The difference between post-test scores of the concerning theoretical training about medical errors and patient safety was statistically significant (p<0.05). Pre-assessment of the groups concerning practical training on nursing skills and medical errors revealed no statistically significant difference (p>0.05), while there was a significant difference between their final assessments (p<0.05). CONCLUSIONS: Theoretical education increased students' levels of knowledge regarding medical errors and patient safety, and the the practical simulation training reduced malpractices by improving skills. PMID- 30410142 TI - Surgical outcomes of decompressive laminectomy by transspinous approach for degenerative lumbar spinal stenosis. AB - OBJECTIVE: To assess clinical and radiographical outcomes of transspinous decompression technique for the treatment of degenerative central lumbar spinal stenosis. METHODS: The single-centre, non-randomised interventional, prospective, observational study was conducted Neurosurgery Clinic of Mazhar Osman Research and Training Hospital for Psychiatry and Neurology, Istanbul, Turkey from May 2013 and May 2016 and comprised adult patients with refractory symptoms from degenerative central lumbar spinal stenosis who underwent lumbar spinous processsplitting laminectomy. Pre- and post-operative Oswestry Disability Index score, visual analogue scale for overall pain, maximum walking distance and anteroposterior diameter of the spinal canal on magnetic resonance imaging were assessed on follow up examination. SPSS 22 was used for data analysis. RESULTS: Of the 89 patients, 7(7.86%) were lost to follow-up, while 82(92.14%) completed the study. Of them, 42(51%) were women and 40(49%) were men. Overall mean age was 63.86+/-10.02 years (range: 40-85 years). A total of 95 transspinous decompressive laminectomies were performed. Mean number of decompressed spinal segments was 1.16. Median duration of surgical procedure was 45 min, while mean length of hospital stay was 1.22+/-0.47 days. Mean decrease in pre operative Oswestry Disability Index scoreat 1-year was 56.4% and overall visual analogue scale was 55.9%.Mean increase of 155.2% was documented over pre-operative maximum walking distance. Radiological assessment revealed a 40.7% increase in the mean and anteroposteriordiameter of the spinal canal at the level of the target lesion. The improvement in various parameters was statistically significant (p<0.001).. CONCLUSIONS: Lumbar spinous process-splitting laminectomy led to significant improvement with respect to patient-reported perceived recovery, functional disability and radiological evidence of effective surgical decompression in patients with lumbar spinal stenosis.. PMID- 30410143 TI - Recombinant Domain V of beta (2)-Glycoprotein I Inhibits OxLDL-induced TF Expression in Macrophages. AB - OBJECTIVE: To investigate if lectin-like oxidised low density lipoprotein receptor is implicated in oxidised low density lipoprotein induced up regulation of tissue factor and whether recombinant domain V of beta (2)-Glycoprotein I expressed in Pichia pastoris inhibits the binding of oxidised and lectin-like low density lipoprotein. METHODS: The expression of tissue factor and lectin-like oxidised low density lipoprotein receptor was detected using Western blot methods. Small interference ribonucleic acid of lectin-like oxidised low density lipoprotein receptor was used to block lectin-like oxidised low density lipoprotein receptor expression. Flow cytometry was used to test the effect of beta (2)-Glycoprotein I expressed in Pichia pastoris on the binding of oxidised low density lipoprotein with lectin-like oxidised low density lipoprotein receptor by using the lectin-like oxidised low density lipoprotein receptor expressing 293T cells. RESULTS: Oxidised low density lipoprotein at 5-10 ?g/mL increased tissue factor and lectin-like oxidised low density lipoprotein receptor expression, whereas 20-50 ?g/mL oxidised low density lipoprotein attenuated tissue factor expression. Inhibiting lectin-like oxidised low density lipoprotein receptor expression by small interference ribonucleic acid of lectin-like oxidised low density lipoprotein receptor impaired oxidised low density lipoprotein-induced tissue factor over expression in macrophages. Pretreatment with beta (2)-Glycoprotein I expressed in Pichia pastoris led to a strong inhibition of tissue factor and lectin-like oxidised low density lipoprotein receptor expression in a dose-dependent manner in macrophages. Flow cytometry analysis showed that beta (2)-Glycoprotein I expressed in Pichia pastoris attenuated the interaction of oxidised low density lipoprotein with lectin-like oxidised low density lipoprotein receptor in lectin-like oxidised low density lipoprotein receptor-expressing 293T cells. CONCLUSIONS: Lectin-like oxidised low density lipoprotein receptor was implicated in the expression of tissue factor induced by oxidised low density lipoprotein, and beta (2)-Glycoprotein I expressed in Pichia pastoris inhibited oxidised low density lipoprotein-induced tissue factor and lectin-like oxidised low density lipoprotein receptor expression, at least in part, via inhibition of the interaction between oxidised low density lipoprotein and lectin-like oxidised low density lipoprotein receptor. PMID- 30410144 TI - The use of traditional and complementary medicine among diabetes patients, and the awareness and attitudes of physicians. AB - OBJECTIVE: To determine the frequency and reasons for use of traditional and complimentary medicines in diabetic patients, and the attitudes and behaviours of physicians towards the issue. METHODS: This cross-sectional study was conducted from April 2015 to April 2016 at Van Yuzuncu Yil University, Van, Turkey, and comprised people aged 18 or more with an existing diagnosis of diabetes. A semi structured questionnaire was used as the data-collection tool.. RESULTS: There were 386 respondents, and 179(46.4%) of them said they had used at least one type of traditional and complimentary medicine related to their diabetic condition. A significant relationship was noted between such usage and age, educational level, type of diabetes, monthly income, duration of diabetes, diabetic complications, gylcated haemoglobin (HbA1c) levels <10 and ?10, and prescribed treatment. Besides, 135(75.41%) participants said they had not discussed their use of traditional and complimentary medicines with their physicians. CONCLUSIONS: When evaluating diabetic patients, physicians should ask their patients about their use of traditional and complimentary medicines, and should provide them with detailed information on the subject. PMID- 30410145 TI - Training on Biodex balance system improves balance and mobility in the elderly. AB - OBJECTIVE: To determine the effects of balance training with visual feedback using static and dynamic Biodex balance system for fall risk and mobility.. METHODS: The two-arm pilot randomised controlled trial was conducted from July to October 2016 at Fauji Foundation Hospital Rawalpindi and comprised community dwelling elderly individuals. Subjects having no major co-morbid conditions were recruited via non-probability purposive sampling. Subjects were randomly divided in two equal groups. The intervention group received 8-week training on Biodex balance system and the control group received no intervention. Data was collected using Biodex fall risk score, Berg balance scale and Timed Up and Go Test before and after the treatment. Data was analysed using SPSS 20. RESULTS: There were 18 subjects in two groups of 9(50%) each. Analysis within the groups showed significant improvement in the intervention group (p<0.001) while no significant improvement (p>0.05) was observed in the control group. Post-intervention the result remained unchanged while comparing the two groups (p<0.05). CONCLUSIONS: Dynamic postural training using static and dynamic Biodex balance system had a positive effect on mobility and balance in the elderly. PMID- 30410146 TI - Raftlin, presepsin levels and thiol-disulphide homeostasis in acute appendicitis: A pilot study. AB - OBJECTIVE: To investigate some of the new inflammatory and oxidative stress markers in acute appendicitis. METHODS: This clinical pilot study was conducted at the emergency department of Bezmialem Vakif University, Istanbul, Turkey, between January and July 2015, and comprised patients with definitive diagnosis of acute appendicitis and as many healthy controls. Venous blood was collected to assess white blood cell count, C-reactive protein, raftlin, presepsin, total thiol, native thiol and disulphide levels. Alvarado scores of patients were determined at the time of admission. Surgical excisions were sent for pathological examination. The results of histopathology of appendectomy specimens were categorised as non-perforated or perforated appendicitis. RESULTS: There were130 subjects with 65(50%) patients and 65(50%) controls. Serum raftlin, presepsin, white blood count, C-reactive protein and disulphide levels were higher, and the total and native thiol levels were significantly lower in patients compared to controls (p<0.05). There was no significant difference between the non-perforated and perforated appendicitis patients regarding all the measured parameters (p>0.05) except mean Alvarado scores which were higher in perforated than non-perforated appendicitis (p<0.05). CONCLUSIONS: Inflammatory and oxidative stress markers were significantly different in acute appendicitis patients compared to healthy controls. PMID- 30410147 TI - TB case notification by private health-sector; retrospective study in 13 metro districts of Pakistan. AB - OBJECTIVE: To evaluate the impact of structured engagement of private providers in tuberculosis case notification and to investigate demographic profile, disease pattern and treatment outcome of tuberculosis patients seeking care from private care providers. METHODS: This retrospective study was carried out in 13 districts of Pakistan with the data of tuberculosis patients registered and diagnosed from July 2015 to June 2016 at directly observed treatment, short-course trained private providers. These facilities in collaboration with Greenstar Social Marketing Pakistan, a private organisation and the National Tuberculosis Control Programme, Pakistan, provided free anti-tuberculosis drugs and sputum smear microscopy. Study variables included socio-demographic character, disease patterns and treatment outcomes of patients along with details of the registering facility. Data was analysed using SPSS 23. RESULTS: There were 1317 directly observed treatment, short-course trained private health facilities and 123 private laboratories. Of the health facilities, 880(67%) reported 13769 tuberculosis patients. Of them, 7388(53.65%) were females and 6381(46.34%) were males. Overall, 10232(74.31%) were diagnosed with pulmonary tuberculosis and 3537(25.68%) were extra pulmonary tuberculosis patients. Among the pulmonary patients, 4195(41%) were diagnosed through sputum smear microscopy as bacteriologically confirmed (B+ve), while the remaining 6037(59%) were diagnosed through X-ray or other tests. Out of all the diagnosed patients 13218(96%) were treated successfully.. CONCLUSIONS: Private healthcare sector has great potential of supporting tuberculosis control. Gender and age had critical implications in service utilisation. PMID- 30410148 TI - Findings from Healthcare in Danger Project: Pakistan security assessment of a public and private tertiary care hospital in Karachi: Gaps and way forward. AB - OBJECTIVE: To identify and compare security gaps in a public and private tertiary care hospital. METHODS: The study was conducted in January 2016 using a tool adopted from Ingersoll Rand Security Technologies, Occupational Safety and Health Association and findings of baseline research carried out by Health Care in Danger Project at a public and private sector hospital in Karachi. The names of hospitals were kept confidential. Areas assessed included adequacy of workforce, existing institutional mechanisms and campus security. The tool was completed by interviewing administration, security department, and healthcare workers in wards and the emergency departments as well as patients, attendants and through observation visits. RESULTS: The burden of doctors at the private-sector hospital was higher compared to the publicsector hospital (40 versus 22 patients per doctor per day) in the outpatient department. Privatesector hospital scored better than public-sector hospital with regards to compliance to security management standards (68% versus 50%), security perception of staff (90% versus 50%), security staffing (60% versus 50%), and visitor management (80% versus 40%). Campus security was better at private-sector hospital (56% versus 31%). Scores for employee orientation and training were low (30% and 20%), while scores for organisational partnerships were high in both hospitals (80% each). . CONCLUSIONS: Four-pronged strategic framework is recommended that shall comprise restricting access of attendants/visitors/vendors, improving interaction between patients/healthcare workers/guards, mechanisms of reporting and responding to violent events, and maintaining sufficient resources for enhancing and improving security in hospitals. PMID- 30410149 TI - Age and stage of breast cancer in Pakistan: An experience at a tertiary care center. AB - OBJECTIVE: To determine the age and stage of breast cancer in a tertiary care center in Karachi, Pakistan. METHODS: This retrospective, descriptive study was conducted at Breast Unit, Department of Surgery, Liaquat National Hospital Karachi, Pakistan. From 1994 to 2016 all biopsy-proven breast cancer patients were reviewed and their age and stage at presentation were noted . RESULTS: In the given time period 10, 018 patients with Breast cancer were registered. The most frequent age at diagnosis was in the fourth decade of life (28.51%). The majority of patients were diagnosed in stage 2 (47.26%) and only less than 4% were detected in stage 1. The stage of presentation did not differ between young and older age group of women. CONCLUSIONS: Breast cancer is diagnosed at a younger age group in Pakistan, at least a decade earlier than the west and at an advanced stage, commonest being stage 2. PMID- 30410150 TI - Non-pharmacological interventions to combat exercise-induced muscle damage, a little natural tax on work out. AB - Debilitating pain, stiffness, tenderness, fatigue, impaired muscle function, lack of strength subsequent to exercise are not welcomed by those not accustomed to it. It may discourage an individual from participating in regular exercise. Numerou s ph armacological and non - pharmacological strategies have been used to alleviate symptoms of muscle soreness, muscle pain, improving muscle function, the range of motion and recovery time. Non-steroidal anti-inflammatory drugs are suggested to have a beneficial impact on muscle soreness, but fail to rejuvenate muscle weakness and range of motion coupled with muscle soreness. Furthermore, oral antiinflammatory drugs are widely used to mitigate muscle soreness symptoms, but chronic use can lead to different side effects in terms of peptic ulcer and liver toxicity. Non-pharmacological remedies and interventions can be a better choice. This narrative review is intended to provide insight into the non pharmacological strategies to combat exercise-induced muscle damage. PMID- 30410151 TI - Predatory conferences: Addressing researchers from developing countries. AB - Publishing a manuscript or presenting at a conference are considered valuable accomplishments in one's professional career. However, it is necessary that the outlet be a legitimate rather than a fraudulent or predatory one. Predatory journals have been explored previously to a greater extent but the conference version of predatory entities is the newest iteration. To date, very few studies have endeavored to address the nuisance of predatory conferences and to explain the full magnitude of their significance. Our study addresses the issue of predatory conferences as an educational article for the readership of the Journal of Pakistan Medical Association, and highlights their features, available literature on predatory conferences, and puts forward several new suggestions to avoid falling prey to these illegal entities. PMID- 30410152 TI - Expectations, requirements, and problems of family health care workers providing home services in Turkey. AB - Life expectancy is increasing globally with the increase of aging populations. Care-dependent elderly and those with chronic illnesses and disabilities are increasing in numbers. Hospitalization to manage these problems lead to a heavy economic burden. Thus, the demand for home health care is rising causing a heavy workload for home workers. This study was aimed to assess problems of personnel engaged in providing home care. Data was colllected from 120 family physicians and nurses/midwives from 25 clinics. The results showed that most visits were provided for postnatal controls (69%), with only 13% provided for the elderly and disabled people despite high demands (for the elderly 73%; for those with disabilities 66%). Additionally, factors affecting workers emotionally in visits were evaluated. Difficulties and suggestions of home care workers should be considered that the quality of health care depends on the satisfaction of the care professionals as well as that of patients. PMID- 30410153 TI - Spectrum, management and outcomes of structural and functional uropathies in children attending a tertiary care center in Karachi; Pakistan. AB - Causes and outcomes of children diagnosed with hydronephrosis in resource-limited countries with a low utilization of antenatal ultrasonography remain unexplored. We performed a retrospective, crosssectional study of all paediatric patients diagnosed with hydronephrosis and managed at a tertiary care center in Karachi, Pakistan between 2005 and 2010. Data relating to demographics, clinical features, etiologies and treatment modalities were systematically collected. Of a total of 234 cases (74.4% male), 83 (35.5%) and 42 (17.9%) were neonates and infants respectively. Congenital urinary tract pathologies were noted in 192(72.2%) patients, of which only 96(50%) had undergone foetal ultrasonography and 77(40.1%) first presented after the age of 1 year. At a median follow-up of 4 years, 24(12.5%) of these patients had evidence of renal dysfunction. Worse urologic outcomes in this study were most likely attributable to delayed diagnosis of congenital urinary tract abnormalities. PMID- 30410154 TI - Prevalence, antibiotic sensitivity and phenotypic screening of ESBL/MBL producer E. coli strains isolated from urine; District Swabi, KP, Pakistan. AB - The study aimed to record the prevalence of Urinary Tract Infection caused by E. coli, its antibiotic sensitivity and phenotypic detection of ESBL and MBL producer E. coli. Total of 240 urine samples were collected from Bacha Khan medical complex, Swabi. Antibiotic sensitivity and production of ESBL and MBL according to CLSI guidelines 2017 were performed. Out of 75 E. coli strains, only 25 (33.3%) isolates were positive for ESBL. Similarly, 25 were resistant to Imipenem, in which 12 (16%) isolates were positive for MBL production. E. coli isolates were found more sensitive to Amikacin 57 (76%) followed by Imipenem 50 (66.67%), Ofloxacin 48 (64%), Ciprofloxacin 44 (58.67%), Norfloxacin 42 (56%) and were 100% resistant to Penicillin, Ceftriaxone, Ceftazidime and Cefotaxime. The current study recorded the prevalence rate of UTI caused by E. coli was 75( 66.96%) and ccurrence rate of ESBL and MBL producers in the total (n=75) E. coli isolates was 25( 33.3%) and 12(48%) respectively. PMID- 30410155 TI - Primary Synovial Sarcoma of the Mediastinum in an 18-year old male: A case report. AB - The study aimed to record the prevalence of Urinary Tract Infection caused by E. coli, its antibiotic sensitivity and phenotypic detection of ESBL and MBL producer E. coli. Total of 240 urine samples were collected from Bacha Khan medical complex, Swabi. Antibiotic sensitivity and production of ESBL and MBL according to CLSI guidelines 2017 were performed. Out of 75 E. coli strains, only 25 (33.3%) isolates were positive for ESBL. Similarly, 25 were resistant to Imipenem, in which 12 (16%) isolates were positive for MBL production. E. coli isolates were found more sensitive to Amikacin 57 (76%) followed by Imipenem 50 (66.67%), Ofloxacin 48 (64%), Ciprofloxacin 44 (58.67%), Norfloxacin 42 (56%) and were 100% resistant to Penicillin, Ceftriaxone, Ceftazidime and Cefotaxime. The current study recorded the prevalence rate of UTI caused by E. coli was 75( 66.96%) and ccurrence rate of ESBL and MBL producers in the total (n=75) E. coli isolates was 25( 33.3%) and 12(48%) respectively. PMID- 30410156 TI - Tracheal injury: late symptom after double-lumen tube intubation - A case report. AB - As a basic skill, endotracheal intubation, performed throughout the world by health care professionals is a relatively safe and effective maneuver. However, this technique is not risk free and could lead to many serious complications. We wanted to report that in a patient with double lumen tube intubation, airway trauma can cause late symptoms . We thought that such complications must be published to share experiences. PMID- 30410157 TI - Community acquired Sphingomonas paucimobilis in a child - A rare case. AB - Sphingomonas paucimobilis is a rare organism that usually infects immunocompromised patients and is known to cause nosocomial infections from mild to severe pathogenicity. Recently a few community acquired infections have been identified in relatively healthy adult patients with diabetes and alcoholics. We report a case of a 10 years old previously healthy child who presented with fever for a month and was found to have a positive blood cu lt ure for Sphi ngomon as pauc imobil is. PMID- 30410158 TI - Transmigration of an intrauterine device into sigmoid colon-surgical management: A case report. AB - We present the case of a 30 years old woman who had an Interauterine Device placed in a fragile uterus (puerperal period) 5 years ago and presented with dull abdominal pain and disturbed bowel habits. Failure to pull out IUD strings on gynecological examination made us suspicious of translocated IUD and its ectopic placement in sigmoid colon was confirmed on colonoscopy and a CT abdomen with contrast. The transmigrated IUD was removed following laparotomy. PMID- 30410159 TI - Extrapyramidal symptoms resulting from risperidone use in a four year old child: A case report. AB - Extrapyramidal symptoms (EPS) are the major constraint in the use of antipsychotic agents. It is usually forewarned whenever therapy with these agents is considered. In this case, we present a child diagnosed with relapsed Wilm's tumour, who developed EPS just after a short duration of initiation of risperidone prescribed as an appetite stimulant. The patient became symptom free after management and risperidone was discontinued. Although risperidone has been approved to treat different indications in adolescents and children, scarce scientific evidence and our case report, are suggestive of further studies to establish safety of risperidone use in preschool children. PMID- 30410161 TI - The DA Vinci Diet. AB - Ample evidence implicating diet as the root cause of diseases exists in the scientific arena. It is always intruiging to know the diet pattern of our ancestors. Leonardo da Vinci was a 'universal genius' with universal appeal. This article describes the basic principles of the diet that he followed. "Dining discipline" and moderation in eating should be coupled with the aim of savouring smell, taste, and texture of food. Fresh, fibre rich, vegetarian food forms the bulk of the da Vinci diet. Saturated fat, salt and sugar use is minimal, but water and water-rich food intake is encouraged. PMID- 30410160 TI - Two neonates with Bartter syndrome. AB - Bartter syndrome is an autosomal recessive disorder caused by gene mutations that involve hypokalaemia, hypochloraemia and metabolic alkalosis along with raised serum renin, hyperaldosteronism and normal blood pressure. We report two cases of neonatal Bartter syndrome. Case 1 was a product of non-consanguineous marriage and mother had unexplained polyhydramnios in pregnancy while case 2 was a product of consanguineous marriage. Both cases were diagnosed based on hypokalaemia, hypochloraemia and metabolic alkalosis along with elevated serum renin and aldosterone levels. Case 1 positively responded to indomethacin while case 2 had Protein C and S deficiency and sepsis as coexisting diseases and thus could not be given indomethacin and expired. Regular antenatal visits can help in diagnosis of the syndrome particularly if unexplained poly hydramniosis investigated . PMID- 30410162 TI - Seven Sinful Sisters: Seven Smart Solutions to Stop Diabetes. AB - This article describes a Seven Sinful Sisters and Smart Solutions (FIVE S) concept, which lists seven contributory factors of diabetes, and seven potential solutions to help prevent its spread. The Seven Sinful Sisters include Sugar, Salt, Saturated fat, Spirits (alcohol), Sitting time (sedentary life style), Steroids (including other drugs) and Stress. Seven Smart salutogenic Solutions are use of Self-restraint, Small size portions, Spices (nutrition -based remedies, including sugar and salt substitutes), Slimnastics (a synonym for aerobic exercise), high Spirit (a positive attitude), health Sleep/Siesta, and enjoyment of Sunday (or Stress management). PMID- 30410163 TI - Tumour Treating Fields (TTFs) for Paediatric Brain Tumours, Brain Metastases and other Novel Applications. AB - Tumour treating fields (TTFs) are now FDA approved for high grade glioma treatment. Novel application of this treatment modality is being assessed for paediatric brain tumours and intracranial metastatic disease. Clinical trials are being conducted to test the efficacy of this treatment modality as adjuvant therapy to current standard of care. Here we will discuss the existing literature on TTF its role in pathologies other than GBM. In addition, aspects of safety, compliance and cost are also discussed. PMID- 30410164 TI - Extracranial and Intracranial Stenting and Angioplasty. PMID- 30410165 TI - Internal jugular phlebectasia in an adult - rare cause of neck swelling. PMID- 30410166 TI - Comments on Umer Draz et al. (J Pak Med Assoc. 2018; 68: 939-41) Presence of pre diabetes in Helicobacter pylori positive versus Helicobacter pylori negative patients having dyspepsia. AB - We have read with great interest the article by Draz et al, reporting the prevalence of Helicobacter pylori (H. pylori) infection, in patients with dyspepsia and pre-diabetic status. The authors found that 58.5% of patients with H. pylori infection versus 45.9% (p=0.03) of patients without H. pylori had pre diabetes. The method used to diagnose H. pylori infection was the histology based on bioptic samples taken in antrum during gastroscopy.1 This latter point raises a crucial criticism. When a patient needs a gastroscopy, due to alarming symptoms or older age (generally >45 years, but age should be determined locally according to gastric cancer risk), H. pylori infection can be detected on biopsies taken in the stomach from two topographical locations, the antrum and the corpus. Since the inherent risk of any biopsy procedure is sampling error, to biopsy both gastric compartments (two biopsies from the antrum and two from the corpus) increases the test's sensitivity, especially if the patient was recently treated with a proton pump inhibitor drug.2 When gastroscopy is not mandatory, C-urea breath test (UBT) is the most accurate tool to detect H. pylori infection and is more cost-effective than endoscopy. This method is based on the principle that, in the presence of H. pylori urease, labelled carbon dioxide is exhaled in the expired breath. In contrast to biopsy-based tests, UBT is not liable to sampling errors (it tests the entire stomach).2 Thus, although the findings of Draz et al agree with a large series of studies,3 the accuracy of their findings could be increased avoiding the risk of false-negative results due to the limited area of stomach investigated for H. pylori infection. PMID- 30410167 TI - Response to comments on Umer Draz et al. (J Pak Med Assoc. 2018; 68: 939-41) Presence of pre-diabetes in Helicobacter pylori positive versus Helicobacter pylori negative patients having dyspepsia. PMID- 30410168 TI - Association of Vaspin levels and its SNP rs2236242 with Gestational Diabetes at a tertiary care setting : RESEARCH ARTICLE. AB - OBJECTIVE: To evaluate and correlate vaspin levels and genotype frequency in gestational diabetes mellitus. METHODS: The case-control study was conducted at Aga Khan University, Karachi, from November 2015 to December 2016, and comprised pregnant women in their second trimester with gestational diabetes mellitus. Healthy pregnant women with similar characteristics were enrolled as the control group. Tetra arms amplification system for vaspin gene was performed. SPSS 21 was used for data analysis. RESULTS: Of the 112 pregnant women, 67(60%) were normo glycaemic and 45(40%) had gestational diabetes. Those with gestational diabetes had a higher body mass index (p=0.047) and fasting blood glucose levels (p<0.01). Serum vaspin concentrations were significantly lower in the healthy group compared to the diabetics (p=0.041). Genotype and allele frequencies followed Hardy Weinberg's Equilibrium but no significant differences were observed in genotype distribution between the groups (p>0.05).. CONCLUSIONS: Higher serum vaspin levels were seen in gestational diabetic females, but genotype and allele frequencies showed no association of vaspin with gestational diabetes mellitus. PMID- 30410170 TI - Our unsung heroes. PMID- 30410169 TI - The Typhoid epidemic: Where are we heading? PMID- 30410171 TI - Veterinary Medical Ethics. PMID- 30410172 TI - Visual inspection of stored canine blood for hemolysis compared with measured plasma-free hemoglobin to assess suitability for transfusion. AB - Canine blood was visually inspected for hemolysis and compared with the Food and Drug Administration's standard of less than 1% hemolysis as measured by plasma free hemoglobin. This was the basis for deciding to transfuse or dispose of stored canine blood. Free hemoglobin was measured in stored red blood cell units and compared to a calculated 1% hemolysis. Veterinarians and technicians determined if they would transfuse units based on visual inspection for hemolysis. Their evaluation was compared to the calculated hemolysis cutoff. The evaluations of veterinarians and technicians were significantly different from the mathematically derived cutoff. The technicians' visual assessments of the usability of samples were significantly different from those of the veterinarians: technicians more frequently judged the sample as unusable. Experienced veterinary personnel both over- and under-estimate the degree of hemolysis in stored canine RBCs. We recommend objective analysis of the amount of free hemoglobin in stored blood prior to transfusion. PMID- 30410173 TI - Vasopressor use in 41 critically ill cats (2007-2016). AB - This study describes the use of vasopressors in critically ill cats. Records of 41 cats hospitalized in the ICU were evaluated. Signalment, blood pressure, underlying conditions, evidence of sepsis, type of treatment (surgical versus non surgical), vasopressor type and duration, adverse events attributed to vasopressors, and survival were recorded. Twenty-one cats (51%) had an underlying disease considered amenable to surgical treatment while 20 (49%) cats did not. Evidence of sepsis was present in 24 (59%) cats. Thirty-four cats developed a Doppler blood pressure (DBP) > 80 mmHg during therapy, and 29 cats became normotensive (DBP > 90 mmHg). Seven cats did not increase their DBP to > 80 mmHg. All cats received dopamine and/or norepinephrine and 6 cats also received other vasopressors. Sixteen cats survived (39%). Surgical intervention was associated with a higher survival (P = 0.004). Critically ill hypotensive cats may benefit from administration of vasopressors. PMID- 30410174 TI - Many Canadian dog and cat foods fail to comply with the guaranteed analyses reported on packages. AB - We compared analyzed nutrient contents of Canadian-specific dry dog and cat foods to the guaranteed analyses on packages and to the Association of American Feed Control Officials (AAFCO) 2018 nutrient targets to assess compliance with the Consumer Packaging and Labelling Act. We also explored differences in macronutrient content between species (dog and cat) and life stage for adult pet foods (all life stages and senior). Extruded dog (n = 16) or cat (n = 11) foods advertised as all life stage or senior, sold only in Canada, and carrying an AAFCO nutritional adequacy statement were selected. Proximate analyses and amino acid analyses were completed on all diets. Of the 27 foods, 25 met or exceeded the AAFCO nutrient recommendations. Only 9 foods met all nutrient content claims listed in their guaranteed analyses. Nutrient content between species or life stages was not different (P > 0.10). PMID- 30410175 TI - Sartorius muscle flap for body wall reconstruction: Surgical technique description and retrospective case series. AB - The objectives of this study were to describe the sartorius muscle flap for body wall reconstruction, including description of the anatomy and surgical technique and to report its clinical application for abdominal wall reconstruction in dogs and cats. The descriptive report involves a retrospective case series for 2 dogs and 3 cats. Inclusion criteria were cats or dogs that had a tumor resection resulting in an abdominal wall defect that was reconstructed using an ipsilateral or contralateral sartorius muscle flap. Signalment, pre-operative clinical signs, location and tumor extent, diagnostic imaging and clinical pathology findings, surgical methods, and complications were recorded. Abdominal wall defect reconstructions using the sartorius muscle flap were successfully performed in all 5 patients with good return to function. All complications were minor and were successfully medically managed. This case series demonstrates that the sartorius muscle flap is a feasible option for the closure of large caudal abdominal wall defects. PMID- 30410177 TI - Correction. AB - [This corrects the article on p. 719 in vol. 59, PMID: 30026618.]. PMID- 30410176 TI - Antimicrobial resistance of bovine Salmonella enterica ssp. enterica isolates from the Alberta Agriculture and Forestry Disease Investigation Program (2006 2014). AB - The objectives of this study were to describe the antimicrobial susceptibility and serotypes of clinical Salmonella spp. isolates from Alberta cattle, to inform antimicrobial stewardship decisions for Alberta bovine veterinarians and to provide data for national surveillance. Isolates were collected from cattle and serotyped by Alberta Agriculture and Forestry from 2006 to 2014. Susceptibility testing was completed using Canadian surveillance breakpoints. There were 81 unique Salmonella isolates from 72 visits to 27 farms. The majority of isolates were S. Typhimurium (66.7%) and S. Dublin (19.8%). The prevalence of multidrug resistance was high in S. Typhimurium (89.1%) and S. Dublin (93.8%), including ceftiofur resistance (43.6% and 68.8%, respectively), while there was no resistance in other serotypes. As ceftiofur is a recommended treatment option for enteritis and septicemia caused by Salmonella in cattle, these results reinforce that obtaining bacterial culture and susceptibility results is critical for suspected cases of bovine salmonellosis in Alberta. PMID- 30410178 TI - A longitudinal investigation of an outbreak of toe tip necrosis syndrome in western Canadian feedlot cattle. AB - This investigation followed a cohort (n = 21) of single-sourced Angus cross yearling heifers diagnosed with toe tip necrosis syndrome (TTNS). The animals were intensively followed for ~7 months, over which time 5 animals were euthanized because of intractable lameness or life-threatening sequelae such as cellulitis and myositis. Treatment consisted of systemic antimicrobial and nonsteroidal anti-inflammatory therapy, removing the necrotic horn tissue to facilitate drainage, and relocating the cattle to an earthen-floor pen. Sixteen of the 21 heifers recovered uneventfully. Upon sectioning the feet after slaughter, all the foot lesions had healed, but in some instances, the 3rd phalangeal bone had undergone bone remodeling, indicative of an earlier pathological process. This study is unique in that it chronicled the clinical and pathological outcomes associated with TTNS over an extended period. PMID- 30410179 TI - Piecemeal endoscopic polypoidectomy for the management of a canine pharyngeal hemangiosarcoma. AB - A 7-year-old castrated male Maltese dog was presented for increased respiratory sounds, inability to bark, dysphagia, and hyporexia. Radiographs revealed an ovoid, opaque mass in the caudal nasopharynx. An airway examination and computed tomography scan were followed by endoscopic polypoidectomy. The mass was a hemangiosarcoma, and the patient survived > 13 months. PMID- 30410182 TI - Companion animal practices versus mixed and large: A 10-year comparison. PMID- 30410180 TI - Successful control of disseminated follicular cysts in a dog with low dose isotretinoin. AB - A case of disseminated cysts in a dog is described. Histopathological examination revealed the presence of follicular infundibular cysts, which were treated with isotretinoin at a dose of 2 mg/kg body weight (BW), q24h for 1 week, followed by a dose of 1 mg/kg BW for 3 months. Symptoms resolved after this course of treatment. PMID- 30410181 TI - Propofol infusion-like syndrome in a dog. AB - An 8-year-old, spayed female Chihuahua mixed breed dog was presented for dyspnea and was subsequently mechanically ventilated. Propofol was utilized as part of the anesthetic protocol. The dog developed rhabdomyolysis, myoglobinuria, cardiac arrhythmias, liver enzyme elevation, and methemoglobinemia. Propofol was discontinued and N-acetylcysteine was administered after which the clinical signs resolved. PMID- 30410183 TI - Diagnostic Ophthalmology. PMID- 30410184 TI - Stay positive and set boundaries. PMID- 30410185 TI - Pseudomonas otitis externa in dogs. PMID- 30410186 TI - Gender Differences in the Benefits of an Influential Early Childhood Program. AB - This paper studies the life-cycle impacts of a widely-emulated high-quality, intensive early childhood program with long-term follow up. The program starts early in life (at 8 weeks of age) and is evaluated by an RCT. There are multiple treatment effects which we summarize through interpretable aggregates. Girls have a greater number of statistically significant treatment effects than boys and effect sizes for them are generally bigger. The source of this difference is worse home environments for girls with greater scope for improvement by the program. Fathers of sons support their families more than fathers of daughters. PMID- 30410187 TI - Growth mechanisms of multiscale, mound-like surface structures on titanium by femtosecond laser processing. AB - Femtosecond laser surface processing (FLSP) can be used to functionalize many surfaces, imparting specialized properties such as increased broadband optical absorption or super-hydrophobicity/-hydrophilicity. In this study, the subsurface microstructure of a series of mound-like FLSP structures formed on commercially pure titanium using five combinations of laser fluence and cumulative pulse counts was studied. Using a dual beam Scanning Electron Microscope with a Focused Ion Beam, the subsurface microstructure for each FLSP structure type was revealed by cross-sectioning. The microstructure of the mounds formed using the lowest fluence value consists of the original Ti grains. This is evidence that preferential laser ablation is the primary formation mechanism. However, the underlying microstructure of mounds produced using higher fluence values was composed of a distinct smaller-grained alpha-Ti region adjacent to the original larger Ti grains remaining deeper beneath the surface. This layer was attributed to resolidification of molten Ti from the hydrodynamic Marangoni effect driven fluid flow of molten Ti, which is the result of the femtosecond pulse interaction with the material. PMID- 30410188 TI - Velocity and acceleration statistics in rapidly rotating Rayleigh-Benard convection. AB - Background rotation causes different flow structures and heat transfer efficiencies in Rayleigh-Benard convection (RBC). Three main regimes are known: rotation-unaffected, rotation-affected and rotation-dominated. It has been shown that the transition between rotation-unaffected and rotation-affected regimes is driven by the boundary layers. However, the physics behind the transition between rotation-affected and rotation-dominated regimes are still unresolved. In this study, we employ the experimentally obtained Lagrangian velocity and acceleration statistics of neutrally buoyant immersed particles to study the rotation-affected and rotation-dominated regimes and the transition between them. We have found that the transition to the rotation-dominated regime coincides with three phenomena; suppressed vertical motions, strong penetration of vortical plumes deep into the bulk and reduced interaction of vortical plumes with their surroundings. The first two phenomena are used as confirmations for the available hypotheses on the transition to the rotation-dominated regime while the last phenomenon is a new argument to describe the regime transition. These findings allow us to better understand the rotation-dominated regime and the transition to this regime. PMID- 30410190 TI - Maternal Employment, Community Contexts, and the Child-Care Arrangements of Diverse Groups. AB - Integrating family and child data from the Early Childhood Longitudinal Study Birth Cohort with contextual data from the Census, this study examined associations among maternal employment, aspects of communities related to child care supply and demand, and the early care and education arrangements of 4-year olds in Mexican-origin, black, and white families. Children with employed mothers were more likely to be in informal care arrangements than in early childhood education, regardless of racial/ethnic background. For children in Mexican-origin families, selection into informal care over early childhood education was more likely in zip codes with greater demand for care as measured by higher female employment. Utilization of parent care versus early childhood education was also more likely for children in Mexican-origin and black families in zip codes with higher female employment. Constraints associated with maternal employment thus hindered children from enrolling in early childhood education, and community contexts posed challenges for some groups. PMID- 30410189 TI - Recent applications of a single quadrupole mass spectrometer in 11C, 18F and radiometal chemistry. AB - Mass spectrometry (MS) has longstanding applications in radiochemistry laboratories, stemming from carbon-dating. However, research on the development of radiotracers for molecular imaging with either positron emission tomography (PET) or single photon emission computed tomography has yet to take full advantage of MS. This inertia has been attributed to the relatively low concentrations of radiopharmaceutical formulations and lack of access to the required MS equipment due to the high costs for purchase and maintenance of specialized MS systems. To date, single quadrupole (SQ)-MS coupled to liquid chromatography (LC) systems is the main form of MS that has been used in radiochemistry laboratories. These LC/MS systems are primarily used for assessing the chemical purity of radiolabeling precursor or standard molecules but also have applications in the determination of metabolites. Herein, we highlight personal experiences using a compact SQ-MS in our PET radiochemistry laboratories, to monitor the small amounts of carrier observed in most radiotracer preparations, even at high molar activities. The use of a SQ-MS in the observation of the low mass associated with non-radioactive species which are formed along with the radiotracer from the trace amounts of carrier found is demonstrated. Herein, we describe a pre-concentration system to detect dilute radiopharmaceutical formulations and metabolite analyses by SQ-MS. Selected examples where SQ-MS was critical for optimization of radiochemical reactions and for unequivocal characterization of radiotracers are showcased. We also illustrate examples where SQ-MS can be applied in identification of radiometal complexes and development of a new purification methodology for Pd-catalyzed radiofluorination reactions, shedding light on the identity of metal complexes present in the labelling solution. PMID- 30410192 TI - Forgotten, but not forgiven: facing immunization challenges in the 21 st century. PMID- 30410191 TI - Direct AFM Visualization of the Nanoscale Dynamics of Biomolecular Complexes. AB - High-speed AFM (HS-AFM) is an advanced technique with numerous applications in biology, particularly in molecular biophysics. Developed as a time-lapse AFM technique for direct imaging fully hydrated biological molecules, HS-AFM is currently capable of visualizing the dynamics of biological molecules and their complexes at a video-data acquisition rate. Spatial resolution at the nanometer level is another important characteristic of HS-AFM. This review focuses on examples of primarily protein-DNA complexes to illustrate the high temporal and spatial resolution capabilities of HS-AFM that have resulted in novel models and/or the functional mechanisms of these biological systems. PMID- 30410193 TI - Concordance analysis between different methodologies used for identification of oral isolates of Candida species. AB - Background: The yeasts species determination is fundamental not only for an accurate diagnosis but also for establishing a suitable patient treatment. We performed a concordance study of five methodologies for the species identification of oral isolates of Candida in Colombia. Methods: Sixty-seven Candida isolates were tested by; API(r) 20C-AUX, Vitek(r)2 Compact, Vitek(r)MS, Microflex(r) and a molecular test (panfungal PCR and sequencing). The commercial cost and processing time of the samples was done by graphical analysis. Results: Panfungal PCR differentiated 12 species of Candida, Vitek(r)MS and Microflex(r) methods identified 9 species, and API(r) 20C-AUX and Vitek(r)2 Compact methods identified 8 species each. Weighted Kappa (wK) showed a high agreement between Panfungal PCR, Vitek(r)MS, Microflex(r) and API(r) 20C-AUX (wK 0.62-0.93). The wK that involved the Vitek(r)2 Compact method presented moderate or good concordances compared with the other methods (wK 0.56-0.73). Methodologies based on MALDI TOF MS required 4 minutes to generate results and the Microflex(r) method had the lowest selling price. Conclusion: The methods evaluated showed high concordance in their results, being higher for the molecular methods and the methodologies based on MALDI TOF. The latter are faster and cheaper, presenting as promising alternatives for the routine identification of yeast species of the genus Candida. PMID- 30410194 TI - Adaptation and validation for Colombia of the WHO safe childbirth checklist. AB - Introduction: Most maternal that deaths occur in developing countries are considered unfair and can be avoided. In 2008, The WHO proposed a checklist for delivery care, in order to assess whether a simple, low-cost intervention had an impact on maternal and neonatal mortality in low-income countries. Aim: To translate, adapt and validate the content of the WHO Safe Childbirth Checklist (SCC) for its use in Colombia. Methods: The translation of the list was carried out, adaptation was made to our context and validation of content through a panel of experts composed of 17 health workers with experience in maternal and neonatal care and safety. The reliability among the judges was calculated (Rwg) and according to the results, items were modified or added to each section of the list. Results: Modifications were made to the wording of 28 items, none was eliminated, and 19 new items were added. The most important modifications were made to the management guidelines that accompany each item and the items included refer to risks inherent to our environment. Conclusion: The Colombian version of the SCC will be a useful tool to improve maternal and neonatal care and thereby will contribute to reducing maternal and neonatal morbidity and mortality in our country. PMID- 30410195 TI - Analysis of lifestyle and bone mineralization in a population of Spanish young adults. AB - Objective: To analyze the environmental factors (nutritional status, levels of physical activity and nutritional habits) and their possible association with bone mass in a population of young adults. Methods: The study population consisted of 200 subjects (117 women and 83 men) aged between 18 and 25 years (mean age 20.4 years +/-2.2 years). Body composition parameters were measured by an electronic balance (TANITA BC-418MA), nutritional habits were estimated by 72 h dietary recall, level of physical activity was assessed by the International Physical Activity Questionnaire (IPAQ) and bone mass was measured by ultrasonography at the calcaneus. Results: There were significant differences in bone mass values according to gender (p= 0.013). Despite the fact that 70% of the subjects had a body mass index (BMI) within the normal range, 20% had overweight or obesity. 49% of the individuals had a moderate level of physical activity, although women had lower levels of physical activity than men (17.9% vs 8.4%). Most diets among young adults were hyperprotic, hyperlipidic and low carbohydrates, with low-calcium and fiber intakes and high-phosphorus. Analysis of bone mass according to BMI showed higher values as the weight category rises, with significant differences in women. Higher values of bone mass were shown as the level of physical activity was higher, showing significant differences in males. Conclusion: Our results show that BMI and level of physical activity are significantly associated with bone health in a population of young adults, suggesting the relevance of promoting healthy lifestyles as a strategy for the early prevention of osteoporosis. PMID- 30410196 TI - 22q11.2 deletion detected by in situ hybridization in Mexican patients with velocardiofacial syndrome-like features. AB - Introduction: Deletion 22q11.2 occurs in 1:4,000-1:6,000 live births while 10p13p14 deletion is found in 1:200,000 newborns. Both deletions have similar clinical features such as congenital heart disease and immunological anomalies. Objective: We looked for a 22q11.2 deletion in Mexican patients with craniofacial dysmorphisms suggestive of DiGeorge or velocardiofacial syndromes and at least one major phenotypic feature (cardiac anomaly, immune deficiency, palatal defects or development delay). Methods: A prospective study of 39 patients recruited in 2012-2015 at the Instituto Mexicano del Seguro Social at Guadalajara, Mexico. The patients with velocardiofacial syndrome-like features or a confirmed tetralogy of Fallot (TOF) or complex cardiopathy were studied by G-banding and fluorescence in situ hybridization (FISH) with a dual TUPLE1(HIRA)/ARSA or TUPLE1(22q11)/22q13(SHANK3) probe, six patients without the 22q11.2 deletion (arbitrarily selected) were tested with the dual DiGeorge II (10p14)/D10Z1 probe. Results: Twenty-two patients (7 males and 15 females) had the 22q11.2 deletion and 17/39 did not have it; no patient had a 10p loss. Among the 22 deleted patients, 19 had congenital heart disease (mostly TOF). Twelve patients without deletion had heart defects such as TOF (4/12), isolate ventricular septal defect (2/12) or other disorders (6/12). Conclusion: In our small sample about ~56% of the patients, regardless of the clinical diagnosis, had the expected 22q11.2 deletion. We remark the importance of early cytogenetic diagnosis in order to achieve a proper integral management of the patients and their families. PMID- 30410198 TI - Born to donate: proposals for "savior sibling" regulation in Latin America. AB - A Savior Sibling is a child who is born to provide an organ, bone marrow or cell transplant, to a sibling that is affected with a fatal disease. There are created with the in vitro fertilization and pre-implantation genetic diagnosis and, in the process, the ethical standards for organ donation of children become less demanding. Therefore, we propose that the authorization of the technique considers, unavoidably, the opinion of an impartial third party that can guarantee the welfare of the child. We develop a critical analysis of the laws that regulate the creation of babies to serve as organ donors. We evaluate under what circumstances the organizations that play a part in the decisions, fulfill the ethical standards to allow the organ donation of children. PMID- 30410197 TI - Paraoxonase-1 polymorphisms and cerebral ischemic stroke: a pilot study in mexican patients. AB - Background: The serum paraoxonase-1 (PON1) associated to HDL presents two common polymorphisms in the positions 192 and 55. These polymorphisms are considered determinant of the capacity of HDL to protect LDL from their oxidative modification. In this context, the PON1 genotype has been associated with cardiovascular diseases, including stroke. Objective: To determine the allelic and genotypic frequencies of PON1 L55M and Q192R as well as the enzymatic activities of PON1 in subjects with and without atherothrombotic stroke. Methods: There were included 28 people with atherothrombotic stroke and 29 without stroke. The genotyping was carried out by PCR-RFLP and the phenotyping by measurement of the activities of paraoxonase and arylesterase in serum. Results: For the polymorphism Q192R, the allelic frequencies (Q/R) were 0.46/0.54 and 0.48/0.52 (p= 0.843) for the control group and the group with stroke, respectively. While for the polymorphism L55M, the allelic frequencies (L/M) were 0.81/0.19 for the control group, and 0.78/0.22 for the group with stroke (p= 0.610). The activity levels of paraoxonase were not significantly different between the control and stroke groups (450 vs. 348 UI/mL, p= 0.093) While the activity levels of arylesterase were significantly different between the studied groups (90 vs. 70 UI/mL, p= 0.001); however, upon adjustment by multiple linear regression, it was not longer significant. Conclusion: The polymorphisms Q192R and L55M, and the paraoxonase activity of PON1 are not risk factors for atherothrombotic stroke according to the results of this study. PMID- 30410199 TI - LRBA in the endomembrane system. AB - Bi-allelic mutations in LRBA (from Lipopolysaccharide-responsive and beige-like anchor protein) result in a primary immunodeficiency with clinical features ranging from hypogammaglobulinemia and lymphoproliferative syndrome to inflammatory bowel disease and heterogeneous autoimmune manifestations. LRBA deficiency has been shown to affect vesicular trafficking, autophagy and apoptosis, which may lead to alterations of several molecules and processes that play key roles for immunity. In this review, we will discuss the relationship of LRBA with the endovesicular system in the context of receptor trafficking, autophagy and apoptosis. Since these mechanisms of homeostasis are inherent to all living cells and not only limited to the immune system and also, because they are involved in physiological as well as pathological processes such as embryogenesis or tumoral transformation, we envisage advancing in the identification of potential pharmacological agents to manipulate these processes. PMID- 30410201 TI - The Cancer Observatory of Cali, a priority. PMID- 30410202 TI - Empirical likelihood ratio tests with power one. AB - In the 1970s, Professor Robbins and his coauthors extended the Vile and Wald inequality in order to derive the fundamental theoretical results regarding likelihood ratio based sequential tests with power one. The law of the iterated logarithm confirms an optimal property of the power one tests. In parallel with Robbins's decision-making procedures, we propose and examine sequential empirical likelihood ratio (ELR) tests with power one. In this setting, we develop the nonparametric one- and two-sided ELR tests. It turns out that the proposed sequential ELR tests significantly outperform the classical nonparametric t statistic-based counterparts in many scenarios based on different underlying data distributions. PMID- 30410200 TI - Prophylaxis with melatonin for primary stabbing headache in pediatrics: a case report. AB - Introduction: Primary stabbing headache (or "ice pick headache") is an alteration characterized by brief jabs (short stabs of pain, lasting ~3 seconds), which appear spontaneously, irregularly, and affecting unilaterally or bilaterally. Indomethacin has traditionally been used as the main therapeutic option. However, this drug is ineffective in a considerable percentage of patients and can generate multiple adverse effects that occur at therapeutic doses. Clinical case: A 7-year-old male patient with primary stabbing headache of mild to moderate intensity, lasting 3 to 4 seconds, without relevant history, with normal neurodevelopment, neurological examination and neuroimaging; no triggers were identified. It was started therapeutic trial with Coenzyme Q10; however, no improvement in the symptoms was identified. Treatment and outcomes: A therapeutic management was carried out with Melatonin, which led to complete remission of the symptoms; without adverse effects in the posterior follow-up months. Clinical and scientific relevance: There is little information regarding effective and safe treatments for primary stabbing headache in children. The present case identifies Melatonin as an innovative, effective and safe therapeutic alternative in the treatment of primary stabbing headache in children. This is a significant advance in the understanding of primary stabbing headache in the pediatric population. Conclusion: Melatonin may be an effective and safe therapeutic option for the treatment of primary stabbing headache in pediatric patients. It is necessary to deepen its research, in order to establish its use in a clinical practice guide. PMID- 30410203 TI - Micro/nanostructures formation by femtosecond laser surface processing on amorphous and polycrystalline Ni60Nb40. AB - Femtosecond laser surface processing is a technology that can be used to functionalize many surfaces, imparting specialized properties such as increased broadband optical absorption or superhydrophilicity/superhydrophobicity. In this study, two unique classes of surface structures, below surface growth (BSG) and above surface growth (ASG) mounds, were formed by femtosecond laser surface processing on amorphous and polycrystalline Ni60Nb40 with two different grain sizes. Cross sectional imaging of these mounds revealed thermal evidence of the unique formation processes for each class of surface structure. BSG mounds formed on all three substrates using the same laser parameters had similar surface morphology. The microstructures in the mounds were unaltered compared with the substrate before laser processing, suggesting their formation was dominated by preferential valley ablation. ASG mounds had similar morphology when formed on the polycrystalline Ni60Nb40 substrates with 100 nm and 2 [H9262]m grain size. However, the ASG mounds had significantly wider diameter and higher peak-to valley heights when the substrate was amorphous Ni60Nb40. Hydrodynamic melting was primarily responsible for ASG mound formation. On amorphous Ni60Nb40 substrates, the ASG mounds are most likely larger due to lower thermal diffusivity. There was clear difference in growth mechanism of femtosecond laser processed BSG and ASG mounds, and grain size does not appear to be a factor. PMID- 30410204 TI - Formation of aggregated nanoparticle spheres through femtosecond laser surface processing. AB - A detailed structural and chemical analysis of a class of self-organized surface structures, termed aggregated nanoparticle spheres (AN-spheres), created using femtosecond laser surface processing (FLSP) on silicon, silicon carbide, and aluminum is reported in this paper. AN-spheres are spherical microstructures that are 20-100 MUm in diameter and are composed entirely of nanoparticles produced during femtosecond laser ablation of material. AN-spheres have an onion-like layered morphology resulting from the build-up of nanoparticle layers over multiple passes of the laser beam. The material properties and chemical composition of the AN-spheres are presented in this paper based on scanning electron microscopy (SEM), focused ion beam (FIB) milling, transmission electron microscopy (TEM), and energy dispersive x-ray spectroscopy (EDX) analysis. There is a distinct difference in the density of nanoparticles between concentric rings of the onion-like morphology of the AN-sphere. Layers of high-density form when the laser sinters nanoparticles together and low-density layers form when nanoparticles redeposit while the laser ablates areas surrounding the AN-sphere. The dynamic nature of femtosecond laser ablation creates a variety of nanoparticles that make-up the AN-spheres including Si/C core-shell, nanoparticles that directly fragmented from the base material, nanoparticles with carbon shells that retarded oxidation, and amorphous, fully oxidized nanoparticles. PMID- 30410205 TI - Towards Closed-Loop Neuromodulation: A Wireless Miniaturized Neural Implant SoC. AB - This work reports a platform technology toward the development of closed-loop neuromodulation. A neural implant based on the SoC developed in our laboratory is used as an example to illustrate the necessary functionalities for the efficacious implantable system. We also present an example of using the system to investigate the epidural stimulation for partial motor function recovery after spinal cord injury in a rat model. This hardware-software co-design tool demonstrate its promising potential towards an effective closed-loop neuromodulation for various biomedical applications. PMID- 30410206 TI - Medicine shortages in Australia - what are we doing about them? PMID- 30410207 TI - Automated adverse drug reaction detection. PMID- 30410208 TI - Reducing medicine waste in aged care. PMID- 30410209 TI - Second steps in managing type 2 diabetes. AB - In type 2 diabetes diet exercise and attaining a healthy weight should be encouraged at every opportunity: Metformin is the usual first-line drug management: Sulfonylureas are appropriate as second-line drugs for many patients Other oral drugs are preferable if weight gain or hypoglycaemia are significant problems: If a combination of metformin and a sulfonylurea is not suitable either a dipeptidyl peptidase-4 inhibitor or sodium-glucose co-transporter 2 inhibitor can be prescribed The patient characteristics and the beneficial and adverse effects of the drug should be considered when selecting second-line therapy: Due to their adverse-effect profiles thiazolidinediones and acarbose should be reserved for patients with contraindications to all other oral drugs and those who will not tolerate injectable drugs: PMID- 30410210 TI - Treatment of irritable bowel syndrome. AB - Irritable bowel syndrome is a chronic functional gastrointestinal disorder that presents with abdominal pain related to defecation accompanied by a change in stool frequency or form Despite its impact on a patient's quality of life it has no effect on mortality: A positive clinical diagnosis should be made if the characteristic symptoms are present and red flags are absent Red flags should prompt specialist referral: Consultations should be provided in an empathetic manner addressing the concerns of the patient while providing reassurance: Manipulating diet with the assistance of a dietitian is an appropriate initial treatment for irritable bowel syndrome A low-FODMAP diet is an effective therapy: PMID- 30410211 TI - Drugs for benign prostatic hypertrophy. AB - Benign prostatic hyperplasia is a common condition It can cause problems with urine storage and voiding and the severity of symptoms may be unrelated to the size of the prostate: When drug treatment is required benign prostatic hyperplasia can be managed with monotherapy or combination therapy Most patients are managed with selective alpha blockers: Patients with larger prostate volumes may benefit from a 5-alpha-reductase inhibitor usually in combination with an alpha blocker: PMID- 30410212 TI - Medical management of metastatic prostate cancer. AB - Androgen deprivation therapy has an important role in the medical treatment of advanced and metastatic prostate cancer: The treatment of metastatic prostate cancer is influenced by whether the patient's disease has progressed on androgen deprivation therapy or not It is considered to be castrate-resistant disease if the cancer has progressed despite adequate suppression of androgens: Chemotherapy using docetaxel or cabazitaxel and anti-androgen drugs such as abiraterone and enzalutamide can be used to treat castrate-resistant disease Radium-223 is an option for patients with bony metastases: Metastatic castrate resistant prostate cancer is now considered a chronic illness as the life expectancy of patients has almost doubled due to the new treatments General practitioners are therefore more likely to encounter patients with disease- and treatment-related complications: PMID- 30410213 TI - Dry eye disease: when to treat and when to refer. AB - Dry eye disease affects one in five adults and can significantly impair quality of life Most patients have mild disease: This condition is multifactorial with an inflammatory component which can markedly worsen the impact on the ocular surface Meibomian gland dysfunction is extremely common in dry eye disease and contributes to the inflammatory process: Management of mild disease includes identifying and removing precipitants and symptomatic treatment with artificial tear supplements: More advanced disease requires management of underlying ophthalmic and systemic conditions as well as more aggressive therapies to protect the ocular surface: PMID- 30410214 TI - Benralizumab for asthma. PMID- 30410215 TI - Dulaglutide for type 2 diabetes. PMID- 30410216 TI - Glecaprevir/pibrentasvir for hepatitis C. PMID- 30410217 TI - Trifluridine/tipiracil for colorectal cancer. PMID- 30410218 TI - Ribociclib for breast cancer. PMID- 30410219 TI - Hybrid Attention based Multimodal Network for Spoken Language Classification. AB - We examine the utility of linguistic content and vocal characteristics for multimodal deep learning in human spoken language understanding. We present a deep multimodal network with both feature attention and modality attention to classify utterance-level speech data. The proposed hybrid attention architecture helps the system focus on learning informative representations for both modality specific feature extraction and model fusion. The experimental results show that our system achieves state-of-the-art or competitive results on three published multimodal datasets. We also demonstrated the effectiveness and generalization of our system on a medical speech dataset from an actual trauma scenario. Furthermore, we provided a detailed comparison and analysis of traditional approaches and deep learning methods on both feature extraction and fusion. PMID- 30410220 TI - Estimation of Supercapacitor Charge Capacity Bounds Considering Charge Redistribution. AB - This paper investigates the impact of charge redistribution on supercapacitor charge capacity by experimentally estimating the charge capacity bounds. An analysis of a physics-based RC ladder circuit model for supercapacitors reveals the theoretical bounds and provides guidelines for designing experiments to estimate the bounds. The upper bound corresponds to a long time constant voltage charging process and the lower bound is established using a charging process with the largest possible current. Bounds of two types of supercapacitor charge capacity are estimated: the total charge stored in the supercapacitor that can be released during multiple discharging processes and the utilized charge delivered during one discharging action. The relationship between the utilized charge capacity and the discharge current is examined and different patterns are observed depending on the supercapacitor state of charge (SOC). For a fully charged supercapacitor, the utilized capacity increases when the discharge current decreases. For a supercapaictor partially charged by a relatively large current, the utilized capacity is dependent on both the discharge current and the supercapacitor operation voltage range. The difference between the bounds is significant for both types of charge capacity. These observations provide guidelines for optimizing the supercapacitor charging and discharging policies for different applications. PMID- 30410221 TI - Nanoparticle probes for quantifying supramolecular determinants of biosurface affinity. AB - Interactions between macromolecular systems and biosurfaces are complicated by both the complexity of these multivalent interactions and challenges in quantifying affinities. A library of gold nanoparticles (AuNPs) as multivalent probes is used to quantify biosurface affinity, using hair as a model targeted substrate. PMID- 30410223 TI - Clinical, molecular detection and phylogenetic analysis study of local foot-and mouth disease virus in Al-Qadisiyah province of Iraq. AB - Aim: This study was directed during an outbreak of suspected foot-and-mouth disease (FMD) in cattle in Al-Qadisiyah province, Iraq 2016. The disease has made a huge economic loss in livestock. It was suspected that the vaccination has failed to protect the animals from the infection because of the difference in the strains. Consequently, we designed the study to make the diagnosis and detect the strain of the causative virus. Materials and Methods: The extraction of the DNA was done on 73 samples and Reverse Transcriptase Polymerase Chain Reaction (RT PCR) was used in the detection of FMD virus (FMDV) for primary diagnosis, and serotype-specific diagnosis was done with universal primer sets 1F/1R, A-1C612, and O-ARS4 with the expected band of 329, 865, and 1301 bp, respectively. Results: Universal primer pair 1F/1R detected FMD in 55 of 73 (75.3%); of these, 37 (67.3%) were females and 18 (32.7%) were males, with high significance (p<0.01) between males and females in the PCR positivity ratio. The tested samples with positive universal primer were amplified with specific primers A IC612 with no reaction for serotype O-ARS4. Conclusion: The products of RT-PCR were sent for RNA sequencing, and the results were 100% positive to serotype A which means that it is the predominant type in Iraq. It may help in the importing or production of the vaccine to make a preventive plan for the disease. The virus of FMD is contagious and dangerous due to its role in the huge economic loses. The detection of this virus is widely explained in lots of articles, but it is more specific and sensitive in RT-PCR and sequencing. Consequently, the authorities responsible for importing and/or production vaccines have to avoid the importing of other serotypes because it will be losing money and more outbreaks will explode. PMID- 30410222 TI - An innovative approach to predict immune-associated genes mutually targeted by cow and human milk microRNAs expression profiles. AB - Aim: Milk is rich in miRNAs - the endogenous small non-coding RNA responsible for gene post-transcriptional silencing. Milk miRNAs were previously evidenced to affect consumer's immune response. While most studies relied on a few well characterized milk miRNAs to relate their immunoregulatory roles on target genes among mammals, this study introduced a procedure to predict the target genes based on overall milk miRNA expression profiles - the miRNome data of cow and human. Materials and Methods: Cow and human milk miRNome expression datasets of cow and human milk lipids at 2, 4, and 6 months of lactation periods were preprocessed and predicted for their target genes using TargetScanHuman. Enrichment analysis was performed using target genes to extract the immune associated gene ontology (GO) terms shared between the two species. The genes within these terms with more than 50 different miRNAs of each species targeting were selected and reviewed for their immunological functions. Results: A total of 146 and 129 miRNAs were identified in cow and human milk with several miRNAs reproduced from other previous reports. Enrichment analysis revealed nine immune related GO terms shared between cow and human (adjusted p<=0.01). There were 14 genes related to these terms with more than 50 miRNA genes of each species targeting them. These genes were evidenced for their major roles in lymphocyte stimulation and differentiation. Conclusion: A novel procedure to determine mutual immune-associated genes targeted by milk miRNAs was demonstrated using cow and human milk miRNome data. As far as we know, this was the 1st time that milk miRNA target genes had been identified based on such cross-species approach. Hopefully, the introduced strategy should hereby facilitate a variety of cross species miRNA studies in the future. PMID- 30410224 TI - Prevalence, toxigenic potential and antimicrobial susceptibility profile of Staphylococcus isolated from ready-to-eat meats. AB - Aim: An epidemiological surveillance for Staphylococci contamination of ready-to eat (RTE) meats from Enugu State, Nigeria, was carried out to determine the prevalence, species distribution, toxigenic potential and antimicrobial susceptibility profile of the organisms and hence the microbiological and toxicological safety of the meats. Materials and Methods: Isolation and phenotypic Staphylococcus detection were done according to standard microbiological methods. Phenotypic resistance to 17 commonly used antimicrobial agents was determined by disc diffusion method. Molecular characterization of the isolates to species level and detection of selected toxigenic and antimicrobial resistance genes were done by PCR methods. Results: Twenty-four (9.4%) of the 255 meat samples investigated were contaminated with Staphylococcus species. Twenty four Staphylococcus isolates belonging to six species of coagulase-negative Staphylococcus (CoNS) were identified. Four (16.7%) isolates harbored genes coding for exfoliative toxin-A. Ten (41.7%) isolates were multidrug resistant, while mecA, tetK, mphC, ermT and ermC were the antimicrobial-resistance genes detected in the isolates. Meat samples sourced from motor parks (16.7%) and open markets (8.5%) were the most contaminated. Conclusion: 9.4% of RTE meats sampled were contaminated with toxigenic and multidrug resistance CoNS. Beef was the most contaminated RTE meat type and harbored all the toxigenic and most of the antibiotic-resistant genes detected. Meat samples from motor parks had the highest staphylococcal contamination (16.7%), while those from mechanic village had the least (2.4%). Majority (79.2%) of the isolates were not susceptible to fusidic acid but none exhibited antimicrobial-resistance to chloramphenicol, ciprofloxacin, linezolid or teicoplanin. Food safety authorities in the study area should work proactively to massively improve the hygienic practices of meat vendors; in order to limit staphylococcal contamination of RTE meats and the associated public health problems. PMID- 30410225 TI - Assessment of in vitro potency of inactivated Newcastle disease oil-adjuvanted vaccines using hemagglutination test and blocking ELISA. AB - Aim: The present study was aimed to establish a protocol for the evaluation of the in vitro potency of commercial inactivated Newcastle disease virus (NDV) oil adjuvanted vaccines using hemagglutination test (HA) and blocking ELISA (B-ELISA) based on polyclonal antibodies. Materials and Methods: Aqueous phases from a total of 47 batches of inactivated NDV vaccines manufactured by 20 different companies were extracted with isopropyl myristate. The viral antigen in each sample was detected and quantified by a standard HA test and a B-ELISA assay. To verify the efficiency of the antigen extraction method used in the batches which showed HA and to test the validity of using in vitro antigen quantification by HA and B-ELISA tests, a subset of 13 batches (selected from the total 47 batches) was inoculated in groups of 3-4-week-old specific pathogen-free chickens using the recommended vaccine dose. The immunogenicity of the selected vaccine batches was assessed by the NDV-hemagglutination inhibition antibody titers in individual serum samples collected 4 weeks after vaccination. Further, the efficacy of the vaccines and their protection rates were determined by a challenge test carried out for the vaccinated chickens with the Egyptian 2012 isolate of the virulent NDV genotype VII. Results: A strong correlation was observed between HA titers and B-ELISA mean titers in the tested 47 batches (R2=0.817). This indicated the possibility of using the latter in vitro assays for vaccine potency assessment. The recommended protective NDV antigen titer measured by B-ELISA was determined to be 28 ELISA units per dose. The comparison between the HA titers of the aqueous extracts of test vaccines and the corresponding results of in vivo potency assays (i.e., immunogenicity and efficacy), including antibody titers in the serum of vaccinated birds, indicated that the efficiency of the antigen extraction used may interfere with obtaining a strong correlation between the in vitro and in vivo results. Conclusion: HA or B-ELISA tests can be used as rapid and cost-effective alternatives to traditional in vivo potency tests for vaccine potency assessment by quantifying the NDV antigen present in aqueous phase extracts of the tested vaccines. The latter in vitro protocol, however, requires efficient extraction of the antigen to be able to obtain good correlation with the traditional in vivo potency tests. PMID- 30410226 TI - Epizootiological study on spatiotemporal clusters of Schmallenberg virus and Lumpy skin diseases: The case of Russia. AB - Aim: The submitted article attempts to highlight and specify the development of Schmallenberg virus (SBV) and lumpy skin disease (LSD) in cartographic illustrations, as well as to assess the epizootic situation of these diseases in the world, especially in Russia. Materials and Methods: Outbreaks (samples were collected from clinically healthy as well as suspected animals in infected areas) were confirmed and reported to the World Organization for Animal Health by veterinary officials representing countries in different geographical regions in the world. The reports showed that ELISA and polymerase chain reaction were used to identify SBV and LSD, taking into account number of infected, dead, and susceptible animals in infection foci since their first registration including in Russia. Once conventional statistical population (arrange data according to the main goal by regions, infected, and dead animals) was defined, a model was installed. A geo-information system, QuickMAP, was used to clarify the disease distribution map, and through the illustrations, analysis values were obtained. Results: Using information clusters of some epizootological criteria in various territories has demonstrated 1.302 focus of infection of SBV, of which 63.22% were registered in Europe and 36.78% in Russia. The seroprevalence in Russia was about 7.92% of the examined animals. According to the morbidity structure, the causative agent mainly affected cattle (64.76%), small ruminants (33.68%), and goats (1.56%). A global assessment of the effectiveness of primary epizootic diagnosis by practicing veterinarians was 63.19%, i.e., of 100 suspicion reports of SBV, 63.19 cases are confirmed by laboratory methods. A detailed assessment of the types of animals affected by the disease showed that it was easily diagnosed in sheep (70.38%), cattle (60.4%), and goats (48.57%), respectively. In the wild animal species, a significant prevalence was recorded as- 54.5%. In 2016, 1.209 foci of LSD were registered in the world, with 20.548 heads of cattle affected, while 8.5% of them identified in Russia (in 2017, the figure was 7.5%). Different maps had been generated in QuickMAP. Cluster analysis of the infected livestock in different regions in Russia showed that, in 2016, the Chechen Republic, Krasnodar, and Volgograd regions were, respectively, severely, moderately, and mildly affected. In 2017, the situation changed and Saratov, Orenburg regions, and Bashkiria were severely affected. However, the number of outbreaks decreased by 84.81% by contribution to the previous year. Eritrea, Namibia, and South Africa were leading in a cluster of most infected areas in 2017. Conclusion: Infectious diseases do not know borders. The emergence of SBV and LSD in the territory of the Russian Federation has followed the most common general dynamics of transborder diseases without ignoring details. The epizootic risk from wild animals and favorable climatic conditions is critical to fight against transmission of these diseases in Russia. PMID- 30410227 TI - The neuroprotective effect of Ocimum sanctum Linn. ethanolic extract on human embryonic kidney-293 cells as in vitro model of neurodegenerative disease. AB - Aim: This study aimed to analyze the neuroprotective effect of Ocimum sanctum Linn. ethanolic extract (OSE) on human embryonic kidney-293 (HEK-293) cells as the in vitro model of neurodegenerative diseases. Materials and Methods: In this research, HEK-293 cells divided into five groups consisting of normal and healthy cells (NT), cells treated with Camptothecin 500 uM as the negative control, cells treated with trimethyltin 10 uM (TMT), cells treated with OSE 75 ug/ml, and cells pre-treated with OSE 75 ug/ml then induced by TMT 10 uM (OSE+TMT). MTT assay and phase contrast microscopy were applied to observe the cell viability quantitatively and morphological after Ocimum sanctum Linn extract treatment. Finally, the reverse transcription polymerase chain reaction was employed to study the expression of choline acetyltransferase (ChAT). Results: The MTT assay and phase contrast microscopy showed that OSE pre-treatment significantly increased the viability of TMT-induced apoptotic cells and maintained cell viability of the normal HEK-293 cells. Expression of ChAT markedly reduced on TMT treatment group, but OSE administration stabilized ChAT expression in TMT-induced HEK-293 cells. Conclusion: This present study proved that OSE administration has neuroprotective effect by increased HEK-293 cells viability and maintain ChAT expression. PMID- 30410228 TI - Differential diagnosis and surgical management of cecal dilatation vis-a-vis cecal impaction in bovine. AB - Aim: The present study was undertaken to study the clinical and hemato biochemical alterations, ultrasonography, and surgical treatment of bovine suffering from cecal dilatation and cecal impaction. Materials and Methods: The present study was conducted on 11 bovines (9 buffaloes and 2 cattle) suffering from cecal dilatation (n=6) and cecal impaction (n=5). The diagnosis of surgical affections of cecum was made on the basis of clinical examination, hematobiochemistry, ultrasonography, and exploratory laparotomy. Results: A marked decrease in serum total protein, albumin, chloride, potassium, and calcium levels while an increase in lactate concentrations was recorded. Peritoneal fluid examination revealed an increase in total protein concentration. Per rectal examination along with ultrasonography was used as a confirmatory diagnostic tool for cecal dilatation and cecal impaction. Ultrasonographic features of cecal dilatation and cecal impaction were recorded. Left flank laparorumenotomy was performed in six animals with dilated cecum along with colonic fecalith. Post rumenotomy, these animals were treated with massage of cecum along with kneading of colonic fecalith. Right flank typhlotomy was done in the remaining five animals having impacted cecum for decompression of the dilated cecum. 9 of 11 animals survived which underwent surgery and remained healthy up to 3-month follow-up. Conclusion: Ultrasonography was reliable in the diagnosis of cecal dilatation and cecal impaction in bovine. Left flank exploration after laparorumenotomy is an ideal surgical technique for the management of cecal dilatation, while right flank typhlotomy is ideal for the management of cecal impaction in bovine. PMID- 30410229 TI - n-Propanol extract of boiled and fermented koro benguk (Mucuna pruriens seed) shows a neuroprotective effect in paraquat dichloride-induced Parkinson's disease rat model. AB - Aim: n-Propanol extracts from fresh, boiled, and fermented seeds were studied to evaluate their neuroprotective effects in a Parkinson's disease (PD) rat model, based on the total number of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Materials and Methods: Rats were induced with paraquat dichloride at a dosage of 7 mg/kg BW intraperitoneally twice a week and at the same time supplemented with extract at a dosage of 70 mg/kg BW orally every day for 3 weeks. On the 24th day, all rats were perfused and fixed with 4% paraformaldehyde. The left part of the SNpc was processed for immunohistochemical staining with tyrosine hydroxylase (TH)-antibody. The total number of DA neurons in SNpc was evaluated with a stereological method. Results: TH-immunoreactive cells found in the SNpc were identified as DA neurons. The average total number of DA neurons in the SNpc increased significantly in the PD rat model that was given an n-propanol extract of boiled and fermented seeds compared with a control PD rat model. Surprisingly, there was no significant difference in the average total number of DA neurons in SNpc between the PD rat model that was given n propanol extract of fresh seeds and the control PD rat model. Conclusion: n Propanol extract of boiled and fermented seeds could produce a higher neuroprotective effect against DA neuron than fresh seeds in a PD rat model. PMID- 30410230 TI - Cloning and sequencing gB, gD, and gM genes to perform the genetic variability of bovine herpesvirus-1 from Indonesia. AB - Aim: Previous research has shown that bovine herpesvirus-1 (BHV-1) in Indonesia was closely related to subtype-1 based on glycoprotein D genes. This study aimed to analyze the genetic variability of the BHV-1 isolated from the recent case in Indonesia not only based on gD but also other genes such as gB and gM and to study the homology and similarity of the sample to other BHV-1 isolated in other countries or regions. Materials and Methods: Samples were drawn from the tracheal organ in recent field case and prepared for DNA extraction. The gB, gD, and gM were amplified using nested polymerase chain reaction (nPCR) with our specifically designed primer pair and based on the specified bands of 350 bp gB, 325 bp gD, and 734 bp gM confirmed as BHV-1. The PCR product was ligated into pGEM-T and transformed into competent Escherichia coli. The purified plasmid was subsequently sequenced. Results: The virus sample isolated from the recent field case of infectious bovine rhinotracheitis (IBR) from Indonesia showed variability based on the gB, gD, and gM sequences. However, all of the genes had high similarity (98-100%) to BHV-1.2. Conclusion: The recent field case of IBR in Indonesia was similar to BHV-1.2. PMID- 30410231 TI - Occurrence of Toxoplasma gondii in raw goat, sheep, and camel milk in Upper Egypt. AB - Background and Aim: Toxoplasmosis is a worldwide zoonotic disease with harmful effects on animal and human health. Ingestion of contaminated raw milk has been suggested as a vehicle for transmission of Toxoplasma gondii to human. The present study was performed for the detection of T. gondii in raw milk samples of goat, sheep, and camel in Upper Egypt using two different techniques (enzyme linked immunosorbent assay [ELISA] and quantitative polymerase chain reaction [qPCR]). Materials and Methods: This study was conducted to determine the T. gondii prevalence using ELISA and qPCR in raw goat, sheep, and camels milk (30 samples for each) collected from different locations in Upper Egypt. Results: T. gondii IgG antibodies were detected in 90.0, 60.0, and 3.33% of goat, sheep, and camel milk samples, respectively. From the positive samples of T. gondii IgG, the parasitic DNA was detected only in two examined milk samples, one of them was present in goat milk sample and another one was found in sheep milk sample. On the other hand, the parasite was not detected in camels' milk samples. Conclusion: These results concluded that the raw milk was contaminated by T. gondii tachyzoites which could be a source of human infection. Restricted hygienic programs should be implemented in the animal farms to decrease the risk of milk contamination by this parasite. PMID- 30410232 TI - The effect of dry cow therapy using systemic tylosin in combination with common intramammary medications on mastitis rate, cull rate, somatic cell count, and milk production in dairy cows affected with subclinical mastitis. AB - Aims: This study was performed to evaluate the effect of systemic tylosin on mastitis rates, cull rates because of mastitis, and quality and quantity of milk production in dairy cows affected with subclinical mastitis. Materials and Methods: A total of 130 California mastitis test (CMT)-positive cows were randomly selected and divided into four different treatment groups. All treatments were performed on the day of drying off. Cows in Group 1 (n=34) received 12 g of tylosin intramuscularly (IM) and intramammary (IMM) 400 mg novobiocin sodium and 200,000IU penicillin G procaine. Group 2 (n=33) received 12 g tylosin IM and IMM 280 mg benethamine penicillin, 100 mg penethamate hydriodide, and 100 mg framycetin sulfate. Group 3 (n=33) received IMM alone with 400 mg novobiocin sodium and 200,000 IU penicillin G procaine. Group 4 (n=30) received IMM alone with 280 mg benethamine penicillin, 100 mg penethamate hydriodide, and 100 mg framycetin sulfate. The incidence and severity of clinical mastitis (CM), incidence of chronic mastitis, and cow cull rate because of mastitis were recorded during the first 100 days in milk (DIM). In addition, somatic cell count (SCC) and milk production parameters including the average days to peak milk yield, the average milk yield at peak, the average milk yield during the first 100 DIM, and the average 305-corrected milk yield were reported. Results: The rate of CM was significantly (p<=0.05) less in Group 2 when compared between the current and previous lactations (30% vs. 64%). In Group 1 and 4, the rate of CM was decreased but not significant between the two lactations (59% vs. 79% and 63% vs. 77%, respectively) while in Group 3, the rate of CM was slightly increased (82% vs. 91%). When compared between the four groups in the current lactation, CM rate was significantly (p<=0.05) less in Group 2 compared to the other groups. A significant (p<=0.05) percentage of CM cases in Group 2 was classified as mild. In Groups 1 and 3, a significant (p<=0.05) percentage of CM cases was classified as moderate while severe clinical signs were recorded more significantly (p<=0.05) in Groups 3 and 4. The rate of chronic mastitis was significantly less in Group 1 and Group 2 in the current lactation compared to that in the previous lactation (6% vs. 12% and 0% vs. 6%, respectively). In Groups 3 and 4, the rate of chronic mastitis was not changed significantly when compared between the current and previous lactations. No cows were culled because of mastitis in Groups 1 and 3 while one cow was culled in each of Groups 2 and 4 during the first 100 DIM in the current lactation. The average milk yield during the first 100 DIM and the 305-corrected milk yield were significantly (p<=0.05) increased in Group 2 when compared between the previous and current lactations. Furthermore, cows in Group 2 produced significantly (p<=0.05) more milk during the first 100 DIM and significantly (p<=0.05) more 305-corrected milk yield compared to the other groups. In Group 2, the average SCC dropped significantly (p<=0.05) from 1,600,000 cells/ml at the start of the study to <200,000 cells/ml at 100 DIM. Conclusions: In dairy herds with subclinical mastitis, dry cow therapy of CMT-positive cows using a combination of tylosin (12 g, IM) and IMM administration of benethamine penicillin, penethamate hydriodide, and framycetin sulfate (Ubrostar; Boehringer Ingelheim, Germany) may result in a significant reduction of the rate and severity of acute and chronic mastitis and cull rates due to mastitis within the first 100 DIM. Furthermore, treated cows may produce significantly more milk with less SCC during the first 100 DIM and therefore produce significantly more 305-corrected milk in the lactation following treatment. PMID- 30410233 TI - Evaluation of specific and non-specific immune response of four vaccines for caseous lymphadenitis in sheep challenged. AB - Background: Caseous lymphadenitis (CLA) is a serious disease affects sheep and goat, caused by Corynebacterium pseudotuberculosis. Due to it is non-treatable disease, so the effective preventive vaccines are considered a significant way to combat the disease. All strains of C. pseudotuberculosis have several virulence factors that associated with their cell invasion, survival, and proliferation such as phospholipase D (PLD), outer lipid coat, and secreted proteases. Aim: The present study was directed to perform a comparative innate and acquired immune response assessment of different four vaccine formulas to evoke protection against induced (CLA) challenge in sheep. Materials and Methods: Negative ELISA (free of CLA) 15 local breed male (Balady) sheep were divided into five groups, each has received a different vaccine while the control has received saline buffer. The first vaccine composed of toxoid PLD alone the second composed of toxoid PLD with bacterin (formalinkilled bacteria), the third vaccine composed of toxoid PLD plus covaccine 8, while the fourth one composed of toxoid PLD plus locally produced polyvalent clostridial vaccine. The specific immune response was evaluated through lymphocyte proliferation assay using ELISA BrdU kit, while the non-specific response was estimated by superoxide anion production and lysozyme activity assays. Results: The study revealed that PLD toxoid could evoke the highest specific immune response, showing a stimulation index (9.12%). On the other hand, combined toxoid ?PLD with bacterin followed by PLD toxoid showed a significant increase in the non-specific innate immune response. Conclusion: The present study indicated that the toxoid PLD alone vaccine was most efficient and provided innate and acquired immune response in animals against CLA. PMID- 30410234 TI - Dystroglycan 1: A new candidate gene for patellar luxation in Chihuahua dogs. AB - Aim: The objective of this study was to uncover new candidate genes related to patellar luxation (PL) in dogs to select for those with low susceptibility for breeding purposes. Materials and Methods: The inter simple sequence repeat (ISSR) technique was performed to construct DNA fingerprints of 61 Chihuahua dogs with PL and 30 healthy Chihuahua dogs. DNA polymorphisms were detected by comparing the sequences between the affected and unaffected dogs, using the pairwise alignments in MultAlin. Genotyping was performed using allele-specific polymerase chain reaction (AS-PCR). The association analysis of ISSR DNA fingerprints and genotypes or phenotypes was performed using the Chi-square (chi 2) model and generalized linear model (GLM), respectively. Results: Two single nucleotide polymorphisms (SNPs), namely SNP1UBC811 (g.91175C>G) and SNP2UBC811 (g.92259T>C), were found in the intron of the Dystroglycan 1 (DAG1) gene, which was obtained using the PL-related marker UBC811 primer (p=0.02), and genotyped by AS-PCR. When investigated using the GLM, g.91175C>G had a significant association with PL (p=0.0424), whereas g.92259T>C did not have such an association (p=0.0959). Conclusion: DAG1 might be one of the genes related to PL in Chihuahuas and could aid the process of marker-assisted selection in genetic breeding for Chihuahua dogs without PL. PMID- 30410235 TI - Occurrence of human e nterovirus in tropical fish and shellfish and their relationship with fecal indicator bacteria. AB - Aim: Human enteroviruses in fish and shellfish are a health concern worldwide. Human infections occur due to the consumption of raw or insufficiently cooked fish or shellfish. The objective of this study was to determine the occurrence of human enteric viruses belonging to Enterovirus (EV) group in seafood in Mumbai and to correlate their occurrence with the bacterial indicators of fecal contamination. Materials and Methods: Samples of fresh fish and shellfish collected from fish landing centers and retail fish markets were analyzed by virus concentration, nucleic acid extraction, and reverse transcription polymerase chain reaction (RT-PCR). Bacterial indicators of fecal contamination were estimated by the most probable number technique. The relationship between the presence of virus and fecal indicators was determined by statistical analysis. Results: A total of 89 samples comprising of fish, shrimps, oysters, clams, and mussels were screened in this study. EV was detected in 32 (35.95%) samples, and all the virus-positive samples belonged to bivalve molluscan group. None of the finfish and crustacean shellfish samples was positive for the enteric viruses. Clams were found to be the most contaminated with 48.4% of the samples being positive for EV. The prevalence of enteric viruses in seafood samples showed a strong positive correlation with the bacteriological indicators of fecal contamination, suggesting that fecal coliform bacteria are good indicators of EVs in tropical seafood. Conclusion: The presence of EVs in seafood is a public health hazard. Increasing level of coastal water contamination from anthropogenic sources is the primary reason for the contamination of seafood with EVs. Continuous monitoring of coastal waters and seafood for enteric viruses will help to ensure the safety of fish and shellfish for human consumption. PMID- 30410236 TI - Acute oral toxicity of pesticide combination (acephate 50% and imidacloprid 1.8% as active ingredients) in Sprague-Dawley rats. AB - Aim: The aim of this study was to assess the acute toxic interaction and lethal dose (LD50) of pesticide combination product (acephate 50% and imidacloprid 1.8% as active ingredients) available in the market in Sprague-Dawley female rats by oral route. Materials and Methods: A total of 10 Sprague-Dawley female rats were divided into two groups, comprising five rats in each dose group. Both groups were identified as control and test groups, respectively. Control group received sterile water as vehicle and test group received pesticide combination (acephate 50% and imidacloprid 1.8% as active ingredients) at a dose of 0 and 2000 mg/kg body weight. As per the Organization for Economic Cooperation and Development Guideline 420, initially one animal each from both the control and test groups were dosed with 0 and 2000 mg/kg, respectively, as sighting study. Based on the results of sighting study, additionally, four animals each from both groups were dosed with the same dose to make a total of five animals in each group. Dose volume was constant as 10 mL/kg. All animals were observed daily twice for clinical signs and mortality. Body weight was recorded on day 0 and weekly thereafter during 14 days' observation period; last body weight (fasted) was recorded on day 15. All the rats of both the groups were humanely sacrificed on day 15 for gross pathology, collection of organs for histopathology, organ weighing, and morphometry. Organ weights were taken as absolute values, and relative organ weights to last fasted body weights were calculated. Results: Pesticide combination (acephate 50% and imidacloprid 1.8% as active ingredients) treated rats showed cholinergic signs with one mortality in the test group. No significant difference was observed in body weight, relative organ weights, and organ morphometry between pesticide combination exposed and non-exposed groups. Gross pathology of the treated rats was also comparable with respect to control group. Histopathological changes in the liver, kidneys, heart, lung, adrenaline, spleen, and ovaries of test group rats were found to be comparable with control group rats. Conclusion: The present study demonstrated the LD50 of one of the combination products available in the market having acephate 50% and imidacloprid 1.8% as active ingredients in Sprague-Dawley female rats which is >2000 mg/kg body weight. Furthermore, gross, histopathology and histoarchitectural alterations of all the vital organs of the test group were comparable to the control. PMID- 30410237 TI - The prevalence and intensity of external and internal parasites in working donkeys (Equus asinus) in Egypt. AB - Aim: This study aims to record and update the prevalence and intensity of external and internal parasites in working donkeys (Equus asinus) in Egypt during the period from January to December 2017. Materials and Methods: A total of 120 donkeys (10 donkeys each month) were examined at Giza zoo abattoir through bimonthly visits. The examined donkeys were obtained from five governorates (Giza [20], Fayoum [40], Beni Suef [30], Monofia [20], and Assiut [10]). The animals were grouped according to age and sex. Results: All examined donkeys were positive with at least one internal or even external parasitic species. The overall prevalence rate was 100%. A total of 11 helminths species (10 nematodes and 1 metacestode); 7 protozoal and 7 arthropod species were collected. The number of each parasite and intensity of infection with regard to age and sex was recorded. Conclusion: All examined donkeys were infected with parasites with an overall prevalence of 100%. So, we recommended following up and continuous treatment of such diseased animal. PMID- 30410238 TI - Ruminal impaction due to plastic materials - An increasing threat to ruminants and its impact on human health in developing countries. AB - Ruminal impaction due to plastic materials is a condition, in which indigestible plastic foreign bodies accumulate in the rumen of ruminants leading to ruminal impaction, indigestion, recurrent tympany, and many other adverse health effects. It is caused by the indiscriminate feeding of ruminants on indigestible plastic waste materials. The disease is primarily noticed in stray animals residing in urban areas of developing countries. Ingested plastic materials in the rumen slowly release the chemicals in rumen fluid, which intern enter the food chain through milk and meat products. These chemicals have a detrimental effect on human health. At present, exploratory rumenotomy is the only choice for both diagnosis and treatment of ruminal impaction due to plastic materials in ruminants. Control measures include good animal husbandry practices and proper disposal of plastic waste materials. The present review discusses in depth about the epidemiology, pathophysiology, diagnosis, treatment, prevention, and control of ruminal impaction due to plastic materials in ruminants and also highlights its impact on human health. PMID- 30410239 TI - Effect of Newcastle disease virus level of infection on embryonic length, embryonic death, and protein profile changes. AB - Background and Aim: Newcastle disease virus (NDV) is an obligate intracellular parasite. Virus can only live on living cells. The embryonated chicken eggs (ECEs) are one of the growth media of virus that is a cheap, easy to do, and accurate for showing patterns of virus change in the host. Higher virus titers indicate the higher number of viruses and more virulent to infect host. This research aimed to investigate the effect of different level of NDV titer infection in ECEs on protein profile, embryonic length, mortality, and pathological change. Materials and Methods: The study used a completely randomized design of six treatments and seven replications. The treatments were different level of NDV titer infection in allantoic fluid (AF) of 9-11 days ECEs, i.e., P1=20, P2=26, P3=27, P4=28, P5=29, and P6=210 hemagglutination unit (HAU). All samples were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Data were analyzed using one-way ANOVA with p=0.05 for length of the embryo and descriptive analysis for embryo mortality, pathology change, and protein band. Results: The result showed that protein profile of NDV-infected ECEs of all different levels is more complex than protein profile of no NDV infected ECEs. NDV infected of all different levels showed longer size embryo, higher mortality embryo at the first 2 days, and higher occurrence of hemorrhagic in all part of bodies of embryo than those of no NDV infected. Conclusion: It was concluded that NDV infection of all different level decreased health conditions of chicken embryo of ECEs of 9-11 days old. Different level of NDV infection of ECEs of 9-11 days old showed no significantly different embryo profiles. However, all of the NDV-infected embryos were shorter, death on the 2nd day, and suffered more hemorrhage on all body surfaces than uninfected NDV embryos. PMID- 30410240 TI - Prevalence of antibodies against visceralizing Leishmania spp. in brown rats from Grenada, West Indies. AB - Background and Aim: Leishmania spp. are known to cause disease in man and animals. Rats are considered important reservoir hosts and transmission takes place through the bite of female sand fly, Phlebotomus spp. To the best of our knowledge, there is no published information on Leishmania infection in rats in Grenada. This study was conducted to estimate the antibodies for visceralizing Leishmania spp. (VL) in rats (Rattus norvegicus) from Grenada. Materials and Methods: A total of 146 brown rats (R. norvegicus) were trapped live from two parishes (St. George and St. David) in Grenada. Following anesthesia, blood was collected from the heart through thoracic puncture. The serum was collected after the centrifugation of blood. Serum was tested for antibodies to VL. with a commercially available immunochromatographic dipstick test which is licensed for use in animals and humans. Results: The seroprevalence of antibodies against Leishmania spp. was found in 34 of 146 rats (23.3%; CI 95% from 16.70 to 30.99). No significant differences were found between sexes and young or adults. The prevalence between parishes (St. George and St. David) was also not significant. Conclusion: The results show that rats (R. norvegicus) in Grenada are exposed to Leishmania spp. The rats could play an important role in the transmission of leishmaniasis to humans and other animals in Grenada. PMID- 30410241 TI - First-time serological and molecular detection of Helicobacter pylori in milk from Algerian local-breed cows. AB - Aim: The present study was conducted to detect and identify Helicobacter pylori within local cow breeds in the central region of Algeria. Materials and Methods: Two hundred (n=200) cows from three provinces of the central region of Algeria were studied, between January 2016 and September 2017. Each cow was subject to stool, milk, and blood sampling. Milk and fecal samples were used to detect and identify H. pylori using bacteriology culture method. Blood and milk samples were used to detect H. pylori immunoglobulin G (IgG) antibody using enzyme-linked immunosorbent assay. Polymerase chain reaction was used to confirm the abundance of H. pylori in milk by detecting glmM gene. Results: Out of 200 sera and 200 milk samples, 12% (24) and 4% (8/200) were positive for the H. pylori IgG antibody. glmM gene was detected in the milk of 13% of cows and was confirmed in all cows presenting IgG in milk. Conclusion: From the present study, we concluded that the glmM gene is an important marker for detecting H. pylori in milk. Moreover, Algerian local-breed cows are a source of H. pylori and could be responsible for serious zoonosis. PMID- 30410242 TI - Epidemiological surveillance of bovine viral diarrhea and rift valley fever infections in camel. AB - Aim: This study was designed to investigate the current epidemiological situation of bovine viral diarrhea virus (BVDV) and rift valley fever virus (RVFV) infection of camels originating from Sudan "smuggler" and Egypt as part of our future plan for a national surveillance program in Egyptian provinces, which will aid in establishment of control strategy for animal diseases. Materials and Methods: This investigation was accomplished using serological diagnostic and molecular biology techniques. A total number of 200 blood samples were collected from camel (120 originated from Sudan "smuggler" and 80 from local breed) and were subjected for testing both BVDV and RVFV occurrence with different age and sex. Results: Sixty-six of the 200 camels (33%) were positive for BVDV antibodies, and 44 (22%) for BVDV antigen (Ag), and 27 of the 200 camels (13.5%) were positive for RVFV immunoglobulin G (IgG) antibodies. On the other hand, the seroprevalence of BVDV for antibodies (47.5%), Ag (31.6%), and RVFV IgG antibodies (16.6%) was higher in camel originated from Sudan "smuggler" than of local breed which was 11.2% for BVDV antibodies and 7.5% for BVDV Ag, while it was 8.7% for RVFV IgG antibodies. The incidence of BVDV antibodies, Ag, and RVFV IgG antibodies was the highest in male, up to 9 years of age. The frequency of positive cases was significantly different according to the origin of samples and sex and age of camel for BVDV and RVFV. In addition, seven serologically positive samples for BVDV and five serologically positive samples for RVFV were submitted as a buffy coat for molecular detection by one-step - reverse transcription polymerase chain reaction (RT-PCR). The results demonstrated that three samples were positive for BVDV of camel originated from Sudan (smuggler), while no RVFV Ag was detected in all five samples. Sequencing and phylogenetic analysis of the amplicons obtained from positive RT-PCR samples (three samples) indicated 100% nucleotide homology with Sudan strain 2015 except only one (missense point mutation) by substitution of A to T at position 345 that changed the coded amino acids from T (Threonine) to S (Serine) at residue 115. Conclusion: Camels act as risk animals for the introduction of many infectious diseases from Sudan to Egypt, especially transboundary animal diseases, so strict quarantine measures should be taken during importation of live animals from Sudan to prevent the spread of such diseases. PMID- 30410244 TI - Dietary encapsulated probiotic effect on broiler serum biochemical parameters. AB - Aim: The study aimed to evaluate the effect of encapsulated probiotic bacteria (Lactobacillus lactis and Bifidobacterium bifidum) on broiler serum biochemical parameters. Materials and Methods: Encapsulation protects the probiotics and increases their livability on exposure to unfavorable processing and storage temperatures and gastrointestinal pH. Hence, an in vitro study was undertaken to encapsulate the probiotic bacteria L. lactis and B. bifidum with sodium alginate and chitosan and evaluate the encapsulation efficiency. This experiment was conducted with 288-day-old broiler chicken; they were distributed randomly into eight treatments and six replicates in each treatment (six birds in each replicate) and given with standard feed. Results: Supplementation of the encapsulated bacteria either alone or in combination (T4, T6, and T8) significantly (p<0.05) increased mean total serum protein, albumin, and globulin as compared to the birds that were not supplemented with any probiotic (T1 and T2) or supplemented with non-encapsulated bacteria (T3, T5, and T7). Supplementation of the encapsulated bacteria either alone or in combination (T4, T6, and T8) significantly (p<0.05) lowered mean total serum cholesterol, serum low-density lipoprotein (LDL) cholesterol, and serum triglycerides, as compared to the birds that were not supplemented with any probiotic (T1 and T2) or supplemented with non-encapsulated bacteria (T3, T5, and T7). Conclusion: It may be concluded that supplementation of the encapsulated probiotic bacteria either alone or in combination significantly increased total serum protein, albumin, and globulin and significantly lowered mean total serum cholesterol, serum LDL cholesterol, and serum triglycerides as compared to the birds that were not supplemented with any probiotic or supplemented with non-encapsulated bacteria. PMID- 30410243 TI - Detection of Toxoplasma gondii copro-prevalence by polymerase chain reaction using repetitive 529 bp gene in feces of pet cats (Felis catus) in Yogyakarta, Indonesia. AB - Aim: The aim of this research was to determine the copro-prevalence of Toxoplasma gondii using polymerase chain reaction (PCR) with repetitive 529 bp gene and to construct the phylogenetic tree of Toxoplasma oocyst from pet cats in Yogyakarta. Materials and Methods: 9 of 132 pet cat samples which serologically positive for Toxoplasma were used in this research. To determine the copro-prevalence of T. gondii in pet cat, 10 g of feces samples taken from practitioners and household cats in Yogyakarta were used in the PCR method utilizing repetitive 529 bp gene sequences. Results: The result shows that copro-prevalence by PCR using repetitive 529 bp gene was 33.3% (3/9). The phylogenetic tree of Toxoplasma grouped into two clades, which clade 1 consists of Toxoplasma isolates collected from pet cats in Yogyakarta Indonesia and T. gondii isolates from China and in clade 2 consist of the T. gondii isolates from India. Conclusion: Copro prevalence of T. gondii in pet cats in Yogyakarta by means of PCR using repetitive 529 bp gene is around 33.3%. PMID- 30410245 TI - Effects of secretome on cisplatin-induced testicular dysfunction in rats. AB - Background: Testicular dysfunction is a degenerative disorder characterized by failure in the synthesis of reproductive hormones and spermatogenesis. Secretome derived from the human umbilical mesenchymal stem cell (MSC) has been reported to repair some degenerative disorders. Aim: This study aimed to investigate the effect of secretome derived from the human umbilical MSCs on cisplatin-induced testicular dysfunction in rats. Materials and Methods: Thirty-six male Wistar rats were divided into the control and secretome-treated groups. In the secretome treated group, testicular dysfunction was induced by 3 mg/kg BW of cisplatin intraperitoneally 3 times with 3-day intervals. The secretome-treated group was divided according to dose: Low-dose (0.2 mL/kg BW) and high-dose (0.5 mL/kg BW) groups. Secretomes were injected intraperitoneally once a week for 3 weeks. 1 week after the injection of secretome, the cauda epididymis of the rats was removed for spermatozoa evaluation and histological examination. Result: After the injection of secretome, the sperm motility of the high-dose group showed thin wave-like, rare, and slow movements. No abnormal sperm morphology was observed in all the treated groups. The number of spermatozoa increased gradually in the high dose group after the injection of secretome. The developmental stages of the spermatogenic cells were complete in both spermatozoa groups after the injection of secretome. However, the spermatozoa in the seminiferous tubules of the high dose group were denser. Vimentin and cytokeratin immunoreactivities were very strong in the high-dose group 1 week after the second secretome injection. Conclusion: High-dose secretome derived from the human fetal umbilical cord could increase the number and motility of sperms in rats with cisplatin-induced testicular dysfunction. The administration of high-dose secretome was effective 1 week after the second dose, as indicated by very strong immunoreactivity for vimentin and cytokeratin. Moreover, secretome could promote the regeneration of the seminiferous tubules of both the groups. PMID- 30410246 TI - Hard tick (Acari: Ixodidae) species of livestock and their seasonal activity in Boyer-Ahmad and Dena cities of Kohgiluyeh and Boyer-Ahmad Province, Southwest of Iran. AB - Aim: The present study was carried out to identify the Ixodidae ticks fauna of livestock and their seasonal activity in the cities of Boyer-Ahmad and Dena of Kohgiluyeh Province, south-west of Iran. Materials and Methods: Hard ticks from sheep, goats, and cattle were collected manually, stored in 70% ethanol, and identified using morphological characters. Results: During the study, a total of 1273 hard ticks from four genera, including Rhipicephalus, Hyalomma, Dermacentor, and Haemaphysalis, were collected. Rhipicephalus sanguineus (s.l.) had the highest frequencies in both cities with 62.08 and 62.88% of collected specimens, followed by Hyalomma scupense with 14.36 and 13.54% in Boyer-Ahmad and Dena, respectively. Furthermore, Hyalomma marginatum with only one sample or 0.12% of collected ticks showed the lowest frequencies in the studied areas. Dermacentor marginatus with three samples or 0.37% was recorded only in Boyer-Ahmad, and Haemaphysalis sulcata with two samples or 0.43% was recorded only in Dena. In both cities, sheep were the most infested ruminant, and the ears in sheep and goats were the most affected areas. The highest activity was observed in spring, and the lowest activity was observed in winter and autumn. Conclusion: The results of the present study showed that Hyalomma and Rhipicephalus genera were the most widespread genera in the study areas. Regarding the importance of genera, such as Rhipicephalus, Hyalomma, and Haemaphysalis, in transmitting disease agents and the location of Kohgiloyeh and Boyer-Ahmad Province in the routes of migrant birds, further studies are required to elucidate their exact roles in human and livestock health in these areas. PMID- 30410247 TI - Clear, Simple, Precise, Meaningful: A Quick Guide to Writing for Publication. PMID- 30410248 TI - Identifying People in Need of Palliative Care Services in Rural Tamil Nadu: A Survey. AB - Background: As a part of initiating community-based palliative care program in the field practice areas of Urban Health Training Centre (UHTC), Villupuram, it was necessary for us to identify people who need palliative care to plan our services. Aim: This study aims to assess the need for palliative care and its determinants in the villages under the UHTC, Villupuram, and to know their sociodemographic characteristics and morbidity profile. Materials and Methods: A community-based cross-sectional survey was conducted in the four villages under UHTC between April and September 2016. A house-to-house survey was conducted by a trained team using a structured questionnaire. The available member of the households was interviewed about the need for palliative care and the morbidity profile among all the members of their household. Written informed consent was obtained before the interview. Data were entered and analyzed using EpiInfo (version 7.2.2.6) software. Prevalence ratio, age- and gender-wise prevalence of people in need of palliative care was calculated. Results: The overall prevalence of people in need of palliative care was found to be 4.5/1000 population (95% confidence interval: 3.2-6.3). Among them, 73.5% were elderly people. The most common condition requiring palliative care was old age-related weakness (41.2%). Conclusion: The need for palliative care services among elderly people was found to be high. This data can be used for planning and implementing community-based palliative care services for the people in our field practice areas. PMID- 30410249 TI - Cluster Analysis of Symptoms of Bangladeshi Women with Breast Cancer. AB - Background: Breast cancer (BC) patients may experience multiple symptoms due to the disease itself, cancer treatment or combination of both. Aim: The aim of the present study was to express multiple symptoms experienced by the patients with BC as clusters. Methods: This was a retrospective study. We examined symptom profiles of 120 patients with BC who attended the Centre for Palliative Care, Bangabandhu Sheikh Mujib Medical University in Dhaka, Bangladesh, from January 2009 to December 2013. We included all case sheets of BC patients, which had documentation of needed information. Following symptoms were analyzed: pain, nausea, loss of appetite, constipation, weakness, cough, breathlessness, sleeplessness, lymphedema, sadness, anxiety, and depression. Hierarchical cluster analysis was used to identify the natural groupings within the set. Results: We could identify three clusters, namely (1) "neuropsychiatric," (2) "gastro respiratory," and (3) "miscellaneous" symptom clusters. The symptoms in cluster 2 comprised of cough, breathlessness, nausea, and constipation. Cluster 1 was characterized by pain, depression, anxiety, weakness, sleeplessness, and loss of appetite. Cluster 2 was comprised of cough, breathlessness, nausea, and constipation. Cluster 3 consisted of two symptoms lymphedema and sadness. The results revealed that the multiple symptoms of patients with BC experienced had been clustered together. Neuropsychiatric symptoms and weakness formed a significant strong relationship with each other. Conclusion: Knowledge obtained from this study could be beneficial for better understanding, assessment, and management of symptom clusters in women with BC. It may also help patients to plan ahead for them to seek management of concurrent symptoms to improve their quality of life. PMID- 30410250 TI - End-of-life Care and Social Security Issues among Geriatric People Attending a Tertiary Care Hospital of Eastern India. AB - Context: The care of sick members is the hallmark of a civilized society. End-of life care and social security for elderly are emerging issues nowadays. Aims: The aim of this study is to explore the desires of the elderly regarding the end-of life care decisions along with to find out social security measures among the study population. Settings and Design: The cross-sectional study conducted in the geriatric outpatient department of a tertiary care hospital. Subjects and Methods: The study period was 4 months from August to November 2017. The geriatric patients attending geriatric outpatient department were interviewed using a predesigned and pretested questionnaire. Convenient sampling was used and a total of 138 participants were included in the study. Statistical Analysis Used: Proportions were used in the study. Results: A total of 63.77% participants expected to die at home surrounded by their family members during their time of death followed by hospital (31.88%). Majority (63.77%) stated their opinions to die a senile death. Organ donation after death was the willingness shown by as high as 70.3%, but registered organ donors were 6.5%. 94.2% participants expected to be cremated after their death while others buried in accord to their religious practices. Only 7.24% of participants had a legal will of their financial establishments. It was observed that even half of the population (47.8%) did not have any form of health or life insurance. Conclusion: Home-based care of the elderly is needed so that they can live their last days of life peacefully. Awareness about health and life insurance should be increased by urgent intervention. PMID- 30410251 TI - Validation of the Caregiving Knowledge Questionnaire-My: Measuring Knowledge Regarding Positioning and Feeding among Malaysian Informal Caregivers of Stroke Patients. AB - Aim: The majority of caregivers for stroke patients in Malaysia are informal caregivers, although there are no valid tools to measure their knowledge regarding caregiving. Therefore, this study validated the Caregiving Knowledge Questionnaire (CKQ-My) as an assessment of Malaysian stroke caregivers' knowledge regarding patient positioning and feeding. Methods: Back-to-back translation was used to produce a bilingual version of the questionnaire. Hand drawings were used to replace photographs from the original questionnaire. Face validity and content validity were assessed, and construct validity was determined by comparing responses from informal caregivers, medical students, and primary care doctors. Finally, the internal consistencies of the subscales were determined. Results: Pretesting showed that the translated version was sufficiently easy to understand. Internal consistency for the positioning subscale (28 items, Cronbach's alpha = 0.70) and feeding subscale (15 items, Cronbach's alpha = 0.70) was good. Mean scores for the positioning subscale for caregivers (mean: 17.1 +/- 3.9), medical students (mean: 18.9 +/- 3.1), and doctors (mean 21.5 +/- 2.2) were significantly different (F = 5.28, P ' = 0.011). Mean scores for the feeding subscale for caregivers (mean 13.1 +/- 2.5), medical students (mean 16.1 +/- 1.9), and doctors (mean 16.1 +/- 2.4) also differed significantly (F = 6.217, P = 0.006). Conclusions: CKQ-My has good internal consistency and construct validity for the subscales measuring stroke caregivers' knowledge about positioning and feeding of stroke patients. It has potential as an assessment of effectiveness of caregiver training and for future studies on long-term stroke outcomes in Malaysia. PMID- 30410252 TI - Impact of Educational Training in Improving Skills, Practice, Attitude, and Knowledge of Healthcare Workers in Pediatric Palliative Care: Children's Palliative Care Project in the Indian State of Maharashtra. AB - Background: The "Children's Palliative Care Project" was initiated in October 2010 in the Indian state of Maharashtra with a view to improve the quality of life of children with life-limiting conditions. This study evaluates its education and training component through a questionnaire. Materials and Methods: A cross-sectional survey was carried out pre-/post-training among 258 doctors, nurses, social workers, and counselors at three sites in Maharashtra in March 2015. Descriptive statistics were used for data analysis. Results: Sixty-two participants responded. Posttraining, doctors and the nurses had a better level of knowledge, skill set, and attitude; whereas social workers and counselors fared better with prevailing care practices. Participants advocated using morphine only when other analgesics had failed and suggested ways for better service delivery of care. Conclusion: The study gives a rough idea of the prevailing practice of pediatric palliative care among the health-care workers (who participated in the survey) and suggests practical ways to improve it. PMID- 30410253 TI - Impact of Different Sociodemographic Factors on Mental Health Status of Female Cancer Patients Receiving Chemotherapy for Recurrent Disease. AB - Context: Deterioration in mental health and poor quality of life (QOL) among women suffering from breast and ovarian cancer is not a direct result of the illness but mediated by many other psychosocial variables. Aims: The study intended to examine if there was any effect of educational level, residential status, family type, duration of treatment, and income level of family on anxiety, depression, and QOL among the breast and ovarian cancer patients, undergoing second- or subsequent-line chemotherapy. Subjects and Methods: Forty married female cancer patients with breast and ovarian cancer, aging between 40 and 60 years, education level ranges from no formal education to postgraduate degree, income level ranges from Rs. 1000 per month to Rs. 20000 per month, and undergoing second- or subsequent-line chemotherapy for the past 1-10 years were studied. Levels of anxiety and depression were determined by Hospital Anxiety and Depression Scale. The QOL was measured by using WHO QOLBREF scale. Statistical Analysis Used: Mean and standard deviation and Levene's F values were calculated. If Levene's F value was significant, then Mann-Whitney U-test was done or else independent samples t-test was used. Results: Among all the variables, education, residential status, and income affect significantly on anxiety, depression, and QOL. Conclusions: Early detection of psychosocial variables is essential for better screening of the cancer patients undergoing chemotherapy, and therefore, further psychological intervention can be planned accordingly. PMID- 30410254 TI - End-of-life Care: Beliefs, Attitudes, and Experiences of Iranian Physicians. AB - Context: Most of the patients suffering from cancer are diagnosed at late stages of cancer, which curative interventions are unable to improve their quality of life. Aim: To survey Iranian physicians' attitudes and practices toward end-of life (EOL) care. Subjects And Methods: We conducted a cross-sectional survey among physicians participating in a national annually conducted educational seminar. Results: The survey results show that 80% of physicians had between 1 and 3 EOL patients. About 72% of patients received medical care in hospitals. The difference in best setting for care of terminally ill patients was statically significant after controlling for the length of practice and physician belief. The results also showed that that the participants believed that that the level of physicians' knowledge in this field was unacceptable. Conclusion: Physicians of our study were interested to participating in continuing education programs focused on EOL patients. PMID- 30410256 TI - Early Competing Deaths in Locally Advanced Head-and-Neck Cancer. AB - Introduction: The competing (noncancer) deaths have increased with aggressive treatment approach and better disease control in locally advanced head-and-neck cancer. Aim: The aim of this study is to find incidence, cause and predictors of early competing mortality in locally advanced head-and-neck cancer patients undergoing combined modality therapy. Subjects and Methods: In this retrospective study, a total of 125 locally advanced head-and-neck patients treated from January 2013 to June 2017 were analyzed. The total number of deaths, cause, and the time of death from the start of therapy was recorded. To study the risk factors of competing deaths, univariate and multivariate logistic regression was applied. Data were analyzed using SPSS v. 24 software. Results: A total of 51 deaths (31 cancer deaths and 20 competing deaths) recorded at a median follow-up of 16 months (1-62 months). The incidence of early competing mortality was 12% (n = 15) with a median time of 2.7 months from treatment initiation. Sepsis was major cause of early competing death (n = 13). On univariate and multivariate logistic regression analysis, competing death was significantly associated with pharyngeal (oropharynx, hypopharynx, and larynx) site primary (odds ratio [OR] = 3.562; 95% confidential interval [CI] = 1.207-10.517; P = 0.016), and Stage IVA/IVB disease (OR = 5.104; 95% CI = 1.123-23.202; P = 0.021). Conclusion: Competing deaths is one of the multifaceted problems in locally advanced head-and neck cancer patients. Sepsis being single most cause of early competing deaths in Stage IVA/IVB pharyngeal and laryngeal cancer. PMID- 30410255 TI - The Development of the Community-based Palliative Care Model in a District Health System, Phitsanulok Province, Thailand. AB - Context: Palliative care (PC) refers to a set of basic health services in Thailand and is in the early stage of implementation. Aim: The aim of this study is to develop a community-based PC model in a district health system (DHS) based on the form of action and evaluation. Methods: A three-step action research: look, think, and act was designed with mixed methods of data collection. Results: A key finding was the confusion on the terminology of the PC, challenge of the referral system of PC patients in DHS, medical equipment and supplies for the PC patients, and insufficient access to opioid analgesics at home. The model of development comprised the training of health professionals, the management of the medical equipment and supplies by people sector, and the development of a referral guideline of the PC patient in DHS. The evaluation showed the higher score of the accessibility to PC than the score of accommodation for patients. It also showed the higher score of the care continuity over the longitudinal continuity for patients. For the carers, the score of guilt is higher than the score of the care burden. Conclusions: A community-based PC model should be monitored by district health managment. The methods of this study are expected to be useful advice on how to solve similar problems in the other regions of similar context. PMID- 30410257 TI - A Comparison of Symptom Management for Children with Cancer in Iran and in the Selected Countries: A Comparative Study. AB - Aim: The aim of this study is to describe the experiences of other countries regarding the status of pediatric palliative care in the field of symptom management and to compare it with the current status in Iran to achieve an appropriate level of symptom management for children with cancer. Materials and Methods: This is a comparative study. The research population includes the palliative care systems of Jordan, England, Australia, and Canada, which were ultimately compared with Iran's palliative care system. Results: The results showed that in the leading countries in the field of palliative care, such as Australia and Canada, much effort has been made to improve palliative care and to expand its service coverage. In the UK, as a pioneer in the introduction of palliative care, a significant portion of clinical performance, education and research, is dedicated to childhood palliative care. Experts in this field and policymakers are also well aware of this fact. In developing countries, including Jordan, palliative care is considered a nascent specialty, facing many challenges. In Iran, there is still no plan for providing these services coherently even for adults. Conclusion: Children with cancer experience irritating symptoms during their lives and while they are hospitalized. Regarding the fact that symptom management in developed countries is carried out based on specific and documented guidelines, using the experiences of these successful countries and applying them as an operational model can be useful for developing countries such as Iran. PMID- 30410258 TI - Management of Malignant Wound Myiasis with Ivermectin, Albendazole, and Clindamycin (Triple Therapy) in Advanced Head-and-Neck Cancer Patients: A Prospective Observational Study. AB - Introduction: Myiasis, tissue infestation by housefly larvae, is commonly found in malignant fungating wounds of cancer patients from climatic condition and lower socio-economic strata. Aim of study: It was aimed to study the effectiveness of systemic Ivermectin, Albendazole& Clindamycin (Triple Therapy) in reducing signs & symptoms associated with maggots in malignant head and neck wounds. Method: 25 adult, advanced head and neck cancer patients presenting with maggots either from wound, oral cavity or nostril, with ECOG score 3 or less were enrolled in this study. Symptoms were assessed using Edmonton Symptom Assessment Scale (ESAS) and wound by Wound Assessment Tool - Hospice, at baseline and then Days 1, 3, 5, and 7. All patients received 3 days course of oral Ivermectin 12 mg per day, Albendazole 400 mg twice per day and Clindamycin 300 mg three times per day for 5 days along with Terpentine oil dressing. All patients received oral Morphine as per their pain score. Results: Mean age (yrs) and weight (Kg) were 42.15 +/- 8.23 and 52.31 +/- 5.18 respectively. 84% patients were male. Mean oral morphine dose was 100.38 mg. There was significant decrease in number of maggots from day 0 (77.28 +/- 13.465) to day 1 (20.60 +/- 7.263; 73.34% reduction) to day 3 (1.52 +/- 2.104; 92.62% reduction). We found statistically significant improvement (P = <0.05) in scores of wound and all other related symptoms on days 1, 3, 5 & 7, except bleeding, edema, nausea, anxiety, appetite loss and feeling of wellbeing, which remained same on Day 1, but improved afterward. Side effects were self-limiting. Conclusion: Systemic treatment with Ivermectin, Albendazole and Clindamycin (Triple Therapy) enhances the removal of maggots, early recovery and relief from distress and associated symptoms. PMID- 30410259 TI - How "Elderly Staying Alone" Cope Up with their Age and Deteriorating Health: A Qualitative Exploration from Rural Wardha, Central India. AB - Background: This study is done to explore the various changes and problems faced by the "elderly people staying alone" and how they cope up to maintain their life amidst the physical, familial, social, and financial crisis in their lives. Materials and Methods: This qualitative study was carried out in the villages surrounding Bhidi Rural Health and Training Center, located in the Vidarbha region of Maharashtra. A triangulation of free listing and pile sorting exercise was used. Elderly >65 years of age of either sex, living alone in their own houses, for at least 2 years were included in the study. Twenty-four such individuals were selected purposively who could figure out the different words and concepts regarding the three domains of our study for the purpose of line listing, namely, change of life since staying alone, problems faced while staying alone, and how they cope up with the problem of living alone. The data were analyzed using Anthropac software. The study findings were presented to the participants, who later pointed out few recommendations to be made. Results: The "elderly staying alone" face the problems of lack of family, social, and financial support in their day-to-day life. They cope with these problems by a number of ways. Although there are a number of government schemes to protect the elderly, none of these policies are dedicated to this special group of elderlies. Conclusion: There is no social structure that can take care of this vulnerable group of elderlies in rural India. It is high time for the government to step in to bring some societal and familial reforms that will safeguard the elderly staying alone from the ongoing familial, social, and financial hardship. PMID- 30410260 TI - The Prevalence of Chronic Pain among Adults in India. AB - Background: The prevalence of chronic pain (CP) is well described in Europe, America, and Australia. However, little knowledge is available of the prevalence of CP within Asia or Southeast Asia. Given the cultural and genetic variation in pain causation, manifestation, and reporting, the findings of previous western studies cannot be extrapolated to Asian countries. A prevalence study was needed to be carried out to quantify the magnitude and impact of CP in the adult population in India. Methods: Two sets of questionnaires were designed. The first, a screening questionnaire was used telephonically to identify the prevalence of CP, and should there be CP; the second, a detailed questionnaire was administered, to characterize the features and impact of pain. The interviews were carried out face-to-face. Results: A total of 4326 Indian patients were screened, and 836 completed a detailed pain questionnaire during 2006. The prevalence of CP was found to be 19.3% (n = 836). There was a higher prevalence in females (25.2%). Pain prevalence increased steeply beyond the age of 65 years old. There was a significant impact of CP on work and daily function. Conclusion: This Indian adults' population survey about CP found a higher prevalence of CP as compared to other Asian pain prevalence studies; however, the impact of pain was just as significant. In a rapidly aging population, CP is emerging as a significant healthcare problem which may likely to exert an increasing toll on the existing social infrastructure within the next two decades. PMID- 30410261 TI - Comparative Impact of Nonpharmacological Interventions on Pain of Knee Osteoarthritis Patients Reporting at a Tertiary Care Institution: A Randomized Controlled Trial. AB - Context: Nonpharmacological interventions (NPIs) have been advocated for knee osteoarthritis (KOA). There are many gaps in the evidence to their efficacy in India. Aims: The study aims to compare the impact of two packages of NPIs on various outcome variables of KOA patients. Settings and Design: This was a randomized controlled trial in a tertiary care hospital. Subjects and Methods: A study population (n = 123) of KOA patients aged 40-65 years. Stratified block randomization was done for mild or moderate KOA into two groups. Group "A" patients received a package of NPIs including a set of supervised exercise sessions, kinesthesia, balance, and agility (KBA), meditation, weight reduction advice, and weekly telephonic reminders. Group "B" patients received the same package except for KBA & meditation. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), visual analog scale (VAS) and performance-based measures were measured. Analysis: t-test and repeat measures ANOVA were undertaken. Results: A significant intragroup reduction in WOMAC score was seen from baseline in Group A (P = 0.00, mean difference: -9.7) as well as in Group B (P = 0.00, -12.9). There was also significant reduction inVAS scores at the end of intervention in Group A and Group B as compared from baseline (-3.62, -3.8, P = 0.00). No intergroup difference was observed in either of the scores. VAS score reduction to 0 at different stages of intervention was noticed in 46% (n = 57) cases. There was a significant intergroup difference for 50-Foot Walk Test (P = 0.055, F = 3.28) at 12 months. Conclusion: Both packages of NPIs were effective in providing relief in symptoms. No specific benefit of KBA or meditation was seen except for 50FWT. PMID- 30410262 TI - Dedication in Caring of Hemodialysis Patients: Perspectives and Experiences of Iranian Family Caregivers. AB - Background: Although dialysis treatment is considered as a life-saving treatment for chronic renal failure patients, the caregivers face challenges in caretaking of these patients. Objectives: This study is aimed to explain the perspectives and experiences among caregivers of the patients undergoing hemodialysis in Iran. Methods: A qualitative design, based on a thematic analysis approach, was used to reach the study aim. In this study, 25 hemodialysis family caregivers were selected by purposeful sampling. The data were gathered through in-depth and unstructured interview and field observation and analyzed by the inductive thematic approach. Results: The three main themes were generated from the analysis of the data indicating that the caregivers face challenges such as heavy burden of care, tension in care, and emotional exhaustion. Conclusion: Caretaking of the hemodialysis patients is constantly accompanied with challenges and concerns regarding the effective care for patients. Health-care providers need to address these concerns based on both patient- and caregiver-focused approaches, rather than only patient focused, to the design and planning for helping the patients and their caregivers. PMID- 30410263 TI - Coping Styles and Life Satisfaction in Palliative Care. AB - Background: Patients in palliative care suffer variously due to underassessment of needs and suboptimal intervention, coupled with lack of access to palliative care. This study attempts to identify effective coping strategies which lead to life satisfaction, among those afflicted with terminal cancer. Materials and Methods: This observational, cross-sectional study was carried out among terminally-ill cancer patients undergoing palliative care. Cancer patients receiving palliative care who give consent and were aged 18 years or older were included in the study. Those with cognitive deficits, delirium, or psychosis were excluded from the study. COPE scale, Temporal Satisfaction with Life Scale, and sociodemographic Performa were administered and analyzed. Pearson's r correlation coefficient test and multiple linear regression analyses were used to evaluate correlation and effect of coping strategies on life satisfaction. Results: Religious coping was the most frequently used coping strategy by patients, followed by acceptance. Females showed higher problem-focused coping, whereas males had higher emotion-focused and avoidant coping strategies. Females manifested more religious coping. Males showed more acceptance of their illness. Those without a partner had significantly higher emotion-focused coping strategies and higher religious coping. Income, social support, and problem oriented coping were positively related to quality of life. Life satisfaction showed significant negative correlation with denial, substance use, and venting utilized as coping methods. Conclusion: Problem-focused coping (religious coping and acceptance) was found to be more effective than other methods. Patients in palliative care could be instructed for the use of problem-focused coping. Such training might enhance their life satisfaction, helping them experience greater control over the course of illness. PMID- 30410264 TI - An Observational Study to Assess the Socioeconomic Status and Demographic Profile of Advanced Cancer Patients Receiving Palliative Care in a Tertiary-Level Cancer Hospital of Eastern India. AB - Introduction: Socioeconomic status (SES) comprises of not just gross income but also educational qualification, financial security and individual perceptions of social status and class. It has been observed that people with low SES have less access and utilization of palliative care services. With this background, this observational study was carried out at SGCCRI to assess and evaluate the SES of patients attending the palliative care department and analyse the major social concerns of patients in the last days of life. Objectives: Assessment of socio- economic status and demographic profile of patients with advanced cancer receiving palliative care. Materials and Methods: From May 2017 to October 2017 we assessed the demographic features and socio-economic status of 80 advanced cancer patients receiving palliative care by interviewing them face to face with the help of a self designed social assessment sheet. Results: A total of 80 patients consented to be interviewed with regards to assessment of their socio economic conditions. Majority were male patients (64%) with the highest percentage in the age group of 60-70years (33%). 38% of the patients interviewed were from rural surroundings. Only 38% of the patients had completed their basic education. Approximately 30% of the patients interviewed had income less than 1lakh/month while majority (>60%) had income in the bracket of 1lakh- 2lakh. In 30% of cases, the patient was the sole earner in the family. Conclusion: It was observed that majority of patients and their family were constrained with regards to financial resources and large percentage of patients had social insecurity with respect to future of family members. PMID- 30410265 TI - A Comparative Study of Transdermal Buprenorphine and Oral Morphine in the Treatment of Chronic Pain of Malignant Origin. AB - Background and Objective: The study was designed to compare the efficacy and adverse effects of buprenorphine transdermal (TD) against oral morphine in pain management of cancer patient. Methods: A randomized open-labeled prospective study was done in palliative cancer pain clinic in a tertiary care medical college between August 2017 and January 2018, to compare the efficacy (pain assessed by VAS) and adverse events (CTCAEv4) between arm A, buprenorphine TD, (20 MUg/h, extended 7 days formulation) and arm B, oral morphine (10mg immediate releasing formulation). Patients with solid tumour malignancies with VAS score >40 (moderate to severe pain) were included in study. Results: 63 patients were analyzed. Commonest primary cancers were breast in females and head and neck in male individuals in both arms. Initial VAS score of arm A and arm B were 81.25 and 82.26 respectively. By 1st week, 11 arm A patients were relieved from pain. Another 17 patients of arm A became pain free by 2nd week, total dose of 40 MUg/h. Only 4 patients needed 60 MUg/h for pain relief. In arm B, 2 patients were relieved by 1 week with total 30mg/day morphine, 11patients were relieved with 60 mg/day by 2nd week and 12 patients with 90 mg/day. 6 patients were relieved with 120 mg/day dose at the end of 4th week. Nausea and constipation were stastically higher in Arm B compared to that of Arm-A. Conclusions: TD Buprenorphine had similar efficacy with oral morphine, with better toxicity profile and better compliance. PMID- 30410266 TI - Decubitus Ulcer Development: An Investigation on Its Effect and Evidence in Home Care Patients. AB - Background and Aims: Decubitus ulcer (DU) is one of the commonly observed health problems among home care patients. As well as deteriorating social, physical, and psychological conditions of the patients, it is a cause of severe economic loss due to long-term bed occupancy and high care costs. This study aimed to examine the factors which affect the development of decubitus ulcer among home care patients and provide extensive data to the literature. Patients and Methods: This study was conducted with on home care patients aged over 40 years old who were registered at Etimesgut Ankara Sehit Sait Erturk State Hospital. Following the face-to-face interviews with the patients at home, the scores of Subjective Global Assessment (SGA), Mini Nutritional Assessment (MNA), Daily Life Activities (DLA), and Geriatric Depression Scale (GDS) were recorded. Development of DU was monitored through routine examinations in the home care patients. It was encountered how SGA, MNA, DLA and GDS functioned in predicting the development of DU using logistic regression during effort and also how status of equipment and presence of comorbid diseases affected its development. Results: It was determined that malnutrition affected development of DU by decreasing mobility while the presence of psychological problems increased the risk for development. Furthermore, number of comorbid diseases and status of health equipment used by the patients were found effective in the development of DU. Conclusion: It is obvious that decreased inability of independent mobility in DLA increase the risk for malnutrition and consequently two assessments show a negative impact on psychology of the patient. PMID- 30410267 TI - Initial Perceptions about Palliative Care in Patients with Advanced Cancer: A Prospective Cross-Sectional Audit. AB - Introduction: There is enough evidence to suggest that early introduction to palliative care (PC) for patients with advanced cancer is beneficial. However, despite this, the patients often come late to PC physicians. There are a number of studies examining the preferences and practices of the physicians with respect to PC. However, there is limited literature exploring the patients' preferences and awareness regarding the PC services. This audit was done to identify the understanding and perceptions of PC in patients visiting PC outpatient department (OPD) and identify strategies to enhance their understanding. Materials and Methods: This prospective cross-sectional study was conducted in 200 advanced cancer patients visiting PC OPD in a tertiary care hospital. The patients were asked to fill a questionnaire to assess their knowledge and expectations form PC on their first visit. Results: Majority of the patients were from nearby areas and around 20% of them had to travel more than 300 km to receive palliative consultation. Unfortunately, majority of the patients had not heard the term PC before and were not aware of its meaning. Most of them (90%) were send to control pain which was too severe to be managed by the oncologists. We think that the major reason for the lack of awareness about PC services is limited availability across the country and lack of coordinated approach. Conclusions: The main problem identified in the audit was the inadequate information, lack of PC setups, and late referral of the patients to PC. Hence, we should make a model where PC services are integrated with the curative services and offered throughout the illness after cancer diagnosis. PMID- 30410268 TI - Who Can Provide Spiritual Counseling? A Qualitative Study from Iran. AB - Background and Aim: Given the increased prevalence of mental illnesses in recent years, many therapists and researchers use spiritual counseling (SC), which is one of the spiritual interventions. However, unfortunately, the use of this intervention by the therapists is nonscientific because the ambiguities of this issue are high in the mental health field of Iran. The aim of this study is to survey the following most important challenges: what groups are qualified to provide SC, what kind of knowledge should be known by suitable individuals, who can train spiritual counselors, what they should teach, and what teaching methods should be used. Methods: The present conventional qualitative content analysis used deep semi-structured interview to collect data from the view of stakeholders. A total of 15 people were selected through purposive sampling. After transcription of the interviews, the data were analyzed based on the Graneheim and Lundman model. Results: Results obtained from data analysis covered five main themes including SC candidates, general conditions, sciences required, SC curriculum, and spiritual counselors' training method. Conclusions: The present study has answered to the most basic questions in SC scope. Since spiritual services are rooted in our culture and religion, native guidelines should be created for them as soon as possible through conducting similar qualitative researches. Furthermore, it is worth considering teaching and training case in this scope to make spiritual service providers concern about solutions to promote these services. PMID- 30410269 TI - Effectiveness of the MELD/Na Score and the Child-Pugh Score for the Identification of Palliative Care Needs in Patients with Cirrhosis of the Liver. AB - Objective: Identification of palliative care needs in patients with liver cirrhosis using the MELD/Na score and the Child-Pugh score. Materials and Methods: A retrospective study of hospitalized patients with hepatic cirrhosis between January 2015 and December 2016 using the Child-Pugh score and the MELD/Na score in January 2018. Results: Recognizing end-of-life patients (the past 12 months of life) is a challenge for health professionals, especially in diseases with poorly defined criteria, such as cirrhosis of the liver. The verification of rapid functional decline and health indicators can be verified using already defined scales such as the Child-Pugh score and the MELD/Na score. Patients were classified according to the Child-Pugh score in Class A (17%), Class B (48.9%), and Class C (34%). The corresponding survival rate was as follows: class A (87.5%), Class B (30.4%), and Class C (31.25%). The MELD/Na score intervals were >9 (2.15%), score 10-19 (46.8%), score 20-29 (27.7%), score 30-40 (19.1%), and score >40 (4.3%). Nearly 51.1% had a MELD/Na score >20 and 48.9% <20. The study revealed that 59.6% of patients died before 12 months. They were end-of-life patients who needed palliative care to reduce the impact of the disease. Conclusions: The Child-Pugh score and the MELD/Na score represent a viable and easy-to-use tool to identify patients in need of palliative care, among those with liver cirrhosis. Early identification, timely evaluation, and effective treatment of physical, spiritual, family, and social problems improve the quality of life of people with incurable diseases and their families. PMID- 30410270 TI - Telerehabilitation for Chronic Obstructive Pulmonary Disease Patients: An Underrecognized Management in Tertiary Care. AB - Pulmonary rehabilitation (PR) is proved to be best supportive management in chronic obstructive pulmonary disease (COPD) individuals. The literature claims the reduction of dyspnea, fatigue, exacerbations, and improved functional capacity and quality of life. Home-based PR is being prescribed widely than hospital-based rehab due to be less cost and ease of caregiver burden, but efficacy is usually questioned. The poor efficacy may be probably due to recurrent exacerbation and poor quality of life even after years of home rehabilitation. Telerehabilitation is an excellent rehab measure where the COPD patients exercise at his home, while expertise from the tertiary care centers monitors the rehab sessions remotely. In India, the tele-PR is at its budding state. This review shall enable the readers with the basics of telerehabilitation in comparison with the other available rehab measures and evidence in the management of COPD. PMID- 30410271 TI - Purple Urine Bag Syndrome: A Scary but Easily Manageable Condition in a Patient with Prolonged indwelling Urinary Catheter. AB - "Purple urine bag syndrome" (PUBS) is a rare but distressing presentation of urinary tract infection (UTI) among moribund patients on indwelling urinary catheter. A 56-year-old woman with carcinoma of the left breast and metastasis in vertebrae and liver was bed ridden. She was on Foley's catheter for 9 months, with the last catheter changed 3 weeks back. A 75-year-old woman presented with non-Hodgkin's lymphoma for 2 years and moderately differentiated squamous cell carcinoma of the right parotid region (8 months). She experienced fall and fracture of femur, bed ridden, and on Foley's catheter for 7 years. She had facial wound with maggots for 3 days. Both the women developed purple-colored urine with no other symptoms of UTI. No investigations were carried out and they were empirically treated with nitrofurantoin, catheter change reassurance, and increased fluid intake. Urine color was normal by a week. PUBS can be managed easily at home with simple antibiotics, adequate hydration, and family/patient counseling in palliative care settings. PMID- 30410272 TI - Does Palliative Sedation Produce an Ethical Resolution to Avoid the Demand for Euthanasia in a Muslim Country? AB - One of the major purposes of palliative sedation is to reduce demand for euthanasia. The present paper analyzes a grievous case which demonstrates the killing of a 23-year-old son by his father due to the son's unbearable pain resulting from metastatic colorectal cancer. The article aimed to elaborate the case to figure out whether palliative sedation can be an alternative to euthanasia in a Muslim country. Nevertheless, the analysis of these two end-of life issues revealed that the limitation of palliative sedation to an expected lifespan of less than 2 weeks as well as the Islamic view on the importance of protecting consciousness preclude reaching a conclusion that palliative sedation can be an alternative to euthanasia in this particular case. Furthermore, in such cases, the primary problem may be the lack of adequate and appropriate palliative care services, rather than the need for euthanasia or palliative sedation. PMID- 30410273 TI - Magic Word "Palliative:" An End to Cure but No End to Care. PMID- 30410274 TI - Lofexidine for Treating Opioid Withdrawal Syndrome in Palliative Care Patients. PMID- 30410275 TI - Feasibility of Chronotherapy for Preventing Delirium in Patients with Cancer: An Idea for Future Clinical Trials. PMID- 30410276 TI - Ultrafast Transient Absorption Spectra of Photoexcited YOYO-1 molecules call for additional investigations of their fluorescence quenching mechanism. AB - In this report, we observed that YOYO-1 immobilized on a glass surface is much brighter when dried (quantum yield 16+/-4% in the ambient air) or in hexane than in water (quantum yield ~%).YOYO-1 is a typical cyanine dye that has a photo isomerization reaction upon light illumination. In order to understand this quenching mechanism, we use femtosecond transient absorption spectroscopy to measure YOYO-1's electron dynamics after excitation directly. By deconvoluting the hot-ground-state absorption and the stimulated emission, the dynamics of electronic relaxation and balance are revealed. The results support the intermolecular charge transfer mechanism better than the intramolecular relaxation mechanism that has been widely believed before. We believe that the first step of the relaxation involves a Dexter charge transfer between the photo excited YOYO-1 molecule and another guest molecule that is directly bound to the YOYO-1 giving two radicals with opposite signs of charges. The charges are recombined either directly between these two molecules, or both molecules start to rotate and separate from each other. Eventually, the two charges recombined non-radiatively via various pathways. These pathways are reflected on the complicated multi-exponential decay curves of YOYO-1 fluorescence lifetime measurements. This charge transfer mechanism suggests that (1) electrical insulation may help improve the quantum yield of YOYO-1 in polar solutions significantly and (2) a steric hindrance for the intramolecular rotation may have a less significant effect. PMID- 30410277 TI - Selected Medication Safety Risks That Can Easily Fall Off the Radar Screen-Part 3. AB - The final part of a 3-part series discusses medication safety risks related to labeling, patient education, and medication storage. PMID- 30410278 TI - Federal Safe Harbor for Value-Based Contracts Being Considered: P&T Committees Can Receive Data Beyond the Drug Label. AB - P&T committees may soon have access to more than drug-label information as HHS considers implementing a safe harbor for value-based contracts between drug manufacturers and health insurers. PMID- 30410279 TI - Drug and Device News. AB - Approvals, new indications, regulatory activities, and more. PMID- 30410280 TI - Pharmaceutical Approval Update. AB - Arakoda (tafenoquine) for malaria; Annovera (segesterone acetate and ethinyl estradiol vaginal system) for contraception; and Oxervate (cenegermin-bkbj) for neurotrophic keratitis. PMID- 30410281 TI - BaxdelaTM (Delafloxacin): A Novel Fluoroquinolone for the Treatment of Acute Bacterial Skin and Skin Structure Infections. AB - Baxdela (delafloxacin) for treatment of acute bacterial skin and skin structure infections. PMID- 30410282 TI - Contemporary Prescription Patterns of Adenosine Diphosphate Receptor Inhibitors in Acute Coronary Syndrome. AB - Purpose: To assess the contemporary use of adenosine diphosphate (ADP) receptor inhibitors in acute coronary syndrome at a large, quaternary academic medical center. Methods: A retrospective observational study was conducted using health records to compare patients who were treated with ticagrelor (Brilinta, AstraZeneca), prasugrel, or clopidogrel for a primary diagnosis of new-onset acute coronary syndrome between January 2014 and December 2014. Results: A total of 275 patients were identified. Clopidogrel was the most commonly prescribed ADP receptor antagonist (52%), followed by ticagrelor (26%) and prasugrel (22%). Patients who were prescribed clopidogrel were more likely female (P < 0.01), 75 years of age or older (P < 0.01), and 60 kg or less in weight (P = 0.02), and they had more comorbidities. Of the patients on clopidogrel prior to admission, 21% were switched to prasugrel or ticagrelor for inadequate platelet inhibition, restenosis, or new stent placement. Of the patients on ticagrelor or prasugrel prior to admission, 17% were switched to clopidogrel for concerns about bleeding or cost. Clopidogrel was prescribed 13% of the time, prasugrel 13% of the time, and ticagrelor 4% of the time (P = 0.13) outside the recommended use per Food and Drug Administration-approved prescribing information based on relative or absolute contraindications. Conclusion: Clopidogrel continues to be the most commonly prescribed antiplatelet agent, particularly in older patients with more comorbidities. PMID- 30410283 TI - Improving Medication History at Admission Utilizing Pharmacy Students and Technicians: A Pharmacy-Driven Improvement Initiative. AB - Background: Because of the frequency of medication errors related to care transitions, patient-safety initiatives have recently focused on improving the patient medication list. Pharmacy student and technician participation in the medication-history process has been shown to improve the quality of medication histories. To improve patient care, a pharmacy-driven medication-history service utilizing a unique hybrid team of pharmacy students and technicians was launched at Inova Loudoun Hospital (ILH). Objective: The objective of the service was to improve patient safety and therapy by providing the Best Possible Medication History (BPMH) for admitted acute-care patients. Methods: Data for the medication history service was collected for six months from July 2015 to January 2016. The service included pharmacy technicians and fourth-year pharmacy students using the BPMH approach to verify patients' allergies, medications, doses, and frequencies, and to ensure optimal documentation in the Electronic Health Record (EHR). Data on types and numbers of discrepancies and interventions were collected during the process. Readmission rates for the study group were calculated and compared to readmission rates for all patients. Results: Out of 4,070 patients interviewed, 77.7% (3,162) had at least one discrepancy in their medication list. Per patient, the average number of medications was 7.47, with an average of 1.8 discrepancies. Pharmacy students identified more discrepancies per patient than pharmacy technicians, 2.3 versus 1.5, respectively. Readmission rates for patients interviewed by the medication-history team was lower than for all patients during the same period, as well as for all patients during the same period in the previous year. Conclusion: This pharmacy-driven medication-history service, staffed with pharmacy technicians and students using a structured BPMH approach, increased the accuracy of home-medication lists on patient admission. The service demonstrated a difference in the types of interventions provided by pharmacy students and technicians. Readmission rates were also lower for patients with completed BPMH. PMID- 30410284 TI - Angiotensin II Brings More Questions Than Answers. AB - The approval of synthetic human angiotensin II (Giapreza, LaJolla Pharmaceuticals) by the FDA in December 2017 provides clinicians with a new tool in the treatment of distributive shock. Angiotensin II (ATII) was approved based on the results of the ATHOS-3 trial. In this trial, patients who received angiotensin II were more likely to achieve a mean arterial pressure of 75 mmHg or an increase in mean arterial pressure of 10 mmHg above that seen in patients who received a placebo. However, the results of ATHOS-3 also highlighted important concerns about thrombotic and infectious complications associated with ATII. Given that the cost of medication acquisition is approximately $1,500 per vial, practitioners must also decide how to implement ATII into practice in the most cost-effective manner. This commentary examines the current controversies surrounding both the safety and efficacy of ATII. PMID- 30410285 TI - 2018 European Association for the Study of Diabetes. AB - We review sessions on the association of diuretic use and amputations, albiglutide and cardiovascular outcomes with diabetes and cardiovascular disease, how lorcaserin affects diabetes in overweight patients, how testosterone therapy improves diabetes in hypogonadal men, the pros and cons of gastric bypass surgery, how low-calorie sweeteners affect the gut microbiome, and more. PMID- 30410286 TI - Research Briefs. PMID- 30410287 TI - Indications for Thoracic EndoVascular Aortic Repair (TEVAR): A Brief Review. AB - The utility of Thoracic EndoVascular Aortic Repair (TEVAR) continues to progress at a very rapid rate. Initially implemented for the treatment of thoracic aortic aneurysms, TEVAR has evolved to treat a variety of aortic pathologies and reduce overall morbidity and mortality rates compared with traditional open surgical repair. Given the rapidly evolving nature of endovascular thoracic intervention, we hereby briefly review the current literature on the evolving applications of TEVAR. TEVAR continues to rapidly evolve and is being applied to a growing number of aortic pathologies. Given the perioperative, short- and mid-term morbidity and mortality rates, TEVAR is quickly surpassing traditional open surgical intervention as the ideal procedure for patients undergoing intervention of the descending thoracic aorta and applicability to ascending and arch pathologies is being explored. However, as more data becomes available TEVAR may be associated with higher rates of reoperative requirements. Data remains limited on the long term efficacy of the intervention and should continue to be investigated. PMID- 30410289 TI - Role of Moderate Hypothermia and Antegrade Cerebral Perfusion during Repair of Type A Aortic Dissection. AB - The goal of this study was to compare early postoperative outcomes and actuarial survival between patients who underwent repair of acute type A aortic dissection with deep or moderate hypothermia. A total of 132 consecutive patients from a single academic medical center underwent repair of acute type A aortic dissection between January 2000 and June 2014. Of those, 105 patients were repaired under deep hypothermia (< 24 C degrees ), while 27 patients were repaired under moderate hypothermia (>=24 C degrees ). Median ages were 62 years (range: 27-86) and 59 years (range: 35-83) for patients repaired under deep hypothermia compared with patients repaired under moderate hypothermia, respectively ( p = 0.451). Major morbidity, operative mortality, and 10-year actuarial survival were compared between groups. Operative mortality was 17.1 and 7.4% in the deep and moderate hypothermia groups, respectively ( p = 0.208). Incidence of permanent stroke was 12.4% in the deep hypothermic circulatory arrest group and 0% in the moderate hypothermia group ( p = 0.054). Actuarial 5- and 10-year survival demonstrated a trend for lower long-term mortality with moderate hypothermia compared with deep hypothermia (69% 5-year and 54% 10-year for deep hypothermia vs. 79% 5-year and 10-year for moderate hypothermia, log-rank p = 0.161). Moderate hypothermia is a safe and efficient alternative to deep hypothermia and may have protective benefits. Stroke rate was lower with moderate hypothermia. PMID- 30410288 TI - Vein Size and Disease Severity in Chronic Venous Diseases. AB - Given the high prevalence of chronic venous diseases (CVD), defining criteria to screen patients who are in need for intervention is attaining primacy. An important clinical criterion for treating CVD is incompetence of larger veins. We have assessed the association of size of afflicted veins with disease severity in patients with CVD to define an acceptable criterion to identify patients who need intervention. Demographic characteristics and risk factors were recorded from 6350 patients. Based on physical examination and venous duplex ultrasound study, patients were classified into clinical severity, etiology, anatomy, and pathophysiology (CEAP) classes and grouped according to the size of the veins which had varicosities. Patients with reflux in smaller veins (vein size <4 mm diameter) were considered as type I and those with varicosities in truncal veins (>4 mm diameter) as type II. Risk ratio was determined by multivariate regression analysis. About 47.67% of patients in this study were found to have CEAP class 3 disease. Compared with varicose veins of large truncal veins, patients with varicosities in smaller superficial veins had 2.85-fold ( p < 0.01) more risk of edema and 5.71-fold ( p < 0.01) higher prevalence of hyperpigmentation. Varicosities in small superficial veins were associated with higher risk of ulceration (odds ratio 3.93, 95% confidence interval 2.51-6.18) compared with truncal vein reflux. Our study reveals that presence of small varicose veins in patients without truncal saphenous reflux involvement is associated with severe manifestations of venous insufficiency such as edema and skin lesions even in the absence of varicosities in truncal saphenous veins. PMID- 30410290 TI - Sarcolemmal Alterations in Unloaded Rat Heart after Heterotopic Transplantation. AB - Following heterotopic transplantation, the rat heart undergoes atrophy and exhibits delayed cardiac relaxation without any changes in contraction and systolic Ca 2+ transients. Furthermore, the sarcoplasmic reticular Ca 2+ uptake and release activities were reduced and Ca 2+ influx through L-type Ca 2+ channels was increased in the atrophied heart. Since Ca 2+ movements at sarcolemma are intimately involved in the regulation of intracellular Ca 2+ concentration, the present study was undertaken to test if sarcolemma plays any role to maintain cardiac function in the atrophied heart.The characteristics of sarcolemmal Ca 2+ pump and Na + -Ca 2+ exchange activities were examined in 8 weeks heterotopically isotransplanted rat hearts which did not support hemodynamic load and underwent atrophy. Sarcolemmal ATP (adenosine triphosphate) dependent Ca 2+ uptake and Ca 2+ -stimulated ATPase (adenosine triphosphatase) activities were increased without any changes in Na + -K + ATPase activities in the transplanted hearts. Although no alterations in the Na + -dependent Ca 2+ uptake were evident, Na + -induced Ca 2+ release was increased in the transplanted heart sarcolemmal vesicles. The increase in Na + -induced Ca 2+ release was observed at different times of incubation as well as at 5, 20, and 40 mM Na + . The sarcolemma from transplanted hearts also showed higher contents of phosphatidic acid, sphingomyelin, and cholesterol.These results indicate that increases in the sarcolemmal, Ca 2+ transport activities in unloaded heart may provide an insight into adaptive mechanism to maintain normal contractile behavior of the atrophic heart. PMID- 30410291 TI - Results of Ten-Year Follow-Up of Alcohol Septal Ablation in Patients with Obstructive Hypertrophic Cardiomyopathy. AB - This study looks at 10-year follow-up outcomes of alcohol septal ablation in patients with obstructive hypertrophic cardiomyopathy. Between 2000 and 2008, 40 patients with obstructive hypertrophic cardiomyopathy (27 males, 13 females) underwent alcohol septal ablation. The median follow-up period was 123 (2-179) months. The mean age ran to 43.8 + 13.9 years. The initial dose of ethanol (3 mL) was chosen for ablation in all cases. The hospital mortality was 0%. Permanent pacemakers were implanted in 3 of 40 (7.5%) cases in the hospital period. The median clinical follow-up was 123 (2-179) months. Survival rates at 1, 5, 10, and 15 years after the procedure were as follows: 97.5% (95% confidence interval [CI], 95.1-99.9%), 92.5% (95% CI, 94.8-90.2%), 85.0% (95% CI, 82.9-87.1%), and 81.3% (95% CI, 79.3-83.3%), respectively. Seven patients died during follow-up. Sudden death was observed in two cases. Permanent pacemakers were implanted in 2 of 40 (5%) cases in the follow-up. The log-rank test revealed no statistically significant difference between the 15-year survival rate in our cohort and age- and sex-matched general Russian population ( p = 0.11113). Alcohol septal ablation provides long-term survival rates that look comparable with age- and sex matched general population in the 15-year follow-up period. PMID- 30410292 TI - Exploring the Outcomes of Portal Vein Thrombosis in the Clinical Setting of Cirrhosis, Malignancy, and Intra-abdominal Infections with and without Anticoagulation: A Retrospective 5-Year Study. AB - The aim of this study was to understand the differences in clinical outcomes in portal vein thrombosis (PVT) patients with cirrhosis, malignancy, and abdominal infections, with or without anticoagulation. This study was approved by ethics committee. Data were collected from 2011 to 2016. Patients were classified into three groups: PVT with cirrhosis, malignancy, and infections. Primary outcomes measures collected were clot resolution, bleeding, recurrence, and death. Frequency, means, and percentages were calculated. In total, 30 patients were analyzed in this study. Mean age was 60.8 years (range of 30-91 years). There were 19 (63.3%) males and 11 (36.7%) females with ethnicity: 21 (70.0%) Chinese, 2 (6.7%) Malay, 2 (6.7%) Indian, and 5 (16.7%) other race. Fifteen patients received anticoagulation and 15 did not receive anticoagulation. Of the 15 patients who received anticoagulation, there was complete resolution of thrombus in 5 (33.3%), partial resolution in 1 (6.7%), and no resolution in 9 (60.0%). Of these 15 patients, there was bleeding in 3 (20.0%), there was no recurrence in 9 (60.0%), and 3 (20.0%) died during the period of follow-up. Of the 15 patients who did not receive anticoagulation, there was complete resolution of thrombus in 2 (13.3%), partial resolution in 0 (0.0%), and no resolution in 13 (86.7%). Of these 15 patients, there was bleeding in 0 (0%), there was recurrence in 2 (13.3%), and 6 (40.0%) died during the period of follow-up. Anticoagulation is effective in PVT. It reduces mortality with lower rate of recurrence. However, it is associated with increased risk of bleeding. PMID- 30410293 TI - Advanced Glycation End Products:Receptors for Advanced Glycation End Products Axis in Coronary Stent Restenosis: A Prospective Study. AB - This study was aimed to correlate the pre- and 6-month postpercutaneous coronary intervention (PCI) serum concentrations of advanced glycation end products (AGE), soluble receptors for advanced glycation end products (sRAGE), AGE/sRAGE ratio, and serum malondialdehyde (MDA) levels with in-stent restenosis (ISR) among patients receiving either a drug-eluting stent (DES) or a bare-metal stent (BMS).In-stent restenosis remains as an adverse outcome following PCI. Sixty consecutive nondiabetic, Caucasian male patients, diagnosed with a non-ST elevation myocardial infarction who received either a DES or BMS via PCI, were enrolled. Baseline levels of serum AGE, sRAGE, AGE/sRAGE ratios, MDA, and angiographic parameters were determined at stenting and at 6 months. Patients with and without ISR at 6 months were compared on both baseline and 6-month biomarker levels and within stent types.The pre-PCI serum AGE levels and AGE/sRAGE ratios were higher in ISR patients compared with non-ISR patients, while the pre-PCI and post-PCI serum sRAGE levels were lower in ISR patients compared with non-ISR patients. The pre and post-PCI levels of MDA were also higher in ISR patients. Comparing stent types, relative levels of MDA between those with and without ISR at the respective time points were similar, although changes between time points appeared type specific.Post-PCI ISR correlates with low serum values of sRAGE and high serum values of AGE, MDA, and AGE/sRAGE ratio which are present at stenting. The associations of baseline AGE, sRAGE, AGE/sRAGE, and MDA levels with ISR appear consistent between stent types. PMID- 30410294 TI - Triple Coronary Artery Thrombosis Presenting as Acute Anterior ST-Segment Elevation Myocardial Infarction. AB - Simultaneous multivessel epicardial coronary artery thrombosis is an uncommon finding in acute ST-segment elevation myocardial infarction (STEMI). It generally leads to cardiogenic shock and sudden cardiac death in the hospital. We report a 42-year-old male patient presenting with acute anterior STEMI with triple coronary artery thrombosis. An emergency coronary angiogram showed total occlusion of the left anterior descending artery (LAD) with thrombus formation. At the same time, thrombus formations were also seen in the circumflex artery (CXA), the second obtuse marginal (OM2) branch, and the distal right coronary artery (RCA). We unsuccessfully attempted thrombus aspiration of the LAD. Subsequently, we decided to stent the LAD, and a successful percutaneous coronary intervention (PCI) was performed for the LAD. In a second procedure, RCA thrombosis regressed with 24-hour tirofiban (glycoprotein IIb/IIIa receptor inhibitor) perfusion, although CXA thrombosis and OM thrombosis did not regress. Therefore, we performed stenting of the CXA and OM with a newer provisional technique called the flower petal technique. Thrombolysis in myocardial infarction (TIMI) flow grade III was seen after stenting. The patient was discharged from the hospital 5 days after PCI without any symptoms. PMID- 30410295 TI - Distal-to-Snuffbox Arteriovenous Fistula. AB - The dogma for optimal arteriovenous fistula (AVF) creation is based on starting as distally as possible on the upper limb and progressing proximally. We herein present our findings of an AVF that is as distal as possible on the hand. To document primary patency rates of the distal-to-snuffbox AVF. A 10-year prospective study (2006-2016) involving 31 patients whose distal cephalic vein diameter was >=3 mm with a normal Allen's test was conducted. Patients were excluded if the radial artery in the wrist was highly calcified, the cephalic vein did not dilate more than 3 mm with proximal compression, and there was previously failed AVF of the limb or previous trauma to the limb. The procedure was performed under local anesthetic, and the anastomosis performed with a 6.0 polypropylene suture in an end-to-side fashion. Thirty-one patients with end stage renal disease underwent distal vascular access using the distal-to-snuffbox (Hitchhiker's) AVF (HAVF). During follow-up, eight patients died with an adequately functioning HAVF. The primary patency rates at 12, 24, 48, and 60 months were 90, 87, 85, and 82%, respectively. Failure occurred in six (19%) cases over the follow-up period, two in the first 2 weeks and four over a span of 60 months. Conclusion The creation of radiocephalic AVFs in the first web space, distal to the tendon of the extensor pollicis longus, serves as a viable option with acceptable success rates. This allows the surgeon more options with proper patient selection for this procedure. PMID- 30410296 TI - Balloon-Anchored CoKatte (r) for Successfully Delivering Balloons for an Occluded Anomalous Right Coronary Artery. AB - Percutaneous coronary intervention (PCI) for anomalous right coronary artery (RCA), originating from the left coronary cusp is challenging, because of the difficulty in engaging the guiding catheter coaxially, and delivering balloons and stents. A 65-year-old man with effort angina underwent PCI for anomalous RCA. This report describes the method we used. Although, delivering the balloon was difficult in short of the guiding catheter's backup force, we finally succeeded by using one more guiding catheter and the balloon-anchored CoKatte (r) , a novel, straight 4.5-French child catheter, to strengthen the backup force. PMID- 30410297 TI - Associations between Parental Relocation Following Separation in Childhood and Maladjustment in Adolescence and Young Adulthood. AB - Petitions by custodial parents to relocate children away from non-custodial parents present difficult choices for family courts. In the current study, the sample (N = 81) was randomly recruited through the children's schools according to the following criteria: Children were 12 years old and at the time resided primarily with their mothers; mothers had been living with a male partner "acting in a father role" for at least the previous year. Thirty-eight children had been separated by more than an hour's drive from their biological fathers due to either their mothers or fathers relocating. The data were collected from two reporters (children and mothers) at five time points (child ages 12.5, 14, 15.5, 19.5, and 22) by trained interviewers using standardized measures with adequate reliability and validity. Long-distance separation from biological fathers prior to age 12 was linked in adolescence and young adulthood to serious behavior problems, anxiety and depression symptoms, and disturbed relationships with all three parental figures (i.e., biological fathers, mothers, and step-fathers). These associations held after controlling for mother-stepfather conflict and domestic violence, mothers' family income, and mother-biological father relationship quality. These longitudinal findings over time replicated the cross sectional findings of Braver, Ellman, and Fabricius (2003) and Fabricius and Braver (2006). Policy implications for parental long-distance relocation following separation are discussed. PMID- 30410298 TI - Can resource dilution explain differences in height by birth order and family size? A study of 389,287 male recruits in twentieth-century Netherlands. AB - 'Resource dilution' has been invoked as a possible mechanism to explain the inverse relation between sibship size and sibling heights in European populations (Oberg, 2015). Alternative explanations include confounding of the relation by other measured or unmeasured family characteristics including socio-economic position or birth order. It is difficult to quantify the contribution of any factor in isolation. To examine the question, we accessed data from the national birth cohort of 389,287 Dutch conscripts born in 1944-1947 and examined for military service at age 18. The records include all men of Dutch nationality born between January 1, 1944 and December 31, 1947 examined for military service in the Netherlands. The birth cohorts provide a well-defined study population to reliably assess the impact of family size and birth order on adult height, accounting for potential confounders. The cohorts include a large number of high parity families, provide reliable information on both family size and birth order, and differentiate between all birth orders. The military examinations provide reliable information on height for all study subjects and uniform measurements at age 18. We show that recruits from larger families are shorter than recruits from smaller families; that birth order effects are small in relation to family size effects; and that birth order and family size effects are comparable in recruits from higher to lower socio-economic backgrounds. Recruits from higher backgrounds are significantly taller however. Our findings are compatible with a 'resource dilution' hypothesis, but our data provide no information on any specific differences in the childhood environment in terms of nutrition, education, or other family behaviours could explain the observed height differences at age 18. Additional studies will be needed to identify what differences in specific family behaviours could lead to changes in height development. PMID- 30410299 TI - Optimal Initial Trocar Placement for Morbidly Obese Patients. AB - Background and Objectives: Rates of morbid obesity are skyrocketing worldwide. Not only bariatric surgeons, but also general surgeons are often operating on morbidly obese patients. Many general surgeons still use the same anatomic landmarks for patients with body mass index (BMI) over 35 mg/kg2 as they do for patients of normal weight and can therefore find accessing the morbidly obese abdominal organs difficult. This paper will describe a technique that is easily reproducible and applicable in a wide range of laparoscopic cases. Method: The xiphoid process is the only landmark referenced. From the xiphoid process, the surgeon puts 2 fists together and places the first trocar inferiorly 2 cm lateral to the midline in either direction. The umbilicus is not used as a landmark. This placement is 15-18 cm inferior to the xiphoid process, but allows adequate visualization for any foregut case. An optical trocar is used. Results: In over 1400 bariatric cases, the initial trocar was safely placed with this technique. Most of these cases were performed with the method, but some had one modification: the first trocar was placed in the midclavicular line in the subcostal area if there were previous midline scars. In no cases was an extra long, or bariatric, trocar used. Conclusions: Laparoscopic access in morbidly obese patients does not have to be difficult. Using an optical trocar off the midline 15-18 cm below the xiphoid process will provide reliable, safe access in the morbidly obese patient, with excellent visualization of the target anatomy. PMID- 30410300 TI - A Regional and National Database Comparison of Colorectal Outcomes. AB - Background and Objectives: The traditional open approach is still a common option for colectomy and the most common option chosen for rectal resections for cancer. Randomized trials and large database studies have reported the merits of the minimally invasive approach, while studies comparing laparoscopic and robotic options have reported inconsistent results. Methods: This study was designed to compare open, laparoscopic, and robotic colorectal surgery outcomes in protocol driven regional and national databases. Logistic and multiple linear regression analyses were used to compare standard 30-day colorectal outcomes in the Michigan Surgical Quality Collaborative (MSQC) and American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) databases. The primary outcome was overall complications. Results: A total of 10,054 MSQC patients (open 37.5%, laparoscopic 48.8%, and robotic 13.6%) and 80,535 ACS-NSQIP patients (open 25.0%, laparoscopic 67.1%, and robotic 7.9%) met inclusion criteria. Overall complications and surgical site infections were significantly favorable for the laparoscopic and robotic approaches compared with the open approach. Anastomotic leaks were significantly fewer for the laparoscopic and robotic approaches compared with the open approach in ACS-NSQIP, while there was no significant difference between robotic and open approaches in MSQC. Laparoscopic complications were significantly less than robotic complications in MSQC but significantly more in ACS-NSQIP. Laparoscopic 30-day mortality was significantly less than for the robotic approach in MSQC, but there was no difference in ACS NSQIP. Conclusion: Minimally invasive colorectal surgery is associated with fewer complications and has several other outcomes advantages compared with the traditional open approach. Individual complication comparisons vary between databases, and caution should be exercised when interpreting results in context. PMID- 30410301 TI - Perceived Barriers to Antepartum HIV Medication Adherence in HIV Infected Pregnant Women. AB - Introduction: Although rare, perinatal HIV transmission still occurs in the United States and most transmissions are preventable. We aim to identify patient barriers to antiretroviral therapy (ART) adherence during pregnancy and assess patient understanding of perinatal transmission. Methods: This cross-sectional survey recruited HIV positive postpartum women at a large safety net hospital in Atlanta, Georgia, between January 2016 and February 2018. Survey questions included demographic characteristics, HIV history, knowledge of perinatal transmission, and ART adherence. Perinatal and HIV outcomes were assessed using chart abstraction. Results: Of the 70 HIV infected postpartum women delivered at a large safety net hospital in Atlanta, GA, 45 women were eligible and consented to participate. Participating women were aged 18 to 40 years with an average age of 29 years old, 93% of participants were African-American, and 68% had >=3 pregnancies. The majority of participants (75%) reported daily ART adherence. "Forgetting" was the most frequent reason for missing pills (57%). Thirteen women had a detectable viral load at the time of delivery and nine of those women had a viral load greater than 1000 copies/mL. Approximately 85% of women who correctly stated ART medications decrease perinatal transmission risk reported daily adherence compared with 50% of women without that knowledge (OR 5.6, 95% CI 1.17, 26.7). Almost half of women (40%) either did not know or believed a vaginal delivery, regardless of viral load, would increase their risk of perinatal transmission. Conclusion: Overall, women who were diagnosed with HIV during the current pregnancy, those with planned pregnancies, and those who were on medications prior to pregnancy were more likely to report daily ART adherence. Detectable viral load at delivery is the greatest risk factor for perinatal transmission; therefore strategies to increase ART adherence are needed. PMID- 30410302 TI - Evaluation of microvascular changes in the macular area of eyes with rhegmatogenous retinal detachment without macular involvement using swept-source optical coherence tomography angiography. AB - Purpose: To evaluate microvascular changes in the macular area of eyes with rhegmatogenous retinal detachment (RRD) without macular involvement (macula-on RRD) using swept-source optical coherence tomography angiography (SS-OCTA). Patients and methods: Five patients with macula-on RRD were eligible for analysis. All patients underwent SS-OCTA examination (Triton) for the macular area. The healthy fellow eyes were included as controls. The vessel density (VD) was calculated using binarization, and the foveal avascular zone (FAZ) was measured. The VD and FAZ area were compared between the eyes with RRD and the fellow eyes using the Wilcoxon signed rank test. Results: The patients' clinical characteristics were as follows: age, 49.0 years (21.0, 54.0) (median [25, 75th percentile]); preoperative best-corrected visual acuity, -0.08 (-0.08, 0.11) for RRD and -0.08 (-0.08, -0.03) for the fellow eye (P=0.50); and axial length, 27.0 (25.1, 28.7) mm for RRD and 27.4 (25.6, 28.5) mm for the fellow eye (P=0.31). The parafoveal VD was not significantly different between the eyes with RRD and the fellow eyes (P=1.00 for the superficial retina and P=0.44 for the whole retina). The FAZ area was also similar for the eyes with RRD and the fellow eyes (P=0.31 for the superficial retina and P=0.13 for the whole retina). Conclusion: The findings of this study suggest that the macular microvasculature remains intact in eyes with macula-on RRD. PMID- 30410303 TI - Intraocular lens intracapsular fixation with unilateral loop suture for 180 degree Zinn's zonule dialysis. AB - We developed intraocular lens (IOL) fixation procedure that only uses one suture during Zinn's zonule dialysis portion of the combined surgery for IOL intracapsular fixation and unilateral loop suture for preserving the lens capsule. We treated 15 eyes in 15 patients which were confirmed to have almost 180 degrees zonular dialysis during cataract surgery. After removing the lens, a scleral flap was created on the dialysis side. A straight needle for suturing was then inserted into the anterior chamber from the opposite side of the dialysis. The needle was used to attach the equatorial segment of the capsule on the dialysis side from the inside to the outside and then pull the suture thread under the scleral flap. After the thread was bound to a preceding loop of IOL, the IOL was inserted into the bag. Our procedure was found to be simple and less invasive, as our technique required no vitrectomy to be performed. PMID- 30410304 TI - Two-year outcomes of a pilot glaucoma suspect telemedicine monitoring program. AB - Purpose: The purpose of this study was to characterize a pilot program using e health to monitor glaucoma suspects in a large integrated health system. Methods: A retrospective chart review of patients enrolled in the first 2 years of a new glaucoma suspect telemedicine monitoring program was conducted. Patients were enrolled in the program after being diagnosed as glaucoma suspects in the regular clinic setting and were eligible for the program if they had better than 20/40 vision, intraocular pressure (IOP) <25 mmHg, a normal baseline visual field, and an optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) without clear evidence of glaucomatous optic nerve damage. Patients were followed annually thereafter with measurements of vision, IOP, and OCT RNFL, which were reviewed at a centralized telemedicine reading center. Patients were retained within the program unless there was evidence of disease progression, in which case they were referred to an ophthalmologist for further evaluation. The first 100 patients received a survey assessing their satisfaction with the program after their first visit. The number of patients who adhered to follow-up recommendations, who were referred to an ophthalmologist for additional evaluation, and who began on IOP-lowering medications was evaluated. Results: A total of 225 patients were enrolled in this program. Of eligible patients, 97.3% attended their 1-year follow-up visit and 92.5% attended their 2-year follow-up visit. Over the course of 2 years, five patients were referred for further clinic evaluation due to concern for progressive RNFL loss, of which two were started on IOP-lowering medications. No patients were referred to the clinic for vision loss or elevated IOP. In all, 87% of patients said that they would be extremely or quite likely to recommend the program to a friend. More than 80% of patients said that the program was extremely or very helpful, convenient, and professional. Conclusion: This novel telemedicine program for monitoring low-risk glaucoma suspects achieved high patient retention. Significant disease progression was rare with a few patients requiring referrals back to the clinic setting or initiation of IOP-lowering therapy. Telemedicine is a promising method to follow patients who are glaucoma suspects. PMID- 30410305 TI - Amniotic membrane transplantation with or without autologous cultivated limbal stem cell transplantation for the management of partial limbal stem cell deficiency. AB - Purpose: To compare the outcomes of amniotic membrane transplantation (AMT) vs cultivated limbal stem cell transplantation (LSCT) in eyes with partial limbal stem cell deficiency (LSCD) following chemical burns. Methods: Eyes with unilateral partial LSCD (#180 degrees involvement) were randomized in two groups to undergo either pannus resection combined with AMT or pannus resection combined with LSCT in a tertiary eye care hospital. Primary outcome measures were time to corneal epithelialization and absence of conjunctivalization of the cornea. Patients were followed up at 1 week, 1, 3, 6, and 12 months after the surgical procedure. Results: There was no difference between mean age (30.85+/-5.8 vs 28.64+/-6.4 years, P=0.40) and sex distribution of patients between the two groups at baseline. Mean time to corneal epithelialization was 10.45+/-5.8 days in the AMT group and 11+/-3.9 days in the LSCT group (P=0.43). At the end of 1 year, there was no significant difference between the degree of conjunctivalization of cornea, (P=0.06) corneal vascularization, (P=0.08), and clarity (P=0.07) in both groups. Conclusion: Our study showed that AMT alone is a useful therapeutic modality in cases with partial LSCD due to ocular chemical injury. Stem cell transplantation may not be required in these cases. PMID- 30410306 TI - Low vision, visual impairments and metropolitan urban planning: example of a topographic enhancement, need and monitoring in an Italian city. AB - Significance: The purpose of the study was to analyze all the steps needed to manage partially sighted or blind persons. Purpose: The aim of the first research was to collect and analyze data and opinions regarding the mobility of visually disabled people in Turin. The aim of the second research was to assess issues, daily needs and expectations regarding the urban reclassification plan for Via Nizza (Turin). Materials and methods: In the first study, we proposed a survey, partially structured and partially unstructured, of 100 patients enrolled in the Visual Rehabilitation Center of the Ophthalmic Hospital of Turin. In the second study, we collected data from a survey of eleven patients enrolled in the Turin section of the Italian Confederation of Blind. Results: It was observed that the visually disabled population was not necessarily elderly (46% of the population was less than 60 years of age); it was observed that the visually disabled people were active frequently. Environmental aids considered more useful were sound traffic lights (30%) and gradient signaling (29%); the first was not widespread in urban areas and was the aid most requested by the patients enrolled (49%); 48% of enrolled patients did not use tactile maps. As regards the reclassification of the urban plan of the area in Turin, important needs and expectations were highlighted. Conclusion: As regards urban planning in Turin as well as in other Italian cities, many changes in public facilities are to be done to ensure an increasing independence and safety of visually impaired people. PMID- 30410307 TI - Realgar, a traditional Chinese medicine, induces apoptosis of HPV16-positive cervical cells through a HPV16 E7-related pathway. AB - Purpose: In this study, we investigated the effect of Realgar on the apoptosis of HPV16-positive cervical cells in vitro. Methods: The effect of Realgar on the apoptosis of HPV16-positive cervical cells was investigated by annexin V fluorescein isothiocyanate/propidium iodide staining and growth inhibition assays using HPV16-positive cervical cancer cell line SiHa and HPV16-positive immortalized cervical epithelial cell line S12. The expression of genes was measured by real-time PCR, and the expression of corresponding proteins was detected by Western blotting. The adhesion and invasion of cells were detected by adhesion assay and Transwell invasion assay, respectively. Results: The Realgar inhibited the proliferation and induced the apoptosis of SiHa and S12 cells in a dose- and time-dependent manner. The Realgar suppressed the expression of HPV16 E7 and caspase-3. The Realgar suppressed the adhesion and invasion of both cells. Conclusion: The Realgar induced apoptosis, inhibited the proliferation of HPV16 positive cell lines through a HPV16 E7-dependent pathway, and inhibited cell adhesion and invasion. PMID- 30410308 TI - The efficacy and safety of aflibercept and conbercept in diabetic macular edema. AB - Diabetic macular edema (DME) has shown an increasing prevalence during the past years and is the leading cause of diabetic retinopathy blindness. Traditional treatment modalities include laser and corticosteroid therapy, which, however, either act through unclear mechanisms or cause cataracts and elevated intraocular pressure. In recent years, as the pathogenic role of VEGF in DME has been well recognized, the intravitreal injection of anti-VEGF drugs has become the first line treatment of DME due to their great efficacy in improving visual acuity and mitigating macular edema. Advantages have been shown for aflibercept and conbercept, the two recombinant decoy receptors that can bind VEGF with high specificity and affinity, in DME treatment in clinical trials conducted both worldwide and in People's Republic of China. This review introduces the structural characteristics and molecular mechanisms of action of these two anti VEGF drugs, and summarizes the clinical trials evaluating their efficacy and safety, with the hope to provide clues for designing optimal and personalized therapeutic regimens for DME patients. PMID- 30410309 TI - The retinoprotective role of phenytoin. AB - Phenytoin is a non-sedative barbiturate derivate and has been recently rediscovered as a neuroprotective and retinoprotective compound in patients affected by optic neuritis secondary to multiple sclerosis. However, currently there are still no neuroprotective compounds registered and available in the clinic. We reviewed the literature supporting the retinoprotective properties of phenytoin and analyzed the various approaches and definitions from the first research periods onwards. The retinoprotective role of phenytoin was already known in the 1970s, but only recently has this effect been rediscovered, confirming that it could indeed provide structural protection of the retinal cells. PMID- 30410310 TI - Intranasal niosomes of nefopam with improved bioavailability: preparation, optimization, and in-vivo evaluation. AB - Objective: One of the greatest challenges drug formulation is facing is poor bioavailability via oral route. In this regard, nasal drug delivery has been commonly used as an alternative route to improve drug bioavailability. Nefopam hydrochloride (NF) is an analgesic drug that suffers from poor bioavailability due to extensive metabolism in liver. Accordingly, the goal of the present study was to improve NF bioavailability via niosomal-based formulation designed for intranasal delivery. Materials and methods: Vesicles were developed by mixing surfactants (Span 20, Span 40, Span 80, and Span 85) at four molar ratios of 1:1, 1:2, 1:3, and 1:4 of cholesterol to surfactant. Entrapment efficiency, particle size, zeta potential, release percentage, ex-vivo permeation parameters, and niosomes' stability were determined. Also, the pharmacokinetic parameters of the optimized formula in in-situ gel base were measured in rats. Results: Niosomes showed entrapment efficiency .80%, particle size ,550 nm, and zeta potential ranging from -16.8+/-0.13 to -29.7+/-0.15. The produced vesicles showed significantly higher amounts of drug permeated across nasal mucosa (2.5 folds) and prolonged NF release compared with NF solution. Stability studies of optimum formula showed nonsignificant changes in niosomes parameters over a storage period of 6 months. The in-vivo studies showed a 4.77-fold increase in bioavailability of optimized nasal niosomes compared with oral solution of drug. Conclusion: The obtained results revealed the great ability of the produced NF loaded nio-somes to enhance drug penetration through nasal mucosa and improve its relative bioavailability compared with NF oral solution. PMID- 30410313 TI - Home administration of filgrastim (NivestimTM) in primary prophylaxis of chemotherapy-induced febrile neutropenia. AB - Background: The granulocyte-colony stimulating factor (G-CSF) biosimilar filgrastim (NivestimTM) reduces the duration and severity of neutropenia and the frequency of occurrence of febrile neutropenia (FN). Administration of this biosimilar filgrastim and the patient population receiving it at home have not been sufficiently documented in day-to-day medical practice. Insight into home administration may help optimize the management of FN in this setting, potentially at a reduced cost and patient burden vs hospital administration. Materials and methods: This was a prospective, non-interventional, non comparative, multisite study involving 171 patients across 29 sites treated with at least one dose of filgrastim. Mean age was 59.3 years, and most patients were female and G-CSF-naive. The data collected originated from paper-based patient questionnaires and routine documentation by the treating physicians. The primary endpoint was the characterization of patients treated with filgrastim. Secondary endpoints were satisfaction with filgrastim, effectiveness, safety and tolerability, and compliance with prescription. Results: Most patients had solid tumors (95.9%), mainly located in the breast, while 4.7% had malignant hematological disease. Solid tumors were recorded as grade 1 (7.9%), grade 2 (28.0%), grade 3 (45.7%), and grade 4 (3.0%), and the majority of patients classified at TNM Stages I and II. Many patients (71.0%) could self-inject filgrastim and 72.2% found the handling instructions "extremely straightforward and easy to understand" at least once. Nearly all (99.4%) patients found the syringes "easy to use" at least once and 91.7% were willing to continue home administration. The mean patient satisfaction score for home administration was 1.9+/-0.9, ranging from 1 (very satisfied) to 6 (absolutely dissatisfied). No cases of neutropenia were observed and only one event of FN occurred. Conclusion: Home-based prophylaxis for FN with filgrastim was found to be effective, well tolerated, and well received by patients (ClinicalTrials.gov Identifier: NCT02956967). PMID- 30410311 TI - Patients', physicians', nurses', and pharmacists' preferences on the characteristics of biologic agents used in the treatment of rheumatic diseases. AB - Objective: To estimate preferences in relevant treatment characteristics evaluated by different groups involved in the management of patients with rheumatic diseases. Subjects and methods: We surveyed patients with rheumatic diseases, and rheumatologists, nurses, and pharmacists with experience in treatment with/provision of biologic drugs for these patients. Through a discrete choice experiment, participants evaluated 16 possible scenarios in which pairs of similarly efficacious treatments were described with six characteristics: 1) frequency of administration; 2) mode and place of administration; 3) manner, helpfulness, efficiency, and courtesy of health personnel; 4) frequency of reactions at the site of drug administration; 5) severity of generalized undesired/allergic reactions; and 6) additional cost. The direction and strength of preferences toward each characteristic level and the relative importance of each characteristic were estimated through a random-effects conditional logistic regression model. Results: In total, 513 patients, 110 rheumatologists, 51 nurses, and 46 pharmacists from 30 centers in Italy participated. Characteristics 3, 4, and 6 were the most important for every subgroup; 1 was least important for patients and rheumatologists, 2 was least important for pharmacists, and 2 and 5 were least important for nurses. For characteristic 2, pharmacists preferred subcutaneous self-injection with a syringe; nurses preferred assisted infusion at an infusion center close to the patient's home; patients and rheumatologists preferred subcutaneous self-injection with a pen. Conclusion: The different preferences for some characteristics shown by the different groups can play an important role, together with purely clinical aspects, in the choice and consequent benefit of treatments, contributing also to a more satisfactory use of resources. PMID- 30410312 TI - Integrating factors associated with hypertensive patients' self-management using structural equation modeling: a cross-sectional study in Guangdong, China. AB - Purpose: Hypertension is considered a major public health issue worldwide because of its high frequency and concomitant risk of cardiovascular disease (CVD). Chronic-disease self-management has been proven to be cost-effective, but influencing factors and pathways remain complex and unclear. The purpose of this study was to integrate factors associated with hypertension self-management to provide a theoretical reference for community hypertension management. Methods: A total of 268 community-dwelling hypertensive patients were enrolled in a cross sectional study conducted from July to September in 2017. A questionnaire on demographic-disease characteristics, disease knowledge, social support, self efficacy, and self-management was completed by patients. Structural equation modeling was performed to verify multiple factors in self-management based on the self-efficacy theory. Results: The final model showed a good fit to sample data, ie, younger patients with lower CVD risk, shorter disease course, and less disease knowledge and social support predicted less self-efficacy, less hypertension self-management, and less controlled hypertension. Furthermore, social support was negatively correlated with age, CVD risk, and disease course and positively with disease knowledge. Conclusion: Medication adherence is the lowest dimension in self-management, and self-efficacy is vital to consider in the development of self-management interventions. Self-management education and mutual-help groups may be potential solutions with the power of technology. Younger patients with lower CVD risk and shorter disease course are vulnerable and need more attention. PMID- 30410314 TI - Functioning and quality of life in Dutch oldest old with diverse levels of dependency. AB - Background: Frequently, a questionnaire like the EQ-5D is applied to investigate elderly health-related quality of life (HRQoL), but current literature suggests that inputs that go beyond these traditional health aspects might be of importance. The capability approach is a different method, which integrates several non-health-related factors to define the well-being of the oldest old. Objective: We propose to investigate the differences in oldest old functionings and quality of life (QoL), given different levels of dependency, using both a utility-based (EQ-5D+C) and capability-based (Currently Achieved Functioning) questionnaire. Methods: We interviewed 99 Dutch elderly, living in the Groningen, Veendam, and Hoogeveen areas. The average age of the elderly was 80 years, who were living independently, still looking after themselves; living semi dependently with moderate care; or living in a nursing home requiring consistent care. Results: The utility score for the dependent group is the lowest of all three groups, across the diseases investigated in this study. The respective average utility scores calculated for the dependent, semi-dependent, and independent subgroups were 0.56 (SD +/-0.10); 0.84 (SD +/-0.11), and 0.69 (SD +/ 0.13). Mobility and pain were reported to be the major domains where problems appeared across the three groups. Additionally, dependent elderly experience deficits in the role and control functionings while the other two subgroups experience deficits in pleasure and security. Conclusion: The results suggest that it is important to take note of the achievability of functionings and HRQoL, in addition to care dependency, to obtain QoL and well-being outcomes of the oldest old. PMID- 30410315 TI - Feasibility of vitamin D supplementation interventions to mitigate HIV pre exposure prophylaxis-related bone mineral density loss: a cross-sectional survey. AB - Background: Daily tenofovir disoproxil fumarate (TDF)/emtricitabine as HIV pre exposure prophylaxis (PrEP) causes subclinical decreases in bone mineral density (BMD). We surveyed PrEP users to assess feasibility for a clinical trial of vitamin D supplementation to mitigate TDF-induced BMD loss. Methods: We recruited participants using or starting PrEP in Toronto and Vancouver. The primary objective was to assess the acceptability of daily or weekly vitamin D supplementation. We also assessed the acceptability of calcium supplementation, existing use of non-pharmacological bone health interventions, prevalence of osteoporosis risk factors, and bone health knowledge (Osteoporosis Knowledge Test, OKT). Results: Of 161 participants, 72.1% were current PrEP users, 18.0% were starting PrEP, and 9.9% did not indicate their PrEP status. All identified as males, 88.8% as gays, and 67.1% as Whites. Median (IQR) age was 32.0 (29.0, 40.0) years, and 62.1% reported family income $$60,000/year. Among those not already using the interventions, willingness to supplement with daily vitamin D, weekly vitamin D, or daily calcium was very high at 90.9%, 96.4%, and 93.0 %, respectively. Only 31.0% reported adequate dietary calcium intake, while 42.9% reported $1 osteoporosis risk factor (most commonly, alcohol and smoking). Overall bone health knowledge was low, as median (IQR) OKT score was 16/32. In post hoc comparisons, current PrEP users may have been more likely than new PrEP users to engage in bone loading exercise (Bone-specific Physical Activity Questionnaire score=12.5 vs 3.6, P=0.001) and have greater bone health knowledge (OKT=17 vs 14, P=0.08), but they had similar levels of current vitamin D supplementation (37.4% vs 21.4%, P=0.11), calcium supplementation (11.2% vs 13.8%, P=0.70), and adequate dietary calcium intake (32.7% vs 25.0%, P=0.43). Discussion: The high acceptability of vitamin D and calcium supplementation in this cohort suggests that enrollment into a clinical trial of such interventions to mitigate PrEP-induced BMD loss is feasible. PMID- 30410316 TI - A qualitative exploration of barriers to medication adherence among patients with uncontrolled diabetes in Qatar: integrating perspectives of patients and health care providers. AB - Purpose: To develop an in-depth understanding of the barriers to medication adherence among patients with uncontrolled diabetes attending primary health care (PHC) centers in Qatar by exploring and integrating patients' and health care providers' perspectives. Participants and methods: A descriptive qualitative methodology was used in this study. A trained researcher conducted semi structured face-to-face interviews at two PHC centers. Patients with uncontrolled diabetes (with varied sociodemographic characteristics) and their respective health care providers (physicians, pharmacists, nurses, dieticians, and others) were purposively selected from the two PHC centers. All interviews were audio recorded, transcribed verbatim, and analyzed using thematic content analysis. Results: Thirty interviews (14 patients and 16 health care providers) were conducted. A number of barriers to medication adherence were identified and classified broadly under three main themes: 1) patient-related factors, which included patients' individual characteristics and patients' perception, attitude, and behavior; 2) patient-provider factors, which included communication and having multiple health care providers caring for the patient; and 3) societal and environmental factors, which included social pressure and traveling to visit friends and relatives. Conclusion: Patients with uncontrolled diabetes face multiple barriers to medication adherence. Similar themes emerged from both patients and their care providers. This research highlights the need for concerted multidimensional efforts and series of interventions to overcome these barriers. One vital intervention is expanding the scope of pharmacists' role within the PHC centers through providing medication reconciliation, patient tailored medication counseling, and medicines use review, which may improve treatment outcomes among patients with diabetes. PMID- 30410317 TI - Risk factors for polypharmacy in older adults in a primary care setting: a cross sectional study. AB - Purpose: Polypharmacy (PP) is a clinical challenge in older adults. Therefore, assessment of daily drug consumption (DDC) and its relationships is important. First-line health services have a crucial role in monitoring and preventing PP. In this study, we aimed to assess DDC and investigate the risk factors for higher DDC among older adults in a primary care setting. Patients and methods: A total of 1,000 patients aged >=65 years who visited Melek Hatun Family Practice Center between December 1, 2014, and August 1, 2017, were enrolled in the study. All patients were seen either at the center or in their homes, and informed consent was obtained. Comprehensive geriatric assessment was performed for each subject. Data were analyzed using SPSS software (version 17). The daily number of medicines that each patient used (DDC) regardless of whether they were prescribed was the dependent variable. Relationships between DDC and other continuous variables were examined using Pearson's correlation. For between-group comparisons of DDC, Student's t-tests were performed. Results: Univariate tests showed relationships between DDC and various demographic and clinical parameters. The variables that remained significant at the last step of a stepwise linear regression analysis were metabolic syndrome, chronic pain, incontinence, increased serum creatinine level, increased Geriatric Depression Scale scores, reported gastric disturbances, and neutrophil/lymphocyte ratio. Conclusion: Along with certain chronic conditions, depressive symptoms and an inflammatory marker (neutrophil/lymphocyte ratio) were significantly and independently related to higher DDC. Longitudinal and larger studies are needed to further explore the multifaceted relationships of PP. PMID- 30410318 TI - Elevated serum IL-6 and adiponectin levels are associated with frailty and physical function in Chinese older adults. AB - Purpose: Frailty is associated with adverse health outcomes. Its biological markers are essential to enhance diagnostic ease and would contribute to surveillance of the condition. Considering the involvement of pro-inflammatory and nutritional states in frailty, we aimed to investigate whether inflammatory mediators and adipokines are associated with frailty and their relationship with physical function. Patients and methods: We recruited 130 older adults (90 nonfrail participants and 40 frail participants, mean age: 72.80+/-8.61 years) who underwent a comprehensive medical history and frailty assessment. The biochemical indicators (eg, blood urea nitrogen [BUN], high-density lipoprotein [HDL], and hemoglobin [HGB]), insulin pathway (glucose, insulin, and insulin-like growth factor 1 [IGF-1]), circulating inflammatory biomarkers (IL-6, tumor necrosis factor receptor 1, and C-reactive protein), and adipokines (adiponectin, vaspin, and leptin) were compared between the two groups. We further analyzed their correlation with physical function. Results: Frail older adults showed higher levels of BUN, IL-6, adiponectin, vaspin, and glucose and lower levels of IGF-1, HDL, and HGB compared with nonfrail participants. Serum IL-6 levels were negatively correlated with both grip strength (P=0.03) and gait speed (P=0.04). Levels of circulating adiponectin and leptin were adversely correlated with grip strength (P=0.01) and gait speed (P=0.03), respectively. After adjustment for age and sex, the only markers correlated with physical function were IL-6 (r=-0.180, P=0.044) and adiponectin (r=-0.195, P=0.029). Conclusion: High levels of IL-6, adiponectin, vaspin, and glucose as well as low levels of IGF-1 were found in frail older adults. Furthermore, IL-6, adiponectin, and leptin levels were negatively correlated with physical function, suggesting that inflammatory mediators and adipokines are biomarkers for frailty and decreased function in older adults. PMID- 30410320 TI - Prevalence of functional dependence in Chinese centenarians and its relationship with serum vitamin D status. AB - Background: Functional dependence (FD) and vitamin D deficiency are common conditions in older adults. However, little is known about the relationship between FD and serum vitamin D status in centenarians. The current study was designed to evaluate the prevalence of FD and examine its relationship with serum vitamin D status among centenarians in China. Subjects and methods: A cross sectional study of a large sample of Chinese centenarians including 180 men and 822 women was conducted from June 2014 to December 2016. Home interviews, physical examinations, and blood analyses were performed in 958 centenarians following standard procedures. FD was evaluated using the Barthel index of activities of daily living (ADL). Serum 25-hydroxyvitamin D (25OHD) concentrations were measured as a marker of vitamin D status. Results: The prevalence of centenarians with FD was 71.2%. Vitamin D deficiency, lack of tea consumption, lack of outdoor activities, visual impairment, and fracture were predictors of FD. Centenarians in the lowest quartile of serum 25OHD concentration had an approximately threefold greater likelihood of FD than those in the highest quartile in multiple logistic regression models (OR =2.88; 95% CI 1.75-4.73; P<0.001). The multivariable OR with a 1 ng/mL decrease in serum 25OHD concentration was 1.06 (95% CI 1.04-1.08; P<0.001) for FD. Conclusion: Serum 25OHD levels have important associations with FD in Chinese centenarians. Future research could focus on the value of intervening in the case of low serum 25OHD levels through vitamin D supplementation and improving ADL in the older population. PMID- 30410319 TI - Assessment of late-life depression via self-report measures: a review. AB - Depression in later life is a significant and growing problem. Age-related differences in the type and severity of depressive disorders continue to be questioned and necessarily question differential methods of assessment and treatment strategies. A host of geropsychiatric measures have been developed for diagnostic purposes, for rating severity of depression, and monitoring treatment progress. This literature review includes the self-report depression measures commonly and currently used in geropsychological practice. Each of the included measures is considered according to its psychometric properties. In particular, information about reliability; convergent, divergent, and factorial validity evidence based on data from clinical and nonclinical samples of older adults; and availability of age-appropriate norms was provided along with the strengths and weaknesses of each measure. Results highlighted that in cognitively intact or mildly impaired patients over 65 years, the Geriatric Depression Scale and the Geriatric Depression Scale-15 currently seem to be the preferred instruments. The psychometric functioning of the Beck Depression Inventory-II and the Center for Epidemiological Studies Depression Scale, instead, is mixed in this population. Most importantly, this review may be a valuable resource for practicing clinicians and researchers who wish to develop state-of-the-science assessment strategies for clinical problems and make informed choices about which instruments best suit their purposes in older populations. PMID- 30410321 TI - The impact on health status in short- and long-terms of a novel and non-orthodox real-world COPD rehabilitation effort in rural India: an appraisal. AB - Background: Rehabilitation has been an integral part of management of COPD. Since the implementation of the standard rehabilitation protocol is hardly possible in the rural developing world, aiming to make a feasible alternate effort may be worthwhile. Methods: COPD patients diagnosed through spirometry were first stabilized with 6 weeks of uniform pharmacotherapy. Subsequently, they were subjected to a curriculum-based intensive single-session intervention with education, bronchial hygiene, and exercise training. The latter involved whole body exercise, pursed lip breathing, and diaphragmatic exercise. The participants continued to practice the exercises under real-world encouragement and supervision from trained volunteers. The impact was appraised in terms of change in health status through COPD assessment test (CAT) score measurements at stabilization, and after 6 weeks and 1 year of the intensive training and education. Results: At stabilization, 70 out of 96 selected COPD subjects (73%) turned up (with mean age 62+/-9 years and mean FEV1 as 1.16+/-0.39 L) showing improvement as per CAT score (p=0.0001) from pharmacotherapy. After practicing the imparted education and training for 6 weeks, all these 70 participants had further significant improvement in the health status (n=70, p=0.00001). This improvement, been reinforced and supervised, continued to last even at 1 year (n=54, p=0.0001). Conclusion: The self-managed practice of a single-session education and training under real-world supervision can bring forth significant long-term improvement in the health status of COPD sufferers. Such simple and feasible intervention may substitute formal COPD rehabilitation programs in resource constraint situations. PMID- 30410322 TI - Ectopic adiposity and cardiometabolic health in COPD. AB - Rationale: Obesity/overweight is the most prevalent body composition abnormality in COPD. However, little is known about the impact of fat distribution on cardiometabolic health in COPD. Objective: To study the associations between ectopic adiposity, cardiometabolic health, and COPD. Methods: A total of 263 subjects (166 males; age=65+/-9 years) were randomly selected from the general population. Subjects were classified as non-COPD controls and COPD, according to the Global initiative for chronic Obstructive Lung Disease (GOLD) classification, and the presence of cardiometabolic comorbidities was recorded. Ectopic fat accumulation was documented from computed tomography measurements of visceral adipose tissue cross-sectional areas and muscle mean attenuation, assessed at L4 L5. Blood glucose, lipid, and adipokine profiles were also evaluated. Results: After correcting for age, sex, and tobacco exposure, visceral adipose tissue cross-sectional area was higher in GOLD 2+ compared to GOLD 1 individuals. Consistent with this, mean muscle tissue attenuation was lower in GOLD 2+ vs GOLD 1 and non-COPD controls (P<0.001). In multiple regression models, visceral adipose tissue cross-sectional area was strongly associated with hypertension (P<0.001) and diabetes (P<0.001), while muscle attenuation was associated with coronary artery disease (P<0.001). Blood glucose, lipid, and adipokine profiles were similar across groups with the exception of leptin level which was higher in GOLD 2+ subjects compared to GOLD 1 and controls. Conclusion: GOLD 2+ COPD was associated with ectopic fat accumulation which modulated cardiometabolic health. PMID- 30410323 TI - Serum endocan levels in patients with stable COPD. AB - Background: Endothelial cell specific molecule-1, also called as endocan, is a dermatan sulfate proteoglycan, which is expressed by endothelial cells in alveolar walls of the lung and kidney. High endocan levels are found associated with endothelial dysfunction and inflammation. We hypothesize that endocan level is also high in COPD due to systemic inflammation and endothelial dysfunction. We aimed to investigate the expression of endocan in patients with stable COPD. Material and methods: The study included patients with COPD and control subjects. COPD patients were classified according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 criteria. Demographics, body mass index, smoking history, and comorbidities were recorded. Endocan levels of COPD patients and controls were compared. Results: Totally, 88 subjects (47 stable COPD patients, 41 controls) were evaluated. Endocan levels were significantly higher in COPD patients than control group (860.1+/-259.8 vs 647.3+/-316.9 pg/mL, P=0.001). There was no relationship between GOLD COPD categories and endocan levels. Also endocan levels were similar between COPD patients with or without hypoxemia. Conclusion: Serum endocan level was significantly higher in patients with stable COPD. Further studies should be performed to better understand the relationship between endocan and COPD. PMID- 30410324 TI - Predictors of mortality in patients with COPD after 9 years. AB - Background: COPD is one of the leading causes of morbidity and mortality in the world; however, the most varied amounts of clinical and laboratory characteristics acts in different ways in the mortality among over time. Therefore, this study aimed to evaluate the predictors of mortality in patients with COPD after 9 years. Patients and methods: One hundred and thirty-three patients with COPD were assessed at baseline by spirometry, pulse oximetry (SpO2), body composition, intensity of dyspnea, distance walked in the 6-minute walk test (6MWT), and Charlson Comorbidity Index (CCI). Results: After 9 years, it was not possible to identify the lifetime of 4 patients who died and of 19 patients who stopped follow-up; thus, 110 patients were included in the analysis of predictors of mortality (67% male, 65+/-9 years old, and FEV1: 52.5 [40% 73%]). Male sex, age, SpO2, Body mass index, airway Obstruction, Dyspnea, and Exercise capacity (BODE) index, and frequency of exacerbations in the first 3 years of follow-up were considered in the model. Patients classified at baseline with BODE class 2 (HR: 2.62, 95% CI: 1.36-5.04; P=0.004), BODE class 3 (HR: 2.54, 95% CI: 1.15-5.61; P=0.02), and BODE class 4 (HR: 15.35, 95% CI: 3.11-75.75; P=0.001) showed increased risk of death compared to those with BODE class 1. The CCI (HR: 1.29, 95% CI: 1.00-1.68; P=0.04) and the number of exacerbations in the first 3 years (HR: 1.32, 95% CI: 1.00-1.76; P=0.04) also showed increased risk of death. By replacing the BODE index for the variables that compose it, those with body mass index <=21 kg/m2 showed increased risk of death compared to those with body mass index (BMI)>21 kg/m2 (HR: 2.70, 95% CI: 1.38-5.25; P=0.003). Conclusion: After 9 years, we identified that those with high BODE index, greater CCI, greater frequency of exacerbations in the first 3 years, and BMI <=21 kg/m2 showed increased risk of death. PMID- 30410325 TI - Personalized nanomedicine: a rapid, sensitive, and selective UV-vis spectrophotometry method for the quantification of nanostructured PEG asparaginase activity in children's plasma. AB - Purpose: PEGylated asparaginase (PEG-ASNase), which hydrolyzes asparagine to ammonia and aspartic acid, is an effective nanostructured antitumor agent for acute lymphoblastic leukemia (ALL). In order to monitor the activity of PEG ASNase in plasma and design an individualization project, a rapid and sensitive method to determine PEG-ASNase activity in plasma using ultraviolet-visible spectrophotometry was established. Methods: PEG-ASNase is commonly used in acute lymphoblastic leukemia. With Nessler's reagent as the chromogenic reagent of ammonia, a stable yellow complex was produced. The units of enzyme activity were defined as micromoles of ammonia released per minute. Results: Calibration curves fitted by plotting the OD at 450 nm of the Nessler product vs concentration were linear in the range of 27.8-1,111.0 IU/L with r 2=0.999. The lower limit of quantification for PEG-ASNase activity in human plasma was 20 IU/L with good accuracy and precision. The intra- and interday precision (relative standard deviation) values were below 10% and accuracy ranged from 90% to 110% at all quality control levels. Analytical recoveries were determined between 90% and 110% for all quality control samples. Conclusion: This study proved that the Nessler method is well validated and can be successfully applied in the determination of plasma samples in the clinical setting for patients with ALL. It takes personalized nanomedicine to an entirely new level. PMID- 30410326 TI - Short duration cancer treatment: inspired by a fast bio-resorbable smart nano fiber device containing NIR lethal polydopamine nanospheres for effective chemo photothermal cancer therapy. AB - Background: The objective of this study was to evaluate the efficacy of a combination of Photothermal therapy (PTT) and chemotherapy in a single nano-fiber platform containing lethal polydopamine nanopheres (PD NPs) for annihilation of CT 26 cancer cells. Method: Polydioxanone (PDO) nanofiber containing PD and bortezomib (BTZ) was fabricated via electrospinning method. The content of BTZ and PD after optimization was 7% and 2.5% respectively with respect to PDO weight. PD NPs have absorption band in near-infrared (NIR) with resultant rapid heating capable of inducing cancer cell death. The samples was divided into three groups - PDO, PDO+PD, and PDO+PD-BTZ for analysis. Results: In combined treatment, PDO nanofiber alone could not inhibit cancer cell growth as it neither contain PD or BTZ. However, PDO+PD fiber showed a cell viability of approximately 20% after 72 hr of treatment indicating minimal killing via hyperthermia. In the case of PDO composite fiber containing BTZ, the effect of NIR irradiation reduced the viability of cancer cells down to around 5% after 72 h showing the efficiency of combination therapy on cancer cells elimination. However, due to higher photothermal conversion that may negatively affect normal cells above 46 degrees C, we have employed 1 s "OFF" and 2 s "ON" after initial 9 s continuous irradiation to maintain the temperature between 42 and 46 degrees C over 3 mins of treatment using 2 W/cm2; 808 nm laser which resulted to similar cell death. Conclusion: In this study, combination of PTT and chemotherapy treatment on CT 26 colon cancer cells within 3 min resulted in effective cell death in contrast to single treatment of either PTT and chemotherapy alone. Our results suggest that this nanofiber device with efficient heating and remote control drug delivery system can be useful and convenient in the future clinical application for localized cancer therapy. PMID- 30410327 TI - Biomimetic quantum dot-labeled B16F10 murine melanoma cells as a tool to monitor early steps of lung metastasis by in vivo imaging. AB - Background: Numerous studies have proposed the use of fluorescent semiconductor nanoparticles or quantum dots (QDs) as novel tools to label cells and tumors. However, QD applications are limited by their toxicity in biological systems and little is known about whether QDs affect the capacity of cancer cells to metastasize. Previously, we described the "biomimetic" synthesis of CdTe-QDs (QDs glutathione [GSH]) with increased biocompatibility and the potential utility in labeling cells. Purpose: In order to determine the feasibility of using QDs-GSH as a tool for tracking tumor cells during early metastasis, we characterized here for the first time, the in vitro and in vivo effects of the incorporation of green or red biomimetic QDs-GSH into B16F10 cells, a syngeneic mouse melanoma line for metastasis assays in C57BL/6 mice. Methods: B16F10 cells were labeled with green or red biomimetic QDs-GSH in the presence or absence of n acetylcysteine. Then, migration, invasion and proliferation of labeled B16F10 were evaluated in vitro. Finally, the B16F10 cells labeled with red QDs-GSH were used to monitor in vivo lung metastasis at early time points (5 minutes to 24 hours) or after 21 days in C57BL/6 mice. Results: We developed a methodology that allows obtaining QDs-GSH-labeled B16F10 cells (nearly 100% viable labeled cells), which remained viable for at least 5 days and migrated similarly to control cells. However, proliferation, invasion, and the capacity to form metastatic nodules in the lungs were severely attenuated. Fluorescence imaging revealed that distribution/accumulation of QDs-GSH-labeled B16F10 cells could be tracked following injection into C57BL/6 mice (syngeneic preclinical metastasis model) and that these cells preferentially accumulated in the perialveolar area in lungs as early as 5 minutes post-injection. Conclusion: The methodology described here represents a useful alternative for monitoring initial events during tumor cell metastasis. PMID- 30410328 TI - Photothermal exposure of polydopamine-coated branched Au-Ag nanoparticles induces cell cycle arrest, apoptosis, and autophagy in human bladder cancer cells. AB - Purpose: Polydopamine-coated branched Au-Ag nanoparticles (Au-Ag@PDA NPs) exhibit good structural stability, biocompatibility, and photothermal performance, along with potential anticancer efficacy. Here, we investigated the cytotoxicity of Au Ag@PDA NPs against human bladder cancer cells (T24 cells) in vitro and in vivo, as well as the underlying molecular mechanisms of photothermal therapy-induced T24 cell death. Materials and methods: T24 cells were treated with different doses of Au-Ag@PDA NPs followed by 808 nm laser irradiation, and the effects on cell proliferation, cell cycle, apoptosis, and autophagy were analyzed. To confirm the mechanisms of inhibition, real-time PCR and Western blot analysis were used to evaluate markers of cell cycle, apoptosis, autophagy, and the AKT/ERK signaling pathway. Moreover, we evaluated the effects of the treatment on mitochondrial membrane potential and ROS generation to confirm the underlying mechanisms of inhibition. Finally, we tested the T24 tumor inhibitory effects of Au-Ag@PDA NPs plus laser irradiation in vivo using a xenograft mouse model. Results: Au-Ag@PDA NPs, with appropriate laser irradiation, dramatically inhibited the proliferation of T24 cells, altered the cell cycle distribution by increasing the proportion of cells in the S phase, induced cell apoptosis by activating the mitochondria-mediated intrinsic pathway, and triggered a robust autophagy response in T24 cells. Moreover, Au-Ag@PDA NPs decreased the expression of phosphorylated AKT and ERK and promoted the production of ROS that function upstream of apoptosis and autophagy. In addition, Au-Ag@PDA NP-mediated photothermolysis also significantly suppressed tumor growth in vivo. Conclusion: This preclinical study can provide a mechanistic basis for Au-Ag@PDA NP-mediated photothermal therapy toward promotion of this method in the clinical treatment of bladder cancer. PMID- 30410329 TI - Cancer drug therapy and stochastic modeling of "nano-motors". AB - Background: Controlled inhibition of kinesin motor proteins is highly desired in the field of oncology. Among other interventions, there exists "targeted chemotherapeutic regime/options" of selective Eg5 competitive and allosteric inhibitors, inducing cancer cell apoptosis and tumor regression with improved safety profiles. Research question: Though promising, such studies are still under clinical trials, for the discovery of efficient and least harmful Eg5 inhibitors. The aim of this research was to bridge the computational modeling approach with drug design and therapy of cancer cells. Methods: A computational model, interfaced with the clinical data of "Eg5 dynamics" and "inhibitors" via special functions, is presented in this article. Comparisons are made for the drug efficacy, and the threshold values are predicted through numerical simulations. Results: Results are obtained to depict the dynamics induced by ispinesib, when used as an inhibitor of kinesin Eg5, on cancer cell lines. PMID- 30410330 TI - Effect of CCR2 inhibitor-loaded lipid micelles on inflammatory cell migration and cardiac function after myocardial infarction. AB - Background: After myocardial infarction (MI), inflammatory cells infiltrate the infarcted heart in response to secreted stimuli. Monocytes are recruited to the infarct via CCR2 chemokine receptors along a CCL2 concentration gradient. While infiltration of injured tissue with monocytes is an important component of the reparatory response, excessive or prolonged inflammation can adversely affect left ventricular remodeling and worsen clinical outcomes. Materials and methods: Here, we developed poly(ethylene glycol) (PEG)-distearoylphos phatidylethanolamine (PEG-DSPE) micelles loaded with a small molecule CCR2 antagonist to inhibit monocyte recruitment to the infarcted myocardium. To specifically target CCR2-expressing cells, PEG-DSPE micelles were further surface decorated with an anti-CCR2 antibody. Results: Targeted PEG-DSPE micelles showed eight-fold greater binding to CCR2-expressing RAW 264.7 monocytes than plain, non targeted PEG-DSPE micelles. In a mouse model of MI, CCR2-targeting PEG-DSPE micelles loaded with a CCR2 small molecule antagonist significantly decreased the number of Ly6Chigh inflammatory cells to 3% of total compared with PBS-treated controls. Furthermore, CCR2-targeting PEG-DSPE micelles significantly reduced the infarct size based on epicardial and endocardial infarct arc lengths. Conclusion: Both non-targeted and CCR2-targeting PEG-DSPE micelles showed a trend toward improving cardiac function. As such, PEG-DSPE micelles represent a promising cardiac therapeutic platform. PMID- 30410331 TI - Nanohybrid hydrogels designed for transbuccal anesthesia. AB - Background: Local anesthesia in dentistry is by far the most terrifying procedure for patients, causing treatment interruption. None of the commercially available topical formulations is effective in eliminating the pain and phobia associated to the needle insertion and injection. Materials and methods: In this work we prepared a nanostructured lipid-biopolymer hydrogel for the sustained delivery of lidocaine-prilocaine (LDC-PLC) for transbuccal pre-anesthesia. The lipid was composed of optimized nanostructured lipid carriers (NLC) loaded with 5% LDC-PLC (NLC/LDC-PLC). The biopolymer counterpart was selected among alginate, xanthan (XAN), and chitosan matrices. The XAN-NLC hydrogel presented the most uniform aspect and pseudoplastic rheological profile, as required for topical use; therefore, it was selected for subsequent analyses. Accelerated stability tests under critical conditions (40 degrees C; 75% relative humidity) were conducted for 6 months, in terms of drug content (mg/g), weight loss (%), and pH. Results: In vitro LDC-PLC release profile through Franz diffusion cells revealed a bimodal kinetics with a burst effect followed by the sustained release of both anesthetics, for 24 hours. Structural analyses (fourier transform infrared spectroscopy, differential scanning calorimetry and scanning electron microscopy) gave details on the molecular organization of the hybrid hydrogel, confirming the synergic interaction between the components. Safety and efficacy were evaluated through in vitro cell viability (3T3, HaCat, and VERO cells) and in vivo antinociceptive (tail-flick, in mice) tests, respectively. In comparison to a control hydrogel and the eutectic mixture of 5% LDC-PLC cream (EMLA(r)), the XAN NLC/LDC-PLC hybrid hydrogel doubled and quadrupled the anesthetic effect (8 hours), respectively. Conclusion: Considering such exciting results, this multifaceted nanohybrid system is now ready to be further tested in clinical trials. PMID- 30410332 TI - Development of a kojic monooleate-enriched oil-in-water nanoemulsion as a potential carrier for hyperpigmentation treatment. AB - Introduction: Kojic monooleate (KMO) is an ester derived from a fungal metabolite of kojic acid with monounsaturated fatty acid, oleic acid, which contains tyrosinase inhibitor to treat skin disorders such as hyperpigmentation. In this study, KMO was formulated in an oil-in-water nanoemulsion as a carrier for better penetration into the skin. Methods: The nanoemulsion was prepared by using high and low energy emulsification technique. D-optimal mixture experimental design was generated as a tool for optimizing the composition of nanoemulsions suitable for topical delivery systems. Effects of formulation variables including KMO (2.0%-10.0% w/w), mixture of castor oil (CO):lemon essential oil (LO; 9:1) (1.0% 5.0% w/w), Tween 80 (1.0%-4.0% w/w), xanthan gum (0.5%-1.5% w/w), and deionized water (78.8%-94.8% w/w), on droplet size as a response were determined. Results: Analysis of variance showed that the fitness of the quadratic polynomial fits the experimental data with F-value (2,479.87), a low P-value (P<0.0001), and a nonsignificant lack of fit. The optimized formulation of KMO-enriched nanoemulsion with desirable criteria was KMO (10.0% w/w), Tween 80 (3.19% w/w), CO:LO (3.74% w/w), xanthan gum (0.70% w/w), and deionized water (81.68% w/w). This optimum formulation showed good agreement between the actual droplet size (110.01 nm) and the predicted droplet size (111.73 nm) with a residual standard error <2.0%. The optimized formulation with pH values (6.28) showed high conductivity (1,492.00 uScm-1) and remained stable under accelerated stability study during storage at 4 degrees C, 25 degrees C, and 45 degrees C for 90 days, centrifugal force as well as freeze-thaw cycles. Rheology measurement justified that the optimized formulation was more elastic (shear thinning and pseudo plastic properties) rather than demonstrating viscous characteristics. In vitro cytotoxicity of the optimized KMO formulation and KMO oil showed that IC50 (50% inhibition of cell viability) value was >100 ug/mL. Conclusion: The survival rate of 3T3 cell on KMO formulation (54.76%) was found to be higher compared to KMO oil (53.37%) without any toxicity sign. This proved that the KMO formulation was less toxic and can be applied for cosmeceutical applications. PMID- 30410334 TI - Erratum: Antibacterial properties and toxicity from metallic nanomaterials [Corrigendum]. AB - [This corrects the article on p. 3941 in vol. 12, PMID: 28579779.]. PMID- 30410333 TI - CAIX aptamer-functionalized targeted nanobubbles for ultrasound molecular imaging of various tumors. AB - Purpose: Targeted nanobubbles can penetrate the tumor vasculature and achieve ultrasound molecular imaging (USMI) of tumor parenchymal cells. However, most targeted nanobubbles only achieve USMI of tumor parenchymal cells from one organ, and their distribution, loading ability, and binding ability in tumors are not clear. Therefore, targeted nanobubbles loaded with carbonic anhydrase IX (CAIX) aptamer were fabricated for USMI of various tumors, and the morphological basis of USMI with targeted nanobubbles was investigated. Materials and methods: The specificity of CAIX aptamer at the cellular level was measured by immunofluorescence and flow cytometry. Targeted nanobubbles loaded with CAIX aptamer were prepared by a maleimidethiol coupling reaction, and their binding ability to CAIX-positive tumor cells was analyzed in vitro. USMI of targeted and non-targeted nanobubbles was performed in tumor-bearing nude mice. The distribution, loading ability, and binding ability of targeted nanobubbles in xenograft tumor tissues were demonstrated by immunofluorescence. Results: CAIX aptamer could specifically bind to CAIX-positive 786-O and Hela cells, rather than CAIX-negative BxPC-3 cells. Targeted nanobubbles loaded with CAIX aptamer had the advantages of small size, uniform distribution, regular shape, and high safety, and they could specifically accumulate around 786-O and Hela cells, while not binding to BxPC-3 cells in vitro. Targeted nanobubbles had significantly higher peak intensity and larger area under the curve than non-targeted nanobubbles in 786-O and Hela xenograft tumor tissues, while there was no significant difference in the imaging effects of targeted and non-targeted nanobubbles in BxPC-3 xenograft tumor tissues. Immunofluorescence demonstrated targeted nanobubbles could still load CAIX aptamer after penetrating the tumor vasculature and specifically binding to CAIX-positive tumor cells in xenograft tumor tissues. Conclusion: Targeted nanobubbles loaded with CAIX aptamer have a good imaging effect in USMI of tumor parenchymal cells, and can improve the accuracy of early diagnosis of malignant tumors from various organs. PMID- 30410335 TI - pH and redox dual-responsive copolymer micelles with surface charge reversal for co-delivery of all-trans-retinoic acid and paclitaxel for cancer combination chemotherapy. AB - Background: Co-delivery all-trans-retinoic acid (ATRA) and paclitaxel (PTX) is an effective strategy for cancer therapy. However, in many previous reported ATRA conjugated co-delivery systems, the ATRA was released slower than PTX, and the total drug release of ATRA far lower than that of PTX. Purpose: We designed and prepared a pH and redox dual responsive drug delivery system (DA-ss-NPs) co delivery ATRA and PTX for cancer therapy. The surface charge of DA-ss-NPs could change from negative to positive under tumor slightly acidic microenvironment, and both drugs could be quickly released from DA-ss-NPs under intracellular high concentration of glutathione (GSH). Methods: The DA-ss-NPs were constructed by encapsulating PTX into the hydrophobic core of the polymer micelles, in which the polymer was synthesized by conjugating ATRA and 2,3-Dimethylmalefic anhydride (DMA) on side chains of Cystamine dihydrochloride (Cys) modified PEG-b-PAsp (named DA-ss-NPs). The surface charge of DA-ss-NPs under different pH conditions were detected. And the drug release was also measured under different concentration of GSH. The therapeutic effect of DA-ss-NPs were investigated in Human lung cancer A549 cells and A549 tumor-bearing mice. Results: The zeta potential of DA-ss-NPs was -16.3 mV at pH 7.4, and which changed to 16 mV at pH 6.5. Cell uptake experiment showed that more DA-ss-NPs were internalized by A549 cells at pH 6.5 than that at pH 7.4. In addition, in presence of 10 mM GSH at pH 7.4, about 75%-85% ATRA was released from DA-ss-NPs within 48 h; but less than 20% ATRA was released without GSH. In vivo antitumor efficiency showed that the DA-ss-NPs could affectively inhibite the tumor in compared with control groups. Conclusion: The charge-reversal and GSH-responsive DA-ss-NPs provide an excellent platform for potential tumor therapy. PMID- 30410336 TI - Inducing angiogenesis with the controlled release of nitric oxide from biodegradable and biocompatible copolymeric nanoparticles. AB - Purpose: Nitric oxide (NO) can be clinically applied at low concentrations to regulate angiogenesis. However, studies using small molecule NO donors (N diazeniumdiolate, S-nitrosothiol, etc) have yet to meet clinical requirements due to the short half-life and initial burst-release profile of NO donors. In this study, we report the feasibility of methoxy poly(ethylene glycol)-b-poly(lactic co-glycolic acid) (mPEG-PLGA) nanoparticles (NPs) as NO-releasing polymers (NO NPs) for inducing angiogenesis. Materials and methods: The mPEG-PLGA copolymers were synthesized by typical ring-opening polymerization of lactide, glycolide and mPEG as macroinitiators. Double emulsion methods were used to prepare mPEG-PLGA NPs incorporating hydrophilic NONOate (dieth-ylenetriamine NONOate). Results: This liposomal NP encapsulates hydrophilic diethylenetriamine NONOate (70%+/-4%) more effectively than other previously reported materials. The application of NO NPs at different ratios resulted in varying NO-release profiles with no significant cytotoxicity in various cell types: normal cells (fibroblasts, human umbilical vein endothelial cells and epithelial cells) and cancer cells (C6, A549 and MCF-7). The angiogenic potential of NO-NPs was confirmed in vitro by tube formation and ex vivo through an aorta ring assay. Tubular formation increased 189.8% in NO-NP-treated groups compared with that in the control group. Rat aorta exhibited robust sprouting angiogenesis in response to NO-NPs, indicating that NO was produced by polymeric NPs in a sustained manner. Conclusion: These findings provide initial results for an angiogenesis-related drug development platform by a straightforward method with biocompatible polymers. PMID- 30410337 TI - Coated electrospun alginate-containing fibers as novel delivery systems for regenerative purposes. AB - Aim: The aim of the present work was to develop biodegradable alginate (ALG) containing fibrous membranes intended for tissue repair, acting as both drug delivery systems and cell growth guidance. Methods: Membranes were prepared by electrospinning. Since ALG can be electrospun only when blended with other spinnable polymers, dextran (DEX) and polyethylene oxide (PEO) were investigated as process adjuvants. ALG/DEX mixtures, characterized by different rheological and conductivity properties, were prepared in phosphate buffer or deionized water; surfactants were added to modulate polymer solution surface tension. The Design of Experiments (DoE) approach (full factorial design) was used to investigate the role of polymer solution features (rheological properties, surface tension, and conductivity) on electrospun fiber morphology. A high viscosity at 1,000 s-1 (1.3-1.9 Pa.s) or a high pseudoplasticity index (>=1.7), combined with a low surface tension (30-32 mN/m) and a low conductivity (800 1,000 MUS/cm), was responsible for the production of ALG/DEX homogeneous fibers. Such ranges were successfully employed for the preparation of ALG-containing fibers, using PEO, instead of DEX, as process adjuvant. ALG/DEX and ALG/PEO fibers were subsequently subjected to cross-linking/coating processes to make them slowly biodegradable in aqueous medium. In particular, ALG/PEO fibers were cross-linked and coated with CaCl2/chitosan solutions in water/ethanol mixtures. Due to DEX high content, ALG/DEX fibers were soaked in a polylactide-co-glycolide (PLGA) solution in ethyl acetate. Results: Both cross-linking and coating processes made fibers insoluble in physiological medium and produced an increase in their mechanical resistance, assessed by means of a tensile test. PLGA-coated ALG/DEX and chitosan-coated ALG/PEO fibers were biocompatible and able to support fibroblast adhesion. Conclusion: The DoE approach allowed to draw up guidelines useful for the preparation of homogeneous fibers, starting from mixtures of ALG and non-ionic polymers. Such fibers, upon coating, resulted to be good cell substrates, allowing cell adhesion and growth. PMID- 30410338 TI - Silver-coated gold nanorods as a promising antimicrobial agent in the treatment of cancer-related infections. AB - Background: Many cancer patients suffer from cancer-related life-threatening infections due to immune system damage. Therefore, researchers are continuously looking for new options to treat cancer-related infections. As nanotechnology has gained tremendous interest over the past several decades, silver nanoparticles have been investigated as an effective antimicrobial agent. Here, silver-coated gold nanorods were synthesized to share similar optical properties as gold nanopar-ticles for cancer diagnosis and treatment, with an added advantage of antibacterial properties. Results: Their dose-dependent antimicrobial properties were demonstrated on both Gram-negative and Gram-positive bacteria species. These nanorods were found to be highly efficient in killing bacteria and suppressing biofilm formation. Conclusion: Collectively, such results suggest that silver coated gold nanorods should be further investigated as a novel material, which can both decrease cancer cell functions and reduce the risk of infection for cancer patients. PMID- 30410339 TI - The correlation between longitudinal changes in hypothalamic-pituitary-adrenal (HPA)-axis activity and changes in neurocognitive function in mixed-state bipolar II disorder. AB - Introduction: In this study, we aim to determine 1) the differences in cortisol in patients with bipolar II disorder (BD-II) and control subjects and 2) the correlation between cortisol levels and cognitive function in patients with BD-II during a 24-week follow-up period. Methods: We recruited a total of 32 BD-II patients and 30 healthy control subjects. The BD-II patients were assessed for clinical severity and serum cortisol level at baseline and at weeks 8, 16, and 24. The Brief Assessment of Cognition in Affective Disorders (BACA) was adopted to evaluate cognitive function at baseline and endpoint (week 24). Meanwhile, we assessed the controls for serum cortisol level and BACA at baseline. Results: We observed that the BD-II group had a higher serum cortisol level and lower BACA composite scores compared with the healthy controls at baseline. A significant correlation was found between changes in Verbal Fluency, a subset of BACA, and changes in serum cortisol level after the 24-week follow-up, controlling for age, gender, years of education, and clinical severity (P<0.001). Conclusion: We propose that serum cortisol may be involved in the psychopathological mechanisms of cognitive decline in BD-II. PMID- 30410340 TI - Are 24-hour motor activity patterns associated with continued rapid response to ketamine? AB - Purpose: This study examined the links between 24-hour activity patterns (specifically, amplitude and timing of wrist activity) and the persisting qualities of clinical antidepressant response to the glutamatergic modulator ketamine. Methods: Twenty-four-hour activity patterns were compared across 5 days of 24-hour activity rhythms in patients with major depressive disorder who displayed either a brief antidepressant response (24-48 hours), a continued antidepressant response (>72 hours), or no antidepressant response to ketamine. These postinfusion-response profiles were then used retrospectively to examine cohort-specific fitted parameters at baseline, postinfusion day 1 (D1), and postinfusion D3. Results: Relative to the nonresponders, the cohort experiencing a brief antidepressant response had blunted 24-hour amplitude that extended from baseline through D3 and postketamine phase advance of activity on D1 that reverted to baseline on D3. Relative to the nonresponders, the cohort experiencing a continued antidepressant response to ketamine had phase-advanced activity at both baseline and D1, as well as increased amplitude on D1 and D3. Conclusion: Taken together, the results suggest that the time course of antidepressant response to ketamine is influenced by underlying biological differences in motor activity timekeeping. These differences may provide clues that link durable mood response with the molecular machinery of the circadian system, thus leading to more effective interventions. In addition, biomarkers of preinfusion motor activity (eg, amplitude, timing) may be useful for recommending future individualized treatment interventions, to the extent that they help identify patients who may relapse quickly after treatment. PMID- 30410342 TI - Does perioperative intravenous dextrose reduce postoperative nausea and vomiting? A systematic review and meta-analysis. AB - Purpose: Perioperative dextrose-containing fluid administration has been used as a non-pharmacologic preventive measure against postoperative nausea and vomiting (PONV), a common and distressing complication of anesthesia. However, its efficacy remains unclear as previous studies reported inconsistent results. Our objective was to compare dextrose-containing fluid with non-dextrose-containing fluid in terms of PONV for 24 hours after surgery under general anesthesia. The effects of dextrose according to different types of surgery and the fluid volume were also examined. Methods: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing dextrose-containing fluid with non-dextrose-containing fluids after general anesthesia in terms of PONV incidence and the need for rescue anti-emetic therapies for 24 hours after surgery. A literature search was performed, using Medline, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus, up to February 2018. Results: We included seven RCTs. Compared with the control group, perioperative dextrose administration did not reduce the risk for PONV, with a relative risk (RR) of 0.72 (95% CI: 0.50-1.03). However, perioperative dextrose reduced the requirement for anti-emetics, compared with the control group, with a RR of 0.60 (95% CI: 0.44-0.83). The quality of evidence in this meta-analysis was poor due to high risks of selection and performance biases and substantial statistical heterogeneity. After subgroup analysis, the risk for PONV was reduced in patients who had undergone laparoscopic cholecystectomy, but not other surgeries, and the effects of dextrose on the risk for PONV did not differ according to the fluid volume administered. Conclusion: Perioperative intravenous (i.v.) dextrose did not reduce the risk for PONV. However, it did reduce the need for anti-emetics after general anesthesia. Furthermore, the effects of dextrose varied according to the surgery type. Further studies are needed to determine the benefits of perioperative i.v. dextrose administration as a preventive measure against PONV. PMID- 30410341 TI - Videolaryngoscopy versus fiberoptic bronchoscope for awake intubation - a systematic review and meta-analysis of randomized controlled trials. AB - Background: Awake intubation with videolaryngoscopy (VL) is a novel method that is drawing more and more attention as an alternative to awake intubation with fiberoptic bronchoscope (FOB). This meta-analysis is designed to determine the performance of VL compared to the FOB for awake intubation. Methods: The Cochrane Central Register of Controlled Trials, PubMed, Embase, and Web of science were searched from database inception until October 30, 2017. Randomized controlled trials comparing VL and FOB for awake intubation were selected. The primary outcome was the overall success rate. Rev-Man 5.3 software was used to perform the pooled analysis and assess the risk of bias for each eligible study. The GRADE system was used to assess the quality of evidence for all outcomes. Results: Six studies (446 patients) were included in the review for data extraction. Pooled analysis did not show any difference in the overall success rate by using VL and FOB (relative risk [RR], 1.00; P=0.99; high-quality evidence). There was no heterogeneity among studies (I 2=0). Subgroup analyses showed no differences between two groups through nasal (RR, 1.00; P=1.00; high quality evidence) and oral intubations (RR, 1.00; P=0.98; high-quality evidence). The intubation time was shorter by using VL than by using FOB (mean difference, 40.4 seconds; P<0.01; low-quality evidence). There were no differences between groups for other outcomes (P>0.05). Conclusion: For awake intubation, VL with a shorter intubation time is as effective and safe as FOB. VL may be a useful alternative to FOB. PMID- 30410344 TI - Frequency of vital sign measurement among intubated patients in the general ward and nurses' attitudes toward vital sign measurement. AB - Purpose: The lack of recognition of respiratory distress may result in emergency tracheal intubation in the general ward. However, few studies have examined the differences in the frequency of vital sign measurement between patients with and without emergency tracheal intubation in the general ward. Thus, this study aimed to investigate the differences in the frequency of vital sign measurements between patients with and without emergency tracheal intubation. Patients and methods: This is a single-center, retrospective, observational study of unplanned intensive care unit (ICU) admissions from the general wards between December 2015 and February 2017. This study included patients with emergency medical intubations in the general ward who were then transferred to the ICU. Vital signs measured within 24 hours prior to ICU admission were compared between patients who did and did not require emergency tracheal intubation in the general ward. A survey was also conducted to explore the nurses' attitudes toward vital sign measurements. Results: Compared with other vital signs, the respiratory rate was significantly less frequently measured. Moreover, the frequency of respiratory rate measurement was lower in the 38 patients who were intubated than in the 102 patients who were not intubated in the general ward (P=0.07). The survey revealed that 54% of the participating nurses considered assessment of the respiratory rate as the most troublesome nursing task and ~15% of nurses did not routinely measure respiratory rates. Conclusion: Respiratory rate was less frequently assessed in deteriorating patients in the general ward, possibly because it was considered a troublesome task. PMID- 30410345 TI - Use of social media in the Department of Radiology at Johns Hopkins Aramco Healthcare in Saudi Arabia. AB - Purpose: The objective of this study was to evaluate the use of social media in the Radiology Department at Johns Hopkins Aramco Healthcare in Saudi Arabia. Methods: The research was a cross-sectional study in which 90 workers from the staff personnel of the Radiology Department at Johns Hopkins Aramco Healthcare were invited to a web-based survey using Google Forms. Fifty-seven participants responded to the survey (63%). Basic descriptive statistics were used to analyze the responses. Results: More than half of the participants (54.8%) were technologists. The majority of the respondents (61.4%) had a Bachelor's degree, and 50.8% of them had more than 10 years of experience. Also, 36.8% of the participants were between 30 and 40 years old, and 57.9 of them were males. Similarly, most of the participants (61.4%) were from Saudi Arabia. Additionally, the most frequently used application was WhatsApp (59.6%). Likewise, almost half of the participants (47.4%) managed social media multiple times a day and more than half of them used these tools to communicate with friends (68.4%) and family members (61.4%). As well, 12% of the respondents employed these media to study and 20% used them for professional reasons. Also, 38.6% of respondents had no barriers to use social media. However, the rest considered that time, private matters, negative replies, lack of information and experience, and uncertainty about the usefulness of social media were barriers. Conclusion: According to the survey, most of the personnel of the Radiology Department at Johns Hopkins Aramco Healthcare often used WhatsApp to communicate with family (61.4%) and friends (68.4%), and less than half of them employed these tools for educational purposes (21.1%) and professional issues (35.1%). Additionally, participants considered that there were some barriers related to the use of these tools. PMID- 30410346 TI - Health care quality from the patients' perspective: a comparative study between an old and a new, high-tech hospital. AB - Purpose: Previous studies show that the hospital environment and the behavior of health care personnel may predict patients' perceptions of care quality. The aim of the study was to explore changes in perceived care quality from the patients' perspective (QPP) when hospital services are relocated from an old to a new high tech hospital and to describe what is important for patients in the high-tech hospital. Patients and methods: A comparative cross-sectional design was used. The questionnaire QPP, which is based on a theoretical model of the quality of care comprising four quality dimensions, was used. Data were collected in 2015 (old hospital) and 2016 (new hospital), with 253 and 324 respondents, respectively, by consecutive sampling. Comparative statistics was used to test differences between patients' care quality perceptions (perceived reality [PR] and subjective importance [SI]) (P<=0.05). Results: The patients rated PR of all four quality dimensions (the care organization's physical-technical conditions and sociocultural approach and the caregivers' medical-technical competence and identity-oriented approach) higher in the new hospital. However, only the two quality dimensions concerning the care organization were rated significantly more highly. On an item level, five of the 27 items scored significantly higher on patients' SI than on patients' PR of the care in the new hospital, indicating a quality deficiency from the patients' perspective. This comprised receiving effective pain relief, receiving examination and treatment within an acceptable waiting time, receiving useful information on self-care, receiving useful information on which doctors were responsible for their medical care, and having a comfortable bed. Conclusion: The increase in care QPP was associated with improved environmental conditions, and no significant improvement in care quality was associated with the health care personnel. The results indicate that being in a high-tech environment does not improve patients' perceptions of care quality provided by health care personnel. The results gave valuable information for quality improvement in clinical practice, based on the patients' perspective. PMID- 30410343 TI - Role of androgens in cardiovascular pathology. AB - Cardiovascular effects of android hormones in normal and pathological conditions can lead to either positive or negative effects. The reason for this variation is unknown, but may be influenced by gender-specific effects of androids, heterogeneity of the vascular endothelium, differential expression of the androgen receptor in endothelial cells (ECs) and route of androgen administration. Generally, androgenic hormones are beneficial for ECs because these hormones induce nitric oxide production, proliferation, motility, and growth of ECs and inhibit inflammatory activation and induction of procoagulant, and adhesive properties in ECs. This indeed prevents endothelial dysfunction, an essential initial step in the development of vascular pathologies, including atherosclerosis. However, androgens can also activate endothelial production of some vasoconstrictors, which can have detrimental effects on the vascular endothelium. Androgens also activate proliferation, migration, and recruitment of endothelial progenitor cells (EPCs), thereby contributing to vascular repair and restoration of the endothelial layer. In this paper, we consider effects of androgen hormones on EC and EPC function in physiological and pathological conditions. PMID- 30410347 TI - Synergistic suppression effect on tumor growth of acute myeloid leukemia by combining cytarabine with an engineered oncolytic vaccinia virus. AB - Background: In consideration of the drug resistance and side effects associated with cytarabine, one of the most effective drugs for the treatment of acute myeloid leukemia (AML), there is a need for safer and effective strategies. Methods: In the present investigation, we fabricated a new oncolytic vaccinia virus (oVV-ING4), which expresses the inhibitor of growth family member 4 (ING4) and explored its antitumor activity individually and in combination with cytarabine in AML cells. Results: The experiments confirmed that oVV can efficiently and specifically infect leukemia cells, and augment the ING4 gene expression. Flow cytometry and western blot demonstrated that oVV-ING4 enhances apoptosis and G2/M phase arrest in AML cells, and causes remarkable cancer cell death. In addition, the synergistic efficiency of oVV-ING4 and cytarabine was investigated in vitro and in vivo; the combination significantly inhibited the survival of leukemia cells in vitro and xenografted KG-1 AML tumor growth in vivo. Conclusion: In brief, oVV-ING4 can increase the sensitivity of leukemia cells to cytarabine and induce cell apoptosis in vitro and in vivo. Thus, oVV ING4 may be a promising therapeutic candidate for leukemia and in combination with cytarabine represents a potential antitumor therapy. PMID- 30410349 TI - NFATC2 is a novel therapeutic target for colorectal cancer stem cells. AB - Background: Colorectal cancer stem cells (CRC-SCs) contribute to the initiation and progression of colorectal cancer (CRC). However, the underlying mechanisms for the propagation of CRC-SCs have remained elusive. Purpose: The objective of this study was to study the role of NFATC2 in maintenance of the stemness in CRC SCs. Method: The expression levels of mRNA and protein were determined by qRT-PCR and western-blot, respectively. CRC-SCs were isolated by spheroid formation assay and flowcytometry. The sphere-forming and self-renewal abilities of CRC-SCs were determined by spheroid formation assay. The tumorigenicity of CRC-SCs was determined by cell-derived xenograft model. Gene manipulation was performed by lentivirus-mediated delivery system. Results: We first found that NFATC2 is upregulated in primary CRC-SCs. Overexpression of NFATC2 promotes self-renewal and the expression of stem cell markers of CRC-SCs. Conversely, knockdown of NFATC2 attenuates stem cell-like properties of CRC-SCs. Mechanistic analysis indicated that NFATC2 upregulates the expression of AJUBA, downregulates the phosphorylation level of YAP, and therefore activates the transcriptional activities of YAP and promotes the stemness of CRC-SCs. Conclusion: Our findings demonstrate NFATC2 as an oncogene that can promote the stemness of CRC-SCs. This work suggests a novel therapeutic strategy against CRC caused by aberrant expression of NFATC2. PMID- 30410348 TI - Targeting VEGF pathway to normalize the vasculature: an emerging insight in cancer therapy. AB - Vascular normalization is a new concept of targeting angiogenesis to restore vessel structure and function and to increase blood perfusion and delivery of drugs. It has been confirmed that vascular normalization can decrease relapse and benefit other cancer therapy, including chemotherapy, radiotherapy, and immune cell therapy. The key point of this therapy is to inhibit pro-angiogenic factors and make it be balanced with anti-angiogenic factors, resulting in a mature and normal vessel characteristic. Vascular endothelial growth factor (VEGF) is a key player in the process of tumor angiogenesis, and inhibiting VEGF is a primary approach to tumor vessel normalization. Herein, we review newly uncovered mechanisms governing angiogenesis and vascular normalization of cancer and place emphasis on targeting VEGF pathway to normalize the vasculature. Also, important methods to depress VEGF pathway and make tumor vascular are discussed. PMID- 30410350 TI - SMAGP a novel biomarker of cervical cancer development and progression. AB - Introduction: Cervical cancer, one of the most common malignant gynecological tumors, is a significant burden on the health of females worldwide. The purpose of this study was to investigate genes associated with lymph node metastasis in cervical cancer. Methods: We report on the lymph node metastasis-associated gene, small cell adhesion glycoprotein (SMAGP), as a key regulator of cervical cancer development and progression. SMAGP expression levels were investigated in 70 cervical squamous cell carcinoma samples and 10 normal cervical squamous epithelium samples. Results: Immunohistochemistry analysis revealed that SMAGP protein levels were significantly elevated in cervical cancer tissue compared with normal cervical squamous epithelium. Silencing of SMAGP induced cell cycle arrest, inhibited the cell proliferation and colony formation ability of cervical cancer cells in vitro and suppressed their tumorigenic potential in nude mice. In addition, SMAGP knockdown reduced expression of epithelial mesenchymal transition related proteins, including vimentin, beta-cadherin, MMP2, and Twist. Conclusion: Together, our findings demonstrate that SMAGP plays a critical role in cell proliferation and tumorigenesis and could be a new therapeutic target in cervical cancer. PMID- 30410351 TI - Crizotinib presented with promising efficacy but for concomitant mutation in next generation sequencing-identified ROS1-rearranged non-small-cell lung cancer. AB - Introduction: Data of standard tyrosine kinase inhibitor (TKI) treatment outcome in next-generation sequencing (NGS)-identified ROS1-rearranged non-small-cell lung cancer (NSCLC) were rare. Thus, it is practical and necessary to evaluate the efficacy and influential factors of crizotinib in real-world practice. Patients and methods: A total of 1,466 NSCLC patients with positive targeted NGS test results from September 2015 to January 2018 were enrolled in this real-world retrospective study. Twenty-two patients had ROS1 rearrangement detected by NGS. The efficacy and safety of crizotinib were evaluated. Subgroups of concomitant mutations, brain metastasis, and fusion variants were also analyzed. Results: Among all the patients, the occurrence rate of ROS1 rearrangement was 1.5% (22 of 1,466). Ten ROS1 fusion partners were detected, and the most common variant was CD74, which accounted for 50% (11 of 22). Five patients were found to carry dual ROS1 fusion partners, and 23% (5 of 22) of patients were detected with concomitant mutations, including TP53&PIK3CA&mTOR mutation, TP53&CDKN2A mutation, TP53&BRCA2 mutation, ALK missense mutation (p.R311H), and MET amplification. Among 22 patients with ROS1-rearranged NSCLC, 20 patients were diagnosed at stage IV, and 19 patients received crizotinib treatment. The average follow-up period was 16 months. The overall response rate (ORR) of crizotinib in unselected crizotinib-treated patients was 89%, and the median progression-free survival time (mPFS) was 13.6 months. It was shown that NSCLC patients with exclusive ROS1 rearrangement had a longer PFS than those carrying concomitant mutations (15.5 vs 8.5 months, P=0.0213). There were no newly occurring intolerant adverse events in this study. Conclusion: Crizotinib is highly effective in NGS-identified ROS1 rearranged advanced NSCLC in real-word clinical practice, and the data are consistent with previous clinical trials applying fluorescence in situ hybridization/real-time PCR for ROS1 companion diagnosis. Concomitant mutations may not be rare and may deteriorate the PFS of crizotinib in patients with ROS1 rearranged NSCLC. PMID- 30410352 TI - Identification of driver genes associated with chemotherapy resistance of Ewing's sarcoma. AB - Background: The aim of this study was to identify the driver genes associated with chemotherapy resistance of Ewing's sarcoma and potential targets for Ewing's sarcoma treatment. Methods: Two mRNA microarray datasets, GSE12102 and GSE17679, were downloaded from the Gene Expression Omnibus database, which contain 94 human Ewing's sarcoma samples, including 65 from those who experienced a relapse and 29 from those with no evidence of disease. The differen tially expressed genes (DEGs) were identified using LIMMA package R. Subsequently, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed for DEGs using Database for Annotation, Visualization and Integrated Analysis. The protein-protein interaction network was constructed using Cytoscape software, and module analysis was performed using Molecular Complex Detection. Results: A total of 206 upregulated DEGs and 141 downregulated DEGs were identified. Upregulated DEGs were primarily enriched in DNA replication, nucleoplasm and protein kinase binding for biological processes, cellular component and molecular functions, respectively. Downregulated DEGs were predominantly involved in receptor clustering, membrane raft, and ligand dependent nuclear receptor binding. The protein-protein interaction network of DEGs consisted of 150 nodes and 304 interactions. Thirteen hub genes were identified, and biological analysis revealed that these genes were primarily enriched in cell division, cell cycle, and mitosis. Furthermore, based on closeness centrality, betweenness centrality, and degree centrality, the three most significant genes were identified as GAPDH, AURKA, and EHMT2. Furthermore, the significant network module was composed of nine genes. These genes were primarily enriched in mitotic nuclear division, mitotic chromosome condensation, and nucleoplasm. Conclusion: These hub genes, especially GAPDH, AURKA, and EHMT2, may be closely associated with the progression of Ewing's sarcoma chemotherapy resistance, and further experiments are needed for confirmation. PMID- 30410354 TI - Genome-scale analysis identifies SERPINE1 and SPARC as diagnostic and prognostic biomarkers in gastric cancer. AB - Background: Gastric cancer (GC) is one of the most common types of malignancy and is associated with high morbidity and mortality rates around the world. With poor clinical outcomes, potential biomarkers for diagnosis and prognosis are important to investigate. Objective: The aim of this study is to investigate the gene expression module of GC and to identify potential diagnostic and prognostic biomarkers. Method: Microarray data (GSE13911, GSE29272, GSE54129, and GSE79973), including 293 stomach tumor tissues and 196 normal tissues, were analyzed to identify differentially expressed genes (DEGs). DEGs were identified in four profiles by intersecting four overlapping subsets, including 90 downregulated and 45 upregulated DEGs in common. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway analyses have been showed that extracellular matrix was the most enriched signal pathway. Furthermore, hub genes were analyzed by protein protein interaction network and clinical outcomes were assessed by Kaplan-Meier survival analysis. Two independent datasets were used to validate the differential expression of two hub genes: Serpin Family E Member 1 (SERPINE1) and Secreted Protein Acidic and Cysteine Rich (SPARC). Results: Validation of independent datasets indicated that SERPINE1 and SPARC expression were drastically increased in gastric tumor tissues and associated with poor outcomes in GC patients. The expression of SERPINE1 was related to race (Asian and White) (P< 0.05). Conclusion: SERPINE1 and SPARC were significantly upregulated in gastric tissues and associated with poor outcomes. The investigations of SERPINE1 and SPARC may promote their predictive and prognostic value in GC. PMID- 30410353 TI - Identification of critically carcinogenesis-related genes in basal cell carcinoma. AB - Background: Basal cell carcinoma (BCC) is a frequent malignant tumor of skin cancers with high morbidity. The objective of this study was to identify critical genes and pathways related to the carcinogenesis of BCC and gain more insights into the underlying molecular mechanisms of BCC. Materials and methods: The gene expression profiles of GSE7553 and GSE103439 were downloaded from the Gene Expression Omnibus database with 19 tumors and 6 normal skin tissues. Differentially expressed genes (DEGs) were screened between BCC samples and normal tissues, followed by gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Subsequently, protein-protein interaction (PPI) network was constructed for these DEGs, and module analysis was performed. Results: A total of 313 DEGs were obtained. Among them, 222 genes were upregulated and 91 genes were downregulated. Enrichment analysis indicated that the upregulated genes were significantly enriched in cell cycle and mitosis, while the downregulated genes were mainly associated with unsaturated fatty acid metabolic process and cell differentiation. In addition, TOP2A, CDK1, and CCNB1 were identified as the top three hub genes ranked by degrees in the PPI network. Meanwhile, three subnetworks were derived, which indicated that these DEGs were significantly enriched in pathways, including "cell cycle", "extracellular matrix receptor interaction", "basal cell carcinoma", and "hedgehog signaling pathway". Conclusions: The novel critical DEGs and pathways identified in this study may serve pivotal roles in the carcinogenesis of BCC and indicate more molecular targets for the treatment of BCC. PMID- 30410355 TI - Inhibition of miR-10a-5p suppresses cholangiocarcinoma cell growth through downregulation of Akt pathway. AB - Backgrounds: Cholangiocarcinoma (CCA) is epithelial cell malignancy with very poor prognosis. A lot of patients were diagnosed at advanced stage of CCA and no risk factors were identified. There are limited treatment options available for the management of CCA patients. It is urgent to develop effective targeted therapies for the treatment of CCA. miRNAs are small noncoding RNAs that negatively regulate the target genes. In this study, we investigated the role and mechanism of miR-10a-5p in CCA. Methods: Human CCA cell lines (CCLP1 and SG-231) were transfected with miR-10a-5p mimic or miR-10a-5p inhibitor. qRT-PCR was performed to detect the miR-10a-5p level. Proliferation, colony formation, and apoptosis were analyzed. Luciferase reporter assay was used to explore the targeting of miR-10a-5p on PTEN. For in vivo tumorigenesis assay, CCLP1 cells with stable knockdown of miR-10a-5p or control CCLP1 cells were injected subcutaneously into the flank of the SCID mice and animals were monitored for tumor growth. Results: miR-10a-5p expression was significantly upregulated in human CCA cell lines (CCLP1 and SG-231). Inhibition of miR-10a-5p significantly suppressed the proliferation and induced apoptosis in CCLP1 and SG-231. PTEN is a direct target of miR-10a-5p in CCA cells. Conclusion: Inhibition of miR-10a-5p can decrease CCA cells growth by downregulation of Akt pathway. These results indicate that miR-10a-5p may serve as a potential target for the treatment of CCA and help to develop effective therapeutic strategies. PMID- 30410356 TI - Decreased pretherapy serum apolipoprotein A-I is associated with extent of metastasis and poor prognosis of non-small-cell lung cancer. AB - Background: Apolipoprotein A-I (ApoA-I), which recently attracted great attention as an important protein related to the increasing risk of various cancers, is a factor closely related to metabolic diseases such as ardiovascular diseases and atherosclerosis. However, the diagnostic and prognostic value of pretherapy serum ApoA-I levels in non-small-cell lung cancer (NSCLC) patients is still not very clear. Methods: In 325 NSCLC patients and 312 healthy controls, pretherapy serum ApoA-I was measured by turbidimetric immunoassay. The association of serum ApoA-I levels with the clinicopathologic characteristics and clinical outcomes of NSCLC patients was analyzed. Receiver-operating characteristic (ROC) curve analysis and univariate and multivariate Cox regression analyses were used to assess the diagnostic and prognostic significance of serum ApoA-I levels. Results: Serum ApoA-I levels were obviously decreased in NSCLC patients compared with healthy controls (1.22+/-0.27 vs 1.46+/-0.22 g/L, P<0.0001). Pretherapy serum ApoA-I levels were significantly decreased in the NSCLC patients with increased pretherapy C-reactive protein levels (P=0.046), lower albumin serum level (P=0.040), advanced TNM stage (P=0.004), poorer Eastern Cooperative Oncology Group PS: performance status scores (P=0.007), and more than two sites of distant metastasis (P<0.0001). ROC curve showed the optimal cut-off for ApoA-I was 1.26 g/L (Area under ROC curve=0.69, 95% CI=0.54-0.65) with a specificity of 0.75 and a sensitivity of 0.59. The whole cohort was divided into two groups: low ApoA-I levels group (ApoA-I <=1.26 g/L) consisted of 193 (59.4%) patients and high ApoA I levels group (ApoA-I >1.26 g/L) consisted of 132 (40.6%) patients. The median survival time of low and high ApoA-I levels patients were 16.45 and 20.90 months, respectively, which indicated a statistically significant difference (chi 2=0.609, P<0.0001) between the two groups. The multivariate analysis results showed that CRP levels (HR=1.273, P=0.038), ApoA-I levels (HR=0.761, P=0.030), Eastern Cooperative Oncology Group performance status (HR=1.486, P=0.016), and extent of metastasis (HR=1.394, P=0.009) were significant independent predictors of favorable overall survival. Conclusion: A decreased level of pretherapy ApoA-I was associated with a worse survival in patients with NSCLC. Serum ApoA-I measurement before initial treatment may be a novel and routine biomarker to evaluate for metastasis and predict prognosis for NSCLC patients in daily clinical practice. PMID- 30410357 TI - TIM-3, a promising target for cancer immunotherapy. AB - Patients with malignant tumor treated with immunotherapy have received significant clinical benefits over the years. Immune checkpoint blocking agents, such as anti-cytotoxic T-lymphocyte-associated protein-4 (anti-CTLA-4) and anti programmed cell death protein-1 (anti-PD-1) monoclonal antibodies, have produced impressive clinical results in different types of cancer. T-cell immunoglobulin and mucin domain-3 (TIM-3), another immune checkpoint, could inhibit cancer immunity. Recent studies have highlighted that TIM-3 has an important role to play in T-cell exhaustion and correlates with the outcome of anti-PD-1 therapy. Targeting TIM-3 might be a promising approach for cancer immunotherapy. Here, we review the role of TIM-3 in cancer and clinical trials with TIM-3 inhibitors. PMID- 30410358 TI - Research progress of the clinicopathologic features of lung adenosquamous carcinoma. AB - Adenosquamous carcinoma (ASC) of the lung, a biphasic malignant tumor arising from lung tissue, is a special subtype of non-small-cell lung cancer (NSCLC) with low incidence but high tendency of invasion and poor prognosis. ASC contains components of lung adenocarcinoma (AC) and lung squamous cell carcinoma (SCC). However, there is a remarkable difference between ASC and other NSCLCs in clinical features, suggesting that ASC is not a simple mixture of AC and SCC, but is rather a more complex carcinoma with a unique molecular phenotype. At present, the research on ASC is still rare, mostly because of its complicated molecular mechanism and unclear pathological origin. The lack of cognition of ASC limits its early diagnosis and treatment, and a set of mature and effective treatment programs has not been proposed yet. In-depth study of the molecular characteristics and clinical features of ASC will not only help to better understand the scientific issues, including phenotype switching of lung cancer, the origin of tumor development, and tumor heterogeneity, but also contribute to the development of its individualized treatment. This review summarizes the recent studies concerning the clinicopathologic features and the molecular mechanisms of ASC to further facilitate the development of its individualized treatment. PMID- 30410359 TI - Zileuton suppresses cholangiocarcinoma cell proliferation and migration through inhibition of the Akt signaling pathway. AB - Background: Inflammatory lipid mediators play an important role in several cancer types. Leukotrienes (LTs), pro-inflammatory lipid mediators, are involved in chronic inflammation and cancer progression. They are derived from arachidonic acid by 5-lipoxygenase (5-LOX) activity. On the other hand, 15-lipoxygenase (15 LOX-1) converts LTs into lipoxins (LXs), pro-resolving lipid mediators. LXs are involved in the attenuation of inflammation and cancer development. Purpose: We aimed to investigate the lipid mediator pathways, especially the LTs and LXs pathways, by studying 5-LOX and 15-LOX-1 expression in human cholangiocarcinoma (CCA) tissue. We also investigated the efficiency of zileuton (5-LOX inhibitor) treatment and BML-111 (LXA4 analog) addition on CCA cell lines properties. Patients and methods: The expression of 5-LOX and 15-LOX-1 in fifty human cholangiocarcinoma (CCA) tissue was analyzed using immunohistochemical staining. In addition, the effect of zileuton and BML-111 on CCA cell growth and migration was demonstrated using a cell viability assay and wound-healing assay, respectively. Furthermore, the molecular mechanism by which zileuton inhibits CCA cell migration was revealed using immunofluorescent staining and western blot analysis, respectively. Results: We demonstrate that the upregulation of 5-LOX is significantly correlated with CCA recurrent status. A positive 15-LOX-1 signal was significantly associated with a longer survival time in CCA patients. We found that co-expression of 5-LOX and 15-LOX-1 resulted in a relatively good prognosis in CCA patients. In addition, zileuton could inhibit CCA cell migration as well as BML-111. Interestingly, zileuton treatment not only downregulated 5 LOX, but also upregulated 15-LOX-1, together with reversing the epithelial mesenchymal transition to mesenchymal-epithelial transition phenotype as observed in EMT marker western blot. Conclusion: These findings suggest that 5-LOX and 15 LOX-1 play a key role in CCA and may serve as targets for CCA therapy. PMID- 30410360 TI - Brevilin A promotes oxidative stress and induces mitochondrial apoptosis in U87 glioblastoma cells. AB - Background: Sesquiterpene lactones are plant-derived, natural, bioactive molecules often used against inflammatory diseases in traditional Chinese medicines. Recently, sesquiterpene lactones have been reported to exhibit potent anticancer activity. In the present study, we have investigated the anticancer activity of Brevilin A, a sesquiterpene lactone component of Centipeda minima, against U87 glioblastoma cells. Materials and methods: The cell proliferation was determined by MTT assay. Cell morphological changes were observed by phase contrast microscopy. Flow cytometry was used to measure apoptosis. Glutathione (GSH), ROS generation, and mitochondrial membrane potential were measured using commercially available kits. The expression of proteins was measured by Western blotting analysis. Results: Brevilin A inhibited the proliferation of, and induced severe morphological changes and apoptotic cell death in, U87 glioblastoma cells in a dose-dependent manner. Further mechanistic study revealed that Brevilin A induces oxidative stress, as evident from ROS generation, GSH depletion, and increased phosphorylation of stress-activated proteins p38 and JNK. Furthermore, Brevilin A bcl-xl/bak ratio, decreased mitochondrial membrane potential and induced cytochrome c release from mitochondria into cytosol in a dose-dependent manner. Finally, Brevilin A decreased the expression of Xiap and increased the expression of cleaved forms of caspase-9 and -3 and PARP in a dose dependent manner. Conclusion: Collective findings demonstrated that Brevilin A is a potent, anticancer, bioactive molecule and it effectively induces apoptosis in U87 glioblastoma cells, which is associated with induction of oxidative stress and mitochondrial dysfunction. PMID- 30410361 TI - Clinical use of FLT3 inhibitors in acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a highly heterogeneous disease. Mutation with internal tandem duplication of fms-like tyrosine kinase-3 (FLT3-ITD) is one of the two most common driver mutations and the presence of FLT3-ITD delivers poor prognosis. A number of ongoing clinical efforts are focused on FLT3 inhibitor use to improve the outcomes of this otherwise difficult leukemia. Midostaurin has been shown to improve outcomes in FLT3-mutated AML in the frontline setting. Several FLT3 inhibitors, especially second-generation agents, have shown clinically meaningful activity in relapsed or refractory AML and in patients not amenable to intensive therapy. In this article, we briefly review the biology of FLT3 in the physiological state and its role in leukemogenesis. We present a detailed review of current clinical evidence of FLT3 inhibitors and their use in the induction, treatment of relapsed or refractory disease, and maintenance setting. PMID- 30410362 TI - The functional verification of EGFR-CAR T-cells targeted to hypopharyngeal squamous cell carcinoma. AB - Background: The aim of this study was to validate the antitumor function of EGFR chimeric antigen T-cells (CART) targeted to FaDu cells, a hypopharyngeal squamous cell carcinoma cell line, and to provide a preclinical basis for the application of CART cell technology in hypopharyngeal squamous cell carcinoma. Methods: Detection of cytokine secretions of EGFR-CAR T and CART-controls in the presence of target cells and nontarget cells as an indicator of CART cell activation. Detection of the cytotoxic effects of EGFR-CAR T on specific tumors in the presence of target cells was evaluated by LDH release and CART cell proliferation. Results: The results showed that cytokine secretion increased significantly after EGFR-CAR T-cells were incubated with target cells, and EGFR CAR T-cells has higher cytotoxic effect on target cells than the CART-control group. The target cell lysis rate was 52.66%. The proliferation of EGFR-CAR T cells in the presence of target cells was not distinctly observed. Conclusion: In this study, we validated the antitumor function of EGFR-CAR T-cells targeted to the FaDu cell line and provided the foundation for application of the CART technique in the treatment of hypopharyngeal carcinoma. PMID- 30410363 TI - Platelet-to-lymphocyte ratio and lymphocyte-to-white blood cell ratio predict the efficacy of neoadjuvant chemotherapy and the prognosis of locally advanced gastric cancer patients treated with the oxaliplatin and capecitabine regimen. AB - Background: Many studies have discussed the relationship between routine blood parameters and the prognosis of gastric cancer patients; however, few studies focused on the association of routine blood parameters with the efficacy of neoadjuvant chemotherapy (NAC). Patients and methods: We retrospectively collected routine blood parameters and other clinicopathological data of 104 patients with locally advanced gastric cancer (LAGC) who received the oxaliplatin and capecitabine regimen as NAC from June 2010 to March 2016. The objective response rate (ORR), pathological remission rate (pRR), overall survival (OS), and time to recurrence (TTR) were analyzed through different statistical methods, such as Chi-squared test, log-rank test, logistic regression, and Cox regression. Results: In the multivariate analysis, a high platelet-to-lymphocyte ratio (PLR) (>=130.7) predicted a low ORR (OR =5.927, 95% CI: 2.184-16.089) and a low pRR (OR =8.343, 95% CI: 2.178-31.962), while a high lymphocyte-to-white blood cell ratio (LWR) (>=0.228) independently predicted a high ORR (OR =0.118, 95% CI: 0.031 0.448) and a high pRR (OR =0.096, 95% CI: 0.021-0.426). High lymphocyte level (>=1.750*109/L) was an independent predictor of long OS (HR =0.428, 95% CI: 0.190 0.964) and long TTR (HR =0.328, 95% CI: 0.156-0.690). High monocyte level (>=0.215*109/L) was associated with a high pRR (OR =0.072, 95% CI: 0.008-0.636) and a long OS (HR = 0.506, 95% CI: 0.257-0.997). Conclusion: In patients with LAGC treated with the oxaliplatin and capecitabine regimen as NAC, a low PLR (<130.7) and a high LWR (>=0.228) independently predicted a high ORR and pRR. High monocyte level (>=0.215*109/L) was an independent predictor for a high pRR and long OS, while patients with high lymphocyte level (>=1.750*109/L) tended to have a long OS and TTR. PMID- 30410364 TI - A systematic review and meta-analysis on the effect of angiogenesis blockade for the treatment of gastric cancer. AB - Introduction: To date, anti-vascular endothelial growth factor (VEGF) monoclonal antibody (mAb, bevacizumab), anti-VEGF receptor mAb (ramucirumab) and selective vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (sunitinib, sorafenib and apatinib) have been tested in the clinical trials. Materials and methods: In the current study, results of 32 clinical trials (24 Phase I or II, 8 Phase III) were systematically reviewed and meta-analysis was performed in 8 Phase III trial results. Results: It was found that median overall survival (OS) time and progression-free survival (PFS) time were significantly longer in the patients treated with antiangiogenic reagents compared to that in the patients with placebo when all of 8 Phase III clinical trials were analyzed together (OS: odds ratio = 0.805, 95% CI: 0.719-0.901, P < 0.001; PFS: odds ratio = 0.719, 95% CI: 0.533-969, P = 0.030). Conclusion: Meta-analysis on bevacizumab (4 out 8 Phase III trials) indicated that neither OS nor PFS was significantly different between the groups treated with bevacizumab or placebo with or without combination of other chemotherapeutic reagents (OS: odds ratio = 0.909, 95% CI: 0.780-1.059, P = 0.221; PFS: odds ratio = 0.985, 95% CI: 0.865-1.122, P = 0.826). By contrast, meta-analysis on ramucirumab (3 out of 8 Phase III trials) revealed that ramucirumab was significantly favored in the treatment of gastric cancer with significant different OS between the two groups (odds ratio = 0.720, 95% CI: 0.604-0.858, P < 0.001). In addition, patients treated with VEGF or VEGFR blockers had higher morbidity of hypertension and neutropenia, but lower risk of side effects of vomiting and anemia. These findings suggest that addition of antiangiogenesis reagents, especially anti-VEGFR-mAb, to the first- or second line chemotherapy could prolong patient's OS and PFS time in the advanced or metastatic gastric cancer. PMID- 30410365 TI - Novel EXO-T vaccine using polyclonal CD4+ T cells armed with HER2-specific exosomes for HER2-positive breast cancer. AB - Breast cancer is the leading cause of death in women globally. The human epidermal growth factor receptor 2 (HER2)-positive breast cancer is often associated with poor prognosis and high mortality. Even though anti-HER2 monoclonal antibodies have improved the clinical outcome, resistance to the antibody therapy becomes a major obstacle in the treatment of HER2-positive breast cancer patients. Alternative approaches are therefore needed. HER2 specific vaccines have been developed to trigger patient's immune system against HER2-positive breast cancer. This article describes the development of novel HER2 specific exosome (EXO)-T vaccine using polyclonal CD4+ T cells armed with HER2 specific dendritic cell-released EXO and demonstrates its therapeutic effect against HER2-positive tumor in double-transgenic HER2/HLA-A2 mice with HER2 specific self-immune tolerance. Therefore, our novel HER2-specific EXO-T vaccines are likely to assist in the treatment of HER2-positive breast cancer patients. PMID- 30410368 TI - Overexpression of APC11 predicts worse survival in lung adenocarcinoma. AB - Background: Anaphase-promoting complex subunit 11 (APC11) plays an important role in gathering E2 and catalyzing ubiquitin-chain formation to support ubiquitination of substrates by acting as a catalytic core subunit of anaphase promoting complex (APC/C). However, whether APC11 is implicated in the tumorigenesis of lung cancer is never known. Materials and methods: In this study, we used an online survival analysis software to estimate the prognostic value of APC11 mRNA expression level for lung cancer. Cell Counting Kit-8 assay, colony-forming assay, and transwell assay were used to assess the biological functions of APC11 in lung cancer cells. Then, 107 lung cancer patient tissues were collected to examine the expression level of APC11 by immunohistochemistry staining. Kaplan-Meier method and univariate Cox regression analysis were performed to reveal the prognostic value of APC11 protein expression in lung cancer. Results: Higher mRNA level of APC11 was significantly associated with worse survival for lung adenocarcinoma, but not for lung squamous cell carcinoma. Knockdown of APC11 by siRNA apparently inhibited cell proliferation and colon formation in both H1299 and H358 cells. In addition, silencing of APC11 decreased cell migrative and invasive abilities. Moreover, immunohistochemical analysis showed that APC11 was highly expressed in lung cancer tissues, and multivariate analysis suggested that APC11 overexpression was an independent prognostic factor in lung adenocarcinoma. Conclusion: We suggest that APC11 could serve as a prognostic biomarker and a novel target in treating lung adenocarcinoma. PMID- 30410369 TI - Lentivirus-mediated overexpression of HSDL2 suppresses cell proliferation and induces apoptosis in cholangiocarcinoma. AB - Background: Cholangiocarcinoma (CCA) is a malignant tumor of the bile duct epithelium, including intrahepatic, perihilar, and distal CCA based on anatomical location. Hydroxysteroid dehydrogenase-like 2 (HSDL2) belongs to the SDR subfamily of oxidoreductases, and it is involved in glioma oncogenesis, as it can promote cell proliferation and inhibit cell apoptosis. The purpose of this study was to explore the underlying molecular mechanisms of HSDL2 in the process of CCA. Methods: HSDL2 expression levels were observed in CCA and adjacent (normal control) tissues by analyzing data from The Cancer Genome Atlas and Gene Expression Omnibus databases. A receiver operating characteristic curve analysis was carried out. In vitro, we overexpressed HSDL2 in RBE cells (a human CCA cell line) using a stable lentivirus-mediated transduction strategy. We then used quantitative real-time-PCR and Western blotting methods to detect the efficiency of HSDL2 overexpression. Cell proliferation was assessed using a Celigo Image Cytometer, MTT assays, and the expression of PCNA. Cell apoptosis was assessed by flow cytometry analysis, caspase3/7 activity, and the expression of the apoptotic markers BCL-2 and BAX. Results: We observed a downregulation of HSDL2 in CCA tissues based on The Cancer Genome Atlas and Gene Expression Omnibus data analysis. The receiver operating characteristic curve analysis showed that HSDL2 could be an excellent efficacy biomarker for CCA. In vitro, HSDL2 overexpression largely suppressed the proliferation of RBE cells. In addition, apoptosis was induced by HSDL2 overexpression. Conclusion: The results of the data analysis indicated that, compared with adjacent tissues, HSDL2 was downregulated in CCA tissues, and overexpressing HSDL2 in CCA cells suppressed growth and proliferation, which involved activating apoptosis. This helps to understand the underlying HSDL2-related molecular mechanisms in the process of CCA. PMID- 30410366 TI - Mechanisms of resistance to BRAF and MEK inhibitors and clinical update of US Food and Drug Administration-approved targeted therapy in advanced melanoma. AB - Approximately 50% of melanomas harbor an activating BRAF mutation. Combined BRAF and MEK inhibitors such as dabrafenib and trametinib, vemurafenib and cobimetinib, and encorafenib and binimetinib are US Food and Drug Administration (FDA)-approved to treat patients with BRAF V600-mutated advanced melanoma. Both genetic and epigenetic alterations play a major role in resistance to BRAF inhibitors by reactivation of the MAPK and/or the PI3K-Akt pathways. The role of BRAF inhibitors in modulating the immunomicroenvironment and perhaps enhancing the efficacy of checkpoint inhibitors is gaining interest. This article provides a comprehensive review of mechanisms of resistance to BRAF and MEK inhibitors in melanoma and summarizes landmark trials that led to the FDA approval of BRAF and MEK inhibitors in metastatic melanoma. PMID- 30410370 TI - Tumoral response and tumoral phenotypic changes in a rat model of diethylnitrosamine-induced hepatocellular carcinoma after salirasib and sorafenib administration. AB - Background: Several intracellular signaling pathways that are deregulated during hepatocarcinogenesis might constitute potential targets for hepatocellular carcinoma (HCC) therapy. The aim of this study was to test the potential synergic antitumor effect of salirasib and sorafenib in a diethylnitrosamine (DEN)-induced HCC model in rat. The hypothesis of tumor phenotype changes during treatment was also analyzed. Materials and methods: DEN was administered to Wistar rats during 9 weeks to induce cirrhosis and liver cancer. After tumor development, rats were treated with intraperitoneal injections of dimethyl sulfoxide (DMSO), or salirasib, and/or with oral sorafenib 5 days/week, during 4 weeks. At sacrifice, number and size of liver tumors as well as tumor burden were recorded, and all liver tumors were processed for histological and immunohistological analyses. Results: Mortality rate was significantly higher in rats treated with salirasib and/or sorafenib than in the control group (P=0.001). Tumor burden was smaller in the treated group compared with the DMSO control group (P=0.044), but a synergistic effect of the two chemotherapies could not be observed. In 62.5% of rats (10/16) treated with salirasib and/or sorafenib, a cytokeratin-7 and -19 positive hepatocholangiocellular carcinoma (HCC/CHC) was found vs 20% (5/25) developing such phenotype in the DMSO control group (P=0.018). Ki67 immunostaining showed significantly reduced tumor cell proliferation in treated rats (P=0.001), whereas apoptosis as assessed by caspase-3 activity in cell lysate was similar in all groups. Conclusions: The addition of sorafenib to salirasib did not seem to provide any synergistic therapeutic effect in this study. Both chemotherapeutic agents, administered alone or in combination, induced tumoral phenotypic changes in the majority of rats, a finding not associated with an increased tumor cell proliferation or decreased apoptosis. The rat model described in this work constitutes the first experimental tool generating putatively more aggressive combined HCC/CHC tumors following chemotherapy. Further work is required to better characterize this clinically relevant phenomenon. PMID- 30410371 TI - Computational analysis of ligand-receptor interactions in wild-type and mutant erythropoietin complexes. AB - Background: Erythropoietin (EPO), a pleiotropic cytokine, binds to its receptor (EPOR) in bone marrow, activating a signaling cascade that results in red blood cell proliferation. A recently discovered naturally occurring EPO mutation (R150Q) at active site 1 (AS1) of the protein was shown to attenuate its canonical downstream signaling, eliminating its hematopoietic effects and causing a fatal anemia. The purpose of this work was to analyze the EPO-EPOR complex computationally to provide a structural explanation for this signaling change. Materials and methods: Computational structural biology analyses and molecular dynamics simulations were used to determine key interaction differences between the R150Q mutant and the wild-type form of EPO. Both were compared to another variant mutated at the same position, R150E, which also lacks hematopoietic activity. Results: The ligand-receptor interactions of the R150Q and R150E mutants showed significant variations in how they interacted with EPOR at AS1 of the EPO-EPOR complex. Both lost specific reported salt bridges previously associated with full complex activation. Conclusion: This work describes how the ligand-receptor interactions at AS1 of the EPO- EPOR complex respond to mutations at the 150th position. The interactions at AS1 were used to propose a potential mechanism by which the binding of EPO to the extracellular domain of EPOR influences its cytosolic domain and the resulting signaling cascade. PMID- 30410367 TI - MicroRNA-195: a review of its role in cancers. AB - MicroRNAs (miRNAs) are small and highly conserved noncoding RNAs that regulate gene expression at the posttranscriptional level by binding to the 3'-UTR of target mRNAs. Recently, increasing evidence has highlighted their profound roles in various pathological processes, including human cancers. Deregulated miRNAs function as either oncogenes or tumor suppressor genes in multiple cancer types. Among them, miR-195 has been reported to significantly impact oncogenicity in various neoplasms by binding to critical genes and signaling pathways, enhancing or inhibiting the progression of cancers. In this review, we focus on the expression of miR-195 in regulatory mechanisms and tumor biological processes and discuss the future potential therapeutic implications of diverse types of human malignancies. PMID- 30410372 TI - Utility of a thin bronchoscope in facilitating bronchial thermoplasty. AB - Background: A significant correlation has been previously demonstrated between the quantum of radiofrequency treatment delivered at bronchial thermoplasty and the degree of improvement in an asthmatic patient's symptoms. The standard bronchoscope used for bronchial thermoplasty has an outer diameter of 4.8 mm at the distal tip. Thinner bronchoscopes are now available with the same internal channel size (2.0 mm). This study assesses whether using a thinner bronchoscope facilitates bronchial thermoplasty by increasing the radiofrequency activations delivered. Patients and methods: This was a sequential study in a single center, conducted in 27 patients with very severe asthma. The first 12 patients (Group 1) underwent bronchial thermoplasty using the standard bronchoscope, Olympus BF Q190. In the next group of eight patients (Group 2), the standard bronchoscope was used for all procedures except the left upper lobe, while the left upper lobe was treated with a smaller bronchoscope, Olympus BF-P190, with an outer diameter of 4.2 mm. In the last group of seven patients (Group 3), the smaller bronchoscope was used for every lobe. The quantum of radiofrequency treatment was measured by activations delivered to each lung lobe in each patient, and patient groups were compared by ANOVA. Results: In this group of 27 patients, the mean age was 56.5+/-12.9 years, the mean Asthma Control Questionnaire-5 item version score was 3.2+/-1.0 and the mean FEV1% predicted was 55.2+/-15.7. Bronchial thermoplasty treatment resulted in significant improvements in predicted Asthma Control Questionnaire-5 item version score (to 1.8+/-1.3, P<0.005), salbutamol rescue usage and oral corticosteroid requiring exacerbations, with no significant change in lung function. Use of the smaller bronchoscope resulted in greater radiofrequency treatment (total activations Group 1: 155+/-21, Group 2: 176+/-46, Group 3: 213+/-37; P<0.01). There were no significant differences in efficacy or safety outcomes among groups. Conclusion: Using a thinner bronchoscope facilitates access to the bronchial tree and increases the radiofrequency treatment delivered at bronchial thermoplasty. PMID- 30410373 TI - Real-world analysis of cost, health care resource utilization, and supportive care in Hodgkin lymphoma patients with frontline failure. AB - Purpose: The purpose of this study was to evaluate the economic burden of frontline failure (FLF) among classical Hodgkin lymphoma (HL) patients during and after treatment. Patients and methods: The population consisted of adult HL patients identified from January 2010 through September 2015 without any other primary cancer prior to HL diagnosis, who also had a frontline (FL) regimen indicative of curative intent. Patients were characterized as FLF (those who restart, switch to any chemotherapy; had a hematopoietic stem cell transplant; or newly initiated radiation therapy [RT] after discontinuing FL) or non-FLF (those not considered as FLF). Direct health care utilization and expenditures were measured over both fixed and variable length follow-up periods and during FL therapy. Results: There were 77 FLF and 602 non-FLF patients who met the final inclusion criteria. FLF and non-FLF patients were demographically similar with mean age 38.5 years and 47.5% females. Average per patient per month (PPPM) costs were significantly higher for FLF patients during all follow-up (US$20,266 vs US$7,772, P<0.05). Annual total expenditures were significantly higher among FLF patients (US$198,388) vs non-FLF patients (US$37,549). FLF (vs non-FLF) patients had a significantly shorter duration of FL therapy (116 vs 131 days, P=0.024) and higher total PPPM expenditures during FL (US$29,040 vs US$16,369, P<0.05). Annual cost varied by failure type with those who failed due to restart incurring the highest cost (US$269,189) and those who switched incurring the lowest cost (US$46,951). FLF patients had a significantly greater utilization in every health care resource category during follow-up. Conclusion: FLF (vs non-FLF) patients utilized substantially more health care resources and incurred a substantially higher economic burden. Over 5 years, FLF patients with at least two lines of treatment were projected to incur US$535,846 of health care costs. Further research is needed to determine optimal treatment that could reduce the risk of progression, need for treatment after FL, and enhance long-term clinical and economic outcomes. PMID- 30410374 TI - Sacroiliac joint fusion health care cost comparison prior to and following surgery: an administrative claims analysis. AB - Purpose: To assess real-world expenditures on surgical and non-surgical treatment for sacroiliac joint (SIJ) pain by comparing direct health care costs before and after surgery in patients who underwent an SIJ fusion (SIJF) procedure. Materials and methods: This retrospective observational study examined administrative claims data (January 1, 2010 to February 28, 2017) for adult commercial health plan members with a medical claim for SIJF. Identified patients were included if they had continuous enrollment in the health plan for 12 months pre-SIJF (baseline period) and 12 months post-SIJF (follow-up period). The outcomes of interest were low back pain-related health care costs in the first three quarters of the baseline period (pre-surgery period; excludes the quarter immediately preceding surgery) and last three quarters of the follow-up period (post-surgery period; excludes the quarter in which SIJF was performed). Results: Some 302 patients met inclusion criteria: 159 patients had the index SIJF in an inpatient hospital setting, 122 in an outpatient hospital setting, 18 in a surgery center, and three in other settings. Mean and median costs in the pre-surgery period were US$16,803 and US$5,849, respectively, and US$13,297 and US$2,269 in the post surgery period. Median costs were significantly different in the pre- and post surgery periods (P<0.001), while mean costs were not. Median health care costs in the pre-surgery and post-surgery periods were lower than the corresponding means due to the highly skewed nature of the cost data. Conclusion: This health care claims data analysis shows the potential for lower post-operative health care costs compared to pre-operative costs in patients undergoing SIJF. Median low back pain-related costs in the post-surgery period were approximately US$400 per quarter overall and US$250 per quarter for those undergoing SIJF in the non inpatient setting. Future studies with larger sample sizes and longer follow-up will improve the precision of the cost data. PMID- 30410375 TI - To fast or not to fast during the month of Ramadan? A comprehensive survey on religious beliefs and practices among Moroccan diabetic patients. AB - Background: Diabetes represents a major public health concern. According to the International Diabetes Federation, about 8%-9% of the population have diabetes, and rates are even higher among Muslim communities. Despite the risks, about half (43%) with type 1 diabetes and most (86%) of those with type 2 diabetes fast during Ramadan. However, there is a dearth of information concerning the determinants that drive diabetic people to fast. Therefore, the present study was designed to fill this gap in knowledge. Materials and methods: A sample of 201 subjects volunteered to take part in this study. Mean age was 45.39+/-15.74 years. Most participants were female, married and had received at least primary education. They fasted for 22.98+/-8.53 days. Results: For the overall questionnaire, the Cronbach's alpha coefficient was found to be excellent (alpha=0.910). The coefficient was good, yielding a value of 0.879, for the items concerning Ramadan fasting beliefs and practices, whereas the subscale for religious beliefs and practices obtained a score of 0.847. At the univariate analysis, patients with complicated diabetes (n=66, 32.8% of the sample) fasted for 20.77+/-9.21 days vs subjects with diabetes (n=135, 67.2% of the interviewees), who fasted for 24.05+/-7.99 days. The difference was statistically significant (P=0.014). The multivariate analysis indicated that religious beliefs and practices influenced the number of fasting days in a statistically significant way, after adjusting for confounders (beta coefficient =-0.199, t= 2.917, P=0.004). Another variable that impacted on the number of fasting days was the presence of complications (beta coefficient=-0.194, t=-2.775, P=0.006). Conclusion: Our results warrant further studies in the field. PMID- 30410376 TI - Quick guide to type 2 diabetes self-management education: creating an interdisciplinary diabetes management team. AB - Type 2 diabetes is a chronic disease that requires several daily self-management decisions and complex care activities. Clinical management of diabetes and teaching patients diabetes self-management skills are necessary for optimal type 2 diabetes control. Diabetes self-management education (DSME) and support require time and resources. While there is a plethora of education material for health care professionals to use, very few guides compile the information in a practical way to relay the information to the patient. This quick guide to DSME has been developed to give physicians and their staff the tools to teach basic type 2 diabetes self-management skills in three 15-minute clinic visits. PMID- 30410377 TI - Associations between eating habits and glycemic control and obesity in Japanese workers with type 2 diabetes mellitus. AB - Purpose: To investigate the impact of poor eating habits on glycemic and metabolic control, we analyzed the associations between eating behaviors and HbA1c and body mass index (BMI) in Japanese workers with type 2 diabetes mellitus (T2DM). Subjects and methods: The Japan Medical Data Center database of workers' medical health insurance claims was used to identify individuals with T2DM who were receiving antidiabetic medication between April 2012 and March 2015 (the primary analysis population). The database included routine medical check-up results and responses to questions on lifestyle and eating habits. Using these, we retrospectively analyzed the associations between the individuals' eating habits and their HbA1c levels and BMIs. Results: In total, 31,722 individuals were included in the primary analysis. The mean values of HbA1c and BMI were 7.27% and 26.29 kg/m2, respectively; these tended to be higher among the younger population. Approximately 36% of the individuals regularly ate supper within 2 hours of bedtime, 14.5% regularly consumed late-night snacks, and 13.4% regularly skipped breakfast. Each of these eating habits correlated significantly with higher HbA1c and BMI. In addition, the population with two or all three of these poor dietary habits showed the highest association with HbA1c >=7.0% and BMI >=25 kg/m2. Approximately 38% of workers ate fast. Fast eating was significantly associated with BMI >=25 kg/m2 but not with HbA1c >=7.0%. Conclusion: Poor eating habits were significantly associated with poor glycemic and body weight control in Japanese workers with T2DM. Improved eating habits may help with glycemic and body weight management. PMID- 30410378 TI - Skin hydration is significantly increased by a cream formulated to mimic the skin's own natural moisturizing systems. AB - Background: Moisturizers are topical products designed to improve and maintain the skin barrier function and to help prevent dry skin. Materials and methods: A new moisturizer (Ceramide cream) was formulated containing ingredients which mimic the skin's own natural moisturizing systems. Corneometry was performed at baseline, 2, 4, 6 and 24 hours following a single application of Ceramide cream to healthy skin, and compared to three reference moisturizers available over-the counter, and placebo. Transepidermal water loss (TEWL) was also measured following a single application of Ceramide cream compared to baseline, and its safety was assessed by repeat insult patch test, ophthalmologist and pediatric testing. Results: A single topical application of either the Ceramide cream or the three reference moisturizers resulted in a significant increase in skin hydration over time (P<0.001). The placebo cream did not significantly increase skin hydration at any time point. At 24 hours post-application, skin hydration measured for Ceramide cream was significantly greater (P<0.05) than that measured for all three of the reference moisturizers tested. Ceramide cream was also found to significantly decrease TEWL (P<0.001) over 24 hours, and was shown to be non sensitizing to the skin of both adults and children and non-irritating to the skin, eyes and related eye area. Conclusion: Ceramide cream increases skin hydration and improves barrier function which may make it suitable for use on dry skin. PMID- 30410379 TI - Cryolipolysis: patient selection and special considerations. AB - Cryolipolysis is considered a safe and effective procedure, with high patient satisfaction rates, especially when compared to other procedures for localized adiposity, such as high-intensity focused ultrasound and shock waves. Although this statement is present in the literature, the importance of the selection of suitable patients for this type of treatment is not well known. The objective of this study was to discuss the criteria to be considered in the selection of patients who are candidates for cryolipolysis and assess their profile regarding their anthropometric data, age, skin characteristics, cutaneous sensitivity, and risk pathologies for this type of treatment. Assessing the amount of localized adiposity requires safe and validated methods that are significant in measuring results. The aim is to achieve success in the process of reducing adiposity guaranteeing patient satisfaction and assurance of results. PMID- 30410380 TI - Potential protective effects of rhEGF against ultraviolet A irradiation-induced damages on human fibroblasts. AB - Background: Ultraviolet A (UVA) rays reach the dermal skin layer and generate oxidative stress, DNA damage, and cell inflammation, which in turn lead to photo aging and photo-carcinogenesis. While there have been many studies about the beneficial effects of topical epidermal growth factor (EGF) treatment in the healing of wounds, the effect of EGF on UVA-induced skin irritation remains unknown. To clarify the effects of EGF on UVA-induced skin damage, it was investigated whether EGF signaling can affect intracellular reactive oxygen species (ROS) and DNA damages in UVA-irradiated human dermal fibroblasts. Materials and methods: Fibroblasts cultured with or without rhEGF were UVA irradiated at 40 mJ/cm2 twice per day for 5 days. After the irradiation, the intracellular ROS levels and expression of catalase and superoxide dismutase-1 (SOD-1) in the fibroblasts were ascertained. Further investigation to determine the effects of EGF on UVA-induced DNA damage, including a single cell gel electrophoresis assay and an enzyme-linked immunosorbent assay (ELISA), was carried out. Moreover, the NF-kappaB activity was ascertained in order to investigate the effects of EGF on UVA-irradiated fibroblasts. Results: As a result, it was revealed that recombinant human EGF (rhEGF) inhibited UVA- increased intracellular ROS in the fibroblasts and increased the expression of catalase and SOD-1. Moreover, in UVA-irradiated fibroblasts, the longest DNA damaged tails were observed, but this phenomenon was not detected in cells cotreated with both UVA and rhEGF. Also, it was observed that DNA damage induction, including that of cyclobutene pyrimidine dimers, pyrimidine (6-4) pyrimidone photoproducts, and 8-hydroxy-2-deoxyguanosine, was caused by UVA irradiation. Similar to previous results, it was downregulated by rhEGF. Furthermore, rhEGF also inhibited NF-kappaB gene expression and the NF-kappaB p65 protein level in the nucleus induced by UVA irradiation. Conclusion: These results suggest that EGF might be a useful material for preventing or improving photo-aging. PMID- 30410381 TI - Agreement of triage decisions between gastroenterologists and nurses in a hospital endoscopy unit. AB - Introduction: Efficient and accurate triage of endoscopy referrals is essential. Many of the decisions made are based on national and local triage criteria. Standardizing this approach for nurse use could maintain quality, address clinical risk and significantly improve resource utilization. Aims: This study aimed to compare gastroenterologist and nurse triage of unselected gastroenterology referrals in order to evaluate the proportion of referrals felt able to be triaged to endoscopy and the inter-rater agreement between a triage gastroenterologist and endoscopy nurses for clinical triage decisions regarding the urgency of gastroscopy and colonoscopy. Methods: The proportion of referrals triaged to endoscopy by a consultant gastroenterologist performing triage as a part of normal practice and two endoscopy nurses using a decision algorithm was measured. The inter-rater agreement for the triage category decision (urgency of referral) between the three triage clinicians was assessed. An adjudication panel provided a consensus decision triage category decision in cases where there was not complete agreement between the three triage clinicians. Results: Each clinician assessed 105 referrals. Nurse A was able to triage 54 (51%) referrals to a triage category and Nurse B 44 (42%) referrals. Cohen's kappa was run to determine if there was agreement between clinicians for the triage categories allocated. The agreement between the two nurses was substantial (k=0.645, P<0.0005). Between the gastroenterologist and each nurse, moderate agreement was seen (Nurse A, k=0.589, P<0.0005; Nurse B, k=0.437, P<0.0005). Moderate agreement was seen between the nurses and an adjudication panel (Nurse A, k=0.423, P<0.0005; Nurse B, k=0.464, P<0.0005). However, there was only slight agreement between the adjudication panel and the gastroenterologist (k=0.099, P=0.010). Conclusion: Nurse triage using a decision algorithm is feasible, and inter-rater agreement is substantial between nurses and moderate to substantial between the nurses and a gastroenterologist. An adjudication panel demonstrated moderate agreement with the nurses but only slight agreement with the triage gastroenterologist. This suggests that nurse triage using a decision algorithm can approximate decision making by an experienced gastroenterologist. PMID- 30410382 TI - Aortic calcification in Gaucher disease: a case report. AB - Gaucher disease is the most common sphingolipid storage disease and is present in all ethnic groups. Its symptoms span all systems including the cardiovascular system. The health care provider should be vigilant regarding this potentially fatal complication. Gaucher disease type IIIC has been linked to causing oculomotor apraxia and cardiac calcification. We report a Saudi girl who developed valvular and aortic calcification in late childhood and died as a result of her cardiovascular complications. This report further strengthens the association and reminds the clinicians that patients with D409H mutation need echocardiographic evaluation annually. PMID- 30410383 TI - Renal transplantation in patients with Alport syndrome: patient selection, outcomes, and donor evaluation. AB - Alport syndrome is an inherited disorder of basement membrane collagen IV that frequently results in end-stage renal disease. Patients with Alport syndrome who undergo renal transplantation have generally excellent outcomes. Posttransplant antiglomerular basement membrane nephritis is a rare complication of renal transplantation for Alport syndrome. Because Alport syndrome is a genetic disorder, potential related donors must be carefully evaluated in order to minimize harm. PMID- 30410384 TI - Low aquaporin-2 excretion in the nephrotic syndrome: an escape from the vasopressin regulating effect. AB - Purpose: Experimental studies suggest that the nephrotic syndrome is associated with "vasopressin escape", characterized by low aquaporin-2 (AQP2) expression in the collecting duct despite high vasopressin secretion. We investigated this phenomenon in patients with the nephrotic syndrome. Patients and methods: We recruited 47 patients with proteinuric kidney disease who were distributed into the following four groups: 1) nephrotic syndrome with kidney dysfunction (n=10); 2) nephrotic syndrome with normal kidney function (n=16); 3) partial remission of nephrotic syndrome (n=10); and 4) minimal proteinuria (n=11). Nine healthy volunteers comprised a control group. Serum copeptin level (as a marker of vasopressin secretion) and urinary AQP2 were measured using ELISA. Results: Nephrotic syndrome was associated with a significant increase in serum copeptin levels compared with those in the other groups (all P<0.05). In patients with nephrotic syndrome and a partial remission of nephrotic syndrome combined, there was more than a ten-fold decrease in the median urinary AQP2 excretion (0.03 ng/mL) compared with healthy volunteers (0.41 ng/mL; P<0.001) and more than a five-fold decrease compared with patients with minimal proteinuria (0.21 ng/mL; P<0.05). Unlike copeptin levels, the median urinary AQP2 excretion in patients with minimal proteinuria also decreased but less significantly than in those with nephrotic syndrome. There was a negative correlation between the urinary AQP2 excretion and daily proteinuria (R=-0.41; P=0.005). Conclusion: Our clinical study was the first to demonstrate low AQP2 excretion in nephrotic syndrome that may indicate an escape from the vasopressin regulating effect. PMID- 30410385 TI - Creating and validating a warfarin pharmacogenetic dosing algorithm for Colombian patients. AB - Purpose: Warfarin is an oral anticoagulant associated with adverse reaction to drugs due to wide inter- and intra-individual dosage variability. Warfarin dosage has been related to non-genetic and genetic factors. CYP2C9 and VKORC1 gene polymorphisms affect warfarin metabolism and dosage. Due to the central role of populations' ethnical and genetic origin on warfarin dosage variability, novel algorithms for Latin American subgroups are necessary to establish safe anticoagulation therapy. Patients and methods: We genotyped CYP2C9*2 (c.430C > T), CYP2C9*3 (c.1075A > C), CYP4F2 (c.1297G > A), and VKORC1 (-1639 G > A) polymorphisms in 152 Colombian patients who received warfarin. We evaluated the impact on the variability of patients' warfarin dose requirements. Multiple linear regression analysis, using genetic and non-genetic variables, was used for creating an algorithm for optimal warfarin maintenance dose. Results: Median weekly prescribed warfarin dosage was significantly lower in patients having the VKORC1-1639 AA genotype and poor CYP2C9*2/*2,*2/*3 metabolizers than their wild type counterparts. We found a 2.3-fold increase in mean dose for normal sensitivity patients (wild-type VKORC1/CYP2C9 genotypes) compared to the other groups (moderate and high sensitivity); 31.5% of the patients in our study group had warfarin sensitivity-related genotypes. The estimated regression equation accounted for 44.4% of overall variability in regard to warfarin maintenance dose. The algorithm was validated, giving 45.9% correlation (R 2=0.459). Conclusion: Our results describe and validate the first algorithm for predicting warfarin maintenance in a Colombian mestizo population and have contributed toward the understanding of pharmacogenetics in a Latin American population subgroup. PMID- 30410387 TI - Quantitative sensory testing in physically active individuals and patients who underwent multidisciplinary pain therapy in the longitudinal course. AB - Objective: The aim of this study was to evaluate possible differences of quantitative sensory testing (QST) results in healthy individuals (group control, n=20), physically active individuals (group sport, n=30) and in patients suffering from chronic musculoskeletal pain (group pain, n=30). Methods: Thermal detection thresholds, thermal pain thresholds and blunt pressure pain thresholds were measured at various sites (T0). Additionally, group pain was treated in multidisciplinary pain therapy for 4 weeks. All groups were retested after 4 weeks to evaluate the reliability of QST measurements and to investigate possible early changes following treatment (T1). Results: Importantly, QST-measurements showed stable test results for group sport and group control at both time points. Athletes demonstrated the highest pain thresholds in general (cold pain threshold mean in degree Celsius for the hand: 5.76, lower back right: 7.25, lower back left: 7.53; heat pain threshold mean in degree Celsius for the hand: 46.08, lower back right: 45.77, lower back left: 45.70; and blunt pressure pain mean in kilograms for the hand: 3.54, lower back right: 5.26, lower back left: 5.46). Patients who underwent therapy demonstrated significant differences at T1 (cold pain threshold hand mean in degree Celsius for the hand: 11.12 [T0], 15.12 [T1]; and blunt pressure pain mean in kilograms for the lower back right: 2.87 [T0], 3.56 [T1]). They were capable of enduring higher blunt pressure, but on the other hand cold pain tolerance had decreased (P=0.045 and P=0.019, respectively). Conclusions: In conclusion, we were able to demonstrate significant differences of QST results among the three groups and we detected early changes following multidisciplinary pain therapy, which will be discussed. PMID- 30410386 TI - Effect of a do-not-resuscitate order on the quality of care in acute heart failure patients: a single-center cohort study. AB - Background: A do-not-resuscitate (DNR) order is reportedly associated with a decrease in performance measures, but it should not be applied to noncardiopulmonary resuscitation procedures. Good performance measures are associated with improvement in heart failure outcomes. Aim: To analyze the influence of DNR order on performance measures of heart failure at our hospital, where lectures on DNR order are held every 3 months. Design: Retrospective cohort study. Methods: The medical report of patients with acute heart failure who were admitted between April 2013 and March 2015 were retrospectively analyzed. We collected demographic data, information on the presence or absence of DNR order within 24 hours of admission, and inhospital mortality. Performance measures of heart failure, including assessment of cardiac function and discharge prescription of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and beta-blocker for left ventricular systolic dysfunction and anticoagulant for atrial fibrillation, were collected and compared between groups with and without DNR orders. Results: In 394 total patients and 183 patients with left ventricular systolic dysfunction, 114 (30%) and 44 (24%) patients, respectively, had a DNR order. Patients with a DNR order had higher inhospital mortality. There were no significant differences between the two groups in terms of the four quality measures (left ventricular function assessment, angiotensin converting enzyme inhibitor or angiotensin receptor blocker, beta-blocker, and anticoagulant). Conclusion: DNR orders did not affect performance measures, but they were associated with higher inhospital mortality among acute heart failure patients. PMID- 30410388 TI - Clinical observation of CT-guided intra-articular conventional radiofrequency and pulsed radiofrequency in the treatment of chronic sacroiliac joint pain. AB - Background: Sacroiliac joint pain (SIJP) is an important cause of low back pain and seriously affects the patients' quality of life. Therefore, it is urgent to find effective treatment methods. Objective: To observe the efficacy of intra articular (IA) conventional radiofrequency (CRF) and pulsed radiofrequency (PRF) treatment of Sacroiliac joint syndrome (SIJS) under computed tomography (CT) guidance. Study design: Retrospective comparative study. Setting: Shengjing Hospital of China Medical University. Patients and methods: Sixty-four patients with SIJS were enrolled in the Pain management. Patients were randomized into two groups: CRF (CRF group, n=32) and PRF (PRF group, n=32). At each observation time, the general condition, visual analog scale (VAS), the total efficiency rate, Oswestry disability index (ODI), and 36-item short-form health survey were followed up. Results: Compared to the pretreatment value, the VAS and the ODI decreased in both groups after treatment (P<0.05). In the CRF group, the VAS and the ODI decreased significantly at 1 week after treatment (P<0.05); at 6 and 12 months after treatment, the VAS and the ODI were lower than that in the PRF group (P<0.05). The total efficiency rate in the CRF group and PRF group was 56.3% and 31.3%, respectively (P<0.05). After the relief of pain, both groups received different degrees of improvement in the quality of life. Compared to the pretreatment value, physical component summary (PCS) and the mental component summary (MCS) in both groups were increased after treatment (P<0.05); in the CRF group, PCS and MCS increased significantly at 1 week after treatment (P<0.05); and at 6 and 12 months after treatment, PCS and MCS were higher than those in the PRF group (P<0.05). Conclusion: CT-guided IA PRF and CRF in the treatment of sacroiliac pain are safe and effective. CRF is superior to PRF in the early and late stage. It is recommended for the treatment of SIJP. PMID- 30410389 TI - Clinical effect and safety of pulsed radiofrequency treatment for pudendal neuralgia: a prospective, randomized controlled clinical trial. AB - Background: Pudendal neuralgia is an intractable pain related to the pudendal nerve. The clinical effect and safety evaluation of pudendal neuralgia were investigated by pulse radiofrequency (PRF) treatment of pudendal nerve. Patients and methods: Eighty patients who were diagnosed with pudendal neuralgia were randomly divided into PRF group (PRF and pudendal nerve block [NB]) and NB group. After surgery, the patients were followed up to evaluate the visual analog scale (VAS) score and the Patient Health Questionnaire score on the postoperative day and at 2 weeks, 1 and 3 months. Meanwhile, the patients' efficacy assessment and the usage of pain medication were also recorded for 3 months during follow-up. All the surgical complications were recorded. Results: A total of 77 patients were followed up, 38 in the PRF group and 39 in the NB group. On the postoperative day, the VAS scores was significantly decreased in both groups than before (P<0.01), whereas there was no statistical difference within the two groups (P>0.05). However, the VAS score of PRF group was significantly lower than that of NB group in 2 weeks, 1 and 3 months after surgery, respectively (P<0.01). In the meanwhile, the Patient Health Questionnaire score of PRF group was also significantly lower than that of NB group (P<0.01) in 3 months after the operation. The clinical effective rate of PRF group was 92.1% in 3 months after surgery, while this rate was only 35.9% in the NB group. The postoperative analgesic usage of PRF group was superior to that of NB group (P<0.01). No severe adverse events were observed in either group. Conclusion: Compared with the single NB treatment, pudendal nerve PRF combined with NB therapy could provide more long-lasting relief from pain symptoms of pudendal neuralgia and improve the depression symptoms in patients. PMID- 30410390 TI - Caudal epidural block instead of general anesthesia in an adult with Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD), first described in 1834, is an X-linked dystrophinopathy, leading to early onset skeletal muscle weakness. Life expectancy is reduced to early adulthood as a result of involvement of voluntary skeletal muscles with respiratory failure, orthopedic deformities, and associated cardiomyopathy. Given its multisystem involvement, surgical intervention may be required to address the sequelae of the disease process. We present a 36-year-old adult with DMD, who required anesthetic care during surgical debridement of an ischial pressure sore. Given his significant respiratory muscle involvement, ultrasound-guided caudal epidural anesthesia was used instead of general during the surgical procedure. The technique and its applications are discussed, with particular emphasis on the feasibility and safety of using regional anesthetic techniques in patients with DMD. PMID- 30410391 TI - Impact of thoracic epidural sympathetic block on cardiac repolarization. AB - Purpose: The interval from the peak to the end of the T wave (Tp-Te) on electrocardiography is considered a marker of ventricular arrhythmias. A previous study suggested that right stellate ganglion block prolonged QT and QT dispersion (QTD). We investigated the effect of thoracic epidural sympathetic block with 1% mepivacaine on QT, QTD, Tp-Te, and Tp-Te/QT by using computerized measurement. Patients and methods: After obtaining the approval of the ethics committee of Dokkyo Medical University Hospital, 23 patients with American Society of Anesthesiologists physical status I or II who were scheduled to undergo thoracic surgery were enrolled. An epidural catheter was inserted at the Th4-5 or 5-6 level and then used for injection of 7 mL of 1% mepivacaine. Changes in RR interval, QT, corrected QT (QTc), QTD, QTc dispersion (QTcD), Tp-Te, Tp-Te/QT, and Tp-Te/QTc before and after epidural injection were assessed by computerized measurement. Statistical analysis was performed by one-way ANOVA. Results: Systolic blood pressure was consistently suppressed 10-15 minutes after injection (baseline: 136+/-10 mmHg, 11 minutes: 113+/-12 mmHg, 12 minutes: 112+/-13 mmHg, 13 minutes: 112+/-12 mmHg, 14 minutes: 108+/-17 mmHg, 15 minutes: 111+/-14 mmHg; P<0.05). However, RR interval, QT, QTc, QTD, QTcD, Tp-Te, Tp-Te/QT, and Tp-Te/QTc were not changed after epidural block. Conclusion: Thoracic epidural injection of 1% mepivacaine did not alter QT, QTc, QTD, QTcD, Tp-Te, Tp-Te/QT, or Tp-Te/QTc. These results emphasize the safety of thoracic epidural sympathetic block with 1% mepivacaine for patients compared with right stellate ganglion block, in terms of cardiac repolarization. PMID- 30410392 TI - Intracellular aggregated TRPV1 is associated with lower survival in breast cancer patients. AB - Background: Breast cancer is a malignant disease that represents an important public health burden. The description of new molecular markers can be important to diagnosis, classification, and treatment. Transient receptor potential vanilloid 1 (TRPV1) polymodal channel is expressed in different neoplastic tissues and cell lines of breast cancer and associated with the regulation of tumor growth, tumor neurogenesis, cancer pain, and malignant progression of cancer. In primary and metastatic breast cancer tumors, TRPV1 is expressed during neoplastic transformation, invasive behavior, and resistance to cytotoxic therapy. Objective: The objective of this study was to describe the subcellular distribution of TRPV1 in invasive breast carcinomas and its association with survival. Methods: In 33 cases of invasive breast carcinomas, we identified immunohistochemical and immunofluorescent expression patterns of TRPV1 compared to healthy breast tissue. We characterized the expression of TRPV1 induced by estrogens in breast cancer cell lines MCF-7 and MDA to establish a model of the TRPV1-estrogen relationship regarding the malignant potential. We examined the association of TRPV1 patterns with patients' survival with the Kaplan-Meyer model, using the log-rank test at 5 years of follow-up. The relation of TRPV1 expression patterns to the St. Gallen breast cancer subtypes was also tested. Results: Based on immunohistochemical expression pattern of TRPV1, we distinguished two main categories of breast cancer tissue, a "classical category" that exhibited diffuse expression of the channel and a "non-classical category" that expressed the channel in aggregates at the ER/Golgi and/or surrounding these structures. The classical pattern of TRPV1 was associated with a higher survival rate. In breast cancer cell lines, increasing doses of estrogens induced increased TRPV1 expression with nonclassical patterns at higher doses via a mechanism dependent on ER alpha. Conclusion: The expression and distribution of TRPV1 in invasive breast carcinomas may be considered as a biomarker for prognosis of the disease and a probable therapeutic target. PMID- 30410393 TI - Incidence and prognosis factors of extragonadal choriocarcinoma in males: a population-based study. AB - Background: Choriocarcinoma usually occurs in females and sometimes occurs in the testicles of males. Extragonadal choriocarcinoma in males was previously described in case reports, and our understanding of this type of cancer has remained limited. The purpose of this study was to explore the incidence, treatment and prognostic factors of extragonadal choriocarcinoma in males. Materials and methods: Two cohorts were identified from the Surveillance, Epidemiology, and End Results (SEER) Program by histology, tumor site and sex. One cohort of 115 patients was created using the SEER nine registries (1973-2014) to estimate the incidence. The other cohort of 197 patients was created using the SEER 18 registries (1973-2013) to estimate the patient demographics and survival. Results: The median age at diagnosis was 30 years. The most common primary tumor location was the mediastinum followed by the retroperitoneum and the brain. Approximately 23% of patients underwent beam radiation therapy, whereas 63.5% underwent surgery. The estimated one- and 5-year cause-specific survival rates were 49% and 35%, respectively. The multivariate analysis showed that the age at diagnosis, ie, a younger age of 0-19 years old, and the primary tumor site, ie, the brain, were the independent prognostic factors and were correlated with a favorable prognosis. The median survival time of patients was 186 months, 13 months and 4 months in the 0-19, 20-49 and 50+ years of age, respectively. Conclusion: Extragonadal choriocarcinoma in males is a rare malignancy with a poor prognosis. A young age at diagnosis and primary tumor site in the brain were the independent prognostic factors. PMID- 30410394 TI - MicroRNA-365 suppresses cell growth and invasion in esophageal squamous cell carcinoma by modulating phosphoserine aminotransferase 1. AB - Background: A number of studies have indicated that expression of miRNA-365 (miR 365) is suppressed in various cancers, suggesting its cancer-suppressive role. In the present investigation, we evaluated the regulation and character of miR-365 in human esophageal squamous cell carcinoma (ESCC). Patients and methods: The tumor tissues and adjacent nontumor tissue samples were collected from 30 patients having ESCC, and the expression levels of miR-365 were studied by quantitative real-time polymerase chain reaction (PCR). MTT and cell invasion by Matrigel assay were done to study the effect of miR-365 on proliferation and metastasis of ESCC cells. An in vivo tumor model was generated by inoculating ESCC cells subcutaneously into BALB nude mice. A study of various biomarkers such as quantitative polymerase chain reaction (qPCR), luciferase activity assay, and Western blot was done to confirm the targets of miR-365. Results: In tumor tissues, a significant downregulation of miR-365 was observed versus the nontumor adjacent tissues and ESCC cells versus the selected esophageal endothelial cells. It was observed that higher expression levels of miR-365 inhibited the cell invasion, colony formation, growth in esophageal cancer cell lines in vitro, and tumor development in vivo. The study of biomarkers suggests involvement of phosphoserine aminotransferase 1 (PSAT1) as a favorable target for miR-365, and its abnormal expression inverted the miR-365-arbitrated suppression of invasion, viability, and epithelial-mesenchymal transition in esophageal cancer cells. A negative correlation existed with expression of miR-365 and PSAT1 in human esophageal cancer tissue samples. Conclusion: The study established that miR-365 exhibits tumor-suppressive action via regulating the levels of PSAT1 and leads to invasion and progressiveness of esophageal cancer. PMID- 30410396 TI - CAV3.1 knockdown suppresses cell proliferation, migration and invasion of prostate cancer cells by inhibiting AKT. AB - Background: Aberrant expression of CAV3.1, one of T-type Ca2+ channels, is reported to exert important functions in pathological processes, including carcinogenesis. However, its expression pattern and function in prostate cancer (PCa) remains unclear. Materials and methods: The expression pattern of CAV3.1 was analyzed in multiple ways, including online analysis in Oncomine database, experimental analyses in cell lines, and collected clinical specimens using immunohistochemistry, quantitative reverse transcription polymerase chain reaction, and Western blot. Then, CAV3.1 was downregulated in PCa cells to explore its functions. Results: Upregulated CAV3.1 in PCa tissues and cells was confirmed by analyzing mRNA expression datasets from Oncomine and quantitative reverse transcription polymerase chain reaction detection, respectively. Accordingly, significantly higher CAV3.1 protein level in PCa tissues specimens than that in benign prostatic hyperplasia tissues was indicated by immunohistochemical staining. In addition, CAV3.1 upregulation was positively associated with metastasis. Depletion of CAV3.1 impaired the proliferation, migration, and invasion ability of PCa cells demonstrating by cell functional experiments, such as CCK-8, cell cycle distribution, plate clone formation, scratch wound healing, and transwell invasion assays. Mechanistically, due to constrained Akt activity, CAV3.1 knockdown resulted in decreased level of CCND1, N-cadherin, and Vimentin, and increased level of E-cadherin whose expressions could be reversed by ectopic Akt expression. Similarly, ectopic Akt expression also rescued the inhibitory effects of CAV3.1 knockdown on cell functions like proliferation and migration in PCa cells. Conclusion: Upregulated CAV3.1 is positively associated with the development of PCa. CAV3.1 knockdown can inhibit PCa cell proliferation, migration, and invasion by suppressing AKT activity. PMID- 30410395 TI - The role of biosimilars in value-based oncology care. AB - Biopharmaceuticals (biologics) represent one of the fastest growing sectors of cancer treatment. They are recommended for treating underlying cancer and as supportive care for management of treatment side effects. Given the high costs of cancer care and the need to balance health care provision and associated budgets, patient access and value are the subject of discussion and debate in the USA and globally. As the costs of biologics are high, biosimilars offer the potential of greater choice and value, increased patient access to treatment, and the potential for improved outcomes. Value-based care aims to improve the quality of care, while containing costs. The Centers for Medicare & Medicaid Services (CMS) has developed value-based care programs as alternatives to fee-for-service reimbursement, including in oncology, that reward health care providers with incentive payments for improving the quality of care they provide. It is anticipated that CMS payments in oncology care will be increasingly tied to measured performance. This review provides an overview of value-based care models in oncology with a focus on CMS programs and discusses the contribution of biosimilars to CMS value-based care objectives. Biosimilars may provide an important tool for providers participating in value-based care initiatives, resulting in cost savings and efficiencies in the delivery of high-value care through expanded use of biologic treatment and supportive care agents during episodes of cancer care. PMID- 30410397 TI - DJ-1 promotes survival of human colon cancer cells under hypoxia by modulating HIF-1alpha expression through the PI3K-AKT pathway. AB - Background: Protein/nucleic acid deglycase (DJ-1) and hypoxia-inducible factor 1alpha (HIF-1alpha) play significant roles in the progression of various types of cancer and are associated with the phosphatidylinositol 3-kinase (PI3K) pathway. However, their functions in colorectal cancer (CRC) have not been identified. The aim of this study was to analyze the putative signaling pathway encompassing DJ 1, PI3K, and HIF-1alpha in a series of CRC tissues and cell lines. Purpose: This study aimed at exploring the expression status of DJ-1 in colon cancer and its role in survival of cancer cell lines. Methods: The expression and localization of DJ-1, PI3K-p110alpha, phosphorylated Akt (p-AKT), and HIF-1alpha were determined by immunohistochemistry in 73 resected CRC tissues. The effect of DJ-1 on cell activity was explored by in vitro knockdown and overexpression experiments in SW480 and HT-29 cells. The cells were treated with a PI3K inhibitor (LY294002 or wortmannin), and p-AKT and HIF-1alpha protein expression were then analyzed. Apoptosis was analyzed by flow cytometry. The expression levels of several HIF-1 target genes were assessed under hypoxic conditions by reverse transcription-PCR and Western blot. Xenograft tumor growth studies were conducted in DJ-1 knockdown or overexpression cells. Results: High DJ-1 expression was found in 68.49% (50/73) of CRC tissues and associated with larger tumor size and advanced clinical stages. DJ-1 expression was positively associated with PI3K-p110alpha, p-AKT, and HIF-1alpha expression in CRC. HIF 1alpha and p-AKT protein levels were lower in SW480 and HT-29 cells with stable DJ-1 knockdown than in those with DJ-1 overexpression. PI3K inhibitors almost completely blocked DJ-1-induced AKT phosphorylation. However, the expression of HIF-1alpha was partially preserved after treatment with PI3K inhibitors. We also show that DJ-1 is necessary for the transcriptional ability of HIF-1alpha and CRC cell survival after hypoxic stress. Moreover, DJ-1 promoted the growth of established tumor xenografts in nude mice. Conclusion: Our findings are the first to show that DJ-1 is overexpressed in CRC. We suggest a model in which DJ-1 mediates CRC cell survival by regulating the PI3K-AKT-HIF-1alpha pathway. PMID- 30410398 TI - Advances in antitumor effects of NSAIDs. AB - In recent years, the reports on using nonsteroidal anti-inflammatory drugs (NSAIDs) for cancer prevention and treatment have been on the rise. In 2017, the US Preventive Services Working Group issued primary prevention guidelines on the use of NSAIDs, especially aspirin, for cardiovascular disease and colorectal cancer, and formally established the role and status of aspirin in cancer prevention. However, the mechanism of NSAIDs on preventing cancer is still not clear. In this paper, the progress of the application of NSAIDs, especially aspirin, in the prevention and treatment of tumors in recent years is summarized, and new ideas and directions for the follow-up study are also discussed. PMID- 30410400 TI - Systematic review and meta-analysis of cancer studies evaluating diagnostic test accuracy and prognostic values: approaches to improve clinical interpretation of results. PMID- 30410399 TI - Long noncoding RNA ROR as a novel biomarker for progress and prognosis outcome in human cancer: a meta-analysis in the Asian population. AB - Background: Long intergenic non-protein coding RNA, a regulator of reprogramming (ROR), has been found to play an oncogene role in various human malignant tumors. This meta-analysis aimed to synthesize available data to verify the association between clinical prognosis value and ROR expression level. Materials and methods: We performed a systematic search by using PubMed (Medline), Embase, Cochrane Library, ScienceDirect, Springer, and ISI Web of Knowledge from inception to November 15, 2017. Eleven studies with 903 patients were included in this meta analysis according to the exclusion and inclusion criteria, and the quality of the publications was assessed by using the Newcastle-Ottawa Scale. Pooled odds ratios (OR) and hazard ratios (HR) with 95% CI were used to describe the effect. Results: The results showed that overexpression of ROR is positively associated with lymph node metastasis (OR=4.472, 95% CI: 3.212-6.225, Z=8.87, P=0.000), tumor invasion depth (OR=9.93, 95% CI: 5.33-18.47, Z=7.24, P<0.001), TNM stage (III/IV vs I/II, OR=2.96, 95% CI: 2.18-4.02, Z=6.95, P<0.001), distant metastasis (OR=3.142, 95% CI: 2.187-4.513, Z=6.20, P<0.001) respectively. Additionally, high expression of ROR was significantly correlated with unfavorable disease-free survival (DFS) (HR=2.74, 95% CI: 1.65-3.82, Z=4.93, P=0.000) and overall survival (OS) (HR=2.09, 95% CI: 1.64-2.54, Z=9.07, P<0.001). Subgroup analysis demonstrated that neither cancer type (digestive or respiratory system) nor sample size (more or less than 100) did not alter the prognostic value of ROR. Furthermore, we performed publication bias and sensitivity analysis in order to examine the stability of meta-analysis of ROR along with OS, which showed that the shape of the funnel plot was nearly symmetrical and the resulting pattern was not significantly influenced while disconnecting each suitable study. Conclusion: In accordance with these results, we suggested that the overexpression of long noncoding RNA ROR could act as a novel biomarker for predicting poor prognosis in different human cancers. PMID- 30410401 TI - Preoperative PROSTATE scoring system: a potential predictive tool for the risk of biochemical recurrence after radical prostatectomy. AB - Purpose: To study the association between the preoperative PROSTATE scoring system and the prediction of biochemical recurrence (BCR) risk, after radical prostatectomy (RP) in prostate cancer patients. Patients and methods: A total of 340 patients who underwent a laparoscopic radical prostatectomy in Peking University First Hospital between November 2007 and March 2016 were included in the study. The preoperative PROSTATE scoring system was measured and calculated. The performance of the scoring system to predict BCR risk was estimated using the receiver operating characteristic curve (ROC curve). BCR-free survival was analyzed using the Kaplan- Meier method, and the log-rank test was applied to compare the differences in risk among the patient groups. The Cox proportional hazards regression was used to analyze the performance of the grouped PROSTATE scores. Results: Of the total population, 91 (26.8%) patients had BCR. The PROSTATE score was significantly different between the BCR-developed and BCR-free groups (P<0.001). The ROC curve analysis of the scoring system showed an accuracy of 70.7% (95% CI 0.643-0.771) (P<0.001). The percentage of BCR in the high-risk (10-15), moderate-risk (5-9) and low-risk (0-4) groups was 63.3%, 24.6% and 10.3% respectively (P<0.001). The Cox proportional hazards regression analysis revealed that the grouped score was an independent predictor of BCR after RP (HR=2.002; 95% CI 1.222-3.280) (P=0.006). Conclusion: The PROSTATE scoring system performed adequately in predicting the risk of BCR after RP. The scoring system can assist in decision-making about the operation and post- operative follow-up for patients with high-risk. PMID- 30410402 TI - An ioMRI-assisted case of cervical intramedullary diffuse glioma resection. AB - Purpose: To date, application of intraoperative magnetic resonance imaging (ioMRI) to enhance surgical quality for spinal intramedullary neoplastic lesions has been rarely reported. Moreover, in developing countries or regions, ioMRI accessibility remains very limited. This report describes a technology design of high-field ioMRI accessible for multioperation rooms via a case presentation of an imaging-assisted surgical excision of human cervical spinal cord diffuse glioma. Patient and methods: The patient was a 44-year-old woman with symptomatic and progressive C2-5 intramedullary diffuse glioma (IDG). Our ioMRI system was designed and arranged with accessibility to multiple operation rooms, which was used to assure more complete spinal cord or brain tumor removal. The intraoperational diagnostic aspects and the system setup technical details are presented for future applications of the system in hospitals where a designated ioMRI suite is not available. Results: After a conventionally defined complete removal of C2-C5 IDG using a well-established surgical approach, ioMRI examination was able to detect residual tumor tissues that were indistinguishable under the surgical microscope. The IDG clusters were subsequently excised. The operation regimen resulted in a gross total elimination of the tumor, which enabled the patient to show very satisfactory postsurgery recovery and prognosis. Conclusion: ioMRI-assisted surgical removal of cervical spinal cord diffuse glioma should be systematically developed and applied to enhance therapeutic efficacy. The reported logistic flow of operating room tasks and imaging technical management are innovative for performing the tumor removal procedures in hospitals where designated ioMRI surgical suites do not exist. Critically, we emphasize implementation of stringent quality control measures for patient transportation safety and contamination prevention in establishing and maintaining such a system. PMID- 30410403 TI - Preoperative albumin-to-globulin ratio as a significant prognostic indicator in urologic cancers: a meta-analysis. AB - Background: Emerging studies reported that preoperative albumin-to-globulin ratio (AGR) correlated with tumor progression and prognosis in several types of cancer. The aim of this study was to systematically explore the association between preoperative AGR and clinical outcomes in cancers of the urinary system. Methods: Relevant articles were searched in PubMed, Embase and Web of Science by two independent investigators from inception to June 1, 2018. Eligible studies were selected based on predetermined selection criteria. Summarized HRs or ORs and 95% CIs were calculated for prognosis and clinicopathologic features with the fixed effects or random-effects models. Results: Eight cohort studies comprising 2,668 patients were included for analysis. The pooled results showed that a low AGR significantly correlated with poor OS (HR: 0.38, 95% CI: 0.27-0.48, P<0.001), worse cancer-specific survival (CSS) (HR: 0.36, 95% CI: 0.22-0.50, P<0.001) and inferior event-free survival (EFS) (HR: 0.36, 95% CI: 0.25-0.48, P<0.001) in urologic cancers. In addition, patients in low and high AGR groups showed significant differences in lymphovascular invasion (P<0.001), pT status (P<0.001) and pN status (P<0.001). Conclusion: Preoperative AGR might be a valuable, cheap and reproducible prognostic bio-marker in urologic cancers following surgical resection. PMID- 30410404 TI - Impact of the new FIGO 2013 classification on prognosis of stage I epithelial ovarian cancers. AB - Purpose: The stage of disease is one of the strongest prognostic factors in epithelial ovarian cancer. The International Federation of Gynecology and Obstetrics (FIGO) classification was revised in 2013; stage IC was subdivided into IC1 (intraoperative surgical spill), IC2 (capsule rupture before surgery or tumor on surface), and IC3 (positive peritoneal washing or ascites). Our aim was to compare the outcome of patients in the new FIGO stage I subgroups, as this might influence adjuvant therapy decisions. Patients and methods: Patient databases of three gynecological oncology centers were retrospectively analyzed. Patients with FIGO stage I ovarian cancers were restaged according to the revised classification, based on operative and pathological reports, and determined patient outcomes. Results: We analyzed 128 patients with ovarian cancers. In FIGO IA, we found 11.3% recurrences and 4.2% deaths. In FIGO IC, 21.8% of the patients recurred and 7.3% died. There was a trend toward a shorter time to recurrence when comparing IA to IC (P=0.076). Within all new subgroups of FIGO IC, there was no difference in time to recurrence (P=0.59). There was also no significant difference in survival when FIGO IA was compared to FIGO IC in comparison with the new individual classifications (IA to IC, IA to IC1, 2, or 3; P=0.60, P=0.15, P=0.61, P=0.66, respectively) or within the different subgroups (P=0.56). Platinum-based chemotherapy was given to the majority (82.6%, n=38/46) of the FIGO IC patients compared to 30.9% in FIGO IA (n=17/55). There was no significant difference within the new subgroups of FIGO IC (P=0.88). Conclusion: In our retrospective analysis, the new FIGO staging of IC ovarian cancers did not predict prognosis, but the use of adjuvant chemotherapy in 82.6% of the stage IC patients may have biased the outcome. PMID- 30410405 TI - Transarterial chemoembolization for hepatocellular carcinoma combined with portal vein tumor thrombosis. AB - Objectives: To explore the efficacy and influencing factors of transarterial chemoembolization (TACE) in the treatment of hepatocellular carcinoma (HCC) combined with portal vein tumor thrombosis (PVTT). Materials and methods: The clinical data of 3,126 consecutive patients who suffered from advanced HCC and underwent TACE were retrospectively analyzed. A total of 685 patients had a combination of HCC and PVTT. Of these patients, 475 were treated with TACE (Group A) and 210 were given a supportive care (Group B). The local response and overall survival of the two groups were observed and compared, and the influencing factors were examined through Cox regression analysis. Results: The median survival time and cumulative survival rate at 6, 12, and 24 months of Group A were higher than those of Group B (P=0.002). Multiple Cox regression analysis revealed that Child-Pugh classes and PVTT grades were the independent prognostic factors affecting a patient's survival. Stratified analysis demonstrated that the survival time of patients diagnosed with grades I/II PVTT and treated with TACE was superior to that of patients provided with supportive care (P=0.001), but the survival time of patients with grades III/IV PVTT with or without TACE did not significantly differ (P=0.662). Conclusion: TACE can significantly improve local response, increase cumulative survival rate, and prolong the survival duration of patients with HCC and grades I/II PVTT, whereas the efficacy of TACE for patients with grades III/IV PVTT should be further verified, although their local responses were improved. Child-Pugh classes and PVTT grades are essential factors influencing patient prognosis. PMID- 30410406 TI - A pilot study on secondhand tobacco exposure: parental knowledge about health impact and feasibility of cessation. AB - Introduction: As the primary source of smoke exposure is in the home, the smoking behaviors of parents and other caregivers are key determinants of a child's exposure to secondhand smoke. The perioperative period offers an opportunity to discuss smoking cessation strategies. Methods: This prospective study included 97 parents or caregivers of patients undergoing dental surgery. Caregivers were surveyed in the dental waiting room during the preoperative phase. The primary aim was to determine the feasibility of using the preoperative encounter to offer smoking cessation resources to parents of pediatric patients. The secondary aim was to compare willingness to receive smoking cessation resources according to the knowledge of the risks of secondhand smoking (ie, being aware of secondhand smoking and knowing that it posed a risk to their child). Results: Awareness of risks due to secondhand smoking was 65% in the overall cohort and 58% among current smokers (P=0.284 vs nonsmokers). Among smokers in our study, only a small percentage (12%) were interested in smoking cessation help. Knowledge of the risks of secondhand smoke may not be sufficient for smokers to express willingness to receive help. Conclusion: The outpatient clinic may be a teaching opportunity for smoking cessation for caregivers. However, we found that only a small percentage of caregivers were interested in receiving information about smoking cessation. This was despite the fact they were aware of the potential adverse effects of secondhand smoke on their children. PMID- 30410407 TI - Visceral leishmaniasis and HIV coinfection: current perspectives. AB - Visceral leishmaniasis (VL) is caused by Leishmania donovani and Leishmania infantum. The burden of VL is concentrated in tropical and subtropical areas; however, HIV infection has spread VL over a hyperendemic area. Several outcomes are observed as a result of VL-HIV coinfection. Impacts are observed in immunopathogenesis, clinical manifestation, diagnosis, and therapeutic response. Concerning clinical manifestation, typical and unusual manifestation has been observed during active VL in HIV-infected patient, as well as alteration in immunoresponse, inducing greater immunosuppression by low CD4 T-lymphocyte count or even by induction of immunoactivation, with cell senescence. Serological diagnosis of VL in the HIV-infected is poor, due to low humoral response, characterized by antibody production, so parasitological methods are more recommended. Another important and even more challenging point is the definition of the best therapeutic regimen for VL in HIV-coinfected patients, because in this population there is greater failure and consequently higher mortality. The challenge of better understanding immunopathogenesis in order to obtain more effective therapies is one of the crucial points to be developed. The combination of drugs and the use of secondary prophylaxis associated with highly active antiretroviral therapy may be the best tool for treatment of HIV coinfection. Some derivatives from natural sources have action against Leishmania; however, studies have been limited to in vitro evaluation, without clinical trials. PMID- 30410409 TI - Predictors of pregnancy after HIV-positive diagnosis among women in western Jamaica. AB - Background: Antiretroviral therapy has minimized mother-to-child transmission of HIV and given hope to HIV-positive women considering pregnancy. In Jamaica, 36% of HIV-positive pregnant women enrolled in a pediatric/perinatal HIV/AIDS program had repeat pregnancies. Objective: To describe the epidemiology and identify factors associated with pregnancy after HIV diagnosis among HIV-positive women in Western Jamaica. Methods: A cross-sectional study was designed among HIV-positive women 18-54 years old who either had or did not have at least one pregnancy after HIV-positive diagnosis. A questionnaire was used to collect information on sociodemographic factors and health-seeking, reproductive, and sexual risk behaviors. Results: A total of 219 HIV-positive women participated in this study. Length of time since HIV diagnosis, CD4 count, and birth-control methods used were significant predictors of pregnancy after HIV diagnosis. Women diagnosed with HIV <5 years previously had lower odds for pregnancy after HIV diagnosis (adjusted OR 0.12, 95% CI 0.02-0.84) compared to those who had been diagnosed >=8 years previously. Women with CD4 count <350 were over six times as likely to have a pregnancy after HIV diagnosis (adjusted OR 6.94, 95% CI 1.18-40.66). The odds for pregnancy after HIV diagnosis for a woman decreased by 93% if her children shared the same father (adjusted OR 0.07, 95% CI 0.006-0.77). Conclusion: This study identified significant predictors of pregnancy after HIV diagnosis that indicate that integrative family-planning interventions with supportive reproductive counseling are likely to help HIV-positive women obtain early appropriate care and plan the pregnancies they desire. PMID- 30410408 TI - Perspectives and attitudes of Jordanian medical and paramedical students toward surrogate pregnancy. AB - Purpose: This study aims at investigating the perspectives of Jordanian medical and paramedical students on surrogate pregnancy. Methods: A questionnaire-based cross-sectional study design was used. The sample consisted of n=328 students of both genders. The questionnaire responses were numerically coded and analyzed across gender and the level of education. Results: Approximately, 18% of the students reported good awareness about the ethical dilemmas of surrogacy. The results showed a general reluctance to accept surrogate pregnancy as the majority (80.5% of male students and 97.6% of female students) had a negative attitude toward surrogacy. In addition, undergraduate students were less supportive to surrogate pregnancy than graduate students. Religious considerations were the main reason (accounts for about 70%) for driving negative attitude toward surrogacy. Conclusion: The findings of the study indicate a general reluctance toward accepting the concept of surrogate pregnancy, which is mainly due to religious reasons. PMID- 30410410 TI - Responsibility toward affordable healthcare: disposable versus reusable methods for pelvic floor repair. AB - Background: The adverse publicity surrounding the use of mesh for correction of pelvic organ prolapse has driven a renewed interest in native tissue repair. Established techniques used reusable instruments, while recent innovations have generally involved disposable equipment. Here, we compare outcomes between the two techniques used for sacrospinous ligament fixation for the correction of apical prolapse: Miya Hook (reusable) and Capio(r) (single-use) suturing devices. Methods: A prospective cohort study of women undergoing vaginal sacrospinous colpopexy or hysteropexy was undertaken. The patients were assessed preoperatively and 1 year post-operatively. The primary outcomes were improvement in vaginal scores and patient-reported absence of a vaginal bulge. Secondary outcomes included impact on sexual function, quality of life, perioperative complications and apical recurrence. The cost of instruments, operative times and length of stay were analyzed. Results: In total, 133 women with advanced prolapse in the apical compartment underwent colpopexy or hysteropexy (63 using the reusable Miya Hook and 40 with the disposable Capio device). Mean follow-up was 16.9 months (SD 7.8) and 14 months (SD 3.1), respectively. There were no significant differences in baseline characteristics or preoperative Pelvic Organ Prolapse Quantification staging between the two cohorts. Significant improvements in vaginal scores, sexual function and quality of life (International Consultation on Incontinence Questionnaire - Vaginal Symptoms) were observed in both groups postoperatively (P<0.01). Both groups had low apical recurrence in the medium term (<3%). There were no significant differences in operative times or length of stay. The use of disposable equipment was associated with higher cost. Conclusion: Sacrospinous fixation using either the Miya Hook or the Capio device is equally effective for the management of apical prolapse. In the absence of clinical benefit, the choice of instrument should reflect the cost in a financially constrained health-sector environment. PMID- 30410411 TI - The efficacy and safety outcomes of the 0.19 mg fluocinolone acetonide implant after prior treatment with the 0.7 mg dexamethasone implant in patients with diabetic macular edema. AB - Purpose: There are little or no published data comparing the outcomes of ILUVIEN(r) (0.19 mg fluocinolone acetonide [FAc]) and OZURDEX(r) (0.7 mg dexamethasone [DEX]) implants in patients with diabetic macular edema (DME), and this case sought to compare their outcomes. Methods: This case was extracted from a monocentric audit involving a pool of 25 patients (33 eyes) with DME and treated with a single FAc implant between October 2013 and December 2016. This case, a 61-year-old male with a pseudophakic lens, is from a patient that had received 4 intravitreal injections of a DEX implant prior to FAc implant and then was monitored for 3 years until re-treatment with a second FAc implant. Parameters measured included visual acuity (VA), central retinal thickness (CRT), and intraocular pressure (IOP). Results: After the DEX implants, CRT transiently improved. In March 2014, the decision was taken to administer an FAc implant, and this led to a reduction in CRT below 300 um (from a baseline of 748 um), and this was sustained for 30 months. VA remained above 65 Early Treatment Diabetic Retinopathy Study letters to month 36, after which time a second FAc implant (in April 2017) was administered due to recurrence of edema and CRT decreased to below 300 um and VA improved to 70 letters. Side effects included elevated IOP, which was effectively managed with IOP-lowering drops. Conclusion: A single injection of FAc implant led to sustained improvements in CRT and VA that lasted for between 30 and 36 months, which is in contrast to the DEX implant where re treatment was generally required within 6-7 months. After 36 months, re-treatment with the FAc implant again led to improved VA and CRT, and responses that were similar to those achieved with the first FAc implant. PMID- 30410412 TI - Detection of a new reaction by-product in BDDE cross-linked autoclaved hyaluronic acid hydrogels by LC-MS analysis. AB - Background: Hyaluronic acid (HA), a naturally occurring polysaccharide, is used in the production of dermal fillers for esthetic purposes. As it has a few days of half-life in human tissues, HA-based dermal filler is chemically modified to increase its lifetime in the body. The most common modification used in commercial HA-based filler is the cross-linking of HA chains using 1,4-butanediol diglycidyl ether (BDDE) as cross-linking agent. Residual, or unreacted, BDDE is considered nontoxic when it is <2 parts per million (ppm); therefore, the quantification of residual BDDE in the final dermal filler is mandatory to ensure the safety of the patients. Materials and methods: The present study describes the detection and characterization of one by-product of the cross-linking reaction between BDDE and HA in alkaline conditions by combining both liquid chromatography and mass spectroscopy (LC-MS). Results: After different analyses, it was found that the alkaline conditions and the high temperatures employed to sterilize the HA-BDDE hydrogel promote the formation of this new by-product, a "propene glicol-like" compound. LC-MS analysis confirmed that this by-product have the same monoisotopic mass as that of BDDE, a different retention time (tR), and also a different UV absorbance (lambda=200 nm) pattern. Unlike BDDE, it was observed in the LC-MS analysis that this by-product had a higher detection at 200 nm in the same assay conditions. Conclusion: These results suggest that this new compound does not have an epoxide on its structure. The discussion is open to assess the risk of this new by-product found in the production of HA-BDDE hydrogels (HA dermal fillers) for commercial purposes. PMID- 30410413 TI - Prehospital dexamethasone administration in children with croup: a medical record review. AB - Objectives: Croup is one of the most common childhood respiratory illnesses. Early dexamethasone administration in croup can improve patient outcomes. The objective of this study was to assess the clinical impact of prehospital administration of dexamethasone to children with croup. Methods: A medical record review that included children between 6 months and 6 years, who were brought via emergency medical services (EMS) to the emergency department (ED) with a final diagnosis of croup, between January 2010 and December 2012, was conducted. Data were collected regarding prehospital management and ED management, length of stay (LOS), final disposition, and patient demographics. Results: A total of 188 patients with an ED diagnosis of croup were enrolled, 35.1% (66/188) of whom received a prehospital diagnosis of croup. The mean age of the participants was 32.96+/-17.18 months and 10.6% (20/188) were given dexamethasone in the prehospital setting by EMS, while 30.3% (57/188) were given epinephrine nebulizations. Out of the 66 patients with a prehospital diagnosis of croup, 10.6% (7/66) were given dexamethasone by EMS. In ED, dexamethasone was administered to 88.3% (166/188) while 29.8% of participants (56/188) received epinephrine nebulizations. There was no significant difference in ED LOS between those who received prehospital dexamethasone (2.6+/-1.6 hours, n=18) and those who did not (3.3+/-2.7 hours, n=159) (P=0.514). The number of in-hospital epinephrine doses per patient was significantly influenced by the administration of prehospital dexamethasone (P=0.010). Conclusions: Prehospital administration of dexamethasone results in less ED epinephrine use and may reflect dexamethasone's positive influence on the severity and short-term persistence of croup symptoms. PMID- 30410415 TI - Postoperative swallowing disorder after thyroid and parathyroid resection. AB - Introduction: Dysphagia is frequently reported after thyroidectomy. Here, we investigated the incidence of postoperative dysphagia after uncomplicated thyroidectomy and parathyroidectomy. Further, we analyzed diagnosis and types of therapy to identify possible patients at risk. Patients and methods: A questionnaire was sent to 372 consecutive patients whose thyroid or parathyroid glands were operated on between May 2013 and October 2014 at Ulm University Hospital. Patients were questioned at least 6 months postoperatively. Results: In the evaluation, 219 questionnaires could be included. Fifty-three (21.3%) patients reported that the overall postoperative swallowing process was better or more trouble-free. In 110 (50.2%) patients, dysphagia was reported only immediately postoperative and disappeared later spontaneously. Sixteen patients (7.3%) stated that after a maximum of 3 months after surgery they suffered from dysphagia. One (0.5%) patient stated that up to 3 months postoperatively, swallowing problems had been successfully treated by logopedic therapy. In 39 (17.6%) patients, the complaints persisted for more than 3 months or still existed at the time of the interview. We found no correlation between dysphagia and patients' age or gender, the specimen volume, and patients' body mass index. The more invasive the operation was, the more patients suffered from dysphagia. Analyzing the frequency of dysphagia according to different diagnoses, we found a significant risk of postoperative dysphagia in patients with Graves' disease and carcinoma. Patients operated on for hyperparathyroidism were at significantly decreased risk of dysphagia. Conclusion: Nearly 20% of patients reported postoperative dysphagia after uncomplicated thyroidectomy and parathyroidectomy, especially after major surgical intervention. We found a significant risk of postoperative dysphagia in patients with Graves' disease and carcinoma and a decreased risk for patients operated on for hyperparathyroidism. PMID- 30410414 TI - The role of inhaled methoxyflurane in acute pain management. AB - Methoxyflurane is an inhaled analgesic administered via a disposable inhaler which has been used in Australia for over 40 years for the management of pain associated with trauma and for medical procedures in children and adults. Now available in 16 countries worldwide, it is licensed in Europe for moderate to severe pain associated with trauma in conscious adults, although additional applications are being made to widen the range of approved indications. Considering these ongoing developments, we reviewed the available evidence on clinical usage and safety of inhaled analgesic methoxyflurane in trauma pain and in medical procedures in both adults and children. Published data on methoxyflurane in trauma and procedural pain show it to be effective, well tolerated, and highly rated by patients, providing rapid onset of analgesia. Methoxyflurane has a well-established safety profile; adverse events are usually brief and self-limiting, and no clinically significant effects on vital signs or consciousness levels have been reported. Nephrotoxicity previously associated with methoxyflurane at high anesthetic doses is not reported with low analgesic doses. Although two large retrospective comparative studies in the prehospital setting showed inhaled analgesic methoxyflurane to be less effective than intravenous morphine and intranasal fentanyl, this should be balanced against the administration, supervision times, and safety profile of these agents. Given the limitations of currently available analgesic agents in the prehospital and emergency department settings, the ease of use and portability of methoxyflurane combined with its rapid onset of effective pain relief and favorable safety profile make it a useful nonopioid option for pain management. Except for the STOP! study, which formed the basis for approval in trauma pain in Europe, and a few smaller randomized controlled trials (RCTs), much of the available data are observational or retrospective, and further RCTs are currently underway to provide more robust data. PMID- 30410416 TI - Bio-efficacy of DuraNet(r) long-lasting insecticidal nets against wild populations of Anopheles arabiensis in experimental huts. AB - Background: Mosquitoes have developed resistance to multiple classes of insecticides for malaria vector control. A new generation of long-lasting insecticidal bed nets (LLINs) has been developed with increased efficacy against these resistant mosquitoes. The present study therefore evaluated the efficacy of the pyrethroid-based LLINs, DuraNet versus PermaNet 3.0, in an Eastern Africa hut design in Magugu in northern Tanzania where mosquitoes' population higher proportion (69.3%) has been identified as Anopheles gambiae s.l. Methods: Standard World Health Organization bioefficacy evaluations were conducted in both laboratory and experimental huts. Experimental hut evaluations were conducted in an area with high populations of Anopheles arabiensis. All nets used were subjected to laboratory cone bioassays and then to experimental hut trials. Mosquito mortality, blood-feeding inhibition, and personal protection rate were compared between untreated nets, unwashed LN, and LN that were washed 20 times. Results: Standard WHO laboratory bioefficacy evaluations of DuraNet and PermaNet(r) 3.0 which were untreated, washed, or 20 times washed showed optimal knockdown and mortality for both net types against a susceptible strain of An. arabiensis. In standard experimental hut evaluations, the blood feeding inhibition for PermaNet(r) 3.0 unwashed and washed was 82.4% (76.3-88.6%) to 91.5% (84.1-98.8%) while for DuraNet was 98.3% (97.0-99.5%) to 96.0% (94.1-88.2%) respectively. The DuraNet LLINs showed a significantly higher killing effect than the other treatment of 90.0% (86.1-94.2%) and 94.0% (90.2-97.9%) for unwashed and washed nets respectively. No significant difference in deterrence or induced exophily was detected between the treatment arms. There were no adverse effects reported among sleepers in the experimental huts. Conclusion: The findings of this study indicate that the pyrethroid-based net DuraNet LLINs attained required efficacy when evaluated against wild population of An. arabiensis from Northern Tanzania. This adds value to the existing vector control tool box which gives community wider choice for vector control. PMID- 30410417 TI - Mild encephalitis/encephalopathy with a reversible splenial lesion due to Plasmodium falciparum malaria: a case report. AB - Background: Neurological complications from malaria cause significant morbidity and mortality. Severe cerebral malaria occurs as a result of intense sequestration of infected erythrocytes in the cerebral capillaries. However, the pathology of the reversible neurological symptoms remains unclear. We report the case of a patient with malaria who also had mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) causing transient neurological symptoms. Case presentation: A 55-year-old Japanese man was admitted to our hospital with acute fever upon returning from Nigeria. Blood smears and PCR analysis revealed ring forms in the erythrocytes, indicative of Plasmodium falciparum infection. He presented with dysarthria, expressive aphasia, and truncal ataxia, all of which were suggestive of cerebellar ataxia. He had no other signs or symptoms of severe malaria. Artemether/lumefantrine was started on the first day of illness. Although the parasites were undetectable on day 3 of illness, his neurological symptoms persisted. Brain magnetic resonance imaging (MRI) demonstrated a high signal lesion in the splenium of the corpus callosum on diffusion-weighted images along with a decreased apparent diffusion coefficient. The neurological symptoms gradually improved by day 12. Brain MRI on day 16 showed complete regression of the splenic lesion. Therefore, the patient was diagnosed with MERS due to malaria. Conclusions: MERS often causes transient headaches, seizures, and/or impaired consciousness. The symptoms are compatible with the reversible symptoms of cerebral malaria. PMID- 30410418 TI - Deconvoluting the Innocent vs. Non-innocent Behavior of N,N diethylphenylazothioformamide Ligands with Copper Sources. AB - Redox-active ligands lead to ambiguity in often clearly defined oxidation states of both the metal centre and the ligand. The arylazothioformamide (ATF) ligand class represents a redox-active ligand with three possible redox states (neutral, singly reduced, and doubly reduced). ATF-metal interactions result in strong colorimetric transitions allowing for the use of ATFs in metal detection and/or separations. While previous reports have discussed dissolution of zerovalent metals, the resulting oxidation states of coordination complexes have proved difficult to interpret through X-ray crystallographic analysis alone. This report describes the X-ray crystallographic analysis combined with computational modelling of the ATF ligand and metal complexes to deconvolute the metal and ligand oxidation state of metal-ATF complexes. Metal(ATF)2 complexes that originated from zerovalent metals were found to exist as dicationic metal centers containing two singly reduced ATF ligands. When employing Cu(I) salts instead of Cu(0) to generate copper-ATF complexes, the resulting complexes remained Cu(I) and the ATF ligand remained "innocent", existing in its neutral state. Although the use of CuX (where X = Br or I) or [Cu(NCMe)4]Y (where Y = BF4 or PF6) generated species of the type: [(ATF)Cu(MU-X)]2 and [Cu(ATF)2]Y, respectively, the ATF ligand remained in its neutral state for each species type. PMID- 30410419 TI - Role of the Soluble Receptor for Advanced Glycation End Products (sRAGE) as a Prognostic Factor for Mortality in Hemodialysis and Peritoneal Dialysis Patients. AB - End-stage renal disease patients on dialysis (CKD-G5D) have a high mortality rate due to cardiovascular diseases (CVD). In these patients, inflammation, oxidative stress, and uremia increase the production of glycation products (AGEs) which in turn accelerate CVD onset and progression. Recently, attention has been given to the soluble receptor for AGEs (sRAGE) as a marker of inflammation, oxidative stress, atherosclerosis, and heart failure in CKD-G5D. However, its association with patient outcomes is still under debate. Our aim is to explore whether sRAGE may be a predictor of mortality in CKD-G5D. We studied 123 CKD-G5D for 24 months. Of these patients, 56 were on hemodialysis (HD) and 67 on peritoneal dialysis (PD). Demographic, anthropometric, biochemical, and clinical data were recorded. sRAGE was quantified by enzyme-linked immunosorbent assay. sRAGE was a predictor of mortality at 2-year follow-up. Each increase of 100 pg/mL in sRAGE levels was associated with an approximately 7% increased risk of mortality. Furthermore, in the entire study group, as well as in PD and HD patient subgroups, sRAGE was positively correlated with brain natriuretic peptide (BNP) levels. Mortality rates as well as sRAGE levels in patients who died did not differ between PD and HD patients. In conclusion, the positive association observed with BNP levels suggests a role for sRAGE as a prognostic factor for mortality in CKD-G5D patients displaying an active process of cardiac remodeling. PMID- 30410420 TI - Variation of Bacterial and Archaeal Community Structures in a Full-Scale Constructed Wetlands for Wastewater Treatment. AB - Microorganisms play important roles in the reduction of organic and inorganic pollutants in constructed wetlands used for the treatment of wastewater. However, the diversity and structure of microbial community in constructed wetland system remain poorly known. In this study, the Illumina MiSeq Sequencing of 16S rDNA was used to analyze the bacterial and archaeal microbial community structures of soil and water in a free surface flow constructed wetland, and the differences of bacterial communities and archaeal compositions between soil and water were compared. The results showed that the Proteobacteria were the dominant bacteria, making up 35.38%~48.66% relative abundance. Euryarchaeotic were the absolute dominant archaea in the influent sample with the relative abundance of 93.29%, while Thaumarchaeota showed dominance in the other three samples, making up 50.58%~75.70%. The relative abundances of different species showed great changes in bacteria and archaea, and the number of dominant species in bacteria was much higher than that in archaea. Compared to archaea, the community compositions of bacteria were more abundant and the changes were more significant. Meanwhile, bacteria and archaea had large differences in compositions between water and soil. The microbial richness in water was significantly higher than that in soil. Simultaneously, soil had a significant enrichment effect on some microbial flora. PMID- 30410421 TI - Prognostic role of galectin-3 expression in patients with solid tumors: a meta analysis of 36 eligible studies. AB - Background: Galectin-3 as a beta-galactoside-binding protein, has been found to be involved in tumor cell growth, anti-apoptosis, adhesion, angiogenesis, invasion, and distant metastases, indicating that it may play a pivotal role in cancer development and progression. However, their results remain debatable and inconclusive. Hence, this meta-analysis was performed to clarify the precise predictive value of galectin-3 in various cancers. Methods: PubMed, Web of Science, Embase, Cochrane Library, CNKI and Wanfang databases were searched comprehensively for eligible studies up to July 15, 2018. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) of OS or DFS/PFS/RFS were calculated to demonstrate their associations. Results: A total of 36 relevant studies were ultimately enrolled in this meta-analysis. Our results shed light on the significant association of elevated galectin-3 expression with reduced OS or DFS/RFS/PFS in overall cancer patients (pooled HR = 1.79, 95% CI 1.42-2.27, I 2= 67.3%, p < 0.01; pooled HR = 1.57, 95% CI 1.04-2.37, I 2= 67.1%, p = 0.001). In tumor type subgroup analysis, we found high expression of galectin-3 was correlated with shorter OS or DFS/RFS/PFS in colorectal cancer (pooled HR = 3.05, 95% CI 2.13-4.35, I 2= 0.0%, p = 0.734; pooled HR = 2.49, 95% CI 1.82-3.41, I 2 = 0.0%, p = 0.738; respectively) and meanwhile it merely associated with reduced OS in ovarian cancer or non-small cell lung cancer (pooled HR = 2.24, 95% CI 1.38 3.64, I 2= 0.0%, p = 0.910; pooled HR = 2.07, 95% CI 1.48-2.88, I 2= 0.0%, p = 0.563; separately). Conclusions: Taken together, our results suggested that galectin-3 played an oncogenic role in colorectal cancer, ovarian cancer and non small cell lung cancer, indicating it could be a promising biomarker and a novel therapeutic target for them. Further studies were warranted to validate our findings. PMID- 30410422 TI - Integrated whole genome microarray analysis and immunohistochemical assay identifies COL11A1, GJB2 and CTRL as predictive biomarkers for pancreatic cancer. AB - Background: Pancreatic cancer is characterized by its unsatisfying early detection rate, rapid disease progression and poor prognosis. Further studies on molecular mechanism and novel predictive biomarkers for pancreatic cancer based on a large sample volume are required. Methods: Multiple bioinformatic analysis tools were utilized for identification and characterization of differentially expressed genes (DEGs) from a merged microarray data (100 pancreatic cancer samples and 62 normal samples). Data from the GEO and TCGA database was utilized to validate the diagnostic and prognostic value of the top 5 upregulated/downregulated DEGs. Immunohistochemical assay (46 paired pancreatic and para- cancerous samples) was utilized to validate the expression and prognostic value of COL11A1, GJB2 and CTRL from the identified DEGs. Results: A total number of 300 DEGs were identified from the merged microarray data of 100 pancreatic cancer samples and 62 normal samples. These DEGs were closely correlated with the biological characteristics of pancreatic cancer. The top 5 upregulated/downregulated DEGs showed good individual diagnostic/prognostic value and better combined diagnostic/prognostic value. Validation of COL11A1, GJB2 and CTRL with immunohistochemical assay showed consistent expression level with bioinformatics analysis and promising prognostic value. Conclusions: Merged microarray data with bigger sample volume could reflect the biological characteristics of pancreatic cancer more effectively and accurately. COL11A1, GJB2 and CTRL are novel predictive biomarkers for pancreatic cancer. PMID- 30410423 TI - Routine Outcome Monitoring in CAMHS: How Can We Enable Implementation in Practice? AB - Background: Many CAMHS teams across the UK are now required to use Routine Outcome Monitoring (ROM). However, some clinicians hold negative attitudes towards ROM and various practical implementation issues have been identified. Method: The aim of this study was to explore clinician experiences of using ROM in the context of an 'enforced' initial implementation initiative. Twenty clinicians were surveyed at the beginning (T1) and end (T2) of the six-month period in a large UK CAMHS network adopting CYP-IAPT practice. Changes in the use of and attitudes towards ROM were investigated, as well as barriers to implementation. Results: Overall, a small but significant increase in clinician use of ROM was observed from T1 to T2, but attitudes towards ROM did not change significantly. On the whole, clinicians were more positive than negative about ROM during the implementation period, but key implementation challenges included clinician concerns about the value and (mis)use of ROM data, poor technological support and additional workload demands. Conclusions: CAMHS clinicians will not necessarily become more receptive to ROM simply as a by-product of being asked to use it more. Seeking clinician feedback at the early stages of implementation can help provide a focus for improvement efforts. Ideas for future research and important limitations of the study are discussed. PMID- 30410425 TI - Comparative cost-effectiveness of surgery, angioplasty, or medical therapy in patients with multivessel coronary artery disease: MASS II trial. AB - Background: The costs for treating coronary artery disease (CAD) are high worldwide. We performed a prespecified analyses of cost-effectiveness of three therapeutic strategies for multivessel CAD. Methods: From May 1995 to May 2000, a total of 611 patients were randomly assigned to coronary artery bypass graft (CABG), n = 203; percutaneous coronary intervention (PCI), n = 205; or medical treatment (MT), n = 203. This cost analysis study was based on the perspective of the Public Health Care System. Initial procedural and follow-up costs for medications, cardiology examinations, and hospitalizations for complications were calculated after randomization. Life-years and quality-adjusted life years (QALYs) were used as effectiveness measures. Incremental cost-effectiveness ratios (ICER) were obtained by using nonparametric bootstrapping methods with 5000 resamples. Results: Initial procedural costs were lower for MT. However, the subsequent 5-year cumulative costs were lower for CABG. Compared with baseline, the three treatment options produced significant improvements in QALYs. After 5 years, PCI and CABG had better QALYs results compared with MT. The ICER results favored CABG and PCI, and favored PCI over CABG in 61% of the drawings. On the other hand, sensitivity analysis showed MT as the preferred therapy compared with CABG and PCI, in the analysis considering higher costs. Conclusions: At 5-year follow-up, the three treatment options yielded improvements in quality of life, with comparable and acceptable costs. However, despite higher initial costs, the comparison of cost-effectiveness after 5 years of follow-up among the three treatments showed both interventions (CABG and PCI) to be cost-effective strategies compared with MT.Trial registration ISRCTN, ISRCTN66068876, Registered 06/10/1994, http://www.controlled-trials.com/ISRCTN66068876. PMID- 30410424 TI - Clinical presentation and therapeutic management of venous thrombosis in young children: a retrospective analysis. AB - Background: Venous thromboembolism (VTE) in young children is not well documented. Methods: Clinicians from 12 institutions retrospectively evaluated the presentation, therapeutic management, and outcome of VTE in children younger than 2 years seen in 2011-2016. Feasibility of recruiting these children in EINSTEIN-Jr. phase III, a randomized trial evaluating rivaroxaban versus standard anticoagulation for VTE, was assessed. Results: We identified 346 children with VTE, of whom 227 (65.6%) had central venous catheter-related thrombosis (CVC VTE), 119 (34.4%) had non-CVC-VTE, and 156 (45.1%) were younger than 1 month. Of the 309 children who received anticoagulant therapy, 86 (27.8%) had a short duration of therapy (i.e. < 6 weeks for CVC-VTE and < 3 months for non-CVC-VTE) and 17 (5.5%) had recurrent VTE during anticoagulation (n = 8, 2.6%) or shortly after its discontinuation (n = 9, 2.9%). A total of 37 (10.7%) children did not receive anticoagulant therapy and 4 (10.5%) had recurrent VTE.The average number of children aged < 0.5 years and 0.5-2 years who would have been considered for enrolment in EINSTEIN-Jr is approximately 1.0 and 0.9 per year per site, respectively. Conclusions: Young children with VTE most commonly have CVC-VTE and approximately one-tenth and one-fourth received no or only short durations of anticoagulant therapy, respectively. Recurrent VTE rates without anticoagulation, during anticoagulation or shortly after its discontinuation seem comparable to those observed in adults. Short and flexible treatment durations could potentially increase recruitment in EINSTEIN-Jr. phase III. PMID- 30410427 TI - Fuzzy Logic Tool to Forecast Soil Fertility in Nigeria. AB - The soil is composed of several nutrients which are important for the effective growth of plants. Nitrogen, phosphorus, and potassium are micronutrients which are very important for plant growth. There have been several methods and soil tests developed to test the compositions of these nutrients in the soil. Interpreting the results gotten from such tests has been a herculean task for farmers. Employing the use of a soft computing method to interpret such result would be a noble idea. In this paper, we describe the use of fuzzy logic to interpret the values of nitrogen, phosphorus, and potassium (NPK) gotten from conventional soil test to know their levels in the soil and predict possible NPK inputs. PMID- 30410426 TI - CRISPR/Cas9 Knockout Strategies to Ablate CCAT1 lncRNA Gene in Cancer Cells. AB - Background: With the increasing discovery of long noncoding RNAs (lncRNAs), the application of functional techniques that could have very specific, efficient, and robust effects and readouts is necessary. Here, we have applied and analyzed three gene knockout (KO) strategies to ablate the CCAT1 gene in different colorectal adenocarcinoma cell lines. We refer to these strategies as "CRISPR excision", "CRISPR HDR", and "CRISPR du-HITI". Results: In order to obstruct the transcription of lncRNA or to alter its structure, in these strategies either a significant segment of the gene is removed, or a transcription termination signal is inserted in the target gene. We use RT-qPCR, RNA-seq, MTT, and colony formation assay to confirm the functional effects of CCAT1 gene ablation in knockout colorectal adenocarcinoma cell lines. We applied three different CRISPR/Cas9 mediated knockout strategies to abolish the transcription of CCAT1 lncRNA. CCAT1 knockout cells displayed dysregulation of genes involved in several biological processes, and a significant reduction for anchorage-independent growth. The du-HITI strategy introduced in this study removes a gene segment and inserts a reporter and a transcription termination signal in each of the two target alleles. The preparation of donor vector for this strategy is much easier than that in "CRISPR HDR", and the selection of cells in this strategy is also much more practical than that in "CRISPR excision". In addition, use of this technique in the first attempt of transfection, generates single cell knockouts for both alleles. Conclusions: The strategies applied and introduced in this study can be used for the generation of CCAT1 knockout cell lines and in principle can be applied to the deletion of other lncRNAs for the study of their function. PMID- 30410429 TI - Unique divergence of the breast cancer 2 (BRCA2) gene in Neanderthals. AB - Unique divergence of the BRCA2, a tumor suppressor gene, in Neanderthals relative to other primates, including modern humans, is highlighted. This divergence with potentially pathogenic consequences raises a question about cancer susceptibility in the archaic species that was replaced by modern humans about 40,000 years ago. PMID- 30410430 TI - Self-propelled droplets on heated surfaces with angled self-assembled micro/nanostructures. AB - Directional and ratchet-like functionalized surfaces can induce liquid transport without the use of an external force. In this paper, we investigate the motion of liquid droplets near the Leidenfrost temperature on functionalized self-assembled asymmetric microstructured surfaces. The surfaces, which have angled microstructures, display unidirectional properties. The surfaces are fabricated on stainless steel through the use of a femtosecond laser-assisted process. Through this process, mound-like microstructures are formed through a combination of material ablation, fluid flow, and material redeposition. In order to achieve the asymmetry of the microstructures, the femtosecond laser is directed at an angle with respect to the sample surface. Two surfaces with microstructures angled at 45 degrees and 10 degrees with respect to the surface normal were fabricated. Droplet experiments were carried out with deionized water and a leveled hot plate to characterize the directional and self-propelling properties of the surfaces. It was found that the droplet motion direction is opposite of that for a surface with conventional ratchet microstructures reported in the literature. The new finding could not be explained by the widely accepted mechanism of asymmetric vapor flow. A new mechanism for a self-propelled droplet on asymmetric three-dimensional self-assembled microstructured surfaces is proposed. PMID- 30410428 TI - Using matrix assisted laser desorption ionisation mass spectrometry (MALDI-MS) profiling in order to predict clinical outcomes of patients with heart failure. AB - Background: Current risk prediction models in heart failure (HF) including clinical characteristics and biomarkers only have moderate predictive value. The aim of this study was to use matrix assisted laser desorption ionisation mass spectrometry (MALDI-MS) profiling to determine if a combination of peptides identified with MALDI-MS will better predict clinical outcomes of patients with HF. Methods: A cohort of 100 patients with HF were recruited in the biomarker discovery phase (50 patients who died or had a HF hospital admission vs. 50 patients who did not have an event). The peptide extraction from plasma samples was performed using reversed phase C18. Then samples were analysed using MALDI MS. A multiple peptide biomarker model was discovered that was able to predict clinical outcomes for patients with HF. Finally, this model was validated in an independent cohort with 100 patients with HF. Results: After normalisation and alignment of all the processed spectra, a total of 11,389 peptides (m/z) were detected using MALDI-MS. A multiple biomarker model was developed from 14 plasma peptides that was able to predict clinical outcomes in HF patients with an area under the receiver operating characteristic curve (AUC) of 1.000 (p = 0.0005). This model was validated in an independent cohort with 100 HF patients that yielded an AUC of 0.817 (p = 0.0005) in the biomarker validation phase. Addition of this model to the BIOSTAT risk prediction model increased the predictive probability for clinical outcomes of HF from an AUC value of 0.643 to an AUC of 0.823 (p = 0.0021). Moreover, using the prediction model of fourteen peptides and the composite model of the multiple biomarker of fourteen peptides with the BIOSTAT risk prediction model achieved a better predictive probability of time-to event in prediction of clinical events in patients with HF (p = 0.0005). Conclusions: The results obtained in this study suggest that a cluster of plasma peptides using MALDI-MS can reliably predict clinical outcomes in HF that may help enable precision medicine in HF. PMID- 30410431 TI - Estimating the Timing of Cognitive Operations With MEG/EEG Latency Measures: A Primer, a Brief Tutorial, and an Implementation of Various Methods. AB - The major advantage of MEG/EEG over other neuroimaging methods is its high temporal resolution. Examining the latency of well-studied components can provide a window into the dynamics of cognitive operations beyond traditional response time (RT) measurements. While RTs reflect the cumulative duration of all time consuming cognitive operations involved in a task, component latencies can partition this time into cognitively meaningful sub-steps. Surprisingly, most MEG/EEG studies neglect this advantage and restrict analyses to component amplitudes without considering latencies. The major reasons for this neglect might be that, first, the most easily accessible latency measure (peak latency) is often unreliable and that, second, more complex measures are difficult to conceive, implement, and parametrize. The present article illustrates the key advantages and disadvantages of the three main types of latency-measures (peak latency, onset latency, and percent-area latency), introduces a MATLAB function that extracts all these measures and is compatible with common analysis tools, discusses the most important parameter choices for different research questions and components of interest, and demonstrates its use by various group analyses on one planar gradiometer pair of the publicly available Wakeman and Henson (2015) data. The introduced function can extract from group data not only single-subject latencies, but also grand-average and jackknife latencies. Furthermore, it gives the choice between different approaches to automatically set baselines and anchor points for latency estimation, approaches that were partly developed by me and that capitalize on the informational richness of MEG/EEG data. Although the function comes with a wide range of customization parameters, the default parameters are set so that even beginners get reasonable results. Graphical depictions of latency estimates, baselines, and anchor points overlaid on individual averages further support learning, understanding and trouble-shooting. Once extracted, latency estimates can be submitted to any analysis also available for (averaged) RTs, including tests for mean differences, correlational approaches and cognitive modeling. PMID- 30410432 TI - Deep Learning With Spiking Neurons: Opportunities and Challenges. AB - Spiking neural networks (SNNs) are inspired by information processing in biology, where sparse and asynchronous binary signals are communicated and processed in a massively parallel fashion. SNNs on neuromorphic hardware exhibit favorable properties such as low power consumption, fast inference, and event-driven information processing. This makes them interesting candidates for the efficient implementation of deep neural networks, the method of choice for many machine learning tasks. In this review, we address the opportunities that deep spiking networks offer and investigate in detail the challenges associated with training SNNs in a way that makes them competitive with conventional deep learning, but simultaneously allows for efficient mapping to hardware. A wide range of training methods for SNNs is presented, ranging from the conversion of conventional deep networks into SNNs, constrained training before conversion, spiking variants of backpropagation, and biologically motivated variants of STDP. The goal of our review is to define a categorization of SNN training methods, and summarize their advantages and drawbacks. We further discuss relationships between SNNs and binary networks, which are becoming popular for efficient digital hardware implementation. Neuromorphic hardware platforms have great potential to enable deep spiking networks in real-world applications. We compare the suitability of various neuromorphic systems that have been developed over the past years, and investigate potential use cases. Neuromorphic approaches and conventional machine learning should not be considered simply two solutions to the same classes of problems, instead it is possible to identify and exploit their task-specific advantages. Deep SNNs offer great opportunities to work with new types of event based sensors, exploit temporal codes and local on-chip learning, and we have so far just scratched the surface of realizing these advantages in practical applications. PMID- 30410434 TI - A Comprehensive Analysis of the Association Between SNCA Polymorphisms and the Risk of Parkinson's Disease. AB - Background: Various studies have reported associations between synuclein alpha (SNCA) polymorphisms and Parkinson's disease (PD) risk. However, the results are inconsistent. We conducted a comprehensive meta-analysis of the associations between SNCA single-nucleotide polymorphisms (SNPs) and PD risk in overall populations and subpopulations by ethnicity. Methods: Standard meta-analysis was conducted according to our protocol with a cutoff point of p < 0.05. To find the most relevant SNCA SNPs, we used a cutoff point of p < 1 * 10-5 in an analysis based on the allele model. In the subgroup analysis by ethnicity, we divided the overall populations into five ethnic groups. We conducted further analysis on the most relevant SNPs using dominant and recessive models to identify the contributions of heterozygotes and homozygotes regarding each SNP. Results: In our comprehensive meta-analysis, 24,075 cases and 22,877 controls from 36 articles were included. We included 16 variants in the meta-analysis and found 12 statistically significant variants with p < 0.05. After narrowing down the variants using the p < 1 * 10-5 cutoff, in overall populations, seven SNPs increased the risk of PD (rs2736990, rs356220, rs356165, rs181489, rs356219, rs11931074, and rs2737029, with odds ratios [ORs] of 1.22-1.38) and one SNP decreased the risk (rs356186, with an OR of 0.77). In the East Asian group, rs2736990 and rs11931074 increased the risk (with ORs of 1.22-1.34). In the European group, five SNPs increased the risk (rs356219, rs181489, rs2737029, rs356165, and rs11931074, with ORs of 1.26-1.37) while one SNP decreased the risk (rs356186, with an OR of 0.77). The heterozygotes and homozygotes contributed differently depending on the variant. Conclusions: In summary, we found eight SNCA SNPs associated with PD risk, which had obvious differences between ethnicities. Seven SNPs increased the risk of PD and one SNP decreased the risk in the overall populations. In the East Asian group, rs2736990 and rs11931074 increased the risk. In the European group, rs356219, rs181489, rs2737029, rs356165, and rs11931074 increased the risk while rs356186 decreased the risk. Variants with the highest ORs and allele frequencies in our analysis should be given priority when carrying out genetic screening. PMID- 30410435 TI - Erratum: Characterization of the Zebrafish Glycine Receptor Family Reveals Insights Into Glycine Receptor Structure Function and Stoichiometry. AB - [This corrects the article DOI: 10.3389/fnmol.2018.00286.]. PMID- 30410436 TI - Cerebrovascular Pathology in Hypertriglyceridemic APOB-100 Transgenic Mice. AB - Hypertriglyceridemia is not only a serious risk factor in the development of cardiovascular diseases, but it is linked to neurodegeneration, too. Previously, we generated transgenic mice overexpressing the human APOB-100 protein, a mouse model of human atherosclerosis. In this model we observed high plasma levels of triglycerides, oxidative stress, tau hyperphosphorylation, synaptic dysfunction, cognitive impairment, increased neural apoptosis and neurodegeneration. Neurovascular dysfunction is recognized as a key factor in the development of neurodegenerative diseases, but the cellular and molecular events linking cerebrovascular pathology and neurodegeneration are not fully understood. Our aim was to study cerebrovascular changes in APOB-100 transgenic mice. We described the kinetics of the development of chronic hypertriglyceridemia in the transgenic animals. Increased blood-brain barrier permeability was found in the hippocampus of APOB-100 transgenic mice which was accompanied by structural changes. Using transmission electron microscopy, we detected changes in the brain capillary endothelial tight junction structure and edematous swelling of astrocyte endfeet. In brain microvessels isolated from APOB-100 transgenic animals increased Lox-1, Aqp4, and decreased Meox-2, Mfsd2a, Abcb1a, Lrp2, Glut-1, Nos2, Nos3, Vim, and in transgenic brains reduced Cdh2 and Gfap-sigma gene expressions were measured using quantitative real-time PCR. We confirmed the decreased P-glycoprotein (ABCB1) and vimentin expression related to the neurovascular unit by immunostaining in transgenic brain sections using confocal microscopy. We conclude that in chronic hypertriglyceridemic APOB-100 transgenic mice both functional and morphological cerebrovascular pathology can be observed, and this animal model could be a useful tool to study the link between cerebrovascular pathology and neurodegeneration. PMID- 30410438 TI - The Neural Basis of Individual Differences in Directional Sense. AB - Individuals differ greatly in their ability to learn and navigate through environments. One potential source of this variation is "directional sense" or the ability to identify, maintain, and compare allocentric headings. Allocentric headings are facing directions that are fixed to the external environment, such as cardinal directions. Measures of the ability to identify and compare allocentric headings, using photographs of familiar environments, have shown significant individual and strategy differences; however, the neural basis of these differences is unclear. Forty-five college students, who were highly familiar with a campus environment and ranged in self-reported sense-of direction, underwent fMRI scans while they completed the Relative Heading task, in which they had to indicate the direction of a series of photographs of recognizable campus buildings (i.e., "target headings") with respect to initial "orienting headings." Large individual differences were found in accuracy and correct decision latencies, with gender, self-reported sense-of-direction, and familiarity with campus buildings all predicting task performance. Using linear mixed models, the directional relationships between headings and the experiment location also impacted performance. Structural scans revealed that lateral orbitofrontal and superior parietal volume were related to task accuracy and decision latency, respectively. Bilateral hippocampus and right presubiculum volume were related to self-reported sense-of-direction. Meanwhile, functional results revealed clusters within the superior parietal lobule, supramarginal gyrus, superior frontal gyrus, lateral orbitofrontal cortex, and caudate among others in which the intensity of activation matched the linear magnitude of the difference between the orienting and target headings. While the retrosplenial cortex and hippocampus have previously been implicated in the coding of allocentric headings, this work revealed that comparing those headings additionally involved frontal and parietal regions. These results provide insights into the neural bases of the variation within human orientation abilities, and ultimately, human navigation. PMID- 30410433 TI - Imaging Biomarkers for the Diagnosis and Prognosis of Neurodegenerative Diseases. The Example of Amyotrophic Lateral Sclerosis. AB - The term amyotrophic lateral sclerosis (ALS) comprises a heterogeneous group of fatal neurodegenerative disorders of largely unknown etiology characterized by the upper motor neurons (UMN) and/or lower motor neurons (LMN) degeneration. The development of brain imaging biomarkers is essential to advance in the diagnosis, stratification and monitoring of ALS, both in the clinical practice and clinical trials. In this review, the characteristics of an optimal imaging biomarker and common pitfalls in biomarkers evaluation will be discussed. Moreover, the development and application of the most promising brain magnetic resonance (MR) imaging biomarkers will be reviewed. Finally, the integration of both qualitative and quantitative multimodal brain MR biomarkers in a structured report will be proposed as a support tool for ALS diagnosis and stratification. PMID- 30410437 TI - Methods for Mapping Neuronal Activity to Synaptic Connectivity: Lessons From Larval Zebrafish. AB - For a mechanistic understanding of neuronal circuits in the brain, a detailed description of information flow is necessary. Thereby it is crucial to link neuron function to the underlying circuit structure. Multiphoton calcium imaging is the standard technique to record the activity of hundreds of neurons simultaneously. Similarly, recent advances in high-throughput electron microscopy techniques allow for the reconstruction of synaptic resolution wiring diagrams. These two methods can be combined to study both function and structure in the same specimen. Due to its small size and optical transparency, the larval zebrafish brain is one of the very few vertebrate systems where both, activity and connectivity of all neurons from entire, anatomically defined brain regions, can be analyzed. Here, we describe different methods and the tools required for combining multiphoton microscopy with dense circuit reconstruction from electron microscopy stacks of entire brain regions in the larval zebrafish. PMID- 30410440 TI - Sweroside Alleviated Aconitine-Induced Cardiac Toxicity in H9c2 Cardiomyoblast Cell Line. AB - Aconitine is the main bioactive ingredient of Aconitum plants, which are well known botanical herbs in China. Aconitine is also notorious for its high cardiotoxicity, as it can induce life-threatening ventricular arrhythmias. Unfortunately, there are few effective antidotes to aconitine toxicity. This study aimed to evaluate the potent protective effects of the ingredients from V. baillonii on aconitine toxicity on H9c2 cell line. Cell viability was assessed by methylthiazoltetrazolium bromide (MTT). Intracellular Ca2+ concentration alteration and reactive oxygen species (ROS) generation were observed by confocal microscopy and flow cytometry, respectively. Cellular oxidative stress was analyzed by measuring malondialdehyde (MDA) and superoxide dismutase (SOD) levels. Mitochondrial membrane potential (DeltaPsi) was determined using JC-1 kit. RT-PCR and Hoechst staining techniques were conducted to determine the levels of autophagy/apoptosis. The mRNA levels of dihydropyridine receptor (DHPR), ryanodine receptors (RyR2) and sarcoplasmic reticulum Ca2+-ATPase (SERCA) were measured by RT-PCR. We screened six components from V. baillonii, among which, sweroside exhibited the strongest protective effects on aconitine-induced cardiac toxicity. Sweroside suppressed the aconitine-induced mRNA expressions of NaV1.5 (encoded by SCN5A), RyR2 and DHPR, and reversed the aconitine-induced decrease in mRNA level of SERCA, thus preventing the aconitine-induced persistent intracellular Ca2+ accumulation and avoiding intracellular Ca2+ overload. We further found that sweroside restabilized the aconitine-disrupted mitochondrial membrane potential (DeltaPsi) and reversed the aconitine-induced increase in the mRNA levels of cell autophagy-related factors (Beclin-1, Caspase-3, and LC3- II) in H9c2 cells. In the whole-animal experiments, we observed that sweroside (50 mg/kg) alleviated effectively aconitine-induced arrhythmias by analysis of electrocardiogram (ECG) recording in rats. Our results demonstrate that sweroside may protect cardiomyocytes from aconitine toxicity by maintaining intracellular Ca2+ homeostasis, restabilizing mitochondrial membrane potential (DeltaPsi) and avoiding cell autophagy/apoptosis. PMID- 30410439 TI - Inhibitory Control, Task/Rule Switching, and Cognitive Planning in Vascular Dementia: Are There Any Differences From Vascular Aging? AB - Recent studies have shown that patients diagnosed with Vascular Dementia (VaD) exhibit deficits in executive functions. According to "vascular hypothesis of cognitive aging," community-dwelling older adults having risk factors for vascular disease development (RVD) may suffer from cognitive decline of the same type. The aim of the study was to assess the level of specific executive functions (EF) that have been revealed as most affected by vascular abnormalities, in older adults with incipient VaD and RVD. Subsequently specific ways of EF measuring could be suggested for more accurate diagnosis of early stage VaD. The study compared three adult groups (N = 60): (a) patients diagnosed with incipient VaD, according to DSM-5 criteria (n = 20); (b) community-dwelling older adults presenting cardiovascular risk factors (RVD; n = 20); (c) healthy young adult controls (n = 20). Three types of executive functions were examined: inhibitory control, cognitive flexibility as rule/task switching, and planning. The following D-KEFS subtests were administered for their evaluation: The 'Color Word Interference Test,' the 'Verbal Fluency Test,' and the 'Tower Test.' Mixed measures ANOVA, MANOVA, and one-way ANOVA as well as Scheffe post hoc test were applied to the data of the scores in each condition of each test. The results showed that VaD patients had significantly lower performance in test conditions requiring switching and planning, compared to RVD group and young controls. The specific deficits of VaD patients, compared to older adults presenting RVD according to multiple-group path analyses were: more uncorrected errors in inhibition, the use of semantic knowledge primarily instead of switching ability to switch between semantic categories, as well as a lower level of movement precision in planning. PMID- 30410441 TI - HBK-17, a 5-HT1A Receptor Ligand With Anxiolytic-Like Activity, Preferentially Activates beta-Arrestin Signaling. AB - Numerous studies have proven that both stimulation and blockade of 5-HT1A and the blockade of 5-HT7 receptors might cause the anxiolytic-like effects. Biased agonists selectively activate specific signaling pathways. Therefore, they might offer novel treatment strategies. In this study, we investigated the anxiolytic like activity, as well as the possible mechanism of action of 1-[(2,5 dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-17). In our previous experiments, HBK-17 showed high affinity for 5-HT1A and 5-HT7 receptors and antidepressant-like properties. We performed the four plate test and the elevated plus maze test to determine anxiolytic-like activity. Toward a better understanding of the pharmacological properties of HBK-17 we used various functional assays to determine its intrinsic activity at 5-HT1A, 5-HT2A, 5-HT7, and D2 receptors and UHPLC-MS/MS method to evaluate its pharmacokinetic profile. We observed the anxiolytic-like activity of HBK-17 in both behavioral tests and the effect was reversed by the pretreatment with WAY-100635, which proves that 5 HT1A receptor activation was essential for the anxiolytic-like effect. Moreover, the compound moderately antagonized D2, weakly 5-HT7 and very weakly 5-HT2A receptors. We demonstrated that HBK-17 preferentially activated beta-arrestin signaling after binding to the 5-HT1A receptor. HBK-17 was rapidly absorbed after intraperitoneal administration and had a half-life of about 150 min. HBK-17 slightly penetrated the peripheral compartment and showed bioavailability of approximately 45%. The unique pharmacological profile of HBK-17 encourages further experiments to understand its mechanism of action fully. PMID- 30410442 TI - Recent Update on the Pharmacological Effects and Mechanisms of Dihydromyricetin. AB - As the most abundant natural flavonoid in rattan tea, dihydromyricetin (DMY) has shown a wide range of pharmacological effects. In addition to the general characteristics of flavonoids, DMY has the effects of cardioprotection, anti diabetes, hepatoprotection, neuroprotection, anti-tumor, and dermatoprotection. DMY was also applied for the treatment of bacterial infection, osteoporosis, asthma, kidney injury, nephrotoxicity and so on. These effects to some extent enrich the understanding about the role of DMY in disease prevention and therapy. However, to date, we still have no outlined knowledge about the detailed mechanism of DMY, which might be related to anti-oxidation and anti-inflammation. And the detailed mechanisms may be associated with several different molecules involved in cellular apoptosis, oxidative stress, and inflammation, such as AMP activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK), protein kinase B (Akt), nuclear factor-kappaB (NF-kappaB), nuclear factor E2-related factor 2 (Nrf2), ATP-binding cassette transporter A1 (ABCA1), peroxisome proliferator-activated receptor-gamma (PPARgamma) and so on. Here, we summarized the current pharmacological developments of DMY as well as possible mechanisms, aiming to push the understanding about the protective role of DMY as well as its preclinical assessment of novel application. PMID- 30410443 TI - Ganoderma: A Cancer Immunotherapy Review. AB - Ganoderma is a significant source of natural fungal medicines and has been used for the treatment of various diseases for many years. However, the use of Ganoderma in cancer immunotherapy is poorly elucidated. In this study, we have analyzed 2,398 English-language papers and 6,968 Chinese-language papers published between 1987 and 2017 by using bibliometrics. A steady growth in the number of publications was observed before 2004, followed by an exponential increase between 2004 and 2017. The most common category for publications about Ganoderma was "Pharmacology & Pharmacy," in which immunomodulation (25.60%) and cancer treatment (21.40%) were the most popular subcategories. Moreover, we have provided an overview of the bioactive components and combinatorial immunomodulatory effects for the use of Ganoderma in the treatment of cancer, including the major pathways of immune cells. Immunomodulatory protein and polysaccharides are the key bioactive factors responsible for cancer immunotherapy, and the NF-kappaB and MAPK pathways are the most comprehensively investigated major pathways. Our results indicate that Ganoderma has a broad spectrum application for the treatment of cancer through the regulation of the immune system. This review provides guidance for future research into the role of Ganoderma in cancer immunotherapy. PMID- 30410444 TI - Molecular Identification of Two Thioredoxin Genes From Grapholita molesta and Their Function in Resistance to Emamectin Benzoate. AB - Thioredoxins (Trxs), a member of the thioredoxin system, play crucial roles in maintaining intracellular redox homeostasis and protecting organisms against oxidative stress. In this study, we cloned and characterized two genes, GmTrx2 and GmTrx-like1, from Grapholita molesta. Sequence analysis showed that GmTrx2 and GmTrx-like1 had highly conserved active sites CGPC and CXXC motif, respectively, and shared high sequence identity with selected insect species. The quantitative real-time polymerase chain reaction results revealed that GmTrx2 was mainly detected at first instar, whereas GmTrx-like1 was highly concentrated at prepupa day. The transcripts of GmTrx2 and GmTrx-like1 were both highly expressed in the head and salivary glands. The expression levels of GmTrx2 and GmTrx-like1 were induced by low or high temperature, E. coli, M. anisopliae, H2O2, and pesticides (emamectin benzoate). We further detected interference efficiency of GmTrx2 and GmTrx-like1 in G. molesta larvae and found that peroxidase capacity, hydrogen peroxide content, and ascorbate content all increased after knockdown of GmTrx2 or GmTrx-like1. Furthermore, the hydrogen peroxide concentration was increased by emamectin benzoate and the sensitivity for larvae to emamectin benzoate was improved after GmTrx2 or GmTrx-like1 was silenced. Our results indicated that GmTrx2 and GmTrx-like1 played vital roles in protecting G. molesta against oxidative damage and also provided the theoretical basis for understanding the antioxidant defense mechanisms of the Trx system in insects. PMID- 30410445 TI - Transcriptome Analysis of Cardiac Hypertrophic Growth in MYBPC3-Null Mice Suggests Early Responders in Hypertrophic Remodeling. AB - Rationale: With a prevalence of 1 in 200 individuals, hypertrophic cardiomyopathy (HCM) is thought to be the most common genetic cardiac disease, with potential outcomes that include severe hypertrophy, heart failure, and sudden cardiac death (SCD). Though much research has furthered our understanding of how HCM-causing mutations in genes such as cardiac myosin-binding protein C (MYBPC3) impair contractile function, it remains unclear how such dysfunction leads to hypertrophy and/or arrhythmias, which comprise the HCM phenotype. Identification of early response mediators could provide rational therapeutic targets to reduce disease severity. Our goal was to differentiate physiologic and pathophysiologic hypertrophic growth responses and identify early genetic mediators in the development of cardiomegaly in the cardiac myosin-binding protein C-null (cMyBP-C /-) mouse model of HCM. Methods and Results: We performed microarray analysis on left ventricles of wild-type (WT) and cMyBPC-/- mice (n = 7 each) at postnatal day (PND) 1 and PND 9, before and after the appearance of an overt HCM phenotype. Applying the criteria of >=2-fold change, we identified genes whose change was exclusive to pathophysiologic growth (n = 61), physiologic growth (n = 30), and genes whose expression changed >=2-fold in both WT and cMyBP-C-/- hearts (n = 130). Furthermore, we identified genes that were dysregulated in PND1 cMyBP-C-/- hearts prior to hypertrophy, including genes in mechanosensing pathways and potassium channels linked to arrhythmias. One gene of interest, Xirp2, and its protein product, are regulated during growth but also show early, robust prehypertrophic upregulation in cMyBP-C-/- hearts. Additionally, the transcription factor Zbtb16 also shows prehypertrophic upregulation at both gene and protein levels. Conclusion: Our transcriptome analysis generated a comprehensive data set comparing physiologic vs. hypertrophic growth in mice lacking cMyBP-C. It highlights the importance of extracellular matrix pathways in hypertrophic growth and early dysregulation of potassium channels. Prehypertrophic upregulation of Xirp2 in cMyBP-C-/- hearts supports a growing body of evidence suggesting Xirp2 has the capacity to elicit both hypertrophy and arrhythmias in HCM. Dysregulation of Xirp2, as well as Zbtb16, along with other genes associated with mechanosensing regions of the cardiomyocyte implicate stress-sensing in these regions as a potentially important early response in HCM. PMID- 30410446 TI - Interplay Between Sub-Cellular Alterations of Calcium Release and T-Tubular Defects in Cardiac Diseases. AB - Asynchronous Ca2+ release promotes non-homogeneous myofilament activation, leading to mechanical dysfunction, as well as initiation of propagated calcium waves and arrhythmias. Recent advances in microscopy techniques have allowed for optical recordings of local Ca2+ fluxes and action potentials from multiple sub cellular domains within cardiac cells with unprecedented spatial and temporal resolution. Since then, sub-cellular local information of the spatio-temporal relationship between Ca2+ release and action potential propagation have been unlocked, providing novel mechanistic insights in cardiac excitation-contraction coupling (ECC). Here, we review the promising perspectives arouse from repeatedly probing Ca2+ release at the same sub-cellular location while simultaneously probing multiple locations at the same time within a single cardiac cell. We also compare the results obtained in three different rodent models of cardiac diseases, highlighting disease-specific mechanisms. Slower local Ca2+ release has been observed in regions with defective action potential conduction in diseased cardiac cells. Moreover, significant increment of Ca2+ variability (both in time and in space) has been found in diseased cardiac cells but does not directly correlate with local electrical defects nor with the degree of structural aberrations of the cellular membrane system, suggesting a role for other players of the ECC machinery. We finally explore exciting opportunities provided by the technology for studying different cardiomyocyte populations, as well as for dissecting the mechanisms responsible for subcellular spatio-temporal variability of Ca2+ release. PMID- 30410447 TI - A Ciliary Protein EVC2/LIMBIN Plays a Critical Role in the Skull Base for Mid Facial Development. AB - Ellis-van Creveld (EvC) syndrome is an autosomal recessive chondrodysplastic disorder. Affected patients present a wide spectrum of symptoms including short stature, postaxial polydactyly, and dental abnormalities. We previously disrupted Evc2, one of the causative genes for EvC syndrome, in mice using a neural crest specific, Cre-mediated approach (i.e., P0-Cre, referred to as Evc2 P0 mutants). Despite the fact that P0-Cre predominantly targets the mid-facial region, we reported that many mid-facial defects identified in Evc2 global mutants are not present in Evc2 P0 mutants at postnatal day 8 (P8). In the current study, we used multiple Cre lines (P0-Cre and Wnt1-Cre, respectively), to specifically delete Evc2 in neural crest-derived tissues and compared the resulting mid-facial defects at multiple time points (P8 and P28, respectively). While both Cre lines indistinguishably targeted the mid-facial region, they differentially targeted the anterior portion of the skull base. By comprehensively analyzing the shapes of conditional mutant skulls, we detected differentially affected mid-facial defects in Evc2 P0 mutants and Evc2 Wnt1 mutants. Micro-CT analysis of the skull base further revealed that the Evc2 mutation leads to a differentially affected skull base, caused by premature closure of the intersphenoid synchondrosis (presphenoidal synchondrosis), which limited the elongation of the anterior skull base during the postnatal development of the skull. Given the importance of the skull base in mid-facial bone development, our results suggest that loss of function of Evc2 within the skull base secondarily leads to many aspects of the mid-facial defects developed by the EvC syndrome. PMID- 30410448 TI - Effect of Central Sympathoinhibition With Moxonidine on Sympathetic Nervous Activity in Polycystic Ovary Syndrome-A Randomized Controlled Trial. AB - Sympathetic nervous system (SNS) activity is increased in polycystic ovary syndrome (PCOS). Moxonidine is a centrally acting sympatholytic drug with known beneficial effects on hypertension, insulin sensitivity, dyslipidemia and inflammation. In this double-blind placebo controlled randomized clinical trial we examined the effect of moxonidine on modulating sympathetic activity and downstream metabolic abnormalities in 48 pre-menopausal women with PCOS (Rotterdam diagnostic criteria), recruited from the community (January 2013 August 2015). Participants received moxonidine (0.2 mg daily initially, up titrated to 0.4 mg daily in 2 weeks) (n = 23) or placebo (n = 25) for 12 weeks. Multiunit muscle sympathetic activity (by microneurography) and plasma noradrenaline levels were measured (primary outcomes). Fasting lipids, insulin resistance, serum androgens, and inflammatory markers were measured as secondary outcomes. Forty three women completed the trial (19 moxonidine, 24 placebo). Mean change in burst frequency (-3 +/- 7 vs. -3 +/- 8 per minute) and burst incidence (-3 +/- 10 vs. -4 +/- 12 per 100 heartbeat) did not differ significantly between moxonidine and placebo groups. Women on moxonidine had a significant reduction in hs-CRP compared to placebo group (-0.92 +/- 2.3 vs. -0.04 +/- 1.5) which did not persist post Bonferroni correction. There was a significant association between markers of insulin resistance at baseline and reduction in sympathetic activity with moxonidine. Moxonidine was not effective in modulating sympathetic activity in PCOS. Anti-inflammatory effects of moxonidine and a relationship between insulin resistance and sympathetic response to moxonidine are suggested which need to be further explored. Clinical Trial Registration Number: (NCT01504321). PMID- 30410449 TI - Bacteriocyte Reprogramming to Cope With Nutritional Stress in a Phloem Sap Feeding Hemipteran, the Pea Aphid Acyrthosiphon pisum. AB - Nutritional symbioses play a central role in the ability of insects to thrive on unbalanced diets and in ensuring their evolutionary success. A genomic model for nutritional symbiosis comprises the hemipteran Acyrthosiphon pisum, and the gamma 3-proteobacterium, Buchnera aphidicola, with genomes encoding highly integrated metabolic pathways. A. pisum feeds exclusively on plant phloem sap, a nutritionally unbalanced diet highly variable in composition, thus raising the question of how this symbiotic system responds to nutritional stress. We addressed this by combining transcriptomic, phenotypic and life history trait analyses to determine the organismal impact of deprivation of tyrosine and phenylalanine. These two aromatic amino acids are essential for aphid development, are synthesized in a metabolic pathway for which the aphid host and the endosymbiont are interdependent, and their concentration can be highly variable in plant phloem sap. We found that this nutritional challenge does not have major phenotypic effects on the pea aphid, except for a limited weight reduction and a 2-day delay in onset of nymph laying. Transcriptomic analyses through aphid development showed a prominent response in bacteriocytes (the core symbiotic tissue which houses the symbionts), but not in gut, thus highlighting the role of bacteriocytes as major modulators of this homeostasis. This response does not involve a direct regulation of tyrosine and phenylalanine biosynthetic pathway and transporter genes. Instead, we observed an extensive transcriptional reprogramming of the bacteriocyte with a rapid down-regulation of genes encoding sugar transporters and genes required for sugar metabolism. Consistently, we observed continued overexpression of the A. pisum homolog of RRAD, a small GTPase implicated in repressing aerobic glycolysis. In addition, we found increased transcription of genes involved in proliferation, cell size control and signaling. We experimentally confirmed the significance of these gene expression changes detecting an increase in bacteriocyte number and cell size in vivo under tyrosine and phenylalanine depletion. Our results support a central role of bacteriocytes in the aphid response to amino acid deprivation: their transcriptional and cellular responses fine-tune host physiology providing the host insect with an effective way to cope with the challenges posed by the variability in composition of phloem sap. PMID- 30410450 TI - Ratings of Perceived Exertion Misclassify Intensities for Sedentary Older Adults During Graded Cycling Test: Effect of Supramaximal High-Intensity Interval Training. AB - The present study aims (1) to evaluate ratings of perceived exertion (RPE) and corresponding intensities during a maximal graded cycling test and (2) to determine the effects of 6 weeks of supramaximal cycling exercise (SCE) intervention on RPE and associated physiological factors in young and older sedentary groups. Two healthy groups of 17 young adults [average (SD) age: 26.2 (2.4) year] and 13 older adults [average (SD) age: 54.5 (2.3) year] completed a 6 week SCE intervention on an ergocycle. Physiological values and RPE were collected across stages corresponding to ventilator thresholds 1 (VT1) and 2 (VT2) of the graded cycling test and 10 min following the end of test and during the six bouts of SCE. The relative intensity for both VT1 and VT2 were also objectively calculated based on the percent of maximal heart rate %HRmax and peak oxygen consumption % V O2peak. Before SCE intervention, RPE values were significantly higher for the older group compared to younger at VT1 [p < 0.01] and VT2 [p < 0.01], although both groups were working at similar relative intensities (% V O2). After 6 weeks of SCE, the older group's perceived effort values were normalized to the actual estimated ones and were similar to those observed in younger individuals. The intervention elicited physiological changes at rest and submaximal intensities, while no improvements were noted for both groups in aerobic fitness (i.e., V O2peak). For both groups, RPE decreases with SCE at 10 min following graded test correlated significantly to V O2 (r = 0.61, p < 0.01). Our study revealed that the initial over-estimation of the exertion levels found for the older sedentary group at the tested submaximal intensities was no longer present after 6 weeks of SCE training, therefore matching RPE values of the young group and those estimated by %HRmax and % V O2peak methods. Therefore, combining the RPE method with other commonly used methods of estimating exercise intensity is highly recommended for sedentary older adults to suitably monitor the exercise intensity. PMID- 30410452 TI - Criminalization Through Transinstitutionalization: A Critical Review of the Penrose Hypothesis in the Context of Compensation Imprisonment. AB - In 1939, the Penrose hypothesis suggested that the number of psychiatric hospital beds was inversely related to the size of prison populations. Central to a causal interpretation of the Penrose hypothesis is the idea that a small proportion of any population requires institutional mental care. Several studies re-examining longitudinal and cross-sectional data found that a fall in available psychiatric hospital beds occurred over the same period as a rise in prisoner numbers. The observed inverse relationship was mostly interpreted as being the consequence of a lack of compassion for the disadvantaged in society, while other studies concluded that the correlation was spurious and determined by confounders. In Germany, Austria, and Switzerland, lawbreakers who are unwilling or unable to pay a fine for committing a petty crime such can face compensation imprisonment. Every tenth German detainee serves compensation imprisonment with an average incarceration time of 2-3 months. We analyzed the social-economic backgrounds and the levels of mental disorders in four populations of compensation prisoners, consisting of 100 participants each, in the German capital Berlin in 1999, 2004, 2010, and 2017. Largely, the compensation prisoners were homeless, single, and unemployed, exhibited a high degree of substance abuse and showed an extraordinary high prevalence of mental disorders. Unfortunately, as the average stay in prison is short, there are no decisive concepts for social rehabilitation after imprisonment. In addition to a lack of resocialization, potential job loss, and social stigmatization, the newly acquired subcultural contacts facilitate reoffending. This study aims to give an overview of the medical, sociologic, and psychopathologic examinations on compensation prisoners. By analyzing trends in the prevalence of mental disorders, we will discuss the medical appropriateness and sociologic sense of compensation imprisonment with respect to the Penrose hypothesis. Thereby, we aim at shedding light on the question whether compensation imprisonment is an indispensable tool for law enforcement or if it is a punishment of the poor or mentally ill, which further deteriorates their unfavorable socio-economic situation. Finally, we will propose measures to reduce the number of reoffenders and to enable the compensation detainees to reintegrate successfully into society. PMID- 30410453 TI - Connect 4: A Novel Paradigm to Elicit Positive and Negative Insight and Search Problem Solving. AB - Researchers have typically defined insight as a sudden new idea or understanding accompanied by an emotional feeling of Aha. Recently, examples of negative insight in everyday creative problem solving have been identified. These are seen as sudden and sickening moments of realization experienced as an Uh-oh rather than Aha. However, such experiences have yet to be explored from an experimental perspective. One barrier to doing so is that methods to elicit insight in the laboratory are constrained to positive insight. This study therefore aimed to develop a novel methodology that elicits both positive and negative insight solving, and additionally provides the contrasting experiences of analytic search solving in the same controlled conditions. The game of Connect 4 was identified as having the potential to produce these experiences, with each move representing a solving episode (where best to place the counter). Eighty participants played six games of Connect 4 against a computer and reported each move as being a product of positive search, positive insight, negative search or negative insight. Phenomenological ratings were then collected to provide validation of the experiences elicited. The results demonstrated that playing Connect 4 saw reporting of insight and search experiences that were both positive and negative, with the majority of participants using all four solving types. Phenomenological ratings suggest that these reported experiences were comparable to those elicited by existing laboratory methods focused on positive insight. This establishes the potential for Connect 4 to be used in future problem solving research as a reliable elicitation tool of insight and search experiences for both positive and negative solving. Furthermore, Connect 4 may be seen to offer more true to life solving experiences than other paradigms where a series of problems are solved working toward an overall superordinate goal rather than the presentation of stand-alone and un-related problems. Future work will need to look to develop versions of Connect 4 with greater control in order to fully utilize this methodology for creative problem solving research in experimental psychology and neuroscience contexts. PMID- 30410451 TI - An Overview on Current Non-invasive Diagnostic Devices in Oral Oncology. AB - Oral squamous cell carcinoma (OSCC) is the most common head and neck malignancy, and despite advances in cancer therapies, the overall 5-year survival rate has remained below 50% over the past decades. OSCC is typically preceded by potentially malignant disorders (PMD), but distinguishing high-risk from low-risk PMD is challenging. In the last years, several diagnostic methods as light-based detection systems (LBDS) have been proposed to facilitate the detection of OSCC and PMD. Furthermore, the recent evolution of nanotechnology may provide new opportunities to detect PMD and OSCC at an early stage. Indeed, several preclinical studies showed the potential of nanotechnology to enhance diagnostic accuracy. For these reasons, it is fundamental to conduct studies to evaluate the efficacy of nanotechnology implementation in LBDS. The aim of this article is to review the current literature on LBDS and to provide a summary of the sensitivity and specificity of each technique, and possible future applications of nanotechnologies. The LBDS showed great potential for screening and monitoring oral lesions, but there are several factors that hinder an extensive use of these devices. These devices seem to be useful in assessing lesion margins that must be biopsied. However, to date, conventional oral examination, and tissue biopsy remain the gold standard for OSCC diagnosis. The use of nanotechnologies could be the next step in the evolution of LBDS, thus providing devices that can help clinicians to detect and better monitor oral lesions. PMID- 30410455 TI - Effective Educational Strategies to Promote Life-Long Musical Investment: Perceptions of Educators. AB - While research has broadly considered the wide-ranging intellectual, social, personal, and physical benefits of active musical participation across the lifespan, there is little research that explores how music educators work to promote participant investment inside school and beyond. The present research, therefore, aimed to investigate the practices employed by leading music educators within a range of cultural and pedagogical contexts that facilitate investment toward life-long engagement in music. Interviews with North American, European, and Australian music educators with both practitioner and research expertise from within school as well as higher education institutions were undertaken to gather reflections on participants' own practices and beliefs. Content analysis of the interview transcripts revealed deep knowledge and skills relating to teaching music, education philosophy and pedagogy, and strong recognition of the support of peers, supervisors, institution/school, and local community. It was clear that interviewees were deeply influenced by local, national, and cultural trends. Further, the advice they offered for new/beginning music educators was to think beyond the structure of their own music education and to explore culturally diverse educational experiences for students. Educational approaches that fostered co-production were favored, thus guiding students in their pursuits in learner-directed environments. While the beliefs and practices described are not "new" - echoing well-established educational philosophies - all interviewees argue for a shift from the prevailing pedagogical practice based on expertise training to the promotion cultural connectedness and sharing in and through musical experience. These findings are discussed in terms of Self-Determination Theory, to provide a framework for how music educators can facilitate long-term musical investment through the development of autonomous engagement to generate personal meaning and value in music, which can translate to deeper, longer musical investment. Exploring these pedagogical practices and beliefs in terms of Self-Determination Theory is a significant addition to the literature, enabling the consideration of the type of motivation required to stimulate and develop long-term interest in music. PMID- 30410454 TI - Frequency Specific Cortical Dynamics During Motor Imagery Are Influenced by Prior Physical Activity. AB - Motor imagery is often used inducing changes in electroencephalographic (EEG) signals for imagery-based brain-computer interfacing (BCI). A BCI is a device translating brain signals into control signals providing severely motor-impaired persons with an additional, non-muscular channel for communication and control. In the last years, there is increasing interest using BCIs also for healthy people in terms of enhancement or gaming. Most studies focusing on improving signal processing feature extraction and classification methods, but the performance of a BCI can also be improved by optimizing the user's control strategies, e.g., using more vivid and engaging mental tasks for control. We used multichannel EEG to investigate neural correlates of a sports imagery task (playing tennis) compared to a simple motor imagery task (squeezing a ball). To enhance the vividness of both tasks participants performed a short physical exercise between two imagery sessions. EEG was recorded from 60 closely spaced electrodes placed over frontal, central, and parietal areas of 30 healthy volunteers divided in two groups. Whereas Group 1 (EG) performed a physical exercise between the two imagery sessions, Group 2 (CG) watched a landscape movie without physical activity. Spatiotemporal event-related desynchronization (ERD) and event-related synchronization (ERS) patterns during motor imagery (MI) tasks were evaluated. The results of the EG showed significant stronger ERD patterns in the alpha frequency band (8-13 Hz) during MI of tennis after training. Our results are in evidence with previous findings that MI in combination with motor execution has beneficial effects. We conclude that sports MI combined with an interactive game environment could be a future promising task in motor learning and rehabilitation improving motor functions in late therapy processes or support neuroplasticity. PMID- 30410456 TI - Pride and Social Status. AB - Pride is a status-related self-conscious emotion. The present study aimed to investigate the nature of status behind pride in four studies with using the two facet model of pride, status maintenance strategies and with differentiating subjective social status (SSS) and objective social status (OSS). In Studies 1 and 2, we used questionnaire methods with structural equation modeling (SEM) in order to identify the relationship patterns between SSS, OSS, status maintenance strategies and pride. In Studies 3 and 4, we used vignette method and SEM to identify these links. All four studies gave evidence for the SSS -> prestige status maintenance strategy -> authentic pride relationship pattern. Similarly consistent result was found regarding the dominance status maintenance strategy > hubristic pride link. Depending on the assessment method (questionnaire vs. vignette) and the evaluative frame of reference (self vs. other), OSS was related to either authentic and hubristic pride, only hubristic pride, or neither of them. Based on these results, one thing can be taken for granted: pride is a subjective status-related emotion. However, the present results suggest that it is not necessarily true for OSS. PMID- 30410457 TI - Dyadic Dynamics: The Impact of Emotional Responses to Facial Expressions on the Perception of Power. AB - Emotion expressions play a central role in social communication, which, by definition is a dynamic process. Social communication involves the exchange of signals with temporal dynamic properties between two or more individuals. Nonetheless, emotion perception research has strongly focused on the study of single, static, unidirectional images. The goal of this research is to illustrate the dynamic nature of emotion communication by showing how the back and forth of a dyadic emotional interaction affects its perception by uninvolved observers. To that aim, we conducted three studies that investigated how observer's inferences of social power are influenced by an exchange of emotions between members of a dyad. In Study 1, participants saw one person showing either anger or sadness to which the second member of the dyad reacted by showing either anger, fear or neutrality. In Study 1, only still photos were shown in sequence. In Studies 2 and 3, more dynamic stimuli and other emotions were included. Even though an angry expresser was always perceived as more powerful than a sad expresser, the emotional reactions of the interaction partner modulated perceived power. Across all three studies and different levels of dynamic stimuli, fear reactions always increased perceived power. Happiness, contempt and neutrality affected perceived power more selectively. This effect was mediated by the extent to which participants felt that the reaction of the second interaction partner suggested that the second interaction partner agreed with regard to the power differential between the two. Taken together, these experiments show that the social signal value of emotion expressions changes meaningfully as a function of the emotional response of the expressions' target. Thus, the social signal value of emotions does not stand alone but has to be understood in the fuller context of the interaction. PMID- 30410460 TI - Stability of, and Associations Between, Parent and Child Locus of Control Expectancies. AB - The purpose of the present study was to assess the stability of locus of control (LOC) scores over time using data gathered from tests constructed to be consistent with Rotter's definition of LOC. We compared LOC scores of parents (measured prior to the birth of the index child and at 6 and 18 years later) and their offspring (at ages 8 and 16) to explore how stable adult and child LOC was over time and to see how parental LOC was associated with the LOC of the child aged 8 and again at 16. Locus of control was measured using modified versions of adult (ANSIE, Nowicki and Duke, 1974) and child (CNSIE, Nowicki and Strickland, 1973) LOC scales, administered to participants in the Avon Longitudinal Study of Parents and Children in the United Kingdom. We predicted that: (1) adult scores would be more stable than children's and (2) parents' and children's LOC scores would be related to one another. Analyses of the data found that individual's LOC scores were significantly associated over time, with adult scores (r ~ 0.50) more highly correlated than children's (r ~ 0.20). Correlations suggest more stability for adults than children, but also indicate the occurrence of substantial change across time. Although statistically significant, correlations between family members were small at both childhood and adolescent time points. Additional analyses suggested that mother and father LOC scores were more highly correlated with opposite rather than with same sex children, but again though significant the coefficients were small. We also analyzed the binary outcomes of externality to assess parental contributions to externality in the 8 and 16-year-old children and found correlations were significant, but small. Possible explanations are offered for why the associations between parent and child LOC were not higher. We concluded that researchers need to focus more on clarifying how children's LOC is acquired. PMID- 30410459 TI - The Multimodal Go-Nogo Simon Effect: Signifying the Relevance of Stimulus Features in the Go-Nogo Simon Paradigm Impacts Event Representations and Task Performance. AB - Numerous studies have shown that stimulus-response-compatibility (SRC) effects in the go-nogo version of the Simon task can be elicited as a result of performing the task together with another human or non-human agent (e.g., a Japanese-waving cat, a working-clock, or a ticking-metronome). A parsimonious explanation for both social and non-social SRC effects is that highlighting the spatial significance of alternative (non-/social) action events makes action selection more difficult. This holds even when action events are task-irrelevant. Recent findings, however, suggest that this explanation holds only for cases of a modality correspondence between the Simon task as such (i.e., auditory or visual) and the alternative (non-/social) action event that needs to be discriminated. However, based on the fact that perception and action are represented by the same kind of codes, an event that makes the go-nogo decision more challenging should impact go-nogo Simon task performance. To tackle this issue, the present study tested if alternative stimulus events that come from a different sensory modality do impact SRC effects in the go-nogo version of the Simon task. This was tested in the presence and absence of alternative action events of a human co-actor. In a multimodal (auditory-visual) go-nogo Simon paradigm, participants responded to their assigned stimulus - e.g., a single auditory stimulus while ignoring the alternative visual stimulus or vice versa - in the presence or absence of a human co-actor (i.e., joint and single go-nogo condition). Results showed reliable SRCs in both, single and joint go-nogo Simon task conditions independent of the modality participants had to respond to. Although a correspondence between stimulus material and attention-grabbing event might be an efficient condition for SRCs to emerge, the driving force underlying the emergence of SRCs rather appears to be whether the attentional focus prevents or facilitates alternative events to be integrated. Thus, under task conditions in which the attentional focus is sufficiently broad to enable the integration and thus cognitive representation of alternative events, go-nogo decisions become more difficult, resulting in reliable SRCs in single and joint go-nogo Simon tasks. PMID- 30410458 TI - Brain Responses to Emotional Faces in Natural Settings: A Wireless Mobile EEG Recording Study. AB - The detection of a human face in a visual field and correct reading of emotional expression of faces are important elements in everyday social interactions, decision making and emotional responses. Although brain correlates of face processing have been established in previous fMRI and electroencephalography (EEG)/MEG studies, little is known about how the brain representation of faces and emotional expressions of faces in freely moving humans. The present study aimed to detect brain electrical potentials that occur during the viewing of human faces in natural settings. 64-channel wireless EEG and eye-tracking data were recorded in 19 participants while they moved in a mock art gallery and stopped at times to evaluate pictures hung on the walls. Positive, negative and neutral valence pictures of objects and human faces were displayed. The time instants in which pictures first occurred in the visual field were identified in eye-tracking data and used to reconstruct the triggers in continuous EEG data after synchronizing the time axes of the EEG and eye-tracking device. EEG data showed a clear face-related event-related potential (ERP) in the latency interval ranging from 165 to 210 ms (N170); this component was not seen whilst participants were viewing non-living objects. The face ERP component was stronger during viewing disgusted compared to neutral faces. Source dipole analysis revealed an equivalent current dipole in the right fusiform gyrus (BA37) accounting for N170 potential. Our study demonstrates for the first time the possibility of recording brain responses to human faces and emotional expressions in natural settings. This finding opens new possibilities for clinical, developmental, social, forensic, or marketing research in which information about face processing is of importance. PMID- 30410461 TI - Linking Empowering Leadership to Task Performance, Taking Charge, and Voice: The Mediating Role of Feedback-Seeking. AB - Drawing upon social exchange theory, the present study focuses on the role of feedback-seeking in linking empowering leadership to task performance, taking charge, and voice. We tested the hypothesized model using data from a sample of 32 supervisors and 197 their immediate subordinates. Performing CFA, SEM, and bootstrapping, the results revealed that: (1) empowering leadership was positively associated with followers' feedback-seeking; (2) employees' feedback seeking was positively correlated with task performance, taking charge, and voice; and (3) employees' feedback-seeking mediated the positive relationships between empowering leadership and task performance, taking charge, and voice. We make conclusions by discussing the theoretical and practical implications of these findings, alongside a discussion of the present limitations and directions for future studies. PMID- 30410463 TI - Corrigendum: Targeted Temperature Management and Multimodality Monitoring of Comatose Patients After Cardiac Arrest. AB - [This corrects the article DOI: 10.3389/fneur.2018.00768.]. PMID- 30410462 TI - The Positive Personality Model (PPM): Exploring a New Conceptual Framework for Personality Assessment. AB - The aim of this paper is to explore a new framework for personality assessment that may function as sanity nosology of personality traits: the Positive Personality Model (PPM). The recent publication of DSM-5 created the opportunity to assess personality traits as dimensional constructs (American Psychiatric Association, 2013). In Section III, five maladaptive personality traits are proposed as the maladaptive versions of Five Factor Model (FFM) traits (Costa and McCrae, 1985). This approach draws on the existing idea of conceptualizing pathological and typical personality traits as part of a continuum. It places DSM 5's maladaptive traits in a sickness pole and FFM's traits in a "typical" pole. This spectrum, however, does not include a positive perspective that represents healthy behavior: a sanity nosology. The Positive Traits Inventory-5 (PTI-5; de la Iglesia and Castro Solano, 2018) is a measure designed to assess the positive reverse of the Personality Inventory for DSM-5-Adult (PID-5; Krueger et al., 2013). The 220 positive personality criteria were studied psychometrically using a sample of 1902 Argentinean adults from the general population (M age = 39.10, SD = 13.81, Min = 18, and Max = 83; 50.1% females, 49.9% males). Exploratory and confirmatory factor analyses resulted in a five-factor solution. The dimensions were labeled Sprightliness, Integrity, Serenity, Moderation, and Humanity and subsumed under the denomination of PPM. Analyses of convergent validity provided some grounds for interpreting the five positive traits as positive versions of the pathological traits and the typical traits. When tested for its predictive capability on mental health, the PPM outperformed the variance explained by the FFM. It is concluded that the PPM may constitute a positive pole in the continuum of personality traits -possibly functioning as a sanity nosology- and that it is somewhat more related to optimal functioning than typical trait models. The PPM should be confirmed in other populations, its predictive capability ought to be tested with other relevant variables, and longitudinal studies should be done to analyze the stability of the traits over time. PMID- 30410465 TI - Impulse Control Behaviors in Parkinson's Disease: Drugs or Disease? Contribution From Imaging Studies. AB - Impulse control behaviors (ICB) are recognized as non-motor complications of dopaminergic medications in patients with Parkinson's disease (PD). Compelling evidence suggests that ICB are not merely due to the PD-related pathology itself. Several risk factors have been identified, either demographic, clinical, genetic or neuropsychological. Neuroimaging studies have yielded controversial results regarding ICB correlates in PD and still it is not clear whether they can be triggered by the PD biology or the dopaminergic treatment stimulation. We provided an overview of the imaging studies that offered the most relevant insights into the debate about the role of drugs and disease in ICB pathophysiology. Understanding neural correlates and potential predisposing factors of these severe neuropsychiatric symptoms will be crucial to guide clinical practice and to foster preventive strategies. PMID- 30410464 TI - Sham-Controlled Study of Optokinetic Stimuli as Treatment for Mal de Debarquement Syndrome. AB - Introduction: Mal de Debarquement Syndrome (MdDS) is a condition characterized by a perception of self-motion in the absence of a stimulus, with two onset types: Motion-Triggered and Spontaneous. Currently, the pathophysiology is unknown and consequently, the therapeutic options are limited. One proposed treatment protocol, developed by Dai and colleagues is based on optokinetic stimulation, which aims to re-adapt the vestibular ocular reflex. This study aimed to reproduce the treatment protocol developed by Dai and colleagues and to assess if a placebo effect is present in the treatment protocol and lastly, aimed to further investigate the treatment on MdDS patient outcomes. Method: Twenty-five MdDS patients (13 Motion-Triggered and 12 Spontaneous) were exposed to 5 consecutive days of optokinetic treatment (consisting of exposure to optokinetic stimuli with head movements). Eleven of these 25 patients were also exposed to 2 days of a sham treatment prior to the OKN treatment. Posturography measurements and reported symptoms [e.g., using the visual analog scale (VAS)] of patients were assessed throughout the treatment. Posturography data of the patients was compared with the data of 20 healthy controls. Results: No placebo effect was recorded with any changes in postural data and VAS scale. After the optokinetic treatment, a significant improvement in postural control was observed in 48% of patients, of whom 70% were of the Motion-Triggered subtype (p-values: Area under the Curve-Anterior Posterior < 0.001; Area under the Curve-Medio Lateral p < 0.001, Confidence Ellipse Area (CEA) < 0.001, Velocity < 0.001). Conclusion: The protocol was effective in approximately half of the MdDS patients that took part in the study, with no placebo effect recorded. The Motion-Triggered group responded better to treatment than the Spontaneous group. In addition to this, this study indicates that the greatest postural changes occur within the first 3 days of treatment, suggesting that a shorter protocol is possible. Overall, these findings support what was previously observed in Dai's studies, that optokinetic stimulation can reduce and ease self-motion perception in those with MdDS. Thus, validating the reproducibility of this protocol, suggesting that a consistent and uncomplicated implementation across treatment centers is possible. PMID- 30410466 TI - Elevated Soluble Fas and FasL in Cerebrospinal Fluid and Serum of Patients With Anti-N-methyl-D-aspartate Receptor Encephalitis. AB - Objective: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune disorder that mainly affects children and young women. The Fas system contains both membrane-bound versions of Fas (mFas) and Fas ligand (mFasL), and soluble versions (sFas and sFasL), which play important roles in apoptosis and regulation of the immune system. Both the levels of sFas and sFasL and the role they play in anti-NMDAR disease pathogenesis remain unclear. Methods: Forty-eight pairs of cerebrospinal fluid (CSF) and serum were collected from patients with anti-NMDAR encephalitis, encephalitis of other causes or peripheral neuropathy. The CSF and serum concentrations of sFas and sFasL were determined with enzyme linked immunosorbent assay. Results: CSF concentrations of sFas and sFasL were both increased in anti-NMDAR encephalitis patients compared with controls patients. Serum sFas levels were also elevated in anti-NMDAR encephalitis patients relative to controls. sFas and sFasL concentrations in CSF positively correlated with the modified Rankin scale (mRS) both at onset and 6-months follow up. Conclusion: CSF sFas and sFasL levels were elevated in anti-NMDAR encephalitis patients, and reflect the disease severity of anti-NMDAR encephalitis. PMID- 30410467 TI - Thyroid Screening in Early Pregnancy: Pros and Cons. AB - Universal thyroid screening in pregnancy is a key debate in thyroidology and obstetrics. It is well-established that thyroid hormones are essential for maintaining pregnancy and optimal fetal development. Thyroid dysfunction is common in women of child-bearing age and also results in substantial adverse obstetric and child neurodevelopmental outcomes. Furthermore, thyroid dysfunction is readily diagnosed with reliable blood tests and easily corrected with inexpensive and available treatments. Screening only high-risk patients appears to miss the majority of cases and economic models show that compared to high-risk screening, universal screening is cost effective even if only overt hypothyroidism was assumed to have adverse obstetric effects. As a result, several countries now implement universal screening. Opponents of universal thyroid screening argue that asymptomatic borderline thyroid abnormalities such as subclinical hypothyroidism and isolated hypothyroxinemia form the bulk of cases of thyroid dysfunction seen in pregnancy and that there is a lack of high quality evidence to support their screening and correction. This review critically appraises the literature, examines the pros and cons of universal thyroid screening using criteria laid down by Wilson and Jungner. It also highlights the growing evidence for universal thyroid screening and indicates the key challenges and practicalities of implementation. PMID- 30410468 TI - Neuropeptidergic Systems in Pluteus Larvae of the Sea Urchin Strongylocentrotus purpuratus: Neurochemical Complexity in a "Simple" Nervous System. AB - The nervous system of the free-living planktonic larvae of sea urchins is relatively "simple," but sufficiently complex to enable sensing of the environment and control of swimming and feeding behaviors. At the pluteus stage of development, the nervous system comprises a central ganglion of serotonergic neurons located in the apical organ and sensory and motor neurons associated with the ciliary band and the gut. Neuropeptides are key mediators of neuronal signaling in nervous systems but currently little is known about neuropeptidergic systems in sea urchin larvae. Analysis of the genome sequence of the sea urchin Strongylocentrotus purpuratus has enabled the identification of 38 genes encoding neuropeptide precursors (NP) in this species. Here we characterize for the first time the expression of nine of these NP genes in S. purpuratus larvae, providing a basis for a functional understanding of the neurochemical organization of the larval nervous system. In order to accomplish this we used single and double in situ hybridization, coupled with immunohistochemistry, to investigate NP gene expression in comparison with known markers (e.g., the neurotransmitter serotonin). Several sub-populations of cells that express one or more NP genes were identified, which are located in the apica organ, at the base of the arms, around the mouth, in the ciliary band and in the mid- and fore-gut. Furthermore, high levels of cell proliferation were observed in neurogenic territories, consistent with an increase in the number of neuropeptidergic cells at late larval stages. This study has revealed that the sea urchin larval nervous system is far more complex at a neurochemical level than was previously known. Our NP gene expression map provides the basis for future work, aimed at understanding the role of diverse neuropeptides in control of various aspects of embryonic and larval behavior. PMID- 30410469 TI - Sodium Butyrate Ameliorates Streptozotocin-Induced Type 1 Diabetes in Mice by Inhibiting the HMGB1 Expression. AB - Type 1 diabetes (T1D) is an autoimmune disease characterized by the immune cell mediated progressive destruction of pancreatic beta-cells. High-mobility group box 1 protein (HMGB1) has been recognized as a potential immune mediator to enhance the development of T1D. So we speculated that HMGB1 inhibitors could have anti-diabetic effect. Sodium butyrate is a short fatty acid derivative possessing anti-inflammatory activity by inhibiting HMGB1. In the current study, we evaluated the effects of sodium butyrate in streptozotocin (STZ)-induced T1D mice model. Diabetes was induced by multiple low-dose injections of STZ (40 mg/kg/day for 5 consecutive days), and then sodium butyrate (500 mg/kg/day) was administered by intraperitoneal injection for 7 consecutive days after STZ treatment. Blood glucose, incidence of diabetes, body weight, pancreatic histopathology, the amounts of CD4+T cell subsets, IL-1beta level in serum and pancreatic expressions levels of HMGB1, and NF-kappaB p65 protein were analyzed. The results showed that sodium butyrate treatment decreased blood glucose and serum IL-1beta, improved the islet morphology and decreased inflammatory cell infiltration, restored the unbalanced Th1/Th2 ratio, and down-regulated Th17 to normal level. In addition, sodium butyrate treatment can inhibit the pancreatic HMGB1 and NF-kappaB p65 protein expression. Therefore, we proposed that sodium butyrate should ameliorate STZ-induced T1D by down-regulating NF-kappaB mediated inflammatory signal pathway through inhibiting HMGB1. PMID- 30410470 TI - The Chance of Permanent Cure for Micro- and Macroprolactinomas, Medication or Surgery? A Systematic Review and Meta-Analysis. AB - Background: This meta-analysis aims to evaluate the long-term efficacy of medication treatment vs. surgery treatment in patients with prolactinomas. Methods: An electronic literature search was performed using MEDLINE, EMBASE and Web of Science databases for studies dated before July in 2018. Patients with prolactinomas received primary dopamine agonists (DAs) treatment or primary surgical interventions were included in this study. A systematic review and meta analysis were performed in pertinent studies meeting eligible criteria. The clinical outcome was measured by the long-term remission rate of prolactin (PRL) in each cohort. The pooled data was analyzed according to a random effect model. Results: Thirteen publications with total 809 patients were included in the final meta-analysis. In the overall patients with prolactinomas, long-term remission rate was achieved in 88% patients treated with surgeries and in 52% patients treated with DAs (P = 0.001). The long-term remission rates in surgery cohort were also significantly higher than medication cohort in both microprolactinomas and macroprolactinomas (91 vs. 60%, P = 0.002; 77 vs. 43%, P = 0.003). Conclusions: Patients with prolactinomas, especially microprolactinomas, can consider transsphenoidal surgery as an alternative first-line treatment strategy. After receiving primary surgical intervention, administration of DAs should be considered based on the postoperative PRL level to achieve the best long-term remission rate. PMID- 30410472 TI - Discovery on Antibiotic Resistance Patterns of Vibrio parahaemolyticus in Selangor Reveals Carbapenemase Producing Vibrio parahaemolyticus in Marine and Freshwater Fish. AB - Vibrio parahaemolyticus, a Gram-negative halophilic bacterium is often associated with fish and fishery products, thus causing gastroenteritis in humans upon ingestion of contaminated food. V. parahaemolyticus has become a globally well known pathogen with yearly reported cases in many countries. This study aimed to discover the antibiotic resistance patterns of V. parahaemolyticus as well as detect Carbapenem resistant isolates from marine and freshwater fish in Selangor. A total of 240 freshwater and marine fish samples collected from wet market and supermarket in Selangor were tested for the presence of V. parahaemolyticus. All the fish samples were determined positive for V. parahaemolyticus using conventional microbiological culture-based method. The toxR gene were detected via polymerase chain reaction (PCR) in 165/240 (69%) isolates. The two-virulence factor of V. parahaemolyticus, thermostable direct hemolysin (tdh) and TDH related hemolysin (trh) was screened via PCR. As such, four isolates were trh+and none were tdh+. Majority of the isolates presented high resistance to ampicillin (88%), amikacin (64%), and kanamycin (50%). In addition, this study identified 19 imipenem resistant isolates isolated from freshwater and marine fish samples. Further analysis of these 19-imipenem resistant isolates revealed that the resistance toward imipenem was plasmid mediated after plasmid curing assay. The multiple antibiotics resistance index was >0.2 for 70% of the isolates. In summary, the results confirm the presence of V. parahaemolyticus in freshwater and marine fish samples in Selangor, Malaysia. To our best knowledge, this is the first report discovering the antibiotic resistant patterns and Carbapenem resistant isolates of V. parahaemolyticus isolated from marine and freshwater fish samples in Selangor. PMID- 30410473 TI - Evolution of Bacterial Gene Transfer Agents. AB - Bacterial gene transfer agents (GTAs) are small virus-like particles that package DNA fragments and inject them into cells. They are encoded by gene clusters resembling defective prophages, with genes for capsid head and tail components. These gene clusters are usually assumed to be maintained by selection for the benefits of GTA-mediated recombination, but this has never been tested. We rigorously examined the potential benefits of GTA-mediated recombination, considering separately transmission of GTA-encoding genes and recombination of all chromosomal genes. In principle GTA genes could be directly maintained if GTA particles spread them to GTA- cells often enough to compensate for the loss of GTA-producing cells. However, careful bookkeeping showed that losses inevitably exceed gains for two reasons. First, cells must lyse to release particles to the environment. Second, GTA genes are not preferentially replicated before DNA is packaged. A simulation model was then used to search for conditions where recombination of chromosomal genes makes GTA+ populations fitter than GTA- populations. Although the model showed that both synergistic epistasis and some modes of regulation could generate fitness benefits large enough to overcome the cost of lysis, these benefits neither allowed GTA+ cells to invade GTA- populations, nor allowed GTA+ populations to resist invasion by GTA- cells. Importantly, the benefits depended on highly improbable assumptions about the efficiencies of GTA production and recombination. Thus, the selective benefits that maintain GTA gene clusters over many millions of years must arise from consequences other than transfer of GTA genes or recombination of chromosomal genes. PMID- 30410471 TI - Prospects on the Use of Schizochytrium sp. to Develop Oral Vaccines. AB - Although oral subunit vaccines are highly relevant in the fight against widespread diseases, their high cost, safety and proper immunogenicity are attributes that have yet to be addressed in many cases and thus these limitations should be considered in the development of new oral vaccines. Prominent examples of new platforms proposed to address these limitations are plant cells and microalgae. Schizochytrium sp. constitutes an attractive expression host for vaccine production because of its high biosynthetic capacity, fast growth in low cost culture media, and the availability of processes for industrial scale production. In addition, whole Schizochytrium sp. cells may serve as delivery vectors; especially for oral vaccines since Schizochytrium sp. is safe for oral consumption, produces immunomodulatory compounds, and may provide bioencapsulation to the antigen, thus increasing its bioavailability. Remarkably, Schizochytrium sp. was recently used for the production of a highly immunoprotective influenza vaccine. Moreover, an efficient method for transient expression of antigens based on viral vectors and Schizochytrium sp. as host has been recently developed. In this review, the potential of Schizochytrium sp. in vaccinology is placed in perspective, with emphasis on its use as an attractive oral vaccination vehicle. PMID- 30410474 TI - Clostridioides difficile Activates Human Mucosal-Associated Invariant T Cells. AB - Clostridioides difficile infection (CDI) causes severe inflammatory responses at the intestinal mucosa but the immunological mechanisms underlying CDI-related immunopathology are still incompletely characterized. Here we identified for the first time that both, non-toxigenic strains as well as the hypervirulent ribotypes RT027 and RT023 of Clostridioides difficile (formerly Clostridium difficile), induced an effector phenotype in mucosal-associated invariant T (MAIT) cells. MAIT cells can directly respond to bacterial infections by recognizing MR1-presented metabolites derived from the riboflavin synthesis pathway constituting a novel class of antigens. We confirmed functional riboflavin synthesis of C. difficile and found fixed bacteria capable of activating primary human MAIT cells in a dose-dependent manner. C. difficile activated MAIT cells showed an increased and MR1-dependent expression of CD69, proinflammatory IFNgamma, and the lytic granule components granzyme B and perforin. Effector protein expression was accompanied by the release of lytic granules, which, in contrast to other effector functions, was mainly induced by IL-12 and IL-18. Notably, this study revealed hypervirulent C. difficile strains to be most competent in provoking MAIT cell responses suggesting MAIT cell activation to be instrumental for the immunopathology observed in C. difficile associated colitis. In conclusion, we provide first evidence for a link between C. difficile metabolism and innate T cell-mediated immunity in humans. PMID- 30410475 TI - Vibrio natriegens as Host for Expression of Multisubunit Membrane Protein Complexes. AB - Escherichia coli is a convenient host for the expression of proteins, but the heterologous production of large membrane protein complexes often is hampered by the lack of specific accessory genes required for membrane insertion or cofactor assembly. In this study we introduce the non-pathogenic and fast-growing Vibrio natriegens as a suitable expression host for membrane-bound proteins from Vibrio cholerae. We achieved production of the primary Na+ pump, the NADH:quinone oxidoreductase (NQR), from V. cholerae in an active state, as indicated by increased overall NADH:quinone oxidoreduction activity of membranes from the transformed V. natriegens, and the sensitivity toward Ag+, a specific inhibitor of the NQR. Complete assembly of V. cholerae NQR expressed in V. natriegens was demonstrated by BN PAGE followed by activity staining. The secondary transport system Mrp from V. cholerae, another membrane-bound multisubunit complex, was also produced in V. natriegens in a functional state, as demonstrated by in vivo Li+ transport. V. natriegens is a promising expression host for the production of membrane protein complexes from Gram-negative pathogens. PMID- 30410476 TI - Antimicrobial and Antibiofilm Activity of Synergistic Combinations of a Commercially Available Small Compound Library With Colistin Against Pseudomonas aeruginosa. AB - Biofilm-associated Pseudomonas aeruginosa infections remain a significant clinical challenge since the conventional antibiotic treatment or combination therapies are largely ineffective; and new approaches are needed. To circumvent the major challenges associated with discovery of new antimicrobials, we have screened a library of compounds that are commercially available and approved by the FDA (Prestwick Chemical Library) against P. aeruginosa for effective antimicrobial and anti-biofilm activity. A preliminary screen of the Prestwick Chemical Library alone did not yield any repositionable candidates, but in a screen of combinations with a fixed sub-inhibitory concentration of the antibiotic colistin we observed 10 drugs whose bacterial inhibiting activity was reproducibly enhanced, seven of which were enhanced by more than 50%. We performed checkerboard assays of these seven drugs in combination with colistin against planktonic cells, and analysis of their interactions over the complete combination matrix using the Zero Interaction Potency (ZIP) model revealed interactions that varied from highly synergistic to completely antagonistic. Of these, five combinations that showed synergism were down-selected and tested against preformed biofilms of P. aeruginosa. Two of the five combinations were active against preformed biofilms of both laboratory and clinical strain of P. aeruginosa, resulting in a 2-log reduction in culturable cells. In summary, we have identified synergistic combinations of five commercially available, FDA approved drugs and colistin that show antimicrobial activity against planktonic P. aeruginosa (Clomiphene Citrate, Mitoxantrone Dihydrochloride, Methyl Benzethonium Chloride, Benzethonium Chloride, and Auranofin) as well as two combinations (Auranofin and Clomiphene Citrate) with colistin that show antibiofilm activity. PMID- 30410478 TI - Characterization and Genomic Analyses of Pseudomonas aeruginosa Podovirus TC6: Establishment of Genus Pa11virus. AB - Phages have attracted a renewed interest as alternative to chemical antibiotics. Although the number of phages is 10-fold higher than that of bacteria, the number of genomically characterized phages is far less than that of bacteria. In this study, phage TC6, a novel lytic virus of Pseudomonas aeruginosa, was isolated and characterized. TC6 consists of an icosahedral head with a diameter of approximately 54 nm and a short tail with a length of about 17 nm, which are characteristics of the family Podoviridae. TC6 can lyse 86 out of 233 clinically isolated P. aeruginosa strains, thus showing application potentials for phage therapy. The linear double-stranded genomic DNA of TC6 consisted of 49796 base pairs and was predicted to contain 71 protein-coding genes. A total of 11 TC6 structural proteins were identified by mass spectrometry. Comparative analysis revealed that the P. aeruginosa phages TC6, O4, PA11, and IME180 shared high similarity at DNA sequence and proteome levels, among which PA11 was the first phage discovered and published. Meanwhile, these phages contain 54 core genes and have very close phylogenetic relationships, which distinguish them from other known phage genera. We therefore proposed that these four phages can be classified as Pa11virus, comprising a new phage genus of Podoviridae that infects Pseudomonas spp. The results of this work promoted our understanding of phage biology, classification, and diversity. PMID- 30410479 TI - The Occurence of Colistin-Resistant Hypervirulent Klebsiella pneumoniae in China. AB - Hypervirulent Klebsiella pneumoniae strains are usually susceptible to many antimicrobial agents including colistin. Here we report the isolation and characterization of several colistin-resistant hypervirulent K. pneumoniae clinical strains. K. pneumoniae strains recovered from blood samples were collected at a university hospital in China. MICs of colistin were determined using microdilution. Colistin-resistant strains were subjected to whole genome sequencing to reveal their clonal background, antimicrobial resistance determinants and virulence factors. Virulence assays were performed with strains carrying the mucoid phenotype regulator gene rmpA using wax moth larvae. The pmrB gene encoding a P344L substitution was cloned into a colistin-susceptible K. pneumoniae strain to examine whether the substitution confers colistin resistance. Five colistin-resistant hypervirulent K. pneumoniae were recovered from blood samples of patients in China, belonging to four sequence/capsular types (ST23:K1, ST412:K57, ST660:K16, and ST700:K1) and carried the virulence factor rmpA. Three strains had the known colistin-resistant D150G substitution in PhoQ including one ST700:K1 strain also carrying mcr-1. The remaining two isolates had a P344L substitution of PmrB but cloning of pmrB encoding the substitution into a colistin-susceptible isolate did not alter MICs of colistin, suggesting that such a substitution did not confer resistance to colistin. In conclusion, the convergence of colistin resistance and hypervirulence in K. pneumoniae of multiple clonal backgrounds has emerged and may warrant further surveillance. PMID- 30410477 TI - Genome Structure of the Opportunistic Pathogen Paracoccus yeei (Alphaproteobacteria) and Identification of Putative Virulence Factors. AB - Bacteria of the genus Paracoccus are common components of the microbiomes of many naturally- and anthropogenically shaped environments. One species, Paracoccus yeei, is unique within the genus because it is associated with opportunistic human infections. Therefore, strains of P. yeei may serve as an interesting model to study the transition from a saprophytic to a pathogenic lifestyle in environmental bacteria. Unfortunately, knowledge concerning the biology, genetics and genomic content of P. yeei is fragmentary; also the mechanisms of pathogenicity of this bacterium remain unclear. In this study we provide the first insight into the genome composition and metabolic potential of a clinical isolate, P. yeei CCUG 32053. This strain has a multipartite genome (4,632,079 bp) composed of a circular chromosome plus eight extrachromosomal replicons pYEE1-8: 3 chromids and 5 plasmids, with a total size of 1,247,173 bp. The genome has been significantly shaped by the acquisition of genomic islands, prophages (Myoviridae and Siphoviridae phage families) and numerous insertion sequences (ISs) representing seven IS families. Detailed comparative analysis with other complete genomic sequences of Paracoccus spp. (including P. yeei FDAARGOS_252 and TT13, as well as non-pathogenic strains of other species in this genus) enabled us to identify P. yeei species-specific genes and to predict putative determinants of virulence. This is the first attempt to identify pathoadaptive genetic information of P. yeei and to estimate the role of the mobilome in the evolution of pathogenicity in this species. PMID- 30410481 TI - Complete Genome Sequence and Characterization of Linezolid-Resistant Enterococcus faecalis Clinical Isolate KUB3006 Carrying a cfr(B)-Transposon on Its Chromosome and optrA-Plasmid. AB - Linezolid (LZD) has become one of the most important antimicrobial agents for infections caused by gram-positive bacteria, including those caused by Enterococcus species. LZD-resistant (LR) genetic features include mutations in 23S rRNA/ribosomal proteins, a plasmid-borne 23S rRNA methyltransferase gene cfr, and ribosomal protection genes (optrA and poxtA). Recently, a cfr gene variant, cfr(B), was identified in a Tn6218-like transposon (Tn) in a Clostridioides difficile isolate. Here, we isolated an LR Enterococcus faecalis clinical isolate, KUB3006, from a urine specimen of a patient with urinary tract infection during hospitalization in 2017. Comparative and whole-genome analyses were performed to characterize the genetic features and overall antimicrobial resistance genes in E. faecalis isolate KUB3006. Complete genome sequencing of KUB3006 revealed that it carried cfr(B) on a chromosomal Tn6218-like element. Surprisingly, this Tn6218-like element was almost (99%) identical to that of C. difficile Ox3196, which was isolated from a human in the UK in 2012, and to that of Enterococcus faecium 5_Efcm_HA-NL, which was isolated from a human in the Netherlands in 2012. An additional oxazolidinone and phenicol resistance gene, optrA, was also identified on a plasmid. KUB3006 is sequence type (ST) 729, suggesting that it is a minor ST that has not been reported previously and is unlikely to be a high-risk E. faecalis lineage. In summary, LR E. faecalis KUB3006 possesses a notable Tn6218-like-borne cfr(B) and a plasmid-borne optrA. This finding raises further concerns regarding the potential declining effectiveness of LZD treatment in the future. PMID- 30410480 TI - Extracellular Vesicles in Herpes Viral Spread and Immune Evasion. AB - Extracellular vesicles (EVs) are involved in numerous processes during infections by both enveloped and non-enveloped viruses. Among them, herpes simplex virus type-1 (HSV-1) modulates secretory pathways, allowing EVs to exit infected cells. Many characteristics regarding the mechanisms of viral spread are still unidentified, and as such, secreted vesicles are promising candidates due to their role in intercellular communications during viral infection. Another relevant role for EVs is to protect virions from the action of neutralizing antibodies, thus increasing their stability within the host during hematogenous spread. Recent studies have suggested the participation of EVs in HSV-1 spread, wherein virion-containing microvesicles (MVs) released by infected cells were endocytosed by naive cells, leading to a productive infection. This suggests that HSV-1 might use MVs to expand its tropism and evade the host immune response. In this review, we briefly describe the current knowledge about the involvement of EVs in viral infections in general, with a specific focus on recent research into their role in HSV-1 spread. Implications of the autophagic pathway in the biogenesis and secretion of EVs will also be discussed. PMID- 30410482 TI - Effect of Natural Zeolite (Clinoptilolite) on in vitro Biogenic Amine Production by Gram Positive and Gram Negative Pathogens. AB - The effect of two levels of clinoptilolite (1 and 5%) on the production of biogenic amines (BA) and ammonia (AMN) by Gram positive (Staphylococcus aureus, Enterococcus faecalis, and Listeria monocytogenes) and Gram negative bacteria (Aeromonas hydrophila, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, and Salmonella Parathypi A), in tyrosine decarboxylase broth (TDB) was studied. A. hydrophila and E. coli produced the highest amounts of amines which were 1223.06 and 2627.90 mg/l, respectively. All strains were able to decarboxylate tyrosine to tyramine (TYR) with E. coli being the highest (1657.19 mg/l). A. hydrophila formed >50 mg/l histamine (HIS) while the other strains produced none or very low concentrations (<4 mg/l). Among Gram-positive pathogens, E. faecalis was characterized as the main amine producer (478.23 mg/l). Although dependent on bacterial strain and level used, the natural zeolite clinoptilolite can be used to decrease BA and AMN production by bacterial strains that are of health concern. Practical Applications: Uses of natural prodcuts for biogenic amines inhibition. Clinoptilolite was used to reduce the amounts of amines such as spermine, putrescine, and dopamine produced by pathogenic and spoilage bacteria. PMID- 30410484 TI - A Natural Variant of the Signaling Molecule Vav1 Enhances Susceptibility to Myasthenia Gravis and Influences the T Cell Receptor Repertoire. AB - The guanine nucleotide exchange factor Vav1 is essential for transducing T cell receptor (TCR) signals and plays an important role in T cell development and activation. Previous genetic studies identified a natural variant of Vav1 characterized by the substitution of an arginine (R) residue by a tryptophane (W) at position 63 (Vav1R63W). This variant impacts Vav1 adaptor functions and controls susceptibility to T cell-mediated neuroinflammation. To assess the implication of this Vav1 variant on the susceptibility to antibody-mediated diseases, we used the animal model of myasthenia gravis, experimental autoimmune myasthenia gravis (EAMG). To this end, we generated a knock-in (KI) mouse model bearing a R to W substitution in the Vav1 gene (Vav1R63W) and immunized it with either torpedo acetylcholine receptor (tAChR) or the alpha146-162 immunodominant peptide. We observed that the Vav1R63W conferred increased susceptibility to EAMG, revealed by a higher AChR loss together with an increased production of effector cytokines (IFN-gamma, IL-17A, GM-CSF) by antigen-specific CD4+ T cells, as well as an increased frequency of antigen-specific CD4+ T cells. This correlated with the emergence of a dominant antigen-specific T cell clone in KI mice that was not present in wild-type mice, suggesting an impact on thymic selection and/or a different clonal selection threshold following antigen encounter. Our results highlight the key role of Vav1 in the pathophysiology of EAMG and this was associated with an impact on the TCR repertoire of AChR reactive T lymphocytes. PMID- 30410483 TI - Harnessing the Induction of CD8+ T-Cell Responses Through Metabolic Regulation by Pathogen-Recognition-Receptor Triggering in Antigen Presenting Cells. AB - Cytotoxic CD8+ T-cells are key players of the immune responses against viruses. During the priming of a CD8+ T-cell response, the activation of a naive T-cell by a professional antigen presenting cell (APC) involves the induction of various intracellular and metabolic pathways. The modulation of these pathways at the level of APCs or T-cells offers great potential to enhance the induction of robust effector cells and the generation of long-lived memory cells. On the one hand, signaling through pathogen recognition receptors (PRRs) expressed by APCs can greatly influence T-cell priming, and the potential of several PRR ligands as adjuvants are being studied. On the other hand, the engagement of several metabolic processes, at play in APCs and T-cells upon stimulation, implies that modulating cellular metabolism can impact on priming efficacy. Here, we review recent efforts to understand the interplay between PRR mediated signaling and metabolic pathway modulation in this context, through three examples: interplay between TLR4 and fatty acid metabolism, between TLR9 and IDO, and between STING and autophagy. These initial works highlight the potential for harnessing the induction of antiviral CD8+ T-cell responses using synergistic modulation of metabolic and PRR pathways. PMID- 30410486 TI - Impact of Disease-Modifying Treatments on the Longitudinal Evolution of Anti-JCV Antibody Index in Multiple Sclerosis. AB - Background: Risk of natalizumab-related progressive multifocal leukoencephalopathy is associated with the presence of anti-JC-virus (JCV) antibodies. Objective: To investigate the impact of disease-modifying treatments (DMT) on the longitudinal evolution of anti-JCV antibody index. Methods: Patients with multiple sclerosis who had serum sampling at intervals of 6 +/- 3 months over up to 6 years and who either started DMT (interferon-beta, glatiramer acetate or natalizumab) during the observation period with at least one serum sample available before and after treatment initiation or received no DMT during the observation period were included. Anti-JCV antibody serological status and index were determined by 2-step second-generation anti-JCV antibody assay. Results: A total of 89 patients were followed for a median time of 55.2 months. Of those, 62 (69.7%) started DMT and 27 (30.3%) were without therapy during the observation period. Variation of longitudinal anti-JCV antibody index ranged from 9 to 15% and was similar in patients with and without DMT. Applying a mixed model considering the combined effects of treatment and time as well as individual heterogeneity did not show a significant change of anti-JCV antibody index by the start of treatment with interferon-beta, glatiramer acetate, or natalizumab. Conclusion: Evaluated DMTs do not impact longitudinal anti-JCV antibody index evolution. PMID- 30410485 TI - From Mice to Men: How B Cell Immunology Helped the Understanding of Leukemia Development. PMID- 30410487 TI - Vaginal Lactobacilli Induce Differentiation of Monocytic Precursors Toward Langerhans-like Cells: in Vitro Evidence. AB - Lactobacilli have immunomodulatory mechanisms that affect the host cell immune system, leading to inhibition of HIV-1 transmission. Thus, lactobacilli as mucosal delivery vehicles for developing HIV-1 vaccines have attracted interest in recent years. Herein, we investigated the immunomodulatory effects of six strains of Lactobacillus naturally isolated from vaginal samples, including Lactobacillus crispatus (L. crispatus), L. fermentum, L. jensenii, L. gasseri, L. delbrueckii and L. johnsonii, on differentiation of monocytic precursors. L. crispatus, L. fermentum and L. delbrueckii could drive human monocytic cell line THP-1 cells to differentiate into dendritic-like cells according to the morphology. Moreover, L. crispatus increased costimulatory molecules including CD40, CD80 and CD86, and Langerhans cell specific C-type lectin receptors CD207, while L. fermentum decreased these molecules in THP-1 cells. Furthermore, L. crispatus promoted the differentiation of THP-1 cells with specific markers, phagocytic features, cytokine production ability and reduced the expression of receptors for HIV-1 entry of Langerhans cells. However, in the presence of L. fermentum, THP-1 cells did not show the above alterations. Moreover, similar effects of L. crispatus and L. fermentum were observed in CD14+ monocytes. These data suggested that L. crispatus facilitates the differentiation of monocytic precursors toward Langerhans-like cells in vitro. We further identified the cell wall components of Lactobacillus and found that peptidoglycans (PGNs), rather than bacteriocins, S-layer protein and lipoteichoic acid, were key contributors to the induction of CD207 expression. However, PGNs originating from Bacillus subtilis, E. coli JM109 and E. coli DH5alpha did not elevate CD207 expression, indicating that only PGN derived from Lactobacillus could enhance CD207 expression. Finally, the recognized receptors of L. crispatus (such as TLR2 and TLR6) and the upstream transcription factors (PU.1, TAL1, TIF1gamma, and POLR2A) of CD207 were examined, and the expression of these molecules was enhanced in THP 1 cells following L. crispatus treatment. Thus, this study offers powerful evidence that vaginal lactobacilli modulate monocytic precursor differentiation into Langerhans-like cells probably via activating the TLR2/6-TFs-CD207 axis. These data provide clues for further investigation of the original occurrence, development and differentiation of Langerhans cells from monocytes. PMID- 30410489 TI - Choline Regulates the Function of Bovine Immune Cells and Alters the mRNA Abundance of Enzymes and Receptors Involved in Its Metabolism in vitro. AB - Dietary choline can impact systemic immunity, but it remains unclear whether this is primarily via direct impacts on immune cells or secondary effects of altered metabolic function. To determine whether increased choline concentrations (3.2, 8.2, 13.2 MUM) in cell culture alter the function of bovine innate and adaptive immune cells, we isolated cells from dairy cows in early and mid-lactation as models of immuno-compromised and competent cells, respectively. Phagocytic and killing capacity of isolated neutrophils were linearly diminished with increasing doses of choline. In contrast, lymphocyte proliferation was linearly enhanced with increasing doses of choline. Furthermore, increasing doses of choline increased the mRNA abundance of genes involved in the synthesis of choline products (betaine, phosphatidylcholine, and acetylcholine) as well as muscarinic and nicotinic acetylcholine receptors in a quadratic and linear fashion for neutrophils and monocytes, respectively. Phagocytic and killing capacity of neutrophils and proliferation of lymphocytes were not affected by stage of lactation or its interaction with choline or LPS. In neutrophils from early lactation cows, choline linearly increased the mRNA abundance of muscarinic and nicotinic cholinergic receptors, whereas choline-supplemented monocytes from mid lactation cows linearly increased the mRNA abundance of several genes coding for choline metabolism enzymes. These data demonstrate that choline regulates the inflammatory response of immune cells and suggest that the mechanism may involve one or more of its metabolic products. PMID- 30410488 TI - Frequency of Circulating CD4+Ki67+HLA-DR- T Regulatory Cells Prior to Treatment for Multidrug Resistant Tuberculosis Can Differentiate the Severity of Disease and Predict Time to Culture Conversion. AB - Identifying a blood circulating cellular biomarker that can be used to assess severity of disease and predict the time to culture conversion (TCC) in patients with multidrug resistant tuberculosis (MDR-TB) would facilitate monitoring response to treatment and may be of value in the design of future drug trials. We report on the frequency of blood Ki67+HLA-DR- CD4+ T regulatory (Treg) cells in predicting microbiological outcome before initiating second-line treatment for MDR-TB. Fifty-one patients with MDR-TB were enrolled and followed over 18 months; a subset of patients was sputum culture (SC) negative at baseline (n = 9). SC positive patients were divided into two groups, based on median TCC: rapid responders (<=71 days TCC; n = 21) and slow responders (>71 days TCC; n = 21). Whole blood at baseline, months 2 and 6 was stimulated with M tuberculosis (Mtb) antigens and Treg cells were then identified as CD3+CD4+CD25hiFoxP3+CD127-CD69- and further delineated as Ki67+HLA-DR- Treg. The frequency of these cells was significantly enlarged at baseline in SC positive relative to SC negative and smear positive relative to smear negative patients and in those with lung cavitation. This difference was further supported by unsupervised hierarchical clustering showing a significant grouping at baseline of total and early differentiated memory Treg cells in slow responders. Conversely, there was a clustering of a lower proportion of Treg cells and activated IFNgamma-expressing T cells at baseline in the rapid responders. Examining changes over time revealed a more gradual reduction of Treg cells in slow responders relative to rapid responders to treatment. Receiver operating curve analysis showed that baseline Mtb-stimulated Ki67+HLA-DR- Treg cells could predict the TCC of MDR-TB treatment response with 81.2% sensitivity and 85% specificity (AUC of 0.87, p < 0.0001), but this was not the case after 2 months of treatment. In conclusion, our data show that the frequency of a highly defined Mtb-stimulated blood Treg cell population at baseline can discriminate MDR-TB disease severity and predict time to culture clearance. PMID- 30410491 TI - A Wide Spectrum of Autoimmune Manifestations and Other Symptoms Suggesting Immune Dysregulation in Patients With Cartilage-Hair Hypoplasia. AB - Background: Mutations in RMRP, encoding a non-coding RNA molecule, underlie cartilage-hair hypoplasia (CHH), a syndromic immunodeficiency with multiple pathogenetic mechanisms and variable phenotype. Allergy and asthma have been reported in the CHH population and some patients suffer from autoimmune (AI) diseases. Objective: We explored AI and allergic manifestations in a large cohort of Finnish patients with CHH and correlated clinical features with laboratory parameters and autoantibodies. Methods: We collected clinical and laboratory data from patient interviews and hospital records. Serum samples were tested for a range of autoantibodies including celiac, anti-cytokine, and anti-21-hydroxylase antibodies. Nasal cytology samples were analyzed with microscopy. Results: The study cohort included 104 patients with genetically confirmed CHH; their median age was 39.2 years (range 0.6-73.6). Clinical autoimmunity was common (11/104, 10.6%) and included conditions previously undescribed in subjects with CHH (narcolepsy, psoriasis, idiopathic thrombocytopenic purpura, and multifocal motor axonal neuropathy). Patients with autoimmunity more often had recurrent pneumonia, sepsis, high immunoglobulin (Ig) E and/or undetectable IgA levels. The mortality rates were higher in subjects with AI diseases ( chi(2)2 = 14.056, p = 0.0002). Several patients demonstrated serum autoantibody positivity without compatible symptoms. We confirmed the high prevalence of asthma (23%) and allergic rhinoconjunctivitis (39%). Gastrointestinal complaints, mostly persistent diarrhea, were also frequently reported (32/104, 31%). Despite the history of allergic rhinitis, no eosinophils were observed in nasal cytology in five tested patients. Conclusions: AI diseases are common in Finnish patients with CHH and are associated with higher mortality, recurrent pneumonia, sepsis, high IgE and/or undetectable IgA levels. Serum positivity for some autoantibodies was not associated with clinical autoimmunity. The high prevalence of persistent diarrhea, asthma, and symptoms of inflammation of nasal mucosa may indicate common pathways of immune dysregulation. PMID- 30410490 TI - Role of Osteocytes in Myeloma Bone Disease: Anti-sclerostin Antibody as New Therapeutic Strategy. AB - Osteocytes are terminally differentiated cells of the osteoblast lineage. They are involved in the regulation of bone remodeling by increasing osteoclast formation or decreasing bone formation by the secretion of the osteoblast inhibitor sclerostin. Monoclonal antibody anti-sclerostin, Romosozumab, has been developed and tested in clinical trials in patients with osteoporosis. In the last years, the role of osteocytes in the development of osteolytic bone lesions that occurs in multiple myeloma, have been underlined. Myeloma cells increase osteocyte death through the up-regulation of both apoptosis and autophagy that, in turn, triggers osteoclast formation, and activity. When compared to healthy controls, myeloma patients with bone disease have higher osteocyte cell death, but the treatment with proteasome inhibitor bortezomib has been shown to maintain osteocyte viability. In preclinical mouse models of multiple myeloma, treatment with blocking anti-sclerostin antibody increased osteoblast numbers and bone formation rate reducing osteolytic bone lesions. Moreover, the combination of anti-sclerostin antibody and the osteoclast inhibitor zoledronic acid increased bone mass and fracture resistance synergistically. However, anti-sclerostin antibody did not affect tumor burden in vivo or the efficacy of anti-myeloma drugs in vitro. Nevertheless, the combination therapy of anti-sclerostin antibody and the proteasome inhibitor carfilzomib, displayed potent anti-myeloma activity as well as positive effects on bone disease in vivo. In conclusion, all these data suggest that osteocytes are involved in myeloma bone disease and may be considered a novel target for the use of antibody-mediated anti-sclerostin therapy also in multiple myeloma patients. PMID- 30410492 TI - Regulation of the Germinal Center Response. AB - The germinal center (GC) is a specialized microstructure that forms in secondary lymphoid tissues, producing long-lived antibody secreting plasma cells and memory B cells, which can provide protection against reinfection. Within the GC, B cells undergo somatic mutation of the genes encoding their B cell receptors which, following successful selection, can lead to the emergence of B cell clones that bind antigen with high affinity. However, this mutation process can also be dangerous, as it can create autoreactive clones that can cause autoimmunity. Because of this, regulation of GC reactions is critical to ensure high affinity antibody production and to enforce self-tolerance by avoiding emergence of autoreactive B cell clones. A productive GC response requires the collaboration of multiple cell types. The stromal cell network orchestrates GC cell dynamics by controlling antigen delivery and cell trafficking. T follicular helper (Tfh) cells provide specialized help to GC B cells through cognate T-B cell interactions while Foxp3+ T follicular regulatory (Tfr) cells are key mediators of GC regulation. However, regulation of GC responses is not a simple outcome of Tfh/Tfr balance, but also involves the contribution of other cell types to modulate the GC microenvironment and to avoid autoimmunity. Thus, the regulation of the GC is complex, and occurs at multiple levels. In this review we outline recent developments in the biology of cell subsets involved in the regulation of GC reactions, in both secondary lymphoid tissues, and Peyer's patches (PPs). We discuss the mechanisms which enable the generation of potent protective humoral immunity whilst GC-derived autoimmunity is avoided. PMID- 30410495 TI - TRIM21 Restricts Coxsackievirus B3 Replication, Cardiac and Pancreatic Injury via Interacting With MAVS and Positively Regulating IRF3-Mediated Type-I Interferon Production. AB - Tripartite motif-containing 21 (TRIM21) is a regulator of tissue inflammation and pro-inflammatory cytokine production, and has been implicated in negative regulation of IRF3-dependent type I interferon signaling. However, the antiviral activity of TRIM21 varies among diverse viruses and its role on regulation of type I interferon remains inconsistent in different microbial infections. Here, we investigate the potential role for TRIM21 in controlling Coxsackievirus B3 (CVB3) replication and susceptible organ pathology. We found that CVB3 infection up-regulated the expression of TRIM21 in hearts of mice and cardiomyocytes at early phase of infection. Knock-down of TRIM21 resulted in increased viral replication, while overexpression led to increased phosphorylation and dimerization of IRF3, increased IFN-beta transcription and reduced viral replication in vitro. We demonstrate that TRIM21 promotes the activation of IRF3 in CVB3-infected cells via interacting with MAVS and catalyzing the K27-linked polyubiquitination of MAVS, thereby enhancing type I interferon signaling. The RING domain of ubiquitin ligase activity and PRY-SPRY domain of TRIM21 are critical for its anti-viral effect. In vivo overexpression of TRIM21 significantly protected mice against viral myocarditis by suppressing CVB3 replication and reducing cardiac inflammatory cytokine production. While TRIM21 deficient mice exhibited a decreased IFN-beta production, an increased cardiac and pancreatic CVB3 replication, and aggravated pancreatic injury as well as myocarditis during acute infection. Thus, our results demonstrate TRIM21 as a positive regulator of IFN-beta signaling by targeting MAVS during CVB3 infection and suggest it as a potent host defense against CVB3 infection and viral-induced injury in hearts and pancreas. PMID- 30410494 TI - Plasmacytoid Dendritic Cells Are Largely Dispensable for the Pathogenesis of Experimental Inflammatory Bowel Disease. AB - Inflammatory bowel disease (IBD) is a chronic inflammatory condition caused by an aberrant immune response to microbial components of the gastrointestinal tract. Plasmacytoid dendritic cells (pDCs) are innate immune cells specialized in the production of type I interferons and were recently implicated in the pathogenesis of autoimmune disorders such as lupus and scleroderma. While pDCs were shown to infiltrate intestinal mucosa of IBD patients and proposed to participate in intestinal inflammation, their net contribution to the disease remains unclear. We addressed this question by targeting the pDC-specific transcription factor TCF4 (E2-2) in experimental IBD caused by deficiency of Wiskott-Aldrich syndrome protein (WASP) or of interleukin-10 (IL-10). Monoallelic Tcf4 deletion, which was previously shown to abrogate experimental lupus, did not affect autoimmunity manifestations or colitis in WASP-deficient animals. Furthermore, conditional biallelic Tcf4 targeting resulted in a near-complete pDC ablation, yet had no effect on the development of colitis in IL-10-deficient mice. Our results suggest that, in contrast to other inflammatory and autoimmune diseases, pDCs do not play a major role in the pathogenesis of intestinal inflammation during IBD. PMID- 30410493 TI - Molecular Control of Follicular Helper T cell Development and Differentiation. AB - Follicular helper T cells (Tfh) are specialized helper T cells that are predominantly located in germinal centers and provide help to B cells. The development and differentiation of Tfh cells has been shown to be regulated by transcription factors, such as B-cell lymphoma 6 protein (Bcl-6), signal transducer and activator of transcription 3 (STAT3) and B lymphocyte-induced maturation protein-1 (Blimp-1). In addition, cytokines, including IL-21, have been found to be important for Tfh cell development. Moreover, several epigenetic modifications have also been reported to be involved in the determination of Tfh cell fate. The regulatory network is complicated, and the number of novel molecules demonstrated to control the fate of Tfh cells is increasing. Therefore, this review aims to summarize the current knowledge regarding the molecular regulation of Tfh cell development and differentiation at the protein level and at the epigenetic level to elucidate Tfh cell biology and provide potential targets for clinical interventions in the future. PMID- 30410496 TI - Resolving the Speciation Patterns and Evolutionary History of the Intercontinental Disjunct Genus Corylus (Betulaceae) Using Genome-Wide SNPs. AB - Understanding the underlying mechanisms of species origin, divergence, and distribution patterns of the intercontinental disjunct taxa has long fascinated botanists. Based on 4,894 genome-wide single-nucleotide polymorphism dataset, we present a molecular phylogenetic reconstruction of genus Corylus (Betulaceae), which have a disjunct distribution between Eurasia and North America (NA). The aim is to explore the speciation patterns and evolutionary relationships of Corylus species by establishing a general phylogenetic framework with extensive sampling. Both the molecular phylogeny inferred from recombination-free dataset and structure analysis support the division of Corylus into four major clades (A D). Recombination tests and hybridization detection reveal extensive recombination and hybridization events among different clades, which have potentially influenced the speciation process of Corylus. Divergence time estimation indicates that recent common ancestor (MRCA) of Corylus occurred in late Eocene (~36.38 Ma) and subsequent rapid diversification began during Miocene. Ancestral area reconstruction shows that Corylus originated from southwest China. The arrival of two clades (Clades B and C) to NA was well supported by the long distance dispersal crossing the Bering land bridge. The Himalayas, European-Mediterranean area, and other distribution regions are primarily the recipients of dispersal taxa. Vicariance after dispersal plays an important role in speciation. PMID- 30410497 TI - Recovery of a Common Bean Landrace (Phaseolus vulgaris L.) for Commercial Purposes. AB - The "Caparrona" bean is a landrace that was grown largely in Monzon, and for that reason, it is also known by the name of "Caparrona de Monzon." Historical references mention that in the thirties of the last century, Caparrona beans reached a production higher than 200,000 kg. Nevertheless, the increasing modernization of agriculture at the end of the 20th century enhanced its replacement by newer varieties. As a result, only a few local growers continued producing Caparrona beans mainly for family use. However, in recent years, the high demand for local products, grown with environmentally friendly farming techniques, has reawakened interest in this local bean. In order to recover the Caparrona bean crop, a study was conducted with the aim of assessing this landrace, along with all the processes, from collecting seeds to securing the in situ and ex situ conservation. Six bean samples were initially collected from local farmers and the traditional knowledge was also recorded. After the first seed-borne virus test, two samples were rejected because of the positive results for Bean Common Mosaic Virus (BCMV). The four remaining samples were evaluated in a randomized complete block design with three replications at two locations. All through the growth phase of the plants, samples were taken for a virus test. Two samples tested positive for BCMV and were discarded. Between the two healthy seed samples, regarding morphology, chemical composition, and agronomic data, no significant statistical differences were found. Therefore, both samples were selected for commercial production. The seeds obtained from the assays were transferred to a recently created producers' association, which registered a private label to commercialize the Caparrona beans as a gourmet product. Seeds are also available from the Spanish BGHZ-CITA public genebank. PMID- 30410500 TI - Post-drought Resilience After Forest Die-Off: Shifts in Regeneration, Composition, Growth and Productivity. AB - A better understanding on the consequences of drought on forests can be reached by paying special attention to their resilience capacity, i.e., the ability to return to a state similar to pre-drought conditions. Nevertheless, extreme droughts may surpass the threshold for the resilience capacity triggering die-off causing multiple changes at varying spatial and temporal scales and affecting diverse processes (tree growth and regeneration, ecosystem productivity). Combining several methodological tools allows reaching a comprehensive characterization of post-drought forest resilience. We evaluated the changes in the abundance, regeneration capacity (seedling abundance), and radial growth (annual tree rings) of the main tree species. We also assessed if drought-induced reductions in growth and regeneration of the dominant tree species scale-up to drops in vegetation productivity by using the Normalized Difference Vegetation Index (NDVI). We studied two conifer forests located in north-eastern Spain which displayed drought-induced die-off during the last decades: a Scots pine (Pinus sylvestris) forest under continental Mediterranean conditions and a Silver fir (Abies alba) forest under more temperate conditions. We found a strong negative impact of a recent severe drought (2012) on Scots pine growth, whereas the coexisting Juniperus thurifera showed positive trends in basal area increment (0.02 +/- 0.003 cm2 yr-1). No Scots pine recruitment was observed in sites with intense die-off, but J. thurifera and Quercus ilex recruited. The 2012 drought event translated into a strong NDVI reduction (32% lower than the 1982-2014 average). In Silver fir we found a negative impact of the 2012 drought on short term radial growth, whilst long-term growth of Silver fir and the coexisting Fagus sylvatica showed positive trends. Growth rates were higher in F. sylvatica (0.04 +/- 0.003 cm2 yr-1) than in A. alba (0.02 +/- 0.004 cm2 yr-1). These two species recruited beneath declining and non-declining Silver fir trees. The 2012 drought translated into a strong NDVI reduction which lasted until 2013. The results presented here suggest two different post-drought vegetation pathways. In the Scots pine forest, the higher growth and recruitment rates of J. thurifera correspond to a vegetation shift where Scots pine is being replaced by the drought-tolerant juniper. Conversely, in the Silver fir forest there is an increase of F. sylvatica growth and abundance but no local extinction of the Silver fir. Further research is required to monitor the evolution of these forests in the forthcoming years to illustrate the cumulative impacts of drought on successional dynamics. PMID- 30410498 TI - Climatic and Soil Factors Shape the Demographical History and Genetic Diversity of a Deciduous Oak (Quercus liaotungensis) in Northern China. AB - Past and current climatic changes have affected the demography, patterns of genetic diversity, and genetic structure of extant species. The study of these processes provides valuable information to forecast evolutionary changes and to identify conservation priorities. Here, we sequenced two functional nuclear genes and four chloroplast DNA regions for 105 samples from 21 populations of Quercus liaotungensis across its distribution range. Coalescent-based Bayesian analysis, approximate Bayesian computation (ABC), and ecological niche modeling (ENM) were integrated to investigate the genetic patterns and demographical history of this species. Association estimates including Mantel tests and multiple linear regressions were used to infer the effects of geographical and ecological factors on temporal genetic variation and diversity of this oak species. Based on multiple loci, Q. liaotungensis populations clustered into two phylogenetic groups; this grouping pattern could be the result of adaptation to habitats with different temperature and precipitation seasonality conditions. Demographical reconstructions and ENMs suggest an expansion decline trend of this species during the Quaternary climatic oscillations. Association analyses based on nuclear data indicated that intraspecific genetic differentiation of Q. liaotungensis was clearly correlated with ecological distance; specifically, the genetic diversity of this species was significantly correlated with temperature seasonality and soil pH, but negatively correlated with precipitation. Our study highlights the impact of Pleistocene climate oscillations on the demographic history of a tree species in Northern China, and suggests that climatic and soil conditions are the major factors shaping the genetic diversity and population structure of Q. liaotungensis. PMID- 30410499 TI - Starch Synthesis in Ostreococcus tauri: The Starch-Binding Domains of Starch Synthase III-B Are Essential for Catalytic Activity. AB - Starch is the major energy storage carbohydrate in photosynthetic eukaryotes. Several enzymes are involved in building highly organized semi-crystalline starch granules, including starch-synthase III (SSIII), which is widely conserved in photosynthetic organisms. This enzyme catalyzes the extension of the alpha-1,4 glucan chain and plays a regulatory role in the synthesis of starch. Interestingly, unlike most plants, the unicellular green alga Ostreococcus tauri has three SSIII isoforms. In the present study, we describe the structure and function of OsttaSSIII-B, which has a similar modular organization to SSIII in higher plants, comprising three putative starch-binding domains (SBDs) at the N terminal region and a C-terminal catalytic domain (CD). Purified recombinant OsttaSSIII-B displayed a high affinity toward branched polysaccharides such as glycogen and amylopectin, and to ADP-glucose. Lower catalytic activity was detected for the CD lacking the associated SBDs, suggesting that they are necessary for enzyme function. Moreover, analysis of enzyme kinetic and polysaccharide-binding parameters of site-directed mutants with modified conserved aromatic amino acid residues W122, Y124, F138, Y147, W279, and W304, belonging to the SBDs, revealed their importance for polysaccharide binding and SS activity. Our results suggest that OT_ostta13g01200 encodes a functional SSIII comprising three SBD domains that are critical for enzyme function. PMID- 30410501 TI - M6AMRFS: Robust Prediction of N6-Methyladenosine Sites With Sequence-Based Features in Multiple Species. AB - As one of the well-studied RNA methylation modifications, N6-methyladenosine (m6A) plays important roles in various biological progresses, such as RNA splicing and degradation, etc. Identification of m6A sites is fundamentally important for better understanding of their functional mechanisms. Recently, machine learning based prediction methods have emerged as an effective approach for fast and accurate identification of m6A sites. In this paper, we proposed "M6AMRFS", a new machine learning based predictor for the identification of m6A sites. In this predictor, we exploited a new feature representation algorithm to encode RNA sequences with two feature descriptors (dinucleotide binary encoding and Local position-specific dinucleotide frequency), and used the F-score algorithm combined with SFS (Sequential Forward Search) to enhance the feature representation ability. To predict m6A sites, we employed the eXtreme Gradient Boosting (XGBoost) algorithm to build a predictive model. Benchmarking results showed that the proposed predictor is competitive with the state-of-the art predictors. Importantly, robust predictions for multiple species by our predictor demonstrate that our predictive models have strong generalization ability. To the best of our knowledge, M6AMRFS is the first tool that can be used for the identification of m6A sites in multiple species. To facilitate the use of our predictor, we have established a user-friendly webserver with the implementation of M6AMRFS, which is currently available in http://server.malab.cn/M6AMRFS/. We anticipate that it will be a useful tool for the relevant research of m6A sites. PMID- 30410502 TI - Pathologic Replication-Independent Endogenous DNA Double-Strand Breaks Repair Defect in Chronological Aging Yeast. AB - Reduction of physiologic replication-independent endogenous DNA double strand breaks (Phy-RIND-EDSBs) in chronological aging yeast increases pathologic RIND EDSBs (Path-RIND-EDSBs). Path-RIND-EDSBs can occur spontaneously in non-dividing cells without any inductive agents, and they must be repaired immediately otherwise their accumulation can lead to senescence. If yeasts have DSB repair defect, retention of Path-RIND-EDSBs can be found. Previously, we found that Path RIND-EDSBs are not only produced but also retained in chronological aging yeast. Here, we evaluated if chronological aging yeasts have a DSB repair defect. We found a significant accumulation of Path-RIND-EDSBs around the same level in aging cells and caffeine treated cells and at a much higher level in the DSB repair mutant cells. Especially in the mutant, some unknown sequence was found inserted at the breaks. In addition, % difference of cell viability between HO induced and non-induced cells was significantly greater in aging cells. Our results suggested that RIND-EDSBs repair efficiency declines, but is not absent, in chronological aging yeast which might promote senescence phenotype. When a repair protein is deficient, an alternative pathway might be employed or an end modification process might occur as inserted sequences at the breaks were observed. Restoring repair defects might slow down the deterioration of cells from chronological aging. PMID- 30410503 TI - Six NSCL/P Loci Show Associations With Normal-Range Craniofacial Variation. AB - Objectives: Orofacial clefting is one of the most prevalent craniofacial malformations. Previous research has demonstrated that unaffected relatives of patients with non-syndromic cleft lip with/without cleft palate (NSCL/P) show distinctive facial features, which can be an expression of underlying NSCL/P susceptibility genes. These results support the hypothesis that genes involved in the occurrence of a cleft also play a role in normal craniofacial development. In this study, we investigated the influence of genetic variants associated with NSCL/P on normal-range variation in facial shape. Methods: A literature review of genome wide association studies (GWAS) investigating the genetic etiology of NSCL/P was performed, resulting in a list of 75 single nucleotide polymorphisms (SNPs) located in 38 genetic loci. Genotype data were available for 65 of these selected SNPs in three datasets with a combined sample size of 7,418 participants of European ancestry, whose 3D facial images were also available. The effect of each SNP was tested using a multivariate canonical correlation analysis (CCA) against 63 hierarchically-constructed facial segments in each of the three datasets and meta-analyzed. This allowed for the investigation of associations between SNPs known to be involved in NSCL/P and normal-range facial shape variations in a global-to-local perspective, without preselecting specific facial shape features or characteristics. Results: Six NSCL/P SNPs showed significant associations with variation in normal-range facial morphology. rs6740960 showed significant effects in the chin area (p = 3.71 * 10-28). This SNP lies in a non coding area. Another SNP, rs227731 near the NOG gene, showed a significant effect in the philtrum area (p = 1.96 * 10-16). Three SNPs showed significant effects on the shape of the nose. rs742071 (p = 8.71 * 10-14), rs34246903 (p = 6.87 * 10 12), and rs10512248 (p = 8.4 * 10-9). Respectively, these SNPs are annotated to PAX7, MSX1, and PTCH1. Finally, rs7590268, an intron variant of THADA, showed an effect in the shape of the supraorbital ridge (p = 3.84 * 10-7). Conclusions: This study provides additional evidence NSCL/P-associated genetic variants influence normal-range craniofacial morphology, with significant effects observed for the chin, the nose, the supraorbital ridges and the philtrum area. PMID- 30410504 TI - Next-Generation Sequencing Based HLA Typing: Deciphering Immunogenetic Aspects of Sarcoidosis. AB - Unraveling of the HLA-related immunogenetic basis of several immune disorders is complex due to the extensive HLA polymorphism and strong linkage-disequilibrium between HLA loci. A lack of in phase sequence information, a relative deficiency of high resolution genotyping including non-coding regions and ambiguous haplotype assignment make it difficult to compare findings across association studies and to attribute a causal role to specific HLA alleles/haplotypes in disease susceptibility and modification of disease phenotypes. Earlier, historical antibody and DNA-based methods of HLA typing, primarily of low resolution at antigen/alellic group levels, yielded "indicative" findings which were partially improved by high-resolution DNA-based typing. Only recently, next generation sequencing (NGS) approaches based on deep-sequencing of the complete HLA genes combined with bioinformatics tools began to provide the access to complete information at an allelic level. Analyzing HLA with NGS approaches, therefore, promises to provide further insight in the etiopathogenesis of several immune disorders in which HLA associations have been implicated. These range from coeliac disease and rheumatological conditions to even more complex disorders, such as type-1 diabetes, systemic lupus erythematosus and sarcoidosis. A systemic disease of unknown etiology, sarcoidosis has previously been associated with numerous HLA variants and also other gene polymorphisms, often in linkage with the HLA region. To date, the biological significance of these associations has only partially been defined. Therefore, more precise assignments of HLA alleles/haplotypes using NGS approaches could help to elucidate the exact role of HLA variation in the multifaceted etiopathogenesis of sarcoidosis, including epigenetic mechanisms. NGS-based HLA analyses may be also relevant for defining variable clinical phenotypes and for predicting the disease course or the response to current/plausible novel therapies. PMID- 30410505 TI - High-Risk Features of Delayed Clinical Progression in Cerebral Venous Thrombosis: A Proposed Prediction Score for Early Intervention. AB - Background: Anticoagulation is the mainstay treatment for cerebral venous thrombosis (CVT). A subset of patients might deteriorate despite anticoagulation, and in such cases, endovascular therapy is recommended. Methods: A retrospective review was performed on subjects with CVT from January 2005 to October 2016. The primary outcome was clinical deterioration. Bivariate analysis, multiple logistic regression modeling, and linear discriminant analysis were used to determine a predictive model for deterioration; the results from these models were used to construct a CVT score in order to measure the individual likelihood of deterioration. Results: We identified 147 subjects with CVT. The majority were treated with anticoagulation (n = 109, 74.15%); 38 (25.85%) were found to have deterioration, 12 (8.16%) of whom underwent endovascular intervention. The most important risk factors of deterioration, per bivariate analysis, included decreased level of consciousness (odds ratio [OR] = 5.76; 95% confidence interval [CI] 2.59-12.77) and papilledema (OR = 4.52; 95% CI 1.55-13.18). The final multivariable model also included CVT location score (number of sinuses involved), oral contraceptive pill use, sodium level, platelet count, and seizure activity on presentation. This model had a predictive ability to identify deterioration of 83.2%, with a sensitivity of 71.4% and a specificity of 76.2%. Patients with a CVT score of >=5 have at least 50% chance of deterioration. Conclusions: Decreased mental status, seizure activity, papilledema, number of involved sinuses, as well as sodium level and platelet count are the most important factors in predicting deterioration after CVT. This group may represent a subset of patients in whom early endovascular therapy may be considered. PMID- 30410506 TI - 5-French SOFIA: Safe Access and Support in the Anterior Cerebral Artery, Posterior Cerebral Artery, and Insular Middle Cerebral Artery. AB - Introduction: Distal access catheters are an infrequent focus of technical notes in neurointervention. The 5-French SOFIA's unique design allows for compatibility with 6-French guide catheters, while its supple construction allows for remarkably distal access for a catheter with a 0.055-inch inner diameter. Methods: The authors reviewed a prospectively maintained endovascular database for cases utilizing the 5-French SOFIA from February 2017 through November 2017. Case type, SOFIA location, microcatheter used, and catheter-related complications were noted. Results: Over the evaluated period, the 5-French SOFIA was utilized in 33 cases, including 13 aneurysm treatments, 10 arteriovenous shunt embolizations, 5 stroke thrombectomies, and 5 other cases. Of 5 flow diversion cases, 1 was for a symptomatic cavernous internal carotid artery aneurysm necessitating transradial access, another for a ruptured A3 aneurysm, and another for a middle cerebral artery (M2) aneurysm; 2 were more proximal aneurysms. Thrombectomies were for M2 (n = 3) or A2 (n = 2) occlusions. In all cases, the 5 French SOFIA reached its anticipated distal target without complication or the need to utilize a smaller/alternative catheter. Of these 33 cases, there were 10 cases of distal SOFIA target locations: 6 M2/M3, 3 anterior cerebral arteries (ACA), and 1 posterior cerebral artery (PCA). M2/M3 and PCA catheterization was achieved over 2.1-Fr microcatheters; ACA catheterization employed a 2.9-Fr microcatheter for pipeline embolization and a deployed stentriever in the setting of two thrombectomies. Conclusion: The 5-French SOFIA can be safely utilized for distal, superselective catheterization in the context of complex neurointervention, including aneurysm and arteriovenous shunt embolization and distal thrombectomy. PMID- 30410507 TI - Transvenous Embolization of Dural Arteriovenous Fistulas of the Hypoglossal Canal: Report of Three Cases and Review of the Literature. AB - In this article, we report three cases of dural arteriovenous fistulas of the hypoglossal canal treated via transvenous approach. We also perform a review of the literature on the endovascular management of this type of lesions with particular attention to the dangerous extracranial-intracranial anastomoses that can occur at this level. PMID- 30410508 TI - A Serpiginous Pericallosal Anterior Cerebral Artery. AB - The anterior cerebral artery (ACA) is a unique artery with many important variations with substantial clinical significance. Tortuous intracranial arteries usually occur in basilar, communicating, anterior, posterior cerebral arteries and in the white matter arterioles. This could happen for many reasons including but not limited to ageing, hypertension, patients with Moyamoya disease, congenital malformation, or increased flow associated with elastin degradation. While dolichoectasia of the ACA has been described even in children, to our knowledge, a serpiginous ACA without ectasia has not been reported, especially in the pediatric population. PMID- 30410509 TI - Endovascular Acute Ischemic Stroke Treatment with FlowGate Balloon Guide Catheter: A Single-Center Observational Study of FlowGate Balloon Guide Catheter Use. AB - Background: Treatment of large vessel occlusion acute ischemic stroke with mechanical thrombectomy has become the standard of care after recent clinical trials. However, the degree of recanalization with stent retrievers remains very important in overall outcomes. We sought to review the utility of a new balloon guide catheter (BGC) in improving the degree of recanalization in conjunction with mechanical thrombectomy. Methods: The medical records of a prospectively collected endovascular ischemic stroke database were reviewed. All consecutive strokes when a FlowGate BGC was used with a thrombectomy stent retriever were identified. Use of a FlowGate BGC, number of passes, final Thrombolysis in Cerebral Infarction (TICI) score, trackability, and use of adjunct devices were all collected and analyzed. Results: Use of a FlowGate BGC resulted in 64% (33/52) first-pass effect (FPE) of TICI 2b/3, and specifically 46% (24/52) TICI 3 FPE (true FPE). A total of 52/62 (84%) of thrombectomy cases were treated with BGCs. In the remaining 10, the BGC was not inflated or used due to the clot not being visualized or the lesions being distal and BGC use thus not deemed appropriate. Adjunct use of an aspiration catheter was seen in 12% (6/52) of cases. The overall success with FlowGate BGCs with one or more passes of TICI 2b/3 was 94% (49/52). Trackability was achieved in 92% (57/62) of cases. Conclusions: Use of the FlowGate BGC as an adjunct to mechanical thrombectomy was associated with good FPE and an overall recanalization of TICI 2b/3 of 94%. PMID- 30410510 TI - Automated CT Perfusion Prediction of Large Vessel Acute Stroke from Intracranial Atherosclerotic Disease. AB - Background and Purpose: We have observed that large vessel occlusion acute strokes (LVOS) due to intracranial atherosclerotic disease (ICAD) present with more benign CT perfusion (CTP) profiles, which we presume to potentially represent enhanced collateralization compared to embolic LVOS. We aim to determine if CTP profiles can predict ICAD in LVOS. Methods: Retrospective review of a prospectively collected interventional stroke database from September 2010 to March 2015. Patients with intracranial ICA/MCA-M1/M2 occlusions and CTP were dichotomized into ICAD versus non-ICAD etiologies. Ischemic core (relative cerebral blood flow < 30%) and hypoperfusion volumes were estimated by automated CTP. Results: A total of 250 patients met the inclusion criteria, comprised of 21 (8%) ICAD and 229 non-ICAD etiologies. Baseline characteristics were similar between groups, except for higher HbA1c levels (p < 0.01), LDL cholesterol (p < 0.01), systolic blood pressure (p < 0.01), and lower rate of atrial fibrillation (p < 0.01) in ICAD patients. There were no significant differences in volumes of baseline ischemic core (p = 0.54) among groups. ICAD patients had smaller Tmax > 4 s, Tmax > 6 s, and Tmax > 10 s absolute lesions, and a higher ratio of Tmax > 4 s/Tmax > 6 s volumes (median 2 [1.6-2.3] vs. 1.6 [1.4-2.0]; p = 0.02). A Tmax > 4 s/Tmax > 6 s ratio >=2 showed specificity = 73%/sensitivity = 52% for ICAD and was observed in 47.6% of ICAD versus 26.1% of non-ICAD patients (p = 0.07). Clinical outcomes were comparable amongst groups. Multivariate logistic regression revealed that Tmax > 4 s/Tmax > 6 s ratio >=2 (OR 3.75, 95% CI 1.05 13.14, p = 0.04), higher LDL cholesterol (OR 1.1, 95% CI 1.01-1.03, p = 0.01), and higher systolic pressure (OR 1.03, 95% CI 1.01-1.04, p = 0.01) were independently associated with ICAD. Conclusion: An automated CTP Tmax > 4 s/Tmax > 6 s ratio >=2 profile was found independently associated with underlying ICAD LVOS. PMID- 30410511 TI - Seeing Is Believing: Headway27 as a Highly Visible and Versatile Microcatheter with Ideal Dimensions for Stroke Thrombectomy. AB - Introduction: Microcatheter selection is an infrequent focus of stroke thrombectomy technique evaluation. The Headway27 microcatheter strikes an excellent balance of microcatheter dimensions (156 cm length, 2.6 Fr distal OD, ID 0.027 inches) and visibility, making it ideal for stroke thrombectomy. Methods: We evaluated a prospectively maintained acute stroke thrombectomy database containing 50 consecutive cases using the Headway27 microcatheter. From the database, patient demographics, clinical and angiographic information as well as procedural technical details and complications were extracted. Results: Manual aspiration thrombectomy (MAT) was performed alone in 72% of cases, stentriever assisted MAT was performed in 6% of cases, and a combination was used in 22% of cases. Median groin puncture to final recanalization time was 27 min and mTICI 2B/3 recanalization was achieved in 94% of cases. There were 2 intra-procedural complications, neither related to the microcatheter. In all cases, the Headway27 reached the intended target vessel: M1 (n = 4), M2 (n = 26), M3 (n = 13), P2 (n = 3), P3 (n = 1), and basilar artery (n = 3). There were no cases requiring usage of an additional or alternative microcatheter. In 45/47 cases of MAT, the reperfusion catheter tracked over the Headway to the clot/intended target; in two cases, the microcatheter was used to deploy a stentriever that then allowed the reperfusion catheter to track to the clot. Conclusion: The Headway27 microcatheter reliably facilitated rapid clot access in anterior and posterior circulation acute large vessel occlusions with no microcatheter-associated complications. PMID- 30410512 TI - Review of the Mobile Stroke Unit Experience Worldwide. AB - Background: The treatment of stroke is dependent on a narrow therapeutic time window that requires interventions to be emergently pursued. Despite recent "FAST" initiatives that have underscored "time is brain," many patients still fail to present within the narrow time window to receive maximum treatment benefit from advanced stroke therapies, including recombinant tissue plasminogen activator (tPA) and mechanical thrombectomy. The convergence of emergency medical services, telemedicine, and mobile technology, including transportable computed tomography scanners, has presented a unique opportunity to advance patient stroke care in the prehospital field by shortening time to hyperacute stroke treatment with a mobile stroke unit (MSU). Summary: In this review, we provide a look at the evolution of the MSU into its current status as well as future directions. Our summary statement includes historical and implementation information, economic cost, and published clinical outcome and time metrics, including the utilization rate of thrombolysis. Key Messages: Initially hypothesized in 2003, the first MSUs were launched in Germany and adopted worldwide in acute, prehospital stroke management. These specialized ambulances have made the diagnosis and treatment of many neurological emergencies, in addition to ischemic and hemorrhagic stroke, possible at the emergency site. Providing treatment as early as possible, including within the prehospital phase of stroke management, improves patient outcomes. As MSUs continue to collect data and improve their methods, shortened time metrics are expected, resulting in more patients who will benefit from faster treatment of their acute neurological emergencies in the prehospital field. PMID- 30410513 TI - Pipeline Embolization for Salvage Treatment of Previously Stented Residual and Recurrent Cerebral Aneurysms. AB - Introduction: This study assessed the safety and effectiveness of the Pipeline embolization device (PED) for persistent and recurrent aneurysms previously treated with either a vascular reconstruction device (VRD) or a flow diverter (FD). Methods: A prospective, IRB-approved database was analyzed for patients treated with PED for aneurysms previously treated with a stent. Results: Twenty procedures were performed on 18 patients, 11 with prior FD, 7 with VRD, and 2 previously treated with both. Overall, 15 aneurysms were saccular (75%), and size was 13.5 +/- 7.6 mm. Location was internal carotid artery (ICA) in 14 cases (70%) and posterior circulation in 6 cases (30%). Average prior treatments were 1.7. Previously FD cases were re-treated at an average of 18.1 months from most recent treatment. Each case used 1 device, 82% with distal coverage and 82% with proximal coverage of prior stent. Balloon remodeling was performed in 3 cases (27%) and no in-stent thrombosis was observed. Previously VRD stent-coiled cases were re-treated at an average of 87.5 months. These cases used on average 1.9 devices, 89% with distal and 100% proximal coverage. Adjunctive coiling was performed in 1 case (11%), balloon remodeling in 5 cases (56%), and 2 cases (28%) developed thrombosis that resolved with abciximab. Re-VRD cases were longer (59.1 vs. 33.7 min, p = 0.02) than re-FD. Angiographic follow-up was available for 16 cases (80%). In re-FD, occlusion was complete in 56% and partial progressive in 33% at 17.1 months digital subtraction angiography. In re-VRD, occlusion was complete in 57% and partial progressive in 27% at 8.1 months. Two complications occurred (10%), including one asymptomatic cervical ICA occlusion and one stent occlusion with associated mortality (5%). Clinical follow-up was 17.8 months on average (range 0.5-51.9). Conclusions: Salvage flow diversion for previously stented aneurysms is technically challenging but offers good prospects of aneurysm obliteration with acceptable complication rates. PMID- 30410514 TI - Active Reperfusion Hemorrhage during Thrombectomy: Angiographic Findings and Real Time Correlation with the CT "Spot Sign". AB - Introduction: Symptomatic intracranial hemorrhage represents one of the most feared complications of endovascular reperfusion. We aim to describe a series of patients that experienced immediate reperfusion injury with active intraprocedural extravasation within the territory of the deep penetrating arteries and provide real-time correlation with CT "spot sign." Methods: This was a retrospective analysis of patients that suffered reperfusion injury with active arterial extravasation during endovascular stroke treatment in two tertiary care centers. Results: Five patients were identified. Median age was 63 (58-71) years, 66% were male. Median NIHSS was 13.5 (9.5-23.0), platelet level 212,000 (142,000 235,000), baseline systolic blood pressure 152 (133-201) mm Hg, and non-contrast CT ASPECTS 7.0 (6.5-9.0). Two patients were taking aspirin and one had received intravenous thrombolysis. There were three middle cerebral artery M1, one internal carotid artery terminus, and one vertebrobasilar junction occlusion. Three patients had anterior circulation tandem occlusions. Stroke etiology was extracranial atherosclerosis (n = 2), intracranial atherosclerosis (n = 2), and cervical dissection (n = 1). The median time from onset to puncture was 5.5 (3.9 8.6) h. Intravenous heparin was administered in all patients (median dose of 4,750 [3,250-6,000] units) and intravenous abciximab in four. All tandem cases had the cervical lesion addressed first. Four lenticulostriates and one paramedian pontine artery were involved. Intraprocedural flat-panel CT was performed in four (80%) cases and provided real-time correlation between the active contrast extravasation and the "spot sign." The bailout included use of protamine, blood pressure control, and balloon guide catheter or intracranial compliant balloon inflation plus coiling of targeted vessel. All patients had angiographic cessation of bleeding at the end of the procedure with parenchymal hemorrhage type 1 in one case and type 2 in four. Three patients had modified Rankin score of 4 and two were dead at 90 days. Conclusions: Active reperfusion hemorrhage involving perforator arteries was observed to correlate with the CT "spot sign" and to be associated with poor outcomes. PMID- 30410515 TI - Carotid Revascularization with and without the Use of an Embolic Protection Device: A Single-Center Experience from Pakistan. AB - Background: To assess the safety and clinical efficacy of carotid artery stenting with and without an embolic protection device (EPD) in both symptomatic and asymptomatic carotid disease cases. Methods: Retrospective data of 55 symptomatic (>=50% occlusion by digital subtraction angiography [DSA], >=70% by ultrasound, computed tomography angiography [CTA], and magnetic resonance angiography [MRA]) and asymptomatic (>=60% by DSA, >=70% by ultrasound, >=80% by CTA and MRA) carotid disease cases undergoing carotid stenting/angioplasty revascularization from February 2014 to October 2017 was reviewed. All symptomatic patients either experienced recurrent transient ischemic attacks or one or more stroke attacks. An EPD protocol was designed for its selective use based on plaque morphologies and working diameters. The primary end points at 30 days of follow-up were a periprocedural incidence of any stroke, myocardial infarction or death, and ipsilateral stroke during the follow-up period. Results: Of the 55 cases, 39 were males and 16 females; mean age was 64.8 years. Fifty-one patients (92.7%) were symptomatic, with a mean stenosis of 80.1%. EPD was used in only 11 cases (20%). Minor stroke rate during the first 30 postoperative days was 1.8% (1 case) with EPD; no myocardial infarction or mortality. No stroke occurred during the median 1.5 years' follow-up. Conclusion: Based on our single-center experience and findings of a relatively small sample size, carotid revascularization with stenting and angioplasty without EPD in experienced hands was found to be safe and efficacious. In addition, it proves cost-effective for patients by limiting the use of unnecessary disposables. These results are comparable to those reported in major trials and are well within the complication thresholds suggested in current guidelines. These results also show promise and illustrate the need for a larger, randomized controlled trial in order to thoroughly address this aspect of carotid revascularization. PMID- 30410517 TI - Cervical Origin of the Right Subclavian Artery with a Nonbifurcating Left Cervical Carotid Artery. PMID- 30410516 TI - Endovascular Therapy and Ethnic Disparities in Stroke Outcomes. AB - Background and Purpose: Ethnic disparities in stroke are well described, with a higher incidence of disability and increased mortality in Blacks versus Whites. We sought to compare the clinical outcomes between those ethnic groups after stroke endovascular therapy (ET). Methods: We performed a retrospective review of the prospectively acquired Grady Endovascular Stroke Outcomes Registry between September 1, 2010 and September 30, 2015. Patients were dichotomized into two groups - Caucasians and African-Americans - and matched for age, pretreatment glucose level, and baseline National Institutes of Health Stroke Scale (NIHSS) score. Baseline characteristics as well as procedural and outcome parameters were compared. Results: Out of the 830 patients treated with ET, 308 pairs of patients (n = 616) underwent primary analysis. African-Americans were younger (p < 0.01), had a higher prevalence of hypertension (p < 0.01) and diabetes (p = 0.04), and had higher Alberta Stroke Program Early CT Score values (p = 0.03) and shorter times to treatment (p = 0.01). Blacks more frequently had Medicaid coverage and less private insurance (29.6 vs. 11.4% and 41.5 vs. 60.3%, respectively, p < 0.01). The remaining baseline characteristics, including baseline NIHSS score and CT perfusion-derived ischemic core volumes, were well balanced. There were no differences in the overall distribution of 90-day modified Rankin scale scores (p = 0.28), rates of successful reperfusion (84.7 vs. 85.7%, p = 0.91), good outcomes (49.1 vs. 44%, p = 0.24), or parenchymal hematomas (6.5 vs. 6.8%, p = 1.00). Blacks had lower 90-day mortality rates (18 vs. 24.6%, p = 0.04) in univariate analysis, which persisted as a nonsignificant trend after adjustment for potential confounders (OR 0.52, 95% CI 0.26-1.03, p = 0.06). Conclusions: Despite unique baseline characteristics, African-Americans treated with ET for large vessel occlusion strokes have similar outcomes as Caucasians. Greater availability of ET may diminish the ethnic/racial disparities in stroke outcomes. PMID- 30410518 TI - Direct Thrombectomy versus Bridging for Patients with Emergent Large-Vessel Occlusions. AB - Background and Aims: Patients with emergent large-vessel occlusion (ELVO) that present earlier than 4 h from onset are usually treated with bridging systemic thrombolysis followed by endovascular thrombectomy (EVT). Whether direct EVT (dEVT) could improve the chances of favorable outcome remains unknown. Methods: Consecutively, prospectively enrolled patients with ELVO presenting within 4 h of onset were entered into a National Acute Stroke Registry of patients undergoing revascularization. Patients treated with bridging were compared to those treated with dEVT. Excellent outcome was defined as having a modified Rankin Scale score <=1 at 90 days following stroke. Results: Out of 392 patients that underwent thrombectomy, 270 (68%) presented within 4 h and were included. Of those, 159 (59%) underwent bridging and 111 (41%) underwent dEVT. Atrial fibrillation and congestive heart failure were more common in the dEVT group (43 vs. 30%, p = 0.04 and 20 vs. 8%, p = 0.009, respectively), but other risk factors, demographics, stroke severity and subtypes as well as baseline vessel patency state and time metrics did not differ. Excellent target vessel recanalization defined as TICI 3 (thrombolysis in cerebral infarction score) was more common in the dEVT group (75 vs. 61%, p = 0.03), but in-hospital mortality, discharge destinations, short- and long-term excellent outcome rates did not differ. On multivariate regression analysis, treatment modality did not significantly modify the chances of excellent outcome at discharge (OR 0.7; 95% CI 0.3-1.5) or at 3 months (OR 0.78 95% CI 0.4-1.4). Conclusions: The chances of attaining excellent functional outcomes are similar in ELVO patients undergoing dEVT or bridging. PMID- 30410519 TI - Multicenter Experience with Stenting for Symptomatic Carotid Web. AB - Background: A carotid web (CaW) is a shelf-like lesion in the posterior aspect of the internal carotid bulb and represents an intimal variant of fibromuscular dysplasia. CaW has been associated with recurrent strokes and conventionally treated with surgical excision. We report a multicenter experience of stenting in patients with symptomatic CaWs. Methods: Retrospective review of consecutive patients admitted to 5 comprehensive stroke centers who were identified to have a symptomatic CaW and treated with carotid stenting. A symptomatic CaW was defined by the presence of a shelf-like/linear, smooth filling defect in the posterior aspect of the carotid bulb diagnosed by neck CT angiography (CTA) and confirmed with conventional angiography in patients with negative stroke workup. Results: Twenty-four patients with stented symptomatic CaW were identified (stroke in 83% and transient ischemic attack in 17%). Their median age was 47 years (IQR 41-61), 14 (58%) were female, and were 17 (71%) black. The degree of stenosis by NASCET was 0% (range 0-11). All patients were placed on dual antiplatelets and stented at a median of 9 days (IQR 4-35) after the last event. Closed-cell stents were used in 18 (75%) of the cases. No periprocedural events occurred with the exception of 2 cases of asymptomatic hypotension/bradycardia. Clinical follow-up after stent placement occurred for a median of 12 months (IQR 3-19) with no new cerebrovascular events noted. Functional independence at 90 days was achieved in 22 (91%) patients. Follow-up vascular imaging (ultrasound n = 18/CTA n = 5) was performed at a median of 10 months (IQR 3-18) and revealed no stenosis. Conclusions: Stenting for symptomatic CaW appears to be a safe and effective alternative to surgical resection. Further studies are warranted. PMID- 30410520 TI - Neurointerventional "Near Morbidity": A Candid Appraisal of an Early Case Series. AB - Background: Modern case series often focus on emphasizing low complication rates, "safety," and "efficacy." Although patients may not suffer significant or obviously apparent neurological complications, many lessons are buried in the "no complications" cohort. Methods: The junior author's prospectively maintained caselog was reviewed over a 1-year period for both symptomatic and "minor"/technical complications of neurointerventional cases, the latter referring to an intraprocedural inability to treat a lesion, suboptimal result, or potentially morbid angiographic occurrence/finding that did not result in permanent neurological morbidity - neurointerventional "near morbidity" (NNM). Results: Of 602 treatments performed over the reviewed period, 163 were interventional neuroendovascular procedures. The most common neuroendovascular procedure performed was stroke thrombectomy (67 cases). Major neurological complications, defined as symptomatic stroke or hemorrhage, occurred in 7 cases (4%). NNM, consisting of instructive, technical issues arose in an additional 9 cases that did not result in neurological morbidity (6%). Overall, in 20/163 cases (12%), there were either major neurological complications, NNM, groin complications, or major medical complications. Conclusions: "Minor"/technical complications - NNM - can be as instructive and illustrative as major complications despite not resulting in permanent morbidity. In reviewing case series, particularly early in one's career, these cases should be highlighted. PMID- 30410522 TI - Safety and Feasibility of Balloon-Assisted Embolization with Onyx of Brain Arteriovenous Malformations Revisited: Personal Experience with the Scepter XC Balloon Microcatheter. AB - Background/Objective: Compliant dual-lumen balloon microcatheters have been used to perform balloon-assisted embolization (BAE) of brain arteriovenous malformations (AVMs) with ethylene vinyl alcohol copolymer (Onyx). However, vessel rupture and microcatheter retention have been reported from BAE using these microcatheters. Using an extra-compliant balloon microcatheter (Scepter XC; Microvention, Tustin, CA, USA) could help avoid pial vessel rupture during BAE. We herein report our experience using this balloon microcatheter for BAE. Methods: This retrospective study included patients who underwent BAE of brain AVMs at our institution between June 2012 and March 2017. Results: The extra compliant Scepter XC balloon microcatheter was used for BAE of brain AVMs in 23 patients aged 44.3 +/- 16.7 years (range 0-65 years). A total of 40 intracranial vessels (39 pial arteries and 1 pial vein) were catheterized and embolized during 30 separate sessions. In all instances, the balloon microcatheter could be successfully advanced to the AVM nidus. A mean volume of 2.4 +/- 1.7 mL (range 0.65-4.6 mL) of Onyx was injected per session. There were no instances of vessel rupture, microcatheter retention, or stroke. Conclusion: Utilization of the extra compliant balloon microcatheter results in safe and effective BAE, which adds to the growing experience with BAE for AVM treatment. PMID- 30410521 TI - Endovascular Therapy versus Thrombolysis in Patients with Mild Strokes and Large Vessel Occlusions within the Anterior Circulation. AB - Background: In patients with large vessel occlusions, endovascular treatment (ET) has been shown to be superior to intravenous thrombolysis (IVT) in recent trials. However, it is currently unclear if patients with mild strokes also benefit from ET. Methods: We compared the discharge rates of good outcome (modified Rankin scale [mRS] <=2), very good outcome (mRS 0-1), symptomatic intracranial hemorrhages (SICH), and infarct sizes in patients with mild strokes (admission National Institutes of Health Stroke Scale <=10) and distal intracranial carotid artery, M1, and M2 occlusions during two time periods. Results: From 1/2008 to 10/2012 160 patients (mean age: 72 +/- 12 years) were treated with IVT, and from 11/2012 to 11/2016 145 patients (mean age: 71 +/- 13 years,) received ET with or without IVT. The clinical results were comparable between both treatment groups (59% after ET vs. 56% after IVT, p = 0.5 for an mRS 0-2) and (38% after ET vs. 32% after IVT, p = 0.3 for an mRS 0-1). In the subgroup of patients with an mRS <=6, the early outcome did not differ significantly between ET and IVT either. The rates of SICH as well as the infarct sizes were not significantly different after ET compared with IVT. Conclusion: Compared with IVT, the routine use of ET did not significantly improve the early clinical or radiological outcome in patients with mild strokes and anterior circulation large vessel occlusions. Further randomized trials are urgently needed to determine the role of ET in this cohort. PMID- 30410523 TI - Acute Ischemic Stroke due to Common Carotid Ostial Disease with Tandem Intracranial Occlusions Treated with Thrombectomy and Staged Retrograde Stenting. AB - Background: Acute ischemic stroke due to tandem occlusive lesions of the anterior circulation involves an intracranial large vessel occlusion as well as a concurrent occlusion or high-grade stenosis of the proximal carotid system. The vast majority of proximal lesions in tandem occlusive cases involve the extracranial internal carotid artery, although the lesion can theoretically exist anywhere along the carotid artery pathway, including the common carotid ostium. Summary: To the best of our knowledge, only 1 report describes common carotid artery ostial lesions in the setting of acute ischemic stroke due to tandem occlusions, in which the authors describe an anterograde treatment paradigm. We present the first 2 cases of acute ischemic stroke secondary to common carotid ostial disease with tandem intracranial occlusion, treated with intracranial thrombectomy followed by subsequent staged balloon-mounted stenting of the common carotid ostium. We review the pathophysiology of tandem occlusions, the controversy surrounding treatment techniques, and various approaches used in the treatment of ostial occlusive lesions. Key Message: In certain situations where acute carotid stenting is not safe or technically possible, immediate intracranial thrombectomy with a subsequent staged balloon-mounted stenting of the ostial lesion may be a reasonable and safe option. PMID- 30410524 TI - Incidence of Aneurysmal Subarachnoid Hemorrhage with Procedures Requiring General Anesthesia in Patients with Unruptured Intracranial Aneurysms. AB - Background: The role of general anesthesia in precipitating aneurysm rupture is not clearly defined. In this study, we aimed to assess the natural history of unruptured aneurysms in patients undergoing non-aneurysm-related procedures requiring general anesthesia. Methods: Retrospective review of consecutive patients with untreated intracranial aneurysms that underwent unrelated surgery with operative note documentation of general anesthesia. Events of intraoperative and postoperative subarachnoid hemorrhage were recorded to determine the incidence of rupture. Results: A total of 110 patients harboring 134 unsecured aneurysms were studied. The mean age was 56.5 years (range, 17-92), and 68% were women (n = 75/110). Mean aneurysm size was 3.5 mm (range 1.5-17). A total of 208 procedures were performed under general anesthesia. There were no events of subarachnoid hemorrhage in 5.7 years of follow-up. Conclusion: In our study, general anesthesia did not precipitate aneurysm rupture, and there were no instances of subarachnoid hemorrhage during the follow-up period. Our results suggest a benign natural history for aneurysms undergoing unrelated general anesthesia. However, this should be interpreted with caution given limitations related to our small sample size and retrospective study design. PMID- 30410525 TI - Usefulness of Cone Beam Intra-Arterial CTA for Evaluation of Flow Diverters: A Practical Approach for Daily Use. AB - Cone beam computed tomography (CBCT), initially used for evaluation of intraprocedural complications such as hemorrhage, has evolved to provide details of implanted devices such as flow diverters. The study aim is to present our experience in using CBCT with intra-arterial injection and provide a step-by-step approach for postprocessing in a practical protocol for daily use. IRB approval was obtained, and the neurointerventional database was retrospectively reviewed from July 2012 to June 2017. Patients who underwent cone beam intra-arterial CT angiography for evaluation of implanted flow diverter devices were reviewed. Patient demographics, aneurysm location (internal carotid artery [ICA]-cavernous, ICA-paraclinoid, and ICA-distal; middle cerebral artery [MCA], anterior cerebral artery [ACA]-acom, ACA-pericallosal, vertebral artery [VA]), type (saccular, dissecting fusiform, or blister) and size, device, injection technique (contrast dilution, rate, and volume), and reconstruction protocol were recorded. Acquired images were postprocessed using a Philips Xtravision workstation. Eighty patients (63 women and 17 men) met the inclusion criteria of our study. Age range was 25 80 years old. Treated aneurysms were located in the ICA-paraclinoid in 48 cases (60%), ICA-distal in 12 cases, ICA-cavernous in 8 cases, MCA in 4 cases, VA in 4 cases, ACA-acom in 2 cases, ACA-pericallosal in 2 cases; 69 were saccular, 8 fusiform, and 3 ruptured blister aneurysms. There were 52 small, 20 large, and 8 giant aneurysms. Pipeline (Medtronic, MN, USA) was the predominant device used in 77 procedures. Two injection techniques were used: 2.5 mL/s for a total volume of 55 mL with a 2-s imaging delay or 3 mL/s for a total volume of 70 mL with a 3-s imaging delay; contrast (Ioxilan 300 mgI/mL) dilution was 10-20% in all cases. The device's landing zones, conformability, presence of deformities, and wall apposition were successfully visualized in all cases. Metal artifact reduction program was applied in 9 coiled aneurysms, and this was satisfactory as well. PMID- 30410526 TI - Geospatial Visualization of Mobile Stroke Unit Dispatches: A Method to Optimize Service Performance. AB - Background: Timely treatment of acute ischemic stroke is crucial to optimize outcomes. Mobile stroke units (MSU) have demonstrated ultrafast treatment compared to standard emergency care. Geospatial analysis of the distribution of MSU cases to optimize service delivery has not been reported. Methods: We aggregated all first-year MSU dispatch occurrences and all cases classified by clinical teams as true stroke by zip code and calculated dispatch and true stroke incidence rates. We mapped dispatch and stroke cases and symbolized incidence rates by standard deviation. We confirmed visual impressions of clusters from map inspection by local Moran's I, boxplot inspection, and t test. We calculated service areas using drive times to meet dispatch and true stroke need. Results: A significant cluster of high dispatch incident rate was confirmed around our MSU base in urban Memphis within a 5-min driving area supporting the initial placement of the MSU based on 911 activation. A significant cluster of high true stroke rate was confirmed to the east of our MSU base in suburban Memphis within a 10-min driving area. Mean incident longitude of cases of true stroke versus disregarded status was significantly eastward (p = 0.001785). Conclusion: Our findings will facilitate determination of socio-spatial antecedents of neighborhood overutilization of 911 and MSU services in our urban neighborhoods and service delivery optimization to reach neighborhoods with true stroke burden. PMID- 30410527 TI - Retention of Stroke Education Provided during Hospitalization: Does Provision of Required Education Increase Stroke Knowledge? AB - Background: Provision of stroke education to patients is a Centers for Medicare/Medicaid (CMS) requirement. However, little is known about retention of the educational content. Methods: Two pilot studies were conducted: Pilot A delivered CMS-required stroke education during hospitalization in a standardized manner and tested knowledge retention in patients returning to the Stroke Clinic for 1-month follow-up; Pilot B randomized patients to either a control group with standardized education or a test-enhanced learning group (target), with measurement of stroke knowledge retention at hospital discharge. Results: A total of 198 patients/caregivers participated in Pilot A, with only 25% scoring 100% correct on required stroke education items. The question most commonly answered incorrectly (n = 117; 59%) was "personal risk factors for stroke," and 74 (37%) could not correctly identify stroke signs and symptoms. Pilot B found that significantly more target group patients could identify their personal stroke risk factors (100 vs. 67%; p = 0.04) and the purpose of their secondary prevention medications (87 vs. 40%; p = 0.02) compared to controls. Discussion: While stroke education is required during hospitalization, its ability to produce retention may be poor. We propose study of test-enhanced learning methods through the Targeted Education in Stroke Trial (TEST) to examine the effect of novel teaching methods on patient/caregiver knowledge retention. PMID- 30410528 TI - Isolated Intraventricular Hemorrhage Associated with Cerebral Vasospasm and Delayed Cerebral Ischemia following Arteriovenous Malformation Rupture. AB - Background: Although it is well characterized in aneurysmal subarachnoid hemorrhage, vasospasm is exceedingly rare following cerebral arteriovenous malformation (AVM) rupture. Subsequently, this complication is poorly characterized with regard to delayed cerebral ischemia (DCI). We review cases of ruptured AVM to assess the frequency and severity of vasospasm on cerebral angiography, and DCI. Summary: We reviewed our institutional database of acute intracranial hemorrhages between 2005 and 2014. We identified patients with cerebral AVM rupture and evidence of vasospasm, which was confirmed with digital subtraction angiography (DSA). Cerebral angiograms were evaluated by 2 blinded neurointerventionalists for vasospasm. Statistical analyses were conducted on the angiographic results and variables of interest to determine predictors and associations of vasospasm and DCI. Thirty-six patients with acute intracranial hemorrhage due to ruptured cerebral AVM subsequently underwent cerebral angiography. The interrater reliability for vasospasm was 0.81. The incidence of vasospasm was 13.9% and the incidence of subsequent DCI was 11.1%. A significant relationship existed between isolated intraventricular hemorrhage and vasospasm (p = 0.001) and subsequent DCI (p = 0.006). Radiographic vasospasm was associated with DCI in 80% of the patients (p < 0.0001). No statistical significance existed between subarachnoid hemorrhage and the development of vasospasm or DCI (p = 1.000 and p = 0.626, respectively). All differences were significant at a 99% level of significance. Key Message: In cases of ruptured AVM, isolated intraventricular hemorrhage appears to be an independent risk factor for vasospasm and DCI. Vasospasm must be considered during late neurological deterioration following AVM hemorrhage, especially in the setting of isolated intraventricular hemorrhage. PMID- 30410529 TI - Stent Survival and Stent-Adjacent Stenosis Rates following Venous Sinus Stenting for Idiopathic Intracranial Hypertension: A Systematic Review and Meta-Analysis. AB - Background: Idiopathic intracranial hypertension (IIH) is characterized by an elevated intracranial pressure without any identifiable causative factor such as an intracranial mass. Dural venous sinus stenosis (DVSS) has been suggested to be associated with IIH. Objective: We performed an updated systematic review and meta-analysis to determine clinical outcomes as well as stent survival and stent adjacent stenosis rates in patients undergoing DVSS for the management of medically refractory IIH. Methods: We searched PubMed, Embase, and Cochrane databases to identify prospective or retrospective cohorts or case series of patients with IIH treated with DVSS between 2000 and 2017. Results: A total of 473 patients were included from 24 studies. Headache was present in 429 (91.8%) patients and resolved or improved in 319/413 (77.2%) after the procedure. Headache, papilledema, visual acuity, and tinnitus improved in 256/330 (77.6%), 247/288 (85.8%), 121/172 (70.3%), and 93/110 (84.5%) patients following DVSS at the final follow-up (mean of 18.3 months). In a meta-analysis of 395 patients with available follow-up data on stenting outcome (mean of 18.9 months), the stent survival and stent-adjacent stenosis rates were 84% (95% confidence interval [CI] 79-87%) and 14% (95% CI 11-18%), respectively. The rate of major neurological complications was less than 2%. Conclusion: Stent-adjacent stenosis is an important complication following venous stenting in patients with DVSS and IIH. Further studies are needed to identify determinants of stent-adjacent stenosis and stent nonsurvival. PMID- 30410530 TI - Comparison of Subacute Vascular Damage Caused by ADAPT versus Stent Retriever Devices after Thrombectomy in Acute Ischemic Stroke: Histological and Ultrastructural Study in an Animal Model. AB - Objectives: To assess the delayed (15 days) histological and ultrastructural changes occurring following endovascular treatment with a direct aspiration first pass technique (ADAPT) or stent retrievers (SRs) and to compare the findings in order to determine which is the least harmful technique and what changes occur. Materials and Methods: Damage to the wall of swine extracranial arteries was evaluated after ADAPT with the Penumbra system or thrombectomy with various SRs. The procedures were performed using two pigs as animal models; extracranial cervical arteries were selected based on their diameters in order to reproduce the procedures as in human intracranial arteries, and endovascular thrombectomies were done after the injection of autologous thrombi. Two weeks later, the animals were euthanized, and 60 arterial samples were obtained for analysis by optical and electron microscopy. Results: Optical and electron microscopy revealed that both techniques cause, in different way, alterations to the structure of the vessel wall. Conclusions: Both techniques caused damage to the vessel wall. The main damages were localized at the level of the tunica media and adventitia, instead of the tunica intima as in the acute phase. Further investigation is required to better understand whether these alterations could have chronic consequences. PMID- 30410532 TI - 2D Parametric Parenchymal Blood Flow as a Predictor of the Hemorrhagic Events after Endovascular Treatment of Acute Ischemic Stroke: A Single-Center Retrospective Study. AB - Background and Purpose: Intracranial hemorrhage (ICH) is one of the major adverse events related to the endovascular management of acute ischemic stroke. It is important to evaluate the risk of ICH as it may result in clinical deterioration of the patients. Development of tools which can predict the risk of ICH after thrombectomy can reduce the procedure-related morbidity and mortality. 2D parenchymal blood flow could potentially act as an indicator for ICH. Methods: 2D parenchymal blood flow was used to evaluate pre- and postthrombectomy digital subtraction angiography series of patients with acute ischemic stroke in the anterior circulation. A recently developed software allows the separation of the vascular filling and parenchymal blush signals using band-pass and band-reject filtering to allow for greater visibility of the parenchyma offering a better visual indicator of the effect of treatment. The "wash-in rate" was selected as the parameter of interest to predict ICH. Results: According to the presence or absence of signs of intracranial parenchymal hemorrhage in the follow-up dual energy CT brain scans, the patients were classified into a hemorrhagic and nonhemorrhagic group (15 patients each). The only significant difference between the groups is the calculated wash-in rate after thrombectomy (p = 0.024). The cutoff value of the wash-in rate after thrombectomy was suggested to be 11,925.0, with 60% sensitivity to predict the hemorrhage and 93.3% specificity. Conclusions: Elevated parametric parenchymal blood flow wash-in rates after thrombectomy may be associated with increased risk of hemorrhagic events. PMID- 30410531 TI - Ghost Infarct Core and Admission Computed Tomography Perfusion: Redefining the Role of Neuroimaging in Acute Ischemic Stroke. AB - Background: Determining the size of infarct extent is crucial to elect patients for reperfusion therapies. Computed tomography perfusion (CTP) based on cerebral blood volume may overestimate infarct core on admission and consequently include ghost infarct core (GIC) in a definitive lesional area. Purpose: Our goal was to confirm and better characterize the GIC phenomenon using CTP cerebral blood flow (CBF) as the reference parameter to determine infarct core. Methods: We performed a retrospective, single-center analysis of consecutive thrombectomies of middle cerebral or intracranial internal carotid artery occlusions considering noncontrast CT Alberta Stroke Program Early CT Score >=6 in patients with pretreatment CTP. We used the RAPID(r) software to measure admission infarct core based on initial CBF. The final infarct was extracted from follow-up CT. GIC was defined as initial core minus final infarct > 10 mL. Results: A total of 123 patients were included. The median National Institutes of Health Stroke Scale score was 18 (13-20), the median time from symptoms to CTP was 188 (67-288) min, and the recanalization rate (Thrombolysis in Cerebral Infarction score 2b, 2c, or 3) was 83%. Twenty patients (16%) presented with GIC. GIC was associated with shorter time to recanalization (150 [105-291] vs. 255 [163-367] min, p = 0.05) and larger initial CBF core volume (38 [26-59] vs. 6 [0-27] mL, p < 0.001). An adjusted logistic regression model identified time to recanalization < 302 min (OR 4.598, 95% CI 1.143-18.495, p = 0.032) and initial infarct volume (OR 1.01, 95% CI 1.001-1.019, p = 0.032) as independent predictors of GIC. At 24 h, clinical improvement was more frequent in patients with GIC (80 vs. 49%, p = 0.01). Conclusions: CTP CBF < 30% may overestimate infarct core volume, especially in patients imaged in the very early time window and with fast complete reperfusion. Therefore, the CTP CBF technique may exclude patients who would benefit from endovascular treatment. PMID- 30410533 TI - Regional Contributions to Poststroke Disability in Endovascular Therapy. AB - Background and Purpose: The relative contribution of each Alberta Stroke Program Early CT Score (ASPECTS) region to poststroke disability likely varies across regions. Determining the relative weights of each ASPECTS region may improve patient selection for endovascular stroke therapy (EST). Methods: In the combined Solitaire Flow Restoration with the Intention for Thrombectomy (SWIFT), Solitaire Flow Restoration Thrombectomy for Acute Revascularization (STAR), and Solitaire Flow Restoration with the Intention for Thrombectomy as Primary Endovascular Treatment (SWIFT PRIME) databases, we identified patients treated with the Solitaire stent retriever. Using 24-h CT scan, a multivariate ordinal regression was used to determine the relative contribution of each ASPECTS region to clinical outcome separately in each hemisphere. The coefficients from the regression were used to create a weighted ASPECTS (wASPECTS), which was compared with the original ASPECTS to predict 90-day modified Rankin Scale disability outcomes in an independent validation cohort. Results: Among 342 patients treated with EST, the average age was 67 years, 57% were female, and the median National Institutes of Health Stroke Scale (NIHSS) score was 17 (IQR 13-20). The median ASPECTS at presentation was 8 (IQR 7-10). The most commonly involved ASPECTS regions on 24-h CT were the lentiform nuclei (70%), insula (55%), and caudate (52%). In multivariate analysis, preservation of M6 (beta = 9.7) and M4 (beta = 4.4) regions in the right hemisphere was most strongly predictive of good outcome. For the left hemisphere, M6 (beta = 5.5), M5 (beta = 4.1), and M3 (beta = 3.1) generated the greatest parameter estimates, though they did not reach statistical significance. A wASPECTS incorporating all 20 parameter estimates resulted in improved discrimination against the original ASPECTS in the independent cohort (C-statistic 0.78 vs. 0.67, right hemisphere). Conclusions: For both right and left hemisphere, preservation of the high cortical regions was more strongly associated with improved outcomes compared to the deep regions. Our findings support taking into consideration the location and relative weightings of the involved ASPECTS regions when evaluating a patient for EST. PMID- 30410534 TI - Aortic Arch Variants: A Practical Guide to Safe and Timely Catheterization. AB - Background: Variations in aortic arch anatomy have been extensively described from multiple perspectives including gross anatomy, embryology, associated cardiac and other anomalies, early life presentation, and cross-sectional diagnosis. There is however a paucity of literature with an emphasis on safe and timely catheterization, particularly when the variants are found during emergent or other catheter angiographic procedures without benefit of prior cross sectional vascular imaging. The purpose of this review is to try to fill this gap. Methods: A review of past 1,000 diagnostic and therapeutic catheterizations was performed to identify arch variants, which are presented in order of frequency encountered at our institutions. Results: The variants are presented as illustrations and catheter angiographic images, with emphasis on safe and efficient intraprocedural diagnosis and catheterization. Conclusion: Familiarity with more and less common arch variants, along with low threshold for performance of pigtail aortic arch angiography and comfort in use of general purpose and recurved catheters, will ensure success in the vast majority of encountered variations. PMID- 30410535 TI - Cytotoxic and Bactericidal Effect of Silver Nanoparticles Obtained by Green Synthesis Method Using Annona muricata Aqueous Extract and Functionalized with 5 Fluorouracil. AB - Nanomaterials obtained by green synthesis technologies have been widely studied in recent years owing to constitute cost-effective and environmental-friendly methods. In addition, there are several works that report the simultaneous performance of the reducer agent as a functionalizing agent, modifying the properties of the nanomaterial. As a simple and economical synthesis methodology, this work presents a method to synthesize silver nanoparticles (AgNPs) using Annona muricata aqueous extract and functionalized with 5-fluorouracil (5-FU). The processes of reduction, nucleation, and functionalization of the nanoparticles were analyzed by UV-Vis absorption spectroscopy, and it was found that they are the function of the contact time of the metal ions with the extract. The structural characterization was carried out by transmission electron microscopy (TEM) and X-ray diffraction patterns (XRD). The antibacterial properties of the synthetized nanomaterials were tested using minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Enterococcus faecalis, Staphylococcus aureus, and Escherichia coli growth. PMID- 30410536 TI - Cholinergic Mechanisms of Target Oddball Stimuli Detection: The Late "P300-Like" Event-Related Potential in Rats. AB - Event-related potentials (ERPs) and oscillations (EROs) provide powerful tools for studying the brain's synaptic function underlying information processing. The P300 component of ERPs indexing attention and working memory shows abnormal amplitude and latency in neurological and psychiatric diseases that are sensitive to pharmacological agents. In the active auditory oddball discriminant paradigm, behavior and auditory-evoked potentials (AEPs) were simultaneously recorded in awake rats to investigate whether P300-like potentials generated in rats responding to rare target oddball tones are sensitive to subcutaneous modulation of the cholinergic tone by donepezil (1 mg/kg) and scopolamine (0.64 mg/kg). After operant training, rats consistently discriminate rare target auditory stimuli from frequent irrelevant nontarget auditory stimuli by a higher level of correct lever presses (i.e., accuracy) in target trials associated with a food reward. Donepezil attenuated the disruptive effect of scopolamine on the level of accuracy and premature responses in target trials. Larger P300-like peaks with early and late components were revealed in correct rare target stimuli trials as compared to frequent tones. Donepezil enhanced the peak amplitude of the P300 like component to target stimuli and evoked slow theta and gamma oscillations, whereas scopolamine altered the amplitude of the P300-like component and EROs to target stimuli. Pretreatment with donepezil attenuated effects of scopolamine on the peak amplitude of the P300-like component and on EROs. This study provides evidence that AEP P300-like responses can be elicited by rats engaged in attentive and memory processing of target stimuli and outline the relevance of the cholinergic system in stimulus discrimination processing. The findings highlight the sensitivity of this translational index for investigating brain circuits and/or novel pharmacological agents, which modulate cholinergic transmission associated with increased allocation of attentional resources. PMID- 30410537 TI - The Key Transcription Factor Expression in the Developing Vestibular and Auditory Sensory Organs: A Comprehensive Comparison of Spatial and Temporal Patterns. AB - Inner ear formation requires that a series of cell fate decisions and morphogenetic events occur in a precise temporal and spatial pattern. Previous studies have shown that transcription factors, including Pax2, Sox2, and Prox1, play important roles during the inner ear development. However, the temporospatial expression patterns among these transcription factors are poorly understood. In the current study, we present a comprehensive description of the temporal and spatial expression profiles of Pax2, Sox2, and Prox1 during auditory and vestibular sensory organ development in mice. Using immunohistochemical analyses, we show that Sox2 and Pax2 are both expressed in the prosensory cells (the developing hair cells), but Sox2 is later restricted to only the supporting cells of the organ of Corti. In the vestibular sensory organ, however, the Pax2 expression is localized in hair cells at postnatal day 7, while Sox2 is still expressed in both the hair cells and supporting cells at that time. Prox1 was transiently expressed in the presumptive hair cells and developing supporting cells, and lower Prox1 expression was observed in the vestibular sensory organ compared to the organ of Corti. The different expression patterns of these transcription factors in the developing auditory and vestibular sensory organs suggest that they play different roles in the development of the sensory epithelia and might help to shape the respective sensory structures. PMID- 30410539 TI - Overexpression of IRS-4 Correlates with Procaspase 3 Levels in Tumoural Tissue of Patients with Colorectal Cancer. AB - We reported that insulin receptor substrate 4 (IRS-4) levels increased in tissue from colorectal cancer (CRC) patients and promoted retinoblastoma-cyclin dependent kinase activation. The aim of the present study was to evaluate the effect of IRS-4 on IGF-1 receptor pathway and its impact on procaspase 3 and PARP expression in RKO and HepG2 cancer cell lines. The results obtained in vitro were compared with those obtained from biopsies of patients with CRC (n = 18), tubulovillous adenomas (TA) (n = 2) and in matched adjacent normal colorectal (MANC) tissue (n = 20). IRS-4 overexpression in cultured cells induced the overactivation of IGF-1/BRK/AKT/GSK-3/beta-catenin/cyclin D1 pathways, which led to increased expression of procaspase 3 and PARP protein levels. Studies carried out on CRC and TA tissues revealed the overactivation of the IGF-1 receptor signalling pathway, as well as the overexpression of procaspase 3 and PARP in tumoural tissue with respect to MANC tissue. The upregulation of IRS-4 in tumoural samples correlated significantly with the increase in pIGF-1 receptor (Tyr 1165/1166) (r = 0.84; p < 0.0001), procaspase 3 (r = 0. 77; p < 0. 0005) and PARP (r = 0. 89; p < 0. 0005). Similarly, we observed an increase in the proteolysis of procaspase 3 in tumoural tissue with respect to MANC tissue, which correlated significantly with the degradation of PARP (r = 0.86; p < 0.0001), p53 (r = 0.84; p < 0.0001), and GSK-3 (r = 0.78; p < 0.0001). The stratification of patient samples using the TNM system revealed that procaspase 3 and caspase 3 increased gradually with T values, which suggests their involvement in the size and local invasion of primary tumours. Taken together, our findings suggest that IRS-4 overexpression promotes the activation of the IGF-1 receptor pathway, which leads to the increase in procaspase 3 levels in CRC. PMID- 30410540 TI - Accuracy of Periapical Radiography and CBCT in Endodontic Evaluation. AB - Introduction: A radiological evaluation is essential in endodontics, for diagnostic purposes, planning and execution of the treatment, and evaluation of the success of therapy. The periapical radiography is nowadays the main radiographic investigations used but presents some limits as 3D anatomic alteration, geometric compression, and possible anatomical structures overlapping that can obscure the area of interest. CBCT (cone beam computed tomography) in endodontics allows a detailed assessment of the teeth and surrounding alveolar anatomy for endodontic diagnosis, treatment planning, and follow-up. Objective: The purpose of this study was to evaluate the accuracy of CBCT in comparison with conventional intraoral radiographs used in endodontic procedures. Materials and Methods: Statistical analysis was performed on 101 patients with previous endodontic treatments with the relative radiographic documentation (preoperative, postoperative, and follow-up intraoral X-ray) that had underwent at CBCT screening for surgical reasons. The CBCT scans were evaluated independently by two operators and compared with the corresponding periapical images. Results: Our analysis shows that the two radiological investigations statistically agree in 100% of cases in the group of patients without any endodontic sign. In the group of patients with an endodontic pathology, detected with CBCT, endodontic under extended treatments (30.6%), MB2 canals in nontreated maxillary molars (20.7%), second canals in nontreated mandibular incisors (9%), root fractures (2.7%), and root resorption (2.7%) were not always visible in intraoral X-ray. Otherwise, positivity in the intraoral X-ray was always confirmed in CBCT. A radiolucent area was detected in CBCT exam in 46%, while the intraoral X-ray exam was positive only in 18%. Conclusions: Our study shows that some important radiological signs acquired using CBCT are not always visible in periapical X ray. Furthermore, CBCT is considered as a II level exam and could be used to solve diagnostic questions, essential to a proper management of the endodontic problems. PMID- 30410538 TI - What Roles Do Probiotics Play in the Eradication of Helicobacter pylori? Current Knowledge and Ongoing Research. AB - With the rising global prevalence of antibiotic resistance, the eradication rate of Helicobacter pylori (HP) is continuing to decrease. Probiotics are beneficial to human health and may be an adjunct therapy to increase the eradication rate of HP, lower treatment-associated side effects, and reduce HP-associated gastric inflammation. However, inconsistent test results have prevented conclusions about the therapeutic prowess of probiotics for HP. The mechanisms of actions of probiotics include the production of substances that inhibit or kill HP or compete with HP for the adhesion site on gastric epithelial cells. Probiotics can also reduce the release of inflammatory factors by regulating the local immune response of the host. We searched the available literature for full-length articles focusing on the role of probiotics in HP management. This review presents the latest advances in this area. PMID- 30410541 TI - Augmentation versus No Augmentation for Immediate Postextraction Implants. AB - Purpose: To assess the effects of augmentation versus no augmentation in patients restored with immediate postextraction single-tooth implants on implant failure and patient satisfaction. Materials and methods: We searched the Cochrane Oral Health Group Trial Register, Cochrane Central Register of Controlled Trials, MEDLINE, and the WHO International Clinical Trial Registry Platform (22 March 2017). Two reviewers independently assessed trials for inclusion and risk of bias, extracted data, and checked for accuracy. We have expressed results as risk ratio or mean differences, together with their 95% confidence intervals. Results: We included six studies (287 participants). Two trials compared no augmentation versus bone graft augmentation and reported no implant failures in both groups after a follow-up period of 6 months (20 implants) and 1 year (34 implants). One trial compared bone graft augmentation versus membrane augmentation and reported no difference in implant failure between both groups after 6 months (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.06 to 15.31) or 1 year of follow-up (RR 0.33, 95% CI 0.01 to 7.86), and no implants were lost after 3 years. Three trials compared membrane augmentation versus combined bone graft and membrane augmentation, and there was no difference between the groups after six months of follow-up in implant failure (RR 5.13, 95% CI 0.63 to 41.93) or after 1 year (RR 0.38, 95% CI 0.02 to 9.05). There was insufficient evidence regarding patient satisfaction in all the included trials. Conclusions: In patients restored with immediate postextraction single-tooth implants, there is insufficient evidence to recommend simultaneous augmentation or a certain augmentation protocol to enhance implant survival and patient satisfaction. This trial is registered with PROSPERO (CRD42017054439). PMID- 30410542 TI - Unilateral and Bilateral PNIF in Quality Control of Nasal Septal Surgery. AB - The aim of this study was to explore the usefulness of unilateral, combined unilateral (left + right), and bilateral peak nasal inspiratory flow (PNIF) measurements in assessing the results of nasal septal surgery. Nasal obstruction was recorded subjectively and objectively before and 4 months after nasal septoplasty using a visual analogue scale (VAS) and a PNIF meter. Nasal septoplasty (58 patients) and septoplasty with turbinoplasty (68 patients) were performed on 126 patients (85 males; 41 females) with a mean age of 32.8 years. The results showed a significant improvement in VAS scores, as well as unilateral, combined unilateral, and bilateral PNIF values after both septoplasty and septoplasty with turbinoplasty. Septoplasty with turbinoplasty showed better improvement in VAS and PNIF scores than septoplasty alone and this was significant for bilateral PNIF scores. The best unilateral pre- and postoperative correlations between VAS and PNIF measurements were found using the lower of the two unilateral PNIF scores, irrespective of side. In the total material, VAS/PNIF correlations were mostly significant, but weak (all r<0.30). We found VAS and PNIF to be useful instruments in reporting results of surgery. The weak correlations between VAS and PNIF measurements suggest that these subjective and objective instruments may target different aspects of nasal obstruction. PMID- 30410543 TI - Environmental and Life-Style Related Risk Factors for Sinonasal and Nasopharyngeal Malignancies among a Prospective Cohort in Jos, Nigeria. AB - Background: Worldwide evidence indicates that environmental and life-style related factors are associated with increased risk for cancers in the head and neck region. We aim to study the association between these risk factors and cancers in the sinonasal and nasopharyngeal regions in our environment. Methods: Longitudinal prospective cohort study at the Jos University Teaching Hospital, Jos, Nigeria. Risk exposures were classified based on the International Agency for the Research on Cancer (IARC) classification of suspected carcinogens. Associations between variables were analyzed using logistic regression. Results: We studied 44 patients with malignancies in nasopharynx (n= 24; 54.5%) and sinonasal regions (n= 20; 45.5%). Male to female ratio is 1.9:1 and mean age is 45.2 years. Alcohol was the commonest risk factor in males (n= 19; 43.2%) while cooking wood fumes were the commonest in females (n= 14; 31.8%) which was associated with increased risk for malignancies for all sites, showing ten times risk in nasal cancers (OR= 9.67; 95% CI 1.87- 9.88; p= 0.01). Tobacco was associated with elevated risk of malignancies in the nasomaxillary and nasal regions. Other risks were herbicides, pesticides, and chemical fertilizers in farmers. Conclusion: The significant risk exposures in females were cooking wood fumes and alcohol, tobacco, and exposure to agricultural chemicals in males. Life style modification and environmental changes to ensure clean air in Nigeria are essential to reduce risks. PMID- 30410544 TI - Notch Signaling Activation Enhances Human Adipose-Derived Stem Cell Retinal Differentiation. AB - Retinal disease treatment by stem cell-based replacement relies on stem cell differentiation into retinal cells. We previously demonstrated that human periodontal ligament-derived stem cells can be directed into retinal lineage upon induction. Here, we report the transdifferentiation potential of human adipose derived stem cells (ASCs) into retinal lineage and its enhancement by Notch signaling modulation. Human ASCs, isolated from abdominal fat, expressed mesenchymal but not hematopoietic stem cell markers, and they can differentiate into adipocytes, chondrocytes, and osteoblasts in vitro. Upon noggin/Dkk-1/IGF-1 induction, the treated ASCs showed elevated expression of retinal progenitor, retinal ganglion, and photoreceptor cell markers as well as the glutamate-evoked calcium response, which was not observed in the noninduced cells. Compared to the regular induction treatment, Notch signaling activation by JAG1 enhanced the expression of retinal progenitor and precursor markers without affecting the glutamate-evoked calcium response. In contrast, Notch signaling inhibition by DAPT showed more retinal ganglion cells, but delayed the response to glutamate stimulation. In summary, our results revealed that human ASCs possess a retinal transdifferentiation potential upon noggin/Dkk-1/IGF-1 induction, which can further be enhanced by Notch signaling activation. PMID- 30410545 TI - Validation of a Modified Triage Scale in a Norwegian Pediatric Emergency Department. AB - Objective: Triage is a tool developed to identify patients who need immediate care and those who can safely wait. The aim of this study was to assess the validity and interrater reliability of a modified version of the pediatric South African triage scale (pSATS) in a single-center tertiary pediatric emergency department in Norway. Methods: This prospective, observational study included all patients with medical conditions, referred to the pediatric emergency department of a tertiary hospital in Norway from September 1, 2015, to November 17, 2015. Their assigned triage priority was compared with rate of hospitalization and resource utilization. Validity parameters were sensitivity, specificity, positive and negative predictive value, and percentage of over- and undertriage. Interrater agreement and accuracy of the triage ratings were calculated from triage performed by nurses on written case scenarios. Results: During the study period, 1171 patients arrived at the hospital for emergency assessment. A total of 790 patients (67 %) were triaged and included in the study. The percentage of hospital admission increased with increasing level of urgency, from 30 % of the patients triaged to priority green to 81 % of those triaged to priority red. The sensitivity was 74 %, the specificity was 48 %, the positive predictive value was 52 %, and the negative predictive value was 70 % for predicting hospitalization. The level of over- and undertriage was 52 % and 26 %, respectively. Resource utilization correlated with higher triage priority. The interrater agreement had an intraclass correlation coefficient of 0.99 by Cronbach's alpha, and the accuracy was 92 %. Conclusions: The modified pSATS had a moderate sensitivity and specificity but showed good correlation with resource utilization. The nurses demonstrated excellent interrater agreement and accuracy when triaging written case scenarios. PMID- 30410546 TI - Asthma Risk Associated with Indoor Mold Contamination in Hispanic Communities in Eastern Coachella Valley, California. AB - Indoor mold contamination has been associated in many studies with an increased risk of asthma and respiratory illness. This study investigated indoor mold contamination and the prevalence of asthma/respiratory illness in two low-income, Hispanic communities, Mecca and Coachella City, in the Eastern Coachella Valley (ECV) of California. The study consisted of a questionnaire to assess asthma/respiratory illness and the quantification of mold contamination in house dust samples using the Environmental Relative Moldiness Index (ERMI) scale. About 11% of the adults and 17% of the children in both Mecca and Coachella City met our definitions of asthma/respiratory illness. The average ERMI values in Mecca and Coachella City housing (10.3 and 6.0, respectively) are in the top 25% of ERMI values for the United States (US) homes. Overall, the homes surveyed in these ECV communities had an average prevalence of occupant asthma of 12.8% and an average ERMI value of 9.0. The prevalence of asthma/respiratory illness in the Hispanic communities of Mecca and Coachella City and the mold contamination in their homes appear to be greater than the averages for the rest of the US. The higher levels of mold contamination in their homes appear to be associated with a greater risk of asthma/respiratory illness for these low-income, Hispanic communities. PMID- 30410547 TI - Elevated IL-33 promotes expression of MMP2 and MMP9 via activating STAT3 in alveolar macrophages during LPS-induced acute lung injury. AB - Background: Pulmonary inflammation and endothelial barrier permeability increase in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) induced by pro-inflammatory cytokines and matrix metalloproteinases (MMPs). However, the relationship between pro-inflammatory cytokines and MMPs in ALI/ARDS remains poorly understood. Methods: A lipopolysaccharide (LPS)-induced ALI rat model was established through intratracheal instillation. The wet/dry ratios of lung tissues were measured, and bronchoalveolar lavage fluid (BALF) was collected to test protein concentrations, total cell/macrophage numbers, and pro-inflammatory cytokine levels. LPS-treated alveolar macrophages were utilized in in vitro experiments. The expression and secretion of MMPs were respectively detected using quantitative PCR, Western blotting and ELISA assays. Results: The levels of IL-33 and MMP2/9 in BALF increased in all the ALI rats with severe lung injury. LPS-induced IL-33 autocrine upregulated the expression of MMP2 and MMP9 through activating STAT3. Neutralizing IL-33 in culture medium with specific antibodies suppressed the expression and secretion of MMP2 and MMP9 in LPS-treated alveolar macrophages. Consistently, eliminating IL-33 decreased the levels of MMP2 and MMP9 in BALF and alleviated lung injury in ALI rats. Conclusion: The IL 33/STAT3/MMP2/9 regulatory pathway is activated in alveolar macrophages during acute lung injury, which may exacerbate the pulmonary inflammation. PMID- 30410548 TI - Perinatal antibiotic exposure alters composition of murine gut microbiota and may influence later responses to peanut antigen. AB - Background: Accumulating evidence suggests that the gut microbiota shapes developmental processes within the immune system. Early life antibiotic use is one factor which may contribute to immune dysfunction and the recent surge in allergies by virtue of its effects on gut microbiota. Objective and methods: As a first step towards determining whether a relationship exists between perinatal antibiotic induced changes in the gut microbiota and the later development of a peanut allergy, we exposed newborn mice to either the broad-spectrum antibiotic vancomycin or to a vehicle for 6 weeks and then used a novel murine model of peanut allergy. Results: Early-life treatment with vancomycin resulted in a significant shift in the gut microbiota community characterized by a reduction in the abundance of firmicutes and preponderance of inflammatory proteobacteria. Mice with an antibiotic-altered microbiota, showed a localized allergic-like response characterized by ear swelling and scratching following intra-dermal peanut antigen challenge. Likewise, circulating IgE levels were increased in antibiotic-treated mice, but no evidence of a systemic allergic or anaphylactic like response was observed. Importantly, we utilized the naturally occurring pro inflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), rather than the more commonly used cholera toxin, as an adjuvant together with the peanut antigen. Conclusion: Our data suggest that early antibiotic exposure promotes a shift in the gut microbiota community that may in turn, influence how mice later respond to a TNF-alpha + antigen challenge. However, further studies verifying the capacity of microbiota restoration to protect against allergic responses will be needed to confirm a causal role of antibiotic-induced microbiota variations in promoting allergic disease phenotypes. PMID- 30410549 TI - Hyper IgE recurrent infection syndrome in South Asia: is there a different outcome? AB - Background: Hyper IgE recurrent infection syndrome (HIES) is a rare immune deficiency, characterized by recurrent staphylococcal skin and lung abscesses, pneumonia and increased IgE levels. The majority of autosomal dominant HIES (AD HIGE) is due to hypomorphic mutations in the signal transducer and the activator of transcription 3 (STAT3) gene. Case presentation: Five patients were diagnosed with HIES, based on the clinical criteria and scoring system developed at the National Institutes of Health (NIH), USA. The STAT3 gene was sequenced and previously described mutations were identified in all five patients. We compare the clinical features of our patients with those from Asia, Europe and the US. Conclusion: Even though the number of patients is limited, there are some clinical differences in patients from South Asia compared to European and even East Asian patients. However, the mutations detected are located at hot spots seen in western and Asian patients with AD HIGE. PMID- 30410551 TI - First-reported pediatric cases of American ginseng anaphylaxis and allergy. AB - Background: Ginseng is a perennial herb used in traditional Chinese medicine, which has become increasingly popular world-wide due to its proposed medicinal effects. There are two major species of ginseng, Panax ginseng (Korean or Asian ginseng), and Panax quinquefolius (American ginseng). Although cases of allergy due to Korean ginseng have been reported in adults, there are no reported cases of allergy to American ginseng, and no reported cases of ginseng allergy in pediatric patients. Case presentation: We present two unique cases of pediatric patients with suspected allergic reactions to American ginseng. The first patient is a 6-year-old girl who presented to the emergency department in anaphylaxis (urticaria and respiratory symptoms) minutes after inhaling powdered American ginseng. There was evidence of sensitization to American ginseng on skin prick testing (SPT) (13 * 12 mm wheal) and evidence of allergy to American ginseng on basophil activation testing, with a dose-dependent increase in expression of CD63 on basophils in response to American ginseng extract. The second patient is a 3 year-old boy who presented with recurrent allergic conjunctivitis upon exposure to aerosolized powdered ginseng, with evidence of sensitization to American ginseng on SPT (13 * 7 mm wheal), but with no evidence of IgE-mediated allergic reaction during oral challenge with American ginseng powder. Conclusions: These cases highlight two different allergic responses to American ginseng in pediatric patients. To our knowledge, these are the first reported cases of allergy to American ginseng, in addition to the first reported cases of allergy to ginseng in pediatric patients. PMID- 30410550 TI - Anaphylactic reaction in patient allergic to mango. AB - Background: An allergy to mango is extremely rare. The antigenic composition of the fruit is not fully known. Profilin from mango has a structure similar to birch tree profiling: it is responsible for cross-reactions between mango and pear, apple, and peach. A panallergen with a structure similar to mugwort defensin (Art v 1) which cross-reacts with celery, carrot, peanuts, pepper, aniseed, and caraway has been previously described. Case study: A female patient, 30 years old, was admitted in February 2017 because of recurrent allergic reactions following consumption of various foods. The most severe allergic reaction in the patient's life occurred after eating a mango fruit. Within several minutes the patient developed a generalised urticaria, followed by facial oedema, strong stomach pain and watery diarrhoea. The diagnostics involved skin tests with a set of inhalatory and food allergens, including native skin tests. The patient also experienced symptoms of recurrent, generalized urticaria in connection with consumption of various types of food, especially complex dishes containing many different ingredients. Additionally, an interview revealed that the patient was experiencing symptoms of the oral allergy syndrome after ingesting various fruit and vegetables, especially during late summer and fall. Diagnostics was extended by determining the levels of IgE specific for allergen components, using the ImmunoCap ISAC method. In order to confirm the occurence of a cross-reaction between mugwort and mango allergens, we performed the inhibition test of IgE specific for mugwort using a mango allergen extract and ImmunoCap matrix. Results: Skin prick tests (SPT) were positive for allergens of grass 7 mm; weeds 8 mm; cat's fur 5 mm; mugwort 6 mm. SPT were also positive for mango. The level of specific IgE was increased for allergens of mugwort, grass, celery, pepper, carrot, mango, banana, peach, and apple. The ImmunoCap ISAC test demonstrated a high level of specific IgE rPhl p 1 (timothy grass) and Art v 1 (mugwort). We also performed the IgE inhibition test using both mango extract and ImmunoCap matrix and confirmed a cross-reaction with Art v 1 in the pathogenesis of symptoms observed in the patient. Conclusions: An anaphylactic reaction to consumed mango, resulting from cross-allergy with mugwort Art v 1 was diagnosed in the patient. Acute urticarial in this case is a manifestation of IgE-mediated food allergy. During in vitro diagnostic procedures we found an elevated concentration of IgE specific to several food allergens (including celery, peppers, carrot, banana, peach, apple, shrimp). The elimination diet removing allergens the patient was allergic to was recommended. Considering the anaphylactic reaction the patient was instructed to carry a rescue set composed of an adrenaline autosyringe, steroids, and antihistamines. PMID- 30410552 TI - Endocrine Modulation in Long-Term Karate Practitioners. AB - Purpose: Karate is a martial arts discipline which is widely practiced in the Western world as a form of self-defense, as well as a discipline to achieve physical and mental balance. However, little is known with respect to its specific psychobiological effects, particularly in relation to the influence that it may exert on the endocrine system. Thus, in the present study, we examined the effects of karate on several hormonal parameters of the Hypothalamic-Pituitary Adrenal and Hypothalamic-Pituitary-Thyroid axes in long-time practitioners. Methods: Twenty-two healthy volunteer subjects (12 experimental and 10 controls) participated in the study. Experimental subjects were karate players with a minimum of 3 years of practice in this discipline. Blood samples for the quantification of hormonal parameters were taken in both groups. The Mann-Whitney U test was performed for each variable in order to analyze the differences between groups. Results: Statistically significant differences were found in cortisol and thyroid hormones, with the karate group showing lower levels of these hormones as compared to control. Conclusions: These findings, therefore, reveal that long-term karate practice is associated with a significant endocrine modulation, which suggests interesting psychobiological and clinical implications. Further research is needed to verify these preliminary results, as well as properly assessing its possible use as a psychosomatic intervention tool. PMID- 30410553 TI - Study of the Treatment Effects of Compound Tufuling Granules in Hyperuricemic Rats Using Serum Metabolomics. AB - The study aimed to investigate the mechanism of the effect of Compound Tufuling Granules (CTG) to lower the serum uric acid level in a rat model of hyperuricemia. The rat model was established by administering hypoxanthine through oral gavage and potassium oxonate through intraperitoneal injection. Rats were divided into the normal group, model group, CTG group, and allopurinol group. Serum uric acid, creatinine, urea nitrogen, and inflammatory cytokine levels were determined in each group. In the model group, ultrahigh performance liquid chromatography-mass spectrometry was used to analyze the metabolic profiles and delineate the action mechanism of CTG; in addition, the orthogonal projection method was used to perform latent structure-discrimination analysis to screen the related metabolites. The results indicated significant differences in the metabolic profiles between the model and normal groups. A total of seven related metabolites were identified through screening in the model group, mainly related to the pathways of bile secretion, pyrimidine, purine, and phenylalanine metabolism, pantothenate and CoA biosynthesis, and pentose and glucuronate interconversions; these related pathways were reversed in the CTG group. In the metabolic networks, uracil and acetyl-coenzyme A were the nodal molecules. In addition, the test results of the evaluation of serum biochemical and inflammatory factors confirmed that CTG had significant effect in reducing the levels of serum uric acid and protecting renal function. These results confirmed that CTG primarily regulated the recruitment of nodal molecules to achieve anti inflammatory effects, reduced uric acid level, and renal protection. PMID- 30410555 TI - Xingnao Jieyu Decoction Ameliorates Poststroke Depression through the BDNF/ERK/CREB Pathway in Rats. AB - Background. The neurotrophic pathway regulated by the brain-derived neurotrophic factor (BDNF) plays a crucial role in the pathogenesis of poststroke depression (PSD). How the traditional Chinese medicine compound preparation Xingnao Jieyu (XNJY) decoction regulates the neurotrophic pathway to treat PSD is unclear. Objective. This study aimed to investigate the antidepressant effect of XNJY decoction on a rat model of PSD and the molecular mechanism intervening in the neurotrophic pathway. Methods. After a middle cerebral artery occlusion model was established, chronic unpredictable mild stress was applied for 21 days to prepare a PSD model. XNJY groups and a fluoxetine (Flu) group of rats were intragastrically administered with XNJY and Flu, respectively, for 21 consecutive days. Depressive-like behaviors, including sucrose preference, open field test, and forced swimming test, were assessed. The survival and apoptosis of cortical and hippocampal neurons were evaluated by immunofluorescence assay and TUNEL staining. The contents of serotonin (5-HT), norepinephrine (NE), and BDNF in the cortex and hippocampus were determined by ELISA. The protein levels of BDNF, p ERK/ERK, and p-CREB/CREB in the cortical and hippocampal regions were tested by Western blot. Results. The depressive-like behaviors markedly improved after XNJY and Flu treatment. XNJY and Flu promoted neuronal survival and protected cortical and hippocampal neurons from apoptosis. XNJY also increased the contents of 5-HT, NE, and BDNF and recovered the protein levels of p-ERK/ERK, p-CREB/CREB, and BDNF in the cortical and hippocampal regions. Conclusion. These results indicated that the XNJY decoction exerts an obvious antidepressant effect, which may be due to the regulation of the BDNF/ERK/CREB signaling pathway. PMID- 30410556 TI - Cordycepin Accelerates Osteoblast Mineralization and Attenuates Osteoclast Differentiation In Vitro. AB - Bone homeostasis destruction is triggered by the uncontrolled activity of osteoblasts and osteoclasts. Targeting both the regulation of bone formation and resorption is a promising strategy for treating bone disorders. Cordycepin is a major component of Chinese caterpillar fungus Cordyceps militaris. It exerts a variety of biological actions in various cells and animal models. However, its function on bone metabolism remains unclear. In the present study, we discovered a dual-action function of cordycepin in murine MC3T3-E1 and RAW264.7 cells. MC3T3 E1 cells were cultured in an osteogenic medium in the presence of 1 MUM cordycepin for up two weeks. Cordycepin was used for effects of osteoblast and osteoclast differentiation. Cell viability was measured using the MTT assay. Osteoblast differentiation was confirmed by alizarin red staining, ALP activity, western blot, and real-time PCR. Osteoclast differentiation and autophagic activity were confirmed via TRAP staining, pit formation assay, confocal microscopy, western blot, and real-time PCR. Cordycepin promoted osteoblast differentiation, matrix mineralization, and induction of osteoblast markers via BMP2/Runx2/Osterix pathway. On the other hand, RAW264.7 cells were differentiated into osteoclast by RANKL treatment for 72 h. 1 MUM cordycepin significantly inhibited RANKL-induced osteoclast formation and resorption activity through disturbing the actin ring-formatted sealing zone and activating cathepsin K and MMP9. These findings indicate that cordycepin might be an innovative dual-action therapeutic agent for bone disease caused by an imbalance of osteoblasts and osteoclasts. PMID- 30410557 TI - Immunotoxicological Evaluation of Schinus molle L. (Anacardiaceae) Essential Oil in Lymphocytes and Macrophages. AB - Schinus molle L. is used to treat various diseases; however, the literature lacks information regarding its possible immunotoxic effects. The aim of the study was to investigate the immunotoxic effects of essential oil from leaves of Schinus molle L. in cultures of human lymphocytes and macrophages. The cultures were treated with essential oil (EO) of Schinus molle L. and subsequently subjected to genotoxic analysis (comet assay), mutagenic analysis (micronucleus frequency and chromosomal aberration), and cytotoxic (cell viability) and functional parameters (interleukins secretions). Our analyses have determined that the essential oil from leaves of Schinus molle L. presents several compounds with alpha-pinene being the major compound; in addition, the compound verbenene was firstly identified; genotoxic effects were detected only in macrophages and only at the two highest concentrations tested. An important finding is that Schinus molle L. oil causes an activation of the immune system. This action has its mechanism centered by the cascade nitric oxide-interleukin-10-tumor necrosis factor alpha. PMID- 30410554 TI - A Network Pharmacology Approach to Uncover the Molecular Mechanisms of Herbal Formula Ban-Xia-Xie-Xin-Tang. AB - Ban-Xia-Xie-Xin-Tang (BXXXT) is a classical formula from Shang-Han-Lun which is one of the earliest books of TCM clinical practice. In this work, we investigated the therapeutic mechanisms of BXXXT for the treatment of multiple diseases using a network pharmacology approach. Here three BXXXT representative diseases (colitis, diabetes mellitus, and gastric cancer) were discussed, and we focus on in silico methods that integrate drug-likeness screening, target prioritizing, and multilayer network extending. A total of 140 core targets and 72 representative compounds were finally identified to elucidate the pharmacology of BXXXT formula. After constructing multilayer networks, a good overlap between BXXXT nodes and disease nodes was observed at each level, and the network-based proximity analysis shows that the relevance between the formula targets and disease genes was significant according to the shortest path distance (SPD) and a random walk with restart (RWR) based scores for each disease. We found that there were 22 key pathways significantly associated with BXXXT, and the therapeutic effects of BXXXT were likely addressed by regulating a combination of targets in a modular pattern. Furthermore, the synergistic effects among BXXXT herbs were highlighted by elucidating the molecular mechanisms of individual herbs, and the traditional theory of "Jun-Chen-Zuo-Shi" of TCM formula was effectively interpreted from a network perspective. The proposed approach provides an effective strategy to uncover the mechanisms of action and combinatorial rules of BXXXT formula in a holistic manner. PMID- 30410558 TI - Shenqi Fuzheng Injection Reverses Cisplatin Resistance through Mitofusin-2 Mediated Cell Cycle Arrest and Apoptosis in A549/DDP Cells. AB - The goal of this evaluation was to examine the mechanisms of Shenqi Fuzheng injection (SFI), an extract made from the plants Radix Astragali and Radix Codonopsis, in the process of chemotherapy sensitivity in non-small-cell lung cancer (NSCLC) cells. We investigated the expression of mitofusin-2 (Mfn2), a mitochondrial GTPase that may be related to chemoresistance, and found that Mfn2 expression was lower in human cisplatin-resistant lung carcinoma A549/DDP cells than in cisplatin-susceptible A549 cells. Chemosensitivity to cisplatin was restored in A549/DDP cells following supplementation in conjunction with SFI treatment, the effect of which we evaluated via cell cycle, apoptosis, and cell signaling analysis. We found that the combined use of A549/DDP cells with SFI and cisplatin enhanced cell cycle arrested in the G2/M phase, which was accompanied by upregulation of p53 and p21 protein expression and induced mitochondrial apoptosis in conjunction with the upregulation of Bax and the downregulation of Bcl-2 protein expression. Moreover, cell cycle arrest and mitochondrial apoptosis coincided with the upregulation of Mfn2 expression, which, in turn, was related to the increased mitochondrial membrane permeabilization and elevated reactive oxygen species. In summary, our findings suggest that the effect of SFI in increasing chemotherapy sensitivity in cisplatin resistance of NSCLCs occurs through cell cycle arrest and the initiation of mitochondrial apoptosis involved in the upregulation of Mfn2 expression. PMID- 30410559 TI - Berberine Combined with Triple Therapy versus Triple Therapy for Helicobacter pylori Eradication: A Meta-Analysis of Randomized Controlled Trials. AB - Objective: To assess the effects and safety of berberine combined with triple therapy on Helicobacter pylori (H. pylori) eradication in adults. Methods: PubMed, MEDLINE, EMBASE, Cochrane Library, and Chinese databases including China National Knowledge Infrastructure (CNKI), Wanfang data, Chinese Technology Journal Full-text Database (VIP), and China biomedical literature database (CBM) were searched to obtain the eligible studies published up to October 10, 2017. The primary outcome was eradication rate of H. pylori. The secondary outcome was incidence of adverse effects. Data analysis was conducted by RevMan5.2 and Stata V.9.0 software. Trial sequential analysis (TSA) was performed to assess the risk of random error and the validity of conclusion with TSA program version 0.9 beta. Results: The meta-analysis results indicated berberine combined with triple therapy could improve the eradication rates of H. pylori (urea breath test subgroup: RR=1.18, 95%CI=(1.12,1.24), P < 0.00001, biopsy subgroup: RR=1.23, 95%CI=(1.13,1.34), P < 0.00001) and reduce the total occurrence of adverse effects (OR=0.59, 95%CI(0.46, 0.75), P < 0.0001) when compared with only using triple therapy. Besides, the incidence of nausea (OR=0.59, 95%CI(0.41, 0.86), P < 0.05) and diarrhea (OR=0.41, 95%CI(0.24, 0.71) was remarkably lower in experimental group while that of abdominal distention (OR=0.64, 95%CI(0.40,1.04), P > 0.05) and vomiting (OR=0.65, 95%CI(0.37, 1.15), P > 0.05) had no significant change. TSA of H. pylori eradication rates and adverse effects incidence illustrated that the cumulative value of Z-curve went across the conventional boundary value, trial sequential monitoring boundary for benefit, and required information size, suggesting the results were stable. Conclusion: Evidence from meta-analysis suggested that berberine combined with triple therapy can be an option for increasing H. pylori eradication rates and reducing overall therapy related adverse effects incidence, particularly nausea and diarrhea, whereas more randomized controlled trials designed according to CONSORT statement are demanded to support the efficacy in further studies. PMID- 30410560 TI - Antioxidant Potential of Herbal Preparations and Components from Galactites elegans (All.) Nyman ex Soldano. AB - Galactites is a genus of flowering plants belonging to Asteraceae family. This genus is mainly represented by the Galactites elegans (All.) Nyman ex Soldano, the milky thistle, a plant of Mediterranean origin. Galactites elegans is consumed as a monofloral boar thistle honey. Chromatography separation of CHCl3 and n-BuOH extracts of aerial parts of G. elegans led to isolation of 18 pure compounds. Their structures were elucidated by 1D-and 2D-NMR spectroscopy and confirmed by mass spectrometry analysis. Sinapic aldehyde, abietin, chlorogenic acid, neochlorogenic acid, 8alpha-hydroxypinoresinol, 9alpha-hydroxypinoresinol, pinoresinol, 4-ketopinoresinol, nortrachelogenin, and erythro-guaiacylglycerol beta-O-4'-dihydroconiferyl alcohol were isolated from CHCl3 extract, while luteolin 4'-O-glucuronide, naringenin-7-O-neohesperidoside, kaempferol-3-O-alpha L-rhamnopyranosyl-(1->6)-beta-D-glucopyranoside, apigenin-7-O-alpha-L rhamnopyranosyl-(1->6)-beta-D-glucopyranoside, quercitrin, quercetin-3-O-alpha-L rhamnopyranosyl-(1->6)-beta-D-glucopyranoside, ciwujiatone, and nortrachelogenin 4,4'-di-O-beta-D-glucopyranoside were obtained from n-BuOH extract. The majority of isolated compounds displayed a significant antioxidant potential in vitro test (DPPH). The ability of compounds to reduce the level of peroxides in control and BHP-treated Jurkat cells was studied. The lignan derivatives were also able to reduce at 50 MUM the basal level of peroxides in Jurkat cells as well as counteract peroxide increase induced by BHP treatment. Particularly 8alpha hydroxypinoresinol was the most active showing 70% of peroxide level inhibition. PMID- 30410561 TI - Correlation study of thyroid nodule cytopathology and histopathology at two institutions in Jordan. AB - Background: Fine-needle aspiration (FNA) plays a fundamental role in determining the appropriate management for patients presenting with thyroid nodules. Aims: The aims of this study are to evaluate thyroid FNA test performance parameters through a cytohistological correlation. Materials and Methods: A retrospective analysis of all thyroid FNAs received over a period of 18 months was carried out. The findings were compared to their subsequent definite diagnoses on surgical specimens as well as to their follow-up repeat FNA results. A total of 499 thyroid FNAs were collected and reviewed against The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). The percentage of each diagnostic category was calculated, and the implied risk of malignancy was determined by comparing the cytology results to their definite diagnoses obtained on the resection specimens. Analytical procedures were performed using Microsoft Excel. Results: Out of 499 thyroid FNAs, a benign interpretation was found in 273 patients (54.7%), atypia of undetermined significance in 81 (16.2%), follicular neoplasm in 20 (4%), suspicious for malignancy in 36 (7.2%), malignant in 32 (6.4%) and were nondiagnostic in 57 patients (11.4%). Only 101 patients (20.2%) underwent surgical resection and 47 (9.4%) underwent a follow-up FNA. After cytohistological correlation, FNA test performance, calculated by excluding the inadequate and undetermined categories revealed test sensitivity, specificity, and diagnostic accuracy of 95.6%, 54.8%, and 78.9%, respectively. The positive predictive value was 75.4%, and the negative predictive value was 89.5%. Conclusions: Our results are comparable to those previously published figures. The rate of atypia of undetermined significance/follicular lesion of undetermined significance is higher than what is currently recommended in TBSRTC. PMID- 30410562 TI - Endometrial carcinoma with pleural fluid metastasis: A rare phenomenon. PMID- 30410563 TI - Cytologic examination of ascitic fluid in a patient with pleural-based mass: A unique presentation of a rare tumor. PMID- 30410564 TI - The seasonal sensitivity of brown bear denning phenology in response to climatic variability. AB - Background: For brown bears (Ursus arctos), hibernation is a critical part of the annual life cycle because energy savings during hibernation can be crucial for overwintering, and females give birth to cubs at that time. For hibernation to be a useful strategy, timing is critical. However, environmental conditions vary greatly, which might have a negative effect on the functionality of the evolved biological time-keeping. Here, we used a long-term dataset (69 years) on brown bear denning phenology recorded in 12 Russian protected areas and quantified the phenological responses to variation in temperature and snow depth. Previous studies analyzing the relationship between climate and denning behavior did not consider that the brown bear response to variation in climatic factors might vary through a period preceding den entry and exit. We hypothesized that there is a seasonal sensitivity pattern of bear denning phenology in response to variation in climatic conditions, such that the effect of climatic variability will be pronounced only when it occurs close to den exit and entry dates. Results: We found that brown bears are most sensitive to climatic variations around the observed first den exit and last entry dates, such that an increase/decrease in temperature in the periods closer to the first den exit and last entry dates have a greater influence on the denning dates than in other periods. Conclusions: Our study shows that climatic factors are modulating brown bear hibernation phenology and provide a further structuring of this modulation. The sensitivity of brown bears to changes in climatic factors during hibernation might affect their ability to cope with global climate change. Therefore, understanding these processes will be essential for informed management of biodiversity in a changing world. PMID- 30410565 TI - Lipid deposition pattern and adaptive strategy in response to dietary fat in Chinese perch (Siniperca chuatsi). AB - Background: Previous studies in teleost have demonstrated the adaptive strategy to maintain hepatic lipid homeostasis within certain limit. The excess of fat intake could induce abnormal lipid deposition in liver but not adipose tissue. However, the molecular mechanism between the impaired lipid homeostasis and the aggravated lipid deposition in liver has not been elucidated well in fish. Methods: Four isonitrogenous diets with different fat levels (2, 7, 12 and 17%) were formulated, named L2, L7, L12 and L17 respectively, and fed Chinese perch (44.50 +/- 0.25 g) to apparent satiation for five weeks. Growth index, triglyceride concentrations and expression of genes involved in lipid metabolism were measured. Results: The maximal growth performance and food intake were observed in L12 group. The lipid content in liver and serum were comparable in L2, L7 and L12 groups, while they were increased significantly in L17 group. Histology analysis also demonstrated that mass lipid droplets emerged in hepatocyte and then induced hepatic steatosis in L17 group. Compared to L2 group, the lipolytic genes related to fatty acids (FAs) transport (lpl & hl) and FAs beta-oxidation (cpt1 & cs) were increased in L7 and L12 group. Relative mRNA levels of the gluconeogenesis (pc, pepck & g6pase) were also increased, in contrast, the lipogenic genes (srebp1, accalpha & fas) were decreased. Compared to L12 group, L17 group had higher mRNA levels of the FAs transport and the lipogenesis. But the lipolytic genes related to FAs beta-oxidation were steady and the mRNA levels of gluconeogenesis were down-regulated instead. Conclusions: Within certain limit, the increase of dietary fat in L7 and L12 group was propitious to reduce the consumption of protein and improve growth performance in Chinese perch. It was due to the homeostasis of hepatic triglyceride (TG) pool and serum glucose through promoting the FAs beta-oxidation and gluconeogenesis respectively. Both the increase of lipogenesis and the absence of FAs beta oxidation in L17 group could trigger the esterification of FAs, indeed, the inhibition of gluconeogenesis could also aggravate triglyceride accumulation in liver and induce hepatic steatosis. PMID- 30410566 TI - Fruits and vegetables intake and its subgroups are related to depression: a cross sectional study from a developing country. AB - Background: The association of fruits and vegetables (FV) specific subgroups consumption and depression has not been investigated in healthy adult populations. Therefore, the aim of our study was to determine the relationship between intake of FV as well as their subgroups and depression. Methods: This cross-sectional study was conducted on 400 women attending healthcare centers. The scores of depression, anxiety, and stress were measured using the 21-item depression, anxiety and stress scales questionnaire. The participants' anthropometric and physical activity data were collected and the 147-item semi quantitative FFQ was used for estimating the FV intake. Results: After adjustment for confounding variables, the participants in the lower quartiles of total FV, total vegetables, total fruits, citrus, other fruits and green leafy vegetables intake were more likely to experience depression compared to those in the higher quartiles (p trend < 0.03). Conclusion: Our findings suggest that higher intake of total FV and some of its specific subgroups might be associated with depression. PMID- 30410567 TI - Whole plant chamber to examine sensitivity of cereal gas exchange to changes in evaporative demand. AB - Background: Improving plant water use efficiency (WUE) is a major target for improving crop yield resilience to adverse climate change. Identifying genetic variation in WUE usually relies on instantaneous measurements of photosynthesis (An) and transpiration (Tr), or integrative measurements of carbon isotope discrimination, at the leaf level. However, leaf gas exchange measurements alone do not adequately represent whole plant responses, especially if evaporative demand around the plant changes. Results: Here we describe a whole plant gas exchange system that can rapidly alter evaporative demand when measuring An, Tr and intrinsic WUE (iWUE) and identify genetic variation in this response. An was not limited by VPD under steady-state conditions but some wheat cultivars restricted Tr under high evaporative demand, thereby improving iWUE. These changes may be ABA-dependent, since the barley ABA-deficient mutant (Az34) failed to restrict Tr under high evaporative demand. Despite higher Tr, Az34 showed lower An than wild-type (WT) barley because of limitations in Rubisco carboxylation activity. Tr and An of Az34 were more sensitive than WT barley to exogenous spraying with ABA, which restricted photosynthesis via substrate limitation and decreasing Rubisco activation. Conclusions: Examining whole plant gas exchange responses to altered VPD can identify genetic variation in whole plant iWUE, and facilitate an understanding of the underlying mechanism(s). PMID- 30410569 TI - Phase Synchronization Dynamics of Neural Network during Seizures. AB - Epilepsy has been considered as a network-level disorder characterized by recurrent seizures, which result from network reorganization with evolution of synchronization. In this study, the brain networks were established by calculating phase synchronization based on electrocorticogram (ECoG) signals from eleven refractory epilepsy patients. Results showed that there was a significant increase of synchronization prior to seizure termination and no significant difference of the transitions of network states among the preseizure, seizure, and postseizure periods. Those results indicated that synchronization might participate in termination of seizures, and the network states transitions might not dominate the seizure evolution. PMID- 30410568 TI - Transient co-expression with three O-glycosylation enzymes allows production of GalNAc-O-glycosylated Granulocyte-Colony Stimulating Factor in N. benthamiana. AB - Background: Expression of economically relevant proteins in alternative expression platforms, especially plant expression platforms, has gained significant interest in recent years. A special interest in working with plants as bioreactors for the production of pharmaceutical proteins is related to low production costs, product safety and quality. Among the different properties that plants can also offer for the production of recombinant proteins, protein glycosylation is crucial since it may have an impact on pharmaceutical functionality and/or stability. Results: The pharmaceutical glycoprotein human Granulocyte-Colony Stimulating Factor was transiently expressed in Nicotiana benthamiana plants and subjected to mammalian-specific mucin-type O-glycosylation by co-expressing the pharmaceutical protein together with the glycosylation machinery responsible for such post-translational modification. Conclusions: The pharmaceutical glycoprotein human Granulocyte-Colony Stimulating Factor can be expressed in N. benthamiana plants via agroinfiltration with its native mammalian specific mucin-type O-glycosylation. PMID- 30410570 TI - Are public hospitals reforming efficiently in West Bank? AB - Background: The structure, function, and capacity of the health care system in the Occupied Palestinian Territories (OPT) had been largely shaped by the complex political history of the country. Since the establishment of the Palestinian Authority in 1994, the reform efforts were subsidized much by the international aids to rebuild the country's institutional capacity. No previous studies have provided a realistic evaluation of Palestinian achievements in the conduct of public healthcare, we examine the relative productive efficiency of public hospitals (their managers' success in the usage of resources) during 2010-2015 within West Bank and Jordan. Then, we estimate the efficiency of policies within which managers operate (the program efficiency) across the two countries. Methods: We employ the Data Envelopment Analysis (DEA) models to distinguish between within-country managerial efficiencies and public policy "program" efficiencies across the two countries. The study follows two key steps, the first step evaluates managerial efficiencies and explores trends in performance within each country. Then, we examine the program efficiencies across the two countries. Results: Public hospitals improved their year-specific overall efficiency from 75 to 80% in the West Bank and from 78 to 86% in Jordan in 2010 and 2015 respectively. Changes in efficiency are driven by scale effects in West Bank and by managerial enhancements in Jordan. Program efficiency in West Bank outperformed Jordan during 2010-2012, there was no significant difference in mean program efficiencies between the two countries during 2013-2015. Conclusions: This work addresses a gap in the DEA literature by empirically investigating the efficiency of public hospitals as distinct from program efficiency in a developing country, namely, Palestine. Findings stimulate hospital managers to enhance potential improvements, policymakers to allocate resources, and international donors to focus on the right adoption of new technology to get better benefits from their considerable investments in public hospitals. PMID- 30410571 TI - Feasibility and acceptability of strategies to address mental health and mental ill-health in the Australian coal mining industry. AB - Background: To evaluate the feasibility, acceptability and effectiveness of implementing a peer-based, multi-component mental health program in the Australian coal mining industry. Methods: The multicomponent program included MATES in mining (a peer-based mental health and suicide prevention program) and supervisor training. Eight Australian coal mines participated in the research, with four mines receiving the mental health program. Primary outcome variables including mental health stigma, help-seeking behaviour and perception of the workplace commitment to mental health were measured prior to program implementation, and then again 10 months following using a paper based survey. Process evaluation of the mental health program was measured using a pre test/post-test survey. Results: MATES in mining 1275 miners participated in the MATES general awareness and connector training. Participants were more confident that they could identify a workmate experiencing mental ill-health; help a workmate, family member or themselves identify where to get support and were more willing to start a conversation with a workmate about their mental health. Supervisor training 117 supervisors completed the supervisor training and were subsequently more confident that they could: identify someone experiencing mental ill-health in the workplace; identify and recommend support services to a person experiencing mental ill-health; and have an effective conversation about performance issues that may be due to mental ill-health. Conclusions: Our findings show evidence to support the use of peer-based mental health programs in the mining industry, and for male-dominated industry more broadly. PMID- 30410572 TI - Correction to: Somatic symptom and related disorders in children and adolescents: evaluation of a naturalistic inpatient multidisciplinary treatment. AB - [This corrects the article DOI: 10.1186/s13034-018-0239-y.]. PMID- 30410573 TI - A novel FC17/CESA4 mutation causes increased biomass saccharification and lodging resistance by remodeling cell wall in rice. AB - Background: Rice not only produces grains for human beings, but also provides large amounts of lignocellulose residues, which recently highlighted as feedstock for biofuel production. Genetic modification of plant cell walls can potentially enhance biomass saccharification; however, it remains a challenge to maintain a normal growth with enhanced lodging resistance in rice. Results: In this study, rice (Oryza sativa) mutant fc17, which harbors the substitution (F426S) at the plant-conserved region (P-CR) of cellulose synthase 4 (CESA4) protein, exhibited slightly affected plant growth and 17% higher lodging resistance compared to the wild-type. More importantly, the mutant showed a 1.68-fold enhancement in biomass saccharification efficiency. Cell wall composition analysis showed a reduction in secondary wall thickness and cellulose content, and compensatory increase in hemicelluloses and lignin content. Both X-ray diffraction and calcofluor staining demonstrated a significant reduction in cellulose crystallinity, which should be a key factor for its high saccharification. Proteomic profiling of wild-type and fc17 plants further indicated a possible mechanism by which mutation induces cellulose deposition and cell wall remodeling. Conclusion: These results suggest that CESA4 P-CR site mutation affects cell wall features especially cellulose structure and thereby causes enhancement in biomass digestion and lodging resistance. Therefore, CESA4 P-CR region is promising target for cell wall modification to facilitate the breeding of bioenergy rice. PMID- 30410574 TI - Refined soybean oil wastewater treatment and its utilization for lipid production by the oleaginous yeast Trichosporon fermentans. AB - Background: The release of refined soybean oil wastewater (RSOW) with a high chemical oxygen demand (COD) and oil content burdens the environment. The conversion of RSOW into lipids by oleaginous yeasts may be a good way to turn this waste into usable products. Results: The oleaginous yeast Trichosporon fermentans was used for treating the RSOW without sterilization, dilution, or nutrient supplementation. It was found that the COD and oil content of the RSOW were removed effectively; microbial oil was abundantly produced in 48 h; and the phospholipids in the RSOW tended to contribute to a higher biomass and microbial lipid content. With Plackett-Burman design and response surface design experiments, the optimal wastewater treatment conditions were determined: temperature 28.3 degrees C, amount of inoculum 5.9% (v/v), and initial pH 6.1. The optimized conditions were used in a 5-L bioreactor to treat the RSOW. The maximum COD degradation of 94.7% was obtained within 40 h, and the removal of the oil content was 89.9%. The biomass was 7.9 g/L, the lipid concentration was 3.4 g/L, and the lipid content was 43% (w/w). The microbial oil obtained, with a main component of unsaturated fatty acids, was similar to vegetable oils and was suggested as a potential raw material for biodiesel production. Conclusion: Trichosporon fermentans can be effectively used for RSOW treatment, and lipid production and can complete pretreatment and biochemical treatment simultaneously, allowing the utilization of RSOW, which both solves an environmental problem and positively impacts the use of resources. These results provide valuable information for developing and designing more efficient waste into-lipid bioprocesses. PMID- 30410575 TI - Firmicutes-enriched IS1447 represents a group of IS3-family insertion sequences exhibiting unique + 1 transcriptional slippage. AB - Background: Bacterial insertion sequences (ISs) are ubiquitous mobile genetic elements that play important roles in genome plasticity, cell adaptability, and function evolution. ISs of various families and subgroups contain significantly diverse molecular features and functional mechanisms that are not fully understood. Results: IS1447 is a member of the widespread IS3 family and was previously detected to have transposing activity in a typical thermophilic and cellulolytic microorganism Clostridium thermocellum. Phylogenetic analysis showed that IS1447-like elements are widely distributed in Firmicutes and possess unique features in the IS3 family. Therefore, IS1447 may represent a novel subgroup of the IS3 family. Unlike other well-known IS3 subgroups performing programmed - 1 translational frameshifting for the expression of the transposase, IS1447 exhibits transcriptional slippage in both the + 1 and - 1 directions, each with a frequency of ~ 16%, and only + 1 slippage results in full-length and functional transposase. The slippage-prone region of IS1447 contains a run of nine A nucleotides following a stem-loop structure in mRNA, but mutagenesis analysis indicated that seven of them are sufficient for the observed slippage. Western blot analysis indicated that IS1447 produces three types of transposases with alternative initiations. Furthermore, the IS1447-subgroup elements are abundant in the genomes of several cellulolytic bacteria. Conclusion: Our result indicated that IS1447 represents a new Firmicutes-enriched subgroup of the IS3 family. The characterization of the novel IS3-family member will enrich our understanding of the transposition behavior of IS elements and may provide insight into developing IS-based mutagenesis tools for thermophiles. PMID- 30410577 TI - Dexamethasone and postoperative hyperglycemia in diabetics undergoing elective hip or knee arthroplasty: a case control study in 238 patients. AB - Background: Dexamethasone has been routinely used in the pre-operative setting to enhance analgesia and decrease the incidence of nausea and vomiting in patients undergoing primary arthroplasty. However, dexamethasone has the potential to increase blood glucose levels postoperatively, which is a known risk factor for complications after total joint arthroplasty. The aim of this study was to analyze the effect of dexamethasone administration on post-operative blood glucose levels in diabetic patients after primary hip and knee arthroplasty. Methods: This study was a retrospective review of 238 diabetic patients who underwent primary hip and knee arthroplasty between May 1, 2014 and September 30, 2016 at a single urban academic medical center. A total of 77 patients (32.4%) received dexamethasone and 161 (67.7%) did not. Oral hyperglycemic agents were held during the inpatient stay and blood glucose was controlled either with sliding scale insulin or home insulin regimens were continued. All analyses were adjusted for age, BMI, gender, type of diabetes, pre-operative diabetic medication, type of surgical procedure, and pre-operative HgbA1c level. The primary outcome was post-operative hyperglycemia within 72 h of surgery defined as any blood glucose level greater than or equal to 200 mg/dL. Results: Post operative hyperglycemia was observed in 17.1 and 20.6% of the measurements during the first 24 and 72 h respectively. After controlling for confounding variables, patients who received dexamethasone had 4.07 (95% CI: 2.46, 6.72) and 3.08 (95% CI: 2.34, 4.04) higher odds of post-operative hyperglycemia in the first 24 and 72 h respectively. Conclusions: Dexamethasone administration in diabetic patients undergoing primary arthroplasty increases post-operative hyperglycemia during the first 24 and 72 h. While our data did not investigate causation, dexamethasone use in this patient population should be thoughtfully considered, as post operative hyperglycemia is a known risk factor for complications. PMID- 30410576 TI - The physiological effect of heavy metals and volatile fatty acids on Methanococcus maripaludis S2. AB - Background: Methanogenic archaea are of importance to the global C-cycle and to biological methane (CH4) production through anaerobic digestion and pure culture. Here, the individual and combined effects of copper (Cu), zinc (Zn), acetate, and propionate on the metabolism of the autotrophic, hydrogenotrophic methanogen Methanococcus maripaludis S2 were investigated. Cu, Zn, acetate, and propionate may interfere directly and indirectly with the acetyl-CoA synthesis and biological CH4 production. Thus, these compounds can compromise or improve the performance of M. maripaludis, an organism which can be applied as biocatalyst in the carbon dioxide (CO2)-based biological CH4 production (CO2-BMP) process or of methanogenic organisms applied in anaerobic digestion. Results: Here, we show that Cu concentration of 1.9 umol L-1 reduced growth of M. maripaludis, whereas 4.4 and 6.3 umol L-1 of Cu even further retarded biomass production. However, 1.0 mmol L-1 of Zn enhanced growth, but at Zn concentrations > 2.4 mmol L-1 no growth could be observed. When both, Cu and Zn, were supplemented to the medium, growth and CH4 production could even be observed at the highest tested concentration of Cu (6.3 umol L-1). Hence, it seems that the addition of 1 mmol L-1 of Zn enhanced the ability of M. maripaludis to counteract the toxic effect of Cu. The physiological effect to rising concentrations of acetate (12.2, 60.9, 121.9 mmol L-1) and/or propionate (10.3, 52.0, 104.1 mmol L-1) was also investigated. When instead of acetate 10.3 mmol L-1 propionate was provided in the growth medium, M. maripaludis could grow without reduction of the specific growth rate (u) or the specific CH4 productivity (qCH4). A combination of inorganic and/or organic compounds resulted in an increase of u and qCH4 for Zn/Cu and Zn/acetate beyond the values that were observed if only the individual concentrations of Zn, Cu, acetate were used. Conclusions: Our study sheds light on the physiological effect of VFAs and heavy metals on M. maripaludis. Differently from u and qCH4, MER was not influenced by the presence of these compounds. This indicated that each of these compounds directly interacted with the C-fixation machinery of M. maripaludis. Until now, the uptake of VFAs other than acetate was not considered to enhance growth and CH4 production of methanogens. The finding of propionate uptake by M. maripaludis is important for the interpretation of VFA cycling in anaerobic microenvironments. Due to the importance of methanogens in natural and artificial anaerobic environments, our results help to enhance the understanding the physiological and biotechnological importance with respect to anaerobic digestion, anaerobic wastewater treatment, and CO2-BMP. Finally, we propose a possible mechanism for acetate uptake into M. maripaludis supported by in silico analyses. PMID- 30410578 TI - Safety and efficacy of a two-screw cephalomedullary nail for intertrochanteric femur fracture fixation: a retrospective case series in 264 patients. AB - Introduction: Recent advances have led to the design of a new cephalomedullary nail, which aims to decrease the risk of failures in patients with intertrochanteric hip fractures by allowing for insertion of two interdigitating screws into the head segment. The goal of this study is to evaluate the safety and efficacy of this two-screw cephalomedullary nailing system. Patients/participants: Patients 18 years of age and older who underwent intramedullary nailing of their intertrochanteric femoral fracture using the InterTAN nailing system (Smith and Nephew, Memphis, TN) from 2012 to 2016 were included in this retrospective study which was performed at two urban certified level-1 trauma centers and one urban certified level-3 trauma center. The study data was collected through a retrospective chart review and review of the existing radiographic studies. Primary outcome measure was mechanical hardware failure and screw cutout. Secondary outcome measures included nonunion, malunion, medical and surgical complications. Results: A total of 264 patients were included in this analysis. Two patients (0.75%) were found to have a screw cut out requiring revision surgery. Two other revision surgeries were performed for malrotation (n = 1) and malunion (n = 1). Other implant-related complications occurred in 19 cases (7.9%), which included broken distal screws (n = 9), distal screw loosening (n = 8), and loose lag screws (n = 2). There was a total of 10 (3.8%) surgical wound complications, including four deep and six superficial infections. Discussion: This modified cephalomedullary nail is a reliable, safe, and effective implant for management of intertrochanteric hip fractures. Surgical treatment of patients with intertrochanteric hip fractures can be performed in a safe fashion using this implant. PMID- 30410579 TI - Cytogenomic characterization of 1q43q44 deletion associated with 4q32.1q35.2 duplication and phenotype correlation. AB - Background: Microdeletion of 1q43q44 causes a syndrome characterized by intellectual disability (ID), speech delay, seizures, microcephaly (MIC), corpus callosum abnormalities (CCA) and characteristic facial features. Duplication of 4q is presented with minor to severe ID, MIC and facial dysmorphism. We aimed to verify the correlation between genotype/phenotype in a patient with 1q43q44 deletion associated with 4q32.1q35.2 duplication. Case presentation: We report on a 3 year-old female patient with delayed motor and mental milestones, MIC and facial dysmorphism. She is a child of non-consanguineous parents and no similarly affected family members. CT brain showed abnormal gyral patterns, hypogenesis of corpus callosum and bilateral deep Sylvian fissure. Electroencephalogram showed frontotemporal epileptogenic focus. Her karyotype was revealed as 46,XX,add(1)(q44). Fluorescence in situ hybridization (FISH) using whole chromosome paint (WCP1) and subtelomere 1q revealed that the add segment was not derived from chromosome 1 and there was the deletion of subtelomere 1q. Multiple ligation probe amplification (MLPA) subtelomere kit revealed the deletion of 1q and duplication of 4q. Array CGH demonstrated the 6.5 Mb deletion of 1q and 31 Mb duplication of chromosome 4q. Conclusion: The phenotype of our patient mainly reflects the effects of haploinsufficiency of AKT3, HNRNPU, ZBTB18 genes associated with duplication of GLRA3, GMP6A, HAND2 genes. Patients presented with ID, seizures, MIC together with CCA are candidates for prediction of 1q43q44 microdeletion and cytogenomic analysis. PMID- 30410580 TI - Transition-transversion encoding and genetic relationship metric in ReliefF feature selection improves pathway enrichment in GWAS. AB - Background: ReliefF is a nearest-neighbor based feature selection algorithm that efficiently detects variants that are important due to statistical interactions or epistasis. For categorical predictors, like genotypes, the standard metric used in ReliefF has been a simple (binary) mismatch difference. In this study, we develop new metrics of varying complexity that incorporate allele sharing, adjustment for allele frequency heterogeneity via the genetic relationship matrix (GRM), and physicochemical differences of variants via a new transition/transversion encoding. Methods: We introduce a new two-dimensional transition/transversion genotype encoding for ReliefF, and we implement three ReliefF attribute metrics: 1.) genotype mismatch (GM), which is the ReliefF standard, 2.) allele mismatch (AM), which accounts for heterozygous differences and has not been used previously in ReliefF, and 3.) the new transition/transversion metric. We incorporate these attribute metrics into the ReliefF nearest neighbor calculation with a Manhattan metric, and we introduce GRM as a new ReliefF nearest-neighbor metric to adjust for allele frequency heterogeneity. Results: We apply ReliefF with each metric to a GWAS of major depressive disorder and compare the detection of genes in pathways implicated in depression, including Axon Guidance, Neuronal System, and G Protein-Coupled Receptor Signaling. We also compare with detection by Random Forest and Lasso as well as random/null selection to assess pathway size bias. Conclusions: Our results suggest that using more genetically motivated encodings, such as transition/transversion, and metrics that adjust for allele frequency heterogeneity, such as GRM, lead to ReliefF attribute scores with improved pathway enrichment. PMID- 30410581 TI - A fast forward 3D connection algorithm for mitochondria and synapse segmentations from serial EM images. AB - Background: It is becoming increasingly clear that the quantification of mitochondria and synapses is of great significance to understand the function of biological nervous systems. Electron microscopy (EM), with the necessary resolution in three directions, is the only available imaging method to look closely into these issues. Therefore, estimating the number of mitochondria and synapses from the serial EM images is coming into prominence. Since previous studies have achieved preferable 2D segmentation performance, it holds great promise to obtain the 3D connection relationship from the 2D segmentation results. Results: In this paper, we improve upon Matlab's function bwconncomp and propose a fast forward 3D connection algorithm for mitochondria and synapse segmentations from serial EM images. To benchmark the performance of the proposed method, two EM datasets with the annotated ground truth are produced for mitochondria and synapses, respectively. Experimental results show that the proposed method can achieve the preferable connection performance that closely matches the ground truth. Moreover, it greatly reduces the computational burden and alleviates the memory requirements compared with the function bwconncomp. Conclusions: The proposed method can be deemed as an effective strategy to obtain the 3D connection relationship from serial mitochondria and synapse segmentations. It is helpful to accurately and quickly quantify the statistics of the numbers, volumes, surface areas, and lengths, which will greatly facilitate the data analysis of neurobiology research. PMID- 30410582 TI - Association of sleep duration with metabolic syndrome and its components in children and adolescents; a propensity score-matched analysis: the CASPIAN-V study. AB - Objective: This study aims to evaluate the association of sleep duration with metabolic syndrome (MetS) and its components in a pediatric population. Methods: This multi-centric cross-sectional study was conducted in 2015 in 30 provinces of Iran. Participants consisted of 4200 school students aged 7-18 years, studied in a national school-based surveillance program (CASPIAN-V). Physical examinations and laboratory tests were performed using standard protocols. The analysis was conducted based on the propensity score matching and conditional logistic regression was used to evaluate the association of short sleep (less than 8 h a day) and the onset of sleep with MetS and its components. Results of conditional logistic regression was reported as odds ratios (OR) and 95% confidence intervals (CI). Results: Overall, 3843 of participants completed the survey (response rate: 91.5%). Their mean (SD) age was 12.3 (3.2) years and 50.6% were boys. In the multivariate model, individuals who slept less than 8 h a day had significantly higher odds of MetS (OR 2.05, 95% CI 1.19-3.63) and high blood pressure (BP) (OR 1.46, 95% CI 1.04-2.06). Association between short sleep duration with other MetS components (including abdominal obesity, hypertriglyceridemia, hyperglycemia, and low levels of high-density lipoprotein-cholesterol was not statistically significant (P > 0.05). Moreover, association between the onset of sleep with MetS and its components was not statistically significant (P > 0.05). Conclusion: Short sleep duration is associated with increased risk of MetS and high BP in children and adolescents. The clinical impact of current findings should be assessed in future longitudinal studies. PMID- 30410583 TI - LIPC variants as genetic determinants of adiposity status, visceral adiposity indicators, and triglyceride-glucose (TyG) index-related parameters mediated by serum triglyceride levels. AB - Background: Visceral adiposity indicators and the product of triglyceride and fasting plasma glucose (TyG) index-related parameters are effective surrogate markers for insulin resistance (IR) and are predictors of metabolic syndrome and diabetes mellitus. However, their genetic determinants have not been previously reported. Pleiotropic associations of LIPC variants have been observed in lipid profiles and atherosclerotic cardiovascular diseases. We aimed to investigate LIPC polymorphisms as the genetic determinants of adiposity status, visceral adiposity indicators and TyG index-related parameters. Methods: A total of 592 participants from Taiwan were genotyped for three LIPC single nucleotide polymorphisms (SNPs). Results: The LIPC SNPs rs2043085 and rs1532085 were significantly associated with body mass index (BMI), waist circumference (WC), lipid accumulation product, visceral adiposity index, and TyG index-related parameters [including the TyG index, TyG with adiposity status (TyG-BMI), and TyG WC index], whereas the rs1800588 SNP was only significantly associated with the TyG index. The associations became nonsignificant after further adjustment for serum TG levels. No significant association was observed between any the studied LIPC SNPs and IR status. Conclusion: Our data revealed a pleiotropic association between the LIPC variants and visceral adiposity indicators and TyG index-related parameters, which are mediated by serum TG levels. PMID- 30410584 TI - The value of long noncoding RNA CASC2 as a biomarker of prognosis in carcinomas: a meta-analysis. AB - Lnc RNA Cancer Susceptibility Candidate 2(CASC2) has been shown to be aberrantly expressed in multiple types of cancer and might serve as a prognosis biomarker. The present meta-analysis was conducted to investigate whether the expression of CASC2 was associated with prognosis or clinicopathological features in correlative cancers. A total of 11 studies with 765 cancer patients were included by searching the electronic databases, the results found a significant association between high expression of CASC2 and longer OS in cancer patients (HR=0.43, 95% CI: 0.33-0.55, P =0.000).In addition, a significant correlation was observed between high level of CASC2 and earlier TNM stage(OR = 0.30, 95% CI =0.21-0.43, P < 0.001), smaller tumor size(OR = 0.28, 95% CI =0.12-0.66, P =0.004), better tumor differentiation(OR = 0.42, 95% CI =0.27-0.66, P =0.0002). In conclusion, CASC2 can serve as a novel marker predicting the prognosis and clinicopathological features in various cancers. PMID- 30410585 TI - Retroperitoneal dedifferentiated liposarcoma: Analysis of 61 cases from a large institution. AB - Background: To describe the clinical features of retroperitoneal dedifferentiated liposarcoma (RP DDLS) and further evaluate the prognostic factors. Methods: The clinicopathological variables and treatment strategies of 61 RP DDLS patients who underwent surgical resections at a single institution between September 2005 and September 2016 were reviewed. Kaplan-Meier and Cox regression methods were conducted for survival analyses. Results: The average patients' age was 52 years (range, 27-81), and there was almost no gender predilection (30 males vs. 31 females). 51 (83.6%) patients got gross tumor resections (R0/R1 resection), and the median tumor size was 19 cm (range, 4.3-50 cm). 39(63.9%) patients were with intermediate-grade sarcoma and 22(36.1%) were with high-grade sarcoma. The median intraoperative blood loss was 400 ml (range, 50-2700ml). 19 (31.1%) patients presented multifocal diseases. Tumors were removed intactly in 42 (68.9%) patients. In order to obtain gross tumor resections, 33 (54.1%) of the patients underwent excisions of at least one adjacent organ, of which kidney (n=21, 63.6%) was the most common one. 6 (9.8%) patients developed distant metastases during follow-up. The overall 5-year progression-free survival (PFS) rate was 3.7%, with the median PFS of 19 months. The 5-year overall survival (OS) rate was 43.5%, with the median OS of 58 months. Updating to November 2017, 30 (49.2%) patients remained alive. The median follow-up time was 49 months. Multivariate analysis using Cox proportional hazards model revealed that tumor grade, blood loss, resection extent, and tumor integrity were independently associated with OS (p=0.032, p=0.018, p=0.020, p=0.005, respectively). Tumor grade, tumor integrity and multifocality were significant predictors for PFS (p=0.013, p=0.080, p=0.009, p=0.028, respectively). Conclusion: Intermediate-grade histology, intraoperative blood loss < 400 ml, complete tumor resection, and tumor integrity were independently associated with better OS. Intermediate-grade histology, tumor integrity and unifocal disease independently predicted favorable PFS. PMID- 30410586 TI - S100A4-MYH9 Axis Promote Migration and Invasion of Gastric Cancer Cells by Inducing TGF-beta-Mediated Epithelial-Mesenchymal Transition. AB - Driver genes conducing to peritoneal metastasis in advanced gastric cancer remain to be clarified. S100A4 is suggested to evolve in metastasis of gastrointestinal cancer, we aim to explore the role of S100A4 plays in metastasis of advanced gastric cancer and the potential mechanism. Transfection of siRNA or cDNA was applied to alter the expression of protein S100A4 and MYH9, investigation of the expression of epithelial and mesenchymal transition (EMT) associated markers was followed. Cell migration assay was used to screen the alteration of migration ability regulated by S100A4 and MYH9. IHC analysis for tissue sample microarray was performed to reveal their relationship with clinical pathological parameters and potential capacity of predicting survival. Consistent overexpression of S100A4 and MYH9 were found in peritoneal metastasis and primary site compared with adjacent normal tissue. Low expression of S100A4 led to increased epithelial markers as wells as decline of mesenchymal makers, while overexpression of S100A4 led to inverse impact. S100A4 expression was closely correlated with increased migration ability and EMT process induced by TGF-beta stimulation. Interference of S100A4 led to downregulation of MYH9 and inactivation of Smad pathway through participating in EMT process, which could be reversed by overexpression of MYH9. Moreover, co-expression of S100A4 and MYH9 was identified in tissue microarray and confirmed by immunofluorescence assay. In conclusion, overexpression of S100A4 and downstream molecular MYH9 in advanced gastric cancer predicted poor prognosis; oncogene S100A4 facilitate EMT process induced by TGF-beta stimulation, suggesting a potential target in management of peritoneal metastasis of gastric cancer. PMID- 30410587 TI - Prolonging Gastrointestinal-Stromal-Tumor-free life, an optimal suggestion of imatinib intervention ahead of operation. AB - Background: Imatinib has been regarded as the first successful synthetic small molecule targeting at blocking tyrosine kinase. Its high efficacy stabilized disease in above 80% of chronic myeloid leukemia (CML) patients over 10 years survival. Due to the similar canceration of gastrointestinal stromal tumor (GIST) as to CML, imatinib has been approved to be used as first-line treatment. Study design: Our retrospective study was proposed to enroll 191 GIST patients with larger tumor size (>=8 cm) who preoperative accepted imatinib from those with direct operation. Analysis included demographics, cancer specific survival and relationship of their risk factors. Results: Male patients and gastrointestinal (GI) tract location took higher proportion in total cases, detection of KIT mutant took 89.7% among all traceable genetic testing. Patients with preoperative imatinib can achieve higher cancer specific survival (CSS) after both in 1 year and 3 years duration than their counterpart. Tumor size above its threshold of 8 cm would be a hazardous factor for poor prognosis. Conclusion: In conclusion, as for regressing tumor progression and creating operative chance, preoperative imatinib should be considered for the patients with high risk, although the precise duration of this intervention needs further validation. PMID- 30410588 TI - Runs of homozygosity associate with decreased risks of lung cancer in never smoking East Asian females. AB - Although genome-wide association studies (GWASs) have identified some risk single nucleotide polymorphisms in East Asian never-smoking females, the unexplained missing heritability is still required to be investigated. Runs of homozygosity (ROHs) are thought to be a type of genetic variation acting on human complex traits and diseases. We detected ROHs in 8,881 East Asian never-smoking women. The summed ROHs were used to fit a logistic regression model which noteworthily revealed a significant association between ROHs and the decreased risk of lung cancer (P < 0.05). We identified 4 common ROHs regions located at 2p22.1, which were significantly associated with decreased risk of lung cancer (P = 2.00 * 10-4 - 1.35 * 10-4). Functional annotation was conducted to investigate the regulatory function of ROHs. The common ROHs were overlapped with potential regulatory elements, such as active epigenome elements and chromatin states in lung-derived cell lines. SOS1 and ARHGEF33 were significantly up-regulated as the putative target genes of the identified ROHs in lung cancer samples according to the analysis of differently expressed genes. Our results suggest that ROHs could act as recessive contributing factors and regulatory elements to influence the risk of lung cancer in never-smoking East Asian females. PMID- 30410589 TI - microRNA biomarkers in colorectal cancer liver metastasis. AB - Liver metastasis is a primary factor of prognosis and long-term survival for patients diagnosed with colorectal cancer (CRC). Colorectal cancer liver metastasis (CRCLM), is a complex biological process involving multiple factors and steps, and its mechanisms are yet to be discovered. In recent years, small noncoding RNAs, especially microRNAs (miRNAs) have been proven to play an important role in tumorigenesis, progression and metastasis in a variety of cancers, including CRC. Increasing evidence suggests that miRNAs, including those from exosomes secreted by tumor cells in circulation, could be used as promising biomarkers in early cancer detection, treatment, and prognosis. In this review, we focus on the functional roles and clinical applications of miRNAs, especially those from circulating exosomes secreted by tumor cells related to CRCLM. PMID- 30410592 TI - Classification of Solitary Plasmacytoma, Is it more Intricate than Presently Suggested? A Commentary. AB - A query regarding the definition and the classification of solitary plasmacytoma is apparently still pending. The clinical course, the response to treatment and the propensity to progress to plasma cell myeloma, are all a function of the classification which must be established on a firm basis. Solitary plasmacytoma should be recognized in the continuum of the plasma cell neoplasms. Moreover, whether the solitary plasmacytoma of bone and the extramedullary type of the tumor represent two distinct disease entities, exhibiting separate biological characteristics, has not been finally established. To appraise the similarities and differences between these two types of lesion, we have scrutinized recent investigations relating their classification. A commentary highlighting our conclusions follows. PMID- 30410591 TI - Impact of the Receptor for Advanced Glycation End Products Genetic Polymorphisms on the Progression in Uterine Cervical Cancer. AB - To date, few studies have explored the effects of single nucleotide polymorphisms (SNPs) of the receptor for advanced glycation end products (RAGE) in uterine cervical cancer. Therefore, we conducted this study to investigate the involvement of RAGE SNPs in cervical cancer. In total, 117 patients with cervical invasive cancer, 84 with precancerous lesions, and 320 normal women were recruited consecutively. Real-time polymerase chain reaction was used to examine the genotypic frequencies of RAGE SNPs. The results indicated that among the four RAGE SNPs, only the GT/TT genotype of rs184003 was distributed differently between patients with cervical neoplasias and the normal controls, with GG as a reference. Moreover, cervical cancer patients with genotypes TA/AA in rs1800624 exhibited a lower risk of parametrium invasion, moderate-to-poor cell differentiation, and pelvic lymph node metastasis. In conclusion, RAGE SNPs rs1800624 was associated with some clinicopathological variables in cervical cancer. PMID- 30410590 TI - Ethanol Enhances Estrogen Mediated Angiogenesis in Breast Cancer. AB - Angiogenesis, a highly regulated process, is exploited by tumors like breast cancer to ensure a constant supply of oxygen and nutrients and is key for tumor survival and progression. Estrogen and alcohol independently have been observed to contribute to angiogenesis in breast cancer but their combinatorial effects have never been evaluated. The exact mechanism by which estrogen and alcohol contribute to breast cancer angiogenesis remains to be elucidated. In this study, we defined the in vitro effects of the combination of estrogen and alcohol in breast cancer angiogenesis using the tubulogenesis and scratch wound assays. Conditioned media, generated by culturing the murine mammary cancer cell line, TG1-1, in estrogen and ethanol, enhanced tubule formation and migration as well as modulated the MAP Kinase pathway in the murine endothelial cell line, SVEC4 10. Additionally, estrogen and ethanol in combination enhanced the expression of the pro-angiogenic factors VEGF, MMP-9, and eNOS, and modulated Akt activation. These observations suggest that TG1-1 cells secrete pro-angiogenic molecules in response to the combination of estrogen and ethanol that modulate the morphological and migratory properties of endothelial cells. The data presented in this study, is the first in attempting to link the cooperative activity between estrogen and ethanol in breast cancer progression, underscoring correlations first made by epidemiological observations linking the two. PMID- 30410593 TI - The Role of CXCL12 Axis in Lung Metastasis of Colorectal Cancer. AB - This study aimed to explore the mechanism of lung metastases of colorectal cancer. The expression of CXCR4, CXCR7, and CXCL12 in colorectal cancer and lung metastases was analyzed by the immunohistochemical (IHC) method. Further, the study aimed at getting new insights into the role of CXCL12 in lung metastasis. A total of 41 patients who underwent surgical resections for both colorectal cancer and lung metastasis were retrospectively selected for this study. Also, 41 patients who underwent lung resection for benign lung disease were selected as the control group. In the in vivo experiment, the mice were injected with exosomes isolated from CT26. The mice with and without injection were sacrificed 3 weeks later. The lung tissue was analyzed by the IHC method and quantitative real-time PCR. The expression of CXCR7 and CXCL12 was significantly higher in lung metastases than in paired primary lesions. The expression of CXCL12 was significantly higher in the noncancerous lung tissue of patients with CRC than in patients with benign lung disease. Also, the expression of CXCL12 in the lung was higher in mice with exosome education. The results inferred that the expression of CXCR7 and CXCL12 was significantly higher in lung metastases than in primary tumors. Their combination could promote colorectal cancer lung metastasis. The expression of CXCL12 was elevated before metastasis. And this effect was induced by exosomes. PMID- 30410594 TI - Prognostic Value of Plasma Fibrinogen in Lung Cancer Patients: A Meta-Analysis. AB - Background: The prognostic role of plasma fibrinogen in lung cancer remains controversial. The aim of this meta-analysis was to assess the prognostic value of plasma fibrinogen in lung cancer. Methods: We performed a systematic literature search to identify eligible studies in PubMed, Embase and the Cochrane Library database. The hazard ratios (HR) and their 95% confidence intervals (CI) were collected from these eligible studies and were used to assess the relationship between plasma fibrinogen and lung cancer. Results: A total of 16 studies including 6,881 patients were selected in this meta-analysis. The results showed that elevated plasma fibrinogen in lung cancer patients was correlated with poor overall survival (OS) (HR = 1.38, 95% CI: 1.22-1.55, P < 0.001) and disease-free survival (DFS) / progress-free survival (PFS). (HR = 1.29, 95% CI: 1.01-1.65, P = 0.042). When stratified by cut-off value for OS and DFS/PFS, there was no significant heterogeneity. And the results of "cut-off value >= 400mg/dl" group showed that the high level of fibrinogen in serum was associated with worse OS and DFS/PFS of lung cancer. In further subgroup analysis by tumor histology, high plasma fibrinogen was also associated with worse OS in non-small cell lung cancer (NSCLC) (HR = 1.32, 95% CI: 1.14-1.53, P < 0.001). However, there was no significant association between high plasma fibrinogen and poor DFS in NSCLC patients (HR = 1.24, 95% CI: 0.97-1.57, P = 0.08). The Egger's regression test indicated evidence of publication bias for DFS/PFS. Conclusions: Elevated plasma fibrinogen, particularly defined as a plasma fibrinogen concentration of >= 400mg/dl, could be a promising indicator for worse OS in lung cancer patients, including NSCLC. PMID- 30410596 TI - A Prognostic Nomogram for Cervical Cancer after Surgery from SEER Database. AB - Background: To develop and validate a nomogram based on the conventional measurements and log of odds between the number of positive lymph node and the number of negative lymph node (LODDS) in predicting prognosis for cervical cancer patients after surgery. Methods: A total of 8202 cervical cancer patients with pathologically confirmed between 2004 and 2014 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. All the patients were divided into training (n=3603) and validation (n=4599) cohorts based on consecutive age of diagnosis. Demographic and clinical pathological factors were evaluated the association with overall survival (OS). Parameters significantly correlating with OS were used to create a nomogram. An independent external validation cohort was subsequently used to assess the predictive performance of the model. Results: In the training set, age at diagnosis, race, marital status, tumor grade, FIGO stage, histology, size and LODDS were correlated significantly with outcome and used to develop a nomogram. The calibration curve for probability of survival showed excellent agreement between prediction by nomogram and actual observation in the training cohort, with a bootstrap-corrected concordance index of 0.749(95% CI, 0.731-0.767). Importantly, our nomogram performed favorably compared to the currently utilized FIGO model, with concordance indices of 0.786 (95% CI, 0.764 to 0.808) vs 0.685 (95%CI, 0.660 to 0.710) for OS in the validation cohort, respectively. Conclusions: By incorporating LODDS, our nomogram may be superior to the currently utilized FIGO staging system in predicting OS in cervical cancer patients after surgery. PMID- 30410597 TI - FEZF1 is an Independent Predictive Factor for Recurrence and Promotes Cell Proliferation and Migration in Cervical Cancer. AB - The Fez family zinc finger protein 1 (FEZF1), a critical transcription factor in nervous system development, has been implicated in cancer progression recently. However, its clinical significance remains unknown. By analyzing gene expression data of eight most common cancer types from The Cancer Genome Atlas (TCGA), we found that FEZF1 prominently associated with the recurrence-free survival of cervical cancer patients (P<0.001) and was an independent diagnostic factor for cervical cancer recurrence (P=0.002). Moreover, FEZF1 expression was significantly higher in the tumor samples from cervical cancer patients with relapse in TCGA(P=0.015). By RNA interference, we knocked down FEZF1 and found that cell proliferation, growth and migration were significantly decreased in C33A and SiHa cells. Meanwhile, FEZF1 knockdown also attenuated the growth of C33A cells in nude mice. In contrast, expression of FEZF1 promoted cell proliferation, growth and migration in HeLa cells. Using chromatin immunoprecipitation (ChIP) assay, we revealed that FEZF1 could bind to multiple key genes in the Wnt signaling pathway in HeLa cells. Furthermore, analysis of the levels of beta-catenin protein, the core component of the Wnt pathway, and downstream effector genes of the pathway showed that FEZF1 could activate the Wnt pathway. Together, these results suggest that FEZF1 promotes cell proliferation and migration possibly by acting as a transcriptional activator of the Wnt signaling pathway in cervical cancer, and also provide a valuable molecular predictive marker for cervical cancer recurrence. PMID- 30410595 TI - Identifying a Novel Biomarker TOP2A of Clear Cell Renal Cell Carcinoma (ccRCC) Associated with Smoking by Co-Expression Network Analysis. AB - Although it is well known that smoking is one of pathogenesis of clear cell renal cell carcinoma (ccRCC), the underlying molecular mechanism is still unclear. In our study, the microarray dataset GSE46699 is analyzed by weighted gene co expression network analysis (WGCNA). Then we identify 15 co-expressed gene modules in which the lightcyan module (R2 = 0.30) is the most significant. Combined with the protein-protein interaction (PPI) network and WGCNA, two hub genes are identified. Meanwhile, linear regression analyses indicate that TOP2A has a higher connection with smoking in ccRCC, survival analysis proved that overexpression of TOP2A in ccRCC could lead to shorter survival time. Furthermore, bioinformatical analyses based on GSE46699 and GSE2109 as well as qRT-PCR experiment show similar results that TOP2A is significantly up-regulated in smoking ccRCC compared to non-smoking ccRCC samples. In addition, Functional analysis, pathway enrichment analysis and gene set enrichment analysis (GSEA) indicate that high expression of TOP2A is related to cell cycle and p53 signaling pathway in ccRCC samples. Moreover, in vitro experiments revealed that TOP2A induced cell cycle arrest at G2 phase and proliferation inhibition via p53 phosphorylation. Taken together, by using WGCNA, we have identified a novel biomarker named TOP2A, which could affect the development of smoking-related ccRCC by regulating cell cycle and p53 signaling pathway. PMID- 30410598 TI - Overexpression of Peroxiredoxin 6 (PRDX6) Promotes the Aggressive Phenotypes of Esophageal Squamous Cell Carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies. Peroxiredoxin 6 (PRDX6), a member of peroxidase superfamily, has a function of eliminating the reactive oxygen species (ROS), and participates in development of multiple diseases, including tumors. The purpose of this study was to investigate the expression of PRDX6 in normal and cancerous esophageal tissues and to characterize its role in ESCC progression. We found significantly higher expression of PRDX6 in ESCC tissues than in normal esophageal tissues or tumor adjacent tissues and that the PRDX6 expression level was positively correlated with the proliferation-related markers. In ESCC cells, PRDX6 distribution was more pronounced in the nucleus region. PRDX6 overexpression by an adenovirus significantly promoted cell proliferation, migration and invasion in TE-1 and Eca 109 cells. Conversely, lentivirus-mediated knock-down of PRDX6 expression significantly reduced cell growth, colony formation and metastasis in ESCC cells. PRDX6 modulated the phosphorylation of Akt and Erk1/2, and the expression of MMP2. We also found that PRDX6 and Erk1/2 pathway were mutually regulated in ESCC cells. In addition, PRDX6 overexpression eliminated radiation-induced ROS and decreased consequent cell apoptosis, indicative of a role in radioresistance. Finally, the role of PRDX6 in promoting tumor growth was further confirmed in nude mice with ESCC xenografts. Taken together, we demonstrated that overexpression of PRDX6 promotes the progression of ESCC through Erk1/2, which provides a potential therapeutic target for human ESCC. PMID- 30410600 TI - Huaier Augmented the Chemotherapeutic Sensitivity of Oxaliplatin via Downregulation of YAP in Hepatocellular Carcinoma. AB - For unresectable Hepatocellular carcinoma (HCC), chemotherapy is still an important treatment strategy. Oxaliplatin (Oxa) is an effective treatment of HCC after sorafenib treatment failure. However, the intrinsic or acquired resistance of Oxa affected the chemotherapeutic sensitivity. By analyzing the data of GEO Database, we found that Oxa aberrantly increased the expression of Cysteine rich61 (Cyr61) in HCC cell lines. Subsequently, in Bel-7404 and SMMC-7721 cells after treated with Oxa, it was verified that the expression of Cyr61 and Yes associated protein (YAP) was increased. Moreover, we found that blockade of YAP promoted Oxa-induced cell apoptosis for the first time. Meanwhile, our previous study demonstrated that Huaier (HE) inhibited the expression of YAP. Further study found that combination treatment of Oxa and HE had a significantly synergistic anti-cancer effect and significantly inhibited the expression of YAP and apoptosis related proteins. Taken together, we have observed that overexpression of YAP significantly reduced the chemotherapeutic sensitivity of Oxa in HCC for the first time. Combination treatment of Oxa and HE solved this problem. PMID- 30410599 TI - CDK5 Functions as a Tumor Promoter in Human Lung Cancer. AB - Cyclin-dependent kinase 5 (CDK5), an atypical member of the cyclin-dependent kinase family, plays an important role in the nervous system. Recent studies have shown that CDK5 is also associated with tumors. However, few studies have been done to investigate the mechanism underlying the connection between CDK5 and cancers. To explore the role of CDK5 in cancers by using an extensive bioinformatics data mining process. We mined the transcriptional, survival, functions and structure of CDK5 gene through databases and in vitro experiments. We found that higher CDK5 expression levels in most cancer cell lines while lower expression in liver and brain cancer cell lines. High expression of CDK5 was associated with shorter overall survival (OS) in lung cancer. In addition, high expression level of CDK5 promoted lung cancer cells proliferation and metastasis. Inhibited CDK5 decreases CAP1 phosphorylation. CDK5 may prove to be a valid target of anticancer therapies. PMID- 30410601 TI - Multiple Machine Learnings Revealed Similar Predictive Accuracy for Prognosis of PNETs from the Surveillance, Epidemiology, and End Result Database. AB - Background: Prognosis prediction is indispensable in clinical practice and machine learning has been proved to be helpful. We expected to predict survival of pancreatic neuroendocrine tumors (PNETs) with machine learning, and compared it with the American Joint Committee on Cancer (AJCC) staging system. Methods: Data of PNETs cases were extracted from The Surveillance, Epidemiology, and End Result (SEER) database. Statistic description, multivariate survival analysis and preprocessing were done before machine learning. Four different algorithms (logistic regression (LR), support vector machines (SVM), random forest (RF) and deep learning (DL)) were used to train the model. We used proper imputations to manage missing data in the database and sensitive analysis was performed to evaluate the imputation. The model with the best predictive accuracy was compared with the AJCC staging system using the SEER cases. Results: The four models had similar predictive accuracy with no significant difference existed (p = 0.664). The DL model showed a slightly better predictive accuracy than others (81.6% (+/- 1.9%)), thus it was used for further comparison with the AJCC staging system and revealed a better performance for PNETs cases in SEER database (Area under receiver operating characteristic curve: 0.87 vs 0.76). The validity of missing data imputation was supported by sensitivity analysis. Conclusions: The models developed with machine learning performed well in survival prediction of PNETs, and the DL model have a better accuracy and specificity than the AJCC staging system in SEER data. The DL model has potential for clinical application but external validation is needed. PMID- 30410602 TI - Tumor deposit is an independent prognostic indicator in patients who underwent radical resection for colorectal cancer. AB - Background: Tumor deposits are one of the promising factors among the different edition of Tumor, Node, Metastasis classification. Despite improvement in the treatment of various types of metastatic disease the source and prognostic significance of tumor deposits in staging has not been deliberating the agreeable opinion. We investigated the possibility of tumor deposit as independent prognostic factor and evaluating its prognostic value in colorectal carcinoma patients. Methods: Author studied 313 colorectal cancer patients clinocopathological data and outcome who underwent radical resection. Data between 2011-2015 were retrospectively collected from Shanghai East Hospital, affiliated with Tongji University data information centre. The analysis was used to calculate 2 years disease free survival(DFS) and relation of tumor deposit with number of lymph node positive. Cox-regression analysis was performed to assess the prognostic factor. Results: Out of 313 colorectal patients included in the study, tumor deposits were detected in 17%. Tumor deposits (TDs) are relevantly associated with significant poor outcomes. The tumor deposit were significantly correlated with T-stage(P=<0.001), N-stage(P=<0.001), PLNC(P=<0.001), venous invasion(P=<0.001), TNM staging(P=<0.001), CEA(P=0.021) and CA19-9(P=0.042) of primary tumor. The Kaplan-Meier analysis revealed that disease-free survival of CRC patients with positive tumor deposit were significantly poorer that those with negative tumor deposit cohort(P=<0.001) And with multivariate analysis in different model, we found that positive tumor deposit were significantly associated with shorter DSF which is totally independent with lymph node status (P=0.001 and P=0.023 respectively). Subgroup analysis found that of 179 CRC patients with negative lymph node status, the DFS of patients with positive tumor deposit were significantly shorter that those with negative tumor deposit(P=,0.001). Of 134patients with positive lymph node status, the DFS of patients shows similar result. (P=<0.001). Conclusion: We have shown that TDs are not equal to lymph node metastasis with respect to biology and outcome. Tumor deposits are an independent adverse prognostic factor in CRC patient who have undergone radical resection. PMID- 30410603 TI - A nomogram to predict long-time survival for patients with M1 diseases of esophageal cancer. AB - Objective: To evaluate the clinicopathologic characteristics of the long-time survivals and construct a clinical nomogram using the Surveilance, Epidemiology, and End Results (SEER) database. Materials and Methods: Information of patients diagnosed with M1 stage esophageal cancer from 2010-2014 was retrieved from SEER database. Patients with unknown information of AJCC TNM stage or metastatic sites or marital status or surgery or survival were excluded. Demographic and clinicopathologic characteristics were compared between LTS (long time survivals: patients who have survived for no less than 2 years) and STS (shorter time survivals: patients who have survived for less than 2 years). Cox regression analysis was performed to evaluate prognostic factors. A nomogram comprising demographic and clinicopathologic factors was established to predict 1-year survival and 2-year survival for patients with M1 diseases. Results: A total of 2981 patients from the SEER database were included for analysis. Compared with the STS, married people and patients with well differentiated tumors or oligometastatic site were more likely to be LTS. Also, LTS were associated with significantly less bone metastasis and more surgery. The OS nomogram, which had a c-index of 0.633, was based on the eleven variables: gender, age, marital status, T stage, N stage, histology, grade, number of important metastatic organs and primary surgery. Conclusions: Married patients, patients with well differentiated tumors, patients with oligometastatic site, patients without bone metastasis or liver metastasis and those who underwent surgery are associated with long time survivals. We developed a nomogram predicting 1- and 2-year OS and CSS for M1 stage esophageal cancer. The prognostic model may improve clinicians' abilities to predict individualized survival and to make treatment recommendations. PMID- 30410604 TI - Serum level of co-expressed hub miRNAs as diagnostic and prognostic biomarkers for pancreatic ductal adenocarcinoma. AB - Background: Sensitive and specific non-invasive biomarkers are urgently needed in order to improve the survival of patients with pancreatic ductal adenocarcinoma (PDAC), which is the fourth leading cause of cancer-related death. We aim to identify serum hub miRNAs as potential diagnostic and prognostic biomarkers for PDAC. Methods: A total of 2578 serum miRNA expression data from 88 PDAC patients and 19 healthy subjects were downloaded from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA) was constructed and significant modules were extracted from the network by WGCNA R package. Network modules and hub miRNAs closely related to PDAC were identified. The prognostic value of hub miRNAs was assessed by Kaplan-Meier overall survival analysis. Results: Two modules strongly associated with PDAC were identified by WGCNA, which were labeled as turquoise and brown respectively. Within each module, twenty hub miRNAs were found. At the functional level, turquoise module was mainly associated with tumorigenesis pathways such as P53 and WNT signaling pathway, while the brown module was mostly related to the pathways of cancer such as RNA transport and MAPK signaling pathway. Utilizing overall survival analyses, five "real" miRNAs were able to stratify PDAC patients into low-risk and high risk groups. Conclusions: The association of specific Hub miRNAs with the development of pancreatic cancer was established by WGCNA analysis. Five miRNAs (mir-16-2-3p, mir-890, mir-3201, mir-602, and mir-877) were identified as potential diagnostic and prognostic biomarkers for PDAC. PMID- 30410605 TI - The efficacy and safety of long- versus short-interval transarterial chemoembolization in unresectable hepatocellular carcinoma. AB - Background: To compare the efficacy and safety of long- versus short-interval of transarterial chemoembolization (TACE) in unresectable hepatocellular carcinoma (HCC) patients. Methods: This retrospective analysis enrolled 574 patients with unresectable HCC who underwent at least two sessions of TACE between January 2007 and December 2014. The patients were divided into a short-interval group (SIG) and a long-interval group (LIG) based on the median TACE interval of the first two sessions. Propensity score matching (PSM) identified 476 patients for a comparison of overall survival (OS) and safety. Results: Before matching, the LIG had a longer OS than the SIG (Median: 12.1 vs. 8.7 months; P = 0.003). After matching, median OS in the SIG and LIG were 9.1 and 14.2 months (P < 0.001). The 1-, 2-, and 3-year survival rates were 37.5%, 17.1%, and 9.9% for SIG and 50.1%, 19.3%, and 11.6% for LIG, respectively. The TACE interval was an independent prognostic factor for OS. The LIG had a longer OS than the SIG in Barcelona Clinic liver cancer (BCLC) stage C patients (Median: 10.2 vs. 5.8 months; P < 0.001), but not in BCLC-A or B. The postoperative adverse rates were similar in matched SIG and LIG patients (29.4% vs. 33.6%, P = 0.324). Conclusions: A long interval between the first two sessions of TACE resulted in a better OS than a short interval in patients with unresectable BCLC C-stage HCC. PMID- 30410606 TI - Cause-specific mortality prediction model for patients with basaloid squamous cell carcinomas of the head and neck: a competing risk analysis. AB - Purpose: Basaloid squamous cell carcinoma (BSCC) is a rare, high-grade variant of squamous cell carcinoma (SCC). Most published studies based on population-based datasets focus on prognostic differences between SCC and BSCC. Competing risk analyses for this disease have not been performed. We used Surveillance Epidemiology and End Results (SEER) data to calculate and model the cumulative incidence of death for patients with head and neck BSCC (HNBSCC) with competing risk approaches, and built a model to predict probability of cause-specific death for these patients. Methods: We analyzed data on 1163 patients who were diagnosed with primary lip and oral cavity, oropharynx, or hypopharynx and larynx BSCC and registered in the SEER program between 2004 and 2013. We calculated crude cumulative incidence function (CIF) for mortality after diagnosis of HNBSCC. We built a Fine and Gray's proportional sub-distribution hazard model and nomogram to predict their probability of cause-specific death. We calculated concordance indexes (c-index) and plotted calibration curves to evaluate model performance. Results: Five-year cumulative incidence of cause-specific death after diagnosis of HNBSCC was 26.5% (95% CI: 23.4-29.8%); cumulative incidence of other causes of death was 11.8% (95% CI: 9.4-14.3%). Old age, large tumor size, hypopharynx and larynx sites, lymph node-positive, distant metastasis, and non-radiotherapy were significant factors for high probability of cause-specific death. The model was well calibrated. The bootstrap-corrected c-index for the model was 0.71. Conclusions: We built the first competing risk nomogram for HNBSCC. The model performance was found to be good. This individualized prognostic predictive tool will aid physicians in clinical counseling, and will assist patients in planning for their future lives. PMID- 30410608 TI - CIP2A Promotes Proliferation, Invasion and Chemoresistance to Cisplatin in Renal Cell Carcinoma. AB - CIP2A is a well-known oncoprotein whose expression is elevated in multiple human solid tumor types. However, its role in renal cell carcinoma (RCC) development is poorly understood. Thus, in our present study, we used the renal cancer cell lines 786-O, A498 and CAKI-1 and the renal epithelial cell line HK-2 to clarify the function of CIP2A in RCC. We found that CIP2A expression is much higher in the RCC cells than in the normal renal epithelial cell. Lentivirus covered coding region CIP2A cDNA sequence and CIP2A siRNA were used to up and down regulate CIP2A expression in vitro. We found that overexpression of CIP2A promoted G1/S transition and cell proliferation. In addition, up-regulation of CIP2A significantly enhanced the invasion and migration capabilities of the cells. Furthermore, CIP2A promoted epithelial-mesenchymal transformation (EMT) and chemoresistance to cisplatin in RCC cells. Taken together, our findings demonstrate that CIP2A plays an important role in proliferation, invasion and chemoresistance to cisplatin in RCC cells. CIP2A may serve as an ideal molecular target for RCC therapeutics. PMID- 30410607 TI - Roles of Smads Family and Alternative Splicing Variants of Smad4 in Different Cancers. AB - Transforming Growth Factor beta (TGF-beta) is one of the most common secretory proteins which are recognized by membrane receptors joined to transcription regulatory factor. TGF-beta signals are transduced by the Smads family that regulate differentiation, proliferation, early growth, apoptosis, homeostasis, and tumor development. Functional study of TGF-beta signaling pathway and Smads role is vital for certain diseases such as cancer. Alternative splicing produces a diverse range of protein isoforms with unique function and the ability to react differently with various pharmaceutical products. This review organizes to describe the general study of Smads family, the process of alternative splicing, the general aspect of alternative splicing of Smad4 in cancer and the possible use of spliceoforms for the diagnosis and therapeutic purpose. The main aim and objective of this article are to highlight some particular mechanisms involving in alternatives splicing of cancer and also to demonstrate new evidence about alternative splicing in different steps given cancer initiation and progression. PMID- 30410609 TI - Tongue Coating Microbiota Community and Risk Effect on Gastric Cancer. AB - Background: Although oral hygiene and health have long been reported to be associated with increased risk of gastric cancer (GC), the direct relationship of oral microbes with the risk of GC have not been evaluated fully. We aimed to test whether tongue coating microbiome was associated with GC risk. Methods: Pyrosequencing of 16S rRNA gene of tongue coating microbiome was used in 57 newly diagnosed gastric adenocarcinomas and 80 healthy controls. Benjamini-Hochberg (BH) was applied for multiple comparison correction. Co-abundance group (CAGs) analysis was adopted. Results: We found that higher relative abundance of Firmicutes, and lower of Bacteroidetes were associated with increased risk of GC. In genus level, Streptococcus trended with a higher risk of GC, the four other genera (Neisseria, Prevotella, Prevotella7, and Porphyromonas) were found to have a decreased risk of GC. Different from overall GC and non-cardia cancer, Alloprevotella and Veillonella trended with the higher risk of cardia cancer. Finally, we analyzed the microbiota by determining CAGs and six clusters were identified. Except the Cluster 2 (mainly Streptococcus and Abiotrophia), the other clusters had an inverse association with GC. Of them, the Cluster 6 (mainly Prevotella and Prevotella7 etc) had a relatively good classification power with 0.76 of AUC. Conclusion: Microbiome in tongue coating may have potential guiding value for early detection and prevention of GC. PMID- 30410610 TI - VEGFR-2 Inhibitor Apatinib Hinders Endothelial Cells Progression Triggered by Irradiated Gastric Cancer Cells-derived Exosomes. AB - Background: Radiotherapy is a standard treatment for a significant fraction of cancer patients. Nonetheless, to this day radiation resistance is a key impediment in gastric cancer (GC) treatment. Moreover, GC is characterized by its substantial neo-angiogenesis, driven by high levels of vascular endothelial growth factor (VEGF) correlated with the presence of stomach cancer. The aim of our study was to address if VEGFR inhibitors treatments impact the negative effect of radiotherapy regiments of gastric cancer. Materials and methods: Isolation of exosomes released by SGC-7901 and BGC-823 lines after irradiation at 0 Gy or 6 Gy was performed by differential ultra-centrifugation. Incubation of Human Umbilical Vein Endothelial Cells (HUVEC) was carried out with different concentrations of exosomes from non- or irradiated GC cells to address their proliferation and survival fraction (SF) by MTS. 6 Gy irradiated cells exosomes at concentration of 20 ug/ml were compared to EC incubated with the same exosome concentration from non-irradiated human GC cells over 72-hour time course. Wound healing and Transwell assays were performed in a migration buffer consisting of exosomes released by non- or irradiated SGC-7901 and BGC-823 cells over 24-hour time course. HUVEC cells stained with DAPI that have passed through a gluten gel were counted in order to monitor their invasion capacity. Employing IC50, 60 ug/ml was determined as the optimal Apatinib (YN968D1) concentration for the half life of HUVEC, and incubated with exosomes from irradiated GC cells. The aforementioned assays were performed in the background of the same conditions in order to analyse the effect of Apatinib on HUVEC progression. Results: We show that proliferation, motility and invasive capacity of HUVEC are enhanced upon incubation with exosomes released by irradiated GC cell lines. Importantly, the latter is counteracted by the VEGFR-2 inhibitor Apatinib which hinders ECs progression. Conclusion / Significance: Combining radiotherapy and VEGFR inhibitors treatment can provide potentially a substantial impact in decreasing cancer death rates by averting the negative effect of radiotherapy regiments and provide better standard for cancer patients. PMID- 30410611 TI - Development of a Novel Autophagy-related Prognostic Signature for Serous Ovarian Cancer. AB - Purpose: Considerable evidence suggests that autophagy plays a crucial role in the biological processes of ovarian cancer. The aim of this study was to develop a novel autophagy-related prognostic signature for serous ovarian cancer. Methods: A univariate Cox proportional regression model was used to analyze mRNA microarray and clinical data in The Cancer Genome Atlas (TCGA) for the purpose of selecting autophagy-related prognostic genes. A multivariate Cox proportional regression model and the survival analysis were used to develop an eight-gene prognostic signature. The multivariate Cox and stratification analysis suggested that this signature was an independent prognostic factor for serous ovarian cancer patients. Bioinformatics functions were investigated by a principal components analysis and gene set enrichment analysis (GSEA). Finally, the correlation between the prognostic signature and gene mutation status was further analyzed in serous ovarian cancer, and especially with regard to the mutation status of BRCA1 and BRCA2 (BRCA1/2) genes. Results: Distinctly different autophagy-related gene expression profiles were identified in normal ovarian tissues and serous ovarian cancer tissues. We profiled an autophagy-related gene set and identified eight genes with significant prognostic values for serous ovarian cancer. Subsequently, an autophagy-related ovarian cancer risk signature was constructed, and patients at a high-risk or low-risk for poor prognosis were identified based on their signature. High-risk patients had significantly shorter overall survival (OS) and disease-free survival (DFS) times than low-risk patients. GSEA results suggested an enhanced intensity of autophagy regulation in high-risk patients when compared with low-risk patients. When studied as an independent prognostic factor for serous ovarian cancer, the significant prognostic value of this signature could be seen in the stratified cohorts. For clinical use, we developed a nomogram that included the prognostic classifier and seven clinical risk factors. Additionally, we identified the 10 most frequently mutated genes found in serous ovarian cancer patients, and analyzed them for their differences in high-risk and low-risk patients. Among 293 patients, 62 had BRCA1/2 gene mutations, and this result was significantly correlated with the autophagy-related prognostic signature. Conclusions: Our findings suggest that the eight-gene autophagy-related signature could serve as an independent prognostic indicator for cases of serous ovarian cancer. PMID- 30410613 TI - Impact of the Time Interval from Neoadjuvant Chemotherapy to Surgery in Primary Ovarian, Tubal, and Peritoneal Cancer Patients. AB - Neoadjuvant chemotherapy (NACT) plays an important role in ovarian cancer. The appropriate time interval from the completion of NACT to interval debulking surgery (TTS) in ovarian cancer is still unknown. The aim of this retrospective study was to evaluate the effect of the time interval between the end of NACT and surgery (TTS <= 4 weeks vs TTS > 4 weeks) on the survival outcomes among patients with advanced-stage ovarian, tubal, and peritoneal cancers. 152 patients with stage III or IV ovarian, tubal, and peritoneal cancers were included in this retrospective cohort study: 115 in the TTS <=4 weeks and 37 in the TTS >4 weeks groups. The Kaplan-Meier analysis showed that the progression-free survival in the TTS <=4 weeks group was longer than that in the TTS >4 weeks group (26 vs 14 months, P=0.04). However, the overall survival was not different between the two groups (66 vs 36 months, P=0.105). The multivariate analysis presented that delay in surgery after NACT (TTS >4 weeks) was associated with a shorter progression free (P=0.002) but not overall survival (P=0.231). Our findings demonstrated no relationship between the NACT to surgery interval and OS, while a detrimental effect of TTS >4 weeks on PFS was observed. PMID- 30410612 TI - Cytoplasmic SQSTM1/ P62 Accumulation Predicates a Poor Prognosis in Patients with Malignant Tumor. AB - Aims: SQSTM1/p62, as an autophagy marker, is a key molecule involved in the autophagy process. Recent studies have demonstrated that p62 has a close relationship with tumorigenesis and progression, but the impact of p62 on patients' survival has not been comprehensively understood. Therefore, we conducted this study to assess the expression level of p62 in tumor cells and the prognostic role of p62 expression in various malignant tumors. Methods: We searched PubMed, PubMed Central (PMC), Embase, Ovid and Web of Science databases and identified 30 eligible studies containing 14,072 patients to include in the meta-analysis. The p62 mRNA and protein expression profiles in various tumor tissues and normal tissues were presented according to the Human Protein Atlas (HPA) and the Gene Expression Profiling Interactive Analysis (GEPIA). We also tested the association between p62 mRNA level and patients' survival based on the Cancer Genome Atlas (TCGA) and the Human Protein Atlas (HPA) databases. Results: The expression levels of p62 mRNA and protein varied in different tissues. The p62 proteins were elevated and mainly located in the cytoplasm in some types of tumor compared with the normal tissues. The pooled results indicated that p62 overexpression in tumor tissues was associated with a worse prognosis. In the subgroup analysis, a significant relationship was observed between cytoplasmic p62 accumulation and both overall survival (HR 1.53, 95% CI: 1.03-2.27, P < 0.05) and disease-specific survival (HR 1.60, 95% CI: 1.15-2.24, P < 0.01). The relationship between p62 and worse survival was more evident in early stage tumors. P62 mRNA expression had no significant effect on the patient's survival except of liver cancer. Conclusions: The findings of this meta-analysis highlight the role of p62 as a useful prognostic biomarker for some types of tumor according to different clinicopathologic features, which may contribute to the selection of effective treatment methods for different malignant tumors. PMID- 30410614 TI - Design and synthesis of C 3-symmetric molecules bearing propellane moieties via cyclotrimerization and a ring-closing metathesis sequence. AB - We have developed an efficient synthetic strategy to assemble C 3-symmetric molecules containing propellane moieties as end groups and a benzene ring as a central core. The synthesis of these C 3-symmetric molecules involves simple starting materials. Our approach to C 3-symmetric compounds relies on a Diels Alder reaction, cyclotrimerization and ring-closing metathesis as key steps. PMID- 30410615 TI - Synthesis of 3-aminocoumarin-N-benzylpyridinium conjugates with nanomolar inhibitory activity against acetylcholinesterase. AB - A series of 3-amino-6,7-dimethoxycoumarins conjugated with the N-benzylpyridinium moiety through an amide-bond linkage was synthesized and evaluated for their acetylcholinesterase inhibitory activity. A number of the benzylpyridinium derivatives exhibited potent activities with inhibitory concentration (IC50) values in the nanomolar concentration range. Among them, the 2,3 difluorobenzylpyridinium-containing compound was the most potent inhibitor with an IC50 value of 1.53 +/- 0.01 nM. Docking studies revealed that the synthesized compounds inhibit the target enzyme by a dual binding site mechanism whereby the coumarin portion binds with the peripheral anionic site while the N benzylpyridinium residue binds with the catalytic anionic site of the enzyme. PMID- 30410617 TI - Carbonylonium ions: the onium ions of the carbonyl group. AB - The nomenclature of cations R1C(=O+R3)R2 (R1, R2, R3 = H or organyl) has been examined and shown to be in a state of immeasurable confusion: a pragmatic recommendation is made that the generic term "carbonylonium ions" should be adopted for these intermediates, which comprises the terms "aldehydium" (R1 = H, R2, R3 = H or organyl) and "ketonium ions" (R1, R2 = organyl, R3 = H or organyl) for the corresponding aldehyde- and ketone-based intermediates, respectively. PMID- 30410616 TI - Learning from B12 enzymes: biomimetic and bioinspired catalysts for eco-friendly organic synthesis. AB - Cobalamins (B12) play various important roles in vivo. Most B12-dependent enzymes are divided into three main subfamilies: adenosylcobalamin-dependent isomerases, methylcobalamin-dependent methyltransferases, and dehalogenases. Mimicking these B12 enzyme functions under non-enzymatic conditions offers good understanding of their elaborate reaction mechanisms. Furthermore, bio-inspiration offers a new approach to catalytic design for green and eco-friendly molecular transformations. As part of a study based on vitamin B12 derivatives including heptamethyl cobyrinate perchlorate, we describe biomimetic and bioinspired catalytic reactions with B12 enzyme functions. The reactions are classified according to the corresponding three B12 enzyme subfamilies, with a focus on our recent development on electrochemical and photochemical catalytic systems. Other important reactions are also described, with a focus on radical-involved reactions in terms of organic synthesis. PMID- 30410618 TI - Gold-catalyzed post-Ugi alkyne hydroarylation for the synthesis of 2-quinolones. AB - A series of propargylamides containing an electron-rich benzene ring was prepared through the Ugi reaction of 3,5-dimethoxyaniline with various propiolic acids, aldehydes and isocyanides. Subjecting these adducts to a gold-catalyzed intramolecular alkyne hydroarylation process allowed to efficiently construct the 2-quinolone core bearing a branched substituent on the nitrogen atom. PMID- 30410619 TI - Impact of Pseudomonas aeruginosa quorum sensing signaling molecules on adhesion and inflammatory markers in endothelial cells. AB - Pseudomonas aeruginosa relies on the quorum sensing (QS) signaling system as a central regulator mechanism of virulence expression that contributes to the formation and maintenance of biofilms and tolerance to conventional antimicrobials. QS Signaling molecules (QSSMs) may be recognized and may function also within the host cells, being potentially involved in the progression of the infectious process. In this study we evaluate the expression of adhesion and inflammatory molecules in endothelial cells treated with P. aeruginosa QSSMs, in order to bring new insights on the mechanisms involved in the interaction of P. aeruginosa with host cells during the infectious process. Endothelial cells were stimulated with 20 uM of main P. aeruginosa QSSMs (OdDHL = N-(3-oxododecanoyl)-L homoserine lactone, C4HSL = N-butyryl-L-homoserine lactone, PQS = 2-heptyl-3 hydroxy-4(1H)-quinolone and HHQ = 2-heptyl-4-quinolone). Adherence to endothelial cells, inert substratum and biofilm formation was evaluated. The expression of adhesion molecules (VE-cadherin, PECAM-1, ICAM-1, and P-selectin) and inflammatory response molecules (IL-1beta, IL-6, TNFalpha, TGFbeta, and eNOS) was assessed by qRT-PCR and flow cytometry. Our results showed that bacterial adherence to inert substratum and biofilm were decreased in the presence of all tested QSSMs. The adherence index of PAO1 laboratory strain to host cells was decreased between 10-40% in the presence of QSSMs, as compared to untreated control. Expression of eukaryotic cells adhesion molecules ICAM-1 and P-selectin was stimulated by QSSMs, whereas VE-cadherin and PECAM-1 levels were increased only by C4HSL. The inflammatory response of endothelial cells was also modulated, as observed by the modified expression of IL-1beta (for C4HSL, PQS and HHQ), IL-6 (for C4HSL and HHQ), TNFalpha (for C4HSL and HHQ), TGFbeta, and eNOS factors. Our results demonstrate that the main pseudomonadal QSSMs differentially modulate endothelial cells adhesion and proinflammatory cytokine expression. These observations provide new insights in the mechanisms by which different QSSMs activate endothelial cells and modulate the infectious process, and support the importance of recent studies aiming to develop anti-QS therapeutic strategies to fight against P. aeruginosa infections. PMID- 30410620 TI - Microwave-assisted synthesis of biologically relevant steroidal 17-exo-pyrazol-5' ones from a norpregnene precursor by a side-chain elongation/heterocyclization sequence. AB - Multistep syntheses of novel 17beta-pyrazol-5'-ones in the Delta5-androstane series were efficiently carried out from pregnenolone acetate. A steroidal 17 carboxylic acid was first synthesized as a norpregnene precursor by the bromoform reaction and subsequent acetylation. Its CDI-activated acylimidazole derivative was then converted to a beta-ketoester containing a two carbon atom-elongated side chain than that of the starting material. A Knorr cyclization of the bifunctional 1,3-dicarbonyl compound with hydrazine and its monosubstituted derivatives in AcOH under microwave heating conditions led to the regioselective formation of 17-exo-heterocycles in good to excellent yields. The suppression of an acid-catalyzed thermal decarboxylation of the beta-ketoester and thus a significant improvement in the yield of the desired heterocyclic products could be achieved by the preliminary liberation of the arylhydrazines from their hydrochloride salts in EtOH in the presence of NaOAc. The reaction rates were found to depend on the electronic character of the substituent present in the phenylhydrazine applied. The antiproliferative activities of the structurally related steroidal pyrazol-5'-ones and their deacetylated analogs were screened on three human adherent breast cancer cell lines (MCF7, T47D and MDA-MB-231): the microculture tetrazolium assay revealed that some of the presented derivatives exerted cell growth inhibitory effects on some of these cell lines comparable to those of the reference compound, cisplatin. PMID- 30410622 TI - Synthesis of functionalised beta-keto amides by aminoacylation/domino fragmentation of beta-enamino amides. AB - Ethylenediamine-derived beta-enamino amides are used as equivalents of amide enolate synthons in C-acylation reactions with N-protected amino acids. Domino fragmentation of the obtained intermediates leads to functionalised beta-keto amides, bearing a protected amino group in their side chain. PMID- 30410621 TI - Synthesis of cis-hydrindan-2,4-diones bearing an all-carbon quaternary center by a Danheiser annulation. AB - A straightforward synthetic entry to functionalized hydrindane compounds based on a rapid assembly of the core nucleus by a Danheiser cycloaddition is reported. Valuable bicyclic building blocks containing the fused five and six-membered carbocyclic ring system can be achieved in only four steps from a simple acyclic beta-keto ester. PMID- 30410624 TI - Transition metal-free oxidative and deoxygenative C-H/C-Li cross-couplings of 2H imidazole 1-oxides with carboranyl lithium as an efficient synthetic approach to azaheterocyclic carboranes. AB - The direct C-H functionalization methodology has first been applied to perform transition metal-free C-H/C-Li cross-couplings of 2H-imidazole 1-oxides with carboranyllithium. This atom- and step-economical approach, based on one-pot reactions of nucleophilic substitution of hydrogen (SN H) in non-aromatic azaheterocycles, affords novel imidazolyl-modified carboranes of two types (N oxides and their deoxygenative analogues), which are particularly of interest in the design of advanced materials. PMID- 30410623 TI - Pathoblockers or antivirulence drugs as a new option for the treatment of bacterial infections. AB - The rapid development of antimicrobial resistance is threatening mankind to such an extent that the World Health Organization expects more deaths from infections than from cancer in 2050 if current trends continue. To avoid this scenario, new classes of anti-infectives must urgently be developed. Antibiotics with new modes of action are needed, but other concepts are also currently being pursued. Targeting bacterial virulence as a means of blocking pathogenicity is a promising new strategy for disarming pathogens. Furthermore, it is believed that this new approach is less susceptible towards resistance development. In this review, recent examples of anti-infective compounds acting on several types of bacterial targets, e.g., adhesins, toxins and bacterial communication, are described. PMID- 30410626 TI - The design and synthesis of an antibacterial phenothiazine-siderophore conjugate. AB - Siderophore-antibiotic conjugates consist of an antibiotic covalently linked by a tether to a siderophore. Such conjugates can demonstrate enhanced uptake and internalisation to the bacterial cell resulting in significantly reduced MIC values and extended spectrum of activity. Phenothiazines are a class of small molecules that have been identified as a potential treatment for multidrug resistant tuberculosis and latent TB. Herein we report the design and synthesis of the first phenothiazine-siderophore conjugate. A convergent synthetic route was developed whereby the functionalised phenothiazine component was prepared in four steps and the siderophore component also prepared in four steps. In M. smegmatis the functionalised phenothiazine demonstrated an equipotent MIC value in direct comparison to the parent phenothiazine from which it was derived. The final conjugate was synthesised by amide bond formation between the two components and global deprotection of the PMB protecting groups to unmask the catechol iron chelating groups of the siderophore. The synthesis is readily amenable to the preparation of analogues whereby the siderophore component of the conjugate can be modified. The route will be used to prepare a library of siderophore-phenothiazine conjugates for full biological evaluation of much needed new antibacterial agents. PMID- 30410625 TI - Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers. AB - The Gram-negative opportunistic pathogen Pseudomonas aeruginosa causes severe nosocomial infections. It uses quorum sensing (QS) to regulate and coordinate population-wide group behaviours in the infection process like concerted secretion of virulence factors. One very important signalling network is the Pseudomonas quinolone signal (PQS) QS. With the aim to devise novel and innovative anti-infectives, inhibitors have been designed to address the various potential drug targets present within pqs QS. These range from enzymes within the biosynthesis cascade of the signal molecules PqsABCDE to the receptor of these autoinducers PqsR (MvfR). This review shortly introduces P. aeruginosa and its pathogenicity traits regulated by the pqs system and highlights the published drug discovery efforts providing insights into the compound binding modes if available. Furthermore, suitability of the individual targets for pathoblocker design is discussed. PMID- 30410628 TI - Novel solid-phase strategy for the synthesis of ligand-targeted fluorescent labelled chelating peptide conjugates as a theranostic tool for cancer. AB - In this article, we have successfully designed and demonstrated a novel continuous process for assembling targeting ligands, peptidic spacers, fluorescent tags and a chelating core for the attachment of cytotoxic molecules, radiotracers, nanomaterials in a standard Fmoc solid-phase peptide synthesis in high yield and purity. The differentially protected Fmoc-Lys-(Tfa)-OH plays a vital role in attaching fluorescent tags while growing the peptide chain in an uninterrupted manner. The methodology is versatile for solid-phase resins that are sensitive to mild and strong acidic conditions when acid-sensitive side chain amino protecting groups such as Trt (chlorotrityl), Mtt (4-methyltrityl), Mmt (4 methoxytrityl) are employed to synthesise the ligand targeted fluorescent tagged bioconjugates. Using this methodology, DUPA rhodamine B conjugate (DUPA = 2-[3 (1,3-dicarboxypropyl)ureido]pentanedioic acid), targeting prostate specific membrane antigen (PSMA) expressed on prostate, breast, bladder and brain cancers and pteroate rhodamine B, targeting folate receptor positive cancers such as ovarian, lung, endometrium as well as inflammatory diseases have been synthesized. In vitro studies using LNCaP (PSMA +ve), PC-3 (PSMA -ve, FR -ve) and CHO-beta (FR +ve) cell lines and their respective competition experiments demonstrate the specificity of the newly synthesized bioconstructs for future application in fluorescent guided intra-operative imaging. PMID- 30410627 TI - Non-native autoinducer analogs capable of modulating the SdiA quorum sensing receptor in Salmonella enterica serovar Typhimurium. AB - Quorum sensing (QS) allows many common bacterial pathogens to coordinate group behaviors such as virulence factor production, host colonization, and biofilm formation at high population densities. This cell-cell signaling process is regulated by N -acyl L-homoserine lactone (AHL) signals, or autoinducers, and LuxR-type receptors in Gram-negative bacteria. SdiA is an orphan LuxR-type receptor found in Escherichia, Salmonella, Klebsiella, and Enterobacter genera that responds to AHL signals produced by other species and regulates genes involved in several aspects of host colonization. The inhibition of QS using non native small molecules that target LuxR-type receptors offers a non-biocidal approach for studying, and potentially controlling, virulence in these bacteria. To date, few studies have characterized the features of AHLs and other small molecules capable of SdiA agonism, and no SdiA antagonists have been reported. Herein, we report the screening of a set of AHL analogs to both uncover agonists and antagonists of SdiA and to start to delineate structure-activity relationships (SARs) for SdiA:AHL interactions. Using a cell-based reporter of SdiA in Salmonella enterica serovar Typhimurium, several non-natural SdiA agonists and the first set of SdiA antagonists were identified and characterized. These compounds represent new chemical probes for exploring the mechanisms by which SdiA functions during infection and its role in interspecies interactions. Moreover, as SdiA is highly stable when produced in vitro, these compounds could advance fundamental studies of LuxR-type receptor:ligand interactions that engender both agonism and antagonism. PMID- 30410629 TI - Synthesis and biological evaluation of 1,2-disubsubstituted 4-quinolone analogues of Pseudonocardia sp. natural products. AB - A series of analogues of Pseudonocardia sp. natural products were synthesized, which have been reported to possess potent antibacterial activity against Helicobacter pylori and induce growth defects in Escherichia coli and Staphylococcus aureus. Taking inspiration from a methodology used in our total synthesis of natural products, we applied this methodology to access analogues possessing bulky N-substituents, traditionally considered to be challenging scaffolds. Screening of the library provided valuable insights into the structure activity relationship of the bacterial growth defects, and suggested that selectivity between bacterial species should be attainable. Furthermore, a structurally related series of analogues was observed to inhibit production of the virulence factor pyocyanin in the human pathogen Pseudomonas aeruginosa, which may be a result of their similarity to the Pseudomonas quinolone signal (PQS) quorum sensing autoinducer. This provided new insights regarding the effect of N-substitution in PQS analogues, which has been hitherto underexplored. PMID- 30410630 TI - Assembly of fully substituted triazolochromenes via a novel multicomponent reaction or mechanochemical synthesis. AB - A new metal-free one-pot three-component procedure towards fully substituted triazolochromenes has been developed, starting from commercially available materials. Salicylaldehydes and nitroalkenes were reacted under solvent-free conditions, followed by a 1,3-dipolar cycloaddition of the intermediate 3-nitro 2H-chromenes with organic azides in a one-pot two-step sequence. The triazolochromenes were formed with complete regioselectivity and new biologically relevant structures were synthesized via extension of the developed procedure and via postfunctionalization. The mechanochemical synthesis was carried out for several salicylaldehydes and gave a clear improvement in the yield of the corresponding triazolochromenes and consequently showed to be a viable alternative for solid salicylaldehydes. PMID- 30410631 TI - Ring-opening metathesis of some strained bicyclic systems; stereocontrolled access to diolefinated saturated heterocycles with multiple stereogenic centers. AB - Ring-opening metathesis (ROM) of various unsaturated, constrained bicyclic ring systems has been investigated with the use of commercial ruthenium-based catalysts. Starting from various cyclodienes, the corresponding derived bicyclic lactone, lactam, and isoxazoline derivatives were submitted to ROM under ethenolysis. These functionalized, strained bicyclic systems afforded novel highly-functionalized diolefinated heterocyclic scaffolds in ROM reactions with stereocontrol, through the conservation of the configuration of the stereogenic centers of the starting compounds. PMID- 30410632 TI - Domino ring-opening-ring-closing enyne metathesis vs enyne metathesis of norbornene derivatives with alkynyl side chains. Construction of condensed polycarbocycles. AB - The metathesis of norbornene derivatives with alkynyl side-chain with Grubbs' ruthenium alkylidine as catalyst has been investigated with the objective of constructing condensed polycyclic structures. This investigation demonstrated that the generally observed domino reaction course involving a ring-opening metathesis of the norbornene unit and a ring-closing enyne metathesis is influenced to a great extent by the nature of the functional group and the substrate structure and may follow a different reaction course than what is usually observed. In cases where ROM-RCEYM occurred, the resulting 1,3-diene reacts in situ with the dienophile to provide condensed tetracyclic systems. PMID- 30410633 TI - Dispersion-mediated steering of organic adsorbates on a precovered silicon surface. AB - The chemistry of organic adsorbates on surfaces is often discussed in terms of Pauli repulsion as limiting factor regarding the packing of molecules. Here we show that the attractive part of the van der Waals potential can be similarly decisive. For the semiconductor surface Si(001), an already covalently bonded molecule of cyclooctyne steers a second incoming molecule via dispersion interactions onto the neighbouring adsorption site. This helps in understanding the nonstatistical pattern formation for this surface-adsorbate system and hints toward an inclusion of dispersion attraction as another determining factor for surface adsorption. PMID- 30410634 TI - Intravenous Immunoglobulin Therapy Administered Early after Narcolepsy Type 1 Onset in Three Patients Evaluated by Clinical and Polysomnographic Follow-Up. AB - Narcolepsy type 1 is a rare disabling sleep disorder mainly characterized by excessive daytime sleepiness and cataplexy, an emotion-triggered sudden loss of muscle tone. Patients have a selective degeneration of hypocretin-producing neurons in the dorsolateral posterior hypothalamus with growing evidence supporting the hypothesis of an autoimmune mechanism. Few case studies that reported intravenous immunoglobulin therapy (IVIg) suggest the efficacy of IVIg when administered early after disease onset, but the results are controversial. In these retrospective case observations, IVIg cycles were initiated within one to four months after cataplexy onset in a twenty-seven-year-old man, a ten-year old girl, and a seven-year-old boy, all three with early onset typical narcolepsy type 1. Efficacy of treatment (three IVIg cycles of 1 g/kg administered at four week intervals) was evaluated based on clinical, polysomnographic, and multiple sleep latency test (mean latency and SOREM) follow-up. Two patients reported decreased cataplexy frequency and ameliorated daytime sleepiness, but no significant amelioration of polysomnographic parameters was observed. Given the possibility of spontaneous improvement of cataplexy frequency with self behavioral adjustments, these observations would need to be confirmed by larger controlled studies. Based on the present study and current literature, proof of concept is still missing thus prohibiting the consideration of IVIg as an efficient treatment option. PMID- 30410635 TI - Trends in Survival of Patients with Primary Gastric Diffuse Large B-Cell Lymphoma: An Analysis of 7051 Cases in the SEER Database. AB - Treatment modalities for primary gastric diffuse large B-cell lymphoma (PG-DLBCL) have changed significantly during the past decades. However, limited information on the trends of clinical outcome of PG-DLBCL patients has been reported. Here, we conducted a retrospective analysis using the Surveillance, Epidemiology, and End Results (SEER) database to compare the survival trends of PG-DLBCL patients from 1973 to 2014. Patients were divided into 2 eras based on the year of diagnosis in relation to immunotherapy with the anti-CD20 antibody rituximab that was approved in 1997 and became a widely used drug in 2000. There was a significant improvement in survival among PG-DLBCL patients diagnosed in the 2001 2014 era (n = 4186) compared to patients diagnosed in the 1973-2000 era (n = 2865), with the 5-year overall survival rates of 53% and 47%, respectively (p = 0.001). Multivariable analysis revealed that the 2001-2014 era (HR = 0.892, p = 0.001) was associated with lower mortality and that patients of older age, Black race, advanced stage, and male gender were associated with poor prognosis. Although outcome of PG-DLBCL has significantly improved over time, more effective therapies are needed for older patients to further improve their survival. PMID- 30410637 TI - Elevated Serum Total Bilirubin Level Is Associated with Poor Outcomes in Pediatric Patients with Sepsis-Associated Liver Injury. AB - Aims: The aim of this study was to assess the prognostic value of the serum total bilirubin (TBIL) level in pediatric patients with sepsis-associated liver injury (SALI). Methods: We performed a retrospective study of patients with SALI admitted to the pediatric intensive care unit (PICU) in Shanghai Children's Hospital between December 2012 and December 2015. Serum TBIL concentration was determined within 72 h after PICU admission. Results: Seventy-two patients with SALI were included in this study. The overall mortality rate was 36.1% (26/72). The serum levels of TBIL of patients were significantly higher in the nonsurvivor group than the survivor group. Cox regression analysis indicated that the elevated serum TBIL level within 72 hours after admission was an independent risk factor of mortality in patients with SALI. Furthermore, the area under the receiver-operating characteristic (ROC) curve (AUC) for TBIL was 0.736 (95% confidence interval (CI): 0.614-0.858, P=0.001), in which the optimal cut-off value was 64.5 MUmol/L. The combined index named "TBIL" and "TBA" showed an AUC of 0.745 (0.626-0.865) for predicting the prognosis in patients with SALI. In addition, the Kaplan-Meier curve indicated that the 28-day survival rate was significantly lower in patients with higher serum TBIL levels (>=64.5 MUmol/L) or higher value of TBIL and TBA (>=-0.8902). Conclusions: Elevated serum TBIL level is associated with poor outcomes in pediatric SALI. PMID- 30410638 TI - Relationship between Cervical Spine and Skeletal Class II in Subjects with and without Temporomandibular Disorders. AB - Aim: To assess changes in the craniocervical structure and in hyoid bone position in skeletal Class II subjects with and without temporomandibular disorders (TMD). Materials and Methods: The cephalometric analysis of 59 subjects with skeletal Class II was evaluated and compared. The measurements considered were ANB as a parameter of Class II and C0-C1 distance, C1-C2 distance, craniocervical angle, and hyoid bone position for the cervical spine analysis. Patients were divided into patients with TMD (group A) and patients without TMD (group B). TMD were evaluated with Diagnostic Criteria for TMD (DC/TMD). Descriptive statistics and Pearson's and Spearman's correlation analysis, with p value <0,005, were performed. Results: C0-C1 and C1-C2 distance values and hyoid bone position resulted within the normal range in the majority of patients examined. Craniocervical angle was altered in 33 patients. The reduction of this angle with the increase of the ANB value resulted to be statistically significant in group A, according to Pearson's correlation index. No other data were statistically significant. Conclusions: The significant relationship between skeletal Class II and cervical spine cannot be highlighted. The alteration of craniocervical angle seems to be mildly present, with backward counterclockwise rotation of the head upon the neck in the sample (groups A and B). The presence of TMD as a key factor of changes in neck posture could explain the different result between the two groups about the relationship between ANB and craniocervical angle. This result should be further analyzed in order to better understand if cervical spine changes could be related to mandibular postural ones in the craniocervical space or to temporomandibular joint retropositioning, more recognizable in Class II with TMD, which could determine functional changes in other structures of this unit; neck posture could be the result of a compensatory/antalgic mechanism in response to TMD. PMID- 30410636 TI - Transcriptome analysis of peripheral blood from patients with rheumatoid arthritis: a systematic review. AB - In the era of precision medicine, transcriptome analysis of whole gene expression is an essential technology. While DNA microarray has a limited dynamic range and a problem of background hybridization, RNA sequencing (RNA-seq) has a broader dynamic range and a lower background signal that increase the sensitivity and reproducibility. While transcriptome analyses in rheumatoid arthritis (RA) have generally focused on whole peripheral blood mononuclear cells (PBMC), analyses of detailed cell subsets have an increased need for understanding the pathophysiology of disease because the involvement of CD4+ T cells in the pathogenesis of RA has been established. Transcriptome analysis of detailed CD4+ T cell subsets or neutrophils shed new light on the pathophysiology of RA. There are several analyses about the effect of biological treatment. Many studies report the association between type I interferon signature gene expression and response to therapy. PMID- 30410639 TI - Improvement of patient-reported outcomes in severe allergic asthma by omalizumab treatment: the real life observational PROXIMA study. AB - Background: Data on the prevalence of perennial versus seasonal allergic asthma in Italy are lacking; moreover, there is limited evidence on the effect of omalizumab on patient-reported outcomes in Italian patients with severe allergic asthma. PROXIMA, an observational, multicenter study, was designed to assess the prevalence of perennial versus seasonal allergic asthma (cross-sectional phase) and the effect of omalizumab on improving illness perception, quality of life (QoL) and asthma control of Italian patients with severe allergic asthma (longitudinal phase). Methods: The study included a cross-sectional phase (n = 357) and a longitudinal phase (n = 123): during the longitudinal phase, patients received omalizumab (75-600 mg subcutaneously every month) and were followed-up for 12 months. The primary parameter of cross-sectional phase was prevalence of perennial allergic asthma and that of longitudinal phase was proportion of patients with asthma control (assessed using asthma control questionnaire [ACQ]). Secondary parameters assessed were patients' disease perception, level of asthma control, exacerbation rate during both cross-sectional and longitudinal phases, and patients' compliance to and persistence with omalizumab, and patients' QoL during the longitudinal phase. Results: Most patients (95.8%) had perennial allergies; 81% had polysensitization. Of 99 patients in the per-protocol set, 95 (95.96% [95% CI: 89.98-98.89%]) achieved asthma control (ACQ < 4) at both 6 and 12 months of omalizumab treatment; ACQ score decreased after 6 and 12 months (P < 0.0001). Omalizumab treatment resulted in a significant improvement in QoL and patients' illness perception and 87% decrease in exacerbation rate. The compliance rate with omalizumab was high (73.2%). No new safety signals were identified during treatment. Conclusion: This study demonstrated that in severe allergic asthma, omalizumab improves patient-reported outcomes such as patients' illness perception and QoL, while confirming improvement of asthma control and exacerbation rate reduction in Italian patients. PMID- 30410640 TI - Isobavachalcone Induces ROS-Mediated Apoptosis via Targeting Thioredoxin Reductase 1 in Human Prostate Cancer PC-3 Cells. AB - Prostate carcinoma causes a great number of deaths every year; therefore, there is an urgent need to find new drug candidates to treat advanced prostate cancer. Isobavachalcone (IBC) is the chalcone composition of Psoralea corylifolia Linn used in traditional Chinese medicine. Although IBC demonstrates potent anticancer efficacy in numerous types of human cancer cells, the cellular targets of IBC have not been fully defined. In our study, we found that IBC may induce reactive oxygen species- (ROS-) mediated apoptosis via interaction with a selenocysteine (Sec) containing the antioxidant enzyme thioredoxin reductase 1 (TrxR1), and induce lethal endoplasmic reticulum (ER) stress by inhibiting TrxR1 activity and increasing ROS levels in human prostate cancer PC-3 cells. Furthermore, we also observed that knocking down TrxR1 would sensitized cancer cells to IBC treatment. Our study provides evidence for the anticancer mechanism of IBC with TrxR1 as a potential target. PMID- 30410641 TI - Hydroxysafflor Yellow A Shows Protection against PPARgamma Inactivation in Nitrosative Neurons. AB - Peroxynitrite-mediated nitrosative stress in the brain has been associated with various neurodegenerative disorders. Recent evidence highlights peroxisome proliferator-activated receptor gamma (PPARgamma) as a critical neuroprotective factor in neurodegenerative diseases. Here, we observed the effect of the herb hydroxysafflor yellow A (HSYA) during nitrosative stress in neurons and investigated the mechanism based on PPARgamma protection. We found that a single exposure of primary neurons to peroxynitrite donor SIN-1 caused neuronal injury, which was accompanied by the increase of PPARgamma nitration status and lack of activation of the receptor, as measured by PPARgamma DNA-binding activity, by agonist (15d-PGJ2 or rosiglitazone) stimulation. The crucial role of PPARgamma in neuronal defense against nitrosative stress was verified by showing that pretreatment with 15d-PGJ2 or rosiglitazone attenuated SIN-1-induced neuronal injury but pretreatment with GW9662, a PPARgamma antagonist, aggravated SIN-1 induced neuronal injury. The addition of HSYA not only inhibited SIN-1-induced neuronal damage but prevented PPARgamma nitrative modification and resumed PPARgamma activity stimulated by either 15d-PGJ2 or rosiglitazone. Furthermore, HSYA also showed the ability to rescue the neuroprotective effect of 15d-PGJ2 or rosiglitazone when the agonists were coincubated with SIN-1. Finally, in vivo experiments demonstrated that the administration of HSYA also efficiently blocked PPARgamma nitration and loss of activity in the SIN-1-injected hippocampus and reversed the increased neuronal susceptibility which was supported by the inhibition of Bcl-2 protein downregulation induced by SIN-1. The results suggest that HSYA protects neurons from nitrosative stress through keeping PPARgamma as a functional receptor, allowing a more effective activation of this neuroprotective factor by the endogenous or exogenous agonist. Our findings provide new clues in understanding the role of the neuroprotective potential of the herbal HSYA. PMID- 30410643 TI - Jean Bismuth Spearheads Issue on Venous Interventions. PMID- 30410644 TI - It's Time We Reassess Our Primitive Understanding of the Venous System. PMID- 30410642 TI - Draft genome sequence of Bacillus amyloliquefaciens subsp. plantarum strain Fito_F321, an endophyte microorganism from Vitis vinifera with biocontrol potential. AB - Bacillus amyloliquefaciens subsp. plantarum strain Fito_F321 is a naturally occurring strain in vineyard, with the ability to colonise grapevine and which unveils a naturally antagonistic potential against phytopathogens of grapevine, including those responsible for the Botryosphaeria dieback, a GTD disease. Herein we report the draft genome sequence of B. amyloliquefaciens subsp. plantarum Fito_F321, isolated from the leaf of Vitis vinifera cv. Merlot at Bairrada appellation (Cantanhede, Portugal). The genome size is 3,856,229 bp, with a GC content of 46.54% that contains 3697 protein-coding genes, 86 tRNA coding genes and 5 rRNA genes. The draft genome of strain Fito_F321 allowed to predict a set of bioactive compounds as bacillaene, difficidin, macrolactin, surfactin and fengycin that due to their antimicrobial activity are hypothesized to be of utmost importance for biocontrol of grapevine diseases. PMID- 30410645 TI - Central Venous Pathologies: Treatments and Economic Impact. AB - Chronic venous insufficiency (CVI) is responsible for significant costs to society in the form of medical and surgical treatment and, importantly, unmeasurable lost work productivity due to pain and disability. Symptomatic chronic central vein obstruction, a cause of CVI, is potentially treatable using open surgical and endovascular techniques to restore vessel patency. Although upper extremity central vein obstruction often requires an open surgical procedure for durable relief, endovascular stents have proven remarkably useful for iliofemoral disease. Containment of healthcare resources requires accurate diagnosis, durable treatment modalities, and appropriate patient selection so that therapy is targeted to those individuals most likely to benefit. In this regard, identification of appropriate lesions should be based on intravascular ultrasound and 3-dimensional imaging studies. Treatment with dedicated venous stents offers the potential for long-term symptomatic improvement and increased work productivity when used in a well-defined, anatomically appropriate population with significant, symptomatic CVI. PMID- 30410646 TI - Venous Thrombosis and Post-Thrombotic Syndrome: From Novel Biomarkers to Biology. AB - Deep vein thrombosis (DVT) is a common disease that carries serious ramifications for patients, including pulmonary embolism and post-thrombotic syndrome (PTS). Although standard treatment for DVT is anticoagulation, this carries an added risk of bleeding and increased medication monitoring. Identifying those at risk for DVT and PTS can be difficult, and current research with murine models is helping to illuminate the biologic changes associated with these two disorders. Potential novel biomarkers for improving the diagnosis of DVT and PTS include ICAM-1, P-selectin, and cell-free DNA. Inhibition of factor XI, P- and E selectin, and neutrophil extracellular traps holds promise for novel clinical treatment of DVT. Experimental research on PTS suggests potential cellular and mediator therapy targets of TLR9, MMP-2 and-9, PAI-1, and IL-6. Although many important concepts and mechanisms have been elucidated through research on DVT and PTS, more work must be done to translate experimental findings to the clinical arena. This review examines the currently used murine models of DVT, biomarkers involved in the pathophysiology and diagnosis of DVT and PTS, and potential pharmacologic targets for PTS treatment. PMID- 30410647 TI - Mechanical Properties of Diseased Veins. AB - Extensive research exists on arterial mechanical properties and how they change in disease conditions, but substantially less is known about venous mechanics in healthy and disease states. Although the mechanics of both vessel types are determined by the unique layered composition of the vessel wall, the precise distribution of the layers differs greatly between arteries and veins. Thus, vein mechanics must be analyzed and understood independently from those of arteries. This review discusses the compositional attributes that are unique to veins, how these attributes contribute to venous mechanics, and the alterations that occur to both composition and material properties during venous thrombosis and insufficiency. In general, changes to the venous wall during thrombosis increase wall stiffness and decrease extensibility. During venous insufficiency, however, both the stiffness and the extensibility of the venous wall decrease. Characterizing these changes is essential to better understand disease progression and build vein-specific devices for treating venous disease. PMID- 30410648 TI - Use of Computed Tomography and Magnetic Resonance Imaging in Central Venous Disease. AB - Successful management of acute deep vein thrombosis and post-thrombotic syndrome depends on careful patient selection and detailed investigation of thrombus extent, composition, and anatomy. This article reviews the use of computerized tomography and magnetic resonance imaging in the assessment of central deep veins of the pelvis and addresses new developments within the field. Despite drawbacks of each imaging modality, when contemplating deep venous reconstruction, cross sectional imaging should be considered for preoperative planning and to compliment intraoperative imaging tools, including intravascular ultrasound and contrast venography. PMID- 30410649 TI - Application of Intravascular Ultrasound in End-Stage Renal Patients with Central Venous Occlusive Disease. AB - Central venous occlusive disease is frequently observed in patients with end stage renal disease. Venography remains the gold standard for diagnosis, but intravascular ultrasound is a potentially beneficial adjunct that may positively influence intervention. PMID- 30410650 TI - Intraoperative Imaging and Image Fusion for Venous Interventions. AB - Advanced imaging for intraoperative evaluation of venous pathologies has played an increasingly significant role in this era of evolving minimally invasive surgical and interventional therapies. The evolution of dedicated venous stents and other novel interventional devices has mandated the need for advanced imaging tools to optimize safe and accurate device deployment. Most venous interventions are typically performed using a combination of standard 2-dimensional (2D) fluoroscopy, digital-subtraction angiography, and intravascular ultrasound imaging techniques. Latest generation computer tomography (CT) and magnetic resonance imaging (MRI) scanners have been shown to provide high-resolution 3D and 4D information about venous vasculature. In addition to morphological imaging, novel MRI techniques such as 3D time-resolved MR venography and 4D flow sequences can provide quantitative information and help visualize intricate flow patterns to better understand complex venous pathologies. Moreover, the high fidelity information from multiple imaging techniques can be integrated using image fusion to overcome the limitations of current intraoperative imaging techniques. For example, the limitations of standard 2D fluoroscopy and luminal angiography can be compensated for by perivascular and soft-tissue information from MRI during complex venous interventions using image fusion techniques. Intraoperative dynamic evaluation of devices such as venous stents and real-time understanding of changes in flow patterns during venous interventions may be routinely available in future interventional suites with integrated multimodality CT or MR imaging capabilities. The purpose of this review is to discuss the outlook for intraoperative imaging and multimodality image fusion techniques and highlight their value during complex venous interventions. PMID- 30410651 TI - Endovascular Treatment for Venous Diseases: Where are the Venous Stents? AB - There is a growing need for dedicated endovascular devices to treat pathologies affecting the venous system. However, because of a lack of research into venous diseases and treatments, the optimal design, material, and mechanical properties of venous stents remain unknown. Development of the ideal venous stent should be based on a thorough understanding of the underlying venous pathology. There are multiple venous diseases that differ from each other depending on their location (iliocaval, superior vena cava), mechanism (thrombotic versus nonthrombotic lesions), and chronicity. Thus, it is likely that stent material, design, and features should differ according to each underlying disease. From a mechanical point of view, the success of a venous stent hinges on its ability to resist crushing (which requires high global and local radial rigidity) and to match with the compliant implant environment (which requires high flexibility). Device oversizing, textile coverage, and drug coating are additional features that should be considered in the context of venous diseases rather than directly translated from the arterial world. This review examines the unique forces affecting venous stents, the problems with using arterial devices to treat venous pathologies, preliminary results of a study comparing crush resistance of commercially available laser-cut stents with a novel braided stent design, and its applicability to venous interventions. PMID- 30410652 TI - Endovascular Therapy for Central Venous Thrombosis. AB - Central vein thrombosis is defined as thrombosis of the major vessels draining either the upper or lower extremities. It presents most commonly in the upper limb, where it affects the subclavian veins and the superior vena cava; in the lower limb, it affects the common iliac veins and the inferior vena cava. These different anatomical segments pose unique challenges in both acute and chronic settings, and this article will summarize the current best practice treatment options. PMID- 30410653 TI - Pharmacologic and Pharmacomechanical Thrombolysis for Acute Deep Vein Thrombosis: Focus on ATTRACT CME. AB - Systemically delivered pharmacologic thrombolysis for acute deep vein thrombosis long ago gave way to catheter delivery of plasminogen activators within the clot. This simple concept resulted in markedly improved efficacy and safety. In an effort to accelerate thrombus dissolution or extraction, mechanical methods were developed, but the initial techniques left substantial residual thrombus that required subsequent catheter-directed thrombolysis (CDT). It was soon observed that combined pharmacomechanical thrombolysis was more effective than either one alone. Randomized trials of catheter-based strategies for thrombus removal have documented objective benefit, including improved patency, preserved valve function, and reduced post-thrombotic syndrome. The largest randomized study is the ATTRACT trial published at the end of 2017. Although mild post-thrombotic syndrome (PTS) was no different between the pharmacomechanical catheter-directed thrombolysis (PCDT) and control groups, acute pain and swelling and moderate-to severe PTS were reduced with PCDT. Additional analyses from this robust data set are forthcoming. PMID- 30410655 TI - Persistent Left Superior Vena Cava with Absent Right Superior Vena Cava. AB - Persistent left superior vena cava (PLSVC) is the most common congenital abnormality of the thoracic systemic venous drainage; in fact, cardiology fellows in training are often quizzed on this when a dilated coronary sinus is noted on an echocardiogram. However, its association with an absent right superior vena cava (RSVC) and how to diagnose this combined condition is less commonly known. We present two cases of PLSVC with an absent RSVC, describe how to recognize and confirm this diagnosis, and discuss its clinical relevance. PMID- 30410656 TI - Incision and Drainage of a Forgotten Vascular Graft. PMID- 30410654 TI - Primary Nonbacterial Thrombotic Endocarditis Presenting with Bowel Infarction Secondary to Superior Mesenteric Artery Embolism. AB - Nonbacterial thrombotic endocarditis (NBTE) is a rare antemortem diagnosis that is commonly associated with hypercoagulable states such as advanced malignancies, disseminated intravascular coagulation, and autoimmune diseases such as antiphospholipid syndrome and systemic lupus erythematosus. We present a case of a previously healthy 42-year-old man who presented with small bowel infarction caused by embolic occlusion of the superior mesenteric artery and was subsequently diagnosed with NBTE. Despite thorough investigation, efforts to find an underlying cause failed to reveal any associated systemic illnesses. This case report emphasizes the importance of further investigation into the possible underlying causes of NBTE, as it can manifest without any apparent systemic factors. PMID- 30410658 TI - Poet's Pen: Elegy Written in a Country Churchyard. PMID- 30410657 TI - Venous Thrombosis in Nephrotic Syndrome. AB - The column in this issue is supplied by Whitney Sharp, D.O., and Juan Jose Olivero, M.D. Dr. Sharp is chief medical resident in internal medicine at Houston Methodist Hospital and earned her Doctor of Osteopathic Medicine degree at Nova Southeastern University in Fort Lauderdale, Florida. Dr. Olivero is a nephrologist at Houston Methodist Hospital and a member of the hospital's Nephrology Training Program. He obtained his medical degree from the University of San Carlos School of Medicine in Guatemala, Central America, and completed his residency and nephrology fellowship at Baylor College of Medicine in Houston, Texas. PMID- 30410659 TI - Dr. Phil's Art Corner: The Thunderbirds Over a Canyon and Eagle Canyon. AB - Philip Alexander, M.D., is a native Texan, retired physician, and accomplished musician and artist. After 41 years as an internal medicine physician, Dr. Phil retired from his practice in College Station in 2016. A lifelong musician and former music professor, he often performs as an oboe soloist for the Brazos Valley Symphony Orchestra. He began exploring visual art in 1980, evolving from pencil sketches-including an official White House portrait of President Ronald Reagan-to the computer-generated drawings featured in this journal. His images, which first appeared in this journal in the spring of 2012, are his own original creations. To learn more about Dr. Phil and his art, read "Art and Medicine with Dr. Phil" in issue 13.2. PMID- 30410660 TI - Essay on Being a Doctor: Patient Mentor. AB - Through the generosity of Charles R. Millikan, D. Min., vice president for Spiritual Care and Values Integration, an annual award competition was established at Houston Methodist Hospital among the resident staff. To enter the writing competition, residents must submit a poem or essay of 1,000 words or less on the topic, "On Being a Doctor." A committee of seven was selected from Houston Methodist Hospital Education Institute to establish the judging criteria and select the winning entries. The following is the second-place winning entry for 2018; the third-place entry will be published in the next issue of this journal. PMID- 30410661 TI - Immune Checkpoint Inhibitor-Related Cardiotoxicity. PMID- 30410662 TI - Tyrosine Kinase Inhibitor-Induced Acute Myocarditis, Myositis, and Cardiogenic Shock. PMID- 30410663 TI - Mothers' Attachment is Linked to their Children's Anti-Inflammatory Gene Expression via Maternal Warmth. AB - Research has demonstrated links between adult romantic attachment and one's own physical health; little is known about links between adult attachment orientations and offspring health. Prior work has shown that parents' greater attachment anxiety and avoidance predicts less warmth toward their children. Extensive work has also shown that lower maternal warmth has negative downstream effects on offspring health. We tested the novel hypothesis that mothers' dispositional romantic attachment would be linked-via maternal warmth-to their children's expression of the glucocorticoid receptor gene NR3C1, higher expression of which is associated with healthier stress-regulation and inflammatory response. In a sample of 132 youth with asthma, we found that mothers' attachment anxiety and avoidance were both negatively associated with children's expression of NR3C1, explained by lower youth-rated maternal warmth. Effects held after adjusting for demographic and psychosocial covariates. Implications for parents' attachment influencing the health of offspring are discussed. PMID- 30410664 TI - Influence of Scribble polarity complex on hematopoiesis and leukemia - a matter of where, when and how. PMID- 30410666 TI - The anti-cancer effect of retinoic acid signaling in CRC occurs via decreased growth of ALDH+ colon cancer stem cells and increased differentiation of stem cells. AB - Background: Tumorigenesis is driven by stem cell (SC) overpopulation. Because ALDH is both a marker for SCs in many tissues and a key enzyme in retinoid acid (RA) signaling, we studied RA signaling in normal and malignant colonic SCs. Hypothesis: RA signaling regulates growth and differentiation of ALDH+ colonic SCs; dysregulation of RA signaling contributes to SC overpopulation and colorectal cancer (CRC) development. Methods: We analyzed normal and malignant colonic tissues and CRC cell lines to see if retinoid receptors (RXR & RAR) are exclusively expressed in ALDH+ SCs, and if RA signaling changes during CRC development. We determined whether RA signaling regulates cancer SC (CSC) proliferation, differentiation, sphere formation, and population size. Results: RXR & RAR were expressed in ALDH+ colonic SCs, but not in MCM2+ proliferative cells. Western blotting/immunostaining of CRCs revealed that RA signaling components become overexpressed in parallel with ALDH overexpression, which coincides with the known overpopulation of ALDH+ SCs that occurs during, and drives, CRC development. Treatment of SCs with all-trans retinoic acid (ATRA) decreased proliferation, sphere formation and ALDH+ SC population size, and induced differentiation along the neuroendocrine cell (NEC) lineage. Conclusions: Retinoid signaling, by regulating ALDH+ colonic CSCs, decreases SC proliferation, sphere formation, and population size, and increases SC differentiation to NECs. Dysregulation of RA signaling in colonic SCs likely contributes to overpopulation of ALDH+ SCs and CRC growth. Implications: That retinoid receptors RXR and RAR are selectively expressed in ALDH+ SCs indicates RA signaling mainly occurs via ALDH+ SCs, which provides a mechanism to selectively target CSCs. PMID- 30410665 TI - Circulating cell-free miR-494 and miR-21 are disease response biomarkers associated with interim-positron emission tomography response in patients with diffuse large B-cell lymphoma. AB - MicroRNA (miRNA)s are dysregulated in Diffuse large B-cell lymphoma (DLBCL), where they reflect the malignant B-cells and the immune infiltrate within the tumor microenvironment. There remains a paucity of data in DLBCL regarding cell free (c-f) miRNA as disease response biomarkers. Immunosuppressive monocyte/macrophages, which are enriched in DLBCL, are disease response markers in DLBCL, with miRNA key regulators of their immunosuppressive function. Our aim was to determine whether plasma miRNA that reflect the activity of the malignant B-cell and/or immunosuppressive monocytes/macrophages, have value as minimally invasive disease response biomarkers in DLBCL. Quantification of 99 DLBCL tissues, to select miRNA implicated in immunosuppressive monocytes/macrophage biology, found miR-494 differentially elevated. In a discovery cohort (22 patients), pre-therapy c-f miR-494 and miR-21 but not miR-155 were raised relative to healthy plasma. Both miR-494 and miR-21 levels 3-6 months reduced post immuno-chemotherapy. The validation cohort (56 patients) was from a prospective clinical trial. Interestingly, in sequential samples both miRNAs decreased in patients becoming Positron Emission Tomography/Computerized Tomography (PET/CT)-ve, but not in those remaining interim-PET/CT+. Patient monocytes were phenotypically and functionally immunosuppressive with ex-vivo monocyte depletion enhancing T-cell proliferation in patient but not healthy samples. Pre-therapy monocytes showed an immunosuppressive transcriptome and raised levels of miR-494. MiR-494 was present in all c-f nanoparticle fractions but was most readily detectable in unfractionated plasma. Circulating c-f miR-494 and miR-21 are disease response biomarkers with differential response stratified by interim-PET/CT in patients with DLBCL. Further studies are required to explore their manipulation as potential therapeutic targets. PMID- 30410667 TI - The transgenic expression of the beta-subunit of human chorionic gonadotropin influences the growth of implanted tumor cells. AB - The beta subunit of human chorionic gonadotropin (betahCG) is secreted by various tumors, and its presence associated with poor prognosis. Though exogenous hCG elicits the synthesis of molecules associated with angiogenesis, invasion, immune suppression and chemoresistance from responsive tumor cells in vitro, the influence of cell-extrinsic betahCG on tumorigenesis in vivo has not been adequately explored. Female C57BL/6-/- * FVBbetahCG/- F1 transgenic mice demonstrated ovarian hyperplasia and pituitary adenomas; transcripts of hCG driven, tumor-associated molecules were heightened in the pituitary. Upon the implantation of Lewis Lung Carcinoma cells (murine lung tumor cells derived from C57BL/6 mice) in transgenic mice, tumor incidence and volume were enhanced, and increased transcription and expression of hCG-driven, tumor-associated molecules was observed in excised tumors. While treatment of these mice with Cabergoline (a potent dopamine receptor agonist) had no significant effects, ovariectomy resulted in a reduction in the lag phase, accompanied by an increase in tumor incidence and volume upon Lewis Lung Carcinoma cell implantation. In tumors derived from Lewis Lung Carcinoma cell-implanted ovariectomized, transgenic mice, the transcription and expression of hCG-driven, tumor-associated molecules remained elevated and enhanced animal mortality was observed. Cell-extrinsic betahCG can therefore induce pro-tumorigenic effects in vivo (even on tumor lineages not part of the reproductive axis), with ovarian products mediating an ameliorating influence. PMID- 30410668 TI - ATR suppresses the pro-tumorigenic functions of breast stromal fibroblasts. AB - The ATR protein kinase is a master regulator of the cellular responses to DNA damage and replication stresses. Despite these crucial physiological roles, the implication of ATR in human carcinogenesis remains elusive. We have shown here that the ATR level is reduced in most cancer-associated fibroblasts (CAFs) as compared to their adjacent normal counterparts. Importantly, specific ATR knockdown activated breast fibroblasts, and enhanced their paracrine pro carcinogenic effects via strong increase in the expression/secretion of SDF-1 and IL-6. Furthermore, ATR-deficient fibroblasts enhanced tumor growth and aggressiveness in orthotopic breast tumor xenografts. On the other hand, ectopic expression of ATR suppressed the expression/secretion of several cancer-promoting proteins such as IL-6, TGF-beta1 and SDF-1, and inhibited the migration and invasion capacities of breast myofibroblast cells. Furthermore, ATR up-regulation in active breast fibroblasts reduced their paracrine pro-migratory/-invasive effects on breast cancer cells. Interestingly, the cancer promoting effects of ATR-deficient cells were repressed by ectopic expression of the ATR effector p53. These results indicate that ATR is a major target of cancer cells in breast fibroblasts wherein this protein kinase represses both autocrine and paracrine pro-carcinogenic effects. This indicates that the ATR status in these cells could be of great prognostic/diagnostic values. PMID- 30410669 TI - Obesity and Alzheimer's disease, does the obesity paradox really exist? A magnetic resonance imaging study. AB - Mid-life obesity is an established risk factor for Alzheimer's disease (AD) dementia, whereas late-life obesity has been proposed as a protective state. Weight loss, which predates cognitive decline, might explain this obesity paradox on AD risk. We aimed to assess the impact of late life obesity on brain structure taking into account weight loss as a potential confounder. We included 162 elderly controls of the Alzheimer's Disease Neuroimaging Initiative (ADNI) with available 3T MRI scan. Significant weight loss was defined as relative weight loss >=5% between the baseline and last follow-up visit. To be able to capture weight loss, only subjects with a minimum clinical and anthropometrical follow-up of 12 months were included. Individuals were categorized into three groups according to body mass index (BMI) at baseline: normal-weight (BMI<25 Kg/m2), overweight (BMI 25-30 Kg/m2) and obese (BMI>30 Kg/m2). We performed both an interaction analysis between obesity and weight loss, and stratified group analyses in the weight-stable and weigh-loss groups. We found a significant interaction between BMI and weight loss affecting brain structure in widespread cortical areas. The stratified analyses showed atrophy in occipital, inferior temporal, precuneus and frontal regions in the weight stable group, but increased cortical thickness in the weight-loss group. In conclusion, our data support that weight loss negatively confounds the association between late-life obesity and brain atrophy. The obesity paradox on AD risk might be explained by reverse causation. PMID- 30410670 TI - beta-amyloid wall deposit of temporal artery in subjects with spontaneous intracerebral haemorrhage. AB - Background: Cerebral Amyloid Angiopathy has been indicated as an important cause of spontaneous non-hypertensive intracerebral haemorrhage (ICH). Aims: to analyze the presence of beta-amyloid deposit in the temporal artery of consecutive patients with ICH in comparison to control subjects and its relation to APO-E haplotype frequency. Methods: We enrolled consecutive patients admitted to Neurosurgery Ward of University Hospital "P. Giaccone" of Palermo with a diagnosis of spontaneous non hypertensive ICH and as control 12 subjects without brain haemorrhage. Biopsy of superficial temporal artery has been performed and beta-amyloid deposit was quantified. Results: Among 25 subjects with ICH, 10 (40%) had APOE epsilon 2 allele and among these subjects 7 (70%) showed amyloid accumulation on temporal artery specimens, 8 (32%) subjects had APOE epsilon 3 allele and among these subjects only 2 (25%) showed amyloid accumulation on temporal artery specimens, whereas 7 (28%) had APOE epsilon 4 allele and of these, 7 (100%) showed amyloid accumulation on temporal artery specimens. At multivariable logistic regression analysis for the presence of amyloid, predictive factors for the presence of amyloid in temporal artery biopsies were: age, hypertension, intralobar site of haemorrhage, APOE epsilon 2 and APOE epsilon 4 alleles. Discussion: Our findings of a higher frequency of amyloid deposition in temporal artery specimens in subjects with spontaneous intracerebral haemorrhage indicate a possible role of temporal artery as a possible diagnostic site of biopsy in subjects at high risk to develop intracranial haemorrhage related to Cerebral Amyloid Angiopathy. PMID- 30410671 TI - DDB2 regulates Epithelial-to-Mesenchymal Transition (EMT) in Oral/Head and Neck Squamous Cell Carcinoma. AB - DDB2 is a sensor of DNA damage and it plays an important role in Global Genomic Repair (GG-NER). Our previous studies show that DDB2 is involved in the regulation of metastasis in colon adenocarcinoma. Squamous Cell Carcinomas in the Oral/Head & Neck region (HNSCC) are particularly aggressive due to high incidence of recurrence and distant metastasis. In this study, we show that DDB2 expression is downregulated in advanced HNSCCs and loss of DDB2 expression coincides with reduced survival. Recent meta-analysis of gene expression data characterized the mesenchymal-type (EMT-type) as one most aggressive cancer cluster in HNSCC. Here, we report that DDB2 constitutively represses mRNA expression of the EMT- regulatory transcription factors SNAIL, ZEB1, and angiogenic factor VEGF in HNSCC cells. As a result, re-expression of DDB2 in metastatic cells reversed EMT with transcriptional upregulation of epithelial marker E-cadherin, and downregulation of mesenchymal markers N-cadherin, Vimentin, and Fibronectin. Interestingly, in a reverse assay, depletion of DDB2 in non-metastatic cells induced expression of the same EMT-regulatory transcription factors. TGFbetas are major regulators of Snail and Zeb1, and we observed that DDB2 transcriptionally regulates expression of TGFB2 in HNSCC cells. Re-expression of DDB2 in mouse embryonic fibroblasts (MEFs) isolated from Ddb2 (-/-) knockout-mice resulted in repression of EMT regulatory factors Zeb1, Snail and Tgfb2. Taken together, these results support the active role of DDB2 as a candidate suppressor of the EMT-process in HNSCC. Early detection leads to significantly higher survival in HNSCC and DDB2 expression in tumors can be a predictor of EMT progression. PMID- 30410672 TI - H19 long non-coding RNA contributes to sphere formation and invasion through regulation of CD24 and integrin expression in pancreatic cancer cells. AB - The long non-coding RNA H19 is highly expressed in several cancers, and the functions of H19 vary among cancer cell types. Recently, we reported that H19 contributes to the metastasis of pancreatic ductal adenocarcinoma (PDAC) cells and that inhibition of H19 reduces metastasis in vivo. However, the molecular mechanisms underlying the metastasis-promoting role of H19 in PDAC cells remain poorly elucidated. In this study, we clarified the mechanisms by which H19 regulates PDAC metastasis, with a focus on cancer stem cells (CSCs), by using H19 overexpressing and knockdown PDAC cells. Whereas the sphere-formation and invasion abilities of PDAC cells depended on H19 expression levels, other CSC characteristics of the cells, including stemness-marker expression and anticancer drug resistance, were unaffected by H19 levels. Furthermore, metalloproteinase activity, a key mediator of invasion, was also independent of H19 expression. By contrast, H19 promoted cell adhesion through regulation of integrin and CD24 expression. Notably, the increased adhesion of H19-overexpressing cells was blocked by an anti-beta1-integrin antibody, and this resulted in the inhibition of sphere formation and invasion. Thus, H19 plays critical roles in the CSC self renewal and cell adhesion of PDAC that lead to invasion and metastasis. Our findings suggest that H19 represents a novel therapeutic target for the metastasis of pancreatic cancer. PMID- 30410673 TI - Modelling ponatinib resistance in tyrosine kinase inhibitor-naive and dasatinib resistant BCR-ABL1+ cell lines. AB - TKI resistance remains a major impediment to successful treatment of CML. In this study, we investigated the emerging modes of ponatinib resistance in TKI-naive and dasatinib resistant BCR-ABL1+ cell lines. To investigate potential resistance mechanisms, ponatinib resistance was generated in BCR-ABL1+ cell-lines by long term exposure to increasing concentrations of ponatinib. Two cell lines with prior dasatinib resistance demonstrated BCR-ABL1 kinase domain (KD) mutation(s) upon exposure to ponatinib. In one of these cell lines the T315I mutation had emerged during dasatinib exposure. When further cultured with ponatinib, the T315I mutation level and BCR-ABL1 mRNA expression level were increased. In the other cell line, compound mutations G250E/E255K developed with ponatinib exposure. In contrast, the ponatinib resistant cell lines that had no prior exposure to other TKIs (TKI-naive) did not develop BCR-ABL1 KD mutations. Rather, both of these cell lines demonstrated Bcr-Abl-independent resistance via Axl overexpression. Axl, a receptor tyrosine kinase, has previously been associated with imatinib and nilotinib resistance. Ponatinib sensitivity was restored following Axl inhibition or shRNA-mediated-knockdown of Axl, suggesting that Axl was the primary driver of resistance and a potential target for therapy in this setting. PMID- 30410674 TI - Leukemia inhibitory factor via the Toll-like receptor 5 signaling pathway involves aggravation of cachexia induced by human gastric cancer-derived 85As2 cells in rats. AB - Cancer cachexia is highly prevalent in gastric cancer patients and characterized by decreased food consumption and body weight. We previously created a rat model of cancer cachexia using MKN45cl85 and 85As2 cells derived from human gastric cancer. The 85As2 cells induced cachexia more potently compared to MKN45cl85 cells. To clarify the mechanism underlying the difference in the cachexia inducing ability of these cells, we conducted DNA microarray analysis, focusing on cell proliferation and the production of leukemia inhibitory factor (LIF), a cachexia-inducing factor. The plasma human LIF levels of 85As2-induced cachexic rats increased as symptoms worsened, whereas the plasma levels of MKNcl85 were low. 85As2 cells displayed more genetic changes compared to MKN45cl85 cells, which were related to Toll-like receptor (TLR) 4/5 signaling. Stimulation of both cells with TLR4 (lipopolysaccharide) or TLR5 (flagellin) agonists did not affect proliferation. However, in 82As2 cells, LIF production was significantly increased by stimulation with TLR5, which was suppressed by an inhibitor of interleukin-1 receptor-associated kinase-1/4, which are important factors in the TLR5 signaling pathway. The increase in LIF production resulting from activation of the TLR5 signaling pathway may contribute to the cachexia-inducing ability of 85As2 cells. PMID- 30410675 TI - Does afatinib plus bevacizumab combination therapy induce positive conversion of T790M in previously-negative patients? AB - Third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are markedly effective for T790M-positive patients. To confer their clinical benefit to more patients, a novel therapy to induce positive conversion in T790M-negative patients may be possible. We retrospectively reviewed medical records of patients who had received rebiopsy after completion of ABC-study: a prospective phase II study of Afatinib plus Bevacizumab Combination (ABC)-therapy after acquired resistance to EGFR-TKI. Between October 2014 and September 2016, 32 eligible patients were enrolled in ABC-study at our institutes. Eighteen patients were T790M-negative and 14 were T790M-positive before ABC-therapy. Rebiopsy was performed on 13 T790M-negative and 5 T790M positive patients after progression of ABC-therapy. In 8 (62%) of 13 T790M negative patients, T790M status changed from negative to positive after ABC therapy. Seven of these 8 patients underwent osimertinib therapy. The response rate and median time to treatment failure were 86% and 12.2 months, respectively. There were no adverse events >=grade 3, nor any treatment-related deaths. On the other hand, T790M remained positive after ABC-therapy in all 5 previous T790M positive patients. ABC-therapy could induce positive conversion of T790M even in previously-negative patients. We hypothesize that ABC-therapy could provoke "clonal selection", which purifies T790M-positive cancer cells in heterogeneous tumors. Further studies are warranted to confirm this phenomena. PMID- 30410676 TI - Deletion of the glucocorticoid receptor chaperone FKBP51 prevents glucocorticoid induced skin atrophy. AB - FKBP51 (FK506-binding protein 51) is a known co-chaperone and regulator of the glucocorticoid receptor (GR), which usually attenuates its activity. FKBP51 is one of the major GR target genes in skin, but its role in clinical effects of glucocorticoids is not known. Here, we used FKBP51 knockout (KO) mice to determine FKBP51's role in the major adverse effect of topical glucocorticoids, skin atrophy. Unexpectedly, we found that all skin compartments (epidermis, dermis, dermal adipose and CD34+ stem cells) in FKBP51 KO animals were much more resistant to glucocorticoid-induced hypoplasia. Furthermore, despite the absence of inhibitory FKBP51, the basal level of expression and glucocorticoid activation of GR target genes were not increased in FKBP51 KO skin or CRISPR/Cas9-edited FKBP51 KO HaCaT human keratinocytes. FKBP51 is known to negatively regulate Akt and mTOR. We found a significant increase in AktSer473 and mTORSer2448 phosphorylation and downstream pro-growth signaling in FKBP51-deficient keratinocytes in vivo and in vitro. As Akt/mTOR-GR crosstalk is usually negative in skin, our results suggest that Akt/mTOR activation could be responsible for the lack of increased GR function and resistance of FKBP51 KO mice to the steroid induced skin atrophy. PMID- 30410677 TI - Clinical impact of serum soluble SLAMF7 in multiple myeloma. AB - The signaling lymphocytic activation molecule family (SLAMF7; also known as CS1 or CD319) is highly expressed on plasma cells from multiple myeloma (MM) as well as natural killer (NK) cells and is a well-known therapeutic target of elotuzumab. The objective of this study was to evaluate the clinical significance of serum soluble SLAMF7 (sSLAMF7) levels in patients with MM (n=103) and furthermore the impact of sSLMF7 on the antitumor activity of anti-SLAMF7 antibody. Thirty-one percent of MM patients, but not patients with monoclonal gammopathy of undetermined significance and healthy controls, had detectable levels of serum sSLAMF7, which were significantly increased in advanced MM patients. Further, MM in sSLAMF7-postive patients exhibited aggressive clinical characteristics with shorter progression-free survival times in comparison with sSLAMF7-negative patients. In responders to MM therapy, the levels of sSLAMF7 were undetectable or decreased compared with those before treatment. In addition, the anti-SLAMF7 antibody-mediated antibody-dependent cellular cytotoxicity of NK cells against MM cell lines was inhibited by recombinant SLAMF7 protein. Thus, our findings suggest that high concentrations of sSLAMF7, which could transiently suppress the therapeutic effects of elotuzumab, may be a useful indicator of disease progression in MM patients. PMID- 30410678 TI - Multi-omic based molecular profiling of advanced cancer identifies treatable targets and improves survival in individual patients. AB - A proof-of-concept study was conducted to assess whether patients with advanced stage IV cancer for whom predominantly no standard therapy was available could benefit from comprehensive molecular profiling of their tumor tissue to provide targeted therapy. Tumor samples of 83 patients were collected under highly standardized conditions and analyzed using immunohistochemistry, next-generation sequencing and phosphoprotein profiling. Expression and phosphorylation of key oncogenic pathways were measured to identify targets at the (phospho-) proteomic level. At genomic level, 50 oncogenes and tumor suppressor genes were analyzed. Based on molecular profiling, targeted therapies were decided by the attending oncologist. Accordingly, 28 patients who met the defined criteria fell in two equal-sized groups. One group received targeted therapies while the other did not. Following six months of treatment, disease control was achieved by 49% of patients receiving targeted therapy (complete remission, 14%; partial remission, 21%; stable disease, 14%; disease progression, 36%; death, 14%) and 21% of patients receiving non-targeted therapy (stable disease, 21%; disease progression, 64%; death, 14%). Individual patients experienced dramatic responses to a therapy which otherwise would not have been applied. This approach clarifies the value of multi-omic molecular profiling for cancer diagnostics. PMID- 30410679 TI - Peritoneal NK cells are responsive to IL-15 and percentages are correlated with outcome in advanced ovarian cancer patients. AB - The demonstration that ovarian carcinoma (OC) is an immunogenic disease, opens opportunities to explore immunotherapeutic interventions to improve clinical outcome. In this regard, NK cell based immunotherapy could be promising as it has been demonstrated that OC cells are susceptible to killing by cytokine-stimulated NK cells. Here, we evaluated whether percentage, phenotype, function and IL-15 responsiveness of ascites-derived natural killer (NK) cells is related to progression-free survival (PFS) and overall survival (OS) of advanced stage OC patients. Generally, a lower percentage of NK cells within the lymphocyte fraction was seen in OC ascites (mean 17.4 +/- 2.7%) versus benign peritoneal fluids (48.1 +/- 6.8%; p < 0.0001). Importantly, a higher CD56+ NK cell percentage in ascites was associated with a better PFS (p = 0.01) and OS (p = 0.002) in OC patients. Furthermore, the functionality of ascites-derived NK cells in terms of CD107a/IFN-gamma activity was comparable to that of healthy donor peripheral blood NK cells, and stimulation with monomeric IL-15 or IL-15 superagonist ALT-803 potently improved their reactivity towards tumor cells. By showing that a higher NK cell percentage is related to better outcome in OC patients and NK cell functionality can be boosted by IL-15 receptor stimulation, a part of NK cell immunity in OC is further deciphered to exploit NK cell based immunotherapy. PMID- 30410682 TI - Erratum: Targeting Metabolic Remodeling in Glioblastoma Multiforme. AB - [This corrects the article DOI: 10.18632/oncotarget.190.]. PMID- 30410681 TI - Extracellular vesicles in oral squamous carcinoma carry oncogenic miRNA profile and reprogram monocytes via NF-kappaB pathway. AB - Extracellular vesicles (EVs) are carriers of different biomacromolecules that participate in cellular signaling and disease pathogenesis. Although it has been shown that EVs can play an active role in cellular communication and different stages of cancer progression, the role of EVs in oral squamous cell carcinoma (OSCC) cancer pathogenesis, especially in the crosstalk of cancer cells with immune cells is unknown. Here, we present a detailed analysis of findings regarding the profile of EVs in OSCC and the role of EVs and associated miRNAs in the crosstalk of malignant cells with monocytes. We demonstrate that EVs are detectable in significantly higher quantities in the plasma of patients with OSCC. Oncogenic miRNAs (such as miR-21, miR-27) were detectable in high quantities in the circulating EVs and plasma of patients with OSCC. EVs isolated from the circulation of OSCC patients and OSCC cell lines showed comparable miRNA signature, indicating the tumor origin of EVs in the circulation of patients with OSCC. Danger signals such as LPS and ethanol increased the production of EVs. EVs were taken up by monocytes after co-culture. Mechanistically, uptake of EVs derived from oral cancer cells by monocytes caused activation of the inflammatory pathway, NF-kappaB activation, and establishment of a pro-inflammatory and pro tumorigenic milieu marked by increased levels of IL-6, CCL2, PEG2 and MMP9 levels. Series of experiments involving the introduction of exogenous oncogenic miR-21 mimic induced a similar pro-inflammatory and pro-tumorigenic profile in monocytes. Inhibiting miR-21 function in monocytes attenuated the pro inflammatory phenotype of monocytes after EV challenge. These results indicate the role of EV-associated miR-21 in modulating the immune response in monocytes. PMID- 30410680 TI - PARP1 is required for preserving telomeric integrity but is dispensable for A NHEJ. AB - Poly-ADP ribose polymerase 1 (PARP1) is clinically important because of its synthetic lethality with breast cancer allele 1 and 2 mutations, which are causative for inherited breast and ovarian cancers. Biochemically, PARP1 is a single-stranded DNA break repair protein that is needed for preserving genomic integrity. In addition, PARP1 has been implicated in a veritable plethora of additional cellular pathways and thus its precise contribution(s) to human biology has remained obscure. To help address this deficiency, we utilized gene editing to construct genetically-null PARP1 human cancer cells. We found a minor role for PARP1 in an alternative form of DNA double-strand break (DSB) repair, but only when these cells were deficient for the classical form of DSB repair. Despite being proficient for DSB repair, however, cell cycle progression defects and elevated endogenous DNA damage signaling were observed. These deficiencies were instead linked to telomere defects, where PARP1 -/- cells had short telomeres that co-localized with markers of endogenous DNA damage and were compromised in their ability to escape a telomere-driven crisis. Our data suggest that while PARP1 does not participate significantly in DNA DSB repair itself, it does prevent the incidence of telomeric DSBs, which, in turn, can drive genomic instability. PMID- 30410683 TI - Erratum: Drug Discovery Approaches to Target Wnt Signaling in Cancer Stem Cells. AB - [This corrects the article DOI: 10.18632/oncotarget.191.]. PMID- 30410685 TI - Medications Without Harm? PMID- 30410684 TI - General synthesis of silica-based yolk/shell hybrid nanomaterials and in vivo tumor vasculature targeting. AB - Multifunctional yolk/shell-structured hybrid nanomaterials have attracted increasing interest as theranostic nanoplatforms for cancer imaging and therapy. However, because of the lack of suitable surface engineering and tumor targeting strategies, previous research has focused mainly on nanostructure design and synthesis with few successful examples showing active tumor targeting after systemic administration. In this study, we report the general synthetic strategy of chelator-free zirconium-89 (89Zr)-radiolabeled, TRC105 antibody-conjugated, silica-based yolk/shell hybrid nanoparticles for in vivo tumor vasculature targeting. Three types of inorganic nanoparticles with varying morphologies and sizes were selected as the internal cores, which were encapsulated into single hollow mesoporous silica nanoshells to form the yolk/shell-structured hybrid nanoparticles. As a proof-of-concept, we demonstrated successful surface functionalization of the nanoparticles with polyethylene glycol, TRC105 antibody (specific forCD105/endoglin), and 89Zr (a positron-emitting radioisotope), and enhanced in vivo tumor vasculature-targeted positron emission tomography imaging in 4T1murine breast tumor-bearing mice. This strategy could be applied to the synthesis of other types of yolk/shell theranostic nanoparticles for tumor targeted imaging and drug delivery. PMID- 30410687 TI - Patterns and Complications of Ingested Foreign Bodies in Omani Children. AB - Objectives: We sought to describe the frequency of encounters and complications of foreign body (FB) ingestion in children seen at Royal Hospital, Oman. Methods: Medical records of all children (<= 13 years) who presented to Royal Hospital between 1 January 2011 and 31 December 2014 diagnosed with FB ingestion were reviewed. Children with FBs in their mouth or airway, with esophageal food impaction, and caustic ingestion were excluded from the analysis. Parameters including age, sex, type of FB, anatomical location of the FB on X-ray, endoscopic findings, and all complications were reviewed. Results: Of the 585 children diagnosed with FB ingestion, 385 were included in the study; 58.4% were males and 41.6% were females giving a male to female ratio of 1.4:1.0. Half (50.9%) of the children were less than three years old. Coins were the most frequently ingested objects (41.3%) followed by disc batteries (12.2%). Sixty three patients (16.3%) required urgent esophagogastroduodenoscopy (EGD). EGD was performed mainly for coins (44.4%) followed by disc batteries (14.3%) in the esophagus or stomach. The complication rate was 5.2% in total, and 3.6% for clinically significant complications. We had no mortality cases. Conclusions: FB ingestion is common in toddlers in Oman. Coins and disc batteries are most commonly ingested calling for strict family vigilance. Endoscopy is done in a small number of children and clinically significant complications, in general, are low. However, these findings should not lead to a false sense of security, and ingested FBs should always be taken seriously. PMID- 30410686 TI - Hypocalcemia in Pregnancy: A Clinical Review Update. AB - Though hypocalcemia in pregnancy is not often reported in the literature, it occurs in cases of hypoparathyroidism and in mothers with severe dietary inadequacy. Hypocalcemia during pregnancy can pose numerous problems to the mother and fetus. It is associated with hypertensive disorders and can increase the risk of numerous problems such as preeclampsia and fetal growth disorders. In this review, we summarize the challenges physicians face diagnosing and managing hypocalcemia during pregnancy. A multidisciplinary team including endocrinologists and obstetricians is warranted to ensure appropriate treatment and optimal outcomes. PMID- 30410688 TI - Epidemiological and Clinical Features of Salmonella Typhi Infection Among Adult Patients in Qatar: A Hospital-based Study. AB - Objectives: We sought to describe the epidemiological and clinical features of typhoid fever in Qatar. Methods: We conducted a retrospective study of adult patients treated for typhoid fever at Hamad General Hospital and Alkhor Hospital between 2005 and 2012. Results: The mean age of the 354 patients enrolled in the study was 28.4+/-9.3 years; 296 (83.6%) were males. There were 42, 48, 39, 44, 46, 47, 52, and 36 cases of adults with typhoid fever in 2005, 2006, 2007, 2008, 2009, 2010, 2011, and 2012, respectively. Overall, 343 (96.9%) patients had a history of travel to endemic areas. Among them, 93.0% acquired typhoid fever in the Indian subcontinent. Fever was observed in all cases, and the other predominant symptoms were abdominal pain (38.1%), diarrhea (35.6%), and headache (33.1%). Salmonella typhi, showed high resistance to ciprofloxacin (n = 163; 46.0%), and low resistance to ceftriaxone (n = 2; 0.6%). Four patients developed intestinal perforation, which was surgically repaired in two cases. Two patients (0.6%) died. Conclusions: Typhoid fever was frequent among immigrants to endemic areas. Travelers returning from endemic areas with suspected typhoid fever should be treated empirically with third-generation cephalosporin after obtaining appropriate cultures. Moreover, preventive measurements such as education on food and water hygiene, and effective vaccination of travelers should be practiced widely among travelers to endemic areas to reduce morbidity and mortality. PMID- 30410690 TI - Patent Contralateral Processus Vaginalis in Infants and Children: Is Herniotomy Justified? AB - Objectives: Contralateral inguinal exploration in pediatric unilateral inguinal hernia has been an issue of debate. Controversy still exists on whether contralateral patent processus vaginalis (CPPV) is justifiable for herniotomy. This study was conducted to investigate the hypothesis that CPPV always necessitates herniotomy. Methods: This prospective study was conducted on 200 pediatric patients aged 2-120 months old. All patients clinically diagnosed with a unilateral inguinal hernia underwent a clinical examination of both inguinoscrotal regions followed by ultrasonography to elucidate CPPV in both sides. Herniotomy was then performed on the hernia site with laparoscopic evaluation of CPPV. Contralateral herniotomy was performed in 44 patients with Chin's type III CPPV while the rest were followed-up for three years to detect the appearance of any contralateral inguinal hernia. Results: The current study included 158 boys and 42 girls (ratio of 3.8:1.0). Hernia was more common on the right side (n = 136) than the left side (n = 64). Bilateral herniotomy was performed on 44 patients with Chin's type III CPPV, while the remaining 156 patients underwent unilateral herniotomy. During the follow-up period, contralateral hernia appeared in 58 patients; the remaining 98 patients, proved to have CPPV did not complain of a clinical hernia during that period. Conclusions: Inguinal herniotomy for CPPV seems not to be necessary in all cases. This would decrease the use of anesthesia and surgical morbidity in young infants and save hospital resources through avoidance of ?unnecessary operations. PMID- 30410689 TI - The Effects of Omega-3 and Vitamin E Co-supplementation on Carotid Intima-media Thickness and Inflammatory Factors in Patients with Polycystic Ovary Syndrome. AB - Objectives: We sought to evaluate the effects of omega-3 and vitamin E co supplementation on carotid intima-media thickness (CIMT) and inflammatory factors in patients with polycystic ovary syndrome (PCOS). Methods: This randomized, double-blind, placebo-controlled trial was done among 60 women with PCOS. Participants were randomly assigned into two groups (n = 30 each group) and assigned to take either 1000 mg omega-3 plus 400 IU vitamin E supplements or a placebo for 12 weeks. Results: Compared with placebo, omega-3 and vitamin E co supplementation led to significant decreases in maximum levels of left CIMT ( 0.006+/-0.006 vs. +0.002+/-0.007 mm, p < 0.001), mean levels of left CIMT ( 0.005+/-0.006 vs. +0.002+/-0.010 mm, p = 0.010), maximum levels of right CIMT ( 0.006+/-0.010 vs. +0.006+/-0.010 mm, p = 0.010), and mean levels of right CIMT ( 0.005+/-0.005 vs. +0.001+/-0.010 mm, p = 0.020). Change in high-sensitivity C reactive protein (hs-CRP) (-390.6+/-942.9 vs. +237.0+/-754.3 ng/mL, p = 0.006) was significantly different between the supplemented patients and placebo group. We did not observe any significant effect in plasma nitric oxide (NO) values following supplementation with omega-3 plus vitamin E compared with the placebo. Conclusions: Co-supplementation with omega-3 and vitamin E for 12 weeks among patients with PCOS had beneficial effects on CIMT and serum hs-CRP values, but unchanged NO values. PMID- 30410691 TI - Interprofessional Competency Framework for Health Service Managers in Oman: An e Delphi Study. AB - Objectives: This study aimed to develop the required interprofessional competencies for health service managers in Oman. Methods: Experts (n = 20) were selected based on their years' experience, position, fluency in English (both verbal and written), and who had completed higher education at either masters or doctorate levels in the relevant field. The data collection consisted of three rounds. Responses were collected and extracted from a web-based designed survey and subsequently analyzed. Results: Experts agreed on the nine interprofessional domains and 41 competencies based on the inclusion of means (M) 3 4.4, an interquartile distribution (IQD) <= 1.25, and > 80.0% agreement. Findings revealed that there were levels of agreement (90.0% to 95.0%) among the experts in the nine interprofessional competency domains namely: resilience (M = 4.7, IQD = 0.40), research leverage (M = 4.7, IQD = 0.60), interprofessional ethics (M = 4.7, IQD = 0.80), quality improvement (M = 4.7, IQD = 0.80), information technology (M = 4.6, IQD = 0.80), leadership (M = 4.5, IQD = 1.00), management skills (M = 4.5, IQD = 0.80), communication (M = 4.5, IQD = 1.00), and team dynamics (M = 4.5, IQD = 1.00). Conclusions: The development of interprofessional competencies for health service managers is an impetus to strengthen the human resources capabilities, sustain a high level of quality patient outcomes, and to achieve the Ministry of Health's Health Vision 2050. PMID- 30410692 TI - Childbirth Fear and Associated Factors in a Sample of Pregnant Iranian Women. AB - Objectives: Fear of childbirth is common during pregnancy and may contribute to several adverse outcomes. We aimed to investigate childbirth fear and associated factors in a sample of pregnant Iranian women. Methods: This cross-sectional study was conducted on 525 pregnant women in Sabzevar, Iran from December 2016 to March 2017. The Wijma Delivery Expectancy/Experience Questionnaires (W-DEQ) was used to investigate fear of childbirth. Results: The mean W-DEQ score was 67.6+/ 23.5. Of 525 women, 19.6% and 6.1% experienced moderate (mean W-DEQ score >= 85) and severe (mean W-DEQ score >= 100) fear of childbirth, respectively. W-DEQ scores were not different in the categories of gestational age, parity, maternal age, educational level, body mass index, and employment status (p > 0.050). The mean score of childbirth fear was significantly higher in multiparas who preferred cesarean in comparison to those who preferred vaginal delivery (p < 0.032). The mean score of childbirth fear was significantly higher in nulliparas with a lower family income compared to those with a higher family income (p < 0.011). In nulliparas, predictors of moderate and severe childbirth fear were women's description of their present pregnancy (odds ratio (OR) = 2.600; 95% confidence interval (CI): 1.323-5.112), and receiving a low level of emotional support from their husband (OR = 4.450; 95% CI: 1.349-14.674), respectively. In multiparas, predictors of childbirth fear were unwanted pregnancy (OR = 2.930; 95% CI: 1.549-3.541), experiencing moderate to severe dyspareunia in the first intercourse (OR = 2.829; 95% CI: 1.479-5.414), having a low level of physical activity (OR = 1.942; 95% CI: 1.014-3.716), and perceived a low level of health (OR = 3.415; 95% CI: 1.172-9.950). Conclusions: We observed a relatively high prevalence of childbirth fear in pregnant women in Iran. Interventions should be implemented in high-risk women considering psychological variables. PMID- 30410693 TI - Delayed Start Protocol with Gonadotropin-releasing Hormone Antagonist in Poor Responders Undergoing In Vitro Fertilization: A Randomized, Double-blinded, Clinical Trial. AB - Objectives: We sought to determine the effects of the delayed start protocol with gonadotropin-releasing hormone (GnRH) antagonists in poor responders undergoing in vitro fertilization (IVF). Methods: This randomized clinical trial was conducted during a 15-month period from April 2014 to July 2015 in clinics in Shiraz, Iran. A total of 42 poor responders with primary infertility were randomly assigned to the controlled ovarian stimulation group utilizing the delayed start protocol (n = 21) or the traditional group (n = 21) using GnRH antagonist, Cetrotide. The primary endpoint was the number of patients undergoing oocyte pick-up, implantation, and the rate of pregnancy. Results: The baseline characteristics of the two study groups were comparable including age, infertility duration, and body mass index. The number of follicles measuring > 13 mm in diameter (p = 0.057), retrieved oocytes (p = 0.564), mature metaphase II oocytes (p = 0.366), embryos (p = 0.709), and transferred embryos (p = 0.060) were comparable between the two groups. The number of patients undergoing oocyte pick-up (p = 0.311), the rates of implantation (p = 0.407), and pregnancy (p = 0.596) were also comparable between the two groups. Conclusions: The delayed start protocol was not associated with better conception results or cycle outcomes in poor responders with primary infertility undergoing IVF cycles. PMID- 30410694 TI - Characteristics and Correlates of Psychiatric Problems in Wives of Men with Substance-related Disorders, Kermanshah, Iran. AB - Objectives: We sought to evaluate the characteristics and correlates of psychiatric problems in the wives of men with substance-related disorders. Methods: Four-hundred and fifty women whose husbands had substance-related disorders were selected by purposive sampling for inclusion in the study. Results: The prevalence of psychiatric symptoms in our sample was 67.1% (n = 302). Depression was the most prevalent symptom ?(n = 63) and the least was psychosis (n = 5). The prevalence of psychiatric symptoms was highest (26.0%) among women with opiate-dependent spouses (n = 117), and those with hallucinogen dependent spouses had the lowest prevalence (4.2%). We found a significant relationship between the prevalence of psychiatric disorders and demographic factors including age, women's education, spouse's education, women's job, duration of marriage, number of children, monthly income, and history of psychiatric disorders with the exception of spouses' jobs. Conclusions: There is a high prevalence of psychiatric symptoms among the wives of men with substance related disorders and there is need to devise mechanism to reduce the high prevalence of psychiatric disorders. PMID- 30410695 TI - Cervical Aerocele: A Rare Delayed Complication of Tracheostomy. AB - Acquired cervical aerocele in adults is a rare condition and its delay development after tracheostomy decannulation is reported rarely. Our patient presented eight years after tracheostomy decannulation with a compressible anterior neck mass that only appeared when she coughed and could be deflated using manual compression. The mass was situated suprasternal at the previous tracheostomy scar. Computed tomography scan showed a paratracheal air sac without significant defect at the tracheal wall. Surgical intervention is the best treatment for symptomatic patients. As in this patient, we advise direct laryngoscopy and bronchoscopy for diagnostic and therapeutic purposes in such cases. However, our patient refused any surgical intervention. PMID- 30410696 TI - Lemierre's Syndrome. AB - Lemierre's syndrome is a rare, life-threatening condition, which may be fatal if not properly treated. This disease refers to thrombophlebitis of the internal jugular vein, which is the result of bacterial sore throat infection (usually in the form of pharyngitis) that extends into the parapharyngeal space. However, it can result from other infective foci in the ear, nose, parotid glands, and paranasal sinuses. The bacteria typically responsible is Fusobacterium necrophorum. Here, we describe a case of Lemierre's syndrome that occurred in a 20-year-old female who presented with neurological deficits following a two-week history of upper respiratory tract infection. Our case displayed typical findings of this rare condition with a review of the previous literature and also to emphasize the importance of high index of suspicion to reduce the mortality of this disease. PMID- 30410697 TI - Massive Gastrointestinal Bleeding from Choriocarcinoma of the Ovary. AB - Choriocarcinoma of the ovary is a rare neoplasm and tends to metastasize early to involve the lungs, brain, and liver. Metastasis to the gastrointestinal tract is rare. We report the case of a young lady, who presented with life-threatening gastrointestinal bleeding, secondary to jejunal involvement. The site of bleeding was localized using a computed tomography angiogram following inconclusive upper and lower gastrointestinal endoscopies. The bleeding jejunal segment was resected and the metastatic disease responded to combination chemotherapy. Metastatic choriocarcinoma of the ovary should be considered a possible diagnosis in patients presenting with gastrointestinal bleeding. PMID- 30410698 TI - Percutaneous Carillon Mitral Contour System Deployment Followed by CRT-D Implantation: First Case Report from Oman. AB - Mitral valve regurgitation (MR) is a common problem in patients with cardiac issues especially those with dilated cardiomyopathy (DCM) due to mitral annular dilatation and malcoaptation of the mitral valve leaflets. Although DCM is associated with high mortality rates, there has been no global agreement about the best method of treatment. Treatment of MR in such cases can be done by surgery, which has many limitations due to high-risk concerns. MR may also be managed by other alternatives such as mitral-clip and transcoronary venous mitral annuloplasty using the Carillon(r) Mitral Contour System(r). Combined therapy with a cardiac resynchronization therapy defibrillator (CRT-D) and mitral contour can be used in such cases with valuable improvement in general condition in many patients. In our case, we used the Carillon Mitral Contour System for treatment of severe MR in a 64-year-old patient with severely impaired systolic function after implantation of a CRT-D. PMID- 30410699 TI - Radiology Quiz: Right Thoracic Cavity Mass. PMID- 30410700 TI - Thrombophilic Evaluation in Cases of Cerebral Venous Sinus Thrombosis. PMID- 30410701 TI - Letter in Reply: Thrombophilic Evaluation in Cases of Cerebral Venous Sinus Thrombosis. PMID- 30410702 TI - Trifecta St. Jude medical(r) aortic valve in pulmonary position. AB - Introduction: To evaluate an aortic pericardial valve for pulmonary valve (PV) regurgitation after repair of congenital heart defects. Methods: From July 2012 to June 2016 71 patients, mean age 24 +/- 13 years (four to years) underwent PV implantation of aortic pericardial valve, mean interval after previous repair = 21 +/- 10 years (two to 47 years). Previous surgery at mean age 3.2 +/- 7.2 years (one day to 49 years): tetralogy of Fallot repair in 83% (59/71), pulmonary valvotomy in 11% (8/71), relief of right ventricular outflow tract (RVOT) obstruction in 6% (4/71). Pre-operative echocardiography and MRI showed severe PV regurgitation in 97% (69/71), moderate in 3% (2/71) with associated RVOT obstruction. MRI and knowledge-based reconstruction 3D volumetry (KBR-3D volumetry) showed mean PV regurgitation = 42 +/- 9% (20-58%), mean indexed RV end diastolic volume = 169 +/- 33 (130-265) ml m-2 BSA and mean ejection fraction (EF) = 46 +/- 8% (33-61%). Cardio-pulmonary exercise showed mean peak O2/uptake = 24 +/- 8 ml kg-1 min-1 (14-45 ml kg-1 min-1), predicted max O2/uptake 66 +/- 17% (26-97%). Pre-operative NYHA class was I in 17% (12/71) patients, II in 70% (50/71) and III in 13% (9/71). Results: Mean cardio-pulmonary bypass duration was 95 +/- 30' (38-190'), mean aortic cross-clamp in 23% (16/71) 46 +/- 31' (8-95'), with 77% (55/71) implantations without aortic cross-clamp. Size of implanted PV: 21 mm in seven patients, 23 mm in 33, 25 mm in 23, and 27 mm in eight. The z score of the implanted PV was -0.16 +/- 0.80 (-1.6 to 2.5), effective orifice area indexed (for BSA) of native PV was 1.5 +/- 0.2 (1.2 to -2.1) vs. implanted PV 1.2 +/- 0.3 (0.76 to -2.5) (p = ns). In 76% (54/71) patients surgical RV modelling was associated. Mean duration of mechanical ventilation was 6 +/- 5 h (0-26 h), mean ICU stay 21 +/- 11 h (12-64 h), mean hospital stay 6 +/- 3 days (three to 19 days). In mean follow-up = 25 +/- 14 months (six to 53 months) there were no early/late deaths, no need for cardiac intervention/re-operation, no valve-related complications, thrombosis or endocarditis. Last echocardiography showed absent PV regurgitation in 87.3% (62/71) patients, trivial/mild degree in 11.3% (8/71), moderate degree in 1.45% (1/71), mean max peak velocity through RVOT 1.6 +/- 0.4 (1.0-2.4) m s-1. Mean indexed RV end-diastolic volume at MRI/KBR 3D-volumetry was 96 +/- 20 (63-151) ml m-2 BSA, lower than pre-operatively (p < 0.001), and mean EF = 55 +/- 4% (49-61%), higher than pre-operatively (p < 0.05). Almost all patients (99% = 70/71) remain in NYHA class I, 1.45% = 1/71 in class II. Conclusion: (a) Aortic pericardial valve is implantable in PV position with an easy and reproducible surgical technique; (b) valve size adequate for patient BSA can be implanted with simultaneous RV remodelling; (c) medium-term outcomes are good with maintained PV function, RV dimensions significantly reduced and EF significantly improved; (d) adequate valve size will allow later percutaneous valve-in-valve implantation. PMID- 30410703 TI - Glia and gliotransmitters on carbon nanotubes. AB - Introduction: Functionalised carbon nanotubes (CNTs) have been shown to be promising biomaterials in neural systems, such as CNT -based nerve scaffolds to drive nerve regeneration. CNTs have been shown to modulate neuronal growth and improve electrical conductivity of neurons. Methods: Cultured astrocytes on the functionalized CNTs (PEG, caroboxyl group) were assessed for distribution of GABA, glutamate uptake assay using isotope and change of conductance of CNTs by ATP. Immunostaining of GABA using anti-GABA (red), anti-GFAP (green) antibody in primary cortical astrocytes on MW-CNT and PDL coverslips. Results: The functionalization of CNTs has improved their solubility and biocompatibility and alters their cellular interaction pathways. Recently, CNTs have been shown to modulate morphofunctional characteristics of glia as well as neurons. Among the various types of glia, astrocytes express diverse receptors for corresponding neurotransmitters and release gliotransmitters, including glutamate, adenosine triphosphate, and gamma-amino butyric acid. Gliotransmitters are primarily released from astrocytes and play important roles in glia-neuron crosstalk. Conclusion: This review focuses on the effects of CNTs on glial cells and discusses how functionalized CNTs can modulate morphology and gliotransmitters of glial cells. Based on exciting new findings, they look to be a promising material for use in brain disease therapy or neuroprosthetics. PMID- 30410704 TI - Transfersomes as versatile and flexible nano-vesicular carriers in skin cancer therapy: the state of the art. AB - Introduction: The skin acts as a barrier and prevents transcutaneous delivery of therapeutic agents. Transfersomes are novel vesicular systems that are several times more elastic than other vesicular systems. These are composed of edge activator, phospholipids, ethanol, and sodium cholate and are applied in a non occlusive manner. Areas covered: This article covers information such as merits/demerits of transfersomes, regulatory aspects of materials used in preparation, different methods of preparation, mechanism of action, review of clinical investigations performed, marketed preparations available, research reports, and patent reports related to transfersomes. Expert opinion: Research over the past few years has provided a better understanding of transfersomal permeation of therapeutic agents across stratum corneum barrier. Transfersomes provides an essential feature of their application to variety of compositions in order to optimize the permeability of a range of therapeutic molecules. This is evidenced by the fact that there are several Transfersome products being processed in advanced clinical trials. It is noteworthy that a number of Transfersome products for dermal and transdermal delivery will gain a global market success in near future. PMID- 30410705 TI - Nano-sized carriers in gene therapy for renal fibrosis in vivo. AB - Renal fibrosis is the final common pathway leading to end-stage renal failure regardless of underlying initial nephropathies. No specific therapy has been established for renal fibrosis. Gene therapy is a promising strategy for the treatment of renal fibrosis. Nano-sized carriers including viral vectors and non viral vectors have been shown to enhance the delivery and treatment effects of gene therapy for renal fibrosis in vivo. This review focuses on the mechanisms of renal fibrosis and the in vivo technologies and methodologies of nano-sized carriers in gene therapy for renal fibrosis. RESPONSIBLE EDITOR Alexander Seifalian Director of Nanotechnology & Regenerative Medicine Ltd., The London BioScience Innovation Centre, London, UNITED KINGDOM. PMID- 30410706 TI - Nano-sized carriers in gene therapy for peritoneal fibrosis in vivo. AB - Peritoneal fibrosis is a crucial complication in patients receiving peritoneal dialysis. It is a major pathological feature of peritoneal membrane failure, which leads to withdrawal of peritoneal dialysis. No specific therapy has yet been established for the treatment of peritoneal fibrosis. However, gene therapy may be a viable option, and various nano-sized carriers, including viral and non viral vectors, have been shown to enhance the delivery and efficacy of gene therapy for peritoneal fibrosis in vivo. This review focuses on the use of nano sized carriers in gene therapy of peritoneal fibrosis in vivo. PMID- 30410708 TI - Nonlinear optics on nano/micro-hierarchical structures on metals: focus on symmetric and plasmonic effects. AB - In this review, the authors study their creation of nano/micro-hierarchical structures on Ag and Ni substrates by femtosecond laser treatment and their investigation of their optical second-harmonic generation (SHG) signal intensities by SHG spectroscopy. The authors obtained the nanostructure-covered microgroove and microcube structures. These hierarchical surface structures were found to modify significantly the optical nonlinearity of the metal surfaces. The macroscopic symmetry of the surface's shapes influenced SHG, and the excitation of surface plasmons enhanced SHG. On the other hand, the nanostructures on the microstructures had an additional effect on the generated SHG. For the microcube structures, the additional SHG emission was suppressed by removing a large amount of nanostructures. Left SHG was discussed by the effect of the propagating delay. PMID- 30410707 TI - Possible role of nanocarriers in drug delivery against cervical cancer. AB - Introduction: Cervical cancer is the second most common cancer and the largest cancer killer among women in most developing countries including India. Although, various drugs have been developed for cervical cancer, treatment with these drugs often results in a number of undesirable side effects, toxicity and multidrug resistance (MDR). Also, the outcomes for cervical cancer patients remain poor after surgery and chemo radiation. Methods: A literature search (for drugs and delivery systems against cervical cancer) was performed on PubMed and through Google. The present review discuss about various methods including its current conventional treatment with special reference to recent advances in delivery systems encapsulating various anticancer drugs and natural plant products for targeting towards cervical cancer. The role of photothermal therapy, gene therapy and radiation therapy against cervical cancer is also discussed. Results: Systemic/targeted drug delivery systems including liposomes, nanoparticles, hydrogels, dendrimers etc. and localized drug delivery systems like cervical patches, films, rings etc. are safer than the conventional chemotherapy which has further been proved by the several drug delivery systems undergoing clinical trials. Conclusion: Novel approaches for the aggressive treatment of cervical cancer will optimistically result in decreased side effects as well as toxicity, frequency of administration of existing drugs, to overcome MDR and to increase the survival rates. PMID- 30410709 TI - Transgene and islet cell delivery systems using nano-sized carriers for the treatment of diabetes mellitus. AB - Gene therapy that targets the pancreas and intestines with delivery systems using nano-sized carriers such as viral and non-viral vectors could improve the control of blood glucose levels, resulting in an improved prognosis for patients with diabetes mellitus. Allogenic pancreatic islet cell transplantations using such delivery systems have been developed as therapeutic options for diabetes mellitus. This review focuses on transgenes and islet cell delivery systems using nano-sized carriers for the treatment of diabetes mellitus. PMID- 30410711 TI - Beyond the smiley face: applications of structural DNA nanotechnology. AB - Since the development of DNA origami by Paul Rothemund in 2006, the field of structural DNA nanotechnology has undergone tremendous growth. Through DNA origami and related approaches, self-assembly of specified DNA sequences allows for the 'bottom-up' construction of diverse nanostructures. By utilizing different sets of small 'staple' DNA strands to direct the folding of a long scaffold strand in diverse ways, DNA origami has particularly been incorporated into a variety of prototypical applications beyond the two-dimensional (2D) smiley face. In this review, the basis of DNA nanotechnology, methods of self assembly, and Rothemund's DNA origami breakthrough are discussed first. Next, some of the most promising applications of structural DNA nanotechnology since 2006 are summarized. These include utilizing DNA origami as a tool for creating 3D nanostructures (including DNA bricks), as well as structural (ligand capsid binding, viral capsid binding, DNA NanoOctahedron, DNA mold, photonic devices, energy transfer units), and dynamic (DNA box-with-lid, DNA nano-robot, DNA barges, amphipathic DNA structures, DNA nanocircuits) applications of DNA origami. PMID- 30410710 TI - Application of nanoparticles in cancer detection by Raman scattering based techniques. AB - In vitro detection technique Raman spectroscopy (Rs), in one number times another Rs based expert ways of art and so on, are useful instruments for cancer discovery. top gave greater value to Raman spectroscopy sers is a relatively new careful way for in vitro and in vivo discovery that takes away bad points of simple Raman spectroscopy (Rs). Raman spectroscopy (RS) and in particular, multiple RS-based techniques are useful for cancer detection. Surface enhanced Raman spectroscopy (SERS) is a relatively new method for both in vitro and in vivo detection, which eliminates the drawbacks of simple RS. Using nanoparticles has elevated the sensitivity and specificity of SERS. SERS has the potential to increase sensitivity, specificity and spatial resolution in cancer detection, especially in cooperation with other diagnostic imaging tools such as magnetic resonance imaging (MRI) and PET-scan polyethylene terephthalate. Developing a hand held instrument for detecting cancer or other illnesses may also be feasible by using SERS. Frequently, novel nanoparticles are used in SERS. With a focus on nanoparticle utilization, we review the benefits of RS in cancer detection and related biomarkers. With a focus on nanoparticles utilizations, the benefits of RS in cancer detection and related biomarkers were reviewed. In addition, Raman applications to detect some of prevalent were discussed. Also more investigated cancers such as breast and colorectal cancer, multiple nanostructures and their possible special biomarkers, especially as SERS nano-tag have been reviewed. The main purpose of this article is introducing of most popular nanotechnological approaches in cancer detection by using Raman techniques. Moreover, have been caught up on detection and reviewed some of the most prevalent and also more investigated cancers such as breast, colorectal cancer, multiple intriguing nanostructures, especially as SERS nano-tag, special cancer biomarkers and related approaches. The main purpose of this article is to introduce the most popular nanotechnological approaches in cancer detection by using Raman techniques. PMID- 30410714 TI - Privacy Preserving k-Nearest Neighbor for Medical Diagnosis in e-Health Cloud. AB - Cloud computing is highly suitable for medical diagnosis in e-health services where strong computing ability is required. However, in spite of the huge benefits of adopting the cloud computing, the medical diagnosis field is not yet ready to adopt the cloud computing because it contains sensitive data and hence using the cloud computing might cause a great concern in privacy infringement. For instance, a compromised e-health cloud server might expose the medical dataset outsourced from multiple medical data owners or infringe on the privacy of a patient inquirer by leaking his/her symptom or diagnosis result. In this paper, we propose a medical diagnosis system using e-health cloud servers in a privacy preserving manner when medical datasets are owned by multiple data owners. The proposed system is the first one that achieves the privacy of medical dataset, symptoms, and diagnosis results and hides the data access pattern even from e-health cloud servers performing computations using the data while it is still robust against collusion of the entities. As a building block of the proposed diagnosis system, we design a novel privacy preserving protocol for finding the k data with the highest similarity (PE-FTK) to a given symptom. The protocol reduces the average running time by 35% compared to that of a previous work in the literature. Moreover, the result of the previous work is probabilistic, i.e., the result can contain some error, while the result of our PE-FTK is deterministic, i.e., the result is correct without any error probability. PMID- 30410712 TI - Polyethylenimine-based nanocarriers in co-delivery of drug and gene: a developing horizon. AB - The meaning of gene therapy is the delivery of DNA or RNA to cells for the treatment or prevention of genetic disorders. The success rate of gene therapy depends on the progression and safe gene delivery system. The vectors available for gene therapy are divided into viral and non-viral systems. Viral vectors cause higher transmission efficiency and long gene expression, but they have major problems, such as immunogenicity, carcinogenicity, the inability to transfer large size genes and high costs. Non-viral gene transfer vectors have attracted more attention because they exhibit less toxicity and the ability to transfer large size genes. However, the clinical application of non-viral methods still faces some limitations, including low transmission efficiency and poor gene expression. In recent years, numerous methods and gene-carriers have been developed to improve gene transfer efficiency. The use of Polyethylenimine (PEI) based transfer of collaboration may create a new way of treating diseases and the combination of chemotherapy and gene therapy. The purpose of this paper is to introduce the PEI as an appropriate vector for the effective gene delivery. PMID- 30410716 TI - Wound Fluid Matrix Metalloproteinase-9 as a Potential Predictive Marker for the Poor Healing Outcome in Diabetic Foot Ulcers. AB - Background and Objective: Evidence for the roles of matrix metalloproteinases-9 (MMP-9) in the healing process of diabetic foot ulcers has remained unclear. We therefore aimed to demonstrate the relationship of MMP-9 with the wound healing process and determine its potential usefulness in predicting the wound healing outcome. Methods: Twenty-two patients with diabetic foot ulcer were recruited. The wound size was determined, and the wound fluid was collected for the measurement of MMP-9 levels using an ELISA during the 12-week follow-up period regularly. The patients were categorized as good healers and poor healers when the wound area reduction was >= 50% and < 50% at week 4 when compared to the initial wound size at week 0. Results: Median wound fluid MMP-9 levels in the poor healer group were shown to be significantly higher than those in the good healer group (1.03 pg/ug protein vs. 0.06 pg/ug protein, p = 0.001), and the levels fluctuated throughout the 12-week follow-up period. In contrast to the poor healer group, the MMP-9 levels were demonstrated to be constantly low throughout the follow-up period in the good healer group. ROC analysis showed that the MMP-9 level of 0.38 pg/ug protein was able to predict the wound healing outcome with the sensitivity of 81.8%, the specificity of 64.6%, and the area under the curve of 0.901 (CI 0.78-1.03, p = 0.001). Conclusion: These findings suggested that determination of wound fluid MMP-9 levels might become a promising biomarker predicting wound healing outcomes and a novel potential therapeutic target for diabetic foot ulcers. PMID- 30410715 TI - A cross-cultural study of autistic traits across India, Japan and the UK. AB - Background: There is a global need for brief screening instruments that can identify key indicators for autism to support frontline professionals in their referral decision-making. Although a universal set of conditions, there may be subtle differences in expression, identification and reporting of autistic traits across cultures. In order to assess the potential for any measure for cross cultural screening use, it is important to understand the relative performance of such measures in different cultures. Our study aimed to identify the items on the Autism Spectrum Quotient (AQ)-Child that are most predictive of an autism diagnosis among children aged 4-9 years across samples from India, Japan and the UK. Methods: We analysed parent-reported AQ-Child data from India (73 children with an autism diagnosis and 81 neurotypical children), Japan (116 children with autism and 190 neurotypical children) and the UK (488 children with autism and 532 neurotypical children). None of the children had a reported existing diagnosis of intellectual disability. Discrimination indices (DI) and positive predictive values (PPV) were used to identify the most predictive items in each country. Results: Sixteen items in the Indian sample, 15 items in the Japanese sample and 28 items in the UK sample demonstrated excellent discriminatory power (DI >= 0.5 and PPV >= 0.7), suggesting these items represent the strongest indicators for predicting an autism diagnosis within these countries. Across cultures, good performing items were largely overlapping, with five key indicator items appearing across all three countries (can easily keep track of several different people's conversations, enjoys social chit-chat, knows how to tell if someone listening to him/her is getting bored, good at social chit-chat, finds it difficult to work out people's intentions). Four items indicated potential cultural differences. One item was highly discriminative in Japan but poorly discriminative (DI < 0.3) in the UK and India, and a further item had excellent discrimination properties in the UK but poorly discriminated in the Indian and Japanese samples. Two additional items were highly discriminative in two cultures but poor in the third. Conclusions: Cross-cultural overlap in the items most predictive of an autism diagnosis supports the general notion of universality in autistic traits whilst also highlighting that there can be cultural differences associated with certain autistic traits. These findings have the potential to inform the development of a brief global screening tool for autism. Further development and evaluation work is needed. PMID- 30410717 TI - Frequency of Trypanosoma cruzi Infection in Synanthropic and Wild Rodents Captured in a Rural Community in Southeast of Mexico. AB - The protozoan parasite Trypanosoma cruzi is the causative agent of the Chagas disease, which is endemic in southeastern Mexico and is transmitted by the vector Triatoma dimidiata (triatomide). T. cruzi infect a great variety of domestic and wild mammals; rodents are considered one of the most important reservoirs of the parasite in the transmission cycles of T. cruzi. The objective of this study was to determine the frequency of T. cruzi infection and to determine the parasitic load in synanthropic and wild rodents from the rural community of southern Mexico. A total of 41 blood samples and 68 heart tissue samples were collected from various species of synanthropic (n= 48 in 2 species) and wild rodents (n= 35 in 5 species). DNA was extracted from samples to detect the presence of T. cruzi through quantitative PCR (qPCR). T. cruzi DNA was detected in the 9.75% of the blood samples of the synanthropic species (4/41) (14.28%) for Rattus rattus samples and 25% for Ototylomys phyllotis samples, with an average of parasitic load of 4.80 +/- 1.17 parasites/MUL. In the case of heart tissue samples, 10.29% were positive for T. cruzi (7/68) (8.7% for Rattus rattus, 40% for Peromyscus yucatanicus, and 42.8% for Ototylomys phyllotis) with an average parasite load of 3.15 +/- 1.98 eq-parasites/mg. The active and chronic infection of T. cruzi in synanthropic or wild rodents of the rural community of southern Mexico evidences the natural infection in these reservoirs which contribute to maintaining the agent in the wild and domestic environments and can represent a risk of infection for the human population when the vector is present. PMID- 30410718 TI - Pisa Syndrome in Parkinson's Disease: Evidence for Bilateral Vestibulospinal Dysfunction. AB - Introduction: Pisa syndrome (PS) is a postural complication of Parkinson's disease (PD). Yet, its pathophysiology remains unclear, although a multifactorial component is probable. Cervical vestibular evoked myogenic potentials (cVEMPs) explore vestibulospinal pathway, but they have not been measured yet in PD patients with PS (PDPS) to assess a potential vestibular impairment. Materials and Methods: We enrolled 15 PD patients, 15 PDPS patients, and 30 healthy controls (HCs). They underwent neurological examination and were examined with Unified Parkinson's Disease Rating Scale II-III (UPDRSII-III), audiovestibular workup, and cVEMP recordings. Data were analysed with Chi-square, one-way ANOVA, multinomial regression, nonparametric, and Spearman's tests. Results: cVEMPs were significantly impaired in both PD and PDPS compared with HCs. PDPS exhibited more severe cVEMP abnormalities with prevalent bilateral loss of potentials, compared with the PD group, in which a prevalent unilateral loss was instead observed. No clinical-neurophysiological correlations emerged. Conclusions: Differently from HC, cVEMPs are altered in PD. Severity of cVEMPs alterations increases from PD without PS to PDPS, suggesting an involvement of vestibulospinal pathway in the pathophysiology of PS. Our results provide evidence for a significant impairment of cVEMPs in PDPS patients and encourage further studies to test validity of cVEMPs as diagnostic and prognostic biomarkers of PD progression. PMID- 30410719 TI - A rare skin condition masquerading as a serious wound infection. AB - Pyoderma gangrenosum is a rare, serious and commonly missed condition that can effect post-operative surgical patients. The condition is commonly misdiagnosed as a wound infection, with subsequent inappropriate antibiotic therapy and wound debridement. We present the case of a 46-year-old patient who suffered this delayed diagnosis and multiple unnecessary interventions. We present this in an effort to raise awareness of the rare but serious condition, pyoderma gangrenosum. PMID- 30410720 TI - A phase II study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and soft tissue sarcomas. AB - Background: Relapsed and refractory sarcomas continue to have poor survival rates. The cancer stem cell (CSC) theory provides a tractable explanation for the observation that recurrences occur despite dramatic responses to upfront chemotherapy. Preclinical studies demonstrated that inhibition of the mechanistic target of rapamycin (mTOR) sensitizes the CSC population to chemotherapy. Methods: Here we present the results of the Phase II portion of a Phase I/II clinical trial that aimed to overcome the chemoresistance of sarcoma CSC by combining the mTOR inhibitor temsirolimus (20 mg/m2 weekly) with the chemotherapeutic agent liposomal doxorubicin (30 mg/m2 monthly). Results: Fifteen patients with relapsed/refractory sarcoma were evaluable at this recommended Phase 2 dose level. The median progression free survival was 315 days (range 27 799). Response rate, defined as stable disease or better for 60 days, was 53%. Nine of the patients had been previously treated with doxorubicin. Therapy was well tolerated. In a small number of patients, pre- and post- treatment tumor biopsies were available for assessment of ALDH expression as a marker of CSCs and showed a correlation between response and decreased ALDH expression. We also found a correlation between biopsy-proven inhibition of mTOR and response. Conclusions: Our study adds to the literature supporting the addition of mTOR inhibition to chemotherapy agents for the treatment of sarcomas, and proposes that a mechanism by which mTOR inhibition enhances the efficacy of chemotherapy may be through sensitizing the chemoresistant CSC population. Further study, ideally with pre- and post-therapy assessment of ALDH expression in tumor cells, is warranted.Trial registration The trial was registered on clinicaltrials.gov (NCT00949325) on 30 July 2009. http://www.editorialmanager.com/csrj/default.aspx. PMID- 30410722 TI - Circ_0027599/PHDLA1 suppresses gastric cancer progression by sponging miR-101 3p.1. AB - Background: Pleckstrin homology-like domain family A member 1 (PHLDA1) is a tumor suppressor gene in gastric cancer, but its role regulated by circular RNAs (circRNAs) is not known. CircRNAs are important regulators in cancer growth and progression, however, the molecular roles of circRNAs in gastric cancer are rarely known. The study was aimed to investigate the role of circRNAs in regulating PHLDA1 expression in gastric cancer. Results: The circRNA expression profile in the gastric cancer tissues by circRNA microarray showed that hsa_circ_0027599 (circ_0027599) was significantly down-regulated in gastric cancer patients and cells when comparing with the controls. Circ_0027599 overexpression suppressed gastric cancer cell proliferation and metastasis. By using bioinformatics tools and luciferase reporter assays, circ_0027599 was verified as a sponge of miR-101-3p.1 (miR-101) and suppressed cancer cell survival and metastasis. It was also verified that PHLDA1 was regulated by circ_0027599 in gastric cancer cells. Conclusions: The study uncovered that PHLDA1 was regulated by circ_0027599/miR-101, which suppressed gastric cancer survival and metastasis in gastric cancer. PMID- 30410723 TI - Alpha 1 antitrypsin distribution in an allergic asthmatic population sensitized to house dust mites. AB - Background and objective: Severe alpha1 antitrypsin deficiency has been clearly associated with pulmonary emphysema, but its relationship with bronchial asthma remains controversial. Some deficient alpha 1 antitrypsin (AAT) genotypes seem to be associated with asthma development. The objective of this study was to analyze the distribution of AAT genotypes in asthmatic patients allergic to house dust mites (HDM), and to asses a possible association between these genotypes and severe asthma. Methods: A cross-sectional cohort study of 648 patients with HDM allergic asthma was carried out. Demographic, clinical and analytical variables were collected. PI*S and PI*Z AAT deficient alleles of the SERPINA1 gene were assayed by real-time PCR. Results: Asthma was intermittent in 253 patients and persistent in 395 patients (246 mild, 101 moderate and 48 severe). One hundred and forty-five asthmatic patients (22.4%) with at least one mutated allele (S or Z) were identified. No association between the different genotypes and asthma severity was found. No significant differences in all clinical and functional tests, as well as nasal eosinophils, IgA and IgE serum levels were observed. Peripheral eosinophils were significantly lower in patients with the PI*MS genotype (p = 0.0228). Neither association between deficient AAT genotypes or serum ATT deficiency (AATD) and development of severe asthma, or correlation between ATT levels and FEV1 was observed. Conclusion: In conclusion, the distribution of AAT genotypes in HDM allergic asthmatic patients did not differ from those found in Spanish population. Neither severe ATTD or deficient AAT genotypes appear to confer different clinical expression of asthma. PMID- 30410724 TI - Test-retest reliability of nerve and muscle morphometric characteristics utilizing ultrasound imaging in individuals with unilateral sciatica and controls. AB - Background: Ultrasound imaging has been suggested for studying the structure and function of nerves and muscles; however, reliability studies are limited to support the usage. The main aim of this study was to explore the intrarater within-session reliability of evaluating the sciatic nerve and some related muscles morphology by ultrasound imaging. Methods: Three B-mode images from two scans (transverse and longitudinal) were acquired from the multifidus, biceps femoris, soleus and medial gastrocnemius muscles bilaterally from 15 participants with sciatica and 15 controls in one session, 1-h apart. The data were collected from March to July 2017. Contraction ratio was measured only by longitudinal scan, while the echo intensity was measured using maximum rectangular region of interest in two scans (transverse and longitudinal) for all muscles. Cross sectional area, direct (tracing) and indirect (ellipsoid formula) methods were used to measure the sciatic nerve. Intraclass correlation coefficient (ICC 3,1), standard error of measurement and minimal detectable change were calculated. Results: Good to high ICCs (0.80-0.96) were found for muscle contraction ratio in the longitudinal scans in all the muscles in both sciatica and control groups. For echo intensity measurements ICCs ranged from moderate to high, with higher ICCs seen with the maximum region of interest in the transverse scans. The minimal detectable change values ranged between 0.11 and 0.53 cm for contraction ratio. Conclusions: Ultrasound imaging has high intrarater within-session reliability for assessing the sciatic nerve Cross-sectional area and muscle contraction ratios. Transverse scans with the maximum region of interest result in higher reliability. The sciatic Cross-sectional area is most accurately measured utilizing the direct tracing method rather than the indirect ellipsoid method. PMID- 30410725 TI - Cancer complaints: The profile of patients from the emergency department of a Brazilian oncology teaching hospital. AB - Background: With the increase in prevalence of cancer in our society, we aim to clarify through primary data use what drives emergency department (ED) utilization among patients with cancer. Methods: This is a cross-sectional study. A direct survey was applied to cancer patients over 277 visits in 2015. Variables including chief complaint for current and last visit, frequency of visits, primary tumor site, and demographics were collected. Results: Pain was the most common complaint, responsible for 40% of visits, followed by constitutional symptoms (17%), and gastrointestinal complaints (11%). Abdominal pain was the single most noted pain type, with 18.4%, and had the highest rate of recurrence. It was followed by back pain, dyspnea, asthenia and fever, accounting for 8.5%, 8.5%, 8.1% and 7%, respectively. Cervical cancer represented 14.8% of patients, followed by breast (11.6%) and lung (7.6%) cancers. The majority of patients visited the emergency department less than once a month. Conclusion: The drivers of emergency department utilization among patients with cancer found through primary use data mostly confirm findings from larger studies with secondary use data. Our research underscores the burden of pain to patients with cancer, as it is the most common complaint leading to ED visits, and generally requires multiple visits. Abdominal pain was more likely to recur than other complaints. Patients could benefit from focused outpatient pain management, and from more research and education targeting cancer-related pain. PMID- 30410721 TI - Essential roles of mitochondrial and heme function in lung cancer bioenergetics and tumorigenesis. AB - Contrary to Warburg's hypothesis, mitochondrial oxidative phosphorylation (OXPHOS) contributes significantly to fueling cancer cells. Several recent studies have demonstrated that radiotherapy-resistant and chemotherapy-resistant cancer cells depend on OXPHOS for survival and progression. Several cancers exhibit an increased risk in association with heme intake. Mitochondria are widely known to carry out oxidative phosphorylation. In addition, mitochondria are also involved in heme synthesis. Heme serves as a prosthetic group for several proteins that constitute the complexes of mitochondrial electron transport chain. Therefore, heme plays a pivotal role in OXPHOS and oxygen consumption. Further, lung cancer cells exhibit heme accumulation and require heme for proliferation and invasion in vitro. Abnormalities in mitochondrial biogenesis and mutations are implicated in cancer. This review delves into mitochondrial OXPHOS and lesser explored area of heme metabolism in lung cancer. PMID- 30410726 TI - Multimodality treatment of malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is a rare disease of the pleura and is largely related to asbestos exposure. Despite recent advancements in technologies and a greater understanding of the disease, the prognosis of MPM remains poor; the median overall survival rate is about 6 to 9 months in untreated patients. The main therapeutic strategies for MPM are surgery, chemotherapy, and radiation therapy (RT). The two main surgical approaches for MPM are extrapleural pneumonectomy (EPP), in which the lung is removed en bloc, and pleurectomy/decortication, in which the lung stays in situ. Chemotherapy usually consists of a platinum-based chemotherapy, such as cisplatin, often combined with a folate antimetabolite, such as pemetrexed. More recently, immunotherapy has emerged as a possible therapeutic strategy for MPM. Evidence suggests that single modality treatments are not an effective therapeutic approach for MPM. Therefore, researchers have started to explore different multimodality treatment approaches, in which often combinations of surgery, chemotherapy, immunotherapy, and RT are investigated. There is still no definitive answer to the question of which multimodality treatment combinations are most effective in improving the poor prognosis of MPM. Research into the effects of trimodality treatment approaches have found that radical approaches such as EPP and hemithoracic RT post-EPP are less effective than was previously assumed. In general, there are still a great number of unanswered questions and unknown factors regarding the ideal treatment approach for MPM. Hopefully, more research into multimodality therapy will provide insight into which combination of treatment modalities is most effective. PMID- 30410727 TI - What is the hologenome concept of evolution? AB - All multicellular organisms are colonized by microbes, but a gestalt study of the composition of microbiome communities and their influence on the ecology and evolution of their macroscopic hosts has only recently become possible. One approach to thinking about the topic is to view the host-microbiome ecosystem as a "holobiont". Because natural selection acts on an organism's realized phenotype, and the phenotype of a holobiont is the result of the integrated activities of both the host and all of its microbiome inhabitants, it is reasonable to think that evolution can act at the level of the holobiont and cause changes in the "hologenome", or the collective genomic content of all the individual bionts within the holobiont. This relatively simple assertion has nevertheless been controversial within the microbiome community. Here, I provide a review of recent work on the hologenome concept of evolution. I attempt to provide a clear definition of the concept and its implications and to clarify common points of disagreement. PMID- 30410728 TI - Fuchs heterochromic iridocyclitis-associated glaucoma: a retrospective comparison of primary Ahmed glaucoma valve implantation and trabeculectomy with mitomycin C. AB - Background: The aim of this study was to compare the safety and efficacy of primary trabeculectomy with mitomycin C and Ahmed glaucoma valve (AGV) implantation in patients with Fuchs heterochromic iridocyclitis (FHIC)-related glaucoma, a rare complication of an uncommon form of uveitis. Methods : In this retrospective comparative case series, 26 FHIC-associated glaucoma patients received trabeculectomy (n=12) or an AGV (n=14). Primary outcome measures were surgical success, defined as intraocular pressure (IOP) <=21 mmHg, decreasing >=20% from baseline, and no secondary glaucoma surgery. Secondary outcome measures were the number of glaucoma medications, complications, best corrected visual acuity (BCVA), and IOP. Results: The follow-up was 34.0+/-17.7 months in patients that received trabeculectomy and 33.4+/-18.6 months in AGV (P= 0.837). The cumulative probability of success rate was 41.7% for trabeculectomy and 85.7% for AGV, with no significant difference in complications (P>0.05). The IOP in patients that received trabeculectomy dropped from 23.4+/-3.3 mmHg to 21.6+/-5.2 mmHg at the final visit (P= 0.041). In patients that received AGV, the IOP decreased from 24+/-7.8 to 17.1+/-2.6 mmHg (P= 0.003). The number of glaucoma medications at baseline were 3.3+/-0.5 in those that received trabeculectomy and 3+/-0.6 in those that received AGV (P=0.233), and decreased to 2.4+/-1.0 (P=0.008) and 1.7+/-0.6 (P=0.002), respectively. BCVA was equal in both groups and did not change (P>0.05). Conclusion: Primary AGV had a higher success rate than trabeculectomy, with patients also needing fewer medications for the management of FHIC-associated glaucoma. PMID- 30410729 TI - Factors influencing malignant mesothelioma survival: a retrospective review of the National Mesothelioma Virtual Bank cohort. AB - Background: Malignant mesothelioma (MM) is a rare but deadly malignancy with about 3,000 new cases being diagnosed each year in the US. Very few studies have been performed to analyze factors associated with mesothelioma survival, especially for peritoneal presentation. The overarching aim of this study is to examine survival of the cohort of patients with malignant mesothelioma enrolled in the National Mesothelioma Virtual Bank (NMVB). Methods: 888 cases of pleural and peritoneal mesothelioma cases were selected from the NMVB database, which houses over 1400 cases that were diagnosed from 1990 to 2017. Kaplan Meier's method was performed for survival analysis. The association between prognostic factors and survival was estimated using Cox Hazard Regression method and using R software for analysis. Results: The median overall survival (OS) rate of all MM patients, including pleural and peritoneal mesothelioma cases is 15 months (14 months for pleural and 31 months for peritoneal). Significant prognostic factors associated with improved survival of malignant mesothelioma cases in this NMVB cohort were below the age of 45, female gender, epithelioid histological subtype, stage I, peritoneal occurrence, and had treatment that consisted of combining surgical therapy with chemotherapy. Combined surgical and chemotherapy treatment was associated with improved survival of 23 months in comparison to single line therapies. Conclusions: There has not been improvement in the overall survival for patients with malignant mesothelioma over many years with current available treatment options. Our findings show that combined surgical and chemotherapy treatment is associated with improved survival compared to local therapy alone. PMID- 30410730 TI - sPop: Age-structured discrete-time population dynamics model in C, Python, and R. AB - This article describes the sPop packages implementing the deterministic and stochastic versions of an age-structured discrete-time population dynamics model. The packages enable mechanistic modelling of a population by monitoring the age and development stage of each individual. Survival and development are included as the main effectors and they progress at a user-defined pace: follow a fixed rate, delay for a given time, or progress at an age-dependent manner. The model is implemented in C, Python, and R with a uniform design to ease usage and facilitate adoption. Early versions of the model were previously employed for investigating climate-driven population dynamics of the tiger mosquito and the chikungunya disease spread by this vector. The sPop packages presented in this article enable the use of the model in a range of applications extending from vector-borne diseases towards any age-structured population including plant and animal populations, microbial dynamics, host-pathogen interactions, infectious diseases, and other time-delayed epidemiological processes. PMID- 30410732 TI - Dengvaxia controversy: impact on vaccine hesitancy. PMID- 30410731 TI - Glioma cell proliferation is enhanced in the presence of tumor-derived cilia vesicles. AB - Background: The mechanisms by which primary cilia affect glioma pathogenesis are unclear. Depending on the glioma cell line, primary cilia can promote or inhibit tumor development. Here, we used piggyBac-mediated transgenesis to generate patient-derived glioblastoma (GBM) cell lines that stably express Arl13b:GFP in their cilia. This allowed us to visualize and analyze the behavior of cilia and ciliated cells during live GBM cell proliferation. Results: Time-lapse imaging of Arl13b:GFP+ cilia revealed their dynamic behaviors, including distal tip excision into the extracellular milieu. Recent studies of non-cancerous cells indicate that this process occurs during the G0 phase, prior to cilia resorption and cell cycle re-entry, and requires ciliary recruitment of F-actin and actin regulators. Similarly, we observed ciliary buds associated with Ki67- cells as well as scattered F-actin+ cilia, suggesting that quiescent GBM cells may also utilize an actin network-based mechanism for ciliary tip excision. Notably, we found that the proliferation of ciliated GBM cells was promoted by exposing them to conditioned media obtained from ciliated cell cultures when compared to conditioned media collected from cilia-defective cell cultures (depleted in either KIF3A or IFT88 using CRISPR/Cas9). These results suggest that GBM cilia may release mitogenic vesicles carrying factors that promote tumor cell proliferation. Although Arl13b is implicated in tumor growth, our data suggest that Arl13b released from GBM cilia does not mediate tumor cell proliferation. Conclusion: Collectively, our results indicate that ciliary vesicles may represent a novel mode of intercellular communication within tumors that contributes to GBM pathogenesis. The mitogenic capacity of GBM ciliary vesicles and the molecular mediators of this phenomenon requires further investigation. PMID- 30410733 TI - Addressing the health of vulnerable populations: social inclusion and universal health coverage. PMID- 30410734 TI - Towards universal health coverage and sustainable financing in Afghanistan: progress and challenges. PMID- 30410735 TI - Health risks of Rohingya refugee population in Bangladesh: a call for global attention. PMID- 30410736 TI - African perspectives: modern complexities of emerging, re-emerging, and endemic zoonoses. PMID- 30410737 TI - Medical research productivity in the Arab countries: 2007-2016 bibliometric analysis. AB - Background: The aim of this study was to assess recent trends in medical research productivity in Arab countries. Methods: We collected bibliometric data for the world countries, Arab countries, and Arab institutions for 2007-2016, using Essential Science Indicators, Journal Citation Reports, and Web of Science database. We collected the number of published papers overall and per year, citations per paper, and number of papers published in top quartile and top 10% journals. For the 10 most productive institutions, we additionally collected the number of papers with correspondence authors affiliated with the institution. Results: The Arab world produced 189 papers per one million people, about a quarter of the value for other world countries. Four Arab countries (Qatar, Tunisia, Lebanon, and Kuwait) produced more than 695 papers per one million people, exceeding the world average. The average number of citations per paper was 9.2; it rose to more than 15 for papers with international collaboration. At the institutional level, the number of citations showed upward trends, with six institutions having an average citation per paper higher than that of all Arab countries. For the 10 most productive institutions in Arab countries, the percentage of papers involving international collaborations ranged from 42% to 79%; of these, 9% to 29% were led by authors from the same institution. For these 10 most productive institutions, the percentage of papers published in the top quartile journals and with a lead/corresponding author from the institution ranged from 7 to 32%; that percentage drops to 1% to 10% for papers published in top 10% journals. Conclusions: Although medical research output in Arab countries at both the country and the institution levels has increased over the past 10 years, it is still lagging behind the rest of the world. The percentage of papers involving international collaborations was relatively high, but the majority of these papers were led by authors from outside the local institution, particularly when published in the top 10% journals. PMID- 30410738 TI - Analysis of results from the Joint External Evaluation: examining its strength and assessing for trends among participating countries. AB - Background: The Joint External Evaluation (JEE) is part of the World Health Organization's (WHO) new process to help countries assess their ability to prevent, detect and respond to public health threats such as infectious disease outbreaks, as specified by the International Health Regulations (IHR). How countries are faring on these evaluations is not well known and neither is there any previous assessment of the performance characteristics of the JEE process itself. Methods: We obtained JEE data for 48 indicators collectively across 19 technical areas of preparedness for 55 countries. The indicators are scored on a 1 to 5 scale with 4 indicating demonstrated capacity. We created a standardized JEE index score representing cumulative performance across indicators using principal components analysis. We examined the state of performance across all indicators and then examined the relationship between this index score and select demographic and health variables to better understand potential drivers of performance. Results: Among our study cohort, the median performance on 43 of the 48 (89.6%) indicators was less than 4, suggesting that countries were failing to meet demonstrated capacity on these measures. The two weakest indicators were related to antimicrobial resistance (median score = 1.0, interquartile range = 1.0-2.0) and biosecurity response (median score = 2.0, interquartile range = 2.0 3.0). JEE index scores correlated with various metrics of health outcomes (life expectancy, under-five year mortality rate, disability-adjusted life years lost to communicable diseases) and with standard measures of social and economic development that enable public health system performance in the total sample, but in stratified analyses, these relationships were much weaker in the AFRO region. Conclusions: We find large variations in JEE scores among countries and WHO regions with many nations still unprepared for the next disease outbreak with pandemic potential The strong correlations between JEE performance and metrics of both health outcomes and health systems' performance suggests that the JEE is likely accurately measuring the strength of IHR-specific, public health capabilities. PMID- 30410739 TI - Newborn resuscitation in Gombe State, northeastern Nigeria. AB - Background: Basic newborn resuscitation for babies not breathing at birth is a highly effective intervention and its scale-up identified as a top research priority. However, tracking progress on the scale-up and coverage of this intervention is compromised by limitations in measuring both the number of newborns receiving the intervention and the number of newborns requiring the intervention. Using data from a facility and birth attendant survey in Gombe State, Nigeria, we aimed to advance the measurement agenda by developing a proxy indicator defined as the "percent of newborns born in a facility with the potential to provide newborn resuscitation". Methods: The indicator's denominator was defined as: the total number of births in facilities during a defined time period (facility records). The numerator was constructed from the number of those births that occurred in appropriately equipped facilities (facility inventory), where a birth attendant demonstrated basic resuscitation competence (assessed by a simulation exercise). The proportion of facility-births that took place in a setting with the potential to provide newborn resuscitation was then calculated. Results: The analysis included 17 383 births that occurred during May-October 2015 in 117 primary and referral facilities surveyed in November 2015. Overall 81% of the facilities did not have all items of essential equipment required for resuscitation; the items of equipment least frequently present included a timing device and resuscitation bag with two sizes of neonatal face mask. Only 3% of 117 birth attendants interviewed demonstrated competence to undertake resuscitation, all of whom were classified as skilled attendants and worked in referral facilities. We found that 20% of the 17 383 births took place in a facility with the potential to provide lifesaving resuscitation care. Conclusions: The indicator definition of neonatal resuscitation presented here responds to the need to advance the measurement agenda for newborn care and importantly adjusts for the volume of births occurring in different facilities. Its application in this setting revealed substantial missed opportunities to providing lifesaving care and highlights the need for a greater focus on input as well as process quality in all levels of health facilities. PMID- 30410741 TI - Identifying potential uses of crowdsourcing in global health, conflict, and humanitarian settings: an adapted CHNRI (Child Health and Nutrition Initiative) exercise. AB - Background: Crowdsourcing, outsourcing problems and tasks to a crowd, has grown exponentially since the term was coined a decade ago. Being a rapid and inexpensive approach, it is particularly amenable to addressing problems in global health, conflict and humanitarian settings, but its potential has not been systematically assessed. We employed the Child Health and Nutrition Research Initiative's (CHNRI) method to generate a ranked list of potential uses of crowdsourcing in global health and conflict. Process: 94 experts in global health and crowdsourcing submitted their ideas, and 239 ideas were scored. Each expert scored ideas against three of seven criteria, which were tailored specifically for the exercise. A relative ranking was calculated, along with an Average Expert Agreement (AEA). Findings: On a scale from 0-100, the scores assigned to proposed ideas ranged from 80.39 to 42.01. Most ideas were related to problem solving (n = 112) or data generation (n = 91). Using health care workers to share information about disease outbreaks to ensure global response had the highest score and agreement. Within the top 15, four additional ideas related to containing communicable diseases, two ideas related to using crowdsourcing for vital registration and two to improve maternal and child health. The top conflict ideas related to epidemic responses and various aspects of disease spread. Wisdom of the crowds and machine learning scored low despite being promising in literature. Interpretations: Experts were invited to generate ideas during the Ebola crisis and to score during reports of Zika, which may have affected the scoring. However, crowdsourcing's rapid, inexpensive characteristics make it suitable for addressing epidemics. Given that many ideas reflected Sustainable Development Goals (SDGs), crowdsourcing may be an innovative solution to achieving some of the SDGs. PMID- 30410740 TI - Evolution of Iran's health research system over the past 50 years: a narrative review. AB - Background: A substantial growth has been reported in Iran's health research output over the last recent decades, throughout the times of economic, social, and political instability. This study reviewed the existing literature to provide a better understanding of the evolution of Iran's health research system over this period. Methods: A narrative review of studies addressing health research system (HRS) in Iran was performed. The search strategy and categorization of the retrieved data was informed by the HRS framework of the World Health Organization (WHO). This framework proposes four functions for HRS: (i) stewardship; (ii) financing; (iii) creating and sustaining resources; and (iv) producing and using research. Searches in MEDLINE through PubMed (using MeSH terms) complemented with semantic searches through PubMed and Google Scholar were conducted. Results: After removing the duplicates, 805 articles were retrieved, of which 601 were irrelevant, and 204 were reviewed. Conclusions: Iran has made substantial progress in different components of its HRS over the last few decades, such as starting a discourse surrounding health research ethics, priority-setting, and placing monitoring mechanisms while increasing the capacity for conducting and publishing research. However, there is still room for improvements, or even a need for fundamental changes, in several components, such as regarding increasing the research budget and improving the funding allocation mechanisms; improving the education curriculum; and promoting the use of evidence. The findings emphasized that improvement of HRS functions requires addressing context-specific problems. This review provides essential lessons to share with other low- and middle-income countries and international organizations, eg, the WHO. PMID- 30410742 TI - Concordance between GPS-based smartphone app for continuous location tracking and mother's recall of care-seeking for child illness in India. AB - Background: Traditionally, health care-seeking behaviour for child illness is assessed through population-based national demographic and health surveys. GPS based technologies are increasingly used in human behavioural research including tracking human mobility and spatial behaviour. This paper assesses how well a care-seeking event to a health care facility for child illness, as recalled by the mother in a survey setting using questions sourced from Demographic and Health Surveys, concurs with one that is identified by TrackCare, a GPS-based location-aware smartphone application. Methods: Mothers residing in the Vadu HDSS area in Pune district, India having at least one young child were randomly assigned to receive a GPS-enabled smartphone with a pre-installed TrackCare app configured to record the device location data at one-minute intervals over a 6 month period. Spatio-temporal parameters were derived from the location data and used to detect a care-seeking event to any of the health care facilities in the area. Mothers were asked to recall a child illness and if, where and when care was sought, using a questionnaire during monthly visits over a 6-month period. Concordance between the mother's recall and the TrackCare app to identify a care seeking event was estimated according to percent positive agreement. Results: Mean concordance for a care-seeking event between the two methods (mother's recall and TrackCare location data) ranged up to 45%, was significantly higher (P value <0.001) for care-seeking at a hospital as compared to a clinic and for a health care facility in the private sector compared to that in the public sector. Overall, the proportion of disagreement for a care-seeking event not detected by TrackCare but reported by mother ranged up to 77% and was significantly higher (P value <0.001) compared to those not reported by mother but detected by TrackCare. Conclusions: Given the uncertainty and limitations in use of continuous location tracking data in a field setting and the complexity of classifying human activity patterns, additional research is needed before continuous location tracking can serve as a gold standard substitute for other methods to determine health care seeking behaviour. Future performance may be improved by incorporating other smartphone-based sensors, such as Wi-Fi and Bluetooth, to obtain more precise location estimates in areas where GPS signal is weakest. PMID- 30410743 TI - Linking household survey and health facility data for effective coverage measures: a comparison of ecological and individual linking methods using the Multiple Indicator Cluster Survey in Cote d'Ivoire. AB - Background: Population-based measures of intervention coverage are used in low- and middle-income countries for program planning, prioritization, and evaluation. There is increased interest in effective coverage, which integrates information about service quality or health outcomes. Approaches proposed for quality adjusted effective coverage include linking data on need and service contact from population-based surveys with data on service quality from health facility surveys. However, there is limited evidence about the validity of different linking methods for effective coverage estimation. Methods: We collaborated with the 2016 Cote d'Ivoire Multiple Indicator Cluster Survey (MICS) to link data from a health provider assessment to care-seeking data collected by the MICS in the Savanes region of Cote d'Ivoire. The provider assessment was conducted in a census of public and non-public health facilities and pharmacies in Savanes in May-June 2016. We also included community health workers managing sick children who served the clusters sampled for the MICS. The provider assessment collected information on structural and process quality for antenatal care, delivery and immediate newborn care, postnatal care, and sick child care. We linked the MICS and provider data using exact-match and ecological linking methods, including aggregate linking and geolinking methods. We compared the results obtained from exact-match and ecological methods. Results: We linked 731 of 786 care-seeking episodes (93%) from the MICS to a structural quality score for the provider named by the respondent. Effective coverage estimates computed using exact-match methods were 13%-63% lower than the care-seeking estimates from the MICS. Absolute differences between exact match and ecological linking methods were +/-7 percentage points for all ecological methods. Incorporating adjustments for provider category and weighting by service-specific utilization into the ecological methods generally resulted in better agreement between ecological and exact match estimates. Conclusions: Ecological linking may be a feasible and valid approach for estimating quality-adjusted effective coverage when a census of providers is used. Adjusting for provider type and caseload may improve agreement with exact match results. There remain methodological questions to be addressed to develop guidance on using linking methods for estimating quality adjusted effective coverage, including the effect of facility sampling and time displacement. PMID- 30410745 TI - Health Care Workers in the setting of the "Arab Spring": a scoping review for the Lancet-AUB Commission on Syria. AB - Background: "Health Care Workers in Conflict Areas" emerged as one of the priority themes for a Lancet Commission addressing health in conflict. The objective of our study was to conduct a scoping review on health workers in the setting of the Syrian conflict, addressing four topics of interest: violence against health care workers, education, practicing in conflict setting, and migration. Methods: Considering the likelihood of scarcity of data, we broadened the scope of the scoping review to include indirect evidence on health care workers from other countries affected by the "Arab Spring". We electronically searched six electronic databases. We conducted descriptive analysis of the general characteristics of the included papers. We also used the results of this scoping review to build an evidence gap map. Results: Out of the 11 165 identified citations, 136 met our eligibility criteria. The majority of the articles tackled the issue of violence against health care workers (63%) followed by practicing in conflict setting (19%), migration (17%) and education (10%). Countries in focus of most articles were: Syria (35%), Iraq (33%), and Bahrain (29%). News, editorials, commentaries and opinion pieces made up 81% of all included papers, while primary studies made up only 9%. All the primary studies identified in this review were conducted on Iraq. Most of the articles about violence against health care workers were on Bahrain, followed by Syria and Iraq. The first and corresponding authors were most frequently affiliated with institutions from non-Arab countries (79% and 79% respectively). Conclusions: Research evidence on health care workers in the setting of the "Arab Spring" is scarce. This review and the gap map can inform the research agendas of funders and researchers working in the field of health care workers in conflict setting. More well-designed primary studies are needed to inform the decisions of policymakers and other interested parties. PMID- 30410746 TI - Association between availability of children's book and the literacy-numeracy skills of children aged 36 to 59 months: secondary analysis of the UNICEF Multiple-Indicator Cluster Surveys covering 35 countries. AB - Background: Stimulating home environments that have children's books, pictures and play toys facilitate caregiver-child interactions and enhance children's development. Although this has been demonstrated in small-scale intervention studies, it is important to document whether book ownership is beneficial at large scale in low and middle-income settings. Methods: We conducted a secondary analysis using data from the multiple-indicator cluster survey, covering 100 012 children aged 36-59 months, from 35 countries. The outcome was children being on track for a literacy-numeracy index (LNI) constructed from three questions assessing children's ability to identify/name at least 10 letters of the alphabet, read at least four simple popular words and know the names and symbols of all numbers from 1-10. The main exposure was availability of children's book to the child within household. Analysis considered the survey design, assessed and ranked risk ratios of being on track, adjusting for potential confounders such as child's age (in months), maternal education, household wealth index quintile and area of residence (rural/urban). Ecological analysis was performed using meta-regression after grouping countries by World Bank income groups (low- to high-income). Results: Only half (51.8%) of children from all the countries analysed have at least one children's book at home and less than one-third (29.9%; 95% confidence interval (CI) = 23.5%, 36.3%) are on track for literacy numeracy. After adjusting for confounders, the likelihood of being on track in literacy-numeracy almost doubled if at least one book was available at home compared to when there was none: RR = 1.89 (95% CI = 1.75, 2.03). There was an economic gradient showing that the likelihood of children being on track for LNI decreased with the country's income group: adjusted-RR ranged from 1.65 in upper middle income to 2.23 in LIC (F-test P-value <0.0001). Only three high-income countries were included, and children's books were universally available resulting in wide confidence intervals for the effect. Conclusions: These findings are policy-relevant, as they corroborate the results from small scale experiments. Making children's book available to children is a cheap and feasible intervention that could change home dynamics to improve the future economic fortunes of children especially in the poorest countries. PMID- 30410744 TI - Global and regional estimates of the morbidity due to type I diabetes among children aged 0-4 years: a systematic review and analysis. AB - Background: Epidemiology of type 1 diabetes mellitus (T1DM) among children aged 0 4 years globally is not well understood. We aim to assess the incidence of T1DM in low- and middle-income countries (LMIC) by conducting a systematic review of previous reports. We also aim to address possible contribution to child mortality and to identify any temporal trends. Methods: A systematic review was performed using a carefully designed search strategy to explore MEDLINE, EMBASE and Global Health databases. Data was extracted from all studies that satisfied the inclusion criteria -a total of 83 records extracted from 26 830 sources that were analysed. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) process to assess quality of evidence and applied meta analysis approaches to assess global and regional incidence and time trends. Results: The overall pooled incidence of T1DM in children aged 0-4 years globally is 11.2 (95% CI = 10.0-12.3) per 100 000 child years. The regional incidence were the highest for European Region A (EUR A) at 15.5 (95% CI = 13.5-17.5) per 100 000 child years. EUR C had the incidence of 10.0 (95% CI = 6.5-13.6) and EUR B 5.8 (95% CI = 4.7-7.0), Region of the Americas A (AMR A) 11.4 (95% CI = 7.8 14.9), AMR B of 2.5 (95% CI = 0.2-4.8), Eastern Mediterranean Region (EMR B) 7.1 (95% CI = 4.2-10.0) and Western Pacific Region (WPR A) 7.0 (95% CI = 2.9-11.0) per 100 000 child years, while other regions had very low rates or no data. When data points were categorised in the study periods and re-analysed, an increasing trend of the T1DM incidence was observed, with the incidence of 20.9 (95% CI = 7.8-34.1) per 100 000 child years in the years 2010-2015, preceded by 13.2 (95% CI = 11.0-15.5) in 2000-2009 study period, 10.0 (95% CI = 8.4-11.7) in 1990-1999 and 8.3 (95% CI = 5.1-11.6) in 1980-1989, respectively. Although the data are scarce, and variation and uncertainty are large, we estimated that the number of new cases of T1DM among children aged 0-4 years in the world each year is between 100 000 and 150 000. Conclusions: The identified large variation in incidence estimates for different parts of the world, along with scarcity of information and the identified strong temporal increase in T1DM incidence suggest a clear need for further research into this subject. PMID- 30410747 TI - Optimal timing of surgical antimicrobial prophylaxis in laparoscopic surgery: a before-after study. AB - Background: The optimal timing of preoperative surgical antimicrobial prophylaxis (SAP) remains uncertain. This study aimed to evaluate the impact of changing the timing of SAP on the incidence of surgical site infection (SSI) in laparoscopic surgery. Methods: We performed a before-after study from August 2014 through June 2017 to assess the impact of changes in the timing of SAP on the incidence of SSI at a 790-bed tertiary care center in Japan. The intervention was the administration of SAP immediately after the study patients entered the operating room for laparoscopic surgery. Results: In total, 1397 patients who met the inclusion criteria were analyzed. After the intervention, the median time between the time of SAP completion and the time of surgical incision changed from 8 min to 26 min (p < 0.001), and the number of cases without SAP completion prior to surgical incision decreased (16.8% vs. 1.8%; p < 0.001). However, changes in the overall incidence of SSI did not significantly differ between the pre intervention and the intervention groups (13.8% vs. 13.2%; p = 0.80). Conclusions: Although the timing of preoperative SAP improved, the intervention did not have a significant impact on reducing the incidence of SSI in the current study. Besides preoperative SAP, multidisciplinary approaches should be incorporated into projects aimed at comprehensively improving surgical quality to reduce SSI. PMID- 30410748 TI - Spread of the florfenicol resistance floR gene among clinical Klebsiella pneumoniae isolates in China. AB - Background: Florfenicol is a derivative of chloramphenicol that is used only for the treatment of animal diseases. A key resistance gene for florfenicol, floR, can spread among bacteria of the same and different species or genera through horizontal gene transfer. To analyze the potential transmission of resistance genes between animal and human pathogens, we investigated floR in Klebsiella pneumoniae isolates from patient samples. floR in human pathogens may originate from animal pathogens and would reflect the risk to human health of using antimicrobial agents in animals. Methods: PCR was used to identify floR-positive strains. The floR genes were cloned, and the minimum inhibitory concentrations (MICs) were determined to assess the relative resistance levels of the genes and strains. Sequencing and comparative genomics methods were used to analyze floR gene-related sequence structure as well as the molecular mechanism of resistance dissemination. Results: Of the strains evaluated, 20.42% (67/328) were resistant to florfenicol, and 86.96% (20/23) of the floR-positive strains demonstrated high resistance to florfenicol with MICs >=512 MUg/mL. Conjugation experiments showed that transferrable plasmids carried the floR gene in three isolates. Sequencing analysis of a plasmid approximately 125 kb in size (pKP18-125) indicated that the floR gene was flanked by multiple copies of mobile genetic elements. Comparative genomics analysis of a 9-kb transposon-like fragment of pKP18-125 showed that an approximately 2-kb sequence encoding lysR-floR-virD2 was conserved in the majority (79.01%, 83/105) of floR sequences collected from NCBI nucleotide database. Interestingly, the most similar sequence was a 7-kb fragment of plasmid pEC012 from an Escherichia coli strain isolated from a chicken. Conclusions: Identified on a transferable plasmid in the human pathogen K. pneumoniae, the floR gene may be disseminated through horizontal gene transfer from animal pathogens. Studies on the molecular mechanism of resistance gene dissemination in different bacterial species of animal origin could provide useful information for preventing or controlling the spread of resistance between animal and human pathogens. PMID- 30410749 TI - High frequency and molecular epidemiology of metallo-beta-lactamase-producing gram-negative bacilli in a tertiary care hospital in Lahore, Pakistan. AB - Background: Metallo-beta-lactamase (MBL)-producing isolates have a strong impact on diagnostic and therapeutic decisions. A high frequency of MBL-producing gram negative bacilli has been reported worldwide. The current study was based on determining the incidence of MBL-producing imipenem-resistant clinical isolates and investigating the beta-lactamase gene variants in strains conferring resistance to a carbapenem drug (imipenem). Methods: A total of 924 gram negative isolates were recovered from a tertiary care hospital in Lahore, Pakistan, during a two-year period (July 2015 to February 2017). The initial selection of bacterial isolates was based on antibiotic susceptibility testing. Strains resistant to imipenem were processed for the molecular screening of beta lactamase genes. Statistical analysis for risk factor determination was based on age, gender, clinical specimen and type of infection. Results: The rate of imipenem resistance was calculated to be 56.51%. Among the 142 strains processed, the phenotypic tests revealed that the incidence of MBLs was 63.38% and 86.61% based on the combination disc test and the modified Hodge test, respectively. The frequencies of bla TEM, bla SHV, bla OXA, bla IMP-1, and bla VIM genes were calculated to be 46%, 34%, 24%, 12.5% and 7%, respectively. The co-expression of bla MBL (bla IMP and bla VIM) and bla ESBL (bla TEM, bla SHV, bla OXA) was also detected through multiplex and singleplex PCR. bla OXA, bla TEM and bla SHV coexisted in 82% of the isolates. Co-expression of ESBL and MBL genes was found in 7% of the isolates. Conclusion: To our knowledge, this is the first report from Pakistan presenting the concomitant expression of bla OXA, bla TEM and bla SHV with bla IMP-1 and bla VIM in MBL-producing gram-negative bacilli. PMID- 30410750 TI - Intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome. AB - Background: Down syndrome (DS) individuals, by the age of 40s, are at increased risk to develop Alzheimer-like dementia, with deposition in brain of senile plaques and neurofibrillary tangles. Our laboratory recently demonstrated the disturbance of PI3K/AKT/mTOR axis in DS brain, prior and after the development of Alzheimer Disease (AD). The aberrant modulation of the mTOR signalling in DS and AD age-related cognitive decline affects crucial neuronal pathways, including insulin signaling and autophagy, involved in pathology onset and progression. Within this context, the therapeutic use of mTOR-inhibitors may prevent/attenuate the neurodegenerative phenomena. By our work we aimed to rescue mTOR signalling in DS mice by a novel rapamycin intranasal administration protocol (InRapa) that maximizes brain delivery and reduce systemic side effects. Methods: Ts65Dn mice were administered with InRapa for 12 weeks, starting at 6 months of age demonstrating, at the end of the treatment by radial arms maze and novel object recognition testing, rescued cognition. Results: The analysis of mTOR signalling, after InRapa, demonstrated in Ts65Dn mice hippocampus the inhibition of mTOR (reduced to physiological levels), which led, through the rescue of autophagy and insulin signalling, to reduced APP levels, APP processing and APP metabolites production, as well as, to reduced tau hyperphosphorylation. In addition, a reduction of oxidative stress markers was also observed. Discussion: These findings demonstrate that chronic InRapa administration is able to exert a neuroprotective effect on Ts65Dn hippocampus by reducing AD pathological hallmarks and by restoring protein homeostasis, thus ultimately resulting in improved cognition. Results are discussed in term of a potential novel targeted therapeutic approach to reduce cognitive decline and AD-like neuropathology in DS individuals. PMID- 30410752 TI - A genome-wide landscape of mRNAs, lncRNAs, and circRNAs during subcutaneous adipogenesis in pigs. AB - Background: Preadipocyte differentiation plays a critical role in subcutaneous fat deposition in pigs. However, the roles of different RNAs, such as messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in the differentiation process of subcutaneous preadipocytes, are still largely unclear. In the present study, a transcriptome analysis, including the analysis of mRNAs, lncRNAs, and circRNAs, during different differentiation stages, namely, day 0 (D0), day 2 (D2), day 4 (D4), and day 8 (D8), of subcutaneous preadipocytes from Chinese Erhualian pigs was performed. Results: A total of 1554, 470, 1344, 1777, and 676 differentially expressed (DE) mRNAs, 112, 58, 95, 136, and 93 DE lncRNAs, and 902, 787, 710, 932, and 850 DE circRNAs were identified between D2 and D0, between D4 and D2, between D8 and D4, between D4 and D0, and between D8 and D0, respectively. Furthermore, functional enrichment analysis showed that the common DE mRNAs during the entire differentiation process were mainly involved in lipid metabolic and cell differentiation processes. Additionally, co-expression network analysis identified the potential lncRNAs related to adipogenesis, e.g., MSTRG.131380 and MSTRG.62128. Conclusions: Our study provides new insights of the expression changes of RNAs during adipogenic differentiation, which might contribute to the phenotype of subcutaneous adipogenesis. These results greatly improve our understanding of the molecular mechanisms regulating subcutaneous fat deposition in pigs. PMID- 30410751 TI - Direct conversion of mouse astrocytes into neural progenitor cells and specific lineages of neurons. AB - Background: Cell replacement therapy has been envisioned as a promising treatment for neurodegenerative diseases. Due to the ethical concerns of ESCs-derived neural progenitor cells (NPCs) and tumorigenic potential of iPSCs, reprogramming of somatic cells directly into multipotent NPCs has emerged as a preferred approach for cell transplantation. Methods: Mouse astrocytes were reprogrammed into NPCs by the overexpression of transcription factors (TFs) Foxg1, Sox2, and Brn2. The generation of subtypes of neurons was directed by the force expression of cell-type specific TFs Lhx8 or Foxa2/Lmx1a. Results: Astrocyte-derived induced NPCs (AiNPCs) share high similarities, including the expression of NPC-specific genes, DNA methylation patterns, the ability to proliferate and differentiate, with the wild type NPCs. The AiNPCs are committed to the forebrain identity and predominantly differentiated into glutamatergic and GABAergic neuronal subtypes. Interestingly, additional overexpression of TFs Lhx8 and Foxa2/Lmx1a in AiNPCs promoted cholinergic and dopaminergic neuronal differentiation, respectively. Conclusions: Our studies suggest that astrocytes can be converted into AiNPCs and lineage-committed AiNPCs can acquire differentiation potential of other lineages through forced expression of specific TFs. Understanding the impact of the TF sets on the reprogramming and differentiation into specific lineages of neurons will provide valuable strategies for astrocyte-based cell therapy in neurodegenerative diseases. PMID- 30410753 TI - Mammary cell proliferation and catabolism of adipose tissues in nutrition restricted lactating sows were associated with extracellular high glutamate levels. AB - Background: Persistent lactation, as the result of mammary cellular anabolism and secreting function, is dependent on substantial mobilization or catabolism of body reserves under nutritional deficiency. However, little is known about the biochemical mechanisms for nutrition-restricted lactating animals to simultaneously maintain the anabolism of mammary cells while catabolism of body reserves. In present study, lactating sows with restricted feed allowance (RFA) (n = 6), 24% feed restriction compared with the control (CON) group (n = 6), were used as the nutrition-restricted model. Microdialysis and mammary venous cannulas methods were used to monitor postprandial dynamic changes of metabolites in adipose and mammary tissues. Results: At lactation d 28, the RFA group showed higher (P < 0.05) loss of body weight and backfat than the CON group. Compared with the CON group, the adipose tissue of the RFA group had higher (P < 0.05) extracellular glutamate and insulin levels, increased (P < 0.05) lipolysis related genes (HSL and ATGL) expression, and decreased (P < 0.05) glucose transport and metabolism related genes (VAMP8, PKLR and LDHB) expression. These results indicated that under nutritional restriction, reduced insulin-mediated glucose uptake and metabolism and increased lipolysis in adipose tissues was related to extracellular high glutamate concentration. As for mammary glands, compared with the CON group, the RFA group had up-regulated (P < 0.05) expression of Notch signaling ligand (DLL3) and receptors (NOTCH2 and NOTCH4), higher (P < 0.05) extracellular glutamate concentration, while expression of cell proliferation related genes and concentrations of most metabolites in mammary veins were not different (P > 0.05) between groups. Accordingly, piglet performance and milk yield did not differ (P > 0.05) between groups. It would appear that activation of Notch signaling and adequate supply of glutamate might assist mammogenesis. Conclusions: Mammary cell proliferation and catabolism of adipose tissues in nutrition-restricted lactating sows were associated with extracellular high glutamate levels. PMID- 30410754 TI - Switch to low-fat diet improves outcome of acute lymphoblastic leukemia in obese mice. AB - Background: It is becoming increasingly recognized that weight and nutritional status can impact cancer survival. We have previously shown that obese mice with syngeneic acute lymphoblastic leukemia (ALL) have poorer response to chemotherapy treatment than control mice. We therefore investigated whether dietary intervention could improve outcome from the most common pediatric cancer, ALL. Methods: Diet-induced obese (DIO) mice raised on a 60% calories from fat diet and control mice were implanted with syngeneic ALL cells. Some DIO mice were switched to the low-fat control diet. Survival from ALL was assessed without or with chemotherapy treatment starting at the time of the diet switch. Cells from DIO mice before and after diet switch were assessed by FACS for BrdU incorporation and phosphorylation status of AKT, S6K, and EIF2a. Similar experiments were done with human ALL xenografts. Mouse and human ALL cells were cultured in media with 10% or 5% fetal bovine serum, and sensitivity to chemotherapies assessed. Results: DIO mice had poorer survival (17%) after vincristine monotherapy than control mice on a 10% low fat diet (42%; n = 12/group; p = 0.09, log rank). However, switching obese mice to the low-fat diet prior to initiation of vincristine led to dramatically improved survival (92%, p < 0.01 vs both other groups). In vitro, FBS restriction made murine and human ALL cells more sensitive to vincristine. Interestingly, while serum restriction enhanced ALL sensitivity to dexamethasone and l-asparaginase, dietary switch did not improve survival of DIO mice treated with either drug in monotherapy. Thus, it appears that dietary intervention has a unique effect to improve ALL cell sensitivity to vincristine in vivo. Conclusions: We report herein that a dietary intervention can improve ALL outcome in a preclinical model. Further work is needed to identify the mechanisms of this effect and investigate potential impact on human leukemia in patients. PMID- 30410755 TI - Incorporating environmental variables as precursor background variables of the theory of planned behavior to predict quitting-related intentions: a comparative study between adult and young adult smokers. AB - Background: As previous studies suggest that the theory of planned behavior (TPB) is open to the inclusion of further predictors, identifying a number of additional background variables within the context of the TPB may help improve the predictive power of the theory. The purpose of this study is to incorporate environmental variables as precursor background variables of the TPB to predict quitting-related intentions. Methods: This study consists of two sub-studies. Sub study 1 and 2 analyzed different data sets and were conducted using the similar methodology for the comparison. A total of 395 Texas adult smokers (sub-study 1) and 379 university student smokers (sub-study 2) were analyzed using multiple structural equation modeling. Results: The extent of agreement with regulating smoking in public places had positive indirect effects on intention to quit through subjective norm among both Texas adult smokers (beta = 0.03, p < .01) and university students (beta = 0.01, p < .05), and through attitude among Texas adult smokers only (beta = 0.02, p < .01). The number of smokers among 5 closest friends had negative indirect effect on intention to take measures to quit through subjective norm among Texas adult smokers (beta = - 0.02, p < .05). Conclusions: The results of this study indicate that environmental variables need to be considered as precursor background variables of the TPB to predict quitting related intentions. PMID- 30410756 TI - Developing a workplace lactation promotion model in Indonesia using Delphi technique. AB - Background: Working mothers have a higher risk to terminate breastfeeding earlier than stay-at-home mothers. Researchers reported that support from the workplace by creating lactation facilities and develop supportive programs are necessary to increase the success of exclusive breastfeeding. The aim was to achieve expert consensus on developing a workplace-based lactation promotion model. Methods: A three-round online survey using Delphi approach was conducted to reach consensus on to the development of a lactation program at a workplace. Results: Twenty-two experts from Indonesian health authority, community medicine, child health and obstetrics were invited to join the Delphi study; 15 (68.2%) enrolled in the first round. The response rate in the second and third round was 80.0% (12/15) and 86.7% (13/15), respectively. The first round categorized the workplace-based promotion model into seven dimensions, i.e. policy and regulation, facility, education material, target participants, promotion approach, human resources, and time. In the final round, "maternity leave of 3-6 months" (median (Q1;Q3):2 (1, 4)) and "employees have the right to breast-pumping every 3 hours" (median (Q1;Q3):3 (2, 4)) ranked as the two most important indicators regarding policy and regulation. A dedicated lactation room (median (Q1;Q3):1 (1)) is the highest ranked indicator regarding facility dimension. Regarding education materials, benefits of breast milk for babies ranked as the highest indicator while for the education and delivering methods dimensions, social media and interactive counseling were two highest ranked indicators. The top management in the company and lactation counselor are the two highest-ranked indicators in human resources dimension. Conclusion: In the view of experts, involvement of a dedicated policy maker in the company, a workplace-based lactation counselor, regular promotion with interactive education and dedicated facilities are necessary to develop an effective workplace-based lactation promotion model. PMID- 30410759 TI - Themes arising during implementation consultation with teams applying family based treatment: a qualitative study. AB - Background: This study describes themes arising during implementation consultation with teams providing Family-Based Treatment (FBT) to adolescents with eating disorders. Methods: Participants were implementation teams (one lead therapist, one medical practitioner and one administrator) at four sites. These teams agreed to support the implementation of FBT, and participated in monthly consultation calls which were audio-recorded, transcribed verbatim and coded for themes. Twenty percent of the transcripts were double-coded to ensure consistency. Fundamental qualitative description guided the sampling and data collection. Results: Twenty-five (average per site = 6) transcripts were coded using thematic content analysis. Six major themes emerged: 1) system barriers and facilitators 2) the role of the medical practitioner, 3) research implementation, 4) appropriate cases, 5) communication, and 6) program impact. Conclusions: Implementation themes aligned with previous research examining the adoption of FBT, and provide additional insight for clinical programs seeking to implement FBT, emphasizing the importance of role clarity, and team communication. PMID- 30410758 TI - What can food-image tasks teach us about anorexia nervosa? A systematic review. AB - A salient feature of anorexia nervosa (AN) is the persistent and severe restriction of food, such that dietary intake is inadequate to maintain a healthy body weight. Experimental tasks and paradigms have used illness-relevant stimuli, namely food images, to study the eating-specific neurocognitive mechanisms that promote food avoidance. This systematic review, completed in accordance with PRISMA guidelines, identified and critically evaluated paradigms involving images of food that have been used to study AN. There were 50 eligible studies, published before March 10th 2018, identified from Medline and PsychINFO searches, and reference screening. Studies using food image-based paradigms were categorised into three methodologic approaches: neuropsychology, neurophysiology, and functional magnetic resonance imaging (fMRI). Paradigms were reviewed with a focus on how well they address phenomena central to AN. Across tasks, differences between individuals with AN and healthy peers have been identified, with the most consistent findings in the area of reward processing. Measuring task performance alongside actual eating behaviour, and using experimental manipulations to probe causality, may advance understanding of the mechanisms of illness in AN. PMID- 30410760 TI - Psychometric properties of the Iranian version of mindful eating questionnaire in women who seeking weight reduction. AB - Background: The aim of the present study was to test the validity, reliability and factor structure of the original Mindful Eating Questionnaire (MEQ) for use in an Iranian population. Methods: This was a cross-sectional study conducted on 150 women who attended four athletic gyms and met the inclusion criteria in Ahvaz city in July of 2015. After linguistic validation of the Iranian version of the MEQ, the content validity ratio (CVR) and content validity index (CVI) were assessed by an expert panel. Then, exploratory factor analysis (EFA) was performed on the scale constructs and scale reliability (internal consistency and test-retest reliability) was assessed with respect to the psychometric properties of the scale. Results: The CVR and CVI scores for the MEQ were 0.89 and 0.93, respectively. EFA loaded all 28-items with a 5-factor solution ('awareness', 'distraction', 'disinhibition', 'emotional response' and 'external cues') that jointly accounted for 53.78% of the observed variance. The results of the EFA supported the item 'When a restaurant portion is too large, I stop eating when I'm full' being placed in the external cues rather than the disinhibition subscale. This displacement improved the reliability coefficient for this subscale.The results of internal consistency analysis, including Cronbach's alpha (ranging from 0.73 to 0.81) and intraclass correlation coefficients (ranging from 0.73 to 0.91) were satisfactory. Conclusions: The Persian version of the MEQ appears to be valid and reliable; therefore, it can be an effective tool in designing mindfulness-based interventions for the treatment of individuals with eating disorders, overweight and obesity in an Iranian population. PMID- 30410762 TI - The influenza of 1918: Evolutionary perspectives in a historical context. AB - The 1918 influenza pandemic was the deadliest in known human history. It spread globally to the most isolated of human communities, causing clinical disease in a third of the world's population, and infecting nearly every human alive at the time. Determination of mortality numbers is complicated by weak contemporary surveillance in the developing world, but recent estimates put the death toll at 50 million or even higher. This outbreak is of great interest to modern day epidemiologists, virologists, global health researchers and evolutionary biologists. They ask: Where did it come from? And if it happened once, could it happen again? Understanding how such a virulent epidemic emerged and spread offers hope for prevention and strategies of response. This review uses historical methodology and evolutionary perspectives to revisit the 1918 outbreak. Using the American military experience as a case study, it investigates the emergence of virulence in 1918 by focusing on key susceptibility factors that favored both the influenza virus and the subsequent pneumococcal invasion that took so many lives. This article explores the history of the epidemic and contemporary measures against it, surveys modern research on the virus, and considers what aspects of 1918 human and animal ecology most contributed to the emergence of this pandemic. PMID- 30410761 TI - Binge eating disorder and night eating syndrome in adults with type 2 diabetes: a systematic review. AB - Background: Type 2 diabetes (T2DM) is increasing in prevalence worldwide, and is closely linked to obesity. Binge Eating Disorder (BED) and Night Eating Syndrome (NES) are eating disorders that are common in obesity, and may affect the management as well as long term outcomes of T2DM. Therefore, the aim of this review was to assess the prevalence and associations of BED or NES in adults with T2DM. Methods: We conducted a systematic review. The databases MEDLINE, CINAHL and AMED were searched for articles which met the inclusion criteria; including patients > 18 years old, with T2DM, and BED and/or NES. The reference lists of included studies were also searched. Meta-analysis was not attempted due to the limited number of studies that measured the outcomes of interest. Results: A total of 10 studies (2 included NES) were included in this systematic review. The number screened for BED and NES were 6527 and 1039 participants, respectively. Point prevalence was 1.2-8.0% for BED and 3.8-8.4% for NES. Patients with T2DM and BED had higher BMI than patients with T2DM without BED in the two studies that reported BMI. There was no statistically significant difference in HbA1c between patients with and without BED in the two studies that measured HbA1c. Conclusions: BED and NES are common in adults with T2DM, and BED is associated with higher BMI in patients with T2DM. However, only two studies reported important outcomes measures such as BMI and HbA1c in patients with T2DM. Hence, further well-designed studies are needed to assess the impact of BED and NES in patients with T2DM. Health Care Professionals should consider the diagnosis of BED and NES in patients with T2DM. PMID- 30410763 TI - Aorto-pleural fistula successfully treated by one-lung ventilation and Endobronchial Watanabe Spigots. AB - Aorto-pleural fistula (APF) is a rare, potentially fatal condition that should be immediately treated by an endovascular or surgical approach. In this case, we treated APF using bronchial occlusion with Endobronchial Watanabe Spigots (EWSs) after one-lung ventilation. Notably, EWS is composed of silicon for endobronchial occlusion under bronchoscopy. An 88-year-old man was referred to our hospital for sudden massive hemoptysis. We maintained the airway by emergent intubation into the right main bronchus through guided bronchoscopy. Computed tomography demonstrated an aortic aneurysm at the aortic arch, penetrating the upper lobe of the left lung. On the 18th hospital day, we performed prophylactic endobronchial occlusion with EWS. The patient was extubated shortly thereafter. Endobronchial occlusion with EWS might be effective in patients with APF who exhibit generally poor conditions. Endobronchial occlusion treatment should be performed after controlling massive bleeding by one-lung ventilation. PMID- 30410757 TI - Revisiting cefditoren for the treatment of community-acquired infections caused by human-adapted respiratory pathogens in adults. AB - Fifteen years after its licensure, this revision assesses the role of cefditoren facing the current pharmacoepidemiology of resistances in respiratory human adapted pathogens (Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae and Moraxella catarrhalis). In the era of post- pneumococcal conjugate vaccines and in an environment of increasing diffusion of the ftsI gene among H. influenzae isolates, published studies on the cefditoren in vitro microbiological activity, pharmacokinetic/pharmcodynamic (PK/PD) activity and clinical efficacy are reviewed. Based on published data, an overall analysis is performed for PK/PD susceptibility interpretation. Further translation of PK/PD data into clinical/microbiological outcomes obtained in clinical trials carried out in the respiratory indications approved for cefditoren in adults (tonsillitis, sinusitis, acute exacerbation of chronic bronchitis and community-acquired pneumonia) is commented. Finally, the role of cefditoren within the current antibiotic armamentarium for the treatment of community respiratory tract infections in adults is discussed based on the revised information on its intrinsic activity, pharmacodynamic adequacy and clinical/bacteriological efficacy. Cefditoren remains an option to be taken into account when selecting an oral antibiotic for the empirical treatment of respiratory infections in the community caused by human-adapted pathogens, even when considering changes in the pharmacoepidemiology of resistances over the last two decades. PMID- 30410764 TI - Time-varying predatory behavior is primary predictor of fine-scale movement of wildland-urban cougars. AB - Background: While many species have suffered from the detrimental impacts of increasing human population growth, some species, such as cougars (Puma concolor), have been observed using human-modified landscapes. However, human modified habitat can be a source of both increased risk and increased food availability, particularly for large carnivores. Assessing preferential use of the landscape is important for managing wildlife and can be particularly useful in transitional habitats, such as at the wildland-urban interface. Preferential use is often evaluated using resource selection functions (RSFs), which are focused on quantifying habitat preference using either a temporally static framework or researcher-defined temporal delineations. Many applications of RSFs do not incorporate time-varying landscape availability or temporally-varying behavior, which may mask conflict and avoidance behavior. Methods: Contemporary approaches to incorporate landscape availability into the assessment of habitat selection include spatio-temporal point process models, step selection functions, and continuous-time Markov chain (CTMC) models; in contrast with the other methods, the CTMC model allows for explicit inference on animal movement in continuous-time. We used a hierarchical version of the CTMC framework to model speed and directionality of fine-scale movement by a population of cougars inhabiting the Front Range of Colorado, U.S.A., an area exhibiting rapid population growth and increased recreational use, as a function of individual variation and time-varying responses to landscape covariates. Results: We found evidence for individual- and daily temporal-variability in cougar response to landscape characteristics. Distance to nearest kill site emerged as the most important driver of movement at a population-level. We also detected seasonal differences in average response to elevation, heat loading, and distance to roads. Motility was also a function of amount of development, with cougars moving faster in developed areas than in undeveloped areas. Conclusions: The time varying framework allowed us to detect temporal variability that would be masked in a generalized linear model, and improved the within-sample predictive ability of the model. The high degree of individual variation suggests that, if agencies want to minimize human-wildlife conflict management options should be varied and flexible. However, due to the effect of recursive behavior on cougar movement, likely related to the location and timing of potential kill-sites, kill-site identification tools may be useful for identifying areas of potential conflict. PMID- 30410766 TI - Acute glycemic control in diabetics. How sweet is oprimal? Con: Just as sweet as in nondiabetic is better. AB - This review is for Con side of "Pro-Con debate" on the optimal target of blood glucose levels in patients with chronic hyperglycemia (e.g. premorbid HbA1c level > 7%). Currently, international guideline recommended that blood glucose level <= 180 mg/dL in critically ill patients irrespective of presence or absence of premorbid diabetes. However, there are several studies to generate the hypothesis that liberal glycemic control (e.g., target blood glucose level 180-250 mg/dL) may be beneficial in critically ill patients with premorbid hyperglycemia. Although there is before-after study to report its safety and feasibility, it should be noted that this strategy may have a potential to increase the risk of infection, glycosuria, and polyneuropathy. Furthermore, there is randomized controlled study which showed the potential harm of liberal glycemic control in patients with premorbid hyperglycemia. Additionally, there are lots of uncertainty about the candidate and methodology of such a permissive hyperglycemia. With considering these facts, it might be better to keep target of blood glucose level in patients with diabetes the same as patients without diabetes (<= 180 mg/dL), until randomized control study as like LUCID (the Liberal GlUcose Control in Critically Ill Patients with Pre-existing Type 2 Diabetes) trial will justify its risk and benefit. PMID- 30410765 TI - Epididymal approaches to male contraception. AB - Today, a vast arsenal of contraceptive methods interfering at different levels of the female reproductive axis is available. This is not the case for men for whom, until now, there is no reliable male reversible method and for whom vasectomy, condom and withdrawal are the only options available. Despite this limited supply, more than one third of all contraceptive methods used worldwide rely on the cooperation of the male partner. Besides developing hormonal approaches to stop sperm production, there may be attractive approaches that will interfere with sperm functions rather than production. Sperm functions are primarily established during post-testicular maturation, with the epididymis accounting for the majority. The purpose of this review is to present some of the promising and/or already abandoned leads that emerge from research efforts targeting the epididymis and its activities as potential means to achieve male post-meiotic contraception. PMID- 30410767 TI - Dual androgen receptor (AR) and STAT3 inhibition by a compound targeting the AR amino-terminal domain. AB - Prostate cancer (PCa) often recurs as incurable castration-resistant prostate cancer (CRPC) after the failure of androgen deprivation therapy. CRPC development relies on androgen receptor (AR) signaling. The IL6/STAT3 pathway is also a key driver of CRPC. The crosstalk between IL6/STAT3 and the AR pathways provides opportunities to explore next-generation agents to treat PCa. Through screening of around 600 natural compounds in our newly established prostate tumorigenesis model, potential STAT3 signaling inhibitors were found and additionally examined for effects on AR signaling. The small molecular compound 154 exhibited dual effects on IL6/STAT3 and AR pathways. We show here that compound 154 inhibits AR and STAT3 transcriptional activity, reduces the expression of phosphorylation of STAT3 (Y705) and downregulates the mRNA levels of AR target genes. Compound 154 also inhibits protein expression of AR and AR splice variants (ARv567es and AR V7) without altering AR mRNA levels. Compound 154 binds to AR directly, but not to STAT3 and is identified as an antagonist of the AR amino-terminal domain (NTD) by disrupting protein-protein interactions between STAT3 and the AR NTD. Moreover, compound 154 does not reduce AR nuclear translocation. Compound 154 possesses the potential to become a leading compound in novel therapies against CRPC. PMID- 30410768 TI - Effects of cardiopulmonary bypass on the disposition of cefazolin in patients undergoing cardiothoracic surgery. AB - The aim of the study was to evaluate the disposition of plasma unbound cefazolin in patients undergoing cardiothoracic surgery with cardiopulmonary bypass (CPB). Adult patients undergoing cardiothoracic surgery with CPB were enrolled in the study. Cefazolin sodium was given intravenously before skin incision (1 g) and at the beginning of CPB (2 g). Thereafter, an additional dose (1 g) was given every 4 hours. Seven to ten blood samples were collected before and during surgery. Plasma total and unbound (ultrafiltrated) cefazolin concentrations were analyzed using an HPLC-UV method. Plasma protein binding was analyzed with the Langmuir model. Twenty-seven patients (aged 70 +/- 12 years, body weight 62 +/- 12 kg, mean +/- SD) with GFR >30 mL min-1 completed the study. There was a significant (P < 0.001) increase in median plasma unbound fraction of cefazolin from 21% before skin incision to 45% during CPB (P < 0.001), which was accompanied by a significant (P < 0.001) reduction in median plasma albumin concentration from 36 to 27 g L-1. Plasma concentrations of unbound cefazolin exceeded the assumed target thresholds of 2 MUg mL-1 in all samples and of 8 MUg mL-1 in all but one of 199 samples. The increased plasma unbound fraction of cefazolin would be attributable to dilutional reduction of serum albumin at the beginning of CPB and to saturable plasma protein binding of cefazolin. These data reveal CPB may alter the plasma protein binding and possibly distribution of cefazolin. Further studies are warranted to reappraise the protocol of antimicrobial prophylaxis with cefazolin in patients undergoing surgery with CPB. PMID- 30410769 TI - The influence of kinesiology tape colour on performance and corticomotor activity in healthy adults: a randomised crossover controlled trial. AB - Background: There exists conflicting evidence regarding the impact of kinesiology tape on performance and muscle function. One variable that may account for disparities in the findings of previous studies is the colour of the tape applied. Colour is hypothesised to influence sporting performance through modulation of arousal and aggression. However, few studies have investigated the influence of colour on products designed specifically to enhance athletic performance. Further, no studies have investigated the potential influence of colour on other drivers of performance, such as corticomotor activity and neuromuscular function. Thus, the aim of this study was to investigate the influence of kinesiology tape colour on athletic performance, knee extensor torque, and quadriceps neuromuscular function. Methods: Thirty two healthy participants were assessed under five conditions, applied in random order: (1) no kinesiology tape (control), (2) beige-coloured kinesiology tape applied with tension (sham A), (3) beige-coloured kinesiology tape applied with no tension (sham B), (4) red-coloured kinesiology tape applied with tension, and (5) blue coloured kinesiology tape applied with tension. Athletic performance was assessed using a previously validated hop test, knee extensor torque was measured using an isokinetic dynamometer, and transcranial magnetic stimulation was utilised to provide insight into the neuromuscular functioning of the quadriceps musculature. Results: Kinesiology tape had no beneficial impact on lower limb performance or muscle strength in healthy adults. The colour of the tape did not influence athletic performance (F (4, 120) = 0.593, p = 0.669), quadriceps strength (F (4, 120) = 0.787, p = 0.536), or neuromuscular function (rectus femoris: F (2.661, 79.827) = 1.237, p = 0.301). Conclusion: This study found that kinesiology tape does not alter lower limb performance or muscle function in healthy adults, irrespective of the colour of the tape applied. Future research should seek to confirm these findings beyond the research setting, across a range of sports, and at a range of skill levels. Trial registration: Australian New Zealand Clinical Trials Registry. ACTRN12616001506482. Prospectively registered on 01/11/2016. PMID- 30410771 TI - Occupational cancer claims in Korea from 2010 to 2016. AB - Background: Research on carcinogens causing occupational cancer has been updated. Further, social interest in occupational cancer has increased. In addition, the standard for recognizing cancer as a work-related disease has also been revised. The present study aims to describe the distribution of occupational cancer claims or its approval rate and their association with work-related variables. Methods: We analyzed 1299 claim cases for occupational cancer from 2010 to 2016 provided by the Korea Workers' Compensation and Welfare Service (KCOMWEL). The status of approval rate was shown by year, sex, industry, occupation, age of diagnosis, duration from employment to diagnosis, and cancer site. Results: The approval rate was 39.0% from 2010 to 2016 and tended to increase annually since 2011. Both the number of claims and the approval rate were higher in men. Mining and quarrying showed the highest approval rate (78.4%). The approval rates by age of diagnosis and duration from employment to diagnosis increased as the time periods increased. Respiratory organ had the highest number of claims and the highest approval rate by cancer site. Conclusions: The approval rate of occupational cancer has shown an increasing trend since 2011. The increase of occupational carcinogens and cancer sites and the improvement of social awareness about occupational cancer could have resulted in this trend. The present study provides unique, and the latest and most accurate findings on occupational cancer data of recent 7 years that could be helpful to researchers or policy makers on occupational cancer. PMID- 30410770 TI - Swimming induced pulmonary oedema in athletes - a systematic review and best evidence synthesis. AB - Background: Swimming induced pulmonary oedema is an uncommon occurrence and usually presents during strenuous distance swimming in cold water. The prevalence is most likely underreported and the underlying mechanisms are controversial. The purpose of this study was to summarize the evidence with regards to prevalence, pathophysiology and treatment of swimming induced pulmonary oedema in endurance athletes. Methods: Medline, Embase, Scopus and Google Scholar were searched and level I-IV from 1970 to 2017 were included. For clinical studies, only publications reporting on swimming-induced pulmonary oedema were considered. Risk of bias was assessed with the ROBINS-I tool, and the quality of evidence was assessed with the Cochrane GRADE system. For data synthesis and analysis, a best evidence synthesis was used. Results: A total of 29 studies were included (174 athletes). The most common symptom was cough, dyspnoea, froth and haemoptysis. The risk of bias for the clinical studies included 13 with moderate risk, 3 with serious, and 4 with critical. Four of the pathophysiology studies had a moderate risk, 3 a serious risk, and 1 a critical risk of bias. A best evidence analysis demonstrated a strong association between cold water immersion and in increases of CVP (central venous pressure), MPAP (mean pulmonary arterial pressure), PVR (peripheral vascular resistance) and PAWP (pulmonary arterial wedge pressure) resulting in interstitial asymptomatic oedema. Conclusion: The results of this study suggest a moderate association between water temperature and the prevalence of SIPE. The presence of the clinical symptoms cough, dyspnoea, froth and haemoptysis are strongly suggestive of SIPE during or immediately following swimming. There is only limited evidence to suggest that there are pre-existing risk factors leading to SIPE with exposure to strenuous physical activity during swimming. There is strong evidence that sudden deaths of triathletes are often associated with cardiac abnormalities. PMID- 30410772 TI - Multi-sensor ecological momentary assessment of behavioral and psychosocial predictors of weight loss following bariatric surgery: study protocol for a multicenter prospective longitudinal evaluation. AB - Background: Bariatric surgery is currently the most effective strategy for producing significant and durable weight loss. Yet, not all patients achieve initial weight loss success and some degree of weight regain is very common, sometimes as early as 1-2 years post-surgery. Suboptimal weight loss not fully explained by surgical, demographic, and medical factors has led to greater emphasis on patient behaviors evidenced by clinical guidelines for appropriate eating and physical activity. However, research to inform such guidelines has often relied on imprecise measures or not been specific to bariatric surgery. There is also little understanding of what psychosocial factors and environmental contexts impact outcomes. To address research gaps and measurement limitations, we designed a protocol that innovatively integrates multiple measurement tools to determine which behaviors, environmental contexts, and psychosocial factors are related to outcomes and explore how psychosocial factors/environmental contexts influence weight. This paper provides a detailed description of our study protocol with a focus on developing and deploying a multi-sensor assessment tool to meet our study aims. Methods: This NIH-funded prospective cohort study evaluates behavioral, psychosocial, and environmental predictors of weight loss after bariatric surgery using a multi-sensor platform that integrates objective sensors and self-report information collected via smartphone in real-time in patients' natural environment. A target sample of 100 adult, bariatric surgery patients (ages 21-70) use this multi-sensor platform at preoperative baseline, as well as 3, 6, and 12 months postoperatively, to assess recommended behaviors (e.g., meal frequency, physical activity), psychosocial indicators with prior evidence of an association with surgical outcomes (e.g., mood/depression), and key environmental factors (e.g., type/quality of food environment). Weight also is measured at each assessment point. Discussion: This project has the potential to build a more sophisticated and valid understanding of behavioral and psychosocial factors contributing to success and risk after bariatric surgery. This new understanding could directly contribute to improved (i.e., specific, consistent, and validated) guidelines for recommended pre- and postoperative behaviors, which could lead to improved surgical outcomes. These data will also inform behavioral, psychosocial, and environmental targets for adjunctive interventions to improve surgical outcomes. Trial registration: Registered trial NCT02777177 on 5/19/2016. PMID- 30410774 TI - Safety and feasibility of contained uterine morcellation in women undergoing laparoscopic hysterectomy. AB - Background: Widespread concerns have been raised regarding the safety of power morcellation of uterine specimens because of the potential to disseminate occult malignancy. We sought to assess the safety and feasibility of contained manual uterine morcellation within a plastic specimen bag among women with uterine neoplasms. Methods: A retrospective single-institution descriptive cohort study was conducted from 2003 to 2014. Patients with leiomyoma and/or uterine malignancy who underwent minimally invasive surgery with contained uterine manual morcellation were identified from surgical logs. Demographic data, pathology results, operative details and adjuvant treatments were abstracted. Results: Eighty-eight patients were identified; 35 with leiomyoma and 53 with endometrial cancer. The mean age was 48 and 60, respectively. Uterine size/weight was greater in women with leiomyoma compared to those with cancer (15.1 weeks/448 g vs. 10.7 weeks/322 g). Mean operative time was 206 min (range 115-391) for leiomyoma cases and 238 min (range 131-399) for cancer cases. Median length of stay was 1 day (range 0-3 days). There were no cases of occult leiomyosarcoma and all specimens were successfully manually morcellated within a bag. There were no intraoperative complications. Thirty-day postoperative complications occurred in 7 patients, including one readmission for grade (G) 1 vaginal cuff separation after intercourse, G1 port-site hematoma (1), G2 port-site cellulitis (1), G2 vaginal cuff cellulitis (2), G2 bladder infection (2), G2 pulmonary edema (1), and G1 musculoskeletal injury (1). Conclusions: Contained uterine hand morcellation is a feasible procedure with low peri-operative complication rates that allows for minimally invasive surgical procedures for women with large uterine neoplasms. Further evaluation is needed to assess survival outcomes for uterine malignancies. PMID- 30410775 TI - The role of erlotinib and the Optune device in a patient with an epidermal growth factor receptor viii amplified glioblastoma. AB - The standard treatment for patients diagnosed with glioblastoma is surgical resection of tumor followed by high dose radiation and chemotherapy with temozolomide. For patients who experience allergic reactions to temozolomide despite desensitization protocols, alternative therapies must be considered. In this report, we present such a patient who then received treatment with an epidermal growth factor receptor inhibitor, erlotinib, concurrent with a tumor treating field device, Optune. Through this combination of a targeted molecular therapy and the Optune device, the patient has been able to achieve stable disease 9 months after completing radiation. PMID- 30410776 TI - Bloom syndrome with myelodysplastic syndrome that was converted into acute myeloid leukaemia, with new ophthalmologic manifestations: the first report from Syria. AB - Bloom syndrome is a rare autosomal recessive disease, in which BLM gene is mutated, leading to genome instability and proneness to malignancy. It is characterized by short stature, sun-sensitive rash and immunodeficiency. We present a case of bloom syndrome with myelodysplasia complicated by acute myeloid leukaemia. This case has new ophthalmologic manifestations. We confirmed the diagnosis by detection of high rate of sister chromatid exchange. The patient received chemotherapy but did not tolerate it well and developed fungal pneumonia. PMID- 30410777 TI - Two cases of numb chin syndrome diagnosed as malignant disease. AB - Numb chin syndrome (NCS) is defined as reduced or absent sensation in an area of the chin and lower lip within the distribution of the mental or inferior alveolar nerves. The causes of NCS may be neoplastic, traumatic, dental, toxic, drug induced, inflammatory, autoimmune or infectious. NCS may be the preliminary symptom of malignancy or recurrence/metastasis in patients with cancer. Therefore, the occurrence of NCS warrants careful examination and monitoring of such patients. This article presents two cases of NCS reported in a patient with prostate cancer and in a patient with Burkitt lymphoma/leukaemia. PMID- 30410773 TI - Use of various obesity measurement and classification methods in occupational safety and health research: a systematic review of the literature. AB - Background: This study systematically examined obesity research in occupational safety and health regarding the use of various obesity measurement and classification methods. Methods: A systematic search of the PubMed database on English language publications from 2000 to 2015 using related keywords and search of citations resulted in selection of 126 studies. They were categorized into two groups based on their main research question: 1) general physical or mental work related functioning; and 2) task or body part specific functioning. Results: Regardless of the study group, body mass index (BMI) was the most frequently used measure. Over 63% of the studies relied solely on BMI to define obesity. In only 22% of the studies, body fat was directly measured by methods such as dual energy x-ray absorptiometry. Abdominal obesity was defined using waist circumference in recent years, and waist-hip ratio in earlier years. Inconsistent cut-offs have also been used across studies investigating similar topics. Conclusions: Few authors acknowledged the limitations of using indirect obesity measures. This is in part due to the limited understanding of some occupational safety and health researchers regarding the complex issues surrounding obesity classification and also the mixed recommendations over the past 2-3 decades and across populations. Efforts need to be made to promote appropriate obesity measurement and reporting in this field. PMID- 30410778 TI - Cerebellar radiological abnormalities in children with neurofibromatosis type 1: part 2 - a neuroimaging natural history study with clinical correlations. AB - Background: Focal abnormal signal intensities (FASI) on brain MRI occur commonly in patients with neurofibromatosis type 1 (NF1). The natural history of cerebellar FASI and their correlation with clinical features have not been studied comprehensively. Our aims are to describe the natural history of cerebellar FASI on repeat MRI scans and correlate the findings with the clinical features in children with NF1 and cerebellar FASI. Method: A retrospective review of 226 brain MRI scans and hospital charts was performed in 50 patients with cerebellar FASI, who were diagnosed with NF1 during their childhood between 1999 and 2008. Results: Mean age at the end of the study period was 16.1 years. There were 27 males. Mean duration of clinical follow up was 10.1 years. Mean duration between the first and the last MRI was 6.6 years (n = 36, SD: 2.8 years). FASI were rarely confined to the cerebellum. The number of FASI was highest in early childhood and decreased significantly on subsequent MRI scans in most brain regions with the exception of the cerebrum, where a fewer number of patients with a smaller number of FASI were seen. Four patterns of change in FASI size over time were determined, none correlated with the clinical features. Conclusions: In patients with NF1, the natural history of FASI including their number, age at onset, rate of size changes, and resolution if any, varies by brain region. FASI patterns of change over time showed no clinical correlate. PMID- 30410779 TI - Cerebellar radiological abnormalities in children with neurofibromatosis type 1: part 1 - clinical and neuroimaging findings. AB - Background: Many children with neurofibromatosis type 1 (NF1) have focal abnormal signal intensities (FASI) on brain MRI, whose full clinical impact and natural history have not been studied systematically. Our aims are to describe the clinical and neuroradiological features in children with NF1 and cerebellar FASI, and report on the natural history of FASI that display atypical features such as enhancement and mass effect. Method: A retrospective review of the hospital charts and brain MRIs was performed on children from Manitoba diagnosed between 1999 and 2008 with NF1, who also had cerebellar FASI on MRI. Results: Fifty patients (mean age: 16.1y, minimum-maximum: 6.4 - 30y, 27 M) were identified. Mean duration of follow up was 10.1y. Developmental delay, learning disabilities, tumors, and visual signs occurred commonly. Cerebellar signs were not reported. Mean age of the patients at baseline MRI was 7.8 (SD: 4.5) years. FASI occurred in several brain locations and were rarely confined to the cerebellum. FASI displayed mass effect and enhancement infrequently but were associated with malignancy only once. The number of FASI at baseline MRI was significantly less in patients with attention deficient hyperactivity disorder and more if a first degree relative had NF1 or if they had decreased visual acuity. Discussion: Patients with NF1 and cerebellar FASI do not have motor or consistent non-motor (e.g. developmental delay or learning disabilities) cerebellar features. The number of FASI may correlate with some clinical features. FASI may display enhancement and mass effect but they rarely become malignant. PMID- 30410780 TI - Association between early life antibiotic use and childhood overweight and obesity: a narrative review. AB - Background: Recent research implicates antibiotic use as a potential contributor to child obesity risk. In this narrative review, we examine current observational evidence on the relation between antibiotic use in early childhood and subsequent measures of child body mass. Methods: We searched PubMed, Web of Science and the Cochrane Library to identify studies that assessed antibiotic exposure before 3 years of age and subsequent measures of body mass or risk of overweight or obesity in childhood. Results: We identified 13 studies published before October 2017, based on a total of 6 81 332 individuals, which examined the relation between early life antibiotic exposure and measures of child body mass. Most studies did not appropriately account for confounding by indication for antibiotic use. Overall, we found no consistent and conclusive evidence of associations between early life antibiotic use and later child body mass [minimum overall adjusted odds ratio (aOR) reported: 1.01, 95% confidence interval (95% CI) 0.98-1.04, N = 2 60 556; maximum overall aOR reported: 2.56, 95% CI 1.36 4.79, N = 616], with no clinically meaningful increases in weight reported (maximum increase: 1.50 kg at 15 years of age). Notable methodological differences between studies, including variable measures of association and inclusion of confounders, limited more comprehensive interpretations. Conclusions: Evidence to date is insufficient to indicate that antibiotic use is an important risk factor for child obesity, or leads to clinically important differences in weight. Further comparable studies using routine clinical data may help clarify this association. PMID- 30410781 TI - Pregnancy gestation at delivery and breast milk production: a secondary analysis from the EMPOWER trial. AB - Background: Preterm birth alters the normal sequence of lactogenesis. Lactogenesis I may not yet have started when mothers of very preterm infants (<= 29 weeks gestation) have given birth. Preterm infants are too small or too ill to initiate suckling in the immediate postpartum period thus altering the normal cascade of event for lactogenesis II. With an increasing demand for mother's own milk as a primary source of nutritional support in the care of very small and preterm infants, mothers of these infants are often at risk of expressing inadequate amounts of milk. The use of galactogogues is often considered when mothers of preterm infants are still having challenges in breast milk production. What is not clear in the literature is the role that pregnancy gestation at birth plays in successful response to galactogogues. Our objective for this study was to evaluate the role of pregnancy gestation at birth on a mother's response to the treatment interventions in the EMPOWER trial. Methods: For this analysis, the study participants are the 90 mothers who participated in the EMPOWER trial and were in the stratified in two gestational age groups, 230/7-266/7 weeks and 270/7 296/7 weeks at the time of randomization. The primary outcome measures were the proportion of mothers in each of the gestational age groupings who achieved a 50% increase in breast milk volume on day 14 and day 28 of the study treatment period. Results: On day 14 of the study treatment, there was no significant difference in the proportion of mothers in the 23-26 weeks gestation group (72.9%) compared to those in the 27-29 weeks gestation group (64.2%), OR 1.51 (95% CI 0.60, 3.78; p = 0.38). Similarly, there was no difference in the proportion of mothers between the two gestational age groupings on day 28 of the study treatment, 70.3% compared to 62.3%, OR 1.43 (95% CI 0.58, 3.51; p = 0.43). Conclusion: This secondary analysis was able to demonstrate that mothers of very preterm infants, < 30 weeks gestation at birth, were able to respond to the study treatment in a similar fashion regardless of gestation at birth. If non pharmacologic approaches are unsuccessful, then a 14-day treatment of domperidone may be considered to enhance breast milk production, even in the lowest gestational ages at delivery. Trial registration: EMPOWER has been registered at www.clinicaltrials.gov (identifier NCT 01512225) on January 10, 2012. PMID- 30410782 TI - Effects of feeding naturally contaminated deoxynivalenol diets to sows during late gestation and lactation in a high-yield specific pathogen-free herd. AB - Background: The most prevalent Fusarium mycotoxin in grains is deoxynivalenol (DON). Contamination of swine feed with DON can result in reduced consumption and poor growth performance. Gestating and lactating sows need sufficient feed intake for fetus development during late gestation and milk production and body maintenance during lactation. Therefore, there is considerable concern in modern piglet production about the effects of DON contamination in sow feed. Most previous studies in sows have been done under experimental conditions, with DON levels >=2.8 mg/kg feed. The aim of the current field trial was to investigate the effects of feeding grains that are naturally contaminated with more realistic levels of DON on sows during late gestation and lactation. Methods: In a commercial, high-yield specific pathogen-free piglet production unit, 45 Norwegian Landrace * Yorkshire sows were fed three diets from 93 +/- 1 days of gestation until weaning of the piglets, and average daily feed intake (ADFI), body weight (BW), production and reproduction performance, as well as sow blood parameters were recorded. Diets were made from naturally contaminated oats, with three concentration levels: 1) control (DON < 0.2 mg/kg), 2) DON level 1 (1.4 mg DON/kg), and 3) DON level 2 (1.7 mg DON/kg). Results: Sows that were fed DON level 1 and 2 diets showed a 4-10% reduction in feed consumption during lactation, compared with sows in the control group. However, the DON-contaminated diets did not significantly affect sow BW or backfat thickness. Similarly, there were neither effects on production or reproduction performance, nor on blood parameters in the sows. The effects on skin temperature were variable. Conclusion: Naturally contaminated diets with realistic, moderately increased DON levels, fed during late gestation and lactation in a modern high-yield piglet production farm, had limited effects on sow health and production. PMID- 30410783 TI - Mixed-methods single-arm repeated measures study evaluating the feasibility of a web-based intervention to support family carers of persons with dementia in long term care facilities. AB - Background: Following institutionalization of a relative with Alzheimer disease and related dementias (ADRD), family carers continue to provide care. They must learn to negotiate with staff and navigate the system all of which can affect their mental health. A web-based intervention, My Tools 4 Care-In Care (MT4C-In Care) was developed by the research team to aid carers through the transitions experienced when their relative/friend with ADRD resides in a long-term care (LTC) facility. The purpose of this study was to evaluate MT4C-In Care for feasibility, acceptability, ease of use, and satisfaction, along with its potential to help decrease carer's feelings of grief and improve their hope, general self-efficacy, and health-related quality of life. Methods: The study was a mixed-methods single-arm repeated measures feasibility study. Participants accessed MT4C-In Care over a 2-month period. Data were collected at baseline and 1 and 2 months. Using a checklist, participants evaluated MT4C-In Care for ease of use, feasibility, acceptability, and satisfaction. Measures were also used to assess the effectiveness of the MT4C-In Care in improving hope (Herth Hope Index), general self-efficacy (GSES), loss and grief (NDRGEI), and health-related quality of life (SF12v2) of participants. Qualitative data were collected at 2 months and informed quantitative findings. Results: The majority of the 37 participants were female (65%; 24/37), married (73%; 27/37), and had a mean age of 63.24 years (SD = 11.68). Participants reported that MT4C-In Care was easy to use, feasible, and acceptable. Repeated measures ANOVA identified a statistically significant increase over time in participants hope scores (p = 0.03) and a significant decrease in grief (< 0.001). Although significant differences in mental health were not detected, hope (r = 0.43, p = 0.03) and grief (r = - 0.66, p < 0.001) were significantly related to mental health quality of life. Conclusion: MT4C-In Care is feasible, acceptable, and easy to use and shows promise to help carers of family members with ADRD residing in LTC increase their hope and decrease their grief. This study provides the foundation for a future pragmatic trial to determine the efficacy of MT4C-In Care. Trial registration: ClinicalTrials.gov NCT03571165. June 30, 2018 (retrospectively registered). PMID- 30410784 TI - Blue blocking glasses worn at night in first year higher education students with sleep complaints: a feasibility study. AB - Background: Late adolescence and early adulthood is a period of highest incidence for onset of mental health problems. Transition to college environment has been associated with many risk factors such as the initial disruption-and subsequent irregularity-of the student's sleep and activity schedule. We tested the feasibility of using blue blocking glasses (BBG) at night in first year higher education students with sleep complaints, to obtain preliminary evidence for the impact of BBG on sleep, activity, and mood. Methods: Participants were 13 first year undergraduates (from 10 different academic courses) living on campus for the first time with sleep complaints/disorders confirmed at screening via the Duke Structured Interview Schedule for Sleep Disorders. We used a 2-week, balanced crossover design (BBG vs placebo glasses; participants were unaware which was the active intervention) with computer-generated random allocation. Exploratory analyses provided descriptive and frequency summaries to evaluate feasibility of the intervention. Results: Preliminary evidence supports the feasibility and acceptability of the trial; almost all screened participants consented and completed the protocol with high adherence; missing data were negligible. Additionally, the effectiveness of BBGs to enhance sleep, mood, and activity levels in young adults was supported. Conclusions: The results of this feasibility trial suggest that BBG have potential as an inexpensive and feasible intervention for reducing sleep and circadian dysregulation in young adult students. A larger trial, following this successfully implemented protocol, is necessary to fully test the efficacy of BBG. PMID- 30410785 TI - Acute flares of knee osteoarthritis in primary care: a feasibility and pilot case crossover study. AB - Background: Osteoarthritis (OA) is a leading cause of persistent pain and disability. Traditionally viewed as a slowly progressive disease, the impact of symptom variability on prognosis remains unclear. 'Acute-on-chronic' episodes are a well-recognised feature of many long-term conditions but only recently formally described in OA. This study aimed to develop a web-based data collection platform and establish key methodological design parameters, to develop a larger community based study investigating acute flares of knee OA in England. Methods: The study is a 9-week feasibility and pilot web-based observational case-crossover study. Adults aged >= 40 years registered with two general practices who had consulted their general practitioner for knee pain/OA in the last 2 years were recruited. Participants completed a baseline questionnaire and scheduled (control-period) questionnaires at follow-up weeks 1, 5, and 9. Participants were invited to self declare via the website on any occasion they experienced a knee pain flare-up lasting >= 24 h. Upon notification, an event-driven (case-period) questionnaire comparable to the scheduled questionnaires was completed and daily measurements on the course and consequences were taken until resolution. A sub-study of 10 participants logged daily pain measurements. The analysis estimated key parameters including recruitment (selective non-participation, eligibility, consent), retention, and flare-up capture processes. Questionnaire completeness and website usability were evaluated. Results: Of 442 patients invited, 14 completed baseline questionnaires. Eligibility rate was 26.9% (95% CI 19.3, 36.2), consent rate 53.6% (35.8, 70.5), and overall recruitment rate 3.2% (1.9, 5.2). Compared to those mailed, baseline responders were more likely to be male and >= 65 years, as were those reporting >= 1 flare-up. Eleven scheduled questionnaires were completed (mean response 35%). Although seven participants (50%) self-declared 11 flare-ups, only one event-driven questionnaire was completed and three participants contributed daily flare measurement for four flares. Missing data was <= 3.7% across completed baseline, scheduled, and event driven questionnaires. Aspects of website usability require minor refinement. Conclusions: Recruitment was not feasible with the current strategy. An evaluation of processes has suggested several substantial changes in design that may enhance recruitment, retention, and data quality in a future full-scale study. PMID- 30410786 TI - Women's experiences of medical treatment for endometriosis and its impact on PRE EMPT trial participation: a qualitative study. AB - Background: Endometriosis is a common cause of chronic pelvic pain which can relapse after surgery, yet little research has been conducted on women's experience of medical treatments for prevention of recurrence and the influence of this on participation in clinical trials. Methods: This study explored women's past experiences with medical treatments for endometriosis symptoms and the impact this has on their motivation to enter the pilot phase of a post conservative surgery clinical trial, PRE-EMPT: Preventing Recurrence of Endometriosis by Means of long acting Progestogen Therapy. Qualitative methodology was adopted, involving semi-structured interviews in three UK cities, and one focus group was used to collect data from women with a diagnosis of endometriosis participating in the PRE-EMPT trial. Results: Ten women were interviewed individually and four took part in the focus group discussion. Women's willingness to enter the PRE-EMPT trial was bound up with their previous experiences, present situation and future expectations of medication, as well as the control offered by flexible randomisation which allows the option to reject a particular treatment post-surgery. Conclusion: Women were strongly influenced by previous experience and personal circumstances in their decision to enter the PRE EMPT trial. This decision was facilitated by the ability to 'opt out' of the treatment arm(s) they found unacceptable. This element of choice offered patients a sense of control in the randomisation process and has important implications for clinical trial design and recruitment. Trial registration: ISRCTN97865475. EUDRACT number 2013-001984-21. PMID- 30410787 TI - Acceptability and factors associated with post-partum IUCD use among women who gave birth at bale zone health facilities, Southeast-Ethiopia. AB - Background: The postpartum intrauterine contraceptive devices (PPIUCD) is the only family planning method for couples requesting highly effective, reliable, inexpensive, non-hormonal, immediately reversible, and long-acting contraceptive that can be initiated during the immediate postpartum period and it has no a negative effect on lactation. Despite these benefit, the acceptance and utilization of immediate PPIUCD were very low and the reasons for rejecting immediate PPIUCD usage have not been characterized in Southeast Ethiopia. Therefore, this study determined the level of acceptability and factors associated with immediate PPIUCD use among women who gave birth at Bale zone health facilities, Southeast Ethiopia. Methods: A facility based cross-sectional study was conducted from March to July 2017 in Bale zone health facilities. Four hundred twenty-nine women were successfully interviewed using structured and pre tested questionnaire. Health facilities were selected by lottery method. Study participants were selected systematically. Data were entered into Epi data version 3.1 and exported into SPSS version 21 for analysis. Logistic regression analyses were done. A significant association was declared at a p-value less than 0.05. Results: The acceptance of immediate PPIUCD usage was 12.4%. Non-acceptors reported their reasons for rejecting PPIUCD use; concern and fears of complications (24.8%), religious beliefs (19.8%), and husband refusal (17.7%). Respondents who had completed secondary education were more likely to accept PPIUCD usage than those who had no formal education (AOR = 3, CI = 11.81, 53.91). In addition, the odds of accepting PPIUCD insertion was higher among women who attended 3 antenatal care visits than those who did not attend antenatal care visits for the current birth (AOR = 1.81, CI = 0.34, 0.85). Conclusions: The acceptance of immediate PPIUCD usage was still low. This might be attributed to the low achievement of education, perceived concern and fears of complications towards IUCD insertion. The male partner's refusal and religious beliefs also have a role in the usage of postpartum IUCD. Due attention should be given to enhancing educational level of women and effective IUCDs counseling should be given during antenatal care visits to correct misconceptions and fears of complication about PPIUCD insertion. PMID- 30410788 TI - Task shifting levonorgestrel implant insertion to community midwife assistants in Malawi: results from a non-inferiority evaluation. AB - Background: In 2013, Malawi began task shifting long acting reversible contraception (LARC) insertion from Nurse Midwife Technicians (NMTs), who undergo 3 years of training, to Community Midwife Assistants (CMAs), who undergo 18 months of training. However, there is no evidence on whether CMAs have the same competency as NMTs for LARC insertion. Therefore, we describe a non-inferiority evaluation to determine whether CMAs are non-inferior to NMTs for the insertion of levonorgestrel (LNG) contraceptive implants in Malawi. Methods: One CMA and one matched NMT from 31 health centers across Malawi were selected for training in Malawi's 1-week LARC insertion course in October 2016, and 31 CMAs and 30 NMTs completed the training. After the course, two Family Planning Master Trainers visited the nurses' health centers over a 5-month period and used the Malawi LNG implant insertion checklist to evaluate the first five LNG implant insertions that each nurse performed during the monitoring visit. A non- inferiority margin of 10% was used to compare mean implant scores between CMAs and NMTs. Results: We were able to fully evaluate 29 CMAs and 29 NMTs with the LNG implant insertion checklist. The CMAs and NMTs had mean scores of 90.2% and 89.7%, respectively, which were non-inferior (mean difference - 0.5%; 95% CI -3.4%, 2.4%), even when adjusted for the number of years post-graduation and the number of LNG implants inserted pre-training, during training, and since training (mean difference 1.3%; 95% CI -2.2%, 4.8%). Conclusions: CMAs were non-inferior to NMTs with LNG implant insertion, and both cadres were generally observed to be competent with their insertions after completing their follow-up evaluations. During the evaluations, we generally saw an increase in scores with each insertion. Therefore, for both cadres, it is important to establish continued mentorship and evaluation for LARC insertion after the initial training. PMID- 30410789 TI - Funding approaches for mental health services: Is there still a role for clustering? AB - Funding for mental health services in England faces many challenges including operating under financial constraints where it is not easy to demonstrate the link between activity and funding. Mental health services need to operate alongside and collaborate with acute hospital services where there is a well established system for paying for activity. The funding landscape is shifting at a rapid pace and we outline the distinctions between the three main options - block contracts, episodic payment and capitation. Classification of treatment episodes via clustering presents an opportunity to demonstrate activity and reward it within these payment approaches. We have been engaged in research to assess how well the clustering system is performing against a number of fundamental criteria. Clusters need to be reliably recorded, to correspond to health needs, and to treatments that require roughly similar resources. We find that according to these criteria, clusters are falling short of providing a sound basis for measuring and financing services. Yet, we argue, it is the best available option and is essential for a more transparent funding approach for mental health to demonstrate its claim on resources, and that, as such, clusters should be a starting point for evolving a better funding system. PMID- 30410790 TI - Renin dependent hypertension caused by accessory renal arteries. AB - Background: Hypokalemia in the presence of hypertension is often attributed to primary hyperaldosteronism as a cause of secondary hypertension, however secondary hyperaldosteronism may present similarly. Accessory renal arteries are variants in the vascular anatomy which are often thought to be innocuous but in some circumstances can cause renovascular hypertension leading to secondary hyperaldosteronism. Case presentation: We report 2 cases of hypertension with secondary hyperaldosteronism associated with accessory renal arteries. Both patients presented with hypokalemia and further investigations revealed hyperaldosteronism with unsuppressed renin levels. Imaging studies showed the presence of accessory renal artery. Conclusion: Accessory renal arteries are a potential cause renovascular hypertension which can be detected via CT angiography or magnetic resonance angiography. Hormonal evaluation should be undertaken to determine whether its presence contributes to hypertension in the patient as targeted treatment such as aldosterone antagonist can be initiated. Surgical intervention or renal denervation may be considered in resistant cases. PMID- 30410791 TI - Central subfield thickness and cube average thickness as bioimaging biomarkers for ellipsoid zone disruption in diabetic retinopathy. AB - Background: To evaluate the association of central subfield thickness (CST) and cube average thickness (CAT) with ellipsoid zone (EZ) disruption on spectral domain optical coherence tomography (SD-OCT) in patients of diabetic retinopathy (DR). Methods: Cross sectional study including consecutive patients of type 2 diabetes mellitus [without DR (No DR, n = 97); non-proliferative DR (NPDR, n = 91); proliferative DR (PDR, n = 83)] and healthy controls (n = 82) was undertaken. CST and CAT values were measured using SD-OCT. Data was analyzed using Chi square test, ANOVA and multivariate analysis. Discriminant values of CST and CAT for EZ disruption were evaluated using receiver operator characteristic curve. Area under curve (AUC) was computed. Results: Mean CAT and CST values in the study subjects showed an incremental trend. Multivariate ordinal logistic regression analysis showed increase in CST (OR = 1.022, p < 0.001) and CAT (OR = 1.029, p < 0.001) as significant independent predictors of EZ disruption. Area under curve showed excellent predictive results of CST (AUC = 0. 943 +/- 0.021, 95% CI, 0.902-0.984, p < 0.05) and CAT (AUC = 0.959 +/- 0.012, 95% CI 0.936-0.982, p < 0.05), as bioimaging biomarkers, for EZ disruption. Conclusion: Increase in CST and CAT is associated with increased odds of EZ disruption and these macular parameters serve as bioimaging biomarkers for EZ disruption in DR. PMID- 30410792 TI - In vitro single-unit recordings reveal increased peripheral nerve conduction velocity by focused pulsed ultrasound. AB - Ultrasound that is widely used in medical diagnosis has drawn growing interests as a noninvasive means of neuromodulation. Focused pulsed ultrasound (FPUS) effectively modulates neural encoding and transmission in the peripheral nervous system (PNS) with unclear mechanism of action, which is further confounded by contradictory experimental outcomes from recordings of compound action potentials (CAP). To address that, we developed a novel in vitro set up to achieve simultaneous single-unit recordings from individual mouse sciatic nerve axon and systematically studied the neuromodulation effects of FPUS on individual axon. Unlike previous CAP recordings, our single-unit recordings afford superior spatial and temporal resolution to reveal the subtle but consistent effects of ultrasonic neuromodulation. Our results indicate that, 1) FPUS did not evoke action potentials directly in mouse sciatic nerve at all the tested intensities (spatial peak temporal average intensity, ISPTA of 0.91 to 28.2 W/cm2); 2) FPUS increases the nerve conduction velocity (CV) in both fast-conducting A- and slow conducting C- type axons with effects more pronounced at increased stimulus duration and intensity; and 3) effects of increased CV is reversible and cannot be attributed to the change of local temperature. Our results support existing theories of non-thermal mechanisms underlying ultrasonic neuromodulation with low intensity FPUS, including NICE, flexoelectricity, and solition models. This work also provides a solid experimental basis to further advance our mechanistic understandings of ultrasonic neuromodulation in the PNS. PMID- 30410794 TI - Nail Involvement in Patients with Psoriatic Arthritis in Northern Iran. AB - Background: Psoriatic arthritis (PsA) results in an increased burden of psoriasis and impairs both quality of life and an individual's functional capacity. The relationship between nail involvement and PsA in psoriasis is not fully characterized. Aim: To evaluate the frequency and characteristics of nail involvement in psoriatic patients and to assess the relationship with joint involvement. Methods: A total of 197 patients with moderate-to-severe psoriasis were consecutively invited to participate in this cross-sectional study. The patients are divided into two groups: those with and those without psoriatic arthritis. Results: 69.5% of psoriatic (137 out of 197) patients had nail involvement. The most common nail abnormality was onycholysis, followed by pitting and oil droplet changes. Nail involvement was more common in patients with psoriatic arthritis (82.1% versus 57.8%, p=0.001). Conclusion: Nail involvement is commonly associated with PsA. Onycholysis, splinter hemorrhage, and oil drop were significantly more common in the PsA group as opposed to patients with just skin findings. In general, psoriatic patients with arthritis had more severe disease. PMID- 30410793 TI - Changes and Diurnal Variation of Visual Quality after Orthokeratology in Myopic Children. AB - Purpose: To assess the changes and the diurnal variation of visual quality after orthokeratology in myopic children. Methods: Forty-four eyes of 22 subjects with a mean age of 10.55 +/- 1.53 years (8 to 14 years) were enrolled in this prospective study. Their spherical equivalent ranged from -1.25 to -4.25 diopters (D) and astigmatism was less than 1.00 D. Parameters including corneal curvature, ocular objective scatter index (OSI), the modulation transfer function (MTF), root mean square of ocular and corneal wavefront aberrations, and contrast sensitivity function (CSF) were measured before and at two time points during the same day after 1 month of orthokeratology. Results: After orthokeratology, uncorrected visual acuity (UCVA) and spherical equivalent were significantly improved from baseline (P < 0.001), and their diurnal variation was not significant (P=0.083, 0.568). OSI increased from 0.29 +/- 0.15 to 0.65 +/- 0.31 (P < 0.001). MTF decreased significantly (P < 0.01). Corneal curvature and ocular total aberration decreased (P < 0.001), while the ocular and corneal higher-order aberration increased significantly (P < 0.01). The CSF under photopic condition decreased at 3 cpd (P=0.006) and increased at 18 cpd (P=0.012). The diurnal variation of CSF at 18 cpd under mesopic and high glare conditions and at 12 cpd under photopic condition was significant (P=0.002, 0.01, 0.017). Conclusions: Orthokeratology can effectively improve UCVA and high spatial frequency CSF by decreasing the low-order aberrations. However, MTF and CSF at low spatial frequency decreased because of the increase of intraocular scattering and high order aberrations. Meanwhile, CSF at high spatial frequency fluctuates significantly at two times during the same day after 1 month orthokeratology. PMID- 30410796 TI - Impact of Sleeve Gastrectomy on Psychiatric Medication Use and Symptoms. AB - Background: Sleeve gastrectomy (SG) has become the primary bariatric surgery procedure in the U.S. Over 50% of people presenting for surgery have psychiatric diagnoses. The study purpose was to evaluate change in anxiety and depression symptoms and medication use after SG. Methods: Subjects completing SG with a diagnosis of anxiety and/or depression treated with medication were retrospectively identified from the electronic medical record (EMR) of Synergy Bariatrics, a department of the Erie County Medical Center. Phone outreach was made to complete seven-point global impression of change scale classifying symptom improvement or worsening in the 3- to 6-month postoperative period. Improvement or worsening was defined as either all reported symptoms improving or worsening or >=1 improving or worsening while remaining unchanged. If >=1 symptom improved and worsened, it was classified as mixed. No change required the same profile before and after surgery. Medication, dose, and changes were identified by EMR, verified during interview and classified as no change, discontinued, decreased, or increased. Results: 59 subjects completed the interview. 21 subjects were diagnosed with anxiety. 13 (62%) had no change in therapy and 5 (24%) decreased. Symptoms improved in 12 (57%), worsened in 3 (14%), and mixed in 5 (24%). When symptoms improved, the same dose was present in 7/12 (58%) and dose decreased in 3 (25%). 51 subjects were diagnosed with depression. 32 (63%) had no change in therapy, 11 (21%) discontinued, and 4 (8%) decreased. Symptoms improved in 34 (67%), mixed in 10 (20%), worsened in 4 (8%), and unchanged in 3 (6%). When symptoms improved, the same regimen and dose was present in 21/34 cases (62%) and discontinued in 9 (26%). Conclusion: Anxiety symptoms improved in >50% of subjects at predominantly the same or reduced dosage. Depression symptoms improved in 67% and commonly without therapy change. These data suggest evidence that patients undergoing SG while on medication for anxiety or depression may have early symptom improvement on the same or lessened dosage. PMID- 30410795 TI - Radiation-Induced Coronary Artery Disease and Its Treatment: A Quick Review of Current Evidence. AB - As advances in medical technology arise and the availability of cancer treatment increases, an increased number of patients are receiving cancer treatment. Radiation therapy has evolved to become one of the cornerstones of treatment for various types of cancers. One of the long-term consequences of radiation therapy is radiation-induced coronary artery disease (RICAD). Although the pathophysiology of RICAD may be slightly different and more acute onset than the commonly seen "generic" coronary artery disease, it is common practice to treat RICAD in the same method as nonradiation-induced CAD. This paper summarizes the current research available on the topic and shows there is not enough research to obtain significant data about outcomes and restenosis rates of PCI or outcomes of CABG in RICAD. The aim of this review is to create a concise and easy-to-follow review of the relevant data regarding RICAD and hopefully spark further interest in future studies in this field. PMID- 30410797 TI - Differences between Transdermal Fentanyl and Buprenorphine in the Elderly Hospice Patients. AB - Introduction: Opioids are the most important drugs in treating pain in palliative care patients. Transdermal formulations are especially useful due to their noninvasive nature and minimal interference in daily life. However, studies have shown a controversial relationship of opioids to survival and a rise in deaths associated with the use of transdermal opioids. Although applying precise doses is paramount, we have no clear recommendations for the exact equianalgesic ratio for buprenorphine patch and no recommendation for the type of transdermal opioid to use in hospice. Methods: We analyzed the differences between the transdermal fentanyl and buprenorphine group by analyzing patient characteristics and evaluating the differences in survival in hospice patients over the age of 65, from 2013 to 2017. Results: A total of 292 patients (75.8%) used fentanyl patch and 93 (24.1%) were on buprenorphine patch. Patients had virtually the same characteristics in both groups. However, when using a 1:100 buprenorphine equianalgesic ratio, there were significant differences in initial and final doses, and it seems that a 1:80 conversion rate is more accurate for elderly hospice patients. Finally, there was no difference in survival between the two groups using transdermal opioids, with or without adjuvant analgesics. Discussion: There were no differences in survival between the group using transdermal fentanyl and the group using buprenorphine in the elderly hospice population. Although adjuvant NSAIDs could be useful in the treatment of pain in terminal cancer, they do not affect survival or reduce the opioid doses, while a 1:80 equianalgesic ratio of buprenorphine might be the most appropriate in this population. PMID- 30410798 TI - Synthesis and Evaluation of Baylis-Hillman Reaction Derived Imidazole and Triazole Cinnamates as Antifungal Agents. AB - Allylic acetates derived from Baylis-Hillman reaction undergo efficient nucleophilic isomerization with imidazoles and triazoles to provide imidazolylmethyl and triazolylmethyl cinnamates stereoselectively. Antifungal evaluation of these derivatives against Cryptococcus neoformans exhibits good minimum inhibitory concentration values. These compounds exhibit low toxicity in proliferating MCF-7 breast cancer cell line. Structure activity relationship studies indicate that halogenated aromatic derivatives provide better antifungal activity. PMID- 30410799 TI - Prognostic Factors for Survival and Relapse in ANCA-Associated Vasculitis with Renal Involvement: A Clinical Long-Term Follow-Up Study. AB - Aim: We describe the clinical pattern of ANCA-associated vasculitis (AAV) and assess long-term prognostic factors of patients and renal survival and relapse. Methods: Data from 85 patients with renal biopsy-proven AAV at a single center with up to 20-year [median 16.2 years (95% CI 14.9-17.7)] follow-up were retrospectively collected. Results: Overall, 55% of the patients had microscopic polyangiitis (MPA) and 45% had granulomatosis with polyangiitis (GPA). The histopathological classes were focal in 35%, crescentic in 26%, mixed in 20%, and sclerotic glomerulonephritis in 19% of the patients. As induction treatment, a combination of cyclophosphamide and corticosteroids was given to 82%, while a combination of azathioprine and corticosteroids was maintenance therapy in 79%. The twenty-year patient survival was 45%. In a multivariable analysis, age >=58 years [hazard ratio (HR) 7.64, 95% CI 3.44-16.95] and myeloperoxidase (MPO) ANCA (HR 2.12, 95% CI 1.08-4.17) were associated with shorter patient survival time. Renal survival was 68% overall: 88% in focal, 71% in crescentic, 56% in mixed, and 37% in sclerotic class (p=0.01). Female sex (HR 0.26, 95% CI 0.10-0.73) was a predictor of improved renal survival, whereas GFR <30 ml/min and MPO-ANCA were associated with worse renal survival (HR 4.10, 95% CI 1.35-12.49 and HR 3.10, 95% CI 1.21-7.95, respectively). Relapse-free survival at 20 years was 10%. MPA was associated with a lower risk for relapse (HR 0.48, 95% CI 0.28-0.82). Conclusion: We confirmed the improved patient and renal survival in AAV patients with glomerulonephritis, while relapse remained the primary challenge. Histopathological classification may be relevant for survival. PMID- 30410800 TI - Does Gender Influence Physiological Tolerance in Resuscitators When Using Personal Protection Equipment against Biological Hazards? AB - Introduction: Certain professions, such as those related to emergency services, have usually been performed by men, progressively incorporating women into these professions. The main objective of our study was to determine, according to gender, how the use of level D biohazard personal protection equipment (PPE) affects emergency professionals during the performance of resuscitation. Materials and Methods: An uncontrolled quasi-experimental study was performed on 96 volunteers selected by means of random sampling stratified by gender. Baseline and final vital signs of the assessment activity were analyzed. This activity involves volunteers performing a simulated resuscitation in a controlled environment whilst wearing personal protective suits in a biohazard situation. Results: Analyzing the physiological tolerance pattern parameter by parameter, and according to gender, through a univariate model, we can observe that there is no interaction between tolerance and gender; that is, having good or bad tolerance does not depend on gender. Conclusion. This specialized skilled work can be performed by any properly trained professional. PMID- 30410801 TI - Hyperkalemia Induced by the Sequential Administration of Metoprolol and Carvedilol. AB - This report describes the occurrence of asymptomatic hyperkalemia induced by the sequential administration of metoprolol and carvedilol in an 81-year-old man with type II diabetes and stable stage III renal insufficiency. The potassium level rose to 5.6-5.7 mEq/L with metoprolol and normalized when the agent was discontinued. However, the potassium level rose again to 5.6 mEq/L after the administration of carvedilol but the level normalized by halving the dose. The observations of hyperkalemia induced by two different beta-blocker drugs in the same patient confirm that this side effect is common to all beta-blocker drugs. PMID- 30410802 TI - Epileptic Encephalopathy and Cerebellar Atrophy Resulting from Compound Heterozygous CACNA2D2 Variants. AB - CACNA2D2 encodes an auxiliary subunit of the voltage-dependent calcium channel. To date, there have only been two reports of individuals with early-infantile epileptic encephalopathy due to CACNA2D2 mutations. In both reports, patients were homozygous for the identified variants. Here, we report a patient with epileptic encephalopathy and cerebellar atrophy who was found to have two novel variants in the CACNA2D2 gene: c.782C>T (p.Pro261Leu) and c.3137T>C (p.Leu1046Pro), by whole-exome sequencing. The variants were shown to be inherited in trans and the unaffected parents were confirmed to be heterozygous carriers. This is the third report of recessive CACNA2D2 variants associated with disease and the first report of compound heterozygous variants. The clinical description of this new case highlights the phenotypic similarities amongst individuals with CACNA2D2-related disease and suggests that CACNA2D2 should be considered as a differential diagnosis in individuals with cerebellar dysfunction and multiple seizure types that begin in the first year of life. PMID- 30410803 TI - De Novo Psoriasis Vulgaris Diagnosed after Nivolumab Treatment for Refractory Hodgkin's Lymphoma, Completely Resolved after Autologous Hematopoietic Stem Cell Transplantation. AB - The programmed cell death protein-1 (PD-1) inhibitor nivolumab has been recently approved as an effective and safe treatment for patients with refractory/relapsed Hodgkin's lymphomas. Dermatological adverse events, mainly skin rash, have been reported in 1-5% of patients. We describe a case of de novo psoriasis vulgaris (PsV), diagnosed after nivolumab treatment for refractory Hodgkin's lymphoma. After administration of 6 cycles, skin lesions appeared in the right tibia, forearms, and dorsum of hands, and biopsy confirmed the diagnosis of PsV. The lesions completely resolved after autologous stem cell transplantation (ASCT) which was performed in the context of the treatment for the primary disease. PsV is an inflammatory skin disease, and it is considered to be mediated through cytotoxic T-cells. PD-1 blockage may lead to expansion of such T-cells, resulting thus in PsV appearance. The early published studies showed that nivolumab represents a safe treatment approach. PsV occurrence has not been reported so far in patients treated with nivolumab for hematological diseases, and it seems that long-term follow-up is necessary to fully clarify the entirety of PD-1 inhibitors' skin adverse events. Additionally, this clinical observation provides an evidence for a potential exploitation of ASCT in refractory and severe forms of PsV. PMID- 30410804 TI - Pneumococcal Meningitis Complicated by Cerebral Vasculitis, Abscess, Hydrocephalus, and Hearing Loss. AB - Intracranial abscesses, postinfectious vasculitis, and hydrocephalus are rare complications of Streptococcus pneumoniae (S. pneumoniae) meningitis, and to our knowledge, there have been no case reports where all these 3 complications occurred in a single patient with Streptococcus pneumoniae meningitis. Here, we report a case of a 48-year-old male who developed postinfectious vasculitis, abscess, hydrocephalus, and hearing loss after S. pneumoniae meningitis. Clinicians ought to be aware of the possible adverse outcomes of S. pneumoniae meningitis and the limitations of current treatment options. PMID- 30410805 TI - Renal Tubular Acidosis and Hypokalemic Paralysis as a First Presentation of Primary Sjogren's Syndrome. AB - Sjogren's syndrome is an autoimmune disease with multisystem involvement and varying clinical presentation. We report the clinical course and outcome of a case who presented with repeated episodes of hypokalemia mimicking hypokalemic periodic paralysis and metabolic acidosis, which was later diagnosed as distal renal tubular acidosis secondary to primary Sjogren's syndrome. A 50-year-old lady, who was previously diagnosed as hypokalemic periodic paralysis, presented with generalized weakness and fatigue. She was found to have severe hypokalemia with normal anion-gap metabolic acidosis consistent with distal renal tubular acidosis. Subsequent evaluation revealed Sjogren's syndrome as the cause of her problems. Kidney biopsy done to evaluate significant proteinuria revealed nonproliferative morphology with patchy acute tubular injury and significant chronic interstitial nephritis. The patient responded well to potassium supplementation and oral prednisolone. Presentation of this case highlights the necessity of close vigilance while managing a case of repeated hypokalemia, which could be one of the rare clinical manifestations of Sjogren's syndrome. PMID- 30410806 TI - Interstitial Pregnancy: From Medical to Surgical Approach-Report of Three Cases. AB - Background: Interstitial pregnancy is a rare form of ectopic pregnancy that usually leads to uterine rupture resulting in sudden life-threatening haemorrhage, need for blood transfusion, and admission to intensive care unit. Mortality rate is 6-7 times higher than that in classical ectopic pregnancy. Uterine rupture has been typically reported to occur at more advanced gestational ages compared to tubal pregnancy although several recent reports have shown a high risk of rupture before 12 weeks of gestation. Cases Presentation: We report three cases of women affected by interstitial pregnancy, with different clinical symptoms, and managed to be treated with surgery or medical therapy. An emergency laparotomy was performed in the first case by the general surgeon, while in the second case laparoscopy was made by a gynecologist; last case shows the success of systemic administration of methotrexate. Conclusion: Interstitial pregnancy is still a challenging condition to diagnose and treat; early diagnosis may help to choose the proper management. PMID- 30410807 TI - Spontaneous Ovarian Hyperstimulation Syndrome with FSH Receptor Gene Mutation: Two Rare Case Reports. AB - Development of ovarian hyperstimulation syndrome (OHSS) is very rare in a spontaneous ovulatory cycle and it is usually seen during pregnancy. In the etiology of OHSS, higher hCG (molar pregnancies or multiple pregnancies) and thyroid-stimulating hormone (TSH) levels have been accused. In recent years, some follicle-stimulating hormone (FSH) receptor (FSHR) gene mutations have been described in patients with OHSS in the first trimester with normal hCG levels. Herein, we report two cases of FSHR gene mutation during the investigation of the etiology of spontaneous OHSS. Although OHSS is typically associated with ovulation induction, it should be kept in mind that this condition may also develop in spontaneous pregnancies. PMID- 30410808 TI - Superior and Inferior Ophthalmic Vein Thrombosis in the Setting of Lung Cancer. AB - Superior ophthalmic vein thrombosis is extremely rare and is often associated with orbital inflammation/infection, systemic/local tumors, hypercoagulable states, autoimmune conditions, and rarely carotid cavernous fistula. Clinical features include abrupt onset of painful proptosis, chemosis, ophthalmoplegia, and diminished visual acuity. Prompt diagnosis and treatment are essential to prevent permanent blindness. Management options for this medical emergency include antibiotics, steroids, and/or anticoagulation. We present a case of superior ophthalmic vein thrombosis with left cavernous sinus thrombosis in the setting of newly diagnosed malignancy. PMID- 30410809 TI - TLE1 Positive Clear Cell Sarcoma of the Kidney: A Case Report and Review of the Literature. AB - Clear cell sarcoma of the kidney (CCSK) is an uncommon malignant tumor of uncertain histogenesis that occurs most commonly in childhood. Histologically, CCSK can mimic myxoid variant of synovial sarcoma (SS); however, the double positivity for CD99 and TLE1 in SS helps in excluding CCSK. Herein, we report a rare case of CCSK arising in the left kidney of a 3-year-old girl. The mass grossly measured 9.5 cm in maximum dimension and histologically showed the classic arborizing fibrovascular septae and background myxoid matrix that is usually seen in CCSK. The tumor however was double positive for CD99 and TLE1 which made it difficult to discriminate it from the myxoid variant of SS based on histopathological examination and immunophenotype alone, and genetic analysis for SYT gene rearrangement was required to reach a definitive diagnosis. Although there have been previous case reports of CCSK with positive expression of CD99 and negative TLE1, to our knowledge, this is the first case of CCSK expressing both CD99 and TLE1. PMID- 30410810 TI - Plexiform Schwannoma of the Tongue in a Pediatric Patient with Neurofibromatosis Type 2: A Case Report and Review of Literature. AB - Introduction: Plexiform schwannoma is a rare variant of schwannoma that accounts for only 5% of all schwannomas. Herein, we present a rare case of plexiform schwannoma of the tongue in a pediatric patient with neurofibromatosis type 2 (NF2). Case Presentation: A 13-year-old female presented with a growing left sided tongue mass. The patient has a past medical history of NF2. The tongue mass was excised and histopathological examination revealed a spindle cell tumor with multinodular growth pattern, with Verocay bodies' formation. Tumor cells were strongly positive for S-100 protein and negative for smooth muscle actin (SMA), and EMA highlighted perineural fibroblasts surrounding tumor nodules. These findings were diagnostic of plexiform schwannoma. Conclusion: Plexiform schwannoma of the tongue is an extremely rare tumor seen in patients with NF2. Clinical examination and histopathological evaluation are important for diagnosis of plexiform schwannoma. PMID- 30410811 TI - Massive Spontaneous Hemothorax as a Complication of Apixaban Treatment. AB - Introduction: Hemothorax is usually related to chest or iatrogenic trauma from procedures such as central lines and thoracentesis. Spontaneous hemothorax is defined as pleural fluid hematocrit greater than 50% of serum hematocrit in absence of natural or iatrogenic trauma affecting the lung or pleural space. Coagulopathy secondary to anticoagulant use has been associated with spontaneous hemothorax. We present a case of spontaneous hemothorax in a patient taking apixaban for venous thromboembolism disease. To our knowledge, this is the first case report of apixaban as a cause of spontaneous hemothorax. Case Presentation: A 56-year-old woman with end-stage renal disease (ESRD) was diagnosed with upper extremity deep vein thrombosis (DVT) one month prior to presentation and was started on apixaban presented with dyspnea and left-sided pleuritic chest pain for two weeks. She was found to have left-sided large pleural effusion which was diagnosed as hemothorax. Other etiologies for spontaneous hemothorax were excluded and drainage by 12-French pigtail catheter achieved total resolution of hemothorax in three days. Discussion: Apixaban is a DOAC used to prevent stroke or thromboembolic events in patients with nonvalvular atrial fibrillation and to prevent recurrent venous thromboembolic disease. Events such as gastrointestinal, intracranial, and soft tissue bleeding have been well-documented. However, bleeding manifestation as hemothorax is seldom reported. Our patient presented with isolated left-sided large pleural effusion which was diagnosed as spontaneous hemothorax. 12-Fr pigtail catheter drainage was effective in the management of our patient and provided total resolution in three days. Conclusion: Spontaneous hemothorax is a rare complication of anticoagulant therapy and might not exhibit the usual radiological signs of traumatic hemothorax. Health care providers should have high index of suspicion for spontaneous hemothorax when evaluating new pleural effusion in patients receiving DOACs therapy. Drainage by small bore pigtail catheter might be as effective as larger chest tubes. PMID- 30410812 TI - Laparoscopic Repair of Right Paraduodenal Hernia in Adult Patients: Case Report and Literature Review. AB - A 56-year-old Japanese female presented with vomiting, nausea, and abdominal pain after excessive drinking and eating. Abdominal computed tomography showed an encapsulated circumscribed cluster of jejunal loops in the right upper quadrant. She was diagnosed with a strangulated intestinal obstruction caused by right paraduodenal hernia (PDH) and underwent an emergency laparoscopic repair. A view through the endoscope showed the right PDH, which was encapsulated under the mesocolon. Most of the small bowel was entrapped and adhered inside the sac, requiring careful adhesiolysis. The hernia orifice was expanded to a sufficient degree, and the strangulation was relieved, avoiding the need of resecting the small intestine. Recovery was uneventful, and the patient remains free of symptoms 3 years after surgery. Findings in a total of 29 patients (including this report) who underwent laparoscopic repair of right or left PDHs in Japan are discussed. PMID- 30410813 TI - Expert Opinion on Three Clinical Cases with a Common Urgent Problem: Urge Urinary Incontinence. AB - Urgency is the cornerstone symptom of overactive bladder (OAB) syndrome, which is associated with reduced health-related quality of life (HRQoL) and affects patients with different profiles. We report here three clinical pictures of OAB: a male patient with mixed lower urinary tract symptoms (LUTS), a young woman with comorbidities, and an elderly woman with mixed urinary incontinence. The aim is to analyze the specificities of these real cases, to discuss what would be the most appropriate management, and how treatment with fesoterodine, an antimuscarinic agent with key pharmacological properties, might meet the patients' expectations. Relevant and constructive messages are drawn: urgency, the cornerstone symptom, should be given special attention; fesoterodine is effective and well tolerated in the elderly; before switching to another medication consider increasing the dosage of fesoterodine; the major goal of initial therapy is to meet patient expectations; and involving the patient in the treatment plan increases her/his adherence. PMID- 30410815 TI - Trust in Police Motivations During Involuntary Encounters: An Examination of Young Gang Members of Colour. AB - Problems related to distrust of police, including aggressive and prejudicial police behavior, continue to raise concerns. Using a procedural justice model, the present study examines perceptions of trust or the lack thereof among a subpopulation of young disadvantaged minority youth that routinely come in contact with the police: drug-dealing gang members. In this article, we examine 253 qualitative in-depth interviews comprised primarily of African American and Latino male and female drug-involved gang members, utilizing a comparative analysis, to examine how participants discuss interactions with law enforcement and describe situations where they trust the police or situations where they do not. The findings suggest that the context in which they were stopped operates as a primary differentiating component that shapes their perceptions of trust in the motivations behind police engagement. When stopped by the police for "justifiable" reasons, the participants expressed a trust in the motivations that necessitated the encounter. However, when stopped for reasons, which appeared as unreasonable, our participants voiced a strong sense of distrust in the motivations of the police. These findings suggest that procedural justice scholars should consider the extent to which the type or context of the encounter with the police plays an important role in influencing feelings of trust. PMID- 30410814 TI - Exclusive breastfeeding and rotavirus vaccination are associated with decreased diarrheal morbidity among under-five children in Bahir Dar, northwest Ethiopia. AB - Background: More than one in every ten (14%) of under-five child deaths is associated with diarrheal morbidity in Ethiopia. Although Ethiopia has implemented different health interventions like its immunization program, childhood diarrhea morbidity, on which literature is limited, continues as a public health problem. Hence, the aim of this study was to assess the prevalence of diarrheal morbidity and associated factors among under-five children in Bahir Dar, northwest Ethiopia. Method: A community based cross-sectional study was carried out from March 05 to April 03/2015 in Bahir Dar in which 553 mother-child pairs participated. A structured questionnaire was adapted from the World Health Organization (WHO) and the Ethiopian Demography and Health Survey (EDHS) to collect the data. Bivariate and multivariate logistic regression analyses were carried out to identify the independent predictors of diarrheal morbidity. Result: The overall prevalence of diarrheal morbidity was 9.4% [95% Confidence Interval (CI): 4.8, 14.0%]. No receipt of Rotavirus vaccine dose 2 [AOR = 3.96, 95%CI; 2.13, 7.33], non-exclusive breastfeeding [AOR = 2.69, 95%CI; 1.39, 5.19], unavailability of solid waste disposal system [AOR = 2.62, 95%CI; 1.19, 5.77], employed and private business occupational status of mothers [AOR = 2.10, 95%CI; 1.02, 4.31)], and less than Ethiopia Birr (ETB) 600 household monthly income [AOR = 2.10, 95% CI; 1.2, 7.2] were independently associated with diarrheal morbidity. Conclusion: In Bahir Dar, one in every ten of the under-five children surveyed suffered from diarrheal morbidity. Thus, implementing effective rotavirus vaccination programs, encouraging exclusive breastfeeding and emphasizing appropriate solid waste management would reduce childhood diarrheal morbidity in the region. In addition, the finding suggests that improved child care mechanisms, especially for mothers working outside the home, and efforts to increase household income should be intensified to reduce incidence of diarrhea. PMID- 30410816 TI - Hydrogen-Bonding-Assisted Bronsted Acid and Gold Catalysis: Access to Both (E)- and (Z)-1,2-Haloalkenes via Hydrochlorination of Haloalkynes. AB - We have developed an efficient synthesis of both (Z)- and (E)-chlorohaloalkenes via hydrochlorination of haloalkynes, based on two distinct hydrogen-bond-network assisted catalytic systems: Bronsted acid catalysis and gold catalysis. Both systems offer high stereoselectivity, good chemical yields, and diverse functional group tolerance. PMID- 30410818 TI - Report of an Isolated L5 Radiculopathy Caused by an L2-3 Disc Herniation and Review of the Literature. AB - Intervertebral disc herniation is a common cause of radiculopathy. Disc herniations occurring in the lumbar spine typically affect the nerve root exiting under the pedicle of the vertebral body, one level caudal. However, in rare cases, a disc herniation can cause remote isolated radicular symptoms. The authors present the case of a 70-year-old male who presented with an acute, new onset, left-sided foot drop, low back pain, and a classic L5 monoradiculopathy. Imaging revealed a large, left-sided paracentral extruded L2-3 disc and the absence of any pathology at the L4/5 level. Although the patient's clinical presentation and imaging did not classically correlate, it was felt that the L2 L3 disc was the etiology of the patient's L5 radiculopathy and a left L2-3 microsurgical discectomy was performed. At the six-week follow-up, his foot drop was near normal, sensation was intact with minimal paresthesias, and he remained pain-free. At the one-year follow-up, he experienced full resolution of his foot drop and remained symptom-free. Although rare, disc herniations may cause isolated, remote, painful mononeuropathies not related to the direct level of nerve root compression and should be considered along with other etiologies of peripheral neuropathies. PMID- 30410817 TI - Dentatorubral-pallidoluysian Atrophy: An Update. AB - Background: Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, autosomal dominantly inherited disorder characterized by myoclonus, epilepsy, ataxia, and dementia. Diagnosis is challenging due to the heterogeneous presentation and symptomatic overlap with other spinocerebellar ataxias. Symptoms vary according to age of onset, with a mean age at onset of 31 years. A CAG repeat expansion in the ATN1 gene results in neuronal intranuclear inclusions, variable neuronal loss, and astrocytosis in the globus pallidus, dentate and red nuclei. No disease modifying or curative treatments are currently available. Methods: We performed an online literature search using PubMed for all articles published in an English Language format on the topics of DRPLA or ATN1 over the last 10 years. Where these articles cited other research as support for findings, or statements, these articles were also reviewed. Contemporary articles from related research fields (e.g., Huntington's Disease) were also included to support statements. Results: Forty-seven articles were identified, 10 were unobtainable and 10 provided no relevant information. The remaining 27 articles were then used for the review template: seven case reports, seven case series, six model system articles (one review article), four population clinical and genetic studies (one review article), two general review articles, and one human gene expression study. Other cited articles or research from related fields gave a further 42 articles, producing a total of 69 articles cited: 15 case series (including eight family studies), 14 model systems (one review article), 14 population clinical and genetic studies (two review articles), 10 case reports, eight clinical trials/guidelines, four genetic methodology articles, three general review articles, and one human gene expression study. Discussion: DRPLA remains an intractable, progressive, neurodegenerative disorder without effective treatment. Early recognition of the disorder may improve patient understanding, and access to services and treatments. Large-scale studies are lacking, but are required to characterize the full allelic architecture of the disorder in all populations and the heterogeneous phenotypic spectrum, including neuroimaging findings, possible biomarkers, and responses to treatment. PMID- 30410819 TI - Changes in Transcranial Sonographic Measurement of the Optic Nerve Sheath Diameter in Non-concussed Collegiate Soccer Players Across a Single Season. AB - Introduction Bedside ultrasound measurement of the optic nerve sheath diameter (ONSD) is emerging as a non-invasive technique to evaluate and predict raised intracranial pressure (ICP) in both children and adults. The prognostic value of increased ONSD on brain computed tomography (CT) scan has previously been correlated with increased intensive care unit (ICU) mortality in patients with severe traumatic brain injury (TBI). Previous studies have also evaluated the association between high-contact sports, such as soccer, and TBI; however, the related changes in ONSD are still unknown. The aim of this study was to evaluate for the natural evolution of changes in ONSD in athletes who participate in high contact sports. Methods In this prospective observational study, volunteers from a collegiate women's soccer team underwent the measurement of ONSD with transcranial Doppler (TCD). ONSDs were measured during the initial visit during the pre-season period and again at the three-month follow-up. A single experienced neuro-sonographer performed all measurements to eliminate any operator bias. Results Twenty-four female college soccer players between the ages of 18 and 23 were included in this analysis. Mean ONSD during the initial pre season clinic visit and the three-month follow-up were 4.14+/-0.6 mm and 5.02+/ 0.72 mm, respectively (P < 0.0001). A two-tailed t-test analysis was performed, which resulted in a t-value of 4.76 and P < 0.00001. The average ONSD measured during the post-season follow-up showed a 21.3% increase compared to the baseline. Conclusion The evaluation of high-contact sports athletes is limited due to the lack of objective radiologic and diagnostic tools. Moreover, in an athlete suffering a concussion, return-to-play decisions are heavily dependent on the symptoms reported by the athletes. In our analysis of collegiate women's soccer players, active participation in soccer competitions and practice may be associated with an increase in ONSD, independent of concussions. Further studies are underway to evaluate the clinical significance of these findings as well as possible correlations between concussions and changes in ONSD. PMID- 30410820 TI - Lennox-Gastaut Syndrome: In a Nutshell. AB - Lennox-Gastaut syndrome is one of the rare childhood-onset epileptic encephalopathies, characterized by multiple type seizure disorder, the typical pattern on electroencephalogram and intellectual disability. Tonic-type seizures are most commonly seen in these patients. Behavioral disturbances and cognitive decline are gradual-onset and last long after the first episode of epileptiform activity. In most cases, there is some identifiable cause that has led to the clinical presentation of the patient. Various pharmacological and surgical procedures have been proposed for the treatment of Lennox-Gastaut syndrome and many more to come in the very near future to overcome the drug resistance and to avoid the patient forming a life-long dependency. PMID- 30410822 TI - Using Temporary Prostatic Stents to Eliminate Bacterial Colonization in Men with Chronic Indwelling Catheters: A Pilot Study. AB - Background Chronic urinary catheterization is commonly associated with chronic bacterial colonization and high rates of symptomatic infection that increase morbidity and mortality. This study describes the results of replacing chronic catheters with temporary prostatic stents (TPS) to reduce bacterial colonization rates. Methods Twenty-two chronically catheterized adult male patients were enrolled. Upon removal, the indwelling urinary catheter (IUC) was cultured to identify the presence and type of bacterial flora. The IUC was replaced with a TPS. All patients had five consecutive TPS placed on a 30-day cycle. TPS cultures were obtained at removal of each TPS. Results All patients (100%) demonstrated bacterial colonization at baseline (removal of the IUC). After the third month with TPS, the colonization had fallen to 5% and remained at 5% for the final two months of TPS placement. Conclusions This pilot study suggests that replacing an IUC with a TPS interrupts the cycle of bacterial colonization in the urinary tract. This approach could be a strategy for eliminating multi-drug resistant organisms from the urinary tract of men with urinary retention. PMID- 30410823 TI - Chronic Rhinotillexomania Leading to Unilateral External Nare Stenosis. AB - Compulsive nose picking (rhinotillexomania) is a commonly known condition to general practitioners and pediatricians and is often advised against. This case highlights a 29-year-old individual with a prolonged history of intermittent rhinotillexomania who presented with repetitive viral upper respiratory infections. Physical examinations showed an enlarged nasal turbinate unilaterally with an otherwise normal nasal architecture. Further imaging and investigations showed no abnormalities or evidence of greater pathology. It was hypothesized that the patient's rhinotillexomania induced repetitive inflammation and subsequent hyperplasia of the nasal tissue, narrowing the circumference of an external nare. This case highlights the risks of a common but potentially dangerous habit along with its management. PMID- 30410821 TI - Anterior Techniques in Managing Cervical Disc Disease. AB - Surgical treatment may be indicated for select patients with cervical disc disease, whether it is cervical disc herniation or spondylosis due to degenerative changes, acute cervical injury due to trauma, or other underlying cervical pathology. Currently, there are various surgical techniques, including anterior, posterior, or combined approaches, in addition to new interventions being utilized in practice. Ideally, the surgical approach should be selected in consideration of each patient's clinical presentation, imaging findings, and overall medical comorbidities on an individual basis. But the unique advantages and disadvantages of each surgical technique often complicate the therapy choice in managing cervical disc diseases. Although anterior cervical discectomy and fusion (ACDF) is the most widely accepted procedure performed for both single and multi-level cervical disc diseases, there are multiple modifications to this technique. Surgeons have access to different types of plates, screws, and cages and can adopt newer advances in the field such as stand-alone and minimally invasive techniques when indicated. In short, no consensus exists in terms of a single approach that is preferred for all patients. This article aims to review the standard of care for management of cervical disc disease with a focus on the surgical techniques and, in particular, the anterior approach, exploring the various surgical options within this technique. PMID- 30410824 TI - Acute Myeloid Leukemia: Is That All There Is? AB - Acute myeloid leukemia (AML) is characterized by the clonal proliferation of malignant myeloid blast cells in the marrow along with impaired normal hematopoiesis. With an almost stagnant approach for the management of patients with AML in the last three decades, the main purpose of this paper is to increase our understanding of recent scientific advancements for the enhanced diagnosis and treatment of AML. Existing research data related to different approaches for a possible improvement in AML management has been collected and discussed. The identification of recurrently mutated genes, such as CCAAT-enhancer-binding proteins alpha (CEBPalpha), Fms-related tyrosine kinase 3 (FLT3), and nucleophosmin 1 (NPM1) along with the classic diagnostic karyotype has improved prognostic-risk stratification. Moreover, mutations affecting cellular metabolism like isocitrate dehydrogenase (IDH1), lysine-specific demethylase 1 (LSD 1), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) have become a huge success by providing targets for novel therapeutic drugs. Checkpoint inhibitors (CPI) and vaccination against tumor-associated antigen are added options considered, which require further trials before their efficacy can be determined. An important tool in monitoring early response to therapy, minimal residual disease (MRD) assays can be further refined by including pretreatment parameters such as cytogenetic and molecular markers. Potential side effects and resistance to treatment remains a huge barrier in completely finding success against AML and work needs to be done to find combinations of immunotherapies to possibly reduce adaptive resistance by AML. PMID- 30410825 TI - Pattern of Depression Among Patients of Myocardial Infarction in Karachi, Pakistan: A Cross-sectional Study. AB - Background Depression is a well-known risk factor that aggravates the chances of having various complications of acute coronary syndrome (ACS) such as cardiovascular collapse, heart failure, arrhythmia, recurrent myocardial infarction, and stroke among patients of ACS. ACS is a broad term which includes unstable angina as well as myocardial infarction (MI). The purpose of this study is to analyze the prevalence of depression among the patients of MI admitted to the tertiary care hospitals of Karachi, Pakistan. Methods and materials A hospital-based, cross-sectional study was conducted in which 375 admitted and diagnosed patients of MI with a mean age of 58 years were interviewed at the cardiology department of the Civil Hospital and National Institute of Cardio Vascular Diseases (NICVD) Hospital, Karachi, from June to November 2017 using a self-made validated questionnaire, including patient health questionnaire-9 (PHQ 9). Results Overall, about 12.8% of the cases were screened positive for severe depression, 17.1% for moderately severe depression, 17.6% for moderate depression, and 32% for mild depression (total of 79.5%). Of 146 female subjects, 119 (81.5%) were found to be suffering from some degree of depression while 179 (78.2%) of the 229 males screened positive for some degree of depression. Furthermore, 79 (82.3%) of the 96 smokers were suffering from a range of depression while 219 (78.5%) of the 279 non-smokers suffered the same. In addition, the results of the PHQ-9 were cross-tabbed with age (p=0.34), gender (p=0.66), marital status (p=0.07), living status, smoking (p= 0.72), hypertension (p=0.55), and diabetes (p=0.19). Conclusion This study concludes that many of the patients of MI who were admitted to the tertiary care hospitals in Karachi, Pakistan, are suffering from major depressive behavioral changes following the cardiovascular event, which is known to aggravate the chances of having complications associated with it. PMID- 30410826 TI - Analysis of Milestone-based End-of-rotation Evaluations for Ten Residents Completing a Three-year Anesthesiology Residency. AB - Introduction Faculty are required to assess the development of residents using educational milestones. This descriptive study examined the end-of-rotation milestone-based evaluations of anesthesiology residents by rotation faculty directors. The goals were to measure: (1) how many of the 25 Accreditation Council for Graduate Medical Education (ACGME) anesthesiology subcompetency milestones were included in each of the residency's rotations evaluations, (2) the percentage of evaluations sent to the rotation director that were actually completed by the director, (3) the length of time between the end of the residents' rotations and completion of the evaluations, (4) the frequency of straight line scoring, defined as the resident receiving the same milestone level score for all subcompetencies on the evaluation, and (5) how often a resident received a score below a Level 4 in at least one subcompetency in the three months prior to graduating. Methods In 2013, the directors for each the 24 anesthesia rotations in the Stanford University School of Medicine Anesthesiology Residency Program created new milestone-based evaluations to be used at the end of rotations to evaluate residents. The directors selected the subcompetencies from the list released by the ACGME that were most appropriate for their rotation. End-of-rotation evaluations for the post-graduate year (PGY)-2 to PGY-4 from July 1, 2014 to June 30, 2017 were retrospectively analyzed for a sample of 10 residents randomly selected from 22 residents in the graduating class. Results The mean number of subcompetencies evaluated by each of the 24 rotations in the residency equaled 17.88 (standard deviation (SD): 3.39, range 10-24, median 18.5) from the available possible total of 25 subcompetencies. Three subcompetencies (medical knowledge, communication with patients and families, and coordination of patient care within the healthcare system) were included in the evaluation instruments of all 24 rotations. The three least frequently listed subcompetencies were: "acute, chronic, and cancer-related pain consultation/management" (25% of rotations had this on the end-of-rotation evaluation), "triage and management of critically ill patient in non-operative setting" (33%), and "education of patient, families, students, residents, and others" (38%). Overall, 418 end-of-rotation evaluations were issued and 341 (82%) completed, with 63% completed within one month, 22% between month one and two, and 15% after two months. The frequency of straight line scoring varied, from never occurring (0%) in three rotations to always occurring (100%) in two rotations, with an overall average of 51% (SD: 33%). Sixty-one percent of straight line scoring corresponded to the residents' postgraduate year whereby, for example, a post-graduate year two resident received an ACGME Level 2 proficiency for all subcompetencies. Thirty-one percent of the straight line scoring was higher than the resident's year of training (e.g., a PGY-2 received Level 3 or higher for all the subcompetencies). The remaining 7% of straight line scoring was below the expected level for the year of training. Three of seven residents had at least one subcompetency rated as below a Level 4 on one of the evaluations during the three months prior to finishing residency. Conclusion Formal analysis of a residency program's end-of-rotation milestone evaluations may uncover opportunities to improve competency-based evaluations. PMID- 30410827 TI - Variant of the Anconeus Epitrochlearis Muscle: A Case Report. AB - The anconeus epitrochlearis is a muscle variant sometimes present at the elbow. It is present in up to 34% of individuals and has been implicated in some cases of cubital tunnel syndrome. We report an unusual variant of this muscle with additional proximal attachments in the arm. We will review and discuss the background and the clinical relevance of such a muscle. PMID- 30410828 TI - Effects of Metformin on Symptoms of Polycystic Ovarian Syndrome Among Women of Reproductive Age. AB - Background Metformin is a highly preferred drug that is used to treat the symptoms of polycystic ovarian syndrome among women. Pakistan is facing a continuous rise in the prevalence of polycystic ovarian syndrome. Therefore, the determination of the effectiveness of the drug in this condition is considered ideal as per the presenting situation. Objective The aim of the study was to determine the effects of metformin in patients with polycystic ovarian syndrome. Methods This cross-sectional study has investigated the influence of metformin on the ability to conceive, body weight, mood swings, energy levels, menstrual irregularities, and acne and hirsutism. As per the inclusion criteria, 100 women were evaluated from the outpatient clinics of Jinnah Postgraduate Medical Centre and Civil Centre, Karachi, from November 2016 to January 2017. A structured, pre tested questionnaire was used for data collection. Results The study group had a mean age of 27.2 +/- 4.75 years. Outcomes reported by study participants suggested a significant influence of metformin on menstrual irregularities (p 0.046), acne and hirsutism (p<0.001), mood swings (p<0.001), and daily energy levels (p<0.001). Findings further proposed that metformin does not produce a significant impact on the ability to conceive (p 0.096) and in the change in body weight (p 0.073) of the patients. Conclusion Metformin has been realized to have a significant role in dealing with the symptoms of polycystic ovarian syndrome. It is recommended to conduct more in-depth and longitudinal research on the long term effects of the drug and compliance among these women. PMID- 30410829 TI - Exercise During Pregnancy: Obstetricians' Beliefs and Recommendations Compared to American Congress of Obstetricians and Gynecologists' 2015 Guidelines. AB - Purpose Obesity and excessive weight gain during pregnancy is a growing problem, conferring severe health risks for both mother and fetus. Exercise can help combat this epidemic. However, many pregnant women are not meeting the American Congress of Obstetricians and Gynecologists' (ACOG's) 2015 guidelines for exercise during pregnancy. The objective of this study was to evaluate obstetricians' beliefs and recommendations regarding exercise during pregnancy compared to ACOG's 2015 recommendations. Method Obstetricians were recruited via three different forums to complete a twenty-question survey: at a regional conference for Alabama and Mississippi ACOG members, at the University of Alabama at Birmingham's Obstetrics and Gynecology Department's Grand Rounds, and via telephone. Univariate statistical analysis was conducted with RedCap. Results Seventy-one surveys were completed: 33 from the ACOG conference, 27 from Grand Rounds, and 11 from those recruited by telephone. Eighty-eight percent (n=60) of respondents correctly identified ACOG's recommendation of unrestricted exercise for women with uncomplicated pregnancies. One-fourth (24%; n=16) regularly discuss exercise with most (76%-100%) pregnant patients. Most (57%; n=59) do not consistently ("never," "rarely," or "sometimes") recommend sedentary patients begin exercising during pregnancy. Nearly all (97%; n=66) advise first-trimester patients to perform aerobic exercise two to five days per week, but the recommended duration varies. One-fourth (24%; n=16) do not recommend strength training exercise during the first trimester. Twenty-five percent (n=17) and 32% (n=22) recommend decreased aerobic or strength-training exercise, respectively, in the third trimester. More than half (54%; n=37) recommend pregnant patients limit exercise by heart rate, most commonly 121-140 bpm (25%; n=17) or 141-160 bpm (24%; n=16). Sixty-eight percent (n=46) feel "comfortable" or "very comfortable" providing advice on exercise during pregnancy. Conclusion Despite believing exercise benefits pregnant women, knowing ACOG's 2015 guidelines endorse unrestricted exercise for women with uncomplicated pregnancies, and feeling comfortable discussing this topic with patients, obstetricians are not consistently counseling their pregnant patients on exercise. Notably, physicians are not instructing their sedentary pregnant patients to exercise. While most physicians provide appropriate advice on aerobic exercise, their advice on resistance training, maximum heart rate during exercise and third-trimester exercise are often discordant with ACOG's guidelines. PMID- 30410830 TI - MedsOnCall Pager App: A Pilot Project for Practicing Safe Clinical Decision making. AB - Errors in clinical decision-making contribute to approximately half of in hospital adverse events. The steep learning curve when students transition to residents is particularly susceptible to increased errors. Decision-making skills are a major contributor to preparedness for residency and educators agree that decision-making should be purposefully taught and tested. Despite this, little structured assessment of decision-making currently exists. This innovation report describes the development and piloting of the MedsOnCall (MOC) Pager App, a simulated pager program designed as a learning and assessment tool for senior medical students and junior residents to practice safe clinical decision-making as they transition between these two roles. Learners are randomly "paged" by the app about a list of virtual patients. To answer, they must integrate pertinent patient information efficiently. Learners then receive a page-management question that further probes their decision-making skills by asking them to consider the urgency and their level of confidence when determining the virtual patient's needs. The pilot version of the app was successfully alpha-tested in 2016 and 2017 with twenty fourth year medical students at our institution. Subjectively, students greatly enjoyed using the MOC Pager app to practice answering pages in a safe environment. The app was then adapted for the National Cardiac Surgery Bootcamp in 2017 for use by first-year residents. With demonstrated success as a pilot project, our group aims to rebuild the app for customizable use by multidisciplinary learners anywhere in the world simultaneously. We also plan to collect validity evidence, integrate in-app feedback capability, and disseminate the app on multiple platforms. PMID- 30410831 TI - Gustatory Rhinorrhea: A Rare Presentation of Parkinson's Disease. AB - Non-motor symptoms appear earlier than the motor symptoms of Parkinson's disease. Gustatory rhinorrhea is a rare presentation of Parkinson's disease. We report a case of 70-year-old male who presented to the outpatient department (OPD) with watery secretions on thought or site of food. Symptomatic treatment was advised along with many investigations for the cause. Twenty-two months later the patient developed fine tremors of hands which were evident of Parkinson's disease. PMID- 30410832 TI - A Rare Case of Ibuprofen-induced Acute Liver Injury. AB - Idiosyncratic drug-induced liver injury (iDILI) is the second-most-common cause of acute liver injury. When it is caused by ibuprofen, it is quite rare, especially when not accompanied by systemic signs or symptoms. A young female patient presented with an ibuprofen overdose suicide attempt and then developed an acute liver injury within a few days. Given its rarity, ibuprofen-induced iDILI was initially a secondary differential, but when her course did not improve as expected, she was quickly evaluated for liver transplant. She fully recovered without needing the transplant, but this case highlights the importance of not only early suspicion/detection but also early referral to a transplant hepatology service. PMID- 30410833 TI - Vancomycin-resistant Enterococcus faecium Empyema in an Asplenic Patient. AB - Enterococcal empyema is a rare complication of pneumonia. We report the case of a 67-year-old asplenic man with pneumonia complicated by respiratory failure and empyema requiring decortication and prolonged chest tube drainage. Cultures of the empyema were initially negative, but later grew vancomycin-resistant Enterococcus faecium (VRE), which was successfully treated with linezolid. To our knowledge, this is only the second reported case of an empyema caused by VRE that was not associated with an intra-abdominal infection. We suspect superinfection due to airway or chest tube contamination as the most likely mechanism of infection. Physicians should consider multi-drug resistant organisms such as VRE in patients with empyema that fail to resolve with chest tube drainage and broad spectrum antibiotics. PMID- 30410834 TI - Fok-I, Bsm-I, and Taq-I Variants of Vitamin D Receptor Polymorphism in the Development of Autism Spectrum Disorder: A Literature Review. AB - The role of vitamin D in the development of autism spectrum disorder (ASD) is of intensified interest in medical science in recent years. Vitamin D has a significant role in neurogenesis, neuroprotection, and neurodevelopment. Due to the close association of vitamin D with the brain, it has been found that in the pathophysiology of several neuropsychiatric disorders vitamin D receptor (VDR) polymorphism plays a significant role. In this review article, we looked for a relation between VDR polymorphism and ASD. We systemically reviewed all the potential articles on the relation between VDR polymorphism and ASD. We found that several VDR variants FokI, BsmI, and TaqI polymorphisms are related to ASD. Even paternal VDR polymorphism can be a causative factor for ASD in the offspring. The relation between FokI (ff) genotype polymorphism and increased level of serum 1,25(OH)D3 in ASD patients is a very significant finding. Variation of ASD-related genotypes in different ethnic population raises a big question on whether the environmental factors also can do changes in human genotypes leading to ASD. PMID- 30410835 TI - Rare Fungal Infection Linked to a Case of Juvenile Arthritis. AB - Juvenile arthritis with unknown disease etiology is also known as juvenile idiopathic arthritis. Symptoms include joint pain, swelling, and stiffness, and standard treatment involves immunosuppressant medication. Here we present a case of juvenile idiopathic arthritis with severe malnutrition and worsening of symptoms, which restrained a nine-year-old girl to a wheelchair with minimal movement capacity and low energy during standard immunosuppressant therapies over the course of three years. Our innovative Pathogen Blood Test combining cytology based microscopy and genetic analysis using a pan-fungal primer assay and sequencing identified a systemic fungal infection with Sagenomella species, closely related to Aspergillus, and a soil-dwelling highly pathogenic fungus, which had previously been linked to a fatal veterinary case of arthritis and malnutrition. Our test results encouraged a radical change of the patient's treatment plan, including cessation of the regular immunosuppressants, including steroids, over six months. The patient made a progressive recovery, including complete reversion of the previously swollen and painful joints, development of a good appetite, and return to liveliness. Within the year of change from immunosuppressants to immune-supportive integrative nutritional therapies, including regular intravenous vitamin C, and oral vitamin D, as well as gentle aqua- and physiotherapy, the patient started to gain weight including muscle mass and regained strength and movement in the hands, arms, and legs. She was able to walk again within 18 months. Her mood and energy levels continued to improve and she was able to return to school full-time. PMID- 30410837 TI - Inflammatory Pseudotumor of the Liver Presented in a Patient with Cholelithiasis. AB - An inflammatory pseudotumor of the liver is a rare tumor-like lesion consisting of an inflammatory infiltrate that often can mimic a malignant liver neoplasm. The cause of an inflammatory pseudotumor of the liver is unknown, but it has been reported to be associated with different comorbid conditions most likely inflammatory or infectious in origin. We present an 83-year-old female who presented with a symptomatic gallstones disease and an incidental finding of inflammatory pseudotumor mimicking intrahepatic cholangiocarcinoma in preoperative liver imaging. Differentiating a pseudotumor from hepatic space occupying neoplasms is crucial since it is one of the most important tumor mimicking lesions. The imaging findings of this rare tumor can pose diagnostic difficulties because of the amount of fibrosis and cellular infiltration. If malignancy has been excluded, patients can be treated conservatively with steroids and non-steroidal anti-inflammatory drugs. However, complete surgical resection has been the modality of treatment for most of the cases with an indeterminate diagnosis. PMID- 30410836 TI - American Heart Association High Blood Pressure Protocol 2017: A Literature Review. AB - Hypertension is the most prevalent clinical symptom arising from various cardiovascular disorders. Likewise, it is considered a precursor or sequelae to the development of acute coronary artery disease and congestive heath failure (CHF). Hypertension has been considered a cardinal criterion to determine cardiovascular function. According to the World Health Organization (WHO) global observatory data, hypertension causes more than 7.5 million deaths a year, about 12.8% of the total human mortality. Similarly, the Center for Disease Control (CDC) states that 35% of the American adults have been estimated to have a persistently high blood pressure, which makes it about one in every three adults. Hypertension is a modifiable symptom that can be managed through pharmacological and non-pharmacological methods and standard protocols set forth by the American Heart Association (AHA). With new findings from various clinical trials related to the management of hypertension, new developments and recommendations have been made to update the previously established protocols for hypertension. This article aims to discuss and dissect the modern updates of hypertension management as comprehensively elaborated in the 2017 Hypertension Clinical Practice Guidelines. PMID- 30410838 TI - Resistant Thyrotoxicosis due to Graves' Disease in Pregnancy: Case Report and Review of the Literature. AB - The effective management of Graves' disease (GD) during pregnancy is crucial for maternal and neonatal well-being. Conventional treatment of GD during pregnancy includes antithyroid drugs (ATDs) and surgery, ideally during the second trimester. We report a 27-year-old woman with GD and we present the course of GD during her three consecutive pregnancies. During the first pregnancy, thyrotoxicosis was successfully treated with low doses of antithyroid drugs; in the second pregnancy, thyrotoxicosis was only controlled at the third trimester; while in the third pregnancy, our patient presented with treatment-resistant thyrotoxicosis, which was finally managed with corticosteroids in adjunction with ATDs. Although hyperthyroid, the patient maintained her fertility. Resistance to ATD is a rare condition and in our case was adequately controlled with corticosteroids. PMID- 30410839 TI - Gender Disparities in Out-of-hospital Cardiac Arrests. AB - Background Despite advances in resuscitation science and public health, out-of hospital cardiac arrest (OOHCA) has an average survival rate of only 12% nationwide, compared to 24.8% of patients who suffer from cardiac arrest while in hospital. Additionally, gender is an important element of human health, and there is a clear pattern for gender-specific survivability in cardiac arrest. This study examined differences in presentations, treatment, management, and outcomes. Aim The primary focus of this study was to shed light on differences in presentations, treatments, and outcomes between men and women suffering from an out-of-hospital cardiac arrest and the accompanying contributing factors. Methods All emergency medical services-related data, including age, date, initial rhythm, chemical interventions (i.e., epinephrine, dextrose), blood glucose levels, defibrillations, endotracheal tube (ETT) attempts, final airway management, achievement of return of spontaneous circulation (ROSC), and the conclusion of the case up to the emergency department, were recorded using a standardized emergency medical services (EMS) charting record by the highest-ranking EMS provider on the ambulance. The reports were retrospectively collected and analyzed. Conclusion The study examined demographics, treatments rendered, and outcomes in OOHCA cases that occurred in a major United States (US) city in 2016. Several significant differences in care were noted between men and women. In general, women received less respiratory, chemical, and electrical interventions than men; however, statistically significant differences were only observed in the number of attempts of endotracheal intubations, number of doses of epinephrine per encounter, and number of defibrillations per encounter. In spite of generally receiving less care, women appeared to respond more favorably to cardiac arrest interventions, as demonstrated by higher rates of ROSC. Despite this, women were also found to be eight years older at the time of arrest. Future studies are needed to determine causality in discrepancies between the genders in addition to investigating differences in treatment in other areas of the United States. PMID- 30410840 TI - A Rare Case of Metastases from a High-grade Astrocytoma to the Pleura, Bones, and Liver within Six Months of Diagnosis. AB - High grade astrocytomas such as anaplastic astrocytoma and glioblastoma multiforme are aggressive central nervous system malignancies with a poor prognosis. Due to shortened survival times, their devastating effects are usually localized intracranially and rarely metastasize outside of the central nervous system. When metastases occur, they usually present in patients with longer survival times and they typically coincide with a primary site recurrence. We present a rare case of metastases from a high-grade astrocytoma/glioblastoma to the pleura, bones and liver within six months of diagnosis, without primary site recurrence. PMID- 30410841 TI - A Case of Recurrent Thrombotic Microangiopathy Caused by Hypertensive Urgency. AB - A 26-year-old man presented to the emergency room with abdominal pain, nausea, and vomiting for four days. His medical history was significant for hypertension and end-stage renal disease managed with hemodialysis. He had been noncompliant with the antihypertensive regimen which included nifedipine, hydralazine, and spironolactone. At presentation, his blood pressure was 231/123 mmHg. Laboratory workup showed white blood count 17.3 * 109/L (normal range: 4.5 to 11.0 * 109/L), hemoglobin 7.8 gm/dL (normal range: 13.5 to 17.5 g/dL), platelet count 46 * 109/L (normal range: 150 to 400 * 109/L), reticulocyte count 7.8%, total bilirubin 1 mg/dL (normal range: 0.1 to 1.2 mg/dL), lactate dehydrogenase 1,235 U/L (normal range: 140 to 280 U/L), haptoglobin < 10 mg/dL, and a direct Coomb's test was negative. Numerous schistocytes were identified on the peripheral blood smear. The patient was diagnosed with thrombotic microangiopathy secondary to severe hypertension and was started on intravenous nicardipine. With appropriate blood pressure control, hematological parameters improved with normalization of the platelet count within 10 days. Notably, the patient had one similar episode of hypertension-induced thrombotic microangiopathy within a period of the last three months and ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type 1 motif 13) activity was normal on his previous admission. PMID- 30410842 TI - A Six-month Retrospective Study of Resources Burden by Trauma Victims in the Surgical Intensive Care Unit of a University Hospital in Pakistan. AB - Introduction Trauma is the fourth leading cause of death globally and constitutes a huge burden on limited critical care resources. Aim This study aimed to identify the trauma patient burden in terms of resources used in the surgical intensive care unit (SICU) of Aga Khan University Hospital in Pakistan which also included characteristics and outcomes of trauma and non-trauma patients. Methods We retrospectively reviewed all patient data for adult patients (>16 years old) admitted to the SICU from July through December 2014. Results Of 141 SICU cases included in our study period, 32 (22.7%) trauma patients were identified. On further stratification of trauma patients, road traffic injuries (43.8%), gunshot injuries (43.8%), and blast injuries (6.3%) were the most common, and about 73% of all trauma patients underwent emergency surgical interventions, comprising a huge burden on all resources. The average age of the trauma patients was significantly lower than non-trauma patients (36 years +/- 13 vs. 49 years +/- 19; p < 0.01). The male-to-female ratio was 7:1 in trauma cases and 2:1 in non trauma cases (p = 0.019). There was no statistically significant difference in mortality (31.3% vs. 42.2% p > 0.05) and median length of stay [Median (interquartile range), 5(8) vs. 4(7); p > 0.05] between trauma and non-trauma patients. Conclusions Trauma constitutes a significant burden in terms of resources used for the SICU of the Aga Khan University, Pakistan. Trauma victims are predominantly young men in whom gunshot injuries are as common as road traffic injuries. Emergency surgical interventions comprise the largest draw on resources, followed by use of blood products, radiological, and laboratory investigations. PMID- 30410843 TI - Salvage Stereotactic Body Radiation Therapy for Locally Recurrent Previously Irradiated Head and Neck Squamous Cell Carcinoma: An Analysis from the RSSearch(r) Registry. AB - Objectives To report on overall survival (OS), local control (LC), dose-outcome relationships, and related toxicities following stereotactic body radiation therapy (SBRT) for locally recurrent, previously irradiated squamous cell carcinoma of the head and neck (rSCCHN). Methods We queried the prospectively maintained RSSearch(r) Registry for patients with rSCCHN treated with five fraction SBRT from January 2008 to November 2016. Patients with non-squamous cell histology, missing registry data regarding prior irradiation, those treated with less than five fractions of SBRT, and those treated with SBRT in primary or boost settings were excluded. LC and OS were estimated using the Kaplan-Meier method with comparisons between groups completed using log-rank t-tests and multivariable Cox regression. Logistic regression analyses were used to examine factors predictive of toxicity. Results Forty-five rSCCHN patients treated with SBRT delivered in five fractions at 12 radiotherapy centers were identified. Prescription doses >= 40 Gy were associated with higher one-year rates of OS, LC, and a higher likelihood of experiencing toxicities. Acute and late toxicity rates were low (22.2% and 15.6%, respectively) and were all Grade 1-2 with only one late Grade 3 esophagitis. Conclusion Salvage SBRT for rSCCHN resulted in outcomes comparable to prior single-institutional reports in a multi-institutional cohort across clinical settings with low toxicity, thus supporting more widespread adoption of SBRT with recommended doses >= 40 Gy. PMID- 30410844 TI - A Rare Presentation of Precursor B-cell Lymphoblastic Lymphoma in a Child. AB - Precursor B-cell lymphoblastic lymphoma, a type of non-Hodgkin lymphoma, is common in children. It is mostly extranodal; skin, bone and soft tissue are more often involved. However, isolated peritoneal presentation is rare. In this article a unique pediatric case of isolated omental precursor B-cell lymphobastic lymphoma is presented. PMID- 30410845 TI - Acute Thyroid Storm Following Thymectomy: A Surprising Result of Undiagnosed Graves' Disease. AB - Postoperative thyroid storm represents a diagnostic dilemma in patients with overlooked hyperthyroid state undergoing a nonthyroid surgery. We report a 30 year-old female with a history of mixed connective tissue disease who presented with an anterior mediastinal mass and underwent a thoracoscopic resection of the mass. On postoperative day 1, she had an acute change in mental status with fever, tachycardia and hypercapnic respiratory failure requiring intubation and mechanical ventilation. An elevated free thyroxine concentration and almost undetectable serum thyroid stimulating hormone suggested thyroid storm as the culprit. The patient was rendered euthyroid after initiation of therapy with propylthiouracil/methimazole, potassium iodide oral solution and systemic steroid. Histopathology of the resected anterior mediastinal mass showed thymic hyperplasia. In retrospect, the patient had hyperthyroid symptoms before surgery, but this diagnosis was overlooked. Non-thyroid surgeries can trigger thyroid storm in the setting of poorly controlled or overlooked hyperthyroidism. Although uncommon, thyroid storm should be considered in differential diagnosis of perioperative tachycardia and respiratory failure. We emphasize on the importance of preoperative thyroid workup in patients with tachycardia, palpitation, labile blood pressure, unexplained weight changes or poorly controlled anxiety. The significance of a proper preoperative assessment cannot be overestimated. PMID- 30410846 TI - Insulin Pump in Difficult to Control Type 2 Diabetes: A Single Center, Five Years' Experience. AB - Objective Due to a progressive decline in beta-cell function, a considerable number of patients with type 2 diabetes mellitus (T2D) ultimately require multiple daily injections of large doses of insulin for glycemic control. Majority of studies have reported only short-term benefits of continuous subcutaneous insulin infusion (CSII) using an insulin pump in T2D. Our five-year follow-up data of CSII in T2D is one of the few studies showing persistent benefit in glucose control in this population. Research design and methods We did a chart review of patients treated with an insulin pump for five years. Inclusion criteria were: type 2 diabetes, 18-75 years of age, glycosylated hemoglobin (HbA1c) more than 6.5% (48 mmol/mol) on multiple doses of insulin (MDI > four injections per day) or more than 100 units of insulin/day, wide glycemic excursions, and intractable hypoglycemia. We identified a total of 13 patients. The primary endpoint was change in HbA1c from baseline to five years. We also reviewed the difference in weight, basal insulin requirements, hypoglycemia, and patient satisfaction questionnaire at one year. Exclusion criteria were: type 1 diabetes (T1D) and pregnancy. Results The HbA1c at five years was found to be 7.72% (61 mmol/mol) compared to a baseline of 8.89% (74 mmol/mol), p-value 0.0076. We did not find any increased risk of severe hypoglycemia, weight gain, and insulin requirement. Conclusions The beneficial effect of insulin pump persisted for five years of follow-up, suggesting it as a valuable treatment option for difficult to treat T2D. PMID- 30410847 TI - Cannabis Use Disorder in Young Adults with Acute Myocardial Infarction: Trend Inpatient Study from 2010 to 2014 in the United States. AB - Objective This study determines the trend of acute myocardial infarction (AMI) in cannabis users. Demographic characteristics, hospitalization outcomes, and utilization of primary treatment modalities were evaluated in AMI inpatient population. Methods The study used data from the nationwide inpatient sample (NIS) for the years 2010-2014. We identified patients with AMI as the primary diagnosis (N = 379,843) and patients with cannabis use disorder as the secondary diagnosis. We used Pearson's chi-square (chi2) test and independent sample t-test for measuring the categorical and continuous data, respectively. Results Inpatient admissions for AMI among cannabis users increased by 32% (P = 0.001). The overall mean age of cannabis users with AMI (41 years) remained stable with no significant differences observed across age groups. AMI was predominant in male cannabis users (79.1%), and there was a 38.3% increase in the prevalence in female cannabis users over five years (P < 0.001). About one-third of the cannabis users with AMI were covered by medicaid with a 70.5% pike (21% in 2010 to 37.5% in 2014; P < 0.001). There was a strong linear trend in nonelective admissions for AMI in cannabis users (P = 0.003) along with a moderate-to-severe morbidity (P = 0.001). Mean length of inpatient stay had a decreasing linear trend (P = 0.003), whereas hospitalization costs were increasing (P = 0.024), averaging $65,879 per admission for AMI. Cannabis users had a strong linear increasing trend (P = 0.007), with a 60% increase in in-hospital mortality (1.0% in 2010 to 1.6% in 2014). Conclusion Due to the risk of AMI, as seen in numerous case reports, the trend of emergency admission and severe morbidity due to AMI in cannabis users is also increasing. Also, cannabis users have a higher healthcare cost to manage AMI, yet the in-hospital mortality has risen tremendously over the last few years. It is imperative to know that chronic cannabis worsens the outcomes in AMI patients, and more clinical studies are needed to show the association of episodic use in cannabis abusers and AMI. PMID- 30410848 TI - Late-onset Bipolar I Disorder. AB - Bipolar I disorder is a chronic psychiatric illness in which patients alternate between symptoms of both mania and depression. Most cases are diagnosed when patients are 20 to 50 years old. We describe a patient presenting with symptoms of acute mania at an unusually late age for this condition. After a workup for an organic etiology, including imaging studies, this 71-year-old man was diagnosed with bipolar I disorder. Since diagnosis, his condition has been managed with risperidone. PMID- 30410849 TI - Cardiovascular Autonomic Neuropathy and its Association with Cardiovascular and All-cause Mortality in Patients with End-stage Renal Disease. AB - Background End-stage renal disease frequently leads to increased cardiovascular mortality. Cardiovascular autonomic neuropathy (CAN) may be predictive of cardiac arrhythmias and sudden cardiac death in patients with end-stage renal disease. Methods A total of 70 patients with end-stage renal disease were included in the study. The assessment of cardiac dysautonomia was based on the four standardized tests performed at the baseline and, again, at the end of the study. The criteria for CAN included at least two abnormal test results. Results Fifty of 70 patients completed the study and were followed-up after one year. Out of the 50 patients, 44 (88%) had CAN at baseline. Twelve (24%) patients died at the one-year follow up. Sudden cardiac death was reported in seven out of 12 (58%) patients. All seven patients who died had high dysautonomia scores (three abnormal tests) at the baseline. There was a significantly higher percentage of patients with all four abnormal tests amongst patients who died of any cause (56% vs. 17%; RR 6.07, 95% CI 1.29-28.49; p-value 0.02) or due to sudden cardiac death (43% vs. 10.5%; RR 6.37, 95% CI 1.03-39.36; p-value 0.04). All five patients who did not have CAN at the baseline developed this abnormality on repeat testing after one year. Conclusion The prevalence of CAN in patients with end-stage renal disease on maintenance hemodialysis was significantly higher. CAN was an independent predictor of all-cause and cardiovascular mortality, which highlights it as a risk stratification tool in patients with end-stage renal disease. PMID- 30410850 TI - Revisiting the structure of low-Mach number, low-beta, quasi-perpendicular shocks. AB - A study of the structure of 145 low-Mach number (M <= 3), low-beta (beta <= 1), quasi-perpendicular interplanetary collisionless shock waves observed by the Wind spacecraft has provided strong evidence that these shocks have large-amplitude whistler precursors. The common occurrence and large amplitudes of the precursors raise doubts about the standard assumption that such shocks can be classified as laminar structures. This directly contradicts standard models. In 113 of the 145 shocks (~78%), we observe clear evidence of magnetosonic-whistler precursor fluctuations with frequencies ~0.1-7 Hz. We find no dependence on the upstream plasma beta, or any other shock parameter, for the presence or absence of precursors. The majority (~66%) of the precursors propagate at <=45 degrees with respect to the upstream average magnetic field and most (~87%) propagate >=30 degrees from the shock normal vector. Further, most (~79%) of the waves propagate at least 20 degrees from the coplanarity plane. The peak-to-peak wave amplitudes (deltaB pk-pk) are large with a range of maximum values for the 113 precursors of ~0.4-13 nT with an average of ~2 nT. When we normalize the wave amplitudes to the upstream averaged magnetic field and the shock ramp amplitude, we find average values of ~40% and ~220%, respectively. PMID- 30410851 TI - Synthesis of Metallomacrocycle and Coordination Polymers with Pyridine-Based Amidocarboxylate Ligands and Their Catalytic Activities towards the Henry and Knoevenagel Reactions. AB - The reactions of 3,3'-{(pyridine-2,6-dicarbonyl)bis(azanediyl)}dibenzoic acid (H2L) with zinc(II), cadmium(II), and samarium(III) nitrates were studied, and the obtained compounds, [Zn(1kappaO:2kappaO'-L)(H2O)2] n (1), [Cd(1kappaO 2:2kappaO 2-L)(H2O)2]2 ?6n H2O? n C4H8O2 ?1.5n DMF (2), and [Sm(1kappaO:2kappaO'O'':3kappaO'''-L)(NO3)(H2O)(dmf)] n ? n DMF (3), were characterized by elemental analysis, FTIR spectroscopy, thermogravimetric analysis, and X-ray single-crystal diffraction. Compounds 1 and 3 have 1D zigzag- and double-chain-type structures, respectively, whereas 2 features a dinuclear metallomacrocyclic complex. The ligand (L2-) orients in different conformations, that is, syn-syn for 1 and anti-anti for 2 and 3. Compound 1 is the first example in which the syn-syn conformation for this ligand has been observed. These compounds act as heterogeneous catalysts for the nitroaldol (Henry; in water medium) and Knoevenagel condensation reactions of different aldehydes, and the most effective is zinc coordination polymer 1. Recyclability, heterogeneity, and size-selectivity tests were performed, which showed that the catalyst was highly active over at least four recycling runs. PMID- 30410852 TI - Water-Based Synthesis of Hydrophobic Ionic Liquids [N8888][oleate] and [P666,14][oleate] and their Bioprocess Compatibility. AB - The conversion of organic waste streams into carboxylic acids as renewable feedstocks results in relatively dilute aqueous streams. Carboxylic acids can be recovered from such streams by using liquid-liquid extraction. Hydrophobic ionic liquids (ILs) are novel extractants that can be used for carboxylic acid recovery. To integrate these ILs as in situ extractants in several biotechnological applications, the IL must be compatible with the bioprocesses. Herein the ILs [P666,14][oleate] and [N8888][oleate] were synthesized in water and their bioprocess compatibility was assessed by temporary exposure to an aqueous phase that contained methanogenic granular sludge. After transfer of the sludge into fresh medium, [P666,14][oleate]-exposed granules were completely inhibited. Granules exposed to [N8888][oleate] sustained anaerobic digestion activity, albeit moderately reduced. The IL contaminants, bromide (5-500 ppm) and oleate (10-4000 ppm), were shown not to inhibit the methanogenic conversion of acetate. [P666,14] was identified as a bioprocess-incompatible component. However, our results showed that [N8888][oleate] was bioprocess compatible and, therefore, has potential applications in bioprocesses. PMID- 30410853 TI - Control of CNS functions by RNA-binding proteins in neurological diseases. AB - Purpose of Review: This review summarizes recent studies on the molecular mechanisms of RNA binding proteins (RBPs) that control neurological functions and pathogenesis in various neurodevelopmental and neurodegenerative diseases, including autism spectrum disorders, schizophrenia, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and spinocerebellar ataxia. Recent Findings: RBPs are critical players in gene expression that regulate every step of posttranscriptional modifications. Recent genome-wide approaches revealed that many proteins associate with RNA, but do not contain any known RNA binding motifs. Additionally, many causal and risk genes of neurodevelopmental and neurodegenerative diseases are RBPs. Development of high throughput sequencing methods has mapped out the fingerprints of RBPs on transcripts and provides unprecedented potential to discover new mechanisms of neurological diseases. Insights into how RBPs modulate neural development are important for designing effective therapies for numerous neurodevelopmental and neurodegenerative diseases. Summary: RBPs have diverse mechanisms for modulating RNA processing and, thereby, controlling neurogenesis. Understanding the role of disease-associated RBPs in neurogenesis is vital for developing novel treatments for neurological diseases. PMID- 30410857 TI - Zeolite protects mice from iron-induced damage in a mouse model trial. AB - For centuries, zeolites have been used for their utility in binding metals, and they feature in a multitude of agricultural and industrial applications in which the honeycombed zeolite structures form ideal ion exchangers, catalysts and binding agents. Zeolites are currently in a transition period, moving towards implementation in human ailments and diseases. Here, we postulated that zeolites may be able to counter the effects of excess iron and conducted a mouse model trial to gauge the utility of this notion. We used the transgenic mouse strain MexTAg299 for a thirty-week pilot trial in which iron polymaltose and/or the zeolite clinoptilolite was injected into the peritoneum twice weekly. Mice were sacrificed at the end of the trial period and examined by postmortem and histology for significant physiological differences between mouse subgroups. In this study, we demonstrated that a common zeolite, clinoptilolite, is able to maintain the general health and well-being of mice and prevent iron-induced deleterious effects following iron overload. When zeolites are given with iron biweekly as intraperitoneal injections, mice showed far less macroscopic visual organ discoloration, along with near normal histology, under iron overload conditions when compared to mice injected with iron only. The purpose of the present pilot study was to examine potential alternatives to current iron chelation treatments, and the results indicate an advantage to using zeolites in conditions of iron excess. Zeolites may have translational potential for use in cases of human iron overload. PMID- 30410854 TI - Streptococcus pneumoniae outbreaks and implications for transmission and control: a systematic review. AB - Background: Streptococcus pneumoniae is capable of causing multiple infectious syndromes and occasionally causes outbreaks. The objective of this review is to update prior outbreak reviews, identify control measures, and comment on transmission. Methods: We conducted a review of published S. pneumoniae outbreaks, defined as at least two linked cases of S. pneumoniae. Results: A total of 98 articles (86 respiratory; 8 conjunctivitis; 2 otitis media; 1 surgical site; 1 multiple), detailing 94 unique outbreaks occurring between 1916 to 2017 were identified. Reported serotypes included 1, 2, 3, 4, 5, 7F, 8, 12F, 14, 20, and 23F, and serogroups 6, 9, 15, 19, 22. The median attack rate for pneumococcal outbreaks was 7.0% (Interquartile range: 2.4%, 13%). The median case fatality ratio was 12.9% (interquartile range: 0%, 29.2%). Age groups most affected by outbreaks were older adults (60.3%) and young adults (34.2%). Outbreaks occurred in crowded settings, such as universities/schools/daycares, military barracks, hospital wards, and long-term care facilities. Of outbreaks that assessed vaccination coverage, low initial vaccination or revaccination coverage was common. Most (73.1%) of reported outbreaks reported non susceptibility to at least one antibiotic, with non-susceptibility to penicillin (56.0%) and erythromycin (52.6%) being common. Evidence suggests transmission in outbreaks can occur through multiple modes, including carriers, infected individuals, or medical devices. Several cases developed disease shortly after exposure (< 72 h). Respiratory outbreaks used infection prevention (55.6%), prophylactic vaccination (63.5%), and prophylactic antibiotics (50.5%) to prevent future cases. PPSV23 covered all reported outbreak serotypes. PCV13 covered 10 of 16 serotypes. For conjunctival outbreaks, only infection prevention strategies were used. Conclusions: To prevent the initial occurrence of respiratory outbreaks, vaccination and revaccination is likely the best preventive measure. Once an outbreak occurs, vaccination and infection-prevention strategies should be utilized. Antibiotic prophylaxis may be considered for high-risk exposed individuals, but development of antibiotic resistance during outbreaks has been reported. The short period between initial exposure and development of disease indicates that pneumococcal colonization is not a prerequisite for pneumococcal respiratory infection. PMID- 30410855 TI - Heterologous expression in Toxoplasma gondii reveals a topogenic signal anchor in a Plasmodium apicoplast protein. AB - Glutathione peroxidase-like thioredoxin peroxidase (PfTPxGl) is an antioxidant enzyme trafficked to the apicoplast, a secondary endosymbiotic organelle, in Plasmodium falciparum. Apicoplast trafficking signals usually consist of N terminal signal and transit peptides, but the trafficking signal of PfTPxGl appears to exhibit important differences. As transfection is a protracted process in P. falciparum, we expressed the N terminus of PfTPxGl as a GFP fusion protein in a related apicomplexan, Toxoplasma gondii, in order to dissect its trafficking signals. We show that PfTPxGl possesses an N-terminal signal anchor that takes the protein to the endoplasmic reticulum in Toxoplasma-this is the first step in the apicoplast targeting pathway. We dissected the residues important for endomembrane system uptake, membrane anchorage, orientation, spacing, and cleavage. Protease protection assays and fluorescence complementation revealed that the C terminus of the protein lies in the ER lumen, a topology that is proposed to be retained in the apicoplast. Additionally, we examined one mutant, responsible for altered PfTPxGl targeting in Toxoplasma, in Plasmodium. This study has demonstrated that PfTPxGl belongs to an emergent class of proteins that possess signal anchors, unlike the canonical bipartite targeting signals employed for the trafficking of luminal apicoplast proteins. This work adds to the mounting evidence that the signals involved in the targeting of apicoplast membrane proteins may not be as straightforward as those of luminal proteins, and also highlights the usefulness of T. gondii as a heterologous system in certain aspects of this study, such as reducing screening time and facilitating the verification of membrane topology. PMID- 30410856 TI - Uracil moieties in Plasmodium falciparum genomic DNA. AB - Plasmodium falciparum parasites undergo multiple genome duplication events during their development. Within the intraerythrocytic stages, parasites encounter an oxidative environment and DNA synthesis necessarily proceeds under these circumstances. In addition to these conditions, the extreme AT bias of the P. falciparum genome poses further constraints for DNA synthesis. Taken together, these circumstances may allow appearance of damaged bases in the Plasmodium DNA. Here, we focus on uracil that may arise in DNA either via oxidative deamination or thymine-replacing incorporation. We determine the level of uracil at the ring, trophozoite, and schizont intraerythrocytic stages and evaluate the base-excision repair potential of P. falciparum to deal with uracil-DNA repair. We find approximately 7-10 uracil per million bases in the different parasite stages. This level is considerably higher than found in other wild-type organisms from bacteria to mammalian species. Based on a systematic assessment of P. falciparum genome and transcriptome databases, we conclude that uracil-DNA repair relies on one single uracil-DNA glycosylase and proceeds through the long-patch base excision repair route. Although potentially efficient, the repair route still leaves considerable level of uracils in parasite DNA, which may contribute to mutation rates in P. falciparum. PMID- 30410858 TI - The dipeptidyl peptidase-4 (DPP-4) inhibitor teneligliptin enhances brown adipose tissue function, thereby preventing obesity in mice. AB - To clarify the effects of a dipeptidyl peptidase-4 (DPP-4) inhibitor on whole body energy metabolism, we treated mice fed a high-fat diet (HFD) with teneligliptin, a clinically available DPP-4 inhibitor. Teneligliptin significantly prevented HFD-induced obesity and obesity-associated metabolic disorders. It also increased oxygen consumption rate and upregulated uncoupling protein 1 (UCP1) expression in both brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT), suggesting that it enhances BAT function. Soluble DPP-4 inhibited beta-adrenoreceptor-stimulated UCP1 expression in primary adipocytes, and this inhibition was prevented in the presence of teneligliptin, or an extracellular signal-related kinase inhibitor. These results indicate that soluble DPP-4 inhibits beta-adrenoreceptor-stimulated UCP1 induction and that chronic DPP-4 inhibitor treatment may prevent obesity through the activation of BAT function. PMID- 30410859 TI - Transcriptome analysis of growth heterosis in pearl oyster Pinctada fucata martensii. AB - Heterosis improves growth and survival of shellfish species. Although breeders have widely exploited heterosis, its underlying molecular mechanisms remain unclear. In this study, a 2 * 2 complete diallel cross was facilitated between two full-sib families to produce two inbred families (A and D) and their reciprocal hybrid families (B and C) of pearl oyster Pinctada fucata martensii. Growth traits of the four families were compared at the adult stages. Transcriptome analysis was conducted on the four families using an Illumina sequencing platform. The results revealed that the growth traits of the four families significantly varied (P < 0.05). The mid-parent heterosis values of shell length, shell height, shell width, shell weight, and total weight were 12.9%, 14.9%, 18.2%, 17.2%, and 33.2%, respectively. The B- and C-inbred (A and D) triads had 79 and 68 differentially expressed genes (DEGs), respectively, which were dominantly nonadditive, including overdominance, underdominance, and low-parent dominance. Gene ontology term analysis showed that the DEGs in the B- and C-inbred triads were enriched for metabolic process, cellular process cell part, binding, and catalytic activity. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis indicated that the DEGs in the B- and C-inbred triads were involved in focal adhesion, the P13K-Akt signaling pathway, the mRNA surveillance pathway, and the focal adhesion pathway. The reliability of the sequencing data was confirmed by real-time polymerase chain reaction analysis of six growth-related genes. The findings of this study provide new insights into heterosis for growth traits and the design of genetic breeding programs for this species. PMID- 30410861 TI - Characterization analysis and heavy metal-binding properties of CsMTL3 in Escherichia coli. AB - Members of the metallothionein (MT) superfamily are involved in coordinating transition metal ions. In plants, MT family members are characterized by their arrangement of Cys residues. In this study, one member of the MT superfamily, CsMTL3, was characterized from a complementary DNA (cDNA) library from young cucumber fruit; CsMTL3 is predicted to encode a 64 amino acid protein with a predicted molecular mass of 6.751 kDa. Phylogenetic analysis identified it as a type 3 family member as the arrangement of N-terminal Cys residues was different from that of MT-like 2. Heterologous expression of CsMTL3 in Escherichia coli improved their heavy metal tolerance, particularly to Cd2+ and Cu2+, and led to increased uptake of Cd2+ and Cu2+; increased uptake was also observed for cells expressing Arabidopsis thaliana metallothionein 3 (AtMT3) and phytochelatin-like (PCL), with greatest uptake in PCL-expressing cells. These findings demonstrate that CsMTL3 can improve metal tolerance, especially for Cd2+ ions, when heterologously expressed in E. coli, and suggest that the composition and arrangement of N-terminal Cys residues are associated with binding capacity and preference for different metal ions. PMID- 30410862 TI - In silico identification and biochemical characterization of the human dicarboxylate clamp TPR protein interaction network. AB - Dicarboxylate clamp tetratricopeptide repeat (dcTPR) motif-containing proteins are well-known partners of the heat shock protein (Hsp) 70 and Hsp90 molecular chaperones. Together, they facilitate a variety of intracellular processes, including protein folding and maturation, protein targeting, and protein degradation. An extreme C-terminal sequence, the EEVD motif, is identical in Hsp70 and Hsp90, and is indispensable for their interaction with dcTPR proteins. However, almost no information is available on the existence of other potential dcTPR-interacting proteins. We searched the human protein database for proteins with C-terminal sequences similar to that of Hsp70/Hsp90 to identify potential partners of dcTPR proteins. The search identified 112 proteins containing a Hsp70/Hsp90-like signature at their C termini. Gene Ontology enrichment analysis of identified proteins revealed enrichment of distinct protein classes, such as molecular chaperones and proteins of the ubiquitin-proteasome system, highlighting the possibility of functional specialization of proteins containing a Hsp70/Hsp90-like signature. We confirmed interactions of selected proteins containing Hsp70/Hsp90-like C termini with dcTPR proteins both in vitro and in situ. Analysis of interactions of 10-amino-acid peptides corresponding to the C termini of identified proteins with dcTPR proteins revealed significant differences in binding strength between various peptides. We propose a hierarchical mode of interaction within the dcTPR protein network. These findings describe a novel dcTPR protein interaction networks and provide a rationale for selective regulation of protein-protein interactions within this network. PMID- 30410860 TI - Both Ser361 phosphorylation and the C-arrestin domain of thioredoxin interacting protein are important for cell cycle blockade at the G1/S checkpoint. AB - Thioredoxin interacting protein (TXNIP) is a novel tumor suppressor that is down regulated in several cancer tissues and tumor cell lines. Overexpression of TXNIP causes cell cycle arrest at the G1/S checkpoint in the hepatocellular carcinoma cell line HuH-7. TXNIP contains putative phosphorylation sites, but the effects of its phosphorylation have not been fully characterized. TXNIP also contains two alpha-arrestin domains (N-arrestin and C-arrestin) whose functions are not fully understood. Here, we reveal an association between TXNIP and cell cycle regulatory proteins (p27kip1, Jun activation domain-binding protein 1 (JAB1), Cdk2, and cyclin E), suggesting its participation in cell cycle regulation. We observed phosphorylation of TXNIP and used both in vivo and in vitro kinase assays to demonstrate that TXNIP can be phosphorylated by p38 mitogen-activated protein kinase. Furthermore, we also identified Ser361 in TXNIP as one of the major phosphorylation sites. Cell cycle analysis showed that Ser361 phosphorylation participates in TXNIP-mediated cell cycle arrest. In addition, the C-arrestin domain may also play an important role in cell cycle arrest. We also showed that phosphorylation at Ser361 may be important for the association of TXNIP with JAB1 and that the C-arrestin domain is necessary for the nuclear localization of this molecule. Collectively, these studies reveal that TXNIP participates in cell cycle regulation through association with regulatory proteins, especially JAB1, and that C-arrestin-dependent nuclear localization is important for this function. This work may facilitate the development of a new cancer therapy strategy that targets TXNIP as a key molecule inhibiting cancer cell growth via cell cycle blockade at the G1/S checkpoint. PMID- 30410863 TI - Identification of reference genes for circulating long noncoding RNA analysis in serum of cervical cancer patients. AB - Circulating lncRNAs have attracted considerable attention as potential noninvasive biomarkers for diagnosing cancers. RT-qPCR is the canonical technique for detecting circulating RNA and depends largely on stable reference genes for data normalization. However, no systematic evaluation of reference genes for serum lncRNA has been reported for cervical cancer. Here, we profiled and validated lncRNA expression from serum of cervical cancer patients and controls using microarrays and RT-qPCR. We identified lncRNA RP11-204K16.1, XLOC_012542, and U6 small nuclear RNA as the most stable reference genes based on geNorm, NormFinder, BestKeeper, delta Ct, and RefFinder. These genes were suitable also for samples from different age groups or with hemolysis. Additionally, we discovered lncRNA AC017078.1 and XLOC_011152 as candidate biomarkers, whose expression was down-regulated in cervical cancer. Our findings could aid research on circulating lncRNA and the discovery of blood-based biomarkers for cervical cancer diagnosis. PMID- 30410864 TI - LncRNA UCA1 is necessary for TGF-beta-induced epithelial-mesenchymal transition and stemness via acting as a ceRNA for Slug in glioma cells. AB - The 5-year survival rate of patients with glioma is < 5%, and therefore there is an urgent need to find novel potential targets for facilitating its diagnosis and treatment. The long non-coding RNA (lncRNA) UCA1 has been shown to promote the proliferation and invasion of cervical cancer cells through regulating miR-206 expression, but the involvement of UCA1 in regulating the stemness and epithelial mesenchymal transition (EMT) of glioma cells is unknown. Here, we report that the expression of UCA1 is significantly increased by transforming growth factor-beta (TGF-beta) treatment in glioma cells and is greater in glioma tissues than in normal adjacent tissues. Additionally, TGF-beta induced EMT and the stemness of glioma cells, whereas knockdown of lncRNA UCA1 attenuated these two processes and their enhancement by TGF-beta. Mechanistically, knockdown of UCA1 decreased Slug expression by acting as a competitive endogenous RNA (ceRNA) through competitive binding with miR-1 and miR-203a; this effect was further evidenced by the fact that transfection with miR-1 or miR-203a inhibitors abrogated the effects of UCA1 knockdown on Slug expression, and UCA1 colocalized with miR-1 and miR-203a in glioma tissues. Notably, ectopic expression of Slug rescued the attenuation of UCA1 knockdown on EMT and the stemness of glioma cells. These results indicate that UCA1 may act as a ceRNA to promote Slug expression, which underlies TGF-beta induced EMT and stemness of glioma cells. PMID- 30410865 TI - WNK1 kinase is essential for insulin-stimulated GLUT4 trafficking in skeletal muscle. AB - With-no-lysine 1 (WNK1) kinase is a substrate of the insulin receptor/Akt pathway. Impaired insulin signaling in skeletal muscle disturbs glucose transporter 4 (GLUT4) translocation associated with the onset of type 2 diabetes (T2D). WNK1 is highly expressed in skeletal muscle. However, it is currently unknown how insulin signaling targeting WNK1 regulates GLUT4 trafficking in skeletal muscle, and whether this regulation is perturbed in T2D. Hereby, we show that insulin phosphorylates WNK1 at its activating site via a phosphatidylinositol 3-kinase-dependent mechanism. WNK1 promotes the cell surface abundance of GLUT4 via regulating TBC1D4. Of note, we observed insulin resistance and decreased WNK1 phosphorylation in T2D db/db mice as compared to the control mice. These results provide a new perspective on WNK1 function in the pathogenesis of hyperglycemia in T2D. PMID- 30410867 TI - Erratum to: Metformin treatment ameliorates diabetes-associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1. AB - [This corrects the article DOI: 10.1002/2211-5463.12436.]. PMID- 30410866 TI - Circulating anti-p16a IgG autoantibodies as a potential prognostic biomarker for non-small cell lung cancer. AB - It has been reported that p16 protein is overexpressed in many types of solid cancer and its aberrant expression may trigger the immune response, leading to the secretion of anti-p16 antibodies. Here, we developed an in-house ELISA with three p16-derived linear peptide antigens to examine plasma anti-p16 antibody levels in patients with non-small cell lung cancer (NSCLC). Blood samples were taken from 200 control subjects and 211 patients with NSCLC prior to anticancer therapy. A Mann-Whitney U test demonstrated that plasma anti-p16a IgG levels were significantly higher in NSCLC patients than in control subjects (Z = -11.14, P < 0.001). However, neither plasma anti-p16b nor plasma anti-p16c IgG levels showed significant differences in patients with NSCLC as compared to control subjects. Moreover, further analysis indicated that anti-p16a IgG levels increased with tumor stages, and patients with late stage NSCLC, namely group IV, had the highest IgG levels among four subgroups. Receiver operating characteristic analysis revealed that the anti-p16a IgG assay had a sensitivity of 32.7% against a specificity of 95.0% in group IV, while Kaplan-Meier survival analysis revealed no significant difference in overall survival between patients with high anti p16a IgG levels and those with low anti-p16a IgG levels (chi2 = 0.24, P = 0.63). In conclusion, anti-p16a IgG may be suitable for use as a prognostic biomarker for NSCLC. PMID- 30410868 TI - Corrigendum to: miRNA expression profile of retinal pigment epithelial cells under oxidative stress conditions. AB - [This corrects the article DOI: 10.1002/2211-5463.12360.]. PMID- 30410869 TI - Insect and insect-inspired aerodynamics: unsteadiness, structural mechanics and flight control. AB - Flying insects impress by their versatility and have been a recurrent source of inspiration for engineering devices. A large body of literature has focused on various aspects of insect flight, with an essential part dedicated to the dynamics of flapping wings and their intrinsically unsteady aerodynamic mechanisms. Insect wings flex during flight and a better understanding of structural mechanics and aeroelasticity is emerging. Most recently, insights from solid and fluid mechanics have been integrated with physiological measurements from visual and mechanosensors in the context of flight control in steady airs and through turbulent conditions. We review the key recent advances concerning flight in unsteady environments and how the multi-body mechanics of the insect structure-wings and body-are at the core of the flight control question. The issues herein should be considered when applying bio-informed design principles to robotic flapping wings. PMID- 30410870 TI - Two Missense Variants Detected in Breast Cancer Probands Preventing BRCA2-PALB2 Protein Interaction. AB - PALB2 (partner and localizer of BRCA2) was initially identified as a binding partner of BRCA2. It interacts also with BRCA1 forming a complex promoting DNA repair by homologous recombination. Germline pathogenic variants in BRCA1, BRCA2 and PALB2 DNA repair genes are associated with high risk of developing breast cancer. Mutation screening in these breast cancer predisposition genes is routinely performed and allows the identification of individuals who carry pathogenic variants and are at risk of developing the disease. However, variants of uncertain significance (VUSs) are often detected and establishing their pathogenicity and clinical relevance remains a central challenge for the risk assessment of the carriers and the clinical decision-making process. Many of these VUSs are missense variants leading to single amino acid substitutions, whose impact on protein function is uncertain. Typically, VUSs are rare and due to the limited genetic, clinical, and pathological data the multifactorial approaches used for classification cannot be applied. Thus, these variants can only be characterized through functional analyses comparing their effect with that of normal and mutant gene products used as positive and negative controls. The two missense variants BRCA2:c.91T >G (p.Trp31Gly) and PALB2:c.3262C >T (p.Pro1088Ser) were detected in two breast cancer probands originally ascertained at Breast Cancer Units of Institutes located in Milan and Bergamo (Northern Italy), respectively. These variants were located in the BRCA2-PALB2 interacting domains, were predicted to be deleterious by in silico analyses, and were very rare and clinically not classified. Therefore, we initiate to study their functional effect by exploiting a green fluorescent protein (GFP)-reassembly in vitro assay specifically designed to test the BRCA2-PALB2 interaction. This functional assay proved to be easy to develop, robust and reliable. It also allows testing variants located in different genes. Results from these functional analyses showed that the BRCA2:p.Trp31Gly and the PALB2:p.Pro1088Ser prevented the BRCA2-PALB2 binding. While caution is warranted when the interpretation of the clinical significance of rare VUSs is based on functional studies only, our data provide initial evidences in favor of the possibility that these variants are pathogenic. PMID- 30410871 TI - Seed Extract of Psoralea corylifolia and Its Constituent Bakuchiol Impairs AHL Based Quorum Sensing and Biofilm Formation in Food- and Human-Related Pathogens. AB - The emergence of multi-drug resistance in pathogenic bacteria in clinical settings as well as food-borne infections has become a serious health concern. The problem of drug resistance necessitates the need for alternative novel therapeutic strategies to combat this menace. One such approach is targeting the quorum-sensing (QS) controlled virulence and biofilm formation. In this study, we first screened different fractions of Psoralea corylifolia (seed) for their anti QS property in the Chromobacterium violaceum 12472 strain. The methanol fraction was found to be the most active fraction and was selected for further bioassays. At sub-inhibitory concentrations, the P. corylifolia methanol fraction (PCMF) reduced QS-regulated virulence functions in C. violaceum CVO26 (violacein); Pseudomonas aeruginosa (elastase, protease, pyocyanin, chitinase, exopolysaccharides (EPS), and swarming motility), A. hydrophila (protease, EPS), and Serratia marcescens (prodigiosin). Biofilm formation in all the test pathogens was reduced significantly (p <= 0.005) in a concentration-dependent manner. The beta-galactosidase assay showed that the PCMF at 1,000 MUg/ml downregulated las-controlled transcription in PAO1. In vivo studies with C. elegans demonstrated increased survival of the nematodes after treatment with the PCMF. Bakuchiol, a phytoconstituent of the extract, demonstrated significant inhibition of QS-regulated violacein production in C. violaceum and impaired biofilm formation in the test pathogens. The molecular docking results suggested that bakuchiol efficiently binds to the active pockets of LasR and RhlR, and the complexes were stabilized by several hydrophobic interactions. Additionally, the molecular dynamics simulation of LasR, LasR-bakuchiol, RhlR, and RhlR-bakuchiol complexes for 50 ns revealed that the binding of bakuchiol to LasR and RhlR was fairly stable. The study highlights the anti-infective potential of the PCMF and bakuchiol instead of bactericidal or bacteriostatic action, as the extract targets QS-controlled virulence and the biofilm. PMID- 30410872 TI - Gastric Cancer Cell Lines Have Different MYC-Regulated Expression Patterns but Share a Common Core of Altered Genes. AB - MYC is an oncogene responsible for excessive cell growth in cancer, enabling transcriptional activation of genes involved in cell cycle regulation, metabolism, and apoptosis, and is usually overexpressed in gastric cancer (GC). By using siRNA and Next-Generation Sequencing (NGS), we identified MYC-regulated differentially expressed Genes (DEGs) in three Brazilian gastric cancer cell lines representing the histological subtypes of GC (diffuse, intestinal, and metastasis). The DEGs were picked using Sailfish software, followed by Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analysis using KEGG. We found 11 significantly enriched gene sets by using enrichment score (ES), False Discovery Rate (FDR), and nominal P-values. We identified a total of 5.471 DEGs with correlation over (80%). In diffuse-type and in metastatic GC cell lines, MYC-silencing caused DEGs downregulation, while the intestinal-type GC cells presented overall DEGs upregulation after MYC siRNA depletion. We were able to detect 11 significant gene sets when comparing our samples to the hallmark collection of gene expression, enriched mostly for the following hallmarks: proliferation, pathway, signaling, metabolic, and DNA damage response. When we analyzed our DEGs considering KEGG metabolic pathways, we found 12 common branches covering a wide range of biological functions, and three of them were common to all three cell lines: ubiquitin-mediated proteolysis, ribosomes, and system and epithelial cell signaling in Helicobacter pylori infection. The GC cell lines used in this study share 14 MYC-regulated genes, but their gene expression profile is different for each histological subtype of GC. Our results present a computational analysis of MYC-related signatures in GC, and we present evidence that GC cell lines representing distinct histological subtypes of this disease have different MYC-regulated expression profiles but share a common core of altered genes. This is an important step towards the understanding of MYC's role in gastric carcinogenesis and an indication of probable new drug targets in stomach cancer. PMID- 30410873 TI - Diagnostic Value of lncRNAs as Biomarker in Hepatocellular Carcinoma: An Updated Meta-Analysis. AB - Some long noncoding RNAs (lncRNAs) display aberrantly high or low expression in hepatocellular carcinoma (HCC) and have the potential to serve as diagnostic biomarkers. Here, we accomplished a meta-analysis based on current studies to assess the diagnostic value of lncRNAs in HCC. Eligible literatures were systematically selected from PubMed, Web of Science, and Embase (up to January 20, 2018) according to defined inclusion and exclusion criteria. QUADAS scale was applied to the quality assessment of the included studies. Statistical analysis was performed through bivariate random-effects models based on R software. Publication bias was evaluated by funnel plot and Begg's and Egger's tests. 16 articles containing 2,268 cancer patients and 2,574 controls were selected for the final meta-analysis. Random effect model was used for the meta-analysis due to significant between-study heterogeneity. The pooled sensitivity, specificity, diagnostic odds ratio (DOR), positive likelihood ratio (PLR), and negative likelihood ratio (NLR) were 0.87(0.838-0.897), 0.829(0.794-0.86), 23.085(20.575 25.901), 4.533(4.239-4.847), and 0.176(0.166-0.186), respectively. Summary receiver operating characteristic curve (SROC) was conducted to estimate the diagnostic accuracy of lncRNAs in HCC with the area under curve (AUC) of 0.915. Subgroups analysis showed that lncRNA profiling, sample size, specimen types, and ethnicity might be the sources of heterogeneity. No publication bias existed according to funnel plot symmetry and Begg's (P = 0.187) and Egger's (P = 0.477) tests. In conclusion, lncRNAs can serve as potential diagnostic biomarkers of HCC with high sensitivity and specificity. In addition, lncRNAs panel from serum and plasma has a relatively high diagnostic value for HCC patients from Asia. PMID- 30410874 TI - Ventilation Prior to Umbilical Cord Clamping Improves Cardiovascular Stability and Oxygenation in Preterm Lambs After Exposure to Intrauterine Inflammation. AB - Background: Delaying umbilical cord clamping until after aeration of the lung (physiological-based cord clamping; PBCC) maintains cardiac output and oxygenation in preterm lambs at birth, however, its efficacy after intrauterine inflammation is not known. Given the high incidence of chorioamnionitis in preterm infants, we investigated whether PBCC conferred any benefits compared to immediate cord clamping (ICC) in preterm lambs exposed antenatally to 7 days of intrauterine inflammation. Methods: Ultrasound guided intraamniotic injection of 20 mg Lipopolysaccharide (from E. coli:055:B5) was administered to pregnant ewes at 0.8 gestation. Seven days later, ewes were anesthetized, preterm fetuses exteriorised via cesarean section, and instrumented for continuous measurement of pulmonary, systemic and cerebral pressures and flows, and systemic, and cerebral oxygenation. Lambs were then randomized to either PBCC, whereupon ventilation was initiated and maintained for 3 min prior to umbilical cord clamping, or ICC where the umbilical cord was cut and ventilation initiated 30 s later. Ventilation was maintained for 30 min. Results: ICC caused a rapid fall in systemic (by 25%) and cerebral (by 11%) oxygen saturation in ICC lambs, concurrent with a rapid increase in carotid arterial pressure and heart rate. The overshoot in carotid arterial pressure was sustained in ICC lambs for the first 20 min of the study. PBCC maintained cardiac output and prevented the fall in cerebral oxygen delivery at birth. PBCC lambs had lower respiratory compliance and higher respiratory requirements throughout the study. Conclusion: PBCC mitigated the adverse effects of ICC on oxygenation and cardiac output, and therefore could be more beneficial in preterm babies exposed to antenatal inflammation as it maintains cardiac output and oxygen delivery. The increased respiratory requirements require further investigation in this sub-group of preterm infants. PMID- 30410876 TI - Use of Heated Humidified Gases for Early Stabilization of Preterm Infants: A Meta Analysis. AB - Background: Large observational studies in preterm infants have shown an increase in mortality and morbidity when admission temperature is below 36.5 degrees C. Recent randomized controlled studies have shown a reduction in admission hypothermia and an increase in the number of infants admitted with normal temperature (36.5-37.5 degrees C) when heated humidified gases were used for initial stabilization of preterm infants. Objective: The goal of this study was to perform a meta-analysis of published randomized trials using heated humidified gas compared to cold dry gas in preterm infants immediately after birth and during transport to the neonatal unit. Specific research aims were to determine the magnitude of the reduction in hypothermia and to examine neonatal outcomes including mortality. Methods: A literature search was conducted in accordance with the standard methods of the Cochrane Neonatal Work Group. Randomized trials were identified and data entered into RevMan5. A fixed effects statistical model was used. Risk of bias was assessed for included studies and the GRADE approach used to determine quality of evidence. The primary outcome was admission hypothermia (< 36.5 degrees C). Secondary outcomes included admission temperature in the normothermic range (36.5-37.5 degrees C) and neonatal outcomes including mortality. Results: Two studies met inclusion criteria and a total of 476 preterm infants were enrolled, all of whom were < 32 weeks gestation. Studies were not blinded but the overall risk of bias was low. Admission hypothermia was reduced by 36% (CI 17-50%), while admission normothermia was significantly increased. GRADE quality of evidence was high for these outcomes. The number of infants with more severe hypothermia (< 35.5 degrees C) was significantly reduced (RR 0.32 CI 0.14-0.73). In addition, preterm infants < 28 weeks had significantly less admission hypothermia (RR 0.61 CI 0.42, 0.90) Mortality and measures of respiratory outcome were not significantly different (studies were not powered for these outcomes), though there was a trend to improvement in all respiratory measures assessed. There were no significant adverse events and no increase in admission hyperthermia (>37.5 degrees C). Conclusions: Heating and humidification of inspired gases immediately after birth and during transport to the neonatal unit improves admission temperature in preterm infants. Consideration should be given to incorporating this technique into other strategies (e.g., use of plastic wrap) designed to keep preterm infants warm on admission to the neonatal unit. PMID- 30410875 TI - Fluid Bolus Therapy in Pediatric Sepsis: Current Knowledge and Future Direction. AB - Sepsis is a leading cause of morbidity and mortality in children with a worldwide prevalence in pediatric intensive care units of approximately 8%. Fluid bolus therapy (FBT) is a first line therapy for resuscitation of septic shock and has been a recommendation of international guidelines for nearly two decades. The evidence base supporting these guidelines are based on limited data including animal studies and case control studies. In recent times, evidence suggesting harm from fluid in terms of morbidity and mortality have generated interest in evaluating FBT. In view of this, studies of fluid restrictive strategies in adults and children have emerged. The complexity of studying FBT relates to several points. Firstly, the physiological and haemodynamic response to FBT including magnitude and duration is not well described in children. Secondly, assessment of the circulation is based on non-specific clinical signs and limited haemodynamic monitoring with limited physiological targets. Thirdly, FBT exists in a complex myriad of pathophysiological responses to sepsis and other confounding therapies. Despite this, a greater understanding of the role of FBT in terms of the physiological response and possible harm is warranted. This review outlines current knowledge and future direction for FBT in sepsis. PMID- 30410877 TI - Eliminating Non-linear Raman Shift Displacement Between Spectrometers via Moving Window Fast Fourier Transform Cross-Correlation. AB - Obtaining consistent spectra by using different spectrometers is of critical importance to the fields that rely heavily on Raman spectroscopy. The quality of both qualitative and quantitative analysis depends on the stability of specific Raman peak shifts across instruments. Non-linear drifts in the Raman shifts can, however, introduce additional complexity in model building, potentially even rendering a model impractical. Fortunately, various types of shift correction methods can be applied in data preprocessing in order to address this problem. In this work, a moving window fast Fourier transform cross-correlation is developed to correct non-linear shifts for synchronization of spectra obtained from different Raman instruments. The performance of this method is demonstrated by using a series of Raman spectra of pharmaceuticals as well as comparing with data obtained by using an existing standard Raman shift scattering procedure. The results show that after the removal of shift displacements, the spectral consistency improves significantly, i.e., the spectral correlation coefficient of the two Raman instruments increased from 0.87 to 0.95. The developed standardization method has, to a certain extent, reduced instrumental systematic errors caused by measurement, while enhancing spectral compatibility and consistency through a simple and flexible moving window procedure. PMID- 30410878 TI - High Performance Composite Polymer Electrolytes Doped With Spherical-Like and Honeycomb Structural Li0.1Ca0.9TiO3 Particles. AB - The spherical-like and honeycomb structural Li0.1Ca0.9TiO3 particles are prepared by spray drying combined with following calcination confirmed by X-ray diffraction (XRD) and scanning electron microscopy (SEM) with energy dispersive X ray spectrometer (EDS). The poly (vinylidene fluoride-co-hexafluoropropylene) (P(VDF-HFP))-based composite polymer electrolytes (CPEs) modified with the particles are fabricated by phase inversion and activation processes. The characterization results show that the as-prepared CPE membranes possess the smoothest surface and most abundant micropores with the lowest crystallinity with adding the particles into the polymer matrix, which results in high ionic conductivity (3.947 mS cm-1) and lithium ion transference number (0.4962) at ambient temperature. The interfacial resistance can be quickly stabilized at 508 Omega after 5 days storage and the electrochemical working window is up to 5.2 V. Moreover, the mechanical strength of the membranes gains significant improvement without lowering the ionic conductivity. Furthermore, the assembled coin cell can also deliver high discharge specific capacity and preserve steady cycle performance at different current densities. Those outstanding properties may be ascribed to the distinctive structure of the tailored spherical-like and honeycomb structural Li0.1Ca0.9TiO3 particles, which can guarantee the desirable CPEs as a new promising candidate for the polymer electrolyte. PMID- 30410879 TI - Microvascular Networks From Endothelial Cells and Mesenchymal Stromal Cells From Adipose Tissue and Bone Marrow: A Comparison. AB - A promising approach to overcome hypoxic conditions in tissue engineered constructs is to use the potential of endothelial cells (EC) to form networks in vitro when co-cultured with a supporting cell type in a 3D environment. Adipose tissue-derived stromal cells (ASC) as well as bone marrow-derived stromal cells (BMSC) have been shown to support vessel formation of EC in vitro, but only very few studies compared the angiogenic potential of both cell types using the same model. Here, we aimed at investigating the ability of ASC and BMSC to induce network formation of EC in a co-culture model in fibrin. While vascular structures of BMSC and EC remained stable over the course of 3 weeks, ASC-EC co cultures developed more junctions and higher network density within the same time frame. Both co-cultures showed positive staining for neural glial antigen 2 (NG2) and basal lamina proteins. This indicates that vessels matured and were surrounded by perivascular cells as well as matrix molecules involved in stabilization. Gene expression analysis revealed a significant increase of vascular endothelial growth factor (VEGF) expression in ASC-EC co-culture compared to BMSC-EC co-culture. These observations were donor-independent and highlight the importance of organotypic cell sources for vascular tissue engineering. PMID- 30410881 TI - Analyzing Neuronal Mitochondria in vivo Using Fluorescent Reporters in Zebrafish. AB - Despite their importance for cellular viability, the actual life history and properties of mitochondria in neurons are still unclear. These organelles are distributed throughout the entirety of the neuron and serve many functions, including: energy production (ATP), iron homeostasis and processing, calcium buffering, and metabolite production, as well as many other lesser known activities. Given their importance, understanding how these organelles are positioned and how their health and function is maintained is critical for many aspects of cell biology. This is best illustrated by the diverse disease literature which demonstrates that abnormal mitochondrial movement, localization, size, or function often correlates with neural pathology. In the following methods article, we will describe the techniques and tools we have optimized to directly visualize mitochondria and analyze mitochondrial lifetime, health, and function in neurons in vivo using fluorescent reporters in the zebrafish. The zebrafish system is ideal for in vivo studies of mitochondrial biology as: (1) neuronal circuits develop rapidly, within days; (2) it is genetically accessible; and (3) embryos and larvae are translucent allowing imaging in a completely intact vertebrate nervous system. Using these tools and techniques, the field is poised to answer questions of mitochondrial biology in the context of neuronal health and function in normal and disease states. PMID- 30410880 TI - Epigenetic Control of Endocrine Pancreas Differentiation in vitro: Current Knowledge and Future Perspectives. AB - The raising worldwide prevalence of Type 1 and Type 2 diabetes mellitus (T1DM and T2DM) solicits the derivation of in vitro methods yielding mature and fully functional beta-cells to be used in regenerative medicine. Several protocols to differentiate human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) into human pancreatic beta-like cells have recently been developed. These methods, coupled with a bioengineering approach using biocompatible encapsulating devices, have recently led to experimental clinical trials showing great promises to ultimately end the battle of diabetic patients for managing hyperglycemia. However, in vitro differentiation protocols face the challenge of achieving homogenous population of mono-hormonal insulin-secreting mature beta cells. Major epigenetic events such as DNA methylation, post-translational modification of histones and non-coding RNAs expression, orchestrate physiological endocrine pancreas specification into alpha-, beta-, gamma-, and delta-cells, both in vivo and in vitro. The dysregulation of such epigenetic processes is associated to multiple pancreatic disorders including diabetes. Understanding the epigenomic and transcriptomic landscape underlying endocrine pancreas development could, therefore, improve in vitro differentiation methods. In this review, we summarize the most effective protocols for in vitro differentiation of hESCs/hiPSCs toward pancreatic beta-cells and we discuss the current limitations in the derivation of functional glucose-responsive, insulin releasing beta-cells. Moreover, we focus on the main transcriptional and epigenetic events leading to pancreatic specification and on the applicative potential of novel epigenetic drugs for the establishment of innovative pharmacological therapeutic approaches. PMID- 30410882 TI - Neonatal ECMO. AB - Extracorporeal membrane oxygenation (ECMO) is becoming increasingly utilized to manage neonates with cardiac and respiratory failure. The procedure involves extensive anticoagulation in a sick neonate with underlying disease pathology. In addition, the immature hemostatic system in the neonate adds to the complexity of titrating the necessary anticoagulation. This places the infant at greater risk for life threatening hemorrhage and thrombosis. Managing anticoagulation in these infants is extremely challenging and needs the expertise of a physician with a thorough knowledge of the intricacies of developmental hemostasis and limitations of the current laboratory techniques available to manage anticoagulation. This article provides a brief overview of the developing hemostatic system of the neonate and the challenges associated with managing anticoagulation in this vulnerable population of patients. PMID- 30410883 TI - Functional Status and Quality of Life Determinants of a Group of Elderly People With Food Insecurity. AB - Background: A good functionality is appointed by the elderly as one of the most important factors for a good quality of life, since it is associated with independency and autonomy. Studies show that elderly with food insecurity have greater limitations in daily living activities (DLA) when compared to food security elderly. Moreover, food insecure elderly are 60% more likely to be diagnosed with depression. We aimed to investigate the potential determinants of functional status (HAQ) and quality of life (EQ-5D-3L) in a sample of elderly with food insecurity. Methods: Forty-one participants with food insecurity were evaluated by a multidisciplinary team, in April and May of 2016 (a baseline cross sectional study prior to the intervention program). Results: This study demonstrates correlations of functional status and quality of life to such aspects of elderly assessment as age, BMI, manual strength, among others. It was found that manual strength, gender, family income, anxiety, and depression were correlated to quality of life; and that mobility, manual strength, anxiety and gender were correlated to the functional status. After multivariable adjustment, only mobility (beta = -0.220; p <= 0.01) and quality of life (beta = -1.457; p <= 0.01) remained significantly associated with higher levels of functional disability. With regard to quality of life, only the functional status (beta = 0.242; p <= 0.01), the presence of depression (beta = -0.169; p <= 0.05), and family income (beta = 0.185; p <= 0.05) remained significantly associated with health-related quality of life. Conclusions: The study aims to verify the potential determinants of functional status (HAQ) and quality of life (EQ-5D-3L) in a sample of elderly with food insecurity. Even in a small cohort, the study demonstrated that in an elderly population with food insecurity, functional status is associated with mobility and quality of life, and that health-related quality of life is also associated with symptoms of depression and family income. Larger studies in other populations may be useful to confirm these observations. PMID- 30410884 TI - Storage Temperature Impacts on Anthocyanins Degradation, Color Changes and Haze Development in Juice of "Merlot" and "Ruby" Grapes (Vitis vinifera). AB - This study evaluated the degradation kinetics of selected anthocyanins and the change in polymeric color, browning index, and haze development of grape juices from "Merlot" and "Ruby" grape cultivars stored at 5, 25, and 35 degrees C for up to 360 days. Five major anthocyanins namely malvidin-3-O-glucoside (M3G), delphinidin-3-O-glucoside (D3G), petunidin-3-O-glucoside (Pt3G), peonidin-3-O glucoside (Pn3G), and cyanidin-3-O-glucoside (C3G) were identified. Juice from "Merlot" had significantly higher (p < 0.05) content of all individual anthocyanins as compared to "Ruby." During the long-term storage, total, and individual anthocyanins from both cultivars degraded following first-order reaction kinetics at the rate strongly dependent on temperature. At the end of the storage, noticeably higher loss of anthocyanins (95-99.9%) was observed at 25 and 35 degrees C as compared to storage at 5 degrees C [50-60% ("Merlot"); 74-81% ("Ruby")]. Considerably lower rate of decay was observed at 5 degrees C (k = 0.01 0.04) as compared to 25 (k = 0.04-0.14) and 35 degrees C (k = 0.05-0.14) storage temperatures. The most temperature sensitive anthocyanin compounds were C3G (Ea = 66.5 kJ/mol) and D3G (Ea = 63.3 kJ/mol). At higher storage temperatures, significant (p < 0.05) and strong negative correlations were observed between anthocyanin concentrations and the levels of haze, polymeric and brown color development during storage. Storing grape juice, at lower temperature conditions could reduce the continuous loss of biologically active anthocyanins as well as the development of haze and brown color. PMID- 30410885 TI - Is Biotin Safe for Dermatology Patients? PMID- 30410886 TI - Trichologist, Dermatotrichologist, or Trichiatrist? A Global Perspective on a Strictly Medical Discipline. AB - Few dermatologic problems carry as much emotional overtones as the complaint of hair loss. The best way to alleviate the distress related to hair loss is to effectively treat it. In fact, one of the oldest medical professions is the Egyptian physician who specialized on diseases of the head. And yet, from ancient Egypt down to modern times, human hair has been the object of superstition and mystery. Remarkably and despite the genuine advances in effective medical treatments, hair cosmetics, and surgical procedures, phony hair loss solutions continue to be marketed with an amazing success. In 1860, a quasi-scientific interest in hair loss and hair care originated in a London barbershop and became known as trichology, with the Institute of Trichologists being founded. Other corporations successively followed internationally, but it was only in 2010 that the term dermatotrichologist was proposed for board-certified dermatologists dealing with the scientific study of the hair and scalp, in contrast to the trichologist who is rather associated with laity and cosmetics than with medical professionalism, or - worse - offers opportunities to possible imposters with a primary commercial interest. The new term "trichiatrist" is proposed, literally meaning the "medical treatment of the hair," to designate the strictly medical professional dealing with the hair and scalp in health and disease. Trichiatrists differ from trichologists by virtue of being physicians. The quality and stringency of their graduate medical training is identical to that of other physicians. PMID- 30410887 TI - The Impact of Onychomycosis on Quality of Life: A Systematic Review of the Available Literature. AB - Purpose: Onychomycosis is a nail disorder that is increasing in prevalence worldwide. The psychological and social limitations caused by onychomycosis can potentially undermine the work and social lives of those experiencing these negative effects. This review aimed to evaluate the randomized controlled trials (RCTs) available in the current literature on the impact onychomycosis has on quality of life (QoL). Methods: A systematic review was performed using the databases PubMed, PsycINFO, Scopus, ClinicalTrials.gov, and Cochrane Library on July 18, 2017. Only RCTs with clinical effects described in English were included for review. Results: Ten RCTs reported QoL outcomes for patients suffering from onychomycosis. Treatment satisfaction was statistically significant from baseline to end of treatment in 100.0% (4/4) measures which reported on satisfaction with treatment; mental health was also significant in 100.0% (3/3), symptoms index rating in 100.0% (2/2), symptom frequency in 75.0% (3/4), overall problems in 75.0% (3/4), functional activities in 75.0% (6/8), appearance problems in 66.7% (2/3), symptom distress in 57.1% (4/7), and stigma in 40.0% (2/5). The OnyCOE-tTM and the NailQoL were the most used common outcome measures to describe QoL. Conclusion: The study sanctions that onychomycosis physically and psychologically distresses patients' lives. Further research should include validated outcome measures to more effectively treat onychomycosis. PMID- 30410888 TI - Nail Disorders in Children. AB - Nail diseases in children do not account for a significant proportion of pediatric consultations, and most of the time the nails are not observed by the clinician, overlooking their importance. Specific examination of the nails is neglected, while localization to the nails could be an initial sign of a syndrome or a systemic disorder. Nail diseases in the pediatric population differ from those in adults in terms of diagnostic approach and management; some of them even are manifested mainly or exclusively in children. Pediatric patients with underlying systemic disorders are more likely to manifest acquired disorders of the nails. Although rare, nail diseases in children are a source of anxiety for the parents. Examination of the nails is an essential part of pediatric physical examination. A correct clinical history and careful examination help the clinician to distinguish the different conditions and to decide on the correct management of nail diseases in young patients. A classification of nail dystrophies according to age is somewhat arbitrary and a unique classification does not exist. Nail diseases in the pediatric population can be divided according to age groups where a predilection appears in most of the cases. Moreover, certain abnormalities may be lifelong once acquired, but their presentation may be modified by age, worsening or improving during life. This review describes many of the nail conditions that are seen in the pediatric population aging from newborn to toddler, starting with physiological aspects to better recognize the pathological conditions. PMID- 30410889 TI - Congenital Malalignment of the Great Toenails: A Review. AB - Congenital malalignment of the great toenail is an under-estimated dystrophic disorder of unknown origin characterized by lateral deviation of the nail plates, which are not parallel to the major axis of the distal phalanx. It usually presents in infancy or childhood, while late onset is uncommon. Treatment depends on the degree of deviation. If minimal, a conservative and expectant attitude, based on prevention and treatment of possible complications, is recommended because of the possibility of spontaneous regression of the nail deviation. Surgical therapy may be considered in patients with severe or complicated forms. PMID- 30410892 TI - Does Complement Have a Role in the Pathogenesis of Alopecia Areata? AB - Alopecia areata (AA) is an autoimmune disorder in which immune attack of the anagen follicle causes hair loss in approximately 2% of the population. Although the pathogenesis of AA has not been fully determined, most likely it is mediated by a variety of factors including cellular/humoral immunity and genetic predisposition. Researchers have been interested in the possible role of the complement pathway in AA since the 1970s. Given recent evidence suggesting that complement plays a role in many immunologic and inflammatory dermatologic diseases including systemic lupus erythematosus, bullous diseases, angioedema, lipodystrophy, and skin infections, it is likely that complement also contributes to AA pathogenesis. Although early serum studies and immunohistochemical staining have been unimpressive, recent genetics studies may provide evidence that complement does indeed contribute to AA. By determining if complement plays a role in AA, options for novel targeted treatments will become available for those patients with refractory disease. PMID- 30410891 TI - Alopecia and Associated Toxic Agents: A Systematic Review. AB - Importance/Objective: There are a number of toxic agents that can cause alopecia. In this review we summarize the known substances that cause alopecia as one of the clinical signs of overdose or toxicity. Evidence Review: A search was conducted using PubMed, EMBASE, and Cochrane for studies describing hair loss of any type as a result of exposure to or ingestion of a toxic agent. The search yielded 856 articles, with 47 studies included in this review. Findings: Agents with the strongest evidence of association to alopecia include thallium, mercury, selenium, and colchicine. Agents with described incidents include boric acid, arsenic, vitamin A, botulinum toxin, Podostroma cornu-damae, and the synthetic opioid MT-45. Conclusions and Relevance: Numerous toxic agents have been implicated in alopecia, and the strength of evidence behind each agent varies. Toxic levels of thallium and colchicine have long been established to cause alopecia, as compared to agents such as botulinum toxin A and synthetic recreational drugs which have less literature describing their links to alopecia and will need further investigation to characterize their relationships to hair loss. Knowledge of typical presentations of hair loss will aid in the development of a differential diagnosis for patients presenting with alopecia. PMID- 30410890 TI - Immune Privilege Collapse and Alopecia Development: Is Stress a Factor. AB - Hair is a defining mammalian feature that serves as a hallmark of human communication. Given the critical significance of hair in social, religious, and political contexts, it is important to understand factors that play a role in hair loss disorders. The hair follicle is an immune privileged site, and mounting evidence suggests that the collapse of immune privilege contributes to the pathogenesis of autoimmune hair loss disorders, including alopecia areata and lichen planopilaris. This review comprehensively appraises the current literature to shed light on mechanisms for immune privilege collapse, and examines the role of neurogenic stress in triggering this process. PMID- 30410893 TI - Brachyonychia Associated with Acroosteolysis in Chronic Kidney Disease: How Phalange Shape Influences Nail Morphology. AB - Brachyonychia is a rare manifestation in patients with chronic kidney disease. Longtime disease, secondary hyperparathyroidism, and hemodialysis are common conditions among those who present it. We evaluated 8 cases who presented brachyonychia in the nephrology department and compared the clinical versus the radiographic findings, and evaluated how the tissue adjusts to the underlying bone structure, giving different forms to the nails. We conclude that brachyonychia and acroosteolysis in chronic kidney disease suggest long-term disease, secondary hyperparathyroidism, and hemodialysis, besides it being a good model on how the bony structure defines the soft tissue morphology. PMID- 30410895 TI - Hormonal and Gynecological Risk Factors in Frontal Fibrosing Alopecia: A Case Control Study. AB - Introduction: Frontal fibrosing alopecia (FFA) is a condition that likely involves an interplay of autoimmune, hormonal, and environmental factors in its pathogenesis. There is a lack of comparative studies demonstrating the presence of hormonal background differences in FFA patients compared to the general population. Materials and Methods: A single-center case-control study was designed, including 104 female FFA patients and 208 controls. Patients and controls were interviewed, and extensive data regarding their gynecological and hormonal background were recorded. Results: One hundred four cases and 208 age matched controls were included in the study. A significant difference of 2 years in the age of menopause was detected with a consistent mean increase in fertile life for the control group of 1.7 years. After the multivariate analysis, we found previous intake of tamoxifen to be a risk factor for the development of FFA (OR 14.89). The only protective factor identified was the previous use of an intrauterine device (IUD) (OR 0.22). Conclusions: An earlier menopause and tamoxifen intake might promote or maintain FFA, while the use of an IUD might protect from developing FFA. Our results support the previously proposed hypothesis of an underlying hormonal mechanism in the etiopathogenesis of FFA and point out low-estrogen environments as an ideal condition for FFA development. PMID- 30410894 TI - Evaluation of the Expression of Genes Associated with Inflammation and Apoptosis in Androgenetic Alopecia by Targeted RNA-Seq. AB - Androgenetic alopecia (AGA) or male pattern baldness is the most common form of hair loss in humans. Despite being a very frequent dermatological entity, molecular pathophysiology remains unclear. Several authors relate the presentation of AGA with a premature apoptotic process during the anagen phase and with an inflammatory microenvironment in the hair follicle. We evaluated a panel of 30 genes associated with inflammation and apoptosis in 5 AGA patients by targeted RNA-Seq. WNT7A gene was highly expressed in patients in stages 3V to 5 on the Hamilton-Norwood scale compared to patients with 5A stage. CASP7 and TNF genes were overexpressed in stages 3V and 4 compared to stages 5 and 5A. Overexpression of these genes detected only at early stages of AGA proves the role of WNT pathway, apoptosis, and inflammation in the development of this disorder. PMID- 30410897 TI - Hidradenitis Suppurativa: An Asian Perspective from a Singaporean Institute. AB - Background: Demographic studies of hidradenitis suppurativa (HS) in Western countries have found an association with the female gender and with co morbidities, such as the metabolic syndrome. There are few studies in an Asian context. Objective: This study examines the characteristics of HS at a Singaporean institute and compares them to those of existing studies in the West. Methods: We report a series of 58 patients with HS seen at the University Dermatological Clinic, National University Hospital, Singapore, over a 13-year period between January 2004 and December 2016. Results: Of 58 patients, 34 were male (58.6%). The axilla was the most common site affected, followed by the groin and buttocks. We did not find significant differences in disease characteristics between males and females, such as disease severity or location of disease. Metabolic co-morbidities were common, although paediatric-onset HS patients were less likely to be overweight, obese or smokers. Conclusion: The higher proportion of male HS patients in our cohort compared to the West may reflect differences in the prevalence of obesity and smoking in the 2 populations. Metabolic co morbidities were similarly prevalent in both adult and paediatric HS patients. These findings offer insight into the factors influencing the development of HS. PMID- 30410896 TI - Frontal Fibrosing Alopecia Severity Index: A Trichoscopic Visual Scale That Correlates Thickness of Peripilar Casts with Severity of Inflammatory Changes at Pathology. AB - Background: Frontal fibrosing alopecia (FFA) is a scarring alopecia that mainly affects postmenopausal women characterized by recession of the frontotemporal hairline and eyebrow loss. Current techniques to assess FFA activity are limited and involve noninvasive tools that assess disease progression or an invasive technique such as scalp biopsies. However, since progression of FFA is very slow, it is very important to develop a noninvasive technique to assess disease activity to monitor treatment response. Objectives: To provide a standardized and objective method to assess FFA activity. Methods: We evaluated the correlation between trichoscopy and pathological features (degree of lymphocytic infiltration) in 20 dermoscopy-guided biopsies of FFA. At trichoscopy, we divided the severity of peripilar casts into 3 grades according to their thickness. To validate the trichoscopic visual scale, we showed the images to 7 dermatologists with interest in hair diseases. Concordance was assessed using the Kendall Tau-b concordance test. Results: A strong correlation between severity of peripilar casts at trichoscopy and degree of lymphocytic infiltrate was observed by the Kendall Tau-b test. Validation showed very good inter- and intraobserver agreement. Conclusion: The trichoscopic visual scale allows noninvasive assessment of scalp inflammation in FFA in different scalp regions and therefore provides optimal guidance for treatment. PMID- 30410898 TI - Serum Levels of Interleukin-2 in Patients with Alopecia Areata: Relationship with Clinical Type and Duration of the Disease. AB - Background: Alopecia areata (AA) is a disease characterized by focally, nonscarring hair loss on the scalp or any hair-bearing surface. The etiology is unknown, although the evidence suggests that AA is an immunologically mediated disease. In the pathogenesis of AA, Th1 immune response is predominant. A special cytokine profile is created by Th1 cells, which disturbs the natural balance of the cytokine networks and leads to inflammatory reaction and follicle damage. Objective: The aim of our study was to evaluate serum concentrations of IL-2 in patients with AA and healthy subjects. We also examined a possible association between serum levels of IL-2, disease severity, and duration of AA. Methods: Sixty patients with AA and 20 healthy controls were enrolled in the study. Serum concentrations of IL-2 were measured using enzyme-linked immunoassay techniques. Results: Comparison of mean values of IL-2 has showed that serum concentrations of this cytokine are significantly higher in serum samples of AA patients in relation to the control group (22.2 +/- 1.19 vs. 21.1 +/- 2.68 pg/mL, respectively; p = 0.0142). No correlations were found between clinical type, duration of the disease, and serum levels of IL-2. Conclusion: Our findings support the evidence that elevation of serum IL-2 is associated with AA. The exact role of serum IL-2 in AA should be additionally investigated in future studies. PMID- 30410899 TI - Dermoscopic Findings and Their Therapeutic Implications in Trichostasis Spinulosa: A Retrospective Study of 306 Patients. AB - Background: Data about the contribution and the implications of dermoscopy in trichostasis spinulosa (TS) are lacking in the literature. Objective: To describe dermoscopic features of TS in a large sample of patients and to correlate dermoscopy with clinical characteristics of the patients and therapeutic responses to medical treatments. Methods: A descriptive study was conducted (from October 2015 to June 2016) at the Department of Dermatology of Fez in Morocco. Dermoscopic signs were divided into signs of hair retention (SHR) and follicular keratosis (FK). Results: SHR was severe in 8.8% and minimal in 40.5% of all cases. Vellus hairs were observed in 81.6% of all cases and hair tufts were described in 48.7%. Dermoscopic blackhead-like structures (DBH) were found in 53.9% of all cases. FK was observed as orange-yellowish keratotic plugs in 92.7% of all cases. Therapeutic demand was significantly related to female gender (p = 0.002) and recurrences after medical treatment (p = 0.004). Complete improvement after medical treatment was only described in patients with DBH and minimal SHR (p = 0.001). Conclusion: Dermoscopy not only increases the accuracy of the clinical diagnosis in TS, but a new description of dermoscopic classification has also been proposed leading to therapeutic implications. PMID- 30410900 TI - Clinical and Videodermoscopic Evaluation of the Efficacy, Safety, and Tolerability of a Shampoo Containing Ichthyol, Zanthalene, Mandelic Acid, and Honey in the Treatment of Scalp Psoriasis. AB - Purpose of the Study: The aim of the present prospective multicenter open study was to clinically and instrumentally evaluate the efficacy, safety, and tolerability of a shampoo, Mellis Cap(r) shampoo, containing ichthyol, zanthalene, mandelic acid, and honeydew honey in the treatment of mild to moderate scalp psoriasis. Procedures: Thirty subjects with mild to moderate psoriasis applied the shampoo three times a week for 12 weeks. The outcome was evaluated at 30 days (T1), 60 days (T2), and 90 days (T3) of treatment, comparing it to baseline (T0) by means of clinical and patients' evaluation, digital photographs, and videodermoscopy. Results: Clinical and patients' evaluation showed improvement of scalp psoriasis and itching. This was confirmed by videodermoscopy analysis with a significant reduction of scalp psoriasis severity at T2 and T3 compared to baseline. No side effects were observed or reported. Conclusions: Study treatment was well tolerated and showed significant clinical and instrumental improvement of scalp psoriasis. Mellis Cap(r) shampoo is a good alternative to other medicated shampoos in the treatment of mild to moderate scalp psoriasis. PMID- 30410901 TI - The Spectrum and Sequelae of Acne in Black South Africans Seen in Tertiary Institutions. AB - Introduction: Acne is a chronic disorder of the pilosebaceous unit affecting all ethnic groups. It remains in the top 5 skin conditions seen worldwide. The paucity of data characterizing acne in South African Blacks led us to the documentation of types and sequelae of acne. Methods: This is a cross- sectional study describing the spectrum and variants of acne in 5 tertiary hospitals in the second most populous province in South Africa over 3 months (January 1 - March 31, 2015). Results: Out of 3,814 patients seen in tertiary dermatology clinics, 382 (10%) had a primary diagnosis of acne or rosacea, forming the fourth most common condition seen. Acne accounted for 361 (94.5%); acne vulgaris was the commonest subtype at 273 (75.6%), followed by steroid-induced acne 46 (12.7%), middle-age acne 6 (1.7%), acne excoriee 2 (0.6%), and "undefined" 34 (9.4%). Conclusion: The observation of steroid-induced acne as the second most common variant in Black patients underlines the need to enquire about steroid use and education about the complications of using steroid-containing skin-lightening creams. Treatment of postinflammatory hyperpigmentation should be part of the armamentarium for holistic acne treatment in Blacks, as it remains a major concern even after active acne has resolved. PMID- 30410902 TI - Evaluation of Hair Density in Different Ethnicities in a Healthy American Population Using Quantitative Trichoscopic Analysis. AB - Background: There is limited research into normative hair density values in individuals of Hispanic descent. Methods: In order to help establish baseline density values in these individuals, we evaluated the hair density in 99 Americans of Hispanic descent and compared them with the values in 44 individuals of African descent and 23 Caucasians. Participants were recruited from a New York City medical center and self-identified their ethnicity. Biracial individuals were excluded from the study. Results: The hair density means +/- SD ranged from 169 +/- 31 to 178 +/- 33/cm2 in Americans of Hispanic descent, from 148 +/- 25 to 160 +/- 27/cm2 in individuals of African descent, and from 214 +/- 28 to 230 +/- 33/cm2 in Caucasian individuals. All differences in hair densities between the ethnicities were statistically significant (p values ranging from 3.03 * 10-14 to 0.0249). Conclusion: While trichoscopy is not as accurate as invasive histological assessment of hair density or phototrichogram, it is still a reliable and fast method for assessing hair density. Increased awareness of ethnic variances in hair density can help clinicians and researchers diagnose hair disorders, monitor response to therapy, and conduct hair-related research in these patients. PMID- 30410903 TI - Brunsting-Perry Type Pemphigoid Causing Secondary Cicatricial Alopecia in 2 Patients. AB - Brunsting-Perry type pemphigoid (BPP) is a rare subepidermal blistering disease and a cause of secondary cicatricial alopecia. It was originally described by Brunsting and Perry in 1957 as a rare variant of cicatricial pemphigoid, characterized by bullous lesions limited to the head, neck, scalp, and upper trunk with mild or no mucosal involvement. We report 2 cases of BPP cicatricial alopecia with histopathology of subepidermal blister formation, different clinical presentation, and different salt-split test results. One patient had features of bullous pemphigoid (BP) with important oral mucosal involvement (not yet reported in the literature), and the second patient had typical features of epidermolysis bullosa acquisita (EBA). The secondary cicatricial alopecia may be due to different antigens associated with either BP or EBA. The phenomenon of epitope spreading could explain the association between 2 distinctive bullous diseases in the same patient, justifying the divergent findings of the immunofluorescence. The specific target antigen of BPP is yet to be defined. PMID- 30410905 TI - Asymmetric Acral Spared Phenomenon Related to Systemic Anticancer Therapies. AB - We have observed three patients on anticancer therapies presenting with asymmetric acral spared phenomenon and found six identical cases in the literature. All of them had common features, an alteration of the peripheral nerves affecting a limb unilaterally that was spared by a hand-foot syndrome or hand-foot skin reaction. A drug-induced neurotropic effect sounds logical for developing such alterations with specific chemotherapeutic agents (taxanes, cap ecitabine), while we have not found good explanations concerning the multikinase inhibitor sorafenib nor the topo isomerase inhibitor adriamycin. Nevertheless, we know that clinical manifestations of many inflammatory diseases need intact neural components. PMID- 30410904 TI - Isolated Nail Pigmentation Associated with Chikungunya: A Hitherto Unreported Manifestation. AB - Chikungunya (CHK) fever is a re-emerging RNA viral infection caused by the bite of infected Aedes mosquitoes which presents with a multitude of mucocutaneous manifestations, including a characteristic morbilliform rash, centrofacial pigmentation, aphthae-like lesions, and vesiculobullous lesions sparing mucosae. The majority of these lesions resolve spontaneously and do not require specific therapy. With regular and cyclical outbreaks in many countries for many decades, it is obligatory for dermatologists to be aware of the different skin lesions in the wake of early diagnosis and the need for conservative management. We report 2 cases from India developing isolated melanonychia with CHK fever. PMID- 30410906 TI - The Trichoscopic "Golf Club Set" Sign for Bullous Aplasia Cutis Congenita. AB - Bullous aplasia cutis congenita (BACC) is a rather uncommon entity. The diagnosis can be quite tricky as the entity is not very frequent. Trichoscopy might in these cases be helpful to achieve the correct diagnosis. In this article, we describe for the first time a new sign for BACC that we believe can be useful to arrive at the correct diagnosis. PMID- 30410907 TI - Alopecia Areata and Habit Tic Deformities. AB - Nail involvement is a very common finding in patients with alopecia areata (AA). Most commonly evidenced by nail pitting, nail abnormalities can affect up to 66% of AA patients. We present two cases of the unusual association between habit tic nail deformities and AA. PMID- 30410909 TI - Longitudinal Half-and-Half Nails: Case Report and Review. AB - Half-and-half nails were originally described as a transverse leukonychia in patients with chronic renal disease; other conditions (such as Behcet's and Crohn's disease) and medications (such as isoniazid) have also been associated with the nail changes. However, longitudinal half-and-half nails (affecting the medial aspects of the nails) have previously been reported on the great toes of an older woman and, in the present case, on the thumbs of an elderly man; neither person had Behcet's, Crohn's, or kidney disease or was receiving isoniazid. The woman had a true leukonychia, bilateral hallux valgus deformity, and chronic trauma to her medial nail folds. The man had a nontraumatic apparent leukonychia and bilateral koilonychia; the non-white lateral area of his left thumb also had a linear groove (resulting from a digital mucous cyst on the proximal nail fold) and subun gual hyperkeratosis. In conclusion, longitudinal half-and-half nails are a rare phenomenon that has not been associated with either a systemic disease or medication; the acquired nail change can present either as an idiopathic finding or occur secondary to chronic trauma. PMID- 30410908 TI - Onychogryphosis: Case Report and Review of the Literature. AB - Onychogryphosis is a disorder of nail plate growth that is clinically characterized by an opaque, yellow-brown thickening of the nail plate with associated gross hyperkeratosis, elongation, and increased curvature. It is most common in older adults and patients with poor personal care. It is a relatively common and important condition because patients may suffer from pain, secondary complications, and cosmetic concerns. We present the case of a 67-year-old man with a 30-year history of severe thickening, abnormal growth, and yellow discoloration of his left great toenail, clinically consistent with onychogryphosis. This review highlights the etiology, diagnosis, and treatment options for onychogryphosis. PMID- 30410910 TI - Hyperpigmented Upper Eyelid: A Clue to the Diagnosis of Facial Lichen Planus Pigmentosus in a Patient with Frontal Fibrosing Alopecia. AB - Facial lichen planus pigmentosus (LPPig), a rare variant of classic lichen planus, was first described in patients with frontal fibrosing alopecia (FFA) by Dlova [Br J Dermatol 2013; 168: 439-442] in 2013. The diagnosis of facial LPPig is sometimes not easy, since clinical signs and histopathological features may frequently be confused with melasma or postinflammatory hyperpigmentation. We describe a case of a postmenopausal black woman diagnosed with FFA who presented with an identical brown-grayish pigmentation of the face and upper eyelids and typical dermoscopy analysis on both regions. We suggest that the hyperpigmentation of the upper eyelid with typical LLPig dermoscopy (upper eyelid sign) may be a clue for the diagnosis of LPPig and may avoid a scar-causing face biopsy. PMID- 30410911 TI - Epidermolysis Bullosa Pruriginosa Associated with Folliculitis Decalvans: Case Report and Review of the Literature. PMID- 30410912 TI - Trichoteiromania: An Atypical Case Associated with the Claude Bernard Horner Syndrome. PMID- 30410913 TI - Comment on the Use of Biotin for Hair Loss. PMID- 30410914 TI - Do Not Hurt the Nail Matrix: Safe Technique for Proximal Nail Fold Incision. PMID- 30410916 TI - Central Frontoparietal Band-Like Alopecia in a 40-Year-Old Woman. PMID- 30410915 TI - Use of Minoxidil Sulfate versus Minoxidil Base in Androgenetic Alopecia Treatment: Friend or Foe? PMID- 30410917 TI - Chronic Crusted Scalp Lesion of an Elderly Male. PMID- 30410918 TI - Extracellular Vesicles Secreted by Hypoxic AC10 Cardiomyocytes Modulate Fibroblast Cell Motility. AB - Extracellular vesicles (EVs) are small membrane vesicles secreted by most cell types with important roles in cell-to-cell communication. To assess their relevance in the context of heart ischemia, EVs isolated from the AC10 ventricular cardiomyocyte cell line (CM-EVs), exposed to normoxia (Nx) or hypoxia (Hx), were incubated with fibroblasts (Fb) and endothelial cells (EC). CM-EVs were studied using electron microscopy, nanoparticle tracking analysis (NTA), western blotting and proteomic analysis. Results showed that EVs had a strong preference to be internalized by EC over fibroblasts, suggesting an active exosome-based communication mechanism between CM and EC in the heart. In Matrigel tube-formation assays, Hx CM-EVs were inferior to Nx CM-EVs in angiogenesis. By contrast, in a wound-healing assay, wound closure was faster in fibroblasts treated with Hx CM-EVs than with Nx CM-EVs, supporting a pro-fibrotic effect of Hx CM-EVs. Overall, these observations were consistent with the different protein cargoes detected by proteomic analysis under Nx and Hx conditions and the biological pathways identified. The paracrine crosstalk between CM-EVs, Fb, and EC in different physiological conditions could account for the contribution of CM EVs to cardiac remodeling after an ischemic insult. PMID- 30410919 TI - Evaluation of Arsenic, Cadmium, Lead and Mercury Contamination in Over-the Counter Available Dry Dog Foods With Different Animal Ingredients (Red Meat, Poultry, and Fish). AB - Objectives: To examine the relative levels of heavy metals and arsenic content in commercial dog foods (arsenic, cadmium, lead and mercury) of 51 over-the-counter maintenance or all-life-stage dry dog foods. All products were chosen and segregated based on meat sources (fish, poultry, red-meat-17 products from each category) as animal protein sources being the primary contaminated ingredient due to bioaccumulation. Methods: Inductively coupled plasma mass spectrometry (ICP MS) was performed on products that were classified as fish, red meat (beef, pork, venison, bison) or poultry (chicken, turkey, duck) based. A non-Gaussian data distribution for each heavy metal within category distribution led to non parametric statistical testing and median (range) descriptive statistics. Comparison to average human consumption based on mg/megacalorie (Mcal)was also examined. Results: Based on caloric consumption, total arsenic and heavy metal consumption is higher in dogs than in humans; however chronic toxic exposure levels are highly unlikely. Fish-based diets had significantly higher arsenic, cadmium and mercury content than the poultry or red meat-based diets (p < 0.01). Red meat-based diets (beef, venison and bison) had higher lead concentrations than poultry and fish-based diets (p < 0.03). Clinical Significance: Based on the findings, commercial dog foods appear to be safe for chronic consumption and concentrations of the heavy metals were dependent on primary protein sources. Overall, poultry-based diets had relatively lower heavy metal and arsenic content than red meat and fish-based diets. Despite the safety of most pet foods occasional outliers for lead render some concern for chronic exposure based on other species toxicity data and a lack of data in dogs. PMID- 30410921 TI - Prevalence of Depression and Its Associated Factors among Orphan Children in Orphanages in Ilu Abba Bor Zone, South West Ethiopia. AB - Introduction: Orphans are the special group of children who are generally deprived and prone to develop psychiatric disorders even those reared in well-run institutions. These children and adolescents living as orphans or in stigmatized environments are vulnerable because of the loss of parent figures. The HIV/AIDS epidemic has contributed to a drastic increase in the number of orphans and vulnerable children and other causes in sub-Saharan Africa. However, little is known about the prevalence of depression and associated factors among orphanage children in areas such as Ethiopia. Objective: The aim of this study was to assess the prevalence of depression and its associated factors among orphans in Ilu Abba Bor Zone orphanages, 2016. Methods: An institutional based cross sectional study was conducted among orphan children in orphanages at Mettu and Gore. A total of 220 orphans were included from the two orphanages and make the response rate of 98.2%. Pretested semistructured questionnaire was used for interviewing the study participants. The collected data were coded, entered into EPI-INFO 7.0. Software, and exported to SPSS version 20 for statistical analysis. The strength of association between variables was assessed using crude and Adjusted Odds Ratio by running logistic regression and the cut-off point for declaring statistical significance was P- value <0.05 or 95% confidence interval which does not contain the null value. Results: A total of 216 orphan children were interviewed with response rate of 98.2%. The overall prevalence of depression was 24.1%. The mean age of participants was 14.2 years +/- 9.90 SDs and range from 11 to 17 years. Sex [Adjusted Odds Ratio = 3.29, 95% CI (1.41, 7.46)]; age [Adjusted Odds Ratio=2.09,95% CI (3.7; 5.01)]; duration of stay in foster care [Adjusted Odds Ratio= 2.08 (1.01; 8.33)]; previous physical abuse [Adjusted Odds Ratio= 3.1 (2.1; 5.06)]; having medical illness [Adjusted Odds Ratio=1.94,95% CI (2.01;3.56)]; orphan status [Adjusted Odds Ratio=2.5,95% CI (1.62; 3.56)]; and suicidal tendency [Adjusted Odds Ratio= 4.8 (3.41; 9.03)] were independent predictors of depression among orphans in orphanages. Conclusion and Recommendations: Prevalence of depression was high among orphans and this finding suggests that screening for depression and mental and psychological care should be integrated into routine health care provided to orphans and that there is a further need to establish preventive measures against depression. PMID- 30410922 TI - Prognostic Significance of Neutrophil-to-Lymphocyte Ratio for Repeat Cerclage in Women with Prolapsed Membranes. AB - Objective: Cerclage is a surgical option for preventing preterm birth (PTB). Repeat cerclage (RC) could prevent impending PTB in women with prolapsed membrane who already had primary cerclage. PTB is associated with a state of inflammation. It has been widely known that neutrophil-to-lymphocyte ratio (NLR) and platelet to-lymphocyte ratio (PLR) reflect systemic inflammation. We aimed to investigate whether NLR and PLR could be used as reliable markers in predicting pregnancy outcome following RC. Methods: The study group consisted of 26 patients, who underwent RC resulting from prolapsed membrane after primary cerclage. NLR and PLR at the time of primary cerclage and RC were calculated. ROC curve analysis and multivariate analysis were performed for determining predictive factors. The study group was divided into two groups according to NLR 4.7 at RC: High NLR group was defined as NLR > 4.7, and low NLR group was defined as NLR <= 4.7. We compared pregnancy outcomes, such as delivery at gestational age, and rate of delivery < 28 weeks between two groups. Results: The average gestational age at primary cerclage was 15.7 weeks, and the mean gestational age at RC was 21.0 weeks. NLR at RC was significantly elevated when compared with NLR at primary cerclage (NLR, 4.0 vs. 8.9, p=0.001), but there was no significant difference in terms of PLR (p=0.07). ROC curve showed that there was a significant prediction power of NLR at RC for delivery < 28 weeks (AUC, 0.91; p<0.01). Using NLR cut-off of 4.7, 8 had NLR <= 4.7 (low NLR group), whereas 18 had NLR > 4.7 (high NLR group). High NLR group showed worse pregnancy outcome compared to low NLR group: there were significant differences in gestational age at delivery, and neonatal survival rate between two groups (31.5 weeks vs. 25.9 weeks, p=0.02; 100% (8/8) vs. 55.6% (10/18), p=0.03, respectively). Survival analysis demonstrated a lower incidence of delivery < 28 weeks of gestation in low NLR group compared with high NLR group (p<0.01, log-rank test). Conclusion: NLR might be used as a reliable factor for predicting pregnancy outcome following RC. PMID- 30410920 TI - Bovine Leukemia Virus Infection in Neonatal Calves. Risk Factors and Control Measures. AB - Bovine leukemia virus (BLV) is the causative agent of enzootic bovine leukosis (EBL). Although efficient eradication programs have been successfully implemented in most European countries and Oceania, BLV infection rates are still high worldwide. BLV naturally infects cattle, inducing a persistent infection with diverse clinical outcomes. The virus infects lymphocytes and integrates a DNA intermediate as a provirus into the genome of the cells. Therefore, exposure to biological fluids contaminated with infected lymphocytes potentially spreads the virus. Vertical transmission may occur in utero or during delivery, and about 10% of calves born to BLV-infected dams are already infected at birth. Most frequently, transmission from dams to their offspring occurs through the ingestion of infected colostrum or milk. Therefore, although EBL is not a disease specific to the neonatal period, during this period the calves are at special risk of becoming infected, especially in dairy farms, where they ingest colostrum and/or raw milk either naturally or artificially. Calves infected during the first week of life could play an active role in early propagation of BLV to susceptible animals. This review discusses the main factors that contribute to neonatal BLV infection in dairy herds, as well as different approaches and management practices that could be implemented to reduce the risk of BLV transmission during this period, aiming to decrease BLV infection in dairy herds. PMID- 30410923 TI - Simultaneous Transepithelial Topography-Guided Photorefractive Keratectomy and Accelerated Cross-Linking in Keratoconus: 2-Year Follow-Up. AB - Purpose: To evaluate the visual, refractive, and topographic outcomes after simultaneous topography-guided transepithelial photorefractive keratectomy (transepithelial TG-PRK) using the Amaris Excimer laser platform and accelerated corneal cross-linking (CXL) in eyes with keratoconus. Materials and Methods: Patients with 2 years of follow-up were included in this retrospective case series. Manifest refraction (MR), uncorrected (UDVA) and corrected (CDVA) distance visual acuity, corneal topography, and pachymetry were evaluated at 1, 3, 6, 12, and 24 months after surgery. The root-mean-square of total higher-order aberrations (total HOA-RMS), coma (Coma-RMS), and spherical aberration (SA-RMS) were calculated for 4- and 6-mm diameters. Results: Forty-six eyes of 46 patients were included in the study. Stromal ablation was <=50 MU in all patients. MR was 3.78+/-3.26 preoperatively and -1.39+/-1.82 postoperatively. Significant improvements were seen in the UDVA and Coma-RMS values at 1 month, CDVA and total HOA-RMS values at 3 months, and SA-RMS values at 1 year compared to preoperative levels. UDVA values further improved after 2 years, compared to the 1-year values. No patient lost two or more lines and keratoconus progression was not observed in any patient. Conclusion: Simultaneous transepithelial TG-PRK and accelerated CXL resulted in significant gains in CDVA without compromising CXL efficacy. PMID- 30410924 TI - Linezolid Inhibited Synthesis of ATP in Mitochondria: Based on GC-MS Metabolomics and HPLC Method. AB - Linezolid has been widely used in serious infections for its effective inhibiting effect against multidrug-resistant gram-positive pathogens. However, linezolid caused severe adverse reactions, such as thrombocytopenia, anaemia, optic neuropathy, and near-fatal serotonin syndrome. In order to investigate the toxicity of linezolid, twenty-four Sprague-Dawley rats were randomly divided into: control group (n=7), low-group (n=8), and high-group (n=9). The rats of low group and high-group were given by gavage with linezolid 60 and 120 mg/kg/day for 7 days, respectively. The serum concentration of linezolid was determined by high performance liquid chromatography (HPLC); blood metabolic change was analyzed by gas chromatography-mass spectrometer (GC-MS). Adenosine triphosphate (ATP) concentration in HepG2-C3A after being cultured with linezolid was determined by HPLC. The results showed that there were six metabolites and nine metabolites had statistical differences in low-group and high-group (P<0.05). The trimethyl phosphate was the most significant indicator in those changed metabolites. Except for d-glucose which was slightly increased in low-group, octadecanoic acid, cholest-5-ene, hexadecanoic acid, alpha-linolenic acid, eicosapentaenoic acid, 9,12-Octadecadienoic acid, and docosahexaenoic acid were all decreased in low group and high-group. ATP concentration was decreased in HepG2-C3A after cultured with linezolid. In conclusion, the toxicity of linezolid is related to its serum concentration. Linezolid may inhibit the synthesis of ATP and fatty acid. PMID- 30410925 TI - Preliminary Evaluation of Thulium Doped Fiber Laser in Pig Model of Liver Surgery. AB - Partial liver resection is a treatment of choice for liver tumors; the range of parenchyma excision varies from a small part of the tissue surrounding the neoplasm up to 70% of the organ. One of the major concerns during liver resection is blood loss. Thulium lasers which are characterized by the length of emission wave corresponding to a peak absorption of water create a new possibility of cutting tissues efficiently with minimal thermal damage and concurrently providing a good hemostasis control. The aim of our study was to evaluate an impact of liver transection with thulium doped fiber laser on an intraoperative bleeding and histopathological changes during postoperative period in swine model. Ten animals were subjected to open surgery partial liver resection and an incision of liver tissue with an all-fiber, diode-pumped, and continuous-wave Tm3+-doped fiber laser emitting 37.4 W of output power at ~1.94 MUm wavelength. The macroscopic and histopathological evaluation was performed intraoperatively as well as 7 and 14 days after surgery. Macroscopically almost no bleeding was observed during surgery and no signs of bleeding were stated after 7 and 14 days. Histopathological analysis of the transection margin revealed a thermal damage area ranging in depth from 620.23 +/- 23.82 MUm on the day of surgery to 1817.70 +/- 211.98 MUm after 7 days. In the samples taken intraoperatively and after 7 days a superficial zone of carbonization was visibly separated from the deeper changes. After 14 days one 765.35 MUm deep zone characterized by a granulation was present. In conclusion, thulium doped fiber laser is efficacious in cutting with a narrow zone of thermal injury and provides a good hemostasis during liver transection, thus being a potential tool for oncotic liver surgery. PMID- 30410926 TI - Urinary Metabolomics Study of Patients with Gout Using Gas Chromatography-Mass Spectrometry. AB - Objectives: Gout is a common type of inflammatory arthritis. The aim of this study was to detect urinary metabolic changes in gout patients which may contribute to understanding the pathological mechanism of gout and discovering potential metabolite markers. Methods: Urine samples from 35 gout patients and 29 healthy volunteers were analyzed by gas chromatography-mass spectrometry (GC-MS). Orthogonal partial least-squares discriminant analysis (OPLS-DA) was performed to screen differential metabolites between two groups, and the variable importance for projection (VIP) values and Student's t-test results were combined to define the significant metabolic changes caused by gout. Further, binary logistic regression analysis was performed to establish a model to distinguish gout patients from healthy people, and receiver operating characteristic (ROC) curve was made to evaluate the potential for diagnosis of gout. Result: A total of 30 characteristic metabolites were significantly different between gout patients and controls, mainly including amino acids, carbohydrates, organic acids, and their derivatives, associated with perturbations in purine nucleotide synthesis, amino acid metabolism, purine metabolism, lipid metabolism, carbohydrate metabolism, and tricarboxylic acid cycle. Binary logistic regression and ROC curve analysis showed the combination of urate and isoxanthopterin can effectively discriminate the gout patients from controls with the area under the curve (AUC) of 0.879. Conclusion: Thus, the urinary metabolomics study is an efficient tool for a better understanding of the metabolic changes of gout, which may support the clinical diagnosis and pathological mechanism study of gout. PMID- 30410928 TI - AC-YVAD-CMK Inhibits Pyroptosis and Improves Functional Outcome after Intracerebral Hemorrhage. AB - Intracerebral hemorrhage (ICH) refers to bleeding in the brain and is associated with the release of large amount of inflammasomes, and the activation of different cell death pathways. These cell death pathways lead to removal of inactivated and damaged cells and also result in neuronal cell damage. Pyroptosis is a newly discovered cell death pathway that has gained attention in recent years. This pathway mainly depends on activation of caspase-1-mediated cascades to cause cell death. We tested a well-known selective inhibitor of caspase-1, AC YVAD-CMK, which has previously been found to have neuroprotective effects in ICH mice model, to ascertain its effects on the activation of inflammasomes mediated pyroptosis. Our results showed that AC-YVAD-CMK could reduce caspase-1 activation and inhibit IL-1beta production and maturation, but has no effect on NLRP3 expression, an upstream inflammatory complex. AC-YVAD-CMK administration also resulted in reduction in M1-type microglia polarization around the hematoma, while increasing the number of M2-type cells. Furthermore, AC-YVAD-CMK treated mice showed some recovery of neurological function after hemorrhage especially at the hyperacute and subacute stage resulting in some degree of limb movement. In conclusion, we are of the view that AC-YVAD-CMK could inhibit pyroptosis, decrease the secretion or activation of inflammatory factors, and affect the polarization of microglia resulting in improvement of neurological function after ICH. PMID- 30410927 TI - Papain Ameliorates the MPAs Formation-Mediated Activation of Monocytes by Inhibiting Cox-2 Expression via Regulating the MAPKs and PI3K/Akt Signal Pathway. AB - Monocytes activation and subsequent inflammatory response mediated by monocyte platelet aggregates (MPAs) formation play the key roles in the early pathogenesis of atherosclerosis (AS). Exploration of novel drugs to ameliorate MPAs formation mediated monocytes activation would be helpful for the treatment of AS patients. Papain has definite pharmacological effects including antiplatelet, thrombolysis, and anti-inflammation. However, its effect on MPAs formation and the following monocytes activation remains vague. This study aimed to illustrate the underlying mechanisms of papain on MPAs formation-initiated monocytes activation in vitro. In this study, Papain, Cox-2 inhibitor (NS-398), and NF-kappaB agonist (TNF alpha) were used as the treating agents, respectively. MPAs formation and activated monocytes were measured by flow cytometry (FCM). Cox-2 mRNA, MCP-1, and proteins of Cox-2 and NF-kappaB signal pathway were detected by qRT-PCR, ELISA, and western blotting, respectively. As we observed, papain exhibited the powerful inhibitory effects on thrombin-mediated MPAs formation and monocytes activation in a concentration-dependent manner as what Cox-2 inhibitor demonstrated. However, the inhibitory tendency was significantly reversed by TNF-alpha. We also discovered that both Cox-2 mRNA and protein expression as well as the release of MCP-1 of monocyte was inhibited by either papain or NS-398, but TNF-alpha stimulated Cox-2 expression and release of MCP-1. The results of western blotting assay indicated that thrombin-mediated proteins expression of MAPKs and PI3K/Akt signal pathway was inhibited by papain and NS-398. However, TNF-alpha notably abated the inhibitory effects of papain on the process of MPAs-initiated monocytes activation. Our findings suggest that papain can inhibit the MPAs formation-mediated activation of monocytes by inhibiting the MAPKs and PI3K/Akt signal pathway. PMID- 30410929 TI - Length Scale Matters: Real-Time Elastography versus Nanomechanical Profiling by Atomic Force Microscopy for the Diagnosis of Breast Lesions. AB - Real-time elastography (RTE) is a noninvasive imaging modality where tumor associated changes in tissue architecture are recognized as increased stiffness of the lesion compared to surrounding normal tissue. In contrast to this macroscopic appraisal, quantifying stiffness properties at the subcellular level by atomic force microscopy (AFM) reveals aggressive cancer cells to be soft. We compared RTE and AFM profiling of the same breast lesion to explore the diagnostic potential of tissue elasticity at different length scales. Patients were recruited from women who were scheduled for a biopsy in the outpatient breast clinic of the University Hospital Basel, Switzerland. RTE was performed as part of a standard breast work-up. Individual elastograms were characterized based on the Tsukuba elasticity score. Additionally, lesion elasticity was semiquantitatively assessed by the strain ratio. Core biopsies were obtained for histologic diagnosis and nanomechanical profiling by AFM under near-physiological conditions. Bulk stiffness evaluation by RTE does not always allow for a clear distinction between benign and malignant lesions and may result in the false assessment of breast lesions. AFM on the other hand enables quantitative stiffness measurements at higher spatial, i.e., subcellular, and force resolution. Consequently, lesions that were false positive or false negative by RTE were correctly identified by their nanomechanical AFM profiles as confirmed by histological diagnosis. Nanomechanical measurements can be used as unique markers of benign and cancerous breast lesions by providing relevant information at the molecular level. This is of particular significance considering the heterogeneity of tumors and may improve diagnostic accuracy compared to RTE. PMID- 30410930 TI - Safety of Natural Insecticides: Toxic Effects on Experimental Animals. AB - Long-term application and extensive use of synthetic insecticides have resulted in accumulating their residues in food, milk, water, and soil and cause adverse health effects to human and ecosystems. Therefore, application of natural insecticides in agriculture and public health sectors has been increased as alternative to synthetic insecticides. The question here is, are all natural insecticides safe. Therefore, the review presented here focuses on the safety of natural insecticides. Natural insecticides contain chemical, mineral, and biological materials and some products are available commercially, e.g., pyrethrum, neem, spinosad, rotenone, abamectin, Bacillus thuringiensis (Bt), garlic, cinnamon, pepper, and essential oil products. It can induce hepatotoxicity, renal toxicity, hematotoxicity, reproductive toxicity, neurotoxicity, and oxidative stress. It can induce mutagenicity, genotoxicity, and carcinogenicity in mammals. Some natural insecticides and active compounds from essential oils are classified in categories Ib (Highly hazardous) to U (unlikely toxic). Therefore, the selectivity and safety of natural insecticides not absolute and some natural compounds are toxic and induce adverse effects to experimental animals. In concussion, all natural insecticides are not safe and the term "natural" does not mean that compounds are safe. In this respect, the term "natural" is not synonymous with "organic" and not all-natural insecticide products are acceptable in organic farmers. PMID- 30410931 TI - Comparison of Elution Characteristics and Compressive Strength of Biantibiotic Loaded PMMA Bone Cement for Spacers: Copal(r) Spacem with Gentamicin and Vancomycin versus Palacos(r) R+G with Vancomycin. AB - Purpose: Copal(r) spacem is a new PMMA bone cement for fabricating spacers. This study compares elution of gentamicin, elution of vancomycin, and compressive strength of Copal(r) spacem and of Palacos(r) R+G at different vancomycin loadings in the powder of the cements. We hypothesized that antibiotic elution of Copal(r) spacem is superior at comparable compressive strength. Methods: Compression test specimens were fabricated using Copal(r) spacem manually loaded with 0.5 g gentamicin and additionally 2 g, 4 g, and 6 g of vancomycin per 40 g of cement powder (COP specimens) and using 0.5 g gentamicin premixed Palacos(r) R+G manually loaded with 2 g, 4 g, and 6 g of vancomycin per 40 g of cement powder (PAL specimens). These specimens were used for determination of gentamicin and vancomycin elution (in fetal calf serum, at 22 degrees C) and for determination of compressive strength both prior and following the elution tests. Results: Cumulative gentamicin concentrations (p < 0.005) and gentamicin concentration after 28 days (p <= 0.043) were significantly lower for COP specimens compared to PAL specimens. Cumulative vancomycin concentrations were significantly higher (p <= 0.043) for COP specimens after the second day. Vancomycin concentrations after 28 days were not significantly higher for the Copal specimens loaded with 2 g and 4 g of vancomycin. Compressive strength was not significantly different between COP specimens and PAL specimens before elution tests. Compressive strength after the elution tests was significantly lower (p = 0.005) for COP specimens loaded with 2 g of vancomycin. Conclusion: We could not demonstrate consistent superior antibiotic elution from Copal(r) spacem compared to Palacos(r) R+G for fabricating gentamicin and vancomycin loaded spacers. The results do not favor Copal(r) spacem over Palacos(r) R+G for the use as a gentamicin and vancomycin biantibiotic-loaded spacer. PMID- 30410932 TI - Comparative Analysis of the Gut Microbial Composition and Meat Flavor of Two Chicken Breeds in Different Rearing Patterns. AB - The objective of the study is to compare the effects of free-range (FR) and cage range (CR) breeding on gut microbiota and flavor compounds of Caoke (C) and Partridge Shank chickens (Q). A total of 120 experimental chickens were assigned to FR group and CR group; each group contain both 30 Caoke chickens and 30 Partridge Shank chickens. At 154 d old, 12 chickens of each group were selected and their cecal contents were extracted and examined for the composition of gut microbiota by illumina sequencing of the V3 region of the 16S rDNA genes, and flavor compounds were analyzed through headspace-solid-phase microextraction (HS SPME) method. The results showed that, except for acids, the amount of flavor substances in the FR group was higher than those in the CR group, especially the content of Hexanal and D-limonene. Meanwhile, the higher concentrations of carbonyls including (E,E)-2,4-decadienal, (E)-2-decenal, (E)-2-octenal, and pentanal were in the FR chicken meat, but the differences in concentrations compared with CR were not significant. High levels of ethyl hexanoate and beta ocimene were only detected in FR groups. The Firmicutes had the highest proportion of chicken cecal microbiota, whereas the Fusobacteria was only detected in the cecal samples of Q chicken in FR group. Actinobacteria was more prevalent in FR groups than in CR groups. Meanwhile, in Q chickens, the proportions of Bacteroidetes and Proteobacteria in FR group were higher than those in CR group. Using MG-RAST Subsystem Technology, we found that some genes were associated with the formation of precursors of flavor compounds or with the metabolism and degradation of aromatic compounds. Overall, CR and FR breeding influenced the gut microbiota and flavor compounds, potentially because of the changes in diet and living conditions. PMID- 30410933 TI - A Comparison between the Implant Stability Quotient and the Fractal Dimension of Alveolar Bone at the Implant Site. AB - Objectives: Fractal analysis of the radiographic pattern of bone has been used to evaluate its quantitative properties. However, the relation between initial implant stability and quality of bone remains unclear. The objective of this study was to evaluate RFA values in relation to the fractal dimension of bone where the implant was inserted. Material and Methods: A total of 50 two-stage dental implants were placed in the maxilla and mandible of 32 patients. After implant placement, an implant stability quotient (ISQ) was measured in two perpendicular planes. On intraoral digital periapical radiographs, three 35x35 pixels' regions of interest (ROIs) were chosen covering the bone adjacent to the neck (ROI 1), middle (ROI 2), and apical (ROI 3) part of the implant, respectively. For every ROI, a fractal dimension (FD) was calculated. A linear correlation, as well as a logistic regression analysis, was used to identify a possible relation between the ISQ and FD values for every ROI in the maxilla and mandible. Results: The ISQ and FD values were found to be correlated at ROI 1 for the maxilla. There was no linear correlation between ISQ and FD values in any of the three ROIs in the mandible. However, logistic regression analysis showed that in ROI 1 and ROI 3 the values of FD and ISQ are statistically important and may be used to express the difference between maxilla and mandible. Conclusion: The fractal dimension of alveolar bone measured from intraoral digital radiographs alone may be an insufficient parameter to determine initial implant stability. PMID- 30410936 TI - Chemical Composition and Enzymatic Screening of Micromeria fruticosa serpyllifolia Volatile Oils Collected from Three Different Regions of West Bank, Palestine. AB - Introduction: Volatile oils (VOs) have been commonly used in cosmetics and food as fragrances, flavoring, and preservative agents or in alternative medicine for their therapeutic effects. This necessitates investigating those plants and their VOs. This study was conducted to investigate the chemical compositions of the VOs of Micromeria fruticosa serpyllifolia growing widely in three regions in Palestine (i.e., Hebron, Ramallah, and Nablus districts representing south, middle, and north of West Bank). Afterwards, VOs were subjected to in vitro screening and their enzymatic properties were compared. Methods: The analysis of chemical components of VOs was performed by gas chromatography coupled with mass spectrometry (GC-MS). The antilipase activity was evaluated using porcine pancreatic lipase and p-nitrophenyl butyrate. The antiamylase activity was assessed using porcine pancreatic alpha-amylase, starch, and 3,5 dinitrosalicylic. Results: Plant extracts yield range was 0.67 to 0.99 w/w%. GC MS analysis showed the high percentages of oxygenated components in the range of 86.1-89.88% and nonoxygenated components in the range of 4.38-4.71%. Seven components were observed, pulegone was the most abundant component in the three samples in the range of 74.43-86.04%, and isomenthone was the second most abundant component with the range of 3.16-14.41%. The sample collected from Nablus showed the most potent antilipase and antiamylase activity with IC50 values of 39.81 MUg/mL and 3.31 MUg/mL, respectively. Conclusions: The study showed that Micromeria fruticosa serpyllifolia volatile oils samples from different regions in Palestine contained different proportions of phytochemicals which provided different potential biological activities such as antiobesity and antidiabetes activities that were in line with traditional uses of the plant extracts. The plant extracts showed higher antilipase and antiamylase potency than that of the relative references and there were significant differences in these activities compared to each other. PMID- 30410934 TI - Peri-Implant Bone Resorption during Healing Abutment Placement: The Effect of a 0.20% Chlorhexidine Gel vs. Placebo-A Randomized Double Blind Controlled Human Study. AB - Introduction: Peri-implant marginal bone loss (MBL) seems to be more pronounced in the first year of loading despite all the studies and changes implemented to reduce it. Among the different causes, the presence of a microgap makes the interface between fixture and abutment colonizable by bacteria, causing an inflammatory response and consequent bone resorption. To reduce this several local antiseptics like chlorhexidine digluconate (CHX) were used after surgical procedures. Aim: The objective was to radiologically compare the MBL when a 0.20% CHX gel or a placebo gel was applied to the implant-abutment interface during all surgical and prosthetic phases and for a follow-up period up to 12 months. Method: 32 patients (16 for each Group A and B) were enrolled and rehabilitated with a single implant (Cortex classic, Cortex, Shalomi, Israel). During each of the clinical stages a gel containing 0.20% CHX (Plak (r)Gel; Polifarma Wellness Srl, Rome, Italy) or a placebo gel (Placebo, Polifarma Wellness Srl, Rome, Italy) was used as indicated by the randomization chart. In order to compare radiographic modification intraoral radiographs was taken. Also, clinical data regarding implant or prosthetic failure and gingival index were recorded. Data were presented as means and standard deviations (SD) and used for the statistical analysis. Results: All implants showed no bleeding on probing and a very small plaque score at the 1 year of follow-up. MBL was statistically significantly different between the groups in every stage. Conclusion: Results obtained showed that the use of CHX gel inside the connection significantly reduces MBL during the first year. A rigid disinfection protocol with 0.20% CHX from the time of implant insertion to crown delivery is recommended to reduce host inflammatory response and consequently MBL. This trial is registered with ClinicalTrials.gov Identifier: (Registration Number: NCT03431766). PMID- 30410935 TI - Isolation, Structures, and Bioactivities of the Polysaccharides from Gynostemma pentaphyllum (Thunb.) Makino: A Review. AB - Polysaccharides obtained from Gynostemma pentaphyllum (Thunb.) Makino have promising prospects in functional food and nutraceuticals due to its broad range of biological activities including antioxidant, immunomodulatory, antitumor, hepatoprotective, neuroprotective, and antifatigue activities. These beneficial biological activities are related to chemical composition and structure of the G. pentaphyllum polysaccharides. The molecular weight, monosaccharide composition, and chemical structures could be influenced by both different extraction/purification techniques employed to obtain polysaccharide enriched products. The purpose of this article is to review previous and current literature regarding the extraction, purification, structural characterization, and biological activity of G. pentaphyllum polysaccharides. This review provides a useful bibliography for the further investigation, production, and application of G. pentaphyllum polysaccharides as functional foods and nutraceuticals. PMID- 30410937 TI - The Correlations of Plasma and Cerebrospinal Fluid Amyloid-Beta Levels with Platelet Count in Patients with Alzheimer's Disease. AB - Purpose: Recent study shows that blood-derived amyloid-beta (Abeta) can induce cerebral amyloidosis and is involved in the pathogenesis of Alzheimer's disease (AD). The vast majority of blood Abeta is generated from platelet. Whether blood Abeta levels are associated with the count of platelets remains unknown. Methods: 58 clinically diagnosed AD patients, 18 11C-PIB-PET diagnosed AD patients, and 61 age- and gender-matched cognitively normal controls were included to analyze the correlation of plasma Abeta levels with platelet count. 13 AD patients and 40 controls with cerebrospinal fluid (CSF) samples were included to further analyze the correlation of CSF Abeta levels with platelet count. Abeta40 and Abeta42 levels in plasma and CSF were measured by ELISA kits. Results: The plasma Abeta42 level was positively correlated with platelet count in both AD patients and control group, especially in AD patients with positive PIB-PET, while there was no correlation as to Abeta40. The CSF Abeta levels also had no significant correlation with platelet count. Conclusion: It suggests that platelets may be involved in the pathogenesis of AD and become a potential peripheral biomarker for AD. PMID- 30410939 TI - Inflammatory Myofibroblastic Tumors in Paranasal Sinus and Nasopharynx: A Clinical Retrospective Study of 13 Cases. AB - Background: Inflammatory myofibroblastic tumor (IMT), as a mesenchymal tumor, is common in the lung and abdomen but rare in the paranasal sinus and nasopharynx. Objective: This study aimed to summarize the clinical characteristics of IMT in the paranasal sinus and nasopharynx and analyze the relationship between the treatment and the overall survival (OS). Method: The clinical features, treatment, and follow-up data of patients diagnosed with IMT of the paranasal sinus or nasopharynx from 2006 to 2017 were retrospectively analyzed, and the previous literature was reviewed. Results: IMT often presents as an ill-defined soft-tissue mass with bone destruction and invasion of surrounding structures. The treatment methods used in this study were different combinations of surgery, prednisone, radiotherapy, and chemotherapy or observation alone. Three of the 13 patients were lost and the follow-up time of the remaining 10 cases ranged from 2 to 87 months (median, 39 months). Two patients died of the disease; the other eight patients were stable. The 5-year survival rate was 72%. Among the four methods of treatment, only treatment with prednisone was significantly correlated with better OS (P = 0.046). Conclusions: IMT is an intermediate tumor that often mimics malignancy. We are not sure if IMTs in the nasal cavity are more aggressive because of the biology or if the location and local therapy in the head region is more complicated. Radiologic findings help know the extent of the lesion. For unresectable nasal IMT, combined therapy with glucocorticoids, chemotherapy, and radiotherapy is sometimes a better choice. Glucocorticoids are especially recommended as a basic part of the integrated therapy. However, the standard treatment needs further research. PMID- 30410938 TI - The Role of Wnt Pathway in the Pathogenesis of OA and Its Potential Therapeutic Implications in the Field of Regenerative Medicine. AB - Introduction: Osteoarthritis (OA) is a degenerative joint disease characterized by articular cartilage degradation, subchondral damage, and bone remodelling, affecting most commonly weight-bearing joints, such as the knee and hip. The loss of cartilage leads to joint space narrowing, pain, and loss of function which could ultimately require total joint replacement. The Wnt/beta catenin pathway is involved in the pathophysiology of OA and has been proposed as a therapeutic target. Endogenous and pharmacological inhibitors of this pathway were recently investigated within innovative therapies including the use of platelet-rich plasma (PRP) and mesenchymal stem cells (MSCs). Methods: A review of the literature was performed on the PubMed database based on the following inclusion criteria: article written in English language in the last 20 years and dealing with (1) the role of Wnt-beta catenin pathway in the pathogenesis of osteoarthritis and (2) pharmacologic or biologic strategies modulating the Wnt beta catenin pathway in the OA setting. Results: Evidences support that Wnt signalling pathway is likely linked to OA progression and severity. Its inhibition through natural antagonists and new synthetic or biological drugs shares the potential to improve the clinical condition of the patients by affecting the pathological activity of Wnt/beta-catenin signalling. Conclusions: While further research is needed to better understand the mechanisms regulating the molecular interaction between OA regenerative therapies and Wnt, it seems that biologic therapies for OA exert modulation on Wnt/beta catenin pathway that might be relevant in achieving the beneficial clinical effect of those therapeutic strategies. PMID- 30410940 TI - Zerumbone-Loaded Nanostructured Lipid Carrier Induces Apoptosis of Canine Mammary Adenocarcinoma Cells. AB - Canine mammary gland tumor (CMT) is the most common tumor in intact female dog. Zerumbone (ZER) has promising anticancer properties, but plagued with poor water solubility, poor absorption, bioavailability, and delivery to target tissues. To solubilize, ZER was loaded into nanostructured lipid carrier (NLC) to produce ZER loaded NLC (ZER-NLC). The objectives of this study were to determine the antiproliferative effect and the mode of cell death induced by ZER-NLC and ZER on a canine mammary gland tumor (CMT) adenocarcinoma primary cell line. There was no significant difference (p>0.05) between ZER-NLC and ZER treatments in the inhibition of CMT cell proliferation; thus, the loading of ZER into NLC did not compromise the cytotoxic effect of ZER. Microscopically, ZER-NLC- and ZER-treated CMT cells showed apoptotic cell morphology. ZER-NLC and ZER treatments significantly downregulated the antiapoptotic Bcl-2 and upregulated the proapoptotic Bax gene expressions in CMT cells. Both ZER-NLC and ZER-treated CMT cells showed significant (p<0.0001) increases in caspase-8, -9, and -3/7 protein activities. In conclusion, ZER-NLC induced CMT cell death via regulation of Bcl-2 and Bax gene expressions and caspase activations, indicating the involvement of both the intrinsic and extrinsic pathways of apoptosis. This study provided evidences for the potential of ZER-NLC as an anticanine mammary gland adenocarcinoma chemotherapy. PMID- 30410941 TI - Combination Therapy with EpCAM-CAR-NK-92 Cells and Regorafenib against Human Colorectal Cancer Models. AB - Adoptive chimeric antigen receptor-modified T or NK cells (CAR-T or CAR-NK) offer new options for cancer treatment. CAR-T therapy has achieved encouraging breakthroughs in the treatment of hematological malignancies. However, their therapeutic efficacy against solid tumors is limited. New regimens, including combinations with chemical drugs, need to be studied to enhance the therapeutic efficacy of CAR-T or NK cells for solid tumors. An epithelial cell adhesion molecule- (EpCAM-) specific second-generation CAR was constructed and transduced into NK-92 cells by lentiviral vectors. Immune effects, including cytokine release and cytotoxicity of the CAR-NK-92 cells against EpCAM-positive colon cancer cells, were evaluated in vitro. Synergistic effects of regorafenib and CAR NK-92 cells were analyzed in a mouse model with human colorectal cancer xenografts. The CAR-NK-92 cells can specifically recognize EpCAM-positive colorectal cancer cells and release cytokines, including IFN-gamma, perforin, and granzyme B, and show specific cytotoxicity in vitro. The growth suppression efficacy of combination therapy with regorafenib and CAR-NK-92 cells on established EpCAM-positive tumor xenografts was more significant than that of monotherapy with CAR-NK-92 cells or regorafenib. Our results provided a novel strategy to treat colorectal cancer and enhance the therapeutic efficacy of CAR modified immune effector cells for solid tumors. PMID- 30410942 TI - Preclinical and Clinical Therapeutic Strategies Affecting Tumor-Associated Macrophages in Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) most often develops in patients with underlying liver disease characterized by chronic nonresolving inflammation. Tumor associated macrophages (TAMs) are one of the most abundant immune cell populations within the tumoral microenvironment. As key actors of cancer-related inflammation, they promote tumor growth by suppression of effective anticancer immunity, stimulation of angiogenesis, and tissue remodeling. Therefore, they have become an attractive and promising target for immunotherapy. The heterogeneity of TAM subtypes and their origin and dynamic phenotype during the initiation and progression of HCC has been partially unraveled and forms the base for the development of therapeutic agents. Current approaches are aimed at decreasing the population of TAMs by depleting macrophages present in the tumor, blocking the recruitment of bone marrow-derived monocytes, and/or functionally reprogramming TAMs to antitumoral behavior. In this review, the preclinical evolution and hitherto clinical trials for TAM-targeted therapy in HCC will be highlighted. PMID- 30410943 TI - A population-based comparison study of the mental health of patients with intentional and unintentional burns. AB - Background: A number of studies report high prevalence of mental health conditions among burn patients. However there is a need to understand differences in the temporal relationship between mental health conditions and intentional and unintentional burns to hasten psychological prevention and intervention. This study aims to compare the socio-demographic profile, burn characteristics and pre and post-burn psychiatric morbidity of burn patients by intent-of-injury. Methods: De-identified linked hospital, death and mental health (MH) case registry data of burn patients hospitalised in Western Australia between 1 January 1980 and 30 June 2012 were analysed. Crude (observed) post-burn rates of mental health admissions were generated by burn intent-of-injury. Descriptive statistics were performed to compare the characteristics of the burn patients. Results: A total of 30,997 individuals were hospitalised for a first burn; 360 (1.2%) had self-harm burns and 206 (0.7%) assault burns. Over the study period, admission rates for assault burns increased by 4.8% per year (95% confidence interval (CI) 3.1-6.5%) and self-harm burns increased 6.9% per year (95% CI 4.8 9.1%). Self-harm and assault burns occurred mainly among those aged 15 to 44 years (median age, interquartile range (IQR): self-harm 30 years, 22-40; assault 31 years, 23-38). Those with self-harm burns had a longer index hospital stay (median (IQR): self-harm 15 days (5-35) vs 4 days (1-11) assault vs 4 days (1-10) unintentional) and higher in-hospital mortality (7.2% self-harm vs 1.9% assault burns vs 0.8% unintentional). More than half (55.0%) of self-harm burns had a prior hospitalisation (5-year lookback) for a MH condition vs 10.7% of assault burns and 2.8% of unintentional burns. Crude post-burn rates of MH admissions per 100 person-years (PY) by intent-of-burn subgroups: self-harm 209 per 100 PY, assault burns 11 per 100 PY and unintentional burns 3 per 100 PY. Conclusions: Intentional burn patients experienced significantly higher pre- and post-burn mental health morbidity along with significant adverse outcome in comparison with unintentional burns. Early psychological assessment and intervention could help in improving the MH of these patients. PMID- 30410944 TI - Cellular therapy of the corneal stroma: a new type of corneal surgery for keratoconus and corneal dystrophies. AB - Cellular therapy of the corneal stroma, with either ocular or extraocular stem cells, has been gaining a lot of interest over the last decade. Multiple publications from different research groups are showing its potential benefits in relation to its capacity to improve or alleviate corneal scars, improve corneal transparency in metabolic diseases by enhancing the catabolism of the accumulated molecules, generate new organized collagen within the host stroma, and its immunosuppressive and immunomodulatory properties. Autologous extraocular stem cells do not require a healthy contralateral eye and they do not involve any ophthalmic procedures for their isolation. Mesenchymal stem cells have been the most widely assayed and have the best potential to differentiate into functional adult keratocytes in vivo and in vitro. While embryonic stem cells have been partially abandoned due to ethical implications, the discovery of the induced pluripotent stem cells (iPSC) has opened a new and very promising field for future research as they are pluripotent cells with the capacity to theoretically differentiate into any cell type, with the special advantage that they are obtained from adult differentiated cells. Cellular delivery into the corneal stroma has been experimentally assayed in vivo in multiple ways: systemic versus local injections with or without a carrier. Encouraging preliminary human clinical data is already available although still very limited, and further research is necessary in order to consolidate the clinical applications of this novel therapeutic line. PMID- 30410946 TI - Recurrent esophagogastric variceal bleeding due to portal vein thrombosis caused by protein S deficiency. AB - Background and study aims Esophagogastric variceal bleeding (EGVB) is common in patients with portal vein thrombosis (PVT). Hereditary deficiencies in natural anticoagulant proteins, such as protein S, might contribute to PVT. However, recurrent EGVB caused by PVT in patients with protein S deficiency is seldom reported. Herein, we present the case of a 38-year-old man with protein S deficiency complicated with PVT. The patient suffered recurrent EGVB for 7 years. He underwent splenectomy plus pericardial revascularization and sequential endoscopic therapy, including one gastric variceal obturation (GVO) procedure and two esophageal variceal ligations (EVL) to eradicate the varices. Rivaroxaban was administrated to reduce risk of thrombotic events. The patient is currently well without rebleeding after 1 year of follow-up. To our knowledge there is no consensus on management of recurrent EGVB on the basis of thrombophilia complicated with PVT. According to our practice, sequential endoscopic therapy combined with anticoagulant appears to be effective and safe. PMID- 30410945 TI - Microvascular blood flow velocities measured with a retinal function imager: inter-eye correlations in healthy controls and an exploration in multiple sclerosis. AB - Background: The retinal microcirculation has been studied in various diseases including multiple sclerosis (MS). However, inter-eye correlations and potential differences of the retinal blood flow velocity (BFV) remain largely unstudied but may be important in guiding eye selection as well as the design and interpretation of studies assessing or utilizing retinal BFV. The primary aim of this study was to determine inter-eye correlations in BFVs in healthy controls (HCs). Since prior studies raise the possibility of reduced BFV in MS eyes, a secondary aim was to compare retinal BFVs between MS eyes, grouped based on optic neuritis (ON) history and HC eyes. Methods: Macular arteriole and venule BFVs were determined using a retinal function imager (RFI) in both eyes of 20 HCs. One eye from a total of 38 MS patients comprising 13 eyes with ON (MSON) and 25 eyes without ON (MSNON) history were similarly imaged with RFI. Results: OD (right) and OS (left) BFVs were not significantly different in arterioles (OD: 3.95 +/- 0.59 mm/s; OS: 4.08 +/- 0.60 mm/s, P = 0.10) or venules (OD: 3.11 +/- 0.46 mm/s; OS: 3.23 +/- 0.52 mm/s, P = 0.06) in HCs. Very strong inter-eye correlations were also found between arteriolar (r = 0.84, P < 0.001) and venular (r = 0.87, P < 0.001) BFVs in HCs. Arteriolar (3.48 +/- 0.88 mm/s) and venular (2.75 +/- 0.53 mm/s) BFVs in MSNON eyes were significantly lower than in HC eyes (P = 0.009 and P = 0.005, respectively). Similarly, arteriolar (3.59 +/- 0.69 mm/s) and venular (2.80 +/- 0.45 mm/s) BFVs in MSON eyes were also significantly lower than in HC eyes (P = 0.046 and P = 0.048, respectively). Arteriolar and venular BFVs in MSON and MSNON eyes did not differ from each other (P = 0.42 and P = 0.48, respectively). Conclusions: Inter-eye arteriolar and venular BFVs do not differ significantly in HCs and are strongly correlated. Our findings support prior observations that arteriolar and venular BFVs may be reduced in MS eyes. Moreover, this seems to be the case in both MS eyes with and without a history of ON, raising the possibility of global blood flow alterations in MS. Future larger studies are needed to assess differences in BFVs between MSON and MSNON eyes. PMID- 30410947 TI - Green epithelium revealed by narrow-band imaging (NBI): a feature for practical assessment of extent of gastric cancer after H. pylori eradication. PMID- 30410948 TI - Comparison of outcomes for supine vs. prone position ERCP: a systematic review and meta-analysis. AB - Background While endoscopic retrograde cholangiopancreatography (ERCP) is usually performed in the prone position, some studies have advocated for ERCP in the supine position. Studies comparing the technical success and safety outcomes have shown variable results. We performed a systematic review and meta-analysis of studies reporting the comparison between the two positions for ERCP outcomes. Methods We conducted a search of electronic databases and conference proceedings including PubMed, EMBASE, and Web of Science databases (from inception through October 2016) to identify studies that reported the comparison of technical success and safety outcomes between supine and prone ERCP. The primary outcome was to estimate the pooled rates of technical success. The secondary outcome was to estimate the risks of complications, such as cardiopulmonary and post-ERCP pancreatitis (PEP). Results Six studies reporting on 309 supine and 1415 prone ERCPs were identified. The pooled technical success rates for completion of ERCP in supine and prone positions were 89.1 % (95 %CI = 80.9 - 94.0) and 95.6 % (95 %CI = 91.5 - 97.7), respectively. The pooled rates for complications (cardiopulmonary and PEP) in the supine position were 37.5 % (95 %CI = 19.1 - 60.3) and 3.5 % (95 %CI = 1.6 - 7.3), respectively. The pooled rates for complications (cardiopulmonary and PEP) in the prone position were 41.0 % (95 %CI = 20.9 - 64.8) and 3.9 % (95 %CI = 2.4 - 6.4), respectively. The mean time required for the procedure was 30 minutes and 29.8 minutes for supine and prone positions, respectively. Substantial heterogeneity was noted in the analysis. Conclusion Prone ERCPs have a higher technical success rate with a slightly lower mean duration but a higher number of adverse events. The decision with regard to patient position should be made after evaluating the overall clinical scenario. PMID- 30410949 TI - ADR evaluation of screening colonoscopies during 2016 - 2017 in a private health clinic in Peru. AB - Background and study aims High-quality colonoscopy is fundamental for preventing colorectal cancer (CRC). The adenoma detection rate (ADR) is a key colonoscopy quality measure. The aim of this study was to establish the screening colonoscopy ADR of a tertiary referral center in Peru, identify the relationship between the ADR and patient age, sex and the colonoscopist, and determine the endoscopic and histopathological characteristics of the lesions found. Patients and methods A retrospective observational longitudinal study was undertaken between January 2016 and June 2017. Results Eight colonoscopists performed screening colonoscopies on 620 patients scoring >= 6 points on the Boston Bowel Preparation Scale (BBPS); cecal intubation was complete in 595 patients (cecal intubation rate [CIR] 95.9 %). The overall ADR was 29.7 % (females 25.4 %, males 33.1 %, P = 0.040, 95 %Cl). The ADR colonoscopist range was 25.0 % to 34.4 %. The highest ADR (41.2 %, P = 0.013, 95 %Cl) was for patients aged 65 to 75 years. Adenoma colon locations were: left 49 %, transverse 21.6 % and right 29.4 %. Adenoma dysplasia grades: low 98 %, high 2 %. Sixty-three percent of the lesions were 5 mm to 10 mm. Resections performed: 78.5 % cold biopsy forceps (CBF), 3.4 % cold snare polypectomy (CSP) and 18.1 % endoscopic mucosal resection (EMR). Conclusions The ADR established was in line with the joint American College of Gastroenterology (ACG)/American Society for Gastrointestinal Endoscopy (ASGE) recommendations and related to patient age and gender but not to the colonoscopist. Colonoscopists should ensure rigorous application of the colonoscopy quality actions. ADR should be evaluated frequently. PMID- 30410950 TI - Single-operator cholangioscopy for diagnosis of cholangioadenoma (bile duct adenoma) and its potential impact on surgical management. AB - Background and study aims Cholangioadenoma is not recognized commonly and is often only diagnosed on surgical specimens. Direct per oral single-operator cholangioscopy (SOC) allows characterization of common bile duct (CBD) lesions through direct visualization and directed forceps biopsies with potential for impacting surgical management decisions. This is a retrospective review of all SOC cases diagnosed with cholangioadenoma. Patient demographics and outcomes were recorded. Three patients (all male), average age 68 years (range 62 - 76 years), were identified to have a cholangioadenoma. The clinical indication for SOC was deranged liver enzymes with a dilated CBD and a CBD abnormality identified on biliary imaging. The site of cholangioadenoma was proximal, mid and distal CBD, respectively. All patients had a successful SOC with targeted biopsy-proven diagnosis. One patient had a synchronous cholangiocarcinoma and underwent palliative stenting whereas the other two patients underwent appropriate curative resection based on cholangioadenoma location. We conclude that SOC is safe and effective for diagnosis of cholangioadenoma and has potential impact on decisions for surgical management. PMID- 30410951 TI - First-line endoscopic treatment with over-the-scope clips in patients with either upper or lower gastrointestinal bleeding: a multicenter study. AB - Background and study aims Endoscopic treatment is the mainstay approach for gastrointestinal bleeding, in either upper (UGIB) or lower (LGIB) tract. The over the-scope clip (OTSC) may overcome limitations of standard clips or thermocoagulation in high-risk bleeding lesions. We evaluate the main clinically relevant outcomes following endoscopic hemostasis with OTSC in high-risk lesions and/or patients. Patients and methods This was a retrospective analysis of prospectively collected databases including all patients with UGIB and LGIB who underwent OTCS placement as first-line treatment in eleven tertiary endoscopic referral centers. Technical success, primary hemostasis, rebleeding, blood transfusion, hospital stay, and hemorrhage-related mortality rates were evaluated. Results Data from 286 patients, with either UGIB (N = 214) or LGIB (N = 72) were available. Overall, 112 patients (39.2 %) were receiving antithrombotic therapy. Technical success and primary hemostasis rates were 97.9 % and 96.4 %, respectively. Early rebleeding occurred in 4.4 %, more frequently in those on antithrombotic therapy, and no late rebleeding was observed. Following a successful primary haemostasis, only 5.2 % patients needed blood transfusions, and the median hospital stay was 4 days (range: 3 - 11). Eighteen patients with either technical failure (N = 6) or rebleeding (N = 12) underwent radiological or surgical approaches. Overall, bleeding-related deaths occurred in 5 (1.7 %) patients, including 3 patients with technical procedural failure, and 2 in the rebleeding group. Conclusions Data from our large, multicenter study show that OTSC placement is an effective first-line treatment for hemostasis in high-risk patients and/or lesions both in upper and lower gastrointestinal tract. PMID- 30410954 TI - Successful EUS-guided antegrade stenting for malignant severe biliary obstruction combined with a newly developed plastic stent. AB - Background and study aims We report the effectiveness of a newly developed plastic stent for preventing bile leakage after endoscopic ultrasonography (EUS) guided antegrade stenting. This treatment was performed on a 59-year-old woman with malignant obstructive jaundice caused by peritoneal metastasis. First, we attempted transpapillary drainage using short-type single-balloon enteroscopy assisted endoscopic retrograde cholangiopancreatography, but we could not achieve it. We then attempted EUS-guided antegrade stenting through the intrahepatic bile duct from the esophagojejunal anastomosis. We successfully inserted uncovered metallic stents for common bile duct and a newly plastic stent for hepaticojejunostomy from the antegrade approach. There were no adverse events after the treatment. PMID- 30410953 TI - Enteral self-expandable metal stent placement for malignant afferent limb syndrome using single-balloon enteroscope: report of five cases. AB - Endoscopic enteral self-expandable metal stent (SEMS) placement is a useful alternative treatment option for malignant afferent limb syndrome (ALS). We investigated the safety, efficacy, and follow-up results of enteral SEMS placement using a single-balloon enteroscope for the treatment of malignant ALS. PMID- 30410952 TI - Exclusively endoscopic approach to treating gastric perforation caused by an intragastric balloon: case series and literature review. AB - Background and study aims Obesity is a serious disease, resulting in significant morbidity and mortality. Intragastric balloons (IGBs) have been in use since the 1980s. After the insertion of an IGB, complications such as migration of the device and even severe gastric perforation can occur, requiring laparoscopic surgery. Here, we report three cases of gastric perforation after IGB insertion. In all three cases, the perforation was successfully repaired through an exclusively endoscopic approach. PMID- 30410955 TI - Endoscopic submucosal dissection of 301 large colorectal neoplasias: outcome and learning curve from a specialized center in Europe. AB - Background and study aims Endoscopic submucosal dissection (ESD) allows en bloc resection of large colorectal lesions but ESD experience is limited outside Asia. This study evaluated implementation of ESD in the treatment of colorectal neoplasia in a Western center. Patients and methods Three hundred and one cases of colorectal ESD (173 rectal and 128 colonic lesions) were retrospectively evaluated in terms of outcome, learning curve and complications. Results Median size was 4 cm (range 1 - 12.5). En bloc resection was achieved in 241 cases amounting to an en bloc resection rate of 80 %. R0 resection was accomplished in 207 cases (69 %), RX and R1 were attained in 83 (27 %) and 11 (4 %) cases, respectively. Median time was 98 min (range 10 - 588) and median proficiency was 7.2 cm 2 /h. Complications occurred in 24 patients (8 %) divided into 12 immediate perforations, five delayed perforations, one immediate bleeding and six delayed bleedings. Six patients (2 %), all with proximal lesions, had emergency surgery. Two hundred and four patients were followed up endoscopically and median follow-up time was 13 months (range 3 - 53) revealing seven recurrences (3 %). En bloc rate improved gradually from 60 % during the first period to 98 % during the last period. ESD proficiency significantly improved between the first study period (3.6 cm 2 /h) and the last study period (10.8 cm 2 /h). Conclusions This study represents the largest material on colorectal ESD in the west and shows that colorectal ESD can be implemented in clinical routine in western countries after appropriate training and achieve a high rate of en bloc and R0 resection with a concomitant low incidence of complications. ESD of proximal colonic lesions should be attempted with caution during the learning curve because of higher risk of complications. PMID- 30410956 TI - Peroral cholangioscopy by SpyGlass DS versus CHF-B260 for evaluation of the lateral spread of extrahepatic cholangiocarcinoma. AB - Background and study aims A newly developed peroral cholangioscopy (POCS) system, SpyGlassDS has high maneuverability. This study aimed to evaluate acceptability of the accuracy of SpyGlassDS accompanied by simultaneous POCS guided biopsy compared with that of a traditional POCS scope, CHF-B260, to diagnose the lateral extent of extrahepatic cholangiocarcinoma (LEC). Patients and methods Patients who underwent surgical resection after preoperative examinations to diagnose LEC were evaluated. POCS by CHF-B260 was performed if there was discrepancy between preceding fluoroscopy-guided biopsy findings and other examinations between January 2004 and September 2015 (group A, n = 56); and POCS plus POCS-guided mapping biopsy by SpyGlassDS was performed in all surgical candidates between October 2015 and December 2017 (group B, n = 20). The main outcome measure was the accuracy of overall preoperative diagnosis (OPD) of LEC defined based on all examinations, including POCS. Results Accuracy of OPD for the liver side and the ampullary side was 93 % and 100 %, respectively, in group A, and 84 % and 100 %, respectively, in group B ( P = 0.37 for the liver side; P , not available for the ampullary side). Diagnostic accuracy of simple optical evaluation by POCS for the liver side and the ampullary side was 83 % and 100 %, respectively, in group A, and 58 % and 88 %, respectively, in group B ( P = 0.29 for the liver side; P = 0.40 for the ampullary side). Conclusions POCS by SpyGlassDS was found to be acceptable and could be a standard approach for diagnosis of LEC. PMID- 30410957 TI - Endoscopic submucosal dissection for rectal neoplasia extending to the dentate line: European experience. AB - Background and study aims The ideal treatment strategy for rectal neoplasia extending to the dentate line (RNDL) is not well defined. Endoscopic mucosal resection (EMR) and submucosal dissection (ESD) compete with surgical techniques such as transanal endoscopic microsurgery (TEM). Non-Asian data and prospective data on ESD are lacking. The study aim was to evaluate the role of ESD in treatment of RNDL in a Western center. Patients and methods Eighty-six patients with rectal adenomas were included. ESD was performed in 86 rectal adenomas including 24 RNDLs (27.9 %) and 62 lesions distant from the dentate line (72.1 %). Results En bloc resection rate was comparable (91.7 % vs. 93.5 %, P = 0.670) between ESD for RNDL and non-RNDL. R0 resection rate was significantly lower in ESD for RNDL compared to that for non-RNDL (70.8 % vs 88.7 %; P = 0.039), but most non-R0 resection was unclear margin (Rx) and was not obvious positive margin (R1). Accordingly, the recurrence rate after ESD for RNDL (4.5 %) was not statistically different from that for non-RNDL (0 %, P = 0.275) and was lower than that previously reported for EMR. Median procedure time was 127 vs. 110 minutes ( P = 0.182). Risk of delayed bleeding (20.8 % vs. 0 %, P = 0.001) and postinterventional pain (33.3 % vs. 14.5 %, P = 0.07) increased in RNDL cases, but they were managed conservatively. Incidence of stricture (4.2 % vs. 1.6 %, P = 0.483) and perforation (0 % vs. 1.6 %, P = 1.000) were similar. Conclusions ESD is a feasible and safe resection technique for RNDLs. A randomized controlled trial comparing ESD to other methods (EMR or transanal surgery) is warranted. PMID- 30410958 TI - Booster medication to achieve capsule excretion in colon capsule endoscopy: a randomized controlled trial of three regimens. AB - Background and study aims To achieve a complete colon capsule endoscopy, the entire colon must be visualized, clean and filled with clear fluids. The primary aim was to compare three booster regimens in colon capsule endoscopy in achieving capsule excretion within recording time. Secondary aims were quality of bowel cleansing and completion rate (both adequate cleansing and capsule excretion). Patients and methods Patients scheduled for follow-up colonoscopy due to previous neoplastic findings or familial history of colorectal cancer aged 18 to 70 years were eligible. Bowel preparation was 2-L split doses of polyethylene glycol. Patients were randomized to three booster regimens of either polyethylene glycol (Group A), sulfate-based solution (Group B) or polyethylene glycol with iodine oral contrast (Group C). Results One hundred eighty participants were included and randomized into three groups of 60. Capsule excretion was 70 % (95 % CI: 58 - 80) in Group A, 73 % (95 % CI: 61 - 83) in Group B and in 68 % (95 % CI: 56 - 79) in Group C, no statistically significant differences. Bowel cleansing grade was statistically significant better in Group B compared to Group A ( P = 0.03), but there were no statistically significant differences between Groups C and A ( P = 0.40). Complete examination rate was 65 % (95 % CI: 53 - 77), 72 % (95 % CI: 61 - 83) and 62 % (95 % CI: 50 - 74) in Group A, B and C respectively, not statistically significant different. Conclusions Sulfate-based solution resulted in statistically significant better bowel cleansing compared to polyethylene glycol. Overall the excretion and completion rate was suboptimal. Achieving a high completion rate using patient-tolerable and low-risk compounds is still a challenge. PMID- 30410959 TI - Efficacy of duodenal bulb biopsy for diagnosis of celiac disease: a systematic review and meta-analysis. AB - Background and study aims Although duodenal biopsy is considered the "gold standard" for diagnosis of celiac disease, the optimal location of biopsy within the small bowel for diagnosis remains unclear. The primary aim of this study was to perform a structured systematic review and meta-analysis to evaluate the diagnostic utility of endoscopic duodenal bulb biopsy for celiac disease. Patients and methods Searches of PubMed, EMBASE, Web of Science, and Cochrane Library databases were performed from 2000 through December 2017. Review of titles/abstracts, full review of potentially relevant studies, and data abstraction was performed. Measured outcomes of adult and pediatric patients included location of biopsy, mean number of biopsies performed, and diagnosis of celiac disease as defined by the modified Marsh-Oberhuber classification. Results A total of 17 studies (n = 4050) were included. Seven studies evaluated adults and 11 studies assessed pediatric populations. Mean age of adults and pediatric patients was 46.70 +/- 2.69 and 6.33 +/- 1.26 years, respectively. Overall, sampling from the duodenal bulb demonstrated a 5 % (95 % CI 3 - 9; P < 0.001) increase in the diagnostic yield of celiac disease. When stratified by pediatric and adult populations, duodenal bulb biopsy demonstrated a 4 % (95 % CI: 1 to 9; P < 0.001) and 8 % (95 % CI: 6 to 10; P < 0.001) increase in the diagnostic yield of celiac disease. Non-celiac histologic diagnoses including Brunner gland hyperplasia and peptic duodenitis were reported more commonly in the duodenal bulb as compared to the distal duodenum with an increase in diagnostic yield of 4 % (95 % CI 3 - 5; P < 0.001) and 1 % (95 % CI 1 - 2; P < 0.001), respectively. Conclusions Based upon our results, biopsy and histologic examination of duodenal bulb during routine upper endoscopy increases the diagnostic yield of celiac disease. PMID- 30410960 TI - Mucinous cystic neoplasm diagnosed by EUS-guided microforceps biopsy. AB - Background and study aims Mucinous cystic neoplasms (MCNs) of the pancreas have malignant potential. Current methods for diagnosing MCNs are inadequate. The aim of this case series is to present a novel method for establishing the diagnosis of MCNs. Clinical information from three patients seen at our institution was collected for a case series presentation. Patients were selected retrospectively based on diagnostic results. Three patients were diagnosed with MCNs based on histopathology obtained via microforceps biopsy. Evolving tissue acquisition techniques, such as microforceps intracystic biopsy, have improved the diagnostic yield of endoscopic ultrasound (EUS). PMID- 30410961 TI - Charge-Neutral, Stable, Non-Cytotoxic, Near-Infrared SnS Aqueous Quantum Dots for High Signal-to-Noise-Ratio Biomedical Imaging. AB - We have synthesized charge-neutral, stable, non-cytotoxic, bright, near-infrared (NIR) SnS quantum dots (QDs) by first making Cysteamine-capped SnS QDs in glycerol under acidic conditions followed by lengthening the capping molecule with peptide bonds by reacting the capping molecules with glycine and subsequent heat treatment at 200 degrees C for 4 hours. The obtained stable SnS QDs exhibited a band gap of 1.5 eV and a strong, narrow NIR emission peak at 830 nm with a quantum yield of 4.6%. The suspension could be stable for more than 1 month without aggregation or emission decay. The positively charged SnS QDs were further neutralized by 3-mercaptoproprionic acid (MPA) through electrostatic attraction. The MPA neutralized SnS QDs were shown to be non-cytotoxic at concentrations 6 times the typical QDs concentration for immunostaining. Low noise, optimal NIR immunofluorescent imaging of vascular endothelial growth factor (VEGF) on 3T3 cells and Tn antigen on HT29 cells was achieved by using streptavidin (SA)-linked MPA-neutralized SnS QDs with a SA:QD molar ratio of 22:1 to bind to biotinylated secondary antibody bound on the primary antibody that was bound on the targeted antigen on the cell membrane with a high signal-to noise ratio (SNR) of 35. PMID- 30410963 TI - Is the Nobel Prize in Chemistry Having a Boston Red Sox Moment? PMID- 30410964 TI - A Conversation with Joris van Rossum. PMID- 30410962 TI - Large Variation in Provincial Guidelines for Urine Drug Screening during Opioid Agonist Treatment in Canada. AB - Urine drug screening (UDS) is commonly used to detect or validate self-reported substance use, particularly when beginning and maintaining opioid agonist therapy (OAT). However, there is currently no summary of the published clinical practice guidelines for UDS in Canada, and no measure of the consistency with which different provinces suggest administering UDS. Therefore, we conducted a policy scan of UDS guidelines, examining the published clinical practice guidelines for each Canadian province and extracting all relevant data in March 2017. Our Canadian guideline and policy scan found that UDS frequency recommendations vary greatly among Provinces for persons receiving OAT for opioid use disorder. PMID- 30410965 TI - A Matter of Degree. PMID- 30410966 TI - Attack on the Cell Membrane: The Pointy Ends of DNA Nanostructures Lead the Way. PMID- 30410967 TI - Structure, Dynamics, and Energetics of ATP Hydrolysis by ABC Transporters. PMID- 30410969 TI - The Impact of Nonequilibrium Conditions in Lung Surfactant: Structure and Composition Gradients in Multilamellar Films. AB - The lipid-protein mixture that covers the lung alveoli, lung surfactant, ensures mechanical robustness and controls gas transport during breathing. Lung surfactant is located at an interface between water-rich tissue and humid, but not fully saturated, air. The resulting humidity difference places the lung surfactant film out of thermodynamic equilibrium, which triggers the buildup of a water gradient. Here, we present a millifluidic method to assemble multilamellar interfacial films from vesicular dispersions of a clinical lung surfactant extract used in replacement therapy. Using small-angle X-ray scattering, infrared, Raman, and optical microscopies, we show that the interfacial film consists of several coexisting lamellar phases displaying a substantial variation in water swelling. This complex phase behavior contrasts to observations made under equilibrium conditions. We demonstrate that this disparity stems from additional lipid and protein gradients originating from differences in their transport properties. Supplementing the extract with cholesterol, to levels similar to the endogenous lung surfactant, dispels this complexity. We observed a homogeneous multilayer structure consisting of a single lamellar phase exhibiting negligible variations in swelling in the water gradient. Our results demonstrate the necessity of considering nonequilibrium thermodynamic conditions to study the structure of lung surfactant multilayer films, which is not accessible in bulk or monolayer studies. Our reconstitution methodology also opens avenues for lung surfactant pharmaceuticals and the understanding of composition, structure, and property relationships at biological air-liquid interfaces. PMID- 30410968 TI - Quantitative Nanoplasmonics. AB - Plasmonics, the study of the interactions between photons and collective oscillations of electrons, has seen tremendous advances during the past decade. Controllable nanometer- and sub-nanometer-scale engineering in plasmonic resonance and electromagnetic field localization at the subwavelength scale have propelled diverse studies in optics, materials science, chemistry, biotechnology, energy science, and various applications in spectroscopy. However, for translation of these accomplishments from research into practice, major hurdles including low reproducibility and poor controllability in target structures must be overcome, particularly for reliable quantification of plasmonic signals and functionalities. This Outlook introduces and summarizes the recent attempts and findings of many groups toward more quantitative and reliable nanoplasmonics, and discusses the challenges and possible future directions. PMID- 30410970 TI - Green Tea Catechin Dramatically Promotes RNAi Mediated by Low-Molecular-Weight Polymers. AB - Cytosolic delivery is the major challenge that limits the clinical translation of siRNA-based therapeutics. Although thousands of polymers have been developed for siRNA delivery, the efficiency-toxicity correlation is unsatisfactory. Here, we report a facile strategy to fabricate core-shell-structured nanoparticles with robust siRNA delivery efficiency. The nanoparticle is prepared by entropy-driven complexation of siRNA with a green tea catechin to yield a negatively charged core, followed by coating low-molecular-weight polymers to form the shell. This supramolecular strategy facilitates the polymers condensing siRNA into uniform nanoparticles. The nanoparticle specifically down-regulates target genes in vitro and in vivo, and efficiently attenuates chronic intestinal inflammation in an inflammatory bowel disease model. Notably, the highly efficient nanoparticles are applicable for various polymers with different topologies and chemical compositions, providing a versatile technique to break down the efficiency toxicity correlation of cationic polymers. The proposed strategy in this study permits the development of a promising platform for polymer-mediated siRNA delivery. PMID- 30410971 TI - Molecular Mechanism of ATP Hydrolysis in an ABC Transporter. AB - Hydrolysis of nucleoside triphosphate (NTP) plays a key role for the function of many biomolecular systems. However, the chemistry of the catalytic reaction in terms of an atomic-level understanding of the structural, dynamic, and free energy changes associated with it often remains unknown. Here, we report the molecular mechanism of adenosine triphosphate (ATP) hydrolysis in the ATP-binding cassette (ABC) transporter BtuCD-F. Free energy profiles obtained from hybrid quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simulations show that the hydrolysis reaction proceeds in a stepwise manner. First, nucleophilic attack of an activated lytic water molecule at the ATP gamma phosphate yields ADP + HPO4 2- as intermediate product. A conserved glutamate that is located very close to the gamma-phosphate transiently accepts a proton and thus acts as catalytic base. In the second step, the proton is transferred back from the catalytic base to the gamma-phosphate, yielding ADP + H2PO4 -. These two chemical reaction steps are followed by rearrangements of the hydrogen bond network and the coordination of the Mg2+ ion. The rate constant estimated from the computed free energy barriers is in very good agreement with experiments. The overall free energy change of the reaction is close to zero, suggesting that phosphate bond cleavage itself does not provide a power stroke for conformational changes. Instead, ATP binding is essential for tight dimerization of the nucleotide-binding domains and the transition of the transmembrane domains from inward- to outward-facing, whereas ATP hydrolysis resets the conformational cycle. The mechanism is likely relevant for all ABC transporters and might have implications also for other NTPases, as many residues involved in nucleotide binding and hydrolysis are strictly conserved. PMID- 30410972 TI - DNA Nanostructure-Programmed Like-Charge Attraction at the Cell-Membrane Interface. AB - Cell entry of anionic nano-objects has been observed in various types of viruses and self-assembled DNA nanostructures. Nevertheless, the physical mechanism underlying the internalization of these anionic particles across the negatively charged cell membrane remains poorly understood. Here, we report the use of virus mimicking designer DNA nanostructures with near-atomic resolution to program "like-charge attraction" at the interface of cytoplasmic membranes. Single particle tracking shows that cellular internalization of tetrahedral DNA nanostructures (TDNs) depends primarily on the lipid-raft-mediated pathway, where caveolin plays a key role in providing the short-range attraction at the membrane interface. Both simulation and experimental data establish that TDNs approach the membrane primarily with their corners to minimize electrostatic repulsion, and that they induce uneven charge redistribution in the membrane under the short distance confinement by caveolin. We expect that the nanoscale like-charge attraction mechanism provides new clues for viral entry and general rules for rational design of anionic carriers for therapeutics. PMID- 30410973 TI - PbS Capped CsPbI3 Nanocrystals for Efficient and Stable Light-Emitting Devices Using p-i-n Structures. AB - Cesium lead halide perovskite nanocrystals (NCs) have unique optical properties such as high color purity and high photoluminescence (PL) efficiency. However, the external quantum efficiency (EQE) of the corresponding light-emitting diodes (LEDs) is low, primarily as a result of the NC surface defects. Here, we report a method to reduce the surface defects by capping CsPbI3 NCs with PbS. This passivation significantly enhanced the PL efficiency, reduced the Stokes shift, narrowed the PL bandwidth, and increased the stability of CsPbI3 NCs. At the same time, CsPbI3 NC films switched from n-type behavior to nearly ambipolar by PbS capping, which allowed us to fabricate electroluminescence LEDs using p-i-n structures. The thus-fabricated LEDs exhibited dramatically improved storage and operation stability, and an EQE of 11.8%. These results suggest that, with a suitable surface passivation strategy, the perovskite NCs are promising for next generation LED and display applications. PMID- 30410974 TI - Imaging Mass Spectrometry Reveals Crosstalk between the Fallopian Tube and the Ovary that Drives Primary Metastasis of Ovarian Cancer. AB - High grade serous ovarian cancer (HGSOC) is the fifth leading cause of cancer deaths among women. New evidence suggests that HGSOC arises in the fallopian tube and then colonizes the ovary before spreading into the peritoneal space. Therefore, due to the proximity of this metastasis, an experimental design was optimized using imaging mass spectrometry to capture the spatial composition of small molecules uniquely expressed when fallopian-tube-derived tumor cells were grown in the microenvironment of the ovary as a model of primary metastasis. The observed mass-to-charge ratios (m/z's) that were induced specifically in coculture represent small molecules that may contribute to the metastasis of HGSOC selectively to the ovary. Human fallopian tube epithelial HGSOC and tumorigenic murine oviductal epithelial cells, but not normal cell types, repeatedly induced a signal from the ovary at m/z 170. This signal was identified as norepinephrine, which was confirmed to stimulate invasion of ovarian cancer cells lacking wild-type p53. These molecules may reveal pathways that contribute to metastasis and biological targets for therapeutic intervention to block ovarian metastasis of fallopian-tube-derived HGSOC. The developed mass spectrometry method can be adapted to other mammalian-based model systems for investigation of untargeted metabolomics that facilitate metastasis. PMID- 30410975 TI - In Vivo Two-Photon Voltage Imaging with Sulfonated Rhodamine Dyes. AB - Optical methods that rely on fluorescence for mapping changes in neuronal membrane potential in the brains of awake animals provide a powerful way to interrogate the activity of neurons that underlie neural computations ranging from sensation and perception to learning and memory. To achieve this goal, fluorescent indicators should be bright, highly sensitive to small changes in membrane potential, nontoxic, and excitable with infrared light. We report a new class of fluorescent, voltage-sensitive dyes: sulfonated rhodamine voltage reporters (sRhoVR), synthetic fluorophores with high voltage sensitivity, excellent two-photon performance, and compatibility in intact mouse brains. sRhoVR dyes are based on a tetramethyl rhodamine fluorophore coupled to a phenylenevinylene molecular wire/diethyl aniline voltage-sensitive domain. When applied to cells, sRhoVR dyes localize to the plasma membrane and respond to membrane depolarization with a fluorescence increase. The best of the new dyes, sRhoVR 1, displays a 44% DeltaF/F increase in fluorescence per 100 mV change, emits at 570 nm, and possesses excellent two-photon absorption of approximately 200 GM at 840 nm. sRhoVR 1 can detect action potentials in cultured rat hippocampal neurons under both single- and two-photon illumination with sufficient speed and sensitivity to report on action potentials in single trials, without perturbing underlying physiology or membrane properties. The combination of speed, sensitivity, and brightness under two-photon illumination makes sRhoVR 1 a promising candidate for in vivo imaging in intact brains. We show sRhoVR powerfully complements electrode-based modes of neuronal activity recording in the mouse brain by recording neuronal transmembrane potentials from the neuropil of layer 2/3 of the mouse barrel cortex in concert with extracellularly recorded local field potentials (LFPs). sRhoVR imaging reveals robust depolarization in response to whisker stimulation; concurrent electrode recordings reveal negative deflections in the LFP recording, consistent with the canonical thalamocortical response. Importantly, sRhoVR 1 can be applied in mice with chronic optical windows, presaging its utility in dissecting and resolving voltage dynamics using two-photon functional imaging in awake, behaving animals. PMID- 30410976 TI - Fluorescence Correlation Spectroscopy Reveals Efficient Cytosolic Delivery of Protein Cargo by Cell-Permeant Miniature Proteins. AB - New methods for delivering proteins into the cytosol of mammalian cells are being reported at a rapid pace. Differentiating between these methods in a quantitative manner is difficult, however, as most assays for evaluating cytosolic protein delivery are qualitative and indirect and thus often misleading. Here we make use of fluorescence correlation spectroscopy (FCS) to determine with precision and accuracy the relative efficiencies with which seven different previously reported "cell-penetrating peptides" (CPPs) transport a model protein cargo-the self labeling enzyme SNAP-tag-beyond endosomal membranes and into the cytosol. Using FCS, we discovered that the miniature protein ZF5.3 is an exceptional vehicle for delivering SNAP-tag to the cytosol. When delivered by ZF5.3, SNAP-tag can achieve a cytosolic concentration as high as 250 nM, generally at least 2-fold and as much as 6-fold higher than any other CPP evaluated. Additionally, we show that ZF5.3 can be fused to a second enzyme cargo-the engineered peroxidase APEX2-and reliably delivers the active enzyme to the cell interior. As FCS allows one to realistically assess the relative merits of protein transduction domains, we anticipate that it will greatly accelerate the identification, evaluation, and optimization of strategies to deliver large, intact proteins to intracellular locales. PMID- 30410977 TI - Delivery of Inorganic Polyphosphate into Cells Using Amphipathic Oligocarbonate Transporters. AB - Inorganic polyphosphate (polyP) is an often-overlooked biopolymer of phosphate residues present in living cells. PolyP is associated with many essential biological roles. Despite interest in polyP's function, most studies have been limited to extracellular or isolated protein experiments, as polyanionic polyP does not traverse the nonpolar membrane of cells. To address this problem, we developed a robust, readily employed method for polyP delivery using guanidinium rich oligocarbonate transporters that electrostatically complex polyPs of multiple lengths, forming discrete nanoparticles that are resistant to phosphatase degradation and that readily enter multiple cell types. Fluorescently labeled polyPs have been monitored over time for subcellular localization and release from the transporter, with control over release rates achieved by modulating the transporter identity and the charge ratio of the electrostatic complexes. This general approach to polyP delivery enables the study of intracellular polyP signaling in a variety of applications. PMID- 30410978 TI - Zika Virus Liquid Biopsy: A Dendritic Ru(bpy)3 2+-Polymer-Amplified ECL Diagnosis Strategy Using a Drop of Blood. AB - Zika virus (ZIKV) is a mosquito-borne flavivirus that leads to devastating consequences for fetal development. However, accurate diagnosis of ZIKV is made difficult by the fact that most infected patients are asymptomatic or present with symptoms similar to those of other febrile illnesses. Thus, the development of a simple, accurate, highly sensitive, and reliable method for the biomedical analysis and diagnosis of ZIKV is needed. Herein, a novel ZIKV liquid biopsy system was constructed via a dendritic Ru(bpy)3 2+-polymer-amplified electro chemiluminescence (ECL) strategy. This system accomplished amplification-free analysis of ZIKV using a drop of blood, and simultaneously achieved a high sensitivity of 500 copies and superior specificity. This strategy adopted the humoral biomarker as the diagnostic index, which greatly simplified the analysis process, and established a nondestructive detection mode. Furthermore, the performance index for biomedical analysis of clinical ZIKV samples was investigated, and the results indicated that the dendritic Ru(bpy)3 2+-polymer amplified ECL strategy reliably responded to ZIKV from the body fluid (blood, saliva, and urine). Hence, this system suitably met the strict clinical requirements for ZIKV detection and thus has the potential to serve as a new paradigm for the biomedical analysis and diagnosis of ZIKV. PMID- 30410979 TI - Multimetallic Hollow Mesoporous Nanospheres with Synergistically Structural and Compositional Effects for Highly Efficient Ethanol Electrooxidation. AB - Controlling the nanostructures and chemical compositions of the electrochemical nanocatalysts has been recognized as two prominent means to kinetically promote the electrocatalytic performance. Herein, we report a general "dual"-template synthesis methodology for the formation of multimetallic hollow mesoporous nanospheres (HMSs) with an adjustable interior hollow cavity and cylindrically opened mesoporous shell as a highly efficient electrocatalyst for ethanol oxidation reaction. Three-dimensional trimetallic PdAgCu HMSs were synthesized via in situ coreduction of Pd, Ag, and Cu precursors on "dual"-template structural directing surfactant of dioctadecyldimethylammonium chloride in optimal synthesis conditions. Due to synergistic advantages on hollow mesoporous nanostructures and multimetallic compositions, the resultant PdAgCu HMSs exhibited significantly enhanced electrocatalytic performance toward ethanol oxidation reaction with a mass activity of 5.13 A mgPd -1 at a scan rate of 50 mV s-1 and operation stability (retained 1.09 A mgpd -1 after the electrocatalysis). The "dual"-template route will open a new avenue to rationally design multimetallic HMSs with controlled functions for broad applications. PMID- 30410981 TI - Reduction and Condensation of Aldehydes by the Isolated Cofactor of Nitrogenase. AB - Isolated nitrogenase cofactors can reduce CO, CN-, and CO2 to short-chain hydrocarbons in reactions driven by a strong reductant. Here, we use activity analyses and isotope labeling experiments to show that formaldehyde and acetaldehydes can be reduced as-is or reductively condensed into alkanes and alkenes by the isolated cofactor of Mo-nitrogenase in the presence of EuII diethylenetriamine pentaacetate (DTPA). Further, we demonstrate that aldehydes can be condensed with CO by the isolated cofactor under the same reaction conditions, pointing to aldehyde-derived species as possible intermediates of nitrogenase-catalyzed CO reduction. Our deuterium labeling experiments suggest the formation of a cofactor-bound hydroxymethyl intermediate upon activation of the formaldehyde, as well as the release of C2H4 as a product upon beta-hydride elimination of an acetaldehyde-derived hydroxyethyl intermediate. These findings establish the reductive condensation of aldehydes as a previously unobserved reactivity of a biogenic catalyst while at the same time shed light on the mechanism of enzymatic CO reduction and C-C bond formation, thereby providing a useful framework for further exploration of the unique reactivity and potential applications of nitrogenase-based reactions. PMID- 30410980 TI - Direct Observation of the Interplay of Catechol Binding and Polymer Hydrophobicity in a Mussel-Inspired Elastomeric Adhesive. AB - Marine organisms such as mussels have mastered the challenges in underwater adhesion by incorporating post-translationally modified amino acids like l-3,4 dihydroxyphenylalanine (DOPA) in adhesive proteins. Here we designed a catechol containing elastomer adhesive to identify the role of catechol in interfacial adhesion in both dry and wet conditions. To decouple the adhesive contribution of catechol to the overall adhesion, the elastomer was designed to be cross-linked through [2 + 2] photo-cycloaddition of coumarin. The elastomer with catechol moieties displayed a higher adhesion strength than the catechol-protected elastomer. The contact interface was probed using interface-sensitive sum frequency generation spectroscopy to explore the question of whether catechol can displace water and bond with hydrophilic surfaces. The spectroscopy measurements reveal that the maximum binding energy of the catechol and protected-catechol elastomers to sapphire substrate is 7.0 +/- 0.1 kJ/(mole of surface O-H), which is equivalent to 0.10 J/m2. The higher dry and wet adhesion observed in the macroscopic adhesion measurements for the catechol containing elastomer originates from multiple hydrogen bonds of the catechol dihydroxy groups to the surface. In addition, our results show that catechol by itself does not remove the confined interstitial water. In these elastomers, it is the hydrophobic groups that help in partially removing interstitial water. The observation of the synergy between catechol binding and hydrophobicity in enabling the mussel inspired soft adhesive elastomer to stick underwater provides a framework for designing materials for applications in tissue adhesion and moist-skin wearable electronics. PMID- 30410982 TI - Water Splits To Degrade Two-Dimensional Group-IV Monochalcogenides in Nanoseconds. AB - The experimental exfoliation of layered group-IV monochalcogenides-semiconductors isostructural to black phosphorus-using processes similar to those followed in the production of graphene or phosphorene has turned out unsuccessful thus far, as if the chemical degradation observed in black phosphorus was aggravated in these monochalcogenides. Here, we document a facile dissociation of water by these materials within 10 ns from room-temperature Car-Parrinello molecular dynamics calculations under standard temperature and pressure conditions. These results suggest that humidity must be fully eradicated to exfoliate monolayers successfully, for instance, by placing samples in a hydrophobic solution during mechanical exfoliation. From another materials perspective, these two-dimensional materials that create individual hydrogen ions out of water without illumination may become relevant for applications in hydrogen production and storage. PMID- 30410983 TI - Paralyzed membrane: Current-driven synthesis of a metal-organic framework with sharpened propene/propane separation. AB - Metal-organic framework (MOF) membranes show great promise for propene/propane separation, yet a sharp molecular sieving has not been achieved due to their inherent linker mobility. Here, zeolitic imidazolate framework ZIF-8-type membranes with suppressed linker mobility are prepared by a fast current-driven synthesis (FCDS) strategy within 20 min, showing sharpened molecular sieving for propene/propane separation with a separation factor above 300. During membrane synthesis, the direct current promotes the metal ions and ligands to assemble into inborn-distorted and stiffer frameworks with ZIF-8_Cm (a newly discovered polymorph of ZIF-8) accounting for 60 to 70% of the membrane composition. Molecular dynamics simulations further verify that ZIF-8_Cm is superior to ZIF 8_I 4-3m (the common cubic phase) for propene/propane separation. FCDS holds great potential to produce high-quality, ultrathin MOF membranes on a large scale. PMID- 30410984 TI - Numerical observation of emergent spacetime supersymmetry at quantum criticality. AB - No definitive evidence of spacetime supersymmetry (SUSY) that transmutes fermions into bosons and vice versa has been revealed in nature so far. Moreover, the question of whether spacetime SUSY in 2 + 1 and higher dimensions can emerge in generic lattice microscopic models remains open. Here, we introduce a lattice realization of a single Dirac fermion in 2 + 1 dimensions with attractive interactions that preserves both time-reversal and chiral symmetries. By performing sign problem-free determinant quantum Monte Carlo simulations, we show that an interacting single Dirac fermion in 2 + 1 dimensions features a superconducting quantum critical point (QCP). We demonstrate that the N=2 spacetime SUSY in 2 + 1 dimensions emerges at the superconducting QCP by showing that the fermions and bosons have identical anomalous dimensions 1/3, a hallmark of the emergent SUSY. We further show some experimental signatures that may be measured to test such emergent SUSY in candidate systems. PMID- 30410987 TI - Endoscopic training-is the future three-dimensional? AB - Background/Objectives: Endoscopic surgery has a distinct disadvantage compared to direct vision: loss of binocular vision. Three-dimensional endoscopy has been welcomed due to the promise of improving stereopsis. Methods: Prospective randomized study of junior doctors with minimal endoscopic experience, using both two-dimensional and three-dimensional, zero-degree, 4-mm Storz endoscopes. Data was collected using validated, standardized training models, both objectively and subjectively. Paired comparisons between variables relating to the endoscopes were performed using Wilcoxon's tests. Operators were then split into groups based on their endoscope preference, with comparisons made using Mann-Whitney tests for Likert scale responses, Kendall's tau for ordinal variables, and Fisher's exact tests for nominal variables. Results: Reduction of field of vision of three-dimensional endoscopy by 2%. Significant findings included decreased past-pointing, improved depth and perception and image quality. Conclusion: The use of an endoscopic endonasal approach with three-dimensional technology has measurable advantages for novice users, and highlights potential tailoring of future surgical training. Level of Evidence: 1b. PMID- 30410985 TI - Patient Participation in the Development of a Customized M-Health Intervention to Improve Medication Adherence in Poorly Adherent Individuals with Bipolar Disorder (BD) and Hypertension (HTN). AB - Objective: Individuals living with bipolar disorder (BD) have poorer management of chronic medical conditions such as hypertension (HTN), and worse treatment adherence than the general population. The study objective was to obtain information from patients with both BD and HTN that would inform the development of an m-Health intervention to improve medication adherence for poorly adherent individuals living with both these chronic illnesses. Methods: Focus group methodology was used to collect information from 13 participants on perceived barriers and facilitators to BD and HTN medication adherence, as well as feedback on the demonstration and use of a bidirectional text messaging system for medication reminders. Focus groups were audiotaped, transcribed verbatim, and analyzed using content analysis with an emphasis on dominant themes. Results: Forgetfulness was the most frequently mentioned barrier to taking antihypertensive medications, and decisions about taking them were often influenced by BD mood fluctuations and the burden of having to take "too many pills" for both chronic illnesses. Participants' feedback about the use of a text messaging system to help with medication adherence for BD and HTN was very positive, and their suggestions for modification were incorporated into a more customized system for testing in a Phase 2 trial. Conclusions: Our findings indicate that patient engagement in the development of an m-health intervention has the potential to improve adherence with both BD and HTN medications in individuals with known sub-optimal adherence. Patient engagement in health care is essential if we are to optimize patient outcomes. PMID- 30410986 TI - Multiple polycomb epigenetic regulatory proteins are active in normal and regenerating adult olfactory epithelium. AB - Objectives: To investigate epigenetic mechanisms contributing to regulation of cellular renewal and neurogenesis in adult olfactory epithelium (OE). Study Design: Prospective basic science study. Methods: Olfactory basal cell cultures were prepared from adult mice per established protocols. in vivo studies were performed using the mouse methimazole lesion-regeneration paradigm. Nasal tissue sections were prepared from adult mice 7 days following lesion, or from unlesioned controls. Polycomb proteins were assessed by Western blot from culture or nasal tissue lysates, and by gene expression studies from cultures. In addition, in vivo expression patterns of Polycomb proteins were examined using immunohistochemistry. Chromosome immunoprecipitation (ChIP) was performed to investigate epigenetic modifications and specific chromatin interactions for Polycomb proteins in olfactory basal cells. Results: Subunits of Polycomb Repressive Complex 1 (PRC1) and Polycomb Repressive Complex 2 (PRC2) were identified in basal cell cultures and in vivo. In regenerating OE, basal progenitor cells identified by expression of the c-KIT receptor were found to coexpress the PRC2 protein EZH2. Because multiple variants of PRC1 subunits give rise to diverse PRC1 complexes serving different functions, expression of specific PRC1 variants was further examined. We identified PRC1 components including MEL18 (PCGF2) in immature neurons, and confirm BMI1 (PCGF4) expression in mature neurons. Moreover, we identified CBX8 as a neuron-specific PRC1 subunit. ChIP assays from OE cells demonstrated binding of PRC proteins to regulatory regions of specific transcription factors, consistent with PRC mediated epigenetic silencing mechanisms active in adult OE. Conclusions: Multiple Polycomb proteins have cell type-specific expression patterns in the adult OE. Findings presented here, together with evidence from prior studies, suggest that PRC-mediated epigenetic silencing contributes to regulation of cellular renewal and tissue homeostasis in the OE. Efforts to define the mechanisms that regulate repair in the OE are essential for development of new therapeutic strategies for olfactory disorders. Level of Evidence: N/A. PMID- 30410989 TI - Emergency front-of-neck airway by ENT surgeons and residents: A dutch national survey. AB - Objectives: ENT surgeons and anesthesiologists work closely together in managing challenging airway cases. Sharing knowledge, experiences, and expectations interdisciplinary is essential in order to facilitate decision-making and adequate management in emergency front-of-neck airway cases. Methods: A survey was performed, to analyze level of experience, technique of preference, training, knowledge of material and protocols, and self-efficacy scores of Dutch ENT surgeons and residents in performing an urgent or emergency front-of-neck airway. Results: Within one year (January 2014-2015), 25.7% of the 257 respondents had performed an urgent or emergency front-of-neck airway. Of all reported emergency front-of-neck airways (N = 30), 80% were managed by tracheotomy. In future emergency front-of-neck airway cases, 74% stated cricothyrotomy would be their technique of preference. The majority would choose an uncuffed large-bore cannula technique. Post-academic hands-on training was attended by 42% of respondents. Self-efficacy scores were highest for surgical tracheotomy, and higher when trained or experienced. In case of an emergency scenario, 8.6% would not perform a front-of-neck airway themselves. The main reasons for reluctance to start in general were lack of experience and lack of training. Reported items for improvement were mainly the development of a protocol and training. Conclusion: The chance of encountering an airway emergency scenario requiring front-of-neck airway is realistic. There is inconsistency between advised technique, technique of preference and technique actually performed by ENT surgeons. This study shows that there is both a need and desire for improvement in training and organization of care. Interdisciplinary guidelines and education is needed and could eventually safe lives. Level of evidence: 5. PMID- 30410988 TI - In vivo nerve identification in head and neck surgery using diffuse reflectance spectroscopy. AB - Background: Careful identification of nerves during head and neck surgery is essential to prevent nerve damage. Currently, nerves are identified based on anatomy and appearance, optionally combined with electromyography (EMG). In challenging cases, nerve damage is reported in up to 50%. Recently, optical techniques, like diffuse reflectance spectroscopy (DRS) and fluorescence spectroscopy (FS) show potential to improve nerve identification. Methods: 212 intra-operative DRS/FS measurements were performed. Small nerve branches (1-3 mm), on near-nerve adipose tissue, muscle and subcutaneous fat were measured during 11 surgical procedures. Tissue identification was based on quantified concentrations of optical absorbers and scattering parameters. Results: Clinically comprehensive parameters showed significant differences (<0.05) between the tissues. Classification using k-Nearest Neighbor resulted in 100% sensitivity and a specificity of 83% (accuracy 91%), for the identification of nerve against surrounding tissues. Conclusions: DRS/FS is a potentially useful intraoperative tool for identification of nerves from adjacent tissues. Level of Evidence: Observational proof of principle study. PMID- 30410990 TI - Integrative care of the patient with head and neck cancer. AB - Objective: To review the literature on integrative care of the patient with head and neck cancer. Methods: A review of the English language literature for articles relating to integrative care of patients with head and neck cancer, focusing on treatment of sequelae of surgery and chemoradiation. Results: Many studies show a significant utilization of nontraditional (complementary/integrative) treatments by patients in dealing with head and neck cancer. Treatment of head and neck cancer entails potentially debilitating consequences of surgery and/or chemoradiation on cosmesis, speech, swallowing, breathing, and quality of life. While complementary/integrative treatments for head and neck cancer are not established as effective therapies, their use for relieving sequelae of treatment, improving quality of life, and providing potential chemoprevention is well documented. Conclusion: Given the landscape of increasing use of nontraditional methodologies by patients with head and neck cancer and the complexity of care, the head and neck cancer surgeon should be aware of the uses and abuses of complementary/integrative medicine by patients as they navigate their care. Level of Evidence: 5. PMID- 30410991 TI - Analysis of pharyngeal edema post-chemoradiation for head and neck cancer: Impact on swallow function. AB - Objectives: Edema is a frequent clinical observation following chemoradiation treatment (CRT) of oral/oropharyngeal cancer and is thought to contribute to post CRT swallowing impairment. Our aims were to reliably quantify pharyngeal edema pre- and post-CRT from videofluoroscopic (VF) swallowing studies and to explore the relationship between edema and swallowing impairment. Swallowing impairment was captured using patient-reported swallowing outcomes (EAT-10) and with VF confirmation of impairment (DIGEST). Methods: 40 patients (24 M, age 38-76) with oral/oropharyngeal cancer received radiotherapy (70 Gy, 7 weeks) and 3 weekly doses of cisplatin. VF and EAT-10 were completed pre- and 1-month post-CRT. Edema was captured by measuring posterior pharyngeal wall (PPW) thickness, vallecular space, and pharyngeal area (PA) on a single post-swallow rest frame. Wilcoxon sign rank tests and paired t-tests evaluated within-subject changes in impairment and edema respectively. A linear mixed effect regression model explored the influence of time, patient-reported outcomes, and functional impairment on measures of edema. Results: Swallowing function (EAT-10 and DIGEST) was significantly worse post-CRT. PPW thickness (but not vallecular space and pharyngeal area) was significantly worse post-CRT. PPW thickness was only significantly influenced by time (pre- vs. post-CRT) but not by measures of swallow function. Conclusion: Our findings establish the use of PPW thickness as a reliable measure of acute edema in post-CRT treatment. In this small, retrospective sample, edema was not significantly correlated with either patient reported or measured swallow function. Prospective longitudinal work, examining the relationship between objective measures of edema, patient perception of impairment, and swallow function and biomechanics is warranted. Level of Evidence: 4. PMID- 30410992 TI - The association between auditory nerve neurovascular conflict and sudden unilateral sensorineural hearing loss. AB - Hypothesis: There may be an association between a neurovascular conflict (NVC) of the auditory nerve and unilateral sudden sensorineural hearing loss (SSNHL). Background: Compression of cranial nerves by vascular structures can lead to significant symptomatology that may require surgical decompression. Notable examples are trigeminal neuralgia and hemifacial spasm. Magnetic resonance imaging (MRI) is part of the workup for SSNHL, and it may depict an NVC of the auditory nerve. Here we look into the association between this NVC and unilateral SSNHL. Methods: A retrospective analysis was performed on all consecutive patients with unilateral SSNHL who underwent an MRI scan in our medical center. The data collected included age, gender, side and severity of hearing loss, and accompanying complaints. Each MRI scan was reviewed by a neuroradiologist who was unaware of hearing loss laterality. The presence, side, extent, and location of a potential NVC involving the auditory nerve were determined, and a correlation between radiological findings and auditory parameters was sought. Results: Fifty four patients (male-to-female ratio 26:28, age range 25-80 years) were enrolled into the study. Fourteen of them (25.9%) had normal MRI findings. Twenty-six patients had a unilateral NVC, and the pathology was ipsilateral to the side of hearing loss in only 12 of them (46.2%). Fourteen (25.9%) patients had MRI findings of bilateral NVCs. There was no significant correlation between the side of the SSNHL and any radiological findings (P = .314). Conclusion: The data presented herein support the conclusion that there is no association between CN8 NVC and unilateral SSNHL. Level of Evidence: 2b. PMID- 30410993 TI - Elongated EABR wave latencies observed in patients with auditory neuropathy caused by OTOF mutation. AB - Objectives: We sought to determine how the pathology altered electrically evoked auditory brainstem responses (EABRs) in patients with hearing loss by evaluating EABRs in auditory neuropathy patients with OTOF mutations comparing with various types of congenital deafness. Methods: We included 15 patients with congenital hearing loss, grouped according to pathology: OTOF mutations (n = 4), GJB2 mutations (n = 4), SLC26A4 mutations (n = 4), or cytomegalovirus infections (n = 3). EABRs were recorded when patients underwent cochlear implantation surgery. We evaluated the latencies and amplitudes of the recorded EABRs and compared them statistically between four groups. Results: The EABR latencies of Wave III and Wave V, and of the interval between them, were significantly longer in the OTOF mutation group than in the GJB2 and SLC26A4 mutation groups (Wave III) and in all three other groups (Wave V and Wave III-V latency); amplitudes were not significantly different between groups. Conclusions: Our results suggest OTOF mutations cause delayed (or slowed) postsynaptic neurotransmission, although the presumed mechanism involved reduced presynaptic transmission between hair cells and spiral ganglion neurons. Level of Evidence: Mainly a case report. PMID- 30410994 TI - The development of active middle ear implants: A historical perspective and clinical outcomes. AB - Objective s: Energy emitting, active middle ear implants (aMEI) have taken more than two decades of research to reach technological sophistication, medical safety, and regulatory approval to become a powerful tool in treating sensorineural, conductive, and mixed hearing loss. The present review covers this era. Data Source: Literature found from searching Pubmed (MEDLINE); EMBASE, SciSearch, German Medical Science Journals and Meetings, and The Cochrane Library; and published as of February 2017. Study bibliographies were hand searched to find further materials. Methods: A systematic literature review was conducted to identify studies evaluating the safety, efficacy, effectiveness, and subjective outcomes of partially implantable aMEIs. Data were extracted on systems with regulatory approval and summarized narratively. Meta-analyses were conducted for aMEIs with more than 25 publications. Study selection, data extraction, and quality appraisal for quantitative data synthesis was carried out by two reviewers. Results: Four hundred thirty-one studies included in narrative synthesis describe that albeit good audiological outcomes, clinical safety and (dis)investment are major barriers to continued market access. The synthesised risk of adverse events was three fold with the MET than with the VIBRANT SOUNDBRIDGE. With the latter system, audiological outcomes were stable and similar for all indications and age groups. Conclusion: To date, the majority of the literature covers the clinical application of the VIBRANT SOUNDBRIDGE system as it is applicable to a wide range of otologic and audiological conditions, particularly with the introduction of couplers to extend its clinical reach. The MAXUM and MET still have to find their way into surgical routine.Level of Evidence. PMID- 30410995 TI - Oral L-thyroxine liquid versus tablet in patients submitted to total thyroidectomy for thyroid cancer (without malabsorption): A prospective study. AB - Objective: No consistent data are present in literature about the effectiveness of Levothyroxine (L-T4) liquid formulation in patients without malabsorption after thyroidectomy. The aim of this study is to compare the effectiveness of L T4 liquid formulation, with L-T4 tablets, in thyroid cancer patients after thyroidectomy (without malabsorption or drug interference). Methods: One hundred five patients were recruited; 52 patients were treated with liquid L-T4 formulation, while 53 with L-T4 tablets, at the same dosage (1.5 mcg/kg/day). Patients started to assume the drug the day after surgery, 30 min before breakfast. In both groups circulating levels of thyrotropic hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) were dosed at week 6 (first control), and then at week 12 (second control). Results: We obtained significantly lower TSH values in the liquid L-T4 group patients, compared to the tablet L-T4 group, at the first control (P < .05), and at the second control (P < .01), while FT4 and FT3 levels were not significantly different. Hypothyroid range (TSH > 3.6 mcU/mL) was significantly more prevalent in the patients treated with L-T4 tablet. Conclusions: A better control of TSH was observed in thyroidectomized patients (without malabsorption, gastric disorders, or drug interference) with liquid L-T4 regimen. Level of Evidence: 2c-Outcomes Research. PMID- 30410996 TI - Anterior cervical incision-sparing thyroidectomy: Comparing retroauricular and transoral approaches. AB - Objectives: The robotic retroauricular approach and transoral endoscopic thyroidectomy vestibular approach (TOETVA) have been employed to avoid anterior neck scarring in thyroidectomy with good success. However, outcomes have yet to be compared between techniques. We compare our initial clinical experience with these approaches for thyroid lobectomy at our institution. Methods: A review of initial consecutive patients who underwent robotic facelift thyroidectomy (RFT) (August 2011-August 2016) at our institution was conducted. This was compared with the same number of initial consecutive patients who underwent TOETVA (September 2016-September 2017) at our institution. Demographics, operative time, pathology, complications, and learning curve were compared between cohorts. Learning curve was defined based on the slope of linear regression models of operative time versus case number. Results: There were 20 patients in each cohort. There was no statistically significant difference in demographic data between cohorts. One hundred percent of RFT cases versus 95% TOETVA cases (P = .999) were completed without conversion to standard open technique with median operative times of 201 (124-293) minutes versus 188 (89-343) minutes with RFT and TOETVA, respectively (P = .36). There was no incidence of permanent recurrent laryngeal nerve injury in either cohort. The slopes of the regression models were 0.29 versus -8.32 (P = .005) for RFT and TOETVA, respectively. Conclusion: RFT and TOETVA are safe and feasible options for patients motivated to avoid an anterior neck scar. However, the quicker learning curve without the need for a costly robotic system may make TOETVA the preferred technique for institutions wishing to perform anterior cervical incision-sparing thyroidectomy. Level of Evidence: 4. PMID- 30410997 TI - Minimally Invasive Management of Zinner's Syndrome with Same-Session Robot Assisted Seminal Vesiculectomy and Ipsilateral Nephroureterectomy Using a Single Geometry of Trocars. AB - Background: Seminal vesicle cyst is an extremely rare condition, which is frequently congenital and associated with Zinner's syndrome. This syndrome represents a constellation of seminal vesicle cyst, ipsilateral or contralateral renal agenesis or renal dysplasia, ureteral ectopia, and ejaculatory duct obstruction. We report a young symptomatic patient undergoing robot-assisted laparoscopic excision of a huge seminal vesicle cyst during which an atrophic ipsilateral kidney was discovered incidentally and managed by nephroureterectomy in the same session without changing trocar positions. Case Presentation: A 23 year-old male patient presented with a 2-year history of lower urinary tract symptoms, perineal pain, and recurrent urinary tract infections. Ultrasonography revealed the absence of left kidney and a fluid-filled cystic lesion located behind the bladder on the left side, which was consistent with cystic dilatation of the left seminal vesicle. MRI confirmed the diagnosis of a huge cystic structure originating from the left seminal vesicle and identified the presence of a rudimentary left ureter without an associated renal unit. Cystoscopy revealed bulging of the bladder neck at 6 o'clock position and the ureteral orifices at normal positions and configurations. Based on these findings, the clinical diagnosis was established as Zinner's syndrome. The present case was performed by Da Vinci Si robotic platform using the 5-trocar technique. Conclusion: Robot-assisted laparoscopic excision is a safe and feasible option to treat large seminal vesicle cysts, which may be a component of Zinner's syndrome. Simultaneous upper urinary tract interventions, such as nephroureterectomy, can be employed by redocking the robot and repositioning the patient, using the same layout of robotic trocars. PMID- 30410999 TI - Carbapenems as water soluble organocatalysts. AB - Background: Identification of organocatalysts functioning in aqueous environments will provide methods for more sustainable chemical transformations and allow tandem reactions with biocatalysts, like enzymes. Here we examine three water soluble carbapenem antibiotics (meropenem, doripenem, and ertapenem) as secondary amine organocatalysts in aqueous environments. Methods: The Michael addition of nitromethane to cinnamaldehyde was used as the model reaction. The reactions were monitored by 1H NMR, and the enantioselectivity was determined by chiral HPLC. Results: The effects of buffer components, pH, organic co-solvents and anchoring into a protein scaffold were investigated. Moderate yields of the Michael addition were obtained in buffer alone. The use of methanol as a co-solvent in a ratio of 1:1 increases the yield by 50%. Anchoring of the catalysts into a protein backbone reverses the enatioselectivity of the reaction. Conclusions: Despite only moderate yields and enantioselectivities being obtained, this study lays the foundations for future development of efficient organocatalysis in aqueous environments. PMID- 30410998 TI - Sickle Cell Disease Clinical Trials and Phenotypes. AB - Sickle cell disease, one of the world's most common genetic disorders is prevalent in sub-Saharan Africa. The trans-Atlantic slave trade accounted for the gene movement from Africa to the Caribbean and United States of America and lately, migration has resulted in the introduction of the gene to the United Kingdom and other parts of Europe. Different haplotypes exist, however the differences in these haplotypes are not sufficient to explain the different clinical variations within the same region or different settings. PMID- 30411000 TI - The role of local adaptation in sustainable village chicken production. AB - Village chickens are ubiquitous in smallholder farming systems, contributing to household, local and national economies under diverse environmental, economic and cultural settings. However, they are raised in challenging environments where productivity is low while mortality is high. There is much interest in utilizing indigenous genetic resources to produce a chicken resilient to its environment, whilst providing the basis of an economically sustainable enterprise. Globally, however, a wide variety of interventions have so far proved unable to deliver sustainable improvements. Here, we show that regional differences in trait preferences and parasite burden are associated with distinct chicken genepools, likely in response to interacting natural and human-driven (economic and social) selection pressures. Drivers of regional differences include marketing opportunities, cultural preferences, agro-ecologies and parasite populations, and are evident in system adaptations, such as management practices, population dynamics and bird genotypes. Our results provide sound multidisciplinary evidence to support previous observations that sustainable poultry development interventions for smallholder farmers, including breeding programs, should be locally tailored and designed for flexible implementation. PMID- 30411001 TI - Folding of Galpha Subunits: Implications for Disease States. AB - G-proteins play a central role in signal transduction by fluctuating between "on" and "off" phases that are determined by a conformational change. cAMP is a secondary messenger whose formation is inhibited or stimulated by activated Gialpha1 or Gsalpha subunit. We used tryptophan fluorescence, UV/vis spectrophotometry, and circular dichroism to probe distinct structural features within active and inactive conformations from wild-type and tryptophan mutants of Gialpha1 and Gsalpha. For all proteins studied, we found that the active conformations were more stable than the inactive conformations, and upon refolding from higher temperatures, activated wild-type subunits recovered significantly more native structure. We also observed that the wild-type subunits partially regained the ability to bind nucleotide. The increased compactness observed upon activation was consistent with the calculated decrease in solvent accessible surface area for wild-type Gialpha1. We found that as the temperature increased, Galpha subunits, which are known to be rich in alpha-helices, converted to proteins with increased content of beta-sheets and random coil. For active conformations from wild-type and tryptophan mutants of Gialpha1, melting temperatures indicated that denaturation starts around hydrophobic tryptophan microenvironments and then radiates toward tyrosine residues at the surface, followed by alteration of the secondary structure. For Gsalpha, however, disruption of secondary structure preceded unfolding around tyrosine residues. In the active conformations, a pi-cation interaction between essential arginine and tryptophan residues, which was characterized by a fluorescence-measured red shift and modeled by molecular dynamics, was also shown to be a contributor to the stability of Galpha subunits. The folding properties of Galpha subunits reported here are discussed in the context of diseases associated to G-proteins. PMID- 30411002 TI - Insights into the Folding of Disulfide-Rich MU-Conotoxins. AB - The study of protein conformations using molecular dynamics (MD) simulations has been in place for decades. A major contribution to the structural stability and native conformation of a protein is made by the primary sequence and disulfide bonds formed during the folding process. Here, we investigated MU-conotoxins GIIIA, KIIIA, PIIIA, SIIIA, and SmIIIA as model peptides possessing three disulfide bonds. Their NMR structures were used for MD simulations in a novel approach studying the conformations between the folded and the unfolded states by systematically breaking the distinct disulfide bonds and monitoring the conformational stability of the peptides. As an outcome, the use of a combination of the existing knowledge and results from the simulations to classify the studied peptides within the extreme models of disulfide folding pathways, namely the bovine pancreatic trypsin inhibitor pathway and the hirudin pathway, is demonstrated. Recommendations for the design and synthesis of cysteine-rich peptides with a reduced number of disulfide bonds conclude the study. PMID- 30411003 TI - Anthracene-Based Highly Selective and Sensitive Fluorescent "Turn-on" Chemodosimeter for Hg2. AB - Three pi-extended anthracene-bearing thioacetals (1-3) have been synthesized, and their fluorescence "turn-on" responses to Hg2+ ions are studied. The chemodosimetric fluorescence-sensing behavior and their resulting hydrolysis via a desulfurization reaction mechanism leads to the formation of highly fluorescent respective aldehyde substitutions. Furthermore, this mechanism was supported by increase in the quantum yields of their resulting aldehydes and is correlated to their molecular substitution. The chemosensors 1-3 have exhibited to be promising receptors toward Hg2+ ions in the presence of other competitive metal ions. Moreover, the detection limits of 1-3 have been found to be in the nanomolar range (94, 59, and 235, respectively). Fluorescence microscopic imaging studies show that 1-2 have been found to be effective for fluorescence imaging in live cells. Moreover, compounds 1-3 act as potential candidates for the detection of Hg2+ in environmental and biological systems as well as real samples. PMID- 30411004 TI - The Symmetric Tetravalent Sulfhydryl-Specific Linker NATBA Facilitates a Combinatorial "Tool Kit" Strategy for Phage Display-Based Selection of Functionalized Bicyclic Peptides. AB - The rigid conformation of constrained bicyclic peptides provides a number of advantages over larger protein-based ligands, including better chemical stability, enhanced tissue penetration, and a wider field of possible applications. Selective chemical modification strategies are able to extend the scope of applications not only in a therapeutic manner but also for the development of novel tools for protein capturing, bioimaging, and targeted drug delivery. Herein, we report the synthesis of an adamantane-based, symmetrical, tetravalent, sulfhydryl-specific peptide linker. We have developed an in vitro two-step modification strategy that allows the generation of differently functionalized bicyclic peptides. This "tool kit" strategy was applied to cyclize and functionalize a phage-encoded peptide library bearing the sequence CX6CX6C. After phage display against a model target, isolated peptides show strong consensus sequences, indicating target-specific binding. The newly developed symmetric tetravalent linker opens new avenues for the combinatorial selection and functionalization of bicyclic peptide ligands with affinity to virtually any target. PMID- 30411005 TI - Application of Unsaturated Fatty Acid Molecules Derived from Microalgae toward Mild Steel Corrosion Inhibition in HCl Solution: A Novel Approach for Metal Inhibitor Association. AB - Fatty acid molecules 9,12,15-octadecatrienoic acid (C18:3), 9,12-octadecadienoic acid (C18:2), and hexadecanoic acid (C16:0) possessing active functional groups with the capability of fast electron transfer have been established for effective corrosion inhibition of mild steel. In this regard, a microalga Scenedesmus sp. is isolated and its fatty acids have been studied to corroborate the adsorption behavior, attributing the anticorrosion efficacy on mild steel in 1 M HCl solution by forming metal-inhibitor framework. Electrochemical analysis has been used to ascertain the surpassing corrosion inhibition efficiency at an optimal concentration of 36 ppm with maximum 95.1% inhibitive performance. The results of metallography with or without the inhibitor molecules have indicated significant changes in surface morphology of mild steel specimen for gradual enhancement in immersion time (72 h). Hydrogen evolution reaction has been emphasized to observe the tendency of significant decrease in the bubble formation in the presence of inhibitor compared to 1 M HCl solution only. Surface morphometric studies (scanning electron microscopy and atomic force microscopy) have also revealed the excellent adsorption capacity of Scenedesmus fatty acids on metal surface. Quantum chemical calculations, performed by density functional theory, determined significant adsorption effectiveness, based on the donor-acceptor capability between metallic surface and inhibitor molecules. PMID- 30411006 TI - Controlled Arrangement of Neuronal Cells on Surfaces Functionalized with Micropatterned Polymer Brushes. AB - Conventional in vitro cultures are useful to represent simplistic neuronal behavior; however, the lack of organization results in random neurite spreading. To overcome this problem, control over the directionality of SH-SY5Y cells was attained, utilizing photolithography to pattern the cell-repulsive anionic brush poly(potassium 3-sulfopropyl methacrylate) (PKSPMA) into tracks of 20, 40, 80, and 100 MUm width. These data validate the use of PKSPMA brush coatings for a long-term culture of the SH-SY5Y cells, as well as providing a methodology by which the precise deposition of PKSPMA can be utilized to achieve a targeted control over the SH-SY5Y cells. Specifically, the PKSPMA brush patterns prevented cell attachment, allowing the SH-SY5Y cells to grow only on noncoated glass (gaps of 20, 50, 75, and 100 MUm width) at different cell densities (5000, 10 000, and 15 000 cells/cm2). This research demonstrates the importance of achieving cell directionality in vitro, while these simplistic models could provide new platforms to study complex neuron-neuron interactions. PMID- 30411008 TI - Cellulose Nanocrystal-ZnO Nanohybrids for Controlling Photocatalytic Activity and UV Protection in Cosmetic Formulation. AB - A high-performance semiconductor zinc oxide (ZnO) on melamine formaldehyde-coated cellulose nanocrystals (MFCNCs) was synthesized and evaluated for its application in smart cosmetics. These ZnO@MFCNC hybrid nanostructures were evaluated for their in vitro sun protection factor performance and photocatalytic activity under simulated UV and solar radiation. The photodegradation kinetics of a model pigment (methylene blue) was fitted to the Langmuir-Hinshelwood model. A 4-fold increase in the photocatalytic activity of ZnO@MFCNCs was observed when compared to pure ZnO. This is associated with (i) increased specific surface area provided by the MFCNC template, (ii) confined surface energy and controlled growth of ZnO nanoparticles, and (iii) entrapment of photoinduced charge carriers in the pores of the core-shell MFCNC rod, followed by fast promotion of interfacial e-charge transfer to the surface of the catalyst. The present study demonstrates how an increase in photocatalytic activity can be engineered without the introduction of structural defects or band gap tailoring of the semiconductor. The aqueous-based ZnO@MFCNC hybrid system displayed attractive UV-absorption and photocatalytic characteristics, offering the conversion of this renewable and sustainable technology into intelligent cosmetic formulations. PMID- 30411007 TI - Ivermectin Promotes Peripheral Nerve Regeneration during Wound Healing. AB - Peripheral nerves have the capacity to regenerate due to the presence of neuroprotective glia of the peripheral nervous system, Schwann cells. Upon peripheral nerve injury, Schwann cells create a permissive microenvironment for neuronal regrowth by taking up cytotoxic glutamate and secreting neurotrophic signaling molecules. Impaired peripheral nerve repair is often caused by a defective Schwann cell response after injury, and there is a critical need to develop new strategies to enhance nerve regeneration, especially in organisms with restricted regenerative potential, such as humans. One approach is to explore mechanisms in lower organisms, in which nerve repair is much more efficient. A recent study demonstrated that the antiparasitic drug, ivermectin, caused hyperinnervation of primordial eye tissue in Xenopus laevis tadpoles. Our study aimed to examine the role of ivermectin in mammalian nerve repair. We performed in vitro assays utilizing human induced neural stem cells (hiNSCs) in co-culture with human dermal fibroblasts (hDFs) and found that ivermectin-treated hDFs promote hiNSC proliferation and migration. We also characterized the effects of ivermectin on hDFs and found that ivermectin causes hDFs to uptake extracellular glutamate, secrete glial cell-derived neurotrophic factor, develop an elongated bipolar morphology, and express glial fibrillary acidic protein. Finally, in a corresponding in vivo model, we found that localized ivermectin treatment in a dermal wound site induced the upregulation of both glial and neuronal markers upon healing. Taken together, we demonstrate that ivermectin promotes peripheral nerve regeneration by inducing fibroblasts to adopt a glia like phenotype. PMID- 30411009 TI - Different Oat Ingredients Stimulate Specific Microbial Metabolites in the Gut Microbiome of Three Human Individuals in Vitro. AB - We used a standardized in vitro simulation of the intestinal environment of three human donors to investigate the effect of six oat ingredients, which were produced by the application of different processing techniques, on the gut microbial community. Fructooligosaccharide was used as the positive control. Consistent changes in pH and gas production, on average -0.4 pH units and +32 kPa, indicated the high fermentability of the oat ingredients, and the resulting increased production of metabolites that are considered as beneficial for human health. These metabolites included acetate and lactate, but mostly propionate (+13.6 mM on average). All oat ingredients resulted in increased bifidobacteria levels with an average increase of 0.73 log. Moreover, a decreased production of proteolytic markers was observed, including branched short-chain fatty acids and ammonium. The results were donor-specific and product-specific. The results suggested an association between the total amounts of dietary fiber and the prebiotic potentials of different ingredients. Furthermore, as mechanical processing of oat products has previously been linked to increased extractability of dietary fibers, the obtained results suggest that different processing techniques might have impacted the potential functional properties of the final ingredients. PMID- 30411010 TI - Efficient Synthesis and in Silico Studies of the Benzimidazole Hybrid Scaffold with the Quinolinyloxadiazole Skeleton with Potential alpha-Glucosidase Inhibitory, Anticoagulant, and Antiplatelet Activities for Type-II Diabetes Mellitus Management and Treating Thrombotic Disorders. AB - The current study evaluates antidiabetic, anticoagulant, and antiplatelet activity of novel benzimidazole-containing quinolinyl oxadiazoles. These derivatives are synthesized and characterized using spectroscopy (FT-IR, 1H NMR, and mass spectroscopy) and single-crystal X-ray diffraction methods. The inhibitory effects of these compounds were evaluated by the alpha-glucosidase inhibitory assay and shows the activity in the range of IC50 = 0.66 +/- 0.05 to 3.79 +/- 0.46 MUg/mL. In addition, molecular docking studies revealed that benzimidazole-containing quinolinyl oxadiazoles can correctly dock into the target receptor protein of the human intestinal alpha-glucosidase, while their bioavailability/drug-likeness was predicted to be acceptable but requires further optimization. On the other hand, compound 8a and 8d showed anticoagulant activity as they enhanced the clotting time from control 180-410 and 180-390 s, respectively, in platelet rich plasma and 230-460 and 230-545 s in platelet poor plasma. Furthermore, only 8a showed antiplatelet activity by inhibiting epinephrine-induced platelet aggregation, and the observed aggregation inhibition was found to be 93.4%. Compounds 8a-f show nontoxic properties because of the non hydrolyzing properties in the RBC cells. In addition, 8a and 8d show anti-edema and anti-hemorrhagic properties in the experimental mice. These findings reveal that benzimidazole-containing quinolinyl oxadiazoles act as alpha-glucosidase inhibitors to develop novel therapeutics for treating type-II diabetes mellitus and can act as lead molecules in drug discovery as potential antidiabetic and antithrombotic agents. PMID- 30411011 TI - Pineapple Peel-Derived Carbon Dots: Applications as Sensor, Molecular Keypad Lock, and Memory Device. AB - Herein, the fluorescent carbon dots (CDs) with blue emission were prepared by hydrothermal treatment using pineapple peel as a source of carbon. The as prepared CDs exhibited turn-Off fluorescence behavior toward Hg2+ and subsequent turn-On behavior for l-cysteine along with enhanced biocompatibility and negligible cytotoxicity for cell imaging. The practical applicability of carbon dots was used for the quantification of Hg2+ in water. On the basis of the spectral characteristic changes, we have designed individual elementary logic operations such as NOT and IMP gates, by utilizing CD as probe and Hg2+ and l-Cys as chemical inputs. We have also demonstrated the utility of this system in electronic security devices and as memory element, with the idea of the switching. PMID- 30411012 TI - Combining Breath Figures and Supercritical Fluids To Obtain Porous Polymer Scaffolds. AB - Supercritical fluids technology is a clean methodology to foam polymeric materials. However, this technique provides only the formation of inner porosity, whereas the so-called skin layer is commonly observed at the polymer surface. This article describes a new method for the preparation of outer and inner porous poly(epsilon-caprolactone) (PCL) scaffolds by combination of supercritical CO2 (SCCO2) foaming and the breath figures technique. In the first step, experiments with a SCCO2 reactor were performed at 35-45 degrees C, 100-250 bar, and 1-20 min depressurization time. The effect of these parameters in the formation of inner porosity was investigated for an adequate optimization. In a late stage, to provide also surface porosity to the polymeric samples and remove the skin layer, the breath figures technique was employed. The evaluation of porosity was determined by scanning electronic microscopy, mercury porosimetry, and micro X ray computerized tomography scanning processing the images obtained with the ImageJ software. The results of this study using these two complementary techniques showed the existence of interconnectivity between inner and outer porosity of the samples. Furthermore, thermal transitions and crystallinity of the PCL samples have been analyzed by differential scanning calorimetry. Finally, a preliminary biological evaluation of the resulting scaffolds with mouse endothelial cells (C166-GFP) was performed to assess their biocompatibility and cellular viability. PMID- 30411013 TI - Characterization and Evaluation of Carboxymethyl Cellulose-Based Films for Healing of Full-Thickness Wounds in Normal and Diabetic Rats. AB - Artificial skin substitute made of polymeric films are of great demand in the field of skin tissue engineering. We report here the fabrication of carboxymethyl cellulose (CMC) and poly(ethylene glycol) (PEG) blend films by solution casting method for wound healing applications. The physicochemical characteristics and the thermal stability of the films were analyzed. The surface morphology shows crystalline structures with large hexagonal-like platelet crystals of CMC on the surface of the films. Pure CMC films exhibited higher tensile strength than the CMC/PEG blend films. The swelling ratio (SR) of the films was influenced by the pH of Tris-HCL buffer (2.0, 5.0, and 7.0), which increased with increase in pH. The hemocompatibility assay and cytotoxicity test using NIH 3T3 fibroblast cells showed that the films were biocompatible. To evaluate the wound healing efficacy, the films were applied in full-thickness wounds created in normal and diabetic Wistar albino rats. The wounds healed faster with pure CMC film compared to blend films in both normal and diabetic rats, evidenced by intensive collagen formation in histopathological analysis. Thus, the films have potential application in skin regeneration, thereby to restore the structural and functional characteristics of the skin. PMID- 30411014 TI - Gold Nanorod-Based Nanohybrids for Combinatorial Therapeutics. AB - In this work, multifunctional nanocarriers consisting of poly(sodium-4 styrenesulfonate) (PSS)/doxorubicin (DOXO)/poly-l-lysine hydrobromide (PLL)/hyaluronic acid (HA)-coated and (PSS/DOXO/PLL)2/HA-coated gold nanorods were assembled by the layer-by-layer technique with the aims of coupling the plasmonic photothermal properties of the metal nanoparticles for plasmonic hyperthermia and the chemoaction of drug DOXO for potential intended combinatorial cancer therapeutics in the future as well as providing different strategies for the controlled and sustained release of the cargo drug molecules. To do that, DOXO could be successfully loaded onto the hybrid nanoconstructs through electrostatic interactions with high efficiencies of up to ca. 78.3 +/- 6.9% for the first formed drug layer and 56 +/- 13% for the second one, with a total efficiency for the whole system [(PSS/DOXO/PLL)2/HA-coated NRs] of ca. 65.7 +/- 1.4%. Nanohybrid internalization was observed to be enhanced by the outer HA layer, which is able to target the CD44 receptors widely overexpressed in some types of cancers as lung, breast, or ovarian ones. Hence, these nanohybrid systems might be versatile nanoplatforms to simultaneously deliver sufficient heat for therapeutic plasmonic hyperthermia and the anticancer drug. Two controlled mechanisms were proposed to modulate the release of the chemodrug, one by means of the enzymatic degradable character of the PLL layer and another by the modulation of the interactions between the polymeric layers through the exploitation of the optical properties of the hybrid particles under near infrared (NIR) laser irradiation. The combination of this bimodal therapeutic approach exerted a synergistic cytotoxic effect on both HeLa and MDA-MB-231 cancer cells in vitro. Cell death mechanisms were also analyzed, elucidating that plasmonic photothermal therapy induces cell necrosis, whereas DOXO activates the cell apoptotic pathway. Therefore, the present NIR laser-induced targeted cancer thermo/chemotherapy represents a novel targeted anticancer strategy with easy control on demand and suitable therapeutic efficacy. PMID- 30411016 TI - Revisiting of Benzophenone Ketyl Still: Use of a Sodium Dispersion for the Preparation of Anhydrous Solvents. AB - A facile generation of organic solvents of anhydrous grade can be performed by distillation from sodium-benzophenone ketyl, which is prepared from commercial sodium dispersion and benzophenone. The distilled tetrahydrofuran, diethyl ether, hexane, 1,2-dimethoxyethane, and 1,4-dioxane with water contents less than 10 ppm were obtained by a simple protocol. Safe treatment of the distillation residue also was simply achieved by the addition of methanol. The protocol suits for providing a small amount of an anhydrous solvent at the laboratory scale. PMID- 30411015 TI - Repurposing of a Nucleoside Scaffold from Adenosine Receptor Agonists to Opioid Receptor Antagonists. AB - While screening off-target effects of rigid (N)-methanocarba-adenosine 5' methylamides as A3 adenosine receptor (AR) agonists, we discovered MUM binding hits at the delta-opioid receptor (DOR) and translocator protein (TSPO). In an effort to increase OR and decrease AR affinity by structure activity analysis of this series, antagonist activity at kappa-(K)OR appeared in 5'-esters (ethyl 24 and propyl 30), which retained TSPO interaction (MUM). 7-Deaza modification of C2 (arylethynyl)-5'-esters but not 4'-truncation enhanced KOR affinity (MRS7299 28 and 29, K i ~ 40 nM), revealed MU-OR and DOR binding, and reduced AR affinity. Molecular docking and dynamics simulations located a putative KOR binding mode consistent with the observed affinities, placing C7 in a hydrophobic region. 3 Deaza modification permitted TSPO but not OR binding, and 1-deaza was permissive to both; ribose-restored analogues were inactive at both. Thus, we have repurposed a known AR nucleoside scaffold for OR antagonism, with a detailed hypothesis for KOR recognition. PMID- 30411017 TI - Dual Inhibitors of PARPs and ROCKs. AB - Recent network and system biology analyses suggest that most complex diseases are regulated by robust and highly interconnected pathways that could be better modulated by small molecules binding to multiple biological targets. These pieces of evidence recently led to devote efforts on identifying single chemical entities that bind to two different disease-relevant targets. Here, we first predicted in silico and later confirmed in vitro that UPF 1069, a known bioactive poly(ADP-ribose) polymerase-1/2 (PARP1/2) molecule, and hydroxyfasudil, a known bioactive Rho-associated protein kinase-1/2 (ROCK1/2) molecule, have low micromolar cross-affinity for ROCK1/2 and PARP1/2, respectively. These molecules can now be regarded as chemical seeds from which pharmacological tools could be generated to study the impact of dual inhibition of PARPs and ROCKs in preclinical models of a variety of complex diseases where both targets are involved. PMID- 30411018 TI - Intracellular Delivery of Gold Nanocolloids Promoted by a Chemically Conjugated Anticancer Peptide. AB - We report on the ability of a chemically synthesized anticancer peptide, SVS-1, to promote the rapid uptake of gold nanorods (AuNRs) and gold nanoparticles (AuNPs) by live HeLa cells. For this, AuNPs and AuNRs, surface ligated with a multicoordinating polymer that presents several amine groups per ligand, are simultaneously reacted with SVS-1 and Texas-Red dye; the latter allows fluorescence visualization of the nanocrystals. Using epifluorescence microscopy, we find that incubation of the SVS-1-conjugated AuNPs and AuNRs with a model cancer cell line yields extended staining throughout the cell cytoplasm, even at low conjugate concentrations (~0.1 nM). Furthermore, uptake is specific to the SVS-1-conjugated nanocrystals. Additional endocytosis inhibition experiments, where cells have been incubated with the conjugates at 4 degrees C or in the presence of endocytic inhibitors, show that significant levels of conjugate uptake persist. These results combined indicate an uptake mechanism that does not necessarily rely on endocytosis, a promising finding with implications for the use of nanomaterials in the field of biology and nanomedicine. PMID- 30411019 TI - Aggregation-Enhanced Emission of Gold Nanoclusters Induced by Serum Albumin and Its Application to Protein Detection and Fabrication of Molecular Logic Gates. AB - Exploring aggregation-enhanced emission (AEE) of gold nanoclusters (Au NCs) is beneficial for extending their applications in sensing and molecular information processing. Herein, we present the first report of a protein-induced AEE effect of Au NCs. When human serum albumin (HSA) is mixed with glutathione-capped Au NCs under appropriate pH conditions, the Au NCs undergo extensive aggregation and exhibit significantly enhanced emission, attributed to the electrostatic and hydrophobic interactions between HSA and the NCs. Such an AEE effect is specific to serum albumin over a variety of other proteins, which facilitates the development of a facile approach for HSA determination. This sensing method displays satisfactory recoveries of 96.0-98.7% when it is applied to HSA detection in artificial urine. Moreover, the AEE effect is suited to the fabrication of AND and INHIBIT logic gates by using HSA and pH/protein-binding drug as inputs and the emission as output. PMID- 30411021 TI - Hierarchical Porous Carbon Microfibers Derived from Tamarind Seed Coat for High Energy Supercapacitor Application. AB - The overwhelming interest in supercapacitors has led to the search for various carbonaceous materials, leading to hierarchical porous carbons. Herein, we report a natural biomass (tamarind seed)-based hierarchical porous carbon without any template and activated by a facile scheme. The tamarind seed coat-based hierarchical porous carbon possessed a unique configuration, making the material exhibit superior supercapacitor properties. A single carbon fiber hosting a distinctive micro- and mesoporous structure formed a connecting thread between the pores. This unique structure enabled high surface area and high capacitance. The highest surface area obtained by this method was 1702 m2 g-1, whereas the capacitance was 157 F g-1 in 6 M KOH. Further, an ionic liquid-based electrolyte revealed 78 F g-1 at a current density of 0.5 A g-1. Outstanding capacity retentions of 96 and 93% were obtained over 1000 cycles at a current density of 2 A g-1 for aqueous (6 M KOH) and ionic liquid (1-butyl 3-methyl imidazoliumbistrifluorosulfonylimide) electrolytes, respectively. The high charge storage ability of the porous carbon microfibers (PCMFs) can be ascribed to the coexistence of micro- and mesopores. The power characteristics and the cyclic stability of PCMF materials were appealing in both electrolytes. The synthesis process described is amenable for large-scale applications with less complexity. PMID- 30411020 TI - Microbubble-Mediated Enhanced Delivery of Curcumin to Cervical Cancer Cells. AB - The major bottleneck in the current chemotherapy treatment of cancer is the low bioavailability and high cytotoxicity. Targeted delivery of drug to the cancer cells can reduce the cytotoxicity and increase the bioavailability. In this context, microbubbles are currently being explored as drug-delivery vehicles to effectively deliver drug to the tumors or cancerous cells. Microbubbles when used along with ultrasound can enhance drug uptake and inhibit the growth of tumor cells. Several potential anticancer molecules exhibit poor water solubility, which limits their use in therapeutic applications. Such poorly water soluble molecules can be coadministered with microbubbles or encapsulated within or loaded on the microbubbles surface, to enhance the effectiveness of these molecules against cancer cells. Curcumin is one of such potential anticancer molecules obtained from the rhizome of herbal spice, turmeric. In this work, curcumin-loaded protein microbubbles were synthesized and examined for effective in vitro delivery of curcumin to HeLa cells. Microbubbles in the size range of 1 10 MUm were produced using perfluorobutane as core gas and bovine serum albumin (BSA) as shell material and were loaded with curcumin. The amount of curcumin loaded on the microbubble surface was estimated using UV-vis spectroscopy, and the average curcumin loading was found to be ~54 MUM/108 microbubbles. Kinetics of in vitro curcumin release from microbubble surface was also estimated, where a 4-fold increase in the rate of curcumin release was obtained in the presence of ultrasound. Sonication and incubation of HeLa cells with curcumin-loaded BSA microbubbles enhanced the uptake of curcumin by ~250 times. Further, 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay confirmed ~71% decrease in cell viability when HeLa cells were sonicated with curcumin-loaded microbubbles and incubated for 48 h. PMID- 30411022 TI - Label-Free Aptamer-Based Biosensor for Specific Detection of Chloramphenicol Using AIE Probe and Graphene Oxide. AB - A facile, sensitive, and label-free aptamer-based fluorescent biosensor (aptasensor) for chloramphenicol (CAP) detection was successfully developed based on an aggregation-induced emission (AIE) probe and graphene oxide (GO). In this aptasensor, the specific aptamer of CAP (C-Apt) is used as the recognition part, an AIE molecule, 9,10-distyrylanthracene (DSA) derivative with short alkyl chains (9,10-bis{4-[2-(N,N,N-trimethylammonium)-ethoxy]styrene}anthracene dibromide, DSAC2N), as the fluorescent probe, and GO with a low oxidation degree as the fluorescent quencher. Initially, the AIE probe DSAC2N and C-Apt could be adsorbed on GO through pi-stacking interactions, and the fluorescence of DSAC2N could be efficiently quenched due to the energy transfer between DSAC2N and GO. When CAP is added, C-Apt can preferentially bind with CAP and the newly formed complex (C Apt-CAP) can be released from GO, resulting in the recovery of the fluorescence signal of DSAC2N. Thus, with the aid of GO, turn-on detection of CAP can be readily realized by monitoring the fluorescence signal of DSAC2N from "off" to "on". Under the optimized conditions, the aptasensor exhibits a high sensitivity toward CAP with a limit of detection of 1.26 pg/mL. Besides, we have successfully applied this aptasensor to the detection of CAP in spiked milk. PMID- 30411023 TI - Push-Pull N,N-Diphenylhydrazones Bearing Bithiophene or Thienothiophene Spacers as Nonlinear Optical Second Harmonic Generators and as Photosensitizers for Nanocrystalline TiO2 Dye-Sensitized Solar Cells. AB - A series of push-pull heterocyclic N,N-diphenylhydrazones were prepared to study the effect of structural modifications (different pi-spacers and electron withdrawing groups) on the optical (linear and nonlinear) and electronic properties of the molecules. The photovoltaic response of dye-sensitized solar cells assembled using nanocrystalline titania photosensitized with the synthesized dyes was also studied. These heterocyclic push-pull conjugated dyes involve N,N-diphenylhydrazones as electron donors linked to bithiophene or thieno[3,2-b]thiophene spacers and were functionalized with carboxylic acid, cyanoacetic acid, or dicyanovinyl acceptor groups. A combination of Suzuki Miyaura cross-coupling, Vilsmeier formylation, and condensation reactions was used to synthesize the intermediates and final products. Density functional theory (DFT) and time dependent-DFT calculations were used to obtain information on conformation, electronic structure, and electron distribution, both for the free dyes and those adsorbed on TiO2. The results of this multidisciplinary study indicate that dyes 5b and 6b have the strongest second-order nonlinear optical response with hyperpolarizability values in the range of beta = 2330 * 10-30 to 2750 * 10-30 esu, whereas photovoltaic power conversion efficiencies reach values in the range of 0.7-3.0% for dyes 5a-b and 7c and were enhanced by coadsorbing deoxycholic acid (0.8-5.1%). PMID- 30411024 TI - Enhanced Cancer Theranostics with Self-Assembled, Multilabeled siRNAs. AB - The integration of therapy and diagnostics, termed "theranostics", has recently gained widespread utility in the development of new and improved therapeutics that effectively diagnose and treat diseases, such as cancer. In this study, the covalent attachment of multiple fluorescent labels (i.e., fluorescein isothiocyanate (FITC)) to a wide range of siRNAs, including those adopting linear, V- and Y-shape nanostructures, was successfully accomplished by solid phase bioconjugation for monitoring cell uptake, co-localization, and biological activity in cell culture. The FITC-labeled higher-order V- and Y-shape siRNAs maintained the requisite hybrid stabilities and A-type helical structures for invoking RNAi activity. The FITC-siRNA hybrids with sense-strand modifiers enabled efficient mRNA knockdown (~50-90%), which also translated to increased cell death (~20-95%) in a bone metastatic prostate cancer cell line, over a 72 h incubation period. Significantly, the Y-shaped siRNA containing three FITC probes enhanced fluorescent signaling relative to the siRNA constructs containing single and double fluorophores while retaining potent knockdown and cell death effects post-transfection. Taken together, this data highlights the theranostic utility of the multilabeled FITC-siRNA constructs for potential cancer gene therapy applications. PMID- 30411025 TI - Albumin Abundance and Its Glycation Status Determine Hemoglobin Glycation. AB - Diabetes diagnosis and management majorly depend upon the measurement of glycated hemoglobin (HbA1c) levels. Various factors influence HbA1c levels such as the use of various analytical methods and the presence of various clinical conditions. Plasma albumin levels were known to be negatively associated with HbA1c. However, the precise mechanism by which they affect HbA1c is not well understood. Therefore, we have studied the influence of albumin levels and its glycation status on hemoglobin glycation using erythrocyte culture experiments. Erythrocytes maintained at low albumin concentration exhibited relatively increased albumin and hemoglobin glycation as compared to that in those maintained at higher albumin concentration. Increase in albumin glycation may decrease its ability to protect hemoglobin glycation. This was demonstrated by treatment of erythrocytes with N(epsilon)-(carboxymethyl)lysine-modified serum albumin (CMSA), which failed to protect hemoglobin glycation; instead, it increased hemoglobin glycation. The inability of CMSA to reduce hemoglobin glycation was due to the lack of free lysine residues of albumin, which was corroborated by using N(epsilon)-(acetyl)lysine serum albumin (AcSA) and clinical diabetic plasma. This is the first study which demonstrates that the modification of lysine residues of albumin impairs its ability to inhibit hemoglobin glycation. Furthermore, correlation studies between HbA1c and albumin levels or relative albumin fructosamine from clinical subjects supported our experimental finding that albumin abundance and its glycation status influence hemoglobin glycation. Therefore, we propose albumin level and its glycation status to be quantified in conjunction with HbA1c for better management of diabetes. PMID- 30411026 TI - Morphology-Preferable MoSe2 Nanobrooms as a Sensing Platform for Highly Selective Apta-Capturing of Salmonella Bacteria. AB - The present report employed nanobroom (NB)-shaped two-dimensional molybdenum diselenide (MoSe2) for the preparation of a sensing matrix for the detection of Salmonella paratyphi. An aptamer specific to salmonella was immobilized onto MoSe2NB-modified fluorine-doped tin oxide via glutaraldehyde cross-linking. Structural and morphological characterizations were performed using UV-vis spectroscopy, scanning electron microscopy, Fourier transform infrared spectroscopy, and X-ray diffraction techniques. Characterizations confirmed the nanobroom morphology and nanosize of the MoSe2 material. Electrochemical studies revealed a good linear detection range of 10-2-10-10 CFU/mL with low detection limit of 1 * 10-10 CFU/mL and with R 2 = 0.98. The developed preferable nanobroom shaped sensing matrix can provide a promising platform for rapid and accurate detection of Salmonella in real samples due to its tremendous stability and sensitivity. PMID- 30411027 TI - Al18F-NODA Benzothiazole Derivatives as Imaging Agents for Cerebrovascular Amyloid in Cerebral Amyloid Angiopathy. AB - In this study, we synthesized four novel Al18/19F-labeled 2-phenylbenzothiazole derivatives conjugated to 1,4,7-triazacyclononane-1,4-diacetic acid via alkyl linkers and evaluated them as imaging agent targets to amyloid-beta (Abeta) plaques deposited in the blood vessels of cerebral amyloid angiopathy (CAA) brain. The four ligands exhibited moderate-to-high binding ability to Abeta1-42 aggregates, of which complex 17 possessing the most potent affinity (K i = 11.3 nM) was selected for further biological evaluations. In vitro fluorescent staining and in vitro autoradiography studies on brain sections from CAA patients proved that this ligand could label Abeta deposits in blood vessels selectively. In biodistribution study, [18F]17 can hardly penetrate the blood-brain barrier (brain2 min = 0.3% ID/g) and displayed a rapid blood washout rate (blood2 min/blood60 min = 25.2), which is favorable as CAA imaging agents. In conclusion, this Al18F-labeled 2-phenylbenzothiazole complex was developed and proved to be a promising CAA positron emission tomography agent. PMID- 30411028 TI - Assessment of the Physical Properties of Inclusion Complexes of Forchlorfenuron and gamma-Cyclodextrin Derivatives and Their Promotion of Plant Growth. AB - The current study prepared solid dispersions of forchlorfenuron (CPPU) and gamma cyclodextrin (gammaCD) or CPPU and 2-hydroxypropyl-gamma-cyclodextrin (HPgammaCD) via cogrinding and coprecipitation to assess their physicochemical properties and their effect on plant growth. According to phase solubility diagrams, both CPPU/gammaCD and CPPU/HPgammaCD formed an inclusion complex at a molar ratio of 1/1. According to differential scanning calorimetry and powder X-ray diffraction, a ground mixture (GM) of CPPU and gammaCD (molar ratio = 1/1), a GM of CPPU and HPgammaCD (molar ratio = 1/1), and a coprecipitate (CP) of CPPU and gammaCD (molar ratio = 1/1) formed an inclusion complex. According to 1H-1H nuclear Overhauser effect spectroscopy NMR spectroscopy of the GMs and CP, the aromatic rings of the CPPU molecule are presumably included in CD from the wider to the narrower rim of its ring. Cultivation of broccoli sprouts with the GMs and CP resulted in no differences in the length of sprouts in comparison to a commercial preparation (Fulmet). PMID- 30411029 TI - Synthesis of Water-Soluble Far-Red-Emitting Amphiphilic BODIPY Dyes. AB - We report the synthesis of two water-soluble BODIPY dyes with far-red absorption and near-infrared fluorescence following cell membrane insertion. Introduction of dicationic or dianionic groups imparts water solubility and prevents translocation of the dye through the plasma membrane for highly effective labeling. The dicationic form is particularly well localized to the plasma membrane and resists quenching even after >8 min of continuous light exposure. The dyes are almost completely nonemissive in water and other highly polar solvents, but display high-fluorescence yields in chloroform and upon insertion into the extracellular leaflet. PMID- 30411030 TI - Synthesis and Evaluation of Antiplasmodial Efficacy of beta-Carboline Derivatives against Murine Malaria. AB - The difficulty of developing an efficient malaria vaccine along with increasing spread of multidrug resistant strain of Plasmodium falciparum to the available antimalarial drugs poses the need to discover safe and efficacious antimalarial drugs to control malaria. An alternative strategy is to synthesize compounds possessing structures similar to the active natural products or marketed drugs. Several biologically active natural products and drugs contain beta-carboline moiety. In the present study, few selected beta-carboline derivatives have been synthesized and tested for their in vitro and in vivo antiplasmodial activity against the rodent malaria parasite Plasmodium berghei (NK-65). The designed analogs exhibited considerable in vitro antimalarial activity. Two compounds (1R,3S)-methyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4 b]indole-3-carboxylate (9a) and (1R,3S)-methyl 1-(pyridin-3-yl)-2,3,4,9 tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate (9b) were further selected for in vivo studies. Both the lead compounds (9a and 9b) were observed to be safe for oral administration. The therapeutic effective dose (ED50) for 9a and 9b were determined and in the animal model, 9a (at 50 mg/kg dose) exhibited better activity in terms of parasite clearance and enhancement of host survival. Biochemical investigations also point toward the safety of the compound to the hepatic and renal functions of the rodent host. Further studies are underway to explore its activity alone as well as in combination therapy with artesunate against the human malaria parasite P. falciparum. PMID- 30411031 TI - Subgram-Scale Synthesis of Biomass Waste-Derived Fluorescent Carbon Dots in Subcritical Water for Bioimaging, Sensing, and Solid-State Patterning. AB - Fluorescent carbon dots (FCDs) have received considerable attention because of the great potential for a wide range of applications, from bioimaging to optoelectronic devices. In this work, we reported the synthesis of nitrogen-doped FCDs with an average size of 2 nm in a subcritical water apparatus by using biomass waste (i.e., expired milk) as the precursor. The obtained FCDs were highly dispersed in aqueous solution because of the presence of O-containing functional groups on their surfaces. Under the excitation of ultraviolet and blue light, the FCDs exhibited excitation wavelength-dependent fluorescence in the emission range of 400-550 nm. The FCDs could be easily taken up by HeLa cells without additional surface functionalization, serving as fluorescent nanoprobes for bioimaging. The applications of FCDs as sensing agents for the detection of Fe3+, solid-state fluorescent patterning, and transparent hybrid films were also performed, demonstrating their potential for solid-state fluorescent sensing, security labeling, and wearable optoelectronics. PMID- 30411032 TI - Analytical and Quantitative in Vivo Monitoring of Brain Neurochemistry by Electrochemical and Imaging Approaches. AB - Quantitative monitoring of brain neurochemistry is aimed at an accurate measurement of chemical basal levels and dynamics defining neuronal activities. Analytical tools must be endowed with high selectivity, sensitivity, and spatiotemporal resolution to tackle this task. On one hand, in vivo electroanalysis combined with miniature electrodes has evolved into a minimally invasive method for probing transient events during neural communication and metabolism. On the other hand, noninvasive imaging techniques have been widely adopted in visualizing the neural structure and processes within a population of neurons in two or three dimensions. This perspective will give a concise review of the inspiring frontiers at the interface of neurochemistry and electrochemistry (microvoltammetry, nanoamperometry, galvanic redox potentiometry and ion transport-based sensing) or imaging (super-resolution single nanotube tracking, deep multiphoton microscopy, and free animal imaging). Potential opportunities with these methods and their combinations for multimodal brain analysis will be discussed, intending to draw a brief picture for future neuroscience research. PMID- 30411033 TI - Resveratrol Sustains Insulin-Degrading Enzyme Activity toward Abeta42. AB - Alzheimer's disease (AD), the most common cause of dementia in the elderly, is the sixth leading cause of death in the United States. We hypothesize that the impaired clearance of Abeta42 from the brain is partly responsible for the onset of sporadic AD. In this work, we evaluated the activity of insulin-degrading enzyme (IDE) toward Abeta42 in the presence of resveratrol, a polyphenol found in red wine and grape juice. By liquid chromatography/mass spectrometry, we identified initial cleavage sites in the absence and presence of resveratrol that carry biological relevance connected to the amyloidogenic properties of Abeta42. Incubation with resveratrol results in a substantial increase in Abeta42 fragmentation compared to the control, signifying that the polyphenol sustains IDE-dependent degradation of Abeta42 and its fragments. Our findings suggest that therapeutic and/or preventative approaches combining resveratrol and IDE may hold promise for sporadic AD. PMID- 30411034 TI - Reflex Carbocation Release from Covalent Molecules by Endogenous Free Radicals. AB - Carbocations are pervasive in contemporary organic synthesis, so new and innocuous methods of making them are always desirable. A theoretical approach revealed that compounds in which radical generation takes place may release carbocations advantageously. The radical types and molecular substructures that promote this effect were identified. The best substructures were found to be 1,3 dicarbonyl compounds, particularly those based on the Meldrum's acid theme. Sulfate esters and dithiane rings could also be employed. Radicals generated on oxygen atoms or ethyne units were particularly effective. For these species, carbocation release could be reflex, that is, concurrent with radical generation. Only small radical enhancements were observed for release of lithium cations because of the ionic character of most of the precursors. Ethyne units could be incorporated as spacers between the radical center and the site of carbocation generation. Moreover, the enhancement was transmitted down polyethyne chains of at least six units. PMID- 30411035 TI - Binding Analysis of the Inositol-Requiring Enzyme 1 Kinase Domain. AB - Inositol-requiring enzyme 1 (IRE1) is an orchestrator of the unfolded protein response (UPR), the cellular response to endoplasmic reticulum (ER) stress that plays a crucial role in tumor development. IRE1 signaling is the most evolutionary conserved branch of the UPR. Under ER stress, the IRE1 luminal domain undergoes a conformational change to multimerize, resulting in trans autophosphorylation and activation of the cytosolic kinase and endoribonuclease domain. Adenosine triphosphate-competitive inhibitors that bind to the IRE1 kinase site can modulate the activity of the RNase domain through an allosteric relationship between the IRE1 kinase and RNase domains. The current study aims at the investigation of available structural data of the IRE1 kinase domain and provides insights into the design of novel kinase inhibitors. To this end, a detailed analysis of IRE1 kinase active site and investigation of suitable structures for virtual screening studies were performed. The results indicate in silico target fishing as an appropriate strategy for the identification of novel IRE1 kinase binders, further validating the robustness of the in silico protocol. Importantly, the study highlights the kinase-inhibiting RNase attenuator (KIRA) bound protein data bank 4U6R structure as the best protein structure to perform virtual screening to develop diverse and more potent KIRA-like IRE1 kinase inhibitors that are capable of allosterically affecting the RNase activity. PMID- 30411036 TI - Bioactive Heterometallic CuII-ZnII Complexes with Potential Biomedical Applications. AB - A series of multinuclear heterometallic Cu-Zn complexes of molecular formula [(CuL)2Zn(dca)2] (1), [(CuL)2Zn(NO3)2] (2), [(CuL)2Zn2(Cl)4] (3), and [(CuL)2Zn2(NO2)4] (4) have been synthesized by reacting [CuL] as a "metalloligand (ML)" (where HL = N,N'-bis(5-chloro-2-hydroxybenzylidene)-2,2-dimethylpropane-1,3 diamine) and by varying the anions or coligands using the same molar ratios of the reactants. All of the four products including the ML have been characterized by infrared and UV-vis spectroscopies and elemental and single-crystal X-ray diffraction analyses. By varying the anions, different structures and topologies are obtained which we have tried to rationalize by means of thorough density functional theory calculations. All of the complexes (1-4) have now been applied for several biological investigations to verify their therapeutic worth. First, their cytotoxicity properties were assessed against HeLa human cervical carcinoma along with the determination of IC50 values. The study was extended with extensive DNA and protein binding experiments followed by detailed fluorescence quenching study with suitable reagents to comprehend the mechanistic pathway. From all of these biological studies, it has been found that all of these heterometallic complexes show more than a few fold improvement of their therapeutic values as compared to the similar homometallic ones probably because of the simultaneous synergic effect of copper and zinc. Among all of the four heterometallic complexes, complex 3 exhibits highest binding constants and IC50 values suggest for their better interaction toward the biological targets and hence have better clinical importance. PMID- 30411037 TI - Assessing Binary Mixture Effects from Genotoxic and Endocrine Disrupting Environmental Contaminants Using Infrared Spectroscopy. AB - Benzo[a]pyrene (B[a]P), polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs) are persistent contaminants and concern has arisen over co-exposure of organisms when the chemicals exist in mixtures. Herein, attenuated total reflection Fourier transform infrared spectroscopy was used to identify biochemical alterations induced in cells by single and binary mixtures of these environmental chemicals. It was also investigated as a method to identify if interactions are occurring in mixtures and as a possible tool to predict mixture effects. Mallard fibroblasts were treated with single and binary mixtures of B[a]P, PCB126, PCB153, BDE47, and BDE209. Comparison of observed spectra from cells treated with binary mixtures with expected additive spectra, which were created from individual exposure spectra, indicated that in many areas of the spectrum, less-than-additive binary mixture effects may occur. However, possible greater-than-additive alterations were identified in the 1650-1750 cm-1 lipid region and may demonstrate a common mechanism of B[a]P and PCBs or PBDEs, which can enhance toxicity in mixtures. PMID- 30411038 TI - Facile Conversion of Toxic Cigarette Butts to N,S-Codoped Carbon Dots and Their Application in Fluorescent Film, Security Ink, Bioimaging, Sensing and Logic Gate Operation. AB - The present work is emphasized on converting toxic cigarette butts (CBs) into highly fluorescent N,S-codoped carbon dots by a facile hydrothermal approach and exploring their multiple applications. The as-produced carbon dots (CBCDs) exhibited bright and stable fluorescence with a quantum yield of 26% and used as a label-free probe for "on-off-on" sequential detection of Fe3+ and ascorbic acid (AA). The fluorescence of CBCDs can be significantly quenched by Fe3+ ions through static quenching and restored upon the subsequent addition of AA due to the reduction of Fe3+ to Fe2+ by AA. This nanoprobe presented great selectivity and excellent sensitivity to Fe3+ and AA with a detection limit of 0.13 and 0.2 MUM, respectively. Furthermore, the nanoprobe was extended to biosystem (intracellular detection) and successfully applied for the detection of Fe3+ in real water (tap, bore, and pond) and AA in biological samples (human urine and serum). In addition, we have constructed an IMPLICATION logic gate based on these unique sensing characteristics. The "visible-invisible" and "UV-visible" property explored their use as invisible ink for security applications. Furthermore, highly photostable fluorescent polymer films were prepared by incorporating CBCDs in poly(vinyl alcohol). It is anticipated that the strong and stable fluorescence emission nature of these films might find direct or indirect applications in various optical/optoelectronic devices, ranging from fluorescent displays to light-emitting diodes. PMID- 30411039 TI - Synthesis and Evaluation of Protein-Phenylboronic Acid Conjugates as Lectin Mimetics. AB - Glycan-binding molecules, such as lectins, are very important tools for characterizing, imaging, or targeting glycans and are often involved in either physiological or pathological processes. However, their availability is far less compared to the diversity of native glycans. Therefore, development of lectin mimetics with desired specificity and affinity is in high demand. Boronic acid reacts with 1,2- and 1,3-diols of saccharides in aqueous media through reversible boronate ester formation and are regarded as synthetic lectin mimetics. In this study, bovine serum albumin (BSA)-phenylboronic acid (PBA) conjugates were synthesized in a density-controlled manner by targeting both aspartic and glutamic acids to afford lectin mimetics with multivalent PBA, as multivalency is a key factor for glycan recognition in both specificity and affinity. The resultant BSA-PBA conjugates were characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis. Their macrophage cell surface glycan-binding capacity was characterized by a competitive lectin binding assay examined by flow cytometry, and 3-(4,5-di-methylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay showed biocompatibility. These novel lectin mimetics will find a broad range of applications as they can be wittingly modified, altering binding specificity and capacity. PMID- 30411040 TI - Overriding Phthalate Decomposition When Exploring Mycophenolic Acid Intermediates as Selenium-Based ROS Biological Probes. AB - Hypochlorous (OCl-) acid is the most well-known bacterial oxidant to be produced by neutrophils. Excess amounts of OCl- can cause various disorders in living systems. Herein, we have designed, synthesized, and characterized two novel organoselenium-based target molecules (Probe-1 and Probe-OCl) based on a synthetic intermediate of mycophenolic acid for the aqueous detection of OCl-. Probe 1 has been recently reported (Org. Lett. 2018, 20, 3557-3561); both probes show immediate "turn-on" fluorescence (<1 s) upon the addition of OCl-, display an increase in the fluorescence quantum yield (3.7-fold in Probe-1 and 11.6-fold in Probe-OCl), and are completely soluble in aqueous media without the help of any cosolvent. However, a decrease in the "turn-on" intensity with the oxidized version of Probe-1 in cell assays due to the anhydride/phthalate functionality suggests that probe degradation occurs based on hydrolytic action (a probe degradation half-life of ~1500 s at 15 MUM Probe-1 and 150 MUM OCl). Thus, the change of "anhydride" to "methylamide" begets Probe-OCl, which possesses more stability without sacrificing its water solubility properties and responses at short times. Further studies suggest that Probe-OCl is highly stable within physiological pH (pH = 7.4). Surprisingly, in live cell experiments involving U-2 OS cells and HeLa cells, Probe-OCl accumulated and aggregated in lipid droplets and gives a "turn-on" fluorescence response. 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assays confirmed that Probe-OCl is not toxic. Cuvette aggregation studies were also performed (tetrahydrofuran/H2O) to demonstrate aggregation-induced fluorescence at longer times. Our current hypothesis is that the "turn-on" fluorescence effect is caused by the aggregation-induced emission mechanism available for Probe-OCl. In this case, in tandem, we reanalyzed the Mes BOD-SePh derivative to compare and contrast cell localization as imaged by confocal microscopy; fluorescence emission occurs in the absence of, or prior to, Se oxidation. PMID- 30411042 TI - Evaporation-Induced Biomolecule Detection on Versatile Superhydrophilic Patterned Surfaces: Glucose and DNA Assay. AB - We introduce a droplet-based biomolecular detection platform using robust, versatile, and low-cost superhydrophilic patterned superhydrophobic surfaces. Benefitting from confinement and evaporation-induced shrinkage of droplets on wetted patterns, we show enrichment-based biomolecular detection using very low sample volumes. First, we developed a glucose assay using fluorescent polydopamine (PDA) based on enhancement of PDA emission by hydrogen peroxide (H2O2) produced in enzyme-mediated glucose oxidation reaction. Incubation in evaporating droplets resulted in brighter fluorescence compared to that in bulk solutions. Droplet assay was highly sensitive toward increasing glucose concentration while that in milliliter-volume solutions resulted in no fluorescence enhancement at similar time scales. This is due to droplet evaporation that increased the reaction rate by causing enrichment of PDA and glucose/glucose oxidase as well as increased concentration of H2O2 generated in shrinking droplet. Second, we chemically functionalized wetted patterns with single-stranded DNA and developed fluorescence-based DNA detection to demonstrate the adaptability of the patterned surfaces for a different class of assay. We achieved detection of glucose and DNA with concentration down to 130 MUM and 200 fM, respectively. Patterned superhydrophobic surfaces with their simple production, sensitive response, and versatility present potential for bioanalysis from low sample volumes. PMID- 30411041 TI - Bran-New Four-Molecule and Five-Molecule Cascade Reactions for One-Pot Synthesis of Pyrano[3,2-c]chromen-5-ones and Spiro[benzo[b][1,4]diazepine-2,2'-pyrano[3,2 c]chromen]-5'-ones under Catalyst- and Solvent-Free Conditions. AB - Herein, two versatile bran-new methods have been developed for building three new kinds of complicated-framework compounds including 2,4,4-trimethyl-2 (phenylamino)-3,4-dihydro-2H,5H-pyrano[3,2-c]chromen-5-ones, 4,4,4',4' tetramethyl-1,3,3',4,4',5-hexahydro-5'H-spiro-[benzo[b][1,4]diazepine-2,2' pyrano[3,2-c]-chromen]-5'-ones, and 2,2,4',4'-tetramethyl-2,3,3',4'-tetrahydro 5H,5'H-spiro[benzo[b][1,4]-oxazepine-4,2'-pyrano[3,2-c]chromen]-5'-ones in a one pot manner via four-molecule and five-molecule cascade reactions of commercially available 4-hydroxychromen-2-one, substituted anilines, and acetone. In consideration of these impressive features including no need of additional catalysts and solvents, moderate to good yields, excellent site-selectivity, and broad substrate/functional group tolerance, we believe that the two present protocols should have the potential for broad synthetic utility. PMID- 30411043 TI - Intercellular Connectivity and Multicellular Bioelectric Oscillations in Nonexcitable Cells: A Biophysical Model. AB - Bioelectricity is emerging as a crucial mechanism for signal transmission and processing from the single-cell level to multicellular domains. We explore theoretically the oscillatory dynamics that result from the coupling between the genetic and bioelectric descriptions of nonexcitable cells in multicellular ensembles, connecting the genetic prepatterns defined over the ensemble with the resulting spatio-temporal map of cell potentials. These prepatterns assume the existence of a small patch in the ensemble with locally low values of the genetic rate constants that produce a specific ion channel protein whose conductance promotes the cell-polarized state (inward-rectifying channel). In this way, the short-range interactions of the cells within the patch favor the depolarized membrane potential state, whereas the long-range interaction of the patch with the rest of the ensemble promotes the polarized state. The coupling between the local and long-range bioelectric signals allows a binary control of the patch membrane potentials, and alternating cell polarization and depolarization states can be maintained for optimal windows of the number of cells and the intercellular connectivity in the patch. The oscillatory phenomena emerge when the feedback between the single-cell bioelectric and genetic dynamics is coupled at the multicellular level. In this way, the intercellular connectivity acts as a regulatory mechanism for the bioelectrical oscillations. The simulation results are qualitatively discussed in the context of recent experimental studies. PMID- 30411044 TI - In Vitro Selection and Characterization of a Single-Stranded DNA Aptamer Against the Herbicide Atrazine. AB - Atrazine is an herbicide that is widely used in crop production at about 70 million pounds per year in the United States. Its widespread use has led to contamination of groundwater and other aquatic systems. It has resulted in many serious environmental and human health issues. This study focuses on the identification and characterization of a single-stranded DNA (ssDNA) aptamer that binds to atrazine. In this study, a variation of the systematic evolution of ligands by exponential enrichment (SELEX) process was used to identify an aptamer, which binds to atrazine with high affinity and specificity. This SELEX focused on inducing the aptamer's ability to change conformation upon binding to atrazine, and stringent negative target selections. After 12 rounds of in vitro selection, the ssDNA aptamer candidate R12.45 was chosen and truncated to obtain a 46-base sequence. The binding affinity, specificity, and structural characteristics of this truncated candidate was investigated by using isothermal titration calorimetry, circular dichroism (CD) analysis, SYBR Green I (SG) fluorescence displacement assays, and gold nanoparticles (AuNPs) colorimetric assays. The truncated R12.45 candidate aptamer bound to atrazine with high affinity (K d = 3.7 nM) and displayed low cross-binding activities on structurally related herbicides. In addition, CD analysis data indicated a target induced structural stabilization. Finally, SG assays and AuNPs assays showed nonconventional binding activities between the truncated R12.45 aptamer candidate and atrazine, which warrants future studies. PMID- 30411045 TI - Discovery of the Orally Effective Thyrotropin-Releasing Hormone Mimetic: 1-{N [(4S,5S)-(5-Methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-l-alanyl} (2R)-2-methylpyrrolidine Trihydrate (Rovatirelin Hydrate). AB - We have explored orally effective thyrotropin-releasing hormone (TRH) mimetics, showing oral bioavailability and brain penetration by structure-activity relationship (SAR) study on the basis of in vivo antagonistic activity on reserpine-induced hypothermia in mice. By primary screening of the synthesized TRH mimetics, we found a novel TRH mimetic: l-pyroglutamyl-[3-(thiazol-4-yl)-l alanyl]-l-prolinamide with a high central nervous system effect compared with TRH as a lead compound. Further SAR optimization studies of this lead compound led to discovery of a novel orally effective TRH mimetic: 1-{N-[(4S,5S)-(5-methyl-2 oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-l-alanyl}-(2R)-2-methylpyrrolidine trihydrate (rovatirelin hydrate), which was selected as a candidate for clinical trials. PMID- 30411047 TI - Biomass-Mediated Synthesis of Cu-Doped TiO2 Nanoparticles for Improved Performance Lithium-Ion Batteries. AB - Pure TiO2 and Cu-doped TiO2 nanoparticles are synthesized by the biomediated green approach using the Bengal gram bean extract. The extract containing biomolecules acts as capping agent, which helps to control the size of nanoparticles and inhibit the agglomeration of particles. Copper is doped in TiO2 to enhance the electronic conductivity of TiO2 and its electrochemical performance. The Cu-doped TiO2 nanoparticle-based anode shows high specific capacitance, good cycling stability, and rate capability performance for its envisaged application in lithium-ion battery. Among pure TiO2, 3% Cu-doped TiO2, and 7% Cu-doped TiO2 anode, the latter shows the highest capacity of 250 mAh g-1 (97.6% capacity retention) after 100 cycles and more than 99% of coulombic efficiency at 0.5 A g-1 current density. The improved electrochemical performance in the 7% Cu-doped TiO2 is attributed to the synergetic effect between copper and titania. The results reveal that Cu-doped TiO2 nanoparticles might be contributing to the enhanced electronic conductivity, providing an efficient pathway for fast electron transfer. PMID- 30411046 TI - RNA Aptamers with Specificity for Heparosan and Chondroitin Glycosaminoglycans. AB - In this study, two respective groups of RNA aptamers have been selected against two main classes of glycosaminoglycans (GAGs), heparosan, and chondroitin, as they have proven difficult to specifically detect in biological samples. GAGs are linear, anionic, polydisperse polysaccharides found ubiquitously in nature, yet their detection remains problematic. GAGs comprised repeating disaccharide units, consisting of uronic acid and hexosamine residues that are often also sulfated at various positions. Monoclonal antibodies are frequently used in biology and medicine to recognize various biological analytes with high affinity and specificity. However, GAGs are conserved across the whole animal phylogenic tree and are nonimmunogenic in hosts traditionally used for natural antibody generation. Thus, it has been challenging to obtain high affinity, selective antibodies that recognize various GAGs. In the absence of anti-GAG antibodies, glycobiologists have relied on the use of specific enzymes to convert GAGs to oligosaccharides for analysis by mass spectrometry. Unfortunately, while these methods are sensitive, they can be labor-intensive and cannot be used for in situ detection of intact GAGs in cells and tissues. Aptamers are single-stranded oligonucleotide (DNA or RNA) ligands capable of high selectivity and high affinity detection of biological analytes. Aptamers can be developed in vitro by the systematic evolution of ligands by exponential enrichment (SELEX) to recognize nonimmunogenic targets, including neutral carbohydrates. This study utilizes the SELEX method to generate RNA aptamers, which specifically bind to the unmodified GAGs, heparosan, and chondroitin. Binding confirmation and cross screening with other GAGs were performed using confocal microscopy to afford three specific GAGs to each target. Affinity constant of each RNA aptamer was obtained by fluorescent output after interaction with the respective GAG target immobilized on plates; the K D values were determined to be 0.71-1.0 MUM for all aptamers. Upon the success of chemical modification (to stabilize RNA aptamers in actual biological systems) and fluorescent tagging (to only visualize RNA aptamers) of these aptamers, they would be able to serve as a specific detection reagent of these important GAGs in biological samples. PMID- 30411048 TI - Core-Shell Nanostructured Fe3O4-Poly(styrene-co-vinylbenzyl chloride) Grafted PPI Dendrimers Stabilized with AuNPs/PdNPs for Efficient Nuclease Activity. AB - Four different novel magnetic core-shell nanocomposites stabilized with Au/Pd nanoparticles (NPs) were prepared by a simple procedure and demonstrated their catalytic activity for effective cleavage of pBR322 DNA. Initially, the Fe3O4 poly(styrene-divinylbenzene-vinylbenzyl chloride) (ST-DVB-VBC) matrix functionalized with 3-aminobenzoic acid was prepared and grafted with PPI-G(2) and PPI-G(3) dendrimers. Each core-shell matrix was immobilized with AuNPs and PdNPs separately. The resulting composites were characterized by FT-IR, UV-vis, SEM, TEM, XRD, VSM, XPS, Raman, and TGA. The magnetic core-shell nanocomposites at concentrations from 30 to 50 MUM were employed separately to study DNA cleavage by agarose gel electrophoresis. Among the four magnetic core-shell nanocomposites, Fe3O4-poly(ST-DVB-VBC)-PPI-G(3)-AuNPs showed higher activity than others for DNA cleavage, and formed Form-II and -III DNA. When the concentration of Fe3O4-poly(ST-DVB-VBC)-PPI-G(3)-AuNPs was increased from 40 to 45 and 45 to 50 MUM, Form-III (linear) DNA was observed with 10 and 22%, respectively, in addition to Form-II. This observation suggests formation of linear DNA from the supercoiled DNA via nicked DNA-intermediated consecutive cleaving process. The magnetic core-shell nanocomposites were stable and monodispersed, and exhibited rapid magnetic response. These properties are crucial for their application in biomolecular separations and targeted drug-delivery in the future. PMID- 30411049 TI - Analysis of the Binding of Aripiprazole to Human Serum Albumin: The Importance of a Chloro-Group in the Chemical Structure. AB - Aripiprazole (ARP), a quinolinone derivative, is an atypical antipsychotic drug that is used in the treatment of schizophrenia. ARP has an extensive distribution and more than 99% of the ARP and dehydro-ARP, the main active metabolite, is bound to plasma proteins. However, information regarding the protein binding of ARP is limited. In this study, we report on a systematic study of the protein binding of ARP. The interaction of ARP and structurally related compounds with human serum albumin (HSA) was examined using equilibrium dialysis, circular dichroism (CD) spectroscopy, fluorescent probe displacement, and an X-ray crystallographic analysis. The binding affinities (nK) for ARP and its main metabolite, dehydro-ARP with HSA were found to be significantly higher than other structurally related compounds. The results of equilibrium dialysis experiments and CD spectral data indicated that the chloro-group linked to the phenylpiperazine ring in the ARP molecule plays a major role in the binding of these ligands to HSA. Furthermore, fluorescent probe displacement results indicated that ARP appears to bind at the site II pocket in subdomain III. A detailed CD spectral analysis suggests that the chloro-group linked to the phenylpiperazine ring may control the geometry of the ARP molecule when binding in the site II binding pocket. X-ray crystallographic analysis of the ARP-HSA complex revealed that the distance between the chlorine atom at the 3-positon of dichlorophenyl-piperazine on ARP and the sulfur atom of Cys392 in HSA was 3.4-3.6 A. A similar halogen bond interaction has also been observed in the HSA structure complexed with diazepam, which also contains a chloro-group. Thus, the mechanism responsible for the binding of ARP to a protein elucidated here should be relevant for assessing the pharmacokinetics and pharmacodynamics of ARP in various clinical situations and for designing new drugs. PMID- 30411050 TI - Exploring Exercise- and Context-Induced Peptide Changes in Mice by Quantitative Mass Spectrometry. AB - Recent research suggests that exercise may help facilitate abstinence from cocaine addiction, though the mechanisms are not well understood. In mice, wheel running accelerates the extinction of conditioned place preference (CPP) for cocaine, providing an animal model for evaluating potential neurological mechanisms. The objective of this study was to quantify dynamic changes in endogenous peptides in the amygdala and dentate gyrus of the hippocampus in mice exposed to a context paired with the effects of cocaine, and in response to exercise. Male C57BL/6J mice conditioned to cocaine were housed with or without running wheels for 30 days. Following a CPP test and final exposure to either a cocaine- or saline-associated context, peptides were measured in brain tissue extracts using label-free matrix-assisted laser desorption/ionization mass spectrometry (MS) and stable isotopic labeling with liquid chromatography and electrospray ionization MS. CPP in mice was significantly reduced with running, which correlated to decreased myelin basic protein derivatives in the dentate gyrus extracts, possibly reflecting increased unmyelinated granule neuron density. Exposure to a cocaine-paired context increased hemoglobin-derived peptides in runners and decreased an actin-derived peptide in sedentary animals. These results allowed us to characterize a novel set of biomarkers that are responsive to exercise in the hippocampus and in a cocaine-paired context in the amygdala. PMID- 30411051 TI - Storing Energy in Biodegradable Electrochemical Supercapacitors. AB - The development of green and biodegradable electrical components is one of the main fronts of research to overcome the growing ecological problem related to the issue of electronic waste. At the same time, such devices are highly desirable in biomedical applications such as integrated bioelectronics, for which biocompatibility is also required. Supercapacitors for storage of electrochemical energy, designed only with biodegradable organic matter would contemplate both aspects, that is, they would be ecologically harmless after their service lifetime and would be an important component for applications in biomedical engineering. By means of atomistic simulations of molecular dynamics, we propose a supercapacitor whose electrodes are formed exclusively by self-organizing peptides and whose electrolyte is a green amino acid ionic liquid. Our results indicate that this supercapacitor has a high potential for energy storage with superior performance than conventional supercapacitors. In particular its capacity to store energy was estimated to be almost 20 times greater than an analogue one of planar metallic electrodes. PMID- 30411052 TI - Inositol Monophosphatase: A Bifunctional Enzyme in Mycobacterium smegmatis. AB - Inositol monophosphatase (IMPase) is a crucial enzyme for the biosynthesis of phosphatidylinositol, an essential component in mycobacterial cell walls. IMPase A (ImpA) from Mycobacterium smegmatis is a bifunctional enzyme that also functions as a fructose-1,6-bisphosphatase (FBPase). To better understand the bifunctional nature of this enzyme, point mutagenesis was conducted on several key residues and their enzyme activity was tested. Our results along with active site models support the fact that ImpA is a bifunctional enzyme with residues Gly94, Thr95 hypothesized to be contributing to the FBPase activity and residues Trp220, Asp221 hypothesized to be contributing to the IMPase activity. Double mutants, W220A + D221A reduced both FBPase and IMPase activity drastically while the double mutant G94A + T95A surprisingly partially restored the IMPase activity compared to the single mutants. This study establishes the foundation toward obtaining a better understanding of the bifunctional nature of this enzyme. PMID- 30411054 TI - Transport Properties of Commercial Cellulose Nanocrystals in Aqueous Suspension Prepared from Chemical Pulp via Sulfuric Acid Hydrolysis. AB - A cellulose nanocrystal (CNC) sample prepared from chemical pulp via sulfuric acid hydrolysis procedures has been supplied by InnoTech Alberta Inc. in the shape of white dry powder as a prototype product. Some transport coefficients were precisely investigated for the CNC sample in aqueous suspensions at the room temperature of 25 degrees C such as the average rotational and translational diffusion coefficients (D r and D t) and viscoelastic relaxation times (tauv) at dilute conditions. The determined values, D r ~ 2.3 * 103 s-1 and D t ~ 1.0 * 10 11 m2 s-1, using depolarized and usual dynamic light scattering (DLS) techniques, respectively, proposed the consistent length and width of L ~ 170 nm and W ~ 7.6 nm via a theoretical model for monodisperse rigid rods dispersed in pure water. The viscoelastic behavior for aqueous CNC suspensions containing spherical probe particles was examined using DLS rheological techniques. The obtained value of tauv = 1.0 * 10-4 s fairly agrees with that of (6D r)-1 ~ 7.4 * 10-5 s. Because the theoretical model for monodisperse rods denotes the relationship tauv = (6D r)-1, this observation strongly confirms that the CNC sample behaves as approximately monodisperse rigid rodlike particles. Transmission electron microscopy (TEM) images clearly demonstrated a bimodal distribution in rod length with major and small minor peaks at ca. 150 and 240 nm, respectively. Then, the reason for the observed disagreement between the L values resulted from the transport coefficients and the major peak in TEM images is the presence of the small minor component with L ~ 240 nm. Consequently, individual nanosize rodlike crystalline particles in the CNC sample well disperse without forming large aggregations because of strong interactions and behave as isolated individual rods in dilute aqueous suspensions. PMID- 30411053 TI - Encapsulation and Delivery of Neutrophic Proteins and Hydrophobic Agents Using PMOXA-PDMS-PMOXA Triblock Polymersomes. AB - Polymersomes are attractive nanocarriers for hydrophilic and lipophilic drugs; they are more stable than liposomes, tunable, and relatively easy to prepare. The copolymer composition and molar mass are critical features that determine the physicochemical properties of the polymersomes including the rate of drug release. We used the triblock-copolymer, poly(2-methyl-2-oxazoline)-block-poly (dimethysiloxane)-block-poly(2-methyl-2-oxazoline) (PMOXA-PDMS-PMOXA), to form amphipathic polymersomes capable of loading proteins and small hydrophobic agents. The selected agents were unstable neurotrophins (nerve growth factor and brain-derived neurotrophic factor), a large protein CD109, and the fluorescent drug curcumin. We prepared, characterized, and tested polymersomes loaded with selected agents in 2D and 3D biological models. Curcumin-loaded and rhodamine bound PMOXA-PDMS-PMOXA polymersomes were used to visualize them inside cells. N Methyl-d-aspartate receptor (NMDAR) agonists and antagonists were also covalently attached to the surface of polymersomes for targeting neurons. Labeled and unlabeled polymersomes with or without loaded agents were characterized using dynamic light scattering (DLS), UV-vis fluorescence spectroscopy, and asymmetrical flow field-flow fractionation (AF4). Polymersomes were imaged and tested for biological activity in human and murine fibroblasts, murine macrophages, primary murine dorsal root ganglia, and murine hippocampal cultures. Polymersomes were rapidly internalized and there was a clear intracellular co localization of the fluorescent drug (curcumin) with the fluorescent rhodamine labeled polymersomes. Polymersomes containing CD109, a glycosylphosphatidylinositol-anchored protein, promoted cell migration in the model of wound healing. Nerve growth factor-loaded polymersomes effectively enhanced neurite outgrowth in dissociated and explanted dorsal root ganglia. Brain-derived neurotrophic factor increased dendritic spine density in serum deprived hippocampal slice cultures. NMDAR agonist- and antagonist-functionalized polymersomes targeted selectively neurons over glial cells in mixed cultures. Collectively, the study reveals the successful incorporation into polymersomes of biologically active trophic factors and small hydrophilic agents that retain their biological activity in vitro, as demonstrated in selected central and peripheral tissue models. PMID- 30411055 TI - Folic Acid-Conjugated Cellulose Nanocrystals Show High Folate-Receptor Binding Affinity and Uptake by KB and Breast Cancer Cells. AB - The study evaluates cellulose nanocrystals (CNCs) as nanocarriers for targeted, intracellular delivery of molecular agents. CNCs were labeled with fluorescein-5' isothiocyanate as an imaging agent and conjugated to folic acid (FA) as a targeting ligand. The CNC conjugates were characterized by UV-vis spectroscopy, zeta-potential analysis, dynamic light scattering, and atomic force microscopy. Cellular binding/uptake of the FA-conjugated CNCs by KB and MDA-MB-468 cells was quantified with cellular uptake assays. Internalization of the particles was confirmed by confocal microscopy. Uptake mechanisms were determined by inhibition studies with chlorpromazine and genistein. Binding affinity was qualitatively assessed with a free folate inhibition assay. Both KB and MDA-MB-468 cells exhibited significant and folate-receptor specific binding/uptake of FA conjugated CNCs. Clathrin-mediated endocytosis was a significant uptake mechanism in both cell types, whereas caveolae-mediated endocytosis only played a significant role in MDA-MB-468 cells. Uptake inhibition of FA-conjugated CNCs by KB cells required high concentrations (>1 mM) of free FA. The observed FR specific internalization of FA-conjugated CNCs by FR-positive cancer cells and tumors and their remarkable high affinity for the FR demonstrate the great potential of CNCs as novel nanocarriers for imaging agents and chemotherapeutics in the early detection and treatment of cancer. PMID- 30411056 TI - Identification of Nanomolar Lectin Ligands by a Glycodendrimer Microarray. AB - Carbohydrate-protein interactions play key roles in a wide variety of biological processes. These interactions are usually weak, with dissociation constants in the low millimolar to high micromolar range. Nature uses multivalency to reach high avidities via the glycoside cluster effect. Capitalizing on this effect, numerous synthetic multivalent glycoconjugates have been described and used as ligands for carbohydrate-binding proteins. However, valency is only one of the several parameters governing the binding mechanisms that are different for every biological receptor, making it almost impossible to predict. In this context, ligand optimization requires the screening of a large number of structures with different valencies, rigidities/flexibilities, and architectures. In this article, we describe a screening platform based on a glycodendrimer array and its use to determine the key parameters for high-affinity ligands of lectin. Several glycoclusters and glycodendrimers displaying varying numbers of alpha-N acetylgalactosamine residues were covalently attached on glass slides, and their bindings were studied with the fluorophore-functionalized Helix pomatia agglutinin (HPA) used as a lectin model. This technique requires minimal quantities of glycoconjugate compared to those for other techniques and affords useful information on the binding strength. Building of the glycodendrimer array and quantification of the interactions with HPA are described. PMID- 30411057 TI - iEDDA Conjugation Reaction in Radiometal Labeling of Peptides with 68Ga and 64Cu: Unexpected Findings. AB - The inverse electron demand Diels-Alder conjugation reaction has gained increasing importance over the past few years for efficient in vivo and ex vivo radiometal labeling of antibodies. However, the application of this very fast reaction type has not been studied for radiolabeling of peptides so far. We show here the synthesis of 3-benzyl-1,2,4,5-tetrazine-comprising ((1,4,7,10 tetraazacyclododecane-4,7,10-triyl)triacetic acid-1-glutaric acid) (DOTA-GA) and ((1,4,7-triazacyclononane-4,7-diyl)diacetic acid-1-glutaric acid) (NODA-GA) chelators and their radiometal labeling with 68Ga3+ and 64Cu2+. The secondary labeling precursors 68Ga-DOTA-GA-Tz, 68Ga-NODA-GA-Tz, and 64Cu-DOTA-GA-Tz were obtained in high radiochemical yields (RCYs) and purities as well as molar activities for further labeling of trans-cyclooctene (TCO)-modified peptides. However, the following reactions of the radiometal-labeled tetrazines with different TCO-comprising model peptide analogs unexpectedly resulted in the formation of a considerable amount of side products (20-55%) which limits the overall achievable RCYs and purities as well as molar activities of the target radiopeptides. Under otherwise identical, nonradioactive reaction conditions, this effect could however not be observed. In contrast, the corresponding one step radiolabeling protocols provided the target 68Ga-labeled radiopeptides in exceptionally high RCYs and purities of >=99% and molar activities of 68-72 GBq/MUmol starting from activities of 340-358 MBq of 68Ga. Thus, the usefulness of the two-step labeling of TCO-modified peptides with radiometal-labeled chelator-tetrazines seems to be limited. PMID- 30411058 TI - Design and Potency of Dual Soluble Epoxide Hydrolase/Fatty Acid Amide Hydrolase Inhibitors. AB - Fatty acid amide hydrolase (FAAH) is responsible for regulating concentrations of the endocannabinoid arachidonoyl ethanolamide. Multiple FAAH inhibitors have been developed for clinical trials and have failed to demonstrate efficacy at treating pain, despite promising preclinical data. One approach toward increasing the efficacy of FAAH inhibitors is to concurrently inhibit other targets responsible for regulating pain. Here, we designed dual inhibitors targeting the enzymes FAAH and soluble epoxide hydrolase (sEH), which are targets previously shown to synergize at reducing inflammatory and neuropathic pain. Exploration of the sEH/FAAH inhibitor structure-activity relationship started with PF-750, a FAAH inhibitor (IC50 = 19 nM) that weakly inhibited sEH (IC50 = 640 nM). Potency was optimized resulting in an inhibitor with improved potency on both targets (11, sEH IC50 = 5 nM, FAAH IC50 = 8 nM). This inhibitor demonstrated good target selectivity, pharmacokinetic properties (AUC = 1200 h nM, t 1/2 = 4.9 h in mice), and in vivo target engagement. PMID- 30411059 TI - Synthesis and Purification of Homogeneous Lipid-Based Peptide Nanocarriers by Overcoming Phospholipid Ester Hydrolysis. AB - Despite the therapeutic promise of phospholipid-based nanocarriers, a major obstacle to their widespread clinical translation is a susceptibility to fatty acid ester hydrolysis, leading to lack of quality control and inconsistencies in self-assembly formulations. Using electrospray ionization mass spectrometry fragmentation in combination with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, we have demonstrated a method to detect hydrolysis of one or both of the fatty acid esters in a PEGylated phospholipid, DSPE-PEG, in conditions commonly applied during nanocarrier production. Because such carriers are increasingly being used to deliver peptide-based therapeutics, we further investigated the hydrolysis of phospholipid esters in conditions used for solid-phase peptide synthesis and high-performance liquid chromatography of peptides. We ultimately detail a synthetic strategy to reliably produce pure phospholipid-peptide bioconjugates (peptide amphiphiles), while avoiding unintended or unnoticed hydrolyzed byproducts that could lead to polymorphic nanotherapeutics with dampened therapeutic efficacy. We believe that such an approach could help standardize phospholipid-peptide-based therapeutic development, testing, and clinical translation. PMID- 30411060 TI - Aqueous MEA and Ammonia Sorption-Induced Damage in Keratin Fibers. AB - The sorption of aqueous monoethanolamine (MEA) and ammonia solutions in keratin fibers and its subsequent effect on their mechanical performance has been investigated. The diffusion kinetics of MEA into keratin fibers for 0.1, 1.0, and 5 v/v % MEA in water at 30 and 50 degrees C were found to exhibit two clear regimes of absorption behavior: a linear Fickian diffusion regime for initial times up to 100 min, after which a second slower uptake process was observed. Single fiber tensile tests showed that the Young's modulus and the tensile failure stress for 5% MEA-treated fibers, compared to untreated fibers, were 25% lower after 1 h of treatment and 50% lower after 9 h of treatment. Aqueous treatments of 0.1 and 1% MEA, as well as 0.6 and 3% aqueous ammonia, had no measurable effect on either Young's modulus or tensile failure stress for the fibers. Scanning electron microscopy images and protein content analysis confirmed that keratin fibers exposed to 5% MEA solution exhibited significant surface damage as well as high levels of protein loss. This study confirms for the first time the important damage hair treatments containing 5% aqueous MEA can cause on keratin fibers. PMID- 30411062 TI - Tuning the Balance between Fibrillation and Oligomerization of alpha-Synuclein in the Presence of Dopamine. AB - The aggregates of alpha-synuclein bear a close connection with Parkinson's disease, which is largely characterized by the loss of the dopaminergic neurons. Dopamine promotes the formation of undesirable sodium dodecyl sulfate (SDS) resistant oligomers of alpha-synuclein. In this study, we have shown that the inhibition of fibrillation by an additive may not always be the ultimate deciding factor in the context of its potential as a successful additive. Copper promotes the fibrillation of alpha-synuclein in buffer alone but inhibits the formation of SDS-resistant oligomers in the presence of dopamine. Glycerol, on the other hand, increases the population of such dopamine-mediated SDS-resistant oligomers. We speculate such an effect to be a manifestation of the distinct oxidation pathway of dopamine in the presence of copper. PMID- 30411061 TI - Reproducible Plasmonic Nanopyramid Array of Various Metals for Highly Sensitive Refractometric and Surface-Enhanced Raman Biosensing. AB - Localized surface plasmon resonance (LSPR) biosensors show great potential for practical/commercial use in clinical diagnosis, home healthcare, environmental analysis, and public healthcare. However, two main issues, that is, low refractometric sensitivity and low reproducibility (large-area uniformity and batch-to-batch consistency), hinder the extensive applications of LSPR biosensors. Therefore, plasmonic nanostructures with high sensitivity and excellent reproducibility are desirable for preparing reliable LSPR sensors. Herein, we have fabricated plasmonic nanopyramid arrays (NPAs) for several batches with reproducible morphology and optical properties by elastic soft lithography and metal thermal evaporation. NPAs of various metals (i.e., Al, Au, and Ag) were also prepared by thermal evaporation with the according metals. The transmission spectra of these NPAs showed several narrow LSPR peaks in the visible-infrared wavelength region. The refractometric sensitivities of the LSPR peaks were systematically studied, and high refractometric sensitivities of 774.0, 472.8, and 421.0 nm/RIU were achieved on Al, Au, and Ag NPAs, respectively. To demonstrate the potential of the NPAs for multiplex applications, we first applied this highly sensitive Al NPA biosensor to monitoring the process of proliferation of HeLa cancer cells, in situ and in real time. Then, we demonstrated that the Au NPA was able to identify the absorbed analytes on its surface through the surface-enhanced Raman scattering spectrum. In addition, the finite difference time domain simulations were performed to reveal the electromagnetic field enhancement on NPAs. Because of the properties of high sensitivity and excellent reproducibility of the metal NPA LSPR substrates, as well as the simplicity and cost efficiency of the fabrication method, our proposed work will accelerate the practical use of LSPR sensors. PMID- 30411063 TI - Single Cell Encapsulation via Pickering Emulsion for Biopesticide Applications. AB - A new approach for single cell microencapsulation in an oil-in-water (o/w) Pickering emulsion is presented. The water/paraffin emulsions were stabilized by amine-functionalized silica nanoparticles. The droplet size of the emulsions was highly tunable, and ranged from 1 to 30 MUm in diameter. The controllable droplet size along with the high colloidal stability of the Pickering emulsionswas harnessed to obtain single cell microencapsulation. Successful encapsulation of the conidia entomopathogenic fungus Metarhizium brunneum by the studied Pickering emulsions was confirmed via confocal laser scanning microscopy. The resulting systems were implemented to develop a novel biopesticide formulation for arthropod pest control. The conidia incorporated in the emulsions were applied to Ricinus communis leaves by spray assay. After drying of the emulsion, a silica based honeycomb-like structure with an ordered hierarchical porosity is formed. This structure preserves the individual cell encapsulation. The successful single cell encapsulation has led to a high distribution of conidia cells on the leaves. The Pickering emulsion-based formulation exhibited significantly higher pest control activity against Spodoptera littoralis larvae compared to the control systems, thus making it a promising, cost-effective, innovative approach for tackling the pest control challenge. PMID- 30411064 TI - Kinetic Model under Light-Limited Condition for Photoinitiated Thiol-Ene Coupling Reactions. AB - Thiol-ene click chemistry has become a powerful paradigm in synthesis, materials science, and surface modification in the past decade. In the photoinitiated thiol ene reaction, an induction period is often observed before the major change in its kinetic curve, for which a possible mechanism is proposed in this report. Briefly, light soaking generates radicals following the zeroth-order reaction kinetics. The radical is the reactant that initializes the chain reaction of thiol-ene coupling, which is a first-order reaction. Combining both and under the light-limited conditions, a surprising kinetics represented by a Gaussian-like model evolves that is different from the exponential model used to describe the first-order reaction of the final product. The experimental data are fitted well with the new model, and the reaction kinetic constants can be pulled out from the fitting. PMID- 30411065 TI - Quantifying Release from Lipid Nanocarriers by Fluorescence Correlation Spectroscopy. AB - Understanding the release of drugs and contrast agents from nanocarriers is fundamental in the development of new effective nanomedicines. However, the commonly used method based on dialysis frequently fails to quantify the release of molecules poorly soluble in water, and it is not well-suited for in situ measurements in biological media. Here, we have developed a new methodology for quantifying the release of fluorescent molecules from lipid nanocarriers (LNCs) using fluorescence correlation spectroscopy (FCS). LNCs based on nanoemulsion droplets, encapsulating the hydrophobic Nile red derivative NR668 as a model cargo, were used. Our studies revealed that the standard deviation of fluorescence fluctuations in FCS measurements depends linearly on the dye loading in the nanocarriers, and it is insensitive to the presence of less-bright molecular emissive species in solution. In sharp contrast, classical FCS parameters, such as the number and the brightness of emissive species, are strongly influenced by the fluorescence of molecular species in solution. Therefore, we propose to use the standard deviation of fluorescence fluctuations for the quantitative analysis of dye release from nanocarriers, which is unaffected by the "parasite" fluorescence of the released dyes or the auto fluorescence of the medium. Using this method, we found that LNCs remain intact in water, whereas in serum medium, they release their content in a temperature dependent manner. At 37 degrees C, the release was relatively slow reaching 50% only after 6 h of incubation. The results are corroborated by qualitative observations based on Forster resonance energy transfer between two different encapsulated dyes. The developed method is simple because it is only based on the standard deviation of fluorescence fluctuations and, in principle, can be applied to nanocarriers of different types. PMID- 30411066 TI - Secondary Structure-Dependent Physicochemical Interaction of Oligonucleotides with Gold Nanorod and Photothermal Effect for Future Applications: A New Insight. AB - We investigate the physicochemical interactions of gold nanorod (GNR) with single stranded, double-stranded, and hairpin DNA structures to improve the biological compatibility as well as the therapeutic potential, including the photothermal effect of the conjugates. Studies have demonstrated that different DNA secondary structures, containing thiol group, have different patterns of physicochemical interaction. Conjugation efficiency of paired oligonucleotides are significantly higher than that of oligonucleotides with naked bases. Furthermore, hairpin shaped DNA structures are most efficient in terms of conjugation and increased dispersion, with least interference on GNR near-infrared absorbance and photothermal effect. Our conjugation method can successfully exchange the overall coating of the GNR, attaching the maximum number of DNA molecules, thus far reported. Chemical mapping depicted uniform attachment of thiolated DNA molecules without any topological preference on the GNR surface. Hairpin DNA-coated GNR are suitable for intracellular uptake and remain dispersed in the cellular environment. Finally, we conjugated GNR with 5-fluoro-2'-deoxyuridine-containing DNA hairpin and the conjugate demonstrated significant cytotoxic activity against human cervical cancer cell line (KB). Thus, hairpin DNA structures could be utilized for optimal dispersion and photothermal effect of GNR, along with the delivery of cytotoxic nucleotides, developing the concept of multimodality approach. PMID- 30411067 TI - Cerium Oxide Nanoparticles Decrease Drought-Induced Oxidative Damage in Sorghum Leading to Higher Photosynthesis and Grain Yield. AB - Drought is a major abiotic stress affecting crop growth and yield worldwide. Drought-induced oxidative stress results in the reduction of plant photosynthesis and reproductive success. Cerium oxide nanoparticles (nanoceria) possess potent antioxidant properties that can alleviate drought-induced oxidative stress by catalytic scavenging reactive oxygen species (ROS), thereby protecting sorghum [Sorghum bicolor (L.) Moench] photosynthesis and grain yield. Drought was imposed at the booting stage by withholding water for 21 d. Foliar-sprayed nanoceria (10 mg L-1) efficiently reduced leaf superoxide radical (41%) and hydrogen peroxide (36%) levels and decreased cell membrane lipid peroxidation (37%) under drought. Nanoceria increased leaf carbon assimilation rates (38%), pollen germination (31%), and seed yield per plant (31%) in drought-stressed plants relative to water-sprayed controls. Translocation study indicated that nanoceria can move from root to shoot of sorghum plants. Toxicity assays in mammalian cells indicated that nanoceria effective concentration (EC)50 of >250 mg L-1 is well above the concentration used in this study. Foliar-sprayed nanoceria protect sorghum plants from oxidative damage under drought stress leading to higher grain yield. PMID- 30411068 TI - Aggregation-Induced Emission-Based Fluorescence Probe for Fast and Sensitive Imaging of Formaldehyde in Living Cells. AB - Formaldehyde (FA), as a reactive carbonyl species and signaling molecule, plays an important role in living systems. Here, an FA-responsive probe with fast response and great selectivity is designed based on aggregation-induced emission. The probe is prepared by functionalizing tetraphenylethene (TPE) with two amine groups. FA is detected based on the solubility differences between the amine functionalized TPE and the corresponding Schiff bases after reaction with FA. The probe exhibits a limit of detection of 40 nM and a response time of ~90 s. Furthermore, its ability to detect both endogenous and exogenous FA is demonstrated in living cells with high specificity. Moreover, the probe is also introduced to image endogenous FA in real time with fast response. These results suggest that our probe holds great potential for tracking FA in living systems under various physiological conditions as well as related biomedical applications. PMID- 30411069 TI - Fabrication of Bis-Quaternary Ammonium Salt as an Efficient Bactericidal Weapon Against Escherichia coli and Staphylococcus aureus. AB - Combating bacterial pathogens has become a global concern, especially the emergence of drug-resistant bacteria have made conventional antibiotics lose their efficiency. This grim situation suggests the necessity to explore novel antibacterial agents with favorable safety and strong antibacterial activity. Here, we took the advantage of quaternary ammonium compounds and synthesized a long-chain high-molecular organic bis-quaternary ammonium salt (BQAS) with a broad-spectrum bactericidal activity through a facile one-pot reaction. The bactericidal effect of BQAS was evaluated by two bacterial human pathogens: Escherichia coli (Gram-negative) and Staphylococcus aureus (Gram-positive), which are the major cause of diarrheal infections in children and adults. Our experimental results indicate that the bactericidal activity of BQAS is linked to the strong contact between the positively charged quaternary ammonium groups and the bacterial cells, thus leading to a temporary and locally high concentration of reactive oxygen species, which subsequently triggers oxidative stress and membrane damage in the bacteria. This mechanism was further confirmed by several assays, such as the membrane permeabilization assay, fluorescent-based cell live/dead test, scanning electron microscopy, transmission electron microscopy, together with the lactate dehydrogenase release assay, which all indicated that BQAS induced damage to the cytoplasmic membrane and the leakage of intracellular fluid containing essential molecules. The excellent bactericidal activity of BQAS suggests its great application potential as a promising candidate against the rapid emergence of drug-resistant bacterial pathogens. PMID- 30411071 TI - Special Issue on the TASK3 Preclinical epilepsy Common Data Elements (CDEs) of the ILAE/AES Joint Translational Task Force: Peer review process, acknowledgement to reviewers, and community feedback. PMID- 30411070 TI - Phytofabrication of Iron Nanoparticles for Hexavalent Chromium Remediation. AB - Hexavalent chromium is a genotoxic and carcinogenic byproduct of a number of industrial processes, which is discharged into the environment in excessive and toxic concentrations worldwide. In this paper, the synthesis of green iron oxide nanoparticles using extracts of four novel plant species [Pittosporum undulatum, Melia azedarach, Schinus molle, and Syzygium paniculatum (var. australe)] using a "bottom-up approach" has been implemented for hexavalent chromium remediation. Nanoparticle characterizations show that different plant extracts lead to the formation of nanoparticles with different sizes, agglomeration tendencies, and shapes but similar amorphous nature and elemental makeup. Hexavalent chromium removal is linked with the particle size and monodispersity. Nanoparticles with sizes between 5 and 15 nm from M. azedarach and P. undulatum showed enhanced chromium removal capacities (84.1-96.2%, respectively) when compared to the agglomerated particles of S. molle and S. paniculatum with sizes between 30 and 100 nm (43.7-58.7%, respectively) in over 9 h. This study has shown that the reduction of iron salts with plant extracts is unlikely to generate vast quantities of stable zero valent iron nanoparticles but rather favor the formation of iron oxide nanoparticles. In addition, plant extracts with higher antioxidant concentrations may not produce nanoparticles with morphologies optimal for pollutant remediation. PMID- 30411073 TI - Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Trial of Synthetic Preimplantation Factor in Autoimmune Hepatitis. AB - Preimplantation factor (PIF) is an evolutionary conserved peptide secreted by viable embryos which promotes maternal tolerance without immune suppression. Synthetic PIF (sPIF) replicates native peptide activity. The aim of this study was to conduct the first-in-human trial of the safety, tolerability, and pharmacokinetics of sPIF in patients with autoimmune hepatitis (AIH). We performed a randomized, double-blind, placebo-controlled, prospective phase I clinical trial. Patients were adults with documented AIH with compensated chronic liver disease. Diagnosis of AIH was confirmed by either a pretreatment International Criteria for the Diagnosis of AIH score of 15 or more, or a posttreatment score of 17 or more. Patients were divided into three dosing cohorts (0.1, 0.5, or 1.0 mg/kg) of 6 patients in each group. Three patients in each group had normal liver tests and 3 patients had abnormal liver tests. They were randomized to receive a single, subcutaneous dose of either sPIF or a matching placebo. Eighteen patients were enrolled, and all successfully completed the trial. There were no clinically significant adverse events and all doses were well tolerated. Ascending doses of sPIF produced a linear increase in the respective serum levels with a half-life of 90 minutes. There were no grade 2, 3 or 4 laboratory abnormalities. No patient developed detectable anti-sPIF antibodies. Conclusion: This first-in-human trial of the safety and pharmacokinetics of sPIF (a novel biologic immune modulatory agent) demonstrated both excellent safety and tolerability. The data support further studies of multiple ascending doses of sPIF in autoimmune hepatitis and potentially other autoimmune disorders. PMID- 30411074 TI - Treatment of Adolescents With Chronic Hepatitis C Virus Infection: New Regimen on the Block. AB - BLURB FOR ETOC: Editorial to Leung et al. "Ombitasvir/Paritaprevir/Ritonavir With or Without Dasabuvir and With or Without Ribavirin for Adolescents With HCV Genotype 1 or 4". PMID- 30411072 TI - A companion to the preclinical common data elements for physiologic data in rodent epilepsy models. A report of the TASK3 Physiology Working Group of the ILAE/AES Joint Translational Task Force. AB - The International League Against Epilepsy/American Epilepsy Society (ILAE/AES) Joint Translational Task Force created the TASK3 working groups to create common data elements (CDEs) for various aspects of preclinical epilepsy research studies, which could help improve standardization of experimental designs. This article concerns the parameters that can be measured to assess the physiologic condition of the animals that are used to study rodent models of epilepsy. Here we discuss CDEs for physiologic parameters measured in adult rats and mice such as general health status, temperature, cardiac and respiratory function, and blood constituents. We provide detailed CDE tables and case report forms (CRFs), and with this companion manuscript we discuss the monitoring of different aspects of physiology of the animals. The CDEs, CRFs, and companion paper are available to all researchers, and their use will benefit the harmonization and comparability of translational preclinical epilepsy research. The ultimate hope is to facilitate the development of biomarkers and new treatments for epilepsy. PMID- 30411075 TI - Niacin-Induced Anicteric Microvesicular Steatotic Acute Liver Failure. AB - Niacin (vitamin B3) is available as a prescription medication and over-the counter supplement. Although it is well known for its vasodilatory effect, it has also been associated with mild hepatotoxicity and, rarely, acute liver failure. We present the case of a 74-year-old Hispanic woman who developed acute liver failure (anicteric encephalopathy and coagulopathy) after her home dose of immediate-release niacin was replaced with an extended-release formulation during an inpatient hospital stay. This is the first reported case of niacin toxicity associated with a histopathologic finding of diffuse microvesicular steatosis. This unique phenotype strongly implicates mitochondrial impairment as a mechanism of niacin-induced hepatotoxicity. PMID- 30411077 TI - Evaluating Women's Preferences for Hepatitis C Treatment During Pregnancy. AB - There is a rising prevalence of hepatitis C (HCV) among women of child-bearing age nationally, which prompted a recommendation by national guidelines to screen all women for HCV during pregnancy. Women with HCV during pregnancy are at risk of perinatal transmission of HCV. Directly acting antiviral (DAA) therapy during pregnancy can potentially reduce the risk of perinatal transmission as well as cure women while they are engaged in antenatal care. However, data on the safety and efficacy of DAAs during pregnancy are limited. We aimed to evaluate the preferences of women with HCV regarding potential DAA treatment during pregnancy. We conducted a survey of women with a history of HCV followed in the University of California, San Francisco HCV clinic and in the Women's Interagency HIV Study (most of whom are coinfected with HIV) to determine their preferences for DAA treatment during pregnancy. A total of 141 women completed the survey. Sixty percent reported that they would be willing to take antepartum DAA therapy if it lowered the risk of perinatal transmission. Only 21% reported that they would agree to take DAA therapy during pregnancy for self-cure; 20% of women stated that they would not, yet indicated that they might change their minds if there were more human data available regarding use of DAAs during pregnancy. In multivariable analysis, having a previous history of taking DAAs and being of childbearing age at the time of the survey were associated with willingness to take DAA medication during pregnancy (odds ratios 4.29 and 4.11, respectively). Conclusion: These results point to the need for further investigation of the role of HCV therapy during pregnancy. PMID- 30411076 TI - Outcomes of Pregnancy in Mothers With Cirrhosis: A National Population-Based Cohort Study of 1.3 Million Pregnancies. AB - There are limited data on pregnancy outcomes in women with cirrhosis. To address this gap, we examined the records of singleton births from Sweden's National Patient Register (NPR), Cause of Death Register (CDR), and Medical Birth Register (MBR) between 1997 and 2011 to assess exposure and pregnancy-related and liver related outcomes of pregnant women with cirrhosis. Exposure status was defined as having an International Classification of Diseases (ICD) code for cirrhosis obtained prior to or during pregnancy. Poisson regression with cluster-robust standard errors was used to estimate relative risks (RRs) adjusted for maternal age, smoking, and body mass index (BMI). We identified 103 pregnancies in women with cirrhosis and compared these to 1,361,566 pregnancies in women without cirrhosis. Pregnancies in women with cirrhosis were at increased risk of caesarean delivery (36% versus 16%, respectively; adjusted RR [aRR], 2.00; 95% confidence interval [CI], 1.47-2.73), low birth weight (15% versus 3%; aRR, 3.87; 95% CI, 2.11-7.06), and preterm delivery (19% versus 5%; aRR, 3.51; 95% CI, 2.16 5.72). Rates of maternal mortality during pregnancy (no cases), gestational diabetes, preeclampsia, small for gestational age, congenital malformations, and stillbirth were not increased when compared to the pregnant women without cirrhosis. There were 12 hospitalizations during pregnancy due to liver-related events, including one case with bleeding esophageal varices. Conclusion: Women with cirrhosis are at increased risk for adverse pregnancy outcomes. However, severe maternal and fetal adverse events were rare in our study, and most pregnancies in women with cirrhosis ended without complications. PMID- 30411078 TI - Ombitasvir/Paritaprevir/Ritonavir With or Without Dasabuvir and With or Without Ribavirin for Adolescents With HCV Genotype 1 or 4. AB - In adults, treatment of hepatitis C virus (HCV) infection with ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) with or without dasabuvir (DSV) and +/ ribavirin (RBV) results in high rates of sustained virologic response (SVR). However, these regimens have not been investigated in adolescents. This ongoing, open-label, phase 2/3 study evaluated the pharmacokinetics, safety, and efficacy of OBV/PTV/r+DSV+/-RBV treatment for 12 weeks in adolescents infected with HCV genotype (GT) 1 without cirrhosis (part 1) and the safety and efficacy of OBV/PTV/r+/-DSV+/-RBV treatment for 12 or 24 weeks in adolescents infected with GT1 or GT4 without cirrhosis or with compensated cirrhosis (parts 1 and 2). Patients were 12-17 years of age and treatment naive or interferon experienced. Treatment regimens were based on HCV GT and cirrhosis status. Endpoints were SVR at posttreatment week 12 (SVR12), adverse events (AEs), and pharmacokinetic parameters. Thirty-eight adolescents were enrolled, 66% were female patients, and 76% were White; 42%, 40%, and 18% of patients had HCV GT1a, GT1b, and GT4 infections, respectively. Median age was 15 years (range, 12-17 years), and 1 patient had cirrhosis. The SVR12 rate was 100% (38/38; 95% confidence interval [CI], 90.8%-100%). No treatment-emergent grade 3 or 4 laboratory abnormalities were reported. No serious AEs occurred on treatment, and no AEs led to study drug discontinuation. The most common AEs were headache (21%), fatigue (18%), nasopharyngitis (13%), pruritus (13%), and upper respiratory tract infection (11%). Intensive pharmacokinetic results showed OBV, PTV, DSV, and ritonavir drug exposures were comparable to those seen in adults. Conclusion: Treatment with OBV/PTV/r+/-DSV+/-RBV was well tolerated and highly efficacious in adolescents with HCV GT1 or GT4 infection. PMID- 30411079 TI - Morphometry Confirms Fibrosis Regression From Sustained Virologic Response to Direct-Acting Antivirals for Hepatitis C. AB - Sustained virologic response (SVR) after direct-acting antiviral (DAA) therapy for chronic hepatitis C results in significant decreases in liver stiffness measured by transient elastography (TE). The aim of this study was to clarify if TE can guide post-SVR management in patients with advanced fibrosis or cirrhosis prior to treatment as current guidelines are unclear on the role of TE after SVR. In total, 84 patients with hepatitis C virus and advanced fibrosis or cirrhosis and from a single center underwent DAA treatment and achieved SVR. Overall, 62% had improved liver stiffness that was consistent with regression of at least one stage of fibrosis. In the cirrhosis group, 48% showed fibrosis regression by at least two stages by TE (<9.5 kPa). In the F3 fibrosis group, 39% regressed by at least two stages (<7 kPa). The median time from SVR to regression by TE was 1 year. Fifteen patients with liver biopsies prior to SVR underwent a biopsy after SVR; 13 of these patients had improved liver stiffness (to <9.5 kPa). The post SVR liver biopsies of only 4 patients showed F1-F2 while 11 patients showed F3 F4; however, morphometry of the first 11 biopsied patients revealed that 10 patients had an average 46% decrease in collagen content. Conclusion: This is the first DAA study that also has paired liver biopsies showing fibrosis regression. After SVR is achieved, improvements in liver stiffness measured by TE are seen in a majority of patients with advanced fibrosis/cirrhosis within 2 years. TE improvements are overstated when compared to histologic staging but confirmed with morphometric analysis. It is unclear whether TE following SVR can reliably predict when patients no longer require advanced fibrosis/cirrhosis monitoring after SVR. PMID- 30411080 TI - Liver Fibrosis Markers Improve Prediction of Outcome in Non-Acetaminophen Associated Acute Liver Failure. AB - A prognostic system for acute liver failure (ALF) with a higher predictive value is urgently needed. The role of extracellular matrix (ECM) remodeling in ALF has not been fully elucidated. We hypothesized that serologic fibrosis markers, which reflect ECM remodeling, are predictive of ALF outcome at first presentation. This observational study included 110 patients with acute liver dysfunction, of which 73 had non-acetaminophen-associated ALF (NAA-ALF). We evaluated serum levels of hyaluronic acid, 7S domain of type IV collagen (4COL7S), and Wisteria floribunda agglutinin-positive Mac-2-binding protein at first presentation to a tertiary center. Serologic fibrosis markers were significantly higher in NAA-ALF compared with acute hepatitis. Elevated hyaluronic acid and 4COL7S levels at first presentation correlated significantly with worse clinical outcomes. 4COL7S, along with age, ammonia, and the Model for End-Stage Liver Disease (MELD) score, was a significant prognostic factor in multivariate analysis; 4COL7S correlated significantly with coagulopathy, decreased hepatic synthetic functions, advanced hepatic encephalopathy, and liver atrophy and also predicted 180-day transplant free survival. Cox regression models incorporating 4COL7S with the MELD system had profoundly improved predictive values that significantly surpassed the MELD system alone. Conclusion: Elevation of serologic fibrosis markers reflecting ECM remodeling in NAA-ALF predicted a worse clinical outcome. Incorporation of 4COL7S at first presentation to a transplant center improves the specificity while retaining the sensitivity of the MELD system. External validation of a fibrosis marker as part of a clinical prediction tool in ALF warrants further investigation. PMID- 30411081 TI - Serum Interleukin-8, Osteopontin, and Monocyte Chemoattractant Protein 1 Are Associated With Hepatic Fibrosis in Patients With Nonalcoholic Fatty Liver Disease. AB - The severity of hepatic fibrosis is the primary predictor of liver-related morbidity and mortality in patients with nonalcoholic fatty liver disease (NAFLD). Unfortunately, noninvasive serum biomarkers for NAFLD-associated fibrosis are limited. We analyzed baseline serum samples for 24 cytokines of 97 patients with biopsy-proven NAFLD. These patients were prospectively enrolled in a clinical study (ClinicalTrials.gov NCT00794716) to identify cytokines associated with liver fibrosis in patients with nonalcoholic steatohepatitis. Patients were stratified according to severity of hepatic fibrosis (mild, stage 0 1, n = 37; moderate, stage 2, n = 40; and advanced, stage 3-4, n = 20) while controlling for age, race, sex, body mass index, and diabetes mellitus. Interleukin-8 (IL-8), osteopontin (OPN), and monocyte chemoattractant protein 1 (MCP1) were associated with liver fibrosis (P < 0.001, P = 0.005, P = 0.016, respectively). After controlling for steatosis, lobular inflammation, hepatocyte ballooning, age, sex, body mass index, diabetes mellitus, hypertension, and metabolic syndrome status, IL-8 remained strongly associated with fibrosis (P = 0.001). Furthermore, IL-8 was also a strong predictor of increased fibrotic liver injury compared to established markers of hepatic fibrosis. Hepatic gene expression from 72 patients with NAFLD (n = 40 mild fibrosis; n = 32 advanced fibrosis) from the Duke University Health System NAFLD Clinical Database and Biorepository revealed IL-8, MCP1, and OPN gene expression to be increased and differentially expressed in patients with advanced hepatic fibrosis. Thus, serum IL-8, MCP1, and OPN may reflect up-regulated gene expression during liver fibrosis in NAFLD. Conclusion: Serum IL-8, MCP1, and OPN may serve as a test for advanced hepatic fibrosis in NAFLD and thus reveal novel targets for antifibrotic therapies. The increased serum IL-8, MCP1, and OPN that correspond with associated hepatic gene expression lend strength to such analytes as ideal surrogate serum biomarkers for severity of hepatic fibrosis. PMID- 30411082 TI - H19 Is Expressed in Hybrid Hepatocyte Nuclear Factor 4alpha+ Periportal Hepatocytes but Not Cytokeratin 19+ Cholangiocytes in Cholestatic Livers. AB - Long noncoding RNA (lncRNA) H19 is abundantly expressed in fetal liver. Its expression is significantly diminished in adult healthy liver but is re-induced in chronic liver diseases, including cholestasis. In this study, we developed a new method with combined in situ hybridization (ISH) and immunofluorescence (IF) colabeling to establish an H19 expression profile with both parenchymal and nonparenchymal cell-specific markers in the livers of cholestatic mouse models and patients with cholestasis. H19RNA+ cells showed no colocalization with biliary epithelial cell marker cytokeratin 19 (CK19)+ cholangiocytes but were immediately adjacent to biliary structures in bile duct ligation (BDL), 3,5 diethoxycarbony1-1,4-dihydrocollidine (DDC), and multidrug-resistant gene 2 knockout ( Mdr2 -/- ) mouse models and in human primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) liver specimens. In contrast, double-positive H19RNA+/sex-determining region Y (SRY)-box 9 (SOX9)+ ductal progenitor cells, H19RNA+/hepatocyte nuclear factor 4alpha (HNF4alpha)+ hepatocytes, H19RNA+/F4/80+ Kupffer cells, HNF4alpha+/SOX9+ hybrid hepatocytes, as well as triple-positive H19 RNA+/HNF4alpha+/SOX9+ periportal hepatocytes were identified. In addition, H19 RNA could not be detected in mesenchymal cell marker desmin+ cells. Furthermore, H19 RNA was predominately detected in cytoplasm with a small amount at the interspace with neighboring cells. Conclusion: H19RNA is localized in HNF4alpha+ periportal hepatocytes, SOX9+ ductal progenitor cells, and F4/80+ Kupffer cells but not in CK19+ cholangiocytes and desmin+ stellate cells in cholestatic livers. PMID- 30411084 TI - FXR and TGR5 Agonists Ameliorate Liver Injury, Steatosis, and Inflammation After Binge or Prolonged Alcohol Feeding in Mice. AB - Bile acids (BAs) activate various dedicated receptors, including the farnesoid X receptor (FXR) and the Takeda G protein-coupled receptor 5 (TGR5). The FXR agonist obeticholic acid (OCA) is licensed for the treatment of primary biliary cholangitis and has shown promising results in NASH patients, whereas TGR5 agonists target inflammation and metabolism. We hypothesized that FXR and/or TGR5 agonists may be therapeutic in early alcoholic liver disease (ALD) in mice, in which hepatic inflammation plays a major role. OCA, INT-777, and INT-767 are BA derivatives with selective agonist properties for FXR, TGR5, or both, respectively. These compounds were tested in two mouse models (3-day binge model and prolonged Lieber DeCarli diet for 12 days) of early ALD. Serum alanine aminotransferase and liver histology were used to assess liver injury, Oil Red O staining of liver sections to assess steatosis, and real-time polymerase chain reaction to assess changes in gene expression. In the ethanol binge model, treatment with OCA and INT-777 decreased hepatic macrovesicular steatosis and protected from ethanol-induced liver injury. After prolonged ethanol administration, mice treated with OCA, INT-767, or INT-777 showed decreased hepatic steatosis, associated with reduced liver fatty acid synthase protein expression, and protection from liver injury. Treatment with BA receptor agonists in both models of ethanol administration modulated lipogenic gene expression, and decreased liver interleukin-1beta mRNA expression associated with increased ubiquitination of NLRP3 inflammasome through cyclic adenosine monophosphate induced activation of protein kinase A. Conclusion: OCA, INT-767, or INT-777 administration is effective in reducing acute and chronic ethanol-induced steatosis and inflammation in mice, with varying degrees of efficacy depending on the duration of ethanol administration, indicating that both FXR and TGR5 activation can protect from liver injury in ALD models. PMID- 30411083 TI - Gamma Glutamyltransferase Reduction Is Associated With Favorable Outcomes in Pediatric Primary Sclerosing Cholangitis. AB - Adverse clinical events in primary sclerosing cholangitis (PSC) happen too slowly to capture during clinical trials. Surrogate endpoints are needed, but no such validated endpoints exist for children with PSC. We evaluated the association between gamma glutamyltransferase (GGT) reduction and long-term outcomes in pediatric PSC patients. We evaluated GGT normalization (< 50 IU/L) at 1 year among a multicenter cohort of children with PSC who did or did not receive treatment with ursodeoxycholic acid (UDCA). We compared rates of event-free survival (no portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or liver-related death) at 5 years. Of the 287 children, mean age of 11.4 years old, UDCA was used in 81% at a mean dose of 17 mg/kg/day. Treated and untreated groups had similar GGT at diagnosis (314 versus 300, P= not significant [NS]). The mean GGT was reduced at 1 year in both groups, with lower values seen in treated (versus untreated) patients (99 versus 175, P= 0.002), but 5-year event-free survival was similar (74% versus 77%, P= NS). In patients with GGT normalization (versus no normalization) by 1 year, regardless of UDCA treatment status, 5-year event-free survival was better (91% versus 67%, P< 0.001). Similarly, larger reduction in GGT over 1 year (> 75% versus < 25% reduction) was also associated with improved outcome (5-year event-free survival 88% versus 61%, P= 0.005). Conclusion:A GGT < 50 and/or GGT reduction of > 75% by 1 year after PSC diagnosis predicts favorable 5-year outcomes in children. GGT has promise as a potential surrogate endpoint in future clinical trials for pediatric PSC. PMID- 30411086 TI - Down-regulation of TROP-2 Predicts Poor Prognosis of Hepatocellular Carcinoma Patients. AB - Hepatocellular carcinoma (HCC) is one of the most common and lethal cancer types worldwide, especially in Asian countries. Genetic alterations, including hyperactivation of oncogenes and loss of expression of tumor suppressor genes, greatly contribute to the initiation and progression of HCC. Here we report that down-regulation of trophoblast cell surface antigen 2 (TROP-2) was frequently detected in HCC. Transcriptome sequencing of non-tumor and HCC patient samples revealed down-regulation of TROP-2 in tumor tissues. Immunohistochemical staining showed nearly undetectable levels of TROP-2 in HCC tissues but distinct and strong staining of TROP-2 in adjacent non-tumor tissues. The frequent down regulation of TROP-2 expression was further confirmed in an in-house cohort of 205 pairs of HCC patient samples and in the Cancer Genome Atlas (TCGA) databases. Furthermore, the down-regulation of TROP-2 was associated with poor overall survival of HCC patients, severe adjacent organ invasion, and poor differentiation of HCC. Using bisulfite genomic sequencing and methylation specific polymerase chain reaction analyses, we show that higher levels of promoter methylation were detected in the DNA samples of HCC tissues (low TROP-2 expression) than that of the non-tumor tissues (high TROP-2 expression). Conclusion: Taken together, our data suggest that promoter hypermethylation contributes to the frequent down-regulation of TROP-2 in HCC, and that TROP-2 down-regulation predicts poor prognosis of HCC patients. PMID- 30411085 TI - Lymphoid Enhancer Factor 1 Contributes to Hepatocellular Carcinoma Progression Through Transcriptional Regulation of Epithelial-Mesenchymal Transition Regulators and Stemness Genes. AB - Lymphoid enhancer factor 1 (LEF1) activity is associated with progression of several types of cancers. The role of LEF1 in progression of hepatocellular carcinoma (HCC) remains poorly known. We investigated LEF1 expression in HCC and its interactions with epithelial-mesenchymal transition (EMT) regulators (e.g., Snail, Slug, Twist) and stemness genes (e.g., octamer-binding transcription factor 4 [Oct4], sex determining region Y-box 2 [Sox2], Nanog homeobox [Nanog]). Microarray analysis was performed on resected tumor samples from patients with HCC with or without postoperative recurrence. LEF1 expression was associated with postoperative recurrence as validated by immunohistochemical staining in another HCC cohort. Among 74 patients, 44 displayed a relatively high percentage of LEF1 staining (>30% of HCC cells), which was associated with a reduced recurrence-free interval (P < 0.001) and overall survival (P = 0.009). In multivariate analysis, a high percentage of LEF1 staining was significantly associated with low albumin level (P = 0.035), Twist overexpression (P = 0.018), Snail overexpression (P = 0.064), co-expression of Twist and Snail (P = 0.054), and multinodular tumors (P = 0.025). Down-regulation of LEF1 by short hairpin RNA decreased tumor sphere formation, soft agar colony formation, and transwell invasiveness of HCC cell lines Mahlavu and PLC. Xenotransplant and tail vein injection experiments revealed that LEF1 down-regulation in Mahlavu reduced tumor size and metastasis. LEF1 up-regulation in Huh7 increased sphere formation, soft agar colony formation, and transwell invasiveness. LEF1 was shown to physically interact with and transcriptionally activate promoter regions of Oct4, Snail, Slug, and Twist. Furthermore, Oct4, Snail, and Twist transactivated LEF1 to form a regulatory positive-feedback loop. Conclusion: LEF1 plays a pivotal role in HCC progression through transcriptional regulation of Oct4 and EMT regulators. PMID- 30411089 TI - Review of cone beam computed tomography guidelines in North America. AB - OBJECTIVE: The aim of this article is to investigate, study, and summarize cone beam computed tomography (CBCT)-related guidelines offered by relevant organizations and associations within North America to provide the dental practitioner a clearer direction on the practice of CBCT-related procedures in North America. DATA SOURCES: Scientific databases including PubMed, Science Direct, Scopus, MedLine, and Web of Science were used for the search of relevant literature on the CBCT guidelines developed in North America. In addition, the World Wide Web was searched for comparative CBCT guidelines nationally or internationally using the same search strategies. CONCLUSION: In 1999, the American Dental Association (ADA) recognized Oral and Maxillofacial Radiology as the ninth dental specialty in the United States. The American Academy of Oral and Maxillofacial Radiology (AAOMR) issued their first statement on the use of CBCT in 2008. There have since been several statements issued, independently or jointly with other specialty organizations, related to the use and interpretation of the CBCT volumes. The guidelines identified Oral and Maxillofacial Radiologists (OMR) as providers of interpretative services, portrayed as key players in the dissemination of information related to CBCT, implementation of CBCT-related services and radiation protection, as well as interpretation assistance for CBCT volumes, especially medium to large volumes covering anatomical areas of head and neck, considered beyond the scope of a general dentist. Regulations concerning radiation-producing devices are promulgated through state health codes and practice acts. Selection criteria and interpretation of imaging studies are left to the clinician's choice and abilities. PMID- 30411088 TI - Activity and Circadian Rhythm of Sepsis Patients in the Intensive Care Unit. AB - Early mobilization of critically ill patients in the Intensive Care Unit (ICU) can prevent adverse outcomes such as delirium and post-discharge physical impairment. To date, no studies have characterized activity of sepsis patients in the ICU using granular actigraphy data. This study characterizes the activity of sepsis patients in the ICU to aid in future mobility interventions. We have compared the actigraphy features of 24 patients in four groups: Chronic Critical Illness (CCI) sepsis patients in the ICU, Rapid Recovery (RR) sepsis patients in the ICU, non-sepsis ICU patients (control-ICU), and healthy subjects. We used a total of 15 statistical and circadian rhythm features extracted from the patients' actigraphy data collected over a five-day period. Our results show that the four groups are significantly different in terms of activity features. In addition, we observed that the CCI and control-ICU patients show less regularity in their circadian rhythm compared to the RR patients. These results show the potential of using actigraphy data for guiding mobilization practices, classifying sepsis recovery subtype, as well as for tracking patients' recovery. PMID- 30411090 TI - Effect of framework design and firing cycle on the success rate of bilayered zirconia crowns. AB - OBJECTIVE: This study investigated the effect of framework design and modification of porcelain firing cycle on the occurrence of fractures of metal ceramic and bilayered zirconia crowns after cyclic loading. METHOD AND MATERIALS: Twenty-four zirconia crowns with two different apicocoronal incisal veneering porcelain lengths (ZS = 2.0 mm and ZL = 4.0 mm) were fabricated. Twenty-four metal-ceramic crowns with the same apicocoronal incisal veneering porcelain lengths (MS = 2.0 mm and ML = 4.0 mm) served as the control. All the specimens (n = 48) were thermally and mechanically cycle-loaded (49 N) for 1,200,000 cycles, and then evaluated for cracks and/or bulk fractures with an optical stereomicroscope (*10). In the second part of the study, the influence of firing cycle modification on the success rate of twenty-four bilayered zirconia crowns was also evaluated. Finally, two specimens from each group (n = 12) were sectioned and analyzed using a scanning electron microscope. Load-to-failure of the specimen that did not present bulk fracture was further assessed using a universal testing machine. Statistical analysis was performed with Fisher exact test and Kruskal-Wallis test. RESULTS: A statistically significant lower occurrence of fractures (P < .05) was found after cyclic loading for bilayered zirconia versus metal-ceramic crowns. Modification of the firing cycle did not significantly influence the outcome after cyclic loading for zirconia bilayered crowns (P > .05). CONCLUSION: Within the limitations of this study, porcelain firing cycle with an extended cooling time did not appear to influence the occurrence of cracks and fractures of bilayered zirconia crowns. PMID- 30411087 TI - Human metacognition across domains: insights from individual differences and neuroimaging. AB - Metacognition is the capacity to evaluate and control one's own cognitive processes. Metacognition operates over a range of cognitive domains, such as perception and memory, but the neurocognitive architecture supporting this ability remains controversial. Is metacognition enabled by a common, domain general resource that is recruited to evaluate performance on a variety of tasks? Or is metacognition reliant on domain-specific modules? This article reviews recent literature on the domain-generality of human metacognition, drawing on evidence from individual differences and neuroimaging. A meta-analysis of behavioral studies found that perceptual metacognitive ability was correlated across different sensory modalities, but found no correlation between metacognition of perception and memory. However, evidence for domain-generality from behavioral data may suffer from a lack of power to identify correlations across model parameters indexing metacognitive efficiency. Neuroimaging data provide a complementary perspective on the domain-generality of metacognition, revealing co-existence of neural signatures that are common and distinct across tasks. We suggest that such an architecture may be appropriate for "tagging" generic feelings of confidence with domain-specific information, in turn forming the basis for priors about self-ability and modulation of higher-order behavioral control. PMID- 30411091 TI - Gingival squamous cell carcinoma: an unexpected clincal presentation. AB - Squamous cell carcinoma (SCC) is an aggressive tumor and represents the most common oral malignancy found by dental health care providers. Timely detection is paramount to reduce patient comorbidities of regional and distant metastases and improve survival rates. To augment recognition of early stage of gingival SCC (GSCC), this article features the somewhat innocuous clinical findings in a 60 year-old female. PMID- 30411092 TI - Lack of evidence for the necessity of root canal obturation. AB - OBJECTIVE: Root canal obturation still is a relevant research topic and patients spend substantial amounts of financial resources for this step of endodontic treatment. Three experiments were conducted challenging the necessity of root canal obturation. METHOD AND MATERIALS: Applying micro computed tomography, the volume of dentin tubules that cannot be instrumented during root canal therapy was determined. Using a simple biofilm model of human tooth segments, the effect of root canal obturation on the persistency of bacteria was evaluated and freshly extracted root canal treated teeth were examined for bacteria remaining in dentin. RESULTS: The volume of dentinal canals was found to be at least three times greater than the volume of the root canal itself. Bacterial growth was observed both in specimens with and without root canal obturation implying that the treatment rendered was ineffective in removing bacterial biofilm and the obturation material was incapable of hindering bacterial regrowth. CONCLUSION: Despite showing adequate root canal obturation radiographically, persistent bacteria could be identified in all teeth extracted. While perfect disinfection of root canals is mandatory, root canal obturation seems questionable as current materials have no antibacterial activity, do not stabilize the tooth, and cannot seal the canal system if a coronal restoration is missing. PMID- 30411093 TI - Endosseous (dental) implants in an oncologic population: a primer for treatment considerations. AB - Successful intraoral rehabilitation for patients with head and neck cancer can be extremely challenging to both the patient and the physician due to anatomical, functional, and esthetic changes from the cancer and its treatment. The measures with optimal oral hygiene to prevent or minimize the sequelae of cancer treatments are fundamental to preservation of function and avoidance of complications of therapy. In patients with loss of teeth, endosseous (dental) implants offer an option to improve intraoral rehabilitation. This review presents the indications, problems, and relevant issues pertaining to the use of endosseous implants in a head and neck oncologic population. The problems associated with the traditional approaches for cancer treatment including surgery, radiotherapy, and chemotherapy, as well as those with antiresorptive medications are discussed as they relate to consideration for endosseous implants. This information can aid dental practitioners to select appropriate candidates for implant surgery, minimize postoperative complications, and maximize the successful oral rehabilitation of this patient population. PMID- 30411094 TI - Undesirable course of an oral implant rehabilitation in a patient with a long history of bulimia nervosa: case report and review of the literature. AB - BACKGROUND: Bulimia nervosa is an eating disorder resulting in an intended weight loss due to decreased food intake, induced vomiting, or hyperactivity, and is observed frequently between 12 and 25 years of age. One of the complications is early tooth loss. Moreover, since bulimia nervosa patients suffer from increased atrophy of the alveolar processes, oral rehabilitation even with short dental implants may be impossible. In these cases, lateralization or transposition of the inferior alveolar nerve (IAN) followed by implant placement can be useful. CASE PRESENTATION: A 40-year-old woman with a long-lasting history of bulimia nervosa requested a fixed rehabilitation of her partially edentulous mandible. In 2012, a bilateral IAN transposition approach was performed using piezosurgery, and without any postoperative neurosensory alterations. Two years later, bilateral insertion of each two implants was followed by an inflammatory destabilization of the lower left mandible; subsequent to the implant removal, a fracture occurred, and the latter was stabilized by osteosynthesis plates. In 2017, three additional implants were placed, finally providing the patient with a fixed restoration on five implants. CONCLUSION: Eating disorders may have a tremendous impact on both physical condition and oral health, resulting in early tooth loss and severe bone atrophy. IAN transposition is a viable treatment option to enable installing fixed prostheses via dental implants, but the latter will clearly increase the risk of inflammation and interruption of mandibular continuity. Close clinical and radiologic monitoring is mandatory to adequately respond to complications such as peri-implant mucositis, peri-implantitis, osteomyelitis, or concomitant fractures. PMID- 30411095 TI - Maltol, a food flavor enhancer, attenuates diabetic peripheral neuropathy in streptozotocin-induced diabetic rats. AB - SCOPE: Maltol (3-hydroxy-2-methy-4-pyrone), a potent antioxidative agent, typically is used to enhance flavor and preserve food. This study evaluated its effects on preventing diabetic peripheral neuropathy (DPN) in streptozotocin (STZ)-induced diabetic rats and explored its mechanisms. METHODS AND RESULTS: We intraperitoneally injected Sprague-Dawley (SD) rats with STZ (65 mg kg-1, ip) and treated the rats with different doses of maltol after 4 weeks of injection. During treatment, we evaluated motor nerve conduction velocity (MNCV) and thermal and mechanical hyperalgesia and assayed the oxidative stress, Na+-K+-ATPase activity, and apoptosis. Repeated treatment with maltol for 12 weeks significantly improved thermal and mechanical hyperalgesia, increased the MNCV, elevated the Na+-K+-ATPase activity, and ameliorated oxidative stress and apoptosis in STZ-induced diabetic rats. We coincubated RSC96 cells, a Schwann cell line, with maltol and hydrogen peroxide (H2O2, 0.6 mM). Evidently, maltol increased cell viability and inhibited apoptosis after injury by H2O2. CONCLUSIONS: Maltol was demonstrated to prevent DPN development and may provide a new alternative for the treatment of DPN. PMID- 30411096 TI - Photo-polymerization properties of type-II photoinitiator systems based on 2 chlorohexaaryl biimidazole (o-Cl-HABI) and various N-phenylglycine (NPG) derivatives. AB - A series of p-substituted NPG derivatives (Cl-NPG, OMe-NPG and NO2-NPG) comprising different push-pull characteristics have been synthesized and characterized. The NPG derivatives have good thermal stability and red shifted absorption when compared with the original N-phenyl glycine (NPG) compound. These NPGs were selected in combination with 2-chlorohexaaryl biimidazole (o-Cl-HABI) for Type II free radical polymerization (FRP). Commercial NPG was also mixed with o-Cl-HABI for comparison. Their photo-polymerization properties were investigated by the gel fraction method in a nitrogen atmosphere. Electron transfer efficiencies for those Type II packages were studied by cyclic voltammetry (CV) and free energy change DeltaG results. PMID- 30411097 TI - Rapid assembly of cyclopentene spiroisoindolinones via a rhodium-catalysed redox neutral cascade reaction. AB - An unprecedented strategy of a rhodium-catalysed redox-neutral cascade reaction starting from benzamides and cyclopropenones via addition of a C-H bond into a polar carbonyl group for the rapid assembly of cyclopentene spiroisoindolinones has been developed. Water was produced as the sole by-product. Metal migration and abstraction of a H-atom from the arylcyclopropenone's aromatic ring are the key steps in building the spirocycle. Two C-C bonds, one C-N bond and an N substituted quaternary carbon center were formed sequentially in a one pot manner. PMID- 30411098 TI - Ab initio investigation of O2 adsorption on Ca-doped LaMnO3 cathodes in solid oxide fuel cells. AB - We present a Hubbard-corrected density functional theory (DFT+U) study of the adsorption and reduction reactions of oxygen on the pure and 25% Ca-doped LaMnO3 (LCM25) {100} and {110} surfaces. The effect of oxygen vacancies on the adsorption characteristics and energetics has also been investigated. Our results show that the O2 adsorption/reduction process occurs through the formation of superoxide and peroxide intermediates, with the Mn sites found to be generally more active than the La sites. The LCM25{110} surface is found to be more efficient for O2 reduction than the LCM25{100} surface due to its stronger adsorption of O2, with the superoxide and peroxide intermediates shown to be energetically more favorable at the Mn sites than at the Ca sites. Moreover, oxygen vacancy defect sites on both the {100} and {110} surfaces are shown to be more efficient for O2 reduction, as reflected in the higher adsorption energies calculated on the defective surfaces compared to the perfect surfaces. We show from Lowdin population analysis that the O2 adsorption on the pure and 25% Ca doped LaMnO3 surfaces is characterized by charge transfer from the interacting surface species into the adsorbed oxygen pig orbital, which results in weakening of the O-O bonds and its subsequent reduction. The elongated O-O bonds were confirmed via vibrational frequency analysis. PMID- 30411099 TI - Ta3N5/Co(OH)x composites as photocatalysts for photoelectrochemical water splitting. AB - Ta3N5 nanotubes (NTs) were obtained from nitridation of Ta2O5 NTs, which were grown directly on Ta foil through a 2-step anodization procedure. With Co(OH)x decoration, a photocurrent density as high as 2.3 mA cm-2 (1.23 V vs. NHE) was reached under AM1.5G simulated solar light; however, the electrode suffered from photocorrosion. More stable photoelectrochemical (PEC) performance was achieved by first loading Co(OH)x, followed by loading cobalt phosphate (Co-Pi) as double co-catalysts. The Co(OH)x/Co-Pi double co-catalysts may act as a hole storage layer that slows down the photocorrosion caused by the accumulated holes on the surface of the electrode. A "waggling" appearance close to the "mouth" of Ta2O5 NTs was observed, and may indicate structural instability of the "mouth" region, which breaks into segments after nitridation and forms a top layer of broken Ta3N5 NTs. A unique mesoporous structure of the walls of the Ta3N5 NTs, which is reported here the first time, is also a result of the nitridation process. We believe that the mesoporous structure makes it difficult for the nanotubes to be fully covered by the co-catalyst layer, hence rationalizing the remaining degradation by photocorrosion. PMID- 30411100 TI - Probing chirality recognition of protonated glutamic acid dimers by gas-phase vibrational spectroscopy and first-principles simulations. AB - The homochirality of the amino acid metabolism still puzzles biochemists. Vibrational spectroscopy of mass-selected gas-phase amino acids and their clusters can precisely reveal their conformation and might ultimately help to decode the interactions responsible for chirality recognition. Infrared photodissociation (IRPD) and conformer-selective IR-IR hole burning spectra of protonated glutamic acid dimers (LL-/LD-Glu2H+) recorded in the fingerprint and XH stretch ranges (1100-1900 and 2600-3600 cm-1) provide direct insight into their stereospecific interactions. Glu2H+ dimers are generated by electrospray ionization and stored in a cryogenic quadrupole ion trap held at 10 K. The assignment of the IRPD spectra is supported by vibrational analysis using many body dispersion-corrected hybrid density-functional theory. Sampling of the conformational space is accomplished by basin hopping and replica-exchange molecular dynamics simulations. The most stable LD-Glu2H+ dimer (LD1) is predicted to be more stable than the most stable LL-Glu2H+ dimer (LL1) by DeltaE0 = 4.0 kJ mol-1, which relies on stronger secondary interactions in LD1 as demonstrated by the noncovalent interaction method. IR-IR hole burning spectroscopy reveals the coexistence of at least four LD-Glu2H+ and three LL Glu2H+ conformers. Their IR-dip spectra are assigned to the most stable conformers at room and cryogenic temperature, revealing incomplete thermalization of the ions by kinetic trapping in the cold trap. We observe different population ratios of LL and LD conformers of Glu2H+, as revealed by specific nuNH2 and nuCO intensities (fingerprints of chirality recognition). PMID- 30411101 TI - Colossal dielectric permittivity in Co-doped ZnO ceramics prepared by a pressure less sintering method. AB - Dielectric properties and impedance spectroscopic studies of single phase Zn1- xCoxO (0 <= x <= 0.05) ceramics, synthesized by a pressure-less solid state reaction method, have been carried out to investigate the origin of colossal dielectric permittivity (CP), epsilon' ~ 105, in a wide frequency (2 * 101-2 * 106 Hz) range. These results show that a defect density within the grain is present in the materials due to the use of pressure-less sintering at high temperature for a long duration of time. The colossal dielectric response is essentially due to this electronic inhomogeneous conduction mechanism within the material due to the production of absorption current in the thin grain boundary region which accumulates charge at the interface and induces Maxwell-Wagner interfacial polarization. Moreover, this defect structure further increases with the addition of Co ions and enhances the CP property. An effective way to control the colossal dielectric properties is to control the defect density within a grain by using a proper sintering method. PMID- 30411102 TI - A general approach for encapsulating organic crystals in a polyaniline shell. AB - The hydrophobicity and instability of organic crystals restrict their further applications. Here, we present a general and scalable method to encapsulate different organic crystals in a conductive polyaniline (PANI) shell. The shell significantly improves the stability and dispersity of the nanocrystals, without compromising their luminescence intensity. PMID- 30411103 TI - Hollow carbon anchored highly dispersed Pd species for selective hydrogenation of 3-nitrostyrene: metal-carbon interaction. AB - Constructing Pd-C bond between Pd particles and defective hollow nanocarbons (h NCs) not only enables facile H2 dissociation but also diffusion of the dissociated H species, which makes the Pd/h-NC highly active with a TOF of 21 845 h-1 (>80 times higher than that of the best catalyst in literature), selective (97%), and stable (4 cycles) for selective hydrogenation of 3-nitrostyrene to 3 ethylnitrobenze. PMID- 30411104 TI - An integrated immobilization strategy manipulates dual active centers to boost enantioselective tandem reactions. AB - Manipulation of dual active centers via an integrated immobilization strategy can overcome the restriction of homogeneous catalysis in a sequential organic transformation. Herein, by utilizing hollow-shell-structured silica, hydrogen bonding immobilization via a ship-in-a-bottle synthesis locks a Pd(carbene) center in a nanocage and covalent-bonding immobilization tethers chiral Ru(diamine) centers within the nanochannels, constructing a hetero-bifunctional catalyst. The benefit of this dual center manipulation enables a challenging Suzuki coupling-asymmetric transfer hydrogenation tandem reaction, and the advantage of this process provides various chiral biarylols with enhanced reactivity and enantioselectivity. PMID- 30411105 TI - Diethylenediamine-assisted template-free synthesis of a hierarchical TiO2 sphere in-sphere with enhanced photocatalytic performance. AB - With the assistance of diethylenediamine (DETA), a template-free solvothermal approach is employed to one-step synthesize a hierarchical TiO2 sphere-in-sphere, which has a unique structure: an interior nanosized sphere is contained in the cavity of another hollow microsphere, and numerous nanosheets of width ca. 20-26 nm vertically distribute on the surface. It is proved that DETA added in solution plays an important inducing role in the formation of both the hollow sphere-in sphere structure and surface sheet-assembled network. Therefore, a DETA-assisted formation mechanism of the hierarchical TiO2 sphere-in-sphere has been described in detail. The unique hierarchical sphere-in-sphere structure endows the TiO2 product with increasing light-harvesting efficiency and specific surface area, resulting in its enhanced photocatalytic activity for the degradation of various organic pollutants under the illumination of UV light. PMID- 30411106 TI - Unraveling doping induced anatase-rutile phase transition in TiO2 using electron, X-ray and gamma-ray as spectroscopic probes. AB - The present work reports the microscopic details of anatase (A) to rutile (R) phase transformation in a Mn-doped TiO2 system. Titanium dioxide (TiO2) powder was synthesized at three different dopant percentages, namely 1, 5, and 10 atom% of Mn, by a coprecipitation technique. Time differential perturbed angular correlation (TDPAC) spectroscopy was used to identify the formation of the rutile like phase (R*) during the phase-transition process and revealed interface nucleation to be promoted by the Mn dopant. Electron paramagnetic resonance (EPR) spectroscopy, synchrotron-based X-ray absorption near edge structure (XANES), and extended X-ray absorption fine structure (EXAFS) studies showed that Mn exhibited a mixed valence states of 2+ and 4+ at different stages of the annealing process. The rutile onset temperature gradually decreased with the increase in the Mn content. The present report proposes the mechanism for the phase transformation and details the effect of Mn on the A to R phase-transformation process. This can assist in gaining a fundamental understanding of the A to R phase-transformation process and the role of the dopant in stabilizing one phase over the other. PMID- 30411107 TI - N-Doped porous carbon nanosheets decorated with graphitized carbon layer encapsulated Co9S8 nanoparticles: an efficient bifunctional electrocatalyst for the OER and ORR. AB - Electrocatalysts with highly effective activity for the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) are considered to be the key factor of renewable energy technologies. Herein, we designed and synthesized bi-functional electrocatalyst Co9S8/C nanosheets (NSs) by reducing the Co3O4/C NS precursor with sodium sulfide. From the structural characterization, Co9S8 is anchored on the graphitized carbon NSs homogeneously. According to the electrochemical measurements, the Co9S8/C NSs show excellent electrocatalytic activity towards both the ORR (Eonset = 0.892 V vs. RHE and E1/2 is 0.778 V vs. RHE) and OER (Eonset = 1.50 V vs. RHE and the overpotential is 0.434 V vs. RHE at 10 mA cm-2) in 0.1 M KOH solution. In the ORR, Co9S8/C catalyzes through a 4-electron process like the commercial Pt-based catalyst. In addition, the Co9S8/C NSs show great long-term stability. The Co9S8/C NSs show excellent catalytic performance due to the rich active sites and two-dimensional sheet structure. The developed strategy offers an effective method for preparing bi-functional electrocatalysts for both the OER and ORR. PMID- 30411108 TI - A highly selective and sensitive fluorescent probe for simultaneously distinguishing and sequentially detecting H2S and various thiol species in solution and in live cells. AB - A novel dual-channel fluorescent probe (NCR) based on differences in reactivity among H2S, Cys/Hcy, and GSH was rationally designed for simultaneously distinguishing and sequentially sensing H2S, Cys/Hcy, and GSH using two emission channels, which also demonstrated that NCR can be used for targeting mitochondria in mammalian cells. PMID- 30411110 TI - A stereoselective sequential organocascade and multicomponent approach for the preparation of tetrahydropyridines and chimeric derivatives. AB - A stereoselective multicomponent approach leading to a novel class of pentasubstituted tetrahydropyridines is described. Variation of the components enabled the incorporation of peptide, sugar and steroid moieties to access chimeric derivatives. DFT calculations provide insights about the unprecedented high diastereoselectivity of the MCR. PMID- 30411109 TI - Interaction of a trinuclear copper(i) pyrazolate with alkynes and carbon-carbon triple bond activation. AB - The trinuclear copper(i) pyrazolate {[3,5-(CF3)2Pz]Cu}3 forms eta2-copper/alkyne triple bond coordinated structures in the presence of acetylenes. There is no coordination of copper atoms to the phenyl ring of phenylacetylene and copper(i) acetylide formation during the interaction. It was observed that the complexes formed are the active catalytic species in click reactions. PMID- 30411111 TI - Correction: Organic semiconductor perylenetetracarboxylic diimide (PTCDI) electrodes for electrocatalytic reduction of oxygen to hydrogen peroxide. AB - Correction for 'Organic semiconductor perylenetetracarboxylic diimide (PTCDI) electrodes for electrocatalytic reduction of oxygen to hydrogen peroxide' by Magdalena Warczak et al., Chem. Commun., 2018, 54, 1960-1963. PMID- 30411112 TI - [Condylar adaptation triggered by SGTB orthopedic therapy-Biological mechanism and clinical significance]. AB - Endochondral ossification constitutes biological and phenotypic foundation for condylar growth. Adaptive response of condylar cartilage to mandibular advancement, on the other hand, facilities condylar remodeling generated by SGTB (sagittal-guided twin block)orthopedic therapy. This enables SGTB to correct increased overjet and overbite by eliminating jaws discrepancy. It is also an encouraging advance that SGTB therapy is used to intervene temporo-mandibular joint disorders (TMD) by regenerating the degraded condylar cartilage. PMID- 30411113 TI - [Expression of Forkhead boxO1 and Runt-related transcription factor 2 in periodontal tissue during orthodontic movement of teeth in rats]. AB - PURPOSE: To investigate the expression of FoxO1 and Runx2 in periodontal tissue and their effect during orthodontic teeth movement(OTM) in rats. METHODS: Forty 8 week old male Sprague-Dawley (SD) rats were used to establish animal models of orthodontic teeth movement and divided into 5 groups randomly. The right side of jaws of each rat was set as experimental side, and the left side as control side. At 1, 3, 5, 7, 14 d after orthodontic treatment, the rats were sacrificed and the maxillary bone containing the first molar was dissected. H-E staining and immunohistochemical staining were used to detect the morphological changes, the expression of FoxO1 and Runx2 of the periodontal tissue at different points. Computer image analysis was used to evaluate the expression of FoxO1 and Runx2 in the periodontal tissues of the rats. The differences were analyzed by using SPSS19.0 software package. RESULTS: The expression of FoxO1 in periodontal ligament was mainly in osteoblasts and cementoblasts; and the expression of Runx2 was mainly in osteoblasts, fibroblasts and cementoblasts. In the experimental group,the expressions of FoxO1 and Runx2 in the periodontal tissues of rats increased significantly, reached the peak within 3-5 days, then decreased. There was no significant difference between the experimental group and the control group at 14th day (P>0.05), but significant difference was found between other group and control group (P<0.05). CONCLUSIONS: FoxO1 and Runx2 play a role in the reconstruction of periodontal tissue during orthodontic movement of teeth, and they are mainly involved in the process of osteoblast formation and bone formation. PMID- 30411114 TI - [Effect of catalase on marginal microleakage of resin restoration after external bleaching]. AB - PURPOSE: To investigate the effect of catalase on marginal microleakage of resin restoration after external tooth bleaching with 10% carbamide peroxide. METHODS: Forty extracted human premolars, both intact and health, were randomly divided into 4 groups: group 1, direct composite resin filling without bleaching; group 2, composite resin filling immediately after external bleaching; group 3, immersed in artificial saliva for 3 weeks after external bleaching ,then filling with composite resin; group 4 ,cavity treated with catalase after external bleaching and then filled with composite resin. After 2000 thermal cycles, the teeth were immersed in 2% methylene blue for 24 hours, then the microleakage of interface of resin restorations was observed under stereomicroscope. The data were analysed with SPSS17.0 software package. RESULTS: Group 1 displayed the least amount of microleakage, while group 2 showed the greatest amount of microleakage, group 3 behaved similarly as group 2, having great amount of microleakage, with no significant difference (P>0.05); the microleakage of group 4 decreased significantly (P<0.05) compared to group 2. CONCLUSIONS: The microleakage increases significantly after external bleaching with 10% carbamide peroxide, then decreases if cavities are treated with catalase, but delay filling can not improve microleakage effectively. PMID- 30411115 TI - [Effect of fluoride-resistant strains of Streptococcus mutans on the bonding strength of dental resin composite]. AB - PURPOSE: The aim of this study was to determine the influence of fluoride resistant strains of S. mutans on the bonding strength of dental resin composite. METHODS: Standardized specimens of resin composite (Z350), and self-etch adhesives (Single bond Universal, 3M) were incubated with S. mutans UA159, fluoride-resistant strains of S. mutans UA159 (UA159-FR) or uninoculated culture medium (Control) or PBS for up to 14 days. Resin-dentin bonded disks were subjected to push-out test. Fractured surface analysis of the specimens was performed by scanning electron microscopy(SEM). SPSS18.0 software package was used for statistical analysis. RESULTS: UA159-FR and UA159 were shown to decrease the bond strengths in levels comparable with those found in the control groups (P<0.05). SEM confirmed the increased degradation of all materials with UA159-FR and UA159, compared with control and PBS. CONCLUSIONS: The results suggest that resin-dentin interface can be compromised by oral bacteria that contribute to the progress of secondary caries. Fluoride-resistant strains of S. mutans and its parental strains both decrease bonding strengths in a short time, but no significant difference in the extent of damage. PMID- 30411116 TI - [Analysis of the biocompatibility of a new PLGA/fish skin collagen conjugated electrostatic spinning film]. AB - PURPOSE: To study the biocompatibility of a new polylactic acid-glycolic acid(PLGA)/fish skin collagen conjugated electrostatic spinning film. METHODS: PLGA and medical-grade fish skin-I collagen were used as raw materials to prepare nanometer fiber films by conjugated electrostatic spinning technique. Mouse fibroblast L929 was used as a model to evaluate its cell and histocompatibility, which provided experimental basis for application in guided bone regeneration (GBR). RESULTS: Fibroblasts showed good adhesion and growth on the surface of fiber membrane; there were a large number of deep pseudopodias, which were arranged along the orientation of fibers. CONCLUSIONS: PLGA/fish skin collagen conjugated electrostatic spinning membrane is beneficial to fibroblast growth and is expected to be used for GBR. PMID- 30411117 TI - [Influence of tribochemical silica coating on shear bond strength of a dental zirconia ceramic to resin cements]. AB - PURPOSE: To evaluate the effect of tribochemical silica coating for zirconia bonding. METHODS: Sixty cut and fully sintered Lava frame zirconia blocks were randomly divided into 6 groups and subjected to 3 different surface treatments and 2 kinds of resin cement.The surface treatments were airborne-particle abrasion/silane, airborne-particle abrasion/CoJet Sand (tribochemical silica coating) /silane and no treatment(control), resin cements were RelyX Unicem and Panavia F2.0. Half of the specimens in each group were randomly chosen and stored in 37C distilled water for 24h, the others were thermocycled (5C and 55C) for 5000 cycles. All specimens were subjected to shear bond strength(SBS) testing. SBS values were analyzed by two-way ANOVA and t test, and multiple pairwise comparisons were then completed with post hoc Tukey test. Statistical analysis was performed using SPSS23.0 software package for Windows. RESULTS: Airborne particle abrasion/CoJet sand/silane group resulted in a significantly higher SBS than those in other groups (P<0.001). After thermocycling, the bond strengths in the airborne-particle abrasion/CoJet Sand/silane groups bonded with RelyX Unicem showed no significantly decrease while marked drop appeared in all other groups. CONCLUSIONS: Combination of tribochemical silica coating with silane coupling can effectively enforce the bond strengths of zirconia (Y-TZP). Attention should be paid to the interaction between surface treatments and resin cements. PMID- 30411118 TI - [Hydrogen rich water attenuates pregnancy gingivitis induced by ligation in SD rats]. AB - PURPOSE: To investigate the effect of hydrogen rich water on experimental gingivitis in SD rats during pregnancy. METHODS: Female SD rats mated with male ones were chosen to induce experimental gingivitis after ligation for 2 weeks. The pregnant rats were randomly divided into control group, model group and HW group. In the control and model group, rats were given pure water, while animals in the HW group were given hydrogen-rich water twice a day. All pregnant animals were sacrificed on day 16 of pregnancy. The level of Prog, SOD and TNF-alpha in the gingiva of different groups were measured by ELISA, the expression of PR, NFkappaB and TNF-alpha were determined by immunohistochemistry and Western blot. SPSS 13.0 software package was used for data analysis. RESULTS: Pregnancy gingivitis of SD rats could be induced by thread ligation. PR was mainly distributed in the gingival epithelium, while there was no significant difference of Prog and PR in the gingiva among different groups(P>0.05). Furthermore, in the model group, lower SOD level as well as higher NFkappaB and TNF-alpha level were found in the gingiva. Compared with the model group, the inflammatory response of pregnancy gingivitis in HW group was significantly suppressed along with decreased NFkappaB and TNF-alpha. CONCLUSIONS: Progesterone and its receptor may play an indirect role in the process of pregnancy gingivitis of rats. Hydrogen rich water may be beneficial in suppressing pregnancy gingivitis progress by decreasing inflammatory response related to gingival oxidative stress. PMID- 30411119 TI - [Comparative study of enamel discoloration related to bonding with different orthodontic adhesives and cleaning-up with different procedures]. AB - PURPOSE: The aim of this study was to compare if there was any difference in the enamel discoloration after staining when three orthodontic adhesives and 4 enamel clean-up methods were tested. METHODS: Three types of orthodontic adhesives were used: chemically cured resin, light-cured resin and resin-modified glass-ionomer cement. A total of 120 human extracted premolars were included. Ten teeth of each orthodontic adhesive were randomly cleaned-up with 1 of 4 different procedures and stained in coffee for 7 days: carbide bur (TC), carbide bur and Sof-Lex polishers (TC+SL), carbide bur and One Gloss polishers (TC+OG), carbide bur and PoGo polishers (TC+PG). Colour measurements were made with Crystaleye dental spectrophotometer at baseline and after storage in a coffee solution for 1 week. Two way ANOVA and Bonferroni test were used for statistical analysis with SPSS 13.0 software package. RESULTS: The colour change values of adhesive materials in the TC group were the greatest. The lowest DeltaE* values were obtained from the TC+SL group. However, there was no significant difference between the TC+SL and TC+PG group (P>0.05). The resin-modified glass-ionomer cement group showed the lowest colour differences and chemically cured resin group showed the highest DeltaE* values among all orthodontic adhesives (P<0.05). CONCLUSIONS: The colour change of enamel surface is affected by the type of adhesive materials and clean up procedures. PMID- 30411120 TI - [Effect of anti-inflammatory flavonoid chrysin on osteogenesis of preosteoblast MC3T3-E1 cells]. AB - PURPOSE: To investigation the effect of flavonoid chrysin on osteogenesis of preosteoblast MC3T3-E1 cells. METHODS: After evaluation of the toxic effect of chrysin, preosteoblast MC3T3-E1 cell suspension was prepared with DMEM and then the cells were cultured with 0 and 25 MUmol/L chrysin. Real-time quantitative PCR was used to detect the expression of osteogenic marlcers including Runx2, ColA1 and OCN. Statistical analysis was performed using SPSS17.0 software package. RESULTS: 25 MUmol/L chrysin had no toxic effect on preosteoblast MC3T3-E1 cells. After co-culture with 25 MUmol/L chrysin,the expression of Runx2, ColA1 and OCN was highest at the 7th,14th and 21th day,respectively. CONCLUSIONS: 25 MUmol/L chrysin can promote osteogenic gene expression of preosteoblast MC3T3-E1 cell. PMID- 30411121 TI - [miR-199b-5p inhibits proliferation and invasion of head and neck cancer cells]. AB - PURPOSE: This study identified the differentially expressed miR-199b-5p in the progressing of head and neck squamous cell carcinoma(HNSCC) and investigated its biological characters. METHODS: The expression of miR-199b-5p in 128 HNSCC tissues samples was evaluated. The association between clinicopathological parameters and the expression levels of the candidated miRNAs was analyzed by using Kaplan-Meier survival analysis. Cell growth, invasion and migration potential, and clone formation were observed to detect the functions of the miRNAs in HNSCC cells. Statistical analysis was performed using SPSS 19.0 software package. RESULTS: In 79 HNSCC tissues with cervical lymph node metastasis, the expression level of miR-199b-5p was 1.68+/-0.21; while the expression level was 2.64+/-0.24 in 28 tissues without lymph node metastasis (P=0.001). In patients with HNSCC, lower level of miR-199b-5p expression significantly correlated with worse overall survival rate (P=0.01). Overexpression of miR-199b-5p inhibited HNSCC cell proliferation and invasion. CONCLUSIONS: miR-199b-5p plays a key role in cell invasion and metastasis and its expression correlated with overall survival in patients with HNSCC. PMID- 30411122 TI - [Changes of upper airway in ClassIIchildren with high mandibular plane angle before and after functional treatment by high headgear-activator]. AB - PURPOSE: This study was performed to investigate the changes of upper airway before and after functional correction in ClassIImalocclusion children with high mandibular plane angle at growth and development peak. METHODS: Cone-beam CT (CBCT) data of the upper airway were inputted into Minics 17.0 software for measurement of changes in the upper airway before and after functional treatment by high headgear-activator. The changes of upper airway before and after treatment were analyzed with SPSS22.0 software package. RESULTS: The change of the total volume of the upper airway, the volume of the velopharynx, glossopharynx, laryngopharynx; the sectional area of the tip of soft palate, roof of the epiglottis, the minimum sectional area of the oropharynx were significant (P<0.05). The upper airway morphology tended to be circular in the soft palate tip plane(P<0.05), but there was no significant difference in the plane of epiglottis(P>0.05). CONCLUSIONS: High headgear-activator corrected mandibular hypoplasia in children with increased airway volume, increased ventilation, improved respiratory function to prevent occurrence of obstructive sleep apnea hypopnea syndrome after adult. PMID- 30411123 TI - [Effects of Dnmt1 and Dnmt3b in mucoepidermoid carcinoma of salivary glands]. AB - PURPOSE: To investigate the effects of DNA methyltransferase in mucoepidermoid carcinoma of human salivary glands tissues. METHODS: Forty-three samples from mucoepidermoid carcinoma of salivary glands and 17 normal salivary gland tissues were collected from January 2010 to September 2013. Immunohistochemistry and Western blot were used to detect the expression of Dnmt1 and Dnmt3b in normal tissues and specimen of mucoepidermoid carcinoma of salivary glands. The data were analysed with SPSS 22.0 software package. RESULTS: The positive expression rate of Dnmt1 in mucoepidermoid carcinoma tissue was 37.21%, and that in normal salivary gland tissues was 17.65%, there was no significant difference between them; the positive expression rate of Dnmt3b in mucoepidermoid carcinoma tissue was 83.72%, which was significantly higher than that in normal salivary gland tissue (11.76%, P<0.01). However, there was no significant correlation between high expression of Dnmt1 and Dnmt3b and clinicopathological parameters. CONCLUSIONS: Dnmt3b may play a role in the tumorigenesis of mucoepidermoid carcinoma in salivary glands. PMID- 30411124 TI - [Evaluation of the effects of two different modes of orthognathic surgery on upper airway morphology in patients with skeletal Class III malocclusion]. AB - PURPOSE: To establish three-dimensional models of upper airway pre- and post orthognathic surgery in patients with skeletal Class III malocclusion, and to compare the effects of different modes of orthognathic surgery on the cross sectional areas and volumes of upper airway. METHODS: Twenty-eight patients with skeletal Class III malocclusion were divided into 2 groups. Group A (12 patients) underwent bilateral sagittal split ramus osteotomy(BSSRO) for mandibular setback, named single jaw surgery group; group B (16 patients) underwent BSSRO + Le Fort I osteotomy for mandibular setback and maxillary advancement, named bimaxillary surgery group. All patients received CT scanning before (T1) and 3 months after surgery (T2). The three-dimensional models of the upper airway containing velopharynx, glossopharynx and laryngopharynx were established by using Dolphin Imaging 11.7 software. The changes of sagittal diameters, coronal diameters, cross-sectional areas and volumes of the upper airway were measured and compared between the two groups pre- and post- surgery (T1, T2) using SPSS 16.0 software package, respectively. RESULTS: In velopharynx, the values of group A were decreased after surgery, while the other values of group B were increased except the value of coronal diameter. There was a significant difference between the two groups (P<0.05). In glossopharynx and laryngopharynx, the values of group A and group B were both decreased after surgery. The reduction of the cross-sectional areas and volumes in group A were more obvious than group B (P<0.05). CONCLUSIONS: The amount of narrowing of the upper airway is smaller in patients undergoing bimaxillary surgery than in patients undergoing mandibular setback surgery. PMID- 30411125 TI - [Impact of oral health promotion project on periodontal condition and life quality of the elderly in long-term care institutions]. AB - PURPOSE: To assess the impact of oral health promotion project on periodontal condition and life quality of the elderly in long-term care institutions. METHODS: Elder people from 5 nursing homes in Wuhan city were selected and assigned to either the experimental group or the control group by random cluster grouping method. A six-month oral health promotion project was provided to the experimental group. The changes of geriatric oral health assessment index (GOHAI), oral hygiene index-simplified (OHI-S), gingival index (GI), bleeding on probing (BOP) and probing depth (PD) were compared with student's t test and repetitive measure analysis of variance using SPSS21.0 software package. RESULTS: A total of 322 subjects completed the study for 6 months, with 144 from the experimental group and 178 from the control group. No significant difference was observed between the two groups in social demographic characteristics, GOHAI scores, OHI-S, GI, BOP and PD at baseline(P>0.05). Greater improvements were observed in GOHAI scores, OHI-S, GI and BOP in the experimental group than the control group after interventions (P<0.05). CONCLUSIONS: Oral health promotion project can improve the elderly's oral health-related quality of life and periodontal condition. PMID- 30411126 TI - [A long-term clinical evaluation of comprehensive physiotherapy for patients with chronic anterior disc displacement of the temporomandibular joint without reduction]. AB - PURPOSE: To observe the long-term clinical efficacy of comprehensive physiotherapy for patients with chronic anterior disc displacement of the temporomandibular joint (TMJ) without reduction (ADDWoR). METHODS: A total of 256 patients with chronic ADDwoR (the course of disease was 8.4+/-9.6 months) who completed the treatment in our hospital from January 2014 to December 2015 were followed up. Symptoms and function pre-treatment, post-treatment and during follow-up including the maximum active mouth opening (mm), visual analog scale(VAS), mandibular function impairment questionnaire (MFIQ) score were recorded and compared; recurrent frequency and symptoms were recorded and compared, too. SPSS 17.0 software package was used for analysis of variance of repeated measurement. RESULTS: The follow-up period was 30.5+/-4.6 months, the patients' maximum mouth opening: pre-treatmentpost-treatment>follow-up (P<0.05); the patients' MFIQ: pre-treatment>post-treatment> follow-up (P<0.05). 82.8% patients didn't have recurrent symptoms, 14.5% had recurrence and the symptoms were not improved in 2.7% of patients. Among 37 patients with symptomatic recurrent disease, 70.3% had pain, 13.5% had mouth opening limitation, and 13.6% had pain with mouth opening limitation. CONCLUSIONS: Comprehensive physical therapy can significantly relieve pain and improve mouth limitation in patients with chronic ADDwoR of TMJ, and long-term efficacy was good. The causes of recurrence in some patients need further study. PMID- 30411127 TI - [Analysis of caries and its risk factors of the first permanent molar among primary school students in Pudong, Shanghai and Lichuan, Jiangxi Province]. AB - PURPOSE: To Investigate the current situation of caries of primary school students in Shanghai Pudong and Lichuan, Jiangxi province, and analyze the risk factors of dental caries, in order to provide scientific evidence for prevention and treatment of dental caries. METHODS: A stratified cluster sampling method was applied to choose 10 primary schools from Lichuan and 2 primary schools from Pudong area, respectively. A total of 1922 pupils aging from 6 to 12 were selected. Oral health examination was applied to each student and questionaire survey was conducted among their parents. The results were analyzed with SPASS 21.0 software package. RESULTS: Two hundred and sixty-one caries was found in Lichuan pupils, with the caries rate of 23.6% and DMFT being 0.37+/-0.766. 96 caries was found in Pudong pupils, with the caries rate of 11.8% and DMFT being 0.19+/-0.582. There was significant difference between two areas. Analysis of risk factors showed a significant correlation between children's pre-bedtime sweets and other bad habits, as well as low level of education of children's parents and dental caries. CONCLUSIONS: The caries of primary school students in rural areas are significantly worse than those in urban areas; bad living habits are risk factors of caries and the knowledge of caries prevention should be popularized in school students to enhance the awareness of oral health among pupils. PMID- 30411128 TI - [Evaluation of the clinical effect of fluoride coating combined with pit and fissure sealing or preventive resin filling on prevention of first permanent molars caries]. AB - PURPOSE: To explore the clinical effect of fluoride coating combined with pit and fissure sealing or preventive resin filling on prevention of young first permanent molars caries. METHODS: Three hundred suspicious first permanent molars caries in 90 children (6-8 years old) who received oral health examination in our hospital from February 2015 to January 2016 were included as the study subject, and randomly divided into group A, B, C, D and E. Group A received pit and fissure sealing, group B received preventive resin filling, group C received 0.5% fluoride coating combined with pit and fissure sealing, group D received 0.5% fluoride combined with preventive resin filling, group E as control group with nursing daily brushing. 6, 12 and 18 months after treatment, caries rate in each group was evaluated and preservation of pit and fissure sealing or resin filling in group A, B, C, D was examined. The data were analyzed using SPSS 21.0 software package. RESULTS: Six and 12 months after treatment, there was no significant difference (P>0.05) in the preservation rate of pit and fissure sealing or resin filling and caries rate in group A, B, C, D. Eighteen months after treatment, caries rate in group E was significantly higher than that of group A, B, C, D; there was significant difference between group A and group C, group B and group D (P<0.01); caries rate of group A, B was relatively high, the preservation rate was lower than that of group C and D, the differences were statistically significant (P<0.05). CONCLUSIONS: For suspected young permanent molars caries, fluoride coating combined with pit and fissure sealing or separate pit and fissure sealing has a certain effect on prevent dental caries, but the fluoride coating combined with preventive resin filling is better. PMID- 30411129 TI - [Application of panoramic film in predicting orthodontic treatment time for impacted maxillary canine]. AB - PURPOSE: To evaluate the influence of pretreatment radiographic features (angle, distance, and location) on the duration of active orthodontic traction. METHODS: Sixty maxillary unilateral impacted canines were selected to analyze the panoramic features(angle, line spacing, and location) in pre-treatment patients, the results were evaluated using SPSS19.0 software package for multivariate regression analysis. RESULTS: Pretreatment radiographic variables (angle, line spacing, and location) were significantly associated with the duration of orthodontic traction. The sex and site of impaction did not significantly affect the duration of traction. CONCLUSIONS: Impacted canine angle, distance and position can predict the orthodontic traction time. PMID- 30411130 TI - [Efficacy of Nd:Yap laser combined with composite resin for restoring hypersensitive wedge-shaped defect in 70 patients]. AB - PURPOSE: The purpose of this study was to explore the effect of Nd:Yap laser combined with composite resin filling on reducing hypersensitivity of dental wedge-shaped defect. METHODS: Seventy cases, 144 teeth with sensitive wedge shaped defects were selected. The patients were randomly divided into 2 groups and treated as below: 35 cases, 74 teeth in group A were treated with composite resin directly; 35 cases, 70 teeth in group B were treated with Nd:Yap laser combined with composite resin. After treatment, the effective rates under clinical examination standard (immediately, 1, 3 and 6 months after treatment) in both groups were collected and statistically analysed with SPSS 13.0 software package. RESULTS: In group A, one and 2 teeth fillings fell off 3 months and 6 months after treatment,respectively. In group B, one and 1 tooth fillings fell off 3 months and 6 months after operation. There was no significant difference between the two groups (P>0.05). The effective rates of desensitization were 95.71%,91.43%,87.14% and 81.43% in group B, respectively, which were significantly higher than those in group A (82.43%,78.38%,72.97% and 64.86%)(P<0.05). CONCLUSIONS: Nd:Yap laser combined with composite resin filling can treat sensitive wedge-shaped defect effectively and improve the symptoms of tooth sensitivity significantly. PMID- 30411131 TI - [Expression of miR-146a in saliva of chronic periodontitis patients and its influence on gingival crevicular inflammation and MMP-8/TIMP-1 levels]. AB - PURPOSE: To study the expression of miR-146a in saliva of chronic periodontitis patients and its influence on gingival crevicular inflammation and MMP-8/TIMP-1 levels. METHODS: Sixty-eight patients with chronic periodontitis treated in our hospital during March 2015 to January 2017 were chosen as the experimental group, while 50 healthy volunteers for physical examination were chosen as the control group. The level of miR-146a in saliva and inflammatory factors, MMP-8/TIMP-1 in gingival crevicular fluid were detected. Pearson test was used to assess the correlation between expression of miR-146a in saliva and the severity of disease with SPSS24.0 software package. RESULTS: The expression of miR-146a in saliva in the experimental group was significantly higher than that in the control group(P<0.05). The level of inflammatory cytokines (IL-1beta, IL-6 and IL- 35, TNF-alpha), the indexes of periodontal clinical symptoms (PD, AL, PLI, BI) in the experimental group were significantly higher than those in the control group (P<0.05); and MMP-8 and TIMP-1 in gingival crevicular fluid in the experimental group were significantly higher than those in the control group(P<0.05). Pearson test found that the expression of miR-146a in saliva of patients with chronic periodontitis was positively correlated with the degree of gingival inflammation, the severity of periodontal symptoms and the level of MMP-8/TIMP-1. CONCLUSIONS: The expression of miR-146a in saliva of chronic periodontitis patients is abnormally high, and the specific expression is consistent with the degree of gingival inflammation and periodontal injury. PMID- 30411132 TI - [A clinical investigation of plaque control efficacy and safety of Sonicare toothbrush in children]. AB - PURPOSE: To provide theoretical basis for children's oral health instruction and children's dental prophylaxis by comparing the plaque control efficacy and safety of Sonicare and manual toothbrush in 3-9 years old children. METHODS: One hundred and eighty healthy children were included in this study and were divided into 2 groups with 90 children in each group: aged 3-6 years and 6-9 years respectively. In each group, the subjects were randomly instructed to use either Sonicare for kids (SFK) or manual tooth brush (MTB). During a 28-day clinical trial period, oral hygiene was examined and plaque index(Rustogi modified Navy plaque index,RMNPI) was recorded at baseline, and at visits on the 7th and the 28th day (D0, D7, D28). The data were analyzed by R software. RESULTS: Both MTB and SFK could remove a certain amount of dental plaque. In the group of 3-6 years old children, the plaque reduction rates of children using SFK were 17.09%+/ 14.4%(D0), 27.14%+/-11.4%(D7), 33.52%+/-18.3%(D28), respectively, which were significantly higher than that of children using MTB [11.86%+/-9.7%(D0), 11.83%+/ 9.1%(D7), 13.73%+/-11.0%(D28)] (P<0.05). Similarly, in the group of 6-9 years old children, the plaque reduction rates of children using SFK were 20.05%+/ 10.52%(D0), 22.76%+/-13.46%(D7), 22.31%+/-9.74% (D28), which were significantly higher than that of children using MTB [9.15%+/-7.07%(D0), 7.26%+/-6.81%(D7), 11.54%+/-8.27%(D28)] (P<0.05). Further analysis revealed that the plaque index was decreased gradually in 3-6 years old children using SFK after 3 months of follow-up (P<0.05). In addition, there was better compliance and safety in children using SFK. CONCLUSIONS: Sonicare can remove plaque efficiently, and can control plaque and improve oral hygiene quality effectively in children in a long period, which implies that the application of Sonicare is worthy of promoting to control dental plaque in children. PMID- 30411133 TI - [Effect of full crown preparation with ultrasound instrument on marginal adaption: a randomized controlled trial]. AB - PURPOSE: To study the effect of full crown ultrasound preparation on crown margin. METHODS: Thirty-two patients with 35 units of full crown were randomly divided into 2 groups. Teeth in the experimental group were prepared with ultrasound diamond instrument while teeth in the control group were prepared with a high-speed hand piece with regular diamond burs. Teeth in both groups were restored using Zirconia full ceramic crowns. Then all patients were evaluated for morphology of finishing line, marginal adaptation and marginal gingival coloration in the proximal side after 6-month of follow-up, respectively. SPSS17.0 software package was used for statistical analysis. RESULTS: Marginal adaptation did not show significant difference between the experimental and control group (P>0.05). Morphology of finishing line and marginal gingival coloration in the proximal side showed significant difference (P<0.05). CONCLUSIONS: It is recommended to perform tooth preparations with ultrasound diamond instruments, which may produce significantly less marginal gingival coloration in the proximal margin after 6-month of follow-up. PMID- 30411134 TI - [Role of corticotomy in assisting space closure with atrophic alveolar ridge]. AB - PURPOSE: To study the effect of corticotomy in assisting space closure in cases whose alveolar ridge atrophy was obvious after extraction. METHODS: Twenty two cases whose canine's distal movement<0.2mm/m were selected, 12 accepted corticotomy and the other 12 were selected as the control group. All the spaces were closed with sliding mechanics under the help of microscrews. SPSS 13.0 software package was used for statistical analysis. RESULTS: All the spaces were closed. The canine's movement speed in the experimental group was superior to the control group(P<0.05), and the canine's movement was almost bodily movement (P<0.05); there was no obvious gingiva fold after space closure (P<0.05). There was no significant difference in the sulcus depth on the distal surface of the upper canine(P>0.05). PMID- 30411135 TI - [Analysis of articles published in Shanghai Journal of Stomatology form 2012 to 2016]. AB - PURPOSE: To analyze the advantages and disadvantages of Shanghai Journal of Stomatology(SJOS), and provide some suggestions for its sustainable development. METHODS: The volumes, issues, the first authors, author affiliation, date of reception, fund, the frequency of cited and downloaded articles published in SJOS from 2012 to 2016 were recorded. The data were analyzed by bibliometric methods. RESULTS: Seven hundred and eighty-nine papers were published in SJOS in 5 years. The total number of the first authors was 702, which were distributed in 29 provinces, autonomous regions or municipalities. All 789 papers were from 222 research institutions, key laboratory, medical universities and their affiliations. 37 papers (4.69%) were written by the first authors in top 10, while 88 papers (11.15%) by the corresponding authors in top 10. 118/789 (14.96%) were funded by national projects and 339/789 (42.97%) by regional projects. The average time of delay in publication of articles (DPA) was 282.44 days (9.41 months) in 5 years. 615/789 (77.95%) papers were cited, the total frequency of cited and downloaded articles were 2388 and 75866, respectively. The impact factors were increased year by year gradually. CONCLUSIONS: SJOS has strong academic influence in the field of stomatology with a core group of authors, and highly recognized in society. PMID- 30411136 TI - [Application and exploration of micro-class combined with flipped classroom in cardiopulmonary resuscitation teaching for dental students]. AB - PURPOSE: To explore the application of micro-class combined with flipped classroom in cardiopulmonary resuscitation teaching for dental students. METHODS: The experimental group included 46 students from grade 2014 in college of stomatology, Shanghai Jiao Tong University. The control group included 45 students from grade 2013. Students in the control group were taught in traditional method, while those in the experimental group were taught in micro class combined with flipped classroom teaching. After the course, we compared the outcome of didactic test and skill evaluation about CPR. A questionnaire survey was conducted in the experimental group. SPSS16.0 software was employed for statistical analysis. RESULTS: The results of didactic test and skill evaluation in the experimental group was significantly better than that in the control group(P<0.05). The results of questionnaire showed that application of micro class combined with flipped classroom was appreciated by over 80% students. CONCLUSIONS: The implementation of micro-class combined with flipped classroom can achieve a better teaching effect in cardiopulmonary resuscitation teaching for dental students. PMID- 30411137 TI - [Skin cancer screening in Germany: review after ten years]. AB - In 2008, a nationwide population-based skin cancer screening program was introduced in Germany. Its potential to reduce the skin cancer-related burden of disease is the subject of a controversial debate. This article gives an overview on the epidemiology of cutaneous melanoma of the skin and nonmelanoma skin cancer, on the history and practice of the current program, and appraises the evidence of screening for skin cancer based on a selective search for literature and data.The incidence of skin cancer has increased markedly throughout the last decades. The available evidence indicates efficacy of screening for skin cancer, but on a low level. Randomized controlled trials are lacking and the available evidence is based largely on the pilot study SCREEN which was conducted in 2003/2004 in Schleswig-Holstein, Germany. Following this pilot study, a marked decline of melanoma mortality was observed. After implementation of nationwide skin cancer screening, a mortality reduction has not appeared so far.A comparison of nationwide skin cancer screening and the SCREEN project suggests a lower intensity of the current screening program. Its process and outcome quality requires further investigations. Improved documentation allowing for a linkage between screening procedures conducted by nondermatologists and dermatologists is desirable. Personal invitations could help to reach individuals who currently make little or no use of skin cancer screening but might benefit from it. PMID- 30411138 TI - [Perioperative music-induced analgesia : Comparison of the effect of music on pain between preoperative, intraoperative and postoperative application]. AB - BACKGROUND: Despite suitable analgesia procedures and interventions only approximately 24% of inpatients with strong to very strong pain receive adequate treatment. Besides opioids, which are associated with numerous side effects and risks, non-pharmacological approaches are increasingly being used. In this context, one of the oldest known methods are music interventions; however, the state of evidence is heterogeneous and there are no explicit manuals and recommendations for the effective implementation of music interventions. OBJECTIVE: This review aimed to determine the optimal time point at which perioperative music interventions can most effectively relieve pain. MATERIAL AND METHODS: A PubMed search was conducted and publications investigating the effect of music during the preoperative, intraoperative and postoperative stages of various interventions were identified. RESULTS: During the preoperative phase, only positive effects of music on pain relief have been reported but availability of data is sparse. During the intraoperative stage of a medical intervention the effect of music seems to be mediated by the type of anesthesia procedure and sedation depth. Only patients who can consciously perceive the music seem to profit from it. Positive alleviating effects on subjective pain perception and analgesia needs were shown in the postoperative stage. CONCLUSION: Music is a non pharmacological method to alleviate pain, which is free of side effects. Important considerations for the use of music interventions for relief of acute pain associated with surgery are discussed taking into account numerous mediating factors, which influence the efficacy of the treatment. PMID- 30411139 TI - Phosphoproteomic analysis of cocaine memory extinction and reconsolidation in the nucleus accumbens. AB - RATIONALE: Environmental stimuli, or cues, associated with the use of drugs such as cocaine are one of the primary drivers of relapse. Thus, identifying mechanisms to reduce the motivational properties of drug cues is an important research goal. OBJECTIVES: The purpose of this study was to identify cellular signaling events in the nucleus accumbens (NAc) that are induced when a cocaine cue memory is either extinguished through repeated cue presentation in the absence of drug, or when the memory is reactivated and reconsolidated by a brief cue re-exposure. Signaling events specific to extinction or reconsolidation represent potential targets for pharmacotherapeutics that may enhance extinction or disrupt reconsolidation to reduce the likelihood of relapse. METHODS: Male Sprague-Dawley rats were trained to self-administer cocaine paired with an audiovisual cue. Following a period of self-administration, the memory for the cocaine-associated cue was either extinguished, reactivated, or not manipulated (control) 15 min before sacrifice. Tissue from the NAc was subsequently analyzed using mass spectrometry based phosphoproteomics to identify cellular signaling events induced by each condition. RESULTS: Extinction and reconsolidation of the cocaine cue memory produced both common and distinct changes in protein phosphorylation. Notably, there were no significant changes in protein phosphorylation that were modulated in the opposite direction by the two behavioral conditions. Comparison of NAc phosphoproteomic changes to previously identified changes in the basolateral amygdala (BLA) revealed that cue extinction increases phosphorylation at serine (S) 883 of the GABAB receptor subunit 2 and on S14 of syntaxin 1a in both regions, while no common regional signaling events were identified in the reconsolidation group. CONCLUSIONS: Phosphoproteomics is a useful tool for identifying signaling cascades involved in different memory processes and revealed novel potential targets for selectively targeting extinction versus reconsolidation of a cocaine cue memory. Furthermore, cross region analysis suggests that cue extinction may produce unique signaling events associated with increased inhibitory signaling. PMID- 30411140 TI - Juvenile exposure to methylphenidate and guanfacine in rats: effects on early delay discounting and later cocaine-taking behavior. AB - RATIONALE: Both methylphenidate (MPH), a catecholamine reuptake blocker, and guanfacine, an alpha2A agonist, are used to treat attention-deficit hyperactivity disorder (ADHD). Childhood impulsivity, including delay discounting, is associated with increased substance use during adolescence. These effects can be mitigated by juvenile exposure to MPH, but less is known about the long-term effects of developmental exposure to guanfacine in males and females. OBJECTIVE: This study aims to determine sex differences and dose-dependent effects of juvenile exposure to MPH or guanfacine on delay-discounting and later cocaine self-administration. METHODS: The dose-dependent effects of vehicle, MPH (0.5, 1, and 2 mg/kg p.o.) or guanfacine (0.003, 0.03, and 0.3 mg/kg, i.p.) on discounting were determined in male and female Sprague-Dawley rats beginning at postnatal day (P)20. At P90, the amount, motivation, and sensitivity to cocaine following early drug exposure were determined with self-administration. RESULTS: Guanfacine, but not MPH, significantly reduced weight by 22.9 +/- 4.6% in females. MPH dose dependently decreased delay discounting in both juvenile males and females, while guanfacine was only effective in males. Discounting was associated with cocaine self-administration in vehicle males (R2 = -0.4, P < 0.05) and self administration was reduced by guanfacine treatment (0.3 mg/kg). Guanfacine significantly decreased cocaine sensitivity in both sexes. CONCLUSIONS: These data suggest that MPH is effective in reducing delay discounting in both sexes. Due to both weight loss and ineffectiveness on discounting in females, guanfacine should be used only in males to reduce delay discounting and later cocaine use. PMID- 30411141 TI - Minimal rest activity for SPECT myocardial perfusion imaging in a one-day stress first protocol. AB - PURPOSE: Guidelines propose different rest-stress activity ratios (RSAR) for one day stress-first SPECT myocardial perfusion imaging (MPI), but evidence is limited. Our aim was to determine and validate the minimal RSAR resulting in the same diagnostic outcome in one-day stress-first SPECT MPI. METHODS: Forty-seven patients referred for rest after stress CZT-SPECT/CT MPI were prospectively included. Rest acquisitions were performed 3 h after stress. In addition to the stress and rest acquisitions, the first 22 patients underwent an additional acquisition prior to the rest injection to determine the remaining stress activity. Next, we simulated six RSARs varying from 1.0 to 3.5 in both patients and a phantom and compared the images to those using the reference RSAR of 4.0. Differences in summed difference score (SDS) >2 or ischemic defect interpretation were considered to significantly influence diagnostic outcome. After deriving the minimal RSAR, it was validated in 25 additional patients by comparing it to a RSAR of 4.0. RESULTS: After 3 h only 26% of the stress activity was still present in the myocardium. SDS differences >2 were found in one (4%) patient using RSAR of 3.5, 2.5 and 2.0, in three (12%) using 1.5 and in five (20%) using SRAR of 1.0. These results were consistent with the phantom study showing SDS differences >2 for RSARs <=1.5 and with the visual interpretation which showed an increased number of deviating scans for RSAR 1.0. Validating the RSAR of 2.0 resulted in a different SDS in one patient (SDS of 30 versus 11). Moreover, two scans were interpreted as ischemic instead of normal when using RSAR 2.0 and in two other scans the opposite was the case. CONCLUSIONS: A RSAR of 2.0 in one-day stress first MPI SPECT seems sufficient to obtain accurate diagnostic outcomes and is therefore recommended to reduce radiation exposure. PMID- 30411142 TI - Relevance of erythrocyte sedimentation rate and C-reactive protein in patients with active uveitis. AB - PURPOSE: To relate erythrocyte sedimentation rates (ESR) and C-reactive protein (CRP) values to different uveitis entisties. METHODS: A retrospective study of patients with a first episode of active uveitis visiting the Erasmus University Medical Center, uveitis clinic, Rotterdam, the Netherlands, was performed. Levels of ESR and CRP were determined within 2 weeks and 1 week after onset of uveitis, respectively. Uveitis had to be of unknown origin at that moment. The specific etiologic groups were related to ESR and CRP values. RESULTS: The majority of patients with uveitis had ESR and/or CRP values within the normal limits and no association of ESR and/or CRP with the specific cause of uveitis was observed. However, elevation of ESR >= 60 mm/h and/or CRP >= 60 mg/L was mostly seen in patients with systemic immune-mediated diseases (8/59, 14% of all with immune mediated diseases) or systemic infectious causes (7/38, 18% of all infectious uveitis). Patients with ocular toxoplasmosis typically exhibited normal ESR and CRP (9/11, 82%) while patients with endogenous endophthalmitis had elevated ESR and/or CRP in 6/7, 86%. Sarcoidosis-associated uveitis showed predominantly elevated ESR (13/24, 54%; range 20-59 mm/h in 11/13, 85%). Human immunodeficiency virus-positive patients had more often elevated ESR values when compared to the remainder of patients (9/11, 82% vs. 64/163, 39%, 18%, P = 0.009). The cause of uveitis was established in 19/20 (95%) of patients with ESR >= 60 mm/h and/or CRP >= 60 mg/L. CONCLUSIONS: The majority of patients with first attack of uveitis had ESR and CRP within the normal limits. Elevated levels of ESR and CRP reflected systemic involvement and high levels of both values were associated with established uveitis cause. PMID- 30411143 TI - Improved cellulosic ethanol production from corn stover with a low cellulase input using a beta-glucosidase-producing yeast following a dry biorefining process. AB - A low-cost and sustainable cellulosic ethanol production is vital for fermentation-based industrial applications. Reducing the expenses of cellulose deconstruction enzymes is one of the significant challenges to economic cellulose to-ethanol conversion. Here, we report the improved ethanol production from corn stover after dry biorefining using a natural beta-glucosidase-producing strain Clavispora NRRL Y-50464 with a low cellulase dose of 5 mg protein/g glucan under separate enzymatic hydrolysis and fermentation (SHF) and simultaneous saccharification and fermentation (SSF) conditions. Strain Clavispora NRRL Y 50464 exhibited a superior ethanol fermentation performance over Saccharomyces cerevisiae DQ1 under both conditions. It produced an ethanol titer of 38.1 g/L within 96 h at a conversion efficiency of 55.5% with 25% solids loading (w/w) via SSF without addition of extra beta-glucosidase supplement. Improved performance of Y-50464 on a bioreactor with a helical stirring apparatus confirmed its advantage over the conventional bioreactors originally designed for liquid fermentations in cellulosic ethanol conversion by SSF. The results of this study suggested that the strain Clavispora NRRL Y-50464 has a potential as a candidate for lower-cost cellulosic ethanol production from lignocellulosic materials. PMID- 30411144 TI - Melanoma in children, adolescents and young adults: anatomo-clinical features and prognostic study on 426 cases. AB - PURPOSE: This study was conducted to determine the difference in anatomo pathological and prognostic features of cutaneous melanoma in children, adolescents and young adults. METHODS: This is a retrospective review on 383 young patients <= 39 years of age with cutaneous melanoma, in a period from 2006 to 2016 in Area Vasta Nord Ovest, Tuscany, Italy. We subdivided patients in three groups (children <= 14 years, adolescents 15-21 years, young adults 22-39 years). We correlated all the anatomo-pathological parameters with age groups. RESULTS: We identified a total of 426 cases of cutaneous melanoma on an overall total of 383 patients. Mean age at diagnosis for all the patients <= 39 years of age was 31.2 years: in group A was 11.2 years, in group B 19.2 years and in group C 32.5 years. Incidence, in the subjects between 0 and 14 years, is 14 cases per million inhabitants, between 15 and 21 years of 145, and between 22 and 39 years of 394. Global incidence was 1.6 case per million for group A, 8.9 cases per million for group B, 105 cases per million for group C. No statistically significative correlation could be described for clinical parameters and age groups. CONCLUSIONS: Incidence of melanoma in our casuistry results as the highest in the world. These data open new study for this kind of cancer. PMID- 30411146 TI - Tuberous Breast Deformity Correction: 12-year Experience. AB - BACKGROUND: This article shows our 12-year experience in application of the technique of breast parenchyma modification with simultaneous augmentation on the tuberous breast. We undertook the study, and with the results of this study we can say that tuberous breast deformation is a common pathology that is caused not only by a thickening of the superficial fascia but also by breast parenchyma fibrosis. When traditional techniques without parenchyma modification are used during the surgery, it is often that patients come back to treat complications. METHODS: A total of 208 patients (414 breasts) with tuberous breast deformation treated from 2005 to 2017 were included. The mean patient age was 31 years (range, 22-53 years). A periareolar approach, vertical and horizontal glandular scoring, dual-plane pocket creation, and anatomic implants were used in all cases. RESULTS: The mean follow-up was 36 months (range, 3-144 months). Deformities of the types I-IV by Von Heimburg were corrected. The global complication rate for all patients in this study was 8.9%-1.4% had capsular contracture, 1.5% had postoperative malposition, 2% had "double bubble" , 2% had rippling, 2% had areola and nipple sensitivity disorder. CONCLUSION: The authors' experience demonstrates that the described one-stage approach combining mammary gland parenchyma modification (glandular scoring) with dual-plane pocket and anatomic implants provides satisfactory results for treatment of tubular breast deformity with minimal complications and other effects that require repeated treatment. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 30411147 TI - The impact of R353Q genetic polymorphism in coagulation factor VII on the initial anticoagulant effect exerted by warfarin. AB - BACKGROUND: The initial rise in INR following warfarin is attributed to rapid decline in coagulation factor VII (F7). The R353Q polymorphism in F7 accounts for approximately 1/3 of the variability in F7 activity (FVIIc). OBJECTIVE: Evaluate the role of R353Q in the initial response to warfarin. METHODS: Twenty-eight healthy, males, carrying CYP2C9*1/*1 (n = 14), CYP2C9*1/*2 (n = 4) or CYP2C9*1/*3 (n = 10) genotypes, received single 20 mg warfarin. S&R-warfarin concentrations, INR, and FVIIc were monitored periodically for 7 days. RESULTS: Baseline and maximal INR were 5.6% and 33.5% higher among carriers of the RQ (n = 12) as compared with those carrying the RR (n = 16) genotype (p = 0.032, p = 0.003, respectively). Baseline and nadir FVIIc were 21.6% and 42.0% lower among subjects carrying the RQ as compared with carriers of the RR genotype (p = 0.001, p = 0.007 respectively). In multiple regression analysis, R353Q predicted 36.6% of the variability in peak INR whereas 20.2%, 9.9%, and 5.9% were attributed to VKORC1 genetic polymorphism, cholesterol concentration, and S Warfarin concentration after 24 h, respectively. CONCLUSIONS: R353Q genetic polymorphism plays a key role in determining the initial response to warfarin. The incorporation of this genetic variant into warfarin loading algorithm should be further investigated. PMID- 30411148 TI - A pyrene-inhibitor fluorescent probe with large Stokes shift for the staining of Abeta1-42, alpha-synuclein, and amylin amyloid fibrils as well as amyloid containing Staphylococcus aureus biofilms. AB - Amyloid fibrils formed by a variety of peptides are biological markers of different human diseases, such as Alzheimer's disease, Parkinson's disease, and type II diabetes, and are structural constituents of bacterial biofilms. Novel fluorescent probes offering improved sensitivity or specificity toward that diversity of amyloid fibrils or providing alternative spectral windows are needed to improve the detection or the identification of amyloid structures. One potential source for such new probes is offered by molecules known to interact with fibrils, such as the inhibitors of amyloid aggregation found in drug discovery projects. Here we show the feasibility of the approach by designing, synthesizing, and testing several pyrene-based fluorescent derivatives of a previously discovered inhibitor of the aggregation of the Abeta1-42 peptide. All the derivatives tested retain the interaction with the amyloid architecture and allow its staining. The most soluble derivative, N-acetyl-2-(2-methyl-4-oxo 5,6,7,8-tetrahydro-4H-benzo[4,5]thieno[2,3-d][1,3]oxazin-7-yl)-N-(pyren-1 ylmethyl)acetamide (compound 1D), stains similarly well amyloid fibrils formed by Abeta1-42, alpha-synuclein, or amylin, provides a sensitivity only slightly lower than that of thioflavin T, displays a large Stokes shift, allows efficient excitation in the UV spectral region, and is not cytotoxic. Compound 1D can also stain amyloid fibrils formed by staphylococcal peptides present in biofilm matrices and can be used to distinguish, by direct staining, Staphylococcus aureus biofilms containing amyloid-forming phenol-soluble modulins from those lacking them. Graphical abstract ?. PMID- 30411149 TI - Carbon exchange responses of a mesic grassland to an extreme gradient of precipitation. AB - Growing evidence indicates that ecosystem processes may be differentially sensitive to dry versus wet years, and that current understanding of how precipitation affects ecosystem processes may not be predictive of responses to extremes. In an experiment within a mesic grassland, we addressed this uncertainty by assessing responses of two key carbon exchange processes aboveground net primary production (ANPP) and soil respiration (Rs)-to an extensive gradient of growing season precipitation. This gradient comprised 11 levels that specifically included extreme values in precipitation; defined as the 1st, 5th, 95th, and 99th percentiles of the 112-year climate record. Across treatments, our experimental precipitation gradient linearly increased soil moisture availability in the rooting zone (upper 20 cm). Relative to ANPP under nominal precipitation amounts (defined as between the 15th and 85th percentiles), the magnitude of ANPP responses were greatest to extreme increases in precipitation, with an underlying linear response to both precipitation and soil moisture gradients. By contrast, Rs exhibited marginally greater responses to dry versus wet extremes, with a saturating relationship best explaining responses of Rs to both precipitation and soil moisture. Our findings indicate a linear relationship between ANPP and precipitation after incorporating responses to precipitation extremes in the ANPP-precipitation relationship, yet in contrast saturating responses of Rs. As a result, current linear ANPP-precipitation relationships (up to ~ 1000 mm) within mesic grasslands appear to hold as appropriate benchmarks for ecosystems models, yet such models should incorporate nonlinearities in responses of Rs amid increased frequencies and magnitudes of precipitation extremes. PMID- 30411150 TI - Phylogeny, fruit traits, and ecological correlates of fruiting phenology in a Neotropical dry forest. AB - In tropical dry forests, a high interspecific variation in the strategies of fruiting phenology has been documented. Therefore, phenological responses may be mediated by influence of environmental variables, functional plant attributes or phylogenetic inertia. During 2 years, we recorded the fruiting phenology of 151 species belonging to 5 different growth forms of a Neotropical dry forest in Mexico. We evaluated the relationships between fruiting phenology, abiotic factors (precipitation, temperature, day-length) and functional attributes (growth form, dispersal syndrome, size and time for fruit development) using phylogenetic least squares models (PGLS). More species had ripe fruits during the dry season (92%) than during rainy months and dispersed their seeds by autochory and endozoochory. We found that fruit development time was positively correlated with fruit size and together the morphological fruit traits (size and dispersal syndrome) showed an important relationship with the growth form, but with a strong phylogenetic signal. Environmental seasonality had a strong influence on fruit ripening time, without a relevant association to the phylogeny of plant species. However, the phenological response to the environment (rainfall and day length) at the community level was mediated by growth form. In woody species, we documented a high interspecific fruiting variation linked with the different dispersal syndromes. In herbaceous species, fruiting phenology is a trait restricted by the duration of their life cycle by rainfall seasonality, which in turn might have selected some traits (e.g., dry fruit, presence of spines, explosive dehiscence) for maximizing seed dispersal during the dry season. PMID- 30411152 TI - Endovascular Treatment of Arterial Complications After Liver Transplantation: Long-Term Follow-Up Evaluated on Doppler Ultrasound and Magnetic Resonance Cholangiopancreatography. AB - PURPOSE: To evaluate long-term arterial patency and abnormalities of bile ducts in patients that had endovascular treatment for arterial complications after liver transplantation (LT). MATERIALS AND METHODS: Between 2004 and 2014, 1048 LTs were consecutively performed in our institution and 53 patients (42 men; age range 19-69) were diagnosed and treated by endovascular techniques for arterial complications such as stenosis, thrombosis, dissection or kinking of the hepatic artery (HA). Radiological and surgical data were retrospectively analyzed, and survivors were contacted to undergo follow-up Doppler ultrasound (DUS) of the HA and magnetic resonance cholangiopancreatography. RESULTS: The primary technical success of endovascular treatment was 94% (n = 50). The patency rate of HA at 5 year was 81%. After a median follow-up of 58 months, 17 patients (32%) developed radiological features of ischemic cholangiopathy (IC), including 7 patients with abnormal DUS and 10 with normal DUS. Patients who presented with complications of the HA in the first 3 months after LT developed IC more frequently (42%) than others (12%) (p = 0.028). No other factor was associated with the development of IC. CONCLUSION: IC was more often observed when HA complication occurred within the first 3 months after LT. The presence of IC was not excluded by a normal DUS during follow-up. PMID- 30411151 TI - Zilver PTX Post-market Surveillance Study of Paclitaxel-Eluting Stents for Treating Femoropopliteal Artery Disease in Japan: 2-Year Results. AB - PURPOSE: A prospective, multicenter post-market surveillance study in Japan evaluated the 2-year safety and effectiveness of the DES in real-world patients with complex femoropopliteal artery lesions. METHODS: There were no exclusion criteria, and consecutive symptomatic patients with femoropopliteal lesions treated with the DES were enrolled in the study. Clinically driven target lesion revascularization (TLR) was defined as reintervention performed for > 50% diameter stenosis after recurrent clinical symptoms of peripheral arterial disease. Clinical benefit was defined as freedom from persistent or deteriorating ischemic symptoms. Patency was evaluated by duplex ultrasound where physicians considered this standard of care. RESULTS: In this study, 905 patients were enrolled at 95 institutions in Japan. There were numerous comorbidities including a high incidence of diabetes (58.8%) and chronic kidney disease (43.6%). Additionally, 21.4% of patients were classified with critical limb ischemia. Lesions were complex, with an average length of 14.6 +/- 9.6 cm (range 0.5-40 cm), 41.5% total occlusions, and 18.7% in-stent restenosis. In total, 1861 DES were placed in 1080 lesions. Two-year follow-up was obtained for > 90% of eligible patients. Freedom from TLR was 83.7%, and clinical benefit was 80.0% through 2 years. The 2-year primary patency rate was 70.3%. Rutherford classification significantly improved (p < 0.01), with approximately 80% of patients classified as Rutherford class 0 or 1 at 2 years. CONCLUSION: Despite more challenging lesion characteristics, 2-year results from the current study are similar to outcomes from the previous Zilver PTX studies, confirming the efficacy of the Zilver PTX DES in a complicated femoropopliteal lesion (Zilver PTX Post-Market Study in Japan; NCT02254837). LEVEL OF EVIDENCE: Post-market surveillance study, Level III. PMID- 30411153 TI - Predictors of Recurrent Biliary Obstruction Following Percutaneous Uncovered Metal Stent Insertion in Patients with Distal Malignant Biliary Obstruction: An Analysis Using a Competing Risk Model. AB - OBJECTIVE: To evaluate predictive factors of recurrent biliary obstruction (RBO) following percutaneous uncovered metal stent placement for unresectable distal malignant biliary obstruction (MBO) by using a competing risk model. MATERIALS AND METHODS: Between March 2012 and March 2016, 119 patients underwent percutaneous uncovered metal stent placement with distal MBO at our institution. Univariate and multivariate analyses were conducted to identify the prognostic factors for RBO using a competing risk model. RESULTS: The median overall survival period was 170 days (range 19-775 days). Recurrent biliary obstruction before death was observed in 34 patients (28.6%). The 3-, 6-, and 12-month cumulative incidences of RBO were 14.3%, 21.0%, and 27.7%, respectively. A multivariate analysis indicated that ampullary carcinoma compared with metastatic carcinoma (hazard ratio [HR] = 4.86; 95% confidence interval [CI], 1.74-13.54; P = 0.003) and a stent insertion above the sphincter of Oddi (HR 2.49; 95% CI, 1.11 5.62; P = 0.028) were the independent risk factors for RBO when we considered death to be a competing risk. CONCLUSION: Ampullary carcinoma and stent insertion above the sphincter of Oddi were risk factors for RBO in these patients who received percutaneous transhepatic stent placement. PMID- 30411154 TI - [Modern principles of neurocritical care]. AB - Neurological diseases frequently demanding admittance to a dedicated neurological intensive care unit (neurocritical care) comprise space-occupying ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, traumatic brain injury, status epilepticus, bacterial meningitis, myasthenic crisis and Guillain Barre syndrome. Due to often necessary analgesia, sedation and mechanical ventilation, neuromonitoring should ideally be employed. This consists of bedside invasive and non-invasive methods for monitoring cerebral perfusion, oxygenation, metabolism and neurophysiology. Modern treatment principles in neurocritical care mainly aim at avoiding or attenuating secondary neurological brain damage, in particular directed at sufficient perfusion and oxygenation. These include measures such as neuroprotective ventilation, stabilization of the circulation, decreasing intracranial pressure in brain edema and space-occupying processes, anticonvulsive treatment, temperature management and targeted disease-specific treatment. PMID- 30411155 TI - Prognostic value of the fibrinogen-to-platelet ratio as an inflammatory and coagulative index in patients with gastric cancer. AB - PURPOSE: We assessed the prognostic value of the fibrinogen-to-platelet ratio (FPR) as an inflammatory and coagulative index by examining its clinicopathologic and prognostic efficiency in patients with gastric cancer (GC). METHODS: The subjects of this retrospective study were 182 GC patients whose FPR was measured preoperatively between January, 2001 and December, 2006. The FPR was defined as the plasma fibrinogen divided by the platelet counts. RESULTS: Patients aged >= 65 years and with venous invasion had a significantly higher FPR (p = 0.02 and p < 0.01, respectively) than those aged < 65 years and without venous invasion. We found a correlation between the FPR and all recurrences (p < 0.01). Patients with a low FPR had significantly better overall survival (OS) and relapse-free survival (RFS) rates than patients with a high FPR (p = 0.001 for both). Furthermore, the FPR was an independent predictor of OS and RFS (p = 0.02 and 0.001, respectively), but the fibrinogen level was not. In a subgroup analysis, the FPR was a significant prognostic factor for OS and RFS in patients with pathological stages II/III disease and in patients aged < 65 years. CONCLUSION: The FPR can be calculated easily and is more useful than the fibrinogen level for predicting the prognosis of GC patients. Patients with a high FPR, particularly those with undifferentiated tumors, those with pStage II/III disease, and those aged < 65 years, require more intensive chemotherapy. PMID- 30411156 TI - Spin-Polarized Transport and Spin Seebeck Effect in Triple Quantum Dots with Spin Dependent Interdot Couplings. AB - We study the spin-dependent electronic and thermoelectric transport through a structure composed of triple quantum dots (TQDs) coupled to two metallic leads in the presence of spin-dependent interdot couplings, which is reliable by applying a static magnetic field on the tunnel junctions between different dots. When the TQDs are serially connected, a 100 % spin-polarized conductance and thermopower emerge even for very small spin-polarization of the interdot coupling as the dots are weakly coupled to each other. Whereas if the TQDs are connected in a ring shape, the Fano antiresonance will result in sharp peaks in the conductance and thermopower. In the presence of spin-dependent interdot couplings, the peaks of the spin-up and spin-down thermopowers will shift to opposite directions in the dot level regime, resulting large either 100 % spin-polarized or pure spin thermopowers. The latter generally arises at low temperatures and is robust against the level detuning, the dot-lead coupling, and the system equilibrium temperature. PMID- 30411157 TI - A 9 years comparison of weight loss, disappearance of obesity, and resolution of diabetes mellitus with biliointestinal bypass and with adjustable gastric banding: experience of a collaborative network. AB - AIMS: Long-term comparisons between bariatric surgical techniques have been performed for gastric bypass (RYGB), sleeve gastrectomy (LSG), and biliopancreatic diversion (BPD) vs gastric banding (LAGB), but short-term studies (6 months-4 years) have only compared biliointestinal bypass (BIBP) and LAGB. The participating institutions regularly perform both BIBP and LAGB with a common protocol, and the aim of this retrospective study was to compare long-term effects of the two procedures on body weight, on clinical and metabolic variables, and on resolution of obesity and of diabetes. METHODS: All procedures performed between 01/01/1998 and 31/12/2005 were considered; 73 out of 91 patients undergoing BIBP, and 154 out of 249 patients undergoing LAGB were evaluable up to 9 years. RESULTS: BIBP was significantly more effective than LAGB in terms of weight loss and of resolution of obesity (BMI < 30 kg/m2), in terms of decrease of systolic blood pressure and of serum cholesterol, and similar in terms of resolution of diabetes. In addition, the effect of BIBP was stable, while the effect of LAGB decreased with time. CONCLUSIONS: Both BIBP and LAGB exert long-term effects on body weight, on blood pressure, and on resolution of diabetes mellitus; the effect of BIBP is significantly greater than the effect of LAGB in terms of weight loss, resolution of obesity, of control of systolic blood pressure and of serum cholesterol, but not in terms of resolution of diabetes. PMID- 30411159 TI - Influences of adjuvant treatments in hormone receptor positive breast cancer on receptor conversion in recurrent breast cancer. AB - BACKGROUND: To examine influences on the receptor status of a local cohort of patients with recurrent breast cancer after primary diagnosis of hormone receptor positive breast cancer. METHODS: We retrospectively analyzed 2078 female patients with primary hormone receptor positive breast cancer treated at the university hospital of Wuerzburg between 2000 and 2013. Main focus was on discordance in receptor status in recurrent disease. RESULTS: 196 patients with the primary diagnosis of hormone receptor positive breast cancer developed recurrent disease. 29.1% of patients revealed discordance in estrogen receptor (ER), progesterone receptor (PgR) or HER2 receptor (ER+ to -: 33.3%; PgR+ to -: 59.6%; HER2+ to -: 8.8%; HER2- to +: 17.5%). Aggressive tumor biology such as low grading or involvement of axillary lymph nodes showed increased risk of receptor conversion in relapse. Premenopausal patients with adjuvant application of tamoxifen and the application of chemotherapy had a significantly lower risk for the development of ER negative recurrent disease. Receptor changes to ER and PgR negativity in recurrent disease showed a trend to worse overall survival (OS). CONCLUSIONS: Histological analysis of recurrent disease is indispensable, since one-third of patients with hormone receptor positive breast cancer develop change in the receptor status. PMID- 30411158 TI - A multiscale scheme for simulating polymer Tg. AB - All-atomistic (AA) molecular dynamics (MD) is considered as one of the desirable methods for studying glass transition temperatures (Tg) of specific polymers. However, heavy computational efforts are generally required, and the simulated Tg values are not always in good agreement with the experimental data. In this work, a multiscale scheme is proposed: first, the structural and volumetric properties based multiscale modeling is employed to parameterize the coarse-grained (CG) potentials against the AA simulations of an oligomeric melt; with the CG potentials, MD simulations are then carried out on a serial of oligomer bulks and polymer systems of interests, for which the dynamical Tg values are determined. With poly(ethylene oxide) and poly(methyl methacrylate) as typical examples, the simulated dynamical Tg values of the oligomeric bulks exhibit a linear relation with the empirical values, which is used to determine the "actual Tg" for the polymer bulk. The so-obtained Tg is found to compare very well with the experimental data. Such a computational framework can be quite promising in investigating the effects of various complex factors on polymer Tg. Graphical Abstract The actual Tg for a polymer can be reliably predicted by rescaling the simulated dynamical Tg. PMID- 30411160 TI - A clinical analysis of small-cell neuroendocrine carcinoma of the gynecologic tract: report of 20 cases. AB - OBJECTIVE: The aim of this retrospective observational study was to analyze the clinical and pathological characteristics of small-cell neuroendocrine carcinoma of the gynecologic tract (SCNCGT). METHODS: Twenty patients with SCNCGT were enrolled and their clinic-pathological features were analyzed. All patients were treated at the Beijing Obstetrics and Gynecology Hospital, Capital Medical University, China, and were followed up until December 31, 2017. RESULTS: (1) Patient characteristics: The incidence of SCNCGT was 0.3% (20/6578) of gynecologic cancer in our hospital from January 1, 2007, to December 31, 2017. The average age of the patients was 42.0 +/- 11.8 (23-63 years). Out of 20 patients enrolled, seven (35.0%) had lymph node metastasis. Out of 17 patients treated with complete surgery, 14 (82.4%) had lymph-vascular space invasion. (2) Treatment: Eleven out of the 14 patients with small-cell neuroendocrine carcinoma of the cervix (SCNCC) were treated with radical surgery; all the 11 patients received chemotherapy and radiotherapy postoperatively. The remaining three patients received comprehensive chemotherapy and/or radiotherapy instead of radical surgery. The six patients who had one or the other type of SCNCGT (involving the ovary, endometrium, or vagina) were all treated with comprehensive surgery. (3) Prognosis: The follow-up time for the study ranged from 8 to 87 months. Three (15.0%) of the 20 patients were diagnosed with distant metastasis at the beginning of the study. Eight (40.0%) patients died as of December 31, 2017, while the other 12 patients were in follow-up. The average survival time was 43.6 months (16-77 months). CONCLUSION: SCNCGT is a highly malignant tumor characterized by rare morbidity, a propensity for metastasis, and poor prognosis. Comprehensive treatment may be a good approach to prolong survival in some patients. PMID- 30411161 TI - Establishment of a Mucin Secreting Cell Line Cx-03 from an Uterine Carcino Sarcoma. AB - PURPOSE: The identification of novel cell lines which combine the most important properties of mucosal membranes in terms of drug absorption, transmembrane transport and mucus secretion can help to establish improved and meaningful test systems for pharmacological and infectiological studies. METHODS: We have established a novel mucus secreting tumor cell line (Cx-03) derived from a female patient who underwent radical hysterectomy after diagnosis of a large malignant carcino sarcoma (Muellerian mixed tumor). Via xenotransplantation in SCID beige mice, recultivation and subcloning a stable cell line was established from primary tumor cells. RESULTS: Human origin and novelty of the cell line was determined by karyotype analysis and STR fingerprint. During growth cells produce considerable amounts of a PAS positive viscoelastic mucus. Immunostaining revealed expression of mucins and the mucin modifier CLCA1. We demonstrate in initial electrophysiological experiments that confluent, polarized monolayers of Cx-03 are formed (on PCF-filter supports) that exhibit stable electrical resistance (> 600 Omega cm2). Confluent Cx-03 monolayers express barrier-forming tight junction proteins claudin-1 and -4 which co-localize with zonula occludens protein-1 (ZO-1) at cell-cell contacts. CONCLUSIONS: Mucus secretion is a rare property among mammalian cell lines. In combination with its ability to form polarized monolayers Cx-03 might contribute as a novel cell based model for drug absorption, transport and barrier studies. PMID- 30411162 TI - Radiation-Related Alterations of Taste Function in Patients With Head and Neck Cancer: a Systematic Review. AB - OPINION STATEMENT: Taste sensation is vital for a healthy body as it influences our food intake, acts as a defense mechanism and elicits pleasure. Majority of the head and neck cancer (HNC) patients undergoing radiotherapy suffer from altered taste function and often complain of inability to taste their food, reduced food intake, and weakness. However, there are not many studies conducted to assess this commonly reported side effect. Furthermore, clinical research on radiotherapy-induced taste alterations has proven to be difficult, considering a lack of reliable and validated study tools for assessing objective and subjective outcomes. Developing standardized tools for assessment of taste function and conducting prospective studies in larger population of HNC is the need of the hour. Taste sensation being critically important for sustenance, we need to focus on ways to preserve it. The physical properties of proton particle enable localization of the radiation dose precisely to the tumor and minimizing the exposure of the adjacent healthy tissues. By using Intensity-Modulated Proton Therapy in HNC patients, we anticipate preserving the taste sensation by reducing the dose of radiation to the taste buds. PMID- 30411163 TI - Facile Solution Synthesis of Red Phosphorus Nanoparticles for Lithium Ion Battery Anodes. AB - Red phosphorus (RP) has attracted extensive attention as an anodic material for lithium-ion batteries (LIBs) due to its high theoretical specific capacity of 2596 mA h g- 1 and earth abundance. However, the facile and large-scale preparation of the red phosphorus nanomaterials via a solution synthesis remains a challenge. Herein, we develop a simple and facile solution method to prepare red phosphorus nanoparticles (RP NPs). PCl3 readily reacts with HSiCl3 in the presence of amines at room temperature to produce amorphous RP NPs with sizes about 100-200 nm in high yields. When used as an anode for rechargeable lithium ion battery, the RP NP electrode exhibits good electrochemical performance with a reversible capacity of 1380 mA h g- 1 after 100 cycles at a current density of 100 mA g- 1, and Coulombic efficiencies reaching almost 100% for each cycle. The study shows that this solution synthesis is a facile and convenient approach for large-scale production of RP NP materials for use in high-performance Li-ion batteries. PMID- 30411164 TI - Selected persistent organic pollutants levels in the Ankara River by months. AB - Persistent organic pollutants (POPs) are banned in almost all countries due to their adverse health effects while they are still present in the environment due to their persistence. As the dissipation and the emission factors of POPs change by temperature and other environmental factors current study aimed to determine selected POPs, including polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and organochlorine pesticides (OCPs) in water and sediment samples collected from 12 stations located in Ankara River, Turkey, for 12 months. C-18 solid-phase extraction technique was used to extract organic pollutants and the analysis were performed using a validated gas chromatography mass spectrometry method. DDE was the most frequently detected contaminant in water samples. Even though no PCB residues were present in water samples, PCB101 was the most common contaminant in sediment. Although both matrices had the least load of pollutants in winter, there was an increase in presence and concentration of pollutants from late spring to autumn. PMID- 30411166 TI - The development of an overlay model to predict soil salinity risks by using remote sensing and GIS techniques: a case study in soils around Idku Lake, Egypt. AB - Soil salinization is one of the major environmental problems facing agricultural lands in arid and semiarid areas of the world because of its detrimental impacts on agricultural production and on the sustainable development of land resources. Hence, predicting soil salinity is essential to avoiding further soil degradation. The present study is intended to develop a model for predicting soil salinity in soils around Idku Lake by using remote sensing and geographic information system techniques. This lake is a shallow brackish basin located in the western part of the Nile Delta. For this purpose, Landsat 8-OLI images and shuttle radar topography mission 1Arc-Second Digital Elevation Model data were utilized in this research. A total of 91 surface samples were collected across the study area at a depth between 0 and 30 cm and were analyzed via traditional laboratory analysis methods. Five environmental parameters were used in the design of the soil salinity model. A pairwise comparison matrix was used to calculate the factor weight value for each of the layers. A linear regression model was used to plot the relationship between the EC value and raster value of the salinity map derived from the overlay model. According to the results obtained from a pairwise comparison of the factor layers, water table level was the greatest influential factor of soil salinity, followed by landforms. The validation of the model demonstrated a high degree of correlation (R2 = 0.72) between the measured EC values and the salinity values derived from the model. Furthermore, this model could be a useful tool for predicting soil salinity with a suitable validation. PMID- 30411167 TI - Statement of the Professional Association of German Ophthalmologists (BVA), the German Society of Ophthalmology (DOG) and the German Retina Society (RG) on central serous chorioretinopathy : Situation January 2018. PMID- 30411165 TI - Restless Legs Syndrome and Other Movement Disorders of Sleep-Treatment Update. AB - PURPOSE OF REVIEW: The purpose of this review article is to summarize and discuss the recent advances in the treatment of restless legs syndrome (RLS), as well as REM sleep behavior disorder (RBD), and periodic leg movement disorder (PLMD). RECENT FINDINGS: Traditionally, dopaminergic therapy has been considered the sole option for first-line treatment of RLS due to their impressive acute efficacy. Dopamine agonists such as oral pramipexole and ropinirole, as well as transdermal rotigotine are all effective treatment options. However, augmentation of the RLS symptoms is a major limitation of oral dopaminergic therapy. Recently, gabapentinoid agents such as gabapentin enacarbil and pregabalin have shown comparable short-term efficacy to dopaminergics with lower risk of augmentation of the RLS symptoms. Recent evidence on the efficacy of oxycodone-naloxone in treatment-resistant RLS provides an additional therapeutic avenue. The increasing understanding of the role of iron in RLS pathophysiology has led to new options in iron supplementation therapy in RLS, including treatment with ferric carboxymaltose. With emerging evidence of augmentation being a side effect specific to dopaminergic treatment, gabapentinoids are considered a safer option as initial treatment. In severe refractory RLS, oxycodone-naloxone can be used. If iron stores are low, IV iron formulations should be the initial treatment choice. New treatment options are needed to address issues with current therapies. PMID- 30411168 TI - Carbon Dots @ Platinum Porphyrin Composite as Theranostic Nanoagent for Efficient Photodynamic Cancer Therapy. AB - Photosensitizers are light-sensitive molecules that are highly hydrophobic, which poses a challenge to their use for photodynamic therapy. Hence, considerable efforts have been made to develop carriers for the delivery of PSs. Herein, we synthesized a new theranostic nanoagent (CQDs@PtPor) through the electrostatic interaction between the tetraplatinated porphyrin complex (PtPor) and the negatively charged CQDs. The size and morphology of as-prepared CQDs and CQDs@PtPor were characterized by a series of methods, such as XRD, TEM, XPS, and FTIR spectroscopy. The CQDs@PtPor composite integrates the optical properties of CQDs and the anticancer function of porphyrin into a single unit. The spectral results suggested the effective resonance energy transfer from CQDs to PtPor in the CQDs@PtPor composite. Impressively, the CQDs@PtPor composite showed the stronger PDT effect than that of organic molecular PtPor, suggesting that CQDs@PtPor is advantageous over the conventional formulation, attributable to the enhanced efficiency of 1O2 production of PtPor by CQDs. Thus, this CQDs-based drug nanocarrier exhibited enhanced tumor-inhibition efficacy as well as low side effects in vitro, showing significant application potential in the cancer therapy. PMID- 30411169 TI - Genome-wide identification, characterization, and expression analysis of the expansin gene family in Chinese jujube (Ziziphus jujuba Mill.). AB - Main conclusion 30 expansin genes were identified in the jujube genome. Phylogenetic analysis classified expansins into 17 subgroups. Closely related expansins share a conserved gene structure. ZjEXPs had different expression patterns in different tissues. Plant-specific expansins were first discovered as pH-dependent cell-wall-loosening proteins involved in diverse physiological processes. No comprehensive analysis of the expansin gene family has yet been carried out at the whole genome level in Chinese jujube (Ziziphus jujuba Mill.). In this study, 30 expansin genes were identified in the jujube genome. These genes, which were distributed with varying densities across 10 of the 12 jujube chromosomes, could be divided into four subfamilies: 19 ZjEXPAs, 3 ZjEXPBs, 1 ZjEXLA, and 7 ZjEXLBs. Phylogenetic analysis of expansin genes in Arabidopsis, rice, apple, grape, and jujube classified these genes into 17 subgroups. Members of the same subfamily and subgroup shared conserved gene structure and motif compositions. Homology analysis identified 20 homologous gene pairs between jujube and Arabidopsis. Further analysis of ZjEXP gene promoter regions uncovered various growth, development and stress-responsive cis-acting elements. Expression analysis and transcript profiling revealed that ZjEXPs had different expression patterns in different tissues at various developmental stages. ZjEXPA4 and ZjEXPA6 were highly expressed in young fruits, ZjEXPA3 and ZjEXPA5 were significantly expressed in flowers, and ZjEXPA7 was specifically expressed in young leaves. The results of this study, the first systematic analysis of the jujube expansin gene family, can serve as a strong foundation for further elucidation of the physiological functions and biological roles of jujube expansin genes. PMID- 30411171 TI - Cone-beam computed tomography guidance with navigational overlay for percutaneous lung nodule biopsy. AB - BACKGROUND: Cone-beam CT is increasingly used in pediatric interventional radiology procedures. However, the feasibility or safety of using this mode of imaging guidance for percutaneous lung nodule biopsy in children has not been assessed. OBJECTIVE: To retrospectively evaluate safety and diagnostic accuracy of percutaneous lung nodule biopsy in people treated at a pediatric hospital using cone-beam CT with navigational overlay. MATERIALS AND METHODS: Thirty-six consecutive patients from two large tertiary-care children's hospitals with lung nodules of 48 mm or smaller underwent percutaneous lung nodule biopsy using cone beam CT with navigational overlay. We evaluated patient demographics, pre- and post-biopsy diagnoses, number of biopsy passes, complications, radiation exposure and technical success. RESULTS: Percutaneous lung nodule biopsy was performed for 37 nodules in 36 patients (23 males, 13 females, median age 15.5 years, range 8 months to 23 years). One patient underwent biopsy of two nodules at a single procedure. Median patient weight was 55 kg (range 8-97 kg). Pre-biopsy diagnoses included metastatic sarcoma or other solid tumor (n=11), leukemia/lymphoma (n=13), infection (n=10), chronic granulomatous disease (n=2) and post-transplant lymphoproliferative disorder (PTLD; n=1). Mean number of passes was 5 (range 2 15). Mean pre-procedure international normalized ratio (INR) was 1.1 and platelet count 193 * 109/L. Diagnostic specimens were obtained in 32 of 36 patients (89%). Thirteen complications were encountered in 12 patients (33% of cohort), including 9 pneumothoraces (4 requiring chest tubes); 1 hemothorax, which required a chest tube; and 3 self-limited pulmonary hemorrhages. Mean and median radiation doses were as follows: fluoroscopy time 3 min and 2.4 min, dose-area product (DAP) (recorded in 31 patients) 23,402 Gy.cm2 and 12,453 Gy.cm2, and air kerma 88 mGy and 58 mGy. CONCLUSION: Percutaneous lung nodule needle biopsy can be performed accurately using cone-beam CT with navigational overlay. PMID- 30411172 TI - ?. PMID- 30411173 TI - Melatonin prevents chronic intermittent hypoxia-induced injury by inducing sirtuin 1-mediated autophagy in steatotic liver of mice. AB - BACKGROUND: Hepatic steatosis that occasionally results in nonalcoholic steatohepatitis (NASH) is related to obstructive sleep apnea (OSA). Many studies have shown that autophagy exerts protective effects on liver damage caused by various diseases and melatonin exhibits hepatoprotective properties. However, the mechanisms of liver injury induced by chronic intermittent hypoxia (CIH) and the effect of melatonin on the regulation of liver injury remain unclear. PURPOSE: This study was aimed to evaluate the role of CIH in steatohepatitis progression and the regulatory function of melatonin on fatty liver sensitivity to CIH injury, mainly focusing on autophagy signaling. METHODS: A high-fat diet (FD) induced obesity mouse model was subjected to intermittent hypoxia/normoxia events for approximately 8 h per day using an autophagy agonist, rapamycin, or an inhibitor, 3-methyladenine (3-MA), and SRT1720, a sirtuin 1 (SIRT1) activator, or sirtinol, a SIRT1 inhibitor, with or without melatonin for a total of six successive weeks, followed by assessment of expression of autophagy-related genes and activity of serum aminotransferase as well as histological evaluation of tissue morphology. RESULTS: Neither FD nor CIH alone causes significant liver injury; however, the combination yielded higher serum aminotransferase activities and more severe histological changes, accompanied by a decrease in autophagy activity. Melatonin markedly inhibited FD/CIH-stimulated liver injury by enhancing autophagy. In contrast, SIRT1 inhibition resulted in a decrease in the expression of melatonin-induced autophagy-related genes as well as diminished its protective effects on FD/CIH-induced liver injury. CONCLUSION: These results suggest that melatonin could ameliorate FD/CIH-induced hepatocellular damage by activating SIRT1-mediated autophagy signaling. PMID- 30411170 TI - Novel Surgical Strategies in the Treatment of Gynecological Malignancies. AB - OPINION STATEMENT: The main advancement in the surgical treatment of early cervical cancer has been a de-escalation in the radical surgical approach of early stage disease. Similarly, sentinel lymph node detection with cervical tracer injection can be performed alone in microscopic tumors (stage IA) while additional lymphadenectomy is still performed in macroscopic tumors (IB1 and IIA). Parametrial resection has been progressively reduced in tumors less than 2 cm, and simple procedures, conservative (trachelectomy) or not (simple hysterectomy), are currently being evaluated in several phase III trials. Since the preliminary results of the LACC (locally advanced cervical cancer) trial, the value of minimally invasive surgery as the standard approach for the treatment of early stage cervical cancer has been questioned and patients should be aware when discussing the approach for radical hysterectomy. While awaiting the results of ongoing clinical trials comparing radiological and surgical staging in locally advanced cervical cancer patients, surgical staging with paraaortic lymphadenectomy remains the standard of care before definitive chemoradiotherapy in patients with negative aortic PET/TDM. Patients undergoing salvage surgeries for isolated pelvic recurrences of cervical cancer benefit from advanced reconstructive techniques as DIEP flaps and continent reconstructive urinary techniques. In selected patients, a minimally invasive approach can be considered. Surgery is the mainstay of the treatment of endometrial cancer. The major evolution in surgical strategy has occurred in lymph node staging. The standard surgical staging includes pelvic and paraaortic lymph node dissection to the level of the left renal vein. Sentinel lymph node dissection has been validated as a less morbid alternative of systematic lymphadenectomy, indicated in patients with low and intermediate risk of lymph node involvement. In advanced ovarian cancer, complete cytoreduction is the main objective of surgery. To achieve this goal, upper abdominal complex procedures have been developed. Best survival rates are obtained with primary debulking surgery. Exploratory laparoscopy may be performed before cytoreduction to evaluate resectability and thus avoid unnecessary laparotomy. Although systematic pelvic and paraaortic lymphadenectomy is being questioned in patients with advanced ovarian cancer and clinically negative lymph nodes undergoing complete primary debulking surgery, this procedure is still recommended. While waiting publication of the GOG 252 trial, IP chemotherapy after complete CRS is under debate. HIPEC after interval debulking surgery in patients undergoing complete cytoreduction is an intriguing new option. Patients within the first recurrence of ovarian cancer, with score AGO-positive, benefit from a second complete cytoreductive surgery followed by chemotherapy. Ovarian cancer survival rates are higher in specialized high-volume centers, and thus cases should be centralized and quality indicators used. PMID- 30411174 TI - Should a patient with rheumatoid arthritis be a kidney donor? AB - We cared for a woman with sero-positive rheumatoid arthritis (RA), in clinical remission on oral methotrexate (MTX) and hydroxychloroquine, who wished to donate a kidney to a brother with end-stage renal disease (ESRD). We could find scant literature about this unusual clinical circumstance, and therefore review pertinent aspects of renal disease in RA, perioperative medical management, maintenance of disease remission, outcomes for RA patients who have donated kidneys, and relevant ethical issues. Renal complications in RA are not uncommon, with as many as 50% of patients at risk of reduced eGFR. This reflects anti rheumatic and analgetic medication use (non-steroidal anti-inflammatory drugs, acetaminophen, DMARDs [cyclosporine and, historically, D-penicillamine and gold compounds], and others), glomerulitis, interstitial nephritis, complicating Sjogren's syndrome, vasculitis, or amyloidosis, and/or emergence of an "overlap" syndrome or other rheumatic disorder. The literature suggests that MTX need not be interrupted for surgery. The risk of perioperative infection to our patient would be low and remission should be sustained. We are aware of one study of six patients with RA who donated kidneys; they experienced no complications, ESRD, or deaths after a median follow-up of 8.2 years. Our ethical responsibilities are to balance patient autonomy of decision-making while assuring clinical beneficence and minimizing potential maleficence. Our perspective was that it would not be unreasonable to support this patient donating a kidney if, when fully informed, that remained her wish. PMID- 30411175 TI - Double factor single shot to diminish complications in cryoballoon ablation procedures for atrial fibrillation. AB - PURPOSE: Cryoballoon ablation (CBA) has become a standard treatment for recurrent atrial fibrillation (AF). There is need for improved CBA protocols. We aimed to demonstrate that a new protocol including minimum temperature (minT) reached could reduce procedure times and complications. METHODS: A new double factor protocol (DFP), based on the performance of one single shot per vein with variable duration, and conditional bonus shot, determined by time-to-effect (TTE) and minT, was compared with the conventional protocol (CP), with at least two shots per vein. Procedure parameters, complications, and efficacy were compared. RESULTS: We prospectively included 88 consecutive patients treated with the DFP. These were compared to the previous consecutive 69 patients treated with CP. All procedures were performed with 28-mm second-generation balloon. Acute pulmonary vein (PV) isolation was similar (98.6% vs. 98.9% in CP vs. DFP, p = 0.687). Procedure and ablation times favored DFP over CP (120 vs. 134 min, p = 0.003; and 1051 vs. 1475 s, p < 0.001; respectively). A composite of major and minor complications was significantly reduced in the DFP compared to the CP (18.8% vs. 6.8%, p = 0.02; respectively). Within a follow-up of 18 months, freedom from AF was 79.7% in CP and 78.4% in DFP (Log-rank 0.501). Paroxysmal AF and absence of PV potentials predicted better arrhythmia outcomes (HR 2.14 for paroxysmal vs. persistent, p = 0.031; and HR 1.61 for absence vs. presence of PV potentials, p = 0.01). CONCLUSIONS: The novel DFP results in reduced complication rates and procedure times, with similar success rates compared with a conventional strategy. PMID- 30411176 TI - Development of New SSR (Simple Sequence Repeat) Markers for Lentils (Lens culinaris Medik.) from Genomic Library Enriched with AG and AC Microsatellites. AB - Simple sequence repeat (SSR) markers are the major molecular tools for genetic and genomic researches that have been extensively developed and used in major crops. However, few are available for lentils (Lens culinaris M.), economically an important cool-season legume. The lack of informative simple sequence repeat (SSR) markers in lentil has been a major limitation for lentil molecular breeding studies. Therefore, in order to develop SSR markers for lentil, an enriched genomic libraries for AC and AG repeats were constructed from the Lens culinaris cv Kafkas. A total of 350 clones were inquired for the detection of SSRs. Of 350 clones, 68 had SSR motifs. In polymorphism analysis using 53 newly developed SSRs, a total of 144 alleles across 24 lentil cultivars were detected with an average of 4.64 per locus. The average heterozygosity was 0.588 and polymorphism information contents ranged from 0.194 to 0.895 with an average value of 0.520. These newly developed SSRs will constitute useful tools for molecular breeding, mapping, and assessments of genetic diversity and population structure of lentils. PMID- 30411177 TI - Assessing liver function: diagnostic efficacy of parenchymal enhancement and liver volume ratio of Gd-EOB-DTPA-enhanced MRI study during interstitial and hepatobiliary phase. AB - AIM: To assess the efficacy of signal intensity in interstitial and hepatobiliary phase normalized for liver volume, on gadolinium-ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) study, for the evaluation of liver function through the comparison with Child-Pugh (CP), model for end-stage liver disease (MELD), and biochemical tests. METHODS: All dynamic Gd-EOB-DTPA MRI studies performed in patients with suspected liver lesions were retrospectively reviewed. The rate of liver-to muscle ratio on T1 sequence 70 s (interstitial phase) and 20 min (hepatobiliary phase) after injection of Gd-EOB-DTPA was calculated for each MRI study and then normalized for liver volume (irINTnorm and irHEPnorm). Pearson correlation coefficient was computed to assess the correlation among these values and CP and MELD scores, and biochemical tests. RESULTS: A total of 303 MRI studies, performed on 221 patients, were included. Mean age was 63.8 years +/- 12.9 with a majority of male patients (186; 61.4%). A total of 186 out of 303 (61.4%) were cirrhotic patients. The irHEPnorm was significantly lower in cirrhotic than non cirrhotic patients (0.0004 +/- 0.0002 to 0.0005 +/- 0.0003, p = 0.010). This value had a moderate, significant correlation with Child-Pugh and MELD scores (R = - 0.292, p < 0.0001 and R = - 0.192, p = 0.010, respectively). In particular, irHEPnorm progressively decreased from Child-Pugh A to C (0.0004-0.0002, p < 0.0001) and from MELD <= 10 to 19-24 (0.0004-0.0003, p = 0.018). Among biochemical parameters, total bilirubin, GOT, and albumin had the strongest correlation with irHEPnorm (R = - 0.258, - 0.291, and 0.262, p < 0.0001, respectively). No correlations were found between irINTnorm and CP and MELD scores. CONCLUSION: irHEPnorm value derived from Gd-EOB-DTPA-enhanced MRI is a reliable, non-invasive, useful tool to quantify liver function and to assess the degree of cirrhosis, offering a strict relationship with clinical scores and biochemical parameters. This could help surgeons in clinical decision-making, allowing them to choose the more suitable surgical approach for cirrhotic patients. PMID- 30411178 TI - Repetitive Transcranial Magnetic Stimulation Over the Left Posterior Middle Temporal Gyrus Reduces Wrist Velocity During Emblematic Hand Gesture Imitation. AB - Results from neuropsychological studies, and neuroimaging and behavioural experiments with healthy individuals, suggest that the imitation of meaningful and meaningless actions may be reliant on different processing routes. The left posterior middle temporal gyrus (pMTG) is one area that might be important for the recognition and imitation of meaningful actions. We studied the role of the left pMTG in imitation using repetitive transcranial magnetic stimulation (rTMS) and two-person motion-tracking. Participants imitated meaningless and emblematic meaningful hand and finger gestures performed by a confederate actor whilst both individuals were motion-tracked. rTMS was applied during action observation (before imitation) over the left pMTG or a vertex control site. Since meaningless action imitation has been previously associated with a greater wrist velocity and longer correction period at the end of the movement, we hypothesised that stimulation over the left pMTG would increase wrist velocity and extend the correction period of meaningful actions (i.e., due to interference with action recognition). We also hypothesised that imitator accuracy (actor-imitator correspondence) would be reduced following stimulation over the left pMTG. Contrary to our hypothesis, we found that stimulation over the pMTG, but not the vertex, during action observation reduced wrist velocity when participants later imitated meaningful, but not meaningless, hand gestures. These results provide causal evidence for a role of the left pMTG in the imitation of meaningful gestures, and may also be in keeping with proposals that left posterior temporal regions play a role in the production of postural components of gesture. PMID- 30411179 TI - Incidentally found brain tumors in the pediatric population: a case series and proposed treatment algorithm. AB - PURPOSE: With the increasing use of imaging, there has been an increase in the number of incidentally found brain lesions in pediatric patients resulting in a treatment dilemma for physicians and emotional strain for patients and families. Adult studies support initial surveillance of incidentally found low grade appearing lesions as the most appropriate approach. The aim of this study was to evaluate incidental lesions in the pediatric population and propose an initial treatment algorithm for such lesions. METHODS: Pediatric records were retrospectively reviewed at Johns Hopkins All Children's Hospital for incidentally found brain tumors between 2000 and 2017. Demographic data, presenting symptoms, treatment approach, and outcomes were reviewed for 55 patients, age 0-18. RESULTS: Of the 55 patients included in the study, 14 underwent surgical resection, 3 underwent biopsy, and 38 with benign imaging characteristics at presentation were monitored with radiology alone. Only one patient, out of the 17 that underwent resection or biopsy, had pathology consistent with a high grade glioma. Of the patients monitored radiographically 10 total patients showed an increase in the overall size of the lesion; however after a median follow up of 34.2 months only 2 increased to a degree that required surgical intervention. CONCLUSIONS: The majority of incidentally found brain lesions with benign imaging characteristics at presentation may be managed conservatively. Surveillance is an important part of the initial management of incidental lesions in the pediatric population, but careful scrutiny must be paid to the potential for higher grade lesions or malignant transformation. PMID- 30411180 TI - Quality of Life for 19,114 participants in the ASPREE (ASPirin in Reducing Events in the Elderly) study and their association with sociodemographic and modifiable lifestyle risk factors. AB - PURPOSE: To explore the relationship between sociodemographic and lifestyle variables with health-related quality of life (HRQoL) of a large cohort of 'healthy' older individuals. METHODS: The sample included individuals aged 65+ years from Australia (N = 16,703) and the USA (N = 2411) enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) multicentre placebo-controlled trial study and free of cardiovascular disease, dementia, serious physical disabilities or 'fatal' illnesses. The associations with the physical (PCS) and mental component scores (MCS) of HRQoL (SF-12 questionnaire) were explored using multiple linear regression models from data collected at baseline (2010-2014). RESULTS: The adjusted PCS mean was slightly higher in the USA (49.5 +/- 9.1) than Australia (48.2 +/- 11.6; p < 0.001), but MCS was similar in both samples (55.7 +/- 7.5 and 55.7 +/- 9.6, respectively; p = 0.603). Males, younger participants, better educated, more active individuals, or those currently drinking 1-2 alcoholic drinks/day showed a better HRQoL (results more evident for PCS than MCS), while current heavy smokers had the lowest physical HRQoL in both countries. Neither age, walking time, nor alcohol intake was associated with MCS in either cohort. CONCLUSIONS: Baseline HRQoL of ASPREE participants was higher than that reported in population-based studies of older individuals, but the associations between sociodemographic and lifestyle variables were consistent with the published literature. As the cohort ages and develops chronic diseases, ASPREE will be able to document HRQoL changes. PMID- 30411181 TI - On the disenchantment of medicine: Abraham Joshua Heschel's 1964 address to the American Medical Association. AB - In 1964, the American Medical Association invited liberal theologian Abraham Joshua Heschel (1907-1972) to address its annual meeting in a program entitled "The Patient as a Person" [1]. Unsurprisingly, in light of Heschel's reputation for outspokenness, he launched a jeremiad against physicians, claiming: "The admiration for medical science is increasing, the respect for its practitioners is decreasing. The depreciation of the image of the doctor is bound to disseminate disenchantment and to affect the state of medicine itself" [1, p. 35]. Heschel's reference to "disenchantment" suggests that he may have been familiar with the work, or at least the outlook, of sociologist Max Weber, whose 1917 address "Science as a Vocation" portrays the modern world as disenchanted by the progress of rationalism. Heschel's life's vocation had been to uncover the inner meaning of religious faith and to translate that faith into principled action. Heschel saw disenchantment not as an inescapable aspect of modern life but rather as the byproduct of physicians' conscious choices to seek worldly success and material comfort. Yet, because of their privileged position as witnesses to human vulnerability, physicians possess an obligation to develop their own personhood, to re-enchant medicine, and through medicine to spark a positive transformation in all of modern life. As Heschel says, "The doctor must realize the supreme nobility of his vocation, to cultivate a taste for the pleasures of the soul. ... The doctor is a major source of moral energy affecting the spiritual texture and substance of the entire society" [1, pp. 34, 38]. While Heschel's conception of the physician's role is romanticized and idealized, changes in the organization and practice of medicine have validated his concerns. PMID- 30411182 TI - Rana grylio virus 43R encodes an envelope protein involved in virus entry. AB - Rana grylio virus (RGV), a member of genus Ranavirus in the family Iridoviridae, is a viral pathogen infecting aquatic animal. RGV 43R has homologues only in Ranavirus and contains a transmembrane (TM) domain, but its role in RGV infection is unknown. In this study, 43R was determined to be associated with virion membrane. The transcripts encoding 43R and the protein itself appeared late in RGV-infected EPC cells and its expression was blocked by viral DNA replication inhibitor, indicating that 43R is a late expressed protein. Subcellular localization showed that 43R-EGFP fusion protein distributed in cytoplasm of EPC cells and that TM domain is essential for its distribution in cytoplasm. 43R-EGFP fusion protein colocalized with viral factories in RGV-infected cells. A recombinant RGV deleting 43R (Delta43R-RGV) was constructed by homologous recombination to investigate its role in virus infection. Compared with wild type RGV, the ability of Delta43R-RGV to induce the cytopathic effect and its virus titers were significantly reduced. Furthermore, it is revealed that 43R deletion significantly inhibited viral entry but did not influence viral DNA replication by measuring and comparing the DNA levels of RGV and Delta43R-RGV in the infected cells at the early stage of infection. RGV neutralization with anti-43R serum reduced the virus titer. Therefore, these data showed that RGV 43R is a late gene that encodes an envelope protein involved in RGV entry. PMID- 30411183 TI - Review of Biosimilar Trials and Data on Etanercept in Rheumatoid Arthritis. AB - PURPOSE OF REVIEW: Etanercept was the first tumour necrosis factor inhibitor approved to treat rheumatoid arthritis (RA) in the United States (US) and Europe. The recent patent expiration of the etanercept originator ENBREL in Europe has facilitated the development of biosimilar products, creating the prospect of reduced treatment costs. In this article, we review the original trials for etanercept in RA to facilitate critical appraisal of biosimilar trial data. RECENT FINDINGS: Two etanercept biosimilars are currently approved in Europe and/or the US, SB4 (Benepali) and GP2015 (Erelzi), having met the pre-specified equivalence criteria for biosimilarity. Trial data demonstrates subtle differences in clinical outcomes and adverse events between the biosimilars and the reference product (RP). The development of etanercept biosimilars may reduce the financial burden of treating RA, but real-world data regarding efficacy and safety in comparison to the RP will be vital to assess for meaningful differences. PMID- 30411185 TI - Predictors for INR-control in a well-managed warfarin treatment setting. AB - Warfarin is well studied in patients with non-valvular atrial fibrillation (AF). It has low complication rates for patients achieving individual Time in Therapeutic Range (iTTR) > 70%. The risk scores SAMe-TT2R2 and PROSPER are designed to predict future TTR, but are derived from a heterogeneous population with generally low iTTR. The aim of this study was to evaluate predictors for high and low iTTR in an AF population in Sweden, where there is a generally good anticoagulation control. A retrospective register study based on Swedish warfarin dosing system AuriculA, including 28,011 AF patients starting treatment during 1 January 2006 to 31 December 2011. Complications and risk factors were analysed and related to iTTR. Mean age was 73.7 (SD +/- 9.5) years, with 42.0% women. Mean CHA2DS2-VASc score (SD) was 3.6 (+/- 1.7). For patients with iTTR < 60% there were over three times higher prevalence of excessive alcohol consumption than for patients with iTTR > 70% (3.7% vs. 1.1%). Previous stroke were more prevalent for patients with high than low iTTR (17.1% vs. 20.3%). Concomitant comorbidities were associated with increased risk of poor iTTR. In Swedish AF patients, excessive alcohol use is clearly associated with iTTR below 60%. Patients with previous stroke are more likely to get iTTR above 70%, unlike those with concomitant disorders who more often have poor anticoagulation control. The SAMe TT2R2-score cannot be applied in Sweden. PMID- 30411186 TI - Post-extrasystolic characteristics in the arterial blood pressure waveform are associated with right ventricular dysfunction in intensive care patients. AB - Right ventricular dysfunction (RVD) is associated with end-organ dysfunction and mortality, but has been an overlooked condition in the ICU. We hypothesized that analysis of the arterial waveform in the presence of ventricular extrasystoles could differentiate patients with RVD from patients with a normally functioning right ventricle, because the 2nd and 3rd post-ectopic beat could reflect right ventricular state (pulmonary transit time) during the preceding ectopy. We retrospectively identified patients with echocardiographic evidence of moderate to-severe RVD and patients with a normal functioning right ventricle (control) from the MIMIC database. We identified waveform records where ECG and arterial pressure were available in combination, simultaneously with echocardiographic evaluation. Ventricular extrasystoles were visually confirmed and the median systolic blood pressure (SBP) of the 2nd and 3rd post-ectopic beats compared with the median SBP of the ten sinus beats preceding the extrasystole. We identified 34 patients in the control group and 24 patients in the RVD group with ventricular extrasystoles. The mean SBP reduction at the 2nd and 3rd beat was lower in the RVD group compared with the control group [- 1.7 (SD: 1.9) % vs. - 3.6 (SD: 1.9) %, p < 0.001], and this characteristic differentiated RVD subjects from control subjects with an AUC of 0.76 (CI [0.64; 0.89]), with a specificity of 91% and sensitivity of 50%. In this proof-of-concept study, we found that post extrasystolic ABP characteristics were associated with RVD. PMID- 30411184 TI - Consecutive unilateral recording of the two eyes affects dark-adapted ERG responses, when compared to simultaneous bilateral recording. AB - PURPOSE: Our aim was to compare the electroretinographic (ERG) responses of two eyes obtained by consecutive unilateral recordings to those obtained by a simultaneous bilateral recording in sheep. METHODS: Eight sheep underwent two full-field ERG recordings, using two recording strategies of the standard ISCEV protocol: consecutive unilateral recordings of one eye after the other, and simultaneous bilateral recording of both eyes. The order of recording strategy within an animal (unilateral/bilateral), eye recording sequence in the unilateral session (OD/OS), and amplifier channel assignment for each eye were all randomized. To test whether duration of dark adaptation and/or anesthesia affect the results, the ISCEV protocol was recorded bilaterally in six additional eyes following 38 min of patched dark adaptation, as was done for the second eye recorded in the consecutive unilateral recordings. RESULTS: The second recorded eye in the unilateral session had significantly higher scotopic b-wave amplitudes compared to the first recorded eye and to the bilaterally recorded eyes. A-wave amplitudes of the dark-adapted mixed rod-cone responses to a high-intensity flash were also significantly higher in the second eye compared to the first eye recorded unilaterally and to the bilaterally recorded eyes. Light-adapted responses were unaffected by the recording strategy. When the ISCEV protocol was recorded after 38 min of dark adaptation, the scotopic responses were higher than in the first eyes, and similar to those of the second eyes recorded unilaterally, suggesting that indeed the longer duration of anesthesia and dark adaptation are responsible for the increased scotopic responses of the second eye. CONCLUSIONS: Consecutive unilateral ERG recordings of two eyes result in higher amplitudes of the dark-adapted responses of the eye recorded second, compared to the eye recorded first and to bilaterally recorded eyes. The differences in scotopic responses can be attributed to different duration of dark adaptation and/or anesthesia of the two consecutively recorded eyes. Photopic responses are not affected. Therefore, simultaneous bilateral ERG responses should be recorded when possible, especially for evaluation of scotopic responses. PMID- 30411188 TI - Variations in Gut Microbiota of Siberian Flying Squirrels Correspond to Seasonal Phenological Changes in Their Hokkaido Subarctic Forest Ecosystem. AB - Gut microbial communities of animals are influenced by diet and seasonal weather changes. Since foraging strategies of wild animals are affected by phenological changes, gut microbial communities would differ among seasons. However, interactions of plant-animal-microbiota with seasonal changes have not been well characterized. Here, we surveyed gut microbial diversity of Siberian flying squirrels (Pteromys volans orii) from a natural forest in Hokkaido during spring and summer of 2013 and 2014. Additionally, we compared microbial diversity to temperature changes and normalized difference vegetation index (NDVI). Changes in both seasonal temperature and phenology were significantly associated with alterations in gut microbiota. There were two clusters of OTUs, below and above 20 degrees C that were significantly correlated with low and high temperatures, respectively. Low-temperature cluster OTUs belonged to various phyla, whereas the high-temperature cluster was only constituted by Firmicutes. In conclusion, gut microbiota of Siberian flying squirrels varied with environmental changes on an ecological scale. PMID- 30411189 TI - Core and Dynamic Microbial Communities of Two Invasive Ascidians: Can Host Symbiont Dynamics Plasticity Affect Invasion Capacity? AB - Ascidians (Chordata, Ascidiacea) are considered to be prominent marine invaders, able to tolerate highly polluted environments and fluctuations in salinity and temperature. Here, we examined the seasonal and spatial dynamics of the microbial communities in the inner-tunic of two invasive ascidians, Styela plicata (Lesueur 1823) and Herdmania momus (Savigny 1816), in order to investigate the changes that occur in the microbiome of non-indigenous ascidians in different environments. Microbial communities were characterized using next-generation sequencing of partial (V4) 16S rRNA gene sequences. A clear differentiation between the ascidian-associated microbiome and bacterioplankton was observed, and two distinct sets of operational taxonomic units (OTUs), one core and the other dynamic, were recovered from both species. The relative abundance of the dynamic OTUs in H. momus was higher than in S. plicata, for which core OTU structure was maintained independently of location. Ten and seventeen core OTUs were identified in S. plicata and H. momus, respectively, including taxa with reported capabilities of carbon fixing, ammonia oxidization, denitrification, and heavy metal processing. The ascidian-sourced dynamic OTUs clustered in response to site and season but significantly differed from the bacterioplankton community structure. These findings suggest that the associations between invasive ascidians and their symbionts may enhance host functionality while maintaining host adaptability to changing environmental conditions. PMID- 30411190 TI - Detecting Associations Between Ciliated Protists and Prokaryotes with Culture Independent Single-Cell Microbiomics: a Proof-of-Concept Study. AB - Symbioses between prokaryotes and microbial eukaryotes, particularly ciliated protists, have been studied for a long time. Nevertheless, researchers have focused only on a few host genera and species, mainly due to difficulties in cultivating the hosts, and usually have considered a single symbiont at a time. Here, we present a pilot study using a single-cell microbiomic approach to circumvent these issues. Unicellular ciliate isolation followed by simultaneous amplification of eukaryotic and prokaryotic markers was used. Our preliminary test gave reliable and satisfactory results both on samples collected from different habitats (marine and freshwater) and on ciliates belonging to different taxonomic groups. Results suggest that, as already assessed for many macro organisms like plants and metazoans, ciliated protists harbor distinct microbiomes. The applied approach detected new potential symbionts as well as new hosts for previously described ones, with relatively low time and cost effort and without culturing. When further developed, single-cell microbiomics for ciliates could be applied to a large number of studies aiming to unravel the evolutionary and ecological meaning of these symbiotic systems. PMID- 30411187 TI - Mycobacterium Tuberculosis and Interactions with the Host Immune System: Opportunities for Nanoparticle Based Immunotherapeutics and Vaccines. AB - Tuberculosis (TB) caused by Mycobacterium tuberculosis remains a deadly infectious disease. The thin pipeline of new drugs for TB, the ineffectiveness in adults of the only vaccine available, i.e. the Bacillus Calmette-Guerin vaccine, and increasing global antimicrobial resistance, has reinvigorated interest in immunotherapies. Nanoparticles (NPs) potentiate the effect of immune modulating compounds (IMC), enabling cell targeting, improved transfection of antigens, enhanced compound stability and provide opportunities for synergistic action, via delivery of multiple IMCs. In this review we describe work performed in the application of NPs towards achieving immune modulation for TB treatment and vaccination. Firstly, we present a comprehensive review of M. tuberculosis and how the bacterium modulates the host immune system. We find that current work suggest great promise of NP based immunotherapeutics as novel treatments and vaccination systems. There is need to intensify research efforts in this field, and rationally design novel NP immunotherapeutics based on current knowledge of the mycobacteriology and immune escape mechanisms employed by M. tuberculosis. PMID- 30411191 TI - Anticancer potential of Ferula hezarlalehzarica Y. Ajani fraction in Raji lymphoma cell line: induction of apoptosis, cell cycle arrest, and changes in mitochondrial membrane potential. AB - BACKGROUND: Cancer is a major cause of mortality. The present study evaluates the antitumor effects of Ferula hezarlalehzarica Y. Ajani fractions on various cancer cell lines, including the Raji Burkitt's lymphoma cells. METHODS: We evaluated the cytotoxic activity of various fractions of F. hezarlalehzarica against tumor cell lines by the MTT assay. Annexin V-PE/7-AAD and cell cycle analysis were assessed by flow cytometry. Expressions of genes associated with cell death and proliferation (Bax, Bcl-2, Fas, and c-Myc) were determined using real-time PCR. Alteration in mitochondrial membrane potential (MMP) was examined by JC-1 dye staining. RESULTS: The hexane fraction of F. hezarlalehzarica showed the highest degree of cytotoxicity against Raji cells (IC50 = 31.6 MUg/ml). Flow cytometry analysis showed that 200 MUg/ml of the fraction induced apoptosis in >96% of Raji cells after 24 h. In cell cycle analysis, at the same concentration, the percentage of apoptotic cells in the sub G1phase increased to 95.25 +/- 1.76% at 48 h of treatment. The fraction induced cell cycle arrestat the G0/G1phase. Exposure to 100 MUg/ml of the fraction after 48 h increased the percentage of G0/G1 cells (76.3 +/- 6.08%) compared to the negative control (<50%). Treatment with75MUg/ml of fraction reduced the expressions of Bcl-2 (0.23 +/- 0.008-fold) and c-Myc (0.68 +/- 0.07-fold) and increased Bax (1.75 +/- 0.31-fold) and Fas (5.02 +/- 0.74-fold; p < 0.01). We observed a decrease in MMP (~0.4, p < 0.05) at >=100 MUg/ml and this effect remained almost unchanged until 48 h. CONCLUSIONS: The F. hezarlalehzarica hexane fraction induced apoptosis in Raji cells by changing the expression of apoptosis-related genes, cell cycle distribution, and MMP. These data suggested a potential effectiveness of F. hezarlalehzarica for inducing cell death in lymphoma cells. Graphical abstract ?. PMID- 30411193 TI - The endothelin 1 and endothelin receptor A gene polymorphisms increase the risk of developing papillary thyroid cancer. AB - The endothelin (EDN) axis (EDN1 and EDN1 receptor A, EDNRA) is involved in cellular growth, differentiation, invasiveness, and tumor progression in several cancers. We wanted to examine the possible impact of single nucleotide polymorphisms (SNPs) of EDN1 and EDNRA genes on papillary thyroid cancer (PTC) development and general characteristics of PTC. Study population consist of 113 PTC patients and 185 controls. EDN1 (G5665T, T-1370G) and EDNRA (C TT70G, G-231A) SNPs were investigated by real-time PCR. The GG genotype of EDNRA + 70 SNP was associated with threefold increased PTC risk (p = 0.01), and the combined CG + GG genotype was 2.48 fold higher among PTC patients compared to controls. The variant EDNRA - 231 allele was overrepresented in PTC patients according to controls (p = 0.05). The combined GT + TT genotype of EDN1 5665 SNP was related with late (age after 40 years) PTC onset (p = 0.04), and was more prominent among male patients with PTC according to females (p = 0.03). No significant associations between PTC and - 1370 SNP were found. There were no relationships between laboratory parameters and investigated polymorphisms. The EDNRA + 70 SNP was associated with PTC development. The EDN1 5665 SNP was linked with increased risk for late PTC onset and was more prominent among male patients with PTC. PMID- 30411192 TI - Genetic diversity and genetic variation in morpho-physiological traits to improve heat tolerance in Spring barley. AB - Heat stress is one of the abiotic stresses that limit the production and productivity of barley. Understanding the genetic variation, changes in physiological processes and level of genetic diversity existing among genotypes are needed to produce new cultivars not only having a high tolerance to heat stress, but also displaying high yield. To address this challenge, a set of 60 highly homozygous, diverse barley genotypes were evaluated under normal and heat stress conditions in two seasons of 2014/2015 and 2015/2016. Seedling vigor (SV) as a morphological trait was visually scored under normal conditions. Plant height (Ph), days to flowering (DOF), 1000-kernel weight (TKW), grain yield per spike (GYPS), yield per plot (YPP) and biological yield (BY) were measured. Moreover, proline content (ProC), soluble carbohydrate content (SCC), starch content, soluble protein (SP), and amino acid (AA) content as physiological parameters were analyzed from the grains. High genetic variation was observed among genotypes for all traits scored in this study. All traits had high broad sense heritability estimates ranging from 0.59 (SV) to 0.97 (TKW) for yield traits. Seedling vigor was significantly correlated with all yield traits under both conditions. Among all physiological traits, the increase in ProC and reduction in starch content due to heat stress had significant correlations with the reduction due to heat stress in YPP, GYPS, TKW, and BY. Furthermore, the genetic diversity based on genetic distance (GD) among genotypes was investigated using 206 highly polymorphic SSR marker alleles. The GD ranged from 0.70 to 0.98 indicating that these genotypes are highly and genetically dissimilar. The combination of analyses using molecular markers, genetic variation in yield traits, and changes in physiological traits provided useful information in identifying the tolerant genotypes which can be used to improve heat tolerance in barley through breeding. PMID- 30411194 TI - Effect of reduced photon count levels and choice of normal data on semi-automated image assessment in cardiac SPECT: Doing more with fewer counts. PMID- 30411195 TI - Molecular Characterization of High Molecular Weight Polyesters by Matrix-Assisted Laser Desorption/Ionization High-Resolution Time-of-Flight Mass Spectrometry Combined with On-plate Alkaline Degradation and Mass Defect Analysis. AB - Matrix-assisted laser desorption ionization high-resolution time-of-flight mass spectrometry (MALDI HR TOF MS) is a powerful tool for the molecular characterization of industrial polymers. However, accurate mass determination and resolution of isobaric ions are possible for oligomer samples only typically below m/z 3000. To cut long polymer chains into oligomers suitable for high resolution mass spectrometry, we propose a simple "on-plate" alkaline degradation of polyesters as a sample pretreatment technique prior to the MALDI TOF MS measurement. This pretreatment can be performed on a MALDI target using a small amount of sample (MUg or less) and 1 MUL of alkaline reagent by simple pipetting. Informative mass spectra in the oligomeric mass range are successfully recorded but complicated by the variation of end-groups and the copolymeric composition of the degradation products. Data processing is assisted by a series of advanced Kendrick mass defect (KMD) analyses recently proposed by the authors to plot visually understandable two-dimensional maps. On-plate degradation pretreatment, high-resolution MALDI TOF MS measurements, and advanced KMD analyses are innovatively combined for the compositional characterization of bacterial poly(3 hydroxybutyric acid-co-3-hydroxyvaleric acid) and industrial poly(ethylene terephthalate) samples. Graphical Abstract ?. PMID- 30411197 TI - Optimal or not; depends on the task. AB - Decision-making involves a tradeoff between pressures for caution and urgency. Previous research has investigated how well humans optimize this tradeoff, and mostly concluded that people adopt a sub-optimal strategy that over-emphasizes caution. This emphasis reduces how many decisions can be made in a fixed time, which reduces the "reward rate". However, the strategy that is optimal depends critically on the timing properties of the experiment design: the slower the rate of decision opportunities, the more cautious the optimal strategy. Previous studies have almost uniformly adopted very fast designs, which favor very urgent decision-making. This raises the possibility that previous findings-that humans adopt strategies that are too cautious-could either be ascribed to human caution, or to the experiments' design. To test this, we used a slowed-down decision making task in which the optimal strategy was quite cautious. With this task, and in contrast to previous findings, the average strategy adopted across participants was very close to optimal, with about equally many participants adopting too-cautious as too-urgent strategies. Our findings suggest that task design can play a role in inferences about optimality, and that previous conclusions regarding human sub-optimality are conditional on the task settings. This limits claims about human optimality that can be supported by the available evidence. PMID- 30411196 TI - New Classes of Polycationic Compounds as Preservatives for Ophthalmic Formulations. AB - PURPOSE: The purpose of this research work was to develop new polycationic compounds based on pyridine and piperidine structures with high antimicrobial activities against bacteria and fungi. Furthermore, the compounds should offer a lower toxicity than the commonly used preservatives for ophthalmic formulations, such as benzalkonium chloride (BAC) and polyquaternium-1 (PQ1). METHODS: Two polymers and three dimeric compounds were developed. Minimum inhibitory concentrations were determined for Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans and Aspergillus brasiliensis. The compounds were characterized regarding their impact on cell viability, cytotoxicity, epithelial integrity and surface tension. MTT and CytoTox-GloTM assays, permeation studies with mannitol and transepithelial electrical resistance (TEER) measurements were performed on human corneal epithelial or MDCK I cells. BAC and PQ1 were used as references. RESULTS: Three polycationic compounds exhibited high antimicrobial activity against the tested microorganisms comparable to that of BAC. Four compounds were tolerated as well as or better than PQ1. In addition, the TEER, permeability and surface tension were only affected by compounds with amphiphilic properties. CONCLUSION: The pyridine- and piperidine-based polycationic compounds are promising candidates as new preservatives for ophthalmic formulations. Their high antimicrobial efficacy and good tolerability indicate a different mechanism of action compared to BAC. PMID- 30411198 TI - Fumonisin B1-induced oxidative stress triggers Nrf2-mediated antioxidant response in human hepatocellular carcinoma (HepG2) cells. AB - Fumonisin B1 (FB1), a causative agent for animal-related mycotoxicoses, has been implicated in human and animal cancer. FB1 induces oxidative stress but the related survival responses are not well established. Central to this response is the transcription factor, nuclear factor erythroid 2 p45-related factor 2 (Nrf2). The effects of FB1 on Nrf2-related survival responses in human hepatoma (HepG2) cells were investigated. HepG2 cells were treated with 200 MUmol/l FB1 (IC50-24 h). Cellular redox status was assessed via the quantification of intracellular reactive oxygen species (ROS), lipid peroxidation, protein oxidation and the antioxidant glutathione (GSH). The protein expression of oxidative stress and mitochondrial stress response proteins [Nrf2, phosphorylated-Nrf2 (pNrf2), superoxide dismutase 2 (SOD2), catalase (CAT), sirtuin 3 (Sirt 3) and Lon protease 1 (Lon-P1)] were quantified by western blotting, while gene expression levels of SOD2, CAT and GPx were assessed using quantitative polymerase chain reaction (qPCR). Lastly, the fluorometric, JC-1 assay was used to determine mitochondrial polarisation. FB1 significantly increased ROS (p <= 0.001), and induced lipid peroxidation (p < 0.05) and protein carbonylation (p <= 0.001), which corresponded with the increase in GSH levels (p < 0.05). A significant increase in pNrf2, SOD2, SOD2, CAT (p < 0.05), CAT (p <= 0.01) and GPx (p <= 0.001) expression was observed; however, total Nrf2 (p > 0.05) was reduced. There was also a minor reduction in the mitochondrial membrane potential of HepG2 cells (p < 0.05); however, the expression of Sirt 3 and Lon-P1 (p <= 0.001) were upregulated. Exposure to FB1 induced oxidative stress in HepG2 cells and initiated Nrf2-regulated transcription of antioxidants. PMID- 30411199 TI - Exposure of human lymphoma cells (U-937) to the action of a single mycotoxin as well as in mixtures with the potential protectors 24-epibrassinolide and selenium ions. AB - The progressive contamination of food products by mycotoxins such as zearalenone (ZEN) has prompted the search for specific substances that can act as protectors against an accumulation of these toxins. This paper discusses the effect of selenium ions and 24-epibrassinolide (EBR) as non-organic and organic compounds that preserve human lymphoblastic cells U-937 under ZEN stressogenic conditions. Based on measurements of cell viability and a DAPI test, concentrations of ZEN at 30 MUmol/l, Se at 2.5 MUmol/l and EBR at 0.005 MUmol/l were selected. The addition of both protectors resulted in an increase in the viability of ZEN treated cells by about 16%. This effect was connected with a decrease in lipid peroxidation (a decrease in the malonyldialdehyde content) and the generation of reactive oxygen species, which were determined by a cellular ROS/superoxide detection assay and the SOD activity. The Se protection was observed as the blocking of the all excess ROS, while the EBR action was mainly concentrated on something other than the superoxide radical itself. The experiments on the model lipid membranes that mimic the environment of U-937 cells confirmed the affect of ZEN on the structure and physicochemical properties of human membranes. Although the presence of both Se and EBR reduced the effect of ZEN by blocking its interaction with a membrane, the action of Se was more evident. PMID- 30411200 TI - Skin Color and Social Mobility: Evidence From Mexico. AB - In many Latin American countries, census data on race and skin color are scarce or nonexistent. In this study, we contribute to understanding how skin color affects intergenerational social mobility in Mexico. Using a novel data set, we provide evidence of profound social stratification by skin color, even after controlling for specific individual characteristics that previous work has not been able to include, such as individual cognitive and noncognitive abilities, parental education and wealth, and measures of stress and parenting style in the home of origin. Results indicate that people in the lightest skin color category have an average of 1.4 additional years of schooling and 53 % more in hourly earnings than their darkest-skinned counterparts. Social mobility is also related to skin color. Individuals in the darkest category are 20 percentile ranks lower in the current wealth distribution than those in the lightest category, conditional on parental wealth. In addition, results of a quantile regression indicate that the darkest group shows higher downward mobility. PMID- 30411201 TI - Selective changes in moral judgment by noninvasive brain stimulation of the medial prefrontal cortex. AB - Multiple cortical networks intervene in moral judgment, among which the dorsolateral prefrontal cortex (DLPFC) and the medial prefrontal structures (medial PFC) emerged as two major territories, which have been traditionally attributed, respectively, to cognitive control and affective reactions. However, some recent theoretical and empirical accounts disputed this dualistic approach to moral evaluation. In the present study, to further assess the functional contribution of the medial PFC in moral judgment, we modulated its cortical excitability by means of transcranial direct current stimulation (tDCS) and tracked the change in response to different types of moral dilemmas, including switch-like and footbridge-like moral dilemmas, with and without personal involvement. One hundred participants (50 males) completed a questionnaire to assess the baseline levels of deontology. Next, participants were randomly assigned to receive anodal, sham, or cathodal tDCS over the medial prefrontal structures and then were asked to address a series of dilemmas. The results showed that participants who received anodal stimulation over the medial PFC provided more utilitarian responses to switch-like (but not footbridge-like) dilemmas than those who received cathodal tDCS. We also found that neurostimulation modulated the influence that deontology has on moral choices. Specifically, in the anodal tDCS group, participants' decisions were less likely to be influenced by their baseline levels of deontology compared with the sham or cathodal groups. Overall, our results seem to refute a functional role of the medial prefrontal structures purely restricted to affective reactions for moral dilemmas, providing new insights on the functional contribution of the medial PFC in moral judgment. PMID- 30411202 TI - Comment on: 'Clinical and Economic Impact of a Potential Switch from 13-Valent to 10-Valent Pneumococcal Conjugate Infant Vaccination in Canada', Wilson et al., 22 June 2018. PMID- 30411204 TI - Identification and Field Testing of Volatile Components in the Sex Attractant Pheromone Blend of Female House Mice. AB - Recently, it was reported (i) that the sex pheromone blend of male house mice, Mus musculus, comprises not only volatile components (3,4-dehydro-exo-brevicomin; 2-sec-butyl-4,5-dihydrothiazole) but also a component of low volatility (the sex steroid testosterone), and (ii) that the sex steroids progesterone and estradiol are sex pheromone components of female house mice. Here we tested the hypothesis that the sex attractant pheromone blend of female mice, analogous to that of male mice, also comprises volatile pheromone components. Analyzing by GC-MS the head space volatiles of bedding soiled with urine and feces of laboratory-kept females and males revealed three candidate pheromone components (CPCs) that were adult female-specific: butyric acid, 2-methyl butyric acid and 4-heptanone. In a two choice laboratory experiment, adult males spent significantly more time in the treatment chamber baited with both the synthetic steroids (progesterone, estradiol) and the synthetic CPCs than in the paired control chamber baited only with the synthetic steroids. In field experiments, trap boxes baited with both the CPCs and the steroids captured 6.7-times more adult males and 4.7-times more juvenile males than trap boxes baited with the steroids alone. Conversely, trap boxes baited with both the CPCs and the steroids captured 4.3-times more adult males and 2.7-fold fewer adult females than trap boxes baited with the CPCs alone. In combination, these data support the conclusion that butyric acid, 2 methyl butyric acid and 4-heptanone are part of the sex attractant pheromone of female house mice. With progesterone and estradiol being pheromone components of both female brown rats, Rattus norvegicus, and female house mice, these three volatile components could impart specificity to the sexual communication system of house mice, brown rats and possibly other rodent species. PMID- 30411205 TI - Indian Society of Gastroenterology. PMID- 30411203 TI - Response to McGirr et al.'s Comment on "Clinical and Economic Impact of a Potential Switch from 13-Valent to 10-Valent Pneumococcal Conjugate Infant Vaccination in Canada". PMID- 30411206 TI - Maximizing the use of Hemospray. PMID- 30411207 TI - Pupillometry tracks fluctuations in working memory performance. AB - In 3 experiments, we examined fluctuations in working memory (WM) performance and associated changes in pretrial and task-evoked pupil diameter. Additionally, we examined whether particularly poor trials were accompanied by self-reports of off task attentional states. The results demonstrated that task-evoked pupillary responses can be used to measure moment-to-moment fluctuations in the success of WM maintenance during delay intervals. Further, when individuals reported being in an off-task attentional state, their WM performance suffered. Additionally, when probed directly after a particularly poor trial, participants reported being in an off-task attentional state more often than at random intervals throughout the task. So behavioral, subjective, and physiological data converged when people experienced WM failures. Although pretrial pupil diameter did not consistently differentiate between successful and unsuccessful trials, variability in pretrial pupil diameter accounted for a significant portion of variance in WM task performance. This effect persisted after controlling for mean task-evoked pupillary response and variability in task-evoked pupillary responses. Thus, one of the major reasons people varied in the consistency with which they utilized their WM system was variability in arousal. Such variability in arousal is potentially due to variation in the functioning of the locus coeruleus norepinephrine (LC-NE) neuromodulatory system, and thus may underlie individual differences in WM capacity and attention control. PMID- 30411208 TI - Kinesins in neurological inherited diseases: a novel motor-domain mutation in KIF5A gene in a patient from Southern Italy affected by hereditary spastic paraplegia. AB - Kinesins are a family of proteins for anterograde transport of the molecules from the neuronal cell body and their impairment has been widely associated with neurodegeneration of the motor neurons. KIF5A gene causes autosomal dominant spastic paraplegia 10, a neurological disorder characterized by spasticity and weakness of the lower limbs (SPG10). We carried out a screening of KIF5A gene in 50 subjects affected by HSP negative to diagnostic test for SPG4, ATL1 and REEP1. We identified a novel variation p.Ile255Met in a 58-year-old man who developed progressive gait disturbance due to spastic paraparesis complicated by axonal neuropathy. PMID- 30411209 TI - The origin of the "dark" absorption band near 675 nm in the purple bacterial core light-harvesting complex LH1: two-photon measurements of LH1 and its subunit B820. AB - A comparative two-photon excitation spectroscopic study of the exciton structure of the core antenna complex (LH1) and its subunit B820 was carried out. LH1 and its subunit B820 were isolated from cells of the carotenoid-less mutant G9 of Rhodospirillum rubrum. The measurements were performed by two-photon pump-probe spectroscopy. Samples were excited by 70 fs pulses at 1390 nm at a frequency of 1 kHz. Photoinduced absorption changes were recorded in the spectral range from 780 to 1020 nm for time delays of the probe pulse relative to the pump pulse in the - 1.5 to 11 ps range. All measurements were performed at room temperature. Two photon excitation caused bleaching of exciton bands (k = 0, k = +/- 1) of the circular bacteriochlorophyll aggregate of LH1. In the case of the B820 subunit, two-photon excitation did not cause absorption changes in this spectral range. It is proposed that in LH1 upper exciton branch states are mixed with charge transfer (CT) states. In B820 such mixing is absent, precluding two-photon excitation in this spectral region. Usually, CT states are optically "dark", i.e., one photon-excitation forbidden. Thus, their investigation is rather complicated by conventional spectroscopic methods. Thus, our study provides a novel approach to investigate CT states and their interaction(s) with other excited states in photosynthetic light-harvesting complexes and other molecular aggregates. PMID- 30411210 TI - CPEB1 Expression Correlates with Severity of Posttraumatic Ankle Osteoarthritis and Aggravates Catabolic Effect of IL-1beta on Chondrocytes. AB - Most cases of posttraumatic ankle osteoarthritis (PTAOA) represent a sequela of ankle fractures. The cytoplasmic polyadenylation element-binding protein 1 (CPEB1) is an RNA binding protein that controls protein expression. Here, we report the previously unappreciated association of CPEB1 with PTAOA. We found that CPEB1 was upregulated in articular cartilage from patients with PTAOA. Additionally, its expression level positively correlated with disease severity. In human primary chondrocytes cultured in vitro, CPEB1 was upregulated when treated with pro-inflammatory cytokines, i.e., IL-1beta and TNF-alpha, suggesting that the observed CPEB1 upregulation in articular cartilage of PTAOA patients may be attributed to local inflammatory milieu. Functionally, CPEB1 overexpression aggravated the catabolic effect of IL-1beta on chondrocytes in vitro, and vice versa, its knockdown reduced this effect, together implying a detrimental role of CPEB1 involved in OA progression. In sum, our study identifies CPEB1 as a potential regulator of disease progression of PTAOA. PMID- 30411211 TI - MicroRNA-92a Drives Th1 Responses in the Experimental Autoimmune Encephalomyelitis. AB - Dysregulation of microRNAs (miRNAs) has been linked to the progress of a number of autoimmune diseases including multiple sclerosis (MS), and its animal model, experimental autoimmune encephalomyelitis (EAE). IFN-gamma-producing Th1 cells are major players in MS/EAE pathogenesis. It is known that differentiation of T cells towards the Th1 phenotype is influenced by various factors including miRNAs. The miR-92a shows substantial upregulation in MS; however, little is known about its role in the development of autoimmune and inflammatory responses. Herein, we investigated the role of miR-92a in the pathogenesis of MS, focusing on its potential effects on differentiation of Th1 cells. The expression levels of miR-92a were assessed in the spinal cord tissues and splenocytes from mice with EAE using real-time RT-PCR. Next, using transfection with miR-92a mimic sequences, the potential involvement of miR-92a in Th1 polarization was investigated by flow cytometric analysis. Moreover, the expression levels of miR 92a targets were explored in spinal cord tissues of EAE mice. miR-92a expression was enhanced in mouse spinal cord samples at the peak of EAE disease. Overexpression of miR-92a in splenocytes led to increased differentiation of Th1 cells compared with cells transfected with negative control sequences. Enhanced miR-92a expression was accompanied by reduced expression TSC1 or DUSP10, predicted miR-92a targets, in EAE spinal cords. Our data point to a potential role for miR-92a in neuroinflammatory responses in EAE. Our results indicate that miR-92a might affect Th1 differentiation, likely due to downregulation of TSC1 and DUSP10. PMID- 30411212 TI - Alcohol Binge Reduces Systemic Leukocyte Activation and Pulmonary PMN Infiltration After Blunt Chest Trauma and Hemorrhagic Shock. AB - Blunt chest (thoracic) trauma (TxT) and hemorrhagic shock (HS)-induced local and systemic inflammation with increased neutrophil activity often result in an impaired organ function. Next to increasing the trauma risk, binge drinking causes anti-inflammatory effects due to immunomodulatory properties of alcohol (ethanol, EtOH). The impact of clinically relevant acute binge drinking scenario on local and systemic inflammatory changes, notably regarding the activity and longevity of leukocytes, has been analyzed in a combinatory trauma model of TxT + H/R. Twenty-four female Lewis rats (190-240 g) received alcohol (5 g/kg, 30%) or saline gavage. Two hours after alcohol gavage, TxT with subsequent HS (60 min) and resuscitation (TxT + H/R) were induced. Sham-operated animals underwent surgical procedures. Bronchoalveolar lavage fluid (BAL), lung tissue, and blood were harvested 2 h after resuscitation. Pulmonary infiltration with PMN, IL-6 gene expression, systemic PMN activation, neutrophil and monocyte apoptosis (caspase-3/7), and pyroptosis/inflammasome activation (caspase-1) were evaluated. Lung damage was evaluated by hematoxylin-eosin (H/E) staining and determination of the total protein content in BAL (ANOVA, p < 0.05 was significant). TxT + H/R induced increases in IL-6, PMN infiltration and BAL-protein concentration were significantly reduced by EtOH; however, histological morphology changes after trauma remained unaltered by EtOH. TxT + H/R-induced systemic leukocyte activation (increased CD11b and CD31, reduced CD62L expression) as well as inflammasome activation in monocytes were significantly diminished by EtOH. Apoptosis was prolonged only in PMN after TxT + H/R and was further prolonged by EtOH, an effect that was observed in sham animals as a trend as well. Acute EtOH exposure inhibits the activation of circulating leukocytes after trauma compared to controls. These EtOH-driven systemic changes may be associated with reduced infiltration with PMN after trauma as well as reduced local tissue inflammation. PMID- 30411213 TI - Acute Exposure to Diesel-Biodiesel Particulate Matter Promotes Murine Lung Oxidative Stress by Nrf2/HO-1 and Inflammation Through the NF-kB/TNF-alpha Pathways. AB - Air pollution caused by fuel burning contributes to respiratory impairments that may lead to death. We aimed to investigate the effects of biodiesel (DB) burning in mouse lungs. DB particulate matter was collected from the exhaust pipes of a bus engine. Mice were treated with 250 MUg or 1000 MUg of DB particulate matter by intranasal instillation over 5 consecutive days. We demonstrated that DB particulate matter penetrated the lung in the 250-MUg and 1000-MUg groups. In addition, the DB particulate matter number in pulmonary parenchyma was 175-fold higher in the 250-MUg group and 300-fold higher in the 1000-MUg group compared to control mice. The instillation of DB particulate matter increased the macrophage number and protein levels of TNF-alpha in murine lungs. DB particulate matter enhanced ROS production in both exposed groups and the malondialdehyde levels compared to the control group. The protein expression levels of Nrf2, p-NF-kB, and HO-1 were higher in the 250-MUg group and lower in the 1000-MUg group than in control mice and the 250-MUg group. In conclusion, DB particulate matter instillation promotes oxidative stress by activating the Nrf2/HO-1 and inflammation by p-NF-kB/TNF-alpha pathways. PMID- 30411215 TI - A new affordable and easy-to-make pelvic model for training in complex urogynecological laparoscopic procedures. AB - INTRODUCTION AND HYPOTHESIS: Our aim was to introduce a new affordable and easy to-make pelvic model for training in complex urogynecological laparoscopic procedures. METHODS: We modified a commercial female pelvic model consisting of sacrum, coccyx, two hip bones, the pubic symphysis, the fifth lumbar vertebra with intervertebral disc, and certain pelvic ligaments. We used sponge foam paper, felt fabric pieces, chenille stems, foam, plastic ties, fabric glue, and a thick, coated wire to create pelvic floor, uterus/vaginal cuff, bladder, both ureters, and anterior longitudinal and pectineal ligaments. RESULTS: We created two different pelvic models: one with the uterus and one with the vaginal cuff. They enable training for laparoscopic pectopexy and hysteropexy/sacrocolpopexy. Trainees can practice proper mesh placement and suture the mesh to the corresponding anatomical structures. Because of the wire inserted in the uterus/vaginal cuff, it is possible to move the uterus/vaginal cuff in the anterior-posterior direction, thus mimicking the use of the manipulator during surgery. Besides the basic pelvis, all other parts of the model can be easily replaced when necessary. CONCLUSIONS: We believe that our pelvic model could provide a valuable tool for training complex urogynecological laparoscopic procedures and help to reduce the long learning curve of these procedures. PMID- 30411214 TI - Stearic Acid-Grafted Chitooligosaccharide Nanomicelle System with Biocleavable Gadolinium Chelates as a Multifunctional Agent for Tumor Imaging and Drug Delivery. AB - PURPOSE: Theranostic nanoplatforms are promising approaches for diagnosis and treatment. Here, we report a drug-loaded nanomicelle system with biocleavable gadolinium (Gd) chelates as a multifunctional biodegradable agent for simultaneous magnetic resonance imaging (MRI) and drug delivery. METHODS: Self assembled nanomicelles based on stearic acid-grafted chitooligosaccharide were utilized as vehicles. Gd chelates, DTPA-Gds, were linked to the nanomicelles via redox-responsive disulfide bonds, and hydrophobic drugs were encapsulated in the micelle cores. MRI and cargo delivery were investigated in orthotopic pancreatic tumor-bearing mice. RESULTS: In vivo MRI demonstrated that the biodegradable agent was cleaved by endogenous thiols after intravenous injection, and the released DTPA-Gds were eliminated rapidly. At the same time, the agent resulted in a greater contrast enhancement of T1-weighted MR signal intensity at the tumor region than Magnevist(r), and the tumor boundaries were clearly defined for at least 2 h. In addition, the agent possessed high drug-loading and tumor-targeting capacities. Loading content and encapsulation efficiency of docetaxel were 3.2% and 99.4%, respectively. Compared with Taxotere(r), the commercially available docetaxel injection, the docetaxel-loaded agent significantly increased the drug concentration in tumor tissue in vivo. CONCLUSION: The fabricated multifunctional agent may serve as a biodegradable nanoscale MRI contrast agent and as a drug delivery system for tumor diagnosis and treatment. PMID- 30411216 TI - The Continuing Evolution of Molecular Functional Imaging in Clinical Oncology: The Road to Precision Medicine and Radiogenomics (Part I). AB - The present era of precision medicine sees 'cancer' as a consequence of molecular derangements occurring at the commencement of the disease process, with morphologic changes happening much later in the process of tumorigenesis. Conventional imaging techniques, such as computed tomography (CT), ultrasound, and magnetic resonance imaging (MRI), play an integral role in the detection of disease at a macroscopic level. However, molecular functional imaging (MFI) techniques entail the visualisation and quantification of biochemical and physiological processes occurring during tumorigenesis, and thus has the potential to play a key role in heralding the transition from the concept of 'one size fits all' to 'precision medicine'. Integration of MFI with other fields of tumour biology such as genomics has spawned a novel concept called 'radiogenomics', which could serve as an indispensable tool in translational cancer research. With recent advances in medical image processing, such as texture analysis, deep learning, and artificial intelligence (AI), the future seems promising; however, their clinical utility remains unproven at present. Despite the emergence of novel imaging biomarkers, a majority of these require validation before clinical translation is possible. In this two-part review, we discuss the systematic collaboration across structural, anatomical, and molecular imaging techniques that constitute MFI. Part I reviews positron emission tomography, radiogenomics, AI, and optical imaging, while part II reviews MRI, CT and ultrasound, their current status, and recent advances in the field of precision oncology. PMID- 30411217 TI - A phase II trial of gemcitabine, S-1 and LV combination (GSL) therapy in patients with advanced pancreatic cancer. AB - Purpose Our previous phase I trial suggested feasibility of addition of leucovorin (LV) to S-1 and gemcitabine therapy in advanced pancreatic cancer. The aim of this phase II trial was to assess the efficacy and toxicity of gemcitabine, S-1 and LV (GSL) combination therapy for advanced pancreatic cancer. Methods Chemotherapy-naive patients with histologically or cytologically proven advanced pancreatic cancer were enrolled. Gemcitabine was administered at a dose of 1000 mg/m2 by 30 min infusion on days 1, S-1 40 mg/m2 orally twice daily and LV 25 mg orally twice daily on days 1 to 7 every 2 weeks. Primary end point was progression free survival (PFS). Results A total of 49 patients with advanced pancreatic cancer (19 locally advanced and 30 metastatic) were enrolled. Overall response rate and disease control rate were 32.7% and 87.8%. The median PFS and overall survival (OS) were 10.8 (95% confidence interval [CI], 7.4-13.5) and 20.7 (95% CI 13.0-NA) months with 1-year survival rate of 73.4%. Major Grade 3-4 toxicities were neutropenia (22.4%) and stomatitis (14.3%). No toxicity related death was observed. Conclusions In this single center, phase II trial, gemcitabine, S-1 and LV combination therapy was tolerable and can potentially be a treatment option for advanced pancreatic cancer. PMID- 30411219 TI - Interpretation of very low avidity indices acquired with the Liaison XL Toxo IgG avidity assay in dating toxoplasmosis infection. AB - Congenital toxoplasmosis is an important cause of complications in pregnancy. Toxoplasmosis is often asymptomatic and thus serological tests are usually performed to screen for it. A first serum which exhibit both IgG and IgM may be due to nascent toxoplasmosis seroconversion, non-specific IgM reaction, or residual IgM. The IgG avidity test has been proposed to identify latent infections. A high index excludes recent toxoplasmosis whereas an intermediate or low index only suggests a recent infection, the caveats being that some people with latent Toxoplasma gondii infection show IgG with low or intermediate avidity. In this study, we investigated the ability of the Liaison XL Toxo IgG avidity (DiaSorin, Saluggia, Italy) assay to confirm recent infection when IgG avidity index is very low (<= 0.1). Four thousand two hundred ninety-seven sera exhibiting both IgG and IgM were included and avidity was performed on the Liaison device according to the manufacturer's recommendations. One hundred twenty-six sera on the 297 sera which exhibited very low IgG avidity indices (<= 0.1) could be exploited: 97% of sera with IgG avidity indices < 0.05 actually corresponded to recent infection (less than 3 months). A similar but less pronounced trend was observed for the sera exhibiting indices between 0.05 and 0.1 (69% corresponded to recent infections). The IgG avidity index data we obtained with the Liaison XL Toxo device are similar to those obtained with other devices. This body of consistent results underlines the interest of very low IgG avidity indices as a sign of probable recent toxoplasmosis. PMID- 30411218 TI - First-in-human phase I study of the microtubule inhibitor plocabulin in patients with advanced solid tumors. AB - Background Plocabulin (PM060184) is a novel marine-derived microtubule inhibitor that acts as an antitumor agent. This first-in-human study evaluated dose limiting toxicities (DLT) to define the maximum tolerated dose (MTD) and phase II recommended dose (RD) of plocabulin given as a 10-min infusion on Day (D) 1, D8 and D15 every four weeks. Patients and methods Forty-four patients with advanced solid tumors received plocabulin following an accelerated titration design. Results Plocabulin was escalated from 1.3 mg/m2 to 14.5 mg/m2, which was defined as the MTD. No RD was confirmed, because frequent dose delays and omissions resulted in low relative dose intensity (66%) at the 12.0 mg/m2 expansion cohort. The main DLT was grade 3 peripheral sensory neuropathy (PSN); other DLTs were grade 4 tumor lysis syndrome, grade 4 cardiac failure and grade 3 myalgia. Toxicities were mainly mild to moderate, and included abdominal pain, myalgia, fatigue, nausea, and vomiting. Myelosuppression was transient and manageable. Plocabulin had a half-life of ~4 h and a wide diffusion to peripheral tissues. Antitumor response was observed in cervix carcinoma and heavily pretreated metastatic non-small cell lung cancer patients, and disease stabilization (>=3 months) in patients with colorectal, thymic, gastrointestinal stromal and breast tumors, among others. The clinical benefit rate was 33%. Conclusion The main DLT of plocabulin was PSN, as anticipated for a tubulin-binding agent. Since encouraging antitumor activity was observed, efforts to improve toxicity and to find the RD were planned in other trials evaluating D1&D8 and D1-D3 plus D15-D17 schedules. PMID- 30411220 TI - Rapid detection of carbapenemases directly from positive blood cultures by the beta-CARBA test. AB - The rapid detection of blood stream infections (BSI) by carbapenemase-producing Enterobacterales (CPE) is indispensable to early optimize antibiotic treatment and to improve survival. While phenotypic tests are time-consuming and PCR is expensive and not available in many routine laboratories, colorimetric tests (e.g., Carba NP test) can provide rapid results at moderate cost. However, up to now, the detection of CPE-BSI requires a further 3-h incubation in broth supplemented with zinc sulfate and imipenem after a blood culture has become positive, thereby causing delay and additional hands-on time. The purpose of this study was to develop and evaluate a new method for the detection of CPE directly from positive blood culture without the need for incubation in broth, based on the commercially available colorimetric beta-CARBA test. For the evaluation, blood cultures spiked with 140 different Enterobacterales isolates producing diverse beta-lactamases were tested with the new method. Of these, 70 were CPE (OXA-48-like, NDM, KPC, VIM, and GIM). After blood cultures turned positive, blood culture fluid was drawn, and erythrocytes were hemolyzed with SDS, washed, and equilibrated before the beta-CARBA was performed on the bacterial pellet. All carbapenemases were reliably detected, including weak carbapenemases of the OXA 48 group. The sensitivity was 100% (95% CI 94.9-100) and the specificity 94.3% (95% CI 89.2-99.4). The time to result was 20 to 45 min. Carbapenemases can rapidly and reliably be detected directly from blood cultures using the new method, which could help to improve the outcome of these difficult-to-treat infections. PMID- 30411221 TI - Intensifying the intensity illusion in judgments of learning: Modality and cue combinations. AB - We showed that judgments of learning (JOLs) were not affected by presentation modality in a list-learning task, although the typical font-size and loudness illusions emerged in that large-font visual presentations and loud auditory presentations elicited higher JOLs than their less intense counterparts. Further, when items were presented in both modalities simultaneously, large-font/quiet and small-font/loud items received similar JOLs (and were recalled similarly). Most importantly, when the intensity manipulation was compounded across modalities, the magnitude of the illusion increased beyond that observed in a single modality, showing the influence of combining cues. Whereas recall was still the same, large-font/loud items received higher JOLs than either small-font/loud items or large-font/quiet items, and not-intense items received very low JOLs. These differences emerged only when all conditions were presented within a single list and not in a between-subjects design, underscoring the importance of comparative judgments. PMID- 30411222 TI - Handedness modulates proprioceptive drift in the rubber hand illusion. AB - Preference for use of either the left or right hand ('handedness') has been linked with modulations of perception and sensory processing-both of space and the body. Here we ask whether multisensory integration of bodily information also varies as a function of handedness. We created a spatial disparity between visual and somatosensory hand position information using the rubber hand illusion, and use the magnitude of illusory shifts in hand position (proprioceptive 'drift') as a tool to probe the weighted integration of multisensory information. First, we found drift was significantly reduced when the illusion was performed on the dominant vs. non-dominant hand. We suggest increased manual dexterity of the dominant hand causes greater representational stability and thus an increased resistance to bias by the illusion induction. Second, drift was generally greatest when the hand was in its habitual action space (i.e., near the shoulder of origin), compared to when it laterally displaced towards, or across the midline. This linear effect, however, was only significant for the dominant hand in both left- and right-handed groups. Thus, our results reveal patterns of habitual hand action modulate drift both within a hand (drift varies with proximity to action space), and between hands (differences in drift between the dominant and non-dominant hands). In contrast, we were unable to find conclusive evidence to support, or contradict, an overall difference between left- and right handers in susceptibility to RHI drift (i.e., total drift, collapsed across hand positions). In sum, our results provide evidence that patterns of daily activity and the subsequent patterns of sensory input-shape multisensory integration across space. PMID- 30411223 TI - AMP Kinase Activation is Selectively Disrupted in the Ventral Midbrain of Mice Deficient in Parkin or PINK1 Expression. AB - Parkinson's disease (PD) is a prevalent neurodegenerative movement disorder that is characterized pathologically by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) of the midbrain. Despite intensive research, the etiology of PD remains poorly understood. Interestingly, recent studies have implicated neuronal energy dysregulation as one of the key perpetrators of the disease. Supporting this, we have recently demonstrated that pharmacological or genetic activation of AMP kinase (AMPK), a master regulator of cellular energy homeostasis, rescues the pathological phenotypes of Drosophila models of PD. However, little is known about the role of AMPK in the mammalian brain. As an initial attempt to clarify this, we examined the expression of AMPK in rodent brains and found that phospho-AMPK (pAMPK) is disproportionately distributed in the adult mouse brain, being high in the ventral midbrain where the SN resides and relatively lower in regions such as the cortex-reflecting perhaps the unique energy demands of midbrain DA neurons. Importantly, the physiologically higher level of midbrain pAMPK is significantly reduced in aged mice and also in Parkin-deficient mice; the loss of function of which in humans causes recessive Parkinsonism. Not surprisingly, the expression of PGC-1alpha, a downstream target of AMPK activity, and a key regulator of mitochondrial biogenesis, mirrors the expression pattern of pAMPK. Similar observations were made with PINK1-deficient mice. Finally, we showed that metformin administration restores the level of midbrain pAMPK and PGC-1alpha expression in Parkin deficient mice. Taken together, our results suggest that the disruption of AMPK PGC-1alpha axis in the brains of individuals with Parkin or PINK1 mutations may be a precipitating factor of PD, and that pharmacological AMPK activation may represent a neuroprotective strategy for the disease. PMID- 30411224 TI - Safety and Feasibility of a Lower-Cost Stapler in Bariatric Surgery. AB - BACKGROUND: Laparoscopic staplers are integral to bariatric surgery. Their pricing significantly impacts the overall cost of procedures. An independent device company has designed a stapler handle and single-use reloads for cross compatibility and equivalency with existing manufacturers, at a lower cost. OBJECTIVES: We aim to demonstrate non-inferior function and cross-compatibility of a newly introduced stapler handle and reloads compared to our institution's current stapling system in a large animal survival study. SETTING: University affiliated animal research facility, USA. METHODS: Matched small bowel anastomoses were created in four pigs, one with each stapler (a total of two per animal). After 14 days, investigators blinded to stapler type evaluated the anastomoses grossly and microscopically. Each anastomosis was scored on multiple measures of healing. Individual parameters were added for a global "healing score." RESULTS: Clinical stapler function and gross quality of anastomoses were similar between stapler groups. Individual scores for anastomotic ulceration, reepithelialization, granulation tissue, mural healing, eosinophilic infiltration, serosal inflammation, and microscopic adherences were also statistically similar. The mean "healing scores" were equal. While this study was underpowered for subtle differences, safe and reliable performance in large animals still supports the feasibility of introducing new devices into human use. CONCLUSIONS: The new stapler system delivers a similar technical performance and is cross-compatible with currently marketed stapling devices. An equivalent quality device at a lower price point should enable case cost reduction, helping to maintain hospital case margin and procedure value in the face of potentially declining reimbursement. This device may provide a safe and functional alternative to currently used laparoscopic surgical staplers. PMID- 30411225 TI - Letter to Editor on "Taste Changes after Bariatric Surgery: a Systematic Review". PMID- 30411226 TI - Improvement in Nocturnal Hypoxemia in Obese Patients with Obstructive Sleep Apnea after Bariatric Surgery: a Meta-Analysis. AB - OBJECTIVE: To conduct a meta-analysis examining the effects of bariatric surgery on nocturnal hypoxemia in obese patients with obstructive sleep apnea (OSA). METHODS: PubMed, EMBASE, Cochrane Library, and Web of Science were searched (the last search date was June 10, 2018) to identify relevant clinical studies. The mean arterial oxygen saturation (MeanSaO2), nadir oxygen saturation (NadirSaO2), apnea hypopnea index (AHI), and body mass index (BMI) data during the perioperative period were extracted and analyzed using a random effects model. Then, we performed subgroup and sensitivity analyses and calculated the publication bias to assess the between-study heterogeneity. RESULTS: In total, 15 studies with 636 patients were included; 13 were prospective observational trials, 1 was a randomized controlled trial (RCT), and 1 was a retrospective trial. After surgery, the MeanSaO2 and NadirSaO2 increased by 1.36 [95% CI (0.72, 2.00)] and 1.08 [95% CI (0.68, 1.49)], respectively, and the AHI and BMI decreased by 1.11 [95% CI (0.82, 1.40)] and 1.97 [95% CI (1.67, 2.27)], respectively. However, the heterogeneity across all trials was high; we identified some of the sources of that heterogeneity through subsequent subgroup and sensitivity analyses. CONCLUSIONS: Bariatric surgery is effective at improving nocturnal hypoxemia in obese patients with OSA; it also reduces body weight and the number of apnea events. More randomized controlled and comparative trials are necessary in the future to confirm our findings and to explore the potential underlying mechanisms. PMID- 30411227 TI - 1D CNN with BLSTM for automated classification of fixations, saccades, and smooth pursuits. AB - Deep learning approaches have achieved breakthrough performance in various domains. However, the segmentation of raw eye-movement data into discrete events is still done predominantly either by hand or by algorithms that use hand-picked parameters and thresholds. We propose and make publicly available a small 1D-CNN in conjunction with a bidirectional long short-term memory network that classifies gaze samples as fixations, saccades, smooth pursuit, or noise, simultaneously assigning labels in windows of up to 1 s. In addition to unprocessed gaze coordinates, our approach uses different combinations of the speed of gaze, its direction, and acceleration, all computed at different temporal scales, as input features. Its performance was evaluated on a large scale hand-labeled ground truth data set (GazeCom) and against 12 reference algorithms. Furthermore, we introduced a novel pipeline and metric for event detection in eye-tracking recordings, which enforce stricter criteria on the algorithmically produced events in order to consider them as potentially correct detections. Results show that our deep approach outperforms all others, including the state-of-the-art multi-observer smooth pursuit detector. We additionally test our best model on an independent set of recordings, where our approach stays highly competitive compared to literature methods. PMID- 30411228 TI - Steady Flow in a Patient-Averaged Inferior Vena Cava-Part I: Particle Image Velocimetry Measurements at Rest and Exercise Conditions. AB - PURPOSE: Although many previous computational fluid dynamics (CFD) studies have investigated the hemodynamics in the inferior vena cava (IVC), few studies have compared computational predictions to experimental data, and only qualitative comparisons have been made. Herein, we provide particle image velocimetry (PIV) measurements of flow in a patient-averaged IVC geometry under idealized conditions typical of those used in the preclinical evaluation of IVC filters. METHODS: Measurements are acquired under rest and exercise flow rate conditions in an optically transparent model fabricated using 3D printing. To ensure that boundary conditions are well-defined and to make follow-on CFD validation studies more convenient, fully-developed flow is provided at the inlets (i.e., the iliac veins) by extending them with straight rigid tubing longer than the estimated entrance lengths. Velocity measurements are then obtained at the downstream end of the tubing to confirm Poiseuille inflow boundary conditions. RESULTS: Measurements in the infrarenal IVC reveal that flow profiles are blunter in the sagittal plane (minor axis) than in the coronal plane (major axis). Peak in-plane velocity magnitudes are 4.9 cm/s and 27 cm/s under the rest and exercise conditions, respectively. Flow profiles are less parabolic and exhibit more inflection points at the higher flow rate. Bimodal velocity peaks are also observed in the sagittal plane at the elevated flow condition. CONCLUSIONS: The IVC geometry, boundary conditions, and infrarenal velocity measurements are provided for download on a free and publicly accessible repository at https://doi.org/10.6084/m9.figshare.7198703 . These data will facilitate future CFD validation studies of idealized, in vitro IVC hemodynamics and of similar laminar flows in vascular geometries. PMID- 30411229 TI - Toxicity of wine effluents and assessment of a depuration system for their control: assay with tadpoles of Rhinella arenarum (BUFONIDAE). AB - We evaluated the toxicity of the winery effluent and the efficiency of a symbiotic depuration system by means an experiment with Rhinella arenarum tadpoles. The studied effluent was taken from warehouses during the cleaning season. These effluents subsequently subjected to the purification treatment under evaluation. The effluent samples differentiated into two treatment levels: "raw" where the effluent was evaluated with field conditions and "treated" where the effluent was previously filtered with the symbiotic depuration system. The results of the bioassays compared with the physicochemical parameters determined in the effluent samples. The lethal response had a clear-cut correspondence with the effluent quality assessed utilizing physicochemical parameters. In all cases, dilution of the samples resulted in a significant reduction of their toxicity. It concluded that (a) winery effluents could be harmful to tadpoles of R. arenarum, (b) the symbiotic purification system used to treat wine effluents it would produce a significant reduction in the contaminant levels of the effluent. However, this reduction in contaminant levels does not provide sufficient safety for the release of the effluents into the environment. PMID- 30411231 TI - Lipid metabolism in adipose tissue and liver from diet-induced obese rats: a comparison between Wistar and Sprague-Dawley strains. AB - Some researchers have proposed important variations in adipose tissue among different strains of rats and mice in response to a high-caloric (hc) diet, but data concerning the mechanisms underlying these differences are scarce. The aim of the present research was to characterize different aspects of triacylglycerol (TG) metabolism and clock genes between Sprague-Dawley and Wistar rats. For this purpose, 16 male Sprague-Dawley and 16 male Wistar rats were divided into four experimental groups (n = 8) and fed either a normal-caloric (nc) diet or a hc diet for 6 weeks. After sacrifice, liver and epididymal, perirenal, mesenteric, and subcutaneous adipose tissue depots were dissected, weighed and immediately frozen. Liver TG content was quantified, RNA extracted for gene expression analysis and fatty acid synthase enzyme activity measured. Two-way ANOVA and Student's t test were used to perform the statistical analyses. Under hc feeding conditions, Wistar rats were more prone to fat accumulation in adipose tissue, especially in the epididymal fat depot, due to their increased lipogenesis and fatty acid uptake. By contrast, both strains of rats showed similarly fatty livers after hc feeding. Peripheral clock machinery seems to be a potential explanatory mechanism for Wistar and Sprague-Dawley strain differences. In conclusion, Wistar strain seems to be the best choice as animal model in dietary induced obesity studies. PMID- 30411232 TI - Spatial and temporal variations of nutrition in representative river networks in Southwest China. AB - To control pollutants in rivers, we need to have an understanding of the spatial and temporal variations on nutrients and environmental processes in complex river networks. In this study, 177 sampling sites were located in Jinjiang River in 2017, 15 monitoring stations in Jinjiang River from 2011 to 2016 were also collected. According to the data from the monitoring station, the total phosphorus (TP) and total nitrogen (TN) were the dominant contaminants. By analyzing historical water quality data and up-to-date information about the nutrient concentrations, the secondary canals of the Jinjiang River system, most of which were black and odorous, were much more seriously polluted than the main channel and tributaries. Correlation analysis indicated that the NH3, CODcr, TN, and TP had similar sources (R2NH3-CODcr = 0.572, R2NH3-TN = 0.543, R2NH3-TP = 0.537, p < 0.01). The vertical banks of urban rivers and the inadequate and poorly maintained pipe network systems promote deterioration of water quality in these secondary canals. Overall, our results suggest that the river water quality could be improved if the municipal pipe network systems were better maintained and if the vertical banks were transformed into vegetated buffer strips. This study will support initiatives to improve the water quality and function of the river network ecosystem. PMID- 30411233 TI - Child Psychotherapy Training in the United States: A National Survey of Child and Adolescent Psychiatry Fellowship Program Directors. AB - OBJECTIVES: Training in child and adolescent psychotherapy continues to be emphasized by accrediting organizations (ACGME and ABPN) but it is not known how these skills are taught and what types of therapy are highlighted in fellowships across the United States. METHODS: A 16-question anonymous online survey was developed by the authors and covered six main areas: demographics, the priority of psychotherapy in training, the competency goals for different psychotherapy modalities, training strategies, types of supervision, and program directors' satisfaction of their training implementation and assessment of trainees. The survey was sent to every identified CAP program director during a three-month period in early 2017. RESULTS: Data was gathered from 53 of the 131 program directors surveyed, giving a 40% response rate. Ninety percent of CAP program directors strongly agree or agree that it is important to preserve and promote training and practice of psychotherapy. Most (83%) program directors indicated competence or expertise as a training goal for CBT with more variability among programs for other psychotherapies. Seventy percent of program directors agree that their program provides adequate time for learning and practicing psychotherapy but the allotted time for psychotherapy is low across majority of programs over both years of training. CONCLUSIONS: These results indicate that there is a gap between the goals of providing optimal training in psychotherapy with the low amount of protected time for the practice of psychotherapy. These results should provide a foundation for program directors to learn from each other about developing, improving, and implementing effective psychotherapy training. PMID- 30411234 TI - Biological Background of Block Periodized Endurance Training: A Review. AB - Block periodized (BP) training is an innovative and prospective approach that is drawing increasing attention from coaching scientists and practitioners. However, its further dissemination and implementation demands serious scientific biological underpinnings. More specifically, the fundamental scientific concepts of homeostatic regulation, stress adaptation and the law of supercompensation determine the biological essence and content of appropriate block mesocycles, i.e., the accumulation, transmutation and realization cycles, respectively. Such a separation is intended to prevent conflicting physiological responses and provide a favorable interaction for training effects. Several studies have evaluated the metabolic effects of various training programs, and the superiority of the BP model has been confirmed in terms of significant gains of maximal oxygen uptake, maximal power output and positive trends in athletic performance. It was found that the endocrine status of athletes is strictly dependent on appropriate blocks such as voluminous extensive workloads combined with resistance training (accumulation), lower-volume intense training (transmutation), and event-specific precompetitive training (realization). Evidence from molecular biology indicates the major regulators that determine meaningful adaptive events within specific block mesocycles. Specifically, voluminous extensive accumulation blocks stimulate mitochondrial biogenesis and protein synthesis in slow-twitch muscle fibres, whereas lower-volume intense workloads of the transmutation blocks evoke adaptive modifications in fast-twitch glycolytic and oxidative-glycolytic muscle fibers. Furthermore, such a training program causes a remarkable elevation of myonuclear content in muscle fibers that enables athletes to regain previously acquired abilities. The precompetitive realization block produces accentuated expression of stress-related and myogenic genes that affect protein synthesis and increase muscle glycogen. In addition, such a program stimulates and increases the size, force and power of fast-twitch fibers. PMID- 30411235 TI - Review of WADA Prohibited Substances: Limited Evidence for Performance-Enhancing Effects. AB - The World Anti-Doping Agency is responsible for maintaining a Prohibited List that describes the use of substances and methods that are prohibited for athletes. The list currently contains 23 substance classes, and an important reason for the existence of this list is to prevent unfair competition due to pharmacologically enhanced performance. The aim of this review was to give an overview of the available evidence for performance enhancement of these substance classes. We searched the scientific literature through PubMed for studies and reviews evaluating the effects of substance classes on performance. Findings from double-blind, randomized controlled trials were considered as evidence for (the absence of) effects if they were performed in trained subjects measuring relevant performance outcomes. Only 5 of 23 substance classes show evidence of having the ability to enhance actual sports performance, i.e. anabolic agents, beta2 agonists, stimulants, glucocorticoids and beta-blockers. One additional class, growth hormone, has similar evidence but only in untrained subjects. The observed effects all relate to strength or sprint performance (and accuracy for beta blockers); there are no studies showing positive effects on reliable markers of endurance performance. For 11 classes, no well-designed studies are available, and, for the remaining six classes, there is evidence of an absence of a positive effect. In conclusion, for the majority of substance classes, no convincing evidence for performance enhancement is available, while, for the remaining classes, the evidence is based on a total of only 266 subjects from 11 studies. PMID- 30411236 TI - Impact of Targeted Temperature Management on ED Patients with Drug Overdose Related Cardiac Arrest. AB - INTRODUCTION: Drug overdose is the leading cause of non-traumatic out-of-hospital cardiac arrest (OHCA) among young adults. This study investigates whether targeted temperature management (TTM) improves hospital survival from presumed overdose-related cardiac arrest. METHODS: Retrospective chart review of consecutive cardiac arrests presenting to an urban tertiary care hospital ED from 2011 to 2015. ED patients with cardiac arrest were included if < 50 years old, and excluded if there was a non-overdose etiology (e.g., trauma, ST-elevation myocardial infarction, subarachnoid hemorrhage). The main intervention was TTM, carried out with a combination of the Arctic Sun device and refrigerated crystalloid/antipyretics (goal temperature 33-36 degrees C). The primary outcome was survival to hospital discharge; neurologically intact survival was the secondary outcome. RESULTS: Of 923 patients with cardiac arrest, 802 (86.9%) met exclusion criteria, leaving 121 patients for final analysis. There were 29 patients in the TTM group (24.0%) vs 92 patients in the non-TTM group (76.0%). Eleven patients (9.1%) survived to hospital discharge. TTM was associated with increased odds of survival to hospital discharge (OR 11.3, 95% CI 2.8-46.3, p < 0.001), which increased substantially when palliative outcomes were excluded from the cohort (OR 117.3, 95% CI 17.0-808.4, p < 0.001). Despite achieving statistical significance (OR 1.1, 95% CI 1.0-1.3), TTM had no clinically significant effect on neurologically intact survival. CONCLUSIONS: TTM was associated with improved survival in ED patients with presumed drug overdose related cardiac arrest. The impact of TTM on neurologically intact survival among these patients requires further study. PMID- 30411237 TI - "Treat us with dignity": a qualitative study of the experiences and recommendations of lesbian, gay, bisexual, transgender, and queer (LGBTQ) patients with cancer. AB - PURPOSE: Despite indications that lesbian, gay, bisexual, transgender, and queer (LGBTQ) patients have unique needs when seeking healthcare, the experiences of LGBTQ patients in the context of cancer care have not been fully explored. This qualitative study investigated recommendations offered by LGBTQ patients with cancer for improving cancer care. METHODS: Two hundred seventy-three LGBTQ people across the USA who had been diagnosed with cancer completed an online survey that included open-ended questions. Using responses to these questions, two researchers independently conducted open coding. A code book was generated collaboratively and the data were coded independently. Codes were clustered and refined and the data were independently re-coded. RESULTS: Five themes emerged. LGBTQ patients with cancer: (1) are affected by providers' LGBTQ-specific knowledge and skills, assumptions, and mistreatment; (2) negotiate disclosure of identities based on safety of clinical encounters; (3) have differing experiences based on multiple intersecting identities; (4) receive more effective care when members of their support networks are included; and (5) are self-advocates and undergo transformative experiences in the face of morbidity and marginalization. CONCLUSIONS: LGBTQ cancer survivors report challenges accessing competent cancer treatment. To address this, cancer care providers should provide safe clinical encounters, inquire about and respond professionally to patients' identities and identifiers, include chosen support people, provide care relevant to patients' gender identities, and address treatments' effects on sexuality. Training providers about diverse LGBTQ communities and acknowledging the strengths of LGBTQ patients with cancer may improve provider/patient relationships. Provider training could be created based on these principles. PMID- 30411238 TI - Sexual desire of French representative prostate cancer survivors 2 years after diagnosis (the VICAN survey). AB - PURPOSE: The prostate cancer impacts on the future life of survivors. The complexity of sexual health problems in prostate cancer survivors is underestimated or often reduced to the erectile dysfunction. Especially, factors influencing sexual desire of patients have to be more explored. This study aims to describe the therapeutic management of patients with prostate cancer and assess their sexual desire 2 years after diagnosis. METHODS: This study is part of the National VICAN survey (Vie apres le CANcer) implemented in France in 2012. This analysis was performed on a population of 414 men who had prostate cancer. The questionnaire dealt with several topics including socioeconomic status, treatments received, and sexual desire. RESULTS: Prostatectomy (42.8%), radiotherapy + hormonotherapy (17.6%), and radiotherapy alone (12.8%) were the main treatments used. 41.3% of men stated that their sexual desire was all gone since disease. The "satisfying" perceived financial situation was significantly associated to a sexual desire loss (p = 0.008). Radiotherapy + hormonotherapy treatment only is significantly associated with a loss of sexual desire (P = 0.003). CONCLUSIONS: Two years after diagnosis, the sexual desire of prostate cancer survivors is deteriorated with the cancer experience. However, clinical characteristics do not seem to be decisive unlike a "satisfying" financial situation. Research about the impact of socio economics characteristics on sexual health should probably be engaged. Programs have to be developed in France to have personalized sexual support progressed for survivors and take spouses into consideration in this context. PMID- 30411240 TI - Enhanced Understanding of Pharmaceutical Materials Through Advanced Characterisation and Analysis. AB - The impact of pharmaceutical materials properties on drug product quality and manufacturability is well recognised by the industry. An ongoing effort across industry and academia, the Manufacturing Classification System consortium, aims to gather the existing body of knowledge in a common framework to provide guidance on selection of appropriate manufacturing technologies for a given drug and/or guide optimization of the physical properties of the drug to facilitate manufacturing requirements for a given processing route. Simultaneously, material scientists endeavour to develop characterisation methods such as size, shape, surface area, density, flow and compactibility that enable a stronger understanding of materials powder properties. These properties are routinely tested drug product development and advances in instrumentation and computing power have enabled novel characterisation methods which generate larger, more complex data sets leading to a better understanding of the materials. These methods have specific requirements in terms of data management and analysis. An appropriate data management strategy eliminates time-consuming data collation steps and enables access to data collected for multiple methods and materials simultaneously. Methods ideally suited to extract information from large, complex data sets such as multivariate projection methods allow simpler representation of the variability contained within the data and easier interpretation of the key information it contains. In this review, an overview of the current knowledge and challenges introduced by modern pharmaceutical material characterisation methods is provided. Two case studies illustrate how the incorporation of multivariate analysis into the material sciences workflow facilitates a better understanding of materials. PMID- 30411241 TI - [Adjuvant chemotherapy with cisplatin and gemcitabine after radiochemotherapy with curative intent does not improve relapse-free survival in nasopharyngeal cancer patients with persistently detectable EBV DNA]. PMID- 30411239 TI - Finding My Way: results of a multicentre RCT evaluating a web-based self-guided psychosocial intervention for newly diagnosed cancer survivors. AB - PURPOSE: This multicentre randomised controlled trial examined the efficacy of Finding My Way (FMW), a 6-week/6-module online self-guided psychotherapeutic intervention for newly diagnosed curatively treated cancer survivors, in reducing cancer-related distress and improving quality of life compared to an online attention control. METHODS: Participants were randomised on a 1:1 ratio using a gender-stratified block design to intervention (n = 94) or attention control (n = 97), and were blinded to condition. Assessments were completed at baseline (T0), post-intervention (T1), 3 months (T2), and 6 months (T3) post-intervention. Mixed model repeated measures analyses examined differences between groups for cancer specific distress (primary outcome) and general distress, quality of life (QoL), coping, and health service utilisation (secondary outcomes). RESULTS: While both groups reported reduced cancer-specific and general distress over time, between group differences were not significant. Intervention participants reported lower total health service utilisation and supportive care utilisation post intervention than controls (total HS use: between-group mean difference = - 1.07 (- 1.85 to - 0.28); supportive care use: between-group mean difference = - 0.64 ( 1.21 to - 0.06)) and significantly higher emotional functioning at 3 months (between-group mean difference = 7.04 (0.15 to 13.9)). At 6 months, the supportive care utilisation finding reversed (between-group mean difference = 0.78 points (0.19 to 1.37). Across remaining QoL and coping outcomes, no significant group differences emerged. CONCLUSIONS: While both groups experienced reductions in distress, between-group differences were not significant. This contrasts with the significantly improved emotional functioning observed in FMW participants at 3 months and the short-term reductions in health service utilisation. Long-term increases in supportive care service utilisation suggest FMW only met needs while being actively used. TRIAL REGISTRATION: ACTRN12613000001796; http://www.ANZCTR.org.au/ACTRN12613000001796.aspx. PMID- 30411242 TI - CYP2D6 as a treatment decision aid for ER-positive non-metastatic breast cancer patients: a systematic review with accompanying clinical practice guidelines. AB - PURPOSE: Tamoxifen is one of the principal treatments for estrogen receptor (ER) positive breast cancer. Unfortunately, between 30 and 50% of patients receiving this hormonal therapy relapse. Since CYP2D6 genetic variants have been reported to play an important role in survival outcomes after treatment with tamoxifen, this study sought to summarize and critically appraise the available scientific evidence on this topic. METHODS: A systematic literature review was conducted to identify studies investigating associations between CYP2D6 genetic variation and survival outcomes after tamoxifen treatment. Critical appraisal of the retrieved scientific evidence was performed, and recommendations were developed for CYP2D6 genetic testing in the context of tamoxifen therapy. RESULTS: Although conflicting literature exists, the majority of the current evidence points toward CYP2D6 genetic variation affecting survival outcomes after tamoxifen treatment. Of note, review of the CYP2D6 genotyping assays used in each of the studies revealed the importance of comprehensive genotyping strategies to accurately predict CYP2D6 metabolizer phenotypes. CONCLUSIONS AND RECOMMENDATIONS: Critical appraisal of the literature provided evidence for the value of comprehensive CYP2D6 genotyping panels in guiding treatment decisions for non-metastatic ER positive breast cancer patients. Based on this information, it is recommended that alternatives to standard tamoxifen treatments may be considered in CYP2D6 poor or intermediate metabolizers. PMID- 30411244 TI - Postoperative MRI findings 5 years after lumbar microdiscectomy. AB - BACKGROUND: Lumbar microdiscectomy is a common procedure with satisfactory results; however, postoperative events like progressive adjacent level degeneration and perineural fibrosis can contribute to long-term pain. The purpose of the study was to evaluate MRI changes 5 years after lumbar microdiscectomy and assess their association with clinical parameters. MATERIALS AND METHODS: A prospective study enrolling 61 patients who underwent microdiscectomy. Changes between preoperative and postoperative MRI findings were recorded, and these findings were tested for associations with demographic, clinical and perioperative parameters. The measured imaging parameters were degeneration of the operated and adjacent discs and endplates, morphology of the disc herniation, facet joints arthritis and the presence of postoperative perineural fibrosis. RESULTS: Statistically significant differences were found between preoperative and postoperative morphology of the operated disc, facet joints arthritis and degeneration of the operated and caudal adjacent disc. There were no differences between preoperative and postoperative disc degeneration of the superior adjacent disc and in degeneration of the operated and adjacent endplates. Postoperatively perineural fibrosis was common; however, thecal sac compression and nerve root impingement were reduced. Age at the time of surgery was the only parameter associated with postoperative changes. CONCLUSION: Five years after microdiscectomy, several postoperative MRI changes including operated disc's morphology, facet joints arthritis and degeneration of the operated and caudal adjacent disc were shown. Taking into consideration that participants were on average middle-aged, these changes could be attributed not only to the impact of the surgery but also to the natural history of lumbar spine degeneration. PMID- 30411243 TI - Mean arterial pressure and mortality in patients with distributive shock: a retrospective analysis of the MIMIC-III database. AB - BACKGROUND: Maintenance of mean arterial pressure (MAP) at levels sufficient to avoid tissue hypoperfusion is a key tenet in the management of distributive shock. We hypothesized that patients with distributive shock sometimes have a MAP below that typically recommended and that such hypotension is associated with increased mortality. METHODS: In this retrospective analysis of the Medical Information Mart for Intensive Care (MIMIC-III) database from Beth Israel Deaconess Medical Center, Boston, USA, we included all intensive care unit (ICU) admissions between 2001 and 2012 with distributive shock, defined as continuous vasopressor support for >= 6 h and no evidence of low cardiac output shock. Hypotension was evaluated using five MAP thresholds: 80, 75, 65, 60 and 55 mmHg. We evaluated the longest continuous episode below each threshold during vasopressor therapy. The primary outcome was ICU mortality. RESULTS: Of 5347 patients with distributive shock, 95.7%, 91.0%, 62.0%, 36.0% and 17.2%, respectively, had MAP < 80, < 75, < 65, < 60 and < 55 mmHg for more than two consecutive hours. On average, ICU mortality increased by 1.3, 1.8, 5.1, 7.9 and 14.4 percentage points for each additional 2 h with MAP < 80, < 75, < 65, < 60 and < 55 mmHg, respectively. Multivariable logistic modeling showed that, compared to patients in whom MAP was never < 65 mmHg, ICU mortality increased as duration of hypotension < 65 mmHg increased [for > 0 to < 2 h, odds ratio (OR) 1.76, p = 0.005; >= 6 to < 8 h, OR 2.90, p < 0.0001; >= 20 h, OR 7.10, p < 0.0001]. When hypotension was defined as MAP < 60 or < 55 mmHg, the associations between duration and mortality were generally stronger than when hypotension was defined as MAP < 65 mmHg. There was no association between hypotension and mortality when hypotension was defined as MAP < 80 mmHg. CONCLUSIONS: Within the limitations due to the nature of the study, most patients with distributive shock experienced at least one episode with MAP < 65 mmHg lasting > 2 h. Episodes of prolonged hypotension were associated with higher mortality. PMID- 30411245 TI - Early clinical and radiological outcomes for the Taperloc Complete Microplasty stem. AB - The use of short stem designs in total hip arthroplasty is not a new concept, but its popularity has increased as a bone-sparing alternative to traditional stems. This study analyzed the midterm clinical and radiological results of the Taperloc Complete Microplasty stem (Zimmer Biomet(r) Warsaw, IN, USA). A total of 32 patients (20 men and 12 women) were retrospectively documented and received 40 stems (eight bilateral). The median patient age was 50 years (interquartile range 43-58) at the time of surgery. The median follow-up was 36.5 months (interquartile range 26.75-50.25). Indication for total hip arthroplasty was osteoarthritis (62.5% of patients), avascular necrosis (25%), and developmental dysplasia of the hip (12.5%). The Merle d'Aubigne score improved from a mean 11.5 preoperatively to a mean 17.5 at the latest follow-up. During X-ray assessment, we observed one subsidence of the stem (3 mm) and four cases of varus malalignment without clinical consequences. No cases of osteolysis were reported, and no stems were revised. According to our results, this short tapered stem shows a good early-term outcome. Prospective results and a longer follow-up are needed to assess the long-term survival of this stem fully. PMID- 30411246 TI - Clinical impact of disinvestment in hydroxyethyl starch for patients undergoing coronary artery bypass surgery: a retrospective observational study. AB - PURPOSE: To examine the effect of discontinuing hydroxyethyl starch (HES) solutions on length of hospital stay, transfusion, risk of death, acute kidney injury (AKI), and dialysis. METHODS: We conducted a historical cohort study of linked administrative and clinical databases in patients undergoing coronary artery bypass surgery (CABG) on cardiopulmonary bypass. We used propensity scores to match patients who did not receive HES (after discontinuation) with patients exposed to HES (before discontinuation) and also controlled for albumin exposure. Hospital length of stay (the primary outcome) was analyzed using Fine-Gray proportional hazard regression, with hospital discharge as the outcome and death as a competing risk. Adverse outcomes were compared between matched patients using conditional logistic regression. RESULTS: We compared 1,085 propensity score-matched pairs (n = 2,170) from a pool of 2,757 patients. Discontinuation of HES was associated with shorter length of hospital stay, as evidenced by an increased probability of discharge (hazard ratio, 1.24; 95% confidence interval [CI], 1.14 to 1.35) and a reduced risk of red blood cell transfusion (odds ratio [OR], 0.68; 95% CI, 0.55 to 0.84), plasma transfusion (OR, 0.48; 95% CI, 0.34 to 0.66), and platelet transfusion (OR, 0.62; 95% CI, 0.44 to 0.87). Discontinuation of HES was not associated with in-hospital mortality (OR, 0.74; 95% CI, 0.36 to 1.54), AKI (OR, 0.84; 95% CI, 0.57 to 1.25), or dialysis (OR, 0.83; 95% CI, 0.25 to 2.73). CONCLUSIONS: For patients undergoing CABG on cardiopulmonary bypass, discontinuation of HES was associated with reduced hospital length of stay and reduced blood product transfusion, without measurable change in renal failure, dialysis rate, or in-hospital mortality. Our results should be interpreted with caution, though we found no evidence of harms associated with discontinuing HES. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT02329158); registered 31 December, 2014. PMID- 30411247 TI - Cervical disc herniation: which surgery? AB - PURPOSE: Cervical disc herniation is a common pathology. It can be treated by different surgical procedures. We aimed to list and analyzed every available surgical option. We focused on the comparison between anterior cervical decompression and fusion and cervical disc arthroplasty. RESULTS: The anterior approach is the most commonly used to achieve decompression and fusion by the mean of autograft or cage that could also be combined with anterior plating. Anterior procedures without fusion have shown good outcomes but are limited by post-operative cervicalgia and kyphotic events. Posterior cervical foraminotomy achieved good outcomes but is not appropriate in a case of a central hernia or ossification of the posterior ligament. Cervical disc arthroplasty is described to decrease the rate of adjacent segment degeneration. It became very popular during the last decades with numerous studies with different implant device showing encouraging results but it has not proved its superiority to anterior cervical decompression and fusion. Anterior bone loss and heterotopic ossification are still to be investigated. CONCLUSION: Anterior cervical decompression and fusion remain the gold standard for surgical treatment of cervical disc herniation. PMID- 30411248 TI - Fourteen-year experience with short cemented stems in total hip replacement. AB - PURPOSE: The age of the population requiring total hip replacement (THR) is increasing and this may lead to a return of cemented stems. Advantages of a short cemented femoral device include preservation of metaphyseal bone, easier insertion, and easier cement removal in case of revision. The purpose of this study is to describe the rationale and assess midterm results of unique innovative short cemented double-tapered polished stem applied with contemporary cementing techniques. METHODS: Our experience with this short cemented stem includes two different groups of elderly patients. Group 1 (prototype version of the short stem) from January 2005 to January 2008 counts 43 THR. Group 2 (final commercial version of the short stem) from January 2013 to January 2015 counts 54 THR. The average age in groups 1 and 2 was 79 and 75 respectively. Patients underwent clinical follow-up with the Harris Hip Score (HHS) and completed radiographic evaluation. RESULTS: Thirty-one patients of group 1 had died for reasons unrelated to their THR. The surviving 9 hips have a follow-up of 11.2 years. In group 2, eight patients died for reasons unrelated to their THR. Follow-up for the surviving 40 patients is 4.6 years. HHS improved in both groups. In 34/43 hips of group 1 and in 41/54 of group 2 we observed a Barrack grade A cement mantle. Survival with revision of the stem for aseptic loosening as the endpoint was 100%. CONCLUSIONS: This study confirms the effectiveness of a short, polished, collarless, tapered cemented stem implanted with contemporary cementing techniques which appears as successful as the standard sized components. PMID- 30411249 TI - Climate conditions and work-related fatigue among professional drivers. AB - The possible associations between climate parameters and drivers' fatigue have not been subject to specific studies thus far. We have undertaken a study to investigate whether the particular climate parameters are related to fatigue perception by motor vehicle drivers. The study was performed from July to October. Each driver was surveyed four times: before and after workshift on a monotonous route outside the city center (MR), and on a heavy traffic route in the city center (HTR). The study was conducted among 45 city bus drivers aged 31 58 years (43.7 +/- 7.9), seniority as driver 3-34 years (14.7 +/- 8.6). Data on climate conditions (ambient temperature, air pressure, humidity, wind speed, precipitations) on particular study days was obtained from the Institute of Meteorology and Water Management, National Research Institute Warsaw, Poland. Fatigue was assessed using the Fatigue Assessment Questionnaire, developed at Nofer Institute of Occupational Medicine (Lodz, Poland). The total level of fatigue was significantly (p = 0.045) higher after driving on HTR than on MR. The number of symptoms was also significantly higher (p < 0.05) among drivers working on HTR. After MR, significant correlations were found between wind speed and heavy eyelid feeling, being prone to forgetting, eye strain, frequent blinking, and between ambient temperature and feeling thirsty. After HTR feeling thirsty, tiredness and difficulty in making decisions correlated with ambient temperature and feeling thirsty with wind speed. Climate conditions can modify the drivers fatigue; therefore, we should be aware of their impact on well-being. PMID- 30411250 TI - Extreme temperature and mortality: evidence from China. AB - The frequency, intensity, and duration of extreme temperature events are expected to rise in the future and increase the related health risks of human beings. Using a novel, nationwide dataset that links extreme temperature and mortality, we estimated the short-term and long-term effects of extreme temperature on mortality in China during 2002-2013. Both extreme hot and extreme cold had immediate and long-term effects on all-cause mortality. Annual deaths per 100,000 people due to extreme hot and cold in the long term were considerably larger compared to the short term. The change in cold spell duration indicator exhibited the greatest effects on annual deaths per 100,000 people among a set of extreme weather indicators. Furthermore, cities with low economic development levels were more vulnerable to extreme temperature, compared to cities with high economic development levels. Our results offer important policy implications for developing a regional-specific extreme weather plan to handle extreme temperature events in China. PMID- 30411251 TI - Deterministic and Stochastic Models of Arabidopsis thaliana Flowering. AB - Experimental studies of the flowering of Arabidopsis thaliana have shown that a large complex gene regulatory network (GRN) is responsible for its regulation. This process has been mathematically modelled with deterministic differential equations by considering the interactions between gene activators and inhibitors (Valentim et al. in PLoS ONE 10(2):e0116973, 2015; van Mourik et al. in BMC Syst Biol 4(1):1, 2010). However, due to complexity of the model, the properties of the network and the roles of the individual genes cannot be deducted from the numerical solution the published work offers. Here, we propose simplifications of the model, based on decoupling of the original GRN to motifs, described with three and two differential equations. A stable solution of the original model is sought by linearisation of the original model which contributes to further investigation of the role of the individual genes to the flowering. Furthermore, we study the role of noise by introducing and investigating two types of stochastic elements into the model. The deterministic and stochastic nonlinear dynamic models of Arabidopsis flowering time are considered by following the deterministic delayed model introduced in Valentim et al. (2015). Steady-state regimes and stability of the deterministic original model are investigated analytically and numerically. By decoupling some concentrations, the system was reduced to emphasise the role played by the transcription factor Suppressor of Overexpression of Constants1 ([Formula: see text]) and the important floral meristem identity genes, Leafy ([Formula: see text]) and Apetala1 ([Formula: see text]). Two-dimensional motifs, based on the dynamics of [Formula: see text] and [Formula: see text], are obtained from the reduced network and parameter ranges ensuring flowering are determined. Their stability analysis shows that [Formula: see text] and [Formula: see text] are regulating each other for flowering, matching experimental findings. New sufficient conditions of mean square stability in the stochastic model are obtained using a stochastic Lyapunov approach. Our numerical simulations demonstrate that the reduced models of Arabidopsis flowering time, describing specific motifs of the GRN, can capture the essential behaviour of the full system and also introduce the conditions of flowering initiation. Additionally, they show that stochastic effects can change the behaviour of the stability region through a stability switch. This study thus contributes to a better understanding of the role of [Formula: see text] and [Formula: see text] in Arabidopsis flowering. PMID- 30411252 TI - Stochastic Mechanochemical Description of a Bioinspired Polymerization Process. AB - We present a theoretical investigation of a polymerization process catalyzed by an enzyme. A structural model of enzyme, sliding along the polymer chain as a Brownian particle, is proposed, and a stochastic approach is employed to describe the kinetics of the whole process. The key point of this work is the coupling mechanics/chemistry obtained by assuming that (1) some rates of chemical reaction depend on the position of the enzyme with respect to the polymer chain and (2) the potential energy and the friction coefficient in the Langevin equation depend on the chemical state of the polymerizing complex. We describe an algorithm for computing our stochastic model and a methodology to solve the Langevin equation numerically. We predict in particular: (1) the sudden arrest of the polymerization, (2) the decrease in the relative polydispersity with the increase in the length of the polymer chain, (3) the occurrence of four regimes, (4) the manifestation of the coupling mechanics/chemistry for one regime and (5) the possibility to evaluate the mechanical variables through classical chemical analysis. Although essentially devoted to the elongation phase, this work also briefly addresses the problem of phase termination and we propose a new device aimed at reducing the polydispersity of technical origin in actual polymerization processes. PMID- 30411253 TI - CAD/CAM implant surgical guides: maximum errors in implant positioning attributable to the properties of the metal sleeve/osteotomy drill combination. AB - BACKGROUND: The purpose of this study is to provide the relevant equations and the reference tables needed for calculating the maximum errors in implant positioning attributed to the properties of the mechanical parts of any CAD/CAM implant surgical guide, especially the in-office manufactured ones. METHODS: An algorithm was developed and implemented in C programming language in order to accurately calculate the maximum error at the apex, error at the neck, vertical error at the apex and deviation of implant axis, between the planned and the actual implant position. The calculations were based on the parameters of total length (= implant length + offset), offset (distance from neck of implant to the lip of the metal sleeve), clearance (space between the bur and the sleeve), sleeve length. The variability of the parameters was constrained: (1) implant length, 8-18 mm; (2) sleeve length, 4-7 mm; (3) clearance, 50-410 MUm; and (4) offset values, 6-17 mm. Multiple regression analysis was conducted to quantify the relationship between the error at the apex and the error at the neck and various predictors. RESULTS: The equations used for the bespoke estimation of the errors in implant positioning along with three reference tables of the various errors tabulated are presented. The maximum error at the apex of the implant was computed 2.8 mm, the maximum deviation of the implant axis 5.9 degrees and the maximum error at the neck (entrance) of the implant was estimated 1.5 mm. The vertical error between the planned and actual implant position can be considered negligible (< 0.1 mm). CONCLUSIONS: The results of this study compute part of the expected differences in final clinical implant position when any CAD/CAM surgical guide is used. Given that the implantologist, with the capability of an in-office digital designed and 3d printed surgical guide, can readily decide upon the dimensions of the metal sleeve, the clearance between the osteotomy bur and the sleeve, and the design of the guide in relation to the distance of the lip of the sleeve to the implant neck (offset), in order to minimise the inevitable errors. PMID- 30411254 TI - Prostaglandin E2/EP2 receptor signalling pathway promotes diabetic retinopathy in a rat model of diabetes. AB - AIMS/HYPOTHESIS: Diabetic retinopathy is a common microvascular complication of diabetes mellitus and is initiated by inflammation and apoptosis-associated retinal endothelial cell damage. Prostaglandin E2 (PGE2) has emerged as a critical regulator of these biological processes. We hypothesised that modulating PGE2 and its E-prostanoid receptor (EP2R) would prevent diabetes mellitus-induced inflammation and microvascular dysfunction. METHODS: In a streptozotocin (STZ) induced rat model of diabetes, rats received intravitreal injection of PGE2, butaprost (a PGE2/EP2R agonist) or AH6809 (an EP2R antagonist). Retinal histology, optical coherence tomography, ultrastructure of the retinal vascular and biochemical markers were assessed. RESULTS: Intravitreal injection of PGE2 and butaprost significantly accelerated retinal vascular leakage, leucostasis and endothelial cell apoptosis in STZ-induced diabetic rats. This response was ameliorated in diabetic rats pre-treated with AH6809. In addition, pre-treatment of human retinal microvascular endothelial cells with AH6809 attenuated PGE2- and butaprost-induced activation of caspase 1, activation of the complex containing nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) and apoptosis-associated speck-like protein containing a C terminal caspase-activation and recruitment domain (ASC), and activation of the EP2R-coupled cAMP/protein kinase A/cAMP response element-binding protein signalling pathway. CONCLUSIONS/INTERPRETATION: The PGE2/EP2R signalling pathway is involved in STZ-induced diabetic retinopathy and could be considered as a potential target for diabetic retinopathy prevention and treatment. PMID- 30411255 TI - Physicochemical Characterization and Pharmacokinetics of Agomelatine-Loaded PLGA Microspheres for Intramuscular Injection. AB - PURPOSE: The aim of this study was to design agomelatine loaded long acting injectable microspheres, with an eventual goal of reducing the frequency of administration and improving patient compliance in treatment of depression. METHODS: AGM-loaded microspheres were prepared by an O/W emulsion solvent evaporation method. The physicochemical properties and in vitro performance of the microspheres were characterized. The pharmacokinetics of different formulations with various particle sizes and drug loadings were evaluated. RESULTS: AGM-loaded microspheres with drug loading of 23.7% and particle size of 60.2 MUm were obtained. The in vitro release profiles showed a small initial burst release (7.36%) followed by a fast release, a period of lag time and a second accelerated release. Pore formation and pore closure were observed in vitro, indicating that the release of drug from microspheres is dominated by water-filled pores. Pharmacokinetic studies showed that AGM microspheres could release up to 30 days in vivo at a steady plasma concentration. As well, particle size and drug loading could significantly influence the in vivo release of AGM microspheres. CONCLUSIONS: AGM-loaded microspheres are a promising carrier for the treatment of major depressant disorder. PMID- 30411257 TI - Epigenetic and Pluripotency Aspects of Disseminated Cancer Cells During Minimal Residual Disease. AB - Our understanding of the minimal residual disease (MRD) in solid cancers indicates that it can persist in the system for years or even decades. We now know that the persistence of MRD might depend on the dormancy of the disseminated cancer cells (DCCs). Once DCCs exit dormancy, they become metastatic and the survival rates of the patients inevitably decrease. Thus, innovative treatments are required to extend the asymptomatic phase of MRD after the initial therapeutic intervention. With the latest advances in cancer research, there is a greater need to explore and understand the biology, timing of dissemination, and origin of DCCs during tumor progression. These important aspects of DCCs impact the selection, design, administration, and timing of effective therapies. Herein, we summarize the current understanding of MRD biology in solid tumors, with a focus on epigenetics and pluripotency, presenting an overall view of the direction the field is taking to reach the goal of reducing cancer-related mortalities that result from metastasis. PMID- 30411256 TI - On the p-AlGaN/n-AlGaN/p-AlGaN Current Spreading Layer for AlGaN-based Deep Ultraviolet Light-Emitting Diodes. AB - In this report, AlGaN-based deep ultraviolet light-emitting diodes (DUV LEDs) with different p-AlGaN/n-AlGaN/p-AlGaN (PNP-AlGaN) structured current spreading layers have been described and investigated. According to our results, the adopted PNP-AlGaN structure can induce an energy barrier in the hole injection layer that can modulate the lateral current distribution. We also find that the current spreading effect can be strongly affected by the thickness, the doping concentration, the PNP loop, and the AlN composition for the inserted n-AlGaN layer. Therefore, if the PNP-AlGaN structure is properly designed, the forward voltage, the external quantum efficiency, the optical power, and the wall-plug efficiency for the proposed DUV LEDs can be significantly improved as compared with the conventional DUV LED without the PNP-AlGaN structure. PMID- 30411258 TI - Anti-angiogenic Therapy-Mediated Endothelial Damage: A Driver of Breast Cancer Recurrence? AB - Anti-angiogenic therapy was conceived originally as a silver bullet able to maintain tumor dormancy indefinitely. By targeting new blood vessel formation, anti-angiogenic agents were expected to suppress the growth of any type of primary or metastatic tumor, independent of their subtype or genetic landscape. However, more that 20 years after the first anti-angiogenic preclinical trial, the astonishing inhibition of metastatic outgrowth originally observed in mouse models never translated into clinics. Indeed, whereas anti-angiogenic agents (sometimes) prolong progression-free survival, they fail to impact overall survival, particularly in breast cancer. This observation revealed to be true in early- and advanced-stage breast cancer patients treated either in adjuvant or neo-adjuvant settings, suggesting that the effect of anti-angiogenic therapy on repressing growth of overt metastases - and also on preventing outgrowth of disseminated tumor cells and micrometastases - is limited. What are the reasons underlying this failure? And, more importantly, is there still room for improvement? PMID- 30411259 TI - Minimal Residual Disease in Prostate Cancer. AB - Detection of minimal residual disease (MRD) in prostate cancer over several decades has greatly informed our understanding of dissemination and recurrence, but has not yet been routinely used in clinical care. Investigators have detected MRD by identification of prostate cancer cells in the bone marrow; termed disseminated tumor cells (DTCs) and blood; termed circulating tumor cells (CTCs). Various techniques including PSA-RT PCR, PSA immunocytochemistry, cytokeratin immunocytochemistry, and immune-magnetic depletion of hematopoietic cells followed by EPCAM based positive selection, have been used. Importantly, detection of DTCs correlates with recurrence. Research into prostate cancer CTCs has intensified recently, but their use in MRD evaluation has been more limited. Investigators are using semi-automated platforms to detect and begin to study prostate cancer CTCs in patients with no evidence of disease. PSA immunocytochemistry also detects CTCs and correlates with recurrence. Emerging technologies have the potential to greatly aid research in this exciting field. PMID- 30411260 TI - Minimal Residual Disease in Head and Neck Cancer and Esophageal Cancer. AB - Malignant epithelial tumors of the upper digestive tract are a major cause of cancer-related death worldwide. The most common of these cancers are head and neck squamous cell carcinomas (HNSCC) and esophageal cancers (EC), which are both characterized by early dissemination and poor prognosis. Although patients with early detected cancers can be subjected to multimodal therapies with curative intention, they are endangered by lethal relapses that frequently occur. These relapses originate from minimal residual cancer (MRD) cells that can only be traced by highly sensitive molecular methods as rare disseminated tumor cells (DTC). The aim of this chapter is to comprehensively inform the reader about the detection, the mode of spread, the clinical relevance, and the biology of DTCs in HNSCC and EC. A better understanding of DTCs will be key to suppress progression of the upper digestive tract cancers more effectively. PMID- 30411261 TI - Detection of Minimal Residual Disease and Its Clinical Applications in Melanoma and Breast Cancer Patients. AB - Melanoma and breast cancer (BC) patients face a high risk of recurrence and disease progression after curative surgery and/or therapeutic treatment. Monitoring for minimal residual disease (MRD) during a disease-free follow-up period would greatly improve patient outcomes through earlier detection of relapse or treatment resistance. However, MRD monitoring in solid tumors such as melanoma and BC are not well established. Here, we discuss the clinical applications of MRD monitoring in melanoma and BC patients and highlight the current approaches for detecting MRD in these solid tumors. PMID- 30411262 TI - Preservation of Quiescent Chronic Myelogenous Leukemia Stem Cells by the Bone Marrow Microenvironment. AB - The majority of leukemia patients achieving remission ultimately relapse. Persistence of leukemia stem cells (LSC) capable of regenerating leukemia is a major cause of relapse. There is a pressing need to better understand mechanisms of LSC regulation and their resistance to therapy in order to improve outcomes for leukemia. Chronic myelogenous leukemia (CML) is a lethal myeloproliferative disorder that that is caused by hematopoietic stem cell (HSC) transformation by the BCR-ABL tyrosine kinase. Treatment with tyrosine kinase inhibitors (TKI) has revolutionized CML treatment, but fails to eliminate LSC responsible for propagating and regenerating leukemia. Therefore, patients require continued treatment to prevent relapse. Leukemic and normal stem cells share properties of quiescence and self-renewal, that are supported by bone marrow niches. Persistence of LSC after TKI treatment is related to tyrosine kinase independent mechanisms which include intrinsic properties of LSCs determined by epigenetic alterations, altered transcriptional regulatory networks or mitochondrial/metabolic changes. In addition to cell intrinsic changes, signals from the bone marrow microenvironment (BMM) play a critical role in protecting LSC from TKI treatment. Each type of alteration may offer potential points of intervention for therapeutic targeting of LSC. PMID- 30411263 TI - Minimal Residual Disease in Acute Myeloid Leukemia. AB - Monitoring measurable (minimal) residual disease (MRD) in acute myeloid leukemia (AML) has greatly increased our ability to assess chemosensisitivity to treatment as well as the duration of treatment responses. There is strong evidence to support its prognostic value for long-term outcomes at different time points and across assays and targets. It's role as a surrogate endpoint to define risk adapted strategies is still under evaluation. In this chapter, we will discuss the definition of MRD in AML, the potential contribution of leukemia stem cells (LSCs) to MRD and we will review all the current approaches to assess residual disease including the 2018 European Leukemia Network (ELN) working group recommendations for MRD standardization in AML. In addition, a summary of MRD studies associated to prognosis will be described. PMID- 30411264 TI - Characteristics and Therapeutic Targeting of Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia. AB - Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Early response to therapy, especially the measurement of minimal residual disease (MRD), remains the most reliable and strongest independent prognostic parameter. Intriguingly, little is known on the mechanisms sustaining MRD in that disease. Here, we summarize existing evidence on the influences of molecular genetics and clonal architecture of childhood ALL on disease persistence. Also, the impact of the leukemic niche on residual leukemia cells in the bone marrow and extramedullary compartments is reviewed. We further discuss existing in vivo models of minimal residual disease based on different cellular labelling strategies and engraftment of ALL cells in immunodeficient mouse strains. We finally draw some conclusions on potential strategies targeting residual ALL cells, with a focus on cellular and antibody-based immunotherapy. PMID- 30411265 TI - Minimal Residual Disease in Multiple Myeloma: Impact on Response Assessment, Prognosis and Tumor Heterogeneity. AB - Multiple Myeloma (MM) therapy has evolved rapidly over the past decade. With current multidrug combinations and autologous transplant, rates of overall response exceed 90% and complete response (CR) more than 50% in some studies. Unfortunately, despite higher rates of CR, relapse rates remain high suggesting that persistent disease may not be measured by current techniques. Traditionally, response rates were defined by urine and serum protein electrophoresis, immunofixation and histopathological absence of clonal plasma cells in the bone marrow. Currently, there are several validated sensitive assays to evaluate for MRD (minimal residual disease); multiparameter flow cytometry (MFC) including nextgeneration flow cytometry (NGF), next-generation sequencing (NGS), and allele specific oligonucleotide quantitative polymerase chain reaction (ASO-qPCR). These methods have provided a means to quantitatively assess residual disease and accurately prognosticate PFS and OS in myeloma. In this chapter, we will discuss the current techniques for MRD detection as well as describe techniques that are emerging for improved characterization of drug resistant residual populations that could be adapted for MRD monitoring in the future. While improved therapies are able to eradicate the dominant clone, resistant sub-clones persist and remain undetectable even by MRD techniques. Characterization of these clones will help design therapies against drug-resistant clones and move us closer to a cure in MM. PMID- 30411267 TI - Comprehensive Lateral Neck Dissection in Papillary Thyroid Carcinoma may Reduce Lateral Neck Recurrence Rates. AB - OBJECTIVE: To Identify predictors of recurrent disease following lateral neck dissection (LND) for papillary thyroid carcinoma (PTC). METHODS: A retrospective review of patients who underwent first-time LND for PTC at our institution (2000 2015) was performed. Medical records were examined for biopsy or pathologically proven lateral neck recurrence. Differences between the groups with and without recurrence were compared. All LNDs were then classified in to two groups: "comprehensive" (CND), involving levels IIa-Vb at minimum, or "selective", labelling less extensive dissection (SND). RESULTS: Four hundred nine patients underwent 467 LNDs. Surveillance data were available for 317 patients who underwent 362 LNDs (mean age 45 +/- 16; range 18-88). The median follow-up was 64 +/- 48 months (range 3-197). Recurrence was detected in 71 lateral necks (20%). The total number of lymph nodes was greater in the group without recurrence compared to those with recurrence (23 vs. 19, p = 0.02). Among patient demographics, radioactive iodine treatment, primary tumor characteristics and characteristics of nodal metastases, only an older patient age (mean 50 vs. 43 years) was associated with lateral neck recurrence (p < .01). CND was performed in 102 lateral necks and SND in 143 necks. There were 12 recurrences recorded in the CND group (12%) vs. 31 in the SND group (22%, p = .04). The majority of recurrences (70%) involved levels included in the original dissection. CONCLUSIONS: Younger patients, more extensive dissection and a higher total number of lymph nodes removed are associated with a lower incidence of lateral neck recurrence after LND for papillary thyroid carcinoma. PMID- 30411268 TI - ASO Author Reflections: The Future of Isolated Limb Perfusion. PMID- 30411269 TI - ASO Author Reflections: Recurrence Predictors in Mucinous Appendiceal Tumors. PMID- 30411270 TI - ASO Author Reflections: Tailoring of Targeted Axillary Dissection-Intraoperative Nodal Evaluation Reduces Second Operations. PMID- 30411271 TI - ASO Author Reflections: Low-Volume Sentinel Node Disease After Neoadjuvant Chemotherapy is Still an Indication for Axillary Dissection. PMID- 30411272 TI - An Overview of Bundled Payments for Surgical Oncologists: Origins, Progress to Date, Terminology, and Future Directions. PMID- 30411273 TI - Establishment of novel patient-derived models of dermatofibrosarcoma protuberans: two cell lines, NCC-DFSP1-C1 and NCC-DFSP2-C1. AB - Dermatofibrosarcoma protuberans (DFSP) is a common type of dermal sarcoma, characterized by the presence of the unique collagen type I alpha 1 chain (COL1A1)-PDGFB translocation, which causes constitutive activation of the platelet-derived growth factor beta (PDGFB) signaling pathway. Patients with DFSP exhibit frequent local recurrence, and novel therapeutic approaches are required to achieve better clinical outcomes. Patient-derived cancer cell lines are essential in the preclinical research. Here, we established novel patient-derived DFSP cell lines from two patients with DFSP and designated these cell lines NCC DFSP1-C1 and NCC-DFSP2-C1. Tumors of the two patients with DFSP had COL1A1-PDGFB translocations with distinct COL1A1 breakpoints, e.g., in exons 33 and 15, and the translocations were preserved in the established cell lines. NCC-DFSP1-C1 and NCC-DFSP2-C1 cells exhibited similar morphology and limited capability of proliferation in vitro, forming spheroids when seeded on low-attachment tissue culture plates. In contrast, NCC-DFSP1-C1 cells had considerably higher invasive capability than NCC-DFSP2-C1 cells. Overall proteome contents were similar between NCC-DFSP1-C1 and NCC-DFSP2-C1 cells. Notably, in vitro screening studies identified anticancer drugs that showed antiproliferative effects at considerably low concentrations in the DFSP cell lines. Bortezomib, mitoxantrone, ponatinib, and romidepsin were more cytotoxic to NCC-DFSP1-C1 cells than to NCC-DFSP2-C1 cells. These cell lines will be useful tools for developing novel therapeutic strategies to treat DFSP. PMID- 30411274 TI - Concentrations, Sources, and Risk Assessment of Organohalogen Compounds in Soils from Kiambu to Mombasa, Kenya. AB - Concentrations, sources, and risk assessment of 16 organochlorinated pesticides (OCPs), seven polychlorinated biphenyls (PCBs) and seven polybrominated diphenyl ethers (PBDEs) were determined in soils from Kiambu to Mombasa in Kenya. The total concentrations of OCPs ranged between 7.62 and 76.09 ng/g, dominated by HCHs. Source identification displayed recent inputs and historical use of DDTs and lindane. The total concentrations of PCBs ranged from 9.90 to 20.8 ng/g with an average of 14.40 ng/g dominated by penta-PCBs from old transformers leakages. The total PBDEs concentrations were in the range of 1.89-38.36 ng/g and with a mean of 11.38 ng/g. Electric and electronic equipment waste and PBDE containing materials as sources of PBDE. The risk assessment of OCPs and PCBs showed low potential human health risk from OCPs, while PCBs indicated to pose a high risk. PMID- 30411275 TI - Chromosomal scan of single sperm cells by combining fluorescence-activated cell sorting and next-generation sequencing. AB - PURPOSE: The purpose of this study was to develop a feasible approach for single sperm isolation and chromosome analysis by next-generation sequencing (NGS). METHODS: Single sperm cells were isolated from semen samples of normozoospermic male and an infertile reciprocal translocation (RcT) carrier with the 46,XY,t(7;13)(p12;q12.1) karyotype using the optimized fluorescence-activated cell sorting (FACS) technique. Genome profiling was performed using NGS. RESULTS: Following whole-genome amplification, NGS, and quality control, the final chromosome analysis was performed on 31 and 6 single cell samples derived from the RcT carrier and normozoospermic male, respectively. All sperm cells from normozoospermic male showed a normal haploid 23-chromosome profile. For the RcT carrier, the sequencing data revealed that 64.5% of sperm cells harbored different variants of chromosome aberrations, involving deletion of 7p or 7q, duplication of 7p, and duplication of 13q, which is concordant with the expected chromosome segregation patterns observed in balanced translocation carriers. In one sample, a duplication of 9q was also detected. CONCLUSIONS: We optimized FACS protocol for simple and efficient isolation of single human sperm cells that subsequently enabled a successful genome-wide chromosome profiling and identification of segmental aneuploidies from these individual cells, following NGS analysis. This approach may be useful for analyzing semen samples of infertile men or chromosomal aberration carriers to facilitate the reproductive risk assessment. PMID- 30411276 TI - Complete genome sequence of a putative novel potyvirus isolated from Platycodon grandiflorum. AB - The complete 9,556-nt genomic sequence of a putative new potyvirus, tentatively named "platycodon mild mottle virus" (PlaMMV), infecting Platycodon grandiflorum was determined (GenBank accession no. MH779625). A single large open reading frame (ORF; nt 121-9360, 3079 aa) encoding a polyprotein that was predicted to be cleaved into 10 mature proteins was detected. By comparison with other potyviruses, nine cleavage sites and conserved domains/motifs were identified. PlaMMV also has a highly conserved GA6 motif (nt 2857-2863) that could enable a small overlapping ORF (PIPO) embedded within the P3 cistron to be translated by a viral polymerase slippage mechanism. A BLAST analysis showed that the complete PlaMMV nucleotide sequence shared 70% identity (40% query coverage) with carrot thin leaf virus (JX156434) and that the complete amino acid sequence of the PlaMMV polyprotein shared 54% identity (98% query coverage) with Thunberg fritillary mosaic virus (CAI59123). These results suggest that PlaMMV is a new member of the genus Potyvirus in the family Potyviridae. PMID- 30411277 TI - Complete genome sequences of two strains of classical swine fever virus of subgenotype 2.3 detected during outbreaks in 2005 and 2006 in Serbia. AB - Two strains of classical swine fever virus (CSFV) (SRB/CSFV/1264/2005 and SRB/CSFV/6168/2006), producing serious clinical signs of disease during outbreaks in 2005 and 2006 in Serbia, were isolated on porcine kidney cells, and their complete genomes were determined by next-generation sequencing. This first complete genome characterization of Serbian CSFV strains provides new data about the evolution of CSFV in the Balkan region and enables further detailed phylogenetic studies of the various strains. PMID- 30411278 TI - Breast imaging surveillance after curative treatment for primary non-metastasised breast cancer in non-high-risk women: a systematic review. AB - OBJECTIVES: The article summarises the available guidelines on breast imaging surveillance after curative treatment for locoregional breast cancer. METHODS: A systematic review of practice guidelines published from 1 January 2007 to 1 January 2017 was performed according to PRISMA methodology. The search was conducted for the EMBASE, MEDLINE, Cochrane and Centre for Reviews and Dissemination databases. On 8 July 2018, all included guidelines were updated to the most recent version. RESULTS: Twenty-one guidelines originating from 18 publishing bodies matched criteria. Publishing bodies consisted of seven governmental institutions, nine medical societies and two mixed collaborations. Publishing boards consisted of six radiological, four oncological, and 11 multidisciplinary teams. Annual bilateral mammography surveillance after breast conserving therapy was recommended by 17/18 (94.4%) publishing bodies. Annual contralateral mammography surveillance after mastectomy was recommended by 13/18 (72.2%) publishing bodies. Routine use of digital breast tomosynthesis was recommended by 1/18 (5.6%) publishing bodies. Routine breast ultrasound surveillance was recommended by 2/18 (11.1%), deemed optional by 4/18 (22.2%) and not supported by 8/18 (44.4%) publishing bodies. Routine breast magnetic resonance imaging (MRI) surveillance was not recommended by 16/18 (88.9%) publishing bodies, although 6/18 (33.3%) specified subgroups for systematic MRI surveillance. CONCLUSIONS: Annual mammography is currently the 'gold standard' for breast imaging surveillance. The role of digital breast tomosynthesis (DBT) remains to be further investigated. Most guidelines do not recommend routine breast ultrasound or MRI surveillance, unless indicated by additional risk factors. PMID- 30411279 TI - Common artefacts encountered on images acquired with combined compressed sensing and SENSE. AB - Various techniques have been proposed which aim at scan time reduction and/or at improved image quality by increasing the spatial resolution. Compressed sensing (CS) takes advantage of the fact that MR images are usually sparse in some transform domains and recovers this sparse representation from undersampled data. CS may be combined with parallel imaging such as sensitivity encoding (SENSE), hereafter referred to as Compressed SENSE, to further accelerate image acquisition since both techniques rely on different ancillary information. In practice, Compressed SENSE may reduce scan times of two-dimensional (2D) and three-dimensional (3D) scans by up to 50% depending on the sequence acquired and it works on 1.5-T or 3-T scanners. Compressed SENSE may be applied to 2D and 3D sequences in various anatomies and image contrasts. Image artefacts (i.e. motion, metal and flow artefacts, susceptibility artefacts) frequently appear on magnetic resonance images. The Compressed SENSE technique may cause special artefacts, which might influence image assessment if they go undetected by imaging readers. Our institution has been using Compressed SENSE for over half a year, both in a neuroradiological setting and for musculoskeletal examinations. So far, three special image artefacts-called the wax-layer artefact, the streaky-linear artefact and the starry-sky artefact-have been encountered and we aim to review these main artefacts appearing in sequences acquired with Compressed SENSE. TEACHING POINTS: * Compressed SENSE combines compressed sensing and SENSE technique. * Compressed SENSE permits scan time reduction and increases spatial image resolution. * Images acquired with Compressed SENSE may present with special artefacts. * Knowledge of artefacts is necessary for reliable image assessment. PMID- 30411280 TI - Brain tumour post-treatment imaging and treatment-related complications. AB - PURPOSE: The imaging of primary and metastatic brain tumours is very complex and relies heavily on advanced magnetic resonance imaging (MRI). Utilisation of these advanced imaging techniques is essential in helping clinicians determine tumour response after initiation of treatment. Many options are currently available to treat brain tumours, and each can significantly alter the brain tumour appearance on post-treatment imaging. In addition, there are several common and uncommon treatment-related complications that are important to identify on standard post treatment imaging. METHODS: This article provides a review of the various post treatment-related imaging appearances of brain neoplasms, including a discussion of advanced MR imaging techniques available and treatment response criteria most commonly used in clinical practice. This article also provides a review of the multitude of treatment-related complications that can be identified on routine post-treatment imaging, with an emphasis on radiation-induced, chemotherapy induced, and post-surgical entities. Although radiological evaluation of brain tumours after treatment can be quite challenging, knowledge of the various imaging techniques available can help the radiologist distinguish treatment response from tumour progression and has the potential to save patients from inappropriate alterations in treatment. In addition, knowledge of common post treatment-related complications that can be identified on imaging can help the radiologist play a key role in preventing significant patient morbidity/mortality. TEACHING POINTS: * Contrast enhancement does not reliably define tumour extent in many low-grade or infiltrative gliomas. * Focal regions of elevated cerebral blood volume (rCBV) on dynamic susceptibility contrast (DSC) perfusion-weighted imaging are suggestive of tumour growth/recurrence. * Brain tumour treatment response criteria rely on both imaging and clinical parameters. * Chemotherapeutic agents can potentiate many forms of radiation-induced injury. * Ipilimumab-induced hypophysitis results in transient diffuse enlargement of the pituitary gland. PMID- 30411281 TI - Prolyl hydroxylase inhibitor DMOG suppressed inflammatory cytokine production in human gingival fibroblasts stimulated with Fusobacterium nucleatum. AB - OBJECTIVE: Fusobacterium nucleatum (F. nucleatum) is one of the most common bacteria involved in the initiation and progression of periodontal diseases. Pharmacological inhibitor of prolyl hydroxylases (PHDs), dimethyloxallyl glycine (DMOG), has been reported to exert anti-inflammatory effects. The aim of this investigation was to evaluate the role of DMOG in inflammatory cytokine production of human gingival fibroblasts (HGFs) stimulated with F. nucleatum. MATERIAL AND METHODS: HGFs were pretreated with 10, 50, and 100 MUM DMOG for 24 h before infected with F. nucleatum (MOI = 100). Cell morphology and survival after infection with F. nucleatum were determined by crystal violet staining assay. The mRNA levels of interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-alpha, and IL-1beta were evaluated by quantitative real-time polymerase chain reaction (qRT PCR). The production of IL-6, IL-8, TNF-alpha, and IL-1beta was assessed by enzyme-linked immunosorbent assay (ELISA). RESULTS: F. nucleatum did not affect the morphology and survival of HGFs by the concentrations of MOI (multiplicity of infection) = 10, 50, and 100. The mRNA levels of IL-6, IL-8, TNF-alpha, and IL 1beta were significantly enhanced with the stimulation of F. nucleatum, and the maximal effect reached at 6 h. The secretion of IL-6, IL-8, and TNF-alpha was significantly upregulated by the infection of F. nucleatum while the production of IL-1beta was nearly unchanged. Above all, DMOG suppressed F. nucleatum stimulated IL-6, IL-8, TNF-alpha, and IL-1beta expressions. CONCLUSIONS: These data indicate that prolyl hydroxylase inhibitor DMOG partly downregulates inflammatory cytokine expression in F. nucleatum-infected HGFs. CLINICAL RELEVANCE: DMOG may provide a novel strategy for the therapy of periodontitis. PMID- 30411282 TI - Conservative management of septic complication after internal Delorme procedure for occult rectal prolapse and rectocele in obstructed defecation syndrome. PMID- 30411283 TI - Influenza Vaccination in Older Adults: Recent Innovations and Practical Applications. AB - Influenza can lead to serious illness, particularly for older adults. In addition to short-term morbidity and mortality during the acute infection, recovery can be prolonged and often incomplete. This may lead to persistent declines in health and function, including catastrophic disability, which has dramatic implications for the well-being and support needs of older adults and their caregivers. All of this means that prevention of infection and effective treatment when illness has occurred are of paramount importance. In this narrative review, we discuss the effectiveness of influenza vaccines for the prevention of influenza illness and serious outcomes in older adults. We review evidence of vaccine effectiveness for older adults in comparison with younger age groups, and also highlight the importance of frailty as a determinant of vaccine effectiveness. We then turn our attention to the question of why older and frailer individuals have poorer vaccine responses, and consider changes in immune function and inflammatory responses. This sets the stage for a discussion of newer influenza vaccine products that have been developed with the aim of enhancing vaccine effectiveness in older adults. We review the available evidence on vaccine efficacy, effectiveness and cost benefits, consider the potential place of these innovations in clinical geriatric practice, and discuss international advisory committee recommendations on influenza vaccination in older adults. Finally, we highlight the importance of influenza prevention to support healthy aging, along with the need to improve vaccine coverage rates using available vaccine products, and to spur development of better influenza vaccines for older adults in the near future. PMID- 30411284 TI - Serum Concentrations and Elimination Rates of Direct-Acting Oral Anticoagulants (DOACs) in Older Hip Fracture Patients Hospitalized for Surgery: A Pilot Study. AB - BACKGROUND: Use of direct-acting oral anticoagulants (DOACs) is increasing, but knowledge about pharmacokinetics and safety in frail patients is lacking. OBJECTIVE: The aim was to determine serum concentrations and elimination rates of DOACs in older hip fracture patients hospitalized for surgery. METHODS: The study included patients >= 65 years of age hospitalized for acute hip fracture surgery over a period of 6 months. Use of antithrombotic drugs was registered and serum samples collected for analysis of DOACs (apixaban, dabigatran and rivaroxaban) at admission and surgery. Measured concentrations were assessed in relation to reference (therapeutic) ranges of the respective drugs and applied for half-life calculations. Furthermore, waiting time for surgery was compared between DOAC and warfarin users. RESULTS: Of 167 patients included (median age 84 years), 11 and 14 used DOACs and warfarin, respectively. Seven of the DOAC-treated patients had concentrations above the upper reference range (> 300 nM) at admission, and concentrations were still in the reference range for five of these at surgery. Elimination half-lives could be estimated in eight patients and ranged between 14.6 and 59.7 h (median 21.6). The observed waiting time for surgery was longer for patients using DOACs than warfarin (median 44 vs. 25 h). CONCLUSION: This pilot study indicates that older patients prone to hip fracture are at risk of being exposed to therapeutic serum concentrations of DOACs during surgery due to reduced drug elimination rates. The observation that almost 50% of the patients had therapeutic concentrations at surgery should be investigated further regarding safety of DOAC use in this frail elderly population. PMID- 30411285 TI - Pesticides as the drivers of neuropsychotic diseases, cancers, and teratogenicity among agro-workers as well as general public. AB - The need to maximize agricultural productivity has made pesticides an indispensable part of current times. Farmers are unaware of the lurking consequences of the pesticide exposure, which endanger their health. It also puts the unsuspecting consumers in peril. The pesticides (from organophosphates, organochlorine, and carbamate class) disrupt the immune and hormonal signaling, causing recurrent inflammation, which leads to a wide array pathologies, including teratogenicity. Numerous farmers have fallen victim to neural disorders driven suicides and lungs, prostate/breast cancer-caused untimely deaths. Green revolution which significantly escalated agricultural productivity is backfiring now. It is high time that environmental and agricultural authorities act to restrain the excessive usage of the detrimental chemicals and educate farmers regarding the crisis. This review discusses the biological mechanisms of pesticide-driven pathogenesis (such as the activation or inhibition of caspase, serine protease, acetylcholinesterase) and presents the pesticide-exposure-caused health deterioration in USA, India, and Africa. This holistic and critical review should be an eye-opener for general public, and a guide for researchers. PMID- 30411286 TI - Zinc, copper, cadmium, and lead levels in cattle tissues in relation to different metal levels in ground water and soil. AB - The objective of the present study was to investigate the interaction between environmental (water and soil) levels of zinc, copper, cadmium, and lead levels, as well as their content in Hereford beef cattle tissues in five districts (D1 western area, D2 and D3-central area, D4 and D5-eastern area) of the Orenburg region. Soil metal levels were assessed using atomic emission spectrometry, whereas water and tissue (liver, kidney, muscle, heart) metal content was studied using inductively coupled plasma-mass spectrometry. The obtained data demonstrate that the highest levels Zn in soil and water (p < 0.001), as well as cattle muscle, liver, and kidney (p < 0.05) were observed in D4 and D5 (eastern area), exceeding the maximum permissible concentration levels (MPCL) for drinking water and muscle for all regions. Similar associations were found for Cu levels. The highest soil and water Cd and Pb content were observed in D2 (central area) and D5 (eastern area), respectively. At the same time, cattle tissue Cd and Pb content did not correspond to the respective environmental levels. Correlation analysis demonstrated that water and soil Zn and Cu content directly correlated with muscle, liver, and kidney, but not heart metal content. At the same time, water Cd levels were negatively interrelated with muscle cadmium content but correlated directly with hepatic metal content. Both water and soil Pb levels positively correlated with renal metal levels in cattle. In turn, soil lead content was inversely associated with muscle metal levels. Regression analysis also demonstrated a significant association between environmental and tissue levels of Zn and Cu. The models adjusted for all studied elements demonstrated a significant effect of metal interaction on tissue metal levels. Hypothetically, excessive environmental Zn, and possibly Cu, levels may affect the uptake of heavy metals including Cd and Pb from the environment. PMID- 30411287 TI - Sludge nematodes, cestodes, and trematodes eggs variation from lagooning, activated sludge and infiltration-percolation wastewater treatment system under semi-arid climate. AB - The prevalence and the identification of the helminth eggs load of raw sewage sludge was assessed of three different wastewater treatment systems. The results showed a variety of parasite species with following average concentrations; five taxa belonging to three classes nematodes, cestodes and trematodes were inventoried. The class of nematodes is the most diverse with 5 taxa. It is represented by the eggs of Ascaris sp., Capillaria sp., Trichuris sp., Toxocara sp., and Ankylostome sp., then comes the cestodes class, this is represented by the eggs of Taenia sp. The trematode class is represented by Schistosoma sp. The lagooning station of Chichaoua shows the highest load 7 species with Ascaris 21 eggs/g; Capillaria sp., 11 eggs/g; Trichuris sp., 6 eggs/g; Toxocara sp., 2 eggs/g and Ankylostome sp., 1 egg/g; Taenia sp., 2eggs/g; and Schistosoma sp., 1 egg/g. Infiltration-percolation sludge show the presence of 4 species of helminths eggs in sludge from anaerobic settling with different rates: 15 eggs/g for Ascaris sp., 15 eggs/g for Trichuris sp., 13 eggs/g for Capillaria sp., and 8 eggs/g for Taenia sp. However, in sand filter pool, the sludge helminth eggs load was decreased by 47% of Ascaris sp., 85% of Capillaria sp., and 75% of Taenia sp., Nevertheless, an increase of Trichuris eggs load was noted in the second sludge by 17%. Five helminth eggs was detected in primary sludge coming from decantation pools in activated sludge plant in Marrakech, that is Ascaris sp., with a load of 16 eggs/g; Capillaria sp., with 3 eggs/g, Trichuris eggs with 2 eggs/g; Taenia sp., with 4 eggs/g; and Schistosoma sp., with 2 eggs/g. The abatement load of Ascaris sp. with 81% and Schistosoma and Taenia sp., with 100% was noted in biological sludge. Nevertheless, an increase load of Capillaria and Trichuris eggs 81% and 75% respectively was observed in this sludge coming from biological pools. The distribution of parasitic helminth eggs is linked to the differences in demographic and socio-economic status, seasonal variation, physico chemical characteristic of helminth eggs, and the purification wastewater system performance. PMID- 30411288 TI - Efficiency of sequential UV/H2O2 and biofilm process for the treatment of secondary effluent. AB - In response to the shortage of water resources, multiple processes have been applied to turn wastewater secondary effluent (SE) into potable water. However, trace organic contaminants (TOrCs) and high concentrations of organic matter contained in SE pose a significant challenge to the reclamation. In this manuscript, combined UV-based and biofilm processes were used to treat the SE spiked with ibuprofen (IBU) and clofibric acid (CA). The efficiency of these sequential treatments was characterized in terms of changes in dissolved organic carbon (DOC), absorbance at 254 nm (A254), fluorescence excitation-emission matrix (FEEM), the concentration of IBU and CA, and molecular weight of SE. Parallel factor (PARAFAC) was applied as the analysis method for FEEM of the samples and two fluorescent components were successfully identified: humic-like substances (C1) and protein-like matter (C2). Large reductions in A254, C1, C2, IBU, and CA were observed during the UV-based processes, especially with the addition of H2O2. Nearly 50% of A254, 80% of the component C1 were decreased and almost complete removal of the component C2 and TOrCs was achieved by UV/2.0 mM H2O2 after 90-min treatment. During the oxidation processes, the formation of lower molecular weight (LMW) compounds was detected, and the biodegradability of the organic matters was greatly increased. Although no significant DOC reduction was obtained in UV-based processes, an obvious further DOC reduction (30~60%) was achieved by biofilm treatment following UV-based processes, especially after UV/H2O2 treatments. In the meantime, large amounts of LMW were removed in the biofilm treatment process. This manuscript provides an effective advanced treatment of SE for the removal of DOC and TOrCs, facilitating the wastewater reclamation. PMID- 30411289 TI - The use of biochar and crushed mortar in treatment wetlands to enhance the removal of nutrients from sewage. AB - An experimental study was carried out using in pilot-scale constructed wetland systems, operated in parallel to treat raw sewage. Each system consisted of a vertical flow (VF) unit that was filled with biochar as the main media, followed by a horizontal flow (HF) unit filled with crushed cement mortar. Hydraulic loading (HL) ranged 340-680 mm/day was applied on the VF wetland units, where high total nitrogen (TN) mass removal rate (20-23 g N/m2 d) was obtained, demonstrating that biochar media had a beneficial effect on the degradation of nitrogenous pollutants. Total phosphorus (TP) removal percentage (concentration based) was >= 86% in HF wetlands packed with mortar materials. In one system, the flow direction of the sewage was directed by the deployment of downflow pipes and vertical baffles, aiming to facilitate the formation of aerobic and anaerobic zones in the wetland matrices. The effects of such arrangement were analyzed by comparing pollutant removal efficiencies in the two systems. On average, 99, 96, 93, and 86 percentage removals were obtained for ammonia (NH4-N), TN, biochemical oxygen demand (BOD), and TP, respectively, during the experiments. Biochar and crushed mortar proved to be a highly effective combination as media in subsurface flow constructed wetlands for wastewater treatment. PMID- 30411290 TI - Sub-lethal effects induced by a mixture of different pharmaceutical drugs in predicted environmentally relevant concentrations on Lithobates catesbeianus (Shaw, 1802) (Anura, ranidae) tadpoles. AB - The increasing consumption of medications by humans has negative effects such as the increased disposal of these compounds in the environment. Little is known about how the disposal of a "drug mix" (DM) in aquatic ecosystems can affect their biota. Thus, we evaluated whether the exposure of Lithobates casteibeianus tadpoles to a DM composed of different medication classes (antibiotic, anti inflammatory, antidepressant, anxiolytic, analgesic, and antacid drugs)-at environmentally relevant concentrations-may change their oral morphology, trigger behavioral disorders, and have mutagenic effects on erythrocyte cells. Based on our data, animals exposed to the DM showed changes in mandibular sheath pigmentation, dentition, and swimming activity, as well as atypical behavior in the social aggregation test [with co-specific and interspecific (Physalaemus cuvieri) individuals] and antipredatory defensive response deficit (chemical stimulus from Odonata larvae), after 15 exposure days. The mutagenic analysis revealed higher frequency of nuclear abnormalities in the erythrocytes of tadpoles exposed to the DM (e.g., multilobulated, blebbed, kidney-shaped, notched nucleus, binuclear, and micronucleated erythrocytes). Given the chemical complexity of the DM, we assumed that several organic functions may have been affected, either by the isolated, synergistic, antagonistic, or additive action of DM compounds. Finally, our study confirms the toxicological potential of DM in L. catesbeianus tadpoles, with emphasis to impacts that can affect the fitness of individuals and their natural populations. Thus, we suggest that more attention should be given to the disposal of medications in the environment and reinforce the need of improving water and sewage treatment systems. PMID- 30411291 TI - Transformation of cadmium-associated schwertmannite and subsequent element repartitioning behaviors. AB - Schwertmannite is an important sink for cadmium (Cd) in acid mine drainage (AMD) environments and is unstable when environmental conditions change. However, the release and redistribution of Cd during schwertmannite transformation with respect to pre-bound Cd are poorly understood. In this work, the transformation of cadmium-associated schwertmannite and subsequent Cd repartitioning behaviors were investigated. The way of schwertmannite associated with Cd was predominant by absorption, and the diffuse layer model (DLM) showed that Cd2+ existed as monodentate complexes =Fe(1)OCd+ and =Fe(2)OCd+ on schwertmannite surfaces. Kinetics of SO42- release and mineralogical characterization both showed that the mineral transformation rates decreased and more lepidocrocite aggregated with increasing adsorbed Cd levels. The shrinking core model revealed that Fe(II) induced process would affect mineral dissolution by changing surface reaction controlled step to internal diffusion-controlled step, and significantly promote the dissolution rate of Cd-adsorbed schwertmannite. Adsorbed Cd blocked the surface sites for later Fe(II) adsorption and the Fe(II)-Fe(III) electron transfer, then resulted in the decelerated transformation and the accumulation of intermediate phase lepidocrocite. The maximum release of aqueous Cd occurred after 1 mM Fe2+ addition, then over 69% of initial added Cd(aq) re-bound to solid phase accompanying with mineral transformation, and finally, Cd was mainly associated with the secondary minerals by complexation with surficial OH groups. These findings are useful for developing the strategies for treating Cd contamination in AMD affected areas. PMID- 30411292 TI - Growth and biochemical changes in quail bush (Atriplex lentiformis (Torr.) S.Wats) under Cd stress. AB - Halophytes have several advantages to be more effective in metal phytoextraction. Little is known about the Cd-phytoextraction potential of Atriplex lentiformis under different levels of Cd. Seven levels of Cd (0, 40, 80, 120, 160, 200, and 240 mg per kg of soil) were added to A. lentiformis plants grown on pots filled with 5 kg of sandy loam soil. A. lentiformis plants achieve different defense mechanisms to meet the high concentration of Cd in the soil and plant. These mechanisms include reducing the number and area of leaves, minimizing chlorophyll synthesis, and enhancing synthesizing of oxalic acid, phenols, and proline. The critical point of Cd was 9.35 and 183 mg kg-1 for available soil Cd and leaves concentrations, respectively. The maximum level of Cd displayed a 66% decrease in the chlorophyll content of the leaves. On the other hand, the oxalic acid, phenols, and proline in the leaves were increased significantly by 129, 100, and 200% when Cd increased from 0 to 240 mg. The tested plant removed 3.6% of the total soil Cd under the low Cd concentration (40 mg) but under the high level of Cd (240 mg), it only removed a negligible amount of soil Cd (0.74%). The current study confirmed that A. lentiformis plants lost the ability to cleanup Cd from contaminated soil under the high levels of contamination due to the high reduction in the production of dry matter. PMID- 30411293 TI - Methylococcaceae are the dominant active aerobic methanotrophs in a Chinese tidal marsh. AB - Although coastal marshes are net carbon sinks, they are net methane sources. Aerobic methanotrophs in coastal marsh soils are important methane consumers, but their activity and populations are poorly characterized. DNA stable-isotope probing followed by sequencing was used to determine how active methanotrophic populations differed in the main habitats of a Chinese coastal marsh. These habitats included mudflat, native plant-dominated, and alien plant-dominated habitats. Methylococcaceae was the most active methanotroph family across four habitats. Abundant methylotroph sequences, including methanotrophs and non methane-oxidizing methylotrophs (Methylotenera and Methylophaga), constituted 50 70% of the 16S rRNA genes detected in the labeled native plant-dominated and mudflat soils. Methylotrophs were less abundant (~ 20%) in labeled alien plant dominated soil, suggesting less methane assimilation into the target community or a different extent of carbon cross-feeding. Canonical correspondence analysis indicated a significant correlation between the active bacterial communities and soil properties (salinity, organic carbon, total nitrogen, pH, and available phosphorus). Importantly, these results highlight how changing vegetation or soil features in coastal marshes may change their resident active methanotrophic populations, which will further influence methane cycling. PMID- 30411294 TI - Comparative on plant stoichiometry response to agricultural non-point source pollution in different types of ecological ditches. AB - Long-term agricultural development has led to agricultural non-point source (NPS) pollution. Ecological ditches (eco-ditch), as specific wetland systems, can be used to manage agricultural NPS water and achieve both ecological and environmental benefits. In order to understand which type of eco-ditch systems (Es, soil eco-ditch; Ec, concrete eco-ditch; Eh, concrete eco-ditch with holes on double-sided wall) is more suitable for plant nutrient balance meanwhile reducing NPS water (total nitrogen [TN], about 10 mg/L; total phosphorus [TP], about 1 mg/L), it is essential to evaluate the plant (Vallisneria natans) stoichiometry response to water in different types of eco-ditches under static experiment. The results indicated that there were no significant differences in TP removal efficiency among three eco-ditches, yet Eh systems had the best TN removal efficiency during the earlier experimental time. Addition of agricultural NPS water had varying effects on plants living in different types of eco-ditch systems. Plant organ stoichiometry of V. natans varied in relation to eco-ditch types. Plant stoichiometry (C:N, C:P, and N:P) of V. natans in Eh systems could maintain the homeostasis of nutrients and was not greatly affected by external changing environment. V. natans in Es systems can more easily modify the nutrient contents of organs with regard to nutrient availability in the environment. Our findings provide useful plant stoichiometry information for ecologists studying other specific ecosystems. PMID- 30411295 TI - Contaminated sites, waste management, and green chemistry: new challenges from monitoring to remediation. PMID- 30411296 TI - Identification of Differentially Expressed Genes under the Regulation of Transcription Factors in Osteosarcoma. AB - The present study was to investigate and identify the differentially expressed genes (DEGs) in the transcriptional regulatory network of osteosarcoma (OS). The gene expression dataset from Gene Expression Omnibus (GEO) datasets was downloaded. DEGs were identified and their functional annotation was also conducted. In addition, differentially expressed transcription factors (TFs) and the regulatory genes were identified. The electronic validation was used to verify the expression of selected genes. The integrated analysis led to 932 DEGs. The results of functional annotation indicated that these DEGs significantly enriched in the p53 signaling pathway, Jak-STAT signaling pathway and Wnt signaling pathway. ZNF354C, NFIC, NFATC2, SP2, FOXO3, EGR1, ZEB1, RREB1, EGR2 and SRF were covered by most TFs. The expression levels of NFIC and EGR2 in electronic validation were compatible with our bio-informatics result. In conclusion, the deregulation of these genes may provide valuable information in understanding the underlying molecular mechanism in the OS. PMID- 30411297 TI - Desumoylating Isopeptidase 2 (DESI2) Inhibits Proliferation and Promotes Apoptosis of Pancreatic Cancer Cells through Regulating PI3K/AKT/mTOR Signaling Pathway. AB - This study aimed to investigate the effects of desumoylating isopeptidase 2 (DESI2) on tumor cell proliferation, apoptosis and invasion of pancreatic cancer, and to assess the signaling pathway involved. Overexpression and silence of DESI2 were designed and the experiments were divided into 5 groups: a normal control group, an interference control group (shRNA-NC); an interference group (sh DESI2); an overexpression control group (NC), an overexpression group (DESI2). Quantitative real time polymerase chain reaction (qRT-PCR) was used to screen the appropriate interference sequence. The silencing and overexpression of DESI2 were confirmed by qRT-PCR and western blotting. Cell cycling, apoptosis, invasion, and the expression of phosphatidylinositol-3-kinase (PI3K)-protein kinase B (AKT) mammalian target of rapamycin (mTOR) pathway and caspase 3 were measured. Overexpression and silence of DESI2 were successfully designed in two pancreatic cancer cells, and the interference effect of sh-DESI2-3 showed the best silencing effects. The biological activities of DESI2 were detected in both ASPC-1 and PANCE-1 cells. Our results showed that cell proliferation was significantly increased in the sh-DESI2 group, while decreased in DESI2 group compared with the control group in both cell lines. In ASPC-1 cells, the events in G1 phase decreased and in S phase increased obviously in the sh-DESI2 group, compared with control group. An opposite result was found when DESI2 was overexpressed. In PANCE-1 cells, the events in G2 phase were higher in the sh-DESI2 group, while in the DESI2 group was significantly lower than that in control group. In ASPC-1 and PANCE-1 cells, sh-DESI2 group showed decreased apoptosis, increased cell invasion and increased expression of AKT, p-Akt, PI3K, p-PI3K, p-mTOR and mTOR and decreased caspase 3 expression compared with the control group, while overexpression of DESI2 leaded to increased apoptosis, decreased cell invasion and reduced expression of AKT, p-Akt, PI3K, p-PI3K, p-mTOR and mTOR and increased expression of caspase 3. DESI2 regulates the proliferation and apoptosis of pancreatic cancer cells through PI3K/AKT/mTOR signaling pathway. PMID- 30411298 TI - MicroRNA Expression in Focal Nodular Hyperplasia in Comparison with Cirrhosis and Hepatocellular Carcinoma. AB - The liver disease focal nodular hyperplasia (FNH) has several histological features that resemble hepatic cirrhosis. Since cirrhosis may develop further into hepatocellular carcinoma (HCC) contrary to FNH, the aim of the present study was to identify microRNAs (miRNA), which, by their altered expression levels, may be associated with the benign, tumor-like nature of FNH. Altogether 106 surgically removed formalin-fixed paraffin-embedded liver samples were selected, including 22 FNH, 45 cirrhosis, 24 HCC and 15 normal liver tissues. Etiology of the cases of cirrhosis and HCC includes hepatitis C and alcoholism and the HCC cases developed in cirrhotic livers. Relative expression levels of 14 miRNAs were determined using TaqMan MicroRNA Assays. In comparison to normal liver, the levels of miR-34a and miR-224 were elevated not only in FNH but also in cirrhosis and HCC, while the expression of miR-17-5p, miR-18a and miR-210 was decreased in FNH. Further, the levels of miR-21 and miR-222 were increased in cirrhosis and HCC but were decreased in FNH and the expression of miR-17-5p, miR-18a, miR-195 and miR-210 was decreased in FNH as compared with cirrhosis and/or HCC. In conclusion, the elevation of miR-34a and miR-224 may be associated with both benign and malignant proliferative processes, nevertheless the increased expression of oncomiRs miR-21 and miR-222 in cirrhosis and HCC but not in FNH may be related to malignant processes of the liver. The decreased levels of miR-18a, miR-195 and miR-210 may further differentiate FNH from cirrhosis, reflecting the different pathogenesis of these two entities contrary to some histologically similar features. PMID- 30411299 TI - The Overexpression of CD80 and ISG15 Are Associated with the Progression and Metastasis of Breast Cancer by a Meta-Analysis Integrating Three Microarray Datasets. AB - Breast cancer is a common cancer and could result in a substantial mortality. The study aimed to screen gene signatures associated with the development and metastasis of breast cancer and explore their regulation mechanisms. Three datasets of GSE10797, GSE8977 and GSE3744 were downloaded from GEO (Gene Expression Omnibus) database, containing 55 breast cancer samples and 27 normal samples. After data preprocessing using limma software and RMA (robust multi array average) algorithm, DEGs (differentially expressed genes) between breast tumor and normal tissues in three individual experiments were identified using MADAM package. Function and pathway enrichment analyses were performed for the DEGs. Transcription factors and TAGs (tumor associated genes) among the DEGs were recognized and the PPI (protein-protein-interaction) network for the DEGs was constructed using Cytoscape software. The mRNA expression was analyzed via real time quantitative PCR and protein expression was measured by western blotting. Totally, 100 DEGs were identified, including 33 up-regulated genes and 67 down regulated genes. Among them, up-regulated DEGs such as CD80 was enriched in toll like receptor (TLR) interaction pathway and the TAG, ISG15 was related to RIG-I like receptor signaling pathway, while CXCL10 was involved in both of the two pathways. Whereas, the down-regulated DEG, CXCL12 was significantly associated with axon guidance pathway. Additionally, these DEGs were also pivotal nodes in the PPI network with high degrees. Besides, CXCL10 and CD80 were both interacted with IFNG. The mRNA expression of ISG15 was obviously enhanced in human breast cancer cells MCF-7, while no significant difference of CXCL10 mRNA level was found between MCF10A and MCF-7 cells. Moreover, the proteins expression levels of CD80 and ISG15 were significantly increased in MCF-7, MDA-MB-468 and MDA-MB-231 breast cancer cells than in normal MCF10A cells. CD80 might be responsible for the breast cancer's progression and metastasis via regulating innate immune system. In addition, ISG15 is identified as a crucial gene signature associated with breast cancer development and metastasis via RIG-I-like receptor signaling pathway. PMID- 30411300 TI - Hepatic Cytochrome P450 Activity and Nitric Oxide Production During Multiple Ovalbumin Challenges. AB - BACKGROUND AND OBJECTIVES: Mast cell-mediated allergic diseases are a significant global health problem. Nitric oxide (NO) produced by acute type 1 allergies greatly suppresses hepatic cytochrome P450 (CYP) metabolism. A recent in vitro study demonstrated that repeated FcepsilonRI-mediated activation intrinsically modulates mast cell function. We investigated the effect of ovalbumin (OVA) challenges on CYP activity and NO production under real immune responses. METHODS: After repeated sensitization with OVA once a week, serum nitrate plus nitrite (NOx) and total plasma immunoglobulin E concentrations were measured using commercially available kits. Hepatic microsomal CYP-specific activities and protein expression were determined using typical substrates and by western blot, respectively. In the liver, the levels of inducible NO synthase (iNOS), F4/80, and c-kit mRNA were determined by real-time polymerase chain reaction. Hepatic total NOS activity was measured using a colorimetric assay kit. RESULTS: When mice received multiple OVA challenges, the 11th sensitization elevated NOx concentrations in serum and suppressed the activities of five major CYPs without altering protein expression levels. After the 7th, 11th, and 15th sensitizations, F4/80-positive Kupffer cell and hepatic c-kit-dependent mast cell mRNA levels were similar to those of the control. The 7th and 11th sensitizations increased hepatic iNOS mRNA expression to 15-fold and threefold above control levels, respectively, but did not enhance the total NOS activity in the liver. CONCLUSIONS: Multiple OVA challenges, unlike acute sensitization, greatly reduced serum NOx levels. The challenge-suppressed hepatic CYP metabolism was likely related to the increased serum NOx. Serum NOx may be an endogenous marker for CYP metabolism inhibition in type 1 allergic diseases. PMID- 30411302 TI - The Full Outline of UnResponsiveness (FOUR) Score and Its Use in Outcome Prediction: A Scoping Systematic Review of the Adult Literature. AB - BACKGROUND: The Full Outline of UnResponsivness (FOUR) score is a neurological assessment score. Its theoretical benefit over preexisting scores is its evaluation of brainstem reflexes and respiratory pattern which may allow better assessment of patients with severe neurologic impairment. OBJECTIVE: Our goal was to perform a scoping systematic review on the available literature for FOUR score and outcome prediction in critically ill patients. The primary outcome of interest was patient global outcome, as assessed by any of: mortality, modified Rankin Score, Glasgow Outcome Score, or any other functional or neuropsychiatric outcome. Information on interobserver reliability was also extracted. METHODS: MEDLINE and five other databases were searched. Inclusion criteria were: humans, adults, and children; prospective randomized controlled trial; prospective cohort, cohort/control, case series, prospective, and retrospective studies. Two reviewers independently screened the results. Full texts for citations passing this initial screen were obtained. Inclusion and exclusion criteria were applied to each article to obtain final articles for review. Results on adult populations are presented here. Data are reported following the preferred reporting items for systematic reviews and meta-analyses guidelines. RESULTS: The initial search yielded 1709 citations. Of those used, 49 were based on adult and 6 on pediatric populations. All but 8 retrospective adult studies were performed prospectively. Patient categories included traumatic brain injury, intraventricular hemorrhage, intracerebral hemorrhage, subarachnoid hemorrhage, ischemic stroke, general/combined neurology and neurosurgery, post-cardiac arrest, medicine/general critical illness, and patients in the emergency department. A total of 9092 adult patients were studied. Fourteen studies demonstrated good interobserver reliability of the FOUR score. Nine studies demonstrated prognostic value of the FOUR score in predicting mortality and functional outcomes. Thirty two studies demonstrated equivalency or superiority of the FOUR score compared to Glasgow Coma Score in prediction of mortality and functional outcomes. CONCLUSIONS: The FOUR score has been shown to be a useful outcome predictor in many patients with depressed level of consciousness. It displays good inter-rater reliability among physicians and nurses. PMID- 30411303 TI - Spatiotemporal Analyses of Cellular Tractions Describe Subcellular Effect of Substrate Stiffness and Coating. AB - Cells interplay with their environment through mechanical and chemical interactions. To characterize this interplay, endothelial cells were cultured on polyacrylamide hydrogels of varying stiffness, coated with either fibronectin or collagen. We developed a novel analysis technique, complementary to traction force microscopy, to characterize the spatiotemporal evolution of cellular tractions: We identified subpopulations of tractions, termed traction foci, and tracked their magnitude and lifetime. Each focus consists of tractions associated with a local single peak of maximal traction. Individual foci were spread over a larger area in cells cultured on collagen relative to those on fibronectin and exerted higher tractions on stiffer hydrogels. We found that the trends with which forces increased with increasing hydrogel stiffness were different for foci and whole-cell measurements. These differences were explained by the number of foci and their average strength. While on fibronectin multiple short-lived weak foci contributed up to 30% to the total traction on hydrogels with intermediate stiffness, short-lived foci in such a number were not observed on collagen despite the higher tractions. Our approach allows for the use of existing traction force microscopy data to gain insight at the subcellular scale without molecular probes or spatial constraining of cellular tractions. PMID- 30411304 TI - The Effect of Medical Insurance on Outpatient Visits by the Elderly: An Empirical Study with China Health and Retirement Longitudinal Study Data. AB - BACKGROUND: As the largest developing country in the world, China is still on its way towards building an adequate system of health insurance through continuous reforms. For the elderly in China, an effective medical security system might be especially helpful. OBJECTIVE: This study investigates the effect of medical insurance on outpatient visits by elderly Chinese in order to identify effective policies to improve the Chinese medical security system. METHODS: Based on data taken from the China Health and Retirement Longitudinal Study, eleven candidate models were analyzed, among which a finite mixture negative binomial model with two components was chosen as the theoretical foundation for an analysis of the effect of medical insurance on outpatient visits by elderly Chinese. RESULTS: The significant variables were found to be basic medical insurance (BMI), sex, surveyed area, education level, health status, economic area, income level, and the number of living children for the elderly aged 60-69 years; BMI, age, health status, number of household members, and income level for the elderly aged 70-79 years; and BMI, age, sex, and the presence of chronic disease for the elderly aged 80 years and above. CONCLUSION: Enrollment in BMI was found to be significantly associated with an increased number of outpatient visits, whereas supplementary medical insurance membership did not have a significant effect. The effects of BMI enrollment also differed by scheme and age. For those with a high rate of outpatient medical services utilization, the enhancing effect of BMI on the number of outpatient visits was not significant, so new medical insurance policies should be provided to the elderly population in China. PMID- 30411305 TI - Standardized Operational Protocol for Human Brain Banking in China. PMID- 30411306 TI - Sirtuin3 Protected Against Neuronal Damage and Cycled into Nucleus in Status Epilepticus Model. AB - In pathological conditions such as status epilepticus (SE), neuronal cell death can occur due to oxidative stress that is caused by an excessive production and accumulation of reactive oxygen species (ROS). Sirtuin3 (Sirt3) plays an important role in maintaining appropriate ROS levels by regulating manganese superoxide dismutase (MnSOD), which scavenges ROS in mitochondria. Using a SE model, we demonstrated that Sirt3 directly regulated MnSOD activity by deacetylation, which protects hippocampal cells against damage from ROS. Furthermore, we showed that after formation in the nucleus, Sirt3 is primarily located in the mitochondria, where it is activated and exerts its major function. Sirt3 then completed its pathway and moved back into the nucleus. Our data indicate that Sirt3 has an important function in regulating MnSOD, which results in decreased ROS in hippocampal cells. Sirt3 may have potential as an effective therapeutic target in SE conditions that would delay the progression of epileptogenesis. PMID- 30411307 TI - Salmonella, E. coli, and Citrobacter Type III Secretion System Effector Proteins that Alter Host Innate Immunity. AB - Bacteria deliver virulence proteins termed 'effectors' to counteract host innate immunity. Protein-protein interactions within the host cell ultimately subvert the generation of an inflammatory response to the infecting pathogen. Here we briefly describe a subset of T3SS effectors produced by enterohemorrhagic Escherichia coli (EHEC), enteropathogenic E. coli (EPEC), Citrobacter rodentium, and Salmonella enterica that inhibit innate immune pathways. These effectors are interesting for structural and mechanistic reasons, as well as for their potential utility in being engineered to treat human autoimmune disorders associated with perturbations in NF-kappaB signaling. PMID- 30411309 TI - Perioperative Management of Patients with Colovesical Fistula. AB - BACKGROUND: Colovesical fistula (CVF) is an uncommon complication of diverticulitis. Substantial heterogeneity exists in the perioperative management of this condition. We seek to evaluate the role of bladder leak testing, closed suction drainage, prolonged bladder catheter usage, and routine postoperative cystogram in the management of CVF. STUDY DESIGN: This is a retrospective study from a single academic health center investigation patients undergoing operation for diverticular CVF from 2005 to 2015 (n = 89). RESULTS: Patients undergoing operative repair for diverticular CVF resection had a mortality of 4% and overall morbidity of 46%. Intraoperative bladder leak test was performed in 36 patients (40%) and demonstrated a leak in 4 patients (11%). No patients with a negative intraoperative bladder leak test developed a urinary leak. Overall, five (6%) patients developed postoperative bladder leak. Three were identified by elevated drain creatinine and two by cystogram. The diagnostic yield of routine cystogram was 3%. All bladder leaks were diagnosed between postoperative day 3 and 7. Of patients with a postoperative bladder leak, none required reoperation and all resolved within 2 months. CONCLUSIONS: There is significant variability in the management of patients undergoing operation for CVF. Routine intraoperative bladder leak test should be performed. Cystogram may add cost and is low yield for routine evaluation for bladder leak after operation for CVF. Urinary catheter removal before postoperative day 7 should be considered. PMID- 30411308 TI - The effects of normovolemic anemia and blood transfusion on cerebral microcirculation after severe head injury. AB - BACKGROUND: Cerebral regional microcirculation is altered following severe head injury. In addition to tissue disruption, partial pressure of tissue oxygenation is impaired due to an increase in the oxygen tissue gradient. The heterogenic distribution of cerebral microcirculation is multifactorial, and acute anemia challenges further the delivery of oxygen to tissues. Currently, a restrictive transfusion threshold is globally applied; however, it is unclear how anemia modifies regional cerebral microcirculation; hence, it is unclear if by aiming to a global endpoint, specific anatomical regions undergo ischemia. This study aims to quantify the temporal changes in cerebral microcirculation after severe head injury, under the effect of anemia and transfusion. It also aims to assess its effects specifically at the ischemic penumbra compared to contralateral regions and its interactions with axonal integrity in real time. Twelve ovine models were subjected to a severe contusion and acceleration-deceleration injury. Normovolemic anemia to a restrictive threshold was maintained after injury, followed by autologous transfusion. Direct quantification of cerebral microcirculation used cytometric count of color-coded microspheres. Axonal injury was assessed using amyloid precursor protein staining. RESULTS: A mixed-effect regression model from pre-transfusion to post-transfusion times with a random intercept for each sheep was used. Cerebral microcirculation amongst subjects with normal intracranial pressure was maintained from baseline and increased further after transfusion. Subjects with high intracranial pressure had a consistent reduction of their microcirculation to ischemic thresholds (20-30 ml/100 g/min) without an improvement after transfusion. Cerebral PtiO2 was reduced when exposed to anemia but increased in a 9.6-fold with transfusion 95% CI 5.6 to 13.6 (p value < 0.001). CONCLUSIONS: After severe head injury, the exposure to normovolemic anemia to a restrictive transfusion threshold, leads to a consistent reduction on cerebral microcirculation below ischemic thresholds, independent of cerebral perfusion pressure. Amongst subjects with raised intracranial pressure, microcirculation does not improve after transfusion. Cerebral oxymetry is impaired during anemia with a statistically significant increase after transfusion. Current transfusion practices in neurocritical care are based on a rigid hemoglobin threshold, a view that excludes cerebral metabolic demands and specific needs. An RCT exploring these concepts is warranted. PMID- 30411310 TI - Cholecystectomy Risk in Crohn's Disease Patients After Ileal Resection: a Long term Nationwide Cohort Study. AB - BACKGROUND: The risk of gallstone disease necessitating cholecystectomy after ileal resection (IR) in Crohn's disease (CD) patients is not well established. We studied the incidence, cumulative and relative risk of cholecystectomy after IR in CD patients, and associated risk factors. METHODS: CD patients with a first IR between 1991 and 2015 were identified in PALGA, a nationwide pathology database in the Netherlands. Details on subsequent cholecystectomy and IR were recorded. Yearly cholecystectomy rates from the general Dutch population were used as a reference. RESULTS: A cohort of 8302 (3466 (41.7%) males) CD patients after IR was identified. During the 11.9 (IQR 6.3-18.0) years median follow-up, the post IR incidence rate of cholecystectomy was 5.2 (95% CI 3.5-6.4)/1000 persons/year. The cumulative incidence was 0.5% at 1 year, 2.4% at 5 years, 4.6% at 10 years, and 10.3% after 20 years. In multivariable analyses, female sex (HR 1.9, CI 1.5 2.3), a later calendar year of first IR (HR/5-year increase, HR 1.27, CI 1.18 1.35), and ileal re-resection (time-dependent HR 1.37, CI 1.06-1.77) were associated with cholecystectomy. In the last decade, cholecystectomy rates increased and were higher in our postoperative CD population than in the general population (relative incidence ratio 3.13 (CI 2.29-4.28; p < 0.0001) in 2015). CONCLUSIONS: Although higher in females, increasing in recent years, and higher than in the general population, the overall risk of cholecystectomy in CD patients following IR is low and routine prophylactic measures seem unwarranted. PMID- 30411311 TI - Vibegron: First Global Approval. AB - Vibegron is a selective beta 3 adrenergic receptor (beta3AR) agonist that is being developed in Japan jointly by Kyorin Pharmaceutical Co., Ltd and Kissei Pharmaceutical Co., Ltd and in other regions worldwide (except in several other Asian countries) by Urovant Sciences for the treatment of overactive bladder (OAB). Based on results from Japanese phase III trials, vibegron received approval in Japan in September 2018 for this indication. This article summarizes the milestones in the development of vibegron leading to this first global approval for the treatment of OAB. PMID- 30411312 TI - Evaluation of retinal injury in a rat model of transient ischemic stroke. AB - Stroke-associated ocular disorders are vision-threatening. This study was designed to evaluate in vivo retinal injury induced by transient global cerebral ischemia/reperfusion (I/R). A stroke-induced retinal injury model in Wistar rats was established by electrocoagulation of bilateral vertebral arteries, combined with transient ligation of the bilateral common carotid arteries. Rats were randomly divided into groups based on the time post cerebral perfusion (3 h, 24 h, 48 h, 72 h, and 7 days). Retinal injury was evaluated by histological analysis, examination of eye fundus, and TUNEL staining. The expression of protein kinase C-alpha (PKCalpha) and fibrillary acidic protein (GFAP) was determined using qRT-PCR and immunofluorescence analysis. Both retinal neurons and the vasculature underwent significant damage in the cerebral-I/R groups when compared to rats in the sham group. Moreover, when compared to non-stroke rats, TUNEL staining revealed signs of apoptosis in the retina after transient ischemic stroke was induced (P<0.001). In these rats, the expression of PKCalpha and GFAP in the retinas was enhanced and peaked at 72 h after induction of cerebral-I/R (P<0.001). In this study, we found that retinas are very susceptible to transient global cerebral-I/R injury. The expression of PKCalpha and GFAP may be implicated in the pathogenesis of ischemic stroke-induced retinal injury. PMID- 30411313 TI - Rebound pain following peripheral nerve block anaesthesia in acute ankle fracture surgery: An exploratory pilot study. AB - BACKGROUND: Peripheral nerve blocks (PNB) are increasingly used for anaesthesia and postoperative pain control in acute orthopaedic limb surgery but rebound pain upon cessation of PNBs may challenge the benefits on the pain profile. We aimed to explore the pain profile following acute ankle fracture surgery under PNB anaesthesia and investigate if rebound pain could pose a clinical problem. METHODS: Exploratory, observational study of adults scheduled for acute primary internal fixation of an ankle fracture under ultrasound-guided popliteal sciatic and saphenous ropivacaine block anaesthesia. Postoperatively, patients regularly registered pain scores while receiving a fixed analgesics regimen and patient controlled morphine on-demand. We analysed morphine consumption and depicted the detailed pain profiles as graphs allowing for visual analysis of pain courses, including rebound pain. Secondly, we compared the area under the curve and peak pain between relevant age-subgroups. RESULTS: We included 21 patients aged 20-83. Depicted pain profiles reveal that PNB supplied effective and long lasting postoperative pain control, but cessation of the PNB led to intense rises in pain scores with six out of nine 20-60-year-olds reaching severe pain levels. The rebound was less pronounced in patients >60 years old, but nearly all reached moderate pain levels. Morphine consumption rates were high during the rebound. CONCLUSIONS: This study thoroughly analyses the post-PNB pain profile and suggests rebound pain is a clinically relevant and problematic issue with the potential to outweigh the PNB benefits, especially for younger patients. The conclusions are tentative, and a randomised study is pending. PMID- 30411314 TI - Clinical and financial evaluation of carbetocin as postpartum haemorrhage prophylaxis at caesarean section: A retrospective cohort study. AB - BACKGROUND: The long-acting oxytocic agent; carbetocin, has been consistently shown to reduce the need for additional uterotonics at caesarean section, but not postpartum haemorrhage (PPH). While promising, current evidence is limited by heterogenicity in study design and findings. AIMS: To examine whether carbetocin confers clinical or economic benefit compared to oxytocin at caesarean section in an all-risk Australian population. MATERIALS AND METHODS: A retrospective cohort study was undertaken of all singleton caesarean sections at a public tertiary hospital from 2008 to 2010 (n = 2499). From 1 January 2008 to 24 March 2009 all women received prophylactic oxytocin 5-10 units slow push intravenously at delivery, after which all patients received 100 MUg intravenous carbetocin. Outcomes were PPH (>=1000 mL) and the requirement of secondary uterotonics. A post hoc cost analysis was also performed. RESULTS: A total of 1467 and 1024 patients received carbetocin and oxytocin, respectively. Incidence of PPH >=1000 mL was 7.8% for carbetocin compared to and 9.7% for oxytocin (odds ratio (OR) 0.79, 95% CI 0.59-1.05). Moderate blood loss >500 mL was significantly reduced with carbetocin; occurring in 27.3% versus 39.4% (OR 0.57, 95% CI 0.49-0.68). There was a 20.0% reduction in secondary uterotonic treatment with carbetocin (OR 0.42, 95% CI 0.35-0.49). Average drug costs were lower with oxytocin at $4.74 versus $36.42/patient. However, the 1.9% reduction in PPH with carbetocin resulted in a $63.46 reduction in cost per patient, with a cost-effectiveness ratio of $1667 to prevent one case of PPH >=1000 mL. CONCLUSIONS: Carbetocin reduced moderate blood loss >500 mL, but not PPH >=1000 mL. Carbetocin conferred a 20% reduction in secondary uterotonic treatment, as well as lowering direct medical costs. PMID- 30411315 TI - An ultra scale-down method to investigate monoclonal antibody processing during tangential flow filtration (TFF) using ultrafiltration membranes. AB - The availability of material for experimental studies is a key constraint in the development of full-scale bioprocesses. This is especially true for the later stages in a bioprocess sequence such as purification and formulation, where the product is at a relatively high concentration and traditional scale-down models can require significant volumes. Using a combination of critical flow regime analysis, bioprocess modelling and experimentation, ultra scale-down (USD) methods can yield bioprocess information using only millilitre quantities prior to embarking on highly demanding full-scale studies. In this study the performance of a pilot-scale tangential flow filtration (TFF) system based on a membrane flat-sheet cassette using pumped flow was predicted by devising an USD device comprising a stirred cell using a rotating disc. The USD device operates with just 2.1 cm2 of membrane area and for example just 1.7 mL of feed for diafiltration studies. The novel features of the design involve optimisation of the disc location and the membrane configuration to yield an approximately uniform shear rate. This is as characterised using computational fluid dynamics for a defined layer above the membrane surface. A pilot-scale TFF device operating at ~500-fold larger feed volume and membrane area was characterised in terms of the shear rate derived from flow rate-pressure drop relationships for the cassette. Good agreement was achieved between the USD and TFF devices for the flux and resistance values at equivalent average shear rates for a monoclonal antibody diafiltration stage. This article is protected by copyright. All rights reserved. PMID- 30411316 TI - Supervised exercise training with multimodal pre-habilitation leads to earlier functional recovery following colorectal cancer resection. AB - BACKGROUND: Exercise training is a component of the pre-habilitation program. While in one previous study the training was home-based, in a subsequent investigation it was supervised in hospital. The hypothesis of this secondary analysis of the two studies was to determine whether supervised exercise further accelerates the return to baseline walking ability. METHODS: Data from two consecutive randomized control trials (RCT) comparing pre-habilitation to the rehabilitation of cancer patients scheduled for colorectal surgery were pooled for analysis. The interventions were similar and included home-based exercise training, nutritional counseling and protein supplementation, and relaxation techniques administered either before surgery (pre-habilitation) or after surgery (rehabilitation). Patients in the second RCT received additional supervised exercise sessions. Functional capacity was assessed with the 6-minute walk test (6 MWT) at baseline, before surgery, and at 4 and 8 weeks after surgery. Adjusted logistic regression was used to determine the improvement of the 6-minute walk distance (6MWD). RESULTS: Baseline mean 6MWD of 63 patients in the supervised group was 465.1 m (SD, 115), and that of 77 patients in the nonsupervised group was 407.8 m (SD, 109) (P < 0.01). Perioperative supervised exercise training enhanced further functional capacity and muscle strength when compared with the nonsupervised group (P < 0.01). Those receiving exercise supervision had over two times higher chances to return to baseline after surgery. Supervised pre habilitation was the best combination (4 weeks OR = 7.71, and at 8 weeks OR = 8.62). CONCLUSION: Supervised exercise training leads to meaningful changes in functional capacity thus accelerating the postoperative return to baseline activities. PMID- 30411317 TI - Multiple cutaneous reticulohistiocytomas after haematopoietic cell transplantation: contribution of donor and host-derived cells. AB - Reticulohistiocytoma or reticulohistiocytosis of the skin is a histiocytic disorder which is histologically characterized by the presence of numerous reticulohistiocytes: large histiocytes with an abundant eosinophilic cytoplasm. The aetiology of reticulohistiocytosis and the origin of reticulohistiocytes are unknown. Multiple cutaneous reticulohistiocytomas (MCR) is a reticulohistiocytosis of the skin that is characterized by generalized eruptions and an absence of articular symptoms or internal malignancies. Around 20 MCR cases have been reported in the literature, but the association between reticulohistiocytosis and haematopoietic cell transplantation (HCT) has not been described. This article is protected by copyright. All rights reserved. PMID- 30411318 TI - Emergency peripartum hysterectomy in a Western Australian population: Ten-year retrospective case-note analysis. AB - BACKGROUND: Emergency peripartum hysterectomy (EPH) is a life-saving obstetric procedure reserved for conditions where medical treatment and conservative surgery have failed. EPH is associated with significant morbidity and mortality. AIM: To examine the incidence, indications, risk factors, maternal and neonatal outcomes of EPH in a tertiary hospital in Western Australia (WA). METHODOLOGY: A retrospective case-note analysis of all cases of EPH performed at King Edward Memorial Hospital in WA between the years 2006 and 2016. The incidence, indications, risk factors, maternal and neonatal outcomes were reviewed. All cases were ascertained via our hospital obstetric database. RESULTS: A total of 72 cases of EPH were identified among 64 999 births. The incidence of EPH in WA was 1.1 per 1000 deliveries. Abnormal placentation was the main indication for EPH accounting for 66.7% of cases. Among women undergoing an EPH, 22.2% had a history of one previous caesarean section and 33.3% had two or more caesarean sections, respectively. Maternal morbidity was significant. There was one cardiac arrest secondary to hypovolaemia, and 84% of the women received blood transfusions with more than half of these women meeting the criteria for massive transfusion protocol (>=4 units of packed red cells). Urinary tract injury and venous thromboembolism were some of the other complications among our cohort of women. CONCLUSION: EPH is associated with significant morbidity. Our study identifies abnormal placentation as the leading cause of EPH. PMID- 30411319 TI - Acrodermatitis continua of Hallopeau with dense infiltration of IgG4 -positive cells in the lesional dermis. AB - Acrodermatitis continua of Hallopeau (ACH) is a rare acropustular subtype of psoriasis. The characteristic feature of ACH is chronic, painful and destructive disease affecting the hands and feet, especially the fingertips and toes. The pathogenic mechanisms of ACH have not been fully elucidated. We report a case of ACH whose skin lesions showed dense infiltration of IgG4 -positive cells in the dermis. This article is protected by copyright. All rights reserved. PMID- 30411320 TI - Multicentre retrospective study to assess diagnostic accuracy of ultrasound for superficial endometriosis-Are we any closer? AB - BACKGROUND: To establish whether the ultrasound findings of minimal endometriosis are confirmed at laparoscopy and that a correlation can be established as to the anatomical sites in this mild form of the disease. AIMS: Patients with pain and suspicion of endometriosis had an ultrasound scan by a sonologist with expertise in endometriosis as part of their pre-operative workup. MEASUREMENTS AND MAIN RESULTS: The clinical histories of 53 patients who had laparoscopy to investigate pelvic pain were reviewed. Ultrasounds were performed between 2012 and 2015 by a single sonologist with expertise in endometriosis assessments. The ultrasound findings were divided into subgroups as follows - presence of uterosacral ligament thickness, thickened pericolic fat, ovarian mobility and focal tenderness. These were compared with operative findings of those patients with superficial endometriosis. Evidence Level 3 - observational studies with controls and health services research that includes adjustment for likely confounding factors. RESULTS: Seventy-nine percent (42/53) of the patients had laparoscopic findings consistent with their ultrasound findings (95% CI 68-90%, P < 0.0001). Of the subgroups that we reviewed, uterosacral thickening (P < 0.05) and thickened pericolic fat (P < 0.05) were the most associated with superficial endometriosis at the time of laparoscopy. CONCLUSION: Markers on ultrasound that reliably demonstrated inflammation (thickened uterosacral ligaments and thickened pericolic fat) were shown to be significantly associated with the disease. PMID- 30411321 TI - Response to Dr. Kaliyadan's comment on "Teaching & Learning Tips 7: small-group discussion". PMID- 30411322 TI - Metabolic flux balance analysis during lactate and glucose concomitant consumption in HEK293 cell cultures. AB - At early stages of the exponential growth phase in HEK293 cell cultures, the tricarboxylic acid cycle is unable to process all the amount of NADH generated in the glycolysis pathway, being lactate the main by-product. However, HEK293 cells are also able to metabolize lactate depending on the environmental conditions. It has been recently observed that one of the most important modes of lactate metabolization is the cometabolism of lactate and glucose, observed even during the exponential growth phase. Extracellular lactate concentration and pH appear to be the key factors triggering the metabolic shift from glucose consumption and lactate production to lactate and glucose concomitant consumption. The hypothesis proposed for triggering this metabolic shift to lactate and glucose concomitant consumption is that HEK293 cells metabolize extracellular lactate as a response to both extracellular protons and lactate accumulation, by means of cotransporting them (extracellular protons and lactate) into the cytosol. At this point, there exists a considerable controversy about how lactate reaches the mitochondrial matrix: the first hypothesis proposes that lactate is converted into pyruvate in the cytosol, and afterward, pyruvate enters into the mitochondria; the second alternative considers that lactate enters first into the mitochondria, and then, is converted into pyruvate. In this study, lactate transport and metabolization into mitochondria is shown to be feasible, as evidenced by means of respirometry tests with isolated active mitochondria, including the depletion of lactate concentration of the respirometry assay. Although the capability of lactate metabolization by isolated mitochondria is demonstrated, the possibility of lactate being converted into pyruvate in the cytosol cannot be excluded from the discussion. For this reason, the calculation of the metabolic fluxes for an HEK293 cell line was performed for the different metabolic phases observed in batch cultures under pH controlled and noncontrolled conditions, considering both hypotheses. The main objective of this study is to evaluate the redistribution of cellular metabolism and compare the differences or similarities between the phases before and after the metabolic shift of HEK293 cells (shift observed when pH is not controlled). That is from a glucose consumption/lactate production phase to a glucose-lactate coconsumption phase. Interestingly, switching to a glucose and lactate cometabolization results in a better-balanced cell metabolism, with decreased glucose and amino acids uptake rates, affecting minimally cell growth. This behavior could be applied to further develop new approaches in terms of cell engineering and to develop improved cell culture strategies in the field of animal cell technology. PMID- 30411323 TI - Efficacy of erbium glass laser in the treatment of Old World cutaneous leishmaniasis: A case series. AB - BACKGROUND: Treatment of cutaneous leishmaniasis remains a challenge; new physical treatment modalities including laser systems are of interest in the treatment of localized lesions. METHOD: Fourteen patients (10 females) with 20 lesions of Old World cutaneous leishmaniasis underwent weekly treatments of 1540 nm erbium glass fractional laser (Palomar) using 10 mm spot size hand piece in four passes of 50-70 mJ/cm2 fluence and 10 ms pulse duration. RESULTS: Twelve lesions were available for assessment: six (50%) improved at 6 weeks and eleven lesions (91.7%) at 12 weeks. There were no recurrences at 6- and 12-month follow ups. CONCLUSION: Erbium glass fractional laser may be an alternative treatment for localized cases of Old World cutaneous leishmaniasis. PMID- 30411324 TI - Comment on: teaching and learning tips 7: small-group discussion. PMID- 30411325 TI - Who should write and endorse clinical practice guidelines if our patients are to benefit from them? PMID- 30411326 TI - The use of pre-caesarean prophylactic intra-arterial balloon catheters for suspected placenta accreta. AB - INTRODUCTION: The incidence of placenta accreta (PA) has markedly increased in the United States, from 1/30 000 in 1950 to 1/731 deliveries in 2011. Although placenta praevia after prior caesarean sections (CS) is the most important risk factor for PA, other risk factors make up 1-5% of PA occurrences. At our referral hospital, we use the pre-caesarean prophylactic balloon catheter with or without post-surgery embolisation in a hybrid room. Here, we evaluate the role of prior CS and placenta praevia on the outcome of this procedure. MATERIALS AND METHODS: This retrospective cohort analysis included 61 women during the years 2004-2016 with sonographic suspicion of PA who underwent balloon catheterisation prior to CS. RESULTS: Eleven women had no previous CS (18%). Mean previous CS rate was 1.85. Six women (9.8%) had previous dilatation and curettage (D&C); 36.4% of women with no previous CS had previous D&C compared with 4% of women with previous CS (P = 0.008). Placenta praevia was sonographically diagnosed in 55 women (90.2%). There was a higher rate of caesarean hysterectomy in women with previous CS than in those without (32% vs 0%, P = 0.052) but no significant difference in blood product requirements (45.5% vs 66%, P = 0.303). There was no significant difference in hysterectomy rate, blood transfusion or surgery duration between women with and without placenta praevia (P = 0.648, 0.594, 0.995, respectively). CONCLUSION: Previous CS rather than placenta praevia is a strong indicator of hysterectomy in cases of PA. Different risk factors for PA do not affect blood transfusion rates or surgery duration. PMID- 30411327 TI - Development of hand function during the first year of life in children with unilateral cerebral palsy. AB - AIM: To identify developmental trajectories of hand function in infants aged 3 months to 12 months with unilateral cerebral palsy (CP). METHOD: Infants at high risk of unilateral CP were recruited from 3 months of age from follow-up programmes and clinics in Sweden, the Netherlands, Italy, and Australia. Measurements on the Hand Assessment for Infants (HAI) were completed until 12 months of age. Group-based trajectory modelling was used to identify subgroups of infants with similar trajectories of development. Multinomial logistic regression determined associations between demographic variables and trajectory membership. RESULTS: Ninety-seven infants (52 males, 45 females; median gestational age 38wks [interquartile range 30-40wks]) were included. Infants were assessed between two and seven times (mean 4, SD 1.2) with a total of 387 observations. A three-group trajectory model identified a 'low-functioning group' (n=45: 46%), 'moderate functioning group' (n=30: 31%), and 'high-functioning group' (n=22: 23%). Mean posterior probabilities (0.91-0.96) and odds of correct classification (26.3 33.2) indicated good model fit. Type of brain lesion, sex, side of hemiplegia, country, gestational age, and access to intensive intervention were not associated with group membership. INTERPRETATION: Three trajectories of hand function development for infants with unilateral CP were identified and indicate some greater distinctions between groups with increasing age. The HAI is a valuable measure, capturing development of hand function of infants with unilateral CP over time. WHAT THIS PAPER ADDS: Three distinct developmental trajectories of hand function in infants with unilateral cerebral palsy were identified. A low-functioning group made little progress in development of hand function in the first year of life. The degree of impairment on the impaired hand at 6 months of age is highly associated with trajectory membership. Infants with all types of brain lesion were represented across each trajectory group. PMID- 30411328 TI - The incidence of fatal breast cancer measures the increased effectiveness of therapy in women participating in mammography screening. AB - BACKGROUND: Women and their health care providers need a reliable answer to this important question: If a woman chooses to participate in regular mammography screening, then how much will this choice improve her chances of avoiding a death from breast cancer compared with women who choose not to participate? METHODS: To answer this question, we used comprehensive registries for population, screening history, breast cancer incidence, and disease-specific death data in a defined population in Dalarna County, Sweden. The annual incidence of breast cancer was calculated along with the annual incidence of breast cancers that were fatal within 10 and within 11 to 20 years of diagnosis among women aged 40 to 69 years who either did or did not participate in mammography screening during a 39-year period (1977-2015). For an additional comparison, corresponding data are presented from 19 years of the prescreening period (1958-1976). All patients received stage-specific therapy according to the latest national guidelines, irrespective of the mode of detection. RESULTS: The benefit for women who chose to participate in an organized breast cancer screening program was a 60% lower risk of dying from breast cancer within 10 years after diagnosis (relative risk, 0.40; 95% confidence interval, 0.34-0.48) and a 47% lower risk of dying from breast cancer within 20 years after diagnosis (relative risk, 0.53; 95% confidence interval, 0.44-0.63) compared with the corresponding risks for nonparticipants. CONCLUSIONS: Although all patients with breast cancer stand to benefit from advances in breast cancer therapy, the current results demonstrate that women who have participated in mammography screening obtain a significantly greater benefit from the therapy available at the time of diagnosis than do those who have not participated. PMID- 30411329 TI - Treatment of alopecia areata: An Australian expert consensus statement. AB - Alopecia areata (AA) severity varies from a single small patch to complete loss of scalp hair, body hair, eyelashes and eyebrows. While 40% of all affected individuals only ever get one patch and will achieve a spontaneous complete durable remission within 6 months, 27% will develop additional patches but still achieve complete durable remission within 12 months and 33% will develop chronic AA. Without systemic treatment, 55% of individuals with chronic AA will have persistent multifocal relapsing and remitting disease, 30% will ultimately develop alopecia totalis and 15% will develop alopecia universalis. The unpredictable course and psychological distress attributable to AA contributes to the illness associated with AA. Numerous topical, intralesional and systemic agents are currently used to treat AA; however, there is a paucity of data evaluating their use, effectiveness and tolerability. Topical therapy, including topical glucocorticosteroids, minoxidil and immunotherapy, can be used in cases of limited disease. There are no universally agreed indications for initiating systemic treatment for AA. Possible indications for systemic treatment include rapid hair loss, extensive disease (>=50% hair loss), chronic disease, severe distress or a combination of these factors. Currently available systemic treatments include glucocorticosteroids, methotrexate, ciclosporin, azathioprine, dapsone, mycophenolate mofetil, tacrolimus and sulfasalazine. The optimal treatment algorithm has not yet been described. The purpose of this consensus statement is to outline a treatment algorithm for AA, including the indications for systemic treatment, appropriate choice of systemic treatment, satisfactory outcome measures and when to discontinue successful or unsuccessful treatment. PMID- 30411330 TI - Monocytes show immunoregulatory capacity on CD4+ T cells in a human in-vitro model of extracorporeal photopheresis. AB - Extracorporeal photopheresis (ECP) is a widely used immunomodulatory therapy for the treatment of various T cell-mediated disorders such as cutaneous T cell lymphoma (CTCL), graft-versus-host disease (GvHD) or systemic sclerosis. Although clinical benefits of ECP are already well described, the underlying mechanism of action of ECP is not yet fully understood. Knowledge on the fate of CD14+ monocytes in the context of ECP is particularly limited and controversial. Here, we investigated the immunoregulatory function of ECP treated monocytes on T cells in an in-vitro ECP model. We show that ECP-treated monocytes significantly induce proinflammatory T cell types in co-cultured T cells, while anti-inflammatory T cells remain unaffected. Furthermore, we found significantly reduced proliferation rates of T cells after co-culture with ECP-treated monocytes. Both changes in interleukin secretion and proliferation were dependent on cell-contact between monocytes and T cells. Interestingly, blocking interactions of programmed death ligand 1 (PD-L1) to programmed death 1 (PD-1) in the in-vitro model led to a significant recovery of T cell proliferation. These results set the base for further studies on the mechanism of ECP, especially the regulatory role of ECP treated monocytes. PMID- 30411331 TI - Hydroxychloroquine sulphate therapy of erosive oral lichen planus. AB - BACKGROUND/OBJECTIVES: Erosive oral lichen planus (LP) may be painful and debilitating. Symptomatic oral LP has been treated with a wide spectrum of topical and systemic therapies, but few have been evaluated in large series. Hydroxychloroquine is suggested to be effective in oral LP. METHODS: Twenty-one consecutive patients with erosive, biopsy-confirmed oral LP were prescribed. hydroxychloroquine sulphate 400 mg/day. Symptomatic improvement was evaluated by means of a visual analogue scale into three groups: no change, moderate to marked improvement and complete remission. RESULTS: Five (24%) patients obtained complete remission, 12 (57%) patients showed moderate to marked improvement, 3 (14%) patients did not improve at all and in one patient therapy was terminated after 1 month due to side effects. Response to therapy was observed after 2-4 months. Side effects which ultimately led to termination of therapy in three patients were elevated creatinine serum levels (after 1 month), visual field defects (after 8 months) and hyperpigmentation (after 24 months). Among six patients who responded to therapy, three flared on stopping. CONCLUSIONS: Hydroxychloroquine sulphate may be effective and relatively safe treatment for erosive oral LP. PMID- 30411332 TI - Firm digital papulonodules in a young boy. PMID- 30411333 TI - Money as a social relation beyond the state: a contribution to the institutionalist approach based on the Argentinian trueque. AB - This paper provides a contribution to the institutionalist approach to money through ethnographic research carried out in two local currency systems in Argentina (known as trueque). It argues that Argentinian local currencies must be considered as monies in their own right even if they differ from state and bank issued currencies, because they can be understood as systems of evaluation and settlement of debts denominated in a specific unit of account (the credito). Money is said to be an ambivalent social relation because in the two cases studied it mediates very different dynamics, exacerbating inequality in one context and promoting collective emancipation in another. This difference is due to the kind of political communities that the credito tends to forge. In both Rosario and Poriajhu, the political community is defined by a set of values that legitimizes ongoing monetary practices and institutions rather than the State's coercion. PMID- 30411334 TI - Feeding and swallowing impairment in children with stroke and unilateral cerebral palsy: a systematic review. AB - AIM: This systematic review targeted frequency estimates of dysphagia (feeding and swallowing problems), related health outcomes, and caregiver burden in children with stroke or unilateral cerebral palsy (CP). METHOD: Six electronic databases were searched from their inception to November 2017 along with a manual search of eight relevant journals. Two blinded raters assessed abstracts and full articles for eligibility. Discrepancies were resolved by consensus. Accepted articles were evaluated for quality. Data were extracted and analysed descriptively. RESULTS: Of 1660 abstracts, five met inclusion criteria, of which three focused on stroke and two unilateral CP. Across studies, operational definitions of feeding and swallowing varied. Insufficient details were provided on assessment methods and timing. Reported frequencies of dysphagia ranged from 24.2% to 88.6%. One study reported dysphagia-related health outcomes and none reported caregiver burden. INTERPRETATION: These results suggest that dysphagia is common in children with stroke and unilateral CP; however, its frequency is yet unknown as is its impact on health and caregiver burden. Availability of a standardized tool to identify dysphagia in these children accurately is a recommended first step to address this evidence gap. WHAT THIS PAPER ADDS: There is limited data on the incidence of dysphagia after childhood stroke and unilateral cerebral palsy. Available evidence shows reported dysphagia frequencies from 24.2% to 88.6%. Only one study reported on dysphagia-related health outcomes. No study reported on caregiver burden. PMID- 30411335 TI - Mast cells at the crossroads of microbiota and IBD. AB - The human gut harbors a wide range of microorganisms that play a fundamental role in the well-being of their host. A dysregulation of the microbial composition can lead to the development or exacerbation of gastrointestinal (GI) disorders. Emerging evidence supports the hypothesis that mast cells (MCs) play a role in host-microbiota communication, modulating the mutual influence between the host and its microbiota through changes in their activation state. The ability of some bacteria to specifically affect MC functions and activation has been extensively studied, with different and sometimes conflicting results, while only little is known about MC-fungi interactions. In this review, the most recent advances in the field of MC-bacteria and MC-fungi interactions will be discussed, with a particular focus on the role of these interactions in the onset of GI disorders such as inflammatory bowel diseases (IBD). Moreover, the connection between some MC-targeting drugs and IBD was discussed, suggesting probiotics as reasonable and promising therapy in the management of IBD patients. PMID- 30411336 TI - Cutaneous sarcoidosis after Hodgkin lymphoma. PMID- 30411337 TI - A meta-analysis of the agents of selection on floral traits. AB - Floral traits are hypothesized to evolve primarily in response to selection by pollinators. However, selection can also be mediated by other environmental factors. To understand the relative importance of pollinator-mediated selection and its variation among trait and pollinator types, we analyzed directional selection gradients on floral traits from experiments that manipulated the environment to identify agents of selection. Pollinator-mediated selection was stronger than selection by other biotic factors (e.g., herbivores), but similar in strength to selection by abiotic factors (e.g., soil water), providing partial support for the hypothesis that floral traits evolve primarily in response to pollinators. Pollinator-mediated selection was stronger on pollination efficiency traits than on other trait types, as expected if efficiency traits affect fitness via interactions with pollinators, but other trait types also affect fitness via other environmental factors. In addition to varying among trait types, pollinator mediated selection varied among pollinator taxa: selection was stronger when bees, long-tongued flies, or birds were the primary visitors than when the primary visitors were Lepidoptera or multiple animal taxa. Finally, reducing pollinator access to flowers had a relatively small effect on selection on floral traits, suggesting that anthropogenic declines in pollinator populations would initially have modest effects on floral evolution. PMID- 30411338 TI - The role of infectious disease in the evolution of females: Evidence from anther smut disease on a gynodioecious alpine carnation. AB - In flowering plants, the evolution of females is widely hypothesized to be the first step in the evolutionary pathway to separate male and female sexes, or dioecy. Natural enemies have the potential to drive this evolution if they preferentially attack hermaphrodites over females. We studied sex-based differences in exposure to anther-smut (Microbotryum), a sterilizing pollinator transmitted disease, in Dianthus pavonius, a gynodioecious perennial herb. We found that within a heavily diseased population, females consistently had lower levels of Microbotryum spore deposition relative to hermaphrodites and that this difference was driven by rapid floral closing in females following successful pollination. We further show that this protective closing behavior is frequency dependent; females close faster when they are rare. These results indicate that anther-smut disease is an important source of selection for females, especially since we found in a common garden experiment no evidence that females have any inherent fecundity advantages over hermaphrodites. Finally, we show that among populations, those where anther-smut is present have a significantly higher frequency of females than those where the disease is absent. Taken together our results indicate that anther-smut disease is likely an important biotic factor driving the evolution and maintenance of females in this gynodioecious species. PMID- 30411339 TI - Clinicopathological, microenvironmental and genetic determinants of molecular subtypes in KEAP1/NRF2-mutant lung cancer. AB - Somatic KEAP1-NRF2 pathway alterations are frequently detected in both lung adenocarcinomas and squamous cell carcinomas. However, the biological characteristics and molecular subtypes of KEAP1/NRF2-mutant lung cancer remain largely undefined. Here, we performed a stepwise, integrative analytic and experimental interrogation of primary tumors and cancer cell lines harboring KEAP1 or NFE2L2 (encoding NRF2) gene mutations. First, we discovered that KEAP1/NRF2-mutant lung cancer presented APOBEC-mediated mutational signatures, impaired tumor angiogenesis, elevated hypoxic stress and deficient immune-cell infiltrates. Second, gene expression-based subtyping revealed three molecular subsets of KEAP1/NRF2-mutant lung adenocarcinomas and two molecular subsets of KEAP1/NRF2-mutant lung squamous cell carcinomas, each associated with distinguishing genetic, differentiation, immunological and clinicopathological properties. Third, single-sample prediction allowed for de novo identification of KEAP1/NRF2-active tumors within KEAP1/NRF2-wild-type samples. Our data demonstrate that KEAP1/NRF2-mutant lung cancer is a microenvironmentally distinct, biologically heterogeneous, and clinically underestimated disease. These new pathological and molecular insights may accelerate the development of efficacious therapeutic strategies against human malignancies featured by KEAP1 NRF2 pathway activation. PMID- 30411340 TI - Comorbidities, age and period of diagnosis influence treatment and outcomes in early breast cancer. AB - Survival for breast cancer (BC) is lower in eastern than northern/central Europe, and in older than younger women. We analysed how comorbidities at diagnosis affected whether selected standard treatments (STs) were given, across Europe and over time, also assessing consequences for survival/relapse. We analysed 7,581 stage I/IIA cases diagnosed in 9 European countries in 2009-13, and 4 STs: surgery; breast-conserving surgery plus radiotherapy (BCS+RT); reconstruction after mastectomy; and prompt treatment (<=6 weeks after diagnosis). Covariate adjusted models estimated odds of receiving STs and risks of death/relapse, according to comorbidities. Pearson's R assessed correlations between odds and risks. The z-test assessed the significance of time-trends. Most women received surgery: 72% BCS; 24% mastectomy. Mastectomied patients were older with more comorbidities than BCS patients (P<0.001). Women given breast reconstruction (25% of mastectomies) were younger with fewer comorbidities than those without reconstruction (P<0.001). Women treated promptly (45%) were younger than those treated later (P=0.001), and more often without comorbidities (P<0.001). Receiving surgery/BCS+RT correlated strongly (R=-0.9), but prompt treatment weakly (R=-0.01/-0.02), with reduced death/relapse risks. The proportion receiving BCS+RT increased significantly (P<0.001) with time in most countries. This appears to be the first analysis of the influence of comorbidities on receiving STs, and of consequences for outcomes. Increase in BCS+RT with time is encouraging. Although women without comorbidities usually received STs, elderly patients often received non-standard less prompt treatments, irrespective of comorbidities, with increased risk of mortality/relapse. All women, particularly the elderly, should receive ST wherever possible to maximize the benefits of modern evidence-based treatments. PMID- 30411342 TI - NME proteins regulate class switch recombination. AB - Class switch recombination (CSR) in B cells involves deletion-recombination at switch (S) region DNA and is important for the diversification of antibody isotypes during an immune response. Here, we identify two NME [NM23/NDPK (nucleoside diphosphate kinase)] isoforms, NME1 and NME2, as novel players in this process. Knockdown of NME2 leads to decreased CSR, while knockdown of the highly homologous NME1 results in increased CSR. Interestingly, these NME proteins also display differential occupancy at S regions during CSR despite their homology; NME1 binds to S regions prior to stimulation, while NME2 binds to S regions only after stimulation. To the best of our knowledge, this represents the first report of a role for these proteins in the regulation of CSR. PMID- 30411341 TI - Phrenic motoneuron structural plasticity across models of diaphragm muscle paralysis. AB - Structural plasticity in motoneurons may be influenced by activation history and motoneuron-muscle fiber interactions. The goal of this study was to examine the morphological adaptations of phrenic motoneurons following imposed motoneuron inactivity while controlling for diaphragm muscle inactivity. Well-characterized rat models were used including unilateral C2 spinal hemisection (SH; ipsilateral phrenic motoneurons and diaphragm muscle are inactive) and tetrodotoxin phrenic nerve blockade (TTX; ipsilateral diaphragm muscle is paralyzed while phrenic motoneuron activity is preserved). We hypothesized that inactivity of phrenic motoneurons would result in a decrease in motoneuron size, consistent with a homeostatic increase in excitability. Phrenic motoneurons were retrogradely labeled by ipsilateral diaphragm muscle injection of fluorescent dextrans or cholera toxin subunit B. Following 2 weeks of diaphragm muscle paralysis, morphological parameters of labeled ipsilateral phrenic motoneurons were assessed quantitatively using fluorescence confocal microscopy. Compared to controls, phrenic motoneuron somal volumes and surface areas decreased with SH, but increased with TTX. Total phrenic motoneuron surface area was unchanged by SH, but increased with TTX. Dendritic surface area was estimated from primary dendrite diameter using a power equation obtained from three-dimensional reconstructed phrenic motoneurons. Estimated dendritic surface area was not significantly different between control and SH, but increased with TTX. Similarly, TTX significantly increased total phrenic motoneuron surface area. These results suggest that ipsilateral phrenic motoneuron morphological adaptations are consistent with a normalization of motoneuron excitability following prolonged alterations in motoneuron activity. Phrenic motoneuron structural plasticity is likely more dependent on motoneuron activity (or descending input) than muscle fiber activity. PMID- 30411343 TI - Refining the nuclear localization signal within the Egr transcriptional coregulator NAB2. AB - NAB1 and 2 are coregulators for early growth response (Egr) transcription factors. The NAB1 nuclear localization signal (NLS) was previously described as a bipartite NLS of sequence R(X2 )K(X11 )KRXK. The sequence is conserved in NAB2 as K(X2 )R(X11 )KKXK; however, whether it functions as the NAB2 NLS has not been tested. We show that the KKXK motif in NAB2 is necessary and sufficient to mediate nuclear localization. Mutation of the KKXK motif to AAXA causes cytoplasmic localization of NAB2, while Lys/Arg-to-Ala mutations of the upstream K(X2 )R motif have no effect. Fusion of the KKXK motif to cytoplasmic protein eIF2Bepsilon causes nuclear localization. Altogether, this study refines our knowledge of the NAB2 NLS, demonstrating that KKXK343-346 is necessary and sufficient for nuclear localization. PMID- 30411344 TI - Advancing the deer calcaneus model for bone adaptation studies: ex vivo strains obtained after transecting the tension members suggest an unrecognized important role for shear strains. AB - Sheep and deer calcanei are finding increased use as models for studies of bone adaptation, including advancing understanding of how the strain (deformation) environment influences the ontogenetic emergence of biomechanically relevant structural and material variations in cortical and trabecular bone. These artiodactyl calcanei seem ideal for these analyses because they function like simply loaded short-cantilevered beams with net compression and tension strains on the dorsal and plantar cortices, respectively. However, this habitual strain distribution requires more rigorous validation because it has been shown by limited in vivo and ex vivo strain measurements obtained during controlled ambulation (typically walking and trotting). The conception that these calcanei are relatively simply and habitually loaded 'tension/compression bones' could be invalid if infrequent, though biologically relevant, loads substantially change the location of the neutral axis (NA) that separates 'compression' and 'tension' regions. The effect on calcaneus strains of the tension members (plantar ligament and flexor tendon) is also not well understood and measuring strains after transecting them could reveal that they significantly modulate the strain distribution. We tested the hypothesis that the NA location previously described during simulated on-axis loads of deer calcanei would exhibit limited variations even when load perturbations are unusual (e.g. off-axis loads) or extreme (e.g. after transection of the tension members). We also examined regional differences in the predominance of the three strain modes (tension, compression, and shear) in these various load conditions in dorsal, plantar, medial, and lateral cortices. In addition to considering principal strains (tension and compression) and maximum shear strains, we also considered material-axis (M-A) shear strains. M-A shear strains are those that are aligned along the long axis of the bone and are considered to have greater biomechanical relevance than maximum shear strains because failure theories of composite materials and bone are often based on stresses or strains in the principal material directions. We used the same load apparatus from our prior study of mule deer calcanei. Results showed that although the NA rotated up to 8 degrees medially and 15 degrees laterally during these off-axis loads, it did not shift dramatically until after transection of all tension members. When comparing results based on maximum shear strain data vs. M-A shear strain data, the dominant strain mode changed only in the plantar cortex - as expected (in accordance with our a priori view) it was tension when M-A shear strains were considered (shear : tension = 0.2) but changed to dominant shear when maximum shear strain data were considered (shear : tension = 1.3). This difference leads to different conclusions and speculations regarding which specific strain modes and magnitudes most strongly influence the emergence of the marked mineralization and histomorphological differences in the dorsal vs. plantar cortices. Consequently, our prior simplification of the deer calcaneus model as a simply loaded 'tension/compression bone' (i.e. plantar/dorsal) might be incorrect. In vivo and in finite element analyses are needed to determine whether describing it as a 'shear-tension/compression' bone is more accurate. Addressing this question will help to advance the artiodactyl calcaneus as an experimental model for bone adaptation studies. PMID- 30411345 TI - Functional and solution structure studies of amino sugar deacetylase and deaminase enzymes from Staphylococcus aureus. AB - N-Acetylglucosamine-6-phosphate deacetylase (NagA) and glucosamine-6-phosphate deaminase (NagB) are branch point enzymes that direct amino sugars into different pathways. For Staphylococcus aureus NagA, analytical ultracentrifugation and small-angle X-ray scattering data demonstrate that it is an asymmetric dimer in solution. Initial rate experiments show hysteresis, which may be related to pathway regulation, and kinetic parameters similar to other bacterial isozymes. The enzyme binds two Zn2+ ions and is not substrate inhibited, unlike the Escherichia coli isozyme. S. aureus NagB adopts a novel dimeric structure in solution and shows kinetic parameters comparable to other Gram-positive isozymes. In summary, these functional data and solution structures are of use for understanding amino sugar metabolism in S. aureus, and will inform the design of inhibitory molecules. PMID- 30411346 TI - Melanosome diversity and convergence in the evolution of iridescent avian feathers-Implications for paleocolor reconstruction. AB - Some of the most varied colors in the natural world are created by iridescent nanostructures in bird feathers, formed by layers of melanin-containing melanosomes. The morphology of melanosomes in iridescent feathers is known to vary, but the extent of this diversity, and when it evolved, is unknown. We use scanning electron microscopy to quantify the diversity of melanosome morphology in iridescent feathers from 97 extant bird species, covering 11 orders. In addition, we assess melanosome morphology in two Eocene birds, which are the stem lineages of groups that respectively exhibit hollow and flat melanosomes today. We find that iridescent feathers contain the most varied melanosome morphologies of all types of bird coloration sampled to date. Using our extended dataset, we predict iridescence in an early Eocene trogon (cf. Primotrogon) but not in the early Eocene swift Scaniacypselus, and neither exhibit the derived melanosome morphologies seen in their modern relatives. Our findings confirm that iridescence is a labile trait that has evolved convergently in several lineages extending down to paravian theropods. The dataset provides a framework to detect iridescence with more confidence in fossil taxa based on melanosome morphology. PMID- 30411348 TI - Usefulness of repeat pelvic ultrasonography before surgery for benign ovarian mass. AB - OBJECTIVE: To evaluate the results of repeat pelvic ultrasonography before surgery in patients with suspicion of benign ovarian tumor. METHODS: A retrospective study included premenopausal women who were scheduled to undergo surgery for a benign-appearing ovarian mass and who had repeat ultrasonography on the day before surgery at Samsung Medical Center, Seoul, South Korea, between January 1, 2007, and December 31, 2011, to check for any change in the mass. Ultrasonography findings and final histology were evaluated by medical record review. RESULTS: Of 1854 women studied, regression of mass was detected before surgery for 27 patients, and 105 patients had histologically proven functional cysts; considered together, 132 patients had functional cysts, and the remaining 1722 women had benign ovarian tumors. Evaluation of the findings of initial ultrasonography revealed that mean size (P=0.008) and proportion of bilateral cysts (P<0.001) were lower in the presence of functional cysts than benign tumors. Additionally, an anechoic pattern was more common among regressed functional cysts than among histologically proven functional cysts (P<0.001). In total, 105 (5.7%) patients required surgery for a functional cyst despite repeat ultrasonography. CONCLUSION: Repeating ultrasonography prior to surgery may have only a limited ability to prevent unnecessary surgeries for functional cysts. PMID- 30411347 TI - Synergistic effect of PCPE1 and sFRP2 on the processing of procollagens via BMP1. AB - Procollagen processing is essential for organ development and tissue functions. Both procollagen C-proteinase enhancer 1 (PCPE1) and secreted frizzled-related protein 2 (sFRP2) play vital roles in collagen formation via regulating the procollagen C-proteinase activity of bone morphogenetic protein 1 (BMP1). However, whether the two proteins exert a synergistic effect on BMP1 activity remains unclear. Here, simultaneous knockdown of sFRP2 and PCPE1 led to less collagen formation in mouse embryonic fibroblasts and dorsalized phenotypes in zebrafish embryos. Further studies revealed a direct interaction between the Frizzled domain of sFRP2 and the complement/Uegf/BMP-1 domain of PCPE1, which enhances the cleavage activity of BMP1 on procollagen. These results suggest that double silencing of sFRP2 and PCPE1 may provide a strategy for treating fibrosis diseases caused by collagen deposition. PMID- 30411349 TI - Comparison group selection in the presence of rolling entry for health services research: Rolling entry matching. AB - OBJECTIVE: To demonstrate rolling entry matching (REM), a new statistical method, for comparison group selection in the context of staggered nonuniform participant entry in nonrandomized interventions. STUDY SETTING: Four Health Care Innovation Award (HCIA) interventions between 2012 and 2016. STUDY DESIGN: Center for Medicare and Medicaid Innovation HCIA participants entering these interventions over time were matched with nonparticipants who exhibited a similar pattern of health care use and expenditures during each participant's baseline period. DATA EXTRACTION METHODS: Medicare fee-for-service claims data were used to identify nonparticipating, fee-for-service beneficiaries as a potential comparison group and conduct REM. PRINCIPAL FINDINGS: Rolling entry matching achieved conventionally-accepted levels of balance on observed characteristics between participants and nonparticipants. The method overcame difficulties associated with a small number of intervention entrants. CONCLUSIONS: In nonrandomized interventions, valid inference regarding intervention effects relies on the suitability of the comparison group to act as the counterfactual case for the intervention group. When participants enter over time, comparison group selection is complicated. Rolling entry matching is a possible solution for comparison group selection in rolling entry interventions that is particularly useful with small sample sizes and merits further investigation in a variety of contexts. PMID- 30411350 TI - The moment arms of the muscles spanning the glenohumeral joint: a systematic review. AB - The moment arm of a muscle represents its leverage or torque-producing capacity, and is indicative of the role of the muscle in joint actuation. The objective of this study was to undertake a systematic review of the moment arms of the major muscles spanning the glenohumeral joint during abduction, flexion and axial rotation. Moment arm data for the deltoid, pectoralis major, latissimus dorsi, teres major, supraspinatus, infraspinatus, subscapularis and teres minor were reported when measured using the geometric and tendon excursion methods. The anterior and middle sub-regions of the deltoid had the largest humeral elevator moment arm values of all muscles during coronal- and scapular-plane abduction, as well as during flexion. The pectoralis major, latissimus dorsi and teres major had the largest depressor moment arms, with each of these muscles exhibiting prominent leverage in shoulder adduction, and the latissimus dorsi and teres major also in extension. The rotator cuff muscles had the largest axial rotation moment arms regardless of the axial position of the humerus. The supraspinatus had the most prominent elevator moment arms during early abduction in both the coronal and scapular planes as well as in flexion. This systematic review shows that the rotator cuff muscles function as humeral rotators and weak humeral depressors or elevators, while the three sub-regions of the deltoid behave as substantial humeral elevators throughout the range of humeral motion. The pectoralis major, latissimus dorsi and teres major are significant shoulder depressors, particularly during abduction. This study provides muscle moment arm data on functionally relevant shoulder movements that are involved in tasks of daily living, including lifting and pushing. The results may be useful in quantifying shoulder muscle function during specific planes of movement, in designing and validating computational models of the shoulder, and in planning surgical procedures such as tendon transfer surgery. PMID- 30411351 TI - Assisted reproductive outcomes in women with different polycystic ovary syndrome phenotypes. AB - OBJECTIVE: To explore assisted reproductive outcomes among women with different polycystic ovary syndrome (PCOS) phenotypes. METHODS: A retrospective cohort study included women with PCOS who were treated at Yazd Research and Clinical Center for Infertility, Yazd, Iran, using the GnRH antagonist protocol between April 1, 2015, and August 31, 2017. Clinical pregnancy was the primary outcome, and chemical pregnancy, implantation rate, fertilization rate, and spontaneous abortion rate, were the secondary outcomes that were evaluated among four defined phenotypes of women with PCOS. RESULTS: Significant differences were observed between the phenotypes for the levels of luteinizing hormone, anti-Mullerian hormone, fasting blood sugar, and total testosterone concentration; similarly, the percentage of women with luteinizing hormone/follicle stimulating hormone ratio of at least 2.5 differed between PCOS phenotypes (all P<0.001). There were also significant differences in estradiol level (P<0.001) and the number of matured follicles (P=0.002) between different phenotypes. No significant differences were observed in the fertilization and implantation rates, as well as chemical and clinical pregnancy rates (all P>0.05). CONCLUSION: No significant differences were observed in assisted reproductive technique outcome among women with different phenotypes of PCOS undergoing frozen-thawed embryo transfer. PMID- 30411352 TI - Pre- and postnatal development of the otic ganglion in humans. AB - Only a few papers exist dealing with the development and aging of the autonomic nervous system - and even rarer are studies that investigated the otic ganglion. Using a special trepan, we removed and investigated 172 samples from 86 corpses, ranging from 20 weeks of gestational age (GA) to 95 years of age. The aim of the study was to measure different morphometric parameters of the ganglionic neurons in order to study age-related changes from early development until old age. Fetuses show the highest numerical density of neurons. Then, in the first years of life, a rapid growth of the cytoplasm takes place, which is the main reason for the neuronal growth and the increase of the general size of the otic ganglion at this age. Also, the number of satellite cells increases till puberty. In adults, the parameters are relatively stable over decades and decrease slowly, in contrast to the steep increase in the first years of life. Moreover, neuronal degeneration, storage of pigments, neuro-axonal dystrophy, and lymphocytic infiltrates increase with age. PMID- 30411353 TI - Association between Helicobacter pylori gastritis and dental diseases: A cross sectional, hospital-based study in Eastern Saudi Arabia. AB - BACKGROUND: There is inconsistent evidence about the association between Helicobacter pylori (H. pylori) and dental diseases with possible effect of environmental factors. OBJECTIVE: The aims of the study were to assess (1) the association between gastric and oral H. pylori colonization and (2) the association between oral colonization of H. pylori and dental diseases. MATERIALS AND METHODS: A cross sectional study was conducted in King Fahad University hospital in Khobar, Eastern Saudi Arabia in 2017. Patients admitted to the Endoscopy Unit were recruited and clinically examined for plaque, decayed teeth (D), filled teeth (F), missing teeth (M), periodontal pocket depth (PPD), attachment loss (AL), and gingival bleeding in addition to assessing their age, gender, education, tooth brushing, flossing, and tobacco use with a questionnaire. Pooled dental plaque samples were collected and analyzed using nested polymerase chain reaction PCR to detect oral H. pylori. Gastroscopy was used to extract biopsies to assess gastritis and the presence of gastric H. pylori using Giemsa stain. Regression analysis was used to assess differences between patients with and without gastritis, oral H. pylori and gastric H. pylori in the percentage of sites with gingival bleeding, PPD, CAL, D, M, and F with adjustment for confounders. RESULTS: One hundred twenty patients were included. Most of them brushed daily (82.6%) and had university education (45.7%). Of these, 34.2% had gastric H. pylori and 5% had oral H. pylori. No significant association was observed between the percentage of sites with gingival bleeding, mean PPD, AL, F, and either gastritis, the presence of oral or gastric H. pylori. Patients with gastritis had significantly higher number of D and M than patients without gastritis (P = 0.03). CONCLUSION: In this study, the presence of gastric and oral H. pylori in patients with good oral hygiene and moderate socioeconomic status is not significantly associated with periodontal diseases. Patients with gastritis tend to have a higher number of decayed and missing teeth. PMID- 30411354 TI - Is tioconazole contact dermatitis still a concern? Bringing allergic contact dermatitis caused by topical tioconazole back into the spotlight. PMID- 30411355 TI - Effect of sequential twin screw extrusion and fungal pretreatment to release soluble nutrients from soybean residue for carotenoids production. AB - BACKGROUND: Soybean residue (okara) is an agricultural by-product, which is rich in protein and fiber. This study evaluated a novel sequential process which combined fungal pretreatment (F) and twin screw extruder (E), to hydrolyze okara. The sequence of the pretreatment steps, and extruder at screw speeds 200 rpm (200) or 600 rpm (600), were tested. Next, soluble nutrients were extracted to create Fokara, EFokara200, EFokara600, FEokara200 and FEokara600 okara media. RESULTS: All the prepared okara media could support the growth and carotenoids production by the yeast Rhodosporidium toruloides (R. toruloides). This suggested that okara proteins and polysaccharides were successfully hydrolyzed by extrusion and fungal pretreatment, into soluble nutrients. R. toruloides accumulated the highest biomass of 23.7 mg mL-1 DCW, when grown on FEokara600 media. This was higher as compared to commercial YPG media (18.7 mg mL-1 DCW). On the other hand, R. toruloides accumulated the highest carotenoids production of 13.2 MUg mL-1 when grown on EFokara200 media as the nutrient source. This was comparable to the carotenoids production of 13.1 MUg mL-1 when R. toruloides was grown on YPG media. CONCLUSION: Extrusion in combination with fungal pretreatment, is a low cost process, to hydrolyze and re-use okara, for carotenoids production. This article is protected by copyright. All rights reserved. PMID- 30411356 TI - A tale of 2 poles. PMID- 30411357 TI - Inter-professional education - Building respect and cooperation between future health-care colleagues. PMID- 30411358 TI - Fetal lipomyelomeningocele: A closed neural tube defect diagnosed at second trimester ultrasound examination. AB - Fetal lipomyelomeningocele was suspected during the second-trimester ultrasound and confirmed by magnetic resonance imaging. The pregnancy took its course and a term neonate was delivered. At 2 years of age lipomyelomeningocele surgical removal was performed. The patient is now 4 years old and, despite neurogenic bladder, is a healthy boy with normal psychomotor development for his age. This case illustrates the favorable prognosis of this entity and the importance of prompt diagnosis and multidisciplinary counseling. PMID- 30411359 TI - Bacterial endocarditis and increased cardiac troponin I levels in a brown howler monkey (Alouatta guariba clamitans) with an interventricular septal defect. AB - A brown howler monkey (Alouatta guariba clamitans) was presented with lethargy, hyporexia, cough and heart murmur. The complementary tests and necropsy revealed pleuropneumonia, bacterial endocarditis and interventricular septal defect. To the best of our knowledge, this is the first report of increased cardiac troponin I levels in this species. PMID- 30411360 TI - Transient heat stress during tuber development alters post-harvest carbohydrate composition and decreases processing quality of chipping potatoes. AB - BACKGROUND: Adverse air and soil temperatures are abiotic stresses that occur frequently and vary widely in duration and magnitude. Heat stress limits productivity of cool-weather crops such as potato (Solanum tuberosum) and may degrade crop quality. Stem-end chip defect is a localized discoloration of potato chips that adversely affects finished chip quality. The causes of stem-end chip defects are poorly understood. RESULTS: Chipping potatoes were grown under controlled environmental conditions to test the hypothesis that stem-end chip defect is caused by transient heat stress during the growing season. Heat stress periods with 35 degrees C days and 29 degrees C nights were imposed approximately 3 months after planting and lasted for 3, 7 or 14 days. At harvest and after 1, 2 and 3 months of storage at 13 degrees C, potato tubers were evaluated for glucose, fructose, sucrose and dry matter contents at the basal and apical ends. Chips were fried and rated for defects at the same sampling times. Differences in responses to heat stress were observed among four varieties of chipping potatoes. Heat stress periods of 7 and 14 days increased reducing sugar content in the tuber basal and apical ends, decreased dry matter content, and increased the severity of stem-end chip defects. CONCLUSION: Transient heat stress during the growing season decreased postharvest chipping potato quality. Tuber reducing sugars and stem-end chip defects increased while dry matter content decreased. Planting varieties with tolerance to transient heat stress may be an effective way to mitigate these detrimental effects on chipping potato quality. This article is protected by copyright. All rights reserved. PMID- 30411361 TI - Image features and DUS testing traits for peanut pods variety identification and pedigree analysis. AB - BACKGROUND: DUS (Distinctness, Uniformity and Stability) testing of new varieties is an important method for peanut germplasm evaluation and identification of varieties. In order to verify the feasibility of variety identification for peanut DUS testing based on image processing, 2000 peanut pod images from 20 varieties were obtained by a scanner. First, 6 DUS testing traits were quantified using mathematical method based on image processing technology, and then, size, shape, color and texture features (totally 31) were also extracted. Fisher algorithm was used as feature selection method to select "good" features from the extracted features to expand DUS testing traits set. Then, SVM and K-means algorithm were respectively used as recognition model and clustering method for variety identification and pedigree clustering. RESULTS: It can be found that, by Fisher selection method, a number of significant candidate features for DUS testing have been selected which can be used in the DUS testing further; using the half top of these features (about 18) ordered by Fisher discrimination ability, the recognition rate of SVM model is more than 90%, which is better than unordered features. In addition, a pedigree clustering tree of 20 peanut varieties has been built based on K-means clustering method, which can be used in deeper study of the genetic relationship of different varieties. CONCLUSION: This paper can provide a novel reference method for future DUS testing, peanut varieties identification and study of peanut pedigree. This article is protected by copyright. All rights reserved. PMID- 30411363 TI - Author Response to "Addition of Insulin to Parenteral Nutrition Is Not Universally Safe". PMID- 30411362 TI - Short-term perioperative iron in major orthopedic surgery: state of the art. AB - In major orthopaedic surgery, it is recommended to detect and correct preoperative anaemia several weeks prior to surgery. However, in many cases, the procedure is urgent or the patient is evaluated shortly before the intervention. As iron deficiency is the leading cause of perioperative anaemia, an exhaustive review of the literature was performed to assess the efficacy and safety of short term perioperative intravenous, with or without erythropoietin, or postoperative oral or intravenous supplementation in major orthopaedic surgery. Overall, 20 studies met the inclusion criteria. There were 13 randomized trials (moderate quality) and seven observational studies (low to very low quality). The primary outcomes were reduction in transfusion requirements, haemoglobin increase and medication side-effects during the study period. Data analysis showed that postoperative oral iron administration neither increased haemoglobin nor reduced transfusion requirements, and it was associated with significant gastrointestinal adverse effects (15%). In contrast, for some patient populations, perioperative or postoperative administration of intravenous iron, with or without recombinant erythropoietin, may reduce transfusion requirements and/or hasten the recovery from postoperative, with few clinically relevant adverse effects (<2%). However, discrepancies between randomized trials and observational studies on the possible beneficial effects of short-term perioperative intravenous iron administration were found for patients undergoing surgery for hip fracture repair. Further studies are needed to elucidate when the treatment should be started, which combination of drugs should be used, and which patient groups would be most benefit. PMID- 30411364 TI - Serological evidence of human infection by bat orthoreovirus in Singapore. AB - To determine whether Pteropine orthoreovirus (PRV) exposure has occurred in Singapore, we tested 856 individuals from an existing serum panel collected from 2005-2013. After an initial screen with luciferase immunoprecipitation system and secondary confirmation with virus neutralization test, we identified at least seven individuals with specific antibodies against PRV in both assays. Our findings confirm that PRV spillover into human populations is relatively common in this region of the world. PMID- 30411365 TI - Quality characteristics of pomegranate juice concentrates produced by ohmic heating assisted vacuum evaporation. AB - BACKGROUND: Vacuum evaporation (VE) process is widely utilized in fruit juice evaporation to preserve quality attributes of final product. However, it has some disadvantages such as possible degradation of aroma components or volatile fatty acids due to long process time, and low energy efficiency of process. Pomegranate juice having 17.5% total soluble solid (TSS) content was evaporated to 40% TSS by ohmic heating assisted vacuum evaporation (OVE; 7.5, 10 and 12.5 V cm-1 ) and VE in the present study. The effects of the evaporation methods on pH, titratable acidity and colour values, antioxidant activity (AA), total monomeric anthocyanin (TMA), total phenolic content (TPC), hydroxymethylfurfural (HMF) and invert sugar content of pomegranate juice concentrates were compared. RESULTS: The colour properties, TMA, TPC and AA values of pomegranate juice concentrates evaporated by OVE were more influenced than those evaporated by VE. The degradation of sugars was minimized for OVE processes at high voltage gradients (10 and 12.5 V cm-1 ), and HMF content of pomegranate juice concentrated by OVE was lower than VE. CONCLUSION: It is thought that electrochemical reactions occurred because of the use of titanium electrodes during the OVE process caused these quality changes in pomegranate juice concentrates having high acidity. Hence, it was concluded that the utilization of relatively more electrochemically inert electrodes should be investigated in further studies to better evaluate the of influence of OVE method on quality attributes of different fruit juices. (c) 2018 Society of Chemical Industry. PMID- 30411366 TI - Erythema multiforme-like contact dermatitis caused by herbal medicine. AB - Allergic contact dermatitis (ACD) may sometimes present as non-eczematous morphology, such as pigmented, lichenoid, erythema multiforme-like, pustular or sclerodermoid type (1). Although the eliciting allergens are variable, erythema multiforme-like contact dermatitis has often been linked to exotic woods (2). In this report, we will illustrate two cases of erythema multiform-like contact dermatitis induced by local contact with herbal medicine. PMID- 30411367 TI - Using Stable Isotope Signatures to Delineate the Geographic Point-of-Origin of Keemun Black Tea. AB - BACKGROUND: Confirmation of food labeling that claims production in a small geographic region is critical to traceability, quality control and brand protection. In the current study, isotope ratio mass spectrometry (IRMS) was used to generate profiles of delta13 C and delta15 N to determine if the stable isotope signatures of Keemun black tea differ within the three counties that claim production. Other factors (cultivar type, leaf maturity and manufacturing process) were considered for their potential effects. RESULTS: Both cultivar type and leaf maturity have remarkable impact on the delta15 N values of tea leaves, and that the cultivar influenced the delta13 C values. Keemun black tea from Qimen county could be easily discriminated from samples from Dongzhi and Guichi counties based on delta15 N signatures. The k-NN model was cross-validated with an accuracy of 91.6%. Environmental factors and/or genotype seem to be the major reasons for delta15 N differences in Keemun black tea from the selected regions. CONCLUSION: This article provides a potential effective method to delineate the geographic point-of-origin of Keemun black tea based on delta15 N signatures. This article is protected by copyright. All rights reserved. PMID- 30411368 TI - New Zealand rickettsia-like organism (NZ-RLO) and Tenacibaculum maritimum: Distribution and phylogeny in farmed Chinook salmon (Oncorhynchus tshawytscha). AB - A total of 777 fish from three growing regions of New Zealand Chinook salmon farms comprising of five sites were tested. Quantitative PCR was used to determine the distribution of New Zealand rickettsia-like organism and Tenacibaculum maritimum. Genetic information from these bacteria were then compared with strains reported worldwide. Using this information, suggested associations of pathogens with clinically affected fish were made. NZ-RLO was detected in two of the three regions, and T. maritimum was detected in all regions. Three strains of NZ-RLO were identified during this study. Based on analysis of the ITS rRNA gene, NZ-RLO1 appears to be part of an Australasian grouping sharing high similarity with the Tasmanian RLO, NZ-RLO2 was shown to be the same as an Irish strain, and NZ-RLO3 was shown be closely related to two strains from Chile. Based on multi-locus sequence typing, the New Zealand T. maritimum was the same as Australian strains. NZ-RLOs were detected more frequently in fish with skin ulcers than fish without skin ulcers. While additional research is required to investigate the pathogenicity of these organisms, this is the first time that NZ-RLOs have been associated with the development of clinical infections in farmed Chinook salmon. PMID- 30411369 TI - Dynamics of non-structural glycoprotein-1 in dengue patients presenting with different clinical manifestations from 1986 to 2012 in Rio de Janeiro, Brazil. AB - The hyperendemicity and co-circulation of different dengue serotypes in Brazil have increased the number of severe dengue cases and the rate of hospitalization for dengue. Virological and individual factors are associated with the disease's complexity. Antigenemia levels of non-structural glycoprotein-1 (NS1) have been associated with severe dengue. Aiming to identify a severity marker during the acute phase (0-5 days of disease), the association of NS1 antigenemia with clinical presentation, sex, age range, immune response, number of days of disease and serotype RNA levels was evaluated in serum samples of patients from the state of Rio de Janeiro clinically classified as having dengue without warning signs (DWWS) or dengue with warning signs/severe dengue (DWWS/SD). Immune response was classified by in-house ELISA, antigenemia determined by quantification of NS1 and viremia quantified by real-time PCR. Of the total number of patients, 36.6% (74/202) presented warning signs/severe dengue and 72.3% (146/202) were classified with primary infection. DENV-2 presented an association between clinical presentation and antigenemia (p=0.02). DENV-3 had higher levels of NS1 (p<0.0001). This study has shown that the infecting serotype influences circulating NS1 levels in the host, as well as NS1 antigenemia may vary as to the clinical presentation of the DENV-2 infected patient. However, the criterion used to screen patients for clinical presentation, in DWWS and DWWS/SD patients, was not a good marker for dengue severity in our study. This article is protected by copyright. All rights reserved. PMID- 30411370 TI - Addressing the conundrums of p-phenylenediamine hair dye allergy by applying Friedmann's principles of contact sensitization. AB - In the first conundrum, permanent hair dyeing uses aromatic amines such as p phenylenediamine (PPD), whose oxidation is pivotal to the dyeing process, but also generates potent allergens. Despite prolonged industry effort searching for safer alternatives, hair dyeing is still reliant on this type of aromatic amine. In the second conundrum, patch testing with 1% PPD remains the most useful screen for hair dye contact allergy. However, there is a very small but real risk of actively sensitising the patient. Lowering the PPD concentration below 1% significantly reduces test sensitivity and diagnostic utility. Here we argue that by applying Friedmann's principles of contact sensitisation each conundrum can be addressed from a new perspective. These principles indicate that where the exposed area of skin is small (<1cm2 ), induction of contact allergy is sharply reduced, whereas elicitation of allergy is unaffected. Careful reflection on this principle suggests that we can predict where hair dye sensitisation is most likely to occur, indicates a strategy to reduce the chances of contact sensitisation in consumers from hair dyeing, and how we might mitigate the risk of active sensitisation from diagnostic patch testing. PMID- 30411371 TI - JPEN Journal Club 40. Differences in Nominal Significance. PMID- 30411372 TI - Long-Term Outcomes in Children With Intestinal Failure-Associated Liver Disease Treated With 6 Months of Intravenous Fish Oil Followed by Resumption of Intravenous Soybean Oil. AB - BACKGROUND: Intravenous soybean oil (SO) is a commonly used lipid emulsion for children with intestinal failure (IF); however, it is associated with IF associated liver disease (IFALD). Studies have demonstrated that intravenous fish oil (FO) is an effective treatment for IFALD. However, there is a lack of long term data on children who stop FO and resume SO. This study's objective was to investigate our institution's outcomes for children with IFALD treated with 6 months of FO and who then restarted SO. METHODS: Inclusion criteria for FO included children with IFALD. Parenteral nutrition (PN)-dependent children resumed SO after FO and were prospectively followed for 4.5 years or until death, transplant, or PN discontinuation. The primary outcome was the cumulative incidence rate (CIR) for cholestasis after FO. RESULTS: Forty-eight subjects received FO, and conjugated bilirubin decreased over time (-0.22 mg/dL/week; 95% confidence interval [CI]: -0.25, -0.19; P < .001). The CIR for cholestasis resolution after 6 months of FO was 71% (95% CI: 54%, 82%). Twenty-seven subjects resumed SO and were followed for a median of 16 months (range 3-51 months). While the CIR for enteral autonomy after 3 years of follow-up was 40% (95% CI: 17%, 26%), the CIR for cholestasis and transplant was 26% (95% CI: 8%, 47%) and 6% (95% CI: 0.3%, 25%), respectively. CONCLUSION: In this study, FO effectively treated cholestasis, and SO resumption was associated with cholestasis redevelopment in nearly one-fourth of subjects. Long-term FO may be warranted to prevent end-stage liver disease. PMID- 30411373 TI - Addition of Insulin to Parenteral Nutrition Is Not Universally Safe. PMID- 30411374 TI - Three cases of photoallergic contact dermatitis induced by benzophenone in amusement park wristbands. AB - Ketoprofen is known to cause allergic and photoallergic contact dermatitis and to co-react with several chemicals, including benzophenone-type UV absorbers (1) and octocrylene. Three patients who wore the same type of amusement park wristband in the same summer developed dermatitis at the site of the wristband. PMID- 30411375 TI - Statistical modeling and prediction of clinical trial recruitment. AB - Real-time prediction of clinical trial accrual can support logistical planning, ensuring that studies meet but do not exceed sample size targets. We describe a novel, simulation-based prediction method that is founded on a realistic model for the underlying processes of recruitment. The model reflects key features of enrollment such as the staggered initiation of new centers, heterogeneity in enrollment capacity, and declining accrual within centers. The model's first stage assumes that centers join the trial (ie, initiate accrual) according to an inhomogeneous Poisson process in discrete time. The second part assumes that each center's enrollment pattern reflects an early plateau followed by a slow decline, with a burst at the end of the trial following the announcement of an imminent closing date. By summing up achieved and projected enrollment, one can predict accrual as a function of time and, thereby, the time when the trial will achieve a planned enrollment target. We applied our method retrospectively to two real world trials: NSABP B-38 and REMATCH (Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure). In both studies, the proposed method produced prediction intervals for time to completion that were more accurate than those from conventional predictions that assume a constant rate of enrollment, estimated either from the entire trial to date or over a recent time window. The advantage is substantial in the early stages of NSABP B 38. We conclude that a method based on a realistic accrual model offers improved accuracy in the prediction of enrollment landmarks, especially at the early stages of large trials that involve many centers. PMID- 30411376 TI - Penalized variable selection for accelerated failure time models with random effects. AB - Accelerated failure time (AFT) models allowing for random effects are linear mixed models under the log-transformation of survival time with censoring and describe dependence in correlated survival data. It is well known that the AFT models are useful alternatives to frailty models. To the best of our knowledge, however, there is no literature on variable selection methods for such AFT models. In this paper, we propose a simple but unified variable-selection procedure of fixed effects in the AFT random-effect models using penalized h likelihood (HL). We consider four penalty functions (ie, least absolute shrinkage and selection operator (LASSO), adaptive LASSO, smoothly clipped absolute deviation (SCAD), and HL). We show that the proposed method can be easily implemented via a slight modification to existing h-likelihood estimation procedures. We thus demonstrate that the proposed method can also be easily extended to AFT models with multilevel (or nested) structures. Simulation studies also show that the procedure using the adaptive LASSO, SCAD, or HL penalty performs well. In particular, we find via the simulation results that the variable selection method with HL penalty provides a higher probability of choosing the true model than other three methods. The usefulness of the new method is illustrated using two actual datasets from multicenter clinical trials. PMID- 30411377 TI - Differences between activities of coagulation factors after one month of therapy with different direct oral anticoagulant in pulmonary embolism patients. AB - WHAT IS KNOWN AND OBJECTIVE: Direct oral anticoagulants (DOACs) are frequently used for the treatment of pulmonary embolism (PE), but both clinical and laboratory data comparing their efficacy and safety are conflicting. This study investigated and compared the impact of three DOACs (apixaban, rivaroxaban and dabigatran) on coagulation cascade in acute PE patients. METHODS: After the initial treatment, acute PE patients were randomly allocated to one of three groups, and treatment continued using one of the three DOACs. Following 1 month of treatment, the activity of factors II, VII and VIII, as well as protein C, antithrombin, D-dimer and fibrinogen, were measured, and the values were compared between the groups. RESULTS AND DISCUSSION: One hundred consecutive PE patients were included. The mean values for the activity of factors II and VII and protein C were higher in patients on apixaban than in patients on rivaroxaban (1.45 +/- 1.12 (IU/mL) vs 1.13 +/- 0.92 (IU/mL), P < 0.001; 1.24 +/- 1.10 (IU/mL) vs 1.05 +/- 0.98 (IU/mL), P = 0.024 and 1.15 +/- 0.62 vs 1.02 +/- 0.68 (IU/mL), P = 0.019, respectively). The mean of factor II activity and the median of factor VIII activity were also significantly higher in patients on apixaban than in patients on dabigatran (1.45 +/- 1.12 vs 1.20 +/- 0.96 (IU/mL), P = 0.003 and 2.9 (2.0-4.0) vs 2.1 (1.5-2.7) (IU/mL), P = 0.001, respectively). No difference was noticed in D-dimer concentrations, or in the activity of the other factors measured. Additionally, no difference was noticed between the rivaroxaban and dabigatran groups. WHAT IS NEW AND CONCLUSION: Apixaban had a significantly higher thrombin activity, above the laboratory determined normal range, compared to patients on rivaroxaban and dabigatran. This higher thrombin activity in patients on apixaban may contribute to a better haemostatic response during the therapy or increased prothrombotic state after therapy interruption. PMID- 30411378 TI - Human CD96 correlates to NK cell exhaustion and predicts the prognosis of human hepatocellular carcinoma. AB - Immune checkpoint blockade has become a promising therapeutic approach to reverse immune cell exhaustion. Co-inhibitory CD96 and TIGIT, together with co stimulatory CD226, bind to common ligand CD155. The balancing between three receptors fine tunes the immune responses against tumors. In this study, we investigated the expression of CD96, TIGIT and CD226 in 55 fresh human hepatocellular carcinoma (HCC) samples, 236 paraffin-embedded HCC samples, and 20 normal human livers. The cumulative percentage, absolute count, and MFI of CD96+ NK cells are significantly increased in the intratumoral tissues of HCC, and break the balance between three receptors. Human CD96+ NK cells are functionally exhausted with impaired IFN-gamma and TNF-alpha production, high gene expression of IL-10 and TGF-beta1, and low gene expression of T-bet, IL-15, perforin and granzyme B. In addition, blocking CD96-CD155 interaction specifically increases lysis of HepG2 cells by NK cells. HCC patients with high level of CD96 or CD155 expression within tumor are strongly associated with deteriorating disease condition, shorter disease-free survival (DFS) and overall survival (OS) times. Patients with higher cumulative percentage of CD96+ NK cells within tumor also exhibit shorter DFS. High plasma level of TGF-beta1 in HCC patients up-regulates CD96 expression and dynamically shifts the balance between CD96, TIGIT and CD226 in NK cells. Blocking TGF-beta1 specifically restores normal CD96 expression and reverses the dysfunction of NK cells. Conclusion: these findings indicate that human intratumoral CD96+ NK cells are functionally exhausted and patients with higher intratumoral CD96 expression exhibit poorer clinical outcomes. Blocking CD96-CD155 interaction or TGF-beta1 restores NK cell immunity against tumors by reversing NK cell exhaustion, suggesting a possible therapeutic role of CD96 in fighting liver cancer. This article is protected by copyright. All rights reserved. PMID- 30411379 TI - Practical issues in using generalized estimating equations for inference on transitions in longitudinal data: What is being estimated? AB - Generalized estimating equations (GEEs) are commonly used to estimate transition models. When the Markov assumption does not hold but first-order transition probabilities are still of interest, the transition inference is sensitive to the choice of working correlation. In this paper, we consider a random process transition model as the true underlying data generating mechanism, which characterizes subject heterogeneity and complex dependence structure of the outcome process in a very flexible way. We formally define two types of transition probabilities at the population level: "naive transition probabilities" that average across all the transitions and "population-average transition probabilities" that average the subject-specific transition probabilities. Through asymptotic bias calculations and finite-sample simulations, we demonstrate that the unstructured working correlation provides unbiased estimators of the population-average transition probabilities while the independence working correlation provides unbiased estimators of the naive transition probabilities. For population-average transition estimation, we demonstrate that the sandwich estimator fails for unstructured GEE and recommend the use of either jackknife or bootstrap variance estimates. The proposed method is motivated by and applied to the NEXT Generation Health Study, where the interest is in estimating the population-average transition probabilities of alcohol use in adolescents. PMID- 30411381 TI - CD8-positive Pseudolymphoma in Lues maligna and HIV with monoclonal TCR-beta rearrangement. AB - A 42-year-old Caucasian man suffered from disseminated plaques and ulcerated nodules for six weeks. He had weight loss and generalized lymphadenopathy. Underlying diseases were not known up till then. Based on a skin biopsy the diagnosis of CD8-positive cutaneous T-cell lymphoma, type mycosis fungoides was made in a pathological reference center for lymphoma. A reproducible TCR-beta rearrangement was detectable. Before starting therapy, a new biopsy was taken and the previous diagnosis was re-evaluated taking clinical images and symptoms into account. Based on both, the diagnosis of a CD8+ pseudolymphoma in lues maligna and HIV was made. We highlight histopathologic clues for the correct diagnosis, and we emphasize the indispensability of clinical-pathological correlation. Furthermore, we discuss the differential diagnosis of CD8+ lymphoproliferative disorders. This article is protected by copyright. All rights reserved. PMID- 30411382 TI - Systematic review: efficacy and safety of switching patients between reference and biosimilar infliximab. AB - BACKGROUND: Biosimilar versions of widely prescribed drugs, including the tumour necrosis factor antagonist infliximab, are becoming increasingly available. As biosimilars are not identical copies of reference products, evidence may be required to demonstrate that switching between a reference biologic and biosimilars is safe and efficacious. To establish interchangeability, US Food and Drug Administration guidance states that studies must demonstrate that biosimilars remain equivalent or non-inferior to a reference product after multiple switches between products. AIMS: To investigate the evidence evaluating the safety and efficacy of switching between reference and biosimilar infliximab in patients with inflammatory disorders, including Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis. METHODS: Published studies presenting data on switching between reference and biosimilar infliximab were identified by searching the MEDLINE database. Congress abstracts were identified by searching the EMBASE database and manually searching abstracts from relevant congresses. RESULTS: A total of 113 journal articles and 149 abstracts were found. Of these, 70 were considered relevant and included in this analysis. Most of the publications were uncontrolled, observational studies. Data from six randomised, controlled trials were identified. In general, the evidence revealed no clinically important efficacy or safety signals associated with switching. CONCLUSIONS: While available data have not identified significant risks associated with a single switch between reference and biosimilar infliximab, the studies available currently report on only single switches and were mostly observational studies lacking control arms. Additional data are needed to explore potential switching risks in various populations and scenarios. PMID- 30411380 TI - The epidermal growth factor receptor ligand amphiregulin protects from cholestatic liver injury and regulates bile acids synthesis. AB - Intrahepatic accumulation of bile acids (BA) causes hepatocellular injury. Upon liver damage, a potent protective response is mounted to restore the organ's function. Epidermal growth factor receptor (EGFR) signaling is essential for regeneration after most types of liver damage, including cholestatic injury. However, EGFR can be activated by a family of growth factors induced during liver injury and regeneration. We evaluated the role of the EGFR ligand amphiregulin (AREG) during cholestatic liver injury and the regulation of AREG expression by BA. First, we demonstrated increased AREG levels in livers from patients with primary biliary cholangitis and primary sclerosing cholangitis. In two murine models of cholestatic liver injury, bile duct ligation (BDL) and alpha-naphthyl isothiocyanate (ANIT) gavage, hepatic AREG expression was markedly upregulated. Importantly, Areg-/- mice showed aggravated liver injury after BDL and ANIT administration compared to Areg+/+ mice. Recombinant AREG protected from ANIT and BDL-induced liver injury and reduced BA-triggered apoptosis in liver cells. Oral BA administration induced ileal and hepatic Areg expression, and interestingly cholestyramine feeding reduced postprandial Areg upregulation in both tissues. Most interestingly, Areg-/- mice displayed high hepatic CYP7A1 expression, reduced serum cholesterol and high BA levels. Postprandial repression of Cyp7a1 was impaired in Areg-/- mice, and recombinant AREG downregulated Cyp7a1 mRNA in hepatocytes. On the other hand, BA promoted AREG gene expression and protein shedding in hepatocytes. This effect was mediated through the farnesoid X receptor (FXR), as demonstrated in Fxr-/- mice, and involved EGFR transactivation. Finally, we show that hepatic EGFR expression is indirectly induced by BA-FXR through the activation of suppressor of cytokine signaling-3. Conclusion: AREG-EGFR signaling protects from cholestatic injury and participates in the physiological regulation of BA synthesis. This article is protected by copyright. All rights reserved. PMID- 30411383 TI - LRRK2 impairs autophagy by mediating phosphorylation of leucyl-tRNA synthetase. AB - Leucine-rich repeat kinase 2 (LRRK2) is a causal gene of Parkinson disease. G2019S pathogenic mutation increases its kinase activity. LRRK2 regulates various phenotypes including autophagy, neurite outgrowth, and vesicle trafficking. Leucyl-tRNA synthetase (LRS) attaches leucine to tRNALeu and activates mTORC1. Down-regulation of LRS induces autophagy. We investigated the relationship between LRRK2 and LRS in regulating autophagy and observed interaction between endogenous LRRK2 and LRS proteins and LRS phosphorylation by LRRK2. Mutation studies implicated that T293 in the LRS editing domain was a putative phosphorylation site. Phospho-Thr in LRS was increased in cells overexpressing G2019S and dopaminergic neurons differentiated from induced pluripotent stem (iPS) cells of a G2019S carrier. It was decreased by treatment with an LRRK2 kinase inhibitor (GSK2578215A). Phosphomimetic T293D displayed lower leucine bindings than wild type (WT), suggesting its defective editing function. Cellular expression of T293D increased expression of GRP78/BiP, LC3B-II, and p62 proteins and number of LC3 puncta. Increase of GRP78 and phosphorylated LRS was diminished by treatment with GSK2578215A. Levels of LC3B, GRP78/BiP, p62, and alpha synuclein proteins were also increased in G2019S transgenic (TG) mice. These data suggest that LRRK2-mediated LRS phosphorylation impairs autophagy by increasing protein misfolding and endoplasmic reticulum stress mediated by LRS editing defect. SIGNIFICANCE OF THE STUDY: Leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of Parkinson disease (PD), and the most prevalent pathogenic mutation, G2019S, increases its kinase activity. In this study, we elucidated that leucyl-tRNA synthetase (LRS) was an LRRK2 kinase substrate and identified T293 as an LRRK2 phosphorylation site. LRRK2-meidated LRS phosphorylation or G2019S can lead to impairment of LRS editing, increased ER stress, and accumulation of autophagy markers. These results demonstrate that LRRK2 kinase activity can facilitate accumulation of misfolded protein, suggesting that LRRK2 kinase might be a potential PD therapeutic target along with previous studies. PMID- 30411384 TI - Eosinophilic dermatosis of hematologic malignancy: Correlation of molecular characteristics of skin lesions and extracutaneous manifestations of hematologic malignancy. AB - BACKGROUND: Skin diseases are frequent in patients with chronic lymphocytic leukemia and other hematological neoplasias. Eosinophilic dermatosis of hematologic malignancy (ED) has long been considered a nonspecific cutaneous reaction pattern. Recently neoplastic cells have been shown to be present in ED thus challenging the classification as a nonspecific dermatosis. METHODS: We report 5 patients with ED in association with chronic lymphocytic leukemia (CLL). We further investigated the presence of neoplastic B-cells in the skin infiltrate by immunohistochemistry and immunoglobulin heavy chain rearrangement and compared these to extracutaneous manifestations of CLL. RESULTS: The phenotype of the lymphocytic infiltrate was predominately CD3+ (range: 60-90%). CD20+ and CD79a+ lymphocytes were less frequent accounting for up to 15% (range: absent - 15%). CD23+ lymphocytes represented up to 20% (range: absent - 20%) of the infiltrate. The analysis of the immunoglobulin heavy chain rearrangement in the skin specimens showed clonal rearrangements in 4/5 patients and in 3 of these 4 patients clones were identical to extracutaneous CLL manifestations. CONCLUSION: Our data show that neoplastic B-cells are very frequently found in ED when systematically evaluated. This findings support the hypothesis that leukemic cells play a pathogenetic role in eosinophilic dermatosis of hematologic malignancy. This article is protected by copyright. All rights reserved. PMID- 30411385 TI - Role of estradiol and testosterone in Ucp1 expression in brown/beige adipocytes. AB - Activity of brown/beige adipocytes is higher in women than in men. The expression level of uncoupling protein 1 (UCP1) is largely consistent with the thermogenic activity in brown/beige adipocytes. The present study examined the direct effects of sex hormones on Ucp1 expression in brown adipocytes and beige adipocytes, which were differentiated from HB2 brown preadipocytes and 3T3-L1 white preadipocytes, respectively; treatment with estradiol or testosterone was used during the early (days 0-8) or late stage (days 8-12) of brown adipogenesis and beige adipogenesis. On day 8 or day 12, cells were treated with or without isoproterenol (Iso), an agonist for the beta-adrenergic receptor, for 4 hours. Furthermore, the sex of cells was examined; the sex-determining region y gene, which is located on the y chromosome, was present in HB2 cells, but not in 3T3-L1 cells, suggesting that HB2 cells and 3T3-L1 cells are male and female cells, respectively. Treatment with 17beta-estradiol during the early stage of brown adipogenesis enhanced the responsiveness to Iso on Ucp1 induction, whereas treatment during the late stage of brown adipogenesis decreased Ucp1 expression in unstimulated brown adipocytes. Estradiol decreased Iso-induced Ucp1 expression during the early stage of beige adipogenesis. Treatment with testosterone during the early stage of brown adipogenesis did not affect Ucp1 expression but increased the responsiveness to Iso on Ucp1 induction by the treatment during the late stage of brown adipogenesis. The present results suggest that sex hormones modulate the expression level of Ucp1 in brown/beige adipocytes in a stage dependent manner. Direct effects of sex hormones in brown/beige adipogenesis were evaluated. Treatment with 17beta-estradiol during the early stage of brown adipogenesis enhanced the responsiveness to isoproterenol (Iso), an agonist for the beta-adrenergic receptor, on Ucp1 induction, whereas treatment during the late stage of brown adipogenesis decreased Ucp1 expression in unstimulated brown adipocytes. Estradiol decreased Iso-induced Ucp1 expression during the early stage of beige adipogenesis. Testosterone during the late stage of brown adipogenesis increased the responsiveness to Iso on Ucp1 induction. Sex hormones modulate the expression level of Ucp1 in brown/beige adipocytes in a stage dependent manner. PMID- 30411386 TI - Effects of anoxic exposure on the nuclear factor of activated T cell (NFAT) transcription factors in the stress-tolerant wood frog. AB - The wood frog, Lithobates sylvaticus (also known as Rana sylvatica), is used for studying natural freeze tolerance. These animals convert 65% to 70% of their total body water into extracellular ice and survive freezing for weeks in winter. Freezing interrupts oxygen delivery to organs; thus, wood frogs limit their ATP usage by depressing their metabolism and redirecting the available energy only to prosurvival processes. Here, we studied the nuclear factor of activated T cell (NFAT) transcription factor family in response to 24-hour anoxia, and 4-hour aerobic recovery in liver and skeletal muscle. Protein expression levels of NFATc1-c4, calcineurin A and glycogen synthase kinase 3beta (NFAT regulators), osteopontin, and atrial natriuretic peptide (ANP) (targets of NFATc3 and NFATc4, respectively) were measured by immunoblotting, and the DNA-binding activities of NFATc1-c4 were measured by DNA-protein interaction ELISAs. Results show that NFATc4, calcineurin, and ANP protein expression as well as NFATc4 DNA binding increased during anoxia in liver where calcineurin and ANP protein levels and NFATc4 DNA binding remaining high after aerobic recovery. Anoxia caused a significant increase in NFATc3 protein expression but not DNA-binding activity in muscle. Our results show that anoxia can increase NFATc4 transcriptional activity in liver, leading to the increase in expression of cytoprotective genes in the wood frog. Understanding the molecular mechanisms involved in mediating survival under anoxia/reoxygenation conditions in a naturally stress-tolerant model, such as the wood frog, provides insightful information on the prosurvival regulatory mechanisms involved in combating stress. This information will also further our understanding of metabolic rate depression and answer the question of how frogs tolerate prolonged periods of oxygen deprivation and resume to full function upon recovery without facing any detrimental side effects as other animals would. PMID- 30411387 TI - Rapid separation of post-blast explosive residues on glass electrophoresis microchips. AB - This study describes the development of an analytical methodology based on the use of microchip electrophoresis (ME) devices integrated with capacitively coupled contactless conductivity detection (C4 D) for the separation and detection of inorganic anions in post-blast explosive residues. The best separation condition was achieved using a running buffer composed of 35 mmol/L lactic acid, 10 mmol/L histidine and 0.070 mmol/L cetyl(trimethyl ammonium) bromide. For C4 D measurements, the highest sensitivity was obtained applying a 700 kHz sinusoidal wave with excitation voltage of 20 Vpp . The separation of Cl- , NO3 - , NO2 - , SO4 2- , ClO4 - and ClO3 - was performed within ca. 150 s with baseline resolution and efficiencies between 4.4 * 104 and 1.7 * 105 plates/m. The found limits of detection ranged between 2.5 and 9.5 MUmol/L. Last, real samples of post-blast explosive residues were analyzed on the ME-C4 D devices obtaining successfully the determination of Cl- , NO3 - and SO4 2- . The achieved concentration values varied between 12.8-72.5 mg/L for Cl- , 1.7-293.1 mg/L for NO3 - and 1.3-201.3 mg/L for SO4 2- . The data obtained using ME-C4 D devices were in good agreement with the concentrations found by ion chromatography. The approach reported herein has provided short analysis time, instrumental simplicity, good analytical performance and low cost. Furthermore, the ME-C4 D devices emerge as a powerful and portable analytical platform for on-site analysis demonstrating to be a promising tool for the crime scene investigation. PMID- 30411388 TI - Urotensin II receptor expression in prostate cancer patients: A new possible marker. AB - BACKGROUND: Urotensin II receptor has been poorly studied in prostate cancer. To evaluate the expression of urotensin II receptor (UII-R) in patients undergoing radical prostatectomy. METHODS: Overall, we identified 140 patients treated with retropubic radical prostatectomy (RP) in one center. UII-R was evaluated in prostate biopsies with immunohistochemical staining, resulting in a granular cytoplasmic positivity, through automated system using the kit Urotensin II Receptor Detection System provided by Pharmabullet srl. Immunostained slides were independently and blindly evaluated by ten uro-pathologists. To evaluate UTII-R expression three different parameters were considered: localization, granules dimensions and intensity of expression. A score from 0 to 3 was applied to each parameter to obtain a score from 0 to 9. Each parameter and the total score were evaluated as predictors of high grade disease on surgical pathology and of advanced stage disease. Accuracy of total score for the prediction of upgrading and upstaging was analyzed using receiver operator characteristics curve and decision curve analysis (DCA). RESULTS: On radical prostatectomy 92/140 (66%) presented high grade disease on surgical pathology. Patients with high grade disease presented an apical distribution of the receptor, larger granules and a more intense expression when compared to patients with low grade disease. A well they presented a higher total score. Subscores and total scores were found to be predictors of upgrading and upstaging. On ROC analysis total score presented an AUC of 0.72 and 0.70, respectively, for the prediction of upgrading and upstaging. On DCA total score showed a clinical benefit in the prediction of adverse pathological outcomes. CONCLUSION: Urotensin II receptor is a potential marker of adverse pathological outcomes. Further studies should confirm our data and evaluate its role as a prognostic marker. PMID- 30411389 TI - Systematic review: the consequences of psychosocial effects of inflammatory bowel disease on patients' reproductive health. AB - BACKGROUND: High levels of voluntary childlessness and pregnancy-related fears have been reported amongst inflammatory bowel disease (IBD) patients. AIMS: To investigate what factors determine IBD patients' childbearing decisions; and to examine psychosocial consequences of IBD on various aspects of patients' reproductive health. METHODS: Six electronic databases were searched in a pre specified and structured manner. RESULTS: A total of 41 articles with data on 7122 patients were included. Between one-fifth to one-third of IBD patients had chosen voluntary childlessness. Around 50% of all IBD patients have poor knowledge of pregnancy-related issues in IBD. Poor knowledge of pregnancy-related issues in IBD was associated with voluntary childlessness. Observational studies have found preconception counselling is associated with patients choosing parenthood. Pregnancy-related fears and concerns are multifaceted, stemming partly from lack of knowledge of pregnancy-related issues in IBD. Many female patients are considered at increased risk for pregnancy because between one-fifth to one-third of patients do not use contraception. Research evidence for sexual dysfunction after disease diagnosis and treatment is inconsistent. There are limited data on patients' pregnancy, postpartum and parenting experiences. A few shortcomings of the literature are evident; sample sizes were small, participation rates were low, use of non-validated questionnaires was common, and few studies included men and/or ethnic minority groups. The design of intervention studies is also weak. CONCLUSION: This review recommends pre conception counselling for all IBD patients of childbearing age to tackle poor knowledge and allow patients to make an informed decision on their reproductive health. PMID- 30411390 TI - Evaluation of pubertal onset and characteristics in Egyptian boys: A cross sectional study. AB - The objective of this study was to evaluate pubertal onset and characteristics in Egyptian boys. Examination of schoolboys (9-18 years) included height (cm), penile length (cm) and testicular volume (ml). Pubertal onset was considered at gonadal (G) stage 2 (G2 indicated testicular volume from 4-8 ml). Out of 1,078 boys, 270 (25%) were residents in urban areas, 414 (38.4%) in suburban areas and 394 (36.5%) in rural areas. The mean (+/-SD) age of G2 was 11.1 +/- 1.2 years (5th and 95th percentiles were 10 and 13 years respectively). The age of 10.5 years was predictive of G2 with 89.9% sensitivity and 86.2% specificity (95% confidence interval; p < 0.001). The changes in testicular volumes and penile lengths, at the age interval from 16 to 18 years, were not significant. Pubertal onset was earlier among Egyptian boys in urban areas, with smaller family size, less crowding conditions, adequate illumination and good ventilation, although the difference was not statistically significant (p > 0.05). In conclusion, the mean age of pubertal onset among Egyptian boys was 11.1 years. A tendency towards earlier pubertal onset was observed in Egyptian boys who lived in urban areas and had better socio-demographic conditions. PMID- 30411391 TI - Loss of tolerance to glycoprotein 2 isoforms 1 and 4 is associated with Crohn's disease of the pouch. AB - BACKGROUND: Zymogen granule glycoprotein 2 (GP2) is a major autoantigen of Crohn's disease-specific pancreatic autoantibodies. AIM: To test a link between loss of tolerance to isoforms of GP2 and pouch disorders in a cross-sectional study in ulcerative colitis patients with ileal pouch-anal anastomosis (IPAA). METHODS: Serum samples of 117 consecutive ulcerative colitis patients after IPAA were tested for presence of Anti-GP2 isoforms 1 (GP21 ) & 4 (GP24 ) IgG and IgA as well as anti-Saccaromyces cervisiae (ASCA) IgG and IgA antibodies in a blinded fashion via enzyme-linked immunosorbent assay. Pouch disorders were diagnosed based on clinical, endoscopic, histological and radiographic criteria. Crohn's disease of the pouch was defined as involvement of the small bowel mucosa proximal to the ileal pouch with Crohn's disease, development of perianal complications or pouch fistula more than 3 months after ileostomy closure. RESULTS: Positivity and level of Anti-GP21 IgG (AUC 0.77; P < 0.001 & P = 0.02, respectively), Anti-GP24 IgG (AUC 0.74; P < 0.001 & P = 0.025, respectively) and Anti-GP24 IgA (AUC 0.77; P < 0.001 to P = 0.018, respectively) were specifically associated with Crohn's disease of the pouch. Anti-GP2 was not associated with endoscopic or histological pouch disease activity index. Neither positivity nor levels of ASCA IgG (AUC 0.63; P = 0.12 & P = 0.35, respectively) or ASCA IgA (AUC 0.67; P = 0.38 & P = 0.53) were associated with pouch phenotypes. CONCLUSIONS: The novel anti-GP21 and GP24 antibodies are associated with Crohn's disease of the pouch in ulcerative colitis patients after IPAA. Serological anti-GP2 antibodies could aid in diagnosis of Crohn's disease of the pouch. PMID- 30411392 TI - Androgen receptor gene mutations are associated with male infertility in Northeast China: Clinical features and identification of two novel mutations. AB - The purpose of this study was to investigate the prevalence of androgen receptor gene mutations in idiopathic male infertility in north-east China and to analyse the relationship between genotype and phenotype. Cohorts of 400 male patients with idiopathic infertility and 200 fertile controls were recruited. Clinical investigations were carried out by experienced andrologists. Targeted exome sequencing was used to detect androgen receptor gene mutations, and reproductive hormone levels were measured. We found four mutations in 8/400 patients (2%) and no mutations in controls. In addition, two recurrent mutations (p.S176R and p.A403V) were found in four patients and two patients respectively. Of four mutations, two (p.S233F and p.H715N) represented novel mutations. Almost all of the men with androgen receptor gene mutations showed smaller testicular volumes. However, the reproductive hormone levels were normal or lightly higher in seven men with mutation, apart from one man (P24) who had high follicle-stimulating hormone and luteinising hormone levels but a low testosterone level. In north east China, there was a higher androgen receptor gene mutation rate among these infertile men, and the mutation of p.S176R deserved more attention particularly. Hormone levels and clinical phenotypes did not help in screening patients at risk of mutations. PMID- 30411393 TI - Effects of branched-chain amino acid supplementation and/or aerobic exercise on mouse sperm quality and testosterone production. AB - Individuals who regularly exercise utilise dietary supplements to enhance their exercise routine and to increase lean mass. Branched-chain amino acids (BCAAs) are a popular supplement and have been shown to produce a number of beneficial effects in rodent and human models. Therefore, in the present study, the effect of exercise and/or BCAA on sperm parameters and testes tissue was assessed. C57BL6 male mice were divided to six groups; Control, Exercise (Exc), BCAA (consumes 20 mg BCAAs), BCAA+ (consumes 60 mg BCAAs), BCAA/Exc (consumes 20 mg BCAAs during aerobic training) and BCAA+/Exc (consumes 60 mg BCAAs during aerobic training). After 8 weeks of exercise and oral treatment with BCAA; testes and epididymides were dissected, and sperm function and plasma testosterone were assessed. Exercise significantly improved sperm motility and plasma testosterone in Exercise groups with or without BCAA. Percentage of sperm lipid peroxidation was significantly decreased in Exercise group, while intensity of lipid peroxidation at the same group has significantly increased. Epithelium diameters, meiotic index and Johnson' grade did not show any changes between groups. Unlike intensive exercise, endurance exercise along with modest supplementation of BCAAs, but not an overdose, may have some synergic effect on sperm function and testosterone production. PMID- 30411394 TI - Hydroxyurea-induced dermatomyositis koebnerizing at the site of previous shingles. PMID- 30411395 TI - Orchidopexy for bilateral undescended testes: A multicentre study on its effects on fertility and comparison of two fixation techniques. AB - To evaluate fertility potential after orchidopexy for bilateral undescended testis and compare two surgical fixation techniques for effect on fertility. Men older than 22 years who had either tunica albuginea orchidopexy (TAO) or "no touch" technique (NTO) in childhood for bilateral undescended testis (BUDT) were selected. Participants filled out a questionnaire followed by physical examination, had testicular ultrasound, blood sample and semen analysis. Statistical testing was performed using general linear modelling. Sixty-seven out of 166 individuals responded. Forty-nine completed the questionnaire, and nine (18.3%) reported having fathered children. Thirty-six showed up for further examination, 26 had TAO and 10 NTO. Impaired hormonal spermatogenesis regulation (34.6% vs. 20%), higher subfertility rate (46% vs. 20%) and lower means of motile spermatozoa (58.1 * 106 spz vs. 177.9 * 106 spz) were observed in the TAO versus the NTO group; none of these were statistically significant. Four (15.4%) of the TAO and two (20%) of the NTO group have azoospermia. Although the operation technique did not have a significant impact on fertility, unfavourable outcomes were more common after surgery involving the tunica albuginea of the testis. Larger sample sizes are needed to ascertain whether the trends favouring the NTO technique are of any significance. PMID- 30411396 TI - Will donor-derived neoplasia be problematic after clinical pig organ or cell xenotransplantation? AB - There is an increased incidence of certain tumors and other neoplastic disease in organ allotransplant recipients receiving immunosuppressive therapy. Following clinical pig organ xenotransplantation, will there be a risk of the development of neoplasia in the pig graft or in other tissues transplanted with it, eg, lymph nodes? The incidence of neoplasia in young slaughterhouse pigs is very low (<0.005%), but in older pigs is largely unknown (as most pigs are killed within the first six months of life). However, lymphosarcoma, nephroblastoma, and melanoma have been reported in pigs. These tumors should be readily identified by ultrasound or direct inspection and palpation before an organ is excised for clinical xenotransplantation, and so transfer to the human recipient should be unlikely. Post-transplant lymphoproliferative disorder (PTLD) has been reported in pigs receiving intensive immunomodulatory therapy, particularly if this includes whole body irradiation, in an effort to induce mixed hematopoietic chimerism and immunological tolerance. However, the pigs used as sources of organs in xenotransplantation should be free of the porcine lymphotropic herpesvirus that is a key causative factor for PTLD in pigs, and so donor-derived PTLD should not occur. We conclude that the risk of a malignant tumor developing in a transplanted organ from a young pig is small. PMID- 30411398 TI - Open access and academic imperialism. PMID- 30411397 TI - First-time isolation and quantification of Basidiobolus spp. from reptile faeces in KwaZulu-Natal (South Africa) using selective media. AB - Members of the genus Basidiobolus are potentially pathogenic fungi, known to cause mycoses in tropical and subtropical countries. Basidiobolus spp. can be associated with animals, and reptiles and amphibians are candidate vectors for the distribution of this fungus. The presence of Basidiobolus spp. was described for different reptiles in several African countries, although not for South Africa. In addition, quantitative data are scarce. The aim of this study was to analyse faeces of selected South African reptiles for the presence and quantity of "viable Basidiobolus units." Faecal samples of gecko and agama lizards were collected and analysed using spread plating, with confirmation by PCR. The addition of dichloran and benomyl to standard fungal media improved the selectivity and allowed quantification of Basidiobolus spp. in reptile faeces. The amount of Basidiobolus spp. varied between 300 and 1.4 * 106 CFU per gram of pooled gecko faeces, which mostly corresponds to >1000 CFU per outside dropping and <100 CFU per inside dropping. About 60% of analysed agama faeces carried Basidiobolus spp., ranging from 150 to 1.2 * 105 CFU per dropping. Our results show for the first time that faeces of South African reptiles frequently carry Basidiobolus spp., confirming that they can contribute to the distribution of this fungus. PMID- 30411399 TI - Compassionate versus consequentialist conservation. AB - Ethical treatment of wildlife and consideration of animal welfare have become important themes in conservation but ethical perspectives on how best to protect wild animals and promote their welfare are diverse. We present the advantages offered by the consequentialist 'harms' ethical framework applied to managing wild herbivores for conservation purposes. We argue that, to minimize harms while achieving conservation goals, overabundant wild herbivores should in many cases be managed through consumptive in situ killing. This argument is based on six advantages: 1) imposing negative welfare states on animals being killed for only very short durations, 2) not depriving the remaining animals of positive welfare states (e.g., linked to rearing offspring), 3) preventing overpopulation and poor welfare states facing overabundant populations (e.g., starvation), 4) preventing welfare impacts imposed on heterospecifics through resource depletion (i.e., competition), 5) harvesting meat and thereby not requiring other (agricultural) animals to be raised to supply that meat, and 6) incurring minimal costs and thereby maximizing funding available for other wildlife management and conservation priorities. Alternative ethical approaches to our consequentialist framework comprise deontology (including animal rights), and forms of virtue ethics, some of which underpin 'compassionate conservation'. These alternative ethical approaches emphasize the importance of avoiding intentional killing of animals but, if no management occurs, are likely to impose considerable unintentional harms on overabundant wildlife and indirectly harm heterospecifics through ineffective population reduction. If non-lethal ontrol is used, they are likely to deprive overabundant animals of positive welfare states and incur prohibitive economic costs. We encourage all with a stake in conservation to consider animal welfare consequentialism as an ethical approach to minimize harms to the animals under their duty of care as well as other animals that policies may affect while at the same time pursuing conservation goals. This article is protected by copyright. All rights reserved. PMID- 30411400 TI - Influence of mildly and moderately elevated pulmonary artery systolic pressure on post-renal transplantation survival and graft function. AB - BACKGROUND: Severe pulmonary hypertension (PH) has been associated with decreased post-kidney transplant survival and increased rate of long-term cardiovascular complications. Despite a high prevalence of PH in patients with end-stage renal disease, data on post-transplant renal allograft survival in recipients with pre existing mild-to-moderate PH are limited. METHODS: The single-center retrospective study cohort consisted of 192 consecutive (2008-2015) renal transplant recipients with documented pretransplantation transthoracic echocardiogram (TTE) pulmonary artery systolic pressure (PASP). Mean age was 50.9 +/- 12.4 years, 36.5% were females, and 81.25% were Caucasians. RESULTS: Elevated PASP >= 37 mm Hg was present in 51 patients. Elevated PASP was more common in patients with decreased <50% left ventricular ejection fraction (13.73% vs 3.55%, P = 0.010); otherwise, there were no significant differences in baseline demographic (age, ethnicity, gender, and donor status) and clinical parameters between patients with normal and elevated PASP. Four-year mortality (5.7%) was not significantly affected by elevated PASP. However, elevated PASP was associated with significantly decreased estimated glomerular filtration rate (eGFR) at 1 year (52.26 vs 60.13 mL/min, P = 0.019) and 2 years (51.04 vs 60.28 mL/min, P = 0.006) post-transplant. CONCLUSION: Mild and moderately elevated pre kidney transplant PASP does not affect 4-year post-transplant mortality or graft loss. However, elevated pretransplant PASP is significantly associated with decreased 1 year and 2 years post-transplant eGFR. Preoperative echocardiographic evaluation for PH may be useful in predicting the probability of short-term renal graft and long-term graft dysfunction in these patients. PMID- 30411401 TI - Inhibitors in haemophilia A and B: Management of bleeds, inhibitor eradication and strategies for difficult-to-treat patients. AB - The standard therapy for patients with haemophilia is prophylactic treatment with replacement factor VIII (FVIII) or factor IX (FIX). Patients who develop inhibitors against FVIII/FIX face an increased risk of bleeding, and the likelihood of early development of progressive arthropathy, alongside higher treatment-related costs. Bypassing agents can be used to prevent and control bleeding, as well as the recently licensed prophylaxis, emicizumab, but their efficacy is less predictable than that of factor replacement therapy. Antibody eradication, by way of immune tolerance induction (ITI), is still the preferred management strategy for treating patients with inhibitors. This approach is successful in most patients, but some are difficult to tolerise and/or are unresponsive to ITI, and they represent the most complicated patients to treat. However, there are limited clinical data and guidelines available to help guide physicians in formulating the next treatment steps in these patients. This review summarises currently available treatment options for patients with inhibitors, focussing on ITI regimens and those ITI strategies that may be used in difficult to-treat patients. Some alternative, non-ITI approaches for inhibitor management, are also proposed. PMID- 30411402 TI - Evidence-based diabetes care for older people with Type 2 diabetes: a critical review. AB - In our ageing society diabetes imposes a significant burden in terms of the numbers of people with the condition, diabetes-related complications including disability, and health and social care expenditure. Older people with diabetes can represent some of the more complex and difficult challenges facing the clinician working in different settings, and the recognition that we have only a relatively small (but increasing) evidence base to guide us in diabetes management is a limitation of our current approaches. Nevertheless, in this review we attempt to explore what evidence there is to guide us in a comprehensive scheme of treatment for older adults, often in a high-risk clinical state, in terms of glucose lowering, blood pressure and lipid management, frailty care and lifestyle interventions. We strive towards individualized care and make a call for action for more high-quality research using different trial designs. PMID- 30411403 TI - Two-dimensional speckle tracking to image ventricular-arterial coupling in uremia. AB - OBJECTIVE: To study ventricular-arterial coupling(VAC) in uremic patients by application of two-dimensional speckle tracing imaging (2DSTI). METHODS: One hundred uremic patients were divided into two groups based on left ventricular ejection fraction (LVEF): group 1 with LVEF >= 5%, and group 2 with LVEF < 55%. Forty healthy subjects were recruited as a control group. Conventional echocardiography was performed; VAC components and myocardial performance index were calculated. Longitudinal strain (LS) of 17 segments was measured using 2DSTI. Mean base (LSBA ), papillary muscle (LSPM ), and apex values (LSAP ) were calculated. RESULTS: Compared to subjects in the control group and group 1, subjects in group 2 exhibited decreased LV end-diastolic volume (EDV), end systolic volume (ESV), LV mass index (LVMI), and VAC (P < 0.05). EF, fractional shortening (FS), end-systolic elastance (Ees) were significantly higher in group 2 (P < 0.05). SLBA , SLPM , and SLAP differed significantly among the groups (all P < 0.05). SLBA , SLPM , and SLAP correlated positively with Ees, EF, and FS (all P < 0.05) but negatively with arterial elastance (Ea), VAC, systemic vascular resistance index (SVRI), and rate-pressure product (RPP) (all P < 0.05). Multiple regression analysis revealed that relative wall thickness (RWT), LVMI, LSAP , and stroke works (SW) were independent predictors of VAC (b' = -0.443, 0.537, -0.470, and -0.491, all P < 0.05). CONCLUSIONS: In patients with uremia, LV myocardial LS gradually decreased as LV systolic dysfunction decreased. VAC correlated negatively with left ventricular LS, and LSAP was an independent predictor for VAC. PMID- 30411404 TI - Historical perspectives on contemporary human-environment dynamics in southeast Africa. AB - The human communities and ecosystems of island and coastal southeast Africa face significant and linked ecological threats. Socio-ecological conditions of concern to communities, governments, non-governmental organizations (NGO's), and researchers include declining agricultural productivity, deforestation, introductions of exotic flora and fauna, coastal erosion and sedimentation, damage to marine habitats, illegal fishing and overfishing, waste pollution, salinization of fresh water supplies and rising energy demands, among others. Human-environment challenges are connected to longer, often ignored, histories of social and ecological dynamics in the region. We argue that these challenges are more effectively understood and addressed within a longer-term historical ecological framework. We review cases from Madagascar, coastal Kenya and the Zanzibar Archipelago grouped under the themes of fisheries, forests and waste to encourage increased engagement between historical ecologists, conservation scientists and policy makers. PMID- 30411405 TI - Optimal promising zone designs. AB - Clinical trials with adaptive sample size reassessment based on an unblinded analysis of interim results are perhaps the most popular class of adaptive designs (see Elsabetaer et al., 2007). Such trials are typically designed by prespecifying a zone for the interim test statistic, termed the promising zone, along with a decision rule for increasing the sample size within that zone. Mehta and Pocock (2011) provided some examples of promising zone designs and discussed several procedures for controlling their type-1 error. They did not, however, address how to choose the promising zone or the corresponding sample size reassessment rule, and proposed instead that the operating characteristics of alternative promising zone designs could be compared by simulation. Jennison and Turnbull (2015) developed an approach based on maximizing expected utility whereby one could evaluate alternative promising zone designs relative to a gold standard optimal design. In this paper, we show how, by eliciting a few preferences from the trial sponsor, one can construct promising zone designs that are both intuitive and achieve the Jennison and Turnbull (2015) gold-standard for optimality. PMID- 30411408 TI - Historical Perspective on Nutrition and Intensive Care. PMID- 30411407 TI - Autopsied centenarian case of Alzheimer's disease combined with hippocampal sclerosis, TDP-43, and alpha-synuclein pathologies. AB - A Japanese woman showed slowly progressive memory disturbance starting at the age of 84 years, and disorientation gradually appeared. Head computed tomography revealed severe hippocampal atrophy, whereas the atrophy of the frontal lobe was considerably mild for her age. Behavioral and psychological symptoms of dementia were relatively inconspicuous during the disease course. Apolipoprotein E gene analysis showed epsilon3/epsilon4 heterozygosity. She died at the age of 100 years and she was clinically diagnosed as having Alzheimer's disease (AD). Autopsy revealed numerous neurofibrillary tangles, particularly in the hippocampal region, and extensively distributed senile plaques in the brain. Although the findings were compatible with the pathological criteria for AD, combined pathologies of hippocampal sclerosis, trans-activation response DNA binding protein 43 kDa, and alpha-synuclein were also revealed. We believe that the clinicopathological findings of the present case are of significance for the diagnosis of elderly dementia and pathogenesis of AD. PMID- 30411406 TI - Apolipoprotein A-Ib as a biomarker of focal segmental glomerulosclerosis recurrence after kidney transplantation: diagnostic performance and assessment of its prognostic value - a multi-centre cohort study. AB - Recurrence of idiopathic focal segmental glomerulosclerosis (FSGS) is a serious complication after kidney transplantation. FSGS relapse is suspected by a sudden increase in proteinuria but there is not an accurate noninvasive diagnostic tool to confirm this entity or to detect patients at risk. We aimed to validate the diagnostic performance of ApoA-Ib to detect FSGS relapses by measuring urinary ApoA-Ib in a retrospective cohort of 61 kidney transplanted patients (37 FSGS and 24 non-FSGS). In addition, to assess the ApoA-Ib predictive ability, ApoA-Ib was measured periodically in a prospective cohort of 13 idiopathic FSGS patients who were followed during 1 year after transplantation. ApoA-Ib had a sensitivity of 93.3% and a specificity of 90.9% to diagnose FSGS relapses, with a high negative predictive value (95.2%), confirming our previous results. In the prospective cohort, ApoA-Ib predated the recurrence in four of five episodes observed. In the nonrelapsing group (n = 9), ApoA-Ib was negative in 37 of 38 samples. ApoA-Ib has the potential to be a good diagnostic biomarker of FSGS relapses, providing a confident criterion to exclude false positives even in the presence of high proteinuria. It has also the potential to detect patients at risk of relapse, even before transplantation. PMID- 30411409 TI - Wheat particle size, insoluble fibre sources and whole wheat feeding influence gizzard musculature and nutrient utilisation to different extents in broiler chickens. AB - A 21-day experiment was conducted to investigate the effects of wheat particle size, insoluble fibre source and whole wheat (WW) inclusion on the gizzard musculature, intestinal architecture and nutrient utilisation of broiler chickens. The following seven treatments, all in mash form, were tested: control diet using finely ground wheat (Fine); control diet using medium-ground wheat (Medium); control diet using coarsely ground wheat (Coarse); fine diet diluted with 10 g/kg lignocellulose (LC); fine diet diluted with 30 g/kg oat hulls (OH); fine diet diluted with 30 g/kg wood shavings (WS); and ground wheat in the fine diet replaced with 50 and 100 g/kg WW during the second (day 8-14) and third (day 15-21) weeks of the study respectively. Except for the LC diet, all treatments increased (p < 0.05) the thickness of the caudodorsal thick muscle of gizzard compared to the fine diet. The highest (p < 0.05) caudoventral thin and cranioventral thick muscle diameters in the gizzard walls were achieved with the OH and WS diets. Feeding OH, WS and WW diets improved (p < 0.05) starch digestibility compared with the fine diet, while medium, coarse and LC diets had no effect (p > 0.05). All diets containing fibre sources (LC, OH and WS) reduced (p < 0.05) the energy digestibility compared to the fine diet. Birds fed OH and WS diets gained the lowest (p < 0.05) weights. Feeding LC, OH, WS and WW diets increased (p < 0.05) the feed per gain compared with the fine diet. The current results suggest that there is a potential for coarse particles, insoluble fibre sources and WW feeding to improve the gizzard musculature and digestibility of some nutrients, with the effect being more pronounced with the inclusion of structural fibre sources. PMID- 30411410 TI - Construction of a DNA-Based Supramolecular Nanosheet That Emits Bluish-White Light from Charge-Transfer Excited States of the Nucleobases. AB - 1,omega-Inosinic acid-bearing bolaamphiphiles (dI(18), dI(19), and dI(20)) with a 3'-phosphorylated inosine as a universal base connected to each end of an oligomethylene chain were synthesized for the first time. Single-component self assemblies of these bolaamphiphiles and their binary self-assemblies with salmon sperm DNA were studied by atomic force microscopy; temperature-dependent UV absorption, fluorescence, and circular dichroism spectroscopy; and gel electrophoresis. The binary self-assembly of dI(20) and salmon sperm DNA (dI(20) DNA) had a nanosheet structure with a homogeneous thickness of ca. 6 nm and several micrometers widths. Interestingly, an aqueous solution of the nanosheets displayed a broad absorption band originating from the charge-transfer (CT) states of the nucleobase in the long-wavelength region (> 300 nm), and the molar absorptivity per nucleobase was calculated to be ~150 times that of single stranded (dT20 and dA20) and double-stranded (dT20-dA20) oligonucleotides. In addition, a continuous and broad emission band originating from CT excited states of the nucleobases was observed in the visible region. These observations indicate that CT states of the nucleobases were formed and stabilized in the supramolecular nanosheet and that bluish-white light was emitted from CT excited states of the nucleobases. PMID- 30411411 TI - Seasonality in Saint Croix male lamb reproductive development in northern Mexico. AB - The aim of this study was to determine the influence of the season of birth on the body weight, testicular size, testosterone concentrations, semen output and sexual behaviour in Saint Croix male lambs. Thirty-three lambs were born in spring (n = 10), summer (Sum; n = 12) or autumn (n = 11). Body weight and the scrotal circumference were weekly recorded; semen was also weekly collected by electroejaculation; and sexual behaviour towards oestrous ewes was weekly evaluated. Data were recorded from 15 to 33 weeks of age. The reproductive development of Saint Croix male lambs differed according to the period in which they were born. More lambs born in spring than in summer and autumn achieved puberty during this study and were also more precocious in semen production and displayed sexual behaviour earlier. Lambs born in summer delayed their semen production; however, season-related negative effects were less pronounced at the end of the study than in autumn born lambs born. In conclusion, despite the apparently low seasonality of the breed, Saint Croix male lambs showed in this study a seasonal pattern in their reproductive development at least until they achieve the puberty. PMID- 30411412 TI - Hydroxychloroquine-induced autophagic vacuolar myopathy with mitochondrial abnormalities. AB - Hydroxychloroquine (HCQ) and chloroquine are used worldwide for malaria as well as connective and rheumatological disorders. They have been reported to be linked to myopathy in patients. We report four patients who were receiving HCQ as part of treatment for connective tissue disorder and who presented with myopathy. The muscle biopsy in these patients was consistent with findings of HCQ toxicity. HCQ muscle toxicity is usually self-limiting after discontinuation of the drug. It also usually tends to be under-reported due to presence of various confounding factors. This warrants close monitoring and consideration of muscle biopsy as part of initial work up of patients who present with myopathy while receiving HCQ. PMID- 30411413 TI - Ca(II), Yb(II) and Sm(II) bis(Amido) Complexes Coordinated by NHC Ligands - Efficient Catalysts for Highly Regio- and Chemoselective Consecutive Hydrophosphinations with PH3. AB - The first example of intermolecular hydrophosphination of styrene, 2 vinylpyridine and phenylacetylene with PH3 catalyzed by bis-(amido) complexes [(Me3Si)2N]2M(NHC)2 (M = Ca, Yb, Sm) coordinated by NHC ligands is described. The reactions of styrene with PH3 proceed under mild conditions in quantitative yields to afford only anti-Markovnikov product and allow for the chemoselective synthesis of primary, secondary and tertiary phosphines. Addition of phenylacetylene to PH3 regardless the initial molar substrates ratio results in the exclusive formation of tertiary tris-(Z-styryl)-phosphine. Crucial effect of the Lewis base coordinated to the metal ion in precatalyst on catalytic activity in styrene hydrophosphination with PH3 was demonstrated. PMID- 30411415 TI - Joint breeding value evaluation for fertility in Finnish and Norwegian blue foxes. AB - We developed a multiple-trait animal model for blue fox fertility evaluation and estimated genetic parameters simultaneously for seven traits: first three litter sizes (LS), pregnancy rate (PREG), whelping success (WHELP), grading size (gSI) and fur quality (gQU). Grading size and quality were included into the new multiple-trait model as correlated traits. Litter size of the first parity had the highest unfavourable genetic correlations with gSI (-0.57) and gQU (-0.56). Thus, selection for higher gSI and gQU slows down the genetic gain in fertility traits. WHELP had moderate to fairly high negative genetic correlations with gSI and gQU (-0.44 and -0.36, respectively), indicating that larger animals are more likely to lose their pups during pregnancy or immediately after birth. Our new model corrected the slight overestimation of estimated breeding values (EBVs) especially for first litter size. The accuracy of LS, PREG and WHELP estimation is likely to benefit from the new multiple-trait animal model. PREG and WHELP improved steadily from 1998 to 2014, and LS traits have shown a moderate genetic trend since 2007, whereas the positive genetic trend for gSI has levelled down, at least temporarily. The fairly high effective population size (150) allows to increase selection intensity, and the new fertility evaluation enables further improvement of fertility traits. PMID- 30411414 TI - Systemic features of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations: a monogenic small vessel disease. AB - BACKGROUND: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a small vessel disease caused by C-terminal truncating TREX1 mutations. The disease is typically characterized by vascular retinopathy and focal and global brain dysfunction. Systemic manifestations have also been reported but not yet systematically investigated. METHODS: In a cross-sectional study, we compared the clinical characteristics of 33 TREX1 mutation carriers (MC+) from three Dutch RVCL-S families with those of 37 family members without TREX1 mutation (MC-). All participants were investigated using personal interviews, questionnaires, physical, neurological and neuropsychological examinations, blood and urine tests, and brain MRI. RESULTS: In MC+, vascular retinopathy and Raynaud's phenomenon were the earliest symptoms presenting from age 20 onwards. Kidney disease became manifest from around age 35, followed by liver disease, anaemia, markers of inflammation and, in some MC+, migraine and subclinical hypothyroidism, all from age 40. Cerebral deficits usually started mildly around age 50, associated with white matter and intracerebral mass lesions, and becoming severe around age 60-65. CONCLUSIONS: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations is a rare, but likely underdiagnosed, systemic small vessel disease typically starting with vascular retinopathy, followed by multiple internal organ disease, progressive brain dysfunction, and ultimately premature death. PMID- 30411416 TI - Fisher's quantitative genetic model and the molecular genetics of multifactorial traits. PMID- 30411417 TI - The fundamental theorem of natural selection. PMID- 30411418 TI - Y-chromosome haplotype analysis revealing multiple paternal origins in swamp buffaloes of China and Southeast Asia. AB - To further probe into the paternal origins and domestication area of swamp buffaloes, we examined Y-chromosome diversity of 482 bulls representing 22 populations from China and Southeast Asia. A total of 40 bovine Y-chromosome specific microsatellite (Y-STR) markers were screened in this study. The results showed that seven Y-STR markers (UMN2405, UMN0504, UMN0103, UMN1307, BC1.2, UMN0304 and INRA008) were specific and polymorphic in male swamp buffaloes, which can define 9 Y-haplotypes corresponding to four Y-haplogroups (Y1, Y2, Y3 and Y4). Haplogroup Y1 was predominant (83.4%) in all swamp buffalo populations, indicating haplogroup Y1 was the major domestication event of swamp buffalo. In addition, the abundant genetic background and backbone of haplogroup Y1 suggested Yangtze Valley as the major domestication area of swamp buffalo. Interestingly, haplogroup Y4 was only confined in Hainan Island which was more ancient than other haplogroups. We hypothesized that haplogroup Y4 was the descendants of the wild Asian buffalo trapped on Hainan Island in prehistoric glacier period and preserved by later introgression into domesticated cows after the domestication. In conclusion, our findings revealed four divergent paternal origins in swamp buffaloes based on Y-STR markers. PMID- 30411419 TI - The FRA14B common fragile site maps to a region prone to somatic and germline rearrangements within the large GPHN gene. AB - Common fragile sites (cFSs) represent parts of the normal chromosome structure susceptible to breakage under replication stress. Although only a small number of cFSs have been molecularly characterised, genomic damage of cFS genes appears to be critical for the development of various human diseases. In this study, we fine mapped the location of FRA14B and showed that the fragile region spans 765 kb at 14q23.3, containing the large gephyrin (GPHN) gene. The FRA14B sequence is enriched in perfect A/T>24 stretches and R-loop forming sequences (RLFS), and harbours a large palindromic motif in the core region. FRA14B instability is not limited to lymphocytes, but also occurs in neuroblastoma and breast epithelial cells. Using array comparative genomic hybridization (CGH), we examined copy number alteration patterns within FRA14B in a panel of 180 cancer cell lines and primary tumours. Our CGH data and a survey of 1046 Cancer Cell Line Encyclopedia profiles demonstrate that focal deletions cluster within FRA14B and disrupt the genomic integrity of GPHN in approximately 5% of cancer cells. Moreover, germline CNVs (copy number variants) profiles provided by the Database of Genomic Variants and available literature suggest that germline CNVs and rare pathogenic deletions associated with neurodevelopmental disorders cluster within the core fragile region of GPHN. Overall, our data provide insight into the molecular structure of FRA14B, and identify GPHN, as a large cFS gene in the human genome, whose disruption appears to trigger various neurodevelopmental diseases. This article is protected by copyright. All rights reserved. PMID- 30411420 TI - Feeding cluster preferences in four genera of Lories and Lorikeets (Loriinae) that should be considered in the diet of nectarivorous psittacine species in captivity. AB - Lories and lorikeets are popular birds in the pet bird trade, captured from the wild and exported worldwide. Their captive propagation has not been so successful for many species due to health issues, low breeding success and reduced longevity. As a result, uptake from the wild is currently the only way to meet the market's demand. Field studies on Asian species of loris and lorikeets are limited; therefore, dietary recommendations are based on the well-studied Australian species such as the rainbow lorikeet (Trichoglossus moluccanus). We aimed to provide an ad libitum diet to diverse Loriinae species at Jurong Bird Park (Singapore) which allowed for them to select between a low and moderate protein diet to compare their nutrient and energy intake with other Loriinae species. We measured the following variables: daily dry matter (DM) intake, nectar-to-fruit energy intake ratio (NF ratio), metabolisable energy (ME), protein and non-protein energy (NPE)-to-protein energy (PE) ratio intake (all by kg metabolic body weight MBW, kg0.75 ) for 36 pairs over a 1-month period. A Kruskal-Wallis test revealed every genus had significantly different intakes of DM, NF ratio, NPE-to-PE ratio, ME and protein than each other. Post hoc Mann Whitney U tests confirmed that the majority of variables were ingested in different amounts for each genus except for NF ratio, NPE/PE ratio which Lorius spp. are not different to Charmosyna sp. or Trichoglossus spp. and protein intake of Eos spp. does not differ from Trichoglossus spp. Our conclusion is that no species should be used as a model for a species from another genus of Loriinae; future studies should be species-specific for each genus to increase captive propagation success. PMID- 30411421 TI - Effective attenuation of glyphosate-induced oxidative stress and granulosa cell apoptosis by vitamins C and E in caprines. AB - Pesticides are known to cause a wide range of reproductive problems that possess degenerative effects on mammalian fertility. Glyphosate (GLP), a broad-spectrum organophosphate herbicide, is known to be a potent mammalian toxicant. The present study aims at assessing the GLP-induced (0.1, 2.0, and 4.0 mg/ml) granulosa cells toxicity and evaluating the mitigating effects of vitamins C and E (0.5 mM and 1.0 mM) in healthy caprine antral follicles, cultured in vitro in a dose- and time-dependent manner (24, 48, and 72 hr) and subjected to various cytotoxic and geno-toxic analysis, namely, classic histology, EB/AO differential staining, oxidative stress parameters, and antioxidant enzymatic activity. The histomorphological analysis and EB/AO staining elucidated increase in the incidence of apoptotic attributes within granulosa cells with increasing dose and duration of the GLP treatment. The highest apoptotic frequency was observed at 4.0 mg/ml GLP after 72-hr exposure duration in comparison with the control. GLP exposure also led to a significant decline in the antioxidant enzymes' activity, namely, SOD, catalase, and GST along with enhanced lipid peroxidation and reduced FRAP activity in a dose- and time-dependent manner. Vitamins C and E supplementation decreased oxidative stress-mediated granulosa cells apoptosis, suggesting its efficiency to diminish GLP-mediated GCs cytotoxicity and thereby, preventing associated fertility disorders. PMID- 30411422 TI - Pregnenolone as a potential candidate for hormone therapy for female reproductive disorders targeting ERbeta. AB - Many steroid hormones such as estrogen (E2) bind to their receptors for the regulation of biological processes. Pregnenolone (P5) is the precursor form of almost all steroid hormones and is often used to treat skin disorders and neurological complications. However, the mechanism and physiological function of P5 in reproductive organs are not well established. In this study, we investigated the effects of P5 on activation and expression of E2 receptor (ER) in the uteri and ovaries. To study the mechanism of P5 directly, Ishikawa cells were transfected with E2 response element (ERE)-luciferase plasmid and isoforms of ER. ERE-luciferase activity induced by P5 was similar to that induced by E2, and P5 showed high activity for ERbeta without any relevance to P5-metabolizing hormones such as progesterone (P4) and E2. In an animal study, immature female rats treated with P5 showed upregulation of ERalpha and downregulation of ERbeta in the uteri, which is the main organ expressing ERalpha. In ERbeta-expressing organ ovaries, estrogen receptor 1, estrogen receptor 2, and P4 receptor were all downregulated by P5 and E2. Also, a decrease of ovarian cell proliferation and viability was observed in response to P5 relative to the control, suggesting that P5 may be a candidate for antiproliferative hormone of ovarian cancer. These findings suggest that P5 stimulates ERE promoter by ERbeta-mediated signaling in the uteri and ovaries. Activation of ERbeta by P5 may help in understanding the mechanism of ER-related female reproductive diseases such as endometriosis and ovarian cancer. PMID- 30411423 TI - Does the offer of e-cigarettes benefit smoking cessation among unselected smokers? PMID- 30411424 TI - Patterns and costs of health-care utilisation in Australian children: The first 5 years. AB - AIM: To describe patterns of health-care utilisation and costs of a cohort of Australian children in the first 5 years of life and to investigate demographic factors associated with high health-care utilisation. METHODS: This was a secondary data analysis of prospectively linked health-care utilisation data, including primary and secondary health-care consults, hospitalisations and emergency. The subjects were 350 children from a disadvantaged area of Sydney. Outcomes were the frequency and cost of all health-care consults from birth to 5 years of age. Multivariable logistic regression examined the odds of being a high health-care user in relation to child and family characteristics. RESULTS: Children had more health-care consults and higher annual health-care costs in the first 2 years of life (mean 12 health-care visits per year, mean cost Australian dollars (AUD) 1400 per child) than in the next 3 years (8 visits per year, AUD 900 per child). Primary care consults formed 86% of all health-care encounters but only contributed to 30% of the total costs. Factors positively associated with frequent use of health care in the first 2 years of life included being male, mother not married/de facto and annual household income of less than AUD 40000. Frequent users mostly accessed primary care services. There was no association between demographic factors and frequent use of health care in years 3-5 of life. CONCLUSIONS: Children from low-income or single-parent families may require additional support services during the first 2 years of life. Maintaining or increasing access to free or very low-cost primary health-care services for disadvantaged families will promote equity in health. PMID- 30411425 TI - Expression profiles of interferon-stimulated gene 15 and prostaglandin synthases in the ovine lymph nodes during early pregnancy. AB - Lymph nodes are distributed all over the body and are part of the lymphatic system. The interferon-stimulated gene 15 kDa protein (ISG15) and prostaglandins (PGs) are involved in the establishment of pregnancy and are expressed in the uterus during early pregnancy in sheep. In this study, the ovine lymph nodes were obtained on Day 16 of the estrous cycle, and Days 13, 16, and 25 of pregnancy, and the expression of ISG15 and PG synthases, including cyclooxygenase 1 (COX-1), COX-2, prostaglandin E (PGE) synthase (PTGES), and a PGF synthase (aldo-keto reductase family 1, member B1, AKR1B1) were detected by quantitative real-time polymerase chain reaction, western blot analysis, and immunohistochemistry analysis. Our results showed that there were peaks in the expression of mRNAs and the proteins of ISG15, COX-1, COX-2, PTGES, and AKR1B1 in the lymph nodes during early pregnancy and that the COX-2 and AKR1B1 proteins were limited to the subcapsular sinus and lymph sinuses. In conclusion, the ISG15, COX-1, COX-2, PTGES, and AKR1B1 were upregulated in the maternal lymph nodes, which may be beneficial for the development of conceptus, maternal systemic immunoregulation, and anti-luteolysis during early pregnancy in sheep. PMID- 30411426 TI - The eggstraordinary story of how life begins. AB - More than 15 years have elapsed since the identification of phospholipase C zeta1 (PLCzeta) from a genomic search for mouse testis/sperm-specific PLCs. This molecule was proposed to represent the sperm factor responsible for the initiation of calcium (Ca2+ ) oscillations required for egg activation and embryo development in mammals. Supporting evidence for this role emerged from studies documenting its expression in all mammals and other vertebrate species, the physiological Ca2+ rises induced by injection of its messenger RNA into mammalian and nonmammalian eggs, and the lack of expression in infertile males that fail intracytoplasmic sperm injection. In the last year, genetic animal models have added support to its role as the long sought-after sperm factor. In this review, we highlight the findings that demonstrated the role of Ca2+ as the universal signal of egg activation and the experimental buildup that culminated with the identification of PLCzeta as the soluble sperm factor. We also discuss the structural-functional properties that make PLCzeta especially suited to evoke oscillations in eggs. Lastly, we examine unresolved aspects of the function and regulation of PLCzeta and whether or not it is the only sperm factor in mammalian sperm. PMID- 30411427 TI - Changes in social networks are associated with lesbian, bisexual and queer women quitting smoking: An analysis of Australian survey data. AB - INTRODUCTION AND AIMS: Lesbian, bisexual and queer (LBQ) women in Australia and internationally are smoking at least twice the rate of women in the general population. An understanding of smoking behaviours in this population is essential in order to develop effective interventions. Our analysis aimed to investigate differences in smoking patterns and contexts of smoking between current smokers and recent quitters (<2 years to 1 month). DESIGN AND METHODS: Data were collected through an online anonymous survey conducted in mid-2015. Participants were recruited online from a variety of social networking sites and community-based mailing groups. RESULTS: Overall 257 lesbian, bisexual and queer women completed the survey, 73% current smokers and 27% recent quitters; nearly all had smoked daily at some point in their lives. Multivariate analysis showed recent quitters were less likely to have some (adjusted odds ratio [aOR] 0.19, 95% confidence interval [CI] 0.05-0.71) or half/most/all (aOR 0.12, 95% CI 0.03 0.048) close friends who smoked compared to none, and were more likely to have a non-smoking (aOR 10.2, 95% CI 3.86-27.0) or no regular partner (aOR 4.01, 95% CI 1.47-10.9) than one who smoked. Non-Anglo-Australian women were also more likely to be recent quitters (aOR 2.45 [95% CI 1.10-5.42]) than Anglo-Australian women. DISCUSSION AND CONCLUSIONS: Understanding the social significance of partners and friends in lesbian, bisexual and queer women's smoking and cessation efforts will be important for developing meaningful, effective and targeted interventions to address the persistent high rates of smoking in this population. PMID- 30411428 TI - Response to Brown et al. 'Does the offer of e-cigarettes benefit smoking cessation among unselected smokers?' PMID- 30411429 TI - A Comprehensive Review of Dorsomedial Prefrontal Cortex rTMS Utilizing a Double Cone Coil. AB - BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has become increasingly popular during the last decades mainly driven by the antidepressant effects of dorsolateral prefrontal cortex stimulation with "butterfly" coils. Only recently, alternative targets such as the dorsomedial prefrontal cortex (dmPFC) have been brought into focus and innovative coil designs such as the angled geometry of the double cone coil (DCC) have raised hope to reach even deeper located targets. OBJECTIVE: To provide a systematic and comprehensive review on the application of rTMS stimulation of the dmPFC using the DCC in neuropathological and healthy samples. METHODS: We systematically searched the MEDLINE(r) database (http://www.ncbi.nlm.nih.gov/pubmed/). Due to the heterogeneous naming of DCC stimulation over the dmPFC a variety of search terms was applied resulting in a numeral quantity of 340 hits. RESULTS: DCC stimulation over the dmPFC has been proven to be safe and feasible in various neuropsychiatric disorders and in healthy subjects. Clinical results are encouraging, but have to be considered as preliminary as data from sham controlled clinical trials and knowledge about the neurobiological underpinnings are still scarce. CONCLUSION: DCC stimulation over the dmPFC represents a promising approach in the fast evolving noninvasive brain stimulation techniques aiming at the functional modulation of brain areas vitally involved in affect, sensory autonomic, cognitive, and salience regulation. This may hold potential for both neuroscientific research and clinical applications in the treatment of psychiatric disorders. PMID- 30411430 TI - Paediatric immunisation and chemoprophylaxis in a Ugandan sickle cell disease clinic. AB - AIM: We aimed to assess the receipt of recommended care for young children with sickle cell disease (SCD) in a central SCD clinic in Kampala Uganda, focusing on standard vaccination and antibacterial and antimalarial prophylaxis. METHODS: A cross-sectional assessment of immunisation status and timeliness and prescribed antibacterial and antimalarial prophylaxis was performed in a sample with SCD aged <=71 months in Mulago Hospital SCD Clinic. Government-issued immunisation cards and clinic-issued visit records for prescribed prophylaxis were reviewed. RESULTS: Vaccinations were documented by immunisation cards in 104 patients, mean age 31.7 months (range 3-70 months). Only 48 (46.2%) received all doses of each of the four recommended vaccine types, including pneumococcal 10-valent conjugate vaccine (pneumococcal conjugate vaccine (PCV)-10), which became available in 2014. Vaccination completion was associated with younger age and, for polio, maternal employment. PCV-10 series was completed in 54.8% of the sample and in 18.2% of those aged 48-71 months. Of children completing all vaccination types, an average 68.8% were immunised on time, defined as <60 days beyond the recommended age. Only 17 (13.5%) children were both fully and timely vaccinated. In an overlapping sample of 147 children, with a mean age of 38.4 months (4-70 months), 81.6% had >=1 documented prescription for penicillin and/or antimalarial prophylaxis. CONCLUSIONS: Standardised vaccination and antibacterial and antimalarial protective measures for young children at this central SCD clinic were incomplete, especially PCV-10 for age >=24 months, and often late. Child age, but not general maternal demographics, were associated with vaccination and chemoprophylaxis. Clinic-based oversight may improve timely uptake of these preventative measures. PMID- 30411431 TI - Predictive model algorithms identifying early and advanced stage ER+/HER2- breast cancer in claims data. AB - PURPOSE: Claims databases offer large populations for research, but lack clinical details. We aimed to develop predictive models to identify estrogen receptor positive (ER+) and human epidermal growth factor negative (HER2-) early breast cancer (ESBC) and advanced stage breast cancer (ASBC) in a claims database. METHODS: Female breast cancer cases in Anthem's Cancer Care Quality Program served as the gold standard validation sample. Predictive models were developed from clinical knowledge and empirically from claims data using logistic and lasso regression. Model performance was assessed by classification rates and c statistics. Models were applied to the HealthCore Integrated Research Database (claims) to identify cohorts of women with ER+/HER2- ESBC and ASBC. RESULTS: The validation sample included 3184 women with ER+/HER2- ESBC and 1436 with ER+/HER2- ASBC. Predictive models for ER+/HER2- ESBC and ASBC included 25 and 20 factors, respectively. Models had robust discrimination in identifying cases (c-stat = 0.92 for ESBC and 0.95 for ASBC). Compared with a traditional a priori algorithm developed with clinical insight alone, the ER+/HER2- ASBC-predictive model had better positive predictive value (PPV) (0.91, 95% CI, 0.90-0.93, vs 0.69, 95% CI, 0.66-0.73) and sensitivity (0.54 vs 0.35). Models were applied to the claims database to identify cohorts of 33 001 and 3198 women with ER+/HER2- ESBC and ASBC. CONCLUSION: We conducted a validation study and developed predictive models to identify in a claims database cohorts of women with ER+/HER2- ESBC and ASBC. The models identified large cohorts in the claims data that can be used to characterize indications in the evaluation of targeted therapies. PMID- 30411432 TI - Implementing recovery-oriented interventions with staff in a psychiatric hospital: A mixed-methods study. AB - WHAT IS KNOWN ON THE SUBJECT?: Recovery-oriented care is a means of providing mental health treatment, focused on the patient's individual needs and active involvement in one's own care. However, this approach presents with challenges, particularly in psychiatric hospitals, which tend to be focused on symptom reduction. WHAT DOES THE PAPER ADDS TO EXISTING KNOWLEDGE?: This study examines the influence of three different recovery-oriented training programmes/interventions (namely, illness management and recovery, peer support, and psychiatric advance directives) on the attitudes and practice of mental health staff (including nurses) in an inpatient setting, using a mixed-methods methodology. We quantitatively assess the knowledge, attitudes and practices developed following recovery-oriented training, compared to staff not trained in these interventions. We interviewed staff exposed to the different interventions to learn about their personal views and characterized the benefits and challenges they experienced. Mainly, the illness management and recovery training created a positive change in the work attitude and some work-related practices of mental health staff and the increased presence of a person-centred approach supporting patient autonomy. However, and contrary to expectations, there was no increase in practices that support personal goals or provide individually tailored services. Peer support had an experiential impact among mental health staff, initiating a more humane, positive approach to patients. Psychiatric advance directives were reported as more challenging to implement and with limited impact. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Recovery-oriented trainings can be internalized and implemented by staff in medical model psychiatric settings. Despite recovery oriented training, challenges do occur-notably, they are hardest to implement in acute wards/patient states and by psychiatric nurses. Using multiple recovery oriented programmes/interventions can accelerate the momentum for change in traditional settings and promote positive practice. Ongoing comprehensive mental health staff training on recovery-oriented care programmes is essential in order to sustain change over time. Training is not enough in itself-hospital administrations need to be actively involved in promoting recovery-oriented policies. ABSTRACT: Introduction Developing person-centred recovery-oriented care is a challenge in mental health systems, particularly psychiatric hospitals. Aim To assess the knowledge, attitudes and practices developed following recovery oriented training of nurses and other staff; to identify the benefits and challenges involved in the implementation of recovery-oriented intervention in psychiatric wards. Method A mixed-methods study compared recovery knowledge, attitudes and practices of 37 mental health ward staff trained in recovery oriented intervention, against 35 staff not trained. Fifteen staff were interviewed about their experiences, and protocols were qualitatively analysed. Results The quantitative outcomes partially confirmed positive changes in attitudes and some practices. Qualitative interviews complemented these findings, revealing greater use of a person-centred approach and support for patient autonomy. However, we did not find differences between groups in quantitative outcomes pertaining to personal goals or providing individually tailored services. Discussion This study validates the implementation of recovery training and practices in psychiatric settings, and identifies the challenges involved. We discuss psychiatric nurse conflicts in implementation in acute wards. Implications for practice Our findings support the need for broader staff training in recovery-oriented interventions. Recruiting the support of the hospital administration for recovery-oriented intervention programmes is key, both ethically and structurally. PMID- 30411433 TI - Micronucleus formation in human cancer cells is biased by chromosome size. AB - Chromosomal instability is one of the hallmarks of cancer and caused by chromosome missegregation during mitosis, a process frequently associated with micronucleus formation. Micronuclei are formed when chromosomes fail to join a daughter nucleus during cell division and are surrounded by their own nuclear membrane. Although it has been commonly assumed that the gain or loss of specific chromosomes is random during compromised cell division, recent data suggest that the size of chromosomes can impact on chromosome segregation fidelity. To test whether chromosome missegregation rates scale with chromosome size in primary human cancer cells, we assessed chromosome sequestration into micronuclei in patient-derived primary NCH149 glioblastoma cells, which display high-level numerical chromosome instability (CIN), pronounced spontaneous micronucleus formation but virtually no structural CIN. The cells were analysed by interphase fluorescence-in-situ-hybridization (FISH) using chromosome-specific painting probes for all chromosomes. Overall, 33% of early passage NCH149 cells harbored micronuclei. Entrapment within a micronucleus clearly correlated with chromosome size with larger chromosomes being significantly more frequently missegregated into micronuclei than smaller chromosomes in primary glioblastoma cells. These findings extend the concept that chromosome size determines segregation fidelity by implying that size-specific micronucleus entrapment occurs in primary human cancer cells as well. This article is protected by copyright. All rights reserved. PMID- 30411434 TI - Coiled-coil Peptide Beacon: A Tuneable Conformational Switch for Protein Detection. AB - The understanding of protein folding and assembly is of central importance for the design of proteins and enzymes with novel or improved functions. Minimalistic model systems, such as coiled-coils, provide an excellent platform to improve this understanding and to construct novel molecular devices. Along those lines, we designed a conformational switch which is composed of two coiled-coil forming peptides and a central binding epitope. In the absence of a binding partner, this switch adopts a hairpin-like conformation which opens upon receptor binding. We show that variation of the coiled-coil length modulates the strength of the intramolecular constraint. The two conformational states of this switch have been linked with characteristic fluorescent properties which enables the detection of the receptor in real-time. PMID- 30411436 TI - The Darmstadt Science Declaration: Make Science Not War. AB - "... We will only be able to solve significant challenges with further progress in science and technology applied to the benefit of humanity. The Darmstadt Science Declaration is a global call to action to devote more resources to the advancement of science and technology to enable humanity to solve the challenges of today and to realize the dreams of a better tomorrow ... Read more in the Guest Editorial by Ulrich A. K. Betz. PMID- 30411435 TI - Persistent amnion-chorion membrane separation. AB - AIM: Fetal membranes are composed of the amnion and chorion, which fuse during the early second trimester. Persistent separation confers increased risk of adverse perinatal outcomes. This study characterizes sonographic and placental findings associated with persistent amnion-chorion (AC) membrane separation. METHODS: This is a case series of 23 patients carrying singleton pregnancies with persistent AC membrane separation after 16 weeks' gestation diagnosed by ultrasound from 2010 to 2016 at our institution. Twenty placentas were available for analysis. RESULTS: Obstetrical complications occurred in 13 (56.5%) cases; two (8.7%) cases resulted in intrauterine fetal demise. Fetal malformations were reported in eight (34.8%) cases. Four (17.4%) neonates were small-for-gestational age (SGA; <10th percentile). Placental size measured <=10th percentile for gestational age in eight (40%) cases. Placental cord insertion was marginal or velamentous in eight (34.8%) cases. Maternal and/or fetal placental perfusion abnormalities occurred in 11 (55%) cases. CONCLUSION: AC membrane separation is associated with adverse obstetrical outcomes, placental abnormalities, including marginal and velamentous cord insertion, placental growth restriction and placental perfusion defects. This membrane complication is associated with increased incidence of fetal malformations in the absence of identifiable genetic etiologies. PMID- 30411437 TI - Amount, not strength of recollection, drives hippocampal activity: A problem for apparent word familiarity-related hippocampal activation. AB - The role of the hippocampus in recollection and familiarity remains debated. Using functional magnetic resonance imaging (fMRI), we explored whether hippocampal activity is modulated by increasing recollection confidence, increasing amount of recalled information, or both. We also investigated whether any hippocampal differences between recollection and familiarity relate to processing differences or amount of information in memory. Across two fMRI tasks, we separately compared brain responses to levels of confidence for cued word recall and word familiarity, respectively. Contrary to previous beliefs, increasing confidence/accuracy of cued recall of studied words did not increase hippocampal activity, when unconfounded by amount recollected. In contrast, additional recollection (i.e., recollecting more information than the word alone) increased hippocampal activity, although its accuracy matched that of word recall alone. Unlike cued word recall, increasing word familiarity accuracy did increase hippocampal activity linearly, although at an uncorrected level. This finding occurred although cued word recall and familiarity memory seemed matched with respect to information in memory. The detailed characteristics of these effects do not prove that word familiarity is exceptional in having hippocampal neural correlates. They suggest instead that participants fail to identify some aspects of recollection, misreporting it as familiarity, a problem with word-like items that have strong and recallable semantic associates. PMID- 30411438 TI - A Dy4 Cubane: A New Member in the Single-Molecule Toroics Family. AB - Molecular materials that possess a toroidal moment associated to a non-magnetic ground state are known as single-molecule toroics (SMTs) and are usually planar molecules. Herein, we report a Dy4 cubane, namely [Dy4 (Bppd)4 (MU3 -OH)4 (Pa)4 (H2 O)4 ]?0.333 H2 O (where BppdH=1,3-Bis(pyridin-4-yl)propane-1,3-dione and PaH=2-Picolinic acid) for which magnetometry measurements and state-of-art ab initio calculations highlight SMT behavior in a tridimensional structure (3D SMT). The in-depth theoretical analysis on the resulting low-lying energy states, along with their variation in function of the magnetic exchange pathways, allows further light to be shed on the description of single-molecule toroics and identify the coupling scheme that better reproduces the observed data. PMID- 30411439 TI - Visible-Light-Mediated Metal-Free Difunctionalization of Alkenes with CO2 and Silanes or C(sp3 )-H Alkanes. AB - Catalytic alkene difunctionalization via Si-H and C-H activations represents an ideal atom- and step-economic pathway for quick assembly of molecular complexity. We herein developed a visible-light-promoted metal-free difunctionalization of alkenes using abundant CO2 and readily available Si-H and C(sp3 )-H bonds as feedstocks. Through the merger of photoredox and hydrogen-atom-transfer catalysis, a variety of value-added compounds, such as beta-silacarboxylic acids and acids bearing a gamma-heteroatom (e.g., N, O, S) could be directly accessed from simple alkenes in a redox-neutral fashion. PMID- 30411440 TI - Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9-mediated kif15 mutations accelerate axonal outgrowth during neuronal development and regeneration in zebrafish. AB - KIF15, the vertebrate kinesin-12, is best known as a mitotic motor protein, but continues to be expressed in neurons. Like KIF11 (the vertebrate kinesin-5), KIF15 interacts with microtubules in the axon to limit their sliding relative to one another. Unlike KIF11, KIF15 also regulates interactions between microtubules and actin filaments at sites of axonal branch formation and in growth cones. Our original work on these motors was done on cultured rat neurons, but we are now using zebrafish to extend these studies to an in vivo model. We previously studied kif15 in zebrafish by injecting splice-blocking morpholinos injected into embryos. Consistent with the cell culture work, these studies demonstrated that axons grow faster and longer when KIF15 levels are reduced. In the present study, we applied CRISPR/Cas9-based knockout technology to create kif15 mutants and labeled neurons with Tg(mnx1:GFP) transgene or transient expression of elavl3:EGFP-alpha tubulin. We then compared by live imaging the homozygotic, heterozygotic mutants to their wildtype siblings to ascertain the effects of depletion of kif15 during Caudal primary motor neuron and Rohon-Beard (R-B) sensory neuron development. The results showed, compared to the kif15 wildtype, the number of branches was reduced while axon outgrowth was accelerated in kif15 homozygotic and heterozygotic mutants. In R-B sensory neurons, after laser irradiation, injured axons with loss of kif15 displayed significantly greater regenerative velocity. Given these results and the fact that kif15 drugs are currently under development, we posit kif15 as a novel target for therapeutically augmenting regeneration of injured axons. PMID- 30411441 TI - Different Silver Nanoparticles in One Crystal: Ag210 (i PrPhS)71 (Ph3 P)5 Cl and Ag211 (i PrPhS)71 (Ph3 P)6 Cl. AB - Two pure silver nanoparticles (Ag210 (i PrPhS)71 (Ph3 P)5 Cl and Ag211 (i PrPhS)71 (Ph3 P)6 Cl labeled as SD/Ag210 and SD/Ag211 (SD=SunDi), were found to co-crystallize in forming compound 1. Single-crystal X-ray diffraction (SCXRD) revealed that they differ by only one Ag(PPh3 ). Their four-shell nanoparticles consist of three pure Ag metal shells (Ag19 @Ag52 @Ag45 ) shielded by a silver organic Ag89 (i PrPhS)71 Cl[Ag(Ph3 P)]n outermost shell. The number (n) of Ag(Ph3 P) is five for SD/Ag210 and six for SD/Ag211. The pseudo-fivefold symmetric Ag nanoparticles exhibit surface plasmon absorption similar to a true metallic state but at the nanoscale. This work exemplifies the important effects of phosphine in stabilizing large silver nanoparticles; and offers a platform to investigate the origin of differences in nanoscale metal materials, even differing by only one metal atom; it also sheds light on the regioselective binding of auxiliary Ph3 P on the surface of silver nanoparticles. PMID- 30411442 TI - Recommendations for the use of pegylated interferon-alpha in the treatment of classical myeloproliferative neoplasms. AB - The classical myeloproliferative neoplasms (MPN) are uncommon clonal haematopoietic malignancies characterised by excessive production of mature blood cells. Clinically they are associated with thrombosis, haemorrhage, varying degrees of constitutional disturbance, and a risk of progression to myelofibrosis or acute myeloid leukaemia. Many of the disease manifestations may be ameliorated by treatment with interferon-alpha (IFN) but its use in Australian MPN patients has been limited due to the inconvenience of frequent injections and side effects. The pegylated form of IFN is a long-acting preparation which is better tolerated and its Pharmaceutical Benefits Scheme listing is likely to lead to increased usage. We review the literature on risks and benefits of IFN treatment for MPNs, suggest criteria for patient selection in each of these diseases, and discuss strategies to manage the side effects of pegylated IFN. This article is protected by copyright. All rights reserved. PMID- 30411443 TI - Maternal Dietary Supplement Use and Development of Islet Autoimmunity in the offspring: the TEDDY Study. AB - OBJECTIVE: We investigated the association between maternal use of vitamin D and omega-3 fatty acids (n-3 FAs) supplements during pregnancy and risk of islet autoimmunity (IA) in the offspring. METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) Study is prospectively following 8676 children with increased genetic risk for type 1 diabetes in Finland, Germany, Sweden, and the US. Blood samples were collected every 3 months between 3 and 48 months of age then every 6 months thereafter to determine persistent IA. Duration, frequency, and supplement dose during pregnancy were recalled by mothers at 3-4 months postpartum. Cumulative intakes of supplemental vitamin D and n-3 FAs were analyzed as continuous or binary variables. We applied time-to-event analysis to study the association between maternal supplement use and IA, adjusting for country, HLA DR-DQ genotype, family history of type 1 diabetes and sex. Secondary outcomes included IAA or GADA as the first appearing autoantibody. RESULTS: As of February 2018, there were 747 (9.0%) children with IA. Vitamin D supplement intake during pregnancy (any vs none) was not associated with risk for IA (hazard ratio (HR) 1.11; 95% CI 0.94, 1.31); neither was cumulative vitamin D supplement intake. Supplemental n-3 FA intake was similarly not associated with IA risk (HR: 1.19, 95% CI 0.98, 1.45). Similar lack of association was observed for either IAA or GADA as the first appearing autoantibody. CONCLUSIONS: The TEDDY cohort showed no evidence of benefit regarding IA risk for vitamin D or n-3 FA supplementation during pregnancy. This article is protected by copyright. All rights reserved. PMID- 30411444 TI - Camouflaging Structural Diversity: Co-crystallization of Two Different Nanoparticles having Different Cores but the Same Shell. AB - Two ligand-protected nanoscale silver moieties, [Ag46 (SPhMe2 )24 (PPh3 )8 ](NO3 )2 and [Ag40 (SPhMe2 )24 (PPh3 )8 ](NO3 )2 (abbreviated as Ag46 and Ag40 , respectively) with almost the same shell but different cores were synthesized simultaneously. As their external structures are identical, the clusters were not distinguishable and become co-crystallized. The occupancy of each cluster was 50 %. The outer shell of both is composed of Ag32 S24 P8 , which is reminiscent of fullerenes, and it encapsulates a well-studied core, Ag14 and a completely new core, Ag8 , which correspond to a face-centered cube and a simple cube, respectively, resulting in the Ag46 and Ag40 clusters. The presence of two entities (Ag40 and Ag46 clusters) in a single crystal and their molecular formulae were confirmed by detailed electrospray ionization mass spectrometry. The optical spectrum of the mixture showed unique features which were in good agreement with the results from time-dependent density functional theory (TD DFT). PMID- 30411445 TI - Exploring professional decision making in relation to safeguarding: A grounded theory study of social workers and community nurses in community learning (intellectual) disability teams in wales. AB - BACKGROUND: People with intellectual disabilities are at increased risk of abuse which may not always be responded to appropriately. This study therefore sought to explore how nurses and social workers make decisions when safeguarding adults with intellectual disabilities. METHOD: A situational analysis grounded theory study. Semi-structured interviews were undertaken with social workers (n = 16) and community nurses (n = 9) working in Community Learning (Intellectual) Disability Teams in Wales. Data were transcribed and analysed thematically and cartographically in keeping with situational analysis. RESULTS: Four key themes emerged: The official line; Expectation and perception; Non-vulnerable adult process options; Confidence and competence. Sites of silence were also identified: not making a decision, not asking further questions, preserving family relationships and the individual with intellectual disabilities. CONCLUSION: Decision making in relation to safeguarding adults with intellectual disabilities is a complex process, influenced by many factors and in which discretion is exercised by professionals. PMID- 30411446 TI - Development of a proforma to improve quality of handover of surgical patients at the weekend. AB - RATIONALE, AIMS, AND OBJECTIVES: The introduction of shift pattern of working in the medical profession has led to an increase in reliance on effective handover of patient information. We evaluated the use of a weekend handover proforma in General Surgical patients at a University Teaching Hospital. METHODS: A standardized weekend handover proforma was implemented. A pre-post survey of medical staff and prospective observational study on the use of the proforma was carried out. The impact of three strategies to reinforce change in clinical practice was investigated at random time-points. These were (1) presentation at a clinical governance meeting; (2) email; and (3) induction training on handover combined with one-to-one interactive training. The two outcome measures were compliance with the proforma, and "handover score," which was the amount of data transferred per patient. RESULTS: The survey highlighted inadequate provision for handover at the weekend. National guidelines were used to design the weekend handover proforma. There was 70% compliance with the new standardized proforma with a median handover score of 83% (IQR = 0-100). The results were presented at a clinical governance meeting, and the proforma was refined. After this change, the proforma was used in 71% of patients, and the median score was 65% (IQR = 0 80, P = 0.0516). Compliance after an email reminder was 69%, and median handover score was 80% (IQR = 0-90, P = 0.1037). After induction training, there was a significant improvement in proforma compliance (94%) and median score (90%, IQR = 80-90, P = 0.013). CONCLUSION: Effective transfer of handover information can be achieved over the weekend with the use of a standardized proforma. Use of the proforma was greatest after providing junior doctors with didactic training on handover combined with interactive guidance on completing the proforma. PMID- 30411448 TI - Characteristics and outcomes of oncology unit patients requiring admission to an Australian intensive care unit. AB - BACKGROUND: Patients with advanced malignancies have historically been considered poor candidates for admission to the intensive care unit (ICU), however prognosis is continually improving and requirements for ICU access is increasing. AIM: To understand the characteristics and outcomes of oncology unit patients admitted to an Australian ICU and identify potential prognostic factors. METHODS: A single centre, retrospective, cohort study conducted at a tertiary public hospital with a quaternary ICU in Sydney, Australia. All patients admitted under the medical oncology team requiring ICU admission between June 2014 and June 2016 were evaluated. Clinical outcomes were determined including mortality, ICU requirements (ventilation, dialysis, vasopressors, infection) and prognostic scores (APACHE II and SOFA score). RESULTS: There were 96 patients with mean age 61 years, 58% were male and 76% had metastatic disease. Most were receiving palliative treatment (89%), with recent chemotherapy (43%), immunotherapy (10%) and other therapies (5%). Of the 10 patients with recent immunotherapy, three (all with melanoma) required ICU admission due to immunotoxicity. 13% were admitted due to an oncological emergency. Mean APACHE II score was 17 (SD 5.33), mean SOFA score was 3.99 (SD 2.70), ICU mortality was 5% and hospital mortality was 22%. Using multivariate logistic regression analysis, cancer stage, infection during ICU admission, intracranial mass effect on ICU admission and SOFA score were associated with 30-day mortality. CONCLUSION: Our patient population had good short-term survival outcomes despite most receiving palliative treatment. Cancer patients can achieve positive outcomes after ICU admission and appropriate selection of patients is crucial. This article is protected by copyright. All rights reserved. PMID- 30411447 TI - Reading in a transparent second language with limited orality: The case of high school students with dyslexia in Latin. AB - Research has shown that individuals with dyslexia have difficulty in reading not only in their native language but also in a second language (L2). The considered L2, however, has always been a language acquired through exposure to both written and oral forms. The present study examines the case of Italian adolescents reading in Latin as an L2, which is the special case of a dead language with very limited use of orality. As the learning of Latin is mainly based on the acquisition of grammar, this study also examined the relationship between grammatical proficiency and reading ability in Latin. Results suggested that, compared with control peers, students with dyslexia had difficulty in reading words and non-words in Latin. Interestingly, in spite of Latin being learnt mainly through written language, the extent of their difficulty was no larger than they encountered when reading in their native language. Also, despite the fact that students with dyslexia showed relatively less severe difficulties with Latin grammar (as compared to reading), this did not support them when reading Latin words, unlike typical readers. The theoretical and educational implications of these results are discussed. PMID- 30411449 TI - Carbon sequestration in riparian forests: A global synthesis and meta-analysis. AB - Restoration of deforested and degraded landscapes is a globally recognized strategy to sequester carbon, improve ecological integrity, conserve biodiversity, and provide additional benefits to human health and well-being. Investment in riparian forest restoration has received relatively little attention, in part due to their relatively small spatial extent. Yet, riparian forest restoration may be a particularly valuable strategy because riparian forests have the potential for rapid carbon sequestration, are hotspots of biodiversity, and provide numerous valuable ecosystem services. To inform this strategy, we conducted a global synthesis and meta-analysis to identify general patterns of carbon stock accumulation in riparian forests. We compiled riparian biomass and soil carbon stock data from 117 publications, reports, and unpublished data sets. We then modeled the change in carbon stock as a function of vegetation age, considering effects of climate and whether or not the riparian forest had been actively planted. On average, our models predicted that the establishment of riparian forest will more than triple the baseline, unforested soil carbon stock, and that riparian forests hold on average 68-158 Mg C/ha in biomass at maturity, with the highest values in relatively warm and wet climates. We also found that actively planting riparian forest substantially jump-starts the biomass carbon accumulation, with initial growth rates more than double those of naturally regenerating riparian forest. Our results demonstrate that carbon sequestration should be considered a strong co-benefit of riparian restoration, and that increasing the pace and scale of riparian forest restoration may be a valuable investment providing both immediate carbon sequestration value and long term ecosystem service returns. PMID- 30411451 TI - Impact of increased access to novel agents on the survival of multiple myeloma patients treated at a single New Zealand centre. AB - AIM: The impact of changes in novel agent (NA) usage on the survival of multiple myeloma (MM) patients in real world hospital settings is unclear. In New Zealand (NZ) in 2011, front-line Bortezomib became available and thalidomide availability was expanded. This retrospective study analyses the impact these change had on the survival of MM patients treated at a NZ hospital. METHODS: Clinical and overall survival (OS) data were collected on MM patients who were treated at Christchurch Hospital during 2000-2009 (pre-Cohort, n=337) and 2011-2017 (post Cohort, n=343). Outcomes were compared using pre-Cohort data truncated at 2011. RESULTS: Patients in the post-Cohort had significant increases (p<0.001) in not only NA usage (85% vs 55%) and OS (median = 56 vs 44 months) but also the proportion (74% vs 49%) of young patients (age<70) who received an autologous stem cell transplant (ASCT). Separate analysis of older patients demonstrated that those in the post-Cohort had significantly longer OS (median OS 28 vs 17, p<0.001) although 5-year relative survival remained <50%. Separate analysis of young patients demonstrated that those in the post-Cohort had significantly increased initial OS with the survival curves converging at 5 years. Although ASCT treated patients had similar OS in each cohort, their progression free survival (PFS) was significantly increased in the post-Cohort (median 40 vs 20 months, p<0.0001). CONCLUSION: In the setting of a NZ hospital the increased availability of NA was associated with a significant improvement in both the OS of older patients and the PFS of ASCT patients. This article is protected by copyright. All rights reserved. PMID- 30411450 TI - How oncology teams can be patient-centred? opportunities for theoretical improvement through an empirical examination. AB - BACKGROUND: In the context of interprofessional practice, a patient-centred approach is recommended, which generally means power-sharing, shared decision making and involving patients as part of the health-care team. These aspects, which are essential to "patient-centred" practice, do not appear to be sufficient to illustrate the full richness of this practice. OBJECTIVE: This article aimed to understand how interprofessional patient-centred (IPPC) practice in oncology teams contributes to creating a more positive experience for patients. Objectives were to (a) describe the IPPC practice of oncology teams using the IPPC Practice Framework; (b) determine the usefulness of this framework; and (c) offer alternative proposals for expanding our understanding of IPPC practice. DESIGN: A secondary analysis was performed with data from a multicase study designed to explore the effects of interdisciplinary work among oncology teams. Data were provided from six focus groups with professionals (n = 22) and patients diagnosed with cancer (n = 16). An iterative content analysis was performed. RESULTS: Applying the theoretical framework to data analysis enabled us to distinguish between the IPPC practice of the different teams and structure the data collected in order to show the processes and place them in context. However, it proved to be difficult to describe the central component of the theoretical framework, patient-centred processes. This situation raises new hypotheses for representing practice in a real-life context. An alternative perspective for illustrating IPPC practice is therefore proposed. CONCLUSION: This study emphasizes the importance of exploring the utility of theoretical frameworks and refining them in order to broaden our understanding of IPPC practice. PMID- 30411452 TI - Identifying the abiotic and biotic drivers behind the elevational distribution shift of a parasitic plant. AB - Climate change will alter the biotic and abiotic environment and dissipate ecological barriers, reorganising maps of current distribution of parasites and their hosts. In this study, we analyse the population dynamics of the parasitic plant Viscum album subsp. austriacum and explore key biotic (host availability and seed dispersal) as well as abiotic (temperature) factors influencing elevational distribution. The study was conducted along an elevational gradient of a Mediterranean mountain, covering the distribution belts of three potential pine hosts: Pinus halepensis (1300-1500 m), P. nigra (1300-1900 m) and P. sylvestris var. nevadensis (1600-2000 m). Along this gradient, we measured multiple variables of mistletoe population (prevalence, abundance and demographic profile) and different factors that might define the current mistletoe distribution (host suitability and availability, temperature and seed dispersal services). We found a decline in mistletoe prevalence and abundance with increasing elevation, detecting larger values of both variables at lower elevations of the most suitable host (Pinus nigra). Pinus sylvestris var. nevadensis was a suboptimal but suitable host for the parasite at high elevations. Mistletoe found suitable temperatures and seed dispersal services all along the gradient, being able to recruit at any site. With warming temperatures, the presence of suitable vectors for parasite dispersion, and the presence of a sub-optimal host (P. sylvestris var. nevadensis) at the mountain top, mistletoe currently has a window of opportunity to expand its present geographic distribution to the summits. PMID- 30411453 TI - Probing Adsorption Configurations of Small Molecules on Surfaces by Single Molecule Tip-Enhanced Raman Spectroscopy. AB - Determining the adsorption configurations of organic molecules on surfaces, especially for relatively small molecules, is a key issue for understanding the microscopic physical and chemical processes in surface science. In this work, we have applied low-temperature ultrahigh-vacuum tip-enhanced Raman scattering (TERS) technique to distinguish the configurations of small 4,4'-bipyridine (44BPY) molecules adsorbed on the Ag(111) surface. The observed Raman spectra exhibit notable differences in the spectral features which can be assigned to three different molecular orientations, each featuring a specific fingerprint pattern based on the TERS selection rule that determines the distribution of the relative intensities of different vibrational peaks. Furthermore, such a small molecule can in turn act as a local probe to provide information on the local electric field distribution at the tip apex. Our work showcases the capability of TERS technique for obtaining information on adsorption configurations of small molecules on surfaces down to the single-molecule level, which is of fundamental importance for many applications in the fields of molecular science and surface chemistry. PMID- 30411454 TI - Time to colonoscopy for patients accessing the Direct Access Colonoscopy Service compared to the normal service in Newcastle, Australia. AB - BACKGROUND: The 2017 NBCSP report records a median time from positive faecal occult blood test to colonoscopy of 53 days. There is some intrinsic delay in accessing specialist medical opinion prior to colonoscopy. The aim of this study was to examine the effect of the introduction of a Direct Access Colonoscopy Service (DACS). METHODS: Using prospectively maintained databases, patients undergoing normal service (NS) colonoscopy and those referred to DACS were compared. The primary outcome measure was the time from GP referral to colonoscopy. Secondary outcome measures included the proportion of patients who met the current recommended 30 days from GP referral to colonoscopy, and the proportion of patients who waited longer than 90 days. RESULTS: There were 289 patients in the NS group, and 601 patients who progressed on the DACS pathway. The demographics of both groups were comparable. DACS patients had a median waiting time of 49 days, significantly shorter than NS patients whose median wait was 79 days (p<0.0001). 15.1% patients in the DACS group had their colonoscopy within 30 days from GP referral, significantly better than in the NS group (4.5%, p<0.001). In the NS group 41.2% patients waited longer than 90 days from GP referral to colonoscopy, compared to 16.3% in the DACS group (p<0.001). CONCLUSION: DACS reduces waiting times to colonoscopy, and is associated with an increased proportion of patients undergoing colonoscopy in a timely manner. This article is protected by copyright. All rights reserved. PMID- 30411455 TI - Primavera: A new therapeutical approach to vulvo-vaginal atrophy. AB - Vulvovaginal atrophy is a condition that affects women, although it is mainly associated with the onset of menopause mainly due to hormonal changes vulvovaginal laxity and mucosal atrophy can also affect women at different life stages such as after pregnancy or for cancer patients who have undergone chemo or endocrine therapy. This condition negatively influence quality of life, sexual desire, and self-confidence. Many therapies have been considered mainly with inconclusive or transient results in terms of benefit factor. Recently, a new non invasive product, containing hyaluronic acid, oligopeptides, and antioxidants was introduced to the market. Its name is "Primavera," by Renaissance, Italy. The aim of this product is to allow a vulvo-vaginal biostimulation and considered simple, safe, and satisfactory. PMID- 30411456 TI - Drought legacies are dependent on water table depth, wood anatomy and drought timing across the eastern US. AB - Severe droughts can impart long-lasting legacies on forest ecosystems through lagged effects that hinder tree recovery and suppress whole-forest carbon uptake. However, the local climatic and edaphic factors that interact to affect drought legacies in temperate forests remain unknown. Here, we pair a dataset of 143 tree ring chronologies across the mesic forests of the eastern US with historical climate and local soil properties. We found legacy effects to be widespread, the magnitude of which increased markedly in diffuse porous species, sites with deep water tables, and in response to late-season droughts (August-September). Using an ensemble of downscaled climate projections, we additionally show that our sites are projected to drastically increase in water deficit and drought frequency by the end of the century, potentially increasing the size of legacy effects by up to 65% and acting as a significant process shaping forest composition, carbon uptake and mortality. PMID- 30411457 TI - Local adaptation primes cold-edge populations for range expansion but not warming induced range shifts. AB - According to theory, edge populations may be poised to expand species' ranges if they are locally adapted to extreme conditions, or ill-suited to colonise beyond range habitat if their offspring are genetically and competitively inferior. We tested these contrasting predictions by transplanting low-, mid-, and high elevation (edge) populations of an annual plant throughout and above its elevational distribution. Seed from poor-quality edge habitat (one of two transects) had inferior emergence, but edge seeds also had adaptive phenology (both transects). High-elevation plants flowered earlier, required less heat accumulation to mature seed, and so achieved higher lifetime fitness at and above the range edge. Experimental warming improved fitness above the range, but eliminated the advantage of local cold-edge populations, supporting recent models in which cold-adapted edge populations do not facilitate warming-induced range shifts. The highest above-range fitness was achieved by a 'super edge phenotype' from a neighbouring mountain, suggesting key adaptations exist regionally even if absent from local edge populations. PMID- 30411458 TI - Preparation of (S)-beta-nitro alcohols by a (R)-selective HNL via enantioselective C-C bond cleavage. AB - Hydroxynitrile lyase (HNL) catalysed stereoselective synthesis of beta-nitro alcohols is considered as an efficient biocatalytic approach. However, there exist only one (S)-selective HNL i.e. Hevea brasiliensis (HbHNL) to synthesize (S)-beta-nitro alcohols from corresponding aldehydes. Further, HbHNL synthesis is limited by long reaction time (48 h) and moderate yield. We prepared a number of (S)-beta-nitro alcohols using a (R)-selective HNL from Arabidopsis thaliana (AtHNL). Optimization of the reaction conditions of AtHNL catalyzed stereoselective C-C bond cleavage of racemic 2-ntro-1-phenylethanol (NPE) produced (S)-NPE up to 99% ee and 47% conversion. We believe this is the fastest biocatalytic route known so far to synthesize a series of (S)-beta-nitro alcohols. This approach widens the application of AtHNL not only to synthesize (R)- but also (S)-beta-nitro alcohols starting with appropriate substrate. Without discovering a new enzyme, rather using a different approach, it synthesized a number of (S)-beta-nitro alcohols by taking the advantage of the substrate selectivity of AtHNL. PMID- 30411459 TI - Extracellular cyclic adenosine monophosphate-dependent protein kinase A autoantibody and C-reactive protein as serum biomarkers for diagnosis of cancer in dogs. AB - Protein kinase A, a cyclic adenosine monophosphate (AMP)-dependent enzyme, normally exists within mammalian cells; however, in cancer cells, it can leak out and be found in the serum. Extracellular cyclic AMP-dependent protein kinase A (ECPKA) has been determined to increase in the serum of cancer-bearing dogs. However, there have been no reports in the veterinary literature on serum ECPKA autoantibody (ECPKA-Ab) expression in dogs with cancer. The aim of this study was to evaluate ECPKA-Ab and C-reactive protein (CRP) as serum biomarkers for cancer in dogs. ECPKA-Ab and CRP levels were detected by an enzyme-linked immunosorbent assay in serum samples from dogs with malignant tumours (n = 167), benign tumours (n = 42), or non-tumour disease (n = 155) and from healthy control dogs (n = 123). ECPKA-Ab and CRP levels were significantly higher in the dogs with malignant tumours than in those with benign tumours or non-tumour diseases, as well as in the healthy controls (P < 0.001, Kruskal-Wallis test). There was a significant positive correlation between the neoplastic index, which was developed using ECPKA-Ab and CRP levels, and the presence of cancer in dogs (P < 0.001); the area under the receiver-operating characteristic curve was estimated to be >0.85 (P < 0.001). In conclusion, ECPKA-Ab is a potential serum biomarker for a broad spectrum of cancers. Combined measurement of CRP and ECPKA-Ab levels in serum improves the sensitivity and accuracy of a diagnosis of cancer in dogs. PMID- 30411460 TI - Moving beyond small solute clearance: What evidence is there for more permeable dialyzers and haemodiafiltration? AB - Dialyzers were initially developed for diffusive clearance of uraemic toxins. Diffusion most effectively clears small uncharged solutes from plasma water, such as urea. Sessional urea clearance targets have been shown to be important for short-term patient survival, but over the longer term, although low-flux dialysis can prolong patient survival, accumulation of middle-sized uraemic toxins, such as beta2 microglobulin can lead to disabling arthropathy. Although the introduction of high-flux dialyzers, designed to increase beta2 microglobulin clearance, has reduced the prevalence of arthropathy; this has not been translated into a demonstrable significant improvement in patient survival. However, analysis of individual patients recruited into trials of haemo diafiltration reported that greater convective clearance was associated with better survival, although the individual trials reported mixed outcomes. Most haemodiafiltration trials were not designed to study the effect of convective dose, so although reported patient survival was greater for those receiving greater convective volume exchange, these results could potentially be confounded by patient or center effects. An alternative approach to increasing middle-sized solute clearances would be to use more permeable dialyzers, but as yet there are no trials reporting survival with larger cutoff dialyzers. As such, although there is increasing evidence that increasing middle-sized molecular uraemic solute clearance is associated with improved patient survival, further prospective trials are required to determine whether as with Kt/Vurea there is a threshold effect of how much convective or middle-sized solute clearance is required to improve patient survival. PMID- 30411461 TI - Oncological outcomes before and after the ELAPE-era in rectal cancer patients treated with abdominoperineal excision in a single center, high volume unit. AB - AIM: The extralevator abdominoperineal excision (ELAPE) has been expected to reduce the risk of positive circumferential resection margins (CRM) and local recurrence in locally advanced distal rectal cancer. The aim was to determine whether there is any difference in local recurrence rates between the patients who were operated on for distal rectal cancer, before and after the introduction of ELAPE in our unit. PATIENTS AND METHODS: 206 patients with distal rectal cancer without distant metastases (T1-4N0-2M0) were treated with curative intent. The patients were divided into two cohorts operated in 2000-2007(A) and 2008 2014(B). The ELAPE procedure was introduced in 2008. Since then it has been used in cases of T4 and T3 tumors with threatened margins. In T1-T3 tumors, without threatened margins, a conventional APE has been performed. RESULTS: There was no significant difference in overall survival or cancer specific survival between the two time periods. The local recurrence rate was 15.5% in group A and 6.7% in group B (p=0.048), although there was no significant difference in the cumulative local recurrence rate. Intraoperative tumor perforation occurred significantly more often during the earlier period when ELAPE was not in use: in group A 15/71 (21.1%) vs. B 11/135 (8.1%), p=0.01. CRM was more often positive in group A (16.4%) vs. group B (7.4%), p=0.054. CONCLUSION: The local recurrence rate, intraoperative tumor perforation and positive CRM rate, were significantly lower during the later period when more extensive surgery (ELAPE) was performed for locally advanced T3-T4 rectal cancer with threatened margins. This article is protected by copyright. All rights reserved. PMID- 30411462 TI - Scurvy in a hemodialysis patient. Rare or ignored? AB - Chronic kidney disease and dialysis brings with it a plethora of complications, including malnutrition. Strict dietary restrictions in hemodialysis (HD) patients further complicate the picture as it increases the risk of deficiency of micronutrients, specifically water-soluble vitamins. Today, there is a lack of concrete guidelines concerning recommendations on vitamin supplementation in HD patients. This lack of data is partly due to our incomplete understanding of handling of vitamins in a uremic state. There is a dire need for more data on the impact of dialysis and uremic state on water-soluble vitamins to facilitate appropriate preventative supplementation. We present a case of scurvy in a HD patient that will contribute toward the understanding of vitamin status in HD. We hope it will aid in screening HD patients for vitamin C deficiency and individualizing supplementation of vitamin C. PMID- 30411463 TI - Tau-induced nuclear envelope invagination causes a toxic accumulation of mRNA in Drosophila. AB - The nucleus is a spherical dual-membrane bound organelle that encapsulates genomic DNA. In eukaryotes, messenger RNAs (mRNA) are transcribed in the nucleus and transported through nuclear pores into the cytoplasm for translation into protein. In certain cell types and pathological conditions, nuclei harbor tubular invaginations of the nuclear envelope known as the "nucleoplasmic reticulum." Nucleoplasmic reticulum expansion has recently been established as a mediator of neurodegeneration in tauopathies, including Alzheimer's disease. While the presence of pore-lined, cytoplasm-filled, nuclear envelope invaginations has been proposed to facilitate the rapid export of RNAs from the nucleus to the cytoplasm, the functional significance of nuclear envelope invaginations in regard to RNA export in any disorder is currently unknown. Here, we report that polyadenylated RNAs accumulate within and adjacent to tau-induced nuclear envelope invaginations in a Drosophila model of tauopathy. Genetic or pharmacologic inhibition of RNA export machinery reduces accumulation of polyadenylated RNA within and adjacent to nuclear envelope invaginations and reduces tau-induced neuronal death. These data are the first to point toward a possible role for RNA export through nuclear envelope invaginations in the pathogenesis of a neurodegenerative disorder and suggest that nucleocytoplasmic transport machinery may serve as a possible novel class of therapeutic targets for the treatment of tauopathies. PMID- 30411464 TI - Prevention of hemodialysis catheter infections: Ointments, dressings, locks, and catheter hub devices. AB - Tunneled central venous catheters used for the provision of hemodialysis are associated with excess morbidity and mortality. Catheter related exit site and blood stream infections are major risks of their use. Although catheter-avoidance is the best strategy to reduce infections and mortality in the hemodialysis population, the use of catheters remains unacceptably high. In this review, the existing clinical practice guidelines for the prevention of hemodialysis catheter associated infections are outlined, and a comprehensive evidenced-based summary of interventions is provided. This includes details about the use of topical antimicrobial ointments and dressings, intranasal ointment application, prophylactic use of antibiotic and non-antibiotic catheter lock solutions, and catheter hub devices for the prevention of catheter blood stream infections. PMID- 30411465 TI - A Prospective Study on the Effects of Medicaid Regulation and Other Barriers to Obtaining Postpartum Sterilization. AB - INTRODUCTION: This study aimed to assess unfulfilled sterilization requests, specifically regarding issues with the Medicaid consent for sterilization, and determine the proportion of women who subsequently received interval sterilization by 3 months postpartum. METHODS: The authors conducted a prospective observational cohort study of women who gave birth over an 8-month period and requested immediate postpartum sterilization. Records of women with unfulfilled requests were reviewed up to 3 months postpartum to determine rates of postpartum follow-up and interval sterilization. Primary analysis examined unfulfilled sterilization requests associated with the Medicaid consent form and, secondarily, all other reasons for unfulfilled requests, as well as alternative contraceptive methods chosen. RESULTS: Of the 334 women who requested immediate postpartum sterilization, 173 (52%) received the requested sterilization and 161 (48%) did not. Among those whose request was unfulfilled, 91 (56.5%) still wanted the procedure, and of those women, more than two-thirds were unable to receive it because of Medicaid consent issues. Within this group, only 6 received interval sterilization by 3 months postpartum; more than one-third received a form of long acting reversible contraception, and 24.6% did not receive postpartum care. DISCUSSION: A sizable proportion of women requesting postpartum sterilization have unfulfilled requests because of an issue with the Medicaid consent and also have a low likelihood of receiving interval sterilization by 3 months postpartum. The Medicaid consent may create barriers for women requesting postpartum sterilization, the vast majority of whom face subsequent barriers obtaining interval sterilization, thereby increasing the risk for unintended pregnancy in an at-risk population. This has important implications for reproductive justice efforts to protect vulnerable populations while minimizing barriers to desired care. PMID- 30411466 TI - An Exploratory Study of the Relationship between Facility Design and the Provision of Childbirth Care. AB - INTRODUCTION: Across health care, facility design has been shown to significantly affect quality of care; however, in maternity care, the mechanisms of how facility design affects provision of care are understudied. We aim to identify and illustrate key mechanisms that may explain how facility design helps or hinders clinicians in providing childbirth care. METHODS: We reviewed the literature to select design elements for inclusion. Using a modified Delphi consensus process, we engaged an interdisciplinary advisory board to prioritize these elements with regard to potential effect on care provision. The advisory board proposed mechanisms that may explain how the prioritized facility design elements help or hinder care, which the study team organized into themes. We then explored these themes using semistructured interviews with managers at 12 diverse birth centers and hospital-based labor and delivery units from across the United States. RESULTS: The design of childbirth facilities may help or hinder the provision of care through at least 3 distinct mechanisms: 1) flexibility and adaptability of spaces to changes in volume or acuity; 2) physical and cognitive anchoring that can create default workflows or mental models of care; and 3) facilitation of sharing knowledge and workload across clinicians. DISCUSSION: Facility designs may intentionally or unintentionally influence the workflows, expectations, and cultures of childbirth care. PMID- 30411467 TI - Comparison of biocompatibility in polysulfone dialysis membranes with different sterilization. AB - INTRODUCTION: Polysulfone (PSf) membrane has been widely used for hemodialysis. A few studies have been reported in which a method of sterilization may affect biocompatibility. In this study, the comparison was made between two PSf membranes in order to evaluate the effect of sterilization from the biocompatibility point of view. METHODS: We investigated the biocompatibility of the following two dialyzers, that is, APS-11SA (Asahi Kasei medical Co., Tokyo, Japan), sterilized by gamma-ray irradiation, and RENAK PS-1.0 (Kawasumi laboratories, Tokyo, Japan), sterilized by autoclave. Heparin of 40 units/mL was put in a syringe, and test blood was collected from healthy volunteers. Then, the dialyzer and blood circuit were filled with the test blood. Subsequently, the blood was circulated by a roller pump at the rate of 200 mL/min. We measured the platelet counts, CD41 and CD42b platelet surface markers, beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) at 30, 120, and 240 minutes, respectively. FINDINGS: The platelet counts at 30, 120, and 240 minutes decreased significantly from the initiation of blood circulation in both dialyzers. The average beta-TG and PF4 increased from 61.3 +/- 22.1 and 17.0 +/- 6.4 ng/mL to 680.7 +/- 217.1 and 550.7 +/- 116.7 ng/mL with APS-11SA and to 454.3 +/- 85.6 and 402.0 +/- 58.0 ng/mL with RENAK PS-1.0, respectively. The average expression of CD41 and CD42b in APS-11SA and RENAK PS-1.0 was similar. DISCUSSION: There are some reports that the gamma-ray irradiation changes the membrane structure of the PSf membrane, crosslinking the polyvinylpyrrolidone (PVP), a hydrophilic agent, on to the membrane. On the other hand, excess amount of PVP may have been eluted during the rinsing procedure in RENAK PS-1.0 because it was sterilized with autoclave. Because both these factors influenced on our results, APS-11SA and RENAK PS-1.0 dialyzers showed excellent blood compatibility. PMID- 30411468 TI - Using meta-omics of contaminated sediments to monitor changes in pathways relevant to climate regulation. AB - Microbially mediated biogeochemical processes are crucial for climate regulation and may be disrupted by anthropogenic contaminants. To better manage contaminants we need tools that make real-time causal links between stressors and altered microbial functions, and the potential consequences for ecosystem services such as climate regulation. In a manipulative field experiment, we used metatranscriptomics to investigate the impact of excess organic enrichment and metal contamination on the gene expression of nitrogen and sulfur metabolisms in coastal sediments. Our gene expression data suggest that excess organic enrichment results in higher transcript levels of genes involved in the production of 1) toxic ammonia and hydrogen sulfide, and 2) a greenhouse gas (nitrous oxide). However, metal contamination did not have any significant impacts on gene expression. We reveal the genetic mechanisms that may lead to altered productivity and greenhouse gas production in coastal sediments due to anthropogenic contaminants. Our data highlight the applicability of metatranscriptomics as a management tool that provides an immense breadth of information and can identify potentially impacted process measurements that need further investigation. This article is protected by copyright. All rights reserved. PMID- 30411469 TI - The global regulator Crc orchestrates the metabolic robustness underlying oxidative stress resistance in Pseudomonas aeruginosa. AB - The remarkable metabolic versatility of bacteria of the genus Pseudomonas enable their survival across very diverse environmental conditions. P. aeruginosa, one of the most relevant opportunistic pathogens, is a prime example of this adaptability. The interplay between regulatory networks that mediate these metabolic and physiological features is just starting to be explored in detail. Carbon catabolite repression, governed by the Crc protein, controls the availability of several enzymes and transporters involved in the assimilation of secondary carbon sources. Yet, the regulation exerted by Crc on redox metabolism of P. aeruginosa (hence, on the overall physiology) had hitherto been unexplored. In this study, we address the intimate connection between carbon catabolite repression and metabolic robustness of P. aeruginosa PAO1. In particular, we explored the interplay between oxidative stress, metabolic rearrangements in central carbon metabolism and the cellular redox state. By adopting a combination of quantitative physiology experiments, multi-omic analyses, transcriptional patterns of key genes, measurement of metabolic activities in vitro, and direct quantification of redox balances both in the wild-type strain and in an isogenic Deltacrc derivative, we demonstrate that Crc orchestrates the overall response of P. aeruginosa to oxidative stress via reshaping of the core metabolic architecture in this bacterium. This article is protected by copyright. All rights reserved. PMID- 30411470 TI - Frailty is associated with reduced prospect of discharge home after in-hospital cardiac arrest. AB - OBJECTIVE: To assess the relationship between hospital admission characteristics, including frailty, and discharge outcome after in-hospital cardiac arrest. DESIGN, SETTING, PARTICIPANTS: Prospectively collected data were retrospectively analysed for all separations from a tertiary hospital during 2008-2017 that involved rapid response team attendance for cardiac arrest. Hospital Frailty Risk Score (HFRS) and Charlson index of comorbidity were calculated from 'primary' and 'associated' ICD-10-AM diagnoses. HFRS >= 5 was taken to signify frailty. OUTCOMES: Discharge home from hospital and death in hospital, modelled using logistic regression. RESULTS: There were 388 in-hospital arrest patients; age >= 50 years 91%, previously discharged in the past six months 34%, unplanned admission 66%, non-cardiology-cardiothoracic admission 63%, Charlson comorbidity index >= 2 45% and frailty 19%. Discharge home occurred in 22%, discharge to another hospital 17% and death 62%. Of the frail patients, only 3 (4%) were discharged home, 12 (17%) were discharged to another hospital and 57 (79%) died in hospital. Fewer frail patients were discharged home compared to non-frail patients (4% vs. 26%; OR 0.13, P 0.001). On multivariable analysis, patients were less likely to be discharged home if they had frailty (OR 0.24, P 0.02), age >= 50 years (OR 0.36, P 0.01), non-cardiology-cardiothoracic unit admission (OR 0.40, P 0.001) and unplanned admission (OR 0.57, P 0.04). Frail patients discharged to another hospital spent a median of 15 days (IQR 11-23) in the hospital post-arrest before leaving to continue inpatient care elsewhere. Frailty was associated with death in hospital on univariate analysis (79% vs. 58%; OR 2.80, P 0.001) but not after controlling for other factors. CONCLUSIONS: Frail patients are unlikely to make a good recovery after in-hospital arrest and this should be taken into account when planning care with patients and their families. This article is protected by copyright. All rights reserved. PMID- 30411472 TI - Calculation of confidence intervals for a finite population size. AB - For any estimate of response, confidence intervals are important as they help quantify a plausible range of values for the population response. However, there may be instances in clinical research when the population size is finite, but we wish to take a sample from the population and make inference from this sample. Instances where you can have a fixed population size include when undertaking a clinical audit of patient records or in a clinical trial a researcher could be checking for transcription errors against patient notes. In this paper, we describe how confidence interval calculations can be calculated for a finite population. These confidence intervals are narrower than confidence intervals from population samples. For the extreme case of when a 100% sample from the population is taken, there is no error and the calculation is the population response. The methods in the paper are described using a case study from clinical data management. PMID- 30411471 TI - High risk of permanent stoma after anastomotic leakage in anterior resection for rectal cancer. AB - AIM: This study investigates how often bowel continuity was restored after anastomotic leakage in anterior resection for rectal cancer and assesses the clinical factors associated with permanent stoma. METHOD: The Swedish Colorectal Cancer Registry was used to identify cases of anastomotic leakage registered in southern Sweden between January 2001 and December 2011. Patient characteristics, surgical details and clinical information about the anastomotic leakages were retrieved from medical records. RESULTS: Of the 1442 patients operated on with anterior resection in 11 hospitals, 144 (10%) were diagnosed with anastomotic leakage after anterior resection for rectal cancer. After a median follow-up of 87 months (range 21-165), the overall rate of permanent stoma among patients with anastomotic leakage was 65%. Age >= 70 years (P = 0.02) and re-laparotomy (P < 0.001) were independently related to permanent stoma. Compared with nondefunctioned patients with anastomotic leakage, defunctioned patients with anastomotic leakage at the index procedure less often required re-laparotomy at some point during the entire clinical course (P < 0.001), but nondefunctioned and defunctioned patients with anastomotic leakage both had permanent stoma to the same extent (67% and 62%, respectively). CONCLUSION: Anastomotic leakage is highly associated with permanent stoma after anterior resection, especially in patients aged >= 70 years. In this cohort of patients with anastomotic leakage, 65% had permanent stoma at long-term follow-up. A defunctioning stoma ameliorates the clinical course but does not affect the end result of bowel continuity in established anastomotic leakage after anterior resection. PMID- 30411473 TI - Effects of organic matter and low oxygen on the mycobenthos in a coastal lagoon. AB - Fungi living in sediments ("mycobenthos") are hypothesized to play a role in the degradation of organic matter deposited at the land-sea interface, but the environmental factors influencing the mycobenthos are poorly understood. We used mock community calibrated Illumina sequencing to show that the mycobenthos community structure in a coastal lagoon was significantly changed after exposure to a lignocellulose extract and subsequent development of benthic anoxia over a relatively short (10-hour) incubation. Saprotrophic taxa dominated and were selected for under benthic anoxia, specifically Aquamyces (Chytridiomycota) and Orbilia (Ascomycota), implicating these genera as important benthic saprotrophs. Protein encoding genes involved in energy and biomass production from Fungi and the fungal-analog group Labyrinthulomycetes had the highest increase in expression with the added organic matter compared to all other groups, indicating that lignocellulose stimulates metabolic activity in the mycobenthos. Flavobacteria dominated the active bacterial community that grew rapidly with the lignocellulose extract and crashed sharply upon O2 depletion. Our findings indicate that the diversity, activity, and trophic potential of the mycobenthos changes rapidly in response to organic matter and decreasing O2 concentrations, which together with heterotrophic Flavobacteria, undergo "boom and bust" dynamics during lignocellulose degradation in estuarine ecosystems. This article is protected by copyright. All rights reserved. PMID- 30411475 TI - Acute kidney injury in HIV-infected patients: a critical review. AB - Acute kidney injury (AKI) is characterized by a rapid decline of renal function associated with worse outcomes. The purpose of the authors is to perform a critical review of the incidence, risk factors, pathogenesis and outcome of AKI in HIV-infected patients. Human immunodeficiency virus (HIV)-infected patients have an increased risk of developing AKI, to which contribute both HIV-dependent and HIV-independent factors as well as the nephrotoxicity of drugs used. The increased risk of AKI in HIV-infected patients and its negative impact on prognosis highlights the need for identification of patients at risk, creation of prevention strategies and management. HIV-infected patients have an increased risk of developing AKI, to which both HIV-dependent and HIV-independent factors contribute, as well as the nephrotoxicity of drugs used. The increased risk of AKI in HIV-infected patients and its negative impact on prognosis highlight the need for identification of patients at risk, creation of prevention strategies and management. PMID- 30411474 TI - Importance of flagella in acute and chronic Pseudomonas aeruginosa infections. AB - Pseudomonas aeruginosa is an environmental microorganism and a causative agent of diverse acute and chronic, biofilm-associated infections. Advancing research based knowledge on its adaptation to conditions within the human host is bound to reveal novel strategies and targets for therapeutic intervention. Here, we investigated the traits that P. aeruginosa PA14 as well as a virulence attenuated DeltalasR mutant need to survive in selected murine infection models. Experimentally, the genetic programs that the bacteria use to adapt to biofilm associated versus acute infections were dissected by passaging transposon mutant libraries through mouse lungs (acute) or mouse tumours (biofilm-infection). Adaptive metabolic changes of P. aeruginosa were generally required during both infection processes. Counter-selection against flagella expression was observed during acute lung infections. Obviously, avoidance of flagella-mediated activation of host immunity is advantageous for the wildtype bacteria. For the DeltalasR mutant, loss of flagella did not confer a selective advantage. Apparently, other pathogenesis mechanisms are active in this virulence attenuated strain. In contrast, the infective process of P. aeruginosa in the chronic biofilm model apparently required expression of flagellin. Together, our findings imply that the host immune reactions against the infectious agent are very decisive for acuteness and duration of the infectious disease. They direct disease outcome. PMID- 30411476 TI - Treatment of anal fissure: a survey of surgical practice in Australia and New Zealand. AB - AIM: The aim was to determine whether or not the clinical management of anal fissure in Australia and New Zealand accords with published guidelines. METHODS: A comprehensive survey based on common clinical scenarios was distributed to 206 colorectal surgeons in Australia and New Zealand. RESULTS: The response rate was 44% (91 surgeons). For 19 topic areas, only seven (37%) reached consensus (defined as > 70% majority opinion). Of these, six (86%) agreed with guideline recommendations. Twelve (63%) topic areas demonstrated community equipoise (defined as less than or equal to 70% majority opinion), of which five (42%) agreed with guideline recommendations and seven (58%) disagreed with guidelines. Of the seven topics that disagreed with guidelines, three were based on moderate quality evidence (first line management of acute anal fissure in a young patient, fissure healing and faecal incontinence rates following anocutaneous flap) and four were based on low quality evidence (length of sphincter division during a lateral sphincterotomy in women, management of chronic low-pressure anal fissures postpartum, fissure healing rate following anoplasty with botulinum toxin or sphincterotomy and faecal incontinence rates following repeat sphincterotomy for recurrence). Consensus and/or agreement with guidelines were more prevalent in management when medical therapy failed. CONCLUSION: While areas of consensus mostly agreed with guideline recommendations, there remain many areas of community equipoise which warrant further research. PMID- 30411477 TI - Development and evaluation of a novel MR-compatible pelvic end-to-end phantom. AB - MR-only treatment planning and MR-IGRT leverage MRI's powerful soft tissue contrast for high-precision radiation therapy. However, anthropomorphic MR compatible phantoms are currently limited. This work describes the development and evaluation of a custom-designed, modular, pelvic end-to-end (PETE) MR compatible phantom to benchmark MR-only and MR-IGRT workflows. For construction considerations, subject data were assessed for phantom/skeletal geometry and internal organ kinematics to simulate average male pelvis anatomy. Various materials for the bone, bladder, and rectum were evaluated for utility within the phantom. Once constructed, PETE underwent CT-SIM, MR-Linac, and MR-SIM imaging to qualitatively assess organ visibility. Scans were acquired with various bladder and rectal volumes to assess component interactions, filling capabilities, and filling reproducibility via volume and centroid differences. PETE simulates average male pelvis anatomy and comprises an acrylic body oval (height/width = 23.0/38.1 cm) and a cast-mold urethane skeleton, with silicone balloons simulating bladder and rectum, a silicone sponge prostate, and hydrophilic poly(vinyl alcohol) foam to simulate fat/tissue separation between organs. Access ports enable retrofitting the phantom with other inserts including point/film based dosimetry options. Acceptable contrast was achievable in CT-SIM and MR Linac images. However, the bladder was challenging to distinguish from background in CT-SIM. The desired contrast for T1-weighted and T2-weighted MR-SIM (dark and bright bladders, respectively) was achieved. Rectum and bone exhibited no MR signal. Inputted volumes differed by <5 and <10 mL from delineated rectum (CT SIM) and bladder (MR-SIM) volumes. Increasing bladder and rectal volumes induced organ displacements and shape variations. Reproduced volumes differed by <4.5 mL, with centroid displacements <1.4 mm. A point dose measurement with an MR compatible ion chamber in an MR-Linac was within 1.5% of expected. A novel, modular phantom was developed with suitable materials and properties that accurately and reproducibly simulate status changes with multiple dosimetry options. Future work includes integrating more realistic organ models to further expand phantom options. PMID- 30411478 TI - Response to: Gender differences and the association between right ventricular strain and arterial hypertension-A commentary. PMID- 30411479 TI - Nursing Diagnoses as Predictors of Hospital Length of Stay: A Prospective Observational Study. AB - PURPOSE: To investigate whether the number of nursing diagnoses on hospital admission is an independent predictor of the hospital length of stay. DESIGN: A prospective observational study was carried out. A sample of 2,190 patients consecutively admitted (from July to December 2014) in four inpatient units (two medical, two surgical) of a 1,547-bed university hospital were enrolled for the study. METHODS: Data were collected from a clinical nursing information system and the hospital discharge register. Two regression analyses were performed to investigate if the number of nursing diagnoses on hospital admission was an independent predictor of length of stay and length of stay deviation after controlling for patients' sociodemographic characteristics (age, gender), clinical variables (disease groupers, disease severity morbidity indexes), and organizational hospital variables (admitting inpatient unit, modality of admission). FINDINGS: The number of nursing diagnoses was shown to be an independent predictor of both the length of stay (beta = .15; p < .001) and the length of stay deviation (beta = .19; p < .001). CONCLUSIONS: The number of nursing diagnoses is a strong independent predictor of an effective hospital length of stay and of a length of stay longer than expected. CLINICAL RELEVANCE: The systematic inclusion of standard nursing care data in electronic health records can improve the predictive ability on hospital outcomes and describe the patient complexity more comprehensively, improving hospital management efficiency. PMID- 30411480 TI - Does external beam radiation therapy to the pelvis portend worse ileal pouch outcomes? An international multi-institution collaborative study. AB - AIM: Short-term morbidity and long-term functional outcome of patients with an ileal pouch-anal anastomosis (IPAA) exposed to pelvic external beam radiation therapy (EBRT) remains unknown. We report the largest series to date regarding the effects of pelvic EBRT on: (i) 30-day postoperative outcomes; and (ii) long term functional outcome following IPAA. METHOD: A retrospective chart review was conducted of patients who received EBRT before or after IPAA between 1980 and 2017 across three international inflammatory bowel disease referral centres. RESULTS: Nineteen patients were included. Indications for EBRT were rectal adenocarcinoma (n = 13), prostate adenocarcinoma (n = 4) or anal squamous cell carcinoma (ASCC) (n = 2). EBRT was given prior to IPAA in 12 (63%) patients and after IPAA in seven (37%). In EBRT before IPAA, patients had a median of 5 (range: 4-8) daytime bowel movements, 1 (range: 0-5) night-time bowel movement, no daytime incontinence, and only one patient used pads at a median follow up of 25 (range: 11-163) months; one patient underwent pouch excision 15 months after IPAA. In EBRT after IPAA, patients reported a median of 8 (range: 5-10) daytime and 2 (range: 0-5) night-time bowel movements, 80% had either daytime or night time incontinence and 80% used pads at a median follow up of 90 (range: 25-315) months. CONCLUSION: Pelvic EBRT administered prior to IPAA is associated with acceptable long-term function outcome. However, when pelvic EBRT is given to an IPAA in situ, most patients experience poor long-term pouch function without pouch failure. PMID- 30411481 TI - Biological applications of phytosynthesized gold nanoparticles using leaf extract of Dracocephalum kotschyi. AB - In this work, biosynthesis potentials of Dracocephalum kotschyi leaf extract for the production of gold nanoparticle (AuNPs) were studied, and the biological (catalytic, antibacterial, antioxidant, and anticancer) activities of studied AuNPs were evaluated. Different analytical techniques including UV-visible spectroscopy, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscope (SEM), energy dispersive X-ray analysis, and transmission electron microscopy (TEM) were used for the characterization of AuNPs. Moreover, Different testing methods were used for evaluating biological activities of biosynthesized AuNPs. The formation of AuNPs was confirmed by color change and UV-visible spectroscopic analysis. Field emission (FE)-SEM and TEM images were used to characterize phytosynthesized AuNPs which were predominantly spherical in shape with size in the range of 5-21 nm. These spherical NPs were found to be 39.79 +/- 5 nm in size as determined by dynamic light scattering particle size analyzer. XRD pattern confirms the crystalline nature of the biosynthesized nanoparticles. The phytoconstituents involved in the reduction and stabilization of nanoparticles have been identified using FTIR spectra. The phytosynthesized AuNPs showed effective antioxidant, antibacterial and catalytic reduction activities. Furthermore, they have inhibited H1229 and MCF-7 cancer cell lines proliferation in a dose-dependent manner. These results have supported that D. kotschyi leaf extract was very efficient for the synthesis of AuNPs, and synthesized NPs showed enhanced biological activities which make them suitable for biomedical applications. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 00A: 1-11, 2018. PMID- 30411482 TI - A simple test for the treatment effect in clinical trials with a sequential parallel comparison design and negative binomial outcomes. AB - In placebo-controlled, double-blinded, randomized clinical trials, the presence of placebo responders reduces the effect size for comparison of the active drug group with the placebo group. An attempt to resolve this problem is to use the sequential parallel comparison design (SPCD). Although there are SPCDs with dichotomous or continuous outcomes, an SPCD with negative binomial outcomes-with which investigators deal eg, in clinical trials involving multiple sclerosis, where the investigators are still concerned about the presence of placebo responders-has not yet been discussed. In this article, we propose a simple test for the treatment effect in clinical trials with an SPCD and negative binomial outcomes. Through simulations, we show that the analysis method achieves the nominal type I error rate and power, whereas the sample size calculation provides the sample size with adequate power accuracy. PMID- 30411483 TI - Simultaneous determination of levofloxacin and ciprofloxacin in human urine by ionic liquid-based, dual-template molecular imprinted coated graphene oxide monolithic solid-phase extraction. AB - A novel method was developed to simultaneously determine the ciprofloxacin and levofloxacin levels in human urine using an ionic liquid-based, dual-molecular imprinted polymer-coated graphene oxide solid-phase extraction monolithic column coupled with high performance liquid chromatography. The molecular imprinted monolithic column was prepared using ciprofloxacin and levofloxacin as templates, 1-vinyl-3-ethylimidazolium bromide as the functional monomer, and graphene oxide as the core material. The resulting imprinted monolithic were characterized by scanning electron microscopy and fourier transform-infrared spectroscopy. The efficiency and capacity of the ionic liquid-based imprinted monolithic column were investigated by varying the synthesis conditions (ciprofloxacin: levofloxacin ratio and template: functional monomer: cross-linker ratio). The solid-phase extraction process was optimized by changing the washing and eluting conditions. The results suggested that the proposed ionic liquid-based molecularly imprinted solid-phase extraction monolithic-HPLC method could separate ciprofloxacin and levofloxacin efficiently and simultaneously from human urine. The mean recoveries of ciprofloxacin and levofloxacin ranged from 89.2% to 93.8% and 86.7% to 94.6%, respectively. The intra-day and inter-day relative standard deviation ranged from 0.9% to 3.2%, and 0.8% to 2.9%, respectively. Under the optimized conditions, the recoveries of ciprofloxacin and levofloxacin were more than 93.8%. This article is protected by copyright. All rights reserved. PMID- 30411484 TI - Biomarkers for major depressive and bipolar disorders using metabolomics: A systematic review. AB - Major depressive disorder (MDD) and bipolar disorder (BD) lack robust biomarkers useful for screening purposes in a clinical setting. A systematic review of the literature was conducted on metabolomic studies of patients with MDD or BD through the use of analytical platforms such as in vivo brain imaging, mass spectrometry, and nuclear magnetic resonance. Our search identified a total of 7,590 articles, of which 266 articles remained for full-text revision. Overall, 249 metabolites were found to be dysregulated with 122 of these metabolites being reported in two or more of the studies included. A list of biomarkers for MDD and BD established from metabolites found to be abnormal, along with the number of studies supporting each metabolite and a comparison of which biological fluids they were reported in, is provided. Metabolic pathways that may be important in the pathophysiology of MDD and BD were identified and predominantly center on glutamatergic metabolism, energy metabolism, and neurotransmission. Using online drug registries, we also illustrate how metabolomics can facilitate the discovery of novel candidate drug targets. PMID- 30411485 TI - Gender differences and the association between right ventricular strain and arterial hypertension-A commentary. PMID- 30411486 TI - Surface Engineering of Nanomaterials for Photo-Electrochemical Water Splitting. AB - Photo-electrochemical water splitting represents a green and environmentally friendly method for producing solar hydrogen. Semiconductor nanomaterials with a highly accessible surface area, reduced charge migration distance, and tunable optical and electronic property are regarded as promising electrode materials to carry out this solar-to-hydrogen process. Since most of the photo-electrochemical reactions take place on the electrode surface or near-surface region, rational engineering of the surface structures, physical properties, and chemical nature of photoelectrode materials could fundamentally change their performance. Here, the recent advances in surface engineering methods, including the modification of the nanomaterial surface morphology, crystal facet, defect and doping concentrations, as well as the deposition of a functional overlayer of sensitizers, plasmonic metallic structures, and protective and catalytic materials are highlighted. Each surface engineering method and how it affects the structural features and photo-electrochemical performance of nanomaterials are reviewed and compared. Finally, the current challenges and the opportunities in the field are discussed. PMID- 30411487 TI - Chemical Constituents from Tabernaemontana bufalina Lour. AB - A new monoterpenoid indole alkaloid, namely (3R,7S,14R,19S,20R)-19 hydroxypseudovincadifformine (1), together with nine known compounds (2-10) were isolated and identified from the branch and leaves of Tabernaemontana bufalina Lour. Their structures were established using extensive spectroscopic methods, and the absolute configuration of compound 1 was confirmed by modified mosher's and calculated electronic circular dichroism (ECD) methods. The cytotoxic activities of these isolated metabolites were evaluated on two cancer cell lines. As the results, cytotoxic activities on B16 and MDA-MB-231 cells showed IC50 values of 0.13 and 8.9 MUM for 6, and of 11.7 and 20.3 MUM for 9, respectively. PMID- 30411488 TI - Advances in the development of molecularly imprinted polymers for the separation and analysis of proteins with liquid chromatography. AB - This review documents recent advances in the design, synthesis, characterization, and application of molecularly imprinted polymers in the form of monoliths and particles/beads for the use in the separation and analysis of proteins with solid phase extraction or liquid chromatography. The merits of three-dimensional molecular imprinting, whereby the molecular template is randomly embedded in the polymer, and two-dimensional imprinting, in which the template is confined to the surface, are described. Target protein binding can be achieved by either using the entire protein as a template or by using a protein substructure as template, that is, a peptide, as in the "epitope" approach. The intended approach and strategy then determine the choice of polymerization method. A synopsis has been provided on methods used for the physical, chemical, and functional characterizations and associated performance evaluations of molecularly imprinted and nonimprinted control polymers, involving a diverse range of analytical techniques commonly used for low and high molecular mass analytes. Examples of recent applications demonstrate that, due to the versatility of imprinting methods, molecularly imprinted monoliths or particles/beads can be adapted to protein extraction/depletion and separation procedures relevant to, for example, protein biomarker detection and quantification in biomedical diagnostics and targeted proteomics. PMID- 30411489 TI - Hepcidin/Ferritin Ratios Differ Among Non-dialyzed Chronic Kidney Disease Patients, and Patients on Hemodialysis and Peritoneal Dialysis. AB - The serum levels of hepcidin generally increase in patients with chronic kidney disease (CKD) due to inflammation or a decline in the glomerular filtration rate. However, the differences in the ferrokinetics among dialysis modalities are unclear. We investigated the relationship between serum levels of hepcidin and ferritin among non-dialyzed CKD (ND), hemodialysis (HD), and peritoneal dialysis (PD) patients. We recruited 285 CKD patients (117 ND, 80 HD, and 88 PD patients) and measured the serum levels of hepcidin-25, ferritin, hemoglobin, iron, transferrin saturation (TSAT), albumin, and high sensitivity C-reactive protein (hs-CRP). Hepcidin-25 levels were elevated in all CKD patients and were significantly higher in PD than in ND and HD patients. The hepcidin/ferritin ratio was significantly higher in PD patients independent of TSAT, hemoglobin, hs CRP and serum albumin. Hepcidin/ferritin ratio, associated with both dialysis modality and inflammation, is expected to be a useful indicator of anemia in CKD. PMID- 30411490 TI - Capillary electrophoresis, high-performance liquid chromatography, and thin-layer chromatography analyses of phenolic compounds from rapeseed plants and evaluation of their antioxidant activity. AB - Rapeseed plants, known for oil production, are also known to contain phenolic compounds such as phenolic acids and flavonoids, with potential antioxidant and anticancer activities. The separation and identification of 11 phenolic acids in rapeseed extracts (including leaves, flowers, Chinese seeds, Belgian seeds, and cake) by capillary electrophoresis were investigated. The results were compared with those obtained with high-performance liquid chromatography and thin-layer chromatography and showed that the capillary electrophoresis technique offers several advantages for the identification of phenolic compounds in various rapeseed extracts. The antioxidant activity of rapeseed extracts and reference compounds was evaluated using four different approaches, namely, 2,2'-azinobis- (3-ethylbenzohiazoline-6-sulfonic acid assay, free radical 2,2-diphenyl-1 picrylhydrazyl assay, electron paramagnetic resonance spectroscopy and the measurement of the total polyphenol content. The contents of total polyphenols in the tested extracts were ranging between 5.4 and 21.1% m/m and ranked as follows: Chinese seeds ? Belgian seeds ? Flowers ? Cake ? Leaves. PMID- 30411491 TI - Nutritionally Derived Metabolic Cues Typical of the Obese Microenvironment Increase Cholesterol Efflux Capacity of Adipose Tissue Macrophages. AB - BACKGROUND: Cholesterol retention within plasma membranes of macrophages is associated with increased inflammatory signaling. Cholesterol efflux via the transporters ABCA1, ABCG1, and SR-BI to high-density lipoprotein (HDL) particles is a critical mechanism to maintain cellular cholesterol homeostasis. Little is known about the impact of the obese microenvironment on cholesterol efflux capacity (CEC) of macrophages. In this study, the CEC of obese-derived primary adipose-tissue macrophages (ATM) is evaluated and the in vivo microenvironment is modeled in vitro to determine mechanisms underlying modulated CEC. MATERIALS AND METHODS: F4/80+ ATM are labeled with 3 H-cholesterol ex vivo, and CEC and ABCA1/ABCG1 protein levels are determined. Total, ABCA1-dependent, and ABCA1 independent CECs are determined in J774 macrophages polarized to M1 (LPS&IFNgamma), M2 (IL-4&IL-13), or metabolic phenotypes (glucose, insulin, and palmitic acid). RESULTS: Obese ATM exhibit enhanced CEC and ABCA1 and ABCG1 expression compared to lean ATM. In contrast, ABCA1-CEC is suppressed from M1 polarized macrophages compared to untreated in vitro, by activation of the JAK/STAT pathway. Incubation of macrophages in vitro in high glucose augments cAMP-induced ABCA1 protein expression and ABCA1-CEC. CONCLUSIONS: These novel findings demonstrate remarkable plasticity of macrophages to respond to their environment with specific modulation of ABCA1 depending on whether classical pro inflammatory or metabolic cues predominate. PMID- 30411492 TI - The Anti-Arthritis Effect of Olive-Derived Maslinic Acid in Mice is Due to its Promotion of Tissue Formation and its Anti-Inflammatory Effects. AB - SCOPE: A previous study demonstrated that intake of olive pomace extract containing maslinic acid (MA), a triterpene, effectively prevents and alleviates arthritis in animals and humans. Here, the molecular mechanisms involved in the anti-arthritis effect of MA have been elucidated by determining gene expression changes induced by olive-derived MA intake in collagen antibody-induced arthritis (CAIA) mice. METHODS AND RESULTS: Mice are divided into the untreated (CT), CAIA (CA), and CAIA administered MA (CA + MA) groups. The CA + MA mice are fed MA at a daily dose of 200 mg kg-1 of body weight from day 1. CAIA is then induced on day 8 and evaluated on day 12. Arthritis symptoms are alleviated, and the gene expression of inflammatory cytokines is reduced in the CA + MA group compared with the CA group. A DNA microarray analysis of synovial membranes reveals that MA alters the expression levels of genes related to inflammation, including glucocorticoid responses, immune responses, and the extracellular matrix. CONCLUSIONS: The preventive effect of MA on arthritis is attributable to the promotion of tissue formation as well as suppression of inflammation in the synovium via inactivation of Toll-like receptor signaling and downregulation of leukotrienes through the glucocorticoid receptor. PMID- 30411493 TI - Improving the Sensitivity of Fluorescence-Based Immunoassays by Photobleaching the Autofluorescence of Magnetic Beads. AB - In fluorescence-based assays, usually a target molecule is captured using a probe conjugated to a capture surface, and then detected using a second fluorescently labeled probe. One of the most common capture surfaces is a magnetic bead. However, magnetic beads exhibit strong autofluorescence, which often overlaps with the emission of the reporter fluorescent dyes and limits the analytical performance of the assay. Here, several widely used magnetic beads are photobleached and their autofluorescence is reduced to 1% of the initial value. Their autofluorescence properties, including their photobleaching decay rates and autofluorescence spectra pre- and post-photobleaching, and the stability of the photobleaching over a period of two months are analyzed. The photobleached beads are stable over time and their surface functionality is retained. In a high sensitivity LX-200 system using photobleached magnetic beads, human interleukin-8 is detected with a threefold improvement in detection limit and signal-to-noise ratio over results achievable with nonbleached beads. Since many contemporary immunoassays rely on magnetic beads as capture surfaces, prebleaching the beads may significantly improve the analytical performance of these assays. Moreover, nonmagnetic beads with low autofluorescence are also successfully photobleached, suggesting that photobleaching can be applied to various capture surfaces used in fluorescence-based assays. PMID- 30411494 TI - 3D perspective into MIA-QSAR: A case for anti-HCV agents. AB - Quantitative structure-activity relationship (QSAR) is a molecular modeling technique widely used in the discovery of novel drugs. Currently, there are many approaches for performing such analysis, which are commonly classified from 1D to 6D. 2D and 3D techniques are among the most exploited ones. Multivariate image analysis applied to QSAR (MIA-QSAR) is an example of 2D methodology that has presented a satisfactory performance in the generation of effective prediction models for biological/physicochemical properties. However, once this is a 2D method, conformational information is not explicitly considered, despite the well known role of such type of information in explaining the biochemical behavior. Thus, the importance of conformation is undeniable, but the requirement of this information for QSAR analysis still needs to be studied. Therefore, this work aimed to provide a method for encoding 3D information into MIA-QSAR descriptors and analyze the consequences of this inclusion on this methodology. The strategy consisted in fully optimizing the molecular geometries of anti-HCV compounds and three-dimensionally align them before performing the MIA-QSAR procedure. As a result, it was possible to verify that this type of information does not improve the MIA-QSAR modeling performance; instead, the traditional procedure consisting of maximally congruent substructures generated a more reliable prediction model. PMID- 30411495 TI - Development and validation of an optimized prediction of mortality for candidates awaiting liver transplantation. AB - Since 2002, the Model for End-Stage Liver Disease (MELD) has been used to rank liver transplant candidates. However, despite numerous revisions, MELD allocation still does not allow for equitable access to all waitlisted candidates. An optimized prediction of mortality (OPOM) was developed (http://www.opom.online) utilizing machine-learning optimal classification tree models trained to predict a candidate's 3-month waitlist mortality or removal utilizing the Standard Transplant Analysis and Research (STAR) dataset. The Liver Simulated Allocation Model (LSAM) was then used to compare OPOM to MELD-based allocation. Out-of sample area under the curve (AUC) was also calculated for candidate groups of increasing disease severity. OPOM allocation, when compared to MELD, reduced mortality on average by 417.96 (406.8-428.4) deaths every year in LSAM analysis. Improved survival was noted across all candidate demographics, diagnoses, and geographic regions. OPOM delivered a substantially higher AUC across all disease severity groups. OPOM more accurately and objectively prioritizes candidates for liver transplantation based on disease severity, allowing for more equitable allocation of livers with a resultant significant number of additional lives saved every year. These data demonstrate the potential of machine learning technology to help guide clinical practice, and potentially guide national policy. PMID- 30411496 TI - Fisetin decreases TET1 activity and CCNY/CDK16 promoter 5hmC levels to inhibit the proliferation and invasion of renal cancer stem cell. AB - As a natural flavonol, fisetin has significant inhibitory effects on many cancers. Although fisetin can inhibit kidney cancer, its effects on kidney renal stem cells (HuRCSCs) remain unknown. Our study found that renal cancer tissues and CD44+/CD105+ HuRCSCs both show high TET1 protein expression. Both in vivo and in vitro experiments showed that fisetin can effectively inhibit HuRCSC cell division and proliferation, invasion, in vivo tumourigenesis and angiogenesis. Our findings showed that fisetin can significantly decrease TET1 expression levels in HuRCSCs and overall 5hmC levels in the genomes of these cells. At the same time, ChIP-PCR results showed that fisetin can effectively inhibit 5hmC modification levels at the CpG islands in cyclin Y (CCNY) and CDK16 and reduce their transcription and activity. Thus, we conclude that fisetin inhibits the epigenetic mechanism in renal cancer stem cells, that is, fisetin inhibits TET1 expression and reduces 5hmC modification in specific loci in the promoters of CCNY/CDK16 in HuRSCs. This in turn inhibits transcription of these genes, causing cell cycle arrest and ultimately inhibiting renal cancer stem cell activity. PMID- 30411497 TI - Plastic waste management, a matter for the 'community'. PMID- 30411498 TI - The O-Directed Free Radical Hydrostannation of Propargyloxy Dialkyl Acetylenes with Ph3 SnH/cat. Et3 B. A Refutal of the Stannylvinyl Cation Mechanism. AB - In this Personal Account, we will give an overview of the room temperature O directed free radical hydrostannation reaction of propargylically-oxygenated dialkyl acetylenes with Ph3 SnH and catalytic Et3 B/O2 in PhMe. We will show how this excellent reaction evolved, and how it has since been used to stereoselectively construct the complex trisubstituted olefin regions of three synthetically challenging natural product targets: (+)-pumiliotoxin B, (-)-(3R) inthomycin C, and (+)-acutiphycin. Throughout this Account, we will pay special attention to highlighting important facets of the I-SnPh3 exchange processes that have so far been used in the various different steric settings that we have addressed, and we will document the range of cross coupling protocols that have critically underpinned the first successful applications of this method in complex natural product total synthesis. Last, but not least, we will comment on various aspects of the O-directed free radical hydrostannation mechanism that have been published by ourselves, and others, and we will discuss all of the factors that can contribute to the observed stereo-and regio-chemical outcomes. We will also challenge and refute the recent non-directed stannylvinyl cation mechanism put forward by Organ, Oderinde and Froese for our reaction, and we will show how it cannot be operating in these exclusively free radical hydrostannations. PMID- 30411499 TI - Bilateral sympathetic stellate ganglionectomy attenuates myocardial remodelling and fibrosis in a rat model of chronic volume overload. AB - Reducing sympathetic neurohormone expression is a key therapeutic option in attenuating cardiac remodelling. Present study tested the feasibility of attenuating cardiac remodelling through reducing sympathetic neurohormone level by partial cardiac sympathetic denervation in a rat model of chronic volume overload. Male Sprague-Dawley rats were randomized into sham group (S, n = 7), aortocaval fistula group (AV, n = 7), and aortocaval fistula with bilateral sympathetic stellate ganglionectomy group (AD, n = 8). After 12 weeks, myocardial protein expression of sympathetic neurohormones, including tyrosine hydroxylase, neuropeptide Y, growth associated protein 43, and protein gene product 9.5, were significantly up-regulated in AV group compared to S group, and down-regulated in AD group. Cardiac remodelling was aggravated in AV group compared to S group and attenuated in AD group. The myocardial deposition of extracellular matrix, including collagen I and III, was enhanced in AV group, which was reduced in AD group. Myocardial angiotensin II and aldosterone expressions were significantly up-regulated in AV group and down-regulated in AD group. Our results show that bilateral sympathetic stellate ganglionectomy could attenuate cardiac remodelling and fibrosis by down-regulating sympathetic neurohormones expression in this rat model of chronic volume overload. PMID- 30411500 TI - Benzene induces haematotoxicity by promoting deacetylation and autophagy. AB - Chronic exposure to benzene is known to be associated with haematotoxicity and the development of aplastic anaemia and leukaemia. However, the mechanism underlying benzene-induced haematotoxicity, especially at low concentrations of chronic benzene exposure has not been well-elucidated. Here, we found that increased autophagy and decreased acetylation occurred in bone marrow mononuclear cells (BMMNCs) isolated from patients with chronic benzene exposure. We further showed in vitro that benzene metabolite, hydroquinone (HQ) could directly induce autophagy without apoptosis in BMMNCs and CD34+ cells. This was mediated by reduction in acetylation of autophagy components through inhibiting the activity of acetyltransferase, p300. Furthermore, elevation of p300 expression by Momordica Antiviral Protein 30 Kd (MAP30) or chloroquine reduced HQ-induced autophagy. We further demonstrated that in vivo, MAP30 and chloroquine reversed benzene-induced autophagy and haematotoxicity in a mouse model. Taken together, these findings highlight increased autophagy as a novel mechanism for benzene induced haematotoxicity and provide potential strategies to reverse this process for therapeutic benefits. PMID- 30411501 TI - The influences of age, gender and geometric pattern of visual image on the verticality perception: A subjective visual vertical (SVV) study among Malaysian adults. AB - OBJECTIVES: Subjective visual vertical (SVV) is a simple, quick and reliable test for measuring utricular function. The literature on the effects of fundamental demographic variables such as age and gender on SVV is inconclusive and should be supported by research with larger samples. The aim of the present study was to determine the influences of age, gender and geometric pattern of visual image on SVV among healthy adults. STUDY DESIGN: This study employed a repeated measures design. SETTINGS: Otorhinolaryngology Clinic, Hospital Universiti Sains Malaysia, Malaysia. PARTICIPANTS: Eligible Malaysian adults (N = 187, aged 21-75 years) were recruited and categorised into young (N = 60), middle-aged (N = 66) and older (N = 61) groups. Most of them were Malay, and 51.3% were men. MAIN OUTCOME MEASURES: Subjective visual vertical angles (in degrees) were determined from each participant in a static upright condition using a computerised SVV device. They were asked to indicate their verticality perception for three types of visual images (solid line, dotted line and arrow pattern). RESULTS: Three-way mixed ANOVA revealed insignificant influences of age and gender on SVV results (P > 0.05). In contrast, mean SVV angles were significantly higher for the arrow pattern than for other visual images (P = 0.004). CONCLUSION: While the insignificant influences of age and gender on static SVV are further ascertained with larger samples, the perception of verticality is less accurate when aligning a more geometrically complex visual image (ie, arrow pattern). Further SVV research on vestibular-disordered patients is beneficial, particularly to verify the normative data obtained with this complex visual image. PMID- 30411502 TI - Opposite acute potassium and sodium shifts during transplantation of hypothermic machine perfused donor livers. AB - Liver transplantation is frequently associated with hyperkalemia, especially after graft reperfusion. Dual hypothermic oxygenated machine perfusion (DHOPE) reduces ischemia/reperfusion injury and improves graft function, compared to conventional static cold storage (SCS). We examined the effect of DHOPE on ex situ and in vivo shifts of potassium and sodium. Potassium and sodium shifts were derived from balance measurements in a preclinical study of livers that underwent DHOPE (n = 6) or SCS alone (n = 9), followed by ex situ normothermic reperfusion. Similar measurements were performed in a clinical study of DHOPE-preserved livers (n = 10) and control livers that were transplanted after SCS only (n = 9). During DHOPE, preclinical and clinical livers released a mean of 17 +/- 2 and 34 +/- 6 mmol potassium and took up 25 +/- 9 and 24 +/- 14 mmol sodium, respectively. After subsequent normothermic reperfusion, DHOPE-preserved livers took up a mean of 19 +/- 3 mmol potassium, while controls released 8 +/- 5 mmol potassium. During liver transplantation, blood potassium levels decreased upon reperfusion of DHOPE-preserved livers while levels increased after reperfusion of SCS preserved liver, delta potassium levels were -0.77 +/- 0.20 vs. +0.64 +/- 0.37 mmol/L, respectively (P = .002). While hyperkalemia is generally anticipated during transplantation of SCS-preserved livers, reperfusion of hypothermic machine perfused livers can lead to decreased blood potassium or even hypokalemia in the recipient. PMID- 30411503 TI - Secondary hyperparathyroidism: Pathogenesis and latest treatment. AB - The classic pathogenesis of secondary hyperparathyroidism (SHPT) began with the trade-off hypothesis based on parathyroid hormone (PTH) hypersecretion brought about by renal failure resulting from a physiological response to correct metabolic disorder of calcium, phosphorus, and vitamin D. In dialysis patients with failed renal function, physiological mineral balance control by PTH through the kidney fails and hyperparathyroidism progresses. In this process, many significant genetic findings have been established. Abnormalities of Ca-sensing receptor and vitamin D receptor are associated with the pathogenesis of SHPT, and fibroblast growth factor 23 has also been shown to be involved in the pathogenesis. Vitamin D receptor activators (VDRAs) are widely used for treatment of SHPT. However, VDRAs have calcemic and phosphatemic effects that limit their use to a subset of patients, and calcimimetics have been developed as alternative drugs for SHPT. Hyperphosphatemia also affects progression of SHPT, and control of hyperphosphatemia is therefore thought to be fundamental for control of SHPT. Currently, a combination of a VDRA and a calcimimetic is recognized as the optimal strategy for SHPT, and for other outcomes such as reduced cardiovascular disease and improved survival. The latest findings on the pathogenesis and treatment of SHPT are summarized in this review. PMID- 30411504 TI - Favorable 10-year outcomes of image-guided intensity-modulated radiotherapy combined with long-term androgen deprivation for Japanese patients with nonmetastatic prostate cancer. AB - AIM: To investigate 10-year outcomes of high-dose image-guided intensity modulated radiation therapy (IG-IMRT) combined with long-term androgen deprivation therapy (ADT) for Japanese patients with nonmetastatic prostate cancer. METHODS: A retrospective analysis was performed on 208 Japanese patients with T1-4N0M0 prostate cancer, who underwent definitive IG-IMRT from 2006 to 2010 at our single institution. The median dose was 78 Gy (74-78) and median ADT time was 32 months (6-151). The risk stratification followed the National Comprehensive Cancer Network criteria. A biochemical relapse was defined as nadir plus 2.0 ng/mL. Toxicity was scored with the Radiation Therapy Oncology Group morbidity scale. RESULTS: The median follow-up time was 102 months. For low-, intermediate-, high-, and very-high-risk groups, the 10-year biochemical disease free survival rates were 100%, 84%, 90%, and 72%, respectively (P = 0.008); clinical relapse-free survival rates were 100%, 100%, 100%, and 81%, respectively (P < 0.001); and cancer-specific survival rates were 100%, 100%, 100%, and 89%, respectively (P = 0.13). The independent prognostic factors influencing biochemical relapse were younger age, Gleason score >= 8, and radiation dose < 78 Gy in the multivariate analysis (P = 0.006, 0.014, and 0.013). The 10-year cumulative incidence of late grade 2 or higher gastrointestinal and genitourinary toxicities were 12% and 13%, respectively. No events of grade 4 or 5 were observed. CONCLUSIONS: This study suggest that high-dose IG-IMRT combined with long-term ADT is effective and implementable, leading to excellent 10-year outcomes for Japanese patients with nonmetastatic prostate cancer. PMID- 30411506 TI - In vitro reconstitution of the bacterial cytoskeleton: expected and unexpected new insights. AB - In vitro reconstitution of bacterial cytoskeletal elements, primarily supposed to reveal detailed mechanistic insights, has been an invaluable source of unexpected new protein functionalities. This may be particularly beneficial in the context of a potential construction of artificial cells from the bottom-up. PMID- 30411505 TI - Rare copy number variation in extremely impulsively violent males. AB - The genetic correlates of extreme impulsive violence are poorly understood, and there have been no studies that have systematically characterized a large group of affected individuals both clinically and genetically. We performed a genome wide rare copy number variant (CNV) analysis in 281 males from four Czech prisons who met strict clinical criteria for extreme impulsive violence. Inclusion criteria included age >= 18 years, an ICD-10 diagnosis of Dissocial Personality Disorder, and the absence of an organic brain disorder. Participants underwent a structured psychiatric assessment to diagnose extreme impulsive violence and then provided a blood sample for genetic analysis. DNA was genotyped and CNVs were identified using Illumina HumanOmni2.5 single-nucleotide polymorphism array platform. Comparing with 10851 external population controls, we identified 828 rare CNVs (frequency <= 0.1% among control samples) in 264 participants. The CNVs impacted 754 genes, with 124 genes impacted more than once (2-25 times). Many of these genes are associated with autosomal dominant or X-linked disorders affecting adult behavior, cognition, learning, intelligence, specifically expressed in the brain and relevant to synapses, neurodevelopment, neurodegeneration, obesity and neuropsychiatric phenotypes. Specifically, we identified 31 CNVs of clinical relevance in 31 individuals, 59 likely clinically relevant CNVs in 49 individuals, and 17 recurrent CNVs in 65 individuals. Thus, 123 of 281 (44%) individuals had one to several rare CNVs that were indirectly or directly relevant to impulsive violence. Extreme impulsive violence is genetically heterogeneous and genomic analysis is likely required to identify, further research and specifically treat the causes in affected individuals. PMID- 30411507 TI - Health benefits conferred by the human gut microbiota during infancy. AB - Development of the human gut throughout the entire life. PMID- 30411508 TI - Laparoscopic rectal tumor surgery after administration of a new sclerosing therapy (aluminum potassium sulfate and tannic acid injection) for internal hemorrhoids: A report of three cases. AB - Aluminum potassium sulfate and tannic acid (ALTA) injection is a new sclerosing therapy for internal hemorrhoids that has been gaining widespread use. However, there have been few reports about rectal cancer after ALTA injection. We performed laparoscopic surgery for three patients who had underwent ALTA therapy 6 months or 1 year earlier: (i) a 51-year-old man with neuroendocrine tumor; (ii) a 44-year-old woman with rectal cancer; and (iii) 77-year-old man with rectal cancer. All three patients had sclerosis of the resected rectal wall stump, making transection of the rectum difficult. Histological examination of the specimens also showed an inflammatory reaction and/or fibrosis of the resection stump. Although laparoscopic low anterior resection was planned for all three patients, we had to construct a diverting stoma for two patients and could not perform sphincter-preserving surgery for the other. We must be well prepared for laparoscopic rectal surgeries after ALTA therapy, and these cases suggest sigmoidoscopy before ALTA therapy should be recommended. PMID- 30411509 TI - Association between PD-L1 expression and lymph node metastasis in cutaneous squamous cell carcinoma. AB - AIM: To clarify the relationship between programmed cell death ligand 1 (PD-L1) expression in cutaneous squamous cell carcinoma (cSCC) and clinicopathological variables. METHODS: We examined PD-L1 expression in tumor cells (TCs) and tumor infiltrating immune cells (ICs) in 46 cases of cSCC by immunohistochemistry. In each case, we employed two methods-intensity and proportion scores-to evaluate PD L1 expression in TCs. For the evaluation of PD-L1 expression in ICs, only the proportion score was used. Association between PD-L1 expression and clinicopathological variables was analyzed using Fisher's exact test. RESULTS: High intensity scores in TCs were observed in 18 of the 46 cases (39.1%) and low intensity scores were observed in 28 cases (60.9%). Applying the proportions, using cut-off values of >=1% and 50%, positive scores in TCs were observed in 36 (78.3%) and 20 cases (43.5%), respectively. PD-L1-positive ICs were observed in 29 (63%) and seven cases (15.2%), using cut-off values of >=1% and 10%, respectively. The high intensity scores in TCs correlated with lymph node metastasis (P = 0.008) and female gender (P = 0.017), although positive proportions in TCs or ICs were not significantly related to lymph node metastasis. A multivariate analysis showed that high intensity of PD-L1 expression in TCs was an independent risk factor for lymph node metastasis. CONCLUSIONS: The results suggested that high intensity of PD-L1 expression in TCs is associated with lymph node metastasis in cSCC. PMID- 30411510 TI - Traumatic dental injuries are now the 5th most prevalent disease/injury in the world-But they are being neglected!! PMID- 30411511 TI - Recent advances in Pediatric Rheumatology: April to June 2018. PMID- 30411512 TI - Diversity and distribution of Klebsiella capsules in Escherichia coli. AB - E. coli strains responsible for elevated counts (blooms) in freshwater reservoirs in Australia carry a capsule originating from Klebsiella. The occurrence of Klebsiella capsules in E. coli was about 7% overall and 23 different capsule types were detected. Capsules were observed in strains from phylogroups A, B1 and C, but were absent from phylogroup B2, D, E and F strains. In general, few A, B1 or C lineages were capsule-positive, but when a lineage was encapsulated multiple different capsule types were present. All Klebsiella capsule-positive strains were of serogroups O8, O9 and O89. Regardless of the phylogroup, O9 strains were more likely to be capsule-positive than O8 strains. Given the sequence similarity, it appears that both the capsule region and the O-antigen gene region are transferred to E. coli from Klebsiella as a single block via horizontal gene transfer events. Pan genome analysis indicated that there were only modest differences between encapsulated and non-encapsulated strains belonging to phylogroup A. The possession of a Klebsiella capsule, but not the type of capsule, is likely a key determinant of the bloom status of a strain. PMID- 30411513 TI - Operative outcomes after laparoscopic splenectomy with special reference to prophylactic antibiotics. AB - INTRODUCTION: We conducted a retrospective study to investigate the progress of the operative outcome after laparoscopic splenectomy (LS), with a special reference to the administration of prophylactic antibiotics (PA). METHODS: The study included 123 patients who underwent elective LS. Operative outcomes before and after the operative procedure was standardized and the impact of treatment with PA on surgical-site infection were investigated. RESULTS: With regard to complications, wound infection developed in one (0.8%), portal trunk thrombosis in one (0.8%), pancreatic fistula in one (0.8%), postoperative bleeding in two (1.6%), pleural effusion in one (0.8%), and reoperation because of bowel injury in one (0.8%). Although morbidity did not differ between patients in the early (until the end of 2010) and late (after the beginning of 2011) periods, intraoperative blood loss was lower in patients in the late period. During the late period, no patients required conversion to open surgery. The proportion of patients with surgical-site infection did not differ between those who received PA 1 h before the start of surgery and every 3 h during surgery and those who received PA 1 h before the start of surgery, every 3 h during surgery, and twice a day for 24-72 h after surgery. CONCLUSION: Operative outcomes after LS improved after the standardization of the operative procedure. The administration of PA 1 h before surgery and every 3 h during surgery seems to be sufficient to prevent surgical-site infection during LS. PMID- 30411514 TI - Mediastinoscopic salvage esophagectomy for recurrent esophageal squamous cell carcinoma after definitive chemoradiotherapy in a previously pneumonectomized patient. AB - We herein report a case of mediastinoscopic salvage esophagectomy for recurrent esophageal squamous cell carcinoma after definitive chemoradiotherapy in a previously pneumonectomized patient. A 66-year-old man with a medical history of left-sided pneumonectomy for lung cancer was diagnosed with local recurrence of lower esophageal squamous cell carcinoma (cT3N0M0 cStage II) 9 years after definitive chemoradiotherapy. The mediastinoscopic cervical approach and laparoscopic transhiatal approach were combined, and the thoracic esophagus was safely mobilized to separate the esophagus from the stump of the left bronchus and to divide dense adhesions between the esophagus and fibrotic tissue at the site of the previous left mediastinal pleural resection. The esophagectomy was uneventful and followed by reconstruction with a gastric conduit via the retrosternal route. The pathological diagnosis was esophageal squamous cell carcinoma (pT3-AD, pN1, M0, pStage III), indicating R0 resection. Even as salvage surgery, mediastinoscopic esophagectomy is a safe and curative treatment strategy for esophageal cancer patients who have previously undergone pneumonectomy. PMID- 30411516 TI - Another Look at Looking Time: Surprise as Rational Statistical Inference. AB - Decades of developmental research have capitalized on the fact that infants are surprised (i.e., look longer) at some events but not others. Differences in looking time have been considered to be a reflection of perceptual discrimination, or a reaction toward witnessing a violation of prior expectations. Here, we provide an overview of a new perspective on infant surprise that examines the underlying cognitive processes that drive this response. We suggest that looking time may reflect sophisticated statistical inference, and we review empirical evidence and computational modeling results from several recent studies to support this conjecture (Kidd, Piantadosi, & Aslin, ; Piantadosi, Kidd, & Aslin, ; Sim, Griffiths, & Xu, ; Sim & Xu, ; Teglas et al., ). We also discuss how our view relates to other new developmental research on surprise and learning (Stahl & Feigenson, , ) and outline some suggestions for future research. PMID- 30411515 TI - Decreased serum neuregulin 4 levels associated with non-alcoholic fatty liver disease in children with obesity. AB - Neuregulin 4 (Nrg4), a newly identified adipokine secreted by brown adipose tissue, is hypothesised to play a crucial role in metabolism. The present study aimed to evaluate the association between serum Nrg4 levels and non-alcoholic fatty liver disease (NAFLD) in children with obesity in China. A total of 123 children with obesity were included in this study. Anthropometric and biochemical parameters were measured in all subjects. NAFLD was diagnosed using ultrasonography. The serum levels of Nrg4, leptin and adiponectin were measured by enzyme-linked immunosorbent assay. NAFLD was identified in 58 children with obesity (47.2%). Serum Nrg4 levels were significantly lower in the NAFLD group (2.24 [1.20, 3.22] ng/mL) than in the control group (5.50 [2.45, 10.85] ng/mL) (p < 0.001). Serum Nrg4 levels were negatively correlated with most of the anthropometric and biochemical parameters (p < 0.05) but were positively correlated with high-density lipoprotein cholesterol (p < 0.05). In multiple stepwise regression analyses, serum Nrg4 levels were independently related with WHtR (beta = -2.009, p = 0.048) and homeostasis model assessment of insulin resistance (beta = -0.524, p = 0.005). Furthermore, a multivariable logistic regression analysis of NAFLD prediction by Nrg4 revealed an odds ratio of 0.129 (95% confidence interval: 0.028-0.587, p < 0.01). The receiver operating characteristic curve analysis of the diagnostic value of using serum Nrg4 levels to differentiate NAFLD in children with obesity showed that the area under the curve was 0.723; the cutoff for serum Nrg4 levels to have diagnostic value for predicting NAFLD in children with obesity was 3.39 ng/mL. Elevated Nrg4 is associated with a decreased risk of NAFLD in children with obesity. PMID- 30411517 TI - Cadmium and arsenic responses in the ectomycorrhizal fungus Laccaria bicolor: glutathione metabolism and its role in metal(loid) homeostasis. AB - Ectomycorrhizal fungi play an important role in protecting their host plant from metal(loid) stresses by synthesizing various thiol rich compounds like metallothioneins and glutathione. We investigated the effect of cadmium (Cd) and arsenic (As) stress with a specific interest on glutathione (GSH) in the ectomycorrhizal fungus Laccaria bicolor. The total GSH levels inside the cell were significantly increased with increase in external metal(loid) stress. An analysis of the transcript levels of genes responsible for GSH synthesis, gamma glutamylcysteine synthetase (Lbgamma-GCS) and glutathione synthetase (LbGS), using qPCR revealed that expression of both genes increased as a function of external metal(loid) concentration. The enzyme activity of both Lbgamma-GCS and LbGS were increased with increase in external Cd and As concentration. Further, the functional role of Lbgamma-GCS and LbGS genes in response to Cd and As stress was studied using their respective yeast mutant strains gsh1 Delta and gsh2 Delta . The mutant strains successfully expressed the two genes resulting in wild-type phenotype restoration of Cd and As tolerance. From these results, it was concluded that GSH act as a core component in the mycorrhizal defence system under Cd and As stress for metal(loid) homeostasis and detoxification. PMID- 30411518 TI - The tick sign - a new and simple test to diagnose keratoconus at the slit lamp. PMID- 30411519 TI - Masked pemphigus among pediatric patients with Castleman's disease. AB - AIM: Paraneoplastic pemphigus (PNP) is a mucocutaneous autoimmune disorder accompanied with a neoplasm. Castleman's disease (CD), although rare, is the most common cause of PNP in children. It can be life-threatening when pulmonary involvement occurs. Our study aimed to describe the features of PNP resulting from CD and to find clues for the early diagnosis in pediatric patients. METHOD: We report the case of a 13-year-old girl who initially presented with oral ulcers and lichen planus, with progression to respiratory failure. A literature review of PNP and CD in children between 1997 and 2016 was performed. The clinical manifestations, pathological findings, treatment, and outcome were analyzed. RESULTS: Thirty-two children were included in our study: 16 boys and 16 girls. Intractable mucocutaneous lesions developed early before CD was diagnosed. The clinical manifestations comprised oral ulcers (100%), polymorphous skin rash (86.7%) and genital (62.5%) erosion. Histopathological findings revealed lymphoplasmacytic cells infiltration (92%), vacuolar interface change (72%), acantholysis (68%), and keratinocytes necrosis (36%). Thirty patients underwent tumor resection. These patients mainly had unicentric CD, with the hyaline vascular variant dominant. Twenty-six patients (81.2%) exhibited pulmonary involvement. The mortality rate was 70.0%. Among them, 90.5% exhibited pulmonary involvement, and 81.0% died of respiratory failure. CONCLUSION: Intractable mucocutaneous lesions with a concurrent tumor in children strongly indicate PNP resulting from CD. Because stomatitis or skin erosion may be the first presentation, mucocutaneous tissue biopsy and early detection of the underlying tumor are important. Earlier diagnosis is mandatory for the effective treatment of PNP and pulmonary involvement. PMID- 30411520 TI - Association between chest computed tomography findings and respiratory adverse events in rheumatoid arthritis patients undergoing long-term biological therapy. AB - OBJECTIVE: This study aimed to assess the association between chest computed tomography (CT) findings and incidence of respiratory adverse events (RAEs), and to detect risk factors for RAEs, in RA patients treated with long-term biological therapy. METHODS: Clinical and radiological data of 332 RA patients who were treated with biological disease-modifying antirheumatic drugs were collected. CT data were assessed by an experienced radiologist. Patients were categorized into the interstitial lung disease (ILD) group (n = 29), airway disease (AD) group (n = 76), co-existing ILD and AD (Co-existing) group (n = 6), and the group without detectable change (WDC, n = 221) based on CT findings and scores. The incidence of RAEs was calculated for each group, and risk factors for RAEs from CT findings were explored. RESULTS: We identified 41 RAEs, including acute onset or exacerbation of ILD (ILD events, n = 15), respiratory tract infection events (infection events, n = 21), and other events (n = 6). Cumulative incidences of ILD events were 20.2, 3.75, 47.2, and 1.94 (/1000 patient-years: PY) in the ILD, AD, Co-existing, and WDC groups, respectively, and those of infection events were 11.3, 17.6, 23.6, and 2.39 (/1000PY), respectively. Severity, as assessed by CT scores, was correlated with the incidence of RAEs. Risk factors for ILD events were reticular and honeycomb changes, and those for infection events were consolidation, bronchial wall thickening, bronchiectasis, bronchiolitis, air trapping, and atelectasis after adjusting for background factors. CONCLUSION: Our findings highlight particular CT findings that are associated with RAEs in RA patients undergoing long-term biological therapy. PMID- 30411521 TI - Learning Acetabular Fracture Classification using a Three-Dimensional Interactive Software: A Randomized Controlled Trial. AB - Acetabular fractures are a real challenge for junior doctors as well as experienced orthopedic surgeons. Correct fracture classification is crucial for appreciating the fracture type, surgical planning, and predicting prognosis. Although three-dimensional (3D) tutorial is believed to improve the understanding of the complex anatomy structure, there have been few applications and randomized controlled trials to confirm it in orthopedics. This study aims to develop a 3D interactive software system for teaching acetabular fracture classification and evaluate its efficacy. Participants were randomly but evenly allocated into either the experimental group (who learned the acetabular fracture classification using a 3D software) or the control group (who used a traditional two-dimensional [2D] tutorial). Both groups were then tasked to classify 10 acetabular fractures and complete a five-point Likert scale on their satisfaction of each learning modality. To calculate significance (P < 0.05), independent t-test was used for normally distributed data whereas Mann-Whitney U test for non-normally distributed data. The experimental group significantly outperformed the control group (t (28) = 2.526, P = 0.017) with identifying correct acetabular fracture classification. Moreover, Likert scale score in the experimental group was also significantly higher than in the control group (Z = 2.477, P = 0.013). This 3D classification software has objectively and subjectively showed an advantage over the traditional 2D tutorial, resulting in an improved classification accuracy and higher Likert scale score. The 3D software has the potential to improve both clinical knowledge as well as identifying correct patient management in orthopedics. PMID- 30411523 TI - Recent advances in pediatric rheumatology: January to March 2018. PMID- 30411522 TI - Stigma and access to care in first-episode psychosis. AB - AIM: Mental health-related stigma is considered a significant barrier to help seeking and accessing care in those experiencing mental illness. Long duration of untreated psychosis is associated with poorer outcomes. The impact of stigma on the duration of untreated psychosis, in first-episode psychosis remains unexplored. To examine the association between mental health-related stigma and access to care in people experiencing first-episode psychosis in Birmingham, UK. METHODS: We collected data on a prospective cohort of first-episode psychosis. The Stigma Scale was used as a measure of mental health-related stigma, and duration of untreated psychosis as a measure of delay in accessing care. We performed logistic and linear regression analyses to explore the relationship between mental health-related stigma and duration of untreated psychosis, adjusting for sex, age, educational level, religion and ethnicity. RESULTS: On the 89 participants included in this study, linear regression analysis revealed that overall stigma and the discrimination sub-factor were significant predictors of longer duration of untreated psychosis, whereas logistic regression identified the disclosure sub-factor to be a significant predictor of longer duration of untreated psychosis. CONCLUSIONS: These findings demonstrate that stigmatizing views of mental illness from the patient's perspectives can result in delayed access to care. This emphasizes the importance of tackling mental health-related stigma to ensure early treatment and improved outcomes for people experiencing first-episode psychosis. PMID- 30411524 TI - Laparoscopic distal gastrectomy in a patient with gastric cancer complicated by eventration of the diaphragm: A case report. AB - Diaphragmatic eventration refers to an abnormal elevation of the diaphragm. Here, we report the case of a patient with gastric cancer who underwent successful laparoscopic distal gastrectomy despite the presence of diaphragmatic eventration. The patient was a 72-year-old man diagnosed with early gastric cancer in the antrum, as detected by upper gastrointestinal endoscopy. Preoperative imaging revealed an elevation of the left side of the diaphragm, which was diagnosed as diaphragmatic eventration. Laparoscopic surgery is beneficial for obtaining an optimal field of view. However, there are critical points that must be considered when laparoscopic distal gastrectomy is performed in patients with gastric cancer complicated by diaphragmatic eventration. There were difficulties that affected manipulation because the elevated diaphragm drew the intraperitoneal organs into the thoracic cavity, causing displacement of the normal anatomical position. We found it beneficial to secure the lesser curvature of the stomach given the possible effects of gastric deformation. PMID- 30411525 TI - A qualitative study of quality of life domains and subdomains relevant to patients with spondyloarthritis. AB - AIMS: To identify quality of life (QoL) domains and subdomains relevant to patients with different spondyloarthritis (SpA) subtypes in Singapore, and to assess how identified QoL domains and subdomains map onto currently used patient reported outcome measures (PROMs). METHODS: Nine focus group discussions (FGDs), including two previously conducted FGDs from the Updating the Psoriatic Arthritis Core Domain Set Study, were conducted with patients with SpA in Singapore. The FGDs were organized by SpA subtype and language spoken. All FGDs were audio taped, transcribed verbatim. After thematic analysis through open and axial coding, the domains were organized using the World Health Organization Quality of Life (WHOQOL) framework. Identified QoL domains and subdomains were mapped to currently used PROMs. RESULTS: The nine FGDs included 51 patients. In total, 27 domains and 92 subdomains were identified and then organized within the 7 broad categories of the WHOQOL framework. Patients in Singapore were more concerned about "financial resources, " "work satisfaction" and "positive feelings" while less concerned about "freedom, physical safety and security" than patients in Western countries. "Home environment" and "work satisfaction" emerged as unique QoL domains relevant to patients with axial SpA (axSpA). PROMs for psoriatic arthritis (PsA) can capture both identified domains of PsA and axSpA. CONCLUSIONS: A wide range of QoL domains and subdomains are relevant to SpA patients in Singapore, and there appears to be minimal differences in their relative importance between SpA subtypes. This study supports the development and validation of common QoL-specific PROMs for usage in SpA. PMID- 30411526 TI - Laparoscopic para-aortic lymphadenectomy for colorectal cancer with clinically suspected lymph node metastasis. AB - INTRODUCTION: The optimal surgical management strategy for isolated para-aortic lymph node (PALN) metastases from colorectal cancer (CRC) remains unclear. However, the complication rates for open approaches remain high. In this study, the outcomes of laparoscopic para-aortic lymphadenectomy in patients with clinically suspected PALN metastasis were evaluated. METHODS: Between April 2013 and April 2018, we performed laparoscopic primary resection and para-aortic lymphadenectomy in 11 patients with advanced colorectal cancer and clinically suspected PALN metastasis. This study was a single-center, retrospective, case series analysis, and the surgical outcomes were reviewed. RESULTS: There were no cases of perioperative mortality, and conversion to open surgery was necessary in only one patient (9%) because of invasion into a rib. One patient (9%) required a blood transfusion. Postoperative complications occurred in three patients, and the morbidity rate was 27% (3/11). Pathologically, PALN metastasis was confirmed in five patients (45%), all of whom received postoperative chemotherapy. The median survival time for all patients was 25 months, and one patient died of recurrence at 25 months after the initial surgery. Two other patients were alive with recurrence after 47 and 36 months, and two patients were alive without recurrence after 17 and 2 months. CONCLUSION: Laparoscopic para-aortic lymphadenectomy for advanced colorectal cancer with clinically suspected PALN is technically feasible and may be beneficial in selected patients. It is necessary to investigate the feasibility of this procedure in a future case series, and information regarding true oncologic outcome will require long-term follow-up. PMID- 30411527 TI - Screening and Identification of Pregnancy Zone Protein and Leucine-Rich Alpha-2 Glycoprotein as Potential Serum Biomarkers for Early-Onset Myocardial Infarction using Protein Profile Analysis. AB - PURPOSE: The present study aims to discover novel serum biomarkers of early-onset myocardial infarction (MI) using proteomic analysis. EXPERIMENTAL DESIGN: In the first stage, the iTRAQ-coupled LC-MS/MS technique is utilized to investigate protein profiles of patients with early-onset MI. In the second stage, these candidate proteins are validated using ELISA. RESULTS: A total of 538 proteins are quantified, with pregnancy zone protein (PZP), leucine-rich alpha-2 glycoprotein (LRG) and Apolipoprotein C-I (Apo C-I) being upregulated and Apolipoprotein A-I (Apo A-I) and Apolipoprotein A-IV (Apo A-IV) downregulated in early-onset MI patients. Results from the validation stage demonstrate that the serum concentrations of PZP and LRG are significantly increased in the early onset MI group. The correlation between the concentrations of C-reactive protein (CRP) and the two candidate biomarkers is positive. Area under the curve values used to diagnose early-onset MI for LRG and PZP are 0.939 and 0.874, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Five differential serum proteins are identified in early-onset MI using proteomic analysis. Lipoprotein related biomarkers further demonstrate the close relationship between lipid metabolism and the disease. Inflammation-associated LRG and PZP may be novel biomarkers of the disease. In addition, changes in these proteins may partly reveal the possible mechanisms in the pathogenesis and pathophysiology of early onset MI. PMID- 30411528 TI - Clinical features and potential relevant factors of renal involvement in primary Sjogren's syndrome. AB - OBJECTIVE: To investigate distinct features of renal involvement in patients with primary Sjogren's syndrome (pSS) and to identify potential factors associated with renal involvement. METHODS: Four hundred and thrity-four pSS patients from the Rheumatology Department of the First Affiliated Hospital of Wenzhou Medical University from 2013 to 2017 were included in a cross-sectional study. Patients with renal involvement were compared with their age- and gender-matched controls (pSS without renal involvement). Demographic, clinical, histological, nephritic, immunological features of renal involvement in pSS were systematically analyzed. Possible factors related to renal involvement were identified using multivariate logistic regression analyses. RESULTS: One hundred and ninety-two pSS patients (88.48%) with renal involvement were women with mean age of nearly 58 years and mean disease duration of above 4 years. Clinical manifestation, serologic and immunological features and renal biopsy class of the pSS patients with renal involvement were presented. By multivariate analyses, xerophthalmia, histological positivity for lower salivary gland biopsy (LSGB), anti-SSA/Ro52-positive, reduced complement 3 (C3) levels, hypoalbuminemia and anemia retained significant association with renal involvement in pSS (all P < 0.05). CONCLUSION: In addition to LSGB pattern, anti-SSA/Ro52-positivity, reduced C3 levels, hypoalbuminemia and anemia, also indicate significant association with renal involvement in pSS. Therefore, early vigilance is required for patients with these clinical manifestations. PMID- 30411529 TI - Physical, chemical, and synthetic virology: Reprogramming viruses as controllable nanodevices. AB - The fields of physical, chemical, and synthetic virology work in partnership to reprogram viruses as controllable nanodevices. Physical virology provides the fundamental biophysical understanding of how virus capsids assemble, disassemble, display metastability, and assume various configurations. Chemical virology considers the virus capsid as a chemically addressable structure, providing chemical pathways to modify the capsid exterior, interior, and subunit interfaces. Synthetic virology takes an engineering approach, modifying the virus capsid through rational, combinatorial, and bioinformatics-driven design strategies. Advances in these three subfields of virology aim to develop virus based materials and tools that can be applied to solve critical problems in biomedicine and biotechnology, including applications in gene therapy and drug delivery, diagnostics, and immunotherapy. Examples discussed include mammalian viruses, such as adeno-associated virus (AAV), plant viruses, such as cowpea mosaic virus (CPMV), and bacterial viruses, such as Qbeta bacteriophage. Importantly, research efforts in physical, chemical, and synthetic virology have further unraveled the design principles foundational to the form and function of viruses. This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Biology-Inspired Nanomaterials > Protein and Virus-Based Structures. PMID- 30411530 TI - Successful single-stage laparoscopic surgery using a preoperative self-expanding metallic stent in patients with obstructive colorectal cancer. AB - INTRODUCTION: Although a self-expanding metallic stent (SEMS) or a transnasal or transanal decompression tube is sometimes used as a bridge to surgery in patients with obstructive colorectal cancer, the optimal decompression procedure to achieve successful laparoscopic surgery remains unclear. METHODS: Forty-two patients with obstructive colorectal cancer who were preoperatively decompressed by using SEMS (the SEMS group, n = 20) or a decompression tube (the DT group, n = 22) between January 2010 and February 2017 were included in this retrospective study. RESULTS: In the SEMS group, 20 patients (100%) were able to eat and 17 patients (85%) were able to undergo total colonoscopy preoperatively, but no patients could do so in the DT group (P < 0.01 and P < 0.01, respectively). The serum albumin level increased in the time between admission and just before surgery in five patients in the SEMS groups (25%), whereas it decreased in all patients in the DT group (P = 0.037). Laparoscopic surgery was performed more frequently in the SEMS groups (19 patients, 95%) than in the DT group (13 patients, 59.1%) (P = 0.018). Primary anastomosis without stoma was also achieved more frequently in the SEMS groups (19 patients, 95%) than in the DT group (15 patients, 68.2%) (P = 0.047). Anastomotic leakage did not occur in the SEMS group, but it did occur in one patient in the DT group. The recurrence-free survival rate did not differ between the groups (median follow-up period: 21 months). CONCLUSION: In patients with obstructive colorectal cancer, SEMS appears to be more effective than a decompression tube as a preoperative treatment to achieve successful laparoscopic resection without stoma. PMID- 30411531 TI - Simultaneous transabdominal preperitoneal hernia repair and laparoscopic cholecystectomy: A report of 17 cases. AB - INTRODUCTION: Inguinal hernia repair and cholecystectomy are frequently performed in the field of gastrointestinal surgery. However, reports describing surgical procedures that involve simultaneous transabdominal preperitoneal hernia repair (TAPP) and laparoscopic cholecystectomy (LC), as well as the safety and usefulness of this combination, are limited. Herein, we report a surgical procedure involving simultaneous TAPP and LC (TAPP + LC) and present the outcomes of patients who have undergone this combined surgical procedure, with a particular focus on its safety and usefulness. METHODS: We simultaneously performed TAPP + LC in 17 patients (mean age, 66.5 +/- 8.1 years) with concomitant inguinal hernia and gallbladder stones. We assessed surgical outcomes. RESULTS: The mean operative time was 157 +/- 39 min, and mean postoperative hospital stay was 3.2 +/- 0.6 days. The median cost was $7673 for TAPP + LC. The mean postoperative length of hospital stay was 1.1 +/- 0.6 day for TAPP alone and 3.4 +/- 1.4 days for LC alone. The median costs of TAPP alone and LC alone were $4932 and $5453, respectively. Regarding intraoperative complications, the inferior epigastric vessels were damaged in two patients, and seroma was detected as a postoperative complication in one; these complications were spontaneously resolved. No mesh- or infection-related complications were noted. CONCLUSION: Simultaneous TAPP + LC is safe and can be regarded as a standard surgical procedure for patients with concomitant inguinal hernia and gallbladder stones. The TAPP + LC combination appears to help prevent the need for two hospitalizations and, thereby, reduces hospital stay and economic burden. PMID- 30411532 TI - Radiation effects on male fertility. AB - BACKGROUND: Spermatogenesis is a process of dynamic cell differentiation. Ionizing radiation impairs spermatogenesis, and spermatogonia are more radiosensitive than spermatocytes or spermatids. Consistent with this assumption and due to improvement in tumor curability, nowadays, fertility preservation represents a public health need. OBJECTIVES: To discuss radiotherapy-induced risk to male fertility and raise oncologic awareness of male fertility in daily clinical practice. MATERIALS AND METHODS: PubMed and Clinicaltrials.gov databases were searched for papers in English. RESULTS: We provide an overview of clinical landscape. Four main issues were proposed: (i) spermatogenesis and radiobiological general concepts; (ii) impairment of spermatogenesis; (iii) impairment of testosterone-producing Leydig cells; (iv) clinical radiotherapy evidence in oncology. CONCLUSION: This review can be useful in daily clinical work and offer some directions for future research. PMID- 30411533 TI - Maternal hypertension and hypospadias in offspring: A systematic review and meta analysis. AB - BACKGROUND: Several studies have reported an association between maternal hypertensive disorders and hypospadias in offspring; however there is still debate on the role of maternal hypertension and preeclampsia on this relatively common congenital malformation. Therefore, we conducted a systematic review and meta-analysis to comprehensively evaluate the relationship between these frequent maternal conditions and hypospadias in offspring. METHODS: Fifteen articles meeting the eligibility criteria were identified in our search and included in the analysis. A meta-analysis was conducted and pooled odds ratio (OR) estimates were calculated separately for hypertension and preeclampsia using meta-analysis. We also conducted several secondary analyses, including (a) studies conducted before versus after January 1, 1998; (b) studies in United States versus other countries; and (c) studies that accounted for >=3 versus fewer or no potential confounders, among others. RESULTS: Significant positive associations were observed between hypertension and hypospadias (OR 1.68; 95% CI 1.46-1.93), as well as preeclampsia and hypospadias (OR 2.18; 95% CI 1.63-2.91). The direction and magnitude of effect was comparable for the majority of secondary analyses conducted. CONCLUSIONS: Our results indicate that maternal hypertensive disorders are positively associated with hypospadias in offspring. Further research is needed to better understand the mechanisms involved, and to ultimately develop public health strategies geared toward prevention of hypospadias. PMID- 30411534 TI - Age-dependent variation of female preponderance across different phenotypes of multiple sclerosis: A retrospective cross-sectional study. AB - INTRODUCTION: Multiple sclerosis (MS) is an autoimmune disease of the CNS, which predominantly affects women. Studies investigating the sex distribution in MS are sparse. We aim to analyze the female-to-male ratio (F/M ratio) in different MS phenotypes in association with age at diagnosis and year of birth. METHODS: We performed a retrospective cross-sectional analysis by cumulating data (sex, year of birth, age at diagnosis, and MS phenotypes) from unpublished and published studies of the participating centers. RESULTS: Datasets of 945 patients were collected. The overall F/M ratio was 1.9:1.0 and female preponderance was present in all phenotypes except for primary progressive MS (PPMS), in which men were predominantly affected (F/M ratio: 0.5:1.0). Female preponderance declined with increasing age at diagnosis and was no longer present in relapsing-remitting MS (RRMS) patients > 58 years of age. CONCLUSION: Our data demonstrate an age dependency of female preponderance in MS except for PPMS. This could be influenced by the lifecycle of sex hormone secretion in women. In PPMS, a male preponderance was observed in all age-groups, which might point to pathophysiological mechanisms being less influenced by sex hormones. PMID- 30411535 TI - Mutation profile of FLNC gene and its prognostic relevance in patients with hypertrophic cardiomyopathy. AB - BACKGROUND: Filamin C (FLNC) mutation was reported as a cause of HCM, with a high probability of sudden cardiac death. However, the mutation profile of FLNC, and its relationship with phenotypic expression in HCM, remains to be elucidated. METHODS: In this study, FLNC gene was sequenced in 540 HCM patients and 307 healthy controls. RESULTS: We found that 39 (7.2%) patients carried FLNC mutations, with a similar frequency to that of controls (4.2%, p = 0.101). Pedigree analysis showed that mutations were not well segregated with HCM. The baseline characteristics between HCM patients, with and without mutations, were comparable. FLNC mutations did not increase the risk for either all-cause mortality (HR 0.746, 95% CI 0.222-2.295, p = 0.575) or cardiac mortality (HR 0.615, 95% CI 0.153-1.947, p = 0.354) in HCM patients during a follow-up of 4.7 +/- 3.2 years. Moreover, there was no significant difference in survival free from sudden cardiac arrest (HR 0.721, 95% CI 0.128-3.667, p = 0.660) and heart failure (HR 0.757, 95% CI 0.318-1.642, p = 0.447). CONCLUSIONS: FLNC mutations were common in both HCM patients and healthy population. The pathogenicity of FLNC mutations detected in HCM patients and its association with the clinical outcomes should be cautiously interpreted. PMID- 30411536 TI - Whole-exome sequencing of nevoid basal cell carcinoma syndrome families and review of Human Gene Mutation Database PTCH1 mutation data. AB - BACKGROUND: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder with variable expression and nearly complete penetrance. PTCH1 is the major susceptibility locus and has no known hot spots or genotype-phenotype relationships. METHODS: We evaluated 18 NBCCS National Cancer Institute (NCI) families plus PTCH1 data on 333 NBCCS disease-causing mutations (DM) reported in the Human Gene Mutation Database (HGMD). National Cancer Institute families underwent comprehensive genomic evaluation, and clinical data were extracted from NCI and HGMD cases. Genotype-phenotype relationships were analyzed using Fisher's exact tests focusing on mutation type and PTCH1 domains. RESULTS: PTCH1 pathogenic mutations were identified in 16 of 18 NCI families, including three previously mutation-negative families. PTCH1 mutations were spread across the gene with no hot spot. After adjustment for multiple tests, a statistically significant genotype-phenotype association was observed for developmental delay and gross deletion-insertions (p = 9.0 * 10-6 ), and suggestive associations between falx cerebri calcification and all transmembrane domains (p = 0.002) and severe outcomes and gross deletion-insertions (p = 4.0 * 10-4 ). CONCLUSION: Overall, 89% of our NCI families had a pathogenic PTCH1 mutation. The identification of PTCH1 mutations in previously mutation-negative families underscores the importance of repeated testing when new technologies become available. Additional clinical information linked to mutation databases would enhance follow-up and future studies of genotype-phenotype relationships. PMID- 30411537 TI - Open Source PKPD Frame Work: Tutorial on the BioGears Engine. AB - BioGears is an open-source, lumped parameter, full-body human physiology engine. Its purpose is to provide realistic and comprehensive simulations for medical training, research, and education. BioGears incorporates a physiologically-based pharmacokinetic/pharmacodynamic (PK/PD) model that is designed to be applicable to a diversity of drug classes and patients and is extensible to future drugs. In addition, BioGears also supports drug interactions with various patient insults and interventions allowing for a realistic research framework and accurate dose patient responses. This tutorial will demonstrate how the generic BioGears PK/PD model can be extended to a new substance for prediction of drug administration outcomes. This article is protected by copyright. All rights reserved. PMID- 30411538 TI - Model-informed Drug Discovery and Development (MID3): Current Industry Good Practice & Regulatory Expectations and Future Perspectives. AB - Good practices around model-informed drug discovery development (MID3) aim to improve the implementation, standardization, and acceptance of these approaches within drug development and regulatory review. A survey targeted to clinical pharmacology and pharmacometric colleagues across industry, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) was conducted to understand current and future role of MID3. The documented standards were generally affirmed as a "good match" to current industry practice and regulatory expectations; with some identified gaps that are discussed. All have seen at least a "modest" step forward in MID3 implementation associated with greater organizational awareness, and share the expectation for a future wider use and impact. The priority within organisations was identified as a limitation with respect to the future of MID3. Finally, potential solutions, including a global overarching MID3 regulatory guideline, to facilitate greater acceptance by industry and regulatory decision makers are discussed. This article is protected by copyright. All rights reserved. PMID- 30411539 TI - MicroRNA-590-3p inhibits trophoblast-dependent maternal spiral artery remodeling by repressing low-density lipoprotein receptor-related protein 6. AB - BACKGROUND: The remodeling of maternal spiral artery following embryo implantation, which relies on well-regulated trophoblast functions, is a pivotal process to ensure a successful pregnancy. Low-density lipoprotein receptor related protein 6 (LRP6) and microRNAs (miRNAs, miRs) are suggested to be involved in angiogenesis and several vascular diseases; however, their functions in the control of trophoblast remain elusive. We therefore aimed to examine the roles of LRP6 and miR-590-3p in the regulation of trophoblast during the remodeling of maternal spiral artery. METHODS: HTR-8/SVneo cell, a trophoblast cell line, was utilized to study the effects of LRP6 and miR-590-3p on apoptosis, cell proliferation, migration, invasion, as well as tube formation. Expression of angiogenic factors placental growth factor (PlGF), matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), and activities of canonical Wnt/beta-catenin signaling pathway, which were implicated in the process of artery remodeling, were also examined. RESULTS: MiR-590-3p directly targeted 3' untranslated region (3'-UTR) of LRP6 mRNA and repressed LRP6 expression, which in turn inhibited proliferation, migration, invasion, as well as tube formation, and resulted in apoptosis in HTR-8/SVneo cells. Further, inhibition of LRP6 through miR-590-3p significantly suppressed the expression of PlGF, MMPs, and VEGF and reduced the activation of Wnt/beta-catenin signaling pathway. CONCLUSION: MicroRNAs-590-3p may inhibit trophoblast-dependent maternal spiral artery remodeling, via both trophoblast invasion and endovascular formation, by repressing LRP6. PMID- 30411540 TI - Application of stereotactic body radiotherapy in advanced pancreatic cancers in Australia. AB - INTRODUCTION: The majority of pancreatic cancers present locally advanced and carry a high mortality rate. Treatment is challenging, with mixed data suggesting use of chemotherapy alone or in combination with radiotherapy. The use of radiotherapy has previously been limited due to lack of ability to deliver radiation to the tumour mass without causing significant toxicity to surrounding organs. Stereotactic body radiotherapy (SBRT) allows delivery of higher biologically equivalent dose in a shorter treatment duration. We sought to investigate the safety and application of this technique in our centre. METHOD: We enrolled 27 patients from 2015, identified as locally advanced unresectable with histologically confirmed, non-metastatic, pancreatic adenocarcinoma. All patients had endoscopically inserted fiducial markers and where possible concurrent chemotherapy was administered. Dose schedules ranged from 25 to 42 Gy in 5 or 3 fractions. RESULTS: With an overall median follow up of 9 months (range, 3-32.7), the median survival was 11.6 months. Of those alive at 1 year, the local control rate was 67%. Six patients had Grade 3 toxicity, and other six had Grade 2 toxicity. None had Grade 4 or above toxicity. The most common symptom recorded was fatigue. CONCLUSION: SBRT for locally advanced pancreatic cancer is technically complex but feasible in a high volume centre. SBRT is unique, allowing safe delivery of high radiation dose resulting in good local control and decreases treatment time making it an attractive option for patients with unresectable pancreatic cancer. PMID- 30411541 TI - Associations of genetic variants in endocytic trafficking of epidermal growth factor receptor super pathway with risk of nonsyndromic cleft lip with or without cleft palate. AB - BACKGROUND: The genetic etiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P) has not been fully clarified to date. Epidermal growth factor receptor (EGFR) was reportedly involved in its biological establishment and regulation of cell migration during the embryonic stage. METHODS: We selected a super pathway of endocytic trafficking of EGFR and investigated the associations of single-nucleotide polymorphisms (SNPs) in the super pathway with the risk of NSCL/P by analyzing our published genome-wide association study (GWAS) data from 504 NSCL/P individuals and 455 controls. After the false discovery rate (FDR) control, we conducted linkage disequilibrium (LD) analyses and conditional regression analyses to obtain independent lead SNPs. We performed LD analyses between the lead SNPs and the reported SNPs to find novel ones from our study. We annotated the lead SNPs and investigated their mapped genes in silico. RESULTS: A total of 82 SNPs showed a statistical association with the risk of NSCL/P after FDR control. They contained three reported SNPs which were g.117068049G>A (rs7078160), g.117086783C>G (rs10886040), and g.117101266G>T (rs17095681). Four independent lead SNPs were obtained, including g.116979803 T>C (rs1905539) and g.117037960A>G (rs7902502) at 10q25.3, g.35720163G>C (rs75656820) at 17q12, and g.156864512G>A (rs1800877) at 1q23.1. Three of them were in low LD (r2 < 0.5) with the reported SNPs except g.117037960A>G (rs7902502), so these three were newly identified. Lead SNPs were mapped to three genes: SHTN1, AP2B1, and NTRK1. The three genes were relatively more highly expressed in the human craniofacial region and in the proximal maxillary location during the craniofacial development stage of the embryonic mouse. CONCLUSION: Our results suggested that SHTN1, AP2B1, and NTRK1 might be associated with the development of NSCL/P. PMID- 30411542 TI - Evaluating the effectiveness of intensive versus non-intensive image interpretation education for radiographers: a randomised controlled trial. AB - INTRODUCTION: The purpose of this randomised controlled trial was to compare the effectiveness of intensive and non-intensive formats of delivery of image interpretation education for radiographers. METHODS: A multi-centre, stratified (by years of experience) two group parallel arm, single blind, randomised controlled trial was conducted. Participants (n = 48) were allocated to one of two groups to receive image interpretation education: (1) intensive format (13.5 h over two consecutive days) (2) non-intensive (sequential 90-min tutorials delivered 1 week apart). Participants undertook x-ray interpretation tests before education, at 1-week post-education completion and at 12-week post-education completion. RESULTS: Image interpretation performance was not significantly different between groups at baseline. A generalised linear model indicated that participants who received intensive education format improved image interpretation performance by a greater margin than the group that received non intensive education at 1-week (P = 0.002) and 12-week (P < 0.001) follow-up assessments. CONCLUSIONS: Although both formats of education delivery may be beneficial, the findings of this study have indicated that the intensive format of delivery was more effective at improving radiographers' ability to interpret trauma radiographs in the weeks after completion of the image interpretation program. PMID- 30411543 TI - Risk factors for brain metastases in patients with non-small-cell lung cancer. AB - Brain metastases (BM) are severe incidents in patients with non-small-cell lung cancer (NSCLC). The controversial value of prophylactic cranial irradiation (PCI) in NSCLC in terms of survival benefit prompted us to explore the possible risk factors for BM in NSCLC and identify the potential population most likely to benefit from PCI. Risk factors for brain metastases in NSCLC are reviewed in this article. Identifying patients with a higher risk of BM could possibly increase the benefit of PCI while reducing the discomfort and risks caused by unnecessary invasive procedures in the NSCLC patient population. Future studies might focus on finding a solid basis for the prediction of the occurrence of brain metastases and for the therapeutic decision on the use of PCI. PMID- 30411545 TI - The usefulness of SPECT-CT with radioisotope-labeled leukocytes in diagnosing lead-dependent infective endocarditis. AB - BACKGROUND: Lead-dependent infective endocarditis (LDIE) is a life-threatening complication of permanent transvenous cardiac pacing. According to the 2015 European Society of Cardiology (ECS) guidelines, the diagnosis of LDIE is based on the modified Duke criteria (MDC), while single-photon emission computed tomography with conventional computed tomography (SPECT-CT) with radioisotope labeled leukocytes serves as an additional tool in difficult cases. The major challenge is to differentiate between true vegetation and a thrombus. OBJECTIVES: The aim of the study was to evaluate the usefulness of SPECT-CT with radioisotope labeled leukocytes in diagnosing LDIE in patients with intracardiac masses (ICMs). MATERIAL AND METHODS: The prospective registry included 40 consecutive patients admitted with an ICM on the lead and suspicion of LDIE. The confirmation or rejection of the LDIE diagnosis was made according to an algorithm based on the MDC. The cohort was divided into 2 groups: patients with definite and possible LDIE diagnoses based on the MDC (the LDIE-positive group), and patients with negative LDIE diagnoses according to the MDC (the LDIE-negative group). All patients underwent SPECT-CT with radioisotope-labeled leukocytes. The diagnostic ability of SPECT-CT was compared to the gold standard MDC. RESULTS: The LDIE positive group with diagnosis based on the MDC consisted of 19 patients (LDIE definite - 11; LDIE possible - 8). The LDIE diagnosis was rejected on the basis of the MDC in 21 patients. The SPECT-CT results were compared with the MDC results and showed 73.7% sensitivity, 81.0% specificity, 77.5% accuracy, 77.8% positive predictive value (PPV), 77.3% negative predictive value (NPV), likelihood ratio positive (LR+) 3.868, likelihood ratio negative (LR-) 0.325, and moderate agreement (kappa = 0.548, p < 0.001). After the exclusion of 5 patients treated with antibiotics at the time of the SPECT-CT, LR+ and LRimproved to 5.250 and 0, respectively, and inter-test agreement amounted to almost perfect concordance (kappa = 0.773, p < 0.001). CONCLUSIONS: Single-photon emission computed tomography with conventional CT with radioisotopelabeled leukocytes is a useful, efficient, single-step test for diagnosing LDIE. PMID- 30411544 TI - Pathological tumor infiltrative pattern and sites of initial recurrence in stage II/III gastric cancer: Propensity score matching analysis of a multi institutional dataset. AB - BACKGROUND: Advanced gastric cancer frequently recurs even after radical resection followed by adjuvant chemotherapy. The aim of this study was to evaluate the relationship between pathological infiltrative pattern (INF) and initial recurrence patterns in patients with stage II/III gastric cancer using a large multicenter database. METHODS: We retrospectively analyzed 1098 eligible patients who underwent curative gastrectomy for stage II/III gastric cancer at nine institutions between 2010 and 2014. Patients were categorized into the INF a/b and INF-c groups and adjusted using propensity score matching. RESULTS: After propensity score matching, 686 patients (343 for each) were classified in the INF a/b and INF-c groups. There were no significant differences in overall and disease-free survival between the two groups. In the INF-a/b group, frequencies of recurrence at the peritoneum, lymph node, and liver were equivalent. In contrast, the peritoneum was the most frequent site and accounted for 60% of the total recurrences in the INF-c group. The cumulative peritoneal recurrence rate was significantly higher in the INF-c group than in the INF-a/b group (hazard ratio 2.47). INF-c was a significant risk factor for peritoneal recurrences in most subgroups including age, sex, macroscopic type, tumor differentiation, and disease stage, and whether the postoperative treatment was given. Multivariate analysis identified INF-c as an independent risk factor for peritoneal recurrences. The cumulative liver recurrence rate was significantly higher in the INF-a/b group than in the INF-c group (hazard ratio 3.44). CONCLUSIONS: INF may represent an important predictor of recurrence patterns after curative resection of stage II/III gastric cancer. PMID- 30411546 TI - Making HIV clinic appointments for clients with positive HIV results at testing sites can improve referral rates. AB - BACKGROUND: The percentage of people living with undiagnosed HIV infection remains very high in Poland and exceeds 50% - one of the highest rates in Europe. At the same time, the number of HIV tests performed by medical doctors per 1000 inhabitants is the lowest in Europe. Thus, every effort should be made to keep diagnosed patients in care. However, a number of patients are lost to care (LTC), with the percentage depending on the testing modality used (voluntary counseling and testing sites - VCTs, private laboratories, medical clinics, clubs) and communication skills of persons giving the results. Until now, there was only 1 prospective study in Poland that looked into the problem of continuum of care. OBJECTIVES: The objective of the study was to assess VCT clients' willingness to accept help with making the first appointment at a local HIV clinic after receiving positive results and the percentage of patients getting into care at the clinic after referral. MATERIAL AND METHODS: Referral efficacy analysis between 2010 and 2014 was a joint venture between VCT site and the largest HIV clinic in Wroclaw. Every patient diagnosed with HIV infection was offered personal help with making the first appointment at the HIV clinic. Later, it was assessed whether the first visit actually took place. RESULTS: All the patients who collected their positive results came for their first visit at the HIV clinic with a referral rate reaching 100%, falling to 97.1% only in 2013. Most visits took place during 1-2 weeks. CONCLUSIONS: Patients were willing to use counselors' help with making appointments at the HIV clinic, which in turn increased referral rates and numbers of patients retained in care. PMID- 30411547 TI - The application of capillary electrophoresis, mass spectrometry and Brdicka reaction in human and rabbit metallothioneins analysis. AB - BACKGROUND: Metallothioneins (MTs) constitute a family of evolutionary conserved low molecular weight proteins with small variations in their amino acid sequences. They play a role in the regulation of trace metals metabolism, in the detoxification of heavy metal ions and in mechanisms controlling growth, differentiation and proliferation of cells. OBJECTIVES: The aim of this study was to evaluate the human and rabbit MTs purity and characterization using advanced analytical approaches. Due to the common use of MT from rabbit liver as a model protein, the properties of the rabbit and human MTs were compared. MATERIAL AND METHODS: Capillary electrophoresis (CE), matrix-assisted laser desorption and ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and Brdicka reaction were used for human and rabbit MTs characterization. RESULTS: In chip CE analysis, changes in the range of 5-8 kDa corresponding to the MT monomer, as well as some peaks of 13-14 kDa corresponding to dimers in both species, were observed. Using MALDI-MS, rabbit (MT-2D) and human (MT-1A, MT-1G, MT-1G + Cd and MT-2A) MTs were identified. In the Brdicka reaction analysis, a lower concentration of MTs from both organisms coincided with a decrease in the signal corresponding to MT level (Cat2). However, human MT gave higher Cat2 peak than the same concentration (0.025 mg/mL) of rabbit MT. CONCLUSIONS: The applied methods allowed for the characterization of MTs and gave complementary information about MT isoforms. Altered electrochemical activity of human and rabbit MTs, despite the same number of -sulfhydryl (-SH) groups, was observed, which may be due to different availability of MT cysteinyl groups. PMID- 30411549 TI - Anti-neoplastic effects of aprotinin on human breast cancer cell lines: In vitro study. AB - BACKGROUND: Aprotinin is a nonspecific serine protease inhibitor, which can inhibit plasminogen-plasmin system and matrix metalloproteinases. Aprotinin has been investigated as an antitumor agent. However, its antineoplastic effects on breast cancer (BC) have not been investigated yet. OBJECTIVES: The objective of this study was to assess the inhibitory effects of aprotinin on human BC cell lines. We assessed the effects of aprotinin on local invasion and survival of human BC cell lines MDA-MB-231, SK-BR-3 and MCF-7 in vitro. MATERIAL AND METHODS: CHEMICON cell invasion assay kit was used to assess local invasion, and (3-(4,5 dimethylthiazol2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium reduction (MTT) assay was used to determine the antiproliferative activity of aprotinin. Human dermal fibroblast (HDF-1) cell line was used as control normal cells. RESULTS: Cancer cell lines showed more invasion characteristics compared to HDF-1. Aprotinin significantly decreased the invasiveness of MDA-MB-231 in concentrations of 1 trypsin inhibitor unit (TIU)/mL, 1.3 TIU/mL and 1.7 TIU/mL in comparison with the untreated group (analysis of variance (ANOVA) p < 0.001). Treatment of SK-BR-3 with 1.3 TIU/mL aprotinin caused no significant reduction in invasiveness (p = 0.06). Treatment with different concentrations of aprotinin significantly decreased the surviving fraction and inhibited the growth of all cell lines tested in this study (analysis of variance (ANOVA) p < 0.001). Compared to cancer cell lines, normal HDF-1 cell line showed less sensitivity to antiproliferative effects of aprotinin, both in low and high doses. CONCLUSIONS: Aprotinin significantly inhibited the growth of human breast cancer cell lines MDA-MB-231, SK-BR-3 and MCF-7, and normal fibroblast cell line HDF-1. The growth inhibitory effect was more dominant in cancer cell lines. Inhibition of local invasion by aprotinin was significant only in the case of MDA-MB-231. Future molecular studies could shed further lights on mechanisms underlying antineoplastic effects of aprotinin and its potential therapeutic effects. PMID- 30411548 TI - Adipose tissue miRNA level variation through conjugated linoleic acid supplementation in diet-induced obese rats. AB - BACKGROUND: Conjugated linoleic acid (CLA), which is an octadecadienoic acid isomer, is believed to play different positive physiological roles, such as lowering body fat. Due to some reported side effects of CLA, like lipodystrophy and impaired glucose metabolism, it is important to establish its safety by understanding detailed molecular mechanisms. One of these mechanisms may be the role of this dietary agent in modifying the function and activity of microRNAs (miRNAs). OBJECTIVES: The aim of the study was to investigate how adipocyte miR 27a and miR-143 expression may be influenced by CLA in obese rats. MATERIAL AND METHODS: In this study, 24 male Wistar rats were randomly divided into normal-fat diet (NFD) and high-fat diet (HFD) groups. After 8 weeks, the rats were weighed and half of the diet-induced obese rats were randomly selected to receive 500 mg CLA per 1 kg body weight for 4 weeks. At the end of this period, epididymal fat was isolated to investigate the expression level of miRNAs by real-time polymerase chain reaction (RT-PCR). RESULTS: After 12 weeks, the obese rats in the HFD group, compared with rats in the NFD group, demonstrated a significant decrease in the expression of miR-27a (p < 0.05) and a significant increase in the expression of miR-143 (p < 0.05). In the group which had received CLA for a 4 week period, these events were reversed. Moreover, the rats in this group gained less weight than other rats in HFD groups, although the difference was not statistically significant. CONCLUSIONS: In conclusion, this study demonstrated that CLA, as an anti-obesity agent, may minimize abnormal changes in miRNA expression in obesity. This suggests a new pathway for weight loss; however, further studies are needed. PMID- 30411550 TI - Interactions between platelets and leukocytes in pathogenesis of multiple sclerosis. AB - Neurodegenerative diseases are an increasing problem in the modern world. Multiple sclerosis (MS) is a major human demyelinating and degenerative disease of the central nervous system (CNS). There are many reports that point to the significant role of platelet-leukocyte interaction in neurodegenerative diseases and cardiovascular disturbances. Epidemiological studies confirm the high risk of cardiovascular diseases in patients with MS. The pathophysiology mechanisms of this multi-component disease are very complex and involve various types of cells. There is increasing evidence that some co-stimulatory pathways affect the function of inflammatory cells, both in the periphery and in the CNS. Interactions of leukocytes and endothelial cells (ECs) could be significantly modulated in the presence of activated blood platelets. The supposed role of activated platelets in the development of vessel inflammatory response is due to their ability to adhere to inflamed ECs or proteins included in the subendothelial layer of the blood vessel wall, as well as to the ability of platelets to form aggregates with leukocytes. Blood platelets are able to directly activate leukocytes through a receptor-dependent mechanism or, indirectly, by biologically active compounds secreted from their granules. Cell cell interactions provide critical mechanisms by which platelets link thrombosis, inflammation and related processes, such as diapedesis and leukocyte infiltration, to the affected vessel. Determining the relationship between platelet-leukocyte interactions and the development of neuroinflammation in the course of MS may provide new therapeutic targets in the future. PMID- 30411552 TI - Nanoscale photoacoustic tomography for label-free super-resolution imaging: simulation study. AB - Resolutions higher than the optical diffraction limit are often desired in the context of cellular imaging and the study of disease progression at the cellular level. However, three-dimensional super-resolution imaging without reliance on exogenous contrast agents has so far not been achieved. We present nanoscale photoacoustic tomography (nPAT), an imaging modality based on the photoacoustic effect. nPAT can achieve a dramatic improvement in the axial resolution of the photoacoustic imaging. We derive the theoretical resolution and sensitivity of nPAT and demonstrate that nPAT can achieve a maximum axial resolution of 9.2 nm. We also demonstrate that nPAT can theoretically detect smaller numbers of molecules (~273) than conventional photoacoustic microscopy due to its ability to detect acoustic signals very close to the photoacoustic source. We simulate nPAT imaging of malaria-infected red blood cells (RBCs) using digital phantoms generated from real biological samples, showing nPAT imaging of the RBC at different stages of infection. These simulations show the potential of nPAT to nondestructively image RBCs at the nanometer resolutions for in vivo samples without the use of exogenous contrast agents. Simulations of nPAT-enabled functional imaging show that nPAT can yield insight into malarial metabolism and biocrystallization processes. We believe that the experimental realization of nPAT has important applications in biomedicine. PMID- 30411551 TI - Two-channel autofluorescence analysis for oral cancer. AB - We created a two-channel autofluorescence test to detect oral cancer. The wavelengths 375 and 460 nm, with filters of 479 and 525 nm, were designed to excite and detect reduced-form nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) autofluorescence. Patients with oral cancer or with precancerous lesions, and a control group with healthy oral mucosae, were enrolled. The lesion in the autofluorescent image was the region of interest. The average intensity and heterogeneity of the NADH and FAD were calculated. The redox ratio [(NADH)/(NADH + FAD)] was also computed. A quadratic discriminant analysis (QDA) was used to compute boundaries based on sensitivity and specificity. We analyzed 49 oral cancer lesions, 34 precancerous lesions, and 77 healthy oral mucosae. A boundary (sensitivity: 0.974 and specificity: 0.898) between the oral cancer lesions and healthy oral mucosae was validated. Oral cancer and precancerous lesions were also differentiated from healthy oral mucosae (sensitivity: 0.919 and specificity: 0.755). The two-channel autofluorescence detection device and analyses of the intensity and heterogeneity of NADH, and of FAD, and the redox ratio combined with a QDA classifier can differentiate oral cancer and precancerous lesions from healthy oral mucosae. PMID- 30411553 TI - Aminoglycosides rapidly inhibit NAD(P)H metabolism increasing reactive oxygen species and cochlear cell demise. AB - Despite causing permanent hearing loss by damaging inner ear sensory cells, aminoglycosides (AGs) remain one of the most widely used classes of antibiotics in the world. Although the mechanisms of cochlear sensory cell damage are not fully known, reactive oxygen species (ROS) are clearly implicated. Mitochondrial specific ROS formation was evaluated in acutely cultured murine cochlear explants exposed to gentamicin (GM), a representative ototoxic AG antibiotic. Superoxide (O2.-) and hydrogen peroxide (H2O2) were measured using MitoSOX Red and Dihydrorhodamine 123, respectively, in sensory and supporting cells. A 1-h GM exposure significantly increased O2.- formation in IHCs and increased H2O2 formation in all cell types. At the same time point, GM significantly increased manganese superoxide dismutase (MnSOD) levels while significantly decreasing copper/zinc superoxide dismutase (CuZnSOD) in cochlear sensory cells. This suggests (1) a rapid conversion of highly reactive O2.- to H2O2 during the acute stage of ototoxic antibiotic exposure and (2) that the endogenous antioxidant system is significantly altered by AGs. Fluorescence intensity-based measurements of reduced nicotinamide adenine dinucleotide (phosphate) [NAD(P)H] and mitochondrial membrane potential were measured to determine if increases in GM induced ROS production were correlated with changes in mitochondrial metabolism. This project provides a basis for understanding the mechanisms of mitochondrial ROS production in cochlear cells exposed to ototoxic antibiotics. Understanding the nature of ototoxic antibiotic-induced changes in mitochondrial metabolism is critical for developing hearing loss treatment and prevention strategies. PMID- 30411555 TI - [Spatio-temporal variations and influencing factors of thermal comfort at different elevations.] AB - Thermal comfort is one of the ways assessing heat changes in climate change scenarios. Based on the daily observation data of 84 meteorological stations from Guizhou Province, the universal thermal climate index (UTCI) was used to examine the spatio-temporal variations and main influencing factors of thermal comfort at different elevations under the scenarios of climate change. Moreover, the impacts of different climatic factors on UTCI at different elevations were quantitatively analyzed. The results showed that the spatial distribution of annual UTCI in Guizhou Province had a strong consistency with that of annual temperature, which was decreasing with the increased elevation. The number of thermally comfortable days in most parts of the province was between 180 d and 240 d. UTCI increased with the increases of elevation, with the overall trends of UTCI [-0.58-1.38 C.(10 a)-1] being higher than the trends of temperature [-0.36-0.45 C.(10 a)-1] from 1984 to 2013. In general, the correlation coefficients between UTCI and climatic factors air tempe-rature, wind speed, atmosphere pressure, relative humidity and cloud cover were 0.899, -0.855, 0.818, -0.373, and -0.042, respectively. The correlations between climatic factors and UTCI varied across different elevations. The UTCI was affected lightly by air temperature and heavily by wind speed with increasing elevation. PMID- 30411554 TI - [Responses of soil nitrogen transformation to long-term nitrogen fertilization and precipitation changes in a broad-leaved Korean pine forest in Changbai Mountains, China.] AB - Soil nitrogen (N) cycling, one of the most important biogeochemical processes in forest ecosystems, has significant environmental effects. However, little is known about how it responds to N deposition and precipitation changes. Here, we examined the main effects of N deposition (NF), rainfall reduction (RR) and their interactive effect (RF) on soil N cycling by N addition and transparent V-shaped board interception in a broad-leaved Korean pine forest in Changbai Mountains. The responses of soil nitrification, denitrification, nitrifying functional genes (ammonia-oxidizing archaea AOA and ammonia-oxidizing bacteria AOB), denitrifying functional genes (nirK, nirS and nosZ) and N fixing function genes (nifH) to NF, RR and RF treatments were analyzed. We found significant positive correlations between nitrification and soil NH4+-N, denitrification and and NO3--N, respectively. Soil nitrification and denitrification were not significantly influenced by the three treatments, while denitrification showed an obvious seasonal dynamics. Long-term RR treatment inhibited soil net nitrification, while NF and RF treatments promoted soil net nitrification; nifH and nosZ genes of bacteria were strong resistant to stress, and their diversity was not susceptible to the changes of N and rainfall. Under drought condition, nirK gene of soil bacteria was more susceptible to N deposition. AOA had a higher sensitivity to drought, while AOB had higher sensitivity to NF and RF treatments. The three treatments affected soil net nitrification and altered the diversity of AOB, AOA and nirK-harboring denitrifier in varying degrees, which might affect the release of N-containing gas and ecosystem services. PMID- 30411556 TI - [Relationship between vegetation C, N, P stoichiometry and species diversity in sand land.] AB - Vegetation stoichiometry represents plant nutrition limitation status. Whether it can affect the species diversity of plant community remains to be explored. In this study, we examined plant carbon (C), nitrogen (N), phosphorus (P) concentrations and stoichiometry, and further analyzed the relationship between stoichiometry and species diversity in Artemisia ordosica community and Salix psammophila community in sand land of the Ningxia Habahu National Nature Reserve. The results showed that, for the S. psammophila community growing in mobile and semi-fixed sand dunes, there was a significant negative correlation between Simpson index and vegetation C/N ratio, but no significant correlation between Simpson index and vegetation N/P ratio. For A. ordosica community distributed in semi-fixed and fixed dunes, the Shannon index had a significant positive correlation with vegetation N/P ratio and a significant negative correlation with vegetation C/N ratio. Combined the vegetation stoichiometry with the results of regression analysis (RDA), P concentration and thus N/P ratio had different influences on the species diversity for A. ordosica community and S. psammophila community. Our results showed that vegetation stoichiometry has an important influence on species diversity of plant community in sand land. PMID- 30411557 TI - [Stand-level biomass estimation models for the tree layer of main forest types in East Daxing'an Mountains, China.] AB - Forest biomass estimation methods of regional scale attract most attention of the resear-chers, with developing stand-level biomass model being a research trend. Based on the biomass data from fix forest types, two additive systems of biomass equations based one- and two-variable were developed. The model error structure (additive vs. multiplicative) of the allometric equation was evaluated using the likelihood analysis. The nonlinear seemingly unrelated regression (NSUR) was used to estimate the parameters in the additive system of stand-level biomass equations. The results showed that the assumption of multiplicative error structure was strongly supported for the stand-level biomass equations of total and components for those forest types. Thus, the additive system of log transformed biomass equations was developed. The adjusted coefficient of determination of the additive system of biomass equations was 0.78-0.99, the mean relative error was between -2.3%-6.9%, and the mean absolute relative error was between 6.3%-43.3%. Adding mean tree height in the additive systems of biomass equations could significantly improve the model fitting performance and predicting precision for most of the models. The biomass equations of total, aboveground and stem were better than biomass equations of root, branch, foliage and crown. In order to estimate model parameters more effectively, the additivity property of estimating tree total, sub-totals, and component biomass should be taken into account. Overall, the stand-level biomass models established in this study would be suitable for predicting stand-level biomass of six forest types in Daxing'an mountains. PMID- 30411558 TI - [Hyperspectral prediction model of soil nutrient content in the loess hilly-gully region, China.] AB - Rapid and accurate estimation of soil nutrient content based on hyperspectral data is an optimal method for the monitoring of soil nutrient and inversion of soil physical and chemical characters. The relationship between soil nutrient content and spectral reflectance was analyzed with soil samples being collected from the loess hilly-gully region of northern Shaanxi Province. The prediction models of the content of soil organic matter, total nitrogen, total phosphorus and total potassium were constructed by the combination of three techniques, including partial least squares (PLS), multiple linear regression (MLR), and support vector machine (SVM). Then, the optimal model was selected by comparison analysis. The results showed good correlations between the content of soil nutrients and spectral reflectance in visible region (400-760 nm) and near infrared region (760-1100 nm). The maximum values of correlation coefficient located in both spectral regions. The SPA-SVM model had the best applicability and highest inversion accuracy for the contents of all soil nutrients, with simple and efficient modeling process. Our results provided a reference for applying machine learning algorithm in the construction of hyperspectral prediction model of soil nutrient content in the loess hilly-gully region. PMID- 30411559 TI - [Predicting models of leaf area for trees in Larix olgensis plantation.] AB - Leaf area influences dry matter production of trees, as well as the growth of trees and forest stands. The accurate estimation of leaf area plays an important role in analyzing the growth of trees and forest stands. Based on data of 76 Larix olgensis trees in a plantation of Heilongjiang Province, predicting models of branch leaf area (BLA) and crown leaf area (CLA) were constructed, respectively. The results showed that a form of lnBLA=beta1+(beta2+b2)lnBD+(beta3+b3)lnRDINC+beta4lnDBH+beta5lnHT/DBH+(beta6+b6)l CR was selected as the optimal BLA mixed-effect model with the considera-tion of tree-level random effects, composed of three random-effect on lnBD, lnRDINC and lnCR (betai represented model fixed parameters, bi represented model random effect parameters, BD was branch diameter, RDINC was the relative depth into crown from tree apex, DBH was tree diameter at breast height, HT/DBH represented the ratio of tree height to DBH, and CR represented the ratio of crown length to tree height). The adjusted coefficient of determination (Ra2), residual mean squares error (RMSE), mean error (ME), mean absolute error (MAE) and precision estimation (P) of the optimal BLA mixed model were 0.90, 0.5477, -0.03, 0.24 and 91%, respectively, indicating the model had a good performance in predicting. The CLA was calculated by predicted values of all branches based on developed BLA model and the final form of CLA model was as follows: lnCLA=gamma0+gamma1lnDBH+gamma2CR (gammai, model parameters). Results of likelihood ratio test (P>0.05) showed that plot-level random effect had no influence on the model performance, which can be ignored. The CLA model got a good-fitting effect with R2 and RMSE being 0.87 and 0.3847, respectively. The CLA predicting model developed in this study could provide a good prediction of CLA for L. olgensis trees and provided a theoretical basis for the research on distribution of leaf area and photosynthesis. PMID- 30411560 TI - [Landscape pattern analysis and optimum design of park green space in Nanchang City, China based on GIS.] AB - Based on the current map data of park green space in the main urban area of Nanchang, the spatial database of park green space was set up with GIS technique, with the corresponding landscape indices being calculated by FRAGSTATS, the software of landscape pattern. Based on analyzing current landscape pattern of green space in Nanchang, the optimization strategy and scheme were proposed and the optimized landscape pattern was evaluated. The results indicated that the spatial distribution of patches in current park green space was uneven and area discrepancy was large, which is especially true in densely populated areas with less patch number of park green space and obviously low available area for disaster shelter. By substantially increasing the quantity and area of patches, improving the inter-patch connectivity, and increasing landscape fragmentation index appropriately, the "point-line-plane" pattern of park green space system in Nanchang would be optimized and the spatial distribution would be more rational, which could effectively enhance its role in biodiversity conservation, disaster prevention, and risk avoidance. The optimized indices of patch diversity, evenness and aggregation would be significantly increased, the dominance index would be reduced, and the landscape diversity would be more abundant. PMID- 30411561 TI - [A multi-scale study on the formation mechanism and main controlling factors of urban thermal field based on urban big data.] AB - The composition and structure of urban landscape and human activity intensity are key factors shaping urban thermal fields, whereas the relative importance of influencing factors for urban thermal distribution remains unclear. We carried out a case study in Yixing City. Land surface temperature (LST), ecological infrastructure (including vegetation and water cover), building volume and point of interest data were extracted from the RS interpretation, field mapping and programming technique. Using Pearson correlation analysis, univariete regression analysis, multiple regression analysis and relative weight analysis, we quantitatively analyzed the relationships between urban land surface temperature to ecological infrastructure, building volume, POI density at multiple scales (500, 1000, 2000 m) as well as their relative importance. The results showed that ecological infrastructure had a significant cooling effect, and the building volume and POI density were positively correlated with LST. Among the influence factors of urban heat field, ecological infrastructure had the highest relative weight (21.3%-43.8%), followed by building volume (20.7%-22.6%) and POI density (13.7%-21.7%). Our results would help to understand the relative importance of factors driving urban thermal field and offer important reference for taking mitigation measures to alleviate urban heat island effect. PMID- 30411562 TI - [Relationship between land use and nutrients in surface runoff in upper catchment of Miyun Reservior, China.] AB - Quantifying the relationship between the land use and water nutrient concentrations would help guide land use management and water eutrophication control. Previous studies mainly focus on the quantitative structure of land use and lack a comprehensive characterization of the intensity and spatial distribution of land use. Taking the upper catchment of Miyun Reservoir as the study area, we analyzed the impacts of land use on surface runoff nutrient concentrations. We set 52 water quality monitoring sites within sub-basins of the entire upper catchment of Miyun Reservoir and collected water samples in each month. Using the remote sensing interpretation and spatial analy-sis techniques, land use information was extracted, which included the intensity, slope, distance to the rivers and sampling sites, and spatial arrangement. The land use information was used as independent variables for the multiple regression models to predict the changes of total nitrogen, total phosphorus and chemical oxygen demand concentrations. The consideration of the above four aspects of land use information significantly promoted the explanatory capability of models, with the coefficients of determination of multiple linear regression models changing from 0.294, 0.471 and 0.223 to 0.532, 0.685 and 0.489, respectively. We also compared the mean cumulative contribution rates of land use to nutrients and the corresponding cumulative area percentages with different flow path distances to river. Results showed that the flowing migration path distance to the river in the range of one kilometer was the key area to control water eutrophication in the upper catchment of Miyun Reservoir. Finally, we proposed three measures to control and regulate the water eutrophication, including optimizing the farmland fertilizer management, strengthening the livestock manure handling, building forested filter strips and riparian buffer zones. PMID- 30411563 TI - [Impacts of climate and land use change on water and sediment load in the Northwest arid region, China: With Xiaonanchuan River Basin as a case.] AB - Understanding regional water and sediment transport patterns and their responses to climate and land use changes can provide a theoretical basis for the prevention and control of soil erosion, and is an important prerequisite for the integrated development of land and water resources. Based on monthly monitoring meteorological, runoff, and sediment data from 1963 to 2013, combined with the land use data in the 1980s and 2000 and NDVI data, using the Mann-Kendall trend analysis and abrupt change test method, we systematically analyzed the long-term variations of the climate, runoff and sediment transport, with the changes of land use and vegetation coverage being identified in the Xiaonanchuan (XNC) River basin, a typical watershed in the Northwest arid region. Based on the analysis of single element change, the impacts of climate and land use change on water and sediment transport were quantified by the multiple linear regression analysis. Simultaneously, the key action factors were identified. Results showed that air temperature was developing to the polarization, the precipitation increased gradually. A generally warm and wet tendency of climate change and an increased frequency of extreme climate events were found in the XNC River basin. Moreover, the speed and magnitude of climate change were intensified after the 1990s, which was the abrupt change point of the climate. Since the 1980s, with economic and social development, the area of arable land and built land expanded, that of the forest area increased, and the ecological environments were improved in the XNC River basin. Under the dominant driving effects of land use and vegetation coverage change, the runoff and sediment load gradually reduced with the average rate of 1.7*106 m3.(10 a)-1 and 1.5*108 m3.(10 a)-1, respectively. Quantifying the influence of land use and climate change on the water and sediment transport indicated that vegetation cove-rage and mean daily maximum temperature were the two key factors affecting the runoff change, while the vegetation coverage and maximum daily precipitation were the two key factors affecting the sediment load change. Under the condition of current climate change, ecological restoration could be one of the most effective ways to prevent water and soil losses in the arid area. PMID- 30411564 TI - [Effects of land use change on soil organic carbon and total nitrogen storage in Karst immigration regions of Guangxi Province, China.] AB - Land use change is an important factor affecting soil carbon and nitrogen cycle, and this is a hot spot in the study of global climate change. Based on the fixed depth method (FD) and the equivalent mass method (ESM), we explored the effects of land use change on soil organic carbon (SOC) and total nitrogen (TN) storage from the perspectives of forest reclamation and farmland vegetation restoration in Karst area. The storage of SOC and TN significantly decreased after the fore sts were converted to grassland, eucalyptus and farmland. On average, the SOC and TN losses calculated by the FD method were 47.4% and 41.6%, respectively, the losses of SOC and TN calculated by ESM method were 54.8% and 49.7%. The SOC and TN storage increased significantly after abandonment of farmland to grassland or planting eucalyptus. On average, the SOC and TN stocks calculated based on the FD method increased by 60.5% and 49.7%, while the SOC and TN calculated by the ESM method increased by 85.5% and 70.8% respectively. The difference between FD method and ESM method was analyzed, it was concluded that FD method ignored the difference of soil bulk density after land use change. Soil bulk density was significantly increased after forest destruction. The loss of SOC and TN storage was overestimated by the FD method. Soil bulk density decreased after vegetation restoration, FD method will underestimate the enhancement of SOC and TN storage. It is suggested that the ESM method should be used to estimate the impacts of land use change on SOC and TN storage. PMID- 30411565 TI - [Assessment of ecological vulnerability in multi-scale and its spatial correlation: A case study of Bailongjiang Watershed in Gansu Province, China.] AB - The study of ecological vulnerability is of great significance to regional ecological environment protection and sustainable development. Bailongjiang Watershed (BLJW) of Gansu Pro-vince is a vital area for water conservation and environmental fragile in the upper Yangtze River. Therefore, it is necessary to understand the ecological vulnerability of BLJW for local sustainable development. Based on the sensitivity-recovery-pressure (SRP) model, landscape pattern index and the typical ecosystem type, we constructed the assessment system of ecological vulnerability by taking township as the spatial unit to analyze the spatiotemporal pattern of ecological vulnerability from the township, county, watershed scales in BLJW of Gansu Province in 2002 and 2014 via the auxi liary regression, entropy weight, synthetic index, and spatial autocorrelation methods. The results showed that from the view of the township scale, the townships of severe or extreme vulnerability were concentrated in the northwestern Tanchang and most of Wudu in 2002 and 2014. The ecological vulnerability in the watershed had changed from moderate vulnerability to light vulnerability at township scale. At the county scale, the change of ecological vulnerability in Zhouqu was relatively stable, while that of Wudu, Wenxian, Tanchang and Diebu were relatively violent from 2002 to 2014. The ecological vulnerability of Wudu, Wenxian and Diebu improved to a certain extent, while that of Tanchang was deteriorating gradually. On watershed scale, the average value of ecological vulnerability index in the watershed were 0.2976 and 0.2904 in 2002 and 2014, respectively, showing a small downward trend, indicating that the ecological vulnerability in the watershed decreased in the past 12 years. The coefficients of variation were 0.3905 and 0.4358, respectively, with an increasing trend, suggesting that the spatial pattern of ecological vulnerability in the watershed developed in an unbalanced way. In 2002, the Moran I of ecological vulnerability index in the watershed was 0.5460, implying that the ecological vulnerability in the watershed was spatially agglomerated. Specifically, the areas of high-high were mainly distributed in the northern and central Wudu, and northwestern Tanchang. In 2014, the Moran I of ecological vulnerability index in the watershed increased to 0.5635, which indicated that the spatial agglomeration was more significant, and the areas of high-high were concentrated in central Wudu and northwestern Tanchang. PMID- 30411566 TI - [Spatiotemporal changes of landscape pattern using impervious surface in Guangdong-Hong Kong-Macao Greater Bay Area, China.] AB - Impervious surface is a key indicator for urbanization degree and the quality of urban environment. It is of great ecological significance to study the evolution of urban landscape based on impervious surface. We explored the spatiotemporal changes of impervious surface landscape pattern in Guangdong-Hong Kong-Macao Greater Bay Area from 2006 to 2016 using multi-temporal Landsat images based on landscape pattern index. The results showed that the impervious surface area (ISA) significantly increased in Guangdong-Hong Kong-Macao Greater Bay Area from 12127.69 km2 in 2006 to 20188.87 km2 in 2016, with an annual growth rate of 806.12 km2. High-density ISA was distributed in Guangzhou-Foshan and Shenzhen Dongguan districts on the east and west of the Pearl River, respectively. In general, patch numbers, patch density, and edge density, as well as shape complexity and its fragmentation kept increasing during the past decade. The landscape pattern tended to be disordered, fragmented, and irregular. Moreover, the difference of impervious surface landscape pattern is obvious between cities. The areas with highest connectivity, stability and regularization were distributed in Hong Kong and Macao, while the landscape pattern in Huizhou and Jiangmen trended to be fragmentized and complex. PMID- 30411567 TI - [Effect of film mulching and microbial inoculation on maize growth and water use efficiency under drought stress.] AB - To resolve the problem of soil nutrient and water deficiency in arid and semiarid regions of Northwest China, and considering the symbiotic relationship between microbes and crops, we set up two water regimes: drought stress (35% of the soil water holding capacity) and normal water supply (75% of the soil water holding capacity), two film mulching patterns (non-film mulching and film mulching), and four levels of microbial inoculation [single inoculation with AM fungi (AM), single inoculation with phosphate solubilizing bacteria (PSB), co-inoculation of AM fungi with phosphate solubilizing bacteria (AM+PSB) and the control (CK)]. This study aimed to evaluate the effects of microbial inoculation on maize growth, nutrient absorption, and water use efficiency under different treatments of water regime and film mulching. Results showed that drought stress significantly increased the mycorrhizal colonization of inoculated plants, but significantly decreased soil external hyphal length, T-GRSP and EE-GRSP content. Under drought stress, AM inoculation showed the best promoting and mycorrhizal effect on maize growth by increasing biomass and water use efficiency, soil organic carbon content, the absorption and transportation of soil N, P, K, and thus increasing the N, P, K uptake. Under normal water supply, the inoculation effect of AM+PSB was better than that of AM or PSB treatment, especially combined with film mulching. Results from correlation analysis showed that plant biomass, leaf SPAD value, and nutrient uptake of maize aboveground were significantly positively correlated with soil external hyphal length, whereas water use efficiency was significantly negatively correlated with soil external hyphal length. PMID- 30411568 TI - [Comprehensive assessment of soil fertility characteristics under different long term conservation tillages of wheat field in Weibei Highland, China.] AB - Soil fertility properties described by four physical indices and seven chemical indices in the 10-year long-term experiment of wheat fields in Weibei Highland were used to investigate the cumulative effect of 11 soil indices under six long term conservation tillage treatments. The principal component analysis was performed to comprehensively evaluate the cumulative effect of soil fertility under different tillage treatments, so as to provide scientific basis for soil sustainable utilization and management in Weibei Highland. The results showed that, compared with continuous conventional tillage (CT/CT), soil bulk density by no-tillage/subsoiling rotational tillage (NT/ST), subsoiling/conventional tillage rotational tillage (ST/CT) and conventional tillage/no-tillage rotational tillage (CT/NT) decreased by 6.6%, 5.9% and 6.6%, respectively, and no significant difference was found between continuous no-tillage (NT/NT) and CT/CT. NT/NT had the highest content of >0.25 mm mechanical stable aggregate, and no tillage/subsoiling rotational tillage (NT/ST) had the highest content of >0.25 mm water stable aggregate. Compared with CT/CT, the mechanical stable aggregate contents under other five tillage treatments increased by 1.7%-10.1%, soil organic matter increased by 0.6%-11.2%, and the contents of nitrogen, phosphorus, and potassium contents also increased. By principal component analysis, 11 soil indices were divided into two principal components to comprehensively characterize soil quality. The contribution rate of the first principal component was 75.5%, where the major contributors were soil organic matter, water stable aggregate, total nitrogen, total phosphorus, total potassium, alkaline hydrolysis nitrogen, available phosphorus, available potassium, bulk density and soil porosity. The contribution rate of the second principal component was 13.2%, where the major contributor was mechanical stable aggregate. Together, those two principal components accounted for 88.6% of the original variables. The soil fertility performance was in the sequence of NT/ST>ST/CT>CT/NT>NT/NT>ST/ST>CT/CT after gradually accumulating the effects of long-term conservation tillage. NT/ST was the most appropriate tillage patterns for the wheat fields in Weibei Highland, due to the resulting balanced and high-quality soil environment. PMID- 30411569 TI - [Optimizing fertilization scheme of N, P2O5 and K2O concentration for eggplant under soilless culture.] AB - To get optimal nitrogen (N), phosphorus (P2O5) and potassium (K2O) concentrations range for high quality and yield of eggplant with vermiculite as cultivation substrate, three factors and quadratic saturation D-optimal regression (310) were used to establish a ternary quadratic mathematical model with N, P2O5 and K2O concentrations as independent variables and eggplant yield and quality as objective functions. The results showed that yield and quality of eggplants were significantly influenced by N, P2O5 and K2O concentrations. The yield was most influenced by K2O concentration, and followed by N and then P2O5. The quality was also most influenced by K2O concentration, and followed by P2O5 and then N. There were significant interactive effects of N+P2O5, N+K2O and P2O5+K2O on yield, and significant interaction of N+K2O on eggplant quality. Under lower concentrations, the yield and quality of eggplants enhanced with the increasing N, P2O5 and K2O concentrations. When the nutrient concentrations exceeded a threshold, both yield and quality decreased. According to computer simulations, the yield could reach to 3600 g.plant-1 when the fertilization schemes were N 16.0-20.0 mmol.L-1, P2O5 2.2-2.6 mmol.L-1 and K2O 9.9-12.9 mmol.L-1; the fertilization scheme needed to obtain a comprehensive quality score of higher than 90 were N 18.0-21.1 mmol.L-1, P2O5 1.9-2.6 mmol.L-1 and K2O 10.6-13.3 mmol.L-1. In summary, fertilization scheme of high yield (43.2 kg.plot-1) and high quality(comprehensive score of higher than 90) of eggplants were N 18.0-20.0 mmol.L-1, P2O5 2.2-2.6 mmol.L-1, K2O 10.6-12.9 mmol.L-1, with an appropriate N, P2O5 and K2O proportion of 1:0.13:0.62. PMID- 30411570 TI - [Effect of long-term straw mulching and no-tillage on physical properties of meadow soil in cold region.] AB - The effects of different straw returning technology and farming system on soil physical properties is not clear in Heilongjiang Province, which is located in middle temperature zone with large amount of straw. Here, the effects of straw mulching on soil physical properties in meadow soil under no tillage conditions were studied in field experiments for eight consecutive years (2010-2017). The no straw covering (0%), 30% coverage (30%), 60% coverage (60%) and 100% coverage (100%) were disposed in the experiment. The results showed that straw mulching under no tillage significantly increased soil bulk density by 0.10-0.20 g.cm-3, which increased with the increases of coverage amount. Straw mulching increased soil solid fraction by 2.5%-7.8%. Soil temperature decreased with the increases of coverage amount, and this trend was more apparent on the surface of soil. The temperature reduction in 0-5 cm soil layer was 1.87-2.90 C. Soil water content significantly increased with the increases of straw mulching, with an enhancement of 6.4%-10.2%. Straw mulch decreased the total porosity and diameter of >0.05 mm aeration pores, increased the effective pore size of 0.05-0.002 mm, with the magnitude of such effects being positively dependent on coverage amount. There was no significant effect of straw mulching on inactive porosity of soil. Long term straw mulching increased soil compaction and soil moisture, reduced soil temperature and total soil porosity, and increased soil available porosity in 0-5 cm soil layer. PMID- 30411571 TI - [Effect of straw belt-mulching on soil temperature and yield of winter wheat in rain-fed semiarid region.] AB - To evaluate the effects of straw belt-covering on soil temperature and yield of winter wheat in rain-fed semiarid region in Northwest China, five mulching modes, including flat field planting without any mulching (CK), whole plastic film mulching (PM), straw mulching by 30 cm covering belt with an interval of 30 cm planting belt with three-row sowing (SM1), straw mulching by 40 cm covering belt with an interval of 40 cm planting belt with four-row sowing (SM2), and straw mulching by 50 cm covering belt with an interval of 50 cm planting belt with five row sowing (SM3), were set by two-year fixed-site trails in 2013-2015. The results showed that soil temperature significantly varied among different growth stages and soil layers in all treatments. SM1, SM2 and SM3 significantly decreased soil temperature by 1.0-1.3 C, 0.7-0.9 C and 0.7-1.1 C in the 0-25 cm soil layer, respectively. The mulching had double effects with increasing and decreasing soil temperatures. The straw mulching significantly increased soil temperature in the duration of seedling to overwintering stage, but greatly decreased soil temperature in the duration of reviving to mature stage. The temperature-increasing effect of film mulching was stronger than that of straw mulching, which was opposite to the temperature-decreasing effect. Straw mulching significantly reduced in the effective accumulated temperature and the daily temperature variations during the whole growth stages. The effective accumulated temperature under straw mulching decreased by 3.4-33.5 C.d, and the soil temperature difference decreased by 0.6-2.0 C. During over-wintering stage, the straw mulching showed a higher average soil temperature (0.2-0.3 C) and negative accumulated temperature (0.4-17.0 C.d) than those under the CK. The straw mulching significantly increased grain yield by 11.9%-19.5%. The variations of spikes per unit area were the main factor responsible for yield difference. The findings indicated that that straw mulching method is suitable for winter wheat production in rain-fed region of Northwest China. PMID- 30411572 TI - [Effects of elevated CO2 concentration on production and water use efficiency of spring wheat in semi-arid area.] AB - In the present study, the response of spring wheat production and water use efficiency (WUE) to the elevated CO2 concentrations was investigated based on the open-top chamber (OTC) experiment platform in Dingxi, a typical semi-arid area. Three different CO2 concentrations (390 MUmol.mol-1, 480 MUmol.mol-1 and 570 MUmol.mol-1) were involved. The results showed that the air temperature above plant canopy increased and the soil temperature at depth of 10 cm decreased by elevated CO2. The increased CO2 concentration substantially enhanced the total and each component biomass. The aboveground dry mass under the increased CO2 concentrations (480 and 570 MUmol.mol-1) was increased by 20.6% and 41.5%, respectively, and the total dry mass was increased by 19.3% and 39.6%, respectively. The biomass enhacement was mainly due to the increases of dry mass of stems and leaves, which was strongly related to the material production capacity during the middle growth stage. The root/shoot ratio under the increased CO2 concentrations (480 and 570 MUmol.mol-1) was decreased by 7.3% and 11.8%, respectively, indicating that the elevated CO2 affected the dry matter accumulation of aboveground more than that of belowground. The yields of spring wheat under the increased CO2 concentrations (480 and 570 MUmol.mol-1) were higher than that of the control by 8.9% and 19.9%, respectively, mainly due to the increase of grains per spike. The long-term effect of elevated CO2 concentration on the photosynthesis of spring wheat was not obvious. The photosynthetic rate significantly increased, the transpiration rate decreased and the evapotranspiration reduced with the increases of CO2 concentration. WUE at the leaf, population, and yield levels increased under elevated CO2 concentration, with the increase range of WUE being the largest at the population level and the lowest at the yield level. PMID- 30411573 TI - [Effects of short-chain polyphosphate fertilization on inorganic P transformation and mobilization of Fe, Mn and Zn in soils.] AB - Understanding the transformation of P in polyphosphate form in the soil and its effect on P availability is the prerequisite for reasonable polyphosphate fertilizer application. A pot experiment was conducted to explore the effects of polyphosphate fertilizers and MAP on soil available-P, inorganic P transformation in soils, soil micro-nutrient availabilities of Fe, Mn and Zn. Meanwhile, the effects of different P fertilizer on rape P nutrition and PUE in both calcareous and acid soils were investigated. Compared with the MAP treatment, polyphosphate fertilizers significantly increased plant available P concentrations in calcareous soil. Soil water soluble-P and Olsen-P were increased by 19.0% and 25.4%, respectively, and soil resin-P and NaHCO3-P (high labile P) and NaOH-P (medium labile P) increased by 22.8%, 43.3% and 33.8%, respectively. Those results implied that polyphosphate could reduce the fixation of P in calcareous soil. However, there was no significant effect of polyphosphate fertilization on improving P availability and reducing P fixation in acid soil. In comparison with MAP treatment, polyphosphate treatments significantly mobilized micronutrient in soils and increased the uptake of Fe, Mn and Zn by rape plants. In the calcareous soil, the available Fe, Mn, and Zn increased by 2.1%, 16.2% and 20.8%, respectively. In acid soil, the available Fe, Mn, and Zn increased by 6.6%, 11.9% and 9.2%, respectively. In addition, polypho-sphate treatments significantly increased dry mass, P uptake concentrations and P use efficiency (PUE) of rape in calcareous soil, but not in acid soil. In conclusion, polyphosphate fertilizer could significantly increase P availability and micronutrient availability, plant P nutrition and PUE, especially in calcareous soil. Thus, polyphosphate could be used as alternative of P source substituting the orthophosphate-based P fertilizer in calcareous soil. PMID- 30411574 TI - [Effects of selenium fertilization on selenium availability in rice soil.] AB - Selenium (Se) is easy to be fixed in acidic rice soil of South China, and thus its availability is low. The aim of this study was to investigate the influence of Se fertilizer on Se availability in rice rhizosphere and non-rhizosphere soils. The results showed that Se application increased yield and rice Se concentration. The water soluble, exchangeable, Fe/Mn oxide-bound, organic matter/sulfide-bound, and residual Se contents of the rhizosphere soil were lower than those of the non-rhizosphere soil. There was no significant difference in the migration coefficient of Se between the rhizosphere and non-rhizosphere soils. Se application had no significant effect on the migration coefficient of Se between roots and leaves but improved its migration coefficient between leaves and grains. The secretion of organic acids was increased by the application of 0.5 mg.kg-1 and decreased by the application of 1.0 and 5.0 mg.kg-1 Se. The secretion of organic acids had no significant effect on the rhizosphere soil pH. The pH of rhizosphere soil was higher than that of the non-rhizosphere soil, while the application of Se decreased the pH of the rhizosphere soil. With the increases of Se application, the intensity of the infrared absorption of clay mineral (kaolinite) in the rhizosphere soil showed an increasing trend. In this study, most of the Se was transformed into forms that were difficult to be absorbed and utilized by rice and difficult to move to rhizosphere soil. The enhancement of soil Se availability following the secretion of organic acids was not due to its effects on soil pH. PMID- 30411575 TI - [Effects of glyphosate-resistant transgenic soybean on soil rhizospheric bacteria and rhizobia.] AB - Transgenic soybean is the most widely grown genetically modified crop in the world, with herbicide resistance being the major modified trait. Microbial community is one of the most important indicators for soil quality. The effects of glyphosate-resistant transgenic soybean and glyphosate application on rhizospheric bacteria and rhizobia still remained unknown. In this study, with the non-transgenic parent Zhongdou 32 as control (CK), we investigated the effects of the G10-epsps transgenic glyphosate-resistance soybean SHZD32-01 without or with glyphosate application (abbreviated as GR and GR+G, respectively) on rhizospheric bacteria and rhizobia at different growth stages of soybean in field. Compared with CK, GR and GR+G had effects on soil pH, total organic carbon, total nitrogen and ammonium contents at the seedling and mature stages. GR significantly increased the abundance and diversity of soil rhizospheric bacterial community at the podding stage. GR+G significantly increased the abundance of soil rhizospheric bacterial community at the podding stage but decreased its diversity at the seeding and podding stages. GR and GR+G changed the relative abundance of dominant bacteria populations. Proteobacteria, Acidobacteria, Bacteroidetes, Chloroflexi, Planctomycetes and Actinobacteria were generally the dominant ones among the three treatments across all growth stages. Furthermore, GR and GR+G changed the relative abundance of rhizobia but did not change that of soybean-nodulating rhizobia, Bradyrhizobium and Sinorhizobium. The relative abundance of rhizobia in GR+G was decreased significantly at the podding stage. The abundance of actinobacteria and rhizobia was mainly affected by soil pH. Glyphosate-resistant transgenic soybean without or with glyphosate application altered soil rhizospheric bacteria and rhizobia at the podding stage, but the effects disappeared along with the growth of soybean. PMID- 30411576 TI - [Screening genotypes and identifying indicators of different Fagopyrum tataricum varieties with low phosphorus tolerance.] AB - Soil phosphorus (P) deficiency is one of the main factors that diminish the yield of crops on the Loess Plateau. Fagopyrum tataricum is a dominant cereal plant on the Loess Plateau, whose responses to low-P stress are significantly different and dependent on its genotypes. Therefore, screening genotypes with efficient P utilization is an important approach to increase the yield of F. tataricum and promote the sustainable development of local agriculture. With fourteen F. tataricum genotypes, the agronomic traits, physiology and biochemical characters of F. tataricum at seedling stage under normal (2 mmol.L-1) and low-P treatment (0.2 mmol.L-1) were studied by using sand culture. By examining the characters of selected F. tataricum at seedling stage, the varieties of F. tataricum with low-P tolerance were screened out and their evaluation indices were assessed to provide theoretical basis for the breeding of F. tataricum with high P-efficiency and the infertile soil cultivation on the Loess Plateau. The results showed that under low-P stress, the shoots of all genotypes were more affected than roots, with the decline of shoot aboveground index, average root diameter, root surface area and root volume, whereas the length of main root was elongated. Root activity and soluble protein content were decreased. In contrast, other physiological and biochemical indicators were increased. Moreover, plant total phosphorus content and plant phosphorus accumulation reduced, but phosphorus use efficiency increased. The principal component analysis divided the 22 individual indicators into four mutually independent comprehensive indicators (cumulative contribution rate of 90.1%). Cluster analysis divided 14 kinds of F. tataricum into three categories: Low phosphorus tolerant, intermediate and phosphorus sensitive. In order to investigate the index of low-P tolerance of F. tataricum at seedling stage, the optimal regression equation was established with the comprehensive evaluation value of low-P tolerance (D value) as the dependent variable and the low-P tolerance index of each indicator as the independent variables. Seven indicators of root surface area, root length, plant height, aboveground dry mass, acid phosphatase, phosphorus accumulation and POD activity were examined, which could be used for the rapid identification of low-P tolerance of F. tataricum at seedling stage. PMID- 30411577 TI - [Effect of thinning and reshaping on the canopy structure and leaf quality at late growth stage in dense apple orchard in Loess Plateau of eastern Gansu, China.] AB - In order to examine the effects of thinning and reshaping on canopy structure, leaf physio-logical property at late growth stage, characteristic of nutrient accumulation and distribution in leaf, and the spatial and temporal distribution of soil moisture, 18 year-old 'Fuji' apple trees in dense apple orchards were used to measure the canopy size, types and numbers of branches, leaf area index before and after the thinning and reshaping practices. The results showed that before pruning, the photosynthesis was limited by non-stomatal factors, with a reduction in Fv/Fm, Fv/Fo PIabs by 1.2%, 11.5%, 13.9%, respectively. However, the thinning and reshaping practices reduced leaf area index and canopy coverage, increased light interception up to 79% and improved tree construction. The total number of shoots decreased to 1100400 per hectare, while the individual shoot numbers were increased by 5.0% and the ratio of spur increased up to 73%. Due to the improvement of canopy lighting distribution, the average leaf area, specific leaf quality, hundred leaf mass and chlorophyll content were increased. With the increases of photosynthesis, the accumulation of photosynthate such as starch was increased by 143.5%. There was a close correlation between leaf development and light interception. Our results indicated that tree structure and canopy light interception could be improved by thinning and reshaping the dense trees, which resulted in higher leaf growth, development and photosynthetic capability but less water loss. Thinning and reshaping should be recommended to the renewal of the dense apple orchards in Loess Plateau of eastern Gansu. PMID- 30411578 TI - [Effect of soil salinity on insecticidal protein expression in flower buds of Bt cotton.] AB - To clarify the effects of soil salinity on the insect-resistance of flower buds in transgenic Bt cotton of Xinmian 33B (salt-sensitive) and Zhong 07 (salt tolerant), five levels (0, 0.15%, 0.30%, 0.45% and 0.60%) of soil salinity were set to investigate the impacts of soil salinity on Bt protein content, relative expression of Bt gene, activities of nitrogen metabolism-related enzymes and substances in flower buds during flowering stage. The results showed that Bt protein contents of flower buds decreased with increasing soil salinity. The Bt protein contents of flower buds decreased significantly when the soil salinity level was above 0.30% in both cotton cutivars. Greater reduction of Bt protein content occurred under severe than moderate soil salinity stress. However, the relative expression of Cry1Ac gene increased in flower buds of both cultivars when the stress level increased. Greater decreases of Bt protein content of flower buds was observed in Xinmian 33B compared to Zhong 07 under the same salinity level. The cultivars with greater reduction in Bt protein contents of flower buds also had greater reduction in the soluble protein content, glutamate pyruvate transaminase (GPT) and glutamic oxaloacetic transaminase (GOT) activities, and greater increments in free amino acid contents, protease activities and peptidase activities. Therefore, the decrease of Bt protein content was caused by decreased synthesis and increased decomposition of protein in flower buds of Bt cotton under soil salinity stress. PMID- 30411579 TI - [Priority conservation pattern of wetlands in the Yellow River basin based on systematic conservation planning.] AB - Yellow River basin is a significant habitat for biodiversity conservation in China. Here, we established a integrated classification system of wetlands based on climate types and geomorphological units, with which as the coarse-filter surrogates of biodiversity elements to complement the fine-filter surrogates of distribution of focal bird species. Then, we applied the theoretical framework of systematic conservation planning (SCP), with those two biodiversity surrogates as protection objects and watershed as planning units. We calculated social and economic costs (including roads, railroads, towns, rural settlements, dams) and set targets of 30% to input Marxan to figure out the optimal set of planning units, which met the protection target with the minimum of social economy cost and land resources. We identified a conservation priority pattern by calculating the irreplaceability of each unit by Marxan. Then, we compared the priority pattern with the existing reserve system to analyze conservation gap in the Yellow River basin. The results showed that most marsh wetlands were concentrated in the upper reaches of the Yellow River. The coverage of reserves in the source area was large. Some rare wetland types in Inner Mongolia, Gansu and Sichuan were separated from the protection system. The main wetland types in the middle reaches of the Yellow River were riverine wetlands, with low protection coverage rate and large conservation gaps. After protection network system being optimized, the protection effect was improved by29.1%-37.6%. The wetland in the lower reaches of the Yellow River was mainly concentrated in the Yellow River Delta area. The protection system was good and the conservation gaps was small. Overall, riverine wetlands in the middle reaches of the Yellow River basin had the highest area proportion of conservation gaps which needed more attention. Based on the priority conservation pattern, our results provided scientific suggestions for the protection planning and management of wetlands in the Yellow River basin, which would lay a foundation for the water ecological protection of the Yellow River basin from the macro scale. PMID- 30411580 TI - [Genetic structure and diversity of Harmonia axyridis populations in Shaanxi Province, China.] AB - Harmonia axyridis, one of the most important insect predators, has been widely used in biological control in agriculture. In this study, the mitochondrial COII gene was used as genetic marker to investigate the genetic structure and diversity of H. axyridis geographic populations distributed in Shaanxi Province. Level of genetic differentiation and gene flow among different populations of H. axyridis were analyzed. For all the 529 H. axyridis individuals from 21 populations, 15 haplotypes were observed (named as Hap1-Hap15). Hap1 and Hap2 were dominant haplotypes in all sampled individuals, accounting for 34.4% and 37.6% respectively. The overall haplotype diver-sity was 0.732, and it ranged from 0.652 to 0.786 within population. The average gene flow (Nm) among 21 populations was 10.13, and the overall FST value was 0.024, implying low genetic diffe-rentiation among all populations. Results from neutrality tests suggested that H. axyridis populations followed the neutral evolution model and the population size remained stable. Molecular variance analysis (AMOVA) showed high proportion of total genetic variance attributed to variations within populations. Phylogenetic tree based on Nei's genetic distance of different geographic populations showed clear divergence between northern, central, and southern Shaanxi groups. Results from Mantel test suggested that the genetic distance was weakly correlated with geographical distance between populations. Geographical pattern of genetic structure and diversity in populations from different regions indicated weak gene flow between northern, central, and southern Shaanxi due to Qinling Mountains barrier and climate difference. PMID- 30411581 TI - [Coupling analysis between new-type urbanization and ecological environment in Fujian Pro-vince, China.] AB - Identifying and revealing the coupling relationship between urbanization and ecological environment and its forming mechanism, and then putting forward regulation measures, will benefit urban management in making decisions. We examined the coupling process between new-style urbanization and ecological environment system of Fujian Province through the coupling model and coupling coordination model, and realized the spatial visualization based on the index system of urbanization and ecological environment, in which the index weight was based on the variation coefficient. The results showed that the variation of coupling degree between new-type urbanization and ecological environment system was relatively stable, ranging from 0.77 to 0.99 during 2000 to 2015. There was no obvious difference among the cities except for the Putian in 2000 and Zhangzhou in 2010 were in the break-in stage. The coupling-coordination degree between new-type urbanization and ecological environment system fluctuated around 0.50 during 2000 to 2015 with significant spatial differentiation and shorter evolution time from east to west. The coupling-coordination types of Fujian Province were dominated by the harmonious development type, accompanied by the types of moderate unadjusted recession, moderate coordinated development, and high coordinated development. There was transformation phenomenon among different types. Xiamen was the only one deve-loped into the high coordinated development type in 2015. The city development was mainly featured by lagged urbanization, with the lagged ecological environment in Xiamen in 2010 and in both Fuzhou and Xiamen in 2015. PMID- 30411582 TI - [Permissible pollution bearing capacity model of water function zone based on the perspective of municipal wastewater discharge and its application.] AB - Permissible pollution bearing capacity was an important basis for the prohibiting pollution discharge and assessing responsibility in the regional water function zone. In order to adapt to the current 'county-based' water environmental management mode in water function zone, we exami-ned the permissible pollution bearing capacity from the perspective of municipal permissible pollution discharge. A municipal pollution discharge model was established to predict the permissible pollution bearing capacity, which was then applied to Liquan and Jingyang counties in the downstream of Jinghe River. The results showed that the permissible pollution discharge in Liquan and Jingyang counties were closely related to the river discharge, with the permissible pollution discharge in the flood season being higher than that in the dry season. The COD concentration in the water function zone of Liquan County exceeded water quality target from November to next March. Therefore, the pollution discharge in this period of Liquan County should be reduced. The value of the pollution discharge would affect the results for the calculation of permissible pollution bearing capacity. The municipal wastewater discharge model could obtain more reasonable results of permissible pollution bearing capacity by using relatively stable pollution concentration data. Overall, our results could provide the scientific basis for the strict system of water resource management. PMID- 30411583 TI - [Combined effects of fluoxetine and triclosan on Pseudorasbora parva.] AB - We examined the effects of binary mixture of two different pharmaceutical and personal care products (PPCPs) on aquatic organisms. The topmouth gudgeon Pseudorasbora parva, native to northeast China, was used to study the combined effects of fluoxetine (FLX) and triclosan (TCS) on its different organs. After acute (4 h) and chronic (42 d) treatments, the combined effects of FLX/TCS on phase I and phase II detoxification enzymes, nervous system, digestive system and antioxidant system were evaluated. The results showed that the AChE activity in the brain of P. parva was transiently inhibited, whereas the activity of EROD in the liver was continuously inhi-bited. The activity of alpha-Glu in the intestine was induced after acute exposure but was inhibited after chronic exposure. Meanwhile, the level of lipid peroxidation in the liver was elevated after chronic exposure. In conclusion, the mixture of fluoxetine and triclosan produced toxic effects on multiple organs of P. parva, which could be alleviated after prolonged exposure, indicating an acclimation. However, the mechanisms of this acclimation needed further study. PMID- 30411584 TI - [Invertebrate assemblage structure associated with key environmental factors in the Yangtze River Estuary, China.] AB - Yangtze River Estuary plays a key role in linking the river and ocean ecosystems. Our understanding on its biodiversity and associated ecological processes remains poor, which is especially true for the invertebrate assemblage. Here, we investigated invertebrate assemblage pattern and associated environmental drivers based on four different seasonal comprehensive investigations across this region in 2014. A total of 35 species, belonging to 20 families, 10 orders and three phylums were identified. Crustaceans (19 species) and mollusks (13 species) were the taxa with higher richness. Dominant invertebrate included Palaemon gravieri, Crangon affinis, Ovalipes punctatus, Acetes chinensis, Portunus trituberculatus and Charybdis bimaculata. Total density and biomass was 4518.96 kN.km-2 and 173.09 kg.km-2 respectively, with the highest value in spring and the lowest in autumn. Biodiversity indices peaked in winter and spring and reached the lowest in summer. Invertebrate assemblage structure showed significant seasonal variation, appearing in a significant difference between the near-shore and the off-shore in spring, and between the northern-waters and southern-waters in other seasons. Results from ordination analysis showed that the spatial variation of invertebrate was mainly regulated by temperature and dissolved oxygen, whereas Chla and nutrient factors played key roles in driving the temporal community assemblage in this region. PMID- 30411585 TI - [Community structure of zooplankton in adjacent area of Changjiang Estuary, China in summer 2016.] AB - Based on the data of zooplankton samples from 27 stations in the offshore area of Changjiang Estuary in August 2016, we analyzed the community structure and diversity of zooplankton and examined the relationship between zooplankton community structure and environmental factors. A total of 108 species of zooplankton belonging to 12 groups in six phyla, together with 15 types of pelagic larvae and fish eggs were identified. The main groups were copepods, thaliacea, chaetognaths, cladocladus and medusae, with the average abundance being 273.9, 115.0, 67.1, 63.6 and 61.1 ind.m-3. The most dominant group of zooplankton was copepods (48 species), accounting for 44.4% of the total zooplankton abundance. Medusae ranked second with a total of 12 species, accounting for 11.1% of the total zooplankton abundance. Furthermore, the absolute dominant group was copepods, with the highest contribution to the zooplankton community (20.3%). According to the clustering results of environmental factors, the area could be divided into Changjiang diluted water and offshore water mass. The results of analysis of similarities showed that the difference of zooplankton community between the two regions was significant (the average diffe-rence was 4%), and the contribution to the difference was 20.3%, 18.0%, 14.1%, 13.4%, and 11.8% for copepod, thaliacea, cladocera, chaetognaths, and medusae, respectively. PMID- 30411586 TI - [The breadth and overlap of ecological niche of major fish species in the Minjiang River Estuary, China.] AB - Based on the seasonal bottom trawl surveys in the Minjiang River Estuary in 2015, the breadth and overlap of ecological niche of major fish species were analyzed. Those fish species were identified based on the index of relative importance (IRI). A total of 137 species belonging to 37 families and 16 orders were collected. Fifteen major fish species were determined by the IRI, including six dominant species Polydactylus sextarius, Harpadon nehereus, Pennahia argentata, Secutor ruconius, Cynoglossus abbreviates, Coilia mystus, and nine important species Collichthys lucidus, Amblychaeturichthys hexanema, Upeneus japonicas, Lagocephalus spadiceus, Pampus argenteus, Larimichthys crocea, Thryssa kammalensis, Takifugu oblongus, Lepturacanthus savala. Seven species whose spatio temporal niche breadth was higher than 1 in a declining order were C. abbreviates, C. lucidus, S. ruconius, A. hexanema, T. kammalensis, C. mystus, H. nehereus. The ecological niche of major fish species in the Minjiang River Estuary showed obvious seasonal dynamics. The percentage of species pairs with spatio-temporal niche overlap at the meaningful level was as high as 81.9%. Six species pairs reached significant ecological niche overlap, indicating that major fish species had similar distribution at the spatial and temporal scales and the existence of resource utilization competition. The species pairs of U. japonicus L. savalawas had the highest spatio-temporal niche overlap value, whereas U. japonicus-C. lucidus had the lowest niche overlap value. The spatio-temporal niche overlap of major fish species in the Minjiang River Estuary had substantial seasonal variation. PMID- 30411587 TI - [Comparison between traditional sequencing and high-throughput sequencing on the dietary analysis of juvenile fish.] AB - Feeding analysis of fish at early growth stages is helpful to understand its food source and functional role. Comprehensively and accurately obtaining the information of food species is critical for this endeavor. The development of high-throughput sequencing (HTS) technology has brought unprecedented opportunities and challenges to dietary analysis of animals. Molecular techniques have been widely used for analyzing diet composition of different animals, among which HTS has been successfully used on marine fish. But the accuracy and suitability of HTS have not been confirmed and compared with traditional Sanger sequencing on the dietary analysis of juvenile fish yet. In this study, a comprehensive comparison was performed between traditional Sanger sequencing and HTS on the diet analysis of Scatophagus argus juveniles, an important commercial fish in South and Southeast Asia. The juvenile fish were collected near a wharf in Daya Bay, China, and analyzed both by traditional Sanger sequencing and HTS methods targeting 18S rDNA gene. Results showed that the diet composition was complicated and dominated by ciliates and bryozoans, indicating an omnivorous feeding of juveniles. Sixty-seven effective sequences were obtained and 21 food species were identified by Sanger sequencing, while 35 food species from 17000 effective sequencings were identified by HTS. The food groups obtained by both techniques were similar. HTS had advantages in dietary coverage due to the large amount of data. HTS detected preys of dinoflagellates and brown algae which were not found in Sanger sequencing. In addition, HTS could provide semi-quantitative information to some extent based on a large amount of data, overcoming the deficiency of Sanger sequencing in quantitative research. Our results suggested that HTS is much more powerful than Sanger sequencing on diet analysis of juvenile fish, which can provide more details and comprehensive information about the feeding of juvenile fish. PMID- 30411588 TI - [Antioxidant responses of rainbow trout with different ploidies to acute temperature stress.] AB - Rainbow trout (Oncorhynchus mykiss) is a cold-water fish species with optimal temperature of 12-18 C. Temperature stress is a common issue in commercial culture of the Salmonid fish in summer. Both maple trout and steelhead trout are rainbow trout breeding species with good quality. The purpose of this study was to explore the impact of acute temperature stress on antioxidant responses of two kinds of rainbow trout. The juvenile maple trout was diploid, and the juvenile steelhead trout was triploid. The fishes were exposed to four different temperature treatments: 13, 17, 21, and 25 C, and hepatic samples were collected at 0, 1, 6, and 12 h. After acute heat stress, the fish were transferred to the tank with optimal temperature (13 C) and hepatic samples were collected after 1, 12, 24, and 48 h. The biomarkers, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), lipid peroxidation (LPO), malondialdehyde (MDA), and heat shock protein 70 kDa (HSP70) were measured. Results showed that the activities of SOD, CAT, and GPx in both maple trout and steelhead trout in 17 C treatment had no significant increase after acute temperature stress. The SOD activities of maple trout and steelhead trout in 21 C treatment significantly increased in response to acute temperature stress, but the SOD activity of maple trout returned to normal during the recovery process. The activities of SOD, CAT, and GPx for both species in 25 C treatment were significantly increased after acute temperature stress, which returned to normal for 24 h recovery. The amount of HSP70 produced by maple trout at 17, 21, and 25 C treatments was significantly higher than that at 13 C treatment, while that of steelhead trout was significantly higher for the 21 and 25 C treatments than that at 13 C treatment. A variety of antioxidant parameters were analyzed by integrated biomarker response (IBR) values. Results showed that the antioxidant response of maple trout was significantly higher than that of steelhead trout in 17 C and 21 C treatments, but significantly lower than steelhead trout in 25 C treatment. Such a result indicated that the antioxidant responses of different ploidy rainbow trouts were different under acute stress at different temperatures. PMID- 30411589 TI - [Spatial distribution of cladoceran assemblages in surface sediments of shallow lakes in Yunnan.] AB - Shallow lakes, sensitive to environmental changes due to low environmental carrying capacity, generally experience decreases in ecosystem function and even regime shifts after over-exploitation. Surface sediments of 18 shallow lakes in Yunnan were collected and analyzed to identify the spatial pattern and the influencing factors of cladoceran communities. The results showed that there was significant heterogeneity in the spatial distribution of cladocera in those lakes. For example, the cladoceran community was generally dominated by benthic taxa in alpine lakes, while there was a clear replacement of benthic cladocerans by planktonic ones with increasing nutrient levels across lakes from Southeast Yunnan. Altitude and total phosphorus were the main driving factors, which independently explained 22.0% and 7.7% of the change in cladocera communities, respectively. The altitude gradient and related changes in climate and catchment features were the main factors in structuring cladocerans for shallow lakes of Yunnan, while the anthropogenic impacts on cladoceran distribution was significant via the processes such as catchment development, pollutant input and macrophyte changes. Meanwhile, the interaction between elevation and total phosphorus explained 26.3% of the total variance in cladoceran community shift, indicating that the increase in human activity intensity in lakes at lower altitudes would have stronger impact on cladocerans through anthropogenic nutrient inputs. PMID- 30411590 TI - [Spatial distributions and environmental control of diatom functional groups in sediments of Haixi Lake, Southwest China.] AB - Functional group classification based on the morphological, physiological and ecological characteristics of diatoms is advanced in describing the tolerance and sensibility of diatoms to environmental stressors. In this study, we examined the spatial distribution of diatom functional groups in surface sediments of Haixi Lake and explored the relationships between diatom distributions and environmental variables using multivariate analyses. Principal components analysis (PCA) and redundancy analysis (RDA) results showed that water depth and total nitrogen (TN) were the key drivers for the heterogeneous distribution of diatom functional groups. Water depth of ca. 8 m was the threshold depth in influencing diatom functional group structures linking with thermal stratification. These results provided a basis for fossil record interpretation of the short core. Diatom functional groups fluctuated over the last century, in keeping with mean annual temperature, sediment TN, and median grain size. Climate warming, accelerated nutrient enrichment and intensified hydrological changes led to the dominance of functional group D, MP and P. Additionally, climate warming and nutrient enrichment led to increased diatom functional group diversity, while increased water depth (led by damming and reservoir reinforcement) contributed to diversity loss around 1957 and 1990 AD, respectively. PMID- 30411591 TI - [Ecological carrying capacity of shellfish in the Yellow River estuary and its adjacent waters.] AB - Yellow River Estuary and adjacent waters are famous shellfish production areas. Mactra veseriformis, Ruditapes philippinarum, and Meretix meretrix are important species for stocking enhancement. At present, the annual output of shellfish bottom sowing culture has reached 300 thousand tons, with an output value of 1.54 billion RMB. Over stocking of shellfish will cause environmental changes in marine, increase shellfish mortality and endanger ecosystem health. Accordingly, the assessment of the carrying capacity for shellfish based on ecosystem underpins responsible marine fisheries enhancement. In this study, an Ecopath mass-balance model of the Yellow River estuary and adjacent waters ecosystem constructed by Ecopath with Ecosim software was used to analyze the summary statistics parameters of the ecosystem, mixed trophic interactions, and to calculate the ecological carrying capacity of shellfish. The results showed that the ratio of total primary production/total respiration (TPP/TR) was 3.45, that of total primary production/total biomass (TPP/B) was 38.91, with the low Finn cycling index (0.028), high surplus production being 961.24 t.km-2.a-1 and low system connecting index (0.38), indicating that this ecosystem was at an unstable development stage. The increases of shellfish biomass would have positive impacts on Gobiidae, shrimps, crabs, and negative impacts on pelagic fishes, demersal fishes, edible jellyfish, zooplankton. Current biomass of shellfish was 5.5 t.km 2, with the potential enhancement. Based on the Ecopath model, the primary assessment of carrying capacity of shellfish was 18.22 t.km-2 in Yellow River estuary and its adjacent waters. This study provides scientific references for the sustainable development of fisheries resources in the Yellow River estuary. PMID- 30411592 TI - [Occurrence, degradation and potential ecological risks of triclosan in environment.] AB - Triclosan (TCS) is widely used in many kinds of personal care products due to its good antibacterial properties. However, TCS can enter environment in many ways through the consumption of those personal care products, and result in a series of environmental problem. TCS and its metabolites have their own characteristics such as environmental persistence, bioaccumulation and ecological toxicity, which may bring some potential risks to the ecosystem and human health. We summarized the occurrence and distribution characteristics of TCS in the environment, as well as the possible degradation pathways and products. Furthermore, we systemically introduced the bioavai-lability and the ecotoxicological effects of TCS and its metabolites on the reproduction and genetics of organism, and their potential risks to the ecosystem and human health. Finally, we proposed brief suggestions for further studies of TCS. PMID- 30411593 TI - [Amino acids in marine particulate matters and sediments and their role as indicators for organic matter degradation.] AB - As important components of marine organic matters especially of organic nitrogen, amino acids play an important role in organic matter cycles owing to their lability. The concentration, composition, and distribution of amino acids have been widely used to indicate the degradation state of organic matters in particulates and sediments of marine. Here, the distribution, influencing factors of amino acids and their role in indicating degradation of organic matters were systematically summarized. Gly, Glu, Ala, and Asp were the major components of amino acids in marine particulates and sediments. The contents of amino acids in the particles and sediments showed a decreasing tendency from the coastal waters to the open sea, and adecreased with the water depth. The lower value of %AA C/TOC, %AA-N/TN and degradation index (DI) based on changes in the composition of amino acids indicated the higher degradation degrees of organic matters. The reactivity index (RI) and ratios of D-AA and L-AA (D/L) based on non-protein amino acids and D-AA were used to indicate the degradation of organic matter according to the bacterial transformation of amino acids, in which RI value closer to 0, higher D/L, and lower ratios of protein amino acids to non-protein amino acids (Asp/beta-Ala and Glu/gamma-Aba) indicated the higher degree of degradation in organic matters. The migration and transformation of amino acid were mainly affected by dissolved oxygen, nutrient concentrations, sources of organic matter, depositional environments and microbial activities. Further studies should focus on the synergistic effects of particles and sediments, and also the effects and the specific regulatory roles of microorganisms on amino acids. PMID- 30411594 TI - Match analysis in Rugby Union: performance indicators of rugby championship and Super Rugby teams. AB - BACKGROUND: A number of Key Performance Indicators (KPIs) have been found to discriminate between winning and losing performances in Rugby Union competitions. This study aimed to investigate the KPIs of winning and losing teams during recent Rugby Championship and Super Rugby seasons. METHODS: Data from 139 matches during the 2014-2015 Rugby Championship and 2015 Super Rugby were extracted from the SANZAAR website and retrospectively analysed. 17 KPIs were used to describe the differences between winning and losing performances in different aspects of the game. Magnitude-based inferences, effect size (ES) with 90% Confidence Limits (CL), percentage changes (Diff %), and statistical significance were calculated. RESULTS: Winning teams during the Rugby Championship were most likely to score more tries, and very likely to gain more meters, beat more defenders, and miss less tackles compared to losing teams. In Super Rugby, winning teams were most likely to score more tries, execute more clean breaks, kicks in play and very likely to win more turnovers and concede a lower number of turnovers. The number of tackles made, and meters gained were also likely higher in Super Rugby winning teams compared to the losing counterparts. CONCLUSIONS: Limited differences were observed between winning and losing performances in the Rugby Championship, whereas various attacking and defensive KPIs were found to discriminate between winning and losing teams during Super Rugby. The method of data extraction, analysis and interpretation used herein could assist with game strategies and in turn better prepare teams and players for competition. PMID- 30411595 TI - Prevalence of vitamin D deficiency amongst soccer athletes and effects of 8 weeks supplementation. AB - BACKGROUND: High prevalence of vitamin D deficiency is well known around the world in risk populations. Although less is known about the athletic population, some studies report vitamin D deficiency amongst athletic population and adequate vitamin D levels are crucial for athletic population as it can prevent injuries such as stress fractures and might even have ergogenic effects for example on muscle function. The main objectives were to evaluate the basal serum levels of 25(OH)D and calcium in professional soccer athletes on the latitude 40 N, to evaluate the effects in 25(OH)D and calcium serum levels following supplementation of 1667 IU/day of cholecalciferol during a period of 8 weeks and evaluate eventual toxicity arising from it. METHODS: 28 professional athletes were evaluated according to the skin type. Basal serum levels of 25(OH)D and calcium were evaluated during winter months. Athletes were then supplemented with cholecalciferol 25.000 IU every two weeks. Serum levels of 25(OH)D and calcium were evaluated after supplementation. RESULTS: 25(OH)D initially ranged between 9.9 ng/mL and 32.9 ng/mL with a median of 19.2 IQR 7.24 ng/mL. A statistically significant inverse correlation exists between vitamin D deficiency and the Fitzpatrick scale (rho= - 0,555 p=0.003). After 8 weeks, 25(OH)D ranged between 10.6 ng/mL and 43.4 ng/mL with a median of 33.2 ng/mL IQR 6.1 ng/mL. We verified a statistically significant increase of serum 25(OH) D levels (11.74 +/- 5.988; IC95% [9,02; 14,47]; p<0,001. In addition, there was a statistically significant reduction of calcium: -0,36 +/- 0,457; IC95% [- 0,57; -0,15]; p=0,002. CONCLUSIONS: Professional athletes have a high prevalence of vitamin D. Supplementation with cholecalciferol in winter months during 8 weeks is safe and effective in raising 25(OH)D serum levels. However, it may not be sufficient for athletes to reach adequate vitamin D levels. PMID- 30411596 TI - Fitness effects of one year soccer training of 8-10 and 10-12 years old school children. AB - BACKROUND: The purpose of the study was to investigate the effect of one year soccer training on physical fitness performance, of U10 and U12 youth levels. METHODS: 28, 10-year-old and 28, 12-year-old children participated in the study. In the U12 group, 19 children participated only in the physical fitness sessions at school (control group - CG) and 9 children in four extra soccer trainings (Soccer group - SG). In the U10 group, 11 children participated only in the physical fitness sessions at school (control group - CG) and 17 children in four extra soccer trainings (Soccer group - SG). Height, body weight, body fat, standing long jump, 30 m sprint, sit and reach test, abdominal test and Yo-Yo IE1 tests were performed at the beginning and at the end of the season. RESULTS: School physical education programs and soccer training cannot affect anthropometric characteristics like body fat and body mass index. Soccer groups improve their performances at all fitness tests (p<0.05). The U10 control group didn't increase its performance in abdominal test and the U12 level control group didn't improve in the abdominal test nor Yo-Yo IE1 test. Soccer groups in all ages indicated greater improvements than control groups (p<0.05). CONCLUSIONS: In conclusion soccer training four times per week can improve the physical fitness of U10 and U12 children's. PMID- 30411597 TI - The influence of ageing and diabetic peripheral neuropathy on posture sway, tremor, and the time to achieve balance equilibrium. AB - BACKGROUND: It is well recognized that ageing and diabetes are associated with reduced balance and impaired gait. However, one important factor may be not just balance, but how long it takes to achieve balance equilibrium after a balance challenge. This study examined the relationship between balance, tremor, and time to achieve balance after a challenge to stability in young and old individuals without and without diabetes. METHODS: Twenty-four of the subjects were young controls, 22 were older controls, 23 were individuals with diabetes, and 21 were young people with diabetes. Posture sway, tremor, and time to achieve stability were assessed on a force plate during 8 progressively challenging balance tasks. RESULTS: For postural sway, tremor and time to reach postural stability, there was a significant difference in all groups with the increased balance challenge of the 8 tests (p<0.01). However, ageing and diabetes made balance, tremor and time to reach stability worse. In general, the young group with diabetes, for example, had similar responses to the old group without diabetes. CONCLUSIONS: In the subjects with diabetes, balance was poorer than the non-diabetes groups. The young subjects with diabetes showed similar results to the older subjects without diabetes. Diabetes subjects had more muscle tremor and a slower response time of the body to a balance challenge. This may account for increased falls in individuals with diabetes. PMID- 30411598 TI - Tissue flossing: a new short-duration compression therapy for reducing exercise induced delayed-onset muscle soreness. A randomized, controlled and double-blind pilot cross-over trial. AB - OBJECTIVES: The symptomatic reduction of exercise-induced delayed onset muscle soreness (DOMS) is of great interest in the fields of Sports Medicine and Physical Therapy. At this time, few therapeutic interventions have proven their effectiveness. One of the most promising interventions is Compression Therapy. The object of this study is Tissue Flossing, a therapeutic short-term compression method and whether its post-exercise application can reduce the extent of perceived DOMS. DESIGN: randomized, controlled, and double-blind pilot cross-over trial. METHODS: Participants (n = 17) without any musculoskeletal injuries were recruited from university students. Participants performed an exercise protocol and obtained the intervention subsequently on one of both arms. Participants had to return for a second day to perform the whole procedure again, this time receiving the flossing intervention on the other arm. At both time points their opposite arms served as the control. The primary outcome measure was a patient reported visual analogue scale 100mm. RESULTS: The mean value of DOMS of the flossed arm was 42mm compared to the non-flossed arm with 48mm. Differences were found to be statistically significant at 24 hours- (p=0,036; alpha=0.05), as well as at 48 hours post-intervention (p=0,035; alpha=0.05). Effect sizes were dz=0,408 at 24 hours-and dz=0,411 at 48 hours post-intervention. The clean language effect size was 0.66. CONCLUSIONS: Tissue flossing appears to be an effective method for treating DOMS which is slightly less effective but much more practicable than gold standard treatment. PMID- 30411599 TI - Effects of sexual activity on several measures of physical performance in young adult males. AB - BACKGROUND: There has been considerable debate as to whether sexual activity prior to an athletic event can affect physical performance. The goal of the study was to determine if sexual activity the evening before several physical performance tests affected the results compared to the same performance tests after five days of abstinence. METHODS: Ten, monogamous, married young men (28 +/ 7 years old, body mass index = 25.5 +/- 2.7 kg/m2) underwent a six-physical performance / balance /agility tests (forearm grip strength, balance, lateral movement, reaction time, anaerobic power, and maximal oxygen uptake) on three different days. The first day was a familiarization session, where the subjects familiarized themselves with the performance tests. Then, two randomized, single blind mornings sessions occurred there was either no sexual intercourse on the five days prior to the tests (control condition) or sexual intercourse on the night before the tests (experimental condition) in a randomized counterbalanced, fashion. The six performance tests were performed in the same order for each of the three sessions. A paired-t-test was used to compare each fitness test between conditions. RESULTS: The results showed that sexual activity had no effect on any of the six physical performance tests. CONCLUSIONS: This suggests that physical performance is unaffected by sexual activity within 24 hours prior to competition in young men. PMID- 30411600 TI - Muscular recruitment is associated with muscular function and swelling following eccentric contractions of human elbow flexors. AB - BACKGROUND: This study investigated the relationship between muscle fiber recruitment and the magnitude of muscle damage by isotonic eccentric contractions (ECCs). METHODS: Ten healthy men (age: 27.2 +/- 6.0 y, height: 174. 0 +/- 5.3 cm, body mass 70.1 +/- 2.1 kg) were recruited in this study. Subjects performed 30 ECCs of the elbow flexors using a dumbbell adjusted to 40% and 80% one Repetition Maximum of each individual. The dependent variables maximal voluntary isometric contraction (MVC) torque, range of motion (ROM), delayed onset muscle soreness (DOMS), cross-sectional area (CSA) and transverse relaxation time (T2) of magnetic resonance imaging (MRI) were measured immediately before, immediately after and 1, 3, and 5 days after each exercise. RESULTS: The decreased MVC and limited ROM were significantly greater for 80% than that 40% (P<0.05) at immediately after ECCs. However, no significant difference between 40% and 80% was found for DOMS. CSA at 5 days after ECCs was significantly higher 80% (P<0.05) than 40% (P<0.05). No significant changes in post T2 (acute T2) was found for 40%, but an increased acute T2 was observed in 80% (P<0.05). We found a significant correlation between the change in T2 at immediately after and MVC at immediately after (r = 0.77, P<0.05). In addition, a significant correlation between the change in T2 at immediately after and change in CSA at 3 days after (r = -0.83, P<0.05) was found. CONCLUSIONS: We conclude that the muscle strength loss and swelling following ECCs are related to the muscle fiber recruitment. PMID- 30411601 TI - Physiological and perceptual effects of self-selected and classical relaxing music on resting metabolic rate: a crossover trial. AB - BACKGROUND: A common recommendation for assessing resting metabolic rate (RMR) is that measurements be undertaken while avoiding activities like reading and listening to music. Listening to music, however, is sometimes used to reduce boredom or keep subjects awake, although it remains unclear whether music significantly alters RMR. METHODS: This randomized crossover trial enrolled 32 subjects and examined the impact of relaxing music during RMR tests. Indirect calorimetry was used to quantify RMR, oxygen consumption, carbon dioxide production (VCO2), ventilation (VE), respiratory rate, and respiratory exchange ratio (RER); the Karolinska Sleepiness Scale (KSS) and boredom- excitement scale (BES) assessed perceptual responses. Subjects were randomized to three 15- minute conditions in a counter-balanced order: control (no music), classical relaxing music, and self-selected relaxing music. RESULTS: There was no significant effect of music on RMR (ANOVA, F[2,60] = 2.4, p = 0.10). The difference in RMR between control and classical conditions was 9 kilocalories (95% confidence interval [CI], -33 to 51), while the difference between control and self-selected conditions was 34 kilocalories (95% CI, -5 to 73). Compared to control, both music conditions caused small, statistically significant increases in most cardiorespiratory parameters (VCO2, VE, respiratory rate, RER, heart rate) and reduced boredom on BES. No effects on the KSS were found. VE and BES ratings were slightly higher with self-selected music than classical music. CONCLUSIONS: Listening to relaxing music elicits small changes in physiological and perceptual responses during RMR testing but doesn't likely cause clinically meaningful fluctuations in RMR. PMID- 30411602 TI - Effect of high- and low-resistance inspiratory muscle training on physiological response to exercise in cross-country skiers. AB - BACKGROUND: The aim of the study was to evaluate the effect of different kinds of respiratory muscle training (RMT) on work capacity and selected spirometric indices in trained male cross-country skiers. METHODS: The study involved 13 competitively trained, elite Polish male cross-country skiers. The subjects were randomly divided into two groups who completed 7 weeks of RMT: one with gradually increasing resistance (power RMT) and the other with constant resistance (endurance RMT). Both groups' training programmes consisted of 30 inspiratory manoeuvres performed twice a day, 6 days a week. The first week of RMT started with a low resistance (29 cmH2O). In the following weeks, resistance in the power RMT group was gradually increased, while in the endurance RMT group, inspiratory resistance was maintained at a constant level of 53 cm H2O (36+/-8% PImax). Maximal inspiratory pressure (PImax), peak inspiratory flow rate (PIF), and stress test indices were measured before and after RMT. The stress test was conducted on a ski ergometer, with a gradual increase in intensity in all-out effort. RESULTS: A significant increase in PImax, PIF, and exercise work capacity (test time, work output, and peak power) was noted in both groups. No significant changes were observed in the VO2max or the selected respiratory variables. CONCLUSIONS: During a short training period (up to 7 weeks), the use of gradual and constant inspiratory resistance during RMT improves exercise and spirometric parameters in a similar way. RMT did not have a considerable impact on breathing efficiency in maximal effort. PMID- 30411603 TI - Effects of kinesiology taping on shoulder girdle muscle activity and sports performance during badminton forehand overhead strokes in amateur badminton players with shoulder impingement syndrome. AB - BACKGROUND: This study aimed to examine the influence of kinesiology taping (KT), various overhead stroke techniques, and their interactions on shoulder girdle muscle activity and on sports performance in badminton players with shoulder impingement syndrome. METHODS: Twenty-five amateur badminton players with shoulder impingement syndrome participated in the study. Each was exposed to two KT conditions (no taping and taping) while performing four badminton strokes (defensive clear, attacking clear, smash, and drop shot) in a random order. Surface electromyography (EMG) was used to evaluate the activity of the pectoralis major, anterior deltoid, infraspinatus, and latissimus dorsi muscles. The EMG data are expressed as a percentage of the EMG amplitude recorded during a maximal voluntary isometric contraction of the respective muscles. The shuttlecock speed was also measured via video analysis. RESULTS: The pectoralis major, anterior deltoid, infraspinatus, and latissimus dorsi EMG amplitudes were greatest during smashes (p < 0.05), followed in general by attacking clearances (p < 0.05) and defensive clearances (p < 0.05). Drop shots induced the lowest EMG amplitudes in the shoulder girdle muscles (p < 0.05). No significant main effect of the KT condition or KT-badminton stroke interaction effects were found (p > 0.05). CONCLUSIONS: The use of KT conferred no immediate benefits in improving shoulder girdle muscle activity or sports performance in amateur badminton players with shoulder impingement syndrome. Shoulder girdle muscle activity and sports performance were primarily influenced by the badminton overhead stroke techniques. PMID- 30411604 TI - Spectator injuries in sports. AB - BACKGROUND: Injury documentation and prevention has largely focused on the athletes participating in the sporting event. However, spectators are at risk for injury as well depending on the sport and venue. No study to date has recorded and analyzed spectator injuries in sports. The purpose of this study was to document spectator injuries across different sports METHODS: Scholarly articles and internet search engines were used to generate a list of spectator injuries across a variety of sports. Information gathered regarding each specific spectator injury included sport type, injury type, and injury mechanism. RESULTS: A total of 181 spectator injuries were collected. The sport with the most spectator injuries found was automobile/motorcycle racing (n = 123), followed by cycling (n = 25), cricket (n=12), baseball (n = 10), and hockey (n = 8). The majority of spectator injuries were related to the sport and not the behavior of the surrounding spectators. Among documented injuries sustained by spectators, automobile/motorcycle racing had the greatest number of mortalities (n = 38), followed by cycling (n =17), hockey (n = 4), baseball (n = 2), and cricket (n=1). CONCLUSIONS: Although uncommon, spectators at sporting events are at risk for injury. Some of these injuries are serious and even fatal. Future work needs to focus on implementing safety measures to protect spectators while still allowing them to enjoy live sporting events. PMID- 30411605 TI - The use of intravascular lithotripsy for the treatment of severely calcified lower limb arterial CTOs. AB - The endovascular management of complex lower limb arterial occlusive disease is generally associated with poorer acute results, a higher incidence of provisional stenting and subsequent restenosis compared to more simple arterial lesions. Even more challenging results can be expected when two complex features are combined such as chronic total occlusion (CTO) and severe calcification. Intravascular lithotripsy (IVL) with the Shockwave? system has recently been evaluated as a familiar angioplasty balloon based but effective technique for the management of arterial calcification. In the Disrupt PAD clinical trials, excellent acute results were obtained in moderate to severely calcified femoro-popliteal lesions, including a group of patients with CTOs. The incidence of provisional stenting was very low, despite the lesion complexity. There was a high incidence of subsequent restenosis, suggesting an anti- restenotic therapy with drug coated balloon is a necessary adjunct. This is being currently assessed in the Disrupt PAD III randomized trial. There has also been positive experience in calcified tibial artery CTOs in the Disrupt BTK trial and further clinical experience is currently being accumulated. PMID- 30411606 TI - Effects of Environmental Water Absorption by Solution-Deposited Al2O3 Gate Dielectrics on Thin Film Transistor Performance and Mobility. AB - In recent years, many solution-processed oxide transistors have been reported with mobility rivaling or exceeding their vacuum-deposited counterparts. Here, we show that water absorption from the environment by solution-processed dielectric materialsexplains this enhanced mobility. By monitoring the water content of Al2O3, ZrO2, and bilayer dielectric materials, we demonstrate how water absorption by the dielectric affects electrical characteristics in solution processed metal oxide transistors. These effects, including capacitance-frequency dispersion, counterclockwise hysteresis in transfer curves, and high channel mobility, are elucidated by electron transfer between the gate/channel and trap states within the band gap of the dielectric created by the water. PMID- 30411607 TI - High-Efficiency Spray-Coated Perovskite Solar Cells Utilizing Vacuum-Assisted Solution Processing. AB - We use ultrasonic spray-coating to fabricate cesium-containing triple-cation perovskite solar cells with a power-conversion efficiency of up to 17.8%. Our fabrication route involves a brief exposure of the partially wet spray-cast films to a low vacuum, a process that is used to control film crystallization. We show that films that are not vacuum-exposed are relatively rough and inhomogeneous, while vacuum-exposed films are smooth and consist of small and densely packed perovskite crystals. The process techniques developed here represent a step toward a scalable and industrially compatible manufacturing process capable of creating stable and high-performance perovskite solar cells. PMID- 30411608 TI - Clostridium difficile ClpP Homologues are Capable of Uncoupled Activity and Exhibit Different Levels of Susceptibility to Acyldepsipeptide Modulation. AB - Caseinolytic protease P (ClpP) has emerged as a promising new target for antibacterial development. While ClpPs from single isoform expressing bacteria have been studied in detail, the function and regulation of systems with more than one ClpP homologue are still poorly understood. Herein, we present fundamental studies toward understanding the ClpP system in C. difficile, an anaerobic spore-forming pathogen that contains two chromosomally distant isoforms of ClpP. Examination of proteomic and genomic data suggest that ClpP1 is the primary isoform responsible for normal growth and virulence, but little is known about the function of ClpP2 or the context required for the formation of functional proteases. For the first time in a pathogenic bacterium, we demonstrate that both isoforms are capable of forming operative proteases. Interestingly, ClpP1 is the only homologue that possesses characteristic response to small molecule acyldepsipeptide activation. On the contrary, both ClpP1 and ClpP2 respond to cochaperone activation to degrade an ssrA-tagged substrate. These observations indicate that ClpP2 is less susceptible to acyldepsipeptide activation but retains the ability to interact with a known cochaperone. Homology models reveal no obvious characteristics that would allow one to predict less efficient acyldepsipeptide binding. The reported findings establish the uniqueness of the ClpP system in C. difficile, open new avenues of inquiry, and highlight the importance of more detailed structural, genetic, and biological characterization of the ClpP system in C. difficile. PMID- 30411609 TI - Hydrothermal Synthesis of Urchin-like W-V-O Nanostructures with Excellent Catalytic Performance. AB - Urchinlike W-V-O microspheres have been successfully synthesized for the first time by a one-pot hydrothermal approach. The as-synthesized W-V-O material was characterized by several techniques such as XRD, SEM, TEM, FTIR, EDS, BET, and Raman spectroscopy. The characterization results have revealed that the W-V-O microspheres consist of numerous one-dimensional nanobelts radially grown from the center. The typical nanobelts display rectangular cross sections with lengths of several micrometers, widths of about 50 nm, and thicknesses of approximately 10-20 nm. Vanadium oxides are dispersed highly either on the external surface or inside the channel surface of the hexagonal WO3 structure. In addition, the as obtained urchin-like W-V-O material was explored as a catalyst for the ammoxidation of 2,4- and 2,6-dichlorotoluene to the corresponding nitriles. The catalytic results have indicated that the W-V-O nanostructures show excellent performance with yields of 2,4- and 2,6-dichlorobenzonitrile respectively reaching up to 77.3 and 75.1%, which are the highest among the previously reported catalysts with two components. The formation process of the urchinlike W V-O microspheres was simply investigated. PMID- 30411610 TI - Position Makes the Difference: Electronic Effects in Nickel-Catalyzed Ethylene Polymerizations and Copolymerizations. AB - A series of phosphine-sulfonate ligands and the corresponding nickel complexes are prepared and characterized. These ligands are specifically designed to bear systematically varied electron-donating and -withdrawing substituents (H, OMe, NMe2, CF3, and Me). More importantly, these substituents are installed at different positions on the ligand framework, namely, the para-position of the phenylphosphino group (position X), and para to the arylsulfonate group of the main ligand (position Y). These nickel complexes are highly active single component catalysts for the polymerization of ethylene. An electron-donating substituent at position X or an electron-withdrawing substituent at position Y is beneficial to the properties of these nickel catalysts. Specifically, the catalyst bearing the NMe2 substituent at position X exhibits high stability and high activity (3.3 * 106 g mol-1 h-1), and catalyzes the formation of polyethylene of high molecular weight ( Mn 405 000) and high melting point ( Tm 138.5 degrees C). This catalyst also mediates the efficient copolymerizations of ethylene with methyl 10-undecenoate, 6-chloro-1-hexene, and trimethoxyvinylsilane. PMID- 30411611 TI - Correction to In Situ Observation of Atomic Redistribution in Alloying Gold Silver Nanorods. PMID- 30411612 TI - Heterojunction Area-Controlled Inorganic Nanocrystal Solar Cells Fabricated Using Supra-Quantum Dots. AB - A supra-quantum dot (SQD) is a three-dimensional structure formed by the attachment of quantum dots. The SQDs have sizes of tens of nanometer and they maintain the characteristics of the individual quantum dots fairly well. Moreover, their sizes and elemental compositions can be tuned precisely. Based on their unique features, in this work, SQDs are used as constituents of the interpenetrating photoactive layers of inorganic nanocrystal p-n heterojunction solar cells in order to control the p-type and n-type domain sizes (i.e., p-n heterojunction areas) for optimizing the charge-carrier collection. SQD containing p-n heterojunction solar cells exhibit improved charge transport and thereby, higher power conversion efficiency (PCE) (3.03%), owing to their intermediate p-type and n-type domain sizes, which are between those of a bilayer nanorod p-n heterojunction solar cell (PCE: 1.21%) and an interpenetrating nanorod p-n heterojunction solar cell (PCE: 2.40%). This work demonstrates that the self-assembly of nanoscale materials can be utilized for tailoring the spatial distributions of charge carriers, which is beneficial for obtaining an enhanced device performance. PMID- 30411613 TI - Building Material Use and Associated Environmental Impacts in China 2000-2015. AB - A rapidly increasing use of building materials poses threats to resources and the environment. Using novel, localized life cycle inventories and building material intensity data, this study quantifies the resource use of building materials in mainland China and evaluates their embodied environmental impacts. Newly built floor area and related material consumption grew 11% per annum from 2000 to 2015, leveling off at the end of this period. Concrete, sand, gravel, brick, and cement were the main materials used. Spatially, construction activities expanded from east China into the central part of the country. Cement, steel, and concrete production are the key contributors to associated environmental impacts, e.g., cement and steel each account for around 25% of the global warming potential from building materials. Building materials contribute considerably to the impact categories of human toxicity, fossil depletion, and global warming, emphasizing that greenhouse gas emissions should not be the sole focus of research on environmental impacts of building materials. These findings quantitatively shed light on the urgent need to reduce environmental impacts and to conserve energy in the manufacturing processes of building materials on the national scale. PMID- 30411614 TI - Diterpenoids from Euphorbia dulcis with Potassium Ion Channel Inhibitory Activity with Selective G Protein-Activated Inwardly Rectifying Ion Channel (GIRK) Blocking Effect. AB - Nine new (1-9) and two known (10, 11) jatrophane diterpenoids were isolated from the methanol extract of Euphorbia dulcis. The structure elucidation of the compounds was performed by means of extensive spectroscopic analysis, including HRESIMS, 1D (1H, JMOD), and 2D (HSQC, HMBC, 1H-1H-COSY, NOESY) NMR experiments. The absolute configuration of compound 1 was determined by single-crystal X-ray diffraction. The electrophysiological effects of compounds 1-11 and the five diterpenoids (12-16) previously isolated from Euphorbia taurinensis were investigated on stable transfected HEK-GIRK1/4 (Kir3.1/3.4) and HEK-hERG (Kv11.1) cell lines using automated patch-clamp equipment. The majority of the diterpenoids showed significant blocking activity on GIRK channels (60.8-88.7% at 10 MUM), while compounds 1, 2, 9-11, 13, and 14 exerted notable inhibitory effects even at 1 MUM concentration. None of the jatrophane diterpenoids interfered with the function of hERG proteins; however, compound 14 remarkably hampered K+ flow through hERG channels. These selective activities suggest that jatrophane diterpenoids may represent a group of potential lead compounds for the development of novel therapeutic agents against atrial fibrillation. PMID- 30411615 TI - Self-Assembled Carcerand-like Cage with a Thermoregulated Selective Binding Preference for Purification of High-Purity C60 and C70. AB - Fullerene molecules have attracted considerable interest because of the unique curved aromatic pi-conjugated systems. However, the complicated and costly technologies for purification of highly pure fullerenes hamper easy access to these attractive molecules and consequently limit most of the fullerene applications. Here, we report the discovery of a carcerand-like cage acting as a stand-alone host for efficient separation and purification of C60 and C70 from fullerene soot. The cage, built through the self-assembly of metal coordination, is capable of quantitatively encapsulating fullerenes C60 and C70. The fullerene complexes are highly stable at high temperatures because of the small crevices with precisely defined sizes, multiple favorable CH-pi interactions, and concave convex aromatic interaction between fullerenes and corannulenes. Importantly, the carcerand-like cage shows a temperature-dependent selective binding preference for C60 over C70, which allows us to develop an efficient and green procedure for isolating C60 and C70 with high purity and low mass loss from fullerene soot without the help of recrystallization or high-performance liquid chromatography. PMID- 30411616 TI - Ferromagnetism of 1T'-MoS2 Nanoribbons Stabilized by Edge Reconstruction and Its Periodic Variation on Nanoribbons Width. AB - Nanoribbons (NRs) of two-dimensional (2D) materials have attracted intensive research interests because of exotic physical properties at edges as well as tunable properties via width control. In this paper, using density functional theory (DFT) calculations, we discover sensitive dependence of magnetic properties of 1T'-MoS2 NRs, that is, periodic variation of magnetic moments between 0.1 and 1.2 MU B, on NR width (even or odd number of MoS2 units). Our results reveal that a special edge reconstruction, which is not recognized before, stabilizes the ferromagnetic (FM) ground state. Our results also suggest that the FM state could be stable under ambient condition. This study indicates a promising means to integrate multiple magnetic units for small-scale functional devices, such as information storage and spintronics, on a single piece of MoS2 NR by designing segments with different width. PMID- 30411617 TI - Electrochemical Aptasensor Based on Sulfur-Nitrogen Codoped Ordered Mesoporous Carbon and Thymine-Hg2+-Thymine Mismatch Structure for Hg2+ Detection. AB - A renewable electrochemical aptasensor was proposed for super-sensitive determination of Hg2+. The novel aptasensor, based on sulfur-nitrogen codoped ordered mesoporous carbon (SN-OMC) and thymine-Hg2+-thymine (T-Hg2+-T) mismatch structure, used ferrocene as signal molecules to achieve the conversion of current signals. In the absence of Hg2+, the thiol-modified T-rich probe 1 spontaneously formed a hairpin structure by base pairing. After being hybridized with the ferrocene-labeled probe 2 in the presence of Hg2+, the hairpin structure of probe 1 was opened due to the preferential formation of the T-Hg2+-T mismatch structure, and the ferrocene signal molecules approached the modified electrode surface. SN-OMC with high specific surface area and ample active sites acted as a signal amplification element in electrochemical sensing. The sensitive determination of Hg2+ can be actualized by analyzing the relationship between the change of oxidation current caused by ferrocene signal molecules and the Hg2+ concentrations. The aptasensor had a fine linear correlation in the range of 0.001-1000 nM with a detection limit of 0.45 pM. The aptasensor also displayed a good response in real sample detection and provided a promising possibility for in situ detection. PMID- 30411618 TI - Theoretical Elucidation of Am(III)/Cm(III) Separation Mechanism with Diamide-type Ligands Using Relativistic Density Functional Theory Calculation. AB - We elucidated the separation mechanism between Am(III) and Cm(III) ions by using two different types of diamide ligands, diglycolamide (DGA) and alkylated diamide amine (ADAAM), by means of the density functional theory technique and electron density analysis. The molecular geometries and formation reactions of the metal ligand complexes were modeled by using [M(DGA)3]3+ and [M(ADAAM)(NO3)3(H2O)]. We successfully reproduced Cm(III) selectivity over Am(III) with DGA and Am(III) selectivity over Cm(III) with ADAAM. Furthermore, we analyzed the bonding properties between the metal ion and the diamide-type ligands by using model complexes, [M(DGA)3]3+ and [M(ADAAM)(NO3)3(H2O)], and revealed the differences in terms of the bond dissociation energy and the metal 5f orbital participation in the covalency between the Am(III) and the Cm(III) complexes. It was suggested that the differences were key factors to understand the Am(III)/Cm(III) selectivity. PMID- 30411619 TI - A Cerium Doped Scandate Broad Orange-Red Emission Phosphor and its Energy Transfer-Dependent Concentration and Thermal Quenching Character. AB - A series of BaSr2Sc4O9 and Ce3+-doped BaSr2Sc4O9 phosphors were synthesized via the high temperature solid state reaction. Crystal structure information on BaSr2Sc4O9 is first refined using the Rietveld method based on the XRD data, and it is assigned to the trigonal system with the R3 space-group. The photoluminescence properties were investigated in detail, including the emission and excitation spectra, site occupation, decay lifetime, thermal quenching, and quantum efficiency. There are three Ba2+/Sr2+ sites and four Sc3+ sites in this structure. The Ce3+ ions in the 6-fold coordinated Sr2+/Ba2+ sites show a near ultraviolet-blue emission with a peak at around 407 nm under ultraviolet excitation. The Ce3+ ions in Sc3+ sites exhibit a bright broad orange-red emission with the peak at around 615 nm under near-ultraviolet and blue excitation. The energy transfer process between the different sites is demonstrated based on the spectral analysis, theoretical calculation, and decay lifetime variation. Under excitation of 345 nm, the energy transfer phenomenon and distribution of activator ions lead to the invalidation of part of the Ce3+ ions, and then it causes a higher concentration quenching point. The participation of the energy transfer in the thermal quenching phenomenon causes the abnormal intensity variation, which is ascribed to the energy compensation by the increasing energy transfer efficiency at high temperature. The internal quantum efficiency is 45% under the 420 nm excitation wavelength. An excellent white light emitting diode lamp is obtained by fabricating BaSr2Sc4O9:Ce3+ with BAM:Eu2+, beta-sialon:Eu2+, and a 395 nm GaN chip; its CIE coordinate ( x, y), CCT, and Ra are (0.3708, 3463), 4023 K, and 84. These results reveal the correlation between energy transfer and luminescent property and provide a practical foundation to comprehend and adjust the photoluminescence performance. PMID- 30411620 TI - Improved Soluble Expression and Catalytic Activity of a Thermostable Esterase Using a High-Throughput Screening System Based on a Split-GFP Assembly. AB - The thermostable esterase Aaeo1 displays a low expression level and forms a great amount of inclusion bodies in E. coli. Herein, a split-GFP system was established in which the fluorescence intensity exhibited a good linear correlation with the soluble protein expression level and the esterase activity. In the primary high throughput screening, the mutant library was screened by flow cytometry via detection of a split-GFP reporter. Then, through a secondary screening against esterase activity, two mutants with improved soluble expression and catalytic activity were obtained. The soluble expression of the mutant enzymes in E. coli was improved by 2-fold. The kcat/ Km values of the mutant enzymes were 2-fold higher than that of the parent. We explored the relationship between the amino acid mutations in the two mutants and the enzyme activity. The enzyme activity of mutant I51V-E170D was 4.5 times higher than that of the parent. PMID- 30411621 TI - Two-Dimensional Microfluidic System for the Simultaneous Quantitative Analysis of Phototactic/Chemotactic Responses of Microalgae. AB - Microalgae have been spotlighted as a renewable energy source to produce biofuels from CO2 by photosynthesis. However, their innate inefficiency of CO2 conversion using light energy has been a challenge to the commercialization of algae-based biofuel production. Photosynthetic organisms have evolved behavioral responses, including phototaxis and chemotaxis, to find optimal conditions for capturing light energy and inorganic carbon (Ci) sources for photosynthesis. In this context, investigation of phototaxis and chemotaxis to HCO3-, the predominant form of Ci in neutral aqueous solutions, is necessary to understand the physiological role of tactic responses in photosynthesis. In this study, a two dimensional microfluidic system enabled efficient analysis of phototactic and chemotactic responses by investigation of cell distribution in the outlet chambers. From statistical analysis (skewness and kurtosis) of tactic responses of different algal strains to external stimuli, the preferred concentrations of HCO3- for Chlamydomonas reinhardtii CC125 (wild type), PTS42 (random insertional mutant of C. reinhardtii, high photosynthetic activity), and CC2702 ( cia5 mutant of C. reinhardtii, unable to acclimate to low CO2 concentration) were determined to be 27.22, 43.23, and 36.95 mM, respectively. From the analysis of tactic responses of wild type and 14 mutant strains, it was found that the photosystem II (PSII) operating efficiency and CO2 fixation rate were strongly correlated with the phototactic ( R2 = 0.931) and chemotactic response ( R2 = 0.857), respectively. Finally, this system can be applied to high-throughput screening strategies for the rapid isolation of high photosynthetically productive microalgal strains based on their tactic responses. PMID- 30411622 TI - Mechanism of Transformation of Ferrocene into Carbon-Encapsulated Iron Carbide Nanoparticles at High Pressures and Temperatures. AB - A mechanism was established for the formation of nanosized iron carbide particles encapsulated in carbon shells via the processes of ferrocene thermal conversions at high pressures. At a pressure of 8.0 GPa, products of ferrocene decomposition were studied as a function of temperature by X-ray diffraction, Raman and Mossbauer spectroscopy, scanning and transmission electron microscopy. It was shown that the mechanism of formation of the carbon-encapsulated iron carbide nanoparticles at high pressures and temperatures differs qualitatively from the known mechanism of their formation in the gas-phase processes of laser pyrolysis or photolysis of ferrocene. At high pressures and temperatures, the formation of iron carbide nanoparticles occurs not due to the primary growth of pure iron particles and the subsequent dissolution of carbon in iron. Nanoparticles are formed due to the direct fusion of iron-carbon clusters, which are formed at intermediate stages of ferrocene thermal destruction. Then, obtained amorphous iron carbides Fe1- xC x with a high carbon content start to crystallize. Two crystalline carbon-encapsulated forms of iron carbide (Fe7C3 and Fe3C) are the main products of crystallization of the amorphous Fe1- xC x depending on the temperature of the ferrocene treatment. PMID- 30411623 TI - EBprotV2: A Perseus Plugin for Differential Protein Abundance Analysis of Labeling-Based Quantitative Proteomics Data. AB - We present EBprotV2, a Perseus plugin for peptide-ratio-based differential protein abundance analysis in labeling-based proteomics experiments. The original version of EBprot models the distribution of log-transformed peptide-level ratios as a Gaussian mixture of differentially abundant proteins and nondifferentially abundant proteins and computes the probability score of differential abundance for each protein based on the reproducible magnitude of peptide ratios. However, the fully parametric model can be inflexible, and its R implementation is time consuming for data sets containing a large number of peptides (e.g., >100 000). The new tool built in the C++ language is not only faster in computation time but also equipped with a flexible semiparametric model that handles skewed ratio distributions better. We have also developed a Perseus plugin for EBprotV2 for easy access to the tool. In addition, the tool now offers a new submodule (MakeGrpData) to transform label-free peptide intensity data into peptide ratio data for group comparisons and performs differential abundance analysis using mixture modeling. This approach is especially useful when the label-free data have many missing peptide intensity data points. PMID- 30411624 TI - Correction to "Continuum Microkinetic Rate Theory of Lattice Systems: Formalization, Current Limitations, and a Possible Basis for Continuum Rate Theory". PMID- 30411625 TI - Orientational Pair Correlations in a Dipolar Molecular Liquid: Time-Resolved Resonant and Nonresonant Pump-Probe Spectroscopies. AB - Orientational pair correlations (OPCs), when they are sufficiently strong in a liquid, contain information on the interplay between structure and dynamics that arise from intermolecular interactions. Consequently, the quantification of OPCs remains a subject of substantial interest in current experimental and theoretical works. In the case of benzonitrile, the importance of OPCs remains ambiguous, owing to the use of model-dependent analyses or reliance on a single spectroscopic technique. Here, IR polarization-selective pump-probe (PSPP) and optical heterodyne-detected optical Kerr effect (OHD-OKE) experiments were used to quantify OPCs in benzonitrile. These methods measure single molecule and collective orientational relaxation dynamics, respectively. A comparison of the orientational correlation function (PSPP) of the naturally abundant 13CN stretching mode and the polarizability anisotropy relaxation (OHD-OKE) of the liquid revealed that the collective reorientation time was a factor of 1.56 +/- 0.08 slower than the single molecule reorientation time. The two types of measurements on dilute benzonitrile in carbon tetrachloride were the same within experimental error. These results support the proposition that OPCs exist and arise from the formation of parallel-aligned intermolecular structures in the neat liquid. PMID- 30411626 TI - Palladium-Catalyzed Asymmetric Intramolecular Dearomative Heck Reaction of Pyrrole Derivatives. AB - The Pd-catalyzed asymmetric intramolecular dearomatization of pyrroles via the Heck reaction in the presence of commercially available Pd(OAc)2 and the Feringa ligand is described. Diverse pyrroline derivatives were obtained in excellent yields (up to 99%) with high enantioselectivity (up to 96% ee). The reaction features a wide substrate scope, relatively mild conditions, and useful transformations of the products. PMID- 30411627 TI - How Did These Data Get Here? Recommendations for the Analysis of Data From ClinicalTrials.gov. AB - A paper by Drs Okada and Sengoku that appears in this issue of TIRS shows how data from Clinicaltrials.gov can be used for research on the pharmaceutical industry. This commentary identifies several challenges associated with using these data for research and concludes with 3 recommendations from a statistical perspective. PMID- 30411628 TI - The fear of Alzheimer's disease: mediating effects of anxiety on subjective memory complaints. AB - OBJECTIVES: To determine if the fear of developing Alzheimer's disease (FDAD) construct, in combination with similar psychoemotional factors, could help elucidate the nature of older adults' subjective memory complaints (SMCs) and subsequent objective memory performance. METHODS: One hundred ninety-three healthy older adults (aged 65-93) were administered clinician and self-report measures of depression, worry, anxiety, illness attitudes, and memory, and each rated their concern with developing AD. RESULTS: Self-reported FDAD was not associated with objective memory performance (p > .05). FDAD, trait anxiety, general anxiety, and general and illness-related worry were independently associated with subjective memory report (ps < .05). The relationship between FDAD and subjective memory report was mediated by measures of general trait and state anxiety, but not general worry or illness-specific worry. CONCLUSIONS: FDAD was not associated with objective memory functioning, suggesting AD concerns were not reflective of memory pathology. The mediating effect of anxiety on the relationship between FDAD and subjective memory report suggests that assessment of anxiety, beyond AD fear, may help identify older adults at risk for developing negative perceptions of memory and related distress. PMID- 30411629 TI - A network analysis of the General Health Questionnaire. AB - The General Health Questionnaire-28 is a well-known symptom-based rating scale of mental health. Several studies have investigated its latent structure using confirmatory factor analysis. This study questions this approach on several substantive points, most notably the inability for symptoms to interact using confirmatory factor analysis, and argues for the use of network analysis instead. Network results demonstrate the method's utility to improve our understanding of the rating scales' symptom structure. Insights include a much richer understanding of comorbidity on the General Health Questionnaire-28 and the identification of particularly salient symptoms affecting the network. It yields substantive information of interest to researchers and practitioners alike. PMID- 30411630 TI - Corrigendum. PMID- 30411631 TI - Novel nicotinamide skin-adhesive hot melt extrudates for treatment of acne. AB - OBJECTIVES: Hot melt extrusion is a continuous process with wide industrial applicability. Till current date, there have been no reports on the formulation of extrudates for topical treatment of dermatological diseases. METHODS: The aim of the present work was to prepare and characterize medicated hot melt extrudates based on Soluplus polymer and nicotinamide, and to explore their applicability in acne treatment. The extrudates were characterized using DSC, FTIR, XRD, and DVS. The extrudates were also tested for their skin adhesion potential, ability to deposit nicotinamide in different skin layers, and their clinical efficacy in acne patients. RESULTS: The 10% nicotinamide extrudates exhibited amorphous nature which was reserved during storage, with no chemical interaction between nicotinamide and Soluplus. Upon contrasting the skin adhesion and drug deposition of extrudates and nicotinamide gel, it was evident that the extrudates displayed significantly higher adhesion and drug deposition reaching 4.8 folds, 5.3 folds, and 4.3 folds more in the stratum corneum, epidermis and dermis, respectively. Furthermore, the extrudates significantly reduced the total number of acne lesions in patients by 61.3% compared to 42.14% with the nicotinamide gel. CONCLUSION: Soluplus extrudates are promising topical drug delivery means for the treatment of dermatological diseases. PMID- 30411632 TI - Combination immunotherapy in metastatic renal cell carcinoma. Are we leaving something back? PMID- 30411633 TI - Tumor-specific methylations in circulating cell-free DNA as clinically applicable markers with potential to substitute mutational analyses. AB - INTRODUCTION: Analysis of circulating tumor DNA is a promising approach to guide the treatment of cancer patients but despite large efforts it has not been broadly applied in the clinic. Technical obstacles and lack of standardization have hampered the process and it has proved challenging to make highly sensitive analyses available for all patients. Research has focused on the use of somatic mutations but because of large mutational diversity among patients the setup becomes unmanageable for daily routine use. Areas covered: Methylations are key events in cancer development and can be used as markers for the presence of circulating tumor DNA similar to how mutations have been used. This review focuses on analytical aspects and possible clinical applications of methylated ctDNA in plasma from cancer patients. Expert commentary: Technical and clinical challenges of mutation and methylation analyses are similar. However, the possibility to analyze a limited number of methylations present in all tumors of a certain type allows for proper validation and standardization of the analyses. Tumor-specific methylation analyses could supplement or substitute mutation analyses for certain clinical applications and assist the progress of the clinical use of circulating tumor DNA. PMID- 30411634 TI - Initial psychometric evaluation of the Community Participation Activation Scale. AB - BACKGROUND.: Current assessments do not capture the dynamic and complex process of managing different individual and environmental factors influencing community participation post-stroke. PURPOSE.: The purpose of this study was to examine the psychometric properties of the Community Participation Activation Scale (CPAS) in persons with stroke. METHOD.: Rating scale structure, unidimensionality, reliability and precision, construct validity, and differential item functioning of the CPAS were examined with 93 community-dwelling people with stroke. FINDINGS.: The CPAS consists of 15 action items and 10 attitude items. Person separation reliabilities of the action and attitude domains were .75 and .72, respectively, and internal consistency reliabilities were good (>.80). The CPAS showed low to moderate correlation with community integration and enfranchisement constructs. IMPLICATIONS.: The CPAS may be used as an assessment to better understand an individual's level of activation and to inform individually designed, participation-focused interventions, although it needs further improvement to be used as a clinical measure. PMID- 30411635 TI - Present and emerging pharmacotherapies for non-alcoholic steatohepatitis in adults. AB - INTRODUCTION: Multiple parallel factors are implicated in the pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). Currently recommended therapies for NASH include vitamin E and pioglitazone, besides dietary and lifestyle changes. Areas covered: This review focuses on the clinical development of several emerging drugs for the treatment of NASH and the impact of these drugs on current treatment standards. Expert opinion: Four drug classes (FXR agonists, CCR2/CCR5 antagonists, ASK1 inhibitors, and PPARalpha/delta agonists) have moved into phase 3 trials for their investigation as NASH treatments. Results from phase 2 trials of other therapeutic agents with other pharmacological actions are also expected. The importance of combinational therapies with synergistic benefits engaging different targets, is now understood. Furthermore, studies have determined that the Mediterranean diet is beneficial for patients with NAFLD, while the traditional Okinawan diet is also considered useful. In the future, it will be important to establish new biomarkers to assess NAFLD activity, furthermore non invasive diagnostic methods will promote the development of new drugs for NASH. PMID- 30411636 TI - Orthostatic hypotension in internal medicine wards. AB - OBJECTIVES: Most studies of orthostatic hypotension (OH) have focused on community-dwelling and institutionalized patient populations. Less is known about OH in hospitalized patients. Moreover, a comprehensive review of OH in internal medicine wards has not been published in the English literature. Our purpose is to provide current information regarding OH in internal medicine inpatients. METHODS: A comprehensive search of medical databases was performed for potentially relevant articles, using the following keywords: postural or orthostatic hypotension, with the combination of hospitalization or internal medicine. Inclusion criteria were: population of patients hospitalized for acute disorders in internal medicine or geriatric wards with a sample size of >=50 and publication as an original full-length article in the English language. Data from 14 selected studies are reviewed, including: pathophysiology, evaluation, prevalence, manifestations, risk factors, prognosis and management. RESULTS: OH is a common and often symptomatic disorder in elderly internal medicine patients. The prevalence of OH in this population ranges from 22% to 75%. There are substantial discrepancies between the studies reviewed regarding definitions and means of evaluating OH. OH in internal medicine wards is largely nonneurogenic and multifactorial. The main predisposing factors for OH are prolonged bed rest, hypertension and heart failure. OH in internal medicine wards is managed mainly with nonpharmacologic interventions and is frequently reversible. CONCLUSIONS: In internal medicine inpatients, OH warrants attention because this disorder is common, potentially dangerous and treatable. In the hospital setting, OH should be routinely assessed on ambulation, following the current guidelines for OH definition and meaning. PMID- 30411637 TI - Sodium-glucose co-transporter 2 inhibitors and serum uric acid. PMID- 30411638 TI - Physiological, biochemical and histopathological changes associated with heatstroke in the Galah (Eolophus roseicapilla) and Rock Dove (Columba livia). AB - The pathophysiology of heat illnesses in birds has not been well characterised. In this study, we describe the changes in heart rate, respiratory rate, blood biochemistry and histopathological findings in galahs and rock doves after heat exposure under standardized conditions designed to induce heatstroke. Birds in the heat exposed group were exposed to environmental heat stress and compared to control birds. Both groups of birds were under general anaesthesia throughout the experiment and serial blood collections were performed for biochemical analyses, while organs were collected at the end of the experiment for histopathology. No electromyography traces consistent with the onset of heat cramps were observed in any of the birds. Biochemical changes suggestive of skeletal muscle and hepatocellular injury, including hyperkalaemia and increased serum muscle and hepatic enzyme activities, were often observed in heat exposed galahs and rock doves at the onset of heatstroke. Microscopic analyses did not reveal any significant cardiac changes, although some lungs had signs of acute congestion. Some heat exposed rock doves had microscopic changes indicative of necrosis in the pectoral muscle. There were significant hepatic changes in some heat exposed galahs, but not in rock doves. This suggests that there may be species differences amongst birds in the organs most affected by heatstroke. The observed species differences in the physiological, biochemical and histopathological changes indicate that bird species should be studied separately for clinical syndromes such as heatstroke. PMID- 30411639 TI - In silico study directed towards identification of novel high-affinity inhibitors targeting an oncogenic protein: BRD4-BD1. AB - Bromodomain-containing protein 4 (BRD4) is a member of the bromodomain and extra terminal domain (BET) family of proteins. It epigentically regulates the transcription of growth-promoting genes and has become an attractive target for the development of anticancer and anti-inflammatory agents. In the current study, we performed an in silico screening of a small-molecule chemical library against the acetyl-lysine binding site of the first bromodomain (BD1) in BRD4 protein. Potential inhibitors identified through virtual screening were further studied through molecular dynamics simulations, water entrapment analysis and Molecular Mechanics (MM)/Poisson-Boltzmann surface area (PBSA) binding free energy calculations. Many of the identified compounds exhibit better G-score (-11.64 kcal?mol-1 to -10.31 kcal?mol-1) and predicted binding affinity (-9.66 kcal?mol-1 to -6.63 kcal?mol-1) values towards BRD4-BD1 than that of the reference compound (+)-JQ1. Molecular dynamics simulation studies show that in free-form BRD4 the reported conserved water molecules are not retained at their specific positoins due to flexibiliy in the ZA-loop. In BRD4-ligand complexes the number and positions of conserved water molecules depends on the bound ligand. Identified potential inhibitors bind stably at the acetyl-lysine binding pocket of BRD4 and form direct and water-mediated hydrogen bonds with higher occupancy which may contribute to ligand specificity towards BRD4-BD1. Further, through MM/PBSA we calculated the binding free energies of selected compounds, which shows that they have comparable energies to that of (+)-JQ1, while NSC744713 shows better binding free energy. PMID- 30411640 TI - An exploratory study using QICAR models for prediction of adsorption capacity of multi-walled carbon nanotubes for heavy metal ions. AB - The Quantitative Ion Character-Activity Relationship (QICAR) method was used for correlating metal ionic characteristics with the maximum adsorption capacity (qmax) of multi-walled carbon for heavy metals. The experimental values of qmax for 25 heavy metal ions, estimated by the Langmuir isotherm model, were used to construct a QICAR model. The genetic algorithm, enhanced replacement method and successive projection algorithm procedures were applied as variable selection algorithms to choose the optimal subsets of descriptors. The selected variables were correlated with qmax values by using partial least squares (PLS) regression. Orthogonal signal correction was applied as a pre-processing technique. Among of different variable selection methods, the enhanced replacement method displayed noticeable statistical parameters of the final model. The results of the enhancement replacement method-orthogonal correction signal-PLS model, with RMSEC = 0.733, r2c = 0.999 and r2p = 0.946, were excellent and dramatically better than those of other models. The developed QICAR model satisfied the internal and external validation criteria. The importance of electronegativity, ionic radius and atomic number of the heavy metal ions indicated the impact of the tendency to accept electrons and the size of ions in adsorption on carbon nanotubes. PMID- 30411641 TI - DFT-based theoretical prediction of intrinsic viscosity of polymer solutions. AB - A four-descriptor quantitative structure-property relationship model was constructed to predict 65 intrinsic viscosities [eta] of polymer solutions. Four quantum chemical descriptors, the traceless quadrupole moment theta(R), the hydrogen bond or electrostatic attraction descriptor QH, the partition function QBOT(R) and the frontier orbital descriptor EHOMO, were calculated with density functional theory at the B3LYP/6-31G(d) level and used to develop the model by multivariate linear regression (MLR) analysis. The model possesses coefficients of determination r2 of 0.827 for the training set and 0.808 for the test set, and shows better statistical characteristics than the existing MLR models of intrinsic viscosities [eta] of polymer-solvent combinations. Moreover, the four descriptors were used to develop a support vector machine model for [eta] that possesses a coefficient of determination r2 of 0.911 for the whole data set. PMID- 30411643 TI - Executive Summary of Key Concepts. PMID- 30411642 TI - EBD at the Macro Level: How Research Informs Policy. PMID- 30411644 TI - Creating a Culture of Inquiry in Your Organization. PMID- 30411645 TI - From Evolutive Paranoia, by August Wimmer (1902). AB - Literature on the history of 'paranoia' (as a clinical concept) is large and confusing. This is partly explained by the fact that over the centuries the word 'paranoia' has been made to participate in several convergences (clinical constructs), and hence it has named different forms of behaviour and been linked to different explanatory concepts. The Classic Text that follows provides information on the internal clinical evolution of the last convergence in which 'paranoia' was made to participate. August Wimmer maps the historical changes of ' Verrucktheit' as it happened within the main European psychiatric traditions since the early 19th century. After World War II, that clinical profile was to become reified and renamed as 'delusional disorder'. PMID- 30411646 TI - Time for patient reported outcomes assessment in routine hematology practice: the case of chronic myeloid leukemia. PMID- 30411647 TI - Chemical management of levodopa-induced dyskinesia in Parkinson's disease patients. AB - INTRODUCTION: Levodopa-induced dyskinesias (LID) appears in more than 50% of Parkinson's disease patients after 5 years of treatment and clinicians always have to ensure that there is a balance between the beneficial effect of the treatment and the potential complications. Areas covered: In this review, the authors discuss the treatment of LID. Treatment can be divided into strategies for preventing their occurrence, modification of dopaminergic therapy, and providing more continuous dopaminergic stimulation as well as the use of nondopaminergic drugs. Expert opinion: Amantadine is currently considered the most effective drug for the treatment of LID. Several compounds developed to target adenosine, adrenergic, glutamatergic, and serotonergic receptors have shown to significantly decrease dyskinesias in animal models. However, despite promising preclinical results, translation to clinical practice remains challenging and majority of these compounds failed to decrease LID in randomized controlled trials with moderate-to-advanced parkinsonian patients. Despite promising results with nondopaminergic drugs, treatment of dyskinesias is still challenging and largely due to their side effects. Future research should focus on developing treatments that can provide continuous dopaminergic delivery throughout the day in a noninvasive manner. Studies on the impact of the early administration of long-acting formulations of levo-3,4-dihydroxy-phenylalanine on dyskinesias are also necessary. PMID- 30411648 TI - Oncologic Emergencies-The Old, the New, and the Deadly. AB - Cancer continues to be a leading cause of death despite a broader understanding of its biology and the development of novel therapies. Nonetheless, with an increasing survival of this population, intensivists must be aware of the associated emergencies, both old and new. Oncologic emergencies can be seen as an initial presentation of the disease or precipitated by its treatment. In this review, we present key oncologic emergencies that may be encountered in daily practice, complications associated with innovative therapies, and treatment related adverse events. PMID- 30411649 TI - Gustav Born: pioneer in imaging platelet and leukocyte biology. AB - Gustav Born achieved scientific fame for his application of light transmission aggregometry to the study of platelet function, but also led interdisciplinary research teams in pioneering quantitative in vivo imaging studies of platelet aggregation and leukocyte adhesion, and in conducting the first research into the biomechanical factors underlying atherosclerotic plaque rupture. Gus Born also communicated both current research findings and an integrated understanding of cardiovascular biology to a wide audience through acting as scientific advisor on several television productions. Using footage from two of these films, we discuss Gustav Born's scientific achievements and legacy. PMID- 30411650 TI - Update on current approaches to diagnosis and treatment of onychomycosis. AB - INTRODUCTION: Onychomycosis is a chronic fungal infection of the nail bed, matrix or plate. It accounts for roughly 50% of all nail disease. As the prevalence of onychomycosis is increasing, a critical review of diagnostic techniques and treatment options is required. Areas covered: This review discusses the current diagnostic techniques associated with diagnosing onychomycosis, such as microscopy, culture, periodic acid Schiff stain (PAS) and polymerase chain reaction (PCR). Oral and topical therapies are also discussed, as well as, the utility of device-based treatments and combination therapy. Expert commentary: Culture for the diagnosis of onychomycosis is the gold standard; however, PCR is more sensitive and should be considered. In general, topical treatments are recommended for mild to moderate disease and oral treatments should be considered for moderate to severe disease. Combination therapy and device-based treatments may enhance cure rates, further study is required. PMID- 30411651 TI - Pornography consumption and psychosomatic and depressive symptoms among Swedish adolescents: a longitudinal study. AB - BACKGROUND: The aims of this longitudinal study were to identify predictors for continued pornography consumption and to investigate pornography consumption in relation to psychosomatic and depressive symptoms among a group of adolescents in Sweden. METHODS AND MATERIALS: A longitudinal study in classroom environment in 53 randomly selected senior high school classes in mid-Sweden in years 2011 and 2013. Out of 477 participating boys and 400 girls in 2011, 224 boys (47%) and 238 girls (60%) participated in 2013. RESULTS: Higher pornography consumption at baseline and being born outside Sweden predicted continued pornography consumption at follow-up (adjusted R2 = 0.689). Psychosomatic symptoms at follow up were predicted by higher pornography consumption at baseline (adjusted R2 = 0.254), being a girl, living with separated parents, and attending a vocational high school program. By contrast, depressive symptoms at follow-up were predicted by less pornography consumption at baseline (adjusted R2 = 0.122) and being a girl. CONCLUSIONS: Pornography consumption may, for some individuals, be associated to mental health issues. Differences between teenage boys and girls and between adolescents with diverse ethnic backgrounds imply that counseling and discussion about pornography need to be adjusted and individualized. PMID- 30411652 TI - From sameness to difference: Swedish Somalis' post-migration perceptions of the circumcision of girls and boys. AB - In every society where non-therapeutic female circumcision (FC) occurs, so too does non-therapeutic male circumcision (MC). In the past few decades, the norm in Euro-American societies has been to distinguish between the practices: FC is banned, while MC is condoned or encouraged. We explored Somalis' post-migration perceptions of FC and MC, while considering that they once lived in a society where both practices were widely accepted and now live in a society where there is a legal ban on FC alongside acceptance of MC. Eighteen individual interviews and seven focus group discussions were conducted with Somali men and women in three Swedish cities. There seemed to be a continuity of values across male and female forms of genital cutting concerning being a good Muslim, not inflicting harm and upholding respectability. Following migration, however, a renegotiation of how these values relate to MC and FC resulted in a conceptual split between the two: MC was perceived as an unquestionably required practice, but FC was viewed as a practice that can be adapted or abandoned. In a new cultural context after migration, perceptions of ideal male and female genitals, and what kinds of inscriptions on the body are desired, seem to have changed. PMID- 30411653 TI - Avatars in Pain: Visible Harm Enhances Mind Perception in Humans and Robots. AB - Previous research has shown that when people read vignettes about the infliction of harm upon an entity appearing to have no more than a liminal mind, their attributions of mind to that entity increased. Currently, we investigated if the presence of a facial wound enhanced the perception of mental capacities (experience and agency) in response to images of robotic and human-like avatars, compared with unharmed avatars. The results revealed that harmed versions of both robotic and human-like avatars were imbued with mind to a higher degree, irrespective of the baseline level of mind attributed to their unharmed counterparts. Perceptions of capacity for pain mediated attributions of experience, while both pain and empathy mediated attributions of abilities linked to agency. The findings suggest that harm, even when it appears to have been inflicted unintentionally, may augment mind perception for robotic as well as for nearly human entities, at least as long as it is perceived to elicit pain. PMID- 30411654 TI - Adalimumab versus adalimumab and methotrexate for the treatment of juvenile idiopathic arthritis: long-term data from the German BIKER registry. AB - OBJECTIVE: Adalimumab (ADA) has become a valuable treatment option for juvenile idiopathic arthritis (JIA). The importance of combination with methotrexate (MTX) is unclear. METHOD: Data from the German Biologics in Paediatric Rheumatology (BIKER) registry are reported. Response to treatment was analysed using JIA American College of Rheumatology (ACR) scores, 10-joint Juvenile Arthritis Disease Activity Score (JADAS10), and improvement of functional status and ACR inactive disease criteria. Compa-risons between rates of adverse events (AEs) and serious adverse events (SAEs) provided data for the safety assessment. RESULTS: Overall, 584 patients with non-systemic JIA started ADA therapy, 61% of whom received concomitant MTX treatment at baseline. The latter patients were younger (p < 0.001), with shorter disease duration (p = 0.001), more frequently had antinuclear antibodies (p = 0.04), and had higher baseline JADAS10 scores (p = 0.03). In patients with ADA monotherapy, enthesitis-related arthritis (p = 0.004) and presence of human leucocyte antigen-B27 (p = 0.008) were documented more often. Mean treatment duration in both cohorts was 15 months. Comparable last follow-up rates for JIA ACR 30/50/70/90% response, JADAS minimal disease activity, JADAS remission, and ACR inactive disease were, respectively, 75/72/64/49%, 66%, 46%, and 58% for ADA monotherapy, and 77/72/61/45%, 64%, 48%, and 55%, for ADA + MTX. During 1082 patient-years (PY) of ADA exposure, 725 AEs (67/100 PY), including 57 SAEs (5.3/100 PY), were reported. Serious infections were reported in 10 patients (0.9/100 PY) and 11 (1.0/100 PY) had varicella infections/zoster reactivation. Rates of AEs, SAEs, infectious events, and serious infections did not differ between the cohorts. Elevated transaminases (p = 0.005) and gastrointestinal events (p < 0.0001) were reported more often in the combination cohort. Two pregnancies and no deaths were reported. CONCLUSION: ADA demonstrated an acceptable risk profile and high percentages of patients in both cohorts showed sufficient treatment response. No differences in treatment response or adherence to treatment were found. PMID- 30411655 TI - Patient reported outcome measures of upper limb function in multiple sclerosis: A critical overview. PMID- 30411656 TI - Theoretical foundations of narrative care: Turning towards relational ethics. AB - In the past decades, narrative practices have been developed, and care has been conceptualized as being narrative in nature. More recently, narrative care has been developing both as a practice and a field of study. It is necessary to make the theoretical foundations of narrative care visible to avoid the risk of narrowly defining narrative care as a matter of storytelling and listening. In this article, we develop an understanding of narrative care grounded in early feminist pragmatist philosophy, with a focus on social and political activism and experience. Pragmatism holds the possibilities to open spaces for realities that are constantly in flux and for emergent situations that must be considered across time, diverse places and social contexts. With the aid of Vera's stories about her relationship with Tammy, we demonstrate the importance of recognizing that realities are multiple, complex and uncertain. Furthermore, we discuss how the stronghold of formula stories and issues of power, positioning and inequities, restrict people's possibilities to be, become and co-author their stories. We also argue that the playfulness, imagination and world travelling of narrative care are in line with early feminist pragmatism, which draws on a wide and diverse range of experiences. Jane Addams linked democracy to dialogue, joint experiences and social equality. This calls for the development of ethical frameworks grounded in care that are more specifically focused on relational ethics and a commitment to dialogical and relational democracy and the prioritization of community. PMID- 30411657 TI - Structural justice and nursing: Inpatient nurses' obligation to address social justice needs of patients. AB - As inpatient nurses spend the majority of their work time caring for patients at the bedside, they are often firsthand witnesses to the devastating outcomes of inadequate preventive healthcare and structural injustices within current social systems. This experience should obligate inpatient nurses to be involved in meeting the social justice needs of their patients. Many nursing codes of ethics mandate some degree of involvement in the social justice needs of society, though how this is to be achieved is not detailed in these general guidelines. Acknowledging an explicit obligation for inpatient nurses to address the social justice issues of their patients would facilitate better overall understanding of social justice issues and reduce preventable admissions. If implementation of such an obligation is done with care, having inpatient nurses participate in justice projects could also mitigate compassion fatigue, allow for better job satisfaction among these nurses, and provide a sense of revitalization in nurses' role as health promoters. PMID- 30411658 TI - Development of the Arm Function in Multiple Sclerosis Questionnaire-Short Form (AMSQ-SF): A static 10-item version. AB - BACKGROUND:: Assessing arm and hand function of multiple sclerosis (MS) patients is important as impaired functioning may impact daily activities and reduce quality of life. OBJECTIVE:: A short-form of the Arm Function in Multiple Sclerosis Questionnaire (AMSQ), a recently developed patient-reported outcome measure containing 31 items, is developed to allow non-adaptive application. METHODS:: Complete data from 690 patients with MS, recruited via outpatient clinics, a residential center or via a Dutch website aimed at MS patients, were included in the analyses. A graded response model was fit to these data to estimate item response theory (IRT) parameters, which were used to perform post hoc computerized adaptive test (CAT) simulations with a cutoff standard error of measurement (SEM) of 0.32. The optimal test length was determined by the correlation between the static short-form and full-length theta, the mean SEM, and the amount of patients reaching a satisfactory SEM in CAT simulations. RESULTS AND CONCLUSION:: Based on five selection criteria (i.e. discrimination parameters, total information, times selected in CAT simulations, raw item means, and item content), 10 items were selected for inclusion in the short-form. The score on the final 10-item short-form correlated strongly with the full-length AMSQ and provided reliable ability estimations, indicating its usefulness instrument in research and clinical settings. PMID- 30411659 TI - Perioperative point of care platelet function testing and postoperative blood loss in high-risk cardiac surgery patients. AB - Postoperative coagulopathic bleeding is common in cardiac surgery and associated with increased morbidity and mortality. Platelet function is affected by multiple factors, including patient and procedural characteristics. Point-of-care (POC) multiple electrode aggregometry (MEA) can rapidly detect and quantify platelet dysfunction and could contribute to optimal patient blood management. In patients undergoing CABG and heart valve surgery platelet function was assessed using POC MEA at four different perioperative timepoints in response to stimulation with four specific receptor agonists (ADP, AA, COL, TRAP). Postoperative bleeding was recorded during 24 h after surgery. Regression analyses were performed to establish associations between perioperative platelet function and postoperative blood loss. Ninety-nine patients were included in the study. Fifty-nine patients (60%) were on antiplatelet therapy (APT) at time of surgery. ADP- and AA-induced platelet aggregation declined during CPB and after decannulation from CPB, with a maximum decrease of 55% for ADP (35 vs. 77 AU at baseline; P < 0.001) and 78% for ASPI (14 vs. 64 AU at baseline; P < 0.001). A linear relationship was present between ADP-induced platelet aggregometry at baseline and postoperative blood loss (r = -0.249; P = 0.015). In aspirin users, the maximum decline in platelet function between baseline and CPB decannulation was related to postoperative blood loss (r = 0.308; P = 0.037). In multivariate analysis, a reduced ADP platelet function prior to surgery remained associated with postoperative blood loss (r = -0.239; P = 0.012). Reduced ADP-induced platelet aggregation at baseline is associated with increased postoperative blood loss in high-risk cardiac surgery patients. PMID- 30411660 TI - Moral distress in paediatric oncology: Contributing factors and group differences. AB - BACKGROUND:: Providing oncological care to children is demanding and ethical issues concerning what is best for the child can contribute to moral distress. OBJECTIVES:: To explore healthcare professionals' experiences of situations that generate moral distress in Swedish paediatric oncology. RESEARCH DESIGN:: In this national study, data collection was conducted using the Swedish Moral Distress Scale-Revised. The data analysis included descriptive statistics and non parametric analysis of differences between groups. PARTICIPANTS AND RESEARCH CONTEXT:: Healthcare professionals at all paediatric oncology centres in Sweden were invited to participate. A total of 278 healthcare professionals participated. The response rate was 89%. ETHICAL CONSIDERATIONS:: In its advisory statement, the Regional Ethical Review Board decided that the study was of such a nature that the legislation concerning ethical reviews was not applicable. All participants received written information about the aim of the study and confidentiality. Participants demonstrated their consent by returning the survey. FINDINGS:: The two situations with the highest moral distress scores concerned lack of competence and continuity of personnel. All professional groups reported high levels of disturbance. Nurses rated significantly higher frequencies and higher total Moral Distress Scale scores compared to medical doctors and nursing assistants. DISCUSSION:: Lack of competence and continuity, as the two most morally distressing situations, confirms the findings of studies from other countries, where inadequate staffing was reported as being among the top five morally distressing situations. The levels of total Moral Distress Scale scores were more similar to those reported in intensive care units than in other paediatric care settings. CONCLUSION:: The two most morally distressing situations, lack of competence and continuity, are both organisational in nature. Thus, clinical ethics support services need to be combined with organisational improvements in order to reduce moral distress, thereby maintaining job satisfaction, preventing a high turnover of staff and ensuring the quality of care. PMID- 30411661 TI - Diagnostic pathway efficacy for urinary tract cancer: population-based outcome of standardized evaluation for macroscopic haematuria. AB - OBJECTIVE: This study assessed a national healthcare intervention launched in Sweden in 2015 to reduce the time between macroscopic haematuria, diagnosis and treatment of urinary tract cancer. METHODS: The outcome of the first 11 months was evaluated in 1697 individuals referred to a standardized care pathway for urinary tract cancer compared with 174 patients with conventionally diagnosed urothelial carcinoma. RESULTS: Among the referred individuals, 317 (19%) were diagnosed with cancer, 1034 (61%) had a benign diagnosis and 345 (20%) had a negative evaluation. Bladder cancer was the most common malignant diagnosis [262/317 (83%)]. Cancers were diagnosed in 23% of males and 13% of females, and showed a strong correlation with age: cancer diagnosis in 2% aged <50 years and in 44% aged >=90 years. Results were affected by bacteriuria but not by anticoagulant medication, with 12%/22% and 19%/19% cancer detection, respectively. The standardized care pathway shortened the diagnostic delay to a median of 25 days compared to 35 days for regular referral (p = .01). However, median time to treatment was unchanged: 39 days from referral to transurethral resection, 42 days from primary resection to re-resection for stage TaG3/T1 disease and 100 days from referral to curative treatment for muscle-invasive disease. CONCLUSIONS: Macroscopic haematuria had a cancer capture rate of 19%, with higher predictive values in men and at older age, whereas anticoagulant therapy did not influence the diagnostic yield. The demonstrated lack of effect on time to treatment underscores the need to consider the entire patient process when initiating healthcare reforms to improve outcome. PMID- 30411663 TI - Supported housing for persons with serious mental illness and personal recovery: What do families think? AB - BACKGROUND AND AIMS:: Previous research on supported housing for people with serious mental illness focuses primarily on tenant/client experiences. The aim of this article is to present families' perspectives on the role of supported housing in recovery, utilizing the CHIME framework of personal recovery. METHOD:: Qualitative interviews were conducted with 14 families of individuals with serious mental illness living in supported housing. Participants were across five supported housing sites in four Canadian provinces. RESULTS:: Families credited supported housing with helping tenants redefine a positive sense of identity, re establish social relationships and regain control over their lives. Families were less confident about supported housing facilitating future employment or 'full' recovery, focusing on stability rather than continual improvement. CONCLUSION:: This is one of the first studies to report family perspectives on the role of supported housing in their loved one's recovery processes - both strengths and weaknesses. PMID- 30411662 TI - Prognostic Value of Mismatch Repair Genes for Patients With Colorectal Cancer: Meta-Analysis. AB - DNA mismatch repair was proposed to play a pivotal role in the development and prognosis of colorectal cancer. However, the prognostic value of mismatch repair on colorectal cancer is still unknown. The PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched. The articles about mismatch repair (including hMLH1, hMSH2, hMSH3, hMSH6, hPMSH1, and hPMSH2) deficiency for the prognosis of patients with colorectal cancer were included in the study. The hazard ratio and its 95% confidence interval were used to measure the impact of mismatch repair deficiency on survival time. Twenty-one articles were included. The combined hazard ratio for mismatch repair deficiency on overall survival was 0.59 (95% confidence interval: 0.50-0.69) and that on disease-free survival was 0.57 (95% confidence interval: 0.43-0.75). In subgroup analysis, there were a significant association between overall survival and mismatch repair deficiency in Asian studies (hazard ratio: 0.67; 95% confidence interval: 0.50-0.91) and Western studies (hazard ratio: 0.56; 95% confidence interval: 0.46-0.67). For disease-free survival, the hazard ratios in Asian studies and Western studies were 0.55 (95% confidence interval: 0.38-0.81) and 0.62 (95% confidence interval: 0.50-0.78), respectively. Our meta-analysis indicated that mismatch repair could be used to evaluate the prognosis of patients with colorectal cancer. PMID- 30411664 TI - Long-term control of abdominal pain related to POTS: two case reports in pediatrics. AB - AIM: To describe two consecutive cases of Postural Orthostatic Tachycardia Syndrome (POTS)-related chronic abdominal pain control in children after bilateral splanchnic block. PATIENTS & METHODS: Two pediatric patients with chronic abdominal pain related to POTS received celiac and T11 splanchnic plexus block for pain control. RESULTS: While celiac plexus block did not provide any substantial relief of their pain, splanchnic block provided a long-term improvement in pain scores, nausea and vomiting cessation. CONCLUSION: Bilateral T11 splanchnic block should be considered in patients with POTS-related chronic abdominal pain, nausea and vomiting. PMID- 30411665 TI - Oral pain associated with cancer therapy, a pain medicine perspective. AB - Cancer therapy-induced oral mucositis (CTIOM) can cause intolerable oral pain resulting in difficulty in chewing, swallowing and speaking. Thus, leading to patients requiring aggressive measures, such as parenteral feeding, the placement of gastric feeding tubes and discontinuation of oncologic treatments. Although, pain is the debilitating symptom, current efforts seem to focus independently in the histological damage, not in pain and symptom care. Current strategies for managing pain from CTIOM entail maintaining oral hygiene and the use of oral rinses, topical anesthetics, prophylactic antimicrobials and systemic analgesics such as opioids. Novel therapies, such as methylene blue oral rinse, are being investigated, with positive outcomes. Therefore, there is a need to identify treatment modalities for pain of CTIOM. Ideally, this should be noninvasive, safe and cost-effective, while providing sustained analgesia. PMID- 30411667 TI - The problem or the solution? Early fertility and parenthood in the transition to adulthood in Khayelitsha, South Africa. AB - In South Africa, early fertility and teenage pregnancy have become a central focus of both political and public health concern. In this article, we explore the ways that young men and women have used their fertility and performance of parenthood to navigate the transition from childhood to adulthood. For these young people, the persistent inequities related to income poverty, inadequate education, lack of employment opportunities and a high burden of disease remain significant barriers to achieving this transition. This article draws on ethnographic data collected between 2014 and early 2016 with young adults (17-25 years) in Town Two, Khayelitsha. Participant observation was the primary data collection method. Narratives and experiences of 15 young people are presented here. We argue that in addition to immediate fertility desires, young people's contraceptive decision-making was significantly shaped by gendered ideals and social norms. Young women's fertility operated as both an aspiration and a threat within partnerships. Some couples partially achieved relationship stability or longevity through having a child. Entering parenthood in the context of a seemingly stable relationship was perceived as a movement towards an accepted, albeit tenuous, form of social adulthood. Although living up to the ideal of good parent was challenging, it was partially achieved by young mothers who provided care and young fathers who provided financially for children. In the absence of other accepted markers of transition to adulthood and within a context of deprivation and exclusion, early fertility, though clearly a public health problem, can become a solution to social circumstances. PMID- 30411666 TI - Performance Comparison of Knowledge-Based Dose Prediction Techniques Based on Limited Patient Data. AB - PURPOSE:: The accuracy of dose prediction is essential for knowledge-based planning and automated planning techniques. We compare the dose prediction accuracy of 3 prediction methods including statistical voxel dose learning, spectral regression, and support vector regression based on limited patient training data. METHODS:: Statistical voxel dose learning, spectral regression, and support vector regression were used to predict the dose of noncoplanar intensity-modulated radiation therapy (4pi) and volumetric-modulated arc therapy head and neck, 4pi lung, and volumetric-modulated arc therapy prostate plans. Twenty cases of each site were used for k-fold cross-validation, with k = 4. Statistical voxel dose learning bins voxels according to their Euclidean distance to the planning target volume and uses the median to predict the dose of new voxels. Distance to the planning target volume, polynomial combinations of the distance components, planning target volume, and organ at risk volume were used as features for spectral regression and support vector regression. A total of 28 features were included. Principal component analysis was performed on the input features to test the effect of dimension reduction. For the coplanar volumetric modulated arc therapy plans, separate models were trained for voxels within the same axial slice as planning target volume voxels and voxels outside the primary beam. The effect of training separate models for each organ at risk compared to all voxels collectively was also tested. The mean squared error was calculated to evaluate the voxel dose prediction accuracy. RESULTS:: Statistical voxel dose learning using separate models for each organ at risk had the lowest root mean squared error for all sites and modalities: 3.91 Gy (head and neck 4pi), 3.21 Gy (head and neck volumetric-modulated arc therapy), 2.49 Gy (lung 4pi), and 2.35 Gy (prostate volumetric-modulated arc therapy). Compared to using the original features, principal component analysis reduced the 4pi prediction error for head and neck spectral regression (-43.9%) and support vector regression (-42.8%) and lung support vector regression (-24.4%) predictions. Principal component analysis was more effective in using all/most of the possible principal components. Separate organ at risk models were more accurate than training on all organ at risk voxels in all cases. CONCLUSION:: Compared with more sophisticated parametric machine learning methods with dimension reduction, statistical voxel dose learning is more robust to patient variability and provides the most accurate dose prediction method. PMID- 30411668 TI - Regional Draining Lymph Nodes: Considerations for Medical Device Studies. AB - Lymph nodes and associated lymphatics filter extracellular fluid and lymph to maintain tissue-fluid balance and detect distant tissue injury. Examination of regional draining lymph nodes (RDLs; lymph nodes that drain the route of article dosing) is an important step in detecting immunotoxicity and other associated changes during general toxicology studies. Similarly, evaluation of RDLs is often a key component of evaluating medical devices. Nonclinical medical device studies can present challenges for RDL evaluation, due to the wide variety of tissues and organs that are implanted with devices, the potential for wear debris/degradation products, and the likely disruption of normal lymphatic drainage by surgical procedures. This article discusses concepts for consideration when designing a nonclinical medical device study that includes the macroscopic evaluation, collection, histologic processing, microscopic assessment, and documentation of findings within RDLs. References describing RDLs for common implantation sites are reported, as are considerations for specific tissues and species commonly used in medical device biocompatibility and functional testing. PMID- 30411669 TI - BiPAP Noninvasive Ventilation in Patients With Acute Heart Failure and Left Ventricular Systolic Dysfunction Without Control of Confusing Variables. PMID- 30411670 TI - Cytomorphometric Neutrophil and Monocyte Markers May Strengthen the Diagnosis of Sepsis. AB - BACKGROUND:: The diagnosis of sepsis is challenging in the absence of a gold standard test. Recent studies have explored the role of neutrophil and monocyte volume, conductivity, and scatter (VCS), derived from automated hematology analyzers, in diagnosing sepsis. We assessed the diagnostic accuracy of VCS parameters in critically ill patients with sepsis. METHODOLOGY:: In this prospective study, VCS parameters, procalcitonin, and C-reactive protein (CRP) were assessed in patients with proven sepsis (cases) and 2 control groups (intensive care unit [ICU] patients without sepsis and healthy blood donors). The diagnostic property of each test was explored by calculating sensitivity, specificity, negative and positive predictive values, and area under the curve (AUC). RESULTS:: The study included 65 patients with sepsis, 58 nonseptic ICU controls, and 98 blood donors. Procalcitonin and CRP were not significantly different ( P > .06) between patients with sepsis and nonseptic patients. Mean (95% confidence interval [CI]) neutrophil volume (MNV) was significantly higher ( P < .001) in patients with sepsis (165.5; 95%CI 161.6-169.4) than in nonseptic (157.3; 95%CI 154.6-160.1) patients and donors (148.9; 95%CI 147.9-150). A similar pattern was seen with mean monocyte volume (MMoV). Neutrophil and monocyte conductivity and scatter parameters were variably associated. The AUC was highest for MMoV (0.74) and lowest for CRP (0.62). Among all parameters, MNV and MMoV had the highest specificity of 85% and 80%, respectively. CONCLUSION:: In critically ill patients with suspected sepsis, VCS parameters may help strengthen the diagnostic probability of sepsis. Future studies may explore the role of serial monitoring of VCS to track response to antimicrobial therapy. PMID- 30411671 TI - Hyperacute Hemodynamic Effects of BiPAP Noninvasive Ventilation: To(o) Di(uretics) or Not To(o) Di(uretics)? PMID- 30411672 TI - Interhospital Transfer of Children in Septic Shock: A Clinician Interview Qualitative Study. AB - OBJECTIVE:: To determine the factors that influence the decision to transfer children in septic shock from level II to level I pediatric intensive care unit (PICU) care. DESIGN:: Interviews with level II PICU physicians in Michigan and Northwest Ohio. A hypothetical scenario of a 14-year-old boy in septic shock was presented. BASELINE:: 40 mL/kg fluid resuscitation, central venous and peripheral arterial access, and high-dose vasopressor infusions were provided. ESCALATION POINT:: After 2 hours. When the patient is in catecholamine-resistant shock and oliguric, invasive mechanical ventilation is initiated. MEASUREMENTS AND MAIN RESULTS:: All 19 eligible physicians participated. At baseline, respondents would assess measures of perfusion and hemodynamics: blood pressure (BP; 15 [79%]), lactate (12 [63%]), and central venous oxygen saturation (ScvO2; 10 [53%]). Poor clinical response was signified by low BP (11 [58%]), elevated lactate (9 [47%]), low urine output (8 [42%]), and low ScvO2 (6 [32%]). At the escalation point, 13 of 18 respondents felt there was <50% probability of clinical turnaround without escalating treatment, though only 3 (16%) would call to discuss transfer. Seven (37%) respondents would give more fluid, whereas 8 (42%) would use central venous pressure to guide fluid resuscitation. Ultimately, 15 (79%) respondents would transfer for extracorporeal membrane oxygenation (ECMO) or renal replacement therapy if there was no response to escalated care. Four (21%) respondents would not transfer the patient: 1 felt appropriate care could be provided in the level II PICU, 2 felt transfer was unconventional, and 1 was unaware ECMO could be provided in refractory septic shock. CONCLUSIONS:: Level II to level I PICU transfer of children with septic shock is triggered by perceived nonresponse to locally available therapies. Few referring physicians do not transfer children in refractory septic shock. This study provides new insight into decision-making that influences the interhospital transfer of children with septic shock. PMID- 30411674 TI - Reduced Gait Variability and Enhanced Brain Activity in Older Adults With Auditory Cues: A Functional Near-Infrared Spectroscopy Study. AB - BACKGROUND: Aging is associated with declining mobility, which negatively affects quality of life and incurs substantial economic costs. Techniques to maintain safe mobility in older adults are therefore essential. Rhythmic auditory cueing (RAC) can improve walking patterns in older adults. However, the neural correlates associated with RAC, how they are influenced by repeated exposure and their relationships with gait response, cognitive function, and depressive symptoms are unclear. OBJECTIVES: This study aimed to investigate the effects of RAC during walking on cortical activation and the relationship between RAC related cortical changes and cognitive function, depressive symptoms, and gait response. METHODS: Seventeen young adults and eighteen older adults walked on a motorized treadmill for 5 minutes (5 trials with alternating 30-second blocks of usual walking and RAC walking). Changes in oxygenated hemoglobin (HbO2) in the frontal cortex were recorded using functional near-infrared spectroscopy. Cognitive domains were assessed through validated tests. A triaxial accelerometer measured gait parameters. RESULTS: Gait variability decreased and prefrontal HbO2 levels increased during cued walking relative to usual walking. Older adults showed greater HbO2 levels in multiple motor regions during cued walking although the response reduced with repeated exposure. In older adults, lower depression scores, higher cognitive functioning, and reduced gait variability were linked with increased HbO2 levels during RAC walking. CONCLUSION: These findings suggest that walking improves with RAC in older adults and is achieved through increased activity in multiple cortical areas. The cortical response decline with repeated exposure indicates older adults' ability to adapt to a new task. PMID- 30411673 TI - Electroporation of the Liver: More Than 2 Concurrently Active, Curved Electrodes Allow New Concepts for Irreversible Electroporation and Electrochemotherapy. AB - Irreversible electroporation and electrochemotherapy are 2 innovative electroporation-based minimally invasive therapies for the treatment of cancer. Combining nonthermal effects of irreversible electroporation with local application of chemotherapy, electrochemotherapy is an established treatment modality for skin malignancies. Since the application of electrochemotherapy in solid organs is a promising approach, this article describes a novel electrode configuration and field generating method. For the treatment of hepatic malignancies, the shape of the electric field should resemble a spherical 3 dimensional geometry around the target tissue inside the liver. To adapt the actual shape of the field, the probe is designed in computer-aided design with a live link to a computer simulation software: Changes in design can be revalued quickly, regarding different quality criteria for field strength inside and outside the tumor. To rate these criteria, a set of formulas with weighting coefficients has been included. As a result of this design process, a needle shaped prototype applicator has been built, designed for an intracorporal electroporation-based treatment. It can be used as percutaneous, image-guided, minimally invasive treatment option for malignant liver tumors. The shaft of the probe is used as central electrode and fitted with additional 4 expandable electrodes. These satellite electrodes are hollow, thus serving as injectors for chemotherapeutic agents within the area of the electric field. This configuration can be used for electrochemotherapy as well as irreversible electroporation. By placing 5 electrodes with just one needle, the procedure duration as well as the radiation dose can be reduced tremendously. Additionally, the probe offers an option to adapt the field geometry to the tumor geometry by connecting the 5 electrodes to 5 individually chosen electric potentials: By fine-tuning the ablation zone via the potentials instead of adjusting the location of the electrode(s), the procedure duration as well as the radiation dose will decrease further. PMID- 30411675 TI - Relationships Between Affected-Leg Motor Impairment, Postural Asymmetry, and Impaired Body Sway Control After Unilateral Supratentorial Stroke. AB - BACKGROUND: The relationships between motor impairment of the affected leg, postural control asymmetry, and impaired body sway control after stroke are not well understood. OBJECTIVE: To examine the relationship between motor impairment of the affected leg and reduced contribution of this leg to body sway control (ie, dynamic control asymmetry [DCA]) and to determine the relationships between impaired body sway control, DCA, and weight-bearing asymmetry (WBA). METHODS: We assessed quiet-standing balance with eyes open in 70 persons with a unilateral supratentorial chronic stroke using 2 force plates. Center-of-pressure (COP) velocity was calculated for both feet together in the anteroposterior (AP) and mediolateral (ML) directions as a measure of body sway control. Bilateral AP COP velocities were used to calculate an index for DCA and weight borne on each side to calculate WBA. Fugl-Meyer assessment of the lower extremity (FMA-LE; range: 0 28) served as a measure of affected-leg motor impairment. RESULTS: All participants with FMA-LE <24 showed pronounced DCA, but this was also true for 21% of those with FMA ?24. Higher DCA values were related to more WBA ( rs = 0.496; P < .001), and less ML sway control ( rs = 0.268; P = .025). AP sway control was not significantly related to either DCA or WBA. CONCLUSIONS: Even clinically well-recovered stroke survivors with (near) maximal FMA-LE scores may show clear postural asymmetry in terms of the relative contribution of the affected leg to body sway control. WBA seems to be an effective compensatory mechanism to optimize the contribution of the less-affected leg to balance, particularly in the AP direction. PMID- 30411677 TI - Emerging trends in Advanced Nanomaterials based electrochemical genosensors. AB - Advanced nanomaterials indubitably represent one of the most propitious classes of new materials due to their intriguing optical, electronic and redox properties. The incredible progress achieved in this research area has been propelled by the development of novel synthetic procedures owing to the emergence of nanotechnology and by the wide range of applications. These nanostructured materials possess high surface area, biocompatibility, nontoxicity and charge sensitive conductance which have led to the development of simple, rapid, highly sensitive, inexpensive and portable electrochemical genosensors. This review accentuates on the development and validation of various advanced nanomaterials based electrochemical genosensors that utilizes unique properties of nanomaterials for signal transduction purpose or as an electroactive species for direct detection of analyte. The intent is to highlight the recent progress on highly sensitive and flexible nanostructured material based electrochemical genosensors that have the potential to be developed as the next generation field deployable analytical tools. PMID- 30411678 TI - Metabolic Stress and Inflammation: Implication in Treatment for Neurological Disorders. AB - [. PMID- 30411679 TI - Aryl hydrocarbon receptor: its regulation and role in tumorigenesis. AB - AhR is an environmental response gene that mediates cellular responses to a variety of xenobiotic compounds that frequently function as AhR ligands. Many AhR ligands are classified as carcinogens or pro-carcinogens. Thus, AhR itself acts as a major mediator of the carcinogenic effect of many xenobiotics in vivo. In this concise review, mechanisms by which AhR trans-activates downstream target gene expression, modulates immune responses, and mediates malignant transformation and tumor development are discussed. Moreover, activation of AhR by post-translational modifications and crosstalk with other transcription factors or signaling pathways are also summarized. PMID- 30411680 TI - Circular RNAs Serve as Novel Biomarkers and Therapeutic Targets in Cancers. AB - Circular RNAs (circRNAs) are a class of non-coding RNAs (ncRNAs) that structurally form closed loops without 5'-end cap and 3'-end poly(A) tail unlike linear RNAs. CircRNAs are widely present in eukaryotic cells and are presented with capabilities and characteristics of structural stability, high abundance and cell-/tissue-specific expression. A growing body of research now suggests that the aberrant expression of circRNA is intimately relevant to the occurrence and development of cancer. In this review, we mainly discuss the differentially expressed circRNAs in cancer tissues, plasma and exosomes, which makes it possible for clinicians to use certain circRNAs as novel biomarker for cancer diagnosis and prognosis. In particular, we focus primarily on circRNAs as potential therapeutic targets, which will provide promising applications in cancer gene therapy. PMID- 30411682 TI - Emerging Therapeutic Approaches for Diamond Blackfan Anemia. AB - Diamond Blackfan Anemia (DBA) is an inherited erythroid aplasia with onset in childhood. Patients carry heterozygous mutations in one of 19 ribosomal protein (RP) genes, that lead to defective ribosome biogenesis and function. Standard treatments include steroids or blood transfusions but the only definitive cure is allogenic hematopoietic stem cell transplantation (HSCT). Although advances in HSCT have greatly improved the success rate over the last years, the risk of adverse events and mortality is still significant. Clinical trials employing gene therapy are now in progress for a variety of monogenic diseases and the development of innovative stem cell-based strategies may open new alternatives also for DBA treatment. In this review we summarize the most recent progress towards the implementation of new therapeutic approaches for this disorder. We present different DNA- and RNA-based technologies as well as new candidate pharmacological treatments and discuss their relevance and potential applicability for the cure of DBA. PMID- 30411681 TI - Clinical-Grade Oncolytic Adenovirus Purification Using Polysorbate 20 as an Alternative for Cell Lysis. AB - Oncolytic virus therapy is currently considered as a promising therapeutic approach for cancer treatment. Adenovirus is well-known and extensively characterized as an oncolytic agent. The increasing number of clinical trials using this virus generates the demand for the development of a well-established purification approach. Triton X-100 is commonly used in cell lysis buffer preparations. The addition of this surfactant in the list of substances with very high concern of the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) regulation promoted the research for effective alternatives. In this work a purification strategy for oncolytic adenovirus compatible with phase I clinical trials, using an approved surfactant - Polysorbate 20 was developed. The proposed downstream train, composed by clarification, concentration using tangential flow filtration, intermediate purification with anion exchange chromatography, followed by a second concentration and a final polishing step was evaluated for both Triton X-100 and Polysorbate 20 processes. The impact of cell lysis with Polysorbate20 and Triton X-100 for each downstream step was evaluated in terms of product recovery and impurities removal. Overall, 65% of infectious viral particles were recovered. Depletion of host cell proteins and ds-DNA was 99.9% and 97.1%, respectively. The results indicated that Polysorbate 20 can be used as a replacement for Triton X-100 during cell lysis with no impact on product recovery, potency, and purity. Moreover, the developed process is scalable and able to provide a highly purified product to be used in phase I and II clinical trials. PMID- 30411683 TI - Comparison of small-incision femtosecond laser-assisted intrastromal keratoplasty and lamellar keratoplasty in rhesus monkeys using xenogenic corneal lamellae. AB - BACKGROUND: In our previous study, both allogeneic and xenogeneic small-incision femtosecond laser-assisted intrastromal keratoplasty were demonstrated to be safe and effective surgeries. Glycerol-dehydrated corneal lamellae could serve as alternative xenogeneic inlay grafts. However, these xenogeneic lamellae have not been explored in lamellar keratoplasty (LK). The immunoreactivity differences between corneal intrastromal xenotransplantation and xenogeneic LK have not been assessed. METHODS: Rabbit lamellae were formed by femtosecond laser-assisted surgeries and dehydrated in glycerol for 1 week at 4 degrees C. The lamellae were used in two surgical approaches in the small incision lenticule extraction (SMILE) group and the LK group. Postoperatively, slit-lamp examinations, corneal topography, anterior segment optical coherence tomography (AS-OCT), in vivo confocal microscopy and tear inflammatory mediator assays were performed. RESULTS: Throughout the 12-month observation period, all rejection index ratings were higher in the LK group than in the SMILE group. No signs of graft rejection were observed in the SMILE group, but obvious neovascularization and corneal rejection occurred in the LK group. Corneal topography showed that the anterior curvatures at the central cornea and the mid-peripheral cornea were significantly increased in the SMILE group but decreased in the LK group. All the grafts from both groups were clearly visible on AS-OCT. In vivo confocal microscopy showed few dendritic cells in the subepithelial region in the SMILE group. Numerous dendritic cells and inflammatory cells were observed in the basal epithelium and stroma in the LK group. In the LK group, the levels of TGF-beta1, CD40, ICAM-1, CD14 and IL-10 changed more than those in the SMILE group. The levels of VEGF were significantly elevated 1 month after surgery in the LK group. CONCLUSION: Small-incision femtosecond laser-assisted intrastromal keratoplasty minimized invasiveness and improved surgical efficiency. This small-incision intrastromal keratoplasty technique is superior to LK in terms of xenogeneic lamellae biocompatibility. Moreover, glycerol-dehydrated corneal lamellae might be viable xenogenic corneal inlay graft. PMID- 30411684 TI - Research of gene delivery mediated by ultrasound, microbubble and folate-modified chitosan nanoparticles. AB - Objective-To study transfection efficiency of folate-modified chitosan (FA-CS) nanoparticles as a non-viral vector delivering pEGFP-C3plasmid (FA-CS/P) to 293T cells with or without the combination of ultrasound and microbubble. Method-pEGFP C3 was used as reporter gene and FA-CS nanoparticles, which prepared by complex coagulation method were used as biological carriers. Transfection efficiency to 293T cells mediated by FA-CS/P nanoparticles, ultrasound (US) and microbubble (MB) was assessed by fluorescence microscopy and flow cytometry. Result-FA-CS/P nanoparticles have a particle size of 355.1 nm and zeta potential of 10.4 mV. Significant green fluorescence could be observed in CS/P group, FA-CS/P group, US+MB/P group, US+FA-CS/P group, Liposome 2000 (L) group under inverted fluorescence microscope, while US+MB+FA-CS/P group only scattered fluorescence observed. Result of flow cytometry showed that transfection rate of US+MB+FA-CS/P group was (2.0 +/- 0.2)%, which was significantly lower than other groups (P<0.05). CCK-8 experiments showed that cell vitality of US+MB+FA-CS/P was (64.1+/-4.6)%, which was also lower than other groups (P<0.05). Conclusion-In this study, FA-CS was successfully synthesized. FA-CS could combine with pEGFP-C3 effectively forming nanoparticles with nanoparticle size, well dispersion, high encapsulation efficiency and no significant toxicity to cells. The application of ultrasound increased the transfection rate of FA-CS/P. However, while exposed to ultrasound and microbubble, the transfection rate of FA-CS/P decreased obviously, may indicating that there was no synergistic effect for gene transfection by the combination of ultrasound, folate modified chitosan and microbubbles. PMID- 30411685 TI - Role of HIF-1 in cancer progression: novel insights. A review. AB - Hypoxia is a condition always present in tumor environment owing to the fast growth of tumor cells not supported by adequate blood supply. There is increasing evidence that hypoxia plays an important role in cancer dormancy and cancer metabolism, increasing stemness activity and bringing about cancer initiation and progression . This condition may influence the production of hypoxia inducible factor (HIF) a helix transcription factor which is involved in carcinogenesis and tumor growth through the regulation of genes involved in angiogenesis, glycolytic metabolism and other biological mechanisms. In normoxia condition HIF is inactivated by prolyl hydroxylase enzymes (EGLN 1-3, also known as PHD 1-3) using oxygen as a substrate. Once hydroxilated it binds to a protein called Von Hippel Lindau protein (VHL) for its degradation, whereas in hypoxia condition stabilization and nuclear translocation occur, leading to oncogenes activation. It has got three isoforms HIF-1 HIF-2 and HIF-3. The most studied factor is HIF-1 which is a heterodimer consisting of two forms, the form alpha is expressed in manner oxygen dependent, the form beta is expressed constitutively. Its presence in tumor microenvironment could foster among other the expression of VEGF, HGF, Met protoncogene which induces degradation of the extracellular matrix and TWIST gene, which is in turn involved in a mechanism of cancer cell metastasis called epithelial-mesenchimal transition(EMT). In this review, we summarize the most important findings in HIF action in different types of cancer focusing on its properties to induce tumor cell growth and highlighting its poor prognostic value in different cancers sites. PMID- 30411686 TI - Alterations in the Expression of Amyloid Precursor Protein Cleaving Enzymes mRNA in Alzheimer Peripheral Blood. AB - BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in elderly populations. Changes in the expression of amyloid precursor protein (APP) cleaving enzymes directly affect the formation of amyloid beta (Abeta) plaques, a neuropathological hallmark of AD. OBJECTIVE: We used peripheral blood from AD patients to investigate the expression of genes related to APP-processing [(beta site APP-cleaving enzyme 1 (BACE1), presenilin1 (PSEN1), and a disintegrin and metalloproteinase family 10 (ADAM10) and 17 (ADAM17)] and the epigenetic genes sirtuin (SIRT)1-3, which regulate Abeta production. METHOD: Real-time polymerase chain reactions were performed to determine the specific mRNA levels in plasma. The mRNA levels in AD patients were compared to those in healthy persons and assessed in relation to the subjects' cognitive performance. RESULTS: BACE1 mRNA level in AD subjects was significantly higher than those of healthy controls, whereas ADAM10 level was significantly lower in the AD subjects. SIRT1 level was significantly decreased, while that of SIRT2 was increased in AD subjects and elderly controls compared to levels in healthy young control. In addition, correlations were found between the expression levels of BACE1, ADAM10 and SIRT1 and cognitive performance scores. Total Abeta (Abeta40+Abeta42) levels and the Abeta40/Abeta42 ratio were significantly increased in the AD subjects, whereas decreases in plasma Abeta42 was found in AD subjects. There was a negative correlation between Abeta40 or total Abeta and Thai Mental State Examination (TMSE) while there was no correlation between Abeta40/Abeta42 ratio or Abeta42 and TMSE. CONCLUSION: The present findings provide evidence and support for the potential roles of these enzymes that drive Abeta synthesis and for epigenetic regulation in AD progression and development, which can possibly be considered peripheral markers of AD. PMID- 30411687 TI - Design, synthesis, antimicrobial and anti-biofilm evaluation, and molecular docking of new substituted fluoroquinazolinones. AB - BACKGROUND: Quinazolines and quinazolinones derivatives are well known for their important range of therapeutic activities. OBJECTIVE: Synthesis of some derivatives of substituted fluoroquinazolinones based on structure-based design and evaluation of their antibacterial, antifungal, and anti-biofilm activities. METHOD: Compounds were chemically synthesized by conventional methods. Structures were established on the basis of spectral and elemental analyses. Antimicrobial potential was tested against various microorganisms using the agar disc-diffusion method. MIC and MBC as well as anti-biofilm activity for the highly active compounds were assessed. Moreover, the computational studies were performed using Auto dock free software package (version 4.0) to explain the predicted mode of binding. RESULT: All derivatives (5-8), (10a-g), and (A-H) were biologically tested and showed significant antimicrobial activity comparable to the reference compounds. Compounds 10b, 10c, and 10d had a good MIC and MBC against Gram positive bacteria, whereas 10b and 10d showed significant MIC and MBC against Gram-negative bacteria. However, compounds E and F exhibited good MIC and MBC against fungi. Compound 10c and 8 exhibited significant anti-biofilm activity towards S. aureus and M. luteus. Molecular docking study revealed a strong binding of these derivatives with their receptor-site and detected their predicted mode of binding. CONCLUSION: The synthesized derivatives showed promising antibacterial, antifungal, and anti-biofilm activities. Modeling study explained their binding mode and showed strong binding affinity with their receptor-site. The highly active compounds 5 and 10c could be subjected to future optimization and investigation to be effective antimicrobial agents. PMID- 30411689 TI - Spirocyclohexadienones as an Uncommon Scaffold for Acetylcholinesterase Inhibitory Activity. AB - The potential of inhibition of a set of some spirocyclohexadienones, readily synthesized in two steps and good overall yield from Morita-Baylis-Hillman adducts, was evaluated in vitro against acetylcholinesterase. We found that eight of them are able to inhibit the acetylcholinesterase activity, with IC50 values ranging from 0.12 to 12.67 MUM. Molecular docking study indicated that the spirocyclohexadienone, 9e (IC50 = 0.12 MUM), a mixed-type AChE inhibitor, showed a good interaction at active site of the enzyme, including the cationic (CAS) and the peripheral site (PAS). Thus, we have found bioactive compounds for further studies aimed at the discovery of more potent acetylcholinesterase inhibitors. As far as we know, this is the first report describing the anti-cholinesterase effect of this class of compounds. PMID- 30411688 TI - Synthesis, Anti-varicella-zoster virus and Anti-cytomegalovirus Activity of 4,5 Disubstituted 1,2,3-(1H)-Triazoles. AB - BACKGROUND: Clinical drugs for herpesvirus exhibit high toxicity and suffer from significant drug-resistantance. The development of new, effective, and safe anti herpesvirus agents with different mechanisms of action is greatly required. OBJECTIVE: Novel inhibitors against herpesvirus with different mechanisms of action from that of clinical drugs. METHODS: A series of novel 5-(benzylamino)-1H 1,2,3-triazole-4-carboxamides were efficiently synthesized and EC50 values against human cytomegalovirus (HCMV), varicella-zoster virus (VZV) and herpes simplex virus (HSV) were evaluated in vitro. RESULTS: Some compounds present antiviral activity. Compounds 5s and 5t are potent against both HCMV and VZV. Compounds 5m, 5n, 5s, and 5t show similar EC50 values against both TK+ and TK- VZV strains. CONCLUSION: 5-(Benzylamino)-1H-1,2,3-triazole-4-carboxamides are active against herpesviruses and their activity is remarkably affected by the nature and the position of substituents in the benzene ring. The results indicate that these derivatives are independent of the viral thymidine kinase (TK) for activation, which is indispensable for current drugs. Their mechanisms of action may differ from those of the clinic anti-herpesvirus drugs. PMID- 30411690 TI - Virtual Screening Strategy Combined Bayesian Classification Model, Molecular docking for Acetyl-CoA Carboxylases Inhibitors. AB - Acetyl-CoA Carboxylases (ACC) has been an important target for therapy of metabolic syndrome, such as obesity, hepatic steatosis, insulin resistance, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), type 2 diabetes (T2DM), and some other disease. In this study, virtual screening strategy combined Bayesian categorization modeling, molecular docking and binding site analysis with protein ligand interaction fingerprint (PLIF) was adopted to validate some potent ACC inhibitors. First, the best Bayesian model with an excellent value of area under curve (AUC) value (training set AUC: 0.972, test set AUC: 0.955) was used to screen compounds of validation library. Then the compounds screened by best Bayesian model were further screened by molecule docking again. Finally, the hit compounds evaluated with four percentages (1%, 2%, 5%, 10%) were verified to reveal enrichment rates for the compounds. The combination of the ligand-based Bayesian model and structure-based virtual screening resulted in the identification of top four compounds which exhibited excellent IC50 values against ACC in top 1% of the validation library. In summary, the whole strategy is of high efficiency, and would be helpful for the discovery of ACC inhibitors and some other target inhibitors. PMID- 30411691 TI - Delayed Hemolytic Anemia after Treatment with Artesunate: Case Report and Literature Review. AB - BACKGROUND: In recent years, few cases of post-artemisinin delayed hemolysis have been reported. OBJECTIVE: All cases of post-artemisinin delayed hemolysis were reported from non-middle east areas. No case of post-artemisinin delayed hemolysis has yet been reported from this region. In this paper, we describe a case of post-artemisinin delayed hemolysis in an Iranian female. Also previous reports have been reviewed. METHOD: Patient's data including demographic characteristics, past medical, drug and travelling history, present illness, vital signs, laboratory data, clinical course of current illness and follow-up findings were considered. RESULTS: A 27-year-old female with a recent travel history to Ghana admitted with severe falciparum malaria. She was successfully treated with parenteral artesunate. However, 12 days post artesunate treatment she returned with dark urine, malaise and fatigue. CONCLUSION: Considering clinical course and base on a reliable causality assessment scale, post artesunate delay hemolytic anemia was possible. PMID- 30411692 TI - Report Of Adverse Events In Colombia: A Successful Case. AB - The Colombian National Food and Drug Surveillance Institute (INVIMA) is responsible for monitoring the safety and efficacy of medicines circulating in the Colombian market. This article summarizes the strategies implemented by INVIMA to strengthen the National Pharmacovigilance Program, including the expansion of the National Pharmacovigilance Network and the implementation of the electronic submission of adverse events. Results: the number of adverse events reported in Colombia increased from 5,447 in 2013 to 95,658 in 2017, reaching a population-based reporting ratio within international standards. PMID- 30411693 TI - New Strategies for Therapeutic Cancer Vaccines. AB - BACKGROUND: Patients with low response rates to cancer vaccines, short duration of anti-tumor response after vaccination, and relatively weak curative effects are problems that have not been resolved effectively during the development and application of cancer vaccines. With the continuous improvement of knowledge and awareness regarding the immune system and cancer cells, many researches have helped to explain the reasons for poor vaccine efficacy. Input from researchers accompanied by some newly emerged strategies could bring hope to improve the therapeutic effects of vaccines. METHODS: Data were collected from Web of Science, Medline, Pubmed, through searching of these keywords: "cancer vaccine", "cancer stem cell", "targeted agent", "immune checkpoint blockade" and "neoantigen". RESULTS: It may be more effective in immunotherapy of human cancers, including cancer stem cell vaccines, combination vaccines with targeted agents or immune checkpoint blockade, and neoantigen-based vaccines. CONCLUSION: Personalized vaccines will become the mainstream solution of cancer treatment program with the continuous improvement of human understanding of the immune system and the progress of related experiments. PMID- 30411694 TI - Hybrid Magnetic Nanostructures For Cancer Diagnosis And Therapy. AB - Cancer is the second disease in the world from the point of view of mortality. The conventional routes of treatment were found to be not sufficient and thus alternative ways are imposed. The use of hybrid, magnetic nanostructures is a promising way for simultaneous targeted diagnosis and treatment of various types of cancer. For this reason, the development of core@shell structures was found to be an efficient way to develop stable, biocompatible, non-toxic carriers with shell-dependent internalization capacity in cancer cells. So, the multicomponent approach can be the most suitable way to assure the multifunctionality of these nanostructures to achieve the desired/necessary properties. The in vivo stability is mostly assured by the coating of the magnetic core with various polymers (including polyethylene glycol, silica etc.) while the targeting capacity is mostly assured by the decoration of these nanostructures with folic acid. Unfortunately, there are also some limitations related to the multilayered approach. For instance, the increasing of the thickness of layers leads to a decreasing of the magnetic properties, (hyperthermia and guiding ability in magnetic field, for instance), the outer shell should contain the targeting molecules (as well as the agents helping the internalization into the cancer cells), etc. PMID- 30411696 TI - "Nous sommes forts" Un poeme sur la resilience en medecine d'urgence. PMID- 30411695 TI - Anti-inflammatory and Antioxidant Activities of the Extracts from Leaves and Stems of Polygonum odoratum Lour. AB - BACKGROUND: Polygonum odoratum is an indigenous vegetable that has been used as a favoring agent and also used as a Thai traditional medicine to treat flatulence. OBJECTIVE: To analyze active ingredients, total phenolic and total flavonoid contents, anti-inflammatory and antioxidant activities from leaf and stem extracts of P. odoratum. METHODS: Leaves and stems were dried and extracted by using methanol, dichloromethane and water for obtaining methanolic leaf extract (MLE), methanolic stem extract (MTE), dichloromethane leaf extract (DLE), dichloromethane stem extract (DTE), water leaf extract (WLE) and water stem extract (WTE). The extracts were quantified for total phenolic and total flavonoid contents by spectrophotometry and active compounds were analyzed by using GC-MS. Antioxidant activity was determined by ABTS and DPPH radicals scavenging assays. Anti-inflammatory activity was tested by the inhibition of nitric oxide production in RAW 264.7 macrophage cells induced by lipopolysaccharide. RESULTS: The DLE exhibited the most potent anti-inflammatory effect by inhibiting nitric oxide production in a concentration-dependent manner (IC50 = 53.75+0.72 ug/mL). MLE exhibited strong antioxidant activity and contained the highest concentration of phenolic compounds (52.59+0.58 mg gallic acid equivalent/g extract) and flavonoid (19.97+0.11 mg quercetin equivalent/g extract). E-15-Heptadecenal and 3, 7, 11, 15-tetramethyl-2-hexadecen-1-ol were found predominantly in the methanol extracts. CONCLUSION: The leaf extract of P. odoratum showed potent anti-inflammatory and antioxidant activities, mediated by DLE and MLE, respectively. PMID- 30411697 TI - Attenuation of maternal weight gain impacts infant birthweight: systematic review and meta-analysis. AB - Despite many interventions aiming to reduce excessive gestational weight gain (GWG), it is currently unclear the impact on infant anthropometric outcomes. The aim of this review was to evaluate offspring anthropometric outcomes in studies designed to reduce GWG. A systematic search of seven international databases, one clinical trial registry and three Chinese databases was conducted without date limits. Studies were categorised by intervention type: diet, physical activity (PA), lifestyle (diet + PA), other, gestational diabetes mellitus (GDM) (diet, PA, lifestyle, metformin and other). Meta-analyses were reported as weighted mean difference (WMD) for birthweight and birth length, and risk ratio (RR) for small for gestational age (SGA), large for gestational age (LGA), macrosomia and low birth weight (LBW). Collectively, interventions reduced birthweight, risk of macrosomia and LGA by 71 g (WMD: -70.67, 95% CI -101.90 to -39.43, P<0.001), 16% (RR: 0.84, 95% CI 0.73-0.98, P=0.026) and 19% (RR: 0.81, 95% CI 0.69-0.96, P=0.015), respectively. Diet interventions decreased birthweight and LGA by 99 g (WMD -98.80, 95% CI -178.85 to -18.76, P=0.016) and 65% (RR: 0.35, 95% CI 0.17 0.72, P=0.004). PA interventions reduced the risk of macrosomia by 51% (RR: 0.49, 95% CI 0.26-0.92, P=0.036). In women with GDM, diet and lifestyle interventions reduced birthweight by 211 and 296 g, respectively (WMD: -210.93, 95% CI -374.77 to -46.71, P=0.012 and WMD:-295.93, 95% CI -501.76 to -90.10, P=0.005, respectively). Interventions designed to reduce excessive GWG lead to a small reduction in infant birthweight and risk of macrosomia and LGA, without influencing the risk of adverse outcomes including LBW and SGA. PMID- 30411698 TI - Implementing electronic medical records in Canadian emergency departments. PMID- 30411699 TI - The relationship between maternal obesity and diabetes during pregnancy on offspring kidney structure and function in humans: a systematic review. AB - Evidence from animal models indicates that exposure to an obesogenic or hyperglycemic intrauterine environment adversely impacts offspring kidney development and renal function. However, evidence from human studies has not been evaluated systematically. Therefore, the aim of this systematic review was to synthesize current research in humans that has examined the relationship between gestational obesity and/or diabetes and offspring kidney structure and function. Systematic electronic database searches were conducted of five relevant databases (CINAHL, Cochrane, EMBASE, MEDLINE and Scopus). Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines were followed, and articles screened by two independent reviewers generated nine eligible papers for inclusion. Six studies were assessed as being of 'neutral' quality, two of 'negative' and one 'positive' quality. Observational studies suggest that offspring exposed to a hyperglycemic intrauterine environment are more likely to display markers of renal dysfunction and are at higher risk of end-stage renal disease. There was limited and inconsistent evidence for a link between exposure to an obesogenic intrauterine environment and offspring renal outcomes. Offspring renal outcome measures across studies were diverse, with a large variation in offspring age at follow-up, limiting comparability across studies. The collective current body of evidence suggests that intrauterine exposure to maternal obesity and/or diabetes adversely impacts renal programming in offspring, with an increased risk of kidney disease in adulthood. Further high-quality, longitudinal, prospective cohort studies that measure indicators of offspring renal development and function, including fetal kidney volume and albuminuria, at standardized follow-up time points, are warranted. PMID- 30411701 TI - Re-evolution of asthma management: dilemmas and new paradigms. AB - Asthma is one of the most common inflammatory diseases in the world, and the main treatment goal is to achieve the best level of control for each patient. Although every patient is different, there are several clinical practice guidelines that can help physicians to manage this respiratory condition. However, the recommendations made by the different guidelines are not always identical, and new data on different management strategies are being continuously released, which can mislead both patients and physicians. Our aim with this article is to summarize the main controversies in terms of management and treatment recommendations in asthma guidelines, revise the most recent scientific evidence published so far and pinpoint some possible solution to these dilemmas. This review, however, does not aim to issue new recommendations or to challenge evidence-based guidelines. As a conclusion of this article, the authors considered that more tools are necessary to reach and measure optimal asthma control, to better assess the impact of asthma in patients' lives. In addition, it would be of utmost importance to appraise more accurately the short-term and long-term effectiveness and safety of asthma therapies, and the possibilities of successful immunomodulation. PMID- 30411702 TI - Isolated superior mesenteric artery dissection: An unusual presentation quashed by an unusual approach. PMID- 30411700 TI - Epidemiological data of anaphylaxis in french emergency departments. AB - BACKGROUND: Although anaphylaxis has been pointed as a high priority public health issue in the allergy world community, morbidity and mortality epidemiological data are still not optimal. This first multi-centric epidemiological study performed in 7 French emergency departments for one year intended to map the key issues to substantiate the need for changes and support ongoing national and international efforts for better diagnosis, management and prevention of anaphylaxis. METHODS: This is a descriptive study using data routinely reported to French institutional administrative databases reported from 7 French public health institutions of the Lorraine region from January to December 2015, based on International Classification of Diseases (ICD)-10 pre selected anaphylaxis-related codes and clinically validated as anaphylaxis cases. RESULTS: From the 202,079 ED admissions, 4,817 had ICD-10 anaphylaxis-related codes, 323 of those have been clinically validated as anaphylaxis cases. Although 45.8% presented severity criteria, adrenaline has been prescribed only in 32.4% of these cases. Overall 323 cases, 57.9% were subsequently referred to allergy work-up or evaluation (after or during hospitalization) and 17.3% received a prescription of auto-injectable adrenaline. CONCLUSION: Taken the results of this study, there is an urgent and pressing need for improved public health initiatives regarding anaphylaxis recognition and treatment. Timely, we strongly believe that this document flags key problems, which may be managed in the forthcoming years by implementing national and international actions. PMID- 30411703 TI - Screening for hepatic fibrosis and steatosis in Turkish patients with type 2 diabetes mellitus: A transient elastography study. AB - BACKGROUND/AIMS: Non-alcoholic fatty liver disease is highly prevalent in patients with type 2 diabetes mellitus (T2DM). The aim of the present study was to investigate the potential usefulness of transient elastography (TE), which is a technique that allows measuring both fibrosis and liver fat content simultaneously, as a screening tool for hepatic involvement in Turkish patients with T2DM. MATERIALS AND METHODS: We obtained liver stiffness measurements (LSMs, as a measure of fibrosis) and controlled attenuation parameter (CAP, as a marker of steatosis) in 124 (46 males and 78 females; mean body mass index (BMI): 33.2+/ 6.6 kg/m2) Turkish patients with T2DM. The prevalence rates of overweight, obesity, and metabolic syndrome in our sample were 28.2%, 64.5%, and 77.4%, respectively. Probe-specific LSM cut-off values were used to define advanced fibrosis (>=F3) and cirrhosis (F4) (M probe: F3=9.6-11.4 kPa, F4 >=11.5 kPa and XL probe: F3=9.3-10.9 kPa, F4 >=11.0 kPa). Mild, moderate, and severe steatosis were defined as CAP 222-232 dB/m, CAP 233-289 dB/m, and CAP >=290 dB/m, respectively. RESULTS: Advanced fibrosis and cirrhosis were identified in 21 (16.9%) and 10 (8.0%) patients, respectively. TE-defined hepatic steatosis (CAP>222 dB/m) was detected in 117 (94.3%) patients. Mild, moderate, and severe steatosis were identified in 0, 29, and 88 patients, respectively. CONCLUSION: TE is a useful non-invasive imaging modality to screen for liver involvement in Turkish patients with T2DM. High rates of TE-defined fibrosis and steatosis in our sample reflect the presence of an elevated mean BMI. PMID- 30411704 TI - Auditory Late Latency Response in Individuals with Type 2 Diabetes Mellitus. AB - OBJECTIVES: The study was done to compare Auditory late latency response (ALLR) in normal-hearing individuals without diabetes mellitus and normal-hearing individuals with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: A total of 50 participants within the age range of 40-60 years were enrolled in the study based on the inclusion and exclusion criteria. They were divided into two groups with one group consisting of 25 individuals with T2DM and the other group consisted of 25 individuals without diabetes as the control group. RESULTS: The results revealed prolonged latencies and reduced amplitude of P1, N1 and P2 wave among individuals with T2DM compared to control group. There was a significant positive correlation observed for ALLR latency and duration of T2DM, and a negative correlation observed for ALLR amplitude and duration of T2DM. CONCLUSION: The present study concluded that there is a problem in the encoding of speech at the cortical level despite normal hearing in individuals with type 2 diabetes mellitus. PMID- 30411705 TI - Evaluation of the Effects of Chronic Kidney Disease and Hemodialysis on the Inner Ear Using Multifrequency Tympanometry. AB - OBJECTIVES: To evaluate the effects of chronic kidney disease (CKD) and hemodialysis (HD) on the inner ear using the G width (the width between the bimodal peaks of the conductance (G) tympanogram at 2,000 Hz), which reflects the inner ear pressure and/or the existence of endolymphatic hydrops. MATERIALS AND METHODS: We selected five patients (10 ears) from the patients with CKD who were hospitalized for creation of arteriovenous fistula prior to initiation of HD (non HD group), and we selected seven patients (14 ears) from the patients with CKD who were undergoing HD (the HD group). As a control group, we selected 80 healthy individuals (160 ears); these were mainly the medical staff of the hospital. We measured the G width of the control group and that of patients with CKD using multifrequency tympanometry. RESULTS: The mean G widths of the HD (measured just before an HD session), non-HD, and control groups were 210.7, 128.4, and 97.0 daPa, respectively. The G width of the HD group was significantly greater than that of the control and non-HD groups (p<0.01 and p<0.01, respectively; Tukey Kramer test after one-way analysis of variance). The non-HD group also had a greater G width than the control, but it was not significant (p=0.20; Tukey Kramer). No significant changes were observed in the G widths of the HD group, just before and after a single HD session (p=0.423; paired t-test). CONCLUSION: The greater G width observed in hemodialyzed CKD patients suggests either an increased inner ear pressure or the existence of endolymphatic hydrops in these patients, which is probably related to their otologic symptoms. PMID- 30411706 TI - Normalization of Bone Conduction Auditory Brainstem Evoked Responses in Normal Hearing Individuals. AB - OBJECTIVES: Auditory brainstem responses (ABR) are used to evaluate the peripheral and central functions of the auditory tract. Air and bone-conduction auditory stimuli are used to evaluate the type and degree of hearing loss. The wave latencies and interpeak latencies (IPLs) are the important diagnostic data in ABR tests. Gender and age of the patients are some of the factors affecting these latencies. This study investigated the effects of age and gender on the wave and IPLs of bone-conduction ABR. MATERIALS AND METHODS: One hundred healthy individuals (50 women and 50 men) aged between 10 and 60 years were enrolled into this study, and both ears of all subjects (200 ears total) were included in the assessments. Based on their age, the subjects were equally divided into five groups, and each group consisted of 10 men and 10 women. RESULTS: The findings showed a significant difference in wave latencies and IPLs between the two genders (p<0.05). Depending on stimulus intensity, wave latencies also showed statistically significant differences between the age groups (p<0.05). However, no significant difference was noted between the age groups regarding IPLs. CONCLUSION: Normative values that covered wave latencies and IPLs evoked at stimulus intensities of 50, 30, and 10 dB nHL were established for the clinical use and use as a reference for the bone-conduction ABR testing procedure. PMID- 30411707 TI - Two-Hour Follow-Up is Equivalent to One-Day Follow-Up of Posterior Canal Benign Paroxysmal Positional Vertigo. AB - OBJECTIVES: To evaluate short-term outcome for posterior canal benign paroxysmal positional vertigo (p-BPPV) after modified Epley's maneuver (mEM). MATERIALS AND METHODS: Patients who were diagnosed with p-BPPV between September 2017 and January 2018 in a tertiary care center were included. Patients were treated with mEM. Five follow-up points were set at one hour, two hours, one day, three days and one week. If Dix-Hallpike test (DH) was positive, mEM was performed and patient was scheduled for follow-up at the next follow-up point. If negative, the patient was accepted as completely resolved and scheduled for follow-up at one week. The proportion of completely resolved patients at each follow-up point, recurrence, lateral canal conversion rate and time were noted. A retrospective control group was created from patients treated for p-BPPV between April and August 2017. The outcome of the study and control groups were compared. RESULTS: There were 93 patients in study group. 63 (67.7%), 8 (8.6%), 3 (3.2%), 0 (0%) and 9 (9.7%) patients completely resolved at one-hour, two-hour, one-day, three-days and one-week follow-ups. 1.96+/-1.60 (1-5) mEMs were performed. Control group included 61 patients. At one-week follow-up a total of 83 (89.2%) patients in study group and 48 (78.7%) in control group were completely resolved(p=0.1043). In study group 5 (5.37%) of patients had lateral canal conversion within one day. 2(2.15%) had recurrence one day later after two-hour follow-up. The number of patients completely resolved at two-hour follow-up and before (76.34%) compared to the patients completely resolved at one-day follow-up and before (79.56%) were not significantly different (p=0.7235). CONCLUSION: Two-hour follow-up is equivalent to one-day follow-up of p-BPPV in terms of therapy outcome and adverse affects. PMID- 30411708 TI - Uncommon Post-Meningitis Hearing Threshold Improvement: A Case Report. AB - Bacterial meningitis may cause inner ear fibrosis and progressive cochlear ossification with irreversible profound hearing loss (HL). Recognition of potential ossification is essential for effective management. We present a clinical case of a 4 year old boy who developed a progressive HL starting 3 weeks after meningitis. For the prospective risk of cochlear ossification, bilateral cochlear implantation (CI) was performed. Unexpectedly, unaided hearing threshold began to show improvement on the left ear, starting 4 months after meningitis and continuing for years post CI surgery. In order to explore the residual cochlear function, a trial of exclusively acoustic amplification was performed on the improved left side 5 years post implantation, providing good results. A certain degree of hearing recovery may be expected after meningitis related deafness. This case encourages surgeons to always adopt atraumatic surgical techniques that can enable the preservation of cochlear structure and residual function after CI surgery. PMID- 30411709 TI - Electrochemiluminescent detection of Escherichia coli O157:H7 based on Ru(bpy)3 2+/ZnO nanorod arrays. AB - Foodborne pathogens are perpetual threats to human and animal health. Detection of pathogens requires accurate, sensitive, rapid and point-of-care diagnostic assays. In this study, we described a simple and sensitive electrochemiluminescent (ECL) assay to detect the deadly bacteria Escherichia coli O157:H7 by [Formula: see text]-coated ZnO nanorods arrays (NAs). The [Formula: see text]-coated ZnO NAs were fabricated by immobilizing [Formula: see text] on ZnO NAs with a large specific surface area and good conductivity. An [Formula: see text]-2-(dibutylamino)-ethanol (DBAE) system coated on ZnO NAs exhibits high ECL intensity, rapid response and good stability. This system was further developed as an ECL immunosensor used in the detection of E. coli O157:H7. The proposed ECL immunosensor exhibits a broad detection range within the scope of 200-100 000 CFU ml-1 and quite a low detection limit of 143 CFU ml 1. The high specificity, remarkable reproducibility and good stability offer a sensitive, selective, and convenient pathway for detecting E. coli O157:H7 in the field of food safety and clinical diagnosis. PMID- 30411710 TI - The dynamics of hovering flight in hummingbirds, insects and bats with implications for aerial robotics. AB - We analyze the effects of morphology and wing kinematics on the performance of hovering flight. We present a simplified dynamical model with body translational and rotational degrees of freedom that incorporates the flapping, long-axis wing rotation and folding of the wing. To validate our simulation, we compare our results with direct measurements from hovering insects, hummingbirds and bats. Results show that long-axis wing rotation angle (a proxy for pronation) has a significant effect on energy efficiency. For a given wing rotation amplitude, the hovering system has a power-optimal flapping frequency for each stroke-plane orientation, and that frequency closely corresponds to the wingbeat frequencies observed in a diverse range of hummingbird species. We find that larger animals (with larger total mass and wing size), such as bats, require more power to maintain a stable hovering orbit and that hovering with a constant wingspan becomes increasingly impractical with increasing body size. We show, as an exemplar, that for a system of the size of a hovering bat, e.g. Glossophaga soricina, hovering with constant wingspan is dynamically possible, but is implausible and inefficient. For these conditions, hovering with varying wingspan, retracting the wing on the upstroke, is a more realistic hovering modality. PMID- 30411711 TI - Robust, reproducible, recyclable SERS substrates: monolayers of gold nanostars grafted on glass and coated with a thin silica layer. AB - We prepared and characterized recyclable surface enhanced Raman spectroscopy (SERS) active glass chips. Gold nanostars were grafted on properly functionalized glasses by means of electrostatic interactions and then they were coated with a silica layer of controllable thickness in the nanometer range. The SERS activity of the obtained substrates were tested in terms of reproducibility and homogeneity intra-samples and inter-samples from different batches using the Raman reporter as the model compound rhodamine 6G. The uncoated substrates were used as reference to evaluate the effect of silica spacers on SERS enhancement factors (EFs). The chemical route to obtain silica-coated SERS chips is described in detail, and the morphology and the optical response of substrates have been characterized. We demonstrate that SERS substrates coated with 1 nm silica conserve a good EF, and that the coating confers to the SERS platform an extreme robustness leading to reusability of the substrates. PMID- 30411712 TI - Modal analysis of resonant and non-resonant optical response in semiconductor nanowire arrays. AB - Nanowire array solar cells have reached efficiencies where it becomes feasible to talk about creating tandem solar cells in order to achieve even higher efficiencies. An example of such a tandem solar cell could be a nanowire array embedded in a membrane and integrated on top of a Si bottom cell. Such a system, however, requires understanding and control of its interaction with light, especially to make sure that the low energy photons are transmitted to the bottom cell. The dependence of the optical response of a nanowire array on the nanowire length, diameter, array pitch, materials surrounding the nanowires, and absorption coefficient of the nanowire material is very strong and possibly resonant, indicating the complexity of the optical response. In this work, we use an eigenmode-based analysis to reveal underlying physics that gives rise to observed resonant and non-resonant behavior. First, we show that an effective refractive index can be defined at long wavelengths, where only a single mode propagates. Second, we analyze the origin of the resonant reflection when the next optical mode becomes propagating and can be 'trapped' in the array and interact with the fundamental mode. Additionally, we define two simple boundaries for the wavelength range of the resonant response: the resonances can only occur if there is more than 1 propagating mode in the array, and they disappear if the 1st diffracted order is propagating in the top or bottom material. Such resonance effects could be detrimental for tandem solar cells. We thus provide recommendations for tuning the geometry of the array and the nanowire materials in order to push the resonant regime to the absorbing regime of the nanowire, where absorption in the nanowires dampens the resonances. Finally, this work demonstrates the strength of an eigenmode-based analysis of the optical response of periodic nanostructures in terms of simplifying the analysis of a complex system. PMID- 30411713 TI - Electron induced nanoscale engineering of rutile TiO2 surfaces. AB - Electron stimulated modifications of the rutile TiO2(110) surface have been investigated using scanning tunnelling microscopy tip pulses and electron beam irradiation. Tip pulses on the 'as-prepared' surface induce local surface reconstruction and removal of surface hydroxyls in a region around the reconstruction. A defocused beam from an electron gun as well as tip pulses have been used to generate a number of oxygen deficient surfaces. All tip pulse features display an oval profile, which can be attributed to the anisotropic conductivity of the TiO2(110) surface. A novel oxygen deficient phase with well ordered defective 'nano-cracks' has been identified, which can be produced by either electron beam irradiation or low flash anneal temperatures (~570 K). Annealing such surfaces to moderate temperatures (~850 K) leads to mixed 1 * 1 and 1 * 2 surfaces, until now only achievable by annealing in oxygen or ageing by repeated sputter/anneal cycles. Heating to normal preparation temperatures (1000 K) reforms the clean, well-ordered 1 * 1 surface termination. Our results demonstrate the potential of electron induced processes to modify the oxygen composition and structure of the TiO2(110) surface in a controllable and reversible way for selective surface patterning and surface reactivity modification. PMID- 30411714 TI - Few-layer bismuthene for femtosecond soliton molecules generation in Er-doped fiber laser. AB - Bismuthene, a mono-elemental two-dimensional material with a novel kind of few layer structure purely consisting of bismuth, has been predicted to have a prominent optical response and enhanced stability in theory. In this paper, few layer bismuthene is employed as the saturable absorber. The mode-locker is fabricated by dropping bismuthene on a microfiber in a passively mode-locked, Er doped fiber laser. The single pulse can be obtained at 122.1 mW, with 621.5 fs pulse duration at 1557.5 nm central wavelength, 10.35 nm spectral width and fundamental repetition of 22.74 MHz. Thanks to the outstanding nonlinear effect and semimetal of the bismuthene, dual-pulses, octonary-pulses and fourteen-pulses soliton molecules with tightly and loosely temporal separation can be achieved for the first time, to the best of our knowledge. The preceding indicates that bismuthene will have wide potential in many applications, such as optical fiber communications, optical logical gate, and laser materials processing, etc. PMID- 30411715 TI - Self-assembled gold micro/nanostructure arrays based on superionic conductor RbAg4I5 films. AB - Herein, we propose a new strategy to fabricate gold (Au) micro/nanostructure arrays by photocatalytic solid-state electrochemical reaction between superionic conductor RbAg4I5 and Au films. The Au and RbAg4I5 films were successively deposited on a clean quartz substrate by vacuum thermal deposition method. A copper microgrid possessing periodic holes 100 MUm in diameter was put above the RbAg4I5 film as a mask plate, whereupon irradiation from a 405 nm wavelength laser was used to diffuse gold ions (Au+ ions) into vacant silver sites of RbAg4I5 and transfer Au+ through ion passageways in the RbAg4I5 film. When the laser was turned off, the Au+ ions were easily reduced due to low activity compared to the silver (Ag+) ions. After multiple on/off cycles of the 405 nm laser, the irradiated area of uniform Au film exhibited a periodic structural unit array whose period was the same as that of the mask plate hole array. Atomic force microscope and scanning electron microscope images revealed that a self assembled needle-like nanostructure array grew perpendicular to the substrate surface inside each circle's structural unit. The height of the grown nanostructure array increased with laser power density. Raman enhancement of the gold nanostructure array as substrate was detected using Rhodamine 6G (R6G) ethanol solutions as probe molecules. The enhancement effect increased with the height of the grown nanostructure array, and could increase by two orders of magnitude greater than that of unirradiated Au film. This strategy offers a new method for the micro/nanostructure processing of gold and provides microscale array-mediated surface-enhancement Raman-scattering (SERS) substrates comprising Au nanostructures for application in high-sensitivity spectrum analysis. PMID- 30411716 TI - Negative transconductance in multi-layer organic thin-film transistors. AB - Negative transconductance (NTC) refers to the phenomenon of the N-shape transfer characteristic appearing with a current peak and valley. It has been extensively studied in the past few decades due to its applications in logic and memory devices. Here, we observe unique antibipolar transfer characteristics and NTC behavior in multi-layer 2,6-diphenyl anthracene organic thin-film transistors grown on h-BN, which is due to the vertical potential barrier between the charge accumulation region near the substrate and the neutral bulk region under the contacts. The applied extrinsic electric field could effectively modulate the barrier height, resulting in a competition for charge carrier transport between lateral and vertical directions. Based on the NTC and antibipolar properties, a frequency doubler has been fabricated on a single transistor, which provides a new building block for organic logic circuits. PMID- 30411717 TI - Initial stage of cubic GaN for heterophase epitaxial growth induced on nanoscale v-grooved Si(001) in metal-organic vapor-phase epitaxy. AB - The initial stages of the nucleation of cubic (c-) GaN in heterophase epitaxy on a Si v-groove are investigated. Growth of GaN on a nanoscale {111}-faceted v groove fabricated into a Si(001) substrate proceeds in the hexagonal (h-) phase that induces a secondary v-groove replicating the substrate topography with two opposing {0001} facets. The secondary v-groove is then orientationally mismatched at the junction of the h-GaN facets (h -h junction) resulting in structural instability. This instability is relieved either by the formation of voids that reduce the actual junction area or by the transition to c-phase (h-c transition) suppressing further extension of the h-h junction. The distribution of voids that is locally affected by the island growth mode of h-GaN on Si(111) and the imperfection in the groove geometry impacts the initial stage of heterophase epitaxy. Primarily, The h-c transition is observed as a non-local phenomenon; it occurs homogeneously and simultaneously along the bottom of the entire secondary groove and forms a one-dimensional (1D) seed layer except for some interruptions where the h-h junction is defected by gaps or incomplete voids. Between these interruptions, epitaxy retains a single crystal but results in a series of c-GaN nanodots on the seed layer with large fluctuation in size and spacing. The adatom incorporation observed in this heterophase epitaxy is a 1D analog to the wetting of a substrate followed by the self-assembly in conventional quantum dot epitaxy. The surface morphology of the c-GaN nanodots is governed by the faceting mostly composed of (001)- and (11n)-orientations and the roughening between these facets that ultimately affect the morphology of the final top surface of the c-III-N. The interruptions interfere with the homogeneity of the h-c transition and can cause antiphase defects and mosaicity. Based on experimental results, a solution to improve these issues is proposed. PMID- 30411719 TI - Acute kidney injury: a clinical issue in hospitalized heart failure patients with mid-range ejection fraction. AB - Introduction Acute kidney injury (AKI) during hospitalization is associated with a mortality increase in patients with acute heart failure (AHF). In 2016, the European Society of Cardiology introduced the category of HF with mid-range ventricular ejection fraction (HFmrEF) as a distinct stratum, between the HF conditions with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). Objectives Evaluating the AKI-associated in-hospital mortality risk in AHF patients, with a focus on the HFmrEF group. Patients and methods A total of 365 health records of patients with a primary diagnosis of acute decompensated heart failure (ADHF) were reviewed and evaluated. AKI was defined according to Acute Kidney Injury Network criteria. HF was diagnosed based on the Framingham criteria. ADHF patients were evaluated as three separate groups, based on their ventricular ejection fraction: HFpEF (? 50%), HFmrEF (40 - 49%), and HFrEF (< 40%). Risk and survival analyses were conducted on de-identified data. Results The AKI-associated in-hospital mortality ORs for the HFmrEF and HFrEF groups were high and statistically significant: 4.55 (95%CI 1.46 - 14.18) and 2.59 (95%CI 1.05 - 6.41), respectively, with a highly significant difference between these two ejection fraction strata (Mantel-Haenszel test; p=0.002). Cox proportional hazards modeling HRs were: 4.79 (95%CI 1.54 - 14.96) and 2.94 (95%CI 1.27 - 6.80) for HFmrEF and HFrEF groups, respectively. Conclusions AKI was significantly associated with higher risk of mortality in patients with HFmrEF when compared to those with HFrEF condition, suggesting a stronger prognostic impact of AKI in the HFmrEF borderline condition. PMID- 30411718 TI - Electrochemical fabrication of a biomimetic elastin-containing bi-layered scaffold for vascular tissue engineering. AB - Biomimetic tissue-engineered vascular grafts (TEVGs) have immense potential to replace diseased small-diameter arteries (<4 mm) for the treatment of cardiovascular diseases. However, biomimetic approaches developed thus far only partially recapitulate the physicochemical properties of the native vessel. While it is feasible to fabricate scaffolds that are compositionally similar to native vessels (collagen and insoluble elastic matrix) using freeze-drying, these scaffolds do not mimic the aligned topography of collagen and elastic fibers found in native vessels. Extrusion-based scaffolds exhibit anisotropic collagen orientation but these scaffolds are compositionally dissimilar (cannot incorporate insoluble elastic matrix). In this study, an electrochemical fabrication technique was employed to develop a biomimetic elastin-containing bi layered collagen scaffold which is compositionally and structurally similar to native vessels and the effect of insoluble elastin incorporation on scaffold mechanics and smooth muscle cell (SMC) response was investigated. Further, the functionality of human umbilical vein endothelial cells (HUVECs) on the scaffold lumen surface was assessed via immunofluorescence. Results showed that incorporation of insoluble elastin maintained the overall collagen alignment within electrochemically aligned collagen (ELAC) fibers and this underlying aligned topography can direct cellular orientation. Ring test results showed that circumferential orientation of ELAC fibers significantly improved scaffold mechanics. Real-time PCR revealed that the expression of alpha-smooth muscle actin (Acta2) and myosin heavy chain (MyhII) was significantly higher on elastin containing scaffolds suggesting that the presence of insoluble elastin can promote contractility in SMCs. Further, mechanical properties of the scaffolds significantly improved post-culture indicating the presence of a mature cell synthesized and remodeled matrix. Finally, HUVECs expressed functional markers on collagen lumen scaffolds. In conclusion, electrochemical fabrication is a viable method for the generation of a functional biomimetic TEVG with the potential to be used in bypass surgery. PMID- 30411720 TI - A Potential Competitive Endogenous RNA Pathway Involved in Chronic Spinal Cord Injury. AB - BACKGROUND Chronic spinal cord injury (CSCI) is a worldwide clinical problem. We aimed to reveal differentially expressed (DE) lncRNAs and to find associated pathways that may function as targets for CSCI therapy. MATERIAL AND METHODS After a CSCI rat model was confirmed by the Basso Beattie Bresnahan (BBB) scale and the Magnetic Resonance Imaging (MRI) test, microarray analysis was used to obtain the expression profile of DE lncRNAs between CSCI rats and corresponding control rats. Then, bioinformatics analyses, including GO and KEGG pathway analysis, DE lncRNAs-mRNAs co-expression analysis, and several databases, were used to examine the function of these DE lncRNAs. Finally, quantitative real-time PCR (qRT-PCR) was used to evaluate the expressions of the 5 most significantly changed lncRNAs, Col6a1, and miR-330-3p. RESULTS Our study identified 1266 DE lncRNAs and 847 DE mRNAs, among which lncRNA6032 was significant up-regulated. Furthermore, the expressions of miR-330-3p and Col6a1 associated with lncRNA6032 were down-regulated and up-regulated, respectively. CONCLUSIONS Our results showed that the abundance of DE lncRNAs may be associated with the risk of CSCI outcome and revealed a potential competitive endogenous RNA (ceRNA) pathway involved in CSCI. Further experiments in vivo and in vitro were essential to uncover the exact mechanism of this ceRNA pathway. PMID- 30411721 TI - Colonoscopy quality: continuous improvement towards perfection. PMID- 30411722 TI - Conformationally Constrained Bis(oxazoline) Derived Chiral Catalyst : A Highly Effective Enantioselective Diels-Alder Reaction. AB - The reaction of cyclopentadiene with various bidentate dienophiles in the presence of 4-10 mol% of copper(II)-bis(oxazoline) complexes afforded excellent endo/exo selectivity as well as endo enantioselectivity (95-99% ee) and isolated yields. On the other hand, Diels-Alder reaction with Mg(II)-complexes afforded a modest ( 61% ee) reversal in enantioselectivity. PMID- 30411723 TI - Safer dispensing labels and paediatric prednisolone. PMID- 30411724 TI - ERCP: does patient position count? PMID- 30411725 TI - Is fluorine-18-fluorocholine PET/CT suitable for the detection of skeletal involvement of multiple myeloma? AB - Our limited experience suggests that fluorine-18-fluorocholine (18F-FCH) may perform better in the detection of skeletal involvement by multiple myeloma compared to fluorine-18-fluorodeoxyglucose (18F-FDG) and that standard uptake ratio (SUR) might be considered in the semi-quantitative comparison of tracer uptake. PMID- 30411726 TI - Comparison of atherosclerotic inflammation and calcification in subjects with end stage renal disease (ESRD) on hemodialysis to normal controls utilizing 18F-FDG PET/CT. AB - OBJECTIVE: Subjects with end stage renal disease (ESRD) are exposed to increased morbidity and mortality due to cardiovascular events. The primary underlying mechanism has been suggested as accelerated atherosclerosis in these patients. Our aim was to compare the atherosclerotic inflammation and calcification in subjects with ESRD on hemodialysis to that in normal controls utilizing fluorine 18-2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT). SUBJECTS AND METHODS: Forthy two subjects who underwent 18F-FDG PET/CT imaging were retrospectively studied. Twenty one were subjects with ESRD on hemodialysis (67+/-11 years old; 14 male, 7 female) and 21 were age- and gender-matched controls. Average standardized uptake value maximum (SUVmax) and SUVmean for 4 segments of the aorta (ascending, arch, descending, abdominal) and for the common iliac arteries and common femoral arteries were measured. Standardized uptake value maximum and SUVmean for right atrial blood pool were also measured as the background. Average SUVmax, average SUVmean, average SUVmax/background ratio, and average SUVmean/background ratio were compared between subject groups for all segments. Presence or absence of macroscopic calcification on CT images for each arterial segment based on visual qualitative assessment was also noted and compared. For statistical analysis, two-sided t test was used for continuous variables, and chi-square test was used for categorical variables. We considered a P value of <0.05 as statistically significant. RESULTS: Average SUVmax and SUVmean were statistically significantly greater in subjects with ESRD than in controls in all arterial segments. Average SUVmax/background ratios were statistically significantly greater in subjects with ESRD compared to normal controls in all arterial segments except for the left femoral artery. Average SUVmean/background ratios were statistically significantly greater in subjects with ESRD compared to normal controls in all arterial segments except for the right and left femoral arteries. Presence of calcification on CT was more frequently encountered in all arterial segments in subjects with ESRD, and was statistically significantly greater for the aortic arch, descending aorta, and right and left femoral arteries. CONCLUSION: SUV measurements representing the atherosclerotic inflammatory changes and macroscopic atherosclerotic calcifications appear to be accelerated in subjects with ESRD on hemodialysis compared to normal controls. Fluorine-18 FDG PET/CT is a valuable diagnostic tool for verifying and quantifying accelerated atherosclerosis secondary to ESRD. PMID- 30411727 TI - Normal patterns of regional brain 18F-FDG uptake in normal aging. AB - OBJECTIVE: Normal aging alters the brain function even in the absence of recognizable structural changes, which can be detected using modern in vivo functional imaging modalities such as fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) scan. It is highly important to recognize normal age-dependent changes in order to correctly diagnose pathologic states. The goal of the current study was to evaluate the age-related changes in regional brain 18F-FDG uptake in normal healthy population. SUBJECTS AND METHODS: This study was part of the cardiovascular molecular calcification assessed by 18F sodium fluoride (NaF) (CAMONA) PET/computed tomography (CT) study. This study was approved by the Danish National Committee on Health Research Ethics registered at ClinicalTrials.gov (NCT01724749). Forty normal healthy subjects were prospectively recruited in group A (22-32 years) and B (56-75 years) and underwent 18F-FDG PET/CT. Static images were obtained 180 minutes following 18F FDG injection. Supratentorial (including individual measurements for frontal, parieto-occipital and temporal lobes) and cerebellar 18F-FDG uptakes were measured by manual placement of region of interest (ROI) over these regions based on predefined criteria for each and standardized uptake value (SUVmean) values were calculated using OsiriX software. RESULTS: The mean ages of the patients in group A was 26.1+/-3.4 versus 61+/-4.4 for group B. There were 10 females in group A and 10 females in group B. Mean SUV of cerebellum was 6.80+/-1.21 for the young subjects compared to 6.08+/-0.7 among old subjects (independent t-test, P=0.028). Mean SUV of supratentorial brain was 9.14+/-1.83 for the young subjects compared to 6.92+/-072 among old subjects (P<0.001). Mean SUV of frontal (9.72+/ 1.97 vs. 7.03+/-0.69), temporal (7.37+/-1.52 vs. 5.65+/-0.68) and parieto occipital region (10.7+/-2.28 vs. 7.41+/-0.79) was higher among young patients (P<0.001). More interestingly, SUVmean of supratentorial brain was significantly higher among female healthy volunteers in both groups (P= 0.025 and 0.047 for group A and B, respectively). CONCLUSION: In conclusion, these findings confirm a significant age dependent reduction of supratentorial 18F-FDG uptake among healthy individuals. However, cerebellum 18F-FDG uptake reduction was not so redundant. Fluorine-18-FDG uptake of all cerebral lobes including frontal, parieto-occipital and temporal decreases with normal aging in a same fashion. Interestingly, among both young and old female subjects, higher uptake was seen in supratentorial brain. PMID- 30411728 TI - Efficacy of 18F-FDG and 18F-NaF PET/CT imaging: A novel semi-quantitative assessment of the effects of age and obesity on hip joint inflammation and bone degeneration. AB - OBJECTIVE: Osteoarthritis (OA) is characterized by synovial tissue inflammation and underlying bone degeneration in the joints. Aging and obesity are among the major risk factors. This study evaluated the effects of aging and body mass index (BMI) on hip joint inflammation and bone degeneration using fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and fluorine-18 sodium fluoride (18F-NaF) PET/CT imaging, respectively. SUBJECTS AND METHODS: In this retrospective study, a total of 116 subjects (58 males and 58 females) who had undergone both 18F-FDG and 18F-NaF PET/CT imaging were analyzed. The mean age of these subjects was 48.6+/-14.5 with an age range of 21-75 years. Fluorine-18-FDG and 18F-NaF PET/CT imaging was conducted 180min and 90min (respectively) after intravenous administration of the appropriate tracer. The hip joint was segmented on fused PET/CT images using OsiriX MD v.9.5 (DICOM viewer and image-analysis program, Pixmeo SARL; Bernex, Switzerland). The region of interest (ROI) for the hip joint was indicated by using a 3D-growing region algorithm with upper/lower Hounsfield Units (HU) followed by a morphological closing algorithm. The metabolic activity for the left and right side of the joint was measured and correlated with age and BMI. RESULTS: Fluorine 18-FDG uptake in the hip was 0.83+/-0.22 (right side: 0.83+/-0.23, left side: 0.83+/-0.22, P=0.82). Fluorine-18-NaF uptake in the hip was 3.20+/-1.07 (right side: 3.25+/-1.14, left side: 3.15+/-1.04, P=0.02). Body mass index positively correlated with both 18F-FDG (r=0.29, P=0.001) and NaF (r=0.26, P=0.005) uptake. No significant correlation was seen between age and either 18F-FDG (r=0.12, P=0.19) or 18F-NaF (r=0.03, P=0.78) uptake. CONCLUSION: Body mass index had a significant impact on 18F-FDG and 18F-NaF uptake, whereas age had no correlation with either tracer uptake. Obesity increases the mechanical forces applied on weight-bearing joints such as the hip. Body mass index was related to increased joint inflammation and bone degeneration. These findings further support the studies explaining the role of adipose tissue in promoting OA. PMID- 30411729 TI - 18F-FDG PET/CT in therapy response and in predicting responders or non-responders in malignant pleural mesothelioma patients, by using semi-quantitative mRECIST and EORTC criteria. AB - OBJECTIVE: To evaluate the role of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in therapy response assessment according modified response evaluating criteria of solid tumors (mRECIST) and the predictive role of volume-based semi-quantitative parameters in patients with malignant pleural mesothelioma (MPM). Furthermore modified RECIST criteria for MPM mRECIST and the European Organization for Research and Treatment of Cancer (EORTC) criteria were compared and the predictive role of 18F-FDG PET/CT in the post-therapy outcome. SUBJECTS AND METHODS: Thirty five selected patients with MPM underwent 18F-FDG PET/CT scan at baseline (1) and after therapy (2). Semi-quantitative 18F-FDG PET/CT parameters were collected for each scan and also differences (Delta) DeltaSUVmax, DeltaSUVav, DeltaMTV, DeltaTLG, response index (RI)max% and RIav% were evaluated. Radiologic response to therapy was assessed by using the mRECIST and EORTC. RESULTS: The correlation between response to therapy assessed by EORTC and mRECIST criteria was moderate (K=0.418; 95%CI:0099-0736). According to mRECIST, statistical differences between responders and non-responders were significant in the analysis of semi quantitative parameters. According mRECIST criteria, all parameters defined a good area under the curve (AUC) but the better AUC resulted for DeltaMTV (cut off<=11.3, sensitivity=91.3%, specificity=91.7%) and DeltaTLG (cut-off<=59.1, sensitivity=82.6%, specificity=100%). Kaplan-Meier curves between responders and non-responders did not show statistically significant differences. CONCLUSION: The semi-quantitative analysis of 18F-FDG PET/CT has an important role in MPM therapy response assessment and has a predictive role in distinguishing responders and non-responders. PMID- 30411730 TI - An overview of the neurosurgical implications, pathophysiology, diagnosis and recent treatment strategies for Grade IV idiopathic osteolysis, also known as Gorham-Stout or phantom bone disease. AB - OBJECTIVE: Gorham-Stout disease (GSD), commonly referred as vanishing bone or phantom bone disease, is a rare disorder characterized by spontaneous bone osteolysis due to proliferation of lymphangiomatous tissue. This disease can involve multiple bones and cause pathologic fractures. The exact cause of GSD is unknown and its severity is unpredictable; the disorder can potentially cause disfigurement or functional disability. According to CARE guidelines, we studied a 46 years old lady with a progressive defect of the skull. Differential diagnosis included: benign and malignant diploic lesions (eosinophylic granuloma of the skull, myeloma, lytic metastasis from unknown primary tumour, etc) and osteomyelitis. A suspicion of GSD was raised by coupling information from laboratory and nuclear medicine investigations, and eventually confirmed histologically. CONCLUSION: We included early in the investigation protocols a total body fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET) scan that was extremely helpful to promptly rule out malignant or infective nature of osteolysis. An update on the diagnostic and management options available for GSD, with particular reference to the role of nuclear medicine and the latest clinical trials from international patients registries and classification of idiopathic osteolysis is provided. PMID- 30411731 TI - Tc-99m-PSMA imaging allows successful radioguided surgery in recurrent prostate cancer. AB - OBJECTIVE: The introduction of the prostate specific membrane antigen (PSMA) offers the possibility to discover prostate cancer recurrences being frequently so small that they cannot be detected by conventional imaging modalities, such as magnetic resonance or computed tomography. SUBJECTS AND METHODS: A 78 years old patient after radical prostatectomy and lymphadenectomy suffered from recurrence of the disease and galium-68-PSMA (68Ga-PSMA) showed a single hot spot. Therefore, the first time in this indication in Austria radioguided surgery was performed after application of technetium-99m (99mTc)-PSMA, which confirmed the single lesion already shown by 68Ga-PSMA. RESULTS: The lymph node was located dorsal to the urinary bladder dome in the presacral area, where normally no lymphadenectomy is performed, he was identified by the probe and removed. Postoperatively PSA-monitoring showed a decline from 13,1ng/mL (preoperatively) to <0,1ng/mL within 1 month. CONCLUSION: The use of radiolabeled PSMA (primary diagnosis with 68Ga, radioguided surgery with 99mTc and finally treatment with 177Lu) seems to be a major breakthrough in diagnosis and treatment of prostate cancer. PMID- 30411732 TI - Osteoarticular tuberculosis in children. A fast reappearing disease diagnosed by 18F-FDG PET/CT and other modalities. The cover page of Nicholas Andry booklet L' Orthopedie. AB - Osteoarticular tuberculosis (OAT) is not uncommon in children. Early diagnosis and treatment are essential to avoid ultimately long-term disabilities. Nicolas Andry (1658-1742) gave for the first time the name of the specialty of Orthopedics (L'Orthopedie) and its symbol of the crooked tree, in a paper in which he suggested how to avoid and to treat rachitis in children. We review the correlative-imaging findings and provide insights regarding the strengths and limitations of the conventional imaging modalities and those of nuclear medicine for the diagnosis of OAT and its differential diagnosis from other diseases. PMID- 30411733 TI - Images in two prostate cancer patients of second primary cancers: Hodgkin's lymphoma and lung adenocarcinoma. AB - Hodgkin's lymphoma and lung adenocarcinoma as second primary cancers in prostate cancer (PC) patients although are rare should be considered as important for the future of the PC patients. PMID- 30411735 TI - Directional control of charge and valley currents in a graphene-based device. AB - We propose a directional switching effect in a metallic device. To this end we exploit a graphene-based device with a three-terminal geometry in the presence of a magnetic field. We show that unidirectional charge and valley currents can be controlled by the Fermi energy and the magnetic field direction in the active device. Interestingly, unidirectional transport of charges and valleys is generated between two-terminals at the same bias voltage. Furthermore, we quantify the valley depolarization as a function of disorder concentration. Our results open a way for active graphene-based valleytronics devices. PMID- 30411734 TI - Synthesis, design and sensing applications of nanostructured ceria-based materials. AB - Cerium-based materials possess redox properties due to the presence of dual valence states of Ce3+ and Ce4+. In the last few years, the scientific community has paid much attention to designing and synthesizing cerium-based materials through advantageous routes for widespread catalytic and sensing applications in many fields. Cerium materials have been synthesized in many different forms, shapes and sizes. The catalytic and sensing capabilities of cerium nanostructures are highly dependent on their morphologies and can be improved significantly by modifying the sizes and shapes of the nanostructures to develop sensing scaffolds with improved sensing performance. These nanostructures provide a basis for applications in many fields. From a literature survey (2010 to 2015), it can be concluded that the fundamental morphologies, ratios, and capping of cerium nanostructures (CeNSs) constructively affect their properties and applications. Designed sensors utilizing CeNSs exhibit outstanding stability, high selectivity and eminent reproducibility in relation to time and temperature. This review will provide a perspective insight on the future trends in the design of different morphologies of CeNSs and their promising applications. PMID- 30411736 TI - Defect engineering on electrocatalysts for gas-evolving reactions. AB - The hydrogen evolution reaction (HER) and oxygen redox reaction, including the oxygen reduction reaction (ORR) and the oxygen evolution reaction (OER) are the core processes used for water splitting and in metal-air batteries. Thus, the design of electro-catalysts for use in the oxygen redox reaction and HER have received a lot attention around the world. Many strategies have been developed to improve these catalysts, including increasing the surface area, creating unique facet structures, enhancing the conductivities and so on. Among these improvements defect engineering on catalysts has been proven to be an effective and feasible way to accelerate the reaction rate. Herein, a short overview of the recent advances in defect engineering on electro-catalysts for ORR, OER and HER is presented, and the outlook for the defect engineering field is also summarized. PMID- 30411738 TI - Highly-active, graphene-supported platinum catalyst for the solventless hydrosilylation of olefins. AB - Herein we report the development of the first graphene-supported platinum catalyst that has demonstrated exceptional catalytic activity and stability for hydrosilylation reactions of olefins (TOF 4.8 * 106 h-1, TON = 9.4 * 106). The catalyst also exhibited functional group tolerance over a broad range of industrially relevant substrates with minimal metal leaching. In addition, the catalyst system was successfully translated into a packed bed platform for continuous hydrosilylation reactions. PMID- 30411739 TI - A naphthoimidazolium-cholesterol derivative as a ratiometric fluorescence based chemosensor for the chiral recognition of carboxylates. AB - Fluorescent chemosensors for sensing chiral molecules have been actively studied in recent years. In the current study, we report a naphthoimidazolium-cholesterol derivative (NI-chol 1) as a fluorescence based chemosensor for chiral recognition, in which the naphthoimidazolium serves not only as a fluorophore but also as a recognition moiety for anions via imidazolium (C-H)+-anion binding and the cholesterol unit acts as a chiral barrier. In particular, NI-chol 1 displayed unique and distinct ratiometric changes with Boc-d-Phe, on the other hand, Boc-l Phe induced a negligible change. Furthermore, a distinct downfield shift (from 9.64 ppm to 9.96 ppm) of the imidazolium C-H peak was observed for Boc-d-Phe (5 eq.) with severe broadening, which indicates strong ionic hydrogen bonding between the C-H proton and the carboxylate. PMID- 30411740 TI - Effects of calcium on the kinetics of a model disjunctive ligand exchange reaction: implications for dynamic trace metal ion speciation. AB - Trace metal ion speciation in natural waters is often under kinetic control due to slow exchange reactions involving multidentate ligands (both natural and anthropogenic) and constituent ions (e.g. calcium). Incomplete understanding of the kinetic behavior (rates, rate laws, and mechanisms) of multidentate ligand exchange reactions hinders prediction of metal ion bioavailability and mobility in these systems. Here, we aim to improve understanding (1) by examining the mechanism by which calcium suppresses ligand exchange rates and (2) by developing conceptual tools for predicting the kinetic behavior in environmental systems. Using capillary electrophoresis, we examined the effect of calcium concentration on the kinetics of a model disjunctive multidentate ligand exchange reaction between nickel(ii)-nitrilotriacetate (NiNTA) and trans-1,2 cyclohexylenedinitrilotetraacetate (CDTA) at constant temperature (25 degrees C) and ionic strength (10 mM). Initial NiCDTA formation rates under varying reactant and calcium concentrations were fit with a single disjunctive ligand exchange kinetic model. While the overall reaction pathway is disjunctive under all conditions studied, the presence of calcium causes a non-linear decrease in reaction rates and alters the overall reaction order with respect to free multidentate ligand concentration. The overall rate law is affected by the relative calcium affinity of exchanging ligands, which controls the balance of product formation and reactant reformation rates from the free metal ion intermediate. The log ratio of these rates is proposed as a metric for determining the appropriate simplified form of the rate law for disjunctive ligand exchange reactions. The implications for in situ ligand lability assays and metal ion bioavailability are discussed. PMID- 30411741 TI - Water induces the same crown shapes as Li+ or Na+ in 15-crown-5 ether: a broadband rotational study. AB - 15-Crown-5 ether (15C5) and its complexes with water have been studied using broadband Fourier transform microwave spectroscopy in a supersonic jet. A new conformer of 15C5 has been observed and established as the new global minimum out of a total of nine isolated structures. In addition, two 15C5-H2O and two 15C5 (H2O)2 clusters have been observed. The cluster structures have been unambiguously identified through the observation of water 18O isotopologue spectra. In all the clusters, at least one water molecule, located close to the axis of the 15C5 ring, interacts through two simultaneous hydrogen bonds to the endocyclic oxygen atoms. This interaction reshapes the 15C5 ring to reduce its rich conformational landscape to only two open structures, related to those found in complexes with Li+ or Na+ ions. In the most abundant 15C5-(H2O)2 form, the two water molecules repeat the same interaction scheme while binding to opposite sides of the ring. In the second most abundant dihydrated form the two water molecules lie on the same side of the ring. This finding is exceptionally rare because water-water interactions typically prevail over the formation of additional solute-water contacts, and it showcases the particular binding features of crown ethers. PMID- 30411742 TI - Carbon nanospheres with dual-color emission and their application in ratiometric pyrophosphate sensing. AB - Herein, we employ pH-dependent solubility equilibrium to develop the one-pot aqueous synthesis of dual-color emission fluorescent carbon nanosphere (DFCSs) with novel physicochemical properties. Unexpectedly, some of the DFCSs have a regular nanosphere shape, containing uniform carbon dots (~20 nm) on their surface. This may be attributed to the change in the surface composition of the carbon nanospheres under the strong alkaline conditions (pH 13), which results in dual-wavelength emission by single-wavelength excitation. Interestingly, the fluorescence intensities of the two emission peaks of the DFCSs at 315/410 nm can be simultaneously quenched upon the addition of Co2+ due to the strong coordination between Co2+ and the O-containing luminescent groups from the carbon dots and DFCSs. Also, the results demonstrate that one Co2+ simultaneously combines with two chromophoric groups. Furthermore, the quenched DFCSs exhibit high sensitivity for pyrophosphate (PPi) in the range of 0.075-200.0 MUM through a fluorescence recovery process, which can be attributed to the stronger Co2+ O[double bond, length as m-dash]P bond. This results in the removal of Co2+ from the surface of DFCSs-Co2+ system via competitive adsorption interactions. Meanwhile, this sensor shows high selectivity for PPi over mercapto amino acid and phosphate in aqueous solution. These results indicate the DFCSs can act as a dual-signal PPi-selective sensor via a ratiometric competitive mechanism. PMID- 30411743 TI - A novel cocrystal composed of CL-20 and an energetic ionic salt. AB - A novel nitroamine/energetic ionic salt cocrystal explosive containing CL-20 and 1-AMTN in a 1 : 1 molar ratio is presented. The structure of this cocrystal is determined by single-crystal X-ray diffraction (SC-XRD). The predicted detonation performance is slightly higher than that of RDX, a state-of-the-art explosive. In small-scale impact drop tests, the cocrystal exhibits a surprisingly low sensitivity relative to CL-20. These features make this cocrystal a very promising explosive to replace RDX. PMID- 30411744 TI - Iron-catalyzed synthesis of cyclopropanes by in situ generation and decomposition of electronically diversified diazo compounds. AB - The modular synthesis of a variety of trans 1,2-disubstituted cyclopropanes in a safe and user-friendly one-pot iron-catalyzed cyclopropanation reaction is described. Easily synthesized N-nosylhydrazones are used as diazo precursors, allowing the in situ generation of electron-rich diazo compounds under mild reaction conditions and their direct participation in the cyclopropanation reaction. PMID- 30411745 TI - A polyfluoroalkyl substituted phthalocyanine based supramolecular light switch for photothermal and photodynamic antibacterial activity against Escherichia coli. AB - A polyfluoroalkyl substituted phthalocyanine based supramolecular light switch was assembled by the host-guest interaction between the novel polyfluoroalkyl substituted silicon phthalocyanine and pyrene-beta-cyclodextrin, which was attached on the sidewalls of SWNTs through the pyrene groups. This supermolecule can not only absorb light to convert its energy into heat energy, but also respond to light, control the release of phthalocyanine and restore fluorescence and produce singlet oxygen for a synergistic photothermal and photodynamic effect against Escherichia coli. PMID- 30411746 TI - The dp type pi-bond and chiral charge density waves in 1T-TiSe2. AB - Based on the atomic electronic configuration and Ti-Se coordination, a valence bond model for the layered transition metal dichalcogenide (TMDC) 1T-TiSe2 is proposed. 1T-TiSe2 is viewed as being composed of edge-sharing TiSe4-plaquettes as TiSe2-ribbon chains in each layer via a directional valence shell electron distribution as chemical bonds, in contrast to the conventional layer view of face-sharing TiSe6-octahedra. The four valence electrons per Ti in the hybridized dsp2-orbitals of square coordination form sigma-bonds with the four nearest neighbor Se atoms in the chain. The electrons in the lone pair of the Se-4pz orbital are proposed to form a dp type pi-bond via side-to-side orbital overlap with the empty Ti-3dxz/3dyz orbitals within each chain, which is positively supported by quantum chemistry calculations. A study of electron energy loss spectroscopy (EELS) with transmission electron microscopy (TEM) for 1T-TiSe2 is presented to show an energy loss near ~7 and ~20 eV, which confirms the existence of collective plasmon oscillations with the predicted effective electron numbers for the pi- and (pi + sigma)-bond electrons, respectively. PMID- 30411747 TI - Catalytic oxidation of alcohols with novel non-heme N4-tetradentate manganese(ii) complexes. AB - We report the preparation and characterisation of a series of novel non-heme N4 tetradentate Mn(OTf)2 complexes of the type, [(L)MnOTf2], where L = R,R and S,S enantiomers of BPMCN, its 6-methyl and 6-bromo derivatives as well as the novel ligand BMIMCN (BPMCN = N,N'-dimethyl-N,N'-bis(2-pyridylmethyl)-(R,R/S,S)-1,2 diaminocyclohexane, BMIMCN = N,N'-dimethyl-N,N'-bis(1-methyl-2-imidazolemethyl) (R,R/S,S)-1,2-diaminocyclohexane). Solid state structural analysis of the BMIMCN ligated Mn-triflate complexes (R,R-C4 and S,S-C4) revealed opposite helicity but identical metal site accessibility. This feature was exploited in the catalytic oxidation of primary and secondary alcohols, with hydrogen peroxide as oxidant and acetic acid as co-catalyst. Complexes R,R-C4 and S,S-C4 displayed the highest activity in benzyl alcohol oxidation, attributed to the electron-donating property of the BMIMCN ligand. Complex S,S-C4, displayed high activity for a variety of primary alcohol substrates, but the reaction suffered from reduced selectivity and side-reactions due to the presence of acetic acid. In contrast, secondary alcohol substrates could be oxidised to the corresponding ketone products in excellent isolated yields under mild reaction conditions and short reaction times. PMID- 30411748 TI - Highly luminescent 2-phenylpyridine-free diiridium complexes with bulky 1,2 diarylimidazole cyclometalating ligands. AB - While a number of highly emissive dinuclear Ir(iii) complexes have been reported, they have generally been restricted to structures based on 2-phenylpyridine (Hppy) cyclometalates. We now present a series of new hydrazide-bridged diiridium complexes (5-8) which incorporate bulky 1,2-diarylimidazole cyclometalating ligands in the place of Hppy. Complexes 6-8 are strongly emissive when doped into poly(methyl methacrylate) (PMMA), displaying the highest PLQYs yet reported for ppy-free diiridium emitters (PhiPL = 47-55 +/- 10%). Notably, complex 8 has an emission peak at 452 nm and CIExy colour coordinates in the sky-blue region (0.18, 0.27), which is competitive with state-of-the-art monoiridium analogues. X ray crystallography and solution-state 19F NMR spectra reveal the presence of rigidifying intramolecular pi-pi interactions for complexes 6-8, which explains their improved photophysical performance compared to 5 which does not have these interactions. Structure-property relationships are further rationalised through density functional theory (DFT) and cyclic voltammetry (CV) data. All the complexes studied in this work display aggregation induced phosphorescent emission (AIPE). This series of compounds increases the structural diversity of highly luminescent dinuclear Ir(iii) complexes to include luminophoric ligands that are not restricted to Hppy-type fragments. The colour range accessible to AIPE-active diiridum complexes has also been substantially broadened. PMID- 30411750 TI - Nitrostyrenes as 1,4-CCNO-dipoles: diastereoselective formal [4+1] cycloaddition of indoles. AB - An unusual reactivity of nitrostyrenes in phosphorous acid was discovered, which permits the employment of these readily available synthons as 1,4-CCNO-dipole surrogates in a highly diastereoselective (4+1)-cycloaddition of indoles to afford 4'H-spiro[indole-3,5'-isoxazoles] in a diastereomerically pure form. PMID- 30411749 TI - Towards a 3D GeSbTe phase change memory with integrated selector by non-aqueous electrodeposition. AB - We have recently reported a new method for the electrodeposition of thin film and nanostructured phase change memory (PCM) devices from a single, highly tuneable, non-aqueous electrolyte. The quality of the material was confirmed by phase cycling via electrical pulsed switching of both 100 nm nano-cells and thin film devices. This method potentially allows deposition into extremely small confined cells down to less than 5 nm, 3D lay-outs that require non-line-of-sight techniques, and seamless integration of selector devices. As electrodeposition requires a conducting substrate, the key condition for electronic applications based on this method is the use of patterned metal lines as the working electrode during the electrodeposition process. In this paper, we show the design and fabrication of a 2D passive memory matrix in which the word lines act as the working electrode and nucleation site for the growth of confined cells of Ge-Sb Te. We will discuss the precursor requirement for deposition from non-aqueous, weakly coordinating solvents, show the transmission electron microscopy analysis of the electrodeposition growth process and elemental distribution in the deposits, and show the fabrication and characterisation of the Ge-Sb-Te memory matrix. PMID- 30411752 TI - A conjugated carbon-dot-tyrosinase bioprobe for highly selective and sensitive detection of dopamine. AB - In this work, a bioprobe for the detection of dopamine was designed and fabricated through covalently linking fluorescent carbon dots (CDs) and tyrosinase (TYR). The bioprobe (named CDs-TYR) can catalyze oxidation of dopamine and produce dopaquinone, and consequently the fluorescence of the CDs was quenched due to an efficient electron transfer mechanism from excited CDs to dopaquinone. The fluorescence intensity of CDs decreased in a dopamine concentration-dependent manner, which built the foundation of dopamine quantification. The bioprobe provided a wide linear range from 0.1 to 6.0 MUM for dopamine sensing. Additionally, excellent selectivity of the bioprobe to dopamine was achieved because of the specific catalytic character of the conjugated TYR. Furthermore, the bioprobe was successfully employed for the detection of dopamine in spiked human serum. To the best of our knowledge, this is the first example of the construction of a bioprobe through conjugating CDs and an enzyme. This work would open new opportunities to develop CD-based photoinduced electron transfer bioprobes for other analytes via linking typical enzymes onto CDs. PMID- 30411751 TI - Effect of adding milk to black tea on vascular function in healthy men and women: a randomised controlled crossover trial. AB - BACKGROUND: Tea consumption may improve endothelial function and blood pressure via increased bioavailability and bioactivity of nitric oxide. However, questions remain as to the impact of the common practice of adding milk. OBJECTIVE: To investigate the effect of regular consumption of black tea, with and without milk, on vascular function and blood pressure in healthy volunteers. DESIGN: A randomised, controlled, crossover study was performed in 17 healthy volunteers; 7 men and 10 women, mean age 22.4 +/- 3.0 years. Participants received each of the following treatments in random order for 4 weeks, with no washout period in between, (i) hot water, (ii) black tea and (iii) black tea with milk. Vascular function was assessed using flow-mediated dilatation (FMD) of the brachial artery at the end of each treatment period. In addition, participants monitored their home blood pressure for the last 7 days of each treatment period. A blood and urine sample was also collected at the end of each treatment period. RESULTS: Black tea increased FMD compared to the hot water control group (1.00 +/- 0.18%, P < 0.0001). Black tea with milk decreased FMD compared to both the hot water control (-0.64 +/- 0.19%, P = 0.001) and black tea (-1.64 +/- 0.19%, P < 0.0001). Compared with hot water, black tea did not alter blood pressure, while black tea with milk increased systolic (1.1 +/- 0.5 mmHg, P = 0.03) and diastolic blood pressure (2.0 +/- 0.5 mmHg, P < 0.0001). Black tea (-1.8 +/- 0.5 bpm, P < 0.001) and black tea with milk (-1.8 +/- 0.6 bpm, P < 0.001) lowered heart rate compared to hot water. No significant difference for plasma nitrate or nitrite was observed between treatment groups. CONCLUSIONS: The addition of milk to black tea alters the acute/short-term impact of regular tea consumption on vascular function and blood pressure in young healthy men and women. The exact mechanism for this affect remains unknown and longer-term trials to establish this effect in a range of populations are warranted. PMID- 30411753 TI - Nucleation and growth of gold nanoparticles initiated by nanosecond and femtosecond laser irradiation of aqueous [AuCl4]. AB - Irradiation of aqueous [AuCl4]- with 532 nm nanosecond (ns) laser pulses produces monodisperse (PDI = 0.04) 5 nm Au nanoparticles (AuNPs) without any additives or capping agents via a plasmon-enhanced photothermal autocatalytic mechanism. Compared with 800 nm femtosecond (fs) laser pulses, the AuNP growth kinetics under ns laser irradiation follow the same autocatalytic rate law, but with a significantly lower sensitivity to laser pulse energy. The results are explained using a simple model for simulating heat transfer in liquid water and at the interface with AuNPs. While the extent of water superheating with the ns laser is smaller compared to the fs laser, its significantly longer duration can provide sufficient energy to dissociate a small fraction of the [AuCl4]- present, resulting in the formation of AuNPs by coalescence of the resulting Au atoms. Irradiation of initially formed AuNPs at 532 nm results in plasmon-enhanced superheating of water, which greatly accelerates the rate of thermal dissociation of [AuCl4]- and accounts for the observed autocatalytic kinetics. The plasmon enhanced heating under ns laser irradiation fragments the AuNPs and results in nearly uniform 5 nm particles, while the lack of particles' heating under fs laser irradiation results in the growth of the particles as large as 40 nm. PMID- 30411754 TI - Blueberry, combined with probiotics, alleviates non-alcoholic fatty liver disease via IL-22-mediated JAK1/STAT3/BAX signaling. AB - Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent diseases worldwide. Blueberry, combined with probiotics (BP), might be a potential candidate for NAFLD treatment, due to its anti-inflammatory and anti-apoptotic properties. Here, we investigated whether the anti-inflammatory cytokine, IL-22, was involved in the therapeutic process of BP, using cell and rat models of NAFLD. Results indicated that BP significantly reduced lipid droplets and triglyceride (TG) accumulation in NAFLD cells. However, when IL-22 was deficient, the lipid droplets and TG content were significantly increased. In vivo, the serum parameters and pathological degree of NAFLD rats were significantly improved by BP, while IL-22 silencing significantly abolished the BP effect. Immunohistochemistry, immunofluorescence, qRT-PCR, and western blotting showed that the NAFLD group expressed significantly lower levels of IL-22, JAK1, and STAT3, and higher levels of BAX, than the normal group. Furthermore, BP significantly elevated the levels of IL-22, JAK1 and STAT3, and reduced the level of BAX in NAFLD, while IL-22 silencing prevented BP from restoring the expression of JAK1, STAT3, and BAX. We conclude that IL-22 is vital for the therapeutic effect of BP, and acts via activation of JAK1/STAT3 signaling and inhibition of the apoptosis factor BAX, which makes IL-22 a promising target for therapy of NAFLD. PMID- 30411755 TI - Negative/zero thermal expansion in black phosphorus nanotubes. AB - Black phosphorus nanotubes (BPNTs) as new 1D materials have very promising prospects in nanoelectronic devices. Taking into account that the effect of finite temperature on nanoelectronic devices is indispensable, we perform a comprehensive first-principles study of thermal expansion of BPNTs. It is surprisingly found that the thermal expansion can be tuned from positive thermal expansion (PTE) to zero thermal expansion (ZTE) and even to negative thermal expansion (NTE) by changing the diameter and bonding in the unique configurations of armchair and zigzag BPNTs. The thermal expansion of zigzag BPNTs is diameter independent, in contrast, the size effect of thermal expansion is evidently presented in the armchair BPNTs. Accordingly, it is more manageable to adjust the coefficient of thermal expansion (CTE) in the armchair BPNTs. Unusual phonon hardening with the increase of temperature can be detected in both types of nanotubes. The unique dynamical modes and different vibrational amplitudes are analyzed. Underlying physical mechanisms have been explored. This work can provide some inspiration for exploring the abnormal thermal expansion in nanotubes and how to regulate these properties. PMID- 30411756 TI - New applications of the mathematical model of a permeation passive sampler: prediction of the effective uptake rate and storage stability. AB - As the applications of passive sampling in environmental analysis are increasing, it is crucial to ensure that the methods applied in the measurement of pollutant concentrations provide sufficient accuracy in compliance with existing regulations. Additionally, as with any sampling method in an analytical process, sample integrity is essential for accurate determination of contaminants and their concentrations. In a recent study, a mathematical model was developed to describe the sampling process in permeation passive samplers. The model was able to predict the significance of potential uptake rate changes during sampling. The model also predicted the distribution of the sampled analyte within the different compartments of the sampler. In the present work, the model was extended to include two practical applications. In the first part, a novel method allowing prediction of the effective uptake rate of the sampler is presented. The method accounts for changes in the uptake rate during the exposure time caused by resistance to mass transfer in the sorbent bed, allowing accurate calculation of the time weighted average concentrations. The method was proven to be successful through experimental verification that involved sampling toluene and trichloroethylene using the Waterloo Membrane Sampler (WMS). In the second part, the post-sampling storage period of analytes in the WMS was evaluated. It was found both theoretically and experimentally that analyzing the sorbent only is sufficient to quantify the analytes collected, as the amount retained in the remaining compartments of the sampler (PDMS membrane, air inside the sampler and the storage vial) is negligible after sampling. The amounts of analytes collected by the sorbent were stable over up to three-weeks of storage at room temperature. These findings establish confidence in the use of the WMS for sampling Volatile Organic Compounds (VOCs). PMID- 30411757 TI - A PCR-free technology to detect and quantify microRNAs directly from human plasma. AB - A novel sensitive, specific and rapid method for the detection and quantification of microRNAs without requiring extraction from their biological sources is now available using a novel chemical based, PCR-free technology for nucleic acid testing. In this study, we both demonstrate how this method can be used to profile miR-451a, an important miRNA in erythropoiesis, and compare with the gold standard RT-qPCR. PMID- 30411758 TI - General existence of flexural mode doublets in nanowires targeting vectorial sensing applications. AB - Nanowires (NWs) are one of the fundamental building blocks for nanoscale devices, and have been frequently utilized as mechanical resonators. Earlier studies show that ultra-sensitive vectorial sensing toolkits can be fabricated by changing the flexural mode of NWs to oscillation doublets along two orthogonal directions. Based on in silico studies and the Timoshenko beam theory, this work finds that the dual orthogonal flexural mode of NWs can be effectively controlled through the proper selection of their growth direction. It is found that metallic NWs with a directional-independent shear modulus possess a single flexural mode. However, NWs with a directional-dependent shear modulus naturally exhibit flexural mode doublets, which do not disappear even with increasing slenderness ratio. Further studies show that such a feature generally exists in other NWs, such as Si NWs. Mimicking a pendulum configuration as used in NW-based scanning force microscopy, the cantilevered 110 Si NW demonstrates zeptogram mass resolution and a force sensitivity down to the order of 10-24 N Hz-1/2 (yN Hz 1/2) in both transverse directions. The findings in this work open up a new and facile avenue to fabricate 2D vectorial force sensors, which could enable ultra sensitive and novel detection devices/systems for 2D effects, such as the anisotropy strength of atomic bonds. PMID- 30411759 TI - A facile route to prepare functional mesoporous organosilica spheres with electroactive units for chiral recognition of amino acids. AB - Conductive materials are valuable supports and widely applied in electrochemical analysis. In the current article, a mesoporous organosilica sphere (S,S)-CPMO-3 with the chiral group and electroactive units is presented. The organosilicon framework is composed of free ions belonging to the ionic liquid and the chiral group arising from (1S,2S)-1,2-diaminocyclohexane. Next, a bare electrode was modified by the as-synthesized composite material to construct the new electrochemical sensor (S,S)-CPMO-3-GCE. It was observed that (S,S)-CPMO-3-GCE exhibited favourable enantioselective recognition in the response of the peak current (Ip) and the peak potential (Ep) to the different configurations of amino acids. Taking tryptophan as an example, the value of IL/ID is 13.84 and the peak to-peak potential approaches 48 mV. In addition, cysteine and tyrosine were successfully distinguished by the sensor. In summary, this study not only introduces a route for the synthesis of a conductive material, but also opens up its further potential in enantioselective recognition. PMID- 30411760 TI - Synthesis and improved photoluminescence of hexagonal crystals of Li2ZrF6:Mn4+ for warm WLED application. AB - A series of red-emitting phosphors composed of Li2ZrF6:Mn4+ (LZF:Mn) have been synthesized via an ionic-exchange reaction route at room temperature. The microstructure and optical characterizations have been investigated according to the detailed experiments. The morphology of the phosphor LZF:Mn changes with the concentration of HF, the reaction time and temperature. The uniform crystals of LZF:Mn with regular hexagonal tablets have been obtained in 30-40 wt% HF solutions by conducting the reaction at room temperature for about 8 h. The influences of reaction parameters on the morphology and photoluminescence properties of LZF:Mn have been systematically investigated. The luminescence intensity of LZF:Mn has been optimized by controlling the synthesis procedure and parameters. The white light-emitting diode (WLED) fabricated with LZF:Mn and Y3Al5O12:Ce3+ (YAG:Ce) on InGaN LED chip displays a warm white light with correlated color temperature (CCT) at 3789.4 K and color rendering index (CRI) of 91. PMID- 30411761 TI - An efficient strategy for improving the luminescent sensing performance of a terbium(iii) metal-organic framework towards multiple substances. AB - By anchoring triazole units onto its skeleton, the luminescent sensing properties of a terbium(iii) metal-organic framework could be efficiently improved, including not only an expansion of the scale of analytes such as Fe3+, anions and nitroaromatic molecules, but also enhanced selectivity and sensitivity. PMID- 30411762 TI - Merging metabolomics and lipidomics into one analytical run. AB - A novel integrated metabolomics/lipidomics workflow is introduced enabling high coverage of polar metabolites and non-polar lipids within one analytical run. Dual HILIC and RP chromatography were combined to high-resolution mass spectrometry. As a major advantage, only one data file per sample was obtained by fully automated simultaneous analysis of two extracts per sample. Hence, the unprecedented high coverage without compromise on analytical throughput was not only obtained by the orthogonality of the chromatographic separations, but also by the implementation of dedicated sample preparation procedures resulting in optimum extraction efficiency for both sub-omes. Thus, the method addressed completely hydrophilic sugars and organic acids next to water-insoluble triglycerides. As for the timing of the dual chromatography setup, HILIC and RP separation were performed consecutively. However, re-equilibration of the HILIC column during elution of RP compounds and vice versa reduced the overall analysis time by one third to 32 min. Application to the Standard Reference Material SRM 1950 - Metabolites in Frozen Human Plasma resulted in >100 metabolite and >380 lipid identifications based on accurate mass implementing fast polarity switching and acquiring data dependent MS2 spectra with the use of automated exclusion lists. Targeted quantification based on external calibrations and 13C labeled yeast internal standards was successfully accomplished for 59 metabolites. Moreover, the potential for lipid quantification was shown integrating non endogenous lipids as internal standards. In human plasma, concentrations ranging over 4 orders of magnitude (low nM to high MUM) were assessed. PMID- 30411763 TI - Hepatoprotective mechanism of freshwater clam extract alleviates non-alcoholic fatty liver disease: elucidated in vitro and in vivo models. AB - Freshwater clams (Corbicula fluminea) have long been used as a folk remedy in Chinese tradition. Their hot-water extract has been commercialized as a functional drink for liver protection. The objective of this study was to develop a product of the residual clam meat (FCR) and assess its functional compounds. The ethanol extract of FCR, designated FCRE, was identified to comprise phytosterols, polyunsaturated fatty acids (PUFAs) and carotenoids. FCRE significantly reduced lipid accumulation and cell death in HepG2 cells via decreased fatty acid synthase (FAS) activity and increased activities of carnitine palmitoyltransferase (CPT) and acyl-CoA oxidase (ACO), indicative of suppressed lipogenesis and increased beta-oxidation of fatty acids. In tilapia fed with high-fat diet (HFD), FCRE mitigated nonalcoholic steatohepatitis (NASH), which was evidenced by decreased levels of plasma aspartate transaminase (AST) and alanine transaminase (ALT), in addition to reduced total cholesterol and accumulation of triacylglycerols, particularly those of saturated and monounsaturated fatty acids. FCRE also suppressed stearoyl-CoA desaturase-1 (SCD 1) index, increased the PUFAs' n3/n6 ratio, and reduced prostaglandin E2 (PGE2) and inflammatory infiltrates in tilapia liver. Tilapia fed with HFD for 2 weeks displayed NASH symptoms, while mice took 10 weeks to display NASH symptoms. No previous study has been reported on the potential use of tilapia as an NASH model for pre-screening hepatoprotective-functional foods. PMID- 30411764 TI - Halogen substitution effects on optical and electrical properties in 3D molecular perovskites. AB - Both 3D organic-inorganic perovskites ([Et3P(CH2)2Cl][Cd(dca)3] (1) and [Et3P(CH2)2F][Cd(dca)3] (2) [dca = dicyanamide, N(CN)2-]) display two sequentially reversible high-temperature phase transitions and switchable dielectric properties. Through halogen substitution, 1 shows exceptional switching behaviour of second harmonic generation effects and remarkably 2 represents the first above-room-temperature 3D ferroelastic material characterized by two ferroelastic phases. PMID- 30411765 TI - Correction: Metal enhanced fluorescence biosensing: from ultra-violet towards second near-infrared window. AB - Correction for 'Metal enhanced fluorescence biosensing: from ultra-violet towards second near-infrared window' by Sarah Madeline Fothergill et al., Nanoscale, 2018, DOI: 10.1039/c8nr06156d. PMID- 30411766 TI - Molecular ejection transition in liquid crystal columns self-assembled from wedge shaped minidendrons. AB - Fan-shaped molecules with aromatic head-groups and two or more flexible pendant chains often self-assemble into columns that form columnar liquid crystals by packing on a 2d lattice. Such dendrons or minidendrons are essential building blocks in a large number of synthetic self-assembled systems and organic device materials. Here we report a new type of phase transition that occurs between two hexagonal columnar phases, Colh1 and Colh2, of Na-salt of 3,4,5-tris-dodecyloxy benzoic acid. Interestingly, the transition does not change the symmetry, which is p6mm in both phases, but on heating it involves a quantised drop in the number of molecules n in the cross-section of a column. The drop is from 4 to 3.5, with a further continuous decrease toward n = 3 as temperature increases further above Tc. The finding is based on evidence from X-ray diffraction. Using a transfer matrix formulation for the interactions within a column, with small additional mean field terms, we describe quantitatively the observed changes in terms of intermolecular forces responsible for the formation of supramolecular columns. The driving force behind temperature-induced molecular ejection from the columns is the increase in conformational disorder and the consequent lateral expansion of the alkyl chains. The asymmetry of the transition is due to the local order between 4-molecule discs giving extra stability to purely n = 4 columns. PMID- 30411767 TI - Disinfection performance using a UV/persulfate system: effects derived from different aqueous matrices. AB - The development of advanced photochemical processes has experienced the emergence of a promising alternative for water disinfection, different from traditional methods. The applicability has primarily been investigated in drinking and wastewater; however, new challenges related to microbiological control in marine waters necessitate evaluating the applicability of this process in such water matrices. In this study, the efficacy of persulfate (PDS) activated with UV-light against E. faecalis has been tested on the bench scale. Firstly, optimization of the different PDS concentrations (1-10 mM) and exposure times (0-5 min) was performed in distilled water. 1 mM of PDS was selected as the best dosage within the range tested. Secondly, in order to evaluate the effects of different inorganic compounds usually found in natural waters, the efficiency of the UV/PDS system was tested in three different matrices: mineral water, saltwater, and marine saltwater. Finally, different bacteria were evaluated in consortium (E. coli + E. faecalis), suggesting the same inactivation level independently on the bacterial groups and structures. The results suggest that PDS is an attractive alternative to other photochemical processes currently in use for seawater treatment and this application deserved further research. PMID- 30411768 TI - Iron-catalyzed protodehalogenation of alkyl and aryl halides using hydrosilanes. AB - A simple and efficient iron-catalyzed protodehalogenation of alkyl and aryl halides using phenylhydrosilane is disclosed. The reaction utilizes FeCl3 without the requirement of ligands. Unactivated alkyl and aryl halides were successfully reduced in good yields; sterically hindered tertiary halides were also reduced including the less reactive chlorides. The scalability of this methodology was demonstrated by a gram-scale synthesis with a catalyst loading as low as 0.5 mol%. Notably, disproportionation of phenylsilane leads to diphenylsilane that further reduces the halides. Preliminary mechanistic studies revealed a non radical pathway and the source of hydrogen is PhSiH3 via deuterium labeling studies. Our methodology represents simplicity and provides a good alternative to typical tin, aluminum and boron hydride reagents. PMID- 30411769 TI - Synthesis of functionalized cyclopentenes through allenic ketone-based multicomponent reactions. AB - A novel and efficient synthesis of diversely functionalized cyclopentene derivatives through the multicomponent reactions of 1,2-allenic ketones with 4 chloroacetoacetate and malononitrile/cyanoacetate under mild and metal-free conditions is presented. Mechanistically, the formation of title compounds involves a cascade process including nucleophilic substitution, Michael addition and intramolecular aldol type reaction. Interestingly, when 1-phenyl allenic ketones bearing electron-donating groups on the phenyl ring were reacted with 4 chloroacetoacetate and cyanoacetate, methylenecyclo-pentanes, the regioisomer of cyclopentenes, were formed with good selectivity and high efficiency. PMID- 30411770 TI - Corygaline A, a hexahydrobenzophenanthridine alkaloid with an unusual carbon skeleton from Corydalis bungeana Turcz. AB - A novel hexahydrobenzophenanthridine alkaloid, corygaline A (1), was isolated from Corydalis bungeana Turcz. Its structure and absolute configuration were elucidated by spectroscopic data analysis and electronic circular dichroism (ECD) calculations. Corygaline A (1) is the first example of an alkaloid which features a 6/6/6/6/6-fused pentacyclic skeleton in nature. It exhibited significant NO production inhibitory activity in LPS-activated RAW264.7 macrophages with an IC50 value of 2.9 MUM. A plausible biosynthetic pathway for 1 is also discussed. PMID- 30411771 TI - Convergent total synthesis of (+/-) myricanol, a cyclic natural diarylheptanoid. AB - Myricanol 1, a constituent of Myrica species, has been reported to lower the levels of the microtubule-associated protein tau (MAPT), whose accumulation plays an important role in some neurodegenerative diseases, such as Alzheimer's disease (AD). Herein we described a new synthetic route to prepare myricanol in 9 steps and 4.9% overall yield starting from commercially available 2,3-dimethoxyphenol and methyl 3-(4-benzyloxyphenyl)propanoate. The key steps are a cross-metathesis to obtain a linear diarylheptanoid intermediate and a Suzuki-Miyaura domino reaction to generate the challenging macrocycle. PMID- 30411772 TI - Asymmetric synthesis of beta-amino ketones by using cinchona alkaloid-based chiral phase transfer catalysts. AB - A highly enantioselective nucleophilic addition of ketones to imines catalyzed by chiral phase-transfer catalysts (N-quaternised cinchona alkaloid ammonium salts) has been developed, and the process affords the Mannich reaction products with tertiary stereocenters in good to high yields (up to 95%) with excellent enantioselectivities (up to 97% ee). PMID- 30411773 TI - Rh(iii)-Catalyzed dual C-H functionalization of 3-(1H-indol-3-yl)-3 oxopropanenitriles with sulfoxonium ylides or diazo compounds toward polysubstituted carbazoles. AB - A rhodium-catalyzed annulation of 3-(1H-indol-3-yl)-3-oxopropanenitriles with sulfoxonium ylides or diazo compounds has been developed, leading to a series of polysubstituted carbazoles in moderate to good yields. This procedure proceeded with formal Rh(iii)-catalyzed (4 + 2) cycloaddition, with the functionalization of 2-C-H bonds of indole in a step-economical procedure. Additionally, this reaction could also be conducted under acidic conditions when diazo compounds were employed as the reaction partners, which was a complement to the annulation of sulfoxonium ylides under weak basic conditions. PMID- 30411774 TI - Synthesis and self-sensitized photo-oxidation of 2-fulleropyrrolines by palladium(ii)-catalyzed heteroannulation of [60]fullerene with benzoyl hydrazone esters. AB - A convenient and efficient Pd(OAc)2-catalyzed N-heteroannulation reaction of [60]fullerene with benzoyl hydrazone esters was exploited to synthesize novel and scarce N-unsubstituted 2-fulleropyrrolines via the formation of C-C and C-N bonds. Besides, the self-sensitized photo-oxidation of 2-fulleropyrrolines was first discovered under very mild conditions to yield a ketoamide fullerene derivative in high yields. The reaction kinetics of this self-sensitized photo oxidation has been explored, indicating that this photo-oxidation process is a first-order reaction possessing a low reaction activation energy (2.79 kJ mol-1). Moreover, a possible mechanism related to the observed products was proposed. PMID- 30411775 TI - RNA-based boronate internucleosidic linkages: an entry into reversible templated ligation and loop formation. AB - The use of templates able to control the assembly and disassembly of supramolecular biopolymers is an attractive approach with applications ranging from engineering new biopolymers to the modulation of complex biological systems. Self-assembled nucleic acid-based systems hold thus substantive potential for the construction of well-defined and stimuli-responsive molecular architectures. We report here for the first time the synthesis of a 5'-boronoribonucleotidic phosphoramidite building block, its incorporation at the 5' extremities of RNA sequences, and its ability to generate boronate internucleosidic linkages by RNA- and DNA-templated ligation. Moreover, melting denaturation studies also revealed that 5'-boronic acid ended RNA sequences are able to promote the formation of RNA loops in the presence of RNA templating partners. Molecular-dynamics (MD) simulations were used to model the structural parameters governing these processes. PMID- 30411776 TI - Iron-catalyzed cascade addition/cyclization of 2-biphenyl isocyanides with toluenes: a highly efficient approach to 6-benzylated phenanthridines. AB - A highly efficient Fe-catalyzed cascade addition/cyclization of 2-biphenyl isocyanides with toluenes for the synthesis of 6-benzylated phenanthridines has been reported. Di-tert-butyl peroxide (DTBP) was employed as both a radical initiator and an oxidant. The procedure tolerates various functional groups, providing the corresponding products in moderate to good yields. The proposed mechanism involves the cascade addition of benzyl radicals to the isocyanides and the following radical aromatic cyclization. PMID- 30411777 TI - Site-specific near-infrared fluorescent labelling of proteins on cysteine residues with meso-chloro-substituted heptamethine cyanine dyes. AB - Near-infrared (NIR) fluorescence imaging is a promising new medical imaging modality. Associated with a targeting molecule, NIR fluorophores can accumulate selectively in tissues of interest and become valuable tools for the diagnosis and therapy of various pathologies. To facilitate the design of targeted NIR imaging agents, it is important to identify simple and affordable fluorescent probes, allowing rapid labelling of biovectors such as proteins, ideally in a site-specific manner. Here, we demonstrate that heptamethine cyanine based fluorophores, such as IR-783, that contain a chloro-cyclohexyl moiety within their polymethine chain can react selectively, at neutral pH, with cysteine residues in proteins to give stable, site-specifically labelled conjugates, that emit in the NIR spectral window. This reaction is exemplified with the labelling of peptides and two protein models: albumin and a Fab' antibody fragment. The resulting fluorescent proteins are stable and suitable for in vivo NIR imaging applications, as shown on a mice model. This straightforward one-step procedure, that does not require the prior derivatisation of the fluorophore with a bioconjugatable handle, should facilitate the production and use of near-infrared labelled proteins in life sciences. PMID- 30411778 TI - Surface conversion of ZnO nanorods to ZIF-8 to suppress surface defects for a visible-blind UV photodetector. AB - ZnO nanomaterials are promising building blocks for an efficient UV photodetector; however, their slow sensing behavior and undesired response to visible light, which are attributed to surface defects, such as oxygen or zinc vacancies, are challenges that remain to be addressed. Here, we transformed the ZnO nanorod surface into a zeolitic imidazolate framework-8 (ZIF-8) to eliminate ZnO surface defects. Vertical-type photodetectors were fabricated incorporating a Schottky junction at the ZIF-8/gold (Au) top electrode and could respond to UV light with a rapid response and recovery (1-2 s) and demonstrated a UV-to-visible rejection ratio in the order of 103, qualifying them as efficient visible-blind UV photodetectors. It is noteworthy that the ZIF-8 layer effectively separated the photogenerated electron-hole pairs, and thus reduced their recombination probability. The enhanced photodetector displayed excellent figures-of-merit: a responsivity of 291 A W-1 and a detectivity of 5.9 * 1013 cm Hz1/2 W-1 under illumination at 295 nm. PMID- 30411779 TI - Asymmetric Michael addition between kojic acid derivatives and unsaturated ketoesters promoted by C2-symmetric organocatalysts. AB - An efficient sterically hindered C2-symmetric bifunctional tertiary amine squaramide organocatalyst for the asymmetric Michael addition/hemiketalization domino reaction of kojic acid derivatives with beta,gamma-unsaturated alpha ketoesters has been designed. Pharmacology-relevant functionalized 2,3,4,8 tetrahydropyrano[3,2-b]pyran derivatives were produced over the catalyst in as low as 1 mol% with up to 99% yield and 99% ee. The procedure is at least 30-fold scalable and the catalyst is readily reusable in the catalytic reaction via acid base extraction. Acylation of the products with (S)- or rac-ibuprofen and with undec-10-enoic acid afforded the corresponding chiral esters containing two privileged pharmacophoric motifs. PMID- 30411780 TI - Weather fluctuations affect the impact of consumers on vegetation recovery following a catastrophic die-off. AB - Prolonged droughts exacerbated by climate change have been widely documented to interact with consumers to decimate vegetation in many ecosystems. Although climate change is also increasing within-year variation in precipitation and temperature, how weather fluctuations affect the impact of consumers on vegetation processes remains poorly understood. In a salt marsh that has recently experienced drought-associated vegetation die-off, we investigated how top-down control of plant recovery by a prominent salt marsh grazer varies with weather. Our results showed that grazing-driven plant mortality varied strongly with weather in spring, with intense grazing occurring during cool, wet days immediately following rain. Intense grazing in cool, wet days across the generally dry, spring season had a strong impact that eliminated plant seedlings that could otherwise have become tolerant of grazing in the following summer, thereby restricting vegetation recovery and contributing to the persistence of an unvegetated salt barren state. Thus, weather fluctuations can modulate the impact of consumers on vegetation recovery, a fundamental process underlying the fate of ecosystems after disturbances. A multi-timescale perspective on top-down control that combines the impact of short-term fluctuations in weather and that of long term variation in mean climate can not only help understand ecosystem dynamics in an increasingly variable climate, but may also inform conservation strategies or recovery plans for ecosystems that are already lost to climate change. This article is protected by copyright. All rights reserved. PMID- 30411781 TI - Vesicle-bound EBV-BART13-3p miRNA in circulation distinguishes nasopharyngeal from other head and neck cancer and asymptomatic EBV-infections. AB - Cell-free microRNA (miRNA) in biofluids released by tumors in either protein or vesicle-bound form, represent promising minimally-invasive cancer biomarkers. However, a highly abundant non-tumor background in human plasma and serum complicates the discovery and detection of tumor-selective circulating miRNAs. We performed small RNA sequencing on serum and plasma RNA from Nasopharyngeal Carcinoma (NPC) patients. Collectively, Epstein Barr virus-encoded miRNAs, more so than endogenous miRNAs, signify presence of NPC. However, RNAseq-based EBV miRNA profiles differ between NPC patients, suggesting inter-tumor heterogeneity or divergent secretory characteristics. We determined with sensitive qRT-PCR assays that EBV miRNAs BART7-3p, BART9-3p and BART13-3p are actively secreted by C666.1 NPC cells bound to extracellular vesicles (EVs) and soluble ribonucleoprotein complexes. Importantly, these miRNAs are expressed in all primary NPC tumor biopsies and readily detected in nasopharyngeal brushings from both early and late-stage NPC patients. Increased levels of BART7-3p, BART9-3p and particularly BART13-3p, distinguish NPC patient sera from healthy controls. Receiver operating characteristic curve analysis using sera from endemic NPC patients, other head and neck cancers and individuals with asymptomatic EBV infections reveals a superior diagnostic performance of EBV miRNAs over anti EBNA1 IgA serology and EBV-DNA load (AUC 0.87-0.96 vs 0.86 and 0.66 respectively). The high specificity of circulating EBV-BART13-3p (97%) for NPC detection is in agreement with active secretion from NPC tumor cells. We conclude EV-bound BART13-3p in circulation is a promising, NPC-selective, biomarker that should be considered as part of a screening strategy to identify NPC in endemic regions. PMID- 30411782 TI - Geographical variation of parental-reported sleep bruxism among children: comparison between the Netherlands, Armenia and Indonesia. AB - OBJECTIVE: The aim of this study was to investigate whether geographical variation exists in the prevalence rates and associated factors of parental reported sleep bruxism (SB) among 7- to 12-year-old children living in three culturally different countries. METHODS: An identical questionnaire was completed by parents or guardians of children in the Netherlands (Europe), Armenia (West Asia) and Indonesia (Southeast Asia). Pearson's chi-square tests were used to investigate geographical variation in occurrence; logistic regression analyses were performed to study associations. RESULTS: In total, data of 2,562 questionnaires were analysed. The overall prevalence of parental-reported SB was significantly higher in Armenia (36.5%) than in the Netherlands and Indonesia (19.5% and 24.2%, respectively; P < 0.001). However, differences between countries seemed to have disappeared in children around the age of 12. Geographical variation in associated factors is reflected in the fact that, depending on the country, a variety of variables were positively related with parental-reported SB (i.e. younger age, and/or having male gender, and/or experiencing pressure or tension from the home situation, and/or being more easily scared and/or having difficulties in falling asleep). CONCLUSIONS: Considerable geographical variation can exist in the epidemiology of parental reported SB in children. Cultural rules and standards could explain these findings. PMID- 30411783 TI - Genetic variants in CCL5 and CCR5 genes and serum VEGF-A levels predict efficacy of bevacizumab in metastatic colorectal cancer patients. AB - Early VEGF-A reduction (EVR) by targeting abundant VEGF-A is a potential predictive marker of bevacizumab (BEV). The CCL5/CCR5 axis modulates VEGF-A production via endothelial progenitor cells migration. We tested whether genetic polymorphisms in the CCL5/CCR5 pathway could predict efficacy of BEV in patients with metastatic colorectal cancer (mCRC) in a first-line setting. Genomic DNA was extracted from 215 samples from three independent cohorts: 61 patients receiving FOLFOX+BEV (evaluation cohort); 83 patients receiving FOLFOX (control cohort); 71 patients receiving FOLFOX/XELOX+BEV (exploratory cohort) for validation and serum biochemistry assay (n=48). Single nucleotide polymorphisms of genes in the CCL5/CCR5 pathway were analyzed by PCR-based direct sequencing. Considering the unbalanced distribution of patient baseline characteristics between the evaluation and control cohorts, propensity score matching analysis was performed. Serum VEGF-A levels during treatment were measured using ELISA. Among the evaluation and control cohorts, patients with any CCL5 rs2280789 G allele had longer progression-free survival (PFS) and overall survival (OS) when receiving FOLFOX+BEV than FOLFOX (PFS: 19.8 vs. 11.0 months, HR 0.44, 95%CI: 0.24-0.83, P=0.004; OS: 41.8 vs. 24.5 months, HR: 0.50, 95%CI: 0.26-0.95, P=0.024). No significant difference was shown in patients with the A/A variant. In the exploratory cohort, CCL5 rs2280789 G alleles were associated with higher VEGF-A levels at baseline and a greater decrease in VEGF-A levels at day 14 compared with the A/A variant. CCL5 and CCR5 impact the angiogenic environment, and the genotypes in CCL5/CCR5 genes may identify specific populations who will benefit from BEV in first-line treatment for mCRC. This article is protected by copyright. All rights reserved. PMID- 30411784 TI - Asymmetric interactions and their consequences for vital rates and dynamics: the smaller tea tortrix as a model system. AB - Asymmetric interactions among conspecifics can have diverse effects on population dynamics including stabilization, generation of cycles and induction of chaotic fluctuations. A difficult challenge, however, is establishing the link between the impact of asymmetric interactions on life history and the consequences for population dynamics. The smaller tea tortrix, Adoxophyes honmai, is a good example. Larval instars differ dramatically in size and have a tendency for cannibalism, which suggests the potential for strong asymmetric interactions among instars. Yet whether these asymmetries have any role in generating the distinct single-generation cycles observed in the field and laboratory is unclear. Here we report on the development of a new experimental approach to characterize the impact of asymmetric interactions on life history that can be directly embedded into stage-structured population models. The experiments use donor-replacement protocols in which focal individuals are challenged to complete their life-cycles in competitive environments where the instar and density of the competitors is held constant. The experimentally-derived interaction surface contains all the information about stage-specific interactions and provides a straightforward framework for evaluating alternative ways of abstracting the interactions into traditional models of asymmetric competition. Working with the smaller tea tortrix, we found strong evidence of asymmetric interactions and identified critical 'tipping points' in the competitive environment that strongly affected survival but not development. We incorporated the experimentally-derived interaction surface into a stage-structured population model and found that despite the strong impact that asymmetric interactions have on tea tortrix life history, they do not scale-up to impact the predicted asymptotic population dynamics. Comparing these dynamics with two abstracted models of stage-structured interactions revealed that while the quantitative details of the emergent dynamics depends on the shape of the interaction surface, the qualitative features - such as the emergence of single-generation cycles and rapid synchronization of development among individuals - are pleasingly robust. This article is protected by copyright. All rights reserved. PMID- 30411785 TI - Past the climate optimum: Recruitment is declining at the world's highest juniper shrublines on the Tibetan Plateau. AB - Alpine biomes are climate change hotspots, and treeline dynamics in particular have received much attention as visible evidence of climate-induced shifts in species distributions. Comparatively little is known, however, about the effects of climate change on alpine shrubline dynamics. Here, we reconstruct decadally resolved shrub recruitment history (age structure) through the combination of field surveys and dendroecology methods at the world's highest juniper (Juniperus pingii var. wilsonii) shrublines on the south-central Tibetan Plateau. A total of 1899 shrubs were surveyed at 12 plots located in four regions along an east-to west declining precipitation gradient. We detected synchronous recruitment with 9 out of 12 plots showing a gradual increase from 1600 to 1900, a peak at 1900 1940, and a subsequent decrease from the 1930s onwards. Shrub recruitment was significantly and positively correlated with reconstructed summer temperature from 1600 to 1940, whereas it was negatively associated with temperature in recent decades (1930-2000). Recruitment was also positively correlated with precipitation, except in the 1780-1830 period, when a trend towards wetter climate conditions began. Warming-induced drought limitation has likely reduced the recruitment potential of alpine juniper shrubs in recent decades. Ongoing warming without a simultaneous increase in precipitation is expected to further impair recruitment at the world's highest juniper shrublines and alter the dynamics and competitive balance between woody plant species throughout these alpine biomes. This article is protected by copyright. All rights reserved. PMID- 30411786 TI - Flower movement balances pollinator needs and pollen protection. AB - Flower signaling and orientation are key characteristics that determine a flower's pollinator guild. However, many flowers actively move during their daily cycle, changing both their detectability and accessibility to pollinators. The flowers of the wild tobacco Nicotiana attenuata orientate their corolla upward at sunset and downward after sunrise. Here, we investigated the effect of different flower orientations on a major pollinator of N. attenuata, the hawkmoth Manduca sexta. We found that although flower orientation influenced the flight altitude of the moth in respect to the flower, it did not alter the moth's final flower choice. These behavioral observations were consistent with the finding that orientation did not systematically change the spatial distribution of floral volatiles, which are major attractants for the moths. Moreover, hawkmoths invested the same amount of time into probing flowers at different orientations, even though they were only able to feed and gather pollen from horizontally and upward-oriented flowers, but not from downward-facing flowers. The orientation of the flower was hence crucial for a successful interaction between N. attenuata and its hawkmoth pollinator. Additionally, we also investigated potential adverse effects of exposing flowers at different orientations to natural daylight levels, finding that anther temperature of upward-oriented flowers was more than 7 degrees C higher than for downward-oriented flowers. This increase in temperature likely caused the significantly reduced germination success that was observed for pollen grains from upward-oriented flowers in comparison to those of downward and horizontally oriented flowers. These results highlight the importance of flower reorientation to balance pollen protection and a successful interaction of the plant with its insect pollinators by maintaining the association between flower volatiles and flower accessibility to the pollinator. PMID- 30411787 TI - Modern HIV Therapy: Progress and Prospects. AB - Safe and effective lifelong treatment to control HIV infection is one of the greatest scientific and public health achievements of the past century. The majority of infected individuals able to maintain a daily oral regimen now have a normal or near-normal life expectancy. More than 30 approved drugs and dozens of formulations have produced thousands of possible drug combinations used clinically in the past, but today most patients receive only a handful of high priority and rigorously tested regimens. Unique features of antiretroviral therapy include the need for lifelong treatment to control virus replication, and the possibility of rapid emergence of permanent drug resistance if these agents are not properly used. Although 3-drug combination oral regimens have radically altered the course of this epidemic, the future will include long acting injectable and implantable drugs and devices to treat and prevent infection. This article is protected by copyright. All rights reserved. PMID- 30411788 TI - Comprehensive analysis of HPV infection, EGFR exon 20 mutations and LINE1 hypomethylation as risk factors for malignant transformation of sinonasal inverted papilloma to squamous cell carcinoma. AB - Different risk factors are suspected to be involved in malignant transformation of sinonasal papillomas and include HPV infection, tobacco smoking, occupational exposure, EGFR/KRAS mutations and DNA methylation alterations. In our study, 25 inverted sinonasal papillomas (ISPs), 5 oncocytic sinonasal papillomas (OSP) and 35 squamous cell carcinomas (SCCs) from 54 patients were genotyped for 10 genes involved in EGFR signalling. HPV-DNA detection was performed by in-situ hybridisation and LINE-1 methylation was quantitatively determined by bisulphite pyrosequencing. High-risk HPV was observed only in 13% of ISP-associated SCC and in 8% of de novo-SCC patients. EGFR mutations occurred in 72% of ISPs, 30% of ISP associated SCCs and 17% of de novo-SCCs. At 5-year follow-up, SCC arose in only 30% (6/20) of patients with EGFR-mutated ISPs compared to 76% (13/17) of patients with EGFR-wild-type ISP (p = 0.0044). LINE-1 hypomethylation significantly increased from papilloma/early stage SCC to advanced stage SCC (p = 0.03) and was associated with occupational exposure (p = 0.01) and worse prognosis (p = 0.09). In conclusion, our results suggest that a small subset of these tumours could be related to HPV infection; EGFR mutations characterise those ISPs with a lower risk of developing into SCC; LINE-1 hypomethylation is associated with occupational exposure and could identify more aggressive nasal SCC. PMID- 30411789 TI - Antiretroviral resistance testing in HIV-positive people. AB - BACKGROUND: Resistance to antiretroviral therapy (ART) among people living with human immunodeficiency virus (HIV) compromises treatment effectiveness, often leading to virological failure and mortality. Antiretroviral drug resistance tests may be used at the time of initiation of therapy, or when treatment failure occurs, to inform the choice of ART regimen. Resistance tests (genotypic or phenotypic) are widely used in high-income countries, but not in resource-limited settings. This systematic review summarizes the relative merits of resistance testing in treatment-naive and treatment-exposed people living with HIV. OBJECTIVES: To evaluate the effectiveness of antiretroviral resistance testing (genotypic or phenotypic) in reducing mortality and morbidity in HIV-positive people. SEARCH METHODS: We attempted to identify all relevant studies, regardless of language or publication status, through searches of electronic databases and conference proceedings up to 26 January 2018. We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov to 26 January 2018. We searched Latin American and Caribbean Health Sciences Literature (LILACS) and the Web of Science for publications from 1996 to 26 January 2018. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) and observational studies that compared resistance testing to no resistance testing in people with HIV irrespective of their exposure to ART.Primary outcomes of interest were mortality and virological failure. Secondary outcomes were change in mean CD4-T-lymphocyte count, clinical progression to AIDS, development of a second or new opportunistic infection, change in viral load, and quality of life. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed each reference for prespecified inclusion criteria. Two review authors then independently extracted data from each included study using a standardized data extraction form. We analysed data on an intention-to-treat basis using a random-effects model. We performed subgroup analyses for the type of resistance test used (phenotypic or genotypic), use of expert advice to interpret resistance tests, and age (children and adolescents versus adults). We followed standard Cochrane methodological procedures. MAIN RESULTS: Eleven RCTs (published between 1999 and 2006), which included 2531 participants, met our inclusion criteria. All of these trials exclusively enrolled patients who had previous exposure to ART. We found no observational studies. Length of follow-up time, study settings, and types of resistance testing varied greatly. Follow-up ranged from 12 to 150 weeks. All studies were conducted in Europe, USA, or South America. Seven studies used genotypic testing, two used phenotypic testing, and two used both phenotypic and genotypic testing. Only one study was funded by a manufacturer of resistance tests.Resistance testing made little or no difference in mortality (odds ratio (OR) 0.89, 95% confidence interval (CI) 0.36 to 2.22; 5 trials, 1140 participants; moderate-certainty evidence), and may have slightly reduced the number of people with virological failure (OR 0.70, 95% CI 0.56 to 0.87; 10 trials, 1728 participants; low-certainty evidence); and probably made little or no difference in change in CD4 cell count (mean difference (MD) -1.00 cells/mm3, 95% CI -12.49 to 10.50; 7 trials, 1349 participants; moderate-certainty evidence) or progression to AIDS (OR 0.64, 95% CI 0.31 to 1.29; 3 trials, 809 participants; moderate-certainty evidence). Resistance testing made little or no difference in adverse events (OR 0.89, 95% CI 0.51 to 1.55; 4 trials, 808 participants; low certainty evidence) and probably reduced viral load (MD -0.23, 95% CI -0.35 to 0.11; 10 trials, 1837 participants; moderate-certainty evidence). No studies reported on development of new opportunistic infections or quality of life. We found no statistically significant heterogeneity for any outcomes, and the I2 statistic value ranged from 0 to 25%. We found no subgroup effects for types of resistance testing (genotypic versus phenotypic), the addition of expert advice to interpretation of resistance tests, or age. Results for mortality were consistent when we compared studies at high or unclear risk of bias versus studies at low risk of bias. AUTHORS' CONCLUSIONS: Resistance testing probably improved virological outcomes in people who have had virological failure in trials conducted 12 or more years ago. We found no evidence in treatment-naive people. Resistance testing did not demonstrate important patient benefits in terms of risk of death or progression to AIDS. The trials included very few participants from low- and middle-income countries. PMID- 30411790 TI - Basal biomarkers nestin and INPP4B predict gemcitabine benefit in metastatic breast cancer: Samples from the phase III SBG0102 clinical trial. AB - In a formal prospective-retrospective analysis of the phase III SBG0102 clinical trial randomizing metastatic breast cancer patients to gemcitabine-docetaxel or to single agent docetaxel, patients with basal-like tumors by PAM50 gene expression had significantly better overall survival in the gemcitabine arm. By immunohistochemistry (IHC), triple negative status was not predictive, but more specific biomarkers have since become available defining basal-like by nestin positivity or loss of inositol-polyphosphate-4-phosphate (INPP4B). Here, we evaluate their capacity to identify which patients benefit from gemcitabine in the metastatic setting. Nestin and INPP4B staining and interpretation followed published methods. A prespecified statistical plan evaluated the primary hypothesis that patients with basal-like breast cancer, defined as "nestin+ or INPP4B-", would have superior overall survival on gemcitabine-docetaxel when compared to docetaxel. Interaction tests, Kaplan-Meier curves and forest plots were used to assess prognostic and predictive capacities of biomarkers relative to treatment. Among 239 cases evaluable for our study, 36 (15%) had been classified as basal-like by PAM50. "Nestin+ or INPP4B-" was observed in 41 (17%) of the total cases and was significantly associated with PAM50 basal-like subtype. Within an estimated median follow-up of 13 years, patients assigned as IHC basal "nestin+ or INPP4B-" had significantly better overall survival on gemcitabine-docetaxel versus docetaxel monotherapy (HR = 0.31, 95%CI: 0.16-0.60), whereas no differences were observed for other patients (HR = 0.99), p interaction<0.01. In the metastatic setting, women with IHC basal breast cancers defined as "nestin+ or INPP4B-" have superior overall survival when randomized to gemcitabine-containing chemotherapy compared to docetaxel alone. These findings need to be validated using larger prospective-retrospective phase III clinical trials series. PMID- 30411791 TI - Frequency of virus-resistant hosts determines experimental community dynamics. AB - Parasites, such as bacterial viruses (phages), can have large effects on host populations both at the ecological and evolutionary levels. In the case of cyanobacteria, phages can reduce primary production and infected hosts release intracellular nutrients influencing planktonic food web structure, community dynamics, and biogeochemical cycles. Cyanophages may be of great importance in aquatic food webs during large cyanobacterial blooms unless the host population becomes resistant to phage infection. The consequences on plankton community dynamics of the evolution of phage resistance in bloom forming cyanobacterial populations are still poorly studied. Here, we examined the effect of different frequencies of a phage-resistant genotype within a filamentous nitrogen-fixing Nodularia spumigena population on an experimental plankton community. Three Nodularia populations with different initial frequencies (0%, 5%, and 50%) of phage-resistant genotypes were inoculated in separate treatments with the phage 2AV2, the green alga Chlorella vulgaris, and the rotifer Brachionus plicatilis, which formed the experimental plankton community subjected to either nitrogen limited or nitrogen-rich conditions. We found that the frequency of the phage resistant Nodularia genotype determined experimental community dynamics. Cyanobacterial populations with a high frequency (50%) of the phage-resistant genotype dominated the cultures despite the presence of phages, retaining most of the intracellular nitrogen in the plankton community. In contrast, populations with low frequencies (0% and 5%) of the phage-resistant genotype were lysed and reduced to extinction by the phage, transferring the intracellular nitrogen held by Nodularia to Chlorella and rotifers, and allowing Chlorella to dominate the communities and rotifers to survive. This study shows that even though phages represent minuscule biomass, they can have key effects on community composition and eco-evolutionary feedbacks in plankton communities. PMID- 30411792 TI - Circulating 25-hydroxyvitamin D, vitamin D binding protein and risk of advanced and lethal prostate cancer. AB - We previously found that higher total 25-hydroxyvitamin D [25(OH)D] levels were associated with lower risk of lethal prostate cancer. However, the relationships of bioavailable 25(OH)D and vitamin D binding protein (VDBP) with risk of advanced and lethal prostate cancer are unclear. In a prospective case-control study of 156 pairs of advanced prostate cancer cases and controls, we directly measured prediagnostic circulating 25(OH)D and VDBP and calculated bioavailable 25(OH)D using a validated formula. We examined the association of bioavailable 25(OH)D and VDBP levels with risk of advanced and lethal prostate cancer and whether total 25(OH)D levels interacted with VDBP levels to affect the risk. Conditional logistic models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Compared to total 25(OH)D (ptrend = 0.02), bioavailable 25(OH)D levels were not more strongly associated with risk of advanced prostate cancer (ptrend = 0.14). Although VDBP levels were not associated with risk of advanced prostate cancer (ptrend = 0.16), we observed an interaction between total 25(OH)D levels and VDBP levels in relation to risk of advanced prostate cancer (pinteraction = 0.03). Compared to those with total 25(OH)D levels below the median and VDBP levels above the median (at highest risk), men with both levels above the median had a multivariable-adjusted OR of 0.31 (95% CI, 0.15-0.65) for advanced prostate cancer. We observed similar results when we restricted the analyses to 116 lethal prostate cancer cases and their controls. Our data suggest that VDBP levels may modify the association between total 25(OH)D levels and risk of advanced and lethal prostate cancer. PMID- 30411793 TI - Quantitative ROS bioreporters: a robust toolkit for studying biological roles of ROS in response to abiotic and biotic stresses. AB - While the accumulation of reactive oxygen species (ROS) through spontaneous generation or as the by-products of aerobic metabolism can be toxic to plants, recent findings demonstrate that ROS act as signaling molecules that play a critical role in adapting to various stress conditions. Tight regulation of ROS homeostasis is required to adapt to stress and survive, yet in vivo spatiotemporal information of ROS dynamics are still largely undefined. In order to understand the dynamics of ROS changes and their biological function in adapting to stresses, two quantitative ROS transcription-based bioreporters were developed. These reporters use ROS-responsive promoters from RBOHD or ZAT12 to drive green fluorescent protein (GFP) expression. The resulting GFP expression is compared to a constitutively expressed mCherry that is contained on the same cassette with the ROS-responsive promoter: This allows for the generation of ratiometric images comparing ROS changes (GFP) to the constitutively expressed mCherry. Both reporters were used to assess ROS levels to oxidative stress, salt stress, and the pathogen defense elicitor flg22. These bioreporters showed increases in the ratio values of GFP to mCherry signals between 10 and 30 min poststress application. Such stress-associated ROS signals correlated with the induction of abiotic/biotic stress responsive markers such as RbohD, ZAT12, SOS2 and PR5 suggesting these ROS bioreporters provide a robust indicator of increased ROS related to stress responses. Based upon the spatiotemporal response patterns of signal increase, ZAT12 promoter-dependent ROS (Zat12p-ROS) bioreporter appears to be suitable for cellular mapping of ROS changes in response to abiotic and biotic stresses. PMID- 30411794 TI - "They Destroy the Reproductive System": Exploring the Belief that Modern Contraceptive Use Causes Infertility. AB - A common reason for nonuse of modern contraceptives is concern about side effects and health complications. This article provides a detailed characterization of the belief that modern contraceptives cause infertility, and an examination of how this belief arises and spreads, and why it is so salient. We conducted focus group discussions and key informant interviews in three rural communities along Kenya's eastern coast, and identified the following themes: (1) the belief that using modern contraception at a young age or before childbirth can make women infertile is widespread; (2) according to this belief, the most commonly used methods in the community were linked to infertility; (3) when women observe other women who cannot get pregnant after using modern contraceptives, they attribute the infertility to the use of contraception; (4) within the communities, the primary goal of marriage is childbirth and thus community approval is rigidly tied to childbearing; and, therefore (5) the social consequences of infertility are devastating. These findings may help inform the design of programs to address this belief and reduce unmet need. PMID- 30411795 TI - X11 and X11-like proteins regulate the level of extrasynaptic glutamate receptors. AB - X11/Mint 1 and X11-like (X11L)/Mint 2 are neuronal adaptor protein to regulate trafficking and/or localization of various membrane proteins. By analyzing the localization of neuronal membrane proteins in X11-, X11L-, and X11/X11L doubly deficient mice with membrane fractionation procedures, we found that deficient of X11 and X11L decreased the level of glutamate receptors in non-PSD fraction. This finding suggests that X11 and X11L regulate the glutamate receptor micro localization to the extrasynaptic region. In vitro coimmunoprecipitation studies of NMDA receptors lacking various cytoplasmic regions with X11 and X11L proteins harboring domain deletion suggest that extrasynaptic localization of NMDA receptor may be as a result of the multiple interactions of the receptor subunits with X11 and X11L regulated by protein phosphorylation, while that of alpha-amino 3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunits is not dependent on the binding with X11 and X11L proteins. Because the loss of X11 and X11L tends to impair the exocytosis, but not endocytosis, of glutamate receptors, NMDA receptors are likely to be supplied to the extrasynaptic plasma membrane with a way distinct from the mechanism regulating the localization of NMDA receptors into synaptic membrane region. Reduced localization of NMDA receptor into the extrasynaptic region increased slightly the phosphorylation level of cAMP responsible element binding protein in brain of X11/X11L doubly deficient mice compare to wild-type mice, suggesting a possible role of X11 and X11L in the regulation of signal transduction pathway through extrasynaptic glutamate receptors. Open Data: Materials are available on https://cos.io/our-services/open science-badges/ https://osf.io/93n6m/. PMID- 30411796 TI - New use for old drugs: the protective effect of atypical antipsychotics on hepatocellular carcinoma. AB - It has been encouraged to use large existing data like insurance claims data to investigate the new indications of old drugs. New strategies of research are warranted to identify feasible drugs. We conducted a dual research model with a population-based case-control study using Taiwan's National Health Insurance Research Database and an in-vitro study to investigate the association between atypical antipsychotic and Hepatocellular carcinoma (HCC) risk. The study herein consists of two components. The first is a population-based case-control study using existing data from the Taiwan National Health Insurance Research Database. The second component was an in-vitro study in which HCC cell lines (Huh7 and Hep G2) were treated with risperidone, quetiapine, and clozapine. Following treatment of the foregoing antipsychotics, the HCC cell lines were assessed for cell proliferation, invasion, and apoptosis. Multivariate conditional logistic regression analysis revealed that antipsychotic use was independently and inversely associated with HCC risk (adjusted odds-ratio [aOR]:0.85, 95% CI: 0.81 0.89). The protective effect was dose-dependent: compared to the low cumulative defined daily dose (cDDD) group (0-29 cDDD), the 30-89 cDDD and >=90 cDDD groups were associated with significantly reduced risk for HCC (aOR: 0.56, 95% CI: 0.41 0.76; aOR: 0.37, 95% CI: 0.27-0.50, respectively). In-vitro study results indicated that risperidone, quetiapine and clozapine significantly inhibited cell proliferation, invasion and induced apoptosis in human HCC cell lines. Our results herein suggested that antipsychotic use might reduce the risk of HCC and may provide evidence for new uses of old drugs. This article is protected by copyright. All rights reserved. PMID- 30411797 TI - Effects of Photobiomodulation on Functionality in Wistar Rats with Sciatic Nerve Injury. AB - A peripheral nerve injury (PNI) can result in motor or sensory disorders. Low level laser therapy (LLLT) has demonstrated positive results as a treatment option for PNI. Wistar rats were divided into five groups: Control, Injury, Injury+LLLTn (nerve), Injury+LLLTm (muscle) and Injury+LLLTn+m (nerve and muscle irradiation). The groups were analyzed after one, two, three and four weeks. PNI was achieved by crushing the sciatic nerve. Laser treatment (780nm, 3.2J) was realized over the nerve and/or tibialis anterior muscle. In gait analyses, the groups irradiated over the nerve demonstrated an improvement after two weeks. In the analysis of mechanical sensitivity, the Injury+LLLTn demonstrated a reduction after one week in comparison to Injury group; the Injury+LLLTn+m and Injury+LLLTm demonstrated an increase after two weeks in comparison to Injury group; and the irradiated groups demonstrated a reduction in nociception after four weeks in comparison to Injury group. In the analysis of muscle atrophy, the Injury+LLLTn demonstrated more muscle mass after two weeks. LLLT improve functional aspects related to gait, mechanical sensitivity and muscle mass, with better results regarding motor aspects and muscle mass when administered over the injured nerve and better results regarding sensory aspects when administered over the muscle. This article is protected by copyright. All rights reserved. PMID- 30411798 TI - The quaternary structure of human tyrosine hydroxylase: effects of dystonia associated missense variants on oligomeric state and enzyme activity. AB - Tyrosine hydroxylase (TH) is a multi-domain, homo-oligomeric enzyme that catalyses the rate-limiting step of catecholamine neurotransmitter biosynthesis. Missense variants of human TH are associated with a recessive neurometabolic disease with low levels of brain dopamine and noradrenaline, resulting in a variable clinical picture, from progressive brain encephalopathy to adolescent onset DOPA-responsive dystonia (DRD). We expressed isoform 1 of human TH (hTH1) and its dystonia-associated missense variants in E. coli, analysed their quaternary structure and thermal stability using size exclusion chromatography, circular dichroism, multi-angle light scattering, transmission electron microscopy (TEM), small-angle X-ray scattering, and assayed hydroxylase activity. Wild-type (WT) hTH1 was a mixture of enzymatically stable tetramers (85.6%) and octamers (14.4%), with little interconversion between these species. We also observed small amounts of higher-order assemblies of long chains of enzyme by TEM. To investigate the role of molecular assemblies in the pathogenesis of DRD, we compared the structure of WT hTH1 with the DRD-associated variants R410P and D467G that are found in vicinity of the predicted subunit interfaces. In contrast to WT hTH1, R410P and D467G were mixtures of tetrameric and dimeric species. Inspection of the available structures revealed that Arg410 and Asp467 are important for maintaining the stability and oligomeric structure of TH. Disruption of the normal quaternary enzyme structure by missense variants is a new molecular mechanism that may explain the loss of TH enzymatic activity in DRD. Unstable missense variants could be targets for pharmacological intervention in DRD, aimed to re-establish the normal oligomeric state of TH. This article is protected by copyright. All rights reserved. PMID- 30411799 TI - Factors Associated with False Positive Fecal Immunochemical Tests in a Large German Colorectal Cancer Screening Study. AB - In recent years fecal immunochemical tests (FITs) have been offered as a primary screening test for colorectal cancer (CRC) in a growing number of countries. This study aims to identify factors associated with apparently false positive results of FITs. In this cross-sectional study within the German population-based screening colonoscopy program, participants were invited to provide a stool sample for FIT prior to colonoscopy. 4656 participants aged 50-79 years with no known history of CRC or inflammatory bowel disease (IBD) and no findings of neoplasms at screening colonoscopy were included in the current analyses. Main outcome measures were rates and factors associated with apparently false positive FIT results. Apparently false positive FIT results were found for 378 participants (8.1%). Male sex (OR=1.30, 95%CI 1.03, 1.62), age >= 65 years (OR=1.27, 95%CI 1.01, 1.59), a BMI >= 30 kg/m2 (OR=1.81, 95%CI 1.36, 2.40), current smoking (OR=1.63, 95%CI 1.18, 2.25), use of aspirin (OR=1.36, 95%CI 1.02, 1.82) and a new diagnosis of IBD (OR=9.13, 95%CI 2.18, 38.19) or other non neoplastic findings (OR=1.86, 95%CI 1.37, 2.51) at screening colonoscopy were independently associated with significantly increased odds of a positive FIT. Although considered false-positive in the context of CRC screening, the identified factors associated with apparently false positive FIT results are known risk factors for and may point to conditions other than colorectal neoplasms that may be potential sources of gastrointestinal bleeding, potentially requiring further medical follow up. The study was registered in the German Clinical Trials Register (DRKS-ID: DRKS00008737). This article is protected by copyright. All rights reserved. PMID- 30411800 TI - A Simplified Gas Chromatographic Fatty-Acid Analysis by the Direct Saponification/Methylation Procedure and Its Application on Wild Tuna Larvae. AB - A method for the direct preparation of fatty-acid methyl esters (FAME) was simplified for fatty-acid analysis of a single fish larva using gas chromatography (GC). The method included the isolation of a larval trunk and drying in a glass vial, followed by saponification of all the contents without prior lipid extraction. Thereafter, the fatty acids released were methylated by trimethylsilyldiazomethane. This method has advantages over another method, direct acid-catalyzed transesterification, because both the saponification and methylation at room temperature can reduce loss of unsaturated fatty acids and formation of artifacts unavoidable in acidic reaction at high temperature. GC of the products showed that the simplified method can yield methyl esters without artifacts interfering analysis. More than 50 fatty acids were determined, which are twice as many as those previously analyzed using high-performance liquid chromatography. Observation of consistent small impurities in GC of blank tests allowed the accurate determination of fatty acids by correcting the peak areas. Dry matter weights (<3 mg) and the total fatty-acid contents displayed a linear relationship. Fatty-acid analysis of wild larvae of bluefin tuna, yellowfin tuna, and skipjack tuna collected from the waters around Japan (n = 100) revealed that the eicosapentaenoic acid (EPA) level in bluefin tuna collected from the Japan Sea was significantly higher than that in the three species collected from Nansei Islands. The simplified direct saponification/methylation method will be a powerful tool for investigating growth and survival of individual larval tuna and other fish species. PMID- 30411801 TI - Parthenogenetic female populations in the brown alga Scytosiphon lomentaria (Scytosiphonaceae, Ectocarpales): decay of a sexual trait and acquisition of asexual traits. AB - In isogamous brown algae, the sexuality of populations needs to be tested by laboratory crossing experiments, as the sexes of gametophytes are morphologically indistinguishable. In some cases, gamete fusion is not observed and the precise reproductive mode of the populations is unknown. In the isogamous brown alga Scytosiphon lomentaria in Japan, both asexual (gamete fusion is unobservable) and sexual populations (gamete fusion is observable) have been reported. In order to elucidate the reproductive mode of asexual populations in this species, we used PCR-based sex markers to investigate the sex ratio of three asexual and two sexual field populations. The markers indicated that the asexual populations consisted only of female individuals, whereas sexual populations are composed of both males and females. In culture, female gametes of most strains from asexual populations were able to fuse with male gametes; however, they had little to no detectable sexual pheromones, significantly larger cell sizes, and more rapid parthenogenetic development compared to female/male gametes from sexual populations. Investigations of sporophytic stages in the field indicated that alternation of gametophytic and parthenosporophytic stages occur in an asexual population. These results indicate that the S. lomentaria asexual populations are female populations that lack sexual reproduction and reproduce parthenogenetically. It is likely that females in the asexual populations have reduced a sexual trait (pheromone production) and have acquired asexual traits (larger gamete sizes and rapid parthenogenetic development). PMID- 30411802 TI - Assessing the Time Dependence of Prognostic Values of Cytology and Human Papillomavirus Testing in Cervical Cancer Screening. AB - Accurate assessment of risks for developing cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) following a given set of screening test results is instrumental to reaching valid conclusions and informing cervical cancer screening recommendations. Using data from the Canadian Cervical Cancer Screening Trial (CCCaST), we assessed prognostic values of enrollment screening test results to predict CIN2+ among women attending routine cervical screening using multivariable Cox proportional hazards (PH) regression and its flexible extension during each of two follow-up periods (protocol-defined and extended). Non proportional (time-dependent (TD)) and/or non-linear effects were modeled, as appropriate. Women with abnormal cytology had hazard ratios (HRs) for CIN2+ detection of 17.61 (95% CI: 11.25-27.57) and 10.46 (95% CI: 5.41-20.24) relative to women with normal cytology during the protocol-defined and extended follow-up periods, respectively. High-risk human papillomavirus (HR-HPV) positivity was an even stronger predictor of CIN2+ risk, with significant TD effects during both follow-up periods (p<0.001 for both TD effects). Risks among women co-testing HR HPV+ with and without abnormal cytology (relative to women co-testing negative) were highest immediately following baseline, and decreased significantly thereafter (p<0.001 for both TD effects). HRs for HPV16+ and HPV18+ women (relative to those testing HR-HPV-) did not vary significantly over time (HR=182.96; 95% CI: 95.16-351.77 and HR=111.81; 95% CI: 44.60-280.31, respectively). Due to TD effects, conventional Cox model estimates considerably underestimated adjusted HRs associated with positive HR-HPV testing results early on in the follow-up periods. This article is protected by copyright. All rights reserved. PMID- 30411803 TI - Nuclear protein phylogenies support the monophyly of the three bryophyte groups (Bryophyta Schimp.). AB - Unraveling the phylogenetic relationships between the four major lineages of terrestrial plants (mosses, liverworts, hornworts, and vascular plants) is essential for an understanding of the evolution of traits specific to land plants, such as their complex life cycles, and the evolutionary development of stomata and vascular tissue. Well supported phylogenetic hypotheses resulting from different data and methods are often incongruent due to processes of nucleotide evolution, which are difficult to model: for example, substitutional saturation and composition heterogeneity. We reanalyse a large published dataset of nuclear data and model these processes using degenerate codon recoding and tree-heterogeneous composition substitution models. Our analyses resolve bryophytes as a monophyletic group and show that the non-monophyly of the clade, that is supported by the analysis of nuclear nucleotide data, is due solely to fast-evolving synonymous substitutions. The current congruence among phylogenies of both nuclear and chloroplast analyses lend considerable support to the conclusion that the bryophytes are a monophyletic group. An initial split between bryophytes and vascular plants implies that the bryophyte life cycle (with a dominant gametophyte nurturing an unbranched sporophyte) may not be ancestral to all land plants and that stomata are likely a symplesiomorphy among embryophytes. This article is protected by copyright. All rights reserved. PMID- 30411804 TI - Maternal position in the second stage of labour for women with epidural anaesthesia. AB - BACKGROUND: Epidural analgesia in labour prolongs the second stage and increases instrumental delivery. It has been suggested that a more upright maternal position during all or part of the second stage may counteract these adverse effects. This is an update of a Cochrane Review published in 2017. OBJECTIVES: To assess the effects of different birthing positions (upright or recumbent) during the second stage of labour, on maternal and fetal outcomes for women with epidural analgesia. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (5 June 2018), and the reference lists of retrieved studies. SELECTION CRITERIA: All randomised or quasi-randomised trials including pregnant women (primigravidae or multigravidae) in the second stage of induced or spontaneous labour receiving epidural analgesia of any kind. Cluster randomised controlled trials would have been eligible for inclusion but we found none. Studies published in abstract form only were also eligible.We assumed the experimental intervention to be maternal use of any upright position during the second stage of labour, compared with the control condition of remaining in any recumbent position. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, assessed risks of bias, and extracted data. We contacted study authors to obtain missing data. We assessed the quality of the evidence using the GRADE approach.We carried out a planned sensitivity analysis of the three studies with low risks of bias for allocation concealment and incomplete outcome data reporting, and further excluded one study with a co-intervention (this was not prespecified). MAIN RESULTS: We include eight randomised controlled trials, involving 4464 women, comparing upright positions versus recumbent positions in this update. Five were conducted in the UK, one in France and two in Spain.The largest UK trial accounted for three quarters of all review participants, and we judged it to have low risk of bias. We assessed two other trials as being at low risk of selection and attrition bias. We rated four studies at unclear or high risk of bias for both selection and attrition bias and one study as high risk of bias due to a co-intervention. The trials varied in their comparators, with five studies comparing different positions (upright and recumbent), two comparing ambulation with (recumbent) non ambulation, and one study comparing postural changes guided by a physiotherapist to a recumbent position.Overall, there may be little or no difference between upright and recumbent positions for our combined primary outcome of operative birth (caesarean or instrumental vaginal): average risk ratio (RR) 0.86, 95% confidence interval (CI) 0.70 to 1.07; 8 trials, 4316 women; I2 = 78%; low quality evidence. It is uncertain whether the upright position has any impact on caesarean section (RR 0.94, 95% CI 0.61 to 1.46; 8 trials, 4316 women; I2 = 47%; very low-quality evidence), instrumental vaginal birth (RR 0.90, 95% CI 0.72 to 1.12; 8 trials, 4316 women; I2 = 69%) and the duration of the second stage of labour (mean difference (MD) 6.00 minutes, 95% CI -37.46 to 49.46; 3 trials, 456 women; I2 = 96%), because we rated the quality of the evidence as very low for these outcomes. Maternal position in the second stage of labour probably makes little or no difference to postpartum haemorrhage (PPH), (PPH requiring blood transfusion): RR 1.20, 95% CI 0.83 to 1.72; 1 trial, 3093 women; moderate-quality evidence. Maternal satisfaction with the overall childbirth experience was slightly lower in the upright group: RR 0.95, 95% CI 0.92 to 0.99; 1 trial, 2373 women. Fewer babies were born with low cord pH in the upright group: RR 0.43, 95% CI 0.20 to 0.90; 2 trials, 3159 infants; moderate-quality evidence.The results were less clear for other maternal or fetal outcomes, including trauma to the birth canal requiring suturing (average RR 1.00, 95% CI 0.89 to 1.13; 3 trials, 3266 women; I2 = 46%; low-quality evidence), abnormal fetal heart patterns requiring intervention (RR 1.69, 95% CI 0.32 to 8.84; 1 trial, 107 women; very low-quality evidence), or admission to neonatal intensive care unit (RR 0.54, 95% CI 0.02 to 12.73; 1 trial, 66 infants; very low-quality evidence). However, the CIs around some of these estimates were wide, and we cannot rule out clinically important effects.In our sensitivity analysis of studies at low risk of bias, upright positions increase the chance of women having an operative birth: RR 1.11, 95% CI 1.03 to 1.20; 3 trials, 3609 women; high-quality evidence. In absolute terms, this equates to 63 more operative births per 1000 women (from 17 more to 115 more). This increase appears to be due to the increase in caesarean section in the upright group (RR 1.29; 95% CI 1.05 to 1.57; 3 trials, 3609 women; high-quality evidence), which equates to 25 more caesarean sections per 1000 women (from 4 more to 49 more). In the sensitivity analysis there was no clear impact on instrumental vaginal births: RR 1.08, 95% CI 0.91 to 1.30; 3 trials, 3609 women; low-quality evidence. AUTHORS' CONCLUSIONS: There may be little or no difference in operative birth between women who adopt recumbent or supine positions during the second stage of labour with an epidural analgesia. However, the studies are heterogeneous, probably related to differing study designs and interventions, differing adherence to the allocated intervention and possible selection and attrition bias. Sensitivity analysis of studies at low risk of bias indicated that recumbent positions may reduce the need for operative birth and caesarean section, without increasing instrumental delivery. Mothers may be more satisfied with their experience of childbirth by adopting a recumbent position. The studies in this review looked at left or right lateral and semi-recumbent positions. Recumbent positions such as flat on the back or lithotomy are not generally used due to the possibility of aorto-caval compression, although we acknowledge that these recumbent positions were not the focus of trials included in this review. PMID- 30411805 TI - Dry conditions and disturbance promote liana seedling survival and abundance. AB - Species composition and community structure in neotropical forests have been severely affected by increases in climate change and disturbance. Among the most conspicuous changes is the proliferation of lianas. These increases have affected not only the carbon storage capacity of forests but also tree dynamics by reducing tree growth and increasing mortality. Despite the importance of lianas in neotropical forests, most of the studies on lianas have focused on adult stages, ignoring dynamics at the seedlings stage. Here, we asked whether observed increases in liana abundance are associated with a demographic advantage that emerges early in liana ontogeny and with decreased precipitation and increased disturbance. To test this, we compared patterns of growth and survival between liana seedlings and tree seedlings using a long-term dataset of seedling plots from a subtropical wet forest in Puerto Rico. Then, we examined the effect of precipitation and land use history on these demographic variables. We found evidence for liana seedling survival advantage over trees, but no growth advantages. This survival advantage exhibited significant temporal variation linked with patterns of rainfall, as well as differences associated with land-use history in the study area. Furthermore, we found that neighborhood density has a negative effect on liana survival and growth. Our results indicate that liana proliferation is likely related to a survival advantage that emerges in early stages, and is influenced by climatic conditions and past disturbance. Predicted climatic changes in rainfall patterns, including more frequent and severe droughts, together with increases in disturbance, could have a significant effect on seedling tropical communities by favoring lianas. This article is protected by copyright. All rights reserved. PMID- 30411806 TI - Diagnostic Performance and Accuracy of the 3 Interpreting Methods of Breast Strain Elastography: A Systematic Review and Meta-analysis. AB - There are 3 methods of interpreting breast strain elastography: the elastographic to-B-mode length ratio (E/B), a 5-point color scale (5P), and the strain ratio (SR). This meta-analysis assessed which method is superior to the others. A systematic search of the medical literature was performed in July 2017. Studies were eligible for inclusion if they fulfilled the following criteria: (1) had biopsy-proven or long-term stability as the reference standard; (2) used either the E/B, 5P, or SR to interpret results; and (3) had at least 50 cases. A total of 220 records were retrieved; 60 full-text articles were examined, and 46 were included in the meta-analysis. Publication years ranged from 2007 and 2017. The quality of studies was generally high. The mean age of women was 48 years; 12,398 lesions (4242 malignant) were analyzed. For the 5P method, the sensitivity was 77%; specificity, 87%; positive likelihood ratio (LR), 5.3; and negative LR, 0.24. For the SR method, sensitivity was 87%; specificity, 81%; positive LR, 4.8; and negative LR, 0.16. For the E/B method, sensitivity was 96%; specificity, 88%; positive LR, 7.1; and negative LR, 0.03. Of the 3 methods, the E/B had the highest sensitivity, and the E/B and 5P had the highest specificity. With a negative LR of 0.03, the E/B method can downgrade lesions with a pretest probability of 50% to a 2% probability of malignancy. PMID- 30411807 TI - Prevalence of Shiga toxin-producing Escherichia coli in pasture-based dairy herds. AB - Shiga toxin-producing Escherichia coli strains (STEC) are food-borne pathogens. While E. coli O157:H7 is commonly associated with cattle, less is known about the prevalence of non-O157 STEC serogroups in bovines. This study evaluated the prevalence and virulence status of O157:H7 and six E. coli O-serogroups (O26, O103, O45, O145, O121, O111) in New Zealand dairy farms using molecular as well as culture-based methods. Fresh farm dairy effluent (FDE) (n = 36) and composite calf faeces (n = 12) were collected over three samplings from 12 dairy farms. All seven target serogroups were detected through molecular techniques. Of the 202 isolates which were serologically confirmed following traditional culturing and immunomagnetic separation (IMS), O103, O26, O45 and O121 were the most common serogroups, being found in 81, 47, 42 and 32% of the FDE and in 17, 33, 25 and 9% of the calf faeces respectively. The majority (157/202) of the isolates were negative for stx and eae virulence genes. The prevalence of the seven target STEC was low, and only nine O26 isolates (4%) were recovered from four of the farms. The study has highlighted the need for improving the isolation of Top 7 STEC from the stx-negative populations present in fresh dairy effluent and calf faeces. SIGNIFICANCE AND IMPACT OF THE STUDY: Shiga toxin-producing Escherichia coli (STEC) are important food-borne pathogens that can cause severe illness in humans. Cattle are asymptomatic reservoirs for STEC, and transmission to humans can be by consumption of food products or water contaminated with cattle faeces. Our study investigated the prevalence of O157:H7 and six E. coli serogroups of STEC (O26, O103, O45, O145, O121, O111) over time in the dairy reservoir and increases the knowledge and understanding of these pathogens on pasture-based farms. Such information is required to develop risk-assessment models aiming at limiting transmission of these STEC to human. PMID- 30411808 TI - A Time to Heal: The EMPROVE Protocol. PMID- 30411809 TI - Serum pentraxin-3 levels and flow-mediated dilation in dipper and non-dipper hypertension. AB - BACKGROUND: Endothelial dysfunction is one of the main pathological processes of hypertension. The association of serum pentraxin-3 (PTX3) levels and endothelial dysfunction becomes a more interesting scientific research issue due to high potential of PTX3 as a diagnostic and prognostic biomarker. We aimed to investigate the relationship between serum PTX3 levels and flow-mediated dilation results in patients with dipper and non-dipper hypertension. METHODS: This study included 90 hypertensive patients were divided into two groups based on 24 hours ambulatory blood pressure monitoring (ABPM): 38 patients with a dipper pattern and 52 patients with non-dipper pattern. Noninvasive evaluation of the endothelial functions was performed using flow-mediated dilation (FMD) method. RESULTS: Serum pentraxin-3 levels were higher in patients with non-dipper HT compared to dipper hypertension (P = 0.028). In addition, we found negative correlation between serum PTX3 and FMD basal/FMD hyperemia ratio (r = -0.297, P = 0.05 for FMD basal/FMD hyperemia ratio, respectively). CONCLUSIONS: Serum PTX3 levels are closely related with the measures of indirect noninvasive evaluation methods (FMD) in both DH and NDH patients. PMID- 30411810 TI - Spinal cord stimulation ameliorates detrusor over-activity and visceromotor pain responses in rats with cystitis. AB - AIM: Interstitial cystitis/painful bladder syndrome/(IC/PBS) results in recurring pain in the bladder and surrounding pelvic region caused by abnormal excitability of micturition reflexes. Spinal cord stimulation (SCS) is currently clinically used for the attenuation of neuropathic and visceral pain. The present study examined whether SCS at upper lumbar segments modulates detrusor overactivity and visceral hyperalgesia associated with cystitis in a rat model of cyclophosphamide (CYP)-induced cystitis. METHODS: Cystitis was induced by intraperitoneal injection of CYP (200 mg/kg) in six adult female Sprague Dawley rats 48 h prior to urodynamic recordings. Another six rats served as-controls with saline injection. Cystometry and the external urethral sphincter (EUS) electromyography during bladder infusion were evaluated under urethane anesthesia. The visceromotor reflexes (VMR) obtained from the external abdominal oblique muscle were quantified during bladder infusion and isotonic bladder distension (IBD), respectively. After baseline recordings were taken, SCS was applied on the dorsal surface of L3 for 25 min. Urodynamic recordings and VMR during bladder infusion and IBD were repeated 2 h after SCS. RESULTS: CYP resulted in detrusor overactivity, stronger EUS tonic contractions, and increased VMR. SCS significantly reduced non-voiding contractions, prolonged EUS relaxation, and delayed VMR appearance during bladder infusion as well as significantly decreased VMR during IBD in cystitis rats. CONCLUSION: SCS improved bladder function and EUS relaxation during bladder infusion and significantly attenuated visceral nociceptive-related VMR during IBD in cystitis rats. SCS may have therapeutic potential for patients with hyperalgesia and IC/PBS. PMID- 30411811 TI - Caffeine improves bladder function in streptozotocin-induced diabetic rats. AB - AIMS: To examine the protective effects of caffeine in rats with diabetes mellitus (DM) by using urodynamics. METHODS: Female Sprague-Dawley rats (n = 24) were divided into four groups: control group, DM group, DM + caffeine (5 mg/kg/day), and DM + caffeine (10 mg/kg/day). DM was induced by streptozotocin (STZ). Cystometric studies were conducted on all rats. After 8 weeks of treatment with caffeine, the urodynamic parameters, including bladder capacity, residual urine volume, voiding time, and peak voiding pressure, were measured. RESULTS: DM rats had a higher bladder capacity and post-void residual urine volume (PVR), an increased voiding time and peak voiding pressure, and a markedly lower voiding efficiency than the control group rats. After treatment with caffeine, bladder capacity, post-void residual urine volume, and peak voiding pressure were significant lower than those in the DM group, but voiding efficiency was markedly higher. CONCLUSION: The results suggested that caffeine (5 or 10 mg/kg/day) may improve the bladder function at 8 weeks after STZ induction. Thus, this may represent a potential strategy to increase voiding efficiency in diabetes. PMID- 30411812 TI - Correlation of MRI features of urethral diverticulum and pre- and post-operative stress urinary incontinence. AB - AIMS: The complexity of urethral diverticulectomy depends on location, size, and degree of circumferential involvement. MRI features were examined to predict functional outcome after surgery for urethral diverticulum (UD). METHODS: A prospectively acquired database was of all patients who have had surgical excision of UD at a tertiary center since 2004 was reviewed. Particular focus was pre- and post-operative urodynamically proven stress urinary incontinence (USUI), and pre-operative MRI features. MRI parameters included diverticular volume, degree of circumferential involvement around the urethra, distance of the Os of UD to bladder neck and urethral length. Students t-test and Mann-Whitney U-test were used to compare rates of de novo USUI. RESULTS: There were 100 patients (mean age 45.8 yrs), who had excision of UD since 2004, with a minimum follow-up of 10 months (range 10-112 months). Full MRI data was available for 83 patients. Fourteen were of simple configuration (16.8%), 32 were horseshoe (38.6%), and 37 (44.6%) were circumferential. Twenty-five (25%) patients had pre-operative USUI, while 12 (12%) patients developed de novo USUI post-excision. While, the majority of patients with de novo USUI (67%) had >270 degrees circumferential involvement of urethra, the pre-operative diverticular volume did not predict the likelihood of USUI developing (P = 0.3). A shorter urethral length was associated with pre operative USUI. CONCLUSIONS: 25% of all patients had pre-op USUI, and diverticular volume and urethral length was significantly smaller in this group. The majority of patients with de novo USUI had complex diverticula configuration with higher baseline circumferential angle around urethra, with 67% of angle's between 270 and 360 degrees . PMID- 30411813 TI - Hyperbaric oxygen significantly improves frequent urination, hyperalgesia, and tissue damage in a mouse long-lasting cystitis model induced by an intravesical instillation of hydrogen peroxide. AB - AIM: To investigate whether hyperbaric oxygen (HBO) is effective for the pathophysiological findings in an IC/PBS-like mouse model induced by intravesical hydrogen peroxide (H2 O2 ). METHODS: Six-week-old ICR female mice (N = 16) were divided into four experimental groups: (1) sham control with intravesical vehicle instillation twice, and without subsequent treatment (N = 4); (2) H2 O2 instillation twice, followed by HBO (100% O2 , 2 ATA, 30 min per session) (N = 4); (3) H2 O2 instillation twice, followed by dummy hyperbaric treatment (air, 2ATA, 30 min per session) (N = 4); and (4) H2 O2 instillation twice, followed by no treatment (N = 4). Body weight, voiding frequency, tidal voiding volume, and individual bladder pain threshold using the von-Frey test were measured. Whole body uptake of an inflammation-specific fluorescent pan-cathepsin was assessed by an in vivo imaging. Immunohistochemical staining and the mRNA expression of several biomarkers associated with chronic inflammation in resected bladders were evaluated. RESULTS: The HBO-treated group showed significant improvement in voiding frequency, tidal voiding volume, and the individual bladder pain threshold. Moreover, HBO markedly suppressed H2 O2 -induced inflammation, edema, and fibrosis in bladder wall, concomitant with a significant decrease in mRNA expressions of inflammation biomarkers and a significant increase in endothelial nitric oxide synthase expression. HBO also inhibited the expression of transient receptor potential channels induced by H2 O2 instillation. CONCLUSION: These results suggest that HBO contributes to elimination of H2 O2 -induced long lasting cystitis through the repair of chronically inflamed bladder tissue and inhibition of the bladder sensory system. PMID- 30411814 TI - RE: Pastuszka et al. Prenatal myelomeningocele repair improves urinary continence and reduces the risk of constipation. PMID- 30411815 TI - Serine hydroxymethyltransferase 1 promoter hypermethylation increases the risk of essential hypertension. AB - BACKGROUND: Serine hydroxymethyltransferase 1 (SHMT1) is an enzyme involved in folic acid metabolism and is known to contribute to the development of hypertension. We evaluated the relationship between SHMT1 promoter methylation and essential hypertension (EH). METHODS: Quantitative methylation-specific polymerase chain reaction was used to measure the SHMT1 promoter methylation level in 241 EH patients and 288 age- and gender-matched healthy individuals. The diagnostic value of SHMT1 promoter hypermethylation was analyzed using a receiver operating characteristic (ROC) curve. The Gene Expression Omnibus (GEO) database and dual-luciferase reporter assay were used to validate our findings. RESULTS: Compared with the control group, significant differences in SHMT1 promoter methylation were found in both EH and hyperhomocysteinemia groups (P < 0.001 and P = 0.029, respectively). The area under the curve of the diagnosis of SHMT1 promoter hypermethylation for EH was 0.808, with a sensitivity and specificity of 73.9% and 77.8%, respectively. The risk of SHMT1 promoter hypermethylation was significantly higher in the >65-year group than in the <=65-year group (odds ratio = 3.925; 95% confidence interval = 2.141-7.196). In addition, GEO database analysis showed that 5-aza-deoxycytidine increased gene expression in several carotid endothelial cell lines. A dual-luciferase reporter assay revealed that the target sequence in the SHMT1 promoter upregulated gene expression. CONCLUSION: Our findings indicate that SHMT1 promoter hypermethylation increases the risk of EH and may be a promising biomarker for EH. PMID- 30411816 TI - Early prediction of severity in acute ischemic stroke and transient ischemic attack using platelet parameters and neutrophil-to-lymphocyte ratio. AB - BACKGROUND: It is still not easy to predict severity promptly in patients with acute ischemic stroke (AIS) and transient ischemic attack (TIA). We investigated that platelet parameters or combinations of them could be a useful tool for early prediction of severity of AIS and TIA at admission and after 3 months. METHODS: We prospectively recruited 104 patients newly diagnosed with AIS and TIA. We investigated their neutrophil-to-lymphocyte ratio (NLR) and platelet parameters. According to the Modified Rankin Scale scores, the patients were divided into two groups. RESULTS: In receiver operating characteristic (ROC) curve analyses, mean platelet volume (MPV), NLR/platelet count (PLT), MPV/PLT, MPV*NLR, and MPV*NLR/PLT showed statistically significant results in both at admission and after 3 months. Values of area under ROC curves for those tests at admission were 0.646, 0.697, 0.664, 0.708, and 0.722, respectively. Also, values after 3 months were 0.591, 0.661, 0.638, 0.662, and 0.689, respectively. CONCLUSION: MPV*NLR/PLT could be used as a relatively good tool for predicting severity at the time of admission and after 3 months than other parameters or combinations of them. Further studies have to be carried out to investigate the best parameter for predicting the severity of AIS and TIA. PMID- 30411817 TI - Predictors of mortality and outcomes in transvenous lead extraction for systemic and local infection cohorts. AB - BACKGROUND: Transvenous lead extraction (TLE) may be necessary due to infective and noninfective indications. We aim to identify predictors of 30-day mortality and risk factors between infective versus noninfective groups and systemic versus local infection subgroups. METHODS: A total of 925 TLEs between October 2000 and December 2016 were prospectively collected and dichotomized (infective group n = 505 vs noninfective group n = 420 and systemic infection n = 164 vs local infection n = 341). RESULTS: All-cause major complication including deaths was significantly higher (5.1%, n = 26 vs 1.2%, n = 5, P = 0.001) as well as 30-day mortality (4.0%, n = 20 vs 0.2%, n = 1, P < 0.001) in the infective group compared to the noninfective group. Both subgroups (systemic vs local infection) were balanced for demographics. All-cause major complication including deaths was significantly higher (9.1%, n = 15 vs 3.2%, n = 11, P = 0.008) as well as all cause 30-day mortality (7.9%, n = 13 vs 2.1%, n = 7, P = 0.003) in the systemic infection subgroup compared to the local infection subgroup. CONCLUSION: Patients undergoing TLE for infective indications are at greater risk of 30-day all-cause mortality compared to noninfective patients. Patients undergoing TLE for systemic infective indications are at greater risk of 30-day all-cause mortality compared to patients with local infection. Renal impairment, systemic infection, and elevated preprocedure C-reactive protein are independent predictors of 30-day all cause mortality in patients undergoing TLE for an infective indication. PMID- 30411818 TI - Conventional or minimized cardiopulmonary bypass support during coronary artery bypass grafting? - An analysis by means of perfusion and body mass index. AB - : The use of minimized cardiopulmonary bypass support to reduce the side effects of extracorporeal circulation is still contradictorily discussed. This study compares perfusion operated by conventional (CCPB) and minimized (MCPB) cardiopulmonary bypass support during coronary artery bypass grafting (CABG). METHODS: This study includes the data of 5164 patients treated at our department between 2004 and 2014. Tissue perfusion during cardiopulmonary bypass support and cardiac arrest was assessed by means of body mass index, hemodilution, blood pressure with corresponding pump flow and venous oxygen saturation, serum lactate, and serum pH. RESULTS: Hemodilution was more pronounced after CCPB: hemoglobin had dropped to 4.47+/-0.142 g/dL after CCPB and to 2.77+/-0.148 g/dL after MCPB (p=0.0022). Despite the higher pump flow in conventional circuits (4.86-4.95 L/min vs. 4.1-4.18 L/min), mean blood pressure was higher during minimized bypass support (53+/-10 vs. 56+/-13 mmHg [aortic clamping], 57+/-9 vs. 61+/-12 mmHg [34 degrees C], 55+/-9 vs.59+/-11 mmHg [aortic clamp removal], p<0.0001) at all time points. Venous oxygen saturation remained on comparable levels of >70% during both conventional and minimized cardiopulmonary bypass support. The increase in serum lactate was more pronounced after CCPB (8.98+/ 1.28 vs. 3.66+/-1.25 mg/dl, p=0.0079), corresponding to a decrease in serum pH to acidotic levels (7.33+/-0.06 vs. 7.35+/-0.06, p<0.0001). These effects were evident in all BMI ranges. CONCLUSION: Minimized cardiopulmonary bypass support provides efficient perfusion in all BMI ranges and is thus equivalent to conventional circuits. This article is protected by copyright. All rights reserved. PMID- 30411819 TI - Understanding multi-pill ingestion of prescription opioids: Prevalence, characteristics, and motivation. AB - PURPOSE: Oral use is the primary route of administration among non-medical prescription opioid users. While progression to non-oral routes and shifts to stronger opioids have been previously studied as ways to cope with tolerance, the prevalence and patterns of those who cope by increasing the number of pills/tablets ingested at one time (ie, multi-pill use) has not been assessed. METHODS: A subset (N = 231) of treatment-seeking opioid users from a national opioid surveillance system, participating in the Researchers and Participants Interacting Directly (RAPID) Program, completed an online survey centered on multi-pill use. RESULTS: Over two-thirds of non-medical prescription opioid users had a history of multi-pill use (67.7%), defined as ingesting four or more of the same pill, intact and at the same time. Among these (n = 154), the median maximum number of pills taken at one time was eight, with over 20% ingesting 11 or more pills in a single instance. Nearly half engaged in multi-pill ingestion more than once a day in the past month (43.8%), with accessibility to lower dose pills being the primary motivator (85.4%). Hydrocodone immediate-release (IR) compounds were by far the most frequently endorsed (90.3%), followed by oxycodone IR tablets with acetaminophen (76.0%) and oxycodone IR tablets containing no acetaminophen/ibuprofen (56.5%). CONCLUSIONS: These results indicate that the ingestion of multiple opioid pills/tablets is extremely common among treatment seeking opioid users. This, and other forms of non-medical oral use of prescription opioids, should be taken under consideration when developing prevention and intervention efforts targeting the opioid epidemic. PMID- 30411820 TI - The evolution of abdominal microbiomes in fungus-growing ants. AB - The attine ants are a monophyletic lineage that switched to fungus-farming ca. 55 60 MYA. They have become a model for the study of complex symbioses after additional fungal and bacterial symbionts were discovered, but their abdominal endosymbiotic bacteria remain largely unknown. Here we present a comparative microbiome analysis of endosymbiotic bacteria spanning the entire phylogenetic tree. We show that, across 17 representative sympatric species from eight genera sampled in Panama, abdominal microbiomes are dominated by Mollicutes, alpha- and gamma-Proteobacteria, and Actinobacteria. Bacterial abundances increase from basal to crown branches in the phylogeny reflecting a shift towards putative specialized and abundant abdominal microbiota after the ants domesticated gongylidia-bearing cultivars, but before the origin of industrial-scale farming based on leaf-cutting herbivory. This transition coincided with the ancestral single colonization event of Central/North America ca. 20 MYA, documented in a recent phylogenomic study showing that the entire crown-group of the higher attine ants, including the leaf-cutting ants, evolved there and not in South America. Several bacterial species are located in gut tissues or abdominal organs of the evolutionarily derived, but not the basal attine ants. The composition of abdominal microbiomes appears to be affected by the presence/absence of defensive antibiotic-producing actinobacterial biofilms on the worker ants' cuticle, but the significance of this association remains unclear. The patterns of diversity, abundance, and sensitivity of the abdominal microbiomes that we obtained explore novel territory in the comparative analysis of attine fungus-farming symbioses and raise new questions for further in-depth research. This article is protected by copyright. All rights reserved. PMID- 30411821 TI - Phosphorus vs sulphur: discovery of benzenephosphonamidates as new versatile sulfonamide-mimic chemotypes acting as carbonic anhydrase inhibitors. AB - The first zinc binding group (ZBG) to have been identified as inhibitor of the metallo-enzymes carbonic anhydrases (CA, EC 4.2.1.1) was the sulfonamide. From then on several classes of zinc-binders have been described. Herein we propose the benzenephosponamidates as a new chiral aromatic sulfonamide-mimic ZBG able to meet the requirements for effectively binding the enzyme active site. Several low micromolar CA I, II, VII, IX inhibitors were thus detected. Kinetic studies, QM polarized ligand docking and MM-GBSA in silico methods were used to characterize this newly identified CA inhibitor chemotype. PMID- 30411822 TI - Quantifying long-term recurrence in planktonic microbial eukaryotes. AB - How much temporal recurrence is present in microbial assemblages is still an unanswered ecological question. Even though marked seasonal changes have been reported for whole microbial communities, less is known on the dynamics and seasonality of individual taxa. Here, we aim at understanding microbial recurrence at three different levels: community, taxonomic group and Operational Taxonomic Units (OTUs). For that, we focused on a model microbial eukaryotic community populating a long-term marine microbial observatory using 18S rRNA-gene data from two organismal size-fractions: the picoplankton (0.2-3 MUm) and the nanoplankton (3-20 MUm). We have developed an index to quantify recurrence in particular taxa. We found that community structure oscillated systematically between two main configurations corresponding to winter and summer over the 10 years studied. A few taxonomic groups like Mamiellophyceae or MALV-III presented clear recurrence (i.e. seasonality), whereas 13-19% of the OTUs in both size fractions, accounting for ~40% of the relative abundance, featured recurrent dynamics. Altogether, our work links long-term whole community dynamics with that of individual OTUs and taxonomic groups, indicating that recurrent and non recurrent changes characterize the dynamics of microbial assemblages. This article is protected by copyright. All rights reserved. PMID- 30411823 TI - Genomic and transcriptomic signals of thermal tolerance in heat-tolerant corals (Platygyra daedalea) of the Arabian/Persian Gulf. AB - Scleractinian corals occur in tropical regions near their upper thermal limits and are severely threatened by rising ocean temperatures. However, several recent studies have shown coral populations can harbor genetic variation in thermal tolerance. Here we have extended these approaches to study heat tolerance of corals in the Persian/Arabian Gulf, where heat-tolerant local populations experience extreme summer temperatures (up to 36 degrees C). To evaluate whether selection has depleted genetic variation in thermal tolerance, estimate potential future adaptive responses and understand the functional basis for these corals' unusual heat tolerance, we conducted controlled crosses in the Gulf coral Platygyra daedalea. Heat tolerance is highly heritable in this population (h2 =0.487-0.748), suggesting substantial potential for adaptive responses to selection for elevated temperatures. To identify genetic markers associated with this variation, we conducted genome-wide SNP genotyping in parental corals and tested for relationships between paternal genotype and offspring thermal tolerance. Resulting multilocus SNP genotypes explained a large fraction of variation in thermal tolerance in these crosses (69%). To investigate the functional basis of these differences in thermal tolerance, we profiled transcriptional responses in tolerant and susceptible families, revealing substantial sire effects on transcriptional responses to thermal stress. We also studied sequence variation in these expressed sequences, identifying alleles and functional groups of differentially expressed genes associated with thermal tolerance. Our findings demonstrate that corals in this population harbor extensive genetic variation in thermal tolerance, and heat-tolerant phenotypes differ in both gene sequences and transcriptional stress responses from their susceptible counterparts. This article is protected by copyright. All rights reserved. PMID- 30411824 TI - Liquid-Alloy-Assisted Growth of 2D Ternary Ga2 In4 S9 toward High-Performance UV Photodetection. AB - 2D ternary systems provide another degree of freedom of tuning physical properties through stoichiometry variation. However, the controllable growth of 2D ternary materials remains a huge challenge that hinders their practical applications. Here, for the first time, by using a gallium/indium liquid alloy as the precursor, the synthesis of high-quality 2D ternary Ga2 In4 S9 flakes of only a few atomic layers thick (~2.4 nm for the thinnest samples) through chemical vapor deposition is realized. Their UV-light-sensing applications are explored systematically. Photodetectors based on the Ga2 In4 S9 flakes display outstanding UV detection ability (R lambda = 111.9 A W-1 , external quantum efficiency = 3.85 * 104 %, and D* = 2.25 * 1011 Jones@360 nm) with a fast response speed (tauring ~ 40 ms and taudecay ~ 50 ms). In addition, Ga2 In4 S9 -based phototransistors exhibit a responsivity of ~104 A W-1 @360 nm above the critical back-gate bias of ~0 V. The use of the liquid alloy for synthesizing ultrathin 2D Ga2 In4 S9 nanostructures may offer great opportunities for designing novel 2D optoelectronic materials to achieve optimal device performance. PMID- 30411825 TI - Lowering the Schottky Barrier Height by Graphene/Ag Electrodes for High-Mobility MoS2 Field-Effect Transistors. AB - 2D transition metal dichalcogenides (TMDCs) have emerged as promising candidates for post-silicon nanoelectronics owing to their unique and outstanding semiconducting properties. However, contact engineering for these materials to create high-performance devices while adapting for large-area fabrication is still in its nascent stages. In this study, graphene/Ag contacts are introduced into MoS2 devices, for which a graphene film synthesized by chemical vapor deposition (CVD) is inserted between a CVD-grown MoS2 film and a Ag electrode as an interfacial layer. The MoS2 field-effect transistors with graphene/Ag contacts show improved electrical and photoelectrical properties, achieving a field-effect mobility of 35 cm2 V-1 s-1 , an on/off current ratio of 4 * 108 , and a photoresponsivity of 2160 A W-1 , compared to those of devices with conventional Ti/Au contacts. These improvements are attributed to the low work function of Ag and the tunability of graphene Fermi level; the n-doping of Ag in graphene decreases its Fermi level, thereby reducing the Schottky barrier height and contact resistance between the MoS2 and electrodes. This demonstration of contact interface engineering with CVD-grown MoS2 and graphene is a key step toward the practical application of atomically thin TMDC-based devices with low-resistance contacts for high-performance large-area electronics and optoelectronics. PMID- 30411826 TI - Robust Tin-Based Perovskite Solar Cells with Hybrid Organic Cations to Attain Efficiency Approaching 10. AB - The stability of a tin-based perovskite solar cell is a major challenge. Here, hybrid tin-based perovskite solar cells in a new series that incorporate a nonpolar organic cation, guanidinium (GA+ ), in varied proportions into the formamidinium (FA+ ) tin triiodide perovskite (FASnI3 ) crystal structure in the presence of 1% ethylenediammonium diiodide (EDAI2 ) as an additive, are reported. The device performance is optimized at a precursor ratio (GAI:FAI) of 20:80 to attain a power conversion efficiency (PCE) of 8.5% when prepared freshly; the efficiencies continuously increase to attain a record PCE of 9.6% after storage in a glove-box environment for 2000 h. The hybrid perovskite works stably under continuous 1 sun illumination for 1 h and storage in air for 6 days without encapsulation. Such a tin-based perovskite passes all harsh standard tests, and the efficiency of a fresh device, 8.3%, is certified. The great performance and stability of the device reported herein attains a new milestone for lead-free perovskite solar cells on a path toward commercial development. PMID- 30411827 TI - An emerging novel virus: Atypical porcine pestivirus (APPV). AB - Emerging porcine pestivirus diseases frequently challenge prevention and control strategies in the swine industry. Over the past decade, a few novel pestiviruses have been identified in pigs. This article focuses on the recently emerging atypical porcine pestivirus (APPV) that potentially threatens global swine herd health security. The virus was first identified in 2016, in the United States and thereafter, accumulated evidence shows that it is currently distributed in three continents. The clinical presentation of APPV-infected pigs is characterized by congenital tremor (CT) type A-II in piglets, while adult pigs may become persistent carriers and shedders. Here, a literature review is conducted to summarize the published findings in the virus genomic biology, transmission, epidemiology, pathogenesis, and diagnosis, which would shed light on acceleration of development of anti-APPV strategies. PMID- 30411828 TI - The genomic basis of adaptation to calcareous and siliceous soils in Arabidopsis lyrata. AB - Edaphic conditions are important determinants of plant fitness. While much has been learnt in recent years about plant adaptation to heavy-metal contaminated soils, the genomic basis underlying adaptation to calcareous and siliceous substrates remains largely unknown. We performed a reciprocal germination experiment and whole-genome re-sequencing in natural calcareous and siliceous populations of diploid Arabidopsis lyrata to test for edaphic adaptation and detect signatures of selection at loci associated with soil-mediated divergence. In parallel, genome scans on respective diploid ecotypes from the A. arenosa species complex were undertaken, to search for shared patterns of adaptive genetic divergence. Soil ecotypes of A. lyrata display significant genotype-by treatment responses for seed germination. Sequence (SNPs) and copy-number variants (CNVs) point towards loci involved in ion transport as the main targets of adaptive genetic divergence. Two genes exhibiting high differentiation among soil types in A. lyrata further share trans-specific single-nucleotide polymorphisms with A. arenosa. This work applies experimental and genomic approaches to study edaphic adaptation in A. lyrata and suggests that physiological response to elemental toxicity and deficiency underlies the evolution of calcareous and siliceous ecotypes. The discovery of shared adaptive variation between sister species indicates that ancient polymorphisms contribute to adaptive evolution. This article is protected by copyright. All rights reserved. PMID- 30411829 TI - Pd-Catalyzed Atroposelective C-H Allylation through beta-O Elimination: Diverse Synthesis of Axially Chiral Biaryls. AB - Biaryl atropisomers are of great importance in natural products, pharmaceuticals, and asymmteric synthesis. The efficient synthesis of these chiral scaffolds with full enantiocontrol and high diversity remains challenging. Reported herein is a Pd-catalyzed atroposelective C-H allylation with tert-leucine as an efficient catalytic chiral transient auxiliary. A wide range of enantioenriched biaryl aldehydes were prepared in synthetically useful yields with excellent enantioselectivity (up to >99 % ee) through beta-O elimination. The reaction could be carried out on a gram scale without erosion of the ee value. A variety of axially chiral carboxylic acids could be obtained with high enantiopurity. The resulting axially chiral biaryl aldehydes and carboxylic acids might be used in asymmetric synthesis as chiral ligands and/or organocatalysts. PMID- 30411830 TI - Target of Rapamycin (TOR), a master regulator of multiple signaling pathways and a potential candidate gene for crop improvement. AB - The Target of Rapamycin (TOR) protein regulates growth and development in photosynthetic and non-photosynthetic eukaryotes. Though the TOR regulatory networks are involved in nutrient and energy signaling, and transcriptional and translational control of multiple signaling pathways, the molecular mechanism of TOR regulation of plant abiotic stress responses is still unclear. The TOR mediated transcriptional regulation of genes encoding Ribosomal Proteins (RPs) is a necessity under stress conditions for balanced growth and productivity in plants. The activation of SnRKs (Sucrose non-Fermenting-Related kinases) and the inactivation of TOR signaling in abiotic stresses is in line with the accumulation of ABA and transcriptional activation of stress responsive genes. Autophagy is induced under abiotic stress conditions, which results in the degradation of proteins and the release of amino acids, which might possibly induce the phosphorylation of TOR and hence, its activation. TOR signaling also has a role in regulating ABA biosynthesis for transcriptional regulation of stress-related genes. The switch between activation and inactivation of TOR by its phosphorylation and de-phosphorylation maintains a balanced growth in response to stresses. In the present review, we have discussed the important signaling pathways that are regulated by TOR and tried to assess the relationship between TOR signaling and tolerance to abiotic stresses in plants. The review also discusses a possible cross-talk between TOR and RP genes in response to abiotic stresses. This article is protected by copyright. All rights reserved. PMID- 30411831 TI - Effects of grab bars and backrests on independent wheelchair transfer performance and technique. AB - OBJECTIVE: For individuals who rely on wheeled mobility devices for primary mobility, the ability to transfer independently greatly enhances participation in activities within and outside of the home. Nonlevel transfers are challenging and inevitable as not all surfaces in all settings can be made level with an individual's seat to floor height. The purpose of this study was to investigate the effects of two transfer aids, grab bars, and backrests, on the performance and quality of nonlevel transfers. METHODS: This study employed a repeated measures design with transfer setup as the independent variable. Sixty-eight (53 men and 15 women) wheeled mobility device users performed level and nonlevel transfers to a bare surface, a surface with grab bars present, a surface with grab bars, and a backrest present. For each condition, participants were asked to transfer as high and as low as they could go while still performing an independent and safe transfer. The transfer assessment instrument was used to evaluate the quality of their transfer technique. RESULTS: Participants were able to transfer an absolute height up to 2.5 cm (1") higher and lower when grab bars or grab bars and a backrest were present on the surface (p < 0.042) and 2.3 cm (~1") higher relative to their wheelchair level seat high when grab bars were present on the surface (p < .001). Transfer technique significantly improved for both uphill and downhill transfers with the presence of grab bars and a backrest as shown by the transfer assessment instrument scores (p < 0.046). CONCLUSIONS: The presence of grab bars and a backrest on transfer surfaces may help mobility device users to achieve higher and lower absolute transfer heights and facilitate better transfer technique. PMID- 30411832 TI - Virus detection by transmission electron microscopy: Still useful for diagnosis and a plus for biosafety. AB - Transmission electron microscopy (TEM) is the only imaging technique allowing the direct visualization of viruses, due to its nanometer-scale resolution. Between the 1960s and 1990s, TEM contributed to the discovery of many types of viruses and served as a diagnostic tool for identifying viruses directly in biological samples, either in suspension or in sections of tissues or mammalian cells grown in vitro in contact with clinical samples. The diagnosis of viral infections improved considerably during the 1990s, with the advent of highly sensitive techniques, such as enzyme-linked immunosorbent assay (ELISA) and PCR, rendering TEM obsolete for this purpose. However, the last 20 years have demonstrated the utility of this technique in particular situations, due to its "catch-all" nature, making diagnosis possible through visualization of the virus, without the need of prior assumptions about the infectious agent sought. Thus, in several major outbreaks in which molecular techniques failed to identify the infectious agent, TEM provided the answer. TEM is also still occasionally used in routine diagnosis to characterize infections not diagnosed by molecular assays. It is also used to check the microbiological safety of biological products. Many biopharmaceuticals are produced in animal cells that might contain little-known, difficult-to-detect viruses. In this context, the "catch-all" properties of TEM make it possible to document the presence of viruses or virus-like particles in these products. PMID- 30411833 TI - Innovative imaging methods in heart failure: a shifting paradigm in cardiac assessment. Position statement on behalf of the Heart Failure Association of the European Society of Cardiology. AB - Myriad advances in all fields of cardiac imaging have stimulated and reflected new understanding of cardiac performance, myocardial damage and the mechanisms of heart failure. In this paper, the Heart Failure Association assesses the potential usefulness of innovative imaging modalities in enabling more precise diagnostic and prognostic evaluation, as well as in guiding treatment strategies. Many new methods have gradually penetrated clinical practice and are on their way to becoming a part of routine evaluation. This paper focuses on myocardial deformation and three-dimensional ultrasound imaging; stress tests for the evaluation of contractile and filling function; the progress of magnetic resonance techniques; molecular imaging and other sound innovations. The Heart Failure Association aims to highlight the ways in which paradigms have shifted in several areas of cardiac assessment. These include reassessing of the simplified concept of ejection fraction and implementation of the new parameters of cardiac performance applicable to all heart failure phenotypes; switching from two dimensional to more accurate and reproducible three-dimensional ultrasound volumetric evaluation; greater tissue characterization via recently developed magnetic resonance modalities; moving from assessing cardiac function and congestion at rest to assessing it during stress; from invasive to novel non invasive hybrid techniques depicting coronary anatomy and myocardial perfusion; as well as from morphometry to the imaging of pathophysiologic processes such as inflammation and apoptosis. This position paper examines the specific benefits of imaging innovations for practitioners dealing with heart failure aetiology, risk stratification and monitoring, and, in addition, for scientists involved in the development of future research. PMID- 30411834 TI - Recent Progress in Polymeric Carbonyl-Based Electrode Materials for Lithium and Sodium Ion Batteries. AB - Advancement in mobile electronics is driving progress in lithium ion batteries. Recently, organic electrode materials have emerged as promising candidates for lithium ion batteries due to their high theoretical capacity, ease of synthesis, versatility of structure, and abundance. Polymerization is a strategy used to overcome the issues associated with small organic molecules for charge storage application. The focus of this review is on the most recent progress in the field of polymeric carbonyl materials for lithium ion batteries (LIBs) and sodium ion batteries (SIBs). Advantages of organic electrode materials, device architecture, and charge storage mechanism are discussed. Challenges associated with carbonyl based electrodes and some recent solutions are outlined. Later, a comparison of theoretical capacity, practical capacity, and cyclic life are presented for different carbonyl systems. Capacity-fading phenomena and structural degradation during charging are discussed where necessary. Some key parameters for the design of flexible batteries are highlighted and an overview of some recent contributions of our group in this field are reported. Finally, some future prospects for researchers in this field are outlined. PMID- 30411835 TI - Facile Synthesis of Pyridines from Propargyl Amines: Concise Total Synthesis of Suaveoline Alkaloids. AB - A general and efficient protocol was developed for the synthesis of polysubstituted pyridines from propargyl amines and unsaturated carbonyl compounds through a tandem condensation/ alkyne isomerization/ 6pi-3-azatriene electrocyclization sequence. This process displays a wide scope of readily available substrates (30 examples, up to 95% yield) and could be easily performed at preparative scale (20 gram scale). Taken advantage of the late-stage pyridine incorporation protocol, the synthetic utility of this chemistry has been successfully applied to the collective total synthesis of suveoline, norsuveoline and macrophylline. PMID- 30411836 TI - Predictors of therapeutic failure among patients with acute brucellosis treated by dual therapy with doxycycline-rifampin. AB - OBJECTIVE: To determine the frequency of therapeutic failure among patients with acute and subacute brucellosis and to explore the predictors of failure. METHODS: The study included 213 consecutive, naive patients with acute and subacute brucellosis. All participants underwent clinical evaluation, chest radiography, stool microscopic examination and interferon-gamma release assay. Patients received the WHO-recommended therapy of doxycycline 200 mg/day and rifampin 900 mg/day, for 6 weeks. RESULTS: Mean age of the study population was 39.8 +/- 12.2 years; 64.8% of them were males. The therapeutic failure rate was 16.4%. Adverse effects were reported by 13.1%. Multivariate analysis of factors associated with therapeutic failure revealed latent tuberculosis infection (LTBI) (OR 3.1, 95% CI, 1.9-24.6, P: 0.009), ascariasis (OR 2.6, 95% CI 1.5-17.9, P: 0.012), and the use of acid suppressive therapy (OR 2.1, 95% CI 1.2-19.5, P: 0.037) as the predictors of therapeutic failure. CONCLUSIONS: The prevalence of therapeutic failure among the Egyptian patients with acute/subacute brucellosis is increasing. Predictors of therapeutic failure are LTBI, ascariasis, and the use of acid suppressive therapy. PMID- 30411837 TI - Colloidal Fluorophore Aggregates for the Selective Detection of Albumins in Solution and on Electrophoresis Gels. AB - We report a fluorescent probe that is highly sensitive and selective for serum albumins. Signal transduction results from the disassembly of fluorescence quenched aggregates upon binding to human serum albumin (HSA). The probe offers a rapid (<= 2 s) fluorimetric assay of HSA in either PBS buffer, urine or blood serum with a high signal-to-noise ratio. It is also useful as a wash-free prestaining reagent for detecting HSA on electrophoresis gels. PMID- 30411838 TI - Autonomous Ultrafast Self-Healing Hydrogels by pH-Responsive Functional Nanofiber Gelators as Cell Matrices. AB - The synthesis of hybrid hydrogels by pH-controlled structural transition with exceptional rheological properties as cellular matrix is reported. "Depsi" peptide sequences are grafted onto a polypeptide backbone that undergo a pH induced intramolecular O-N-acyl migration at physiological conditions affording peptide nanofibers (PNFs) as supramolecular gelators. The polypeptide-PNF hydrogels are mechanically remarkably robust. They reveal exciting thixotropic behavior with immediate in situ recovery after exposure to various high strains over long periods and self-repair of defects by instantaneous reassembly. High cytocompatibility, convenient functionalization by coassembly, and controlled enzymatic degradation but stability in 2D and 3D cell culture as demonstrated by the encapsulation of primary human umbilical vein endothelial cells and neuronal cells open many attractive opportunities for 3D tissue engineering and other biomedical applications. PMID- 30411839 TI - Comparative study of ink photoinitiators in food packages using gas chromatography with vacuum ultraviolet detection and gas chromatography with mass spectrometry. AB - This work focused on the development and validation of the analytical procedure using gas chromatography equipped with vacuum-ultraviolet detection for the specific and sensitive determination of nine photoinitiators in food packages. Subsequently, a comparison of the combination of vacuum ultraviolet spectroscopy with gas chromatography and a developed gas chromatography with mass spectrometry method was performed. The vacuum-ultraviolet spectra of all tested photoinitiators were collected and found to be highly distinct, even for isomers. Under the optimal conditions, the limits of detection for nine photoinitiators ranged from 1 to 5 mg/L using vacuum ultraviolet detection and from 0.15 to 0.5 mg/L using mass spectrometric detection. Both techniques were successfully applied for screening of photoinitiators in seven kinds of food packages and the obtained data showed good agreement (the relative difference was between 3 and 18%). The variability in concentrations found in triplicate samples was assessed to be below 18%. Predominantly benzophenone was found in all analysed samples in the range of 0.31-4.23 mg/g. It appears to be preferably selected by food packaging manufacturers. This study proposes a new simple and sensitive technique used for analysis of photoinitiators that could be a good alternative to gas chromatography with mass spectrometry. PMID- 30411840 TI - Refinement of Humoral Rejection effector mechanisms to identify specific pathogenic histological lesions with different graft outcomes. AB - In this issue, Senev and colleagues reported a large retrospective study of kidney transplant patients (n=935), in whom the impact on graft outcome of the histological phenotype of antibody-mediated rejection following the 2015 Banff classification (ABMRh ) was investigated according to the presence or absence of circulating HLA-DSA (DSApos ABMRh and DSAneg ABMRh , respectively) (1). Additionally, authors assessed if C4d-positivity in peritubular capillaries (PTCs) could be used as a surrogate for circulating DSA, as proposed by the 2017 Banff classification. Interestingly, while authors found that 208(22.2%) patients were diagnosed as ABMRh , only 85/208(40.8%) fulfilled the complete ABMR criteria as they also showed HLA-DSA (DSApos ABMRh ). This article is protected by copyright. All rights reserved. PMID- 30411841 TI - Clinical and radiographic peri-implant variables around short dental implants in type 2 diabetic, prediabetic, and non-diabetic patients. AB - BACKGROUND: Clinical and radiographic status around short dental implants in patients with different glycemic levels remains unexplored. PURPOSE: To determine the clinical and radiographic bone level (RBL) around short dental implants in type-2 diabetes mellitus (T2DM), prediabetic, and non-diabetic patients. MATERIALS AND METHODS: Participants were grouped into three groups based on HbA1c levels: T2DM (Group-1); prediabetic patients (Group-2); and non-diabetic subjects (Group-3). Clinical recordings included the assessment of peri-implant plaque index (PI), bleeding on probing (BOP), probing depth (PD). Radiographic analysis included evaluation of standardized periapical digital radiographs using specialized software and image analyzer. RESULTS: Clinical peri-implant parameters including PI and BOP were statistically significantly higher in group 1 (P < .01) and group 2 (P < .05) as compared to group-3. Mean PD was statistically significantly higher in group-1 patients compared to group-3 (P < .01). Radiographic bone loss was significantly higher in both group-1 (P < .01) and group-2 (P < .05) patients as compared to patients in group 3. RBL showed statistically significant difference among T2DM patients even after adjusting for HbA1c, total cholesterol, and body mass index (P < .05) and statistically significant difference in prediabetic patients after adjusting for only HbA1c (P < .05). CONCLUSION: Clinical and radiographic peri-implant parameters are compromised around short dental implants in type-2 diabetes mellitus patients. Further longitudinal studies are needed to compare clinical performance of short dental implants with standard dental implants placed in patients with different glycemic level. PMID- 30411842 TI - Anterior maxillary sandwich osteotomy technique with simultaneous implant placement: A novel approach for management of vertical deficiency. AB - BACKGROUND: The introduction of sandwich osteotomy technique with simultaneous implant placement allowed various procedures to be carried out with a level of great precision and accuracy thus saving time for the patient and clinician. PURPOSE: The aim of the current study is to evaluate the efficacy of this new technique regarding increasing the anterior maxillary alveolar height with simultaneous implant placement. MATERIALS AND METHODS: Nine patients suffering from multiple missing anterior maxillary teeth were selected with vertical dimension not less than 10 mm. anterior maxillary sandwich osteotomy technique was carried out for all patients using xenograft bone particulate with simultaneous implant placement at single stage surgery. RESULTS: For two patients, four implants showed significant marginal bone loss with maximum marginal bone loss up to 2.8 mm. However, the immediate postoperative follow up went uneventful for all nine patients included in the present study. None of them showed any complication regarding postoperative wound dehiscence, infection, or segment mobility. Four months postoperative upon the prosthetic phase, all the 18 placed implant were clinically osseointegtated. CONCLUSION: All 18 implants were successfully integrated in the present study. The prosthetic phase started after 4 months for all cases and there was no need for harvesting of autogenous bone from the patient. But further studies are required to evaluate the viability of such approach in single implant placement cases. PMID- 30411843 TI - A fast-evolving X-linked duplicate of importin-alpha2 is overexpressed in sex ratio drive in Drosophila neotestacea. AB - Selfish genetic elements that manipulate gametogenesis to achieve a transmission advantage are known as meiotic drivers. Sex-ratio X-chromosomes (SR) are meiotic drivers that prevent the maturation of Y-bearing sperm in male carriers to result in the production of mainly female progeny. The spread of an SR chromosome can affect host genetic diversity and genome evolution, and can even cause host extinction if it reaches sufficiently high prevalence. Meiotic drivers have evolved independently many times, though only in a few cases is the underlying genetic mechanism known. In this study we use a combination of transcriptomics and population genetics to identify widespread expression differences between the standard (ST) and sex-ratio (SR) X-chromosomes of the fly Drosophila neotestacea. We found the X-chromosome is enriched for differentially expressed transcripts, and that many of these X-linked differentially expressed transcripts had elevated Ka /Ks values between ST and SR, indicative of potential functional differences. We identified a set of candidate transcripts, including a testis-specific, X linked duplicate of the nuclear transport gene importin-alpha2 that is overexpressed in SR. We find suggestions of positive selection in the lineage leading to the duplicate and that its molecular evolutionary patterns are consistent with relaxed purifying selection in ST. As these patterns are consistent with involvement in the mechanism of drive in this species, this duplicate is a strong candidate worthy of further functional investigation. Nuclear transport may be a common target for genetic conflict, as the mechanism of the autosomal Segregation Distorter drive system in D. melanogaster involves the same pathway. This article is protected by copyright. All rights reserved. PMID- 30411844 TI - Sequential occurrence of primary and secondary hypothyroidism during treatment with nivolumab: pitfalls in immuno-oncological therapy and endocrinological diagnostic procedures. PMID- 30411845 TI - Long-term results of carotid stenting and risk factors in patients with severe carotid artery stenosis undergoing subsequent cardiac surgery. AB - AIMS: To identify risk factors for composite outcome of mortality, stroke or myocardial infarction in patients with severe carotid stenosis undergoing staged carotid artery stenting (CAS) with subsequent cardiac surgery. METHODS AND RESULTS: In this prospective observational study, we enrolled 643 consecutive patients with both symptomatic (i.e., with history of stroke) and asymptomatic severe carotid artery disease, who required cardiac surgery. Generally, cardiac surgery was planned 30 days after the CAS procedure. The composite outcome consisted of death, stroke and myocardial infarction. The composite outcome rate was 26.3% at 5 years and 47% at 8 years after CAS. Age >= 80 years (hazard ratio [HR] = 1.89; 95%CI, 1.18-3.03; P = 0.008), history of stroke (HR = 1.66, 1.16 2.37; P = 0.006), chronic obstructive pulmonary disease (HR = 1.86; 1.07-3.24; P = 0.03) and kidney disease (HR = 1.83, 1.11-3.04; P = 0.02) were independent risk factors for the composite outcome during long-term follow-up. CONCLUSIONS: In this study with staged CAS followed by cardiac surgery, we confirm previously reported event-free survival rates and identify several risk factors for the composite outcome. Future studies are needed to confirm the importance of the identified risk factors and to assess their predictive ability. PMID- 30411846 TI - Carbon monoxide attenuates amyloidogenesis via down-regulation of NF-kappaB mediated BACE1 gene expression. AB - Amyloid-beta (Abeta) peptides, the major constituent of plaques, are generated by sequential proteolytic cleavage of the amyloid precursor protein (APP) via beta secretase (BACE1) and the gamma-secretase complex. It has been proposed that the abnormal secretion and accumulation of Abeta are the initial causative events in the development of Alzheimer's disease (AD). Drugs modulating this pathway could be used for AD treatment. Previous studies indicated that carbon monoxide (CO), a product of heme oxygenase (HO)-1, protects against Abeta-induced toxicity and promotes neuroprotection. However, the mechanism underlying the mitigative effect of CO on Abeta levels and BACE1 expression is unclear. Here, we show that CO modulates cleavage of APP and Abeta production by decreasing BACE1 expression in vivo and in vitro. CO reduces Abeta levels and improves memory deficits in AD transgenic mice. The regulation of BACE1 expression by CO is dependent on nuclear factor-kappa B (NF-kappaB). Consistent with the negative role of SIRT1 in the NF kappaB activity, CO fails to evoke significant decrease in BACE1 expression in the presence of the SIRT1 inhibitor. Furthermore, CO attenuates elevation of BACE1 level in brains of 3xTg-AD mouse model as well as mice fed high-fat, high cholesterol diets. CO reduces the NF-kappaB-mediated transcription of BACE1 induced by the cholesterol oxidation product 27-hydroxycholesterol or hydrogen peroxide. These data suggest that CO reduces the NF-kappaB-mediated BACE1 transcription and consequently decreases Abeta production. Our study provides novel mechanisms by which CO reduces BACE1 expression and Abeta production and may be an effective agent for AD treatment. PMID- 30411847 TI - Socially Shared Regulation of Learning and Quality of Talk: Age Differences in Collaborative Group Work in Classroom Contexts. AB - Collaborative group work has been recognized as a way of fostering the development of metacognition and self-regulation. Moreover, it has been claimed that these regulatory processes have an interpersonal level in which the regulation of the activity is shared with others (Iiskala et al., 2004). There has also been a considerable body of research on talk within small groups in the classroom. This approach has built a considerable amount of research, given the demonstrated effect of certain types of talk on academic learning. However, very few studies look at both aspects of collaboration (Mercer, 2013). The present research aims to investigate the relationship between socially shared regulation of learning (SSRL) and type of talk. Two hundred and thirty-one groups of three students were videotaped solving a problem in collaboration. Videos were analyzed qualifying exploratory talk and two dimensions of SSRL: metacognitive regulation and symmetry and reciprocity. Results show that the dimensions of SSRL and quality of talk correlate significantly when the whole sample is considered. However, when the sample is segmented by age, differential patterns start to emerge. Theoretical, methodological, and practical implications are discussed. PMID- 30411848 TI - Liver decompensation in HIV/Hepatitis B coinfection in the combination antiretroviral therapy era does not seem increased compared to hepatitis B mono infection. AB - BACKGROUND & AIMS: HIV/hepatitis B virus (HBV) coinfected subjects are thought to have faster progression to end-stage liver disease (ESLD) than HBV mono-infected subjects. We assessed whether this remains in the current cART-era. METHODS: Data from subjects with follow-up completion post-2003 were compared between HIV/HBV coinfected subjects in the Dutch HIV Monitoring database and HBV mono-infected subjects from two centres. The primary outcomes of composite ESLD included portal hypertension, decompensated cirrhosis, hepatocellular carcinoma, liver transplantation and liver-related mortality. Outcomes were analysed using time dependent cause-specific Cox regression models adjusted for follow-up time and relevant covariates. Subset-analyses were done in subjects with follow-up pre 2003. RESULTS: In the 1336 co- vs 742 mono-infected subjects, coinfected subjects had no increased probability for ESLD compared to mono-infected subjects (cHR 0.7 (95% CI 0.4-1.1), but had increased probabilities for all-cause (cHR 7.4 [4.9 11.1]) and liver-related mortality (cHR 3.4 [1.6-7.5]). In the current combined cohort, treatment with tenofovir or entecavir was inversely associated with ESLD, all-cause and liver-related mortality (cHR 0.4 [95% CI 0.3-0.7], cHR 0.003 [0.001 0.01]), cHR 0.007 [0.001-0.05]). Other predictors for ESLD were older age, being of Sub-Sahara African descent, increased alanine aminotransferase levels and hepatitis C virus coinfection. While the probability for all-cause mortality was increased in coinfected subjects, this rate decreased compared to pre-2003 (HR 40.2 (95% CI: 8.7-186.2). CONCLUSIONS: HIV/HBV coinfected patients no longer seem to be at increased risk for progression to ESLD compared to HBV mono-infected patients, likely due to widespread use of highly effective cART with dual HBV and HIV activity. PMID- 30411849 TI - Red and itchy bilateral supraorbital swellings. PMID- 30411850 TI - Identification of Proteomic Markers in Head and Neck Cancer Using MALDI-MS Imaging, LC-MS/MS, and Immunohistochemistry. AB - PURPOSE: The heterogeneity of squamous cell carcinoma tissue greatly complicates diagnosis and individualized therapy. Therefore, characterizing the heterogeneity of tissue spatially and identifying appropriate biomarkers is crucial. MALDI-MS imaging (MSI) is capable of analyzing spatially resolved tissue biopsies on a molecular level. EXPERIMENTAL DESIGN: MALDI-MSI is used on snap frozen and formalin-fixed and paraffin-embedded (FFPE) tissue samples from patients with head and neck cancer (HNC) to analyze m/z values localized in tumor and nontumor regions. Peptide identification is performed using LC-MS/MS and immunohistochemistry (IHC). RESULTS: In both FFPE and frozen tissue specimens, eight characteristic masses of the tumor's epithelial region are found. Using LC MS/MS, the peaks are identified as vimentin, keratin type II, nucleolin, heat shock protein 90, prelamin-A/C, junction plakoglobin, and PGAM1. Lastly, vimentin, nucleolin, and PGAM1 are verified with IHC. CONCLUSIONS AND CLINICAL RELEVANCE: The combination of MALDI-MSI, LC-MS/MS, and subsequent IHC furnishes a tool suitable for characterizing the molecular heterogeneity of tissue. It is also suited for use in identifying new representative biomarkers to enable a more individualized therapy. PMID- 30411851 TI - High-Saturated Fat High-Sugar Diet Accelerates Left-Ventricular Dysfunction Faster than High-Saturated Fat Diet Alone via Increasing Oxidative Stress and Apoptosis in Obese-Insulin Resistant Rats. AB - SCOPE: We hypothesized that high-saturated fat high-sugar diet (HFHS) causes worse cardiometabolic dysfunction than high-saturated fat diet (HFD) due to severe mitochondrial dysfunction, oxidative stress, and apoptosis in obese insulin resistant rats. METHODS AND RESULTS: Rats were divided into 3 groups to receive normal diet (ND) or HFD, or HFHS for 24 weeks. Cardiometabolic parameters were determined at baseline and every 4 weeks until the end of the feeding protocol. At week 24, hearts were removed to determine mitochondrial function and dynamics, apoptosis, and insulin signaling. HFD and HFHS rats developed obese insulin resistance at week 8. However, fasting plasma glucose level was increased only in HFHS rats. Myocardial insulin signaling was markedly impaired in HFHS rats, compared to other groups. Cardiac autonomic imbalance was observed in both HFD and HFHS rats beginning at week 8. However, cardiac dysfunction was observed earlier (week 8) in HFHS rats, and later at week 12 in HFD rats. Moreover, cardiac and mitochondrial oxidative stress levels, and apoptosis were greater in HFHS rats than HFD rats. CONCLUSION: Both HFD and HFHS caused cardiometabolic dysfunction. HFHS caused more severe metabolic disturbance, oxidative stress, and apoptosis than HFD, which led to an accelerated LV dysfunction in HFHS rats. This article is protected by copyright. All rights reserved. PMID- 30411852 TI - Design of Skin Islands for a Myocutaneous Serratus Anterior Free Flap - An Anatomical Study and Clinical Implication for Pharyngeal Reconstruction after Laryngopharyngectomy. AB - OBJECTIVES: The main purpose of this study was to evaluate flap size and flap design of skin islands in myocutaneous serratus anterior free flaps (SAFFs) in fresh cadavers and to further investigate whether myocutaneous SAFFs are suitable flaps for pharyngeal reconstruction after laryngopharyngectomy. METHODS: Dissection and injection of methylene blue was performed in 20 hemithoraces of 13 fresh cadavers to evaluate flap size and location of skin islands. Based on these preclinical data, we performed pharyngeal reconstruction with myocutaneous SAFF in 5 patients after laryngopharyngectomy. RESULTS: Perfused skin paddles were found in all specimens with a mean size of perfused skin islands of 85.6 +/- 49.8 cm2 . Lengths and widths of skin islands ranged from 10-21 cm and 6-20.5 cm, respectively. Flap size did not significantly differ between males and females (p=0.998), left compared to right hemithoraces (p=0.468) and between paired specimens (p=0.915). All skin islands were found within the upper 29.3% to 51.7% of hemithorax (calculated from axilla to costal arch), and between latissimus dorsi muscle posteriorly and anterior axillary line anteriorly. Accordingly, myocutaneous SAFFs were used for pharyngeal reconstruction after laryngopharyngectomy in 5 patients with advanced hypopharyngeal carcinomas. Three patients had uneventful courses, while one patient developed immediate intraoperative flap loss and another patient developed partial necrosis of SAFF on postoperative day 7. CONCLUSION: Skin islands of SAFF have reliable blood supply, which allow harvest of large myocutaneous SAFFs that can be used also for pharyngeal reconstruction after laryngopharyngectomy. This article is protected by copyright. All rights reserved. PMID- 30411853 TI - Feasibility Study for the MALDI-MSI Analysis of Thyroid Fine Needle Aspiration Biopsies: Evaluating the Morphological and Proteomic Stability Over Time. AB - PURPOSE: MALDI-MS imaging (MALDI-MSI) is an emerging technology that enables the spatial distribution of biomolecules within tissue to be combined with the traditional morphological information familiar to clinicians. Thus, for diagnostic or prognostic purposes, along with predicting response to therapeutic treatment, it is important to properly collect and handle biological specimens in order to avoid degradation or the formation of artifacts in the morphological structure and proteomic profile. EXPERIMENTAL DESIGN: In this work, the morphological and proteomic stability of thyroid fine needle aspiration biopsies in PreservCyt (up to 14 days) and CytoLyt (up to 7 days) solutions at 4 degrees C has been verified, by MALDI-MSI analysis. Moreover, a new measure has been introduced in order to assess the similarity of the obtained MALDI-MSI spectra, by equally taking into account the number of signals (fit and retrofit), and their intensities (Spearman's correlation and spectra overlap). RESULTS: Results show no degradation of the cellular morphology and a good stability of the samples up to 14 days in PreservCyt solution. CONCLUSIONS AND CLINICAL RELEVANCE: Moreover, this protocol can be easily implemented in pathological units, allowing simple sample collection and shipment to be used not only for the proteomic MALDI MSI analysis of thyroid FNABs but also for other biological liquid based specimens. PMID- 30411854 TI - Efficacy and toxicities of gemcitabine and cisplatin combined with endostar in advanced thymoma and thymic carcinoma. AB - BACKGROUND: Thymoma and thymic carcinoma are rare thymic epithelial tumors. We investigated the efficacy of first-line gemcitabine and cisplatin (GP) chemotherapy versus gemcitabine and cisplatin chemotherapy combined with the anti angiogenic drug endostar (GP + E) in advanced thymoma and thymic carcinoma. METHODS: The records of 45 patients with invasive metastatic thymomas or thymic carcinomas treated with GP as first-line therapy between August 2008 and July 2017 at the Department of Respiratory Medicine, Peking University Cancer Hospital and Institute were retrospectively reviewed. RESULTS: Eighteen patients (75%) in the GP + E group achieved a partial response and six (25%) had stable disease. In GP only group, nine (42.8%) patients achieved a partial response, 11 (52.4%) had stable disease, and one (4.8%) had progressive disease. The GP + E group had a significantly higher overall response rate (75% vs. 42.9%; P = 0.028), and median progression-free survival (PFS) and overall survival (OS) of 19 and 76 months, respectively. In the GP only group, median PFS and OS were 16 and 29 months, respectively. PFS and OS were not significantly different between the groups. CONCLUSIONS: GP has moderate efficacy and could represent a suitable first-line therapy for thymic carcinoma and thymoma. Chemotherapy combined with endostar could improve the overall response rate, but did not prolong PFS or OS. PMID- 30411855 TI - DRD4 methylation as a potential biomarker for physical aggression: An epigenome wide, cross-tissue investigation. AB - Epigenetic processes that regulate gene expression, such as DNA methylation (DNAm), have been linked to individual differences in physical aggression. Yet, it is currently unclear whether: (a) DNAm patterns in humans associate with physical aggression independently of other co-occurring psychiatric and behavioral symptoms; (b) whether these patterns are observable across multiple tissues; and (c) whether they may function as a causal versus noncausal biomarker of physical aggression. Here, we used a multisample, cross-tissue design to address these questions. First, we examined genome-wide DNAm patterns (buccal swabs; Illumina 450k) associated with engagement in physical fights in a sample of high-risk youth (n = 119; age = 16-24 years; 53% female). We identified one differentially methylated region in DRD4, which survived genome-wide correction, associated with physical aggression above and beyond co-occurring symptomatology (e.g., ADHD, substance use), and showed strong cross-tissue concordance with both blood and brain. Second, we found that DNAm sites within this region were also differentially methylated in an independent sample of young adults, between individuals with a history of chronic-high versus low physical aggression (peripheral T cells; ages 26-28). Finally, we ran a Mendelian randomization analysis using GWAS data from the EAGLE consortium to test for a causal association of DRD4 methylation with physical aggression. Only one genetic instrument was eligible for the analysis, and results provided no evidence for a causal association. Overall, our findings lend support for peripheral DRD4 methylation as a potential biomarker of physically aggressive behavior, with no evidence yet of a causal relationship. PMID- 30411856 TI - Quinic Acid-Conjugated Nanoparticles Enhance Drug Delivery to Solid Tumors via Interactions with Endothelial Selectins. AB - Current nanoparticle (NP) drug carriers mostly depend on the enhanced permeability and retention (EPR) effect for selective drug delivery to solid tumors. However, in the absence of a persistent EPR effect, the peritumoral endothelium can function as an access barrier to tumors and negatively affect the effectiveness of NPs. In recognition of the peritumoral endothelium as a potential barrier in drug delivery to tumors, poly(lactic-co-glycolic acid) (PLGA) NPs are modified with a quinic acid (QA) derivative, synthetic mimic of selectin ligands. QA-decorated NPs (QA-NP) interact with human umbilical vein endothelial cells expressing E-/P-selectins and induce transient increase in endothelial permeability to translocate across the layer. QA-NP reach selectin upregulated tumors, achieving greater tumor accumulation and paclitaxel (PTX) delivery than polyethylene glycol-decorated NPs (PEG-NP). PTX-loaded QA-NP show greater anticancer efficacy than Taxol or PTX-loaded PEG-NP at the equivalent PTX dose in different animal models and dosing regimens. Repeated dosing of PTX loaded QA-NP for two weeks results in complete tumor remission in 40-60% of MDA MB-231 tumor-bearing mice, while those receiving control treatments succumb to death. QA-NP can exploit the interaction with selectin-expressing peritumoral endothelium and deliver anticancer drugs to tumors to a greater extent than the level currently possible with the EPR effect. PMID- 30411857 TI - Differential Scanning Calorimetry of Native Silk Feedstock. AB - Native silk proteins, extracted directly from the silk gland prior to spinning, offer access to a naturally hydrated protein that has undergone little to no processing. Combined with differential scanning calorimetry (DSC), it is possible to probe the thermal stability and hydration status of silk and thus investigate its denaturation and solidification, echoing that of the natural spinning process. It is found that native silk is stable between -10 degrees C and 55 degrees C, and both the high-temperature enthalpy of denaturation (measured via modulated temperature DSC) and a newly reported low-temperature ice-melting transition may serve as useful quality indicators in the future for artificial silks. Finally, compared to albumin, silk's denaturation enthalpy is much lower than expected, which is interpreted within a recently proposed entropic desolvation framework which can serve to unveil the low-energy aquamelt processing pathway. PMID- 30411858 TI - UFLC-derived CSF extracellular vesicle origin and proteome. AB - Cerebrospinal fluid (CSF) extracellular vesicles (EVs) show promise as a source of neurological disease biomarkers, though their precise origin is poorly understood. Current extraction techniques produce disappointing yield and purity. This study describes the application of ultrafiltration liquid chromatography (UFLC) to CSF-EVs, compared with ultracentrifugation (UC), and explores CSF-EV origin. EVs were extracted from human CSF by UC and UFLC and characterized using nanoparticle tracking analysis, electron microscopy and immunoblotting. EV and CSF proteomes were analysed by LC-MS/MS. UFLC-isolated particles have size, morphology and marker expression characteristic of EVs. UFLC provides greater EV yield (UFLC 7.90 * 108 +/- SD 1.31 * 108 EVs/mL CSF, UC 1.06 * 108 +/-0.57 * 108 p<0.001). UFLC enhances purity, proteomic depth (UFLC 704+/-52, UC 340+/-57 identifications, p<0.01) and consistency of quantification (CV 17% vs 23%). EVs contain more intracellular proteins (OR 2.63 p<0.001) and fewer plasma proteins than CSF (OR 0.60, p<0.001). CSF and EV-enriched proteomes show overrepresentation of brain-specific proteins (EV OR 3.18, p<0.001; CSF OR 3.37, p<0.001). Overrepresentation of cerebral white matter (OR 1.99, p = 0.015) and choroid plexus proteins (OR 1.87, p<0.001) is observed in EVs. UFLC provides improves yield and purity of CSF-EVs. The EV-enriched proteome better reflects the intracellular and white matter proteome than whole CSF. This article is protected by copyright. All rights reserved. PMID- 30411859 TI - Three strategies for displaying the postcricoid space and pyriform sinus: a matched case-controlled study of 50 patients. AB - The postcricoid space and pyriform sinus are difficult to completely display under routine laryngoscopy examination. We present the results obtained from 50 patients who were randomly recruited to receive a laryngoscopy examination via a routine, Valsalva manoeuvre combined with anterior cervical skin traction (V ACST), followed by a Valsalva manoeuvre combined with the modified Killian method (V-MK). The routine method is not suitable for displaying the postcricoid space. In general, both the V-ACST and V-MK displayed the postcricoid space and pyriform sinus very well. The V-ACST displayed significantly more of the postcricoid space, whilst the V-MK was clear better at exposing the pyriform sinus. This article is protected by copyright. All rights reserved. PMID- 30411860 TI - Advancing mite phylogenomics: Designing ultraconserved elements for acari phylogeny. AB - Mites (Acari) are one of the most diverse groups of life on Earth, yet their evolutionary relationships are poorly understood. Also, the resolution of broader arachnid phylogeny has been hindered by an underrepresentation of mite diversity in phylogenomic analyses. To further our understanding of Acari evolution, we design targeted ultraconserved genomic elements (UCEs) probes, intended for resolving the complex relationships between mite lineages and closely related arachnids. We then test our Acari UCE baits in-silico by constructing a phylogeny using 13 existing Acari genomes, as well as 6 additional taxa from a variety of genomic sources. Our Acari-specific probe kit improves the recovery of loci within mites over an existing general arachnid UCE probe set. Our initial phylogeny recovers the major mite lineages, yet finds mites to be non monophyletic overall, with Opiliones (harvestmen) and Ricinuleidae (hooded tickspiders) rendering Parasitiformes paraphyletic. This article is protected by copyright. All rights reserved. PMID- 30411861 TI - Recurrent acute hemorrhagic edema of infancy (AHEI) during puberty. PMID- 30411862 TI - Early Archean origin of Photosystem II. AB - Photosystem II is a photochemical reaction center that catalyzes the light-driven oxidation of water to molecular oxygen. Water oxidation is the distinctive photochemical reaction that permitted the evolution of oxygenic photosynthesis and the eventual rise of eukaryotes. At what point during the history of life an ancestral photosystem evolved the capacity to oxidize water still remains unknown. Here, we study the evolution of the core reaction center proteins of Photosystem II using sequence and structural comparisons in combination with Bayesian relaxed molecular clocks. Our results indicate that a homodimeric photosystem with sufficient oxidizing power to split water had already appeared in the early Archean about a billion years before the most recent common ancestor of all described Cyanobacteria capable of oxygenic photosynthesis, and well before the diversification of some of the known groups of anoxygenic photosynthetic bacteria. Based on a structural and functional rationale, we hypothesize that this early Archean photosystem was capable of water oxidation to oxygen and had already evolved protection mechanisms against the formation of reactive oxygen species. This would place primordial forms of oxygenic photosynthesis at a very early stage in the evolutionary history of life. PMID- 30411863 TI - Revascularization of coronary chronic total occlusions with subintimal tracking and reentry followed by deferred stenting: Experience from a high-volume referral center. AB - OBJECTIVES: To determine whether a variation of an abandoned antegrade percutaneous coronary intervention (PCI) technique, termed subintimal tracking and reentry (STAR), could be a safe and effective strategy to contend with complex coronary chronic total occlusions (CTO) when other strategies fail. BACKGROUND: Complex CTOs require advanced techniques such as the retrograde approach, which is associated with higher complication rates than antegrade strategies. METHODS: The medical records of 32 consecutive patients who underwent deferred stenting following STAR (DSS) between January 2015 and May 2017 at a high-volume referral center were retrospectively reviewed. The primary endpoint was technical success at the time of a second procedure following STAR-based balloon angioplasty, defined as successful stenting or the presence of Thrombolysis in Myocardial Infarction Study Group (TIMI) 3 flow with <50% residual stenosis if the vessel caliber was inappropriate for stenting. RESULTS: Of 781 CTO PCI procedures, STAR was performed in 45 (5.8%) and DSS in 32 (4.1%), constituting the analysis cohort. The median Japanese-CTO score was 2.5 [interquartile range (IQR) 1.0-3.0]. Median inter-procedure time was 2.4 months [1.7-3.3 months]. Technical success was achieved in 28 (88%) patients; 23 (72%) patients were treated with stents and 5 (16%) with balloon angioplasty alone. Combined complications included one clinical perforation, one MI, and one stent thrombosis. CONCLUSIONS: Deferred stenting after subintimal plaque modification via the STAR technique is a safe and effective strategy to contend with complex CTO lesions when other techniques are prohibitively high risk or have failed. PMID- 30411864 TI - Corrigendum. PMID- 30411865 TI - Identification of detoxification genes in imidacloprid-resistant Asian citrus psyllid (Hemiptera: Lividae) and their expression patterns under stress of eight insecticides. AB - BACKGROUND: The Asian citrus psyllid, Diaphorina citri, is one of the major pests in citrus-growing areas around the world. The application of insecticides is the most effective method to reduce the population of D. citri. However, D. citri has developed resistance to multiple classes of insecticides. Understanding resistance mechanisms is crucial to the management of D. citri. In this study, molecular assays were performed to characterize imidacloprid resistance mechanisms. RESULTS: Based on the D. citri transcriptome database and other known insect resistance genes, 16 cytochrome P450, 8 glutathione-S-transferases and 6 esterase genes were selected for cloning and sequencing. The gene expression analysis of 30 detoxification genes demonstrated that the relative expression of CYP4g15, CYP303A1, CYP4C62, CYP6BD5, GSTS1 and EST-6 were moderately high (>5 fold increase) in the imidacloprid-resistant strain. Feeding of dsRNAs reduced the expression of the six genes (46.7 - 72.1%) and resulted in significant adult mortality (65.62 - 82.76%). We also determined the ability of different insecticides to induce the six selected genes. The expression of CYP4C62 and GSTS1 genes were the most significantly upregulated in adults treated with all insecticides, except for chlorfenapyr. In chlorfenapyr-treated D. citri, expression of CYP4g15 and CYP303A1 were the most highly induced. CONCLUSION: Overexpressed detoxification genes were associated with imidacloprid resistance, as confirmed by RNAi feeding tests. The induction of the six selected genes when exposed to different insecticides supported the hypothesis that they were involved in metabolism of the tested insecticides. This article is protected by copyright. All rights reserved. PMID- 30411866 TI - Mechanism underlying the effect of long-term exposure to low dose of pesticides on DNA integrity. PMID- 30411867 TI - Role of induction chemotherapy in sinonasal malignancies: a systematic review. AB - BACKGROUND: Cancers of the paranasal sinuses are rare tumors that tend to be aggressive and usually are diagnosed at an advanced stage. Despite being rare, these tumors include a wide spectrum of histological subtypes with different biological behaviors. Choosing the optimal treatment modalities and analyzing the different oncological outcomes is therefore challenging. This study aims to evaluate the role of induction chemotherapy prior to definitive local therapy for sinonasal malignancies. METHODS: A systematic review of the literature in accordance with Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines was conducted. With the assistance of a medical librarian, data sources including MEDLINE, PubMed, Cochrane library, EMBASE, NCBI Bookshelf, National Guideline Clearinghouse, and Clinicaltrials.gov were searched using a customized search strategy that yielded 1758 articles. Inclusion criteria used were as follows: (1) the study has a patient population with 3 or more patients with previously untreated sinonasal malignancies; (2) patients underwent induction chemotherapy prior to definitive local therapy; (3) pretreatment staging information was documented; (4) overall survival was reported by histology type either in table or Kaplan-Meier format. Nine studies with 220 patients ultimately met inclusion criteria and were analyzed in groups based on tumor histology. RESULTS: For squamous cell carcinoma (SCC), the 5-year overall survival was 51%. For neuroendocrine tumors, the 5-year overall survival was 78%. Eighteen percent (18%) of patients with pretreatment orbital involvement ultimately underwent orbital exenteration. CONCLUSION: Induction chemotherapy in the management of sinonasal malignancies has similar overall survival outcomes as other standard treatment modalities and can be offered as an option to patients as part of multimodality therapy. PMID- 30411868 TI - First occurrence of Rift Valley fever outbreak in Niger, 2016. AB - Rift Valley fever (RVF) is a mosquito-borne viral zoonosis causing abortions and high mortality among animals, whereas in humans, the disease is usually mild or asymptomatic. In September 2016, the Republic of Niger declared the first RVF outbreak in the northern region of Tahoua near the Malian border. This study describes the outbreak and reports the results of serological and molecular investigations of the human and animal samples collected. Serum samples from both human and animal suspected cases have been confirmed at the Centre de Recherche Medicale et Sanitaire (CERMES) and the Laboratoire Centrale d'Elevage (LABOCEL) public health and animal reference laboratories, respectively. Techniques for biological confirmation were real time reverse transcription polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA). Phylogenetic trees were established after genetic sequencing of the small and medium segments of the RVF virus (RVFV) genome. Out of the 399 human samples collected, 17 (4.3%) were confirmed positive for RVFV. Overall, 33 (8.3%) deaths occurred out of which five (29%) were among the 17 confirmed cases. Regarding animals, 45 samples were tested, three of which were RT-PCR positive and 24 were IgG positive. The phylogenetic analyses showed that the Niger strains clustered with Senegal 2013 and Mauritania 2015 RVFV strains. This first outbreak of RVF was very challenging for public and animal health laboratories in Niger. Besides resulting in human deaths, important loss of cattle has been reported. Therefore, vigilance has to be strengthened emphasising vector control strategies and active surveillance among animals. PMID- 30411869 TI - "Preserved" glucagon secretion in fulminant type 1 diabetes. AB - Mixed-meal tolerance tests were carried out after an overnight fast. Healthy control participants (?), type 1A diabetespatients (?) and fulminant type 1 diabetic patients (?). Data are presented as the mean +/- standard error of the mean. PMID- 30411870 TI - Changes in cardiac autonomic nervous system activity during a course of electroconvulsive therapy. AB - AIM: Although electroencephalogram (EEG) seizure duration and seizure threshold change during a course of electroconvulsive therapy, the mechanisms by which these factors influence heart rate during subsequent electroconvulsive therapy sessions are currently unclear. In the current study, we investigated changes in heart rate during electroconvulsive therapy. METHODS: We recorded electroencephalography and electrocardiography during electroconvulsive therapy in 12 patients with major depressive disorder. Baseline heart rate was defined as the mean heart rate in the 30 seconds prior to stimulus onset. The TimeMax peak refers to the maximum heart rate after stimulus onset. Time1/2 points represent the time points at which the heart rate had decreased to a value midway between the baseline heart rate and the TimeMax peak. We examined the relationships between EEG seizure duration, TimeMax , and Time1/2 throughout the course of electroconvulsive therapy. RESULTS: Time1/2 decreased as the number of electroconvulsive sessions increased. Time1/2 was positively correlated with EEG seizure duration. CONCLUSION: The duration in which electroconvulsive therapy induced sympathetic nervous system activation returned halfway to baseline levels gradually shortened during the course of electroconvulsive therapy. PMID- 30411871 TI - How Pb2+ Binds and Modulates Properties of Ca2+-Signaling Proteins. AB - Abiogenic lead (Pb2+), present in the environment in elevated levels due to human activities, has detrimental effects on human health. Metal-binding sites in proteins have been identified as primary targets for lead substitution resulting in malfunction of the host protein. Although Pb2+ is known to be a potent competitor of Ca2+ in protein binding sites, why/how Pb2+ can compete with Ca2+ in proteins remains unclear, raising multiple outstanding questions, including the following: (1) What are the physicochemical factors governing the competition between Pb2+ and Ca2+? (2) Which Ca2+-binding sites in terms of the structure, composition, overall charge, flexibility, and solvent exposure are the most likely targets for Pb2+ attack? Using density functional theory combined with polarizable continuum model calculations, we address these questions by studying the thermodynamic outcome of the competition between Pb2+ and Ca2+ in various model Ca2+-binding sites, including those modeling voltage-gated calcium channel selectivity filters and EF-hand and non-EF-hand Ca2+-binding sites. The results, which are in good agreement with experiment, reveal that the metal site's flexibility and number of amino acid ligands dictate the outcome of the competition between Pb2+ and Ca2+: If the Ca2+-binding site is relatively rigid and crowded with protein ligands, then Pb2+, upon binding, preserves the native metal-binding site geometry and at low concentrations, can act as an activator of the host protein. If the Ca2+-binding site is flexible and consists of only a few protein ligands, then Pb2+ can displace Ca2+ and deform the native metal-binding site geometry, resulting in protein malfunction. PMID- 30411872 TI - Influence of the Magnitude of Ferroelectric Domain Polarization on the Photochemical Reactivity of BaTiO3. AB - The spontaneous polarization of domains in ferroelectric materials has been used to spatially separate photogenerated electrons and holes, reducing recombination and thereby improving the efficiency of photochemical reactions. Here, the influence of the magnitude of the polarization on photochemical reactivity is investigated. The magnitude of the out-of-plane component of the polarization was characterized by scanning Kelvin probe force microscopy (KFM). By examining crystals with orientations that deviate by only a few degrees from (001), two types of domains were identified: those with polarization vectors nearly perpendicular to the surface and those with polarization vectors nearly parallel to the surface. The photochemical reactivity was measured using topographic atomic force microscopy to determine the amount of Ag+ (Pb2+) that was photochemically reduced (oxidized) to Ag (PbO2) on the surface. For the reduction reaction, the reactivities of domains with polarizations nearly perpendicular to the surface were only about 3 times greater than the reactivities of the domains with polarizations nearly parallel to the surface, indicating that, for this reaction, the magnitude of the out-of-plane polarization is less important than its sign. For the oxidation of lead, only the domains with polarizations nearly perpendicular to the surface were reactive, indicating that for this reaction, both the sign and magnitude of the polarization are important. PMID- 30411873 TI - Recognition-Enhanced Metastably Shielded Aptamer for Digital Quantification of Small Molecules. AB - Aptamers are recognized as competitive affinity reagents; their application, however, often suffers from their relatively low target binding affinity, especially for small molecules. We herein introduce the concept of a recognition enhanced metastably shielded aptamer probe (RMSApt) and explore its performance for digital quantification of low-affinity small molecules. The RMSApt design employs the idea of constructing an allosteric aptamer probe conferring a minor energy gap in the recognition switch process to facilitate target binding and probe response, in turn significantly improving the recognition efficiency for low-affinity targets. The probe design strategy boosts the application of aptamers for precisely quantifying targets with a dissociation constant Kd ranging from 10-4 to 10-9 M, which would cover most of the small-molecule species that exist binding aptamers. Thus, RMSApt would facilitate the translation of aptamers for medical diagnosis, food safety, and environmental screening. PMID- 30411874 TI - Multifunctional cellulose ester containing hindered phenol groups with free radical scavenging and UV-resistant activities. AB - Excessive radicals and UV irradiation can trigger oxidative and physiological stresses, which cause tissue aging, human disease, food spoilage, and material degradation. In this study, a multifunctional cellulose ester containing hindered phenol groups, cellulose 3,5-di-tert-butyl-4-hydroxybenzoate (CBH), with free radical scavenging and UV-resistant activities was synthesized and used as functional material. The obtained CBHs can effectively scavenge reactive nitrogen free-radicals and hydroxyl free-radicals in both solid and solution states. Moreover, CBHs have no cytotoxicity, and on the contrary, they promote the proliferation of human epidermal keratinocytes (HEK). Benefiting from excellent solubility, processsability and formability, CBHs have been readily processed into flexible films, transparent coatings, and nanoribbons membranes. The highly transparent and flexible CBH film completely absorbs the light of 200-300 nm range and partially absorbs the light of 300-400 nm range, indicating a UV shielding capability. After CBHs were loaded on an ordinary facial mask by electrospinning or added into a hand-cream, the resultant facial-mask and hand cream exhibited outstanding free-radical scavenging properties. In addition, CBHs can also be used to fabricate functional sprays with antioxidative and UV shielding activities. Accordingly, the obtained CBHs have a huge potential in cosmetics, personal care products, biopharmaceuticals, papermaking, and art protection because of their excellent antioxidation, nontoxic, UV-resistance, formability, and odorless properties. PMID- 30411875 TI - Beyond O6-Benzylguanine: O6-(5-Pyridylmethyl)guanine as a Substrate for the Self Labeling Enzyme SNAP-Tag. AB - SNAP-tag is a genetically encoded label for tracking proteins of interest that is known to utilize O6-benzylguanine derivatives as substrates. In this work, mass spectrometric analysis revealed that SNAP-tag also accepts O6-(5 pyridylmethyl)guanine derivatives as substrates. A fluorescently conjugated O6-(5 pyridylmethyl)guanine was synthesized and used to selectively label intracellular compartments. This compound also acts as a zinc(II) ion-sensitive fluorescent indicator and therefore can be used in organelle-specific zinc(II) imaging. PMID- 30411876 TI - Solution-Liquid-Solid Growth of CuInTe2 and CuInSe xTe2- x Semiconductor Nanowires. AB - Ternary CuInTe2 and quaternary CuInSe xTe2- x nanowires were successfully synthesized for the first time by a solution-liquid-solid (SLS) mechanism. Crystalline, straight, and nearly stoichiometric CuInTe2 and CuInSe xTe2- x nanowires were readily achieved by using the molecular precursors and in the presence of molten Bi nanoparticles and coordinating capping ligands. The temperature and reactant order-of-addition of this reaction strongly affected the composition of the reaction product and the morphology obtained. These CuInTe2 and CuInSe xTe2- x nanowires are outstanding light absorbers from the near-IR through the visible and ultraviolet spectral regions and, thereby, comprise new soluble and machinable "building blocks" for applications in solar-light utilization. PMID- 30411877 TI - Peculiar Thermal Behavior of UO2 Local Stucture. AB - Most materials expand with temperature because of the anharmonicity of lattice vibration, and only a few shrink with increasing temperature. UO2, whose thermal properties are of significant importance for the safe use of nuclear energy, was considered for a long time to belong to the first group. This view was challenged by recent in situ synchrotron X-ray diffraction measurements, showing an unusual thermal decrease of the U-O distances. This thermal shrinkage was interpreted as a consequence of the splitting of the U-O distances due to a change in the U local order from Fm3 m to Pa3. In contrast to these previous investigations and using an element-specific synchrotron-based spectroscopic method, we show here that the U sublattice remains locally of the fluorite type from 50 to 1265 K, and that the decrease of the first U-O bond lengths is associated with an increase of the disorder. PMID- 30411878 TI - Enantioselective, Lewis Base-Catalyzed Carbosulfenylation of Alkenylboronates by 1,2-Boronate Migration. AB - A catalytic, enantioselective method for the preparation of chiral, non-racemic, alkylboronic esters bearing two vicinal stereogenic centers is described. The reaction proceeds via a 1,2-migration of a zwitterionic thiiranium-boronate complex to give exclusively anti carbosulfenylation products. A broad scope of aryl groups migrate with good yield and excellent enantioselectivity (up to 99:1 e.r.). Similarly, a range of di- and trisubstituted alkenylboronic esters are competent reaction partners. This method provides access to both secondary and tertiary chiral alkylboronic esters. PMID- 30411879 TI - Flexible Superwettable Tapes for On-Site Detection of Heavy Metals. AB - Bioinspired superwettable micropatterns that combine superhydrophobicity and superhydrophilicity have been proved to exhibit outstanding capacity in controlling and patterning microdroplets and possessed new functionalities and possibilities in emerging sensing applications. Here, we introduce a flexible tape-based superhydrophilic-superhydrophobic tape toward on-site heavy metals monitoring. On such a superwettable tape, capillarity-assisted superhydrophilic microwells allow directly anchoring indicators in fixed locations and sampling into a test zone via simple dip-pull from an origin specimen solution. In contrast, the superhydrophobic substrate could confine the microdroplets in the superhydrophilic microwells for reducing the amount of analytical solution. The tape-based microchip also displays excellent flexibility against stretching, bending, and torquing for expanding wearable and portable sensing devices. Qualitative and quantitative colorimetric assessments of multiplex heavy metal analyses (chromium, copper, and nickel) by the naked eye are also achieved. The superwettable tape-based platforms with a facile operation mode and accessible signal read-out represent unrevealed potential for on-site environmental monitoring. PMID- 30411880 TI - Discriminative Molecular Detection Based on Competitive Absorption by a Luminescent Metal-Organic Framework. AB - Distinguishing specific molecules from similar chemical species with minor structural differences is challenging, and differentiation has typically been based on analyte-dependent host-guest interactions upon irradiation with a single wavelength. In this study, we prepared a Cd-based metal-organic framework exhibiting nearly constant emission intensity over a wide range of excitations. Because of its unique emission characteristics, this material facilitated the differentiation of specific molecules amidst structurally similar chemical species via competitive absorption. Such discriminative identification was uniquely achieved based on the use of different excitation wavelengths and is demonstrated to be applicable to the recognition of a target analyte in sensory applications. PMID- 30411881 TI - Exploiting Synergetic Effects of Graphene Oxide and a Silver-Based Metal-Organic Framework To Enhance Antifouling and Anti-Biofouling Properties of Thin-Film Nanocomposite Membranes. AB - Thin-film composite (TFC) membranes still suffer from fouling and biofouling. In this work, by incorporating a graphene oxide (GO)-silver-based metal-organic framework (Ag-MOF) into the TFC selective layer, we synthesized a thin-film nanocomposite (TFN) membrane that has notably improved anti-biofouling and antifouling properties. The TFN membrane has a more negative surface charge, higher hydrophilicity, and higher water permeability compared with the TFC membrane. Fluorescence imaging revealed that the GO-Ag-MOF TFN membrane kills Escherichia (E.) coli more than the Ag-MOF TFN, GO TFN, and pristine TFC membranes by 16, 30, and 92%, respectively. Forward osmosis experiments with E. coli and sodium alginate suspensions showed that the GO-Ag-MOF TFN membrane by far has the lowest water flux reduction among the four membranes, proving the exceptional anti-biofouling and antifouling properties of the GO-Ag-MOF TFN membrane. PMID- 30411882 TI - Theoretical Insights into Preorganized Pyridylpyrazole-Based Ligands toward the Separation of Am(III)/Eu(III). AB - Pyridylpyrazole ligands have shown excellent competence for partitioning actinides from lanthanides. As far as we know, the preorganization structure of the ligand has a great impact on the extraction separation ability. However, the mechanism that works well for some ligands but fails for others needs to be clearly elucidated. In this work, we designed three various pyridylpyrazole ligands, BPP, BPBP, and BPPhen, and further preorganized one or both side pyrazole rings of these ligands. The properties of these ligands and the coordination structures, bonding nature and thermodynamic behaviors of the related Am(III) and Eu(III) complexes have been systematically studied in a theoretical fashion. All analyses of geometries, charge transfer, QTAIM (quantum theory of atoms in molecules) and NBO (natural bond orbital) suggest that the Am N bonds possess more covalence compared to that of Eu-N bonds. According to the thermodynamic results, increasing the rigidity of the bridging skeleton rather than the side chain can enhance the extraction ability and Am(III)/Eu(III) selectivity of the ligand. This work may identify the reasonability of a useful approach on achieving highly efficient Am(III)/Eu(III) separation through tuning the preorganization level of the ligand and further provide meaningful theoretical basis on the input of preorganization toward ligand design and screening. PMID- 30411883 TI - Gas Chromatography with In Situ Catalytic Hydrogenolysis and Flame Ionization Detection for the Direct Measurement of Formaldehyde and Acetaldehyde in Challenging Matrices. AB - A gas chromatographic strategy to advance the direct detection and quantification of volatile aliphatic aldehydes such as formaldehyde and acetaldehyde in gas phase matrices without the need for sample pretreatment or concentration has been successfully developed. The catalytic hydrogenolysis of aldehydes to alkanes is conducted in situ within the 3D-printed steel jet assembly of the flame ionization detector and without any additional hardware required. Reliable conversion efficiencies of greater than 90% with respectable peak symmetries for the analytes were attained at 400 degrees C. Quantification of formaldehyde and acetaldehyde at parts-per-million levels over a range of 0.5-300 ppm (v/v) for formaldehyde and 0.2-430 ppm (v/v) for acetaldehyde with a respectable precision of less than 5% RSD ( n = 10) was achieved. The total analysis time was less than 10 min. Linearity with a correlation coefficient ( R2) greater than 0.9997 and measured recoveries of >99% for spike tests under the specified conditions were achieved. The 3D-printed steel jet assembly was found to be reliable and resilient to matrices such as air, water, hydrocarbons, and aromatics. An additional benefit realized with this analytical strategy is that the slight restriction induced by the presence of the catalyst in the 3D-printed jet assembly enables backflush via the inlet split vent without the need for additional pressure control or intercolumn-connection devices. The utility of this technique was demonstrated with important aldehyde applications from various segments. PMID- 30411884 TI - Edible Dye-Enhanced Solar Disinfection with Safety Indication. AB - The rural developing world faces disproportional inequity in drinking water access, where point-of-use water treatment technologies often fail to achieve adequate levels of pathogen removal, especially for viruses. Solar disinfection (SODIS) is practiced because of its universal applicability and low implementation cost, though the excessively long treatment time and lack of safety indication hinder wider implementation. This study presents an enhanced SODIS scheme that utilizes erythrosine-a common food dye-as a photosensitizer to produce singlet oxygen for virus inactivation and to indicate the completion of water disinfection through photobleaching color change. Experimental results and predictions based on global solar irradiance data suggest that over 99.99% inactivation could be achieved within 5 min in the majority of developing countries, reducing the time for SODIS by 2 orders of magnitude. Preserving the low cost of traditional SODIS, erythrosine embodies edible dye-enhanced SODIS, an efficient water disinfection method that could potentially be used by governments and non-governmental organizations to improve drinking water quality in rural developing communities. PMID- 30411885 TI - Two-Dimensional Porous Polymers: From Sandwich-like Structure to Layered Skeleton. AB - Inorganic porous materials have long dominated the field of porous materials due to their stable structure and wide applications. In the past decade, porous polymers have generated considerable interest among researchers because of their easily tunable porosity, carbon-rich backbones, and prominent physical properties. These attributes enable porous polymers to be used in various applications such as sensing, gas separation and storage, catalysis, and energy storage. However, poor dispersibility has long hindered the development of porous polymers. A majority of the reported porous polymers can only be synthesized with amorphous structure through direct precipitation from solutions during reactions. The rational design and synthesis of porous polymers with controllable morphology, such as two-dimensional (2D) morphology, remains great challenge. Two dimensional nanomaterials have attracted considerable interest because of their unique properties, which originate from the intrinsic chemical structures and 2D dimensionality. Among 2D nanomaterials, 2D porous polymers, which possess the advanced features of polymers, porous materials, and 2D nanomaterials, have been a rising star. Conventionally, polymerization strategies for generating 2D porous polymers mainly include the cross-linking of multiarmed monomers in 2D-space confined environments, such as crystalline solid surfaces, liquid-liquid interfaces, and liquid-air interfaces. However, these methods always involve complicate operations, e.g., under vacuum, sophisticated equipment, film transfer technology, exfoliation, and so on and, most importantly, are difficult to scale up. To overcome this synthesis obstacle, 2D nanomaterials, such as graphene, can be used as 2D templates for synthesis of sandwich-like 2D porous polymers and porous carbon nanosheets. p-Bromobenzene-, p-cyanobenzene-, polyacrylonitrile-, and amino-functionalized graphene are used as templates for direct surface polymerization through reactions such as Sonogashira-Hagihara coupling reaction, condensation reaction, ionothermal reaction, reversible addition-fragmentation chain transfer polymerization, Friedel-Crafts reaction, and oxidation reaction. Therefore, sandwich-like 2D conjugated microporous polymers, Schiff-base type porous polymers, covalent triazine frameworks, hyper-cross-linked porous polymers, and mesoporous conducting polymers can be easily prepared. Beyond graphene, other excellent 2D nanomaterials, e.g., MoS2, can also act 2D templates to construct 2D porous polymers and corresponding hybrid materials. In addition, 2D morphology for porous polymer can be achieved without 2D templates in a few cases. For instance, olefin-linkage-linked covalent organic frameworks can be synthesized through Knoevenagel condensation reaction. As is known, porous polymers can serve as carbon-rich precursors to generate heteroatom doped porous carbons for energy storage and catalysis. Thus, one benefit of 2D porous polymers is new access toward porous carbon nanosheets through direct pyrolysis without using inorganic porous templates. In this Account, we summarize recent research on 2D porous polymers and corresponding porous carbon nanosheets. PMID- 30411886 TI - Characterization of G-Quadruplexes in Chlamydomonas reinhardtii and the Effects of Polyamine and Magnesium Cations on Structure and Stability. AB - Chlamydomonas reinhardtii is a green alga with a very GC-rich genome (67%) and a high density of potential G-quadruplex-forming sequences (PQSs). Using the Ensembl Plants DNA database, 19 PQSs were selected, and their ability to fold in vitro was examined using four experimental methods. Our results support in vitro folding of 18 of the 19 PQSs selected for study. The high physiological polyamine concentrations in C. reinhardtii create unique conditions for studying G4 folding. We investigated whether high polyamine concentrations affect the stability and structural fold of two polymorphic G4s selected from the cohort of PQSs. The two polymorphic G4s selected were found to be greatly stabilized when studied at the physiologically high polyamine concentrations. Lastly, the effects of physiologically relevant Mg2+ concentrations were tested on both of the polymorphic G4s, and one of the G4s shifted from a dynamic mixture of folds to favor a parallel fold in the presence of Mg2+. Our work supports the concept of folding of G4s under the unique conditions observed in C. reinhardtii, and these structures, being located in promoter regions of DNA repair and photosynthetic genes, might be relevant structures in the physiology of C. reinhardtii. PMID- 30411887 TI - Robust Bifunctional Core-Shell MOF@POP Catalyst for One-Pot Tandem Reaction. AB - A new bifunctional acid-base catalyst, core-shell UiO-66@SNW-1, with robust chemical and thermal stability, recyclability, and durable catalytic activity is synthesized by a convenient, universal strategy. Interestingly, this hybrid material can effectively catalyze deacetalization-Knoevenagel condensation reaction in the presence of excellent compartmentalization to spatially isolate opposing acid-base sites. PMID- 30411888 TI - Pressure-Assisted Method for the Preparations of High-Quality AaGaS2 and AgGaGeS4 Crystals for Mid-Infrared Laser Applications. AB - Recently developed chalcogenides nonlinear optical crystals have potential application in mid- to far-infrared laser fields. However, high-quality single crystals are hard to be prepared because of high vapor pressure of sulfur component and decomposition of chalcogenides during the polycrystalline synthesis and single-crystal growth. A pressure-assisted technique was performed to prepare stoichiometric AgGaS2 and AgGaGeS4 polycrystalline materials. On the basis of the synthesized polycrystalline materials, high-quality AgGaS2 and AgGaGeS4 single crystals were successfully obtained using the seed directional Bridgman method with a well-designed crucible-capsule technique. These single crystals possess high homogeneity and low absorption coefficient, making it can be applied in nonlinear optical experiments. The pressure-assisted method can also be suitable to prepare other chalcogenide and phosphide compounds. The method of polycrystalline synthesis and single crystals growth described in this work will be helpful for preparing other chalcogenides nonlinear optical crystals. PMID- 30411889 TI - Effects of Dietary Fiber Supplementation on Fatty Acid Metabolism and Intestinal Microbiota Diversity in C57BL/6J Mice Fed with a High-Fat Diet. AB - This work was to assess possible impacts of novel insoluble fiber 8% bacterial cellulose (BC), soluble fiber 8% konjac glucomannan (KGM), and their mixture (4% BC/4% KGM) on fatty acid metabolism and intestinal microbiota of C57BL/6J mice fed with a high-fat diet (HFD). HFD-fed mice receiving the dietary fibers (DFs) for 16 weeks exhibited an improvement in lipid-associated cytokines and a decrease in inflammation factors, which was associated with the improved hepatic and serum fatty acid composition. The DFs, notably the mixed BC/KGM, elevated the HFD-caused decrease in the contents of acetic acid (from 23.9 +/- 0.85 to 32.2 +/ 0.84 mM/g; p < 0.05), propionic acid (from 6.53 +/- 0.28 to 12.8 +/- 0.58 mM/g; p < 0.05), and butyric acid (from 7.73 +/- 0.43 to 13.5 +/- 0.47 mM/g; p < 0.05). Furthermore, the mixed BC/KGM significantly decreased the abundance of Firmicutes (from 90.4 to 67.6%) and Mucispirillum (from 4.77 to 1.58%) and dramatically increased the abundance of Bacteroidetes (from 7.83 to 25.0%) and Akkermansia (from 0.69 to 2.80%) in the gut of HFD-fed mice at the genus level. Moreover, correlation analysis revealed that the multiplicity of gut microbiota was useful in sustaining colonic integrity through producing short-chain fatty acids to some extent. This finding suggests that a mixture of insoluble BC and soluble KGM has positive effects on modulation of the intestinal microecosystem in mice. PMID- 30411890 TI - Direct Asymmetric Vinylogous Mannich Addition of 3,5-Disubstituted-4 nitroisoxazoles to Isatin-Derived Imines Catalyzed by a Bifunctional Phase Transfer-Catalyst. AB - Asymmetric Mannich-type addition of 3,5-disubstituted-4-nitroisoxazoles to isatin derived Boc-protected imines has been realized by using 0.01 equiv of amide phosphonium salt as a phase transfer catalyst. Our current methodology allows for the formation of 3-isoxazolylmethyl-substituted 3-aminooxindoles in excellent yields with good to excellent enantioselectivities. The practical value of this methodology was exemplified by a gram-scale synthesis of 5an, a key intermediate for the formal synthesis (+)-AG-041R. PMID- 30411891 TI - Excitation-Dependent Multiple Fluorescence of a Substituted 2-(2' Hydroxyphenyl)benzoxazole. AB - Excitation-dependent multiple fluorescence of a 2-(2'-hydroxyphenyl)benzoxazole (HBO) derivative (1) is described. Compound 1 contains the structure of a charge transfer (CT) 4-hydroxyphenylvinylenebipy fluorophore and an excited-state intramolecular proton transfer capable (ESIPT-capable) HBO component that intersect at the hydroxyphenyl moiety. Therefore, both CT and ESIPT pathways, while spatially mostly separated, are available to the excited state of 1. The ESIPT process offers two emissive isomeric structures (enol and keto) of 1 in the excited state, while the susceptibility of 1 to a base adds another option to tune the composite emission color. In addition to the ground-state acid-base equilibrium that can be harnessed for the control of emission color by excitation energy, compound 1 exhibits excitation-dependent emission that is attributed to solvent-affected ground-state structural changes. Therefore, depending on the medium and excitation wavelength, the emission from the enol, keto, and anion forms could occur simultaneously, which are in the color ranges of blue, green, and orange/red, respectively. A composite color of white with CIE coordinates of (0.33, 0.33) can be materialized through judicious choices of medium and excitation wavelength. PMID- 30411892 TI - Lipid and Protein Oxidation during in Vitro Gastrointestinal Digestion of Pork under Helicobacter pylori Gastritis Conditions. AB - Helicobacter pylori gastritis affects gastric pH and concentrations of ascorbic acid, hydrogen peroxide, hypochlorite, ammonia and urea, pepsin, and mucin. First, the separate effects of each of these altered factors on oxidation of pork were investigated during in vitro gastrointestinal digestion. Lipid and protein oxidation increased (range 23-48%) in duodenal digests of pork previously exposed to elevated (6.1) versus normal acidic stomach pH (2.3 to 3.5) conditions. Salivary nitrite reduced the formation of lipid and protein oxidation products (range 14-20%) under normal acidic but not elevated stomach pH conditions. Higher amounts of hydrogen peroxide and lower amounts of ascorbic acid decreased concentrations of lipid oxidation products in duodenal pork digests, whereas ammonia slightly stimulated protein oxidation during digestion. Second, two H. pylori gastritis-duodenal digestion models were installed using a set of altered compound concentrations at normal acidic or elevated stomach pH. The elevated pH gastritis-duodenal digestion model increased pork protein oxidation compared with the normal pH-gastritis and the normal digestion model (14.3 +/- 2.1 vs 8.2 +/- 1.0 nmol DNPH/mg protein, P < 0.001). Compared with the other models, protein oxidation was also increased when nitrite-cured pork was exposed to the elevated pH-gastritis-duodenal digestion model (10.8 +/- 1.4 vs 5.9 +/- 0.8 nmol DNPH/mg protein, P < 0.001), but no significant effect of the model was observed when the pork was seasoned with herbs. Lipid oxidation was not or was marginally affected by the installed model. PMID- 30411893 TI - Selective Chain-End Functionalization of Polar Polyethylenes: Orthogonal Reactivity of Carbene and Polar Vinyl Monomers in Their Copolymerization with Ethylene. AB - Pd(II)-catalyzed copolymerization of ethylene, carbene species, and polar vinyl monomers is successfully developed for the first time to obtain chain-end functionalized polar polyethylenes, with selective distribution of the polar vinyl monomers within the main chain and carbene at the chain-end. Notably, >99% chain-end-capping with the carbene species can be achieved under the optimized conditions. Mechanistic investigations suggest that the carbene precursor reacts with the generated alkyl palladium complex to terminate the growing chain-end and regenerate the catalyst. PMID- 30411894 TI - An NMR Confirmation for Increased Folded State Entropy Following Loop Truncation. AB - Previous studies conducted on flexible loop regions in proteins revealed that the energetic consequences of changing loop length predominantly arise from the entropic cost of ordering a loop during folding. However, in an earlier study of human acylphosphatase (hmAcP) using experimental and computational approaches, we showed that thermodynamic stabilization upon loop truncation can be attributed mainly to the increased entropy of the folded state. Here, using 15N NMR spectroscopy, we studied the effect of loop truncation on hmAcP backbone dynamics on the picosecond-nanosecond timescale with the aim of confirming the effect of folded state entropy on protein stability. NMR-relaxation-derived N-H squared generalized order parameters reveal that loop truncation results in a significant increase in protein conformational flexibility. Comparison of these results with previously acquired all-atom molecular dynamics simulation, analyzed here in terms of squared generalized NMR order parameters, demonstrates general agreement between the two methods. The NMR study not only provides direct evidence for the enhanced conformational entropy of the folded state of hmAcP upon loop truncation but also gives a quantitative measure of the observed effects. PMID- 30411895 TI - Reducing the Lipophilicity of Perfluoroalkyl Groups by CF2-F/CF2-Me or CF3/CH3 Exchange. AB - Fluorination is commonly employed to optimize bioactivity and pharmaco-kinetic properties of drug candidates. Aliphatic fluorination often reduces the lipophilicity (log P), but polyfluoroalkylation typically increases lipophilicity. Hence, identification of polyfluorinated motifs that nonetheless lead to similar or even reduced lipophilicities is of interest to expand the arsenal of medicinal chemistry tools in tackling properties such as compound metabolic stability or off-target selectivity. We show that changing a CF3-group of a perfluoroalkyl chain to a methyl group leads to a drastic reduction in lipophilicity. We also show that changing a C-F bond of a trifluoromethyl group, including when incorporated as part of a perfluoroalkyl group, to a C-Me group, leads to a reduction in log P, despite the resulting chain elongation. The observed lipophilicity trends were identified in fluorinated alkanol models and reproduced when incorporated in analogues of a drug candidate, and the metabolic stability of these motifs was demonstrated. PMID- 30411896 TI - Plant Metabolomics: Evaluation of Different Extraction Parameters for Nontargeted UPLC-ESI-QTOF-Mass Spectrometry at the Example of White Asparagus officinalis. AB - The extraction of metabolites turns out to be one of the most important key factors for nontargeted metabolomics approaches as this step can significantly affects the informative value of the successive measurements. Compared to metabolomics experiments of various matrices of bacterial or mammalian origins, there are only few studies, which focus on different extraction methods for plant metabolomics analyses. In this study, various solvent extraction compositions were compared and assessed using an UPLC-ESI-QTOF-MS strategy. Exemplary, white asparagus ( Asparagus officinalis) were employed as a low-fat-, low-protein-, high-water-content model commodity with the objective of designing an optimal nontargeted extraction protocol for polar and nonpolar metabolites. Furthermore, the influence of acid addition, mechanical cell disruption methods (ball mill, ultrasonic bath, vortex mixer), and extract stability have been systematically scrutinized too. The different extraction protocols were compared based on sum of features, sum of peak intensities, sum of peak areas, as well as by analyzing individual signals of as many different substance groups as possible to obtain a maximum overview. PMID- 30411897 TI - Blueberry Polyphenols Ameliorate Visible Light and Lipid-Induced Injury of Retinal Pigment Epithelial Cells. AB - Although dietary polyphenols are known to be beneficial to vision, the protective distinctions among different types of polyphenols are unclear. In this work, the visual benefits of various blueberry polyphenols were evaluated using an in vitro model of visible light-lipid-induced injury of retinal pigment epithelial cells. Results showed that, at 10.0 MUg/mL, the phenolic acid-rich fraction was superior in inhibiting cell death (93.6% +/- 2.8% of cell viability). Anthocyanin- and flavonoid-rich fractions shared similar advantages in preventing the expression of senescence-associated beta-galactosidase (34.8% +/- 11.1% and 32.2% +/- 9.7% of aged cells, respectively) and overexpression of vascular endothelial growth factor (51.8 +/- 3.5 and 54.1 +/- 6.5 pg/mL, respectively). The flavonoid-rich fraction also showed high activity in ameliorating phagocytosis (70.3% +/- 12.6%) and cellular oxidative stress. These results were further confirmed by using the corresponding polyphenol standards. Improved inhibitory effects of polyphenol mixture on cell death and senescence-associated beta-galactosidase expression were also observed. Therefore, various polyphenols play diverse roles and exert synergistic effects in nourishing the retina. PMID- 30411898 TI - State of the Art in Respiratory Syncytial Virus Drug Discovery and Development. AB - Respiratory syncytial virus (RSV) is a globally prevalent viral infection with limited treatment options which hospitalizes millions each year. Treatment options have been limited to palivizumab, a monoclonal antibody, approved for prophylaxis in high-risk infants and ribavirin with very limited efficacy and significant safety concerns. This Perspective surveys the range of direct acting antiviral agents (DAAs) that target key steps in the viral life cycle. A number of approaches to DAAs have produced landmark clinical studies over the past few years, notably in fusion and nucleoside inhibitors, and an update of the clinical status of these compounds is provided. Non-nucleoside inhibitors of replication are reviewed in addition to inhibitors of other mechanisms, notably the RSV N and G proteins. This article will provide an informative perspective of the current status of drug discovery targeted at providing an effective therapy for RSV infection. PMID- 30411899 TI - Unraveling and Manipulating the Stereospecific Retro-Aldol Reaction in the Organocatalytic Asymmetric Aldol Reaction of Isatin and Cyclohexanone. AB - An l-pyroglutamic acid-derived bifunctional organocatalyst was designed and applied in an organocatalytic asymmetric direct aldol reaction between isatins and cyclohexanone, in which an erosion of enantiomeric excess of aldol adduct was unexpectedly observed. Through closely monitoring the reaction and performing extensive control experiments, it was determined that the erosion of ee was attributed to a rare stereospecific retro-aldol process. Moreover, effective manipulation of the retro-aldol process by tuning the use of starting materials was ultimately accomplished, leading to evidently upgraded enantioselectivity and functional group tolerance. This study demonstrates the impact of the hidden reaction pathway on the enantioselectivity in asymmetric transformation. PMID- 30411900 TI - Adsorption of Molecular Nitrogen in Electrical Double Layers near Planar and Atomically Sharp Electrodes. AB - The adsorption of gas molecules at electrode-electrolyte interfaces is an important step in electrochemical reactions. Using molecular dynamics simulations, we investigate the adsorption of dissolved N2 in the electrical double layers (EDLs) of an aqueous electrolyte near planar and 1 nm radius spherical carbon electrodes. The adsorption of N2 is found to be overall enriched near neutral electrodes regardless of their surface curvature, although it can be locally enriched or depleted depending on the distance from the electrode surface. In comparison, the adsorption of N2 in the EDL near negatively charged electrodes is found to increase under a moderate surface charge density, but decrease under a high surface charge density, especially near a planar electrode. By analyzing the potential of mean force for dissolved N2, the solvent-induced effects are found to play important roles in influencing the adsorption of N2 in the EDLs. The adsorption behavior of N2 molecules, especially their dependence on the surface charge and curvature of electrodes, is further rationalized by examining the structure of interfacial water molecules, their interference with the hydration shell of N2, and their modification by the electrification of electrodes. PMID- 30411901 TI - Arylation/Intramolecular Conjugate Addition of 1,6-Enynes Enabled by Manganese(I) Catalyzed C-H Bond Activation. AB - An arylation/intramolecular conjugate addition of cyclohexadienone-containing 1,6 enynes has been established through initiation by manganese(I)-catalyzed C-H bond activation. This tandem reaction involved unusual E/ Z-isomerized alkenyl-Mn intermediates and proceeded smoothly with high chemoselectivities and perfect atom economy. The cyclization products could be further transformed to various structures. Mechanistic studies suggested that cleavage of the C-H bond was involved in the turnover-limiting step, and a manganese carbene anion intermediate was proposed to explain such an E/ Z isomerization process. PMID- 30411902 TI - Organocatalytic Asymmetric Allylic Alkylations of Sulfoximines. AB - An enantio- and regioselective allylic alkylation of sulfoximines with Morita Baylis-Hillman carbonates was developed. The asymmetric reaction is directed by a quinidine-derived organocatalyst providing a range of optically active alpha methylene beta-sulfoximidoyl esters in high yields (up to 93%) with good to excellent enantiomeric excesses (up to 95%) under mild reaction conditions. PMID- 30411903 TI - Liquid Combination with High Refractive Index Contrast and Fast Scanning Speeds for Electrowetting Adaptive Optics. AB - Electrowetting adaptive optical devices are versatile, with applications ranging from microscopy to remote sensing. The choice of liquids in these devices governs its tuning range, temporal response, and wavelength of operation. We characterized a liquid system, consisting of 1-phenyl-1-cyclohexene and deionized water, using both lens and prism devices. The liquids have a large contact angle tuning range, from 173 to 60 degrees . Measured maximum scanning angle was realized at +/-13.7 degrees in a two-electrode prism, with simulation predictions of +/-18.2 degrees . The liquid's switching time to reach 90 degrees contact angle from rest, in a 4 mm diameter device, was measured at 100 ms. Steady-state scanning with a two-electrode prism showed linear and consistent scan angles of +/-4.8 degrees for a 20 V differential between the two electrodes, whereas beam scanning using the liquid system achieved +/-1.74 degrees at 500 Hz for a voltage differential of 80 V. PMID- 30411904 TI - Salience network connectivity and social processing in children with nonverbal learning disability or autism spectrum disorder. AB - OBJECTIVE: Nonverbal learning disability (NVLD) is a putative neurodevelopmental disorder characterized by spatial processing deficits as well as social deficits similar to those characteristic of autism spectrum disorder (ASD). Nonetheless, NVLD may be a distinct disorder that is differentially associated with the functioning and connectivity of the salience (SN) and default mode (DMN) networks that support social processing. Thus, we sought to assess and compare connectivity across these networks in children with NVLD, ASD, and typically developing children. METHOD: Resting-state fMRI data were examined in 17 children with NVLD, 17 children with ASD selected from the Autism Brain Imaging Data Exchange (ABIDE), and 40 TD children (20 from ABIDE). Average DMN and SN functional connectivity and pairwise region-to-region connectivity were compared across groups. Associations with social impairment and IQ were assessed. RESULTS: Children with NVLD showed reduced connectivity between SN regions (anterior insula to anterior cingulate and to rostral prefrontal cortex [rPFC]), whereas children with ASD showed greater connectivity between SN regions (supramarginal gyrus to rPFC) relative to the other groups. Both clinical groups showed higher levels of parent-reported social problems, which related to altered SN connectivity in the NVLD group. No differences were detected in overall average connectivity within or between networks. CONCLUSIONS: The social deficits common across children with NVLD and ASD may derive from distinct alterations in connectivity within the SN. Such findings represent the first step toward identifying a neurobiological signature of NVLD. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30411905 TI - Conceptualizing restorative justice for people with mental illnesses leaving prison or jail. AB - Individuals with psychiatric disabilities who are involved in the criminal justice system face a number of challenges to community integration upon release. There is a critical need to develop and evaluate interventions for these individuals that connect them to the community by enhancing naturalistic social connections and helping them to participate meaningfully in valued roles. The purposes of this article are to describe, provide a theoretical rationale, and propose a conceptual model for the use of a particular restorative justice model, circles of support and accountability, to meet this need. We describe the principles of restorative justice (repairing harm, stakeholder involvement, and the transformation of community and governmental roles and relationships) and how these map on to elements of the circles intervention. These elements include a focus on community participation, positive social support, democratic decision making, collective ownership of crime problems, and connection to community-based resources. We then suggest how changes in identity transformation, moral development and motivation, and collective efficacy might mediate relationships between these intervention elements and community integration outcomes. Finally, we encourage the systematic evaluation of the circles intervention for people with mental health conditions leaving custody and provide recommendations for policy and practice. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30411906 TI - Autonomous Actuation of Zero Modes in Mechanical Networks Far from Equilibrium. AB - A zero mode, or floppy mode, is a nontrivial coupling of mechanical components yielding a degree of freedom with no resistance to deformation. Engineered zero modes have the potential to act as microscopic motors or memory devices, but this requires an internal actuation mechanism that can overcome unwanted fluctuations in other modes and the dissipation inherent in real systems. In this Letter, we show theoretically and experimentally that complex zero modes in mechanical networks can be selectively mobilized by nonequilibrium activity. We find that a correlated active bath actuates an infinitesimal zero mode while simultaneously suppressing fluctuations in higher modes compared to thermal fluctuations, which we experimentally mimic by high frequency shaking of a physical network. Furthermore, self-propulsive dynamics spontaneously mobilize finite mechanisms as exemplified by a self-propelled topological soliton. Nonequilibrium activity thus enables autonomous actuation of coordinated mechanisms engineered through network topology. PMID- 30411907 TI - Nonlocal Metasurfaces for Optical Signal Processing. AB - Optical analog signal processing has been gaining significant attention as a way to overcome the speed and energy limitations of digital techniques. Metasurfaces offer a promising avenue towards this goal due to their efficient manipulation of optical signals over deeply subwavelength volumes. To date, metasurfaces have been proposed to transform signals in the spatial domain, e.g., for beam steering, focusing, or holography, for which angular-dependent responses, or nonlocality, are unwanted features that must be avoided or mitigated. Here, we show that the metasurface nonlocality can be engineered to enable signal manipulation in the momentum domain over an ultrathin platform. We explore nonlocal metasurfaces performing basic mathematical operations, paving the way towards fast and power-efficient ultrathin devices for edge detection and optical image processing. PMID- 30411908 TI - Breakdown of Nonrelativistic QCD Factorization in Processes Involving Two Quarkonia and its Cure. AB - We study inclusive processes involving two heavy quarkonia in nonrelativistic QCD (NRQCD) and demonstrate that, in the presence of two P-wave Fock states, NRQCD factorization breaks down, leaving uncanceled infrared singularities. As phenomenologically important examples, we consider the decay Upsilon->chi_{cJ}+X via bb[over -](^{3}P_{J_{b}}^{[8]})->cc[over -](^{3}P_{J}^{[1]})+gg and the production process e^{+}e^{-}->J/psi+chi_{cJ}+X via e^{+}e^{-}->cc[over ](^{3}P_{J_{1}}^{[8]})+cc[over -](^{3}P_{J}^{[1]})+g. We infer that such singularities will appear for double quarkonium hadroproduction at next-to leading order. As a solution to this problem, we introduce to NRQCD effective field theory new types of operators whose quantum corrections absorb these singularities. PMID- 30411909 TI - Trapping and Guiding Bodies by Gravitational Waves Endowed with Angular Momentum. AB - Trapping of bodies by waves is extended from electromagnetism to gravity. It is shown that gravitational waves endowed with angular momentum may accumulate near its axis all kinds of cosmic debris. The trapping mechanism in both cases can be traced to the Coriolis force associated with the local rotation of the space metric. The same mechanism causes the Trojan asteroids to librate around the Sun Jupiter stable Lagrange points L_{4} and L_{5}. Trapping of bodies in the vicinity of the wave center could also be related to the formation of galactic jets. PMID- 30411910 TI - Superradiance-to-Polariton Crossover of Wannier Excitons with Multiple Resonances. AB - We demonstrated the superradiance-to-polariton crossover of the blue excitons in Cu_{2}O by varying the sample thicknesses instead of controlling the cavity quality factor. The crossover behavior was compared with unprecedented calculations based on the nonlocal optical response theory with the inclusion of three exciton resonances. The crossover thickness, found to be 177+/-2 nm, was smaller than the predicted value for a single resonance by a factor of 5. The fact that there was much larger longitudinal-transverse splitting (40+/-5 meV) than in the bulk implies a surprisingly fast radiative recombination even without a cavity structure. PMID- 30411911 TI - Conformer Selection by Matter-Wave Interference. AB - We establish that matter-wave diffraction at near-resonant ultraviolet optical gratings can be used to spatially separate individual conformers of complex molecules. Our calculations show that the conformational purity of the prepared beam can be close to 100% and that all molecules remain in their electronic ground state. The proposed technique is independent of the dipole moment and the spin of the molecule and thus paves the way for structure-sensitive experiments with hydrocarbons and biomolecules, such as neurotransmitters and hormones, which have evaded conformer-pure isolation so far. PMID- 30411912 TI - Simulation of Nonequilibrium Dynamics on a Quantum Computer. AB - We present a hybrid quantum-classical algorithm for the time evolution of out-of equilibrium thermal states. The method depends on classically computing a sparse approximation to the density matrix and, then, time-evolving each matrix element via the quantum computer. For this exploratory study, we investigate a time dependent Ising model with five spins on the Rigetti Forest quantum virtual machine and a one spin system on the Rigetti 8Q-Agave quantum processor. PMID- 30411913 TI - Erratum: Microwave Detection of Electron-Phonon Interactions in a Cavity-Coupled Double Quantum Dot [Phys. Rev. Lett. 120, 097701 (2018)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.120.097701. PMID- 30411914 TI - Quantitative Theory for the Growth Rate and Amplitude of the Compressible Richtmyer-Meshkov Instability at all Density Ratios. AB - Theoretical treatment of the Richtmyer-Meshkov instability in compressible fluids is a challenging task due to the presence of compressibility and nonlinearity. In this Letter, we present a quantitative theory for the growth rate and the amplitude of fingers in Richtmyer-Meshkov instability for compressible fluids based on the methods of the two-point Pade approximation and asymptotic matching. Our theory covers the entire time domain from early to late times and is applicable to systems with arbitrary fluid density ratios. The theoretical predictions are in good agreement with data from several independent numerical simulation methods and experiments. PMID- 30411915 TI - Complex Low Energy Tetrahedral Polymorphs of Group IV Elements from First Principles. AB - The energy landscape of carbon is exceedingly complex, hosting diverse and important metastable phases, including diamond, fullerenes, nanotubes, and graphene. Searching for structures, especially those with large unit cells, in this landscape is challenging. Here we use a combined stochastic search strategy employing two algorithms (ab initio random structure search and random sampling strategy combined with space group and graph theory) to apply connectivity constraints to unit cells containing up to 100 carbon atoms. We uncover three low energy carbon polymorphs (Pbam-32, P6/mmm, and I4[over -]3d) with new topologies, containing 32, 36, and 94 atoms in their primitive cells, respectively. Their energies relative to diamond are 96, 131, and 112 meV/atom, respectively, which suggests potential metastability. These three carbon allotropes are mechanically and dynamically stable, insulating carbon crystals with superhard mechanical properties. The I4[over -]3d structure possesses a direct band gap of 7.25 eV, which is the widest gap in the carbon allotrope family. Silicon, germanium, and tin versions of Pbam-32, P6/mmm, and I4[over -]3d also show energetic, dynamical, and mechanical stability. The computed electronic properties show that they are potential materials for semiconductor and photovoltaic applications. PMID- 30411916 TI - Linear-in-Frequency Optical Conductivity in GdPtBi due to Transitions near the Triple Points. AB - The complex optical conductivity of the half-Heusler compound GdPtBi is measured in a frequency range from 20 to 22 000 cm^{-1} (2.5 meV-2.73 eV) at temperatures down to 10 K in zero magnetic field. We find the real part of the conductivity, sigma_{1}(omega), to be almost perfectly linear in frequency over a broad range from 50 to 800 cm^{-1} (~6-100 meV) for T<=50 K. This linearity strongly suggests the presence of three-dimensional linear electronic bands with band crossings (nodes) near the chemical potential. Band-structure calculations show the presence of triple points, where one doubly degenerate and one nondegenerate band cross each other in close vicinity of the chemical potential. From a comparison of our data with the optical conductivity computed from the band structure, we conclude that the observed nearly linear sigma_{1}(omega) originates as a cumulative effect from all the transitions near the triple points. PMID- 30411917 TI - Thermalization and Heating Dynamics in Open Generic Many-Body Systems. AB - The last decade has witnessed remarkable progress in our understanding of thermalization in isolated quantum systems. Combining the eigenstate thermalization hypothesis with quantum measurement theory, we extend the framework of quantum thermalization to open many-body systems. A generic many body system subject to continuous observation is shown to thermalize at a single trajectory level. We show that the nonunitary nature of quantum measurement causes several unique thermalization mechanisms that are unseen in isolated systems. We present numerical evidence for our findings by applying our theory to specific models that can be experimentally realized in atom-cavity systems and with quantum gas microscopy. Our theory provides a general method to determine an effective temperature of quantum many-body systems subject to the Lindblad master equation and thus should be applicable to noisy dynamics or dissipative systems coupled to nonthermal Markovian environments as well as continuously monitored systems. Our work provides yet another insight into why thermodynamics emerges so universally. PMID- 30411918 TI - Infrared Spectroscopy of the Topological Surface States of Bi_{2}Se_{3} by Use of the Berreman Effect. AB - The Berreman effect (BE) allows one to study the electrodynamics of ultrathin conducting films at the surface of dielectrics by use of grazing-angle infrared spectroscopy and polarized radiation. Here, we first apply the BE to the two dimensional electron system (2DES) at the interface between a high-purity film of the topological insulator Bi_{2}Se_{3} and its sapphire substrate. We determine for the 2DES a charge density n_{s}=(8+/-1)*10^{12} cm^{-2}, a thickness d=0.6+/ 0.2 nm, and a mobility MU^{IR}=290+/-30 cm^{2}/V s. Within errors, all of these parameters result in being independent of temperature between 300 and 10 K. These findings consistently indicate that the 2DES is formed by topological surface states, whose infrared response is then directly observed here. PMID- 30411919 TI - Signature of the s-Wave Regime High above Ultralow Temperatures. AB - Resonant exchange is a general process playing a key role in many-body dynamics and transport phenomena, such as spin, charge, or excitation diffusion. The underlying process is described by the resonant exchange cross section. We show that the s-wave scattering, generally thought to contribute mainly in the ultracold (or Wigner) regime, dictates the overall cross section over a broad range of energies. We derive an analytical expression and explain its applicability high above the Wigner regime. In particular, we demonstrate its relationship to the classical capture (Langevin) cross section and apply it to three very different resonant processes: namely, resonant charge transfer, spin flip, and excitation exchange. This expression explains large variations for different isotopes that cannot otherwise be accounted for by the small change in mass. The s-wave signature also allows us to gain information about the Wigner regime from data obtained at much higher temperatures, which is especially advantageous for systems where the ultracold regime is not reachable. PMID- 30411921 TI - Recovering Quantum Gates from Few Average Gate Fidelities. AB - Characterizing quantum processes is a key task in the development of quantum technologies, especially at the noisy intermediate scale of today's devices. One method for characterizing processes is randomized benchmarking, which is robust against state preparation and measurement errors and can be used to benchmark Clifford gates. Compressed sensing techniques achieve full tomography of quantum channels essentially at optimal resource efficiency. In this Letter, we show that the favorable features of both approaches can be combined. For characterizing multiqubit unitary gates, we provide a rigorously guaranteed and practical reconstruction method that works with an essentially optimal number of average gate fidelities measured with respect to random Clifford unitaries. Moreover, for general unital quantum channels, we provide an explicit expansion into a unitary 2-design, allowing for a practical and guaranteed reconstruction also in that case. As a side result, we obtain a new statistical interpretation of the unitarity-a figure of merit characterizing the coherence of a process. PMID- 30411922 TI - Detection of a Disorder-Induced Bose-Einstein Condensate in a Quantum Spin Material at High Magnetic Fields. AB - The coupled spin-1 chains material NiCl_{2}-4SC(NH_{2})_{2} (DTN) doped with Br impurities is expected to be a perfect candidate for observing many-body localization at high magnetic field: the so-called "Bose glass," a zero temperature bosonic fluid, compressible, gapless, incoherent, and short-range correlated. Using nuclear magnetic resonance, we critically address the stability of the Bose glass in doped DTN, and find that it hosts a novel disorder-induced ordered state of matter, where many-body physics leads to an unexpected resurgence of quantum coherence emerging from localized impurity states. An experimental phase diagram of this new "order-from-disorder" phase, established from nuclear magnetic resonance T_{1}^{-1} relaxation rate data in the 13+/-1% Br doped DTN, is found to be in excellent agreement with the theoretical prediction from large-scale quantum Monte Carlo simulations. PMID- 30411923 TI - General Relativity from Scattering Amplitudes. AB - Weoutline the program to apply modern quantum field theory methods to calculate observables in classical general relativity through a truncation to classical terms of the multigraviton, two-body, on-shell scattering amplitudes between massive fields. Since only long-distance interactions corresponding to nonanalytic pieces need to be included, unitarity cuts provide substantial simplifications for both post-Newtonian and post-Minkowskian expansions. We illustrate this quantum field theoretic approach to classical general relativity by computing the interaction potentials to second order in the post-Newtonian expansion, as well as the scattering functions for two massive objects to second order in the post-Minkowskian expansion. We also derive an all-order exact result for gravitational light-by-light scattering. PMID- 30411924 TI - Nonlinear Kinetic Ion Response to Small Scale Magnetic Islands in Tokamak Plasmas: Neoclassical Tearing Mode Threshold Physics. AB - A new drift-kinetic theory of the ion response to magnetic islands in tokamak plasmas is presented. Small islands are considered, with widths w much smaller than the plasma radius r, but comparable to the trapped ion orbit width rho_{bi}. An expansion in w/r reduces the system dimensions from five down to four. In the absence of an electrostatic potential, the ions follow stream lines that map out a drift-island structure that is identical to the magnetic island, but shifted by an amount ~ few rho_{bi}. The ion distribution function is flattened across these drift islands, not the magnetic island. For small islands, w~rho_{bi}, the shifted drift islands result in a pressure gradient being maintained across the magnetic island, explaining previous simulation results [E. Poli et al., Phys. Rev. Lett. 88, 075001 (2002)PRLTAO0031-900710.1103/PhysRevLett.88.075001]. To maintain quasineutrality an electrostatic potential forms, which then supports a pressure gradient in the electrons also. This influence on the electron physics is shown to stabilize small magnetic islands of width a few ion banana widths, providing a new threshold mechanism for neoclassical tearing modes-a key result for the performance of future tokamaks, including ITER. PMID- 30411925 TI - Strong Purcell Effect on a Neutral Atom Trapped in an Open Fiber Cavity. AB - We observe a sixfold Purcell broadening of the D_{2} line of an optically trapped ^{87}Rb atom strongly coupled to a fiber cavity. Under external illumination by a near-resonant laser, up to 90% of the atom's fluorescence is emitted into the resonant cavity mode. The sub-Poissonian statistics of the cavity output and the Purcell enhancement of the atomic decay rate are confirmed by the observation of a strongly narrowed antibunching dip in the photon autocorrelation function. The photon leakage through the higher-transmission mirror of the single-sided resonator is the dominant contribution to the field decay (kappa~2pi*50 MHz), thus offering a high-bandwidth, fiber-coupled channel for photonic interfaces such as quantum memories and single-photon sources. PMID- 30411927 TI - Precision Test of AdS_{6}/CFT_{5} in Type IIB String Theory. AB - Superconformal field theories (SCFTs) in dimensions greater than 4 have become an integral part in the general understanding of quantum field theory, with many interesting implications in lower dimensions. They are hard to define using traditional methods, but can be engineered in string theory. Recently, a large class of AdS/CFT dualities has been constructed for five-dimensional SCFTs, which further supports their existence and allows for quantitative studies. We confront these dualities with a decisive test. We obtain the partition functions and central charges in gauge theory deformations of the SCFTs and extrapolate the results to the conformal fixed points. In the appropriate large N limits, this precisely matches the AdS/CFT predictions, providing strong support for the proposed dualities. PMID- 30411928 TI - Second-Harmonic Current-Phase Relation in Josephson Junctions with Ferromagnetic Barriers. AB - We report the observation of a current-phase relation dominated by the second Josephson harmonic in superconductor-ferromagnet-superconductor junctions. The exotic current-phase relation is realized in the vicinity of a temperature controlled 0-to-pi junction transition, at which the first Josephson harmonic vanishes. Direct current-phase relation measurements, as well as Josephson interferometry, nonvanishing supercurrent and half-integer Shapiro steps at the 0 pi transition self-consistently point to an intrinsic second harmonic term, making it possible to rule out common alternative origins of half-periodic behavior. While surprising for diffusive multimode junctions, the large second harmonic is in agreement with theory predictions for thin ferromagnetic interlayers. PMID- 30411929 TI - Symmetry Protection of Photonic Entanglement in the Interaction with a Single Nanoaperture. AB - In this work, we experimentally show that quantum entanglement can be symmetry protected in the interaction with a single subwavelength plasmonic nanoaperture, with a total volume of V~0.2lambda^{3}. In particular, we experimentally demonstrate that two-photon entanglement can be either completely preserved or completely lost after the interaction with the nanoaperture, solely depending on the relative phase between the quantum states. We achieve this effect by using specially engineered two-photon states to match the properties of the nanoaperture. In this way we can access a symmetry protected state, i.e., a state constrained by the geometry of the interaction to retain its entanglement. In spite of the small volume of interaction, we show that the symmetry protected entangled state retains its main properties. This connection between nanophotonics and quantum optics probes the fundamental limits of the phenomenon of quantum interference. PMID- 30411930 TI - Fermi Surface Nesting and Phonon Frequency Gap Drive Anomalous Thermal Transport. AB - The lattice thermal conductivity, k_{L}, of typical metallic and nonmetallic crystals decreases rapidly with increasing temperature because phonons interact more strongly with other phonons than they do with electrons. Using first principles calculations, we show that k_{L} can become nearly independent of temperature in metals that have nested Fermi surfaces and large frequency gaps between acoustic and optic phonons. Then, the interactions between phonons and electrons become much stronger than the mutual interactions between phonons, giving the fundamentally different k_{L} behavior. This striking trend is revealed here in the group V transition metal carbides, vanadium carbide, niobium carbide, and tantalum carbide, and it should also occur in several other metal compounds. This work gives insights into the physics of heat conduction in solids and identifies a new heat flow regime driven by the interplay between Fermi surfaces and phonon dispersions. PMID- 30411931 TI - Separating Dipole and Quadrupole Contributions to Single-Photon Double Ionization. AB - We report on a kinematically complete measurement of double ionization of helium by a single 1100 eV circularly polarized photon. By exploiting dipole selection rules in the two-electron continuum state, we observed the angular emission pattern of electrons originating from a pure quadrupole transition. Our fully differential experimental data and companion ab initio nonperturbative theory show the separation of dipole and quadrupole contributions to photo-double ionization and provide new insight into the nature of the quasifree mechanism. PMID- 30411932 TI - Demonstration of Einstein-Podolsky-Rosen Steering Using Hybrid Continuous- and Discrete-Variable Entanglement of Light. AB - Einstein-Podolsky-Rosen steering is known to be a key resource for one-sided device-independent quantum information protocols. Here we demonstrate steering using hybrid entanglement between continuous- and discrete-variable optical qubits. To this end, we report on suitable steering inequalities and detail the implementation and requirements for this demonstration. Steering is experimentally certified by observing a violation by more than 5 standard deviations. Our results illustrate the potential of optical hybrid entanglement for applications in heterogeneous quantum networks that would interconnect disparate physical platforms and encodings. PMID- 30411934 TI - Observation of Subradiant Atomic Momentum States with Bose-Einstein Condensates in a Recoil Resolving Optical Ring Resonator. AB - We experimentally investigate the formation of subradiant atomic momentum states in Bose-Einstein condensates inside a recoil resolving optical ring resonator according to the theoretical proposal of Cola, Bigerni, and Piovella. The atoms are pumped from the side with laser light that contains two frequency components. They resonantly drive cavity assisted Raman transitions between three discreet atomic momentum states. Within a few hundred microseconds, the system evolves into a stationary subradiant state. In this state, the condensate develops two density gratings suitable to diffract the two frequency components of the pump field into the resonator. Both components destructively interfere such that scattering is efficiently suppressed. A series of subradiant states for various amplitude ratios of the two pump components between 0 and 2.1 have been observed. The results are well explained with a three state quantum model in mean field approximation. PMID- 30411933 TI - Focusing of High-Brightness Electron Beams with Active-Plasma Lenses. AB - Plasma-based technology promises a tremendous reduction in size of accelerators used for research, medical, and industrial applications, making it possible to develop tabletop machines accessible for a broader scientific community. By overcoming current limits of conventional accelerators and pushing particles to larger and larger energies, the availability of strong and tunable focusing optics is mandatory also because plasma-accelerated beams usually have large angular divergences. In this regard, active-plasma lenses represent a compact and affordable tool to generate radially symmetric magnetic fields several orders of magnitude larger than conventional quadrupoles and solenoids. However, it has been recently proved that the focusing can be highly nonlinear and induce a dramatic emittance growth. Here, we present experimental results showing how these nonlinearities can be minimized and lensing improved. These achievements represent a major breakthrough toward the miniaturization of next-generation focusing devices. PMID- 30411920 TI - Search for CP Violation in Neutrino and Antineutrino Oscillations by the T2K Experiment with 2.2*10^{21} Protons on Target. AB - The T2K experiment measures muon neutrino disappearance and electron neutrino appearance in accelerator-produced neutrino and antineutrino beams. With an exposure of 14.7(7.6)*10^{20} protons on target in the neutrino (antineutrino) mode, 89 nu_{e} candidates and seven anti-nu_{e} candidates are observed, while 67.5 and 9.0 are expected for delta_{CP}=0 and normal mass ordering. The obtained 2sigma confidence interval for the CP-violating phase, delta_{CP}, does not include the CP-conserving cases (delta_{CP}=0, pi). The best-fit values of other parameters are sin^{2}theta_{23}=0.526_{-0.036}^{+0.032} and Deltam_{32}^{2}=2.463_{-0.070}^{+0.071}*10^{-3} eV^{2}/c^{4}. PMID- 30411935 TI - Particle Collisions and Negative Nonlocal Response of Ballistic Electrons. AB - An electric field that builds in the direction against current, known as negative nonlocal resistance, arises naturally in viscous flows and is thus often taken as a telltale of this regime. Here, we predict negative resistance for the ballistic regime, wherein the ee collision mean free path is greater than the length scale at which the system is being probed. Therefore, negative resistance alone does not provide strong evidence for the occurrence of the hydrodynamic regime; it must thus be demoted from the rank of irrefutable evidence to that of a mere forerunner. Furthermore, we find that negative response is log enhanced in the ballistic regime by the physics related to the seminal Dorfman-Cohen log divergence due to memory effects in the kinetics of dilute gases. The ballistic regime therefore offers a unique setting for exploring these interesting effects due to electron interactions. PMID- 30411936 TI - Jerk Current: A Novel Bulk Photovoltaic Effect. AB - We investigate a physical divergence of the third order polarization susceptibility representing a photoinduced current in biased crystalline insulators. This current grows quadratically with illumination time in the absence of momentum relaxation and saturation; we refer to it as the jerk current. Two contributions to the current are identified. The first is a hydrodynamic acceleration of optically injected carriers by the static electric field, and the second is the change in the carrier injection rate in the presence of the static electric field. The jerk current can have a component perpendicular to the static field, a feature not captured by standard hydrodynamic descriptions of carriers in electric fields. We suggest an experiment to detect the jerk current and some of its interesting features. PMID- 30411937 TI - Dynamo Effect and Turbulence in Hydrodynamic Weyl Metals. AB - The dynamo effect is a class of macroscopic phenomena responsible for generating and maintaining magnetic fields in astrophysical bodies. It hinges on the hydrodynamic three-dimensional motion of conducting gases and plasmas that achieve high hydrodynamic and/or magnetic Reynolds numbers due to the large length scales involved. The existing laboratory experiments modeling dynamos are challenging and involve large apparatuses containing conducting fluids subject to fast helical flows. Here we propose that electronic solid-state materials-in particular, hydrodynamic metals-may serve as an alternative platform to observe some aspects of the dynamo effect. Motivated by recent experimental developments, this Letter focuses on hydrodynamic Weyl semimetals, where the dominant scattering mechanism is due to interactions. We derive Navier-Stokes equations along with equations of magnetohydrodynamics that describe the transport of a Weyl electron-hole plasma appropriate in this regime. We estimate the hydrodynamic and magnetic Reynolds numbers for this system. The latter is a key figure of merit of the dynamo mechanism. We show that it can be relatively large to enable observation of the dynamo-induced magnetic field bootstrap in an experiment. Finally, we generalize the simplest dynamo instability model-the Ponomarenko dynamo-to the case of a hydrodynamic Weyl semimetal and show that the chiral anomaly term reduces the threshold magnetic Reynolds number for the dynamo instability. PMID- 30411938 TI - Engineering Carrier Effective Masses in Ultrathin Quantum Wells of IrO_{2}. AB - The carrier effective mass plays a crucial role in modern electronic, optical, and catalytic devices and is fundamentally related to key properties of solids such as the mobility and density of states. Here we demonstrate a method to deterministically engineer the effective mass using spatial confinement in metallic quantum wells of the transition metal oxide IrO_{2}. Using a combination of in situ angle-resolved photoemission spectroscopy measurements in conjunction with precise synthesis by oxide molecular-beam epitaxy, we show that the low energy electronic subbands in ultrathin films of rutile IrO_{2} have their effective masses enhanced by up to a factor of 6 with respect to the bulk. The origin of this strikingly large mass enhancement is the confinement-induced quantization of the highly nonparabolic, three-dimensional electronic structure of IrO_{2} in the ultrathin limit. This mechanism lies in contrast to that observed in other transition metal oxides, in which mass enhancement tends to result from complex electron-electron interactions and is difficult to control. Our results demonstrate a general route towards the deterministic enhancement and engineering of carrier effective masses in spatially confined systems, based on an understanding of the three-dimensional bulk electronic structure. PMID- 30411939 TI - Attosecond Control of Restoration of Electronic Structure Symmetry. AB - Laser pulses can break the electronic structure symmetry of atoms and molecules by preparing a superposition of states with different irreducible representations. Here, we discover the reverse process, symmetry restoration, by means of two circularly polarized laser pulses. The laser pulse for symmetry restoration is designed as a copy of the pulse for symmetry breaking. Symmetry restoration is achieved if the time delay is chosen such that the superposed states have the same phases at the temporal center. This condition must be satisfied with a precision of a few attoseconds. Numerical simulations are presented for the C_{6}H_{6} molecule and ^{87}Rb atom. The experimental feasibility of symmetry restoration is demonstrated by means of high-contrast time-dependent Ramsey interferometry of the ^{87}Rb atom. PMID- 30411941 TI - Enhancement of Microorganism Swimming Speed in Active Matter. AB - We study a swimming undulating sheet in the isotropic phase of an active nematic liquid crystal. Activity changes the effective shear viscosity, reducing it to zero at a critical value of activity. Expanding in the sheet amplitude, we find that the correction to the swimming speed due to activity is inversely proportional to the effective shear viscosity. Our perturbative calculation becomes invalid near the critical value of activity; using numerical methods to probe this regime, we find that activity enhances the swimming speed by an order of magnitude compared to the passive case. PMID- 30411940 TI - Heavy Physics Contributions to Neutrinoless Double Beta Decay from QCD. AB - Observation of neutrinoless double beta decay, a lepton number violating process that has been proposed to clarify the nature of neutrino masses, has spawned an enormous world-wide experimental effort. Relating nuclear decay rates to high energy, beyond the standard model (BSM) physics requires detailed knowledge of nonperturbative QCD effects. Using lattice QCD, we compute the necessary matrix elements of short-range operators, which arise due to heavy BSM mediators, that contribute to this decay via the leading order pi^{-}->pi^{+} exchange diagrams. Utilizing our result and taking advantage of effective field theory methods will allow for model-independent calculations of the relevant two-nucleon decay, which may then be used as input for nuclear many-body calculations of the relevant experimental decays. Contributions from short-range operators may prove to be equally important to, or even more important than, those from long-range Majorana neutrino exchange. PMID- 30411942 TI - Finite-Temperature Equation of State of Polarized Fermions at Unitarity. AB - We study in a nonperturbative fashion the thermodynamics of a unitary Fermi gas over a wide range of temperatures and spin polarizations. To this end, we use the complex Langevin method, a first principles approach for strongly coupled systems. Specifically, we show results for the density equation of state, the magnetization, and the magnetic susceptibility. At zero polarization, our results agree well with state-of-the-art results for the density equation of state and with experimental data. At finite polarization and low fugacity, our results are in excellent agreement with the third-order virial expansion. In the fully quantum mechanical regime close to the balanced limit, the critical temperature for superfluidity appears to depend only weakly on the spin polarization. PMID- 30411943 TI - Topology and Geometry of Spin Origami. AB - Kagome antiferromagnets are known to be highly frustrated and degenerate when they possess simple, isotropic interactions. We consider the entire class of these magnets when their interactions are spatially anisotropic. We do so by identifying a certain class of systems whose degenerate ground states can be mapped onto the folding motions of a generalized "spin origami" two-dimensional mechanical sheet. Some such anisotropic spin systems, including Cs_{2}ZrCu_{3}F_{12}, map onto flat origami sheets, possessing extensive degeneracy similar to isotropic systems. Others, such as Cs_{2}CeCu_{3}F_{12}, can be mapped onto sheets with nonzero Gaussian curvature, leading to more mechanically stable corrugated surfaces. Remarkably, even such distortions do not always lift the entire degeneracy, instead permitting a large but subextensive space of zero-energy modes. We show that for Cs_{2}CeCu_{3}F_{12}, due to an additional point group symmetry associated with the structure, these modes are "Dirac" line nodes with a double degeneracy protected by a topological invariant. The existence of mechanical analogs thus serves to identify and explicate the robust degeneracy of the spin systems. PMID- 30411944 TI - Accessing the Intrinsic Spin Transport in a Topological Insulator by Controlling the Crossover of Bulk-to-Surface Conductance. AB - We report a method to control contributions of bulk and surface states in the topological insulator Bi_{2}Te_{2}Se that allows accessing the spin-polarized transport endowed by topological surface states. An intrinsic surface dominant transport is established when cooling the sample to low temperature or reducing the conduction channel length, both achieved in situ in the transport measurements with a four-probe scanning tunneling microscope without the need of further tailoring the sample. The topological surface states show characteristic transport behaviors with mobility about an order of magnitude higher than reported before, and a spin polarization approaching the theoretically predicted value. Our result demonstrates accessibility to the intrinsic high mobility spin transport of topological surface states, which paves a way to realizing topological spintronic devices. PMID- 30411945 TI - Brownian Dynamics of Particles "Dressed" by Chiral Director Configurations in Lyotropic Chromonic Liquid Crystals. AB - We study Brownian dynamics of colloidal spheres, with planar anchoring conditions, suspended in the nematic phase of the lyotropic chromonic liquid crystal disodium chromoglycate (DSCG). Unlike typical liquid crystals, the unusually small twist elastic modulus of DSCG permits two energetically distinct helical distortions (twisted tails) of the nematic director to "dress" the suspended spheres. Video microscopy is used to characterize the helical distortions versus particle size and to measure particle mean-square displacements. Diffusion coefficients parallel and perpendicular to the far-field director, and their anisotropy ratio, are different for the two twisted tail configurations. Moreover, the crossover from subdiffusive to diffusive behavior is anomalously slow for motion perpendicular to the director (>100 s). Simple arguments using Miesowicz viscosities and ideas about twist relaxation are suggested to understand the mean-square displacement observations. PMID- 30411946 TI - Implications of an Improved Neutron-Antineutron Oscillation Search for Baryogenesis: A Minimal Effective Theory Analysis. AB - Future neutron-antineutron (n-n[over -]) oscillation experiments, such as at the European Spallation Source and the Deep Underground Neutrino Experiment, aim to find first evidence of baryon number violation. We investigate implications of an improved n-n[over -] oscillation search for baryogenesis via interactions of n n[over -] mediators, parametrized by an effective field theory (EFT). We find that even in a minimal EFT setup there is overlap between the parameter space probed by n-n[over -] oscillation and the region that can realize the observed baryon asymmetry of the Universe. The mass scales of exotic new particles are in the tera-electron-volt-peta-electron-volt regime, inaccessible at the LHC or its envisioned upgrades. Given the innumerable high energy theories that can match, or resemble, the minimal EFT that we discuss, future n-n[over -] oscillation experiments could probe many viable theories of baryogenesis beyond the reach of other experiments. PMID- 30411947 TI - Revealing Tensor Monopoles through Quantum-Metric Measurements. AB - Monopoles are intriguing topological objects, which play a central role in gauge theories and topological states of matter. While conventional monopoles are found in odd-dimensional flat spaces, such as the Dirac monopole in three dimensions and the non-Abelian Yang monopole in five dimensions, more exotic objects were predicted to exist in even dimensions. This is the case of "tensor monopoles," which are associated with tensor (Kalb-Ramond) gauge fields, and which can be defined in four-dimensional flat spaces. In this work, we investigate the possibility of creating and measuring such a tensor monopole in condensed-matter physics by introducing a realistic three-band model defined over a four dimensional parameter space. Our probing method is based on the observation that the topological charge of this tensor monopole, which we relate to a generalized Berry curvature, can be directly extracted from the quantum metric. We propose a realistic three-level atomic system, where tensor monopoles could be generated and revealed through quantum-metric measurements. PMID- 30411948 TI - Geometry of Multiflavor Galileon-Like Theories. AB - We use Lie-algebraic arguments to classify Lorentz-invariant theories of massless interacting scalars that feature coordinate-dependent redundant symmetries of the Galileon type. We show that such theories are determined, up to a set of low energy effective couplings, by specifying an affine representation of the Lie algebra of physical, nonredundant internal symmetries and an invariant metric on its target space. This creates an infinite catalog of theories relevant for both cosmology and high-energy physics thanks to their special properties such as enhanced scaling of scattering amplitudes in the soft limit. PMID- 30411949 TI - Experimental Demonstration of an Ultrabroadband Nonlinear Cloak for Flexural Waves. AB - Broadband cloaking of flexural waves is a major challenge since the governing equation is not form invariant under coordinate transformations. We fabricate a flexural cloaking structure using only a single material composed of homogeneous and isotropic layers, and then present experimental evidence of the first near ideal broadband cloak in thin plates. The 3D-printed structure is shown to effectively disguise an object over a broad frequency range (2 kHz-11 kHz). The proposed cloak has potential applications in shielding sensors and sensitive components from vibrations in bridges, automobiles, and aircraft. PMID- 30411950 TI - Higher-Spin Gauge Theories and Bulk Locality. AB - We present a no-go result on consistent Noether interactions among higher-spin gauge fields on anti-de Sitter space-times. We show that there is a nonlocal obstruction at the classical level to consistent interacting field theory descriptions of massless higher-spin particles that are described in the free limit by the free Fronsdal action, under the assumption that such theories arise from the gauging of a global higher-spin symmetry. Our result suggests that the Fronsdal program for introducing interactions among higher-spin gauge fields cannot be completed without introducing new guiding principles, which could potentially lie beyond the framework of classical field theory. PMID- 30411952 TI - Quadrupolar Exchange-Only Spin Qubit. AB - We propose a quadrupolar exchange-only spin qubit that is highly robust against charge noise and nuclear spin dephasing, the dominant decoherence mechanisms in quantum dots. The qubit consists of four electrons trapped in three quantum dots, and operates in a decoherence-free subspace to mitigate dephasing due to nuclear spins. To reduce sensitivity to charge noise, the qubit can be completely operated at an extended charge noise sweet spot that is first-order insensitive to electrical fluctuations. Because of on-site exchange mediated by the Coulomb interaction, the qubit energy splitting is electrically controllable and can amount to several GHz even in the "off" configuration, making it compatible with conventional microwave cavities. PMID- 30411951 TI - Entanglement Content of Quasiparticle Excitations. AB - We investigate the quantum entanglement content of quasiparticle excitations in extended many-body systems. We show that such excitations give an additive contribution to the bipartite von Neumann and Renyi entanglement entropies that takes a simple, universal form. It is largely independent of the momenta and masses of the excitations and of the geometry, dimension, and connectedness of the entanglement region. The result has a natural quantum information theoretic interpretation as the entanglement of a state where each quasiparticle is associated with two qubits representing their presence within and without the entanglement region, taking into account quantum (in)distinguishability. This applies to any excited state composed of finite numbers of quasiparticles with finite de Broglie wavelengths or finite intrinsic correlation length. This includes particle excitations in massive quantum field theory and gapped lattice systems, and certain highly excited states in conformal field theory and gapless models. We derive this result analytically in one-dimensional massive bosonic and fermionic free field theories and for simple setups in higher dimensions. We provide numerical evidence for the harmonic chain and the two-dimensional harmonic lattice in all regimes where the conditions above apply. Finally, we provide supporting calculations for integrable spin chain models and other interacting cases without particle production. Our results point to new possibilities for creating entangled states using many-body quantum systems. PMID- 30411953 TI - Phase Locking between Different Partial Waves in Atom-Ion Spin-Exchange Collisions. AB - We present a joint experimental and theoretical study of spin dynamics of a single ^{88}Sr^{+} ion colliding with an ultracold cloud of Rb atoms in various hyperfine states. While spin exchange between the two species occurs after 9.1(6) Langevin collisions on average, spin relaxation of the Sr^{+} ion Zeeman qubit occurs after 48(7) Langevin collisions, which is significantly slower than in previously studied systems due to a small second-order spin-orbit coupling. Furthermore, a reduction of the endothermic spin-exchange rate is observed as the magnetic field is increased. Interestingly, we find that while the phases acquired when colliding on the spin singlet and triplet potentials vary largely between different partial waves, the singlet-triplet phase difference, which determines the spin-exchange cross section, remains locked to a single value over a wide range of partial waves, which leads to quantum interference effects. PMID- 30411926 TI - Measurement of the Branching Fraction For the Semileptonic Decay D^{0(+)}->pi^{ (0)}MU^{+}nu_{MU} and Test of Lepton Flavor Universality. AB - Using a data sample corresponding to an integrated luminosity of 2.93 fb^{-1} taken at a center-of-mass energy of 3.773 GeV with the BESIII detector operated at the BEPCII collider, we perform an analysis of the semileptonic decays D^{0(+)}->pi^{-(0)}MU^{+}nu_{MU}. The branching fractions of D^{0}->pi^{ }MU^{+}nu_{MU} and D^{+}->pi^{0}MU^{+}nu_{MU} are measured to be (0.272+/ 0.008_{stat}+/-0.006_{syst})% and (0.350+/-0.011_{stat}+/-0.010_{syst})%, respectively, where the former is of much improved precision compared to previous results and the latter is determined for the first time. Using these results along with previous BESIII measurements of D^{0(+)}->pi^{-(0)}e^{+}nu_{e}, we calculate the branching fraction ratios to be R^{0}=B_{D^{0}->pi^{ }MU^{+}nu_{MU}}/B_{D^{0}->pi^{-}e^{+}nu_{e}}=0.922+/-0.030_{stat}+/-0.022_{syst} and R^{+}=B_{D^{+}->pi^{0}MU^{+}nu_{MU}}/B_{D^{+}->pi^{0}e^{+}nu_{e}}=0.964+/ 0.037_{stat}+/-0.026_{syst}, which are compatible with the theoretical expectation of lepton flavor universality within 1.7sigma and 0.5sigma, respectively. We also examine the branching fraction ratios in different four momentum transfer square regions, and find no significant deviations from the standard model predictions. PMID- 30411954 TI - Temperature-Controlled Slip of Polymer Melts on Ideal Substrates. AB - The temperature dependence of the hydrodynamic boundary condition between a polydimethylsiloxane melt and two different nonattractive surfaces made of either an octadecyltrichlorosilane self-assembled monolayer or a grafted layer of short polydimethylsiloxane chains has been characterized. We observe a slip length proportional to the fluid viscosity. The temperature dependence is deeply influenced by the surfaces. The viscous stress exerted by the polymer liquid on the surface is observed to follow exactly the same temperature dependences as the friction stress of a cross-linked elastomer sliding on the same surfaces. Far above the glass transition temperature, these observations are rationalized in the framework of a molecular model based on activation energies: increase or decrease of the slip length with increasing temperatures can be observed depending on how the activation energy of the bulk viscosity compares to that of the interfacial Navier's friction coefficient. PMID- 30411955 TI - Unconventional Pairing Induced Anomalous Transverse Shift in Andreev Reflection. AB - Superconductors with unconventional pairings have been a fascinating subject of research, for which a central issue is to explore effects that can be used to characterize the pairing. The process of Andreev reflection-the reflection of an electron as a hole at a normal-metal-superconductor interface-offers a basic mechanism to probe the pairing. Here we predict that in Andreev reflection from unconventional superconductors, the reflected hole acquires an anomalous spatial shift normal to the plane of incidence, arising from the unconventional pairing. The transverse shift is sensitive to the superconducting gap structure, exhibiting characteristic features for each pairing type, and can be detected as voltage signals. Our work not only unveils a fundamentally new effect with a novel underlying mechanism, but also suggests a possible new technique capable of probing the structure of unconventional pairings. PMID- 30411956 TI - Three-Dimensional Nuclear Spin Positioning Using Coherent Radio-Frequency Control. AB - Distance measurements via the dipolar interaction are fundamental to the application of nuclear magnetic resonance (NMR) to molecular structure determination, but they provide information on only the absolute distance r and polar angle theta between spins. In this Letter, we present a protocol to also retrieve the azimuth angle phi. Our method relies on measuring the nuclear precession phase after the application of a control pulse with a calibrated external radio-frequency coil. We experimentally demonstrate three-dimensional positioning of individual ^{13}C nuclear spins in a diamond host crystal relative to the central electronic spin of a single nitrogen-vacancy center. The ability to pinpoint three-dimensional nuclear locations is central for realizing a nanoscale NMR technique that can image the structure of single molecules with atomic resolution. PMID- 30411957 TI - Phonon Angular Momentum Induced by the Temperature Gradient. AB - Phonon modes in crystals can have angular momenta in general. It nevertheless cancels in equilibrium when the time-reversal symmetry is preserved. In this Letter, we show that when a temperature gradient is applied and heat current flows in the crystal, the phonon distribution becomes off equilibrium, and a finite angular momentum is generated by the heat current. This mechanism is analogous to the Edelstein effect in electronic systems. This effect requires crystals with sufficiently low crystallographic symmetries, such as polar or chiral crystal structures. Because of the positive charges of the nuclei, this phonon angular momentum induces magnetization. In addition, when the crystal can freely rotate, this generated phonon angular momentum is converted to a rigid body rotation of the crystal, due to the conservation of the total angular momentum. Furthermore, in metallic crystals, the phonon angular momentum will be partially converted into spin angular momentum of electrons. PMID- 30411958 TI - Cytoskeletal Anisotropy Controls Geometry and Forces of Adherent Cells. AB - We investigate the geometrical and mechanical properties of adherent cells characterized by a highly anisotropic actin cytoskeleton. Using a combination of theoretical work and experiments on micropillar arrays, we demonstrate that the shape of the cell edge is accurately described by elliptical arcs, whose eccentricity expresses the degree of anisotropy of the internal cell stresses. This results in a spatially varying tension along the cell edge, that significantly affects the traction forces exerted by the cell on the substrate. Our work highlights the strong interplay between cell mechanics and geometry and paves the way towards the reconstruction of cellular forces from geometrical data. PMID- 30411959 TI - Drastic Reduction of Plasmon Damping in Two-Dimensional Electron Disks. AB - In this Letter, plasmon damping has been investigated using resonant microwave absorption of two-dimensional electrons in disks with different diameters. We have found an unexpected drastic reduction of the plasmon damping in the regime of strong retardation. This finding implies large delocalization of the retarded plasmon field outside the plane of the two-dimensional electron system. A universal relationship between the damping of plasmon polariton waves and the retardation parameter is reported. PMID- 30411960 TI - Dilute Fluid Governed by Quantum Fluctuations. AB - Understanding the effects of interactions in complex quantum systems beyond the mean-field paradigm constitutes a fundamental problem in physics. We show how the atom numbers and interactions in a Bose-Bose mixture can be tuned to cancel mean field interactions completely. The resulting system is entirely governed by quantum fluctuations-specifically the Lee-Huang-Yang correlations. We derive an effective one-component Gross-Pitaevskii equation for this system, which is shown to be very accurate by comparison with a full two-component description. This allows us to show how the Lee-Huang-Yang correlation energy can be accurately measured using two powerful probes of atomic gases: collective excitations and radio-frequency spectroscopy. Importantly, the behavior of the system is robust against deviations from the atom number and interaction criteria for canceling the mean-field interactions. This shows that it is feasible to realize a setting where quantum fluctuations are not masked by mean-field forces, allowing investigations of the Lee-Huang-Yang correction at unprecedented precision. PMID- 30411961 TI - Mapping Topological to Conformal Field Theories through strange Correlators. AB - We extend the concept of strange correlators, defined for symmetry-protected phases in You et al. [Phys. Rev. Lett. 112, 247202 (2014)PRLTAO0031 900710.1103/PhysRevLett.112.247202], to topological phases of matter by taking the inner product between string-net ground states and product states. The resulting two-dimensional partition functions are shown to be either critical or symmetry broken, since the corresponding transfer matrices inherit all matrix product operator symmetries of the string-net states. For the case of critical systems, these nonlocal matrix product operator symmetries are the lattice remnants of topological conformal defects in the field theory description. Following Aasen et al. [J. Phys. A 49, 354001 (2016)JPAMB51751-811310.1088/1751 8113/49/35/354001], we argue that the different conformal boundary conditions can be obtained by applying the strange correlator concept to the different topological sectors of the string net obtained from Ocneanu's tube algebra. This is demonstrated on the lattice by calculating the conformal field theory spectra in the different topological sectors for the Fibonacci (hard-hexagon) and Ising string net. Additionally, we provide a complementary perspective on symmetry preserving real-space renormalization by showing how known tensor network renormalization methods can be understood as the approximate truncation of an exactly coarse-grained strange correlator. PMID- 30411962 TI - Real-Time Reconstruction of the Strong-Field-Driven Dipole Response. AB - The reconstruction of the full temporal dipole response of a strongly driven time dependent system from a single absorption spectrum is demonstrated, only requiring that a sufficiently short pulse is employed to initialize the coherent excitation of the system. We apply this finding to the time-domain observation of Rabi cycling between doubly excited atomic states in the few-femtosecond regime. This allows us to pinpoint the breakdown of few-level quantum dynamics at the critical laser intensity near 2 TW/cm^{2} in doubly excited helium. The present approach unlocks single-shot real-time-resolved signal reconstruction across timescales down to attoseconds for nonequilibrium states of matter. In contrast to conventional pump-probe schemes, there is no need for scanning time delays in order to access real-time information. The potential future applications of this technique range from testing fundamental quantum dynamics in strong fields to measuring and controlling ultrafast chemical and biological reaction processes when applied to traditional transient-absorption spectroscopy. PMID- 30411963 TI - Quantum Ferrofluid Turbulence. AB - We study the elementary characteristics of turbulence in a quantum ferrofluid through the context of a dipolar Bose gas condensing from a highly nonequilibrium thermal state. Our simulations reveal that the dipolar interactions drive the emergence of polarized turbulence and density corrugations. The superfluid vortex lines and density fluctuations adopt a columnar or stratified configuration, depending on the sign of the dipolar interactions, with the vortices tending to form in the low-density regions to minimize kinetic energy. When the interactions are dominantly dipolar, the decay of the vortex line length is enhanced, closely following a t^{-3/2} behavior. This system poses exciting prospects for realizing stratified quantum turbulence and new levels of generating and controlling turbulence using magnetic fields. PMID- 30411964 TI - Selection Rules for Quasiparticle Interference with Internal Nonsymmorphic Symmetries. AB - We study how nonsymmorphic symmetries that commute with lattice translations are reflected in the quasiparticle interference (QPI) maps measured by scanning tunneling microscopy (STM). QPI maps, which result from scattering of Bloch states off impurities, record the interference of incoming and scattered waves as a function of energy and tip's position. Although both the impurity and the tip generically break spatial symmetries, we find that the QPI maps provide universal information on these symmetries. The symmetries impose constraints on the relation between various momentum components of the Bloch functions. These relations result in selection rules on certain momentum transfers in QPI maps. We find that universal information is encoded in the absence of QPI signal, or in the relative intensity of its replications. We show examples for one-dimensional chains and an effective model of the layered compound ZrSiS. We discuss the implications of our theory in the analysis of observed QPI of the Weyl semimetal TaAs. Our theory is particularly relevant for materials in rod and layer space groups, or when a correlated order parameter, such as antiferromagnetism, enlarges the unit cell. PMID- 30411965 TI - Laser Power Stabilization beyond the Shot Noise Limit Using Squeezed Light. AB - High levels of laser power stability are necessary for high precision metrology applications. The classical limit for the achievable power stability is determined by the shot noise of the light used to generate a power control signal. Increasing the power of the detected light reduces the relative shot noise level and allows higher stabilities. However, sufficiently high power is not always available and the detection of high laser powers is challenging. Here, we demonstrate a nonclassical way to improve the achievable power stability without increasing the detected power. By the injection of a squeezed vacuum field of light we improve the classical laser power stability beyond its shot noise limit by 9.4_{-0.6}^{+0.6} dB at Fourier frequencies between 5 and 80 kHz. For only 90.6 MUA of detected photocurrent we achieve a relative laser power noise of 2.0_{-0.1}^{+0.1}*10^{-8}/sqrt[Hz]. This is the first demonstration of a squeezed light-enhanced laser power stabilization and its performance is equivalent to an almost tenfold increase of detected laser power in a classical scheme. The analysis reveals that the technique presented here has the potential to achieve stability levels of 4.2*10^{-10}/sqrt[Hz] with 58 mA photocurrent measured on a single photodetector. PMID- 30411968 TI - Locality Bound for Dissipative Quantum Transport. AB - We prove an upper bound on the diffusivity of a dissipative, local, and translation invariant quantum Markovian spin system: D<=D_{0}+(alphav_{LR}tau+betaxi)v_{C}. Here v_{LR} is the Lieb-Robinson velocity, v_{C} is a velocity defined by the current operator, tau is the decoherence time, xi is the range of interactions, D_{0} is a decoherence-induced microscopic diffusivity, and alpha and beta are precisely defined dimensionless coefficients. The bound constrains quantum transport by quantities that can either be obtained from the microscopic interactions (D_{0}, v_{LR}, v_{C}, xi) or else determined from independent local nontransport measurements (tau, alpha, beta). We illustrate the general result with the case of a spin-half XXZ chain with on-site dephasing. Our result generalizes the Lieb-Robinson bound to constrain the sub ballistic diffusion of conserved densities in a dissipative setting. PMID- 30411967 TI - Orbital Domain Dynamics in Magnetite below the Verwey Transition. AB - The metal-insulator phase transition in magnetite, known as the Verwey transition, is characterized by a charge-orbital ordering and a lattice transformation from a cubic to monoclinic structure. We use x-ray photon correlation spectroscopy to investigate the dynamics of this charge-orbitally ordered insulating phase undergoing the insulator-to-metal transition. By tuning to the Fe L_{3} edge at the (001/2) superlattice peak, we probe the evolution of the Fe t_{2g} orbitally ordered domains present in the low temperature insulating phase and forbidden in the high temperature metallic phase. We observe two distinct regimes below the Verwey transition. In the first regime, magnetite follows an Arrhenius behavior and the characteristic timescale for orbital fluctuations decreases as the temperature increases. In the second regime, magnetite phase separates into metallic and insulating domains, and the kinetics of the phase transition is dictated by metallic-insulating interfacial boundary conditions. PMID- 30411966 TI - Direct Capture Cross Section and the E_{p}=71 and 105 keV Resonances in the ^{22}Ne(p,gamma)^{23}Na Reaction. AB - The ^{22}Ne(p,gamma)^{23}Na reaction, part of the neon-sodium cycle of hydrogen burning, may explain the observed anticorrelation between sodium and oxygen abundances in globular cluster stars. Its rate is controlled by a number of low energy resonances and a slowly varying nonresonant component. Three new resonances at E_{p}=156.2, 189.5, and 259.7 keV have recently been observed and confirmed. However, significant uncertainty on the reaction rate remains due to the nonresonant process and to two suggested resonances at E_{p}=71 and 105 keV. Here, new ^{22}Ne(p,gamma)^{23}Na data with high statistics and low background are reported. Stringent upper limits of 6*10^{-11} and 7*10^{-11} eV (90% confidence level), respectively, are placed on the two suggested resonances. In addition, the off-resonant S factor has been measured at unprecedented low energy, constraining the contributions from a subthreshold resonance and the direct capture process. As a result, at a temperature of 0.1 GK the error bar of the ^{22}Ne(p,gamma)^{23}Na rate is now reduced by 3 orders of magnitude. PMID- 30411969 TI - Cross-subtype Detection of HIV-1 capsid p24 antigen using a Sensitive Europium Nanoparticle Assay. AB - BACKGROUND: Accurate and early detection of diverse HIV-1 subtypes using currently available assays has been a major challenge. We report development of a sensitive Time Resolved Fluorescence (TRF) Europium Nanoparticle Immuno Assay (ENIA) for cross subtype detection of p24 antigen using broadly cross reactive antibodies. METHODS: Several antibodies were tested for optimal reactivity with antigens of diverse HIV-1 subtypes and CRFs. We tested HIV strains using this assay for sensitivity and quantification ability at the pico-gram (pg)/ml level. RESULTS: We identified two broadly cross reactive antibodies C65690M and ANT-152, which detected all strains of HIV tested. These two antibodies also yield a better signal to cut off ratios for the same amount of antigen tested in comparison to a commercial assay. CONCLUSION: Using a combination of appropriate C65690M and ANT-152 p24 antibodies capable of detecting all HIV types and highly sensitive time resolved fluorescence (TRF) based Europium Nano particle assay platform, we developed a sensitive p24 antigen assay that can detect HIV infection of all HIV subtypes and may be useful in early detection. PMID- 30411970 TI - Somatosensory Regions Show Limited Functional Connectivity Differences in Youth with Autism Spectrum Disorder. AB - An estimated 70-90% of children with autism spectrum disorder (ASD) have sensory symptoms, which may present as hyper- or hyporesponsivity in one or more sensory modalities. These sensitivities correlate with social symptoms, activity, and social interaction levels. Interestingly, sensory symptoms appear to be most prevalent in late childhood, suggesting a developmental component. Although the neural basis of sensory sensitivities remains unclear, atypical functional connectivity of sensory brain regions has been suggested as a potential mechanism. Tactile sensitivities are among the most predictive of social functioning, yet no studies to our knowledge have examined somatosensory functional connectivity in children and adolescents with ASD, when symptoms are typically most prominent. In this study, we used human data from the Autism Brain Imaging Data Exchange (ABIDE-I) to assess functional connectivity differences of somatosensory regions during resting state functional magnetic resonance imaging, in youth aged 8-15 years. After head motion exclusion, our sample included 67 participants with ASD and 121 typically developing controls. We additionally examined associations between functional connectivity and age, as well as ASD symptom severity. Together, these seed-based analyses showed limited differences in functional connectivity between groups, either to hypothesized target regions or in terms of global connectivity. Our findings suggest that hyper- or hyposomatosensory functional connectivity at rest is not a population-level feature in ASD. However, this does not preclude increased variability of somatosensory networks across the ASD population. Furthermore, as sensory sensitivities were not specifically assessed in this sample, future studies may be better able to identify patterns of functional connectivity, reflecting individual differences in sensory symptoms. PMID- 30411971 TI - Association of Exclusive Breastfeeding with Risk of Obesity in Childhood and Early Adulthood. AB - OBJECTIVE: To explore the effects of exclusive breastfeeding and its duration on the development of childhood and early adulthood obesity. MATERIALS AND METHODS: A random sample of 5,125 dyad children and their mothers was extracted from a national database. With the use of a standardized questionnaire, telephone interviews were carried out for the collection of maternal lifestyle factors (e.g., breastfeeding). The body mass index was determined based on International Obesity Task Force criteria. Body weight and height of the offspring at the age of 8 was calculated from measurements derived from the national database, while the corresponding body measurements at early adulthood were self-reported. RESULTS: Mothers who had breastfed or exclusively breastfed >=6 months were 22.4% and 15.2%, respectively. Exclusive breastfeeding >=6 months (versus never) was associated with a lower risk of overweight in childhood (8 years old; odds ratio [OR] = 0.89; 95% confidence interval [95% CI], 0.82-0.96) and adolescence/adulthood (15-25 years old; OR = 0.83; 95% CI, 0.68-0.97). Also, exclusive breastfeeding >=6 months (versus never) was associated with a decreased risk of childhood and adolescence obesity by 30% (95% CI, 0.54-0.91) and 38% (95% CI, 0.40-0.83), respectively. CONCLUSIONS: Exclusive breastfeeding had a favorable influence on offspring's overweight and obesity not only in childhood but also in adolescence/adulthood. PMID- 30411972 TI - Real-world evidence for coverage decisions: opportunities and challenges. AB - AIM: To explore current uses of real-world evidence (RWE) in the US healthcare system, summarize key concerns and highlight various opportunities that could be realized through best use of RWE. Materials & methods: Information was gathered via a literature review and interviews to generate a background paper for the 2017 Institute for Clinical and Economic Review Policy Summit meeting. RESULTS: RWE is currently being utilized in drug development decisions, regulatory approval decisions, post-approval monitoring, payer coverage decisions (initial decisions and reassessments) and for outcomes-based contracting. Solutions to key challenges and opportunities for future development are presented. CONCLUSION: Exciting opportunities for the use of RWE exist, yet important reservations remain. Solutions are within reach if effective partnerships between stakeholders can be nurtured. PMID- 30411973 TI - Discordance of HIV-1 viral load from paired blood and seminal plasma samples in a Chinese MSM population. AB - The alarming spread of HIV among men who have sex with men (MSM) has become a national concern in China. Estimating men's sexual HIV infectiousness from blood plasma viral load (BPVL) depends on the association between BPVL and semimal plasma viral load (SPVL). However, previous studies were controversial and few concentrated on MSM. Twenty antiretroviral therapy (ART) naive MSM and 54 MSM under ART were recruited between July and September 2015 in the city of Hangzhou, China. Blood and semen were collected in pairs at the same visit for each individual. BPVL and SPVL were measured by COBAS AmpliPrep/COBAS TaqMan HIV-1 Test ver2.0. The mean viral load in blood plasma was higher than that in semen (4.5+/- 0.9 log10 vs 3.4+/-1.3 log10) in 20 ART-untreated MSM, and a positive correlation was found between BPVL and SPVL, as evaluated by linear regression (R2=0.565, P<0.001). 96.3% (52/54) of ART-treated patients had successful viral suppression (<400 cps/ml) according to the BPVL. Fourteen subjects (25.9%, 14/54) presenting undetectable SPVL showed detectable BPVL, ranging from 20.4 to 7470 copies/ml. Three subjects (5.6%, 3/54) presented detectable SPVL although BPVL was undetectable. MSM could pose a transmission risk despite undetectable BPVL. Consistent use of condoms and other risk reduction strategies should be strongly advocated in MSM throughout all stages of HIV infection, regardless of ART. PMID- 30411974 TI - Effects of Fenugreek, Ginger, and Turmeric Supplementation on Human Milk Volume and Nutrient Content in Breastfeeding Mothers: A Randomized Double-Blind Controlled Trial. AB - BACKGROUND: Exclusive breastfeeding is the best way to accomplish optimal growth and health in infants. Low milk volume is a major problem that leads to nonexclusive breastfeeding. OBJECTIVE: This study aimed to examine the effects of mixed herbal supplementation, including fenugreek, ginger, and turmeric on human milk volume and nutrient content. METHODS: The study design was a randomized double-blind controlled trial. Fifty exclusively breastfeeding mothers were randomly divided into two groups. The herbal group (n = 25) received mixed herbal supplementation containing fenugreek, ginger, and turmeric, three capsules three times daily for 4 weeks. The control group (n = 25) took a placebo. Anthropometric and dietary data, blood pressure, heart rate, and blood and milk samples were collected at baseline and 4 weeks after the intervention. Milk volume was measured using a manual breast pump and recorded for 2 days at baseline, week 2, and week 4. RESULTS: Breastfeeding mothers receiving herbal supplementation had a 49% increase in milk volume at week 2 and a 103% increase at week 4. These increases were greater than mothers in the placebo group (p < 0.05). There was no difference in milk nutrient content for both groups. Moreover, there were no differences in adverse effects observed in the placebo and herbal groups. CONCLUSION: Mixed herbal supplementation that contained fenugreek, ginger, and turmeric can increase human milk volume without adverse effects. PMID- 30411976 TI - Development and validation of the Person-Centeredness of Research Scale. AB - AIM: Person-centeredness shifts the focus of healthcare and research to the needs and priorities of patients and communities, and may improve health outcomes. There are no instruments available, however, with which we can assess the degree to which research is indeed person-centered. Our aim was to develop and validate a quantitative instrument to rate person-centeredness of research. MATERIALS & METHODS: Scale development and validation entailed a multistep approach that led to the seven-item Person Centeredness of Research Scale (PCoR Scale) that uses a 5-point Likert rating scale. The scale was validated using ratings of the Patient Centered Outcomes Research Institute-funded research abstracts or abstracts submitted to a translational science meeting. RESULTS: Psychometric properties of the PCoR Scale showed high internal consistency (alpha = 0.96). All seven items were highly correlated with the total score (rs range from 0.63 to 0.90). An exploratory factor analysis demonstrated that all of the items loaded on a single factor, explaining 80% of the variance. The Patient-Centered Outcomes Research Institute-funded research abstracts had a mean PCoR Scale score of 6.52 (+/-8.01) that was significantly higher than the abstracts submitted to the translational science meeting (-2.56 (+/-9.18); t = 8.09; p < 0.0001). Inter-rater reliability in the validation of the revised instrument was high (Intraclass Correlation Coefficient [ICC](group1) = 0.89; ICC(group2) = 0.95). CONCLUSION: This brief, quantitative rating scale is the first to assess the main constructs that describe person-centeredness of research products. The PCoR Scale can be used to assess person-centeredness in research products; for example, by funders evaluating proposals, data networks evaluating data requests or researchers evaluating their research designs. PMID- 30411977 TI - Breast microcalcifications: biological and diagnostic perspectives. PMID- 30411975 TI - Predictors of Attrition in Longitudinal Neuroimaging Research: Inhibitory Control, Head Movement, and Resting-State Functional Connectivity. AB - Attrition is a major problem in longitudinal neuroimaging studies, as it may lead to unreliable estimates of the stability of trait-like processes over time, of the identification of risk factors for clinical outcomes, and of the effects of treatment. Identification of characteristics associated with attrition has implications for participant recruitment and participant retention to achieve representative longitudinal samples. We investigated inhibitory control deficits, head motion, and resting-state functional connectivity within the cognitive control network (CCN) as predictors of attrition. Ninety-seven individuals with remitted major depressive disorder or healthy controls completed a functional magnetic resonance imaging scan, which included a go/no-go task and resting-state functional connectivity. Approximately 2 months later, participants were contacted and invited to return for a second scan. Seventeen individuals were lost to follow-up or declined to participate in the follow-up scan. Worse inhibitory control was correlated with greater movement within the scanner, and each predicted a greater likelihood of attrition, with movement mediating the effects of inhibitory control on attrition. Individuals who dropped out of the study exhibited greater movement than nondropouts across 9 of the 14 runs of the scan, with medium-to-large effect sizes. Finally, exploratory analyses suggested that attenuated resting-state connectivity with the CCN (particularly in bilateral dorsolateral prefrontal cortex) was associated with greater likelihood of attrition after accounting for head motion at several levels of analysis. Inhibitory control and movement within the scanner are associated with attrition, and should be considered for strategic oversampling and participant retention strategies to ensure generalizability of results in longitudinal studies. PMID- 30411978 TI - Metabolic adaptations to endurance training and nutrition strategies influencing performance. AB - Endurance performance is the result of optimal training targeting cardiovascular, metabolic, and peripheral muscular adaptations and is coupled to effective nutrition strategies via the use of macronutrient manipulations surrounding training and potential supplementation with ergogenic aids. It is important to note that training and nutrition may differ according to the individual needs of the athlete and can markedly impact the physiological response to training. Herein, we discuss various aspects of endurance training adaptations, nutritional strategies and their contributions to towards performance. PMID- 30411980 TI - Inflammatory signature in lung tissues in patients with combined pulmonary fibrosis and emphysema. AB - BACKGROUND: The aetiology and inflammatory profile of combined pulmonary fibrosis and emphysema (CPFE) remain uncertain currently. OBJECTIVE: We aimed to examine the levels of inflammatory proteins in lung tissue in a cohort of patients with emphysema, interstitial pulmonary fibrosis (IPF), and CPFE. MATERIALS AND METHODS: Explanted lungs were obtained from subjects with emphysema, IPF, CPFE, (or normal subjects), and tissue extracts were prepared. Thirty-four inflammatory proteins were measured in each tissue section. RESULTS: The levels of all 34 proteins were virtually indistinguishable in IPF compared with CPFE tissues, and collectively, the inflammatory profile in the emphysematous tissues were distinct from IPF and CPFE. Moreover, inflammatory protein levels were independent of the severity of the level of diseased tissue. CONCLUSIONS: We find that emphysematous lung tissues have a distinct inflammatory profile compared with either IPF or CPFE. However, the inflammatory profile in CPFE lungs is essentially identical to lungs from patients with IPF. These data suggest that distinct inflammatory processes collectively contribute to the disease processes in patients with emphysema, when compared to IPF and CPFE. PMID- 30411981 TI - Effects of chronic marijuana use on driving performance. AB - OBJECTIVES: The effects of marijuana on driving pose a significant public health concern. More studies on chronic marijuana use in driving are needed. The study objectives were to (1) assess differences in the Standardized Field Sobriety Test (SFST) and driving performance outcomes between chronic medical marijuana users and nonusers and (2) identify a cutoff tetrahydrocannabinol (THC) concentration above which chronic medical marijuana users demonstrate driving impairment. METHODS: This prospective cross-sectional study assessed 31 chronic marijuana users and 41 nonusers. Rapid Detect Saliva Drug Screen 10-panel was administered to all participants. Participants were given a simple visual reaction time test (SVRT) and SFST consisting of the horizontal gaze nystagmus (HGN), the one leg stand (OLS), and the walk and turn (WAT) tests. The STISIM Drive M100 driving simulator assessed driving performance. Driving parameters included standard deviation of speed (SDS), deviation of mean lane position, off-road accidents, collisions, pedestrians hit, and car-following modulus, delay, and coherence. Cannabinoid blood plasma was obtained from marijuana users. RESULTS: Marijuana users and nonusers did not differ in age (40.06 +/- 13.92 vs. 41.53 +/- 15.49, P = .6782). Marijuana users were more likely to fail the SFST (P = .005) and the WAT (P = .012) and HGN (P = .001) components. Marijuana users had slower SVRT (P = .031), less SDS (P = .039), and lower modulus (P = .003). Participants with THC >2 ng/mL (P = .017) and TCH >5 ng/mL (P = .008) had lower SDS. Participants with THC >2 ng/mL (P = .021) and THC >5 ng/mL (P = .044) had decreased modulus. CONCLUSION: Chronic marijuana users had slower reaction times, deviated less in speed, and had difficulty matching a lead vehicle's speed compared to nonusers. The effects on SDS and modulus were present at cutoffs of 2 and 5 ng/mL. PMID- 30411979 TI - Eribulin in the treatment of advanced breast cancer: real-world scenario from 39 Italian centers - ESEMPiO study. AB - AIM: We performed a multicenter retrospective cohort study of eribulin mesylate (EM) use in Italy, to describe the current practice for metastatic breast cancer patients (ESEMPiO) in the real-world. PATIENTS & METHODS: Baseline characteristics, treatment administration and safety were summarized using descriptive statistics. RESULTS: No safety concerns were raised in the population enrolled in the ESEMPiO database and treated in a real-life practice. Median progression-free survival and overall survival were 3.2 and 10.1 months, respectively. EM activity was similar between breast cancer subtypes. CONCLUSION: In metastatic breast cancer patients treated with EM in 'real-world' setting, the clinician-registered outcomes were comparable to those reported in pivotal trials. Furthermore, EM maintained clinical activity and a tolerable safety profile. PMID- 30411982 TI - Which Game Narratives Do Adolescents of Different Gameplay and Sociodemographic Backgrounds Prefer? A Mixed-Methods Analysis. AB - OBJECTIVE: The aim of this study was to investigate which narrative elements of digital game narratives are preferred by the general adolescent population, and to examine associations with gender, socioeconomic status (SES), and gameplay frequency. Further, the study aims to discuss how results can be translated to serious digital games. MATERIALS AND METHODS: Adolescents were recruited through school to complete a survey on narrative preferences in digital games. The survey included questions on sociodemographic information, frequency of gameplay, and an open-ended question on what could be an appealing narrative for them. Data were analyzed in a mixed-methods approach, using thematic analysis and chi-square analyses to determine narrative preferences and the associations between game narrative elements and player characteristics (gender, SES, and frequency of gameplay). RESULTS: The sample consisted of 446 adolescents (12-15 years old) who described 30 narrative subthemes. Preferences included human characters as protagonists; nonhuman characters only as antagonists; realistic settings, such as public places or cities; and a strong conflict surrounding crime, catastrophe, or war. Girls more often than boys defined characters by their age, included avatars, located the narrative in private places, developed profession-related skills, and included a positive atmosphere. Adolescents of nonacademic education more often than adolescents of academic education defined characters by criminal actions. Infrequent players more often included human characters defined by their age than frequent players. After performing a Bonferroni correction, narrative preferences for several gender differences remained. CONCLUSION: Different narrative elements related to subgroups of adolescents by gender, SES, and frequency of gameplay. Customization of narratives in serious digital health games should be warranted for boys and girls; yet, further research is needed to specify how to address girls in particular. PMID- 30411983 TI - Noninvasive assessment of carotid arterial wave speed and distensibility. PMID- 30411984 TI - Reply to Mynard et al. PMID- 30411985 TI - Targeted literature review of the humanistic and economic burden of adult growth hormone deficiency. AB - BACKGROUND: Quality of life (QoL) and health economic data are becoming increasingly important factors in healthcare decision-making. While there is a wealth of information establishing the benefit of growth hormone (GH) replacement therapy on adults with growth hormone deficiency (aGHD), recent reviews on the QoL and health economic impact of aGHD and the effect of treatment on these factors is limited. OBJECTIVE: The aim of this article is to summarise the impact of early and sustained treatment on the QoL and economic burden of aGHD by conducting a targeted literature review. METHODS: Standard electronic databases, including PubMed and the Cochrane collaboration website, were searched for publications between January 2006 and July 2016 for evidence of the humanistic and economic burden of aGHD. Search terms included growth hormone deficiency, health-related quality of life, HRQoL, patient-reported outcomes, outcome assessment, well-being and adherence. RESULTS: The literature search identified 732 initial hits and a final 14 publications were included. The analysis showed that the economic burden of aGHD is largely driven by the productivity losses associated with the disease. This is because most patients with aGHD are of working age and the QoL domains (memory & concentration and energy & vitality) most commonly affected by aGHD severely impair a person's ability to work and may limit their contribution to society. CONCLUSION: Untreated aGHD can seriously affect patient's functioning. Early and continued treatment with GH replacement therapy could potentially improve the QoL and reduce the economic burden associated with the aGHD. This review has limitations; only English language articles published since January 2006 were included although many of the studies were conducted in the Nordic countries; it is unclear how representative these studies are of the population as a whole. This was a literature review and not a systematic review, as it was thought to be unlikely that in this rare disease, any additional publications would have been identified. Overall, this review reveals a paucity of data in this underserved population and points to research gaps which could be addressed with new studies. PMID- 30411986 TI - A clinical and immunological study of phototoxic regimen of ultraviolet A for treatment of alopecia areata: A randomized controlled clinical trial. AB - BACKGROUND: Various therapeutic agents have been described for alopecia areata but none is satisfactory. The use of ultraviolet A phototherapy in phototoxic regimens has emerged lately with promising results. OBJECTIVE: Determine the efficacy and safety of phototoxic regimen of psoralen ultraviolet A in comparison to conventional therapy with intralesional corticosteroids in patients with alopecia areata. METHODS: In this randomized controlled clinical trial, fourty patients were randomized to either phototoxic regimen of psoralen ultraviolet A group or potent intralesional corticosteroids group for 3 months. Study ended at 6 months. The primary outcome was treatment success: sustained regrowth of hair in >=80% of the affected areas at 6 months. Tissue cytokines were assessed at 0 and 3 months. RESULTS: At 6 months, treatment success was achieved by 45% of patients, similarly in both groups. Tissue cytokine expression correlated well with clinical response. CONCLUSIONS: Phototoxic regimen of topical PUVA deserves a place among therapeutic tools used in management of alopecia areata especially in more extensive conditions where intralesional corticosteroids would not be suitable. PMID- 30411987 TI - Lichen planopilaris: Retrospective study on the characteristics and treatment of 291 patients. AB - Lichen planopilaris (LPP) is an immune-mediated cicatricial alopecia. The main clinical presentations of LPP include classic form, frontal fibrosing alopecia (FFA), and Graham-Little-Piccardi-Lassueur syndrome (GLPLS). We reviewed medical records of all 291 patients diagnosied with LPP from 2006 to 2017 in Department of Dermatology, Tehran University of Medical Sciences. LPP was more common in women than men. Lichen planus (LP) was seen in 59 of patients (20.3%). Parietal lesions (69.75%), frontal (27.14%), occipital (23.71%), and temporal (21.64%) were frequently seen in LPP patients. However, trunk hair involvement (15.4% vs. 2.7%; P-value = 0.011) and eyebrow involvement (57.7% vs. 0%; P-value < 0.0001) were high in FFA patients. Patients treated with cyclosporine (CSP) achieved partial response (PR) and complete response (CR) faster than with methotrexate (MTX) and mycophenolate mofetil (MMF, P-value=0.0001). So,, CSP and MTX can be considered as effective alternative treatments for non-responders. Moreover, MTX was more effective than MMF but not different in time to reach PR (P-value=0.23) or CR (P-value=0.56). However, CSP and MTX were less safe compared with MMF. 5 alpha reductase inhibitors, systemic retinoids (isotretinoin) or their combination were the most effective therpeutic options for FFA patients. PMID- 30411988 TI - Interprofessional collaboration in mental health settings: a social network analysis. AB - This paper provides the first assessment of patterns of interprofessional collaboration in headspace centres - Australia's youth mental health service - to determine if agencies established to integrate care, deliver collaboration across professional boundaries. The staff of two headspace centres were surveyed to identify with whom they collaborated during routine work, and when faced with uncertain situations. Social network analysis was used to assess interprofessional collaboration within each center and across varying situations. Interprofessional collaboration was identified in both routine and uncertain situations. Staff of headspace (clinical and non-clinical) maintained a tendency to collaborate with colleagues outside of their professional group, compared to within. Networks were well connected when staff collaborated in routine work and when faced with uncertainty related to decision-making. However, there were fewer interactions during times of role uncertainty. The headspace centre that had been in operation for longer showed greater indicators of cohesiveness. Future research should consider context and self-organization when considering the efficacy of networks. PMID- 30411989 TI - Hearing distressing voices simulation: students' perspectives. AB - The aim of this qualitative study was to describe nursing students' experiences of hearing distressing voices through content analysis of essays regarding changes they encountered during simulation. Data, obtained from undergraduate (n = 237) and graduate (n = 128) students' short self-reflection papers, were analysed using a six-step thematic analysis. The following six themes emerged: (a) experiencing cognitive and perceptual challenges, (b) feeling unpleasant emotions, (c) dealing with functional changes and hardships, (d) experiencing somatic changes, (e) making attempts to cope, and (f) facing lingering impact. The findings suggest that students' experiences of voice-hearing simulation closely resembled the voice-hearers' actual experience. Simulation is an effective teaching modality to introduce nursing students to the world voice hearers live in and to prepare them for clinical practice enlightened through understanding of what it is like to hear distressing voices. PMID- 30411990 TI - How does the Cox maze procedure compare? Cost-effectiveness analysis of alternative treatments of atrial fibrillation. AB - OBJECTIVES: Data related to the cost effectiveness of surgical interventions and catheter ablation are sparse. This model-based analysis assessed the clinical and economic trade-offs involved in using catheter ablation or the Cox maze procedure in treating patients with atrial fibrillation. METHODS: A deterministic model was developed to project one-year and lifetime health-related outcomes, costs, quality-adjusted life years (QALYs), and cost effectiveness of each treatment in patients with atrial fibrillation. Using previously unpublished Inova Heart and Vascular Institute (IHVI) data for patients undergoing either procedure, one-year cost and clinical efficacy inputs were estimated. These data were supplemented with published literature and used to estimate costs, utilities, mortality, and likelihood of patient improvement. Results were reported as cost-effectiveness ratios in $/QALY. Sensitivity analyses were conducted to assess robustness of results. RESULTS: Patients initially treated with a Cox maze procedure were estimated to have higher costs than those treated with catheter ablation, both after one year and over the lifetime. However, patients undergoing the Cox maze procedure also had lower rates of one-year mortality than catheter ablation patients (3.5% vs. 8.5%) and the highest rate of improvement following treatment, resulting in the higher QALYs (12.4 vs. 10.2). Compared to catheter ablation, the lifetime incremental cost-effectiveness ratio for the Cox maze surgical procedure was $12,794 per QALY gained. Without quality adjustment, the ratio was $11,315. Results were most sensitive to the likelihood of improvement following each intervention and the cost of the initial procedure. CONCLUSIONS: At a societal willingness to pay of $100,000/QALY, Cox maze procedure was found to both increase overall and quality-adjusted survival and constitute an effective use of resources in patients with atrial fibrillation. PMID- 30411991 TI - Enhancing oral bioavailability of poorly soluble drugs with mesoporous silica based systems: opportunities and challenges. AB - Porous silica-based drug delivery systems have shown considerable promise for improving the oral delivery of poorly water-soluble drugs. More specifically, micro- and meso-porous silica carriers have high surface areas with associated ability to physically adsorb high-drug loads in a molecular or amorphous form; this allows molecular state drug release in aqueous gastrointestinal environments, potential for supersaturation, and hence facilitates enhanced absorption and increased bioavailability. This review focuses primarily on the ability of porous silica materials to modulate in vitro drug release and enhance in vivo biopharmaceutical performance. The key considerations identified and addressed are the physicochemical properties of the porous silica materials (e.g. the particle and pore size, shape, and surface chemistry), drug specific properties (e.g. pKa, solubility, and nature of interactions with the silica carrier), potential for both immediate and controlled release, drug release mechanisms, potential for surface functionalization and inclusion of precipitation inhibitors, and importance of utilizing relevant and effective in vitro dissolution methods with discriminating dissolution media that provides guidance for in vivo outcomes (i.e. IVIVC). PMID- 30411992 TI - Risk assessment due to various terrestrial radionuclides concentrations scenarios. AB - PURPOSE: The purpose of this paper is to evaluate the morbidity excess cancer risk (ECR) due to internal and external exposure to three category levels of natural radionuclides in soil like 238U, 232Th and 40K. Although the exposure rate in soil is low but effect this radiation over time can lead to cancer risk and this risk can be calculated. MATERIALS AND METHODS: Natural activity concentration levels of 40K, 238U and 232Th in soil were selected from last reports in three concentration categories including: low, medium and high levels. The excess cancer risks of three concentration levels were calculated by means of Residual-Radioactive-Material-Guidelines (RESRAD) code. RESULTS AND CONCLUSIONS: The calculated average morbidity ECR from 40K, 238U and 232Th in three concentration categories levels in soil were 1.40*10-4, 8.56*10-4 and 1.35*10-3, respectively. This calculation shows that the excess cancer risk value is the highest value in 100 years' time in all categories. Overall ECR from 40K radionuclide was maximal and the highest exposure pathways was through plant pathway; however, these pathway changes over 60 years to the drinking water pathway. The results of this study may be useful to risk assessment and for decision making for public health protection against high-level radiation. PMID- 30411994 TI - Correction. PMID- 30411993 TI - The effect of eyebrow stenting on the measurement of levator excursion in normal and ptotic eyelids. AB - INTRODUCTION: Levator function is classically estimated by measuring upper eyelid excursion (ULE) with digital brow stenting. The purpose of this study is to compare ULE with and without brow stenting in normal and ptotic eyelids. METHODS: In this prospective observational study, normal and ptotic eyelids were recruited. Subjects were photographed with and without digital brow stenting in primary position, downgaze, and upgaze. Measurements were conducted on digital photographs. The primary outcome measure was ULE (distance travelled by the eyelid margin between downgaze and upgaze). Normal and ptosis (MRD1 <= 2.5 mm or asymmetry >= 1 mm) subgroups were defined. Independent one-way ANOVA and independent samples t-tests were performed. This study was powered to detect a 1 mm difference in the primary outcome measure, assuming SD = 1 mm, with alpha = 0.05 and beta-error = 0.95. RESULTS: Twenty-eight normal eyelids of 22 subjects and 28 ptotic eyes of 18 subjects were included. Stenting significantly (p < 0.01) increased ULE in the overall sample (+0.9 mm) and in controls (+1.2 mm), but not (p > 0.05) in ptotic eyelids (+0.5 mm). Post hoc analysis revealed a beta error of 0.08 in the latter. CONCLUSION: ULE was significantly higher with brow stenting in normal eyelids (approximately +1.2 mm) but not in ptotic eyelids, possibly due to increased levator tone secondary to increased effort in the coupled frontalis. PMID- 30411995 TI - Metabolomics study on the effects of salvianolic acid B and borneol for treating cerebral ischemia in rats by UPLC-Q/TOF-MS. AB - Salviae miltiorrliza-borneol Jun-Shi coupled-herbs have been widely used for treatment of ischemia stroke. Salvianolic acid B was the most abundant and bioactive compound of Salviae miltiorrliza and used for prevention and treatment of cerebrovascular diseases. However, the scientific intension and compatible mechanism of Salvianolic acid B - borneol combination were still unknown. A metabolomics study approach based on UPLC-Q/TOF-MS combined with a pathological study has been applied to study the metabolic disturbances of cerebral ischemia and evaluate the efficacies of Sal B and Sal B/ borneol against cerebral ischemia in MCAO rats. The neuroprotection of Sal B and Sal B/ borneol was reversed through the evaluation of neurological deficits, infarct volume, and neuronal apoptosis in MCAO model. The metabonomic analysis revealed the MCAO-induced cerebral ischemia could be ameliorated by Sal B through improving the energy metabolism, lipids metabolism, inflammatory responses and oxidant stress. Borneol could enhance the neuroprotective effects was associated with the increased concentration of Sal B and attenuated the function of sphingolipid metabolism pathway in cerebral ischemia rats. These findings perhaps clarify the mechanism of neuroprotective effects of treating ischemia stroke by Sal B or Sal B/ borneol preliminarily through metabolomics, and push the quality promotion and the composition of borneol- Sal B in secondary development of prescription. PMID- 30411996 TI - Perceptions of Reducing Tube Feeding for Persons with Advanced Dementia among Various Professions in a Teaching Hospital. AB - BACKGROUND: Even though no evidence suggests tube feeding is beneficial for individuals with advanced dementia, many are still tube fed. OBJECTIVE: To assess perceptions of hospital staff regarding reducing tube feeding (RTF) of patients with advanced dementia. DESIGN: Cross-sectional survey. SETTING: A regional teaching hospital in Taipei, Taiwan. SUBJECTS: Hospital staff (n = 624), including physicians, nurses, dieticians, paramedical personnel, social workers, volunteers, attendants, and administrators. MEASUREMENTS: Anonymous questionnaires. RESULTS: The overall awareness of RTF for advanced dementia patients averaged 10.2 +/- 3.74 points (maximum, 19 points) among all respondents. Among the different hospital professions, dieticians scored the highest, whereas nurses and attendants/volunteers had relatively low scores. Over half of respondents (57%) agreed tube feeding is the best choice for advanced dementia with dysphagia. Physicians of different specialties had significantly different responses toward RTF with regard to the belief that tube feeding reduces the risk of aspiration pneumonia, referring patients who refuse tube feeding to other health care team members, and the belief that family members would be able to accept the patient's death along with insufficient food/fluid intake. Only 35.1% of respondents believed they were able to implement comfort feeding. CONCLUSIONS: The present survey shows a persistent knowledge gap among various health care professions regarding tube feeding of patients with advanced dementia. Also, there is insufficient awareness about this subject, indicating that promotion of comfort feeding by enhanced training and communication within medical teams is essential to achieving better person-centered care and preventing unnecessary suffering. PMID- 30411997 TI - The pi-pi stacking-guided supramolecular self-assembly of nanomedicine for effective delivery of antineoplastic therapies. AB - In traditional nano drug-delivery systems, the complex chemical bonds between drug and carrier often complicate the preparation process and are less prone to rupture upon entry into the target, which is detrimental to the timely release of the drug. The pi-pi stacking provides us with a promising alternative as it is a weak interaction between the aromatic rings. Since most antitumor drugs are hydrophobic molecules with complex aromatic pi-pi-conjugated structures, the construction of self-assembly based on pi-pi stacking between drugs and carriers has the advantage of improving the stability and drug loading capacity as well as the improvement of hydrophilicity and biosafety. This article introduces the recent advances in pi-pi stacking-guided nano self-assembly for antineoplastic delivery. PMID- 30411998 TI - Principal component analysis identifies differences in ice hockey skating stride between high- and low-calibre players. AB - The objective was to compare joint angles during full stride skating on ice between high- and low-calibre hockey players. High (n = 8) and low (n = 8) calibre male participants completed full stride skating on ice for two to five trials. A 10-camera motion capture system collected kinematic data. Ankle, knee, and hip angles were calculated. Principal component analysis (PCA) identified important angle characteristics and each trial was scored against principal components (PC-scores). Hierarchical linear models examined relationships between PC-scores and skill level with and without controlling for speed. High-calibre participants were associated with greater ankle inversion during push-off and recovery (p < 0.001), greater knee extension (p = 0.051) and external rotation at push-off (p = 0.038), and greater hip flexion throughout stride (p = 0.027) after controlling for speed. Interactions existed between speed and skill level including faster skating speeds were associated with increased plantarflexion at push-off in low-calibre participants while there was no relationship in high calibre participants. Skating pattern differences between skill levels provide an indication of ideal joint motion during skating. Players should be encouraged to plantarflex the ankle during push-off, extend and externally rotate the knee during push-off, and increase hip flexion throughout stride. PMID- 30411999 TI - Effect of high volume stretch-shortening cycle exercise on vertical leg stiffness and jump performance. AB - The study aims were to investigate the effects of muscle damage induced by high volume stretch-shortening cycle exercise on countermovement jump (CMJ) performance and vertical leg stiffness during squat and landing phases. Changes in the peak torque of knee extensor muscles, soreness, plasma CK activity, vertical leg stiffness, and CMJ characteristics were measured in recreationally active men after 50, 100, 150 and 200 drop jumps (DJs) and again 24 h later. The isometric voluntary peak torque after 50 DJs decreased by 22 +/- 12% (p < 0.01). However, during the squat phase of CMJ eccentric peak power and rate of force development together with the concentric mean force during the push-off phase increased after 50 DJs (all p < 0.05). After 200 DJs, jump height and concentric peak power during push-off were decreased (p < 0.05). At 24 h after exercise, jump height, peak eccentric force, the rate of eccentric force development and the mean concentric force in CMJ and vertical leg stiffness in the squat all remained decreased (p < 0.05), while vertical leg stiffness in the landing phase was increased (p < 0.05). Muscle damaging exercise volume is associated with changes in vertical leg stiffness and CMJ performance. PMID- 30412000 TI - Alterations in scapulothoracic and humerothoracic kinematics during the tennis serve in adolescent players with a history of shoulder problems. AB - The tennis serve generates high musculoskeletal loads at the shoulder complex, making athletes particularly vulnerable to chronic injuries, especially adolescent players. Chronic injuries are commonly related to altered scapular kinematics. This study explored the effects of a history of shoulder problems involving humerothoracic and scapulothoracic kinematics during the tennis serve at low speed in adolescent competitive players with and without a history of dominant shoulder problems. Totally, 28 adolescent tennis players were split into two groups, those with and those without a history of shoulder problems. Data on humeral and scapular kinematics relative to the thorax were collected using an electromagnetic system during slow velocity serves. The two groups's humerothoracic and scapulothoracic 3D joint angles were compared both at the end of the cocking phase and at the end of the acceleration phase of the tennis serve. At the end of the cocking phase, the players with a 30 history of shoulder problems showed less humeral abduction and external rotation and more scapular upward rotation. This group also showed less humeral abduction at the end of the acceleration phase. Players with a history of shoulder problems adapted their humerothoracic and scapulothoracic orientations to preserve shoulder integrity during the tennis serve. PMID- 30412001 TI - TREK-2 mediates the neuroprotective effect of isoflurane preconditioning against acute cerebral ischemia in the rat. AB - : It is known that preconditional treatment with volatile anesthetics can induce tolerance of the brain to stroke. A previous study demonstrated that the involvement of TREK-1, a two-pore domain K+ channel, in sevoflurane preconditioning-induced neuroprotection against focal cerebral ischemia in rats. The present study testified whether TREK-2, another anesthetics-target K+ channels, is also associated with volatile anesthetics-induced neuroprotection, and further explored its potential mechanism. METHODS: Rats preconditioned with isoflurane were subjected to 1.4vol% isoflurane plus 98% O2 (1.5L/min) inhalation for 1hour daily and continuing for 5 consecutive days. Then, these rats were subjected to middle cerebral artery occlusion (MCAO) as focal cerebral ischemia model. The expression of TWIK related K+ channel 2 (TREK-2) was analyzed by Western blotting and qRT-PCR, and its downstream signaling molecules protein kinase C (PKC) alpha, extracellular signal-regulated kinase 1/2 (ERK1/2), and pERK1/2 was detected by Western blotting either. Subsequently, the expression of TREK-2 was regulated by siRNA transfection in the brain to clarify its role in the neuroprotection of isoflurane preconditioning. Neurological scores, infarction volume, and TdT-mediated dUTP Nick-End Labeling (TUNEL) staining were examined to evaluate the outcomes. The impact of TREK-2 on the expression of its downstream signaling molecules was also examined for preliminary analysis of the possible mechanisms. RESULTS: Isoflurane preconditioning reduced the infarct volume, inhibited the cell apoptosis, and improved the neurological outcome in the rats subjected to MCAO. These effects were parallel with the increase in TREK 2 protein and inhibition of the ERK1/2 phosphorylation. The down-regulation of TREK-2 via siRNA could significantly attenuate the isoflurane preconditioning induced neuroprotective effects. CONCLUSIONS: Isoflurane preconditioning-induced neuroprotective effects against ischemia-reperfusion injury are associated with the increase in TREK-2 channels activation. These effects depend on the attenuation of PKC alpha and inhibition of ERK1/2 phosphorylation. Results enrich our understanding on the mechanism of TREK-2 in preconditioning-induced neuroprotection. PMID- 30412003 TI - Systemic treatments for metastatic urothelial carcinoma. AB - INTRODUCTION: Urothelial carcinoma is one of the most common cancers in the western world and, until recently, had limited therapeutic options. The contemporary advancement of immune checkpoint inhibitors (ICI) has heralded a new era for these patients and represents a major shift in the evolving treatment landscape. Areas covered: This article provides a comprehensive summary of the currently available treatments for metastatic urothelial carcinoma (mUC). The authors also review ongoing, phase-III studies with novel therapeutic targets and highlight recent insights into tumor biology that may help better understand the disease. Expert opinion: The treatment landscape for first-line therapy of mUC continues to include platinum-based chemotherapy for patients who are eligible. While the approval of ICI has changed the management in those who are post platinum or platinum-ineligible, the wider use of ICI in the first-line setting requires further clarity given recent FDA announcements. Maintaining the remarkable progress in mUC may depend upon ongoing phase-III studies evaluating treatment options beyond ICI. Better prognostication and identification of those unlikely to respond to ICI remain important unanswered questions, particularly as this class of agents moves further along the disease spectrum of non-metastatic UC. PMID- 30412004 TI - Validity of judo-specific tests to assess neuromuscular performance of judo athletes. AB - Uchi-komi Fitness Test (UFT) is a specific judo test that evaluates physiological fitness of judo athletes in similar conditions to judo matches. Neuromuscular parameters obtained by generic and judo-specific tests would aid to get more information about its criterion validity. This study aimed to analyse the relationship between UFT and shoulder external (PTEX) and internal (PTINT) rotation torque, handgrip strength (HGS) and vertical jumps (VJs) performance. The relationship between UFT and Judogi grip strength test (JGST) was also investigated. Eighteen male judo athletes participated in this study. Athletes performed neuromuscular tests (VJ, PTEX, PTINT and HGS) and judo-specific tests (JGST and UFT). Pearson's correlation was used with the level set at p < 0.05. Significant correlation was found between UFT and all VJ variables (r = 0.50 0.72, p < 0.004), UFT a + b (two first series of UFT) and PTEX (r = 0.49, p = 0.033), UFT and PTINT (r = 0.47, p = 0.044). Also, UFT was correlated to JGST (r = 0.50-0.72, p < 0.044, respectively). We conclude that muscle power of lower limbs, PTEX and PTINT was related to UFT. Strength-endurance in the upper limbs (JGST) was also related to the UFT performance. PMID- 30412002 TI - DNA methylation in blood as a mediator of the association of mid-childhood body mass index with cardio-metabolic risk score in early adolescence. AB - Obesity is associated with higher cardio-metabolic risk even in childhood and adolescence; whether this association is mediated by epigenetic mechanisms remains unclear. We examined the extent to which mid-childhood body mass index (BMI) z-score (median age 7.7 years) was associated with cardio-metabolic risk score in early adolescence (median age 12.9 years) via mid-childhood DNA methylation among 265 children in the Project Viva. We measured DNA methylation in leukocytes using the Infinium Human Methylation450K BeadChip. We assessed mediation CpG-by-CpG using epigenome-wide association analyses, high-dimensional mediation analysis, and natural effect models. We observed mediation by mid childhood DNA methylation at 6 CpGs for the association between mid-childhood BMI z-score and cardio-metabolic risk score in early adolescence in the high dimensional mediation analysis (accounting for 10% of the total effect) and in the natural effect model (beta = 0.04, P = 3.2e-2, accounting for 13% of the total effect). The natural direct effect of BMI z-score on cardio-metabolic risk score was still evident (beta = 0.27, P = 1.1e-25). We also observed mediation by mid-childhood DNA methylation at 5 CpGs that was in the opposite direction from the total effect (natural effect model: beta = -0.04, P = 2.0e-2). Mediation in different directions implies a complex role of DNA methylation in the association between BMI and cardio-metabolic risk and needs further investigation. Future studies with larger sample size and greater variability in cardio-metabolic risk will further help elucidate the role of DNA methylation for cardio-metabolic risk. PMID- 30412005 TI - What Psilocybin Taught Me About Dying. PMID- 30412006 TI - IS IT TIME TO REFLECT, NOT ON THE "WHAT" BUT THE "WHY" IN EMERGING WILDLIFE DISEASE RESEARCH? PMID- 30412007 TI - Obtaining Vital Status and Cause of Death on a Million Persons. AB - PURPOSE: To present the methodology used to determine vital status and obtain cause of death within the Million Person Study of Low-Dose Health Effects (MPS). Data sources and vital status tracing techniques used to obtain vital status and cause of death for six (n=424,238 subjects) of the ~20+ cohorts under study are described. METHODS AND MATERIALS: A multistage approach using multiple sources of vital status information was used to determine vital status (or 'trace') study participants from as early as 1940 to the present. Mortality records from state departments of vital statistics and the Social Security Administration Death Master File (SSA-DMF) were matched to study participants by Social Security Number, full name, date of birth, and/or sex using deterministic and probabilistic algorithms. The National Death Index (NDI) and SSA Service for Epidemiological Researchers (SSA-SER) were used to obtain cause of death (after 1978) and verification of alive status, respectively. Online public records and ancestry services, death certificates, and specialized mortality sources were also utilized. RESULTS: For the MPS cohorts traced to date (nuclear power plant workers, industrial radiographers, atomic veterans, and workers at Rocketdyne /Atomics International, Mound nuclear facility, and Mallinckrodt Chemical Works), vital status was confirmed for over 90% of all study subjects in all but one cohort (88%). The ascertainment of cause of death was over 96% for all cohorts. CONCLUSIONS: A hallmark of a high-quality epidemiologic cohort mortality study is a low percentage of subjects with unknown vital status and a low percentage of deaths without a cause of death. The sources and methods used for vital status tracing and cause of death determination for the MPS have been successful and should be useful for other investigators tracing large, historic study populations. Some of the approaches would be applicable for use in all cohort studies using regional-specific mortality data or modifications to the approach. PMID- 30412008 TI - Pharmacoeconomic evaluation of sodium-glucose transporter-2 (SGLT2) inhibitors for the treatment of type 2 diabetes. AB - INTRODUCTION: Clinicians have many safe and effective options for the treatment of type 2 diabetes that can improve glycemic control and effect other cardio metabolic parameters. Sodium-glucose transporter-2 inhibitors (SGLT-2) are the most recent class of therapies, have a novel mechanism of action, and provide good glycemic efficacy and a favorable cardiovascular risk profile. Cost effectiveness data can play an important role in assessing the benefits of this class of therapy in anti-diabetes treatment regimens. Areas covered: This review summarizes all the available evidence regarding the cost-effectiveness of SGLT-2 inhibitors. For the purposes of this article, the authors have performed a systematic review of pharmacoeconomic analyses through a non-restricted literature until June 2018. Expert opinion: The available analyses demonstrate that SGLT-2 inhibitors are a more cost-effective option compared to other oral anti-diabetes therapies and insulin in the treatment of individuals with uncontrolled type 2 diabetes. Future studies should examine populations with renal and liver disease and expand data of some SGLT-2 inhibitors to patients at high cardiovascular risk and hard endpoint data. PMID- 30412009 TI - Should real-world evidence be incorporated into regulatory approvals? PMID- 30412010 TI - Expression of GAF sensor, CAZymes, elicitins, and RXLRs differs markedly between two Phytophthora cactorum isolates. AB - The phytopathogen Phytophthora cactorum infects economically important herbaceous and woody plant species. The P. cactorum isolates differ in host-specificity; for example, strawberry crown rot is often caused by a specialized pathotype. Here we compared the transcriptomes of two P. cactorum isolates that differ in their virulence to garden strawberry (Pc407: high virulence; Pc440: low virulence). De novo transcriptome assembly and clustering of contigs resulted in 19 372 gene clusters. Two days after inoculation of Fragaria vesca roots, 3 995 genes were differently expressed between the P. cactorum isolates. One of the genes that were highly expressed only in Pc407 encodes a GAF sensor protein potentially involved in the membrane trafficking processes. Two days after inoculation, elicitins were highly expressed in Pc407 and lipid catabolism appeared to be more active than in Pc440. Of the carbohydrate-active enzymes, those that degrade pectin were often more highly expressed in Pc440, whereas members of glycosyl hydrolase family 1, potentially involved in the metabolism of glycosylated secondary metabolites, were more highly expressed in Pc407 at the time point studied. Differences were also observed among the RXLR effectors: Pc407 appears to rely on a smaller set of key RXLR effectors, whereas Pc440 expresses more numerous RXLRs. This study is the first step towards the understanding of the molecular basis of differences in the virulence of P. cactorum isolates. Identification of the key effectors is important as it enables effector-assisted breeding strategies towards crown rot resistant strawberry cultivars. PMID- 30412011 TI - The effects of nutrition and environmental factors on conidial germination and appressorium formation of Phyllosticta citricarpa, the causal agent of citrus black spot. AB - Citrus black spot caused by Phyllosticta citricarpa has been identified in Florida since 2010 and can reduce fruit yield and marketability. The conditions required for conidial germination have been poorly understood for P. citricarpa, limiting further biological studies. In this study, the effects of citrus juices, concentration, pH, various carbon and nitrogen sources, and environmental conditions were evaluated in vitro. All tested juices, especially 'Valencia' (> 85%, P < 0.05), favored germination and appressorium formation, whereas sterile water rarely stimulated germination (< 1%). The 'Valencia' juice effect was concentration- and pH-dependent, and the maximum rate was reached in 1.5% juice with pH of 3.4. Most carbon, nitrogen, or complex sources did not favor germination or appressorium formation with the exception of potato dextrose broth (PDB). An incubation period of 18 to 24 h at 24 degrees C was required for peak germination and appressorium formation. The further analysis of critical juice components using synthetic citrus juice revealed that sugars, salts, citric acid, and thiamine were most important for germination and appressorium formation (> 80%, P > 0.05). These results provide a better understanding of fungal biology of P. citricarpa and a robust and convenient system for further applications such as screening for efficacious fungicides. PMID- 30412012 TI - Trichoderma species: versatile plant symbionts. AB - Because of the need to provide food for the growing population, agricultural activity is faced with the huge challenge of counteracting the negative effects generated by adverse environmental factors and diseases caused by pathogens on crops, while avoiding environmental pollution due to the excessive use of agrochemicals. The exploitation of biological systems that naturally increase plant vigor, preparing them against biotic and abiotic stressors that also promote their growth and productivity represents a useful and viable strategy to help face these challenges. Fungi from the genus Trichoderma have been widely used in agriculture as biocontrol agents because of their mycoparasitic capacity and ability to improve plant health and protection against phytopathogens, which makes it an excellent plant symbiont. The mechanisms employed by Trichoderma include secretion of effector molecules and secondary metabolites that mediate the beneficial interaction of Trichoderma with plants, providing tolerance to biotic and abiotic stresses. Here we discuss the most recent advances in understanding the mechanisms employed by this opportunistic plant symbiont as biocontrol agent and plant growth promoter. In addition, through genome mining we approached a less explored factor that Trichoderma could be using to become successful plant symbionts, the production of phytohormones -auxins, cytokinins, abscisic acid, gibberellins, among others. This approach allowed us to detect sets of genes encoding proteins potentially involved in phytohormone biosynthesis and signaling. We discuss the implications of these finding in the physiology of the fungus and in the establishment of its interaction with plants. PMID- 30412013 TI - Medical students as human resources for health to promote effective physician patient communication. PMID- 30412014 TI - The social gradient of invitation. PMID- 30412015 TI - Challenges and opportunities for e- and m-health-based behaviour change interventions. PMID- 30412016 TI - Attitudes towards smokefree high streets: a survey of local shoppers in a northern UK town. AB - OBJECTIVE:: As a local authority we wanted to practically determine the perception of the public to smokefree zones in shopping high streets and other local outdoor public places. METHODS:: A survey was carried out by students on a convenience sample of shoppers on a single busy market day in Barnsley. RESULTS:: In all, 142 responses were collected; 28% were smokers and 15% e-cigarette users. The majority (69%) of respondents were not against smokefree high streets, including 68% of smokers; 69% of respondents (including 61% of smokers) were not against all public areas becoming smokefree; 70% of respondents (including 63% of smokers) were not against outdoor seating areas, such as those outside pubs and cafes becoming smokefree. There was a marginal preference that smokefree outdoor zones should be voluntary (42%) rather than enforced (39%). Most respondents believed that people smoking around children was influential in determining whether those children go on to take up smoking when they get older. Most smokers (92%) said they already moderated their smoking behaviour in some way when children were present, including 44% who claimed that when children are around they do not smoke at all. CONCLUSION:: This study gives strength to the argument for local authorities to implement voluntary outdoor smokefree zones in public places such as shopping high streets, as a part of a comprehensive tobacco control plan. Shoppers were generally supportive of smokefree zones and in particular where the rationale for their implementation is to protect children from taking up smoking. PMID- 30412017 TI - RE: Medical students are well placed to promote health. PMID- 30412018 TI - Blue light leadership: developing public health consensus agreements with the fire, ambulance and police services. PMID- 30412019 TI - Behaviour change. PMID- 30412020 TI - Gamification for physical activity behaviour change. PMID- 30412021 TI - Sleep deprivation in adults and children: what can be done to tackle the increasingly worrying problem in the UK? PMID- 30412024 TI - Reviewing the evidence of effective peer education among young people. PMID- 30412025 TI - Reducing crime - a call for action for public health leaders. PMID- 30412027 TI - HIGHLIGHTED TOPIC: THE PASSIVE MECHANICAL PROPERTIES OF MUSCLE. PMID- 30412028 TI - Adaptations in the passive mechanical properties of skeletal muscle to altered patterns of use. AB - The aim of this mini-review is to describe the current state of knowledge regarding the effects of chronic changes in the patterns of muscle use (defined as changes lasting >1 week), including muscle stretching, strengthening and others, on the passive mechanical properties of healthy human skeletal muscles. Various forms of muscle stretch training and some forms of strength training (especially eccentric training) are known to strongly impact the maximum elongation capacity of muscles in vivo (i.e. maximum joint range of motion), largely by increasing our ability to tolerate higher stretch loads. However, only small effects are observed in the passive stiffness of the muscle-tendon unit (MTU) or the muscle itself, although a reduction in muscle stiffness has been observed in the plantar flexors after both stretching and eccentric exercise interventions. No changes have yet been observed in viscoelastic properties such as the MTU stress-relaxation response, although a minimum of evidence indicates that hysteresis during passive stretch-relaxation cycles may be reduced by muscle stretching training. Importantly, data exist for relatively few muscle groups, and little is known about the effects of age and sex on the adaptive process of passive mechanical properties. Despite the significant research effort afforded to understanding the effects of altered physical activity patterns on the maximum range of motion at some joints, further information is needed before it will be possible to develop targeted physical activity interventions with the aim of evoking specific changes in passive mechanical properties in individuals or in specific muscles and muscle groups. PMID- 30412029 TI - Breathing pattern during sequential swallowing in healthy adult humans. AB - Sequential liquid swallowing is a common daily occurrence during which coordination of deglutition and breathing would be highly regulated to avoid pulmonary aspiration and to maintain hematosis. We studied the effects of sequential water swallowing (SWS) at fixed swallowing rates and with regular succession of swallows on respiration in healthy subjects. Thirty one normal adults (19 men) with a mean age of 27.96 +/- 3.68 years were explored at rest and during SWS (at 12 and 24 swallows/min). Respiration was recorded by intranasal air pressure changes and timing of deglutition by an acoustic method. Oxygen saturation (SpO2) was monitored with a finger probe. During SWS, we determined the respiratory phase (inspiration or expiration) before and after each ingestion cycle (IC) (period of sustained apnea including 1 or more swallows). We also measured inspiratory time (TI), expiratory time (TE), respiratory cycle duration (TT), respiratory rate (RR) and SpO2 at rest and during SWS. We showed that respiration was interrupted by sequential swallows determining a succession of ICs that were often preceded and followed by expiration. During SWS, TI decreased and TE increased compared to rest (p<0.01). However, TT, RR and SpO2 did not change. It seems that the preferential coupling of swallowing with expiration during SWS is favored by an increase in TE to ensure airway protection. Although the repetitive swallows, RR and SpO2 were not altered during SWS. These data may be useful to study the effects of aging and pathological conditions on swallowing and breathing coordination during SWS. PMID- 30412030 TI - Microvascular Mechanisms Limiting Skeletal Muscle Blood Flow with Advancing Age. AB - Effective oxygen delivery to active muscle fibers requires that vasodilation initiated in distal arterioles, which control flow distribution and capillary perfusion, ascends the resistance network into proximal arterioles and feed arteries, which govern total blood flow into the muscle. With exercise onset, ascending vasodilation reflects initiation and conduction of hyperpolarization along endothelium from arterioles into feed arteries. Electrical coupling of endothelial cells to smooth muscle cells evokes the rapid component of ascending vasodilation, which is sustained by ensuing release of nitric oxide during elevated luminal shear stress. Concomitant sympathetic neural activation inhibits ascending vasodilation by stimulating alpha-adrenoreceptors on smooth muscle cells to constrict the resistance vasculature. We hypothesized that compromised muscle blood flow during advanced age reflects impaired ascending vasodilation through actions on both cell layers of the resistance network. In the gluteus maximus muscle of old (24 months) vs. young (4 months) male mice (corresponding to mid-60s vs. early 20s in humans), inhibiting alpha-adrenoreceptors in old mice restored ascending vasodilation while even minimal activation of alpha adrenoreceptors in young mice attenuated ascending vasodilation in the manner seen with aging. Conduction of hyperpolarization along the endothelium is impaired in old vs. young mice due to "leaky" membranes resulting from the activation of potassium channels by hydrogen peroxide released from endothelial cells. Exposing the endothelium of young mice to hydrogen peroxide recapitulates this effect of aging. Thus, enhanced alpha-adrenoreceptor activation of smooth muscle in concert with electrically leaky endothelium restricts muscle blood flow by impairing ascending vasodilation during advanced age. PMID- 30412031 TI - Computational analysis of airflow dynamics for predicting collapsible sites in the upper airways: A preliminary study. AB - The present study aimed to detail the relationship between the flow and structure characteristics of the upper airways and airway collapsibility in obstructive sleep apnea. Using a computational approach, we performed simulations of the flow and structure of the upper airways in two patients having different facial morphologies: retruding and protruding jaws, respectively. First, transient flow simulation was performed using a prescribed volume flow rate to observe flow characteristics within upper airways with an unsteady effect. In the retruding jaw, the maximum magnitude of velocity and pressure drop with velocity shear and vortical motion was observed at the oropharyngeal level. In contrast, in the protruding jaw, the overall magnitude of velocity and pressure was relatively small. To identify the cause of the pressure drop in the retruding jaw, pressure gradient components induced by flow were examined. Of note, vortical motion was highly associated with pressure drop. Structure simulation was performed to observe the deformation and collapsibility of soft tissue around the upper airways using the surface pressure obtained from the flow simulation. At peak flow rate, the soft tissue of the retruding jaw was highly expanded, and a collapse was observed at the oropharyngeal and epiglottis levels. PMID- 30412032 TI - Effect of carbohydrate ingestion on central fatigue during prolonged running exercise in moderate hypoxia. AB - To determine if acute exposure to moderate hypoxia alters central and peripheral fatigue, and to test whether carbohydrate ingestion impacts fatigue characteristics, 12 trained runners completed 3 running trials lasting 1 h each at 65% of normoxic VO2max. The first trial was performed in normoxia (FIO2 = 0.21) and the last two trials were completed in hypoxia (FIO2 = 0.15). Participants ingested a placebo drink in normoxia (NORM-PLA), a placebo drink in hypoxia (HYP-PLA), or a carbohydrate solution in hypoxia (HYP-CHO). HYP conditions were randomized. Peripheral (DeltaQtw,pot) and central (DeltaVA) fatigue were assessed via pre- to post-exercise changes in magnetically evoked quadriceps twitch. In HYP, blood was drawn to determine the ratio of free tryptophan (f-TRP) to branched-chain amino acids (BCAA). Following exercise, peripheral fatigue was reduced to a similar degree between normoxia and hypoxia (DeltaQtw,pot = -4.5 +/- 1.3% and -4.0 +/- 1.5% in NORM-PLA and HYP-PLA, respectively; P = 0.61). Central fatigue was present following normoxic and hypoxic exercise, but to a greater degree in HYP-PLA compared to NORM-PLA (DeltaVA: -4.7 +/- 0.9% vs. -1.9 +/- 0.7%, respectively; P < 0.01). Carbohydrate ingestion did not influence central fatigue (DeltaVA in HYP-CHO: -5.7 +/- 1.2%; P = 0.51 vs. HYP-PLA). Following exercise, no differences were observed in the ratio of f-TRP to BCAA between HYP-PLA and HYP-CHO ( P = 0.67). Central fatigue increased during prolonged running exercise in moderate hypoxia despite the ratio of f-TRP to BCAA remaining unchanged. Ingesting carbohydrates while running in hypoxia did not influence fatigue development. PMID- 30412033 TI - Assessment of the influence of lung inflation state on the quantitative parameters derived from hyperpolarized gas lung ventilation MRI in healthy volunteers. AB - In this study, the effect of lung volume on quantitative measures of lung ventilation was investigated using MRI with hyperpolarized 3He and 129Xe. Six volunteers were imaged with hyperpolarized 3He at five different lung volumes (residual volume (RV), RV+1L, functional residual capacity (FRC), FRC+1L and total lung capacity (TLC)), and three were also imaged with hyperpolarized 129Xe. Imaging at each of the lung volumes was repeated twice on the same day with corresponding 1H lung anatomical images. Percentage lung ventilated volume (%VV) and variation of signal intensity (heterogeneity score, Hscore) were evaluated. Increased ventilation heterogeneity, quantified by reduced %VV and increased Hscore, was observed at lower lung volumes with the least ventilation heterogeneity observed at TLC. For 3He MRI data, the coefficient of variation of %VV was less than 1.5% and less than 5.5% for Hscore at all lung volumes, whilst for 129Xe data the values were 4% and 10% respectively. Generally, %VV generated from 129Xe images was lower than that seen from 3He images. The good repeatability of 3He %VV found here supports prior publications showing that percentage lung ventilated volume is a robust method for assessing global lung ventilation. The greater ventilation heterogeneity observed at lower lung volumes indicates that there may be partial airway closure in healthy lungs and that lung volume should be carefully considered for reliable longitudinal measurements of %VV and Hscore. The results suggest that imaging patients at different lung volumes may help to elucidate obstructive disease pathophysiology and progression. PMID- 30412034 TI - Extracellular vesicles from Wharton's jelly mesenchymal stem cells suppress CD4 expressing T cells through transforming growth factor beta and adenosine signaling in a canine model. AB - Mesenchymal stem cells (MSC) are widely investigated as potential therapeutic agents due to their potent immunomodulatory capacity. Although specific mechanisms by which MSC act on immune cells are emerging, many questions remain including the potential of extracellular vesicles (EV) to mediate biological activities. Canine MSCs are of interest for both veterinary and comparative models of disease and have been shown to suppress CD4pos T cell (T helper cell) proliferation. The aim of this study was to determine whether EV isolated from canine Wharton's jelly-derived MSC (WJ-MSC EV) suppress CD4pos T cell proliferation using biochemical mechanisms previously ascribed to soluble mediators (TGF-beta and adenosine). WJ-MSC EV exhibited mode of 125 nm diameter, low buoyant density (1.1 g/mL), and expression of EV proteins Alix and TSG101. Functionally, EV inhibited CD4pos T cell proliferation in a dose-dependent fashion, which was absent in EV-depleted samples and EV from non-MSC fibroblasts. EV suppression of CD4pos T cell proliferation was inhibited by a TGF-betaRI antagonist, neutralizing antibodies to TGF-beta, or A2A adenosine receptor blockade. TGF-beta was present on EV as latent complexes most likely tethered to EV membrane by betaglycan. These data demonstrate that canine WJ-MSC EV utilize TGF-beta and adenosine signaling to suppress proliferation of CD4pos T cell, and will enable further investigation into mechanisms of immune cell modulation, as well as refinement of WJ-MSC and their EV for therapeutic application. PMID- 30412035 TI - Stabilization and sterilization of pericardial scaffolds by UV and low-energy electron irradiation. AB - Pericardial scaffolds have a wide spectrum of clinical applications ranging from patches for vascular reconstruction and abdominal wall defects to bioprosthetic heart valves. The current gold standard of tissue preparation involves disinfection and crosslinking using glutaraldehyde. However, glutaraldehyde associated toxicity as well as rapid calcification and premature graft failure represent the major modes of failure 1. Therefore, a variety of alternative strategies for tissue conservation have been pursued. However, none of those strategies has substituted glutaraldehyde as the method of choice yet. Furthermore, safe sterilization procedures that are non-detrimental to the tissue's functionality are scarce. We have developed a novel procedure to stabilize and sterilize (S) acellular pericardial scaffolds combining photo initiated UV crosslinking (U) with low-energy electron irradiation (LEEI). This SULEEI procedure avoids the use of glutaraldehyde and utilizes LEEI as effective sterilization method. A bioburden of 5.1*105 +/- 4.6*105 viable bacteria could be successfully inactivated by SULEEI treatment applying a surface dose of 30.6 +/- 2.8 kGy. By challenging high-density polyethylene foil stacks with >106 Bacillus pumilus spores in different depths and modelling the dose distribution within the scaffolds, a maximum sample thickness of 175 um was determined for successful sterilization. Moreover, SULEEI treatment appeared non-detrimental to the ultimate tensile strength (17.6 +/- 8.6 MPa vs. 17.4 +/- 9.6 MPa) of the scaffolds compared to glutaraldehyde treated pericardia. Cell number and overall metabolic activity of human endothelial cells was significantly higher on SULEEI treated pericardia as compared to control samples. In contrast, no cell proliferation could be detected on glutaraldehyde treated pericardia. Thus, the SULEEI procedure may be a promising novel procedure for glutaraldehyde-free tissue preparation for pericardium-based tissue transplants and tissue engineering. PMID- 30412036 TI - Investigating Barriers to Family Visitation of Nursing Home Residents: A Systematic Review. AB - Families are integral in helping nursing home residents maintain feelings of social inclusion and an overall sense of belonging, thus reducing consequences of social exclusion. Preliminary research, particularly of the culture change movement in long-term care, shows there are barriers to family engagement and visitation of residents. The objective of this study is to: (1) identify and summarize the barriers most reported to family visitation and (2) synthesize the findings to determine which barriers are most often reported in literature, and which may pose the greatest challenges to family involvement. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a final sample of 15 articles across 11 databases report seven barriers to visitation: psychological, health, staff to family member relationship, employment/finances, travel time, access to transportation, and other. Findings suggest barriers to family visitation and point toward a need for further research as relationships between resident and family member is complex and warrants attention across professions. Interprofessional efforts between social work, allied professionals, and transportation planners are necessary to address this pressing concern experienced by residents in nursing homes, with the ultimate goal of lessening such barriers. PMID- 30412037 TI - Efficacy of Paired Electrochemical Sensors for Measuring Ozone Concentrations. AB - Typical low-cost electrochemical sensors for ozone (O3) are also highly responsive to nitrogen dioxide (NO2). Consequently, a single sensor's response to O3 is indistinguishable from its response to NO2. Recently, a method for quantifying O3 concentrations became commercially available (Alphasense Ltd., Essex, UK): collocating a pair of sensors, a typical oxidative gas sensor that responds to both O3 and NO2 (model OX-B431) and a second similar sensor that filters O3 and responds only to NO2 (model NO2-B43F). By pairing the two sensors, O3 concentrations can be calculated. We calibrated samples of 3 NO2-B43F sensors and 3 OX-B431 sensors with NO2 and O3 exclusively and conducted mixture experiments over a range of 0-1.0 ppm NO2 and 0-125 ppb O3 to evaluate the ability of the paired sensors to quantify NO2 and O3 concentrations in mixture. Although the slopes of the response among our samples of three sensors of each type varied by as much as 37%, the individual response of the NO2-B43F sensors to NO2 and OX-B431 sensors to NO2 and O3 were highly linear over the concentrations studied (R2 >= 0.99). The NO2-B43F sensors responded minimally to O3 gas with statistically non-significant slopes of response. In mixtures of NO2 and O3, quantification of NO2 was generally accurate with overestimates up to 29%, compared to O3, which was generally underestimated by as much as -187%. We observed changes in senor baseline over 4 days of experiments equivalent to 34 ppb O3, prompting an alternate method of calculating concentrations by baseline correcting sensor signal. The baseline-correction method resulted in underestimates of NO2 up to 44% and decreases in the underestimation of O3 up to 107% for O3. Both methods for calculating gas concentrations progressively underestimated O3 concentrations as the ratio of NO2 signal to O3 signal increased. Our results suggest that paired NO2-B43F and OX-B431 sensors permit quantification of NO2 and O3 in mixture, but that O3 concentration estimates are less accurate and precise than those for NO2. PMID- 30412038 TI - Viewpoint: Why you should provide HIV pre-exposure prophylaxis (PrEP) at your college health center. AB - By providing HIV pre-exposure prophylaxis, or PrEP (a single daily oral pill), in a primary care college health setting, clinical providers can make a dramatic contribution to the current and long-term health and well-being of the students they see. This viewpoint article describes the approach taken to instituting primary care PrEP services at two college health programs. It delineates which students might benefit from PrEP and how to prescribe/monitor PrEP over time. Additionally, common barriers to PrEP are reviewed, including concerns about affordability, and the concerns that the use of PrEP will encourage risky sexual activity. Implementation strategies are discussed, including identifying a clinic champion, partnering with knowledgeable colleagues, and developing an educational campaign. PMID- 30412039 TI - Compensation claims for work-related musculoskeletal disorders among hairdressers in France, 2010-2016. AB - BACKGROUND: Hairdressers in France experience occupational illness as well as stressful working conditions which can result in permanent incapacity mainly due to work-related musculoskeletal disorders (WRMSDs) yet WRMSDs in this work force remain largely unstudied. OBJECTIVE: The aim of this study was to analyse trends in compensation claims for WRMSDs among hairdressers. METHODS: Data concerning gender, age, permanent incapacity, working experience, and lost work days (LWD) of claimants were extract from the French National Health Insurance Fund for Salaried Workers. RESULTS: Claim rate increased not significantly by 12.8%. Incidence rate of permanent incapacity increased significantly by 16.0%. In proportion, significant differences were observed between age groups with 35-49 ranking first (45.8%) and also in claimants with working experience >10 years (43.1%). Overall, there were 666,461 LWD during the study period with a significant increase of 16.2% (p < 0.001). CONCLUSION: Although claims rate did not increased significantly, incidence rate of permanent incapacity increased significantly and some groups at risk have being indentified. PMID- 30412040 TI - Standing working posture and musculoskeletal pain among citrus sinensis workers in a low-income country. AB - BACKGROUND: Work-related musculoskeletal pain (WRMP) among citrus sinensis farm workers have barely been studied. Yet most work tasks in such farms are manually performed using awkward standing postures that can contribute to WRMP. AIM: This study assessed the standing working posture in relation to WRMP among citrus sinensis workers. METHODS: Ninety-two workers engaged in manual tasks participated in this cross-sectional study. Postures at the upper limbs were analysed using the Rapid Upper Limb Assessment (RULA) method. Data were analysed using SPSS version 20. RESULTS: Analyses generally showed statistically significant associations (p < 0.05) between a body part RULA score and WRMP at the concerned body part. The upper arm score was > 1 in 77.2% of the workers and caused upper arm pain in 66.3%, the association between the upper score and upper pain was statistically significant (chi2 = 20.57; p < 0.05). Similarly, significant associations were found between the (i) wrist score and wrist pain; (ii) neck score and neck pain and (iii) trunk score and back pain. CONCLUSIONS: Citrus sinensis workers use unsafe postures which contribute to WRMP at the upper arm, trunk, neck and wrists. Ergonomics measures are required to improve their working posture. PMID- 30412041 TI - Effects of short term hypothyroidism on the lipid transfer to HDL and other parameters related to lipoprotein metabolism in patients submitted to thyroidectomy for thyroid cancer. AB - BACKGROUND: Elevation of LDL-cholesterol is the hallmark of hypothyroidism dyslipidemia, but alterations on HDL plasma levels and metabolism are less understood. The aim of this study was to explore aspects of HDL metabolism and enzymes that act on HDL after a short period of overt hypothyroidism. METHODS: Eighteen women (44+/-11 years, BMI 27.9+/-5.2kg/m2) were studied before total thyroidectomy for thyroid cancer, when they were in euthyroid state, and after thyroidectomy, in overt hypothyroidism for 3 weeks, following levothyroxine withdrawal for performance of whole body scan. RESULTS: TSH and FT4 confirmed hypothyroidism; low thyroglobulin and radioiodine uptake indicated near absence of thyroid tissue. LDL-cholesterol (125+/-35 vs 167+/-40 mg/dL, p=0.0002), HDL cholesterol (39+/-8 vs 46+/-10 mg/dL, p=0.0025), non-HDL cholesterol (149+/-38 vs 201+/-46 mg/dL, p<0.0001), unesterified cholesterol (53+/-10 vs 70+/-16 mg/dL, p=0.0003), apolipoprotein (apo) A-I (1.32+/-0.19 vs 1.44+/-0.22 g/L, p<0.04) and apo B (0.97+/-0.25 vs 1.31+/-0.28 g/L, p<0.0001) plasma concentrations were all higher in hypothyroidism compared to values in the euthyroid state, but triglycerides and Lp(a) were unchanged. There were no changes in HDL particle size and lipid composition, CETP and LCAT concentrations and in PON1 activity. Regarding the in vitro assay to estimate lipid transfer to HDL, there were no changes when comparing euthyroid to hypothyroid state, but when adjusted for HDL C, the unesterified cholesterol (0.14+/-0.03 vs 0.11+/-0.02, p<0.0001), triglycerides (0.11+/-0.02vs 0.09+/-0.02, p<0.0001) phospholipids (0.44+/-0.09 vs 0.40+/-0.07, p=0.0205) and esterified cholesterol (0.14+/-0.03 vs 0.13+/-0.03, p=0.0043) transfer to HDL were all diminished in hypothyroidism. CONCLUSION: In short-term hypothyroidism, HDL-cholesterol increased but this did not increase the capacity of the HDL fraction to receive lipids or the activity of PON-1, the anti-oxidation enzyme associated to HDL. PMID- 30412042 TI - A Three-dimensional Cell Culture Method with a Micromesh Sheet and Its Application to Hepatic Cells. AB - In vitro 3D cultures of hepatocytes are increasingly being used to assess human hepatic metabolism and toxicity in drug development. Here, we developed an in vitro 3D cell culture method with a microstructured mesh sheet and applied it to culturing human hepatoma HepG2 cells. The micromesh sheet is constituted of fine mesh strands and apertures that are each much larger than a single cell in size. Proliferating on a micromesh sheet, HepG2 cells spread out in a planar manner and then formed a multilayered cell sheet, so that cell-cell adhesion was dominant over cell-substrate adhesion as being different from 2D cultures. In micromesh cultures, the increase rate in thickness of the cell mass was visually slower than that in spheroid cultures, enabling us to clearly observe inside cells of the cell population by microscopy. Micromesh-cultured HepG2 cells showed higher viability compared with spheroid-cultured cells. The multilayered HepG2 cell sheet increased expression of hepatic marker genes and induced cell polarization with bile canalicular membranes. Furthermore, a combination of micromesh cultures with medium perfusion further induced expression of hepatic marker genes in HepG2 cells; especially CYP1A1 and CYP1A2 mRNA increased 86-fold and 43-fold compared with 2D controls, respectively, which were much higher than those in spheroid cultures. Thus, this simple and versatile micromesh culture method holds some advantages over traditional spheroid cultures and is expected to be instrumental in culturing more differentiated hepatic cells such as HepaRG cells and primary hepatocytes for future preclinical testing. PMID- 30412043 TI - Trans*exualities: Accompaniments, Health Factors, and Educational Resources. PMID- 30412044 TI - Condom use attitude and self-efficacy, and STIs risk perception among Iranian female sex workers: A psychometric study. AB - In this cross-sectional study, we aimed to investigate psychometric properties of the Persian versions of condom use self-efficacy (CUSES), attitude toward condom use (ATCUS), and sexually transmitted infection risk perception (STIsRP) scales among Iranian female sex workers (FSWs). We translated original versions of the scales into Persian, and through census, recruited and interviewed 140 FSWs. Appropriate validity, reliability, functionality and simplicity were demonstrated for the scales. We found the measurement model with a good fit to the data (chi2 [104] = 89.537, p < .01, CFI = 0.978, NFI = 0.931, TLI = 0.981, RMSEA = 0.055 [0.023-0.081]). Our findings supported the applicability of the Persian CUSES, ATCUS, and STIsRP in the Iranian and other Persian-speaking FSW populations. PMID- 30412045 TI - Long-term cryopreservation and revival of tissue engineered skeletal muscle. AB - Tissue engineered skeletal muscle plays an important role not only in the field of regenerative medicine, but also in emerging areas such as soft robotics, organ on-a-chip disease models, and drug testing. However, further expansion of the applications of tissue engineered skeletal muscle models requires a suitable method for their long-term storage and shipment. Cryopreservation has long been the standard for cell storage, but the freezing of 3D tissues is accompanied by many complications due to heat and mass transfer limitations. In this study, we used a tissue engineered skeletal muscle bioactuator as a model to characterize the effects of freezing on muscle viability, gene expression, myotube structure, and force generation. We optimized the protocol for cryopreservation by comparing outcomes when tissue was frozen undifferentiated and differentiated. Our optimized protocol, in which skeletal muscle was frozen undifferentiated, not only maintained cell viability, but led to a 3-fold increase in force production as compared to unfrozen muscle. Furthermore, we enhanced muscle lifetime through inhibition of cysteine proteases. The reported timeline for skeletal muscle tissue fabrication, freezing, revival, and long-term culture not only promotes a more streamlined fabrication process, but enables multi-site collaborative research efforts through the shipment of pre-formed skeletal muscle constructs. PMID- 30412046 TI - Human Synovial MSC Good Manufacturing Practices for Articular Cartilage Regeneration. AB - BACKGROUND: cartilage restoration is a desperately needed bridge for patients with symptomatic cartilage lesions. Chondral lesion is a pathology with high prevalence, reaching as much as 63% of general population and 36% among athletes. Despite Autologous Chondrocyte Implantation (ACI) versatility, it still fails to fully reproduce hyaline articular cartilage characteristics. Mesenchymal stem cells (MSCs) may be isolated from various known tissues, including discarded fragments at arthroscopy such as synovial membrane. Choice of harvesting site is motivated by MSCs abilities to modulate immunologic and inflammatory response via paracrine communication. Synovial MSCs have a greater proliferation and strong chondrogenic potential compared to bone and adipose MSCs and a less hypertrophic differentiation compared to bone MSCs. Good Manufacturing Practice (GMP) laboratory techniques for human clinical trials are still novel. To our knowledge, there are only two clinical trials in humans published since today. PURPOSE: therefore, the present work aimed to isolate and characterize synovial MSCs and evaluated their differentiation properties according to GMP standards. METHODS: one-gram tissue sample from three patients of synovia was harvested at the beginning of arthroscopy surgery. MSCs were isolated, expanded, and characterized by flow cytometry. RESULTS: it was possible to isolate and expand MSCs cultures from synovia, characterize MSCs by flow cytometry using proper monoclonal antibodies, and differentiate MSCs by coloring technique after chondrogenic, adipogenic and osteogenic differentiations. Cartilage treatment may benefit from these tissue-engineering protocols since arthroscopic procedures are routinely performed for different purposes in a previous stage and a favorable chondronegic differentiation cell lineage may be collected and stored in a less invasive way. CONCLUSION: laboratory protocols established according to presented GMP were able to isolate and characterize MSCs obtained from synovia. PMID- 30412047 TI - Detection of novel and recognized RNA viruses in mosquitoes from the Yucatan Peninsula of Mexico using metagenomics and characterization of their in vitro host ranges. AB - A metagenomics approach was used to detect novel and recognized RNA viruses in mosquitoes from the Yucatan Peninsula of Mexico. A total of 1359 mosquitoes of 7 species and 5 genera (Aedes, Anopheles, Culex, Mansonia and Psorophora) were sorted into 37 pools, homogenized and inoculated onto monolayers of Aedes albopictus (C6/36) cells. A second blind passage was performed and then total RNA was extracted and analysed by RNA-seq. Two novel viruses, designated Uxmal virus and Mayapan virus, were identified. Uxmal virus was isolated from three pools of Aedes (Ochlerotatus) taeniorhynchus and phylogenetic data indicate that it should be classified within the recently proposed taxon Negevirus. Mayapan virus was recovered from two pools of Psorophora ferox and is most closely related to unclassified Nodaviridae-like viruses. Two recognized viruses were also detected: Culex flavivirus (family Flaviviridae) and Houston virus (family Mesoniviridae), with one and two isolates being recovered, respectively. The in vitro host ranges of all four viruses were determined by assessing their replicative abilities in cell lines of avian, human, monkey, hamster, murine, lepidopteran and mosquito (Aedes, Anopheles and Culex) origin, revealing that all viruses possess vertebrate replication-incompetent phenotypes. In conclusion, we report the isolation of both novel and recognized RNA viruses from mosquitoes collected in Mexico, and add to the growing plethora of viruses discovered recently through the use of metagenomics. PMID- 30412048 TI - XXV Congresso Nazionale della Societa Italiana per lo Studio dell'Emostasi e della Trombosi (SISET). PMID- 30412049 TI - Tuned polymerization of the transcription factor Yan limits off-DNA sequestration to confer context-specific repression. AB - During development, transcriptional complexes at enhancers regulate gene expression in complex spatiotemporal patterns. To achieve robust expression without spurious activation, the affinity and specificity of transcription factor DNA interactions must be precisely balanced. Protein-protein interactions among transcription factors are also critical, yet how their affinities impact enhancer output is not understood. The Drosophila transcription factor Yan provides a well suited model to address this, as its function depends on the coordinated activities of two independent and essential domains: the DNA-binding ETS domain and the self-associating SAM domain. To explore how protein-protein affinity influences Yan function, we engineered mutants that increase SAM affinity over four orders of magnitude. This produced a dramatic subcellular redistribution of Yan into punctate structures, reduced repressive output and compromised survival. Cell-type specification and genetic interaction defects suggest distinct requirements for polymerization in different regulatory decisions. We conclude that tuned protein-protein interactions enable the dynamic spectrum of complexes that are required for proper regulation. PMID- 30412050 TI - Inhibition of mTORC1 by ER stress impairs neonatal beta-cell expansion and predisposes to diabetes in the Akita mouse. AB - Unresolved ER stress followed by cell death is recognized as the main cause of a multitude of pathologies including neonatal diabetes. A systematic analysis of the mechanisms of beta-cell loss and dysfunction in Akita mice, in which a mutation in the proinsulin gene causes a severe form of permanent neonatal diabetes, showed no increase in beta-cell apoptosis throughout life. Surprisingly, we found that the main mechanism leading to beta-cell dysfunction is marked impairment of beta-cell growth during the early postnatal life due to transient inhibition of mTORC1, which governs postnatal beta-cell growth and differentiation. Importantly, restoration of mTORC1 activity in neonate beta cells was sufficient to rescue postnatal beta-cell growth, and to improve diabetes. We propose a scenario for the development of permanent neonatal diabetes, possibly also common forms of diabetes, where early-life events inducing ER stress affect beta-cell mass expansion due to mTOR inhibition. PMID- 30412052 TI - Insulin mutations impair beta-cell development in a patient-derived iPSC model of neonatal diabetes. AB - Insulin gene mutations are a leading cause of neonatal diabetes. They can lead to proinsulin misfolding and its retention in endoplasmic reticulum (ER). This results in increased ER-stress suggested to trigger beta-cell apoptosis. In humans, the mechanisms underlying beta-cell failure remain unclear. Here we show that misfolded proinsulin impairs developing beta-cell proliferation without increasing apoptosis. We generated induced pluripotent stem cells (iPSCs) from people carrying insulin (INS) mutations, engineered isogenic CRISPR-Cas9 mutation corrected lines and differentiated them to beta-like cells. Single-cell RNA sequencing analysis showed increased ER-stress and reduced proliferation in INS mutant beta-like cells compared with corrected controls. Upon transplantation into mice, INS-mutant grafts presented reduced insulin secretion and aggravated ER-stress. Cell size, mTORC1 signaling, and respiratory chain subunits expression were all reduced in INS-mutant beta-like cells, yet apoptosis was not increased at any stage. Our results demonstrate that neonatal diabetes-associated INS mutations lead to defective beta-cell mass expansion, contributing to diabetes development. PMID- 30412051 TI - New tools for automated high-resolution cryo-EM structure determination in RELION 3. AB - Here, we describe the third major release of RELION. CPU-based vector acceleration has been added in addition to GPU support, which provides flexibility in use of resources and avoids memory limitations. Reference-free autopicking with Laplacian-of-Gaussian filtering and execution of jobs from python allows non-interactive processing during acquisition, including 2D classification, de novo model generation and 3D-classification. Per-particle refinement of CTF parameters and correction of estimated beam tilt provides higher resolution reconstructions when particles are at different heights in the ice, and/or coma-free alignment has not been optimal. Ewald sphere curvature correction improves resolution for large particles. We illustrate these developments with publicly available data sets: together with a Bayesian approach to beam-induced motion correction it leads to resolution improvements of 0.2-0.7 A compared to previous RELION versions. PMID- 30412054 TI - Outcomes of a Quality Improvement Program to Reduce Hospital-acquired Pressure Ulcers in Pediatric Patients. AB - : Hospital-acquired pressure injuries (PIs) present a significant challenge to pediatric providers. PURPOSE: The purpose of this quality improvement program was to develop and implement a debrief protocol and to evaluate compliance with and the implementation of a comprehensive prevention bundle to decrease the overall incidence and severity of pediatric pressure ulcers (PUs)/PIs in a free-standing children's hospital. METHODS: As a member of the Children's Hospitals Solution for Patients Safety national network, a PU Hospital Acquired Conditions (HAC) team was created in 2013, followed by the development and implementation of a PU occurrence debrief tool and discussion guide and implementation of multiple staff educational strategies and a comprehensive prevention bundle. The PU occurrence debriefing occurred within 24 to 48 hours of a PU. Incidence data were collected annually from 2014 until 2017. RESULTS: Compliance on implementation and documentation of bundle elements ranged from 88% to 94%, and PU/PI incidence decreased by 30% from 2014 to 2016 and by 40% in 2017. The overall PU rate was 0.0057 in 2014, 0.0050 in 2015, 0.0036 in 2016, and 0.0023 in 2017; 65% of all PUs were device-related. Of those, >50% were related to respiratory devices, 25% to peripheral intravenous catheters/central lines, 10% to tracheostomies, and 15% to other devices. Respiratory device-related PUs decreased by 50% in the pediatric intensive care unit, by 80% in the neonatal unit, and eliminated completely in extracorporeal membrane oxygenation patients. CONCLUSION: The debriefing process, debriefing tool, educational programs, and prevention bundle reduced the rate of hospital-acquired PIs in pediatric patients and propagated a culture of safety. PMID- 30412055 TI - A Retrospective, Descriptive Analysis of Hospital-acquired Deep Tissue Injuries. AB - : Preventing, identifying, and treating deep tissue injury (DTI) remains a challenge. PURPOSE: The purpose of the current research was to describe the characteristics of DTIs and patient/care variables that may affect their development and outcomes at the time of hospital discharge. METHODS: A retrospective, descriptive, single-site cohort study of electronic medical records was conducted between October 1, 2010, and September 30, 2012, to identify common demographic, intrinsic (eg, mobility status, medical comorbidities, and incontinence), extrinsic (ie, surgical and procedural events, medical devices, head-of-bed elevation), and care and treatment factors related to outcomes of hospital-acquired DTIs; additional data points related to DTI development or descriptive of the sample (Braden Scale scores and subscale scores, hospital length of stay [LOS], intensive care unit [ICU] LOS, days from admission to DTI, time in the operating room, serum albumin levels, support surfaces/specialty beds, and DTI locations) also were retrieved. DTI healing outcomes, grouped by resolved, partial-thickness/stable, and full thickness/unstageable, and 30 main patient/treatment variables were analyzed using Kruskal-Wallis, chi-squared, and Fischer exact tests. RESULTS: One hundred, seventy-nine (179) DTIs occurred in 141 adult patients (132 in men, 47 in women; mean patient age 64 [range 19-94]). Of those patients, 110 had a history of peripheral vascular disease and 122 had hypertension. Sixty-nine (69) DTIs were documented in patients who died within 1 year of occurrence. Most common DTI sites were the coccyx (47 [26%]) and heel (42 [23%]); 41 (22%) were device related. Median hospital LOS was 23 (range 4-258) days and median ICU LOS was 12 (range 1-173) days; 40 DTIs were identified before surgery and 120 after a diagnostic or therapeutic procedure. Data for DTI outcome groups at hospital discharge included 28 resolved, 131 partial-thickness/stable, and 20 full thickness/unstageable; factors significantly different between outcome groups included mechanical ventilation (15/42/12; P = .01), use of a feeding tube (15/46/12; P = .02), anemia (14/30/9; P = .005), history of cerebrovascular accident (12/27/7; P = .03), hospital LOS (67/18/37.5; P <.001), ICU LOS (23/10/12; P = .03), time-to-event (13.5/8/9; P = .001), vasopressor use after DTI (13/31/11; P = .003), low-air-loss surface (10/9/3; P = .005), and device related (14/24/4; P = .002). CONCLUSION: DTI risk factors mirrored those of other PUs, but progression to full-thickness injury was not inevitable. Early and frequent assessment and timely intervention may help prevent DTI progression. PMID- 30412053 TI - T-ALL leukemia stem cell 'stemness' is epigenetically controlled by the master regulator SPI1. AB - Leukemia stem cells (LSCs) are regarded as the origins and key therapeutic targets of leukemia, but limited knowledge is available on the key determinants of LSC 'stemness'. Using single-cell RNA-seq analysis, we identify a master regulator, SPI1, the LSC-specific expression of which determines the molecular signature and activity of LSCs in the murine Pten-null T-ALL model. Although initiated by PTEN-controlled beta-catenin activation, Spi1 expression and LSC 'stemness' are maintained by a beta-catenin-SPI1-HAVCR2 regulatory circuit independent of the leukemogenic driver mutation. Perturbing any component of this circuit either genetically or pharmacologically can prevent LSC formation or eliminate existing LSCs. LSCs lose their 'stemness' when Spi1 expression is silenced by DNA methylation, but Spi1 expression can be reactivated by 5-AZ treatment. Importantly, similar regulatory mechanisms may be also present in human T-ALL. PMID- 30412056 TI - Dual enkephalinase inhibitor (DENKI) PL265: a novel topical treatment to alleviate corneal pain and inflammation. AB - Ocular pain is a core symptom of inflammatory or traumatic disorders affecting the anterior segment. To date, the management of chronic ocular pain remains a therapeutic challenge in ophthalmology. The main endogenous opioids (enkephalins) play a key role in pain control but exhibit only transient analgesic effects due to their rapid degradation. The aim of the present study was to explore the anti nociceptive and anti-inflammatory effects of topical administration of PL265 (a dual enkephalinase inhibitor) on murine models of corneal pain. On healthy corneas, chronic PL265 topical administration did not alter corneal integrity nor modify corneal mechanical and chemical sensitivity. Then, on murine models of corneal pain, we showed that repeated instillations of PL265 (10 mM) significantly reduced corneal mechanical and chemical hypersensitivity. PL265 induced corneal analgesia was completely antagonized by naloxone methiodide, demonstrating that PL265 antinociceptive effects were mediated by peripheral corneal opioid receptors. Moreover, flow cytometry (quantification of CD11b+ cells) and in vivo confocal microscopy analysis revealed that instillations of PL265 significantly decreased corneal inflammation in a corneal inflammatory pain model. Chronic PL265 topical administration also decreased Iba1 and neuronal injury marker (ATF3) staining in the nucleus of primary sensory neurons of ipsilateral trigeminal ganglion. These results open a new avenue for ocular pain treatment based on the enhancement of endogenous opioid peptides' analgesic effects in tissues of the anterior segment of the eye. Dual enkephalinase inhibitor PL265 appears to be a promising topical treatment for safe and effective alleviation of ocular pain and inflammation. PMID- 30412057 TI - Simultaneous Bilateral Microtia Reconstruction Using Single-Expanded Postauricular Flap Without Skin Grafting. AB - BACKGROUND: Auricular reconstruction in patients with congenital microtia permits craniofacial balance and harmony, especially in patients with bilateral microtia. However, published techniques usually require skin grafting, which can lead to color mismatch and visible scarring. Some surgeons prefer to reconstruct the auricle of each side separately, which prolongs the complete cycle of surgery and increases suffering of the patient. In this study, we introduce a modified technique using single expanded flaps without skin grafting to achieve simultaneous bilateral auricular reconstruction. METHODS: Between January 2012 and January 2017, a total of 54 patients with bilateral microtia underwent auricular reconstruction with expanded single flaps. Simultaneous bilateral auricular reconstruction was accomplished through 3 surgical stages. In the first stage, bilateral postauricular skin was expanded using 2 kidney-shaped tissue expanders. In the second stage, bilateral rib cartilage was harvested using minimal incisions, allowing 2 modified 3-layer frameworks to be fabricated. Each framework was then inserted into the pocket through the same incision with subsequent closure using 2-layer suture. In the third stage, the reconstructed ears were further trimmed, if necessary, and the lobules and tragus reconstructed. All the patients were followed up for 6 to 24 months. RESULTS: During follow-up, patients were satisfied with surgical outcome in terms of size, shape, location, detailing, and symmetry of the bilateral ears in more than 50 cases. Only 4 demonstrated postoperative complications. No skin necrosis, exposure of cartilage, or infection was observed or postoperative chest deformities. CONCLUSIONS: Simultaneous bilateral auricular reconstruction using single expanded flaps combined with a modified 3-layer cartilage framework is an effective technique for patients with bilateral microtia. PMID- 30412058 TI - Combined administration of problem- and lecture-based learning teaching models in medical education in China: A meta-analysis of randomized controlled trials. AB - INTRODUCTION: The aim of this meta-analysis is to assess the effectiveness of the combined administration of problem-based learning (PBL) and lecture-based learning (LBL) teaching models in Chinese medical education. MATERIALS AND METHODS: We searched the following Chinese electronic databases: China National Knowledge Infrastructure, WanFang Data, China Science Periodical Database, and the Chinese BioMedical Literature Database. We also searched the following English electronic databases: PubMed, Embase, Cochrane Central Register of Controlled Trials, and Google Search Engine. We searched for published studies involving the combined administration of PBL+LBL teaching models in Chinese medical education. All randomized controlled trials were included. The focus of the meta-analysis was on the outcomes of knowledge scores, skill scores, medical writing scores, comprehensive ability scores and teaching satisfaction. A subgroup analysis was also performed. RESULTS: A total of 23 RCTs were included, with a total sample size of 2589 medical students. The PBL+LBL teaching model significantly increased knowledge scores (95% CI, 2.85-5.78; P < .00001), skill scores (95% CI, 0.51-3.71; P = .01), medical writing scores (95% CI, 1.04-4.04; P = .0009), comprehensive ability scores (95% CI, 2.04-8.71; P = .002) and teaching satisfaction (RR, 1.32; 95% CI, 1.10-1.59; P = .003) compared with the LBL teaching model alone. Additionally, a subgroup analysis showed significant differences in the effect of PBL+LBL on knowledge scores, medical writing scores, and comprehensive ability scores when comparing practical and theoretical courses. Another subgroup analysis that looked at the level of training showed that the PBL+LBL teaching model also significantly improved the knowledge scores of Freshman, Sophomore, Junior, Senior and Masters students. DISCUSSION AND CONCLUSIONS: Based on the current evidence, this meta-analysis showed that the PBL+LBL teaching model is an effective way to increase knowledge scores, skill scores, medical writing scores, and comprehensive ability scores and to improve teaching satisfaction. PMID- 30412059 TI - A case report of granulomatous polyangiitis complicated by tuberculous lymphadenitis. AB - RATIONAL: Granulomatous polyangiitis (GPA) is a type of vasculitis involving medium and small arteries, typically affecting the upper and lower respiratory tract with coexisting glomerulonephritis. GPA is also characterized by necrotizing granulomatous inflammation and the presence of antineutrophil cytoplasm antibodies (ANCA). So far, various infections have lead to elevation of titers of serum ANCA, making it difficult to diagnose. PATIENT CONCERNS: We report a 50-year-old woman who was diagnosed as tuberculous lymphadenitis. During the treatment by anti-tuberculosis (TB) drugs, rapidly progressive renal failure and pleurisy had appeared with elevated titer of PR3-ANCA. Renal biopsy revealed crescentic glomerulonephritis. DIAGNOSIS: Renal biopsy revealed crescentic glomerulonephritis and diagnosis of GPA was made. INTERVENTIONS: Steroid therapy had been started with continuation of anti-TB drugs. OUTCOMES: Renal dysfunction had gradually recovered and pleurisy had disappeared with decreasing titer of PR3 ANCA. LESSONS: This is the first report of GPA complicated by TB infection. When we encounter a case with rapidly progressive renal failure during the TB infection, complication of GPA should be suspected as 1 of the different diagnosis. PMID- 30412060 TI - Risk of sexually transmitted infections following depressive disorder: A nationwide population-based cohort study. AB - Depressive disorder is a severe mental disorder associated with functional and cognitive impairment. Numerous papers in the literature investigated associations between sexually transmitted infections (STIs) and psychiatric illnesses. However, the results of these studies are controversial.We explored the relationship between depressive disorder and the subsequent development of STIs including human immunodeficiency virus (HIV) infection, primary, secondary, and latent syphilis, genital warts, gonorrhea, chlamydial infection, and trichomoniasis.We identified patients who were diagnosed with the depressive disorder in the Taiwan National Health Insurance Research Database. A comparison cohort was constructed of patients without the depressive disorder who were matched according to age and sex. The occurrence of subsequent new-onset STIs was evaluated in both cohorts.The depression cohort consisted of 5959 patients, and the comparison cohort consisted of 23,836 matched control patients without depressive disorder. The incidence of subsequent STIs (hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.34-1.76) was higher among the depressed patients than among the patients in the comparison cohort. Furthermore, female gender compared to male (HR 1.58, 95% CI 1.24-2.01) and young age <40-year-old (HR 1.79, 95% CI 1.38-2.32) are both risk factors for acquisition of STIs in depression patient. For individual STI, the results indicated that the patients with depressive disorder exhibited a markedly higher risk for subsequent STIs including HIV infection, syphilis, genital warts, gonorrhea, chlamydial infection, and trichomoniasis.Depressive disorder might increase the risk of subsequent newly diagnosed STIs including HIV infection, syphilis, genital warts, gonorrhea, chlamydial infection, and trichomoniasis in Taiwan population. Clinicians should pay particular attention to STIs in depression patients. Depression patients, especially those with the history of high-risk sexual behaviors, should be routinely screened for STIs. PMID- 30412061 TI - Meditation-based clinical study to determine the correlation of quantitative electroencephalogram (qEEG) and 24-hour EEG activity. AB - BACKGROUND: The heart continuously transmits information to the cerebrum during each pulse, and influences information processing such as perception, cognition, and emotion, which are processed in the cerebrum. This is the basis for the theory of oriental medicine widely used in psychiatric medicine and clinical practice, so-called Simjushinji (heart and brain) theory, that the heart controls the mind. The present study aims to analyze the correlation between heart and brain function by 24-hour active electrocardiogram and quantitative electroencephalogram (EEG) measurement under meditation. METHODS: This randomized, controlled, assessor-blinded, 2-armed, parallel, multicenter clinical trial will analyze a total of 50 subjects, including 25 each for the test group and the active control group. Subjects will be randomly allocated to the test group (performing resource mindfulness) and the control group (performing stress mindfulness) in a 1:1 ratio. The clinical trial consists of 3 stages. The first and third stages are stable states. The second stage is divided into the test and active comparator groups. Quantitative EEG (qEEG) measurements at stages 1 and 3 will be recorded for 10 minutes; measurements at stage 2 will be recorded for 20 minutes with the eyes closed. The 24-hour Holter Monitoring and heart rate variability will be evaluated at each stage. Before the beginning of stage 3, subjects will complete the questionnaires. The primary outcome will be analyzed by independent t tests of both groups. DISCUSSION: Scientific studies based on clinical epistemology are expected to serve as a basis for sustainable medical services in the field of psychiatric medicine in Korea. HRV, blood pressure index, and biometric index in qEEG, as determined by 24-hour Holter monitoring, will complement quantitative biomarkers and be useful in various fields. PMID- 30412062 TI - The association of high D-dimer level with high risk of ischemic stroke in nonvalvular atrial fibrillation patients: A retrospective study. AB - This study aimed to explore the relationship of D-dimer level with the risk stratification of ischemic stroke, and determine whether high D-dimer levels could be used as a risk factor of ischemic stroke in patients with nonvalvular atrial fibrillation (NVAF).This single-center, retrospective study recruited NVAF patients who did not undergo anticoagulant therapy. These patients were divided into 2 groups: ischemic stroke group and no-stroke group. The medical records of each patient were reviewed, demographic and clinical analyses were performed, and the laboratory results were summarized.A total of 323 eligible in-patients with NVAF, who did not receive anticoagulant therapy, were recruited (206 male and 117 female patients, median age was 75.18 +/- 10.46 years old). Among these patients, 78 patients suffered from acute ischemic stroke. D-dimer level increased with age, and was positively correlated with the risk stratification of stroke, CHADS2 score (rs = 0.441, P < .001), and CHA2DS2-VASC score (rs = 0.412, P < .001), even after adjustment for age and gender (rs = 0.422, P < .001). The difference in baseline D-dimer level between these 2 groups was not statistically significant (0.70 vs 0.66 mg/L, P = .330), but this significantly increased when patients suffered from stroke (1.34 vs 0.70 mg/L, P < .001). The D-dimer level after stroke (>=6 months) was also higher than the baseline (1.16 vs 0.68 mg/L, P = .514) in 6 months, and this level nearly returned to baseline level after one year (0.69 vs 0.68 mg/L, P = .158). However, logistic regression revealed that only the D-dimer level at stroke onset and OMI were independent risk factors for ischemic stroke (P < .001), while the increase from baseline D-dimer levels was not an independent risk factor (P = .125).D-dimer level is positively correlated with the risk stratification of ischemic stroke, but has no predictive value on the occurrence of ischemic stroke in patients with NVAF. PMID- 30412064 TI - CARE-Placental site trophoblastic tumor presenting with thrombotic microangiopathy: A case report. AB - RATIONALE: Placental site trophoblastic tumor (PSTT) is a rare form of gestational trophoblastic neoplasm (GTN). PATIENT CONCERNS: A 28-year-old Chinese female with initial presentation of thrombotic microangiopathy (TMA) with symptoms of edema of the lower extremities and eyelid, thrombocytopenia and anemia. DIAGNOSES: The primary diagnosis was chronic glomerulonephritis according to the related laboratory tests and clinical symptoms. INTERVENTIONS: A total abdominal hysterectomy with a bilateral salpingectomy was performed. OUTCOMES: The PSTT patient was cured, which contributed to the symptom relief of TMA. LESSONS: This case report aims to elucidate the relationship between TMA and PSTT, so as to achieve timely diagnosis and treatment and reduce misdiagnosis. PMID- 30412063 TI - Unprotected versus protected high-risk percutaneous coronary intervention with the Impella 2.5 in patients with multivessel disease and severely reduced left ventricular function. AB - Selecting a revascularization strategy in patients with multivessel disease (MVD) and severely reduced left ventricular ejection fraction (LVEF) remains a challenge. PCI with Impella 2.5 may facilitate high-risk PCI, however long-term results comparing unprotected versus protected PCI are currently unknown. We sought to evaluate the outcome of patients undergoing protected compared to unprotected percutaneous coronary intervention (PCI) in the setting of MVD and severely reduced LVEF.We included patients with MVD and severely reduced LVEF (<=35%) in this retrospective, single-centre study. Patients that underwent unprotected PCI before the start of a dedicated protected PCI program with Impella 2.5 were compared to patients that were treated with protected PCI after the start of the program. The primary endpoint was defined as major adverse cardiac and cerebrovascular events (MACCE) during a 1-year follow-up. The secondary endpoints consisted of in-hospital MACCE and adverse events.A total of 61 patients (mean age 70.7 +/- 10.9 years, 83.6% male) were included in our study, of which 28 (45.9%) underwent protected PCI. The primary endpoint was reached by 26.7% and did not differ between groups (P = .90). In-hospital MACCE (P = 1.00) and in-hospital adverse events (P = .12) also demonstrated no significant differences. Multivariate logistic regression identified procedural success defined as complete revascularization and absence of in-hospital major clinical complications as protective parameter for MACCE (OR 0.17, 95% CI 0.04 0.70, P = .02).Patients with MVD and severely depressed LVEF undergoing protected PCI with Impella 2.5 demonstrate similar in-hospital and one-year outcomes compared to unprotected PCI. PMID- 30412065 TI - On-demand versus half-dose continuous therapy with esomeprazole for maintenance treatment of gastroesophageal reflux disease: A randomized comparative study. AB - BACKGROUND AND AIMS: No consensus has been established regarding optimal long term maintenance therapy in symptomatic gastroesophageal reflux disease (GERD). The aim of this study was to compare the efficacies of on-demand and continuous therapy with esomeprazole as maintenance treatments for GERD. METHODS: Patients with upper gastrointestinal (GI) endoscopy-proven GERD who received initial proton pump inhibitor (PPI) therapy for 8 weeks were randomized to an on-demand group (esomeprazole 40 mg) or a continuous group (esomeprazole 20 mg). Intensities and frequencies of heartburn and acid regurgitation were assessed using a 6-point Likert scale (0 = no symptoms; 5 = very severe symptoms) and a 6 point frequency scale (0 = none; 5 = symptoms for > 5 days per week) at baseline (start of maintenance treatment) and after 12 weeks of treatment. Alleviation of symptoms was quantified using percentages of patients with a Likert scale or frequency scale of 0 or 1. RESULTS: Of the 88 patients enrolled, 8 patients were excluded due to follow-up loss in early period of this study, and finally, 39 in the on-demand group and 41 in the continuous group were analyzed. No significant intergroup difference was found between Likert scale or frequency scale of heartburn or regurgitation at baseline. Percentages of symptom alleviations in the on-demand and continuous groups for intensity of heartburn were 56.4%/48.8% at baseline (P = .523) and 82.1%/87.8% at 12 weeks (P = .471), for frequency of heartburn were 61.5%/46.3% at baseline (P = .173) and 76.9%/87.8% at 12 weeks (P = .200), for intensity of regurgitation was 53.8%/43.9% at baseline (P = .374) and 82.1%/87.8% at 12 weeks (P = .471), and for frequency of regurgitation was 61.5%/56.1% at the baseline (P = .621) and 82.1%/82.9% at 12 weeks (P = .918), respectively. Furthermore, no significant intergroup difference was found for convenience of medication or subjective satisfaction. CONCLUSIONS: Intensities and frequencies of heartburn and regurgitation responded well to maintenance treatment in patients in the on-demand and continuous groups. On-demand therapy with esomeprazole 40 mg appears to be sufficient for maintenance treatment in GERD patients. PMID- 30412066 TI - Diagnostic challenges in differentiating intramural gastric abscess from gastric cancer: Two case reports. AB - RATIONALE: Intramural gastric abscess is a rare clinical condition. It is frequently neglected because of the absence of specific clinical symptoms and misdiagnosed due to the difficulty in differentiating a benign lesion from a malignant one on the gastric wall. Several imaging techniques are helpful for identifying an intramural gastric abscess. Nevertheless, a definite diagnosis is still challenging, and unnecessary surgery is sometimes performed. Therefore, more information regarding case experiences should be shared to help correctly diagnose intramural gastric abscesses. PATIENT CONCERNS: Two patients, a 47-year old woman and a 31-year-old man, were hospitalized for abdominal pain. DIAGNOSIS AND INTERVENTIONS: In addition to routine blood tests, either two or three imaging examinations, including esophagogastroduodenoscopy (EGD), computed tomography (CT), and endoscopic ultrasonography (EUS), were performed for these patients. The first patient was diagnosed with gastric cancer metastasized to the gastrocolic ligament, and the other was suspected to have a gastric wall abscess secondary to cancer of unknown origin. Both patients underwent surgery. OURCOMES: Surgery revealed a gastric wall abscess involving the colon in the first patient. She recovered after using oral antibiotics for 1 week, and she showed no discomfort or abnormalities during follow-up examinations. The second patient was diagnosed with gastric wall abscess derived from metastasized gastric cancer with a primary tumor located at the splenic flexure of the colon. He was discharged because of intolerance to chemotherapy and died before follow-up. LESSONS: EGD, CT, and EUS/fine-needle aspiration (EUS/FNA) are extremely valuable for differentiating an intramural gastric abscess from gastric cancer, and misdiagnoses can occur if any of these assessments is ignored. Hence, we recommend performing EGD, CT, and EUS/FNA as part of the routine examination when either of these two diseases is suspected clinically. PMID- 30412067 TI - Bronchobiliary fistula following radiofrequency ablation for liver metastases from breast cancer: A case report and literature review. AB - RATIONALE: Bronchobiliary fistula (BBF) is a rare clinical condition which is characterized by a channel between biliary tract and bronchial tree. BBF can present with fever, dyspnea, and cough. However, it can be easily misdiagnosed as biliary vomiting, dyspnea, or even severe pneumonia. PATIENT CONCERNS: A 53-year old woman was diagnosed with breast cancer in April 2011 and underwent radical mastectomy and lymph node dissection, chemotherapy, and radiotherapy. Unfortunately, the patient suffered from bone metastasis during the 1st year and liver metastasis during the 2nd year after radical mastectomy. In 2013, the patient underwent transcatheter arterial chemoembolization therapy twice for liver metastasis. The patient was then treated with radiofrequency ablation (RFA) in 2016. Unfortunately, the patient developed a cough with bitter-tasting yellow sputum and chest tightness 2 weeks after the RFA treatment. Approximately 6 months later, the patient still complained of a cough with yellow sputum and persistent chest tightness. The patient was then admitted to our department. DIAGNOSES: The presence of bile in the sputum supported a diagnosis of BBF. Bronchoscopy was performed, and the presence of bile in the lavage fluid confirmed the diagnosis of BBF. INTERVENTIONS: The patient was treated with antibiotics including sulbactam, cefoperazone, levofloxacin and meropenem, was well as hepatoprotectants, nutritional support and other supportive treatments in our department. OUTCOMES: The patient died because of liver failure. LESSONS: This case demonstrates that we should consider the possibility of BBF when patients experience a recurrent cough with discolored sputum after RFA. In particular, a diagnosis of BBF should be considered in patients who do not respond to antibiotic treatment. PMID- 30412068 TI - Pharmacologic prevention of postoperative delirium after on-pump cardiac surgery: A meta-analysis of randomized trials. AB - BACKGROUND: Postoperative delirium is a prevalent and disabling mental disorder in patients undergoing on-pump cardiac surgery. There is some evidence that the use of pharmacological interventions may reduce the risk of developing of postoperative delirium. Therefore, the aim of this meta-analysis was to determine the effect of pharmacologic agents for the prevention postoperative delirium after cardiac surgery. METHODS: Randomized controlled trials (RCTs) were identified through a systematic literature search of electronic databases and article references up to October 2016. End points included incidence of postoperative delirium, severity of postoperative delirium, cognitive disturbances of postoperative delirium, duration of postoperative delirium, length of stay in intensive care unit (ICU) and hospital, and short-term mortality. RESULTS: A total of 14 RCTs with an aggregate of 14,139 patients were included. The results of the present meta-analysis show that pharmacologic agents significantly decrease postoperative delirium [relative risk (RR), 0.83; 95% confidence interval (95% CI), 0.75-0.91, P < .00001] and duration of postoperative delirium (RR = -0.37, 95% CI = -0.47 to -0.27, P < .00001) after on pump cardiac surgery. In addition, subgroup analysis shows that dexamethasone and dexamethasone were associated with a trend toward a reduction in postoperative delirium (RR, 0.45; 95% CI, 0.30-0.66, P < .0001; RR, 0.80; 95% CI, 0.68-0.93, P = .003, respectively). However, our results fail to support the assumption that pharmacologic prophylaxis is associated with a positively reduction in short-term mortality, length of ICU, or hospital stay. CONCLUSION: This meta-analysis suggests that the perioperative use of pharmacologic agents can prevent postoperative delirium development in patients undergoing cardiac surgery. However, there remain important gaps in the evidence base on a few small studies with multiple limitations. Further large-scale, high-quality RCTs are needed in this area. PMID- 30412069 TI - Preliminary study of urinary arsenic concentration and arsenic methylation capacity effects on neurodevelopment in very low birth weight preterm children under 24 months of corrected age. AB - The neurological prognoses of very low birth weight preterm (VLBWP) children during the first 2 years of life will influence their neurodevelopment during subsequent childhood years and adolescence. The objective of this study was to systemic investigate relationships of urinary arsenic (As) concentrations, the As methylation capability, and toenail As concentrations on cognitive, language, and motor development in VLBWP children under 24 months of corrected age.Participants (n = 60) in our study were recruited from October 2010 to April 2013. Urine and toenail samples were collected for evaluation to assess As exposure. The Bayley scales of infant development III were used to evaluate neurodevelopment at 2 years of corrected age. Concentrations of As species in urine and the As concentration in toenails were, respectively, analyzed using HPLC-HG-AAS and ICP MS.The mean concentration of total As was 28.6 MUg/g creatinine, and inorganic As was 1.01 MUg/L in urine. The urine contained an average of 3% inorganic As, 2% monomethylarsonic acid, and 95% dimethylarsinic acid (DMA). The mean concentration of As in toenails was 225 ng/g. Children with a longer gestational age (>=28 weeks) and higher DMA % levels appeared to have the highest unadjusted cognitive and fine motor scores.Our study results suggest that gestational age is associated with neurodevelopment in VLBWP children. We recommend that further study simultaneously analyze multiple environmental contaminants that may have adverse effects on neurodevelopment, use biomarkers for the mother-child pair, and determine whether prenatal or postnatal As exposure has a greater influence on the neurological development of VLBWP children. PMID- 30412070 TI - Using an informatics education strategy to resolve the dilemma of teaching transplantation in medical institutions: Multidisciplinary medical team perspectives. AB - In Taiwan, the current survival rate 1 year after transplantation exceeds 80%. However, the number of organ/tissue donors per year in Taiwan is extremely low, resulting in increased mortality. This is also true in Europe and in the United States. Recently, data from the Taiwan Organ Registry and Sharing Center showed that, although fundraising for organs/tissues slightly increased, the number of donors did not exhibit a corresponding growth trend. Identifying appropriate donors and the provision of good quality transplantation care by medical team members are current challenges. Hence, the application of information technology to in-service education for organ transplantation professionals has been suggested.This was a qualitative study that employed qualitative content analysis with purposive and snowball sampling. The study participants (n = 8, mean age 39.88 +/- 3.06 years) included medical staff involved in tissue/organ transplantation from 4 leading medical centers and 3 regional teaching hospitals, and those who participated in the informatics education system.The interviewees from multidisciplinary medical teams showed the status of and dilemma in organ fundraising/donation/transplantation, noting 6 core themes. Regarding relevant education and training, 4 core themes were identified.Current educational courses for organ fundraising/donation/transplantation are inadequate and seem to provide insufficient information to multidisciplinary medical teams. Hence, it is necessary to develop a theoretical construct to create a complete curriculum framework and to establish complete fit-in professional and ethical organ transplantation learning programs based on informatics technology to increase the interdisciplinary exchange of experience. PMID- 30412071 TI - Association of lymphocyte to monocyte ratio with severity of coronary artery disease. AB - The aim of this study was to investigate the relationship between lymphocyte to monocyte ratio (LMR) and the severity of coronary artery disease (CAD) by using Gensini score.A total of 199 patients, who had undergone coronary angiography, were included in the study and retrospectively analyzed. Among them, 49 patients who had normal coronary arteries were selected as the control group. Patients with CAD were divided into 2 groups, those with low Gensini score (<=40) and those with high Gensini score (>=40).Our results showed that LMR in the severe atherosclerosis group was significantly lower than those of the mild atherosclerosis group and the control group. There was a closely significant correlation between the Gensini score and LMR (r = -0.362, P < .001). Furthermore, multivariate logistic regression analysis demonstrated that LMR (odds ratio, 0.715; 95% confidence interval [CI], 0.551-0.927; P = .012) was independent predictors of severe atherosclerosis. Using an optimal LMR cut-off value of 5.06, LMR predicted severe atherosclerosis with a sensitivity of 57.1% and specificity of 69.7% (area under curve = 0.634; 95% CI, 0.545-0.724; P = .005). Then patients with CAD group was divided into 2 groups according to the LMR value of 5.06. Patients with LMR <= 5.06 had worse prognosis, with a higher rate of cardiovascular events during up to 1 year follow-up.Our study demonstrated that LMR was independently and positively associated with the severity of coronary atherosclerosis, providing a new insight in the application of inflammation index evaluating the severity of CAD. And LMR may be a useful predictor of future cardiovascular events in patients with CAD. PMID- 30412072 TI - Comparative effectiveness of extracorporeal shock wave, ultrasound, low-level laser therapy, noninvasive interactive neurostimulation, and pulsed radiofrequency treatment for treating plantar fasciitis: A systematic review and network meta-analysis. AB - BACKGROUND: Plantar fasciitis is one of the most common causes of adult heel pain. The aim of this study is to comprehensively compare the effectiveness of various therapies for plantar fasciitis using network meta-analysis. METHODS: Studies were comprehensively searched on Embase, MEDLINE via PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and the Physiotherapy Evidence Database (PEDro) up to December 4, 2017. Randomized controlled trials that used extracorporeal shock wave therapy, ultrasound, ultrasound-guided pulsed radiofrequency treatment (UG-PRF), intracorporeal pneumatic shock therapy (IPST), low-level laser therapy (LLLT), and noninvasive interactive neurostimulation (NIN) for the treatment of plantar fasciitis were included. The primary outcome is change in pain relief. Risk of bias was assessed using the Cochrane risk of bias tool. Quality assessment was performed using the GRADE system. RESULTS: Nineteen trials with 1676 patients with plantar fasciitis plantar fasciitis were included. In the pair-wise meta-analysis, radial extracorporeal shock wave therapy (RSW), LLLT, and IPST showed a significant pooled reduction in the visual analogue scale (VAS) compared with placebo at 0 to 6 weeks [mean difference (MD) = 6.60, 95% confidence interval (CI): (6.04, -7.16); MD = 2.34, 95% CI: (1.60, 3.08); MD = 2.24, 95% CI: (1.44, 3.04), respectively]. Compared with placebo, UG PRF [MD = 2.31, 95% CI: (1.26, 3.36)] and high-intensity focused extracorporeal shock wave (H-FSW) [MD = 0.82, 95% CI: (0.20, 1.45)] showed superior pain relieving effects at 2 to 4 months; UG-PRF [MD = 1.11, 95% CI: (0.07, 2.15)] and IPST [MD = 4.92, 95% CI: (4.11, 5.73)] showed superior effects at 6 to 12 months. In the network meta-analysis, only RSW induced significant pain reduction compared with placebo at 0 to 6 weeks [MD = 3.67, 95% CI: (0.31, 6.9)]. No significant differences were found for the 2 to 4-month and 6 to 12-month periods because of the wide 95% CIs. CONCLUSIONS: We recommend treating plantar fasciitis with RSW. The commonly used ultrasound and focused extracorporeal shock wave (FSW) therapies can be considered as alternative treatment candidates. IPST, NIN, and LLLT may potentially be better alternatives, although their superiority should be confirmed by additional comprehensive evidence.PROSPERO registration number: PROSPERO (CRD42015017353). PMID- 30412073 TI - Phlebosclerotic colitis: Our clinical experience of 25 patients in China. AB - The aim of the current study was to enhance the awareness of phlebosclerotic colitis (PC) through our clinical experience.A retrospective review of 25 patients who were diagnosed as PC in our 2 affiliated hospitals from January 2013 to October 2017 was conducted.The patients were found at a mean age of 63.5 years, range 47 to 87years. The majority of patients were male (23 cases). Only 4 patients (16%, 4/25) had the history about long-term use of Chinese herbs and medical liquor. The most common symptoms were abdominal pain (40%) and intestinal obstruction (16%), followed by diarrhea (12%), and gastrointestinal bleeding (12%), etc. Three cases (12%) had no symptoms. The varying degrees of calcifications along the colon and mesenteric venous were found in all of their computed tomography (CT) images. The lesions mainly located in transverse and ascending colon (60%, 15/25). The terminal ileum, the whole colon and rectum involvement were also been found. Fourteen patients had the examination of colonoscopy which all presented characteristic dark purple-colored endoscopic findings. Conservative treatment with close follow-up was preferred in our group. Three cases had the surgery of colectomy due to the repeatedly intestinal obstruction, perforation.The PC was a very rare but characteristic entity with unclear etiopathogenesis. Examination of abdomen CT and colonoscopy could help you to make clinical diagnosis. PMID- 30412074 TI - Cutaneous comorbidities in patients with multiple myeloma: A 10-year retrospective cohort study from a Korean population. AB - Multiple myeloma (MM) is a common hematologic malignancy characterized by the presence of the clonal proliferation of tumor cells. Studies on cutaneous comorbidities in Asian patients with MM have yet to be conducted.This study aimed to analyze the prevalences, characteristics, overall survivals, and risk factors of various cutaneous comorbidities in patients with MM.A retrospective cohort study using medical records from January 1, 2008, to December 31, 2017, in patients with MM was conducted.Of 1438 patients with MM, 354 patients (24.61%) had one or more cutaneous comorbidities. Among them, herpes zoster infection was found to be the most common cutaneous comorbidity. The development of herpes zoster was found to be a possible candidate for good prognostic factor for overall survival [hazard ratio, 0.62; 95% confidence interval (95% CI), 0.44 0.86], while the occurrence of cutaneous malignant tumor was found to be a possible candidate for poor prognostic factor for overall survival (hazard ratio, 3.13; 95% CI, 1.76-5.56).The development of some cutaneous comorbidities heralds the prognostic importance in patients with MM. A better understanding of the prevalences, clinical characteristics, and risk factors of various cutaneous comorbidities in patients with MM may help clinicians identify the clinical course and prognosis of the disease. PMID- 30412075 TI - Correlation of tumor uptake on breast-specific gamma imaging and fluorodeoxyglucose PET/CT with molecular subtypes of breast cancer. AB - Mechanisms of technetium-99m sesta-methoxyisobutylisonitrile (sestamibi) and F fluorodeoxyglucose (FDG) uptake by tumor are different. The purpose of this study was to investigate the association between the tumor uptake of these 2 tracers in invasive ductal carcinoma and to examine thecorrelation of uptake of each tracer with prognostic factors and tumor molecular subtypes.A total of 96 patients with invasive ductal carcinoma who underwent preoperative breast-specific gamma imaging and FDG positron-emission tomography/computed tomography were retrospectively enrolled. Tumor-to-background ratio (TBR) of sestamibi and maximum standardized uptake value (SUVmax) of FDG were correlated with each other. Each of them was then compared with prognostic factors and molecular subtypes.In all tumors, there was a moderate positive correlation between TBR and SUVmax (r = 0.520, P < .001). Both TBR and SUVmax were significantly correlated with tumor size, incidence of axillary lymph node metastasis, histologic grade, estrogen receptor, progesterone receptor status, and Ki-67.There is a moderate degree of association between TBR of sestamibi and SUVmax of FDG in the invasive breast cancer. Two imaging indexes showed the similar tendency related with prognostic factors and molecular subtypes. While both TBR and SUVmax were significantly different between luminal A and nonluminal A tumors, neither of them had high enough sensitivity or specificity to obviate pathologic and molecular diagnosis. PMID- 30412076 TI - Efficacy and safety of empagliflozin for type 2 diabetes mellitus: Meta-analysis of randomized controlled trials. AB - BACKGROUND: This study was designed to evaluate the efficiency and tolerability of empagliflozin (EMPA) as monotherapy or add-on to existing therapy in patients with type 2 diabetes mellitus (T2DM). METHODS: Randomized controlled trials (RCTs) comparing efficacy and safety of EMPA vs placebo or EMPA plus other antidiabetes drugs vs placebo plus other oral antidiabetes drugs (OADs) in T2DM were recruited from electronic database Pubmed, Web of Knowledge, and Cochrane Central Register of Controlled Trials (CENTRAL), supplemented by a hand search of the reference lists of selected articles. Main effect sizes were change from baseline on glycemia control, body weight, blood pressure, and complications (i.e., incidence of urinary and genital tract infections, and morbidity of hypoglycemia and hyperglycemia). Random-effects model was used to account for clinical or methodologic heterogeneity across studies. RESULTS: Fifteen RCTs with a total number of 7891 individuals (5374 in EMPA group and 2517 in control group) were suitable for this meta-analysis. The results demonstrated that significant improvements in glycemia control, body weight, and blood pressure were associated with EMPA application (i.e., monotherapy and add-on therapy) in patient with T2DM when compared with placebo. Meanwhile, EMPA 10 and 20 mg improved glycemia, body weight, and blood pressure control for patients with T2DM. There was no significant difference in incidence of hypoglycemia and urinary tract infections across EMPA and placebo group. Significant reduced risk of hyperglycemia was revealed in EMPA group vs placebo (risk ratio: 0.34, 95%confidence interval: 0.23 0.49, P < .00001), except in patients on background insulin therapy. However, increased risk of genital infection was noted across EMPA vs placebo (risk ratio: 2.59, 95% confidence interval: 1.80-3.71, P < .00001). CONCLUSION: Our evidence supports the application of EMPA in treatment of patients with T2DM who are obesity or at risk of weight gain. PMID- 30412077 TI - The effect of dexmedetomidine on the perioperative hemodynamics and postoperative cognitive function of elderly patients with hypertension: Study protocol for a randomized controlled trial. AB - INTRODUCTION: Cognitive dysfunction after surgery, a common clinical manifestation of postoperative psychonosema. It usually occurs after heart surgery, hip replacement, mandibular fractures, and other major operations. Dexmedetomidine can exert sedative, analgesic, anxiolytic effect, inhibits the sympathetic activity, maintains hemodynamic balance, helps reduce the amount of anesthetic agents, and relatively slightly depresses respiration. Preoperative administration of dexmedetomidine for sedation has been reported to reduce the incidence of acute postoperative delirium. But currently there is no study on the effect of dexmedetomidine on the postoperative cognitive function of elderly patients with essential hypertension. METHODS/DESIGN: This study is a prospective, single-center, double-blind controlled clinical trial. Elderly patients aged between 60 and 80 years old, diagnosed with primary hypertension for 1 year or longer will be included, and randomized into 2 groups. Patients in observational group will be given a loading dose of dexmedetomidine at 0.8 MUg/kg, pumped for over 10 minutes. Although patients in control group will be pumped of the same volume of normal saline within 10 minutes, before the induction of anesthesia. Minimental state examination and levels of interleukin 6, tumor necrosis factor alpha, and C-reactive protein will be set as primary endpoints. Baseline characteristics of patients will be summarized by groups and compared using Chi-square or Fisher exact tests for categorical variables and 2 sample t tests or Wilcoxon rank sum test for the continuous variables. Repeated measurement analysis of covariance model will also be used for the comparison of endpoints between 2 groups. CONCLUSION: The present study is designed to investigate the effect of the application of dexmedetomidine on postoperative myocardial injury and postoperative cognitive dysfunction, also to explore the association between inflammatory factors and postoperative cognitive function. With this study, we are expecting to find out an appropriate anesthesia method for elderly people with hypertension to alleviate the postoperative adverse effects caused by medical treatments. TRIALS REGISTRATION: This study was registered on Chinese Clinical Trial Registry (http://www.chictr.org.cn/) with the ID ChiCTR-IPR-16009156. PMID- 30412078 TI - Prognostic significance of programmed cell death ligand 1 expression in patients with ovarian carcinoma: A systematic review and meta-analysis. AB - BACKGROUND: Programmed cell death ligand 1 (PD-L1) overexpression has been reported to be associated with poor prognosis in several human cancers. However, studies on the prognostic value of PD-L1 expression in ovarian carcinoma (OC) remain controversial. This meta-analysis aimed to evaluate comprehensively the prognostic value of PD-L1 in OC. METHODS: Electronic databases, including PubMed, EMBASE, and the Cochrane Library, were searched up until March 28, 2018. Hazard ratio (HR), along with 95% confidence interval (CI), was used to analyze the included outcomes. RESULTS: A total of 10 studies with 1179 OC patients were included in this meta-analysis. There was no significant correlation between PD L1 expression and overall survival (OS) (HR 1.23, 95% CI 0.85-1.79) and progression-free survival (PFS) (HR 0.88, 95% CI 0.52-1.47) of OC patients. However, the subgroup analysis suggested that positive PD-L1 expression was significantly associated with poor OS (HR 1.66, 95% CI 1.08-2.55) and PFS (HR 2.17, 95% CI 1.31-3.61) among OC patients from Asian countries. Increased PD-L1 expression was also a favorable factor for OS (HR 0.73, 95% CI 0.53-0.99) and PFS (HR 0.58, 95% CI 0.45-0.75) in OC patients from non-Asian regions. No evidence of publication bias was detected by the Egger linear regression test and Begg funnel plot. Sensitivity analyses suggested that the results of this meta-analysis were robust. CONCLUSIONS: The results indicated that PD-L1 expression may be a negative predictor for prognosis of OC patients from Asian countries, and a good predictor for favorable prognosis of OC patients from non-Asian countries. PD-L1 expression has potential to be a prognostic biomarker to guide clinicians for the selection of individuals who may get clinical benefit from anti-PD-1/PD-L1 immunotherapy. Prospective clinical studies are needed to support these findings. PMID- 30412079 TI - Prognostic value of 18F-fluorodeoxyglucose bone marrow uptake in patients with solid tumors: A meta-analysis. AB - BACKGROUND: Several studies have reported the prognostic value of F fluorodeoxyglucose (F-FDG) bone marrow uptake (BMU) measured by F-FDG positron emission tomography (F-FDG PET) in various cancers. We performed a meta-analysis to evaluate the prognostic value of F-FDG BMU in patients with solid tumors. METHODS: Systematic searches of MEDLINE and Embase databases were performed using the keywords "F-FDG," "bone marrow," and "prognosis." All published human studies of the prognostic value of F-FDG BMU in patients with solid tumors were searched. The primary outcome was event-free survival (EFS), and the secondary endpoint was overall survival (OS); both of these were extracted directly from each study. The effects of F-FDG BMU on survival were assessed by using hazard ratios (HRs). RESULTS: Ten studies with 1197 patients (8 studies reporting EFS in 1096 patients and 7 studies reporting OS in 836 patients) were included. In the EFS analysis, the combined HR was 1.75 (95% confidence interval [CI]: 1.45-2.11, P < .00001) in the random effects model (I = 51%, P = .05). The combined HR of OS was 1.40 (95% CI: 1.13-1.73, P = .002) in the random effects model (I = 52%, P = .05). CONCLUSION: This meta-analysis has demonstrated that patients with a low level of F-FDG BMU have better EFS and OS than those with a high level of F-FDG BMU. Based on our results, we suggest that F-FDG BMU could be used as a biomarker for stratifying the risk of tumor progression in patients with solid tumors. PMID- 30412080 TI - A special superior cortex compressive fracture of femoral neck: Two case reports. AB - RATIONALE: Garden type I femoral neck fractures are incomplete stable fractures with impaction in valgus fractures that the question of whether there exists Garden type I femoral neck fracture is currently uncertain. There is still disagreement on the existence of the Garden type I fractures. PATIENT CONCERNS: Herein we report 2 cases with the Garden type I femoral neck fractures. Both of them had a history of simple fall. DIAGNOSES: The X-ray showed incomplete fractures of the femoral neck and the Garden classification is type I. Further computed tomography and magnetic resonance imaging were used to confirm the diagnosis of this type fracture, which showed that the superior cortex of femoral neck was discontinuous and the inferior cortex remains intact. INTERVENTIONS: The conservative treatment schedule including immobilization of the affected lower limb, strict bed rest, bed-to-wheelchair transfer training, and half-to-full weight bearing mobilization were chosen to treat the patients. OUTCOMES: Both of them achieved fracture union with conservative treatment at 3-month follow-up. No secondary displacement, signal of osteonecrosis of the femoral head or other complications occurred during 24-month follow-up in 2 cases. LESSONS: Although the Garden type I femoral neck fractures are rare, our report is in line with the real existence of it. PMID- 30412081 TI - Remarkable improvement in a very severe chronic obstructive pulmonary disorder patient after use of noninvasive intermittent positive pressure ventilator: A case report. AB - RATIONAL: Chronic obstructive pulmonary disease (COPD) impairs lung function and induces systemic effects, resulting in impaired quality of life. Skeletal muscle dysfunction-characteristic of advanced COPD patients-limits a patient's ability to perform activities of daily living (ADL). In addition, dysphagia is commonly observed in COPD patients. PATIENT CONCERN: This case report documents a 42-year old man with very severe COPD. He experienced aggravation of the symptoms during standard medical treatment and his ability to perform the ADL was significantly impaired. Furthermore, his dysphagia worsened despite oromotor training. DIAGNOSIS: He was diagnosed as very severe COPD have a problem with swallowing and respiratory function. INTERVENTION: Upon NIPPV treatment, the patient's ability to perform the ADL, as well as his dysphagia, showed improvement. OUTCOMES: Thus, we report the remarkable improvement of physical function, as well as dysphagia, in a very severe COPD patient after NIPPV treatment. LESSONS: NIPPV may be useful as a treatment option for such patients. PMID- 30412082 TI - The association between TNF-alpha 238A/G and 308A/G polymorphisms and juvenile idiopathic arthritis: An updated PRISMA-compliant meta-analysis. AB - OBJECTIVE: A previous meta-analysis concluded that TNF-alpha 238A/G and TNF-alpha 308A/G polymorphisms were not associated with the risk of juvenile idiopathic arthritis (JIA) in the overall population or Caucasian subjects. With the publication of a fair number of studies on the association between TNF-alpha polymorphisms and JIA in recent years, we conducted this updated meta-analysis to make a more accurate evaluation of such relationship. METHODS: We adopted PubMed, EMBASE, ISI Web of Science and CNKI to identify observational studies that addressed the association between TNF-alpha polymorphisms and risk for JIA. The allelic effect of variant A for the risk of JIA was expressed as odds ratio (OR) along with the associated 95% confidence interval (95% CI). Meta-analyses were performed by pooling ORs and 95%CI from included studies using RevMan 5.3 software. The stratified-analysis based on ethnicity was performed to confirm the ethnicity-dependent effect on the relationship. RESULTS: A total of 15 case control studies including 2845 patients in JIA groups and 4771 patients in control groups were included in our study. The findings indicated a statistically significant association between the A allele of the TNF-alpha 238A/G polymorphism and the decreased JIA risk in Caucasians (P = .0002). The study in Iranian showed similar results (P = .0002) whereas the studies in other ethnicities failed to replicate this finding: Han (P = .29), Mexican (P = .64) and Turkish population (P = .32). TNF-alpha 308A/G was not statistically associated with JIA in overall subjects or Caucasians. CONCLUSION: Our study confirmed the protective role of the A allele in TNF-alpha 238A/G but not TNF-alpha 308A/G against the occurrence of JIA in the Caucasian population. To exactly validate the correlation between TNF-alpha polymorphisms and JIA in other ethnic backgrounds, additional studies are required. PMID- 30412083 TI - The genetic association between apolipoprotein E gene polymorphism and Parkinson disease: A meta-Analysis of 47 studies. AB - OBJECTIVE: Although the relationship between apolipoprotein E (ApoE) gene polymorphisms and the risk of Parkinson disease (PD) has been established, the results were inconsistent and inconclusive. METHODS: A comprehensive search examining the association between APOE polymorphisms and PD through PubMed, Embase, Chinese National Knowledge Infrastructure (CNKI), and Cochrane Library databases was performed without published year limited. RESULTS: A total of 47 studies with 7533 cases and 14442 controls were included in present study. The results showed statistically significant association between risk factor ApoE epsilon4 allele and PD in Asian population (P = .003, odds ratio, OR [95% confidence interval, CI] = 1.43 [1.13,1.80]). Genotype epsilon2epsilon4 have significantly associated with PD in Asian population (P = .004, OR [95% CI] = 4.43 [1.62,12.10]). Genotype epsilon3epsilon4 was significantly associated with PD in Latin-American population (P = .01, OR [95% CI] = 1.44 [1.08,1.91]). In addition, the frequency of the genotype epsilon3epsilon4 is lower in PD group than that in the control group in Caucasian population, and the difference of genotype epsilon3epsilon4 is also statistically significant (P = .006, OR [95% CI] = 0.86 [0.77,0.96]). Although significant heterogeneity was observed among all studies, the results were shown to be stabilized by sensitive analysis. No publish bias was observed. CONCLUSIONS: This meta-analysis suggests that the APOE epsilon4, but no epsilon2, might be a risk factor for PD in Asian population. Furthermore, the genotype epsilon2epsilon4 may be a susceptible factor for PD in Asian population, and the genotype epsilon3epsilon4 may be a susceptible factor for PD in both Caucasian and Latin-American populations. PMID- 30412084 TI - Choroidal thickness changes in non-treated acute and ranibizumab-treated chronic central serous chorioretinopathy. AB - To evaluate the changes in subfoveal retinal, and choroidal thicknesses (CT) in the non-treated acute and the ranibizumab-treated chronic central serous chorioretinopathy (CSCR) patients.This retrospective study included 32 eyes of 32 consecutive patients with CSCR. There were 12 patients who presented with a spontaneous resolution of CSCR (Group 1) and 20 patients who were treated with ranibizumab for persistent subretinal fluid (SRF) (Group 2). Optical coherence tomography (OCT) imaging of subfoveal retinal thickness and enhanced depth imaging OCT of CT at subfoveal; at nasal and temporal 500 MUm (T500); at nasal and temporal 1500 MUm (T1500) were analyzed. The Student t test and multivariate analysis were used to compare variables within and between groups, respectively and correlations were analyzed using Pearson correlation coefficient. A P value of P < .05 was accepted as significant.The mean patient age was 38.94 +/- 8.41 years (range, 20-53 years). Female/male ratio was 4/28. The mean duration of follow-up was 21.6 +/- 8.2 months in the chronic CSCR group. Visual acuity improved and central foveal thickness (FT) decreased significantly in both groups. CT decreased significantly only at nasal 1500 MUm (N1500) in the acute group and at all measured points in the chronic group compared with baseline, except at T500 (P = .07). No significant difference in central FT was detected between the 2 groups. Compared with the acute group, baseline subfoveal CT was significantly higher in chronic patients. There was a significant difference between the groups in baseline and final CT at T500. No significant difference was found at T1500. At nasal 500 MUm and N1500, the difference between the groups was significant only for final CT values.Chronic CSCR was associated with higher baseline CT values in the subfoveal region and at T500. CT significantly decreased at most of the measured points in ranibizumab-treated chronic CSCR patients, whereas it significantly decreased only at 1 point in spontaneously resolved acute CSCR patients. PMID- 30412085 TI - Hemichorea associated with cavernous angioma and a small errhysis: A case report and literature review. AB - RATIONALE: Chorea is a movement disorder characterized by randomly appearing involuntary movements of the face, neck, limbs, or trunk. Hemichorea is unilateral, involving one side of the body. Hemichorea is commonly caused by non ketotic hyperglycemia and/or cerebrovascular injury to the contralateral basal ganglia. PATIENT CONCERNS: Here, we report the case of a patient diagnosed with hemichorea who had diabetes, cavernous angioma, and a small intracranial errhysis. Routine testing showed the patient's blood glucose level was slightly higher than the normal range. INTERVENTIONS: The errhysis was too small to be treated. DIAGNOSES: Brain magnetic resonance imaging showed a cavernous angioma with a small errhysis in the right putamen. OUTCOMES: Hemichorea was completely resolved after 4 months. LESSONS: If diabetes is well controlled and imaging indicates brain lesions suggestive of a recent stroke, a diagnosis of post-stroke hemichorea should be considered. PMID- 30412086 TI - Transesophageal echocardiography and fluoroscopy for percutaneous closure of atrial septal defects: A comparative study. AB - The aim of the study was to compare transesophageal echocardiography (TEE) and fluoroscopy for percutaneous atrial septal defect (ASD) closure.This was a retrospective analysis of children who underwent percutaneous ASD closure. The procedure was guided by TEE without fluoroscopy in 130 patients (TEE group) and by fluoroscopy in 163 patients (fluoroscopy group). Baseline demographic/clinical characteristics were recorded. Patients were followed until hospital discharge. Outcomes were procedure duration, peri/postoperative complications, hospital stay, and costs.The TEE and fluoroscopy groups showed no significant differences in age (71.7 +/- 40.7 vs 62.5 +/- 38.8 months), male/female ratio (54/76 vs 66/97), weight (22.0 +/- 12.0 vs 20.1 +/- 9.0 kg), ASD diameter (9.9 +/- 4.2 vs 9.3 +/- 3.9 cm), distances to the superior vena cava (13.4 +/- 4.6 vs 13.3 +/- 4.2 cm), inferior vena cava (13.4 +/- 4.3 vs 13.9 +/- 4.1 cm) and atrial septal roof (12.1 +/- 4.0 vs 12.3 +/- 3.2 cm), or atrial septal size (38.2 +/- 6.2 vs 39.4 +/- 26.6 cm); distance to the mitral valve was greater in the TEE group (13.2 +/- 4.4 vs 11.3 +/- 3.9 cm; P < .001). The TEE and fluoroscopy groups showed no significant differences in occlusion device size (14.3 +/- 4.6 vs 13.8 +/- 4.0 cm) or sheath size (8.7 +/- 1.8 vs 8.7 +/- 0.9 cm), but procedure duration was shorter in the TEE group (21.5 +/- 14.6 vs 28.6 +/- 10.9 minutes; P < .001). Postoperative fever (>38 degrees C) occurred less frequently in the TEE group than in the fluoroscopy group (0.8% vs 9.2%; P < .001); there were no significant differences for the other complications. No patient had postoperative residual shunt, occlusion device shedding/displacement, or pericardial effusion. The TEE group had longer hospital stay (3.2 +/- 0.6 vs 2.9 +/- 0.6 days; P < .001) and higher procedure cost (29,687 +/- 4218 vs 28,530 +/- 1668 CNY (China Yuan); P = .002) than the fluoroscopy group.TEE-guided percutaneous ASD closure can be used as an alternative to fluoroscopy-guided procedures and avoids the use of radiation or contrast agents. PMID- 30412087 TI - Factors predicting adjacent segment disease after anterior cervical discectomy and fusion treating cervical spondylotic myelopathy: A retrospective study with 5 year follow-up. AB - The purpose of this study is to explore perioperative factors predicting symptomatic adjacent segment disease (ASD) after anterior cervical discectomy and fusion (ACDF) for patients with cervical spondylotic myelopathy (CSM) at 5-year follow-up.This study included 356 patients who underwent ACDF for CSM from Jan.2011 to Jan.2013. Up to Jan. 2018, 39 patients suffered from ASD and 317 did not. Assessments include: age, sex, body mass index (BMI), diabetes, smoking, alcohol, duration of symptoms, preoperative Cobb angle of C2 to 7, T1 slope, C2 to 7 range of motion (C2-7 range of motion [ROM]), C2 to 7 sagittal vertical axis (C2-7 SVA), fusion level involved, superior fusion segment, high signal intensity on T2-WI of magnetic resonance imaging (MRI), preoperative visual analogue scale (VAS)-neck, VAS-Arm, Neck Disability Index (NDI) and Japanese Orthopaedic Association (JOA). Factors were processed by univariate analysis and multivariate linear regression.Data analyzed by univariate and multivariate analysis shows that age (68.9 years old), duration of symptoms (18.8 months), superior fusion segment, more fusion level involved (2.7), high signal intensity on T2-WI (17 of 39 patients), Cobb angle of C2 to C7 (18.7 degrees ), C2 to C7 SVA (31.0 mm), T1 slope (28.4 degrees ), preoperative VAS-neck (5.2), VAS-Arm (5.6) and NDI (36.7) in ASD group are significantly higher than those in non-ASD group, however, preoperative JOA (8.2 vs 11.2, P < .001) has an opposite trend in 2 groups.The rate of ASD after ACDF is 10.9% in 5-year follow up. Patients with cervical sagittal imbalance, advanced age and sever state of CSM, which have a positive relation with ASD before surgery should be paid attention for surgeons. PMID- 30412088 TI - Age-related variations in corneal geometry and their association with astigmatism: The Yamagata Study (Funagata). AB - To investigate how aging affects corneal geometry in Japanese adults, and the association between corneal geometry and astigmatism.We included 421 participants who had undergone systemic and ophthalmological examinations in 2015 in Funagata town, Yamagata, Japan. Corneal topographic data were obtained using anterior segment optical coherence tomography (CASIA SS-1000). Astigmatism was evaluated using power vector analyses where J0 represents the power of the orthogonal astigmatism. Positive values of J0 indicate with-the-rule astigmatism, while negative values indicate against-the-rule (ATR) astigmatism.Regarding age-related variations in corneal geometry, the anterior elevations at axis 0 degrees and 180 degrees decreased, and those at axis 90 degrees and 270 degrees increased with increasing age in linear regression analyses, demonstrating horizontal steepening and vertical flattening of the corneal surface. There were no significant age-related variations in posterior elevations and pachymetry findings, including central corneal thickness. Regarding age-related variations in orthogonal astigmatism, the mean values of J0 and corneal J0 (cJ0) decreased by -0.014 and -0.015 per year of increase in age, indicating astigmatic shift toward ATR. Regarding the correlation between corneal geometry and astigmatism, the shift toward ATR was positively correlated with horizontal steepening and vertical flattening, in accordance with the age-related corneal variations. In addition, the posterior surface of the cornea also has an association with this shift to some extent.The results of our population-based study demonstrated that the age-related variation in astigmatism is associated with geometrical changes in the cornea, especially those in the anterior surface of the cornea. PMID- 30412089 TI - The pretreatment platelet-to-lymphocyte ratio predicts clinical outcomes in patients with cervical cancer: A meta-analysis. AB - INTRODUCTION: The platelet-to-lymphocyte ratio (PLR) has been reported to possess significant prognostic value in multiple types of cancer. However, its prognostic value in patients with cervical remains controversial. We conducted a meta analysis to evaluate the prognostic value of pretreatment PLR in cervical cancer. METHODS: We searched the MEDLINE, EMBASE, and Cochrane databases to identify studies evaluating the prognostic significance of the pretreatment PLR in patients with cervical cancer. The end points were overall survival (OS), disease free survival (DFS), progression-free survival (PFS), and clinicopathological parameters. All statistical analyses were conducted with Stata 13.0. RESULTS: A total of 12 studies comprising 3668 patients with cervical cancer were included. Elevated PLR was significantly correlated with poor OS [hazard ratio (HR): 1.56, 95% confidence interval (CI): 1.32-1.85, P < .001] and DFS/PFS (HR = 1.56; 95% CI = 1.26-1.94; P < .001). In addition, elevated PLR was highly correlated with lymphovascular space invasion (+), lymph node metastasis (+), tumor size (>4 cm), grade (G3). CONCLUSION: The pretreatment PLR could serve as a predicative biomarker of poor prognosis for patients with cervical cancer. PMID- 30412091 TI - The value of magnetic resonance imaging to diagnose pathological complete response of rectal cancer after therapy: A protocol for meta-analysis. AB - BACKGROUND: Although the trends of colorectal incidence rate and mortality have decreased during the past 20 years, however, they are still high. Neoadjuvant chemoradiotherapy is recommended as the standard treatment strategy of local advanced rectal cancer followed by surgery and adjuvant therapy. Predicting pathological complete response (pCR) accurately is relative to the next treatment strategy to avoid extensive therapy. And there are more and more physicians who would like to choose pelvic MRI imaging to evaluate the state of rectal cancer. Therefore, our analysis will aim to assess the value of MRI to predict pCR of rectal cancer after therapy and distinguish which sequence and magnetic strength is the best one to diagnose pCR. METHODS: Comprehensive computer-based search will be performed using the PubMed, EMBASE, Cochrane Library, and CBM database (last updated in April 2018), 2 reviewers will extract the related information respectively. Pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and the area under the hierarchical summary receiver-operating characteristic curves will be calculated to estimate the diagnostic accuracy of different sequences and intensities of magnetic resonance imaging. Methodological quality will be assessed using the Quality Assessment of Diagnostic Accuracy Studies tool. RESULTS: The results of this analysis will be submitted to a peer-reviewed journal for publication. CONCLUSION: The ability of different MRI sequences and magnetic intensities to identify pCR will be evaluated and the best one to diagnose pCR of rectal cancer after therapy will be recommended. ETHICS AND DISSEMINATION: Ethics approval and patient consent are not required, as this study is a meta-analysis based on published studies. PROSPERO REGISTRATION NUMBER: CRD42018105672. PMID- 30412090 TI - Diagnostic accuracy of endoscopic ultrasound, computed tomography, magnetic resonance imaging, and endorectal ultrasonography for detecting lymph node involvement in patients with rectal cancer: A protocol for an overview of systematic reviews. AB - BACKGROUND: Rectal cancer is one of the most common tumors and is the leading cause of cancer-related deaths in developed countries. Lymph node involvement remains the strongest prognostic factor associated with a worse prognosis in patients with rectal cancer. Several systematic reviews have investigated the accuracy of endoscopic ultrasound, computed tomography, magnetic resonance imaging, and endorectal ultrasonography for lymph node involvement of rectal cancer and compared the diagnostic accuracy of different imaging techniques, but there are considerable differences in conclusions. This study aims to assess the methodological quality and reporting quality of systematic reviews and to determine which diagnostic imaging techniques is the optimal modality for the diagnosis of lymph node involvement in patients with rectal cancer. METHODS: We will search PubMed, EMBASE, Cochrane Library, and Chinese Biomedicine Literature to identify relevant studies from inception to June 2018. We will include systematic reviews that evaluated the accuracy of diagnostic imaging techniques for lymph node involvement. The methodological quality will be assessed using AMASAR checklist, and the reporting quality will be assessed using PRISMA-DTA checklist. The pairwise meta-analysis and indirect comparisons will be performed using STATA V.12.0. RESULTS: The results of this overview will be submitted to a peer-reviewed journal for publication. CONCLUSION: This overview will provide comprehensive evidence of different diagnostic imaging techniques for detecting lymph node involvement in patients with rectal cancer. ETHICS AND DISSEMINATION: Ethics approval and patient consent are not required as this study is an overview based on published systematic reviews. PROSPERO REGISTRATION NUMBER: CRD42018104906. PMID- 30412092 TI - The prognostic impact of tumor length in esophageal cancer: Protocol for a systematic review and meta-analysis. AB - BACKGROUND: More and more studies were performed to explore the prognostic role of tumor length in esophageal cancer (EC). However, the results remain controversial. Hence, the aim of the review was to evaluate the association between tumor length and oncologic outcome in EC patients through meta-analysis. METHODS: A systematic literature search for relevant articles published in English language will be conducted in the PubMed, Web of Science, and Embase. Hazard ratio and 95% confidence intervals (CIs) will be employed as effect measures to estimate the correlation between tumor length and the oncologic outcomes including overall survival, disease-free survival, progression-free survival, relapse-free survival, and cancer-specific survival. We will use the software STATA 14.0 to perform the meta-analysis to calculate the data synthesis. RESULTS: The review will provide a high-quality synthesis of current evidence of the prognostic role of tumor length in ECs. The results will be published in a peer-reviewed journal. CONCLUSION: This will be the first systematic review and meta-analysis to evaluate the prognostic role of tumor length in EC patients. The results will better predict EC survival and identify higher-risk patients for postoperative therapy. PROSPERO REGISTRATION NUMBER: This systematic review protocol has been registered in the PROSPERO network (No. CRD42018106851). PMID- 30412093 TI - Association of 18F-FDG PET or PET/CT results with spontaneous remission in classic fever of unknown origin: A systematic review and meta-analysis. AB - BACKGROUND: Spontaneous remission is common in patients with undiagnosed classic fever of unknown origin (FUO). Although identifying reliable predictors of spontaneous remission in such diagnostically challenging cases could improve their management strategies, few studies have assessed such clinical factors. Recently, studies have reported that F-fluorodeoxyglucose positron emission tomography (F-FDG PET) alone and integrated with computed tomography (PET/CT) were useful in localizing the source of FUO. In this systematic review and meta analysis, we assessed the association of results of these imaging modalities with spontaneous remission in patients with classic FUO. METHODS: We searched PubMed and Scopus from inception until June 30, 2018, and studies that evaluated the PET or PET/CT results of >=10 adult or adolescent patients with classic FUO who were followed up for at least 3 months were included. At least 2 investigators extracted data and rated quality using the QUIPS-2 tool. We used a random-effects meta-analysis to calculate summary risk ratios (RRs) with 95% confidence intervals (CIs). RESULTS: Nine studies of PET/CT results (418 patients) and 4 studies of standalone PET results (128 patients) were eligible. None explicitly specified the incidence of spontaneous remission as the primary or secondary outcomes of interest. The risk of bias was considered high in all studies because patients received subsequent diagnostic workup based on imaging results. Patients with negative PET/CT results were significantly more likely to present with spontaneous regression than those with positive results (summary RR = 5.6; 95% CI: 3.4-9.2; P < .001; I = 0%). In contrast, no significant association was found between standalone PET results and spontaneous remission. The random-effects study-level meta-regression found that PET/CT results [relative RR (rRR) = 7.4; 95% CI: 2.5-21.3; P = .002], compared with standalone PET results, and publication year (rRR = 1.2 per 1 year; 95% CI: 1.0-1.3; P = .013) were significantly associated with spontaneous remission. CONCLUSION: Limited data suggest that undiagnosed classic FUO patients with negative PET/CT results had a high likelihood of spontaneous remission after a series of unsuccessful investigations for fever workup. Prospective studies should validate these results. PMID- 30412094 TI - The impact of perioperative allogeneic blood transfusion on prognosis of hepatocellular carcinoma after radical hepatectomy: A systematic review and meta analysis of cohort studies. AB - This meta-analysis aims to clarify the clinical impacts of allogeneic blood transfusion (ABT) on hepatectomy outcome in hepatocellular carcinoma (HCC) patients. A systematic literature search was performed for relevant articles in international and Chinese databases up to May 2018. Random- or fixed-effect meta analysis was used to pool the effect estimates. Publication bias was assessed by Egger's and Peters's test. Heterogeneity was assessed using the I statistic. The strength of evidence was rated by the Grading of Recommendations Assessment, Development, and Evaluation system. A total of 29 studies met the eligibility criteria. Meta-analysis showed HCC patients in ABT group had lower survival rate at 1, 3, 5, and 10 years after radical hepatectomy than those in no blood transfusion (NBT) group (RR = 0.9, 95%CI: 0.87-0.93, P < .05; RR = 0.83, 95%CI: 0.77-0.89, P < .05; RR = 0.7, 95%CI: 0.65-0.74, P < .05; RR = 0.64, 95%CI: 0.54 0.75, P < .05). Similar results were observed in disease-free survival (DFS) (respectively: RR = 0.86, 95%CI: 0.82-0.91, P < .05; RR = 0.77, 95%CI: 0.67-0.79, P < .05; RR = 0.71, 95%CI: 0.64-0.79, P < .05; RR = 0.62, 95%CI: 0.48-0.8, P < .05). Cancer recurrence rate was higher for the patients in ABT group at 1 and 3 years (RR = 1.5, 95%CI: 1-2.24, P < .05; RR = 1.27, 95%CI: 1.09-1.49, P < .05, respectively), but not statistically significant at 5years (RR = 1.08, 95%CI: 0.98-1.19, P = .512). The HCC patients in ABT group increased postoperative complications occurrence compared with those in NBT group (RR = 1.87, 95%CI: 1.42 2.45, P < .05). This meta-analysis demonstrated that ABT was associated with adverse clinical outcomes for HCC patients undergoing radical hepatectomy, including poor survival, DFS, and complications. Surgeons should reduce blood loss during hepatectomy and avoid perioperative allogenic blood transfusion. PMID- 30412095 TI - Recurrent, late-onset pleural effusions in elderly patients receiving pacemaker therapy. AB - Late-onset pacemaker-related pleural effusions (PEs) are rare and are often misdiagnosed with other entities. Our study aimed to detail the clinical features and management of PEs long after pacemaker insertion.We conducted a review of 6 consecutive elderly patients with PEs, who had undergone a new pacemaker insertion from September 2014 to January 2017. Also, the clinical characteristics and therapeutic courses of PEs were summarized.Two cases involved fluids after the first implantations, with pacing durations of 3 and 7 months. Two other cases developed PEs 3 or 4 months after the first replacement, with pacing durations of 6 and 11 years. Another 2 cases developed PEs 3 or 5 months following the second replacement, with total pacing durations of 16 and 18 years, respectively. The average interval was 4.17 months for the 6 cases from the time of the new pacemaker insertion to the occurrence of PEs. During the course, they had to be hospitalized repeatedly for thoracenteses because conventional treatments had only short-term effects. After the pacing settings were adjusted, PEs in all cases disappeared gradually. No patients were readmitted for PEs during the median follow-up period of 13 months.For elderly patients following implantation of a new pacemaker, PEs should be considered due to improper pacing settings, and corresponding adjustments to the device should be made. PMID- 30412096 TI - Relationship between the IADPSG-criteria-defined abnormal glucose values and adverse pregnancy outcomes among women having gestational diabetes mellitus: A retrospective cohort study. AB - To explore the influence of the 75 g oral glucose tolerance test (OGTT) on pregnancy outcomes and to determine the risk factors for adverse outcomes among women with gestational diabetes mellitus (GDM).This retrospective cohort study was conducted among women who had GDM and were treated between January 1, 2015 and December 31, 2017. The diagnostic criteria for GDM were proposed by the International Diabetes and Pregnancy Research Organization (IADPSG) in 2010. Women with GDM were stratified according to the number of abnormal OGTT values or the presence/absence of adverse pregnancy outcomes. Maternal characteristics, OGTT values, pregnancy outcomes, and the relationship between the latter 2 were analyzed.In total, 3221 pregnant women with GDM were included. The incidence of adverse outcomes was affected by maternal age (28-37 years, in particular; odds ratio [OR], 1.403; 95% confidence interval [CI], 1.037-1.899; P = .028), days of pregnancy (OR, 0.904; 95% CI, 0.894-0.914; P < .001), gestational weight gain (OR, 1.018; 95% CI, 1.000-1.036;, P = .048), and age of menarche (OR, 0.925; 95% CI, 0.863-0.992; P = .029). Both fasting plasma glucose (FPG) and 2-h OGTT were positively correlated with adverse outcomes, of which FPG was more predictive (FPG: OR, 1.143; 95% CI, 1.007-1.297; P = .038; 2-h OGTT: OR, 1.074; 95% CI, 1.018-1.133; P = .009). Meanwhile, higher abnormal OGTT values were associated with significantly increased risks of antenatal insulin treatment, cesarean delivery, premature delivery, gestational hypertension, premature rupture of membranes, preeclampsia, macrosomia, neonatal asphyxia, and full term low weight infants.OGTT values and the number of abnormal glucose are associated with various adverse pregnancy outcomes. Stratified management is recommended for pregnant women with GDM, especially those with fasting hyperglycemia and/or 3 abnormal OGTT values. PMID- 30412097 TI - Muscle oxygenation during hybrid arm and functional electrical stimulation-evoked leg cycling after spinal cord injury. AB - This study compared muscle oxygenation (StO2) during arm cranking (ACE), functional electrical stimulation-evoked leg cycling (FES-LCE), and hybrid (ACE+FES-LCE) exercise in spinal cord injury individuals. Eight subjects with C7 T12 lesions performed exercises at 3 submaximal intensities. StO2 was measured during rest and exercise at 40%, 60%, and 80% of subjects' oxygen uptake (VO2) peak using near-infrared spectroscopy. StO2 of ACE showed a decrease whereas in ACE+FES-LCE, the arm muscles demonstrated increasing StO2 from rest in all of VO2) peak respectively. StO2 of FES-LCE displayed a decrease at 40% VO2 peak and steady increase for 60% and 80%, whereas ACE+FES-LCE revealed a steady increase from rest at all VO2 peak. ACE+FES-LCE elicited greater StO2 in both limbs which suggested that during this exercise, upper- and lower-limb muscles have higher blood flow and improved oxygenation compared to ACE or FES-LCE performed alone. PMID- 30412098 TI - An aortic intra mural hematoma in ventilation/perfusion SPECT/CT: A case report. AB - RATIONALE: Ventilation/perfusion (V/Q) single-photon-emission computed tomography (SPECT) has arisen as an alternative to computed tomography pulmonary angiography (CTPA) in patients with pulmonary embolism (PE) suspicion. The addition of low dose CT (ldCT) to V/Q SPECT improves the specificity of the test, allowing for potential alternative diagnosis. PATIENT CONCERNS AND DIAGNOSIS: Here we presented a case of an aortic intramural hematoma (IMH) diagnosed on the ldCT portion of V/Q SPECT combined with CT. A 74-year-old man suffering from sudden onset chest pain was referred to our nuclear medicine department for PE suspicion. INTERVENTION AND OUTCOME: A V/Q SPECT combined with nonenhanced ldCT ruled out PE diagnosis. Nevertheless, ldCT revealed high attenuation aortic wall thickening suggestive of aortic IMH. Chest CT angiography showed mild dilatation and circumferential thickening of aortic wall confirming Stanford type A IMH involving the entire ascending aorta. LESSON: This case illustrates the potential usefulness of combining ldCT to V/Q SPECT in providing alternative diagnosis in suspected PE patients. PMID- 30412099 TI - Diabetes management in a Primary Care Network (PCN) of private general practitioners in Singapore: An observational study. AB - A Primary Care Network (PCN) is a virtual network of general practitioners (GPs), sharing common resources and common clinical governance framework for effective chronic disease management. In this study, we analyzed the frequency of assessment as well as control of HbA1c, blood pressure (BP), and low-density lipoprotein (LDL) over time among adult patients with diabetes managed by a group of private GPs under PCN.Data, including clinical measurements of HbA1c, BP, and LDL from 2012 to 2015, of 943 subjects at 9 GP clinics that piloted PCN in Singapore in 2012 was obtained from the chronic disease register for this analysis.The total number of PCN patients increased from 371 in 2012 to 911 in 2015. The average HbA1c decreased from 7.5% in 2012 to 7.3% in 2015, with a significant yearly improving trend of -0.11% (P < .001). The trends in change for systolic BP and LDL were not statistically significant during the same follow-up period. Regular assessment of HbA1c decreased from 80% in 2012 to 55% in 2015. Such decreases were also found in BP and LDL assessments. We also found that receiving government subsidies under a national scheme was a major determinant for maintaining regular assessment, with patients so covered 3 to 20 times more likely to have regular assessments.The PCN model can help improve care and clinical outcomes in adult patients with diabetes in the private primary care sector. Investing greater financial and human resources to augment service capacity and expanding subsidy coverage may be important to ensure the effectiveness, scalability, and sustainability of such a model of care. PMID- 30412100 TI - Urinary beta2-microglobulin as an early marker of infantile enterovirus and human parechovirus infections. AB - Enterovirus and human parechovirus (HPeV) are RNA viruses belonging to the family Picornaviridae that frequently infect infants. These infections show a wide variety of clinical manifestations, from mild to severe. However, there are no known early clinical markers for diagnosis and prediction of disease severity. The aim of this study was to examine the clinical utility of urinary beta 2 microglobulin (beta2MG) for the early detection and prognosis of infantile enterovirus and HPeV infections.This retrospective study included 108 full-term infants younger than 60 days of age, including 15 with enterovirus or HPeV-3 (enterovirus/HPeV-3), 22 with respiratory syncytial virus (RSV), and 24 with bacterial infections. Laboratory data and clinical characteristics were compared among these 3 groups. Of the 15 patients with enterovirus/HPeV-3, 6 were treated with intravenous immunoglobulin (IVIG subgroup) because of severe clinical conditions.Urinary beta2MG to creatinine ratio (beta2MG/Cr) was significantly higher in the enterovirus/HPeV-3 group compared to bacterial and RSV infection groups (both P < .001). In the enterovirus/HPeV-3 group, mean peak urinary beta2MG/Cr was observed on day 1 or 2. Urinary beta2MG/Cr values were significantly higher in the IVIG subgroup than the non-IVIG subgroup (P < .001).Increased urinary beta2MG/Cr in early-stage infection may be a useful clinical marker for the detection and prediction of infantile enterovirus and HPeV infection severity. PMID- 30412101 TI - The correlation between controlled attenuation parameter and metabolic syndrome and its components in middle-aged and elderly nonalcoholic fatty liver disease patients. AB - This study aims to investigate the correlation between controlled attenuation parameter (CAP) and metabolic syndrome (MetS) and its components in middle-aged and elderly nonalcoholic fatty liver disease (NAFLD) patients.Middle-aged and elderly patients with NAFLD, who visited our hospital from June 2016 to May 2017, were enrolled as study subjects, whereas middle-aged and elderly patients without liver disease were enrolled as controls in the same period. The prevalence of MetS, MetS components, and the different numbers of MetS components were compared among patients with different CAP values.As the CAP value increased, the prevalence of MetS, MetS components, and the different numbers of MetS components significantly increased. The CAP value was positively correlated with the prevalence of MetS, obesity, hypertriglyceridemia, hypertension, hyperglycemia, hyperuricemia, and the number of MetS components, and was negatively correlated with the prevalence of hypo-high-density-lipoprotein cholesterolemia.CAP values are closely correlated to MetS and its components in middle-aged and elder NAFLD patients. CAP may be an indicator of risk of MetS and the severity of metabolic disorders in middle-aged and elderly NAFLD patients. PMID- 30412102 TI - Postoperative morbidity and mortality in patients receiving neoadjuvant chemotherapy for locally advanced gastric cancers: A systematic review and meta analysis. AB - AIM: To investigate the postoperative morbidity and mortality for neoadjuvant chemotherapy (NAC) plus surgery compared with surgery alone. METHODS: PubMed and Embase were searched to capture the incidence of any postoperative complications, pulmonary complications, anastomotic leakage, surgical site infections, and postoperative mortality in randomized clinical trials comparing NAC plus surgery with surgery alone. The meta-analyses were performed with a random effects model. RESULTS: Nine relevant studies were included. Comparing NAC with surgery alone, there were no increases in any postoperative complications, pulmonary complications, anastomotic leakage, surgical site infections, or postoperative mortality attributable to NAC. Sensitivity analysis suggested a possible increased risk of any postoperative complications compared with surgery alone: the risk difference 0.056 (95% confidence interval -0.032 to 0.145). Severe complications such as anastomotic leakage and pulmonary complications were similar in the 2 groups. CONCLUSIONS: NAC for gastric cancer does not increase the risk of postoperative morbidity and mortality compared with surgery alone. PMID- 30412104 TI - Dysphagia with fatal choking in oculopharyngeal muscular dystrophy: Case report. AB - RATIONALE: Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant late-onset progressive muscle disorder typically characterized by ptosis, difficulty in swallowing, and proximal limb weakness. Underdiagnosis of OPMD is common in Asian countries and results in delayed diagnoses and fatal events. PATIENT CONCERNS: Here, we report the case of a 53-year-old female who suffered from progressive dysphagia and experienced several choking events involving solid material. An extensive family history of dysphagia was noted, and 2 family members had died as a result of aspiration. DIAGNOSES: PABPN1 genotyping and DNA sequence analysis revealed a heterozygous (GCG)10(GCA)3GCG mutation that led to the diagnosis of OPMD. INTERVENTIONS: Rehabilitation exercises, namely, the Shaker exercise and the Masako maneuver, were suggested. OUTCOMES: Improved swallowing ability with safe food intake was noted after 2 months of training. Surgical intervention will be considered when progression of the disease is noted. LESSONS: Underdiagnosis and a lack of awareness of OPMD may lead to choking, aspiration pneumonia, and death in multiple members of affected families. Currently, there is no definitive treatment for OPMD, but rehabilitation exercises and surgical intervention are helpful in relieving dysphagia. PMID- 30412103 TI - Huge mucinous tubular and spindle cell carcinoma of kidney: A rare case report and literature review. AB - RATIONALE: Mucinous tubular and spindle cell carcinoma (MTSCC) is a variant of renal cell carcinoma newly added to the WHO classification in 2004. It is a rare variant of renal cell carcinoma and sometimes it is not easy to distinguish MTSCC from papillary renal cell carcinoma, chromophobe renal cell cancer, etc. The prognosis of MTSCC is favorable after surgical resection. PATIENT CONCERNS: A 45 year-old male patient presented with a right renal mass that was detected on ultrasonography incidentally. The computed tomography scan showed a huge homogenous mass with patchy calcification in the central area, and the lesion was slightly enhanced after contrast injection. DIAGNOSES: According to postoperative pathology, the patient was diagnosed with MTSCC. INTERVENTIONS: The patient underwent an open transabdominal radical resection of right kidney and right retroperitoneal lymph node dissection. OUTCOMES: The surgical outcomes were good, and no recurrence or metastasis was observed during the follow-up. LESSONS: MTSCC is a rare malignancy of the kidney and the prognosis is usually favorable. Preoperative enhanced CT and MRI can help differentiate MTSCC from other renal tumors, so as to provide a more suitable surgical approach for those who need to retain renal function as much as possible. PMID- 30412105 TI - Periclitoral accessory breast tissue in a lactating woman: A case report. AB - RATIONALE: The accessory breast is residual mammal tissue which does not regress during the embryonic development. The accessory breast is so rare that it is easily ignored in diagnosis of disease. PATIENT CONCERNS: We report a 29-year-old lactating woman presented with complaints of periclitoral lesions without any pain or discomfort. DIAGNOSES: Periclitoral accessory breast tissue. INTERVENTIONS: We performed wide local resection of the lesions. Pathologic examination confirmed the lesions were ectopic breast tissues with secretory changes. The patient was followed up for 3 months and she was totally recovered. LESSONS: Accessory breast tissue should be considered as a diagnosis when a mass grow fast on the milk line, especially the masses changes obviously with sex hormones according to the clinical findings. PMID- 30412106 TI - Immune checkpoint inhibitors of CTLA4 and PD-1 for malignant melanoma arising in ovarian cystic teratoma: A case report. AB - RATIONALE: Malignant melanoma (MM) arising in ovarian cystic teratoma (OCT) is a rare disease with poor prognosis. Recently, immune checkpoint inhibitors of cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and programmed death 1 (PD-1) have shown promising results in MM. Herein we report a case of MM arising in OCT. PATIENT CONCERNS: A 63-year-old Japanese primigravida had lower abdominal pain. Magnetic resonance imaging revealed the presence of an 85-mm mass at the right ovary. DIAGNOSES: The patient underwent right salpingo-oophorectomy for right ovarian tumor, and histopathological examinations revealed MM arising in OCT. On immunohistochemical analysis, the tumor cells were positive for HMB-45, Melan A, and S-100 protein, and negative for programmed death-ligand 1 (PD-L1). BRAF gene mutations were not detected by the Real-Time PCR. Two months after surgery, liver metastasis was detected. INTERVENTIONS: The patient underwent immune checkpoint inhibitors of CTLA4 (ipilimumab) and PD-1 (pembrolizumab and nivolumab). She had interstitial pneumonia associated with ipilimumab, but she safely underwent the immune checkpoint inhibitors therapy along with oral prednisolone. Pembrolizumab, ipilimumab, and nivolumab therapies had poor effect on the tumor. OUTCOMES: Now, the present case has had tumor-bearing survival for 14 months since the initial diagnosis and 12 months since the detection of liver metastasis. LESSONS: This is the first case of MM arising in OCT treated by immune checkpoint inhibitors, with information of PD-L1 immunohistochemical expression and adverse events. The present case is the longest survivor following the detection of recurrence among all the previous reports. The long survival and slow-growing tumor in the present case may be associated with no PD-L1 expressions. PMID- 30412107 TI - Hypothyroidism induced by phenytoin and gabapentin: A Case Report. AB - RATIONALE: Antiepileptic drugs (AEDs) are one of the causative drugs of drug induced hypothyroidism. In most cases, AED-induced hypothyroidism is subclinical and indicated only by abnormalities of free thyroxine (T4) and/or thyroid stimulating hormone (TSH) levels. Severe symptomatic hypothyroidism following AEDs is rarely reported in the literature. PATIENT CONCERNS: A 75-year-old man experienced neurologic symptoms including memory impairment, ataxic gait, sensory polyneuropathy and myopathy, lethargy, and edema of the face and lower extremities. He had been administered phenytoin and gabapentin for the treatment of symptomatic traumatic epilepsy 8 years before. DIAGNOSES: The patient had low free T4 (0.21 ng/dL) and high TSH (113.2 MUIU/mL), which indicated hypothyroidism. Negative thyroid-related autoantibody tests and the lack of goiter excluded the possibility of Hashimoto disease. Phenytoin and/or gabapentin were strongly suspected as causing his hypothyroidism. INTERVENTION: The patient was treated with replacement therapy (levothyroxine 25 MUg/day). OUTCOMES: His symptoms markedly and promptly improved alongside continued antiepileptic therapy. LESSONS: In this case, the patient's hypothyroidism was assumed to result from different mechanisms of the 2 AEDs leading to thyroid hormone reduction. AEDs can not only cause asymptomatic thyroid hormone abnormalities but also clinically observable hypothyroidism. Therefore, clinicians should be aware of the association between anticonvulsants and symptomatic hypothyroidism. PMID- 30412108 TI - Oriental herbal medicine and moxibustion for polycystic ovary syndrome: A meta analysis. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most common disorders of reproductive endocrinology in women of reproductive age. Lifestyle intervention and oral contraceptives are the first-line treatments for PCOS. Recent studies have suggested that complementary and alternative medicine (CAM) therapies including acupuncture, herbal medicine, and mind-body therapy have the potential to alleviate the symptoms and/or pathology of PCOS and to improve the quality of life of women with PCOS. This meta-analysis aimed to quantitatively summarize the efficacy and safety of moxibustion combined with oriental herbal medicine (OHM), common CAM therapies, for treating PCOS. METHODS: Four databases were searched from their inception to June 22, 2018. Randomized controlled trials (RCTs) and quasi-RCTs using both OHM and moxibustion as experimental intervention, and western medication (WM) as control intervention were included. Studies involving OHM plus moxibustion combined with WM as the experimental intervention were also included. The quality of included studies was assessed using risk of bias tool. RESULTS: Owing to the heterogeneity of reporting, meta analysis was only performed for pregnancy rate, rate of normal biphasic basal body temperature (BBT), and total effective rate (TER). The results showed that compared to the WM group, the OHM combined with moxibustion group was associated with significantly higher pregnancy rate (risk ratio [RR] 1.95, 95% confidence interval [CI] 1.55-2.47; I = 0%), normal biphasic BBT rate (RR 1.66, 95% CI 1.34 2.05; I = 0%), and TER (RR 1.19, 95% CI 1.08-1.31; I = 0%). When OHM combined with moxibustion was used as an adjunctive therapy to WM, pregnancy rate (RR 1.65, 95% CI 1.29-2.11; I = 0%), and TER (RR 1.35, 95% CI 1.13-1.61; I = 43%) were significantly higher than those of the WM group. CONCLUSION: According to current evidence, OHM combined with moxibustion might be beneficial for treating PCOS. Moreover, the treatment might improve the therapeutic effects of conventional WMs including clomiphene citrate, oral contraceptives, and/or metformin. However, the findings should be interpreted with caution, owing to poor methodological quality of the included studies. Further larger, high quality, rigorous RCTs should be conducted in this regard. PMID- 30412109 TI - Tpeak-Tend/QT interval predicts ST-segment resolution and major adverse cardiac events in acute ST-segment elevation myocardial infarction patients undergoing percutaneous coronary intervention. AB - Elevated ST-segment and increased Tpeak-Tend interval (Tp-e) were prognostic predictors in major adverse cardiac events (MACEs) in ST-segment elevation myocardial infarction (STEMI). The electrophysiologic relationship between them during percutaneous coronary intervention (PCI) needs to elucidate.Patients with STEMI admitted to hospital were prospectively evaluated. ST-segment resolution (STR) (defined as >=50% reduction as the complete-STR [CSTR] group, <50% as incomplete-STR [ISTR] group), Tp-e interval, and ratio of Tp-e to QT interval (Tp e/QT) were measured, calculated and analyzed with MACEs.Tp-ec interval (corrected Tp-e interval, P < .001) and Tp-e/QT ratio (P < .001) were significantly increased by myocardial infarction and partly recovered post-PCI. Patients with ISTR showed more increased Tp-ec interval (P < .001) and Tp-e/QT ratio (P < .001) than those in CSTR groups post-PCI. In multivariate analysis and receiver operating characteristic curves analysis, Tp-e/QT was an independent and strongest predictor for STR. STR and electrocardiogram parameters with a cutoff value for predicting STR showed prognostic value for MACE in STEMI in Kaplan Meier survival analysis.Both STR and change of Tp-e parameters were not only predictors of arrhythmia, but also prognostic factors of MACE in patients with STEMI after PCI. PMID- 30412110 TI - Excellent long-term outcomes of endovascular treatment in budd-chiari syndrome with hepatic veins involvement: A STROBE-compliant article. AB - This study aimed to evaluate the long-term efficacy and safety of percutaneous transhepatic balloon angioplasty (PTBA) and transjugular intrahepatic portosystemic stent-shunt (TIPSS) in the treatment of Budd-Chiari syndrome (BCS) with hepatic veins involvement. Between June 2008 and August 2016, a total of 60 BCS patients with hepatic vein involvement in our department were enrolled in this study. Thirty-three cases underwent hepatic vein balloon angioplasty in PTBA Group and 27 cases underwent TIPSS. Data were retrospectively collected, and follow-up observations were performed. TIPSS Group showed significantly higher thrombotic/segmental obstruction and peripheral stenosis/obstruction compared with PTBA Group. The success rates were 93.9% and 100.0% in PTBA Group and TIPSS Group, respectively. The mean portal vein pressure decreased significantly after stenting. Except for 1 patient died from repeated hemorrhage, other sever complications had not been observed in both group. Twenty-six patients and 21 patients were clinically cured in PTBA Group and TIPSS Group, respectively. The primary patency rates were 89.7%, 79.3%, and 79.3% for short-term, mid-term and longterm in PTBA Group, which were significantly higher than TIPSS Group for long term follow up. The second patency rates were 100.0%, 96.6% and 96.6% for short term, mid-term and long-term in PTBA Group, which were similar to TIPSS Group (P = 1.0000). In conclusion, PTBA and TIPSS are safe and effective in the treatment of BCS with hepatic veins involvement, with an excellent long-term patency rate of hepatic vein and TIPSS shunt. TIPSS can be used to treat patients with all 3 hepatic veins lesion and failure PTBA. PMID- 30412111 TI - Vitamin D and bisphosphonates therapies for osteoporosis are associated with different risks of atrial fibrillation in women: A nationwide population-based analysis. AB - Osteoporosis and atrial fibrillation (AF) are common in post-menopausal women. Vitamin D and bisphosphonates are widely used to treat osteoporosis, and these may have different effects on the risk of AF.The goal of this study was to evaluate whether different agents for treating osteoporosis modulate the risk of AF in a population-based database.We identified 20,788 female patients suffering from osteoporosis who were or were not treated with vitamin D or bisphosphonates using the Taiwan National Health Insurance nationwide database from 2000 to 2008 and followed them up for 5 consecutive years to determine if they had a new diagnosis of AF after the diagnosis of osteoporosis.There were 14 (2.67%) new AF diagnoses in osteoporosis patients treated with bisphosphonates, one (0.28%) new AF diagnosis in patients treated with vitamin D, and 279 (1.40%) new AF diagnoses in patients who were not treated with vitamin D or bisphosphonates (neither group). Osteoporosis patients who received bisphosphonates showed a higher incidence of AF occurrence than those that were not treated with bisphosphonates (P = .015). In contrast, 1 patient who received vitamin D had a new diagnosis of AF during the study period; thus, the incidence was significantly lower than that in the patients treated with bisphosphonates (P = .007). In addition, the patients who were treated with vitamin D had a lower incidence of AF than did those who were not treated with either vitamin D or bisphosphonates (P = .074). Kaplan-Meier analysis also showed a significant difference in AF occurrence in different groups during the 5-year follow-up (P = .010).Different treatment for osteoporosis may carry diverse risks of AF occurrence. Vitamin D may have potential beneficial effects of reducing AF occurrence in osteoporosis patients. PMID- 30412112 TI - Solitary thin-walled cystic lung cancer with extensive extrapulmonary metastasis: A case report and review of the literature. AB - RATIONALE: Asymptomatic, isolated, and thin-walled cystic lung cancer with extensive extrapulmonary metastasis is rare, and the risk of pulmonary cyst developing into lung cancer is poorly understood. The efficacy of apatinib for end-stage pulmonary adenosquamous carcinoma has not been clarified yet. PATIENT CONCERNS: We herein report a rare case of primary lung cancer that appeared as an isolated thin-walled cystic lesion on computed tomography (CT) image, who was initially misdiagnosed as having pulmonary cyst empirically. DIAGNOSES: Fluorine 18-fluorodeoxyglucose-positron emission tomography and CT-guided liver biopsy of the patient revealed extra-pulmonary metastasis of lung cancer. INTERVENTIONS: Eight cycles of cisplatin-based chemotherapy were administered, followed by oral apatinib for 6 months. Thereafter, best supportive care was given for this patient. OUTCOMES: The pulmonary cystic lesion indicated stable disease through the therapy, but the hepatic tumors were progressed gradually after anticancer treatment. The patient died 16 months after the correct diagnosis. LESSONS: Solitary thin-walled cystic lung cancer should be kept in mind during the differential diagnosis of pulmonary cavitary lesions. Chest CT alone is insufficient for surveillance of these cystic diseases. Timely biopsy and resection are essential to avoid delayed management. Besides, apatinib may play a role in the treatment of end-stage pulmonary adenosquamous carcinoma. PMID- 30412113 TI - Prognostic value of osteopontin in patients with hepatocellular carcinoma: A systematic review and meta-analysis. AB - PURPOSE: The prognostic value of tissue and serum osteopontin (OPN) in hepatocellular carcinoma (HCC) remain controversial. The aim of present meta analysis was to evaluate the prognostic value of OPN in patients with HCC. METHODS: Eligible studies were systematically searched by PubMed, EMBASE, and Google scholar. A meta-analysis of 12 studies included 2117 cases was performed to estimate the association between OPN level and overall survival (OS), disease free survival (DFS) in HCC patients. Subgroup analyses were also performed in the meta-analysis. RESULTS: The pooled data of studies showed that high OPN level was significantly associated with poor OS (hazard ratios [HR] 1.84; 95% confidence intervals [CI] 1.54-2.20; P = .000) and DFS (HR 1.67; 95% CI 1.40-1.98; P = .000) in HCC. Furthermore, in subgroup analysis, high tissue based OPN by immunohistochemistry detection and serum-based OPN by enzyme-linked immunosorbent assay (ELISA) detection were both significantly associated with OS (tissue: HR 1.88; 95% CI 1.53-2.31; P < .0001; serum: HR 2.38; 95% CI 1.58-3.59; P < .0001). Simultaneously, we also found that OPN expression was positively associated with stage (odds ratios [OR] 5.68; 95% CI 3.443-7.758), tumor size (Size<=5 cm vs >5 cm; OR 2.001; 95% CI1.036-3.867). CONCLUSION: The current evidence indicates that OPN could serve as a prognostic biomarker and a potential therapeutic target for HCC. PMID- 30412115 TI - Paths of femoral nerve catheters placed using ultrasound-guided in plane vs out of plane techniques: A randomized controlled clinical trial. AB - BACKGROUND: Continuous blockade of the femoral nerve is widely used for postoperative analgesia after hip surgery. It can be achieved by ultrasound guided placement of a femoral nerve catheter via either the in plane (IP) or out of plane (OOP) technique. On the basis of postoperative radiographs, we evaluated the paths of femoral nerve catheters with respect to both techniques and its effect on postoperative analgesia. METHODS: Thirty-four patients were randomized to receive a radiopaque femoral nerve catheter via either the IP or OOP technique. The paths and tip position of the catheters were evaluated in postoperative frontal radiographs of the operated hip joint concerning a predefined target region and four neighboring regions. Pain scores were assessed using a numeric rating scale (0-10). RESULTS: Sixteen IP patients and 18 OOP patients were included in the study. The catheter path was radiographically evaluated in 13 IP patients and in 10 OOP patients. The catheter tips were located within the target region in 39% of the IP group and in 50% of the OOP group. The catheter tip was 0.00 cm [-3.80 to 3.84] and -1.19 cm [-12.27 to 0.00] (median [range]) from the target region in the OOP group and IP group, respectively (P = .045). Catheters flipped distally more often in the IP group (IP: 61.5%, OOP: 10.0%; P = .01). There were no marked differences in the pain scores of either group. CONCLUSION: Femoral nerve catheters inserted by the ultrasound-guided IP technique flip distally more frequently than catheters inserted by the OOP technique. Moreover, the distance between the catheter tip and the trunk of the femoral nerve is greater for IP catheters than for OOP catheters. Despite these findings, postoperative analgesia did not seem to differ between the 2 techniques. PMID- 30412114 TI - Evaluation of the healthy median nerve elasticity: Feasibility and reliability of shear wave elastography. AB - The present study applied the shear wave elastography (SWE) to the median nerve in order to investigate the feasibility and reliability of its use in 40 healthy volunteers. Shear wave velocities of the median nerve on bilateral forearms and right carpal tunnel were obtained with relaxing or stretching conditions. The inter- and intraobserver agreements and differences of nerve elasticity among groups were evaluated using intraclass correlation coefficients, the paired t test, and the Wilcoxon signed-rank test, respectively. The stiffness of the site was expressed by 3 types of values: mean, minimum, and maximum shear-wave velocities. The inter- and intraobserver agreements were excellent (0.852-0.930) on the right forearm. No differences were detected between the bilateral forearm (mean: P = .14), while the values of different body sites and postures were statistically different (P < .001). SWE, as a noninvasive and objective tool, reached a good consistency in evaluating the healthy median nerve. Further studies are essential to investigate the detailed influencing factors and provide an insight of SWE to estimate both the normal nerve and peripheral neuropathy. PMID- 30412116 TI - Evaluation of the clinical outcomes of telehealth for managing diabetes: A PRISMA compliant meta-analysis. AB - INTRODUCTION: The objective of this study was to systematically review the literature and perform a meta-analysis comparing the clinical outcomes of telehealth and usual care in the management of diabetes. METHODS: Multiple strategies, including database searches (MEDLINE, PsycINFO, PubMed, EMBASE, and CINAHL), searches of related journals and reference tracking, were employed to widely search publications from January 2005 to December 2017. The change in hemoglobin A1c (HbA1c) levels was assessed as the primary outcome, and changes in blood pressure, blood lipids, body mass index (BMI), and quality of life were examined as secondary outcomes. RESULTS: Nineteen randomized controlled trials (n = 6294 participants) were selected. Telehealth was more effective than usual care in controlling the glycemic index in diabetes patients (weighted mean difference = -0.22%; 95% confidence intervals, -0.28 to -0.15; P < .001). This intervention showed promise in reducing systolic blood pressure levels (P < .001) and diastolic blood pressure levels (P < .001), while no benefits were observed in the control of BMI (P = .79). For total cholesterol and quality of life, telehealth was similar or superior to usual care. CONCLUSION: Telehealth holds promise for improving the clinical effectiveness of diabetes management. Targeting patients with higher HbA1c (>=9%) levels and delivering more frequent intervention (at least 6 times 1 year) may achieve greater improvement. PMID- 30412117 TI - Changes in background parenchymal enhancement in HER2-positive breast cancer before and after neoadjuvant chemotherapy: Association with pathologic complete response. AB - This study aimed to analyze the relationship between pathologic complete response (pCR) and changes in background parenchymal enhancement (BPE) levels in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer and who received neoadjuvant chemotherapy (NAC).The pre- and post-NAC magnetic resonance imaging results of 51 patients with confirmed unilateral HER2-positive breast cancer were retrospectively analyzed by 2 experienced radiologists. Pre- and post-NAC of contralateral BPE levels were classified into 4 categories (1 = minimal, 2 = mild, 3 = moderate, and 4 = marked). The 4 categories of BPE were defined by the visually estimated enhancement of fibroglandular tissue of the breast. Changes in BPE before and after NAC were compared between the premenopausal and postmenopausal groups and between the pCR and non-pCR groups. The associations between BPE and pCR and between BPE and tumor size were analyzed before and after NAC.Twenty-three patients achieved pCR, and 28 patients achieved non-pCR. Premenopausal patients had significantly higher baseline BPE levels than postmenopausal women (P = .023). The post-NAC BPE levels of premenopausal patients significantly decreased relative to those of postmenopausal patients (P = .027). The baseline BPE levels of the pCR group were not significantly different from those of the non-pCR group (P = .892). However, the decrease in BPE levels in the pCR group was more drastic than that in the non-pCR group (P < .001). Decreased BPE levels were directly associated with pCR and tumor size reduction (P < .05). Women with hormone receptor (HR)-negative tumors were more likely to exhibit pCR than those with HR-positive tumors (P = .007).Decreased BPE of patients with HER2-positive breast cancer may serve as an indicator of NAC effectiveness. Furthermore, women with HR-negative tumors were more likely to exhibit pCR than women with HR-positive tumors. PMID- 30412118 TI - Role of Xingnaojing combined with naloxone in treating intracerebral haemorrhage: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Xingnaojing injection (XNJ) sharpen the mind and induce consciousness and are widely used in acute phases of intracerebral hemorrhage (ICH). Naloxone hydrochloride injection (NX) performs equally well and replace the effects of morphine-like substances to promote conscious awareness. The applications of XNJ combined with NX for ICH show some advantages compared with NX applied individually. The aim of this systematic review is to evaluate the effectiveness and safety of XNJ combined with NX for ICH. METHODS: Comprehensive searches were conducted in 8 medical databases (PubMed, Cochrane Library, Web of Science, Embase, CNKI, VIP, CBM and Wanfang database) from inceptions to October 2017 for randomized controlled trials (RCTs) that compared the applications of XNJ and NX with NX applied individually in ICH. Literature screening, assessing risk of bias and data extraction were conducted by 2 reviewers independently. According to the Cochrane Collaboration's RevMan5.3 software to perform the data analysis. RESULTS: 32 RCTs (3068 cases) were selected and the quality of studies were low. All trials compared XNJ and NX with NX applied individually. The overall meta analysis results showed that XNJ combined with NX have significant effect on clinical efficacy (OR 3.78, 95% CI: 3.03-4.73; P < .00001), GCS score (MD 3.86, 95% CI: 3.46-4.25; P < .00001), coma duration (MD -5.59, 95% CI: -6.96 to -4.22; P < .00001), NIHSS score (MD -6.24, 95% CI: -8.05 to -4.42; P < .00001), Barthel Index score (MD 14.12, 95% CI: 6.7-21.54; P < .0002), cerebral hematoma volume (MD -6.05, 95% CI: -6.85 to -5.24; P < .00001) than NX applied individually. Adverse events reported in 4 studies and included mild discomfort symptoms. CONCLUSION: The effectiveness and safety of XNJ combined with NX for ICH cannot be determined due to the low quality of literature, publication bias and heterogeneity. More rigorous RCTs are necessary to verify the role of XNJ combined with NX in the treatment of ICH. PMID- 30412120 TI - The combination of strip meniscometry and dry eye-related quality-of-life score is useful for dry eye screening during health checkup: Cross-sectional study. AB - Strip meniscometry (SM) is a new method for quantification of tear volume using meniscometry strips inserted into the tear meniscus for 5 seconds. The dry eye (DE)-related quality-of-life score (DEQS) questionnaire comprises 15 questions regarding bothersome ocular symptoms and their impact on daily life. These 2 examinations require a relatively short time and are appropriate as screening tests. We evaluated the sensitivity and specificity of SM and DEQS for screening for DE syndrome during general health checkup.This study included 333 right eyes from 333 soldiers (331 men, 2 women; mean age, 42.8 +/- 8.8 years) who underwent health checkups at the Yokosuka Medical Squadron between November and December 2013. We administered the DEQS questionnaire to the subjects. The fluorescein tear film break-up time and fluorescein and rose bengal staining scores were evaluated. A positive outcome was considered when DEQS >15 and SM scores <5 mm. We compared DEQS and SM between a DE group, suspected-DE group and normal group.Thirty-four (11%) soldiers were diagnosed with definite DE based on the Japanese DE diagnostic criteria. The sensitivities of SM, DEQS, and SM combined with DEQS for definite DE were 71%, 79%, and 59%, respectively, whereas the corresponding specificities were 85%, 91%, and 97%, respectively. None of the enrolled subjects experienced complications such as eye pain or discomfort, except for 1 soldier (0.003%) with conjunctivochalasis, who experienced irritation upon SM.The results of our study indicate that the combination of SM and DEQS is useful for the detection of DE with high sensitivity and specificity during routine health check-up. PMID- 30412119 TI - Clinicopathologic features of endometrial cancer in Chinese patients younger than 50 years with a family history of cancer. AB - Genetic factors play an important role in shaping the biologic characteristics of malignant tumors, especially in young patients. We aimed to determine the clinicopathologic features of endometrial cancer (EC) in patients younger than 50 years with a family history of cancer.Overall, 229 patients with EC, including 40 with a positive family history of cancer (PFH) and 189 with a negative family history of cancer (NFH), were enrolled in this case-control study. The family history of cancer in a 2-generation pedigree was recorded for the PFH group. Clinicopathologic features such as menarche age, body mass index, personal cancer history, grade, and histologic type were compared between the 2 groups. Mismatch repair (MMR) proteins including MLH1, PMS2, MSH2, and MSH6 were assessed by immunohistochemistry (IHC) in surgical samples. Univariate (Pearson Chi-squared test, Fisher exact test, T test, Wilcoxon rank sum test, logistic regression) statistics and stepwise multivariate logistic regression were used to identify factors associated with PFH in the analysis.Among young patients with EC, the PFH group had younger age-of-onset age of endometrial cancer (<=40 years) (odds ratio [OR] = 2.21, 95% confidence interval [95% CI]: 1.01-4.82) than the NFH group. The proportion of overweight/obese patients was high in both the NFH (58.7%) and PFH (80%) groups. Colorectal, lung, endometrial, breast, and hepatocellular carcinoma accounted for 58.6% of all cancer types among 1st- and 2nd-degree relatives. Additionally, 19.2% of patients displayed deficiency in at least 1 MMR protein, with a significantly higher proportion of MMR protein deficiency in the PFH group than in the NFH group (adjusted OR = 4.81, 95% CI: 2.14-8.83).Clinicopathologic features differ for young patients with EC with and without a family history of cancer. Surveillance of age-of-onset and family history of endometrial cancer, reduction of barriers to healthy lifestyles, and development of risk-appropriate Lynch syndrome screening tools, such as IHC, are needed for these women in Shanghai and other developing cities in China. PMID- 30412121 TI - Prevalence and outcome of acute gastrointestinal injury in critically ill patients: A systematic review and meta-analysis. AB - BACKGROUND: The aim of the study was to investigate the prevalence and impact of acute gastrointestinal injury (AGI) on clinical outcomes in critically ill patients. METHODS: The PubMed, Cochrane, and Embase databases were searched to identify trials that assessed gastrointestinal injury in critically ill patients. Outcome measures were prevalence of AGI among critically ill patients; incidence of mortality among critically ill patients with AGI, and incidence of mortality stratified by severity of AGI. RESULTS: The meta-analysis included 14 studies. The prevalence of AGI in critically ill patients was 40% [95% confidence interval (CI), 27%-54%]; the incidence of mortality among critically ill patients with AGI was 33% (95% CI, 26%-41%). There was a higher risk of mortality in critically ill patients with AGI compared to those without AGI [risk ratio (RR) = 2.01; 95% CI 1.20-3.37, P = .008). Subgroup analyses of studies that defined AGI according to European Society of Intensive Care Medicine (ESICM) criteria confirmed these findings and showed that the risk of mortality was higher in critically ill patients with more severe AGI (ESICM grade III and IV vs grade II) [RR of 1.86 (95% CI 1.48-2.34), P < .00001]. CONCLUSION: AGI is common in critically ill patients, mortality in critically ill patients with AGI is high, and severity of AGI is associated with mortality. The widespread clinical use of standard criteria with a severity gradation will facilitate the diagnosis and management of AGI in critically ill patients. PMID- 30412122 TI - Branch ostial optimization treatment and optimized provisional t-stenting with polymeric bioresorbable scaffolds: Ex-vivo morphologic and hemodynamic examination. AB - The optimal side-branch (SB) ostium treatment after provisional side-branch scaffolding remains a subject of debate in bioresorbable vascular scaffold (BVS) era. In this study, we evaluated a novel optimized provisional T-stenting technique (OPT) and assessed its feasibility by comparison with T and small protrusion technique (TAP).Two provisional SB scaffolding techniques (OPT, n = 5; TAP, n = 5) were performed using polymeric BVS in a bifurcated phantom. The sequential intermediate snuggling balloon dilation, also called ostial optimal technique, was added to OPT but not TAP to dilate the side-branch ostium while the final snuggling balloon dilation applied for both procedures. Microcomputed tomography (microCT) and optical coherence tomography (OCT) were performed to assess morphology, and computational fluid dynamics (CFD) was performed to assess hemodynamics in the scaffolded bifurcations. Compared with TAP in microCT analysis, OPT created shorter neo-carina length than TAP (0.34 +/- 0.10 mm vs 1.02 +/- 0.26 mm, P < .01), longer valgus struts length (2.49 +/- 0.27 mm vs 1.78 +/- 0.33 mm, P < .01) with larger MB ostial area (9.46 +/- 0.04 mm vs 8.34 +/- 0.09 mm, P < .01). OCT found that OPT significantly decreased the struts mal apposition (13.20 +/- 0.16% vs 1.94 +/- 0.54%, P < .01). CFD revealed that OPT generated more favorable flow pattern than TAP, as indicated by less percent (4.68 +/- 1.40% vs 8.88 +/- 1.21%, P < .01) of low wall shear stress (<0.4 Pa) along the lateral walls.By using BVSs for bifurcation intervention, the sequential intermediate snuggling balloon dilation is feasible for optimizing ostial SB and facilitating subsequent SB scaffolding. Results show OPT is better than TAP for bifurcated morphology and hemodynamics in this ex-vivo study. PMID- 30412123 TI - Prediction model of lymphovascular invasion based on clinicopathological factors in Chinese patients with invasive breast cancer. AB - The aim of this study was to evaluate the correlation between lymphovascular invasion (LVI) and tumor size, histological grade, and the expression statuses of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER-2), Ki67, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), E-cadherin, and P53 in invasive breast cancer, then establish a prediction model of LVI based on the associated clinicopathological factors.A total of 392 patients with primary invasive breast cancers were enrolled, and their paraffin-embedded tissues were manufactured into the tissue microarray. We evaluated the expression statuses of ER, PR, HER-2, Ki67, EGFR, VEGF, E-cadherin, and P53 based on immunohistochemistry, histological grade and LVI based on the hematoxylin and eosin stain, and tumor size.The positivity of LVI was significantly higher in the patients with HER-2 positive expression, Ki67 high expression, and tumor size >2 cm by Chi-square test. HER-2, Ki67, and tumor size were risk factors of LVI by multivariate analysis. The areas under the receiver operating curve of HER-2, Ki67, tumor size, and the combination of the 3 clinicopathological factors were 0.614 [P = .001, 95% confidence interval (CI): 0.544-0.683], 0.596 (P = .006, 95% CI: 0.529-0.662), 0.575 (P = .03, 95% CI: 0.510-0.641), and 0.670 (P < .001, 95% CI: 0.607-0.734), respectively.HER-2 positive expression, Ki67 high expression, and tumor size >2 cm were risk factors of LVI, whereas the power of the prediction model of LVI based on the 3 clinicopathological factors in invasive breast cancer was low. PMID- 30412124 TI - Generalist versus specialist nurses' knowledge, attitudes, and behavioral intentions toward promoting pulmonary rehabilitation for patients with chronic obstructive pulmonary disease: A cross-sectional correlational study. AB - Pulmonary rehabilitation (PR) is an effective strategy to manage chronic obstructive pulmonary disease (COPD), though its utilization rate is low. One reason for this low utilization rate is that nurses do not provide COPD patients with enough health education to increase the patient's motivation for PR participation. This study examined knowledge, attitudes, and behavioral intention toward PR promotion. The study also investigated the correlates of behavioral intentions to promote PR among pulmonary nurses.A cross-sectional correlational design was used. Overall, 284 nurses (all women) from chest medicine and general internal medicine wards in 3 hospitals within Midwest Taiwan were recruited. Data were collected by anonymous, self-administered questionnaires. We aimed to understand if there would be differences in the Chest Medicine and Generalist nurses on these outcomes, given the specialty versus generalist nature of their practice. Results were analyzed using multiple linear regressions.Although the 2 groups of nurses (ie, Chest Medicine, General Medicine) showed no differences in PR knowledge, attitudes, or behavioral intentions, they lacked sufficient PR knowledge and skills. The accuracy rate of PR knowledge was approximately 12% and self-evaluated PR skills were less than 50%. Self-efficacy in promoting PR was above average (ie, 57%-60%), and the strength of attitudes and behavioral intentions was over 70%. A multiple linear regression revealed that behavioral intentions of nurses working in the chest medicine ward were influenced by behavioral attitudes, and also PR skills and self-efficacy (explanatory power 33.3%).Attitudes, skills, and self-efficacy heavily affected pulmonary nurses' ability to promote PR; however, PR knowledge and skills remain low. Therefore, future implementation of practical PR training courses is needed to strengthen nurses' behavioral intentions toward PR promotion.Improved pulmonary rehabilitation-related skill, attitudes, clinical experience of PR programs, and/or practical PR training are needed among both generalist and specialist nurses. Education courses and clinical practice training should be increased in the future to promote pulmonary rehabilitation of COPD patients. PMID- 30412125 TI - Choosing between ticagrelor and clopidogrel following percutaneous coronary intervention: A systematic review and Meta-Analysis (2007-2017). AB - BACKGROUND: Limitations have been observed with the use of clopidogrel following percutaneous coronary intervention (PCI) indicating the urgent need of a more potent anti-platelet agent. We aimed to compare the efficacy and safety of ticagrelor versus clopidogrel following PCI. METHODS: Online databases were searched for relevant studies (published between the years 2007 and 2017) comparing ticagrelor versus clopidogrel following coronary stenting. Primary outcomes assessed efficacy whereas secondary outcomes assessed safety. Odds ratios (OR) with 95% confidence intervals (CIs) based on a random effect model were calculated and the analysis was carried out by the RevMan 5.3 software. RESULTS: A total number of 25,632 patients with acute coronary syndrome (ACS) [12,992 patients with ST segment elevation myocardial infarction (STEMI) and 14,215 patients with non-ST segment elevation myocardial infarction (NSTEMI)] were included in this analysis, of whom 23,714 patients were revascularized by PCI. Results of this analysis did not show any significant difference in all cause mortality, major adverse cardiac events (MACEs), myocardial infarction, stroke and stent thrombosis observed between ticagrelor and clopidogrel with (OR: 0.83, 95% CI: 0.67-1.03; P = .09), (OR: 0.64, 95% CI: 0.41-1.01; P = .06), (OR: 0.77, 95% CI: 0.57-1.03; P = .08), (OR: 0.85, 95% CI: 0.57-1.26; P = .42) and (OR: 0.70, 95% CI: 0.47-1.05; P =.09).However, ticagrelor was associated with a significantly higher minor and major bleeding with (OR: 1.57, 95% CI: 1.30-1.89; P = .00001) and (OR: 1.52, 95% CI: 1.01-2.29; P = 0.04) respectively. Dyspnea was also significantly higher in the ticagrelor group (OR: 2.64, 95% CI: 1.87-3.72; P = .00001). CONCLUSION: Ticagrelor and clopidogrel were comparable in terms of efficacy in these patients with ACS. However, the safety outcomes of ticagrelor should further be investigated. PMID- 30412126 TI - Performance of noninvasive laser Doppler flowmetry and laser speckle contrast imaging methods in diagnosis of Buerger disease: A case report. AB - RATIONALE: Buerger disease (BD) is a nonatherosclerotic, inflammatory, segmental vascular occlusive disease, which affects small and medium-sized arteries and veins and is triggered by substantial tobacco exposure. Angiographic findings consistent with BD are required for diagnosis. Laser Doppler flowmetry (LDF) and laser speckle contrast imaging (LSCI) could represent potential noninvasive alternative techniques to angiography. PATIENT CONCERNS: We report the case of a 49-year-old smoker who developed an ischemic ulcer in the distal segment of the second finger of the left hand. He had no medical history. DIAGNOSES: In our vascular center, LDF and LSCI are conducted routinely for digital artery disease diagnosis. LDF was indicative of digital obstructive artery disease (DOAD). Postocclusive reactive hyperemia, assessed by LCSI, demonstrated no skin blood flow (SBF) perfusion in the distal phalanx of the thumb, index, middle, and auricular fingers. Angiography confirmed BD, showing distally located multisegmental vessel occlusion and corkscrew collaterals in this patient's hands. INTERVENTIONS: Ilomedine treatment was initiated and smoking cessation was definitive. OUTCOMES: Recently, the patient had an improvement in clinical condition despite the persistence of a small zone of necrosis of the left index finger 28 days post-treatment. LESSONS: Our observation suggests that where suspicion of BD is based on clinical criteria, combining LDF and LSCI could represent a noninvasive, safe means of reaching BD diagnosis. Further clinical trials are necessary to confirm this novel observation. PMID- 30412127 TI - Patterns of nystagmus conversion in sudden sensorineural hearing loss with vertigo. AB - The patients with sudden sensorineural hearing loss (SSNHL) may complain of vertigo. Although there have been many reports on SSNHL with vertigo (SSNHL_V), changes in the pattern of nystagmus have not been studied as yet. This study is a retrospective study and aims to investigate the characteristic changes in type of nystagmus and clinical features in patients with SSNHL_V who experienced a change in their nystagmus pattern during follow-up. Among 50 patients with SSNHL_V between January 2012 and December 2015, we identified 15 patients with SSNHL_V whose pattern of nystagmus changed. Initial nystagmus was classified into 5 subgroups: paretic type, irritative type, persistent geotropic direction-changing positional nystagmus (PG-DCPN), persistent apogeotropic direction-changing positional nystagmus (PA-DCPN), and posterior semicircular canal benign paroxysmal positional vertigo. The most common pattern of initial nystagmus was PG-DCPN (n = 7). The change of initial nystagmus pattern occurred on day 2 to 75 from symptom onset, and 2 (of 15) patients showed further conversion. The most common pattern of final nystagmus was PA-DCPN (n = 9). Hearing improvement after treatment was not significantly different (P = .59) between SSNHL_V patients with nystagmus change (25 +/- 17 dB, n = 15) and those without nystagmus change (28 +/ 18 dB, n = 35). In conclusion, clinician's attention is required in evaluating the vertigo symptom in patients with SSNHL_V because the initial patterns of nystagmus can be converted to another type of nystagmus. The presence of nystagmus change during follow-up may not be a prognosticator for hearing recovery in patients with SSNHL_V. PMID- 30412128 TI - Natural prognosis of carbapenem-resistant Acinetobacter baumannii bacteremia in patients who did not receive appropriate antibiotic treatment: A retrospective multicenter study in Korea. AB - Carbapenem-resistant Acinetobacter baumannii (CRAB) infection is a major issues in current era. The aim of study was to investigate the natural prognosis and prognostic factors associated with 28-day mortality in patients with CRAB bacteremia who were not receiving appropriate antibiotic treatment.Adult patients with CRAB bacteremia were retrospectively identified between April 2012 and March 2015 at 5 tertiary hospitals in Republic of Korea. Patients who were transferred to another hospital within 28 days of onset of bacteremia and who receive appropriate antibiotics more than 48 hours were excluded. We investigated prognostic factors associated with 28-day mortality in patients with CRAB bacteremia without appropriate antibiotic treatment.Of enrolled 205 patients, 143 (69.8%) patients died within 28 days after blood culture. Of patients with 28-day mortality, 88.9% (127/143) of patients died within 5 days. Of 78 patients who survived more than 5 days, the 28-day mortality was 20.5% (16/78). Diabetes mellitus (adjusted odds ratio [aOR] 3.81, 95% confidence interval [95% CI] 1.19 12.20), immunocompromised (aOR 8.72, 95% CI 2.62-29.70), sequential organ failure assessment (SOFA) >= 10 (aOR 13.87, 95% CI 3.70-51.96), vasopressor use (aOR 7.03, 95% CI 1.79-27.60), and pneumonia (aOR 4.44, 95% CI 1.67-11.78) were found to be the factors independently associated with the 28-day mortality.The 28-day mortality in patients with CRAB bacteremia without appropriate treatment was high, although some patients could survive. Severity and underlying conditions were important prognostic factors in patients with CRAB bacteremia. PMID- 30412129 TI - Successful low-dosage thrombolysis of massive pulmonary embolism in primigravida: A case report. AB - RATIONAL: Thrombolysis in primigravida with hemodynamic instability is controversial, especially treatment with low-dosage recombinant tissue plasminogen activator (rtPA), and related studies are extremely rare. Here, we report the case of a 26-year-old primigravida diagnosed with an acute massive pulmonary embolism (PE) that prompted initiation of thrombolysis with low-dose alteplase. PATIENT CONCERNS: The patient was admitted to the Emergency Department with chief complaints of a sudden onset of extremely dyspnea, chest tightness, and confusion over a 6-hour period. She was found to have significant dilation of her right ventricle, moderate pulmonary arterial hypotension, as shown by transthoracic echocardiography, and a typical S1-Q3-T3 pattern, as shown by electrocardiogram (ECG). DIAGNOSIS: Acute massive PE in primigravida. INTERVENTION: The patient underwent intravenous thrombolysis with a half dose of alteplase. OUTCOMES: The fetus lived through this severe event during the mother's stay in the Intensive Care Unit; however, surgical abortion was unexpectedly proposed due to long-term hypoxia and high-risk of relapse and exacerbation and was performed successfully after the agreement of her kin. The patient recovered gradually, and results of her laboratory tests and postsurgical, repeated contrast-enhanced computed tomography had normalized by her 3-month follow-up. LESSONS: Administration of low-dosage alteplase in primigravida with hemodynamic instability is extremely rare and controversial; however, our case suggests that this treatment strategy is relatively safe and feasible. In addition, nonradiometric examination played a major role in the diagnosis of PE in this patient. Because radiation use is contraindicated during pregnancy, these examinations could be the first choice for pregnant patients with suspected PE. PMID- 30412130 TI - The differences in epidemiological and psychological features of globus symptoms between urban and rural Guangzhou, China: A cross-sectional study. AB - To compare the epidemiological and psychological features of globus symptoms between individuals from urban and rural areas in Guangzhou.In total, 3360 individuals aged 18 years and over were selected to participate in our questionnaire investigation using random cluster sampling under the stratification of a urban area and a rural area. The questionnaire comprised questions on personal characteristics and globus symptomatology and psychological characteristic and sleep quality scales.Lifetime prevalence and Glasgow-Edinburgh throat scale scores of globus symptoms were greater in the urban area than in the rural area, but no significant differences in sex ratio or onset age between individuals with globus were found. The incidences and severity of anxiety, depression, and sleep disorders were significantly higher among patients who presented with globus in the urban area than among those in the rural area.The lifetime prevalence of globus symptoms and the psychological features of globus patients differ between urban and rural inhabitants. We should pay more attention to these differences. PMID- 30412131 TI - Relapsed/refractory acquired thrombotic thrombocytopenic purpura in a patient with Sjogren syndrome: Case report and review of the literature. AB - RATIONALE: Thrombotic thrombocytopenic purpura (TTP) is a rare, fatal disorder which could be caused by autoimmune diseases. However, TTP secondary to Sjogren syndrome (SS) is extremely rare. PATIENT CONCERNS: A 47-year- old woman with an 8 year history of SS was admitted due to skin ecchymosis and bleeding gums. Then she gradually developed fever and headache. DIAGNOSES: Laboratory investigations suggested anemia, thrombocytopenia, increased lactic dehydrogenase, and a disintegrin-like metalloproteinase with thrombospondin motif type 1 member 13 (ADAMTS13) activity deficiency with high inhibitor titers. Acquired TTP was thus diagnosed. INTERVENTIONS: Plasma exchange (PE) was the first choice for treatment, while glucocorticoid, cyclosporine A (CSA), rituximab, and intravenous immunoglobulin (IVIG) were used simultaneously. Bortezomib, a selective proteasome inhibitor and thereby inducing apoptosis in both B-cells and plasma cells, was added. OUTCOMES: She was discharged from the hospital and then treated with prednisone of 40 mg/d and hydroxychloroquine. The patient remained in full remission. LESSONS: We conclude that bortezomib should be considered for patients with TTP refractory to PE, steroids, and rituximab due to its efficacy and relatively favorable side effect profile. PMID- 30412133 TI - A retrospective pilot study of high-quality nursing care for cervical cancer. AB - This retrospective pilot study investigated the feasible effect of high-quality nursing care (HQNC) for patients with cervical cancer (CC). A total of 58 patients with CC were included in this study. All patients were treated with routine care, and were divided into a treatment group and a control group, according to the different interventions they received. In addition, patients in the treatment group also received HQNC. The primary outcome of anxiety was measured by Beck Anxiety Inventory (BAI). The secondary outcomes were rumination, as measured by ruminative responses scale (RRS); and emotion, as measured by the Emotion Regulation Questionnaire (ERQ). All outcomes were measured before and after 4-week treatment. After treatment, patients in the treatment group showed better outcomes in anxiety, as evaluated by BAI scale (minimal, P = .04), rumination, as measured by RRS (P < .01), and emotion, as assessed by ERQ (P < .01), compared with patients in the control group. The results of this study demonstrated that HQNC might have positive effect in patients with CC after 4 week treatment. PMID- 30412132 TI - Prognostic significance and dynamic change of plasma macrophage migration inhibitory factor in patients with acute ST-elevation myocardial infarction. AB - Macrophage migration inhibitory factor (MIF) has been reported as an inflammatory cytokine in many inflammatory diseases, including rheumatoid arthritis and ischemic diseases. However, dynamic changes of MIF within the first 24 hours on admission and potential prognostic significance following ST-elevation myocardial infarction (STEMI) have been little known. In this study, we examined the dynamic change of MIF level and its potential diagnostic and prognostic value after the onset of STEMI. Plasma MIF levels were evaluated in symptomatic subjects who received coronary angiogram with a median 27 months follow-up for the development of major adverse cardiovascular events (MACEs).Of all 993 subjects, patients with STEMI showed a significantly higher MIF levels than in patients with non-ST elevation acute coronary syndrome, stable angina, and normal coronary artery, respectively (P < .01). Plasma MIF levels elevated as early as 12 hours post onset of STEMI and peaked rapidly within 24 hours, and remained elevated from about day 5 till day 9 during hospitalization. In multivariate analysis, MIF was associated with a decreased risk of MACEs occurrence in STEMI patients after adjustment for traditional cardiovascular risk factors [hazard ratio 0.81, (0.72 0.90), P < .001]. The ROC curve for MACEs was 0.72 (95% CI 0.62-0.80, P < .001) and 0.85 (95% CI 0.80-0.90, P < .001) using Framingham risk factors only and combined with MIF, individually.Measurement of MIF adds potential information for the early diagnosis of acute STEMI and significantly improves risk prediction of MACEs when added to a prognostic model with traditional Framingham risk factors. PMID- 30412135 TI - Women were noninferior to men in cardiovascular outcomes among patients with ST segment elevation myocardial infarction treated with primary percutaneous coronary intervention from Taiwan acute coronary syndrome full-spectrum registry. AB - This study was conducted to compare the survival rate and the influencing factors between women and men following ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI).A national-wide Acute Coronary Syndrome Full Spectrum Registry conducted by the Taiwan Society of Cardiology was used for data collection between October 2008 and January 2010. Details of 1621 patients with STEMI treated with primary PCI, including 1350 (83%) men and 271 (17%) women, were collected. Composite outcomes included all cause death, myocardial reinfarction, and an ischemic stroke. Demographic data, comorbidities, clinical presentations, details of treatment received, and outcomes were recorded at 3-month intervals for 1 year.No significant difference was observed between men and women in the composite endpoints after STEMI during their hospital stay (5.5% vs 2.5%, P = .07). However, women showed significantly higher in-hospital and 1-year mortality rates than those of men (4.1% vs 1.8%, P = .008; 11.0% vs 4.1%, P = .000, respectively). Compared with men, women presented with higher age (mean age 68.9 vs 58.9 years, P = .001), less body weight (58.7 vs 70.9 kg, P < .001), more number of risk factors, delayed diagnosis, and more number of inadequate medical treatments. After adjusting for age and cardiovascular risk factors, the difference in mortality ceased to exist between men and women.Although female patients with STEMI-treated primary PCI had higher in-hospital and 1-year mortality rates than those of males in Taiwan, there was no gender difference after adjusting for age and cardiovascular risk factors. PMID- 30412134 TI - Whole grain diet reduces systemic inflammation: A meta-analysis of 9 randomized trials. AB - BACKGROUNDS: Observational studies had suggested an inverse association between whole grain consumption and concentration of inflammatory markers, but evidence from interventional studies was inconsistent. Therefore, we conducted a meta analysis of randomized trials to have a better understanding of this issue. METHODS: This study has been registered in PROSPERO (ID: CRD42018096533). We searched PubMed, Web of Science, Embase, Medline, and Cochrane Library for articles focusing on the topic from inception to 1 January, 2018. Summary standardized mean difference (SMD) and 95% confidence interval (CI) were calculated by using either random effect model or fixed effect model according to the heterogeneity of included studies. Subgroup analysis was also performed. RESULTS: Totally 9 randomized trials included 838 participants were identified. In a pooled analysis of all studies, consumption of whole grains had an inverse association with inflammatory markers (SMD 0.16, 95% CI, 0.02-0.30), including C reactive protein (CRP), Interleukin-6 (IL-6), Tumor necrosis factor-alpha (TNF alpha), Interleukin-1beta (IL-1beta). Specific analyses for CRP and IL-6 yielded that whole grain diet was related with a significant decrease in the concentration of CRP (SMD 0.29, 95% CI, 0.08-0.50) and IL-6 (SMD 0.19, 95% CI, 0.03-0.36). CONCLUSIONS: The evidence suggested that citizens could benefit from increased whole grain intake for reducing systemic inflammation. Further well designed studies are required to investigate the mechanism under the appearance. PMID- 30412136 TI - Guided intracameral air injection based on 3D reconstructed anterior optical coherence tomography images in iatrogenic Descemet's membrane detachment: Case report. AB - RATIONALE: We emphasize the importance of using anterior optical coherence tomography (OCT) to understand the details of iatrogenic Descemet's membrane detachment (DMD) in 3 dimensions; this allows appropriate air injection into the anterior chamber in terms of both direction and method. PATIENTS CONCERNS: A 74 year-old Korean female presented with progressive visual impairment. On slit-lamp examination, an iridocorneal adhesion was observed, associated with a full thickness corneal opacity 3.0-mm in diameter. Adherence between the crystalline lens (with moderate cortical cataracts) and the iris was evident near the opacity. Therefore, we decided to perform cataract surgery. DIAGNOSIS: Intraoperatively, iatrogenic DMD occurred during removal of the iridocorneal adhesion, as clearly shown on postoperative OCT. However, slit-lamp examination did not reveal the details of the DMD because of the corneal edema. INTERVENTIONS AND OUTCOMES: The DMD was evaluated via 3-dimensional (3D) reconstruction of multiple anterior OCT images. The reconstructed images were used to guide intracameral sterile air injection from an appropriate direction using an optimal method. The patient was asked to maintain an appropriate head position to allow the injected air to re-attach the DM. LESSONS: Three-dimensional (3D) reconstruction of an iatrogenic DMD developing during intraocular surgery is necessary to establish the details of the injury and allow accurate air injection into the anterior chamber; the air stream effectively re-attached the DM. It is important that the iatrogenic DMD can be treated properly only by confirming the accurate 3-dimensional shape as well as the position, height, and width of the DMD. PMID- 30412138 TI - Association between years since manufacture and utilization of computed tomography scanner in South Korea: A cross-sectional study (a STROBE-compliant article). AB - Health care institutions that acquire an expensive, brand-new computed tomography (CT) scanner are likely to perform excessive scanning in an attempt to recover their investment as early as possible. We examined the association between the age of CT scanners and the number of CT scans at small-sized hospitals and clinics in Korea and assessed the notable increase in scanning quantity at health care institutions with a recently manufactured CT scanner.A cross-sectional study designed to analyze whether the age of CT scanners was associated with the number of scans at small-sized hospitals and clinics that were operating a CT scanner for the full year 2008 (n = 703). Data were obtained by linking the National Health Insurance Claims Database and Health Care Institution Statistics.A multiple regression analysis found that the older a CT scanner was, the fewer CT scans were performed in terms of annual total (beta = -34.8; P < .001) and patient average (beta = -0.0018; P = <.001).Health care institutions with newer CT scanners administered more CT scans in terms of annual total and scans per patient. Because this may indicate the practice of excessive scanning with newly acquired equipment, it is necessary to have a system of regularly monitoring the quantity and retake rate of CT scanning in these health care institutions so as to prevent unnecessary use of CT. PMID- 30412137 TI - Spontaneous perforation and intraabdominal abscess due to Meckel's diverticulum revealed on SPECT/CT with 99m-technetium pertechnetate: A case report. AB - RATIONALE: Meckel's diverticulum (MD) is common congenital abnormality of gastrointestinal tract, only about 6.4% of patients become symptomatic. A smaller minority develop potential fatal complications such as hemorrhage, perforation, abscess, and bowel obstruction. PATIENT CONCERNS: A 15-year-old boy with history of appendicitis was admitted due to worsening abdominal pain and nausea for 1 day. The physical examination showed the abdomen was soft, with the diffuse tenderness to palpation and voluntary guarding. DIAGNOSIS: Abdominal computed tomography showed a probable MD in the distal ileum. Single photon emission computed tomography/computed tomography (SPECT/CT) fusion imaging revealed the focal concentration at the right lower quadrant of abdomen region. INTERVENTION: After the initial management including antibiotic administration and intravenous fluid resuscitation, MD with perforation and localized suppurative peritonitis was confirmed in surgery. The patient underwent a diverticulectomy. Histological examination was confirmed as MD with focal heterotopic gastric tissue. OUTCOMES: After surgery, the patient had uneventful recovery during 3 months follow-up. LESSONS: Spontaneous perforation and intraabdominal abscess due to MD is very rare. Accurate diagnosis of MD remains challenging as clinical symptoms from these complications occur nonspecifically. SPECT/CT fusion imaging is critical for prompt recognition and accurate diagnosis in the successful management of this rarely life-threating complication. PMID- 30412139 TI - Safety and efficacy of pharmacomechanical thrombolysis for acute and subacute deep vein thrombosis patients with relative contraindications. AB - To evaluate the safety and efficacy of pharmacomechanical thrombolysis (PMT) performed for patients with relative contraindications.From June 2014 to December 2016, 112 patients with acute or subacute proximal deep vein thrombosis (DVT) were enrolled in this study. 60 patients (including 27 acute DVT patients and 33 subacute DVT patients) were treated with catheter-directed thrombolysis (CDT), and 52 patients with relative contraindications (including 25 acute DVT patients and 27 subacute DVT patients) with PMT. Assessment of venous recanalization was conducted using venography the time Inferior vena cava filter is removed, and complications were used to compare safety and efficacy between the groups.The outcomes of acute DVT patients no matter which kind of therapy performed, CDT or PMT, were significant better than subacute DVT patients (PCDT = .04 and PPMT = .01). However, there was no significant difference between CDT acute group and PMT acute group or between CDT subacute group and PMT subacute group (Pacute = .80 and Psubacute = .84). For complications of all patients, there was no mortality and major bleeding occurred.PMT could be a safe and effective management for DVT patients with relative contraindications, and the acute DVT may achieve better outcomes when they receive CDT or PMT. PMID- 30412140 TI - Integrase inhibitor-based regimens result in more rapid virologic suppression rates among treatment-naive human immunodeficiency virus-infected patients compared to non-nucleoside and protease inhibitor-based regimens in a real-world clinical setting: A retrospective cohort study. AB - The integrase strand transfer inhibitor (INSTI) class of antiretroviral therapy (ART) may result in faster time to virologic suppression compared with regimens that contain protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs). However, differences in time to achieve virologic suppression are not well-defined in routine clinical settings with contemporary antiretroviral agents.Study was a retrospective single-center study of treatment naive human immunodeficiency virus (HIV) patients initiating ART between 2013 and 2016. Among patients on different ART regimen types, we compared rates of and median time to virologic suppression [viral load (VL) <50 copies/mL].A total of 155 patients-45 (29%) female and 110 (71%) male-met study inclusion criteria. Median age was 42 years (interquartile range 31-52), and median baseline CD4 count was 288 cells/MUL and VL was 60,000 copies/mL. Seventy-one (46%) initiated an INSTI-based regimen, 58 (37%) were on NNRTI-based regimens, and 26 (17%) on PI based regimens. In total, 112 (72%) patients achieved virologic suppression at 12 months. Patients on INSTI-based regimens were more likely to achieve virologic suppression by 3, 6, and 12 months (P < .01), and had lower median time to suppression (60 vs 137 days on NNRTI-based regimens and 147 days on PI-based regimens, P < .01).Patients on INSTI-based ART regimens in a real-world setting experienced higher rates of virologic suppression and shorter time from ART initiation to virologic suppression. For HIV patients on INSTI-based ART regimens, virologic failure should be suspected in those with VLs >50 copies/mL before the current recommendation of 48 weeks. PMID- 30412141 TI - Prognostic role of targeting protein for Xklp2 in solid tumors: A PRISMA compliant systematic review and meta-analysis. AB - BACKGROUND: The prognostic role of targeting protein for Xklp2 (TPX2) in solid tumors has been investigated in several researches, but the results remain controversial. Here we present a meta-analysis to systematically review the association between TPX2 expression levels and prognosis of human solid tumors. METHODS: Studies published until December 2017 were searched in PubMed, Web of Science, and EBSCO, 13 studies (2134 patients) were collected for analysis. Odds ratios (ORs) for overall survival (OS) and disease-free survival (DFS) from individual studies were calculated by the application of Mantel-Haenszel random effect model. Pooled ORs were estimated by Z test. Publication bias and interstudy heterogeneity analyses were also performed. RESULTS: TPX2 overexpression was associated with poor OS at 3 and 5 years [OR = 4.63, 95% confidence interval (CI): 3.27-6.56, P < .00001; OR = 4.05, 95% CI: 2.32-7.07, P < .00001, respectively] of solid tumors. Similar results were observed with DFS at 3 and 5 years (OR = 3.35, 95% CI: 1.83-6.14, P < .0001; OR = 2.94, 95% CI: 1.74-4.98, P < .0001, respectively). Subgroup analysis revealed that increased TPX2 expression was related to worse prognosis of gastric cancer and hepatocellular cancer, while irrelevant to esophageal squamous cell cancer at 5 year survival rate. CONCLUSIONS: Overexpression of TPX2 is related to poor survival rate in most solid tumors, which indicates that the expression level of TPX2 is a significant prognostic parameter and potential therapeutic target in various solid tumors. PMID- 30412142 TI - Pulmonary infection caused by Nocardia cyriacigeorgica in a patient with allergic bronchopulmonary aspergillosis: A case report. AB - RATIONALE: Nocardia species is known as conditional pathogenic bacteria. Among Nocardia species, pulmonary infection caused by Nocardia cyriacigeorgica associated with Aspergillus fumigatus complex lung disease is rarely reported. PATIENT CONCERNS: A 55-year-old female with a history of productive cough with recurrent expectoration for 20 years presented with increasing cough for 12 months. The patient presented complaining of respiratory symptoms including increasing cough with yellow phlegm, poor appetite, and generalized fatigue for a week prior to admission. DIAGNOSES: Nocardia cyriacigeorgica pneumonia was identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and 16S rRNA gene sequencing. INTERVENTIONS: Combined treatments (trimethoprim-sulfamethoxazole and meropenem) were administered after identification of N cyriacigeorgica. OUTCOMES: The respiratory symptoms of the patient had improved both clinically and radiologically after 4 weeks of antibacterial therapy. LESSONS: Early precise diagnosis and prompt combined therapy are of vital importance in severe Nocardia pulmonary infection. PMID- 30412143 TI - Management of recalcitrant epithelial ingrowth after laser in situ keratomileusis: A case report. AB - RATIONALE: Surgically lifting and scraping, mitomycin C, fibrin glue, Nd:YAG laser, hydrogel ocular sealant, and amniotic membrane patch are the reported methods for treating epithelial ingrowth after laser in situ keratomileusis (LASIK). Here we report the management of a rare case of recalcitrant epithelial ingrowth using a combined scraping/laser ablation that occurred after LASIK. PATIENT CONCERNS: A female patient underwent uncomplicated bilateral LASIK 10 years before incurring trauma to the right eye. Approximately 2.5 years later, she presented with a complaint of blurred vision and a foreign body sensation. DIAGNOSES: The patient was diagnosed with epithelial ingrowth because of the presence of corneal melting, wrinkling, and scarring. Approximately 6 months after injury, the patient underwent corneal scraping to remove the epithelial ingrowth. Even after 2 more scraping procedures, the epithelial ingrowth recurred. Corneal densitometry was performed (Oculus Pentacam), which revealed a maximum corneal densitometry value of 87.4 gray scale units (GSUs) in the inferonasal quadrant. This reading highly elevated compared to readings from normal cornea (approximately 20 GSU). INTERVENTIONS: We used a combination scraping/laser ablation procedure to correct astigmatism and eliminate any undetected residual corneal epithelial cells. OUTCOMES: Two days following the procedure, the patient developed a mild corneal opacity in the area where the epithelial ingrowth had been located. At this time, visual acuity was 20/40, refractive error (manifest refraction) was -0.50 Diopter (D) sph, and the maximum corneal densitometry value was 79.2 GSU. After 2 months, the central cornea remained slightly blurred, but visual acuity was 20/25. No signs of recurrent epithelial ingrowth were present and the maximum corneal densitometry reading had decreased to 55.4 GSU. LESSONS: This case demonstrates that epithelial ingrowth should be treated as soon as possible after trauma and that thorough scraping combined with laser ablation is effective for treating recalcitrant epithelial ingrowth. Additionally, corneal densitometry can be used to assess epithelial ingrowth severity and treatment efficacy. PMID- 30412144 TI - [The evaluation of the effectiveness of cardiac rehabilitation of the patients after percutaneous coronary interventions]. AB - BACKGROUND: Notwithstanding the current abundance of the methodological approaches to the evaluation of the outcomes of medical rehabilitation, the criteria for the effectiveness of the combined influence of the curative physical factors are still inadequate and remain at variance with the principles of evidence-based medicine. AIM: The objective of the present study was to develop a method for the evaluation of the effectiveness of the rehabilitation activities in the patients presenting with the acute coronary syndrome following endovascular cardiac interventions. MATERIAL AND METHODS: This work is based on the results of a prospective single-center cohort-based clinical study involving the subjects who had undergone myocardial infarction following endovascular cardiac surgical interventions. The duration of the patient's participation in the study was 21 days. RESULTS: We have developed the integrative approach to the creation of the unified multi-criteria system for the evaluation of the effectiveness of the treatment of the patients presenting with cardiovascular diseases after percutaneous coronary interventions (PCI). In addition, the step by-step description of this technology is presented. The algorithm for the calculation of the integrated health index and the evaluation of the overall effect of the rehabilitation activities was proposed based on the assessment of the clinical, laboratory, and functional indicators of the health status together with the psychological characteristics of individual patients. It is proposed to consider an integrated health index as a parameter for estimating the rehabilitation potential of the patients suffering from cardiovascular diseases after percutaneous surgical interventions. CONCLUSION: The proposed system for the evaluating of the effectiveness of comprehensive medical rehabilitation differs from analogous intellectual products in that it excludes the subjective interpretation of the severity of clinical symptoms associated with the concrete pathological process and makes impossible the arbitrary determination of the weight of the peculiar features of the patient's condition. Moreover, it allows to reduce the parameters of different types chosen as the criteria for the evaluation of the effectiveness of rehabilitation to the standardized values, to obtain an unambiguous numerical expression of the results of the rehabilitative treatment, and to compare the outcomes of the rehabilitation activities based at different treatment and prevention settings. PMID- 30412145 TI - [The differential algorithm for the prescription of the stabilizing training to the patients following replacement arthroplasty of the lower extremities]. AB - BACKGROUND: The biological feedback-based stability (balance) training is used for the rehabilitation of the patients following replacement arthroplasty of the lower extremities with the purpose of restoration of their postural balance. AIM: The objective of the present study was to develop a differential algorithm for the prescription of the stability training to the patients after they had undergone the endoprosthetic replacement of the joints of the lower extremities. MATERIAL AND METHODS: The study included 48 patients presenting with the following nosological forms: hip arthrosis with total replacement arthroplasty and gonarthrosis with total replacement arthroplasty. All the patients underwent the biofeedback-based stability training with the use of the dynamic balance Pro Kin system ('Technobody', Italy) using the 'Skiing' No. 10 computer game during 20 minutes every day. The clinical and instrumental methods were employed for the purpose. RESULTS: The rehabilitation subgroups of the patients who had undergone the were distinguished for the first time based on the identification of the main risk factors. It was shown that the main factors having the most pronounced influence on the recovery of postural balance under the conditions of stability training with biological feedback include the age, the time after surgery, the results of evaluation using the Spielberger-Hanin anxiety scale and the Bek depression scale, the level of co-morbidity, the risk of falling estimated from the Morse-Fall scale, and the results of the digit-symbol test based on the Wegsler intelligence scale. CONCLUSION: The distinguishing between rehabilitation subgroups allowed to develop the differentiated algorithm for the prescription of the stability training with biological feedback for the purpose of restoration of the patients' postural balance following total replacement arthroplasty of the lower extremities. PMID- 30412146 TI - [The role of motivational factors in the health promotion training programs for the overweight subjects]. AB - BACKGROUND: The relevance of this ensues from the fact that despite the numerous currently available health promotion training programs for the reduction of body weight, there is still the need for the development of the new forms of the efficacious physical training programs and the methods of motivation for compliance with them among the people of different age, sex and social status. AIM: The objective of the present study was to determine the role of motivational factors, including the assessment of the biological age, in the improvement of the effectiveness of the health promotion training programs for the reduction of the excess body weight. MATERIAL AND METHODS: A total of 82 students with overweight and first-degree obesity at the age from 17 to 21 years (average age 18.5+/-1.4 years) were examined. 42 girls included in the first (main) group spent 9 months performing health promotion training programs on an individual basis developed taking into consideration the motivational factors. The physical training programs included the aerobic exercise in the form of dance classes. 40 students in the control group were engaged in physical training envisaged by the academic curriculum of the university. The third group (the group of comparison) was comprised of 36 practically healthy girls having the normal body weight. We studied the components of the body composition with the use of bioimpedanceometry, evaluated the physical working capacity (the PWC-170 test) and the adaptive reserves of the body (heart rate variability test as proposed by R.M. Baevskyi, Garkavi test). In addition, the psycho-emotional status of the participants was estimated making use of the Lusher test and SAN. The biological age was determined by the original method based on the combination of the morphological and functional indices. RESULTS: The excess body weight in the students comprising group 1 was reduced by 10% on the average; simultaneously the physical working capacity among these students increased by an average of 24.5% while the level of emotional stability and self-esteem increased by 20% and 24%, respectively. We also documented a decrease in the initially increased biological age by 5 years on the average. The students included in group II did not experience any significant changes in the parameters of interest. CONCLUSION: The consideration of the motivational factors for the development of the training programs designed to promote the reduction of the excessive body weight significantly increases their effectiveness, as evidenced by the improvement of the morpho-functional and psychological characteristics in the students of the first group and its absence in their counterparts included in group II. PMID- 30412148 TI - [The evaluation of the effectiveness of the application of bischofite-modified yellow clay (an experimental studi)]. AB - BACKGROUND: The topical problems in balneotherapeutics and health resort activities in general are the development of the yellow clay-based preparations enriched in the natural mineral bischofite and the investigation of their therapeutic effects with the purpose of improvement of their curative potential. AIM: The objective of the present study was to evaluate the effectiveness of the course of the experimental therapeutic applications of the yellow clay obtained by the open pit mining of its deposits located in the vicinity of Pyatigorsk and modified by the addition of bischofite. MATERIAL AND METHODS: The experiments were carried out with the use of 57 eugamic Wistar male rats with adjuvant arthritis. The yellow clay supplemented with bischofite in various concentrations was applied in 12 procedures each 15 minutes in duration every other or every two days beginning from the 38th day of experimentally-induced arthritis. The animals were allocated to five groups as follows: group 1 included the healthy animals that served as controls (n=5), groups 2-5 were comprised of the animals with adjuvant arthritis. The animals included in group 2 served as the experimental model of adjuvant arthritis (n=8), those comprising group 3 were treated by the applications of yellow clay without additives (n=14), group 4 was composed of the animals with adjuvant arthritis treated by the applications of yellow clay containing 10% of bischofite (n=15), the animals in group 5 having adjuvant arthritis were treated by the applications of yellow clay containing 20% of bischofite (n=15). RESULTS: The study has demonstrated the reduction of the reactively enhanced relative abundance of, activated T-cells, and B-lymphocytes down to the respective control values in the animals with adjuvant arthritis after the course of applications of the yellow clay preparations. Simultaneously, normalization of the immunoregulatory index, IRI, (the T-helpers to cytotoxic T lymphocytes ratio) was documented. The treatment was associated with the strong dependence of the interleukin (IL-1beta) contents on the cortisol level and the well apparent relationship between the levels of interleukins and IRI. Specifically, the relation between IL-1beta and IRI following the application of non-modified yellow clay was characterized as (r=+0.8, p=0.03) in comparison with the relation between IL 6 and IRI (r=+0.8, p=0.03) after the treatment with yellow clay containing 10% of bischofite or between IL 6 and IRI (r=+0.8, p=0.004) after the application of yellow clay containing 20% of bischofite. CONCLUSION: The results of the study give evidence of the immunomodulatory action of yellow clay modified by the addition of bischofite. They suggest the promising opportunities for the application of these preparations for the management and rehabilitation of the patients presenting with the diseases of the musculoskeletal system in the future. PMID- 30412147 TI - [The role of the combined balneotherapeutic treatment as the 'add-back therapy' against the background of the anti-hormonal effects of the agonists of gonadotropin-releasing hormone in the women suffering from endometriosis genitalis externa]. AB - BACKGROUND: The use of agonists of gonadotropin-releasing hormone (GnRH) for the rehabilitation treatment of the patients presenting with endometriosis genitalis externa is known to significantly enhance the risk of development of hypoestrogenism. The so-called 'add-back-therapy' is carried out as a preventive measure to eliminate hypoestrogenism caused by the intake of GnRH agonists without detriment to the effectiveness of anti-hormonal therapy. AIM: The objective of the present study was to estimate the effectiveness of the new method ('add-back hormone replacement therapy') in comparison with anti-hormonal therapy with the use of GRH agonists at the stage of the early postoperative medical rehabilitation based on the drinking of mineral waters (MW) and radon therapy (RT) in the patients who had undergone the laparoscopic interventions for the treatment of endometrioid heterotopies of the ovaries (1-3 months post operatively). MATERIAL AND METHODS: To evaluate the effectiveness of the spa and health resort-based rehabilitation measures, the long-term effects of GnRH agonists have been studied in 2 groups of the patients formed by the of simple randomization method. The main group (MG) was comprised of 45 women received medical rehabilitation under conditions of a spa and health resort setting with the application of medium-salt water from the Pyatigorsk spring and radon therapy in the combination with triptorelin. The group of comparison (CG) was composed of 44 women given the treatment with the use of triptorelin under the out-patient conditions. The assessment of the results of the study included: the estimation of the intensity of pelvic pain syndrome, indicators of the hormonal status and the quality of life (QL), ultrasonic examination of the pelvic organs, and the occurrence of adverse effects of triptorelin. The duration of the study was 3 years (2014-2016). RESULTS: The analysis of the long-term results of the rehabilitative treatment has demonstrated that the rehabilitation activities under the spa and health resort conditions within 1-3 months after the surgical intervention including the application of MW and RT in the combination with an agonist of gonadotropin-releasing hormone (triptorelin) greatly contributed to the stability of the results of the treatment: specifically, only 2.5% of the patients suffered the recurrence of cystic ovarian endometriosis whereas 24.5% (p<0.001) reported the restoration of the reproductive function. The patients comprising the control group experienced the recurrence of the pathologic process in 7.5% of the cases and the restoration of the reproductive function in 15.8% of the cases (p<0.001). Simultaneously, the quality of life in the patients in the main group improved 3.4 times on the average in comparison with the initial level (p<0.001). The 2.2-fold improvement of the quality of life was documented in the control patients (p<0.001). At the same time, the frequency of adverse reactions to the treatment with triptorelin in the control patients was higher than in the main group including pain in the epigastric area, headache, irritability, hyperhidrosis, and instability of arterial blood pressure (ABP) that significantly deteriorated the life quality in these women. CONCLUSION: The comparative analysis of the results of the follow-up observations has demonstrated that the application of drinking mineral water and radon therapy for the treatment of the women suffering from endometriosis genitalis externa can be recommended as 'add-back therapy' against the background of anti-hormonal effects of agonists of gonadotropin-releasing hormone. PMID- 30412149 TI - [The experience with the organization of the health resort-based treatment of the children under conditions of a megapolis. The present and the future of the service]. AB - BACKGROUND: The Moscow Health Department organized an efficient and comprehensive three-level system of medical rehabilitation for the children. Health resort based treatment is normatively a component of the third stage of rehabilitation. AIM: The objective of the present study was to substantiate the necessity and validity of the health resort-based treatment as an integral part of the third stage of medical rehabilitation. MATERIAL AND METHODS: We have carried out the analysis of activities of 16 health resorts facilities during the period from 2016 to 2017 that included the evaluation in volume terms of the medical assistance, availability of the health resort-based treatment, and its clinical outcomes. The data thus obtained were systematized and processed with the use of the MS Office software package. RESULTS: The analysis of dynamics of the extent of the provided medical assistance expressed in terms of volume has demonstrated the increase in the overall number of people who had received health resort-based treatment in 2017 in comparison with that in 2016. The analysis of the structure of the pathological conditions in the patients admitted for the treatment in the health resort settings revealed correlation with the profiles of specialization of these facilities and with the structure of newly registered diseases. The analysis of the services rendered within the framework of the health resort-based treatment programs confirmed the effectiveness of medical assistance organized with the use of such approach. The study revealed challenges still facing the services responsible for the provision of the health resort-based treatment of the children in Moscow and the lines of activities in this field to be carried out in the near future. CONCLUSION: The experience gained by the Moscow public healthcare organizations gives evidence that the health resort facilities located directly in the region are necessary for rendering the comprehensive three-level medical rehabilitation as a very important component of its third (final). PMID- 30412150 TI - [The set of International Classification of Functioning, Disability and Health categories for the study of the effectiveness of rehabilitation of breast cancer patients with the main late complications of the surgical treatment]. AB - The author selected the set of ICF (International Classification of Functioning, Disability and Health) categories selected for breast cancer patients presenting with the major late complications of the surgical treatment, such as upper limp lymphedema, pain syndrome, and mobility limitation in the shoulder joint on the side of the intervention. The problems associated with each component of ICF are described including the body functions - 26 categories, body structures - 15, activities and participation - 49, environmental factors - 31 categories. The author's original classifications are adapted to the ICF terminology. The criteria for estimating the determinants of the structure of spinal nerves, lymph nodes and vessels, veins, the mammary gland, upper extremities, muscles of the trunk, the skin and the related structures have been developed. All the changes in the body functions are described and the methods are proposed for the evaluation of the determinants or the mental and sensory functions, the cardiovascular, immune and respiratory systems, neuromuscular and skeletal functions, the functions of the skin and the related structures. The principles of coding for the components of activity and participation are illustrated (general tasks and requirements, mobility, self-service, everyday life, interpersonal interactions and relationships, main spheres of life, community life, social and civil life) and the environmental factors. The coding is presented in the form of detailed and readily intelligible tables with the explanatory remarks. PMID- 30412151 TI - [Carboxytherapy - an innovative trend in resort medicine]. AB - Carboxytherapy (the treatment based on carbon dioxide injections) is a multipurpose and widely used medical technology. The use of CO2 injections (intracutaneous, subcutaneous, and pneumopuncture) have substantially supplemented and increased the practical relevance of carboxytherapy as a method for the treatment of many diseases. Thanks to it physiological properties, CO2 has antihypoxic, antioxidant, vasodilatory, anti-inflammatory, analgesic, and spasmolytic activities; moreover, it improves blood viscosity, stimulates neoangiogenesis, and regenerative processes. Carbon dioxide is a sort of biochemical 'peacemaker' in tissue oxygenation: when blood cells are exposed to high CO2 concentrations (Bohr effect), the rate of gas exchange (CO2 and O2) increases. The human organism interprets carboxytherapy (local hypercapnia) as oxygen deficiency and responses to it by boosting not only the blood flow, but also the vascular endothelial growth factor which stimulates neoangiogenesis and in the long run improves blood supply and tissue trophism. The multiple mechanisms of action, polymodal efficacy, a tool kit with a wide range of detectors and various modes of treatment make carboxytherapy a popular medical technology all over the world, namely in cosmetology, dermatology, aesthetic medicine, angiology, orthopaedics, cardiology, neurology, pulmonology, gynaecology, urology, proctology, plastic and general surgery, and other areas. Carboxytherapy provides a perfect example of the off-label usage in medicine that made it one of the most extensively applied medical technology for the treatment of various diseases despite the lack of the preclinical data and scarce relevant information available in textbooks, reference books and booklets. PMID- 30412152 TI - [Intraoperative mapping of long association fibers in surgery of gliomas of the speech-dominant frontal lobe]. AB - : Surgery of intracerebral tumors involving long association fibers is a challenge. In this study, we analyze the results of intraoperative mapping of the superior longitudinal, arcuate, and frontal aslant tracts in surgery of brain gliomas. PURPOSE: The study purpose was to compare the results of intraoperative mapping and the postoperative speech function in patients with gliomas of the premotor area of the speech-dominant frontal lobe, which involved the superior longitudinal, arcuate, and frontal aslant tracts, who were operated on using awake craniotomy. MATERIAL AND METHODS: Twelve patients with left frontal lobe gliomas were operated on: 11 patients were right-handed, and one patient was a left-hander retrained at an early age. Histological types of tumors were represented by Grade II diffuse astrocytomas (6 patients), Grade III anaplastic astrocytomas (1 patient), Grade IV glioblastoma (1 patient), Grade II oligodendroglioma (1 patient), and Grade III anaplastic oligodendrogliomas (3 patients). The mean age of patients was 45 (29-67) years; there were 6 males and 6 females. All patients underwent preoperative and postoperative MRI with reconstruction of the long association fibers and determination of the topographic anatomical relationships between the fibers and the tumor. Surgery was performed using the asleep-awake-asleep protocol with intraoperative awakening of patients. All patients underwent cortical and subcortical electrophysiological stimulation to control the localization of eloquent structures and to clarify the safe limits of resection. For intraoperative speech monitoring, a computerized naming test was used with naming of nouns or verbs, and automatic speech was evaluated (counting from 1 to 10, enumeration of months and days of the week), which was complemented by a talk with the patient. Speech disorders before, during, and after surgery were evaluated by a neuropsychologist. The mean current strength during direct electrical stimulation was 3 (1.9-6.5) mA. RESULTS: The association fibers were intraoperatively identified in all patients (SLF/AF in 11 patients; FAT in one patient). In 4 patients, the cortical motor speech area was intraoperatively mapped; in three cases, tumor resection was accompanied by speech disturbances outside the stimulation. During direct electrical stimulation, speech disturbances developed in 7 of 12 cases. All patients underwent control MRI within the first 48-72 h: total resection (more than 90% of the tumor) was performed in 7 cases; subtotal resection was achieved in two patients; partial resection was performed in two cases. According to postoperative MR tractography, the resected tumor bed was adjacent to the SLF/AF complex in 7 cases, located near the SLF/AF complex in three cases, and adjacent to the FAT in two cases. Postoperatively, 11 out of 12 patients had worsening of neurological symptoms in the form of various speech disturbances. In one patient, speech disturbances developed 2 days after surgery, which was associated with an increase in edema. On examination 3 months after surgery, severe speech disturbances remained in 1 patient. CONCLUSION: Resection of frontal lobe tumors in the speech-dominant hemisphere using early postoperative awakening is associated with a high rate of complex speech disorders due to injury to the SLF/AF complex and FAT. In these cases, intraoperative speech mapping with allowance for the course of long association fibers is an essential procedure. Preoperative tractography in combination with intraoperative speech mapping enables identification of association fibers of the SLF/AF complex and FAT, which may help to avoid severe conduction aphasia with poor speech recovery after tumor resection. PMID- 30412153 TI - [Evaluation of vascular reactivity to overcome limitations of neurovascular uncoupling in BOLD fMRI of malignant brain tumors]. AB - The sensitivity of fMRI in identification of eloquent cortical centers in the case of large infiltrative growing tumors and pronounced peritumoral edema may be reduced or significantly limited in some cases. The main cause is an attenuated Blood-Oxygen-Level-Dependent response (BOLD) caused by pathological vascular reactivity and subsequent neurovascular uncoupling of fMRI. In our study, we attempted to overcome these limitations and increase the sensitivity of this technique in identification of eloquent cortical areas adjacent to brain tumors by using vasoreactivity features of a breath-holding test and including these data in the BOLD analysis. Local vasoreactivity using a breath-holding paradigm with the same block design of both motor and speech tests was determined in 5 healthy volunteers and 3 patients in the preoperative period (two patients with high grade gliomas and one patient with single metastasis). A coherence-based model was developed for analysis of BOLD fMRI, which took into account altered hemodynamics in peritumoral zones. Obtained coherence maps demonstrated clinically more significant activation zones that were not seen with standard methods of fMRI processing. Thus, neurovascular uncoupling that is known to affect the accuracy of the BOLD fMRI response adjacent to brain tumors may be partially overcome by including an independent measurement of vasoreactivity using a breath-holding test in the BOLD analysis. PMID- 30412154 TI - [Transsphenoidal surgery of suprasellar meningiomas - is there a future for the technique?] AB - : Surgery of suprasellar meningiomas is a challenge and associated with a high risk of injury to the vascular-neural structures lying along the approach and surrounding the tumor. Currently, many foreign clinics and our Center have introduced a technique for resection of suprasellar meningiomas through the anterior extended transsphenoidal endoscopic endonasal approach. OBJECTIVE: The study objective was to evaluate the role of extended transsphenoidal endoscopic endonasal approaches in surgery of suprasellar meningiomas. MATERIAL AND METHODS: The present study is a retrospective analysis of surgical treatment outcomes in 45 patients (11 males and 34 females aged 23 to 70 years (median, 50 years) with suprasellar meningiomas who underwent surgery for skull base tumors using the anterior extended transsphenoidal endoscopic endonasal approach in the Surgery Department of the Burdenko Neurosurgical Institute in the period from 2009 to 2017. In all cases, surgery was the primary method of treatment. RESULTS: Total tumor resection (the tumor was resected completely together with an infiltrated DM - Simpson 1) was achieved in 77.8% (35/45) of cases; subtotal resection (more than 80% of the tumor was removed) was in 17.8% (8/45) of cases; in 4.4% (2/45) of cases, resection was partial (less than 80% of the tumor was resected). Worsening or development of visual impairments immediately after surgery occurred in 13 (28%) of 45 patients. In 3 of them, vision was completely recovered on conservative treatment by the time of hospital discharge. In 4 patients, vision partially improved by the time of discharge. In 6 patients, vision was not recovered by discharge (in 2 of them, vision partially improved during follow up). Therefore, by the time of hospital discharge, deterioration in vision occurred in 10 (22%) of 45 patients. In 7 (21.2%) out of 33 patients who had visual impairments before surgery, there was an improvement in vision in the postoperative period. CONCLUSION: Analyzing the findings and generalizing our experience, we may say that, in surgery of suprasellar meningiomas, the anterior extended transsphenoidal endoscopic endonasal approach should be used for relatively small (up to 3 cm), medially located symmetrical tumors that do not involve large vessels. The efficacy of this technique for tumors extending into the optic nerve canals requires additional analysis in a larger series of cases. PMID- 30412155 TI - [Liquorrhea after removal of fourth ventricle tumors in children. Retrospective analysis of a series of 211 primary surgeries]. AB - : Wound liquorrhea is a serious and dangerous complication developing after neurosurgical interventions. The highest risk group includes patients operated on using approaches to the skull base. In pediatric neurosurgery, approaches to the posterior cranial fossa are some of the most common ones, with wound liquorrhea amounting to 33%. Studies devoted to the wound liquorrhea problem have been performed in heterogeneous patient groups, which complicates evaluation of the results and reduces their practical value. MATERIAL AND METHODS: The analysis included pediatric patients operated on by a single surgeon for posterior cranial fossa (PCF) tumors in the period from 2009 to 2016. There were 472 patients. Criteria for inclusion in the study were as follows: age under 18 years; predominant tumor location in the fourth ventricle; primary surgery. According to the inclusion criteria, the study involved 211 patients. A search for the key words 'liquorrhea', 'pooling', 'meningocele', 'pseudomeningocele', and 'meningitis' was performed through electronic medical records of the involved patients. We analyzed the data on the total bed-day and the number of days spent in the critical care unit. Surgery protocols were the source of the following information: the presence of an external ventricular drain or ventriculoperitoneal shunt before tumor resection; information on DM closure; information on additional sealing of dura sutures. In addition, the patients were divided into two groups, the main difference between which was the use of additional sealing of dura sutures (Tachocomb, fibrin-thrombin glues, and their combination) to minimize the risk of wound liquorrhea. RESULTS: A total of 211 patients were included in the study. Postoperative wound liquorrhea occurred in 6 (2.8%) patients; another 5 (2.4%) patients had significant pseudomeningocele. Most children spent no more than 1 day in the critical care unit - totally 176 (83.4%) patients; the other 35 (16.6%) children spent more than 1 day in the critical care unit. A group of patients without sealing of dura sutures consisted of 144 (68.2%) patients. Liquorrhea occurred in 4 (2.8%) cases; in 3 (2.1%) cases, there was symptomatic pseudomeningocele without liquorrhea. In a group of patients with the use of suture sealing (Tachocomb, fibrin-thrombin glue in various combinations - 67 (31.8%) patients), there was liquorrhea in 2 (3%) cases and pseudomeningocele without liquorrhea in 2 (3%) cases. On the basis of PSM algorithm application, 2 groups of 67 patients each were formed: the group with sealing (A) and the group without sealing (B) of the DM. Of the 67 cases of sealing, Tachocomb was used in 64 (95.5%) patients, and fibrin-thrombin glue was applied in 53 (59.1%) patients. Differences between the groups in the rate of liquorrhea (2 (3.0%) patients in group A and 4 (6.0%) patients in group B) and pseudomenigocele (3 (4.5%) patients in group A and 5 (7.5%) patients in group B) were statistically insignificant (p=0.68 and p=0.58, respectively). CONCLUSION: Wound liquorrhea has remained a topical issue in surgery for posterior cranial fossa tumors and, if develops, doubles the postoperative bed-day. Our strategy of perioperative management of patients proved its efficacy in reducing the rate of postoperative liquorrhea up to 2.8%. A low percentage of liquorrhea did not allow unambiguous evaluation of the effect of additional sealing of dura sutures (Tachocomb and fibrin-thrombin glue). PMID- 30412156 TI - [Comparative analysis of the efficiency of dura mater defect repair in cerebral surgery]. AB - : The need in replacement of a dura mater (DM) defect occurs in more than 40% of cerebral interventions. Various artificial DM substitutes facilitate solving this problem; however, their efficacy compared to that of patient autogenous tissues has been poorly understood. AIM: We aimed to study the efficacy of various substitutes in repair of dura mater defects. MATERIAL AND METHODS: The study included patients with various intracranial pathologies who were operated on at the Neurosurgery Clinic of the Military Medical Academy in the period between 2010 and 2017, and who underwent repair of the DM during surgery. In surgery for the supratentorial structures, patient autogenous tissues, grafted non-resorbable materials, or applicable collagen matrices were used as substitutes. Depending on the type of substitute material, patients were divided into groups to assess the efficacy of DM closure by comparing the rate of postoperative liquorrhea. In surgery for the posterior cranial fossa (PCF), applicable dural substitutes were not used; in this cohort, the efficacy of autogenous tissues and synthetic materials was compared. RESULTS: In 232 patients, the total rate of liquorrhea was 23.7%. In supratentorial surgery (175 cases), the use of autogenous tissues (n=73), synthetic materials (n=42), and collagen matrices (n=60) was associated with CSF exfusion in 13 (17.8%), 13 (31.0%) and 16 (26.7%) cases, respectively; in statistical analysis, these results were comparable (p>0.05). In PCF surgery (57 cases), the use of autogenous tissues (n=34) significantly more effective (p=0.021) prevented liquorrhea compared to synthetic materials (n=23): complications occurred in 4 (11.8%) and 9 (39.1%) cases, respectively. CONCLUSION: If a DM defect is located supratentorially, the choice of a dural substitute affects the rate of CSF exfusion and related complications. The use of autogenous tissues in PCF surgery statistically significantly reduces the rate of liquorrhea compared to that of synthetic materials. PMID- 30412157 TI - [Diagnosis and interventional treatment of pain syndromes after surgery for degenerative lumbar spine diseases]. AB - : Postoperative pain accompanies up to 20% of interventions for degenerative spine diseases (DSDs). The epidemiologic data are contradictory; clinical and radiological diagnostics is often low efficient; capabilities of interventional diagnosis and treatment techniques are poorly understood. PURPOSE: The study purpose was to investigate the structure of pain syndromes after surgery for DSDs of the lumbar spine, based on complex diagnostics, as well as to evaluate the capabilities of interventional treatment. MATERIAL AND METHODS: We examined 310 patients with postoperative pain syndromes. Patients with obvious indications for repeated surgery were excluded from the analysis; the remaining patients underwent selective diagnostic blockades followed by interventional (puncture) treatment. A positive outcome was defined as a reduction in pain by 50% on the numerical rating scale (NRS-11), by 20% in the Oswestry index (ODI), and by 8 points in the sciatica bothersomeness index (SBI), with the effect lasting for 12 months. Predictive factors for the risk of pain syndromes were analyzed. RESULTS: Out of 310 patients, 162 (52.6%) patients had no obvious indications for surgery. Radicular pain was detected in 56 (18.6%) of 310 patients; the positive treatment outcome was achieved in 38 (67.86%) of 56 patients. Facet pain was present in 29 (9.35%) patients; the positive treatment outcome was achieved in 23 (79.31%) patients. Discogenic pain was found in 12 (3.87%) patients; the positive treatment outcome was achieved in 5 (41.63%) patients. sacroiliac joint (SIJ) pain was present in 42 (13.55%) patients; the positive treatment outcome was achieved in 36 (85.71%) patients. Myofascial and competing pain was detected in 12 (3.87%) patients; the causes were not identified in 11 (3.55%) cases. The main risk factors were sagittal balance parameters. CONCLUSION: Complex diagnostics revealed postoperative pain not associated with surgical causes in 52.6% of cases; the origin of pain was identified in 49.95% of cases. Interventional treatment was effective in 64.81% of cases; failed back surgery syndrome was diagnosed in 16.13% of patients. PMID- 30412158 TI - [The effect of spinal cord stretching on development of spondylogenic cervical myelopathy associated with kyphotic spinal deformity]. AB - OBJECTIVE: The study objective was to specify the role of spinal cord stretching in the pathogenesis of spondylogenic cervical myelopathy associated with kyphotic spinal deformity. MATERIAL AND METHODS: We analyzed long-term outcomes of surgical treatment for spondylogenic cervical myelopathy accompanied by kyphotic spinal deformity. RESULTS: The surgical treatment outcomes were significantly better (p<0.000001) in the case of simultaneous decompression/correction of kyphotic deformity and spine stabilization. CONCLUSION: Spinal cord stretching associated with kyphotic spinal deformity significantly contributes to the pathogenesis of clinical manifestations of spondylogenic cervical myelopathy. PMID- 30412159 TI - [Minimally invasive dorsal decompression-stabilization surgery in patients with overweight and obesity]. AB - : Spinal surgery in patients with overweight and obesity is associated with an increased risk of perioperative complications. Minimally invasive (MIS-TLIF) and traditional (O-TLIF) techniques of rigid stabilization are extensively used, but the advantages and disadvantages of MIS-TLIF in patients with an elevated body mass index (BMI) remain controversial. AIM: The study aim was to assess the efficacy of a new low-invasive rigid fixation technique and traditional open spinal fusion in surgical treatment of degenerative lumbar spine diseases in patients with overweight and obesity. MATERIAL AND METHODS: The study included 73 patients (49 males and 24 females, aged 53 (42; 65) years) with a BMI of more than 25 kg/m2. Two study groups were allocated: group I (MIS-TLIF, n=32) included patients operated on using an original technique of spinal canal reconstruction, interbody spinal fusion, and combined transpedicular stabilization; group II (O TLIF, n=41) included patients who underwent single-level rigid stabilization through the median approach. The mean follow-up period was 34 months in group I and 40 months in group II. Comparative analysis assessed clinical parameters, intraoperative indicators, postoperative period specificity, instrumental data, and complications. RESULTS: Compared to the O-TLIF group, the MIS-TLIF group was characterized by a shorter time of surgery, X-ray exposure, activation, and hospital stay as well as by a smaller amount of blood loss. A comparative analysis of the pain severity (visual analogue scale) and performance status (ODI) in the follow-up period revealed significantly better results in group I, which was associated with smaller intraoperative injury to soft tissues. The total rate of postoperative complications was 9% in group I and 17% in group II (p=0.01). In this case, the interbody bone block formed in the long-term postoperative period in 88% of group I patients and in 83% of group II patients (p=0.15). According to the instrumental data, there was statistically significant greater muscular atrophy in the group after O-TLIF (p<0.001). CONCLUSION: The original technique of minimally invasive rigid stabilization is safe and highly effective in surgical treatment of degenerative lumbar spine diseases in patients with overweight and obesity. MIS-TLIF has a number of significant advantages over O-TLIF in the dynamics of clinical parameters and a low number of perioperative complications, which is confirmed by smaller injury to paravertebral tissues and a better performance status in the long-term postoperative period. PMID- 30412160 TI - [The efficacy of botulinum therapy in treatment of delayed facial palsy after resection of vestibular schwannoma]. AB - : Delayed facial palsy is a complication developing 3 or more days after surgery. The etiology and pathogenesis of this condition has not been fully explored, and there are no treatment standards for it. As in the case of Bell's paralysis, glucocorticosteroids (GCSs) are currently used to treat delayed facial palsy. However, patients with contraindications to GCSs need new therapy modalities. AIM: We aimed to evaluate the efficacy and safety of botulinum therapy in patients with delayed facial palsy after neurosurgical interventions. MATERIAL AND METHODS: We examined 33 patients with delayed facial palsy developed 3 or more days after resection of vestibular schwannoma. The main group included 18 patients with contraindications to GCSs who received injections of botulinum toxin A (BTA) into the facial muscles of the healthy side for muscle relaxation. The comparison group consisted of 15 patients who received a course of prednisolone (1 mg/kg/day) for 5-7 days. The efficacy of treatment was assessed using the House-Brackmann scale and Clinical Global Impression Scale. The follow up period after therapy was 3 months. RESULTS: Delayed facial palsy was more common in the following cases: the facial nerve was located near the antero inferior tumor pole; the tumor was adherent to the facial nerve; the tumor extended in the oral direction; the tumor had with unclear borders and was 11 to 30 mm in size. In most patients of both groups, facial muscle palsy developed more than 11 days after surgery. Treatment both in the main and control groups resulted in a significant improvement: complete regression of the facial asymmetry in patients of the main group and comparison groups 3 months after treatment onset was 83.3 and 93.3% (House-Brackmann scale), respectively. CONCLUSION: Botulinum therapy may be recommended for patients with delayed facial palsy developed after vestibular schwannoma resection, who have contraindications to GCSs. PMID- 30412161 TI - [Technical features and complications of cranioplasty in patients after decompressive craniectomy in the acute period of subarachnoid hemorrhage]. AB - Decompressive craniectomy is used for arresting hypertension-dislocation syndrome developing in seriuos patients in the acute period of subarachnoid hemorrhage. After stabilization of the patient's neurological and somatic status, cranioplasty is performed for protective, cosmetic, and therapeutic purposes. The most common surgery in these patients is skull repair using an autologous bone graft. Before cranioplasty, the patient's bone is preserved in two ways: cryopreservation or subcutaneous implantation to the anterior abdominal wall area. Recently, there have been numerous reports of early and delayed complications of cranioplasty with autologous bone grafts. The use of artificial grafts may reduce the risk of postoperative complications compared to an autologous bone graft. Previously, 'freely' or 'manually' simulated biopolymers were used. At present, they are rarely used for repair of extensive defects due to a poor cosmetic result. However, the advent of stereolithographic modeling and computer modeling of artificial grafts has improved the cosmetic result of this surgery. The purpose of this study is to assess the risk of postoperative complications of cranioplasty as well as to define the criteria for choosing a cranioplasty technique. PMID- 30412162 TI - [Lateral extended transsphenoidal endoscopic approach through the pterygopalatine fossa in surgery for meningoencephalocele of the lateral sphenoid recess]. AB - : Meningoencephalocele is a hernial protrusion of the medulla and meninges through a defect in the skull bones. Due to poor accessibility of meningoencephalocele located in the lateral sphenoid recess region, modern surgical treatment of this pathology prefers to use endoscopic transsphenoidal approaches. MATERIAL AND METHODS: The study included 4 patients with meningoencephalocele of the lateral recess of the sphenoid sinus (1 male and 3 females; mean age, 46.8 years). All patients underwent resection of meningoencephalocele and repair of a skull base defect using the lateral extended transsphenoidal endoscopic approach through the pterygopalatine fossa (transpterygoid approach). RESULTS: In all patients, meningoencephalocele was resected to the bone defect level. There was no postoperative liquorrhea. Complications included bacterial meningitis (1 case), asymptomatic imbibition of the temporal lobe pole (1 case), and temporary numbness in the V2 innervation area of the trigeminal nerve (1 case). CONCLUSION: The paper describes and demonstrates advantages of the lateral extended transsphenoidal endoscopic approach through the pterygopalatine fossa (transpterygoid approach) for surgical treatment of patients with meningoencephalocele of the lateral sphenoid recess. PMID- 30412163 TI - [Radicalness and complications of repeated surgery for malignant neuroepithelial tumors of the posterior cranial fossa in children]. AB - : Treatment of primary malignant neuroepithelial tumors of the posterior cranial fossa (PCF) in childhood includes surgical resection, radiation therapy (RT), and chemotherapy (CT). The radicalness of surgery is one of the most important prognostic factors of survival. Despite the significant advances in treatment, many of these tumors recur. Today, oncologists are increasingly recommending repeated surgery for recurrent malignant neuroepithelial tumors of the PCF to achieve gross total resection (GTR). Patients undergo this surgery after RT and palliative CT, which may increase surgical risks. OBJECTIVE: The study objective was to assess the resection extent of recurrent malignant neuroepithelial tumors of the PCF in children as well as the risk and structure of postoperative complications. MATERIAL AND METHODS: The prospective study included 50 patients under the age of 18 who underwent surgery for recurrent malignant neuroepithelial tumors of the PCF at the Neurosurgical Institute (NSI) in the period between 2002 and June 2015. Anaplastic ependymomas were present in 37 patients, and medulloblastomas were detected in 13 patients. A total of 58 repeated surgeries were performed. RESULTS: GTR was achieved in 53 (91.4%) cases, near total resection (NTR) was achieved in 2 (3.4%) cases, and subtotal resection (STR) was achieved in 3 (5.2%) cases. The mean bed-day after surgery was 12 (4-47) days, and the mean critical care stay was 3.2 (0-23) days. Seven patients required tracheostomy; meningitis developed in 3 patients; liquorrhea occurred in 2 cases. Ventriculoperitoneal shunting was used in 8 (13.8%) cases. One (1.7%) patient died in the early postoperative period. CONCLUSION: Our results demonstrate that resection of recurrent malignant neuroepithelial tumors in children can be performed with high radicalness (90%) and acceptable risks. PMID- 30412164 TI - [Anterior stabilization of the CI-CIII vertebrae after transoral removal of an aggressive aneurysmal bone cyst of the CII vertebra (a case report and literature review)]. AB - : Treatment of patients with atlantoaxial instability caused by various diseases of the skull base and craniovertebral junction combined with ventral compression of the brainstem is a complex issue that is ambiguously resolved in different ways. We present a case of stepped treatment, the most important component of which was successful transoral removal of an aggressive aneurysmal bone cyst of the CII vertebra with anterior CI-CIII segment stabilization using an individual system, which was performed through the same approach. CLINICAL CASE: A 31-year old male patient presented with destruction of the CII body and odontoid process affected by an aggressive aneurysmal bone cyst causing disintegration of the CII posterior wall and odontoid process, which clinically manifested by constricted motion and pain in the cervical spine. RESULTS: Three-step surgical treatment was performed. First, we performed a puncture biopsy of the CII body through the submandibular approach as well as posterior occipitospondylodesis with metal instrumentation from the occipital bone level to the CIV vertebra. Two months later, the patient underwent transoral removal of the CII body and odontoid process lesion and anterior CI-CIII segment stabilization using an individual cover metal system through the same approach. Two weeks after the second intervention, the occipitospondylodesis was transformed to a posterior CI-CIII stabilization system. Control CT 8 months after surgery showed the correct position of both stabilization systems. CONCLUSION: The use of individual instrumentation for anterior stabilization of the CI-CIII vertebrae in various diseases of the craniovertebral junction area is an effective and promising technique. PMID- 30412165 TI - [Microsurgical treatment of non-bleeding cerebral arteriovenous malformations]. AB - Treatment of non-bleeding cerebral arteriovenous malformations (AVMs) causes a lot of controversy among neurosurgeons around the world. The most discussed issue is choosing the method and indications for a certain treatment option. Despite the accumulated data, including the results of randomized studies, there is no consensus on this issue among experts. The purpose of this review is to analyze current concepts of the management and reasonability of microsurgical treatment of non-bleeding cerebral AVMs based on the latest published studies. PMID- 30412166 TI - [The Ural school of otorhinolaryngologists. Department of Ototrhinolaryngology of the Federal state budgetary educational institution of higher education 'Ural State Medical University']. AB - The article highlights the main stages of the development of the Department of Otorhinolaryngology of the Federal state budgetary educational institution of higher education 'Ural State Medical University' since its foundation up to the present time. The principal areas of research and clinical activities of the Department at different periods of its history are presented. PMID- 30412167 TI - [The current trends and the tactical-technical approaches to the management of the neoplastic processes in the base of the skull]. AB - The neoplastic processes localized in the base of the skull and the surrounding region have until recently been considered as the inoperable condition. Juvenile angiofibroma of the base of the skull or angiofibroma of the base of the skull (ABS) is most frequently encountered in the otorhinolaryngological practice. In terms of the histological picture, ABS is a benign tumour having a very complicated structure. The multi-disciplinary approach and the application of up to-date medical technologies made it possible to obtain an insight into the deepest-lying areas of the base of the skull. A total of 69 patients presenting with juvenile angiofibroma of the base of the skull were available for the examination in the present study. In all this cases, the presence of the tumour was confirmed by the histological studies. Apart from the routine medical examination, all the patients underwent X-ray investigations including computed tomography with 3D-reconstruction, angiography subtracted VRT-reconstruction, and magnetic resonance tomography with contrast enhancement. Moreover, the trans maxillary-buccal approach was applied with the use of the endovideoscopic equipment. All the patients were discharged from the clinic in the satisfactory condition. Recurrent tumours were documented only in three patients, the lethal cases were altogether absent. The length of the period of follow-up observations amounted to five and more years. It is concluded that the application of the modern medical technologies in the combination with the 'teamwork' interdisciplinary approach greatly contributes to the successful surgical treatment of the pathological processes localized at the base of the skull and the surrounding region. PMID- 30412168 TI - [Age-specific dynamics of the auditory function in the extremely premature babies]. AB - Extremely early premature babies (i.e. those born before the 32nd week of pregnancy) constitute a group at high risk of development of the perceptive forms of hearing impairment represented mostly by chronic sensorineural hearing loss (CSNHL) and hearing neuropathy (HN). The timely diagnostics of these hearing disorders in premature children and, accordingly, their early and adequate rehabilitation provide a basis for the prevention of hearing and speech problems. At the same time, the hearing function in prematurely born babies is known to be highly unstable and can undergo substantial changes with age; these changes are most frequently observed during the early childhood. This paper was designed to report the results of observations of the hearing function dynamics in a cohort of the extremely early premature children. A total of 186 babies were available for the examination. It was shown that 14 (7.5%) of them had hearing problems. They disappeared by the 12th and 24th months of life in 3 children. Three other babies experienced transformation of NH into CSNHL at the age of 12, 14, and 18 months. NH transformed into CSNHL in three children by the age of 12, 24, and 48 months. Five children developed delayed CSNHL by the 10th, 15th, 24th, 28th, and 36th months of the actual life. These findings give evidence that the extremely premature children may experience both the improvement of the hearing function due largely to the processes of maturation in the auditory system and its deterioration or delayed formation of hearing impairment. It is concluded that the extremely early premature children born before the 32nd week of pregnancy should remain under the dynamic audiological observation at least as long as the third or fourth years of life. PMID- 30412169 TI - [The effectiveness of the intra-tympanic administration of methylprednisolone and gentamycin for the treatment of Meniere's disease]. AB - Meniere's disease is an inner ear pathology characterized by periodic fits of systemic dizziness, fluctuating low-frequency sensorineural loss of hearing, stuffiness in the ear and tympanophonia. The objective of the present study was to evaluate the effectiveness of the intra-tympanic administration of methyl prednisolone in the combination with gentamycin used to treat the patients presenting with Meniere's disease. The study included 18 patients at the age varying from 18 to 70 years presenting with this condition. Group 1 was formed to treat the patients with gentamycin, group 2 was comprised of the patients treated with methyl prednisolone. Special emphasis was placed on the recording of dynamics of the parameters of tonal threshold audiometry and cervical evoked vestibular myogenic potentials. The episodes of dizziness were characterized based on the results of comparison of the number of systemic dizziness episodes within the first 6 months after the first injection of methyl prednisolone or gentamycin with the number of such episodes during one month prior to the onset of the treatment. The results were estimated based on the Dizziness Handicap Inventory (DHI scale). It was shown that the patients comprising group 2 experienced a more pronounced reduction in the number of dizziness episodes compared with those in group 1 (91.56 and 69.81% decrease respectively). Moreover, hearing improved by 35% in the patients of group 2, whereas the improvement was altogether absent the patients of group 1. The patients of both groups reported comparable reduction of subjective tympanophonia estimated based on the DHI scale. The results of the comparison were evaluated based on the DHI scale (54.9% in group 2 and 53.8% in group 1). PMID- 30412170 TI - [The complications of cochlear implantation and the methods for their treatment]. AB - The objective of the present study was to improve the surgical component of cochlear implantation (CI) with special reference to the prevention and correction of its complications. A total of 967 cochlear implantation were performed on 847 patient treated based at the A. Geidarov Republican Hospital, Ministry of Internal Affairs of Azerbaijan, and the Research and Clinical Centre of Otorhinolaryngology, FMBA of Russia during the period from 2014 till 2017. The majority of the patients (n=540) were the children at the age varying from 1 to 4 years. All surgical interventions were carried out under the supervision of a single experienced specialist. The check-up examinations were performed every three months during the postoperative period. The postoperative complications were categorized in terms of severity (as major and minor) and time of the first manifestation (intraoperative and delayed). The detailed analysis of all documented complications was performed including the description of their variants and causes as well as of the surgical strategy applied in each concrete case. The frequency of major and minor complications was estimated at 2.6 and 1.6% respectively. It is concluded that cochlear implantation performed by an experienced surgeon provides a relatively safe method for the treatment of the patients in the clinics with a low frequency of complications of such interventions. The most common cause of the major complications of cochlear implantation is the technical defect of the implants the frequency of which amounted to 68% in the present study. PMID- 30412171 TI - [The medical assistance seeking behaviour of the patients presenting with suppurative chronic otitis media and their treatment in Moscow]. AB - The objective of the present study was the analysis of the medical assistance seeking behaviour of the patients presenting with suppurative chronic otitis media (CSOM) and their treatment in Moscow during the period from 2009 till 2016. The incidence of suppurative chronic otitis media in the city of Moscow in 2016 was estimated to be 0.14 per 1000 population, its prevalence 1.23 per 1000 population. The materials of the statistical reports of Moscow ENT clinics give evidence of the considerable growth in the number of the admitted patients suffering from ear diseases including suppurative chronic otitis media (mean 5.5). The surgical activity of the ENT clinics with respect to CSOM amounted to 46%. The overall increase in the number of surgical interventions is attributable to a rise in the frequency of reconstructive operations. These data give evidence of excellent continuity in the work of outpatient facilities and ENT clinics, intensification of their activities, and a change of the people's attitude toward the care for their health. Suppurative chronic otitis media is the commonest pathology encountered in the specialized ENT hospitals where it accounts for 59.8% of the total number of ENT diseases. The frequency of the surgical interventions performed for the treatment of CSOM amounts to 98.9%. The enhanced attention given to the patients with this pathology resulted in the two-fold increase of the specialized medical assistance provided to the patients presenting with suppurative chronic otitis media. The most frequently practiced form of the surgical treatment employed for the management of CSOM is tympanoplasty (in 72% of the patients on the average). The 'closed' variants of sanitizing operations are performed in 59.8% of the patients presenting with chronic suppurative otitis media and concomitant cholesteatoma whereas the 'open' interventions are used to treat 45.1% of the patients in need of tympano- and mastoidoplasty. On the whole, the priority surgical treatment of the patients with chronic suppurative otitis media in specialized medical facilities is reconstructive operations intended to simultaneously reach the beneficial sanative and functional effects without deterioration of the quality of life of the patients suffering from chronic suppurative otitis media. PMID- 30412172 TI - [The microbiocenosis of the palatal tonsils in the practically healthy people]. AB - The objective of the present study was the investigation of the quantitative and qualitative composition of the cultured microorganisms isolated from the proximal parts of the palatal tonsil lacunes of the practically healthy people. The data obtained made it possible to characterize the microbiocenosis of the palatal tonsil lacunes in the practically healthy subjects at the age from 18 to 30 years. A total of 153 strains were identified with the use of mass spectrometry; they represent six genera of two phylotypes that occur in the form of associations comprised of 4-5 microorganisms with the predominance of the species of the genus Streptococcus. The results of the study expand our knowledge about the oropharyngeal microbiota and create the prerequisites for the better uundderstanding of the contribution of the microbiotic communities to the development of pathology of the upper respiratory tracts. PMID- 30412173 TI - [The robotically-assisted oropharyngeal resection]. AB - The robotic technologies every day exert an increasingly greater influence on the surgical technique, with the well documented clinical applicability in reconstructive plastic surgery and oncology. At the Department of plastic surgery of I.M. Sechenov First Moscow state medical university, we have gained an extensive experience with the surgical treatment of the patients requiring the major oral robotic intervention. A novel application has recently been documented for the purpose of robotic surgical assistance to the patients presenting with oncological pathology including cancer of the oropharyngeal wall at the early stages of development (T1N0M0). The objective of the present study was to develop and introduce into the clinical practice of the robot-assisted methods for the treatment of malignant neoplasms of the head and neck organs. A hybrid technique was applied, i.e. the combination of the robot-assisted trans-oral surgical intervention and the microsurgical radial flap mobilization to correct the postoperative defect following the extraction of the tumour. The combination of these methods provided the excellent clinical results and positive dynamics of the patients' condition, with the swell apparent improvement of the quality of life. The early patient activation was due to the application of the minimally invasive transoral surgical technique, with the swallowing ability being reinstated within 14 days after the intervention by virtue of the proper flap function. All the patients successfully underwent the robot-assisted surgical manipulations without complications. The shorter rehabilitation time during the postoperative period in these patients made it possible to quicker initiate chemotherapy and radiotherapy. This significantly improved the patient's quality of life and prognosis due to the combined approach to the treatment of head and neck oncology. It is concluded that the incorporation of the robotic assistance into the program of surgical treatment significantly increases the effectiveness of the treatment and makes possible the combined approach to the treatment of oncological patients with manageable tumours of the head and neck region. PMID- 30412174 TI - [The specific immunophenotypic features of nasopharyngeal carcinoma]. AB - We have undertaken the retrospective analysis of the medical histories of 119 patients presenting with nasopharyngeal carcinoma (NPC) and the biopsy specimens obtained from them; the wereinvestigated with the use of the histological (staining of the micropreparations with hematoxylin and eosin) and immunehistochemical (monoclonal murine antibodies against Pan-cytokeratin, CK 5/6, EBV, CK7, CK19, p16) techniques. The study has demonstrated the presence of non-differentiated nasopharyngeal carcinoma in 97 patients, diffuse large-cell B lymphoma in 18 ones, melanoma of the nasopharyngeal mucous membrane in 2, and nasopharyngeal rhabdosarcoma in 1 patient. The immunohistochemical study revealed co-expression of the markers of Epstein-Barr virus, Pan-cytokeratin, and CK 5/6 in the non-differentiated nasopharyngeal carcinoma . PMID- 30412175 TI - [The application of the modern technologies for the treatment of precancerous diseases of the larynx]. AB - This article deals with the endolaryngeal methods for the surgical treatment of pre-cancerous diseases of the larynx with the use of up-to-date technologies and anesthetic support. The authors describe the original methods for endolaryngeal interventions based on the use of the CO2-laser. In addition, the results of the analysis of the data obtained during the immediate and delayed postoperative periods are presented. PMID- 30412176 TI - [The influence of the vitamin D3 level in the blood serum of lactase gene polymorphism on the development of chronic polypous rhinosinusitis]. AB - The objective of the present study was to elucidate the possible correlations between the vitamin D3 level in the blood serum and lactase gene polymorphism (LCT-13910 T>C) in the patients presenting with chronic polypous rhinosinusitis (CPRS). The study included 50 patients with this condition and 14 subjects comprising the control group. The variants of lactase gene polymorphism (LCT 13910 T>C) were identified with the use of polymerase chain reaction (PCR) in real time. The total level of serum vitamin D3 (VD3) was determined by means of the immunochemical analysis (the electrochemiluminescence technique). In the group of patients presenting with chronic polypous rhinosinusitis, the level of VD3 in the blood serum ranged from 48 nm/l to 85 nm/l (mean 60 nm/l) compared with that in the patients of the control group (from 78 nm/l to 112 nm/l; mean 97 nm/l) . The level of vitamin D3 'below the normal values' was documented in 71% of the patients with CPRS in comparison with 7% in the control subjects. Lactase gene polymorphism (LCT-13910 CC, CT) suggesting pronounced and latent hypolactasia was identified in 94% of the patients with CPRS compared with 78.6% in the control group. The occurrence of the CC genotype in the patients of both study groups was virtually identical: 52% in the patients presenting with chronic polypous rhinosinusitis and 57% in the control group. CT polymorphism was identified in 42% of the patients with CPRS and in 21% of the control subjects. The significant difference between the patients of the two groups was documented for the occurrence of TT polymorphism: 6% among the patients with CPRS and 21% in the controls (i.e. much higher in the healthy subjects). There was no significant difference between the serum levels of vitamin D3 either among the patients with CPRS having LCT-13910 gene polymorphisms (CC, CT, TT) or among the control subjects. It is concluded that the study revealed the higher levels of vitamin D3 in the blood sera from the control subjects in comparison with that in the patients with chronic polypous rhinosinusitis. Moreover, the patients of the latter group more frequently exhibited the variant of the LCT CT-13910 gene polymorphism suggesting latent hypolactasia whereas the subjects comprising the control group more frequently had the variant of the LCT CT-13910 gene polymorphism indicative of the normal tolerance of lactose. PMID- 30412177 TI - [Allergic rhinitis in the pregnant women]. AB - The objective of the present work was to elucidate the specific features of the clinical picture of allergic rhinitis in the pregnant women. The study included 156 pregnant women presenting with the persisting form of the disease and 63 patients having its intermitting form. The character of the endoscopic manifestations of rhinitis, chronic tonsillitis, and gastroesophageal reflux was evaluated with the use of a scoring system. The progressive development of the clinical symptoms of allergic rhinitis during pregnancy related neither to the contacts with allergens nor to the discontinuation of pharmacotherapy was documented in 33 and 23% of the patients presenting with the persistent and intermitting forms of the disease, respectively. The symptoms of rhinitis in the pregnant women may be influenced by the presence of gastroesophageal reflux (the endoscopic evidence of this condition was documented in 84.6% of the examined patients with persisting form of the disease and in 40.3% of those having intermitting form) and chronic tonsillitis (purulent contents in the palatine tonsil lacunes were found in 46.8 and 40.3% of the women presenting with the persisting and intermitting forms of allergic rhinitis respectively). In 42% of the cases, the cause behind the negative dynamics or the absence of any dynamics during the treatment of allergic rhinitis was the withdrawal of the prescribed pharmacotherapy by the patients themselves. This observation gives evidence of the importance of explaining to the pregnant women suffering from allergic rhinitis the necessity of compliance with the prescribed treatment modalities in order to reduce the probability of development of complications of this condition. PMID- 30412178 TI - [Innovative technology full volume lavage of the nasal cavity in the treatment of allergic and vasomotor rhinitis]. AB - Viewed 60 men and women (mean age 26.2+/-2.4 years) with rhinitis, including: 30 people (18 women and 12 men) 20-45 years with verified diagnoses of persistent allergic rhinitis and 30 patients (16 males and 14 females) 18-35 years (mean age 22.5+/-1.7 years) - neurovegetative form of chronic vasomotor rhinitis in the phase of exacerbation, receiving basic therapy with antihistamines of the II generation, stabilizers of membranes of mast cells and decongestants, divided by random sampling into 4 groups: 1A (20 patients with allergic rhinitis) and 2A (20 patients with vasomotor rhinitis) were received within 30 days in addition to the basic therapy of the nasal cavity washing procedure with the device Dolphin; in the groups 1B (10 patients with allergic rhinitis) and 2B (10 patients with vasomotor rhinitis) only basic treatment was carried out. By the end of the treatment course, the severity of the symptom 'difficulty in nasal breathing' in patients in groups 1A and 2A, decreased 2.6 times and met the criterion of 'minor violation', while in groups 1B-decreased only 1.3 times, and in 2B-changes were not significant and corresponded to 'moderate violation'. Manifestations of rhinorrhea after therapy decreased in the group of 1A 2.0 times, and in the group of 2A 1.7 times, which was regarded as' a slight manifestation of the symptom', whereas in the groups of 1B and 2B only a tendency to improve was revealed. At the end of the follow - up period, the severity of the symptom 'sneezing' decreased in patients in group 1A by 4.0 times, in group 2A-3.3 times and corresponded to 'no disturbance', while in groups 1B and 2B changes were less than 3.0 and 2.7 times respectively. At the end of the treatment course in patients in groups 1A sense of smell was restored in the group 2A -the degree of severity of olfaction decreased 3.0 times, while in the group of 1B-only 1.2 times, and in the group of 2B-has not changed. According to the visual analog scale (VAS), on the background of treatment optimized by nasal lavage with the device Dolphin complex, the greatest decrease in the degree of violations of household activity was revealed in patients with allergic rhinitis - 2.9 times. After treatment, the effect of rhinitis symptoms on sleep disturbance decreased in groups 1A and 2A 1.9 times, while in groups 1B and 2B - only 1.3 times. The use of nasal lavage with device Dolphin complex in the treatment of allergic and vasomotor rhinitis contributed to a decrease in the frequency of use of intranasal vasoconstrictive drugs by the 10th day of observation by 1.8 and 1.6 times, respectively, and by the 15th day-by 2.3 and 2.4 times, respectively. In the groups of standard treatment (1B and 2B) revealed a significant reduction in the frequency of decongestants was observed only after 15 days of treatment. Thus, the inclusion of a full volumetric nasal lavage with the device Dolphin complex in the treatment of patients with persistent allergic and neurovegetative form of chronic vasomotor rhinitis contributes to the reduction of clinical simtomatics, reduces the severity of violations of everyday life and the frequency of decongestants, improves night sleep of patients. PMID- 30412179 TI - [A variant of the modification of the rhinosurgical intervention with the use of the hemostatic glue]. AB - The objective of the present study was to evaluate the dynamics of the nasal breathing function and the quality of life in the patients following septoplastic surgery with the use of the classical method in comparison with the application of the latex tissue glue. The study included 58 patients presenting with diagnosis of deflected septum of the nose and vasomotor rhinitis. The following methods were employed for the purpose: anterior active rhinomanometry, evaluation of the transport function of the nasal cavity, and the questionnaire study for the determination of the patients' quality of life. The patients were allocated to two groups. Group 1 was comprised of the patients who underwent the classical surgical intervention (septal surgery with the mechanical disintegration of the inferior turbinated bones. The patients of the second group were treated with the use of the modified surgical procedure with the use of the latex tisue glue. The study has demonstrated that the patients treated with the use of the modified approach (including the application of the latex glue) recovered faster and reported a higher quality of life during the postoperative period than the patients of the first group treated by the conventional method. PMID- 30412180 TI - [The application of the hidrogel-based medicinal compositions for the targeted delivery of medications in rhino- and otosurgery]. AB - The objective of the present study was the analysis of the application of the hydrogel-based medicinal compositions for the treatment of the patients presenting with pathological changes in the nasal cavity and paranasal sinuses during the postoperative period. A total of 25 patients at the age from 18 to 60 years with the diseases of the nasal cavity and paranasal sinuses were available for the examination including 12 ones with polypous polysinusitis and 13 patients having benign neoplasms in the nasal cavity, paranasal sinuses, and the base of the skull. All these patients underwent endoscopic endonasal polysinusotomy. After the surgical intervention was completed, the postoperative cavities were filled up with a gel containing sodium alginate, sodium hyaluronate, and dioxydin. This procedure was followed by the tamponade with the use of the silicone oil tampons in conformity with the standard method. The application of the polyfunctional depot-materials in the combination with the physiotherapeutic treatment modalities made it possible to accelerate the wound healing processes including epithelization, changes in the mucous membrane of the paranasal sinuses, and the reduction of the postoperative oedema. PMID- 30412181 TI - [The peri-lymphatic labyrinthine fistula in a child]. AB - The objective of the present work was to describe the successful surgical treatment of the peri-lymphatic round window fistula of the labyrinth in the 9 year old child. The authors briefly mention the difficulties of diagnostics of the peri-lymphatic labyrinthine fistulas in the children and the signs suggesting their presence with special reference to the optimal strategies for their treatment. PMID- 30412182 TI - [The modern state and prospects of development of endoscopic otosurgery]. AB - In this review presents data on efficiency endoscopic operations at some ear diseases. Now endoscopic operations are widely applied at primary and residual (or recuring) middle ear cholesteatomas, tympanic membrane perforation, otosclerosis and cochlear implantation. Proceeding from resolving power of endoscopic technology, endoscopic operation can be applied as an independent method, or as an endoscopic assisted, to be combined with otomicrosurgery operation. Efficiency of endoscopic operation in many respects is defined by a possibility of panoramic visualization of anatomical structures of middle and inner ear, and also carrying out high-quality elimination of focus lesion from areas, being remote when performing otomicrosurgery operation. PMID- 30412183 TI - [Etiopathogenesis of obstructive sleep apnoea and its consequences in the children]. AB - The article presents the modern view of etiology of the obstructive sleep apnoea/hypopnoea syndrome (OAHSS) in the children taking into consideration the ontogenetic stage and the principal mechanisms of its formation including the short-term and long-term consequences of sleep apnoea with special reference to the pathogenetic commonness of OAHSS with endothelial dysfunction, metabolic syndrome, cardiac disorders, and systemic chronic inflammation. The role of ENT diseases in the children with obstructive sleep apnoea is discussed. The results of genetic studies of the processes influencing the formation of the risk of development of sleep apnoea/hypopnoea syndrome and its outcomes in the children are discussed. PMID- 30412184 TI - [Papillomatosis of the larynx in children: the current state of the problem]. AB - There is the authors have considered variants of modern methods of medical and surgical treatment of laryngeal papillomatosis in children in the review, based on the etiology of the disease. The analysis of the effectiveness of new methods of combined treatment with the use of modern technologies, taking into account their advantages and disadvantages. The possible prospects for further study problems and develop new methods of adjuvant therapy. PMID- 30412185 TI - An avatar for precision cancer therapy. PMID- 30412186 TI - Another CRISPR win for Zhang and Broad. PMID- 30412187 TI - Nobel work that galvanized an industry. PMID- 30412188 TI - Gilead injects own generics into shrinking HCV drug market. PMID- 30412189 TI - PODCAST: First rounders: Christoph Lengauer. PMID- 30412190 TI - Metagenomics meets read clouds. PMID- 30412191 TI - Around the world in a month. PMID- 30412194 TI - FDA calls for subscription model to pay for anti-infectives. PMID- 30412195 TI - The Reporting Items for Patent Landscapes statement. AB - The reporting quality of patent landscapes is inadequate. The Reporting Items for Patent Landscapes (RIPL) checklist can improve reporting quality. PMID- 30412197 TI - Bandit tusks. PMID- 30412196 TI - Author Correction: Rhizosphere microbiome structure alters to enable wilt resistance in tomato. PMID- 30412198 TI - Proteomics goes parallel. PMID- 30412199 TI - First preventive mAb for hereditary angioedema. PMID- 30412200 TI - Third-quarter biotech job picture. PMID- 30412201 TI - Translating microbiome futures. PMID- 30412203 TI - No added sugar: antibody makers find an upside to 'no fucose'. PMID- 30412202 TI - Evaluation of immune repertoire inference methods from RNA-seq data. PMID- 30412204 TI - Reply to "Evaluation of immune repertoire inference methods from RNA-seq data". PMID- 30412205 TI - Recent patents in endonucleases and genome editing. PMID- 30412206 TI - Wnt is back in drugmakers' sights, but is it druggable? PMID- 30412207 TI - Q3 2018-The beat goes on. PMID- 30412208 TI - Erratum to: Complex endovascular treatment of intact aortic aneurysms. An analysis of health insurance claims data. AB - [This corrects the article DOI: 10.1007/s00772-018-0387-7.]. PMID- 30412210 TI - Electron transfer mediates vibrational relaxation of CO in collisions with Ag(111). AB - We report experimental results on the state-to-state vibrational relaxation of CO(v = 17) in collisions with Ag(111) at incidence translational energies between 0.27 eV and 0.57 eV. These together with previous results provide a comprehensive set of data on two molecules (CO and NO)-one open and one closed shell-and two metals (Ag and Au). In all four cases, the incidence vibrational energy has been varied over several eV. We find a unifying relation between the probability of vibrational relaxation and the energetics of electron transfer from the metal to the molecule. This argues strongly that electronic friction based theories are not capable of explaining these data. PMID- 30412209 TI - Efficient green photoluminescence and electroluminescence of iridium complexes with high electron mobility. AB - Aiming to balance the injection and transport of electrons and holes, nitrogen heterocycle and 1,3,4-oxadiazole derivatives were introduced in iridium(iii) complexes to obtain organic light-emitting diodes (OLEDs) with high performances. Thus, two novel Ir(iii) complexes (Ir(tfmphpm)2(pop) and Ir(tfmppm)2(pop)) with green emissions using 2-(3,5-bis(trifluoromethyl)phenyl)pyrimidine (tfmphpm) and 2-(2,6-bis(trifluoromethyl)pyridin-4-yl)pyrimidine (tfmppm) as cyclometalating ligands, and 2-(5-phenyl-1,3,4-oxadiazol-2-yl)phenol (pop) as an ancillary ligand were synthesized. Both emitters show high photoluminescence efficiencies up to 94% and good electron mobility. The devices using two emitters with the structure of ITO (indium-tin-oxide)/MoO3 (molybdenum oxide, 5 nm)/TAPC (di-[4-(N,N-ditolyl amino)-phenyl]cyclohexane, 30 nm)/mCP (1,3-bis(9H-carbazol-9-yl)benzene, 5 nm)/Ir(iii) complexes (6 wt%) : PPO21 (3-(diphenylphosphoryl)-9-(4 (diphenylphosphoryl)phenyl)-9H-carbazole, 10 nm)/TmPyPB (1,3,5-tri(m-pyrid-3-yl phenyl) benzene, 40 nm)/LiF (1 nm)/Al (100 nm) display good electroluminescence performances with a maximum luminance of 48 981 cd m-2, a maximum current efficiency of 92.79 cd A-1 and a maximum external quantum efficiency up to 31.8%, respectively, and the efficiency roll-off ratio is low, suggesting that they have potential application in OLEDs. PMID- 30412211 TI - Theoretical prediction of the homogeneous ice nucleation rate: disentangling thermodynamics and kinetics. AB - Estimating the homogeneous ice nucleation rate from undercooled liquid water is crucial for understanding many important physical phenomena and technological applications, and challenging for both experiments and theory. From a theoretical point of view, difficulties arise due to the long time scales required, as well as the numerous nucleation pathways involved to form ice nuclei with different stacking disorders. We computed the homogeneous ice nucleation rate at a physically relevant undercooling for a single-site water model, taking into account the diffuse nature of ice-water interfaces, stacking disorders in ice nuclei, and the addition rate of particles to the critical nucleus. We disentangled and investigated the relative importance of all the terms, including interfacial free energy, entropic contributions and the kinetic prefactor, that contribute to the overall nucleation rate. Breaking down the problem into pieces not only provides physical insights into ice nucleation, but also sheds light on the long-standing discrepancy between different theoretical predictions, as well as between theoretical and experimental determinations of the nucleation rate. Moreover, we pinpoint the main shortcomings and suggest strategies to systematically improve the existing simulation methods. PMID- 30412212 TI - Influence of argon and D2 tagging on the hydrogen bond network in Cs+(H2O)3; kinetic trapping below 40 K. AB - The influence of enthalpic and entropic effects as well as of kinetic trapping processes on the structure of Ar/D2-tagged Cs+(H2O)3 clusters is studied by temperature-dependent infrared photodissociation spectroscopy combined with harmonic vibrational spectra calculations and anharmonic free energy profiles from finite temperature metadynamics molecular dynamics simulations. Each tag favors a different hydrogen bond network of water molecules, with Ar-tagging (vs. D2-tagging) of Cs+(H2O)3 leading to the lower energy conformation. The relative population of these conformers can be tuned over a temperature range of 12 to 21 K. The formation mechanisms of these tagged clusters can be deduced from the free energy profiles. This investigation demonstrates that a variety of factors, both thermodynamic and kinetic, play a role in the structure of flexible molecular species, even at cryogenic temperatures. PMID- 30412213 TI - Ultrastructural and SINS analysis of the cell wall integrity response of Aspergillus nidulans to the absence of galactofuranose. AB - With lethal opportunistic fungal infections on the rise, it is imperative to explore new methods to examine virulence mechanisms. The fungal cell wall is crucial for both the virulence and viability of Aspergillus nidulans. One wall component, Galf, has been shown to contribute to important fungal processes, integrity of the cell wall and pathogenesis. Here, we explore gene deletion strains lacking the penultimate enzyme in Galf biosynthesis (ugmADelta) and the protein that transports Galf for incorporation into the cell wall (ugtADelta). In applying gene deletion technology to the problem of cell wall integrity, we have employed multiple micro- and nano-scale imaging tools, including confocal fluorescence microscopy, electron microscopy, X-Ray fluorescence and atomic force microscopy. Atomic force microscopy allows quantification of ultrastructural cell wall architecture while near-field infrared spectroscopy provides spatially resolved chemical signatures, both at the nanoscale. Here, for the first time, we demonstrate correlative data collection with these two emerging modalities for the multiplexed in situ study of the nanoscale architecture and chemical composition of fungal cell walls. PMID- 30412214 TI - Pulse-shaped two-photon excitation of a fluorescent base analogue approaches single-molecule sensitivity. AB - Fluorescent nucleobase analogues (FBAs) have many desirable features in comparison to extrinsic fluorescent labels, but they are yet to find application in ultrasensitive detection. Many of the disadvantages of FBAs arise from their short excitation wavelengths (often in the ultraviolet), making two-photon excitation a potentially attractive approach. Pentacyclic adenine (pA) is a recently developed FBA that has an exceptionally high two-photon brightness. We have studied the two-photon-excited fluorescence properties of pA and how they are affected by incorporation in DNA. We find that pA is more photostable under two-photon excitation than via resonant absorption. When incorporated in an oligonucleotide, pA has a high two-photon cross section and emission quantum yield, varying with sequence context, resulting in the highest reported brightness for such a probe. The use of a two-photon microscope with ultrafast excitation and pulse shaping has allowed the detection of pA-containing oligonucleotides in solution with a limit of detection of ~5 molecules, demonstrating that practical single-molecule detection of FBAs is now within reach. PMID- 30412215 TI - Ab initio molecular dynamics study of solvated electrons in methanol clusters. AB - We performed a series of ab initio molecular dynamics simulations to investigate the physical properties of small methanol cluster anions, [(CH3OH)n]-, (n = 8 32). An excess electron was attached to neutral clusters that were prepared to accommodate the electron in interior cavity states or surface bound states. The computed initial binding energies of the electrons to these clusters indicate appealing similarity to the experimentally observed vertical detachment energies. The tendency of the interior state clusters parallels that of the clusters with strong electron binding in the experiments, while the simulated unrelaxed surface state anions are similar to the observed weakly bound species. This assignment is consistent with a previous identification based on hybrid quantum-classical simulations. The time evolution of the cluster anions suggests that interior state electrons slowly move to and relax on the surface, in excess electronic states that appear significantly more stable than the experimentally assigned putative surface states. Based on this result we predict the existence of relaxed surface state isomers of small methanol cluster anions. Due to the kinetic metastability of the experimentally found weakly bound species, we anticipate a serious technical challenge to prepare and identify small methanol cluster anions with relaxed surface states. These more strongly binding surface states are stabilized by dangling hydroxyl hydrogen atoms pointing to the excess electron's charge distribution. In addition, methyl hydrogens also appear to contribute to the stability of these states. During its transition to the surface, the interior excess electron maintains its initial solvent cavity. No signs of non-cavity interior states are observed in the present first principles ab initio molecular dynamics simulations. PMID- 30412216 TI - Localized molecular orbitals for calculation and analysis of vibrational Raman optical activity. AB - We present a novel method for the calculation of vibrational Raman optical activity (ROA) spectra based on localized molecular orbitals. This allows to split total ROA intensities into contributions of subsets, which can be chosen flexibly depending on the question of interest. It provides an appealing way to gain deeper insight into the factors influencing chirality and associated bands observed in the spectrum. As example, the ROA spectrum of a tryptophan model system, in particular the band arising from its W3 vibration, has been investigated. PMID- 30412217 TI - Patterned formation of enolate functional groups on the graphene basal plane. AB - Chemical functionalization of graphene is one method pursued to engineer new properties into a graphene sheet. Graphene oxide is the most commonly used chemical derivative of graphene. Here we present experimental evidence for the formation of enolate moieties when oxygen atoms are added to the graphene basal plane. The exotic functional groups are stabilized by simultaneous bond formation between the graphene sheet and the underlying Ir(111) substrate. Scanning tunneling microscopy images demonstrate the patterned nature of C-O bond formation and X-ray photoelectron spectroscopy and high-resolution electron energy loss spectroscopy are used to characterize the enolate moiety. The results present a new mechanism for the formation of patterned graphene oxide and provide evidence of a functional group rarely considered for graphene oxide materials. PMID- 30412218 TI - The association between hair cortisol, hair cortisone and cognitive function in a population based cohort of older adults: Results from The Irish Longitudinal Study on Ageing. AB - Experimental evidence to-date largely supports an association between the stress hormone cortisol and cognitive performance. Older adults, in particular, may be vulnerable to the neurotoxic effects of prolonged increases in cortisol, however the assessment of chronic hormone levels has previously been challenging. Hair cortisol analysis has advantages over other cortisol metrics for this purpose as it facilitates the assessment of total hormone secretion over several months. Cortisol and cortisone were measured in the scalp hair of 1,876 older adults from The Irish Longitudinal Study on Ageing. Participants underwent a battery of cognitive tests assessing global function, memory, executive function and processing speed. After adjustment for hair characteristics, demographics, metabolic risk factors, cardiovascular conditions and depression, regression analysis revealed an inverse relationship of hair glucocorticoids to immediate (cortisol:beta = -0.12, p=.032;cortisone: beta=-.021, p=.036) and delayed (cortisol:beta =-0.13, p= .003;cortisone: beta = -0.23, p=.006) word recall performance. They were also associated with more errors on the Mini-Mental State Exam (cortisol: IRR=1.06, p =.008; cortisone: IRR=1.14, p=.002), and Montreal Cognitive Assessment (cortisone: IRR=1.06, p=.015). Higher hair glucocorticoids are inversely associated with memory and global cognition in a population-based sample of older adults. Future work should explore the prognostic significance of these findings. PMID- 30412220 TI - Reply to the letter to the editor 'Small repeated boluses are unreliable to provide rapid analgesia with intravenous morphine titration and mislead conversion ratio to oral morphine' by Mercadante S. PMID- 30412219 TI - Named entity linking of geospatial and host metadata in GenBank for advancing biomedical research. AB - Database URL: : https://zodo.asu.edu/zoophydb/. PMID- 30412221 TI - Induction chemotherapy (IC) followed by radiotherapy (RT) versus cetuximab plus IC and RT in advanced laryngeal/hypopharyngeal cancer resectable only by total laryngectomy-final results of the larynx organ preservation trial DeLOS-II. AB - Background: The German multicenter randomized phase II larynx organ preservation (LOP) trial DeLOS-II was carried out to prove the hypothesis that cetuximab (E) added to induction chemotherapy (IC) and radiotherapy improves laryngectomy-free survival (LFS; survival with preserved larynx) in locally advanced laryngeal/hypopharyngeal cancer (LHSCC). Patients and methods: Treatment-naive patients with stage III/IV LHSCC amenable to total laryngectomy (TL) were randomized to three cycles IC with TPF [docetaxel (T) and cisplatin (P) 75 mg/m2/day 1, 5-FU (F) 750 mg/m2/day days 1-5] followed by radiotherapy (69.6 Gy) without (A) or with (B) standard dose cetuximab for 16 weeks throughout IC and radiotherapy (TPFE). Response to first IC-cycle (IC-1) with >=30% endoscopically estimated tumor surface shrinkage (ETSS) was used to define early responders; early salvage TL was recommended to non-responders. The primary objective was 24 months LFS above 35% in arm B. Results: Of 180 patients randomized (July 2007 to September 2012), 173 fulfilled eligibility criteria (A/B: larynx 44/42, hypopharynx 41/46). Because of 4 therapy-related deaths among the first 64 randomized patients, 5-FU was omitted from IC in the subsequent 112 patients reducing further fatal toxicities. Thus, IC was TPF in 61 patients and TP in 112 patients, respectively. The primary objective (24 months LFS above 35%) was equally met by arms A (40/85, 47.1%) as well as B (41/88, 46.6%). One hundred and twenty-three early responders completed IC+RT; their overall response rates (TPF/TP) were 94.7%/87.2% in A versus 80%/86.0% in B. The 24 months overall survival (OS) rates were 68.2% and 69.3%. Conclusions: Despite being accompanied by an elevated frequency in adverse events, the IC with TPF/TP plus cetuximab was feasible but showed no superiority to IC with TPF/TP regarding LFS and OS at 24 months. Both early response and 24 months LFS compare very well to previous LOP trials and recommend effective treatment selection and stratification by ETSS. Clinical trial information: NCT00508664. PMID- 30412223 TI - 'Optimism bias' in contemporary national clinical trial network phase III trials: are we improving? AB - Background: Previous studies have found that overestimating treatment effects (i.e. 'optimism bias') leads to underpowered clinical trials. The prevalence of 'optimism bias' in contemporary National Clinical Trials Network (NCTN) cancer clinical trials is unknown. Methods: We conducted a systematic review of NCTN phase III randomized trials published from January 2007 to January 2017. We compared the hypothesized versus observed treatment effects in each trial, and examined whether trial-related factors were correlated with the study results. We also reviewed the methods of each protocol to assess whether a rationale for the hypothesized effect size was provided. Results: We identified 161 clinical trials, of which 130 were eligible for analysis. Original protocols could not be located for 8 trials (5.0%). Twenty-eight trials (21.5%) observed a statistically significant difference in the primary end point favoring the experimental treatment. The median ratio of observed-to-expected hazard ratios among trials that observed a statistically significant effect on the primary end point was 1.07 (range: 0.33-1.28) versus 1.32 (range: 0.86-2.02) for trials that did not, compared with 1.34 and 1.86, respectively, for National Cancer Institute (NCI) trials published between 1955 and 2006. An effect size at least as large as the one projected in the protocol trials was observed in 9.8% of trials, compared with 17% of NCI trials published from 1955 to 2006. Most trials (64.6%) provided no rationale to support the magnitude of the proposed treatment effect in the protocol. Conclusions: Despite a reduction in 'optimism bias' compared with previous eras, most contemporary NCTN phase III trials failed to establish statistically significant benefits of new cancer therapies. Better rationalization of proposed effect sizes in research protocols is needed. PMID- 30412222 TI - Adjuvant sunitinib in patients with high-risk renal cell carcinoma: safety, therapy management, and patient-reported outcomes in the S-TRAC trial. AB - Background: Adjuvant sunitinib has significantly improved disease-free survival versus placebo in patients with renal cell carcinoma at high risk of recurrence post-nephrectomy (hazard ratio 0.76; 95% confidence interval, 0.59-0.98; two sided P = 0.03). We report safety, therapy management, and patient-reported outcomes for patients receiving sunitinib and placebo in the S-TRAC trial. Patients and methods: Patients were stratified by the University of California, Los Angeles Integrated Staging System and Eastern Cooperative Oncology Group performance status score, and randomized (1 : 1) to receive sunitinib (50 mg/day) or placebo. Single dose reductions to 37.5 mg, dose delays, and dose interruptions were used to manage adverse events (AEs). Patients' health-related quality of life, including key symptoms typically associated with sunitinib, were evaluated with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Results: Patients maintained treatment for 9.5 (mean, SD 4.4) and 10.3 (mean, SD 3.7) months in the sunitinib and placebo arms, respectively. In the sunitinib arm, key AEs occurred ~1 month (median) after start of treatment and resolved within ~3.5 weeks (median). Many (40.6%) AEs leading to permanent discontinuation were grade 1/2, and most (87.2%) resolved or were resolving by 28 days after last treatment. Patients taking sunitinib showed a significantly lower EORTC QLQ-C30 overall health status score versus placebo, although this reduction was not clinically meaningful. Patients reported symptoms typically related to sunitinib treatment with diarrhea and loss of appetite showing clinically meaningful increases. Conclusions: In S-TRAC, AEs were predictable, manageable, and reversible via dose interruptions, dose reductions, and/or standard supportive medical therapy. Patients on sunitinib did report increased symptoms and reduced HRQoL, but these changes were generally not clinically meaningful, apart from appetite loss and diarrhea, and were expected in the context of known sunitinib effects. Clinical trial registration: ClinicalTrials.gov, NCT00375674. PMID- 30412226 TI - The cross-national measurement invariance of the health literacy for school-aged children (HLSAC) instrument. AB - Background: Health literacy (HL) is an important determinant of health and health behaviours, and there is a need to monitor HL levels among all population groups. It is therefore essential to develop instruments to assess HL during childhood and adolescence. The aim of this study was to examine the cross-national measurement invariance of the instrument Health Literacy for School-aged Children (HLSAC) in four European countries. Methods: The data were collected via standardized self-administered anonymous questionnaires within classrooms in Finland, Poland, Slovakia, and Belgium. There were in total 1468 respondents (aged 13, N = 690; aged 15, N = 778). The HLSAC instrument was used to measure the subjective HL of adolescents in each country. A multigroup confirmatory factor analysis was applied to test measurement invariance. Results: Configural and metric invariance was established, but scalar invariance did not hold. However, the instrument exhibited high internal consistency (alpha = 0.85) and showed adequate fit with the data. Moreover, the partial invariance allowed comparison of mean values across the countries in question. There were significant mean value differences between countries and age-groups. Conclusions: HL mean values (as assessed via the HLSAC instrument) can be compared across countries. The instrument has utility for large-scale international HL studies on adolescents. PMID- 30412224 TI - Colorectal premalignancy is associated with consensus molecular subtypes 1 and 2. AB - Background: Gene expression-based profiling of colorectal cancer (CRC) can be used to identify four molecularly homogeneous consensus molecular subtype (CMS) groups with unique biologic features. However, its applicability to colorectal premalignant lesions remains unknown. Patients and methods: We assembled the largest transcriptomic premalignancy dataset by integrating different public and proprietary cohorts of adenomatous and serrated polyps from sporadic (N = 311) and hereditary (N = 78) patient populations and carried out a comprehensive analysis of carcinogenesis pathways using the CMS random forest (RF) classifier. Results: Overall, transcriptomic subtyping of sporadic and hereditary polyps revealed CMS2 and CMS1 subgroups as the predominant molecular subtypes in premalignancy. Pathway enrichment analysis showed that adenomatous polyps from sporadic or hereditary cases (including Lynch syndrome) displayed a CMS2-like phenotype with WNT and MYC activation, whereas hyperplastic and serrated polyps with CMS1-like phenotype harbored prominent immune activation. Rare adenomas with CMS4-like phenotype showed significant enrichment for stromal signatures along with transforming growth factor-beta activation. There was a strong association of CMS1-like polyps with serrated pathology, right-sided anatomic location and BRAF mutations. Conclusions: Based on our observations made in premalignancy, we propose a model of pathway activation associated with CMS classification in colorectal carcinogenesis. Specifically, while adenomatous polyps are largely CMS2, most hyperplastic and serrated polyps are CMS1 and may transition into other CMS groups during evolution into carcinomas. Our findings shed light on the transcriptional landscape of premalignant colonic polyps and may help guide the development of future biomarkers or preventive treatments for CRC. PMID- 30412225 TI - Training in communication of oncology clinicians: a position paper based on the third consensus meeting among European experts in 2018. AB - Background: Since there is sound evidence that communication skills training (CST) programs modify communication behavior of oncology clinicians, they have been widely implemented over the last decades. However, more recently, certain aspects of this training have been criticized. Methods: Based on this background, a call to re-launch a discussion about the future of CST led to the third European consensus meeting on communication in cancer care, organized by the Swiss Cancer League. During this meeting, which brought together European experts in the field of clinical communication and training of communication in the oncology setting, oncology clinicians, representatives of the European Society of Medical Oncology and a member of the European Oncology Nursing Society, the recommendations of the second European consensus meeting were updated and expanded. Results: The expanded recommendations recall the guiding principles of communication in cancer care, underline the important role of clinician's self awareness, and of relational and contextual factors in clinical communication, and provide direction for the further development of communication training. Conclusion: This third European consensus meeting defines key elements for the development of a next generation of communication training for oncology clinicians. PMID- 30412227 TI - Aging-Related Overactivity of the Angiotensin/AT1 Axis Decreases Sirtuin 3 Levels in the Substantia Nigra, which Induces Vulnerability to Oxidative Stress and Neurodegeneration. AB - Sirtuin 3 (SIRT3) and angiotensin play a major role in aging-related disorders. Both modulate oxidative stress and neurodegeneration. We investigated the interaction between SIRT3 and angiotensin II (AngII) in the dopaminergic system. Both in vivo and in vitro, treatment with AngII decreased SIRT3 expression, which was reversed by angiotensin type 1 receptor (AT1) antagonists. Aged animals showed enhanced pro-oxidative RAS activity and low nigral SIRT3 levels, which significantly increased with treatment with the AT1 antagonist candesartan or AT1 deletion. Consistent with this, AT2 knockout mice and cells treated with AT2 blockers showed downregulation of SIRT3. Treatment with the specific SIRT3 inhibitor AGK7 induced overexpression of AT1 and AT2 in substantia nigra (SN) of rats, and in dopaminergic neuronal MES23.5 and microglial N9 cell lines. The results suggest that SIRT3 may initially counteract low levels of oxidative stress as part of the antioxidant response. However, high or persistent oxidative stress induced by overactivation of the angiotensin/AT1 pro-oxidative axis induces a decrease in nigral SIRT3 levels. Furthermore, a decrease in SIRT3 levels further increases AT1 activity, which may lead to a feed-forward mechanism. This is observed in aged rats, and can be counteracted by treatment with AT1 antagonists such as candesartan. PMID- 30412228 TI - Tofacitinib in Patients with Ulcerative Colitis: Health-Related Quality of Life in Phase 3 Randomised Controlled Induction and Maintenance Studies. PMID- 30412229 TI - 2D/3D echocardiographic determinants of left ventricular reverse remodelling after MitraClip implantation. AB - Aims: The aim of this study was to describe incidence and determinants of left ventricular reverse remodelling (r-LVR) at 6 months follow-up after MitraClip implantation in patients with secondary severe mitral regurgitation (MR) and reduced left ventricular ejection fraction (LVEF). Methods and results: Forty five patients, undergoing MitralClip implantation with low ejection fraction and high surgical risk were enrolled in this study. Three of them died before the scheduled 6 months follow-up period and one patient had cardiac surgery due to MitraClip detachment. All patients underwent transthoracic 2D and 3D echocardiography before and 6 months after the procedure. A significant MR severity reduction and an improvement in New York Heart Association (NYHA) class were detected in all patients. The study population was divided in two groups according to the presence of r-LVR (51%, n = 23 patients) or not (non-rLVR group, 18 patients). Non-significant differences in MR aetiology and number of clips implanted were found. Left ventricular reverse remodelling patients showed significant lower values of logistic EuroSCORE and STS score, left ventricular end-diastolic volume index (LVEDV/i), right ventricular end systolic area, and pulmonary artery systolic pressure (PASp) at baseline evaluation. At multivariable analysis, baseline PASp value resulted to be the only independent predictor of r-LVR [odds ratio 95% confidence interval 0.94 (0.89-0.99), P = 0.021]. In r-LVR patients, a significant improvement in LVEF and global longitudinal strain and a reduction in left atrial volume index were detected after 6 months, whereas in non-rLVR subgroup a significant increase in both LVEDV/i and left ventricular end-systolic volume index was observed at follow-up. Conclusion: Even if a reduction of MR was detected in all patients after MitralClip implant, our findings suggest that end-stage patients presenting with higher left ventricular volumes, logistic scores, and PASp may not benefit from the procedure at longer follow-up in terms of left ventricular function. PMID- 30412230 TI - Prognostic Value of Pain Sensitization During Early Recovery After Distal Radius Fracture in Complex Regional Pain Syndrome. AB - Objective: To evaluate the influence of pain sensitization in the early recovery of distal radius fractures (DRFs) on the occurrence and prognosis of complex regional pain syndrome (CRPS) type I. Methods: We enrolled 58 patients who were diagnosed with CRPS I based on Budapest criteria within six months after sustaining DRF; they were age- and gender-matched with 58 patients with DRF who did not have CRPS I. We commonly measured patients' pressure pain thresholds (PPTs) in the forearm and administered a Pain Sensitivity Questionnaire (PSQ) when patients complained of pain with numeric rating scale >=4 at three-month follow-up. Participants were followed up three, six, and 12 months after injury, and the symptoms and sign of CRPS were evaluated at each follow-up. Results: Patients with CRPS I were more likely to have sustained high-energy injuries, had severe fractures, and had significantly higher PSQ scores and lower PPTs than the age- and gender-matched controls. At 12 months after injury, CRPS symptoms improved in 52% (30/58) of patients who had been diagnosed with CRPS I at three months after injury. The initial degree of pain sensitization and high-energy injury were associated with persistence of CRPS symptoms up to 12 months after initial injury. Conclusions: Patients with CRPS I after DRF exhibited significantly higher pain sensitization in the early post-trauma period, and the degree of initial pain sensitization and high-energy injuries were associated with prolonged CRPS I signs and symptoms up to one year after initial injury. PMID- 30412231 TI - Social determinants of health associated with topical repellent use in pregnancy: a cross-sectional study during a Zika outbreak in Brazil. AB - Background: Repellent use during pregnancy was strongly recommended after uncovering Zika virus (ZIKV) involvement with congenital malformations. In this context, Pernambuco, Brazil played a key role since it was the epicentre for the main studies suggesting ZIKV teratogenicity and one of Brazil's most affected states during the 2014-2016 epidemics. Thus we aimed to identify possible associations between social determinants of health and repellent use in pregnancy during the ZIKV outbreak in Pernambuco. Methods: We conducted a cross-sectional study (July-December 2016) with 539 pregnant women residing in Pernambuco and estimated the associations by prevalence ratio and multivariable logistic regression. Results: Repellents were associated with pregnant women >=30 y; graduates, employed, health professionals, private health system users and with a monthly income per person greater than two minimum wages. Women whose domiciles favour mosquitoes (ground-floor houses, intermittent water supply from general distribution or water trucks and for <=6 d/week, cesspools/open wastewater, indoor household water storage) were less likely to use repellents. There was no association for peridomiciles. Conclusions: Repellents were not associated with ZIKV in most vulnerable pregnant women, despite all the general recommendations made during the Pernambuco epidemic. This study observed a demand for public policies focused on health, education and sanitation problems related to deprived social groups along with their co-responsibility rather than focusing on individual attitudes against mosquitoes. PMID- 30412232 TI - The Influence of a Guideline-Concordant Stepped Care Approach on Downstream Health Care Utilization in Patients with Spine and Shoulder Pain. AB - Background: Stepped care approaches are emphasized in guidelines for musculoskeletal pain, recommending less invasive or risky evidence-based intervention, such as manual therapy (MT), before more aggressive interventions such as opioid prescriptions. The order and timing of care can alter recovery trajectories. Objective: To compare one-year downstream health care utilization in patients with spine or shoulder disorders who received only MT vs MT and opioids. The secondary aim was to compare differences based on order and timing of opioids and MT. Design: Retrospective observational cohort. Methods: Patients with an initial consultation for a spine or shoulder disorder who received at least one visit for MT were included. Person-level data from the Military Health System Management and Reporting Tool (M2) database were aggregated by a senior health care analyst at Madigan Army Medical Center. Groups were created based on the order and timing of interventions provided. Outcomes included health care utilization (medical costs and visits) over the year following initial consultation. Control measures included metabolic, mental health, chronic pain, sleep, and substance abuse comorbidities, as well as prior opioid prescriptions. Generalized linear models with gamma log links were run due to the heavily skewed nature of cost data. Results: From 1,876 unique patients with spine or shoulder disorders receiving MT, 1,162 (61.9%) also received prescription opioids. Mean one-year costs in the MT-only group ($5,410, 95% confidence interval [CI] = $5,109 to $5,730) were significantly lower than in the MT+opioid group ($10,498, 95% CI = $10,043 to $10,973). When patients had both treatments, mean one-year costs in the MT-first ($10,782, 95% CI = $10,050 to $11,567) were significantly lower (P = 0.030) than opioid-first ($11,938, 95% CI = $11,272 to $12,643), and MT-first had a significantly lower mean days' supply of opioids (34.2 vs 70.9, P < 0.001) and mean number of unique opioid prescriptions (3.1 vs 6.5, P < 0.001). Conclusions: MT alone resulted in lower downstream costs than with opioid prescriptions. Both the order of treatment (MT before opioid prescriptions) and the timing of treatment (MT < 30 days) resulted in a significant reduction of resources (costs, visits, and opioid utilization) in the year after initial consultation. Clinicians should consider the implications of first-choice decisions and the timing of care for treatment choices utilized for patients with spine and shoulder disorders. PMID- 30412233 TI - A Community Choir Intervention to Promote Well-being among Diverse Older Adults: Results from the Community of Voices Trial. AB - Objectives: To test effects of the Community of Voices choir intervention on the health, well-being, and healthcare costs of racial/ethnically diverse older adults. Method: Twelve Administration-on-Aging-supported senior centers were cluster randomized into two groups: the intervention group started the choir immediately and a wait-list control group began the choir 6 months later. The 12 month choir program was designed for community-dwelling adults aged 60 and over. The multimodal intervention comprises activities that engage participants cognitively, physically, and socially. Outcome measures assessed these 3 domains as well as healthcare utilization and costs. The intention-to-treat comparison was at 6 months. Results: The sample (N=390) had a mean age of 71.3 years (SD=7.2); 65% were non-white. Six-month retention was 92%. Compared to controls, intervention group members experienced significantly greater improvements in loneliness (p=0.02; standardized effect size (ES=0.34) and interest in life (p=0.008, ES=0.39). No significant group differences were observed for cognitive or physical outcomes or for healthcare costs. Discussion: Findings support adoption of community choirs for reducing loneliness and increasing interest in life among diverse older adults. Further efforts need to examine the mechanisms by which engagement in choirs improves aspects of well-being and reduces health disparities among older adults, including potential longer-term effects. PMID- 30412234 TI - Individual-level determinants of waterpipe smoking demand in four Eastern Mediterranean countries. AB - The prevalence of waterpipe tobacco smoking in the Eastern Mediterranean Region is at alarmingly high levels, especially among young people. The objective of this research was to evaluate the preferences of young adult waterpipe smokers with respect to potential individual-level determinants of waterpipe smoking using discrete choice experiment methodology. Participants were young adult university students (18-29 years) who were ever waterpipe smokers, recruited from universities across four Eastern Mediterranean countries: Jordan, Oman, Palestine and the United Arab Emirates. The Internet-based discrete choice experiment, with 6 * 3 * 2 block design, evaluated preferences for choices of waterpipe smoking sessions, presented on hypothetical waterpipe cafe menus. Participants evaluated nine choice sets, each with five fruit-flavored options, a tobacco flavored option (non-flavored), and an opt-out option. Choices also varied based on nicotine content (0.0% vs. 0.05% vs. 0.5%) and price (low vs. high). Participants were randomized to receive menus with either a pictorial + text health-warning message or no message (between-subjects attribute). Multinomial logit regression models evaluated the influence of these attributes on waterpipe smoking choices.Across all four samples (n = 1859), participants preferred fruit-flavored varieties to tobacco flavor, lower nicotine content and lower prices. Exposure to the health warning did not significantly predict likelihood to opt-out. Flavor accounted for 81.4% of waterpipe smoking decisions.Limiting the use of fruit flavors in waterpipe tobacco, in addition to accurate nicotine content labeling and higher pricing may be effective at curbing the demand for waterpipe smoking among young adults. PMID- 30412236 TI - Stronger responders-uptake and decline of HPV-vaccination in Denmark. AB - Background: The purpose of this study was to identify the stronger responders behind the fluctuating coverage with the HPV-vaccine in Denmark in order to facilitate information campaigns targeted at specific subgroups. Methods: Newspaper articles published from 2006 to 2009 with information about coverage with the HPV-vaccine in Denmark were identified from the database Infomedia.dk. Vaccination coverage of recent years was retrieved from the publically accessible statistics from the State's Serum Institute. Data on average disposable income nationally and for each municipality was retrieved from Statistics Denmark. Results: According to numbers published in newspapers, girls residing in municipalities with a high disposable income were the first ones to secure the HPV-vaccine in Denmark. Years later, at the start of the debate about possible side effects of the HPV-vaccine, the decline in vaccination coverage was slightly steeper for girls from high income municipalities than for girls from low income municipalities. Conclusions: Girls from municipalities with a high disposable income seem to be the stronger responders of the fluctuating coverage with the HPV-vaccine in Denmark. This was the case both during the initial surge in coverage after the vaccine's introduction on the market, and during the later decline following the debate on possible side effects. Identification of this dispersion pattern enables health authorities to initiate targeted information campaigns. PMID- 30412235 TI - Impact of Policy Interventions on Postoperative Opioid Prescribing. AB - Objective: To assess postoperative opioid prescribing in response to state and organizational policy changes. Methods: We used an observational study design at an academic medical center in the Northeast United States over a time during which there were two important influences: 1) implementation of state rules regarding opioid prescribing and 2) changes in organization policies reflecting evolving standards of care. Results were summarized at the surgical specialty and procedure level and compared between baseline (July-December 2016) and postrule (July-December 2017) periods. Results: We analyzed data from 17,937 procedures from July 2016 to December 2017, two-thirds of which were outpatient. Schedule II opioids were prescribed in 61% of cases and no opioids at all in 28%. The median morphine milligram equivalent (MME) prescribed at discharge decreased 40%, from 113 MME in the baseline period to 68 MME in the postrule period. Decreases were seen across all the surgical specialties. Conclusions: Postoperative opioid prescribing at the time of hospital discharge decreased between 2016 and 2017 in the setting of targeted and replicable state and health care organizational policies. Policy Implications: Policies governing the use of opioids are an effective and adoptable approach to reducing opioid prescribing following surgery. PMID- 30412237 TI - Depression in Later Life: The Role of Adult Children's College Education for Older Parents' Mental Health in the United States. AB - Objectives: Research on the socioeconomic gradient in mental health links disadvantaged family background with subsequent symptoms of depression, demonstrating the "downstream" effect of parental resources on children's mental health. This study takes a different approach by evaluating the "upstream" influence of adult children's educational attainment on parents' depressive symptoms. Methods: Using longitudinal data from the U.S. Health and Retirement Study (N=106,517 person-years), we examine whether children's college attainment influences their parents' mental health in later life and whether this association increases with parental age. We also assess whether the link between children's college completion and parents' depression differs by parents' own education. Results: Parents with children who completed college have significantly lower levels of depressive symptoms than parents without college educated children, although the gap between parents narrows with age. In addition, at baseline, parents with less than a high school education were more positively affected by their children's college completion than parents who themselves had a college education, a finding which lends support to theories of resource substitution. Discussion: Offspring education is an overlooked resource that can contribute to mental health disparities among older adults in a country with unequal access to college educations. PMID- 30412238 TI - Immunogenicity of golimumab and its clinical relevance in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. AB - Objective: Golimumab immunogenicity was extensively studied during clinical development. As anti-drug antibody (ADA) detection with the standard bridging EIA (original-EIA) can yield false-negative results or underestimate ADA incidence and titres due to drug interference, a more sensitive assay was needed to determine clinical impact. Methods: A highly sensitive drug-tolerant EIA (DT-EIA) was developed and cross-validated against the original-EIA. Samples from phase-3 subcutaneous golimumab rheumatological trials (GO-FORWARD-rheumatoid arthritis, GO-REVEAL-psoriatic arthritis, GO-RAISE-ankylosing spondylitis) were then retested. Associations between ADAs and golimumab pharmacokinetics, efficacy and safety were assessed. Results: The DT-EIA was more sensitive than the original EIA and capable of detecting ADAs amid golimumab concentrations far exceeding those in immunogenicity test samples. Consequently, an 8-fold increase in the incidence of ADAs was observed with the DT-EIA (31.7%) vs original-EIA (4.1%) in the studies. Most ADA-positive patients identified by the DT-EIA had lower antibody titres, while most with higher titres were previously identified as ADA positive by the original-EIA. With the DT-EIA, ADA-positive patients generally had lower trough serum golimumab concentrations than ADA-negative patients; however, ADA impact on serum golimumab concentrations was more notable at higher ADA titres (?100). No impact of ADAs on clinical efficacy or injection-site reactions was evident. Conclusion: ADA incidence was expectedly higher using the DT-EIA vs original-EIA; newly detected ADAs were characterized mostly by low titres, with no impact on clinical efficacy or injection-site reactions, consistent with previously observed original-EIA results. Golimumab immunogenicity with the DT-EIA is consistent with existing knowledge regarding the clinical relevance of ADAs detected with the original-EIA in patients with rheumatological disorders. Trial registration: NCT00264550, NCT00265096, NCT00265083. PMID- 30412239 TI - Epidemiology, diagnosis, treatment and follow-up of cystic echinococcosis in asymptomatic carriers. AB - Background: Rio Negro Province is endemic for cystic echinococcosis (CE). A CE control program includes early diagnosis in humans. During 1980-1996, screening was done with serology and surgery was the unique choice of treatment. Since 1997, ultrasound (US) has been the method of choice for screening, and new choices of treatment for asymptomatic carriers are discussed in the CE guidelines. Methods: Between 1997 and 2016, 42 734 abdominal USs were performed, 192 new asymptomatic cases were diagnosed and underwent a protocol according to the size, location and type of cyst. Treatment options included active surveillance (US monitoring, 83 [43.3%]), antiparasitic (albendazole, 92 [47.9%]) and surgery (17 [8.8%], including percutaneous treatment). Results: After 7.7 y of follow-up, of the cases under active surveillance, 28 (33.7%) had to change treatment: 5 (6%) to surgery and 22 (26.5%) to albendazole. Of the patients treated with albendazole, 3 (3.2%) were operated on and 13 (14%) were treated with a second cycle of albendazole. Conclusion: As a result of the present study, resolution of CE in a non-surgical way with albendazole is confirmed to be effective in asymptomatic carriers with CE1 or CE3b cysts. An update eliminates the strategy of active surveillance in type CE1 cysts <3 cm and is replaced by treatment with antiparasitic in all asymptomatic cases with CE1 or CE3b cysts <10 cm. The update also limits follow-up to 12-18 months to evaluate those cases with non-response to antiparasitic and switch to a surgical option. PMID- 30412240 TI - Longer sleep duration during infancy and toddlerhood predicts weight normalization among high birth weight infants. AB - Study Objectives: High birth weight (HBW; >= 4000g) is strongly associated with later overweight, yet little is known about how to disrupt this trajectory. The current study examined sleep practices during infancy and toddlerhood among children born HBW or normal birth weight (NBW; 2500-3999g). Methods: Latent growth curve models were used to examine sleep during infancy and toddlerhood among 270 mother-child dyads enrolled in the Health Outcomes and Measures of the Environment Study. Total sleep duration in 24-h, sleep maintenance, and restlessness/vocalizations were collected at 6-month intervals between ages 6 to 24 months. Height and weight were obtained at ages 24 or 36 months, and normal and overweight BMI was derived. Sleep was examined among children with a normal BMI during the preschool years who were either HBW (HBW-Normal, n=36) or NBW (NBW Normal, n=184) compared with overweight preschoolers (Overweight, n=50). It was predicted that the Overweight group would have poorer sleep across infancy and toddlerhood compared to HBW-Normal and NBW-Normal. Results: HBW-Normal had the longest and Overweight had the shortest mean 24-h sleep duration across all time points with NBW-Normal falling in-between the two groups. Compared to Overweight, HBW-Normal exhibited longer 24-h sleep duration at age 6 months with this group difference maintained over infancy and toddlerhood. No group difference was found for NBW-Normal. Conclusions: A longer sleep duration in the first several years of life is associated with development of normal BMI among HBW children. These findings suggest that longer sleep duration may protect HBW children from becoming overweight. PMID- 30412241 TI - Genome-wide association study of cervical cancer suggests a role for ARRDC3 gene in human papillomavirus infection. AB - The development of cervical cancer is initiated by human papillomavirus (HPV) infection and involves both viral and host genetic factors. Genome-wide association studies (GWAS) of cervical cancer have identified associations in the HLA locus and two loci outside HLA, but the principal genes that control infection and pathogenesis have not been identified. In the present study, we performed GWAS of cervical cancer in East Asian populations, involving 2609 cases and 4712 controls in the discovery stage and 1461 cases and 3295 controls in the follow-up stage. We identified novel significant associations at 5q14 with the lead SNP rs59661306 (P = 2.4 * 10-11) and at 7p11 with the lead SNP rs7457728 (P = 1.2 * 10-8). In 5q14, the chromatin region of the GWAS significant SNPs was found to be in contact with the promoter of the ARRDC3 (arrestin domain containing 3) gene. In our functional studies, ARRDC3 knockdown in HeLa cells caused significant reductions in both cell growth and susceptibility to HPV16 pseudovirion infection, suggesting that ARRDC3 is involved in the infectious entry of HPV into the cell. Our study advances the understanding of host genes that are responsible for cervical cancer susceptibility and guides future research on HPV infection and cancer development. PMID- 30412243 TI - Chemotherapy-Induced Peripheral Neuropathy Treated with Dorsal Root Ganglion Stimulation. PMID- 30412242 TI - Changing clinical profiles and in-hospital outcomes of octogenarians undergoing cardiac surgery over 18 years: a single-centre experience?. AB - OBJECTIVES: With an ageing population, increasing numbers of octogenarians are undergoing high-risk cardiac surgery. We examine the changing characteristics and in-hospital outcomes for octogenarians over an 18-year period. METHODS: Clinical data from our prospective database for all octogenarians who had cardiac surgery from March 1999 through May 2016 were reviewed. We examined trends, risk profiles and in-hospital outcomes over 3 eras, namely early (1999-2004), middle (2005 2010) and late (2011-2016). A multivariable analysis was performed to identify independent predictors for adverse outcomes. RESULTS: There were 1022 patients aged 80-94 years in our study cohort. The octogenarian population increased progressively from early to late eras (4.5%, n = 255 vs 7.1%, n = 321 vs 9.3%, n = 446), as the average logistic EuroSCORE predicted mortality (9% vs 9.7% vs 10.1%, P < 0.01). On the contrary, observed mortality declined substantially (9.4% vs 7.8% vs 4.7%, P = 0.04) over this period. While cardiac morbidity and respiratory comorbidities were more prevalent in the late era, chronic renal failure was more frequent in the early era. Over time, more procedures were performed electively (P = 0.05). Common operations across all eras were coronary artery bypass grafting (CABG), aortic valve replacement and CABG + aortic valve replacement. Emergency operation [odds ratio (OR) 4.96, 95% confidence interval (CI) 1.51-16.35; P < 0.01], poor ejection fraction (OR 3.38, 95% CI 1.80-6.32; P < 0.01) and bypass time (OR 1.01, 95% CI 1.00-1.02; P < 0.01) were predictors of in-hospital mortality. The late era of surgery (OR 0.41, 95% CI 0.23-0.73; P < 0.01) was associated with reduced mortality risk. CONCLUSIONS: The operative outcome in this growing surgical population is steadily improving despite the increasing prevalence of comorbidities, and surgery should be performed electively as much as possible. PMID- 30412244 TI - New postoperative conduction abnormalities after the implantation of a rapid deployment aortic valve prosthesis. AB - OBJECTIVES: Sutureless and rapid-deployment aortic valves have enlarged the selection of prostheses available for surgical aortic valve replacement. However, the rate of postoperative pacemaker implantation seems to have increased. METHODS: In addition to pacemaker implantation, we were interested in the incidence of new postoperative conduction abnormalities, namely left bundle branch block, right bundle branch block and atrioventricular block III after the implantation of the EDWARDS INTUITY EliteTM sutureless prosthesis. All patients undergoing isolated or concomitant surgical aortic valve replacement between May 2014 and May 2017 were included in the study. RESULTS: Two hundred patients were operated on. Of them, 14 patients dropped out because of concomitant endocardial or epicardial ablation or because of septal myectomy. Three more patients dropped out because the treatment was converted to conventional aortic valve replacement, and 183 patients remained. At the time of discharge from hospital, 38.1% of the 183 patients had new left bundle branch block, 2.5% of patients had new right bundle branch block and 9.6% had atrioventricular block III requiring either a pacemaker or defibrillator. The postoperative mean transvalvular gradient over the prosthesis was 8.4 +/- 3.4 mmHg, the occurrence of paravalvular leakage more than trivial was 1% and hospital mortality was 3.3%. CONCLUSIONS: The incidence of new postoperative conduction abnormalities is considerable with the EDWARDS INTUITY Elite rapid-deployment aortic valve prosthesis. We will focus our future research on the follow-up of patients with postoperative left bundle branch block, which was the most frequently observed form of new conduction abnormality. PMID- 30412245 TI - Intra-individual effects of food upon the pharmacokinetics of rifampicin and isoniazid. AB - Background: Poor response to TB therapy might be attributable to subtherapeutic levels in drug-compliant patients. Pharmacokinetic parameters can be affected by comorbidities or the interaction of drugs with food. Objectives: This study aimed to determine the effect of food intake upon pharmacokinetics of rifampicin and isoniazid in a Peruvian population with TB. Methods: Rifampicin and isoniazid levels were analysed at 2, 4 and 6 h after drug intake in both fasting and non fasting states using LC-MS methods. Results: Sixty patients participated in the study. The median rifampicin Cmax and AUC0-6 were higher during fasting than non fasting: 7.02 versus 6.59 mg/L (P = 0.054) and 28.64 versus 24.31 mg.h/L (P = 0.002). There was a statistically significant delay overall of non-fasting Tmax compared with the fasting state Tmax (P = 0.005). In the multivariate analysis, besides the effect of fasting, Cmax for females was 20% higher than for males (P = 0.03). Concerning isoniazid, there were significant differences in the Cmax during non-fasting (median = 3.51 mg/L) compared with fasting (4.54 mg/L). The isoniazid dose received had an effect upon the isoniazid levels (1.26, P = 0.038). In the multivariate analysis, isoniazid exposure during fasting was found to be 14% higher than during non-fasting (CI = 1.02-1.28, P < 0.001). Neither radiological extent of the disease nor consumption of food with drug intake nor pharmacokinetics of rifampicin or isoniazid was associated with a poorer treatment outcome. Conclusions: Rifampicin in particular and isoniazid pharmacokinetics were significantly affected by the intake of the drug with food between and within individuals. PMID- 30412246 TI - Soy-based infant formula feeding and menstrual pain in a cohort of women aged 23 35 years. AB - STUDY QUESTION: Is soy formula feeding during infancy associated with menstrual pain in reproductive-age women? SUMMARY ANSWER: Our data suggest that soy formula feeding during infancy is associated with several indicators of severe menstrual pain in reproductive-age women. WHAT IS KNOWN ALREADY: A prior study observed greater severity of menstrual pain in young women who as infants participated in feeding studies and were assigned to soy-based formula feeding. STUDY DESIGN, SIZE, DURATION: We used data from the Study of Environment, Lifestyle & Fibroids (SELF), a cohort of 1696 African-American women ages 23-35 years at enrollment. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Data on infant soy formula feeding was ascertained by self-administered questionnaire for 1553 participants, with 89% of participants receiving assistance from their mothers. Information on menstrual pain indicators was collected by web- and telephone-interview. We estimated the relative risk (RR) and 95% confidence interval (CI) using log-binomial regression, or log-multinomial regression, adjusting for participant age and maternal education. MAIN RESULTS AND THE ROLE OF CHANCE: Women ever fed soy formula as infants were more likely than unexposed women to report ever use of hormonal contraception for menstrual pain (RR 1.4, CI: 1.1-1.9) and moderate/severe menstrual discomfort/pain with 'most periods', but not 'every period', during early adulthood (ages 18-22 when not using hormonal contraception) (RR 1.5, CI: 1.1-2.0). LIMITATIONS, REASONS FOR CAUTION: We relied on retrospective recall to ascertain infant exposure to soy formula feeding and data on menstrual pain indicators. WIDER IMPLICATIONS OF THE FINDINGS: Our observations add to the growing body of literature from animal and human studies on the reproductive health consequences of early-life exposure to soy formula. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences and, in part, by funds allocated for health research by the American Recovery and Reinvestment Act. This research was also supported by grant K99NR017191 (KU). None of the authors has a conflict of interest. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 30412247 TI - Foods, macronutrients and breast cancer risk in postmenopausal women: a large UK cohort. AB - Background: The role of diet in breast cancer aetiology is unclear; recent studies have suggested associations may differ by estrogen receptor status. Methods: Baseline diet was assessed in 2000-04 using a validated questionnaire in 691 571 postmenopausal UK women without previous cancer, who had not changed their diet recently. They were followed by record linkage to national cancer and death databases. Cox regression yielded adjusted relative risks for breast cancer for 10 food items and eight macronutrients, subdivided mostly into five categories of baseline intake. Trends in risk across the baseline categories were calculated, assigning re-measured intakes to allow for measurement error and changes in intake over time; P-values allowed for multiple testing. Results: Women aged 59.9 (standard deviation (SD 4.9)) years at baseline were followed for 12 (SD 3) years; 29 005 were diagnosed with invasive breast cancer. Alcohol intake had the strongest association with breast cancer incidence: relative risk (RR) 1.08 [99% confidence interval (CI) 1.05-1.11] per 10 g/day higher intake, P = 5.8 * 10-14. There were inverse associations with fruit: RR 0.94 (99% CI 0.92 0.97) per 100 g/day higher intake, P = 1.1 * 10-6, and dietary fibre: RR 0.91 (99% CI 0.87-0.96) per 5 g/day increase, P = 1.1 * 10-4. Fruit and fibre intakes were correlated (rho = 0.62) and were greater among women who were not overweight, so residual confounding cannot be excluded. There was no heterogeneity for any association by estrogen receptor status. Conclusions: By far the strongest association was between alcohol intake and an increased risk of breast cancer. Of the other 17 intakes examined, higher intakes of fruit and fibre were associated with lower risks of breast cancer, but it is unclear whether or not these associations are causal. PMID- 30412248 TI - Workplace health beliefs concerning physical activity and sedentary behaviour. AB - Background: Sedentary behaviour (SB) in the form of uninterrupted sitting constitutes a risk factor for chronic disease that is independent of the risks associated with insufficient physical activity (PA). However, little is known about employee and manager health beliefs concerning SB and PA. Aims: We assess health beliefs of desk-based workers concerning PA and SB accrued at work versus during leisure. We ask whether recreational PA attenuates the perceived ill health effects of prolonged occupational SB, and compare attitudes of employees and managers to interventions aimed at reducing/interrupting workplace sitting. Methods: Two hundred and twenty-two desk-based employees and 121 managers located in Melbourne, Australia, rated the healthiness of vignettes describing combinations of uninterrupted sitting, sitting with breaks, light PA and moderate to-vigorous PA accumulated at work and during leisure time. Participants also responded to open-ended questions concerning the implications of reducing workplace sitting. Results: Mixed-model ANOVA revealed that the presence of leisure-time PA greatly diminished the perceived detrimental effects to health of workplace sitting. Subsequent thematic analysis of qualitative data further revealed that participants' concerns with SB were primarily musculoskeletal and workplace performance rather than chronic health. Conclusions: Employees and their managers do not rate uninterrupted sitting as being unhealthy when it is presented to them in the form of an 'active couch potato' lifestyle (a person who meets minimum PA recommendations but spends much of their work time and non-PA time sitting). We recommend that interventions targeting workplace SB take into account the contextual nature of health beliefs. PMID- 30412249 TI - Minocycline susceptibility breakpoints for Acinetobacter baumannii: do we need to re-evaluate them? AB - Minocycline is an old broad-spectrum tetracycline indicated for the treatment of various infections, including those due to minocycline-susceptible Acinetobacter spp. Susceptibility data worldwide are showing increasing rates of resistance of Acinetobacter baumannii to almost all antimicrobial classes, whereas minocycline seems to remain relatively potent against this significant pathogen. Since no new effective drugs have been released against MDR A. baumannii, minocycline is an attractive choice. Tracing back minocycline CLSI susceptibility breakpoints, it is evident that they have been based on old pharmacokinetic approaches. In an attempt to integrate the scarce new pharmacodynamic data, a Monte Carlo simulation was performed. It seems that the currently used breakpoints are, 8 fold elevated according to the approved dosage regimen, giving erroneously higher rates of minocycline susceptibility of A. baumannii. Therefore, current minocycline breakpoints merit re-evaluation in order to deliver reliable susceptibility profiles for selecting the appropriate therapy. PMID- 30412250 TI - Pharmacokinetics and pharmacodynamics of the novel monobactam LYS228 in a neutropenic murine thigh model of infection. PMID- 30412251 TI - Age-responsive human immunodeficiency virus target setting: an opportunity to improve health outcomes among males in Sub-Saharan Africa. AB - While there has been some progress in expanding human immunodeficiency virus (HIV) services for females, HIV prevention and treatment coverage among males remain poor. The widening disparity between males and females has garnered little attention- a cause for concern. In this article, we highlight the need to reach more males with HIV services and the importance of disaggregated data to identify age- and gender-specific gaps in HIV service delivery. PMID- 30412252 TI - Nasal carriage of Staphylococcus pseudintermedius in patients with granulomatosis with polyangiitis. PMID- 30412253 TI - Miltefosine enhances the fitness of a non-virulent drug-resistant Leishmania infantum strain. AB - Objectives: Miltefosine is currently the only oral drug for visceral leishmaniasis, and although deficiency in an aminophospholipid/miltefosine transporter (MT) is sufficient to elicit drug resistance, very few naturally miltefosine-resistant (MIL-R) strains have yet been isolated. This study aimed to make a detailed analysis of the impact of acquired miltefosine resistance and miltefosine treatment on in vivo infection. Methods: Bioluminescent versions of a MIL-R strain and its syngeneic parental line were generated by integration of the red-shifted firefly luciferase PpyRE9. The fitness of both lines was compared in vitro (growth rate, metacyclogenesis and macrophage infectivity) and in BALB/c mice through non-invasive bioluminescence imaging under conditions with and without drug pressure. Results: This study demonstrated a severe fitness loss of MT-deficient parasites, resulting in a complete inability to multiply and cause a typical visceral leishmaniasis infection pattern in BALB/c mice. The observed fitness loss could not be rescued by host immune suppression with cyclophosphamide, whereas episomal reconstitution with a wild-type MT restored parasite virulence, hence linking parasite fitness to MT mutation. Remarkably, in vivo miltefosine treatment or in vitro miltefosine pre-exposure significantly rescued MIL-R parasite virulence. The in vitro pre-exposed MIL-R promastigotes showed a longer and more slender morphology, suggesting an altered membrane composition. Conclusions: The profound fitness loss of MT-deficient parasites most likely explains the low frequency of MIL-R clinical isolates. The observation that miltefosine can reverse this phenotype indicates a drug dependency of the MT-deficient parasites and emphasizes the importance of resistance profiling prior to miltefosine administration. PMID- 30412254 TI - Genetic parameters for variability in the birth of persistently infected cattle following likely in-utero exposure to bovine viral diarrhea virus. AB - Genetic selection is an inexpensive and complementary strategy to traditional methods of improving animal health and welfare. Nonetheless, endeavors to incorporate animal health and welfare traits in international breeding programs have been hampered by the availability of informative phenotypes. The recent eradication program for bovine viral diarrhea (BVD) in the Republic of Ireland has provided an opportunity to quantify the potential benefits that genetic selection could offer BVD eradication programs elsewhere, as well as inform possible eradication programs for other diseases in the Republic of Ireland. Using a dataset of 188,085 Irish calves, the estimated direct and maternal heritability estimates for the birth of persistently infected calves following likely in-utero exposure to BVD virus ranged from not different from zero (linear model) to 0.29 (SE = 0.075; threshold model) and from essentially zero (linear model) to 0.04 (SE = 0.033; threshold model), respectively. The corresponding genetic standard deviation for the direct and maternal effect of the binary trait (0, 1) ranged from 0.005 (linear model) to 0.56 (threshold model) units and ranged from 0.00008 (linear model) to 0.20 (threshold model) units, respectively. The coefficient of direct genetic variation based on the linear model was 21% indicating considerable genetic variation could be exploited. Based on results from the linear model in the present study, there is the potential to reduce the incidence of persistent infection in cattle by on average 0.11 percentage units per year which is cumulative and permanent. Genetic selection can contribute to reducing the incidence of persistent infection in cattle. Moreover, where populations are free from persistent infection, inclusion of the estimated genetic merit for BVD in national breeding indexes could contribute to a preservation of a BVD-free status. Results from the present study can be used to inform breeding programs of the potential genetic gains achievable. Moreover, the approaches used in the present study can be applied to other diseases when data become available. PMID- 30412255 TI - Single-nucleotide-resolution sequencing of human N6-methyldeoxyadenosine reveals strand-asymmetric clusters associated with SSBP1 on the mitochondrial genome. AB - N6-methyldeoxyadenosine (6mA) is a well-characterized DNA modification in prokaryotes but reports on its presence and function in mammals have been controversial. To address this issue, we established the capacity of 6mA Crosslinking-Exonuclease-sequencing (6mACE-seq) to detect genome-wide 6mA at single-nucleotide-resolution, demonstrating this by accurately mapping 6mA in synthesized DNA and bacterial genomes. Using 6mACE-seq, we generated a human genome-wide 6mA map that accurately reproduced known 6mA enrichment at active retrotransposons and revealed mitochondrial chromosome-wide 6mA clusters asymmetrically enriched on the heavy-strand. We identified a novel putative 6mA binding protein in single-stranded DNA-binding protein 1 (SSBP1), a mitochondrial DNA (mtDNA) replication factor known to coat the heavy-strand, linking 6mA with the regulation of mtDNA replication. Finally, we characterized AlkB homologue 1 (ALKBH1) as a mitochondrial protein with 6mA demethylase activity and showed that its loss decreases mitochondrial oxidative phosphorylation. Our results show that 6mA clusters play a previously unappreciated role in regulating human mitochondrial function, despite 6mA being an uncommon DNA modification in the human genome. PMID- 30412256 TI - Fear of catastrophic health expenditures and unrealistic expectations from supplementary health insurance: ethnic differences. AB - Background: In Israel, the whole population is covered by comprehensive universal health insurance. Despite that, most of the population purchases supplementary health insurance (SHI). It has been shown that individuals purchase more health insurance and preventive medicine when they are uncertain of their state of health, while a majority may not fully understand basic concepts in their health insurance coverage. The purpose of this study was to examine the role of fear of catastrophic health expenditures and unrealistic expectations in purchasing SHI, which does not cover expenses for life-threatening illnesses. Methods: A cross sectional survey was conducted among random samples of 814 Jews and 800 Arabs in Israel. A structured questionnaire was administered by telephone using random digit dialling. Log-linear regression was used to identify factors associated with reasons for purchasing SHI and expectations from SHI. Results: The most common reason for purchasing SHI was fear of catastrophic health-related expenditures (41%). The most important service expected from SHI was 'cancer medications' (mean 4.68 [standard deviation 0.87]). Differences in the reasons for purchasing SHI and in expectations from SHI were found according to population group, age, gender and education. Conclusions: Consumers' misconceptions and fear of catastrophic health expenditures are major factors leading to the purchase of SHI, despite universal health coverage. Improved and accessible information should help consumers make informed decisions as to whether or not to purchase SHI. PMID- 30412257 TI - The clinical characteristics of patients with sepsis in a tertiary referral hospital in Yangon, Myanmar. AB - Background: The clinical characteristics and course of patients hospitalised with sepsis in Myanmar and the responsible pathogens remain poorly defined. Methods: We performed an observational study of adults admitted from the community to a tertiary referral hospital in Yangon with fever and dysfunction of at least two organ systems. Results: The 120 patients had a median age of 47 y (interquartile range 28-63); 11 (9%) were human immunodeficiency virus positive. Limited laboratory support meant that a microbiological diagnosis was possible in only 35 (29%) patients, but 18 (13%) had pathogens in blood cultures, including 9 (50%) organisms that were multidrug resistant (4 Escherichia coli, 4 Pseudomonas aeruginosa, 1 Burkholderia pseudomallei). Tuberculosis was confirmed in six patients, with two being rifampicin resistant, and dengue infection was confirmed in five patients. Without access to comprehensive intensive care support, 34 (28%) patients died. An admission National Early Warning Score >=7 (odds ratio [OR] 8.6 [95% confidence interval {CI} 2.6 to 28.2], p=0.001) and quick sequential (sepsis-related) organ failure assessment score >=2 (OR 3.2 [95% CI 1.3 to 8.0], p=0.02) were helpful in predicting death. Conclusions: Tropical pathogens are a common cause of sepsis in Myanmar. The frequent identification of multidrug-resistant organisms and limited diagnostic and intensive care support hinder patient care significantly. However, simple clinical assessment on admission has prognostic utility. PMID- 30412258 TI - Erector Spinae Plane Block in Management of Pain After Kidney Transplantation. PMID- 30412259 TI - Survivorship in Neuro-Oncology. PMID- 30412260 TI - Survivorship care planning and implementation in neuro-oncology. AB - Survivorship has become a significant topic within oncologic care. The tools and means by which the provision of survivorship care can be implemented and delivered are in development and are the focus of significant research oncology wide. These tools and methods include innovations of survivorship care delivery, survivorship care plans, and improving communication among all stakeholders in an individual patient's care as the means to elevate health-related quality of life. The merits of these survivorship care provisions in the field of neuro-oncology and its patients' exigent need for more patient-centric care focused on living with their illness are discussed. Since 2014 there has been a mandate within the United States for adult cancer patients treated with curative intent to receive survivorship care plans, comprising a treatment summary and a follow-up plan, intended to facilitate patients' care after initial diagnosis and upfront treatment. Several cancer-specific survivorship care plans have been developed and endorsed by health care professional organizations and patient advocacy groups. A survivorship care plan specific for neuro-oncology has been collaboratively developed by a multidisciplinary and interprofessional committee; it is endorsed by the Society for Neuro-Oncology Guidelines Committee. It is available as open access for download from the Society for Neuro-Oncology website under "Resources": https://www.soc-neuro onc.org/SNO/Resources/Survivorship_Care_Plan.aspx. Survivorship care offers an opportunity to begin directly addressing the range of issues patients navigate throughout their illness trajectory, an oncology initiative to which neuro oncology patients both need and deserve equitable access. PMID- 30412262 TI - Health literacy of future healthcare professionals: a cross-sectional study among health sciences students in Nepal. AB - Background: There is an assumption that health literacy is higher among health professionals, allowing them to improve the health literacy of their patients. This study explored health literacy profiles of health science students in Nepal, the future health professionals and educators of health literacy. Methods: The multidimensional Health Literacy Questionnaire and demographic questions were administered online to medical and other health science students at the B. P. Koirala Institute of Health Sciences, Dharan, Nepal. Results: More than half (55.8%) of the participants were male, 68.3% were <=19 y of age, 62.2% had parents with a university degree, 73.5% were studying undergraduate courses and 61.6% were pursuing medicine. Students reported having moderate support and skills to manage their health. Health was regarded as important to them. They reported a moderate ability to engage with health professionals and the healthcare system. Medical students reported higher scores for all scales except social support for health, which was similar across the groups. Conclusions: Universities should target interventions to improve students' access to health information and to develop students' ability to engage actively with healthcare providers. This will likely produce health professionals with improved health literacy levels who are sensitive to the health literacy needs of their patients from different population groups. PMID- 30412264 TI - Identification of AGI1-A, a variant of Acinetobacter genomic island 1 (AGI1), in a French clinical isolate belonging to the Enterobacter cloacae complex. AB - Objectives: To characterize the structure of a variant of Acinetobacter genomic island 1 (AGI1) in the Enterobacter cloacae clinical isolate EclC2185 responsible for an 8 year outbreak in Dijon University Hospital. Methods: The genome was sequenced (Miseq) and de novo assembled (Velvet). PCR and Sanger sequencing were performed to determine the sequence of the genomic island. Results: The new variant of AGI1 named AGI1-A (41.7 kb), located at the 3' end of the chromosomal trmE, was detected in an E. cloacae complex isolate identified as Enterobacter hormaechei subsp. oharae. The backbone of AGI1-A lacked A008, part of A025, A026 and the resolvase gene. Its MDR region (19.7 kb) contained two integrons followed by a hybrid transposon Tn502/Tn5053. The former integron was a typical In4-type class 1 integron carrying aadA1 and the latter integron carrying dfrA1 did not belong to a class described to date. The nucleotide sequence intI-dfrA1 was surrounded by a 78 bp imperfect repeat sequence in inverse orientation. An external circular form of AGI1-A was detected, suggesting potential mobility. AGI1-A was also detected in 15 isolates from the outbreak selected at random. They belonged to the ST114 high-risk clone. Conclusions: AGI1-A, a variant of AGI1 described in Acinetobacter baumannii, is the first genomic resistance island belonging to the Salmonella genomic island/Proteus genomic island/Acinetobacter genomic island family detected in E. cloacae. One might, therefore, fear for interspecies dissemination of genomic islands from this family. PMID- 30412261 TI - Updates in prognostic markers for gliomas. AB - Gliomas are the most common primary malignant brain tumor in adults. The traditional classification of gliomas has been based on histologic features and tumor grade. The advent of sophisticated molecular diagnostic techniques has led to a deeper understanding of genomic drivers implicated in gliomagenesis, some of which have important prognostic implications. These advances have led to an extensive revision of the World Health Organization classification of diffuse gliomas to include molecular markers such as isocitrate dehydrogenase mutation, 1p/19q codeletion, and histone mutations as integral components of brain tumor classification. Here, we report a comprehensive analysis of molecular prognostic factors for patients with gliomas, including those mentioned above, but also extending to others such as telomerase reverse transcriptase promoter mutations, O6-methylguanine-DNA methyltransferase promoter methylation, glioma cytosine phosphate-guanine island methylator phenotype DNA methylation, and epidermal growth factor receptor alterations. PMID- 30412263 TI - Proteomic Analysis of Larval Integument in a Dominant Obese Translucent (Obs) Silkworm Mutant. AB - The dominant obese translucent (Obs) mutant of the silkworm (Bombyx mori) results in a short and stout larval body, translucent phenotype, and abnormal pigmentation in the integument. The Obs mutant also displays deficiency in ecdysis and metamorphosis. In the present study, to gain an understanding of multiple Obs phenotypes, we investigated the phenotypes of Obs and performed a comparative analysis of the larval integument proteomes of Obs and normal silkworms. The phenotypic analysis revealed that the Obs larvae were indeed short and fat, and that chitin and uric acid content were lower but melanin content was higher in the Obs mutant. Proteomic analysis revealed that 244 proteins were significantly differentially expressed between Obs and normal silkworms, some of which were involved in uric acid metabolism and melanin pigmentation. Twenty-six proteins were annotated as cuticular proteins, including RR motif-rich cuticular proteins (CPR), glycine-rich cuticular protein (CPG), hypothetical cuticular protein (CPH), cuticular protein analogous to peritrophins (CPAPs), and the chitin_bind_3 motif proteins, and accounted for over 84% of the abundance of the total significantly differentially expressed proteins. Moreover, 22 of the 26 cuticular proteins were downregulated in the Obs mutant. Comparative proteomic analysis suggested that the multiple phenotypes of the Obs mutant might be related to changes in the expression of proteins that participate in cuticular formation, uric acid metabolism, and melanin pigmentation. These results could lay a basis for further identification of the gene responsible for the Obs mutant. The data have been deposited to ProteomeXchange with identifier PXD010998. PMID- 30412265 TI - The Efficacy of an Antioppression Curriculum for Health Professionals. AB - BACKGROUND AND OBJECTIVES: Health professionals increasingly recognize the role that social determinants play in health disparities. However, little focus is placed on how health care professionals themselves contribute to disparities through biased care. We have developed a curriculum based on an antioppression framework which encourages health professionals to evaluate their biases and combat health care disparities through an active process of allyship. METHODS: Teaching methods emphasize skill building and include lectures, guided reflections, and facilitated discussions. Pre- and postsurveys were administered to assess participants' confidence level to recognize unconscious bias and to be an ally to colleagues, patients, and staff. In total, we conducted 20 workshops with a total of 468 participants across multiple disciplines. RESULTS: The survey response rate was 80%. Using a paired t-test, the mean difference in the pre- and postsurveys revealed a statistically significant improvement across all measures. Participants showed the greatest improvements (large effect size d>0.8) in their understanding of the process of allyship, their ability to describe strategies to address, assess, and recognize unconscious bias, and their knowledge of managing situations in which prejudice, power, and privilege are involved. CONCLUSIONS: Results show that an antioppression curriculum can enhance health professionals' confidence in addressing bias in health care through allyship. For those who value social justice and equity, moving from the role of bystander to a place of awareness and solidarity allows for one's behaviors to mirror these values. Allyship is an accessible tool that all health professionals can use in order to facilitate this process. PMID- 30412266 TI - Variations in Sagittal and Coronal Stem Tilt and Their Impact on Prosthetic Impingement in Total Hip Arthroplasty. AB - Optimization of the combined anteversion of cup and stem has been emphasized to avoid prosthetic impingement in total hip arthroplasty. However, no study has focused on the impact of variations in sagittal and coronal stem tilt against the whole femur on prosthetic range of motion. The purposes of the present study were to quantify the anatomical variation of sagittal and coronal tilt of the proximal canal axis against the femoral retrocondylar coordinate system, that is variation of sagittal and coronal stem tilt and 2) to determine their impact on the zone of impingement-free cup position using computer simulation. Preoperative computed tomography images of 477 femurs from 409 consecutive patients who underwent total hip arthroplasty using computed tomography-based computer navigation were stored. Virtual implantation of an anatomical stem was performed on the navigation workstation. The safe zone of the cup position with regard to prosthetic impingement was determined by motion simulation in the range of sagittal and coronal stem tilt of the subjects. The sagittal and coronal stem tilt varied by 10 degrees , which was smaller than the stem anteversion variation. However, there was about three times the difference in the impingement-free zone of cup position in the ranges of sagittal and coronal stem tilt. The safe zone was significantly decreased by posterior tilt and valgus tilt of the stem. Range-of motion simulation revealed that the variations in sagittal or coronal stem tilt significantly influenced the safe zone of the cup. In conclusion, although the variations in sagittal and coronal stem tilt against the femoral retrocondylar coordinate system were small, their impact on prosthetic impingement was significant. This article is protected by copyright. All rights reserved. PMID- 30412267 TI - Continuous laryngoscopy during provocation in the assessment of inducible laryngeal obstruction. PMID- 30412269 TI - Definition and Validation of a Novel Metric of Erythropoiesis-Stimulating Agent Response in Hemodialysis Patients. AB - Erythropoiesis-stimulating agents (eg, epoetin alfa) are the primary treatment for anemia in patients with end-stage renal disease . Hemoglobin variability in and out of a narrow target range is common and associated with higher morbidity and mortality risk. More robust erythropoiesis-stimulating agent response metrics are needed to define optimal dosing and their association with clinical outcomes. In this cross-sectional, single-center, retrospective study, 49 patients with end stage renal disease on hemodialysis were followed over 12 months. To quantify hemoglobin deviations outside the target range (10-12 g/dL), the area under the curve of hemoglobin versus time over a 12-month period (AUC-HGB) was calculated using the trapezoidal rule. Patients were categorized into 4 responder groups based on AUC-HGB quartiles. Comparative analyses of demographic and clinical characteristics between responder groups were performed. Correlations between AUC HGB, erythropoietin resistance index, and time within therapeutic range were calculated. There were no significant differences in laboratory and dialysis parameters between responder groups except hemoglobin concentration and epoetin alfa dose. There was a negative correlation between AUC-HGB and time within therapeutic range (r = -.92; P < .001) and hemoglobin concentration (r = -.85; P < .01), indicating internal validity of the metric. There was a positive correlation between AUC-HGB and erythropoietin resistance index (r = .70; P < .001) indicating external validity. The poor response group received a higher median epoetin alfa dose (160 U/kg/week) compared to the excellent response group (68.8 U/kg/week; P < .001) with a similar number of dose changes between the groups. AUC-HGB is a valid marker of epoetin alfa response and should be considered in future analyses of larger populations. PMID- 30412270 TI - Multiple hemolytic transfusion reactions misinterpreted as severe vaso-occlusive crisis in a patient with sickle cell disease. AB - BACKGROUND: Hemolytic transfusion reactions are a rare, yet serious complication of red blood cell (RBC) transfusion. Patients with sickle cell disease (SCD) are at an increased risk for such reactions, because they are prone to make alloantibodies against transfused RBCs, complicating this integral part of their disease management. These reactions may be missed, and the patient's state may be attributed to vaso-occlusive crisis (VOC), with misguided therapy ensuing. CASE REPORT: Herein, we report the clinical course of a patient with complex SCD with a delayed hemolytic transfusion reaction, followed by multiple acute hemolytic transfusion reactions mistaken for severe VOC. These reactions were diagnosed on retrospective review of the patient's clinical course in consult with the transfusion medicine service. Optimal immunosuppressive therapy ensued and resulted in the stabilization of the anemia and hemolysis laboratory values. Despite these efforts, the patient died 2 months after admission. CONCLUSION: This case provides insight into some of the challenges of managing patients with SCD with multiple comorbidities. Hemolytic transfusion reactions can be difficult to diagnose and may be overlooked in patients with SCD with severe VOC. PMID- 30412268 TI - Simulations of Valproate Doses Based on an External Evaluation of Pediatric Population Pharmacokinetic Models. AB - Valproate is an old-generation antiepileptic drug often used in children. The pharmacokinetics of valproate are noteworthy for a large and difficult to predict interindividual variability in measured serum concentrations and for saturable protein binding. A model-based approach to personalize valproate treatment could be relevant in pediatric patients. The aims of this study were to review all published valproate population pharmacokinetic models in children and assess them by external validation to determine their predictive performance. Through simulations with the best model, we evaluated dosing regimen. A validation data set included valproate serum concentrations assayed during routine therapeutic drug monitoring of epileptic children. We applied to our population 11 published pediatric population pharmacokinetic models. For each model, predictive performance was assessed by external validation, using bias and precision calculations as well as goodness-of-fit plots. Dose simulations were conducted with the best predictive model to evaluate dosing regimen. The validation data set contained 178 valproate concentrations ranging from 13.4 to 128 mg/L from 114 patients. The best model exhibited a mean prediction error of 6.6 mg/L and a root mean squared error of 25.1 mg/L, with no model misspecification evidenced by visual predictive check. In our cohort, half the patients had a trough concentration <50 mg/L. Simulations suggested increasing doses, especially for children <=40 kg. External evaluation of published valproate pharmacokinetic models enabled us to identify a suitable model for simulations and Bayesian forecasting. Dosing regimen should be adjusted to weight, with decreasing doses with increasing weight. PMID- 30412271 TI - Complementary Pharmacokinetic Profiles of Netupitant and Palonosetron Support the Rationale for Their Oral Fixed Combination for the Prevention of Chemotherapy Induced Nausea and Vomiting. AB - NEPA is the first fixed-combination antiemetic composed of the neurokinin-1 receptor antagonist netupitant (netupitant; 300 mg) and the 5-hydroxytryptamine-3 receptor antagonist palonosetron (palonosetron; 0.50 mg). This study evaluated the pharmacokinetic profiles of netupitant and palonosetron. The pharmacokinetic profiles of both drugs were summarized using data from phase 1-3 clinical trials. netupitant and palonosetron have high absolute bioavailability (63%-87% and 97%, respectively). Their overall systemic exposures and maximum plasma concentrations are similar under fed and fasting conditions. netupitant binds to plasma proteins in a high degree (>99%), whereas palonosetron binds to a low extent (62%). Both drugs have large volumes of distribution (cancer patients: 1656-2257 L and 483 679 L, respectively). netupitant is metabolized by cytochrome P450 3A4 to 3 major pharmacologically active metabolites (M1, M2, and M3). palonosetron is metabolized by cytochrome P450 2D6 to 2 major substantially inactive metabolites (M4 and M9). Both drugs have similar intermediate-to-low systemic clearances and long half-lives (cancer patients: netupitant, 19.5-20.8 L/h and 56.0-93.8 hours; palonosetron: 7.0-11.3 L/h and 43.8-65.7 hours, respectively). netupitant and its metabolites are eliminated via the hepatic/biliary route (87% of the administered dose), whereas palonosetron and its metabolites are mainly eliminated via the kidneys (85%-93%). Altogether, these data explain the lack of pharmacokinetic interactions between netupitant and palonosetron at absorption, binding, metabolic, or excretory level, thus highlighting their compatibility as the oral fixed combination NEPA, with administration convenience that may reduce dosing mistakes and increase treatment compliance. PMID- 30412272 TI - Novel SPEG mutations in congenital myopathies: Genotype-phenotype correlations. AB - INTRODUCTION: Centronuclear myopathies (CNMs) are a subtype of congenital myopathies (CMs) characterized by muscle weakness, predominant type 1 fibers, and increased central nuclei. SPEG (striated preferentially expressed protein kinase) mutations have recently been identified in 7 CM patients (6 with CNMs). We report 2 additional patients with SPEG mutations expanding the phenotype and evaluate genotype-phenotype correlations associated with SPEG mutations. METHODS: Using whole exome/genome sequencing in CM families, we identified novel recessive SPEG mutations in 2 patients. RESULTS: Patient 1, with severe muscle weakness requiring respiratory support, dilated cardiomyopathy, ophthalmoplegia, and findings of nonspecific CM on muscle biopsy carried a homozygous SPEG mutation (p.Val3062del). Patient 2, with milder muscle weakness, ophthalmoplegia, and CNM carried compound heterozygous mutations (p.Leu728Argfs*82) and (p.Val2997Glyfs*52). CONCLUSIONS: The 2 patients add insight into genotype phenotype correlations of SPEG-associated CMs. Clinicians should consider evaluating a CM patient for SPEG mutations even in the absence of CNM features. Muscle Nerve, 2018. PMID- 30412273 TI - Silk Enhances Ligamentization of Polyethylene Terephthalate Artificial Ligament in a Canine Anterior Cruciate Ligament Reconstruction Model. AB - Anterior cruciate ligament (ACL) reconstruction is the leading treatment for ACL rupture. LARS (Ligament Advanced Reinforcement System) ligament, which is made of polyethylene terephthalate (PET), is the most frequently used artificial ligament for ACL reconstruction. However, PET is hydrophobic, so it is difficult to induce the ingrowth of autologous tissue. The aim of this study is to explore the effects of silk hybrid on the ligamentization of PET artificial ligament in a canine ACL reconstruction model. Silk/PET hybrid suspensory ligament was fabricated with silk in the weft yarn and PET in the warp yarn, while PET suspensory ligament was fabricated with PET in both the weft and warp yarn. After fabrication, the micromorphology of the ligaments was observed and mechanical testing was performed. Though the failure loads of the degummed silk/PET hybrid suspensory ligaments were significantly lower than those of PET suspensory ligaments (P < 0.001), both of them were enough for ACL reconstructions of beagle dogs. In the animal study, 14 beagle dogs were divided into PET suspensory ligament group and silk/PET hybrid suspensory ligament group randomly, with 7 dogs in each. The dogs underwent ACL reconstructions in their right knees. At 6 months postoperatively the dogs were sacrificed, and the specimens were evaluated with gross observation, histology, immunohistochemistry and mechanical testing. The histological and immunohistochemical results showed that the native ACL of the beagle dog held abundant fibroblasts and collagen. The PET regenerated ligament was loose, and there was a small amount of autologous tissue and collagen. Compared to PET regenerated ligament, the silk/PET hybrid regenerated ligament had a compact structure, and there was more regenerated autologous tissue and collagen. In conclusion, compared to PET ligament, silk/PET hybrid ligament kept greater ability to induce the ingrowth of autologous tissue, indicating that silk hybrid had enhanced the ligamentization of PET artificial ligament. This article is protected by copyright. All rights reserved. PMID- 30412274 TI - Bilateral mini-thoracotomy approach for minimally invasive implantation of HeartMate 3. AB - Left ventricular assist devices (LVADs) are an established option for the treatment of end-stage heart failure. Last generation devices are characterized by a miniaturized pump size, allowing for intra-pericardial placement. This feature enabled the introduction of less-invasive implantation techniques, which have been linked to many favourable effects. The HeartMate 3 LVAD is a continuous flow centrifugal pump, recently introduced for clinical use. Here we describe the minimally invasive implantation of the HeartMate 3 through a bilateral mini thoracotomy. This article is protected by copyright. All rights reserved. PMID- 30412275 TI - Comment on 'New drug candidates for depression - a nationwide population-based study'. AB - I would like to comment on an interesting article by Kessing et al. entitled 'New drug candidates for depression - a nationwide population-based study'(1). It presents a long-term study aimed to screen the Danish population register for the possible association between the exposure to certain clinically approved drugs: such as statins, high-dose aspirin and non aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), which possess anti-inflammatory or neuroprotective properties, and the rate of incident depression. Although there has been increasing evidence that suppressing the ongoing inflammatory process could facilitate the response of patients with refractory depression to standard antidepressant drugs (2), Kessing et al. This article is protected by copyright. All rights reserved. PMID- 30412276 TI - Magnetic resonance imaging with cochlear implants and auditory brainstem implants: Are we truly practicing MRI safety? AB - OBJECTIVE: Our objective is to evaluate the safety in patients with cochlear implants (CIs) and auditory brainstem implants (ABI) undergoing 1.5 Tesla (T) magnetic resonance imaging (MRI). Secondly, we want to raise awareness on CI and MRI safety, and advocate for continued improvement and advancement to minimize morbidity for our CI patients. METHODS: Retrospective case series from 2006 to 2018 at a single tertiary academic center. Data was collected on patients with CI or auditory brainstem implants undergoing MRI. Outcomes collected include demographic data, age at time of MRI, MRI characteristics, complications, CI manufacturer, and image quality. RESULTS: Eighteen patients with CI or ABI collectively underwent a total of 62 MRI scans. Five of 15 (33%) CI patients with magnet had complications: five total of 24 MRI scans (21%). Two patients had magnet removal prior to 29 MRI scans without complications. Four of five MRI related complications were equipped with a U.S. Food and Drug Administration approved head wrap. Three of five required a trip to the operating room to explore and reposition the CI magnet; two could not complete MRI secondary to pain. Of the complications, two were Cochlear (Sydney, Australia), two Advanced Bionics (Valencia, CA), and one MED-EL (Innsbruck, Austria). Synchrony model (MED EL) had 0 of seven complications, with a total of 19 MRI scans, which features a freely rotating and self-aligning magnet. CONCLUSION: Our series offers a diverse number of CI manufacturers and is in accordance with other literature that CI MRI related adverse events are occurring at an unacceptable frequency. We can promote CI MRI safety through our institutions' MRI CI patient protocols, raise awareness that diagnostic MRI benefits must outweigh CI-related complications, and advocate for continued industry technological innovation. LEVEL OF EVIDENCE: 4 Laryngoscope, 2018. PMID- 30412277 TI - Hemodynamic effects of intravenous, high-dose lipid emulsion with and without metoprolol infusion in healthy volunteers: a randomized clinical trial. AB - In a double-blinded, randomized, cross-over trial, we investigated hemodynamic effects of high-dose intravenous lipid emulsion (ILE) with/without metoprolol. Ten healthy volunteers each completed four trial days (placebo+ILE; metoprolol+placebo; metoprolol+ILE; placebo+placebo) in random order. Metoprolol was administered as an initial bolus (10 mg), followed by an infusion (50 mg) from 5 to 30 min. ILE was administered as a bolus at 12.5 min (2.5 ml/kg), followed by a 15-min infusion (0.25 ml/kg/min). On metoprolol+ILE days (compared to metoprolol+placebo) after 120-minutes, mean heart rates were significantly higher (difference: 5.5 beats per minute (bpm) (95% CI: 3.0-8.1) (p<0.001)); and average relative cardiac output was higher (difference: 10 percent point 95% CI: 5-15, p<0.001). Hemodynamic effect of ILE developed gradually. ILE had no effect on plasma metoprolol or major adverse events. In conclusion, high-dose ILE has relatively marginal and delayed hemodynamic effects that may have limited clinical relevance in the acute clinical toxicological setting. This article is protected by copyright. All rights reserved. PMID- 30412278 TI - Accuracy of new recommendations for adrenal incidentalomas in the evaluation of excessive cortisol secretion and follow-up. AB - OBJECTIVE: To evaluate whether the 2016 European Society of Endocrinology (ESE) recommendations for the management of adrenal incidentalomas accurately classifies those patients who do not require further follow-up. DESIGN AND METHODS: Single centre retrospective study. From 2010-2015, 130 patients with adrenal incidentaloma were evaluated and followed-up. Clinical, analytical and radiological data were recorded and the presence of comorbidities was assessed. Patients were grouped as nonfunctional or subclinical Cushing syndrome according to American guidelines; and nonfunctional, possible autonomous cortisol secretion and autonomous cortisol secretion, according to ESE guidelines. RESULTS: Based on American guidelines, 94% of patients had nonfunctional adrenal incidentalomas and 6% had subclinical Cushing syndrome. Based on ESE guidelines, patients were classified into nonfunctional (54%), possible autonomous cortisol secretion (40%) and autonomous cortisol secretion (6%) groups. No differences were observed in demographic characteristics and comorbidities between groups in either classification. Following ESE guidelines, no patient in the nonfunctional group was reclassified into the possible autonomous or autonomous cortisol secretion groups during follow-up, but one patient in the possible autonomous cortisol secretion group was reclassified into the autonomous cortisol secretion group. Also, 30 patients included in the groups of possible autonomous or autonomous cortisol secretion experienced progression of a comorbidity associated with cortisol excess, with diabetes mellitus as the most frequent comorbidity observed. CONCLUSION: Although adrenal incidentalomas with an excess of cortisol secretion were more frequently diagnosed with the new ESE recommendations, patients who did not require longer follow-up after first evaluation were accurately classified. This article is protected by copyright. All rights reserved. PMID- 30412279 TI - Postoperative respiratory complications and racial disparities following inpatient pediatric tonsillectomy: A cross-sectional study. AB - OBJECTIVES/HYPOTHESIS: To study rates of respiratory complications/interventions among inpatient tonsillectomy patients in the United States and identify risk factors for these events. STUDY DESIGN: Retrospective database review. METHODS: Children (age < 18 years) undergoing tonsillectomy with or without adenoidectomy in 2006, 2009, and 2012 were studied using the Kids Inpatient Database, Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality. Outcomes were analyzed for respiratory events (complications/interventions) and racial disparities. Pearson chi test was used to analyze categorical data and regression analysis was used for continuous variables. Respiratory events were analyzed by racial identity using logistic regression analysis. A P < .05 was considered significant. RESULTS: The study included 30,617 patients (41% female, 51% white, 24% African American, 23% Hispanic, 3.0% Asian). The mean age was 5.2 years, and mean length of stay 2.3 days. The overall complication rate was 6.0%, and overall intervention rate was 3.6%. Respiratory events were more common among African American children (odds ratio [OR]: 1.5, 95% confidence interval [CI]: 1.3-1.6) and less common among white children (OR: 0.8, 95% CI: 0.8-0.9). These differences were significant after controlling for age, gender, obesity, obstructive sleep apnea, and asthma. The mortality rate was 0.05% with no ethnic predilection. CONCLUSIONS: Respiratory events after inpatient tonsillectomy included laryngo/bronchospasm, pneumonia, pulmonary edema, intubation, prolonged intubation, and ventilation. Although uncommon, these were more common among African American children. Further research is needed to understand the etiology of this disparity. LEVEL OF EVIDENCE: NA Laryngoscope, 2018. PMID- 30412280 TI - Exosomal circRNA derived from gastric tumor promotes white adipose browning by targeting the miR-133/PRDM16 pathway. AB - Cancer-related cachexia is a metabolic syndrome characterized by a wasting disorder of adipose and skeletal muscle and is accompanied by body weight loss and systemic inflammation. The treatment options for cancer cachexia are limited, and the molecular mechanism remains poorly understood. Circular RNAs (circRNAs) are a novel family of endogenous noncoding RNAs that have been proposed to regulate gene expression in mammals. Exosomes are small vesicles derived from cells, and recent studies have shown that circRNAs are stable in exosomes. However, little is known about the biological role of circRNAs in exosomes. In this study, we showed that circRNAs in plasma exosomes have specific expression features in gastric cancer (GC), and ciRS-133 is linked with the browning of white adipose tissue (WAT) in GC patients. Exosomes derived from GC cells deliver ciRS-133 into pre-adipocytes, promoting the differentiation of pre-adipocytes into brown-like cells by activating PRDM16 and suppressing miR-133. Moreover, knockdown of ciRS-133 reduced cancer cachexia in tumor-implanted mice, decreasing oxygen consumption and heat production. Thus, exosome-delivered circRNAs are involved in WAT browning and play a key role in cancer-associated cachexia. This article is protected by copyright. All rights reserved. PMID- 30412281 TI - Evaluation of a validated methylation triage signature for human papillomavirus positive women in the HPV FOCAL cervical cancer screening trial. AB - Human papillomavirus (HPV)-based cervical cancer screening requires triage of HPV positive women to identify those at risk of cervical intraepithelial neoplasia grade 2 (CIN2) or worse. We conducted a blinded case-control study within the HPV FOCAL randomized cervical cancer screening trial of women aged 25-65 to examine whether baseline methylation testing using the S5 classifier provided triage performance similar to an algorithm relying on cytology and HPV genotyping. Groups were randomly selected from 257 women with known HPV/cytology results and pathology outcomes. Group 1: 104 HPV positive (HPV+), abnormal cytology (54 CIN2/3; 50 0.70) in dichloromethane and tetrahydrofuran. In the solid state, the asymmetric structure induced a unique dimeric structure, and efficient luminescence was also observed. The formation of halogen bonds between carbonyl oxygen and bromine or iodine regulated the stacking mode and enhanced intermolecular interaction, resulting in a decline in the fluorescence quantum yield. In addition, a large Stokes shift was also achieved in these asymmetric BODIQPys. PMID- 30412310 TI - Euvolemia-A critical target in the management of acute kidney injury. AB - It has been clearly established that critically ill patients with sepsis require prompt fluid resuscitation. The optimal amount of fluid and when to taper this resuscitation is less clear. There is a growing evidence that fluid overload leads to acute kidney injury, and increased morbidity and mortality. A clinician's best intentions in resuscitating a patient can lead to too much of a good thing. Currently, there are several bedside tools to aid in determining a patient's response to a fluid challenge as well as in the assessment of the current volume status. Guidelines are not available on the exact rate of fluid overload removal and what medicinal or mechanical modality is most favorable. We discuss our experience and an examination of the literature on the problems with fluid overload, and how a patient may benefit from forced fluid removal. PMID- 30412311 TI - Pain management and safety profiles after preoperative vs postoperative thoracic epidural insertion for bilateral lung transplantation. AB - OBJECTIVE: Thoracic epidural analgesia provides effective pain control after lung transplantation; however, the optimal timing of placement is controversial. We sought to compare pain control and pulmonary and epidural morbidity between patients receiving preoperative vs postoperative epidurals. METHODS: Institutional records were reviewed for patients undergoing a bilateral lung transplant via a bilateral anterior thoracotomy with transverse sternotomy incision between January 2014 and January 2017. Pain control was measured using visual analog scale pain scores (0-10). Pulmonary complications included a composite of pneumonia, prolonged intubation, and reintubation/tracheostomy. RESULTS: Among 103 patients, 72 (70%) had an epidural placed preoperatively and 31 (30%) had an epidural placed within 72 hours posttransplant. There were no differences in the rates of cardiopulmonary bypass (3% vs 0%, P = 0.59); however, patients with a preoperative epidural were less likely to be placed on extracorporeal membrane oxygenation intraoperatively (25% vs 52%, P = 0.01). Pain control was similar at 24 hours (1.2 vs 1.7, P = 0.05); however, patients with a preoperative epidural reported lower pain scores at 48 (1.2 vs 2.1, P = 0.02) and 72 hours posttransplant (0.8 vs 1.7, P = 0.02). There were no differences in primary graft dysfunction (42% vs 56%, P = 0.28), length of mechanical ventilation (19.5 vs 24 hours, P = 0.18), or adverse pulmonary events (33% vs 52%, P = 0.12). No adverse events including epidural hematoma, paralysis, or infection resulted from epidural placement. CONCLUSION: Preoperative thoracic epidural placement provides improved analgesia without increased morbidity following lung transplantation. PMID- 30412312 TI - Identification of inflammatory response patterns in experimental gingivitis studies. AB - We used novel analytical approaches to identify inflammatory response patterns to plaque accumulation in experimental gingivitis studies in humans. Data from two experimental gingivitis studies [Dataset I (n = 40) and Dataset II (n = 42)], which differed in design and recording methods, were used. Both studies comprised a three-phase program as follows: pre-induction period (oral hygiene as usual for Dataset I; professional tooth cleaning for Dataset II); induction period (plaque accumulation); and resolution period (oral hygiene as usual). Clinical recordings of plaque and gingival inflammation were made on days 0, 4, 9, and 14 for Dataset I and on days -14, 0, 7, 21, and 35 for Dataset II. Group-based-trajectory and growth curve modeling were used for data analysis. In Dataset I, gingival response to plaque accumulation was found to be lagged in time. Different group based response patterns for gingival inflammation were not identified. However, in Dataset II, 'fast' and 'slow' gingival inflammation responders were identified. 'Slow' responders had lagged inflammation responses, whereas 'fast' responders seemed to respond immediately to plaque. The findings show that analytical approaches which consider the data structure allow investigation of the dynamics of the relationship between plaque accumulation and gingival inflammation and facilitate the identification of differential patterns of gingival inflammation development. PMID- 30412313 TI - Effect of methacrylated chitosan incorporated in experimental composite and adhesive on mechanical properties and biofilm formation. AB - The lifespan of a resin-based restoration is limited, with the main reason for failure being secondary caries. Biofilm formation at the tooth-material interface is a necessary etiological agent for caries development. Dental materials with antimicrobial properties may reduce formation of biofilm and thus increase the longevity of restorations. This study aimed to investigate the effect of methacrylated chitosan (CH-MA), incorporated into the polymeric network of an experimental dental composite and adhesive, on biofilm growth of Streptococcus mutans and to assess the mechanical properties of the modified materials. The methacrylation of low-molecular-weight chitosan was achieved and biofilm studies confirmed the antibacterial effect of the modified polymer in solution. Methacrylated chitosan was incorporated into an experimental composite and adhesive, and the modified materials reduced the formation of S. mutans biofilm. The incorporation of CH-MA did not alter the bond strength of the adhesives. However, the amount of CH-MA in composite that is required to elicit an antibacterial response challenges the mechanical properties of the material. The hardness and flexural strength of the composite decreased with increasing amounts of CH-MA. However, flexural strength values still met the requirement in the ISO standard. PMID- 30412314 TI - Promoted Glycerol Oxidation Reaction in an Interface-Confined Hierarchically Structured Catalyst. AB - Confined catalysis in a 2D system is of particular interest owing to the facet control of the catalysts and the anisotropic kinetics of reactants, which suppress side reactions and improve selectivity. Here, a 2D-confined system consisting of intercalated Pt nanosheets within few-layered graphene is demonstrated. The strong metal-substrate interaction between the Pt nanosheets and the graphene leads to the quasi-2D growth of Pt with a unique (100)/(111)/(100) faceted structure, thus providing excellent catalytic activity and selectivity toward one-carbon (C1) products for the glycerol oxidation reaction. A hierarchically porous graphene architecture, grown on carbon cloth, is used to fabricate the confined catalyst bed in order to enhance the mass diffusion limitation in interface-confined reactions. Owing to its unique 3D porous structure, this graphene-confined Pt catalyst exhibits an extraordinary mass activity of 2910 mA mgPt -1 together with a formate selectivity of 79% at 60 degrees C. This paves the way toward rational designs of heterogeneous catalysts for energy-related applications. PMID- 30412315 TI - Spin-Orbit Torque Switching in a Nearly Compensated Heusler Ferrimagnet. AB - Ferrimagnetic materials combine the advantages of the low magnetic moment of an antiferromagnet and the ease of realizing magnetic reading of a ferromagnet. Recently, it was demonstrated that compensated ferrimagnetic half metals can be realized in Heusler alloys, where high spin polarization, zero magnetic moment, and low magnetic damping can be achieved at the same time. In this work, by studying the spin-orbit torque induced switching in the Heusler alloy Mn2 Ru1- x Ga, it is found that efficient current-induced magnetic switching can be realized in a nearly compensated sample with strong perpendicular anisotropy and large film thickness. This work demonstrates the possibility of employing compensated Heusler alloys for fast, energy-efficient spintronic devices. PMID- 30412316 TI - Sinus floor elevation in sites with a perforated schneiderian membrane: What is the effect of placing a collagen membrane in a rabbit model? AB - OBJECTIVE: To investigate the healing following sinus grafting in sites with a perforated schneiderian membrane repaired using a collagen membrane, compared to control sites without membrane perforation. MATERIALS & METHODS: Following elevation of the sinus membrane in 16 rabbits, each sinus was assigned to one of the following groups: (i) intentional schneiderian membrane perforation, followed by the placement of a collagen membrane and bone grafting (group SMP), (ii) bone grafting without a perforation of the schneiderian membrane and without a collagen membrane placement (control group). At 2 and 4 weeks (n=8 for each time point), micro-computed tomographic (micro-CT) and histomorphometric analyses were performed. RESULTS: Overall new bone formation in group SMP was significantly delayed compared to the control group at 2 and 4 weeks (1.58+/-1.25 vs. 9.23+/ 2.69% at 2 weeks, 10.43+/-3.55 vs. 17.86+/-4.11% at 4 weeks, p<0.05). At 2 weeks, new bone formation for the areas close to lateral (1.19+/-2.02%) and medial sinus bone walls (3.17+/-1.98%) was markedly delayed in group SMP compared to the control group (13.08+/-6.13 and 12.75+/-5.63%, respectively, p<0.05), but there was no statistical difference in those areas at 4 weeks (p>0.05). The augmented volumes at 2 and 4 weeks were not statistically significantly different in both groups. CONCLUSION: The perforation of the schneiderian membrane and the repair using a collagen membrane delayed new bone formation in the augmented sinuses. However, the extension of the collagen membrane on the sinus bone walls was also attributable to this delayed bone formation. This article is protected by copyright. All rights reserved. PMID- 30412318 TI - Improved Liver Transplant Waitlist Mortality and Lower Risk of Disease Progression Among Chronic Hepatitis C Patients Awaiting Liver Transplantation After the Introduction of Direct Acting Antiviral Therapies in the United States. AB - Direct acting antiviral (DAA) therapies for chronic hepatitis C virus (HCV) infection achieve high cure rates, reducing HCV-related disease progression to cirrhosis and hepatocellular carcinoma. We aim to evaluate the impact of DAAs on U.S. liver transplant (LT) waitlist outcomes. We retrospectively evaluated U.S. adults (age >18) with and without chronic HCV listed for LT before and after the widespread use of sofosbuvir, allowing a 6-month period after approval (Era 1: 1/1/2002-5/31/2014 vs Era 2: 6/1/2014-12/31/2016) using the United Network for Organ Sharing registry. Overall LT waitlist survival and likelihood of receiving LT were evaluated with multivariate Cox regression models. From 2002-2016, 158,045 patients were listed for LT. While the number of patients listed for HCV has been decreasing since 2012, the proportion of HCV patients with concurrent HCC is increasing by 3.33% per year (R2 0.99, p <0.001 by simple linear regression). While there was no difference in likelihood of LT between HCV and non-HCV patients, those listed in Era 2 had lower likelihood of LT (HR 0.91, p<0.001), more pronounced in the HCV cohort (HR 0.83, p<0.001) compared to the non-HCV cohort (HR 0.93, p<0.001). Compared to non-HCV patients, higher waitlist mortality was seen in HCV patients in Era 1 (HR 1.08, p<0.001) but not in Era 2 (HR 1.02, p = 0.75). Since the introduction of DAAs for HCV treatment, number of patients with HCV listed for LT has declined. In the post-DAA era, HCV patients on the LT waitlist had improved waitlist mortality. This article is protected by copyright. All rights reserved. PMID- 30412319 TI - Improved Outcoupling Efficiency and Stability of Perovskite Light-Emitting Diodes using Thin Emitting Layers. AB - Hybrid organic-inorganic perovskite semiconductors have shown potential to develop into a new generation of light-emitting diode (LED) technology. Herein, an important design principle for perovskite LEDs is elucidated regarding optimal perovskite thickness. Adopting a thin perovskite layer in the range of 35-40 nm is shown to be critical for both device efficiency and stability improvements. Maximum external quantum efficiencies (EQEs) of 17.6% for Cs0.2 FA0.8 PbI2.8 Br0.2 , 14.3% for CH3 NH3 PbI3 (MAPbI3 ), 10.1% for formamidinium lead iodide (FAPbI3 ), and 11.3% for formamidinium lead bromide (FAPbBr3 )-based LEDs are demonstrated with optimized perovskite layer thickness. Optical simulations show that the improved EQEs source from improved light outcoupling. Furthermore, elevated device temperature caused by Joule heating is shown as an important factor contributing to device degradation, and that thin perovskite emitting layers maintain lower junction temperature during operation and thus demonstrate increased stability. PMID- 30412317 TI - Biallelic COLGALT1 variants are associated with cerebral small vessel disease. AB - OBJECTIVE: Approximately 5% of cerebral small vessel diseases are hereditary, which include COL4A1/COL4A2-related disorders. COL4A1/COL4A2 encode type IV collagen alpha1/2 chains in the basement membranes of cerebral vessels. COL4A1/COL4A2 mutations impair the secretion of collagen to the extracellular matrix, thereby resulting in vessel fragility. The diagnostic yield for COL4A1/COL4A2 variants is around 20 to 30%, suggesting other mutated genes might be associated with this disease. This study aimed to identify novel genes that cause COL4A1/COL4A2-related disorders. METHODS: Whole exome sequencing was performed in 2 families with suspected COL4A1/COL4A2-related disorders. We validated the role of COLGALT1 variants by constructing a 3-dimensional structural model, evaluating collagen beta (1-O) galactosyltransferase 1 (ColGalT1) protein expression and ColGalT activity by Western blotting and collagen galactosyltransferase assays, and performing in vitro RNA interference and rescue experiments. RESULTS: Exome sequencing demonstrated biallelic variants in COLGALT1 encoding ColGalT1, which was involved in the post-translational modification of type IV collagen in 2 unrelated patients: c.452 T > G (p.Leu151Arg) and c.1096delG (p.Glu366Argfs*15) in Patient 1, and c.460G > C (p.Ala154Pro) and c.1129G > C (p.Gly377Arg) in Patient 2. Three-dimensional model analysis suggested that p.Leu151Arg and p.Ala154Pro destabilized protein folding, which impaired enzymatic activity. ColGalT1 protein expression and ColGalT activity in Patient 1 were undetectable. RNA interference studies demonstrated that reduced ColGalT1 altered COL4A1 secretion, and rescue experiments showed that mutant COLGALT1 insufficiently restored COL4A1 production in cells compared with wild type. INTERPRETATION: Biallelic COLGALT1 variants cause cerebral small vessel abnormalities through a common molecular pathogenesis with COL4A1/COL4A2 related disorders. Ann Neurol 2018. PMID- 30412320 TI - Remake Rates for Single-Unit Crowns in Clinical Practice: Findings from The National Dental Practice-Based Research Network. AB - PURPOSE: Some crowns returned from the laboratory are clinically unacceptable, and dentists must remake them. The objectives of this study were to: 1) quantify the remake rate of single-unit crowns; and 2) identify factors significantly associated with crown remakes and intraoral fit. MATERIALS AND METHODS: Dentists participating in the National Dental Practice-Based Research Network recruited patients needing crowns and documented fabrication techniques, patient characteristics, and outcomes. Crowns were considered clinically acceptable or rejected. Also, various aspects of the clinical fit of the crown were graded and categorized as 'Goodness of Fit (GOF).' Dentist and patient characteristics were tested statistically for associations with crown acceptability and GOF. RESULTS: More than 200 dentists participated in this study (N = 205) and evaluated 3750 single-unit crowns. The mean age (years) of patients receiving a crown was 55. The remake rate for crowns was 3.8%. The range of rejection rates among individual practitioners was 0 to 42%. Most clinicians (118, or 58%) did not reject any crowns; all rejections came from 42% of the clinicians (n = 87). The most common reasons for rejections were proximal misfit, marginal errors, and esthetic failures. Fewer years in practice was significantly associated with lower crown success rates and lower fit scores. GOF was also associated with practice busyness and patient insurance status, patient gender (dentists reported better fit for female patients), and patient ethnicity. CONCLUSIONS: The crown remake rate in this study was about 4%. Remakes and crown GOF were associated with certain dentist and practice characteristics. This article is protected by copyright. All rights reserved. PMID- 30412321 TI - Can abnormal dispersion of ventricular repolarization be a predictor of mortality in arrhythmogenic right ventricular cardiomyopathy: The importance of Tp-e interval. AB - BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by ventricular arrhythmias and specific ventricular pathology. Repolarization abnormalities, the significant contributor to life-threatening arrhythmias and mortality, are frequently observed ECG changes in patients with ARVC. This study aimed to evaluate the changes in Tp-e interval, Tp-e/QT, Tp-e/QTc ratio, and traditional electrocardiographic features of electrical dispersion in patients with ARVC. METHODS: A total of 105 participants were enrolled in the current study. The ARVC group consisted of 40 subjects (30 men, with a median of 35 (26-41) years), and the control group included of 65 age and sex-matched individuals (42 men, with a median of 37 (24 45) years). The Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio were measured by the 12-lead electrocardiogram. RESULTS: Tp-e interval, cTp-e interval, Tp-e/QT, and Tp-e/QTc ratio were significantly higher in ARVC patients compared to the control group (all p < 0.001). Tp-e interval, cTp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio were significantly increased in deceased ARVC patients compared to the survival group (p = 0.038, p < 0.001, p = 0.006, p = 0.032, respectively). In the multivariate analysis, RV-FAC and cTp-e interval level (p < 0.05 for each parameter) were associated with all-cause mortality [odds ratio 1.747 95% CI (1.012-3.018); p = 0.045 and odds ratio 1.166, 95% CI (1.017-1.336); p = 0.027, respectively]. CONCLUSION: Tp-e interval, cTp-e interval, Tp-e/QT ratio, and Tp e/QTc ratio were prolonged in patients with NC. We revealed that abnormal dispersion of ventricular repolarization suggests the increased risk of mortality in ARVC. PMID- 30412322 TI - High-risk symptoms do not predict gastric cancer precursors. AB - BACKGROUND & STUDY AIMS: Gastric intestinal metaplasia (GIM) is the most common precursor of gastric cancer. Our aim is to determine if presenting symptoms predict gastric cancer precursor lesions in a high-risk population. PATIENT AND METHODS: Consecutive unique patients evaluated by endoscopy for upper gastrointestinal symptoms at the Los Angeles County Hospital between 2010 and 2014 were evaluated. Presenting symptoms were classified as low- or high-risk depending on the procedure indication as coded using the Clinical Outcomes Research Initiative (CORI) system. Endoscopy and histology results were used to classify findings as benign, GIM, high-risk GIM, or malignant. The primary outcome was the proportion of patients with premalignant or malignant gastric findings who had high-risk clinical indications for endoscopy relative to those with benign results. RESULTS: A total of 3699 patients underwent endoscopy to evaluate upper gastrointestinal symptoms. There were 373 (10.1%) patients with GIM of which 278 had high-risk GIM. One hundred and sixty (4.3%) patients were diagnosed with gastric cancer. High-risk indications for upper endoscopy predicted gastric cancer (OR 1.8 [95% CI 1.3-2.6]) but not GIM (OR 1.0 [0.8-1.3]) or high-risk GIM (OR 0.9 [0.7-1.2]). Hispanic or Asian patients and patients >50 years old were more likely to have GIM, high-risk GIM, and cancer. CONCLUSIONS: Performance of upper endoscopy for high-risk indications is inadequate to detect GIM and marginal for malignancy. At risk patients should undergo upper endoscopy for both low- and high-risk symptoms. Screening certain populations deserve additional study and may, in fact, be cost-effective. PMID- 30412323 TI - Recruitment of CCR6+ Foxp3+ regulatory gastric infiltrating lymphocytes in Helicobacter pylori gastritis. AB - Helicobacter pylori (H. pylori) infection is associated with an inflammatory response in the gastric mucosa, leading to chronic gastritis, peptic ulcers, and gastric cancer. Increased T-cell infiltration is found at sites of H. pylori infection. The CCR6+ subset of CD4+ regulatory T cells (Tregs), a newly characterized subset of Tregs, has been reported to contribute to local immune inhibition. However, whether CCR6+ Tregs are present in H. pylori gastritis, and what their relationship is to disease prognosis, remains to be elucidated. In this study, gastric infiltrating lymphocytes were isolated from endoscopic biopsy specimens of H. pylori gastritis patients and analyzed. We found that in gastric infiltrating lymphocytes, CCR6+ CD4+ CD25high Tregs, which express high levels of CD45RO, are positively associated with more severe inflammation in gastric mucosa during H. pylori infection. Furthermore, the frequency of CCR6+ Tregs in gastric infiltrating lymphocytes, but not CCR6- Tregs, is significantly increased in inflamed gastric tissues, which is inversely correlated with significantly lower expression of IFN-gamma+ CD8+ T cells. We also found that the frequency of CCR6+ Tregs is positively correlated with the frequency of CD4+ IFN-gamma+ T cells. In addition, the frequency of CCR6+ Tregs, but not that of CCR6- Tregs, is significantly correlated with increased inflammation in H. pylori gastritis. This study demonstrates that immunosuppression in H. pylori gastritis might be related to the activity of CCR6+ Tregs, which could influence disease prognosis. PMID- 30412324 TI - Natural products show diverse mechanisms of action against C. difficile. AB - AIMS: To investigate the mechanisms of action of natural products with bactericidal (cinnamon root powder, peppermint oil, trans-cinnamaldehyde, menthol and zingerone) or bacteriostatic (fresh garlic bulb extract, garlic clove powder, Leptospermum honey and allicin) activity against two C. difficile strains. METHODS AND RESULTS: Bactericidal products significantly reduced intracellular ATP after 1 h (P <= 0.01), quantified using the BacTiter-Glo reagent, and damaged the cell membrane, shown by the leakage of both 260-nm absorbing materials and protein, and the uptake of propidium iodide. Bacteriolysis was not observed, determined by measuring optical density of treated cell suspensions at 620-nm. The effect of three bacteriostatic products on protein synthesis was quantified using an Escherichia coli S30 extract system, with Leptospermum honey (16% w v-1 ) showing significant inhibition (P < 0.01). Lastly, no products showed elevated MICs against antimicrobial-resistant C. difficile, determined by broth microdilution. CONCLUSIONS: Cytoplasmic membrane damage was identified as a mechanism of action that may contribute to the activity of several natural products against C. difficile. SIGNIFICANCE AND IMPACT OF THE STUDY: This study describes the possible mechanisms of action of natural products against C. difficile, yet the efficacy in vivo to be determined. This article is protected by copyright. All rights reserved. PMID- 30412325 TI - The accuracy of baseline viral load for predicting the efficacy of elbasvir/grazoprevir in participants with hepatitis C virus genotype 1a infection: an integrated analysis. AB - European treatment guidelines for hepatitis C virus (HCV) infection recommend that people with genotype (GT)1a infection and baseline viral load <=800,000 IU/mL receive elbasvir/grazoprevir (EBR/GZR) for 12 weeks, and those with baseline viral load >800,000 IU/mL receive EBR/GZR plus ribavirin for 16 weeks. This analysis was conducted to clarify whether baseline viral load can serve as an accurate, sensitive, or specific stratification factor for defining EBR/GZR regimens. In this post hoc, integrated analysis, participants with GT1a infection who received EBR 50 mg/GZR 100 mg for 12 weeks were stratified according to baseline viral load. Sustained virologic response at 12 weeks post-treatment was achieved by 95.2% (911/957) of participants, and was higher among participants with baseline viral load <=800,000 IU/mL versus >800,000 IU/mL (98.5% vs 93.9%). The 800,000 IU/mL threshold had a positive predictive value of 98.5%, a negative predictive value of 6.1%, a specificity of 91.3%, a sensitivity of 28.4%, and an overall accuracy of 31.5%. A baseline viral load cutpoint of 800,000 IU/mL had high positive predictive value and specificity but poor negative predictive value, sensitivity, and accuracy in predicting treatment outcomes in this population. Baseline NS5A resistance-associated substitutions (RASs) were detected in 25% (1/4) of virologic failures with baseline viral load <=800,000 IU/mL and 59.5% (25/42) of those with baseline viral load >800,000 IU/mL. Overall, these data suggest that, compared with the use of a baseline viral load cutpoint, baseline testing for NS5A RASs enables more individuals to receive the 12-week EBR/GZR regimen without compromising the opportunity for SVR. This article is protected by copyright. All rights reserved. PMID- 30412326 TI - Invisibility of the self: Reaching for the telos of nursing within a context of moral distress. AB - Many studies have examined clinical and institutional moral problems in the practice of nurses that have led to the experience of moral distress. The causes and implications of moral distress in nurses, however, have not been understood in terms of their implications from the perspective of virtue ethics. This paper analyzes how nurses reach for the telos of their practice, within a context of moral distress. A qualitative case study was carried out in a private hospital in Brazil. Observation and semi-semistructured interviews were conducted with 13 nurse participants. With the aid of ATLAS.ti software, the data were analyzed by using thematic content analysis using virtue ethics to theorize the findings. These nurses experienced a loss of their nursing identity as they encountered an ambiguous telos and the domination of institutional values. In their reach for the telos of their practice, nurses found an environment permeated by ethical challenges, which not only created moral distress but also created professional invisibility, a phenomenon referred to as 'invisibility of the self'. PMID- 30412327 TI - International survey on growth indices and impacting factors in children with food allergies. AB - BACKGROUND: Elimination diets required for the management of food allergies increase the risk for poor growth in children. Currently, no worldwide data exist on this topic and limited published data exist on the impact of atopic comorbidity, type of allergy and foods eliminated on growth. We therefore set out to perform a worldwide survey on growth and impacting factors in food allergic children. METHODS: A prospective growth survey was performed of children (aged 0 16 years) on an elimination diet with confirmed immunoglobulin (Ig)E and non-IgE mediated food allergies. Data collected included: weight-for-age, weight-for height, height-for-age, head circumference, body mass index, type of food allergy and eliminated foods, allergic comorbidities and replacement milk/breast milk. Multivariable regression analysis was used to establish factors that affected growth. RESULTS: Data from 430 patients from twelve allergy centres were analysed: median age at diagnosis and data collection was 8 months and 23 months, respectively. Pooled data indicated that 6% were underweight, 9% were stunted, 5% were undernourished and 8% were overweight. Cow's milk elimination lead to a lower weight-for-height Z-scores than other food eliminations and mixed IgE and non-IgE mediated allergy had lower height-for-age Z-scores than IgE mediated allergy. Children with only non-IgE mediated allergies had lower weight-for height and body mass index. Atopic comorbidities did not impact on growth. CONCLUSIONS: Stunting is more common in children with food allergies than low weight. Children particularly at risk of poor growth are those with non-IgE and mixed IgE and non-IgE mediated allergies, as well as those with cow's milk allergy. PMID- 30412328 TI - Black walnut alley cropping is economically competitive with row crops in the Midwest USA. AB - The maize-soybean rotation (MSR) dominates the Midwest US and degrades many ecological functions. Black walnut (Juglans nigra L.) plantation forestry (PF) and alley cropping (AC) are two alternative land-uses that can enhance productivity and restore ecosystem services. Given the lack of robust market mechanisms to monetize ecosystems services, we tested whether the profitability of PF and AC could drive adoption in the Midwest. Publically available data on black walnut soil suitability, timber prices, crop productivity, and cash rents were combined in a high-resolution spatial analysis to identify regions where these alternatives can outcompete MSR. To avoid selecting an arbitrary discount rate at which to make comparisons, we determined the threshold discount rate necessary to make PF or AC economically competitive with MSR. We show that, with a 5% discount rate, PF and AC could be more profitable on 17.0% and 23.4% of MSR land, respectively. Contrary to the common assumption that woody agricultural alternatives should first be adopted in marginal row crop areas, the economic competitiveness of PF and AC was not correlated with MSR productivity. Instead, black walnut growth rate was the central driver of PF and AC competitiveness, underscoring a necessary shift away from the current MSR-centric perspective in defining target regions for land-use alternatives. Results reveal major opportunities for landowners and investors to increase profitability by investing in PF and AC on both "marginal" and productive MSR land. This article is protected by copyright. All rights reserved. PMID- 30412329 TI - Small supernumerary marker chromosomes: A legacy of trisomy rescue? AB - We studied by a whole genomic approach and trios genotyping, 12 de novo, nonrecurrent small supernumerary marker chromosomes (sSMC), detected as mosaics during pre- or postnatal diagnosis and associated with increased maternal age. Four sSMCs contained pericentromeric portions only, whereas eight had additional non-contiguous portions of the same chromosome, assembled together in a disordered fashion by repair-based mechanisms in a chromothriptic event. Maternal hetero/isodisomy was detected with a paternal origin of the sSMC in some cases, whereas in others two maternal alleles in the sSMC region and biparental haplotypes of the homologs were detected. In other cases, the homologs were biparental while the sSMC had the same haplotype of the maternally inherited chromosome. These findings strongly suggest that most sSMCs are the result of a multiple-step mechanism, initiated by maternal meiotic nondisjunction followed by postzygotic anaphase lagging of the supernumerary chromosome and its subsequent chromothripsis. PMID- 30412330 TI - A systematic review to assess the methodological quality of studies on measurement properties for caries risk assessment tools for young children. AB - BACKGROUND: At present, there are numerous caries risk assessment tools (CRATs) being promoted for disease management. However, the evidence to inform CRAT selection is unclear. AIM: This review aimed to assess the strength of evidence to inform the selection of CRATs for children ages 6 years and less. DESIGN: MEDLINE was the principal search database for this review. Other key databases, the reference lists of included articles, known cariology literature and experts were also consulted. Peer-reviewed papers describing CRATs and their development methodology were included. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist guided the quality assessment. The reporting of the key measurement properties (reliability, validity and responsiveness) informed the quality assessment. RESULTS: The search resulted in ten papers, reporting on eight different CRATs. The identified CRATs were: Caries Management By Risk Assessment (CAMBRA), Cariogram, National University of Singapore CRAT (NUS-CRAT), MySmileBuddy, Dundee Caries Risk Assessment Model, University of North Carolina Risk Assessment Models, University of Michigan pediatric dental clinic caries risk assessment sheet and American Academy of Pediatric Dentistry (AAPD) CRAT. Common across all CRATs was the lack of information to determine the levels of evidence for the measurement properties of reliability and construct validity. Studies on tools that were assessed as having strong evidence for content validity, identified the relevant risk factors for caries in the population being studied, before developing and testing their respective CRATs. CONCLUSIONS: The evidence to inform the selection of current CRATs for children is mostly yet to be established. Overall, the NUS-CRAT studies reported the most information to inform the assessment of its measurement properties and as a result this tool attained a higher quality rating than other CRATs studied. This article is protected by copyright. All rights reserved. PMID- 30412331 TI - A Literature Review of the Predictive Validity of European Dental School Selection Methods. AB - INTRODUCTION: Selection to dental school is the point at which there is the potential to assess a wide range of candidate attributes and select those most likely to learn, train and work within the profession. Despite this, little is known in terms of what works and what does not work in dental selection in terms of predicting future performance accurately and fairly. Given this, our aim was to synthesize the last 30 years of research investigating the predictive validity of dental school selection methods. METHODS: A search of the electronic databases SCOPUS, Pubmed and Embase was conducted. Results were limited to English language studies published between January 1987 and January 2017. RESULTS: 21 studies were included. Selection tools fell into five broad categories: tests of personal qualities; cognitive ability; academic attainment; psychomotor skills and combined ability tests. Most were retrospective, single site studies limited to early years of dental school. Weak correlations were reported but in most cases these were between small sections of the selection tool and/or the outcome measure. DISCUSSION: There was a notable dearth of published research examining dental schools selection processes across Europe over the last 30 years. Current literature was limited by weak study design and lack of long term follow up. CONCLUSION: There is insufficient high quality evidence from which to draw any conclusions as to the best selection methods to use in dental school selection. Without this, designing selection frameworks for dentistry which are appropriately weighted, reliable and valid remains a challenge. This article is protected by copyright. All rights reserved. PMID- 30412332 TI - Harvesting effects on wild bee communities in bioenergy grasslands depend on nesting guild. AB - Conversion of annual crops to native perennial grasslands for bioenergy production may help conserve wild bees by enhancing nest and food resources. However, bee response to the disturbance of biomass harvesting may depend on their nesting location, thus their vulnerability to nest destruction, and the response of the forb community on which they forage. Moreover, because bees have long foraging ranges, effects of local harvesting may depend on the amount of natural habitat in the surrounding landscape. We performed a large-scale one- and two-year experiment in Michigan and Wisconsin, USA, respectively, to examine how grassland harvesting, landscape context, and study year affect the forb community, above- and belowground-nesting bee species richness, community composition, trap nest emergence, and visitation rate. In Wisconsin, harvesting increased forb richness, cover, and evenness compared to unharvested control sites. Harvesting negatively affected aboveground-nesting bee richness and emergence from trap nests, possibly because of nest destruction during the previous harvest. By contrast, harvesting positively affected belowground-nesting bee richness, possibly because of the greater food resource availability and reduced thatch allowing greater access to nesting sites in the soil. Harvesting also affected bee community composition, reflecting the increase in belowground nesting species at harvested sites. Despite harvesting effects on forb and bee communities, there was no effect on flower visitation rate, indicating little effect on pollination function. We did not find a harvest by landscape context interaction, which, in combination with the negative harvesting effect on trap nest emergence, suggests that harvesting can affect local population growth rather than simply affecting forager aggregation in different resource environments. For bees, there was no harvest by study year interaction, indicating a consistent response over a short timescale. Similarly, in Michigan, belowground-nesting species also responded positively to harvesting, which was more pronounced in sandier soils that are preferred for nesting. However, other components of the Michigan bee and forb communities were not significantly affected by biomass harvesting. Overall, our study demonstrates that harvesting grasslands can positively affect the ~80% of bee species that nest belowground by enhancing nest and/or forage resources, but that conserving aboveground-nesters may require leaving some area unharvested. This article is protected by copyright. All rights reserved. PMID- 30412333 TI - A Peptide Backbone Stapling Strategy Enabled by the Multicomponent Incorporation of Amide N-Substituents. AB - The multicomponent backbone N-modification of peptides on solid-phase is presented as a powerful and general method to enable peptide stapling at the backbone instead of the side chains. We prove that a variety of functionalized N substituents suitable for backbone stapling can be readily introduced by means of on-resin Ugi multicomponent reactions conducted during solid-phase peptide synthesis. Diverse macrocyclization chemistries were implemented with such backbone N-substituents, including the ring-closing metathesis, lactamization and thiol alkylation. The backbone N-modification method was also applied to the synthesis of alpha-helical peptides by linking N-substituents to the peptide N terminus, thus featuring hydrogen-bond surrogate structures. Overall, the strategy proves useful for peptide backbone macrocyclization approaches that show promise in peptide drug discovery. PMID- 30412334 TI - Extragastric diseases correlated with Helicobacter pylori. PMID- 30412335 TI - Porous Core-shell CuCo2S4 Nanospheres as Anode for Enhanced Lithium-ion Battery. AB - Porous core-shell CuCo2S4 nanospheres that exhibit a large specific surface area, sufficient inner space, and nanoporous shell, have been synthesized through a facile solvothermal method. The diameter of core-shell CuCo2S4 nanospheres is ~800 nm and the radius of the core and the thickness of the shell are ~250 and ~45 nm, respectively. Based on the experimental results, the formation mechanism of core-shell structure is also discussed. These CuCo2S4 show excellent Li storage performance when used as anode for lithium-ion battery. It delivers high reversible capacity of 773.7 mA h g-1 after 1000 cycles at a current density of 1 A g-1 and displays a stable capacity of 358.4 mA h g-1 after 1000 cycles even at a higher current density of 10 A g-1. The excellent Li storage performance in terms of high reversible capacity, cycling performance and rate capability, can be attributed to the synergistic effects of both core and shell during Li+ ion insertion/extraction processes. PMID- 30412336 TI - Asymmetric Cyclizative Dimerization of (ortho-Alkynyl Phenyl) (Methoxymethyl) Sulfides with Palladium(II) Bisoxazoline Catalyst. AB - The first example of an asymmetric cyclizative dimerization of (ortho alkynylphenyl) (methoxymethyl) sulfides with a palladium(II) bisoxazoline (box) catalyst has been developed. The box ligand enhances the alkynophilicity of benzothienyl palladium(II) intermediate and thus promotes coordination of the second alkyne substrate, leading to the dimerization. The characteristic properties of the box ligand were supported by density functional theory (DFT) calculations of the intermediate. Axially chiral bibenzothiophenes were obtained in good yields with good enantioselectivities. PMID- 30412337 TI - Toward A Universal Biomedical Data Translator. PMID- 30412338 TI - Uterine RGS2 expression is regulated by exogenous estrogen and progesterone in ovariectomized mice, and downregulation of RGS2 expression in artificial decidualized ESCs inhibits trophoblast spreading in vitro. AB - Embryo implantation is a complicated event that relies on two critical factors: the competent blastocyst and the receptive uterus. Successful implantation results from tight coordination of these two factors. The maternal hormone environment of the uterus and molecular cross-talk between the embryo and uterine tissue play pivotal roles in implantation. Here we showed that regulator of G protein signaling 2 (RGS2), a member of ubiquitous family of proteins that regulate G-protein activation, plays an important role in embryo implantation by interfering in the cross-talk between the embryo and uterine tissue. RGS2 expression increased during the implantation process, and was higher in the implant site than at the nonimplantation site. Meanwhile, ovariectomized (OVX) mice exhibited higher expression of RGS2 in the uterus. Exogenous 17beta estradiol and progesterone in OVX mice downregulated the expression of RGS2. Treatment with exogenous 17beta-estradiol alone caused uterine RGS2 messenger RNA levels of OVX mice to return to those of normal female mice; when these mice were treated with progesterone or 17beta-estradiol plus progesterone, RGS2 levels rose. Downregulation of Rgs2 by small interfering RNA in an in vitro coculture system of decidualized endometrial stromal cells and blastocysts inhibited blastocyst outgrowth by restricting trophoblast spreading, suggesting a mechanism by which RGS2 regulates embryo implantation. PMID- 30412339 TI - Higher Chain Length Distribution in Debranched Type-3 Resistant Starches (RS3) Increases TLR Signaling and Supports Dendritic Cell Cytokine Production. AB - SCOPE: Resistant starches (RSs) are classically considered to elicit health benefits through fermentation. However, it is recently shown that RSs can also support health by direct immune interactions. Therefore, it has been hypothesized that the structural traits of RSs might impact the health benefits associated with their consumption. METHODS AND RESULTS: Effects of crystallinity, molecular weight, and chain length distribution of RSs are determined on immune Toll-like receptors (TLRs), dendritic cells (DCs), and T-cell cytokines production. To this end, four type-3 RSs (RS3) are compared, namely Paselli WFR, JD150, debranched Etenia, and Amylose fraction V, which are extracted from potatoes and enzymatically modified. Dextrose equivalent seems to be the most important feature influencing immune signaling via activation of TLRs. TLR2 and TLR4 are most strongly stimulated. Especially Paselli WFR is a potent activator of multiple receptors. Moreover, the presence of amylose, even to residual levels, enhances DC and T-cell cytokine responses. Paselli WFR and Amylose fraction V influence T-cell polarization. CONCLUSIONS: It has been shown here that chain length and particularly dextrose equivalent are critical features for immune activation. This knowledge might lead to tailoring and design of immune-active RS formulations. PMID- 30412340 TI - The Biomedical Data Translator Program: Conception, Culture, and Community. PMID- 30412341 TI - Nutritional status and risk factors for stunting in preschool children in Bhutan. AB - Childhood malnutrition remains endemic in South Asia, although the burden varies by country. We examined the anthropometric status and risk factors for malnutrition among children aged 0-59 months through the 2015 National Nutrition Survey in Bhutan. We assessed in 1,506 children nutritional status (by z-scores of height-for-age [HAZ], weight-for-height [WHZ], and weight-for-age [WAZ]), estimating prevalence, adjusted for survey design, of stunting, wasting, underweight, and overweight (<-2 for HAZ, WHZ, and WAZ and >2 for WHZ). Children were also assessed for pedal oedema. We conducted multivariable linear/logistic regression analysis to identify child, maternal, and household risk factors for childhood undernutrition and overweight, excluding children with oedema (1.7%). Mean (SE) HAZ, WHZ, and WAZ were -0.82 (0.13), 0.10 (0.04), and -0.42 (0.05), respectively. Prevalence of stunting, wasting, underweight, and overweight were 21.2%, 2.6%, 7.4%, and 2.6%, respectively. In multivariable regressions, risk of stunting significantly increased by age: 5.3% at <6 months (reference), 16.8% at 6-23 months (OR = 3.06, 95% CI [0.63, 14.8]), and 25.0% at 24-59 months (OR = 5.07, [1.16, 22.2]). Risk of stunting also decreased in a dose-response manner with improved maternal education. None of the examined variables were significantly associated with wasting or overweight. Despite a WHZ distribution comparable with the World Health Organization reference (with ~2.6% vs. an expected 2.5% of children beyond 2 z in each tail), stunting persists in one fifth of preschool Bhutanese children, suggesting that other nutrient deficits or nonnutritional factors may be constraining linear growth for a substantial proportion of children. PMID- 30412342 TI - Deconstructing the Translational Tower of Babel. PMID- 30412343 TI - High Selectivity Towards Formate Production by Electrochemical Reduction of Carbon Dioxide at Copper-Bismuth Dendrites. AB - The electrochemical reduction of CO2 provides an alternative carbon-neutral path for renewable synthesis of fuels and value-added chemicals. This work demonstrates that dendritic, bimetallic Cu-Bi electrocatalysts with nanometer sized grains are capable of formate generation with a high selectivity. Optimizing composition of electrocatalyst could achieve a faradic efficiency of 90 % at -0.8 to -0.9 VRHE , and a partial current of more than 2 mA cm-2 . The combination of Cu with Bi enables modulation of the adsorption strength of intermediates. This leads to an increased selectivity and suppressed formation of spurious species, especially hydrogen and CO. Comparison of product distribution for Cu-In versus Cu-Bi indicated that Bi is essential to induce a favorable adsorption configuration of the intermediate species and to promote formate production. PMID- 30412344 TI - Energetic, Topological and Electric Field Analyses of Cation-Cation Nucleic Acid Interactions in Watson-Crick Disposition. AB - A theoretical study of the effect of the diprotonation on the nucleic acid bases (A : U, A : T and G : C) in Watson-Crick conformation has been carried out by means of DFT computational methods in vacuum. In addition, the corresponding neutral and monoprotonated binary complexes have been considered. Most of the diprotonated species studied are stable, even though the binding energy is positive due to the overall repulsive electrostatic term. Local electrostatic attractive forces in the regions of hydrogen bonds (HBs) are responsible for equilibrium geometries, as shown by the electric field lines connecting the electrophilic and nucleophilic sites involved in the HB interactions. Secondary electrostatic effects also affect the assembling of the nucleic acid complexes in either neutral or cationic form. In particular, the electric field lines flowing from electrophilic sites in one base to nucleophilic sites in the other reinforce the linking between them. Hence, when the nucleophilic site concerns the free lone pair of the heteroatom involved in the HB interaction as acceptor, the HB distance shortens. However, if the free lone pair of the HB acceptor interacts with an electrophilic site in the same molecule, the HB distance elongates, weakening the HB interaction. The topological analysis of the electron density distribution in HB regions indicates that neutral, monoprotonated and diprotonated complexes show no differences in the nature of their HB's. PMID- 30412345 TI - Is obesity changing the phenotype of bipolar disorder from predominately euphoric toward mixed presentations? PMID- 30412346 TI - Steeper dose gradients resulting from reduced source to target distance-a planning system independent study. AB - PURPOSE: To quantify the contribution of penumbra in the improvement of healthy tissue sparing at reduced source-to-axis distance (SAD) for simple spherical target and different prescription isodoses (PI). METHOD: A TPS-independent method was used to estimate three-dimensional (3D) dose distribution for stereotactic treatment of spherical targets of 0.5 cm radius based on single beam two dimensional (2D) film dosimetry measurements. 1 cm target constitutes the worst case for the conformation with standard Multi-Leaf Collimator (MLC) with 0.5 cm leaf width. The measured 2D transverse dose cross-sections and the profiles in leaf and jaw directions were used to calculate radial dose distribution from isotropic beam arrangement, for both quadratic and circular beam openings, respectively. The results were compared for standard (100 cm) and reduced SAD 70 and 55 cm for different PI. RESULTS: For practical reduction of SAD using quadratic openings, the improvement of healthy tissue sparing (HTS) at distances up to 3 times the PTV radius was at least 6%-12%; gradient indices (GI) were reduced by 3-39% for PI between 40% and 90%. Except for PI of 80% and 90%, quadratic apertures at SAD 70 cm improved the HTS by up to 20% compared to circular openings at 100 cm or were at least equivalent; GI were 3%-33% lower for reduced SAD in the PI range 40%-70%. For PI = 80% and 90% the results depend on the circular collimator model. CONCLUSION: Stereotactic treatments of spherical targets delivered at reduced SAD of 70 or 55 cm using MLC spare healthy tissue around the target at least as good as treatments at SAD 100 cm using circular collimators. The steeper beam penumbra at reduced SAD seems to be as important as perfect target conformity. The authors argue therefore that the beam penumbra width should be addressed in the stereotactic studies. PMID- 30412347 TI - A comparison between modified and conventional surgical techniques for surgical lip repositioning in the management of the gummy smile. AB - AIM: The aim of this study was to evaluate and compare conventional and modified lip repositioning surgical techniques used for management of gummy smile involving hyperactive lip elevator muscles. METHODS AND MATERIALS: A prospective study was conducted between April 2016 and May 2017. Twenty two adult patients aged 18-38 years with gummy smile ranging from 4 to 6 mm because of soft tissue disorders were included in the study. All patients were treated in the oral and maxillofacial department at Damascus University. The sample was divided into two groups of 11 patients. The first group was treated by the conventional standard technique, and the second group treated by a modified study technique. The amount of gingival display in full smile was evaluated in both groups following each intervention. RESULTS: Both groups exhibited a statistically significant reduction in the measurement of gummy smile at month 1 and 6 postoperatively (P < .05), but there was no significant difference in gingival display at 3 months in either group postoperatively (P > .05). The recent study showed a significant difference in gingival display between 3 and 6 months postoperatively in group 1, but no significant difference in group 2. CONCLUSION: This study showed that the modified technique utilized in treating gummy smile has less relapse after surgery, shows excellent cosmesis and compared to the conventional technique, greater sustainability. CLINICAL SIGNIFICANCE: The recent increase in demand for an esthetic smile has led to the development a modification of conventional lip repositioning for correcting gummy smile by myotomy of lip elevator muscles. This modified technique offers less relapse and greater stability post-operatively than the conventional technique. PMID- 30412348 TI - Maximum Bony Gape in Primates. AB - Maximum jaw gape has important functional implications for behavior and feeding habits in primates. It has been suggested that gape is correlated to canine height and ingested food size. Extending these correlations to the fossil record would provide insights about the diets and/or social behavior of extinct primates. However, this can be problematic due to uncertainty about size and location of musculature, and it depends on reliability and repeatability of maximum gape estimation using only skeletal elements. In this study, maximum bony gape (MBG) was estimated using reliable landmarks and repeatable methods. The cranium was fixed in position and then the mandible was rotated and translated to the point immediately prior to loss of condyle-glenoid contact. Then it was photographed in a steady position using an adjustable wooden frame. This protocol allowed for photographs and linear measurements to be obtained for many museum specimens in a short time. The sample included 203 individuals, representing 42 species of primates. When scaled for body size, linear MBG correlates with maximum anesthetized gape (Hylander: Am J Phys Anthropol 150 (2013) 247-259), ingested food size (Perry and Hartstone-Rose: Am J Phys Anthropol 142 (2010) 625 635), and canine length but not condylar height. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30412349 TI - Evidence of Phosphonium-Carbenium Dications Formation in Superacid: Key Precursors of Fluorinated Phosphine Oxides. AB - Unambiguously confirmed by low-temperature in situ NMR experiments, X-ray diffraction and vibrational spectroscopy, phosphonium-carbenium superelectrophiles are shown to be generated in strong acidic conditions. Representing crucial intermediates, their exploitation allows for the synthesis of unprecedented fluorinated (cyclic) phosphine oxides. PMID- 30412351 TI - Resources for the optimal care of the injured veterinary patient. PMID- 30412352 TI - scil EVECC Research grant Available for 2019: ANNOUNCEMENT - PROPOSALS SOLICITED. PMID- 30412354 TI - EVECCS TRAVEL GRANT. PMID- 30412355 TI - IVECCS 2018 - A SELL-OUT: OVER 4000 ATTENDEES. PMID- 30412357 TI - VETERINARY EMERGENCY & CRITICAL CARE SOCIETY 2018 MEMBERSHIP APPLICATION. PMID- 30412358 TI - ECVECC News. PMID- 30412359 TI - Control Interventions can Impact Alveolarization and the Transcriptome in Developing Mouse Lungs. AB - There is currently much interest in understanding the mechanisms of normal and aberrant lung alveolarization, particularly in the context of bronchopulmonary dysplasia, a common complication of preterm birth where alveolarization is impeded. To this end, the parenteral administration of pharmacological agents that modulate biochemical pathways, or facilitate modulation of gene expression in transgenic animals, has facilitated the discovery and validation of mechanisms that direct lung development. Such studies include control interventions, where the solvent vehicle, perhaps containing an inactive form of the agent applied, is administered; thereby providing a well-controlled point of reference for the analysis of the partner experiment. In the present study, the impact of several widely used control interventions in developing C57Bl/6J mouse pups was examined for effects on lung structure and the lung transcriptome. Parenteral administration of scrambled microRNA inhibitors (called antagomiRs) that are used to control in vivo microRNA neutralization studies, impacted lung volume, septal thickness, and the transcriptome of developing mouse lungs; with some effects dependent upon nucleotide sequence. Repeated intraperitoneal isotonic saline injections altered lung volume, with limited impact on the transcriptome. Parenteral administration of the tamoxifen solvent Miglyol accelerated mouse pup growth, and changed the abundance of 73 mRNA transcripts in the lung. Tamoxifen applied in Miglyol-in the absence of Cre recombinase-decreased pup growth, lung volume, and lung alveolarization and changed the abundance of 298 mRNA transcripts in the lung. These data demonstrate that widely used control interventions can directly impact lung alveolarization and the lung transcriptome in studies on lung development. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30412360 TI - Bioequivalence of the Once-Daily Single-Tablet Regimen of Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Compared to Combined Intake of the Separate Agents and the Effect of Food on Bioavailability. AB - The effect of food on the bioavailability of the components of the once-daily, single-tablet human immunodeficiency virus (HIV) type 1 regimen containing darunavir (DRV 800 mg), cobicistat (COBI 150 mg), emtricitabine (FTC 200 mg), and tenofovir alafenamide (TAF 10 mg) (D/C/F/TAF) (NCT02475135) and the bioequivalence of D/C/F/TAF versus combined intake of the separate agents (NCT02578550) were evaluated. These were 2 phase 1, open-label, randomized, 2 period crossover studies (7-day washout between treatments) in HIV-negative healthy volunteers. Twenty-four participants each received a single dose of D/C/F/TAF in fasted conditions (test) or after a standardized high-fat breakfast (reference). Ninety-six participants each received a single dose of D/C/F/TAF (test) or combined intake of a single DRV 800-mg tablet, a COBI 150-mg tablet, and an FTC/TAF 200/10-mg tablet (reference), both after a standardized regular calorie, regular-fat breakfast. Pharmacokinetic profiles for all D/C/F/TAF components, safety, and tolerability were assessed. Following D/C/F/TAF in fasted conditions, DRV peak concentration, area under the concentration-time curve from time of administration until the last time point with a measurable concentration (AUC)last , and extrapolated to infinity (AUCinf ) were lower by 45%, 34%, and 30%, respectively, compared with fed conditions, with no clinically relevant differences in COBI, FTC, or TAF exposures between fed and fasted conditions. In the bioequivalence study 90% confidence intervals of the geometric mean ratios of all main pharmacokinetic parameters were within the 80.00% to 125.00% bioequivalence limits for DRV, COBI, FTC, and TAF. No grade 3/4 adverse events (AEs), serious AEs, deaths, or discontinuations due to AEs occurred. D/C/F/TAF is bioequivalent to combined administration of the separate agents. Consistent with other (co)formulations of DRV, DRV exposure was lower in fasted than in fed conditions as evaluated when taken with food, so D/C/F/TAF should be taken with food. PMID- 30412361 TI - Recipes and Tools for Culture of Escherichia coli. AB - In this article, we provide information about culture media, including minimal liquid media, rich liquid media, solid media, top agar, and stab agar. We also provide descriptions and useful information about tools used with growth media such as inoculating loops, sterile toothpicks, and spreaders. (c) 2018 by John Wiley & Sons, Inc. PMID- 30412362 TI - An Open-Label, Single-Dose, Human Mass Balance Study of Amenamevir in Healthy Male Adults. AB - Amenamevir is an inhibitor of the helicase-primase enzyme complex developed for the treatment of varicella zoster virus. This mass balance study investigated the absorption, metabolism, and excretion of a single dose (200 mg) of 14 C-labeled amenamevir in healthy male volunteers. Blood, urine, and feces samples were collected for up to 8 days after the dose. Safety and tolerability were assessed through voluntary reporting of adverse events, physical examination, and clinical laboratory testing. Amenamevir was rapidly absorbed, with a median time to peak drug concentration of 1.0 to 1.5 hours and a plasma half-life of 8 to 9 hours. Overall, 95.3% of the administered dose was recovered, with the majority of radiolabeled drug excreted in feces (74.6%) followed by urine (20.6%). The major route of elimination was fecal, with around 70% of the dose excreted as metabolites and <0.1% as the unchanged drug. Metabolic profiling revealed that predominantly radiolabeled amenamevir (80%) and its hydroxyl metabolite R5 (up to 7.1%) were present in plasma. Single-dose amenamevir was well tolerated; 3 transient and mild adverse events were reported in 3 subjects. Overall, >95% of a single 200-mg dose of amenamevir was eliminated by 168 hours after the dose, with the major route of elimination being fecal. PMID- 30412363 TI - Overview of the History of the Cranial Nerves: From Galen to the 21st Century. AB - Throughout history the description and classification of the cranial nerves has been linked to the development and characteristics of anatomy and the role that it played as a tool in providing rationality to medicine, together with social, cultural, religious, and philosophical factors. Anatomists were interested in the cranial nerves, but they disagreed on their number and their paths. We can divide the history of the cranial nerves into three different periods: the first, early or macroscopic period; the second or microscopic period; and the third period or ontogenesis and genoarchitecture. The main aim of this article is to show how the description and knowledge of the cranial nerves were developed in the course of these three periods, and to highlight the main changes produced and the factors related to these changes. We describe how the first period was mainly focused on establishing the definition, number and paths of the cranial nerves, through contributions ranging from Galen's studies in the second century to Sommerring's Doctoral Dissertation in 1778 that described 12 cranial nerves for the first time. Then, the microscopic period was concentrated on the identification of the real nuclei of origin of the different cranial nerves located in the brain stem. Finally came the third period, or ontogenesis and genoarchitecture of the rhombecephalic and mesencephalic cranial nerve nuclei. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30412364 TI - Dynamic Expression Profiles of Sox9 in Embryonic, Post Natal, and Adult Heart Valve Cell Populations. AB - Heart valves are dynamic structures and abnormalities during embryonic development can lead to premature lethality or congenital malformations present at birth. The transcription factor Sox9 has been shown to be critical for early and late stages of valve formation, but its defined expression pattern throughout embryonic, post natal, and adult growth and maturation is incomplete. Here we use an antibody to detect 1-100 amino acids of Sox9 and show that in the developing embryo, Sox9 is not detected in valve endothelial cells (VECs) lining the primitive valve structures, but is highly expressed in the endothelial-derived valve interstitial cell population following endothelial-to-mesenchymal transformation. Expression is maintained in this cell population after birth, but is additionally detected in VECs from post natal day 1. Using a specific antibody to detect a phosphorylated form of Sox9 at Serine 181 (pSox9), we note enrichment of pSox9 in VECs at post natal days 1 and 10 and this pattern correlates with the known upstream kinase RockI, and downstream target, Aggrecan. The contribution of Sox9 to post natal growth and maturation of the valve is not known, but this study provides insights for future work examining the differential functions of Sox9 protein in valve cell populations. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30412365 TI - Corrigendum: Rapid Analysis of Cell-Nanoparticle Interactions using Single-Cell Raman Trapping Microscopy. PMID- 30412366 TI - Corrigendum: Light-Induced Reversible Reconfiguration of DNA-Based Constitutional Dynamic Networks: Application to Switchable Catalysis. PMID- 30412367 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 47/2018. PMID- 30412368 TI - Disruption of RHOA-ROCK Signaling Results in Atrioventricular Block and Disturbed Development of the Putative Atrioventricular Node. AB - The RHOA-ROCK signaling pathway is involved in numerous developmental processes, including cell proliferation, differentiation and migration. RHOA is expressed in the atrioventricular node (AVN) and altered expression of RHOA results in atrioventricular (AV) conduction disorders in mice. The current study aims to detect functional AVN disorders after disturbing RHOA-ROCK signaling in chicken embryos. RHOA-ROCK signaling was inhibited chemically by using the Rho-kinase inhibitor compound Y-27632 in avian embryos (20 experimental and 29 control embryos). Morphological examination of control embryos show a myocardial sinus venosus to atrioventricular canal continuity, contributing to the transitional zone of the AVN. ROCK inhibited embryos revealed lateralization and diminished myocardial sinus venosus to atrioventricular canal continuity and at the severe end of the phenotype hypoplasia of the AVN region. Ex ovo micro-electrode recordings showed an AV conduction delay in all treated embryos as well as cases with first, second (Wenkebach and Mobitz type) and third-degree AV block which could be explained by the spectrum of severity of the morphological phenotype. Laser capture microdissection and subsequent qPCR of tissue collected from this region revealed disturbed expression of HCN1, ISL1, and SHOX2. We conclude that RHOA-ROCK signaling is essential for normal morphological development of the myocardial continuity between the sinus venosus and AVN, contributing to the transitional zone, and possibly the compact AVN region. Disturbing the RHOA-ROCK signaling pathway results in AV conduction disturbances including AV block. The RHOA-ROCK inhibition model can be used to further study the pathophysiology and therapeutic strategies for AV block. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30412369 TI - Growth of E. coli in Liquid Medium. AB - We describe the procedure for inoculating overnight (starter) cultures of E. coli from a single colony, along with considerations for growing larger cultures. We also include two methods for monitoring the number of cells per unit volume (density) of liquid cultures using a spectrophotometer and a hemacytometer or "count slide." (c) 2018 by John Wiley & Sons, Inc. PMID- 30412370 TI - The importance of the polymorphisms of the ABCB1 gene in disease susceptibility, behavior and response to treatment in inflammatory bowel disease: A literature review. AB - Crohn's disease (CD) and ulcerative colitis (UD) are the 2 common clinical subtypes of idiopathic inflammatory bowel disease (IBD) characterized by chronic inflammation of the gastrointestinal tract. The multifactorial etiology and pathogenesis of IBD is still unknown; however, the interaction between genetic, environmental and immunological factors seems to be crucial. A member of the adenosine triphosphate (ATP)-binding cassette family, P-glycoprotein, encoded by the human ABCB1 gene, is among the most extensively studied transporters involved in drug disposition and effects. Single nucleotide polymorphisms (SNPs) located in exons 21, 26 and 12, i.e., G2677T/A, C3435T and C1236T, are of the greatest clinical importance. Functional defects of the intestinal epithelial barrier due to the lack of P-glycoprotein expression may constitute possible reasons for the development of colitis. Given that several drugs central to the therapy of IBD are also P-glycoprotein substrates, it has been hypothesized that its altered expression in IBD patients could modify the response to medical treatment. Nevertheless, there are conflicting reports of an association between these 3 SNPs and IBD. This article aims to review all relevant studies investigating the role of the polymorphisms of the ABCB1 gene in disease susceptibility, behavior and response to treatment in IBD. PMID- 30412371 TI - Hierarchical Porous Fluorinated Graphene Oxide@Metal-Organic Gel Composite: Label Free Electrochemical Aptasensor for Selective Detection of Thrombin. AB - Current research effort aims at developing and designing new sensing platform architectures for effectively assaying biological targets that are significantly important for human healthcare and medical diagnosis. Here, we proposed a novel nanostructured sensor based on the combination of fluorinated graphene oxide and iron-based metal-organic gel (FGO@Fe-MOG). The unique properties including hierarchical porosity along with excellent electron transfer behavior make it an ideal candidate for electrochemical sensing of thrombin with superior detection limits compared to other (electrochemical, fluorescence, and colorimetric) strategies. Specifically, thrombin-binding aptamer was immobilized onto FGO@Fe MOG through strong electrostatic interaction without any special modification or labeling, and the electrochemical impedance spectroscopy was used as the analyzing tool. The introduced aptasensor revealed high selectivity and reproducibility toward thrombin with the detection limit of 58 pM. The effectiveness, reliability, and real applicability of the proposed FGO@Fe-MOG nanohybrid were also confirmed by the determination of thrombin in a complex biological matrix represented by human serum. Taking into account the superior detection limit, high selectivity, reproducibility, and precision, the developed scalable and label-free aptasensor meets the essential requirements for clinical diagnosis of thrombin. PMID- 30412372 TI - Effect of Local Alkaline Microenvironment on the Behaviors of Bacteria and Osteogenic Cells. AB - The interactions between material surfaces and bacteria/cells have been widely investigated, based on which biomaterials with antibacterial and osteogenic abilities can be designed to conquer implant failures. The pH of environments is known to affect bacterial growth and bone formation/resorption, and it is possible that the antibacterial and osteogenic abilities of biomaterials can be simultaneously improved by regulating their surface alkalinity. Herein, we fabricated many kinds of films with various alkalinity levels on titanium surface to explore the effect of local alkaline microenvironments around material surfaces on the behaviors of bacteria and osteogenic cells. Both Gram-positive and -negative bacteria were cultured on sample surfaces to investigate their antibacterial effects. Cell adhesion, proliferation, and alkaline phosphatase (ALP) activities were investigated by culturing both bone mesenchymal stem cells (MSCs) and osteoblast cells on sample surfaces. The results show that an appropriate local alkaline environment can effectively inhibit the growth of both Gram-positive and -negative bacteria through inactivating ATP synthesis and inducing oxidative stress. Meanwhile, it can promote the osteogenic differentiation of bone MSCs and enhance the proliferation and ALP activities of osteoblast cells. In conclusion, material surfaces endowed with appropriate alkalinity can possess antibacterial and osteogenic properties, which provide a novel strategy to design multifunctional biomaterials for bone generation. PMID- 30412373 TI - Bright Yellow Fluorescent Carbon Dots as a Multifunctional Sensing Platform for the Label-Free Detection of Fluoroquinolones and Histidine. AB - Owing to their diverse properties, fluorescent carbon dots (CDs) have attracted more attention and present enormous potential in development of sensors, bioimaging, drug delivery, microfluidics, photodynamic therapy, light emitting diode, and so forth. Herein, a multifunctional sensing platform based on bright yellow fluorescent CDs (Y-CDs) was designed for the label-free detection of fluoroquinolones (FQs) and histidine (His). The Y-CDs with superior optical and biological merits including high chemical stability, good biocompatibility, and low cytotoxicity were simply synthesized via one-step hydrothermal treatment of o phenylenediamine ( o-PD) and 4-aminobutyric acid (GABA). The Y-CDs can be utilized to directly monitor the amount of FQs based on fluorescence static quenching owing to the specific interaction between FQs and Y-CDs. Then, the fluorescence of this system can be effectively recovered upon addition of His. The multifunctional sensing platform exhibited high sensitivity and selectivity toward three kinds of FQs and His with low detection limits of 17-67 and 35 nM, respectively. Benefiting from these outstanding characters, the Y-CDs were successfully employed for trace detection of FQs in real samples such as antibiotic tablets and milk products. Furthermore, the probe was also extended to cellular imaging. All of the above prove that this multifunctional sensing platform presents great prospect in multiple applications such as biosensing, biomedicine, disease diagnosis, and environmental monitoring. PMID- 30412374 TI - Finely Tunable Surface Wettability by Two-Dimensional Molecular Manipulation. AB - Local molecular environment governs material interface properties, especially the substrate's exposing behavior and overall functionality expression. Although current techniques can provide efficient surface property modification, challenges in molecule spatial distribution and composition controls limited the generation of homogeneous and finely tunable molecular environment. In this study, Au-thiolate rupturing operation in chemical lift-off lithography (CLL) is used to manipulate the substrate interface molecular environment. The creation of randomly distributed artificial self-assembled monolayer defects generates vacancies for substrate property modification through back-insertion of molecules with opposite functionalities. Surface wettability adjustment is utilized as an example, where well-controllable molecule distribution provides finely tunable substrate affinity toward liquids with different physical properties. The distinct property difference between two surface regions assists microdroplet formation when liquids flow through, not only water solution but also low-surface tension organic liquids. These microdroplet arrays become a template to guide material assembly in its formation process and act as pH-sensitive platforms for high-throughput detection. Furthermore, the tunability of the molecular pattern in this approach helps minimize the coffee-ring effect and the sweet-spot issue in matrix-assisted laser desorption/ionization mass spectrometry. Two-dimensional molecular manipulation in the CLL operation, therefore, holds the capability toward controlling homogeneous material surface property and toward exhibiting behavior adjustments. PMID- 30412375 TI - A Chromatin-Mimetic Nanomedicine for Therapeutic Tolerance Induction. AB - The undesirable immune response poses a life-threatening challenge to human health. It not only deteriorates the therapeutic performance of biologic drugs but also contributes to various diseases such as allergies and autoimmune diseases. Inspired by the role of chromatin in the maintenance of natural immune tolerance, here we report a DNA-protein polymeric nanocomplex that can mimic the tolerogenic function of chromatin and induce an immune tolerance to its protein cargos. We first proved that the chromatin-mimetic nanomedicine loaded with keyhole limpet hemocyanin (KLH), a highly immunogenic model protein, could elicit a durable antigen-specific immune tolerance to KLH lasting for at least five weeks in mice. Following the proof-of-concept study, we demonstrated that this nanomedicine could be applied to improve the safety and efficacy of a biologic drug, PEGylated uricase, by attenuating the relevant antibody (Ab) responses. Moreover, we also demonstrated that prophylactic treatments with this nanomedicine could tolerize the immune system with the allergen of ovalbumin (OVA) and thus inhibit the occurrence of airway inflammation in an OVA-induced allergic asthma murine model. Collectively, our work illustrates a nature inspired concept of immune tolerance induction and establishes a useful tool to specifically suppress unwanted immune responses for therapeutic purposes. PMID- 30412376 TI - Biomimetic Polymer-Based Method for Selective Capture of C-Reactive Protein in Biological Fluids. AB - Selective capturing and purification of C-reactive protein (CRP) from complex biological fluids plays a pivotal role in studying biological activities of CRP in various diseases. However, obvious nonspecific adsorption of proteins was observed on current affinity sorbents, and thus additional purification steps are often required, which could compromise the recovery of the target protein and/or introduce new impurities. In this study, inspired by the highly specific interaction between CRP and the cell membrane, an excellent anti-biofouling compound 2-(methacryloyloxy)ethyl phosphorylcholine and a highly hydrophilic crosslinker N, N'-methylenebisacrylamide were employed to fabricate a novel cell membrane biomimetic polymer for selective capture of CRP in the presence of calcium ions. Based on the polymer described above, a facile enrichment approach was established after systematic optimization of the washing and elution conditions. With its favorable properties, such as good porosity, weak electrostatic interaction, high hydrophilicity, and biocompatibility, the novel biomimetic polymer exhibits good specificity, selectivity, recovery (near 100%), purity (95%), and a lower nonspecific protein adsorption for CRP in comparison with commercial immobilized p-aminophenyl phosphoryl choline gel and other purification materials. Furthermore, the structural integrity and functionality of CRP in the elution fraction were well preserved and confirmed by circular dichroism spectroscopy, fluorescence spectroscopy, and immunoturbidimetric assay. Finally, the biomimetic polymer was successfully applied to the selective enrichment of CRP from sera of patients with inflammation and rats. The proposed novel enrichment approach based on the versatile biomimetic polymer can be used for effective CRP purification, which will benefit the in-depth study of its biological roles. PMID- 30412377 TI - Designing Stationary Reaction-Diffusion Patterns in pH Self-Activated Systems. AB - Since Alan Turing's 1952 pioneering work, reaction-diffusion (RD) processes are regarded as prototype mechanisms for pattern formation in living systems. Though suspected in many aspects of morphogenetic development, pure RD patterns have not yet been demonstrated in living organisms. The first observations of an autonomous development of stationary chemical patterns were made in the early 1990s. In this Account, we discuss the recent developments for producing stationary pH RD patterns in open spatial reactors. The theoretical analysis of the early experiments anticipated the possibility of finding Turing patterns in a wide range of oscillatory reactions if one could control the kinetic and diffusional rate of some key species. However, no experimentally effective method to produce stationary Turing patterns was attained before 2009, and the number of systems stagnated at two until then. The two precursor reaction systems benefited from unplanned favorable chemical properties of the RD media. Theoretical studies point out that appropriate diffusion rate differences are necessary to produce stationary patterns since a competition between an effective short distance self activation and a long distance inhibitory process is required. This differential diffusion would naturally lead to differential exchange rates between the RD system and its feed environment, an aspect somewhat overlooked in theoretical and in primal experimental approaches. Our pattern design method takes this aspect into account. A slower diffusion of a self-activated species (here, protons), produced in the RD part of the spatial reactor, generates the accumulation of this species compared to the other species. This accumulation has to be at least partly compensated by an independent scavenging reaction. The above requirement naturally brought us to focus on two-substrate pH oscillatory reactions. Stationary RD patterns are now well documented in six pH driven reaction systems. Furthermore, the coupling with a pH dependent metal ion complexing agent led to stationary patterns in calcium ion concentration. Our effective semiempirical design method does not require a detailed knowledge of the reaction kinetics; thus it is applicable to a broad spectrum of reactions and even to synthetic biological systems. It is based on simple dynamic arguments and on general topological characteristics of a nonequilibrium phase diagram. We first illustrate our method with numerical simulations, based on a realistic but idealized general model of the two-substrate pH-oscillator reaction family, and provide a refined view of the topology of the resulting phase diagrams. Then, we exemplify its effectiveness by observations made in distinct pH self-activated systems. Analogies and differences between experiments and the model calculations are pointed out. Besides standard hexagonal arrays of spots and parallel stripes, hitherto undocumented dynamic phenomena, such as randomly blinking areas and complex dynamic and stationary filamentous structures, were observed. The main challenge, to find low-mobility complexing agents that would selectively and reversibly bind a species controlling the self-activatory kinetic path of the reaction, was readily overcome in multiple ways by anions of weak acids: not only by polymeric substances but in some cases by a pH color indicator or even smaller molecules, depending on their proton binding affinity. PMID- 30412378 TI - Porous Cellulose Nanofiber-Based Microcapsules for Biomolecular Sensing. AB - Cellulose nanofibers (CNFs) have recently attracted a lot of attention in sensing because of their multifunctional character and properties such as renewability, nontoxicity, biodegradability, printability, and optical transparency in addition to unique physicochemical, barrier, and mechanical properties. However, the focus has exclusively been devoted toward developing two-dimensional sensing platforms in the form of nanopaper or nanocellulose-based hydrogels. To improve the flexibility and sensing performance in situ, for example, to detect biomarkers in vivo for early disease diagnostics, more advanced CNF-based structures are needed. Here, we developed porous and hollow, yet robust, CNF-based microcapsules using only the primary plant cell wall components, CNF, pectin, and xyloglucan, to assemble the capsule wall. The fluorescein isothiocyanate-labeled dextrans with MW of 70 and 2000 kDa could enter the hollow capsules at a rate of 0.13 +/- 0.04 and 0.014 +/- 0.009 s-1, respectively. This property is very attractive because it minimizes the influence of mass transport through the capsule wall on the response time. As a proof of concept, glucose oxidase (GOx) enzyme was loaded (and cross-linked) in the microcapsule interior with an encapsulation efficiency of 68 +/- 2%. The GOx-loaded microcapsules were immobilized on a variety of surfaces (here, inside a flow channel, on a carbon-coated sensor or a graphite rod) and glucose concentrations up to 10 mM could successfully be measured. The present concept offers new opportunities in the development of simple, more efficient, and disposable nanocellulose-based analytical devices for several sensing applications including environmental monitoring, healthcare, and diagnostics. PMID- 30412379 TI - Reliable Spin Valves of Conjugated Polymer Based on Mechanically Transferrable Top Electrodes. AB - Organic spintronic devices present one of the most appealing technologies for future spintronic devices by taking advantage of the spin degree of freedom. Conjugated polymers are attractive to the exemplified device of organic spin valves (OSVs) due to their weak spin-orbit coupling, solution-processability, low production cost and mechanical flexibility. However, the performance of polymer SVs are a matter of debate as the evaporated top ferromagnetic (FM) electrode will penetrate into the organic layer during typical fabrication process, especially in the device with organic layer thickness of nanometers. It will cause a severe problem in controllable and reproducible spin-manipulations not to mention the clarification of spin-dependent transport mechanism. Here, a universal, simple, and low-cost method based on transferred electrode is developed for polymer spin valve (SV) with stable-and-reliable-state operation. It is demonstrated in an OSV device with vertical structure of La2/3Sr1/3MnO3 (LSMO)/P3HT/AlOx/Co/Au that this approach not only builds a damage-free interface between magnetic electrodes and organic spacer layer, but also can be generalized for other devices with delicate active layers. Furthermore, a multi-state writing and reading prototype is achieved on the premise of robust and quick magnetic response. The results reveal the importance of spinterface and effective thickness of organic layer in fundamental spintronic research and may open up the strong potential in future flexible, large-area, and robust organic multifunctional circuits. PMID- 30412380 TI - Differential Metal Ion Sensing by an Antipyrine Derivative in Aqueous and beta Cyclodextrin Media: Selectivity Tuning by beta-Cyclodextrin. AB - beta-Cyclodextrin (beta-CD) is a nontoxic cyclic oligosachcharide that can encapsulate all or part of organic molecules of appropriate size and specific shape through noncovalent interaction. Herein, we report the influence of beta-CD complex formation of an antipyrine derivative on its metal ion sensing behavior. In aqueous solution, the antipyrine shows a turn-on fluorescence sensing of vanadyl ion, and in cyclodextrin medium it senses aluminum ion. The compound shows an unusual fluorescence quenching on binding with beta-cyclodextrin (log KSV = 2.34 +/- 0.02). The differential metal ion sensing is due to the partial blocking of the chelating moiety by the cyclodextrin molecule. The structure of the antipyrine-cyclodextrin complex is optimized by two-dimensional rotating frame Overhauser effect spectroscopy. The binding constant is determined by isothermal titration calorimetry (log K = 2.09 +/- 0.004). The metal ion binding site is optimized by quanutm mechanical calculations. The lower limit of detection of vanadyl and aluminum ions, respectively, are 5 * 10-8 and 5 * 10-7 mol dm-3. This is the first report of selectivity of two different cations by a chemosensor in water and in beta-CD. PMID- 30412381 TI - NMDA Receptor-Dependent Cholinergic Modulation of Mesolimbic Dopamine Cell Bodies: Neurochemical and Behavioral Studies. AB - Substance abuse disorders are devastating, costly, and difficult to treat. Identifying the neurochemical mechanisms underlying reinforcement promises to provide critical information in the development of effective treatments. Several lines of evidence suggest that striatal dopamine (DA) release serves as a teaching signal in reinforcement learning, and that shifts in DA release from the primary reward to reward-predicting stimuli play a critical role in the self administration of both natural and non-natural rewards. However, far less is known about the reinforcing effects of motivationally neutral sensory stimuli, or how these signals can facilitate self-administration behavior. Thus, we trained rats ( n = 7) to perform a visual stimulus-induced instrumental task, which involved lever pressing for activation of a stimulus light. We then microinfused vehicle (phosphate buffered saline), carbachol (acetylcholine receptor agonist), or carbachol in the presence of an N-methyl-d-aspartate (NMDA) receptor-specific drug (NMDA itself, or the antagonist, AP5) into the ventral tegmental area (VTA). This enabled us to directly evaluate how chemical modulation of dopamine cell bodies affects the instrumental behavior, as well as the nature of extracellular dopamine transients recorded in the nucleus accumbens shell (NAc shell) using fast-scan cyclic voltammetry (FSCV). Intra-VTA infusion of carbachol enhanced the magnitude and frequency of dopamine transients in the NAc shell and potentiated active lever responding without altering inactive lever responding, as compared to infusion of vehicle. Coinfusion of carbachol with AP5 abolished dopamine transients recorded in the NAc and attenuated active lever responding without altering inactive lever responding. Finally, coadministration of carbachol and NMDA into the VTA restored both lever pressing and dopaminergic signals recorded in the striatum. Together, these results suggest that acetylcholine and glutamate synergistically act at dopamine cells in the VTA to modulate VTA-NAc shell dopaminergic output, and this underlies motivation to lever press for a motivationally neutral visual stimulus. PMID- 30412382 TI - NOTA and NODAGA [99mTc]Tc- and [186Re]Re-Tricarbonyl Complexes: Radiochemistry and First Example of a [99mTc]Tc-NODAGA Somatostatin Receptor-Targeting Bioconjugate. AB - With the long-term goal of developing theranostic agents for applications in nuclear medicine, in this work we evaluated the well-known NOTA and NODAGA chelators as bifunctional chelators (BFCs) for the [99mTc/186Re]Tc/Re-tricarbonyl core. In particular, we report model complexes of the general formula fac [M(L)(CO)3]+ (M = Re, 99mTc, 186Re) where L denotes NOTA-Pyr (1) or NODAGA-Pyr (2), which are derived from conjugation of NOTA/NODAGA with pyrrolidine (Pyr). Further, as proof-of-principle, we synthesized the peptide bioconjugate NODAGA sst2-ANT (3) and explored its complexation with the fac-[Re(CO)3]+ and fac [99mTc][Tc(CO)3]+ cores; sst2-ANT denotes the somatostatin receptor (SSTR) antagonist 4-NO2-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH2. Rhenium complexes Re 1 through Re-3 were synthesized and characterized spectroscopically, and receptor binding affinity was demonstrated for Re-3 in SSTR-expressing cells (AR42J, IC50 = 91 nM). Radiolabeled complexes [99mTc]Tc/[186Re]Re-1/2 and [99mTc]Tc-3 were prepared in high radiochemical yield (>90%, determined by radio-HPLC) by reacting [99mTc]/[186Re][Tc/Re(OH2)3(CO)3]+ with 1-3 and correlated well with the respective Re-1 through Re-3 standards in comparative HPLC studies. All radiotracers remained intact through 24 h (99mTc-labeled complexes) or 48 h (186Re-labeled complexes) against 1 mM l-histidine and 1 mM l-cysteine (pH 7.4, 37 degrees C). Similarly, rat serum stability studies displayed no decomposition and low nonspecific binding of 9-24% through 4 h. Biodistribution of [99mTc]Tc-3 in healthy CF-1 mice demonstrated a favorable pharmacokinetic profile. Rapid clearance was observed within 1 h post-injection, predominantly via the renal system (82% of the injected dose was excreted in urine by 1 h), with low kidney retention (% ID/g: 11 at 1 h, 5 at 4 h, and 1 at 24 h) and low nonspecific uptake in other organs/tissues. Our findings establish NOTA and NODAGA as outstanding BFCs for the fac-[M(CO)3]+ core in the design and development of organometallic radiopharmaceuticals. Future in vivo studies of [99mTc]Tc- and [186Re]Re tricarbonyl complexes of NODAGA/NOTA-biomolecule conjugates will further probe the potential of these chelates for nuclear medicine applications in diagnostic imaging and targeted radiotherapy, respectively. PMID- 30412383 TI - Recent Progress in Microfluidics-Based Biosensing. PMID- 30412384 TI - Control of Probe Density at DNA Biosensor Surfaces Using Poly(l-lysine) with Appended Reactive Groups. AB - Biosensors and materials for biomedical applications generally require chemical functionalization to bestow their surfaces with desired properties, such as specific molecular recognition and antifouling properties. The use of modified poly(l-lysine) (PLL) polymers with appended oligo(ethylene glycol) (OEG) and thiol-reactive maleimide (Mal) moieties (PLL-OEG-Mal) offers control over the presentation of functional groups. These reactive groups can readily be conjugated to, for example, probes for DNA detection. Here we demonstrate the reliable conjugation of thiol-functionalized peptide nucleic acid (PNA) probes onto predeposited layers of PLL-OEG-Mal and the control over their surface density in the preceding synthetic step of the PLL modification with Mal groups. By monitoring the quartz crystal microbalance (QCM) frequency shifts of the binding of complementary DNA versus the density of Mal moieties grafted to the PLL, a linear relationship between probe density and PLL grafting density was found. Cyclic voltammetry experiments using Methylene Blue-functionalized DNA were performed to establish the absolute probe density values at the biosensor surfaces. These data provided a density of 1.2 * 1012 probes per cm2 per % of grafted Mal, thus confirming the validity of the density control in the synthetic PLL modification step without the need of further surface characterization. PMID- 30412385 TI - Synergy of Key Properties Promotes Dendrimer Conjugates as Prospective Ratiometric Bioresponsive Magnetic Resonance Imaging Probes. AB - Bioresponsive or smart contrast agents (SCAs) sensitive to Ca2+ are of extreme interest in the development of functional magnetic resonance imaging (MRI) techniques as they can aid in tracking neural activity in vivo. To this end, the design of macromolecular systems based on nanoscaffolds such as dendrimers functionalized with multiple MRI contrast agents has been used to conveniently increase the local concentration of paramagnetic MR reporters and slow the diffusion time of the probe, which are favorable in vivo characteristics. Moreover, previous studies with Ca-sensitive dendrimeric MRI probes revealed favorable properties crucial in the development of a ratiometric T2/ T1-imaging method that provided a higher contrast-to-noise ratio compared to conventional T1 or T2-weighted imaging protocols. We therefore developed a series of novel dendrimeric MRI probes (DCAs) with differing structural properties and charge distributions. We thoroughly studied their features such as the relaxometric behavior and size change and examined their electrostatic behaviors prior to and after the addition of Ca2+. The most active DCA displayed a common increase in r1 (3.11 to 5.72 mM-1 s-1) and a remarkable increase in r2 (7.44 to 34.57 mM-1 s-1), resulting in a r2/ r1 ratio increase of the factor 2.52, which is greater than what was previously achieved. These changes in r1 and r2 were followed with a hydrodynamic diameter increase from 7.1 +/- 1.2 to 8.5 +/- 0.7 nm upon the addition of Ca2+, along with a decrease in the negative surface charge of the nanoparticle. Overall, our findings indicate that highly responsive DCAs can be developed only through a combination of properties such as changes in hydration and size of the molecule, which are a consequence of intramolecular structural and electrostatic changes in the particle. In turn, they provide a model for future preparations of responsive DCAs that can be utilized for both T1-weighted and ratiometric T2/ T1-weighted imaging to visualize essential biological processes in a dynamic fashion. PMID- 30412386 TI - Cytochrome P450 1A1, 2C9, 2C19, and 3A4 Polymorphisms Account for Interindividual Variability of Toxicological Drug Metabolism in Cynomolgus Macaques. AB - Cytochromes P450 (P450s) and their genetic variants in humans are important drug metabolizing enzymes partly accounting for interindividual variations in drug metabolism and toxicity. However, these genetic variants in P450s have not been fully investigated in cynomolgus macaques, a nonhuman primate species widely used in toxicological studies. In this study, genetic variants found in cynomolgus CYP1A1, CYP2C9 (formerly CYP2C43), CYP2C19 (CYP2C75), and CYP3A4 (CYP3A8) were assessed on functional importance. Resequencing of CYP1A1 in cynomolgus macaques found 18 nonsynonymous variants, of which M121I and V382I were located in SRSs, domains potentially important for P450 function. By further analyzing these two variants, V382I was significantly associated with lower drug-metabolizing activities in the liver for the heterozygotes than the wild types. Similarly, the heterozygotes or homozygotes of CYP2C9 variants (A82V and H344R) and CYP2C19 variant (A490V) showed significantly lower drug-metabolizing activities in the liver than the wild types. Moreover, the homozygotes of CYP3A4 variant (S437N) showed significantly higher activities than the wild type in the liver. Kinetic analyses using recombinant proteins revealed that CYP2C9 variants (A82V and H344R) showed substantially lower Ks values than the wild type, although CYP1A1 variant (V382I) showed kinetic parameters similar to the wild type. Likewise, CYP2C19 variant (A490V) showed substantially a lower Vmax/ Km value than the wild type, whereas CYP3A4 variant (S437N) showed a higher Vmax/ Km value than the wild type. These results suggest the toxicologically functional importance of CYP2C9 variants (A82V and H344R), CYP2C19 variant (A490V), and CYP3A4 variant (S437N) for hepatic drug metabolism in cynomolgus macaques. PMID- 30412387 TI - Highly Transparent, Strong, and Flexible Films with Modified Cellulose Nanofiber Bearing UV Shielding Property. AB - This work investigates multifunctional composite films synthesized with cellulose nanofibers (CNFs) and poly(vinyl alcohol) (PVA). First, TEMPO-oxidized CNFs were modified in the heterogeneous phase with benzophenone, diisocyanate, and epoxidized soybean oil via esterification reactions. A thorough characterization was carried out via elemental analysis as well as FT-IR and X-ray photoelectron spectroscopies and solid-state NMR. Following, the surface-modified CNFs were combined with PVA to endow composite films with UV-absorbing capabilities while increasing their thermomechanical strength and maintaining a high light transmittance. Compared to neat PVF films, the tensile strength, Young modulus, and elongation of the films underwent dramatic increases upon addition of the reinforcing phase (maximum values of ~96 MPa, ~ 714 MPa, and ~350%, respectively). A high UV blocking performance, especially in the UVB region, was observed for the introduced multifunctional PVA films at CNF loadings below 5 wt %. The trade-off between modified nanofibril function as interfacial reinforcement and aggregation leads to an optimum loading. The results indicate promising applications, for example, in active packaging. PMID- 30412388 TI - Correction to "Facet-Mediated Adsorption and Molecular Fractionation of Humic Substances on Hematite Surfaces". PMID- 30412389 TI - Long-Lived Hydrated FMN Radicals: EPR Characterization and Implications for Catalytic Variability in Flavoproteins. AB - Until now, FMN/FAD radicals could not be stabilized in aqueous solution or other protic solvents because of rapid and efficient dismutation reactions. In this contribution, a novel system for stabilizing flavin radicals in aqueous solution is reported. Subsequent to trapping FMN in an agarose matrix, light-generated FMN radicals could be produced that were stable for days even under aerobic conditions, and their concentrations were high enough for extensive EPR characterization. All large hyperfine couplings could be extracted by using a combination of continuous-wave EPR and low-temperature ENDOR spectroscopy. To map differences in the electronic structure of flavin radicals, two exemplary proton hyperfine couplings were compared with published values from various neutral and anionic flavoprotein radicals: C(6)H and C(8alpha)H 3. It turned out that FMN*- in an aqueous environment shows the largest hyperfine couplings, whereas for FMNH* under similar conditions, hyperfine couplings are at the lower end and the values of both vary by up to 30%. This finding demonstrates that protein-cofactor interactions in neutral and anionic flavoprotein radicals can alter their electron spin density in different directions. With this aqueous system that allows the characterization of flavin radicals without protein interactions and that can be extended by using selective isotope labeling, a powerful tool is now at hand to quantify interactions in flavin radicals that modulate the reactivity in different flavoproteins. PMID- 30412390 TI - Predicting Aerosol Reactivity Across Scales: from the Laboratory to the Atmosphere. AB - To fully utilize the results of laboratory-based studies of the chemistry of model atmospheric aerosol reactions, it is important to understand how to relate them to the conditions found in nature. In this study, we have taken a validated reaction-diffusion mechanism for oxidation of C30H62 aerosol by OH under flow tube conditions and examined its predictions for another experimental regime (continuous flow stirred tank reactor) and for the atmosphere, spanning alkane aerosol viscosities from liquid to semisolid. The results show that under OH concentration-limited and aerosol-mixing-limited conditions, it should be possible to select laboratory experimental conditions where many aspects of the particle phase and volatile product chemistry under atmospheric conditions can be revealed. If the OH collision and organic diffusion rates are comparable, however, reactivity is highly sensitive to the details of both OH concentration and internal mixing. The characteristics of the transition between limiting conditions provide key insights into which parts of the reaction mechanism dominate in the various kinetic regimes. PMID- 30412391 TI - Effect of Calcium on the Bioavailability of Dissolved Uranium(VI) in Plant Roots under Circumneutral pH. AB - We integrated field measurements, hydroponic experiments, microscopy, and spectroscopy to investigate the effect of Ca(II) on dissolved U(VI) uptake by plants in 1 mM HCO3- solutions at circumneutral pH. The accumulation of U in plants (3.1-21.3 mg kg-1) from the stream bank of the Rio Paguate, Jackpile Mine, New Mexico served as a motivation for this study. Brassica juncea was the model plant used for the laboratory experiments conducted over a range of U (30-700 MUg L-1) and Ca (0-240 mg L-1) concentrations. The initial U uptake followed pseudo second-order kinetics. The initial U uptake rate ( V0) ranged from 4.4 to 62 MUg g-1 h-1 in experiments with no added Ca and from 0.73 to 2.07 MUg g-1 h-1 in experiments with 12 mg L-1 Ca. No measurable U uptake over time was detected for experiments with 240 mg L-1 Ca. Ternary Ca-U-CO3 complexes may affect the decrease in U bioavailability observed in this study. Elemental X-ray mapping using scanning transmission electron microscopy-energy-dispersive spectrometry detected U-P-bearing precipitates within root cell walls in water free of Ca. These results suggest that root interactions with Ca and carbonate in solution affect the bioavailability of U in plants. This study contributes relevant information to applications related to U transport and remediation of contaminated sites. PMID- 30412392 TI - Oxidation of 8-Oxo-7,8-dihydro-2'-deoxyguanosine Leads to Substantial DNA-Histone Cross-Links within Nucleosome Core Particles. AB - 8-Oxo-7,8-dihydro-2'-deoxyguanosine(8-oxodGuo) is a common primary product of cellular oxidative DNA damage. 8-OxodGuo is more readily oxidized than 2' deoxyguanosine (dG); a two-electron oxidation generates a highly reactive intermediate (OGox), which forms covalent adducts with nucleophiles, including OH , free amines, and the side chains of amino acids such as lysine. We determined here that K3Fe(CN)6 oxidation of 8-oxodGuo in nucleosome core particles (NCPs) produces high yields, quantitative (i.e., 100%) in some cases, of DNA-protein cross-links (DPCs). The efficiency of DPC formation was closely related to 8 oxodGuo base pairing and location within the NCP and was only slightly decreased by adding the DNA-protective polyamine spermine to the system. Using NCPs that contained histone mutants, we determined that DPCs result predominantly from OGox trapping by the N-terminal histone amine. The DPCs were stable under physiological conditions and therefore could have important biological consequences. For instance, the essentially quantitative yield of DPCs at some positions within NCPs would reduce the yield of the mutagenic DNA lesions spiroiminodihydantoin and guanidinohydantoin produced from the common intermediate OGox, which in turn would affect mutation signatures of oxidative stress in a position-dependent manner. In summary, our findings indicate that site-specific incorporation of 8-oxodGuo into NCPs, followed by its oxidation, leads to DPCs with an efficiency depending on 8-oxodGuo location and orientation. Given that 8-oxodGuo formation is widespread in genomic DNA and that DPC formation is highly efficient, DPCs may occur in eukaryotic cells and may affect several important biological processes. PMID- 30412394 TI - Phosphorus Competition in Bioinduced Vivianite Recovery from Wastewater. AB - Phosphorus undergoes a one-way flow from minerals to soil to water, which creates a phosphorus crisis as well as aquatic eutrophication. Dissimilatory metal reduction bacterial (DMRB)-induced vivianite recovery from wastewater is a promising route to solve these problems synthetically. In this study, phosphorus competition between biomass growth and bioinduced vivianite mineralization was investigated at the batch scale. Biomass growth leads to phosphorus utilization over vivianite mineralization. Geobacter was selected as the main functional microorganism and presented higher vivianite recovery rates (20-48%) than sewage biomass (7-33%). An optimal Fe/P stoichiometric ratio of 1:1 was observed for both sewage biomass and Geobacter-inoculated batches. The highest vivianite yield of 4.3 mM was obtained in Geobacter-inoculated batches at a Fe:P of 1:1, with values 59% higher than those at a Fe:P of 1:0.67 (equal to the Fe/P molar ratio in vivianite). Sufficient PO43- stimulated cell growth and yielded a higher Fe3+ reduction rate and vivianite yield. Nevertheless, excessive PO43- facilitated the precipitation of KFe3 (PO4)2(OH).8H2O and Fe7 (PO4)6, which inhibited vivianite synthesis. In the optimal Geobacter batch, the MU -S curve indicated a mixed order reaction (0 < x < 1) for both vivianite formation and biomass growth. The vivianite growth series proceeded as follows: tiny blue particles, plain pieces, dark blue nodules, and large spherical crystals. PMID- 30412395 TI - DNA-Encoded Dynamic Chemical Library and Its Applications in Ligand Discovery. AB - Dynamic combinatorial library (DCL) has emerged as an efficient tool for ligand discovery and become an important discovery modality in biomedical research. However, the applications of DCLs have been significantly hampered by low library diversity and limited analytical methods capable of processing large libraries. Here, we report a strategy that has addressed this limitation and can select cooperatively binding small-molecule pairs from large-scale dynamic libraries. Our approach is based on DNA-mediated dynamic hybridization, DNA-encoding, and a photo-cross-linking-based decoding scheme. To demonstrate the generality and performance of this approach, a 10 000-member DNA-encoded dynamic library has been prepared and selected against six protein targets. Specific binders have been identified for each target, and we have validated the biological activities of selected ligands for the targets that are implicated in important cellular functions including protein deacetylation and sumoylation. Notably, a series of novel and selective sirtuin-3 inhibitors have been developed. Our study has circumvented a major obstacle in DCL and may provide a broadly applicable method for ligand discovery against biological targets. PMID- 30412396 TI - Biodegradable Polyglycerol Sulfates Exhibit Promising Features for Anti inflammatory Applications. AB - Inflammatory processes are beneficial responses to overcome injury or illness. Knowledge of the underlying mechanisms allows for a specific treatment. Thus, synthetic systems can be generated for a targeted interaction. In this context, dendritic polyglycerol sulfates (dPGS) have been investigated as anti inflammatory compounds. Biodegradable systems are required to prevent compound accumulation in the body. Here we present biodegradable analogs of dPGS based on hyperbranched poly(glycidol- co-caprolactone) bearing a hydrophilic sulfate outer shell (hPG- co-PCLS). The copolymers were investigated regarding their physical and chemical properties. The cytocompatibility was confirmed using A549, Caco-2, and HaCaT cells. Internalization of hPG- co-PCLS by A549 and Caco-2 cells was observed as well. Moreover, we demonstrated that hPG- co-PCLS acted as a competitive inhibitor of the leukocytic cell adhesion receptor L-selectin. Further, a reduction of complement activity was observed. These new biodegradable dPGS analogs are therefore attractive for therapeutic applications regarding inflammatory diseases. PMID- 30412397 TI - Heterocyclic Allylsulfones as Latent Heteroaryl Nucleophiles in Palladium Catalyzed Cross-Coupling Reactions. AB - Heterocyclic sulfinates are effective reagents in palladium-catalyzed coupling reactions with aryl and heteroaryl halides, often providing high yields of the targeted biaryl. However, the preparation and purification of complex heterocylic sulfinates can be problematic. In addition, sulfinate functionality is not tolerant of the majority of synthetic transformations, making these reagents unsuitable for multistep elaboration. Herein, we show that heterocyclic allylsulfones can function as latent sulfinate reagents and, when treated with a Pd(0) catalyst and an aryl halide, undergo deallylation, followed by efficient desulfinylative cross-coupling. A broad range of allyl heteroarylsulfones are conveniently prepared, using several complementary routes, and are shown to be effective coupling partners with a variety of aryl and heteroaryl halides. We demonstrate that the allylsulfone functional group can tolerate a range of standard synthetic transformations, including orthogonal C- and N-coupling reactions, allowing multistep elaboration. The allylsulfones are successfully coupled with a variety of medicinally relevant substrates, demonstrating their applicability in demanding cross-coupling transformations. In addition, pharmaceutical agents crizotinib and etoricoxib were prepared using allyl heteroaryl sulfone coupling partners, further demonstrating the utility of these new reagents. PMID- 30412398 TI - Total Synthesis of (-)-Mitrephorone A. AB - The first synthesis of (-)-mitrephorone A is disclosed along with discussion and study of synthetic strategies. The natural product includes a highly congested hexacyclic ent-trachylobane diterpenoid framework featuring a rare, embedded oxetane. The synthetic analysis presented dissects a number of approaches for the synthesis of the central oxetane, including carbonyl-olefin photocycloadditions, Prins-type cyclizations, and oxidative ring closures. In the successful route, three [4 + 2] cycloadditions enable rapid construction of all carbocycles. A novel late-stage oxidative cyclization of a hydroxy diosphenol with Koser's reagent furnishes the pivotal oxetane moiety. PMID- 30412399 TI - Photo-induced Decarboxylative Heck-Type Coupling of Unactivated Aliphatic Acids and Terminal Alkenes in the Absence of Sacrificial Hydrogen Acceptors. AB - 1,2-Disubstituted alkenes such as vinyl arenes, vinyl silanes, and vinyl boronates are among the most versatile building blocks that can be found in every sector of chemical science. We herein report a noble-metal-free method of accessing such olefins through a photo-induced decarboxylative Heck-type coupling using alkyl carboxylic acids, one of the most ubiquitous building blocks, as the feedstocks. This transformation was achieved in the absence of external oxidants through the synergistic combination of an organo photo-redox catalyst and a cobaloxime catalyst, with H2 and CO2 as the only byproducts. Both control experiments and DFT calculations supported a radical-based mechanism, which eventually led to the development of a selective three-component coupling of aliphatic carboxylic acids, acrylates, and vinyl arenes. More than 90 olefins across a wide range of functionalities were effectively synthesized with this simple protocol. PMID- 30412400 TI - Experimental and Theoretical Studies on the Implications of Halide-Dependent Aqueous Solvation of Sm(II). AB - The addition of water to samarium(II) has been demonstrated to have a significant impact on the reduction of organic substrates, with the majority of research dedicated to the most widely used reagent, samarium diiodide (SmI2). The work presented herein focuses on the reducing capabilities of samarium dibromide (SmBr2) and demonstrates how the modest change in halide ligand results in observable mechanistic differences between the SmBr2-water and the SmI2-water systems that have considerable implications in terms of reactivity between the two reagents. Quantum chemical results from Born-Oppenheimer molecular dynamics simulations show significant differences between SmI2-water and SmBr2-water, with the latter displaying less dissociation of the halide, which results in a lower coordination number for water. Experimental results are consistent with computational results and demonstrate that the coordination sphere of SmBr2 is saturated at lower concentrations of water. In addition, coordination-induced bond-weakening of the O-H bond is demonstrably different for water bound to SmBr2, leading to an estimated O-H bond-weakening of at least 83 kcal/mol, nearly 10 kcal/mol larger than the bond-weakening observed in SmI2-H2O. Experimental results also demonstrate that the use of alcohols in place of water with SmBr2 leads to substrate reduction, albeit several orders of magnitude slower than for SmBr2-water. The difference in rates resulting from the change in proton donor is attributed to a rate-limiting proton-coupled electron transfer in SmBr2-water and a sequential electron transfer then proton transfer in SmBr2-alcohol systems, where electron transfer is rate-limiting. PMID- 30412401 TI - Enhancing the Potential Exploitation of Food Waste: Extraction, Purification, and Characterization of Renewable Specialty Chemicals from Blackcurrants ( Ribes nigrum L.). AB - Natural colorants were extracted from renewable botanical sources, specifically waste epicarp from the blackcurrant fruit pressing industry. A process was developed which used acidified water extraction followed by a solid-phase extraction (SPE) purification stage which allowed the production of an anthocyanin-rich extract in good yields (ca. 2% w/ w based on dry weight of raw material). The components in the extracts were extensively characterized by HPLC, mass spectrometry, IR, NMR, and UV-vis spectroscopy. HPLC confirmed presence of four anthocyanins: delphinidin-3- O-rutinoside (45%), cyanidin-3- O-rutinoside (31%), and the corresponding glucosides at 16% and 8%, respectively. On sequential liquid-liquid aqueous-organic partitioning of the post-SPE sample, monomeric anthocyanins (54.7%) and polymeric anthocyanins (18%) were found in the aqueous layer with 3- O-rutinosides of myricetin (3.1%) and quercetin (3.2%), while isopropylacetate achieved selective extraction of caffeic acid (3%), p coumaric acid (5%), and myricetin (2.5%) and quercetin (3.2%) aglycons. 3- O Glucosides of myricetin (3.1%) and quercetin (2%), along with nigrumin- p coumarate (1%) and nigrumin ferulate (0.5%) were selectively extracted from the remaining aqueous fraction using ethyl acetate. This allowed for near total quantification of the blackcurrant extract composition. PMID- 30412402 TI - Synthesis of ABBV-168, a 2'-Bromouridine for the Treatment of Hepatitis C. AB - ABBV-168 is a dihalogenated nucleotide under investigation for the treatment of hepatitis C virus. Three synthetic routes aimed at achieving the stereoselective installation of the C2' gem-Br,F substitution and subsequent Vorbruggen glycosylation were explored to prepare the penultimate nucleoside intermediate. Development culminated in a route to ABBV-168 featuring a de novo chromatography free furanose synthesis, protecting group-directed Vorbruggen glycosylation, and highly selective phosphoramidation to furnish the API. PMID- 30412403 TI - Polarizable Charge Equilibration Model for Transition-Metal Elements. AB - The polarizable charge equilibration (PQEq) method was developed to provide a simple but accurate description of the electrostatic interactions and polarization effects in materials. Previously, we optimized four parameters per element for the main group elements. Here, we extend this optimization to the 24 d-block transition-metal (TM) elements, columns 4-11 of the periodic table including Ti-Cu, Zr-Ag, and Hf-Au. We validate the PQEq description for these elements by comparing to interaction energies computed by quantum mechanics (QM). Because many materials applications involving TM are for oxides and other compounds that formally oxidize the metal, we consider a variety of oxidation states in 24 different molecular clusters. In each case, we compare interaction energies and induced fields from QM and PQEq along various directions. We find that the original chi and J parameters (electronegativity and hardness) related to the ionization of the atom remain valid; however, we find that the atomic radius parameter needs to be close to the experimental ionic radii of the transition metals. This leads to a much higher spring constant to describe the atomic polarizability. We find that these optimized parameters for PQEq provide accurate interaction energies compared to QM with charge distributions that depend in a reasonable way on the coordination number and oxidation states of the transition metals. We expect that this description of the electrostatic interactions for TM will be useful in molecular dynamics simulations of inorganic and organometallic materials. PMID- 30412405 TI - Acyclic Remote 1,5- and 1,4,5-Stereocontrol in the Catalytic Stereoselective Reactions of beta-Lactams with Aldehydes: The Effect of the N-Methylimidazole Ligand. AB - The application of the N-methylimidazole ( N-MI) ligand in the Pd(0)/InI-promoted allylations of aldehydes with beta-lactam-derived organoindiums enables the reaction of azetidin-2-ones with diversely substituted allyl moieties, inert under previously reported conditions. As a result, allylations and crotylations of a variety of aromatic and aliphatic aldehydes with previously unavailable chiral epsilon-amido-allylindiums bearing alpha-, beta-, or gamma-substituted allyl fragments were developed. The reactions occur under thermodynamic control with a highly efficient remote 1,5- or 1,4,5-stereocontrol to afford a diversity of (3 Z)-2,5- anti-2,6- syn- or (3 Z)-2,5- syn-2,6- anti-substituted enediols, aminoalcohols, and homoallylic alcohols in moderate to high yields and with an excellent diastereoselectivity. A detailed study on the effect of the beta-lactam and aldehyde structures and chirality on the yield and stereochemistry in the products was carried out. PMID- 30412404 TI - Novel Symmetrical Benzazolyl Derivatives Endowed with Potent Anti-Heparanase Activity. AB - Heparanase is the only mammalian endo-beta-d-glucuronidase involved in a variety of major diseases. The up-regulation of heparanase expression increases tumor size, angiogenesis, and metastasis, representing a validated target in the anti cancer field. To date, only a few small-molecule inhibitors have been described, but none have gotten through pre-clinical development. Previously, we explored 2 (4-(4-(bromo-methoxybenzamido)benzylamino)phenyl) benzazole derivatives as anti heparanase agents, proposing this scaffold for development of broadly effective heparanase inhibitors. Herein, we report an extended investigation of new symmetrical 2-aminophenyl-benzazolyl-5-acetate derivatives, proving that symmetrical compounds are more effective than asymmetrical analogues, with the most-potent compound, 7g, being active at nanomolar concentration against heparanase. Molecular docking studies were performed on the best-acting compounds 5c and 7g to rationalize their interaction with the enzyme. Moreover, invasion assay confirmed the anti-metastatic potential of compounds 5c, 7a, and 7g, proving the inhibition of the expression of proangiogenic factors in tumor cells. PMID- 30412406 TI - Micellar Effects on the Hydrolysis Reaction of an Anionic Surfactant in Aqueous Solution. AB - The hydrolysis mechanisms of 2-sulfoalkanoic acid methyl ester salts (methyl ester sulfonate, MES) were studied. Under acidic, neutral, and alkaline conditions, the hydrolysis rates of MES were strongly affected by the state of aggregation and the hydrolysis rate changed at the critical micelle concentration (CMC). Under acidic conditions, the hydrolysis rates of MES were enhanced by micellar formation and correlated quantitatively with the amount of protons bound on the micellar surfaces being measured by the electric conductivity along with fluorescence and hydrogen-ion electrode measurements. MES having longer acyl chain lengths showed higher hydrolysis rates above the CMC because of the many bound protons and the higher degree of counterion binding to the micelle, beta. The rates were affected by the type of counterion and followed the order of sodium > potassium > calcium salts of MES. In alkaline conditions, the rates of MES hydrolysis were suppressed to lower values by micelle formation and MES with longer acyl chain lengths showed lower rates above the CMC. Additionally, the hydrolysis rates of MES under neutral conditions were suppressed to a very low value by micelle formation. These mechanisms of inhibitory effect of hydrolysis by the aggregation should be dominated by the electrical repulsive interactions between hydroxyl anions and anionic micellar surfaces, as well as by interference with the penetration of the hydroxyl anion to the ester group in the micelles for alkaline hydrolysis and by interference from water molecules for neutral hydrolysis. PMID- 30412407 TI - Shrinking Self-Interaction Errors with the Fermi-Lowdin Orbital Self-Interaction Corrected Density Functional Approximation. AB - The self-interaction error (SIE) is one of the major drawbacks of practical exchange-correlation functionals for Kohn-Sham density functional theory. Despite this, the use of methods that explicitly remove SIE from approximate density functionals is scarce in the literature due to their relatively high computational cost and lack of consistent improvement over standard modern functionals. In this article we assess the performance of a novel approach recently proposed by Pederson, Ruzsinszky, and Perdew [ J. Chem. Phys. 2014, 140, 121103] for performing self-interaction free calculations in density functional theory based on Fermi orbitals. To this end, we employ test sets consisting of reaction energies that are considered particularly sensitive to SIE. We found that the parameter-free Fermi-Lowdin orbital self-interaction correction method combined with the standard local spin density approximation (LSDA) and Perdew Burke-Ernzerhof (PBE) functionals gives a much better estimate of reaction energies compared to their parent LSDA and PBE functionals for most of the reactions in these two sets. They also perform on par with the global PBE0 and range-separated LC-omegaPBE hybrids, which partially eliminate the SIE by including Hartree-Fock exchange. This shows the potential of the Fermi-Lowdin orbital self-interaction correction (FLOSIC) method for practical density functional calculations without SIE. PMID- 30412408 TI - Copper-Mediated N-Arylations of Hydantoins. AB - A set of two broadly applicable procedures for the N-arylation of hydantoins is reported. The first one relies on the use of stoichiometric copper(I) oxide under ligand- and base-free conditions and enables a clean regioselective arylation at the N3 nitrogen atom, while the second one is based on the use of catalytic copper(I) iodide and trans- N, N'-dimethylcyclohexane-1,2-diamine and promotes arylation at the N1 nitrogen atom. Importantly, the combination of these two procedures affords a straightforward entry to diarylated hydantoins. PMID- 30412409 TI - Single-Molecule Studies of Allosteric Inhibition of Individual Enzyme on a DNA Origami Reactor. AB - Unraveling the conformational changes of enzymes together with inhibition kinetics during an enzymatic reaction has great potential in screening therapeutic candidates; however, it remains challenging due to the transient nature of each intermediate step. We report our study on the noncompetitive inhibition of horseradish peroxidase with single-turnover resolution using single molecule fluorescence microscopy. By introducing DNA origami as an addressable nanoreactor, we observe the coexistence of nascent-formed fluorescent product on both catalytic and docking sites. We further propose a single-molecule kinetic model to reveal the interplay between product generation and noncompetitive inhibition and find three distinct inhibitor releasing pathways. Moreover, the kinetic isotope effect experiment indicates a strong correlation between catalytic and docking sites, suggesting an allosteric conformational change in noncompetitive inhibition. A memory effect is also observed. This work provides an in-depth understanding of the correlation between enzyme behavior and enzymatic conformational fluctuation, substrate conversion, and product releasing pathway and kinetics. PMID- 30412410 TI - Surprising Reactivity in NiXantphos/Palladium-Catalyzed alpha-Arylation of Substituted Cyclopropyl Nitriles. AB - alpha-Arylations of cyclopropyl and related nitriles provide access to important synthetic intermediates and pharmacophores for biologically active molecules. However, robust methods for coupling of sterically encumbered partners have remained elusive. Through optimization using high-throughput experimentation (HTE), the NiXantphos ligand was found to be effective in the coupling of sterically hindered beta-substituted cyclopropyl nitriles with a number of aryl groups and heterocycles, including those containing acidic N-H and O-H bonds. PMID- 30412411 TI - Thermal Boundary Conductance Across Heteroepitaxial ZnO/GaN Interfaces: Assessment of the Phonon Gas Model. AB - We present experimental measurements of the thermal boundary conductance (TBC) from 78-500 K across isolated heteroepitaxially grown ZnO films on GaN substrates. This data provides an assessment of the underlying assumptions driving phonon gas-based models, such as the diffuse mismatch model (DMM), and atomistic Green's function (AGF) formalisms used to predict TBC. Our measurements, when compared to previous experimental data, suggest that TBC can be influenced by long wavelength, zone center modes in a material on one side of the interface as opposed to the '"vibrational mismatch"' concept assumed in the DMM; this disagreement is pronounced at high temperatures. At room temperature, we measure the ZnO/GaN TBC as 490[+150,-110] MW m-2 K-1. The disagreement among the DMM and AGF, and the experimental data at elevated temperatures, suggests a non-negligible contribution from other types of modes that are not accounted for in the fundamental assumptions of these harmonic based formalisms, which may rely on anharmonicity. Given the high quality of these ZnO/GaN interfaces, these results provide an invaluable, critical, and quantitative assessment of the accuracy of assumptions in the current state of the art computational approaches used to predict phonon TBC across interfaces. PMID- 30412412 TI - Furfuryl Cation Induced Cascade Formal [3 + 2] Cycloaddition/Double Ring Opening/Chlorination: An Approach to Chlorine-Containing Complex Triazoles. AB - A TiCl4-promoted cascade formal [3 + 2] cycloaddition/double ring opening/chlorination of 2-furylcyclobutanols with alkyl or aryl azides is described. This highly efficient transformation involves the formation/cleavage of several C-N, C-Cl, C-C, and C-O bonds in a single operation. It enables the quick construction of trisubstituted 1,2,3-triazoles with an ( E)-enone moiety and a 3-chloropropyl unit. The chlorinated products are readily transformed into other structurally diverse analogues. PMID- 30412413 TI - Palladium-Catalyzed Double Carbonylative Cyclization of Benzoins: Synthesis and Photoluminescence of Bis-Ester-Bridged Stilbenes. AB - A palladium-catalyzed double carbonylative cyclization of benzoins has been developed, which realizes the synthesis of bis-ester-bridged stilbenes just in two steps from aldehydes. Thus, the obtained fully fused tetracyclic pi-systems have a pyrano[3,2- b]pyran-2,6-dione (PPD) core on their center, showing two reversible reductions at low potentials. In addition, their photoluminescence properties are strikingly affected by the aromatic rings fused to the PPD core; bis- thieno-fused PPDs are found to be excellent fluorophores with quantum yields up to 0.98. PMID- 30412414 TI - Electrowetting of Ionic Liquid on Graphite: Probing via in Situ Electrochemical X ray Photoelectron Spectroscopy. AB - Thin films of ionic liquid 1-ethyl-3-methylimidazolium bis(fluoromethylsulfonyl)imide ([EMIm][FSI]) vapor-deposited on highly oriented pyrographite (HOPG) were studied by X-ray photoelectron spectroscopy and atomic force microscopy. The results revealed a reversible morphological transition from a "drop-on-layer" structure to a "flat-layer" structure at positive, and not at negative, polarization. The effect is rationalized in terms of electric-field induced reduction of the liquid-solid transition temperature in the ionic liquid film, when its thickness is comparable to the charge screening length. The observed bias asymmetry of [EMIm][FSI] electrowetting on HOPG is tentatively explained by the bilayer structure at the interface driven by the affinity of the imidazolium ring to the HOPG surface. PMID- 30412415 TI - Archival May-Grunwald-Giemsa-Stained Bone Marrow Smears Are an Eligible Source for Molecular DNA Research. AB - Biobanking is increasingly important in studying complex heterogeneous diseases. Therefore, it is essential to ensure the sample quality after long-term storage for reliable downstream analyses. The Clinical Biobank of the Jessa Hospital and the University Biobank Limburg (UBiLim) hold a continuously growing collection of hematological samples, including May-Grunwald-Giemsa (MGG)- and Perls' Prussian Blue (PPB)-stained bone marrow (BM) smears, stored at room temperature (RT) for up to 20 years. In this study, we investigated the effect of short- and long-term storage on the quality of DNA and RNA extracted from these BM smears to assess their fitness-for-purpose in downstream molecular applications, including agarose gel electrophoresis, bio-analyzer analysis, quantitative polymerase chain reaction (qPCR), and targeted next-generation sequencing (NGS). The RNA quality was very low for all samples, independent of storage time or staining method. The DNA from PPB-stained BM smears was already degraded after 1 year of storage and correspondingly could not be used for reliable downstream molecular analysis. In contrast, DNA extracted from MGG-stained BM smears stored for up to 10 years was able to generate high-quality data in qPCR and targeted NGS analyses. Longer storage periods (>15 years) of these samples revealed a high degree of degradation and a significant amount of DNA transitions and transversions. In conclusion, the DNA extracted from archival MGG-stained BM smears with a storage time up to at least 10 years was qualitatively good and fit for downstream analysis, including targeted NGS. This indicates that these samples are an eligible source for molecular DNA research and for studying complex diseases. PMID- 30412416 TI - Effect of Follow-Up Intervals on Breastfeeding Rates 5-6 Months Postpartum: A Randomized Controlled Trial. AB - OBJECTIVE: To compare the effect of early versus traditional postpartum follow-up intervals on breastfeeding continuation rates 6 months postpartum. METHODS: This randomized controlled trial enrolled primiparous women planning to breastfeed to a postpartum appointment either 2-3 weeks or 6-8 weeks after delivery. The primary outcome was the breastfeeding rate in each group 5-6 months after delivery. The study was powered to detect a 50% difference between groups assuming a 34% rate of breastfeeding at 6 months. Participants were contacted by phone 5-6 months after delivery to assess outcomes. RESULTS: From March 2014 to July 2016, 649 women were screened and 344 enrolled as follows: 172 to 2-3 week and 172 to 6-8 week follow-up. Demographic, delivery, and support characteristics were similar between groups; however, average infant birth weight and the distribution of gestational ages at the time of delivery were different between groups (p < 0.05). Participants in the 2-3 week group had a breastfeeding rate of 57.7% 6 months following delivery and participants in the 6-8 week group had a rate of 59.3%. Early follow-up was associated with a relative risk of 0.97 (95% CI 0.79-1.19, p = 0.80) and an adjusted relative risk of 1.45 (95% CI 0.71-2.95, p = 0.31), when adjusted for confounding variables, for breastfeeding continuation at 5-6 months. CONCLUSIONS: Breastfeeding rates at 5-6 months postpartum were comparable between both groups; early follow-up was not associated with an increased rate of breastfeeding. At 6 months postpartum, the breastfeeding rate in both groups approximated the Surgeon General's Healthy People 2020 goal of 60.6%. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (Identifier NCT02221895). PMID- 30412417 TI - Advancing Professionalization of Biobank Business Operations: A Worldwide Survey. AB - Quality specimens from biobanks are key resources to support reproducible research. Sustaining biobanks requires robust management. We recently published a pilot survey that indicated that over half the participating biobanks had business plans in place and another third were working on business planning. While the results provided a clue to the status of business planning in biobanking, it was concluded that a longer and more in-depth survey and analysis were required. In April 2017, an extended survey was distributed worldwide in English, French, Chinese, German, and Spanish, through multiple channels. The survey was built using the Survey Monkey tool. Our hypothesis was that those biobanks that already have a business plan also have a more professional management structure. The questions were designed to understand more details about each biobank's business operations and communications. A total of 276 biobanks participated (China 65, France 40, United States 34, Spain 27, Germany 24, Australia 23, and rest of the world 63). About two thirds of the biobanks were established in the last 10 years. The responses provided data on the size of biobanks answering the survey, their status of business planning, and how and through what mediums they are communicating with customers. Biobanks with a business plan or preparing to have one showed a clear trend of having a customer strategy for marketing the samples and communicating with customers. No trend could be seen regarding websites and activities in social media. We confirmed our hypothesis that biobanks that have or are in the process of preparing a business plan are showing a trend toward more professional structures. In the biobanking community, the business mind-set and use of the business plan as a management tool have not quite arrived. PMID- 30412418 TI - Duration of Breastfeeding, Bottle-Feeding, and Parafunctional Oral Habits in Relation to Anxiety Disorders Among Children. AB - OBJECTIVE: The aim of the present study is to investigate the duration of breastfeeding in relation to various parafunctional oral habits in children with anxiety disorders. MATERIALS AND METHODS: The study includes 195 children and adolescents with anxiety disorders and age- and gender-matched 255 healthy control subjects. Diagnoses were made with semistructured interview (K-SADS). Information about breastfeeding and parafunctional oral habits was investigated via a questionnaire prepared for the study. RESULTS: The mean age was 11.50 +/- 2.50 years for clinical group and 11.27 +/- 2.33 years for controls. Fifty-four percent of the clinical group and 56% of the control group were female subjects. Duration of exclusive (4.72 +/- 2.86, 5.55 +/- 2.36; p = 0.002) and total breastfeeding (12.38 +/- 10.32, 15.89 +/- 9.09; p < 0.001) was significantly lower and duration of bottle-feeding (22.30 +/- 19.54, 16.64 +/- 12.79; p = 0.005) was higher than controls in the clinical group. Duration of exclusive breastfeeding was significantly correlated with duration of bottle-feeding (r = 0.263, p < 0.001) and duration of pacifier use (r = -0.249, p = 0.001). Multiple regression analysis showed that duration of exclusive breastfeeding (beta = 0.88, p = 0.006) and bottle-feeding (beta = 1.02, p = 0.005), as well as various oral habits, was associated with diagnosis of an anxiety disorder. CONCLUSION: Nutrition methods in early years of life may result in long-term consequences regarding anxiety disorders for children. Clinicians should encourage parents for a shorter duration of bottle-feeding and a longer duration of exclusive breastfeeding. PMID- 30412419 TI - How to Lead During the Next Health Security Crisis The Public Health Crisis Survival Guide: Leadership and Management in Trying Times , by Joshua M. Sharfstein , Reviewed by Jennifer B. Nuzzo. PMID- 30412420 TI - Social Anhedonia in Children and Adolescents with Autism Spectrum Disorder and Psychiatry Referrals. AB - Social anhedonia (SA) is a widely accepted symptom phenotype in autism spectrum disorder (ASD), depression, and schizophrenia spectrum disorder; nevertheless, its clinical implications are relatively unstudied in populations of clinic referred youth with and without ASD. Youth with ASD (n = 268) and nonASD psychiatry referrals (n = 641) between 6 and 18 years of age were evaluated for SA, ASD severity, co-occurring psychiatric symptom severity, and a wide range of common clinical correlates. Participants were parsed into youth with and without parent-defined SA, and the latter were further subdivided into youth with (SA+ alone) and without (SA/-alone) a preference for being alone. Two thirds of the ASD group met criteria for SA compared with one fourth of psychiatry referrals. SA was associated with higher rates of ASD social skill deficits, social anxiety, depression, and schizophrenia symptoms in both clinic samples. SA+ alone had the highest rates of social anxiety. Among the ASD sample, severity of social anxiety and ASD social skills deficits were relatively small predictors of SA. There was little evidence of divergence between youth with and without SA for a wide range of commonly studied biopsychosocial clinical correlates, for example, youth, family, medical, and treatment characteristics. Although factors associated with the ASD diathesis contribute to an increased risk of SA, they do not in and of themselves explain our results. Lack of syndrome specificity supports the notion that SA is a useful transdiagnostic symptom phenotype in referred youth and challenges traditional conceptualizations of ASD as a categorical clinical phenotype. PMID- 30412421 TI - Glioma response assessment: Classic pitfalls, novel confounders, and emerging imaging tools. AB - Neuroimaging plays a pivotal role in the care of patients with infiltrating gliomas, in whom imaging changes are often the first indications of tumor response or progression. Unfortunately, evaluation of glioma response is often not straightforward, even for experienced radiologists. Post-surgical or radiation-related changes may mimic the appearance of disease progression, while medications such as corticosteroids and antiangiogenic agents may mimic tumor response without truly arresting tumor growth or improving patient survival. Immunotherapy response can result in inflammatory changes which manifest as progressively increasing tumor enhancement and edema over months. Many of these pitfalls can be minimized or avoided altogether by the use of modern brain tumor response criteria, while others will require new imaging tools before they can be fully addressed. Advanced MRI methods and novel positron emission tomography (PET) agents are proving important for this purpose, and their role will undoubtedly continue to grow in the future. PMID- 30412422 TI - MR arthrographic characterization of posterior capsular folds in shoulder joints. AB - METHODS:: This was a retrospective study of 604 consecutive shoulder MR images and MR arthrograms obtained from April 2010 to January 2018. Extension in the vertical-oblique plan of the posterior synovial fold on MR arthrography was identified according to the posterosuperior, posteroinferior, superoposterior, and inferoposterior portions. The morphologies of the posterior synovial folds on MR arthrography were divided three subtypes. Morphologic appearances of the posterior labrocapsular complex on conventional MR images were described with four subtypes. RESULTS:: A posterior synovial fold in the shoulder joint was identified in 35 of 604 (5.8%) MR arthrography patients. 8 of 35 posterior synovial fold identified on MR arthrography were confirmed at arthroscopy. The most common MR arthrographic type of the posterior synovial fold was triangular this was detected in 17 of 35 (48.6%) patients. The most common MRI morphology of the posterior labrocapsular complex was doubled posterior labrum. This was detected in 15 of 35 (42.9%) patients. 17 % of patients with posterior synovial folds who were diagnosed with MR arthrography had normal MRI features. The most common localization of the posterior synovial fold was posterosuperior and posteroinferior portions of the posterior labrocapsular structures. The mean of the shortest distance between the posterior synovial fold and the posterior labrum was significantly higher in the positive arthroscopic synovial fold group than in the negative arthroscopic synovial fold group (p = 0.047). CONCLUSION:: Posterior synovial folds, normal capsular anatomic variants, are seen rarely on MR arthrography, and tend to be in the posterosuperior and posteroinferior portions of the posterior capsule. Some types of the posterior synovial fold can mimic a posterior labral tear in conventional MRI. ADVANCES IN KNOWLEDGE:: On a direct MR arthrographic image, a posterior capsular synovial fold may be a normal anatomic variant. A fold is more commonly occur in the posterosuperior and posteroinferior capsular portions. The results of our study may allow differentiation of normal variations from abnormalities in patients with symptomatic shoulder joint. PMID- 30412423 TI - Imaging features of thalassaemia. AB - This article highlights the range of osseous findings that can be encountered as well as the imaging features of extramedullary haematopoiesis. As iron overload remains a major cause of morbidity and mortality in these disorders, we also discuss the MRI evaluation of hepatic and cardiac hemosiderosis, to aid in the optimization of iron chelation therapy. Future imaging use will be dictated by evolving clinical needs, such as in screening for emerging morbidities, including hepatic fibrosis and hepatocellular carcinoma. PMID- 30412424 TI - Preconditioning with atorvastatin against renal ischemic-reperfusion injury in non-diabetic versus diabetic rats. AB - Acute renal failure complicates renal ischemic-reperfusion (I/R) due to reactive oxygen species production. Atorvastatin (ATO) has antiinflammatory and antioxidant properties. The current study investigated whether ATO alleviated damages induced by renal I/R injury in non-diabetic versus diabetic rat models. Thirty-six rats (18/group) were divided into non-diabetic and diabetic Groups, A and B, respectively: Group A1 (sham), Group A2 (I/R), Group A3 (ATO + I/R), Group B1 (sham), Group B2 (I/R), and Group B3 (ATO + I/R). All groups experienced 45 minutes of renal ischemia, bilaterally, followed by 24 hours of reperfusion. Groups A3 and B3 were treated with intraperitoneal single doses of ATO (10 mg/kg) 30 minutes before ischemia. Histological analysis of kidney tissues, immune expression of caspase 3 and CD44, kidney function tests, and oxidative stress markers, assessed tubular injury. Histological analysis revealed marked tubular damage in Groups A2 and B2 but improvement in Groups A3 and B3. Improvements were also found for immune expression of caspase 3 and CD44, kidney function tests, and oxidative stress markers. Our results suggested ATO may ameliorate renal I/R injury, differently between non-diabetic and diabetic rats. PMID- 30412425 TI - How Alcohol Drinking Affects our Genes: an Epigenetic Point of View. AB - This work highlights recent studies in epigenetic mechanisms that play a role in alcoholism, a complex multifactorial disorder. A large body of evidence has shown that alcohol can modify gene expression through epigenetic processes, namely DNA methylation and nucleosomal remodeling via histone modifications. In that vein, chronic ethanol exposure modifies DNA and histone methylation, histone acetylation, and microRNA expression. The alcohol-mediated chromatin remodeling in the brain promotes the transition from use to abuse and addiction. Unravelling the multiplex pattern of molecular modifications induced by ethanol involves the ability to develop new, epigenetic processes-targeting therapies for alcoholism and drug addiction. PMID- 30412426 TI - Accepted Abstracts. PMID- 30412427 TI - Impact of artificial reefs on sediment bacterial structure and function in Bohai Bay. AB - Artificial reefs have significantly altered ecological and environmental conditions compared with natural reefs, but how these changes affect sediment bacteria structure and function is unknown. Here, we compared the structure and function of sediment bacterial community in the artificial reef area,the future artificial reef area and the control area in Bohai Bay using 16S rRNA genes sequencing. Our results indicated that bacteria communities in the sediment were both taxonomically and functionally different between the reef area and control area. The alpha-diversity was significantly lower in the artificial reef area, whereas the beta-diversity was significantly higher in the artificial reef area. The functional genes relating to chemo-heterotrophy, nitrate reduction, hydrocarbon degradation and the human-pathogens,gut were more abundant, whereas genes relating to the metabolism of sulfur compounds were less abundant in the artificial reef than in the control area. The differences in bacterial communities were primarily determined by depth in the artificial reef area, while the bacterial communities were determined by the TOC. This study provides the first molecular ecology insight for evaluating the impacts of artificial reefs on the bacteria community. PMID- 30412428 TI - Use of gadolinium contrast agents in paediatric population: Donald Rumsfeld meets Hippocrates! AB - Gadolinium is a contrast agent that is used in MRI. There is new evidence that gadolinium accumulates in a patient's body and the effects of this accumulation is unknown. This has resulted in different advice being given by European Medicine Agency and U.S. Food and Drug Administration. The European Medicine Agency recommended stopping the use of linear Gadolinium agents (requiring more proof of safety) while the Food and Drug Administration continues to permit its use (requiring more proof of harm). Gadolinium should be used if deemed clinically necessary. Children and parents should be informed of the benefits and potential harm of using gadolinium-based contrast. It is up for debate whether those imaged before with gadolinium will benefit from being informed of new evidence. PMID- 30412430 TI - Exercise-induced arterial hypoxemia; some answers, more questions. AB - Exercise-induced arterial hypoxemia (EIAH) is characterized by the decrease in arterial oxygen tension and oxyhemoglobin saturation during dynamic aerobic exercise. Since the time of the initial observations, our knowledge and understanding of EIAH has grown, but many unknowns remain. The purpose of this review is to provide an update on recent findings, highlight areas of disagreement and identify where information is lacking. Specifically, this review will place emphasis on: i) the occurrence of EIAH during submaximal exercise, ii) whether there are sex-differences in the development and severity of EIAH, iii) unresolved questions and future directions. PMID- 30412431 TI - Important risk factors for the development of food allergy and potential options for prevention. AB - INTRODUCTION: Food allergy currently affects up to 10% of infants. Identification and implementation of effective food allergy prevention strategies is thus imperative. Areas covered: We focus on five food allergy risk factors/prevention strategies which have been or are currently being tested in randomized controlled trials: (1) timely introduction of allergenic foods into the infant diet; (2) maternal diet and consumption of allergenic foods during pregnancy and breastfeeding; (3) infant skin barrier and the role of moisturizers in early life; (4) infant Vitamin D levels and the role of Vitamin D supplementation; and (5) microbial exposure in early life. Expert commentary: Earlier introduction of allergenic foods, particularly peanut, in the infant diet has been shown to reduce food allergy. Novel intervention strategies, including infant vitamin D supplementation, maternal diet modifications, and moisturizing infants to improve skin barrier, are currently being tested in large-scale clinical trials. As results of these trials become available, we hope strategies that are both efficacious and cost-effective will be revealed and their implementation in the population, along with the timely introduction of allergenic foods, will reduce the burden of food allergy in future generations. PMID- 30412432 TI - Advances in understanding the role of angiotensin-regulated proteins in kidney diseases. AB - INTRODUCTION: Renin-angiotensin system (RAS) blockers are in clinical use to treat high blood pressure and proteinuric chronic kidney disease. However, RAS blockade is limited by the risk of hyperkalemia, angiotensin receptor blockers are not clinically superior to angiotensin-converting enzyme inhibitors and dual RAS blockade is formally contraindicated. Areas covered: We review the regulation of protein expression and activation by angiotensin II and RAS blockers as it contributes to kidney disease. Specifically excluded are direct renin actions as well as aldosterone actions. The search strategy included the terms angiotensin, protein, proteomics, inflammation, fibrosis, and kidney and was complemented by additional searches based on initial results. Expert commentary: Recent developments include an improved understanding of the structure, function, and signaling of angiotensin G-protein-coupled receptors; identification of ligands that behave as agonists, antagonists, and even reverse agonists on specific signaling and functional pathways of the same receptor; characterization of further signaling pathways by applying proteomics and phosphoproteomics; and systems biology approaches to characterize signatures of adequate RAS blockade or resistance of kidney injury to RAS blockade. These developments will allow optimization of clinical RAS targeting to improve kidney outcomes through precision nephrology strategies that may include combined approaches, along the path marked by clinically successful dual RAS/neprilysin blockade. PMID- 30412433 TI - Comparison of Mental Health Nursing Student Academic Achievement and Satisfaction: Classroom Versus Online Education in Teaching Therapeutic Crisis Management Techniques. AB - BACKGROUND: Mental health nurse educators use online education in an effort to offer students the ability to practice varying skills in a safe environment. PURPOSE: The purpose of this study was to compare the effectiveness and student satisfaction of live classroom versus online education in delivering therapeutic crisis management skills content to pre-licensure nursing students as measured by overall grade point average (GPA), test scores, class grade, and student satisfaction survey results. METHODS: This quasi-experimental, post-hoc comparative study had a two-group post-test design. The participants were pre licensure psychiatric mental health nursing students who were presented a 30-min lecture followed by group work with case studies and interventions. RESULTS: There were no statistically significant differences between the live classroom and online education group. CONCLUSIONS: This study indicates that therapeutic crisis management techniques can be taught a variety of ways for academic success and may validate the feasibility of online education within mental health nursing curricula. PMID- 30412434 TI - Pattern of Scleritis in an Egyptian Cohort. AB - PURPOSE: To report the clinical experience with scleritis at four Egyptian tertiary care eye centers. METHODS: Multicenter retrospective chart review of all patients with scleritis visiting four ocular inflammation referral clinics in Egypt between January 2013 and October 2017. RESULTS: A total of 303 scleritis patients were enrolled. These included 76 male and 227 female patients. The most frequent subtype of scleritis was nodular anterior scleritis (44.9%). Rheumatoid arthritis and Wegener granulomatosis were the 2 most common systemic associations among our cohort. Eyes with necrotizing scleritis with inflammation had the lowest mean initial and final BCVA. CONCLUSION: The visual prognosis of an eye with scleritis varies with the subtype of scleral inflammation. In our cohort, it was found to be poorer in eyes with necrotizing scleritis with inflammation compared to other subtypes. PMID- 30412435 TI - Improving the utilisation of nitrous oxide in paediatric patients to manage procedural pain and procedural anxiety. AB - The aim in this study was to understand current practice and use of nitrous oxide for management of procedural-related pain and procedural anxiety, to identify perceived barriers to use of nitrous oxide and to develop an understanding of patients, families, and nurse awareness and knowledge of the use of nitrous oxide in an Australian tertiary pediatric oncology/hematology short stay unit. Three online questionnaires (patients, parents, and nursing staff) were developed and completed between September and November 2015. Most children and young people (61%) report receiving nitrous oxide for at least one procedure. Patients, parents, and nurses rated nitrous oxide as highly effective and would like more access to nitrous oxide for the child's pain management. Several barriers to use were reported. These findings suggest that nitrous oxide is effective for pain management; however, its use is inconsistent. Findings can potentially develop standardized processes and improve nurse education and accreditation, which may increase the safety, efficacy, and utilization of nitrous oxide for children's procedural pain management. PMID- 30412436 TI - Elevated arterial shear rate increases indices of endothelial cell autophagy and nitric oxide synthase activation in humans. AB - Continuous laminar shear stress increases the process of autophagy, activates p eNOSS1177, and generates nitric oxide (NO) in bovine and human arterial endothelial cells (ECs) compared to static controls. However, the translational relevance of these findings has not been explored. In the current study, primary ECs were collected from the radial artery (RA) of 7 adult males using sterile j wires before (Pre) and after (Post) 60-min of rhythmic handgrip exercise (HG) performed with the same arm. After ECs were identified by positive co-staining for VE-cadherin and DAPI, immunofluorescent antibodies were used to assess indices of autophagy, NO generation, and superoxide anion (O2*-) production. Commercially available primary human arterial ECs were stained and processed in parallel to serve as controls. All endpoints were evaluated using 75 ECs from each subject. Relative to Pre-HG, HG elevated arterial shear rate (p<0.05) ~ 3 fold, while heart rate, arterial pressure, and cardiac output were not altered. Compared to values obtained from ECs Pre-HG, Post-HG ECs displayed increased (p<0.05) expression of p-eNOSS1177, NO generation, O2*- production, BECLIN-1, microtubule-associated proteins 1A/1B light chain 3B (LC3B), autophagy-related gene 3 (ATG3), lysosomal associated membrane protein 2A (LAMP2A), and decreased (p<0.05) expression (i.e., enhanced degradation) of the adapter protein p62/SQSTM1. These novel findings provide evidence that elevated arterial shear rate associated with functional hyperemia initiates autophagy, activates p eNOSS1177, and increases NO and O2*- generation in primary human ECs. PMID- 30412437 TI - Maladaptive Aortic Remodeling in Hypertension Associates with Dysfunctional Smooth Muscle Contractility. AB - Intramural cells are responsible for establishing, maintaining, and restoring the functional capability and structural integrity of the aortic wall. In response to hypertensive loading, these cells tend to increase wall content via extracellular matrix turnover in an attempt to return wall stress and/or material stiffness toward homeostatic values despite the elevated pressure. Using a common rodent model of induced hypertension, we found marked mouse-to-mouse differences in thoracic aortic remodeling over two-to-four weeks of pressure elevation, with mechano-adaptation in some but gross maladaptation in most mice despite the same experimental conditions and overall genetic background. Consistent with our hypothesis, we also found a strong correlation between maladaptive aortic remodeling and a dysfunctional ability of the vessel to vasoconstrict, with maladaptation often evidenced by marked adventitial fibrosis. Remarkably, mouse to-mouse variability did not correlate with the degree or duration of pressure elevation over the two-to-four week study period. These findings suggest both a need to study together the structure, mechanical properties, and function across layers of the wall when assessing aortic health and a need for caution in using common statistical comparisons across small seemingly well-defined groups that may mask important underlying individual responses, an area of investigation that demands increasing attention as we move toward an era of precision diagnosis and patient care. PMID- 30412438 TI - Right ventricular dysfunction and remodeling in diabetic cardiomyopathy. AB - The increasing prevalence of diabetic cardiomyopathy (DCM) is an important threat to health world-wide. While left ventricular (LV) dysfunction in DCM is well recognized, the accurate detection, diagnosis, and treatment of changes in right ventricular (RV) structure and function have not been well characterized to date. The pathophysiology of RV dysfunction in DCM may share features with LV diastolic and systolic dysfunction, including pathways related to insulin resistance and oxidant injury, though the RV has unique cellular origin and composition, unique biomechanical properties, and is coupled to the lower impedance pulmonary vascular bed. In this review we provide potential mechanisms responsible for RV dysfunction in DCM and review the imaging approaches useful for early detection, protection, and intervention strategies. Additional data is required from animal models and clinical data and trials to better identify the onset and features of altered RV and pulmonary vascular structure and function during the onset and progression of DCM and to determine the efficacy of early detection and treatment of RV dysfunction on clinical symptoms and outcomes. PMID- 30412439 TI - Reversal of Right Ventricular failure by Chronic alpha1A-Subtype Adrenergic Agonist Therapy. AB - Right ventricular failure (RVF) is serious disease with no effective treatment available. We recently reported a disease prevention study showing that chronic stimulation of alpha1A-adrenergic receptors (alpha1A-ARs), started at the time of RV injury, prevented development of RVF. The current study used a clinically relevant disease reversal design to test if chronic alpha1A-AR stimulation, started after RVF was established, could reverse RVF. RVF was induced surgically by pulmonary artery constriction (PAC) in mice. Two wk. after PAC, in-vivo RV fractional shortening (FS) assessed by MRI, was reduced by half relative to sham operated controls (25 +/- 2%, n=27 vs. 52 +/- 2%, n= 13, P < 10-11). Subsequent chronic treatment with the alpha1A-AR agonist A61603 for a further 2 weeks resulted in substantial recovery of RV fractional shortening (to 41 +/- 2%, n=17, P < 10-7, paired t-test) along with recovery of voluntary exercise capacity. Mechanistically, chronic A61603 treatment resulted in increased activation of the pro-survival kinase ERK, increased abundance of the anti-apoptosis factor BCL-2, and decreased myocyte necrosis evidenced by a decreased serum level of cardiac troponin. Moreover, A61603 treatment caused increased abundance of antioxidant glutathione peroxidase-1, decreased level of reactive oxygen species, and decreased oxidative modification (carbonylation) of myofilament proteins. Consistent with these effects, A61603 treatment resulted in increased force development by cardiac myofilaments which might have contributed to increased RV function. These findings suggest that the alpha1A-AR is a therapeutic target to reverse established RVF. PMID- 30412440 TI - Autophagy in vascular Physiology and Pathology. PMID- 30412441 TI - Non-coding RNAs: potential regulators in cardio-oncology. AB - Cancer is the leading cause of morbidity and mortality in the United States and globally. Owing to improved early diagnosis and advances in oncologic therapeutic options, the number of cancer survivors increases steadily. Such efficient cancer therapies have also lead to alarming increase in cardiovascular complications in a significant proportion of cancer survivors, due to adverse cardiovascular effects such as cardiotoxicity, cardiac atrophy and myocarditis. This has emerged as a notable concern in the healthcare and given rise to the new field of cardio oncology, which aims at understanding the processes that occur in the two distinct disorders and how they interact to influence the progression of each other. A key player in both cancer and heart failure is the genome which is predominantly transcribed to non-coding RNAs (ncRNAs). Since, the emergence of ncRNAs as master regulators of gene expression, several reports have shown the relevance of ncRNAs in cancer and cardiovascular disorders. However, the knowledge is quite limited regarding the relevance of ncRNAs in cardio-oncology. The objective of this review is to summarize the current knowledge of ncRNAs in the context of cardio-oncology. Furthermore, the therapeutic strategies, as well as the prospective translational applications of these ncRNA molecules to the clinic are also discussed. PMID- 30412442 TI - Resistin promotes cardiac homing of mesenchymal stem cells and functional recovery after myocardial ischemia/reperfusion via the ERK1/2-MMP-9 pathway. AB - BACKGROUND: Stem cell therapy is a potentially effective and promising treatment for ischemic heart disease. Resistin, a type of adipokine, has been found to bind to adipose-derived mesenchymal stem cells (ADSCs). However, the effects of resistin on cardiac homing by ADSCs and on ADSC-mediated cardioprotective effects have not been investigated. METHODS: ADSCs were obtained from EGFP transgenic mice. C57BL/6J mice were subjected to myocardial ischemia/reperfusion (I/R) or sham operations. Six hours after the I/R operation, mice were intravenously injected with resistin-treated ADSCs (ADSC-resistin) or vehicle-treated ADSCs (ADSC-vehicle). Cardiac homing by ADSCs and cardiomyocyte apoptosis were investigated 3 days after I/R. Cardiac function, fibrosis, and angiogenesis were evaluated 4 weeks after I/R. Cellular and molecular mechanisms were investigated in vitro using cultured ADSCs. RESULTS: Both immunostaining and flow cytometric studies showed that resistin treatment promoted ADSC myocardial homing 3 days after intravenous injection. Echocardiographic studies showed that ADSC-resistin, but not ADSC-vehicle, significantly improved the left ventricular ejection fraction (LVEF). ADSC-resistin transplantation significantly mitigated I/R induced fibrosis and reduced ANP/BNP mRNA expression. In addition, cardiomyocyte apoptosis was reduced while angiogenesis was increased by ADSC-resistin treatment. At the cellular level, resistin promoted ADSC proliferation and migration, but did not affect H2O2-induced apoptosis. Molecular studies identified the ERK1/2-MMP-9 pathway as a key component mediating the effects of resistin on ADSC proliferation and migration. CONCLUSION: These results demonstrate that resistin can promote homing of injected ADSCs into damaged heart tissue and stimulate functional recovery, an effect mediated through the ERK1/2 signaling pathway and MMP-9. PMID- 30412443 TI - Central Artery Stiffness and Thoracic Aortopathy. AB - Thoracic aortopathy - especially aneurysm, dissection, and rupture - is responsible for significant morbidity and mortality. Uncontrolled hypertension and aging are primary risk factors for such conditions and they contribute, respectively, to increasing the mechanical stress on the wall and increasing its structural vulnerability. Select genetic mutations also predispose to these lethal conditions, and the collection of known mutations suggests that dysfunctional mechanosensing and mechanoregulation of extracellular matrix may contribute to pathogenesis and disease progression. In the absence of a well accepted pharmacotherapy, non-surgical treatments tend to focus on reducing the mechanical loading on the aorta, particularly via the use of anti-hypertensive medications and recommendations to avoid strenuous exercises such as weight lifting. In this brief review, we discuss the important effects of central artery stiffening on global hemodynamics and in particular on increasing the pulse pressure that acts on the proximal thoracic aorta. We consider Marfan syndrome as an illustrative aortopathy but discuss other conditions leading to thoracic aortic aneurysm and dissection. We highlight the importance of phenotyping the aorta biomechanically, not just clinically, and emphasize the utility of mouse models in elucidating molecular and mechanical mechanisms of disease. Notwithstanding the widely recognized role of central artery stiffening in driving end organ disease, we suggest that there is similarly a need to consider its key role in thoracic aortopathy. PMID- 30412444 TI - Elimination or neutralization of endogenous high molecular weight FGF2 mitigates Doxorubicin induced cardiotoxicity. AB - Cardiac FGF2 is exerting multiple paracrine activities related to cardiac response to injury. Endogenous FGF2 is composed of a mixture of 70% high (Hi-) and 30% low (Lo-) molecular weight isoforms; while exogenously added Lo-FGF2 is cardioprotective, the role of endogenous Hi- or Lo- FGF2 is not well defined. Therefore, we investigated the effect of eliminating Hi-FGF2 expression on susceptibility to acute cardiac damage in vivo, caused by an injection of the genotoxic drug Doxorubicin (Dox). Mice genetically depleted of endogenous Hi-FGF2 and expressing only Lo-FGF2 (FGF2(Lo) mice), were protected from the Dox-induced decline in ejection fraction displayed by their wild-type FGF2(WT) mouse counterparts, regardless of sex, as assessed by echocardiography for up to 10 days post-Dox treatment. Because cardiac FGF2 is produced mainly by non-myocytes, we next addressed the contribution of fibroblast-produced FGF2 on myocyte vulnerability to Dox. In co-cultures of neonatal rat cardiomyocytes with mouse fibroblasts from FGF2(WT) or FGF2(Lo) mice only the FGF2(Lo)-fibroblast co cultures protected cardiomyocytes from Dox-induced mitochondrial and cellular damage. When cardiomyocytes were co-cultured with or exposed to conditioned medium from human fibroblasts, neutralizing antibodies for human Hi-FGF-2, but not total FGF2, mitigated Dox-induced injury of cardiomyocytes. We conclude that endogenous Hi-FGF2 reduces cardioprotection by endogenous Lo-FGF2. Antibody-based neutralization of endogenous Hi-FGF2 may offer a prophylactic treatment against agents causing acute cardiac damage. PMID- 30412445 TI - Usefulness of diluted contrast medium for test-scanning of infants scheduled for contrast-enhanced cardiovascular computed tomography angiography. AB - OBJECTIVE:: To compare the ability of test scans with undiluted and diluted contrast medium (CM) to predict contrast enhancement (CE) on cardiovascular CT angiography (CCTA) images of infants. METHODS:: We divided 120 consecutive infants who had undergone CCTA on a 64-MDCT scanner into two equal groups. In one group, the test bolus consisted of undiluted CM [protocol 1 (P1): injection volume = total body weight * 1.2 ml, injection time 5 s], in the other (P2) it was total body weight * 4.0 ml (CM 15%, saline 85%, injection time 16 s). CE on the test scans was recorded on a 3-point visual scale. We investigated the relation for CE in the pulmonary artery and ascending aorta between the P1 or P2 test scans and CCTA images. RESULTS:: While peak CE was observed on all test scans performed with P2, in approximately 10 % of test scans obtained under P1, peak CE was not visualized. There was a strong positive linear correlation for CE of the pulmonary artery and ascending aorta on P2 images (r = 0.61 and r = 0.63, p < 0.01); under P1 the correlation was weak (r = 0.26 and r = 0.33, p < 0.01). CONCLUSION:: Test-scanning with diluted CM revealed the optimal CE peak time and was useful for predicting CE on CCTA scans of the pulmonary artery and ascending aorta in infants with congenital heart disease. ADVANCES IN KNOWLEDGE:: Diluted test scans help to select the optimal scan parameters for the CCTA study of infants by using contrast-to-noise-based scanning. PMID- 30412446 TI - Beyond Right or Wrong: Attitudes and Practices of Physicians, Nurses, Psychologists, and Social Workers Regarding Attendance at Patient Funerals. AB - BACKGROUND: Health professionals' bereavement practices, including funeral attendance, have attracted relatively little attention from researchers. There may be a number of motivations and perceived benefits for health professionals to attend patient funerals. There are no published data comparing different groups of health professionals' perceptions of and practices in attending the funerals of their patients. OBJECTIVE: To understand the attitudes and practices of health professionals toward attendance at patient funerals. DESIGN: Cross-sectional nationwide online survey of attitudes and practices toward attendance at patient funerals based upon data from interviews with health professionals. PARTICIPANTS: Australian health practitioners from medicine, nursing, psychology, social work, and other allied health professions (n = 1098). RESULTS: Attendance at patient funerals was predicted by age, telling colleagues about own funeral attendance practices, having discussions with colleagues about funeral attendance, having long relationships with patients, and having a majority of patients at the end of life. Nonattendance was predicted by believing that if they cannot attend all funerals, they prefer not to attend any, feeling that colleagues disapprove of funeral attendance, believing that attending funerals is crossing the line between the personal and the professional, and being a psychologist. CONCLUSIONS: Our findings emphasize the need for more open discussions and reflection among individuals and groups of health practitioners regarding attendance at funerals. Understanding the motivations of physicians, nurses, social workers, and other allied health practitioners to attend or not attend patient funerals is an important first step in working toward policies, protocols, and guidelines to support best practice. PMID- 30412447 TI - Uterine Fibroids and the Risk of Cardiovascular Disease in the Coronary Artery Risk Development in Young Adult Women's Study. AB - BACKGROUND: Uterine fibroids, the most common reproductive tract tumor in women, have been associated with hypertension and atherosclerotic cardiovascular disease (CVD). Prior studies of fibroids and CVD have examined the subset of women with symptomatic fibroids who undergo hysterectomy, itself a risk factor for CVD. We aimed to study the risk of subclinical CVD, as determined by coronary artery calcification (CAC), carotid intima media thickness (CIMT), and left ventricular (LV) mass, in women with ultrasound-diagnosed uterine fibroids. MATERIALS AND METHODS: Participants were 972 women from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a cohort recruited in 1985-1986. CARDIA screened black and white women aged 35-49 years by ultrasound for fibroids at 16 years of follow-up (2002-2004). Demographics and CVD risk factors were collected in 2000 2001 at 15 years of follow-up (baseline for this analysis). Women were tested at years 15, 20, and 25 for CAC, at year 20 for CIMT, and at year 25 for echocardiographic LV mass. Multivariable logistic regression was used to estimate the odds of CAC, CIMT, and LV mass. RESULTS: Fifty-two percent of women had fibroids (61.7% in black, 38.3% in white women). Most CVD risk factors were more common in women with fibroids. Adjusted odds of subclinical CVD, such as elevated CIMT and elevated LV mass, were not different for women with fibroids compared with those without (CIMT odds ratio [OR] = 1.03; confidence interval [95% CI] 0.7 1.5 and LV mass OR = 1.14; 95% CI 0.77-1.68), when adjusted for confounders. CONCLUSIONS: Although women with fibroids had more CVD risk factors, presence of fibroids was not associated with subclinical CVD. PMID- 30412448 TI - Double-Masked, Randomized, Phase 2 Evaluation of Abicipar Pegol (an Anti-VEGF DARPin Therapeutic) in Neovascular Age-Related Macular Degeneration. AB - PURPOSE: To evaluate safety and efficacy of the vascular endothelial growth factor binding protein abicipar pegol (abicipar) versus ranibizumab for neovascular age-related macular degeneration. METHODS: Phase 2, multicenter, randomized, double-masked comparison (REACH study, stage 3). Patients (n = 64) received intravitreal injections of abicipar 1 mg or 2 mg at baseline, week 4, and week 8 (3 injections) or ranibizumab 0.5 mg at baseline and monthly (5 injections). RESULTS: In the abicipar 1 mg (n = 25), abicipar 2 mg (n = 23), and ranibizumab (n = 16) arms, respectively, least-squares mean best-corrected visual acuity (BCVA) change from baseline was +6.2, +8.3, and +5.6 letters at week 16 (primary endpoint) and +8.2, +10.0, and +5.3 letters at week 20. Least-squares mean central retinal thickness (CRT) reduction from baseline was 134, 113, and 131 MUm at week 16 and 116, 103, and 138 MUm at week 20. Intraocular inflammation adverse events (AEs), reported in 5/48 (10.4%) abicipar-treated patients, resolved without sustained vision loss or other sequelae. CONCLUSIONS: Abicipar demonstrated durability of effect: BCVA and CRT improvements were similar between abicipar and ranibizumab at weeks 16 and 20 (8 and 12 weeks after the last abicipar injection and 4 weeks after the last ranibizumab injection). No serious AEs were reported. PMID- 30412449 TI - Mode of Delivery Preference Among Pregnant Nulliparous Women. AB - BACKGROUND: Nearly a third of women in the United States deliver by cesarean at first childbirth. The extent to which women's prenatal mode of delivery preference contributes to the cesarean decision is not clear. Little research has measured pregnant nulliparous women's prelabor mode of delivery preference in relation to actual mode of delivery in the United States. MATERIALS AND METHODS: A total of 3006 pregnant nulliparous women were asked about mode of delivery preference during pregnancy as part of the First Baby Study, a prospective study of women delivering in Pennsylvania hospitals, 2009-2011. Multivariable regression models were used to assess the association between women's preference for cesarean delivery and two decision stages: (1) the decision to have planned prelabor cesarean and (2) the intrapartum decision to have unplanned cesarean among those attempting vaginal delivery, adjusting for confounders. RESULTS: Overall, 3.1% preferred cesarean delivery, 3.0% had no preference, and 93.9% preferred vaginal. Among those who preferred vaginal delivery, 4% had a planned cesarean; among those with no preference, 13.3% did; and among those who preferred cesarean, 33.7% did. In adjusted models, preference for cesarean was strongly associated with having planned prelabor cesarean (adjusted odds ratio [aOR] = 6.02; 95% confidence interval [CI] = 3.26-11.12), but was not significantly associated with unplanned cesarean among those who attempted vaginal delivery (aOR = 1.35; 95% CI = 0.77-2.38). CONCLUSIONS: Although preference for cesarean delivery among nulliparous women was uncommon, women who preferred cesarean were more likely to have planned prelabor cesarean delivery than those who preferred vaginal delivery. PMID- 30412450 TI - Differences in Attitudes Toward Online Interventions in Psychiatry and Psychotherapy Between Health Care Professionals and Nonprofessionals: A Survey. AB - BACKGROUND: Although the use of e-mental health interventions and their evaluation is already well advanced in countries such as the United States and Australia, research in this area is still in the early stages in Germany. Moreover, existing programs are used only to a small extent by patients, although physicians and therapists generally have a positive attitude toward their use. To help promote the use of online interventions in the future, an analysis of the differences in opinions and attitudes toward e-mental health interventions between health care professionals and nonprofessionals is necessary. OBJECTIVE: This study aimed to examine the differences in attitudes toward online interventions between health care professionals and nonprofessionals. METHODS: This study examined 92 physicians, 36 psychotherapists, and 1,353 randomly recruited nonprofessionals with the eight-item questionnaire entitled "Attitudes on telemedicine in psychiatry and psychotherapy (ATiPP)." RESULTS: The questionnaires of n = 62 physicians, n = 37 psychotherapists, and n = 1,353 nonprofessionals were included in the analysis. Overall, nonprofessionals rate the use of telemedicine more critically than professionals. The itemwise t tests show significant differences between health care professionals and nonprofessionals on six out of eight items. The analyses of variance with post hoc tests for each single item also found differences between the groups (physicians vs. therapists vs. telephone participants vs. practice sample). CONCLUSION: There are significant differences in attitudes toward online interventions between professionals and nonprofessionals. PMID- 30412451 TI - Development of Diagnostic SCAR Markers for Meloidogyne graminicola, M. oryzae, and M. salasi Associated with Irrigated Rice Fields in Americas. AB - Root-knot nematodes (RKN) cause important production losses of rice (Oryza sativa L.) in the world. Together with Meloidogyne graminicola Golden and Birchfield 1965, M. oryzae Maas, Sanders and Dede, 1978 and M. salasi Lopez, 1984 have been causing damages in irrigated rice fields in Central and South America. In addition, six other RKN species may occur in rice fields in other regions of the world. Correct identification of Meloidogyne spp. is difficult but essential for the management of rice RKNs. The objective of this study was to develop some species-specific molecular markers for the diagnosis of South American RKN rice related species. Isozyme phenotypes indicated the occurrence of some RKN species in the Brazilian samples, namely M. graminicola, M. oryzae, M. javanica, and two cryptic species designated as Meloidogyne sp. 2 and Meloidogyne sp. 3. Random amplified polymorphic DNA (RAPD) analysis of 16 isolates revealed interspecific genetic polymorphism between Meloidogyne spp., but isolates belonging to the same species (i.e., sharing the same esterase phenotype) always clustered together, whatever the species considered. Specific SCAR markers of 230, 120, and 160 bp were developed for M. graminicola, M. oryzae, and M. salasi, respectively. These SCAR markers may be potential molecular tools for application in routine diagnostic procedures subject to their validation with other rice RKN field populations in the world. PMID- 30412452 TI - Therapeutic Hypothermia in Cardiac Arrest. PMID- 30412453 TI - Effect of Morinda citrifolia and Annona muricata on Erhlich Tumor Cells in Swiss Albino Mice and In Vitro Fibroblast Cells. AB - Morinda citrifolia (MC) and Annona muricata (AM) are popularly used for the treatment of several diseases, including cancer. Our objective was to evaluate the effects of the juice of the MC fruit, and the ethanolic extract of AM leaves on Erhlich tumor cells, in mice and in vitro fibroblastic cells. The animals were divided into G1 and G2: controls; G3: treated with AM, and G4 juice: treated with MC. The animals were subjected to intraperitoneal inoculation of 103 tumor cells and then treated with the plants. G1 and G2 received a saline solution. Cells were grown in RPMI 1640 medium, supplemented with 10% fetal bovine serum, and maintained at 37 degrees C in 5% CO2 atmosphere. After growth, the cells were trypsinized and incubated again. Subsequently, serial dilution of extracts and juice was performed and incubated again for 48 h. We evaluated the ascites growth, the survival rate, and cytotoxicity in fibroblast cells. AM and MC did not interfere in the ascites pattern. MC, but not AM showed significance in the survival rate. Both AM and MC produced cytotoxicity activity in T3T cells. Despite advances in Medicine, cancer is still one of the leading causes of death in the world and traditional medications are not always effective. The use of MC may bring beneficial effects to patients since they interfere with different mechanisms of action during carcinogenesis. However, we suggest that further investigations should be performed. PMID- 30412454 TI - The Prevalence of Sexual Abuse in Adolescence in Suriname. AB - Studies conducted to ascertain the prevalence of child sexual abuse (CSA) in the Caribbean are poorly synthesized. Present study reports on the lifetime and year prevalence of unwanted sexual experiences, the risk of CSA at different ages within adolescence, and differences between the three largest ethnic groups in Suriname. One thousand one hundred and twenty (1,120) adolescents completed a questionnaire on child maltreatment, including CSA. The study's stratified sample consisted of students (ages 12 to 17) from five districts in Suriname. More than 16% of all boys and 15% of all girls indicated that they had been exposed to some form of CSA in the past 12 months. Girls reported significantly more intrafamilial CSA by a minor than boys. Boys reported significantly more experiences of being touched or forced by a minor outside the family to look at/touch the abuser's private parts than girls. Besides, 16 and 17-year olds were the most vulnerable. An increased risk of CSA (year prevalence) was found as adolescence progresses. A significant portion of CSA constituted peer-to-peer sexual victimization. Afro Surinamese adolescents were found to report the highest rates of CSA. Appropriate legislation, policies, and services for prevention and recovery are needed in Suriname. PMID- 30412455 TI - A Quest for Optimization of Postoperative Triage After Major Surgery. AB - INTRODUCTION: Innovative strategies to reduce costs while maintaining patient satisfaction and improving delivery of care are greatly needed in the setting of rapidly rising health care expenditure. Intensive care units (ICUs) represent a significant proportion of health care costs due to their high resources utilization. Currently, the decision to admit a patient to the ICU lacks standardization because of the lack of evidence-based admission criteria. The objective of our research is to develop a prediction model that can help the physician in the clinical decision-making of postoperative triage. MATERIALS AND METHODS: Our group identified a list of index events that commonly grants admission to the ICU independently of the hospital system. We analyzed correlation among 200 quantitative and semiquantitative variables for each patient in the study using a decision tree modeling (DTM). In addition, we validated the DTM against explanatory models, such as bivariate analysis, multiple logistic regression, and least absolute shrinkage and selection operator. RESULTS: Unlike explanatory modeling, DTM has several unique strengths: tree models are easy to interpret, the analysis can examine hundreds of variables at once, and offer insight into variable relative importance. In a retrospective analysis, we found that DTM was more accurate at predicting need for intensive care compared with current clinical practice. DISCUSSION: DTM and predictive modeling may enhance postoperative triage decision-making. Future areas of research include larger retrospective analyses and prospective observational studies that can lead to an improved clinical practice and better resources utilization. PMID- 30412456 TI - Identification and Molecular Characterization of Recombinant Potato Virus Y (PVY) in Potato from South Korea, PVYNTN Strain. AB - Potato is an important source of food in South Korea, and viruses represent a significant threat to sustainable and profitable potato production. However, information about viruses affecting the potato crop in South Korea is limited. In 2017, potato plants of five cultivars exhibiting foliar mosaic, crinkling, and mottle were collected in two seed potato production areas, in Gangwon-do and Jeollabuk-do Provinces, and subjected to virus testing and characterization. Potato virus Y (PVY) was found associated with mosaic symptoms, and samples were characterized using reverse transcription polymerase chain reaction (RT-PCR) and whole genome sequencing. All analyzed PVY-positive samples were found to represent the same recombinant PVY strain: PVYNTN. Three PVY isolates were subjected to whole genome sequencing using overlapping RT-PCR fragments and Sanger methodology, and all three were confirmed to represent strain PVYNTNa after a recombination analysis of the complete genomes. In phylogenetic analysis, the three South Korean isolates were placed most closely to several PVYNTNa isolates reported from Japan and Vietnam, suggesting a common source of infection. This is the first report and complete molecular characterization of a PVYNTN strain present in the country, and because this strain induces tuber necrotic ringspot disease in susceptible cultivars of potato, appropriate management tools need to be implemented to mitigate potential tuber quality losses. PMID- 30412457 TI - Re-evaluation of Seed Transmission of Clavibacter michiganensis subsp. nebraskensis in Zea mays. AB - The spread of Goss's bacterial wilt and leaf blight of corn (Zea mays), caused by Clavibacter michiganensis subsp. nebraskensis, to a wider geographic range in the early 2000s compared with the late 1960s has generated concern about the possible role of seed transmission in long-distance spread. The objectives of this research were: (1) to determine the percentage of seed infection found in seed harvested from inoculated and noninoculated plants of hybrids that varied in resistance to Goss's wilt; and (2) to estimate the seed transmission rate from these infected seed lots. The greatest percent seed infection was detected in seed from inoculated plants of the most susceptible hybrid and the least in seed from the most resistant hybrid. Seed lots with seed infection that ranged from 3.6 to 37.0% were planted in three field and three greenhouse trials. A total of 12 seed transmission events (Goss's wilt symptomatic seedlings) were identified among 241,850 plants examined, for a seed transmission rate of 0.005%. When the seed transmission rate was recalculated to consider only the infected seed portion of each seed lot, the rate increased to 0.040% (12 events from 30,088 potentially infected plants). Based on the low seed transmission rate observed and previous research on disease spread from a point source, it seems unlikely that seed transmission could introduce enough inoculum to create a serious disease outbreak in a single growing season. However, risk of seed transmission is relevant for phytosanitary restrictions and preventing the introduction of the pathogen to new areas. To date, Goss's wilt has not been detected outside North America, and while the risk of seed transmission is very low, the risk is not zero. Fortunately, the presence of C. michiganensis subsp. nebraskensis in corn seed is readily detectable by established seed health testing methods. PMID- 30412458 TI - Association of physical activity on changes in cognitive function: Boston Puerto Rican Health Study. AB - OBJECTIVE: To evaluate the association of habitual physical activity engagement on changes in cognitive function among Puerto Rican adults. METHODS: Longitudinal data (2-year follow-up) from the Boston Puerto Rican Health Study were analyzed (n = 862; mean age = 56.5 year). A daily energy expenditure score was calculated using the number of hours over a 24-h period engaged in various activities, including sleeping, light activity, and moderate-to-vigorous exercise. Energy expenditure estimates were weighted based on the rate of oxygen consumption associated with each activity. Seven cognitive function outcomes were evaluated, including an assessment of general cognitive function, episodic memory, attention and working memory, cognitive flexibility, response inhibition, processing speed, and visuo-spatial organization. From these, overall executive function and memory capacity were derived using principal components analysis. RESULTS: Physical activity was not associated with changes in overall executive function. However, compared to those with low baseline physical activity, those with moderate physical activity had 48% reduced odds of having >=1 standard deviation decline in memory function (OR = 0.52; 95% CI: 0.32, 0.84; p = 0.008) in 2 years. CONCLUSION: Among Puerto Rican adults, physical activity may help attenuate memory decline. PMID- 30412459 TI - Avoiding amino acid depletion in a complex medium results in improved Escherichia coli BW25113 growth. AB - We studied Escherichia coli BW25113 growth in a complex medium with emphasis on amino acid consumption. The aim was to profile amino acid utilization in acid hydrolysed casein and a defined nutrient-rich medium and based on these measurements modify the medium for better growth performance. Amino acid depletions in both media caused apparent biomass growth stops that prolonged growth duration. Obtained amino acid consumption values enabled a new defined medium to be formulated, where no growth stops were observed, the specific growth rate was constant, and the provided substrates were fully utilized. Similarly, we modified the acid-hydrolysed casein medium by adding pure amino acids that removed the apparent biomass growth stops. Key to our results was the combination of growth medium analysis and process monitoring data, specifically oxygen partial pressure and produced carbon dioxide that were used to track growth changes. Our findings showed the deficiencies of the nutrient-rich medium and how rational medium design, based on consumption values, removed these shortcomings. The resulting balanced medium gives a high specific growth rate and is suitable for studying E. coli physiology at fast growth. PMID- 30412460 TI - Identification of a chimeric emm gene and novel emm pattern in currently circulating strains of emm4 Group A Streptococcus. AB - Group A Streptococcus (GAS) is classified on the basis of the sequence of the gene encoding the M protein (emm) and the patterns into which emm types are grouped. We discovered a novel emm pattern in emm4 GAS, historically considered pattern E, arising from a fusion event between emm and the adjacent enn gene. We identified the emm-enn fusion event in 51 out of 52 emm4 GAS strains isolated by national surveillance in 2015. GAS isolates with an emm-enn fusion event completely replaced pattern E emm4 strains over a 4-year span in Houston (2013 2017). The novel emm-enn gene fusion and new emm pattern has potential vaccine implications. PMID- 30412461 TI - Evaluation of analytical performances using standardized analytical protocols and comparison of clinical results of the new ADVIA BNP and NT-proBNP immunoassays for the Centaur XPT platform. AB - Background The study aim was to evaluate and compare analytical performances and clinical results of ADVIA BNP and PBNP methods using the Centaur XPT platform with those of Access BNP, using the DxI platform and the ECLIA NT-proBNP method, using the Cobas e411 platform, respectively. Methods Limits of blank (LoB), detection (LoD) and quantitation (LoQ) at 20% CV and 10% CV were evaluated according to international standardized protocols. The analytical parameters were assessed throughout a 90-working-day period using three curve calibrations. Results LoB, LoD and LoQ at 20% CV and 10% values of the ADVIA BNP method were 1.0 ng/L, 2.0 ng/L, 3.7 ng/L and 10.2 ng/L, respectively; while those of the ADVIA PBNP method were 1.3 ng/L, 3.0 ng/L, 9.7 ng/L and 22.3 ng/L, respectively. The ADVIA BNP and PBNP methods were able to measure the clinical decision values suggested by international guidelines for diagnosis of heart failure (HF) with an imprecision <=6%. BNP concentrations measured with the ADVIA and Access methods showed a close linear regression (R=0.9923, n=200); a close linear regression was also found between NT-proBNP concentrations measured with the ADVIA and ECLIA methods (R=0.9954, n=202). However, the ADVIA method measured significantly lower BNP values than the Access method (on average -20.9%), while ADVIA PBNP method measured significantly higher NT-proBNP concentrations than the ECLIA method (on average +17.8%). Conclusions Analytical performances of the BNP and PBNP ADVIA methods are well in accordance with the quality specifications required by international guidelines for diagnosis and follow-up of patients with HF. PMID- 30412463 TI - Development of the Point-of-Care Key Evidence Tool (POCKET): a checklist for multi-dimensional evidence generation in point-of-care tests. AB - Background This study aimed to develop the Point-of-Care Key Evidence Tool (POCKET); a multi-dimensional checklist to guide the evaluation of point-of-care tests (POCTs) incorporating validity, utility, usability, cost-effectiveness and patient experience. The motivation for this was to improve the efficiency of evidence generation in POCTs and reduce the lead-time for the adoption of novel POCTs. Methods A mixed qualitative and quantitative approach was applied. Following a literature search, a three round Delphi process was undertaken incorporating a semi-structured interview study and two questionnaire rounds. Participants included clinicians, laboratory personnel, commissioners, regulators (including members of National Institute for Health and Care Excellence [NICE] committees), patients, industry representatives and methodologists. Qualitative data were analysed based on grounded theory. The final tool was revised at an expert stakeholder workshop. Results Forty-three participants were interviewed within the semi-structured interview study, 32 participated in the questionnaire rounds and nine stakeholders attended the expert workshop. The final version of the POCKET checklist contains 65 different evidence requirements grouped into seven themes. Face validity, content validity and usability has been demonstrated. There exists a shortfall in the evidence that industry and research methodologists believe should be generated regarding POCTs and what is actually required by policy and decision makers to promote implementation into current healthcare pathways. Conclusions This study has led to the development of POCKET, a checklist for evidence generation and synthesis in POCTs. This aims to guide industry and researchers to the evidence that is required by decision makers to facilitate POCT adoption so that the benefits they can bring to patients can be effectively realised. PMID- 30412462 TI - Free PAPP-A as a biomarker: heparin-induced release is not related to coronary atherosclerotic burden. PMID- 30412464 TI - Anti-citrullinated protein antibodies are not associated with extent of disease or prognosis in patients with coronary artery disease. PMID- 30412465 TI - Macro-CK type 2 in metastatic prostate cancer. AB - The isoenzyme creatine kinase muscle/brain (CK-MB) still plays an important role for the differential diagnosis of CK elevations and the clarification of their origin from heart or skeletal muscle. Therefore, it is necessary to know the diagnostic pitfalls in interpreting CK-MB results. We demonstrate a case of macro CK type 2 in a 75-year-old patient with metastatic castration-resistant prostate cancer and its identification by isoenzyme electrophoresis, which can be typical for cancer diseases. PMID- 30412466 TI - Clinical chorioamnionitis at term IX: in vivo evidence of intra-amniotic inflammasome activation. AB - Background The inflammasome has been implicated in the mechanisms that lead to spontaneous labor at term. However, whether the inflammasome is activated in the amniotic cavity of women with clinical chorioamnionitis at term is unknown. Herein, by measuring extracellular ASC [apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (CARD)], we investigated whether there is in vivo inflammasome activation in amniotic fluid of patients with clinical chorioamnionitis at term with sterile intra-amniotic inflammation and in those with intra-amniotic infection. Methods This was a retrospective cross-sectional study that included amniotic fluid samples collected from 76 women who delivered after spontaneous term labor with diagnosed clinical chorioamnionitis. Intra-amniotic inflammation was defined as an elevated amniotic fluid interleukin (IL)-6 concentration >=2.6 ng/mL, and intra-amniotic infection was diagnosed by the presence of microbial invasion of the amniotic cavity (MIAC) accompanied by intra-amniotic inflammation. Patients were classified into the following groups: (1) women without intra-amniotic inflammation or infection (n=16); (2) women with MIAC but without intra-amniotic inflammation (n=5); (3) women with sterile intra-amniotic inflammation (n=15); and (4) women with intra amniotic infection (n=40). As a readout of in vivo inflammasome activation, extracellular ASC was measured in amniotic fluid by enzyme-linked immunosorbent assay. Acute inflammatory responses in the amniotic fluid and placenta were also evaluated. Results In clinical chorioamnionitis at term: (1) amniotic fluid concentrations of ASC (extracellular ASC is indicative of in vivo inflammasome activation) and IL-6 were greater in women with intra-amniotic infection than in those without intra-amniotic inflammation, regardless of the presence of MIAC; (2) amniotic fluid concentrations of ASC and IL-6 were also higher in women with sterile intra-amniotic inflammation than in those without intra-amniotic inflammation, regardless of the presence of MIAC; (3) amniotic fluid concentrations of IL-6, but not ASC, were more elevated in women with intra amniotic infection than in those with sterile intra-amniotic inflammation; (4) a positive and significant correlation was observed between amniotic fluid concentrations of ASC and IL-6; (5) no differences were observed in amniotic fluid ASC and IL-6 concentrations between women with and without MIAC in the absence of intra-amniotic inflammation; (6) women with intra-amniotic infection had elevated white blood cell counts and reduced glucose levels in amniotic fluid compared to the other three study groups; and (7) women with intra-amniotic infection presented higher frequencies of acute maternal and fetal inflammatory responses in the placenta than those with sterile intra-amniotic inflammation. Conclusions The intra-amniotic inflammatory response, either induced by alarmins or microbes, is characterized by the activation of the inflammasome - as evidenced by elevated amniotic fluid concentrations of extracellular ASC - in women with clinical chorioamnionitis at term. These findings provide insight into the intra-amniotic inflammatory response in women with clinical chorioamnionitis at term. PMID- 30412467 TI - Translation, cross-cultural adaptation, and psychometric properties of the Hausa version of the Fear-Avoidance Beliefs Questionnaire in patients with low back pain. AB - Background and aims The Fear-Avoidance Beliefs Questionnaire (FABQ) is the most widely used self-reported measure of fear-avoidance beliefs about work and physical activity in low back pain (LBP). However, there is no Hausa version for use in patients with LBP. This study aimed to translate, cross-culturally adapt, and test the psychometric properties of the Hausa version of the FABQ in patients with LBP. Methods The Hausa form of FABQ was developed using a forward-backward translation procedure according to recommended guidelines. The pre-final version of the questionnaire was pre-tested on 10 patients with acute LBP and 10 patients with chronic LBP. Psychometric testing was performed in 70 patients with acute LBP and 130 patients with chronic LBP. Reliability was assessed using internal consistency (Cronbach alpha) and test-retest reliability through intraclass correlation coefficient (ICC). Construct validity was assessed by exploratory factor analysis and divergent validity (Spearman rank correlation coefficient). Responsiveness was also investigated on 40 patients with chronic LBP. Results The Hausa version of the FABQ was successfully translated and proved to be well understood. The internal consistency was adequate for the questionnaire (0.773) and its physical activity (0.816) and work (0.606) subscales. Test-retest reliability was excellent with an ICC value of 0.928 for the questionnaire and values of 0.901 and 0.863 for the physical activity and work subscales, respectively. Exploratory factor analysis yielded a three-factor structure in both acute and chronic LBP samples explaining 66.4% and 58.6% of the total variance, respectively. The first factor represents fear-avoidance beliefs due to work, the second factor represents fear-avoidance beliefs due to physical activity whereas the third factor represents the fear that pain aggravates due to work. Divergent validity showed moderate to weak correlation between the questionnaire and pain intensity (r=0.502), disability (r=0.415), lumbopelvic motion (r=0.00). The physical activity and work subscales weakly correlated (r=0.280). The effect size and standardized response mean were moderate to small with the work subscale having the lowest effect size (0.34) and standardized response mean (0.34) values. The MDC of the questionnaire was 5.4 points. The questionnaire had no ceiling or floor effects. Conclusions The FABQ was successfully translated into Hausa and cross-culturally adapted with acceptable psychometric properties similar to those of existing versions. The results suggest that the Hausa FABQ can be used to evaluate fear-avoidance beliefs about LBP in Hausa-speaking population for both clinical and research purposes. PMID- 30412468 TI - Risk severity moderated effectiveness of pain treatment in adolescents. AB - Background and aims A targeted pain program may prevent the progression and subsequent occurrence of chronic pain in adolescents. This study tested the effectiveness of a new acceptance and commitment therapy -based pain management intervention, using physical and psychological functions as the outcomes. The objective was also to determine whether Pediatric Pain Screening Tool risk profiles function as outcome moderator in the current sample. A valid screening tool would enable the program development. Methods Thirty-two consecutive adolescent patients (13-17 years old) with idiopathic recurrent musculoskeletal pain completed the study. The intervention comprised acceptance and commitment therapy-oriented multidisciplinary treatment. Pediatric Pain Screening Tool, pain frequency, functional disability, school attendance, physical endurance, depressive symptoms, and catastrophizing coping style were measured before treatment (baseline) and again at 6 and 12 months after the initiation of treatment. To test the effectiveness of the new program, we also determined whether the original risk classification of each patient remained constant during the intervention. Results The intervention was effective for high-risk patients. In particular, the pain frequency decreased, and psychosocial measures improved. In post-intervention, the original risk classification of seven patients in the high-risk category changed to medium-risk. PPST classification acted as a moderator of the outcome of the current program. Conclusions The categorization highlighted the need to modify the program content for the medium-risk patients. The categorization is a good tool to screen adolescent patients with pain. Implications The results support using the Pediatric Pain Screening Tool in developing rehabilitation program for pediatric musculoskeletal pain patients. According to the result, for adolescent prolonged musculoskeletal pain patients the use of ACT-based intervention program is warranted. PMID- 30412469 TI - What we talk about when we talk about nanoclusters. AB - Superresolution microscopy results have sparked the idea that many membrane proteins are not randomly distributed across the plasma membrane but are instead arranged in nanoclusters. Frequently, these new results seemed to confirm older data based on biochemical and electron microscopy experiments. Recently, however, it was recognized that multiple countings of the very same fluorescently labeled protein molecule can be easily confused with true protein clusters. Various strategies have been developed, which are intended to solve the problem of discriminating true protein clusters from imaging artifacts. We believe that there is currently no perfect algorithm for this problem; instead, different approaches have different strengths and weaknesses. In this review, we discuss single molecule localization microscopy in view of its ability to detect nanoclusters of membrane proteins. To capture the different views on nanoclustering, we chose an unconventional style for this article: we placed its scientific content in the setting of a fictive conference, where five researchers from different fields discuss the problem of detecting and quantifying nanoclusters. Using this style, we feel that the different approaches common for different research areas can be well illustrated. Similarities to a short story by Raymond Carver are not unintentional. PMID- 30412470 TI - Functionalization of silk fibroin through anionic fibroin derived polypeptides. AB - While silk fibroin (SF)-based fibrous matrices are often considered as templates to mimic the native biomineralization process, their limited ability to induce apatite deposition hinders their potential applications in bone tissue engineering. In this study, it was hypothesized that the incorporation of anionic fibroin derived polypeptides (Cs), generated through the alpha-chymotrypsin digestion of SF, into SF would induce apatite deposition. The effect of Cs incorporation and content on the mineralization of fibrous, electrospun (ES) SF matrices, was assessed in simulated body fluid (SBF). Moreover, the potential role of Cs in mediating the proliferation and osteoblastic differentiation of seeded mesenchymal stem cells (MSCs), in vitro, was also investigated. Methylene blue staining indicated that the ES SF matrices became increasingly negatively charged with an increase in Cs content. Furthermore, the mechanical properties of the ES SF matrices were modulated through variations in Cs content. Their subsequent immersion in SBF demonstrated rapid mineralization, attributable to the carboxyl groups provided by the negatively charged Cs polypeptides, which served as nucleation sites for apatite deposition. Seeded MSCs attached on all scaffold types with differences observed in metabolic activities when cultured in osteogenic medium. Relative to basal medium, there was an up-regulation of alkaline phosphatase, runt related transcription factor 2 and osteocalcin in osteogenic medium (at days 14 and 21). Cell-induced mineralized matrix deposition appeared to be accelerated on Cs incorporated ES SF suggesting an osteoinductive potential of these polypeptides. In sum, the ability to incorporate Cs into SF scaffolds offers promise in bone tissue engineering applications. PMID- 30412471 TI - LET-weighted doses effectively reduce biological variability in proton radiotherapy planning. AB - Variations in proton relative biological effectiveness (RBE) with linear energy transfer (LET) remain one of the largest sources of uncertainty in proton radiotherapy. This work seeks to identify metrics which can be applied to mitigate these effects in treatment optimisation, and quantify their effectiveness. Three different metrics-dose, dose * LET and an LET-weighted dose defined as [Formula: see text] where [Formula: see text] is the dose averaged LET-were compared with in vitro experimental studies of proton RBE and clinical treatment plans incorporating RBE models. In each system the biological effects of protons were plotted against these metrics to quantify the degree of variation introduced by unaccounted-for RBE uncertainties. As expected, the LET dependence of RBE introduces significant variability in the biological effects of protons when plotted against dose alone. Plotting biological effects against dose * LET significantly over-estimated the impact of LET on cell survival, and typically produced even larger spreads in biological effect. LET-weighted dose was shown to have superior correlation to biological effect in both experimental data and clinical plans. For prostate and medulloblastoma treatment plans, the average RBE-associated variability in biological effect is +/-5% of the prescribed dose, but is reduced to less than 1% using LET-weighting. While not a replacement for full RBE models, simplified metrics such as this LET-weighted dose can be used to account for the majority of variability which arises from the LET-dependence of RBE with reduced need for biological parameterisation. These metrics may be used to identify regions in normal tissues which may see unexpectedly high effects due to end-of-range elevations of RBE, or as part of a more general tool for biological optimisation in proton therapy. PMID- 30412472 TI - Virtual electrophysiological study as a tool for evaluating efficacy of MRI techniques in predicting adverse arrhythmic events in ischemic patients. AB - Myocardial infarct (MI) related indices determined by late gadolinium enhancement (LGE) MRI have been widely investigated in determining patients suitable for implantable cardiovascular-defibrillator (ICD) therapy to complement left ventricular ejection fraction (LV EF). In comparison to LGE-MRI using inversion recovery fast-gradient-echo (IR-FGRE), T1 mapping techniques, such as multi contrast late enhancement (MCLE), have been shown to provide more quantitative and reproducible estimates of infarct regions. The objective of this study is to use individualized heart computer models in determining the efficacy of IR-FGRE and MCLE techniques in predicting the occurrence of post-MI ventricular tachycardia (VT). Twenty-seven patients with MI underwent LGE-MRI using IR-FGRE and MCLE prior to ICD implantation and were followed up for 6-46 months. Individualized image-based computational models were built separately for each imaging technique; simulations of propensity to VT were conducted with each model. The imaging methods were evaluated by comparing simulated inducibility of VT to clinical outcome (appropriate ICD therapy) in patients. Twelve patients had at least one appropriate ICD therapy for VT at follow-up. For both MCLE and IR FGRE, the outcomes of the simulations of VT were significantly associated with the events of appropriate ICD therapy. This indicates that, as compared to conventional measurements such as LV EF, the simulations of VT corresponding to both MCLE and IR-FGRE were more sensitive in predicting appropriate ICD therapy in post-MI patients. PMID- 30412473 TI - A multi-scale computational approach based on TMS experiments for the assessment of electro-stimulation thresholds of the brain at intermediate frequencies. AB - In recent years, human exposure to electromagnetic fields (EMF) at intermediate frequencies (300 Hz-10 MHz) has risen, mainly due to the growth of technologies using these fields. The current safety guidelines/standards defined by international bodies (e.g. ICNIRP and IEEE) established basic restrictions for limiting EMF exposure. These limits at intermediate frequencies are derived from threshold values of the internal electric field that may produce transient effects, such as the stimulation of the nervous system. However, there are some discrepancies between the basic restrictions of those guidelines/standards. The aim of this study is to investigate the excitation thresholds of the nervous system exposed to intermediate-frequency electromagnetic fields, with the purpose of extrapolating the threshold-frequency curves which are compared with existing basic restrictions prescribed by the international guidelines/standards. Our investigation was based on transcranial magnetic stimulation (TMS) experiments, physiological measurements, and individualized MRI-based computer simulations for the determination of brain stimulation thresholds. The combined approach with established biological axon models enabled the extrapolation of the measured thresholds for sinusoidally varying electric fields. The findings reveal that the exposure limits are significantly conservative for the brain, especially at frequencies in the range of 300 Hz-5 kHz. PMID- 30412474 TI - Absolute fluorescence quantum yield determined by photothermal deflection spectroscopy. AB - We present a spectroscopic method for measuring the fluorescence quantum efficiency [Formula: see text] of fluorophores that does not require calibration standards. Photothermal Deflection Spectroscopy (PDS) is combined with conventional absorbance spectroscopy, and [Formula: see text] is extracted from fits over the spectral range of interest. This technique obviates the need for multiple measurements-either on calibration standards or as a function of concentration-and yields results of [Formula: see text] in a single measurement consistent with previously reported values. Five different organic dyes are tested whose absorbance/fluorescence profiles span the visible spectrum and whose known quantum efficiencies range from 0 to near 1. The accuracy of the results over significant ranges of wavelength and quantum yield demonstrate the robustness and efficacy of this method. PMID- 30412475 TI - Improved Woodcock tracking on Monte Carlo simulations for medical applications. AB - This paper presents a new variance reduction technique called super voxel Woodcock (SVW), which combines Woodcock tracking technique with the super voxel concept, used in computer graphics. It consists in grouping the voxels of the volume in a super voxel grid (pre-processing step) by associating to each of the super voxels a local value of the most attenuate medium which will later serve to the interaction distances sampling. SVW allows reducing the sampling of the particle path while a high-density material is present within the simulated phantom. In order to evaluate the performance of the SVW method compare to both standard and Woodcock tracking methods, algorithms were implemented within the same GPU MCS framework GGEMS. This method improves the performance of the standard Woodcock method by a factor of 4.5 and 4.3 for x-ray imaging application and intraoperative radiotherapy respectively. The proposed SVW method did not introduce any bias on the simulations. PMID- 30412476 TI - The characterization of a large multi-axis ionization chamber array in a 1.5 T MRI linac. AB - By combining magnetic resonance imaging (MRI) scanners and radiotherapy treatment units the need arises for new radiation measurement equipment that can be used in the magnetic field of the MRI. This study describes the investigation of the influence of the 1.5 T magnetic field from an MRI linac on the STARCHECKMAXI MR, a large 2D ionization chamber detector panel. Measurements were performed on an MRI linac and a conventional linac to investigate the behaviour of the detector panel with and without the 1.5 T magnetic field. We measured reproducibility, linearity, warm-up effect, saturation/recombination and chamber orientation. A comparison with gafchromic film was performed and the effect of motion of the panel during measurements inside a magnetic field was investigated. The reproducibility, linearity, warm-up effect, saturation/recombination show no significant deviations with or without magnetic field. An absolute difference in reading of 2.1% was found between off-axis chambers on different axes. The comparison with film shows good agreement. Spurious readings are induced while the panel is undergoing a motion in the magnetic field during measurements. The STARCHECKMAXI MR is suited for use in a 1.5 T MRI linac. Care must be taken when comparing un-normalized profiles from different axes of the detector panel and when the panel is undergoing motion during measurements. PMID- 30412477 TI - Temporal separation of Cerenkov radiation and scintillation using a clinical LINAC and artificial intelligence. AB - Convolutional neural network (CNN) type artificial intelligences were trained to estimate the Cerenkov radiation present in the temporal response of a LINAC irradiated scintillator-fiber optic dosimeter. The CNN estimate of Cerenkov radiation is subtracted from the combined scintillation and Cerenkov radiation temporal response of the irradiated scintillator-fiber optic dosimeter, giving the sole scintillation signal, which is proportional to the scintillator dose. The CNN measured scintillator dose was compared to the background subtraction measured scintillator dose and ionisation chamber measured dose. The dose discrepancy of the CNN measured dose was on average 1.4% with respect to the ionisation chamber measured dose, matching the 1.4% average dose discrepancy of the background subtraction measured dose with respect to the ionisation chamber measured dose. The developed CNNs had an average time of 3 ms to calculate scintillator dose, permitting the CNNs presented to be applicable for dosimetry in real time. PMID- 30412478 TI - Effects of global postural reeducation exercise and anti-TNF treatments on disease activity, function, fatigue, mobility, sleep quality and depression in patients with active Ankylosing spondylitis: A prospective follow-up study. AB - OBJECTIVE: The purpose of this study was to investigate the effects of combination therapy with global postural reeducation exercise (GPR) and anti-TNF treatments on clinical parameters in patients with active Ankylosing spondylitis (AS). MATERIALS AND METHOD: Sixty patients with active AS were distributed into three groups. Group 1 was given anti-TNF therapy plus GPR program. Group 2 was given anti-TNF and conventional exercise therapy. Group 3 was accepted as the control group. Patients were assessed according to pain, disease activity (Bath Ankylosing Spondylitis Disease Activity Index), functionality (Bath Ankylosing Spondylitis Functional Index and walking performance), mobility (lumbar Schober, chest expansion, hand-finger to floor distance), fatigue (Multidimensional Assessment Questionnaire), sleep quality (Pittsburgh sleep quality index), and depression. RESULTS: The parameters were significantly improved in both groups receiving exercise and anti-TNF therapy compared to the control group after treatment. The anti-TNF plus GPR exercise therapy resulted in greater improvements than the anti-TNF plus conventional exercise therapy in pain, walking performance, and mobility. CONCLUSIONS: Anti-TNF therapy and exercise were efficient in both groups on improving all clinic parameters. However, the improvements in pain, function, and mobility were greater in the active AS patients with GPR exercise method. Therefore, motivated patients should be encouraged to perform this method. PMID- 30412479 TI - Ultrasound therapy: Dose-dependent effects in LBP treatment. AB - BACKGROUND: Low back pain (LBP) affects most people at least once in their lives. OBJECTIVE: To evaluate the efficacy of ultrasound therapy (UD) in patients with LBP receiving two different treatment dosages. METHODS: The study design was a randomized prospective study. Patients were subjected to UD for two weeks. All persons in the study were evaluated at the Outpatient Rehabilitation Clinic at the Antoni Jurasz University Hospital in Bydgoszcz, Poland. Inclusion criteria were lumbosacral pain lasting more than 8 weeks, signs of osteoarthritis on imaging studies, and ages30-65 years. Exclusion criteria were radicular pain, nonmechanical causes of pain, contraindications for UD, or the patient received other LBP therapy during the study. The Oswestry Disability Index (ODI), Roland Morris Disability Questionnaire (RM), and Visual Analog Scale (VAS) were used to evaluate the results. RESULTS: For both groups, the ODI scores were significantly reduced by 13.7% and 8.84%, the RM scores decreased by 3.37 points and 3.59 points, and pain remissions on the VAS scale were 20.28 mm and 16.31 mm (p< 0.05). CONCLUSION: UD decreased patients' disability levels and pain intensity. However, effective ultrasound parameters must be determined because of the wide dosage variations. PMID- 30412480 TI - Generalized hypermobility syndrome (GHS) alters dynamic plantar pressure characteristics. AB - BACKGROUND: In the relevant literature generalized hypermobility syndrome (GHS) has been shown to alter the kinetic and kinematic patterns of the human movement system. Although GHS affects the general body biomechanics of individuals, the body of knowledge in plantar pressure distribution in GHS is far from sufficient. PURPOSE: The aim of this study was to determine whether individuals with joint hypermobility syndrome have abnormal plantar pressure distribution during normal gait compared to healthy individuals. METHODS: A total of 37 participants (mean age: 22.16 +/- 2.58 years) diagnosed with GHS and 37 aged-matched participants (mean age: 23.35 +/- 2.85 years) without GHS were included in the study. Dynamic plantar pressure distribution was obtained as each participant walked in barefoot at a self-selected pace over EMED-m system (Novel GmbH, Munich, Germany). Correlations between hypermobility score (HS) (Beighton score) and plantar pressure variables, and between group differences in peak pressure (PP), pressure time integral (PTI), average pressure (AP) and maximum force (MxF) were computed for 10 regions under the sole. RESULTS: HS was significantly correlated with peak pressure under the mid-foot (MF) (r= 0.24, p= 0.043), 5th metatarsal head (MH5) (r= 0.33, p= 0.001), big toe (BT) (r= 0.44, p< 0.001), and second toe (ST) (r= 0.38, p= 0.001). A similar trend was observed for pressure-time integrals under hindfoot (HF) (r= 0.24, p= 0.04), MF (r= 0.30, p= 0.009), MH5 (r= 0.25, p= 0.033), BT (r= 0.37, p= 0.001) and ST (r= 0.34, p= 0.003). The only significant MxF detected was under the ST (r= 0.23, p= 0.048), and AP was determined to be significantly higher as HS increases indicated by APs under MH5 (r= 0.24, p= 0.042), BT (r= 0.32, p= 0.005) and ST (r= 0.40, p< 0.001).Peak pressure values under HF were significantly higher in the hypermobile group (p= 0.023), MH5 (p= 0.001), BT (p< 0.001) and ST (p= 0.003). AP and PTI were also found to be significantly higher in the hypermobile group under MH5 (p= 0.009), BT (p= 0.037), and ST (p= 0.003). MxF was higher only under MF5 (p= 0.029) and SF (p= 0.041) in the hypermobile group. CONCLUSION: The forefoot regions received a higher load in GHS during gait. This could be useful in clinical evaluation of the foot in GHS, preventing potential injuries of lower extremity, and also in processes related to decision making for foot orthotics and/or rehabilitation protocols. PMID- 30412481 TI - Effect of "Mannitol plus Vitamins B" in the management of patients with piriformis syndrome. AB - BACKGROUND: Piriformis syndrome (PS) is an entrapment of the sciatic nerve by the piriformis muscle, or myofascial pain from the piriformis muscle. OBJECTIVE: The aim of this study was to investigate the effectiveness of "Mannitol plus Vitamins B" regime in the management of PS. METHODS: Twenty two patients were included in this study and received 250 ml of mannitol 20% intravenous infusion for 5 days + Vitamins B (vitamin B1 10 mg + vitamin B2 10 mg + vitamin B12 50 MUg PO) for 6 weeks. Clinical outcomes were assessed systematically by clinical tests (tenderness, FAIR test, Beatty's, Freiberg's and Pace's maneuver), Numeric Rating Scale (NRS), Likert Analogue Scale (LAS), and MR examination. RESULTS: The clinical evaluations showed a significant reduction (p< 0.05) of tenderness, FAIR test, Beatty's maneuver, Freiberg's maneuver and Pace's maneuver when compared with baseline evaluation during the 3rd and 6th month follow-ups. A statistically significant improvement of pain was measured by NRS at resting (p< 0.001), at night (p< 0.001) and during activities (p< 0.001) and LAS with prolonged sitting (p< 0.001), standing (p< 0.001) and lying (p< 0.001). Concomitantly, swelling of SN revealed a significant reduction (p= 0.003) from 86.4% to 18.2%. CONCLUSIONS: Mannitol plus Vitamins B is effective in the management of piriformis syndrome and it could be an alternative regime in treating PS. PMID- 30412482 TI - Visual and instrumental diagnostics using chromokinegraphics: Reliability and validity for low back pain stratification. AB - BACKGROUND: Low back pain patients have been suggested to exhibit dysfunctional spinal movement patterns. However, there is a lack of clinically applicable but valid and reliable assessment tools, helping to discriminate normal and pathologically altered movement. OBJECTIVE: We aimed to examine whether kinematic parameters determined with an ultrasound-based motion analysis and thereof derived chromokinegraphical angle-time matrices (CATMAs) are able to discriminate between non-symptomatic and symptomatic movement behaviour in individuals with non-specific chronic (CLBP), specific low back pain (SLBP), and controls. METHODS: Thoracic and lumbar spine range of motion (ROM [?]); angular velocity (V [?/sec]) and side-to-side differences [%] during a lateral flexion movement were assessed in 17 healthy participants, 16 individuals with CLBP and 11 SLBP patients. CATMAs ratings of two investigators (6-item Likert scale) were dichotomised, classifying the observed movement as physiological or non physiological. Intrarater and interrater reliability were estimated using kappa statistics and Cronbach's Alpha. T-tests and a ROC analysis to determine optimal cut-offs for the separation of the collectives as well as contingency tables for selectivity of the cut-offs (motor outcomes) were calculated. RESULTS: CATMA ratings displayed partly moderate to good (rater B; i.e. CLBP vs. controls) and partly insufficient discriminant validity (rater A). Due to this, inter-rater reliability was poor (k= 0.061 to 0.135), while intra-rater-reliability was moderate to good for both raters (k= 0.329 to 0.625) except for SLBP vs. controls (rater A; k=-0.18). Regarding kinematics, group differences occurred neither in ROM nor in V (p> 0.05), but in the relative side comparison between CLBP and controls (p<0.05). ROC analysis (CLBP vs. controls) revealed an optimal cut-off at side asymmetries of 16.9% (ROM) and 28.9% (V). Between SLBP patients and controls, no significant differences were observed neither in terms of the absolute values nor the relative side differences of both kinematic variables. CONCLUSIONS: Side asymmetries of V and ROM might be used to differentiate between controls and individuals with CLBP. CATMAs appear to be of limited diagnostic value for the identification of pathological spine movement. PMID- 30412483 TI - Analysis of STAT1, STAT2 and STAT3 mRNA expression levels in the blood of patients with multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is the most common chronic, inflammatory, autoimmune disease of the central nervous system (CNS) maintained by the secretion of a large number of cytokines [1]. The signal transducer and activator of transcription (STAT) family has an essential role in transmitting many of the cytokine-mediated signals and failure in the signaling process contributes to the etiopathogenesis of MS. METHODS: This study aimed to assess STAT1, STAT2 and STAT3 gene expression in the blood of 50 relapsing-remitting MS (RR-MS) patients and 50 healthy controls by TaqMan Quantitative Real-Time PCR. RESULTS: The results showed that STAT1 gene expression was significantly up-regulated (p= 0.023), whereas STAT2 gene expression was significantly down-regulated (p< 0.0001) in MS patients compared to controls. On the other hand, there was no significant difference between MS patients and controls for STAT3 gene expression (p= 0.837). In addition, there was no significant correlation between the expression of STAT1, STAT2, STAT3 genes and clinical findings, such as the level of physical disability in MS patients (according to the Kurtzke Expanded Disability Status Scale (EDSS) criterion) and disease duration. CONCLUSION: A significant positive correlation was demonstrated between STAT1 and STAT2 and also between STAT1 and STAT3. This study shows for the first time that a comparison of the relative quantitative expression of three different STAT genes in the blood cells of MS patients compared to controls revealed marked differences in the expression of the STAT family genes that might reflect their different roles in the pathogenesis of MS. These transcripts might be useful biomarkers for evaluating the efficacy of IFN treatment of the MS patients. PMID- 30412485 TI - Subjective Cognitive Decline Is Associated with Greater White Matter Hyperintensity Volume. AB - BACKGROUND: Research in older adults with subjective cognitive decline (SCD) has mainly focused on Alzheimer's disease (AD)-related MRI markers, such as hippocampal volume. However, small vessel disease (SVD) is currently established as serious comorbidity in dementia and its preliminary stages. It is therefore important to examine SVD markers in addition to AD markers in older adults presenting with SCD. OBJECTIVE: The aim of our study was to elucidate the role of SVD markers in late middle-aged to older adults with and without SCD in addition to the commonly found role of AD markers (hippocampal volume). METHODS: 67 healthy late middle-aged to older adults participated in this study (mean age 68 years); 25 participants with SCD and 42 participants without SCD. We evaluated quantitative as well as qualitative AD markers (i.e., hippocampal volume and medial temporal lobe atrophy (MTA) scale) and SVD markers (i.e., white matter hyperintensities (WMH) volume, Fazekas scale, microbleeds, and lacunar infarcts), and neuropsychological function and amount of memory complaints. RESULTS: We found a significant effect of SCD on hippocampal atrophy, as assessed using the MTA scale, but not on hippocampal volume. In addition, we found a significant effect of SCD, and amount of memory complaints, on WMH volume and Fazekas score, suggesting larger WMH volumes in participants with SCD. CONCLUSION: SVD MRI markers are related to amount of memory complaints, in addition to the commonly observed AD MRI markers, as demonstrated by the greater WMHs in healthy late middle-aged to older adults with SCD. PMID- 30412484 TI - The Association Between Body Mass Index, and Cognitive, Functional, and Behavioral Declines for Incident Dementia. AB - BACKGROUND: Association between high adiposity and the clinical progression of dementia remains puzzling. OBJECTIVE: To separately examine the association between body mass index (BMI) and cognitive, functional, and behavioral declines before, at, and after diagnosis of dementia, and further stratified by age groups, and sex. METHODS: A total of 1,141 individuals with incident dementia were identified from the Uniform Data Set of the National Alzheimer's Coordinating Center. Cognitive function was evaluated by Mini-Mental State Exam, functional abilities were assessed using Functional Activities Questionnaire, and behavioral symptoms were captured by Neuropsychiatric Inventory Questionnaire at each follow-up visit. We used separate linear-mixed effects models to examine the association. RESULTS: Compared to moderate baseline BMI, high baseline BMI was associated with 0.30-point slower annual progression rates in functional decline. For individuals aged 76 and over, high baseline BMI was associated with 0.42 point faster progression rates in cognitive decline annually. A U-shaped association between baseline BMI and cognitive decline was observed among men. CONCLUSION: BMI levels before dementia diagnosis may facilitate the identification of different risk profiles for progression rates of cognitive and functional declines in individuals who developed dementia. PMID- 30412486 TI - A Systematic Review and Meta-Analysis on the Prevalence of Dementia in Europe: Estimates from the Highest-Quality Studies Adopting the DSM IV Diagnostic Criteria. AB - BACKGROUND: Dementia, including Alzheimer's disease (AD), is one of the most burdensome medical conditions. Usually, the reviews that aim at calculating the prevalence of dementia include estimates from studies without assessing their methodological quality. Alzheimer's Disease International (ADI) proposed a score to assess the methodological quality of population-based studies aimed at estimating the prevalence of dementia. During the last three years, the European Commission has funded three projects (Eurodem, EuroCoDe, and ALCOVE) in order to estimate the prevalence of dementia in Europe. OBJECTIVE: The aim of this study was to perform a systematic review and meta-analysis of data on the prevalence of dementia in Europe derived from studies that included only subjects with a diagnosis of dementia according to the DSM IV criteria, and that had a high quality score according to ADI criteria. METHODS: We considered the studies selected by the two projects EuroCoDe (1993-2007) and Alcove (2008-2011), and we performed a new bibliographic search. For the systematic review, we only selected the subset of articles that included subjects with a diagnosis of dementia according to the DSM IV criteria. The studies were qualitatively assessed using the ADI tool. RESULTS: The meta-analysis considered 9 studies that were carried out in Europe between 1993 and 2018 including a total of 18,263 participants, of which 2,137 were diagnosed with dementia. The prevalence rate standardized for age and sex resulted 7.1%. DISCUSSION: This is the first systematic review on the prevalence of dementia in Europe considering only high-quality studies adopting the same diagnostic criteria (i.e., DSM IV). PMID- 30412487 TI - Intracellular Targeting of Heat Shock Proteins in Differentiated Human Neuronal Cells Following Proteotoxic Stress. AB - HSPA6 (Hsp70B') is an inducible member of the Hsp70 (HSPA) family of heat shock proteins that is present in the human genome and not found in mouse and rat. Hence it is lacking in current animal models of neurodegenerative diseases. To advance knowledge of the little studied HSPA6, differentiated human neuronal SH SY5Y cells were treated with the proteotoxic stress-inducing agent MG132. A robust induction of HSPA6 was apparent which localized to the periphery of MG132 induced protein aggregates in the neuronal cytoplasm. Components of the protein disaggregation/refolding machine that co-operate with Hsp70 also targeted the periphery of cytoplasmic protein aggregates, including DNAJB1 (Hsp40-1), HSPH1 (Hsp105alpha), and HSPB1 (Hsp27). These data suggest that HSPA6 is involved in the response of human neuronal cells to proteotoxic stress that is a feature of neurodegenerative diseases which have been characterized as protein misfolding disorders. Constitutively expressed HSPA8 (Hsc70) also localized tothe periphery of cytoplasmic protein aggregates following the treatment of differentiated human neuronal cells with MG132. HSPA8 could provide a rapid response to proteotoxic stress in neuronal cells, circumventing the time required to upregulate inducible Hsps. PMID- 30412489 TI - Epitomic Characterization of the Specificity of the Anti-Amyloid Abeta Monoclonal Antibodies 6E10 and 4G8. AB - The monoclonal antibodies 6E10 and 4G8 are among the first anti-amyloid monoclonal antibodies against Abeta and the most widely used antibodies in Alzheimer's disease research. Although the epitopes for 6E10 and 4G8 have been reported to correspond to residues 1-16 and 17-24, a more recent high-resolution mapping approach indicates that 6E10 maps to residues 4-10 while 4G8 maps to residues 18-23. To characterize the binding specificity of both antibodies in greater detail, we used immunoselection of random sequences from phage display library followed by deep sequencing and analysis of resulting patterns from thousands of immunoselected sequences. We found that the minimum sequence required for 6E10 binding is R-x-D with over half (53%) of the immunoselected sequences conforming to this pattern. The vast majority of these sequences contain an H at position x (R-H-D), corresponding to residues 5-7 of the Abeta target sequences, but Y is also permitted at this position in a minority of sequences. For 4G8 we found that the most frequent pattern is F-x-A contained in approximately 30% of the sequences, followed by F-A, L-x(3)-A, L-x-F, and F-F each accounting for approximately 18% of the sequences. The F-x-A motif also occurs in islet amyloid poly peptide which may explain why 4G8 also recognizes amyloid fibrils of this peptide. Immunoselection of random sequences and deep sequencing may also be a facile and efficient means of determining residues critical for antibody binding and validating the specificity of monoclonal antibodies and polyclonal antisera. PMID- 30412488 TI - Default Mode Network Lateralization and Memory in Healthy Aging and Alzheimer's Disease. AB - Lateralization of default mode network (DMN) functioning has been shown to change with age. Similarly, lateralization of frontal lobe function has been shown to decline in age. The impact of amyloid pathology and the progression of Alzheimer's disease (AD) on resting state lateralization has not been investigated. Due to the preferential involvement of the left hemisphere in verbal tasks, there may be a benefit to higher levels of left-lateralization in the performance of verbal memory tasks. Here we compared functional lateralization of the anterior and posterior DMN between four groups of participants: amyloid negative (Abeta-) and amyloid positive (Abeta+) groups with normal cognition (NC), and Abeta+ groups with mild cognitive impairment (Abeta+MCI) or dementia (Abeta+AD). Differences were evident between groups in posterior DMN; the Abeta-NC group was more left-lateralized than both cognitively impaired Abeta+ groups. There was no difference in anterior DMN. No differences in overall network connectivity between groups were observed, suggesting that the functional lateralization finding is not secondary to general changes in connectivity. Left-lateralization of both networks was associated with better verbal recall performance. Older subjects, overall, had less left functional lateralization of the anterior DMN. PMID- 30412490 TI - Aging-Related Calcium Dysregulation in Rat Entorhinal Neurons Homologous with the Human Entorhinal Neurons in which Alzheimer's Disease Neurofibrillary Tangles First Appear. AB - Aging is the leading risk factor for idiopathic Alzheimer's disease (AD), indicating that normal aging processes promote AD and likely are present in the neurons in which AD pathogenesis originates. In AD, neurofibrillary tangles (NFTs) appear first in entorhinal cortex, implying that aging processes in entorhinal neurons promote NFT pathogenesis. Using electrophysiology and immunohistochemistry, we find pronounced aging-related Ca2 + dysregulation in rat entorhinal neurons homologous with the human neurons in which NFTs originate. Considering that humans recapitulate many aspects of animal brain aging, these results support the hypothesis that aging-related Ca2 + dysregulation occurs in human entorhinal neurons and promotes NFT pathogenesis. PMID- 30412491 TI - Severe Agitation in Dementia: An Explorative Secondary Data Analysis on the Prevalence and Associated Factors in Nursing Home Residents. AB - BACKGROUND: The phenomena of severe agitation is not well understood and often not adequately treated. OBJECTIVE: This article determines the prevalence and associated factors of severe agitation in nursing home residents with dementia. METHODS: Secondary data analysis within an observational study in German nursing homes with n = 1,967 participants. We assessed severity of agitation with the Neuropsychiatric Inventory Questionnaire (NPI-Q) and defined the construct of agitation as a composite score of the NPI-Q items agitation/aggression, disinhibition, and irritability/lability; the dependent variable of severe agitation was considered as being present in residents who scored 'severe' in at least one of these symptoms. A binary logistic regression model was calculated to estimate associations. RESULTS: The prevalence of severe agitation was 6.3% (n = 124). The strongest associations were found for elation/euphoria (OR 7.6, CI 3.1 18.5), delusions (OR 7.3, CI 4.0-13.2), apathy/indifference (OR 2.8, CI 1.7-4.7), anxiety (OR 2.2, CI 1.2-3.8), nighttime behaviors (OR 2.4, CI 1.4-4.2), motor disturbances (OR 2.4, CI 1.4-4.1), and male sex (OR 2.4. CI 1.3-4.2). CONCLUSION: Severe agitation in nursing home residents with dementia is a relevant clinical issue as approximately 70% of residents have a dementia. Residents with elation/euphoria and delusions may have a stronger risk of showing severe agitation. We consider delusions as a possible cause of agitation and therefore a prelude to agitation. Although it might be possible that elation/euphoria follows from agitation, we hypothesize that the residents first experience elation/ euphoria and exhibit agitation afterwards. PMID- 30412492 TI - A Review of the Familial Alzheimer's Disease Locus PRESENILIN 2 and Its Relationship to PRESENILIN 1. AB - RESENILIN 1 (PSEN1) and PRESENILIN 2 (PSEN2) genes are loci for mutations causing familial Alzheimer's disease (fAD). However, the function of these genes and how they contribute to fAD pathogenesis has not been fully determined. This review provides a summary of the overlapping and independent functions of the PRESENILINS with a focus on the lesser studied PSEN2. As a core component of the gamma-secretase complex, the PSEN2 protein is involved in many gamma-secretase related physiological activities, including innate immunity, Notch signaling, autophagy, and mitochondrial function. These physiological activities have all been associated with AD progression, indicating that PSEN2 plays a particular role in AD pathogenesis. PMID- 30412493 TI - Clinical Evaluation of Amyloid-Related Imaging Abnormalities in Bapineuzumab Phase III Studies. AB - BACKGROUND: Amyloid-related imaging abnormalities with effusion or edema (ARIA-E) reported in patients with mild-to-moderate Alzheimer's disease in bapineuzumab phase III studies. OBJECTIVES: Assess symptoms, clinical severity, and ARIA-E outcomes, and to evaluate effects on cognition and function. METHODS: A centralized systematic sequential locked procedure and scoring system for assessment of magnetic resonance imaging scans in 1,331 APOE E4 noncarriers and 1,121 carriers was conducted by experienced and trained pairs of neuroradiologists. RESULTS: Treatment-emergent ARIA-E occurred in 15.8% of bapineuzumab and 0.8% placebo-treated patients. In all treated APOE E4 noncarriers, the percentage of patients with ARIA-E was 5.6%, 13.4%, and 19.9% in the 0.5, 1.0, and 2.0 mg/kg groups respectively, and the incidence of symptomatic ARIA-E was 1.5%, 1.5%, and 7.8%, respectively. In carriers, ARIA-E occurred in 21.2% in the 0.5 mg/kg group, and symptomatic ARIA-E occurred in 2.4%. The clinical severity of ARIA-E in those patients in whom it was detected during the study was mild in 57.1%, 61.3%, and 50.0% of cases in 0.5, 1.0, and 2.0 mg/kg noncarriers respectively, and in 73.8% of cases in 0.5 mg/kg carriers. Vascular risk factors did not appear to increase susceptibility to ARIA-E. Rate of decline in cognition and function measured by changes in ADAS-Cog/11 and DAD total scores did not meaningfully differ in patients with ARIA-E versus those without ARIA-E. Extent of cognitive decline was similar over all visit intervals. CONCLUSIONS: Overall, ARIA-E was mild and asymptomatic. ARIA-E did not demonstrate clinically meaningful acute or chronic impact on cognition or function.Registration: NCT00574132 (Bapineuzumab-301), NCT00575055 (Bapineuzumab-302). PMID- 30412494 TI - Neuropsychiatric Symptoms Complicating the Diagnosis of Alzheimer's Disease: A Case Report. AB - Neuropsychiatric symptoms (NPS) are increasingly recognized as a core element of Alzheimer's disease (AD); however, clinicians still consider AD primarily as a cognitive disorder. We describe a case in which the under-recognition of NPS as part of AD resulted in substantial delay of an AD diagnosis, a wrong psychiatric diagnosis, and the organization of inappropriate care. The aim of this paper is to acknowledge NPS as an (early) manifestation of AD and to suggest features that may point toward underlying AD in older adults with late-life behavioral changes. PMID- 30412495 TI - Utility of an Alzheimer's Disease Risk-Weighted Polygenic Risk Score for Predicting Rates of Cognitive Decline in Preclinical Alzheimer's Disease: A Prospective Longitudinal Study. AB - BACKGROUND: With the exception of APOE, genetic variants associated with increased Alzheimer's disease (AD) risk are characterized by small effect sizes. Polygenic risk scores (PRS) have shown utility in predicting AD risk; however, their utility for predicting decline in cognition at preclinical stages of AD is poorly understood. OBJECTIVE: To validate associations of a 22-variant AD-risk weighted PRS with AD risk and related biomarkers and to assess its utility to predict cognitive decline. METHODS: The PRS was evaluated with respect to brain amyloid-beta (Abeta) burden, cerebrospinal fluid (CSF) Abeta42, total-tau, and phospho-tau, and decline in cognition in 643 (570 cognitively normal (CN), 73 AD) PET-imaged participants from the longitudinal Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. Cognition was assessed using three composite measures; global cognition, verbal episodic memory, and a Pre-Alzheimer's Cognitive Composite (PACC). RESULTS: PRS, both with and without APOE, were positively correlated with brain Abeta burden, CSF total-tau, and phospho-tau in CN older adults. Further, in CN biomarker positive (Abetahigh) participants, significant associations were observed with baseline and longitudinal cognition. However, this association was not observed after the removal of APOE. Partitioning the PRS into quartiles revealed that the PRS associations with cognitive decline in Abetahigh CN older adults is due to a saturating effect of APOE genotype. CONCLUSIONS: An AD-risk-weighted PRS is associated with cognitive decline in CN older adults. However, this association is absent when APOE genotype is excluded from the PRS, suggesting that associations with cognitive decline in this model of polygenic risk are driven by APOE genotype alone. Further research is needed to define appropriate PRSs with greater utility for predicting preclinical AD cognitive decline. PMID- 30412496 TI - New Insights into the Spontaneous Human Alzheimer's Disease-Like Model Octodon degus: Unraveling Amyloid-beta Peptide Aggregation and Age-Related Amyloid Pathology. AB - Alzheimer's disease (AD) is the most common cause of dementia worldwide. Despite advances in our understanding of the molecular milieu driving AD pathophysiology, no effective therapy is currently available. Moreover, various clinical trials have continued to fail, suggesting that our approach to AD must be revised. Accordingly, the development and validation of new models are highly desirable. Over the last decade, we have been working with Octodon degus (degu), a Chilean rodent, which spontaneously develops AD-like neuropathology, including increased amyloid-beta (Abeta) aggregates, tau hyperphosphorylation, and postsynaptic dysfunction. However, for proper validation of degu as an AD model, the aggregation properties of its Abeta peptide must be analyzed. Thus, in this study, we examined the capacity of the degu Abeta peptide to aggregate in vitro. Then, we analyzed the age-dependent variation in soluble Abeta levels in the hippocampus and cortex of third- to fifth-generation captive-born degu. We also assessed the appearance and spatial distribution of amyloid plaques in O. degus and compared them with the plaques in two AD transgenic mouse models. In agreement with our previous studies, degu Abeta was able to aggregate, forming fibrillar species in vitro. Furthermore, amyloid plaques appeared in the anterior brain structures of O. degus at approximately 32 months of age and in the whole brain at 56 months, along with concomitant increases in Abeta levels and the Abeta42/Abeta40 ratio, indicating that O. degus spontaneously develops AD-like pathology earlier than other spontaneous models. Based on these results, we can confirm that O. degus constitutes a valuable model to improve AD research. PMID- 30412497 TI - Genetic Interaction with Plasma Lipids on Alzheimer's Disease in the Framingham Heart Study. AB - Epidemiological and genetic studies have pointed to the role of cholesterol in Alzheimer's disease (AD). We explored the interaction of a genetic risk score (GRS) of AD risk alleles with mid-life plasma lipid levels (LDL-C, HDL-C, and triglycerides) on risk for AD in the Framingham Heart Study (FHS). Mid-life (between the ages of 40-60 years old) lipid levels were obtained from individuals in the FHS Original and Offspring cohorts (157 cases and 2,882 controls) with genetic data and AD status available. Cox proportional hazards regression was performed to test the interaction between mid-life lipid levels and an AD GRS, as well as the individual contributing SNPs, on risk of incident AD adjusting for age, sex, and cohort. We found a significant interaction between a GRS of AD loci and log triglyceride levels on risk of clinical AD (p = 0.006), but no interaction of the GRS with HDL-C (p = 0.458) or LDL-C (p = 0.366). We then tested the interaction between the individual SNPs contributing to the GRS and log triglycerides. We found two SNPs that had interactions with triglycerides on AD risk that reached a p-value < 0.05 (rs11218343 and APOEE4). The association between some AD SNPs and risk of AD may be modified by triglyceride levels. Furthermore, sequential testing of a GRS with a set of traits on disease followed by testing individual SNPs for interaction provides a framework for narrowing the associations that need to be tested for interaction analyses. Replication is needed to confirm these findings. PMID- 30412498 TI - Evaluation of Matrix Metalloproteinase-2 (MMP-2) and -9 (MMP-9) and Their Tissue Inhibitors (TIMP-1 and TIMP-2) in Plasma from Patients with Neurodegenerative Dementia. AB - Matrix metalloproteinases (MMPs) are substantial regulators of learning and memory and might be involved in neurodegeneration. It is known that MMPs are involved in pathogenesis of Alzheimer's disease (AD) and are particularly involved in the amyloid-beta processing pathway. However, information on circulating levels of these proteins and their tissue inhibitors (TIMPs) in AD and other neurodegenerative dementia (ND) diseases such as dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) is not clear. Therefore, this study was directed toward finding out how plasma levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 vary in AD, DLB, and FTD; and investigating the correlation of the levels of MMPs and their inhibitors with clinical parameters of the patients. MMP 2, MMP-9, TIMP-1, and TIMP-2 levels were measured by enzyme linked immunosorbent assay (ELISA). Plasma MMP-2 levels were significantly lower in all the patient groups than in the age-matched healthy controls (HCs) (p < 0.05). MMP-9 levels were significantly lower in the FTD patients than in the HCs (p < 0.05). Also, TIMP-1 levels were lower in the AD and FTD patients than in the HCs (p < 0.05). TIMP-2 levels were similar in all the groups. These findings highlight the importance of circulating MMPs in ND and suggest that MMPs and their inhibitors might play a role in impaired amyloid-beta peptide metabolism which is responsible for the genesis and progression of ND. Furthermore, measurement of MMP-2 and MMP-9 and their inhibitors may be of great importance for large scale basic research and clinical studies of ND. PMID- 30412499 TI - Cognitive Impairment is Associated with Mortality in Hemodialysis Patients. AB - BACKGROUND: The prevalence of cognitive impairment in hemodialysis patients is notably high. In previous studises performed in the general population, cognitive impairment has been associated with increased mortality. OBJECTIVE: We evaluated the relationship between global cognitive function tested by a short screening instrument and mortality in hemodialysis patients. METHODS: Cognitive testing was performed in 242 maintenance hemodialysis patients under standardized conditions at baseline using the Montreal Cognitive Assessment (MoCA).Cognitive impairment was defined as a MoCA test score <=24 points, as published previously. All-cause mortality was monitored during a median follow-up of 3.54 years. Kaplan-Meier plot and Cox regression model adjusted for known risk factors for mortality in hemodialysis patients were used to examine a possible association between global cognitive function and all-cause mortality. RESULTS: A MoCA test score <=24 points resulted in a significant almost 3-fold higher hazard for all-cause mortality (unadjusted hazard ratio [HR]: 2.812; 95% confidence interval [95% CI]: 1.683-4.698; p < 0.001). After adjustment, this association was attenuated but remained significant (adjusted HR: 1.749; 95% CI: 1.007-3.038; p = 0.047). CONCLUSION: Impairment of global cognitive function measured by a short screening instrument was identified for the first time as an independent predictor of all cause mortality in hemodialysis patients. Thus, implementing the MoCA test in clinical routine could contribute to a better risk stratification of this patient population. PMID- 30412500 TI - Analysis of Brain Donors' Demographic and Medical Characteristics to Facilitate the Construction of a Human Brain Bank in China. AB - The Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS/PUMC) Human Brain Bank was established in December 2012 and had accomplished 197 brain donations by November 2017. The brain bank was based on a large-scale willed body donation program in CAMS/PUMC starting from 1999. Demographic and medical characteristic analysis of brain donors was conducted to facilitate the construction of the brain bank. The average postmortem delay of brain donors was 17.7 h and 77.7% of these donors died less than 15 km away from the brain bank. Donors were predominantly with higher-level education (p < 0.001) and at an older age when registration (p < 0.001) and donation (p < 0.001) occurred. Our results elucidated the characteristics of donors in the CAMS/PUMC Human Brain Bank, which may provide useful information to target potential donors and improve the quality and quantity of brain specimens. The current study may pave the way for the construction of a nationwide network of standardized human brain banks in China. PMID- 30412501 TI - Clinical-Neuropathological Correlations of Alzheimer's Disease and Related Dementias in Latino Volunteers. AB - Clinical, neuropsychological, and neurological procedures used to diagnose Alzheimer's disease (AD) and related dementias were largely developed and validated in well-educated, non-Latino, English-speaking populations. Sociocultural and genetic differences in Latinos might influence the accuracy of clinical diagnosis of AD and other dementias. We aim to compare the accuracy of the clinical diagnosis of AD and related dementias in Latinos with the corresponding neuropathological diagnosis. From the UCSD Alzheimer's Disease Research Center longitudinal cohort, we selected all Latino participants who had autopsy neuropathological studies from 1991 to 2017. Participants underwent annual neurological clinical evaluations, standard neuropsychological tests, neuroimaging, and genotyping of the Apolipoprotein E. We calculated the sensitivity and specificity for the clinical diagnosis of AD against the primary pathological diagnosis. From the 34 participants with a primary neuropathological diagnosis of AD, 33 (97.1%) were correctly clinically diagnosed as having AD at the last clinical evaluation, and 1 was incorrectly diagnosed with dementia with Lewy bodies. Of the 19 participants without a primary neuropathological diagnosis of AD, 8 were incorrectly clinically diagnosed with probable AD at the last clinic evaluation. The clinical diagnosis of AD at the last clinical evaluation had 97.1% sensitivity and 57.9% specificity against autopsy-verified AD. In this Latino cohort, clinicians predicted AD pathological findings with high sensitivity but moderate specificity. Tangle-only dementia was the most common misdiagnosis. Our study suggests that current procedures and instruments to clinically determine AD in Latinos have high sensitivity compared with neuropathology, but specificity needs to be improved. PMID- 30412502 TI - Patterns of Physical Activity and Sedentary Behavior for Older Adults with Alzheimer's Disease, Mild Cognitive Impairment, and Cognitively Normal in Hong Kong. AB - BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia, and mild cognitive impairment (MCI) is a transitional phase between healthy cognition and dementia. Physical activity (PA) has protective effects on cognitive decline. However, few studies have examined how PA and sedentary behavior is structured throughout the day in older adults across varied cognitive status in Hong Kong. OBJECTIVE: This study aimed to compare patterns of PA and sedentary behavior among individuals with AD, MCI, or normal cognition living in Hong Kong. METHODS: Participants in the MrOs and MsOs Hong Kong cohort study and the Hong Kong AD biomarker study (n = 810) wore a wrist-worn accelerometer for 7 days in free living environment. Patterns of PA in wake time and in-bed time, and detailed analysis of sedentary bouts were compared between groups using analysis of covariance adjusting for covariates. RESULTS: Participants with MCI and low MoCA only did not differ from their cognitively normal peers in PA and sedentary behavior. Nevertheless, when comparing to the others, participants with AD exhibited significantly lower average daily counts per minute during the day (p < 0.05), and tended to start their activity later in the morning. AD participants spent a larger proportion of time in sedentary behavior (p < 0.05) and had more sedentary bouts>=30 minutes (p < 0.05). CONCLUSIONS: The pattern of PA and sedentary behavior was different between individuals with AD and the others. Cognitive status may alter the purpose and type of PA intervention for AD individuals. PMID- 30412504 TI - Abeta42/Abeta40 Ratios of Presenilin 1 Mutations Correlate with Clinical Onset of Alzheimer's Disease. AB - Missense mutations in presenilin 1 cause early onset familial Alzheimer's disease in a way that is not understood. Increased Abeta42/Abeta40 ratios are the most consistent biochemical phenotype of such mutations in cultured cells and in vivo, and are thus considered central to the amyloid hypothesis. Previously, an inverse relation has been observed between the Abeta42/Abeta40 ratio of such mutants and the clinical age of symptom onset in patients carrying the mutation. However, a recent extensive study by Sun et al. of assayed presenilin 1 mutants concluded that such a relationship is not evident. To reconcile the disagreement, three different clinical datasets were compared directly with the data by Sun et al. After considering data noise and measurement uncertainty, we find a clear and highly significant inverse correlation between the Abeta42/Abeta40 ratio and the clinical age of onset in all three datasets even without removing noisy single- and double-patient data. With these data removed, the correlation coefficients increase further. The probability that these relationships are coincidental are approximately 0.1%. PMID- 30412503 TI - Cerebrovascular Disease and Neurodegeneration in Alzheimer's Disease with and without a Strong Family History: A Pilot Magnetic Resonance Imaging Study in Dominican Republic. AB - The incidence and prevalence of Alzheimer's disease (AD) dementia are higher among Caribbean Hispanics than among non-Hispanic Whites. The causes of this health disparity remain elusive, partially because of the relative limited capacity for biomedical research in the developing countries that comprise Caribbean Latin America. To begin to address this issue, we were awarded a Development Research Award from the US NIH and Fogarty International Center in order to establish the local capacity to integrate magnetic resonance imaging (MRI) into studies of cognitive aging and dementia in Dominican Republic, establish collaborations with Dominican investigators, and conduct a pilot study on the role of cerebrovascular markers in the clinical expression of AD. Ninety older adult participants with and without AD dementia and with and without a strong family history of AD dementia received MRI scans and clinical evaluation. We quantified markers of cerebrovascular disease (white matter hyperintensities [WMH], presence of infarct, and presence of microbleed) and neurodegeneration (entorhinal cortex volume) and compared them across groups. Patients with AD dementia had smaller entorhinal cortex and greater WMH volumes compared with controls, regardless of family history status. This study provides evidence for the capacity to conduct MRI studies of cognitive aging and dementia in Dominican Republic. The results are consistent with the hypothesis that small vessel cerebrovascular disease represents a core feature of AD dementia, as affected participants had elevated WMH volumes irrespective of family history status. PMID- 30412505 TI - Non-Phosphorylated Tau in Cerebrospinal Fluid is a Marker of Alzheimer's Disease Continuum in Young Urbanites Exposed to Air Pollution. AB - Long-term exposure to fine particulate matter (PM2.5) and ozone (O3) above USEPA standards is associated with Alzheimer's disease (AD) risk. Metropolitan Mexico City (MMC) children exhibit subcortical pretangles in infancy and cortical tau pre-tangles, NFTs, and amyloid phases 1-2 by the 2nd decade. Given their AD continuum, we measured in 507 normal cerebrospinal fluid (CSF) samples (MMC 354, controls 153, 12.82+/-6.73 y), a high affinity monoclonal non-phosphorylated tau antibody (non-P-Tau), as a potential biomarker of AD and axonal damage. In 81 samples, we also measured total tau (T-Tau), tau phosphorylated at threonine 181 (P-Tau), amyloid-beta1-42, BDNF, and vitamin D. We documented by electron microscopy myelinated axonal size and the pathology associated with combustion derived nanoparticles (CDNPs) in anterior cingulate cortex white matter in 6 young residents (16.25+/-3.34 y). Non-P-Tau showed a strong increase with age significantly faster among MMC versus controls (p = 0.0055). Abeta1 - 42 and BDNF concentrations were lower in MMC children (p = 0.002 and 0.03, respectively). Anterior cingulate cortex showed a significant decrease (p = <0.0001) in the average axonal size and CDNPs were associated with organelle pathology. Significant age increases in non-P-Tau support tau changes early in a population with axonal pathology and evolving AD hallmarks in the first two decades of life. Non-P-Tau is an early biomarker of axonal damage and potentially valuable to monitor progressive longitudinal changes along with AD multianalyte classical CSF markers. Neuroprotection of young urbanites with PM2.5 and CDNPs exposures ought to be a public health priority to halt the development of AD in the first two decades of life. PMID- 30412506 TI - Qualitative Evaluation of the Personal KinetiGraphTM Movement Recording System in a Parkinson's Clinic. AB - BACKGROUND: Wearable-sensors provide accurate, continuous objective measurements, quantifying the variable motor states of patients with Parkinson's disease (PD) in real time. OBJECTIVES: To evaluate the impact of using continuous objective measurement using the Personal KinetiGraphTM (PKGTM) Movement Recording System in the routine clinical care of patients with PD (PwP). METHODS: Physicians employed the use of the PKG in patients for whom they were seeking objective measurement. Patients wore a PKG data logger for >=6 days during routine daily living activities. During the survey period of December 2015 through July 2016, physician surveys were completed by four Movement Disorder Specialists for whom measurements from the PKG were available during a subsequent routine clinic visit. RESULTS: Of 112 completed physician surveys, 46 (41%) indicated the PKG provided relevant additional information sufficient to consider adjusting their therapeutic management plan; 66 (59%) indicated the PKG provided no further information to support a therapeutic decision differing from that made during a routine clinical evaluation. Upon further review of these 46 surveys, 36 surveys (78%) revealed the information provided by the PKG ultimately resulted in adjusting the patient's medical management. CONCLUSIONS: The PKG provided novel additional information beyond that captured during a routine clinic visit sufficient to change the medical management of PwP. Physicians adjusted treatment nearly a third of the time based on data provided by real-time, remote monitoring outside the clinic setting. The use of the PKG may provide for better informed therapeutic decisions, improving the quality of life for PwP. PMID- 30412507 TI - Impact of red blood cell transfusions on intestinal barrier function in preterm infants. AB - OBJECTIVE: To determine the relationships of red blood cell (RBC) transfusion and enteral feeding to changes in intestinal permeability (IP) measured by the relative intestinal uptake of lactulose (La) and rhamnose (Rh) in preterm infants <33 wk gestation. DESIGN/METHODS: Infants 240-326wk gestation received La/Rh solution enterally on study days 1, 8 and 15.Urinary La/Rh ratio was measured by HPLC. Hematocrit preceding transfusion, total RBC transfusion volume, volume/kg, and feeding status during each study interval (birth-d1; d1-d8, and d8-d15) were determined. RESULTS: Of the seventeen (40.5%) subjects who received>=1 transfusion during the study period, 12 (70.6%) infants were <28 wk gestation and 5 (29.4%) infants were>=28 wk gestation, p < 0.0001. Lower pre-transfusion hematocrit was observed in intervals preceding high IP (La/Rh > 0.05) than in intervals preceding low IP (La/Rh<=0.05) measurements (33 vs 35.8, p = 0.1051). RBC transfusions occurred more frequently in intervals preceding high IP than in intervals preceding low IP (26.8%; vs 8.3%, p = 0.0275) with 5-fold higher total RBC volume and volume/kg in intervals preceding any time point with high IP. RBC transfusion during an interval was associated with a three-fold increased risk of high IP (aOR 2.7; 95% C.I 0.564-12.814; p = 0.2143). Exclusive breast milk exposure and post-menstrual age reduced the risk for high IP following RBC transfusion. CONCLUSIONS: Both RBC transfusion number and volume was associated with subsequent high IP measurementsin preterm infants <33 weeks gestation and potentially may contribute to impairment of the preterm intestinal barrier. PMID- 30412508 TI - Immediate effect of kinesio taping on knee extensor torque of children with Cerebral Palsy: Three case reports. AB - BACKGROUND: Kinesiotaping (KT) has been commonly used in clinical setting. However, beneficial KT effects have not been proved yet. OBJECTIVE: We aimed to verify the effects of KT in knee extensor torque in children with CP. METHODS: We evaluated three children diagnosed as spastic CP, classified as level I, II and III, according with GMFCS. Knee extensor peak torque was analyzed by isokinetic evaluation (Biodex Multi Joint System). The test was performed at 60 degrees /s in the concentric passive mode and the children performed maximal contractions. Children with CP were evaluated with and without KT under rectus femoris. RESULTS: After KT application, knee peak torque of the affected limb increased in children with CP. CONCLUSION: KT may increase muscle strength in children with CP. PMID- 30412509 TI - Cognitive rehabilitation, self-management, psychotherapeutic and caregiver support interventions in progressive neurodegenerative conditions: a scoping review. AB - BACKGROUND: Despite their potentially significant impact, cognitive disability may be overlooked in a number of progressive neurodegenerative conditions, as other difficulties dominate the clinical picture. OBJECTIVE: We examined the extent, nature and range of the research evidence relating to cognitive rehabilitation, self-management, psychotherapeutic and caregiver support interventions in Parkinsonian disorders, multiple sclerosis (MS), frontotemporal dementias (FTD), motor neuron disease and Huntington's disease. METHODS: Scoping review based on searches of MEDLINE and CINAHL up to 15 March 2016. RESULTS: We included 140 eligible papers. Over half of the studies, and almost all the randomised controlled trials, related to MS, while a number of single case studies described interventions for people with FTD. CR interventions addressed functional ability, communication and interaction, behaviour or memory. The majority of psychotherapy interventions involved cognitive behavioural therapy for depression or anxiety. Self-management interventions were mainly available for people with MS. There were few reports of interventions specific to caregivers. Numerous methodological challenges were identified. CONCLUSIONS: The limited range of studies for all conditions except MS suggests a need firstly to synthesise systematically the available evidence across conditions and secondly to develop well-designed studies to provide evidence about the effectiveness of CR and other psychological interventions. PMID- 30412510 TI - Dysphagia in cerebral hypoxia. AB - INTRODUCTION: Dysphagia is a frequent problem in various neurological disorders. However, knowledge on swallowing function in patients with cerebral hypoxia is sparse. The objective of this study is to report the development of swallowing function in a series of adolescent and young-adult patients with cerebral hypoxia. METHODS: We recruited eight patients (1 male) who were admitted to our institution after the acute phase following cerebral hypoxia. Each patient underwent detailed neurological evaluation, magnetic resonance imaging (MRI), standardized neurophysiological assessment and repeated clinical and fiber endoscopic evaluation of swallowing. Furthermore, all patients received daily physical and occupational therapy and intensive logopedic therapy for swallowing. RESULTS: Mean age in this case series was 19.9+/-3.6 years (range 16-25). All eight patients initially displayed severe swallowing dysfunction, but the reflexive components of swallowing were intact in seven patients without brainstem lesions. The only patient with additional brainstem involvement initially suffered from absence of an intact swallowing reflex and developed silent aspiration. However, follow-up examinations revealed intact swallowing reflexes in all eight patients. DISCUSSION: Dysphagia is common in patients with cerebral hypoxia, mainly resulting in a delayed oral phase consistent with impaired volitional execution of swallowing. Additional lesions in the brainstem may affect the integrity of the central pattern-generating circuitry for swallowing, resulting in additional dysfunction of the non-volitional reflexive component. In conclusion, dysphagia in patients with cerebral hypoxia is a common complication particularly in the early stages of remission, while long-term prognosis with respect to swallowing is often good. Swallowing function should be closely monitored in patients with acquired brain injury. PMID- 30412511 TI - The utility of clinical criteria in patients with chronic traumatic encephalopathy. AB - BACKGROUND: Repetitive traumatic brain injury (TBI) is associated with chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disorder characterized by Alzheimer-like changes in the brain. CTE has been defined through neuropathological findings among deceased athletes and others exposed to repetitive TBI, but to date there are no definitive clinical criteria for CTE. OBJECTIVE: To evaluate the utility of currently proposed clinical criteria for CTE and suggest improvements. METHODS: We describe two well-characterized patients referred for evaluation of CTE and apply the four major proposed criteria for CTE. These criteria were further assessed in a cohort of patients referred to a neurobehavior clinic with or without a history of TBI. RESULTS: Without a CTE biomarker, the current criteria were of limited utility when applied to the two patient and the Neurobehavior cohort. Six items were extracted as potentially improving the clinical diagnosis of CTE: length of exposure to head impacts, a progressive course, specific psychiatric symptoms, frontal executive dysfunction, parkinsonism and tremors, and targeted findings on neuroimaging. CONCLUSIONS: The prevention and neurorehabilitation of CTE depends on clinical diagnosis, but, without a biomarker, the clinical diagnosis of CTE remains difficult. This report suggests that clinical criteria for CTE may be greatly improved with emphasis on several critical historical and clinical correlates of CTE. PMID- 30412512 TI - Rapid improvement of reading performance in children with dyslexia by altering the reading strategy: A novel approach to diagnoses and therapy of reading deficiencies. AB - BACKGROUND: Reading disability is termed "dyslexia" if it is much lower than other cognitive abilities according to the intelligence quotient (IQ). This means that dyslexia is caused by an impairment of abilities other than those which the IQ requires. Therefore, reading performance should improve immediately if these impairments are either eliminated or compensated. OBJECTIVE: The experiments explore conditions under which these impairments are compensated and dyslexic children's poor reading ability immediately improve. METHODS: Experiment 1 examined if reducing the number of letters in pseudowords, prolonging the time interval during which the gaze is directed to pseudowords, reducing the amplitude of saccades and prolonging the time interval that elapsed between the beginning of the presentation of a pseudoword and the beginning of the pronunciation of that word influences childrens' reading performance. A group of 100 German children (71 boys and 29 girls) aged 8 to 13 years, who suffered from dyslexia according to the Zuerich Reading Test, were divided into a training group (n = 50) and an age-matched control group (n = 50) and tested. Both groups participated in experiment 1. Only the children in the training group participated in experiment 2, in which the children learned a compensatory reading strategy. The age - matched control group did not learn the compensatory reading strategy. In the training group, reading performance was tested before and after having learned the new reading strategy. RESULTS: Conditions were found under which all children were able to read 95% of the pseudowords correctly. After having learned a compensatory reading strategy, a mean 58.9% decrease in words read incorrectly was found after a single training session. The difference between the number of reading mistakes before and after the training session was highly significant (Wicoxon Test: p < 0.00001). The effect size showed that the compensatory reading strategy was highly effective (Hedges g = 1.7). The reading ability of an age-matched dyslexic control group showed no improvement. CONCLUSIONS: Dyslexic subjects' reading performance improves significantly when they learn a new reading strategy. PMID- 30412513 TI - Vestibular rehabilitation has positive effects on balance, fatigue and activities of daily living in highly disabled multiple sclerosis people: A preliminary randomized controlled trial. AB - BACKGROUND: Balance disorders are present in patients with Multiple Sclerosis and part of these disorders could be of vestibular origin. Vestibular Rehabilitation was found to be effective in improving balance in patients with central vestibular dysfunction. OBJECTIVE: To investigate the clinical effects of vestibular rehabilitation on balance skills and secondly on fatigue and activity of daily living in highly disabled multiple sclerosis people. METHODS: Thirty hospitalized participants with severe multiple sclerosis (EDSS 6-7) were randomly assigned to the experimental group (15 patients -9F-; mean age 50.64+/-11.73) and the control group (15 patients -8F-; mean age 45.77+/-10.91). All patients were evaluated before and after treatment with the Expanded Disability Status Scale, Barthel Index Tinetti Balance and Gait scale, Berg Balance Scale, Fatigue Severity Scale, Two Minute Walking Test and Timed 25-foot walk test. Two follow ups (i.e., at 30 and 60 days after treatment) were carried out with Barthel Index. RESULTS: Significant improvement was found in the experimental group with respect to the control group (p < 0,05) in balance, fatigue perception, activities of daily living and short distance gait. No significant improvements were found for gait endurance as measured by Two Minute Walking Test. CONCLUSIONS: Four weeks of Vestibular Rehabilitation training results in less fatigue, improved balance and performance of the activities of daily living in patients with severe Multiple Sclerosis. PMID- 30412514 TI - Randomized, crossover, sham-controlled, double-blind study of transcranial direct current stimulation of left DLPFC on executive functions . AB - BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique commonly used to modulate cognitive functions; so called "anodal" stimulation is considered to increase cortical excitability while "cathodal" stimulation is presumed to have the opposite result. Yet, a growing number of recent studies question the robustness of this polarity-dependent effect, namely because of the important inter-individual variability with regards to tDCS modulatory effects. A plausible reason for this heterogenous response may lay in task impurity issues in the evaluation of cognitive functions. OBJECTIVE: To address the question of task impurity the NIH-Examiner, a neuropsychological test battery that uses latent variables, which assess the common variance across multiple measures of a given concept, was administered to 24 healthy individuals following tDCS. This battery contains 11 tasks and provides latent variables for general executive functioning, fluency, cognitive control and working memory. METHODS: Anodal, cathodal, and sham stimulation (20 minutes, 1.5 mA) was administered over left dorsolateral prefrontal cortex and right supra-orbital area in a randomized, crossover, sham-controlled, double blind protocol. RESULTS: Factorial scores and task performance indices of executive function were not modulated by tDCS. CONCLUSIONS: Offline tDCS has limited impact on executive functions at both the task and factorial levels. This suggests that reducing task impurity does not increase the effectiveness of tDCS in modulating cognitive functions. PMID- 30412515 TI - Residual vision activation and the brain-eye-vascular triad: Dysregulation, plasticity and restoration in low vision and blindness - a review. AB - Vision loss due to ocular diseases such as glaucoma, optic neuropathy, macular degeneration, or diabetic retinopathy, are generally considered an exclusive affair of the retina and/or optic nerve. However, the brain, through multiple indirect influences, has also a major impact on functional visual impairment. Such indirect influences include intracerebral pressure, eye movements, top-down modulation (attention, cognition), and emotionally triggered stress hormone release affecting blood vessel dysregulation. Therefore, vision loss should be viewed as the result of multiple interactions within a "brain-eye-vascular triad", and several eye diseases may also be considered as brain diseases in disguise. While the brain is part of the problem, it can also be part of the solution. Neuronal networks of the brain can "amplify" residual vision through neuroplasticity changes of local and global functional connectivity by activating, modulating and strengthening residual visual signals. The activation of residual vision can be achieved by different means such as vision restoration training, non-invasive brain stimulation, or blood flow enhancing medications. Modulating brain functional networks and improving vascular regulation may offer new opportunities to recover or restore low vision by increasing visual field size, visual acuity and overall functional vision. Hence, neuroscience offers new insights to better understand vision loss, and modulating brain and vascular function is a promising source for new opportunities to activate residual vision to achieve restoration and recovery to improve quality of live in patients suffering from low vision. PMID- 30412516 TI - Morphological analysis of blood vessels near lung tumors using 3-D quantitative CT. AB - BACKGROUND: Improved visualization of lung cancer-associated vessels is vital. OBJECTIVE: To evaluate the efficacy of 3-D quantitative CT in lung cancer associated pulmonary vessel assessment. METHODS: Vascular CT changes were assessed visually and using FACT-Digital lung TM software (n = 162 patients, 178 controls). The total number of pulmonary vessels (TNV) and mean lumen area of pulmonary vessels (MAV) vertical to cross-sections of fifth/sixth-generation bronchioles were measured. RESULTS: Visual investigation revealed fewer ipsilateral pulmonary vascular abnormalities in lung cancer (151/162) than did quantitative CT (162/162), and required more time (3.2+/-1.5 vs. 2.5+/-1.3 min) (P < 0.05). CT measurements revealed that the TNV vertical to the fifth generation bronchial cross-section of the ipsilateral, contralateral, and control groups was 14.58+/-4.75, 9.58+/-3.74, and 10.22+/-4.07 and the MAV in these groups was 99.70+/-26.20, 58.76+/-29.29, and 57.76+/-18.32, respectively. The TNV vertical to the sixth-generation bronchial cross-section of the ipsilateral, contralateral, and control groups was 16.64+/-5.14, 11.59+/-4.06, and 11.75+/ 4.16 and the MAV was 110.22+/-31.47, 67.62+/-30.41, and 60.24+/-16.18, respectively. The TNV and MAV in ipsilateral lung cancer tissues exceeded those in the contralateral side and control group tissues (P < 0.001). CONCLUSIONS: Automated 3-D quantitative CT could successfully characterize pulmonary vessels and their lung cancer-associated changes. PMID- 30412517 TI - Safety evaluation of mobile X-ray equipment using super-capacitor. AB - In this study, we designed mobile X-ray equipment that generates high-power X rays, using an internal power source by means of a super-capacitor, and evaluated its safety. The proposed X-ray equipment uses the charging voltage of a battery to store high density energy, supplementing the electric charge of the super capacitor, which can instantly release a large amount of energy. Further, pulse frequency modulation was applied to produce high voltage and thereby improve energy efficiency. The developed mobile X-ray equipment enables to generate an output of 30 kW and, therefore, can be applied to many diagnostic fields. In addition, various devices and control circuits were employed to ensure convenience and safety of using the equipment in clinical applications. This study analyzed the error ranges regarding tube voltage, tube current, irradiation time, coefficient variation, half-value layer, and the output characteristics. The results showed that the proposed X-ray equipment was able to generate 80mR X ray power under the condition of 30 kW. The coefficient variation was less than 0.05 at all measurement points, which indicates that it is possible to generate the equal amount of X-ray when the driving conditions are same. Results also showed 51.25% of transmittance at 3.5mmAL in the case of the wire, which is thicker than a common reference of 2.3mmAL and indicates that this new mobile equipment is possible to generate X-rays with relatively high permeability. In conclusion, the findings in this study suggest that the new equipment can generate consistent high-power X-rays and, therefore, can be used safely by minimizing unnecessary re-taking of images and radiation exposure. PMID- 30412519 TI - Low investment, high protection. PMID- 30412518 TI - TRIM15 Exerts Anti-Tumor Effects Through Suppressing Cancer Cell Invasion in Gastric Adenocarcinoma. AB - BACKGROUND Recent studies have shown that some members of the tripartite motif containing protein (TRIM) family function as important regulators in several tumors. However, the clinical significance of TRIM15 in gastric adenocarcinoma has not been elucidated. In the present study, we aimed to examine the expression pattern of TRIM15 and explore whether the TRIM15 expression is correlated with clinicopathological characteristics of patients with gastric adenocarcinoma. MATERIAL AND METHODS The expression pattern of TRIM15 was examined in gastric adenocarcinoma tissues and adjacent normal stomach tissues by using immunohistochemistry staining. The prognostic role of TRIM15 in gastric cancer patients was evaluated by univariate and multivariate analyses. Clinical outcomes were assessed by the Kaplan-Meier analysis and log-rank test. The effects of TRIM15 on cancer cell proliferation and invasion were tested through cellular experiments. RESULTS TRIM15 was highly expressed in normal stomach tissues compared to tumor tissues. TCGA database showed that higher TRIM15 RNA transcription indicates poorer overall survival of gastric cancer patients. Besides, low expression of TRIM15 was significantly associated with advanced tumor invasion depth and advanced TNM stage. Moreover, gastric cancer patients with lower KDM5B expression had poorer overall survival, and TRIM15 was identified as an independent prognosis factor according to multivariate analysis. Using the gastric cancer cell lines, we found that overexpression of TRIM15 can inhibits tumor cell invasion. CONCLUSIONS Our study demonstrated that low expression of TRIM15 in gastric adenocarcinoma tissues was significantly associated with poorer prognosis of patients, indicating the potential of TRIM15 as a novel clinical biomarker and therapeutic target. PMID- 30412520 TI - The dental management of a mouth cancer patient. AB - Dentists and dental care professionals have a key role to play in the journey of the mouth cancer patient. Involved in the prevention, diagnosis and delivery of oral healthcare before, during and following mouth cancer treatment, dental professionals are essential to the delivery of patient care. This article will explore and consider the priorities of dental pre-assessment and the subsequent delivery of oral healthcare in the context of the different oncology treatment strategies utilised and in end-of-life care. The significant side effects of radiotherapy will be reviewed and clinical dental considerations presented using the existing evidence base and available guidelines. Ensuring mouth cancer does not result in dental disease is an important role for all members of the dental community. PMID- 30412522 TI - Politicians recognise falling dentist income. PMID- 30412521 TI - Cosmetic dentistry: Facial aesthetic treatments and clinical and radiological implications. PMID- 30412523 TI - Dental and medical complexities: Generalisations over age. PMID- 30412524 TI - Is cosmetic dentistry 'dentistry' at all?: Cosmetic dentistry: a socio-ethical evaluation. AB - The implications for funders are discussed. PMID- 30412526 TI - FGDP(UK) Vice-Dean is made Queen's Honorary Dental Surgeon. PMID- 30412525 TI - Orthodontic treatment need and quality of life: Correlation between oral-health related quality of life and orthodontic treatment need in children and adolescents - a prospective interdisciplinary multi centre cohort study. AB - In this study, IOTN and OHRQoL are positively correlated. PMID- 30412527 TI - IMOS contracts awarded to dental corporate group. PMID- 30412529 TI - Dentist innovation awards open for entries. PMID- 30412528 TI - A psychiatric condition ...: Body dysmorphic disorder: a guide to identification and management for the orthodontic team. AB - ... with implications for all those providing aesthetic treatments. PMID- 30412530 TI - Strong teeth make strong kids. PMID- 30412531 TI - Dental cycle charity effort raises almost L40,000. PMID- 30412532 TI - Oral and maxillofacial surgery: MaxFax training opens up the world of dentistry. PMID- 30412533 TI - Five reasons to choose new corporate. PMID- 30412534 TI - Imaging patients with cancer of the oral cavity. AB - The staging of oral cavity tumours as with all other malignancy subsites is undergoing a revision in the line with the updated American Joint Committee on Cancer guidelines. Of note, the new guidelines incorporate more emphasis on clinical and histopathological data. The aim of the new guidelines is to increase prognostic concordance between stage and survival. This article aims to review the multimodality approach to imaging of oral cavity malignancy. In addition, it will also review the multidisciplinary approach to diagnosis and management of these tumours as multiple specialities are crucial for effective treatment. PMID- 30412535 TI - Infant mutilation: Cultural impact on dental care. PMID- 30412537 TI - Premium stability from collagen gel. PMID- 30412538 TI - Alcohol and mouth cancer. AB - There is now considered to be no safe limit for alcohol intake. Studies have shown that risk of mouth cancer increases with greater alcohol intake (in particular when associated with the use of tobacco). This paper reviews the role for alcohol in the aetiology of mouth cancer both in terms of how it may give rise to cancerous change and the relative risk it carries (arising from various systematic and meta-analyses reported over the last decade). While obtaining a reliable alcohol history can be problematic (with under reporting frequently suspected) greater awareness of the role of alcohol in both local and systemic disease (in particular that of cancer in an ever increasing number of sites) may serve as a motivator for behaviour change within our patients. To that end patients should be aware of the alcohol content in the drinks they consume and consider recording their alcohol intake over a defined period (eg, use of a diary or app over a two to four week period). PMID- 30412536 TI - The pathology of oral cancer. AB - The term 'oral cancer' describes a range of malignancies that may arise in and around the oral cavity. Over 90% of such lesions are squamous cell carcinomas, but even these may be divided into different entities based on site, aetiology and prognosis. In particular, squamous carcinomas in the oral cavity (oral cancer) should be regarded as a different disease to carcinomas arising in the oropharynx. Oropharyngeal cancer is associated with infection by human papillomavirus (HPV) and shows different clinical and histological features. This short review summarises the pathology of oral and oropharyngeal cancer, and describes some of the main prognostic factors that pathologists use to assist clinicians in planning appropriate management. PMID- 30412539 TI - Oral cancer - CPD and the GDC. AB - Oral cancer is a horrible, disfiguring and potentially life-shortening disease. The impact of a late or misdiagnosis of oral cancer is evidently serious for patients, serious for the individual healthcare worker, serious for the maintaining of standards, and serious for the upholding of public confidence in the profession. This paper looks at the General Dental Council's expectations and the role of national guidelines with regard to the responsibility of the individual dental professional in identifying potentially serious oral mucosal abnormalities and timely onward referral of patients. The paper also considers the role of continuing professional development, required by the General Dental Council, in the performance of the dental profession in the correct handling of patients with suspected oral cancer. The numbers of cases before the General Dental Council over the past few years involving complaints of late or misdiagnosis of oral/mouth cancer are explored and reasons for the reduction suggested. PMID- 30412541 TI - Mouth cancer - What's it to you? PMID- 30412540 TI - Restorative aspects of oral cancer reconstruction. AB - The oral rehabilitation of head and neck cancer patients is a vital and pivotal part of their care pathway, helping to restore function, aesthetics and improve patient well-being and quality of life. Patient-reported outcome data demonstrates that such patients consider that many of their continued and unmet needs relate to their oral and dental rehabilitation. It is therefore incumbent on all dental team members to be aware of the entire spectrum of restorative management options that can be utilised in both the prevention and rehabilitation of this patient cohort. The literature highlights that maxillary and mid-face tumours are challenging, as patients often suffer both profound functional and aesthetic consequences with significant physiological and psychological impact. Conversely, mandibular and floor of mouth tumours often result in issues primarily affecting oral function. This paper will summarise commonly encountered functional and aesthetic issues facing the restorative dental team and highlight widespread preventive challenges. PMID- 30412543 TI - New guide for dentists to use social media safely. PMID- 30412542 TI - Never events: Patient safety definitions. PMID- 30412544 TI - Global company recognised for improving oral care. PMID- 30412545 TI - CONFERENCE REPORT: British Orthodontic Conference 2018. PMID- 30412546 TI - Associate specialists: The lost tribe. PMID- 30412547 TI - Perfect for posterior cases - and an alternative to amalgam. PMID- 30412548 TI - At the top of the curve. PMID- 30412549 TI - Most practices provide safe dental care but good prevention varies, says CQC. PMID- 30412550 TI - Screening for mouth cancer: the pros and cons of a national programme. AB - The paper highlights the pros and cons of a national programme for screening for oral cancer. It provides an overview of screening methods and the metrics used to evaluate a screening programme. It then reviews the evidence for mouth cancer screening against the criteria of the United Kingdom National Screening Committee. PMID- 30412551 TI - The BDA First World War Memorial. AB - The First World War cost many lives and the dental profession was not exempt. Some were serving in their professional capacity within the forces, but many were not. The British Dental Association wished to commemorate those members who had sacrificed their lives by providing a Memorial plaque at the association's headquarters. PMID- 30412552 TI - Technology in dental care: Oral health by mobile phone. PMID- 30412553 TI - Air pollution exposure may be linked to higher risk of mouth cancer. PMID- 30412554 TI - Richard Johns: My perspective from the 'departure lounge'. PMID- 30412555 TI - Sir John Walsh and his legacy to the dental profession. PMID- 30412556 TI - Almost 90% of dentists have fears of being sued by patients. PMID- 30412557 TI - Stylish Italian design for a family-friendly surgery. PMID- 30412559 TI - Editorial: So that we remember. PMID- 30412560 TI - Autumn and winter study clubs. PMID- 30412558 TI - The changing epidemiology of oral cancer: definitions, trends, and risk factors. PMID- 30412563 TI - The risk-free payroll solution. PMID- 30412562 TI - Poor access to urgent dental care pushing patients to GPs. PMID- 30412561 TI - Through the patient's eyes - the importance of person-centred care in oral cancer. AB - This opinion paper highlights the value which patients place on the delivery of a person-centred approach within dentistry. Excerpts from a qualitative interview are used to illustrate the level of importance afforded to the soft skills, as viewed through the eyes of a patient with experience of oral cancer. The role of the general dental practitioner in supporting patients with oral cancer is highlighted. Attention is drawn to the importance of the dentist-patient relationship and how this can support identification of risk; delivery of preventative advice; early detection and onward referral; and the provision of ongoing pastoral support. Continuity of care is identified as a key factor in delivering high quality person-centred care where the focus should be on the individual and not the disease. PMID- 30412565 TI - Professionals make joint plea to Chancellor over NHS and social care funding. PMID- 30412566 TI - Eliminating risks - maximising returns. PMID- 30412564 TI - Mouth cancer: presentation, detection and referral in primary dental care. AB - Mouth cancer can present as a variety of abnormalities and visible changes affecting the oral mucosa, including ulceration, swelling and areas of erythema. The five-year survival from mouth cancer is poor at approximately 50%. Detection of the cancer while less than 2 cm in diameter with no metastasis greatly improves the outcome for the patient. Although many cancers in the mouth develop from what was previously an apparently normal mucosa, some arise in pre-existing conditions that are therefore regarded as potentially malignant. Regular assessment of the soft tissues within the mouth and the neck for the presence of abnormalities is an essential component of primary dental care. Any persistent and unexplained abnormality requires referral for definitive diagnosis and specialist management. PMID- 30412567 TI - Titanium strength system. PMID- 30412568 TI - Helping you meet the rising demands. PMID- 30412569 TI - Digital developments highlighted at summit. PMID- 30412571 TI - Dentists willing to sacrifice higher wages to work in richer areas, study shows. PMID- 30412570 TI - Educational aspects of oral cancer. AB - The incidence of oral and oropharyngeal cancer is rising in the UK, its aetiology is changing and early detection and referral saves lives. This article covers how and to what depth oral and oropharyngeal cancer is taught to dental students and other preregistration dental care professionals and examines the threats in the current climate to that education. It also discusses the knowledge of oral and oropharyngeal cancer among general dental practitioners and argues that further continuing professional development regarding the changing aetiology and epidemiology of oral and oropharyngeal cancer is desirable. The article concludes that current levels of education before registration must be maintained so that dentists and dental care professionals can take full advantage of continuing professional development and are able to detect oral and oropharyngeal cancer, refer for specialist treatment and provide appropriate preventive advice to their patients. In this way the potential of all dental professionals to save lives will be maintained. PMID- 30412572 TI - Raising awareness of oral cancer from a public and health professional perspective. AB - Low public awareness of oral cancer and delays in symptomatic patients presenting to health services have been identified as contributing factors to poor survival rates. In order to promote diagnosis and treatment of oral cancer at an earlier stage, public awareness campaigns have been recommended, encouraging those with signs and symptoms to attend primary care services at an earlier stage. This article provides an overview of the evidence of effectiveness of interventions aimed at raising cancer awareness and explores the use of mass media for health behaviour change. The use of awareness campaigns to promote earlier diagnosis of oral cancer is also explored from both a patient and health professional perspective. The findings of the overview suggest that while awareness raising campaigns can increase knowledge of the disease and attendance at health services in the short-term, those at lesser risk often respond, and evidence of longer term impact is very limited. The translation of knowledge into behaviour change is likely to require a more comprehensive, longer-term, multi-faceted approach, acknowledging the social determinants of health and health behaviour theory. More work is required to understand what needs to be included in campaigns to make them effective. Availability and access to appropriately trained and informed primary care personnel is important, particularly for high-risk groups. This is relevant for: supporting those with signs and symptoms to attend services; promoting opportunistic screening; enabling referral of patients to secondary care in a timely manner; and for provision of advice on the major risk factors associated with oral cancer. PMID- 30412574 TI - Correction: Assessment of ab initio models of protein complexes by molecular dynamics. AB - [This corrects the article DOI: 10.1371/journal.pcbi.1006182.]. PMID- 30412573 TI - Analysis of 7,815 cancer exomes reveals associations between mutational processes and somatic driver mutations. AB - Driver mutations are the genetic variants responsible for oncogenesis, but how specific somatic mutational events arise in cells remains poorly understood. Mutational signatures derive from the frequency of mutated trinucleotides in a given cancer sample, and they provide an avenue for investigating the underlying mutational processes that operate in cancer. Here we analyse somatic mutations from 7,815 cancer exomes from The Cancer Genome Atlas (TCGA) across 26 cancer types. We curate a list of 50 known cancer driver mutations by analysing recurrence in our cohort and annotations of known cancer-associated genes from the Cancer Gene Census, IntOGen database and Cancer Genome Interpreter. We then use these datasets to perform binary univariate logistic regression and establish the statistical relationship between individual driver mutations and known mutational signatures across different cancer types. Our analysis led to the identification of 39 significant associations between driver mutations and mutational signatures (P < 0.004, with a false discovery rate of < 5%). We first validate our methodology by establishing statistical links for known and novel associations between driver mutations and the mutational signature arising from Polymerase Epsilon proofreading deficiency. We then examine associations between driver mutations and mutational signatures for AID/APOBEC enzyme activity and deficient mismatch repair. We also identify negative associations (odds ratio < 1) between mutational signatures and driver mutations, and here we examine the role of aging and cigarette smoke mutagenesis in the generation of driver mutations in IDH1 and KRAS in brain cancers and lung adenocarcinomas respectively. Our study provides statistical foundations for hypothesised links between otherwise independent biological processes and we uncover previously unexplored relationships between driver mutations and mutagenic processes during cancer development. These associations give insights into how cancers acquire advantageous mutations and can provide direction to guide further mechanistic studies into cancer pathogenesis. PMID- 30412575 TI - Seasonal and interannual risks of dengue introduction from South-East Asia into China, 2005-2015. AB - Due to worldwide increased human mobility, air-transportation data and mathematical models have been widely used to measure risks of global dispersal of pathogens. However, the seasonal and interannual risks of pathogens importation and onward transmission from endemic countries have rarely been quantified and validated. We constructed a modelling framework, integrating air travel, epidemiological, demographical, entomological and meteorological data, to measure the seasonal probability of dengue introduction from endemic countries. This framework has been applied retrospectively to elucidate spatiotemporal patterns and increasing seasonal risk of dengue importation from South-East Asia into China via air travel in multiple populations, Chinese travelers and local residents, over a decade of 2005-15. We found that the volume of airline travelers from South-East Asia into China has quadrupled from 2005 to 2015 with Chinese travelers increased rapidly. Following the growth of air traffic, the probability of dengue importation from South-East Asia into China has increased dramatically from 2005 to 2015. This study also revealed seasonal asymmetries of transmission routes: Sri Lanka and Maldives have emerged as origins; neglected cities at central and coastal China have been increasingly vulnerable to dengue importation and onward transmission. Compared to the monthly occurrence of dengue reported in China, our model performed robustly for importation and onward transmission risk estimates. The approach and evidence could facilitate to understand and mitigate the changing seasonal threat of arbovirus from endemic regions. PMID- 30412576 TI - Adoption of routine virologic testing and predictors of virologic failure among HIV-infected children on antiretroviral treatment in western Kenya. AB - BACKGROUND: Access to routine virologic monitoring, critical to ensuring treatment success, remains limited in low- and middle-income countries. We report on implementation of routine viral load (VL) monitoring and risk factors for virologic failure among HIV-infected children on antiretroviral treatment (ART) in Western Kenya. METHODS: Routine VL testing was introduced in western Kenya in November 2013. We performed a case-control study among 1190 HIV-infected children <=15 years on ART who underwent routine VL testing June 2014-May 2015. A random sample of 98 cases (virologic failure define as VL >1000 cps/mL) and 201 controls (VL <1000 cps/mL) from five facilities in three high HIV prevalence counties in Kenya were followed for a minimum of 12 months. Data from patient charts were analyzed using logistic regression to determine factors associated with failure to attain virologic suppression at initial routine and subsequent VL testing among cases. RESULTS: Overall, 1190 (94%) children with a median age of 8 years underwent routine VL testing of whom (37%) had virological failure. Among the 299 cases and controls, WHO stage, baseline CD4 count and time since ART initiation were not associated with virologic failure during the follow-up period. In multivariable analysis, unsuppressed children at initial test were more likely to be male (adjusted Odds Ratio (aOR) 2.1, 95% Confidence Interval (CI) 2.1-3.6) and have had an ART regimen change (aOR 2.0, CI 1.0-3.7) than controls. Of the two thirds of children 201/299 who had a subsequent VL performed, VL suppression was greater among those suppressed at initial test 126/135 (93.3%) compared to children with virologic failure 15/66 (22.7%, p<0.0001). Among those failing at first test who achieved viral suppression in follow up, 12/15 (80%) were on a protease inhibitor (PI)-based regimen. In the multivariable analysis of children with subsequent VL testing, children on PI-based 2nd line regimens were 10-fold more likely to achieve viral suppression than children on first-line NNRTI-based ART (adjusted Odds Ratio [aOR] 0.1; 95%CI 0.0-0.4). CONCLUSION: Coverage of initial routine viral load testing among children on ART in western Kenya is high. However, subsequent testing and virologic suppression are low in children with virologic failure on initial routine viral load test. There is an urgent need to improve management and viral load monitoring of children living with HIV experiencing treatment failure to ensure improved long-term outcomes. PMID- 30412577 TI - Cryo-electron tomography of periplasmic flagella in Borrelia burgdorferi reveals a distinct cytoplasmic ATPase complex. AB - Periplasmic flagella are essential for the distinct morphology and motility of spirochetes. A flagella-specific type III secretion system (fT3SS) composed of a membrane-bound export apparatus and a cytosolic ATPase complex is responsible for the assembly of the periplasmic flagella. Here, we deployed cryo-electron tomography (cryo-ET) to visualize the fT3SS machine in the Lyme disease spirochete Borrelia burgdorferi. We show, for the first time, that the cytosolic ATPase complex is attached to the flagellar C-ring through multiple spokes to form the "spoke and hub" structure in B. burgdorferi. This structure not only strengthens structural rigidity of the round-shaped C-ring but also appears to rotate with the C-ring. Our studies provide structural insights into the unique mechanisms underlying assembly and rotation of the periplasmic flagella and may provide the basis for the development of novel therapeutic strategies against several pathogenic spirochetes. PMID- 30412578 TI - Comparative structural dynamic analysis of GTPases. AB - GTPases regulate a multitude of essential cellular processes ranging from movement and division to differentiation and neuronal activity. These ubiquitous enzymes operate by hydrolyzing GTP to GDP with associated conformational changes that modulate affinity for family-specific binding partners. There are three major GTPase superfamilies: Ras-like GTPases, heterotrimeric G proteins and protein-synthesizing GTPases. Although they contain similar nucleotide-binding sites, the detailed mechanisms by which these structurally and functionally diverse superfamilies operate remain unclear. Here we compare and contrast the structural dynamic mechanisms of each superfamily using extensive molecular dynamics (MD) simulations and subsequent network analysis approaches. In particular, dissection of the cross-correlations of atomic displacements in both the GTP and GDP-bound states of Ras, transducin and elongation factor EF-Tu reveals analogous dynamic features. This includes similar dynamic communities and subdomain structures (termed lobes). For all three proteins the GTP-bound state has stronger couplings between equivalent lobes. Network analysis further identifies common and family-specific residues mediating the state-specific coupling of distal functional sites. Mutational simulations demonstrate how disrupting these couplings leads to distal dynamic effects at the nucleotide binding site of each family. Collectively our studies extend current understanding of GTPase allosteric mechanisms and highlight previously unappreciated similarities across functionally diverse families. PMID- 30412579 TI - RepB C-terminus mutation of a pRi-repABC binary vector affects plasmid copy number in Agrobacterium and transgene copy number in plants. AB - A native repABC replication origin from pRiA4b was previously reported as a single copy plasmid in Agrobacterium tumefaciens and can improve the production of transgenic plants with a single copy insertion of transgenes when it is used in binary vectors for Agrobacterium-mediated transformation. A high copy pRi repABC variant plasmid, pTF::Ri, which does not improve the frequency of single copy transgenic plants, has been reported in the literature. Sequencing the high copy pTF::Ri repABC operon revealed the presence of two mutations: one silent mutation and one missense mutation that changes a tyrosine to a histidine (Y299H) in a highly conserved area of the C-terminus of the RepB protein (RepBY299H). Reproducing these mutations in the wild-type pRi-repABC binary vector showed that Agrobacterium cells with the RepBY299H mutation grow faster on both solidified and in liquid medium, and have higher plasmid copy number as determined by ddPCR. In order to investigate the impact of the RepBY299H mutation on transformation and quality plant production, the RepBY299H mutated pRi-repABC binary vector was compared with the original wild-type pRi-repABC binary vector and a multi-copy oriV binary vector in canola transformation. Molecular analyses of the canola transgenic plants demonstrated that the multi-copy pRi-repABC with the RepBY299H mutation provides no advantage in generating high frequency single copy, backbone free transgenic plants in comparison with the single copy wild-type pRi-repABC binary vector. PMID- 30412580 TI - Cellular immune responses in peripheral blood lymphocytes of Giardia infected squirrel monkey (Saimiri boliviensis boliviensis) treated with Fenbendazole. AB - Cellular immune responses were tested to determine the effect of fenbendazole on the function of lymphocytes from Bolivian squirrel monkeys (Samiri boliviensis boliviensis). Giardia-infected squirrel monkeys were treated with commercially available fenbendazole (FBZ)-medicated monkey chow. Immune responses were compared between historical controls (Giardia naive, untreated with FBZ (control animals)) and Giardia-infected, FBZ-treated squirrel monkeys (study animals). Peripheral blood lymphocytes from study monkeys had significantly lower stimulation indices compared to control animals when cultured in vitro with concanavalin A (Con A) (p<0.0001), phytohaemagglutinin (PHA) (p<0.0001) and lipopolysaccharide (LPS) (p<0.0001). PBMCs were also analyzed for IFN-gamma producing cells in response to stimulation with Con A, PHA, PWM, and LPS by the cytokine ELISPOT assay. Significantly higher responses to Con A- (p<0.0001), and PHA- (p<0.001) stimulated cultures from Giardia-infected and fenbendazole treated compared to controls. Flow cytometric analysis for expression of cell surface markers revealed a significant increase in B- and NKT-lymphocytes and significant decrease in CD14+CD16+ monocytes after FBZ treatment. Also, circulating plasma cytokines IFN-gamma, TNF-alpha, IL-12p40, IL-1beta, IL-10, IL-13, IL-1ra, IL-6 and IL-4 were significantly decreased after FBZ treatment. Comparison of hematologic parameters between controls and FBZ-treated squirrel monkeys revealed significantly lower numbers of total leukocytes, neutrophils, monocytes, and eosinophils compared to controls. However, erythrocyte indices (red cell count, hemoglobin and hematocrit were significantly higher in FBZ-treated monkeys. Our findings suggest that fenbendazole treatment may alter sensitive immune and molecular measures of inflammation. Postponing the experimental use of squirrel monkeys until at least 6 weeks after FBZ treatment should be considered. PMID- 30412582 TI - Fetuin-A protein distribution in mature inflamed and ischemic brain tissue. AB - BACKGROUND: The liver-derived plasma protein fetuin-A is strongly expressed during fetal life, hence its name. Fetuin-A protein is normally present in most fetal organs and tissues, including brain tissue. Fetuin-A was neuroprotective in animal models of cerebral ischemia and lethal chronic inflammation, suggesting a role beyond the neonatal period. Little is known, however, on the presence of fetuin-A in mature human brain tissue under different physiological and pathological conditions. METHODS: We studied by immunohistochemistry (IHC) the distribution of fetuin-A protein in mature human brain autopsy tissues from patients without neurological disease, patients with inflammatory brain disorders, and patients with ischemic brain lesions. To identify fetuin-A positive cells in these tissues we co-localized fetuin-A with GFAP (astrocytes) and CD68 (macrophages, activated microglia). RESULTS AND DISCUSSION: Unlike previous reports, we detected fetuin-A protein also in mature human brain as would be expected from an abundant plasma protein also present in cerebrospinal fluid. Fetuin-A immunoreactivity was increased in ischemic white matter and decreased in inflamed cerebellar tissue. Fetuin-A immunostaining was predominantly associated with neurons and astrocytes. Unlike the developing brain, the adult brain lacked fetuin-A immunostaining in CD68-positive microglia. Our findings suggest a role for fetuin-A in tissue remodeling of neonatal brain, which becomes obsolete in the adult brain, but is re-activated in damaged brain tissue. To further assess the role of fetuin-A in the mature brain, animal models involving ischemia and inflammation need to be studied. PMID- 30412581 TI - Cellulose-binding activity of a 21-kDa endo-beta-1,4-glucanase lacking cellulose binding domain and its synergy with other cellulases in the digestive fluid of Aplysia kurodai. AB - Endo-beta-1,4-glucanase AkEG21 belonging to glycosyl hydrolase family 45 (GHF45) is the most abundant cellulase in the digestive fluid of sea hare (Aplysia kurodai). The specific activity of this 21-kDa enzyme is considerably lower than those of other endo beta-1,4-glucanases in the digestive fluid of A. kurodai, therefore its role in whole cellulose hydrolysis by sea hare is still uncertain. Although AkEG21 has a catalytic domain without a cellulose binding domain, it demonstrated stable binding to cellulose fibers, similar to that of fungal cellobiohydrolase (CBH) 1 and CBH 2, which is strongly inhibited by cellohexaose, suggesting the involvement of the catalytic site in cellulose binding. Cellulose bound AkEG21 hydrolyzed cellulose to cellobiose, cellotriose and cellotetraose, but could not digest an external substrate, azo-carboxymethyl cellulose. Cellulose hydrolysis was considerably stimulated by the synergistic action of cellulose-bound AkEG21 and AkEG45, another beta-1,4-endoglucanase present in the digestive fluid of sea hare; however no synergy in carboxymethylcellulose hydrolysis was observed. When AkEG21 was removed from the digestive fluid by immunoprecipitation, the cellulose hydrolyzing activity of the fluid was significantly reduced, indicating a critical role of AkEG21 in cellulose hydrolysis by A. kurodai. These findings suggest that AkEG21 is a processive endoglucanase functionally equivalent to the CBH, which provides a CBH independent mechanism for the mollusk to digest seaweed cellulose to glucose. PMID- 30412583 TI - Conserved motifs in the hypervariable domain of chikungunya virus nsP3 required for transmission by Aedes aegypti mosquitoes. AB - BACKGROUND: Chikungunya virus (CHIKV) is a re-emerging arthropod-borne (arbo)virus that causes chikungunya fever in humans and is predominantly transmitted by Aedes aegypti mosquitoes. The CHIKV replication machinery consists of four non-structural proteins (nsP1-4) that additionally require the presence of a number of host proteins for replication of the viral RNA. NsP3 is essential for CHIKV replication and has a conserved macro, central and C-terminal hypervariable domain (HVD). The HVD is intrinsically disordered and interacts with various host proteins via conserved short peptide motifs: A proline-rich (P rich) motif that has affinity for SH3-domain containing proteins and duplicate FGDF motifs with affinity for G3BP and its mosquito homologue Rasputin. The importance of these motifs for infection of mammalian cells has previously been implicated. However, their role during CHIKV infection of mosquito cells and transmission by mosquitoes remains unclear. METHODOLOGY / PRINCIPAL FINDINGS: Here, we show that in-frame deletion of the P-rich motif is lethal for CHIKV replication in both mosquito and mammalian cells. However, while mutagenesis of the P-rich motif negatively affects replication both in mammalian and mosquito cells, it did not compromise the infection and transmission of CHIKV by Ae. aegypti mosquitoes. Mutagenesis of both FGDF motifs together completely inactivated CHIKV replication in both mammalian and mosquito cells. Importantly, mutation of a single FGDF motif attenuated CHIKV replication in mammalian cells, while replication in mosquito cells was similar to wild type. Surprisingly, CHIKV mutants containing only a single FGDF motif were efficiently transmitted by Ae. aegypti. CONCLUSIONS / SIGNIFICANCE: The P-rich motif in CHIKV nsP3 is dispensable for transmission by mosquitoes. A single FGDF motif is sufficient for infection and dissemination in mosquitoes, but duplicate FGDF motifs are required for the efficient infection from the mosquito saliva to a vertebrate host. These results contribute to understanding the dynamics of the alphavirus transmission cycle and may help the development of arboviral intervention strategies. PMID- 30412584 TI - Bait uptake by wild badgers and its implications for oral vaccination against tuberculosis. AB - The deployment of baits containing vaccines or toxins has been used successfully in the management of wildlife populations, including for disease control. Optimisation of deployment strategies seeks to maximise uptake by the targeted population whilst ensuring cost-effectiveness. Tuberculosis (TB) caused by infection with Mycobacterium bovis affects a broad range of mammalian hosts across the globe, including cattle, wildlife and humans. The control of TB in cattle in the UK and Republic of Ireland is hampered by persistent infection in European badgers (Meles meles). The present study aimed to determine the best strategy for maximising uptake of an oral vaccine by wild badgers, using a surrogate novel bait deployed at 40 badger social groups. Baits contained a blood borne biomarker (Iophenoxic Acid, IPA) in order to measure consumption in badgers subsequently cage trapped at targeted setts. Evidence for the consumption of bait was found in 83% (199/240) of captured badgers. The probability that badgers had consumed at least one bait (IPA >10 MUg ml-1) was significantly higher following deployment in spring than in summer. Lower uptake amongst social groups where more badgers were captured, suggested competition for baits. The probability of bait consumption was significantly higher at groups where main and outlier setts were provided with baits than at those where outliers were present but not baited. Badgers captured 10-14 days post bait feeding had significantly higher levels of bait uptake compared to those caught 24-28 days later. Uptake rates did not vary significantly in relation to badger age and whether bait was placed above ground or down setts. This study suggests that high levels of bait uptake can be achieved in wild badger populations and identifies factors influencing the potential success of different deployment strategies. The implications for the development of an oral badger vaccine are discussed. PMID- 30412585 TI - Characterization of Campylobacter spp. isolated from wild birds in the Antarctic and Sub-Antarctic. AB - A lack of knowledge of naturally occurring pathogens is limiting our ability to use the Antarctic to study the impact human-mediated introduction of infectious microorganisms have on this relatively uncontaminated environment. As no large scale coordinated effort to remedy this lack of knowledge has taken place, we rely on smaller targeted efforts to both study present microorganisms and monitor the environment for introductions. In one such effort, we isolated Campylobacter species from fecal samples collected from wild birds in the Antarctic Peninsula and the sub-Antarctic island of South Georgia. Indeed, in South Georgia, we found Campylobacter lari and the closely related Campylobacter peloridis, but also distantly related human-associated multilocus sequence types of Campylobacter jejuni. In contrast, in the Antarctic Peninsula, we found C. lari and two closely related species, Campylobacter subantarcticus and Campylobacter volucris, but no signs of human introduction. In fact, our finding of human-associated sequence types of C. jejuni in South Georgia, but not in the Antarctic Peninsula, suggests that efforts to limit the spread of infectious microorganisms to the Antarctic have so far been successful in preventing the introduction of C. jejuni. However, we do not know how it came to South Georgia and whether the same mode of introduction could spread it from there to the Antarctic Peninsula. PMID- 30412586 TI - The first year of the global Enhanced Gonococcal Antimicrobial Surveillance Programme (EGASP) in Bangkok, Thailand, 2015-2016. AB - Antimicrobial-resistant Neisseria gonorrhoeae (NG) infection is a global public health threat, and there is a critical need to monitor patterns of resistance and risk factors. In collaboration with the World Health Organization (WHO), the U.S. Centers for Disease Control and Prevention (CDC), and the Thailand Department of Disease Control (DDC), Ministry of Public Health (MoPH) implemented the first Enhanced Gonococcal Antimicrobial Surveillance Programme (EGASP) in November 2015. Men presenting with urethritis at two clinical settings in Bangkok, Thailand (Bangrak Hospital [BH] and Silom Community Clinic @TropMed [SCC @TropMed]) provided demographic and behavioral information and had a urethral swab for Gram's stain and NG culture collected. The NG isolates were evaluated for antimicrobial susceptibility by the Epsilometer test (Etest) to determine minimum inhibitory concentrations (MICs) for cefixime (CFM), ceftriaxone (CRO), azithromycin (AZI), gentamicin (GEN), and ciprofloxacin (CIP). From November 2015 -October 2016, 1,102 specimens were collected from 1,026 symptomatic men; 861 (78.1%) specimens were from BH and 241 (21.9%) specimens were from SCC @TropMed. Among the 1,102 specimens, 582 (52.8%) had intracellular Gram-negative diplococci and 591 (53.6%) had NG growth (i.e., NG infection); antimicrobial susceptibility testing (AST) was performed on 590 (99.8%) NG isolates. Among all symptomatic men, 293 (28.6%) had sex with men only, 430 (41.9%) were ages 18-29 years, 349 (34.0%) had antibiotic use in the last 2 weeks, and 564 (55.0%) had NG infection. Among 23 men with repeat NG infection during this first year of surveillance, 20 (87.0%) were infected twice, 2 (8.7%) were infected three times, and 1 (4.3%) was infected more than four times. All NG isolates were susceptible to CFM and CRO, and had MICs below 2 MUg/mL for AZI and below 16 MUg/mL for GEN. Overall, 545 (92.4%) isolates were resistant to CIP. This surveillance activity assessed individual patients, and included demographic and behavioral data linked to laboratory data. The inclusion of both individual and laboratory information in EGASP could help identify possible persistent infection and NG treatment failures. Expansion of EGASP to additional global settings is critical to assess trends and risk factors for NG, and to monitor for the emergence of resistance. PMID- 30412588 TI - A new method of mark detection for software-based optical mark recognition. AB - Software optical mark recognition (SOMR) is the process whereby information entered on a survey form or questionnaire is converted using specialized software into a machine-readable format. SOMR normally requires input fields to be completely darkened, have no internal labels, or be filled with a soft pencil, otherwise mark detection will be inaccurate. Forms can also have print and scan artefacts that further increase the error rate. This article presents a new method of mark detection that improves over existing techniques based on pixel counting and simple thresholding. Its main advantage is that it can be used under a variety of conditions and yet maintain a high level of accuracy that is sufficient for scientific applications. Field testing shows no software misclassification in 5695 samples filled by trained personnel, and only two misclassifications in 6000 samples filled by untrained respondents. Sensitivity, specificity, and accuracy were 99.73%, 99.98%, and 99.94% respectively, even in the presence of print and scan artefacts, which was superior to other methods tested. A separate direct comparison for mark detection showed a sensitivity, specificity, and accuracy respectively of 99.7%, 100.0%, 100.0% (new method), 96.3%, 96.0%, 96.1% (pixel counting), and 99.9%, 99.8%, 99.8% (simple thresholding) on clean forms, and 100.0%, 99.1%, 99.3% (new method), 98.4%, 95.6%, 96.2% (pixel counting), 100.0%, 38.3%, 51.4% (simple thresholding) on forms with print artefacts. This method is designed for bubble and box fields, while other types such as handwriting fields require separate error control measures. PMID- 30412587 TI - Follow-up ecological studies for cryptic species discoveries: Decrypting the leopard frogs of the eastern U.S. AB - Cryptic species are a challenge for systematics, but their elucidation also may leave critical information gaps about the distribution, conservation status, and behavior of affected species. We use the leopard frogs of the eastern U.S. as a case study of this issue. We refined the known range of the recently described Rana kauffeldi, the Atlantic Coast Leopard Frog, relative to the region's two other leopard frog species, conducted assessments of conservation status, and improved methods for separating the three species using morphological field characters. We conducted over 2,000 call and visual surveys and took photographs of and tissue samples from hundreds of frogs. Genetic analysis supported a three species taxonomy and provided determinations for 220 individual photographed frogs. Rana kauffeldi was confirmed in eight U.S. states, from North Carolina to southern Connecticut, hewing closely to the Atlantic Coastal Plain. It can be reliably differentiated in life from R. pipiens, and from R. sphenocephala 90% of the time, based on such characters as the femoral reticulum patterning, dorsal spot size and number, and presence of a snout spot. However, the only diagnostic character separating R. kauffeldi from R. sphenocephala remains the breeding call described in 2014. Based on our field study, museum specimens, and prior survey data, we suggest that R. kauffeldi has declined substantially in the northern part of its range, but is more secure in the core of its range. We also report, for the first time, apparent extirpations of R. pipiens from the southeastern portion of its range, previously overlooked because of confusion with R. kauffeldi. We conclude with a generalized ecological research agenda for cryptic species. For R. kauffeldi, needs include descriptions of earlier life stages, studies of niche partitioning with sympatric congeners and the potential for hybridization, and identification of conservation actions to prevent further declines. PMID- 30412589 TI - Deficiency of MTMR14 impairs male fertility in Mus musculus. AB - Calcium signalling is critical for successful fertilization. In spermatozoa, capacitation, hyperactivation of motility and acrosome reactions are all mediated by increases in intracellular Ca2+. Our previous reports have shown that deficiency of MTMR14, a novel phosphoinositide phosphatase, induces a muscle disorder by disrupting Ca2+ homeostasis. Recently, we found that MTMR14 is also expressed in the testes; however, whether deficiency of MTMR14 in the testes also alters the Ca2+ concentration and impairs male fertility remains entirely unknown. In the present study, we found that MTMR14 is also expressed in the testes and mature sperm cells, suggesting that deficiency of MTMR14 might have some effect on male fertility. Both in vivo fertility and in vitro fertilization tests were then performed, and we found that MTMR14-/- male mice showed decreased fertility. A series of experiments were then arranged to test the testis and sperm parameters; we found that MTMR14 deficiency caused small size of the testes, small numbers of both total and immotile sperm, expanded membrane of sperm tail, a decreased proportion of acrosome reaction, and in contrast, an increased proportion of abnormal sperm and augmented apoptosis, etc. Further study also found that the muscle force of the vas deferens decreased significantly in KO mice. Intracellular calcium homeostasis in the testes and epididymis was impaired by MTMR14 deletion; moreover, the relative mRNA expression levels of Itpr1, Itpr2, and Ryr3 were dramatically decreased in MTMR14 KO mice. Thus, MTMR14 deletion impairs male fertility by causing decreased muscle force of the vas deferens and intracellular calcium imbalance. PMID- 30412590 TI - Perceptual assessment of environmental stability modulates postural sway. AB - We actively maintain postural equilibrium in everyday life, and, although we are unaware of the underlying processing, there is increasing evidence for cortical involvement in this postural control. Converging evidence shows that we make appropriate use of 'postural anchors', for example static objects in the environment, to stabilise our posture. Visually evoked postural responses (VEPR) that are caused when we counteract the illusory perception of self-motion in space (vection) are modulated in the presence of postural anchors and therefore provide a convenient behavioural measure. The aim of this study is to evaluate the factors influencing visual appraisal of the suitability of postural anchors. We are specifically interested in the effect of perceived 'reality' in VR the expected 'stability' of visual anchors. To explore the effect of 'reality' we introduced an accommodation-vergence conflict. We show that VEPR are appropriately modulated only when virtual visual 'anchors' are rendered such that vergence and accommodation cues are consistent. In a second experiment we directly test whether cognitive assessment of the likely stability of real perceptual anchors (we contrast a 'teapot on a stand' and a 'helium balloon') affects VEPR. We show that the perceived positional stability of environmental anchors modulate postural responses. Our results confirm previous findings showing that postural sway is modulated by the configuration of the environment and further show that an assessment of the stability and reality of the environment plays an important role in this process. On this basis we propose design guidelines for VR systems, in particular we argue that accommodation vergence conflicts should be minimised and that high quality motion tracking and rendering are essential for high fidelity VR. PMID- 30412591 TI - Dynamic modulation of DC-SIGN and FcUpsilonR2A receptors expression on platelets in dengue. AB - Platelet activation has been reported to play a major role in inflammatory response and thrombocytopenia during dengue viral infection. Cells expressing FcUpsilonR2Aand DC-SIGN receptors are reported to be involved in dengue virulence. The present study is designed to assess the expression level of these two receptors on platelet surface collected from dengue patients and to study its association in patients with platelet RNA positive for dengue virus. This was an analytical cross-sectional study carried out in JIPMER hospital, Puducherry. Forty-four patients with dengue infection as cases and 44 patients with non dengue acute other febrile illness(OFI) as controls were recruited. Peripheral venous blood was withdrawn on day of admission, day 3 post admission and day of discharge and serological tests for NS1 dengue antigen and anti IgM antibody were analyzed for diagnosis of dengue infection. Platelet rich plasma was assessed for DC SIGN, FcUpsilonR2A levels and platelets separated from dengue patients were subjected to RNA extraction and detection of presence of viral RNA. The study observed a decreased expression of DC-SIGN and FcUpsilonR2A on platelets in dengue patients compared to OFI group on all the time points. Further, cells expressing DC-SIGN and FcUpsilonR2A were found to be decreased on platelets in dengue patients who were positive for NS1 antigen. DC-SIGN and FcUpsilonR2A expression was also found to be notably decreased in patients positive for platelet DENV RNA when compared with patients negative for platelet DENV RNA. Our results suggest that DC-SIGN and FcUpsilonR2A, which are receptors for viral capture and immune mediated clearance respectively, might be down regulated on platelets in patients with dengue infection. The decreased receptor expression diminishes platelet activation and subsequently has protective action on the host from the ongoing conflict between immune system and dengue virus. PMID- 30412592 TI - Novel models for prediction of benefit and toxicity with FOLFIRINOX treatment of pancreatic cancer using clinically available parameters. AB - BACKGROUND: Despite modern chemotherapy regimens, survival of pancreatic cancer patients remains dismal. Toxicity is a major concern and it is a challenge to upfront identify patients with the highest benefit from aggressive polychemotherapy. We aimed to evaluate ORR and side effects of the FOLFIRINOX regimen, highlighting dose modification and to explore possible prognostic response factors as a clinical tool. METHODS: This retrospective study includes 123 patients with metastatic PC that were treated with FOLFIRINOX between the years 2007 to 2016 in a single academic institution. Survival rates were analysed using the Kaplan-Meier method. Prognostic models including laboratory and clinical parameters were calculated using Cox proportional models in univariate and multivariate analyses. RESULTS: Median age at diagnosis was 64 years (47-78 years), 71 (57, 7%) were male and the majority had an ECOG performance status of 0 or 1 (63 patients; 83.7%). After a median follow up of 17.8 months, median progression free survival (PFS) and overall survival (OS) were 5.7 (4.55-6.84; 95%CI) and 11.8 months (9.35-14.24; 95%CI) respectively. Overall response rate with FOLFIRINOX was 34.9% and stable disease rate was 21.9%. Regarding Grade 3/4 side effects, 62 events, were reported in 37 patients. Looking at risk factors e.g. patient characteristics, tumor marker, inflammatory markers and body composition multivariate analyses proved CEA >4 elevation and BMI > 25 at the time point before palliative chemotherapy to be independent negative prognostic factors for OS. Grouping patients with no risk factor, one or two of these risk factors we analyzed a median OS of 17.4 moths, 9.6 months and 6.7 months (p<0.001) respectively. In addition we identified thrombocytosis and low BMI as predictors of early toxicity. CONCLUSION: This study identifies two easily available factors influencing overall survival with FOLFIRINOX therapy. By combining these two factors to create a score for OS, we propose a prognostic tool for physicians to identify patients, who are unlikely to benefit more from FOLFIRINOX or likely to experience toxicity. PMID- 30412593 TI - Molecular detection and genetic diversity of avian haemosporidian parasites in Iran. AB - BACKGROUND: The mobility of birds across or between continents exposes them to numerous vectors that have the potential to transmit pathogens and spread them into new regions. A combination of rich species diversity of birds along with the small amount of molecular studies in Iran makes observing the blood parasite distribution in wild avian populations indispensable for further estimation and administration of blood parasites. METHODOLOGY/PRINCIPAL FINDINGS: In order to evaluate the infection rate and molecular context of avian blood parasites, bird samples were collected (passerine = 316 and non-passerine = 14) in eight provinces of northern Iran between June to September 2015 and 2016. All bird samples were examined for haematoprotozoan infections by morphological screening using light microscope and mtDNA cytb gene amplification. A total of 115 birds were positive for blood parasites by molecular approach (34.84% overall infection). The infection rate of Haemoproteus, Plasmodium, and Leucocytozoon were 33.03%, 1.21%, and 0.6%, respectively. Sequences analysis has detected 43 lineages in Iranian birds' hosts. Lineages were attributed to three genera Haemoproteus (n = 37), Plasmodium (n = 4), and Leucocytozoon (n = 2), of which 23 lineages fully matched previously recorded sequences in GenBank and MalAvi data reciprocities. Five lineages of ACDUM1, ACDUM2, PARUS1, PYERY01, and SISKIN1 were detected in multiple hosts' species from dissimilar families. In Bayesian tree, all sequences were clustered in three main monophyletic clades as Haemoproteus, Plasmodium, and Leucocytozoon genera. CONCLUSIONS/SIGNIFICANCE: As the first study outlining the molecular detection of hematozoa of passerines from Iran, the current study has recorded 20 new lineages for three genera of Haemoproteus, Plasmodium, and Leucocytozoon. Additional investigations into these taxa in the avifauna for the other parts of Iran may provide extra information on blood parasites, hosts relationships and distribution patterns. PMID- 30412594 TI - Geographic filling delay of the choriocapillaris in the region of dilated asymmetric vortex veins in central serous chorioretinopathy. AB - PURPOSE: To investigate the correlation between geographic filling delays in the choriocapillaris using indocyanine green angiography (ICGA) images and dilated vortex veins in central serous chorioretinopathy (CSC). DESIGN: Observational case series. PARTICIPANTS: Thirty-two eyes of 32 patients, 21 with acute and 11 with chronic CSC. METHODS: Digital ICGA and fluorescein angiography (FA), with videoangiography, and swept-source optical coherence tomography (SS-OCT) for B scan and en-face choroidal imaging were performed. Overlapping of the filling delay areas in the choriocapillaris in the early-phase ICGA images and the region of dilated vortex veins in the en-face images were analyzed. The consistency of both areas was graded as follows. Grade 3: filling delay area is entirely involved in the dilated vortex vein region. Grade 2: 50% or more of filling delay area overlaps with the dilated vortex vein region. Grade 1: less than 50% of filling delay area overlaps with the dilated vortex vein region. Grade 0: no tendency for overlapping of two areas. We evaluated the asymmetry of upper and lower vortex veins in en-face images of the Haller layer. Using the binarization method, we quantified the luminal and stromal areas of the choroid. The ratios of the Haller layer area and luminal areas in the Haller layer to total choroidal area were examined. RESULTS: The consistency of overlapping of the two areas was grade 2.62 +/- 0.49 in acute CSC and grade 1.55 +/- 0.78 in chronic CSC (p = 0.0005). Asymmetry of upper and lower vortex veins was seen in 17 of 22 eyes (81%) with acute CSC and 6 of 11 eyes (54.5%) with chronic CSC (p = 0.114). Central choroidal thickness was 411 +/- 79 MUm in acute CSC and 326 +/- 64 MUm in chronic CSC (p = 0.004). In the posterior fundus with a 4500 MUm diameter, the ratio of the Haller layer area to total choroidal area was 63.7 +/- 8.6% in acute CSC and 57.1 +/- 7.9% in chronic CSC (p = 0.047). The ratio of the luminal area in the Haller layer area to total choroidal area was 46.9 +/- 7.6% in acute CSC and 40.0 +/- 6.9% in chronic CSC (p = 0.014). CONCLUSION: Filling delay areas in the choriocapillaris and dilated vortex vein regions showed marked overlapping in acute CSC. Increased choroidal thickness was attributed to dilated vortex veins. These findings suggest that the blood flow into the choriocapillaris is delayed as a result of congestion of the dominant vortex veins that supply this geographic area. CSC may be a disease characterized by vortex vein congestion that develops in eyes with asymmetric vortex veins. PMID- 30412595 TI - Anxiety and depression in Klinefelter syndrome: The impact of personality and social engagement. AB - Klinefelter syndrome (KS) (47, XXY) is the most common sex chromosome disorder, with a prevalence of 1 in every 660 newborn males. Despite the profound adverse effects of anxiety and depression, and their greater prevalence in KS populations, no research has been conducted to date to identify the determinants of anxiety and depression among patients with KS. We examined the relationships between personality traits, social engagement, and anxiety and depression symptoms among KS patients (n = 69) and a group of male controls (n = 69) matched for age and years of education. KS patients experienced more anxiety and depression symptoms than control participants. Neuroticism was the strongest and most consistent mediator between KS and both anxiety and depression symptoms. This research suggests that neuroticism may play a central role in attention switching, anxiety and depression among patients with Klinefelter syndrome. The central role of neuroticism suggests that it may be used to help identify and treat KS patients at particularly high-risk for attention-switching deficits, anxiety and depression. PMID- 30412596 TI - Cost-effectiveness evaluation of the 45-49 year old health check versus usual care in Australian general practice: A modelling study. AB - OBJECTIVES: To assess the potential cost-effectiveness of the 45-49 year old health check versus usual care in Australian general practice using secondary data sources. METHOD: Risk factor profiles were generated for a hypothetical Australian cohort using data from the National Health Survey. Intervention effects were modelled based on a meta-analysis on risk factor changes in the 5 years after a health check. The Framingham Risk Equation was applied to estimate the 5-year cardiovascular disease (CVD) incidence in the health check and usual care group respectively. A Markov model was then constructed to extrapolate long term CVD outcomes, health care costs and Quality Adjusted Life Years (QALYs) in both groups. Health check-related costs, applied to the health check group, were estimated from clinical guideline and experts' opinion. Lifetime costs, applied to both groups, included costs of hospitalization for CVD events and associated post-event health service use. The Incremental Cost-Effectiveness Ratio (ICER) was calculated for male and female patients respectively. RESULTS: Compared to usual care, the health check reduced CVD incidence for both males (RR = 0.87) and females (RR = 0.91) over a 5-year time. In a lifetime projection, health check led to an average 0.008 and 0.003 QALYs gained per male and female participants respectively. The estimates ICERs were AU $42,355 and AU $133,504 per QALY gained for males and females, respectively. A probabilistic sensitivity analysis demonstrated a probability of cost-effectiveness of 17.5% and 0% for male and female attendees, assuming a willingness to pay threshold of AU $28,000 per QALY gained. CONCLUSION: The 45-49 year old health check is associated with a small expected QALY gain per participant, though the persons avoiding CVD events experience large health gains. The mean ICER is larger than an empirical estimate of the threshold ICER and the evaluated health check is highly unlikely to be cost-effective. PMID- 30412597 TI - Development and characterisation of charcoal briquettes from water hyacinth (Eichhornia crassipes)-molasses blend. AB - Charcoal briquettes are inexpensive solid fuels made from carbonized biomass. The potential of converting water hyacinth (Eichhornia crassipes) charcoal into briquettes with molasses as binder was investigated in this study. Dried water hyacinth was carbonized at a temperature between 350 degrees C to 500 degrees C in a fabricated fine biomass carbonizer. A solution containing 80% by weight molasses was used in the production of briquettes having different charcoal/molasses ratios of 40:60, 30:70, and 20:80. Each briquette was characterized in terms of bulk density, calorific value, compressive strength, proximate analysis and micro-structure by Scanning Electron Microscopy. Charcoal briquettes were tested for their flammable characteristics through their burning rates and ignition time. Altering the molasses to charcoal ratio affected the quality and characteristics of the briquettes. Volatile combustible matter and fixed carbon increased with increasing amount of binder while ash content decreased. The 30:70 charcoal/molasses ratio produced the highest calorific value (16.6 MJ/kg) and compressive strength (19.1 kg/cm2). The results have shown the potential of converting water hyacinth into an alternative fuel source. PMID- 30412598 TI - Expression and localisation of thymosin beta-4 in the developing human early fetal heart. AB - BACKGROUND: The objective of this study was to investigate the expression and localisation of thymosin beta4 (Tbeta4) in the developing human heart. Tbeta4 is a cardioprotective protein which may have therapeutic potential. While Tbeta4 is an endogenously produced protein with known importance during development, its role within the developing human heart is not fully understood. Elucidating the localisation of Tbeta4 within the developing heart will help in understanding its role during cardiac development and is crucial for understanding its potential for cardioprotection and repair in the adult heart. METHODS: Expression of Tbeta4 mRNA in the early fetal human heart was assessed by PCR using both ventricular and atrial tissue. Fluorescence immunohistochemistry was used to assess the localisation of Tbeta4 in sections of early fetal human heart. Co-staining with CD31, an endothelial cell marker, and with myosin heavy chain, a cardiomyocyte marker, was used to determine whether Tbeta4 is localised to these cell types within the early fetal human heart. RESULTS: Tbeta4 mRNA was found to be expressed in both the atria and the ventricles of the early fetal human heart. Tbeta4 protein was found to be primarily localised to CD31-expressing endothelial cells and the endocardium as well as being present in the epicardium. Tbeta4 associated fluorescence was greater in the compact layer of the myocardial wall and the interventricular septum than in the trabecular layer of the myocardium. CONCLUSIONS: The data presented illustrates expression of Tbeta4 in the developing human heart and demonstrates for the first time that Tbeta4 in the human heart is primarily localised to endothelial cells of the cardiac microvasculature and coronary vessels as-well as to the endothelial-like cells of the endocardium and to the epicardium. PMID- 30412599 TI - The APOE epsilon4 allele is associated with a reduction in FEV1/FVC in women: A cross-sectional analysis of the Long Life Family Study. AB - INTRODUCTION: Murine studies have shown that apolipoprotein E modulates pulmonary function during development, aging, and allergen-induced airway disease. It is not known whether the polymorphic human APOE gene influences pulmonary function. OBJECTIVES: We assessed whether an association exists between the polymorphic human APOE epsilon2, epsilon3, and epsilon4 alleles and pulmonary function among participants in the Long Life Family Study. METHODS: Data from 4,468 Caucasian subjects who had genotyping performed for the APOE epsilon2, epsilon3, and epsilon4 alleles were analyzed, with and without stratification by sex. Statistical models were fitted considering the effects of the epsilon2 allele, defined as epsilon2/2 or epsilon2/3 genotypes, and the epsilon4 allele, defined as epsilon3/4 or epsilon4/4 genotypes, which were compared to the epsilon3/3 genotype. RESULTS: The mean FEV1/FVC ratio (the forced expiratory volume in one second divided by the forced vital capacity) was lower among women with the epsilon4 allele as compared to women with the epsilon3/3 genotype or the epsilon2 allele. Carriage of the APOE epsilon4 allele was associated with FEV1/FVC, which implied lower values. Further analysis showed that the association primarily reflected women without lung disease who were older than 70 years. The association was not mediated by lipid levels, smoking status, body mass index, or cardiovascular disease. CONCLUSIONS: This study for the first time identifies that the APOE gene is associated with modified lung physiology in women. This suggests that a link may exist between the APOE epsilon4 allele, female sex, and a reduction in the FEV1/FVC ratio in older individuals. PMID- 30412600 TI - Re-purposing 16S rRNA gene sequence data from within case paired tumor biopsy and tumor-adjacent biopsy or fecal samples to identify microbial markers for colorectal cancer. AB - Microbes colonizing colorectal cancer (CRC) tumors have the potential to affect disease, and vice-versa. The manner in which they differ from microbes in physically adjacent tissue or stool within the case in terms of both, taxonomy and biological activity remains unclear. In this study, we systematically analyzed previously published 16S rRNA sequence data from CRC patients with matched tumor:tumor-adjacent biopsies (n = 294 pairs, n = 588 biospecimens) and matched tumor biopsy:fecal pairs (n = 42 pairs, n = 84 biospecimens). Procrustes analyses, random effects regression, random forest (RF) modeling, and inferred functional pathway analyses were conducted to assess community similarity and microbial diversity across heterogeneous patient groups and studies. Our results corroborate previously reported association of increased Fusobacterium with tumor biopsies. Parvimonas and Streptococcus abundances were also elevated while Faecalibacterium and Ruminococcaceae abundances decreased in tumors relative to tumor-adjacent biopsies and stool samples from the same case. With the exception of these limited taxa, the majority of findings from individual studies were not confirmed by other 16S rRNA gene-based datasets. RF models comparing tumor and tumor-adjacent specimens yielded an area under curve (AUC) of 64.3%, and models of tumor biopsies versus fecal specimens exhibited an AUC of 82.5%. Although some taxa were shared between fecal and tumor samples, their relative abundances varied substantially. Inferred functional analysis identified potential differences in branched amino acid and lipid metabolism. Microbial markers that reliably occur in tumor tissue can have implications for microbiome based and microbiome targeting therapeutics for CRC. PMID- 30412602 TI - The complementary role of affect-based and cognitive heuristics to make decisions under conditions of ambivalence and complexity. AB - Little is known about the interplay between affective and cognitive processes of decision making within the bounded rationality perspective, in particular for the debate on adaptive decision making and strategy selection. This gap in the knowledge is particularly important as affect and deliberation may direct preferences in opposite directions. How do decision makers solve such dissonance? In this paper, we address this question by exploring the use of integral affect as a choice heuristic in comparison with and in conjunction to "take the best," and weighted addition of attributes (WADD). We operationalize theories of reliance on affect in choice through a "Take the emotionally best" algorithm. Its predictive power is experimentally tested against other models, including mixed sequential cognitive/affective procedures. We find that individual decisions are better predicted by a sequential combination of "Take the emotionally best" and "Take the best" with a slight dominance of the former. Conditions of cognitive/affective ambivalence, low discrimination ability and high complexity provide the cognitive architecture where such blended choice strategies predict decisions more precisely. This implies that reliance on integral affect may precede the use of cognitive cues following an ecological rationality perspective rather than supporting a kind of competition between affect and cognition as implied in current literature. PMID- 30412601 TI - Comparative mRNA and miRNA transcriptome analysis of a mouse model of IGFIR driven lung cancer. AB - Mouse models of cancer play an important role in elucidating the molecular mechanisms that contribute to tumorigenesis. The extent to which these models resemble one another and their human counterparts at the molecular level is critical in understanding tumorigenesis. In this study, we carried out a comparative gene expression analysis to generate a detailed molecular portrait of a transgenic mouse model of IGFIR-driven lung cancer. IGFIR-driven tumors displayed a strong resemblance with established mouse models of lung adenocarcinoma, particularly EGFR-driven models highlighted by elevated levels of the EGFR ligands Ereg and Areg. Cross-species analysis revealed a shared increase in human lung adenocarcinoma markers including Nkx2.1 and Napsa as well as alterations in a subset of genes with oncogenic and tumor suppressive properties such as Aurka, Ret, Klf4 and Lats2. Integrated miRNA and mRNA analysis in IGFIR driven tumors identified interaction pairs with roles in ErbB signaling while cross-species analysis revealed coordinated expression of a subset of conserved miRNAs and their targets including miR-21-5p (Reck, Timp3 and Tgfbr3). Overall, these findings support the use of SPC-IGFIR mice as a model of human lung adenocarcinoma and provide a comprehensive knowledge base to dissect the molecular pathogenesis of tumor initiation and progression. PMID- 30412603 TI - Plant immunity in natural populations and agricultural fields: Low presence of pathogenesis-related proteins in Solanum leaves. AB - Plant immunity has mainly been studied under controlled conditions, limiting our knowledge regarding the regulation of immunity under natural conditions where plants grow in association with multiple microorganisms. Plant pathology theory, based on laboratory data, predicts complex biochemical plant-pathogen interactions leading to coevolution of pathogen infectivity vs. plant recognition of microbes in multiple layers over time. However, plant immunity is currently not evaluated in relation to ecological time-scales and field conditions. Here we report status of immunity in plants without visible disease symptoms in wild populations of nightshades, Solanum dulcamara and Solanum nigrum, and in agricultural fields of potato, Solanum tuberosum. We analysed presence of pathogenesis-related proteins in over 500 asymptomatic leaf samples collected in the field in June, July and August over three years. Pathogenesis-related proteins were present in only one-third of the collected samples, suggesting low activity of the immune system. We could also detect an increase in pathogenesis related proteins later in the growing season, particularly in S. tuberosum. Our findings, based on pathogenesis-related protein markers, indicate major gaps in our knowledge regarding the status and regulation of plant immunity under field conditions. PMID- 30412604 TI - An incremental dual-task paradigm to investigate pain attenuation by task difficulty, affective content and threat value. AB - There is accumulating evidence that task demands and psychological states can affect perceived pain intensity. Different accounts have been proposed to explain this attenuation based either on how limited attentional resources are allocated to the pain stimulus or on how the threat value of the pain stimulus biases attention. However, the evidence for both proposals remains mixed. Here we introduce an incremental dual-task paradigm in which participants were asked to detect pain on their fingertip without any additional tasks during baseline phases or while concurrently detecting visual targets during task phases. The force applied to participants' fingertip in all phases increased incrementally until they detected moderate pain. In Experiment 1, we used coloured shapes and in Experiment 2 we used affective images as visual targets. We also manipulated the threat value of the pain stimulus in Experiment 2. For both experiments, we found that a concurrent task attenuated perceived pain intensity: mean force was significantly greater for the same moderate pain during task compared to baseline phases. Furthermore although task difficulty and affective content did not affect pain perception, the threat value of the pain stimulus moderated the magnitude of pain attenuation. PMID- 30412606 TI - Declines in exercise performance are prevented 24 hours after post-exercise ischemic conditioning in amateur cyclists. AB - Brief moments of blood flow occlusion followed by reperfusion may promote enhancements in exercise performance. Thus, this study assessed the 24-h effect of post-exercise ischemic conditioning (PEIC) on exercise performance and physiological variables in trained cyclists. In a randomized, single-blind study, 28 trained cyclists (27.1 +/- 1.4 years) performed a maximal incremental cycling test (MICT). The outcome measures were creatine kinase (CK), muscle soreness and perceived recovery status, heart rate, perceived exertion and power output. Immediately after the MICT, the cyclists performed 1 of the following 4 interventions: 2 sessions of 5-min occlusion/5-min reperfusion (PEIC or SHAM, 2 x 5) or 5 sessions of 2-min occlusion/2-min reperfusion (PEIC or SHAM, 5 x 2). The PEIC (50 mm Hg above the systolic blood pressure) or SHAM (20 mm Hg) treatment was applied unilaterally on alternating thighs. At 24 h after the interventions, a second MICT was performed. In all the groups, the CK levels were increased compared with the baseline (p < 0.05) after the 24-h MICT. The PEIC groups (2 x 5 and 5 x 2) felt more tired at 24 h post intervention (p < 0.05). However, both PEIC groups maintained their performance (2 x 5: p = 0.819; 5 x 2: p = 0.790), while the SHAM groups exhibited decreased performance at 24 h post intervention compared to baseline (2 x 5: p = 0.015; 5 x 2: p = 0.045). A decrease in the maximal heart rate (HR) was found only in the SHAM 2 x 5 group (p = 0.015). There were no other significant differences in the heart rate, power output or perceived exertion after 24 h compared with the baseline values for any of the interventions (p > 0.05). In conclusion, PEIC led to maintained exercise performance 24 h post intervention in trained cyclists. PMID- 30412605 TI - Environmental cues received during development shape dendritic cell responses later in life. AB - Environmental signals mediated via the aryl hydrocarbon receptor (AHR) shape the developing immune system and influence immune function. Developmental exposure to AHR binding chemicals causes persistent changes in CD4+ and CD8+ T cell responses later in life, including dampened clonal expansion and differentiation during influenza A virus (IAV) infection. Naive T cells require activation by dendritic cells (DCs), and AHR ligands modulate the function of DCs from adult organisms. Yet, the consequences of developmental AHR activation by exogenous ligands on DCs later in life has not been examined. We report here that early life activation of AHR durably reduces the ability of DC to activate naive IAV-specific CD8+ T cells; however, activation of naive CD4+ T cells was not impaired. Also, DCs from developmentally exposed offspring migrated more poorly than DCs from control dams in both in vivo and ex vivo assessments of DC migration. Conditional knockout mice, which lack Ahr in CD11c lineage cells, suggest that dampened DC emigration is intrinsic to DCs. Yet, levels of chemokine receptor 7 (CCR7), a key regulator of DC trafficking, were generally unaffected. Gene expression analyses reveal changes in Lrp1, Itgam, and Fcgr1 expression, and point to alterations in genes that regulate DC migration and antigen processing and presentation as being among pathways disrupted by inappropriate AHR signaling during development. These studies establish that AHR activation during development causes long-lasting changes to DCs, and provide new information regarding how early life environmental cues shape immune function later in life. PMID- 30412607 TI - MR findings of microvascular perfusion in infarcted and remote myocardium early after successful primary PCI. AB - OBJECTIVES: The aim of the study was to evaluate CMR myocardial first-pass perfusion in the injured region as well as the non-infarcted area in ST-elevation myocardial infarction (STEMI) patients few days after successful primary percutaneous coronary intervention (PCI). MATERIALS AND METHODS: 220 patients with first time STEMI successfully treated with PCI (with or without postconditioning) were recruited from the Postconditioning in STEMI study. Contrast enhanced CMR was performed at a 1.5 T scanner 2 (1-5) days after PCI. On myocardial first-pass perfusion imaging signal intensity (SI) was measured in the injured area and in the remote myocardium and maximum contrast enhancement index (MCE) was calculated. MCE = (peak SI after contrast-SI at baseline) / SI at baseline x 100. RESULTS: There were no significant differences in first-pass perfusion between patients treated with standard PCI and patients treated with additional postconditioning. The injured myocardium showed a significantly lower MCE compared to remote myocardium (94 +/- 55 vs. 113 +/- 49; p < 0.001). When patients were divided into four quartiles of MCE in the injured myocardium (MCE injured myocardium), patients with low MCE injured myocardium had: significantly lower ejection fraction (EF) than patients with high MCE injured myocardium, larger infarct size and area at risk, smaller myocardial salvage and more frequent occurrence of microvascular obstruction on late gadolinium enhancement. MCE in the remote myocardium revealed that patients with larger infarction also had significantly decreased MCE in the non-infarcted, remote area. CONCLUSION: CMR first-pass perfusion can be impaired in both injured and remote myocardium in STEMI patients treated with primary PCI. These findings indicate that CMR first pass perfusion may be a feasible method to evaluate myocardial injury after STEMI in addition to conventional CMR parameters. PMID- 30412608 TI - Rapid detection of resistance to carbapenems and cephalosporins in Enterobacteriaceae using liquid chromatography tandem mass spectrometry. AB - Carbapenemase producing Enterobacteriaceae (CPE) are becoming a global healthcare concern. Current laboratory methods for the detection of CPE include screening followed by confirmatory phenotypic and genotypic tests. These processes would generally take >=72 hours, which could negatively impact patient care and Infection Control practices. To this end, we developed a protocol for rapid resistance testing (RRT) to detect hydrolysis in a panel of beta lactam antibiotics consisting of ampicillin, cefazolin, cefotaxime and imipenem, using liquid chromatography tandem mass spectrometry. Ninety-nine beta lactamase producing Enterobacteriaceae isolates were used to evaluate the RRT method, 54 isolates were CPE and 45 isolates were Class A or AmpC beta lactamase producing Enterobacteriaceae but not carbapenemase producers. We also tested 10 E.coli isolates that were susceptible to ampicillin, cefazolin, cefotaxime and imipenem. Receiver Operating Characteristic (ROC) Curves analysis showed that imipenem had a sensitivity and a specificity of 100% for crabapenemase detection at hydrolysis cut off values that are greater than 50% and less than or equal to 80%. The RRT protocol can be conducted in a time frame of less than 2 hours. This preliminary study shows that the rapid resistance testing protocol might have utility for the rapid detection of CPE. Additional work with a greater number and variety of beta lactamase producing Enterobacteriaceae isolates is required to validate these preliminary findings. PMID- 30412609 TI - Emotional violence exerted by intimate partners and postnatal depressive symptoms among women in Vietnam: A prospective cohort study. AB - BACKGROUND: Previous studies have shown a relation between intimate partner violence (IPV) and postpartum depression (PPD). However, these studies have primarily focused on physical and sexual violence as predictors for postpartum depression and little attention has been given to emotional violence (EV), despite emotional violence having been well reported as the most common type of violence experienced by women. This present study aimed to investigate the association between various types of emotional experience during life with present partner and postnatal depressive symptoms among women in Vietnam. METHODS: A total of 1,274 pregnant women were recruited from 24 communities in the Dong Anh District, Hanoi, Vietnam. They were interviewed four times: (a) at enrolment (before week 24 of pregnancy); (b) at a gestational age of 30-34 weeks; (c) 24-48 hours after delivery; and (d) 4-12 weeks after delivery. Emotional violence and postnatal depressive symptoms were measured using a questionnaire developed by the World Health Organization (WHO) and the Edinburgh Postpartum Depression Scale (EPDS), respectively. RESULTS: A total of 639 (50.4%) women experienced at least one type of emotional violence with their present partner, whereas 104 women (8.2%) experienced postnatal depressive symptoms. Women exposed to emotional violence were more likely to experience postnatal depressive symptoms (OR = 3.15; 95%CI: 1.17-8.51). Other statistically significant predictors of increased postnatal depressive symptoms included type of employment, lack of family support after delivery, lower level of education, husband's preference for a specific sex of child, presence of mental disorder, and depression during pregnancy. CONCLUSIONS: Among Vietnamese women, there was a statistically significant association between exposure to emotional violence with their present partner and postpartum depression. The findings indicate an urgent need for screening for all acts of emotional violence as risk factors for postnatal depressive symptoms. PMID- 30412610 TI - Social visual stimuli increase infants suck response: A preliminary study. AB - This study investigated whether visual stimuli (FACES vs. CARS) combined with the presence of maternal scent can influence suck patterning in healthy infants. Fifteen healthy full-term infants (six months and younger) were exposed to their mother's scent during a visual preference paradigm consisting of FACES vs. CARS stimuli while sucking on a custom research pacifier. Infants looked significantly longer to the FACES compared to CARS, p = .041. Repeated Measures ANOVA revealed a significant main effect for non-nutritive suck (NNS) bursts and visual stimuli (p = .001) with the largest differences evident between FACES and when the infant looked away from the visual stimuli (p = 0.008) as well as between FACES and CARS (p = 0.026). These preliminary findings suggest that infants have more suck attempts when looking at FACES in the presence of maternal scent thereby indicating potent links between visual preference and suck behavior. PMID- 30412611 TI - Reassessing the role of the Escherichia coli CpxAR system in sensing surface contact. AB - For proper biofilm formation, bacteria must have mechanisms in place to sense adhesion to surfaces. In Escherichia coli, the CpxAR and RcsCDB systems have been reported to sense surfaces. The CpxAR system is widely considered to be responsible for sensing attachment, specifically to hydrophobic surfaces. Here, using both single-cell and population-level analyses, we confirm RcsCDB activation upon surface contact, but find that the CpxAR system is not activated, in contrast to what had earlier been reported. Thus, the role of CpxAR in surface sensing and initiation of biofilm formation should be reconsidered. PMID- 30412612 TI - An exploration into the efficacy of public warning signs: A zoo case study. AB - Unauthorised feeding and touching of the animals by visitors to zoos and wildlife parks pose serious threats to the health of both animals and visitors alike. We tested the efficacy of four different "do not feed" signs designed to prevent zoo visitors from feeding a group of meerkats. Signs consisted of one of two different written messages and imagery of either a pair of watching human eyes, or meerkat pawprints as a control. Covert observation of visitor behaviour in the presence and absence of the signs was analysed. Visitors were significantly less likely to feed the meerkats when signs were present, than when they were absent. The effect of the signs was specific to the targeted behaviour in that feeding was reduced, but attempts to touch the meerkats increased with the presence of the signs. We did not find that the presence of watching eyes or the different wording on the signs affected the likelihood of visitors feeding the meerkats. We also examined factors that influenced the likelihood of visitors attending to the signs. We found that children were more likely to attend to signs than adults which has important implications for the design of such signs. Together our findings show that signs are effective in reducing the unwanted behaviours they target but may also result in displacement of these negative behaviours and that children are more likely to attend to these signs than adults. PMID- 30412613 TI - Mortality prediction in patients with isolated moderate and severe traumatic brain injury using machine learning models. AB - BACKGROUND: The purpose of this study was to build a model of machine learning (ML) for the prediction of mortality in patients with isolated moderate and severe traumatic brain injury (TBI). METHODS: Hospitalized adult patients registered in the Trauma Registry System between January 2009 and December 2015 were enrolled in this study. Only patients with an Abbreviated Injury Scale (AIS) score >= 3 points related to head injuries were included in this study. A total of 1734 (1564 survival and 170 non-survival) and 325 (293 survival and 32 non survival) patients were included in the training and test sets, respectively. RESULTS: Using demographics and injury characteristics, as well as patient laboratory data, predictive tools (e.g., logistic regression [LR], support vector machine [SVM], decision tree [DT], naive Bayes [NB], and artificial neural networks [ANN]) were used to determine the mortality of individual patients. The predictive performance was evaluated by accuracy, sensitivity, and specificity, as well as by area under the curve (AUC) measures of receiver operator characteristic curves. In the training set, all five ML models had a specificity of more than 90% and all ML models (except the NB) achieved an accuracy of more than 90%. Among them, the ANN had the highest sensitivity (80.59%) in mortality prediction. Regarding performance, the ANN had the highest AUC (0.968), followed by the LR (0.942), SVM (0.935), NB (0.908), and DT (0.872). In the test set, the ANN had the highest sensitivity (84.38%) in mortality prediction, followed by the SVM (65.63%), LR (59.38%), NB (59.38%), and DT (43.75%). CONCLUSIONS: The ANN model provided the best prediction of mortality for patients with isolated moderate and severe TBI. PMID- 30412614 TI - EXPANSE: A novel narrative serious game for the behavioral assessment of cognitive abilities. AB - EFs are a set of processes that supports many cognitive domains as goal setting, monitoring, planning, and cognitive-behavioural flexible control. Currently, many standardized paper-and-pencil tests or scales are used to assess EFs. These tests are easy to administer, score, and interpret but present some limitations in terms of generalizability of behaviours in real life. More recently, Information and Communication Technology has provided a higher ecological validity in the EFs assessment. In order to increase the ecological validity, we have developed a serious game (SG), named EXPANSE, which aim was to compare the participants' game performance (latency times, and correct answers) with the results obtained in the traditional tasks and scales. 354 healthy subjects participated to the study and the findings showed significant correlations among standard tasks and the serious game. The exploratory nature of the present study, on one hand, highlighted that SG could be an additional behavioral tool to assess EFs and, on the other, we need further investigations, including clinical populations, for better defining the game sensitivity toward EF components. Finally, the results show that serious games are a promising technology for the evaluation of real cognitive behavior along with traditional evaluation. PMID- 30412615 TI - Increased risk of peptic ulcer in patients with early-onset cataracts: A nationwide population-based study. AB - Early-onset cataracts (EOC) are associated with an increased inflammatory response; therefore, a potential risk of other inflammatory diseases, like peptic ulcer, may be related. This study investigated the risk of peptic ulcer after being diagnosed with EOC. Retrospective claims data from the Taiwan National Health Insurance Research Database were analyzed. Study subjects comprised patients with EOC (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9- CM] codes 366.00, 366.01, 366.02, 366.03, 366.04, 366.09, 366.17 and 366.18), aged 20-55 years and newly diagnosed between 2000 and 2010 (n = 1910), and a comparison cohort without the disease (n = 7515). Both cohorts were followed up until 2010 to estimate the incidences of peptic ulcer. We used the Poisson regression model to compare incidence rate ratios and the 95% confidence interval (CI). Cox proportional hazards regression was used to assess the hazard ratio (HR) of peptic ulcer associated with EOC. The overall incidence rate of peptic ulcer was higher in the EOC cohort than in the comparison cohort (10.3 vs 7.68 per 1000 person-years) with an adjusted HR of 1.33 (95% CI = 1.05, 1.69). The present study suggests that patients with EOC are at an increased risk of being diagnosed with peptic ulcer in subsequent years. PMID- 30412616 TI - Differential expression of mRNA-miRNAs related to intramuscular fat content in the longissimus dorsi in Xinjiang brown cattle. AB - In this study, we examined the role of mRNAs and miRNAs in variations in intramuscular fat content in the longissimus dorsi muscle in Xinjiang brown cattle. Two groups of Xinjiang brown cattle with extremely different intramuscular fat content in the longissimus dorsi were selected for combined of miRNA and mRNA analysis using an RNA-Seq. In total, 296 mRNAs and 362 miRNAs were significantly differentially expressed, including 155 newly predicted miRNAs, 275 significantly upregulated genes, 252 significantly upregulated miRNAs, 21 significantly downregulated genes and 110 significantly downregulated miRNAs. The combined miRNA and mRNA analysis identified 96 differentially expressed miRNAs and 27 differentially expressed mRNAs. In all, 47 upregulated miRNAs had a regulatory effect on 14 differentially downregulated target genes, and 49 downregulated miRNAs had a regulatory effect on 13 upregulated target genes. To verify the sequencing results, 10 differentially expressed genes (DEGs) and 10 differentially expressed miRNAs were selected for qRT-PCR. The qRT-PCR results confirmed the sequencing results. The results of this study shed light on the molecular regulation of bovine adipose tissue, which might help with the development of new strategies for improving meat quality and animal productivity in beef cattle to provide healthier meat products for consumers. PMID- 30412617 TI - Child temperament predicts the adiposity rebound. A 9-year prospective sibling control study. AB - METHODS: We repeatedly examined 25889 siblings within the Norwegian Mother and Child Cohort Study, following them from the mothers' pregnancy through child age 8 years. Information on the children's height and weight was collected by means of health registries and maternal reports. Information on the siblings' temperament was collected by questionnaires completed when they were 1.5, 3, and 5 years old. We examined the associations of temperament at different child ages with the timing of the adiposity rebound among siblings and controls by means of growth curve and multilevel analyses. RESULTS: Within siblings, high scores on the approach trait of sociability predicted an earlier adiposity rebound and high scores on the avoidance trait of shyness predicted a later adiposity rebound with timing differences ranging between 6 and 16 weeks. Surprisingly, negative emotionality did not predict the adiposity rebound. The associations between temperament and the adiposity rebound increased with increasing child age. The results within controls-comparing siblings with the population, broadly paralleled those within siblings. CONCLUSIONS: The findings encourage the notion that child temperament functions as an early marker for the adiposity rebound. Future studies may advance our knowledge by including measures of child personality along the taxonomy of the adult Five Personality Factors. PMID- 30412618 TI - Offending behaviour, health and wellbeing of military veterans in the criminal justice system. AB - BACKGROUND: A small but significant proportion of military veterans become involved in the criminal justice system (CJS) after leaving service. Liaison and Diversion (L&D) services aim to identify vulnerable offenders in order to provide them with the health/welfare support they need, and (where possible) divert them away from custody. An administrative database of L&D service-users was utilised to compare the needs of veterans with those of non-veteran L&D service-users. METHOD: National data collected from 29 L&D services in 2015-2016 was utilised. Of the 62,397 cases, 1,067 (2%) reported previous service in the Armed Forces, and 48,578 had no previous service history. The associations between veteran status and socio-demographic characteristics, offending behaviour, health- and mental health-problems were explored. The associations between specific types of offending and mental health problems within the veterans in the sample were also investigated. RESULTS: Veterans tended to be older, and less likely to be unemployed than non-veterans, but just as likely to have unstable living arrangements (including homelessness). Veteran status was associated with increased levels of interpersonal violence, motoring offences, anxiety disorders and hazardous drinking patterns. Veteran status was associated with decreased levels of acquisitive offending, schizophrenia, ADHD, and substance misuse. Among veterans, the presence of an anxiety disorder (umbrella term which included GAD, Phobias, PTSD etc.) was associated with increased interpersonal violence, alcohol misuse was associated with increased motoring offences, and substance use was associated with increased acquisitive offending. CONCLUSIONS: Our study indicates that among offenders in the CJS who have been identified as needing health or welfare support, veterans differ from non-veterans in terms of their health and welfare needs and offending behaviour. These differences may be influenced by the impact of military service and the transition into civilian life. Our findings support the identification of military personnel within the CJS to provide appropriate interventions and support to improve outcomes and reduce offending. PMID- 30412619 TI - A simple null model for inferences from network enrichment analysis. AB - A prevailing technique to infer function from lists of identifications, from molecular biological high-throughput experiments, is over-representation analysis, where the identifications are compared to predefined sets of related genes often referred to as pathways. As at least some pathways are known to be incomplete in their annotation, algorithmic efforts have been made to complement them with information from functional association networks. While the terminology varies in the literature, we will here refer to such methods as Network Enrichment Analysis (NEA). Traditionally, the significance of inferences from NEA has been assigned using a null model constructed from randomizations of the network. Here we instead argue for a null model that more directly relates to the set of genes being studied, and have designed one dynamic programming algorithm that calculates the score distribution of NEA scores that makes it possible to assign unbiased mid p values to inferences. We also implemented a random sampling method, carrying out the same task. We demonstrate that our method obtains a superior statistical calibration as compared to the popular NEA inference engine, BinoX, while also providing statistics that are easier to interpret. PMID- 30412620 TI - Intraphagolysosomal conditions predispose to Staphylococcus epidermidis small colony variants persistence in macrophages. AB - Staphylococcus epidermidis small colony variants can survive inside macrophages and their survival has been proposed as a pivotal process in the pathogenesis of biomaterial associated infections. In the present study the intracellular location of clinical isolates of SCV and parental wild type strains inside macrophages was determined. Furthermore, the effect of IFN-gamma and rapamycin on the level of SCV/WT as well as lysosomes colocalisation and iNOS induction in THP activated macrophages in response to WT and SCV strains of Staphylococcus epidermidis were examined. It was demonstrated that SCV strain of S. epidermidis can survive and persist inside macrophages and its intracellular survival is supported by the induction of phagosomal acidification. The ability to reduce the high proportion of LysoTracker positive SCV containing phagosomes was exclusively found when IFN-gamma was used. The findings suggest that IFN-gamma mediates SCV killing via two distinct mechanisms, phagosome alkalisation and an increased iNOS synthesis, so the cytokine may control S. epidermidis WT and SCV infection in macrophages. Staphylococcus epidermidis SCV is a less potent stimulus of iNOS than the WT strain and the feature may help SCV to persist in hostile environment of macrophages. Rapamycin treatment did not influence the iNOS synthesis but reduced the percentage of both bacterial strains within acidic organelles. However, the percentage of SCV within LysoTracker positive organelles, even though reduced comparing to non-primed cells, was higher than in the WT strain indicating that Staphylococcus epidermidis possesses unique metabolic features allowing SCV to survive within macrophages. PMID- 30412621 TI - Analyzing the phylogeny of poplars based on molecular data. AB - Methods for constructing trees using DNA sequences, known as molecular phylogenetics, have been applied to analyses of phylogenetic origin, evolutionary relatedness and taxonomic classification. Combining data sequenced in this study and downloaded from GenBank, we sampled 112 (chloroplast data) / 122 (ITS data) specimens belonging to 49 (chloroplast data) / 46 (ITS data) poplar species or hybrids from six (chloroplast data) / five sections (ITS data). Maximum parsimony and Bayesian inference were used to analyze phylogenetic relationships within the genus Populus based on eight chloroplast combinations and ITS regions. The results suggested that Bayesian inference might be more suitable for the phylogenetic reconstruction of Populus. All Populus species could be divided into two clades: clade 1, including subclades 1 and 2, and clade 2, including subclades 3 and 4. Species within clade 1, involving five sections except for Leuce, clustered coinciding with their two specific main geographical distribution areas: China (subclade 1) and North America (subclade 2). Clustering in subclade 3, section Leuce was confirmed to be of monophyletic origin and independent evolution. Its two subsections, namely Albidae and Trepidae, could be separated by chloroplast data but had frequent gene flow based on ITS data. Phylogeny analysis based on chloroplast data demonstrated once more that section Aigeiros was paraphyletic and further showed that the P. deltoides lineage is restricted in subclade 2 and that P. nigra lineage, located in subclade 3, originated from a hybrid of which an Albidae ancestor species was the material parent. Similarly, section Tacamahaca was found to be paraphyletic and had two lineages: a clade 1 lineage, such as P. cathayana, and a clade 2 lineage, such as P. simonii. Section Leucoides was paraphyletic and closely linked to section Tacamahaca. Their section boundaries were not conclusively delimitated by sequencing information. PMID- 30412623 TI - Correction: Cisplatin-Induced Non-Oliguric Acute Kidney Injury in a Pediatric Experimental Animal Model in Piglets. AB - [This corrects the article DOI: 10.1371/journal.pone.0149013.]. PMID- 30412622 TI - A systematic review of clinical practice guidelines on the use of low molecular weight heparin and fondaparinux for the treatment and prevention of venous thromboembolism: Implications for research and policy decision-making. AB - BACKGROUND: Venous thromboembolism (VTE) is a major global cause of morbidity and mortality. Low molecular weight heparin (LMWH) and fondaparinux (FDP) are frequently used to treat and prevent VTE and have a variety of safety and practical advantages over other anticoagulants, including use in outpatient settings. These medications are commonly listed on drug formularies, which act as a gateway for health plan prescription coverage by outlining the circumstances under which patients will be covered for specific drugs and drug products. Because patient access to medications is impacted by the nature of their listing on formularies, they must be rigorously reviewed and modernized as new evidence emerges. METHODS: As part of a broader drug class review team, we completed a systematic review of clinical practice guidelines to determine whether the recommendations they reported aligned with the indications listed for the coverage of LMWH and FDP in an outpatient drug formulary. Guideline quality was assessed using the Appraisal of Guidelines for Research & Evaluation (AGREE) II tool. Recommendation matrices were used to systematically compare, categorize, and summarize included recommendations. RESULTS: Twenty-seven guidelines were included from which 168 eligible recommendations were identified. Generally, AGREE II domains were adequately addressed; however, domain five (applicability) was poorly addressed. Most recommendations were based on moderate- to low quality/limited evidence and reported on the use of LMWHs generally; few reported on specific agents. CONCLUSIONS: Our findings contributed to the recommendation that the formulary listing for LMWH and FDP be streamlined to include coverage for specific outpatient indications. The paucity of available evidence on the comparative efficacy of specific LMWH agents against each other and FDP limited agent-specific listing recommendations, highlighting the need for high-quality comparative studies on this topic. PMID- 30412624 TI - Analysis of bHLH genes from foxtail millet (Setaria italica) and their potential relevance to drought stress. AB - Foxtail millet is very a drought-tolerant crop. Basic helix-loop-helix (bHLH) transcription factors are involved in many drought-stress responses, but foxtail millet bHLH genes have been scarcely examined. We identified 149 foxtail millet bHLH genes in a genome-wide analysis and performed Swiss-Prot, GO, and KEGG pathway analyses for these genes. Phylogenetic analyses placed the genes into 25 clades, with some remaining orphans. We identified homologs based on gene trees and Swiss-Prot annotation. We also inferred that some homologs underwent positive selection in foxtail millet ancestors, and selected motifs differed among homologs. Expression of eight foxtail millet bHLH genes varied with drought stress. One of these genes was localized to a QTL that contributes to drought tolerance in foxtail millet. We also perform a cis-acting regulatory element analysis on foxtail millet bHLH genes and some drought-induced genes. Foxtail millet bHLH genes were inferred to have a possible key role in drought tolerance. This study clarifies both the function of foxtail millet bHLH genes and drought tolerance in foxtail millet. PMID- 30412625 TI - Improved X-ray computed tomography reconstruction of the largest fragment of the Antikythera Mechanism, an ancient Greek astronomical calculator. AB - The Antikythera Mechanism is an extraordinarily complex ancient Greek astronomical calculating device whose mode of operation is now relatively well understood particularly since imaging studies in 2005 revealed gears and inscriptions which were previously illegible. Unfortunately, the highest resolution X-ray computed tomography image of the largest fragment had some errors which meant that the reconstructed images were not as clear as had been expected. Here, the original X-ray data have been reanalysed and reconstructed. The new X-ray computed tomography images have improved contrast and resolution, leading to better clarity and legibility. The improvement in image quality is characterised and some examples of writing on the Mechanism which can now be read with increased confidence are given. PMID- 30412626 TI - Effects of different recovery strategies following a half-marathon on fatigue markers in recreational runners. AB - PURPOSE: To investigate the effects of different recovery strategies on fatigue markers following a prolonged running exercise. METHODS: 46 recreational male runners completed a half-marathon, followed by active recovery (ACT), cold water immersion (CWI), massage (MAS) or passive recovery (PAS). Countermovement jump height, muscle soreness and perceived recovery and stress were measured 24h before the half-marathon (pre), immediately after the recovery intervention (postrec) and 24h after the race (post24). In addition, muscle contractile properties and blood markers of fatigue were determined at pre and post24. RESULTS: Magnitude-based inferences revealed substantial differences in the changes between the groups. At postrec, ACT was harmful to perceived recovery (ACT vs. PAS: effect size [ES] = -1.81) and serum concentration of creatine kinase (ACT vs. PAS: ES = 0.42), with CWI being harmful to jump performance (CWI vs. PAS: ES = -0.98). It was also beneficial for reducing muscle soreness (CWI vs. PAS: ES = -0.88) and improving perceived stress (CWI vs. PAS: ES = -0.64), with MAS being beneficial for reducing muscle soreness (MAS vs. PAS: ES = -0.52) and improving perceived recovery (MAS vs. PAS: ES = 1.00). At post24, both CWI and MAS were still beneficial for reducing muscle soreness (CWI vs. PAS: ES = 1.49; MAS vs. PAS: ES = 1.12), with ACT being harmful to perceived recovery (ACT vs. PAS: ES = -0.68), serum concentration of creatine kinase (ACT vs. PAS: ES = 0.84) and free-testosterone (ACT vs. PAS: ES = -0.91). CONCLUSIONS: In recreational runners, a half-marathon results in fatigue symptoms lasting at least 24h. To restore subjective fatigue measures, the authors recommend CWI and MAS, as these recovery strategies are more effective than PAS, with ACT being even disadvantageous. However, runners must be aware that neither the use of ACT nor CWI or MAS had any beneficial effect on objective fatigue markers. PMID- 30412627 TI - Changes in propulsion technique and shoulder complex loading following low intensity wheelchair practice in novices. AB - BACKGROUND: Up to 80% of wheelchair users are affected by shoulder pain. The Clinical Practice Guidelines for preservation of upper limb function following spinal cord injury suggest that using a proper wheelchair propulsion technique could minimize the shoulder injury risk. Yet, the exact relationship between the wheelchair propulsion technique and shoulder load is not well understood. OBJECTIVE: This study aimed to examine the changes in shoulder loading accompanying the typical changes in propulsion technique following 80 min of low intensity wheelchair practice distributed over 3 weeks. METHODS: Seven able bodied participants performed the pre- and the post-test and 56 min of visual feedback-based low-intensity wheelchair propulsion practice. Kinematics and kinetics of propulsion technique were recorded during the pre- and the post-test. A musculoskeletal model was used to calculate muscle force and glenohumeral reaction force. RESULTS: Participants decreased push frequency (51->36 pushes/min, p = 0.04) and increased contact angle (68->94 degrees , p = 0.02) between the pre- and the post-test. The excursion of the upper arm increased, approaching significance (297->342 mm, p = 0.06). Range of motion of the hand, trunk and shoulder remained unchanged. The mean glenohumeral reaction force per cycle decreased by 13%, approaching significance (268->232 N, p = 0.06). CONCLUSIONS: Despite homogenous changes in propulsion technique, the kinematic solution to the task varied among the participants. Participants exhibited two glenohumeral reaction force distribution patterns: 1) Two individuals developed high force at the onset of the push, leading to increased peak and mean glenohumeral forces 2) Five individuals distributed the force more evenly over the cycle, lowering both peak and mean glenohumeral forces. PMID- 30412628 TI - Changes in hypoxia level of CT26 tumors during various stages of development and comparing different methods of hypoxia determination. AB - The aim of this study was to evaluate hypoxia level at various tumor developmental stages and to compare various methods of hypoxia evaluation in pre clinical CT26 tumor model. Using three methods of hypoxia determination, we evaluated hypoxia levels during CT26 tumor development in BALB/c mice from day 4 till day 19, in 2-3 days intervals. Molecular method was based on the analysis of selected genes expression related to hypoxia (HIF1A, ANGPTL4, TGFB1, VEGFA, ERBB3, CA9) or specific for inflammation in hypoxic sites (CCL2, CCL5) at various time points after CT26 cancer cells inoculation. Imaging methods of hypoxia evaluation included: positron-emission tomography (PET) imaging using [18F]fluoromisonidazole ([18F]FMISO) and a fluorescence microscope imaging of pimonidazole (PIMO)-positive tumor areas at various time points. Our results showed that tumor hypoxia at molecular level was relatively high at early stage of tumor development as reflected by initially high HIF1A and VEGFA expression levels and their subsequent decrease. However, imaging methods (both PET and fluorescence microscopy) showed that hypoxia increased till day 14 of tumor development. Additionally, necrotic regions dominated the tumor tissue at later stages of development, decreasing the number of hypoxic areas and completely eliminating normoxic regions (observed by PET). These results showed that molecular methods of hypoxia determination are more sensitive to show changes undergoing at cellular level, however in order to measure and visualize hypoxia in the whole organ, especially at later stages of tumor development, PET is the preferred tool. Furthermore we concluded, that during development of tumor, two peaks of hypoxia occur. PMID- 30412629 TI - The influence of income and testosterone on the validity of facial width-to height ratio as a biomarker for dominance. AB - Research has indicated that men's facial width-to-height ratio (fWHR) is part of an evolved system of social dominance, aggression, and power. fWHR has been linked to antisocial behavior, measured by self-reported aggression, but recent studies have failed to replicate this finding. To overcome these inconsistencies, influencing factors such as social status have to be taken into account in order to explain the relationship between fWHR and aggression. In particular, income has been shown to be an important influencing factor in this relationship. Furthermore, previous findings suggested that testosterone is linked to fWHR and might be associated with fWHR and dominance-related outcomes. Therefore, this study examined the influence of both social status defined by income and salivary testosterone on the association between fWHR and self-reported dominance-related behavioral traits. In particular, links between fWHR and self-report measures of aggression and the Dark Triad (encompassing psychopathy, Machiavellianism, and narcissism) were investigated in N = 109 men aged 40 to 75 years. fWHR was significantly associated with physical aggression and two of the Dark Triad traits (psychopathy and Machiavellianism) in men reporting low income. The relationship between fWHR and narcissism was moderated by testosterone. The findings highlight the importance of considering social status and neuroendocrine parameters such as testosterone when examining associations between fWHR and complex psychological traits and behaviors. PMID- 30412630 TI - Coagulation biomarkers and prediction of venous thromboembolism and survival in small cell lung cancer: A sub-study of RASTEN - A randomized trial with low molecular weight heparin. AB - Coagulation activation and venous thromboembolism (VTE) are hallmarks of cancer; however, there is an unmet need of improved biomarkers for individualized anticoagulant treatment. The present sub-study of the RASTEN trial was designed to explore the role of coagulation biomarkers in predicting VTE risk and outcome in a homogenous cancer patient population. RASTEN is a multicenter, randomized phase-3 trial investigating the survival effect of low molecular weight heparin enoxaparin when added to standard treatment in newly diagnosed small cell lung cancer (SCLC) patients. Plasma collected at baseline, during treatment, and at follow-up was used in this ad hoc sub-study (N = 242). Systemic coagulation was assessed using four assays reflecting various facets of the coagulation system: Total tissue factor (TF); extracellular vesicle associated TF (EV-TF); procoagulant phospholipids (PPL); and thrombin generation (TG). We found small variations of biomarker levels between baseline, during treatment and at follow up, and appeared independent on low molecular weight heparin treatment. Overall, none of the measured biomarkers at any time-point did significantly associate with VTE incidence, although increased total TF at baseline showed significant association in control patients not receiving low molecular weight heparin (P = 0.03). Increased TG-Peak was significantly associated with decreased overall survival (OS; P = 0.03), especially in patients with extensive disease. Low baseline EV-TF predicted a worse survival in the low molecular weight heparin as compared with the control group (HR 1.42; 95% CI 1.04-1.95; P = 0.03; P for interaction = 0.12). We conclude that the value of the analyzed coagulation biomarkers for the prediction of VTE risk was very limited in SCLC patients. The associations between TG-Peak and EV-TF with patient survival and response to low molecular weight heparin therapy, respectively, warrant further studies on the role of coagulation activation in SCLC aggressiveness. PMID- 30412631 TI - Ecological and evolutionary implications of allometric growth in stomach size of brachyuran crabs. AB - Individual characteristics often scale allometrically with organismal body size and the form of this scaling can be influenced by ecological and evolutionary factors. Examining the specific form of this scaling can therefore yield important insights into organismal ecology and evolution and the ability of organisms to respond to future environmental changes. We examine the intraspecific allometric scaling of stomach volume with body mass for 17 species of brachyuran crabs. We also examine how this scaling is influenced by dietary strategy, maximum body size, and activity level, all while controlling for phylogenetic relationships between the species. We show that the slope and intercept of the allometric scaling relationships vary across species and are influenced by all three ecological factors examined here, as well as by evolutionary relationships. These results highlight potential divergent strategies in stomach growth taken by different groups of crabs and highlight potential limitations that may be imposed on the ability of this group of organisms to respond to warming trends expected with climate change. PMID- 30412632 TI - Synergistic effect of Dermatophagoides pteronyssinus allergen and Escherichia coli lipopolysaccharide on human blood cells. AB - PURPOSE: House dust mites Dermatophagoides pteronyssinus are the main source of major inhalatory allergens inducing inflammatory response. Mite extract contain both allergenic proteins and lipopolysaccharides (LPS). The main allergenic protein, Der p 2, is a functional homolog of sMD-2, a protein providing blood cell response on LPS. Der p 2 may restore the response to LPS in absence of MD-2, but its interaction with LPS in whole blood is unknown. We studied the effect of Der p 2 on LPS-mediated activation of human whole blood cells. METHODS: Interaction of Der p 2 and LPS was studied on eight healthy donors. The whole blood was incubated with extract of house dust mite Dermatophagoides pteronyssinus (DP-e), recombinant antigenic protein Der p 2 variant 5 (rDep 2), Escherichia coli lipopolysaccharide and their combination. Supernatants were collected for ELISA analysis of protein content. Activation degree was determined by change in concentration of TNF-alpha, IL-8, IL-1Ra cytokines and sMD-2 protein. RESULTS: extract of mite Dermatophagoides pteronyssinus (DP-e) possessed weak inherent activity and did not cause significant increase of cytokine production. Simultaneous activation of blood cells by LPS and DP-e led to considerable increase of pro-inflammatory cytokine production. We have shown the intrinsic inducing activity of Der p 2 allergen on sMD-2 protein and TNF-alpha cytokine expression. CONCLUSIONS: Der p 2 allergen enhances the response of human whole blood cells to external LPS by inducing additional expression of LPS transporting protein sMD-2. The obtained data show an important role of LPS contamination of allegrens in the progress of allergic inflammatory response. PMID- 30412633 TI - Mapping maternal mortality rate via spatial zero-inflated models for count data: A case study of facility-based maternal deaths from Mozambique. AB - Maternal mortality remains very high in Mozambique, with estimates from 2015 showing a maternal mortality ratio of 489 deaths per 100,000 live births, even though the rates tend to decrease since 1990. Pregnancy related hemorrhage, gestational hypertension and diseases such as malaria and HIV/AIDS are amongst the leading causes of maternal death in Mozambique, and a significant number of these deaths occur within health facilities. Often, the analysis of data on maternal mortality involves the use of counts of maternal deaths as outcome variable. Previously we showed that a class of hierarchical zero-inflated models were very successful in dealing with overdispersion and clustered counts when analyzing data on maternal deaths and related risk factors within health facilities in Mozambique. This paper aims at providing additional insights over previous analyses and presents an extension of such models to account for spatial variation in a disease mapping framework of facility-based maternal mortality in Mozambique. PMID- 30412634 TI - Surveillance of adverse drug events associated with etanercept prescribed for juvenile idiopathic arthritis in a single center up to 9-years: A retrospective observational study. AB - The introduction of biologic agents opened a new era of treatment of juvenile idiopathic arthritis (JIA) over the past decade. From clinical experience, it appears that biological agents are well tolerated overall, and serious adverse events are rare. However, such clinical studies have not been conducted in Korea. Therefore, we examined the safety profile of JIA patients with biologics in a single center in Korea. All JIA outpatients treated from April 2004 to June 2013 were enrolled and retrospectively reviewed. Pharmacy-based surveillance of adverse drug events (ADEs) was identified by recording the patient's symptoms in the medical record and suspected ADEs were additionally explored by screening laboratory test values and observing changes in medication orders. Finally, 83 patients were enrolled and experienced 109 ADEs in 52 patients. Most ADEs (99.1%) were mild to moderate in severity assessment. The total follow-up time was 328 patient-treatment years and the overall rate of ADEs was 0.33 per patient-years for etanercept. Infection including upper respiratory tract was the most common ADE and concomitant corticosteroids contributed to the risk of infections. If the dose of prednisolone increases 0.34 mg/kg/day, the probability of developing infections increases 3.29 times. Also, all 11 patients who stopped etanercept with injection site reactions were receiving a single use prefilled syringe. In our study, etanercept appears well tolerated and safe. Children affected by JIA should be carefully monitoring so as to limit the risk of ADEs during etanercept as much as possible. To gain further knowledge about risk profiles, national collaboration for the accumulation of long-term data should be encouraged in Korea. PMID- 30412635 TI - Automatic detection and classification of manufacturing defects in metal boxes using deep neural networks. AB - This paper develops a new machine vision framework for efficient detection and classification of manufacturing defects in metal boxes. Previous techniques, which are based on either visual inspection or on hand-crafted features, are both inaccurate and time consuming. In this paper, we show that by using autoencoder deep neural network (DNN) architecture, we are able to not only classify manufacturing defects, but also localize them with high accuracy. Compared to traditional techniques, DNNs are able to learn, in a supervised manner, the visual features that achieve the best performance. Our experiments on a database of real images demonstrate that our approach overcomes the state-of-the-art while remaining computationally competitive. PMID- 30412636 TI - Cost effectiveness of a community based prevention and treatment of acute malnutrition programme in Mumbai slums, India. AB - Children in slums are at high risk of acute malnutrition and death. Cost effectiveness of community-based management of severe acute malnutrition programmes has been demonstrated previously, but there is limited evidence in the context of urban slums where programme cost structure is likely to vary tremendously. This study assessed the cost-utility of adding a community based prevention and treatment for acute malnutrition intervention to Government of India Integrated Child Development Services (ICDS) standard care for children in Mumbai slums. The intervention is delivered by community health workers in collaboration with ICDS Anganwadi community health workers. The analysis used a decision tree model to compare the costs and effects of the two options: standard ICDS services with the intervention and prevention versus standard ICDS services alone. The model used outcome and cost data from the Society for Nutrition, Education & Health Action's Child Health and Nutrition programme in Mumbai slums, which delivered services to 12,362 children over one year from 2013 to 2014. An activity-based cost model was used, with calculated costs based on programme financial records and key informant interviews. Cost data were coupled with programme effectiveness data to estimate disability adjusted life years (DALYs) averted. The community based prevention and treatment programme averted 15,016 DALYs (95% Uncertainty Interval [UI]: 12,246-17,843) at an estimated cost of $23 per DALY averted (95%UI:19-28) and was thus highly cost-effective. This study shows that ICDS Anganwadi community health workers can work efficiently with community health workers to increase the prevention and treatment coverage in slums in India and can lead to policy recommendations at the state, and potentially the national level, to promote such programmes in Indian slums as a cost-effective approach to tackling moderate and severe acute malnutrition. PMID- 30412637 TI - Comparison of proinsulin and C-peptide secretion in healthy versus long-standing type 1 diabetes mellitus cohorts: A pilot study. AB - AIMS: Increased proinsulin (PI) compared to C-peptide (CP) concentrations have been reported, both prior to type 1 diabetes mellitus (T1D) onset, as well as early in disease. In this pilot study, we sought to define the normal PI secretion in a healthy cohort and compare this to a local T1D cohort and a separate well-defined nationally representative T1D cohort with measurable CP. METHODS: Thirteen healthy subjects and 12 T1D subjects with T1D >3 years from the local T1D cohort completed mixed meal tolerance tests (MMTT) with PI and CP measured over 90 and 240 minutes. The change in CP (maximum versus baseline, DeltaCP) during MMTT in the T1D Exchange T1D cohort was stratified according to non-fasting PI concentrations, based on a fasting PI threshold, as defined by the healthy control group. RESULTS: The maximum fasting PI in the control group was 6 pmol/L. Individuals from the T1D Exchange with a non-fasting PI >= 6 pmol/L had a lower DeltaCP during a MMTT, compared to those with a PI < 6 pmol/L. While only three individuals from the local T1D cohort had measurable CP and PI during the MMTT, those with a greater DeltaCP had lower PI secretion. CONCLUSION: While all T1D subjects from the T1D Exchange secreted measurable non-fasting PI, those with a greater non-fasting PI demonstrated a decrease in DeltaCP during the MMTT. PI may be preferentially secreted compared to CP in some individuals with long standing T1D. PMID- 30412638 TI - Design and use of a novel substrate for simple, rapid, and specific early detection of anthrax infection. AB - Bacillus anthracis is a major biological warfare threat. The inhalation form of infection can kill quickly. While antibiotic treatment is effective, if diagnosis is delayed, the rapidly produced toxin may already be present in lethal amounts. This report describes a fast, sensitive, specific and accurate method for detection of active infection by Bacillus anthracis in plasma. One of the virulence factors, anthrax lethal factor, is an endopeptidase present in blood early in the infection. However, the use of peptidic substrates to detect endopetidases is problematic in plasma due to the presence of other proteases and the likelihood of nonspecific cleavage of the substrate. The fluorescently labeled peptide substrate MAPKKide Plus designed in this study is not cleaved by plasma proteases and thus is specific for lethal factor. Three detection strategies are described. Two include enrichment by capture from plasma using lethal factor antibody-coated microtiter plates or similarly coated immuno-tubes. The captured lethal factor is exposed to the MAPKKide Plus, and the amount of cleavage is determined either by HPLC or microplate reader. Concentration of lethal factor using the antibody-coated plates aplnd HPLC allows for detection of less than 5 pg lethal factor/ml of neat plasma after 2 hours of incubation. Using antibody-coated immuno-tubes, 20 pg lethal factor/ml plasma can be detected in 5 hours by a simple end point read of fluorescence in a microplate reader. For a third strategy, the substrate is added directly to diluted plasma, and cleavage is monitored by the increase in fluorescence as a function of time. The limit of detection by this simple method is 25 ng lethal factor/ml of plasma in 15 minutes, 5 ng/ml after 45 minutes, and <1 ng lethal factor/ml of plasma after 5 hours. PMID- 30412641 TI - Some suggestions to non-specialized centers still managing placenta accreta spectrum disorders. PMID- 30412639 TI - Risk factors and outcomes of incidental parathyroidectomy in thyroidectomy: A systematic review and meta-analysis. AB - INTRODUCTION: Postoperative hypocalcemia is the most common complication of thyroidectomy. Incidental parathyroidectomy (IP) was thought to be associated with postoperative hypocalcemia. However, according to previous studies, the risk factors and clinical outcomes of IP remain controversial. METHODS: Eligible studies were searched in databases including PubMed, Web of Science, and EMBASE from January 1990 to September 2017. Articles focusing on the relationship between IP and postoperative hypocalcemia were included. The risk of publication bias was assessed using Begg's test and Egger's regression asymmetry test. Pooled analysis was performed to evaluate the effect of IP on postoperative hypocalcemia and related risk factors. Sensitivity analysis was also conducted to test the stability of our results. The effects of hypocalcemia type, permanent definition, IP incidence, total thyroidectomy, and malignancy operation were also examined using a further subgroup analysis. RESULTS: Thirty-five studies were finally included in the analysis after an exhaustive literature review. Pathology data demonstrate that incidental parathyroidectomy occurred in various locations: intrathyroidal (2.2-50.0%), intracapsular (16.7-40.0%) and extracapsular (15.7 81.1%) regions. Overall, the analysis found that malignancy (RR = 1.60, 95% CI: 1.27 to 2.02; p< 0.0001), central neck dissection (RR = 2.35, 95% CI: 1.47 to 3.75; p = 0.0004), total thyroidectomy (RR = 1.42, 95% CI: 1.20 to 1.67; p< 0.0001) and reoperation (RR = 1.81, 95% CI: 1.20 to 2.75; p = 0.005) were significant risk factors of IP in thyroid surgery. There was an obvious effect of IP on temporary/permanent (RR = 1.59, 95% CI: 1.37 to 1.84; p< 0.0001) and permanent (RD = 0.0220, 95% CI: 0.0069 to 0.0370; p = 0.0042) postoperative hypocalcemia. Sensitivity analysis showed that these results were robust. The subgroup analysis found that IP played a significant role in both biochemical and clinical hypocalcemia in thyroidectomy (p < 0.0001 and p = 0.0003, separately). The association of IP and permanent hypocalcemia using different definitions (6 months or more than 12 months) was also confirmed by the analysis. IP increased the incidence of temporary/permanent and permanent hypocalcemia for cases undergoing total thyroidectomy (40.4% vs 24.8% and 5.8% vs 1.4%, respectively). Thyroidectomy with IP was associated with more permanent hypocalcemia (RR = 3.10, 95% CI: 2.01 to 4.78; p< 0.0001) in malignant cases but was not associated with temporary/permanent hypocalcemia. CONCLUSIONS: Malignancy, central neck dissection, total thyroidectomy and reoperation were found to be significant risk factors of IP. IP increases the risk of postoperative hypocalcemia after thyroidectomy. We recommend a more meticulous intraoperative identification of parathyroid gland in thyroidectomy to reduce IP, particularly for total thyroidectomy and malignancy cases. PMID- 30412640 TI - GutLogo: Agent-based modeling framework to investigate spatial and temporal dynamics in the gut microbiome. AB - Knowledge of the spatial and temporal dynamics of the gut microbiome is essential to understanding the state of human health, as over a hundred diseases have been correlated with changes in microbial populations. Unfortunately, due to the complexity of the microbiome and the limitations of in vivo and in vitro experiments, studying spatial and temporal dynamics of gut bacteria in a biological setting is extremely challenging. Thus, in silico experiments present an excellent alternative for studying such systems. In consideration of these issues, we have developed a user-friendly agent-based model, GutLogo, that captures the spatial and temporal development of four representative bacterial genera populations in the ileum. We demonstrate the utility of this model by simulating population responses to perturbations in flow rate, nutrition, and probiotics. While our model predicts distinct changes in population levels due to these perturbations, most of the simulations suggest that the gut populations will return to their original steady states once the disturbance is removed. We hope that, in the future, the GutLogo model is utilized and customized by interested parties, as GutLogo can serve as a basic modeling framework for simulating a variety of physiological scenarios and can be extended to capture additional complexities of interest. PMID- 30412642 TI - Distribution of disease courses in familial vs sporadic multiple sclerosis. AB - OBJECTIVES: The overall distribution of disease courses in multiple sclerosis (MS) is well established, but little is known about the distribution among familial MS cases. We examine the frequency of the different MS courses among familial and sporadic MS cases and determine whether MS cases within the same family had the same age at diagnosis and have experienced the same disease course. MATERIALS AND METHODS: This is a nationwide register study, based on data from the Danish MS Registry, the Danish Civil Registration System, and the Danish National Patient Registry. The main variables are MS diagnosis, MS course, and first-degree relatives with MS The statistical analyses were carried out using logistic regression analysis, Kappa coefficient, and intraclass correlations coefficient. RESULTS: In total, 7402 MS cases were included in the study, of which 531 have an affected first-degree relatives, and 6871 are sporadic. We found that relapsing-remitting MS including secondary progressive MS was more common among familial MS cases than among sporadic MS cases (Odds ratio = 1.64, 95% CI: 1.20-2.24, P = 0.002). We subsequently analyzed data on 133 MS families and found that MS courses correlate between the first and the second MS case diagnosed, while age at diagnosis does not. CONCLUSION: Familial MS cases are more likely to have relapsing-remitting MS than a progressive course compared to sporadic MS cases. Secondly, we find that within MS families, first-degree relatives are likely to have the same MS course, but we do not find that they are diagnosed at the same age. PMID- 30412643 TI - Theileria highjacks JNK2 into a complex with the macroschizont GPI (GlycosylPhosphatidylInositol)-anchored surface protein p104. AB - Constitutive c-Jun N-terminal kinase (JNK) activity characterizes bovine T and B cells infected with Theileria parva, and B cells and macrophages infected with Theileria annulata. Here, we show that T. annulata infection of macrophages manipulates JNK activation by recruiting JNK2 and not JNK1 to the parasite surface, whereas JNK1 is found predominantly in the host cell nucleus. At the parasite's surface, JNK2 forms a complex with p104, a GPI (GlycosylPhosphatidylInositol)-anchor T. annulata plasma membrane protein. Sequestration of JNK2 depended on Protein Kinase-A (PKA)-mediated phosphorylation of a JNK-binding motif common to T. parva and a cell penetrating peptide harbouring the conserved p104 JNK-binding motif competitively ablated binding, whereupon liberated JNK2 became ubiquitinated and degraded. Cytosolic sequestration of JNK2 suppressed small mitochondrial ARF-mediated autophagy, whereas it sustained nuclear JNK1 levels, c-Jun phosphorylation, and matrigel traversal. Therefore, T. annulata sequestration of JNK2 contributes to both survival and dissemination of Theileria-transformed macrophages. PMID- 30412644 TI - Incurred sample reanalysis in drug discovery bioanalysis. AB - Bioanalysis plays a key role during the drug discovery process to generate the pharmacokinetic data to facilitate unbiased evaluation of leads, optimized leads and drug candidates. Such pharmacokinetic data are used to enable key decisions in the drug discovery process. The aim of the work is to put forward a new strategy of performing the incurred sample reanalysis for select small molecule novel chemical entities at different stages of drug discovery prior to candidate selection. Three discovery programs representing hits, leads and optimized lead candidates were selected for the incurred sample reanalysis (ISR) analysis. From each discovery program, two novel chemical entities were selected for the ISR analysis. The time points considered for ISR generally varied among the programs; however, samples coinciding with drug absorption, distribution and elimination were considered in the ISR assessment. With the exception of a single ISR value that gave a high deviation (about 63%), the observed ISR values supported the discovery bioanalytical assays. While the individual bioanalytical laboratory can draw an algorithm for selecting novel chemical entities and fixing the acceptance criteria for the ISR data, it is proposed that the percentage difference between ISR vs. original concentration for 67% of the repeat samples is contained within +/-30% for discovery bioanalysis. PMID- 30412645 TI - Single-Cell Transcriptomics of Human Mesenchymal Stem Cells Reveal Age-Related Cellular Subpopulation Depletion and Impaired Regenerative Function. AB - Although bone marrow-derived mesenchymal stem cells (BM-MSCs) are widely recognized as promising therapeutic agents, the age-related impacts on cellular function remain largely uncharacterized. In this study, we found that BM-MSCs from young donors healed wounds in a xenograft model faster compared with their aged counterparts (p < .001). Given this significant healing advantage, we then used single-cell transcriptomic analysis to provide potential molecular insights into these observations. We found that the young cells contained a higher proportion of cells characterized by a higher expression of genes involved in tissue regeneration. In addition, we identified a unique, quiescent subpopulation that was exclusively present in young donor cells. Together, these findings may explain a novel mechanism for the enhanced healing capacity of young stem cells and may have implications for autologous cell therapy in the extremes of age. Stem Cells 2018. PMID- 30412646 TI - Soil aggregates as biogeochemical reactors and implications for soil-atmosphere exchange of greenhouse gases-A concept. AB - Soil-atmosphere exchange significantly influences the global atmospheric abundances of carbon dioxide (CO2 ), methane (CH4 ), and nitrous oxide (N2 O). These greenhouse gases (GHGs) have been extensively studied at the soil profile level and extrapolated to coarser scales (regional and global). However, finer scale studies of soil aggregation have not received much attention, even though elucidating the GHG activities at the full spectrum of scales rather than just coarse levels is essential for reducing the large uncertainties in the current atmospheric budgets of these gases. Through synthesizing relevant studies, we propose that aggregates, as relatively separate micro-environments embedded in a complex soil matrix, can be viewed as biogeochemical reactors of GHGs. Aggregate reactivity is determined by both aggregate size (which determines the reactor size) and the bulk soil environment including both biotic and abiotic factors (which further influence the reaction conditions). With a systematic, dynamic view of the soil system, implications of aggregate reactors for soil-atmosphere GHG exchange are determined by both an individual reactor's reactivity and dynamics in aggregate size distributions. Emerging evidence supports the contention that aggregate reactors significantly influence soil-atmosphere GHG exchange and may have global implications for carbon and nitrogen cycling. In the context of increasingly frequent and severe disturbances, we advocate more analyses of GHG activities at the aggregate scale. To complement data on aggregate reactors, we suggest developing bottom-up aggregate-based models (ABMs) that apply a trait-based approach and incorporate soil system heterogeneity. PMID- 30412647 TI - Hg(II)-Mediated Tl(I)-to-Tl(III) Oxidation in Dynamic Pb(II)/Tl Porphyrin Complexes. AB - Compared to their purely organic counterparts, molecular switches based on metal ion translocations have been underexplored and, more particularly, it remains challenging to control the translocation of several particles in multisite receptors. Recently, bimetallic complexes undergoing double translocation processes have been developed with bis-strapped porphyrin ligands and in order to implement a redox control for these systems, we have investigated herein the formation of heteromultimetallic lead/thallium complexes, with thallium stable in the +I and +III oxidation states. Two different complexes were characterized: (i) a Pb(II)/Tl(I) complex with both metal ions interacting with the N-core on its different sides; (ii) a Pb(II)/Tl(III) complex with Tl(III) selectively bound to the N-core and Pb(II) selectively bound to the strap opposite to Tl(III). These two complexes undergo an equilibrium between their two degenerate forms (same coordination of the metal ions but on opposite sides), according to different intra or intermolecular translocation pathways. In addition, conversion of the Pb(II)/Tl(I) complex into its Pb(II)/Tl(III) counterpart was achieved by addition of a stoichiometric amount of Hg(II) salt as a sacrificial electron acceptor. These results further contribute to the elaboration of devices inspired from the working principle of a Newton's cradle. PMID- 30412648 TI - Is the hub-and-spoke model of care delivery a possible answer to geographical variation in liver transplant outcomes? PMID- 30412649 TI - A novel role of angiotensin II in epidermal cell lineage determination: Angiotensin II promotes the differentiation of mesenchymal stem cells into keratinocytes through the p38 MAPK, JNK and JAK2 signalling pathways. AB - BACKGROUND: Recent evidence suggests that angiotensin II (Ang II) plays a role in cutaneous wound healing. Mesenchymal stem cells (MSCs) are known as a rich source of cells that re-establish healed skin. However, the potential impact of Ang II on MSC differentiation into keratinocytes is still unknown. OBJECTIVE: The present study was conducted to explore the effect of Ang II on differentiation of bone marrow-derived MSCs (BM-MSCs) into keratinocytes. METHODS: BM-MSCs were isolated from rat bone marrow and cultured. The expression of Ang II type 1 (AT1 ) and type 2 (AT2 ) receptors was examined by immunofluorescence staining. The differentiation of BM-MSCs into keratinocytes was investigated by flow cytometry or/and histological observation. RESULTS: The BM-MSCs constitutively expressed both AT1 and AT2 receptors. The differentiation of BM-MSCs into keratinocytes was successfully induced. Interestingly, incubation of BM-MSCs with Ang II further promoted the differentiation of BM-MSCs into keratinocyte, which was abolished by pre-treatment with losartan, an AT1 receptor antagonist, but not by PD123319, an AT2 receptor antagonist. Moreover, the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580, the c-Jun N-terminal kinase (JNK) inhibitor SP600125 and the Janus-activated kinase (JAK)2 inhibitor AG490 suppressed Ang II-induced differentiation of BM-MSCs into keratinocytes. The phosphoinositide-3 kinase (PI3K) inhibitor wortmannin and MEK1/2 inhibitor U0126 had no effect on BM-MSC differentiation into keratinocytes. CONCLUSIONS: Our data demonstrated for the first time that Ang II plays a promotive role in the differentiation of BM-MSC into keratinocytes through the AT1 receptor, and that the p38 MAPK, JNK and JAK2 signalling pathways are involved in this process. This article is protected by copyright. All rights reserved. PMID- 30412650 TI - Protease-activated receptor-1 impedes prostate and intestinal tumor progression in mice: comment. PMID- 30412651 TI - Natural multi-target inhibitors of cholinesterases and monoamine oxidase enzymes with antioxidant potential from skin extracts of Hypsiboas cordobae and Pseudis minuta (Anura: Hylidae). AB - Alzheimer's disease (AD) is the most common cause of dementia, characterized by loss of selective neuronal and normal brain functions. Every year, ten million new cases are diagnosed worldwide. AD is a complex disease associated with all kind of different pathways, making their simultaneous modulation necessary. Nowadays anti-AD treatments are focused on enzymatic inhibitors. The study of the amphibians' skin had acquired great importance in the fields of biology and human health and represents an attractive and novel source for natural compounds with high potential in the development of new drugs. The present work exhibits the power of amphibian skins as a source of bioactive compounds. Here in we report the activity of extracts of two species from Hylidae family (H. cordobae and P. minuta) as reversible inhibitors of acetylcholinesterase and butyrylcholinesterase enzymes. Furthermore, the extracts inhibit MAO-B enzyme and showed antioxidant activities, acting on four important pathways of AD. PMID- 30412652 TI - Independent risk factors for pressure ulcer development in a high-risk nursing home population receiving evidence-based pressure ulcer prevention: Results from a study in 26 nursing homes in Belgium. AB - The aim of this study was to identify independent risk factors for pressure ulcer (PU) development in a high-risk nursing home population receiving evidence-based PU prevention. This study was part of a randomised controlled trial examining the (cost-)effectiveness of static air support surfaces compared with alternating pressure air mattresses. The sample consisted of 308 residents at a high risk of PU development (presence of non-blanchable erythema, Braden score <= 12 or Braden subscale "mobility" <= 2). PU incidence was monitored for 14 days. Demographic variables; functional, physical, and psychological characteristics; and data on skin assessment were collected. Independent risk factors were identified using multiple logistic regression analysis. The overall PU incidence (category II-IV) was 8.4% (n = 26), and 1.9% (n = 6) of the residents developed a deep PU (category III-IV). PUs (category II-IV) were significantly associated with non blanchable erythema, a lower Braden score, and pressure area-related pain in high risk residents even if preventive care was provided. These results highlight the need of a systematic risk assessment, including pain assessment and skin observations, in order to determine and tailor preventive care to the needs of high-risk individuals. PMID- 30412653 TI - Crosslinked clots formed independently of factor XIII and without fibrinogen-to fibrin conversion - is this a liver-specific phenomenon? AB - Both basic and applied studies dealing with aspects of hemostasis in liver diseases have spurred significant controversy over the last two decades[1]. Clinically, we have learnt that patients with liver diseases do not necessarily have a hemostatic defect resulting in a bleeding tendency. Instead, these patients appear in hemostatic balance due to a decline in both pro- and antihemostatic pathways, and may experience both bleeding and thrombotic complications when this reset hemostatic balance is offset[2]. This article is protected by copyright. All rights reserved. PMID- 30412654 TI - Long-Term Outcomes of Eculizumab-Treated Positive Crossmatch Recipients: Allograft Survival, Histologic Findings, and Natural History of the Donor Specific Antibodies. AB - We aimed to determine long-term outcomes for eculizumab-treated, positive crossmatch (+XM) kidney transplant recipients compared with +XM and age-matched negative crossmatch (-XM) controls. We performed an observational retrospective study and examined allograft survival, histologic findings, long-term B-cell flow cytometric XM (BFXM), and allograft-loss-associated factors. The mean (SD) posttransplant follow-up was 6.3 (2.5) years in the eculizumab group; 7.6 (3.5), +XM control group; 7.9 (2.5), -XM control group. Overall and death-censored allograft survival were similar in +XM groups (P=.73, P=.48) but reduced compared with -XM control patients (P<.001, P<.001). In the eculizumab-treated group, 57.9% (11/19) of allografts had chronic antibody-mediated rejection, but death censored allograft survival was 76.6%, 5 years; 75.4%, 7 years. Baseline IgG3 positivity and BFXM >=300 were associated with allograft loss. C1q positivity was also associated with allograft loss but did not reach statistical significance. Donor-specific antibodies appeared to decrease in eculizumab-treated patients. After excluding patients with posttransplant plasmapheresis, 42.3% (9/21) had negative BFXMs; 31.8% (7/22), completely negative single-antigen beads 1 year posttransplant. Eculizumab-treated +XM patients had reduced allograft survival compared with -XM controls but similar survival to +XM controls. BFXM and complement-activating DSA (by IgG3 and C1q testing) may be used for risk stratification in +XM transplantation. This article is protected by copyright. All rights reserved. PMID- 30412655 TI - Empagliflozin and kidney outcomes in Asian patients with type 2 diabetes and established cardiovascular disease: results from the EMPA-REG OUTCOME(r) trial. AB - AIMS/INTRODUCTION: In the EMPA-REG OUTCOME(r) trial, empagliflozin added to standard of care improved clinically relevant kidney outcomes by 39%, slowed progression of chronic kidney disease, and reduced albuminuria in patients with type 2 diabetes and established cardiovascular disease. This exploratory analysis investigated kidney effects of empagliflozin in Asian patients. MATERIALS AND METHODS: Participants in EMPA-REG OUTCOME(r) were randomized (1:1:1) to empagliflozin 10 mg, 25 mg, or placebo. In patients of Asian race, we analyzed incident or worsening nephropathy (progression to macroalbuminuria, doubling of serum creatinine, initiation of renal-replacement therapy, or renal death) and its components, estimated glomerular filtration rate (eGFR) and urine albumin-to creatinine ratio (UACR) changes, and renal safety. RESULTS: Of 7020 treated patients, 1517 (26.1%) were Asian. In this subgroup, consistent with the overall trial population, empagliflozin reduced the risk of incident or worsening nephropathy (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.49, 0.83), progression to macroalbuminuria (HR 0.64; 95% CI 0.49, 0.85), and the composite of doubling of serum creatinine, initiation of renal-replacement therapy, or renal death (HR 0.48; 95% CI 0.25, 0.92). Furthermore, empagliflozin-treated participants demonstrated slower eGFR decline versus placebo and showed rapid UACR reduction at Week-12, maintained through Week-164, with effects most pronounced in those with baseline microalbuminuria or macroalbuminuria. The kidney safety profile of empagliflozin in the Asian subgroup was similar to the overall trial population. CONCLUSIONS: In Asian patients from EMPA-REG OUTCOME(r) , empagliflozin improved kidney outcomes, slowed eGFR decline and lowered albuminuria versus placebo, consistent with the overall trial population findings. This article is protected by copyright. All rights reserved. PMID- 30412658 TI - Battling the HIV/AIDS Epidemic: Triumphs and Barriers. AB - Worldwide, over 77 million people have been infected by human immunodeficiency virus (HIV) but its cure remains elusive. Once considered a fatal disease, advances in antiretroviral therapy (ART) have dramatically increased the life expectancy of infected persons. Much progress has been made in the development and utilization of combination ART and preventative pre-exposure prophylaxis products, however, numerous obstacles prevent eradication. Clinical pharmacologists along with world health organizations continue to play a key role in identifying and implementing strategies to combat this disease. PMID- 30412660 TI - Editor's Note. PMID- 30412662 TI - Can health care catch up with technology. PMID- 30412661 TI - Corrigendum to "Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure-FLT3 Relationship". PMID- 30412664 TI - Leukocyte Adhesion Deficiency -A Multicenter National Experience. AB - Leukocyte Adhesion Deficiency (LAD) is a rare, innate autosomal-recessive immunodeficiency with 3 subtypes. Twenty-nine patients with LADs were diagnosed and treated in Israeli Medical Centers and in the Palestinian Authority. We discuss the phenotypic, genotypic and biochemical features of LAD-I, -II and -III diagnosed during the neonatal period and early infancy in 18, 6 and 5 patients, respectively. Consanguinity was frequent. Common features were severe infections of variable etiology, excessive leukocytosis and delayed umbilical cord detachment. In LAD-I the integrin CD18 expression varied from negligible to normal. However, CD11a expression was negligible in all tested patients, suggesting both CD11a and CD18 should be used to assess this subtype. LAD-II patients showed distinctive facial features, physical malformations, short stature and developmental delay. These patients show defective expression of SLeX (CD15a) on cell-surface glycoproteins and lack of H antigen on erythroid cell surfaces resulting in Bombay blood group (hh). LAD-III showed intact but inactive beta2 integrins associated with severe infections and significant bleeding disorders caused by defective platelet aggregation and thrombocytopenia. We report two new unpublished mutations; two LAD-I patients with c.1099delG in ITGB2 and two LAD-III patients with c.1069C>T in FERMT3. LAD-I patients harboring the c.119_128 deletion in ITGB2, seemed to have better outcomes as compared to other LAD-I patients. Eight patients with LAD-I and -III underwent successful hematopoietic stem-cell transplantation. Cumulative survival was 75%, 50% and 40% for LAD-I, -II and -III, with a median follow-up of 4 (0.08-19), 3.25 (1-32) and 6 (0.08-8) years, respectively. Prenatal diagnosis is recommended in families with LAD syndromes. This article is protected by copyright. All rights reserved. PMID- 30412665 TI - Exendin-4 overcomes cytokine-induced decreases in gap junction coupling via protein kinase A and Epac2 in mouse and human islets. AB - KEY POINTS: The pancreatic islets of Langerhans maintain glucose homeostasis through insulin secretion, where insulin secretion dynamics are regulated by intracellular Ca2+ signalling and electrical coupling of the insulin producing beta-cells in the islet. We have previously shown that cytokines decrease beta cell coupling and that compounds which increase cAMP can increase coupling. In both mouse and human islets exendin-4, which increases cAMP, protected against cytokine-induced decreases in coupling and in mouse islets preserved glucose stimulated calcium signalling by increasing connexin36 gap junction levels on the plasma membrane. Our data indicate that protein kinase A regulates beta-cell coupling through a fast mechanism, such as channel gating or membrane organization, while Epac2 regulates slower mechanisms of regulation, such as gap junction turnover. Increases in beta-cell coupling with exendin-4 may protect against cytokine-mediated beta-cell death as well as preserve insulin secretion dynamics during the development of diabetes. ABSTRACT: The pancreatic islets of Langerhans maintain glucose homeostasis. Insulin secretion from islet beta-cells is driven by glucose metabolism, depolarization of the cell membrane and an influx of calcium, which initiates the release of insulin. Gap junctions composed of connexin36 (Cx36) electrically couple beta-cells, regulating calcium signalling and insulin secretion dynamics. Cx36 coupling is decreased in pre diabetic mice, suggesting a role for altered coupling in diabetes. Our previous work has shown that pro-inflammatory cytokines decrease Cx36 coupling and that compounds which increase cAMP can increase Cx36 coupling. The goal of this study was to determine if exendin-4, which increases cAMP, can protect against cytokine induced decreases in Cx36 coupling and altered islet function. In both mouse and human islets, exendin-4 protected against cytokine-induced decreases in coupling and preserved glucose-stimulated calcium signalling. Exendin-4 also protected against protein kinase Cdelta-mediated decreases in Cx36 coupling. Exendin-4 preserved coupling in mouse islets by preserving Cx36 levels on the plasma membrane. Exendin-4 regulated Cx36 coupling via both protein kinase A (PKA)- and Epac2-mediated mechanisms in cytokine-treated islets. In mouse islets, modulating Epac2 had a greater impact in mediating Cx36 coupling, while in human islets modulating PKA had a greater impact on Cx36 coupling. Our data indicate that PKA regulates Cx36 coupling through a fast mechanism, such as channel gating, while Epac2 regulates slower mechanisms of regulation, such as Cx36 turnover in the membrane. Increases in Cx36 coupling with exendin-4 may protect against cytokine mediated beta-cell dysfunction to insulin secretion dynamics during the development of diabetes. PMID- 30412666 TI - Surface-Induced Dissociation: An Effective Method for Characterization of Protein Quaternary Structure. AB - Many mass spectrometry applications make use of tandem mass spectrometry, where two stages of m/z analysis are coupled. In between the two stages of m/z analysis, an activation or reaction step is carried out to cause either structurally-informative fragmentation or structurally-characteristic reaction of the precursor ion of interest. This review focuses on the use of collisions with a surface (surface-induced dissociation, SID) as the activation method in tandem mass spectrometry, with an emphasis on SID papers published over the past four years. SID is described and compared with other activation methods. The major application focused on in this review is the structural characterization of native protein complexes, complexes kinetically trapped that retain native-like solution structures upon transfer to the gas-phase and throughout the relatively short timeframe of the mass spectrometry experiment. Other SID applications currently under investigation are also briefly described. Pioneering work on SID has been summarized previously and thus will not be discussed in detail here. PMID- 30412667 TI - Dissecting Machine-Learning Prediction of Molecular Activity: Is an Applicability Domain Needed for Quantitative Structure-Activity Relationship Models Based on Deep Neural Networks? AB - Deep neural networks (DNNs) are the major drivers of recent progress in artificial intelligence. They have emerged as the machine-learning method of choice in solving image and speech recognition problems, and their potential has raised the expectation of similar breakthroughs in other fields of study. In this work, we compared three machine-learning methods-DNN, random forest (a popular conventional method), and variable nearest neighbor (arguably the simplest method)-in their ability to predict the molecular activities of 21 in vivo and in vitro data sets. Surprisingly, the overall performance of the three methods was similar. For molecules with structurally close near neighbors in the training sets, all methods gave reliable predictions, whereas for molecules increasingly dissimilar to the training molecules, all three methods gave progressively poorer predictions. For molecules sharing little to no structural similarity with the training molecules, all three methods gave a nearly constant value-approximately the average activity of all training molecules-as their predictions. The results confirm conclusions deduced from analyzing molecular applicability domains for accurate predictions, i.e., the most important determinant of the accuracy of predicting a molecule is its similarity to the training samples. This highlights the fact that even in the age of deep learning, developing a truly high-quality model relies less on the choice of machine-learning approach and more on the availability of experimental efforts to generate sufficient training data of structurally diverse compounds. The results also indicate that the distance to training molecules offers a natural and intuitive basis for defining applicability domains to flag reliable and unreliable quantitative structure activity relationship predictions. PMID- 30412668 TI - Pathological Impacts of Chronic Hypoxia on Alzheimer's Disease. AB - Chronic hypoxia is considered as one of the important environmental factors contributing to the pathogenesis of Alzheimer's disease (AD). Many chronic hypoxia-causing comorbidities, such as obstructive sleep apnea syndrome (OSAS) and chronic obstructive pulmonary disease (COPD), have been reported to be closely associated with AD. Increasing evidence has documented that chronic hypoxia may affect many pathological aspects of AD including amyloid beta (Abeta) metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial and synaptic dysfunction, which may collectively result in neurodegeneration in the brain. In this Review, we briefly summarize the effects of chronic hypoxia on AD pathogenesis and discuss the underlying mechanisms. Since chronic hypoxia is common in the elderly and may contribute to the pathogenesis of AD, prospective prevention and treatment targeting hypoxia may be helpful to delay or alleviate AD. PMID- 30412669 TI - Achieving High Crop Yields with Low Nitrogen Emissions in Global Agricultural Input Intensification. AB - Increasing demand for food is driving a worldwide trend of agricultural input intensification. However, there is no comprehensive knowledge about the interrelations between potential yield gains and environmental trade-offs that would enable the identification of regions where input-driven intensification could achieve higher yields, yet with minimal environmental impacts. We explore ways of enhancing global yields, while avoiding significant nitrogen (N) emissions (Ne) by exploring a range of N and irrigation management scenarios. The simulated responses of yields and Ne to increased N inputs (Nin) and irrigation show high spatial variations due to differences in current agricultural inputs and agro-climatic conditions. Nitrogen use efficiency (NUE) of yield gains is negatively correlated with incremental Ne due to Nin additions. Avoiding further intensification in regions where high fractions of climatic yield potentials, >= 80%, are already achieved is key to maintain good NUE. Depending on the intensification scenarios, relative increases in Ne could be reduced by 0.3-29.6% of the baseline Ne with this intensification strategy as compared to indiscriminate further intensification, at the cost of a loss of yield increases by 0.2-16.7% of the baseline yields. In addition, irrigation water requirements and Nin would dramatically decrease by considering this intensification strategy. PMID- 30412670 TI - Direct Lewis Acid Catalyzed Conversion of Enantioenriched N-Acyloxazolidinones to Chiral Esters, Amides, and Acids. AB - The identification of Yb(OTf)3 through a multivariable high-throughput experimentation strategy has enabled a unified protocol for the direct conversion of enantioenriched N-acyloxazolidinones to the corresponding chiral esters, amides, and carboxylic acids. This straightforward and catalytic method has shown remarkable chemoselectivity for substitution at the acyclic N-acyl carbonyl for a diverse array of N-acyloxazolidinone substrates. The ionic radius of the Lewis acid catalyst was demonstrated as a key driver of catalyst performance that led to the identification of a robust and scalable esterification of a pharmaceutical intermediate using catalytic Y(OTf)3. PMID- 30412671 TI - From Fundamental Theories to Quantum Coherences in Electron Transfer. AB - Photoinduced electron transfer (ET) is a cornerstone of energy transduction from light to chemistry. The past decade has seen tremendous advances in the possible role of quantum coherent effects in the light-initiated energy and ET processes in chemical, biological, and materials systems. The prevalence of such coherence effects holds a promise to increase the efficiency and robustness of transport even in the face of energetic or structural disorder. A primary motive of this Perspective is to work out how to think about "coherence" in ET reactions. We will discuss how the interplay of basic parameters governing ET reactions-like electronic coupling, interactions with the environment, and intramolecular high frequency quantum vibrations-impact coherences. This includes revisiting the insights from the seminal work on the theory of ET and time-resolved measurements on coherent dynamics to explore the role of coherences in ET reactions. We conclude by suggesting that in addition to optical spectroscopies, validating the functional role of coherences would require simultaneous mapping of correlated electron motion and atomically resolved nuclear structure. PMID- 30412672 TI - One-Carbon Metabolism: Linking Nutritional Biochemistry to Epigenetic Programming of Long-Term Development. AB - One-carbon (1C) metabolism comprises a series of interlinking metabolic pathways that include the methionine and folate cycles that are central to cellular function, providing 1C units (methyl groups) for the synthesis of DNA, polyamines, amino acids, creatine, and phospholipids. Sadenosylmethionine is a potent aminopropyl and methyl donor within these cycles and serves as the principal substrate for methylation of DNA, associated proteins, and RNA. We propose that 1C metabolism functions as a key biochemical conduit between parental environment and epigenetic regulation of early development and that interindividual and ethnic variability in epigenetic-gene regulation arises because of genetic variants within 1C genes, associated epigenetic regulators, and differentially methylated target DNA sequences. We present evidence to support these propositions, drawing upon studies undertaken in humans and animals. We conclude that future studies should assess the epigenetic effects of cumulative (multigenerational) dietary imbalances contemporaneously in both parents, as this better represents the human experience. Expected final online publication date for the Annual Review of Animal Biosciences Volume 7 is February 15, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30412673 TI - Mammalian Sex Chromosome Structure, Gene Content, and Function in Male Fertility. AB - Mammalian sex chromosomes evolved from an ordinary pair of autosomes. The X chromosome is highly conserved, whereas the Y chromosome varies among species in size, structure, and gene content. Unlike autosomes that contain randomly mixed collections of genes, the sex chromosomes are enriched in testis-biased genes related to sexual development and reproduction, particularly in spermatogenesis and male fertility. This review focuses on how sex chromosome dosage compensation takes place and why meiotic sex chromosome inactivation occurs during spermatogenesis. Furthermore, the review also emphasizes how testis-biased genes are enriched on the sex chromosomes and their functions in male fertility. It is concluded that sex chromosomes are critical to sexual development and male fertility; however, our understanding of how sex chromosome genes direct sexual development and fertility has been hampered by the structural complexities of the sex chromosomes and by the multicopy nature of the testis gene families that also play a role in immunity, cancer development, and brain function. Expected final online publication date for the Annual Review of Animal Biosciences Volume 7 is February 15, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30412674 TI - Incurred sample reproducibility in pharmacokinetic bioanalysis: pros and cons from a CRO perspective. PMID- 30412675 TI - Enzymatic assay of D-mannose from urine. AB - AIM: Urinary tract infections (UTIs) are increasingly antibiotic resistant, and alternate or adjunct therapies are urgently needed. Several studies suggest that D-mannose ingestion and a hypothesized increase in urinary D-mannose reduce UTI frequency. Our goal was to develop a reliable assay for urinary D-mannose, which is needed to assess the effects of supplemental D-mannose on urinary D-mannose and UTIs. RESULTS: We developed an enzymatic assay for D-mannose in urine. Hexoses in urine were phosphorylated, sequentially isomerized and oxidized, and the increases in reduced NADPH were measured in a spectrophotometer. Urinary mannose from ten volunteers was well above the detection limit and ranged from 8 to 700 MUM. CONCLUSION: A rapid, reliable, and sensitive assay was developed, readily detected urinary D-mannose, and is adaptable to high-throughput analysis. If urinary D-mannose is shown to correlate with susceptibility to UTIs, then the assay could assess susceptibility to UTIs and direct mannose therapy. PMID- 30412676 TI - Incurred sample reproducibility: 10 years of experiences: views and recommendations from the European Bioanalysis Forum. AB - With 10 years of experiences on incurred sample reanalysis (ISR) as an integrated part of regulated bioanalysis, the European Bioanalysis Forum has reflected on the implementation and the use of ISR. Three surveys were conducted in 2016 and 2017 as a revisit of the ISR experiences within European pharmaceutical industry and contract research organizations: has ISR become a tool for postvalidation and process check of a bioanalytical method performance and has ISR become a routine in our laboratories? Do we agree on the interpretation of guidelines/guidance and are we aligned in our approach - among others? PMID- 30412677 TI - Analytical Quality by Design-based development and validation of ultra pressure liquid chromatography/MS/MS method for glycopeptide antibiotics determination in human plasma. AB - AIM: An ultra pressure liquid chromatography (UPLC)/MS/MS method for vancomycin and teicoplanin determination in human plasma was developed in accordance with analytical quality by design (AQbD) concept and fully validated. MATERIALS & METHODS: Chromatographic separation was performed on ACQUITY UPLC C18 charge surface hybrid (CSH) column (2.1 mm * 50 mm, 1.7 MUm particle size) in gradient mode and the mobile phase consisted of 0.1% formic acid in water and pure acetonitrile. The experimental design methodology was used for the definition of optimal chromatographic and protein precipitation conditions. RESULTS: The linearity ranges were 0.05-10 MUg ml-1 for vancomycin and 0.5-200 MUg ml-1 for total teicoplanin. The relative standard deviations for precision estimation were below 15% and the accuracy was within 85-115% for all quality control levels. CONCLUSION: The method was utilized for glycopeptide antibiotics bioanalysis. PMID- 30412678 TI - Urinary proteomic biomarkers in oncology: ready for implementation? AB - INTRODUCTION: Biomarkers are expected to improve the management of cancer patients by enabling early detection and prediction of therapeutic response. Proteins reflect a molecular phenotype, have high potential as biomarkers, and also are key targets for intervention. Given the ease of collection and proximity to certain tumors, the urinary proteome is a rich source of biomarkers and several proteins have been already implemented. Areas covered: We examined the literature on urine proteins and proteome analysis in oncology from reports published during the last 5 years to generate an overview on the status of urine protein and peptide biomarkers, with emphasis on their actual clinical value. Expert commentary: A few studies report on biomarkers that are ready to be implemented in patient management, among others in bladder cancer and cholangiocarcinoma. These reports are based on multi-marker approaches. A high number of biomarkers, though, has been described in studies with low statistical power. In fact, several of them have been consistently reported across different studies. The latter should be the focus of attention and be tested in properly designed confirmatory and ultimately, prospective investigations. It is expected that multi-marker classifiers for a specific context-of-use, will be the preferred path toward clinical implementation. PMID- 30412679 TI - A look back at the incurred sample reanalysis. PMID- 30412680 TI - High-Frequency Ultrasound Imaging for Examination of Early Dental Caries. AB - The extent of dental tissue destruction during the treatment of white spot lesions (WSLs) increases with the severity of the lesion. If the depth and shape of WSLs can be predicted with a noninvasive diagnostic method before dental caries treatment, more conservative interventions can be planned. Given the superiority of high-frequency ultrasound (HFUS) imaging in observing the internal structures of the body, the present study aimed to verify the possibility of HFUS imaging to examine the depth and shape of WSLs. We prepared tooth samples and developed a biomicroscopic system with a HFUS transducer to obtain images of normal and WSL regions. HFUS images were compared with conventional ultrasound images and micro-computed tomography images. HFUS distinctly differentiated demineralization within WSL and normal regions. WSL depth calculated in the micro computed tomography image was similar to that in HFUS. This study revealed that HFUS imaging has the potential to detect early dental caries and offer information on the invasion depth of early dental caries quantitatively. PMID- 30412681 TI - Quantitative profiling of cortisol metabolites in human urine by high-resolution accurate-mass MS. AB - Aim, materials & methods: Urinary cortisol profile has the potential as a diagnostic biomarker. We therefore developed a stable-isotope dilution ultraperformance chromatography multistage MS-based method to quantify cortisol and 16 metabolites in human urines. Results & conclusion: The LOD for cortisol and its metabolites ranges from 0.02 to 5.81 pg/MUl urine. The inter- and intraday variations were 3.7-12.9% and 3.5-15.6%, respectively. Among the metabolites analyzed, significant person-to-person heterogeneity was observed, demonstrating the need for comprehensive metabolite profiling in diagnosis. Nevertheless, the glucuronides of dihydrocortisol, dihydrocortisone, tetrahydrocortisol, allo-tetrahydrocortisol and tetrahydrocortisone are the major ones. The sum of the glucuronidated and free forms constitute >93% of the metabolites analyzed, which is termed as total cortisol equivalent. Total cortisol equivalent may serve as a surrogate of cortisol secretion. Clinical trial registration number: NCT02500472. PMID- 30412682 TI - Evaluation of the Mitra microsampling device for use with key urinary metabolites in patients with Alkaptonuria. AB - AIM: Alkaptonuria is a disorder of tyrosine metabolism where elevated circulating homogentisic acid causes progressive dysfunction of collagenous tissues. Logistical, financial and patient experience concerns with collection and transport of specimens to central laboratories makes evaluation of microsampling attractive. METHODOLOGY: Volumetric absorptive microsampling devices were evaluated for accuracy, precision and drying time. Elution methods were evaluated for several urinary metabolites of interest and stability assessed under multiple conditions. Comparison was performed between dried and liquid specimens via LC MS/MS. CONCLUSION: Volumetric absorptive microsampling was found to be highly accurate and precise. Elution methods showed good recovery and reproducibility. Dried and liquid samples compared favorably. Analyte stability was variable, presenting barriers to implementation into routine use in this context. PMID- 30412683 TI - The surviving sepsis controversy: a call to action for hospital medicine. AB - INTRODUCTION: There remains significant controversy behind the Surviving Sepsis Campaign Guidelines, as evidenced by the Infectious Diseases Society of America refusing to endorse the latest iteration put forth by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. An important stakeholder in this debate has not yet been adequately represented: hospitalists. Areas covered: In this perspective piece, we review the key points in this controversy; specifically, the current guidelines for the identification and management of sepsis. Expert commentary: We believe it is time for hospitalists to weigh in on this important issue by formally commenting on the new guidelines, establishing research priorities, and leading future research studies in the field to help achieve consensus among all clinicians in the appropriate management of sepsis. PMID- 30412684 TI - Pathogenesis of antiphospholipid syndrome: recent insights and emerging concepts. AB - INTRODUCTION: Even though our understanding of the antiphospholipid syndrome (APS) has improved tremendously over the last decades, we are still not in a position to replace symptomatic anticoagulation by pathogenesis based causal treatments. Areas covered: Recent years have provided further insights into pathogenetically relevant mechanisms. These include a differentiation of pathogenic subtypes of antiphospholipid antibodies (aPL), novel mechanisms modulating disease activity, e.g. extracellular vesicles and microRNA, and novel players in pathogenesis, e.g. neutrophils and neutrophil extracellular traps (NETs). Expert commentary: It is evident that aPL induce a proinflammatory and procoagulant state and recent data suggest that different aPL species activate different signaling pathways which sometimes converge into a common cellular response. This implies that presence of more than one aPL species may disproportionally increase the risk for the major manifestations of APS, i.e. thrombosis and fetal loss. Further delineation of the pathogenic mechanisms will hopefully provide clues to causal rather than symptomatic treatments of APS. PMID- 30412685 TI - Examining the active ingredients of physical activity interventions underpinned by theory versus no stated theory: a meta-analysis. AB - In this meta-analysis, we sought to examine the 'active ingredients' (or behaviour change techniques; BCTs) used within theory-based physical activity interventions compared to interventions with no stated theory. We retrieved 171 peer-reviewed studies (224 total interventions) that used a controlled experimental design from 68 previous reviews of physical activity interventions. Data from each intervention were coded with regard to their use of theory and inclusion of 16 BCT clusters within the physical activity intervention. There were no significant differences in the overall effect sizes between theory-based (k = 148, d = 0.48) and no-stated-theory (k = 77, d = 0.37) interventions. Theory based interventions incorporated a greater number of BCT clusters on average (6.1) compared to no-stated-theory interventions (4.5). Significant effects were shown for interventions that incorporated at least three BCT clusters (d = 0.48) but not for those that used one or two (d = 0.20). Several BCT clusters were more likely to be present in theory-based interventions than no-stated-theory interventions. Significant effects on physical activity were also shown for theory-based interventions that incorporated any of the 16 BCT clusters coded, but only for 9 out of 11 no-stated-theory interventions in this regard (for which effect sizes could be calculated). Taken together, these findings suggest that although the overall effects on physical activity do not differ significantly between theory-based and no-stated-theory interventions, these interventions often differ in their composition of BCTs. Moreover, for interventions utilising certain BCT clusters (namely, 'self-belief' and 'association'), theory may be necessary to derive significant effects. PMID- 30412686 TI - Quantification of eicosanoids and their metabolites in biological matrices: a review. AB - The quantification of eicosanoids and their metabolites in biological samples remain an analytical challenge, even though a number of methodologies/techniques have been developed. The major difficulties encountered are related to the oxidation of eicosanoids and their low quantities in biological matrices. Among the known methodologies, liquid chromatography-mass spectrometry (LC-MS/MS) is the standard method for eicosanoid quantification in biological samples. Recently advances have improved the ability to identify and simultaneous quantitate eicosanoids in biological matrices. The present article reviews the quantitative analysis of eicosanoids in different biological matrices by LC and ultra performance liquid chromatography (UPLC)-MS/MS and discusses important aspects to be considered during the collection, sample preparation and the generation of calibration curves required for eicosanoid analysis. PMID- 30412687 TI - LC-MS/MS method for screening of intoxication and drug adherence of angiotensin converting enzyme inhibitors in plasma. AB - AIM: Intentional and accidental drug intoxication as well as medication adherence require sensitive and reliable analytical screening methods. Such methods are often lacking in children and adults, therefore, a reliable analytical method has been developed by using low plasma volume. MATERIALS & METHODS: Sample preparation from plasma was achieved by solid-phase extraction process. LC-MS in positive ion mode was performed using X-select CSHTM C18 column. The mobile phase consisted of water and acetonitrile acidified with 1% formic acid using a gradient method with total run time of 10 min. RESULTS: The method showed repeatability for all analytes. The linearity range from 0.78 to 100 ng/ml per analyte was established with recoveries >=87% and matrix effect for all analytes was within guideline limits. CONCLUSION: The screening method was successfully validated for monitoring of intoxication and medication adherence of ten analytes in 50 MUl residual plasma samples of children and adults. PMID- 30412688 TI - A UHPLC-MS/MS method for the quantification of Delta9-tetrahydrocannabinol and cannabidiol in decoctions and in plasma samples for therapeutic monitoring of medical cannabis. AB - AIM: Monitoring of blood levels of Delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is necessary for optimization of administration of medical cannabis. We describe the validation of a ultra-HPLC-MS/MS method for quantifying THC and CBD from plasma and decoctions and its application for therapeutic drug monitoring.Materials & methods: Analyses were performed by using a TSQ QuantivaTM Triple Quadrupole coupled to a Ultimate 3000 UHPLC system with atmospheric pressure chemical ionization after sample preparation with a straightforward method with deuterated internal standards. RESULTS: The method has been validated following EMA guidelines and is linear in plasma from 0.16 to 10 ng/ml for both THC and CBD and in decoctions from 4.7 to 600 ng/ml. CONCLUSION: Given the unpredictable pharmacokinetic behavior of THC and CBD in patients, monitoring of plasma concentrations is strongly recommended for patients under treatment with medical cannabis. PMID- 30412689 TI - Analyzing protein glycosylation using UHPLC: a review. AB - Ultrahigh performance liquid chromatography (UHPLC) uses small stationary-phase particle size (<2 MUm) and high pressure in order to achieve rapid and efficient separations. The speed and high resolution of this method has made it a valuable tool for analyzing the complex glycosylation patterns found in post translationally modified proteins. This article highlights the differences between UHPLC and HPLC and reviews recent UHPLC applications and developments for detecting glycosylated proteins (e.g., glycomics studies) and characterizing glycosylated pharmaceuticals (e.g., monoclonal antibodies). PMID- 30412690 TI - Obesity Among High School Students in the United States: Risk Factors and Their Population Attributable Fraction. AB - INTRODUCTION: The prevalence of obesity among children and adolescents in the United States is high. The aim of this study was to assess the association between modifiable risk factors and obesity and to estimate the population attributable fractions (PAFs) of modifiable risk factors among high school students in the United States. METHODS: For this retrospective study, we used a nationally representative sample of 15,624 students who participated in the 2015 Youth Risk Behavior Survey (YRBS). Obesity was defined as body mass index at or above the 95th percentile, based on sex- and age-specific data from the Centers for Disease Control and Prevention. We examined unhealthy dietary behaviors, physical inactivity, and other modifiable risk factors (tobacco use, alcohol consumption, and sleep). We used multivariable logistic regression, accounting for the complex survey design of YRBS, to assess the association between risk factors and obesity and to calculate PAFs. Confidence intervals of PAFs were estimated by using the jackknife repeated replication method. RESULTS: Among all students included in the study, 13.9% were classified as obese. Not being on a sports team (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.31-1.98), current tobacco use (OR, 1.42; 95% CI, 1.14-1.77), and watching television for 3 hours or more per day (OR, 1.38; 95% CI, 1.09-1.76) were significantly correlated with obesity. The combined PAF for all modifiable risk factors was 34.80% (95% CI, 32.09%-37.51%). The single modifiable risk factor with the largest PAF was not participating on a sports team (PAF, 16.57%; 95% CI, 15.30%-17.84%). CONCLUSION: Findings about PAFs help demonstrate the importance of promoting physical activity, healthy diet, and other healthy lifestyles in reducing obesity among high school students in the United States. PMID- 30412691 TI - Assessing the Relationship Between a Composite Score of Urban Park Quality and Health. AB - INTRODUCTION: Walkable access to parks, sufficient park acreage, and investments in park and recreation resources are 3 indicators of quality city park systems. Few studies, however, have examined the collective effects of these indicators on public health outcomes. METHODS: Combining 3 nationwide public data sets, this study modeled the relationships between a composite score of urban park system quality effects on physical activity and self-reported health while controlling for demographic and lifestyle variables. Data were obtained from the Centers for Disease Control and Prevention's 500 Cities Project, the Trust for Public Land's City Park Facts Report, and the US Census Bureau. RESULTS: Regression analyses indicated that the composite park quality score was significantly related to both physical activity levels and physical health across a sample of 59 cities. Higher scores were associated with fewer physically inactive residents but were not significantly associated with better physical health. CONCLUSION: Assessing the collective contribution of park access, park acreage, and investment suggests that improvements to a city's composite score may correspond with greater physical activity, but more research is needed to establish the long-term relationships between park system quality and physical health. PMID- 30412692 TI - Perceived Social and Built Environment Correlates of Transportation and Recreation-Only Bicycling Among Adults. AB - INTRODUCTION: Research on perceptions of environmental factors in relation to transportation and recreation bicycling is limited in the United States. We explored the association between perceived social and built environment factors with total, transportation, and recreation bicycling in a sample of adult bicyclists in Austin, Texas, and Birmingham, Alabama. The objective of this study was to examine the relationship between perceived social and built environment factors and domain-specific bicycling in a sample of adult bicyclists. METHODS: Adults aged 18 to 65 who rode a bicycle at least once in the past year completed an internet-based survey that was developed for this study to specifically assess correlates of bicycling; the study was conducted from October 2016 through January 2017. Perceived environmental factors assessed were residential density, traffic safety, destination, connectivity, safety from crime, aesthetics, and bicycle infrastructure. Multivariable logistic regression models were used to estimate the association of each perceived environmental factor (tertile 1, lowest; tertile 3, highest) with recreation-only and transportation bicycling. Effect modification of the relation between environmental factors and bicycling outcomes by sex was also examined. RESULTS: The final analytic sample size was 801 participants. All environmental factors examined, including residential density, traffic safety, destinations, connectivity, aesthetics, bicycle infrastructure, and safety from crime showed significantly direct associations with transportation bicycling. Traffic safety, destinations, aesthetics, and bicycle infrastructure showed significant direct and inverse associations with recreation-only bicycling. Effect modification by sex was identified with residential density; a significant direct association with recreation-only bicycling was seen among women. CONCLUSION: These findings illustrate that bicycling for transportation is associated with different perceived environmental factors than is recreation-only bicycling, with some significant modification by sex. Comprehensive tools that assess the perceived environment for bikeability in the United States are warranted. PMID- 30412693 TI - Assessing the role of residue E73 and lipid headgroup charge in VDAC1 voltage gating. AB - The voltage-dependent anion channel (VDAC) is the most abundant protein of the mitochondrial outer membrane (MOM) where it regulates transport of ions and metabolites in and out of the organelle. VDAC function is extensively studied in a lipid bilayer system that allows conductance monitoring of reconstituted channels under applied voltage. The process of switching from a high-conductance state, open to metabolites, to a variety of low-conducting states, which excludes metabolite transport, is termed voltage gating and the mechanism remains poorly understood. Recent studies have implicated the involvement of the membrane solvated residue E73 in the gating process through beta-barrel destabilization. However, there has been no direct experimental evidence of E73 involvement in VDAC1 voltage gating. Here, using electrophysiology measurements, we exclude the involvement of E73 in murine VDAC1 (mVDAC1) voltage gating process. With an established protocol of assessing voltage gating of VDACs reconstituted into planar lipid membranes, we definitively show that mVDAC1 gating properties do not change when E73 is replaced by either a glutamine or an alanine. We further demonstrate that cholesterol has no effect on mVDAC1 gating characteristics, though it was shown that E73 is coordinating residue in the cholesterol binding site. In contrast, we found a pronounced gating effect based on the charge of the phospholipid headgroup, where the positive charge stimulates and negative charge suppresses gating. These findings call for critical evaluation of the existing models of VDAC gating and contribute to our understanding of VDAC's role in control of MOM permeability and regulation of mitochondrial respiration and metabolism. PMID- 30412694 TI - The current clinical and geographical situation of cutaneous leishmaniasis based on species identification in Turkey. AB - Leishmaniases are a group of vector-borne diseases caused by the members of Leishmania genus, and there are three main clinical forms of the infection as visceral, cutaneous, and mucocutaneous. Cutaneous leishmaniasis is a growing public health problem in Turkey due to increasing detection of autochthonous cases caused by L. major and L. donovani in some regions in addition to Syrian imported cases. For this reason, we aimed to evaluate the current epidemiological situation of CL in the view of causative agents and their geographical distribution throughout Turkey. The samples were collected from 356 CL patients admitted to different centers in 18 provinces between January 2013 and December 2016. Direct microscopy, culture (regular and enriched NNN) and molecular techniques (real-time ITS1 PCR and hsp70 PCR/sequencing) were performed. By molecular techniques, 299, 28, 19 and 10 isolates/clinical samples were identified as L. tropica, L. major, L. infantum and L. donovani, respectively. Most of the patients (65.73%) had one lesion usually on their face/head. Dry nodular type lesions (n = 291) were mainly associated with L. tropica while L. major was mainly found related to wet-ulcerative ones. Leishmaniasis recidivans was also detected in 2.52% among 356 patients. L. tropica was detected as most widespread species causing CL in Turkey. L. infantum and L. major was also found in one third of the provinces. Enriched NNN culture was worked well for isolating the parasite and 346 isolates were successfully grown and stored in liquid nitrogen. The comparison of all diagnostic techniques showed that the parasitological positivity rate could increase if the combination of direct microscopy and real-time ITS1 PCR is used. Besides well-known anthroponotic L. tropica cases, the increasing detection of CL cases caused by zoonotic species, L. infantum and L. major, is one of the most important findings in the present study. In our opinion to ensure timely and accurate diagnosis, proper treatment and countrywide effective control of CL in Turkey a systematic approach is needed on the base of information about characteristics of lesions and patients and epidemiological features of the disease. PMID- 30412695 TI - Burden of cancer attributable to obesity, type 2 diabetes and associated risk factors. AB - Overweight and obesity constitute a global pandemic with devastating consequences that affect >2 billion people. Obesity plays a central role in morbidity and mortality of diseases of multiple organs and systems, and it is a major contributor to the growing incidence of cancer. There is now sufficient level of evidence for the association between overweight and 11 types of cancer, among which are two of the most common cancers worldwide, those of the colorectum and postmenopausal breast. Sedentary lifestyle, unhealthy diet, and excessive alcohol intake also account for the burden of cancer by promoting obesity. The risk of specific types of cancer is also directly influenced, regardless of the magnitude of adiposity, by physical inactivity, consumption of red meat, processed meat and ultra-processed foods, dairy products, alcohol, whole grain cereals, nuts, vegetables, and fruits. Type 2 diabetes is another global health threat closely associated with obesity that boosts the risk of cancer driven by high BMI. Education to promote positive choices and physical activity and resolute public health interventions on food delivery are requested to reduce the burden of obesity-related cancer and lighten the unsustainable growing expenses to health systems. PMID- 30412696 TI - Leptin trajectories from birth to mid-childhood and cardio-metabolic health in early adolescence. AB - OBJECTIVES: Leptin is a hormone produced by adipose tissue that promotes satiety, and some evidence suggests that greater early life leptin exposure prevents excessive adiposity gain in later life. However, few studies have analyzed dynamic changes in leptin throughout childhood in relation to later cardio metabolic health. Our study aims to identify distinct leptin trajectories in childhood, and to examine their associations with cardio-metabolic outcomes in adolescence. METHODS: Among children in the Project Viva cohort born 1999-2002 in Massachusetts, we used latent class growth models to identify leptin trajectories independent of maternal BMI, child sex, race/ethnicity, size at birth and current age and size among 1360 children with leptin measured at least once at birth, early childhood (mean 3.3 +/- SD 0.3 years), or mid-childhood (7.9 +/- 0.8 years). At research visits in early adolescence (13.2 +/- 0.9 years), we assessed cardio-metabolic outcomes including adiposity measures, fasting biomarkers, and blood pressure among 855 children. We then applied multiple regression models to examine associations of the leptin trajectories with these cardio-metabolic outcomes in early adolescence, adjusting for child age at outcome, maternal age, education, prenatal smoking and glucose, total gestational weight gain and paternal BMI. RESULTS: The latent class growth model identified 3 distinct leptin trajectories: "low stable" (n = 1031, 75.8%), "high-decreasing" (n = 219, 16.1%) and "intermediate-increasing" (n = 110, 8.1%). In adjusted models, the intermediate-increasing leptin trajectory was associated with higher early adolescence adiposity measures (e.g. BMI z-score: 0.62 units; 95% confidence interval: 0.28, 0.96 and odds of obesity: 2.84: 1.17, 6.94), but lower systolic blood pressure (-0.46 z-score units; -0.74, -0.18), compared to the low-stable group. CONCLUSIONS: Our findings on leptin trajectories in childhood suggest important differences and associations with later metabolic outcomes. PMID- 30412697 TI - A kinetic comparison between E2P and the E2P-like state induced by a beryllium fluoride complex in the Na,K-ATPase. Interactions with Rb. AB - Metal-fluoride complexes have been used to induce E2P-like states with the aim of studying the events that occur during E2P hydrolysis in P-type ATPases. In the present work, we compared the E2P-like state induced by a beryllium fluoride complex (BeFx) with the actual E2P state formed through backdoor phosphorylation of the Na,K-ATPase. Formation of E2P and E2P-like states were investigated employing the styryl dye RH421. We found that BeFx is the only fluorinated phosphate analog that, like Pi, increases the RH421 fluorescence. The observed rate constant, kobs, for the formation of E2P decreases with [Pi] whereas that of E2BeFx increases with [BeFx]. This might wrongly be taken as evidence of a mechanism where the binding of BeFx induces a conformational transition. Here, we rather propose that, like for Pi, binding of BeFx follows a conformational selection mechanism, i.e. it binds to the E2 conformer forming a complex that is much more stable than E2P, as seen from its impaired capacity to return to E1 upon addition of Na+. Although E2P and E2BeFx are able to form states with 2 occluded Rb+, both enzyme complexes differ in that the affinity for the binding and occlusion of the second Rb+ is much lower in E2BeFx than in E2P. The higher rates of Rb+ occlusion and deocclusion observed for E2BeFx, as compared to those observed for other E2P-like transition and product states suggest a more open access to the cation transport sites, supporting the idea that E2BeFx mimics the E2P ground state. PMID- 30412698 TI - The regulatory role of shikimate in plant phenylalanine metabolism. AB - In higher plants, the amino acid phenylalanine is a substrate of both primary and secondary metabolic pathways. The primary pathway that consumes phenylalanine, protein biosynthesis, is essential for the viability of all cells. Meanwhile, the secondary pathways are not necessary for the survival of individual cells, but benefit of the plant as a whole. Here we focus on the monolignol pathway, a secondary metabolic pathway in the cytosol that rapidly consumes phenylalanine to produce the precursors of lignin during wood formation. In planta monolignol biosynthesis involves a series of seemingly redundant steps wherein shikimate, a precursor of phenylalanine synthesized in the plastid, is transiently ligated to the main substrate of the pathway. However, shikimate is not catalytically involved in the reactions of the monolignol pathway, and is only needed for pathway enzymes to recognize their main substrates. After some steps the shikimate moiety is removed unaltered, and the main substrate continues along the pathway. It has been suggested that this portion of the monolignol pathway fulfills a regulatory role in the following way. Low phenylalanine concentrations (viz. availability) correlate with low shikimate concentrations. When shikimate concentratios are low, flux into the monolignol pathway will be limited by means of the steps requiring shikimate. Thus, when the concentration of phenylalanine is low it will be reserved for protein biosynthesis. Here we employ a theoretical approach to test this hypothesis. Simplified versions of plant phenylalanine metabolism are modelled as systems of ordinary differential equations. Our analysis shows that the seemingly redundant steps can be sufficient for the prioritization of protein biosynthesis over the monolignol pathway when the availability of phenylalanine is low, depending on system parameters. Thus, the phenylalanine precursor shikimate may signal low phenylalanine availability to secondary pathways. Because our models have been abstracted from plant phenylalanine metabolism, this mechanism of metabolic signalling, which we call the Precursor Shutoff Valve (PSV), may also be present in other biochemical networks comprised of two pathways that share a common substrate. PMID- 30412699 TI - An ordination approach to explore similarities among communities. AB - Analysis of similarities among communities can help to decipher the biogeographical, evolutionary, and ecological factors that drive local diversity. Recent indices of similarity among communities incorporate not only information on species presence and abundance but also information on how similar species are in their traits and how closely related they are in terms of taxonomy or phylogeny. Towards this aim, trait-based, taxonomic or phylogenetic similarities among species have been defined and bounded between 0 (species are maximally distinct) and 1 (species are similar). A required property for an index of similarity between two communities is that it must provide minimum similarity (0) where communities have maximally distinct species, as well as maximum similarity (1) where communities are equivalent in their trait, taxonomic or phylogenetic compositions. Here, I developed a new ordination methodology that conforms to the requirement: double similarity principal component analysis (DSPCA). DSPCA summarizes multidimensional trait-based, taxonomic or phylogenetic similarities among communities into orthogonal axes. The species that drive each similarity pattern can be identified together with their traits or with their taxonomic or phylogenetic positions. I applied this methodology to theoretical examples and to empirical data sets on bird and bat communities to illustrate key properties of DSPCA. I compared the results obtained with DSPCA with those provided by related approaches. Theoretical and empirical case studies highlight the following additional properties of DSPCA: (i) axes are orthogonal and identify independent (dis)similarity patterns between communities; (ii) the more functionally, taxonomically or phylogenetically similar communities are, the closer they are on an axis; (iii) the coordinate of a species on an axis expresses how representative the species is of the pattern identified by the axis; and (iv) a species is representative of x communities if the functional, taxonomic or phylogenetic characteristics of this species are very common within each of these x communities. DSPCA is an efficient approach to visualize functional, taxonomic and phylogenetic similarities between communities. It is also a useful alternative to recent methods dedicated to phylogenetic diversity patterns. It will be an asset for all studies that aim to compare functional, taxonomic, genetic and phylogenetic diversity. PMID- 30412700 TI - Attachment style: The neurobiological substrate, interaction with genetics and role in neurodevelopmental disorders risk pathways. AB - Literature has suggested that attachment insecurity has been previously associated with subsequent onset of several psychiatric conditions characterized by emotion dysregulation. Nevertheless, only few studies have investigated the neurobiological basis of attachment style and whether attachment insecurity may share a common neurobiological substrate with neurodevelopmental disorders. In this narrative contribution, we aimed to review existing literature on functional neurobiological correlates of attachment style to further understand (1) specific neurobiological patterns associated with attachment security variation, and (2) whether it is possible to identify a neurobiological overlap between attachment insecurity-related and neurodevelopmental disorders-related anomalies. Given the complex etiology of these diseases, we will also review gene by environment studies to investigate how attachment insecurity interacts with genetic factors in determining this common neurobiological substrate. We believe that a better understanding of how early attachment experiences may play a role in the pathophysiology of neurodevelopmental disorders is critical to plan effective clinical interventions to reduce both the likelihood for poor parenting and the risk for the onset of psychiatric conditions. PMID- 30412701 TI - Emotional control, reappraised. AB - We are frequently challenged with situations requiring the control of our emotions, often under substantial time-pressure and rapidly changing contextual demands. Coping with those demands requires the ability to flexibly and rapidly switch between different emotional control strategies. However, this ability has been largely neglected by current neurocognitive models on emotional control. Drawing on the decision-making literature, we propose that rapid switching between alternative emotional control strategies requires the concurrent evaluation of unchosen (counterfactual) options. This model explains how an individual can adaptively change emotional control behavior to meet contextual demands and shifting goals. We propose that the neural implementation of this emotional control mechanism relies on the anterior prefrontal cortex (aPFC/lateral frontal pole), given its known role in monitoring alternative options during cognitive decision-making tasks. We reappraise meta-analytic evidence showing consistent aPFC involvement during emotional control when monitoring of alternative emotional control strategies is required, and when alternative emotional actions have high value. We conclude with emphasizing the clinical and evolutionary implications of this new framework on emotional control. PMID- 30412702 TI - I-SceI Meganuclease-mediated transgenesis in the acorn worm, Saccoglossus kowalevskii. AB - Hemichordates are a phylum of marine invertebrate deuterostomes that are closely related to chordates, and represent one of the most promising models to provide insights into early deuterostome evolution. The genome of the hemichordate, Saccoglossus kowalevskii, reveals an extensive set of non-coding elements conserved across all three deuterostome phyla. Functional characterization and cross-phyla comparisons of these putative regulatory elements will enable a better understanding of enhancer evolution, and subsequently how changes in gene regulation give rise to morphological innovation. Here, we describe an efficient method of transgenesis for the characterization of non-coding elements in S. kowalevskii. We first test the capacity of an I-SceI transgenesis system to drive ubiquitous or regionalized gene expression, and to label specific cell types. Finally, we identified a minimal promoter that can be used to test the capacity of putative enhancers in S. kowalevskii. This work demonstrates that this I-SceI transgenesis technique, when coupled with an understanding of chromatin accessibility, can be a powerful tool for studying how evolutionary changes in gene regulatory mechanisms contributed to the diversification of body plans in deuterostomes. PMID- 30412703 TI - Can Urethral Bulking Agents Salvage Failed Slings? AB - OBJECTIVE: To evaluate the efficacy of urethral bulking agents for stress urinary incontinence (SUI) in the setting of prior failed sling. METHODS: This is a retrospective review of patients who underwent urethral bulking agent injections for a primary complaint of SUI following prior failed sling surgery. The outcomes assessed were patient reported improvement, need for further interventions for incontinence and validated questionnaires. Values for questionnaires were obtained from the patient's preprocedure visit, at the first visit following their last injection and at their most recent visit within our system. RESULTS: Over the study period, 73 patients underwent urethral bulking agent injection following failed sling. Thirty-eight patients received Macroplastique injections and 35 had collagen injections. On average, patients underwent 2.6 injections. Seventy-one percent of patient reported at least partial symptom resolution at first postinjection follow-up. Validated questionnaire responses also improved at short-term follow-up (mean difference in American Urological Association Symptom Index-3.8, Michigan Incontinence Symptom Index-5.1, P <.01). Forty patients had long-term follow-up data available (mean 39.6 months postinjection). Statistically significant improvement persisted on the stress incontinence and quality of life domains of the validated questionnaires. CONCLUSION: In our cohort of patients with persistent or recurrent SUI following urethral sling procedure, 71% experienced short-term improvement or resolution of symptoms following urethral bulking agent injections, with SUI-specific improvement persisting at an average of 35 months in patients with available data. PMID- 30412704 TI - The Effect of Calcium and Vitamin B6 Supplementation on Oxalate Excretion in a Rodent Gastric Bypass Model of Enteric Hyperoxaluria. AB - OBJECTIVES: To test the effect of calcium and vitamin B6 therapies on urinary oxalate excretion in a rodent model of enteric hyperoxaluria (EH) after Roux-en Y gastric bypass (RYGB) surgery. METHODS: Obese male Sprague-Dawley rats underwent sham (n=7) or RYGB (n=10). Animals were maintained on low oxalate (1.5%) and fat (10%; LOF), normal calcium (0.6 %; NC) diet for 8 weeks and then completed a 2 phase crossover metabolic study. In the first 2-week phase, animals were fed a LOF, high calcium (2.4%; HC) diet. After a 2-week washout, rats were fed a LOF/NC diet highly enriched with vitamin B6. Urine was collected before and after each intervention. Plasma pyridoxal 5'-phosphate (PLP) and metabolites were measured baseline and 11 weeks after sham or RYGB. RESULTS: Compared to baseline, sham animals on LOF/HC diet doubled their urinary calcium excretion but not oxalate. RYGB animals on LOF/HC diet decreased urinary oxalate excretion 28% (p=0.001) without a significant rise in urinary calcium. Vitamin B6 supplementation decreased RYGB urinary oxalate by ~15% (p=0.06), and serum PLP explained 63% of urinary oxalate variability. CONCLUSIONS: Based on the findings in this model, calcium supplementation appears to be a reasonable therapy to decrease urinary oxalate in RYGB patients who maintain a low fat and oxalate diet. Serum PLP had a fair correlation to urinary oxalate excretion and may be a useful screening tool in hyperoxaluric RYGB patients. Further experimental human studies after RYGB are necessary to determine whether these commonly employed supplements truly provide a benefit in EH. PMID- 30412705 TI - MIR-144-mediated NRF2 gene silencing inhibits fetal hemoglobin expression in sickle cell disease. AB - Inherited genetic modifiers and pharmacologic agents that enhance fetal hemoglobin (HbF) expression reverse the clinical severity of sickle cell disease (SCD). Recent efforts to develop novel strategies of HbF induction include discovery of molecular targets that regulate gamma-globin gene transcription and translation. The purpose of this study was to perform genome-wide microRNA (miRNA) analysis to identify genes associated with HbF expression in patients with SCD. We isolated RNA from purified reticulocytes for microarray-based miRNA expression profiling. Using samples from patients with contrasting HbF levels, we observed an eightfold upregulation of miR-144-3p (miR-144) and miR-144-5p in the low-HbF group compared with those with high HbF. Additional analysis by reverse transcription quantitative polymerase chain reaction confirmed individual miR-144 expression levels of subjects in the two groups. Subsequent functional studies in normal and sickle erythroid progenitors showed NRF2 gene silencing by miR-144 and concomitant repression of gamma-globin transcription; by contrast, treatment with miR-144 antagomir reversed its silencing effects in a dose-dependent manner. Because NRF2 regulates reactive oxygen species levels, additional studies investigated mechanisms of HbF regulation using a hemin-induced oxidative stress model. Treatment of KU812 cells with hemin produced an increase in NRF2 expression and HbF induction that reversed with miR-144 pretreatment. Chromatin immunoprecipitation assay confirmed NRF2 binding to the gamma-globin antioxidant response element, which was inhibited by miR-144 mimic treatment. The genome-wide miRNA microarray and primary erythroid progenitor data support a miR-144/NRF2 mediated mechanism of gamma-globin gene regulation in SCD. PMID- 30412706 TI - An N-Terminal Extension to UBA5 Adenylation Domain Boosts UFM1 Activation: Isoform-Specific Differences in Ubiquitin-like Protein Activation. AB - Modification of proteins by the ubiquitin-like protein, UFM1, requires activation of UFM1 by the E1-activating enzyme, UBA5. In humans, UBA5 possesses two isoforms, each comprising an adenylation domain, but only one containing an N terminal extension. Currently, the role of the N-terminal extension in UFM1 activation is not clear. Here we provide structural and biochemical data on UBA5 N-terminal extension to understand its contribution to UFM1 activation. The crystal structures of the UBA5 long isoform bound to ATP with and without UFM1 show that the N-terminus not only is directly involved in ATP binding but also affects how the adenylation domain interacts with ATP. Surprisingly, in the presence of the N-terminus, UBA5 no longer retains the 1:2 ratio of ATP to UBA5, but rather this becomes a 1:1 ratio. Accordingly, the N-terminus significantly increases the affinity of ATP to UBA5. Finally, the N-terminus, although not directly involved in the E2 binding, stimulates transfer of UFM1 from UBA5 to the E2, UFC1. PMID- 30412707 TI - Neurochemical fingerprinting of amygdalostriatal and intra-amygdaloid projections: a tracing-immunofluorescence study in the rat. AB - Amygdalostriatal and intra-amygdaloid fiber connectivity was studied in rats via injections of one of the tracers Phaseolus vulgaris leucoagglutinin (PHA-L) or biotinylated dextran amine (BDA) into various amygdaloid nuclei. To determine the neurotransmitter identity of labeled fibers we combined tracer detection with immunofluorescence staining, using antibodies against vesicular transporters (VTs) associated with glutamatergic (VGluT1, VGluT2) or GABAergic (VGAT) neurotransmission. High-magnification confocal laser scanning images were screened for overlap: occurrence inside tracer labeled fibers or axon terminals of immunofluorescence signal associated with one of the VTs. Labeled amygdalostriatal fibers were seen when tracer had been injected into the magnocellular and parvicellular portions of the basal amygdaloid nucleus and the lateral amygdaloid nucleus (nuclei belonging to 'cortical type' amygdaloid nuclei). Intra-amygdaloidal projection fibers were mostly found after tracer injections in the central and medial amygdaloid nuclei ('striatal type' amygdaloid nuclei). Terminals of tracer-labeled amygdalostriatal fibers contained immunofluorescence signal associated mostly with VGluT1 and to a lesser degree with VGluT2 or VGAT. Intra-amygdaloid labeled fibers showed colocalization mostly of VGluT1, followed by VGAT. VGluT2 co-occurred in a minority of intra-amygdaloid tracer-containing fiber terminals. We conclude from our observations that both amygdalostriatal and intra-amygdaloid projections, arising from, respectively, 'cortical type' and 'striatal type' amygdaloid nuclei contain strong glutamatergic and modest GABAergic components. The glutamatergic fibers express either VGluT1 or VGluT2. The absence in large numbers of tracer labeled fibers of expression of one of the selected VTs leads us to suspect that amygdalostriatal projection fibers may contain hitherto neglected neurotransmitters in these connections, e.g., aspartate. PMID- 30412708 TI - Impact of Physiologic Pacing Versus Right Ventricular Pacing Among Patients With Left Ventricular Ejection Fraction Greater Than 35%: A Systematic Review for the 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay. AB - BACKGROUND: It is unclear whether physiologic pacing by either cardiac biventricular pacing (BiVP) or His-bundle pacing (HisBP) may prevent adverse structural and functional consequences known to occur among some patients who receive right ventricular pacing (RVP). AIM: Our analysis sought to review existing literature to determine if BiVP and/or HisBP might prevent adverse remodeling and be associated with structural, functional, and clinical advantages compared with RVP among patients without severe left ventricular dysfunction (>35%) who required permanent pacing because of heart block. METHODS: A literature search was conducted using MEDLINE (through PubMed) and Embase to identify randomized trials and observational studies comparing the effects of BiVP or HisBP versus RVP on measurements of left ventricular dimensions, left ventricular ejection fraction (LVEF), heart failure functional classification, quality of life, 6-minute walk, hospitalizations, and mortality. Data from studies that met the appropriate population, intervention, comparator, and outcomes of interest were abstracted for meta-analysis. Studies that reported pooled outcomes among patients with LVEF both above and below 35% could not be included in the meta-analysis because of strict relationships with industry procedures that preclude retrieval of industry-retained unpublished data on the subset of patients with preserved left ventricular function. RESULTS: Evidence from 8 studies, including a total of 679 patients meeting the prespecified criteria for inclusion, was identified. Results were compared for BiVP versus RVP, HisBP versus RVP, and BiVP+HisBP versus RVP. Among patients who received physiologic pacing with either BiVP or HisBP, the LV end-diastolic and end systolic volumes were significantly lower (mean duration of follow-up: 1.64 years; -2.77 mL [95% CI -4.37 to -1.1 mL]; p=0.001; and -7.09 mL [95% CI -11.27 to -2.91; p=0.0009) and LVEF remained preserved or increased (mean duration of follow-up: 1.57 years; 5.328% [95% CI: 2.86%-7.8%; p<0.0001). Data on clinical impact such as functional status and quality of life were not definitive. Data on hospitalizations were unavailable. There was no effect on mortality. Several studies stratified results by LVEF and found that patients with LVEF >35% but <=52% were more likely to receive benefit from physiologic pacing. Patients with chronic atrial fibrillation who underwent atrioventricular node ablation and pacemaker implant demonstrated clear improvement in LVEF with BiVP or HisBP versus RVP. CONCLUSION: Among patients with LVEF >35%, the LVEF remained preserved or increased with either BiVP or HisBP compared with RVP. However, patient-centered clinical outcome improvement appears to be limited primarily to patients who have chronic atrial fibrillation with rapid ventricular response rates and have undergone atrioventricular node ablation. PMID- 30412709 TI - 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. PMID- 30412710 TI - 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society. PMID- 30412711 TI - MicroRNA-34/449 family and viral infections. AB - MicroRNAs are short, endogenous, nonprotein-coding RNAs that are essential for regulation of cellular processes through gene silencing. The miR-34/449 family is conserved in mammalian organisms and generally comprises six homologous genes: miR-34a, miR-34b, miR-34c, miR-449a, miR-449b and miR-449c, at three genomic loci. Strong similarity in the sequence of these miRNAs, particularly at the seed region, predicts robust functional redundancy. A large proportion of the literature on the miR-34/449 family focuses on its role in regulating cell cycle arrest and apoptosis by modulating E2F- and p53-related signaling pathways. A growing subset of the literature reports that the miR-34/449 family is involved in the regulation of immune responses and viral infections, and data suggest the potential for miR-34/446 as a diagnostic and therapeutic target. In this review, we discuss our current understanding of the conservation and transcriptional regulation of the miR-34/449 family and review the literature on its functions in viral infections. PMID- 30412712 TI - Comparison between decompressed and non-decompressed Chiari Malformation type I patients: A neuropsychological study. AB - BACKGROUND: Previous studies have suggested an association of Chiari Malformation type I (CM-I) and cognitive deficits. CM-I is a neurological disorder characterized by a descent of cerebellar tonsils into the foramen magnum, resulting in overcrowding of the upper cervical spine region. Posterior fossa decompression (PFD) is the surgical treatment of choice, however, the literature on the consequences for patients is mainly reduced to the assessment of physical symptoms. METHODS: Data from a neuropsychological assessment of 76 patients with CM-I, both with PFD (n = 37) and without PFD (n = 39) surgery, and 76 healthy controls, matched by gender, age and years of education are reported. RESULTS: CM I patients show a generally lower cognitive performance in executive function, verbal fluency, spatial cognition, language (naming), verbal memory, processing speed, emotional facial recognition and theory of mind, compared to control group. The results are maintained even after statistically controlling for the influence of perceived physical pain and the presence of anxious-depressive symptomatology. Data also illustrate a similar cognitive profile between both groups with CM-I. CONCLUSION: These findings provide evidence of a deficient cognitive profile associated with CM-I, regardless of the PFD surgery. According to these results, both physical and cognitive consequences must be considered in the treatment of CM-I. PMID- 30412713 TI - Reduction in lower-alpha power during Ganzfeld flicker stimulation is associated with the production of imagery and trait positive schizotypy. AB - Light-flicker Ganzfeld (LFG) induces a lower to upper-alpha frequency shift. However, it is unclear how this neurophysiological response might relate to LFG induced pseudo-hallucinatory phenomena. It is also unknown whether emotional states (e.g., fear) or traits associated with risk for psychosis (e.g., proneness to perceptual anomalies, ability to produce vivid mental imagery) affect such neurophysiological and/or perceptual responses to LFG. The present study investigated alpha sub-bands during LFG across several flicker frequencies, in relation to individual differences in propensity for Ganzfeld-induced imagery (GI), positive schizotypy and trait mental imagery, and in relation to manipulations of affective state. Given previously reported sex differences in risk for psychosis and response to Ganzfeld, the effect of sex on GI was also studied. Forty-six healthy adults (16 men) completed psychometric measures of trait mental imagery and positive schizotypy before undergoing three LFG (20 min each) conditions. In each condition, participants wore white-out goggles and listened to either mood-inducing soundscapes (fear, serenity) or pink noise (control) through headphones. Greatest propensity for GI arose between 13.1 and 16.0 Hz flicker, with a peak at 16.0 Hz flicker. Occipital lower-alpha was reduced for lower flicker frequencies (13.1-16.0 Hz) and was inversely associated with GI. Upper-alpha power was not significantly related to GI or to other measures. Fear-induction was associated with reduction in alpha power, but did not significantly affect GI. Men reported more GI than women. Findings support a role for cortical destabilisation, as reflected in reduced lower-alpha, in perceptual anomalies; and, by extension, LFG as an experimental model of liability for psychosis. PMID- 30412714 TI - Association analysis of ERAP1 gene single nucleotide polymorphism in susceptibility to ankylosing spondylitis in Iranian population. AB - Background Ankylosing spondylitis (AS) is a debilitating spondyloarthropathy that has been associated with variation in several genes. Human leukocyte antigen (HLA)-B27 constructs an impaired structure, culminating in recognition and activation of immune system. Impaired function of Endoplasmic reticulum aminopeptidase (ERAP) 1, which primes peptides to be loaded in HLA molecules, has strongly been associated with AS proneness. Here, we intended to investigate the possible association of ERAP1 gene single nucleotide polymorphisms (SNPs) with AS susceptibility in Iranian patients. Methods Two-hundred and twenty AS patients and 220 healthy controls were enrolled in this study. DNA was extracted from blood samples and then was genotyped for rs27044, rs17482078, and rs10050860 polymorphism by SSP-PCR approach. Results It was seen that G allele and GG genotype of rs27044 SNP significantly increased the risk of AS that was even stronger in HLA-B27 positive patients. Moreover, the T allele and TT genotype of rs10050860 polymorphism were associated with increased risk of the disease in both all and HLA-B27 positive AS group. Two haplotypes were associated with the risk of AS and there was linkage disequilibrium between SNPs. Two SNPs were associated with clinicopathological manifestations of AS subjects. Conclusions This association study replicated the role ofERAP1 gene polymorphisms with the risk of AS in an Iranian population. PMID- 30412715 TI - Autophagy protects against redox-active trace metal-induced cell death in rabbit synovial fibroblasts through Toll-like receptor 4 activation. AB - Reactive oxygen species (ROS) are implicated to play a role in initiating rheumatoid arthritis (RA) pathogenesis. We have investigated the mechanism(s) by which essential redox-active trace metals (RATM) may induce cell proliferation and cell death in rabbit synovial fibroblasts. These fibroblast-like synovial (FLS) cells, which express Toll-like receptor 4 (TLR4), were used as a model system that plays a role in potentially initiating RA through oxidative stress. Potassium peroxychromate (PPC, [Cr5+]), ferrous chloride (FeCl2, [Fe2+]), and cuprous chloride (CuCl, [Cu+]) in the indicated valency states were used as exogenous pro-oxidants that can induce oxidative stress through TLR4 coupled activation that also causes HMGB1 release. We measured the proliferation index (PI) of FLS, and examined the effect of RATM oxidants on apoptosis and autophagy by fluorescence cell-sorting flow cytometry (FC). Cell cycle was analysed by FC and autophagy-related protein expression levels were measured by western blot. Our data showed that as RATM as prooxidants increased intracellular ROS (iROS) that can induce oxidative stress. Whereas iROS increased PI in FLS, these reactive species also protected cells against apoptosis by inducing autophagy. Our results indicate that ROS/TLR4-coupled activation may contribute to the pathogenesis of RA in FLS by induction of autophagy. The signalling pathway by which inflammation and its tissue destructive sequel may occur in RA underlies the need for developing therapeutic agents that can inhibit release of tissue damaging high mobility group box 1 (HMGB1), cytokines, and possess both trace metal chelating capacity and oxidant scavenging properties in a directed combinatorial therapy for RA. PMID- 30412716 TI - Long non-coding RNA HOXA-AS2 promotes the migration, invasion and stemness of bladder cancer via regulating miR-125b/Smad2 axis. AB - Long non-coding RNA HOXA-AS2 (HOXA cluster antisense RNA 2) has been reported to function as an oncogene in different types of cancers including breast cancer, liver cancer, gastric cancer and colorectal cancer, etc. However, its role in the development and progression of bladder cancer remains unknown. This study aimed to examine the expression of HOXA-AS2 in bladder cancer, to explore its role in the migration, invasion and stemness of bladder cancer cells and to further identify the potential downstream target miRNAs of HOXA-AS2 in this type of cancer. Our results firstly demonstrated the upregulation of HOXA-AS2 in both bladder cancer cells and clinical bladder tumors. Such upregulation was also positively correlated with the advanced stage, invasion and lymph node metastasis of bladder cancer as well as the expression of cancer stem cell marker OCT4 in patients. After knockdown of HOXA-AS2 in bladder cancer 5637 and T24 cells, the migration, invasion and stemness of cancer cells were significantly inhibited, indicating the capability of HOXA-AS2 to promote the migration, invasion and stemness of bladder cancer cells. Knockdown of HOXA-AS2 also suppressed in vivo tumor growth in the nude mice. Furthermore, this study also identified miR-125b as a downstream target of HOXA-AS2 and revealed the downregulation of miR-125b by HOXA-AS2 as well as the involvement of HOXA-AS2/miR-125b/Smad2 interactions in the functional role of HOXA-AS2 in mediating the migration, invasion and stemness of bladder cancer cells. Together, our findings suggest that HOXA-AS2 might be a potential biomarker and target for the diagnosis, monitoring and treatment of bladder cancer. PMID- 30412717 TI - Autophagy induced by ionizing radiation promotes cell death over survival in human colorectal cancer cells. AB - Autophagy is commonly described as a cell survival mechanism and has been implicated in chemo- and radioresistance of cancer cells. Whether ionizing radiation induced autophagy triggers tumor cell survival or cell death still remains unclear. In this study the autophagy related proteins Beclin1 and ATG7 were tested as potential targets to sensitize colorectal carcinoma cells to ionizing radiation under normoxic, hypoxic and starvation conditions. Colony formation, apoptosis and cell cycle analysis revealed that knockdown of Beclin1 or ATG7 does not enhance radiosensitivity in HCT-116 cells. Furthermore, ATG7 knockdown led to an increased survival fraction under oxygen and glutamine starvation, indicating that ionizing radiation indeed induces autophagy which, however, leads to cell death finally. These results highlight that inhibition of autophagic pathways does not generally increase therapy success but may also lead to an unfavorable outcome especially under amino acid and oxygen restriction. PMID- 30412718 TI - Tooth loss after periodontal treatment-Mining an insurance database. AB - OBJECTIVES: The aim of this study was to evaluate tooth loss after periodontal treatment. METHODS: The data was collected from the digital database of a major German national health insurance company. Periodontal treatment was the intervention in the treatment group. Kaplan-Meier survival analyses on the patient level with the primary outcome extraction were carried out over four years. A control group without treatment was matched and analysed. Differences were tested with the Log-Rank-test. Extraction incidences were calculated over a matched observation period six years before and four years after treatment for both treatment and control group. RESULTS: A total of 415,718 periodontal treatments could be traced. Focussing on the outcome "extraction", the cumulative four-year survival rate was 63.8% after periodontal treatment. The matched control group without periodontal treatment showed a survival rate of 72.5%. These differences were significant (p < 0.0001). The extraction incidence over time was higher in a four-year period after periodontal treatment compared to a six-year period before periodontal treatment. CONCLUSIONS: The outcome of periodontal treatment was acceptable. In about two thirds of the patients, extractions could be completely avoided within a four year period after treatment. CLINICAL SIGNIFICANCE STATEMENT: This study within the German national health insurance system shows that extractions were not observed after periodontal treatment in the majority of cases. Although periodontitis is a chronic disease, patients suffering from periodontitis have a considerable chance to prevent further tooth loss. PMID- 30412719 TI - Early On-Scene Management of Pediatric Out-of-Hospital Cardiac Arrest Can Result in Improved Chances for Neurologically-Intact Survival. AB - AIM: To evaluate the frequency of neurologically-intact survival (SURV) following pediatric out-of-hospital cardiac arrest (POHCA) when comparing traditional early evacuation strategies to those emphasizing resuscitation efforts being performed on-scene. METHODS: Before 2014, emergency medical services (EMS) crews in a county-wide EMS agency provided limited treatment for POHCA on-scene and rapidly transported patients to appropriate hospitals. After 2014, training strongly enhanced EMS provider comfort levels with on-scene resuscitation efforts including methods to expedite protocols on-site and control positive-pressure ventilation. Frequency of SURV (hospital discharge) was compared for the two years prior to initiating the immediate on-scene care strategy to the ensuing two years following implementation. RESULTS: Between 01/01/2012 and 12/31/2015, 94 children experienced POHCA. There were no significant differences before and after the on-scene focus in terms of age, sex, etiology, presenting electrocardiograph, drug infusions or bystander-performed cardiopulmonary resuscitation and total scene times actually remained similar (14.3 vs. 17.67 minutes). SURV increased significantly upon implementation of the immediate on scene management strategy and was sustained over the next two years (0.0 % to 23%; p = 0.0013). Though statistically-indeterminate in this analysis, the improvement was associated with a shorter mean time to epinephrine administration among resuscitated patients (16.6 vs. 7.65 minutes). CONCLUSION: Facilitating immediate on-scene management of POHCA can result in improvements in life-saving. Although a historically-controlled evaluation, the compelling appearance of neurologically-intact survivors was immediate and sustained. Targeted training, more efficient, physiologically-driven procedures, and trusted encouragement from supervisors, likely played the most significant roles and not necessarily extended scene times. PMID- 30412720 TI - From molecular mechanisms to functional impact: Developing integrated analyses in neurotoxicology - The 16th biennial meeting International Neurotoxicology Association and 8th meeting of the NeuroToxicity Society. PMID- 30412721 TI - Strip-dried blood sampling: applicability for bovine leukemia virus detection with ELISA and real-time PCR. AB - We recently proposed a new so-called strip-dried format aimed for convenient use of dried biomaterial in diagnostic purposes. In this work, 334 blood samples obtained in strip-dried form were used for bovine leucosis analysis with ELISA and real-time PCR methods. High percentage of seropositive animals (18.3%) let us estimate both indirect (serological) and direct methods applicability for the analysis of strip-dried blood samples and also to compare them (PCR results concurred with ELISA in 93.4% cases). Parallel analysis of native and corresponding strip-dried samples approved the proposed format as a reliable analytical way of sampling being in 100% concordance with conventional serum/whole blood ELISA and PCR analysis. Even distribution of antibodies against bovine leukemia virus along the membrane carrier was demonstrated by square-to square analyzing of the sample strip (CV not exceeded 7%). Also, strip-dried blood samples showed enhanced stability at elevated temperatures comparing to liquid serum. The proposed strip-blood format is a promising way of sampling, storage and transportation and can find application in veterinary practice for infectious disease monitoring. PMID- 30412722 TI - Polymeric nanoparticles promote endocytosis of a survivin molecular beacon: Localization and fate of nanoparticles and beacon in human A549 cells. AB - : Polymethylmethacrylate core-shell fluorescent nanoparticles promote, in human lung A549 cancer cells, the internalization of a molecular beacon (MB) specific for survivin mRNA, an anti-apoptotic protein overexpressed in cancer cells. AIMS: To design an effective drug delivery system, the knowledge of the uptake mechanism and of the nanoparticles (NPs) and MB fate is required. MATERIALS AND METHODS AND KEY FINDINGS: Experiments with dextran as marker for endocytosis showed that in the presence of NPs the number of endocytic vesicles per cell doubled and their mean size significantly (p < 0.001) increased with respect to controls in absence of NPs, indicating an involvement of NPs in the endocytotic process. By using LysoTrackerTM Deep Red, as marker of lysosomes, we found that nanoparticles co-localize with lysosomes. Moreover, a cellular release of nanoparticles detected in the culture medium, suggested a role of lysosomal exocytosis in nanoparticle elimination. The MB fluorescence in proximity of the labeled Endoplasmic Reticulum was indicative that the opening of the MB occurs in proximity of its target mRNA. SIGNIFICANCE: The results show the involvement of endocytotic pathway in the uptake of NPs, which are an appropriate delivery system capable of being eliminated by cells. Furthermore the data confirm that the MB can be considered an effective tool for the intracellular sensing. PMID- 30412723 TI - Differential effects of maternal high-fat/high-caloric or isocaloric diet on offspring's skeletal muscle phenotype. AB - : Aim This study sought to investigate the effects of two different maternal high fat diets, during gestation and lactation, on the morphology of the skeletal muscle of the adult offspring rats. METHODS: Female Wistar rats were fed Control (C) or High-fat/high-caloric (HH) or High-fat/isocaloric (HI) diet during gestation and lactation. The somatic growth of the offspring was measured throughout lactation. Glucose and insulin tolerance tests were performed at PND61 and PND65, respectively. At PND70, soleus and extensor digitorum longus (EDL) muscles were removed for myofibrillar ATPase staining analysis. KEY FINDINGS: HH pups were heavier and longer at weaning but presented same body weight at PND70. No difference among groups in glucose or insulin tolerance tests was observed. In the soleus muscle, HH offspring showed increased proportion and size of type 1 fibres and reduced proportion and number with increased size of type 2A fibres. In EDL muscle, there was no difference in proportion and number of fibres. HH and HI animals presented reduced type 1 and 2A fibres size while HH animals presented increased type 2B fibres size, in EDL muscle. SIGNIFICANCE: Maternal HH diet promoted a more oxidative profile in soleus muscle. Though, maternal high fat/isocaloric diet influenced only fibres size. Glycolytic muscle is more resistant to maternal diet influence. These results emphasize the importance of maternal diet during the critical period of development on muscle morphology of the offspring. PMID- 30412724 TI - Monomethyl fumarate alleviates sepsis-induced hepatic dysfunction by regulating TLR-4/NF-kappaB signalling pathway. AB - AIMS: Sepsis is a potentially fatal illness that can lead to impairment of multiple organs such as liver. The condition is deeply associated with oxidative stress and inflammation. Monomethyl fumarate (MMF) has manifested antioxidant and immunomodulatory properties. The aim of current study was to evaluate protective effects of MMF in sepsis-induced hepatic dysfunction. MAIN METHODS: Sepsis was induced by cecal ligation and puncture (CLP). Wistar rats were assigned to one of sham, CLP, CLP + dexamethasone (as positive control of inflammation) and CLP + MMF groups. Levels of serum IL-1beta, IL-6, IL-10, AST, ALT and gamma-GT were quantified. Furthermore, Hepatic levels of GSH and MDA and mRNA expression of TNF and NFKBIA along with hepatic protein level of TLR-4 were assessed. Also, histopathological study of liver was carried out to evaluate hepatic injuries. KEY FINDINGS: Septic rats demonstrated risen levels of IL-1beta, IL-6, IL-10, AST, ALT and gamma-GT, while treatment with dexamethasone or MMF attenuated these levels. Moreover, enhancements in protein level of TLR-4 and mRNA levels of TNF and NFKBIA were observed in CLP rats. These elevations were mitigated in CLP induced rats that were treated with either dexamethasone or MMF. Treatment with dexamethasone or MMF also shifted sepsis-induced disturbance in the levels of GSH and MDA towards sham levels. Hepato-protective effects of dexamethasone and MMF were further confirmed by histopathological observations. SIGNIFICANCE: Our findings imply that MMF alleviates sepsis-induced hepatic dysfunction by mitigating the inflammatory and oxidative state and this effect is at least partly mediated by the inhibition of TLR-4/NF-kappaB signalling pathway. PMID- 30412725 TI - Rigidity controls human desmoplastic matrix anisotropy to enable pancreatic cancer cell spread via extracellular signal-regulated kinase 2. AB - It is predicted that pancreatic ductal adenocarcinoma (PDAC) will become the second most lethal cancer in the US by 2030. PDAC includes a fibrous-like stroma, desmoplasia, encompassing most of the tumor mass, which is produced by cancer associated fibroblasts (CAFs) and includes their cell-derived extracellular matrices (CDMs). Since elimination of desmoplasia has proven detrimental to patients, CDM reprogramming, as opposed to stromal ablation, is therapeutically desirable. Hence, efforts are being made to harness desmoplasia's anti-tumor functions. We conducted biomechanical manipulations, using variations of pathological and physiological substrates in vitro, to culture patient-harvested CAFs and generate CDMs that restrict PDAC growth and spread. We posited that extrinsic modulation of the environment, via substrate rigidity, influences CAF's cell-intrinsic forces affecting CDM production. Substrates used were polyacrylamide gels of physiological (~1.5 kPa) or pathological (~7 kPa) stiffnesses. Results showed that physiological substrates influenced CAFs to generate CDMs similar to normal/control fibroblasts. We found CDMs to be softer than the corresponding underlying substrates, and CDM fiber anisotropy (i.e., alignment) to be biphasic and informed via substrate-imparted morphological CAF aspect ratios. The biphasic nature of CDM fiber anisotropy was mathematically modeled and proposed a correlation between CAF aspect ratios and CDM alignment; regulated by extrinsic and intrinsic forces to conserve minimal free energy. Biomechanical manipulation of CDMs, generated on physiologically soft substrates, leads to reduction in nuclear translocation of pERK1/2 in KRAS mutated pancreatic cells. ERK2 was found essential for CDM-regulated tumor cell spread. In vitro findings correlated with in vivo observations; nuclear pERK1/2 is significantly high in human PDAC samples. The study suggests that altering underlying substrates enable CAFs to remodel CDMs and restrict pancreatic cancer cell spread in an ERK2 dependent manner. PMID- 30412726 TI - White blood cell counts in a geriatric hospitalized population: A poor diagnostic marker of infection. AB - INTRODUCTION: Older people suffer more often and from more severe infections than do younger people. Several studies have shown a correlation between higher white blood cell count (WBCC) and the presence of infection. The usefulness of increased WBCC to assess the presence of infection in geriatric patients is debated. To answer this question, we investigated the correlation between the total and differential WBCC and documented infection in hospitalized geriatric individuals. POPULATION AND METHODS: Clinical data (medical history, comorbidities, treatments, geriatric syndromes) and biological parameters were collected from 166 hospitalized geriatric patients (67-106 yrs) presenting with acute inflammation (C-reactive protein (CRP) > 10 mg/l) and were compared according to the presence/absence of infection. RESULTS: The mean WBCC was not significantly different (p = 0.71) according to the presence of infection or not, although the mean CRP level was higher in the infected group compared to the non infected group (p = 0.0019). In regression analyses, the presence of infection was not associated with an increase in total and differential WBCC. Additionally, we found a positive correlation between cardiovascular risk factor and diseases (CVRF & diseases) and WBCC. CONCLUSION: In geriatric patients, WBCC is not a reliable biomarker for infection; however, combined with CRP, it represents a marker of cardiovascular disorders. PMID- 30412727 TI - MicroRNA-128 knockout inhibits the development of Alzheimer's disease by targeting PPARgamma in mouse models. AB - Alzheimer's disease (AD) is a great threat for the health and life of elderly people. MicroRNA-128 (miR-128) has been reported to be abnormally expressed in the brain of AD patients and associated with the pathogenesis of AD. Our study aimed to have a deep insight into the roles and molecular basis of miR-128 in the development and progression of AD. The cognitive ability and exploratory behaviors were assessed by morris water maze and open-field tests, respectively. The concentrations of amyloid-beta (Abeta) 40, Abeta 42, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-10 and activity of beta-secretase and alpha-secretase were determined by corresponding ELISA commercial kits. RT-qPCR assay was performed to detect miR-128 level and the mRNA expression of peroxisome proliferator-activated receptor gamma (PPARgamma), ionized calcium-binding adaptor molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP). Western blot assay was conducted to determine protein expression of PPARgamma, amyloid precursor protein (APP), beta-APP cleaving enzyme (BACE1), sAPPalpha and sAPPbeta. The effect of miR-128 and PPARgamma on amyloid plaque formation was assessed by immunohistochemistry assay. PPARgamma mean optical density was determined by immunofluorescence assay. The interaction between miR-128 and PPARgamma were validated by bioinformatics analysis and luciferase reporter assay. We found AD mice showed AD-like performance and an increased cerebral cortex Abeta production. MiR-128 expression was upregulated and PPARgamma expression was downregulated in cerebral cortex of AD mice. Moreover, PPARgamma was a target of miR-128. Additionally, miR-128 knockout or PPARgamma upregulation inhibited AD-like performances, amyloid plaque formation, Abeta generation, APP amyloidogenic processing and inflammatory responses in AD mice, while these effects of miR-128 knockout were abrogated by PPARgamma inhibitor. The results indicated MiR-128 knockout weakened AD-like performances, and reduced Abeta production and inflammatory responses by targeting PPARgamma in AD mice. PMID- 30412728 TI - Tectochrysin from Alpinia Oxyphylla Miq. alleviates Abeta1-42 induced learning and memory impairments in mice. AB - Alzheimer's disease (AD), a neurodegenerative disease, is diagnosed by impaired learning and memory in elderly individuals. Tectochrysin (TEC) is a flavonoid compound isolated from Alpinia Oxyphylla Miq., which has been traditionally used for the treatment of diarrhea, salivation, diuresis and dementia. In our study, model mice with AD induced by intracerebroventricular injection of Abeta1-42 were used to determine the role of TEC on memory retrieval. The results revealed that AD mice received intracerebroventricular injection of TEC (140 ug/kg) showed improved spatial memory performance and down-regulated expressions of beta secretase and accumulation of Abeta1-42 in brain tissues. TEC also decreased the concentration of malondialdehyde and total cholinesterase, and increased activities of both antioxidant superoxide dismutase and glutathione peroxidase in hippocampal and cortex. In addition, Abeta1-42 induced injury of neurons in hippocampal CA1 layer was rehabilitated in TEC treated mice. These findings highlight the beneficial role of TEC in amnestic mice induced by Abeta1-42 through the down-regulation of Abeta1-42 accumulation, oxidative stress, and total cholinesterase. Our study indicated a therapeutic potential of TEC in the treatment of AD. PMID- 30412729 TI - The serotonin 2C receptor agonist WAY-163909 attenuates ketamine-induced hypothermia in mice. AB - Anesthesia-Induced Hypothermia (AIH) has been reported to be the cause of many postoperative adverse effects, including increased mortality, decreased immune responses, cardiac events, and a greater prevalence of postoperative surgical wound infections. AIH can in some cases be minimized with pre-warming fluids and gases and forced-air heating systems, but such techniques are not always effective and can result in patient burns or other adverse effects. Stimulation of 5-HT2 receptors has been reported to increase body temperature through a variety of mechanisms, and as such, may be a viable target for pharmacologically minimizing AIH. In the present study, we examined the effects of 5-HT2 receptor stimulation on hypothermia induced by the injectable anesthetic ketamine in Swiss Webster mice using rectal thermometry. We report that ketamine dose-dependently induced hypothermia, and mice did not become tolerant to this effect of ketamine over the course of three injections spaced at once per week. Ketamine-induced hypothermia was significantly attenuated by pretreatment with the selective 5 HT2C receptor agonist WAY-163909 but not by pretreatment with the mixed 5-HT2A/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). Moreover, the blockade of ketamine-induced hypothermia by WAY-163909 was reversed by pretreatment with the selective 5-HT2C receptor antagonist SB-242084. These findings demonstrate that stimulation of 5-HT2C receptors can reduce AIH, at least for ketamine-induced hypothermia. They warrant further study of the pharmacological and neurobiological mechanisms underlying this interaction and its extension to other anesthetics. Furthermore, these findings suggest that the maintenance of body temperature during surgery may be a new clinical use for 5-HT2C receptor agonists. PMID- 30412730 TI - Functional assessments through novel proteomics approaches: Application to insulin/IGF signaling in neurodegenerative disease'. AB - BACKGROUND: Events that instigate disease may involve biochemical events distinct from changes in the steady-state levels of proteins. Even chronic degenerative disorders appear to involve changes such as post-translational modifications. NEW METHOD: We have begun a series of proteomics analyses on proteins that have been fractionated by functional status. Because Alzheimer's disease (AD) is associated with metabolic perturbations such as Type-2 diabetes, fractionation hinged on binding to phosphatidylinositol trisphosphate (PIP3), key to insulin/insulin-like growth factor signaling. We compared mice on normal chow to counterparts subjected to diet-induced obesity (DIO) or to mice expressing human Abeta1-42 from a transgene. RESULTS: The prevailing phenotypic finding in either experimental group was loss of PIP3 binding. Of the 1228 proteins that showed valid PIP3 binding in any group of mice, 55% exhibited a significant quantitative difference in the number of spectral counts as a function of DIO, 63% as function of the Abeta transgene, and 79% as a function of either variable. There was remarkable overlap among the proteins altered in the two experimental groups, and pathway analysis indicated effects on proteostasis, apoptosis, and synaptic vesicles. COMPARISON WITH EXISTING METHODS: Most proteomics approaches only identify differences in the steady-state levels of proteins. Our overlay of a functional distinction permits new levels of discovery that may achieve novel insights into physiology in an unbiased and inclusive manner. CONCLUSIONS: Proteomics analyses have revolutionized the discovery phase of biomedical research but are conventionally limited in scope. The creative use of fractionation prior to proteomic discovery is likely to provide important insights into AD and related disorders. PMID- 30412731 TI - The effect of CO2 in enhancing photosynthetic cofactor recycling for alcohol dehydrogenase mediated chiral synthesis in cyanobacteria. AB - The light harvesting photosystem in cyanobacteria offers a potential pathway for the regeneration of the nicotinamide cofactor NADPH, thereby facilitating the application of cyanobacteria as excellent whole cell biocatalysts in oxidoreductase-mediated biotransformation. The use of cyanobacterial metabolism for cofactor recycling improves the atom economy of the process compared to the commonly employed enzyme-coupled cofactor recycling using enzymes such as glucose dehydrogenase. Here we report the asymmetric conversion of acetophenone to chiral 1-phenylethanol by recombinant Synechococcus elongatus PCC 7942 whole cell biocatalyst that expresses the NADPH dependent L. kefir alcohol dehydrogenase. Besides light, it was observed that carbon dioxide levels play a critical role in improving the bioconversion efficiency possibly due to the enhanced growth rate and improved cofactor availability at elevated CO2 levels. Complete reduction of acetophenone to optically pure (R)-1-phenylethanol at 99% enantiomeric excess was achieved within 6 h with a relatively low cell density of 0.66 g/l by coupling optimum light and CO2 levels and without the need for a co-substrate. PMID- 30412732 TI - 17beta-Estradiol protects mesenchymal stem cells against high glucose-induced mitochondrial oxidants production via Nrf2/Sirt3/MnSOD signaling. AB - 17beta-estradiol (E2) is an important regulator of energy homeostasis and glucose metabolism, thus making it a potential target for preventing or treating metabolic disorders. However, the exact mechanism by which E2 affects high glucose-induced oxidative stress remains unclear. Therefore, the present study investigated the role of E2 in high glucose-induced mitochondrial reactive oxygen species (mtROS) production through estrogen receptor (ER)-mediated signaling in human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) in vitro. In addition, the effect of hUCB-MSC transplantation on mouse skin wound healing induced by E2 in ovariectomized (OVX) diabetic mice in vivo was also studied. High glucose (D-glucose, 25 mM) increased mtROS production, resulting in increase of Beclin1 expression and the LC3-II/LC3-I ratio, leading to decreased cell viability. Conversely, E2 (10 nM) treatment significantly decreased high glucose induced mtROS levels and subsequently restored cell viability, suggesting that E2 serves as a strong antioxidant. High glucose downregulated Nrf2 levels in nucleus, subsequently culminating in Sirt3 downregulation and manganese superoxide dismutase (MnSOD) acetylation. However, we found that E2 induces nuclear Nrf2 expression via interaction with ERalpha. The increased nuclear translocation of Nrf2 triggered Sirt3 upregulation and MnSOD activation, both of which play important roles in decreasing mtROS levels. Thus, the therapeutic effect of hUCB-MSC transplantation on skin wound healing in OVX diabetic mice was enhanced by E2 treatment compared with the findings in OVX diabetic mice treated only with hUCB-MSCs. In addition, blood vessels with well-developed branches were observed in OVX diabetic mice that underwent hUCB-MSC transplantation and E2 treatment compared with the effects of ERalpha siRNA-transfected hUCB-MSC transplantation alone. In conclusion, our results imply that E2 protects cells against high glucose-induced mtROS production and autophagic cell death through increasing nuclear translocation of Nrf2, which was followed by Sirt3 upregulation and MnSOD activation in hUCB-MSCs. PMID- 30412733 TI - Plant-derived medicines for treatment of endometriosis: A comprehensive review of molecular mechanisms. AB - Endometriosis is an estrogen-dependent disease with inflammatory lesions at extra uterine sites, causing pelvic pain and fertility reduction. Conventional therapies primarily focus on reducing systemic levels of estrogens; however, they do not have desirable effectiveness and possess considerable side effects. Therefore, there is a growing interest in the use of herbal medicine for the treatment of endometriosis. In this paper, electronic databases including PubMed, Scopus, Cochrane library and Google Scholar were searched to obtain any studies evaluating any herbal products in the management of endometriosis. Data were collected from 1980 to 2018. Most of studies investigating the effect of herbal medicines in endometriosis were in vitro and animal and only three clinical trials were found; one on Pinus pinaster bark extract (Pycnogenol) and two on Chinese herbal formulas. The studies on phytochemicals had mostly focused on polyphenolic compounds (epigallocatechin-3-gallate, genistein) and sesquiterpenes (beta-caryophyllene, parthenolide). Various molecular mechanisms of action have been involved in beneficial effects of herbal medicines and phytochemicals including anti-inflammatory (via reduction of proinflammatory cytokines such as interleukin -1, interleukin -6, interleukin -8, transforming growth factor-beta, tumor necrosis factor-alpha, nuclear factor-kappa B, growth factors, monocyte chemoattractant protein-1), antioxidant (through downregulation of hydrogen peroxide, malondialdehyde, reactive oxygen species and upregulation of superoxide dismutase), anti-proliferative and apoptotic (via enhancing Bcl-2-associated X protein/ B-cell lymphoma-2 and caspase3, 8 and 9 activity), anti-angiogenic (by downregulation of vascular endothelial growth factor receptors/ vascular endothelial growth factor), anti-invasive (via decreasing expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and matrix metalloproteinases), immunomodulatory, and estrogen modulating activities. So, medicinal plants seem to be a valuable source for identifying new drugs for treatment of endometriosis; however, since most of studies are preclinical, further clinical trials are required to achieve more conclusive results. PMID- 30412734 TI - Incidence, Predictors, and Outcomes of New-Onset Left Ventricular Systolic Dysfunction After Orthotopic Liver Transplantation. AB - BACKGROUND: Adverse cardiovascular events after liver transplantation (LT) are relatively common and are a significant source of early mortality. Although new onset systolic dysfunction after LT is a reported phenomenon, there is little data regarding its incidence, risk factors, and outcomes. METHODS AND RESULTS: This single-center retrospective study included all adult patients from January 2002 to March 2015 with deceased-donor LT and available preoperative transthoracic echocardiograms (TTEs). In total, 1,760 patients were included in the study, 602 (34.2%) of whom had a postoperative TTE. The primary end point was development of new-onset cardiomyopathy, defined as a new left ventricular ejection fraction (LVEF) of <40% within 180 days of transplant. Sixty-nine (11.4%) of the patients who received post-LT TTE had a reduction in LVEF to <40% within 6 months. Clinical parameters of donor and recipient did not show significant impact on development of post-LT LV systolic dysfunction (LVSD). Presence of wall motion abnormalities (P = .004) on preoperative TTE was predictive of development of post-LT LVSD. These patients did not have longer hospitalizations, but they had worse survival. CONCLUSIONS: Post-LT LV systolic dysfunction occurs at higher rates than previously suspected and may develop more frequently in patients with underlying cardiac structural abnormalities, which appear to adversely affect post-LT survival. PMID- 30412735 TI - Antimicrobial resistance and molecular characteristics of Neisseria gonorrhoeae isolates from MSM. AB - OBJECTIVES: To analyze the susceptibility of Neisseria gonorrhoeae isolates to penicillin (Pen), cefixime (Cfm), ceftriaxone (Cro), tetracycline (Tet), ciprofloxacin (Cip), azithromycin (Azm) and spectinomycin (Spt). To verify the presence of mutations in resistant genes. METHODS: Antibiotic susceptibility testing was carried out by Etest method in 30N. gonorrhoeae isolates collected from MSM population. PCR and DNA sequencing were performed to identify mutations within penA, mtrR, gyrA and parC genes in intermediate or full resistance isolates. RESULTS: N. gonorrhoeae isolates showed intermediate or full resistance to Pen (73%), Cfm (3%), Tet (60%), Cip (37%) and Azm (13%). One isolate CfmR presented a PBP2 mosaic XXXIV. All PenI and PenR isolates (except at PBP2 mosaic) presented a D345a in PBP2 and all CipR isolates had a S91F at gyrA gene together with mutations at parC gene. All intermediate or full resistance isolates to substrates of MtrCDE efflux pump had an A39T or G45D mutation in mtrR gene or an adenine deletion within the mtrR promoter. One isolate presented a N. meningitidis-like mtrR promoter sequence. CONCLUSIONS: The results of this study are consisting with the findings of other authors and reinforce the importance of developing new therapeutic options in a short time period. PMID- 30412736 TI - Increase in prevalence of PVL and clonal shift in community onset -MRSA causing skin and soft tissue infections in the Rhine-Neckar-region, Germany, 2012-2016. AB - Methicillin-resistant Staphylococcus aureus (MRSA) remains a major challenge for patient care. Community-associated MRSA (CA)-MRSA often have fitness and virulence advantage compared to their nosocomial counterpart. Increased mobility, travel activities and migration accelerate the intercontinental spread of virulent CA-MRSA. Out-patient clinics are the most important route of entry for CA-MRSA into hospitals. However, systematic data on CA-MRSA in Germany is limited. We characterized community onset MRSA SSTI isolates in the Rhine-Neckar Region from 2012-2016 to gain insight into the molecular epidemiology and monitor potential introduction of virulent and dominant MRSA strains into our hospital. We identified 2475 patients with S. aureus SSTI in the outpatient departments of our hospital, of which 3.8% (94/2475) were MRSA. 40% of the community onset-MRSA harboured the virulence factor Panton-Valentine Leukocidin (PVL). ST8-t008-MRSA IVa/c (26%, 10/38) and ST80-t044-IVc MRSA (16%, 6/38) were the predominant PVL+ MRSA in our hospital. Molecular typing and epidemiological data revealed that 42.5% (n=40/94) of strains could be traced back to local origin and 44.7% (n=42/94) were endemic outside of Europe. Antibiotic resistance to quinolones, clindamycin and macrolides was common, while resistance to trimethoprim sulfamethoxazole, tetracycline, mupirocin, chlorhexidine and fusidic acid was low. No resistance to rifampicin, fosfomycin and linezolid was observed. Our study provides insight into the clonal composition of community onset-MRSA in the Rhine-Neckar Region. The increase of PVL+ MRSA and the introduction of imported strains may affect the local MRSA landscape in the near future and should be monitored closely. PMID- 30412737 TI - The potential role of HO-1 in regulating the MLK3-MKK7-JNK3 module scaffolded by JIP1 during cerebral ischemia/reperfusion in rats. AB - Heme oxygenase (HO-1), which may be induced by Cobaltic protoporphyrin IX chloride (CoPPIX) or Rosiglitazone (Ros), is a neuroprotective agent that effectively reduces ischemic stroke. Previous studies have shown that the neuroprotective mechanisms of HO-1 are related to JNK signaling. The expression of HO-1 protects cells from death through the JNK signaling pathway. This study aimed to ascertain whether the neuroprotective effect of HO-1 depends on the assembly of the MLK3-MKK7-JNK3 signaling module scaffolded by JIP1 and further influences the JNK signal transmission through HO-1. Prior to the ischemia reperfusion experiment, CoPPIX was injected through the lateral ventricle for 5 consecutive days or Ros was administered via intraperitoneal administration in the week prior to transient ischemia. Our results demonstrated that HO-1 could inhibit the assembly of the MLK3-MKK7-JNK3 signaling module scaffolded by JIP1 and could ultimately diminish the phosphorylation of JNK3. Furthermore, the inhibition of JNK3 phosphorylation downregulated the level of p-c-Jun and elevated neuronal cell death in the CA1 of the hippocampus. Taken together, these findings suggested that HO-1 could ameliorate brain injury by regulating the MLK3 MKK7-JNK3 signaling module, which was scaffolded by JIP1 and JNK signaling during cerebral ischemia/reperfusion. PMID- 30412738 TI - Asymmetry of Brain Excitability: A New Biomarker that Predicts Objective and Subjective Symptoms in Multiple Sclerosis. AB - OBJECTIVES: Investigate whether asymmetrical corticospinal excitability exists in Multiple Sclerosis (MS) and its association with MS symptoms. METHODS: Bilateral resting and active motor thresholds (RMT, AMT) were gathered using transcranial magnetic stimulation among 82 MS patients. Corticospinal excitability (CSE) asymmetry was expressed as the ratio between weaker and stronger sides' RMT and AMT. Stronger and weaker side was determined by pinch and grip strength. We examined whether CSE asymmetry predicted symptoms. RESULTS: AMT asymmetry ratio revealed atypical CSE asymmetry whereby the hemisphere associated with the weaker hand was more excitable in early MS. After controlling for MS disease demographics, shifting of CSE asymmetry towards greater excitability in the stronger side significantly predicted more severe symptoms including Expanded Disease Severity Scale, nine-hole peg test, cognitive processing speed, walking speed, heat sensitivity, fatigue, and subjective impact of MS. CONCLUSION: CSE asymmetry significantly predicted the severity of MS-related physical and objective cognitive symptoms. The phenomenon may be related to neuroinflammation mediated hyperexcitability. Shifting of asymmetry toward less excitability on the weaker side may suggest the onset of a more neurodegenerative phase of the disease. SIGNIFICANCE: Shifting of hemispheric excitability, detected using a CSE asymmetry ratio, may be a useful biomarker to track disease progression and understand the benefits of treatments. PMID- 30412739 TI - Food or friends? What motivates zebrafish (Danio rerio) performing a visual discrimination. AB - As a model organism, zebrafish have much to offer neuroscientific research and they are increasingly being used in behavioral neuroscience, for example to study the genetics of learning and memory. As fish are often considered "less clever" than mammals, it is important to understand how they learn and to establish optimal testing conditions. In this study, we compared the efficacy of food reinforcement and social stimuli in supporting Pavlovian conditioning, Pavlovian to-instrumental transfer, and acquisition of a two-alternative forced choice visual discrimination. Although equally effective in conditioning and in motivating discrimination learning, fish responded with shorter latencies when they were anticipating food but responded for a greater number of trials when anticipating the social stimulus. After learning, the reward was changed: food reinforcement was replaced with the social stimulus and vice versa. Performance accuracy did not change, but response latency did: the group previously rewarded with food, but now rewarded with the social stimulus, showed a decrease in response vigor. This is a negative contrast effect, which is well established in rats, but was thought to be absent in fish because they lacked goal representation. Our results show that zebrafish, like rats, do have goal representations. Furthermore, we have shown that whereas food has greater incentive salience than social stimuli, fish become satiated rapidly, but motivation to seek social stimuli is sustained. We conclude that zebrafish are well motivated by a mixed economy of social stimuli and food. PMID- 30412740 TI - US-guided temporomandibular joint injection: Validation of an in-plane longitudinal approach. AB - Ultrasonography of the temporomandibular joint is a non-invasive imaging technic, easy to perform in daily practice. It can be used for diagnosis and to guide intra-articular injections. The objective was to validate a longitudinal in-plane US injection approach of the joint and assess its accuracy. We performed a study in 13 non-embalmed cadavers. The injection was done under real-time US guidance using a needle inserted in-plane with an angulation of 30 degrees and positioned under the capsule until the injection was feasible without resistance. The intra articular injection was successful in all cases and confirmed by a liquid backflow in 96% of cases. The median duration between skin puncture and the intra articular injection was 23 seconds. Our technique allows a direct visualization of the needle throughout its course to the joint with a high accuracy. Other studies will be needed to confirm its feasibility and usefulness in patients with TMJ disorders. PMID- 30412741 TI - Time to pull the trigger? Examining the ethical permissibility of minimum age restrictions for gun ownership and use. AB - A series of prominent mass shootings in the United States (US) has prompted renewed interest in revising gun policy. One proposal that has gained political traction is raising the minimum age for purchase and possession of guns to 21. While some commentators have suggested that the public mood may be shifting on gun policy, proposals to raise the minimum age have nevertheless provoked controversy. In this manuscript, we examine the ethical acceptability of raising the minimum age of purchase and possession of guns to 21. First, we examine the nature of the rights claim at issue. Second, we examine liberty-based objections to minimum age laws, and offer counter-arguments to these claims. Then, we examine the nature of the harm to be prevented via minimum age laws. We conclude that gun ownership is an important right, but one that nevertheless is ethical to regulate. We argue that liberty-based objections to minimum age laws are not as strong as critics of these laws claim. While we acknowledge the data limitations on assessing their likely success in reducing gun-related harms, we argue that minimum age laws are an ethically permissible policy strategy. We conclude with several recommendations for further research and policy responses to addressing the toll of gun-related morbidity and mortality. PMID- 30412742 TI - The impact of maternal BMI, gestational weight gain, and breastfeeding on early childhood weight: Analysis of a statewide WIC dataset. AB - Early childhood obesity is a persistent health concern with more frequent and significant impact on low-income families. Maternal weight factors impact offspring weight status, but evidence on whether breastfeeding protects against this impact is mixed. This analysis examined a model to predict early childhood obesity risk, simultaneously accounting for maternal pre-pregnancy body mass index (BMI), gestational weight gain, and breastfeeding. The team analyzed 27,016 unique maternal-child dyadic records collected via the Supplemental Nutrition Program for Wisconsin Women, Infants, and Children (WIC) between 2009 and 2011. Generalized Linear Modeling, specifically logistic regression, was used to predict a child's risk of obesity given the mother's pre-pregnancy BMI, gestational weight gain, and duration of breastfeeding. For each 1 kg/m2 increase in pre-pregnancy BMI, there was a 4.5% increase in risk of obesity compared to children with mothers of normal BMI. Children whose mothers had excessive gestational weight gain were 50% more likely to have obesity compared to those whose mothers had ideal weight gain. For each week of additional breastfeeding, there was a 1.9% increased risk of obesity. The risk models did not differ by race. In this model, accounting for pre-pregnancy weight, gestational weight gain, and breastfeeding among a diverse, low-income sample, women with pre pregnancy overweight and obesity or who had excessive gestational weight gain had the highest risk of early childhood obesity. While breastfeeding is healthy for many reasons, providers should focus on maternal weight-related behaviors when counseling mothers about how to avoid risk of early childhood obesity. PMID- 30412743 TI - Leveraging technology to address the problem of cigarette smoking among women of reproductive age. AB - Women of reproductive age and particularly pregnant women underutilize evidence based smoking cessation services such as counseling and quit lines. Mobile health (mHealth) may constitute an unexplored and innovative avenue for providing smoking cessation support to a population that is otherwise difficult to reach with evidence-based interventions. Female respondents aged 18-44 years (N = 10,023) were drawn from the first wave of the Population Assessment of Tobacco and Health (PATH) study (2013-2014). We examined prevalence of use of various digital forms of communication (e.g., social media, text messaging, smartphone ownership) among non-pregnant women of reproductive age, pregnant women, and among smokers versus non-smokers within these groups. Multiple logistic regression modeling was conducted to identify correlates of using each digital form adjusting for smoking status, pregnancy, and demographic characteristics. Over two thirds of women overall and within subgroups of non-pregnant and pregnant smokers reported using social media, owning a cell phone, owning a smartphone, downloading apps, and sending/receiving text messages. Current smokers and those with lower educational attainment generally had lower odds of using each digital form relative to non-smokers and those with higher educational attainment, the exception being that smokers had higher odds of using social media relative to non-smokers. The high prevalence of using various digital forms among both non-pregnant smokers of reproductive age and pregnant smokers suggests that leveraging technology to expand access to prevention, education, and treatment resources may reduce smoking-attributable adverse health effects among reproductive-aged women and their offspring. PMID- 30412744 TI - The performance of a community-based colorectal cancer screening program: Evidence from Shanghai Pudong New Area, China. AB - Despite the rising disease burden of colorectal cancer (CRC), CRC screening has not yet been widely introduced as a large organized program in developing countries. To facilitate better delivery of screening in these areas, we investigated the performance of a large community-based CRC screening program implemented in Shanghai Pudong New Area during the period 2013-2016. We conducted a prospective cohort study by following up the screening behavior and results of tested participants in the program. Data from the program reporting system and monthly progress reports were collected. We used standard measures and indicators with modifications to evaluate the performance of the program. Disparities in CRC screening by age categories, primary screening results, and geographic areas were examined. A total of 403,098 individuals participated in the program, 25,764 of them were further screened by diagnostic colonoscopy (COL), and 505 people were eventually diagnosed with CRC as a result of the program. The program produced the following rates: participation (35.18%), primary screening positivity (24.89%), positive primary screening follow-up (26.26%), diagnostic COL (6.37%), and cancer detection (1.250/00). Vast variations in the quality of the program were observed across areas with different socioeconomic environments. The experience and lessons from the program suggest that incorporating the screening with other public health campaigns, using better-developed risk assessment tools, and allowing individual screening decisions for those aged above the target are possible practical ways to promote a better delivery of organized CRC screening programs. PMID- 30412746 TI - MiR-3926 inhibits synovial fibroblasts proliferation and inflammatory cytokines secretion through targeting toll like receptor 5. AB - Rheumatoid arthritis synovial fibroblasts (RASFs) play a key role in the pathogenesis of rheumatoid arthritis (RA). This study was aimed to investigate the effects of miR-3926 on the biological activities of RASFs. The results showed that miR-3926 was significantly down-regulated in RASFs and RA synovial tissue. Overexpression of miR-3926 significantly inhibited RASFs proliferation and decreased the secretion of inflammatory cytokines including TNF-alpha, IL-1beta and IL-6 in RASFs. TLR5 was identified to be a direct target of miR-3926. TLR5 showed an opposite expression trends with miR-3926 in RASFs and RA synovial tissue. Overexpression of miR-3926 led to a reduction of endogenous TLR5 in RASFs, whereas down-regulation of miR-3926 increased TLR5 expression. Knocking down of TLR5 significantly inhibited RASFs proliferation and inflammatory cytokines secretion. Rescue experiments with a miR-3926-resistant variant of TLR5 showed that overexpression of TLR5 restored RASFs proliferation and inflammatory cytokines secretion in miR-3926-overexpressing RASFs. In conclusion, miR-3926 is downregulated in RA synovial tissues and its overexpression caused the inhibitory effects on RASF proliferation and inflammatory cytokines secretion by targeting TLR5. The miR-3926/TLR5 pathway may represent a novel target for prevention and treatment of RA. PMID- 30412745 TI - Genetic variations in inflammation-related genes and their influence on the susceptibility of pediatric acute lung injury in a Chinese population. AB - Acute lung injury (ALI) is a serious clinical syndrome that can cause respiratory failure and threaten the life of the patients. A biomarker that can predict the syndrome can contribute to a better clinical management of the patients. In adults, genetic polymorphisms in inflammatory-response genes have been shown to be a promising biomarker. However, the pathogenesis of ALI in adult is known to be different from that in children and no previous study has investigated the association between inflammatory gene polymorphisms and pediatric ALI (PALI) risk. In this work, we examined the association between 12 polymorphisms in six inflammatory-response genes (TNF, IL6, IL10, IL18, NFKB1 and NFKBIA) and risk of PALI. A total of 1075 children with ALI and 1382 non-ALI controls were recruited. The polymorphisms were genotyped employing RFLP method. The risk association was estimated via logistic regression analysis, with P < 0.004 being statistically significant after Bonferroni correction. A statistically significant association was observed for IL10 rs1800896 (heterozygous, P < 0.0001; homozygous variant, P < 0.0001; allele, P < 0.0001) and TNF rs1800629 (heterozygous, P < 0.0001; homozygous variant, P = 0.0012; allele, P < 0.0001) polymorphisms. On the other hand, no significant association was found for IL6 rs1800795, rs1800796 and rs1800797 polymorphisms, IL10 rs3021097 polymorphism, NFKB1 rs28362491 polymorphism, NFKBIA rs2233406 and rs696 polymorphisms, IL18 rs1946518 and rs187238 polymorphisms, and TNF rs1799964 polymorphism. In conclusion, IL10 rs1800896 and TNF rs1800629 may serve as a risk biomarker for pediatric ALI among Chinese. PMID- 30412747 TI - Analysis of UB and L40, related to deltamethrin stress in the diamondback moth, Plutella xylostella (L.). AB - Pests have been subjected to heavy selection by insecticide pressure, producing greater and more serious resistance. It is extremely valuable to identify the resistance genes that are relevant for pest control. In our previous studies, we reported that UBL40 is the deltamethrin resistance-associated gene. UBL40 is cleaved by specific endopeptidases to release UB and L40. Therefore, further we compared the expression of UB and L40 in different tissues from larvae of the diamondback moth using a deltamethrin-resistant (DR) strain and a deltamethrin sensitive (DS) strain. The results showed that both UB and L40 knockdown significantly reduced the level of resistance to deltamethrin and clearly decreased the survival rate in P. xylostella after 72 h. These results provide evidence that UB and L40 both play roles in the regulation of deltamethrin resistance, which could help elucidate the resistance mechanisms and identify new target genes associated with deltamethrin resistance in P. xylostella. PMID- 30412748 TI - Compound Astragalus and Salvia miltiorrhiza extract inhibits hepatocellular carcinoma progression via miR-145/miR-21 mediated Smad3 phosphorylation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Compound Astragalus and Salvia miltiorrhiza extract (CASE), containing astragalosides, astragalus polysaccharide extracted from Astragalus membranaceus (Fisch.) Bge. and salvianolic acids from Salvia miltiorhiza Bge., has been found to inhibit hepatocarcinogenesis via mediating transforming growth factor-beta (TGF-beta)/Smad signaling, especially Smad3 phosphorylation. The crucial interaction between microRNA-145/microRNA-21 (miR 145/miR-21) and Smad3 phosphorylation is implicated in the pathogenesis and progression of hepatocellular carcinoma (HCC). However, effects of CASE on HCC progression involved in the expression of miR-145/miR-21 and their interaction with Smad3 phosphorylation downstream of TGF-beta/MAPK/Smad pathway remain unclear. This study addressed above questions using in vitro (HepG2 cells) and in vivo (Xenografts of nude mice) models of HCC. MATERIALS AND METHODS: In vivo [Diethylnitrosamine (DEN)-induced HCC in rats] and in vitro [TGF-beta1-stimulated HepG2 cells] models of HCC were established and co-administrated using graded doses/concentrations CASE (60, 120, 240 mg/kg used in rats; 20, 40, 80 ug/ml used in HepG2 cells), miR-145 and miR-21 were measured. HepG2 cells were transfected with miR-145 antagomir, miR-21 agomir and Smad3C/L plasmids (Smad3 EPSM, Smad3 3S A and Smad3 WT related to up-regulated expression of pSmad3C, pSmad3L and pSmad3C/3L respectively) and then treated by CASE (80 ug/ml). Similarly, HepG2 cell xenografted nude mice were administered with miR-145 antagomir, miR-21 agomir and CASE (310 mg/kg); Smad3 WT, Smad3 EPSM and Smad3 3S-A plasmids stably transfected HepG2 cell lines were constructed respectively and their xenografted nude mice were established, and then treated by CASE (310 mg/kg). Cell proliferation, migration, apoptosis, tumor growth and histopathologic characteristics of xenografts were assessed; also, domain-specific Smad3 phosphorylation isoforms (pSmad3C/pSmad3L), activated MAPKs (pERK1/2, pJNK1/2, pp38) and miR-145, miR-21 were measured. RESULTS: CASE up-regulated miR-145 while down-regulated miR-21 expression in both rats with DEN-induced HCC and TGF-beta1 stimulated HepG2 cells; CASE inhibited cell migration, proliferation and tumor growth while facilitated cell apoptosis in TGF-beta1-stimulated HepG2 cells and xenografts of nude mice with miR-145 antagomir/miR-21 agomir treatment via increasing miR-145 and facilitating miR-145 modulated pSmad3L->pSmad3C signaling switch while decreasing miR-21 and inhibiting miR-21 modulated MAPK-dependent Smad3L phosphorylation. Also, up-regulated pSmad3C enhanced inhibited effect of CASE on tumor growth and facilitated effect of CASE on cell apoptosis involved in increased miR-145 while decreased miR-21 expression, however, inverse phenomena were observed when up-regulated pSmad3L. CONCLUSION: Our results suggest that CASE inhibits HCC progression via mediating the interaction of miR-145/miR-21 and Smad3 phosphorylation, especially miR-145/miR-21 mediated Smad3 phosphorylation, which maybe provides an important theoretical foundation for CASE's anti-HCC therapy used for patients in a near future. PMID- 30412749 TI - Ethnobotanical study on medicinal plants used by local Van Kieu ethnic people of Bac Huong Hoa nature reserve, Vietnam. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The ethnobotanical survey was carried out in the Bac Huong Hoa Nature Reserve (BHHNR), Vietnam. The Van Kieu ethnic group, the inhabitant of Nature Reserve, is rich in knowledge about the medicinal plants found in the Nature Reserve. However, their knowledge is less documented. AIM OF THE STUDY: The present study was conducted to document the use of medicinal plants, plant parts used, mode of preparation and delivery by the ethnic group of Van Kieu. The study also aimed at comparing the information generated by this study with the previously published Dictionary of Vietnam Medicinal plants (DVM). MATERIALS AND METHODS: The information was collected through semi-structured and unstructured interviews. The interviews were conducted from April 2016 to March 2017. The number of informants involved in the survey was 93 belonging to age group of 20-81. Species Use-Reports (UR) were analyzed to determine the plant importance in the local and the Informant Consensus Factor (FIC). Local plant uses were listed and compared with the previously published data from Vietnam. RESULTS: Comprehensively 355 Use-Reports were documented in this study. A total of 111 medicinal plant species belonging to 102 genera and 46 families were reported. Out of 46 families, Euphorbiaceae (10 species), Compositae and Leguminosae (9 species each), Apocynaceae (7 species), Rutaceae and Rubiaceae (5 species each) were the dominant families. Leaves were the most frequently used plant part (43.1%) in the preparation of medicines. The most frequent preparation method was decoction (49%) while the oral route of administration (51%) was the most commonly mentioned mode of administration. Artocarpus heterophyllus Lam., Chromolaena odorata (L.) R.M.King & H.Rob., Blumea balsamifera (L.) DC., Psidium guajava L. and Catunaregam spinosa (Thunb.) Tirveng. were shown to be the most useful plants as indicated by their relatively high UR. Eight medicinal plants (7.21%) used by Van Kieu ethnic people have not been previously reported in DVM. CONCLUSION: The Van Kieu ethnic group holds valuable knowledge about uses of medicinal plant resources which is inherited through generations however this knowledge was not documented. The study highlights the need for documenting and publicizing the traditional medicinal knowledge which will provide basic data for further research and conservation. PMID- 30412750 TI - Bioguided identification of triterpenoids and neolignans as bioactive compounds from anti-infectious medicinal plants of the Taira Atacama's community (Calama, Chile). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Previous ethnobotanical surveys from the north Andean part of Chile, where different ethnic groups are co-existing, with the preeminence of Aymara and Atacama traditions, revealed an extensive domestic use of the local flora. In these communities, traditional medicinal uses are mainly related to the treatment of respiratory, gastro-intestinal and urinary disorders, pain and inflammation, which is closely linked to epidemiological observations. AIM OF THE STUDY: As these symptoms may be related to infectious diseases, a bioguided evaluation of antibacterial and antifungal activity was conducted on eighteen species selected with the Taira community, in Ollague. MATERIALS AND METHODS: Screening was performed using a large panel of pathogenic germs involved in the main community acquired infectious diseases, represented by Gram positive and Gram negative bacteria of clinical interest and by human pathogenic fungi, using a bioguided approach. RESULTS AND CONCLUSIONS: Gram positive strains of clinical interest were highly sensitive to Aloysia deserticola (Verbenaceae) and Krameria lappacea (Krameriaceae) extracts. The bioguided approach led us to identify the isolated neolignan from K. lappacea conocarpan (1), and triterpenoids form A. deserticola (oleanolic acid (6) and ursolic acid (10)), as the main bioactive compounds. PMID- 30412751 TI - Combined effects of olfactory dysfunction and chronic stress on anxiety- and depressive- like behaviors in mice. AB - There is a close relationship between olfactory dysfunction and depression, but the underlying mechanism remains unknown. Studies have shown that olfactory deprived animal experience a higher level of stress compared with controls. In the present study, we aimed to investigate whether olfactory deprived mice would be more vulnerable to develop cognitive and emotional impairments under chronic stresses. Mice were treated with intranasal zinc sulfate infusion which resulted in a complete but reversible loss of olfactory function, and then they were treated with either chronic restraint stress (CRS) or chronic unpredictable mild stress (CUMS) for three consecutive weeks. After that, anxiety- and depressive like behavior, as well as spatial learning and memory were measured. We found that olfactory deficit induced depressive-like behavior and impaired spatial learning and memory in mice, and the olfactory scores were significantly correlated with depressive-like behavior or the spatial learning. After CRS, olfactory deprived mice showed less anxiety- and depressive- like behaviors and better olfactory recovery than non-stressed anosmia mice. In contrast, CUMS led to increased anxiety- and depressive-like behavior and deterred the olfactory recovery. These results indicated that transient olfactory deprivation induces emotional and cognitive impairment in mice, which could be modulated by chronic stresses with a stressor intensity dependent way. PMID- 30412752 TI - Relaxin-3 regulates corticotropin-releasing factor gene expression in cultured rat hypothalamic 4B cells. AB - The ancestral insulin/relaxin peptide superfamily member relaxin-3 is an important regulator of food intake and behaviors related to anxiety and motivation. Relaxin family peptide receptor 1 (RXFP1) and RXFP3 are expressed in the rat hypothalamic paraventricular nucleus (PVN). Corticotropin-releasing factor (CRF) is produced in the PVN in response to stressors and promotes adrenocorticotropic hormone secretion from the anterior pituitary. We hypothesized that relaxin-3 directly regulates Crf expression in the hypothalamus and investigated its effect on Crf expression in cultured hypothalamic 4B cells. Relaxin-3 increased Crf mRNA levels and stimulated Crf promoter activity. Both protein kinase A and C pathways contributed to relaxin-3-induced Crf promoter activity. Rxfp1 and Rxfp3 mRNA and their proteins were expressed in cultured hypothalamic 4B cells. Relaxin-3 decreased Rxfp1 mRNA and protein levels and increased Rxfp3 mRNA and protein levels. These results suggested that the action of relaxin-3 in cultured hypothalamic 4B cells may be regulated through both RXFP1 and RXFP3. PMID- 30412753 TI - The interactive effect of valence and context on reversal learning in individuals with Parkinson's disease. AB - Cognitive deficits in Parkinson's disease (PD) have increasingly been recognized over the last decade and reversal learning in particular has received a great deal of attention. In a classical reversal-learning paradigm, participants learn to associate various stimuli with specific responses (i.e. A ->Positive; B-> Negative), and subsequently learn to associate the same stimuli with opposite outcomes (i.e., A->Negative; B-> Positive). Prior studies have revealed that medicated PD patients have a selective impairment with learning from negative, but not positive, outcomes, even when both reward- and punishment-related stimuli were equally relevant. The aim of the present study was to further understand this impairment by applying a novel reversal-learning paradigm, which enables the differentiation between positive/negative and cue/context reversal impairments. Twenty-seven medicated PD patients and twenty-nine healthy individuals matched for age, gender and education completed the cue-context reversal learning paradigm. The results revealed no significant differences in context reversal learning between individuals with PD and healthy controls. However, in cue reversal learning, healthy controls were significantly better at performing positive-to-negative reversal trials compared to individuals with PD, while individuals with PD were significantly better in negative-to-positive reversal trials compared to healthy controls. As such, the present study distinguishes between different types of reversal learning and suggests that different neural circuits are responsible for context and cue learning. These results improve our understanding of the possible effects of dopaminergic medications and may have important clinical implications. PMID- 30412754 TI - The first mitochondrial genome from Scopuridae (Insecta: Plecoptera) reveals structural features and phylogenetic implications. AB - This study determined the first complete mitochondrial genome (mitogenome) of a stonefly, Scopura longa (Plecoptera: Scopuridae), and reconstructed a phylogeny based on two datasets of mitogenomes in eighteen available stoneflies to examine the relationships among Plecoptera. The complete mitogenome of S. longa is a circular molecule of 15,798bp in size. It contains 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs), two ribosomal RNA genes (rRNAs) and a control region (CR). Most PCGs used standard ATN start codons and TAN stop codons. All tRNAs could be folded as typical cloverleaf secondary structures except tRNASer(AGN), with the dihydrouridine (DHU) arm missing. Tandem repeat regions, two potential stem-loop (SL) structures, Poly T structures and G+C-rich regions are detected in the control region. Finally, the phylogenetic relationships among the families within the Arctoperlaria were reconstructed. The topological structures of the two trees were almost identical. The present phylogenetic analysis shows that S. longa belongs to the infraorder Euholognatha. The monophyly of each family is generally well supported based on nucleotide sequences. The Pteronarcyidae is sister to ((Peltoperlidae+Styloperlidae)+(Perlidae+(Perlodidae+Chloroperlidae))). PMID- 30412755 TI - Synthesis and characterization of biopolymer based hybrid hydrogel nanocomposite and study of their electrochemical efficacy. AB - A highly competent material, based on poly lactic acid (PLLA) grafted hydroxypropyl guar gum (HPG-g-PLLA) and polypyrrole/carboxylated multiwalled carbon nanotube (PPy/C-MWCNT) composite of various binary composition and copolymer of one of these nanocomposites have been synthesized successfully by in situ polymerization. The environmentally affable nanocomposites have been characterized by spectroscopy, microscopy and thermogravimetry. Cytotoxicity of bio-nanocomposite has been inquired by cell viability study, which reveals its eco-friendly nature. The electrochemical properties of the biomaterials have been appraised by cyclic voltammetric studies. The PPy/C-MWCNT composite having 1 wt% C-MWCNT appears as the optimum composition from electrochemical studies. The hydrogel nanocomposite (HPG-g-PLLA5/0.5) copolymer behaves as a super ordinate material than pure PPy and PPy/C-MWCNT in every aspect of electrochemical properties like current density, stability, processibility and reversibility. Moreover the hydrogel nanocomposite, making electrode fabrication more simple and binder-free, nullifies all the interfacial complications arising from binders as well. PMID- 30412756 TI - X-ray crystallographic analysis of time-dependent binding of guanidine hydrochloride to HEWL: First steps during protein unfolding. AB - Time-dependent binding of guanidine hydrochloride (GuHCl) to hen egg-white lysozyme (HEWL), and effects of this binding on the protein structure have been investigated by solving X-ray structures of crystalline complexes. The complexes have been prepared by soaking, for different periods of time, native lysozyme crystals in solutions containing 2.5M GuHCl. In the refined structures, the number of water molecules in the protein's first solvent shell has progressively decreased from 152 to 115, showing protein's preference for guanidinium over water. Guanidinium ions preferentially hydrogen bond with the backbone carbonyl oxygen atoms. In their van der Waals interactions, they do not show any preference for apolar residues. Guanidinium ions have replaced water molecules that form cages around exposed hydrophobic residues. Guanidinium binding has decreased the average length of water-water hydrogen bond by 0.1A. The hydrogen bonds between main chain atoms have been weakened by GuHCl, and this may be the reason for increased potency of GuHCl compared to urea. Guanidinium binding destabilizes the beta-domain by causing loss of hydrogen bonds involving Asn 59 side chain. Interestingly, this loss is almost identical to that observed in structures of amyloidogenic variants of human lysozyme. Compounds preventing this loss could be anti-amyloidogenic. PMID- 30412757 TI - Polymeric nanoengineered HBsAg DNA vaccine designed in combination with beta glucan. AB - Antigen-specific immune responses following DNA vaccination are hard to achieve, owing to the difficulty to mediate efficient gene delivery. This study proposed the use of PDMAEMA:PbetaAE/DNA polyplexes (Pol) as the vehicle of a pDNA vaccine encoding the hepatitis B surface antigen (HBsAg), with these Pol designed in combination with a soluble (Glu) or a particulate (GPs) form of beta-glucan. beta Glucans are recognized adjuvants that activate immune cells, a good strategy to improve transfection efficiency and vaccine efficacy. Results showed that Pol produced at a 19:1 polymer:DNA (+/-) charge ratio were positively charged (+41 mV), had a mean size of 180 nm and presented high stability under different storage conditions. These polyplexes resulted in enhanced transfection activity than the positive control, showing even higher luciferase gene expression in the presence of GPs (COS-7 and RAW 264.7 cell lines). Additionally, no alterations in hemolysis and plasma coagulation time of human blood were found in the non cytotoxic working range. Mice vaccination studies (pCMV-S), resulted in a seroconversion rate of 40%, regardless of the additional beta-glucan adjuvants. This work showed the potential of this nanosystem together with GPs to enhance in vitro transfection capacity and to be further studied as a DNA vaccination platform. PMID- 30412758 TI - Influence of thermoplasticized starch on physical-chemical properties of new biodegradable carriers intended for forest industry. AB - In this work, the influence of different concentrations of thermoplasticized starch on thermal, mechanical, biodegradation and phytotoxic properties of biodegradable blend carrier composed of poly(lactic acid) and poly(butylene adipate-co-terephtalate) was investigated. The results showed that the addition of poly(butylene adipate-co-terephtalate) increased elasticity of PLA materials, whereas the presence of thermoplasticized starch promoted higher biodegradation rate of the investigated materials. Moreover, the prepared materials did not show phytotoxic effect on plant, thus proving potential application in forest industry as a biodegradable carrier for multiplication of plants. PMID- 30412759 TI - Water-soluble yeast beta-glucan fractions with different molecular weights: Extraction and separation by acidolysis assisted-size exclusion chromatography and their association with proliferative activity. AB - Pure yeast beta-glucan (YG1) was obtained by drying and defatting the crude beta glucan from Saccharomyces cerevisiae. The YG1 structure was characterized by total sugar content, protein content, FT-IR spectroscopy and monosaccharide composition analysis. Different molecular weight fractions of water-soluble yeast beta-glucan (WYG) were prepared by extraction with 2.0 M NaOH, degradation of the insoluble residue with 1.0 M HCl based on single-factor experiments, and fractionation on a size exclusion chromatography column (SEC, Sephacryl S-400). The molecular sizes of as-obtained fractions were measured by multi-angle laser light scattering combined with SEC and differential refractive index detector (SEC-MALLS-RI). Results indicated that YG1 had a high purity and was almost composed of beta-d-glucose (97.71%) except trace mannose. The WYG yields by alkali extraction and acidolysis were 12.41% and 42.85%, respectively. Fourteen fractions with molecular weight (Mw) from 4590 to 31.61 kDa and low polydispersity index (Mw/Mn of ~1) were successfully separated, showing high recovery rates of 61.9-92.5%. Additionally, these fractions could promote the proliferation of RAW264.7 macrophages, and the fraction (Mw = 2496 kDa) exhibited the highest cell viability of 145.8 +/- 4.3% at a low concentration of 1.56 MUg/mL. This work not only provides an efficient method for separating WYG fractions with different molecular weights and low polydispersity, but also lays a theoretical basis for interpreting the relationship between molecular size and bioactivity. PMID- 30412760 TI - Overexpressed LRIG3 gene ameliorates prostate cancer through suppression of cell invasion and migration. AB - Prostate cancer (PC) is one of the most common human malignancies, which has been steadily rising among males in many countries. The leucine-rich repeats and immunoglobulin-like domains (LRIG) genes were applied in the prognosis of different types of cancers, including PC. In that case, this study is supposed to investigate the effects of LRIG3 on PC cells. LRIG3 was overexpressed or under expressed by the rAd and siRNA to determine the effect of LRIG3 on PC and explore the possible mechanism. The mRNA and protein levels of LRIG3 were tested by RT qPCR and western blot analysis. Cell apoptosis, viability, migration and invasion were measured using MTT assay, flow cytometry and Transwell assay respectively. We observed that LRIG3 mRNA and protein levels were decreased in PC-3 cells. PC-3 cells treated with rAd-LRIG3 exhibited significantly increased cell apoptosis while inhibited viability, adhesion, migration and invasion. However, C4-2 cells treated with siRNA-LRIG3 showed reciprocal results. In conclusion, these data of the current study indicated that overexpressed LRIG3 gene expression might inhibit the viability, adhesion, invasion and migration and promote the apoptosis of PC cells. rAd-mediated LRIG3 may facilitate a novel aspect of the treatment of patients suffering from with PC. PMID- 30412761 TI - Preparation and characterization of novel eggshell membrane-chitosan blend films for potential wound-care dressing: From waste to medicinal products. AB - A series of different eggshell membrane (ESM) and chitosan (CS) blend films (ESM/CS) were prepared for wound-care dressing. The appearance, transparency and microstructure of the films were characterized. Several wound care-related properties such as the film integrity in solution, pH, protein (BSA) and wound fluid absorption capacity as well as the antibacterial property of ESM/CS films were evaluated. The blend films were more stable than CS film after 95 h of incubation in solution. The integrity of the blend films improved significantly at the cost of a small insignificant decrease in wound fluid absorption capacity. Besides, the blend films provided an acidic environment (pH = 5.86) for wound healing. The swelling properties of ESM contributed significantly to the increase of BSA absorption capacity of the blend films (from 46.57 mg/g of CS film to 61.07 mg/g of blend film) and helped absorb more nutrients to promote the proliferation and migration of fibroblasts. Addition of CS to ESM also enhanced the antibacterial activity of the films significantly. The results indicated that the EMS/CS blend films with 0.01 g ESM/mL CS solution showed the highest high potential to be used as a wound-care dressing for humans as well as animals. PMID- 30412762 TI - Photoluminescent lignin hybridized carbon quantum dots composites for bioimaging applications. AB - Carbon quantum dots (CQDs) have attracted considerable interests because of their unique luminescence properties and promising applications in bioimaging. Lignin hybridized CQDs (L-CQDs) are facilely synthesized by one-pot hydrothermal method with different molar ratios of citric acid and ethanediamine. The morphology and chemical structures of L-CQDs are investigated by TEM, FT-IR, XPS, 2D-HSQC NMR spectra. The resultant L-CQDs with near spherical morphology are less than 10 nm in diameter, which are essentially composed of main interunit linkages and aromatic ring structures. The L-CQDs exhibit the excitation-dependent photoluminescence behavior with emission maximum ranging from 454 to 535 nm under excitation at 375-460 nm. The maximum emission of the L-CQDs red-shift to a longer wavelength with a decrease in intensity as the excitation wavelengths are gradually increased. L-CQDs show the low cytotoxicity and good cellular biocompatibility, demonstrating the great potential of the L-CQDs for bioimaging applications. PMID- 30412763 TI - Association of sun and UV exposure with blood pressure and cardiovascular disease: A systematic review. AB - BACKGROUND: Ecological studies show that sun or ultraviolet (UV) exposure have inverse associations with blood pressure (BP) and cardiovascular disease (CVD). Although sunlight is the primary source of vitamin D, recent meta-analyses of clinical trials have not reported a beneficial effect from vitamin D supplementation on BP or CVD. Sunlight may have beneficial effects independent of vitamin D. We carried out a systematic review to appraise the extent and quality of the evidence from human studies. METHODS: Observational and interventional studies that measured sun or UV exposure, along with BP or CVD, were selected after searching databases. RESULTS: Identified studies could not be combined quantitatively in meta-analysis because of different exposure measures. Solar exposure was inversely associated with BP in 3 out of 4 cross-sectional publications, and with CVD and/or total mortality in 5 out of 6 publications of cohort studies. Two of the cohort studies reported inverse associations between sun exposure and CVD, after adjusting for serum 25-hydroxyvitamin D. Five clinical trials with an appropriate control group were identified, the outcome being BP. Two trials compared UVB with UVA (as control), with only one finding a significant reduction in BP (after 6 weeks). Three trials compared short-term UVA exposure (<30 min) with placebo (or crossover control), of which two reported short-term lowering of BP. CONCLUSION: This review has identified a small body of evidence that suggests sun exposure protects against high BP and CVD, but further research is required to determine if this is independent of vitamin D. PMID- 30412764 TI - Determinants of vitamin D receptor gene expression in visceral and subcutaneous adipose tissue in non-obese, obese, and morbidly obese subjects. AB - We aimed to illustrate determinants of VDR gene expression in visceral and subcutaneous adipose tissue among individuals without diabetes. We gathered visceral and subcutaneous adipose tissues during an elective abdominal surgery form 33 morbidly obese (BMI > 40 kg/m2), 23 obese (BMI = 30-40 kg/m2), and 35 non obese (BMI<30 kg/m2) participants who were free of diabetes. Participants were classified according to their degree of obesity. Before the surgery, habitual dietary intake, physical activity, 25(OH)D, body mass index (BMI), waist circumference (WC), and HOMA-IR was gathered. Non-obese participants had significantly lower mean VDR gene expression in visceral adipose tissues than both the obese and morbidly obese ones and had also lower expression in subcutaneous adipose tissues than the morbidly obese participants. In multiple linear regression models, BMI and HOMA-IR were the independent positive predictors of VDR gene expression in subcutaneous fat. Among non-obese subjects, WC and 25(OH)D were the positive and negative independent predictors of visceral adipose tissue VDR gene expression, respectively. Among obese participants, 25(OH)D was negatively, and BMI and HOMA-IR were positively associated with VDR mRNA levels in visceral adipose tissue. In morbidly obese participants, the independent positive predictors of VDR gene expression in visceral fat were BMI and HOMA-IR, and negative predictors were 25(OH)D and calcium intake. Our findings suggested that 25(OH)D concentrations are the fundamental elements to determine VDR gene expression in visceral fat which by increasing fat depots, the subsequent insulin resistance became another predictor of VDR gene expression. PMID- 30412765 TI - The prevalence and risk factors of vitamin D inadequacy among male athletes in Kuwait: A cross-sectional study. AB - The aim of this study was to determine the prevalence of vitamin D inadequacy in male athletes living in Kuwait, and to assess its relationship with possible risk factors including body composition, lifestyle and fasting Ramadan. A Cross- sectional study was conducted on a total of 250 male athletes registered in official sports clubs in Kuwait were included. Blood tests, anthropometric measurements and a lifestyle questionnaire were performed. Serum 25(OH)D level was used as a measure of vitamin D status. Vitamin D inadequacy was defined as serum 25(OH)D < 75 nmol/L, inadequate levels were further classified as vitamin D insufficiency (50-75 nmol/L), vitamin D deficiency (<50 nmol/L) and severe deficiency (<25 nmol/L). Thirty-six percent of the sample were football players, 13% were futsal players and the rest were players of 15 different outdoor and indoor sports. A prevalence of 83% of vitamin D inadequacy (< 75 nmol/L) was observed in male athletes in Kuwait, of which 23% had severe deficiency (< 25 nmol/L). The prevalence increased from 80% (n = 130) before Ramadan to 90% (n = 79) after Ramadan. There was a significant positive association between serum 25(OH)D concentrations and vitamin D intake (p < 0.001). Serum 25(OH)D concentrations were significantly inversely associated with risk of injuries (p = 0.008) and with the concentrations of parathyroid hormone (PTH) (p = 0.029). No statistically significant associations between 25(OH)D concentrations and sun exposure, physical activity or anthropometric levels were found. Similar to other studies in the Middle East, we found that healthy male athletes in Kuwait have a high prevalence of vitamin D inadequacy. The results of this study suggest the need for regular supplement intake and vitamin D awareness campaigns for athletes in Kuwait. More research is needed to assess the effect of Ramadan. PMID- 30412766 TI - Longitudinal Analyses of Pediatrician Burnout. AB - OBJECTIVE: Utilize the unique capabilities of a longitudinal design to 1.) examine whether burnout is increasing over time among two cohorts of pediatricians, and 2.) identify factors associated with decreased burnout. METHODS: Data from a national, longitudinal study, the American Academy of Pediatrics Pediatrician Life and Career Experience Study (PLACES), were used to examine self-reported burnout over a five-year period, 2012 to 2016, among 2002 2004 and 2009-2011 residency graduates (N = 1804). Study participation rates ranged from 94% in 2012 to 85% in 2016. Mixed-effects logistic regression for longitudinal analysis was used to examine burnout over time. RESULTS: In any given year, between 20% and 35% of study pediatricians reported that they were currently experiencing burnout. Significant increases in burnout over time were found for all participants combined and for each subgroup examined. Several factors were associated with reduced burnout. The largest associations with reduced burnout were found for increased flexibility in work schedule (adjusted Odds Ratio [aOR] = .28, 95% Confidence Interval [CI] = .22-.35), decreased work busyness (aOR = .28, 95% CI = .22-.36), or a job change (aOR = .48, 95% CI = .36 .65). CONCLUSIONS: Following five years of participation in a longitudinal study, more than 1 in 3 early to mid-career pediatricians reported experiencing burnout. This represents a 75% relative increase in burnout from the start of the study. Specific characteristics of pediatricians' jobs, such as flexible work schedules and busyness of work settings, were most strongly associated with reduced burnout. PMID- 30412767 TI - Antibacterial defense and sperm quality in boar ejaculates. AB - The aim of the present study was to characterize the lysozyme concentration and the bacterial killing activity (BKA) of boar seminal plasma against E. coli and S. aureus in 119 fertile Pietrain boars (aged: 18.1 +/- 10.5 months). Lysozyme concentration was 2.4 +/- 1.2 MUg/ml in seminal plasma. More than 80% of the samples (97 of 119) showed BKA against E. coli or S. aureus or both bacterial strains: Group 1 (BKA against E. coli and S. aureus, n = 38), Group 2 (BKA against E. coli, n = 13), Group 3 (BKA against S. aureus, n = 46), and Group 4 (no BKA, n = 22). Boars with BKA against E. coli (Group 1 plus 2) were older (P < 0.001) than boars with BKA against S. aureus only or without BKA. Thermo resistance of spermatozoa was lowest in boars without BKA (P = 0.002). Lysozyme concentration was higher in boars with BKA against S. aureus only compared to boars with BKA against both bacterial species (P = 0.005) and boars with BKA against E. coli only (P = 0.047). In Group 2, the ratio of morphologically normal spermatozoa was lower than in all other groups (P < 0.001) and mitochondrial activity of spermatozoa was lower compared to Group 3 (P = 0.023). The results suggest an age related variance of BKA against E. coli in boar semen. BKA is related to different sperm quality characteristics. Further research is necessary to discover the molecular components, which are responsible for BKA of boar seminal plasma. PMID- 30412768 TI - Discovery of nano-piperolactam A: A nonsteroidal contraceptive lead acting through down-regulation of interleukins. AB - Elevated serum interleukins (IL-6, IL-1beta) over baseline concentration help in blastocyst adhesion to the uterine endometrium in the early phase of pregnancy. A nano PLA (Piperolactam A)-HPBCD (2-hydroxy-propyl-beta-cyclodextrin) inclusion complex was developed as an interleukin down-regulator that exhibited 100% anti implantation activity in rodents at a dose as low as 2.5-5.0 mg/kg. On metabolomics study, among major glyco-lipo-protein metabolites, only serum low density lipoprotein (LDL) or very low-density lipoprotein (VLDL) levels revealed alteration by the formulation. Administration of PLA-HPBCD did not cause changes in serum estrogen and progesterone levels. However, IL-6 and IL-1beta failed to increase post PLA-HPBCD administration; hence, it is assumed to be the mode of the drug's abortifacient action. In addition, absence of signs of either acute or chronic toxicity suggests the formulation was considerably non-toxic. Therefore, the nano-PLA conjugate promises as a non-steroidal contraceptive lead apart from ormeloxifene, the only non-steroidal anti-fertility agent currently available globally. PMID- 30412769 TI - Mesenchymal stem cells associated with chitosan scaffolds loaded with rosuvastatin to improve wound healing. AB - In this study we explored the role of rosuvastatin calcium in skin regeneration as statins play important role in the field of tissue engineering. Chitosan hydrochloride was crosslinked with different weight ratios of collagen, beta glycerolphosphate and carboxymethyl cellulose to produce scaffolds by lyophilization technique. Subsequently, the fabricated scaffolds were examined for their morphology, water absorption capacity, water retention, friability and in-vitro drug release as well as in-vivo studies. The results revealed porous 3-D structured scaffolds with maximum water absorption values-ranging between 396 and 2993%. Scaffolds containing carboxymethyl cellulose revealed highest water absorption-values. In-vitro drug release results showed gradual drug release for 60 h with mean dissolution time-values (MDT) between 13 and 21 h. Combination of chitosan, collagen, carboxymethyl cellulose in weight ratio of 40:30:30, respectively achieved gradual disintegration of the scaffold in a simulating medium to an open wound after 4 days. This selected scaffold loaded with rosuvastatin revealed increase proliferation of human dermal fibroblasts compared to placebo scaffold. After 30 days of implantation of selected medicated scaffold loaded with/without mesenchymal stem cells and placebo scaffolds to induced wounds in Albino rats, enhanced skin regeneration and absence of scar formation for drug loaded scaffolds were observed. The histopathological study showed the advantage of stem cells-loaded scaffolds through the normal redistribution of collagen in the epidermal layer. In conclusion, rosuvastatin calcium and stem cells loaded in the tested scaffolds proved their potential effect in enhancing skin healing and regeneration. PMID- 30412770 TI - Interruption in membrane permeability of drug-resistant Staphylococcus aureus with cationic particles of nano-silver. AB - The increasing drug-resistance pathogens among gram-positive bacterial species are becoming a major health concern nowadays. Over the past few years, the bactericidal efficacy of nano-silver against some drug-resistant gram-positive bacteria has been established, however further investigation is needed to determine whether nano-silver could be an option for the treatment of drug resistant gram-positive microbial infections. The purpose of the present study was to determine the bactericidal efficacy of nano-silver with its membrane destroying property using drug-resistant Staphylococcus aureus MTCC 3160. In the present study, bactericidal assessment of nano-silver with different antibiotics was determined by agar well diffusion method. Interaction of nano-silver towards bacterial membrane was carried to understand the probable bactericidal actions of nano-silver, which was further confirmed by respiratory chain dehydrogenase, zeta potential, Scanning Electron Microscopy (SEM) and Gas Chromatography-Mass Spectrometry (GC-MS). The effect of nano-silver on bacterial Deoxyribonucleic Acids (DNA) was evaluated by agarose gel electrophoresis. Bactericidal assessment of nano-silver showed a very strong bactericidal action compare to antibiotics. The binding affinity of nano-silver towards bacterial membrane induced loss of catalytic activity for respiratory chain dehydrogenases. Zeta potential, SEM and GC-MS analysis also revealed extensive damage to the bacterial cell membrane. Moreover, the analysis of agarose gel electrophoresis revealed that nano-silver can enhance the decomposability of bacterial DNA, which was directly attached to the bacterial cell membrane. The present findings suggested that nano-silver directly interact with the bacterial cell surface without the need to penetrate; and this distinctive property raises the hope that nano-silver will remain an important bactericide in bacteria than antibiotics. PMID- 30412771 TI - Heating-induced contraction in airways smooth muscle: A possible causative factor of exercise-induced bronchoconstriction. AB - Asthmatic patients often suffer from bronchoconstriction or asthma following breathing hot air or exposure to exercise due to raises the core body temperature. However, the direct effect of heating airways has not been studied yet. The aim of this study is to investigate the effect of heating on tracheal and bronchiolar smooth muscles. Isolated ovine tracheal strips and bronchiolar segments preparations were suspended in organ baths containing Krebs' solution for isometric tension recording. Tissues responses were examined during decreasing and elevating baths temperature (20 degrees C, 40 degrees C-45 degrees C and 50 degrees C). Cooling or heating induced rapid and reproducible contractions proportional with decreasing or increasing temperature respectively in tracheal and bronchiolar preparations. On reset to 37 degrees C the tone returned rapidly to basal level. Changing the bath's temperature from 37 degrees C to 20 degrees C or to 40 degrees C and 45 degrees C for tracheal strips or to 45 degrees C and 50 degrees C for bronchiolar segments induced contractions in both preparations. Changing the temperature below or above the normal body temperature (37 degrees C), leads to airways contractions. Heating induced contractions in tracheal and bronchiolar smooth muscle proportional to the heating temperature. Therefore, breathing hot air or elevation of body core temperature due to exercise can be considered possible causative factor of heating- or exercise-induced bronchoconstriction. PMID- 30412772 TI - Personalized 3D-Printed Model for Informed Consent for Stage I Lung Cancer: A Randomized Pilot Trial. AB - We conducted a preliminary evaluation of the usefulness of personalized 3D printed models for improving patient comprehension in informed consent for surgical resection of stage I lung cancer. From January through March 2018, we enrolled a total of 20 adult patients who were suspected to have stage I lung cancer on a preoperative multidetector chest computed tomography and decided to undergo elective surgical resection. The patients were randomly assigned to 3D printing and control arms. Informed consent was obtained before surgery with or without a half-life-size patient-specific 3D-printed model depending on the assigned arm. The patients evaluated the quality of the informed consent process in a 5-point scale using a questionnaire regarding patient knowledge, benefit, risk, alternative treatments, and satisfaction. The patient knowledge score was significantly higher in the 3D-printing group than in the control group (13.6 +/- 1.5 vs 11.8 +/- 1.6; P = 0.02), while the total score and the scores of the other 4 categories did not significantly differ between the groups: total score, 61.3 +/- 7.8 vs 55.4 +/- 7.3 (P = 0.12); benefit, 13.1 +/- 0.9 vs 11.6 +/- 2.1 (P = 0.10); risk, 11.3 +/- 2.1 vs 11.7 +/- 1.7 (P = 0.73); alternative treatment, 10.3 +/- 3.1 vs 9.0 +/- 2.7 (P = 0.40); and satisfaction, 13.0 +/- 2.2 vs 11.3 +/- 2.5 (P = 0.10). Personalized 3D printing was technically implementable and had the potential to improve patient comprehension in informed consent for surgical resection in patients suspected of having stage I lung cancer. PMID- 30412773 TI - Independent lung ventilation for the management of unilateral reperfusion pulmonary edema after pulmonary thrombendarterectomy: A case report. PMID- 30412774 TI - Can P300 aid in the differential diagnosis of unipolar disorder versus bipolar disorder depression? A meta-analysis of comparative studies. AB - BACKGROUND: It is difficult to distinguish between bipolar disorder (BD) and unipolar disorder (UD) depression. Given the different pattern of cognitive impairments between BD and UD, P300 is potentially useful for the differential diagnosis. This meta-analysis was performed to estimate the extent of difference in P300 in patients with BD versus UD depression. METHODS: Studies comparing P300 between depressed BD and UD patients with or without healthy controls (HCs) were retrieved from major English and Chinese databases. Studies with BD and UD samples that were comparable in terms of age, gender, and depression severity, were rated as having high quality. Standardized mean differences (SMDs) of P300 latency and amplitude were calculated. RESULTS: In total, eight studies with a total of 397 depressed BD patients, 390 depressed UD patients, and 497 HCs, were included. Among included studies, six were rated as having good quality and three followed BD (n = 146) and UD (n = 144) patients during remission. BD patients had significantly longer P300 latency than UD patients during major depressive episode [SMD (95%CI): 0.580 (0.309, 0.850)] and remission [SMD (95%CI): 1.583 (1.322, 1.844)]. Compared to HCs, remitted BD patients still had significantly longer P300 latency [SMD (95%CI): 0.857 (0.059, 1.656)] but P300 latency of remitted UD patients had decreased to normal [SMD (95%CI): 0.536 (-0.272, 1.343)]. LIMITATIONS: Sample sizes of depressed and remitted patients with BD and UD of included studies are small. CONCLUSIONS: P300 latency can be used as an auxiliary diagnostic marker for differentiating BD from UD depression. PMID- 30412775 TI - White matter hyperintensities in young individuals with bipolar disorder or at high genetic risk. AB - BACKGROUND: Increased white matter hyperintensities (WMHs) is one of the most consistent imaging findings amongst participants with bipolar disorder (BD). This study investigated WMHs in a young population at high genetic risk for bipolar disorder (HR). METHODS: MRI scans were conducted at baseline in HR individuals (n = 131), patients with BD (n = 47) and controls (CON) (n = 108). Most of the HR (n = 77) and CON (n = 74) group completed scans after two years. Scans were examined for the presence of WMHs. RESULTS: There were significantly more periventricular WMHs in the BD compared to the CON group at baseline (p = .04). Although the prevalence of periventricular WMHs was intermediate in the HR group, there were no significant differences between the HR and CON or BD participants. Deep WMHs did not differ significantly between the groups. Over time, there was a significant increase in the prevalence of periventricular WMHs in both the HR and CON groups (p = .02). LIMITATIONS: The use of a visual rating scale to examine WMHs is subjective. As the gradings were collapsed into 'present' or 'absent', we could not ascertain whether the severity of hyperintensities worsened over time. CONCLUSIONS: Periventricular WMHs are more prevalent in young individuals with BD than controls. As these are not more prevalent in HR individuals, it is possible that these are either secondary to the development of bipolar disorder, its treatment, or resulting changes in lifestyle. In a novel finding, there were similar increases in the prevalence of WMHs in controls and HR youth over the 2 year period. PMID- 30412776 TI - Impact of Physiologic Pacing Versus Right Ventricular Pacing Among Patients With Left Ventricular Ejection Fraction Greater Than 35% A Systematic Review for the 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. AB - BACKGROUND: It is unclear whether physiologic pacing by either cardiac biventricular pacing (BiVP) or His-bundle pacing (HisBP) may prevent adverse structural and functional consequences known to occur among some patients who receive right ventricular pacing (RVP). AIM: Our analysis sought to review existing literature to determine if BiVP and/or HisBP might prevent adverse remodeling and be associated with structural, functional, and clinical advantages compared with RVP among patients without severe left ventricular dysfunction (>35%) who required permanent pacing because of heart block. METHODS: A literature search was conducted using MEDLINE (through PubMed) and Embase to identify randomized trials and observational studies comparing the effects of BiVP or HisBP versus RVP on measurements of left ventricular dimensions, left ventricular ejection fraction (LVEF), heart failure functional classification, quality of life, 6-minute walk, hospitalizations, and mortality. Data from studies that met the appropriate population, intervention, comparator, and outcomes of interest were abstracted for meta-analysis. Studies that reported pooled outcomes among patients with LVEF both above and below 35% could not be included in the meta-analysis because of strict relationships with industry procedures that preclude retrieval of industry-retained unpublished data on the subset of patients with preserved left ventricular function. RESULTS: Evidence from 8 studies, including a total of 679 patients meeting the prespecified criteria for inclusion, was identified. Results were compared for BiVP versus RVP, HisBP versus RVP, and BiVP+HisBP versus RVP. Among patients who received physiologic pacing with either BiVP or HisBP, the LV end-diastolic and end systolic volumes were significantly lower (mean duration of follow-up: 1.64 years; -2.77 mL [95% CI -4.37 to -1.1 mL]; p=0.001; and -7.09 mL [95% CI -11.27 to -2.91; p=0.0009) and LVEF remained preserved or increased (mean duration of follow-up: 1.57 years; 5.328% [95% CI: 2.86%-7.8%; p<0.0001). Data on clinical impact such as functional status and quality of life were not definitive. Data on hospitalizations were unavailable. There was no effect on mortality. Several studies stratified results by LVEF and found that patients with LVEF >35% but <=52% were more likely to receive benefit from physiologic pacing. Patients with chronic atrial fibrillation who underwent atrioventricular node ablation and pacemaker implant demonstrated clear improvement in LVEF with BiVP or HisBP versus RVP. CONCLUSION: Among patients with LVEF >35%, the LVEF remained preserved or increased with either BiVP or HisBP compared with RVP. However, patient-centered clinical outcome improvement appears to be limited primarily to patients who have chronic atrial fibrillation with rapid ventricular response rates and have undergone atrioventricular node ablation. PMID- 30412777 TI - 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society. PMID- 30412778 TI - 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. PMID- 30412779 TI - Daylight versus conventional photodynamic therapy for the treatment of actinic keratosis: a meta-analysis of randomized controlled trials. AB - Daylight photodynamic therapy (dPDT) is suggested to be effective for actinic keratosis (AK). We performed a meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of dPDT versus conventional photodynamic therapy (cPDT) in patients with AK. Relevant studies were identified through a systematic search of PubMed, Embase, and the Cochrane Library. A fixed or random effect model was applied, depending on the heterogeneity. Six RCTs with 369 patients with 5,556 A K lesions that were undergoing dPDT or cPDT with red light and methyl aminolevulinate (MAL) were included. Overall, the incidence of complete response (CR) was not significantly different between the two groups (risk ratio [RR]: 0.93, p = 0.07). Subgroup analyses indicated that dPDT was non inferior to cPDT for CR in studies only included grade I-II AK lesions (RR: 0.97, p = 0.41), but less effective for CR in studies which also included grade III lesions (RR = 0.87, p < 0.001). Subsequent meta-analyses showed that dPDT was associated with a significantly reduced maximal pain score (mean difference = 4.51, p < 0.001) and a lower risk of adverse events (RR = 0.70, p < 0.001) as compared with cPDT. These results suggested although dPDT was better tolerated, the treatment efficacy of dPDT is non-inferior to cPDT with red light and MAL only in grade I-II AK lesions. The relative therapeutic efficacy of dPDT in AK of grade III lesions in comparison with cPDT should be further evaluated. PMID- 30412780 TI - Photophysical properties and in vitro photocytotoxicity of disodium salt 2.4 di(alpha-methoxyethyl)-deuteroporphyrin-IX (Dimegine). AB - Photophysical and in vitro photocytotoxicity studies were performed for the photosensitizer Dimegine, a disodium salt 2.4-di(alpha-methoxyethyl) deuteroporphyrin-IX with very low systemic toxicity. The singlet oxygen and luminescence quantum yield were PhiDelta = 0,65 +/- 0,06, and Phif=0,11 +/- 0,01 respectively, and were independent of the excitation wavelength. The photobleaching coefficients for Dimegine dissolved in phosphate buffer (pH 7.4), and DMEM medium at concentration 2 MUM/l and in phosphate buffer (pH 7.0) at concentration 10 MUM/l were 16.10-5, 9.10-5 and 2.10-5 respectively. In vitro cellular distribution and photocytotoxicity was studied in two human (U87 - primary glioblastoma and HT1376 - bladder cancer) and two rat cell lines (RG2 - glioma, and AY27 - bladder carcinoma). Fluorescence microscopy analysis shows primary Dimegine accumulation as small fluorescent inclusion bodies around the nuclei, suggesting an apoptotic over a necrotic cell death mechanism. The PDT efficacy was slightly higher for the rat cell lines over the human-derived cell lines, with LD50 values of 2,5 MUM/l, 2.8 MUM/l, 4.5 MUM/l, 2.8 MUM/l using 530 nm excitation wavelength for AY27, RG2, HT1376 and U87 respectively, and 1.8 MUM/l, 2 MUM/l, 5 MUM/l, 2.4 MUM/l using 625 nm excitation wavelength for AY27, RG2, HT1376 and U87 respectively. Comparison to literature data showed that Dimegine demonstrated improved phototherapeutic characteristics comparing to PpIX mediated PDT. PMID- 30412781 TI - Incidence of single-drug-, multidrug-, and extensively drug-antimicrobial resistance of Escherichia coli urinary tract infections: an Australian laboratory based retrospective study. AB - OBJECTIVES: To evaluate incidence of single-drug resistant, multidrug-resistant, extensively drug-resistant and pandrug-resistant E. coli urinary tract infections (UTI) in a sample of Australian Capital Territory (ACT) residents. METHODS: We utilised laboratory-based retrospective data from all ACT residents whose urine samples were processed from January 2009 to December 2013. Multivariate logistic regression models were constructed to determine the associations of age, sex, urine sample source and socioeconomic status with risk of resistant infections. RESULTS: A total of 146,915 urine samples from 57,837 ACT residents were identified over five years. Mean age of people in the sample was 48 years (standard deviation=26years) and 64.4% were females. Five-year incidence of single-drug resistant E. coli UTI was high for ampicillin, trimethoprim and cefazolin (6.8%, 3.5% and 1.9% respectively). No pandrug-resistant E. coli UTI was detected. Five-year incidences of multidrug- and extensively drug-resistant E. coli UTI were 1.9% and 0.2% respectively, which is low in comparison to international rates. Female sex and age over 38 years were significantly associated with single- and multidrug-resistance. Compared to hospitals, office hours general practices, community and specialist health services, risk of single drug resistance was significantly higher in samples from after-hours general practices (adjusted-odds ratio (OR) and 95% confidence intervals (CI) 2.6 (2.2 3.1)). CONCLUSIONS: Our findings have significant implications for antimicrobial prescribing given identified risk factors for the detection of resistance, especially in patients attending after-hours general practices. PMID- 30412782 TI - Carbapenem-resistant Acinetobacter baumannii: Current status of the problem in four Bulgarian university hospitals (2014-2016). AB - OBJECTIVES: A total of 226 carbapenem-resistant Acinetobacter baumannii (CRAB) isolates was collected during 2014-2016 from in-patients aged 5-88 years in four Bulgarian university hospitals (H1-H4), to assess their antimicrobial susceptibility and to explore carbapenem resistance mechanisms, as well as the molecular epidemiology. METHODS: Antimicrobial susceptibility testing, multiplex polymerase chain reaction (PCR) assay, DNA sequencing, and electrotransformation experiments were performed. Epidemiological typing by Random amplified polymorphic DNA-PCR was also carried out. RESULTS: The antibiotic resistance rates were: to imipenem - 90.7%, meropenem 98.3%, doripenem 100%, amikacin 92.9%, gentamicin 87.2%, tobramycin 55.7%, levofloxacin 98.2%, trimethoprim sulfamethoxazole 86.3%, tigecycline 22.1%, colistin 0%, and ampicillin-sulbactam 41.6%. Intrinsic blaOXA-51-like genes were found in all isolates. The majority of strains harbored blaOXA-23-like associated with the upstream-located ISAba1 (26.1%) or blaOXA-40/24-like (46.7%) genes, forty-five A. baumannii (19.9%) - both genes, and one isolate contained blaOXA-58-like surrounded by ISAba3C (upstream) and ISAba3 (downstream). The blaOXA-58 gene was transferable by electroporation indicating its plasmid location. Epidemiological typing revealed the dissemination of nosocomial CRAB with high clonal relatednesss (threshold of 70% similarity) belonging to six, four, three and two clusters in H1, H2, H3, and H4, respectively. CONCLUSIONS: A. baumanii isolates we studied were problematic nosocomial pathogens. Their multidrug resistance (MDR) poses great limits for therapeutic options. The persistence of endemic clones comprised of OXA carbapenemase-producing MDR A. baumannii in the monitored hospitals over a period of approximately three years is of concern and requires continuous detailed investigations in the future. PMID- 30412783 TI - The impacts of family treatment drug court on child welfare core outcomes: A meta analysis. AB - BACKGROUND: Substance abuse has been prevalent among caregivers involved in child welfare and is a major barrier to their achieving favorable outcomes. Family Treatment Drug Courts (FTDCs) have been viewed as one of the most promising interventions but research has reported mixed effects on child welfare outcomes. No meta-analysis was conducted to synthesize the findings to reach a more generalizable conclusion. OBJECTIVE: The meta-analysis synthesized findings from existing evaluations to examine whether and to what extent FTDC participants achieved better reunification and safety outcomes than non-participants. PARTICIPANTS AND SETTING: Among 17 identified studies dated from 2004 to 2018, the pooled sample subjects in the intervention and comparison groups were 3402 and 3683 for the 16 studies on reunification outcomes, and 842 and 632 for the eight studies on child safety outcomes. METHODS: We first estimated the FTDCs' pooled effects on child reunification and safety outcomes. Furthermore, we conducted a series of subgroup meta-analysis to compare FTDCs' effects across study and program characteristics. RESULTS: Subjects participating in FTDCs were substantially more likely to achieve reunification (OR = 1.75, 95% CI = 1.38, 2.22) without increasing the risk of subsequent foster care reentry or maltreatment re-report. Subgroup meta-analysis suggests factors such as research design, FTDC model, observation length, publication type and period may contribute to FTDCs' disparities on reunification outcomes. CONCLUSIONS: The synthesized findings strengthen evidence for the implementation and expansion of FTDCs for serving substance abusing caregivers in the child welfare system. PMID- 30412784 TI - Role of Regulatory T Cells in Noninherited Maternal Antigen-Related Tolerance in Cord Blood: An in Vitro Study. AB - Cord blood (CB) is an alternative stem cell source for allogeneic hematopoietic stem cell transplantation (HSCT). The unique advantages of using CB as a stem cell source are a degree of permissibility for HLA mismatch, rapid availability, and relatively risk-free cell collection. Because HLA is highly polymorphic and population-specific, optimal HLA-matched unrelated donors or cord blood units (CBUs) might not be available. In view of the possibility that matched CBUs that include noninherited maternal antigens (NIMAs) might contain acceptable HLA mismatches, we attempted to determine the degree of alloreactivity of CB mononuclear cells (MNCs) on stimulation by the maternal, paternal, and unrelated stimulator cells. Suppression of T cell proliferation, cytotoxicity, and a cytokine profile indicating suppressed Th1 and elevated IL-10 and TGF-beta1 responses were observed in the mixed lymphocyte reaction in response to NIMAs. The increases in IL-10 and TGF-beta1 production may be due to the Th2 response and/or regulatory T cells (Tregs). The reduced IL-10 and TGF-beta1 production after CD25 depletion could have been due to removal of Tregs from the CB cells. Thus, Tregs appear to play an important role in the CB MNC response to NIMAs, possibly due to the induction of IL-10 and TGF-beta1. We hope that our work can provide some evidence of the beneficial effect of NIMAs. PMID- 30412785 TI - Thirteen Reasons Why: The impact of suicide portrayal on adolescents' mental health. AB - We aimed to investigate the influence of media portrayals of suicide on adolescents' mood, focusing on the case of 13 Reasons Why, a webseries that raised concerns for approaching suicide explicitly for an audience mostly composed of adolescents. There is already evidence of an increase in suicide related Internet searches shortly following its release. Our study included 7004 individuals aged 12-18 years. Participants were recruited through posts on 13 Reasons Why-themed social media groups. Volunteers filled an online questionnaire made available throughout May 2017 (54-71 days after the show was released). The questionnaire collected data on sociodemographic characteristics, mood (sadness and lack of motivation) in the month previous to watching the series, and prevalence of self-harm, suicidal ideation, or suicide attempts. Changes in mood were considered the main outcome; the variable was derived from a question asking about feelings of sadness and lack of motivation after watching the show. Overall, 23.7% reported worsening in mood after watching 13 Reasons Why. This rate was higher among individuals who, before watching the series, experienced more frequent and intense feelings of sadness and lack of motivation (OR 2.73 for frequent or daily feelings; OR 3.61 for intense feelings) or reported suicidal ideation/self-harm/suicide attempt (OR 1.38), even after controlling for sex and age. In times of easy access to digital content and binge-watching, the way mental health issues are portrayed in fiction needs to be carefully debated and thought out. PMID- 30412786 TI - Bilateral uterine artery ligation plus intravenous tranexamic acid during cesarean delivery for placenta previa: a randomized double-blind controlled trial. AB - OBJECTIVE: To investigate the effect of adjunctive intravenous tranexamic acid (TA) on blood loss during cesarean section (CS) in patients with placenta previa undergone bilateral uterine arteryligation (BUAL). METHODS: The study was double blind randomized controlled trial carried out in a tertiary University Hospital between June 2016 to October 2017. We includedpatients scheduled for CS due to placenta previa. They were randomly allocated to group (I) managed by BUAL alone and group (II) managed by intravenous TA plus BUAL. The primary outcome was the amount of totalestimatedblood loss both intra- and post-operative. RESULTS: Sixty two patients were enrolled (n = 31 in each group). Patients received intravenous TA showed great reduction in total estimated blood loss compared with BUAL alone (p = .001). Additionally, the post-operative pulse was significantly higher in group (I) compared with group (II) (p = .002) and post-operative hemoglobin concentration was significantly lower in the same group compared with the other group (p = .034). More additional uterotonics was needed in group (I) than group (II) (29% vs. 3.2%, p = .006). Blood transfusion >=4 units was required in 17 (54.8%) patients in group (I) versus 4 patients in group (II) (12.9%) (p = .0001). No difference between the study groups regarding the rate of cesarean hysterectomy (p = .27). CONCLUSION: The adjunctive use of intravenousTA in patients undergone BUAL due to placenta previa is associated with decrease blood loss, need for additional uterotonics and blood transfusion during CS compared with BUAL alone. PMID- 30412787 TI - Birth outcomes and usability of Relaxbirth(r) for upright positioning intrapartum: A retrospective case control study. AB - INTRODUCTION: The aim of this study was to pilot Relaxbirth(r) (Relaxbirth(r), Ltd., Helsinki, Finland), an investigational device designed to facilitate upright positioning intrapartum. The objective was to 1) compare birth outcomes with and without the use of Relaxbirth(r), and 2) assess device usability. METHODS AND MATERIALS: Study design: prospective product use and retrospective case control study at one perinatal center in Ohio. INCLUSION CRITERIA: >=18 years old, <300 lbs. women with a low-risk, term gestation of a singleton, vertex fetus, and vaginal birth between January 2013 to June 2016. Participants who used the Relaxbirth(r) device intrapartum (RB group) were retrospectively case-matched to controls (CON group) according to age, race, insurance, gravida/parity, gestational age and labor type. Birth outcomes (primary outcome) were compared between groups. Providers and women who used Relaxbirth(r) assessed usability of the device with the Modified System Usability Scale Tool (secondary outcome). RESULTS: Of the n = 60 included in the final analysis, RB women (n = 30) pushed for a shorter average duration compared to CON women (n = 30) [34 min (+/-48) versus 60 min (+/-63), p = 0.023]. RB women did not experience more adverse birth outcomes including: longer second stage duration, operative vaginal delivery, malpresentation, perineal laceration/episiotomy, higher blood loss, or low Apgars. Usability survey results were favorable (Total Average Scores: providers 74.1; RB 83.6). CONCLUSION: Clinical experience with the Relaxbirth(r) device was positive at this pilot site. The device was associated with favorable birth outcomes and usability, suggesting potential as a safe and novel adjunct to promote intrapartum choices, upright positioning and maternal satisfaction. PMID- 30412788 TI - The impact of a patient's social status on the cost of vaginal deliveries: an observational study in a French university hospital. AB - INTRODUCTION: We aimed to assess the association between a patient's social status and the cost of stay for a single uncomplicated vaginal delivery. Currently, few data have been reported. MATERIAL AND METHODS: We conducted an observational study with data retrieved from the medical and administrative databases of a university hospital in North-West France. We included all patients admitted in 2014 and classified in either Diagnosis-Related Group (DRG) " Single uncomplicated vaginal deliveries in a primiparous patient " or DRG " Single uncomplicated vaginal deliveries in a multiparous patient ". Criteria defining poor social status were: a specific healthcare benefit in relation to low income or for foreign undocumented patients, and/or a consultation with a social worker during the hospital stay except if no social problem was diagnosed. We compared the cost of stay between patients with poor social status and patients with good social status using a multivariate median regression stratified on parity, and adjusted for age, gestational age and neonatal hospitalization. RESULTS: Among 686 primiparous patients, 21% had poor social status, which was associated with an increase in the median cost of stay (+?475; 95% CI [+334 to +616]), mostly explained by a 1-day increase in the median length of stay.Among 899 multiparous patients, 29% had poor social status, which was not associated with the cost of stay. DISCUSSION: Social status had an impact on the cost of vaginal deliveries in primiparous patients. Our findings suggest a need to redefine the DRG classification according to patients' social status. PMID- 30412789 TI - Cytogenetic screening in couples with Habitual Abortions. AB - OBJECTIVE: Habitual abortion (HA) is defined at least three consecutive pregnancy losses. One of the etiologic causes is parental chromosomal anomalies. In this study, we aimed to that investigate the effect of parental chromosomal abnormalities on HA. METHODS: The cytogenetic results of patients with at least three abortions referred to our university hospital between January 2010 - March 2017 were evaluated. A total of 1154 couples with HA were analysed. Peripheral lymphocyte cultures incubated for 72 h were used for karyotype analysis via the Giemsa banding technique. RESULTS: Of a total 1154 couples (2308 patients) 37 female (3.2%) and 17 male (1.47%) had abnormal karyotypes. Reciprocal translocation carriage (n = 26; 1.12%) was the most commonly detected structural anomaly, followed by X chromosome mosaicism (n = 16; 0.69%),Robertsoniantranslocation (n = 9; 0.38%), Chromosomal inversion (n = 6; 0.26%). Chromosomal polymorphisms, which are considered minor chromosomal changes, were detected in 221 (9.57%) individuals. CONCLUSION: Our study exhibits that chromosomal analysis in patient with HA is an appropriate approach to elucidate the aetiology of HA. Data from cytogenetic screening can be used in guiding couples planning future pregnancies and in prenatal diagnosis of chromosomal anomalies in the foetus. PMID- 30412790 TI - BML-111, a lipoxin receptor agonist, protects against acute injury via regulating the renin angiotensin-aldosterone system. AB - BACKGROUND: The renin angiotensin-aldosterone system (RAAS) and lipoxins (LXs) have similar roles in many processes. We previously reported that BML-111, a Lipoxin receptor agonist, inhibited chronic injury hepatic fibrosis by regulating RAAS, but whether LXs are involved in BML-111-mediated protection from acute injury is unclear still. METHODS: We established models of acute liver/lung injury and confirmed them with histopathology and myeloperoxidase (MPO) measurements. BML-111, a lipoxin receptor agonist, was applied to mimic the effects of LXs. The contents and activities of angiotensin converting enzyme(ACE) and angiotensinconverting enzyme 2 (ACE2) were measured through ELISA and activity assay kits respectively. Angiotensin II (AngII), angiotensin-(1-7) (Ang 1-7), AngII type 1 receptor (AT1R), and Mas receptor were quantified with ELISA and Western blot. RESULTS: Models of acute injury were established successfully and BML-111 protected LPS-induced acute lung injury and LPS/D-GalN-induced acute liver injury. BML-111 repressed the activity of ACE, but increased the activity of ACE2. BML-111 decreased the expression levels of ACE, AngII, and AT1R, meanwhile increased the levels of ACE2, Ang-(1-7), and Mas. Furthermore, BOC-2, an inhibitor of lipoxin receptor, reversed all the effects. CONCLUSION: BML-111 could protect against acute injury via regulation RAAS. PMID- 30412791 TI - Post-translational modifications of Parkinson's disease-related proteins: Phosphorylation, SUMOylation and Ubiquitination. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the nigrostriatal pathway. The etiology of PD remains unclear and most cases are sporadic, however genetic mutations in more than 20 proteins have been shown to cause inherited forms of PD. Many of these proteins are linked to mitochondrial function, defects in which are a central characteristic of PD. Post-translational modifications (PTMs) allow rapid and reversible control over protein function. Largely focussing on mitochondrial dysfunction in PD, here we review findings on the PTMs phosphorylation, SUMOylation and ubiquitination that have been shown to affect PD-related proteins. PMID- 30412792 TI - Diminished O-GlcNAcylation in Alzheimer's disease is strongly correlated with mitochondrial anomalies. AB - Uncover the initial cause(s) underlying Alzheimer's disease (AD) pathology is imperative for the development of new therapeutic interventions to counteract AD related symptomatology and neuropathology in a timely manner. The early stages of AD are characterized by a brain hypometabolic state as denoted by faulty glucose uptake and utilization and abnormal mitochondrial function and distribution which, ultimately, culminates in synaptic "starvation" and neuronal degeneration. Importantly, it was recently recognized that the post-translational modification beta-N-acetylglucosamine (O-GlcNAc) modulates mitochondrial function, motility and distribution being proposed to act as a nutrient sensor that links glucose and the metabolic status to neuronal function. Using post-mortem human brain tissue, brain samples from the triple transgenic mouse model of AD (3xTg-AD) and in vitro models of AD (differentiated SH-SY5Y cells exposed to AD-mimicking conditions), the present study is aimed to clarify whether O-GlcNAcylation, the posttranslational modification of intracellular proteins by O-GlcNAc, contributes to "mitochondrial pathology" in AD and its potential as a therapeutic target. A reduction in global O-GlcNAcylation levels was observed in the brain cortex and hippocampus of AD subjects. Moreover, GlcNAcylation levels are higher in mature mice but the levels of this posttranslational modification are lower in 3xTg-AD mice when compared to control mice. The in vitro models of AD also exhibited a marked reduction in global O-GlcNAcylation levels, which was strongly correlated with hampered mitochondrial bioenergetic function, disruption of the mitochondrial network and loss of cell viability. Conversely, the pharmacological modulation of O-GlcNAcylation levels with Thiamet-G restored O-GlcNAcylation levels and cell viability in the in vitro models of AD. Overall, these results suggest that O-GlcNAcylation is involved in AD pathology functioning as a potential link between mitochondrial energetic crisis and synaptic and neuronal degeneration. This posttranslational modification represents a promising therapeutic target to tackle this devastating neurodegenerative disease. PMID- 30412793 TI - Ferutinin directs dental pulp-derived stem cells towards the osteogenic lineage by epigenetically regulating canonical Wnt signaling. AB - Osteoporosis is a silent systemic disease that causes bone deterioration, and affects over 10 million people in the US alone. This study was undertaken to develop a potential stem cell therapy for osteoporosis. We have isolated and expanded human dental pulp-derived stem cells (DPSCs), characterized them, and confirmed their multipotential differentiation abilities. Stem cells often remain quiescent and require activation to differentiate and function. Herein, we show that ferutinin activates DPSCs by modulating the Wnt/beta-catenin signaling pathway and key osteoblast-secreted proteins osteocalcin and collagen 1A1 both mRNA and protein levels. To confirm that ferutinin modulates the Wnt pathway, we inhibited glycogen synthase kinase 3 (GSK3) and found that protein expression patterns were similar to those found in ferutinin-treated DPSCs. To evaluate the role of ferutinin in epigenetic regulation of canonical Wnt signaling, the pathway molecules Wnt3a and Dvl3 were analyzed using chromatin immunoprecipitation (ChIP)-quantitative PCR approaches. We confirmed that active marks of both H3K9 acetylation and H3K4 trimethylation were significantly enhanced in the promoter sites of the WNT3A and DVL3 genes in DPSCs after addition of ferutinin. These data provide evidence that ferutinin activates and promotes osteogenic differentiation of DPSCs, and could be used as an inducer as a potentially effective stem cell therapy for osteoporosis. PMID- 30412794 TI - Design, synthesis and anti-Alzheimer's activity of novel 1,2,3-triazole chromenone carboxamide derivatives. AB - Alzheimer's disease (AD) is a well-known neurodegenerative disorder affecting millions of old people worldwide and the corresponding epidemiological data highlights the significance of the disease. As AD is a multifactorial illness, various single-target directed drugs that have reached clinical trials have failed. Therefore, various factors associated with outset of AD have been considered in targeted drug discovery and development. In this work, a wide range of 1,2,3-triazole-chromenone carboxamides were designed, synthesized, and evaluated for their cholinesterase inhibitory activity. Among them, N-(1 benzylpiperidin-4-yl)-7-((1-(3,4-dimethylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2 oxo-2H-chromene-3-carboxamide (11b) showed the best acetylcholinesterase inhibitory activity (IC50 = 1.80 uM), however, it was inactive toward butyrylcholinesterase. It should be noted that compound 11b was evaluated for its BACE1 inhibitory activity and calculated IC50 = 21.13 uM confirmed desired inhibitory activity. Also, this compound revealed satisfactory neuroprotective effect against H2O2-induced cell death in PC12 neurons at 50 uM as well as metal chelating ability toward Fe2+, Cu2+, and Zn2+ ions. PMID- 30412795 TI - Floating aquatic plants for total nitrogen and phosphorus removal from treated swine wastewater and their biomass characteristics. AB - In this study, the removal of nitrogen and phosphorus from the effluent of treated swine wastewater by Eichhornia crassipes, Pistia stratiotes, Limnobium laevigatum, and Lemna sp. was investigated. This study also aimed to quantify the potential biomass production and lignocellulosic composition of the floating plants cultured in the effluent. Plants were grown in treated swine wastewater effluent or Hoagland's solution. Pistia stratiotes showed the highest total nitrogen removal of 63.15% from the treated effluent. Lemna sp. showed the highest phosphorus removal of 36.15% from the treated effluent. However, Lemna sp. could not be further utilized because the plants could only be cultured for 13 days. The effluent likely had properties that inhibited the growth and nutrient uptake by the plants; further studies would be required to verify these properties. Pistia stratiotes and Eichhornia crassipes have higher tolerance than Lemna sp. to grow in treated swine wastewater. Eichhornia crassipes produced the highest biomass of 5.19 g dry weight/m2/day. Cellulose and lignin contents were higher in the Hoagland's solution treatment when compared with the effluent. However, based on an independent T-test analysis, the cellulose contents of plants grown in different media were not significantly different. Hemicellulose content was significantly different for Pistia stratiotes (p < 0.05). Finally, lignin content was significantly different for Eichhornia crassipes and Lemna sp (p < 0.05). The nutrient composition and available plant nutrients as well as other substances present in the effluent might have influenced the plant cell wall composition. PMID- 30412796 TI - Steering pluripotency and differentiation with N6-methyladenosine RNA modification. AB - Chemical modifications of RNA provide a direct and rapid way to modulate the existing transcriptome, allowing the cells to adapt rapidly to the changing environment. Among these modifications, N6-methyladenosine (m6A) has recently emerged as a widely prevalent mark of messenger RNA in eukaryotes, linking external stimuli to an intricate network of transcriptional, post-transcriptional and translational processes. m6A modification modulates a broad spectrum of biochemical processes, including mRNA decay, translation and splicing. Both m6A modification and the enzymes that control m6A metabolism are essential for normal development. In this review, we summarized the most recent findings on the role of m6A modification in maintenance of the pluripotency of embryonic stem cells (ESCs), cell fate specification, the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs), and differentiation of stem and progenitor cells. This article is part of a Special Issue entitled: mRNA modifications in gene expression control edited by Dr. Soller Matthias and Dr. Fray Rupert. PMID- 30412797 TI - Transcriptional regulation of Translocator protein (18 kDa) (TSPO) in microglia requires Pu.1, Ap1 and Sp factors. AB - Mitochondrial Translocator protein (18 kDa) (TSPO) is strongly expressed in reactive microglia and serves as a therapeutic target for alleviation of neuronal degeneration. However, little is known about TSPO's transcriptional regulation in microglia. The aim of this study was to identify genetic elements and transcription factors required for basal and inducible TSPO expression in microglia. Murine Tspo promoter was cloned into the pGL4.10 luciferase vector and functionally characterized in BV-2 cells. Deletion mutagenesis indicated that 845 bases upstream were sufficient to reconstitute near maximal promoter activity in BV-2. Deletion of -593 to -520 sequences, which harbour an Ap1, Ets.2 and Nkx3.1 site which also serves as a non-canonical binding site for Sp1-family transcription factors, led to a dramatic decrease in both basal and LPS induced promoter activity. Further deletion of -168 to -39 sequences, which contains four GC boxes, also led to a significant decrease in promoter activity. Targeted mutations of Ap1, Ets.2, Nkx3.1/Sp1/3/4 and the GC boxes led to significant decreases in promoter activity. ChIP-qPCR revealed that Pu.1, Ap1, Stat3, Sp1, Sp3 and Sp4 bind to the endogenous Tspo promoter. Notably, binding of these factors, with the exception of Stat3, was significantly enhanced upon LPS treatment. RNAi silencing of Pu.1, cJun, cFos, Sp1, Sp3, Sp4 and Stat3 strongly lowered Tspo promoter activity while Ap1 silencing inhibited LPS induced increase in Tspo protein levels. These findings demonstrate that consensus binding sequences for Ap1, Ets.2, distal as well as proximal Sp1/3/4 sites regulate basal and LPS induced Tspo promoter activity in microglia. PMID- 30412798 TI - m6A: Widespread regulatory control in virus replication. AB - N6-methyladenosine (m6A) is a highly pervasive and dynamic modification found on eukaryotic RNA. Despite the failure to comprehend the true regulatory potential of this epitranscriptomic mark for decades, our knowledge of m6A has rapidly expanded in recent years. The modification has now been functionally linked to all stages of mRNA metabolism and demonstrated to regulate a variety of biological processes. Furthermore, m6A has been identified on transcripts encoded by a wide range of viruses. Studies to investigate m6A function in viral-host interactions have highlighted distinct roles indicating widespread regulatory control over viral life cycles. As a result, unveiling the true influence of m6A modification could revolutionise our comprehension of the regulatory mechanisms controlling viral replication. This article is part of a Special Issue entitled: mRNA modifications in gene expression control edited by Dr. Soller Matthias and Dr. Fray Rupert. PMID- 30412799 TI - Investigating the biochemical and fermentation attributes of Lachancea species and strains: Deciphering the potential contribution to wine chemical composition. AB - Yeasts of various genera are increasingly used alongside Saccharomyces cerevisiae to drive wine fermentations owing to their positive contribution to the organoleptic profile of the resulting wines. One such yeast species is Lachancea thermotolerans. Other species of the genus Lachancea, namely, L. fermentati and L. lanzarotensis have also been isolated from the fermentation environment, but have not received the same degree of attention as L. thermotolerans. The aim of this study was to investigate the oenological potential of these three Lachancea species, regarding their expression of oenologically relevant enzymes, their fermentation attributes and the expression and location of beta-glucosidase during fermentation of synthetic and real grape must (Muscat of Alexandria). In the current study we evaluated three species viz. L. thermotolerans (14 strains), L. fermentati (1 strain) and L. lanzarotensis (2 strains). Our data show that all the species and strains produced beta-glucosidase but with different substrate specificities. Moreover, L. theromotolerans and L. fermentati also produced beta xylosidase. H2S production, SO2 and ethanol tolerance was variable between species and strains, with the L. lanzarotensis and L. fermentati displaying considerably high H2S production while L. thermotolerans and L. fermentati displayed higher ethanol tolerance. Furthermore, L. fermentati showed higher SO2 tolerance and could proliferate at 20 mg/L total SO2. Interestingly, an increase in beta-glucosidase activity during fermentation did not result in a significant increase in monoterpene concentrations. However, mixed-fermentations with L. fermentati and L. thermotolerans Concerto enhanced geraniol levels. The data show that this activity was mostly cell-associated and constitutively expressed. Sequential fermentations with the Lachancea spp. and S. cerevisiae resulted in wines with significantly altered chemical compositions compared to that obtained from S. cerevisiae inoculated alone. Wines produced from L. thermotolerans and L. lanzarotensis mixed culture fermentations exhibited similar volatile compound composition. Conversely, L. fermentati produced chemically distinct wines consistently associated with high isobutanol and isobutyric acid, and higher monoterpenes. In particular, linalool and geraniol had potential to make perceivable aroma contribution (OAV >= 1). PMID- 30412800 TI - Real-time PCR detection and quantification of selected transferable antibiotic resistance genes in fresh edible insects from Belgium and the Netherlands. AB - The occurrence of antibiotic resistance genes in foodstuffs involves a human health risk. Fresh edible insects present an emerging source of human food but they were not yet assessed in a quantitative way for antibiotic resistances as a matter of food safety. In this study, a real-time quantitative PCR assessment was optimised to detect and quantify relevant transferable antibiotic resistance genes [tet(O, K, M, S) and erm(B)] in edible insects. Subsequently, the technology was applied on 30 fresh insect samples, including two mealworm species and two cricket species from different production batches and rearing companies in Belgium and the Netherlands. The sampling periods and the post-harvest treatments applied were also taken into account. Results showed that mealworms contained, on average, higher numbers of tet(K), tet(M), and tet(S) genes than crickets, but tet(O) was almost uniquely present in crickets. The erm(B) gene was only detected in one mealworm sample and the tet(K) gene showed higher abundances in samples originating from the Netherlands than in samples from Belgium. A large difference in antibiotic resistance profile was revealed between mealworms and crickets, but not between different mealworm species or cricket species. Species specific microbiomes and insect feed may have contributed to this distinction. Interestingly, important correlations between the presence of some tet genes and the microbiota previously encountered in the investigated edible insects were uncovered. While a geographical distribution was observed for the tet(K) gene, post-harvest treatments and sampling period were not shown to have a significant influence on the occurrence of the antibiotic resistance genes considered. In conclusion, insects may carry considerable amounts of antibiotic resistance genes, but the health risk in terms of antibiotic resistances is comparable to other food matrices. PMID- 30412801 TI - Chemical profiles and quality evaluation of Buddleja officinalis flowers by HPLC DAD and HPLC-Q-TOF-MS/MS. AB - The dried flowers and inflorescences of Buddleja officinalis Maxim are used as traditional medicines in China, and aqueous extracts of the flowers have also been used since ancient times as a yellow rice colorant at local festivals. In this study, HPLC-Q-TOF-MS/MS was used to determine the overall chemical composition of this medicine-food plant. A total of 54 compounds, including 23 flavonoids, 19 phenylethanoid glycosides, 7 alkaloids and 5 other compounds, were detected in the methanol extracts of the herb using this method. Among them, 35 compounds were found firstly in this herb. HPLC fingerprints were also developed, together with a method for the simultaneous quantification of 11 constituents that could be used for quality evaluation of B. officinalis. Fingerprint analysis, using 28 characteristic fingerprint peaks, was used to assess the similarities among 12 samples collected from different geographic areas and showed that the similarity was >0.900. Simultaneous quantification of 11 markers in B. officinalis was then performed to determine consistency of quality. Additionally, the total phenolic content and antioxidant capacity of extracts of the 12 samples of B. officinalis flowers were measured using spectroscopic methods. B. officinalis was found to have good antioxidant capacity and to be a potential natural antioxidant. The highest antioxidant capacity was found in the samples from Guizhou, Sichuan and Guangxi Province. Our results provide valuable information for further understanding and exploiting the herb. PMID- 30412802 TI - Quantification of 2-aminoisobutyric acid impurity in enzalutamide bulk drug substance using hydrophilic interaction chromatography with fluorescence detection. AB - A rapid procedure for the determination of 2-aminoisobutyric acid in enzalutamide bulk drug substance based on hydrophilic interaction chromatography with fluorescence detection was developed. Fluorescence detection after postcolumn derivatization with o-phthaldialdehyde/2-mercaptoethanol was carried out at excitation and emission wavelength of 345 nm and 450 nm, respectively. The postcolumn reaction conditions such as reaction temperature, mobile phase and derivatization reagent flow rate and the reagents concentrations were studied and optimized due to steric hindrance of amino group of 2-aminoisobutyric acid. The derivatization reaction was applied for the hydrophilic interaction chromatography method which was based on COSMOSIL HILIC column with a mobile phase consisting of a mixture of 25 mmol/L acetic acid adjusted to pH 5.5 (using 1 mol/L potassium hydroxide) and acetonitrile using an isocratic elution (28:72, nu/nu). The benefit of the reported approach consists in a simple sample pretreatment and a quick and sensitive hydrophilic interaction chromatography method. The developed method was validated in terms of linearity, limit of detection, limit of quantification, accuracy, precision and selectivity according to the International Conference on Harmonisation guidelines. The developed method was demonstrated to be applied for the analysis of 2-AIBA in routine quality control evaluation of commercial samples of enzalutamide bulk drug substance. PMID- 30412803 TI - Ultra performance liquid chromatography coupled with principal component and cluster analysis of Swertia chirayita for adulteration check. AB - This article describes the study to standardize phytochemically and distinguish Swertia chirayita from that of possible substitution/adulteration using ultra performance liquid chromatography (UPLC) with photodiode array detector (PDA) and chemometric tools viz. principal component analysis (PCA) and hierarchical clustering analysis (HCA). Five ecotypes of Swertia chirayita and five possible substitutions, e.g.,Swertia bimaculata (SB), Swertia chordata (SCH), Swertia ciliata (SCL), Swertia paniculata (SP), and Halenia elliptica (HE) collected from different Indian Himalayan region. Samples evaluated for 04 marker compounds- swertiamarin (SM), mangiferin (MF), gentiopicroside (GP), and sweroside (SW). Reverse phase column (Waters Acquity BEH C18, 50 mm * 2.1 mm , 1.7 MUm) provided high resolution for all target analytes with binary gradient elution. The detector response was linear (concentration 2.5-125 MUg/mL, R2 > 0.999). The limit of detection (LOD) and quantification (LOQ) of targeted compounds was in the range of 1.40-2.06 and 4.57-6.27 MUg/mL respectively. The combined relative standard deviation (%RSD) for intra-day and inter-day precision values were less than 2%. The recoveries study comply the method suitability. Chromatogram similarity analysis based on congruence coefficient was higher than 0.925 for the chirayita ecotypes while much lower than 0.629 for possible substitutes. HCA showed that the samples could be clustered (all 5 clusters in two-level) reasonably into different ecotypes and substitutes. HCA together with loading plots has indicated different chemical properties of all five groups. PCA results showed that the discrimination of chirayita ecotypes is because of the presence of SW while SM may have more influence on the targeted substitutes to discriminate from chirayita ecotypes. Therefore, UPLC fingerprint in association with chemometric tools provides a reliable and accurate quality assessment and detection of possible adulteration. PMID- 30412804 TI - Succinic acid enhanced quantitative determination of blood modified nucleosides in the development of diabetic nephropathy based on hydrophilic interaction liquid chromatography mass spectrometry. AB - The epigenetic modification of DNA or RNA may have relationship with the development of diabetic nephropathy (DN). We designed to develop a liquid chromatography mass spectrometry (LC-MS) coupled with mobile phase additive sensitization method for the analysis of the dissociative epigenetic modified nucleosides in serum of patients from different periods of DN with the health comparison. Serum samples were collected from 43 healthy volunteers and 156 patients, which divided into four groups. A succinic acid enhanced LC-MS/MS strategy was developed for the quantitative analysis of seven nucleosides in serum samples. The signal intensity of seven nucleosides increased three to seven times, respectively. A series of statistical analysis were carried out to demonstrate the dynamic changes of modified nucleosides in four groups. This method showed good specific, accuracy, and stability. The results were calibrated and presented through the formation of m6A/C, I/C, 5-mdC/C, 5-mC/C, pseU/U to eliminate the individual and age differences. The m6A/C, I/C, and pseU/U were found having the dynamic changes in four groups (p< 0.05). And these five modified nucleosides can also used as one parameter to distinguish these four groups by ROC and LDA analysis. Additionally, they were found to be connected with several clinical biochemical indexes through multiple linear regression analysis. Our LC-MS/MS method assay successfully quantifies the modified nucleosides in serum. And three modified nucleosides can act as the potential biomarkers to describe the development of DN and help to evaluate the diagnosis, treatment, and prognosis of DN in clinical. PMID- 30412805 TI - Preliminary pharmacokinetic study of the anticancer 6BIO in mice using an UHPLC MS/MS approach. AB - Indirubins represent a group of natural and synthetic products with bio activities against numerous human cancer cell lines acting by inhibiting protein kinases. The natural sources of indirubins are plants of Isatis sp., Indigofera sp., and Polygonum sp., recombinant bacteria, mammalian urine and some marine mollusks. Specifically, the halogenated derivative 6-bromo indirubin-3'-oxime (6BIO) possesses increased selectivity against GSK-3. However, to our knowledge, no analytical method to determine 6BIO in biological fluids has been developed till now. Therefore, a rapid, sensitive and high throughput UHPLC-MS/MS methods were developed and validated to evaluate the concentrations of 6BIO in mice plasma. Plasma samples were pre-treated by protein precipation using cold mixture of methanol: acetonitrile (9:1, v/v) and separations were carried out on a Hypersil Gold C18 column (50 * 2.1 mm i.d.; 1.9 MUm p.s.) using 0.1% acetic acid and methanol as mobile phase at a flow rate of 500 mL/min in a gradient mode. For quantitation, a hybrid LTQ-Orbitrap MS equipped with an electro-spray ionization source was used applying a selected reaction monitoring (SRM) option. The monitored transitions were m/z 354.0 -> 324.0 for 6BIO and 297.1 -> 282.1 for afromorsin (used as the internal standard) in the negative mode. Following the EMA, ICH and FDA guidelines for validation of analytical procedures, the assay method was fully validated in terms of selectivity, linearity, recovery, matrix effect, accuracy, precision, stability, and robustness. The validated methods were successfully applied to the pharmacokinetic studies of 6BIO following an oral administration to mice at the dose of 50 mg/kg. The results indicated that 6BIO possesses a Tmax of 30 min, a half-life of 1 h, and low plasma bioavailability. PMID- 30412806 TI - In vitroand in vivo investigation of metabolic fate of riociguat by HPLC-Q TOF/MS/MS and in silico evaluation of the metabolites by ADMET predictorTM. AB - Riociguat, a guanyl cyclase inhibitor, is one of its kind drug regimen approved for management of pulmonary arterial hypertension and chronic thromboembolism pulmonary hypertension. Extensive literature review indicates lack of comprehensive reports on its metabolic fate. The present study reports the in vivo and in vitro identification and characterization of metabolites of riociguat, using high-performance liquid chromatography-quadruple time-of-flight tandem mass spectrometry. In vitro studies were conducted by incubating the drug in human and rat liver microsomes in presence of respective cofactors. In vivo studies were undertaken by oral administration of suspension of drug to male Sprague-Dawley rats followed by collection of urine, feces and blood at specific intervals. A total of 18 metabolites were observed in in vivo and in vitro matrices which includes hydroxyl, N-oxide, desmethyl, defluorinated hydroxyl, glucuronides and N-acetyl cysteine conjugates. Presence of N-acetyl cysteine conjugates strongly points towards the formation of a reactive metabolite intermediate trapped through N-acetyl cysteine and can be considered a matter of concern as the reactive metabolites have been known to manifest toxicities. Their presence was mimicked in in vitro samples as well. The toxicological properties of drug and metabolites were evaluated by using ADMET Predictor TM software. PMID- 30412807 TI - Enhanced visible-light activation of persulfate by Ti3+ self-doped TiO2/graphene nanocomposite for the rapid and efficient degradation of micropollutants in water. AB - In this study, a novel TiO2-x/rGO-PS-Vis process was developed, which utilizes the TiO2-x/rGO (Ti3+ and oxygen vacancies self-doped TiO2 coupled with reduced graphene oxide) nanocomposite as a promising and efficient activator of persulfate (PS) for the enhanced oxidation of micropollutants under visible light irradiation. TiO2-x/rGO exhibited a significantly high activity for PS activation to produce more sulfate radicals (SO4-) and hydroxyl radicals (OH). Therefore, almost 100% BPA (10 mg/L) and 80% TOC can be removed just within 12 min with 1.0 g/L TiO2-x/rGO and 2 mM PS under visible light. Moreover, it was found that many other typical micropollutants, such as phenol, acetaminophen and sulfamethoxazole can also be effectively degraded by this process. Electron paramagnetic resonance (EPR) and radical quenching experiments indicated that both SO4- and OH contribute to the degradation of organics, and the radical process was the main degradation pathway. In addition, the effects of PS concentration, catalyst dosage, initial solution pH and inorganic anions were investigated systematically. Experiments carried out in the real background of water matrix with low-concentration of BPA indicated that the proposed TiO2-x/rGO PS-Vis process has strong non-selective photo-oxidative ability for the removal of micropollutants in water. PMID- 30412808 TI - Co-immobilization of laccase and ABTS onto novel dual-functionalized cellulose beads for highly improved biodegradation of indole. AB - The method developed in this work, for the first time, for the co-immobilization of mediator 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) and laccase, in which the dual-functionalized cellulose beads with network pore structure were constructed by polydopamine (PD) and polymeric glycidyl methacrylate (GMA) to obtain the biocatalyst co-immobilizing ABTS and laccase. ABTS molecules were encapsulated into the dual-functionalized cellulose beads to obtain an efficient carrier (PD-GMA-Ce/ABTS) on which the laccase could be covalently immobilized by means of the coupling between the amino groups of the enzyme and the epoxy groups and ortho-dihydroxyphenyl groups existing on the beads. The as-prepared PD-GMA-Ce/ABTS with network pore structure were characterized by SEM, XRD, FT-IR and EPR. The resultant beaded biocatalyst (PD GMA-Ce/ABTS@Lac) co-immobilizing laccase and ABTS were used in the biodegradation of indole and the degradation rate was up to 99.7%, while indole is difficult to be degraded by free laccase. The PD-GMA-Ce/ABTS@Lac beads displayed considerably reusability and storage stability for indole degradation after cycling of 10 runs or storage of 100 days benefited from the mediation effect of the immobilized ABTS. The effective recovery of both expensive laccase and hazardous ABTS by using PD-GMA-Ce/ABTS@Lac is promising to reduce the cost for the laccase application in wastewater treatment and might be helpful to eliminate the secondary pollution from the free mediator. PMID- 30412809 TI - Continuous removal of the model pharmaceutical chloroquine from water using melanin-covered Escherichia coli in a membrane bioreactor. AB - Environmental release and accumulation of pharmaceuticals and personal care products is a global concern in view of increased awareness of ecotoxicological effects. Adsorbent properties make the biopolymer melanin an interesting alternative to remove micropollutants from water. Recently, tyrosinase-surface displaying Escherichia coli was shown to be an interesting self-replicating production system for melanin-covered cells for batch-wise absorption of the model pharmaceutical chloroquine. This work explores the suitability of these melanin-covered E. coli for the continuous removal of pharmaceuticals from wastewater. A continuous-flow membrane bioreactor containing melanized E. coli cells was used for adsorption of chloroquine from the influent until saturation and subsequent regeneration. At a low loading of cells (10 g/L) and high influent concentration of chloroquine (0.1 mM), chloroquine adsorbed until saturation after 26 +/- 2 treated reactor volumes (39 +/- 3 L). The average effluent concentration during the first 20 h was 0.0018 mM, corresponding to 98.2% removal. Up to 140 +/- 6 mg chloroquine bound per gram of cells following mixed homo- and heterogeneous adsorption kinetics. In situ low-pH regeneration released all chloroquine without apparent capacity loss over three consecutive cycles. This shows the potential of melanized cells for treatment of conventional wastewater or highly concentrated upstream sources such as hospitals or manufacturing sites. PMID- 30412810 TI - Novel synthesis of Bi-Bi2O3-TiO2-C composite for capturing iodine-129 in off-gas. AB - The Bi-Bi2O3-TiO2-C composites were prepared by a sol-gel method and investigated for capturing iodine-129 (129I) in off-gas producing from spent fuel reprocessing. Firstly, the optimal process conditions were operated through the orthogonal experiments, showing that the capturing capacity of the optimal composite was calculated about 504.0 +/- 19.5 mg/g, which is approximately 2.0 fold higher than that of the commercial silver-exchanged zeolites (AgX). Secondly, the structure and morphology of the Bi-Bi2O3-TiO2-C composite were characterized, suggesting that the Bi is regularly spherical in the shape, coating by the Bi2O3, TiO2 and amorphous carbon. Finally, the mechanism for the iodine adsorption in the Bi-Bi2O3-TiO2-C system was revealed, demonstrating that the iodine was captured by physisorption and chemisorption. PMID- 30412811 TI - Biodegradation and toxicity of emerging contaminants: Isolation of an exopolysaccharide-producing Sphingomonas sp. for ionic liquids bioremediation. AB - Ionic liquids (ILs) have been characterized as contaminants of emerging concern (CEC) that often resist biodegradation and impose toxicity upon environmental release. Sphingomonas sp. MKIV has been isolated as an extreme microorganism capable for biodegradation of major classes of ILs. Six imidazolium-, pyridinium- and ammonium-based ILs (pyridinium trifluoromethanesulfonate [Py][CF3SO3], 1-(4 pyridyl)pyridinium chloride [1-4PPy][Cl], 1-butyl-3-methylimidazolium bromide [BMIM][Br], 1-butyl-3-methylimidazolium methanesulfonate [BMIM][MeSO4], tetrabutylammonium iodide [n-Bu4N][I] and tetrabutylammonium hexafluorophosphate [n-Bu4N][PF6]) were used for microbial growth. The strain achieved 91% and 87% removal efficiency for cultures supplemented with 100 mg L-1 of [BMIM][MeSO4] and [n-Bu4N][I] respectively. The metabolic activity of MKIV was inhibited following preliminary stages of cultures conducted using [BMIM][MeSO4], [BMIM][Br], [Py][CF3SO3] and [n-Bu4N][PF6], indicating potential accumulation of inhibitory metabolites. Thus, a comprehensive toxicological study of the six ILs on Aliivibrio fischeri, Daphnia magna and Raphidocelis subcapitata was conducted demonstrating that the compounds impose moderate and low toxicity. The end products from [BMIM][MeSO4] and [n-Bu4N][I] biodegradation were assessed using Aliivibrio fischeri, exhibiting increased environmental impact of the latter following biotreatment. MKIV produced 19.29 g L-1 of biopolymer, comprising mainly glucose and galacturonic acid, from 25 g L-1 of glucose indicating high industrial significance for bioremediation and exopolysaccharide production. PMID- 30412812 TI - The enantioselective environmental behavior and toxicological effects of pyriproxyfen in soil. AB - We synthesized nine pyriproxyfen (PYR) metabolites and developed a chiral residual analysis method for PYR with its metabolites in five soils using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Soil degradation research showed that higher organic matter content and bigger soil particle size were conducive to the degradation of PYR and metabolites. Metabolite A 4'-OH-PYR was mainly found in five soils. PYR and metabolite A performed enantioselective degradation in soil with half-lives ranging from 2.11 d to 9.69 d and 2.80 d to 13.30 d, respectively. The activity of dehydrogenase, sucrase was inhibited and catalase activity was promoted under the disturbance of PYR. Urease was more sensitive to PYR with uncertain influences. Most soil enzymes were not restored to their initial active state after 120 d. The toxicity of metabolites to earthworms was greater than that of the parent compound PYR. This study provides the basic degradation and toxicity data of chiral pesticide PYR and its main metabolites in soil ecosystem, which is of great significance for guiding safe use and comprehensive evaluation of PYR on environmental risk. PMID- 30412813 TI - Assessment of a multimodal analgesia protocol to allow the implementation of enhanced recovery after cardiac surgery: Retrospective analysis of patient outcomes. AB - STUDY OBJECTIVE: To investigate the impact of utilizing a multimodal analgesia protocol to allow the implementation of Enhanced Recovery after Cardiac Surgery (ERACS) in patients requiring cardio-pulmonary bypass. DESIGN: Retrospective analysis of patients treated with the proposed ERACS bundle in comparison to matched controls. SETTING: Single-center study. PATIENTS: A total of 50 patients undergoing elective cardiac surgery limited to on pump coronary artery bypass graft. MEASUREMENTS: Perioperative outcomes of 25 patients that underwent ERACS protocol and 25 controls were measured. In-operating room (OR) extubation, total intubation time, total intra-OP fentanyl given, total post-OP morphine equivalent given, intensive care unit (ICU) length of stay (LOS), hospital LOS and post-OP complications were examined. MAIN RESULTS: The ERACS group and control group were equivalent with regards to age, gender, comorbidities, ASA classification and type of surgery. Mean cardiac bypass time and mean aortic clamp time were similar. Extubation in the OR was achieved for 12 patients in the ERACS group compared to 1 in the control group. Post-operative opioid consumption was lower in ERACS group (27.3 vs. 51.7 morphine equivalents, p = 0.006). Although ICU LOS and hospital LOS were shorter in the ERACS group, this did not reach significance. CONCLUSIONS: The ERACS group showed a significant decrease in opioid use and increased incidence of successful in OR extubation. PMID- 30412814 TI - An unusual complication associated with use of transdermal scopolamine. PMID- 30412815 TI - Ultrasound-guided caudal approach to combined spinal-epidural for major abdominal surgery in high risk premature newborns. PMID- 30412816 TI - Maintenance of piercing tracts in the perioperative period. PMID- 30412817 TI - Pediatric acute ischemic stroke and restrictive cardiomyopathy, a challenge for anesthesiologists. PMID- 30412818 TI - The role of phospholipase A2 in multiple Sclerosis: A systematic review and meta analysis. AB - Phospholipases A2 (PLA2) are a diverse group of enzymes that cleave the fatty acids of membrane phospholipids. They play critical roles in pathogenesis of neurodegenerative diseases such as multiple sclerosis by enhancing oxidative stress and initiating inflammation. The levels of PLA2 activity in MS patients compared to controls and role of inhibiting PLA2 activity on severity scores in different experimental models are not comprehensively assessed in the light of varying evidence from published studies. The objective of this systematic review is to determine the association between PLA2 activity and multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). We performed a systematic review of six studies that assessed PLA2 activity in MS patients compared to controls and nine studies that assessed PLA2 activity in EAE. sPLA2 nor Lp-PLA2 activity were not increased in MS compared to controls in five of those six studies. A difference in sPLA2 activity was only found in a study that measured the enzyme activity in urine. However, inhibiting cPLA2 or sPLA2 led to lower clinical severity or no signs of EAE in mice, and a lower incidence of EAE lesions compared to animals without cPLA2 inhibition. These findings indicate that PLA2 appears to play a role in the pathogenesis of EAE. PMID- 30412819 TI - Use of coping strategies in multiple sclerosis: Association with demographic and disease-related characteristics?. AB - BACKGROUND: Coping positively and negatively influences psychosocial and other outcomes in multiple sclerosis (MS), but there is conflicting evidence about the use of different coping strategies and their associations with demographic and disease characteristics. Our aims were to examine which coping strategies are used by a large sample of people with MS, then to identify any associations between demographic and disease related factors with use of individual coping strategies. METHODS: Participants in the Trajectories of Outcomes in Neurological Conditions (TONiC) study completed the Coping Orientations to Problems Experienced (COPE60) questionnaire. Relationships between demographic and clinical characteristics and coping strategies were examined by multiple ordinal logistic regression to assess the effect of each potential predictor after adjustment for other possible covariates. RESULTS: From 722 patients, the most commonly used strategy was Acceptance, followed by Active Coping, Planning and Positive Reinterpretation and Growth. All but two strategies showed significant associations with demographic and clinical characteristics. The most marked effects were found for Restraint, with people in employment 2.1 times as likely to utilise this strategy compared to those unemployed, and Seeking of Emotional Social Support and Focus on and Venting of Emotions, which were utilised twice as much by women compared to men. Behavioural and Mental Disengagement were highly associated with greater disability and not being in employment. CONCLUSION: Clinicians should be aware of several disease and demographic characteristics that are associated with use of potentially maladaptive coping strategies. PMID- 30412820 TI - Risk analysis of suicidal ideations and postpartum depression with antenatal alpha methyldopa use. AB - Out of the various risk factors for postpartum depression, use of pharmacotherapy during pregnancy is the most poorly understood. The present study aimed to establish risk of postpartum depression and suicidal ideations with antenatal use of alpha methyldopa. Out of the 100 postpartum women assessed, 77.78% of the women who were prescribed alpha methyldopa had significant postpartum depression. There was statistically significant risk of postpartum depression associated with alpha methyldopa (p = 0.026, OR = 6.45). There was no increased suicidal risk with use of alpha methyldopa in these women (p = 1.00). PMID- 30412821 TI - Prevalence and pattern of mental illnesses in Uttar Pradesh, India: Findings from the National Mental Health Survey 2015-16. AB - AIM: To estimate the prevalence and distribution of psychiatric morbidity, and study pattern of help-seeking in a community representative sample from the state of Uttar Pradesh in northern India. METHOD: A multi-stage, stratified, random cluster sampling was used. The survey was conducted on 3508 adults during 2015-16 using M.I.N.I 6.0.0, modified Fagerstrom Nicotine Dependence Scale for all forms of tobacco, questionnaires for epilepsy and intellectual disability. The WHO Pathway Interview Schedule was used to study pattern of help-seeking behaviour. Focused group discussions (FGDs) and key informant interviews (KIIs) were also carried out. RESULT: Current and lifetime prevalence of 'any mental morbidity' (excluding tobacco use disorders) was 6.08% and 7.97%, respectively. The prevalence of substance use disorders, was 16.36%, of which tobacco use disorders alone contributed 16.06%. Neurotic and depressive disorders were the next most common morbidity. Schizophrenia and other psychotic disorders had a current prevalence of 0.09%. High-risk for suicide was reported to be 0.93%. Treatment gap varied between 75 and 100% for different disorders. FGDs and KIIs reflected a higher burden of substance use, including prescription drug abuse, substantial prevalence of cultural mental morbidity, deep rooted stigma, low help-seeking behaviour, and issues surrounding homeless mentally ill persons in the community. CONCLUSION: The survey revealed high mental morbidity and alarming treatment gap. FGDs and KIIs also highlight the burden of morbidity that probably goes un noticed, due to socio-cultural systems and stigma. Findings from this survey are intended to be the groundwork for the (re)planning of mental healthcare infrastructure in the state. PMID- 30412822 TI - Diagnostic analysis of the effects of weather condition on pedestrian crash severity. AB - Pedestrians are vulnerable to severe injury and mortality in road crashes. Numerous studies have attempted to identify factors contributing to crashes and pedestrian injury risks. As an active transport mode, the act of walking is sensitive to changes in weather conditions. However, comprehensive real-time weather data are often unavailable for road safety analysis. In this study, we used a geographical information system approach to integrate high-resolution weather data, as well as their corresponding temporal and spatial distributions, with crash data. Then, we established a mixed logit model to determine the association between pedestrian crash severity and possible risk factors. The results indicate that high temperature and the presence of rain were associated with a higher likelihood of Killed and Severe Injury (KSI) crashes. Also, we found the interaction effects of weather condition (hot weather and presence of rain) on the association between pedestrian crash severity and pedestrian and driver behaviors to be significant. For instance, the effects of jaywalking and risky driving behavior on crash severity were more prevalent under rainy conditions. In addition, the effects of driver inattention and reckless crossing were more significant in hot weather conditions. This has critical policy implications for the development and implementation of proactive traffic management systems. For instance, real-time weather and traffic data should be incorporated into dynamic message signs and in-vehicle warning systems. Doing so will enhance the levels of safety awareness of drivers and pedestrians, especially in adverse weather conditions. As a result, pedestrian safety can be improved over the long term. PMID- 30412823 TI - Cell-free prion protein conversion assays in screening for anti-prion drug candidates. AB - The search for medications to treat prion diseases has lasted more than 30 years but no clinically validated treatments for prion diseases of humans or livestock have been realized. A primary strategy has been to identify molecules that can inhibit the formation of pathological forms of prion protein, for example, protease-resistant forms called PrPres. Such inhibitors can prolong the lives of experimental animals inoculated peripherally with prions, but the practical therapeutic efficacy of known inhibitors against ongoing brain infections has so far been limited by toxicity, insufficient bioavailability to the CNS, and/or strain specificities. Thus, the search continues for clinically applicable inhibitors of PrPres accumulation. Here we highlight key cell-free assays that are useful for the initial screening and mechanistic characterization of such compounds and are relatively high throughput, rapid, and cost-effective. These include cell-free conversions, protein misfolding cyclic amplification (PMCA), real time quaking-induced conversion (RT-QuIC), and fluorescence correlation based competitive binding assays. PMID- 30412824 TI - Biosynthesis of tovarol and other sesquiterpenoids in Thapsia laciniata Rouy. AB - The genus Thapsia produces a wide variety of sesquiterpenoids. The Mediterranean plant Thapsia laciniata Rouy is known to have a product profile that differs from several other species in the genus. Thus, the biosynthesis of sesquiterpenoids in Thapsia laciniata Rouy was investigated. Here we describe three terpene synthases, TlTPS820, TlTPS509 and TlTPS18983. TlTPS18983 is a multi-product enzyme with farnesene as the major product, while TlTPS509 produces guaiol and bulnesol along with other major and several minor unknown products. TlTPS820 is orthologous to TgTPS2 from Thapsia garganica L. and is an epikunzeaol synthase. TgCYP76AE2 from Thapsia garganica performs a triple hydroxylation of epikunzeaol at C-12 to make dihydrocostunolide. It was therefore investigated if the cytochrome P450, TlCYP76AE4 was able to use epikunzeaol as a substrate. It was found that TlCYP76AE4 hydroxylates epikunzeaol at C-8 to yield tovarol instead of dihydrocostunolide. PMID- 30412825 TI - Problematic attention processing and fear learning in adolescent anxiety: Testing a combined cognitive and learning processes model. AB - BACKGROUND AND OBJECTIVES: Anxiety in adolescence is characterised by disturbances in attentional processes and the overgeneralisation of fear, however, little is known about the combined and reciprocal effects of and between these factors on youth anxiety. The present study investigated whether attention (attention allocation and control) and fear generalisation processes together predict more variance on adolescent anxiety symptoms than each factor in isolation, and explored their interrelations. METHODS: 197 adolescents completed a novel conditioning task, which paired balloon cues with mildly aversive or neutral outcomes. A spatial cueing task, and self-report measures of emotional attentional control and anxiety, were also completed. RESULTS: Threat-avoidant attention allocation biases, impaired attention control, and exaggerated fear generalisation together predicted greater variance in anxiety symptoms (55.3%), than each set of fear and attention processes in isolation. Results also provided evidence of an interplay between these factors. Individual differences in threat avoidant attention allocation biases predicted variability in the generalisation of fear, whilst the association between heightened anxiety and the overgeneralization of fear was moderated by poor attention control. CONCLUSIONS: This study provides unique evidence of the combined effects of attention and fear generalisation mechanisms in explaining youth anxiety, and interrelations between these factors. Importantly, results suggested that deficiencies in attention control may bring out anxiety-associated impairments in fear generalisation. LIMITATIONS: We relied on self-reported ratings of fear during generalization and also of attention control. Thus demand effects cannot be discounted. Reaction time measures of attention focus are also indirect assessments of attention that may lack precision. PMID- 30412826 TI - A graph-based lesion characterization and deep embedding approach for improved computer-aided diagnosis of nonmass breast MRI lesions. AB - Nonmass-like enhancements are a common but diagnostically challenging finding in breast MRI. Nonmass-like lesions can be described as clusters of spatially and temporally inter-connected regions of enhancements, so they can be modeled as networks and their properties characterized via network-based connectivity. In this work, we represented nonmass lesions as graphs using a link formation energy model that favors linkages between regions of similar enhancement and closer spatial proximity. However, adding graph features to an existing computer-aided diagnosis (CAD) pipeline incurs an increase of feature space dimensionality, which poses additional challenges to traditional supervised machine learning techniques due to the inability to increase accordingly the number of training datasets. We propose the combination of unsupervised dimensionality reduction and embedded space clustering followed by a supervised classifier to improve the performance of a CAD system for nonmass-like lesions in breast MRI. Our work extends a previoulsy proposed framework for deep embedded unsupervised clustering (DEC) to embedding space classification, with the joint optimization of objective functions for DEC and supervised multi-layered perceptron (MLP) classification. The strength of the method lies in the ability to learn and further optimize an embedded feature representation of lower dimensionality that maximizes the diagnostic accuracy of a CAD lesion classifier to discriminate between benign and malignant lesions. We identified 792 nonmass-like enhancements (267 benign, 110 malignant and 415 unknown) in 411 patients undergoing breast MRI at our institution. The diagnostic performance of the proposed method was evaluated and compared to the performance of a conventional supervised MLP classifier in original feature space. A statistically significant increase in diagnostic area under the ROC curve (AUC) was achieved. Generalization AUC increased from 0.67 +/ 0.08 to 0.81 +/- 0.10 (21% increase, p-value=4.2*10-8) with the proposed graph based lesion characterization and deep embedding framework. PMID- 30412828 TI - Sense and sensor ability: redox-responsive regulators in Listeria monocytogenes. AB - Listeria monocytogenes (Lm) is a Gram-positive bacterium that thrives in nature as a saprophyte and in the mammalian host as an intracellular pathogen. Both environments pose potential danger in the form of redox stress. In addition, endogenous reactive oxygen species (ROS) are continuously generated as by products of aerobic metabolism. Redox stress from ROS can damage proteins, lipids, and DNA, making it highly advantageous for bacteria to evolve mechanisms to sense and detoxify ROS. This review focuses on the five redox-responsive regulators in Lm: OhrR (to sense organic hydroperoxides), PerR (peroxides), Rex (NAD+/NADH homeostasis), SpxA1/2 (disulfide stress), and PrfA (redox stress during infection). PMID- 30412827 TI - Resveratrol as a new inhibitor of immunoproteasome prevents PTEN degradation and attenuates cardiac hypertrophy after pressure overload. AB - Sustained cardiac hypertrophy is a major cause of heart failure (HF) and death. Recent studies have demonstrated that resveratrol (RES) exerts a protective role in hypertrophic diseases. However, the molecular mechanisms involved are not fully elucidated. In this study, cardiac hypertrophic remodeling in mice were established by pressure overload induced by transverse aortic constriction (TAC). Cardiac function was evaluated by echocardiography and invasive pressure-volume analysis. Cardiomyocyte size was detected by wheat germ agglutinin staining. The protein and gene expressions of signaling mediators and hypertrophic markers were examined. Our results showed that administration of RES significantly suppressed pressure overload-induced cardiac hypertrophy, fibrosis and apoptosis and improved in vivo heart function in mice. RES also reversed pre-established hypertrophy and restoring contractile dysfunction induced by chronic pressure overload. Moreover, RES treatment blocked TAC-induced increase of immunoproteasome activity and catalytic subunit expression (beta1i, beta2i and beta5i), which inhibited PTEN degradation thereby leading to inactivation of AKT/mTOR and activation of AMPK signals. Further, blocking PTEN by the specific inhibitor VO-Ohpic significantly attenuated RES inhibitory effect on cardiomyocyte hypertrophy in vivo and in vitro. Taken together, our data suggest that RES is a novel inhibitor of immunoproteasome activity, and may represent a promising therapeutic agent for the treatment of hypertrophic diseases. PMID- 30412829 TI - Improved synthesis of the Kijanimicin oligodeoxytetrasaccharide. AB - By sequential synthesis the four 2,6-dideoxy saccharide moieties of the kijanimicin tetrasaccharide could be stereoselectively assembled. For formation of all required 2-deoxy alpha-glycoside linkages various S-(hexopyranosyl) phosphorodithioates as donor structures could be convincingly employed. The terminal 2-deoxy beta-glycoside linkage was stereoselectively formed following the dibromomethyl methyl ether approach. The target octadeoxy-tetrasaccha-ride could be obtained via nine subsequent steps in 5% overall yield. PMID- 30412830 TI - The edible mushroom Albatrellus ovinus contains a alpha-l-fuco-alpha-d-galactan, alpha-d-glucan, a branched (1 -> 6)-beta-d-glucan and a branched (1 -> 3)-beta-d glucan. AB - Albatrellus ovinus, the sheep polypore, is a large, dense mushroom being rich in cell wall material. Polysaccharides were isolated by sequential extraction, enzymatic treatment and analyzed with respect to monosaccharide composition, glycosidic linkages by methylation and GC-MS as well as NMR spectroscopy. A fucogalactan composed of an (1 -> 6)-alpha-d-galactan backbone with single alpha l-Fucp residues attached at O-2 was identified in the hot water extract obtained after treatment with a protease and size exclusion chromatography. Both the hot water extract and the hot alkali extract contained an (1 -> 4)-alpha-d-glucan whereas beta-d-glucans were mainly present in the latter. Structural analysis suggested the presence of two different beta-d-glucan backbone structures; a (1 > 6)-linked beta-d-glucan with single beta-d-Glcp residues at O-3 and also a (1 > 3)-linked beta-d-glucan with branches in O-6. In addition there were identified short (1 -> 2)-linked beta-d-xylan and (1 -> 3)-alpha-d-mannan chains. PMID- 30412831 TI - Synthesis of a biotinylated probe from biotechnologically derived beta-d mannopyranosyl-(1 -> 2)-d-mannopyranose for assessment of carbohydrate specificity of antibodies. AB - The disaccharide beta-d-mannopyranosyl-(1 -> 2)-d-mannopyranose obtained by chemical cleavage and enzymatic dephosphorylation of biotechnologically available phosphomannan was transformed over six steps into a biotinylated probe suitable for assessment of carbohydrate specificity of antibodies induced by yeast cell wall preparations. PMID- 30412832 TI - Novel glucopyranoside C2-derived 1,2,3-triazoles displaying selective inhibition of O-GlcNAcase (OGA). AB - O-GlcNAcylation or O-GlcNAc modification is a post-translational modification of several proteins responsible for fundamental cellular processes. Dysregulation of the O-GlcNAc pathway has been linked to the etiology of several diseases such as neurodegenerative and cardiovascular diseases, type 2 diabetes and cancer. O GlcNAcase (OGA) catalyzes the removal of O-GlcNAc from the modified proteins and several carbohydrate-based OGA inhibitors have been synthesized to understand the role of O-GlcNAc-modified proteins in physiological and pathological conditions. However, many of the inhibitors lack selectivity for OGA over lysosomal hexosaminidases A and B. Aiming the selectively inhibition of OGA, we propose herein the synthesis of twelve novel glucopyranoside derivatives exploring the bioisosteric replacement of the GlcNAc 2-acetamide group by 1,4-disubstituted 1,2,3-triazole ring, bearing a variety of central chains with different shapes. Compounds were readily prepared through "Copper(I) Catalyzed Azide/Alkyne Cycloaddition" (CuAAC) reaction between a sugar azide and different terminal alkynes. Initial Western Blot analyses and further inhibitory assays proved that compounds 6a (IC50 = 0.50 +/- 0.02 MUM, OGA), 6k (IC50 = 0.52 +/- 0.01 MUM, OGA) and 6l (IC50 = 0.72 +/- 0.02 MUM, OGA) were the most potent and selective compounds of the series. Structure-activity relationship analyses and molecular docking simulations demonstrated that the bridge of two-carbon atoms between the C-4 position of the triazole and the phenyl ring (6a), which may be replaced by heteroatoms such as N (6k) or O (6l), is fundamental for accommodation and inhibition within OGA catalytic pocket. PMID- 30412833 TI - Symptomatic pulmonary embolism following hip fracture: A nationwide study. AB - INTRODUCTION: This study evaluated the incidence of symptomatic pulmonary embolism (PE), subsequent mortality, risk factors, and the effects of pharmacological thromboprophylactic intervention following hip fracture surgery in Taiwan. MATERIALS AND METHODS: A nationwide study was conducted from February 2004 to September 2013. Hip fracture patients were placed into two groups: without symptomatic PE (control group) and with symptomatic PE (PE group). We analyzed the incidence of and risk factors for symptomatic PE, post-operative mortality rate, and effects of pharmacological thromboprophylactic intervention. RESULTS: We identified 165,748 hip fracture patients. The 3-month cumulative incidence of post-operative symptomatic PE was 0.24% (n = 392). The cumulative 1 , 3-, and 6-month mortality rates were significantly higher in the PE group (16.1%, 23.0%, and 28.6%, respectively) than in the controls (3.3%, 6.7%, and 10.2%, respectively). Increased risk of post-operative symptomatic PE was associated with prior history of PE (adjusted odds ratio [OR], 40.00; 95% CI, 24.75-64.67; P < 0.001), female sex (adjusted OR, 1.33; 95% CI, 1.07-1.65; P = 0.009), older age (>75 years) (adjusted OR, 1.51; 95% CI, 1.20-1.91; P < 0.001), and hemiarthroplasty (adjusted OR, 1.23; 95% CI, 1.01-1.51; P < 0.043). Pharmacological thromboprophylaxis significantly reduced the incidence of post operative PE (adjusted hazard ratio, 4.54; 95% CI, 2.08-9.88; P < 0.001). CONCLUSIONS: The incidence of symptomatic PE after hip fracture surgery was not low in Asian patients, and PE significantly decreased patient survival rates. Some groups were at higher risk for PE; in these instances, thromboprophylaxis, prompt diagnosis, and subsequent intervention are advised. PMID- 30412834 TI - A novel fibrinogen gamma-chain mutation, p.Cys165Arg, causes disruption of the gamma165Cys-Bbeta227Cys disulfide bond and ultimately leads to hypofibrinogenemia. AB - BACKGROUND: Congenital hypofibrinogenemia is a type of hereditary disease characterized by impaired fibrinogen synthesis and/or secretion induced by mutations in the fibrinogen gene. OBJECTIVES: We investigated the phenotypes, genotypes, and pathogenesis of congenital hypofibrinogenemia in an affected family. PATIENTS/METHODS: The proband had a risk of bleeding; therefore, conventional coagulation screening was performed for the proband and her family members. Mutation sites in all exons and flanking sequences of FGA, FGB, and FGG were identified, with matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) performed to indicate the expression of abnormal chains. The effect of the mutation sites on fibrinogen structure and function was predicted by molecular modeling, and purified plasma fibrinogen from the proband was analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis and scanning electron microscopy. Thromboelastography was applied to assess the risk of bleeding and clotting in the proband. RESULTS: Fibrinogen levels in the proband were 1.21 g/L, 1.31 g/L, and 1.38 g/L according to Clauss assay, the prothrombin time method, and enzyme-linked immunosorbent assay, respectively. A novel heterozygous mutation (gammaCys165Arg), a heterozygous mutation (AalphaIle6Val), and two genetic polymorphisms (AalphaThr331Ala and BbetaArg478Lys) in fibrinogen were found in the proband, and MALDI-TOF MS indicated absence of the mutated chain in patient plasma. Additionally, the heterozygous mutation (gammaCys165Arg) displayed substitution of a nonpolar gamma165Cys (low mass) with a positively charged Arg (high mass) along with a small fiber diameter and loose network structure. CONCLUSIONS: Fibrinogen gammaCys165Arg mutations cause damage to the interchain disulfide bonds of fibrinogen and hinder fibrinogen secretion, possibly explaining the pathological mechanism associated with congenital hypofibrinogenemia. PMID- 30412835 TI - Characterization of fibrinogen binding on platelet-derived extracellular vesicles. PMID- 30412836 TI - Thromboelastometry. Reproducibility of duplicate measurement performed by the RoTem(r) device. PMID- 30412837 TI - Amniotic fluid as a potent activator of blood coagulation and platelet aggregation: Study with rotational thromboelastometry. AB - INTRODUCTION: Pulmonary thromboembolism (PTE) is a leading cause of maternal death and frequently occurs during early puerperium. Amniotic fluid components are frequently observed in the maternal circulation in parturition; however, it currently remains unclear whether amniotic fluid contamination in maternal blood is related to the high incidence of PTE in early postpartum. OBJECTIVES: To examine the influence of amniotic fluid on blood coagulation and fibrinolysis systems with thromboelastometry. MATERIALS AND METHODS: Twenty-one pregnant women were recruited. We used whole citrated blood in ROTEM(r) (Tem Innovations GmbH, Munich, Germany), including the non-activated assay (NATEM), assessments for extrinsic (EXTEM) and intrinsic pathways (INTEM), fibrin polymerization (FIBTEM), and hyperfibrinolysis (APTEM), with amniotic fluid contamination, and measured the clotting time (CT), clot formation time (CFT), alpha, amplitude at 10 min (A10), maximum clot firmness (MCF), and lysis indices at 30 min (LI30) and 60 min (LI60). RESULTS: Short CT in all assays as well as short CFT, high alpha, and increased A10 and MCF in NATEM were observed with amniotic fluid contamination. A10 and MCF as well as LI30 and LI60 decreased in EXTEM. Decreased LI60 with the mixture of amniotic fluid was not improved by tranexamic acid in APTEM. CONCLUSIONS: Amniotic fluid accelerated thrombin production and activated platelet aggregation without inducing hyperfibrinolysis in whole blood. The activated tissue factor pathway with amniotic fluid produced soft and fragile clots due to its influence on platelets, which may be associated with, at least partly, the high incidence of PTE in early puerperium, particularly after cesarean section. PMID- 30412838 TI - The characteristic release of noble gases from an underground nuclear explosion. AB - Prompt release of gases at the ground surface resulting from explosively propagated vents or large operational releases has typically been considered to be the only mode of transport for detonation gases from an underground nuclear explosion (UNE) giving rise to detectable levels of radioxenon gases in downwind atmospheric samples captured at distances exceeding 100 km. Using a model for thermally and barometrically driven post-detonation transport across the broad surface of a simulated UNE site, we show in conjunction with the results of an atmospheric tracer-release experiment that even deep, well-contained UNEs, without prompt vents or leaks, are potentially detectable tens of kilometers downwind with current technology; distances that are significant for localizing the source of detected atmospheric signals during on-site monitoring or inspection. For a given yield, the bulk permeability of the UNE site and to a lesser extent the depth of detonation appear to be the primary source-term parameters controlling the distance of detection from the detonation point. We find for test-site bulk permeabilities exceeding 1 darcy (10-12 m2) that broad area surface fluxes of radioxenon gas exhibit exponential dependence on permeability resulting in order-of-magnitude enhancements of surface flux for changes in permeability of only a darcy. Simulations of subsurface transport assuming a canonical detonation-depth-versus-nuclear-yield relationship generally resulted in larger atmospheric signals for shallower, lower-yield explosions allowing downwind detection at distances greater than 1000 km. Additionally, atmospheric simulations suggest that the lowest atmospheric boundary layer heights, such as occur at night, produced concentrations above minimum detectable levels at the greatest distances downwind. PMID- 30412839 TI - Everything is worth when it is close to my body: How spatial proximity and stimulus valence affect visuo-tactile integration. AB - The peripersonal space (PPS) is the space surrounding our body, represented in a multisensory fashion by integrating stimuli of different modalities. Recently, it has been demonstrated that PPS is emotionally connoted, being sensitive to the different affective valence of the stimuli located inside it. However, how visuo tactile interactions can be spatially shaped by intrinsic or acquired valence of stimuli is not clear. To investigate this, we conducted three experiments in which participants performed a visuo-tactile interaction task, while the intrinsic valence (Exp. 1 and 2) or the learned valence (Exp. 3) of visual stimuli was manipulated. Participants were asked to respond as fast as possible to a tactile stimulus that was delivered while a visual stimulus was approaching (Exp.1 and 3) or receding (Exp.2) from the hand. Touch was synchronized with different distances of the visual stimulus from the hand. We found that both the expectancy of stimulus and the distance of the visual one from the hand impact RTs to tactile targets. Crucially, we found that spatial modulation was also influenced by stimulus valence, but only for the approaching and not the receding stimuli. At far distances, neutral stimuli yielded overall slower RTs than intrinsically positive or negative stimuli (Experiment 1), while no modulation was exerted by the level of conditioning (Experiment 3). At near distances, response to touches accompanied by looming neutral stimuli became as fast as that occurring with positive and negative ones. Stimulus valence did not interact with the expectancy of a tactile stimulus (Experiment 2). Overall, these findings support the vision that visuo-tactile interactions can be dynamically modulated by the valence of looming visual stimuli when these are located at longer distances from the body. When closer to it, all stimuli acquire saliency, regardless of their intrinsic or acquired valence, due to their proximity, and then relevance, to the body. Overall, a view of PPS as a gradient modulating visuo-tactile integration, also based on stimulus valence, is discussed. PMID- 30412840 TI - Thinking on your feet: An analysis of movement and cognition in a sit to stand task. AB - The maintenance of upright posture involves constant adjustment to external and internal perturbations. This balancing act is often assumed to be an automatic process, but studies suggest that cognitive processes, particularly attention, are necessary for the control of posture. The current study examines the role of attention in balance using a dual-task paradigm. Twenty-four healthy young adults performed a sit-to-stand (STS) task on either a stable or unstable platform while performing a secondary cognitive task of counting backwards aloud. Movement of the upper and lower body was analyzed using the largest Lyapunov exponent (lambda1) and standard deviation (SD). Results replicated earlier findings (Gibbons, Amazeen, & Likens, 2018) that the transition from sit to stand was marked by increased variability and a temporary destabilization of postural control. Participants exhibited greater movement variability overall on the unstable platform (large SD), but small lambda1 indicated that movement was controlled. During second task performance, SD increased for the upper body only. Further research is necessary to understand the interaction between attention and balance in young adults. PMID- 30412841 TI - Charging of electron beam irradiated amorphous carbon thin films at liquid nitrogen temperature. AB - We studied the charging behavior of an amorphous carbon thin film kept at liquid nitrogen temperature under focused electron-beam irradiation. Negative charging of the thin film is observed. The charging is attributed to a local change in the work function of the thin film induced by electron-stimulated desorption similar to the working principle of the hole free phase plate in its Volta potential implementation at elevated temperature. The negative bias of the irradiated film arises from the electron beam induced desorption of water molecules from the carbon film surface. The lack of positive charging, which is expected for non conductive materials, is explained by a sufficient electrical conductivity of the carbon thin film even at liquid-nitrogen temperature as proven by multi-probe scanning tunneling microscopy and spectroscopy measurements. PMID- 30412842 TI - A continuous sampling pattern design algorithm for atomic force microscopy images. AB - Undersampling is an efficient way to increase the imaging rate of atomic force microscopy (AFM). One major challenge in this approach is retaining the quality of the final images while reducing the amount of measurements enough to have a significant improvement in the imaging time. Clearly, the decision of where to acquire data points plays an important role in producing accurate image reconstructions of the sample surface with the best allocation of measurements depending on the specific sample under study. This work focuses on the development of an algorithm to design continuous non-raster scanning patterns for effective undersampled image acquisition in AFM. We assume the frequency structure of the images to be sampled, and in particular the locations of the large frequency coefficients, is partially known. Based on this knowledge, a two stage algorithm is used to find a continuous scan pattern that minimizes the expected reconstruction error assuming reconstruction is performed using an algorithm known as Simplified Matching Pursuit (SMP). In the first stage, a collection of short, disconnected scan paths is designed to minimize the reconstruction error while in the second, these paths are connected into a continuous trajectory by solving a mixed integer linear program (MILP) that minimizes the total scan length. To demonstrate the performance of the proposed method, we design scanning patterns for four groups of sample surface images from four different materials acquired by AFM. In each case a large sample area is tiled into sixteen sub-images. The first image is raster scanned and the results used to design an optimized scan pattern that is then applied to the remaining 15 tiles. The designed patterns sampled 10-15% of the total pixels (depending on the particular sample) leading to an imaging time that was 15-20% of the time to acquire a full raster of the same area. These results were compared to sub sampling using spiral and Lissajous scan patterns designed to have an equivalent scanning time and to sample a similar percentage of the pixels. The results show that our approach yields significantly better reconstruction quality than either of these alternative scan patterns. Finally, the method was implemented and used to image a calibration grating by sampling 18% of the total pixels, using four different tip speeds. The results were compared to full raster-scans of the sample with tip speeds selected so as to match the imaging time of the non-raster scans, showing that the proposed method produces higher-quality images than raster scanning at these fast image rates. PMID- 30412843 TI - Using CuO-MnOx/AC-H as catalyst for simultaneous removal of Hg degrees and NO from coal-fired flue gas. AB - A series of CuO-MnOx modified catalysts were prepared, and proposed for simultaneous removal of Hg degrees and NO from flue gas. As Mn loading value was 5%, the high value of 90% Hg and 60% NOx were removed efficiently. With gradual increasing of reaction temperature, the mercury removal efficiency (Mercury RE) first increased to 92% then decreased slightly, while NOx removal efficiency (NOx RE) exhibited a trend of continuous increase. O2 had promotional effect on the double pollutants removal, while NH3 had slightly negative effect on Hg degrees removal. As 5% O2 was added into system, the removal efficiency of Hg and NOx rose by 30% and 47%, respectively. Unfortunately, Mercury RE decreased to 90% in the presence of 500 ppm NH3. Overall, superior Mercury RE (>90%) and NOx RE (78%) were performed over 8%CuO-5%MnOx/AC-H at 200 degrees C. XRD results revealed calcination affected catalysts activity by playing a role in active components formation at different temperature. In XPS spectra, new formation of HgO and Hg degrees adsorption on spent catalysts revealed the possible reaction processes that the conversion of CuO and MnO2 on fresh catalyst to other species benefited HgO formation. The removal mechanism might be a combination of Langmuir Hinshelwood and Mars-van-Krevelen mechanism. PMID- 30412844 TI - Changes in atrazine speciation and the degradation pathway in red soil during the vermiremediation process. AB - Atrazine (2-chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine) is a triazine herbicide intensively used in agricultural production and is often detected in different environmental matrices at concentrations above the permitted limit. This study investigated the influence of two earthworm species (epigeic Eisenia foetida and endogeic Amynthas robustus) on atrazine speciation and the degradation pathway. Our results revealed that both earthworms significantly accelerated atrazine degradation in a 28-day vermiremediation, and the residual atrazine declined from 4.23 +/- 0.21 mg/kg in bulk soils to 0.51 +/- 0.29 mg/kg (E. foetida) and 0.43 +/- 0.19 mg/kg (A. robustus). By consuming organic matter (from 40.37 +/- 1.14 to 36.31 +/- 1.55 and 34.59 +/- 1.13 g/kg for E. foetida and A. robustus) and neutralizing the soil pH (from 5.37 +/- 0.27 to 6.36 +/- 0.11 and 6.61 +/- 0.30 for E. foetida and A. robustus), both earthworms reduced humus fixed atrazine and increased the available atrazine. The percentage of available atrazine increased from 8.80 +/- 0.21% in bulk soil to 10.30 +/- 0.29% and 16.42 +/- 0.18% in the vermiremediation treatments. Both earthworms promoted the hydroxyatrazine pathway by consuming soil organic matter and encouraged the deethylatrazine/deisopropylatrazine pathway by neutralizing the soil pH. Our findings unravel a new mechanism of vermiremediation by improving the soil physical-chemical properties and altering the atrazine degradation pathway, providing new insights into the influential factors on atrazine bioremediation in red soil. PMID- 30412845 TI - Bi2Se3 decorated recyclable liquid-exfoliated MoS2 nanosheets: Towards suppress smoke emission and improve mechanical properties of epoxy resin. AB - Bimetallic compounds have been proved superior suppression effect on smoke emission during combustion of polymers. In this work, MoS2/Bi2Se3 (MB) hybrids were prepared by a facile wet chemical method and showed superior performance on smoke suppression of EP matrix during combustion. N-vinyl pyrrolidone (NVP) was employed to exfoliate molybdenum disulfide (MoS2) nanosheets in a recyclable method, which showed high efficiency and was recyclable. Exfoliated MoS2 exhibited large surface area and used as carriers to synthesize MB hybrids. Considering the catalytic effect of bismuth and molybdenum, the hybrids had a great influence on the smoke emission behaviors of EP composites. The smoke production was obviously suppressed during the flaming combustion (more than 22% and 23% decrease obtained from cone calorimeter and steady state tube furnace, respectively) or smolder processes (more than 23% decrease obtained from smoke chamber) at only 1 wt% content of MB hybrids. What's more, due to superior dispersion state, the addition of MB hybrids also enhanced the mechanical properties of EP matrix, including wear resistance and tensile property. This work provided a safe and green exfoliation method of MoS2 to prepare polymers/MoS2 composites and also constructed a novel binary hybrids for enhancing combination performances of polymers. PMID- 30412846 TI - Seeing and sensing single G protein-coupled receptors by atomic force microscopy. AB - G protein-coupled receptors (GPCRs) relay extracellular information across cell membranes through a continuum of conformations that are not always captured in structures. Hence, complementary approaches are required to quantify the physical and chemical properties of the dynamic conformations linking to GPCR function. Atomic force microscopy (AFM)-based high-resolution imaging and force spectroscopy are unique methods to scrutinize GPCRs and to sense their interactions. Here, we exemplify recent AFM-based applications to directly observe the supramolecular assembly of GPCRs in native membranes, to measure the ligand-binding free-energy landscape, and how interactions modulate the structural properties of GPCRs. Common trends in GPCR function are beginning to emerge. We envision that technical developments in combining AFM with superresolution fluorescence imaging will provide insights into how cellular states modulate GPCRs and vice versa. PMID- 30412847 TI - An enhanced fluorescence sensor for specific detection Cys over Hcy/GSH and its bioimaging in living cells. AB - Cysteine (Cys) is not only the central matter of sulfur metabolism in cells but also the only amino acid with reduced thiol group in 20 kinds of natural amino acids. In animal cells, Cys is taking part in many important and essential biological functions including protein synthesis, detoxification and metabolism. The development and application of fluorescent probes for the detection of Cys have attracted more and more attention and interest. Herein, we report a new fluorescent probe NFA that utilized naphthyl carboxy fluorescein as fluorophore and acryloyl group as reaction site for Cys specific detection. The probe essentially has weak fluorescence. Cys addition to NFA containing system induced distinct enhanced fluorescence emission which was attributed to the nucleophilic reaction of cysteine and acryloyl to release the fluorophore. The signal fluorescent response detection system allows NFA to be a reliable tool for Cys detection with low detection limit (0.58 MUM). And NFA has been successfully applied for Cys imaging specifically in live Hela cells, which promotes the probe as a potential tool to understand the pathology of Cys related diseases. PMID- 30412848 TI - The nature of photoinduced intermolecular charger transfer in fluorescence resonance energy transfer. AB - In this paper, we report time resolved fluorescence resonance energy transfer (FRET) using femtosecond ultrafast transient absorption spectroscopy. The lifetimes of FRET are strongly dependent on the molecular concentration and ratio of donor and acceptor. Also, in the FRET, photoinduced intermolecular charge transfer (PICT) is also investigated theoretically. The driving force for PICT in FRET system equals the reorganization energy, which gives barrier-less charge transfer according to Marcus theory. The rates of PICT in the FRET system can be estimated with our simplified Marcus equation. Our results of PICT in FRET system provide a new efficient way for the charge transfer in donor-acceptor system. PMID- 30412849 TI - Improving photosynthesis, plant productivity and abiotic stress tolerance - current trends and future perspectives. AB - With unfavourable climate changes and an increasing global population, there is a great need for more productive and stress-tolerant crops. As traditional methods of crop improvement have probably reached their limits, a further increase in the productivity of crops is expected to be possible using genetic engineering. The number of potential genes and metabolic pathways, which when genetically modified could result in improved photosynthesis and biomass production, is multiple. Photosynthesis, as the only source of carbon required for the growth and development of plants, attracts much attention is this respect, especially the question concerning how to improve CO2 fixation and limit photorespiration. The most promising direction for increasing CO2 assimilation is implementating carbon concentrating mechanisms found in cyanobacteria and algae into crop plants, while hitherto performed experiments on improving the CO2 fixation versus oxygenation reaction catalyzed by Rubisco are less encouraging. On the other hand, introducing the C4 pathway into C3 plants is a very difficult challenge. Among other points of interest for increased biomass production is engineering of metabolic regulation, certain proteins, nucleic acids or phytohormones. In this respect, enhanced sucrose synthesis, assimilate translocation to sink organs and starch synthesis is crucial, as is genetic engineering of the phytohormone metabolism. As abiotic stress tolerance is one of the key factors determining crop productivity, extensive studies are being undertaken to develop transgenic plants characterized by elevated stress resistance. This can be accomplished due to elevated synthesis of antioxidants, osmoprotectants and protective proteins. Among other promising targets for the genetic engineering of plants with elevated stress resistance are transcription factors that play a key role in abiotic stress responses of plants. In this review, most of the approaches to improving the productivity of plants that are potentially promising and have already been undertaken are described. In addition to this, the limitations faced, potential challenges and possibilities regarding future research are discussed. PMID- 30412850 TI - Comparative transcriptional analysis and RNA interference reveal immunoregulatory pathways involved in growth of the oriental river prawn Macrobrachium nipponense. AB - A source of premium animal protein, crustaceans are widely distributed and cultivated around the world. Short-term or long-term starvation events occur frequently owing to natural environment changes or manual management strategies in the life cycle of crustaceans. The result induced by starvation is that somatic growth of crustaceans will be retarded, while the immune mechanism is activated in this process. The aim of this study was to investigate whether the immune regulatory pathways are involved in the growth of crustaceans. Twelve muscle tissue transcriptomes of the oriental river prawn Macrobrachium nipponense were sequenced across four fasting stages lasting 0, 7, 14 and 21 d. The results showed that three immune-related pathways were involved in the growth of M. nipponense by regulating actin expression inducing the chemokine signaling pathway, the leukocyte transendothelial migration pathway and the FcR-mediated phagocytosis pathway. Furthermore, we employed RNA interference (RNAi) to further verify the effects that genes involved in the pathways had on regulating growth of M. nipponense. Comparative transcriptional analysis and RNA interference reveal that VASP and WAVE positively regulated the expression of actin; however, WASP negatively regulated the expression of actin. This is the first report that the immune regulatory pathways play key roles in the growth of crustaceans. Our results will not only provide an entirely new understanding of the immune mechanism of crustaceans from a unique angle but also further enrich and develop the theory of growth and developmental biology in crustaceans. PMID- 30412851 TI - Wogonin mitigates intervertebral disc degeneration through the Nrf2/ARE and MAPK signaling pathways. AB - Intervertebral disc degeneration (IVDD) is a prevalent disease characterized by the progressive loss of the extracellular matrix in the local nucleus pulposus region. Metalloproteinases and pro-inflammatory cytokines play an important role in this process. Thus, anti-inflammatory strategies are an important component of IVDD treatment. Wogonin, a naturally existing monoflavonoid, has been reported to have potential anti-inflammatory effects in some inflammatory diseases. Hence, in our present study we investigated the protective effects and potential mechanisms of wogonin in rat nucleus pulposus cells that had been treated with interleukin 1beta (IL-1beta) to induce severe IVDD. An in vivo rat caudal vertebrae needle stab model was also designed and its validity was evaluated as an IVDD model. The results demonstrated that wogonin suppressed IL-1beta-induced inflammatory mediators (iNOS, IL-6 and COX2) and matrix-degrading proteinases (MMP1, MMP3, MMP13 and ADAMTS4). Wogonin also upregulated some of the key components of the extracellular matrix, such as collagen II. Furthermore, we discovered that wogonin exerted anti-inflammatory effects by activating the Nrf2/HO-1-SOD2-NQO1 GCLC signaling axis. Moreover, the IL-1beta-induced stimulation of the MAPK signaling pathway was reversed by wogonin treatment. The in vivo MRI and histological results also revealed that wogonin protected the nucleus pulposus from the progression of IVDD. Therefore, wogonin may be a potential agent for the treatment of IVDD. PMID- 30412852 TI - The renin-angiotensin system in the synovium promotes periarticular osteopenia in a rat model of collagen-induced arthritis. AB - Periarticular osteopenia is the most specific hallmark of rheumatoid arthritis (RA). The renin-angiotensin system (RAS) in the synovium has been found to participate in the pathogenic process of RA. This study examined whether and how RAS regulates periarticular osteopenia in RA. The synovial tissues from patients with RA and osteoarthritis (OA) were prepared. Female Sprague-Dawley rats were treated with either saline, bovine type II collagen (CII) to induce arthritis (CIA), or CII combined with perindopril, an inhibitor of angiotensin-converting enzyme (ACE). Expressions of RAS components, including AT1R, AT2R and ACE, in human and rat synovial tissues were detected. Bone mass of rat joints was examined. Levels of RANKL, OPG and DKK-1 in rat synovium and expressions of TRAF6 and beta-catenin in rat bone were examined. The results showed that AT1R, AT2R and ACE in human and rat synovium were up-regulated, but the increased ACE in rat synovial tissues was abrogated by perindopril. While CIA rats displayed increased bone resorption and decreased bone formation, perindopril treatment almost completely abrogated the RAS-mediated osteopenia, indicating that inhibition of ACE reduced the joint damages in rats. The expressions of RANKL and DKK-1 increased in CIA rats as compared with those in the control; TRAF6 was up regulated and beta-catenin was down-regulated in the bone tissues of CIA rats. The changes were then reversed by the use of perindopril. Our findings demonstrate that RAS in the synovium promotes periarticular osteopenia by increasing bone resorption and decreasing bone formation through modulating the RANKL/RANK/TRAF6 and Wnt/beta-catenin pathways. PMID- 30412853 TI - Corrigendum to "Alpha-Mangostin suppresses interleukin-1beta-induced apoptosis in rat chondrocytes by inhibiting the NF-kappaB signaling pathway and delays the progression of osteoarthritis in a rat model" [Int. Immunopharmacol. 52 (2017) 156-162]. PMID- 30412854 TI - Scenes enable a sense of reliving: Implications for autobiographical memory. AB - Autobiographical memory has been defined by the phenomenological properties of reliving, vividness, and belief that an event occurred. Neuropsychological damage that results in the inability to recall the layout of a scene also results in amnesia suggesting a possible milder effect in people without such neurological damage. Based on this and other observations, we hypothesized that the degree to which the layout of a scene is recalled will correlate positively with ratings of reliving, vividness, and belief, and will explain more variance in multiple regressions than recalling the scene's contents. We also hypothesized that a lack of layout underlies nonspecific autobiographical memories which are common in aging, future events, and clinical disorders, whereas currently such memories are most commonly measured by reports of extended duration. We tested these theory driven novel hypotheses in three studies to replicate our results. In each study, approximately 200 participants rated the layout, content, and other properties of personal events. Correlational analyses in each study and a structural equation model for the combined studies provide strong support for the role of mental scene construction in an integrative neurocognitive approach to clarify cognitive theory and clinical phenomena. PMID- 30412855 TI - Green synthesis of manganese nanoparticles: Applications and future perspective-A review. AB - Nanobiotechnology is a promising and appearing field of nanotechnology. In recent years, the necessity of making biocompatible materials for different applications in various area such as health, medicine, water treatment and purification, etc. caused more attention to this area. Today, green synthesis of different nanoparticles (NPs) has been extensively studied. However, less attention has been paid to manganese as a high-performance metal in various applications such as medicine, biomedicine, biosensors, water treatment and purification, electronics, electrochemistry, photoelectronics, catalysis, and etc. Manganese oxides (Mn-oxides) has wealthy structures such as MnO, Mn5O8, Mn2O3, MnO2, and Mn3O4, and can be used in a variety of fields. Mn-oxide NPs potentially hold great promise for sustainable nanotechnology. This review focusses on the green synthesis, applications and future perspective of Mn NPs. Different methods of green synthesis of Mn NPs, including synthesis using plant extract, synthesis using microorganism, and low-temperature synthesis of Mn NPs have been investigated and presented. Structure, and size, of green synthesized Mn NPs via each method have been compared. Also, various applications of the green synthesized Mn NPs have been reviewed. Furthermore, the future perspective of green synthesis and applications of the green synthesized Mn NPs are expressed. Also, different applications explained for green synthesized Mn NPs are expressed as well as potential applications for green synthesized Mn NPs are suggested. PMID- 30412856 TI - The associations between prenatal exposure to triclocarban, phenols and parabens with gestational age and birth weight in northern Puerto Rico. AB - BACKGROUND: Prenatal exposure to certain xenobiotics has been associated with adverse birth outcomes. We examined the associations of triclocarban, phenols and parabens in a cohort of 922 pregnant women in Puerto Rico, the Puerto Rico Testsite for Exploring Contamination Threats Program (PROTECT). METHODS: Urinary triclocarban, phenols and parabens were measured at three time points in pregnancy (visit 1: 16-20 weeks, visit 2: 20-24 weeks, visit 3: 24-28 weeks gestation). Multiple linear regression (MLR) models were conducted to regress gestational age and birthweight z-scores against each woman's log average concentrations of exposure biomarkers. Logistic regression models were conducted to calculate odds of preterm birth, small or large for gestational age (SGA and LGA) in association with each of the exposure biomarkers. An interaction term between the average urinary biomarker concentration and infant sex was included in models to identify effect modification. The results were additionally stratified by study visit to look for windows of vulnerability. Results were transformed into the change in the birth outcome for an inter-quartile-range difference in biomarker concentration (Delta). RESULTS: Average benzophenone-3, methyl- and propyl-paraben concentrations were associated with an increase in gestational age [(Delta 1.90 days; 95% CI: 0.54, 3.26); (Delta 1.63; 95% CI: 0.37, 2.89); (Delta 2.06; 95% CI: 0.63, 3.48), respectively]. Triclocarban was associated with a suggestive 2-day decrease in gestational age (Delta - 1.96; 95% CI: -4.11, 0.19). Bisphenol A measured at visit 1 was associated with a suggestive increase in gestational age (Delta 1.37; 95% CI: -0.05, 2.79). Triclosan was positively associated with gestational age among males, and negatively associated with gestational age among females. Methyl-, butyl- and propyl-paraben were associated with significant 0.50-0.66 decreased odds of SGA. BPS was associated with an increase in the odds of SGA at visit 3, and a suggestive increase in the odds of LGA at visit 1. CONCLUSION: Benzophenone-3, methyl-paraben and propyl-paraben were associated with an increase in gestational age. Concentrations of triclocarban, which were much higher than reported in other populations, were associated with a suggestive decrease in gestational age. The direction of the association between triclosan and gestational age differed by infant sex. Parabens were associated with a decrease in SGA, and BPS was associated with both SGA and LGA depending on the study visit. Further studies are required to substantiate these findings. PMID- 30412857 TI - The DEK Oncoprotein Functions in Ovarian Cancer Growth and Survival. AB - DNA damage repair alterations play a critical role in ovarian cancer tumorigenesis. Mechanistic drivers of the DNA damage response consequently present opportunities for therapeutic targeting. The chromatin-binding DEK oncoprotein functions in DNA double-strand break repair. We therefore sought to determine the role of DEK in epithelial ovarian cancer. DEK is overexpressed in both primary epithelial ovarian cancers and ovarian cancer cell lines. To assess the impact of DEK expression levels on cell growth, small interfering RNA and short hairpin RNA approaches were utilized. Decreasing DEK expression in ovarian cancer cell lines slows cell growth and induces apoptosis and DNA damage. The biologic effects of DEK depletion are enhanced with concurrent chemotherapy treatment. The in vitro effects of DEK knockdown are reproduced in vivo, as DEK depletion in a mouse xenograft model results in slower tumor growth and smaller tumors compared to tumors expressing DEK. These findings provide a compelling rationale to target the DEK oncoprotein and its pathways as a therapeutic strategy for treating epithelial ovarian cancer. PMID- 30412858 TI - Clinical Validation of Newly Developed Multiplex Kit Using Luminex xMAP Technology for Detecting Simultaneous RAS and BRAF Mutations in Colorectal Cancer: Results of the RASKET-B Study. AB - Detection of RAS and BRAF mutations is essential to determine the optimal treatment strategy for metastatic colorectal cancer (CRC). We prospectively evaluated the MEBGEN RASKET-B KIT (RASKET-B), a novel multiplex kit, simultaneously detecting 48 types of RAS mutations and the BRAF V600E mutation using Luminex xMAP technology. The aim was to obtain market approval for RASKET-B as an in vitro diagnostic (IVD) option in Japan. Genomic DNA was extracted from 302 formalin-fixed paraffin-embedded tissues obtained from CRC patients. The primary endpoints were the concordance rate (CR) between the results from RASKET B and the previously approved IVD kit (RASKET) for RAS mutations, and CR between the results from RASKET-B and direct sequencing (DS) for BRAF mutations. The secondary endpoints included the CR between RASKET-B and DS for RAS mutations and between RASKET-B and the pyrosequencing (PYRO) for the BRAF V600E mutation. Among the 302 samples, 142 RAS mutations (47%) and 18 BRAF V600E mutations (6.0%) were detected by RASKET-B. All mutations detected in the recruited patients were mutually exclusive. Both RAS and BRAF mutation rates were statistically higher in right-sided than left-sided CRC. The CR between RASKET-B and RASKET for RAS gene and RASKET-B and DS for BRAF V600E mutation was 100% for both (95% CI: 99%-100%). The results from RASKET-B were also highly concordant with DS for RAS (97.4%) and with PYRO for the BRAF (V600E) gene (99.7%). RASKET-B thus provides rapid, precise, and simultaneous detection of RAS and BRAF mutations in CRC. PMID- 30412859 TI - Development of disease and immunity at the genital epithelium following intrarectal inoculation of male guinea pigs with herpes simplex virus type 2. AB - Most analyses of genital immunity to herpes simplex virus type 2 (HSV-2) have been performed in females, consequently immune protection of the male genital epithelium is incompletely understood. We developed a model of male genital HSV-2 infection resulting from intrarectal inoculation of guinea pigs. Vesicular lesions developed transiently on the perineum and foreskin concurrent with acute virus shedding. Virus shedding and recurrent genital lesions were also detected after establishment of a latent infection. Analysis of perineum and foreskin RNA detected transcripts for IFNgamma, proinflammatory and regulatory cytokines, and for genes involved in migration and regulation of leukocytes. HSV-specific T cells were detected in lymphoid and genital tissues after resolution of the primary infection whereas virus-specific antibody secreting cells were detected only in lymphoid tissue. Taken together, the ability to quantify pathogenesis and local immunity in this guinea pig model represent an important advance towards understanding immunity to HSV-2 in males. PMID- 30412861 TI - Protective role of l-glutamic acid and l-cysteine in mitigation the chlorpyrifos induced oxidative stress in rats. AB - Exposure to the organophosphorus insecticide chlorpyrifos (CPF) can lead to oxidative stress. The aim of this work was to investigate and compare the protective effects of amino acids (l-glutamic acid (l-Glu) and l-cysteine (L-Cys) alone or in combination) for the purpose of suppression and mitigation of CPF induced oxidative stress in rats. Rats were divided into five groups: CPF, CPF/L Glu, CPF/L-Glu and l-Cys, CPF/L-Cys, control. The level of GSH and the activities of glutathione-related enzymes were determined. The content of lipid peroxidation products was also monitored. The obtained results suggest that level of GSH and activity of GSH-related enzymes was significantly inhibited by CPF. l-Glu and l Cys were able to prevent CPF-induced oxidative stress. In rats treated with amino acids, we observed less significant or no changes in studied parameters. It was established that the above-mentioned amino acids, administered alone and in their combination, can mitigate and suppress CPF-induced oxidative stress. The most significant mitigation effect was found in rats treated with l-Glu only. PMID- 30412860 TI - Suicidal ideation and behaviors among women veterans with recent exposure to intimate partner violence. AB - OBJECTIVE: Women veterans have disproportionately high risk for both suicide and intimate partner violence compared to women non-veterans. The objective of this study was to assess the relationship between intimate partner violence (IPV) and suicidal ideation and suicidal or self-harm behaviors among women veterans. METHOD: Veterans Health Administration (VHA) electronic medical records were extracted for 8427 women veterans who completed screening for past-year IPV between April 2014 and 2016. Risk for suicidal ideation and self-harm behaviors were estimated as function of screening results using logistic regression. RESULTS: Overall, 8.4% screened positive for IPV. Suicidal ideation or self-harm behaviors were recorded for 3.2%. Positive IPV screen was associated with double the odds for suicidal ideation (AOR = 2.04; 95% CI = 1.47-2.86) and self-harm behaviors (AOR = 2.05, 95% CI = 1.10-3.83). Risks did not significantly differ by IPV type. Suicide-related ICD codes were most often recorded prior to IPV screening. CONCLUSIONS: There is a strong association between positive IPV screen and suicidal ideation and self-harm behaviors among VHA-engaged women veterans. Documentation of either event is an important marker for the other. Integration of suicide prevention with IPV services may enhance identification of women at risk and speed service uptake. Suicidal ideation and behaviors should be assessed among women with positive IPV screens, and identification of suicide risk should trigger IPV assessment. PMID- 30412862 TI - Microplastic in marine organism: Environmental and toxicological effects. AB - Microplastics are tiny ubiquitous plastic particles present in marine environments. They are not an individual entity, but constitute a cocktail of polymers and additives that can absorb substances from the surrounding environment, including living substances, nutrients and marine pollutants. Given their small size (< 5 MUm), microplastics can be ingested by a wide range of marine organisms with the potential to cause harms. Microplastics are a growing threat for marine biota and ecosystem. For organisms, the risks associated with microplastic ingestion are not only due to the material itself, but also to its ability to absorb and concentrate environmental contaminants in seawater and subsequently transfer them through food chains. Moreover, microplastics could influence ecological processes. Recently, plastic debris are recognized as emerging pollutants and represent a great risk for marine biodiversity worldwide. Here, we summarize the main effects of plastics and microplastics on some marine organisms and ecosystem. PMID- 30412863 TI - MMP-3 and MMP-8 in rat mandibular condylar cartilage associated with dietary loading, estrogen level, and aging. AB - OBJECTIVES: The structure of the mandibular condylar cartilage (MCC) is regulated by dynamic and multifactorial processes. The aim of this study was to examine the effects of altered dietary loading, estrogen level, and aging on the structure of the condylar cartilage and the expressions of matrix metalloproteinase (MMP) -3 and MMP-8 of rat MCC. METHODS: In this study, Crl:CD (SD) female rats were randomly divided into 3 groups according to dietary hardness: hard diet (diet board), normal diet (pellet), and soft diet (powder). In each group, the rats were further divided into 2 subgroups by ovariectomy at the age of 7 weeks. The rats were sacrificed at 5- and 14-month-old. Histomorphometric analysis of the MCC thickness was performed after toluidine blue staining. Immunochemical staining was done for MMP-3 and MMP-8. A linear mixed model was used to assess the effects of dietary loading, estrogen level, and aging. RESULTS: Increased dietary loading was the main factor to increase the MMP-3 expression and the anterior and central thickness of the MCC. Lack of estrogen was the main factor associated with decreased MMP-8. Aging was associated with the thickness changes of the whole condylar cartilage and the reduced expression of MMP-8. CONCLUSION: The condylar cartilage structure and metabolism of the female rats are sensitive to dietary loading changes, estrogen level as well as aging. The proper balance of these factors seems to be essential for the maintenance of the condylar cartilage. PMID- 30412865 TI - Evaluation of the 2016 ENV57 MetroERM measurement comparison on 137Cs, 134Cs and 131I in air filters. AB - In 2016, the European Commission's Joint Research Centre organised an interlaboratory comparison exercise on the measurement of 137Cs, 134Cs and 131I in air filters. The exercise was conducted in the frame of the MetroERM EMRP project with code ENV57. This paper describes the context of the interlaboratory measurement comparison, the technical implementation, the air filter measurements performed by the participating laboratories and finally the evaluation of the comparison results. The intercomparison exercise results are such that 56 out of the 67 laboratories (i.e. 84%) reported values within the +/-20% range of the reference value for both the 137Cs and 134Cs. The evaluation of the performance of the laboratories on 131I was complicated and the details are explained. Nevertheless, 20 (30%) laboratories reported results for 131I with a percentage difference from the reference value within the +/-20% range. PMID- 30412864 TI - Antibiofilm efficacy of curcumin in combination with 2-aminobenzimidazole against single- and mixed-species biofilms of Candida albicans and Staphylococcus aureus. AB - Mixed fungal and bacterial biofilm associated infections of implants have been a huge challenge in health care because of the increased resistance to antimicrobials and the critical biological differences between fungi and bacteria. In this study, we evaluated the 2-aminobenzimidazole (2ABI) and curcumin (CUR) alone to inhibit planktonic cell growth, adhesion as well as single and mixed species biofilms of Candida albicans and Staphylococcus aureus on silicone. The combined effects between 2ABI and CUR on mixed species biofilm formation and pre-formed biofilm were assessed. Our work showed that 2ABI or CUR alone was effective as a sole agent, inhibiting planktonic growth, adhesion and the biofilm formation of bacteria and fungi on the silicone surface. The combination of 2ABI and CUR exhibited the enhanced effect on mixed biofilm compared to mono-drug therapy. The biofilm architecture was investigated by scanning electron microscopy (SEM) and the distinction of living/dead organisms within biofilm was examined by confocal laser scanning microscopy (CLSM). The combination activity was most potent on mixed biofilm. These results suggest the potential applicability of 2ABI and CUR to treatment of biofilm related device infections. PMID- 30412866 TI - Domestic-setting corpses, an urban problem? AB - This study describes the domestic-setting corpses that remain unnoticed for two weeks or more. It compares the occurrence of this phenomenon in the city of Amsterdam with the surrounding municipalities of Amsterdam (SMA). Data of 437 cases were extracted from the forensic medical register of Amsterdam. Data of size and household situation of the population were extracted from Statistics Netherlands. A 3.7 (95%CI 2.8-4.9) times higher incidence rate, was observed in the city of Amsterdam (n = 379; 5.3/100,000 personyears) compared to the SMA (n = 58; 1.4/100,000 personyears). All but three cases lived alone. After limiting both cases and reference data to single households, the crude rate ratio was 2.1 (95%CI 1.6-2.7). Further adjustment for age and gender resulted in a Standardized Mortality Ratio of 0.36 (95%CI 0.28-0.47). This means the occurrence of domestic setting corpses (14 + days) among people living alone is 2.7 times higher in the city of Amsterdam (95%CI 2.1-3.5). We conclude domestic-setting corpses are more likely to occur in an urban environment. This is partly explained by the higher proportion of single households in the city compared to the more rural areas. However, differences in social cohesion and architecture between urban and rural areas are expected to be important too. PMID- 30412867 TI - Intrusion of chlorinated hydrocarbons and their degradation products from contaminated soil. Measurement of indoor air quality and biomonitoring by analysis of end-exhaled air. AB - A historic soil contamination of chlorinated hydrocarbons from a former dry cleaning shop caused intrusion of vapors into a building currently used as bookshop. The aim of this study was to determine the indoor air quality and the uptake of soil contaminants and their degradation products. Samples of indoor air were collected over one week in the warm and one week in the cold season. Pre shift and post-shift samples of end-exhaled air were collected from two employees. Chlorinated hydrocarbons were analyzed in indoor air and exhaled air samples using thermal desorption gas chromatography mass spectrometry (TD-GC-MS). Tetrachloroethylene (PER), and its degradation products trichloroethylene (TRI), 1,1-dichloroethylene (1,1-DCE), 1,2-cis-dichloroethylene (1,2-cis-DCE), 1,2-trans dichloroethylene (1,2-trans-DCE), methylene chloride (MC) and vinyl chloride (VC) were determined in ambient air. PER was the prime contaminant with a week average (+/-sd) of 805.2 +/- 598.6 MUg/m3 in June 2016 and 1031 +/- 499.3 MUg/m3 in December 2017. MC, 1,2-cis-DCE and TRI were detected at concentrations below 2.3 MUg/m3. 1,1-DCE and VC were not detected. In exhaled air PER, 1,1-DCE, and MC were detected in both June and December, whereas TRI, 1,2-cis-DCE and 1,2-trans DCE were only detected on one or two days in the cold season. VC was not detected in exhaled air. For PER, the mean concentrations (+/-sd) in end-exhaled air increased from a five days (Mon-Fri) average pre-shift value of 22.2 +/- 8.0 to a post-shift value of 52.6 +/- 15.5 ng/L in the male shop owner (p < 0.01) and in the female cashier these values were 26.0 +/- 3.6 and 63.6 +/- 12.7 ng/L, respectively (p < 0.01). Intrusion of chlorinated soil contaminants resulted in contamination of indoor air above the current accepted indoor air level for PER of 250 MUg/m3. For PER in end-exhaled air an accumulation over the workweek was not observed. PMID- 30412868 TI - Spartina alterniflora invasion alters soil bacterial communities and enhances soil N2O emissions by stimulating soil denitrification in mangrove wetland. AB - Chinese mangrove, an important ecosystem in coastal wetlands, is sensitive to the invasive alien species Spartina alterniflora. However, the effects of the S. alterniflora invasion on mangrove soil N2O emissions and the underlying mechanisms by which emissions are affected have not been well studied. In this study, the N2O emitted from soils dominated by two typical native mangroves (i.e. Kandelia obovata: KO; Avicennia marina: AM), one invaded by S. alterniflora (SA), and one bare mudflat (Mud) were monitored at Zhangjiang Mangrove Estuary (where S. alterniflora is exotic). Together with soil biogeochemical properties, the potential denitrification rate and the composition of soil bacterial communities were determined simultaneously by 15NO3- tracer and high-throughput sequencing techniques, respectively. Our results showed that S. alterniflora invasion significantly (p < 0.05) increases soil N2O emissions by 15-28-fold. In addition, isotope results revealed that the soil potential denitrification rate was significantly (p < 0.05) enhanced after S. alterniflora invasion. Moreover, the S. alterniflora invasion significantly (p < 0.05) decreased soil bacterial alpha diversity and strongly modified soil bacterial communities. Indicator groups strongly associated with S. alterniflora were Chloroflexia, Alphaproteobacteria, and Bacilli, each of which was abundant and acts as connector in the co occurrence network. FAPROTAX analysis implied that the S. alterniflora invasion stimulated soil denitrification and nitrification while depressing anaerobic ammonium oxidation (anammox) and dissimilatory nitrate reduction to ammonium (DNRA). Redundancy analysis (RDA) found that soil organic matter (SOM) and pH were the most important environmental factors in altering soil bacterial communities. Taken together, our results imply that the S. alterniflora invasion in mangrove wetlands significantly stimulates soil denitrification and N2O emissions, thereby contributing N2O to the atmosphere and contributing to global climate change. PMID- 30412869 TI - Water scarcity alleviation through water footprint reduction in agriculture: The effect of soil mulching and drip irrigation. AB - Water scarcity has received global attention in the last decade as it challenges food security in arid and semi-arid regions, particularly in the Middle East and North Africa. This research assesses the possible alleviation of water scarcity by reducing the water footprint in crop production through the application of soil mulching and drip irrigation. The study is the first to do so at catchment scale, taking into account various crops, multi-cropping, cropping patterns, and spatial differences in climate, soil, and field management factors, using field survey and local data. The AquaCrop-OS model and the global water footprint assessment (WFA) standard were used to assess the green and blue water footprint (WF) of ten major crops in the Upper Litani Basin (ULB) in Lebanon. The blue water saving and blue water scarcity reduction under these two alternative practices were compared to the current situation. The results show that the WF of crop production is more sensitive to climate than soil type. The annual blue WF of summer crops was largest when water availability was lowest. Mulching reduced the blue WF by 3.6% and mulching combined with drip irrigation reduced it by 4.7%. The blue water saving from mulching was estimated about 6.3 million m3/y and from mulching combined with drip irrigation about 8.3 million m3/y. This is substantial but by far not sufficient to reduce the overall blue WF in summer to a sustainable level at catchment scale. PMID- 30412870 TI - Fungal aerosols at dairy farms using molecular and culture techniques. AB - Occupational exposure to harmful bioaerosols in industrial environments is a real threat to the workers. In particular, dairy-farm workers are exposed to high levels of fungal bioaerosols on a daily basis. Associating bioaerosol exposure and health problems is challenging and adequate exposure monitoring is a top priority for aerosol scientists. Using only culture-based tools does not express the overall microbial diversity and underestimate the large spectrum of microbes in bioaerosols and therefore the extended fungal profile that farmers are exposed to. The aim of this study was to provide an in-depth characterization of fungal exposure at Eastern Canadian dairy farms using qPCR and high-throughput sequencing methods. Specific primers were used for the quantification of Penicillium/Aspergillus and Aspergillus fumigatus in dairy farms air samples. Illumina Miseq sequencing of the ITS1 region provided sequences for the diversity analyses. The minimum and maximum concentration of Penicillium/Aspergillus ranged from 4.6 * 106 to 9.4 * 106 gene copies/m3 and from 1 * 104 gene copies/m3 to 4.8 * 105 gene copies/m3 for Aspergillus fumigatus, respectively. Differences in the diversity profiles of the five dairy farms support the idea that the novel approach identifies a large number of fungal taxa. The most striking differences include Microascus, Piptoporus, Parastagonospora, Dissoconium, Microdochium, Tubilicrinis, Ganoderma, Ustilago, Phlebia and Wickerhamomyces. The presence of a diverse portrait of fungi in air may represent a health risk for workers who are exposed on a daily basis. The broad spectrum of fungi detected in this study includes many known pathogens like Aspergillus, Acremonium, Alternaria and Fusarium. Adequate monitoring of bioaerosol exposure is necessary to evaluate and minimize risks. PMID- 30412871 TI - Nanosorbent of hydroxyapatite for atrazine: A new approach for combating agricultural runoffs. AB - The attention of current work was on the fabrication of effective nanoadsorbent of hydroxyapatite (HAp) for the controlled release of atrazine (ATZ) formulation. The ATZ-HAp complex (ATZ@HAp) was able to inhibit the growth of Brassica sp. under in situ conditions. This developed methodology aspires to cease the agricultural runoffs of ATZ applied with the HAp adjuvant and ensure their effective functioning. The efficacy of the protocol was mainly accomplished by adsorbing ATZ over the surface of HAp NPs that restricted its premature runoff and promoted the prolonged herbicidal efficiency. The influence of fundamental parameters i.e., HAp dose, ATZ dose and initial pH on the adsorption process was investigated systematically. The suitability of ATZ@HAp complex for real world application was adjudged after proofing its toxicological behaviour and its role in Zea mays plantations. The complex was found to be non-toxic and nurturing due to its phosphate rich nature. Further investigations of ATZ@HAp complex and its effect on the non-target species will help in establishing an effective framework for their commercial use in agricultural practices. PMID- 30412872 TI - Gut microbiota dysbiosis correlates with a low-dose PCB126-induced dyslipidemia and non-alcoholic fatty liver disease. AB - There is growing evidence that polychlorinated biphenyl 126 (PCB126) not only has adverse effects on host health but also has the ability to shift gut microbiota, which is recently recognized as a crucial factor determining numerous physiological processes. However, the interplay between the gut microbiota and host health remains largely unknown. Herein, adult female C57BL/6 mice were orally exposed to environmentally relevant low-dose of PCB126, at 50 MUg/kg body weight once per week for 6 weeks. This study aims to illuminate how PCB126 influences gut microbiota variations and host disorders and to further identify the correlation between the gut microbiota and metabolic markers of host disorders. Obtained results demonstrated that the PCB126 administration induced gut microbiota dysbiosis in mice, with changes both in the gut microbiota constitution and structure. PCB126 administration also simultaneously altered the physiological status of serum and liver, as evaluated by dyslipidemia, liver lipid accumulation and injury, and non-alcoholic fatty liver disease. Importantly, Spearman's correlation analysis suggested that several specific bacterial taxa were positively and significantly related to metabolic markers of the mentioned disorders. Moreover, based on the co-occurrence network map, some of the bacterial taxa may synergistically regulate host physiology. This work provides new insight into the mechanism underlying the interaction between the gut microbiota and host disorders. It is expected that gut microbiota modulation should be another novel way used for the prevention and treatment of PCB126 triggered diseases. PMID- 30412873 TI - Dynamic projection of ecological risk in the Manas River basin based on terrain gradients. AB - With large-scale developments, the Manas River Basin (MRB) is in an extreme imbalance especially in land use, thus causing a series of ecological problems. A reliable dynamic ecological risk assessment is expected to provide useful information for the economic development. Through coupling spatial Cellular Automaton-Markov (CA-Markov) model and Landsat satellite images in 2000, 2008 and 2016, we forecasted the land use maps in 2024 and 2032. Based on the ecological risk model, we evaluated the ecological risk at landscape level from 2000 to 2032. More importantly, an improved evaluation of ecological risk was proposed based on terrain gradients and the correlation between terrain niche index (TNI) and future ecological risk was analyzed. The results showed that the artificial oases and urban are expanding, while the natural grassland is shrinking. Corresponding to the rapid development stage and stable consolidation stage, farmland will be followed by a slower increase (2016-2032) after a rapid increase (2000-2016), and water decreases first but then is projected to recover. As the overall spatial diversity increasing, the ecological risk in the whole basin is growing, especially in grassland. Compared with the stable critical state in artificial landscape, the future ecological risks in natural landscape tend to increase due to the cumulative effects of human activities. Also, we found that the great ecological risk mainly happens in "high altitude and complex terrain" or "low altitude and flat terrain" areas. The future ecological risk in medium terrain niche index (TNI) gradient will increase, while it will decrease in the lowest. Above all, the proposed framework can do well in forecasting ecological risk at landscape level, and can help simply infer the changes of ecological risk based on terrain. PMID- 30412874 TI - Delineating the plastic waste status in the State of Qatar: Potential opportunities, recovery and recycling routes. AB - The Qatar's national vision (QNV2030) underlines an unequivocal commitment to maintaining harmony between the three inter-dependent pillars of sustainable development: economic growth, social development and environmental management. Nonetheless, it seems that the country is set on a trajectory of unparalleled and rapid development that most waste management and environmental experts would, possibly, characterise as unsustainable; in addition it seems to repeat many of the "errors" that have been made in other parts of the world, including, for example, a lack of developed recycling and waste management infrastructure. The average Municipal Solid Waste (MSW) generation rate per capita in the Gulf Co operation countries (GCC) reaches almost 1.5 kg/person/d, with the State of Qatar being close to 1.4 kg/person/d during the past years, thereby ranking the Gulf States as some of the highest waste generating countries globally. Plastics, accounting for approx. 13-14% of the total MSW (in these countries), present both a significant amount as well as a valuable resource to be recovered. In the present work, the authors attempt to delineate the plastic recovery status, based on the current waste management and recycling infrastructure existing and operating in Qatar, outlying the drawbacks, but at the same time highlighting the potential opportunities and benefits in developing the waste management and recovery sector in the country. PMID- 30412875 TI - Copper toxicity to blue mussel embryos (Mytilus galloprovincialis): The effect of natural dissolved organic matter on copper toxicity in estuarine waters. AB - Copper (Cu) is a naturally occurring micronutrient of eco-toxicological concern in aquatic ecosystems. Current knowledge of Cu-speciation and bioavailability in natural saline environments is insufficient to adequately inform environmental protection policy for estuarine systems. We assessed the combined effect of two of the main drivers of metal bioavailability, salinity and natural dissolved organic carbon (DOC), on Cu-speciation and associated Cu-toxicity to blue mussel (Mytilus galloprovincialis) embryos in a standard 48-h bioassay. We placed special emphasis on measurement of Cu-speciation rather than modelling. Cu toxicity was found to be a function of DOC and salinity. The varying protective effect of different DOC-types suggests that estuarine DOC is more protective against Cu-toxicity than oceanic DOC. Salinity was negatively correlated with [Cu48-h-EC50], indicating a salinity-induced alteration in the physiology of the exposed mussel embryos and/or Cu-DOC-reactivity. These two assumptions were supported by (1) the relative uniformity of bioavailable copper ([Cu']) across similar salinity treatments despite considerable variation in [Cu48-h-EC50] and DOC-concentrations, and (2) the fact that Cu-toxicity and [Cu'] were slightly higher in the 35 salinity treatment compared to the 25 salinity treatment. Stripping voltammetry studies determined the presence of only one strong Cu binding ligand class (i.e., L1), either actively or passively released by the exposed embryos. [L1] was found to be proportional to the total dissolved Cu concentration ([CuT]), suggesting a protective effect of Cu-binding-ligands, in addition to the protective effect of DOC. There was also a strong positive correlation between [L1] and [Cu48-h-EC50], implying that electrochemically defined ligand concentrations along with measurements of [Cu'], DOC-quality, and salinity can be used as proxies for 48-h-EC50 Cu-values in estuarine waters, which may result in a significant improvement to risk assessments of Cu in estuarine systems. PMID- 30412876 TI - Comparison of lead levels in edible parts of red deer hunted with lead or non lead ammunition. AB - Game meat may contain elevated concentrations of lead especially if lead containing ammunition is used for hunting. Then a health risk is possible for consumer groups with high game meat intake. The lead concentrations in three edible parts (marketable meat from the area close to the wound channel, saddle and haunch) of meat from red deer (Cervus elaphus) between animals hunted either with lead or non-lead ammunition were compared. Furthermore, lead levels in game meat of lead-shot red deer were compared with those of lead-shot roe deer and lead-shot wild boar. Ninety red deer were shot and killed in the context of this study (64 with lead and 26 with non-lead ammunition). Since the lead concentration for a number of the samples was below the limit of detection or the limit of quantification, statistical methods for left-censored data were applied. The median concentrations of lead in game meat did not differ significantly between lead shot and non-lead shot animals. However, when we analyzed the more elevated lead concentrations, they were significantly higher in edible parts of animals shot with lead ammunition than non-lead ammunition. The highest concentrations were found in samples from edible meat from the area close to the wound channel (max 3442 mg Pb/kg), followed by the saddle (max 1.14 mg Pb/kg) and with the lowest levels in the haunch (max 0.09 mg Pb/kg). A comparison of game species revealed that the lead concentration in haunch and saddle of lead shot red deer was higher than in the corresponding samples of lead shot roe deer. Our results have shown that by the use of non-lead ammunition, a significant reduction of the lead concentration especially in edible parts near the wound channel is possible. PMID- 30412877 TI - Characteristics of organic nitrogen fractions in sediments of the water level fluctuation zone in the tributary of the Yangtze River. AB - The contents of different organic nitrogen (N) fractions, their contributions to total N (TN) and the relationship between their mineralizable N (MN) and different organic N fractions in sediments of the water level fluctuation (WLF) zone were investigated. The contents of TN, acid hydrolyzable N (AHN), and nonhydrolyzable N (NHN) decreased in sediments from the lower altitudes of the WLF zone. The AHN and NHN accounted for 70.56 to 82.89% and 17.11 to 29.44% of TN, respectively. The AHN was the main organic N fraction, indicating that these sediments might promote greater water eutrophication in the Three Gorges tributaries. The distribution of amino-acid N (AAN), ammonium N (AN), amino-sugar N (ASN) and hydrolyzable unidentified N (HUN) in the WLF zone was found to be 170 m > 160 m > 150 m. AAN, AN, ASN, and HUN accounted for 34.70, 20.25, 15.52 and 29.24% of AHN, respectively. HUN and ASN were the main contributors of MN to N release. PMID- 30412878 TI - Occurrence of antibiotics in the main rivers of Shenzhen, China: Association with antibiotic resistance genes and microbial community. AB - The occurrence and distribution of antibiotics were investigated in surface water and sediment collected from the main rivers of Shenzhen, China. Total concentrations of 20 selected antibiotics ranged from 36.510 to 1075.687 ng L-1 (mean 244.992 ng L-1) in 31 water samples and from 28.124 to 2728.810 ng g-1 (mean 680.169 ng g-1) in 31 sediment samples. Notably, STZ and SDZ were the dominant antibiotics in both water and sediment as their higher concentrations compared with the other compounds. Furthermore, comprehensive profiling of antibiotic resistance genes (ARGs) and microbial community was performed to gain an understanding of the evolution and dissemination of ARGs in microbial communities caused by the occurrence of antibiotics in sediment samples from Maozhou River. As a result, the sul1 gene was found to be the most abundant ARG and Proteobacteria was the most abundant microorganism in all the samples (37.4 51.7%), followed by Bacteroidetes (15.3-18.4%). Statistical analysis figured out the relations among antibiotics, ARGs and microbial community. A specific conclusion could be drawn from the positive correlations among the bla_d gene, Fusobacteria, and sulfamethoxazole. It suggests that antibiotics may be positively linked to the expression of ARGs in certain bacteria, and thus high reproduction would occur within the bacterial community. Overall, the widespread distribution of ARGs underscores the need for further research on the mechanism of antibiotics influence as emerging contaminants in the environment and the associated risks to microbial community. PMID- 30412879 TI - Achieving completely anaerobic ammonium removal over nitrite (CAARON) in one single UASB reactor: Synchronous and asynchronous feeding regimes of organic carbon make a difference. AB - At least 11% of total nitrogen (TN) remains in the anammox effluent, making it difficult to meet increasingly stringent discharge standards. To overcome this bottleneck, an innovative process to achieve completely anaerobic ammonium removal over nitrite (CAARON) in one single up-flow anaerobic sludge blanket reactor was proposed in this study. The synchronous feeding of acetate at a C/N (nitrite) ratio of 0.6 significantly reduced the nitrogen removal capacity of anammox reactor by limiting the abundance and metabolism of anammox bacteria. In contrast, the asynchronous feeding of acetate optimized the partition of the reactor column into two specific compartments: the lower half favoring anammox and the upper half dominated by DEAMOX (DEnitrifying AMmonium Oxidation). A high TN removal efficiency of 96.2 +/- 0.4% and a low effluent TN concentration of 9.3 +/- 0.9 mg L-1 were obtained under a high TN loading rate of 9.0 kgN m-3 d-1. The dominant functional microbes in the CAARON process were identified as Candidatus Kuenenia and Thauera, which were responsible for the anammox and denitratation reactions, respectively. Overall, the results in this study provide valuable insight into the coupling of anammox with denitratation, which is a cost efficient approach for treating ammonium-rich wastewaters. PMID- 30412880 TI - Perfluoroalkyl acids in fish of Italian deep lakes: Environmental and human risk assessment. AB - Determination of 20 PFASs in a fish species (Alosa agone) of commercial interest has been carried out in five Italian subalpine lakes to assess the risk for humans and predators for fish consumption. PFOS still presents the highest concentrations (0.9-16.6 ng g-1 ww) among the analysed PFASs, in spite of its normative restrictions. PFOS concentrations measured in all lakes, except in Lake Maggiore, are homogeneous with an average of 3.1 +/- 1.9 ng g-1 ww, which could be considered the "anthropogenic background concentration" of PFOS in fish of lakes located in an industrialised and urbanised region but without point sources. In Lake Maggiore, fish concentrations always exceed the EU EQSbiota (9.1 ng g-1 ww) based on human fish consumption. Considering the effective consumption of fish in this area, an actual risk for fish consumption by humans is not evidenced, while a moderate risk of secondary poisoning for predators is highlighted. PFOA has been detected in significant concentration only in one sample in Lake Maggiore, while long chain PFCAs have been detected without significant differences among the lakes (0.3 to 2.7 ng g-1 ww). The present study demonstrates that biota monitoring of fish can be used as a valuable tool to classify the quality status of water bodies regarding bioaccumulative PFAAs, even if the water concentrations are close to the reachable detection limits. PMID- 30412881 TI - Per- and polyfluoroalkyl substances in source and treated drinking waters of the United States. AB - Contaminants of emerging concern (CECs), including per- and polyfluoroalkyl substances (PFAS), are of interest to regulators, water treatment utilities, the general public and scientists. This study measured 17 PFAS in source and treated water from 25 drinking water treatment plants (DWTPs) as part of a broader study of CECs in drinking water across the United States. PFAS were quantitatively detected in all 50 samples, with summed concentrations of the 17 PFAS ranging from <1 ng/L to 1102 ng/L. The median total PFAS concentration was 21.4 ng/L in the source water and 19.5 ng/L in the treated drinking water. Comparing the total PFAS concentration in source and treated water at each location, only five locations demonstrated statistically significant differences (i.e. P < 0.05) between the source and treated water. When the perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) concentrations in the treated drinking water are compared to the existing US Environmental Protection Agency's PFOA and PFOS drinking water heath advisory of 70 ng/L for each chemical or their sum one DWTP exceeded the threshold. Six of the 25 DWTPs were along two large rivers. The DWTPs within each of the river systems had specific PFAS profiles, with the three DWTPs from one river being dominated by PFOA, while three DWTPs on the second river were dominated by perfluorobutyric acid (PFBA). PMID- 30412882 TI - Nutrient dynamics and eutrophication assessment in the tropical river system of Saigon - Dongnai (southern Vietnam). AB - Saigon-Dongnai Rivers in Southern Vietnam is a complex lowland hydrological network of tributaries that is strongly influenced by the tidal cycles. The increasing economic, industrial and domestic developments in and around Ho Chi Minh City (HCMC) have led to serious impacts on water quality due to lack of appropriate wastewaters treatment. Drinking water production is impacted and the large aquaculture production areas may also be affected. We analyzed spatial and seasonal variability of nutrient concentrations (Phosphorus, Nitrogen and Silica) and eutrophication indicators (Organic Carbon, Chlorophyll-a and Dissolved Oxygen) based on bi-monthly monitoring during two hydrological cycles (July 2015 December 2017). Four monitoring sites were selected to assess the impact of HCMC: two upstream stations on the Saigon River and Dongnai River branches to provide the reference water quality status before reaching the urbanized area of HCMC; one monitoring station in the city center to highlight Saigon River water quality within the heart of the megacity; the fourth station downstream of the confluence to evaluate the impact of HCMC on the estuarine waters. This study points to excess nutrients in HCMC's water body with concentrations of NH4+ and PO43- averaging to 0.7 +/- 0.6 mgN L-1 and 0.07 +/- 0.06 mgP L-1, respectively in mean over the monitored period and rising up to 3 mgN L-1 and 0.2 mgP L-1, in extreme conditions. During the dry season, we evidenced that untreated domestic discharges leads to degradation of the Saigon River's water quality with extreme values of algal biomass (up 150 MUChl-a L-1) and hypoxic conditions occurring episodically (DO < 2 mg L-1) in the heart of the megacity. Until now, eutrophication in the urban center has had no clear effect downstream because eutrophic water mass from the Saigon River is efficiently mixed with the Dongnai River and sea water masses during the successive semi-diurnal tidal cycles. PMID- 30412883 TI - Extraction of PAHS from an aged creosote-polluted soil by cyclodextrins and rhamnolipids. Side effects on removal and availability of potentially toxic elements. AB - This study evaluated the effect of several cyclodextrins (CDs) and a rhamnolipid (RL) on the removal of polycyclic aromatic hydrocarbons (PAHs) from a co contaminated soil which had received historically creosote and inorganic wood preservatives for almost 100 years, and the effect of such extractions on the potentially toxic elements (PTEs). The influence on such processes of an electrolyte (0.01 M Ca(NO3)2) was also studied. Up to 15.4% of the ?16 PAHs were extracted using RL in the absence of the electrolyte as washing solution, but decreases until reaching 0.60% in the presence of Ca2+ due to RL precipitation and partial inactivation. Only up to 2% of the ?16 PAHs was extracted with CDs (4 ring PAHs in higher concentrations), but the electrolyte had no effect on extraction. In relation to PTEs, CDs proved to be inefficient for their extraction, and even RL in the presence of the background electrolyte. But in the absence of electrolyte PTEs extraction by RL increased. Apart from that, the availability of Ni, Cr, and As, those more associated to Fe and Al soil surfaces, increased after extraction with RLs in the presence of Ca2+ (about 100% for Cr and Ni and 200% for As). Under these conditions Fe and Al availability increased two- and ten-fold, respectively, indicating that Fe-Al soil surfaces were altered. Therefore, the ionic strength and the cations present in the soil solution of soils have to be considered when RLs are used as extractants for remediation purposes. PMID- 30412884 TI - Obtaining granular activated carbon from paper mill sludge - A challenge for application in the removal of pharmaceuticals from wastewater. AB - In this work, a granular activated carbon (GAC) was produced using primary paper mill sludge (PS) as raw material and ammonium lignosulfonate (AL) as binder agent. PS is a residue from the pulp and paper industry and AL is a by-product of the cellulose pulp manufacture and the proposed production scheme contributes for their valorisation together with important savings in GAC precursors. The produced GAC (named PSA-PA) and a commercially available GAC (GACN), used as reference material, were physically and chemically characterized. Then, these materials were tested in batch experiments for the adsorption of carbamazepine (CBZ), sulfamethoxazole (SMX), and paroxetine (PAR) from ultra-pure water and wastewater. Even though GACN and PSA-PA possess very similar specific surface areas (SBET) (629 and 671 m2 g-1, respectively), PSA-PA displayed lower maximum adsorption capacities (qm) than GACN for the pharmaceuticals here studied (6 +/- 1-44 +/- 5 mg g-1 and 49 +/- 6-106 +/- 40 mg g-1, respectively). This may be related to the comparatively higher incidence of mesopores in GACN, which might have positively influenced its adsorptive performance. Moreover, the highest hydrophobic character and degree of aromaticity of GACN could also have contributed to its adsorption capacity. On the other hand, the performance of both GACs was significantly affected by the matrix in the case of CBZ and SMX, with lower qm in wastewater than in ultra-pure water. However, the adsorption of PAR was not affected by the matrix. Electrostatic interactions and pH effects might also have influenced the adsorption of the pharmaceutical compounds in wastewater. PMID- 30412885 TI - Chromium bioavailability in aquatic systems impacted by tannery wastewaters. Part 1: Understanding chromium accumulation by indigenous chironomids. AB - The tanning industry uses large quantities of Cr whose contribution to the contaminant burden of aquatic organisms is not yet fully understood. The present study investigated Cr bioaccumulation by indigenous chironomids in a freshwater ecosystem impacted by tannery effluents. Total Cr content in sediments and in chironomids was determined on several occasions. Chromium distribution among sediments and pore waters, and Cr speciation in overlying and pore waters were studied in detail to understand possible factors controlling Cr bioavailability to chironomids. Total chromium concentration ranged from 69 to over 3000 MUg g-1 dry weight in sediments and from negligible to over 300 MUg g-1 dry weight in chironomids (values corrected for sediment gut content). Filterable (<0.45 MUm) Cr concentration in overlying waters and pore waters from the surface sediment layers (upper 2 cm) ranged from 3 to 120 MUg L-1, with Cr(VI) representing 0.5 28% of the total filterable Cr. Chromium profiles in pore waters as determined by diffusive equilibration in thin films (DET) and diffusive gradient in thin films (DGT) were comparable. DGT-labile Cr accounted for <2% of the total Cr measured by DET. Although Cr concentrations in sedimentary and aqueous matrices were not directly proportional to Cr levels measured in chironomids, the available findings suggested that Cr inputs from tanneries were bioavailable to resident chironomids. These observations are of particular importance considering that Cr(III), putatively of limited bioavailability and ecotoxicological concern, is the predominant redox form of Cr in bed sediments impacted by tannery discharges. The companion paper provides further insight into Cr bioavailability and effects in tannery impacted ecosystems using a combination of in situ and laboratory approaches. PMID- 30412886 TI - Disentangling the influence of aridity and salinity on community functional and phylogenetic diversity in local dryland vegetation. AB - One of the key hypothesized drivers of community assembly and dynamics is environmental filtering, where environmental stress limits species migration and survival as a result of functional trait convergence. Whereas most such studies focus on large-scale variation in functional traits along a single-factor environmental gradient, the mutual effects of small-scale multiple environmental filtering remain unclear. Furthermore, it has rarely been tested whether the combined effect of aridity and salinity on local dryland vegetation constrains the patterns of functional traits and phylogenetic structures. Across an 8-km long transect in the arid northwest of China, we assessed the role of environmental filtering in shaping community assemblages by testing the hypotheses that aridity and salinity stresses, interspecific competition and phylogenetic structures constrained functional diversity in the local dryland vegetation. Our results showed that aridity significantly increased convergence of the maximum plant height, specific leaf area, leaf area and leaf nitrogen concentration. However, salinity significantly promoted the convergence of only leaf area and leaf nitrogen concentration. In addition, interspecific competition increased the convergence of the maximum plant height and leaf area. Leaf area converged significantly due to phylogenetic history. Aridity filtering, but not salinity filtering, obviously increased the clustering of phylogenetic structure. Interspecific competition and phylogenetic structure had weak effects on functional diversity in local dryland vegetation. In conclusion, compared with salinity filtering, aridity filtering was more important in reducing phylogenetic diversity in dryland vegetation. PMID- 30412887 TI - Spatial, seasonal and particle size dependent variations of PAH contamination in indoor dust and the corresponding human health risk. AB - To investigate the particle size distribution, spatial variation, and corresponding health risks of polycyclic aromatic hydrocarbons (PAHs) in indoor environments, composite settled dust samples were collected from four types of microenvironments (offices, hotels, dormitories and kindergartens) in Beijing, and each pooled dust sample was homogenized and fractionated into 9 fractions (F1 (900-2000 MUm), F2 (500-900 MUm), F3 (400-500 MUm), F4 (300-400 MUm), F5 (200-300 MUm), F6 (100-200 MUm), F7 (74-100 MUm), F8 (50-74 MUm), and F9 (<50 MUm)). The total concentrations of 15 PAHs varied from 388 ng g-1 (kindergarten dust, F1) to 8140 ng g-1 (hotel dust, F7) in the 31 size-segregated samples. Particle size distribution patterns of PAHs were found to vary for the different types of dust samples. The seasonality of PAH contamination in indoor dust was discussed within 36 samples collected weekly and biweekly from two offices of one building in Beijing. Generally, the seasonal trends of PAHs in dust from these two offices were consistent, showing that PAH levels in cold seasons were higher than those in warm seasons. Diagnostic ratios and principal component analysis (PCA) indicated the important contribution of fuel combustion to PAHs in the indoor dust samples. The estimated incremental lifetime cancer risk (ILCR) values ranged from 10-6 to 10-5 for all relevant populations corresponding to the four types of microenvironments. PMID- 30412888 TI - Modeling the effect of land use and climate change on water resources and soil erosion in a tropical West African catch-ment (Dano, Burkina Faso) using SHETRAN. AB - This study investigates the effect of land use and land cover (LULC) and climate change on catchment hydrology and soil erosion in the Dano catchment in south western Burkina Faso based on hydrological and soil erosion modeling. The past LULC change is studied using land use maps of the years 1990, 2000, 2007 and 2013. Based on these maps future LULC scenarios were developed for the years 2019, 2025 and 2030. The observed past and modeled future LULC are used to feed SHETRAN, a hydrological and soil erosion model. Observed and modeled climate data cover the period 1990-2030. The isolated influence of LULC change assuming a constant climate is simulated by applying the seven LULC maps under observed climate data of the period 1990-2015. The isolated effect of climate scenarios (RCP4.5 and 8.5 of CCLM4-8) is studied by applying the LULC map of 1990 to the period 1990-2032. Additionally, we combined past modeled climate data and past observed LULC maps. Two chronological and continuous simulations were used to estimate the impact of LULC in the past and in the future by gradually applying the LULC maps. These simulations consider the combined impact of LULC and climate change. The simulations that assumed a constant climate and a changing LULC show increasing water yield (3.6%-46.5%) and mainly increasing specific sediment yield (-3.3%-52.6%). The simulations that assume constant LULC and climate as changing factor indicate increases in water yield of 24.5% to 46.7% and in sediment yield of 31.1% to 54.7% between the periods 1990-2005 and 2006-2032. The continuous simulations signal a clear increase in water yield (20.3%-73.4%) and specific sediment yield (24.7% to 90.1%). Actual evapotranspiration is estimated to change by between -7.3% (only LUCC) to +3.3% (only climate change). When comparing observed LULC and climate change alone, climate change has a larger impact on discharge and sediment yield, but LULC amplifies climate change impacts strongly. However, future LULC (2019-2030) will have a stronger impact as currently observed. PMID- 30412889 TI - Antibiotic resistance genes allied to the pelagic sediment microbiome in the Gulf of Khambhat and Arabian Sea. AB - Antibiotics have been widely spread in the environments, imposing profound stress on the resistome of the residing microbes. Marine microbiomes are well established large reservoirs of novel antibiotics and corresponding resistance genes. The Gulf of Khambhat is known for its extreme tides and complex sedimentation process. We performed high throughput sequencing and applied bioinformatics techniques on pelagic sediment microbiome across four coordinates of the Gulf of Khambhat to assess the marine resistome, its corresponding bacterial community and compared with the open Arabian Sea sample. We identified a total of 2354 unique types of resistance genes, with most abundant and diverse gene profile in the area that had anthropogenic activities being carried out on shore. The genes with >1% abundance in all samples included carA, macB, sav1866, tlrC, srmB, taeA, tetA, oleC and bcrA which belonged to the macrolides, glycopeptides and peptide drug classes. ARG enriched phyla distribution was quite varying between all the sites, with Proteobacteria, Firmicutes, Actinobacteria and Bacteroidetes among the dominant phyla. Based on the outcomes, we also propose potential biomarker candidates Desulfovibrio, Thermotaga and Pelobacter for antibiotic monitoring in the two of the Gulf samples probable contamination prone environments, and genera Nitrosocccus, Marinobacter and Streptomyces in the rest of the three studied samples. Outcomes support the concept that ARGs naturally originate in environments and human activities contribute to the dissemination of antibiotic resistance. PMID- 30412890 TI - Ocean acidification exacerbates the effects of paralytic shellfish toxins on the fitness of the edible mussel Mytilus chilensis. AB - High latitudes are considered particularly vulnerable to ocean acidification, since they are naturally low in carbonate ions. The edible mussel Mytilus chilensis is a common calcifier inhabiting marine ecosystems of the southern Chile, where culturing of this species is concentrated and where algal blooms produced by the toxic dinoflagellate A. catenella are becoming more frequent. Juvenile Mytilus chilensis were exposed to experimental conditions simulating two environmental phenomena: pCO2 increase and the presence of paralytic shellfish toxins (PST) produced by the dinoflagellate Alexandrium catenella. Individuals were exposed to two levels of pCO2: 380 MUatm (control condition) and 1000 MUatm (future conditions) over a period of 39 days (acclimation), followed by another period of 40 days exposure to a combination of pCO2 and PST. Both factors significantly affected most of the physiological variables measured (feeding, metabolism and scope for growth). However, these effects greatly varied over time, which can be explained by the high individual variability described for mussels exposed to different environmental conditions. Absorption efficiency was not affected by the independent effect of the toxic diet; however, the diet and pCO2 interaction affected it significantly. The inhibition of the physiological processes related with energy acquisition by diets containing PST, may negatively impact mussel fitness, which could have important consequences for both wild and cultured mussel populations, and thus, for socioeconomic development in southern Chile. PMID- 30412891 TI - Metabolic responses in the gills of tongue sole (Cynoglossus semilaevis) exposed to salinity stress using NMR-based metabolomics. AB - Salinity is an important environmental factor affecting fish physiology. Tongue sole (Cynoglossus semilaevis) is a euryhaline species that can survive in a wide range of salinity, and might be used as a promising model animal for environmental science. In this study, by using the nuclear magnetic resonance (1H NMR)-based metabolomics, amino acids analysis and real-time quantitative PCR assay, we investigated the metabolic responses in the gills and plasma of tongue sole subjected to hypo- (0 ppt, S0) and hyper-osmotic stress (50 ppt, S50) from isosmotic environment (30 ppt, S30). The results showed that the metabolic profiles of S50 were significantly different from those of S0 and S30 groups, and a clear overlap was found between the latter two groups. Ten metabolites were significantly different between the salt stress groups and the isosmotic group. Taurine and creatine elevated in both S0 and S50 groups. Choline decreased in S50 group while increased in S0 group. Amino acids and energy compounds were higher in the gills of S50 group. The metabolic network showed that ten metabolic pathways were all found in S50 group, while seven pathways were observed in S0 group. Meanwhile, the transcript levels of the Tau-T and ATP synthase in the gills increased with increasing salinity. Aspartate and methionine exhibited significant differences in the plasma among the groups, but did not show differences in the gills. Comparatively, glutamate exhibited significant differences both in the plasma and the gills. Overall, these findings provide a preliminary profile of osmotic regulation in euryhaline fish. PMID- 30412892 TI - Occurrence, sources, partitioning and ecological risk of short- and medium-chain chlorinated paraffins in river water and sediments in Shanghai. AB - The characteristics of regional environmental pollution of short- and medium chain chlorinated paraffins (SCCPs and MCCPs) in river system from Shanghai were comprehensively investigated in this study for the first time. The total concentrations of SCCPs and MCCPs ranged from 15.0 to 1640 ng L-1 (median: 278 ng L-1) and 40.3 to 3870 ng L-1 (median: 939 ng L-1) in water, and from not detected (ND) to 2020 ng g-1 (median: 89.3 ng g-1) and 10.1 to 10,800 ng g-1 (median: 947 ng g-1) in sediments, respectively. The higher levels of SCCPs and MCCPs were found in water from Jinhui and Yexie rivers, and in sediments from Huangpu River, respectively. The concentrations of MCCPs were higher than those of SCCPs in both water and sediments, suggesting that the river system was mainly contaminated by MCCPs. Compared with other areas around the world, the concentrations of SCCPs and MCCPs were at medium to high levels in water and sediments. Factor analysis results revealed that SCCPs and MCCPs had different sources in both water and sediments. The log Koc values of CPs were significantly correlated with carbon chain lengths (p < 0.01), but not with chlorine number for both SCCPs and MCCPs (p > 0.05). A significant second-order polynomial relationship was observed between log Koc values and molecular weights of homologue groups of SCCPs (p < 0.001) and MCCPs (p < 0.01), respectively. SCCPs in water posed a low ecological risk at all sampling sites, and MCCPs in water posed a moderate ecological risk to aquatic life at nearly a fifth of sampling sites. SCCPs and MCCPs in sediments posed a low ecological risk to sediment dwelling organisms at most sampling sites. PMID- 30412893 TI - Dysregulation of let-7 by PEG modified graphene oxide in nematodes with deficit in epidermal barrier. AB - In nematode Caenorhabditis elegans, epidermal RNA interference (RNAi) knockdown of bli-1 encoding a cuticular collagen caused the toxicity induction of GO-PEG (PEG surface modified graphene oxide). In this study, we further found that epidermal RNAi knockdown of bli-1 increased expression of a microRNA let-7, and let-7 mutation suppressed the susceptibility of bli-1(RNAi) nematodes to GO-PEG toxicity. let-7 regulated the toxicity induction of GO-PEG by suppressing expression and function of its direct targets (HBL-1 and LIN-41). Like the nematodes with epidermal RNAi knockdown of bli-1, epidermal RNAi knockdown of hbl 1 or lin-41 also induced functional abnormality in epidermal barrier. Therefore, a signaling cascade of BLI-1-let-7-HBL-1/LIN-41 was raised to be involved in GO PEG toxicity induction. Our data imply the dysregulation of let-7-mediated molecular machinery for developmental timing control by GO-PEG in nematodes with deficit in epidermal barrier caused by bli-1(RNAi). PMID- 30412894 TI - Is frying oil a dietary source of an endocrine disruptor? Anti-estrogenic effects of polar compounds from frying oil in rats. AB - The objective was to investigate endocrine-disrupting effects of polar compounds from oxidized frying oil. Estrogenicity of polar compounds was tested with a rat uterotrophic bioassay. Dietary oxidized frying oil (containing 51% polar compounds) or polar compounds isolated from it were incorporated into feed (in lieu of fresh soybean oil) and fed to ovariectomized rats, with or without treatment with exogenous ethynyl estradiol. Exogenous estrogen restored uterine weight, and caused histological abnormalities (stratified epithelia and conglomerate glands) as well as proliferation of uterine epithelial cells. However, tamoxifen or polar compounds reduced these effects. Furthermore, tamoxifen or polar compounds down-regulated uterine mRNA expression of estrogen receptor (ER)-target genes, implicating reduced ER activity in this hypo uterotrophic effect. Inhibition of ER signaling and mitosis by polar compounds were attributed to reduced MAPK and AKT activation, as well as a reduced ligand binding domain-transactivity of ERalpha/beta. We concluded polar compounds from frying oil are potential endocrine-disrupting chemicals, with implications for food and environmental safety. PMID- 30412895 TI - Hepatotoxicity and immunotoxicity of MC-LR on silver carp. AB - Microcystins produced by some cyanobacteria can cause damages to the liver and kidneys of aquatic animals. In the natural water with cyanobacterial blooms, silver carp may suffer from the most serious affect of the bloom due to their filtering these cyanobacteria and ingesting them as food. In the present study, silver carp was exposed to microcystin-LR by using the method of intraperitoneal injection first to determine the acute toxicity of microcystin-LR on silver carp and then to determine the activity of inflammatory protein and content of inflammatory factors from the serum of silver carp following a subacute exposure of microcystin-LR at doses of 104.9 MUg kg-1 (1/5 of LD50) or 262.1 MUg kg-1 (1/2 of LD50). The results showed that MC-LR exposure increased fish liver index and promoted the activities of fish serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), indicating the hepatotoxicity of MC-LR on the fish. Moreover, MC-LR exposure also increased the number of leukocytes, complement C3 level, lysozyme activity (at the first 9 h of exposure), and the contents of cytokines TNF-alpha, IL-1beta and IFN-gamma in fish serum. In addition, a significant increase in IgM level was observed in the serum and head kidney of silver carp following MC-LR exposure. This result suggests that semi lethal doses of MC-LR exposure is not only hepatotoxic but also immunotoxic to silver carp. PMID- 30412896 TI - A combined toxicokinetics and toxicodynamics approach to investigate delayed lead toxicity in the soil invertebrate Enchytraeus crypticus. AB - In a previous study, Pb toxicity was found to be delayed compared to Pb bioaccumulation in Enchytraeus crypticus. This study aimed at further investigating the acute and delayed onset of Pb toxicity in E. crypticus by using a combination of toxicokinetics and toxicodynamics approaches. Enchytraeids were exposed to different Pb concentrations (uptake phase) in natural LUFA 2.2 soil for different short-term exposure periods, followed by a 7-d elimination phase in clean soils. Body Pb concentrations and enchytraeid mortality were determined at different time intervals during both the exposure and the elimination phase. Pb uptake kinetics in E. crypticus were well described by a three-stage first-order model with an initial overshoot in body Pb concentrations. At higher exposure concentrations, Pb caused delayed enchytraeid mortality even following short-term exposure. LC50 based on body Pb concentrations appeared no good descriptor of delayed Pb toxicity in E. crypticus. Exposure time had a major impact on Pb bioaccumulation, toxicity and its delayed effects, which argues against relying on ecotoxicity tests for metal toxicity using a fix exposure duration. The presence of delayed toxic effects also suggests that post-exposure observations are necessary to avoid underestimation of metal toxicity. PMID- 30412897 TI - Silicon enhances the salt tolerance of cucumber through increasing polyamine accumulation and decreasing oxidative damage. AB - Silicon can increase salt tolerance, but the underlying mechanism has remained unclear. Here, we investigated the effect of silicon on polyamine metabolism and the role of polyamine accumulation in silicon-mediated salt tolerance in cucumber. Seedlings of cucumber 'JinYou 1' were subjected to salt stress (75 mM NaCl) in the presence or absence of added 0.3 mM silicon. Plant growth, polyamine metabolism and effects of exogenous polyamines and polyamine synthesis inhibitor dicyclohexylammonium sulphate on oxidative damage were investigated. The results showed that salt stress inhibited plant growth and decreased leaf chlorophyll levels and the maximum quantum yield of PSII, and added silicon ameliorated these negative effects. Salt stress increased polyamine accumulation in the leaves and roots. Compared with salt stress alone, overall, silicon addition decreased free putrescine concentrations, but increased spermidine and spermine concentrations in both leaves and roots under salt stress. Silicon application resulted in increased polyamine levels under salt stress by promoting the activities of S adenosylmethionine decarboxylase and arginine decarboxylase while inhibiting the activity of diamine oxidase. Exogenous application of spermidine and spermine alleviated salt-stress-induced oxidative damage, whereas polyamine synthesis inhibitor eliminated the silicon-mediated decrease in oxidative damage. The results suggest that silicon-enhanced polyamine accumulation in cucumber under salt stress may play a role in decreasing oxidative damage and therefore increase the salt tolerance. PMID- 30412899 TI - Relationship between childhood abuse and substance misuse problems is mediated by substance use coping motives, in school attending South African adolescents. AB - BACKGROUND: In adults, it has been shown that the relationship between childhood abuse and substance misuse problems is mediated by the belief that substance use helps cope with negative affective states. By contrast, in adolescents, it is unknown whether drug use coping motives play this same mediating role. METHODS: Secondary analysis of 1149 school attending adolescents in Cape Town, South Africa (average age = 16.24 years, range = 13-23; 60% female). Questionnaire measures obtained during a single test session (among a larger battery) assessed childhood trauma (CTQ), alcohol (AUDIT) and drug problems (DUDIT), and coping orientation (A-COPE) which contained three items assessing drug use to cope with negative affect. RESULTS: The three types of childhood abuse measured by the CTQ emotional, physical and sexual - were positively associated with greater alcohol/drug problems, and drug use coping motives. Drug use coping motives mediated the relationships between childhood abuse types and alcohol/drug problems, and these mediational pathways remained significant when gender and other subscales of the A-COPE were included as covariates. CONCLUSIONS: These data are preliminary insofar as drug use coping motives were assessed with a non validated subscale of the A-COPE. Nevertheless, drug use to cope with negative affect mediated the relationship between all three types of childhood abuse (emotional, physical, sexual) and alcohol/drug problems in school attending adolescents. The implication is that drug prevention programs for this risk group should seek to mitigate drug use coping motives. PMID- 30412898 TI - Approaches for creating comparable measures of alcohol use symptoms: Harmonization with eight studies of criminal justice populations. AB - BACKGROUND: With increasing data archives comprised of studies with similar measurement, optimal methods for data harmonization and measurement scoring are a pressing need. We compare three methods for harmonizing and scoring the AUDIT as administered with minimal variation across 11 samples from eight study sites within the STTR (Seek-Test-Treat-Retain) Research Harmonization Initiative. Descriptive statistics and predictive validity results for cut-scores, sum scores, and Moderated Nonlinear Factor Analysis scores (MNLFA; a psychometric harmonization method) are presented. METHODS: Across the eight study sites, sample sizes ranged from 50 to 2405 and target populations varied based on sampling frame, location, and inclusion/exclusion criteria. The pooled sample included 4667 participants (82% male, 52% Black, 24% White, 13% Hispanic, and 8% Asian/ Pacific Islander; mean age of 38.9 years). Participants completed the AUDIT at baseline in all studies. RESULTS: After logical harmonization of items, we scored the AUDIT using three methods: published cut-scores, sum scores, and MNLFA. We found greater variation, fewer floor effects, and the ability to directly address missing data in MNLFA scores as compared to cut-scores and sum scores. MNLFA scores showed stronger associations with binge drinking and clearer study differences than did other scores. CONCLUSIONS: MNLFA scores are a promising tool for data harmonization and scoring in pooled data analysis. Model complexity with large multi-study applications, however, may require new statistical advances to fully realize the benefits of this approach. PMID- 30412900 TI - Opsoclonus-myoclonus-encephalopathy induced by cefepime. PMID- 30412902 TI - Differences in white matter connectivity between treatment-resistant and treatment-responsive subtypes of schizophrenia. AB - Schizophrenia is a heterogeneous disorder exhibiting variable responsiveness to treatment between individuals. Previous work demonstrated that white matter abnormalities may relate to antipsychotic response but no study to date has examined differences between first-line treatment responders (FLR) and clozapine eligible individuals receiving first-line antipsychotics. The current study aimed to establish whether differences in white matter structure exist between these two cohorts. Diffusion-weighted images were acquired for 15 clozapine-eligible and 10 FLR participants. Measures of fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (AD) were obtained and between-group t tests interrogating differences in FA were conducted. To investigate the neural basis of a decrease in FA, the significant cluster from FA analysis was masked and used to obtain mean RD and AD measures for that region. Those who were clozapine-eligible had significantly lower FA in the body of the corpus callosum (p < 0.05), associated with a significant increase in mean RD compared with FLR (p < 0.001). No difference in mean AD was observed for this region. These data reveal differences in diffusion measures between FLR and those eligible for clozapine and suggest that lower FA and greater RD in the corpus callosum could exist as a biomarker of treatment resistance in people with schizophrenia. PMID- 30412901 TI - Plasma levels of soluble NCAM in multiple sclerosis. AB - In multiple sclerosis (MS), several adhesion molecules are involved within the central nervous system in inflammatory and neurodegenerative processes that are associated to progressive disability and increasing brain atrophy. The neural cell adhesion molecule (NCAM) has been suggested to participate in the reparative mechanisms and in the remyelination processes, key issues in MS pathology. We aimed at investigating plasma levels of the seldom investigated soluble (s)NCAM, and as comparison those of intercellular adhesion molecule-1 (sICAM-1) and vascular adhesion molecule-1 (sVCAM-1), and their association with clinical and MRI measures of lesion volumes and of global and regional atrophy. The cross sectional study was conducted in 85 relapsing-remitting (RR)-MS, 53 progressive (P)-MS patients, and 42 healthy individuals (HI). Correlation of MRI measures with plasma levels of these adhesion molecules were not observed. In the MS and HI groups, sNCAM levels were significantly and positively associated with sVCAM-1 levels. Differently, the correlation between sICAM-1 and sVCAM-1 was observed only in MS patients. sNCAM and sVCAM-1 levels were higher in P-MS compared to HI (P = 0.05 and P = 0.028 respectively). The sVCAM-1 levels differed (P < 0.001) among DMTs groups and HI. The association of sNCAM plasma levels with MS disease, as well as differences in sVCAM-1 levels in patients receiving different DMTs, deserve further investigation. PMID- 30412903 TI - Risk factors for detectable metastatic disease at presentation in Ewing sarcoma - An analysis of the SEER registry. AB - BACKGROUND: Ewing family of tumors (EFT) represents the second-most common primary bone malignancy in children and adolescents. Approximately 25% of patients have radiographically detectable metastatic disease at presentation and experience poorer five-year survival, yet risk factors for metastatic disease at presentation are poorly characterized. We sought to study patient characteristics associated with metastatic disease upon presentation for patients with EFT. METHODS: We identified EFT cases in the Surveillance, Epidemiology, and End Results Program (SEER) registry from 2004 to 2012. Using univariate analyses and multivariable logistic regression, we explored the relationship between demographic and clinical factors and the presence of detectable metastatic disease at presentation. RESULTS: Among 870 EFT cases, 35% (n = 304) presented with detectable metastatic disease. These patients were commonly older (>24 years: 28% vs 19%, p = 0.002) and had a primary tumor site in the axial skeleton (56% vs 44%, p < 0.001). After adjusting for all covariates, compared to patients <11 years, those >24 years old faced a two-fold increase in the odds of metastatic disease (OR = 1.99, 95% CI: 1.17-3.38). Axial (OR = 2.31, 95% CI: 1.58 3.37) and "other" (OR = 2.35, 95% CI: 1.15-4.81) tumor locations had more than twice the likelihood of presenting with metastatic disease, compared to extremity tumor sites. Increasing tumor size conferred up to a three-fold increase in odds of metastatic disease (pTrend <0.001). CONCLUSIONS: Advanced age, axial tumor location, and increasing tumor size are associated with increased odds of detectable metastatic disease upon presentation with EFT. Although these characteristics are not modifiable, they provide objective factors that may inform patient counseling of metastatic risk. PMID- 30412904 TI - External cephalic version after previous cesarean section: A cohort study of 100 consecutive attempts. AB - OBJECTIVE: External cephalic version is commonly not performed in women with a previous cesarean section. Fear of uterine rupture and cesarean section in labor are prominent. The risks, however, of these are unclear. This study aims to document the safety and efficacy of external cephalic version in women with a prior cesarean section in a series of 100 consecutive attempts, and to perform a literature of the existing literature. STUDY DESIGN: This is a retrospective cohort study of prospectively collected data of external cephalic version attempts in women at term with a previous cesarean section, and a literature review of previously published series. External cephalic version was performed by one of 3 experienced operators, with salbutamol tocolysis if appropriate, using ultrasound to visualize the fetal heart and place of fetal parts. RESULTS: 100 women with a prior cesarean section underwent external cephalic version over a 16 year period in one institution. 68% had no previous vaginal delivery. The external cephalic version success rate was 50%, and 30 (63.8%) of these subsequently delivered vaginally. There were no cases of uterine rupture or other complications. A literature review of series containing a total of 549 cases revealed no cases of uterine rupture or perinatal death. CONCLUSIONS: External cephalic version in women with a prior cesarean section is safe but enables a vaginal birth in only about a third of women. PMID- 30412905 TI - Dairy milk proteins attenuate hyperglycemia-induced impairments in vascular endothelial function in adults with prediabetes by limiting increases in glycemia and oxidative stress that reduce nitric oxide bioavailability. AB - Postprandial hyperglycemia (PPH) transiently impairs vascular endothelial function (VEF) in an oxidative stress-dependent manner by decreasing nitric oxide (NO*) bioavailability. Dairy milk and its proteins attenuate PPH, but whether this improves VEF is unknown. We hypothesized that dairy milk, mediated by its whey and/or casein proteins, improves VEF by attenuating PPH-induced oxidative stress that otherwise decreases NO* bioavailability. A randomized, cross-over trial was conducted in adults with prediabetes (n=23) who ingested glucose (75 g, GLU) alone or with 473 mL of non-fat dairy milk (MILK) or isonitrogenous (16.5 g) amounts of whey (WHEY) or casein (CASEIN) in 473 mL of water. Prior to and at 30 min intervals for 180 min postprandially, we assessed brachial artery flow mediated dilation (FMD) and measured biomarkers of glycemic control, oxidative stress, and NO* homeostasis. FMDAUC decreased to the greatest extent during GLU, which was similarly improved in dairy trials. Compared with GLU, AUCs for glucose, malondialdehyde, F2-isoprostanes, methylglyoxal, and endothelin-1 were similarly lower in dairy trials. Plasma arginine and NO* metabolites were greater but methylated arginine metabolites were lower in dairy trials compared with GLU. Postprandial insulin, lipids, and tetrahydrobiopterin redox status did not differ among trials. Thus, dairy milk, mediated by its whey and casein proteins, attenuates PPH-mediated impairments in VEF by limiting oxidative stress. This improves NO* bioavailability to the vascular endothelium by increasing arginine availability and limiting competitive inhibition on NO* biosynthesis by asymmetric dimethylarginine. These findings support observational studies that dairy milk lowers cardiovascular disease risk. PMID- 30412906 TI - A low-protein diet eliminates the circadian rhythm of serum insulin and hepatic lipid metabolism in mice. AB - Insulin is a key molecule that synchronizes peripheral clocks, such as that in the liver. Although we previously reported that mice fed a low-protein diet showed altered expression of lipid-related genes in the liver and induction of hepatic steatosis, it is unknown whether a low-protein diet impairs insulin secretion and modifies the hepatic circadian rhythm. Therefore, we investigated the effects of the intake of a low-protein diet on the circadian rhythm of insulin secretion and hepatic lipid metabolism in mice. Under 12-h light/12-h dark cycle, mice fed a low-protein diet for 7 days displayed enhanced food intake at the end of the light phase, although central and peripheral PER2 expression rhythm was maintained. Serum insulin levels in mice fed a low-protein diet remained low during the day, and the insulin secretion in OGTT was also markedly lower than in normal mice. In mice fed low-protein diet, hepatic TG accumulation was observed during the nighttime, with relatively high levels of ACC1 mRNA and total ACC proteins. Although there were no differences in the activity rhythm of hepatic mTOR between mice fed a normal or low-protein diet, hepatic IRS-2 expression in mice fed a low-protein diet remained low during the day, with no increase at the beginning of the light period. These results suggested that the low-protein diet eliminated the circadian rhythm of serum insulin and hepatic lipid metabolism in mice, providing insights into our understanding of the mechanisms of hepatic disorders of lipid metabolism. PMID- 30412907 TI - Comparative effects of dietary n-3 docosapentaenoic acid (DPA), DHA and EPA on plasma lipid parameters, oxidative status and fatty acid tissue composition. AB - The specific and shared physiologic and metabolic effects of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and even more of n-3 docosapentaenoic acid (DPA) are poorly known. We investigated the physiological effects and the overall fatty acid tissue composition of a nutritional supplementation of DPA compared both to EPA and DHA in healthy adult rats. Rats (n=32) were fed with semisynthetic diets supplemented or not with 1% of total lipids as EPA, DPA or DHA in ethyl esters form from weaning for 6 weeks. Fatty acid tissue composition was determined by gas chromatography-mass spectrometry, and blood assays were performed. The DPA supplementation was the only one that led to a decrease in plasma triglycerides, total cholesterol, non-high-density lipoprotein (HDL) cholesterol, cholesterol esters and total cholesterol/HDL-cholesterol ratio compared to the nonsupplemented control group. The three supplemented groups had increased plasma total antioxidant status and superoxide dismutase activity. In all supplemented groups, the n-3 polyunsaturated fatty acid level increased in all studied tissues (liver, heart, lung, spleen, kidney, red blood cells, splenocytes, peripheral mononucleated cells) except in the brain. We showed that the DPA supplementation affected the overall fatty acid composition and increased DPA, EPA and DHA tissue contents in a similar way than with EPA. However, liver and heart DHA contents increased in DPA-fed rats at the same levels than in DHA fed rats. Moreover, a large part of DPA seemed to be retroconverted into EPA in the liver (38.5%) and in the kidney (68.6%). In addition, the digestibility of DPA was lower than that of DHA and EPA. PMID- 30412908 TI - International differences in patterns of cannabis use among youth: Prevalence, perceptions of harm, and driving under the influence in Canada, England & United States. AB - INTRODUCTION: Cannabis is the most widely used illicit substance in the world. An increasing number of jurisdictions have legalized medical and non-medical cannabis; comparisons across jurisdictions can help evaluate the impact of these policy innovations. The current study examined patterns of cannabis use among youth in Canada (CA), England (EN) and the United States (US). At the time of study, non-medical cannabis use was prohibited federally in all three countries; however, medical cannabis was accessible with varying restrictions in CA, EN and most US states, while non-medical cannabis was legal in four US states. METHODS: Data come from an international online survey conducted in July 2017 (n = 12,064). Youth, aged 16-19, were asked about cannabis consumption, perceived access to cannabis, perceptions of harm, and driving after cannabis use. All estimates represent weighted data. RESULTS: US youth were more likely to report more frequent cannabis consumption, easier access, lower perceptions of harm, and higher rates of driving after cannabis use than CA and EN youth. CA youth reported more frequent consumption, easier access, and higher rates of driving after cannabis use than EN youth. CONCLUSION: CA and US youth had higher prevalence of use, easier access, lower perceived harm and higher driving rates after cannabis use in comparison to EN. These differences may reflect more permissive cannabis policies in CA and US, as well as pre-existing trends. Future waves of the international cannabis study will examine trends over time within the same countries after cannabis legalization in CA and additional US states. PMID- 30412909 TI - Feasibility and acceptability of Indigenous Counselling and Nicotine (ICAN) QUIT in Pregnancy multicomponent implementation intervention and study design for Australian Indigenous pregnant women: A pilot cluster randomised step-wedge trial. AB - BACKGROUND: Many health providers (HPs) lack knowledge, confidence, optimism and skills in addressing smoking with pregnant women. This study aimed to explore the feasibility and acceptability of a) a co-designed multi-component intervention for HPs at Aboriginal Medical Services (AMSs) in culturally-targeted pregnancy specific smoking cessation care and b) the study design. METHODS: Using a randomised step-wedge cluster design, the Indigenous Counselling And Nicotine (ICAN) QUIT in Pregnancy Trial was evaluated across six AMSs in three Australian states. HPs were provided educational resource packages including live interactive webinars, treatment manuals, patient resources, carbon monoxide (CO) meters, and oral Nicotine Replacement Therapy (NRT). Feasibility was assessed through recruitment and retention rates of both pregnant women (12-weeks) and HPs (end of study) as well as the potential to improve women's quit rates. Qualitative interviews with staff post-trial explored acceptability of the intervention and study, based on capability, opportunity and motivation from the Behaviour Change Wheel. RESULTS: Pregnant women (n = 22; 47% (95% CI: 32%, 63%) eligible) and HPs (n = 50; 54% (95% CI: 44%, 64%) eligible) were recruited over 6 months with retention rates of 77% (95% CI: 57%, 90%) and 40% (95% CI: 28%, 54%) respectively. Self-reported 12-week 7-day point-prevalence abstinence was 13.6% (n = 3) and validated abstinent with CO readings <=6 ppm. Staff interviewed regarding intervention implementation highlighted the importance of provision and use of resources, including training materials, patient resources, CO meters and oral NRT. Resources helped increase capability and opportunity, restructure the environment, and provided social comparison and modelling. Staff were motivated by greater engagement with pregnant women and seeing the women's reductions in CO readings. Having the intervention at the AMSs improved organisational capacity to engage with pregnant women. Staff reported changes to their routine practice that were potentially sustainable. Recommendations for improvement to the implementation of the intervention and research included reducing training length and the tasks related to conducting the study. CONCLUSION: ICAN QUIT in Pregnancy was a pilot study with the ability to enrol Indigenous women. It was feasible to implement and acceptable to most staff of the AMSs in three states, with modifications recommended. Smoking in pregnancy is a key challenge for Indigenous health. The intervention needs to be evaluated through a methodologically rigorous fully-powered study to determine the efficacy of outcomes for women. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry, ACTRN12616001603404. Registered 21 November 2016 - retrospectively registered, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371778. PMID- 30412910 TI - Injection opioid use as a predictor of treatment outcomes among methadone maintained opioid-dependent patients. AB - BACKGROUND: Injection opioid use is associated with more severe health and psychosocial consequences relative to non-injection use, but few studies have examined whether injection use is associated with methadone maintenance treatment outcomes. The present study examined differential MMT outcomes among opioid injectors and non-injectors. METHODS: Data were extracted from the clinic charts of opioid-dependent MMT patients (N = 290; n = 115 injectors) enrolled in a university-affiliated, urban MMT clinic. Injection status was examined as a predictor of short- (3-month opioid, cocaine, benzodiazepine and cannabis urine drug screens) and long- (days retained in treatment) term MMT outcomes. RESULTS: Bivariate analyses revealed injection users were less likely to be African American and to have completed high school, were more likely to have started heroin use before age 21, to report having hepatitis C, to report a baseline cocaine use disorder, and had higher methadone doses at 3-months into treatment. Injection status significantly predicted a greater proportion of cocaine-positive urine drug screens in the first 3 months of treatment, but did not significantly predict opioid, benzodiazepine or cannabis drug screens, or length of treatment retention. CONCLUSION: This is one of a handful of studies to examine injection status as a predictor of MMT outcomes. Injection status is associated with cocaine use early in treatment, which has implications for the focus of treatment. PMID- 30412911 TI - Targeting PIM Kinases Affects Maintenance of CD133 Tumor Cell Population in Hepatoblastoma. AB - Hepatoblastoma is the most common primary liver tumor in children, but treatment has not changed significantly in the past 20 years. We have previously demonstrated that Proviral Integration site for Moloney murine leukemia (PIM) kinases promote tumorigenesis in hepatoblastoma. Stem cell-like cancer cells (SCLCCs) are a subset of cells thought to be responsible for chemoresistance, metastasis, relapse, and recurrence. The aim of this study was to identify SCLCCs in hepatoblastoma and determine the role of PIM kinases in SCLCCs. Hepatoblastoma cells were separated into CD133-enriched and CD133-depleted populations and the frequency of SCLCCs was assessed. CD133 expression was determined in the presence or absence of the PIM inhibitor, AZD1208. The effects of AZD1208 on proliferation, apoptosis, and motility were assessed in vitro and the effect of AZD1208 on tumor growth was examined in vivo. We identified CD133 as a marker for SCLCCs in hepatoblastoma and showed that PIM kinases promote a SCLCC phenotype. PIM kinase inhibition with AZD1208 decreased proliferation, migration, and invasion and increased apoptosis in both SCLCCs and non-SCLCCs in a long-term passaged hepatoblastoma cell line and patient-derived xenograft. Additionally, tumor growth in mice implanted with hepatoblastoma SCLCCs was decreased with PIM inhibition such that 57% of the tumors regressed. These findings identify CD133 as a marker for SCLCCs in hepatoblastoma and provide evidence that inhibition of PIM kinases decreases stemness and tumorigenicity of SCLCCs in hepatoblastoma, making them potential therapeutic targets for the treatment of hepatoblastoma. PMID- 30412912 TI - Enhancing the Radiation Response in KRAS Mutant Colorectal Cancers Using the c Met Inhibitor Crizotinib. AB - INTRODUCTION: C-Met plays important roles in treatment resistance, tumor invasion, and metastasis. In this study, we used a small molecule inhibitor of c Met, crizotinib, in cetuximab-resistant, mutant KRAS-driven colorectal cancer cell lines and assessed radiosensitization. MATERIALS AND METHODS: A tissue microarray containing colorectal tumors was used to study the relationship between KRAS mutations and c-Met expression. For in vivo studies, we used the KRAS mutant cell lines HCT116, DLD1, and LoVo. Colony formation assays were performed to assess the effects of crizotinib and cetuximab. Immunoblot analysis was used to determine the effect of crizotinib on c-Met and downstream pathways and DNA damage response. We then selected noncytotoxic doses of crizotinib to assess clonogenic survival with radiation. To study potential mechanisms of radiosensitization, cell cycle analysis was performed using flow cytometry. RESULTS: Analysis of the tissue microarray revealed that KRAS mutant tumors had active c-Met signaling. KRAS mutant cell lines LoVo, HCT116, and DLD1 were resistant to cetuximab but sensitive to crizotinib. Pretreatment with crizotinib for 24 hours radiosensitized LoVo, DLD1, and HCT116 cell lines with enhancement ratios of 1.54, 1.23, and 1.30, respectively. Immunoblot analysis showed that crizotinib blocked radiation-induced c-Met phosphorylation and attenuated downstream signaling pathways. Cell cycle analysis revealed minimal G1 arrest with crizotinib. Additionally, crizotinib completely blocked HGF induced cell migration. CONCLUSIONS: Inhibition of c-Met with crizotinib effectively sensitizes cetuximab-resistant KRAS mutant colorectal cancer cell lines to radiation. Crizotinib has the potential to improve outcomes in locally advanced rectal cancer patients undergoing chemoradiation. PMID- 30412913 TI - A Trial-Based Cost-Effectiveness Analysis of Bevacizumab and Chemotherapy versus Chemotherapy Alone for Advanced Nonsquamous Non-Small-Cell Lung Cancer in China. AB - BACKGROUND: The first-line bevacizumab plus chemotherapy resulted in a clinical efficacy for Chinese patients with advanced nonsquamous non-small-cell lung cancer (NSCLC). Some economic analyses have carried out various methods to evaluate the cost-effectiveness of bevacizumab as the first-line treatment for NSCLC in other countries. Our objective was to assess the cost-effectiveness of bevacizumab plus chemotherapy compared with chemotherapy alone for the first-line treatment of advanced nonsquamous NSCLC. METHODS: A Markov model was applied from the perspective of the Chinese health care system to assess cost-effectiveness. It was based on the clinical trial BEYOND that compared bevacizumab plus carboplatin/paclitaxel (B+CP) with placebo plus carboplatin and paclitaxel (PI+CP) for advanced nonsquamous NSCLC. Ten-year quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) were calculated. One way sensitivity analysis and probabilistic sensitivity analyses (PSA) were performed. RESULTS: QALYs were 1.17 years in the B+CP group and 0.83 years in the PI+CP group, resulting in a difference of 0.34 years. The ICER was $130,937.09/QALY, which was far beyond the willing-to-pay threshold of $24,314/QALY. At a threshold of $130,584/QALY, addition of bevacizumab had a 50% probability of being cost-effective. CONCLUSIONS: Bevacizumab is not cost effective when combined with chemotherapy for patients with advanced nonsquamous NSCLC based on the Chinese health care system, resulting in a less demand in the Chinese market. PMID- 30412914 TI - Economics of Medical Devices in India. AB - Most of the industrial sectors of India have undergone major changes in the post liberalization period. During this period, India has become self-reliant in drugs; however, still, 75% of the medical devices are imported in India. According to WHO, almost all devices present in the developing countries have been designed for use in the industrialized countries. With the increase in incidence of non-communicable diseases and decrease in communicable diseases; increase in survival rates and decrease in mortality rates, and increase in ageing population, the healthcare demands have changed in the last decade. In addition to these parameters, aware patients and healthcare professionals, requirement of achieving national targets of healthcare and close proximity to the developed world, is giving a push to the development of indigenous medical device industry. However, the rules and regulations governing medical devices are ambiguous and vague. The Health Ministry of India has notified Medical Devices Rules, 2016, for regulating manufacturing/import/sale/clinical investigation and other related matters concerning medical devices. In addition, the government is funding the start-up industries in medical devices sector. Furthermore, government has taken the initiative of inverted duty structure in India. Also, special med tech zones are being set-up, which will enhance the production at local levels for the local population and will also generate employment for local people. PMID- 30412915 TI - Comparison of Equity Preferences for Life Expectancy Gains: A Discrete Choice Experiment among the Japanese and Korean General Public. AB - BACKGROUND: Setting priorities for limited public resources has become a topic of heated discussion the world over. Assigning different weights for the health gains of different population groups allows for equity considerations in cost effectiveness analysis. However, only a few empirical works have elicited the preferences of the general public. OBJECTIVE: To compare the equity preferemce assigned by Japanese and Koreans. METHODS: We conducted a Web-based survey in March 2013, including a discrete choice experiment, to elicit the equity preferences of the general public for the life expectancy gains of different population groups. We selected attributes and designed the experiment following Norman et al.'s study (Norman R, Hall J, Street D, Viney R. Efficiency and equity: a stated preference approach. Health Econ 2013;22:568-81). Accordingly, we analyzed preference for sex, smoking status, lifestyle, caring status, income, and age. RESULTS: The Japanese assigned a higher preference for males (P < 0.001), nonsmokers (P < 0.001), those with lower income (P < 0.001), and carers (P < 0 .001), and they assigned a lower preference for those with a life expectancy of 60 years (P = 0.002) and 75-year-olds (P < 0.001). Koreans have the same patterns of preference for lower income (P < 0.001), caring (P < 0.001), and smoking status (P = 0.026). However, they prefer both sexes (P = 0.331) and different age groups equally. In both countries, respondents tend to prefer groups with characteristics similar to their own. CONCLUSIONS: People from the two Asian developed countries, with universal health insurance, show different equity preferences. These may reflect the variations in cultural background and coverage of health care services. PMID- 30412916 TI - Post-menopausal acquired diaphragmatic herniation in the context of endometriosis. AB - INTRODUCTION: Acquired diaphragmatic hernias are most commonly associated with traumatic thoracic injury and rarely heal spontaneously. Conditions that promote peritoneal seeding, such as endometriosis, are associated with spontaneous acquired diaphragmatic hernia formation. Non-traumatic acquired diaphragmatic herniation has previously been described in the context of catamenial pneumothorax, however post-menopausal endometriotic diaphragmatic herniation has not been previously reported. PRESENTATION OF CASE: A 57 year old post-menopausal female presented with a strangulated ischaemic loop of small bowel herniating through an acquired right sided endometriotic diaphragmatic hernia not previously visualised on imaging. Clamshell thoracolaparotomy was conducted and the necrotic section of small bowel was resected. The diaphragm was repaired and the patient recovered post-operatively without complications. DISCUSSION: This patient had a complete intestinal malrotation presenting acutely with a small bowel obstruction and herniation through an acquired diaphragmatic rupture. This was possibly related to a diaphragmatic defect caused by endometriosis. CONCLUSION: We presented a case of a post-menopausal acquired diaphragmatic herniation secondary to endometriosis; resulting in acute intestinal obstruction and bowel infarction. To our knowledge, such a case has not been previously reported in existing literature. PMID- 30412917 TI - Early diagnosis of femoral neck stress fractures may decrease incidence of bilateral progression and surgical interventions: A case report and literature review. AB - INTRODUCTION: Early intervention in femoral neck stress fractures (FNSFs) can be self- limiting, but they have an insidious presentation. High index of suspicion for an occult fracture is necessary to avoid bilateral progression and/or operative interventions. CASE PRESENTATION: A 83-year-old female, non-athlete, presents with multiple comorbidities and progressive bilateral FNSFs. Initially the patient presented with groin pain and radiographs demonstrated a non displaced compression type fracture of the right femoral neck without any inciting events. Subsequently, during a post-operative visit of her right hip, a work-up for new onset contralateral groin pain revealed a non-displaced tension type fracture on the left femoral neck. Both FNSFs were treated with percutaneous cannulated screw fixation. DISCUSSION: Vitamin D deficiency, poor nutrition, and osteoporosis have been associated with developing stress fractures. This presents an interesting question of whether these frequently referenced risk factors play an interrelated role. Treatment algorithms are controversial, but have been successful in preventing the progression of occult stress fractures. Yet, identification of FNSFs represents a major challenge in diagnosis for clinicians. CONCLUSION: This case report documents an uncommon fracture pattern in the elderly population. With an aging population, it is pertinent to avoid missed opportunities for prompt diagnosis and implementation of noninvasive methods of treatment. Therefore, paying attention to the risk factors with a high index of suspicion would be ideal. PMID- 30412918 TI - Liver perivascular epithelioid cell tumor in a patient with systemic lupus erythematosus. AB - INTRODUCTION: Perivascular epithelioid cell tumor (PECOMA) is a rare mesenchymal neoplasm which expresses both myogenic and melanocytic markers showing a benign course,although malignant tumors have also been reported. To date there are approximately 33 cases of published hepatic pecomas. PRESENTATION OF CASE: We describe a 47-year-old man with a 27-year past medical history of systemic lupus erythematosus (SLE) who underwent left liver lobectomy due to a liver pecoma. His postoperative course complicated with infection, thrombosis of hepatic artery and liver ischemia as well as drug fever. DISCUSSION: Treatment protocol especially for hepatic PECOMA has not reached a consensus although surgical resection is the preferred therapy. CONCLUSION: This is the first case of coexistence of liver pecoma and SLE. PMID- 30412919 TI - Sentinel lymph node biopsy in porocarcinoma: A case reports. AB - INTRODUCTION: Eccrine porocarcinoma (EPC) is a slow-growing carcinoma arising from the eccrine sweat glands. Based on its clinical presentation it can be confused with malignant and benign skin lesions, both. Histological examination is essential to formulate a correct diagnosis. Surgical excision with clear margins is the standard therapeutic approach while the role of sentinel lymph node biopsy (SNLB) remains controversial. CASE PRESENTATION: The Authors report two cases of EPC of the lower limbs occurred in two women. Patients were treated by wide surgical excision of the lesion and SNLB. 6 months follow-up was disease free for both patients. CONCLUSION: Although a rare cutaneous tumor, EPC has to be taken into account in the differential diagnosis of malignant skin lesions because of its possible loco-regional aggressiveness and related morbidity. Among the available treatment options, surgical excision is considered the standard approach whereas the role of SNLB is controversial although the Authors discuss a possible usefulness for staging and diagnosis. PMID- 30412921 TI - Laparoscopic treatment of large bowel obstruction due to a self-locating peritoneal dialysis catheter. AB - INTRODUCTION: Peritoneal dialysis has been used in the treatment of end-stage renal disease for a long time. The development of continuous ambulatory peritoneal dialysis (CAPD) has achieved an acceptable device of renal replacement therapy. PRESENTATION OF CASE: We report a 55 year-old patient who was initiated on CAPD in February 2016. Three months later, the Tenckhoff catheter was removed due to its malfunction, and a new self-locating peritoneal dialysis catheter was placed in the left side of the abdomen. In September 2016, the patient presented with symptoms of intestinal obstruction. A CT scan revealed a collapsed sigmoid colon with the tungsten tip of the catheter supported on the mesosigmoid as the cause of the occlusion. DISCUSSION: Herein, a rare but clinically important case of mechanical large bowel obstruction due to self-locating peritoneal dialysis catheter is presented. The weight added to the tip of the self-locating catheter for the purpose of stretching it, can be dangerous if a displacement takes place. A laparoscopic procedure was performed, resolving the obstruction by reinserting the peritoneal catheter in its right position. CONCLUSION: The weight added to the tip of self-locating catheters is a matter of concern, since intimate contact between the peritoneal catheter and the intestinal wall can result in perforation or intestinal occlusion. PMID- 30412920 TI - Can tibial tantalum cones eventually eliminate the adjuvant use of metallic augments for AORI type 2B/3 metaphyseal defects??-A novel surgical technique and case series. AB - BACKGROUND: For extensive metaphyseal defects, the use of tantalum cones is usually combined with adjuvant stems which may be cemented/cementless and metallic bone augments for additional stability. A Tibial baseplate-Cone construct with proud tibial cones and without metallic augments has been described for AORI type 2B/3 tibial defects. METHODS: A case series analysis of 6 patients with AORI type 3 defects treated with unstepped proud Tantalum tibial metaphyseal cones without metallic wedges/full width augments. A follow-up analysis done with clinico-radiographic interpretation. RESULTS: 100% osteointegration noted in final radiographs of all patients at an average follow up of 4.1 years. Preoperative average ROM/KSS of 75/49 improved to postoperative ROM/KSS of 104/79. Outcomes were interpreted as excellent in 50% of cases and good in the remaining 50%. CONCLUSION: The "Tibial base plate-cone without augments (BCCA)"type of a construct may offer a valid long term advantage over the Tibial base plate-Augment-Cone combination in massive tibial bone defects. Simply building up the tantalum cone to the native joint line position by increasing cone height can exclude use of augments or wedges. PMID- 30412922 TI - Use of social network analysis in the development, dissemination, implementation, and sustainability of health behavior interventions for adults: A systematic review. AB - Interest in conceptualizing, measuring, and applying social network analysis (SNA) in public health has grown tremendously in recent years. While these studies have broadened our understanding of the role that social networks play in health, there has been less research that has investigated the application of SNA to inform health-related interventions. This systematic review aimed to capture the current applied use of SNA in the development, dissemination, implementation, and sustainability of health behavior interventions for adults. We identified 52 articles published between 2004 and 2016. A wide variety of study settings were identified, most commonly in the US context and most often related to sexual health and HIV prevention. We found that 38% of articles explicitly applied SNA to inform some aspect of interventions. Use of SNA to inform intervention development (as opposed to dissemination, implementation, or sustainability) was most common. The majority of articles represented in this review (n = 39) were quantitative studies, and 13 articles included a qualitative component. Partial networks were most represented across articles, and over 100 different networks measures were assessed. The most commonly described measures were network density, size, and degree centrality. Finally, very few articles defined SNA and not all articles using SNA were theoretically-informed. Given the nascent and heterogeneous state of the literature in this area, this is an important time for the field to coalesce on terminology, measures, and theoretical frameworks. We highlight areas for researchers to advance work on the application of SNA in the design, dissemination, implementation and sustainability of behavioral interventions. PMID- 30412923 TI - Parenting stress and perceived stigma in mothers of young children with epilepsy: A case-control study. AB - The aim was to provide data on parenting stress and perceived stigma in mothers (n = 47) of young children with epilepsy, and to compare findings with those of mothers (n = 48) of developmental, age- and gender-matched children with nonepilepsy-related neurodisability (neurological and/or neurodevelopmental concerns). The mothers of young children (1-7 years) with epilepsy and mothers of children with neurodisability in a defined geographical area of the UK, completed the Parenting Stress Index-4th Edition (PSI-4) and a measure of perceived stigma. Factors associated with parenting stress and stigma were analyzed using linear regression. Thirty-eight percent of mothers of children with epilepsy scored in the at-risk range (>85th percentile) on the Total Stress score of the PSI-4 (Neurodisability 21%) (p = 0.06). Significantly more mothers of children with epilepsy scored in the at-risk range on the Parent-Child Dysfunctional Interaction subscale than mothers of children with neurodisability (Epilepsy 45% vs. Neurodisability 21%; p = 0.01), but not on the Parental Distress subscale (Epilepsy 32% vs. Neurodisability 23%; p = 0.33) or Difficult Child (Epilepsy 57% vs. Neurodisability 46%; p = 0.26) subscales. There was no statistically significant difference in perceived stigma between mothers in both groups (p = 0.51). Factors significantly associated with increased parenting stress in the group with epilepsy were child behavior difficulties (p < 0.001) and maternal sleep difficulties (p = 0.02). Lower child developmental level was the only factor independently associated with increased stigma in the group with epilepsy (p = 0.08). Mothers of young children with epilepsy report high levels of parenting stress and higher levels of difficulties with parent-child interaction compared with that of mothers of children with nonepilepsy-related neurodisability. Parenting stress and stigma in epilepsy were not associated with epilepsy factors. Efforts at reducing parenting stress and stigma should focus on interventions targeting child development and maternal sleep. PMID- 30412924 TI - Predicting drug-resistant epilepsy - A machine learning approach based on administrative claims data. AB - Patients with drug-resistant epilepsy (DRE) are at high risk of morbidity and mortality, yet their referral to specialist care is frequently delayed. The ability to identify patients at high risk of DRE at the time of treatment initiation, and to subsequently steer their treatment pathway toward more personalized interventions, has high clinical utility. Here, we aim to demonstrate the feasibility of developing algorithms for predicting DRE using machine learning methods. Longitudinal, intersected data sourced from US pharmacy, medical, and adjudicated hospital claims from 1,376,756 patients from 2006 to 2015 were analyzed; 292,892 met inclusion criteria for epilepsy, and 38,382 were classified as having DRE using a proxy measure for drug resistance. Patients were characterized using 1270 features reflecting demographics, comorbidities, medications, procedures, epilepsy status, and payer status. Data from 175,735 randomly selected patients were used to train three algorithms and from the remainder to assess the trained models' predictive power. A model with only age and sex was used as a benchmark. The best model, random forest, achieved an area under the receiver operating characteristic curve (95% confidence interval [CI]) of 0.764 (0.759, 0.770), compared with 0.657 (0.651, 0.663) for the benchmark model. Moreover, predicted probabilities for DRE were well calibrated with the observed frequencies in the data. The model predicted drug resistance approximately 2 years before patients in the test dataset had failed two antiepileptic drugs (AEDs). Machine learning models constructed using claims data predicted which patients are likely to fail >=3 AEDs and are at risk of developing DRE at the time of the first AED prescription. The use of such models can ensure that patients with predicted DRE receive specialist care with potentially more aggressive therapeutic interventions from diagnosis, to help reduce the serious sequelae of DRE. PMID- 30412925 TI - Profiling heterogeneity of Alzheimer's disease using white-matter impairment factors. AB - The clinical presentation of Alzheimer's disease (AD) is not unitary as heterogeneity exists in the disease's clinical and anatomical characteristics. MRI studies have revealed that heterogeneous gray matter atrophy patterns are associated with specific traits of cognitive decline. Although white matter (WM) impairment also contributes to AD pathology, its heterogeneity remains unclear. The Latent Dirichlet Allocation (LDA) method is a suitable framework to study heterogeneity and allows to identify latent impairment factors of AD instead of simply mapping an overall disease effect. By exploring whole brain WM skeleton images by using LDA, three latent factors were revealed in AD: a temporal-frontal impairment factor (temporal and frontal lobes, especially hippocampus and para hippocampus), a parietal factor (parietal lobe, especially precuneus), and a long fibre bundle factor (corpus callosum and superior longitudinal fasciculus). As revealed by longitudinal analysis, the latent factors have distinct impact on cognitive decline: for executive function (EF), the temporal-frontal factor was more strongly associated with baseline EF compared with the parietal factor, while the long-fibre bundle factor was most associated with decline rate of EF; for memory, the three factors showed almost equal effect on the baseline memory and decline rate. For each participant, LDA estimates his/her composition profile of latent impairment factors, which indicates disease subtype. We also found that the APOE genotype affects the AD subtype. Specifically, APOE epsilon4 was more associated with the long fibre bundle factor and APOE epsilon2 was more associated with temporal-frontal factor. By investigating heterogeneity and subtypes of AD through white matter impairment factors, our study could facilitate precision medicine. PMID- 30412927 TI - Anatomy Teaching, a "Model" Answer? Evaluating "Geoff", a Painted Anatomical Horse, as a Tool for Enhancing Topographical Anatomy Learning. AB - Development of new methods for anatomy teaching is increasingly important as we look to modernize and supplement traditional teaching methods. In this study, a life-sized equine model, "Geoff" was painted with surface and deep anatomical structures with the aim of improving students' ability to convert theoretical knowledge into improved topographical anatomy knowledge on the live horse. Third and fourth year veterinary medicine students (n = 45) were randomly allocated into experimental (used "Geoff") and control (used textbook) groups. The efficacy of the model was evaluated through a structured oral exam using a live horse. Questionnaires gathered information on student confidence and enjoyment of the task. There was no significant difference in the performance of experimental and control groups either immediately (44+/-20% vs. 40+/-21%; P = 0.504) or 9 weeks after the learning intervention (55+/-17% vs. 55+/-20%; P = 0.980). There were however specific questions on which the experimental group performed better than controls, and for which gender effects were apparent. The students using "Geoff" showed a transient gain in confidence following the session (Likert scale 2.7 to 3.6) however the initial increase was no longer present at the second test. There was a significant influence of gender on confidence with greater confidence gains in females in the Experimental group. The students found the model to be extremely useful and both groups found the sessions enjoyable. The model will be of benefit as a complementary learning tool for students. Anat Sci Educ 00: 000 000. (c) 2018 American Association of Anatomists. PMID- 30412928 TI - The return of measles to Europe highlights the need to regain confidence in immunisation. PMID- 30412926 TI - "If you are here at the clinic, you do not know how many people need help in the community": Perspectives of home-based HIV services from health care workers in rural KwaZulu-Natal, South Africa in the era of universal test-and-treat. AB - BACKGROUND: Limited engagement in clinic-based care is affecting the HIV response. We explored the field experiences and perceptions of local health care workers regarding home-based strategies as opportunities to improve the cascade of care of people living with HIV in rural South Africa as part of a Universal Test-and-Treat approach. METHODS: In Hlabisa sub-district, home-based HIV services, including rapid HIV testing and counselling, and support for linkage to and retention in clinic-based HIV care, were implemented by health care workers within the ANRS 12249 Treatment-as-Prevention (TasP) trial. From April to July 2016, we conducted a mixed-methods study among health care workers from the TasP trial and from local government clinics, using self-administrated questionnaires (n = 90 in the TasP trial, n = 56 in government clinics), semi-structured interviews (n = 13 in the TasP trial, n = 5 in government clinics) and three focus group discussions (n = 6-10 health care workers of the TasP trial per group). Descriptive statistics were used for quantitative data and qualitative data were analysed thematically. RESULTS: More than 90% of health care workers assessed home-based testing and support for linkage to care as feasible and acceptable by the population they serve. Many health care workers underlined how home visits could facilitate reaching people who had slipped through the cracks of the clinic-based health care system and encourage them to successfully access care. Health care workers however expressed concerns about the ability of home based services to answer the HIV care needs of all community members, including people working outside their home during the day or those who fear HIV-related stigmatization. Overall, health care workers encouraged policy-makers to more formally integrate home-based services in the local health system. They promoted reshaping the disease-specific and care-oriented services towards more comprehensive goals. CONCLUSION: Because home-based services allow identification of people early during their infection and encourage them to take actions leading to viral suppression, HCWs assessed them as valuable components within the panel of UTT interventions, aiming to reach the 90-90-90 UNAIDS targets, especially in the rural Southern African region. TRIAL REGISTRATION: The registration number of the ANRS 12249 TasP trial on ClinicalTrials.gov is NCT01509508. PMID- 30412930 TI - Universal parental support for parents of adolescents: Who wants municipality based parental support and in what form? AB - Parenting a child through adolescence can be a challenge for many parents; adolescents go through notable developmental, physical, and psychological changes that affect the relationships around them. Most parents find parental support during these years important. These young people's relationships with their parents are important to their mental health, but although parental support is universally available to parents of younger children, it is still scarce for parents of adolescents. The aim of this study was to explore what factors are associated with interest in universal parental support through telephone interviews and questionnaires with 223 parents of 13- to 17-year-olds. Parents' interest in parental support was linked to their own anxious mood, their lower perceived parental capacity, their perception of the child as having psychiatric problems, the parents' perception of their adolescents' openness about things and their perception of the adolescent's overall difficulties in daily life due to psychiatric symptoms. The results show that lighter forms of support such as lectures or seminars were more appealing to parents with higher social status. Offering community-based individual counseling and leader-led parent training groups therefore has the potential to reach parents with difficulties more equally, while offering support only through lectures and seminars could increase the inequality between parents in different social situations. PMID- 30412929 TI - Bioanalytical technique for determination of Tasimelteon in human plasma by LC MS/MS and its application to pharmacokinetic study in humans. AB - A highly sensitive, specific and rapid Liquid Chromatography-Tandem Mass Spectrometry technique for the quantification of tasimelteon in human plasma has been developed and validated using tasimelteon-d5 as internal standard. Liquid- liquid extraction technique with ethyl acetate was used for extraction of tasimelteon from the plasma. The chromatographic separation was achieved on Agilent Zorbax, Eclipse, C18, (4.6*50 mm, 5MUm) column using the mobile phase of acetonitrile and 0.02% formic acid buffer (85:15, v/v) with the flow rate of 0.5 mL/min. A detailed method validation was performed as per the United States food & drug administration guidelines. The linear calibration curve was obtained over the concentration range of 0.30-299 ng/mL. The API-4000 Liquid Chromatography Tandem Mass Spectrometry was operated under the multiple monitoring mode during the analysis. The validated method was successfully applied to estimate plasma concentration of TSM after oral administration of single dose of 20mg capsule of tasimelteon in healthy volunteers under fasting conditions, the maximum concentration Cmax of the drug achieved in the plasma is 314+/-147 ng/mL and the Tmax , time at which Cmax is attained at 0.54+/-0.22 h. PMID- 30412932 TI - Neutrophils and IL17A mediate flagellar hook protein FlgE-induced mouse acute lung inflammation. AB - Bacterial flagellar hook and recombinant flagellar hook protein E (FlgE) were reportedly immunostimulatory in mammalian cells or tissues. Current study focused on the mechanisms underlying FlgE stimulation. In an acute lung injury model induced by intranasal FlgE challenge, neutrophils were the predominant infiltrates in lungs, and depletion of neutrophils with anti-Ly6G antibody attenuated FlgE-induced lung damage. However, the FlgE-induced neutrophils recruitment, neutrophils reactive oxygen species (ROS) generation, and neutrophil extracellular traps (NETs) formation were significantly impaired in Il17a-/- mice compared with those in wild-type (WT) mice. In FlgE-treated lung organoids and isolated neutrophils, the phosphorylation levels of signal transfer and activator of transcription protein 3 (STAT3), which was involved in neutrophils functions, were upregulated, but this upregulation was partly impaired upon IL17A deficiency or by IL6 neutralisation. When neutrophils isolated from WT mice were treated with FlgE, the expression of IL17A/IL17RC was increased, but the activation was blocked by STAT3 inhibitor. The NETs formation in FlgE-treated neutrophils was not affected by the ROS inhibitor or recombinant IL17A alone but partly impaired in the presence of STAT3 pathway inhibition. In conclusion, we propose that the pro-inflammatory activities of FlgE are mediated by activating STAT3 phosphorylation and IL17A/IL17R expression and by promoting a ROS-independent NETs formation. PMID- 30412933 TI - Re: Is Early Benign Prostatic Hyperplasia (BPH) Treatment Worthwhile? PMID- 30412934 TI - Re: Relationship among Diet Habit and Lower Urinary Tract Symptoms and Sexual Function in Outpatient-Based Males with LUTS/BPH: A Multiregional and Cross Sectional Study in China. PMID- 30412935 TI - Re: Three-Year Outcomes of the Prospective, Randomized Controlled Rezum System Study: Convective Radiofrequency Thermal Therapy for Treatment of Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia. PMID- 30412936 TI - Re: Fexapotide Triflutate: Results of Long-Term Safety and Efficacy Trials of a Novel Injectable Therapy for Symptomatic Prostate Enlargement. PMID- 30412937 TI - Re: Impact of Body Mass Index on Robot-Assisted Radical Cystectomy with Intracorporeal Urinary Diversion. PMID- 30412938 TI - Re: Feasibility of an Image-Based Mobile Health Protocol for Postoperative Wound Monitoring. PMID- 30412939 TI - Re: Use of Bladder Antimuscarinics in Older Adults with Impaired Cognition. PMID- 30412940 TI - Re: Long-Term Adherence to Antimuscarinic Drugs when Treating Overactive Bladder in the Older: Subjective Reason and Objective Factors. PMID- 30412941 TI - Re: Urinary Incontinence in Alzheimer's Disease. PMID- 30412942 TI - Re: Natural History of Non-Neurogenic Overactive Bladder and Urinary Incontinence over 5 Years in Community-Dwelling Older Men: The Concord Health and Aging in Men Project. PMID- 30412943 TI - Re: A Pooled Analysis of the Efficacy of Fesoterodine for the Treatment of Overactive Bladder, and the Relationship between Safety, Co-Morbidity and Polypharmacy in Patients Aged 65 Years or Older. PMID- 30412944 TI - Re: Comparison of Fosfomycin against Fluoroquinolones for Transrectal Prostate Biopsy Prophylaxis: An Individual Patient-Data Meta-Analysis. PMID- 30412946 TI - Re: Vesico-Urethral Anastomosis (VUA) Evaluation of Short- and Long-Term Outcome after Robot-Assisted Laparoscopic Radical Prostatectomy (RARP): Selective Cystogram to Improve Outcome. PMID- 30412947 TI - Re: The Impact of Lateral Bladder Neck Preservation on Urinary Continence Recovery after Robot-Assisted Radical Prostatectomy. PMID- 30412945 TI - Re: Norwegian Patients and Retail Chicken Meat Share Cephalosporin-Resistant Escherichia coli and IncK/blaCMY-2 Resistance Plasmids. PMID- 30412948 TI - Re: Pharmacist Supply of Sildenafil: Pharmacists' Experiences and Perceptions on Training and Tools for Supply. PMID- 30412949 TI - Re: The Role of Neutrophil-to-Lymphocyte Ratio in Men with Erectile Dysfunction Preliminary Findings of a Real-Life Cross-Sectional Study. PMID- 30412950 TI - Re: Efficacy and Safety of Tadalafil 5 mg Once Daily for the Treatment of Erectile Dysfunction after Robot-Assisted Laparoscopic Radical Prostatectomy: A 2 Year Follow-up. PMID- 30412952 TI - Re: Sperm Donor Anonymity: A Concept Rendered Obsolete by Modern Technology. PMID- 30412951 TI - Re: Abnormal Brain Structure as a Potential Biomarker for Venous Erectile Dysfunction: Evidence from Multimodal MRI and Machine Learning. PMID- 30412953 TI - Re: The Effect of Low-Intensity Extracorporeal Shockwave Therapy in an Obesity Associated Erectile Dysfunction Rat Model. PMID- 30412954 TI - Re: Parental Influences on Sperm Banking Attempts among Adolescent Males Newly Diagnosed with Cancer. PMID- 30412955 TI - Re: Development of the Testis in Pre-Pubertal Boys with Cancer after Biopsy for Fertility Preservation. PMID- 30412956 TI - Re: Improving Sperm Viability after Spinal Cord Injury Using Hyperbaric Therapy. PMID- 30412957 TI - Re: Men with Severe Oligospermia Appear to Benefit from Varicocele Repair: A Cost Effectiveness Analysis of Assisted Reproductive Technology. PMID- 30412958 TI - Re: Quality of Reporting for Randomized Controlled Trials in the Hypospadias Literature: Where do we Stand? PMID- 30412959 TI - Re: Hypospadias Surgery in England: Higher Volume Centres Have Lower Complication Rates. PMID- 30412960 TI - Re: Long-Term Follow-up after Traditional versus Modified Perineal Approach in the Management of Female Epispadias. PMID- 30412961 TI - Re: Rhabdomyosarcoma of the Lower Female Genital Tract: An Analysis of 144 Cases. PMID- 30412962 TI - Re: Race, Risk, and Willingness of End-Stage Renal Disease Patients without Hepatitis C Virus to Accept an HCV-Infected Kidney Transplant. PMID- 30412963 TI - Re: Qualitative Questionnaire on the Psychosocial Wellbeing of Mothers of Children with BEEC. PMID- 30412964 TI - Re: Insurance Type and Access to Health Care Providers and Appointments under the Affordable Care Act. PMID- 30412965 TI - Re: Comparative Analysis of Biopsy Upgrading in Four Prostate Cancer Active Surveillance Cohorts. PMID- 30412966 TI - Re: Association of Health Literacy with Postoperative Outcomes in Patients Undergoing Major Abdominal Surgery. PMID- 30412968 TI - Re: Emergency Management of Priapism in the United Kingdom: A Survey of Current Practice. PMID- 30412967 TI - Re: Medicare Accountable Care Organization Enrollment and Appropriateness of Cancer Screening. PMID- 30412969 TI - Re: Survey on the Contemporary Management of Intraoperative Urethral Injuries during Penile Prosthesis Implantation. PMID- 30412970 TI - Re: A Worldwide Survey on Peyronie's Disease Surgical Practice Patterns among Surgeons. PMID- 30412971 TI - Re: Clinical Utility of Routine Follow-up Cystography in the Management of Traumatic Bladder Ruptures. PMID- 30412973 TI - Re: Comparison of Flexible Ureteroscopy Damage Rates for Lower Pole Renal Stones by Laser Fiber Type. PMID- 30412972 TI - Re: A Rapid Screening of a Recurrent CYP24A1 Pathogenic Variant Opens the Way to Molecular Testing for Idiopathic Infantile Hypercalcemia (IIH). PMID- 30412974 TI - Re: Evaluating Factors That Dictate Struvite Stone Composition: A Multi Institutional Clinical Experience from the EDGE Research Consortium. PMID- 30412975 TI - Re: Three-Dimensional Evaluation of Perirenal Fat Volume in Patients with Nephrolithiasis. PMID- 30412976 TI - Re: Patients' Preferences for Adjuvant Sorafenib after Resection of Renal Cell Carcinoma in the SORCE Trial: What Makes it Worthwhile? PMID- 30412977 TI - Re: Perioperative Morbidity of Lymph Node Dissection for Renal Cell Carcinoma: A Propensity Score-Based Analysis. PMID- 30412979 TI - Re: Comparison between Adjuvant and Early-Salvage Postprostatectomy Radiotherapy for Prostate Cancer with Adverse Pathological Features. PMID- 30412978 TI - Re: Association between Number of Endoscopic Resections and Utilization of bacillus Calmette-Guerin Therapy for Patients with High-Grade, Non-Muscle Invasive Bladder Cancer. PMID- 30412980 TI - Re: Contemporary Use Trends and Survival Outcomes in Patients Undergoing Radical Cystectomy or Bladder-Preservation Therapy for Muscle-Invasive Bladder Cancer. PMID- 30412981 TI - Re: Development and Validation of a Novel Integrated Clinical-Genomic Risk Group Classification for Localized Prostate Cancer. PMID- 30412982 TI - Re: Validation of the 2015 Prostate Cancer Grade Groups for Predicting Long-Term Oncologic Outcomes in a Shared Equal-Access Health System. PMID- 30412983 TI - Re: Peptidoglycan Association of Murein Lipoprotein is Required for KpsD Dependent Group 2 Capsular Polysaccharide Expression and Serum Resistance in a Uropathogenic Escherichia coli Isolate. PMID- 30412984 TI - Re: Surgical Management of Complex Residual Masses following Systemic Chemotherapy for Metastatic Testicular Germ Cell Tumours. PMID- 30412985 TI - Re: AgRP to Kiss1 Neuron Signaling Links Nutritional State and Fertility. PMID- 30412986 TI - Re: An Aberrant SREBP-Dependent Lipogenic Program Promotes Metastatic Prostate Cancer. PMID- 30412987 TI - Re: Efficacy and Safety of Combinations of Mirabegron and Solifenacin Compared with Monotherapy and Placebo in Patients with Overactive Bladder (SYNERGY Study). PMID- 30412988 TI - Re: AUGS Consensus Statement: Association of Anticholinergic Medication Use and Cognition in Women with Overactive Bladder. PMID- 30412990 TI - Re: Modulation of the Rat Micturition Reflex with Transcutaneous Ultrasound. PMID- 30412989 TI - Re: Surgeons' Views on Sling Tensioning during Surgery for Female Stress Urinary Incontinence. PMID- 30412992 TI - Composite Based on Biphasic Calcium Phosphate (HA/beta-TCP) and Nanocellulose from the Acai Tegument. AB - The use of lignocellulosic remnants of the acai agro-business will benefit the environment with a precursor material for biomedical applications. Nanocellulose (NC) allows the biomimetic growth of biphasic ceramics on its surface, with characteristics compatible with bone tissue, including bioactive properties and biocompatibility. In this study, the composites were obtained from acai tegument (Euterpe Oleracea Mart.) NC using acid hydrolysis. The characterization performed by scanning electron microscopy showed the characteristic crystals of hydroxyapatite (HA) and calcium triphosphate (beta-TCP) based on the results of X ray diffraction, with the peak at 22 degrees , showing the NC nucleation of HA and peak at 17 degrees showing tricalcium phosphate (beta-TCP). Fourier transform infrared spectroscopy confirmed the presence of O-H at 3400 cm-1 and C H at 2900 cm-1, which is characteristic of cellulose; peaks were also observed at 1609 cm-1, verifying the reduction in lignin content. Groups PO4-3 at approximately 1070 cm-1, P-OH at 910-1040 cm-1, and HCO3- at 2450 cm-1 confirmed the formation of HA and beta-TCP. The zeta potential had a range of -11 +/- 23.8 mV related to particle size, which had a range of 164.2 * 10-9-4748 * 10-9 m. PMID- 30412993 TI - The Tree Is My Anchor: A Pilot Study on the Treatment of BED through Nature-Based Therapy. AB - Binge eating disorder (BED), characterized by recurrent episodes of binge eating with a subjective experience of lack of control, is the world's most common eating disorder. The aim of the present pilot study was to examine the feasibility of implementing nature-based therapy (NBT) in the treatment of BED. The NBT intervention was compared to Support Group Meetings (SGMs), which are the only publicly available form of support for people diagnosed with BED in Denmark. Twenty participants with a BED diagnosis were included in the study, which had a mixed-methods design including Eating Disorder Examination interviews, semi structured interviews, and questionnaires measuring well-being (The Psychological General Well-Being Index) and self-esteem (Rosenberg's Self-Esteem Scale). Both the NBT and the SGMs showed positive results on all outcome measures (decreases in binge eating episodes and increases in general psychological well-being and self-esteem). The interviews indicated that the NBT context made the psychotherapeutic content more accessible to the participants and further helped them transfer the therapeutic gains to daily life after completing treatment. However, these results should be interpreted with caution due to the small sample size-ideally, they would need to be tested on a larger, randomized sample. PMID- 30412994 TI - Endobronchial Ultrasound under Moderate Sedation versus General Anesthesia. AB - BACKGROUND: Different anesthetic protocols may influence endobronchial ultrasound guided needle aspiration (EBUS-TBNA) outcomes, patient comfort, and even safety. In this study, two anesthesia techniques were assessed and compared for EBUS TBNA. METHODS: A prospective, multicenter study was carried out. Patients were allocated to Group 1 (general anesthesia with neuromuscular blockade and controlled ventilation) and Group 2 (intravenous sedation). EBUS-TBNA accuracy was the primary outcome. Safety, patient comfort and satisfaction, and operators' difficulties were defined as secondary outcomes. RESULTS: Of the 115 patients enrolled (Group 1 = 59, Group 2 = 56), EBUS-TBNA was performed for hilar or mediastinal lesion diagnosis and lung cancer staging in, respectively, 77 (67%) and 38 (33%) patients. The numbers of lymph nodes stations (1.8 +/- 1.0 vs. 1.7 +/- 1.0, p = 0.472) and punctures per station (6.9 +/- 3.1 vs. 6.0 +/- 2.5, p = 0.084) were similar between groups. Adequate samples were obtained from 109 patients (97.3%) with similar diagnostic accuracy. Procedure duration was not significantly different (p = 0.348). Hemodynamic parameters and systolic and diastolic blood pressures were higher in Group 1 at the beginning and at the end of the procedure. Adverse events were equally distributed, and no significant differences were found regarding patient satisfaction and bronchoscopist/anesthesiologist difficulties. CONCLUSIONS: The type of anesthesia used did not influence EBUS-TBNA outcomes. EBUS-TBNA performed under sedation or general anesthesia did not affect the diagnostic yield, complication rate, and patients' comfort and satisfaction. PMID- 30412991 TI - Nano-Mediated Photodynamic Therapy for Cancer: Enhancement of Cancer Specificity and Therapeutic Effects. AB - Deregulation of cell growth and development lead to cancer, a severe condition that claims millions of lives worldwide. Targeted or selective approaches used during cancer treatment determine the efficacy and outcome of the therapy. In order to enhance specificity and targeting and obtain better treatment options for cancer, novel modalities are currently under development. Photodynamic therapy has the potential to eradicate cancer, and combination therapy would yield even greater outcomes. Nanomedicine-aided cancer therapy shows enhanced specificity for cancer cells and minimal side-effects coupled with effective cancer destruction both in vitro and in vivo. Nanocarriers used in drug-delivery systems are very capable of penetrating the cancer stem cell niche, simultaneously killing cancer cells and eradicating drug-resistant cancer stem cells, yielding therapeutic efficiency of up to 100-fold against drug-resistant cancer in comparison with free drugs. Safety precautions should be considered when using nano-mediated therapy as the effects of extended exposure to biological environments are still to be determined. PMID- 30412995 TI - A Modified Kulka Micromethod for the Rapid and Safe Analysis of Fructose and 1 Deoxy-d-xylulose-5-phosphate. AB - The Kulka resorcinol assay (Kulka, R.G., Biochemistry 1956, 63, 542-548) for ketoses has been widely used in the literature but suffers from two major disadvantages: (a) it employs large amounts of potentially harmful reagents for a general biology laboratory environment; and (b) in its original formulation, it is unsuited for modern high-throughput applications. Here, we have developed a modified Kulka assay, which contains a safer formulation, employing approx. 5.4 M HCl in 250 uL aliquots, and is suitable for use in high-throughput systems biology or enzymatic applications. The modified assay has been tested extensively for the measurement of two ketoses-fructose (a common substrate in cell growth experiments) and 1-deoxy-d-xylulose-5-phosphate (DXP), the product of the DXP synthase reaction-which until now has only been assayable using time-consuming chromatographic methods or radioactivity. The Kulka microassay has a sensitivity of 0-250 nmol fructose or 0-500 nmol DXP. The assay is suitable for monitoring the consumption of fructose in bacterial growth experiments but is too insensitive to be used directly for the measurement of DXP in in vitro enzyme assays. However, we show that after concentration of the DXP-enzyme mix by butanol extraction, the Kulka resorcinol method can be used for enzyme assays. PMID- 30412997 TI - Variety Identification of Raisins Using Near-Infrared Hyperspectral Imaging. AB - Different varieties of raisins have different nutritional properties and vary in commercial value. An identification method of raisin varieties using hyperspectral imaging was explored. Hyperspectral images of two different varieties of raisins (Wuhebai and Xiangfei) at spectral range of 874-1734 nm were acquired, and each variety contained three grades. Pixel-wise spectra were extracted and preprocessed by wavelet transform and standard normal variate, and object-wise spectra (sample average spectra) were calculated. Principal component analysis (PCA) and independent component analysis (ICA) of object-wise spectra and pixel-wise spectra were conducted to select effective wavelengths. Pixel-wise PCA scores images indicated differences between two varieties and among different grades. SVM (Support Vector Machine), k-NN (k-nearest Neighbors Algorithm), and RBFNN (Radial Basis Function Neural Network) models were built to discriminate two varieties of raisins. Results indicated that both SVM and RBFNN models based on object-wise spectra using optimal wavelengths selected by PCA could be used for raisin variety identification. The visualization maps verified the effectiveness of using hyperspectral imaging to identify raisin varieties. PMID- 30412996 TI - Almond Allergy: An Overview on Prevalence, Thresholds, Regulations and Allergen Detection. AB - Food allergy has been on the increase for many years. The prevalence of allergy to different foods varies widely depending on type of food, frequency of consumption and geographic location. Data from the literature suggests that the prevalence of tree nut allergy is of the order of 1% in the general population. Almond is one such tree nut that is frequently eaten in many parts of the world and represents a potential allergenic hazard. Given the need to label products that contain allergens, a number of different methods of direct and indirect detection have been developed. However, in the absence of population-based threshold data, and given that almond allergy is rare, the sensitivity of the required detection is unknown and thus aims as low as possible. Typically, this is less than 1 ppm, which matches the thresholds that have been shown for other allergens. This review highlights the lack of quantitative data on prevalence and thresholds for almonds, which is limiting progress in consumer protection. PMID- 30412999 TI - Long-Term Effect of Outdoor Air Pollution on Mortality and Morbidity: A 12-Year Follow-Up Study for Metropolitan France. AB - BACKGROUND: Short-term effects of air pollution are documented more than long term effects. OBJECTIVE: We investigated 12-year impacts of ambient air pollutants on cardiovascular and respiratory morbidity and mortality at the departmental level in metropolitan France. METHODS: Daily air pollution data at 2 km resolution, including concentrations of particulate matter of 10 um or 2.5 um in diameter or less (PM10 and PM2.5), nitrogen dioxide (NO2), and ozone (O3), were accrued from the CHIMERE database for 1999 and 2000. Simultaneously, morbidity (hospitalizations) and mortality data were collected in 2012 using the ESPS (Enquete Sante et Protection Sociale/Health, Health Care and Insurance Survey) survey data and the CepiDc (Centre d'Epidemiologie sur les Causes Medicales de Deces/French Epidemiology Centre on Medical Causes of Death) database. Based on Poisson regression analyses, the long-term effect was estimated. A higher risk of all-cause mortality was observed using CepiDc database, with a relative risk of 1.024 (95% CI: 1.022, 1.026) and 1.029 (95% CI: 1.027, 1.031) for a 10 ug/m3 increase in PM2.5 and PM10, respectively. Mortality due to cardiovascular and respiratory diseases likewise exhibited long-term associations with both PM2.5 and PM10. Using ESPS survey data, a significant risk was observed for both PM2.5 and PM10 in all-cause mortality and all-cause morbidity. Although a risk for higher all-cause mortality and morbidity was also present for NO2, the cause-specific relative risk due to NO2 was found to be lesser, as compared to PM. Nevertheless, cardiovascular and respiratory morbidity were related to NO2, along with PM2.5 and PM10. However, the health effect of O3 was seen to be substantially lower in comparison to the other pollutants. CONCLUSION: Our study confirmed that PM has a long-term impact on mortality and morbidity. Exposure to NO2 and O3 could also lead to increased health risks. PMID- 30412998 TI - Latent Iron Deficiency as a Marker of Negative Symptoms in Patients with First Episode Schizophrenia Spectrum Disorder. AB - Iron deficiency may alter dopaminergic transmission in the brain. This study investigated whether iron metabolism is associated with negative symptoms in patients with first-episode psychosis. The study enrolled 121 patients with first episode schizophrenia spectrum disorder, whose duration of treatment was 2 months or less. Negative symptoms were measured using the Positive and Negative Syndrome Scale (PANSS) and Clinician-Rated Dimensions of Psychosis Symptom Severity (Dimensional) scale of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Prominent negative symptoms were defined as moderate or severe negative symptoms on the Dimensional scale of the DSM-5. Iron deficiency was defined as a serum ferritin <= 20 ng/mL. Patients with iron deficiency were significantly more likely to have prominent negative symptoms (45.2 vs. 22.2%; p = 0.014) and a higher PANSS negative symptoms score (p = 0.046) than those with normal ferritin levels. Patients with prominent negative symptoms had significantly lower ferritin levels (p = 0.025). The significance of these results remained after controlling for the duration of illness and other confounding variables. Our finding of an independent association between iron deficiency and negative symptoms in patients at the very early stage of illness implies that iron dysregulation has an effect on negative symptoms in patients with schizophrenia. The possibility of therapeutic intervention with iron should be further investigated. PMID- 30413000 TI - Surface Plasmon Resonances in Silver Nanostars. AB - The recent development of silver nanostars (Ag-NSs) is promising for improved surface-enhanced sensing and spectroscopy, which may be further exploited if the mechanisms behind the excitation of localized surface plasmon resonances (LSPRs) are identified. Here, we show that LSPRs in Ag-NSs can be obtained with finite difference time-domain (FDTD) calculations by considering the nanostars as combination of crossed nanorods (Ag-NRs). In particular, we demonstrate that an apparent tail at large wavelengths ( lambda ? 700 nm) observed in the extinction spectra of Ag-NSs is due to a strong dipolar plasmon resonance, with no need to invoke heterogeneity (different number of arms) effects as is normally done in the literature. Our description also indicates a way to tune the strongest LSPR at desired wavelengths, which is useful for sensing applications. PMID- 30413001 TI - A Nationwide Survey on Danon Disease in Japan. AB - Danon disease, an X-linked dominant cardioskeletal myopathy, is caused by primary deficiency of lysosome-associated membrane protein-2 (LAMP-2). To clarify the clinicopathological features and management, we performed the first nationwide, questionnaire-based survey on Danon disease in Japan. A total of 39 patients (17 males, 22 females) from 20 families were identified in the analysis. All patients had cardiomyopathy. Of the 21 patients who died, 20 (95%) died of cardiac failure or sudden cardiac arrest. Most patients had hypertrophic cardiomyopathy. Wolf Parkinson-White syndrome was present at a comparatively high incidence (54% in males, 22% in females). Only one female patient received a heart transplant, which is the most effective therapy. Histopathologically, all male patients showed autophagic vacuoles with sarcolemmal features in muscle. Half of the probands showed de novo mutations. Male patients showed completely absent LAMP-2 expression in muscle. In contrast, female patients showed decreased LAMP-2 expression, which is suggested to reflect LAMP-2 haploinsufficiency due to a heterozygous null mutation. In conclusion, Danon disease is an extremely rare muscular disorder in Japan. Cardiomyopathy is the most significant prognostic factor and the main cause of death. Our findings suggest that the present survey can extend our understanding of the clinical features of this rare disease. PMID- 30413003 TI - Ishophloroglucin A, a Novel Phlorotannin for Standardizing the Anti-alpha Glucosidase Activity of Ishige okamurae. AB - Nutraceutical use of algae requires understanding of the diversity and significance of their active compositions for intended activities. Ishige okamurae (I. okamurae) extract is well-known to possess alpha-glucosidase inhibitory activity; however, studies are needed to investigate its active composition in order to standardize its alpha-glucosidase inhibitory activity. In this study, we observed the intensity of the dominant compounds of each I. okamurae extract harvested between 2016 and 2017, and the different potency of each I. okamurae extract against alpha-glucosidase. By comparing the anti-alpha glucosidase ability of the dominant compounds, a novel Ishophloroglucin A with highest alpha-glucosidase inhibitory activity was identified and suggested for standardization of anti-alpha-glucosidase activity in I. okamurae extract. Additionally, a validated analytical method for measurement of Ishophloroglucin A for future standardization of I. okamurae extract was established in this study. We suggest using Ishophloroglucin A to standardize anti-alpha-glucosidase potency of I. okamurae and propose the significance of standardization based on their composition for effective use of algae as marine-derived nutraceuticals. PMID- 30413002 TI - Mixed-Phase MnO2/N-Containing Graphene Composites Applied as Electrode Active Materials for Flexible Asymmetric Solid-State Supercapacitors. AB - MnO2/N-containing graphene composites with various contents of Mn were fabricated and used as active materials for the electrodes of flexible solid-state asymmetric supercapacitors. By scanning electron microscopes (SEM), transmission electron microscope (TEM), energy-dispersive X-ray spectroscopy (EDS), X-ray photoelectron spectrometer (XPS), fourier-transform infrared spectroscopy (FTIR) and Raman spectra, the presence of MnO2 and N-containing graphene was verified. The MnO2 nanostructures decorated on the N-containing graphene were of alpha- and gamma-mixed phases. N-containing graphene was found to reduce the charge transfer impedance in the high-frequency region at the electrode/electrolyte interface (RCT) due to its good conductivity. The co-existence of MnO2 and N-containing graphene led to a more reduced RCT and improved charge transfer. Both the mass loading and content of Mn in an active material electrode were crucial. Excess Mn caused reduced contacts between the electrode and electrolyte ions, leading to increased RCT, and suppressed ionic diffusion. When the optimized mass loading and Mn content were used, the 3-NGM1 electrode exhibiting the smallest RCT and a lower ionic diffusion impedance was obtained. It also showed a high specific capacitance of 638 F.g-1 by calculation from the cyclic voltammetry (CV) curves. The corresponding energy and power densities were 372.7 Wh.kg-1 and 4731.1 W.kg 1, respectively. The superior capacitance property arising from the synergistic effect of mixed-phase MnO2 and N-containing graphene had permitted the composites promising active materials for flexible solid-state asymmetric supercapacitors. Moreover, the increase of specific capacitance was found to be more significant by the pseudocapacitive MnO2 than N-containing graphene. PMID- 30413004 TI - Three-Dimensional Bone Substitutes for Oral and Maxillofacial Surgery: Biological and Structural Characterization. AB - BACKGROUND: Bone substitutes, either from human (autografts and allografts) or animal (xenografts) sources, suffer from inherent drawbacks including limited availability or potential infectivity to name a few. In the last decade, synthetic biomaterials have emerged as a valid alternative for biomedical applications in the field of orthopedic and maxillofacial surgery. In particular, phosphate-based bone substitution materials have exhibited a high biocompatibility due to their chemical similitude with natural hydroxyapatite. Besides the nature of the biomaterial, its porous and interconnected architecture is essential for a correct osseointegration. This performance could be predicted with an extensive characterization of the biomaterial in vitro. METHODS: In this study, we compared the biological, chemical, and structural features of four different commercially available bone substitutes derived from an animal or a synthetic source. To this end, u-CT and SEM were used to describe the biomaterials structure. Both FTIR and EDS analyses were carried out to provide a chemical characterization. The results obtained by these techniques were correlated with cell adhesion and proliferation of the osteosarcoma MG-63 human cell line cultured in vitro. RESULTS: The findings reported in this paper indicate a significant influence of both the nature and the structure of the biomaterials in cell adhesion and proliferation, which ultimately could affect the clinical performance of the biomaterials. CONCLUSIONS: The four commercially available bone substitutes investigated in this work significantly differed in terms of structural features, which ultimately influenced in vitro cell proliferation and may so affect the clinical performance of the biomaterials. PMID- 30413005 TI - Non-Structural Proteins from Human T-cell Leukemia Virus Type 1 in Cellular Membranes-Mechanisms for Viral Survivability and Proliferation. AB - Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of illnesses, such as adult T-cell leukemia/lymphoma, myelopathy/tropical spastic paraparesis (a neurodegenerative disorder), and other diseases. Therefore, HTLV-1 infection is a serious public health concern. Currently, diseases caused by HTLV-1 cannot be prevented or cured. Hence, there is a pressing need to comprehensively understand the mechanisms of HTLV-1 infection and intervention in host cell physiology. HTLV-1-encoded non-structural proteins that reside and function in the cellular membranes are of particular interest, because they alter cellular components, signaling pathways, and transcriptional mechanisms. Summarized herein is the current knowledge about the functions of the membrane-associated p8I, p12I, and p13II regulatory non-structural proteins. p12I resides in endomembranes and interacts with host proteins on the pathways of signal transduction, thus preventing immune responses to the virus. p8I is a proteolytic product of p12I residing in the plasma membrane, where it contributes to T-cell deactivation and participates in cellular conduits, enhancing virus transmission. p13II associates with the inner mitochondrial membrane, where it is proposed to function as a potassium channel. Potassium influx through p13II in the matrix causes membrane depolarization and triggers processes that lead to either T-cell activation or cell death through apoptosis. PMID- 30413006 TI - Influence of Employment Conditions and Length of Residence on Adherence to Dietary Recommendations in Immigrant Workers in Spain. AB - The objective of this article is to analyze the influence of employment conditions on adherence to dietary recommendations among those born in Spain and immigrants by their time of residence. Data were used from the Platform of Longitudinal Studies of Immigrant Families (PELFI) cohort (n = 215) to compare Spaniards and immigrants with <14 and >14 years of residence. The questionnaire on frequency of food consumption (15 items) was used to measure adherence to dietary recommendations. Logistic regression models were used, adjusting for sociodemographic characteristics and employment conditions. Adherence to dietary recommendations was greater among Spaniards, followed by immigrants with >14 years of residence and <14 years of residence. The greatest adherence among Spaniards was for eggs (immigrants >= 14 years: 1/ORa = 2.89, <14 years: 1/ORa = 3.92), fish (immigrants >= 14 immigrants: 1/ORa = 2.33, <14 years: 1/ORa = 4.72), vegetables (immigrants >= 14 years: 1/ORa = 3.26, <14 years: 1/ORa = 4.87), dairy products (immigrants >= 14 years: 1/ORa = 14.34, <14 years: 1/ORa = 26.78), and sugary drinks (immigrants >=14 years: 1/ORa = 2.12, <14 years: 1/ORa = 3.48), and the lowest adherence was for the consumption of sausages and cold cuts (immigrants >= 14 years: Ora = 7.62, <14 years: ORa = 24.65). Adjusting for sociodemographic and employment conditions variables did not result in variation in the observed differences between Spaniards, immigrants with <14 years of residence, and immigrants with >14 years of residence. PMID- 30413007 TI - Isolation of Chavibetol and Methyleugenol from Essential Oil of Pimenta pseudocaryophyllus by High Performance Liquid Chromatography. AB - A high performance liquid chromatography (HPLC) method was developed for the simultaneous isolation, on a semi-preparative scale, of chavibetol and methyleugenol from the crude essential oil of P. pseudocaryophyllus leaves. The purity of the isolated compounds and their quantifications were developed using GC/FID. Chavibetol was isolated with high purity (98.7%) and mass recovery (94.6%). The mass recovery (86.4%) and purity (85.3%) of methyleugenol were lower than those of chavibetol. Both compounds were identified on the basis of spectral analysis. The results suggest that the method can provide chavibetol with high purity, mass recovery, and productivity from crude essential, which will be used in bioassays against stored insect pests. PMID- 30413008 TI - Antiproliferative Activity of Combined Biochanin A and Ginsenoside Rh2 on MDA-MB 231 and MCF-7 Human Breast Cancer Cells. AB - Breast cancer is the most frequently diagnosed cancer in women worldwide. The antiproliferative activities of biochanin A (BA) and ginsenoside Rh2 were determined by evaluating their inhibitory effect on MDA-MB-231 human breast cancer cell proliferation. The combination of BA with Rh2 was also assessed. In MDA cells, combination treatment led to a decrease in the EC50 values of BA and Rh2 to 25.20 MUM and 22.75 MUM, respectively. In MCF-7 cells, the EC50 values of combined BA and Rh2 decreased to 27.68 MUM and 25.41 MUM, respectively. BA combined with Rh2 also improved the inhibition of MDA-MB-231 and MCF-7 cell migration and invasion compared to the individual compounds. Western blot analysis demonstrated upregulation in p-p53, p-p38, and p-ASK1 proteins while levels of TRAF2 were downregulated. These results suggest that BA combined with Rh2 exhibits synergistic effects against MDA-MB-231 and MCF-7 cell proliferation. PMID- 30413009 TI - In Silico Analysis of Bioactive Peptides Released from Giant Grouper (Epinephelus lanceolatus) Roe Proteins Identified by Proteomics Approach. AB - Major proteins contained in dried giant grouper roe (GR) such as vitellogenin (from Epinephelus coioides; NCBI accession number: AAW29031.1), apolipoprotein A 1 precursor (from Epinephelus coioides; NCBI accession number: ACI01807.1) and apolipoprotein E (from Epinephelus bruneus; NCBI accession number: AEB31283.1) were characterized through compiled proteomics techniques (SDS-PAGE, in-gel digestion, mass spectrometry and on-line Mascot database analysis). These proteins were subjected to in silico analysis using BLAST and BIOPEP-UWM database. Sequence similarity search by BLAST revealed that the aligned vitellogenin sequences from Epinephelus coioides and Epinephelus lanceolatus share 70% identity, which indicates that the sequence sample has significant similarity with proteins in sequence databases. Moreover, prediction of potential bioactivities through BIOPEP-UWM database resulted in high numbers of peptides predominantly with dipeptidyl peptidase-IV (DPP-IV) and angiotensin-I-converting enzyme (ACE-I) inhibitory activities. Pepsin (pH > 2) was predicted to be the most promising enzyme for the production of bioactive peptides from GR protein, which theoretically released 82 DPP-IV inhibitory peptides and 47 ACE-I inhibitory peptides. Overall, this work highlighted the potentiality of giant grouper roe as raw material for the generation of pharmaceutical products. Furthermore, the application of proteomics and in silico techniques provided rapid identification of proteins and useful prediction of its potential bioactivities. PMID- 30413010 TI - Optimal Synthesis of Environment-Friendly Iron Red Pigment from Natural Nanostructured Clay Minerals. AB - A series of environment-friendly clay minerals-alpha-Fe2O3 iron-red hybrid pigments-were prepared by a simple one-step hydrothermal reaction process using natural nanostructured silicate clay minerals as starting materials. The influence of structure, morphology and composition of different clay minerals on the structure, color properties, and stability of the pigments was studied comparatively by systematic structure characterizations with X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmittance electron microscope (TEM), X-ray fluorescence spectroscopy (XRF), X-ray photoelectron spectroscopy (XPS) and CIE-L*a*b* Colorimetric analyses. The results showed that the clay minerals act as green precipitants during the hydrothermal reaction to induce in-situ transformation of Fe(III) ions into Fe2O3 crystals. Meanwhile, they also act as the "micro-reactor" for forming Fe2O3 crystals and the supporter for inhibiting the aggregation of Fe2O3 nanoparticles. The color properties of iron-red hybrid pigments are closely related to the surface charges, surface silanol groups, and solid acid sites of clay minerals. The clay minerals with higher surface activity are more suitable to prepare iron-red pigments with better performance. The iron-red hybrid pigment derived from illite (ILL) clay showed the best red color performance with the color values of L* = 31.8, a* = 35.2, b* = 27.1, C* = 44.4 and h degrees = 37.6, and exhibited excellent stability in different chemical environments such as acid, alkaline, and also in high-temperature conditions. PMID- 30413011 TI - Multi-Functional Soft Strain Sensors for Wearable Physiological Monitoring. AB - Wearable devices which monitor physiological measurements are of significant research interest for a wide number of applications including medicine, entertainment, and wellness monitoring. However, many wearable sensing systems are highly rigid and thus restrict the movement of the wearer, and are not modular or customizable for a specific application. Typically, one sensor is designed to model one physiological indicator which is not a scalable approach. This work aims to address these limitations, by developing soft sensors and including conductive particles into a silicone matrix which allows sheets of soft strain sensors to be developed rapidly using a rapid manufacturing process. By varying the morphology of the sensor sheets and electrode placement the response can be varied. To demonstrate the versatility and range of sensitivity of this base sensing material, two wearable sensors have been developed which show the detection of different physiological parameters. These include a pressure sensitive insole sensor which can detect ground reaction forces and a strain sensor which can be worn over clothes to allow the measurements of heart rate, breathing rate, and gait. PMID- 30413012 TI - Within-Subject Consistency of Unimodal and Bimodal Force Application during the Countermovement Jump. AB - Countermovement jump (CMJ) force data are often time-normalized so researchers and practitioners can study the effect that sex, training status, and training intervention have on CMJ strategy: the so-called force-time curve shape. Data are often collected on an individual basis and then averaged across interest-groups. However, little is known about the agreement of the CMJ force-time curve shape within-subject, and this formed the aim of this study. Fifteen men performed 10 CMJs on in-ground force plates. The resulting force-time curves were plotted, with their shape categorized as exhibiting either a single peak (unimodal) or a double peak (bimodal). Percentage-agreement and the kappa-coefficient were used to assess within-subject agreement. Over two and three trials, 13% demonstrated a unimodal shape, 67% exhibited a bimodal shape, and 20% were inconsistent. When five trials were considered, the unimodal shape was not demonstrated consistently; 67% demonstrated a bimodal shape, and 33% were inconsistent. Over 10 trials, none demonstrated a unimodal shape, 60% demonstrated a bimodal shape, and 40% were inconsistent. The results of this study suggest that researchers and practitioners should ensure within-subject consistency before group averaging CMJ force-time data, to avoid errors. PMID- 30413013 TI - Public Health Preparedness for and Response to Nuclear Disasters: An Editorial. AB - In 2011, resilience to nuclear disasters emerged as a core public health challenge. [...]. PMID- 30413014 TI - The Effect of Manufacturing Agglomeration on Haze Pollution in China. AB - Based on panel data on 285 Chinese cities from 2003 to 2012, we use a dynamic spatial panel model to empirically analyze the effect of manufacturing agglomeration on haze pollution. The results show that when economic development levels, population, technological levels, industrial structure, transportation, foreign direct investment, and greening levels are stable, manufacturing agglomeration significantly aggravates haze pollution. However, region-specific analysis reveals that the effects of manufacturing agglomeration on inter regional haze pollution depends on the region: the effect of manufacturing agglomeration on haze pollution is the largest in the Western region, followed by the Central region, and is the least in the Eastern region. Based on the above conclusions, we put forward several specific suggestions, such as giving full play to the technology and knowledge spillover effects of manufacturing agglomeration, guiding manufacturing agglomerations in a scientific and rational way, accelerating the transformation and upgrading of manufacturing industries in agglomeration regions. PMID- 30413015 TI - Combined Channel Estimation with Interference Suppression in CPSS. AB - With social characteristics integrated into cyber-physical systems (CPS), the wireless channel has been a complex electromagnetic environment due to the subjectivity of human behaviour. For the low-power and resource-constrained nodes in cyber-physical-social systems (CPSS), minimum research is available focusing on conquering the issues of computational complexity, external interference and transmission fading simultaneously. This study aims to explore channel estimation with interference suppression based on machine learning. A novel channel estimation scheme is proposed, which combined interference suppression in channel impulse response (CIR) of frequency domain with K-means algorithm and noise cancellation in CIR of time domain with K-nearest neighbor (KNN) algorithm into an integrated process. Complexity analysis and simulation results showed that the proposed scheme has relatively lower complexity and the performance is proven better than traditional schemes, which meets the requirements of CPSS in complex electromagnetic environments. PMID- 30413017 TI - A Mutation in the Mesorhizobium loti oatB Gene Alters the Physicochemical Properties of the Bacterial Cell Wall and Reduces Survival inside Acanthamoeba castellanii. AB - In our previous report, we had shown that the free-living amoeba Acanthamoeba castellanii influenced the abundance, competiveness, and virulence of Mesorhizobium loti NZP2213, the microsymbiont of agriculturally important plants of the genus Lotus. The molecular basis of this phenomenon; however, had not been explored. In the present study, we demonstrated that oatB, the O acetyltransferase encoding gene located in the lipopolysaccharide (LPS) synthesis cluster of M. loti, was responsible for maintaining the protective capacity of the bacterial cell envelope, necessary for the bacteria to fight environmental stress and survive inside amoeba cells. Using co-culture assays combined with fluorescence and electron microscopy, we showed that an oatB mutant, unlike the parental strain, was efficiently destroyed after rapid internalization by amoebae. Sensitivity and permeability studies of the oatB mutant, together with topography and nanomechanical investigations with the use of atomic force microscopy (AFM), indicated that the incomplete substitution of lipid A-core moieties with O-polysaccharide (O-PS) residues rendered the mutant more sensitive to hydrophobic compounds. Likewise, the truncated LPS moieties, rather than the lack of O-acetyl groups, made the oatB mutant susceptible to the bactericidal mechanisms (nitrosative stress and the action of lytic enzymes) of A. castellanii. PMID- 30413016 TI - Exergaming for Children and Adolescents: Strengths, Weaknesses, Opportunities and Threats. AB - Exergaming, or active video gaming, has become an emerging trend in fitness, education and health sectors. It is defined as digital games that require bodily movements to play, stimulating an active gaming experience to function as a form of physical activity (PA). Since exergaming is becoming more popular, claims have been made on the usefulness of exergaming. It has, for example, been entitled as being "the future of fitness" by the American College of Sports Medicine, promoting PA and health in children and adolescents. However, research also suggests that long-term engagement in exergaming is difficult to achieve, and there is a noticeable reservation towards exergaming by parents, teachers and caregivers. To provide an overview and to outline the future directions of exergaming, the aim of this review was to critically illustrate the strengths, weaknesses, opportunities and threats of exergaming to promote PA and health in children and youth. The available evidence indicates that exergaming has the potential to improve health via an increase in PA. However, it seems that this potential is frequently underexploited, and further developments such as customized exergames are needed. PMID- 30413018 TI - Impact of Melatonin in Solid Organ Transplantation-Is It Time for Clinical Trials? A Comprehensive Review. AB - Solid organ transplantation is the "gold standard" for patients with end-stage organ disease. However, the supply of donor organs is critical, with an increased organ shortage over the last few years resulting in a significant mortality of patients on waiting lists. New strategies to overcome the shortage of organs are urgently needed. Some experimental studies focus on melatonin to improve the donor pool and to protect the graft; however, current research has not reached the clinical level. Therefore, this review provides a comprehensive overview of the data available, indicating that clinical evaluation is warranted. PMID- 30413019 TI - Impact of Manufacturing Variability and Washing on Embroidery Textile Sensors. AB - In this work, an embroidered textile moisture sensor is presented. The sensor is based on a capacitive interdigitated structure embroidered on a cotton substrate with an embroidery conductor yarn composed of 99% pure silver plated nylon yarn 140/17 dtex. In order to evaluate the sensor sensitivity, the impedance of the sensor has been measured by means of a impedance meter (LCR) from 20 Hz to 20 kHz in a climatic chamber with a sweep of the relative humidity from 25% to 65% at 20 degrees C. The experimental results show a clear and controllable dependence of the sensor impedance with the relative humidity. Moreover, the reproducibility of the sensor performance subject to the manufacturing process variability and washing process is also evaluated. The results show that the manufacturing variability introduces a moisture measurement error up to 4%. The washing process impact on the sensor behavior after applying the first washing cycle implies a sensitivity reduction higher than 14%. Despite these effects, the textile sensor keeps its functionality and can be reused in standard conditions. Therefore, these properties point out the usefulness of the proposed sensor to develop wearable applications within the health and fitness scope including when the user needs to have a life cycle longer than one-time use. PMID- 30413020 TI - Trichothecene Genotypes of Fusarium graminearum Populations Isolated from Winter Wheat Crops in Serbia. AB - Fusarium graminearum as the main causal agent of Fusarium head blight (FHB) and its ability to produce trichothecenes was investigated by molecular techniques. A total of 37 strains isolated from the wheat, harvested in Serbia in 2005, 2008 and 2015, and previously designated by morphological observation as F. graminearum, were used for trichothecene genotypes characterization. The strains were identified using the species-specific primer set FG16R/FG16F while genotypic characterization was done using specific TRI13 and TRI3 sequences of the trichothecene gene clusters. The PCR assays identified all strains as species of F. graminearum sensu stricto with the DON/15-ADON genotype. The quantification of the mycotoxin (DON) was performed using the biochemical assay. The high levels of DON (>20,000 ug kg-1) were recorded in all of the strains from 2005, four strains from 2008 and two strains from 2015. Weather data of the investigated seasons, showed that the optimal temperature, frequent rains and high relative humidity (RH) was very favourable for the development of F. graminearum, affecting the DON biosynthesis. PMID- 30413021 TI - Effect of SiO2 Nanoparticles on the Performance of PVdF-HFP/Ionic Liquid Separator for Lithium-Ion Batteries. AB - Safety concerns related to the use of potentially explosive, liquid organic electrolytes in commercial high-power lithium-ion batteries are constantly rising. One promising alternative is to use thermally stable ionic liquids (ILs) as conductive media, which are however, limited by low ionic conductivity at room temperature. This can be improved by adding fillers, such as silica or alumina nanoparticles (NPs), in the polymer matrix that hosts the IL. To maximize the effect of such NPs, they have to be uniformly dispersed in the matrix while keeping their size as small as possible. In this work, starting from a water dispersion of silica NPs, we present a novel method to incorporate silica NPs at the nanoscale level (<200 nm) into PVdF-HFP polymer clusters, which are then blended with the IL solution and hot-pressed to form separators suitable for battery applications. The effect of different amounts of silica in the polymer matrix on the ionic conductivity and cyclability of the separator is investigated. A membrane containing 10 wt.% of silica (with respect to the polymer) was shown to maximize the performance of the separator, with a room temperature ionic conductivity of of 1.22 mS cm - 1 . The assembled half-coin cell with LiFePO 4 and Li as the cathode and the anode exhibited a capacity retention of more than 80% at a current density of 2C and 60 ? C. PMID- 30413022 TI - Dexamethasone Inhibits Synergistic Induction of PDE4B Expression by Roflumilast and Bacterium NTHi. AB - Phosphodiesterase 4B (PDE4B) plays an important role in inflammation. Recently we have reported that roflumilast as a PDE4-selective inhibitor, synergizes with nontypeable Haemophilus influenzae (NTHi) to up-regulate PDE4B expression in vitro and in vivo. Clinical evidence and our previous results suggest that synergistic induction of PDE4B could be counterproductive for suppressing inflammation or may contribute to tolerance to roflumilast. We thus investigated if dexamethasone inhibits the synergistic induction of PDE4B by roflumilast and NTHi as well as inflammation. Here, dexamethasone markedly suppressed the synergistic induction of PDE4B in human lung epithelial cells and in vivo. We also found that dexamethasone further suppressed NTHi-induced inflammatory response in vitro and in vivo. Moreover, Compound A, as a dissociating non steroidal glucocorticoid receptor (GR) ligand, inhibited the synergistic induction of PDE4B, thereby suggesting the requirement of dexamethasone-mediated GR activation in the suppression of PDE4B expression. Taken together, our data suggest that dexamethasone may help attenuate inflammation and tolerance through suppressing the PDE4B expression in chronic obstructive pulmonary disease (COPD) patients using roflumilast. PMID- 30413023 TI - Post-Translational Modifications and Diastolic Calcium Leak Associated to the Novel RyR2-D3638A Mutation Lead to CPVT in Patient-Specific hiPSC-Derived Cardiomyocytes. AB - BACKGROUND: Sarcoplasmic reticulum Ca2+ leak and post-translational modifications under stress have been implicated in catecholaminergic polymorphic ventricular tachycardia (CPVT), a highly lethal inherited arrhythmogenic disorder. Human induced pluripotent stem cells (hiPSCs) offer a unique opportunity for disease modeling. OBJECTIVE: The aims were to obtain functional hiPSC-derived cardiomyocytes from a CPVT patient harboring a novel ryanodine receptor (RyR2) mutation and model the syndrome, drug responses and investigate the molecular mechanisms associated to the CPVT syndrome. METHODS: Patient-specific cardiomyocytes were generated from a young athletic female diagnosed with CPVT. The contractile, intracellular Ca2+ handling and electrophysiological properties as well as the RyR2 macromolecular remodeling were studied. RESULTS: Exercise stress electrocardiography revealed polymorphic ventricular tachycardia when treated with metoprolol and marked improvement with flecainide alone. We found abnormal stress-induced contractile and electrophysiological properties associated with sarcoplasmic reticulum Ca2+ leak in CPVT hiPSC-derived cardiomyocytes. We found inadequate response to metoprolol and a potent response of flecainide. Stabilizing RyR2 with a Rycal compound prevents those abnormalities specifically in CPVT hiPSC-derived cardiomyocytes. The RyR2-D3638A mutation is located in the conformational change inducing-central core domain and leads to RyR2 macromolecular remodeling including depletion of PP2A and Calstabin2. CONCLUSION: We identified a novel RyR2-D3638A mutation causing 3D conformational defects and aberrant biophysical properties associated to RyR2 macromolecular complex post-translational remodeling. The molecular remodeling is for the first time revealed using patient-specific hiPSC-derived cardiomyocytes which may explain the CPVT proband's resistance. Our study promotes hiPSC-derived cardiomyocytes as a suitable model for disease modeling, testing new therapeutic compounds, personalized medicine and deciphering underlying molecular mechanisms. PMID- 30413024 TI - Carbonic Anhydrase Inhibitors as Novel Drugs against Mycobacterial beta-Carbonic Anhydrases: An Update on In Vitro and In Vivo Studies. AB - Mycobacteria cause a variety of diseases, such as tuberculosis, leprosy, and opportunistic diseases in immunocompromised people. The treatment of these diseases is problematic, necessitating the development of novel treatment strategies. Recently, beta-carbonic anhydrases (beta-CAs) have emerged as potential drug targets in mycobacteria. The genomes of mycobacteria encode for three beta-CAs that have been cloned and characterized from Mycobacterium tuberculosis (Mtb) and the crystal structures of two of the enzymes have been determined. Different classes of inhibitor molecules against Mtb beta-CAs have subsequently been designed and have been shown to inhibit these mycobacterial enzymes in vitro. The inhibition of these centrally important mycobacterial enzymes leads to reduced growth of mycobacteria, lower virulence, and impaired biofilm formation. Thus, the inhibition of beta-CAs could be a novel approach for developing drugs against the severe diseases caused by pathogenic mycobacteria. In the present article, we review the data related to in vitro and in vivo inhibition studies in the field. PMID- 30413025 TI - Radiothrerapy for Elderly Patients Aged >=75 Years with Clinically Localized Prostate Cancer-Is There a Role of Brachytherapy? AB - We compared radiotherapy outcomes between 241 elderly patients aged >=75 years and 867 younger controls (age <75 years) with clinically localized prostate cancer. The elderly group showed an equivalent actuarial seven-year biochemical failure-free survival rate (7y-bNED) (94.9%) to the younger control group (96.4%, p = 0.593). The incidence of late genitourinary (GU) and gastrointestinal (GI) toxicities grade >=2 was also similar between the elderly and younger cohorts, while no grade >=4 adverse events occurred. We also examined the role of brachytherapy (BT) in the elderly group, in comparison with image-guided intensity-modulated radiotherapy (IG-IMRT). BT showed superior 7y-bNED (94.1%) than IG-IMRT (84.6%, p = 0.0183) in elderly patients, which was 100% (100% for BT and 100% for IG-IMRT, p > 0.999) for the low-risk group, 94.6% (92.8% and 100%, p = 0.203) for the intermediate-risk group, and 80.5% (91.2% and 73.6%, p = 0.0195) for the high-risk group. BT showed higher GU toxicity and equivalent GI toxicity to IG-IMRT. In conclusion, elderly patients showed bNED and toxicity that were equivalent to those observed in younger controls, and BT is a plausible option also for healthy elderly with potential to improve bNED, with higher but acceptable GU toxicity. PMID- 30413026 TI - Genomic and Transcriptomic Analysis of Hypercholesterolemic Rabbits: Progress and Perspectives. AB - Rabbits (Oryctolagus cuniculus) are one of the most widely used animal models for the study of human lipid metabolism and atherosclerosis because they are more sensitive to a cholesterol diet than other experimental animals such as rodents. Currently, two hypercholesterolemic rabbit models are frequently used for atherosclerosis studies. One is a cholesterol-fed wild-type rabbit and the other is the Watanabe heritable hyperlipidemic (WHHL) rabbit, which is genetically deficient in low density lipoprotein (LDL) receptor function. Wild-type rabbits can be easily induced to develop severe hypercholesterolemia with a cholesterol rich diet due to the marked increase in hepatically and intestinally derived remnant lipoproteins, called beta-very low density lipoproteins (VLDL), which are rich in cholesteryl esters. WHHL rabbits are characterized by elevated plasma LDL levels on a standard chow diet, which resembles human familial hypercholesterolemia. Therefore, both rabbit models develop aortic and coronary atherosclerosis, but the elevated plasma cholesterol levels are caused by completely different mechanisms. In addition, cholesterol-fed rabbits but not WHHL rabbits exhibit different degrees of hepatosteatosis. Recently, we along with others have shown that there are many differentially expressed genes in the atherosclerotic lesions and livers of cholesterol-fed rabbits that are either significantly up- or down-regulated, compared with those in normal rabbits, including genes involved in the regulation of inflammation and lipid metabolism. Therefore, dietary cholesterol plays an important role not only in hypercholesterolemia and atherosclerosis but also in hepatosteatosis. In this review, we make an overview of the recent progress in genomic and transcriptomic analyses of hypercholesterolemic rabbits. These transcriptomic profiling data should provide novel insight into the relationship between hypercholesterolemia and atherosclerosis or hepatic dysfunction caused by dietary cholesterol. PMID- 30413027 TI - Thermal Vibration-Induced Rotation of Nano-Wheel: A Molecular Dynamics Study. AB - By bending a straight carbon nanotube and bonding both ends of the nanotube, a nanoring (or nano-wheel) is produced. The nanoring system can be driven to rotate by fixed outer nanotubes at room temperature. When placing some atoms at the edge of each outer tube (the stator here) with inwardly radial deviation (IRD), the IRD atoms will repulse the nanoring in their thermally vibration-induced collision and drive the nanoring to rotate when the repulsion due to IRD and the friction with stators induce a non-zero moment about the axis of rotational symmetry of the ring. As such, the nanoring can act as a wheel in a nanovehicle. When the repulsion is balanced with the intertubular friction, a stable rotational frequency (SRF) of the rotor is achieved. The results from the molecular dynamics simulation demonstrate that the nanowheel can work at extremely low temperature and its rotational speed can be adjusted by tuning temperature. PMID- 30413029 TI - The Spanish Ion Channel Initiative (SICI) Consortium: Ten Years (2008-2018) of a Network of Excellence on Ion Channel Research. AB - The Spanish Ion Channel Initiative consortium (SICI, http://sici. [...]. PMID- 30413028 TI - Inhibitory Effects of Ginsenoside Rb1 on Early Atherosclerosis in ApoE-/- Mice via Inhibition of Apoptosis and Enhancing Autophagy. AB - Inflammation is a major contributing factor to the progression of atherosclerosis. Ginsenoside Rb1 (Rb1), an active saponin of Panax notoginseng, has been found to exert beneficial effects on inflammation and oxidative stress. This study investigated the ability of Rb1 to inhibit the formation of atherosclerotic plaques and the potential mechanisms. In this study, the effects of Rb1 on the development of atherosclerosis were investigated in ApoE-/- deficient mice fed with a western diet. Mice were intragastrically administrated with Rb1 (10 mg/kg) for 8 weeks. This study is that ginsenoside Rb1 exerted an inhibitory effect on early atherosclerosis in ApoE-/- mice via decreasing body weight and food intake daily, upregulating the lipid levels of serum plasma, including those of TC, TG and LDL-C and HDL-C and reducing the atherosclerotic plaque area, suppressing inflammatory cytokines (levels of IL-1beta, IL-6 and TNF alpha) in the serum of ApoE-/- mice, changing the expression levels of BCL-2, BAX, cleaved caspase-3 and cleaved caspase-9 and weakening apoptosis associated with anti-inflammatory activity. Hence, all these effects against atherosclerosis were tightly associated with regulation of necrosis or apoptosis associated with anti-inflammatory activity. Additionally, the results found that ginsenoside Rb1 increased autophagy flux to inhibit apoptosis via acceleration of autophagy by promoting transformation of LC3 from type I to type II in high-fat diet-induced atherosclerosis in ApoE-/- mice. This finding, along with those of the previous study, provides evidence that Rb1 promotes the process of autophagy to protect against atherosclerosis via regulating BCL-2 family-related apoptosis. These results indicate that Rb1 exhibits therapeutic effects in atherosclerosis by reversing the imbalance between apoptosis and autophagy. PMID- 30413030 TI - Projection of Future Extreme Precipitation and Flood Changes of the Jinsha River Basin in China Based on CMIP5 Climate Models. AB - Projecting future changes in extreme flood is critical for risk management. This paper presented an analysis of the implications of the Fifth Coupled Model Intercomparison Project Phase (CMIP5) climate models on the future flood in the Jinsha River Basin (JRB) in Southwest China, using the Xinanjiang (XAJ) hydrologic model. The bias-corrected and resampled results of the multimodel dataset came from the Inter-Sectoral Impact Model Intercomparison Project (ISI MIP). Relatively optimal general circulation models (GCMs) were selected with probability density functions (PDFs)-based assessment. These GCMs were coupled with the XAJ model to evaluate the impact of climate change on future extreme flood changes in the JRB. Two scenarios were chosen, namely: a midrange mitigation scenario (Representative Concentration Pathway 4.5, RCP4.5) and a high scenario (RCP8.5). Results show that: (1) The XAJ model performed well in simulating daily discharge and was suitable for the study area, with ENS and R2 higher than 0.8; (2) IPSL-CM5A-LR and MIROC-ESM-CHEM showed considerable skill in representing the observed PDFs of extreme precipitation. The average skill scores across the total area of the JRB were 0.41 to 0.66 and 0.53 to 0.67, respectively. Therefore, these two GCMs can be chosen to analyze the changes in extreme precipitation and flood in the future; (3) The average extreme precipitation under 20- and 50-year return period across the JRB were projected to increase by 1.0-33.7% under RCP4.5 and RCP8.5 during 2020 to 2050. The Upper basin is projected to experience the largest increase in extreme precipitation indices, possibly caused by a warmer climate. The extreme flood under 20- and 50 year return period will change by 0.8 to 23.8% and -6.2 to 28.2%, respectively, over this same future period. Most of scenarios projected an increase during the near future periods, implying the JRB would be likely to undergo more flooding in the future. PMID- 30413031 TI - 6-Bromoindole Derivatives from the Icelandic Marine Sponge Geodia barretti: Isolation and Anti-Inflammatory Activity. AB - An UPLC-qTOF-MS-based dereplication study led to the targeted isolation of seven bromoindole alkaloids from the sub-Arctic sponge Geodia barretti. This includes three new metabolites, namely geobarrettin A-C (1-3) and four known compounds, barettin (4), 8,9-dihydrobarettin (5), 6-bromoconicamin (6), and l-6 bromohypaphorine (7). The chemical structures of compounds 1-7 were elucidated by extensive analysis of the NMR and HRESIMS data. The absolute stereochemistry of geobarrettin A (1) was assigned by ECD analysis and Marfey's method employing the new reagent l-Nalpha-(1-fluoro-2,4-dinitrophenyl)tryptophanamide (l-FDTA). The isolated compounds were screened for anti-inflammatory activity using human dendritic cells (DCs). Both 2 and 3 reduced DC secretion of IL-12p40, but 3 concomitantly increased IL-10 production. Maturing DCs treated with 2 or 3 before co-culturing with allogeneic CD4+ T cells decreased T cell secretion of IFN gamma, indicating a reduction in Th1 differentiation. Although barettin (4) reduced DC secretion of IL-12p40 and IL-10 (IC50 values 11.8 and 21.0 MUM for IL 10 and IL-12p40, respectively), maturing DCs in the presence of 4 did not affect the ability of T cells to secrete IFN-gamma or IL-17, but reduced their secretion of IL-10. These results indicate that 2 and 3 may be useful for the treatment of inflammation, mainly of the Th1 type. PMID- 30413033 TI - SWAT Modeling of Non-Point Source Pollution in Depression-Dominated Basins under Varying Hydroclimatic Conditions. AB - Non-point source (NPS) pollution from agricultural lands is the leading cause of various water quality problems across the United States. Particularly, surface depressions often alter the releasing patterns of NPS pollutants into the environment. However, most commonly-used hydrologic models may not be applicable to such depression-dominated regions. The objective of this study is to improve water quantity/quality modeling and its calibration for depression-dominated basins under wet and dry hydroclimatic conditions. Specifically, the Soil and Water Assessment Tool (SWAT) was applied for hydrologic and water quality modeling in the Red River of the North Basin (RRB). Surface depressions across the RRB were incorporated into the model by employing a surface delineation method and the impacts of depressions were evaluated for two modeling scenarios, MS1 (basic scenario) and MS2 (depression-oriented scenario). Moreover, a traditional calibration scheme (CS1) was compared to a wet-dry calibration scheme (CS2) that accounted for the effects of hydroclimatic variations on hydrologic and water quality modeling. Results indicated that the surface runoff simulation and the associated water quality modeling were improved when topographic characteristics of depressions were incorporated into the model (MS2). The Nash Sutcliffe efficiency (NSE) coefficient indicated an average increase of 30.4% and 19.6% from CS1 to CS2 for the calibration and validation periods, respectively. Additionally, the CS2 provided acceptable simulations of water quality, with the NSE values of 0.50 and 0.74 for calibration and validation periods, respectively. These results highlight the enhanced capability of the proposed approach for simulating water quantity and quality for depression-dominated basins under the influence of varying hydroclimatic conditions. PMID- 30413032 TI - NF-kappaB Signaling in Targeting Tumor Cells by Oncolytic Viruses-Therapeutic Perspectives. AB - In recent years, oncolytic virotherapy became a promising therapeutic approach, leading to the introduction of a novel generation of anticancer drugs. However, despite evoking an antitumor response, introducing an oncolytic virus (OV) to the patient is still inefficient to overcome both tumor protective mechanisms and the limitation of viral replication by the host. In cancer treatment, nuclear factor (NF)-kappaB has been extensively studied among important therapeutic targets. The pleiotropic nature of NF-kappaB transcription factor includes its involvement in immunity and tumorigenesis. Therefore, in many types of cancer, aberrant activation of NF-kappaB can be observed. At the same time, the activity of NF kappaB can be modified by OVs, which trigger an immune response and modulate NF kappaB signaling. Due to the limitation of a monotherapy exploiting OVs only, the antitumor effect can be enhanced by combining OV with NF-kappaB-modulating drugs. This review describes the influence of OVs on NF-kappaB activation in tumor cells showing NF-kappaB signaling as an important aspect, which should be taken into consideration when targeting tumor cells by OVs. PMID- 30413035 TI - V-RBNN Based Small Drone Detection in Augmented Datasets for 3D LADAR System. AB - A common countermeasure to detect threatening drones is the electro-optical infrared (EO/IR) system. However, its performance is drastically reduced in conditions of complex background, saturation and light reflection. 3D laser sensor LiDAR is used to overcome the problems of 2D sensors like EO/IR, but it is not enough to detect small drones at a very long distance because of low laser energy and resolution. To solve this problem, A 3D LADAR sensor is under development. In this work, we study the detection methodology adequate to the LADAR sensor which can detect small drones at up to 2 km. First, a data augmentation method is proposed to generate a virtual target considering the laser beam and scanning characteristics, and to augment it with the actual LADAR sensor data for various kinds of tests before full hardware system developed. Second, a detection algorithm is proposed to detect drones using voxel-based background subtraction and variable radially bounded nearest neighbor (V-RBNN) method. The results show that 0.2 m L2 distance and 60% expected average overlap (EAO) indexes are satisfied for the required specification to detect 0.3 m size of small drones. PMID- 30413034 TI - A Mechanically-Adaptive Polymer Nanocomposite-Based Intracortical Probe and Package for Chronic Neural Recording. AB - Mechanical, materials, and biological causes of intracortical probe failure have hampered their utility in basic science and clinical applications. By anticipating causes of failure, we can design a system that will prevent the known causes of failure. The neural probe design was centered around a bio inspired, mechanically-softening polymer nanocomposite. The polymer nanocomposite was functionalized with recording microelectrodes using a microfabrication process designed for chemical and thermal process compatibility. A custom package based upon a ribbon cable, printed circuit board, and a 3D-printed housing was designed to enable connection to external electronics. Probes were implanted into the primary motor cortex of Sprague-Dawley rats for 16 weeks, during which regular recording and electrochemical impedance spectroscopy measurement sessions took place. The implanted mechanically-softening probes had stable electrochemical impedance spectra across the 16 weeks and single units were recorded out to 16 weeks. The demonstration of chronic neural recording with the mechanically-softening probe suggests that probe architecture, custom package, and general design strategy are appropriate for long-term studies in rodents. PMID- 30413038 TI - Mechanical Properties of U-Cu Intermetallic Compound Measured by Nanoindentation. AB - The physico-chemical properties of the Uranium intermetallic compound are of technological importance for improvement of the safety and compatibility of nuclear engineering systems. Diffusion couple samples with U and Cu were assembled and U-Cu intermetallic compounds were fabricated at interface by hot pressure diffusion method at a treatment temperature of 350 degrees C to 650 degrees C and at a pressure of 168 MPa in a vacuum furnace. The microstructure and element distribution of the compound phase have been studied by means of SEM, EDS, and XRD. The result showed that a new phase was developed to a thickness of approximately 10 MUm with a ration of U:Cu with 1:5. Mechanical properties such as elastic moduli and hardness of the compound have been studied by means of nanoindentation. The nanoindentation testing on sample indicated that hardness of Uranium intermetallic compound are higher than that of metal U and Cu. Uranium intermetallic compound and U have a Young's moduli with 121 GPa, 160 GPa respectively. The elastic/plastic responses of U-Cu intermetallic compound and U under nanoindentation tests were also discussed in detail. PMID- 30413037 TI - Exploring the Effect of Rotenone-A Known Inducer of Parkinson's Disease-On Mitochondrial Dynamics in Dictyostelium discoideum. AB - Current treatments for Parkinson's disease (PD) only alleviate symptoms doing little to inhibit the onset and progression of the disease, thus we must research the mechanism of Parkinson's. Rotenone is a known inducer of parkinsonian conditions in rats; we use rotenone to induce parkinsonian cellular conditions in Dictyostelium discoideum. In our model we primarily focus on mitochondrial dynamics. We found that rotenone disrupts the actin and microtubule cytoskeleton but mitochondrial morphology remains intact. Rotenone stimulates mitochondrial velocity while inhibiting mitochondrial fusion, increases reactive oxygen species (ROS) but has no effect on ATP levels. Antioxidants have been shown to decrease some PD symptoms thus we added ascorbic acid to our rotenone treated cells. Ascorbic acid administration suggests that rotenone effects may be specific to the disruption of the cytoskeleton rather than the increase in ROS. Our results imply that D. discoideum may be a valid cellular PD model and that the rotenone induced velocity increase and loss of fusion could prevent mitochondria from effectively providing energy and other mitochondrial products in high demand areas. The combination of these defects in mitochondrial dynamics and increased ROS could result in degeneration of neurons in PD. PMID- 30413036 TI - Mood Disorders and Gluten: It's Not All in Your Mind! A Systematic Review with Meta-Analysis. AB - Gluten elimination may represent an effective treatment strategy for mood disorders in individuals with gluten-related disorders. However, the directionality of the relationship remains unclear. We performed a systematic review of prospective studies for effects of gluten on mood symptoms in patients with or without gluten-related disorders. Six electronic databases (CINAHL, PsycINFO, Medline, Web of Science, Scopus and Cochrane Library) were searched, from inception to 8 August 2018, for prospective studies published in English. Meta-analyses with random-effects were performed. Three randomised-controlled trials and 10 longitudinal studies comprising 1139 participants fit the inclusion criteria. A gluten-free diet (GFD) significantly improved pooled depressive symptom scores in GFD-treated patients (Standardised Mean Difference (SMD) -0.37, 95% confidence interval (CI) -0.55 to -0.20; p < 0.0001), with no difference in mean scores between patients and healthy controls after one year (SMD 0.01, 95% CI -0.18 to 0.20, p = 0.94). There was a tendency towards worsening symptoms for non-coeliac gluten sensitive patients during a blinded gluten challenge vs. placebo (SMD 0.21, 95% CI -0.58 to 0.15; p = 0.25). Our review supports the association between mood disorders and gluten intake in susceptible individuals. The effects of a GFD on mood in subjects without gluten-related disorders should be considered in future research. PMID- 30413039 TI - Severe Plastic Deformation of Fe-22Al-5Cr Alloy by Cross-Channel Extrusion with Back Pressure. AB - A new concept of the cross-channel extrusion (CCE) process under back pressure (BP) was proposed and tested experimentally. The obtained by finite element method (FEM) results showed that a triaxial compression occurred in the central zone, whereas the material was deformed by shearing in the outer zone. This led to the presence of a relatively uniformly deformed outer zone at 1 per pass and a strong deformation of the paraxial zone (3-5/pass). An increase in the BP did not substantially affect the accumulated strain but made it more uniform. The FEM results were verified using the physical modeling technique (PMT) by the extrusion of clay billet. The formation of the plane of the strongly flattened, and elongated grains were observed in the extrusion directions. With the increase in the number of passes, the shape of the resulting patterns expanded, indicating an increase in the deformation homogeneity. Finally, these investigations were verified experimentally for Fe-22Al-5Cr (at. %) alloy using of the purposely designed tooling. The effect of the CCE process is the fragmentation of the original material structure by dividing the primary grains. The complexity of the stress state leads to the rapid growth of microshear bands (MSB), grain defragmentation and the nucleation of new dynamically recrystallized grains about 200-400 nm size. PMID- 30413040 TI - Development and Implementation of an Intraoral Device for Occlusal Stability during Sports Performance: A Case Report. AB - INTRODUCTION: Sports dentistry assumes a clinical relevance, not only in the prevention of orofacial trauma by the use of mouthguards, but also with the development of intraoral devices that aim to provide greater occlusal stability, as well as a greater balance in the level of certain structures of the cranio cervical-mandibular complex. In this way, the dentistry can have an intervention action on sports performance. OBJECTIVES: The objective of this research was to verify the existence of a correlation between occlusal stability and an eventual balance of some facial structures during sports performance using a specially developed Occlusal Stability Sports Performance Device. METHODOLOGY: An individualized mandibular intraoral device was manufactured and evaluated on an athlete canoeing. Infrared thermography was the complementary diagnostic method used for this purpose. RESULTS: Greater symmetry of certain regions of interest of the cranio-cervico-mandibular complex was observed with the implementation of the Occlusal Stability Sports Performance Device. These areas were the anterior temporal muscle, the masseter muscle and the temporomandibular joint. No asymmetry decrease was found in the anterior triangle region of the neck. CONCLUSION: The use of this type of intraoral devices may allow greater occlusal stability and consequent balance of anatomical structures constituting the cranio cervical-mandibular complex. Infrared thermography is an effective diagnostic tool for studying the results of the intraoral device on the cranio-cervico mandibular complex use during canoeing. PMID- 30413041 TI - The Association of Poor Oral Health Parameters with Malnutrition in Older Adults: A Review Considering the Potential Implications for Cognitive Impairment. AB - Poor dental status and chewing deficiencies have been associated with cognitive decline. Altered dietary habits and malnutrition have been suggested as linking mechanisms. The aim of the present review was thus to investigate if poor oral health, and in particular tooth loss and impaired masticatory function, may affect dietary selection and nutritional intake in older adults, and moreover, to assess if prosthodontic dental care may improve nutritional status. Extensive tooth loss may impair masticatory function. Several studies in older populations have shown that severe tooth loss and masticatory impairment are associated with limited consumption of various food types (especially fruits and vegetables), increased consumption of sugary and easy-to-chew foods, and lower dietary intake of fibre and vitamins. However, these findings are not consistently reported, due to methodological variation among studies, potential adverse causalities, and the multifactorial nature of food choices. On the other hand, a few interventional studies revealed that prosthetic rehabilitation of missing teeth, when accompanied by dietary counselling, may improve dietary habits and nutritional intake. Further research is required to improve current knowledge of these associations. Under the limitations of the current study, a functional dental arch of natural or artificial teeth is important for maintaining adequate chewing efficiency and ability, but this only partly contributes to food choices and nutritional status. The multifactorial nature of food choices necessitates the interprofessional collaboration of dental professionals, dietetics practitioners, and primary care providers to improve dietary habits and nutritional intake. PMID- 30413042 TI - Macroscopic Observation of Soil Nitrification Kinetics Impacted by Copper Nanoparticles: Implications for Micronutrient Nanofertilizer. AB - The potential agricultural use of metal nanoparticles (NPs) for slow-release micronutrient fertilizers is beginning to be investigated by both industry and regulatory agencies. However, the impact of such NPs on soil biogeochemical cycles is not clearly understood. In this study, the impact of commercially available copper NPs on soil nitrification kinetics was investigated via batch experiments. The X-ray absorption near edge structure spectroscopy analysis showed that the NPs readily oxidized to Cu(II) and were strongly retained in soils with minimum dissolution (<1% of total mass). The Cu2+ (aq) at 1 mg/L showed a beneficial effect on the nitrification similar to the control: an approximately 9% increase in the average rate of nitrification kinetics (Vmax). However Vmax was negatively impacted by ionic Cu at 10 to 100 mg/L and CuNP at 1 to 100 mg/L. The copper toxicity of soil nitrifiers seems to be critical in the soil nitrification processes. In the CuNP treatment, the suppressed nitrification kinetics was observed at 1 to 100 mg/kg and the effect was concentration dependent at >=10 mg/L. The reaction products as the results of surface oxidation such as the release of ionic Cu seem to play an important role in suppressing the nitrification process. Considering the potential use of copper NPs as a slow release micronutrient fertilizer, further studies are needed in heterogeneous soil systems. PMID- 30413043 TI - Colon Bioaccessibility and Antioxidant Activity of White, Green and Black Tea Polyphenols Extract after In Vitro Simulated Gastrointestinal Digestion. AB - The beneficial effects of the tea beverage are well-known and mainly attributed to polyphenols which, however, have poor bioaccessibility and bioavailability. The purpose of the present study was the evaluation of colon bioaccessibility and antioxidant activity of tea polyphenolic extract. An 80% methanolic extract (v/v) of tea polyphenols was obtained from green (GT), white (WT) and black tea (BT). Simulated gastrointestinal (GI) digestion was performed on acid-resistant capsules containing tea polyphenolic extract. The main tea polyphenols were monitored by HPLC-diode-array detector (DAD) method; in addition, Total Phenol Content (TPC) and antioxidant activity were evaluated. After GI digestion, the bioaccessibility in the colon stage was significantly increased compared to the duodenal stage for both tea polyphenols and TPC. Similarly, the antioxidant activity in the colon stage was significantly higher than that in the duodenal stage. Reasonably, these results could be attributable in vivo to the activity of gut microbiota, which is able to metabolize these compounds, generating metabolites with a greater antioxidant activity. Our results may guide the comprehension of the colon digestion of polyphenols, suggesting that, although poorly absorbed in the duodenum, they can exert their antioxidant and anti inflammatory activities in the lower gut, resulting in a novel strategy for the management of gut-related inflammatory diseases. PMID- 30413044 TI - Effects of Staphylococcus aureus Bacteriophage K on Expression of Cytokines and Activation Markers by Human Dendritic Cells In Vitro. AB - A potential concern with bacteriophage (phage) therapeutics is a host-versus phage response in which the immune system may neutralize or destroy phage particles and thus impair therapeutic efficacy, or a strong inflammatory response to repeated phage exposure might endanger the patient. Current literature is discrepant with regard to the nature and magnitude of innate and adaptive immune response to phages. The purpose of this work was to study the potential effects of Staphylococcus aureus phage K on the activation of human monocyte-derived dendritic cells. Since phage K acquired from ATCC was isolated around 90 years ago, we first tested its activity against a panel of 36 diverse S. aureus clinical isolates from military patients and found that it was lytic against 30/36 (83%) of strains. Human monocyte-derived dendritic cells were used to test for an in vitro phage-specific inflammatory response. Repeated experiments demonstrated that phage K had little impact on the expression of pro- and anti inflammatory cytokines, or on MHC-I/II and CD80/CD86 protein expression. Given that dendritic cells are potent antigen-presenting cells and messengers between the innate and the adaptive immune systems, our results suggest that phage K does not independently affect cellular immunity or has a very limited impact on it. PMID- 30413045 TI - Kiwifruit Exchanges for Increased Nutrient Richness with Little Effect on Carbohydrate Intake, Glycaemic Impact, or Insulin Response. AB - BACKGROUND: Kiwifruit are nutrient-rich and have properties which indicate a low glycaemic impact compared with many cooked cereal foods, suggesting that they may be used for dietary enrichment of vitamin C without glycaemic cost. AIM: To develop tables for equi-carbohydrate and equi-glycaemic partial exchange of kiwifruit for glycaemic carbohydrate foods. METHOD: The available carbohydrate content of Zespri(r) Green and Zespri(r) SunGold kiwifruit was determined as sugars released during in vitro digestive analysis. Glycaemic potency was determined as grams of glucose equivalents (GGEs) in a clinical trial using 200 g (a two-kiwifruit edible portion) of each cultivar, non-diabetic subjects (n = 20), and a glucose reference. GGE values were also estimated for a range of carbohydrate foods in the New Zealand Food Composition Database for which available carbohydrate and glycaemic index values were available. The values allowed exchange tables to be constructed for either equi-carbohydrate or equi glycaemic partial exchange of kiwifruit for the foods. RESULTS: GGE values of both kiwifruit cultivars were low ("Hayward", 6.6 glucose equivalents/100 g; "Zesy002", 6.7 glucose equivalents/100 g). Partial equi-carbohydrate substitution of foods in most carbohydrate food categories substantially increased vitamin C with little change in glycaemic impact, while equi-glycaemic partial substitution by kiwifruit could be achieved with little change in carbohydrate intake. CONCLUSION: Equi-carbohydrate partial exchange of kiwifruit for starchy staple foods is a means of greatly increasing nutrient richness in a diet without the physiological costs of increased glycaemia and insulin responses or carbohydrate intake. PMID- 30413046 TI - Insect Antimicrobial Peptides, a Mini Review. AB - Antimicrobial peptides (AMPs) are crucial effectors of the innate immune system. They provide the first line of defense against a variety of pathogens. AMPs display synergistic effects with conventional antibiotics, and thus present the potential for combined therapies. Insects are extremely resistant to bacterial infections. Insect AMPs are cationic and comprise less than 100 amino acids. These insect peptides exhibit an antimicrobial effect by disrupting the microbial membrane and do not easily allow microbes to develop drug resistance. Currently, membrane mechanisms underlying the antimicrobial effects of AMPs are proposed by different modes: the barrel-stave mode, toroidal-pore, carpet, and disordered toroidal-pore are the typical modes. Positive charge quantity, hydrophobic property and the secondary structure of the peptide are important for the antibacterial activity of AMPs. At present, several structural families of AMPs from insects are known (defensins, cecropins, drosocins, attacins, diptericins, ponericins, metchnikowins, and melittin), but new AMPs are frequently discovered. We reviewed the biological effects of the major insect AMPs. This review will provide further information that facilitates the study of insect AMPs and shed some light on novel microbicides. PMID- 30413047 TI - Targeting Groups Employed in Selective Dendrons and Dendrimers. AB - The design of compounds with directed action to a defined organ or tissue is a very promising approach, since it can decrease considerably the toxicity of the drug/bioactive compound. For this reason, this kind of strategy has been greatly important in the scientific community. Dendrimers, on the other hand, comprise extremely organized macromolecules with many peripheral functionalities, stepwise controlled synthesis, and defined size. These nanocomposites present several biological applications, demonstrating their efficiency to act in the pharmaceutical field. Considering that, the main purpose of this review was describing the potential of dendrons and dendrimers as drug targeting, applying different targeting groups. This application has been demonstrated through interesting examples from the literature considering the last ten years of publications. PMID- 30413048 TI - Customer Purchase Intentions and Choice in Food Retail Environments: A Scoping Review. AB - Food purchasing and consumption behaviors have implications for nutrition and obesity. Food retail environments, in particular, shape customer food choices and energy intake. The marketing literature offers insights about how public health practitioners can work within food retail environments to encourage healthy food choices. We reviewed experimental studies in the marketing literature to examine factors influencing customer purchase intentions and choice for food products in retail stores. Database searches were conducted in February 2016 for original, empirical articles published in English from 2000-2015 in marketing journals. Each research article included at least one experimental design study conducted in a real or simulated retail environment with purchase intentions or choice of food products as an outcome variable. Backward and forward reference searches were conducted for articles meeting inclusion criteria. Narrative synthesis methods were used to thematically group and summarize the findings of forty-one articles that met inclusion criteria into three categories: shelf display and product factors, pricing and price promotion factors, and in-store and customer decision-making factors. This research contributes to the literature by providing specific and actionable approaches that can increase/decrease customer purchase intentions and choice for food products in retail environments. Translating marketing strategies into public health applications can provide recommendations for future intervention research and policy related to customer food purchasing behavior. PMID- 30413049 TI - Performance of Excess Heat Factor Severity as a Global Heatwave Health Impact Index. AB - The establishment of an effective policy response to rising heatwave impacts is most effective when the history of heatwaves, their current impacts and future risks, are mapped by a common metric. In response meteorological agencies aim to develop seamless climate, forecast, and warning heat impact services, spanning all temporal and spatial scales. The ability to diagnose heatwave severity using the Excess Heat Factor (EHF) has allowed the Australian Bureau of Meteorology (the Bureau) to publicly release 7-day heatwave severity maps since 2014. National meteorological agencies in the UK and the United States are evaluating global 7-day and multi-week EHF heatwave severity probability forecasts, whilst the Bureau contributes to a Copernicus project to supply the health sector with global EHF severity heatwave projection scenarios. In an evaluation of impact skill within global forecast systems, EHF intensity and severity is reviewed as a predictor of human health impact, and extended using climate observations and human health data for sites around the globe. Heatwave intensity, determined by short and long-term temperature anomalies at each locality, is normalized to permit spatial analysis and inter-site comparison. Dimensionless heatwave event moments of peak severity and accumulated severity are shown to correlate with noteworthy events around the globe, offering new insights into current and future heatwave variability and vulnerability. The EHF severity metric permits the comparison of international heatwave events and their impacts, and is readily implemented within international heatwave early warning systems. PMID- 30413050 TI - Antidiabetic Drugs in NAFLD: The Accomplishment of Two Goals at Once? AB - Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common cause of chronic liver disease in Western countries, accounting for 20-30% of general population and reaching a prevalence of 55% in patients with type 2 diabetes mellitus (T2DM). Insulin resistance plays a key role in pathogenic mechanisms of NAFLD. Many drugs have been tested but no medications have yet been approved. Antidiabetic drugs could have a role in the progression reduction of the disease. The aim of this review is to summarize evidence on efficacy and safety of antidiabetic drugs in patients with NAFLD. Metformin, a biguanide, is the most frequently used drug in the treatment of T2DM. To date 15 randomized controlled trials (RCTs) and four meta-analysis on the use of metformin in NAFLD are available. No significant improvement in histological liver fibrosis was shown, but it can be useful in the treatment of co-factors of NAFLD, like body weight, transaminase or cholesterol levels, and HbA1c levels. A possible protective role in various types of cancer has been reported for Metformin. Thiazolidinediones modulate insulin sensitivity by the activation of PPAR-gamma. The RCTs and the meta-analysis available about the role of these drugs in NAFLD show an improvement in ballooning, lobular inflammation, and perhaps fibrosis, but some side effects, in particular cardiovascular, were showed. GLP-1 analogues stimulate insulin secretion by pancreatic beta cell and inhibit glucagon release; Liraglutide is the most used drug in this class and significantly improves steatosis, hepatocyte ballooning and transaminase levels. Scanty data about the role of DPP-4 and SGLT inhibitors were published. No data about insulin effects on NAFLD are available but it was showed a possible association between insulin use and the development of solid neoplasms, in particular HCC. In conclusion, antidiabetic drugs seem to be promising drugs, because they are able to treat both NAFLD manifestations and diabetes, preventing worsening of hepatic damage, but data are still conflicting. All antidiabetic drugs can be safely used in patients with compensated cirrhosis, while insulin is the preferred drug in decompensated Child C cirrhosis. PMID- 30413052 TI - Teamwork and Safety Climate in Homecare: A Mixed Method Study. AB - A rapidly changing homecare service sector implies difficulties to control safety and health risks for staff and to guarantee standardised deliveries of services to recipients. This study aimed to describe staff perceptions of safety climate and practices in homecare service teams, and suggestions for improvements. A second aim was to identify if and how the appraisals of safety climate were related to individual perceptions of safety, mental strain and adverse events/injury. A convergent parallel mixed methods design was used. Nursing assistants and care aides (133 in total, representing 11 work teams) in the north of Sweden replied to a survey and participated in focus group interviews. Results were analysed with ANOVA (inter-team differences) and by qualitative content analysis. Significant diversity was identified between the teams in five of seven dimensions of safety climate. Important areas for improvement were: a need to define and agree on criteria for a safe working environment; leadership prioritising safety at work; and management able to provide trust, support and time. A prerequisite for these agreements was improved authority and communication between all parties involved. The safety climate dimensions were related to personal perceptions of safety and mental strain and, partly, to adverse events/injuries. PMID- 30413051 TI - Systematic Review and Meta-Analysis on the Impact of Thrombolytic Therapy in Liver Transplantation Following Donation after Circulatory Death. AB - AIM: The livers from DCD (donation after cardiac death) donations are often envisaged as a possible option to bridge the gap between the availability and increasing demand of organs for liver transplantation. However, DCD livers possess a heightened risk for complications and represent a formidable management challenge. The aim of this study was to evaluate the effects of thrombolytic flush in DCD liver transplantation. METHODS: An extensive search of the literature database was made on MEDLINE, EMBASE, Cochrane, Crossref, Scopus databases, and clinical trial registry on 20 September 2018 to assess the role of thrombolytic tissue plasminogen activator (tPA) flush in DCD liver transplantation. RESULTS: A total of four studies with 249 patients in the tPA group and 178 patients in the non-tPA group were included. The pooled data revealed a significant decrease in ischemic-type biliary lesions (ITBLs) (P = 0.04), re-transplantation rate (P = 0.0001), and no increased requirement of blood transfusion (P = 0.16) with a better one year graft survival (P = 0.02). CONCLUSIONS: To recapitulate, tPA in DCD liver transplantation decreased the incidence of ITBLs, re-transplantation and markedly improved 1-year graft survival, without any increased risk for blood transfusion, hence it has potential to expand the boundaries of DCD liver transplantation. PMID- 30413053 TI - Oncogenic H-Ras Expression Induces Fatty Acid Profile Changes in Human Fibroblasts and Extracellular Vesicles. AB - Extracellular vesicles (EVs) are lipid bilayer surrounded particles that are considered an additional way to transmit signals outside the cell. Lipids have not only a structural role in the organization of EVs membrane bilayer, but they also represent a source of lipid mediators that may act on target cells. Senescent cells are characterized by a permanent arrest of cell proliferation, but they are still metabolically active and influence nearby tissue secreting specific signaling mediators, including those carried by EVs. Notably, cellular senescence is associated with increased EVs release. Here, we used gas chromatography coupled to mass spectrometry to investigate the total fatty acid content of EVs released by fibroblasts undergoing H-RasV12-induced senescence and their parental cells. We find that H-RasV12 fibroblasts show increased level of monounsaturated and decreased level of saturated fatty acids, as compared to control cells. These changes are associated with transcriptional up-regulation of specific fatty acid-metabolizing enzymes. The EVs released by both controls and senescent fibroblasts show a higher level of saturated and polyunsaturated species, as compared to parental cells. Considering that fibroblasts undergoing H RasV12-induced senescence release a higher number of EVs, these findings indicate that senescent cells release via EVs a higher amount of fatty acids, and in particular of polyunsaturated and saturated fatty acids, as compared to control cells. PMID- 30413054 TI - Does Delayed Restoration Improve Shear Bond Strength of Different Restorative Protocols to Calcium Silicate-Based Cements? AB - The purpose of the present study was to assess the proper time to perform a restoration (immediately or delayed) after placement of two calcium silicate based cements (CSCs) and to test the performance of two different restorative protocols regarding shear bond strength (SBS). Seventy-five acrylic blocks were randomly divided into five groups (n = 15). Specimens were filled with either ProRoot MTA (Dentsply Tulsa Dental) or Biodentine (Septodont). The restoration was performed at an immediate (12 min) or delayed (seven days) timeframe, using a resin-based flowable composite (SDR) (bonded to the CSC using a universal bonding system) or glass ionomer cement (GIC) as restorative materials. SBS was measured using a universal testing machine. Fractured surfaces were evaluated, and the pattern was registered. Statistical analysis was performed using the Dunn-Sidak post hoc test (P < 0.05). Biodentine/immediate SDR showed the highest mean SBS value (4.44 MPa), with statistically significant differences when compared to mineral trioxide aggregate (MTA)/GIC (1.14 MPa) and MTA/immediate SDR (1.33 MPa). MTA/GIC and MTA/immediate SDR did not present significant differences regarding SBS. No statistical differences were verified concerning mean SBS between both CSCs within the 7 day groups. MTA/delayed SDR (3.86 MPa) presented statistical differences compared to MTA/immediate SDR, whereas no differences were observed regarding Biodentine performance (Biodentine/immediate SDR and Biodentine/delayed SDR (3.09 MPa)). Bonding procedures directly on top of MTA might be preferably performed at a delayed timeframe, whereas Biodentine might allow for immediate restoration. PMID- 30413055 TI - Fast and Reliable Determination of Virgin Olive Oil Quality by Fruit Inspection Using Computer Vision. AB - The presence of minor compounds in virgin olive oils has been proven to play multiple positive roles in health protection, encouraging its production. The key factors that influence the oil quality are ripening stages and the state of health of the fruit. For this reason, at the oil mill's reception yard, fruits are visually inspected and separated according to their external appearance. In this way, the process parameters can be better adjusted to improve the quantity and/or quality of olive oil. This paper presents a proposal to automatically determine the oil quality before being produced from a previous inspection of the incoming fruits. Expert assessment of the fruit conditions guided the image processing. The proposal has been validated through the analysis of 74 batches of olives coming from an oil mill. Best correlation results between the image processing and the analytical data were found in the acidity index, peroxide values, ethyl ester, polyphenols, chlorophylls, and carotenoids. PMID- 30413056 TI - Analysis of the Sugar Content in Food Products by Using Gas Chromatography Mass Spectrometry and Enzymatic Methods. AB - The aim of this study is to develop and optimise a method of sugar content determination in food products. Date juice (syrup) was used as a sample natural food resource for the analysis because of its potential usage as an alternative substrate for a variety of fermentation processes. Hence, qualifying and quantifying its sugar content is a crucial step. Therefore, gas chromatography mass spectrometry (GCMS) was used as a pre-qualitative method to identify the types of sugar in the date sample. The results demonstrate that the analysed date juice contains glucose, fructose and sucrose. This analysis was obtained by measuring the retention time of individual standard sugar samples such as glucose, fructose, mannose and sucrose. In addition, the mass spectra of the standard and date juice samples contained characteristic fragments of glucose, fructose and sucrose. Thus, GCMS results determined the appropriate enzymatic assays for quantifying the sugars in date juice. These results were similar to those of the two enzymatic methods (standard enzymatic assay and measuring the change in pH by CL10 analyser). Therefore, they confirmed the identified sugars and provided the sugar contents of the sample. Consequently, sugar quantification results indicate that 1 g of date juice sample contains a total of 0.5275-0.5507 g of six-carbon sugars (glucose + fructose) and 0.064-0.068 g of sucrose. As a consequence, the total sugar content in 1 g of date juice is 0.600-0.615 g. These results are comparable to the sample analysis that is provided by the date juice production company. PMID- 30413058 TI - Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Thiouracil Derivatives as Potential Antithyroid Agents. AB - Hyperthyroidism is the result of uncontrolled overproduction of the thyroid hormones. One of the mostly used antithyroid agents is 6-n-propyl-2-thiouracil (PTU). The previously solved X-ray crystal structure of the PTU bound to mammalian lactoperoxidase (LPO) reveals that the LPO-PTU binding site is basically a hydrophobic channel. There are two hydrophobic side chains directed towards the oxygen atom in the C-4 position of the thiouracil ring. In the current study, the structural activity relationship (SAR) was performed on the thiouracil nucleus of PTU to target these hydrophobic side chains and gain more favorable interactions and, in return, more antithyroid activity. Most of the designed compounds show superiority over PTU in reducing the mean serum T4 levels of hyperthyroid rats by 3% to 60%. In addition, the effect of these compounds on the levels of serum T3 was found to be comparable to the effect of PTU treatment. The designed compounds in this study showed a promising activity profile in reducing levels of thyroid hormones and follow up experiments will be needed to confirm the use of the designed compounds as new potential antithyroid agents. PMID- 30413057 TI - Maternal RANKL Reduces the Osteopetrotic Phenotype of Null Mutant Mouse Pups. AB - RANKL signalization is implicated in the morphogenesis of various organs, including the skeleton. Mice invalidated for Rankl present an osteopetrotic phenotype that was less severe than anticipated, depending on RANKL's implication in morphogenesis. The hypothesis of an attenuated phenotype, as a result of compensation during gestation by RANKL of maternal origin, was thus brought into question. In order to answer this question, Rankl null mutant pups from null mutant parents were generated, and the phenotype analyzed. The results validated the presence of a more severe osteopetrotic phenotype in the second-generation null mutant with perinatal lethality. The experiments also confirmed that RANKL signalization plays a part in the morphogenesis of skeletal elements through its involvement in cell-to-cell communication, such as in control of osteoclast differentiation. To conclude, we have demonstrated that the phenotype associated with Rankl invalidation is attenuated through compensation by RANKL of maternal origin. PMID- 30413060 TI - Chitosan-MgO Nanocomposite: One Pot Preparation and Its Utility as an Ecofriendly Biocatalyst in the Synthesis of Thiazoles and [1,3,4]thiadiazoles. AB - A chitosan-MgO hybrid nanocomposite was prepared using a simple chemical precipitation method and characterized using Fourier transform spectroscopy (FTIR), elemental analysis (EDX), and scanning electron microscopy (SEM). The nanocomposite was served as a powerful ecofriendly basic catalyst under microwave irradiation in the synthesis of two novel series of 5-arylazo-2 hydrazonothiazoles 4a-j and 2-hydrazono[1,3,4]thiadiazoles 8a-d, incorporating a sulfonamide group. The structures of the synthesized products were elucidated by spectral data and elemental analyses. Also, their yield percentages were calculated using triethylamine (as a traditional catalyst) and chitosan-MgO nanocomposite (as a green recyclable catalyst) in a comparative study. PMID- 30413059 TI - Novel Modelling Approaches to Characterize and Quantify Carryover Effects on Sensory Acceptability. AB - Sensory biases caused by the residual sensations of previously served samples are known as carryover effects (COE). Contrast and convergence effects are the two possible outcomes of carryover. COE can lead to misinterpretations of acceptability, due to the presence of intrinsic psychological/physiological biases. COE on sensory acceptability (hedonic liking) were characterized and quantified using mixed and nonlinear models. N = 540 subjects evaluated grape juice samples of different acceptability qualities (A = good, B = medium, C = poor) for the liking of color (C), taste (T), and overall (OL). Three models were used to quantify COE: (1) COE as an interaction effect; (2) COE as a residual effect; (3) COE proportional to the treatment effect. For (1), COE was stronger for C than T and OL, although COE was minimal. For (2), C showed higher estimates (-0.15 to +0.10) of COE than did T and OL (-0.09 to +0.07). COE mainly took the form of convergence. For (3), the absolute proportionality parameter estimate (lambda) was higher for C than for T and OL (-0.155 vs. -0.004 to -0.039), which represented -15.46% of its direct treatment effect. Model (3) showed a significant COE for C. COE cannot be ignored as they may lead to the misinterpretation of sensory acceptability results. PMID- 30413061 TI - A Bayesian Network Model for Reducing Accident Rates of Electrical and Mechanical (E&M) Work. AB - Accidents in Repair, Maintenance, Alteration, and Addition (RMAA) work have become a growing concern, in recent years. The repair and maintenance works of electrical and mechanical (E&M) installations involves a variety of trades, a large number of practitioners and a series of high-risk activities. The uniqueness of E&M work, in the RMAA sector, requires a discrete and specific research to improve its safety performance. Understanding the causal relationships between safety factors and the number of accidents becomes crucial to develop a more effective safety management strategy. The Bayesian Network (BN) model is proposed to establish a probabilistic relational network between the causal factors, including both safety climate factors and personal experience factors that have influences on the number of accidents related to E&M RMAA work. The data were collected using a survey questionnaire, involving a hundred and fifty-five E&M practitioners. The BN results demonstrated that safety attitude and safety procedures were the most important factors to reduce the number of accidents. The proposed BN provides the ability to find out the most effective strategy with the best utilization of resources, to reduce the chance of a high number of E&M accidents, by controlling a single factor or simultaneously controlling, both, the safety climate and personal factors, to improve safety performance. PMID- 30413063 TI - Optimization of Detergent-Mediated Reconstitution of Influenza A M2 Protein into Proteoliposomes. AB - We report the optimization of detergent-mediated reconstitution of an integral membrane-bound protein, full-length influenza M2 protein, by direct insertion into detergent-saturated liposomes. Detergent-mediated reconstitution is an important method for preparing proteoliposomes for studying membrane proteins, and must be optimized for each combination of protein and membrane constituents used. The purpose of the reconstitution was to prepare samples for site-directed spin-labeling electron paramagnetic resonance (SDSL-EPR) studies. Our goals in optimizing the protocol were to minimize the amount of detergent used, reduce overall proteoliposome preparation time, and confirm the removal of all detergent. The liposomes were comprised of (1-palmitoyl-2-oleyl-sn-glycero phosphocholine (POPC) and 1-palmitoyl-2-oleyl-sn-glycero-3-[phospho-rac-(1 glycerol)] (POPG), and the detergent octylglucoside (OG) was used for reconstitution. Rigorous physical characterization was applied to optimize each step of the reconstitution process. We used dynamic light scattering (DLS) to determine the amount of OG needed to saturate the preformed liposomes. During detergent removal by absorption with Bio-Beads, we quantified the detergent concentration by means of a colorimetric assay, thereby determining the number of Bio-Bead additions needed to remove all detergent from the final proteoliposomes. We found that the overnight Bio-Bead incubation used in previously published protocols can be omitted, reducing the time needed for reconstitution. We also monitored the size distribution of the proteoliposomes with DLS, confirming that the size distribution remains essentially constant throughout the reconstitution process. PMID- 30413064 TI - The Associations between Dietary Patterns and Short Sleep Duration in Polish Adults (LifeStyle Study). AB - Short sleep duration appears to put adults at risk of excessive energy intake and obesity; less is known specifically about how sleep quantity relates to dietary patterns. Therefore, the aim of this study was to assess the associations of dietary patterns (DPs) with short sleep duration. The data were collected in November 2016 through a cross-sectional quantitative survey among 972 Polish adults with both normal weight and excessive weight. Principal components analysis (PCA) was conducted to derive DPs. Logistic regression analysis was used to verify associations between short sleep duration (independent variable) and DPs (dependent variables). Five DPs ('Fast foods & sweets'-FF&S; 'Meat & meat products'-M&MP; 'Fruit & vegetable'-F&V; 'Wholemeal food'-WF; and 'Fruit & vegetable juices'-F&VJ) were identified. Adults whose diet was based both on fruit and vegetables (OR 0.62, 95% CI: 0.44-0.88; p < 0.01) and on fast food and sweets (OR 0.63, 95% CI: 0.44-0.99; p < 0.01) were less likely to be short sleepers on weekdays. On weekdays short sleep duration was associated with smaller odds of FF&S both for men (OR 0.58, 95% CI: 0.33-0.97; p < 0.05) and for women (OR 0.61, 95% CI: 0.38-0.98; p < 0.05), and with smaller odds of F&V (OR 0.34, 95% CI: 0.20-0.58; p < 0.001) for men. Short sleep duration on weekend days was associated with a smaller odds of F&VJ (OR 0.56, 95% CI: 0.30-0.96; p < 0.05- only in crude model) and higher odds of F&V (OR 1.70, 95% CI: 1.02-3.11; p < 0.05) for women, and with a smaller odds of FF&S (OR 0.37, 95% CI: 0.17-0.79; p < 0.05) for men. The number of significant associations between dietary patterns and sleep duration was higher among people with normal weight and overweight compared to those with BMI >= 30. We found that both short sleep duration on weekdays and weekend days was associated with some dietary patterns including both healthy and unhealthy DPs. Gender significantly differed these relationships in groups with normal and excessive weight. Findings of the study confirmed the potential effectiveness of combined use of sleep duration and dietary patterns in the development of recommendations for prevention of obesity. Future studies are called for to evaluate these links using dietary patterns identified according to food intake. PMID- 30413062 TI - Correlation of Nutritional Indices on Admission to the Coronary Intensive Care Unit with the Development of Delirium. AB - BACKGROUND: Delirium is a common occurrence in patients admitted to the intensive care unit and is related to mortality and morbidity. Malnutrition is a predisposing factor for the development of delirium. Nevertheless, whether the nutritional status on admission anticipates the development of delirium in patients with acute cardiovascular diseases remains unknown. OBJECTIVE: This study aims to assess the correlation between the nutritional status on admission using the nutritional index and the development of delirium in the coronary intensive care unit. DESIGN: We examined 653 consecutive patients (mean age: 70 +/- 14 years) admitted to the coronary intensive care unit of Juntendo University Hospital between January 2015 and December 2016. We evaluated three nutritional indices frequently used to assess the nutritional status, i.e., Geriatric Nutritional Risk Index (GNRI), Prognostic Nutritional Index (PNI), and Controlling Nutritional Status (CONUT). We defined delirium as patients with a delirium score >4 using the Intensive Care Delirium Screening Checklist. RESULTS: Delirium was present in 58 patients. All nutritional indices exhibited a tendency for malnutrition in the delirium group compared with the non-delirium group (GNRI, 86.5 +/- 9.38 versus 91.6 +/- 9.89; PNI, 36.4 +/- 6.95 versus 41.6 +/- 7.62; CONUT, 5.88 +/- 3.00 versus 3.61 +/- 2.56; for all, p < 0.001). Furthermore, the maximum delirium score increased progressively from the low- to the high-risk group, as evaluated by each nutritional index (GNRI, PNI, CONUT; for all, p < 0.001). A multivariate analysis revealed that the PNI and CONUT were independent risk factors for the occurrence of delirium. CONCLUSIONS: A marked correlation exists between the nutritional index on admission, especially PNI and CONUT, and the development of delirium in patients with acute cardiovascular diseases, suggesting that malnutrition assessment upon admission could help identify patients at high risk of developing delirium. PMID- 30413065 TI - Effects of Dark Chocolate Intake on Brain Electrical Oscillations in Healthy People. AB - Dark chocolate is rich in flavonoids that can have effects on body composition and cognitive performance. The aim of this study was to analyze the effects of acute and subchronic chocolate intake on electrical brain oscillations. A study with 20 healthy subjects (mean age of 24.15 years) and a control group with five subjects (mean age of 23.2 years) was carried out. In the acute effect study, the subjects' intake was dark chocolate (103.72 mg/kg of body weight) rich in flavonoids and low in calories as in fasting. In the control group, the subjects intake was only low-calorie milk. For the subchronic effect, a daily dose of dark chocolate was given for eight days. The baseline electroencephalogram (EEG) was recorded before dark chocolate intake; at 30 min, the second EEG was carried out; on the eighth day, the third and fourth EEGs were performed before and after the last intake. In acute and subchronic intake, Delta Absolute Power (AP) decrease was observed in most brain regions (p < 0.05), except in the right fronto-centro temporal regions. In the Theta band, there was a generalized decrease of the AP of predominance in the left fronto-centro-temporal regions. In contrast, an increase in AP was observed in the temporo-occipital regions in the Alpha band, and in the right temporal and parieto-occipital regions in the Beta band. The control group did not have significant changes in brain oscillations (p > 0.05). We concluded that acute and subchronic chocolate intake decreased the Delta and Theta AP and increased Alpha and Beta AP in most brain regions. PMID- 30413066 TI - Fusing Infrared and Visible Images of Different Resolutions via Total Variation Model. AB - In infrared and visible image fusion, existing methods typically have a prerequisite that the source images share the same resolution. However, due to limitations of hardware devices and application environments, infrared images constantly suffer from markedly lower resolution compared with the corresponding visible images. In this case, current fusion methods inevitably cause texture information loss in visible images or blur thermal radiation information in infrared images. Moreover, the principle of existing fusion rules typically focuses on preserving texture details in source images, which may be inappropriate for fusing infrared thermal radiation information because it is characterized by pixel intensities, possibly neglecting the prominence of targets in fused images. Faced with such difficulties and challenges, we propose a novel method to fuse infrared and visible images of different resolutions and generate high-resolution resulting images to obtain clear and accurate fused images. Specifically, the fusion problem is formulated as a total variation (TV) minimization problem. The data fidelity term constrains the pixel intensity similarity of the downsampled fused image with respect to the infrared image, and the regularization term compels the gradient similarity of the fused image with respect to the visible image. The fast iterative shrinkage-thresholding algorithm (FISTA) framework is applied to improve the convergence rate. Our resulting fused images are similar to super-resolved infrared images, which are sharpened by the texture information from visible images. Advantages and innovations of our method are demonstrated by the qualitative and quantitative comparisons with six state of-the-art methods on publicly available datasets. PMID- 30413067 TI - WS(1-x)Sex Nanoparticles Decorated Three-Dimensional Graphene on Nickel Foam: A Robust and Highly Efficient Electrocatalyst for the Hydrogen Evolution Reaction. AB - To find an effective alternative to scarce, high-cost noble platinum (Pt) electrocatalyst for hydrogen evolution reaction (HER), researchers are pursuing inexpensive and highly efficient materials as an electrocatalyst for large scale practical application. Layered transition metal dichalcogenides (TMDCs) are promising candidates for durable HER catalysts due to their cost-effective, highly active edges and Earth-abundant elements to replace Pt electrocatalysts. Herein, we design an active, stable earth-abundant TMDCs based catalyst, WS(1 x)Sex nanoparticles-decorated onto a 3D porous graphene/Ni foam. The WS(1 x)Sex/graphene/NF catalyst exhibits fast hydrogen evolution kinetics with a moderate overpotential of ~-93 mV to drive a current density of 10 mA cm-2, a small Tafel slope of ~51 mV dec-1, and a long cycling lifespan more than 20 h in 0.5 M sulfuric acid, which is much better than WS2/NF and WS2/graphene/NF catalysts. Our outcomes enabled a way to utilize the TMDCs decorated graphene and precious-metal-free electrocatalyst as mechanically robust and electrically conductive catalyst materials. PMID- 30413068 TI - Public Key-Based Authentication and En-Route Filtering Scheme in Wireless Sensor Networks. AB - The existing public key-based en-route filtering schemes are vulnerable to report disruption attacks or selective forwarding attacks, and they fail to consider any measure to detect and punish the malicious nodes. The authors propose a series of public key-based security mechanisms for wireless sensor networks (WSNs) in this paper, including a mechanism for verifying the partial signatures, a substitution mechanism, an effective report forwarding protocol, and a trust value-based mechanism to identify and punish the malicious nodes. Finally, the authors develop a public key-based authentication and en-route filtering scheme (PKAEF), which can resist false data injection attacks, report disruption attacks and selective forwarding attacks, and can mitigate the impact of malicious nodes. Detailed performance analysis and evaluation show that, in most cases, PKAEF outperforms previous works in terms of safety, filtering efficiency, and data availability. PMID- 30413069 TI - Multifeature Extraction and Seafloor Classification Combining LiDAR and MBES Data around Yuanzhi Island in the South China Sea. AB - Airborne light detection and ranging (LiDAR) full waveforms and multibeam echo sounding (MBES) backscatter data contain rich information about seafloor features and are important data sources representing seafloor topography and geomorphology. Currently, to classify seafloor types using MBES, curve features are extracted from backscatter angle responses or grayscale, and texture features are extracted from backscatter images based on gray level co-occurrence matrix (GLCM). To classify seafloor types using LiDAR, waveform features are extracted from bottom returns. This paper comprehensively considers the features of both LiDAR waveforms and MBES backscatter images that include the eight feature factors of the LiDAR full waveforms (amplitude, peak location, full width half maximum (FWHM), skewness, kurtosis, area, distance, and cross-section) and the eight feature factors of MBES backscatter images (mean, standard deviation (STD), entropy, homogeneity, contrast, angular second moment (ASM), correlation, and dissimilarity). Based on a support vector machine (SVM) algorithm with different kernel functions and penalty factors, a new seafloor classification method that merges multiple features is proposed for a beneficial exploration of acousto optic fusion. The experimental results of the seafloor classification around Yuanzhi Island in the South China Sea indicate that, when LiDAR waveform features are merged (using an Optech Aquarius system) with MBES backscatter image features (using a Sonic 2024) to classify three types of sands, reefs, and rocks, the overall accuracy is improved to 96.71%, and the kappa reaches 0.94. After merging multiple features, the classification accuracies of the SVM, genetic algorithm SVM (GA-SVM) and particle swarm optimization SVM (PSO-SVM) increase by an average of 9.06%, 3.60%, and 2.75%, respectively. PMID- 30413070 TI - Toxicity Evaluation and Biomarker Selection with Validated Reference Gene in Embryonic Zebrafish Exposed to Mitoxantrone. AB - Notwithstanding the widespread use and promising clinical value of chemotherapy, the pharmacokinetics, toxicology, and mechanism of mitoxantrone remains unclear. To promote the clinical value in the treatment of human diseases and the exploration of potential subtle effects of mitoxantrone, zebrafish embryos were employed to evaluate toxicity with validated reference genes based on independent stability evaluation programs. The most stable and recommended reference gene was gapdh, followed by tubalpha1b, for the 48 h post fertilization (hpf) zebrafish embryo mitoxantrone test, while both eef1a1l1 and rpl13alpha were recommended as reference genes for the 96 hpf zebrafish embryo mitoxantrone test. With gapdh as an internal control, we analyzed the mRNA levels of representative hepatotoxicity biomarkers, including fabp10a, gclc, gsr, nqo1, cardiotoxicity biomarker erg, and neurotoxicity biomarker gfap in the 48 hpf embryo mitoxantrone test. The mRNA levels of gclc, gsr, and gfap increased significantly in 10 and 50 MUg/L mitoxantrone-treated 48 hpf embryos, while the transcript levels of fabp10a decreased in a dose-dependent manner, indicating that mitoxantrone induced hepatotoxicity and neurotoxicity. Liver hematoxylin-eosin staining and the spontaneous movement of embryos confirmed the results. Thus, the present research suggests that mitoxantrone induces toxicity during the development of the liver and nervous system in zebrafish embryos and that fabp10a is recommended as a potential biomarker for hepatotoxicity in zebrafish embryos. Additionally, gapdh is proposed as a reference gene for the 48 hpf zebrafish embryo mitoxantrone toxicity test, while eef1a1l1 and rpl13alpha are proposed as that for the 96 hpf test. PMID- 30413071 TI - Bioactive Natural Spirolactone-Type 6,7-seco-ent-Kaurane Diterpenoids and Synthetic Derivatives. AB - Diterpenoids are widely distributed natural products and have caused considerable interest because of their unique skeletons and antibacterial and antitumor activities and so on. In light of recent discoveries, ent-kaurane diterpenoids, which exhibit a wide variety of biological activities, such as anticancer and anti-inflammatory activities, pose enormous potential to serve as a promising candidate for drug development. Among them, spirolactone-type 6,7-seco-ent kaurane diterpenoids, with interesting molecular skeleton, complex oxidation patterns, and bond formation, exhibit attractive activities. Furthermore, spirolactone-type diterpenoids have many modifiable sites, which allows for linking to various substituents, suitable for further medicinal study. Hence, some structurally modified derivatives with improved cytotoxicity activities are also achieved. In this review, natural bioactive spirolactone-type diterpenoids and their synthetic derivatives were summarized. PMID- 30413072 TI - Ophiopogonin D, a Steroidal Glycoside Abrogates STAT3 Signaling Cascade and Exhibits Anti-Cancer Activity by Causing GSH/GSSG Imbalance in Lung Carcinoma. AB - Natural medicinal plants are multi-targeted in nature and their anti-cancer activities are also complex and varied, thus requiring a more systematic analysis of their modes of action. Since the activation of signal transducer and activator of transcription 3 (STAT3) is often deregulated in non-small cell lung carcinoma (NSCLC) cells and tissue specimens, its negative regulation can form the basis for identification of targeted therapy. In this report, we analyzed the possible anti-cancer effects of ophiopogonin D (OP-D) and the underlying mechanisms by which OP-D exerts its actions in NSCLC. OP-D exhibited substantial suppressive activity on STAT3 signaling and this effect was found to be mediated via oxidative stress phenomena caused by disturbance in GSH/GSSG ratio. In addition, OP-D induced apoptosis, activated caspase mediated apoptotic cascade and decreased expression of various oncogenic genes. Consistently, OP-D treatment significantly reduced NSCLC tumor growth in preclinical mouse model with via decreasing levels of p-STAT3. OP-D was also found to attenuate the expression of STAT3-regulated anti-apoptosis, cell cycle regulator, and angiogenesis biomarkers. Our findings suggest that OP-D can induce apoptosis and exert anti tumor effects by inhibition of STAT3 signaling pathways in NSCLC. PMID- 30413073 TI - Linear Versus Nonlinear Acoustic Probing of Plasticity in Metals: A Quantitative Assessment. AB - The relative dislocation density of aluminum and copper samples is quantitatively measured using linear Resonant Ultrasound Spectroscopy (RUS). For each metallic group, four samples were prepared with different thermomechanical treatments in order to induce changes in their dislocation densities. The RUS results are compared with Nonlinear Resonant Ultrasound Spectroscopy (NRUS) as well as Second Harmonic Generation (SHG) measurements. NRUS has a higher sensitivity by a factor of two to six and SHG by 14-62%. The latter technique is, however, faster and simpler. As a main result, we obtain a quantitative relation between the changes in the nonlinear parameters and the dislocation density variations, which in a first approximation is a linear relation between these differences. We also present a simple theoretical expression that explains the better sensitivity to dislocation content of the nonlinear parameters with respect to the linear ones. X-Ray diffraction measurements, although intrusive and less accurate, support the acoustics results. PMID- 30413074 TI - Perceptions of Health Risks from Hot Weather, and Coping Behaviors among Ethnic Minority Groups in Mountain Areas of China: A Case Study in the Tujia and Miao Autonomous Prefecture. AB - Limited research focuses on risk perceptions of hot weather among ethnic minority groups in remote mountain areas of China. Adopting a multi-stage sampling method, this study received completed questionnaires from 643 participates in Enshi Tujia and Miao Autonomous Prefecture of China in 2017 and 2018. We used multivariate logistic regression models to explore the factors affecting risk perceptions and coping behaviors with regards to hot weather. Results showed that despite a relatively high level of risk perception, the study population in the mountain areas of China had a very low level of preparedness in responding to the risks from heat, and a lack of professional health knowledge in general. In particular, 61.3% (95% CI: 57.1%-5.6%) of the participants felt increasing temperatures in recent years, 73.2% (95% CI: 69.3%-7.0%) thought extreme high temperatures would be a health threat, and 61.3% (95% CI: 57.1%-5.4%) reported physical discomfort during hot weather. However, only 12% (95% CI: 9.5%-4.5%) had the information or knowledge to stay healthy during the extreme high temperatures, and only 24.2% had (95% CI: 20.8%-7.6%) preparation. The logistic regression models suggested that ethnic group, health status, marital status, gender, and employment could affect their perceptions, which could significantly affect the adoption of coping behaviors. In conclusion, our findings have significant implications for developing policies and health education and promotion programs for ethnic minorities in remote regions to maintain good health during hot weather. PMID- 30413075 TI - Zwitterionic Cysteine Drug Coating Influence in Functionalization of Implantable Ti50Zr Alloy for Antibacterial, Biocompatibility and Stability Properties. AB - The present paper aims atincreasing the bioperformance of implantable Ti50Zr alloy using zwitterionic cysteine drug coating. Aspects such as stability, biocompatibility, and antibacterial effects were investigated with the help of various methods such as infrared spectroscopy (FT-IR), scanning electronic microscopy (SEM), electrochemical methods, contact angle determinations and cell response. The experimental data of zwitterionic cysteine coating indicate the existence of a hydration layer due to hydrophilic groups evidenced in FT-IR which is responsible for the decrease of contact angle and antibacterial capabilities. The electrochemical stability was evaluatedbased on Tafel plots and electrochemical impedance spectroscopy (EIS). The cell response to cysteine was determined with gingival fibroblasts measuring lactate dehydrogenase (LDH) activity, concentrations of nitric oxide (NO) and intracellular level of reactive oxygen species (ROS). All experimental results supported the increase of stability and better cells response of implantable Ti50Zr alloy coated with zwitterionic cysteine drug. The antibacterial index was measured against Staphylococcus aureus and Escherichia coli. It was demonstrated that the coating enhanced the production of intracellular ROS in time, which subsequently caused a significant increase in antibacterial index. PMID- 30413076 TI - A Review on Liquid Chromatography-Tandem Mass Spectrometry Methods for Rapid Quantification of Oncology Drugs. AB - In the last decade, the tremendous improvement in the sensitivity and also affordability of liquid chromatography-tandem mass spectrometry (LC-MS/MS) has revolutionized its application in pharmaceutical analysis, resulting in widespread employment of LC-MS/MS in determining pharmaceutical compounds, including anticancer drugs in pharmaceutical research and also industries. Currently, LC-MS/MS has been widely used to quantify small molecule oncology drugs in various biological matrices to support preclinical and clinical pharmacokinetic studies in R&D of oncology drugs. This mini-review article will describe the state-of-the-art LC-MS/MS and its application in rapid quantification of small molecule anticancer drugs. In addition, efforts have also been made in this review to address several key aspects in the development of rapid LC-MS/MS methods, including sample preparation, chromatographic separation, and matrix effect evaluation. PMID- 30413078 TI - Regeneration and Reuse of Immunoaffinity Column for Highly Efficient Clean-Up and Economic Detection of Ochratoxin A in Malt and Ginger. AB - Immunoaffinity columns (IACs) are most popularly used for mycotoxin clean-up in complex matrices prior to chromatographic analysis. But, their high cost has limited their wide application and the regeneration of IACs for multiple instances of reuse is important. This study aimed to investigate the feasibility of regeneration and reuse of IACs for purification of ochratoxin A (OTA) in spiked raw malt and dried ginger samples followed by high performance liquid chromatography-fluorescence detection. After each use, the IACs were filled with phosphate buffer saline (PBS) as the preservation solution and stored at 8 degrees C overnight for regeneration and reuse until the recovery rate was <70%. The results showed that matrix type, preparation procedure, and pH value of sample extraction exhibited major effects on the reuse of IACs for OTA clean-up. While, after modifying the sample preparation procedure using water as the diluent and the solution at a pH of 7 to 8, the IACs could be used eight and three times for the spiked raw malt and dried ginger samples with OTA after regeneration. Regarding the traditional procedure recommended in Chinese Pharmacopoeia (2015 edition), the IACs could be used for three and two times for the spiked raw malt and dried ginger samples with OTA, respectively. Therefore, the corresponding experimental cost could be reduced to one-eighth and one-third of the original cost. This is the first study on the regeneration and reuse of IACs for OTA clean-up in complex Chinese herbal medicines, providing a green and economical tool for a large number of samples analysis with low cost. PMID- 30413077 TI - Folate Receptor-Targeted and GSH-Responsive Carboxymethyl Chitosan Nanoparticles Containing Covalently Entrapped 6-Mercaptopurine for Enhanced Intracellular Drug Delivery in Leukemia. AB - For enhanced intracellular accumulation of 6-mercaptopurine (6-MP) in leukemia, a folate receptor-targeted and glutathione (GSH)-responsive polymeric prodrug nanoparticle was made. The nanoparticles were prepared by conjugating 6-MP to carboxymethyl chitosan via a GSH-sensitive carbonyl vinyl sulfide linkage, ultrasonic self-assembly and surface decoration with folate. The TEM graphs shows that the as-synthesized nanoparticles are spherical with a particle size of 170~220 nm. In vitro drug release of nanoparticles demonstrated acceptable stability in PBS containing 20 MUM GSH at pH 7.4. However, the cumulative drug release rate of the samples containing 20 mM and 10 mM GSH medium reached 78.9% and 64.8%, respectively, in pH 5.0 at 20 h. This indicated that this nano-sized system is highly sensitive to GSH. The inhibition ratio of folate-modified nanoparticles compared to unmodified nanoparticles was higher in cancer cells (human promyelocytic leukemia cells, HL-60) while their cytotoxicity was lower in normal cells (mouse fibroblast cell lines, L929). Furthermore, in vitro cancer cell incubation studies confirmed that folate-modified nanoparticles therapeutics were significantly more effective than unmodified nanoparticles therapeutics. Our results suggest that folate receptor-targeting and GSH-stimulation can significantly elevate tumour intracellular drug release. Therefore, folate modified nanoparticles containing chemoradiotherapy is a potential treatment for leukemia therapy. PMID- 30413079 TI - Heparan Sulfate Mimetics in Cancer Therapy: The Challenge to Define Structural Determinants and the Relevance of Targets for Optimal Activity. AB - Beyond anticoagulation, the therapeutic potential of heparin derivatives and heparan sulfate (HS) mimetics (functionally defined HS mimetics) in oncology is related to their ability to bind and modulate the function of a vast array of HS binding proteins with pivotal roles in cancer growth and progression. The definition of structural/functional determinants and the introduction of chemical modifications enabled heparin derivatives to be identified with greatly reduced or absent anticoagulant activity, but conserved/enhanced anticancer activity. These studies paved the way for the disclosure of structural requirements for the inhibitory effects of HS mimetics on heparanase, selectins, and growth factor receptor signaling, as well as for the limitation of side effects. Actually, HS mimetics affect the tumor biological behavior via a multi-target mechanism of action based on their effects on tumor cells and various components of the tumor microenvironment. Emerging evidence indicates that immunomodulation can participate in the antitumor activity of these agents. Significant ability to enhance the antitumor effects of combination treatments with standard therapies was shown in several tumor models. While the first HS mimetics are undergoing early clinical evaluation, an improved understanding of the molecular contexts favoring the antitumor action in certain malignancies or subgroups is needed to fully exploit their potential. PMID- 30413080 TI - Anti-MRSA Sesquiterpenes from the Semi-Mangrove Plant Myoporum bontioides A. Gray. AB - The striking rise of methicillin-resistant Staphylococcus aureus (MRSA) infections has become a serious threat to public health worldwide. In an effort to search for new anti-MRSA agents from natural products, a bioassay-guided phytochemical study was conducted on the semi-mangrove plant Myoporum bontioides A. Gray, which led to the isolation of two new sesquiterpene alkaloids (1 and 2) and six known furanosesquiterpenes (3-8). Their structures were elucidated on the basis of extensive analysis of their 1D, 2D NMR and mass spectroscopic data. These two new alkaloids (1 and 2) displayed potent anti-MRSA activity with MIC value of 6.25 MUg/mL. This is the first report of sesquiterpene alkaloids from the plants of Myoporum genus and their anti-MRSA activity. PMID- 30413081 TI - Comparative Biology of Centrosomal Structures in Eukaryotes. AB - The centrosome is not only the largest and most sophisticated protein complex within a eukaryotic cell, in the light of evolution, it is also one of its most ancient organelles. This special issue of "Cells" features representatives of three main, structurally divergent centrosome types, i.e., centriole-containing centrosomes, yeast spindle pole bodies (SPBs), and amoebozoan nucleus-associated bodies (NABs). Here, I discuss their evolution and their key-functions in microtubule organization, mitosis, and cytokinesis. Furthermore, I provide a brief history of centrosome research and highlight recently emerged topics, such as the role of centrioles in ciliogenesis, the relationship of centrosomes and centriolar satellites, the integration of centrosomal structures into the nuclear envelope and the involvement of centrosomal components in non-centrosomal microtubule organization. PMID- 30413082 TI - Molecular Analysis of Forensically Important Blow Flies in Thailand. AB - Blow flies are the first insect group to colonize on a dead body and thus correct species identification is a crucial step in forensic investigations for estimating the minimum postmortem interval, as developmental times are species specific. Due to the difficulty of traditional morphology-based identification such as the morphological similarity of closely related species and uncovered taxonomic keys for all developmental stages, DNA-based identification has been increasing in interest, especially in high biodiversity areas such as Thailand. In this study, the effectiveness of long mitochondrial cytochrome c oxidase subunit I and II (COI and COII) sequences (1247 and 635 bp, respectively) in identifying 16 species of forensically relevant blow flies in Thailand (Chrysomya bezziana, Chrysomya chani, Chrysomya megacephala, Chrysomya nigripes, Chrysomya pinguis, Chrysomya rufifacies, Chrysomya thanomthini, Chrysomya villeneuvi, Lucilia cuprina, Lucilia papuensis, Lucilia porphyrina, Lucilia sinensis, Hemipyrellia ligurriens, Hemipyrellia pulchra, Hypopygiopsis infumata, and Hypopygiopsis tumrasvini) was assessed using distance-based (Kimura two-parameter distances based on Best Match, Best Close Match, and All Species Barcodes criteria) and tree-based (grouping taxa by sequence similarity in the neighbor joining tree) methods. Analyses of the obtained sequence data demonstrated that COI and COII genes were effective markers for accurate species identification of the Thai blow flies. This study has not only demonstrated the genetic diversity of Thai blow flies, but also provided a reliable DNA reference database for further use in forensic entomology within the country and other regions where these species exist. PMID- 30413083 TI - The Effects of Different Degrees of Procyanidin Polymerization on the Nutrient Absorption and Digestive Enzyme Activity in Mice. AB - Proanthocyanidins, including polymers with both low and high degrees of polymerization, are the focus of intensive research worldwide due to their high antioxidant activity, medicinal applications, and pharmacological properties. However, the nutritional value of these compounds is limited because they readily form complexes with proteins, polysaccharides, and metal ions when consumed. In this study, we examined the effects of proanthocyanidins with different degrees of polymerization on white mice. Twenty-four male white mice were randomly divided into three groups of eight mice each and fed proanthocyanidins with a low degree of polymerization or a high degree of polymerization or a distilled water control via oral gavage over a 56-day period. We examined the effects of these proanthocyanidins on digestive enzyme activity and nutrient absorption. Compared to the control group, the group fed high-polymer proanthocyanidins exhibited a significant reduction in net body mass, total food intake, food utility rate, amylase activity, protease activity, and major nutrient digestibility (p < 0.05), while the group fed low-polymerization proanthocyanidins only exhibited significant reductions in total food intake, alpha-amylase activity, and apparent digestibility of calcium and zinc (p < 0.05). Therefore, proanthocyanidins with a high degree of polymerization had a greater effect on digestive enzyme activity and nutrient absorption than did those with a low degree of polymerization. This study lays the foundation for elucidating the relationship between procyanidin polymerization and nutrient uptake, with the aim of reducing or eliminating the antinutritional effects of polyphenols. PMID- 30413084 TI - Residual Stress of a TC17 Titanium Alloy after Belt Grinding and Its Impact on the Fatigue Life. AB - Titanium alloy materials are widely used in the design of key parts, such as aeroengine blades and integral blades. The surface residual stress has a great influence on the fatigue life of the parts mentioned above. Presently, abrasive belt grinding can form residual stress on the surface. However, the formation mechanism has not yet been revealed, providing the impetus for the present study. First of all, the surface residual stress is characterized based on Bragg's law. The influence of contact force, reciprocating frequency, and feed speed on the residual stress of a titanium alloy abrasive belt grinding is obtained using an experimental method. The residual stress model is simulated by the tensile force on the surface of the model, and the fatigue life of the bar under a sinusoidal tensile load is analyzed by simulating the fatigue test of the titanium alloy bar. Finally, fatigue testing and fracture analysis are carried out. The experimental results show that with the increase of the grinding contact force, increase of the reciprocating frequency, and decrease of the feed speed, the residual compressive stress on the surface of the parts increases and the fatigue life is higher at the same working stress level. It also shows that the residual compressive stress produced by abrasive belt grinding is in the range of 120-300 MPa. The fatigue simulation curve's inflection point appears at the level of 550 MPa. The error between the simulation data and the experimental data is less than 10%, which shows the accuracy of the simulation experiment. The fracture morphology at room temperature is a ductile fracture with fine equiaxed dimples. PMID- 30413085 TI - Single Molecule FRET: A Powerful Tool to Study Intrinsically Disordered Proteins. AB - Intrinsically disordered proteins (IDPs) are often modeled using ideas from polymer physics that suggest they smoothly explore all corners of configuration space. Experimental verification of this random, dynamic behavior is difficult as random fluctuations of IDPs cannot be synchronized across an ensemble. Single molecule fluorescence (or Forster) resonance energy transfer (smFRET) is one of the few approaches that are sensitive to transient populations of sub-states within molecular ensembles. In some implementations, smFRET has sufficient time resolution to resolve transitions in IDP behaviors. Here we present experimental issues to consider when applying smFRET to study IDP configuration. We illustrate the power of applying smFRET to IDPs by discussing two cases in the literature of protein systems for which smFRET has successfully reported phosphorylation induced modification (but not elimination) of the disordered properties that have been connected to impacts on the related biological function. The examples we discuss, PAGE4 and a disordered segment of the GluN2B subunit of the NMDA receptor, illustrate the great potential of smFRET to inform how IDP function can be regulated by controlling the detailed ensemble of disordered states within biological networks. PMID- 30413086 TI - Augmentation of GNSS by Low-Cost MEMS IMU, OBD-II, and Digital Altimeter for Improved Positioning in Urban Area. AB - This paper proposes an efficient multi-sensor system to complement GNSS (Global Navigation Satellite System) for improved positioning in urban area. The proposed system augments GNSS by low-cost MEMS IMU (Micro Electro Mechanical Systems Inertial Measurement Unit), OBD (On-Board Diagnostics)-II, and digital altimeter modules. For improved availability of time synchronization in urban area, an adaptive synchronization method is proposed to combine the external PPS (Pulse Per Second) signal and the internal onboard clock. For improved positioning accuracy and availability, a 17-state Kalman filter is formulated for efficient multi-sensor fusion, including OBD-II and digital altimeter modules. A strategy to apply different types of measurement updates is also proposed for improved performance in urban area. Four experiment results with field-collected measurements evaluates the performance of the proposed GNSS/IMU/OBD-II/altimeter system in various aspects, including accuracy, precision, continuity, and availability. PMID- 30413087 TI - Degradable and Photocatalytic Antibacterial Au-TiO2/Sodium Alginate Nanocomposite Films for Active Food Packaging. AB - A degradable and antibacterial sodium alginate film containing functional Au-TiO2 nanocomposites for food packaging was successfully developed. The Au-TiO2 nanocomposites are synthesized hydrothermally and mixed with the alginate solution to form the film by a casting method. The Au-TiO2 nanocomposites enable the film with excellent visible light absorption and transfer ability with the light absorption rang covering UV-visible wavelength (300-800 nm) and induce the increase of the film water contact angle from 40 degrees to 74 degrees , which contributes to the film shape stability. Furthermore, compared to the TiO2 nanoparticle-incorporated film, the antibacterial ability of Au-TiO2/sodium alginate composite film is improved approximately by 60% and 50% against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli), respectively, in light conditions. The antibacterial property of the film arises from the increased production of reactive oxygen species (ROS) induced by the surface plasmonic resonance of Au nanoparticles. The degradable and antibacterial properties render the composite film of great application potential in food packaging industry. PMID- 30413088 TI - Dynamics of Frenkel Excitons in Pentacene. AB - The dispersion relation for noninteracting excitons and the influence of perturbative corrections are examined in the case of pentacene structure. The values of exchange integrals are determined by nonlinear fits to the experimental dispersion data, obtained by the inelastic electron scattering reported in recent experiments. We obtain theoretical dispersion curves along four different directions in the Brillouin zone which possess the same periodicity as the experimental data. We also show that perturbative corrections are negligible since the exciton gap in the dispersion relation is huge in comparison to the exchange integrals. PMID- 30413089 TI - Prevalence of Total Physical Activity, Muscle-Strengthening Activities, and Excessive TV Viewing among Older Adults; and Their Association with Sociodemographic Factors. AB - The study aimed to describe the prevalence of meeting moderate-to-vigorous intensity physical activity (MVPA), muscle-strengthening (MS) activities, and television (TV) viewing guidelines, and their association with sociodemographic factors. Data from older adults aged 65 or above were sampled by age and sex to the population aged 65+ years for each area in Taiwan and collected through telephone interviews. The prevalence of meeting MVPA and MS activities, MVPA and MS activities guidelines, and excessive TV viewing were calculated. We also investigated their associations with sociodemographic variables using logistic regression analyses. A total of 1068 older adults (response rate: 32.5%) participated in the present study. 79.4% met the MVPA guidelines (150 min weekly), 25.3% met the MS guidelines (twice a week), 22.4% met both MVPA and MS guidelines, and 53.1% engaged in excessive TV viewing (more than or equal to two hours per day). Overall, in old age, low educational level was associated with lower odds of meeting MVPA and MS activities, and both the MVPA and MS activity guidelines; while living alone and having no full-time job had higher odds of excessive TV viewing. A large number of older adults do not meet the MS recommendations, but are engaged in excessive TV viewing. Our findings may be important for public health interventions to promote MS and avoid excessive TV viewing, especially for at-risk subgroups. PMID- 30413090 TI - Epidemiology of Hepatitis B Virus Infection in Bangladesh: Prevalence among General Population, Risk Groups and Genotype Distribution. AB - Despite a considerable body of published research on hepatitis B in Bangladesh, researchers continue to lament the lack of reliable information about hepatitis B virus (HBV) infection epidemiology. The present review aims to provide a comprehensive survey of the literature with particular focus on a number of epidemiological questions, as well as a commentary on the trends of hepatitis B research as it has taken place in Bangladesh. The key themes to emerge from this review are: first, beyond noting a declining trend, it is difficult to provide conclusive estimates about HBV prevalence in the general population of Bangladesh. The majority of the studies, even the ones conducted on apparently healthy populations, fail to be adequately representative for the reasons explored in the article. Secondly, HBV infection in Bangladesh is sharply stratified across sociodemographic lines, which speaks to the role of awareness and risk exposure in HBV prevalence. Third, more research on occult infection rates is required to estimate the extent of risk posed by the current blood donation screening program, which relies exclusively on hepatitis B surface antigen as a biomarker. The same considerations apply for the comparative importance of vertical versus horizontal transmission and prevalence among particular risk groups like healthcare workers with high occupational exposure. Finally, while recent studies do allow us, albeit with some ambiguity, to draw conclusions about distribution of HBV genotypes in Bangladesh, there needs to be an added emphasis on molecular epidemiology. It is hoped that the present review, the first of its kind in Bangladesh, will serve as an up-to-date summary of the course HBV epidemiology research in Bangladesh has taken thus far, as well as crucial gaps to address going forward. PMID- 30413092 TI - Activation of CREBZF Increases Cell Apoptosis in Mouse Ovarian Granulosa Cells by Regulating the ERK1/2 and mTOR Signaling Pathways. AB - CREBZF, a multifunction transcriptional regulator, participates in the regulation of numerous cellular functions. The aims of the present study were to detect the localization of CREBZF expression in the ovary and explore the role of CREBZF and related mechanisms in the apoptosis of ovarian granulosa cells. We found by immunohistochemistry that CREBZF was mainly located in granulosa cells and oocytes during the estrous cycle. Western blot analysis showed that SMILE was the main isoform of CREBZF in the ovary. The relationship between apoptosis and CREBZF was assessed via CREBZF overexpression and knockdown. Flow cytometry analysis showed that CREBZF induced cell apoptosis in granulosa cells. Western bolt analysis showed that overexpression of CREBZF upregulated BAX and cleaved Caspase-3, while it downregulated BCL-2. Furthermore, overexpression of CREBZF inhibited the ERK1/2 and mTOR signaling pathways through the phosphorylation of intracellular-regulated kinases 1/2 (ERK1/2) and p70 S6 kinase (S6K1). Moreover, we found that CREBZF also activated autophagy by increasing LC3-II. In summary, these results suggest that CREBZF might play a proapoptotic role in cell apoptosis in granulosa cells, possibly by regulating the ERK1/2 and mTOR signaling pathways. PMID- 30413093 TI - Harnessing Rhizobia to Improve Heavy-Metal Phytoremediation by Legumes. AB - Rhizobia are bacteria that can form symbiotic associations with plants of the Fabaceae family, during which they reduce atmospheric di-nitrogen to ammonia. The symbiosis between rhizobia and leguminous plants is a fundamental contributor to nitrogen cycling in natural and agricultural ecosystems. Rhizobial microsymbionts are a major reason why legumes can colonize marginal lands and nitrogen-deficient soils. Several leguminous species have been found in metal-contaminated areas, and they often harbor metal-tolerant rhizobia. In recent years, there have been numerous efforts and discoveries related to the genetic determinants of metal resistance by rhizobia, and on the effectiveness of such rhizobia to increase the metal tolerance of host plants. Here, we review the main findings on the metal resistance of rhizobia: the physiological role, evolution, and genetic determinants, and the potential to use native and genetically-manipulated rhizobia as inoculants for legumes in phytoremediation practices. PMID- 30413091 TI - Recent Progress on Photoacoustic Imaging Enhanced with Microelectromechanical Systems (MEMS) Technologies. AB - Photoacoustic imaging (PAI) is a new biomedical imaging technology currently in the spotlight providing a hybrid contrast mechanism and excellent spatial resolution in the biological tissues. It has been extensively studied for preclinical and clinical applications taking advantage of its ability to provide anatomical and functional information of live bodies noninvasively. Recently, microelectromechanical systems (MEMS) technologies, particularly actuators and sensors, have contributed to improving the PAI system performance, further expanding the research fields. This review introduces cutting-edge MEMS technologies for PAI and summarizes the recent advances of scanning mirrors and detectors in MEMS. PMID- 30413095 TI - Effect of Electric Current Pulse on Microstructure and Corrosion Resistance of Hypereutectic High Chromium Cast Iron. AB - The effect of electric current pulse on the microstructure and corrosion resistance of hypereutectic high chromium cast iron was explored. The morphology of carbides in solidification microstructure was observed by an optical microscope and a scanning electron microscope and the composition was determined by an electron probe micro-analyzer. The microhardness of primary carbides and corrosion resistance of samples were also compared. Under the active of electric current pulse, the microstructure of hypereutectic high chromium cast iron was homogenized and its performance improved accordingly. On treatment by electric current, the morphology of primary carbides changed from thick long rods to hexagonal blocks or granular structures. The interlayer spacing of eutectic carbide decreased from ~26.3 MUm to ~17.8 MUm. Size statistics showed that the average diameter of primary carbide decreased from ~220 MUm to ~60 MUm. As a result, microhardness increased from 1412 HV to 1511 HV. No obvious microcrack propagation was found at the microindentation sites. The average length of microcracks decreased from ~20.7 MUm to ~5.7 MUm. Furthermore, corrosion resistance was remarkably enhanced. The average corrosion rate decreased from 2.65 mg/cm2.h to 1.74 mg/cm2.h after pulse current treatment. PMID- 30413094 TI - A Systematic Review and Meta-Analysis Comparing Liver Resection with the Rf-Based Device HabibTM-4X with the Clamp-Crush Technique. AB - Liver cancer is the sixth most common cancer and third most common cause of cancer-related mortality. Presently, indications for liver resections for liver cancers are widening, but the response is varied owing to the multitude of factors including excess intraoperative bleeding, increased blood transfusion requirement, post-hepatectomy liver failure and morbidity. The advent of the radiofrequency energy-based bipolar device HabibTM-4X has made bloodless hepatic resection possible. The radiofrequency-generated coagulative necrosis on normal liver parenchyma provides a firm underpinning for the bloodless liver resection. This meta-analysis was undertaken to analyse the available data on the clinical effectiveness or outcomes of liver resection with HabibTM-4X in comparison to the clamp-crush technique. The RF-assisted device HabibTM-4X is considered a safe and feasible modality for liver resection compared to the clamp-crush technique owing to the multitude of benefits and mounting clinical evidence supporting its role as a superior liver resection device. The most intriguing advantage of the RF device is its ability to induce systemic and local immunomodulatory changes that further expand the boundaries of survival outcomes following liver resection. PMID- 30413097 TI - Complete Chloroplast Genome Sequence of Malus hupehensis: Genome Structure, Comparative Analysis, and Phylogenetic Relationships. AB - Malus hupehensis belongs to the Malus genus (Rosaceae) and is an indigenous wild crabapple of China. This species has received more and more attention, due to its important medicinal, and excellent ornamental and economical, values. In this study, the whole chloroplast (cp) genome of Malus hupehensis, using a Hiseq X Ten sequencing platform, is reported. The M. hupehensis cp genome is 160,065 bp in size, containing a large single copy region (LSC) of 88,166 bp and a small single copy region (SSC) of 19,193 bp, separated by a pair of inverted repeats (IRs) of 26,353 bp. It contains 112 genes, including 78 protein-coding genes (PCGs), 30 transfer RNA genes (tRNAs), and four ribosomal RNA genes (rRNAs). The overall nucleotide composition is 36.6% CG. A total of 96 simple sequence repeats (SSRs) were identified, most of them were found to be mononucleotide repeats composed of A/T. In addition, a total of 49 long repeats were identified, including 24 forward repeats, 21 palindromic repeats, and four reverse repeats. Comparisons of the IR boundaries of nine Malus complete chloroplast genomes presented slight variations at IR/SC boundaries regions. A phylogenetic analysis, based on 26 chloroplast genomes using the maximum likelihood (ML) method, indicates that M. hupehensis clustered closer ties with M. baccata, M. micromalus, and M. prunifolia than with M. tschonoskii. The availability of the complete chloroplast genome using genomics methods is reported here and provides reliable genetic information for future exploration on the taxonomy and phylogenetic evolution of the Malus and related species. PMID- 30413096 TI - Precipitable Water Vapour Retrieval from GPS Precise Point Positioning and NCEP CFSv2 Dataset during Typhoon Events. AB - Radiosonde is extensively used for understanding meteorological parameters in the vertical direction. Four typhoon events, including three landfalls (MERANTI, NEPARTAK, and MEGI) and one non-landfall (MALAKAS), were chosen in analysing the precipitable water vapour (PWV) characteristics in this study. The spatial distribution of the three radiosonde stations in Zhejiang province does not meet the requirement in analysing changes in PWV during typhoon event. Global position system (GPS) observations are an alternative method for deriving the PWV. This enables improvements in the temporal-spatial resolution of PWV computed by the radiosonde measurements. The National Centers for Environmental Prediction (NCEP) re-analysed data were employed for interpolating temperature and atmosphere pressure at the GPS antennas height. The PWV computed from GPS observations and NCEP re-analysed data were then compared with the true PWV. The maximum difference of radiosonde and GPS PWV was not more than 30 mm at Taiz station. The Root-Mean-Square (RMS) of PWV differences between radiosonde and GPS was not more than 5 mm in January, February, March, November, and December. It was slightly greater than 5 mm in April. High RMS in May, June, July, August, September, and October implies that differences in GPS and radiosonde PWVs are evident in these months. Correlation coefficients of GPS and radiosonde PWVs were more than 0.9, indicating that the changes in GPS and radiosonde PWVs are similar. Radiosonde calculated PWVs were used for GPS PWV calibration for understanding the PWV changes during the period of a typhoon event. The results from three landfall typhoons show that the average PWV over Zhejiang province is increasing and approaching China mainland. In contrast, MALAKAS did not make landfall and shows a decreasing PWV trend, although it was heading to China mainland. Generally, the PWV change can be used to predict whether the typhoon will make landfall in these cases. PWV spatial distribution of MERANTI shows that PWV peaks change along the typhoon epicenter over Zhejiang province. PMID- 30413098 TI - A Survey of Health Disparities, Social Determinants of Health, and Converging Morbidities in a County Jail: A Cultural-Ecological Assessment of Health Conditions in Jail Populations. AB - The environmental health status of jail populations in the United States constitutes a significant public health threat for prisoners and the general population. The ecology of jails creates a dynamic condition in relation to general population health due to the concentrated potential exposure to infectious diseases, difficult access to treatment for chronic health conditions, interruption in continuity of care for serious behavioral health conditions, as well as on-going issues for the prevention and treatment of substance abuse disorders. This paper reports on elements of a cross-sectional survey embedded in a parent project, "Health Disparities in Jail Populations." The overall project includes a comprehensive secondary data analysis of the health status of county jail populations, along with primary data collection that includes a cross sectional health and health care services survey of incarcerated individuals, coupled with collection of biological samples to investigate infectious disease characteristics of a county jail population. This paper reports on the primary results of the survey data collection that indicate that this is a population with complex and interacting co-morbidities, as well as significant health disparities compared to the general population. PMID- 30413100 TI - Indium-Zinc-Tin-Oxide Film Prepared by Reactive Magnetron Sputtering for Electrochromic Applications. AB - This paper reports on the fabrication of indium-zinc-tin-oxide (IZTO) transparent conductive film deposited by direct current (DC) reactive magnetron sputtering. The electrical, structural, and optical properties of IZTO film were investigated by Hall measurement, X-ray diffraction (XRD), and optical transmission spectroscopy with various sputtering powers. The IZTO film prepared used power at 100 W showed the lowest resistivity of 5.2 * 10-4 Omega cm. To accomplish rapid switching and high optical modulation, we have fabricated an electrochromic device (ECD) consisting of an working electrode (WO3 electrode film deposited on IZTO/ITO/glass) and a counter-electrode (Pt mesh) in 0.2 M LiClO4/PC liquid solution. The device demonstrated an optical contrast of 44% and switching times of 4.6 s and 8.1 s for the coloring and bleaching state, respectively, at the wavelength of 550 nm. PMID- 30413099 TI - The Role of Reduced Graphene Oxide toward the Self-Assembly of Lignin-Based Biocomposites Fabricated from Ionic Liquids. AB - Lignin's immiscibility with most polymers along with its unknown association behaviors are major factors that contribute to its disposal and processability for the production of materials. To fully utilize lignin, an improved understanding of its interaction with other materials is needed. In this study, we investigate the morphological and physicochemical properties upon the addition of reduced graphene oxide (rGO) as a function of material composition in a tertiary system comprised of lignin, cellulose and xylan. The main motivation for this work is to understand how the lignin molecule associates and behaves in the presence of other natural macromolecules, as well as with the addition of reduced graphene oxide. The fabricated biocomposites with and without rGO were investigated using Attenuated Total Reflectance Fourier Transform Infrared spectroscopy (ATR-FTIR), Scanning Electron Microscope (SEM) techniques, Thermogravimetric Analysis (TGA), and Differential Scanning Calorimetry (DSC). The results demonstrated that the regenerated films' structural, morphological and thermal character changed as a function of lignin-xylan concentration and upon the addition of rGO. We also observed a dramatic change in the glass transition temperature and topography. Final analysis showed that the addition of rGO prevented the macromolecules to self-assemble through a reduction of pi-pi aggregations and changes in the cellulose crystallinity. PMID- 30413101 TI - Introducing a Dynamic Workstation in the Office: Insights in Characteristics of Use and Short-Term Changes of Well-Being in a 12 Week Observational Study. AB - The present field study evaluates the use of dynamic workstations (cycling devices) in a real-life office environment. Specific characteristics of use were recorded and possible relationships with short-term changes in well-being were investigated. For a period of 12 weeks, 36 employees were given free access to eight devices. Frequency, duration and speed of use were self-determined but registered objectively for every event of use. Immediately before and after using a cycling device, employees rated their well-being with a modified version of the EZ-scale from Nitsch to assess changes in the short-term. In total, 817 events of use were registered. On each day of the intervention period one of the devices was used. Participants used the devices between one day to all days present at the office, for 21.09 (SD 0.58) to 31.58 (SD 2.19) minutes on average per event of use per day. Comparing the pre- and post-measurements, a significant increase in well-being after using a cycling device was found. Results of a Generalized Estimating Equations (GEE) analysis showed mixed effects for the duration of use, the speed and variation of speed on the probability of reporting positive changes in recovery, calmness and mood. Therefore, using cycling devices in the office might improve short-term well-being. PMID- 30413102 TI - The Impact of Psychological Distress on Incident Functional Disability in Elderly Japanese: The Ohsaki Cohort 2006 Study. AB - Background: Although psychological distress is known to be a risk factor for death, there are relatively few data on the impact of psychological distress on incident functional disability in older adults. The aim of this study was to examine the impact of psychological distress on incident functional disability in older adults. Methods: We conducted a cohort study of 12,365 disability-free individuals aged >=65 years who live in Ohsaki City, Japan. In 2006, the level of psychological distress was assessed using the K6 (range: 0-24 points). Data on 10 year functional disability were retrieved from the public Long-term Care Insurance database. The multivariate-adjusted hazard ratios (HRs) and population attributable fractions (PAFs) according to the K6 groups (<5, 5-9, 10-12, and >=13 points) were estimated. Results: Among 94,636 person-years, incident functional disability occurred in 4533 persons (36.7%). Significantly higher risk was observed in higher K6 score groups. The multiple-adjusted HRs (95% CIs) of incident functional disability were 1.14 (1.06-1.22) for 5-9 points, 1.28 (1.15 1.43) for 10-12 points, and 1.62 (1.44-1.84) for >=13 points, in comparison with <5 points (p-trend < 0.001). The PAFs in each of the K6 score groups were 3.0% for 5-9 points, 1.7% for 10-12 points, and 2.6% for >=13 points. Conclusions: Even when mild to moderate, psychological distress had a considerable impact on incident functional disability in this cohort. PMID- 30413103 TI - Vitamin D Status and Analysis of Specific Correlates in Preschool Children: A Cross-Sectional Study in Southern Croatia. AB - Vitamin D deficiency is a globally important problem, particularly in children, but there is a lack of information regarding this deficiency in preschool children from southeastern Europe. This study aimed to establish the levels of 25 hydroxyvitamin D (25(OH)D) and associations of gender, time spent outdoors, physical activity (PA), and body mass index (as predictors) with the 25(OH)D level (outcome) in healthy preschool children. The participants were preschoolers (all 5-6 years of age) from southern Croatia. All the participants were tested during their mandatory medical examination 6-7 months prior to school enrollment. The PA was obtained using the preschool-age physical activity questionnaire (Pre PAQ), which categorizes PA into five levels (from sedentary to vigorous PA). The prevalence of 25(OH)D deficiency was high: 58% of the children had 25(OH)D levels of <50 nmol/L (deficiency), and an additional 29% had an insufficient level of 25(OH)D (50-75 nmol/L). Boys had higher levels of 25(OH)D than girls. A multinomial regression using 25(OH)D categories as the outcome and a sufficient level (>75 nmol/L) as the reference value identified gender as the only significant predictor of 25(OH)D status, with boys being at lower risk for 25(OH)D deficiency than girls. These results showed a high prevalence of 25(OH)D deficiency in preschoolers from the southern part of Croatia, which is additionally alarming based on the geographical position of the studied region (42 degrees N) and its high number of sunshine hours (>2600 h per year). Future studies examining other potential correlates of 25(OH)D in the region are warranted. PMID- 30413104 TI - Streaming MASSIF: Cascading Reasoning for Efficient Processing of IoT Data Streams. AB - In the Internet of Things (IoT), multiple sensors and devices are generating heterogeneous streams of data. To perform meaningful analysis over multiple of these streams, stream processing needs to support expressive reasoning capabilities to infer implicit facts and temporal reasoning to capture temporal dependencies. However, current approaches cannot perform the required reasoning expressivity while detecting time dependencies over high frequency data streams. There is still a mismatch between the complexity of processing and the rate data is produced in volatile domains. Therefore, we introduce Streaming MASSIF, a Cascading Reasoning approach performing expressive reasoning and complex event processing over high velocity streams. Cascading Reasoning is a vision that solves the problem of expressive reasoning over high frequency streams by introducing a hierarchical approach consisting of multiple layers. Each layer minimizes the processed data and increases the complexity of the data processing. Cascading Reasoning is a vision that has not been fully realized. Streaming MASSIF is a layered approach allowing IoT service to subscribe to high-level and temporal dependent concepts in volatile data streams. We show that Streaming MASSIF is able to handle high velocity streams up to hundreds of events per second, in combination with expressive reasoning and complex event processing. Streaming MASSIF realizes the Cascading Reasoning vision and is able to combine high expressive reasoning with high throughput of processing. Furthermore, we formalize semantically how the different layers in our Cascading Reasoning Approach collaborate. PMID- 30413106 TI - An Evaluation of Boar Spermatozoa as a Biosensor for the Detection of Sublethal and Lethal Toxicity. AB - A novel, objective, and rapid computed motility inhibition (CMI) assay was developed to identify and assess sublethal injury in toxin-exposed boar spermatozoa and compared with a subjective visual motility inhibition (VMI) assay. The CMI values were calculated from digital micrographic videos using a custom MATLAB(r) script by contrasting the motility index values of each experiment with those of the background and control experiments. Following a comparison of the CMI and VMI assays results, it was determined that their agreement depended on the shape of the dose-response curve. Toxins that exhibited a steep slope were indicative of good agreement between the assays. Those depicted by a gentle decline in the slope of the dose-response curve, the CMI assay were shown to be two times more sensitive than the VMI assay. The CMI assay was highly sensitive to the inhibition of mitochondrial function and glucose transport activity by sublethal doses of toxins and to disruption of cellular cation homeostasis by carrier ionophoric toxins, when compared to the cytotoxicity and lethal toxicity assays (i.e., that evaluated the inhibition of cell proliferation in somatic cell lines (FL, PK-15, and MNA cells)) and disruption to spermatozoa membrane integrity. The CMI assay recognized subtle sublethal toxicity changes in metabolism, manifested as a decrease in boar spermatozoa motility. Thus, it was feasible to effectively compare the objectively-measured numerical values for motility inhibition using the CMI assay against those reflecting lethal damage in the spermatozoa cells and somatic cell lines using a cytotoxicity assay. PMID- 30413105 TI - Combination of Plasma Biomarkers and Clinical Data for the Detection of Myocardial Fibrosis or Aggravation of Heart Failure Symptoms in Heart Failure with Preserved Ejection Fraction Patients. AB - Background: Heart failure with preserved ejection fraction (HFpEF) is characterized by heart failure symptoms and structural change (including fibrosis). The relationship between novel biomarkers and the above components remains unclear. Methods: Seventy-seven HFpEF patients were recruited. All patients underwent echocardiography with tissue doppler imaging, cardiac magnetic resonance imaging (CMRI), and measurement of plasma inflammatory, remodelling, endothelial function, and heart failure biomarker levels. Myocardial fibrosis was defined by CMRI-extracellular volume. Forward conditional logistic regression was applied to demonstrate the determinants of myocardial fibrosis or heart failure symptoms. Results: The levels of growth differentiation factor, tissue inhibitor of metalloproteinase (TIMP)-1, galectin-3, and N-terminal pro b-type natriuretic peptide (NT-proBNP) were significantly higher in patients with more myocardial fibrosis. Matrix metalloproteinase-2 (MMP-2) and galectin-3 were independent markers of ECV. After adjusting for confounding factors, plasma galectin-3 and MMP-2 levels were correlated with myocardial fibrosis levels (odds ratio (OR): 1.05, 95% confidence interval (CI): 1.02 to 1.09, p = 0.005 and OR: 2.11, 95% CI: 1.35-3.28, respectively), while NT-proBNP level only was associated with heart failure symptoms. We developed a score system consisted of biomarkers and clinical parameters. The area under the curve of the scoring system receiver operating characteristic curve is 0.838 to predict the degree of myocardial diffuse fibrosis. Conclusions: In conclusion, we found that galectin-3 and MMP-2 were significantly associated with global cardiac fibrosis in HFpEF patients. We also combined plasma biomarkers and clinical data to identify HFpEF patients with more severe cardiac fibrosis. PMID- 30413107 TI - Prediction of Acute Kidney Injury after Liver Transplantation: Machine Learning Approaches vs. Logistic Regression Model. AB - Acute kidney injury (AKI) after liver transplantation has been reported to be associated with increased mortality. Recently, machine learning approaches were reported to have better predictive ability than the classic statistical analysis. We compared the performance of machine learning approaches with that of logistic regression analysis to predict AKI after liver transplantation. We reviewed 1211 patients and preoperative and intraoperative anesthesia and surgery-related variables were obtained. The primary outcome was postoperative AKI defined by acute kidney injury network criteria. The following machine learning techniques were used: decision tree, random forest, gradient boosting machine, support vector machine, naive Bayes, multilayer perceptron, and deep belief networks. These techniques were compared with logistic regression analysis regarding the area under the receiver-operating characteristic curve (AUROC). AKI developed in 365 patients (30.1%). The performance in terms of AUROC was best in gradient boosting machine among all analyses to predict AKI of all stages (0.90, 95% confidence interval [CI] 0.86-0.93) or stage 2 or 3 AKI. The AUROC of logistic regression analysis was 0.61 (95% CI 0.56-0.66). Decision tree and random forest techniques showed moderate performance (AUROC 0.86 and 0.85, respectively). The AUROC of support the vector machine, naive Bayes, neural network, and deep belief network was smaller than that of the other models. In our comparison of seven machine learning approaches with logistic regression analysis, the gradient boosting machine showed the best performance with the highest AUROC. An internet based risk estimator was developed based on our model of gradient boosting. However, prospective studies are required to validate our results. PMID- 30413108 TI - Bone Regeneration by Novel Bioactive Glasses Containing Strontium and/or Magnesium: A Preliminary In-Vivo Study. AB - In this work, a set of novel bioactive glasses have been tested in vivo in an animal model. The new compositions, characterized by an exceptional thermal stability and high in vitro bioactivity, contain strontium and/or magnesium, whose biological benefits are well documented in the literature. To simulate a long-term implant and to study the effect of the complete dissolution of glasses, samples were implanted in the mid-shaft of rabbits' femur and analyzed 60 days after the surgery; such samples were in undersized powder form. The statistical significance with respect to the type of bioactive glass was analyzed by Kruskal Wallis test. The results show high levels of bone remodeling, several new bone formations containing granules of calcium phosphate (sometimes with amounts of strontium and/or magnesium), and the absence of adverse effects on bone processes due to the almost complete glass dissolution. In vivo results confirming the cell culture outcomes of a previous study highlighted that these novel bioglasses had osteostimulative effect without adverse skeletal reaction, thus indicating possible beneficial effects on bone formation processes. The presence of strontium in the glasses seems to be particularly interesting. PMID- 30413109 TI - A Mass Conservative Kalman Filter Algorithm for Computational Thermo-Fluid Dynamics. AB - This paper studies Kalman filtering applied to Reynolds-Averaged Navier-Stokes (RANS) equations for turbulent flow. The integration of the Kalman estimator is extended to an implicit segregated method and to the thermodynamic analysis of turbulent flow, adding a sub-stepping procedure that ensures mass conservation at each time step and the compatibility among the unknowns involved. The accuracy of the algorithm is verified with respect to the heated lid-driven cavity benchmark, incorporating also temperature observations, comparing the augmented prediction of the Kalman filter with the Computational Fluid-Dynamic solution found on a fine grid. PMID- 30413110 TI - The Salt-Stress Response of the Transgenic Plum Line J8-1 and Its Interaction with the Salicylic Acid Biosynthetic Pathway from Mandelonitrile. AB - Salinity is considered as one of the most important abiotic challenges that affect crop productivity. Plant hormones, including salicylic acid (SA), are key factors in the defence signalling output triggered during plant responses against environmental stresses. We have previously reported in peach a new SA biosynthetic pathway from mandelonitrile (MD), the molecule at the hub of the cyanogenic glucoside turnover in Prunus sp. In this work, we have studied whether this new SA biosynthetic pathway is also present in plum and the possible role this pathway plays in plant plasticity under salinity, focusing on the transgenic plum line J8-1, which displays stress tolerance via an enhanced antioxidant capacity. The SA biosynthesis from MD in non-transgenic and J8-1 micropropagated plum shoots was studied by metabolomics. Then the response of J8-1 to salt stress in presence of MD or Phe (MD precursor) was assayed by measuring: chlorophyll content and fluorescence parameters, stress related hormones, levels of non enzymatic antioxidants, the expression of two genes coding redox-related proteins, and the content of soluble nutrients. The results from in vitro assays suggest that the SA synthesis from the MD pathway demonstrated in peach is not clearly present in plum, at least under the tested conditions. Nevertheless, in J8-1 NaCl-stressed seedlings, an increase in SA was recorded as a result of the MD treatment, suggesting that MD could be involved in the SA biosynthesis under NaCl stress conditions in plum plants. We have also shown that the plum line J8-1 was tolerant to NaCl under greenhouse conditions, and this response was quite similar in MD-treated plants. Nevertheless, the MD treatment produced an increase in SA, jasmonic acid (JA) and reduced ascorbate (ASC) contents, as well as in the coefficient of non-photochemical quenching (qN) and the gene expression of Non Expressor of Pathogenesis-Related 1 (NPR1) and thioredoxin H (TrxH) under salinity conditions. This response suggested a crosstalk between different signalling pathways (NPR1/Trx and SA/JA) leading to salinity tolerance in the transgenic plum line J8-1. PMID- 30413111 TI - Ginkgolic Acid Rescues Lens Epithelial Cells from Injury Caused by Redox Regulated-Aberrant Sumoylation Signaling by Reviving Prdx6 and Sp1 Expression and Activities. AB - Sumoylation is a downstream effector of aging/oxidative stress; excess oxidative stress leads to dysregulation of a specificity protein1 (Sp1) and its target genes, such as Peroxiredoxin 6 (Prdx6), resulting in cellular damage. To cope with oxidative stress, cells rely on a signaling pathway involving redox sensitive genes. Herein, we examined the therapeutic efficacy of the small molecule Ginkgolic acid (GA), a Sumoylation antagonist, to disrupt aberrant Sumoylation signaling in human and mouse lens epithelial cells (LECs) facing oxidative stress or aberrantly expressing Sumo1 (small ubiquitin-like modifier). We found that GA globally reduced aberrant Sumoylation of proteins. In contrast, Betulinic acid (BA), a Sumoylation agonist, augmented the process. GA increased Sp1 and Prdx6 expression by disrupting the Sumoylation signaling, while BA repressed the expression of both molecules. In vitro DNA binding, transactivation, Sumoylation and expression assays revealed that GA enhanced Sp1 binding to GC-boxes in the Prdx6 promoter and upregulated its transcription. Cell viability and intracellular redox status assays showed that LECs pretreated with GA gained resistance against oxidative stress-driven aberrant Sumoylation signaling. Overall, our study revealed an unprecedented role for GA in LECs and provided new mechanistic insights into the use of GA in rescuing LECs from aging/oxidative stress-evoked dysregulation of Sp1/Prdx6 protective molecules. PMID- 30413112 TI - Evaluation of Thermal-Mechanical Properties of Bio-Oil Regenerated Aged Asphalt. AB - Different proportions of bio-oil (5, 10, 15, and 20 wt%) were added into aged asphalt for its regeneration. Molecular dynamic simulations were used to measure the thermal and mechanical performances of bio-oil regenerated aged asphalt (BRAA). A new, simplified BRAA model was built to calculate the specific heat capacity, thermal expansion coefficient, elastic constant, shear modulus, bulk modulus, and Young's modulus. Simulation results showed that the thermal expansion coefficient (CTE alpha) of asphalt at 298 K decreased by 10% after aging. Bio-oil of 5 wt% could make the CTE alpha restore to the original level of base asphalt, while the addition of bio-oil would further decrease the specific heat capacity of aged asphalt. The shear modulus (G), Young's modulus (K) and bulk modulus (E) of asphalt increased after aging and decreased with the increasing amount of bio-oil. According to the calculated E/G value, the ductility of aged asphalt increased by 6.0% with the addition of 10 wt% bio-oil, while over 15 wt% bio-oil would make the ductility of BRAA decrease. In summary, the regeneration effects of bio-oil to the thermal expansion coefficient, flexibility, and ductility of aged asphalt had been proven, while excessive bio oil would decrease the thermal stability of asphalt. PMID- 30413113 TI - A Novel Venom-Derived Peptide for Brachytherapy of Glioblastoma: Preclinical Studies in Mice. AB - We developed a bacterial expression system to produce a recombinant disintegrin, vicrostatin (VCN), whose structure is based on a natural disintegrin isolated from southern copperhead snake venom. Our goal is to develop VCN for potential clinical translation as an anti-cancer agent. VCN is a peptide of 69 amino acids with a single tyrosine residue. We have employed VCN as integrin-targeted radionuclide therapy (brachytherapy) for treatment of glioblastoma (GBM, glioma). GBM is a deadly brain cancer that doesn't discriminate between sexes and knows no age limit. We established that the tyrosine residue in VCN can be radioiodinated with full retention of bioactivity. 131I-VCN was utilized for integrin-targeted radionuclide therapy using mouse models of glioma. The combination of radioiodinated VCN plus temozolomide (a DNA alkylating agent) significantly prolonged survival of glioma-bearing mice. We also obtained similar results using an immunocompetent mouse model and a murine glioma cell line. In summary, as demonstrated in studies reported here we have shown that VCN as targeted radionuclide therapy for GBM has significant translational potential for therapy of this deadly disease. PMID- 30413114 TI - Enhanced Wear Behaviour of Spark Plasma Sintered AlCoCrFeNiTi High-Entropy Alloy Composites. AB - High hardness and good wear resistance have been revealed for the high-entropy alloy (HEA) system AlCoCrFeNiTi, confirming the potential for surface protection applications. Detailed studies to investigate the microstructure and phase formation have been carried out using different production routes. Powder metallurgical technologies allow for much higher flexibility in the customisation of materials compared to casting processes. Particularly, spark plasma sintering (SPS) enables the fast processing of the feedstock, the suppression of grain coarsening and the production of samples with a low porosity. Furthermore, solid lubricants can be incorporated for the improvement of wear resistance and the reduction of the coefficient of friction (COF). This study focuses on the production of AlCoCrFeNiTi composites comprising solid lubricants. Bulk materials with a MoS2 content of up to 15 wt % were produced. The wear resistance and COF were investigated in detail under sliding wear conditions in ball-on-disk tests at room temperature and elevated temperature. At least 10 wt % of MoS2 was required to improve the wear behaviour in both test conditions. Furthermore, the effects of the production route and the content of solid lubricant on microstructure formation and phase composition were investigated. Two major body centred cubic (bcc) phases were detected in accordance with the feedstock. The formation of additional phases indicated the decomposition of MoS2. PMID- 30413115 TI - An Ultra-Rapid Biosensory Point-of-Care (POC) Assay for Prostate-Specific Antigen (PSA) Detection in Human Serum. AB - Prostate-specific antigen (PSA) is the established routine screening tool for the detection of early-stage prostate cancer. Given the laboratory-centric nature of the process, the development of a portable, ultra rapid high-throughput system for PSA screening is highly desirable. In this study, an advancedpoint-of-care system for PSA detection in human serum was developed based on a cellular biosensor where the cell membrane was modified by electroinserting a specific antibody against PSA. Thirty nine human serum samples were used for validation of this biosensory system for PSA detection. Samples were analyzed in parallel with a standard immunoradiometric assay (IRMA) and an established electrochemical immunoassay was used for comparison purposes. They were classified in three different PSA concentration ranges (0, <4 and >=4 ng/mL). Cells membrane engineered with 0.25 MUg/mL anti-PSA antibody demonstrated a statistically lower response against the upper (>=4 ng/mL) PSA concentration range. In addition, the cell-based biosensor performed better than the immunosensor in terms of sensitivity and resolution against positive samples containing <4 ng/mL PSA. In spite of its preliminary, proof-of-concept stage of development, the cell-based biosensor could be used as aninitiative for the development of a fast, low-cost, and high-throughput POC screening system for PSA. PMID- 30413116 TI - Highly Sensitive Charge Sensor Based on Atom-Assisted High-Order Sideband Generation in a Hybrid Optomechanical System. AB - Realizing highly sensitive charge sensors is of fundamental importance in physics, and may find applications in metrology, electronic tunnel imaging, and engineering technology. With the development of nanophotonics, cavity optomechanics with Coulomb interaction provides a powerful platform to explore new options for the precision measurement of charges. In this work, a method of realizing a highly sensitive charge sensor based on atom-assisted high-order sideband generation in a hybrid optomechanical system is proposed. The advantage of this scheme is that the sideband cutoff order and the charge number satisfy a monotonically increasing relationship, which is more sensitive than the atom-free case discussed previously. Calculations show that the sensitivity of the charge sensor in our scheme is improved by about 25 times. In particular, our proposed charge sensor can operate in low power conditions and extremely weak charge measurement environments. Furthermore, phase-dependent effects between the sideband generation and Coulomb interaction are also discussed in detail. Beyond their fundamental scientific significance, our work is an important step toward measuring individual charge. PMID- 30413117 TI - Rosmarinic Acid Derivatives' Inhibition of Glycogen Synthase Kinase-3beta Is the Pharmacological Basis of Kangen-Karyu in Alzheimer's Disease. AB - Inhibition of glycogen synthase kinase 3beta (GSK-3beta) is considered to be the central therapeutic approach against Alzheimer's disease (AD). In the present study, boiled water extracts of the Kangen-karyu (KK) herbal mixture and its constituents were screened for GSK-3beta inhibitory activity. KK is used in traditional Kampo and Chinese medicines for improving cognitive function. The GSK 3beta inhibition potential was evaluated by using the Kinase-Glo luminescent kinase assay platform. Furthermore, enzyme kinetics and in silico modeling were performed by using AutoDockTools to demonstrate the mechanism of enzyme inhibition. KK extract significantly inhibited GSK-3beta in a concentration dependent manner (IC50: 17.05 +/- 1.14 MUg/mL) when compared with the reference drug luteolin (IC50: 2.18 +/- 0.13 MUM). Among the six components of KK, extracts of Cyperi Rhizoma and Salviae Miltiorrhizae Radix significantly inhibited GSK 3beta with IC50 values of 20.68 +/- 2.50 and 7.77 +/- 1.38 MUg/mL, respectively. Among the constituents of the roots of S. miltiorrhiza water extract, rosmarinic acid, magnesium lithospermate B, salvianolic acid A, salvianolic acid B, and salvianolic acid C inhibited GSK-3beta with IC50 values ranging from 6.97 to 135.5 MUM. Salvianolic acid B was found to be an ATP-competitive inhibitor of GSK 3beta and showed the lowest IC50 value (6.97 +/- 0.96 uM). In silico modeling suggested a mechanism of action by which the hydrophobic, pi-cation, and hydrophilic interactions of salvianolic acid B at ATP and substrate sites are critical for the observed GSK-3beta inhibition. Therefore, one of the mechanisms of action of KK against AD may be the inhibition of GSK-3beta and one of the active components of KK is the root of S. miltiorrhiza and its constituents: rosmarinic acid, magnesium lithospermate B, and salvianolic acids A, B, and C. Our results demonstrate the pharmacological basis for the use of KK against AD. PMID- 30413118 TI - Mitigation Effects of a Novel Herbal Medicine, Hepad, on Neuroinflammation, Neuroapoptosis, and Neuro-Oxidation. AB - Parkinson's disease (PD), a common adult-onset neurodegenerative disorder with complex pathological mechanisms, is characterized by the degeneration of dopaminergic nigrostriatal neurons. The present study demonstrated that the herbal medicines Hepad 1 and 2 protected against 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity in C57BL/6 mice and SH-SY5Y cells. Hepad 1 and 2 remarkably alleviated the enhanced expression of pro inflammatory cytokines (tumor necrosis factor-alpha, interleukin-6, inducible nitric oxide synthase, cyclooxygenase-2, macrophage-1, and phosphorylated ikappaB alpha) and apoptotic signals (Bcl-2-associated X protein, caspase-3, and poly [ADP-ribose] polymerase-1). Additionally, Hepad reduced MPTP-induced oxidative damage by increasing the expression of anti-oxidant defense enzymes (superoxide dismutase and glutathione S-transferase) and downregulating the levels of nicotinamide adenine dinucleotide phosphate oxidase 4. This study also showed that the neuroprotective effects of Hepad include anti-inflammatory, anti apoptotic, and anti-oxidative properties, in addition to activation of the protein kinase B, extracellular-signal-regulated kinase, and c-Jun N-terminal kinase signaling pathways. Furthermore, oral administration of Hepad 1 and 2 attenuated the death of tyrosine hydroxylase-positive substantia nigra neurons that was induced by 20 mg/kg MPTP. Therefore, our results suggest that Hepad 1 and 2 are useful for treating PD and other disorders associated with neuro inflammatory, neuro-apoptotic, and neuro-oxidative damage. PMID- 30413119 TI - The Effect of Ni Addition onto a Cu-Based Ternary Support on the H2 Production over Glycerol Steam Reforming Reaction. AB - In the present study, Ni/Ce-Sm-xCu (x = 5, 7, 10 at.%) catalysts were prepared using microwave radiation coupled with sol-gel and followed by wetness impregnation method for the Ni incorporation. Highly dispersed nanocrystallites of CuO and NiO on the Ce-Sm-Cu support were found. Increase of Cu content seems to facilitate the reducibility of the catalyst according to the H2 temperature programmed reduction (H2-TPR). All the catalysts had a variety of weak, medium and strong acid/basic sites that regulate the reaction products. All the catalysts had very high XC3H8O3 for the entire temperature (400-750 degrees C) range; from ~84% at 400 degrees C to ~94% at 750 degrees C. Ni/Ce-Sm-10Cu catalyst showed the lowest XC3H8O3-gas implying the Cu content has a detrimental effect on performance, especially between 450-650 degrees C. In terms of H2 selectivity (SH2) and H2 yield (YH2), both appeared to vary in the following order: Ni/Ce-Sm-10Cu > Ni/Ce-Sm-7Cu > Ni/Ce-Sm-5Cu, demonstrating the high impact of Cu content. Following stability tests, all the catalysts accumulated high amounts of carbon, following the order Ni/Ce-Sm-5Cu < Ni/Ce-Sm-7Cu < Ni/Ce-Sm 10Cu (52, 65 and 79 wt.%, respectively) based on the thermogravimetric analysis (TGA) studies. Raman studies showed that the incorporation of Cu in the support matrix controls the extent of carbon graphitization deposited during the reaction at hand. PMID- 30413120 TI - The MAPKKK CgMck1 Is Required for Cell Wall Integrity, Appressorium Development, and Pathogenicity in Colletotrichum gloeosporioides. AB - Mitogen-activated protein kinase (MAPK) signaling pathway plays key roles in sensing extracellular signals and transmitting them from the cell membrane to the nucleus in response to various environmental stimuli. A MAPKKK protein CgMck1 in Colletotrichum gloeosporioides was characterized. Phenotypic analyses of the ?Cgmck1 mutant showed that the CgMck1 was required for vegetative growth, fruiting body development, and sporulation. Additionally, the CgMCK1 deletion mutant showed significant defects in cell wall integrity, and responses to osmotic stresses. The mutant abolished the ability to develop appressorium, and lost pathogenicity to host plants. The ?Cgmck1 mutant also exhibited a higher sensitivity to antifungal bacterium agent Bacillus velezensis. The deletion mutants of downstream MAPK cascades components CgMkk1 and CgMps1 showed similar defects to the ?Cgmck1 mutant. In conclusion, CgMck1 is involved in the regulation of vegetative growth, asexual development, cell wall integrity, stresses resistance, and infection morphogenesis in C. gloeosporioides. PMID- 30413122 TI - Bistatic Forward-Looking SAR Moving Target Detection Method Based on Joint Clutter Cancellation in Echo-Image Domain with Three Receiving Channels. AB - In bistatic forward-looking synthetic aperture radar (BFSAR) ground moving target detection (GMTD), the suppression of the strong and heterogeneous ground clutter is one of the most crucial and challenging issues. Due to the bistatic forward looking mode and long observation time, Doppler ambiguity, range and Doppler cells migration and non-stationary characteristics will exist in clutter receives, which leads to severe performance degradation of the traditional method. Hence, this paper proposes a GMTD method based on joint clutter cancellation in echo-image domain for BFSAR to achieve effective GMTD in heterogeneous BFSAR clutter. First, the pre-filtering and keystone transform are applied to suppress Doppler ambiguity and correct range cell migration, respectively. Then, time-division space-time adaptive clutter cancellation is adopted to suppress clutter at the first time in the echo domain, which can eliminate the effect of the migration of Doppler cells. However, its performance will be severely degraded due to the strong non-stationary characteristic of BFSAR clutter. Finally, adaptive displaced phase center antenna is exploited to suppress the residual non-stationary BFSAR clutter in image domain. Experimental results have shown that the strong non-stationary clutter of BFSAR has been sufficiently suppressed by the proposed method and the SCNR provided is enough to detect a moving target well. PMID- 30413121 TI - Study on Water Suitability of Apple Plantations in the Loess Plateau under Climate Change. AB - With the implementation of the Grain for Green Project, the apple plantation area is increasing in Loess Plateau. However, due to severe water scarcity, the sustainability of apple tree growth is threatened. In this paper, we used meteorological data (1990-2013) and forecasted climate data (2019-2050) to estimate water demand and establish a water suitability model to study the water balance between available water and water consumption of the apple trees. The results show that: (i) the order of the average water demand of apple plantation in each subarea is Shaanxi Province > Yuncheng area > Gansu Province > Sanmenxia Region, ranging from 500 to 950 mm; (ii) the temporal variability of water suitability from 1990 to 2013 is large, and the higher values are concentrated in the late growth stage of the apple trees and the lower values are concentrated in the early growth stage; (iii) the temporal and spatial distribution of water suitability is relatively stable and even in the Loess Plateau in the period of 2019-2050; (iv) the water suitability is mainly affected by effective precipitation and reference evapotranspiration and the reference evapotranspiration is mainly affected by the solar radiation (36%) and average temperature (38%). Furthermore, due to the joint influence of precipitation increases and solar radiation (average temperature) increases, the future water suitability of the apple plantation area in the Loess Plateau is showing a non significant downward trend under RCP4.5 scenario. PMID- 30413123 TI - Robust Powerline Equipment Inspection System Based on a Convolutional Neural Network. AB - Electric power line equipment such as insulators, cut-out-switches, and lightning arresters play important roles in ensuring a safe and uninterrupted power supply. Unfortunately, their continuous exposure to rugged environmental conditions may cause physical or electrical defects in them which may lead to the failure to the electrical system. In this paper, we present an automatic real-time electrical equipment detection and defect analysis system. Unlike previous handcrafted feature-based approaches, the proposed system utilizes a Convolutional Neural Network (CNN)-based equipment detection framework, making it possible to detect 17 different types of powerline insulators in a highly cluttered environment. We also propose a novel rotation normalization and ellipse detection method that play vital roles in the defect analysis process. Finally, we present a novel defect analyzer that is capable of detecting gunshot defects occurring in electrical equipment. The proposed system uses two cameras; a low-resolution camera that detects insulators from long-shot images, and a high-resolution camera which captures close-shot images of the equipment at high-resolution that helps for effective defect analysis. We demonstrate the performances of the proposed real-time equipment detection with up to 93% recall with 92% precision, and defect analysis system with up to 98% accuracy, on a large evaluation dataset. Experimental results show that the proposed system achieves state-of-the art performance in automatic powerline equipment inspection. PMID- 30413124 TI - An Enhanced Map-Matching Algorithm for Real-Time Position Accuracy Improvement with a Low-Cost GPS Receiver. AB - This paper proposes a real-time position accuracy improvement method for a low cost global positioning system (GPS), which uses geographic data for forming a digital road database in the digital map information. We link the vehicle's location to the position on the digital map using the map-matching algorithm to improve the position accuracy. In the proposed method, we can distinguish the vehicle direction on the road and enhance the horizontal accuracy using the geographic data composed of the vector point set of the digital map. We use the iterative closest point (ICP) algorithm that calculates the rotation matrix and the translation vector to compensate for the disparity between the GPS and the digital map information. We also use the least squares method to correct the error caused by the rotation of the ICP algorithm and link on the digital map to eliminate the residual disparity. Finally, we implement the proposed method in real time with a low-cost embedded system and demonstrate the effectiveness of the proposed method through various experiments. PMID- 30413125 TI - Nanoscale Morphology, Interfacial Hydrogen Bonding, Confined Crystallization and Greatly Improved Toughness of Polyamide 12/Polyketone Blends. AB - Nanostructured polyamide 12(PA12)/polyketone (PK) blends were fabricated by melt compounding. The nanoscale droplet and domain-in-domain morphologies depending on PK content were observed. When the content of PK was 10 vol%, the impact strength of the blend jumps from 6.8 to 111.9 kJ/m2 and further improved with an increasing content of PK. The toughening mechanism was found to be closely related with the morphology change from nanoscale droplet morphology to domain-in domain morphology owing to the strong interfacial hydrogen bonding. The nanoscale morphology confinement and interfacial hydrogen bonding enhances the crystallization kinetics while lowers down the thermodynamic stability of the crystals. The toughening mechanisms were discussed based on these factors. PMID- 30413126 TI - Ultrastructural and Molecular Analysis of Ribose-Induced Glycated Reconstructed Human Skin. AB - Aging depicts one of the major challenges in pharmacology owing to its complexity and heterogeneity. Thereby, advanced glycated end-products modify extracellular matrix proteins, but the consequences on the skin barrier function remain heavily understudied. Herein, we utilized transmission electron microscopy for the ultrastructural analysis of ribose-induced glycated reconstructed human skin (RHS). Molecular and functional insights substantiated the ultrastructural characterization and proved the relevance of glycated RHS beyond skin aging. In particular, electron microscopy mapped the accumulation and altered spatial orientation of fibrils and filaments in the dermal compartment of glycated RHS. Moreover, the epidermal basement membrane appeared thicker in glycated than in non-glycated RHS, but electron microscopy identified longitudinal clusters of the finest collagen fibrils instead of real thickening. The stratum granulosum contained more cell layers, the morphology of keratohyalin granules decidedly differed, and the stratum corneum lipid order increased in ribose-induced glycated RHS, while the skin barrier function was almost not affected. In conclusion, dermal advanced glycated end-products markedly changed the epidermal morphology, underlining the importance of matrix-cell interactions. The phenotype of ribose-induced glycated RHS emulated aged skin in the dermis, while the two to three times increased thickness of the stratum granulosum resembled poorer cornification. PMID- 30413127 TI - Celiac Male's Gluten-Free Diet Profile: Comparison to that of the Control Population and Celiac Women. AB - The aim of the present work was to analyze the body composition and dietary profile of Spanish celiac men and to compare them to control men and celiac women from our previous studies. Forty-two celiac men (31.5 +/- 11.9 years) were recruited and anthropometric measurements were taken. Analysis of energy consumption, macro- and micronutrient intake and food frequency consumption was carried out. Celiac men were more overweight and obese than celiac women, but less than the control population, reporting the same energy intake and macronutrient distribution. Most micronutrient deficiencies in celiac men were not directly related to a gluten free diet; these were also observed for the entire population. The least adherence to Dietary Reference Intakes in women was reported for iron, iodine, potassium and selenium, whereas magnesium intake was higher than in men. Among celiac participants (both genders), cereal, vegetable and legume consumption was poor and meat intake was contrastingly excessive. In conclusion, the dietary profile of celiac men is as unbalanced as that of control men but slightly more than that of celiac women. General nutritional education should be given to both general and celiac populations, and specific advices to celiac men, in order to decrease the risk of celiac disease-related pathologies. PMID- 30413128 TI - Synthesis and Transformation of (-)-Isopulegol-Based Chiral beta-Aminolactones and beta-Aminoamides. AB - A library of isopulegol-based beta-amino acid derivatives has been developed from commercially-available (-)-isopulegol. Michael addition of primary and secondary amines towards alpha,beta-unsaturated gamma-lactones was accomplished resulting in beta-aminolactones in highly-stereoselective reactions. Ring-opening of beta aminolactones with different amines furnished excellent yields of beta aminoamides. Moreover, the applicability of aminolactones in peptide synthesis was examined by opening the lactone ring with alpha- and beta-aminoesters, providing dipeptides as promising chiral substrates for the synthesis of foldamers. The antiproliferative activities of beta-aminolactones and beta aminoamides were explored, and the structure-activity relationships were studied from the aspects of the stereochemistry of the monoterpene ring and the substituent effects on the beta-aminoamide ring system. The N-unsubstituted (-) isopulegol-based beta-aminoamides exhibited considerable antiproliferative activity against a panel of human adherent cancer cell lines (HeLa, MCF7 and MDA MB-231). PMID- 30413129 TI - Improving Health Promotion Through the Integration of Technology, Crowdsourcing, and Social Media. AB - As Internet accessibility and technological innovations continue to increase communication, new opportunities have emerged to leverage these tools to improve health promotion practice. Advances and utilization of collaborative Internet communication, or social media, have provided global connectivity on an unprecedented scale. Using these innovations to leverage the collective intellect of online communities for specific goals, crowdsourcing is an approach that has the potential to solve complex public health problems. Due to the novelty of crowdsourcing implementations and the relative infancy of its application within public health, it is necessary to examine examples to facilitate practitioner conceptualization and application. This article details the development and application of a crowdsourced effort leveraging social media and technology to assist in relief efforts during Hurricane Harvey. Furthermore, the article presents examples corresponding to a typology of crowdsourcing for public health, including Knowledge Discovery and Management, Distributed Human Intelligence Tasking, Broadcast Search, and Peer-Vetted Creative Production problems. Leveraging these innovative applications has positive implications for health promotion practice, including improved intervention development and evaluation, increased multidisciplinary collaboration, and enhanced facilitation of communication, information exchange, and support. PMID- 30413130 TI - An updated view on the origin and use of angiogenic biomarkers for preeclampsia. AB - INTRODUCTION: The last decade has seen massive efforts towards the identification and the potential use of predictive biomarkers for the pregnancy pathology preeclampsia. The angiogenic factors sFlt-1 and placental growth factor (PGF) have been in focus and have been massively supported. Areas covered: This review describes preeclampsia and intra-uterine growth restriction (IUGR), focusing on sFlt-1 and PGF, their sources during and outside pregnancy and the application of these markers in diseases outside pregnancy. Finally, the specificity of the angiogenic markers for preeclampsia is discussed. Expert commentary: The admixture of the two independent syndromes preeclampsia and IUGR has not helped in identifying the etiologies of either. Rather, it has made the search for new markers and pathways much more complicated as has the constriction on the angiogenic markers. The current markers sFlt-1 and PGF have a clear value once an adverse outcome is diagnosed but are not specific for preeclampsia. Also, they are mostly derived from the maternal vascular system rather than the placenta and are already in use as markers outside pregnancy. A new holistic approach using disease maps and interoperable workflows based on topic-related big data will help in broadening our understanding of the etiology of preeclampsia and hence, develop new markers and therapies. PMID- 30413131 TI - Intermediate-term Experience With the STAR Total Ankle in the United States. AB - BACKGROUND:: Limited intermediate and no real long-term follow-up data have been published for total ankle arthroplasty (TAA) in the United States. This is a report of clinical follow-up data of a prospective, consecutive cohort of patients who underwent TAA by a single surgeon from 1999 to 2013 with the Scandinavian Total Ankle Replacement (STAR) prosthesis. METHODS:: Patients undergoing TAA at a single US institution were enrolled into a prospective study. These patients were followed at regular intervals with history, physical examination, and radiographs; American Academy of Orthopaedic Foot and Ankle Surgeons (AOFAS) Ankle-Hindfoot Scale scores were obtained and recorded. Primary outcomes included implant survivability and functional outcomes scores. Secondary outcomes included perioperative complications such as periprosthetic or polyethylene fracture. Between 1999 and 2013, a total of 138 STAR TAAs were performed in 131 patients; 81 patients were female. The mean age at surgery was 61.5 +/- 12.3 years (range, 30-88 years). The mean duration of follow-up for living patients who retained both initial components at final follow-up was 8.8+/ 4.3 years (range 2-16.9 years). RESULTS:: The mean change in AOFAS Ankle-Hindfoot scores from preoperative to final follow-up was 36.0 +/- 16.8 ( P < .0001). There were 21 (15.2%) implant failures that occurred at a mean 4.9 +/- 4.5 years postoperation. Ten polyethylene components in 9 TAAs (6.5%) required replacement for fracture at an average 8.9 +/- 3.3 years postoperatively. Fourteen patients died with their initial implants in place. CONCLUSION:: This cohort of patients with true intermediate follow-up after TAA with the STAR prosthesis had acceptable implant survival, maintenance of improved patient-reported outcome scores, and low major complication rates. LEVEL OF EVIDENCE:: Level IV, case series. PMID- 30413132 TI - The Temporal Dimension of System Justification: Gender Ideology Over the Course of the 2016 Election. AB - Although psychological science has documented individual and situational factors that affect the process of system justification, the temporal dimension of system justification has not been systematically examined. This study used the 2016 U.S. presidential election as a naturalistic setting in which to test for the existence of a temporal dimension. We propose that the potential for a Clinton victory represented a system threat for individuals who supported traditional gender roles, and the approaching election provided a mechanism for measuring the effect of the temporal proximity of the system-threatening event. The results show that gender role ideology played a substantial role in decision-making during the 2016 election, and they support the existence of a temporal dimension of system justification. Participants who began the study with a stronger gender system justification motive exhibited greater changes in their psychological responses to Clinton over time and greater sensitivity to the temporal proximity of the election. PMID- 30413133 TI - Comparative Results of Percutaneous Calcaneal Osteotomy in Correction of Hindfoot Deformities. AB - BACKGROUND:: Calcaneal osteotomies are often required in the correction of hindfoot deformities. The traditional open techniques, which include a lateral or oblique incision, are occasionally associated with wound healing problems and neurovascular injury. METHODS:: A total of 122 consecutive patients who underwent a calcaneal osteotomy for hindfoot realignment treatment were included. Fifty eight patients were operated using an open incision technique and 64 patients (66 feet) using a percutaneous technique. Clinical and radiologic assessments were performed preoperatively, at 6 weeks, and 1 year postoperatively. RESULTS:: The American Orthopaedic Foot & Ankle Society scale scores and visual analog scale pain scores improved in both groups postoperatively. The difference between the groups was not significant. The results of the radiologic measurements pre- and postoperatively were not significantly different. No pseudarthrosis occurred in either group. The comparison of both groups showed a significantly lower risk for wound healing problems in the percutaneous group. The hospitalization time was significantly shorter in the percutaneous group. CONCLUSION:: Because of the excellent results with the percutaneous calcaneal osteotomy, the authors feel encouraged to establish this procedure as a standard technique for calcaneus osteotomy, especially patients at high risk for wound healing problems. LEVEL OF EVIDENCE:: Level III, comparative series. PMID- 30413134 TI - Effect of Gender, Toe Extension Position, and Plantar Fasciitis on Plantar Fascia Thickness. AB - BACKGROUND:: Ultrasound is a widely used diagnostic tool for patients with plantar fasciitis. However, the lack of standardization during the measurement for plantar fascia thickness has made it challenging to understand the etiology of plantar fasciitis, as well as identify risk factors, such as gender. The purpose of this study was to investigate gender differences regarding plantar fascia thickness while controlling for metatarsophalangeal (MTP) joint position in the healthy and those with unilateral plantar fasciitis. METHODS:: Forty participants (20 with unilateral plantar fasciitis and 20 controls) with plantar fascia thickness (mean age, 44.8 +/- 12.2 years) participated in this study. The majority were females (n = 26, 65%). Plantar fascia thickness was measured via ultrasound 3 times at 3 different MTP joint positions: (1) at rest, (2) at 30 degrees of extension, and (3) at maximal extension. RESULTS:: When comparing gender differences, the males in the plantar fasciitis group had a significantly thicker plantar fascia than the females ( P = .048, eta2 = 2.35). However, no significant differences were observed between healthy males and females. The males with unilateral plantar fasciitis also had significantly thicker asymptomatic plantar fasciae collectively compared with controls ( P < .05), whereas females with unilateral plantar fasciitis had a similar but not significant change. CONCLUSION:: It appears that healthy males and females have similar plantar fascia thickness. However, as plantar fasciitis develops, males tend to develop thicker plantar fasciae than their female counterparts, which could have future treatment implications. LEVEL OF EVIDENCE:: Level III, case control comparative study. PMID- 30413135 TI - The games they play: Observations of children with autism spectrum disorder on the school playground. AB - The playground may be an important context to examine the social functioning of children with autism spectrum disorder. Previous literature on playground peer engagement has used quantitative methods, but there is limited research using qualitative observations to understand the nuances of playground behavior. Using a mixed-methods approach, 55 elementary school-aged children with autism spectrum disorder who are primarily included in general education settings were observed on the school playground using the Playground Observation of Peer Engagement. Quantitative and qualitative data were examined using a mixed-methods approach. The results showed that children with autism spectrum disorder: engage in solitary and peripheral activities; demonstrate appropriate initiations and responses to peers; display self-stimulatory, motoric behaviors most frequently during solitary activities; and often have neutral affect on the playground. These findings suggest that intervention and supports for children with autism spectrum disorder may be important to deliver at recess to address peer engagement. PMID- 30413136 TI - Scaling Up Diabetes Prevention Programs in North Carolina: Perceptions of Demand From Potential Program Recipients and Providers. AB - PURPOSE: The purpose of this study was to assess factors that influence demand for the Diabetes Prevention Program (DPP) from the perspectives of potential program participants and providers. METHODS: A qualitative study guided by a conceptual framework was conducted with potential DPP participants and potential DPP providers. Five focus groups with potential participants (n = 37) and key informant interviews with potential providers (n = 14) were conducted in community settings across North Carolina. RESULTS: Although providers considered prediabetes to be an important health problem, potential DPP participants expressed less urgency related to a diagnosis of prediabetes. Potential participants felt that they were more likely to adopt diabetes prevention programs if affordable and convenient. For potential program providers, funding, collaboration, and staff support were key considerations for DPP adoption. Providers were supportive of DPP features; however, there was concern from both stakeholders on retention in a 16-week program. Both groups cited transportation, cost, and health insurance reimbursement as existing barriers to the uptake of these programs. CONCLUSION: This qualitative study highlights important considerations for scaling up diabetes prevention programs in community settings, including what constraints agencies face in adopting programs, the perceived demand and programmatic needs for these services by customers, and the need for improving patient education on prediabetes. This implementation science study allows us to increase the potential to scale up and sustain diabetes prevention programs that fit available resources and customer needs. PMID- 30413137 TI - Personal Ties and Prejudice: A Meta-Analysis of Romantic Attachment and Ambivalent Sexism. AB - We examine how relational needs underlie sexism by conducting a meta-analysis ( k = 22; N = 4,860) on the links between adults' romantic attachment and endorsement of ambivalent sexism. Results across two random-effects meta-analytic methods supported that men's and women's attachment anxiety predicted stronger endorsement of both benevolent sexism and hostile sexism. Simultaneously, men's attachment avoidance predicted lower endorsement of benevolent sexism, and for men in relationships (vs. single men), stronger endorsement of hostile sexism. Thus, the way that people fulfil their relational goals lead people to adopt particular attitudes about gender, supporting that relationships are one key source of people's adoption of sexism. These results bridge attachment theory and ambivalent sexism theory by illustrating how individual differences in the amplification or suppression of needs for relational security fuel adoption of beliefs that function to maintain gender inequality across the world. PMID- 30413138 TI - Kinematic Effects of Varying Adolescents' Attentional Instructions for Standing Long Jump. AB - Studies examining attentional focus in the motor performance of children and young adolescents have produced mixed results. We studied 26 seventh-grade physical education student volunteers ( Mage = 12.7 years; SD = 0.56) who performed two standing long jumps for maximum displacement in four counterbalanced instructional conditions: (a) no cues provided, (b) focus on rapid knee extension, (c) focus on rapid forward arm swing, and (d) focus to jump as close as possible to a cone placed at 3 meters. The last condition, encouraging an external focus, led to significantly greater jumping distances and significantly lower projection angles (36.9 degrees ) when compared with internal attentional foci on the actions of the legs (40.2 degrees ) and arms (38.6 degrees ). Compared with the leg focus, the arm focus lead to significantly greater jumping distances but no differences for projection angle. While these results are consistent with those of past adult participants, when comparing external and internal attentional foci, this study extended these findings to adolescents and revealed differences in projection angle, indicating that cueing young adolescents to focus on arm action did not appear to constrain movement in the same manner as it has in adults. PMID- 30413139 TI - Numerical Processing and Executive Functioning in Early Versus Middle Childhood: A Japanese Sample. AB - Many previous studies have investigated developmental differences in numerical processing by manipulating numerical distance and physical size in a number sequence. While it has been theorized that children's maturity level in executive functioning affects their numerical processing, the interaction between numerical processing and executive functioning through development remains unclear. We divided 60 Japanese school children, aged 8-12 years, into three age-related groups (second graders, fourth graders, and sixth graders) and had them perform physical and numerical comparison Stroop tasks. In the physical comparison task, the numerical Stroop effect (i.e., automatic numerical processing) was evident in each group, but, in the numerical comparison task, the numerical distance effect (i.e., intentional numerical processing) was evident in each group. Also, in the numerical comparison task, the size congruity effect (an index of the attentional and inhibitory control mechanisms of executive functioning) was more salient among second graders than among fourth or sixth graders. These results suggest that numerical processing matures and then plateaus just before primary school, while executive functioning continues to develop. Thus, these data provide evidence of a developmental dissociation between numerical processing and executive functioning. PMID- 30413140 TI - MOBAK 1 Assessment in Primary Physical Education: Exploring Basic Motor Competences of Portuguese 6-Year-Olds. AB - Children's motor competence is known to have a determinant role in learning and engaging later in complex motor skills and, thus, in physical activity. The development of adequate motor competence is a central aim of physical education, and assuring that pupils are learning and developing motor competence depends on accurate assessment protocols. The MOBAK 1 test battery is a recent instrument developed to assess motor competence in primary physical education. This study used the MOBAK 1 to explore motor competence levels and gender differences among 249 ( Mage = 6.3, SD = 0.5 years; 127 girls and 122 boys) Grade 1 primary school Portuguese children. On independent sample t tests, boys presented higher object movement motor competence than girls (boys: M = 5.8, SD = 1.7; girls: M = 4.0, SD = 1.7; p < .001), while girls were more proficient among self-movement skills (girls: M = 5.1, SD = 1.8; boys: M = 4.3, SD = 1.7; p < .01). On "total motor competence," boys ( M = 10.3, SD = 2.6) averaged one point ahead of girls ( M = 9.1, SD = 2.9). The percentage of girls in the first quartile of object movement was 18.9%, while, for "self movement," the percentage of boys in the first quartile was almost double that of girls (30.3% and 17.3%, respectively). The confirmatory model to test for construct validity confirmed the assumed theoretical two-factor structure of MOBAK 1 test items in this Portuguese sample. These results support the MOBAK 1 instrument for assessing motor competence and highlighted gender differences, of relevance to intervention efforts. PMID- 30413141 TI - Development of the Checklist of Psychomotor Activities for 5- to 6-Year-Old Children. AB - The present research aimed to develop the Checklist of Psychomotor Activities (CPA) to measure psychomotor development in 5-6 year old children. We recruited 694 preschool children in the province of Albacete; their teachers were trained to use and complete this instrument to gather data for testing its psychometric properties (reliability, and content, construct, and discriminant validity). The CPA is composed of three subtests measuring children's performance in motor, perceptual, and emotional-social aspects of psychomotor functioning. To gather evidence of content validity, we applied the Delphi method, based on the comments of seven judges. We assessed construct validity with confirmatory factor analysis, and we tested discriminant validity by comparing the scores of premature and typically developing children and separate groups of children defined by their body mass index. We found adequate item consistency on each scale and evidence of validity from the various methods outlined. We conclude that the CPA is an effective and comprehensive tool for the assessment of psychomotor skills in children at this important stage of development. PMID- 30413142 TI - Length of Hair Affects P1 and N170 Latencies for Perception of Women's Faces. AB - This study investigated the relationship between length of hair in facial stimuli and latency and amplitude of the P1 and N170 components of event-related potentials during facial perception. Electroencephalography was recorded from 21 Japanese participants (four men, 17 women) who were shown pictures of faces with one of three lengths of hair: long, medium length, or short. In addition, we used both fixed-size and variable-size blocks. In fixed-size blocks, the three types of stimuli were matched to have the same overall size; in variable-size blocks, long hair stimuli were the biggest, medium length hair stimuli were medium sized, and short hair stimuli were the smallest. We analyzed P1 latency and amplitude using two-way (6 * 2) repeated-measures analysis of variance over length of hair and electrode; N170 latency and amplitude were analyzed using three-way (6 * 2 * 2) repeated-measures analysis of variance over length of hair, hemisphere, and electrode. The latency of P1 to faces with short hair in variable-size blocks was significantly longer than that to the other five stimulus types ( p < .01 for four of the other types; p = .083 for medium length hair in variable-size blocks). The latency of N170 to faces with long hair in variable-size blocks was significantly shorter than that to faces with medium length hair and short hair in variable-size blocks ( p = .026 and p = .086, respectively). These results indicate that length of hair influenced P1 and N170 latency, supporting the notion that length of hair is a significant external facial feature. Because long hair attracted participants' attention, there was early perceptual processing of this feature. In contrast, because short hair did not attract attention, perceptual processing of this feature was late. PMID- 30413143 TI - Glycine receptors expression in rat spinal cord and dorsal root ganglion in prostaglandin E2 intrathecal injection models. AB - BACKGROUND: Glycine receptors (GlyRs) are involved in the development of spinal pain sensitization. The GlyRalpha3 subunit has recently emerged as a key factor in inflammatory pain pathways in the spinal cord dorsal horn (DH). Our study is to identify the extent of location and cell types expressing different GlyR subunits in spinal cord and dorsal root ganglion (DRGs). To tease out the possible actions of GlyRs on pain transmission, we investigate the effects produced by GlyRs on acute inflammatory pain by behavioral testing using prostaglandin E2 (PGE2) intrathecal injection models. Furthermore, we investigate the changes of GlyR expression in DRGs and spinal cord in rats after the induction of acute inflammatory pain. RESULTS: Compared to the vehicle administration, the PGE2 intrathecal injection model produced significantly higher hyperalgesia, which started 3 h after PGE2 injection and lasted more than 5 h. PGE2 intrathecal injection significantly decreased GlyRalpha1 and GlyRalpha3 protein expressions in the L5 DH at 1 h and lasted to 5 h, and similar results were observed in the L5 DRG at 5 h. Confocal microscopic images showed the co existence of punctate gephyrin and GlyRalpha3 immunoreactivity (IR) throughout the gray matter of the spinal cord, mainly in DH laminae I-III neurons and in ventral horn neurons. It also showed the co-existence of punctate gephyrin and GlyRalpha3 IR in DRG neurons. CONCLUSIONS: In this study, PGE2 intrathecal injection significantly decreased protein expression of gephyrin, GlyRalpha1 and GlyRalpha3 in spinal cord DH and DRG. The gephyrin and GlyRalpha3 were localized on neuron cells both in the DH and DRG. PMID- 30413145 TI - Pseudophakic mini-monovision: high patient satisfaction, reduced spectacle dependence, and low cost. AB - BACKGROUND: Cataract surgery with pseudophakic mini-monovision has lower out-of pocket patient expense than premium multifocal intraocular lenses (IOL). The purpose of this study was to evaluate patient-reported satisfaction and spectacle dependence for key activities of daily living after cataract surgery with pseudophakic mini-monovision. The study also examined statistical relationships between patient demographic variables, visual acuity and satisfaction. METHODS: Prospective cohort study of 56 patients (112 eyes) who underwent bilateral cataract surgery with pseudophakic mini-monovision. Mini-monovision corrects one eye for distance vision and the other eye is focused at near with - 0.75 to - 1.75 D of myopia. All patients with 1 diopter or greater of corneal astigmatism had a monofocal toric IOLs implanted or limbal relaxing incision. The main study outcomes were assessed at the last follow-up appointment and included refraction, visual acuity, patient reported spectacle use, and patient satisfaction. Descriptive statistics, correlation matrixes and Pearson's chi-square tests were examined. RESULTS: Uncorrected visual acuity was significantly better post operatively. Most patients reported the surgery met their expectations for decreased dependence on spectacles (93%). Most patients report little or no use of spectacles post-operatively for computer use (93%), distance viewing (93%) and general use throughout the day (87%). A small number of patients report spectacle use for reading (9%) and night driving (18%). There were no relationships detected between demographic variables and visual acuity or patient satisfaction. CONCLUSIONS: Aging of the population presents one of the biggest challenges in the health sector, which includes a rising number of individuals with chronic vision impairment and increased demand for accessible treatment strategies. Cataract surgery with pseudophakic mini-monovision results in high patient satisfaction and considerable reduction in spectacle dependence. Pseudophakic mini-monovision technique is a low-cost, valuable option for patients who would like to reduce dependence on spectacles post-operatively and should be considered along with premium multifocal IOLs in options available for patients based on their needs, preferences and clinical indicators. Reducing spectacle dependence with the pseudophakic mini-monovision technique could improve the functionality, independence and quality of life for many patients who are unsuitable or are unable to pay additional fees associated with premium multifocal IOLs. PMID- 30413144 TI - A need to improve the assessment of environmental hazards for falls on stairs and in bathrooms: results of a scoping review. AB - BACKGROUND: Falls occurring on stairs or in bathrooms are associated with a high risk of injuries among older adults. Home environmental assessments are frequently used to guide fall-prevention interventions. The aims of this review were to describe how, where, by whom, and for whom environmental hazard checklists are used, and to examine the characteristics of environmental hazard assessment checklists with specific attention to features of bathrooms and stairs/steps assessed in them. METHODS: Studies published before January 5, 2018, were identified using several databases. Publications reporting the use and/or evaluation of environmental hazard checklists were eligible if they assessed bathrooms or stairs/steps in homes of older adults (>=65 years). Content analysis was conducted on publications that provided a complete list of specific environmental hazards assessed. Checklist items related to bathrooms and stairs/steps were extracted and categorized as structural or non-structural and as objective or subjective. RESULTS: 1119 studies were appraised. A pool of 136 published articles and 4 checklists from the grey literature were included in this scoping review. Content analysis was conducted on 42 unique checklists. There was no widely used checklist and no obvious consensus definition of either environmental hazards overall or of single hazards listed in checklists. Checklists varied greatly with respect to what rooms were assessed, whether or not outdoor stair/steps hazards were assessed, and how responses were coded. Few checklists examined person-environment fit. The majority of checklists were not oriented towards structural hazards in bathrooms. Although the majority of checklists assessing stair/steps hazards evaluated structural hazards, most features assessed were not related to the construction geometry of stairs/steps. Objective features of bathrooms and stairs/steps that would deem them safe were rarely specified. Rather, adequacy of their characteristics was mostly subjectively determined by the evaluator with little or no guidance or training. CONCLUSION: The lack of standard definitions and objective criteria for assessing environmental hazards for falls is limiting meaningful cross-study comparisons and slowing advances in this field. To inform population health interventions aimed at preventing falls, such as building code regulations or municipal housing by-laws, it is essential to include objectively-assessed structural hazards in environmental checklists. PMID- 30413146 TI - Unhealthy dietary patterns among healthcare professionals and students in Mexico. AB - BACKGROUND: While dietary patterns (DPs) enable the combination of foods that make up a person's habitual diet to be known, little is known about the DPs of health sector professionals. The objective of this study was to describe the DPs of healthcare students and professionals and assess their association with sociodemographic, lifestyle, anthropometric and biochemical characteristics. METHODS: Cross-sectional design. A sample (n = 319) of healthcare students and professionals in apparent good health who studied or worked at the University of Guadalajara (Mexico) was selected. A semiquantitative food intake frequency questionnaire validated on a Mexican population was administered. Questions covering sociodemographic factors, smoking habits and physical activity were asked. Weight, height, waist circumference, blood pressure, triglycerides, glucose, HDL-cholesterol, LDL-cholesterol and total cholesterol were also measured. DPs were generated from a principal components analysis of 25 food groups, and associations were analyzed using logistic regression adjusted for age and sex. RESULTS: The majority of participants were younger than 29 years (84%), women (71.2%) and students (59.6%). Three DPs were identified: "Traditional Westernized", "Healthy" and "Animal protein and alcoholic beverages". After adjustment, the "Traditional Westernized" DP was positively associated with being younger than 22 years (OR: 2.15; 95%CI: 1.1-4.1); the "Healthy" DP was positively associated with having a daily energy expenditure from physical activity greater than 605 kcal (OR: 4.19; 95%CI: 2.3-7.5), and it was negatively associated with being younger than 22 years (OR: 0.48; 95%CI: 0.2-0.9); and the "Animal protein and alcoholic beverages" DP was positively associated with being male (OR: 3.07; 95%CI: 1.8-5.1) and a smoker (OR: 2.77; 95%CI: 1.2-6.3). No association was found between DPs and anthropometric and biochemical characteristics. CONCLUSIONS: Among the participants evaluated, healthy DP was associated with being physically active while unhealthy DPs were associated with being younger than 22 years, male and a smoker. These data suggest that being knowledgeable about health does not ensure that individuals will engage in healthy behaviors. As is the case among the general population, training and individual efforts aimed at achieving healthy behaviors must be reinforced by initiatives undertaken by social groups, social institutions, the community at large as well as political and business leaders. PMID- 30413147 TI - Insights into the historical assembly of global dryland floras: the diversification of Zygophyllaceae. AB - BACKGROUND: Drylands cover nearly 41% of Earth's land surface and face a high risk of degradation worldwide. However, the actual timeframe during which dryland floras rose on a global scale remains unknown. Zygophyllaceae, an important characteristic component of dryland floras worldwide, offers an ideal model group to investigate the diversification of dryland floras. Here, we used an integration of the phylogenetic, molecular dating, biogeographic, and diversification methods to investigate the timing and patterns of lineage accumulation for Zygophyllaceae overall and regionally. We then incorporated the data from other dominant components of dryland floras in different continents to investigate the historical construction of dryland floras on a global scale. RESULTS: We provide the most comprehensive phylogenetic tree for Zygophyllaceae so far based on four plastid and nuclear markers. Detailed analyses indicate that Zygophyllaceae colonized Africa, Asia, Australia, and the New World at different periods, sometimes multiple times, but Zygophyllaceae lineages in the four regions all experienced a rapid accumulation beginning at the mid-late Miocene (~ 15-10 Ma). Other eleven essential elements of dryland floras become differentiated at the same time. CONCLUSIONS: Our results suggest that the rise of global dryland floras is near-synchronous and began at the mid-late Miocene, possibly resulting from the mid-Miocene global cooling and regional orogenetic and climate changes. The mid-late Miocene is an essential period for the assembly and evolution of global dryland floras. PMID- 30413148 TI - Long-term population persistence of flightless weevils (Eurhoptus pyriformis) across old- and second-growth forests patches in southern Appalachia. AB - BACKGROUND: Southern Appalachian forests are dominated by second-growth vegetation following decades of intensive forestry and agricultural use, although some old-growth patches remain. While it's been shown that second-growth areas may exhibit comparable species richness to old-growth in the area, the extent to which populations of arthropods in second-growth areas have persisted vs. recolonized from other areas remains unexamined. The implications for conservation of both classes of forest are significant. Here we analyze population diversity and relatedness across five old-growth and five second growth populations of flightless, leaf litter-inhabiting beetles in the genus Eurhoptus (Coleoptera: Curculionidae: Cryptorhynchinae). Our main goal is asking whether second-growth areas show diminished diversity and/or signals of recolonization from old-growth sources. RESULTS: Population genetic and phylogenetic analyses do not reveal any consistent differences in diversity between the old-growth and second-growth populations examined. Some second-growth populations retain substantial genetic diversity, while some old-growth populations appear relatively depauperate. There is no phylogenetic indication that second-growth populations have recolonized from old-growth source populations. CONCLUSIONS: Most populations contain substantial and unique genetic diversity indicating long-term persistence in the majority of sites. The results support substantial resilience in second-growth populations, though the geographic scale of sampling may have hindered detection of recolonization patterns. Broad scale phylogeographic patterns reveal a deep break across the French Broad River basin, as has been reported in several other taxa of limited dispersal abilities. In Eurhoptus this break dates to ~ 2-6 Ma ago, on the older end of the range of previously estimated dates. PMID- 30413149 TI - ENHO, RXRA, and LXRA polymorphisms and dyslipidaemia, related comorbidities and survival in haemodialysis patients. AB - BACKGROUND: The energy homeostasis-associated gene (ENHO), retinoid X receptor alpha gene (RXRA), and liver X receptor alpha gene (LXRA) are involved in adipogenic/lipogenic regulation. We investigated whether single-nucleotide polymorphisms in these genes (ENHO rs2281997, rs72735260; RXRA rs749759, rs10776909, rs10881578; LXRA rs2279238, rs7120118, rs11039155) are associated with dyslipidaemia, related comorbidities and survival of haemodialysis (HD) patients also tested for T-helper (Th) cell interleukin genes (IL). METHODS: The study was carried out in 873 HD patients. Dyslipidaemia was diagnosed by the recommendations of the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines (2003); atherogenic dyslipidaemia was referred to if the TG/HDL cholesterol ratio was equal to or higher than 3.8. Genotyping of ENHO SNPs, LXRA SNPs, and IL12A rs568408 was carried out using HRM analysis. RXRA SNPs, IL12B rs3212227, and IL18 rs360719 were genotyped using PCR-RFLP analysis. The circulating adropin concentration was determined in 126 patients by enzyme-linked immunosorbent assay. Survival probability was analysed using the Kaplan-Meier method in 440 patients followed through 7.5 years. RESULTS: Dyslipidaemia by K/DOQI was diagnosed in 459 patients (91% revealed hyper-LDL- cholesterolaemia), atherogenic dyslipidaemia was diagnosed in 454 patients, and 231 patients were free of dyslipidaemia by both criteria. The variant allele (T) of ENHO rs2281997 was associated with the hyper-LDL cholesterolaemic pattern of dyslipidaemia by K/DOQI. The frequency of atherogenic dyslipidaemia was lower in T-allele bearers than in CC-genotype patients. The rs2281997 T allele was associated with lower cardiovascular mortality in HD patients showing atherogenic dyslipidaemia. ENHO, RXRA, and LXRA showed epistatic interactions in dyslipidaemia. Circulating adropin was lower in atherogenic dyslipidaemia than in non-atherogenic conditions. RXRA rs10776909 was associated with myocardial infarction. Bearers of LXRA rs2279238, rs7120118 or rs11039155 minor alleles showed higher mortality. ENHO SNP positions fell within the same DNase 1 hypersensitivity site expressed in the Th1 cell line. Epistatic interactions occurred between rs2281997 and Th1 IL SNPs (rs360719, rs568408). CONCLUSIONS: Atherogenic dyslipidaemia occurs in HD patients in whom ENHO encodes less adropin. ENHO, RXRA, and LXRA SNPs, separately or jointly, are associated with dyslipidaemia, myocardial infarction, and survival in HD patients. Differences in the availability of transcription binding sites may contribute to these associations. PMID- 30413150 TI - Trends in anemia care in non-dialysis-dependent chronic kidney disease (CKD) patients in the United States (2006-2015). AB - BACKGROUND: The objective of the study was to examine overall anemia management trends in non-dialysis patients with chronic kidney disease (CKD) from 2006 to 2015, and to evaluate the impact of Trial to Reduced Cardiovascular Events with Ananesp Therapy (TREAT)'s study results (October 2009) and the US Food and Drug Administration (FDA)'s (June 2011) safety warnings and guidelines on the use of ESA therapy in the current treatment of anemia. METHODS: A retrospective cohort analysis of anemia management in CKD patients using Truven MarketScan Commercial and Medicare Supplemental databases was conducted. Monthly rates and types of anemia treatment for post-TREAT and post-FDA safety warning periods were compared to pre-TREAT period. Anemia management included ESA, intravenous iron, and blood transfusion. A time-series analysis using Autoregressive Integrated Moving Average (ARIMA) model and a Generalized Estimating Equation (GEE) model were used. RESULTS: Between 2006 and 2015, CKD patients were increasingly less likely to be treated with ESAs, more likely to receive intravenous iron supplementation, and blood transfusions. The adjusted probabilities of prescribing ESAs were 31% (odds ratio (OR) = 0.69, 95% confidence interval (CI): 0.67-0.71) and 59% (OR = 0.41, 95% CI: 0.40, 0.42) lower in the post-TREAT and post-FDA warning periods compared to pre-TREAT period. The probability of prescribing intravenous iron was increased in the post-FDA warning period (OR = 1.11, 95% CI: 1.03-1.19) although the increase was not statistically significant in the post-TREAT period (OR = 1.03, 95% CI: 0.94-1.12). The probabilities of prescribing blood transfusion during the post-TREAT and post-FDA warning periods increased by 14% (OR = 1.14, 95% CI: 1.06-1.23) and 31% (OR = 1.31, 95% CI: 1.22-1.39), respectively. Similar trends of prescribing ESAs and iron supplementations were observed in commercially insured CKD patients but the use of blood transfusions did not increase. CONCLUSIONS: After the 2011 FDA safety warnings, the use of ESA continued to decrease while the use of iron supplementation continued to increase. The use of blood transfusions increased significantly in Medicare patients while it remained stable in commercially insured patients. Results suggest the TREAT publication had effected treatment of anemia prior to the FDA warning but the FDA warning solidified TREAT's recommendations for anemia treatment for non- dialysis dependent CKD patients. PMID- 30413151 TI - A phase 3, long-term, open-label safety study of Galcanezumab in patients with migraine. AB - BACKGROUND: Galcanezumab, a humanized monoclonal antibody that selectively binds to the calcitonin gene-related peptide, has demonstrated in previous Phase 2 and Phase 3 clinical studies (<=6-month of treatment) a reduction in the number of migraine headache days and improved patients' functioning. This study evaluated the safety and tolerability, as well as the effectiveness of galcanezumab for up to 12 months of treatment in patients with migraine. METHODS: Patients diagnosed with episodic or chronic migraine, 18 to 65 years old, that were not exposed previously to galcanezumab, were randomized to receive galcanezumab 120 mg or 240 mg, administered subcutaneously once monthly for a year. Safety and tolerability were evaluated by frequency of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events (AEs) leading to study discontinuation. Laboratory values, vital signs, electrocardiograms, and suicidality were also analyzed. Additionally, overall change from baseline in the number of monthly migraine headache days, functioning, and disability were assessed. RESULTS: One hundred thirty five patients were randomized to each galcanezumab dose group. The majority of patients were female (> 80%) and on average were 42 years old with 10.6 migraine headache days per month at baseline. 77.8% of the patients completed the open-label treatment phase, 3.7% of patients experienced an SAE, and 4.8% discontinued due to AEs. TEAEs with a frequency >= 10% of patients in either dose group were injection site pain, nasopharyngitis, upper respiratory tract infection, injection site reaction, back pain, and sinusitis. Laboratory values, vital signs, or electrocardiograms did not show anyclinically meaningful differences between galcanezumab dosesOverall mean reduction in monthly migraine headache days over 12 months for the galcanezumab dose groups were 5.6 (120 mg) and 6.5 (240 mg). Level of functioning was improved and headache-related disability was reduced in both dose groups. CONCLUSION: Twelve months of treatment with self-administered injections of galcanezumab was safe and associated with a reduction in the number of monthly migraine headache days. Safety and tolerability of the 2 galcanezumab dosing regimens were comparable. TRIAL REGISTRATION: ClinicalTrials.gov as NCT02614287 , posted November 15, 2015. These data were previously presented as a poster at the International Headache Congress 2017: PO-01-184, Late-Breaking Abstracts of the 2017 International Headache Congress. (2017). Cephalalgia, 37(1_suppl), 319-374. PMID- 30413152 TI - Suicidal ideations and coping strategies of mothers living with physical disabilities: a qualitative exploratory study in Ghana. AB - BACKGROUND: Suicide is higher among adults with disabilities compared to their counterparts without disabilities and suicide is mostly preceded with suicidal ideations. For each successful suicide, there could be many ideations and attempts. Limited scientific data exist on the issue of mothers with disabilities and suicidal ideations. Therefore, this study explored suicidal ideations and coping strategies of mothers living with physical disabilities in Ghana. METHODS: Qualitative descriptive exploratory design was used and data was collected through individualized in-depth interviews. All participants were purposefully selected after informed consent was sought. Data was audiotaped, transcribed and analyzed inductively using content analysis technique. RESULTS: Almost all the women in this study reported suicidal ideations from time to time. Poisoning was the most predominant means which the women had considered to use if they ever attempted the suicide. Suicidal thoughts were precipitated mainly by discrimination. Their resilience and ability to cope were due to self-motivation, children, counselling, assistance from relatives and prayer. CONCLUSION: We concluded that, it is crucial for all health professionals to explore and identify suicidal intentions among mothers with disabilities for them to be referred to the appropriate units for necessary help. PMID- 30413153 TI - Early predictors of one-year mortality in patients over 65 presenting with ANCA associated renal vasculitis: a retrospective, multicentre study. AB - BACKGROUND: The risk of early death is particularly high in patients over the age of 65 presenting with antineutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis. We hypothesized that by combining disease severity markers, a comorbidity index and serious adverse event reports, we would be able to identify early predictors of one-year mortality in this population. METHODS: We performed a multicentre, retrospective study in the nephrology and internal medicine departments of six tertiary hospitals in northern France. A total of 149 patients (median [interquartile range (IQR)] age: 72.7 [68.5-76.8] years) presenting with ANCA-associated vasculitis and renal involvement were included between January 2002 and June 2015. The primary endpoint was the one-year mortality rate. RESULTS: Renal function was severely impaired at presentation (median [IQR] peak serum creatinine (SCr): 337 [211-522] MUmol/l), and 45 patients required dialysis. The Five-Factor Score (FFS, scored as + 1 point for each poor prognostic factor (age > 65 years, cardiac symptoms, gastrointestinal involvement, SCr >=150 MUmol/L, and the absence of ear, nose, and throat involvement)) was >=3 in 120 cases. The one-year mortality rate was 19.5%. Most of the deaths occurred before month 6, and most of these were related to severe infections. In a univariate analysis, age, a high comorbidity index, a performance status of 3 or 4, a lack of co-trimoxazole prophylaxis, early severe infection, and disease activity parameters (such as the albumin level, haemoglobin level, peak SCr level, dialysis status, and high FFS) were significantly associated with one-year mortality. In a multivariable analysis, the best predictors were a high FFS (relative risk (RR) [95% confidence interval (CI)] = 2.57 [1.30-5.09]; p = 0.006) and the occurrence of a severe infection during the first month (RR [95%CI] = 2.74 [1.27-5.92]; p = 0.01). CONCLUSIONS: When considering various disease severity markers in over-65 patients with ANCA associated renal vasculitis, we found that an early, severe infection (which occurred in about a quarter of the patients) is a strong predictor of one-year mortality. A reduction in immunosuppression, the early detection of infections, and co-trimoxazole prophylaxis might help to reduce mortality in this population. PMID- 30413155 TI - Isolated neonatal bilateral vocal cord paralysis revealing a unilateral medullary defect: a case report. AB - BACKGROUND: Congenital bilateral vocal cord paralysis is a rare occurrence. Approximately half the cases are associated with a major comorbidity, usually neurological, neuromuscular or malformative. CASE PRESENTATION: In a male newborn, respiratory distress syndrome and stridor were observed immediately following birth. The cause was bilateral vocal cord paralysis in the adducted position. Neuroradiological investigation revealed a unilateral discontinuity between the upper pons and the right medulla oblongata. Hypoplasia of the right posterior hemiarches of C1-C2 and the right exo-occipital bone was observed, as was a small clivus. MR angiography showed the absence of the distal right vertebral artery, with hypoplasia and parietal irregularities of the proximal segments. Respiratory autonomy was not obtained despite endoscopic laser cordotomy, corticosteroid therapy and nasal continuous positive airway pressure. The infant died at the age of 4 weeks after treatment was limited to comfort care. CONCLUSIONS: A medullary lesion is an exceptional cause of congenital bilateral vocal cord paralysis. The strictly unilateral neurological and vascular defect and the absence of associated intracranial or extracranial malformation make this clinical case unique and suggest a disruptive mechanism. This case also highlights the help provided by advanced neuroimaging techniques, i.e. fibre tracking using diffusion tensor imaging, in the decision-making process. PMID- 30413156 TI - Retroperitoneal abscess with subcutaneous extension: case report of a rare complication of percutaneous renal biopsy. AB - BACKGROUND: Infective complications following percutaneous renal biopsy are rare, even among immunocompromised. However it is important to be vigilant about such complications, to detect them early and prevent morbidity and mortality. We report a case of retroperitoneal abscess with extension to subcutaneous plane after a renal biopsy. CASE PRESENTATION: A 42-year-old female with long standing cutaneous lupus underwent renal biopsy for evaluation of nephrotic range proteinuria. She was on high dose prednisolone complicated with steroid induced hyperglycaemia. Eight weeks after the biopsy she presented with left flank pain, malaise and fever. There was a tender subcutaneous induration over the biopsy site. Contrast CT abdomen showed a retroperitoneal abscess with subcutaneous extension along the path of the biopsy needle. This was successfully treated with surgical drainage and broad-spectrum antibiotics. CONCLUSIONS: Infections and abscess formation are rare but serious complications of renal biopsy. Immunocompromised state is a potential risk factor. Possible mechanisms and measures for prevention and early detection of this rare complication are discussed. PMID- 30413154 TI - Comparison of clinical outcomes of toric intraocular lens, Precizon vs Tecnis: a single center randomized controlled trial. AB - BACKGROUND: To compare the clinical outcome of Precizon toric intraocular lens (IOL) (Ophtec Inc.) to that of Tecnis toric IOL (Abbott Medical Optics Inc.). METHODS: This randomized comparative study included 40 eyes (Precizon, 20 eyes; Tecnis, 20 eyes) of 40 patients with visually significant cataract and corneal astigmatism who underwent cataract surgery. Changes in uncorrected distant visual acuity (UCDVA), best corrected distant visual acuity (BCDVA), uncorrected intermediate visual acuity (UCIVA), refraction, residual astigmatism, rotation of the IOL axis, and higher order aberrations at 3 months postoperatively were evaluated. Vector analysis was performed using the Alpins method. RESULTS: Both groups showed significant reduction in refractive astigmatism after the surgery (Precizon: - 1.06 +/- 0.94 Diopter (D) to - 0.31 +/- 0.29 D, p = 0.042; Tecnis: - 1.83 +/- 1.29 D to - 0.41 +/- 0.33 D, p = 0.015). There was no significant (p > 0.05) difference in postoperative UCDVA, BCDVA, or residual astigmatism between the two groups, although a tendency of better UCIVA was observed in the Precizon group. Vector analysis parameters showed no statistically significant difference beween groups(P > 0.05). Significant difference in rotation of toric IOL axis was found between the two groups (Precizon: 1.50 degrees +/- 0.84, Tecnis: 2.56 degrees +/- 0.68, p = 0.010). Spherical aberration in the Precizon group was significantly (p = 0.005) lower than that in the Tecnis group. CONCLUSIONS: The Precizon toric IOL group had better rotational stability at 3-month postoperatively. Both Precizon toric IOL and Tecnis toric IOL could be effectively used by cataract surgeons to correct preexisting corneal astigmatism through cataract surgery. TRIAL REGISTRATION: http://clinicaltrials.gov , NCT03085901 , retrospectively registered on 21 March 2017. PMID- 30413157 TI - Impaired growth in rural Gambian infants exposed to aflatoxin: a prospective cohort study. AB - BACKGROUND: Exposure to aflatoxin, a mycotoxin produced by fungi that commonly contaminates cereal crops across sub-Saharan Africa, has been associated with impaired child growth. We investigated the impact of aflatoxin exposure on the growth of Gambian infants from birth to two years of age, and the impact on insulin-like growth factor (IGF)-axis proteins. METHODS: A subsample (N = 374) of infants from the Early Nutrition and Immune Development (ENID) trial (ISRCTN49285450) were included in this study. Aflatoxin-albumin adducts (AF-alb) were measured in blood collected from infants at 6, 12 and 18 months of age. IGF 1 and IGFBP-3 were measured in blood collected at 12 and 18 months. Anthropometric measurements taken at 6, 12, 18 and 24 months of age were converted to z-scores against the WHO reference. The relationship between aflatoxin exposure and growth was analysed using multi-level modelling. RESULTS: Inverse relationships were observed between lnAF-alb and length-for-age (LAZ), weight-for-age (WAZ), and weight-for-length (WLZ) z-scores from 6 to 18 months of age (beta = - 0.04, P = 0.015; beta = - 0.05, P = 0.003; beta = - 0.06, P = 0.007; respectively). There was an inverse relationship between lnAF-alb at 6 months and change in WLZ between 6 and 12 months (beta = - 0.01; P = 0.013). LnAF alb at 12 months was associated with changes in LAZ and infant length between 12 and 18 months of age (beta = - 0.01, P = 0.003; beta = - 0.003, P = 0.02; respectively). LnAF-alb at 6 months was associated with IGFBP-3 at 12 months (r = - 0.12; P = 0.043). CONCLUSIONS: This study found a small but significant effect of aflatoxin exposure on the growth of Gambian infants. This relationship is not apparently explained by aflatoxin induced changes in the IGF-axis. PMID- 30413159 TI - Admissions and surgery as indicators of hospital functions in Sierra Leone during the west-African Ebola outbreak. AB - BACKGROUND: In an attempt to assess the effects of the Ebola viral disease (EVD) on hospital functions in Sierra Leone, the aim of this study was to evaluate changes in provisions of surgery and non-Ebola admissions during the first year of the EVD outbreak. METHODS: All hospitals in Sierra Leone known to perform inpatient surgery were assessed for non-Ebola admissions, volume of surgery, caesarean deliveries and inguinal hernia repairs between January 2014 and May 2015, which was a total of 72 weeks. Accumulated weekly data were gathered from readily available hospital records at bi-weekly visits during the peak of the outbreak from September 2014 to May 2015. The Mann-Whitney U test was used to compare weekly median admissions during the first year of the EVD outbreak, with the 20 weeks before the outbreak, and weekly median volume of surgeries performed during the first year of the EVD outbreak with identical weeks of 2012. The manuscript is prepared according to the STROBE checklist for cross-sectional studies. RESULTS: Of the 42 hospitals identified, 40 had available data for 94% (2719/2880) of the weeks. There was a 51% decrease in weekly median non-Ebola admissions and 41% fewer weekly median surgeries performed compared with the 20 weeks before the outbreak (admission) and 2012 (volume of surgery). Governmental hospitals experienced a smaller reduction in non-Ebola admissions (45% versus 60%) and surgeries (31% versus 53%) compared to private non-profit hospitals. Governmental hospitals realized an increased volume of cesarean deliveries by 45% during the EVD outbreak, thereby absorbing the 43% reduction observed in the private non-profit hospitals. CONCLUSIONS: Both non-Ebola admissions and surgeries were severely reduced during the EVD outbreak. In addition to responding to the EVD outbreak, governmental hospitals were able to maintain certain core health systems functions. Volume of surgery is a promising indicator of hospital functions that should be further explored. PMID- 30413160 TI - Partial reduction of microglia does not affect tau pathology in aged mice. AB - BACKGROUND: Activation of inflammation pathways in the brain occurs in Alzheimer's disease and may contribute to the accumulation and spread of pathological proteins including tau. The goal of this study was to identify how changes in microglia, a key inflammatory cell type, may contribute to tau protein accumulation and pathology-associated changes in immune and non-immune cell processes such as neuronal degeneration, astrocyte physiology, cytokine expression, and blood vessel morphology. METHODS: We used PLX3397 (290 mg/kg), a colony-stimulating factor receptor 1 (CSF1R) inhibitor, to reduce the number of microglia in the brains of a tau-overexpressing mouse model. Mice were fed PLX3397 in chow or a control diet for 3 months beginning at 12 months of age and then were subsequently analyzed for changes in blood vessel morphology by in vivo two-photon microscopy and tissues were collected for biochemistry and histology. RESULTS: PLX3397 reduced microglial numbers by 30% regardless of genotype compared to control diet-treated mice. No change in tau burden, cortical atrophy, blood vessels, or astrocyte activation was detected. All Tg4510 mice were observed to have an increased in "disease-associated" microglial gene expression, but PLX3397 treatment did not reduce expression of these genes. Surprisingly, PLX3397 treatment resulted in upregulation of CD68 and Tgf1beta. CONCLUSIONS: Manipulating microglial activity may not be an effective strategy to combat tau pathological lesions. Higher doses of PLX3397 may be required or earlier intervention in the disease course. Overall, this indicates a need for a better understanding of specific microglial changes and their relation to the disease process. PMID- 30413158 TI - Therapeutic potential of products derived from mesenchymal stem/stromal cells in pulmonary disease. AB - Multipotent mesenchymal stem/stromal cells (MSCs) possess robust self-renewal characteristics and the ability to differentiate into tissue-specific cells. Their therapeutic potential appears promising as evident from their efficacy in several animal models of pulmonary disorders as well as early-phase clinical trials of acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD). Such therapeutic efficacy might be attributed to MSC derived products (the "secretome"), namely conditioned media (CM) and extracellular vesicles (EVs), which have been shown to play pivotal roles in the regenerative function of MSCs. Importantly, the EVs secreted by MSCs can transfer a variety of bioactive factors to modulate the function of recipient cells via various mechanisms, including ligand-receptor interactions, direct membrane fusion, endocytosis, or phagocytosis.Herein, we review the current state-of-the science of MSC-derived CM and EVs as potential therapeutic agents in lung diseases. We suggest that the MSC-derived secretome might be an appropriate therapeutic agent for treating aggressive pulmonary disorders because of biological and logistical advantages over live cell therapy. Nonetheless, further studies are warranted to elucidate the safety and efficacy of these components in combating pulmonary diseases. PMID- 30413161 TI - Significance of intrinsic breast cancer subtypes on the long-term prognosis after neoadjuvant chemotherapy. AB - BACKGROUND: The prognosis of breast cancer and the treatment response to neoadjuvant chemotherapy (NAC) differ depending on the intrinsic molecular subtypes. We evaluated the prognostic significance of immunohistological subtypes in patients with recurrent breast cancer after treatment with NAC and surgery. METHODS: A total of 237 patients with breast cancer treated with NAC and subsequent curative surgery between 2007 and 2015 were analyzed. The correlation between intrinsic molecular subtypes and clinicopathological features, prognosis, and pathological complete response (pCR) rate of NAC were investigated retrospectively. RESULTS: There were 55 (23.2%) patients with recurrence after surgery. No significant difference in post-recurrence survival (PRS) was noted among the subtypes (p = 0.397). In patients with estrogen receptor-positive human epidermal growth factor receptor (HER) 2-negative (luminal) malignancy, PRS was significantly better in the pCR group than in the non-pCR group (p = 0.031). Conversely, pCR was not a significant predictor of improved PRS in patients with triple-negative breast cancer (TNBC; p = 0.329). Multivariate analysis revealed that the efficacy of NAC [hazard ratio (HR) 300.204, p < 0.001] and the initial metastasis site (HR 15.037, p = 0.005) were independent predictors for PRS in patients with luminal breast cancer, while Ki-67 (HR 51.171, p = 0.020) and the initial metastasis site (HR 13.318, p = 0.048) were independent predictors for PRS in patients with TNBC. CONCLUSIONS: The prognostic factors for each intrinsic subtype should be evaluated separately in patients with recurrent breast cancer following NAC and surgery. PMID- 30413162 TI - Comparison of patient and physician perspectives in the management of rheumatoid arthritis: results from global physician- and patient-based surveys. AB - BACKGROUND: In order to better understand the perspectives of patients and physicians regarding the treatment and management of rheumatoid arthritis (RA), we present and compare results from a patient-based and a physician-based survey developed by the RA NarRAtive advisory panel. METHODS: The RA NarRAtive initiative is directed by a global advisory panel of 39 healthcare providers and patient organization leaders from 17 countries. A survey of patients self reporting a diagnosis of RA and a physician-based survey, designed by the advisory panel, were fielded online by Harris Poll from September 2014 to April 2016, and from August 2015 to October 2015, respectively. RESULTS: We present findings from 1805 patients whose RA was primarily managed by a rheumatologist, and 1736 physicians managing patients with RA. Results confirmed that RA carries a substantial disease burden; half of the patients surveyed reported stopping participation in certain activities as a result of their disease. While 90% of physicians were satisfied with their communications with their patients regarding RA treatment, 61% of patients felt uncomfortable raising concerns or fears with their physician. Of the patients providing responses, 52% felt that improved dialogue/discussion would optimize their RA management, and 68% of physicians wished that they and their patients talked more about their RA goals and treatment. Overall, 88% of physicians agreed that patients involved in making treatment decisions tend to be more satisfied with their treatment experience. CONCLUSION: The results of these surveys highlight the impact of RA on patients, and a discrepancy between patient and physician views on communication. Further research, focused on improving patient-physician dialogue, shared goal-setting, and treatment planning, is needed. PMID- 30413163 TI - Specificity of the IgG antibody response to Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, and Plasmodium ovale MSP119 subunit proteins in multiplexed serologic assays. AB - BACKGROUND: Multiplex bead assays (MBA) that measure IgG antibodies to the carboxy-terminal 19-kDa sub-unit of the merozoite surface protein 1 (MSP119) are currently used to determine malaria seroprevalence in human populations living in areas with both stable and unstable transmission. However, the species specificities of the IgG antibody responses to the malaria MSP119 antigens have not been extensively characterized using MBA. METHODS: Recombinant Plasmodium falciparum (3D7), Plasmodium malariae (China I), Plasmodium ovale (Nigeria I), and Plasmodium vivax (Belem) MSP119 proteins were covalently coupled to beads for MBA. Threshold cut-off values for the assays were estimated using sera from US citizens with no history of foreign travel and by receiver operator characteristic curve analysis using diagnostic samples. Banked sera from experimentally infected chimpanzees, sera from humans from low transmission regions of Haiti and Cambodia (N = 12), and elutions from blood spots from humans selected from a high transmission region of Mozambique (N = 20) were used to develop an antigen competition MBA for antibody cross-reactivity studies. A sub set of samples was further characterized using antibody capture/elution MBA, IgG subclass determination, and antibody avidity measurement. RESULTS: Total IgG antibody responses in experimentally infected chimpanzees were species specific and could be completely suppressed by homologous competitor protein at a concentration of 10 MUg/ml. Eleven of 12 samples from the low transmission regions and 12 of 20 samples from the high transmission area had antibody responses that were completely species specific. For 7 additional samples, the P. falciparum MSP119 responses were species specific, but various levels of incomplete heterologous competition were observed for the non-P. falciparum assays. A pan-malaria MSP119 cross-reactive antibody response was observed in elutions of blood spots from two 20-30 years old Mozambique donors. The antibody response from one of these two donors had low avidity and skewed almost entirely to the IgG3 subclass. CONCLUSIONS: Even when P. falciparum, P. malariae, P. ovale, and P. vivax are co-endemic in a high transmission setting, most antibody responses to MSP119 antigens are species-specific and are likely indicative of previous infection history. True pan-malaria cross-reactive responses were found to occur rarely. PMID- 30413165 TI - Primary care utilization in people who experience imprisonment in Ontario, Canada: a retrospective cohort study. AB - BACKGROUND: Access to primary care is an important determinant of health, and data are sparse on primary care utilization for people who experience imprisonment. We aimed to describe primary care utilization for persons released from prison, and to compare utilization with the general population. METHODS: We linked correctional data for all persons released from provincial prison in Ontario, Canada in 2010 with health administrative data. We matched each person by age and sex with four general population controls. We compared primary care utilization rates using generalized estimating equations. We adjusted rate ratios for aggregated diagnosis groups, to explore this association independent of comorbidity. We examined the proportion of people using primary care using chi squared tests and time to first primary care visit post-release using the Kaplan Meier method. RESULTS: Compared to the general population controls, the prison release group had significantly increased relative rates of primary care utilization: at 6.1 (95% CI 5.9-6.2) in prison, 3.7 (95% CI 3.6-3.8) in the week post-release and between 2.4 and 2.6 in the two years after prison release. All rate ratios remained significantly increased after adjusting for comorbidity. In the month after release, however, 66.3% of women and 75.5% of men did not access primary care. CONCLUSIONS: Primary care utilization is high in prison and post release for people who experience imprisonment in Ontario, Canada. Increased use is only partly explained by comorbidity. The majority of people do not access primary care in the month after prison release. Future research should identify reasons for increased use and interventions to improve care access for persons who are not accessing care post-release. PMID- 30413164 TI - Juvenile idiopathic arthritis managed in the new millennium: one year outcomes of an inception cohort of Australian children. AB - BACKGROUND: The advent of new treatments for Juvenile Idiopathic Arthritis (JIA) has prompted interest in systematically studying the outcomes of patients treated in the 'modern era'. Such data provide both benchmarks for assessing local outcomes and important information for use in counselling families of newly diagnosed patients. While data are available for cohorts in Europe and North America, no such data exist for Australian patients. The aim was to examine the demographics, treatment and outcomes at 12 months of an inception cohort of newly diagnosed patients with JIA at a single tertiary referral paediatric rheumatology centre in Australia. METHODS: Retrospective review of prospectively collected data from patients newly diagnosed with JIA between 2010 and 2014 at the Royal Children's Hospital in Melbourne. RESULTS: One hundred thirty four patients were included (62% female). Oligoarthritis was the single largest category of JIA (36%) and rheumatoid factor positive polyarthritis the least common (2%). Undifferentiated JIA accounted for 13% of patients and was the third largest category. Across the cohort 94% received NSAIDs, 53% oral steroids, 62% methotrexate and 15% a biologic DMARD. Intra-articular steroids were used in 62%, most commonly in the oligoarticular subtype (94%). 95% of patients achieved a joint count of zero at a median of 4.1 months, however flares occurred in 42%. At 12 months 65% had no active joint disease, though more than half remained on medication. CONCLUSION: Australian children with JIA managed in the modern era have similar characteristics and achieve short term outcomes comparable to cohorts in Europe and North America, with high rates of joint remission in the first 12 months of follow-up but with a significant relapse rate and requirement for ongoing medication. PMID- 30413166 TI - Simvastatin attenuates tibial bone loss in rats with type 1 diabetes and periodontitis. AB - BACKGROUND: Diabetes induces long bone loss and aggravation of periodontitis induced alveolar bone loss. Simvastatin (SIM), which is a lipid-lowering agent is known to have an anabolic effect on bone. Therefore, we investigated effect of SIM on tibial and alveolar bone loss in type 1 diabetic rats with periodontitis. METHODS: Rats were divided into control (C), diabetes with periodontitis (DP), and diabetes with periodontitis treated with SIM (DPS) groups. DP and DPS groups were intravenously injected with streptozotocin (50 mg/kg), and C group was injected with citrate buffer. Seven days later (day 0), periodontitis was induced by ligatures of mandibular first molars. DP and DPS groups were orally administered vehicle or SIM (30 mg/kg) from day 0 to days 3, 10, or 20. Alveolar and tibial bone loss was measured using histological and m-CT analysis alone or in combination. Osteoclast number and sclerostin-positive osteocytes in tibiae were evaluated by tartrate-resistant acid phosphatase and immunohistochemical staining, respectively. Glucose, triglyceride (TG), cholesterol (CHO), and low density lipoprotein (LDL) were evaluated. RESULTS: Consistent with diabetes induction, the DP group showed higher glucose and TG levels at all timepoints and higher CHO levels on day 20 than C group. Compared to the DP group, the DPS group exhibited reduced levels of glucose (day 3), TG (days 10 and 20), CHO, and LDL levels (day 20). Bone loss analysis revealed that the DP group had lower bone volume fraction, bone mineral density, bone surface density, and trabecular number in tibiae than C group at all timepoints. Interestingly, the DPS group exhibited elevation of these indices at early stages compared to the DP group. The DPS group showed reduction of osteoclasts (day 3) and sclerostin-positive osteocytes (days 3 and 20) compared with the DP group. There was no difference in alveolar bone loss between DP and DPS groups. CONCLUSIONS: These results suggest that SIM attenuates tibial, but not alveolar bone loss in type 1 diabetic rats with periodontitis. Moreover, attenuation of tibial bone loss by SIM may be related to inhibition of osteoclast formation and reduction of sclerostin expression. PMID- 30413167 TI - Institutional effects on nurses' working conditions: a multi-group comparison of public and private non-profit and for-profit healthcare employers in Switzerland. AB - BACKGROUND: In response to the need for competitive recruitment of nurses resulting from the worldwide nursing shortage, employers need to attract and retain nurses by promoting their competitive strengths in their working conditions (WCS) and by addressing their competitive weaknesses. This study investigated workplace differences between public hospitals (PuHs), private for profit hospitals (PrHs), socio-medical institutions (SOMEDs), home care services (HCs), private medical offices (PrOs) and non-profit organisations (NPOs), helping to provide a foundation for competition-oriented institutional employer branding and to increase transparency in the labour market for nurses. METHODS: Data from the Swiss Nurses at Work study of the career paths of 11 232 nurses who worked in Switzerland between 1970 and 2014 were subjected to secondary analysis, assessing the effect of institutional characteristics on self-reported determinants of job satisfaction (such as WCS) using multivariate linear regression and post hoc tests with Bonferroni-adjusted significance levels. Principal component analysis was used to reduce the number of WCS in the original study. RESULTS: Nurses at PuHs and PrHs were less likely to experience autonomy, flexibility of work hours and participation in decision-making than those at other workplaces. Although PuHs were rated higher than PrHs in terms of satisfaction with salary and advancement opportunities, they were associated with more alienating work factors, such as stress and aggression. SOMED workplaces were significantly more often associated with alienating conditions and low job satisfaction, but were rated higher than the other institutions in terms of participation in decision-making. The nurses' ratings implied that PrO workplaces were more likely to offer a mild work environment, social support and recognition than other institutions, but that advancement opportunities were limited. NPO workplaces were associated with the highest degree of autonomy, flexibility, participation, recognition, organisational commitment and job satisfaction. In these respects, HC and NPO workplaces received similar ratings, although the HC workplaces were associated with a significantly lower organisational commitment and significantly lower job satisfaction. CONCLUSIONS: Due to their structural characteristics, NPOs, SOMEDs and HCs can attract nurses seeking greater self determination, PuHs can attract career-oriented nurses, and PrOs and PrHs are likely to attract nurses through offering less-stressful working conditions. PMID- 30413168 TI - Four-year review of presenteeism data among employees of a large United States health care system: a retrospective prevalence study. AB - BACKGROUND: Historically, in an effort to evaluate and manage the rising cost of healthcare employers assess the direct cost burden via medical health claims and measures that yield clear data. Health related indirect costs are harder to measure and are often left out of the comprehensive overview of health expenses to an employer. Presenteeism, which is commonly referred to as an employee at work who has impaired productivity due to health considerations, has been identified as an indirect but relevant factor influencing productivity and human capitol. The current study evaluated presenteeism among employees of a large United States health care system that operates in six locations over a four-year period and estimated loss productivity due to poor health and its potential economic burden. METHODS: The Health-Related Productivity Loss Instrument (HPLI) was included as part of an online Health Risk Appraisal (HRA) administered to employees of a large United States health care system across six locations. A total of 58 299 HRAs from 22 893 employees were completed and analyzed; 7959 employees completed the HRA each year for 4 years. The prevalence of 22 specific health conditions and their effects on productivity areas (quantity of work, quality of work, work not done, and concentration) were measured. The estimated daily productivity loss per person, annual cost per person, and annual company costs were calculated for each condition by fitting marginal models using generalized estimating equations. Intra-participant agreement in reported productivity loss across time was evaluated using kappa statistics for each condition. RESULTS: The health conditions rated highest in prevalence were allergies and hypertension (high blood pressure). The conditions with the highest estimated daily productivity loss and annual cost per person were chronic back pain, mental illness, general anxiety, migraines or severe headaches, neck pain, and depression. Allergies and migraines or severe headaches had the highest estimated annual company cost. Most health conditions had at least fair intra participant agreement (kappa >= 0.40) on reported daily productivity loss. CONCLUSIONS: Results from the current study suggested a variety of health conditions contributed to daily productivity loss and resulted in additional annual estimated costs for the health care system. To improve the productivity and well-being of their workforce, employers should consider presenteeism data when planning comprehensive wellness initiatives to curb productivity loss and increase employee health and well-being during working hours. PMID- 30413169 TI - A comparative study of catastrophic health expenditure in Zhejiang and Qinghai province, China. AB - BACKGROUND: China has made great achievements in health insurance coverage and healthcare financing; however, the rate of catastrophic health expenditure (CHE) was 13.0% in China in 2008, which is higher than that in some other countries. There remain some differences in life-style, national customs, medical conditions, and health consciousness in different provinces in China. This study aimed to compare the rates of households with CHE, further to explore the different performance of factors influencing CHE between Zhejiang and Qinghai province, China. METHODS: Data were derived from the household surveys conducted in Zhejiang and Qinghai. Sampling on multi-stage stratified cluster random method was adopted. Household with CHE occurs when the out-of-pocket payment for health care equals to or exceeds 40% of a household's income. Univariate and multivariate logistic regression analyses were used to identify the performance of factors of CHE. RESULTS: A total of 1598 households were included in this study, including 995 in Zhejiang and 603 in Qinghai. The average rates of CHE in Zhejiang and Qinghai were 9.6 and 30.5%, respectively. We found that economic status of households and households headed by an employed person are the protective factors for CHE; and number of members with chronic diseases and number of inpatients in household are the risk factors for CHE in the two provinces. Besides, poor/low-insured households in Zhejiang; and households having outpatients and households headed by a minority person in Qinghai are more likely to experience the risk of CHE. CONCLUSIONS: This study highlights the importance of improving economic development, expanding employment, and adjusting policies to make greater efforts to protect chronic diseases patients, outpatients, and inpatients, further to reduce the risk of CHE. The Chinese government should pay more attention to the actual conditions in different provinces, further to make policy decisions according to the local knowledge. PMID- 30413170 TI - Vegetables and legumes in new Australasian food launches: how are they being used and are they a healthy choice? AB - BACKGROUND: Despite the health benefits of regular vegetable and legume consumption, on average Australians are consuming only half of the recommended daily intake. The reasons for this low consumption are complex, and are particularly driven by societal shifts towards convenient and ready-to-eat meal options. It is currently unknown how legumes and vegetables are being utilised in food products within the Australian context, and the nutritional value or level of processing of these products. METHODS: The Mintel Global New Food Database was used to identify all new products launched between May 2012 and May 2017 in Australasia which at least 0.5 serves of vegetables and/or legumes per recommended serving. Eligible products were coded using the NOVA food classification system and the Healthy Choices guidelines, and were categorized by the researchers based on the type and proportion of vegetable and legume ingredients used. RESULTS: Overall, 1313 products were identified, which contained a median of 55% vegetable and legume ingredients (IQR = 45%). This translated to approximately 1 (IQR = 1) serves of vegetables and legumes per recommended serving of the products. The product launches were most likely to be classified as an 'amber' choice, and be classified as either 'processed' or 'ultra-processed'. Vegetables and legumes were mainly found in the form of new prepared meals, soups or whole vegetables products, however there were some more innovative uses of these ingredients, such as yoghurts and pastas. CONCLUSIONS: Most of the new products currently released onto the Australian market which contain vegetable and legume ingredients do not provide meaningful amounts of these ingredients, and tend to be highly processed and unhealthier options. A multi-faceted approach is needed to improve vegetable and legume consumption, which includes improving the availability of products which help consumers to meet vegetable and legume consumption recommendations. Future research should consider the acceptability of these products to consumers, and the barriers for food manufacturers in creating products with a higher amount of vegetables and legumes. PMID- 30413171 TI - Associations between ambient air temperature, low birth weight and small for gestational age in term neonates in southern Israel. AB - BACKGROUND: The increase in ambient temperatures (Ta) and emissions of greenhouse gases over the last century has focused attention on the effects of ambient temperatures on health outcomes. We aimed to investigate the association between Ta and the clinical measures of term low birth weight (tLBW) and small for gestational age (SGA) in singleton term infants using a decade of regional hospital data in southern Israel. METHODS: We linked all births in Soroka University Medical Center in the southern district of Israel insured by Clalit Health Services with pregnancy Ta estimated by our novel hybrid spatio-temporally resolved prediction model. Logistic regression generalized additive models and general linear models were used, with either tLBW or SGA as the dependent variable, modeling entire pregnancy and trimester-specific Ta adjusting for seasonality, time trend, particulate matter, maternal age, gravidity, parity, ethnicity, sex, poverty index and population density. RESULTS: The study population included 56,141 singleton term newborns, with 1716 (3.1%) cases of tLBW and 8634 (15.4%) cases of SGA. The average and the median Ta across the entire pregnancy were 19.9 (SD: 1.77, range: 14.6-24.9) degrees centigrade. The lowest Ta quartile (Ta = < 18.5) was associated with higher risk of tLBW (odds ratio = 1.33, 95%CI 1.11-1.58) while the highest Ta quartile (Ta > =21.3) was not significantly associated with tLBW (odds ratio = 1.17, 95%CI 0.99-1.38), in comparison to the two intermediate quartiles. When analyzing SGA as the dependent variable, the lowest Ta quartile was associated with significantly higher risk of SGA (odds ratio = 1.18, 95%CI 1.09-1.29) while the highest quartile was associated with significantly lower risk of SGA (odds ratio = 0.91, 95%CI 0.84 0.99) in comparison to the two intermediate quartiles. CONCLUSIONS: Our findings suggest that lower pregnancy Ta may increase the risk of tLBW and SGA, and higher pregnancy Ta may decrease the risk of SGA in singleton term infants in southern Israel. PMID- 30413172 TI - Age-related deregulation of TDP-43 after stroke enhances NF-kappaB-mediated inflammation and neuronal damage. AB - BACKGROUND: TDP-43 has been identified as a disease-associated protein in several chronic neurodegenerative disorders and increasing evidence suggests its potentially pathogenic role following brain injuries. Normally expressed in nucleus, under pathological conditions TDP-43 forms cytoplasmic ubiquitinated inclusions in which it is abnormally phosphorylated and cleaved to generate a 35 and a 25 kDa C-terminal fragments. In the present study, we investigated age related expression patterns of TDP-43 in neurons and glia and its role as modulator of inflammation following ischemic injury. METHODS: Wild-type and TDP 43 transgenic mice of different age groups were subjected to transient middle cerebral artery occlusion. The role of TDP-43 in modulation of inflammation was assessed using immunofluorescence, Western blot analysis, and in vivo bioluminescence imaging. Finally, post-mortem stroke human brain sections were analyzed for TDP-43 protein by immunohistochemistry. RESULTS: We report here an age-related increase and formation of ubiquitinated TDP-43 cytoplasmic inclusions after stroke. The observed deregulation in TDP-43 expression patterns was associated with an increase in microglial activation and innate immune signaling as revealed by in vivo bioluminescence imaging and immunofluorescence analysis. The presence of ubiquitinated TDP-43 aggregates and its cleaved TDP-35 and TDP-25 fragments was markedly increased in older, 12-month-old mice leading to larger infarctions and a significant increase in in neuronal death. Importantly, unlike the hallmark neuropathological features associated with chronic neurodegenerative disorders, the TDP-43-positive cytoplasmic inclusions detected after stroke were not phosphorylated. Next, we showed that an increase and/or overexpression of the cytoplasmic TDP-43 drives the pathogenic NF-kappaB response and further increases levels of pro-inflammatory markers and ischemic injury after stroke in age dependent manner. Finally, analyses of the post-mortem stroke brain tissues revealed the presence of the cytoplasmic TDP-43 immunoreactive structures after human stroke. CONCLUSION: Together, our findings suggest that the level of cytoplasmic TDP-43 increases with aging and may act as an age-related mediator of inflammation and neuronal injury after stroke. Thus, targeting cytoplasmic TDP-43 may have a therapeutic potential after stroke. PMID- 30413174 TI - Detection of gastric cancer and its histological type based on iodine concentration in spectral CT. AB - BACKGROUND: Computed tomography (CT) imaging is the most common imaging modality for the diagnosis and staging of gastric cancer. The aim of this study is was to prospectively explore the ability of quantitative spectral CT parameters in the detection of gastric cancer and its histologic types. METHODS: A total of 87 gastric adenocarcinoma (43 poorly and 44 well-differentiated) patients and 36 patients with benign gastric wall lesions (25 inflammation and 11 normal), who underwent dual-phase enhanced spectral CT examination, were retrospectively enrolled in this study. Iodine concentration (IC) and normalized iodine concentration (nIC) during arterial phase (AP) and portal venous phase (PP) were measured thrice in each patient by two blinded radiologists. Moreover, intraclass correlation coefficient (ICC) was used to assess the interobserver reproducibility. Differences of IC and nIC values between gastric cancer and benign lesion groups were compared using Mann-Whitney U test. Furthermore, the gender, age, location, thickness and histological types of gastric adenocarcinoma were analyzed by Mann-Whitney U test or Kruskal-Wallis H test. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic efficacy of IC and nIC values, and the optimal cut-off value was calculated with Youden J. RESULTS: An excellent interobserver agreement (ICC > 0.6) was achieved for IC. Notably, the values of ICAP, ICPP, nICAP and nICPP were significantly higher in gastric cancer group (Z = 5.870, 3.894, 2.009 and 10.137, respectively; P < 0.05) than those in benign lesion group. Additionally, the values of ICAP, ICPP, nICAP and nICPP were significantly higher in poorly differentiated gastric adenocarcinoma group (Z = 4.118, 5.637, 6.729 and 2.950, respectively; P < 0.005) than those in well-differentiated gastric adenocarcinoma group. There were no statistically significant differences in the values of ICAP, ICPP, nICAP and nICPP between age, gender, tumor thickness and tumor location. Furthermore, the area under the curve (AUC) values of ICAP, nICAP, ICPP and nICPP were 0.745, 0.584, 0.662, and 0.932, respectively, for gastric cancer detection; while 0.756, 0.919, 0.851 and 0.684, respectively, in discriminating poorly differentiated gastric adenocarcinoma. CONCLUSION: IC values exhibited great potential in the preoperative and non-invasive diagnosis of gastric cancer and its histological types. In particular, nICPP is more effective for the identification of gastric cancer, whereas nICAP is more effective in discriminating poorly differentiated gastric adenocarcinoma. PMID- 30413173 TI - Two histologically colorectal carcinomas subsets from the serrated pathway show different methylome signatures and diagnostic biomarkers. AB - BACKGROUND: Altered methylation patterns are driving forces in colorectal carcinogenesis. The serrated adenocarcinoma (SAC) and sporadic colorectal carcinoma showing histological and molecular features of microsatellite instability (hmMSI-H) are two endpoints of the so-called serrated pathological route sharing some characteristics but displaying a totally different immune response and clinical outcome. However, there are no studies comparing the methylome of these two subtypes of colorectal carcinomas. The methylation status of 450,000 CpG sites using the Infinium Human Methylation 450 BeadChip array was investigated in 48 colorectal specimens, including 39 SACs and 9 matched hmMSI-H. RESULTS: Microarray data comparing SAC and hmMSI-H showed an enrichment in functions related to morphogenesis, neurogenesis, cytoskeleton, metabolism, vesicle transport and immune response and also significant differential methylation of 1540 genes, including CD14 and HLA-DOA which were more methylated in hmMSI-H than in SAC and subsequently validated at the CpG, mRNA and protein level using pyrosequencing, quantitative polymerase chain reaction (qPCR) and immunohistochemistry. CONCLUSIONS: These results demonstrate particular epigenetic regulation patterns in SAC which may help to define key molecules responsible for the characteristic weak immune response of SAC and identify potential targets for treating SAC, which lacks molecular targeted therapy. PMID- 30413175 TI - Early endothelial progenitor cells and vascular stiffness in psoriasis and psoriatic arthritis. AB - BACKGROUND: Both psoriasis (Ps) and psoriasis arthritis (PsA) have been associated with increased cardiovascular risk. Also, both are characterized by increased neovascularization. Endothelial progenitor cells (EPCs) have been implicated in promoting vascular repair in ischemic diseases. The aim of the study was to correlate the EPC system with CV risk factors and with parameters of vascular stiffness in Ps and PsA. METHODS: Twenty-six healthy subjects, 30 patients with Ps, and 31 patients PsA were included in the study. eEPC regeneration was evaluated by a colony-forming assay, circulating eEPCs were measured by cytometric analysis. For vascular analysis, all subjects underwent quantification of pulse wave velocity (PWV) and augmentation index (AIX). RESULTS: Patients were categorized upon the duration of disease, severity of skin involvement (PASI-Ps), individual pain as reflected by the VAS (PsA), CRP values, and history of treatment with one or more biologicals. Regarding the eEPC system, no significant differences were observed between the respective categories. Correlation analyses between parameters of vascular stiffness (PWV and AIX) and patterns of colony formation/circulating eEPCs did not show any correlation at all. CONCLUSION: Parameters of vascular stiffness are not significantly deteriorated in Ps/PsA. Thus, pulse wave analysis may not be suitable for CVR assessment in certain autoimmune-mediated diseases. Regenerative activity of the eEPC system/circulating eEPC numbers are not altered in Ps/PsA. One may conclude that malfunctions of the eEPC are not substantially involved in perpetuating the micro-/macrovascular alterations in Ps/PsA. PMID- 30413176 TI - A recommender system to quit smoking with mobile motivational messages: study protocol for a randomized controlled trial. AB - BACKGROUND: Smoking cessation is the most common preventative for an array of diseases, including lung cancer and chronic obstructive pulmonary disease. Although there are many efforts advocating for smoking cessation, smoking is still highly prevalent. For instance, in the USA in 2015, 50% of all smokers attempted to quit smoking, and only 5-7% of them succeeded - with slight deviation depending on external assistance. Previous studies show that computer tailored messages which support smoking abstinence are effective. The combination of health recommender systems and behavioral-change theories is becoming increasingly popular in computer-tailoring. The objective of this study is to evaluate patients's smoking cessation rates by means of two randomized controlled trials using computer-tailored motivational messages. A group of 100 patients will be recruited in medical centers in Taiwan (50 patients in the intervention group, and 50 patients in the control group), and a group of 1000 patients will be recruited on-line (500 patients in the intervention group, and 500 patients in the control group). The collected data will be made available to the public in an open-source data portal. METHODS: Our study will gather data from two sources. The first source is a clinical pilot in which a group of patients from two Taiwanese medical centers will be randomly assigned to either an intervention or a control group. The intervention group will be provided with a mobile app that sends motivational messages selected by a recommender system that takes the user profile (including gender, age, motivations, and social context) and similar users' opinions. For 6 months, the patients' smoking activity will be followed up, and confirmed as "smoke-free" by using a test that measures expired carbon monoxide and urinary cotinine levels. The second source will be a public pilot in which Internet users wanting to quit smoking will be able to download the same mobile app as used in the clinical pilot. They will be randomly assigned to a control group that receives basic motivational messages or to an intervention group, that receives personalized messages by the recommender system. For 6 months, patients in the public pilot will be assessed periodically with self reported questionnaires. DISCUSSION: This study will be the first to use the I Change behavioral-change model in combination with a health recommender system and will, therefore, provide relevant insights into computer-tailoring for smoking cessation. If our hypothesis is validated, clinical practice for smoking cessation would benefit from the use of our mobile solution. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03108651 . Registered on 11 April 2017. PMID- 30413177 TI - Giant nonfunctioning adrenal tumors: two case reports and review of the literature. AB - BACKGROUND: There are an estimated 1-2 cases per million per year of adrenocortical carcinoma in the USA. It represents a rare and aggressive malignancy; it is the second most aggressive endocrine malignant disease after anaplastic thyroid carcinoma. Non-secretory adrenal masses are diagnosed late due to a mass effect or metastatic disease or found incidentally (adrenal incidentalomas). CASE PRESENTATION: The first case report describes a 39-year-old Greek woman who presented to our department with complaints of repeated symptoms of flatulence and epigastric discomfort over a few months. The second case report is about a 67-year-old Greek woman who presented to our department after being evaluated for fatigue, mass effect, and epigastric discomfort. Both of them were diagnosed as having a nonfunctioning adrenocortical carcinoma and underwent open adrenalectomy. CONCLUSIONS: Approximately 60% of patients with adrenocortical carcinoma present with symptoms and signs of hormonal secretion. Our cases' adrenocortical carcinomas were not functional. Hormone secretion is not a discriminating feature between benign and malignant adrenocortical masses. The silent clinical nature of nonfunctioning adrenocortical carcinoma results in late diagnosis, while the majority of patients present with locally advanced and/or metastatic disease. Adrenocortical carcinoma is a rare endocrine tumor with a poor prognosis that can be diagnostically challenging and demands high clinical suspicion. The work-up for adrenal masses must include determination of whether the mass is functioning or nonfunctioning and whether it is benign or malignant. PMID- 30413178 TI - Combination therapy of human bone marrow-derived mesenchymal stem cells and minocycline improves neuronal function in a rat middle cerebral artery occlusion model. AB - BACKGROUND: The positive effects of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) and minocycline on ischemic stroke models have been well described through numerous studies. The aim of this study was to evaluate the effectiveness of combination therapy of hBM-MSCs with minocycline in a middle cerebral artery occlusion rat model. METHODS: Forty male Sprague-Dawley rats were enrolled in this study. After right middle cerebral artery occlusion, rats were randomly assigned to one of four groups: control, minocycline, hBM-MSCs, or hBM MSCs with minocycline. Rotarod test, adhesive-removal test, and modified neurological severity score grading were performed before and 1, 7, 14, 21, and 28 days after right middle cerebral artery occlusion. All rats were sacrificed at day 28. The volume of the infarcted area was measured with triphenyl tetrazolium chloride staining. Neuronal nuclear antigen (NeuN)- and vascular endothelial growth factor (VEGF)-positive cells in the ischemic boundary zone were assessed by immunofluorescence. RESULTS: Neurological outcome in the adhesive-removal test and rotarod test and modified neurological severity score were better in the combination therapy group than in the monotherapy and control groups. The volume of the infarcted area was smaller in the combination group compared with the others. The proportions of NeuN- and VEGF-positive cells in the ischemic boundary were highest in the combination therapy group. CONCLUSIONS: Early combination therapy of hBM-MSCs with minocycline in an ischemic stroke model may enhance neurological recovery, reduce the volume of the infarcted area, and promote the expression of NeuN and VEGF in ischemic boundary cells. PMID- 30413179 TI - Tropism of mesenchymal stem cell toward CD133+ stem cell of glioblastoma in vitro and promote tumor proliferation in vivo. AB - BACKGROUND: Previous studies have demonstrated remarkable tropism of mesenchymal stem cells (MSCs) toward malignant gliomas, making these cells a potential vehicle for delivery of therapeutic agents to disseminated glioblastoma (GBM) cells. However, the potential contribution of MSCs to tumor progression is a matter of concern. It has been suggested that CD133+ GBM stem cells secrete a variety of chemokines, including monocytes chemoattractant protein-1 (MCP-1/CCL2) and stromal cell-derived factor-1(SDF-1/CXCL12), which could act in this tropism. However, the role in the modulation of this tropism of the subpopulation of CD133+ cells, which initiate GBM and the mechanisms underlying the tropism of MSCs to CD133+ GBM cells and their effects on tumor development, remains poorly defined. METHODS/RESULTS: We found that isolated and cultured MSCs (human umbilical cord blood MSCs) express CCR2 and CXCR4, the respective receptors for MCP-1/CCL2 and SDF-1/CXCL12, and demonstrated, in vitro, that MCP-1/CCL2 and SDF 1/CXC12, secreted by CD133+ GBM cells from primary cell cultures, induce the migration of MSCs. In addition, we confirmed that after in vivo GBM tumor establishment, by stereotaxic implantation of the CD133+ GBM cells labeled with Qdots (705 nm), MSCs labeled with multimodal iron oxide nanoparticles (MION) conjugated to rhodamine-B (Rh-B) (MION-Rh), infused by caudal vein, were able to cross the blood-brain barrier of the animal and migrate to the tumor region. Evaluation GBM tumors histology showed that groups that received MSC demonstrated tumor development, glial invasiveness, and detection of a high number of cycling cells. CONCLUSIONS: Therefore, in this study, we validated the chemotactic effect of MCP-1/CCL2 and SDF-1/CXCL12 in mediating the migration of MSCs toward CD133+ GBM cells. However, we observed that, after infiltrating the tumor, MSCs promote tumor growth in vivo probably by release of exosomes. Thus, the use of these cells as a therapeutic carrier strategy to target GBM cells must be approached with caution. PMID- 30413180 TI - 3,3'-Diindolylmethane protects cardiomyocytes from LPS-induced inflammatory response and apoptosis. AB - BACKGROUND: 3,3'-Diindolylmethane (DIM) has been extensively studied as a potential therapeutic drug with free radical scavenging, antioxidant and anti angiogenic effects. However, whether DIM has similar effects on cardiomyocytes remains unknown. Here we evaluated DIM's influence on inflammation and apoptosis of H9C2 cardiomyocytes induced by LPS and to explore the possible mechanism of the effects. METHODS: H9C2 cells were incubated with DIM (10, 20 and 30 MUM) with or without LPS for 24 h. The cytotoxicity of DIM was detected by CCK-8. The levels of tumour necrosis factor (TNF)-alpha and interleukin (IL)-6 were then measured using RT-qPCR and ELISA. Cell apoptosis rate and reactive oxygen species (ROS) content after DIM treatment were measured by flow cytometry. Expressions of NFkappaB, P-NFkappaB, IkappaBa, P-IkappaBa, Bax and Bcl-2 after DIM treatment were detected by western blot. The rate of NFkappaB nuclear translocation after DIM treatment was determined by immunocytochemical analysis. RESULTS: LPS stimulation promoted TNF-alpha and IL-6 mRNA expression. After treatment with various concentrations of DIM (10, 20 and 30 MUM), TNF-alpha and IL-6 mRNA expression was clearly impaired, especially in the LPS + DIM30(MUM) group. ELISA was used to measure TNF-alpha and IL-6 concentrations in cellular supernatant, and the result was verified to be consistent with RT-qPCR. Additionally, DIM treatment significantly blocked LPS-induced oxidative stress and inhibited LPS induced apoptosis in H9C2 cardiomyocytes according to the results detected by flow cytometry. Moreover, compared with LPS alone, DIM significantly inhibited the LPS-induced phosphorylation of NFkappaB (p-NFkappaB) and Bax expression and increased Bcl-2 expression. CONCLUSIONS: DIM may have a protective effect for H9C2 cardiomyocytes against LPS-induced inflammatory response and apoptosis. DIM may be a new insight into the treatment of septic cardiomyopathy. PMID- 30413181 TI - ALternatives To prophylactic Antibiotics for the treatment of Recurrent urinary tract infection in women (ALTAR): study protocol for a multicentre, pragmatic, patient-randomised, non-inferiority trial. AB - BACKGROUND: At least half of all adult women will experience infective cystitis (urinary tract infection: UTI) at least once in their life and many suffer from repeated episodes. Recurrent urinary tract infection (rUTI) in adult women is usually treated with long-term, low-dose antibiotics and current national and international guidelines recommend this as the 'gold standard' preventative treatment. Although they are reasonably effective, long-term antibiotics can result in bacteria becoming resistant not only to the prescribed antibiotic but to other antimicrobial agents. The problem of antimicrobial resistance is recognised as a global threat and the recent drive for antibiotic stewardship has emphasised the need for careful consideration prior to prescribing antibiotics. This has led clinicians and patients alike to explore potential non-antibiotic options for recurrent UTI prevention. DESIGN /METHODS: This is a multicentre, pragmatic, patient-randomised, non-inferiority trial comparing a non-antibiotic preventative treatment for rUTI in women, methenamine hippurate, against the current standard of daily low-dose antibiotics. Women who require preventative treatment for rUTI are the target population. This group is comprised of those with a diagnosis of rUTI, defined as three episodes in 1 year or two episodes in 6 months, and those with a single severe infection requiring hospitalisation. Participants will be recruited from secondary care urology / urogynaecology departments in the UK following referral with rUTI. Participants will be followed up during a 12-month period of treatment and in the subsequent 6 months following completion of the prophylactic medication. Outcomes will be assessed from patient recorded symptoms, quality of life questionnaires and microbiological examination of urine and perineal swabs. The primary outcome is the incidence of symptomatic antibiotic-treated UTI self-reported by participants during the 12-month period of preventative treatment. Health economic outcomes will also be assessed to define the cost-effectiveness of both treatments. A qualitative study will be conducted in the first 8 months of the trial to explore with participants/non participants' and recruiting clinicians' views on trial processes and identify potential barriers to recruitment, reasons for participating and non participation and for dropping out of the study. DISCUSSION: The study was commissioned and funded by the National Institute for Health Research (NIHR) and approved under the Medicines and Healthcare products Regulatory Agency (MHRA) notification scheme as a 'Type A' study. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN), registry number: ISRCTN70219762 . Registered on 31 May 2016. PMID- 30413182 TI - Fractal properties and morphological investigation of Nano hydrochlorothiazide is used to treat hypertension. AB - PURPOSE: High blood pressure (hypertension) is a relatively common condition that increases blood pressure in the arteries abnormally, causing problems such as heart disease and stroke. Blood pressure is a force that is felt through the walls of the blood vessels and has a direct relationship to the power of pumping the heart and vascular resistance to the blood flow. One of the lowing of blood pressure medications is hydrochlorothiazide (Hctz) which is used to treat high blood pressure and swelling from heart failure, liver damage, and other minor actions. PROCEDURES: This study explains the effectiveness of Hctz with the help of "fractal dimension". To perfect investigate the fractal dimension, we used the Hctz drug nanoparticle form then using MATLAB software, homogeneity levels or heterogeneity of Nano Hctz using SEM images were computed. RESULTS: We calculated histogram plot with SEM image by MATLAB software which that its standard deviation was eclose to zero and it can explain that the scattering of data is low and their amount is in one suffering. Fractal dimensions obtained from Matlab and SPSS software for normal distribution, correlation, standard deviation, mean, cumulative frequency and variance analysis were analyzed. CONCLUSIONS: In this research, the association between Hctz treatment effects with the point of view of the fractal dimension of the drug was demonstrated to prove the properties of the drug in the body. in the near future, drug fractal studies can improve the development of new drugs and treatments with minimal cost than clinical approaches by linking chemistry, mathematical sciences and pharmaceutical sciences. PMID- 30413184 TI - RIVA - a phase IIa study of rituximab and varlilumab in relapsed or refractory B cell malignancies: study protocol for a randomized controlled trial. AB - BACKGROUND: Over 12,000 new cases of B-cell malignancies are diagnosed in the UK each year, with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) being the most common subtypes. Standard frontline therapy consists of immunochemotherapy with a CD20 monoclonal antibody (mAb), such as rituximab, delivered in combination with multi-agent chemotherapy. Despite being considered a treatable and potentially curable cancer, approximately 30% of DLBCL cases will relapse after frontline therapy. Advanced stage FL is incurable and typically has a relapsing and remitting course with a frequent need for re-treatment. Based on supportive preclinical data, we hypothesised that the addition of varlilumab (an anti-CD27 mAb) to rituximab (an anti-CD20 mAb) can improve the rate, depth and duration of the response of rituximab monotherapy in patients with relapsed or refractory B-cell malignancies. METHODS/DESIGN: Combination treatment of varlilumab plus rituximab, in two different dosing regimens, is being tested in the RIVA trial. RIVA is a two-stage open-label randomised phase IIa design in up to 40 patients with low- or high-grade relapsed or refractory CD20+ B-cell lymphoma. The study is open to recruitment in the UK. Enrolled patients are randomised 1:1 to two different experimental varlilumab to rituximab combinations. The primary objective is to determine the safety and tolerability of the combination and the anti-tumour activity (response) in relapsed or refractory B-cell malignancies. Secondary objectives will include an evaluation of the duration of the response and overall survival. Tertiary translational objectives include assessment of B-cell depletion, changes in immune effector cell populations, expression of CD27 as a biomarker of response and pharmacokinetic properties. Analyses will not be powered for formal statistical comparisons between treatment arms. DISCUSSION: RIVA will determine whether the combination of rituximab and varlilumab in relapsed or refractory B-cell malignancies is active and safe prior to future phase II/III trials. TRIAL REGISTRATION: EudraCT, 2017-000302-37. Registered on 16 January 2017. ISRCTN, ISRCTN15025004 . Registered on 16 August 2017. PMID- 30413185 TI - Riboflavin and pyridoxine restore dopamine levels and reduce oxidative stress in brain of rats. AB - BACKGROUND: Neurological disorders suggest that the excitotoxicity involves a drastic increase in intracellular Ca2+ concentrations and the formation of reactive oxygen species. The presence of these free radicals may also affect the dopaminergic system. The aim of this work was to determine if riboflavin (B2) and pyridoxine (B6) provide protection to the brain against free radicals generated by 3-nitropropionic acid (3-NPA) by measuring the levels of dopamine (DA) and selected oxidative stress markers. METHODS: Male Fisher rats were grouped (n = 6) and treated as follows: group 1, control (NaCl 0.9%); group 2, 3-NPA (20 mg/kg); group 3, B2 (10 mg/kg); group 4, B2 (10 mg/kg) + 3-NPA (20 mg/kg); group 5, B6 (10 mg/kg) and group 6, B6 + 3-NPA. All treatments were administered every 24 h for 5 days by intraperitoneal route. After sacrifice, the brain was obtained to measure DA, GSH, and lipid peroxidation, Ca2+, Mg2+, ATPase and H2O2. MAIN FINDINGS: Levels of dopamine increased in cortex, striatum and cerebellum/medulla oblongata of animals that received 3-NPA alone. The lipid peroxidation increased in cortex, striatum, and cerebellum/medulla oblongata, of animals treated with B2 vitamin alone. ATPase dependent on Ca+2, Mg+2 and H2O2 increased in all regions of animals that received 3-NPA alone. CONCLUSION: The results confirm the capacity of 3-NPA to generate oxidative stress. Besides, the study suggests that B2 or B6 vitamins restored the levels of DA and reduced oxidative stress in brain of rats. We believe that these results would help in the study of neurodegenerative diseases. PMID- 30413183 TI - Short and narrow flag leaf1, a GATA zinc finger domain-containing protein, regulates flag leaf size in rice (Oryza sativa). AB - BACKGROUND: The flag leaf of rice (Oryza sativa L.) is an important determinant of plant type characteristics and grain yield. Identification of flag leaf mutants of rice is crucial to elucidate the molecular mechanism of flag-leaf development, and for exploitation of rice germplasm resources. RESULTS: In this study, we describe a mutant designated short and narrow flag leaf 1 (snfl1). Histological analysis showed that the length of epidermal cells and number of longitudinal veins were decreased in the flag leaf of the snfl1 mutant. Map-based cloning indicated that a member of the GATA family of transcription factors is a candidate gene for SNFL1. A single-nucleotide transition at the last base in the single intron of snfl1 led to variation in alternative splicing and early termination of translation. Complemented transgenic plants harbouring the candidate SNFL1 gene rescued the snfl1 mutant. Analysis of RT-PCR and the SNFL1 promoter by means of a GUS fusion expression assay showed that abundance of SNFL1 transcripts was higher in the culm, leaf sheath, and root. Expression of the SNFL1-GFP fusion protein in rice protoplasts showed that SNFL1 was localized in nucleus. CONCLUSIONS: We conclude that SNFL1 is an important regulator of leaf development, the identification of which might have important implications for future research on GATA transcription factors. PMID- 30413186 TI - CT Enterography score: a potential predictor for severity assessment of active ulcerative colitis. AB - BACKGROUND: Evaluate the possibility of CT enterography (CTE) score system as a predictor in assessing active ulcerative colitis (UC) severity. METHODS: Forty six patients with active UC with CTE and colonoscopy were enrolled. Based on modified Mayo score, patients were divided into three groups: mild (n = 10), moderate (n = 17) and severe (n = 19). A cumulative CTE score was calculated in each patient and its correlation with modified Mayo score was analyzed. The optimal cutoff values of CTE score were determined by receiver operating characteristic (ROC) curves analysis. RESULTS: Significant between-group differences were observed in CTE spectrums of mucosal bubbles, mural stratification, loss of haustration, enlarged mesenteric lymph nodes and engorged mesenteric vessels (P < 0.05). The cumulative CTE scores were significant difference between three groups (CTE score:4.9 +/- 2.3, 7.6 +/- 2.6, and 10.9 +/- 2.0, respectively, P < 0.01). The cumulative CTE score showed a positive correlation with modified Mayo score (r = 0.835, P < 0.05). The optimal cut-off value for CTE score predicting moderate and severe UC was 9.5 (area under the curve [AUC]:0.847, sensitivity:78.9%, specificity:82.4%). CONCLUSION: Disease severity assessment by CTE score demonstrates strong positive correlation with severity established modified Mayo score. CTE score system maybe a potential predictor for active UC severity assessment. PMID- 30413187 TI - Efficacy and safety of antagonists for chemoattractant receptor-homologous molecule expressed on Th2 cells in adult patients with asthma: a meta-analysis and systematic review. AB - BACKGROUND: Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonists are novel agents for asthma but with controversial efficacies in clinical trials. Therefore, we conducted a meta-analysis to determine the roles of CRTH2 antagonists in asthma. METHODS: We searched in major databases for RCTs comparing CRTH2 antagonists with placebo in asthma. Fixed- or random-effects model was performed to calculate mean differences (MD), risk ratio (RR) or risk difference (RD) and 95% confidence interval (CI). RESULTS: A total of 14 trails with 4671 participants were included in our final analysis. Instead of add-on treatment of CRTH2 antagonists to corticosteroids, CRTH2 antagonist monotherapy significantly improved pre-bronchodilator FEV1 (MD = 0.09, 95% CI 0.04 to 0.15, P = 0.0005), FEV1% predicted (MD = 3.65, 95% CI 1.15 to 6.14, P = 0.004), and AQLQ (MD = 0.25, 95% CI 0.09 to 0.41, P = 0.002), and reduced asthma exacerbations (RR = 0.45, 95% CI 0.23 to 0.85, P = 0.01). Rescue use of SABA was significantly decreased in both CRTH2 antagonist monotherapy (MD = - 0.04, 95% CI -0.05 to - 0.03, P < 0.00001) and as add-on to corticosteroids (MD = - 0.78, 95% CI -1.47 to - 0.09, P = 0.03). Adverse events were similar between the intervention and placebo groups. CONCLUSIONS: CRTH2 antagonist monotherapy can safely improve lung function and quality of life, and reduce asthma exacerbations and SABA use in asthmatics. PMID- 30413189 TI - VZV-specific T-cell levels in patients with rheumatic diseases are reduced and differentially influenced by antirheumatic drugs. AB - BACKGROUND: Varicella zoster virus (VZV)-specific cellular immunity is essential for viral control, and the incidence of VZV reactivation is increased in patients with rheumatic diseases. Because knowledge of the influence of antirheumatic drugs on specific cellular immunity is limited, we analyzed VZV-specific T cells in patients with rheumatoid arthritis (RA) and seronegative spondylarthritis (SpA), and we assessed how their levels and functionality were impacted by disease-modifying antirheumatic drugs (DMARDs). A polyclonal stimulation was carried out to analyze effects on general effector T cells. METHODS: CD4 T cells in 98 blood samples of patients with RA (n = 78) or SpA (n = 20) were quantified by flow cytometry after stimulation with VZV antigen and the polyclonal stimulus Staphylococcus aureus enterotoxin B (SEB), and they were characterized for expression of cytokines (interferon-gamma, tumor necrosis factor [TNF]-alpha, interleukin [IL]-2) and markers for activation (CD69), differentiation (CD127), or functional anergy programmed death 1 molecule [PD-1], cytotoxic T-lymphocyte antigen 4 [CTLA-4]. Results of patients with RA were stratified into subgroups receiving different antirheumatic drugs and compared with samples of 39 healthy control subjects. Moreover, direct effects of biological DMARDs on cytokine expression and proliferation of specific T cells were analyzed in vitro. RESULTS: Unlike patients with SpA, patients with RA showed significantly lower percentages of VZV-specific CD4 T cells (median 0.03%, IQR 0.05%) than control subjects (median 0.09%, IQR 0.16%; p < 0.001). Likewise, SEB-reactive CD4 T-cell levels were lower in patients (median 2.35%, IQR 2.85%) than in control subjects (median 3.96%, IQR 4.38%; p < 0.05); however, expression of cytokines and cell surface markers of VZV-specific T cells did not differ in patients and control subjects, whereas SEB-reactive effector T cells of patients showed signs of functional impairment. Among antirheumatic drugs, biological DMARDs had the most pronounced impact on cellular immunity. Specifically, VZV-specific CD4 T-cell levels were significantly reduced in patients receiving TNF-alpha antagonists or IL-6 receptor-blocking therapy (p < 0.05 and p < 0.01, respectively), whereas SEB reactive T-cell levels were reduced in patients receiving B-cell-depleting or IL 6 receptor-blocking drugs (both p < 0.05). CONCLUSIONS: Despite absence of clinical symptoms, patients with RA showed signs of impaired cellular immunity that affected both VZV-specific and general effector T cells. Strongest effects on cellular immunity were observed in patients treated with biological DMARDs. These findings may contribute to the increased susceptibility of patients with RA to VZV reactivation. PMID- 30413190 TI - Nutritional status and correlation with academic performance among primary school children, northwest Ethiopia. AB - OBJECTIVE: This study aimed to determine the association between nutritional status and academic performance among primary school children in Debre Markos Town, northwest Ethiopia, 2017. RESULTS: The prevalence of stunting, underweight and wasting were 27.5% (95% CI 23.2-31.9%), 20.4% (95% CI 16.5-24.3%) and 8.7% (95% CI 6.2-11.5%), correspondingly. The low level of educational performance was significantly higher (p < 0.05) among the stunted, underweight and wasted children than that of the normal children. In multivariable logistic regression, age of the child (Adjusted Odds Ratio (AOR) = 0.177, 95% CI 0.07, 0.4), monthly income less < 1000.00 birr (AOR = 0.05, 95% Cl 0.02, 0.15), stunted children (AOR = 0.21, 95% CI 0.10, 0.43) and under-weight (AOR = 0.63, 95% CI 0.26, 0.84) were associated with academic performance. This study revealed that indicators of undernutrition were prevalent among school-age children. Thus, collaboration between the health and education sectors is required to alleviate the problem. PMID- 30413191 TI - Functional consultation and exercises improve grip strength in osteoarthritis of the hand - a randomised controlled trial. AB - BACKGROUND: Evidence for non-pharmacological interventions in hand osteoarthritis is promising but still scarce. Combined interventions are most likely to best cover the clinical needs of patients with hand osteoarthritis (OA). The aim of this study was to evaluate the effect of a combined, interdisciplinary intervention feasible in both primary and specialist care compared to routine care plus placebo in patients with hand OA. METHODS: This was a randomised, controlled 2-month trial with a blinded assessor. In the combined-intervention group, rheumatology-trained health professionals from different disciplines delivered a one-session individual intervention with detailed information on functioning, activities of daily living, physical activity, nutrition, assistive devices, instructions on pain management and exercises. Telephone follow up was performed after 4 weeks. The primary outcome was grip strength after 8 weeks. Secondary outcomes were self-reported pain, satisfaction with treatment, health status, two of the Jebsen-Taylor Hand Function subtests and the total score of the Australian/Canadian Hand Osteoarthritis Index (AUSCAN). Statistical significance was calculated by Student's t test or the Mann-Whitney U test depending on data distribution. Binominal logistic regression models were fitted, with the primary outcome being the dependent and the group allocation being the independent variable. RESULTS: There were 151 participating patients (74 in the combined-intervention and 77 in the routine-care-plus-placebo group) with 2-month follow-up attendance of 84% (n = 128). Grip strength significantly increased in the combined-intervention group and decreased in the routine-care group (dominant hand, mean 0.03 bar (SD 0.11) versus - 0.03 (SD 0.13), p value = 0.001, baseline corrected values) after 8 weeks. CONCLUSION: The combined one-session individual intervention significantly improved grip strength and self-reported satisfaction with treatment in patients with hand OA. It can be delivered by different rheumatology-trained health professionals and is thus also feasible in primary care. TRIAL REGISTRATION: ISRCTN registry, ISRCTN62513257 . Registered on 17 May 2012. PMID- 30413188 TI - Microbiota dysbiosis and barrier dysfunction in inflammatory bowel disease and colorectal cancers: exploring a common ground hypothesis. AB - Inflammatory bowel disease (IBD) is a multifactorial disease which arises as a result of the interaction of genetic, environmental, barrier and microbial factors leading to chronic inflammation in the intestine. Patients with IBD had a higher risk of developing colorectal carcinoma (CRC), of which the subset was classified as colitis-associated cancers. Genetic polymorphism of innate immune receptors had long been considered a major risk factor for IBD, and the mutations were also recently observed in CRC. Altered microbial composition (termed microbiota dybiosis) and dysfunctional gut barrier manifested by epithelial hyperpermeability and high amount of mucosa-associated bacteria were observed in IBD and CRC patients. The findings suggested that aberrant immune responses to penetrating commensal microbes may play key roles in fueling disease progression. Accumulative evidence demonstrated that mucosa-associated bacteria harbored colitogenic and protumoral properties in experimental models, supporting an active role of bacteria as pathobionts (commensal-derived opportunistic pathogens). Nevertheless, the host factors involved in bacterial dysbiosis and conversion mechanisms from lumen-dwelling commensals to mucosal pathobionts remain unclear. Based on the observation of gut leakiness in patients and the evidence of epithelial hyperpermeability prior to the onset of mucosal histopathology in colitic animals, it was postulated that the epithelial barrier dysfunction associated with mucosal enrichment of specific bacterial strains may predispose the shift to disease-associated microbiota. The speculation of leaky gut as an initiating factor for microbiota dysbiosis that eventually led to pathological consequences was proposed as the "common ground hypothesis", which will be highlighted in this review. Overall, the understanding of the core interplay between gut microbiota and epithelial barriers at early subclinical phases will shed light to novel therapeutic strategies to manage chronic inflammatory disorders and colitis-associated cancers. PMID- 30413193 TI - Epidemiology of pulmonary disease due to nontuberculous mycobacteria in Southern China, 2013-2016. AB - BACKGROUND: Pulmonary nontuberculous mycobacteria (NTM) disease is of increasing public health concern in China. Information is limited regarding risk factors associated with this disease in China. The objective of this study was to describe the epidemiology of pulmonary disease due to NTM in Southern China. METHODS: We retrospectively reviewed the medical records of pulmonary NTM patients registered in the Guangzhou Chest Hospital with positive mycobacterial cultures during 2013-2016. We described sex, age, residence, treatment history, laboratory examination results and comorbidities of pulmonary NTM patients. RESULTS: Among the 607 NTM cases, the most prevalent species were Mycobacterium avium complex (44.5%), Mycobacterium abscessus complex (40.5%), Mycobacterium kansasii (10.0%) and Mycobacterium fortuitum (2.8%). The male:female ratio was significantly lower among patients infected with rapidly growing mycobacteria (RGM) than among those with slowly growing mycobacteria (SGM). The risk of developing SGM disease significantly increased with advancing age. In addition, pulmonary RGM diseases were more common in migrant population than resident population. Notably, patients with pulmonary RGM diseases were significantly more likely to have bronchiectasis underlying noted than those with SGM diseases. No significant difference was observed in in vitro drug susceptibility among NTM species. CONCLUSION: Our data illustrate that the M. avium complex is the most predominant causative agent of pulmonary NTM disease in Southern China. Female, migrant population, the presence of bronchiectasis are independent risk factors for pulmonary diseases due to RGM. In addition, the prevalence of SGM increases significantly with advancing age. PMID- 30413192 TI - Study of the anti-allergic and anti-inflammatory activity of Brachychiton rupestris and Brachychiton discolor leaves (Malvaceae) using in vitro models. AB - BACKGROUND: Brachychiton rupestris and Brachychiton discolor (Malvaceae) are ornamental trees native to Australia. Some members of Brachychiton and its highly related genus, Sterculia, are employed in traditional medicine for itching, dermatitis and other skin diseases. However, scientific studies on these two genera are scarce. Aiming to reveal the scientific basis of the folk medicinal use of these plants, the cytotoxicity, anti-inflammatory and anti-allergic activities of Brachychiton rupestris and Brachychiton discolor leaves extracts and fractions were evaluated. Also, phytochemical investigation of B. rupestris was performed to identify the compounds exerting the biological effect. METHODS: Extracts as well as fractions of Brachychiton rupestris and Brachychiton discolor were tested for their cytotoxicity versus hepatoma HepG2, lung A549, and breast MDA-MB-231 cancer cell lines. Assessment of the anti-allergic activity was done using degranulation assay in RBL-2H3 mast cells. Anti-inflammatory effect was tested by measuring the suppression of superoxide anion production as well as elastase release in fMLF/CB-induced human neutrophils. Phytochemical investigation of the n-hexane, dichloromethane and ethyl acetate fractions of B. rupestris was done using different chromatographic and spectroscopic techniques. RESULTS: The tested samples showed no cytotoxicity towards the tested cell lines. The nonpolar fractions of both B. rupestris and B. discolor showed potent anti allergic potency by inhibiting the release of beta-hexosaminidase. The dichloromethane fraction of both species exhibited the highest anti-inflammatory activity by suppressing superoxide anion generation and elastase release with IC50 values of 2.99 and 1.98 MUg/mL, respectively for B. rupestris, and 0.78 and 1.57 MUg/mL, respectively for B. discolor. Phytochemical investigation of various fractions of B. rupestris resulted in the isolation of beta-amyrin acetate (1), beta-sitosterol (2) and stigmasterol (3) from the n-hexane fraction. Scopoletin (4) and beta-sitosterol-3-O-beta-D-glucoside (5) were obtained from the dichloromethane fraction. Dihydrodehydrodiconiferyl alcohol 4-O-beta-D-glucoside (6) and dihydrodehydrodiconiferyl alcohol 9-O-beta-D-glucoside (7) were separated from the ethyl acetate fraction. Scopoletin (4) showed anti-allergic and anti inflammatory activity. CONCLUSIONS: It was concluded that the nonpolar fractions of both Brachychiton species exhibited anti-allergic and anti-inflammatory activities. PMID- 30413195 TI - Vitamin D levels in patients with recurrent aphthous stomatitis. AB - BACKGROUND: Lower serum vitamin D levels, a major public health problem worldwide, has been found to be associated with various infectious diseases, cancers, autoimmune and dermatological diseases. The serum levels of vitamin D in patients with recurrent aphthous stomatitis are not clear. We investigated the vitamin D levels in patients with recurrent aphthous stomatitis. METHODS: Forty patients with recurrent aphthous stomatitis (Group I) and 70 healthy controls (Group II) included in the study. The characteristics of aphthous lesions (duration of disease and remission, frequency, diameter and number of the lesions) and demographics of the participants were recorded. Serum 25 hydroxycholecalciferol levels were measured using electrochemiluminescence binding method. RESULTS: There was no statistically significant difference between the groups in terms of age (p = 0.06) and sex (p = 0.4). Other baseline characteristics were not significantly different between the groups (p > 0.05 for all). The mean diameter of aphthous lesions was 0.5 (0.4-0.6) cm and the mean number of lesions was 2.2 +/- 1.5. Serum vitamin D levels were 11 +/- 7.04 ng/ml in Group I and 16.4 +/- 10.19 ng/ml in Group II. Serum vitamin D levels were significantly lower in patients with recurrent aphthous stomatitis (p = 0.004). CONCLUSIONS: The present study showed lower vitamin D levels in patients with recurrent aphthous stomatitis compared to healthy controls. PMID- 30413194 TI - Epidermal growth factor expression as a predictor of chemotherapeutic resistance in muscle-invasive bladder cancer. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) overexpression is believed to be associated with bladder cancer (BC) progression and poor clinical outcomes. In vivo studies have linked EGFR subcellular trafficking and chemo-resistance to cisplatin-based chemotherapies. This has not been studied in the clinical adjuvant setting. We aimed to investigate the prognostic significance of EGFR expression in patients receiving cisplatin-based adjuvant chemotherapy following radical cystectomy for advanced BC. METHODS: The database from the Urology and Nephrology Center at Mansoura University was reviewed. BC patients who were treated with radical cystectomy and adjuvant chemotherapy for adverse pathological features or node positive disease were identified. Patients who underwent palliative cystectomy, had histological diagnoses other than pure urothelial carcinoma, or received adjuvant radiotherapy were excluded from the study. Immunohistochemical staining for EGFR expression was performed on archived bladder specimens. The following in vitro functional analyses were performed to study the relationship of EGFR expression and chemoresponse. RESULTS: The study included 58 patients, among which the mean age was 57 years old. Majority of patients had node positive disease (n = 53, 91%). Mean follow up was 26.61 months. EGFR was overexpressed in 25 cystectomy specimens (43%). Kaplan-Meier analysis revealed that EGFR over-expression significantly correlated with disease recurrence (p = 0.021). Cox proportional hazard modeling identified EGFR overexpression as an independent predictor for disease recurrence (p = 0.04). Furthermore, in vitro experiments demonstrated that inhibition of EGFR may sensitize cellular responses to cisplatin. CONCLUSIONS: Our findings suggest that EGFR overexpression is associated with disease recurrence following adjuvant chemotherapy for advanced BC. This may aid in patient prognostication and selection prior to chemotherapeutic treatment for BC. PMID- 30413196 TI - Development and pilot testing of a tool to assess evidence-based practice skills among French general practitioners. AB - BACKGROUND: There is currently an absence of valid and relevant instruments to evaluate how Evidence-based Practice (EBP) training improves, beyond knowledge, physicians' skills. Our aim was to develop and test a tool to assess physicians' EBP skills. METHODS: The tool we developed includes four parts to assess the necessary skills for applying EBP steps: clinical question formulation; literature search; critical appraisal of literature; synthesis and decision making. We evaluated content and face validity, then tested applicability of the tool and whether external observers could reliably use it to assess acquired skills. We estimated Kappa coefficients to measure concordance between raters. RESULTS: Twelve general practice (GP) residents and eleven GP teachers from the University of Bordeaux, France, were asked to: formulate four clinical questions (diagnostic, prognosis, treatment, and aetiology) from a proposed clinical vignette, find articles or guidelines to answer four relevant provided questions, analyse an original article answering one of these questions, synthesize knowledge from provided synopses, and decide about the four clinical questions. Concordance between two external raters was excellent for their assessment of participants' appraisal of the significance of article results (K = 0.83), and good for assessment of the formulation of a diagnostic question (K = 0.76), PubMed/Medline (K = 0.71) or guideline (K = 0.67) search, and of appraisal of methodological validity of articles (K = 0.68). CONCLUSIONS: Our tool allows an in-depth analysis of EBP skills, thus could supplement existing instruments focused on knowledge or specific EBP step. The actual usefulness of such tools to improve care and population health remains to be evaluated. PMID- 30413198 TI - Bioprocess optimization for pectinase production using Aspergillus niger in a submerged cultivation system. AB - BACKGROUND: Pectinase enzymes present a high priced category of microbial enzymes with many potential applications in various food and oil industries and an estimated market share of $ 41.4 billion by 2020. RESULTS: The production medium was first optimized using a statistical optimization approach to increase pectinase production. A maximal enzyme concentration of 76.35 U/mL (a 2.8-fold increase compared with the initial medium) was produced in a medium composed of (g/L): pectin, 32.22; (NH4)2SO4, 4.33; K2HPO4, 1.36; MgSO4.5H2O, 0.05; KCl, 0.05; and FeSO4.5H2O, 0.10. The cultivations were then carried out in a 16-L stirred tank bioreactor in both batch and fed-batch modes to improve enzyme production, which is an important step for bioprocess industrialization. Controlling the pH at 5.5 during cultivation yielded a pectinase production of 109.63 U/mL, which was about 10% higher than the uncontrolled pH culture. Furthermore, fed-batch cultivation using sucrose as a feeding substrate with a rate of 2 g/L/h increased the enzyme production up to 450 U/mL after 126 h. CONCLUSIONS: Statistical medium optimization improved volumetric pectinase productivity by about 2.8 folds. Scaling-up the production process in 16-L semi-industrial stirred tank bioreactor under controlled pH further enhanced pectinase production by about 4-folds. Finally, bioreactor fed-batch cultivation using constant carbon source feeding increased maximal volumetric enzyme production by about 16.5-folds from the initial starting conditions. PMID- 30413199 TI - Cross design analysis of randomized and observational data - application to continuation rates for a contraceptive intra uterine device containing Levonorgestrel in adolescents and adults. AB - BACKGROUND: To combine results from a randomized controlled study (RCT) and an observational study (OS) to evaluate discontinuation rate of a levonorgestrel containing intrauterine contraceptive device (LNG IUD) in a real-life setting. METHODS: We included 253 parous and nulliparous women aged 21-40 years from our own phase II RCT. A total of 1607 women of all ages (including adolescents, < 20 years) were recruited from an OS. We applied the cross design synthesis (CDS) method recommended by the United States General Accounting Office. This method combines the different strengths of RCTs and OSs into one single estimate. RESULTS: Combined continuation rates for parous vs nulliparous women could be estimated more precisely as well as overall continuation rates after one (86.6%) and two years (78.5%), irrespective of age and parity. CONCLUSION: Cross design synthesis allowed more precise estimation of continuation rates of an intrauterine device. PMID- 30413197 TI - Age at menarche and prevention of hypertension through lifestyle in young Chinese adult women: result from project ELEFANT. AB - BACKGROUND: Early and late age at menarche are associated with risk of hypertension, but little is known whether modifiable lifestyle can reduce this risk. METHODS: Our study leverages 60,135 healthy young Chinese women from the Environmental and LifEstyle FActors iN metabolic health throughout life-course Trajectories (ELEFANT) study. Menarche age and lifestyle factors were assessed by self-reported questionnaires and hypertension was diagnosed by physicians. We estimated the odds ratios (ORs) of hypertension associated with menarche age using multivariable logistic regression. We further investigated whether modifiable lifestyles (body mass index, BMI; psychological stress; passive smoking; and imbalanced diet) increased risk in joint analyses. RESULTS: The association between age at menarche and hypertension was U-shaped, with age <= 12 at menarche giving the highest OR (1.46, 95% confidence interval [CI], 1.27-1.69) and >= 16 the second highest (OR = 1.36, 95% CI = 1.15-1.62). Simultaneous analysis of lifestyle risk factors and age of menarche showed that having one or more modifiable risk factors increased the menarche age-hypertension association. The risk of hypertension among participants with menarche age <= 12 decreased from OR 13.21 (95% CI = 5.17-29.36) with four high-risk lifestyle factors to 12.36 (95% CI = 9.51-16.05) with three high-risk factors, 5.24 (95% CI = 4.11 6.69) with two, and 2.76 (95% CI = 2.09-3.60) with one, in comparison to individuals with no high-risk lifestyle factors and menarche age 14. CONCLUSIONS: Our results suggest that modification of lifestyle, including maintenance of normal weight and a balanced diet, are associated with substantially reduce the risk of hypertension in high-risk individuals. Early and late age at menarche are risk factors for the development of hypertension in Western populations, and there is limited evidence that this is also true of Chinese populations. Targeted prevention of hypertension in vulnerable populations would be highly beneficial in efforts to reduce the incidence of cardiovascular disease, but it is not currently known whether lifestyle intervention could reduce hypertension risk. In this study, we analysed the risk of hypertension by age at menarche and four modifiable lifestyle factors (BMI, diet, psychological stress, and smoking tobacco) in a cohort of 60,135 young adult Chinese women (mean age 29). We identified that early and late age at menarche are associated with increased risk of hypertension in young Chinese women. There was joint effects between age at menarche and lifestyles on hypertension only participants with age at menarche <=12 and being overweight or obese. Modification of lifestyle, including maintenance of normal weight and a balanced diet, can substantially reduce the risk of hypertension in high-risk individuals. In conclusion, our study has revealed that early and late menarche age are associated with the development of hypertension in young Chinese women, and that this risk is modified by healthy lifestyle traits. PMID- 30413201 TI - Non-ischemic laparoscopic partial nephrectomy using 1318-nm diode laser for small exophytic renal tumors. AB - PURPOSE: Warm ischemia (WI) and bleeding constitute the main challenges for surgeons during laparoscopic partial nephrectomy (LPN). Current literature on the use of lasers for cutting and coagulation remains scarce and with small cohorts. We present the largest case series to date of non-ischemic LPN using a diode laser for small exophytic renal tumors. METHODS: We retrospectively evaluated 29 patients with clinically localized exophytic renal tumors who underwent non ischemic laser-assisted LPN with a 1318-nm wavelength diode laser. We started applying the laser 5 mm beyond the visible tumor margin, 5 mm away from the tissue in a non-contact fashion for coagulation and in direct contact with the parenchymal tissue for cutting. RESULTS: The renal vessels were not clamped, resulting in a WIT (warm ischaemic time) of 0 min, except for one case that required warm ischemia for 12 min and parenchymal sutures. No transfusion was needed, with a mean Hemoglobin drop of 1,4 mg/dl and no postoperative complications. The eGFR did not significantly change by 6 months. Histologically, the majority of lesions (n = 22/29) were renal-cell carcinoma stage pT1a. The majority of malignant lesions (n = 13/22) had a negative margin. However, margin interpretation was difficult in 9 cases due to charring of the tumor base. A mean follow-up of 1.8 years revealed no tumor recurrence. The mean tumor diameter was 19.4 mm. CONCLUSION: The 1318-nm diode laser has the advantages of excellent cutting and sealing properties when applied to small vessels in the renal parenchyma, reducing the need for parenchymal sutures. However, excessive smoke, charring of the surgical margin, and inability to seal large blood vessels are encountered with this technique. PMID- 30413200 TI - The effect of model selection on cost-effectiveness research: a comparison of kidney function-based microsimulation and disease grade-based microsimulation in chronic kidney disease modeling. AB - BACKGROUND: Cost effectiveness research is emerging in the chronic kidney disease (CKD) research field. Especially, an individual-level state transition model (microsimulation) is widely used for these researches. Some researchers set CKD grades as discrete health states, and the transition probabilities between these states were dependent on the CKD grades (disease grade-based microsimulation, MSM dg), while others set estimated glomerular filtration rate value which determines the severity of CKD as a main variable describing patients' continuous status (kidney function-based microsimulation, MSM-kf). MSM-kf seems to reflect the real world more precisely but is more difficult to implement. We compared the calculation results of these two microsimulation models to evaluate the effect of model selection on CKD cost-effectiveness analysis. METHODS: We implemented simplified MSM-dg and MSM-kf emulating natural course of CKD in general, and compared models using parameters derived from an IgA nephropathy cohort. After checking these models' overall behavior, life-years, utilities, and thresholds regarding intervention costs below which the intervention is thought as dominant (V0) or cost-effective (V1) were calculated. In addition, one-way and probabilistic sensitivity analyses were performed. RESULTS: With base-case parameters, the calculated life-years was shorter in MSM-dg (73.89 vs. 75.80 years) while the thresholds were almost equal (86.87 vs. 90.43 (V0), 132.29 vs. 146.25 [V1 in 1000 USD]) compared to MSM-kf. Sensitivity analyses showed a tendency of the MSM-dg to show shorter results in life-years. V0 and V1 were distributed by approximately +/-100,000 USD (V0) and +/- 150,000 USD (V1) between models. CONCLUSIONS: Estimated cost-effectiveness thresholds by both models were not the same and its difference distributed too wide to be ignored. This result indicated that model selection in CKD cost-effectiveness research has large effect on their conclusions. PMID- 30413202 TI - Efficacy of irrigation tubes in the management of para rectal cavities associated with complex fistula-in-ano. AB - BACKGROUND: Surgical management of complex perianal fistula associated with pararectal cavities can be challenging. We hypothesised that healing of the pararectal cavities prior to healing of the fistula leads to a better outcome. We aimed to assess the efficacy of irrigation catheters in the healing of pararectal cavities associated with fistula-in-ano. METHODS: This study design was consistent with IDEAL stage 2a (development) and was conducted at the Professorial Surgical Unit, National Hospital of Sri Lanka, Colombo. Thirty-two patients with complex fistulae with a pararectal cavity (detected by 2D-Endoanal ultrasounography-EAUS) were included. All patients underwent examination under anaesthesia (EUA), during which insertion of an irrigation catheter to the pararectal cavity and tagging of the primary fistula tract with a drainage seton was done. Patients were advised to irrigate with antiseptic solution and were followed-up at three weekly intervals to assess cavity reduction. RESULTS: The majority were males (96.8%, n = 31). The primary fistula tract in 26 patients (81.2%) was trans-sphincteric and was inter-sphincteric in 6 patients (18.7%). Mean time of cavity contraction was 34.78 (range, 21-112) days. Complete healing was seen in 87.5% (n = 28), with 3 patients (9.37%) being lost to follow-up and 1 patient (3.12%) having a persistent perianal fistula after 6 months of follow-up. Those who had complete healing were followed up for a median duration of 6 (range, 3-20) months and there were no recurrences. CONCLUSIONS: Irrigation in the management of pararectal cavities yielded satisfactory results. A case control trial with larger numbers and assessment of cavity size pre and post procedure by 3D-EAUS/MRI evaluation would be necessary for more objective evaluation of the efficacy of this novel intervention. PMID- 30413203 TI - Sexual compulsivity and its relationship with condomless sex among unmarried female migrant workers in Shanghai, China: a cross-sectional study. AB - BACKGROUND: Individuals with high sexual compulsivity are preoccupied with their sexual desire to such an extent that it interferes with their normal daily life and can inhibit self-control. Previous studies have found a close association between sexual compulsivity and condomless sex among different populations; however, no studies have investigated this among unmarried female migrant workers in China. This study aimed to validate the Sexual Compulsivity Scale (SCS) for appropriate use and examine the association between sexual compulsivity and condomless sex in this target population. METHODS: In 2015, we recruited 1325 unmarried female migrant workers in Shanghai, China. Information about sociodemographics, sexual compulsivity, and condomless sex were collected using a structured questionnaire. Exploratory factor analysis and reliability analysis were performed to validate the Chinese version of the SCS. Multiple logistic regression analyses were used to examine the association between sexual compulsivity and condomless sex. RESULTS: The prevalence of condomless sex in the previous 6 months was 66.8% among all participants. The SCS was proven internally consistent for the overall scale (Cronbach's alpha = 0.89), and two factors, Social Disruptiveness (Cronbach's alpha = 0.87) and Perceived Self-Control (Cronbach's alpha = 0.84), were extracted. With mean total score of 18.25 (standard deviation = 4.94) after adjusting for significant sociodemographic factors, the SCS total scores (adjusted odds ratio [AOR] = 1.04, 95% confidence interval [CI] = 1.02-1.07) and two subscale scores (AOR = 1.07, 95% CI = 1.02 1.13; AOR = 1.06, 95% CI = 1.02-1.10) were all related to inconsistent condom use with partners in the previous 6 months. CONCLUSIONS: The Chinese version of the SCS was found to be well adaptable for use among unmarried Chinese female migrant workers and a potential predictor for condomless sex. In addition to safe sex interventions, counselling on managing sexually compulsivity should also be provided in this population. PMID- 30413204 TI - Impact of Progress testing on the learning experiences of students in medicine, dentistry and dental therapy. AB - AIMS: To investigate the impact of progress testing on the learning experiences of undergraduate students in three programs namely, medicine, dentistry and dental therapy. METHODS: Participants were invited to respond to an online questionnaire to share their perceptions and experiences of progress testing. Responses were recorded anonymously, but data on their program, year of study, age, gender, and ethnicity were also captured on a voluntary basis. RESULTS: A total of 167 participants completed the questionnaire yielding a response rate of 27.2% (n = 167). These included 96 BMBS students (27.4%), 56 BDS students (24.7%), and 15 BScDTH students (39.5%). A 3 -Program (BMBS, BDS, BScDTH) by 8 Topic (A-H) mixed analysis of variance (ANOVA) was conducted on the questionnaire responses. This revealed statistically significant main effects of Program and Topic, as well as a statistically significant interaction between the two (i.e. the pattern of topic differences was different across programs). CONCLUSIONS: Undergraduate students in medicine, dentistry, and dental therapy and hygiene regarded PT as a useful assessment to support their learning needs. However, in comparison to students in dentistry and dental therapy and hygiene, the perceptions of medical students were less positive in several aspects of PT. PMID- 30413205 TI - Developing primary care teams prepared to improve quality: a mixed-methods evaluation and lessons learned from implementing a microsystems approach. AB - BACKGROUND: Health systems in the United States are increasingly required to become leaders in quality to compete successfully in a value-conscious purchasing market. Doing so involves developing effective clinical teams using approaches like the clinical microsystems framework. However, there has been limited assessment of this approach within United States primary care settings. METHODS: This paper describes the implementation, mixed-methods evaluation results, and lessons learned from instituting a Microsystems approach across 6 years with 58 primary care teams at a large Midwestern academic health care system. The evaluation consisted of a longitudinal survey augmented by interviews and focus groups. Structured facilitated longitudinal discussions with leadership captured ongoing lessons learned. Quantitative analysis employed ordinal logistic regression and compared aggregate responses at 6-months and 12-months to those at the baseline period. Qualitative analysis used an immersion/crystallization approach. RESULTS: Survey results (N = 204) indicated improved perceptions of: organizational support, team effectiveness and cohesion, meeting and quality improvement skills, and team communication. Thematic challenges from the qualitative data included: lack of time and coverage for participation, need for technical/technology support, perceived devaluation of improvement work, difficulty aggregating or spreading learnings, tensions between team and clinic level change, a part-time workforce, team instability and difficulties incorporating a data driven improvement approach. CONCLUSIONS: These findings suggest that a microsystems approach is valuable for building team relationships and quality improvement skills but is challenged in a large, diverse academic primary care context. They additionally suggest that primary care transformation will require purposeful changes implemented across the micro to macro-level including but not only focused on quality improvement training for microsystem teams. PMID- 30413207 TI - Suture fixation of tracheal stents for the treatment of upper trachea stenosis: a retrospective study. AB - BACKGROUND: Stent migration is a common complication in treating trachea stenosis. There is no report concerning suture fixation of tracheal stent. The aim of this study was to investigate whether suture fixation of tracheal stent could avoid stent migration in patients with upper trachea stenosis. The complications were further investigated. METHODS: The patients with upper trachea stenosis who underwent tracheal stent placement for benign/malignant conditions in our hospital between May 2016 and April 2018 were retrospectively reviewed. Clinical data were collected for each patient, including age, gender, co-morbid diseases, site of tracheal obstruction, degree of tracheal obstruction, success of stent placement, impact on patient's symptoms, complications, etc. RESULTS: Eleven patients (8 males and 3 females; range of age: 17-85, and average age of 63) were enrolled into this study. Six silicone stents and five membrane-covered metal stents were used. The surgery was successfully performed in all the cases. The postoperative recovery was uneventful. All symptoms of the patients were relieved. No complications occurred. The average follow-up for patients was 5 months (range of 1-13 months). During the follow-up, no stent migration was observed according to CT and bronchoscope. CONCLUSION: The results suggested that suture fixation of stents could avoid stent migration in treating upper trachea stenosis with metal stent or silicone stent. This method seemed to be effective without operation complications. PMID- 30413206 TI - Tunicamycin specifically aggravates ER stress and overcomes chemoresistance in multidrug-resistant gastric cancer cells by inhibiting N-glycosylation. AB - BACKGROUND: Multidrug resistance remains a major obstacle to successful treatment for patients with gastric cancer (GC). Recently, glycosylation has been demonstrated to play a vital role in the acquisition of multidrug resistance. As a potent inhibitor of glycosylation, tunicamycin (Tu) has shown marked antitumor activities in various cancers. In the present study, we attempted to determine the exact effect of Tu on the chemoresistance of GC. METHODS: The cytotoxic effects of drugs on GC cells were evaluated by cell viability assays, and apoptosis was detected by flow cytometry. PCR, western blot analysis, immunofluorescence staining and canonical inhibitors were employed to identify the underlying mechanisms of the specific effects of Tu on multidrug-resistant (MDR) GC cells. RESULTS: For the first time, we found that MDR GC cells were more sensitive to Tu-induced cell death than the parental cells and that the increased sensitivity might correlate with basal endoplasmic reticulum (ER) stress. In addition, Tu dramatically increased chemotherapy-induced apoptosis by evoking ER stress in GC cells, particularly MDR cells. Further study indicated that these effects were highly dependent on glycosylation inhibition by Tu, rather than its role as a canonical ER stress inducer. Besides, autophagy was markedly triggered by Tu, and blocking autophagy enhanced the combined effects of Tu and chemotherapy on MDR GC cells. CONCLUSIONS: Our results suggest that tumor targeted glycosylation inhibition may be a feasible strategy to reverse chemoresistance in GC patients. PMID- 30413209 TI - Universal health coverage necessitates a system approach: an analysis of Community-based Health Planning and Services (CHPS) initiative in Ghana. AB - The 9th Global conference on health promotion (Shanghai 2016) reaffirmed the role of primary health care (PHC) in achieving the 2030 Sustainable Development Agenda. Gaining much international recognition, the community-based health planning and services (CHPS) initiative is considered one of the pragmatic strategy in delivering on the promise of universal health coverage (UHC) through the PHC strategy, in Ghana. Yet, certain key factors threaten its successes - renewing the relevance of this study to present the barriers to and facilitators of the initiative. According to our findings, CHPS contribution particularly in bridging geographical access to health cannot be demeaned. Nevertheless, the full functioning of the initiative is limited by factors centered on the following themes: health governance and leadership, provision of services of quality, financial risk protection strategies targeting public health, information and care continuity, and the right mix of trained health professionals of even distribution across communities. Addressing the challenges of CHPS demand a system-approach. Substantial progress is more likely to emerge with improved leadership especially on the part of Governments to take bold political step to provide adequate financial and material resources. However, much will be achieved when stakeholders including the community work in synergies, to manage competing priorities by focusing on the core values and goals of CHPS. PMID- 30413208 TI - Chronic pulmonary exposure to traffic-related fine particulate matter causes brain impairment in adult rats. AB - BACKGROUND: Effects of air pollution on neurotoxicity and behavioral alterations have been reported. The objective of this study was to investigate the pathophysiology caused by particulate matter (PM) in the brain. We examined the effects of traffic-related particulate matter with an aerodynamic diameter of < 1 MUm (PM1), high-efficiency particulate air (HEPA)-filtered air, and clean air on the brain structure, behavioral changes, brainwaves, and bioreactivity of the brain (cortex, cerebellum, and hippocampus), olfactory bulb, and serum after 3 and 6 months of whole-body exposure in 6-month-old Sprague Dawley rats. RESULTS: The rats were exposed to 16.3 +/- 8.2 (4.7~ 68.8) MUg/m3 of PM1 during the study period. An MRI analysis showed that whole-brain and hippocampal volumes increased with 3 and 6 months of PM1 exposure. A short-term memory deficiency occurred with 3 months of exposure to PM1 as determined by a novel object recognition (NOR) task, but there were no significant changes in motor functions. There were no changes in frequency bands or multiscale entropy of brainwaves. Exposure to 3 months of PM1 increased 8-isoporstance in the cortex, cerebellum, and hippocampus as well as hippocampal inflammation (interleukin (IL)-6), but not in the olfactory bulb. Systemic CCL11 (at 3 and 6 months) and IL-4 (at 6 months) increased after PM1 exposure. Light chain 3 (LC3) expression increased in the hippocampus after 6 months of exposure. Spongiosis and neuronal shrinkage were observed in the cortex, cerebellum, and hippocampus (neuronal shrinkage) after exposure to air pollution. Additionally, microabscesses were observed in the cortex after 6 months of PM1 exposure. CONCLUSIONS: Our study first observed cerebral edema and brain impairment in adult rats after chronic exposure to traffic-related air pollution. PMID- 30413210 TI - A prediction model for good neurological outcome in successfully resuscitated out of-hospital cardiac arrest patients. AB - BACKGROUND: In the initial hours after out-of-hospital cardiac arrest (OHCA), it remains difficult to estimate whether the degree of post-ischemic brain damage will be compatible with long-term good neurological outcome. We aimed to construct prognostic models able to predict good neurological outcome of OHCA patients within 48 h after CCU admission using variables that are bedside available. METHODS: Based on prospectively gathered data, a retrospective data analysis was performed on 107 successfully resuscitated OHCA patients with a presumed cardiac cause of arrest. Targeted temperature management at 33 degrees C was initiated at CCU admission. Prediction models for good neurological outcome (CPC1-2) at 180 days post-CA were constructed at hour 1, 12, 24 and 48 after CCU admission. Following multiple imputation, variables were selected using the elastic-net method. Each imputed dataset was divided into training and validation sets (80% and 20% of patients, respectively). Logistic regression was fitted on training sets and prediction performance was evaluated on validation sets using misclassification rates. RESULTS: The prediction model at hour 24 predicted good neurological outcome with the lowest misclassification rate (21.5%), using a cut off probability of 0.55 (sensitivity = 75%; specificity = 82%). This model contained sex, age, diabetes status, initial rhythm, percutaneous coronary intervention, presence of a BIS 0 value, mean BIS value and lactate as predictive variables for good neurological outcome. DISCUSSION: This study shows that good neurological outcome after OHCA can be reasonably predicted as early as 24 h following ICU admission using parameters that are bedside available. These prediction models could identify patients who would benefit the most from intensive care. PMID- 30413211 TI - Preloop trial: study protocol for a randomized controlled trial. AB - BACKGROUND: A temporary loop ileostomy, which is used to decrease the risk of symptomatic anastamotic leakage after anterior resection and total mesorectal excision (TME), is traditionally closed without any mesh. However, as 44% of incisional site hernias need further repair after stoma closure, attention has increasingly been paid to the use of mesh. Research on the prevention of these hernias is scarce, and no studies comparing different meshes exist. METHOD/DESIGN: The Preloop trial (Clinical Trials NCT03445936) is a prospective, randomized, controlled, multicenter trial to compare synthetic mesh (Parietene MacroTM, Medtronic, Minneapolis, MN, USA) and biological implants (PermacolTM, Medtronic) at a retromuscular sublay position for the prevention of incisional site hernias after loop-ileostomy closure. The main endpoints in this trial are infections at 30-day follow-up and the incidence of hernias clinically or on CT scan at 10 months after closure of the stoma. The secondary endpoints are other complications within 30 days of surgery graded with the Clavien-Dindo classification, reoperation rate, operating time, length of stay, quality of life measured with RAND-36, and incidence of hernia over a 5-year follow-up period. A total of 100 patients will be randomized in a 1:1 ratio. DISCUSSION: This is a pilot trial that will be undertaken to provide some novel evidence on the safety profile and efficiency of both synthetic mesh and biological implants for the prevention of incisional hernias after closure by temporary loop ileostomy. The hypothesis is that synthetic mesh is economical but equally safe and at least as effective as biological implants in hernia prevention and in contaminated surgical sites. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03445936 . Registered on 7 February 2018. PMID- 30413213 TI - The accuracy of medical dispatch - a systematic review. AB - BACKGROUND: It is a challenge to dispatch Emergency medical Services (EMS) appropriately with limited resources and maintaining patient safety; this requires accurate dispatching systems. The objective of the current systematic review was to examine the evidence, according to GRADE, for medical dispatching systems to accurately dispatch EMS according to level of acuity and in recognition of specific conditions. A systematic search was performed trough PubMed, Web of Science, Embase (free text in all fields), Centre for Reviews and Dissemination (CRD), and Cochrane Central Register of Controlled Trials up to 16th of May, 2017. A combination of keywords and Medical Subject Heading (MeSH) terms relevant to "emergency medical dispatch criteria" were used, to search for articles published between 2012 and 2017. Publications were included according to the inclusion/exclusion criteria using the Systematic Reviews and Meta-Analyses (PRISMA) protocol. Level of evidence was evaluated in accordance with Grading of Recommendations Assessment, Development and Evaluation (GRADE). Articles included were those that provided evidence for at least one of the measures of dispatch system accuracy; i.e. sensitivity, specificity, positive and negative predictive and/or over- and under-triage. The search identified 1445 articles. After the removal of duplicates, 382 titles were reviewed for relevance and an additional 359 articles were excluded based on manuscript title and abstract. An additional five articles were excluded after review of the full text versions of the remaining articles. The current review included 18 publications which all were based on primary research. CONCLUSIONS: The 18 articles addressed the identification of cardiac arrest, stroke, medical priority and major trauma using different dispatching systems. The results of the current review show that there is a very low to low overall level of evidence for the accuracy of medical dispatching systems. We suggest that it is necessary to create a consensus on common standards for reporting before consensus can be reached for the level of accuracy in medical dispatching systems. PMID- 30413212 TI - Group II innate lymphoid cells and microvascular dysfunction from pulmonary titanium dioxide nanoparticle exposure. AB - BACKGROUND: The cardiovascular effects of pulmonary exposure to engineered nanomaterials (ENM) are poorly understood, and the reproductive consequences are even less understood. Inflammation remains the most frequently explored mechanism of ENM toxicity. However, the key mediators and steps between lung exposure and uterine health remain to be fully defined. The purpose of this study was to determine the uterine inflammatory and vascular effects of pulmonary exposure to titanium dioxide nanoparticles (nano-TiO2). We hypothesized that pulmonary nano TiO2 exposure initiates a Th2 inflammatory response mediated by Group II innate lymphoid cells (ILC2), which may be associated with an impairment in uterine microvascular reactivity. METHODS: Female, virgin, Sprague-Dawley rats (8-12 weeks) were exposed to 100 MUg of nano-TiO2 via intratracheal instillation 24 h prior to microvascular assessments. Serial blood samples were obtained at 0, 1, 2 and 4 h post-exposure for multiplex cytokine analysis. ILC2 numbers in the lungs were determined. ILC2s were isolated and phosphorylated nuclear factor kappa light-chain-enhancer of activated B cells (NF-KB) levels were measured. Pressure myography was used to assess vascular reactivity of isolated radial arterioles. RESULTS: Pulmonary nano-TiO2 exposure was associated with an increase in IL 1beta, 4, 5 and 13 and TNF- alpha 4 h post-exposure, indicative of an innate Th2 inflammatory response. ILC2 numbers were significantly increased in lungs from exposed animals (1.66 +/- 0.19%) compared to controls (0.19 +/- 0.22%). Phosphorylation of the transactivation domain (Ser-468) of NF-kappaB in isolated ILC2 and IL-33 in lung epithelial cells were significantly increased (126.8 +/- 4.3% and 137 +/- 11% of controls respectively) by nano-TiO2 exposure. Lastly, radial endothelium-dependent arteriolar reactivity was significantly impaired (27 +/- 12%), while endothelium-independent dilation (7 +/- 14%) and alpha-adrenergic sensitivity (8 +/- 2%) were not altered compared to control levels. Treatment with an anti- IL-33 antibody (1 mg/kg) 30 min prior to nano-TiO2 exposure resulted in a significant improvement in endothelium-dependent dilation and a decreased level of IL-33 in both plasma and bronchoalveolar lavage fluid. CONCLUSIONS: These results provide evidence that the uterine microvascular dysfunction that follows pulmonary ENM exposure may be initiated via activation of lung-resident ILC2 and subsequent systemic Th2-dependent inflammation. PMID- 30413214 TI - Intentions on contraception use and its associated factors among postpartum women in Aksum town, Tigray region, northern Ethiopia: a community-based cross- sectional study. AB - BACKGROUND: Increased access to contraceptive methods has been established as a cost-effective strategy for developing countries to reduce maternal and child mortality. Intentions to contraceptive uptake appear to be best predictors of actual contraceptive practice than the unmet need. However, intention to contraceptive use in Ethiopia particularly among postpartum women is not well assessed. Therefore, the objective of this study was to assess intention to use modern contraceptive and to identify factors associated among postpartum women in Aksum town. METHODS: A community -based analytical cross-sectional study design was done to collect the data from 604 postpartum mothers using a structured questionnaire. The data was collected from March 25 to April 24, 2015. A multivariable logistic regression was conducted to assess factors associated with intentions to use contraceptive methods. Factors influencing intentions on contraceptive methods use were assessed by computing adjusted odds ratios (AOR) at 95% confidence interval (CI) with statistical significant p- value < 0.05. RESULTS: Intention to use modern contraceptive was 84.3%. Resumed sexual intercourse (AOR = 1.78; 95% CI: 1.34, 3.92) and women whose their husband approved family planning to use (AOR = 1.57; 95% CI: 2.02, 5.57) were more likely to have intention on contraceptive use. In addition, those women who knew at least one method of modern contraceptive (AOR = 5.17; 95% CI: 1.69, 15.82) were more likely to had intention to use modern contraceptive during extended postpartum period compared to their counterparts. CONCLUSION AND RECOMMENDATION: More than eight in ten study participants have intention to use contraceptive in the Aksum town. Resumed sexual intercourse, husband's approval of family planning and knew at least one method of contraceptive are the three major predictors to be an areas when considering interventions to increase of intention on contraceptive. Therefore, this study highlighted that; in order to increase intention and adoption of contraceptive, the family planning services providers and programmers should continue the promotion of partner involvement and increasing family planning knowledge through printed media and mass media. PMID- 30413215 TI - Inhibitor clinical burden of disease: a comparative analysis of the CHESS data. AB - BACKGROUND: Patients with hemophilia and inhibitors generally face greater disease burden compared to patients without inhibitors. While raising awareness of relative burden may improve the standard of care for patients with inhibitors, comparative data are sparse. Analyzing data drawn from the Cost of Haemophilia across Europe - a Socioeconomic Survey (CHESS) study, the aim of this study was to compare the clinical burden of disease in patients with severe hemophilia with and without inhibitors. Hemophilia specialists (N = 139) across five European countries completed an online survey between January-April 2015, providing demographic, clinical and 12-month ambulatory/secondary care activity data for 1285 patients. Patients with hemophilia who currently presented with inhibitors and those who never had inhibitors were matched on baseline characteristics via propensity score matching. Outcomes were compared between the two cohorts using a paired t-test or Wilcoxon signed-rank or McNemar's test. RESULTS: The proportion of patients who currently presented with inhibitors was 4.5% (58/1285). Compared to PS-matched patients without inhibitors, patients with inhibitors experienced more than twice the mean annual number of bleeds (mean +/- standard deviation, 8.29 +/- 9.18 vs 3.72 +/- 3.95; p < .0001) and joint bleeds (2.17 +/- 1.90 vs 0.98 +/- 1.15; p < .0001), and required more hemophilia-related (mean +/- standard deviation, 1.79 +/- 1.83 vs 0.64 +/- 1.13) and bleed-related hospitalizations (1.86 +/- 1.88 vs 0.81 +/- 1.26), hemophilia-related consultations (9.30 +/- 4.99 vs 6.77 +/- 4.47), and outpatient visits (22.09 +/- 17.77 vs 11.48 +/- 16.00) (all, p < .001). More than one-half (53.5%) experienced moderate/severe pain necessitating medication compared to one-third (32.8%) of patients without inhibitors (p = .01). CONCLUSIONS: Patients with hemophilia and inhibitors exhibited greater clinical burden and higher resource utilization compared to their peers without inhibitors. Strategies for improving the standard of care may alleviate burden in this population. PMID- 30413216 TI - Art therapy is associated with sustained improvement in cognitive function in the elderly with mild neurocognitive disorder: findings from a pilot randomized controlled trial for art therapy and music reminiscence activity versus usual care. AB - BACKGROUND: Mild cognitive impairment (MCI) is a phase in cognitive decline when it is still possible to intervene to reverse the decline. Cognitive stimulation delivered through psychosocial interventions provides both psychological intervention and social stimulation to improve cognition. A pilot open-label parallel-arms randomized controlled trial was undertaken to examine the effects of art therapy (AT) and music reminiscence activity (MRA) compared to the control, on the primary outcome of neurocognitive domain assessments in elderly people with MCI. METHODS: Community-living elderly people with MCI (Petersen's criteria), assessed for study eligibility, were randomized using a web-based system with equal allocation to two intervention arms: AT (guided viewing of art pieces and production of visual arts) and MRA (listening, and recalling memories related to music) and a control arm (standard care without any intervention). Interventions were led by trained therapists weekly for 3 months, then fortnightly for 6 months. Neurocognitive domains (mean of memory, attention, and visuo-spatial abilities standardized scores), psychological wellbeing (subsyndromal depression and anxiety) and telomere length as a biological marker of cellular ageing, were assessed by intervention-blinded assessors at baseline, 3 months and 9 months. RESULTS: In total, 250 people were screened and 68 were randomized and included in the analysis. In the AT arm, neurocognitive domains improved compared to the control arm at 3 months (mean difference (d) = 0.40; 90% CI 0.126, 0.679) and were sustained at 9 months (d = 0.31; 90% CI 0.068, 0.548). There was some improvement in depression and anxiety at 3 and 9 months and in telomere length at 9 months, but this was not significant. Similar improvements were observed in the MRA arm over the control arm, but they were not significant. There were no intervention-related adverse effects. CONCLUSIONS: Art therapy delivered by trained staff as "art as therapy" and "art psychotherapy" may have been the significant contributor to cognitive improvements. The findings support cognitive stimulation for elderly people with cognitive decline and signal the need for larger studies and further investigation of carefully designed psycho social interventions for this group. TRIAL REGISTRATION: Clinical Trials.gov, NCT02854085 . Registered on 7 July 2016. PMID- 30413218 TI - Enhancement of dendritic persistent Na+ currents by mGluR5 leads to an advancement of spike timing with an increase in temporal precision. AB - Timing and temporal precision of action potential generation are thought to be important for encoding of information in the brain. The ability of single neurons to transform their input into output action potential is primarily determined by intrinsic excitability. Particularly, plastic changes in intrinsic excitability represent the cellular substrate for spatial memory formation in CA1 pyramidal neurons (CA1-PNs). Here, we report that synaptically activated mGluR5-signaling can modulate the intrinsic excitability of CA1-PNs. Specifically, high-frequency stimulation at CA3-CA1 synapses increased firing rate and advanced spike onset with an improvement of temporal precision. These changes are mediated by mGluR5 activation that induces cADPR/RyR-dependent Ca2+ release in the dendrites of CA1 PNs, which in turn causes an increase in persistent Na+ currents (INa,P) in the dendrites. When group I mGluRs in CA1-PNs are globally activated pharmacologically, afterdepolarization (ADP) generation as well as increased firing rate are observed. These effects are abolished by inhibiting mGluR5/cADPR/RyR-dependent Ca2+ release. However, the increase in firing rate, but not the generation of ADP is affected by inhibiting INa,P. The differences between local and global activation of mGluR5-signaling in CA1-PNs indicates that mGluR5-dependent modulation of intrinsic excitability is highly compartmentalized and a variety of ion channels are recruited upon their differential subcellular localizations. As mGluR5 activation is induced by physiologically plausible brief high-frequency stimulation at CA3-CA1 synapses, our results suggest that mGluR5 induced enhancement of dendritic INa,P in CA1-PNs may provide important implications for our understanding about place field formation in the hippocampus. PMID- 30413219 TI - Sex composition of living children in a matrilineal inheritance system and its association with pregnancy intendedness and postpartum family planning intentions in rural Ghana. AB - BACKGROUND: Sex composition of living children within the context of "sex preference" and its association with various reproductive health outcomes has been extensively studied in South and South East Asia. Although sex preference has been observed in sub-Saharan Africa, there is paucity of research on sex composition of living children and its association with reproductive health behaviours and outcomes, particularly in a matrilineal inheritance system. The purpose of the study was to explore the existence of sex preference in a matrilineal inheritance system. Specifically, the study sought to better understand the issues by examining the sex composition of living children and how it is associated with reproductive outcomes such as pregnancy intendedness and intention to use postpartum family planning among women in a matrilineal area of Ghana. METHODS: This was a cross sectional study conducted at four selected health facilities in the Mfantseman municipality of the Central Region of Ghana. Out of the 1914 pregnant women attending antenatal clinic selected using total enumeration, from 2nd January to 30th April 2012, 1091 with living children and complete socio-demographic data were recruited for this study. Descriptive, chi square and multivariate logistic regression analyses were conducted. RESULTS: The mean age of the 1091 respondents in this study was 28.2 +/- 6.0 years with mean gestational age of 26.7 +/- 6.6 weeks. Whilst 78% of the women had at least a son, 71% had at least a daughter, with those having only sons exceeding those with only daughters by 6.3%. Also, majority of the women with more sons than daughters did not intend their current pregnancies. These observations, coupled with a sex ratio of 109 males to 100 females, inferred the existence of son preference. The levels of unintended pregnancy and intention to use postpartum family planning were high (70% and 78% respectively). There was an association between sex composition of living children and unintended pregnancy but no association between sex composition of living children and intention to use postpartum family planning. Women with only sons were 50% less likely to have unintended pregnancies compared to those with equal number of sons and daughters [AOR 0.5, 95% CI (0.3-0.8)]. Similarly, women over 30 years were 80% less likely to have unintended pregnancies compared to those 15-19 years [AOR 0.2, 95% CI (0.1-0.6)]. The women with parity of 5 or more and resident in Anomabo were more likely to have unintended pregnancy compared to those with parity of up to two [AOR 3.8, 95% CI (1.7-8.59)] and those resident in Saltpond [AOR 1.8, 95%CI (1.1 2.8), respectively. In addition, the women resident in Anomabo were more likely to have intention to use postpartum family planning compared to those in Saltpond [AOR 1.8, 95% CI (1.0-3.3)]. CONCLUSION: There was persistence of more sons than daughters born in a predominantly matrilineal inheritance system and sex composition of living children had significant association with pregnancy intendedness but not with intention to use postpartum family planning. PMID- 30413217 TI - Development of a peptide targeting dopamine transporter to improve ADHD-like deficits. AB - Attention-deficit hyperactivity disorder (ADHD) is a neurocognitive disorder characterized by hyperactivity, inattention, working memory deficits and impulsivity. Its worldwide prevalence is estimated to be 3-5% in children and adolescents. The mainstay treatment for ADHD is stimulant medications (e.g. methylphenidate), which increase synaptic dopamine by directly blocking dopamine transporter (DAT). Although these pharmacological agents are effective, they are often associated with various side effects including risks for future substance use disorders in ADHD patients. Here, we investigated an interaction between DAT and dopamine D2 receptor (D2R) as a novel target to develop potential therapeutics for the treatment of ADHD by using an interfering peptide (TAT DATNT) to dissociate this protein complex. We found that TAT-DATNT promotes locomotor behavior in Sprague-Dawley rats. Furthermore, using in vivo microdialysis and high-performance liquid chromatography, we found that the disruption of D2R-DAT elevates extracellular dopamine level. More importantly, the interfering peptide, TAT-DATNT, attenuates hyperactivity and improves spontaneous alternation behavior in spontaneously hypertensive rats (SHR) ------ a common animal model of ADHD. This work presents a different means (i.e. other than direct blockade by a DAT inhibitor) to regulate the activity of DAT and dopaminergic neurotransmission, and a potential target site for future development of ADHD treatments. PMID- 30413220 TI - Risks and Benefits of Diagnosing and Treating Basal Cell Carcinomas without Biopsy. PMID- 30413221 TI - On "Multicentric Anogenital Bowen's Disease Treated with Imiquimod and CO2 Laser". PMID- 30413222 TI - Comparative Evaluation of Molecular Tests Vis-a-Vis Culture and Treatment Response in the Diagnosis of Cutaneous Tuberculosis. AB - The clinical diagnosis of cutaneous tuberculosis (CT) was based on criteria of reinfection and reactivation. Laboratory tests are mandatory but have limitations, thus demanding continuous innovation. In our study, we took punch biopsies from lesions on 48 patients. Half of these biopsies underwent histopathologic investigation, and the other half were analysed using the BACT Alert 3D system, the Amplified Mycobacterium Tuberculosis Direct Test (AMTDT), and DNA amplification by polymerase chain reaction (PCR) using primers specific for the M. tuberculosis 16SrRNA complex. Patients were given antitubercular therapy for 6 weeks. A positive response was indicative of CT. Histopathology was suggestive, although no acid-fast bacilli could be demonstrated. In vitro culture recovery of M. tuberculosis was possible in six (12.5%); only two (4%) were positive on AMTDT, and 14 (29%) on real-time PCR. Regression of skin lesions was remarkable after antitubercular therapy, irrespective of a laboratory result. AMTDT and real-time PCR are seen to be of low value in the diagnosis of CT. They are limited by high cost, their paucibacillary nature, and technical errors. On comparing has AMTDT and PCR, the latter was found to be superior. High percentages of negative results were also investigated; extensive involvement of skin has yielded positive PCR results, probably due to low immunity and high bacterial load. PMID- 30413223 TI - Occult Patient Intervention Leading to Misleading Histopathology. AB - Patients with skin conditions may apply or consume a wide variety of "remedies" with a similarly wide range of effects that may alter the clinical and/or dermatologic presentations of the lesion. Dermatologists or other clinicians should probe for this and carefully document such treatment, as well as any treatment administered by a health care professional or any other person. The dermatopathologist, however, cannot assume that this has been done or done successfully, and therefore must be on constant alert to recognize the effects of such "remedies." PMID- 30413224 TI - A Unique Pattern of Staphylococcal Scalded Skin Syndrome-Like Erosions in Patients with Atopic Dermatitis: Dermatitis flammeus. AB - We describe the clinical features of a novel complication in patients with atopic dermatitis (AD). Twenty patients, mean age 23 years, with AD who presented with staphylococcal scalded skin syndrome (SSSS)-like lesions were included between January 2008 and September 2010. Skin lesions followed a triphasic progression pattern from erythema to hyperpigmentation and then erosions. A symmetric and predominant flexural involvement was observed. Pseudomonas aeruginosa (PA) (38.9%) and Staphylococcus epidermidis (38.9%) were the most frequently cultured bacteria from skin swabs. Complete resolution was evident in all cases, and the recurrence rate was 35%. In conclusion, a unique complication characterized by triphasic progression to painful erosions was found in a cluster of AD patients. We propose the new term "dermatitis flammeus" to describe this phenomenon, with PA being one of the etiologies. PMID- 30413225 TI - The Role of Dermatoscopy in Infectious Diseases Affecting the Skin, Part 2: Mycologic Infections and Ectoparasitic Infestations. PMID- 30413226 TI - Ilumya(r) (Tildrakizumab): A Newly Approved Interluekin-23 Antagonist for the Treatment of Plaque Psoriasis. PMID- 30413227 TI - Risk Factors for Herpes Zoster: Age, Immunosuppression, and... Statins? PMID- 30413228 TI - Bathing Suit Ichthyosis: A Peculiar Affliction of the Hands and Feet. PMID- 30413229 TI - Multicentric Anogenital Bowen's Disease Treated with Imiquimod and CO2 Laser. AB - A 53-year-old white woman presented to our clinic with skin lesions in the anogenital region that had persisted for 1 year. She had a past medical history of total vulvectomy for a vulvar localization of Bowen's disease. She was otherwise in good health, with no evidence of illness or immunosuppression. Physical examination revealed multiple erythematous papular lesions located in the anogenital region (Figure 1). Dermatoscopy of the anogenital papules revealed glomerular vessels on an erythematous background typical of Bowen's disease (Figure 2A). There were no palpable inguinal lymph nodes. Rectosigmoidoscopy was normal. The biopsy specimen showed full thickness keratinocyte atypia with loss of normal stratification and was conclusive for Bowen's disease (Figure 2B). PMID- 30413230 TI - Acquired Lymphangiectasia of the Scrotum. AB - A 56-year-old man presented with multiple, skin-colored, raised eruptions of the scrotum that had been present for 2 years. Their onset had been gradual, and they had been increasing in size, resulting in cosmetic disfigurement. A year previously, he had been operated on for a bilateral vaginal hydrocele with partial excision and eversion of the sac (Jabouley method).1 There had been no extramarital or unprotected sexual contact, other hospitalizations, or major surgery, swelling of the legs, or long periods of incumbency. Cutaneous examination revealed multiple, discrete and/or coalescing verrucous papules distributed on the upper portion of the scrotum and associated with edema of the penis (Figure 1). The inguinal lymph nodes were not enlarged. Complete blood counts and ultrasonography of the abdomen were normal. Tissue sections stained with hematoxylin and eosin showed hyperkeratosis and multiple ectatic vessels, primarily confined to the papillary dermis, abutting the overlying epidermis, and demarcated by a single endothelial lining. The dilated vessels contained homogenous eosinophillic material (Figure 2). PMID- 30413231 TI - Sunburn Recall Reaction and Mucositis Secondary to Methotrexate Toxicity. AB - A 59-year-old Native American female presented with a 4-day history of malaise, abdominal pain, nausea, jaundice, and a "sunburn-like rash" on the upper chest and back despite lack of recent sun exposure (Figure 1). Medical history was significant for a twenty-year history of universal vitiligo and a five-year history of rheumatoid arthritis (RA) treated with methotrexate (MTX), adalimumab, prednisone, and naproxen sodium. Cutaneous examination revealed hemorrhagic crusting of upper and lower lips (Figure 2), scleral icterus, diffuse jaundice of the skin, and well-demarcated erythematous patches on mid-upper back and anterior neck. The patient had a few scattered erythematous papules with whitish center on bilateral extensor surfaces of the upper extremities and scattered petechiae on both the trunk and upper extremities. PMID- 30413232 TI - Disseminated Cutaneous Mycobacterium chelonae Infection in a Patient with Dermatomyositis. AB - A 39-year-old Caucasian man with a history of dermatomyositis and diabetes mellitus on a regimen of tacrolimus and methylprednisolone presented to our dermatology outpatient clinic with a painful eruption on his left lower leg. Three months before presentation, he had been admitted to the hospital for cellulitis of the left leg. During admission, a needle aspirate of the left leg cellulitis was performed to obtain fluid for culture to guide therapy. The patient was empirically started on vancomycin 1 g every 12 hours and managed by infectious diseases. The culture yielded no growth, however, and the patient was continued on vancomycin for 2 weeks, with resolution of his cellulitis. Two months later, the patient developed multiple painful nodules on his left leg and returned to the infectious disease physician who had managed him during his inpatient stay. He was initially treated with 2 weeks of clindamycin 300 mg twice daily (bid) without improvement. This was then followed by 2 weeks of erythromycin 500 mg every 6 hours, again without improvement. At this point, he was referred to our clinic. PMID- 30413233 TI - Familial Angiofibrohistiocytic Hamartoma Syndrome. AB - A 27-year-old Hispanic man presented with multiple papules and nodules measuring up to 10 cm in diameter. These lesions were widespread (Figure 1), but not on mucosal epithelium. At birth, the patient had had multiple hypopigmented macules that had progressed to papules and nodules over time. Dermatoscopic examination of these papules and nodules showed prominent capillaries. New lesions were constantly developing but were slow-growing. Other family members had similar lesions, including the patient's three brothers, father, paternal aunt, and a 3 year-old niece (daughter of the 2nd eldest brother), although not as extensively as in this patient. The paternal grandparents were not affected (Figure 2). As the patient had been raised in rural Mexico with limited financial resources, access to health care was limited, so the condition had been left undiagnosed and untreated for most of the patient's life. PMID- 30413234 TI - Multiple Eccrine Spiradenomas in a Zosteriform Distribution. AB - A 52-year-old man was referred to our department with a 28-year history of painful nodular lesions located on his left buttock and left inguinal region that had recently increased in size and number. The lesions had developed progressively over many years. Cutaneous examination revealed multiple, well circumscribed, subcutaneous, blue-gray nodules in a zosteriform distribution across the left inguinal region and the left buttock. Some of the painful nodules were large and ulcerated (Figure 1). Computed tomography showed multiple cutaneous nodules but no bone metastases or subcutaneous invasion. Histologic examination of a nodule demonstrated sharply delineated dermal nodules comprising basaloid cells arranged in a trabecular pattern surrounded by eosinophilic fibrous strands (Figure 2). No evidence of malignant transformation was noted. A diagnosis of multiple eccrine spiradenomas was made, and the patient underwent surgical excision of the painful and ulcerated nodules. He was regularly followed up in our department for 12 years. PMID- 30413235 TI - Letters from Botswana: Multiple Skin Tumors in an HIV-Positive Patient. PMID- 30413236 TI - Genetic Testing in Dermatology: Bioethics and Health Policy Implications. PMID- 30413237 TI - Pirfenidone-Related Blue-Gray Pigmentation of the Skin. PMID- 30413238 TI - Wound Grafting for the Treatment of Recessive Dystrophic Epidermolysis Bullosa. PMID- 30413239 TI - Tweet about Skin or a Digital Homage to Skin. PMID- 30413240 TI - An Unusual Late Onset of Ichthyosis Hystrix. PMID- 30413241 TI - A Membrane Burial Potential with H-Bonds and Applications to Curved Membranes and Fast Simulations. AB - We use the statistics of a large and curated training set of transmembrane helical proteins to develop a knowledge-based potential that accounts for the dependence on both the depth of burial of the protein in the membrane and the degree of side-chain exposure. Additionally, the statistical potential includes depth-dependent energies for unsatisfied backbone hydrogen bond donors and acceptors, which are found to be relatively small, ~2 RT. Our potential accurately places known proteins within the bilayer. The potential is applied to the mechanosensing MscL channel in membranes of varying thickness and curvature, as well as to the prediction of protein structure. The potential is incorporated into our new Upside molecular dynamics algorithm. Notably, we account for the exchange of protein-lipid interactions for protein-protein interactions as helices contact each other, thereby avoiding overestimating the energetics of helix association within the membrane. Simulations of most multimeric complexes find that isolated monomers and the oligomers retain the same orientation in the membrane, suggesting that the assembly of prepositioned monomers presents a viable mechanism of oligomerization. PMID- 30413242 TI - Analysis of microstructure-effective diffusivity relationships for the interparticle pore space in physically reconstructed packed beds. AB - We evaluate the effective diffusion coefficient in the interparticle pore space of eight physically reconstructed chromatographic packings of fully porous and core-shell particles, employing an analytical formula that involves the three point microstructural parameter calculated from two-point and three-point correlation functions through an approach based on sampling templates. Diffusivities calculated by the approximate analytical formula are close to those obtained from pore-scale simulations in the reconstructions using a random-walk particle-tracking technique. Diffusivities are affected, apart from the interparticle porosity, by the actual bed microstructure and packing defects like particle oligomers, spalled shells, larger voids, and debris. Importantly, the data for the microstructural parameter and effective diffusion coefficient over the porosity range spanned by the individual packings (0.363-0.444) reveals non monotonic behavior. Our analysis demonstrates that the three-point microstructural parameter reflects this morphological specificity of the packings and, as a result, Eq. (3) provides accurate estimates of the effective diffusion coefficients. The presented numerical approach can therefore be applied to evaluate diffusivities in packed beds with all their salient features just from the geometrical information embodied in the bed porosity and the three-point microstructural parameter. PMID- 30413243 TI - Mandibular Movement Analysis to Assess Efficacy of Oral Appliance Therapy in OSA. AB - RATIONALE: The respiratory effort index derived from vertical mandibular movements (MM-REI) is a potential marker of increased respiratory effort during sleep. We evaluated the effectiveness of mandibular advancement splint therapy using MM-REI, in comparison with the apnea-hypopnea index (AHI) and oxygen desaturation index (ODI). METHODS: Fifty-six subjects (median age, 47 years) with OSA treated with a custom mandibular advancement splint (Herbst appliance) were evaluated at the end of the titration procedure when snoring was reported absent by the sleep partner. We employed a magnetometer to capture mandibular movements (Brizzy; Nomics). Mandibular advancement splint efficacy was assessed as the percent change from baseline, using Bayesian multilevel models. RESULTS: At the end of titration, all indices of OSA severity decreased compared with baseline: AHI (-48.9% to -71.1%), ODI (-49.5% to -77.2%), with obstructive hypopnea index and MM-REI showing the largest responses (-70.6% to -88.5% and -69.5% to -96.3%, respectively). MM-REI normalization via reductions in both mandibular movement event rate and duration accurately reflected efficacy of the appliance. CONCLUSIONS: The reduction of vertical respiratory mandibular movements estimated by MM-REI and sleep respiratory effort duration accompanied the decrease in obstructive hypopneas, AHI, and ODI when snoring resolved in subjects with OSA treated with an optimally titrated mandibular advancement splint. PMID- 30413244 TI - Antibiotic prophylaxis probably reduces the risk of developing postoperative infections but may increase the risk of experiencing adverse events in patients undergoing third-molar surgical extraction. PMID- 30413245 TI - Mineral trioxide aggregate may be superior to calcium hydroxide for histologic dentin bridge formation after pulp capping. PMID- 30413246 TI - Disseminated Tuberculosis in the Differential Diagnosis of Hemophagocytic Syndrome: Author Response. PMID- 30413247 TI - Relation of Platelet Parameters With Incident Cardiovascular Disease (The Dongfeng-Tongji Cohort Study). AB - Prospective studies on the relations between platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), and incident cardiovascular disease (CVD) were still limited. This study aimed to investigate the above mentioned prospective relations in the middle-aged and older Chinese populations based on the Dongfeng-Tongji cohort. We included 31,751 participants who were free of coronary heart disease (CHD), stroke, cancer, or severely abnormal electrocardiogram at baseline. During a median follow-up of 5.9 years, we identified 5,683 incident CVD cases, including 4,423 CHD and 1,260 stroke cases. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% confident intervals (CIs) for the relation analyses. Compared with participants with 146 <= PLT <= 233 10E9/L, the adjusted HR (95% CI) of those with PLT < 146 10E9/L was 0.80 (0.68 to 0.95) for incident stroke. Compared with participants with 7.3 <= MPV <= 10.3 fl, the adjusted HRs (95% CIs) of those with MPV < 7.3 fl were 0.81 (0.75 to 0.88), 0.80 (0.73 to 0.88) and 0.84 (0.71 to 1.00) for incident CVD, CHD and stroke, respectively. Compared with participants with 13.2 <= PDW <= 18.1 %, the adjusted HRs (95% CIs) of those with PDW < 13.2 % were 0.80 (0.73 to 0.87) and 0.78 (0.70 to 0.86) for incident CVD and CHD, respectively. In conclusion, lower levels of PLT and MPV were significantly related to lower risk of stroke, while lower levels of MPV and PDW were significantly related to lower risks of CVD and CHD. PMID- 30413248 TI - Ideal admission electrocardiographic parameters in STEMI: What else do we need to learn? PMID- 30413249 TI - Introduction: Cardiovascular Disease in Chronic Kidney Disease. PMID- 30413250 TI - Update on Chronic Kidney Disease Mineral and Bone Disorder in Cardiovascular Disease. AB - Chronic kidney disease mineral and bone disorder (MBD) encompasses changes in mineral ion and vitamin D metabolism that are widespread in the setting of chronic kidney disease and end-stage renal disease. MBD components associate with cardiovascular disease in many epidemiologic studies. Through impacts on hypertension, activation of the renin-angiotensin-aldosterone system, vascular calcification, endothelial function, and cardiac remodeling and conduction, MBD may be a direct and targetable cause of cardiovascular disease. However, assessment and treatment of MBD is rife with challenges owing to biological tensions between its many components, such as calcium and phosphorus with their regulatory hormones fibroblast growth factor 23 and parathyroid hormone; fibroblast growth factor 23 with its co-receptor klotho; and vitamin D with control of calcium and phosphorus. These complex interactions between MBD components hinder the simple translation to clinical trials, which ultimately are needed to prove the benefits of treating MBD. Deeper investigation using precision medicine tools and principles, including genomics and individualized risk assessment and therapy, may help move the field closer toward clinical applications. This review provides a high-level overview of conventional and precision epidemiology in MBD, potential mechanisms of cardiovascular disease pathogenesis, and guiding therapeutic principles for established and emerging treatments. PMID- 30413251 TI - Cardiovascular Disease in Children and Adolescents With Chronic Kidney Disease. AB - The lifespan of children with advanced chronic kidney disease (CKD), although improved over the past 2 decades, remains low compared with the general pediatric population. Similar to adults with CKD, cardiovascular disease accounts for a majority of deaths in children with CKD because these patients have a high prevalence of traditional and uremia-related risk factors for cardiovascular disease. The cardiovascular alterations that cause these terminal events begin early in pediatric CKD. Initially, these act to maintain hemodynamic homeostasis. However, as the disease progresses, these modifications are unable to sustain cardiovascular function in the long term, leading to left ventricular failure, depressed cardiorespiratory fitness, and sudden death. In this review, we discuss the prevalence of the risk factors associated with cardiovascular disease in pediatric patients with CKD, the pathophysiology that stimulates these changes, the cardiac and vascular adaptations that occur in these patients, and management of the cardiovascular risk in these patients. PMID- 30413252 TI - Dialysis Prescription and Sudden Death. AB - In the United States, end-stage renal disease patients receiving hemodialysis have an exceedingly high risk of sudden cardiac death (SCD), accounting for 29% of death events, likely relating to their uremic milieu, recurring exposure to fluid and electrolyte fluxes, and underlying cardiovascular pathology. Furthermore, epidemiologic studies have shown that SCD events, as well as mortality and hospitalizations, occur most frequently on the first dialysis day after the long interdialytic gap, suggesting that abrupt fluctuations in the accumulation and removal of electrolytes, fluid, and uremic toxins over the dialysis cycle may be contributory. Some population-based observational studies have suggested that lower dialysate potassium concentrations appear to be associated with a heightened risk of postdialysis cardiac arrest in hemodialysis patients, although the optimal serum-to-dialysate potassium gradient remains unclear. Some observational studies have suggested that low dialysate calcium concentrations and high serum-to-dialysate calcium gradients may predispose patients to SCD. There is ongoing controversy about an association between higher dialysate bicarbonate concentrations and higher risk of cardiac arrest, likely owing to confounding by indication. Some observational studies also have shown that large interdialytic weight gains, fluid retention, and high ultrafiltration rates are linked with higher risk of SCD and mortality. However, there remains considerable controversy regarding the pros and cons of designating a specific upper ultrafiltration limit with extended treatment times as a clinical practice measure, and further studies are needed to define the optimal tools, metrics, targets, and implementation measures for volume control in the hemodialysis population. In this review, we highlight the epidemiology and pathophysiology of how specific aspects of the hemodialysis procedure may relate to the risk of SCD, as well as preventative strategies and future research directions that can address this risk. PMID- 30413253 TI - Risk Stratification and Treatment of Coronary Disease in Chronic Kidney Disease and End-Stage Kidney Disease. AB - Patients with advanced chronic kidney disease have an enormous burden of cardiovascular morbidity and mortality, but, paradoxically, their representation in randomized trials for the evaluation and management of coronary artery disease has been limited. Clinicians therefore are faced with the conundrum of synergizing evidence from observational studies, expert opinion, and extrapolation from the general population to provide care to this complex and clinically distinct patient population. In this review, we address clinical risk stratification of patients with chronic kidney disease and end-stage kidney disease using traditional cardiovascular risk factors, noninvasive functional and structural cardiac imaging, invasive coronary angiography, and cardiovascular biomarkers. We highlight the unique characteristics of this population, including the high competing risk of all-cause mortality relative to the risk of major adverse cardiac events, likely owing to important contributions from nonatherosclerotic mechanisms. We further discuss the management of coronary artery disease in patients with chronic kidney disease and end-stage kidney disease, including evidence pertaining to medical management, coronary revascularization with percutaneous coronary intervention, and coronary artery bypass grafting. Our discussion includes considerations of drug-eluting versus bare metal stents for percutaneous coronary intervention and off-pump versus on pump coronary artery bypass graft surgery. Finally, we address currently ongoing randomized trials, from which clinicians are optimistic about receiving guidance regarding the best strategies to incorporate into their practice for the evaluation and management of coronary artery disease in this high-risk population. PMID- 30413254 TI - Heart Failure in End-Stage Kidney Disease: Pathophysiology, Diagnosis, and Therapeutic Strategies. AB - Heart failure (HF) is a major comorbidity in patients with end-stage kidney disease (ESKD). The pathogenesis of HF in patients on renal replacement therapy represents the confluence of several traditional and nontraditional vascular risk factors, unique to the milieu of chronic kidney disease and the dialysis modality. The diagnosis of HF with ESKD is complicated by the background of frequent inevitable fluid shifts superimposed on underlying myocardial pump abnormalities and dialysis-induced myocardial stunning. A careful temporal assessment of symptoms and physical findings, cardiac imaging, hemodynamic data, and biomarkers help establish an accurate diagnosis of HF in ESKD. Accurate volume assessment and its tight management remains the cornerstone of treatment in HF in patients on dialysis. A multidisciplinary approach between the cardiologist and nephrologist in optimizing pharmacologic strategies for HF in this population, and dialysis-based options such as frequent dialysis, may help reduce the burden of HF in this vulnerable population. Finally, including patients with ESKD in clinical trials for HF therapies, and designing pragmatic trials that bring targeted strategies for HF into the daily clinical practice of dialysis, will shed light on the optimal management of the dual burden of cardiomyopathy and advanced kidney disease. PMID- 30413256 TI - Causal Connections From Chronic Kidney Disease to Cardiac Fibrosis. AB - Cardiovascular disease and heart failure are the primary cause of morbidity and mortality in patients with chronic kidney disease. Because impairment of kidney function correlates with heart failure and cardiac fibrosis, a kidney-heart axis is suspected. Although our understanding of the underlying mechanisms still is evolving, the possibility that kidney-heart messengers could be intercepted offers ample reason to focus on this clinically highly relevant problem. Here, we review the current knowledge of how kidney injury causes heart failure and fibrosis. PMID- 30413257 TI - Preface. PMID- 30413255 TI - Oral Anticoagulation in Patients With End-Stage Kidney Disease on Dialysis and Atrial Fibrillation. AB - Patients with end-stage kidney disease (ESKD) have an elevated incidence of atrial fibrillation (AF) and are at increased risk for thromboembolic events. However, these patients are also at increased risk for bleeding and it is unclear whether they benefit from an oral anticoagulant. Point prevalent on July 1, 2015, only ~28% of dialysis patients with AF were on oral anticoagulation. Warfarin was the most commonly used oral anticoagulant, followed by apixaban, while dabigatran and rivaroxaban were rarely used. This article reviews the current evidence regarding each oral anticoagulant especially as they relate to patients with ESKD. PMID- 30413258 TI - Insights into the etiology and embryology of gastroschisis. AB - The development of gastroschisis has long remained an area of interest and controversy. Successive theories about its pathogenesis are herein reviewed and discussed. Two historical assumptions, that omphalocele results from a persistent umbilical hernia, and that gastroschisis does not involve the umbilical cord, are dismissed. Therefore, one can envision gastroschisis for what it is, i.e. a ruptured physiological hernia. The causal agents for this intrauterine accident to occur are yet to be determined. Further bowel damage and complications can be explained by the mesenteric insult. PMID- 30413259 TI - Advances in prenatal and perinatal diagnosis and management of gastroschisis. AB - Gastroschisis is a congenital, ventral wall defect associated with bowel evisceration. The defect is usually to the right of the umbilical cord insertion and requires postnatal surgical correction. The fetus is at risk for complications such as intrauterine growth restriction, preterm delivery, and intrauterine fetal demise. In addition, complex cases, defined by the presence of intestinal complications such as bowel atresia, stenosis, perforation, or ischemia, occur in up to one third of pregnancies affected by gastroschisis. As complex gastroschisis is associated with increased morbidity and mortality, research has focused on the prenatal detection of this high risk subset of cases. The purpose of this review is to discuss the prenatal, diagnostic approach to the identification of gastroschisis, to describe potential signs of complex gastroschisis on prenatal ultrasound, to review current guidelines for antepartum management and delivery planning, and to summarize results of both past and current intervention trials in fetuses with gastroschisis. PMID- 30413260 TI - Risk stratification and outcome determinants in gastroschisis. AB - Selection of outcome determinants and risk stratification are necessary to identify patients at higher risk for morbidity and mortality. This facilitates human and material resource allocation and allows for improved family counseling. While several different factors, including prenatal ultrasonographic bowel features, the timing and mode of delivery, and the features of bowel injury have been investigated in gastroschisis, there is still significant debate as to which of these best predicts outcome. This article reviews the different outcome predictors and risk prognostication schemata currently available in the literature to help guide clinicians caring for infants with gastroschisis. PMID- 30413261 TI - Closure methods in gastroschisis. AB - The expected outcome of gastroschisis has evolved from an almost certain death of the child prior to the use of parenteral nutrition to almost certain survival. The primary goal of the surgical intervention is return of eviscerated contents into the abdominal cavity. The optimal surgical technique is dependent on the status of the intestine and the accommodation of abdominal domain. In this review, the various surgical techniques for management are discussed as they have evolved. Ironically, a minimalist surgical intervention originally practiced due to the poor expected outcome is now being adopted as a minimalist surgical approach for abdominal wall closure associated with an expected excellent outcome. PMID- 30413262 TI - Surgical strategies in complex gastroschisis. AB - Currently, the most important determinant of gastroschisis outcomes in high resource settings is whether the condition is associated with intestinal complications, such as atresia, necrosis, perforation, or volvulus. This form of the anomaly, known as complex gastroschisis, accounts for most of the mortality and a disproportionate burden of the morbidity from gastroschisis. There is some disagreement about what constitutes complex gastroschisis, and little consensus on the type and timing of surgical interventions. This article establishes a clear definition of complex gastroschisis. Surgical approaches to treatment of the diverse presentations of complex gastroschisis will be described and the timing of such interventions will be discussed. Contemporary outcomes of complex gastroschisis will be reviewed. Finally, a non-congenital intestinal complications that may arise in gastroschisis patients will be discussed. PMID- 30413264 TI - Care of infants with gastroschisis in low-resource settings. AB - There is great global disparity in the outcome of infants born with gastroschisis. Mortality approaches 100% in many low income countries. Barriers to better outcomes include lack of antenatal diagnosis, deficient pre-hospital care, ineffective neonatal resuscitation and venous access, limited intensive care facilities, poor access to the operating theatre and safe neonatal anesthesia, and lack of neonatal parenteral nutrition. However, lessons can be learned from the evolution in management of gastroschisis in high-income countries, generic efforts to improve neonatal survival in low- and middle-income countries as well as specific gastroschisis management initiatives in low resource settings. Micro and meso-level interventions include educational outreach programs, and pre and in hospital management protocols that focus on resuscitation and include the delay or avoidance of early neonatal anesthesia by using a preformed silo or equivalent. Furthermore, multidisciplinary team training, nurse empowerment, and the intentional involvement of mothers in monitoring and care provision may contribute to improving survival. Macro level interventions include the incorporation of ultrasound into World Health Organisation antenatal care guidelines to improve antenatal detection and the establishment of the infrastructure to enable parenteral nutrition provision for neonates in low- and middle-income countries. On a global level, gastroschisis has been suggested as a bellwether condition for evaluating access to and outcomes of neonatal surgical care provision. PMID- 30413263 TI - Impact of societal factors and health care delivery systems on gastroschisis outcomes. AB - Care of infants with gastroschisis is associated with a significant burden on health care delivery systems. Mortality rates in patients with gastroschisis have significantly improved over the past few decades. However, the condition is still associated with significant short-term and potentially long-term morbidity. Significant variations in clinical outcomes and resource utilization may be explained by several factors including provider and hospital experience, level of neonatal intensive care, variations in hospital regionalization of care, and differences in healthcare delivery systems. Reviewing and assessing these hospital and healthcare system related factors are paramount in addressing variations in gastroschisis care and improving outcomes for these vulnerable infants. PMID- 30413265 TI - Medium and long-term outcomes of gastroschisis. AB - As survival of gastroschisis patients has improved significantly, it has become apparent that longitudinal follow up strategies need to be developed. Problems concerning patients with gastroschisis are usually associated with gastrointestinal morbidity, but there is mounting evidence that also neurodevelopmental, cognitive, behavioral and late-onset auditory sequelae exist. The presence of associated anomalies, as well as complex features (bowel atresia, necrosis, volvulus, perforation) increase morbidity and impact long-term outcomes. Multidisciplinary follow-up is required, and the key elements of such follow-up are presented here. PMID- 30413267 TI - Editor's Perspectives - November 2018. PMID- 30413268 TI - Prospective evaluation of psychological burden in patients with oral cancer. AB - The high morbidity and mortality that is associated with oral cancer places a huge psychological burden on patients. The purpose of this prospective study was to evaluate levels of depression, anxiety, and stress, at three time points using DASS-21 (Depression, Anxiety and Stress Scale-21). We also compared DASS-21 with HADS (Hospital Anxiety and Depression Scale). A total of 111 patients were enrolled and 75 of them completed the questionnaires at diagnosis, one month after treatment, and three months after discharge. Scores were high for stress at diagnosis, and for depression at the other time points, but were low for anxiety at all three. The results of Friedman's ANOVA showed that mean ranks for depression and stress were significant (p<0.05). Scores for depression and stress rose significantly between diagnosis and three months after operation, but those for anxiety (which had increased between diagnosis and operation p>0.05), were stable three months postoperatively. The DASS-21 was a useful method of evaluating stress. Correlation of the results from the two questionnaires showed a strongly positive association. We therefore recommend psychological intervention to improve overall outcome. PMID- 30413266 TI - Portomesenteric vein thrombosis following laparoscopic greater curve plication for morbid obesity. AB - Portomesenteric venous thrombosis (PMVT) is an uncommon condition associated with intra-abdominal visceral ischemia that is often difficult to manage. While postoperative PMVT has been rarely reported following laparoscopic abdominal surgery, its occurrence in morbidly obese patients is gaining increasing concern due to its relatively higher incidence after laparoscopic bariatric surgery. Diagnosis of PMVT can be readily accomplished by computed tomography scan. Although prompt treatment with recanalisation of portovenous system and reversal of mesenteric venous ischemia can be potentially life-saving, the overall mortality of postoperative PMVT can only be controlled by understanding the underlying etiologies and preventing its occurrence. Here, we report a case of PMVT in a morbidly obese lady who presented at 10days after an uneventful laparoscopic greater curve plication. The potential etiology and management of this rare complication are elucidated in details. PMID- 30413269 TI - Reengineering the patient's environment: Establishment of a "Red Box" to improve communications with patients on isolation precautions. AB - BACKGROUND: Hospitalized patients on isolation precautions are reported to have less frequent health care provider (HCP) visits owing to time required to don and doff personal protective equipment (PPE). Thus, placement on isolation precautions leads to negative patient perception and affects their care. METHODS: A "Red Box" that extended 3 feet beyond the door was marked in 50 patient rooms of a tertiary care hospital and used for patient communication by HCPs without PPE. HCP and patient perceptions of the Red Box were studied via a survey and personal interviews. Compliance was also observed by "secret shoppers." Rates of health care-associated infections (HAIs) were monitored. RESULTS: Over a 1-year period, HCPs reported improved patient communication, utilization of time, and increased interactions. HCPs used the Red Box to communicate with patients 76% of the time. In 92% of the cases, HCPs remembered not to use PPE while in the Red Box and were observed 80% of the time using PPE when venturing beyond the Red Box. Patients reported improved frequency of HCP contact and satisfaction. HAIs in these units did not show any increase compared with those in prior years. CONCLUSIONS: HCP interaction and communication with patients on isolation precautions improved with the reengineering of the patient environment in the form of the Red Box. HAI rates did not increase with this intervention. PMID- 30413270 TI - [The Annales de dermatologie turns 150!] PMID- 30413271 TI - Galectin-Carbohydrate Interactions in Biomedicine and Biotechnology. AB - Cellular communication events are mediated by interactions between cell-surface sugars and lectins, which are carbohydrate-binding proteins. Galectins are beta galactosyl-binding lectins that bridge molecules by their sugar moieties, forming a signaling and adhesion network. Severe changes in glycosylation and galectin expression accompany major processes in oncogenesis, cardiovascular disorders, and other pathologies, making galectins attractive therapeutic targets. Here we discuss advanced strategies of chemo-enzymatic carbohydrate synthesis for creating lead glycomimetics and (neo-)glycoconjugates for galectin-1 and -3 targeting in biomedicine and biotechnology. We will describe the challenges and bottlenecks on the route into biomedical and biotechnological practice and present the first clinical candidates. The coming era will see an exciting translation of selective well-defined high-affinity galectin ligands from bench to bedside. PMID- 30413272 TI - Effect of Trichinella spiralis intervention on TNBS-induced experimental colitis in mice. AB - Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease (CD), are chronic autoimmune diseases with a high recurrence rate. Epidemiological data have shown that the incidence of IBD increases annually because of improved sanitary conditions and reduced parasitic infection rates. In this experiment, experimental colitis was induced in mice by administering 2,4,6 trinitrobenzene sulfonic acid (TNBS) 28 days after they were infected with Trichinella spiralis to confirm that T. spiralis infection could alleviate the severity of TNBS-induced colitis. Thirty-six male BALB/c mice aged 6-8 weeks were randomly divided into four groups: control group (with 50% ethanol, Control), T. spiralis-infected group (TS-Control), TNBS-induced colitis model group (Colitis), and T. spiralis-pre-infected and TNBS-induced colitis group (TS-Colitis). The mice were sacrificed 3, 7, and 14 days after the model was established. Changes in various colitis indicators to investigate the effect of T. spiralis infection on TNBS-induced murine CD model. Results showed that the weight, DAI score, and macroscopic and microscopic colon damage in the TS-Colitis significantly decreased compared with those in the Colitis. ELISA revealed that the IFN-gamma expression decreased and the IL-4 expression increased in the TS-Colitis compared with those in the Colitis. Western Blotting results revealed that the NF-kappaB expression increased in the Colitis and higher than those in the TS-Colitis. And Flow cytometry results revealed that the percentage of CD4+CD25+Foxp3+ Treg cells significantly increased in the TS-Colitis. T. spiralis-infected mice induced Th2 immune responses and balanced Th1 immune responses stimulated by TNBS to ameliorate intestinal inflammation. PMID- 30413273 TI - Intestinal failure associated cholestasis in surgical necrotizing enterocolitis and spontaneous intestinal perforation. AB - BACKGROUND: Surgery for necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) is often complicated by intestinal failure (IF) and intestinal failure associated cholestasis (IFAC). OBJECTIVE: Assessment of incidence, predictors, and mortality associated with IFAC in surgically treated NEC and SIP. METHODS: A retrospective observational study based on hospital records during 1986-2014 in the two largest Finnish neonatal intensive care units was performed. IFAC was defined as conjugated bilirubin >34 MUmol/l (2.0 mg/dl) for >= two postoperative weeks while receiving parenteral nutrition (PN). RESULTS: In total 225 patients underwent surgery for NEC (n = 142; 63%) or SIP (n = 83; 37%). Included were 57 survivors with >=two weeks PN. Sixty-five (42%) patients developed IFAC. Two-year survival with IFAC was 80% and without IFAC 89% (p = 0.13). Of the 65 patients with IFAC, all eight with unresolved IFAC died in comparison to six of 57 (11%) whose IFAC resolved (p < 0.0001), while IFAC resolved in all survivors. Survival among patients with resolved IFAC was 89% and with unresolved IFAC (n = 8) 0%, (p < 0.0001). IFAC lasted for median 83 (IQR 45 120) days and correlated with the duration of PN (R2 = 0.16, p = 0.03), delay of starting enteral feeds (R2 = 0.12, p = 0.05) and PN lipid emulsion (RR = 1.0 (95% CI = 1.0-1.1) (p = 0.02). In multivariate logistic regression analysis, IFAC development associated with septicemias and reoperations. CONCLUSIONS: 42% of prematures who underwent surgery for NEC or SIP developed IFAC. Reoperations and septicemias increased the risk of IFAC. None of the patients with unresolved IFAC survived, but IFAC did not increase overall mortality. TYPE OF STUDY: Retrospective prognosis study. LEVEL OF EVIDENCE: Level II. PMID- 30413274 TI - The Role of the Pulmonologist in a Multidisciplinary Amyotrophic Lateral Sclerosis Unit. Challenge, Opportunity, and Privilege. PMID- 30413275 TI - Mobilizing older adults: A multi-site, exploratory and observational study on patients enrolled in the Hospital Elder Life Program (HELP). AB - The aim of this study was to explore and describe the characteristics of the Hospital Elder Life Program (HELP) sites and how they mobilize patients with volunteers in the United States and other countries. The purpose was to describe: the number of enrollments, modalities, fall and injury rates, and to identify barriers to mobilization. A survey was distributed to 228 international sites. The responding sites enrolled an average of 53.9 (SD 35.3) patients per month. The majority (76%) reported that mobilization included 'active range of motion exercises' and 'ambulation'. Eighteen percent identified volunteer training, safety and liability concerns as barriers. Falls with injury on HELP units was 0 3%, with an average rate of 0.46 per 1,000 patient days. No patient falls while ambulating with the HELP team and/or volunteers were reported. More research and evidence are needed to further determine barriers and safety of mobilization with the HELP during hospitalization. PMID- 30413276 TI - Beyond the medical-Assisting with social determinants of health in the drive to value-based care. PMID- 30413277 TI - Kidney Transplantation in C3 Glomerulopathy: A Case Series. AB - RATIONALE & OBJECTIVE: C3 glomerulopathy (C3G), a form of glomerulonephritis associated with dysregulation of the alternative complement pathway, occurs either as dense deposit disease (DDD) or C3 glomerulonephritis (C3GN). Few studies have reported outcomes of patients with C3G after transplantation since its formal classification and the advent of complement-targeting therapies such as eculizumab. STUDY DESIGN: Case series of C3G. SETTING & PARTICIPANTS: We reviewed laboratory testing, native and allograft biopsy reports, and clinical charts of the 19 patients (12, C3GN; and 7, DDD) from our C3G registry who underwent transplantation between 1999 and 2016. RESULTS: During a median follow up of 76 months, 16 patients had recurrent disease (10 of 12, C3GN; and 6 of 7, DDD), with median time to recurrence of 14 months in C3GN versus 15 months in DDD. Graft failure was more frequent in patients with DDD (6 of 7) than in patients with C3GN (3 of 12), occurred at a median time of 42 months posttransplantation, and was attributed to recurrent disease in half the failures. A rare genetic variant or autoantibody associated with alternative complement pathway abnormalities was detected in 9 of 10 screened patients. Treatment of 7 patients (8 allografts) with eculizumab was associated with variable clinical outcomes. LIMITATIONS: Incomplete testing for complement pathway abnormalities and genetic defects, incomplete records of HLA antigen matching, lack of centralized biopsy review, and limited sample size. CONCLUSIONS: In a case series of C3G transplant recipients, the proportion of disease recurrence was high in both C3GN and DDD, although graft loss appeared to occur more frequently in DDD. In a small subset of study patients, eculizumab therapy was not consistently followed by salutary outcomes. PMID- 30413278 TI - [Transthoracic echocardiographic assessment of cardiac output in mechanically ventilated critically ill patients by intensive care unit physicians]. AB - BACKGROUND AND OBJECTIVES: Transthoracic echocardiography may potentially be useful to obtain a prompt, accurate and non-invasive estimation of cardiac output. We evaluated whether non-cardiologist intensivists may obtain accurate and reproducible cardiac output determination in hemodynamically unstable mechanically ventilated patients. METHODS: We studied 25 hemodynamically unstable mechanically ventilated intensive care unit patients with a pulmonary artery catheter in place. Cardiac output was calculated using the pulsed Doppler transthoracic echocardiography technique applied to the left ventricular outflow tract in apical 5 chamber view by two intensive care unit physicians who had received a basic Transthoracic Echocardiography training plus a specific training focused on Doppler, left ventricular outflow tract and velocity-time integral determination. RESULTS: Cardiac output assessment by transthoracic echocardiography was feasible in 20 out of 25 enrolled patients (80%) and showed an excellent inter-operator reproducibility (Pearson correlation test r=0.987; Cohen's K=0.840). Overall, the mean bias was 0.03L.min-1, with limits of agreement -0.52 and +0.57L.min-1. The concordance correlation coefficient (rhoc) was 0.986 (95% IC 0.966-0.995) and 0.995 (95% IC 0.986-0.998) for physician 1 and 2, respectively. The value of accuracy (Cb) of COTTE measurement was 0.999 for both observers. The value of precision (rho) of COTTE measurement was 0.986 and 0.995 for observer 1 and 2, respectively. CONCLUSIONS: A specific training focused on Doppler and VTI determination added to the standard basic transthoracic echocardiography training allowed non-cardiologist intensive care unit physicians to achieve a quick, reproducible and accurate snapshot cardiac output assessment in the majority of mechanically ventilated intensive care unit patients. PMID- 30413279 TI - Perceptions of middle school youth about school bullying. AB - INTRODUCTION: Bullying prevention remains a major focus for schools yet prevention programs have yielded limited efficacy. This suggests that efforts to make the programs more salient for youth may result in greater reductions in bullying behavior. METHODS: To inform the development of a text messaging-based bullying prevention program for middle school youth, we conducted two online, asynchronous focus groups with 37 youth in grades 6-8. Youth were recruited across the United States using an online panel. Topics and questions were posted twice-daily across three days; youth responded when convenient. RESULTS: Findings suggested: (a) When asked, many youth provided definitions of bullying that were simliar to the CDC's definition (e.g., differential power). At times, these did not align with their school's definition, however. (b) Youth said those who were 'different', quiet, or unpopular were more likely to be targeted by bullies; (c) Central tenants of bullying prevention programs (e.g., help-seeking, bystander interventions) did not always resonate with youth (e.g., becuase they could be hurt by the bully) although youth did share a range of strategies to manage anger; and (d) Many youth reported that bullying prevention efforts at their school were limited to posters and assemblies. CONCLUSIONS: Asking students about their perspectives of the main tenants of bully prevention programs provides opportunities to craft prevention program content that better speaks to the experiences and concerns that youth have when trying to navigate these difficult situations. Focus groups are also useful in identifying the ways in which youth talk about bullying and other types of peer aggression to guide the 'voice' of the program. PMID- 30413280 TI - Atypical presentation of a solid-variant orbital aneurysmal bone cyst with a literature review. AB - INTRODUCTION: Aneurysmal bone cysts (ABCs) are rare, rapidly expansile, benign, vascular lesions capable of causing local bone destruction. The majority of cases present as multi-cystic lytic lesions (with solid-variant ABCs representing<10% of all presentations) of the long bones or vertebrae, rarely occurring in the head/neck region. CLINICAL CASE: A 44-year-old female presented with nine days of worsening pain, ptosis and proptosis in the right eye. CT and MR imaging revealed a 3.2cm extra-axial multiloculated right frontal lobe mass in the orbit with fluid-fluid levels secondary to layering of solid blood components. A right craniotomy was performed and the lesion was resected piecemeal with subsequent high speed burring to remove residual tissue. Histological evaluation revealed spindle and giant cell infiltration of the bone without vascular channels. Based on these findings, the lesion was diagnosed as a solid-variant orbital ABC without paranasal sinus involvement. The patient recovered fully with no residual symptoms. CONCLUSION: This case report details a rare presentation of ABC (solid variant presenting outside of the vertebrae/long bones) with discussion concerning possible treatment modalities and guidance for follow-up. PMID- 30413281 TI - Safety of patient-facing digital symptom checkers. PMID- 30413282 TI - The efficacy of chronic zinc oxide nanoparticles using on testicular damage in the streptozotocin-induced diabetic rat model. AB - Testicular impairment is a common complication of Diabetes mellitus (DM). Zinc Oxide Nanoparticles (ZnO NPs) are a novel agent for Zn delivery with antidiabetic and antioxidant activities. However, few reports were recorded on it. The current study aimed to investigate the possible ameliorating effect of ZnO NPs treatment on testicular tissues alterations in streptozotocin (STZ)-induced diabetic rats. Therefore, thirty mature male Wistar rats were divided into three main groups: Control group (n = 18) was subdivided equally into three subgroups (negative control, vehicle and ZnO NPs), Diabetic group (n = 6) and ZnO NPs-treated diabetic group (n = 6). Induction of diabetes was done by a single intraperitoneal injection of STZ (60 mg/kg bw). The rats were orally treated by ZnO NPs (10 mg/kg bw) for 30 constitutive days. At the end of the experiment, blood glucose and serum testosterone levels were measured. Also, testicular tissues were obtained for histopathological investigations and immunohistochemical staining with anti-PCNA (proliferating cell marker), anti ssDNA (apoptotic cell marker), anti-SOX9 (Sertoli cell marker), anti-Stella (spermatogonia marker), anti-STRA8 (preleptotene and early-leptotene spermatocytes marker), anti-DMC1 (leptotene and zygotene spermatocytes marker), anti-Dnmt3a (a marker for cells under DNA methylation) and anti-alpha-SMA (peritubular myoid cell marker). The biochemical analysis revealed that diabetes resulted in a significant elevation in blood glucose level and a reduction in serum testosterone level. Moreover, histopathological investigations revealed disorganized seminiferous epithelium and sever hyalinization with vacuolization of the testicular interstitium containing Leydig cells. The immunohistochemical findings support spermatogenesis impairment in the diabetic group. However, ZnO NPs treatment restores architecture of seminiferous epithelium and Leydig cells. Furthermore, more PCNA, SOX9, Stella, STRA8, DMC1 and Dnmt3a immunopositive cells with an improvement of peritubular alpha-SMA immunopositive expression, as well as few ssDNA-immunopositive cells were detected in the seminiferous epithelium. This study suggested the possible protective role of orally administered ZnO NPs on testicular alterations in the STZ-induced diabetic group via steroidogenesis and spermatogenesis enhancement. In addition, further researches are acquired for evaluation mechanism of ZnO NPs treatment via oral or parenteral routes in a dose dependent manner to identify the more effective route and dose in the treatment of testicular diabetic complications. PMID- 30413283 TI - State-level variation in the relationship between child removals and opioid prescriptions. AB - BACKGROUND: One of the most devastating impacts of the U.S. opioid crisis is the challenge it creates for dependent parents to care for their children, potentially leading to the child being removed from their home. However, existing studies of the link between child removals and opioid prescriptions have either focused on a single state or estimated a national average. OBJECTIVE: To estimate state-level associations between child removals and opioid prescriptions. PARTICIPANTS AND SETTING: U.S. counties from 2010 to 2015. METHODS: We performed longitudinal regression analysis in which the rates for all removals and removals associated with parental drug abuse were employed as dependent variables. In addition to the opioid prescription rate, additional explanatory variables included child removal risk factors, county fixed effects, year fixed effects, and state-specific time trends. Interaction variables were used to estimate state specific relationships. RESULTS: We found substantial variation in the association between child removals and opioid prescriptions. Twenty-three states had a positive association, fifteen had a negative association, and twelve did not have a statistically significant association. A one-standard deviation increase in the prescription rate was associated with a 37% (p < .001) increase in the removal rate for parental drug abuse in Illinois, while in New Hampshire it was associated with a 28% (p < .001) decrease. CONCLUSIONS: The substantial variation in state-level relationships between child removals and opioid prescriptions may reflect differences in the extent to which states have experienced the opioid crisis and indicate the need for interventions that account for those differences. PMID- 30413284 TI - About congenital myopathies and neuromuscular monitorization. PMID- 30413285 TI - Timing for aortic surgery in rare genetic variants: When prevention warrants intervention? PMID- 30413286 TI - The appendage strikes back: The last surgeon. PMID- 30413287 TI - Hacked by the Russians. PMID- 30413288 TI - Jobelyn(r) ameliorates neurological deficits in rats with ischemic stroke through inhibition of release of pro-inflammatory cytokines and NF-kappaB signaling pathway. AB - The effects of Jobelyn(r) (JB) on neurological deficits and biochemical alterations associated with ischemic stroke induced by bilateral common carotid artery occlusion (BCCAO) in rats were investigated in this study. Male Wistar rats were divided into five groups (n = 8): group 1 served as Sham control; group 2, which served as negative control received normal saline while groups 3-5 were given JB (25, 50 and 100 mg/kg, p.o) daily for 28 days. Then, rats in groups 2-5 were subjected to BCCAO for 30 min and reperfusion afterwards. Neurological deficits were assessed 3 h post-reperfusion using a 9-point neurological scoring scale. The levels of biomarkers of oxidative stress and pro-inflammatory cytokines (tumour necrotic factor-alpha and interleukin-6), expressions of immunopositive cells of nuclear factor-kappa B (NF-kappaB) and acetyl cholinesterase (AChE) activity were determined in brain tissues. Histology of the striatum, prefrontal cortex (PFC) and hippocampus (CA1) was also evaluated. JB improved BCCAO-induced neurological deficits and attenuated increased oxidative stress and AChE activity in rats subjected to BCCAO (p < 0.05). Increased brain levels of tumour necrotic factor-alpha and interleukin-6 as well as expressions of immunopositive cells of NF-kappaB were decreased by JB. JB reduced brain damage and also increased population of viable neurons in the striatum, PFC and hippocampus of ischemic stroke rats. These findings suggest that the positive effect of JB on neurological function in rats with ischemic stroke may be related to inhibition of oxidative stress, release of pro-inflammatory cytokines and expressions of immunopositive cells of NF-kappaB. PMID- 30413289 TI - Native upper lobe-sparing living-donor lobar lung transplantation maximizes respiratory function of the donor graft. AB - BACKGROUND: We have developed a novel method for native upper lobe-sparing living donor lobar lung transplantation (LDLLT) to overcome a small-for-size graft in standard LDLLT with acceptable results. We hypothesized that grafts implanted with this procedure might work more efficiently than those in standard lobe transplantation. METHODS: Bilateral LDLLT was performed in 31 patients with a functional graft matching of less than 60% at our institution between August 2008 and December 2015. Of these, 22 patients were available for evaluation of pulmonary function more than 1 year later: 15 undergoing standard LDLLT with less than 60% functional matching and 7 undergoing native upper lobe-sparing LDLLT. RESULTS: Overall survival at 2 years was 87.5% in the lobe-sparing LDLLT patients and 79.0% in the standard LDLLT patients (p = 0.401). The median forced vital capacity size-matching levels were 50.7% +/- 1.6% in the standard LDLLT and 45.2% +/- 2.3% in the sparing LDLLT group (p = 0.074). The 1-year and 2-year post operative volume ratios of inspiration to expiration were significantly different between the 2 groups, at 1.76 and 1.45 after standard LDLLT (p = 0.019) vs 2.41 and 2.23 after lobe-sparing LDLLT (p = 0.015). CONCLUSIONS: The grafts in lobe sparing LDLLT functioned more effectively than those in standard LDLLT. This advantage was associated with the improvement of pulmonary functions. PMID- 30413290 TI - Comparison of RT-qPCR and Nanostring in the measurement of blood interferon response for the diagnosis of type I interferonopathies. AB - Type I interferonopathies are characterized by an increase of circulating type I interferon (IFN) concentration. Type I interferonopathies refer to rare Mendelian genetic disorders such as Aicardi-Goutieres Syndrome (AGS) as well as more frequent and polygenic auto-immune diseases like systemic lupus erythematosus (SLE). Yet, detection of type I IFN in these patients remains challenging as its amount is usually very low in patients' sera. Thus, the detection of interferon stimulating genes has been proposed as an alternative for the detection of this cytokine but sensitivy, specificity and predictive values of the assay have not been reported so far. In this study, we propose two different methods based on Nanostring or RT-qPCR to measure in the clinical routine the IFN response, defined as a set of transcripts that are systemically induced by IFNs. The IFN signature is composed of 6 IFN stimulated genes (ISGs) and has a strong predictive value for the diagnosis of type I interferonopathies. The use of this simple test might represent a gold standard for the evaluation of various autoimmune diseases. Moreover, this test could also be used to monitor patients treated with drugs targeting type I IFN pathway. When comparing both methods - Nanostring and qPCR - in terms of analytical performance, they provided similar results but Nanostring was quicker, easier to multiplex, and almost fully automated, which represent a more reliable assay for the daily clinical practice. PMID- 30413291 TI - Carotid Artery-Related Perioperative Stroke Following Anterior Cervical Spine Surgery: A Series of 3 Cases and Literature Review. AB - BACKGROUND: Vascular complications following anterior cervical spine surgery are rare but potentially devastating. Complications associated with the carotid artery are even more disastrous but largely anecdotal, with no more than 4 reported cases. MATERIALS AND METHODS: We report 3 new cases of carotid artery related perioperative stroke following anterior cervical spine surgery. All 3 patients had carotid artery atherosclerosis and the time of intraoperative carotid artery retraction was longer than 1 hour. One patient underwent hypotension during surgery. Risk factors as well as prevention and management protocols of carotid artery-related perioperative stroke based on the literature review and our clinical experience are discussed. CONCLUSIONS: Carotid artery related perioperative stroke following anterior cervical spine surgery is extremely rare. Prolonged traction, carotid artery atherosclerosis, and intraoperative hypotension can produce cerebral hypoperfusion and cause ischemic stroke. Preoperative risk assessment, adequate perioperative manipulation, and postoperative management can minimize overall morbidity and mortality. PMID- 30413292 TI - The Effects of Yoga on Patients with Mild Cognitive Impairment and Dementia: A Scoping Review. AB - Yoga is an ancient mind body practice. Although yoga has been used as a complementary health approach for enhancing wellness and addressing a variety of health issues, little is known about the impact of yoga on cognitive functioning in adults with mild cognitive impairment (MCI) and dementia. We conducted a literature review to examine the impact of yoga on persons with MCI and dementia. Eight studies were identified that reported on yoga as either the primary intervention or one component of a multi-component intervention in samples of persons with MCI or dementia. Results suggest that yoga may have beneficial effects on cognitive functioning, particularly on attention and verbal memory. Further, yoga may affect cognitive functioning through improved sleep, mood, and neural connectivity. There are a number of limitations of the existing studies, including a lack of intervention details, as well as variability in the frequency/duration and components of the yoga interventions. A further complicating issue is the role of various underlying etiologies of cognitive impairment. Despite these limitations, providers may consider recommending yoga to persons with MCI or dementia as a safe and potentially beneficial complementary health approach. PMID- 30413293 TI - Leadless Cardiac Pacemaker (LCP) without Diagnostic Relevant Artifacts in DualSource and DualEnergy-CT Examinations in First- to Third-Generation DSCT Scanner. AB - RATIONALE AND OBJECTIVES: To identify the influence and artifact burden in cardiac CT imaging of a leadless cardiac pacemaker (LCP) performed with all three generations of DualSource CT (DSCT) Scanners. MATERIALS AND METHODS: The LCP was examined in DSCT scanners of the first to third generation using DualEnergy (DECT) and DSCT as well as alterations of the current-time product. For DECT examinations, virtual monoenergetic images were computed manually on a dedicated workstation. Virtual voltage was manually selected by subjective assessment of the lowest artifact burden. Systematic variations of the pacemaker angle to the gantry were assessed, too. The angle was successively increased by 10 degrees , ranging from 0 degrees to 90 degrees . Artifact burden was quantified on a five point Likert scale (1- no artifacts, 2- few artifacts, 3- moderate artifacts, 4- many artifacts, and 5- massive artifacts). Likert values of 1-3 were considered diagnostic and assessed by two board-certified radiologists in consensus. RESULTS: In total, 200 examinations were analyzed, a mean Likert value of 1.93 +/ 0.61 was found overall. None of the images were assessed Likert value >3. The positioning evaluation showed a clear and significant reduction of artifact burden toward lower angles, (0 degrees : 1.4 +/- 0.5 vs. 90 degrees 2.55 +/- 0.51). At scanner level, second-generation DSCT performed significantly better (1.68 +/- 0.47) than both other scanners. Comparison of technique (DECT vs. DSCT) revealed a significantly improved image quality in DSCT examinations. CONCLUSION: LCP can be safely examined in DSCT scanner of the first to third generation with the evaluated protocols and techniques, which are currently in use. Artifact burden can be significantly reduced by aligning or approaching the LCP's longitudinal axis toward the scanner's z-axis. PMID- 30413294 TI - First Time Cannabis Use and Sexual Debut in U.S. High School Adolescents. AB - PURPOSE: Use of illicit drugs by adolescents might facilitate or trigger other risky behaviors, including early sexual initiation (ESI), multiple partners, and unprotected sex. This study examines whether the age at which adolescents initiate cannabis use is associated with the age of their first sexual intercourse in the U.S. in 2015. METHODS: A secondary analysis of data from the 2015 Youth Risk Behavior Surveillance Survey, a cross-sectional, nationally representative survey, was conducted (n = 7,664). Exposure of interest was age of initiation of cannabis use (never used cannabis, age 12 or younger, 13-14 years of age, and age 15 or older) and outcome was ESI (14 years old or younger). Unadjusted and adjusted odds ratios (OR) and their 95% confidence intervals were computed. RESULTS: Prevalence of ESI was 15.3%. The proportion of cannabis use was 39.9%. Adolescents starting cannabis use before the age of 15 had higher adjusted odds of ESI (OR ranged 4.2-6.7). This association is modified by sex: while in boys using cannabis before 13 years, the OR is 9 (95% CI 5.2-15.6); in girls, it is 2.8 (95% CI 1.7-4.7). CONCLUSIONS: Our findings suggest that there should be sex and drug education programs instituted before the age of 12 ideally, and no later than by age 15 since this time represents a critical period of initiating both behaviors. PMID- 30413295 TI - Space-time trends of PM2.5 constituents in the conterminous United States estimated by a machine learning approach, 2005-2015. AB - Particulate matter with aerodynamic diameter less than 2.5 MUm (PM2.5) is a complex mixture of chemical constituents emitted from various emission sources or through secondary reactions/processes; however, PM2.5 is regulated mostly based on its total mass concentration. Studies to identify the impacts on climate change, visibility degradation and public health of different PM2.5 constituents are hindered by limited ground measurements of PM2.5 constituents. In this study, national models were developed based on random forest algorithm, one of machine learning methods that is of high predictive capacity and able to provide interpretable results, to predict concentrations of PM2.5 sulfate, nitrate, organic carbon (OC) and elemental carbon (EC) across the conterminous United States from 2005 to 2015 at the daily level. The random forest models achieved high out-of-bag (OOB) R2 values at the daily level, and the mean OOB R2 values were 0.86, 0.82, 0.71 and 0.75 for sulfate, nitrate, OC and EC, respectively, over 2005-2015. The long-term temporal trends of PM2.5 sulfate, nitrate, OC and EC predictions agreed well with their corresponding ground measurements. The annual mean of predicted PM2.5 sulfate and EC levels across the conterminous United States decreased substantially from 2005 to 2015; while concentrations of predicted PM2.5 nitrate and OC decreased and fluctuated during the study period. The annual prediction maps captured the characterized spatial patterns of the PM2.5 constituents. The distributions of annual mean concentrations of sulfate and nitrate were generally regional in the extent that sulfate decreased from east to west smoothly with enhancement in California and nitrate had higher concentration in Midwest, Metro New York area, and California. OC and EC had regional high concentrations in the Southeast and Northwest as well as localized high levels around urban centers. The spatial patterns of PM2.5 constituents were consistent with the distributions of their emission sources and secondary processes and transportation. Hence, the national models developed in this study could provide supplementary evaluations of spatio-temporal distributions of PM2.5 constituents with full time-space coverages in the conterminous United States, which could be beneficial to assess the impacts of PM2.5 constituents on radiation budgets and visibility degradation, and support exposure assessment for regional to national health studies at county or city levels to understand the acute and chronic toxicity and health impacts of PM2.5 constituents, and consequently provide scientific evidence for making targeted and effective regulations of PM2.5 pollution. PMID- 30413297 TI - Corrigendum to "Study on the efficacy and mechanism of triptolide on treating TNF transgenic mice with rheumatoid arthritis" [Biomed. Pharmacother. 106 (2018) 813 820]. PMID- 30413296 TI - Distribution and bioaccumulation of POPs and mercury in the Ga-Selati River (South Africa) and the rivers Gudbrandsdalslagen and Rena (Norway). AB - Biomagnification of Hg and persistent organic pollutants (POPs: polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs)) in aquatic food chains can lead to high pollutant concentrations in top predators, including humans. Despite this threat to human health, research concerning bioaccumulation is still underrepresented in the southern hemisphere and in (sub)arctic and (sub)tropical areas, emphasizing the need for research in these locations. In this study, samples of water, sediment and aquatic biota were analyzed to determine concentrations of POPs and total mercury (THg) in the Ga Selati river (South Africa) and two rivers Rena and Gudbrandsdalslagen in Norway. Trophic magnification factors (TMFs) were determined to evaluate and compare the biomagnification and the threat to human health due to consumption of the fish was assessed. Concentrations of POPs in sediment and biota samples were generally low except for relatively high concentrations of ?DDX (dichlorodiphenyltrichloroethane and metabolites) in aquatic biota from the Ga Selati river (ranging from 1.9 to 133 ng/g ww in invertebrates and 1.9 to 5643 ng/g ww in fish). Dissolved THg concentrations were high in the Ga-Selati river (ranging from 0.009 to 0.036 MUg/l) but THg concentrations in sediment and biota were low in studied rivers compared to other studies. Biomagnification occurred for THg, several DDT-metabolites and PCB compounds, TN and CN. Biomagnification of p,p'-DDT and THg differed significantly between the two countries, supporting existing patterns found in literature, although more data is needed to attribute these differences to climatic or other factors. Concentrations in fish from the rivers Ga-Selati and Rena were under the threshold levels reported for THg and POPs, but caution should be taken when consuming Northern pike (Esox Lucius) from the subarctic river Gudbrandsdalslagen, to avoid harmful effects due to both elevated THg and PBDE exposure. PMID- 30413298 TI - Response to letter of He et al.: Oligomerization status and post-translational modification of adiponectin: A possible association between adiponectin and risk of coronary artery disease. PMID- 30413299 TI - Sensitivity of undetectable level of high-sensitivity troponin T at presentation in a large non-ST-segment elevation myocardial infarction cohort of early presenters. AB - BACKGROUND: We aimed to evaluate the diagnostic sensitivity for myocardial infarction (MI) when using an undetectable level of high-sensitivity cardiac troponin T (hs-cTnT < 5 ng/L) at presentation combined with a non-ischemic electrocardiogram (ECG), to rule out MI in a non-ST-segment elevation MI (NSTEMI) cohort presenting <=2 h from symptom onset. We also aimed to compare baseline characteristics and 30-day outcome in NSTEMI patients presenting with and without hs-cTnT < 5 ng/L. METHODS: All patients admitted to five centers in Sweden 2011 2015, after the introduction of hs-cTnT, who presented <=2 h from symptom onset and received a final diagnosis of NSTEMI, were identified through the SWEDEHEART registry. These data and data of hs-cTnT levels were verified in the hospitals' medical records. The registry provided baseline and outcome data. RESULTS: Twenty four (2.6%) of 911 NSTEMI patients presented with hs-cTnT < 5 ng/L. In patients presenting >1-<=2 h from symptom onset the sensitivity for MI when combining hs cTnT and ECG was 99.4% (95% CI 98.4%-99.8%). In patients presenting <=1 h, and in patients aged <=65 years without prior MI, the sensitivity was insufficient. NSTEMI patients presenting with hs-cTnT < 5 ng/L were younger and had less often a prior MI. A total of 62.5 vs. 63.5% of the NSTEMI patients presenting with and without hs-cTnT < 5 ng/L underwent revascularization within 30 days and 4.5 and 3.2% died respectively. CONCLUSIONS: Hs-cTnT < 5 ng/L at presentation combined with a non-ischemic ECG may be used to rule out MI in patients presenting as early as >1 h from symptom onset with a sufficient sensitivity. PMID- 30413300 TI - Advanced care planning in adult congenital heart disease: Transitioning from repair to palliation and end-of-life care. AB - As a result of advances in pediatric care, the majority of patients born with congenital heart disease (CHD) survive into adulthood [1]. Effective transfer and transition programs assure that patients with CHD remain in follow-up and receive continuous holistic care. Unfortunately, adult patients with CHD carry residual lesions and sequelae putting them at risk for premature death related to re interventions or complications; most commonly heart failure and arrhythmia [2]. The scientific adult CHD (ACHD) community has been working hard to identify variables related to worse outcomes, modifying those where possible in order to improve survival. Indeed, survival in adults with CHD has increased, but consequently, on top of CHD-related complications, patients are increasingly exposed to the standard cardiovascular risk factors. Therefore, a program for lifelong coaching on health behavior and life style management becomes indispensable. More emerging is that a substantial number of patients, in particular those with complex heart defects, will eventually end up in a stage with hardly any medical or interventional options left. Our healthcare provision has to be prepared to organize care for this specific group of patients who will die prematurely and require the timely development and establishment of advanced care planning. Advanced care planning should preferentially be set-up in expert CHD centers. The long-lasting relationship in ACHD care with healthcare providers offers an excellent basis with regards to prognosis, advanced care planning and end-of-life issues. PMID- 30413301 TI - Psychosocial sphere of congenital heart disease patients and the costs of forgetting about it. PMID- 30413302 TI - Call for action to establish standard diagnostic and therapeutic approaches for myocarditis. PMID- 30413303 TI - MALAT1/miR-144/Brg1: A potential regulated axis of inflammation in myocardial ischemia-reperfusion injury. PMID- 30413304 TI - The 3A3B score: The simple risk score for heart failure with preserved ejection fraction - A report from the CHART-2 Study. AB - BACKGROUND: Few simple risk models, without echocardiography have been developed for patients with heart failure (HF) and preserved left ventricular ejection fraction (LVEF) (HFpEF). METHODS: To develop a risk score to predict all-cause death for HFpEF patients, we examined 1277 HF patients with LVEF >=50% and BNP >=100 pg/ml in the CHART-2 Study, a large-scale prospective cohort study for HF in Japan. We selected the optimal subset of covariates for the score with Cox proportional hazard models and random survival forests (RSF). RESULTS: During the median 5.7-year follow-up, 576 deaths occurred. Cox models and RSF analyses consistently indicated age >=75 years, albumin <3.7 g/dl, anemia, BMI <22 kg/m2, BNP >=300 pg/ml (or NT-proBNP >=1400 pg/ml), and BUN >=25 mg/dl, as the important 6 prognostic variables. Incorporating these 6 variables, we developed a scoring system (3A3B score, with 2 points given to age >=75 years and 1 point to the others based on the hazard ratios. The discrimination ability of the risk score was excellent (c-index 0.708). Regarding model goodness-of-fit, the overall gradient in 5-year risk was well captured by the score. The predictive accuracy of the 3A3B score was confirmed in the external validation cohorts from the TOPCAT trial (N = 835, c-index 0.652) and the ASIAN-HF registry (N = 170, c-index 0.741). CONCLUSIONS: We developed a simple risk score to predict long-term prognosis of HFpEF patients. The 3A3B score, comprising 6 commonly available parameters in daily practice, has potential utility in the risk stratification and management of HFpEF patients. PMID- 30413305 TI - Bare-metal coronary stents for patients at high bleeding risk? PMID- 30413306 TI - Individual income, mortality and healthcare resource use in patients with chronic heart failure living in a universal healthcare system: A population-based study in Catalonia, Spain. AB - BACKGROUND: To evaluate the associations between individual income, all-cause mortality and use of healthcare resources in a very large population of chronic heart failure (CHF) patients living in Catalonia (Spain), where access to public healthcare is granted by law. METHODS AND RESULTS: We used 2016 data from the Catalan Health Surveillance System, a large, exhaustive, administrative healthcare database which includes information on medical diagnoses, healthcare resource use, and individual income for all Catalan residents (N = 7,638,524). Individual annual income was categorized as high (>100,000?), medium (18,000 100,000?), low (<18,000?), and very low (welfare support). Among 155,883 CHF patients, lower individual income was associated with a shorter life expectancy at age 50 (life expectancy for high income patients 22.2 years, for very low income patients 12.8), and were independently associated with higher all-cause mortality adjusting for age, sex, comorbidities, and duration of the CHF diagnosis (odds ratio very low vs. medium income 1.21 [95% CI 1.11, 1.33]). Also, in patients with lower income levels the burden of public healthcare resource use was displaced towards urgent hospitalizations and frequent emergency department visits, as opposed to regular, specialized CHF ambulatory-based care. CONCLUSION: In a very large population of CHF patients with access to universal healthcare, lower income was independently associated with higher mortality and with lower use of ambulatory-based healthcare resources. Our findings suggest that CHF patients may benefit from systematic assessment of their socioeconomic status, as this may aid the identification of vulnerable subgroups who may benefit from tailored health education and management. PMID- 30413307 TI - Discrepant myocardial microvascular perfusion and mechanics after acute myocardial infarction: Characterization of the "Tako-tsubo effect" with real-time myocardial perfusion contrast echocardiograph. AB - BACKGROUND: In patients with acute anterior myocardial infarction (MI), sometimes an "apical ballooning" contractile dysfunction pattern that exceeds factual myocardial injury is identified in the ventriculography and bedside echocardiography. The hemodynamic consequences/sequela of this "Tako-tsobu effect" has not been well delineated. Of note, this anatomic imaging finding often misleads frontline physicians who assume reciprocal causation of persistent cardiac pump failure and ventricular pressure overload. METHODS AND RESULTS: Using real-time myocardial perfusion contrast echocardiography (MCE), we investigated myocardial (microvascular) perfusion in 60 patients after acute MI and coronary revascularization. Twenty-eight percent of the studied patients showed significantly mismatched myocardial perfusion and contractile defects. In these patients, an integrated imaging assessment with coronary angiography/ventriculography, deformation echocardiography, and MCE proved that the myocardial mechanic abnormalities significantly exceeded the defected perfusion areas. Compared with 72% of the patients without perfusion contractility mismatch, apparently worse systolic functions (left ventricular ejection, wall motion score, and systolic longitudinal strain) in these patients did not change diastolic ventricular filling pressures (E/E' and E/A) or hemodynamic consequences/adverse events. Both systolic and diastolic functions in patients with perfusion-contractility mismatch appeared to be comparable with those in patients with Tako-tsubo syndrome. CONCLUSIONS: Real-time MCE identifies discrepant myocardial microvascular perfusion and mechanics in patients with acute MI. The "Tako-tsubo effect" in patients with perfusion-contractility mismatch does not cause diastolic filling pressure change or worse hemodynamic consequence/cardiac event. PMID- 30413308 TI - The interpreter's voice: Carrying the bilingual conversation in interpreter mediated consultations in pediatric oncology care. AB - OBJECTIVES: The objective of this study was to explore interpreters' perceived strategies in the interaction in interpreter-mediated consultations between healthcare personnel and patients/families with limited Swedish proficiency in pediatric oncology care. METHODS: This study had an inductive approach using an exploratory qualitative design. A total of eleven semi-structured interviews were performed with interpreters who had experience interpreting in pediatric oncology care. RESULTS: The interpreters' perceived strategies were divided into four generic categories; strategies for maintaining a professional role, strategies for facilitating communication, strategies for promoting collaboration, and strategies for improving the framework of interpreting provision. These four generic categories were then merged into the single main category of carrying the bilingual conversation. CONCLUSIONS: The interpreters stretch their discretionary power in order to carry the bilingual conversation by using strategies clearly outside of their assignment. PRACTICAL IMPLICATIONS: The study contributes to the understanding of the interpreter-mediated consultation in pediatric oncology care, and this can be used to improve the care of patients and families in pediatric oncology care with limited knowledge of a country's majority language. PMID- 30413309 TI - Better understanding the influence and complexity of beliefs on medication adherence in asthma. AB - OBJECTIVE: The aim was to better understand how beliefs influence medication adherence in asthma. METHODS: All participants were prescribed an inhaled corticosteroid for a diagnosis of asthma. Each participant completed a survey consisting of: Beliefs about Medicines Questionnaire (BMQ), Brief-Illness Perception Questionnaire (B-IPQ) and Multi-dimensional Health Locus of Control Scale (MHLCS). Adherence to inhaled corticosteroids was elicited using the Medication Adherence Report Scale (MARS). Multiple linear regression with interaction effects was used to identify significant predictors of medication adherence and interactions between beliefs. RESULTS: A total of 198 participants completed the survey. The mean(+/-SD) MARS score was 19.2(+/-4.5). A multivariable model (adjusted R2 = 0.39) predicted adherence using: age, asthma hospitalisation, timeline (B-IPQ) subscale, necessity and concern (BMQ) subscales, doctor (MHLCS) subscale and the two interaction effects (concerns [BMQ] moderated by chance [MHLCS] and treatment control [B-IPQ] moderated by understanding [B-IPQ]). CONCLUSION: The findings of this study contribute to a better understanding of the role of beliefs in medication adherence in asthma. Certain beliefs meaningfully interrelate and change the relationship they have with medication adherence. PRACTICE IMPLICATIONS: If these beliefs are causally related to medication adherence and can be intervened upon, the findings are useful for providing targets to personalise adherence support. PMID- 30413310 TI - Patient Reported Outcomes Measurement Information System and Quality of Life in Neurological Disorders Measurement System to Evaluate Quality of Life for Children and Adolescents with Neurofibromatosis Type 1 Associated Plexiform Neurofibroma. AB - OBJECTIVE: To assess the health-related quality of life of children with neurofibromatosis type 1-related plexiform neurofibromas (pNF) using a battery of patient-reported outcome measures selected based on a conceptual framework derived from input by patients, parents, and clinicians regarding the most important pNF symptoms and concerns. STUDY DESIGN: There were 140 children with pNF ages 8-17 years who completed the Patient-Reported Outcomes Measurement Information System (including domains anxiety, depressive symptom, psychosocial stress experiences, fatigue, pain interference, meaning and purpose, positive affect, peer relationships, physical function-mobility) and Quality of Life in Neurological Disorders measurement system (stigma) via an online platform. T scores for each measure were compared with US population norms. RESULTS: Children with pNF reported significantly worse scores than the population norms on 8 of 10 domains. Children with at least 1 family member having a diagnosis of neurofibromatosis type 1 and those having pain reported significantly worse symptoms and functioning on all domains. Boys reported significantly worse pain interference, stigma, meaning and purpose, mobility function, and upper extremity function than girls. CONCLUSIONS: Children with pNF experience significantly worse health-related quality of life on all but 1 domain, highlighting the importance of monitoring children's quality of life over time in clinical research and practice. Future research should evaluate the replicability of these findings and evaluate the validity of the Patient-Reported Outcomes Measurement Information System and Quality of Life in Neurological Disorders measurement system in relation to clinical characteristics among children with pNF. PMID- 30413311 TI - Adenovirus-Associated Central Nervous System Disease in Children. AB - OBJECTIVE: To characterize the spectrum and salient clinical features of adenovirus-associated neurologic disease in immunocompetent children. STUDY DESIGN: Previously healthy children (aged 1 month-18 years) with central nervous system (CNS) disease associated with adenovirus infection were identified via the Encephalitis Registry (1996-2016) and Microbiology Database (2000-2016) at The Hospital for Sick Children, Toronto, and by systematic review of the literature. The data were pooled and analyzed to identify the spectrum of illness, clinical outcome, and risk factors for death or neurologic impairment. RESULTS: Neurologic complications associated with adenovirus infection in our institution included febrile seizures, encephalitis, acute disseminated encephalomyelitis, and aseptic meningitis. A total of 48 immunocompetent children with adenovirus-associated CNS disease were included in the pooled analysis-38 from the literature and 10 from our institution. In 85% of cases, the virus was detected in the respiratory or gastrointestinal tract, but not the cerebrospinal fluid. Eighteen of the 48 (38%) patients either died or suffered permanent neurologic sequelae. Predictors of adverse outcome included younger age, coagulopathy, the absence of meningismus, serotype 2 virus, and the presence of seizures. After multivariable adjustment, only seizures remained a significant risk factor. CONCLUSION: Adenovirus is a rare cause of CNS disease in immunocompetent children. Disease spectrum is variable, ranging from mild aspetic meningitis and fully reversible encephalopathy to severe, potentially fatal, acute necrotizing encephalopathy. PMID- 30413312 TI - Different Growth Patterns Persist at 24 Months of Age in Formula-Fed Infants Randomized to Consume a Meat- or Dairy-Based Complementary Diet from 5 to 12 Months of Age. AB - OBJECTIVE: To test the long-term effect on growth status at 24 months of age in formula-fed infants who were randomized to consume a meat- or dairy-based complementary diet from 5 to 12 months of age. STUDY DESIGN: Observational assessments, including anthropometric, dietary, and blood biomarkers, were conducted at 24 months of age, 1 year after the intervention ended. RESULTS: The retention rate at 24 months of age was 84% for the meat group and 81% for the dairy group. Mean (+/-SD) protein intakes at 24 months of age were 4.1 +/- 1.2 and 4.0 +/- 1.1 g/kmeat (n = 27) and dairy (n = 26) groups, respectively, and comparable with the estimates of US population intake. At 24 months of age, weight-for-age z score did not differ significantly between groups and was similar to that at 12 months. Length-for-age z score remained significantly higher in the meat group compared with the dairy group, and the average length was 1.9 cm greater in the meat group. Weight-for-length z score also did not differ significantly between groups. Insulin-like growth factor 1 significantly increased from 12 to 24 months of age in both groups, but insulin-like growth factor-binding protein 3 and blood urea nitrogen did not change significantly from 12 to 24 months of age and were comparable between groups. CONCLUSIONS: The protein source-induced distinctive growth patterns observed during infancy persisted at 24 months of age, suggesting a potential long-term impact of early protein quality on growth trajectories in formula-fed infants. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02142647. PMID- 30413313 TI - Child and Adolescent Suicidal Ideation and Suicide Attempts: Evidence from the Healthcare Cost and Utilization Project. AB - OBJECTIVES: To examine the trends associated with child and adolescent suicidal ideation and suicide attempts and to compare these trends to those among the adult population. STUDY DESIGN: A nationally representative sample of administrative billing data was used for the analysis, which included descriptive statistics, trend data, and logistic regression. RESULTS: There were 874 872 (95% CI, 810 574-939 169) children and adolescents and 5 561 197 (95% CI, 5 271 426-5 850 968) adults admitted to an emergency department who experienced suicidal ideation or suicide attempts between 2010 and 2014, representing 1.20% of admissions for children (95% CI, 1.13-1.37) and adolescents and 1.09% of admissions for adults (95% CI, 1.05-1.13). Children and adolescents were more likely to be female (aOR, 1.74; 95% CI, 1.71-1.78) and to have private insurance (aOR, 1.75; 95% CI, 1.68-1.83) as compared with adults. Although the percentage of admissions increased for adults 25 and older (18.95%) the greatest increases were found among children and adolescents (5-11 years of age, 37.87%; 12-14 years of age, 82.03%; 15-17 years of age, 51.59%; and 18-24 years of age, 26.77%). There is a seasonal trend for children and adolescents such that higher rates are associated with the school year, which is not present for adults. CONCLUSION: Practitioners should be cognizant of the fact that suicidal ideation and suicide attempts for youth present differently than they do for the greater population and they should be vigilant in identifying risk factors, especially during seasons where risk of self-harm increases. PMID- 30413314 TI - Neonatal Lung Disease Associated with TBX4 Mutations. AB - Variable lung disease was documented in 2 infants with heterozygous TBX4 mutations; their clinical presentations, pathology, and outcomes were distinct. These findings demonstrate that TBX4 gene mutations are associated with neonatal respiratory failure and highlight the wide spectrum of clinicopathological outcomes that have implications for patient diagnosis and management. PMID- 30413316 TI - Prospective Cohort Study of Congenital Cytomegalovirus Infection during Pregnancy with Fetal Growth Restriction: Serologic Analysis and Placental Pathology. AB - OBJECTIVE: To investigate prospectively the prevalence of congenital cytomegalovirus (CMV) infection and the pathologic features of the placenta in cases of fetal growth restriction (FGR). STUDY DESIGN: Forty-eight pregnant women who were diagnosed with FGR during pregnancy were enrolled for 15 months. Maternal CMV serologic tests, pathologic examinations of the placenta, and newborn urinary CMV-DNA polymerase chain reaction tests were performed in all the cases. The clinical characteristics and laboratory findings of the pregnant women and their newborns were collected. Biomarkers for inflammation, angiogenesis, and placental hormones were measured in the maternal serum at FGR diagnosis or in the neonatal urine at birth. RESULTS: One of the 48 cases with FGR was a congenital CMV infection. CMV antigen was detected in the placenta of 7 cases with FGR. The change rate of the estimated fetal body weight was significantly lower in FGR cases with placental CMV detection. Placental villitis was observed more frequently in FGR cases with placental CMV detection. Human placental lactogen was significantly decreased in FGR cases with placental CMV detection. Increased C-reactive protein and serum amyloid A levels in the maternal serum were observed more frequently in FGR cases with placental CMV detection. Newborn urine beta-2 microglobulin levels were significantly higher in FGR cases with placental CMV detection. CONCLUSIONS: Serologic tests for maternal CMV, the change rate of the estimated fetal body weight, analysis of several biomarkers, and placental pathologic examinations might be helpful in comprehensively predicting the possibility of congenital CMV infection. PMID- 30413317 TI - One Way to Approach Accessing and Educating the Community for Delivery of Health Care to Attempt to Address the Disparity of Health Care Delivery. PMID- 30413315 TI - Muscle Fitness Cut Points for Early Assessment of Cardiovascular Risk in Children and Adolescents. AB - OBJECTIVES: To study the cross-sectional and longitudinal (2-year follow-up) association between muscle fitness and cardiovascular disease (CVD) risk factors in youth; whether there are muscle fitness cut points associated with CVD risk (cross-sectional); and whether the health-related muscle fitness cut points identified at baseline are associated with CVD risk 2 years later. STUDY DESIGN: In total, 237 children (110 girls) aged 6-10 years and 274 adolescents (131 girls) aged 12-16 years with complete data were included in the study (10.3% drop out). The handgrip strength and the standing long jump tests were used to assess muscle fitness. CVD risk score was computed with sum of 2 skinfolds, systolic blood pressure, insulin, glucose, triglycerides, and total cholesterol/high density lipoprotein cholesterol. RESULTS: Muscle fitness at baseline was associated inversely with single CVD risk factors and CVD risk score at baseline and 2-year follow-up (all P < .05). Receiver operating characteristics curve analyses showed a significant discriminating accuracy of handgrip strength in identifying CVD risk in children and adolescents (boys: >= 0.367 and >=0.473; girls: >= 0.306 and >=0.423 kg/kg body mass, respectively, all P < .001). Similarly, the standing long jump cut points for children and adolescents were >=104.5 and >=140.5 in boys, and >=81.5 and >=120.5 cm in girls, respectively (all P < .05). These cut points were associated with CVD risk 2 years later (all P < .01). CONCLUSIONS: Muscle fitness is associated with present and future cardiovascular health in youth, and is independent of cardiorespiratory fitness. It should be monitored to identify youth at risk who could benefit from intervention programs. PMID- 30413318 TI - Primary aldosteronism with nonlocalizing imaging. AB - BACKGROUND: Unilateral primary aldosteronism is surgically curable. The goal of this study was to examine outcomes based on preoperative imaging findings. METHODS: We performed a retrospective analysis of patients with primary aldosteronism who underwent adrenal vein sampling. Patients were classified by imaging as localized (unilateral adrenal mass) or nonlocalized (no mass/bilateral masses). Outcomes were assessed as complete, partial, or absent clinical success. RESULTS: Of 446 patients, 74.9% were localized. There were no significant demographic or biochemical differences between groups; however the imaged tumor size was larger (median 1.3 vs 1.2 cm, P = .038), and rates of lateralizing adrenal vein sampling were higher (79.0% vs 62.2%, P < .001) in the localized group. Of 289 patients who underwent adrenalectomy, adenoma was the most common finding in both groups (79.7% vs 80.3% respectively, P = .447), but median tumor size was larger in localized patients (1.5 vs 1.0 cm, P < .001). Equivalent rates of partial (94.6% vs 91.7%, P = .456) and complete (8.7% vs 9.8%, P = .801) clinical success were observed. At long-term follow-up, nonlocalized patients experienced partial reversal of clinical improvement. CONCLUSION: Primary aldosteronism patients with nonlocalizing imaging but lateralizing adrenal vein sampling benefit from adrenalectomy. Regardless of imaging findings, adrenal vein sampling is indicated to determine whether patients may be surgically curable. PMID- 30413319 TI - Total versus subtotal parathyroidectomy for secondary hyperparathyroidism. AB - BACKGROUND: It remains unclear whether total or subtotal parathyroidectomy for secondary hyperparathyroidism yields the best outcomes. We investigated mortality, cardiovascular events, hip fracture, and recurrent parathyroidectomy after total versus subtotal parathyroidectomy in patients on renal replacement therapy. METHODS: Using the Swedish Renal Registry, the surgical registry for thyroid and parathyroid surgery, and the National Inpatient Registry, we identified patients who underwent parathyroidectomy between 1991 and 2013. We calculated the risk of outcome after total versus subtotal parathyroidectomy using COX's regression, adjusting for age, sex, cause of renal disease, time with a functioning graft before and after parathyroidectomy, Charlson comorbidity index, year of surgery, prevalent cardiovascular disease, time on dialysis, renal transplantation at parathyroidectomy, and treatment with calcimimetics before parathyroidectomy. RESULTS: There were 824 patients who underwent parathyroidectomy, 388 total and 436 subtotal. There was no difference in mortality or risk of incident hip fracture between groups. Comparing the subtotal with the total parathyroidectomy, the adjusted hazard ratio (95% confidence interval) for cardiovascular events was 0.43 (0.25-0.72) and for recurrent parathyroidectomy 3.33 (1.33-8.32). CONCLUSION: There was a higher risk of cardiovascular events in patients after total parathyroidectomy compared with subtotal parathyroidectomy, but a lower risk of recurrent parathyroidectomy. PMID- 30413320 TI - Over expression of DNA damage and cell cycle dependent proteins are associated with poor survival in patients with adrenocortical carcinoma. AB - BACKGROUND: Adrenocortical carcinoma is a rare and aggressive malignancy with poor survival. With limited treatment options and high risk of relapse, identifying improved targets and therapies for adrenocortical carcinoma is important. We hypothesized that analysis of the database of The Cancer Genome Atlas could identify important novel biomarkers for improved therapeutic targeting of adrenocortical carcinoma. METHODS: We utilized the University of Alabama interactive web resource to identify novel biomarkers observed in 79 adrenocortical carcinoma patients. Identified biomarkers were then examined for prognostic correlations using the cBioPortal and analyzed for statistical significance using STATA 13.0. RESULTS: The Cancer Genome Atlas data mining in the University of Alabama interactive web resource for pathways associated with poor survival of patients with adrenocortical carcinoma revealed significant upregulation of genes involved in DNA damage and regulation of cell-cycle pathways, such as AURKA, AURKB, CDK1, CDK4, CDK6, PLK1, CHEK1, CHEK2, CDC7, BUB3, and MCM3 (P < .001-.05). On outcome correlation, greater expression levels of all the genes except CDK4 were associated with worse survival compared with medium or low levels of gene expression (P < .001 all) irrespective of age orsex. Consistent with our University of Alabama interactive web resource findings, data mining in the cBioPortal also revealed upregulation of genes regulating DNA damage and cell cycle-related genes in 82% of patients (z score = 1.5). CONCLUSION: Large data mining from the The Cancer Genome Atlas and cBioPortal databases identified overexpression of genes involved in DNA damage and those regulating pathways of the cell cycle, which correlated with poorer overall survival in adrenocortical carcinoma patients. PMID- 30413321 TI - Evacuation of postoperative hematomas after thyroid and parathyroid surgery: An analysis of the CESQIP Database. AB - BACKGROUND: A feared complication after thyroid and parathyroid operations is postoperative hematoma that threatens the airway. The aim of this study was to identify factors associated with postoperative hematoma. METHODS: Patients undergoing thyroidectomy or parathyroidectomy were evaluated for postoperative hematoma requiring operative intervention using the database of the Collaborative Endocrine Surgery Quality Improvement Program. Associations between perioperative factors and postoperative hematoma were evaluated with bivariate methodologies and multivariable logistic regression. RESULTS: Among 19,356 patients, 60.4% underwent thyroidectomy +/- lymph node dissection, 34.9% parathyroidectomy, and 4.7% concurrent thyroidectomy/parathyroidectomy. Postoperative hematoma occurred in 0.6% overall: 0.7% of thyroidectomies, 0.3% of parathyroidectomies, and 1.3% of combined thyroid/parathyroid operations (P < .001). The incidence of postoperative hematoma was greater among men (P < .001) and after greater operative times (P < .001) but was not influenced by body mass index, prior neck surgery, or reoperations. Multivariable logistic regression determined that operative complexity, operation >1 hour, male sex, and age were independently associated with postoperative hematoma. Postoperative hematoma were associated with greater rates of other complications as well. CONCLUSION: Large databases such as Collaborative Endocrine Surgery Quality Improvement Program are useful to evaluate rare complications. The risk of postoperative hematoma is associated with extent of operation, greater operative times, age, and male sex. These data may be beneficial in counseling patients and may serve as a benchmark for surgeons to evaluate their practices. PMID- 30413322 TI - Expression of programmed death ligand 1 and 2 in adrenocortical cancer tissues: An exploratory study. AB - BACKGROUND: Inhibition of the interaction of programmed death 1 with programmed death ligand 1 and 2 has been used successfully for treatment of multiple advanced cancers, but expression has not been studied in adrenocortical carcinoma. In this study, we investigated programmed death ligand 1 and 2 expression in adrenocortical carcinoma to determine the potential usefulness of checkpoint inhibitors in these malignant neoplasms. METHODS: A total of 56 tissue samples from patients with adrenocortical carcinoma (34) and benign adrenal tissues (22) were identified. Immunohistochemistry was performed for programmed death ligand 1, programmed death ligand 2, and CD8 and scored for membranous staining on adrenal and stromal tissue according to the immunoreactive score and absolute percentage, respectively. Descriptive statistics, a Mann-Whitney U test, and Fisher exact tests were calculated. RESULTS: In total, 15 adrenocortical carcinoma (44%) stained positive for programmed death ligand 2 and 1 adrenocortical carcinoma for programmed death ligand 1 (P = .03). Adrenocortical carcinoma samples were more likely to express programmed death ligand 2 on tumor cells or in stromal tissues than benign samples (OR = 2.3, P = .03). There was no relationship between programmed death ligand 2 and CD8 expression (P = .08). There were also no relationships between programmed death ligand 2 or CD8 expression and tumor characteristics. CONCLUSION: Programmed death ligand 2, but not programmed death ligand 1, is expressed commonly in adrenocortical carcinoma samples. The utility of certain checkpoint inhibitors should, therefore, be evaluated in further studies. PMID- 30413323 TI - Natural history of papillary thyroid microcarcinoma: Kinetic analyses on tumor volume during active surveillance and before presentation. AB - BACKGROUND: We report on the growth of papillary microcarcinoma during active surveillance and before clinical presentation. METHODS: We conducted a retrospective study of 169 patients with papillary microcarcinoma who were enrolled in active surveillance at our hospital between 2000 and 2004. Patients were followed for a median of 10.1 years using serial ultrasonography (median, 12 examinations), used to calculate the tumor doubling time. To contextualize tumor growth rates during active surveillance, we calculated the hypothetical tumor doubling time before clinical presentation. To resolve the limitations in tumor doubling time, tumor doubling rates were inversely transformed into doubling rates. RESULTS: The doubling rates (per year) during active surveillance (median: 0.0) were >0.5, 0.1 to 0.5, -0.1 to 0.1, and <-0.1 in 5, 38, 97, and 29 cases, respectively. The proportions of tumors with rather rapid growth, slow growth, stable, and a decrease in size were 3%, 22%, 57%, and 17%, respectively. CONCLUSION: Tumor growth of papillary microcarcinomas varies from rather rapid growth to a decrease in size during active surveillance. PMID- 30413324 TI - Treatment strategy of end-stage renal disease related hyperparathyroidism before, during, and after the era of calcimimetics. AB - BACKGROUND: Since 2004, end-stage renal disease related hyperparathyroidism patients are treated mainly with cinacalcet, which ceased to be subsidized through the Australian Pharmaceutical Benefits Scheme in 2015. We aimed to investigate the impact of these changes on the treatment strategy in the Australian end-stage renal disease population. METHODS: The following groups were formed according to the date of parathyroidectomy: A, before calcimimetics; B, during the era of calcimimetics; and C, after cinacalcet removal by the Australian Pharmaceutical Benefits Scheme. The primary outcome was time from start of dialysis to parathyroidectomy. Regression analysis was used to examine trends in parathyroidectomy rates. RESULTS: Between 1998 and 2016, 195 parathyroidectomies were performed. Median time to referral was 69 (33-123), 67 (31-110) and 44 (23-102) months for groups A, B, and C, respectively (P = .55). Parathyroidectomy rates increased throughout the years (CI 0.09-1.13, R2=0.27, P = .02). A trend toward a dip in parathyroidectomy rates was seen during the era of cinacalcet (P = .08). Median preoperative parathyroid hormone levels increased significantly (842 [418-1,553] versus 1,040 [564-1,810] versus 1,350 [1,037 1,923] pg/mL, for groups A, B, and C, respectively [P < .01]). CONCLUSION: Parathyroidectomy rates seem to vary according to the availability of cinacalcet. This change in treatment strategy is accompanied with increased preoperative parathyroid hormone levels, reflecting delayed surgery and increased disease severity. PMID- 30413325 TI - The optimal dosing scheme for levothyroxine after thyroidectomy: A comprehensive comparison and evaluation. AB - BACKGROUND: Patients often struggle to attain euthyroidism after thyroidectomy, and multiple dosing schemes have been proposed to supplant the standard weight based approach for initial levothyroxine dosing after thyroidectomy. The objectives of this study were to review the literature for existing levothyroxine dosing schemes and compare estimation accuracies with novel schemes developed with machine learning. METHODS: This study retrospectively analyzed 598 patients who attained euthyroidism after total or completion thyroidectomy for benign disease. A scoping review identified existing levothyroxine dosing schemes. Thirteen machine learning algorithms estimated euthyroid dose. Using 10-fold cross-validation, we compared schemes by the proportion of patients having a predicted dose within 12.5 ug/day of their euthyroid dose. RESULTS: Of 264 reviewed articles, 7 articles proposed retrospectively implementable dosing schemes. A novel Poisson regression model proved most accurate, correctly predicting 64.8% of doses. Incorporating 7 variables, Poisson regression was significantly more accurate than the best scheme in the literature (body mass index/weight based) that correctly predicted 60.9% of doses (P = .031). Standard weight-based dosing (1.6 ug/kg/day) correctly predicted 51.3% of doses, and the least effective scheme (age/sex/weight based) correctly predicted 27.4% of doses. CONCLUSION: Using readily available variables, a novel Poisson regression dosing scheme outperforms other machine learning algorithms and all existing schemes in estimating levothyroxine dose. PMID- 30413326 TI - Preoperative calcitriol reduces postoperative intravenous calcium requirements and length of stay in parathyroidectomy for renal-origin hyperparathyroidism. AB - BACKGROUND: Patients undergoing subtotal parathyroidectomy for renal-origin hyperparathyroidism often develop postoperative hypocalcemia, requiring calcitriol and intravenous calcium (Postop-IVCa). We hypothesized that in subtotal parathyroidectomy for renal-origin hyperparathyroidism, preoperative calcitriol treatment reduces the use of postoperative administration of intravenous calcium. METHODS: A retrospective chart review compared subtotal parathyroidectomy for renal-origin hyperparathyroidism patients who received preoperative calcitriol treatment with those patietns who did not receive preoperative calcitriol treatment at one institution. Preoperative calcitriol treatment loading doses were 0.5 mcg twice daily for 5 days. All patients received postoperative calcitriol and oral calcium carbonate. Postoperative administration of intravenous calcium was given for symptoms, calcium <7.0 mg/dL, or surgeon preference. The Fisher exact test was used to compare proportions. The Wilcoxon test was used to compare continuous data. Multivariable logistic regression adjusted for confounders. RESULTS: Included were 81 patients who received subtotal parathyroidectomy for renal-origin hyperparathyroidism (41 patients who received preoperative calcitriol treatment, 40 patients who did not receive preoperative calcitriol treatment). Preoperative calcitriol treatment use increased over time (0% 2004-2010, 69% 2011-2016). Groups who received preoperative calcitriol treatment and groups who did not receive preoperative calcitriol treatment were similar in preoperative serum calcium, vitamin D, parathyroid hormone, and median age (P > .05 for all). Patients who received preoperative calcitriol treatment less often required postoperative administration of intravenous calcium (34% vs 90% of patients who did not receive preoperative calcitriol treatment, P < .001). Median length of stay was 2.0 days shorter for patients who received preoperative calcitriol treatment versus patients who did not receive preoperative calcitriol treatment patients (P < .001). Factors associated with postoperative administration of intravenous calcium included not receiving preoperative calcitriol treatment, low preoperative calcium, and high preoperative parathyroid hormone. After multivariable adjustment, preoperative calcitriol treatment remained independently associated with reduced postoperative administration of intravenous calcium (OR 0.02, P < .001). CONCLUSION: Preoperative calcitriol therapy lowered use of postoperative administration of intravenous calcium by 56% and length of stay by 50% in subtotal parathyroidectomy for renal-origin hyperparathyroidism patients. We believe preoperative calcitriol treatment should become standard of care for subtotal parathyroidectomy for renal-origin hyperparathyroidism. PMID- 30413327 TI - [Epidemiology of primary lung cancer among non-smokers in Senegal]. AB - INTRODUCTION: According to global data for 2002, one quarter of new cases of primary bronchopulmonary cancer were non-smokers. We undertook this study with the aim of describing the epidemiological characteristics of non-smokers with primary bronchopulmonary cancer in the Dakar region of Senegal. METHODS: A multicenter descriptive study that included all non-smokers who presented with primary bronchopulmonary cancer between January 1st 2014 and December 31st 2015. The data were captured on an Excel file and then transferred to Epi InfoTM 7 software for analysis. RESULTS: The rate of diagnosis for primary bronchopulmonary cancers was 72.1 %. The prevalence of non-smokers was 33.3 %. The sex ratio was 1.27. The average age was 54.6 years. More than a third of the sample were housewives. Carpenters and craftsmen exposed to metals predominated. Exposure to cooking oils was reported in one case. Three patients presented sequelae of pulmonary tuberculosis. Adenocarcinoma was the most common histological type and predominated in young subjects. CONCLUSION: The proportion of primary bronchopulmonary cancers diagnosed among non-smokers is increasing in Dakar. An analytical study of suspected risk factors would be helpful for prevention. PMID- 30413328 TI - Perceptions of Obesity Prevention Policies: Socioeconomic Assessment in the Turkish Capital. AB - PURPOSE: The purpose of this study was to inform public policy opportunities to reduce childhood obesity by identifying parents' perceptions of factors contributing to childhood obesity, attribution of responsibility, and the extent of their support for public prevention policies with attention to socio-economic status. DESIGN AND METHODS: In 2015, 2066 parent-child dyads across socio economic strata from 43 randomly selected schools in Ankara completed surveys and measurements to examine perceptions, attribution, and prevention policies related to childhood obesity. RESULTS: Parents across the socio-demographic spectrum recognized obesity as a serious problem. Unhealthy food availability was identified as the leading cause of while industry and media were credited with having the greatest responsibility for childhood obesity. There was strong public support for policy strategies targeting schools, marketing, and the built environment, though support tempered as socio-economic status and parental education decreased. CONCLUSIONS: This survey provided insight into parents' knowledge and beliefs surrounding childhood obesity as well as their endorsement of related prevention strategies. Educational messages that address variations in SES to describe the causes of childhood obesity and connect those causes to actionable community prevention strategies may improve community support for enhanced policy actions within and beyond school settings. PMID- 30413329 TI - Successful tissue expansion: A question of complication management. PMID- 30413330 TI - Tissue expansion of the lower limb: Retrospective study of 141 procedures in burn sequelae. PMID- 30413331 TI - [Treating circadian sleep-wake disorders by light]. AB - Phototherapy is one treatment of circadian sleep-wake disorders, which is based on consensual and numerous scientific and clinical evidences. Phototherapy efficiency depends on several light characteristics based on intensity, length of exposure, time of exposure and wavelength. Phototherapy is potentially indicated in the following circadian disorders: advanced sleep-wake phase disorder (ASWPD), delayed sleep-wake phase disorder (DSWPD), non-24-hour sleep-wake rhythm disorder (N24SWD), jet-lag and night-shift work sleep-wake disorders (NSSWD). Phototherapy, acting via the retina, may be avoided in patients with retina disorders, an ophthalmologist should be consulted. PMID- 30413332 TI - Neuromuscular complications of immune checkpoint inhibitors. AB - Immune checkpoint inhibitors have been increasingly used in patients with various cancers. Despite favourable oncological outcomes these treatments have also been associated with immune-related adverse events. Neurological irAE are rare but potentially severe and neuromuscular complications are the most common. This is a new group of neurologic complications of systemic anticancer therapies, often responsive to immune-modulating therapies. Early recognition and treatment are crucial for timely improvement of functional outcome and requires a multidisciplinary approach. PMID- 30413333 TI - A randomized controlled trial comparing femtosecond laser-assisted cataract surgery versus conventional phacoemulsification surgery. AB - PURPOSE: To compare the clinical results of conventional phacoemulsification surgery (CPS) with femtosecond laser-assisted cataract surgery. SETTING: Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom. DESIGN: Single-center prospective randomized interventional case-controlled trial. METHODS: Patients undergoing cataract surgery were randomized to receive either CPS or femtosecond laser-assisted cataract surgery. The surgery was performed with a femtosecond laser (Lensx), and all operations were performed with a gravity-fluidics torsional phacoemulsification machine (Infiniti). The visual acuity, refraction, central corneal thickness (CCT), central foveal thickness (CFT), endothelial cell loss, and rates of intraoperative and postoperative events were recorded. Quality of life outcomes were measured with the EuroQOL 5 dimensions questionnaire (EQ 5D) and patient-reported quality of vision was assessed with a cataract surgery patient-reported outcome measures questionnaire (Cat-PROM5). RESULTS: The study comprised 400 eyes of 400 patients who had CPS (n = 200) or femtosecond laser assisted cataract surgery (n = 200). Seven patients (3.5%) in the femtosecond laser-assisted group were not able to complete the treatment and received CPS. The mean uncorrected distance visual acuity (logarithm of the minimum angle of resolution [logMAR]) 0.15 +/- 0.21 (SD) and 0.15 +/- 0.19 logMAR after CPS and femtosecond laser-assisted surgery, respectively (P = 1.0); the pinhole-corrected visual acuity was 0.04 +/- 0.12 and 0.04 +/- 0.12, respectively (P = 1.0); the increase in CCT was 13 +/- 19 MUm and 15 +/- 25 MUm, respectively (P = .5); and the endothelial cell loss was 9.7 +/- 13.7 % and 10.2% +/- 13.7, respectively (P = .76). The manifest refraction spherical equivalent error was -0.14 +/- 0.60 diopters (D) after CPS and -0.12 +/- 0.60 D after femtosecond laser-assisted surgery (P = .74); the mean change in CFT was 9 +/- 35 MUm and 6 +/- 35 MUm, respectively (P = .55); and the rate of posterior capsule rupture was 3% and 0%, respectively (P = .03). CONCLUSIONS: This study confirms the nonsignificant differences between 2 treatment modalities, notwithstanding a significant reduction in posterior capsule ruptures in the femtosecond laser-assisted surgery group. PMID- 30413334 TI - Optimising sampling patterns for bi-exponentially decaying signals. AB - A recently reported method, based on the Cramer-Rao Lower Bound theory, for optimising sampling patterns for a wide range of nuclear magnetic resonance (NMR) experiments is applied to the problem of optimising sampling patterns for bi exponentially decaying signals. Sampling patterns are optimised by minimizing the percentage error in estimating the most difficult to estimate parameter of the bi exponential model, termed the objective function. The predictions of the method are demonstrated in application to pulsed field gradient NMR data recorded for the two-component diffusion of a binary mixture of methane/ethane in a zeolite. It is shown that the proposed method identifies an optimal sampling pattern with the predicted objective function being within 10% of that calculated from the experiment dataset. The method is used to advise on the number of sampled points and the noise level needed to resolve two-component systems characterised by a range of ratios of populations and diffusion coefficients. It is subsequently illustrated how the method can be used to reduce the experiment acquisition time while still being able to resolve a given two-component system. PMID- 30413335 TI - A Review of Phospholipid Encapsulated Ultrasound Contrast Agent Microbubble Physics. AB - Ultrasound contrast agent microbubbles have expanded the utility of biomedical ultrasound from anatomic imaging to the assessment of microvascular blood flow characteristics and ultrasound-assisted therapeutic applications. Central to their effectiveness in these applications is their resonant and non-linear oscillation behaviour. This article reviews the salient physics of an oscillating microbubble in an ultrasound field, with particular emphasis on phospholipid coated agents. Both the theoretical underpinnings of bubble vibration and the experimental evidence of non-linear encapsulated bubble dynamics and scattering are discussed and placed within the context of current and emerging applications. PMID- 30413336 TI - Resolution of Uterine Arteriovenous Malformation and Maintenance of Reproduction in 20 Women Treated With a GnRH Agonist Concomitantly With an Aromatase Inhibitor and Tranexamic Acid. AB - OBJECTIVE: This study investigated the efficacy of GnRH agonists concomitantly with transient aromatase inhibitor and tranexamic acid to treat women with uterine arteriovenous malformations (AVMs) associated with abnormal uterine bleeding (AUB) to preserve fertility and determine reproductive outcome. METHODS: This was a prospective cohort study in a tertiary centre. Doppler ultrasound demonstrated AVM in 19 women with AUB 1-28 weeks following spontaneous or therapeutic abortion and in one woman 4 years after normal pregnancy while taking an oral contraceptive. On the basis of experience from the first three cases, 17 women were treated with tranexamic acid (1 g three times daily orally for 5 days), a GnRH agonist (3.75-11.25 mg, for 1-3 months), plus an aromatase inhibitor (letrozole 2.5 mg once daily for 5days) with the initial injection of GnRH agonist. Two women required blood transfusion, and one required uterine tamponade with Foley catheter balloon in the first 48 hours to control heavy bleeding (Canadian Task Force Classification II-2). RESULTS: All 20 AVMs resolved within 1-3 months of treatment. Of 16 women who attempted pregnancy, all (100%), including two who had uterine artery embolization (one after hysteroscopic septoplasty), conceived spontaneously with 18 live births. Two women are using contraception (one taking an oral contraceptive, one using a levonorgestrel intrauterine system), and one 40-year-old is not using contraception. One woman had hysteroscopic endometrial ablation followed by vaginal hysterectomy for AUB at 1 and 2 years later. CONCLUSION: A GnRH agonist in combination with transient aromatase inhibitor and tranexamic acid is an effective management strategy to treat and maintain reproduction in women with AVMs associated with AUB. PMID- 30413337 TI - Identification and molecular characterisation of an AMEL-X null allele due to an Alu insertion. PMID- 30413338 TI - The CRIOAc healthcare network in France: A nationwide Health Ministry program to improve the management of bone and joint infection. AB - BACKGROUND: Bone and joint infections (BJIs) have a major clinical and economic impact in industrialized countries. Its management requires a multidisciplinary approach, and a great experience for the most complicated cases to limit treatment failure, motor disability and amputation risk. To our best knowledge there is not currently national specific organization dedicated to manage BJI. Is it possible to build at a national level, a network involving orthopaedic surgeons, infectiologists and microbiologists performing locally multidisciplinary meetings to facilitate the recruitment and the management of patients with complex bone and joint infection in regional centers? HYPOTHESIS: A national healthcare network with regional labeled centers creates a dynamic that improves the recruitment, the management, the education, and the clinical research in the field of complex BJI. PATIENTS AND METHODS: We describe the history of this unique national healthcare network and how it works, specify the missions confided to the CRIOAcs, evaluate the activity of the network over the first decade, and finally discuss perspectives. RESULTS: The labelling of 24 centers in the CRIOAc network allowed for a meshing of the territory, with the possibility of management of complex BJI in each region of France. A dedicated secure national online information system was designed and used to facilitate decision-making during multidisciplinary consultation meetings. Since October 2012 to June 2017, 4553 multidisciplinary consultation meetings have been performed in the structures belonging to the network, with 34,607 cases discussed in 19,961 individual. Prosthetic joint infections represented 38% (7585/19,961) of all BJIs. Among all the cases discussed, the rate of complexity was of 61% (21,110/34,607) (related to antibiotic resistance, infection recurrence, patient co morbidities). A national scientific meeting was created and a national postgraduate diploma in the field of BJI was launched in 2014. The promotion of education, clinical research and interactivity between each academic discipline and between each labeled centers across the country has synergized the strengths and have greatly facilitated the management of patients with BJI. DISCUSSION: The setting up of the CRIOAc network in France took time, and has a cost for the French Ministry of Health. However, this network has greatly facilitated the management of BJI in France, and allowed to concentrate the management of complex BJI in centers that have significantly gained skills. There is, to our knowledge, no other exemple of such nationwide network in the field of BJI. LEVEL OF EVIDENCE: IV, case series without control group. PMID- 30413339 TI - Justifying conservative management of CIN2 in women younger than 25 years - A population-based study. AB - OBJECTIVE: In 2012, the joint clinical practice guideline from the Society of Obstetricians and Gynaecologists of Canada (SOGC) changed from immediate treatment to a more conservative management of Cervical Intraepithelial Neoplasia (CIN) grade 2 in young women. In this study, the outcomes before and after this management change were reviewed in Nova Scotia, Canada. METHODS: A retrospective population-based cohort study was performed among women younger than 25 years with biopsy-proven CIN2, who were diagnosed in one of the colposcopy clinics in Nova Scotia between 2010 and 2014. Regression and progression rates were compared pre- and post-guideline changes. RESULTS: Of the 636 women included in the study, 286 women were diagnosed with CIN2 before and 350 women after the management in Nova Scotia was changed. After implementation of the 2012 guidelines patients were more likely to receive conservative management (78.6% versus 44.1%; p < 0.001); which differs from the patients who underwent treatment during follow-up prior to the change in guidelines (73.4% versus 38.9%; p < 0.001). Regression occurred in 73.1% of all women, but women seen in the post-guideline change period had a higher regression rate and lower progression rate (p < 0.05). Histologic results from treatment specimen did not show a significant difference in low-grade or high-grade lesions before or after the guideline had been changed (p = 0.59). CONCLUSION: Conservative management seems a safe and justified approach for women younger than 25 years with CIN2. PMID- 30413340 TI - Risk-based stratification of carcinomas concurrently involving the endometrium and ovary. AB - OBJECTIVE: Determining whether carcinomas concurrently involving endometrium and ovary are independent primary tumors (IPTs) or endometrial carcinomas with ovarian metastases (at least stage IIIA endometrial cancers, IIIA-EC) using clinicopathologic criteria is often challenging. Recent genomic studies showed that most such tumors are clonally related. We sought to identify clinicopathologic features associated with clinical outcomes, and to separate women with these tumors into clinically low-risk and high-risk groups. METHODS: We reviewed clinical and pathologic data from 74 women who, between 1993 and 2014, underwent primary surgery for endometrial cancer and had concurrent ovarian involvement. RESULTS: The endometrial carcinomas were endometrioid (EECs, n = 41) or non-endometrioid (ENECs, n = 33). Nineteen (26%) cases were originally classified as IPTs using clinicopathologic criteria. Multivariate analysis revealed that lymph node involvement (hazard ratio (HR) = 2.38, 95% CI 1.13-5.02, p = 0.023) and non-endometrioid endometrial tumor histology (HR = 6.27, 95% CI 2.6-15.13, p < 0.001) were associated with poorer progression-free survival (PFS). Multivariate analysis of 65 women with known lymph node status revealed two prognostically distinct groups: a high-risk group comprising ENECs with >=50% myometrial invasion irrespective of lymph node status (n = 21; median PFS 12.7 months, 95% CI, 9.24-19.8); and a low-risk group consisting of all EECs, as well as lymph node-negative ENECs with <50% myometrial invasion (n = 44, median PFS not reached). The risk-based classification was superior to the original classification of endometrial cancers as IPTs vs. IIIA-EC for predicting PFS (log rank test, p < 0.001 vs. p = 0.07). CONCLUSION: Our proposed risk-based stratification enables categorization of women with concurrent endometrial and ovarian tumors according to their likely clinical outcomes. PMID- 30413341 TI - Examining the Quality of Foods and Beverages Across the Food Stream. PMID- 30413342 TI - The Grocery Purchase Quality Index-2016 Performs Similarly to the Healthy Eating Index-2015 in a National Survey of Household Food Purchases. AB - BACKGROUND: Household food purchases are potential indicators of the quality of the home food environment, and grocery purchase behavior is a main focus of US Department of Agriculture (USDA) nutrition education programs; therefore, objective measures of grocery purchases are needed. OBJECTIVE: The objective of the study was to evaluate the Grocery Purchase Quality Index-2016 (GPQI-2016) as a tool for assessing grocery food purchase quality by using the Healthy Eating Index-2015 (HEI-2015) as the reference standard. DESIGN: In 2012, the USDA Economic Research Service conducted the National Household Food Acquisition and Purchase Survey. Members of participating households recorded all foods acquired for a week. Foods purchased at stores were mapped to the 29 food categories used in USDA Food Plans, expenditure shares were estimated, and GPQI-2016 scores were calculated. USDA food codes, provided in the survey database, were used to calculate the HEI-2015. PARTICIPANTS/SETTING: All households in the 48 coterminous states were eligible for the survey. The analytic sample size was 4,276 households. MAIN OUTCOME MEASURES: GPQI-2016 and HEI-2015 scores were compared. STATISTICAL ANALYSES PERFORMED: Correlation of scores was assessed using Spearman's correlation coefficient. Linear regression models with fixed effects were used to determine differences among various subgroups of households. RESULTS: The correlation coefficient for the total GPQI-2016 score and the total HEI-2015 score was 0.70. For the component scores, the strongest correlations were for Total and Whole Fruit (0.89 to 0.90); the weakest were for Dairy (0.67), Refined Grains (0.66), and Sweets and Sodas/Added Sugars (0.65) (all, P<0.01). Both the GPQI-2016 and HEI-2015 were significantly different among subgroups in expected directions. CONCLUSIONS: Overall, the GPQI-2016, estimated from a national survey of households, performed similarly to the HEI-2015. The tool has potential for evaluating nutrition education programs and retail-oriented interventions when the nutrient content and gram weights of foods purchased are not available. PMID- 30413343 TI - Isolation, leishmanicidal evaluation and molecular docking simulations of piperidine alkaloids from Senna spectabilis. AB - Leishmaniasis is one of the most important neglected tropical diseases (NTDs) that are especially common among low-income populations in developing regions of Africa, Asia, and the Americas. Many natural products, particularly alkaloids, have been reported to have inhibitory activity against arginase, the key enzyme in the pathology caused by Leishmania sp. In this way, piperidine alkaloids (-) cassine (1), (-)-spectaline (2), (-)-3-O-acetylcassine (3), and (-)-3-O acetylspectaline (4) were isolated from Senna spectabilis flowers. These compounds (1/2 and 3/4) initially present as homologous mixtures were separated by high performance liquid chromatography and evaluated against the promastigote phase of Leishmania amazonensis. In addition, molecular docking simulations were implemented in order to probe the binding modes of the ligands 1-4 to the amino acids in the active site of L. amazonensis arginase. Alkaloid 2 (IC50 15.81 MUg mL-1) was the most effective against L. amazonensis. Compounds 2 and 4, with larger side chain, were more effective against the parasite than compounds 1 and 3. The cell viability test on Vero cells revealed that compound 2 (CC50 66.67 MUg mL-1) was the most toxic. The acetyl group in the 3-O position of the parent structures reduced the leishmanicidal activity and the toxicity of the alkaloids. Further, molecular docking suggested that Asn143 is essential for arginase to interact with (-)-spectaline-derived compounds, which agreed with the IC50 measurements. Our findings revealed that S. spectabilis is an important source of piperidine alkaloids with leishmanicidal activity. Moreover, the natural compound 3 has been isolated for the first time. Experimental investigation combined with theoretical study advances knowledge about the enzyme binding site mode of interaction and contributes to the design of new bioactive drugs against Leishmania infection. PMID- 30413344 TI - Werner syndrome (WRN) DNA helicase and base excision repair (BER) factors maintain endothelial homeostasis. AB - The accelerated ageing disease Werner Syndrome (WRN) is characterized by pronounced atherosclerosis. Here, we investigated the influence of WRN downregulation on the functionality of non-replicating human endothelial cells. RNAi-mediated downregulation of WRN reduces cell motility and enhances the expression of factors regulating adhesion, inflammation, hemostasis and vasomotor tone. Moreover, WRN influences endothelial barrier function and Ca2+-release, while cell adhesion, Dil-acLDL-uptake and the mRNA expression of NO-synthases (eNOS, iNOS) remained unaffected. Regarding motility, we propose that WRN affects Rac1/FAK/beta1-integrin-related mechanisms regulating cell polarity and directed motility. Since oxidative DNA base damage contributes to aging and atherosclerosis and WRN affects DNA repair, we investigated whether downregulation of base excision repair (BER) factors mimics the effects of WRN knock-down. Indeed, downregulation of particular WRN-interacting base excision repair (BER) proteins (APE1, NEIL1, PARP1) imitates the inhibitory effect of WRN on motility. Knock-down of OGG1, which does not interact with WRN, does not influence motility but increases the mRNA expression of E-selectin, ICAM, VCAM, CCL2 and VEGFR and stimulates adhesion. Thus, individual BER factors themselves differently impact endothelial cell functionality and homeostasis. Impairment of endothelial activities caused by genotoxic stressor (tBHQ) remained largely unaffected by WRN. Summarizing, both WRN, WRN-associated BER proteins and OGG1 promote the maintenance of endothelial cell homeostasis, thereby counteracting the development of ageing-related endothelial malfunction in non-proliferating endothelial cells. PMID- 30413345 TI - Simple percutaneous coronary interventions using the modification of complex coronary lesion with excimer laser. AB - Excimer laser coronary atherectomy (ELCA), a unique percutaneous coronary intervention (PCI) device, comprises a monorail-type system and is compatible with any standard 0.014-inch guidewire. ELCA is the only device that vaporizes the atherosclerotic plaques or modifies underlying plaque located underneath to a hard tissue, such as severe calcification or a stent. Therefore, ELCA differs from other coronary atherectomy devices and is useful for patients with acute coronary syndrome, chronic total occlusion or under-expanded stents. This case series reports on patients treated using ELCA to simplify complex PCI procedures. Furthermore, we review and discuss ELCA in several situations. PMID- 30413346 TI - The left distal trans-radial artery access for coronary angiography and intervention: A US experience. AB - BACKGROUND: The radial artery is the access of choice in many catheterization labs around the world due to its proven benefits over the femoral artery access. There has been growing interest in the left radial artery. We sought to evaluate the feasibility, safety and complication rates of the left distal radial artery (ldTRA) access for cardiac catheterization. METHODS: This is a single arm retrospective study evaluating the feasibility and safety of performing cardiac catheterization through ldTRA. The procedure was completed using standard diagnostic and guiding catheters. Hemostasis was achieved with a radial band. Feasibility was the ability to cannulate the distal left radial artery as well as completing the procedure without requiring an additional arterial access. The safety point included hematoma, bleeding or neuropathy. RESULTS: ldTRA was attempted in 61 patients. 59 patients had successful completion of the procedure through ldTRA. Conversion occurred in 1 patient (1.7%), requiring an additional arterial access to complete the procedure. 34 patients (55.7%) required percutaneous coronary intervention (PCI). There was no access site bleeds post procedure, no hematomas, with 100% successful hemostasis with a radial hemostatic band. There were 2 cases requiring reaccess of the distal left radial artery access for repeat revascularization, with procedure success and good left radial artery patency. CONCLUSION: ldTRA is a safe and feasible arterial access in a radial experienced catheterization lab. ldTRA provides improved operator ergonomics and patient's comfort, in addition to the advantage of being able to cannulate the bypass grafts and with a very low risk of vascular complications. PMID- 30413348 TI - Novel biomarkers GEP/ABCB5 regulate response to adjuvant transarterial chemoembolization after curative hepatectomy for hepatocellular carcinoma. AB - BACKGROUND: Transarterial chemoembolization (TACE) is the most commonly used adjuvant therapy for hepatocellular carcinoma (HCC) after curative resection. Responses to TACE are variable due to tumor and patient heterogeneity. We had previously demonstrated that expression of Granulin-epithelin precursor (GEP) and ATP-dependent binding cassette (ABC)B5 in liver cancer stem cells was associated with chemoresistance. The present study aimed to evaluate the association between GEP/ABCB5 expression and response to adjuvant TACE after curative resection for HCC. METHODS: Patients received adjuvant TACE after curative resection for HCC and patients received curative resection alone were identified from a prospectively collected database. Clinical samples were retrieved for biomarker analysis. Patients were categorized into 3 risk groups according to their GEP/ABCB5 status for survival analysis: low (GEP-/ABCB5-), intermediate (either GEP+/ABCB5- or GEP-/ABCB5+) and high (GEP+/ABCB5+). Early recurrence (recurrence within 2 years after resection) and disease-free survival were analyzed. RESULTS: Clinical samples from 44 patients who had followed-up for more than 2 years were retrieved for further biomarker analysis. Among them, 18 received adjuvant TACE and 26 received surgery alone. Patients with adjuvant TACE in the intermediate risk group was associated with significantly better overall survival and 2-year disease-free survival than those who had surgery alone (P = 0.036 and P = 0.011, respectively). Adjuvant TACE did not offer any significant differences in the early recurrence rate, 2-year disease-free survival and overall survival for patients in low and high risk groups. CONCLUSIONS: Adjuvant TACE can only provide survival benefits for patients in the intermediate risk group (either GEP+/ABCB5- or GEP-/ABCB5+). A larger clinical study is warranted to confirm its role in patient selection for adjuvant TACE. PMID- 30413347 TI - Biliary leakage following pancreaticoduodenectomy: Prevalence, risk factors and management. AB - BACKGROUND: Few studies investigated biliary leakage after pancreaticoduodenectomy (PD) especially when compared to postoperative pancreatic fistula (POPF). This study was to determine the incidence of biliary leakage after PD, predisposing factors of biliary leakage, and its management. METHODS: We retrospectively studied all patients who underwent PD from January 2008 to December 2017 at Gastrointestinal Surgery Center, Mansoura University, Egypt. According to occurrence of postoperative biliary leakage, patients were divided into two groups. Group (1) included patients who developed biliary leakage and group (2) included patients without identified biliary leakage. The preoperative data, operative details, and postoperative morbidity and mortality were analyzed. RESULTS: The study included 555 patients. Forty-four patients (7.9%) developed biliary leakage. Ten patients (1.8%) had concomitant POPF. Multivariate analysis identified obesity and time needed for hepaticojejunostomy reconstruction as independent risk factors of biliary leakage, and no history of preoperative endoscopic retrograde cholangiopancreatiography (ERCP) as protective factor. Biliary leakage from hepaticojejunostomy after PD leads to a significant increase in development of delayed gastric emptying, and wound infection. The median hospital stay and time to resume oral intake were significantly greater in the biliary leakage group. Non-surgical management was needed in 40 patients (90.9%). Only 4 patients (9.1%) required re-exploration due to biliary peritonitis and associated POPF. The mortality rate in the biliary leakage group was significantly higher than that of the non-biliary leakage group (6.8% vs 3.9%, P = 0.05). CONCLUSIONS: Obesity and time needed for hepaticojejunostomy reconstruction are independent risk factors of biliary leakage, and no history of preoperative ERCP is protective factor. Biliary leakage increases the risk of morbidity and mortality especially if concomitant with POPF. However, biliary leakage can be conservatively managed in majority of cases. PMID- 30413349 TI - Discovery and structure-activity-relationship study of novel imidazole cyclopropyl amine analogues for mutant isocitric dehydrogenase 1 (IDH1) inhibitors. AB - The discovery and optimization of imidazole cyclopropyl amime analogues as mutant IDH1 inhibitors via structure-based rational design were reported. The optimal compounds demonstrated both potent inhibition in IDH1R132H enzymatic activity and 2HG production in IDH1 mutant HT1080 cell line, moderate liver microsome stability and PK properties. PMID- 30413350 TI - Counting what counts: the importance of quantitative approaches to studying plant cell biology. PMID- 30413352 TI - Clinical pulmonary function testing in Duchenne muscular dystrophy. AB - In Duchenne muscular dystrophy there is a well-established progressive loss of upper and lower extremity muscle function that is evident from the earliest stages of decline and through permanent loss of function. There is not the same visible evidence of decline in respiratory muscle function decline toward respiratory failure; therefore, comprehensive pulmonary function testing provides a critical component of a comprehensive longitudinal respiratory assessment. There are multiple ways of assessing separate inspiratory and expiratory muscle function and also a summative output of each to provide broad information to help identify disease status and guide intervention as appropriate. PMID- 30413353 TI - DNA Hybridization to Control Cellular Interactions. AB - A key challenge in many biological studies is the inability to control the placement of cells in two and three dimensions. As our understanding of the importance of complexity in cellular communities increases, better tools are needed to control the spatial arrangements of cells. One universal method to govern these interactions is DNA hybridization, which relies on the inherent interaction between complementary DNA sequences. DNA hybridization has long been used to assemble complex structures of nanoparticles and more recently has been applied to the complex arrangements of cells. Using this technology, our understanding of biological interactions has significantly improved. Improvement of methods to control the interactions between cells provides powerful tools to test hypotheses about intercellular interactions, nutrient transfer, and complex diseases. PMID- 30413354 TI - Triplex real-time PCR assay for the detection of Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae directly from clinical specimens without extraction of DNA. AB - This study presents a triplex real-time PCR assay that allows for the direct detection of Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae in one reaction without DNA extraction, with similar sensitivity and specificity to singleplex assays. This approach saves time, specimen volume and reagents while achieving a higher testing throughput. PMID- 30413351 TI - Bystander T Cells: A Balancing Act of Friends and Foes. AB - T cell responses are essential for appropriate protection against pathogens. T cell immunity is achieved through the ability to discriminate between foreign and self-molecules, and this relies heavily on stringent T cell receptor (TCR) specificity. Recently, bystander activated T lymphocytes, that are specific for unrelated epitopes during an antigen-specific response, have been implicated in diverse diseases. Numerous infection models have challenged the classic dogma of T cell activation as being solely dependent on TCR and major histocompatibility complex (MHC) interactions, indicating an unappreciated role for pathogen associated receptors on T cells. We discuss here the specific roles of bystander activated T cells in pathogenesis, shedding light on the ability of these cells to modulate disease severity independently from TCR recognition. PMID- 30413356 TI - Tumor Treating Fields: Adjuvant Treatment for High-grade Gliomas. AB - OBJECTIVE: To introduce effectiveness of tumor treating fields (TTFields), how to care for the patient with this type of treatment, and the critical role the nurse plays in educating the patient about this innovative treatment. DATA SOURCES: Published research and articles in both nursing and medical journals. CONCLUSION: TTFields are an antimitotic therapy delivered via transducer arrays that are worn on the scalp to treat newly diagnosed and recurrent glioblastoma, the most aggressive primary brain cancer. Oncology nurses are integral in educating and supporting the patient in its use and managing its of treatment. IMPLICATIONS FOR NURSING PRACTICE: Nurses are on the front line of educating the patient, caregivers, and the larger body of clinicians who deliver care to these patients. Education provided by nurses increases the patients' knowledge, and thus compliance, as well as the overall outcome through proper usage of TTFields. PMID- 30413355 TI - MERS coronavirus outbreak: Implications for emerging viral infections. AB - In September 2012, a novel coronavirus was isolated from a patient who died in Saudi Arabia after presenting with acute respiratory distress and acute kidney injury. Analysis revealed the disease to be due to a novel virus which was named Middle East Respiratory Coronavirus (MERS-CoV). There have been several MERS-CoV hospital outbreaks in KSA, continuing to the present day, and the disease has a mortality rate in excess of 35%. Since 2012, the World Health Organization has been informed of 2220 laboratory-confirmed cases resulting in at least 790 deaths. Cases have since arisen in 27 countries, including an outbreak in the Republic of Korea in 2015 in which 36 people died, but more than 80% of cases have occurred in Saudi Arabia.. Human-to-human transmission of MERS-CoV, particularly in healthcare settings, initially caused a 'media panic', however human-to-human transmission appears to require close contact and thus far the virus has not achieved epidemic potential. Zoonotic transmission is of significant importance and evidence is growing implicating the dromedary camel as the major animal host in spread of disease to humans. MERS-CoV is now included on the WHO list of priority blueprint diseases for which there which is an urgent need for accelerated research and development as they have the potential to cause a public health emergency while there is an absence of efficacious drugs and/or vaccines. In this review we highlight epidemiological, clinical, and infection control aspects of MERS-CoV as informed by the Saudi experience. Attention is given to recommended treatments and progress towards vaccine development. PMID- 30413357 TI - Methods to detect inappropriate use of MRI and CT for musculoskeletal conditions: A scoping review. AB - OBJECTIVE: Identify and evaluate methods suitable for detecting inappropriate use of MRI or CT in the musculoskeletal system. DESIGN: Systematic review of studies that described methods to measure inappropriate use of MRI or CT in the musculoskeletal system. We used a multi-step strategy to classify identified methods into categories. These categories were then analyzed according to the data needed and their limitations. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: English or German language studies that measured inappropriate use of MRI or CT in the musculoskeletal system. Articles were also included if they reported a general approach to the measurement of inappropriate imaging regardless of body region. Expert opinions, unsystematic reviews, commentaries, articles without abstracts, and studies on cancer were excluded. RESULTS: 47 studies met the inclusion criteria. The categorization of the studies resulted in seven individual approaches to measure inappropriate use: (1) availability of meaningful diagnostic information; (2) predictors associated with imaging use; (3) comparison with guideline recommendations; (4) assessment by experts; (5) comparison or analysis of patients' paths; (6) comparison with surgery findings; (7) geographic variation. All these approaches have specific data requirements and individual advantages and disadvantages regarding risk of bias and needed data. CONCLUSIONS: We could not find a single method of choice to detect inappropriate use of MRI or CT in the musculoskeletal system. A combination of different approaches is the preferred strategy to deal with the advantages and disadvantages of the individual methods. PMID- 30413358 TI - 99mTc-pertechnetate thyroid scintigraphy predicts clinical outcomes in personalized radioiodine treatment for Graves' disease. AB - OBJECTIVE: The aim of this study was, first, to ascertain the efficacy of radioiodine therapy (RIT) for Graves' disease (GD) based on a calculated-dose regime and, second, to determine the value of 99mTc-pertechnetate thyroid scintigraphy in predicting the clinical outcomes of RIT. METHODS: One hundred and thirty 9consecutive GD patients who underwent RIT using a calculated-dose method in our hospital from January 2015 to September 2015 were retrospectively evaluated. Radioiodine dose was calculated based on the Marinelli's formula. 99mTc-pertechnetate uptake, age, gender, thyroid mass, duration of the disease, previous antithyroid drugs treatment, serum levels of TSH, FT3 and FT4, a positive rate of TPOAb and Anti-TRAb, radioiodine dose and follow-up were evaluated as potential interference factors for RIT success. RESULTS: One hundred and 8(77.7%) GD patients including 71 (51.1%) euthyroid and 37 (26.6%) hypothyroid were successful, but 31 (22.3%) remained hyperthyroid (treatment failure). Significant differences were found between the treatment success group and the failure group in 99mTc-pertechnetate uptake (p<0.0001), the duration of disease (P=.0140) and positive rate of Anti-TRAb (P=.0103). 99mTc-pertechnetate uptake is an independent risk factor for predicting treatment failure (P=.0394). Using a cut-off value of 18.4%, 99mTc-pertechnetate uptake could predict treatment failure with a sensitivity of 84.3%, and a specificity of 80.6%. CONCLUSION: Our study has shown that a calculated radioiodine dose is effective in treating GD patients with a consequent low rate of hypothyroid. A 99mTc pertechnetate uptake above 18.4% is a significant predictor of treatment failure and these patients should receive a higher radioiodine dose in this scenario. PMID- 30413359 TI - Single-Blinded Randomized Controlled Study on Use of Interactive Distraction Versus Oral Midazolam to Reduce Pediatric Preoperative Anxiety, Emergence Delirium, and Postanesthesia Length of Stay. AB - PURPOSE: The purpose of this study was to compare effects of tablet-based interactive distraction (TBID; 1 minute preseparation) with oral midazolam (15 to 45 minutes of preseparation) on preoperative anxiety, emergence delirium, and postanesthesia length of stay in children, 4 to 12 years undergoing outpatient surgery. DESIGN: Single-blinded prospective design with randomized assignment to TBID or oral midazolam group was conducted at a large pediatric hospital in southwestern United States. METHODS: A total of 102 children and caregivers were enrolled. Outcome measures included anxiety scores at baseline, separation, and mask induction; postemergence delirium scores; caregiver ratings of child anxiety and satisfaction; and time from postanesthesia care unit arrival to discharge and posthospital behaviors. FINDINGS: The TBID group demonstrated significantly lower anxiety at separation and mask induction (P < .001) and emergence delirium at 15 minutes postawakening (P = .001), were extubated earlier (P = .007), arrived to phase II earlier (P = .03), and discharged earlier (P = .0001). CONCLUSIONS: TBID was more effective than oral midazolam in reducing preoperative anxiety, emergence delirium, and postanesthesia length of stay. PMID- 30413360 TI - Hippo Kinases Mst1 and Mst2 Sense and Amplify IL-2R-STAT5 Signaling in Regulatory T Cells to Establish Stable Regulatory Activity. AB - Interleukin-2 (IL-2) and downstream transcription factor STAT5 are important for maintaining regulatory T (Treg) cell homeostasis and function. Treg cells can respond to low IL-2 levels, but the mechanisms of STAT5 activation during partial IL-2 deficiency remain uncertain. We identified the serine-threonine kinase Mst1 as a signal-dependent amplifier of IL-2-STAT5 activity in Treg cells. High Mst1 and Mst2 (Mst1-Mst2) activity in Treg cells was crucial to prevent tumor resistance and autoimmunity. Mechanistically, Mst1-Mst2 sensed IL-2 signals to promote the STAT5 activation necessary for Treg cell homeostasis and lineage stability and to maintain the highly suppressive phosphorylated-STAT5+ Treg cell subpopulation. Unbiased quantitative proteomics revealed association of Mst1 with the cytoskeletal DOCK8-LRCHs module. Mst1 deficiency limited Treg cell migration and access to IL-2 and activity of the small GTPase Rac, which mediated downstream STAT5 activation. Collectively, IL-2-STAT5 signaling depends upon Mst1 Mst2 functions to maintain a stable Treg cell pool and immune tolerance. PMID- 30413361 TI - High-Dimensional Single-Cell Analysis Identifies Organ-Specific Signatures and Conserved NK Cell Subsets in Humans and Mice. AB - Natural killer (NK) cells are innate lymphoid cells (ILCs) involved in antimicrobial and antitumoral responses. Several NK cell subsets have been reported in humans and mice, but their heterogeneity across organs and species remains poorly characterized. We assessed the diversity of human and mouse NK cells by single-cell RNA sequencing on thousands of individual cells isolated from spleen and blood. Unbiased transcriptional clustering revealed two distinct signatures differentiating between splenic and blood NK cells. This analysis at single-cell resolution identified three subpopulations in mouse spleen and four in human spleen, and two subsets each in mouse and human blood. A comparison of transcriptomic profiles within and between species highlighted the similarity of the two major subsets, NK1 and NK2, across organs and species. This unbiased approach provides insight into the biology of NK cells and establishes a rationale for the translation of mouse studies to human physiology and disease. PMID- 30413364 TI - Effects of seasonality and daylight savings time on emergency department visits for mental health disorders. AB - OBJECTIVES: Emergency Department (ED) utilization accounts for a large portion of healthcare services in the US. Disturbance of circadian rhythms may affect mental and behavioral health (MBH) conditions, which could result in increased ED visits and subsequent hospitalizations, thus potentially inducing staffing shortages and increasing ED wait time. Predicting the burden of ED admissions helps to better plan care at the EDs and provides significant benefits. This study investigates if increased ED visits for MBH conditions are associated with seasonality and changes in daylight savings time. METHODS: Using ED encounter data from a large academic medical center, we have examined univariate and multivariate associations between ED visits for MBH conditions and the annual time periods during which MBH conditions are more elevated due to changes in the seasons. We hypothesize that ED visits for MBH conditions increase within the 2-week period following the daylight savings time changes. RESULTS: Increased MBH ED visits were observed in certain seasons. This was especially true for non-bipolar depressive illness. We saw no significant changes in MBH visits as associated with changes in the daylight savings time. CONCLUSIONS: Data do not provide conclusive evidence of a uniform seasonal increase in ED visits for MBH conditions. Variation in ED MBH visits may be due to secular trends, such as socioeconomic factors. Future research should explore contemporaneous associations between time-driven events and MBH ED visits. It will allow for greater understanding of challenges regarding psychiatric patients and opportunities for improvement. PMID- 30413365 TI - Predicting hospital admission at the emergency department triage: A novel prediction model. AB - BACKGROUND: Emergency department (ED) overcrowding is a growing international patient safety issue. A major contributor to overcrowding is long wait times for inpatient hospital admission. The objective of this study is to create a model that can predict a patient's need for hospital admission at the time of triage. METHODS: Retrospective observational study of electronic clinical records of all ED visits over ten years to a large urban hospital in Singapore. The data was randomly divided into a derivation set and a validation set. We used the derivation set to develop a logistic regression model that predicts probability of hospital admission for patients presenting to the ED. We tested the model on the validation set and evaluated the performance with receiver operating characteristic (ROC) curve analysis. RESULTS: A total of 1,232,016 visits were included for final analysis, of which 38.7% were admitted. Eight variables were included in the final model: age group, race, postal code, day of week, time of day, triage category, mode of arrival, and fever status. The model performed well on the validation set with an area under the curve of 0.825 (95% CI 0.824-0.827). Increasing age, increasing triage acuity, and mode of arrival via private patient transport were most predictive of the need for admission. CONCLUSIONS: We developed a model that accurately predicts admission for patients presenting to the ED using demographic, administrative, and clinical data routinely collected at triage. Implementation of the model into the electronic health record could help reduce the burden of overcrowding. PMID- 30413362 TI - Inhibiting Inflammation with Myeloid Cell-Specific Nanobiologics Promotes Organ Transplant Acceptance. AB - Inducing graft acceptance without chronic immunosuppression remains an elusive goal in organ transplantation. Using an experimental transplantation mouse model, we demonstrate that local macrophage activation through dectin-1 and toll-like receptor 4 (TLR4) drives trained immunity-associated cytokine production during allograft rejection. We conducted nanoimmunotherapeutic studies and found that a short-term mTOR-specific high-density lipoprotein (HDL) nanobiologic treatment (mTORi-HDL) averted macrophage aerobic glycolysis and the epigenetic modifications underlying inflammatory cytokine production. The resulting regulatory macrophages prevented alloreactive CD8+ T cell-mediated immunity and promoted tolerogenic CD4+ regulatory T (Treg) cell expansion. To enhance therapeutic efficacy, we complemented the mTORi-HDL treatment with a CD40-TRAF6 specific nanobiologic (TRAF6i-HDL) that inhibits co-stimulation. This synergistic nanoimmunotherapy resulted in indefinite allograft survival. Together, we show that HDL-based nanoimmunotherapy can be employed to control macrophage function in vivo. Our strategy, focused on preventing inflammatory innate immune responses, provides a framework for developing targeted therapies that promote immunological tolerance. PMID- 30413363 TI - Interleukin-17-Producing gammadelta T Cells Originate from SOX13+ Progenitors that Are Independent of gammadeltaTCR Signaling. AB - Lineage-committed alphabeta and gammadelta T cells are thought to originate from common intrathymic multipotent progenitors following instructive T cell receptor (TCR) signals. A subset of lymph node and mucosal Vgamma2+ gammadelta T cells is programmed intrathymically to produce IL-17 (Tgammadelta17 cells), however the role of the gammadeltaTCR in development of these cells remains controversial. Here we generated reporter mice for the Tgammadelta17 lineage-defining transcription factor SOX13 and identified fetal-origin, intrathymic Sox13+ progenitors. In organ culture developmental assays, Tgammadelta17 cells derived primarily from Sox13+ progenitors, and not from other known lymphoid progenitors. Single cell transcriptome assays of the progenitors found in TCR-deficient mice demonstrated that Tgammadelta17 lineage programming was independent of gammadeltaTCR. Instead, generation of the lineage committed progenitors and Tgammadelta17 cells was controlled by TCF1 and SOX13. Thus, T lymphocyte lineage fate can be prewired cell-intrinsically and is not necessarily specified by clonal antigen receptor signals. PMID- 30413366 TI - The neutrophil-lymphocyte count ratio as a diagnostic marker for bacteraemia: A systematic review and meta-analysis. AB - BACKGROUND: Bacteraemia is a common cause of increased morbidity and mortality in critically ill patients, but its early diagnosis and identification are complicated. The neutrophil-lymphocyte count ratio (NLCR) has been suggested as a useful indicator for the diagnosis of bacteraemia. We performed this meta analysis to investigate the diagnostic accuracy of the NLCR for bacteraemia. METHODS: We searched the PubMed, Embase, Web of Science, and Cochrane Library databases for this meta-analysis. We calculated individual and pooled sensitivities and specificities. I2 statistics and Cochran's Q test were used to evaluate heterogeneity, and the cause of heterogeneity was explored with sensitivity analyses. RESULTS: In total, 8 of 1086 eligible articles were included in the present meta-analysis. The pooled analyses revealed that the diagnostic accuracy of the NLCR in terms of its bacteraemia sensitivity was 0.723 [95% CI: 0.660, 0.777], and its specificity was 0.596 [95% CI: 0.556, 0.634]. The area under the summary receiver operating characteristic curve was 0.69 [95% CI 0.65-0.73]. CONCLUSION: The NLCR is an easy-to-collect marker for bacteraemia. However, the NLCR is inadequate, and only a combination of multiple biomarkers will improve its diagnostic accuracy for bacteraemia. PMID- 30413367 TI - Red cell distribution width and mean platelet volume in carbon monoxide poisoning. PMID- 30413368 TI - Left ventricular perforation with catheter decompression: Case report and review of complications. AB - Thoracostomy tube placement is one of the more common procedures performed in the Emergency Department, most commonly for treatment of pneumothorax or hemothorax but occasionally for drainage of empyema or pleural effusion. Thoracostomy may be a life-saving procedure with a wide range of complication rates reported, ranging from 19.4-37%, most commonly extrathoracic placement. Most recent meta-analyses showed a relatively stable complication rate of 19% over the past three decades with the vast majority being benign in nature. We present a case with the rare complication of thoracostomy in which of a small-caliber thoracostomy tube was placed in the left ventricle. Although thoracotomy was performed to remove the catheter, the patient remained virtually asymptomatic and had an uneventful course. PMID- 30413370 TI - Response: Risk of non-lethal abnormalities should not prevent pregnancies in women of advanced maternal age. PMID- 30413369 TI - Integrating point-of-care ultrasound in the ED evaluation of patients presenting with chest pain and shortness of breath. AB - OBJECTIVE: The differential diagnoses of patients presenting with chest pain (CP) and shortness of breath (SOB) are broad and non-specific. We aimed to 1) determine how use of point-of-care ultrasound (POCUS) impacted emergency physicians' differential diagnosis, and 2) evaluate the accuracy of POCUS when compared to chest radiograph (CXR) and composite final diagnosis. METHODS: We conducted a prospective observational study in a convenience sample of patients presenting with CP and SOB to the Emergency Department (ED). Treating physicians selected possible diagnoses from a pre-indexed list of possible diagnoses of causes of CP and SOB. The final composite diagnosis from a chart review was determined as the reference standard for the diagnosis. The primary analysis involved calculations of sensitivity and specificity for POCUS identifiable diagnoses in detecting cause of CP and SOB. Additional comparative accuracy analysis with CXRs were conducted. RESULTS: 128 patients with a mean age of 64 +/ 17 years were included in the study. Using a reference standard of composite final diagnoses, POCUS had equal or higher specificity to CXR for all indications for which it was used, except for pneumonia. POCUS correctly identified all patients with pneumothorax, pleural effusion and pericardial effusion. In patients with a normal thoracic ultrasound, CXR never provided any actionable clinical information. Adding POCUS to the initial evaluation causes a significant narrowing of the differential diagnoses in which the median differential diagnosis from 5 (IQR 3-6) to 3 (IQR 2-4) p < 0.001. CONCLUSION: In evaluation of patients with CP and SOB, POCUS is a highly feasible diagnostic test which can assist in narrowing down the differential diagnoses. In patients with a normal thoracic ultrasound, the added value of a CXR may be minimal. PMID- 30413371 TI - In Vivo Type 2 Diabetes and Wound-Healing Effects of Antioxidant Gold Nanoparticles Synthesized Using the Insulin Plant Chamaecostus cuspidatus in Albino Rats. AB - BACKGROUND: Gold nanoparticles are known for their many applications in the fields of therapeutics and diagnosis. METHODS: This article focuses mainly on the green method of synthesizing gold nanoparticles by using the leaf powder extract of the insulin plant Chamaecostus cuspidatus and on the characterization of developed plant-mediated synthesis of gold nanoparticles. Furthermore, we investigated the free-radical scavenging activity of green-synthesized gold nanoparticles. RESULTS: The free radicals were exhibited in a dose-dependent manner. The 50% inhibition of free radicals by gold nanoparticles showed that it was similar to that of the standard inhibition. Toxicity studies generally examine changes in blood serum chemistry and cell populations in tissue morphology through histologic analysis without inducing any lethal effects in the mouse model, thereby accomplishing sustained control over the progression of diabetes mellitus, which plays a leading role in vascular complications in patients. The treatment by gold nanoparticles of the mice with diabetes for a period of 21 days restored their blood glucose, glycogen and insulin levels. CONCLUSIONS: The use of gold nanoparticles as antidiabetes materials has been achieved. Further studies are required before gold nanoparticle-based drugs are more widely used. PMID- 30413372 TI - NADPH oxidase 1/4 inhibition attenuates the portal hypertensive syndrome via modulation of mesenteric angiogenesis and arterial hyporeactivity in rats. AB - AIM: NADPH oxidase (NOX)-derived reactive oxygen species (ROS) plays key roles in the development of portal hypertension (PHT) and represents a potential therapeutic method. The objective of this study was to investigate whether pharmacological inhibition of NADPH oxidase activity could ameliorate PHT in rats. METHOD: PHT model was established by partial portal vein ligation (PPVL). Rats were treated with 30 mg/kg GKT137831 (the most specific Nox1/4 inhibitor) or vehicle daily by gavage for 14 days beginning at the day of PPVL or sham operation (SO). Hemodynamics, severity of portal-systemic shunting, vascular contractility, vascular endothelial growth factor (VEGF), VEGFR-2, CD31, AKT, phospho-AKT (p-AKT, at Ser473), endothelial nitric oxide synthase (eNOS), and phospho-eNOS (p-eNOS, at Ser1177) expressions were evaluated. Nitric oxide (NO) production and oxidative stress in mesenteric arteries, and hydrogen peroxide (H2O2) in both mesenteric tissues and arteries were measured. RESULT: Inhibition of NOX1/4 with GKT137831 significantly decreased cardiac index, increased portal flow resistance, reduced portal pressure (PP), portal blood flow, mesenteric angiogenesis and portal-systemic shunting (PSS) in PPVL rats. GKT137831 reduced the production of H2O2, down regulated mesenteric angiogenesis markers (CD31, vascular endothelial growth factor (VEGF) and VEGFR-2 expression. Compared with controls), the mesenteric artery contraction to norepinephrine (NE) was impaired in PPVL rats, which was reversed by exposure to GKT137831. In addition, GKT137831 markedly decrease NADPH oxidase activity and ROS production in mesenteric arteries, and reduced NO production by decreasing the level of phosphor-AKT and eNOS. CONCLUSION: Inhibition of NOX1/4 decreased PP, ameliorated hyperdynamic circulation, mesenteric angiogenesis and arterial hyporesonse in portal hypertensive rats. Pharmacological inhibition of NOX1/4 activity may be a potential treatment for PHT-related complications. PMID- 30413373 TI - Accurate and rapid data -Driven flowcytometry functional assays for improved diagnostic / prognostic of ITP and HIT disorders. PMID- 30413374 TI - [Effectiveness and use of hormonal contraceptives (except for intrauterine devices): CNGOF Contraception Guidelines]. AB - Hormonal contraceptives remain among the most popular methods used by women. The purpose of this work is to review the effectiveness and use of these different methods. In addition, some side-effects are feared and/or frequently reported by users of hormonal contraceptives: unscheduled bleeding, acne, catamenial migraines, weight gain, libido and/or mood disorders. In this review of the literature, the accountability of hormonal contraceptives for the occurrence of some of these side-effects was discussed and a management strategy was proposed. PMID- 30413375 TI - Hand hygiene is linked to microbial keratitis and corneal inflammatory events. AB - Lack of or inadequate hand washing is a risk factor in the development of contact lens related microbial keratitis and corneal inflammatory events. In the public health domain there is compelling evidence that proper hand washing with soap can save lives. The purpose of this review is to draw attention to some of the public health literature in support of hand washing and how education can influence patients' hand hygiene behavior. Contact lens wearers are also guilty of poor hand washing behavior but there is scant evidence that education of hand washing procedures of lens wearers alters patient non-compliance. It is well known that pathogenic microbial contamination of contact lenses, lens cases, care solutions and anterior ocular components have been found with contact lens wear. However while the originating source may be hands or water, it is most likely both of these. Besides proper hand washing this paper will include mitigating strategies for avoiding microbial contamination. PMID- 30413376 TI - Comparison of meibomian gland dropout using two infrared imaging devices. AB - PURPOSE: To measure the degree of meibomian gland (MG) dropout in the lower eyelid determined by analysis of images obtained from the LipiView II (LVII) and the Keratograph 5M (K5M). METHODS: The inferior eyelid of each participant was imaged in a random order using both devices. All images were subjectively assessed by a single-masked investigator to determine the extent of MG loss using the Arita 4-point meiboscore grading scale. The images were also semi-objectively analyzed with ImageJ to calculate the percentage of MG dropout, by tracing around the non-glandular area and the total exposed area of the lower lid. RESULTS: Twenty participants (mean age 37 years, range 23-60, 60% female) completed the study. A significant difference in meiboscore (mean +/- SD) was obtained between the LVII and the K5M (1.43 +/- 0.78 vs. 1.90 +/- 0.81, Z = 3.25, p = 0.001). The meiboscore 95% limit of agreement (LOA) ranged from -1.88 to +0.93. A significant difference was found with mean ImageJ percentage dropout between the LVII and the K5M (31.5% vs 43.4%, t = -4.8, p = 0.00003). The percentage dropout 95% LOA ranged from -42.79% to +19.06%. CONCLUSIONS: LVII images had significantly lower meiboscores and less percentage MG dropout. Varying amounts of dropout were observed between the devices due the amount of eyelid that was typically everted and because of differences in image quality. These results indicate that these devices should not be used interchangeably to evaluate MG dropout. PMID- 30413377 TI - Longitudinal corneal tomographical changes in eyes of patients with unilateral and bilateral non-progressive keratoconus. AB - AIM: To evaluate the tomographic indices changes in keratoconic eyes which were classified as unilateral and bilateral non-progressive keratoconus according to the definition of Global Consensus on keratoconus and ectatic disease. METHODS: Fifty non-progressive fellow eyes of 50 keratoconus patients who underwent corneal cross-linking treatment for the other progressive eyes (group 1), 50 eyes of 50 keratoconus patients who were followed up as bilateral non-progressive keratoconus (group 2), and 50 eyes of 50 control subjects (group 3) were included in this retrospective study. Topographic, topometric, and Belin-Ambrosio Enhanced Ectasia Display-III indices were recorded at baseline and after six months. RESULTS: Groups were similar in terms of age and gender. The changes in topographic parameters and topometric indices were similar among the three groups (p > 0.05 for all values). The maximum pachymetric progression index (PPImax), maximum Ambrosio relational thickness (ARTmax), and final D significantly increased at sixth-months in group 1 (p < 0.001, p = 0.004, and p = 0.02 respectively) but did not change in groups 2 and 3 (p > 0.05 for all values). ARTmax, PPImax, and final D value changes indicated a statistically significant difference among the groups using the one-way ANOVA test (p = 0.03, p = 0.007, and p = 0.03 respectively). The Bonferroni posttest revealed that these values increased at a higher rate in group 1 than in group 2 (p = 0.03, p = 0.01, and p = 0.04 respectively) and group 3 (p = 0.04, p = 0.03, and p = 0.04, respectively). CONCLUSIONS: Fellow eyes of keratoconus patients who have underwent CXL for their progressive eyes may be more prone to progress than the patients who have no progression in both eyes. Screening unilateral non progressive patients more closely than those with bilateral non-progressive patients and evaluating the changes in final D, ARTmax, and PPImax values may be helpful in the follow up of non-progressive keratoconus. PMID- 30413378 TI - Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. AB - BACKGROUND: Lorlatinib is a potent, brain-penetrant, third-generation inhibitor of ALK and ROS1 tyrosine kinases with broad coverage of ALK mutations. In a phase 1 study, activity was seen in patients with ALK-positive non-small-cell lung cancer, most of whom had CNS metastases and progression after ALK-directed therapy. We aimed to analyse the overall and intracranial antitumour activity of lorlatinib in patients with ALK-positive, advanced non-small-cell lung cancer. METHODS: In this phase 2 study, patients with histologically or cytologically ALK positive or ROS1-positive, advanced, non-small-cell lung cancer, with or without CNS metastases, with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and adequate end-organ function were eligible. Patients were enrolled into six different expansion cohorts (EXP1-6) on the basis of ALK and ROS1 status and previous therapy, and were given lorlatinib 100 mg orally once daily continuously in 21-day cycles. The primary endpoint was overall and intracranial tumour response by independent central review, assessed in pooled subgroups of ALK-positive patients. Analyses of activity and safety were based on the safety analysis set (ie, all patients who received at least one dose of lorlatinib) as assessed by independent central review. Patients with measurable CNS metastases at baseline by independent central review were included in the intracranial activity analyses. In this report, we present lorlatinib activity data for the ALK-positive patients (EXP1-5 only), and safety data for all treated patients (EXP1-6). This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865. FINDINGS: Between Sept 15, 2015, and Oct 3, 2016, 276 patients were enrolled: 30 who were ALK positive and treatment naive (EXP1); 59 who were ALK positive and received previous crizotinib without (n=27; EXP2) or with (n=32; EXP3A) previous chemotherapy; 28 who were ALK positive and received one previous non-crizotinib ALK tyrosine kinase inhibitor, with or without chemotherapy (EXP3B); 112 who were ALK positive with two (n=66; EXP4) or three (n=46; EXP5) previous ALK tyrosine kinase inhibitors with or without chemotherapy; and 47 who were ROS1 positive with any previous treatment (EXP6). One patient in EXP4 died before receiving lorlatinib and was excluded from the safety analysis set. In treatment-naive patients (EXP1), an objective response was achieved in 27 (90.0%; 95% CI 73.5-97.9) of 30 patients. Three patients in EXP1 had measurable baseline CNS lesions per independent central review, and objective intracranial responses were observed in two (66.7%; 95% CI 9.4-99.2). In ALK-positive patients with at least one previous ALK tyrosine kinase inhibitor (EXP2-5), objective responses were achieved in 93 (47.0%; 39.9-54.2) of 198 patients and objective intracranial response in those with measurable baseline CNS lesions in 51 (63.0%; 51.5-73.4) of 81 patients. Objective response was achieved in 41 (69.5%; 95% CI 56.1-80.8) of 59 patients who had only received previous crizotinib (EXP2-3A), nine (32.1%; 15.9-52.4) of 28 patients with one previous non-crizotinib ALK tyrosine kinase inhibitor (EXP3B), and 43 (38.7%; 29.6-48.5) of 111 patients with two or more previous ALK tyrosine kinase inhibitors (EXP4-5). Objective intracranial response was achieved in 20 (87.0%; 95% CI 66.4-97.2) of 23 patients with measurable baseline CNS lesions in EXP2-3A, five (55.6%; 21.2-86.3) of nine patients in EXP3B, and 26 (53.1%; 38.3-67.5) of 49 patients in EXP4-5. The most common treatment-related adverse events across all patients were hypercholesterolaemia (224 [81%] of 275 patients overall and 43 [16%] grade 3-4) and hypertriglyceridaemia (166 [60%] overall and 43 [16%] grade 3-4). Serious treatment-related adverse events occurred in 19 (7%) of 275 patients and seven patients (3%) permanently discontinued treatment because of treatment-related adverse events. No treatment-related deaths were reported. INTERPRETATION: Consistent with its broad ALK mutational coverage and CNS penetration, lorlatinib showed substantial overall and intracranial activity both in treatment-naive patients with ALK-positive non-small-cell lung cancer, and in those who had progressed on crizotinib, second-generation ALK tyrosine kinase inhibitors, or after up to three previous ALK tyrosine kinase inhibitors. Thus, lorlatinib could represent an effective treatment option for patients with ALK-positive non-small cell lung cancer in first-line or subsequent therapy. FUNDING: Pfizer. PMID- 30413379 TI - Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open label, randomised, phase 3 trial. AB - BACKGROUND: The optimal chemotherapy backbone for dual HER2 blockade in the neoadjuvant setting for early breast cancer is unknown. We investigated whether the addition of anthracyclines would improve pathological complete response compared with a carboplatin-taxane regimen, when given in combination with the HER2-targeted agents trastuzumab and pertuzumab. METHODS: The TRAIN-2 study is an open-label, randomised, controlled, phase 3 trial being done in 37 hospitals in the Netherlands. We recruited patients aged 18 years or older with previously untreated, histologically confirmed stage II-III HER2-positive breast cancer. Patients were randomly allocated using central randomisation software (1:1 ratio) with minimisation without a random component, stratified by tumour stage, nodal stage, oestrogen receptor status, and age, to receive 5-fluorouracil (500 mg/m2), epirubicin (90 mg/m2), and cyclophosphamide (500 mg/m2) every 3 weeks for three cycles followed by paclitaxel (80 mg/m2 on days 1 and 8) and carboplatin (area under the concentration-time curve [AUC] 6 mg/mL per min on day 1 or optionally, as per hospital preference, AUC 3 mg/mL per min on days 1 and 8) every 3 weeks for six cycles, or to receive nine cycles of paclitaxel and carboplatin at the same dose and schedule as in the anthracycline group. Patients in both study groups received trastuzumab (6 mg/kg, loading dose 8 mg/kg) and pertuzumab (420 mg, loading dose 840 mg) concurrently with all chemotherapy cycles. The primary endpoint was the proportion of patients who achieved a pathological complete response in breast and axilla (ypT0/is ypN0) in the intention-to-treat population. Safety was analysed in patients who received at least one treatment cycle according to actual treatment received. This trial is registered with ClinicalTrials.gov, number NCT01996267, and follow-up for long-term outcome is ongoing. FINDINGS: Between Dec 9, 2013, and Jan 14, 2016, 438 patients were enrolled and randomly assigned to the two treatment groups (219 patients to each group), of whom 418 were evaluable for the primary endpoint (212 in the anthracycline group and 206 in the non-anthracycline group). The median follow-up for all patients was 19 months (IQR 16-23 months). A pathological complete response was recorded in 141 (67%, 95% CI 60-73) of 212 patients in the anthracycline group and in 140 (68%, 61-74) of 206 in the non-anthracycline group (p=0.95). One patient randomly allocated to the non-anthracycline group did receive anthracyclines and was thus included in the anthracycline group for safety analyses; therefore, for the safety analyses there were 220 patients in the anthracycline group and 218 in the non-anthracycline group. Serious adverse events were reported in 61 (28%) of 220 patients in the anthracycline group and in 49 (22%) of 218 in the non-anthracycline group. The most common adverse events of any cause were grade 3 or worse neutropenia (in 131 [60%] of 220 patients in the anthracycline group vs 118 [54%] of 218 in the non-anthracycline group), grade 3 or worse diarrhoea (26 [12%] vs 37 [18%]), and grade 2 or worse peripheral neuropathy (66 [30%] vs 68 [31%]), with no substantial differences between the groups. Grade 3 or worse febrile neutropenia was more common in the anthracycline group than in the non-anthracycline group (23 [10%] vs three [1%], p<0.0001). Symptomatic left ventricular systolic dysfunction was rare in both groups (two [1%] of 220 vs 0 of 218). One patient in the anthracycline group died because of a pulmonary embolism, which was possibly treatment related. INTERPRETATION: In view of the high proportion of pathological complete responses recorded in both groups and the fact that febrile neutropenia was more frequent in the anthracycline group, omitting anthracyclines from neoadjuvant treatment regimens might be a preferred approach in the presence of dual HER2 blockade in patients with early HER2-positive breast cancer. Long-term follow-up is required to confirm these results. FUNDING: Roche Netherlands. PMID- 30413380 TI - Fine-tuning chemotherapy in the era of dual HER2 targeting. PMID- 30413381 TI - Lorlatinib: a new-generation drug for ALK-positive NSCLC. PMID- 30413382 TI - Neoadjuvant chemotherapy versus upfront debulking surgery in advanced tubo ovarian cancer. PMID- 30413384 TI - Patients with large brain infarcts might also benefit from thrombectomy. PMID- 30413383 TI - Neoadjuvant chemotherapy versus debulking surgery in advanced tubo-ovarian cancers: pooled analysis of individual patient data from the EORTC 55971 and CHORUS trials. AB - BACKGROUND: Individual patient data from two randomised trials comparing neoadjuvant chemotherapy with upfront debulking surgery in advanced tubo-ovarian cancer were analysed to examine long-term outcomes for patients and to identify any preferable therapeutic approaches for subgroup populations. METHODS: We did a per-protocol pooled analysis of individual patient data from the European Organisation for Research and Treatment of Cancer (EORTC) 55971 trial (NCT00003636) and the Medical Research Council Chemotherapy Or Upfront Surgery (CHORUS) trial (ISRCTN74802813). In the EORTC trial, eligible women had biopsy proven International Federation of Gynecology and Obstetrics (FIGO) stage IIIC or IV invasive epithelial tubo-ovarian carcinoma. In the CHORUS trial, inclusion criteria were similar to those of the EORTC trial, and women with apparent FIGO stage IIIA and IIIB disease were also eligible. The main aim of the pooled analysis was to show non-inferiority in overall survival with neoadjuvant chemotherapy compared with upfront debulking surgery, using the reverse Kaplan Meier method. Tests for heterogeneity were based on Cochran's Q heterogeneity statistic. FINDINGS: Data for 1220 women were included in the pooled analysis, 670 from the EORTC trial and 550 from the CHORUS trial. 612 women were randomly allocated to receive upfront debulking surgery and 608 to receive neoadjuvant chemotherapy. Median follow-up was 7.6 years (IQR 6.0-9.6; EORTC, 9.2 years [IQR 7.3-10.4]; CHORUS, 5.9 years [IQR 4.3-7.4]). Median age was 63 years (IQR 56-71) and median size of the largest metastatic tumour at diagnosis was 8 cm (IQR 4.8 13.0). 55 (5%) women had FIGO stage II-IIIB disease, 831 (68%) had stage IIIC disease, and 230 (19%) had stage IV disease, with staging data missing for 104 (9%) women. In the entire population, no difference in median overall survival was noted between patients who underwent neoadjuvant chemotherapy and upfront debulking surgery (27.6 months [IQR 14.1-51.3] and 26.9 months [12.7-50.1], respectively; hazard ratio [HR] 0.97, 95% CI 0.86-1.09; p=0.586). Median overall survival for EORTC and CHORUS patients was significantly different at 30.2 months (IQR 15.7-53.7) and 23.6 months (10.5-46.9), respectively (HR 1.20, 95% CI 1.06 1.36; p=0.004), but was not heterogeneous (Cochran's Q, p=0.17). Women with stage IV disease had significantly better outcomes with neoadjuvant chemotherapy compared with upfront debulking surgery (median overall survival 24.3 months [IQR 14.1-47.6] and 21.2 months [10.0-36.4], respectively; HR 0.76, 95% CI 0.58-1.00; p=0.048; median progression-free survival 10.6 months [7.9-15.0] and 9.7 months [5.2-13.2], respectively; HR 0.77, 95% CI 0.59-1.00; p=0.049). INTERPRETATION: Long-term follow-up data substantiate previous results showing that neoadjuvant chemotherapy and upfront debulking surgery result in similar overall survival in advanced tubo-ovarian cancer, with better survival in women with stage IV disease with neoadjuvant chemotherapy. This pooled analysis, with long-term follow-up, shows that neoadjuvant chemotherapy is a valuable treatment option for patients with stage IIIC-IV tubo-ovarian cancer, particularly in patients with a high tumour burden at presentation or poor performance status. FUNDING: National Cancer Institute and Vlaamse Liga tegen kanker (Flemish League against Cancer). PMID- 30413386 TI - Single session pre-post randomized intervention studies: The good, bad, and ugly. PMID- 30413387 TI - Hepatocellular carcinoma in acute hepatic porphyrias: A Damocles Sword. AB - Porphyrias are inherited diseases with low penetrance affecting the heme biosynthesis pathway. Acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP) together constitute the acute hepatic porphyrias (AHP). These diseases have been identified as risk factors for primary liver cancers (PLC), mainly hepatocellular carcinoma (HCC: range 87-100%) but also cholangiocarcinoma, alone or combination with HCC. In AHP, HCC annual incidence rates range from 0.16 to 0.35% according to the populations studied. Annual incidence rates are higher in Swedish and Norwegian patients, due to a founder effect. It increases above age 50. The pathophysiology could include both direct toxic effects of heme precursors, particularly delta-aminolevulinic acid (ALA), compound heterozygosity for genes implied in heme biosynthesis pathway or the loss of oxidative stress homeostasis due to a relative lack of heme. The high HCC incidence justifies radiological surveillance in AHP patients above age 50. Efforts are made to find new biological non-invasive markers. In this respect, we describe here the first report of PIVKA-II clinical utility in the follow-up of an AIP patient that develop an HCC. In this manuscript we reviewed the epidemiology, the physiopathology, and the screening strategy of HCC in AHP. PMID- 30413388 TI - The effect of enzyme replacement therapy on clinical outcomes in female patients with Fabry disease - A systematic literature review by a European panel of experts. AB - BACKGROUND: Heterozygous females with Fabry disease have a wide range of clinical phenotypes depending on the nature of their mutation and their X-chromosome inactivation pattern; it is therefore important to examine outcomes of enzyme replacement therapy (ERT) in the female patient population specifically. This paper presents the findings of a systematic literature review of treatment outcomes with ERT in adult female patients. METHODS: A comprehensive systematic literature review was conducted through January 2017 to retrieve published papers with original data on ERT in the treatment of Fabry disease. The review included all original articles that presented ERT outcomes data on patients with Fabry disease, irrespective of the study type. RESULTS: Clinical evidence for the efficacy of ERT in female patients was available from 67 publications including six clinical trial publications, and indicates significant reductions in plasma and urine globotriaosylceramide (GL-3) accumulation (in female patients with elevated pre-treatment levels) and improvements in cardiac parameters and quality of life (QoL). To date, data are insufficient to conclude on the effects of ERT on the nervous system, gastrointestinal manifestations, and pain in female patients with Fabry disease. CONCLUSIONS: This review of available literature data demonstrates that ERT in adult female patients with Fabry disease has a beneficial effect on GL-3 levels and cardiac outcomes. The current evidence also suggests that ERT may improve QoL in this patient population, though further studies are needed to examine these results. PMID- 30413389 TI - Dissociation of globotriaosylceramide and impaired endothelial function in alpha galactosidase-A deficient EA.hy926 cells. AB - Fabry disease, a rare, X-linked lysosomal storage disease, arises from deficiency of the lysosomal hydrolase, alpha-galactosidase A (GLA) which disrupts the catabolism of globo- series glycosphingolipids (GSLs). One potential link between GLA deficiency and vascular dysfunction may be changes in endothelial nitric oxide synthase (eNOS) function. GLA-deficient EA.hy926 cells were obtained by siRNA knockdown of GLA expression and by mutation of GLA with CRISPR/Cas9 gene editing to investigate the effects of GLA deficiency on eNOS. As previously observed with siRNA knockdown of GLA, globotriaosylceramide (Gb3) accumulated in EA.hy926 cells. In contrast, Gb3 did not accumulate in CRISPR/Cas9 gene edited GLA-deficient cells, but instead, globotetraosylceramide (Gb4). However, in both the siRNA and CRISPR/Cas9 models globotriaosylsphingosine (lyso-Gb3) was elevated. As was previously observed with siRNA knockdown of GLA expression, CRISPR/Cas9 GLA-deficient cells had lower eNOS activity. Restoring GLA activity in GLA-deficient cells with exogenous GLA treatment improved eNOS activity. In contrast, treating cells with the glucosylceramide synthase inhibitor, eliglustat, decreased NOS activity. These results suggest that eNOS uncoupling is due to GLA deficiency, and not necessarily due to elevated Gb3 per se. It was observed that lyso-Gb3 inhibits eNOS activity. PMID- 30413390 TI - Early Catheter Removal After Robot-assisted Radical Prostatectomy: Results from a Prospective Single-institutional Randomized Trial (Ripreca Study). AB - BACKGROUND: The adoption of robotic technology in the treatment of prostate cancer (PCa) could lead to improvement in outcomes. OBJECTIVE: To evaluate feasibility, to compare functional outcomes, and to assess the economic benefits of removing catheter on the postoperative day (POD) 3 versus POD 5 after robot assisted radical prostatectomy (RARP). DESIGN, SETTING, AND PARTICIPANTS: From September 2016 to May 2017, patients selected to undergo RARP for clinically localized PCa at a high-volume center were prospectively randomized into group 1 (POD 3; n=72) versus group 2 (POD 5, n=74). INTERVENTION: All patients underwent RARP with anatomical posterior and anterior reconstruction. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was to compare acute urinary retention (AUR) and urinary leakage rate in the two groups. The secondary endpoints were early and mid-term postoperative functional outcomes assessed through questionnaires (ICIQ-MLUTS, IPSS), early continence rate, and postoperative pain/discomfort (visual analog scale score). The economic impact of early catheter removal was also assessed. RESULTS AND LIMITATIONS: AUR was reported in two (1.4%) cases, one for each study group (p=0.9). One case of vesicourethral leakage was reported (0.7%) in group 1. Urethral discomfort and pain at discharge was significantly higher in group 2 (p=0.03). In our clinical practice, POD 3 catheter removal approach would determine a saving of approximately ?80 000 and 405 d of hospitalization yearly. The main limitation is the small sample size. CONCLUSIONS: Early catheter removal after RARP does not lead to an increase in perioperative complications. No negative effect on early and mid-term functional outcomes was observed. A significant impact on saving economic resources was reported. PATIENT SUMMARY: We demonstrated that early catheter removal has no negative effect on spontaneous voiding, complications, or urinary continence recovery after robot-assisted radical prostatectomy. PMID- 30413391 TI - Type 1 diabetes mellitus prevalence and care in children under 15 years old in Asturias. AB - INTRODUCTION: Prevalence of type 1 diabetes mellitus (T1DM) is increasing worldwide. Care provided appears to have an influence on the course of disease. The aim of this study was to ascertain the prevalence of T1DM and to collect data on the resources and care used in Asturias. MATERIAL AND METHODS: A descriptive, cross-sectional study including patients born between 2000 and 2014 with diagnosis of T1DM at 31/12/2014. Patients were identified using two independent data sources. Information was collected from medical records. A descriptive data analysis was performed to provide frequency distributions and measures of position and dispersion. RESULTS: 146 patients were identified, with a total prevalence of 1.25/1.000 children. Prevalence rates by age group were 0.21, 1.15, and 2.40 by 1000 in children aged 0-4, 5-9, and 10-14 years respectively. Autoimmune thyroid disorders and celiac disease were found in 8.2% and 6.8% respectively, while 14.4% had a family history of T1DM and 29.4% of T2DM. Ninety two children were treated by pediatricians and 34 by endocrinologists. All children were receiving multiple dose insulin treatment and none of them used self-monitoring blood glucose systems. Health education was provided to 37.7% of children. CONCLUSIONS: This study reports the first data on T1DM prevalence in children under 15 years old in Asturias and provides care data that show the disparity in care received depending on healthcare area. PMID- 30413392 TI - Baclofen and alcohol in France. PMID- 30413393 TI - Baclofen and alcohol in France - Authors' reply. PMID- 30413395 TI - Emerging paradigms of treating diabetic nephropathy. PMID- 30413394 TI - Baclofen for the treatment of alcohol use disorder: the Cagliari Statement. PMID- 30413396 TI - Efficacy of a novel inhibitor of vascular adhesion protein-1 in reducing albuminuria in patients with diabetic kidney disease (ALBUM): a randomised, placebo-controlled, phase 2 trial. AB - BACKGROUND: Many patients with diabetic kidney disease have residual albuminuria and are at risk of disease progression. The ALBUM trial investigated the efficacy of a novel, orally active inhibitor of vascular adhesion protein-1, ASP8232, compared with placebo for reducing albuminuria in individuals with type 2 diabetes and chronic kidney disease. METHODS: In this randomised, double-blind, placebo-controlled phase 2 trial, we randomly assigned individuals (aged 18-85 years) from 64 clinical sites in nine European countries to receive ASP8232 40 mg or placebo orally once daily for 12 weeks using a web-based randomisation schedule (block size 4), stratified by country. Eligible patients had a urinary albumin-to-creatinine ratio (UACR) of 200-3000 mg/g, an estimated glomerular filtration rate of at least 25 mL/min per 1.73 m2 but lower than 75 mL/min per 1.73 m2, HbA1c less than 11.0% (97 mmol/mol), and stable treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and antidiabetic medication for 3 months or more. The primary endpoint was mean change from baseline to week 12 in log-transformed first morning void UACR, which was assessed in all patients who received at least one dose of study drug and had at least one post-baseline UACR measurement (full analysis set). Safety was assessed in all patients who received at least one dose of study drug. Participants and investigators were masked to treatment allocation. This trial is registered with ClinicalTrials.gov, number NCT02358096. FINDINGS: 125 participants were randomly assigned to receive ASP8232 (n=64) or placebo (n=61), of whom 120 (60 in each group) were included in the full analysis set; all participants were assessed for safety endpoints. At 12 weeks, UACR decreased by 17.7% (95% CI 5.0 to 28.6) in the ASP8232 group and increased by 2.3% (-11.4 to 18.1) in the placebo group; the placebo-adjusted difference between groups was 19.5% (95% CI -34.0 to -1.8; p=0.033). 39 (61%) patients in the ASP8232 group and 34 (56%) patients in the placebo group had a treatment-emergent adverse event, of which 16 in the ASP8232 group and four in the placebo group were drug-related. The most frequently reported adverse events that were possibly drug-related in the ASP8232 group were renal impairment (five patients) and decreased eGFR (three patients); in the placebo group, no single drug-related treatment-emergent adverse event was reported by more than one participant. INTERPRETATION: ASP8232 is effective in reducing albuminuria in patients with diabetic kidney disease and is safe and well tolerated. These findings warrant further research to ascertain the effect of ASP8232 on delaying progression of diabetic kidney disease. FUNDING: Astellas. PMID- 30413397 TI - Corrections. PMID- 30413398 TI - Using Mobile Phones to Examine and Enhance Perceptions of Control in Mildly Depressed and Nondepressed Volunteers: Intervention Study. AB - BACKGROUND: Perceived control is strongly linked to healthy outcomes, mental healthiness, and psychological well-being. This is particularly important when people have little control over things that are happening to them. Perceived control studies have been performed extensively in laboratory settings and show that perceived control can be increased by experimental manipulations. Although these studies suggest that it may be possible to improve people's mental health by increasing their perceived control, there is very little evidence to date to suggest that perceived control can also be influenced in the real world. OBJECTIVE: The first aim of this study was to test for evidence of a link between noncontrol situations and psychological well-being in the real world using a mobile phone app. The second and arguably more important aim of the study was to test whether a simple instructional intervention on the nature of alternative causes would enhance people's perceptions of their own control in these noncontrol situations. METHODS: We implemented a behavioral action-outcome contingency judgment task using a mobile phone app. An opportunity sample of 106 healthy volunteers scoring low (n=56, no depression) or high (n=50, mild depression) on a depression scale participated. They were given no control over the occurrence of a low- or high-frequency stimulus that was embedded in everyday phone interactions during a typical day lasting 8 hours. The intervention involved instructions that either described a consistent alternative cause against which to assess their own control, or dynamic alternative causes of the outcome. Throughout the day, participants rated their own control over the stimulus using a quantitative judgment scale. RESULTS: Participants with no evidence of depression overestimated their control, whereas those who were most depressed were more accurate in their control ratings. Instructions given to all participants about the nature of alternative causes significantly affected the pattern of perceived control ratings. Instructions describing discrete alternative causes enhanced perceived control for all participants, whereas dynamic alternative causes were linked to less perceived control. CONCLUSIONS: Perceptions of external causes are important to perceived control and can be used to enhance people's perceptions. Theoretically motivated interventions can be used to enhance perceived control using mobile phone apps. This is the first study to do so in a real-world setting. PMID- 30413399 TI - Testing a Web-Based Interactive Comic Tool to Decrease Obesity Risk Among Minority Preadolescents: Protocol for a Pilot Randomized Control Trial. AB - BACKGROUND: Childhood obesity is a public health crisis, particularly in low income, minority populations in the United States. Innovative and technology enhanced interventions may be an engaging approach to reach at-risk youth and their parents to improve dietary behaviors and feeding practices. However, such tools are limited, especially ones that are theory-based; co-developed with user centered approaches; tailored to low-income, minority preadolescents; and include parent-focused content. OBJECTIVE: The objectives of this study include assessing the feasibility and acceptability and exploring the potential impact of the Intervention INC (Interactive Nutrition Comics for urban, minority preadolescents) Web-based tool, which is focused on decreasing childhood obesity risk in black/African American and Latino children aged 9 to 12 years. METHODS: Intervention INC is underpinned by the narrative transportation theory, social cognitive theory, and health belief model, and it was co-developed by children and parents from the intended population. The child component consists of a 6 chapter interactive nutrition comic optimized for use on tablet devices, a goal setting and self-assessment feature, and weekly text/email messages and reminders. The parental component consists of 6 Web-based newsletters, access to the child comic, and weekly text/email messages and reminders. The tool was evaluated using a pilot, single-blind, 2-group randomized controlled study design. Child-parent dyads were randomized to either the experimental or comparison group and assigned to a targeted behavior (increase fruit/vegetable or water intake) based on initial screening questions. Data were collected at 4 time points: baseline (T1), intervention midpoint (T2), intervention endpoint (T3), and 3 months postintervention (T4). Primary measures comprise usage, usability, and feasibility of the Web-based tool. Secondary measures comprise dietary knowledge, preferences, and intake and anthropometric measures (for child) and feeding practices and home food environment (for parent). RESULTS: Study enrollment was completed in November 2017. A total of 89 child-parent dyads were randomized to either the experimental (n=44) or comparison (n=45) group. Data analysis is currently being conducted. CONCLUSIONS: This study aims to implement and assess an innovative approach to deliver health messages and resources to at risk minority preadolescents and their parents. If found to be acceptable, engaging, feasible, and a potential approach to improve dietary behaviors, a full fledged randomized controlled trial will be conducted to assess its efficacy and potential impact. TRIAL REGISTRATION: ClinicalTrials.gov NCT03165474; https://clinicaltrials.gov/ct2/show/NCT03165474 (Archived by WebCite at http://www.webcitation.org/73122IjgP). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/10682. PMID- 30413400 TI - The Generalizability of Randomized Controlled Trials of Self-Guided Internet Based Cognitive Behavioral Therapy for Depressive Symptoms: Systematic Review and Meta-Regression Analysis. AB - BACKGROUND: Self-guided internet-based cognitive behavioral therapies (iCBTs) for depressive symptoms may substantially increase accessibility to mental health treatment. Despite this, questions remain as to the generalizability of the research on self-guided iCBT. OBJECTIVE: We sought to describe the clinical entry criteria used in studies of self-guided iCBT, explore the criteria's effects on study outcomes, and compare the frequency of use of these criteria with their use in studies of face-to-face psychotherapy and antidepressant medications. We hypothesized that self-guided iCBT studies would use more stringent criteria that would bias the sample toward those with a less complex clinical profile, thus inflating treatment outcomes. METHODS: We updated a recently published meta analysis by conducting a systematic literature search in PubMed, MEDLINE, PsycINFO, and EMBASE. We conducted a meta-regression analysis to test the effect of the different commonly used psychiatric entry criteria on the treatment control differences. We also compared the frequency with which exclusion criteria were used in the self-guided iCBT studies versus studies of face-to-face psychotherapy and antidepressants from a recently published review. RESULTS: Our search yielded 5 additional studies, which we added to the 16 studies identified by Karyotaki and colleagues in 2017. Few self-guided iCBT studies excluded patients with severe depressive symptoms (6/21, 29%), but self-guided iCBT studies were more likely than antidepressant (14/170, 8.2%) studies to use this criterion. However, self-guided iCBT studies did not use this criterion more frequently than face-to-face psychotherapy studies (6/16, 38%). Beyond this, we found no evidence that self-guided iCBTs used more stringent entry criteria. Strong evidence suggested that they were actually less likely to use most entry criteria, especially exclusions on the basis of substance use or personality pathology. None of the entry criteria used had an effect on outcomes. CONCLUSIONS: A conservative interpretation of our findings is that the patient population sampled in the literature on self-guided iCBT is relatively comparable with that of studies of antidepressants or face-to-face psychotherapy. Alternatively, studies of unguided cognitive behavioral therapy may sample from a more heterogeneous and representative patient population. Until evidence emerges to suggest otherwise, the patient population sampled in self-guided iCBT studies cannot be considered as less complex than the patient population from face-to face psychotherapy or antidepressant studies. PMID- 30413401 TI - Optimizing Time-to-Treatment to achieve durable biochemical disease control after surgery in prostate cancer - A multi-institutional cohort study. AB - BACKGROUND: The impact of treatment delays on Prostate Cancer (PCa) specific outcomes remains ill-defined. This study investigates the effect of time to treatment on biochemical disease control after prostatectomy. METHODS: This retrospective study includes 1,807 patients who received a prostatectomy as a primary treatment at two large tertiary referral centers from 1987 - 2015. Multivariate cox model with restricted cubic spline were used to identify optimal time to receive treatment and estimate the risk of Biochemical recurrence. RESULTS: Median follow up time of the study was 46 (IQR 18 - 86) months. Time to treatment was subcategorized based on multivariate cubic spline cox model. In multivariate spline model, adjusted for all the pertinent pretreatment variables, inflection point in the risk of biochemical recurrence was observed around 3 month which further increased after 6 months. Based on spline model, time to treatment was then divided into 0-3 months (61.5%), >3-6 months (31.1%) and 6 months (7.4%). In the adjusted cox model, initial delays up to 6 months did not adversely affect the outcome, however, time to treatment >6 month had significantly higher risk of biochemical recurrence, Hazard Ratio = 1.84, 95% CI, 1.30 - 2.60, p < 0.01. CONCLUSIONS: The initial delays up to 6 months in prostate cancer primary treatment may be sustainable without adversely affecting the outcome. However, significant delays beyond 6 months can unfavorably impact biochemical disease control. IMPACT: Time to treatment can aide clinicians in the decision making of PCa treatment recommendation and educate patients against unintentional treatment delays. PMID- 30413402 TI - Audit paints "bleak picture" of diabetes care in England and Wales. PMID- 30413404 TI - ALKBH1 Promotes N 6-methyladenine DNA Modifications in Glioblastoma. AB - The DNA demethylase ALKBH1 promotes glioblastoma stem cell (GSC) growth and tumorigenesis. PMID- 30413403 TI - Correction. PMID- 30413405 TI - Two-Drug Cocktail Active against RCC. AB - The combination of avelumab and axitinib increases progression-free survival by 64% over sunitinib in patients with advanced renal cell carcinoma. The drug duo triggered responses in 51% of patients, whereas sunitinib induced responses in 26%. Side effects of grade 3 or 4 were similar in both groups of patients. PMID- 30413406 TI - MITF Synchronizes UV-Protection Programs in the Skin. AB - MITF controls the balance between the skin stress response and pigmentation in response to UV. PMID- 30413407 TI - Alpelisib Extends PFS in PIK3CA-Mutant Breast Cancer. AB - In a phase III trial, patients with PIK3CA-mutant advanced breast cancer benefited from taking the PI3Kalpha inhibitor alpelisib in addition to fulvestrant endocrine therapy. The combination extended median progression-free survival, elevated response rates, and proved tolerable compared with fulvestrant plus placebo. PMID- 30413408 TI - SPRED1 Is a Tumor Suppressor in Mucosal Melanoma. AB - Targeted sequencing identifies biallelic SPRED1 inactivation in 16 of 43 patients with mucosal melanoma. PMID- 30413409 TI - The SWI/SNF Complex Binds to and Inhibits YAP/TAZ. AB - Cellular mechanotransduction regulates the interaction between ARID1A in the SWI/SNF complex and YAP/TAZ. PMID- 30413410 TI - A Screen of C2H2 Zinc Fingers Reveals Degrons Targeted by Thalidomide. AB - A screen identified 15 C2H2 zinc finger degrons that are degraded by thalidomide analogues. PMID- 30413411 TI - Loss of the BCR-FGFR1 GEF domain suppresses RHOA activation and enhances B lymphomagenesis in mice. AB - Transformation of hematopoietic stem cells by the BCR-FGFR1 fusion kinase found in a variant of Stem Cell Leukemia/Lymphoma (SCLL) syndrome leads to development of B-lymphomas in syngeneic mice and humans. In this study, we show that the relatively rapid onset of this leukemia is potentially related to oncogenic domains within the BCR component. BCR recruited a guanidine nucleotide exchange factor (GEF) domain to the fusion kinase to facilitate activation of small GTPases such as RHOA. Deletion of this GEF domain increased leukemogenesis, enhanced cell survival and proliferation, and promoted stem cell expansion and lymph node metastasis. This suggests that, in an SCLL context, the presence of the endogenous GEF motif leads to reduced leukemogenesis. Indeed, loss of the GEF domain suppressed activation of RHOA and PTEN, leading to increased activation of AKT. Loss of the GEF domain enhanced cell proliferation and invasion potential, which was also observed in cells in which RHOA is knocked down, supported by the observation that overexpression of RHOA leads to reduced viability and invasion. In vivo, depletion of RHOA in SCLL cells significantly increased disease progression and shortened latency. Collectively, these data show that the BCR GEF domain affects phenotypes associated with progression of SCLL through suppression of RHOA signaling. PMID- 30413412 TI - Treatment-induced tumor cell apoptosis and secondary necrosis drive tumor progression in the residual tumor microenvironment through MerTK and IDO-1. AB - Efferocytosis [phagocytic apoptotic cell (AC) clearance] removes AC before they undergo secondary necrosis and leak inflammation-inducing intracellular contents. Efferocytosis concurrently increases immunosuppressive cytokines and leukocytes, limiting tissue damage, promoting tolerance to AC-derived antigens, and maintaining tissue homeostasis. Thus, tumor cell efferocytosis following cytotoxic cancer treatments could have deleterious consequences in tumor residual disease (RD). We report here that efferocytosis clears tumor AC in RD of lapatinib-treated HER2+ mammary tumors, increasing immunosuppressive cytokines, myeloid-derived suppressor cells (MDSC), regulatory T cells (TRegs), and metastasis. Although efferocytosis blockade caused secondary AC necrosis and induced interferon (IFN)-gamma, tumor MDSC, TRegs, and immunosuppressive cytokines remained prevalent due to IFNgamma-induced indoleamine-2,3-dioxegenase (IDO)-1, an immune regulator known for driving maternal-fetal antigen tolerance. Combined inhibition of efferocytosis and IDO-1 in tumor RD decreased AC-induced and NC-induced immunosuppressive phenotypes, blocked tumor metastasis, and caused tumor regression in 60% of cases. This suggests that AC and NC promote tumor 'homeostasis' and progression via efferocytosis. PMID- 30413413 TI - Increased Ripk1-mediated bone marrow necroptosis leads to myelodysplasia and bone marrow failure in mice. AB - Hematopoiesis is a dynamic system that requires balanced cell division, differentiation, and death. The two major modes of programmed cell death (PCD), apoptosis and necroptosis, share molecular machinery, but diverge in outcome with important implications for the microenvironment: apoptotic cells are removed in an immune silent process, whereas necroptotic cells leak cellular contents that incite inflammation. Given the importance of cytokine directed cues for hematopoietic cell survival and differentiation, the impact on hematopoietic homeostasis of biasing cell death fate to necroptosis is substantial and poorly understood. Here we present a mouse model with increased bone marrow necroptosis. Deletion of the pro-apoptotic Bcl-2 family members Bax and Bak inhibits bone marrow apoptosis. Further deletion of the BH3-only member Bid, to generate VavCreBaxBakBid TKO mice, leads to unrestrained bone marrow necroptosis driven by increased Rip1 kinase (Ripk1). TKO mice display loss of progenitor cells leading to increased cytokine production and increased stem cell proliferation and exhaustion, culminating in bone marrow failure (BMF). Genetically restoring Ripk1 to wild type levels restores peripheral red cell counts as well as normal cytokine production. TKO bone marrow is hyper cellular with abnormal differentiation, resembling the human disorder Myelodysplastic syndrome (MDS), and we demonstrate increased necroptosis in MDS bone marrow. Finally, we show that Bid impacts necroptotic signaling through modulation of Caspase-8-mediated Ripk1 degradation. Thus we demonstrate that dysregulated necroptosis in hematopoiesis promotes bone marrow progenitor cell death that incites inflammation, impairs hematopoietic stem cells, and recapitulates the salient features of the bone marrow failure disorder, MDS. PMID- 30413414 TI - Scottish health secretary orders independent inquiry into bullying culture at NHS Highland. PMID- 30413415 TI - Medicaid expands and drug prices are on the agenda after US midterm elections. PMID- 30413416 TI - Domain Requirements and Genetic Interactions of the Mud1 Subunit of the Saccharomyces cerevisiae U1 snRNP. AB - Mud1 is an inessential 298-amino acid protein subunit of the Saccharomyces cerevisiae U1 snRNP. Mud1 consists of N-terminal and C-terminal RRM domains (RRM1 and RRM2) separated by a linker domain. Synthetic lethal interactions of mud1Delta with deletions of inessential spliceosome components Nam8, Mud2, and Msl1, or missense mutations in the branchpoint-binding protein Msl5 enabled us to dissect genetically the domain requirements for Mud1 function. We find that the biological activities of Mud1 can be complemented by co-expressing separately the RRM1 (aa 1-127) and linker-RRM2 (aa 128-298) modules. Whereas RRM1 and RRM2 (aa 197-298) per se are inactive in all tests of functional complementation, the linker-RRM2 by itself partially complements a subset of synthetic lethal mud1Delta interactions. Linker segment aa 155 to 196 contains a nuclear localization signal rich in basic amino acids that is necessary for RRM2 activity in mud1Delta complementation. Alanine scanning mutagenesis indicates that none of the individual RRM1 amino acid contacts to U1 snRNA in the cryo-EM model of the yeast U1 snRNP is necessary for mud1Delta complementation activity. PMID- 30413418 TI - British competitiveness at risk from visa system that rejects conference delegates, warn scientists. PMID- 30413417 TI - Reporting of stepped wedge cluster randomised trials: extension of the CONSORT 2010 statement with explanation and elaboration. PMID- 30413419 TI - Obstructive sleep apnoea and increased risk of non-arteritic anterior ischaemic optic neuropathy. AB - BACKGROUND/AIMS: To determine whether the development of non-arteritic anterior ischaemic optic neuropathy (NAION) is increased among patients newly diagnosed with obstructive sleep apnoea (OSA) in a large general population. METHODS: A 12 year nationwide, population-based, retrospective cohort study including 1 025 340 beneficiaries in the 2002-2013 Korean National Health Insurance Service database was performed. We identified 919 patients newly diagnosed with OSA aged >=40 years and matched 9190 non-OSA controls using estimated propensity scores in reference to age, sex, demographics, comorbidities and co-medications. We applied Kaplan-Meier curves and Cox proportional hazard models to determine the risk of developing NAION in the OSA group compared with the non-OSA group. RESULTS: The 10-year incidence probability of NAION was higher in the OSA group (0.92%; 95% CI 0.88 to 0.97) than the non-OSA group (0.42%; 95% CI 0.41 to 0.44, p=0.002, log rank test). The OSA group was at increased risk of developing NAION compared with the non-OSA group (HR 3.80; 95% CI 1.46 to 9.90) after adjusting for demographics, comorbidities and co-medications. CONCLUSIONS: Our results suggest that patients with newly diagnosed OSA have an increased risk of NAION, although the absolute risk of NAION is low. PMID- 30413421 TI - Physical activity on prescription in accordance with the Swedish model increases physical activity: a systematic review. AB - OBJECTIVES: This study investigates the effects of the core elements of the Swedish model for physical activity on prescription (PAP) by evaluating studies that compared adults who received PAP with adults who did not receive PAP. All participants were adults identified by a healthcare professional as in need of increased physical activity. Primary outcome was level of physical activity. DESIGN: Systematic review. ELIGIBILITY CRITERIA: (1) Published 1999. (2) Systematic review, randomised controlled trial (RCT), non-RCT or case series (for adverse events). (3) >=12 weeks' follow-up. (4) Performed in the Nordic countries. (5) Presented in English, Swedish, Norwegian or Danish. DATA SOURCES: Systematic searches in PubMed, Embase, the Cochrane Library, AMED, CINAHL and SweMed+ in September 2017. Included articles were evaluated using checklists to determine risk of bias. RESULTS: Nine relevant articles were included: seven RCTs, one cohort study and one case series.Primary outcome was reported in seven articles from six studies (five RCTs, one cohort study, 642 participants). Positive results were reported from three of the five RCTs and from the cohort study. No study reported any negative results. Swedish PAP probably results in an increased level of physical activity (GRADE???Omicron). CONCLUSIONS: Although the number of the reviewed articles was relatively modest, this systematic review shows that PAP in accordance with the Swedish model probably increases the level of physical activity. As a model for exercise prescription, Swedish PAP may be considered as part of regular healthcare to increase physical activity in patients. PMID- 30413422 TI - Time-to-event analysis for sports injury research part 1: time-varying exposures. AB - BACKGROUND: 'How much change in training load is too much before injury is sustained, among different athletes?' is a key question in sports medicine and sports science. To address this question the investigator/practitioner must analyse exposure variables that change over time, such as change in training load. Very few studies have included time-varying exposures (eg, training load) and time-varying effect-measure modifiers (eg, previous injury, biomechanics, sleep/stress) when studying sports injury aetiology. AIM: To discuss advanced statistical methods suitable for the complex analysis of time-varying exposures such as changes in training load and injury-related outcomes. CONTENT: Time varying exposures and time-varying effect-measure modifiers can be used in time to-event models to investigate sport injury aetiology. We address four key questions (i) Does time-to-event modelling allow change in training load to be included as a time-varying exposure for sport injury development? (ii) Why is time-to-event analysis superior to other analytical concepts when analysing training-load related data that changes status over time? (iii) How can researchers include change in training load in a time-to-event analysis? and, (iv) Are researchers able to include other time-varying variables into time-to event analyses? We emphasise that cleaning datasets, setting up the data, performing analyses with time-varying variables and interpreting the results is time-consuming, and requires dedication. It may need you to ask for assistance from methodological peers as the analytical approaches presented this paper require specialist knowledge and well-honed statistical skills. CONCLUSION: To increase knowledge about the association between changes in training load and injury, we encourage sports injury researchers to collaborate with statisticians and/or methodological epidemiologists to carefully consider applying time-to event models to prospective sports injury data. This will ensure appropriate interpretation of time-to-event data. PMID- 30413423 TI - Public health guidelines on sedentary behaviour are important and needed: a provisional benchmark is better than no benchmark at all. PMID- 30413420 TI - Inhibitory killer cell immunoglobulin-like receptors strengthen CD8+ T cell mediated control of HIV-1, HCV, and HTLV-1. AB - Killer cell immunoglobulin-like receptors (KIRs) are expressed predominantly on natural killer cells, where they play a key role in the regulation of innate immune responses. Recent studies show that inhibitory KIRs can also affect adaptive T cell-mediated immunity. In mice and in human T cells in vitro, inhibitory KIR ligation enhanced CD8+ T cell survival. To investigate the clinical relevance of these observations, we conducted an extensive immunogenetic analysis of multiple independent cohorts of HIV-1-, hepatitis C virus (HCV)-, and human T cell leukemia virus type 1 (HTLV-1)-infected individuals in conjunction with in vitro assays of T cell survival, analysis of ex vivo KIR expression, and mathematical modeling of host-virus dynamics. Our data suggest that functional engagement of inhibitory KIRs enhances the CD8+ T cell response against HIV-1, HCV, and HTLV-1 and is a significant determinant of clinical outcome in all three viral infections. PMID- 30413424 TI - Recommendations for hamstring injury prevention in elite football: translating research into practice. PMID- 30413425 TI - Prerace medical screening and education reduce medical encounters in distance road races: SAFER VIII study in 153 208 race starters. AB - OBJECTIVES: To examine the efficacy and feasibility of an online prerace medical screening and educational intervention programme for reducing medical complications in long-distance races. METHODS: This was an 8-year observational study of medical encounter rates among 153 208 Two Oceans race starters (21.1 and 56 km) in South Africa. After the first 4-year control (CON) period, we introduced an online prerace medical screening (based on European pre-exercise screening guidelines) and an automated educational intervention programme. We compared the incidence of medical encounters (per 1000 starters; all and serious life threatening) in the CON versus the 4-year intervention (INT) period. RESULTS: In comparison to the CON period (2008-2011: 65 865 starters), the INT period (2012-2015: 87 343 starters) had a significantly lower incidence (adjusted for age group, sex, race distance) of all medical encounters by 29% (CON=8.6 (7.9 9.4); INT=6.1 (5.6-6.7), p<0.0001), in the 21.1 km race by 19% (CON=5.1 (4.4 5.9); INT=4.1 (3.6-4.8), p=0.0356) and in the 56 km race by 39% (CON=14.6 (13.1 16.3); INT=9.0 (7.9-10.1), p<0.0001). Serious life-threatening encounters were significantly reduced by 64% (CON=0.6 (0.5-0.9); INT=0.2 (0.1-0.4); p=0.0003) (adjusted for age group and sex). Registration numbers increased in the INT period (CON=81 345; INT=106 743) and overall % race starters were similar in the CON versus INT period. Wet-bulb globe temperature was similar in the CON and INT periods. CONCLUSION: All medical encounters and serious life-threatening encounters were significantly lower after the introduction of a prescreening and educational intervention programme, and the programme was feasible. PMID- 30413426 TI - Commercialised portable intravenous fluids in sports: placing vulnerable athletes at risk. PMID- 30413427 TI - Time-to-event analysis for sports injury research part 2: time-varying outcomes. AB - BACKGROUND: Time-to-event modelling is underutilised in sports injury research. Still, sports injury researchers have been encouraged to consider time-to-event analyses as a powerful alternative to other statistical methods. Therefore, it is important to shed light on statistical approaches suitable for analysing training load related key-questions within the sports injury domain. CONTENT: In the present article, we illuminate: (i) the possibilities of including time-varying outcomes in time-to-event analyses, (ii) how to deal with a situation where different types of sports injuries are included in the analyses (ie, competing risks), and (iii) how to deal with the situation where multiple subsequent injuries occur in the same athlete. CONCLUSION: Time-to-event analyses can handle time-varying outcomes, competing risk and multiple subsequent injuries. Although powerful, time-to-event has important requirements: researchers are encouraged to carefully consider prior to any data collection that five injuries per exposure state or transition is needed to avoid conducting statistical analyses on time-to event data leading to biased results. This requirement becomes particularly difficult to accommodate when a stratified analysis is required as the number of variables increases exponentially for each additional strata included. In future sports injury research, we need stratified analyses if the target of our research is to respond to the question: 'how much change in training load is too much before injury is sustained, among athletes with different characteristics?' Responding to this question using multiple time-varying exposures (and outcomes) requires millions of injuries. This should not be a barrier for future research, but collaborations across borders to collecting the amount of data needed seems to be an important step forward. PMID- 30413428 TI - Force awakens: a new hope for athletic shoulder strength testing. PMID- 30413429 TI - Subclinical coronary artery disease in veteran athletes: is a new preparticipation methodology required? AB - OBJECTIVE: Preparticipation evaluation of veteran athletes should focus on accurate cardiovascular (CV) risk stratification and subclinical detection of coronary artery disease (CAD), which is the main cause of sudden cardiac death in this population. We aimed to investigate the effectiveness of current preparticipation methodology used to identify veteran athletes with high coronary atherosclerotic burden. METHODS: A total of 105 asymptomatic male athletes aged >=40 years old, with low to moderate CV risk (Systematic Coronary Risk Estimation <5%) who trained >=4 hours/week for at least 5 years, were studied. The screening protocol included clinical evaluation, ECG, transthoracic echocardiogram and exercise testing. Cardiac CT was performed to detect CAD, defined as a high atherosclerotic burden according to coronary artery calcium score and coronary CT angiography. RESULTS: The majority of the athletes (n=88) engaged in endurance sports, with a median volume of exercise of 66 (44; 103) metabolic equivalent task score/hour/week. Exercise testing was abnormal in 13 (12.4%) athletes, 6 (5.7%) with electrocardiographic criteria for myocardial ischaemia and 7 (6.7%) with exercise-induced ventricular arrhythmias. A high coronary atherosclerotic burden was present in 27 (25.7%) athletes, of whom 11 (40.7%) had CV risk factors and 6 had abnormal exercise tests, including 3 who were positive for myocardial ischaemia. CONCLUSIONS: Conventional methodology used in preparticipation evaluation of veteran athletes, based on clinical CV risk factors and exercise testing, was poor at identifying significant subclinical CAD. The inclusion of more objective markers, particularly data derived from cardiac CT, is promising for more accurate CV risk stratification of these athletes. PMID- 30413430 TI - Reduced breast tumor growth after immunization with a tumor-restricted MUC1 glycopeptide conjugated to tetanus toxoid. AB - Preventive vaccination against tumor-associated endogenous antigens is considered to be an attractive strategy for the induction of a curative immune response concomitant with a long-lasting immunological memory. The mucin MUC1 is a promising tumor antigen, as its tumor-associated form differs from the glycoprotein form expressed on healthy cells. Due to aberrant glycosylation in tumor cells, the specific peptide epitopes in its backbone are accessible and can be bound by antibodies induced by vaccination. Breast cancer patients develop per se only low levels of T cells and antibodies recognizing tumor-associated MUC1 and clinical trials with tumor-associated MUC1 yielded unsatisfactory therapeutic effects indicating an urgent need to improve humoral immunity against this tumor entity. Herein, we demonstrate that preventive vaccination against tumor associated human MUC1 results in a specific humoral immune response, a slowdown of tumor progression and an increase in survival of breast tumor-bearing mice. For preventive vaccination, we used a synthetic vaccine containing a tumor associated glycopeptide structure of human MUC1 coupled to Tetanus Toxoid. The glycopeptide consists of a 22mer huMUC1 peptide with two immune dominant regions (PDTR and GSTA), glycosylated with the sialylated carbohydrate STN on serine-17. PyMT (polyomavirus middle T-antigen) and human MUC1-double transgenic mice expressing human tumor-associated MUC1 on breast tumor tissue served as a preclinical breast cancer model. PMID- 30413431 TI - Computational immune monitoring reveals abnormal double negative T cells present across human tumor types. AB - Advances in single-cell biology have enabled measurements of >40 protein features on millions of immune cells within clinical samples. However, the data analysis steps following cell population identification are susceptible to bias, time consuming, and challenging to compare across studies. Here, an ensemble of unsupervised tools was developed to evaluate four essential types of immune cell information, incorporate changes over time, and address diverse immune monitoring challenges. The four complementary properties characterized were: 1) systemic plasticity, 2) change in population abundance, 3) change in signature population features, and 4) novelty of cellular phenotype. Three systems immune monitoring studies were selected to challenge this ensemble approach. In serial biopsies of melanoma tumors undergoing targeted therapy, the ensemble approach revealed enrichment of double-negative (DN) T cells. Melanoma tumor resident DN T cells were abnormal and phenotypically distinct from those found in non-malignant lymphoid tissues, but similar to those found in glioblastoma and renal cell carcinoma. Overall, ensemble systems immune monitoring provided a robust, quantitative view of changes in both the system and cell subsets, allowed for transparent review by human experts, and revealed abnormal immune cells present across multiple human tumor types. PMID- 30413432 TI - Mayo alliance prognostic system for mastocytosis: clinical and hybrid clinical molecular models. AB - Systemic mastocytosis (SM) is a clinically heterogeneous disease with prognosis chiefly assigned based on World Health Organization (WHO) morphologic subclassification. We assessed the feasibility of developing contemporary risk models for SM based on clinical and integrated clinical-genetics information. Diagnosis of SM was per WHO criteria, and karyotype and next-generation sequencing data were available in a subset of the total 580 patients (median age, 55 years; range, 18-88 years) seen at the Mayo Clinic between 1968 and 2015. Morphologic subcategories were indolent/smoldering in 291 (50%) and "advanced" in 289 (50%): SM with an associated hematological neoplasm in 199, aggressive SM in 85, and mast cell leukemia in 5. Multivariable analysis of clinical variables identified age >60 years, advanced SM, thrombocytopenia <150 * 109/L, anemia below sex-adjusted normal, and increased alkaline phosphatase (ALP) as independent risk factors for survival; respective hazard ratios (HRs) 95% confidence intervals (95% CIs) were 2.5 (1.9-3.4), 2.7 (1.8-4.0), 2.5 (1.9-3.4), 2.2 (1.6-3.1), and 2.1 (1.5-3.0). In addition, ASXL1 (HR, 4.5; 95% CI, 2.6-7.6), RUNX1 (HR, 4.3; 95% CI, 1.3-10.8), and NRAS (HR, 5.0, 95% CI, 1.5-13.2) mutations were independently associated with inferior survival. Combined clinical, cytogenetic, and molecular risk factor analysis confirmed the independent prognostic contribution of adverse mutations (2.6, 1.6-4.4), advanced SM (4.0, 1.8-10.0), thrombocytopenia (2.8, 1.7-4.5), increased ALP (2.1, 1.2-4.0), and age >60 years (2.2, 1.3-3.6). These data were subsequently used to develop clinical and hybrid clinical-molecular risk models. The current study advances 2 complementary risk models for SM and highlights the independent prognostic contribution of mutations. PMID- 30413385 TI - Penumbral imaging and functional outcome in patients with anterior circulation ischaemic stroke treated with endovascular thrombectomy versus medical therapy: a meta-analysis of individual patient-level data. AB - BACKGROUND: CT perfusion (CTP) and diffusion or perfusion MRI might assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of irreversibly injured ischaemic core and potentially salvageable penumbra volumes were associated with functional outcome and whether they interacted with the treatment effect of endovascular thrombectomy on functional outcome. METHODS: In this systematic review and meta-analysis, the HERMES collaboration pooled patient-level data from all randomised controlled trials that compared endovascular thrombectomy (predominantly using stent retrievers) with standard medical therapy in patients with anterior circulation ischaemic stroke, published in PubMed from Jan 1, 2010, to May 31, 2017. The primary endpoint was functional outcome, assessed by the modified Rankin Scale (mRS) at 90 days after stroke. Ischaemic core was estimated, before treatment with either endovascular thrombectomy or standard medical therapy, by CTP as relative cerebral blood flow less than 30% of normal brain blood flow or by MRI as an apparent diffusion coefficient less than 620 MUm2/s. Critically hypoperfused tissue was estimated as the volume of tissue with a CTP time to maximum longer than 6 s. Mismatch volume (ie, the estimated penumbral volume) was calculated as critically hypoperfused tissue volume minus ischaemic core volume. The association of ischaemic core and penumbral volumes with 90-day mRS score was analysed with multivariable logistic regression (functional independence, defined as mRS score 0-2) and ordinal logistic regression (functional improvement by at least one mRS category) in all patients and in a subset of those with more than 50% endovascular reperfusion, adjusted for baseline prognostic variables. The meta-analysis was prospectively designed by the HERMES executive committee, but not registered. FINDINGS: We identified seven studies with 1764 patients, all of which were included in the meta-analysis. CTP was available and assessable for 591 (34%) patients and diffusion MRI for 309 (18%) patients. Functional independence was worse in patients who had CTP versus those who had diffusion MRI, after adjustment for ischaemic core volume (odds ratio [OR] 0.47 [95% CI 0.30-0.72], p=0.0007), so the imaging modalities were not pooled. Increasing ischaemic core volume was associated with reduced likelihood of functional independence (CTP OR 0.77 [0.69-0.86] per 10 mL, pinteraction=0.29; diffusion MRI OR 0.87 [0.81-0.94] per 10 mL, pinteraction=0.94). Mismatch volume, examined only in the CTP group because of the small numbers of patients who had perfusion MRI, was not associated with either functional independence or functional improvement. In patients with CTP with more than 50% endovascular reperfusion (n=186), age, ischaemic core volume, and imaging-to-reperfusion time were independently associated with functional improvement. Risk of bias between studies was generally low. INTERPRETATION: Estimated ischaemic core volume was independently associated with functional independence and functional improvement but did not modify the treatment benefit of endovascular thrombectomy over standard medical therapy for improved functional outcome. Combining ischaemic core volume with age and expected imaging-to-reperfusion time will improve assessment of prognosis and might inform endovascular thrombectomy treatment decisions. FUNDING: Medtronic. PMID- 30413433 TI - The endogenous antimicrobial cathelicidin LL37 induces platelet activation and augments thrombus formation. AB - Platelet-associated complications including thrombosis, thrombocytopenia, and hemorrhage are commonly observed during various inflammatory diseases such as sepsis, inflammatory bowel disease, and psoriasis. Despite the reported evidence on numerous mechanisms/molecules that may contribute to the dysfunction of platelets, the primary mechanisms that underpin platelet-associated complications during inflammatory diseases are not fully established. Here, we report the discovery of formyl peptide receptor 2, FPR2/ALX, in platelets and its primary role in the development of platelet-associated complications via ligation with its ligand, LL37. LL37 acts as a powerful endogenous antimicrobial peptide, but it also regulates innate immune responses. We demonstrate the impact of LL37 in the modulation of platelet reactivity, hemostasis, and thrombosis. LL37 activates a range of platelet functions, enhances thrombus formation, and shortens the tail bleeding time in mice. By utilizing a pharmacological inhibitor and Fpr2/3 (an ortholog of human FPR2/ALX)-deficient mice, the functional dependence of LL37 on FPR2/ALX was determined. Because the level of LL37 is increased in numerous inflammatory diseases, these results point toward a critical role for LL37 and FPR2/ALX in the development of platelet-related complications in such diseases. Hence, a better understanding of the clinical relevance of LL37 and FPR2/ALX in diverse pathophysiological settings will pave the way for the development of improved therapeutic strategies for a range of thromboinflammatory diseases. PMID- 30413437 TI - Isolated renal mucormycosis in a patient with Idiopathic CD4 lymphocytopenia. AB - Idiopathic CD4 lymphocytopenia (ICL) is characterised by a low CD4 +lymphocyte count in the absence of HIV or other underlying aetiologies. We report a case of a 17-year-old girl with ICL with autoimmune hepatitis who developed isolated renal mucormycosis, which, to our knowledge, is the first reported case described in literature. Combination therapy with antifungals and surgical resection was done, and the patient improved. This case report illustrates the importance of timely multidisciplinary approach to recognise this highly fatal disease at an early stage. PMID- 30413438 TI - Rare case of a newborn baby with left-sided Erb's palsy and a contralateral/right sided paralysis of the diaphragm. AB - Brachial plexus birth injury (BPBI) and phrenic nerve injury can sometimes occur concurrently in neonates following difficult deliveries like breech presentation, shoulder dystocia, forceps or vacuum extraction. Phrenic nerve palsy should be suspected in a newborn with respiratory distress and an elevated hemidiaphragm on the imaging studies in presence of the associated risk factors. The right side is affected more often than the left side and most of it is associated with BPBI. We present here a rare case of a newborn baby with a left-sided Erb's palsy and a contralateral/right-sided diaphragmatic paralysis who recovered from the persistent respiratory distress and feeding difficulties following plication of the diaphragm. The left-sided Erb's palsy also fully recovered at follow-up examination. PMID- 30413436 TI - Leptomeningeal carcinomatosis as primary presentation of metastatic urothelial cancer. AB - Leptomeningeal spread of carcinoma, referred to here as leptomeningeal carcinomatosis, is an uncommon complication of many cancer types. Its manifestations as the presenting symptoms of a new cancer diagnosis is even less common. This case describes the manifestations of leptomeningeal spread of urothelial carcinoma with review of pathophysiology driving the presenting symptoms of hypertension and headache. In the Discussion section, we address the standard and novel interventions for management of increased intracranial pressure. PMID- 30413434 TI - Antibody-mediated immune suppression by antigen modulation is antigen-specific. AB - Alloantibodies developing after exposure to red blood cell (RBC) alloantigens can complicate pregnancy and transfusion therapy. The only method currently available to actively inhibit RBC alloantibody formation is administration of antigen specific antibodies, a phenomenon termed antibody-mediated immune suppression (AMIS). A well-known example of AMIS is RhD immune globulin prophylaxis to prevent anti-D formation in RhD- individuals. However, whether AMIS is specific or impacts alloimmunization to other antigens on the same RBC remains unclear. To evaluate the specificity of AMIS, we passively immunized antigen-negative recipients with anti-KEL or anti-hen egg lysozyme (HEL) antibodies, followed by transfusion of murine RBC expressing both the HEL-ovalbumin-Duffy (HOD) and human KEL antigens (HOD * KEL RBC). Significant immunoglobulin G deposition on transfused HOD * KEL RBC occurred in all passively immunized recipients. Complement deposition and antigen modulation of the KEL antigen occurred on transfused RBC only in anti-KEL-treated recipients, whereas HEL antigen levels decreased only in the presence of anti-HEL antibodies. Western blot analysis confirmed the specificity of antigen loss, which was not attributable to RBC endocytosis and appears distinct for the 2 antigens. Specifically, removal of KEL was attenuated by clodronate treatment, whereas loss of HEL was unaffected by clodronate in vivo but sensitive to protease treatment in vitro. Antigen-specific modulation correlated with antigen-specific AMIS, with anti-KEL treated recipients forming antibodies to the HOD antigen and anti-HEL-treated recipients developing antibodies to the KEL antigen. Together, these results demonstrate that passively administered antibodies can selectively inhibit the immune response to a specific antigen. PMID- 30413439 TI - Severe haemophilia A in a neonate presenting as haemopneumothorax after tracheo oesophageal fistula-oesophageal atresia repair. AB - A male infant with oesophageal atresia and distal tracheo-oesophageal fistula (TEF type C) underwent right thoracotomy and transpleural repair of TEF on day 4 of life. He did not have a family history of coagulation disorders. A preoperative finding of prolonged partial thromboplastin time (PTT)>200 s was overlooked, and he went to surgery. There were no concerns with haemostasis prior to and even during the operation. The prolonged PTT was treated with one 10 mL/kg dose of fresh frozen plasma in the immediate postoperative period. On the fourth postoperative day, the infant developed a right haemopneumothorax, requiring fresh frozen plasma and packed cell transfusions. He was subsequently diagnosed with severe haemophilia A due to intron 22 inversion in the factor VIII gene, with factor VIII level <0.01 IU/mL. PMID- 30413435 TI - High-resolution mapping of the polyclonal immune response to the human platelet alloantigen HPA-1a (PlA1). AB - Antibodies to platelet-specific antigens are responsible for 2 clinically important bleeding disorders: posttransfusion purpura and fetal/neonatal alloimmune thrombocytopenia (FNAIT). The human platelet-specific alloantigen 1a/1b (HPA-1a/1b; also known as PlA1/A2) alloantigen system of human platelet membrane glycoprotein (GP) IIIa is controlled by a Leu33Pro polymorphism and is responsible for ~80% of the cases of FNAIT. Local residues surrounding polymorphic residue 33 are suspected to have a profound effect on alloantibody binding and subsequent downstream effector events. To define the molecular requirements for HPA-1a alloantibody binding, we generated transgenic mice that expressed murine GPIIIa (muGPIIIa) isoforms harboring select humanized residues within the plexin-semaphorin-integrin (PSI) and epidermal growth factor 1 (EGF1) domains and examined their ability to support the binding of a series of monoclonal and polyclonal HPA-1a-specific antibodies. Humanizing the PSI domain of muGPIIIa was sufficient to recreate the HPA-1a epitope recognized by some HPA 1a-specific antibodies; however, humanizing distinct amino acids within the linearly distant but conformationally close EGF1 domain was required to enable binding of others. These results reveal the previously unsuspected complex heterogeneity of the polyclonal alloimmune response to this clinically important human platelet alloantigen system. High-resolution mapping of this alloimmune response may improve diagnosis of FNAIT and should facilitate the rational design and selection of contemplated prophylactic and therapeutic anti-HPA-1a reagents. PMID- 30413440 TI - Rapid detection of Listeria monocytogenes rhombencephalitis in an immunocompetent patient by multiplexed PCR. AB - A 46-year-old previously healthy man presented with 1 week of headache, nausea, vomiting and dizziness. He was found to have cranial nerve deficits, his cerebrospinal fluid (CSF) demonstrated a lymphocytic pleocytosis and brain MRI suggested rhombencephalitis. Although Gram stains and cultures of his CSF did not identify a pathogen, Listeria monocytogenes DNA was detected by the FilmArray Meningitis/Encephalitis panel within 2 hours of performing a lumbar puncture. He was treated with ampicillin and gentamicin and had a near-complete recovery. This case highlights the importance of recognising L. monocytogenes infection as a cause of acute cranial nerve impairment with MRI findings suggestive of brainstem encephalitis. It also highlights the frequently atypical CSF profile and low yield of culture in L. monocytogenes rhombencephalitis and the value of multiplex PCR testing of CSF to rapidly identify this pathogen and permit targeted therapy. PMID- 30413441 TI - Splenic granulomas: a rare manifestation of Mycobacterium avium complex in an immunocompetent host. AB - Infections caused by Mycobacteriumavium complex (MAC) are commonly seen in immunocompromised individuals. Though disseminated MAC infections with splenic granulomas are seen in some patients, MAC infection clinically manifesting as only splenic granulomas is rare. This presentation is even less common in immunocompetent individuals. We report a case of a young adult who presented with fever of unknown origin and was found to have multiple splenic granulomas. Fine needle aspiration cytology and PCR for Mycobacterium tuberculosis of the granulomas revealed a diagnosis of MAC infection. The patient was not found to have any immunodeficiency on investigations. This case is perhaps the first case of MAC clinically presenting as splenic granulomas in an immunocompetent individual. PMID- 30413442 TI - Large anterior urethral calculus masquerading as periurethral abscess. AB - Urethral calculus causes variety of symptoms from simple dysuria to acute urinary retention. The diagnosis is many times not easy. A plain X-ray of the pelvis may aid in diagnosis. Due to variety of symptomatic presentations sometimes it is not the first diagnosis that comes to one's mind. Management is by removal of the calculus via various methods ranging from endoscopic to open surgery. We present the case of an adult male, who was initially thought to have periurethral abscess due to stricture urethra but during investigations was found to have urethral calculus as the cause for his symptoms. PMID- 30413443 TI - Challenging cause of bullous eruption of the hands in the Arctic. AB - Phytophotodermatitis is caused by deposition of photosensitising compounds on the skin followed by ultraviolet exposure. We present an unusual case of a 29-year old Australian male visiting Greenland who presented with severe itchy bullous eruption on his hands. The cause was a combination of exposure to lime fruit juice and prolonged sun exposure from the Arctic midnight sun. PMID- 30413444 TI - Pelvic pain in young girls: not only dysmenorrhoea! AB - Imperforate hymen is the most frequent cause of haematocolpos, although it is a rare malformation (1:2000). We present two cases of young girls with cyclic abdominal pain and urinary symptoms. At gynaecological examination, they all presented imperforate hymen and ultrasound revealed significant vaginal distension. X-shaped hymenectomy was performed in all patients. The later the diagnosis of imperforate hymen, the higher the risk of complications like haematometra, haematosalpinx, haemoperitoneum and infections such as tubo-ovarian abscesses, peritonitis and endometriosis (retrograde menstruation theory). PMID- 30413445 TI - Large mediastinal mass in a 15-year-old boy. AB - Hyperimmunoglobulin E syndrome is a rare multisystem inherited disorder characterised by high serum IgE levels, skin disorder causing eczema, dermatitis, recurrent staphylococcal infections and pulmonary infections and various skeletal and connective tissue abnormalities. Common presentation is with recurrent skin and sinopulmonary infections. Several features unrelated to immune system such as characteristic facial features, hyperextensibility of joints, multiple bone fractures and craniosynostosis have been described in the literature. We describe a rare presentation of this disease with invasive aspergillosis presenting as mediastinal mass with extension to mediastinal structures and pulmonary vasculature. PMID- 30413446 TI - Bronchoalveolar carcinoma as an unsuspected cause for worsening shortness of breath in a patient with metastatic breast cancer. AB - A 70-year-old woman with lung metastases from a breast cancer presented with worsening cough and dyspnoea. She recently had a pleurodesis for a malignant pleural effusion. Chest CT scans demonstrated various radiological changes leading to diagnostic challenges. Differential diagnoses included empyema, pleural disease progression, pulmonary oedema, pneumonitis, lymphangitis and atypical infections. She deteriorated despite a multimodality treatment strategy. Postmortem examination confirmed that lung changes were consistent with a bronchoalveolar carcinoma unrelated to the known metastatic breast cancer. The eventual knowledge of this diagnosis was reassuring to the treating medical team and a comfort to the relatives who witnessed the lack of response to standard treatment. PMID- 30413447 TI - Successful treatment of central nervous system myeloma manifesting as cauda equina nodules with intrathecal chemotherapy, lenalidomide and dexamethasone. AB - We report a case of central nervous system myeloma manifesting as cauda equina nodules, successfully treated with triple intrathecal (IT) chemotherapy, lenalidomide and dexamethasone. After presenting with multiple plasmacytomas which led to a diagnosis of non-secretory myeloma at age 56, the patient underwent multiple episodes of treatment for relapsing myeloma over a 7-year period. In March 2017, he presented with declining gait over a month with bilateral hip flexion weakness, absent lower limb reflexes and dorsal column loss. MRI of the spine revealed multiple enhancing cauda equina nodules at L1-L3. Cerebrospinal fluid (CSF) examination confirmed a clonal plasma cell population and disease was not found elsewhere. He was treated with radiotherapy, IT and intravenous methotrexate and cytarabine. However, repeat lumbar puncture revealed persistent disease. Clearance of CSF plasma cells was achieved with two times a week IT cytarabine, methotrexate and dexamethasone. He was started on lenalidomide and dexamethasone with no evidence of disease progression at 12 months. PMID- 30413448 TI - Use of Integra dermal substitute to prevent implantable device extrusion in an Olympic athlete. AB - We present a challenging case of imminent metallic implant extrusion in a Paralympic athlete managed with a single-stage procedure using 'Integra' dermal substitute. The patient had hereditary spastic paraparesis, for which a baclofen pump delivering intrathecal medication was vital in the management of his condition. The device had been most recently implanted into the thigh after previous complications. Integra provided robust soft-tissue coverage over the implanted baclofen pump in the thigh. Different operative management strategies were considered but the use of Integra was felt to offer the least morbidity and a quick recovery. The patient was able to successfully compete in a Paralympic canoeing qualifying event the week following surgery and achieve medal success. To the authors' knowledge, this is first case in which Integra has been used in such circumstances. PMID- 30413449 TI - Renal autotransplantation for the management of renal artery in-stent restenosis in an adult patient with Takayasu arteritis. AB - Renovascular hypertension is a common clinical presentation in Takayasu arteritis (TA), when the renal arteries are involved. Although most of the patients respond to optimal antihypertensive drug therapy, certain patients with TA require percutaneous or surgical renal artery revascularisation to manage renovascular hypertension. We, hereby, present a 45-year-old woman, who had resistant hypertension secondary to in-stent restenosis (ISR) of renal artery stent in a single functioning kidney. She had successful renal autotransplantation following a failed endovascular attempt to treat ISR. Endovascular and surgical interventions related to renal artery stenosis in TA are discussed in the article. PMID- 30413450 TI - Lymphangioleiomyomatosis (LAM) presenting as recurrent pneumothorax in an infant with tuberous sclerosis: treated successfully with sirolimus. AB - Lymphangioleiomyomatosis (LAM) either sporadic or a part of tuberous sclerosis complex is rare in paediatric age group. Here, we report a case of LAM with tuberous sclerosis in an infant. She was referred to our institute at the age of 4 months as a case of recurrent bilateral pneumothorax requiring intercostal tube drainage. Detailed history revealed that patient was symptomatic since 1 month of age in the form of seizures. She had respiratory symptoms for last 15 days. General physical examination revealed whitish macular patches. Brain imaging was suggestive of cortical tubers and subependymal nodules. The echocardiography showed right atrial rhabdomyoma. Chest CT revealed multiple cysts suggesting LAM. On the basis of above findings, a diagnosis of tuberous sclerosis complex with LAM was made. The infant was started on sirolimus and there was significant clinical and radiological improvement over a period of 2 and half years without any side effects. PMID- 30413451 TI - In trauma, expect the unexpected: a rare case of post-traumatic pancreatitis associated with salmonellosis and enterocolitis. AB - A 16-year-old Hispanic man was transferred to our level I paediatric trauma centre with pancreatitis. Ten days prior, he had sustained a gunshot wound to the abdomen requiring an exploratory laparotomy for repair of a traumatic left diaphragmatic injury. Additional injuries included gastric, renal, liver and pancreatic lacerations as well as a T12 burst fracture that resulted in paraplegia. Conservative management of pancreatitis was unsuccessful over the next 10 days, resulting in progressive symptoms of severe unresolved pain, nausea, emesis and rising lipase. Workup for post-traumatic, biliary and drug associated causes of pancreatitis was negative, and no anatomical abnormalities were found on imaging. A fever workup on hospital day 10 revealed a urinary tract infection with non-typhoid Salmonella sp, and subsequent stool and imaging studies revealed salmonellosis associated with right-sided colitis and Clostridium difficile infection. Pancreatitis resolved within 48 hours following treatment of salmonellosis and Clostridium. PMID- 30413452 TI - Primary hydatid cyst of the urinary bladder. AB - A 35-year-old man presented with poorly localised lower abdominal pain for 3 months. Abdominal examination revealed lower abdominal tenderness, with normal other parts of examination. CT scan of the abdomen showed irregular multiloculated mass related to the upper part of the urinary bladder with mild rim enhancement in the postcontrast study with no areas of calcifications. During laparotomy, we found a mass attached to the superior part of the urinary bladder and arising from its wall. Complete excision was done without opening the cavity of the bladder. The mass was opened and was a hydatid cyst of the bladder containing multiple daughter cysts. PMID- 30413453 TI - Dulaglutide-induced cerebral venous thrombosis in a patient with type 2 diabetes mellitus. AB - Though patients with diabetes mellitus are at a high risk of atherothrombotic events, every such event should not be attributed to the disease itself. We present a case of a patient with diabetes with headache and blurring of vision for 3 days. Brain imaging revealed right transverse sinus thrombosis and acute infarct of the right posterior parieto-occipital region, predominantly in the posterior cortical watershed zone. The patient was on subcutaneous dulaglutide for 3 weeks and was having nausea and vomiting. Various causes of cerebral venous thrombosis were ruled out with appropriate laboratory investigations. Finally, cerebral venous thrombosis was attributed to dulaglutide-induced nausea and vomiting which led to severe dehydration. PMID- 30413454 TI - De Winter pattern: a forgotten pattern of acute LAD artery occlusion. PMID- 30413455 TI - Case of Donath-Landsteiner haemolytic anaemia in an adult female. AB - Donath-Landsteiner haemolytic anaemia (DLHA), also known as paroxysmal cold haemoglobinuria, is a very rare and difficult condition to diagnose as well as treat. Here, we present a case of a 55-year-old Hispanic woman who presented with severe intravascular haemolytic anaemia in the setting of a viral illness 2 weeks prior to presentation. Direct antiglobulin testing revealed mixed results: positive for either complement, IgG or both on various occasions which led to a battery of tests including the Donath-Landsteiner antibody testing which turned out positive establishing the diagnosis of DLHA. She was initially treated unsuccessfully with supportive care in the form of packed red blood cell transfusions and steroids as well as rituximab for about 4 weeks but her condition improved on cyclophosphamide, and she is on the road to recovery after 10 weeks of hospital stay. PMID- 30413457 TI - Polyglandular endocrine emergency: lessons from a patient, which a book cannot teach. AB - A 30-year-old woman with polyglandular autoimmune type 2 syndrome was found collapsed at home with a cardiac arrest, which required direct current cardioversion. On admission, she was hypothermic, hypotensive and bradycardic. Initial biochemical investigations were consistent with a pre-renal acute kidney injury, metabolic acidosis and a possible sepsis. She had significantly elevated thyroid-stimulating hormone levels on admission with the clinical profile consistent with dual Addisonian and myxoedema crisis. She received intravenous liothyronine and hydrocortisone along with supportive therapy. Echo showed severe left ventricular impairment with apical ballooning although coronary angiogram disclosed nothing abnormal. She made a gradual recovery and was discharged home after 2 weeks. She was diagnosed to have primary autoimmune hypothyroidism, Addison's diseaseand type 1 diabetes and coeliac disease in October 2006, July 2007, May 2010 and September 2016, respectively. Her inability to stick to gluten free diet at her workplace was considered a significant contributory factor for out-of-hospital cardiac arrest. PMID- 30413456 TI - Successful treatment of total placenta previa by multidisciplinary therapy in a Jehovah's Witness patient who refused blood transfusions. AB - A 35-year-old Jehovah's Witness patient with total placenta previa was referred to our hospital at 30 weeks of gestation. She refused autologous and allogeneic blood transfusions, but agreed to receive acute normovolaemic haemodilution, intraoperative blood salvage and biological products. At 35 weeks, she underwent emergent caesarean delivery because of labour pains. Multidisciplinary therapy, including the insertion of balloon catheters into the bilateral common iliac arteries, acute normovolaemic haemodilution and intraoperative blood salvage, avoided hysterectomy; however, blood loss included amniotic fluid which was estimated to be 1910 mL. These treatments may be effective for total placenta previa in blood-refusal patients. PMID- 30413458 TI - Unexpected presentation of Helicobacter pylori in a male child. PMID- 30413459 TI - Adult intussusception secondary to diverticular disease. AB - Intussusception is the invagination of a proximal segment of bowel into the lumen of an adjacent distal segment. It is a common condition in the paediatric age group although it rarely occurs in adults. Organic lesions in the bowel wall are the primary cause of adult intussusceptions with malignant neoplasms being the most common. However, we present a rare case of a 92-year-old man diagnosed with an intussusception of the sigmoid-rectal colon secondary to a diverticular stricture. PMID- 30413460 TI - Double trouble: exudative hypertensive retinopathy in a patient with retinitis pigmentosa. AB - A young female suffering from chronic kidney disease presented with retinal features suggestive of retinitis pigmentosa (RP). Cystoid intraretinal changes were noted at the macula in both eyes on optical coherence tomography. Careful clinical examination and fluorescein angiography revealed disc oedema, macular hard exudates and flower petal leakage in both eyes. A clinical diagnosis of RP with leaking cystoid macular oedema (CMO) because of hypertensive retinopathy was made. Exudation and macular oedema subsided with hypertension control and posterior sub-Tenon steroid injection. Although CMO does not typically leak on fluorescein angiography in RP, this need not always be true. Clinical signs and fluorescein angiography help in the differentiation of macular oedema when more than one aetiology may be responsible. PMID- 30413461 TI - Heterotopic ossification following anterior shoulder dislocation. AB - Heterotopic ossification (HO) is the abnormal growth of extraskeletal bone. Joint involvement may result in chronic stiffness and pain causing considerable functional impairment and the inability to perform the activities of daily living. HO affecting the shoulder joint is rare and little is known about its clinical course or treatment. Here, we describe the first reported case of glenohumeral HO following anterior dislocation. This occurred in a 70-year-old man following a fall onto outstretched hand. Due to persistent stiffness and pain at 8 months from initial injury, he underwent plain radiographs and MRI scans that confirmed rotator cuff tear and HO. He was managed conservatively with physiotherapy and non-steroidal anti-inflammatory drugs. At 1-year follow-up, the patient maintains a good functional outcome. PMID- 30413462 TI - Synchronous endometrioid carcinoma of the endometrium and small cell neuroendocrine carcinoma of the cervix: a rare combination. AB - Synchronous multiple primaries of female genital tract are uncommon, with the most frequently encountered combination being of endometrium and ovary. Concurrent primary tumours of endometrium and cervix are rare. We report a case of coexistent endometrioid carcinoma of the endometrium and small cell neuroendocrine carcinoma of the cervix in 48-year-old woman who presented with menometrorrhagia and was detected to have metastases to distant sites on imaging. She underwent multimodality treatment which resulted in a significant reduction in the tumour bulk. PMID- 30413463 TI - Hydralazine-associated antineutrophil cytoplasmic antibody vasculitis with pulmonary-renal syndrome. AB - Hydralazine, a vasodilator, is commonly used as an adjunctive treatment for moderate to severe hypertension, heart failure and hypertensive emergencies in pregnancy. Hydralazine-induced lupus was first described in 1953. Clinical presentation ranges from arthralgia, myalgia, petechiae, or rash to single or multiorgan involvement. An occurrence of systemic vasculitis is a rare complication. When presented as the pulmonary-renal syndrome, it could have a rapidly progressive course which can be fatal. Here, we describe a case of hydralazine-associated rapidly progressive glomerulonephritis and pulmonary haemorrhage. We use this case to review the current literature and discuss and highlight the importance of a high degree of clinical acumen, early diagnosis and prompt treatment for better clinical outcomes. PMID- 30413464 TI - Primary varicella zoster infection with tongue lesions. PMID- 30413465 TI - Thoracic splenosis: correct imaging diagnosis prevents invasive procedures like biopsy and thoracoscopy. PMID- 30413466 TI - Phantom tumour and heart failure. PMID- 30413467 TI - Right coronary artery pseudoaneurysm post everolimus eluting stent implantation causing tamponade. PMID- 30413468 TI - Paget-Schroetter syndrome. PMID- 30413469 TI - Phytophotodermatitis: still a poorly recognised diagnosis. PMID- 30413470 TI - DIG-seq: a genome-wide CRISPR off-target profiling method using chromatin DNA. AB - To investigate whether and how CRISPR-Cas9 on-target and off-target activities are affected by chromatin in eukaryotic cells, we first identified a series of identical endogenous DNA sequences present in both open and closed chromatin regions and then measured mutation frequencies at these sites in human cells using Cas9 complexed with matched or mismatched sgRNAs. Unlike matched sgRNAs, mismatched sgRNAs were highly sensitive to chromatin states, suggesting that off target but not on-target DNA cleavage is hindered by chromatin. We next performed Digenome-seq using cell-free chromatin DNA (now termed DIG-seq) and histone-free genomic DNA in parallel and found that only a subset of sites, cleaved in histone free DNA, were cut in chromatin DNA, suggesting that chromatin can inhibit Cas9 off-target effects in favor of its genome-wide specificity in cells. PMID- 30413471 TI - Potentially Mobile Denitrification Functional Genes Identified in Azospirillum sp. Strain TSH58. AB - Denitrification ability is sporadically distributed among diverse bacteria, archaea, and fungi. In addition, disagreement has been found between denitrification functional gene phylogenies and the 16S rRNA gene phylogeny. These facts have suggested the potential occurrences of horizontal gene transfer (HGT) for the denitrification functional genes. However, evidence of HGT has not been clearly presented thus far. In this study, we identified the sequences and the localization of the nitrite reductase genes in the genomes of 41 Azospirillum sp. denitrifying strains, and searched for mobile genetic elements that contain denitrification functional genes. All Azospirillum sp. strains examined in this study possessed multiple replicons (4 to 11 replicons) with their size ranging from 7 to 1,031 kbp. Among those, the nitrite reductase gene nirK was located on large replicons (549-941 kbp). Genome sequencing showed that Azospirillum strains that had similar nirK sequences also shared similar nir-nor gene arrangement, especially between TSH58, Sp7T and Sp245 strains. In addition to the high similarity between nir-nor gene clusters among the three Azospirillum strains, a composite transposon structure was identified in the genome of strain TSH58, which contains the nir-nor gene cluster and the novel IS6 family insertion sequences (ISAz581 and ISAz582). The nirK within the composite transposon system was actively transcribed under denitrification-inducing conditions. Although not experimentally verified in this study, the composite transposon system containing nir-nor gene cluster could be transferred to other cells if it is moved to a prophage region and the phage becomes activated and released outside of the cells. Taken together, strain TSH58 most likely acquired its denitrification ability by HGT from closely related Azospirillum sp. denitrifiers.IMPORTANCE Evolutionary history of denitrification is complex. While occurrence of horizontal gene transfer has been suggested for denitrification functional genes, most studies report circumstantial evidences such as disagreement between denitrification functional gene phylogenies and the 16S rRNA gene phylogeny. Based on the comparative genome analyses of Azospirillum sp. denitrifiers, we identified denitrification functional genes including nirK and norCBQD located on a mobile genetic element in the genome of Azospirillum sp. strain TSH58. The nirK was actively transcribed under denitrification-inducing conditions. Since this gene was the sole nitrite reductase gene in strain TSH58, this strain most likely received benefit by acquiring denitrification functional genes via horizontal gene transfer. This finding will significantly advance our scientific knowledge in the ecology and evolution of denitrification. PMID- 30413472 TI - Introduction of the glyoxylate bypass increases hydrogen gas yield from acetate and l-glutamate in Rhodobacter sphaeroides. AB - Rhodobacter sphaeroides produces hydrogen gas (H2) from organic compounds via nitrogenase under anaerobic-light conditions in the presence of poor nitrogen sources such as l-glutamate. R. sphaeroides utilizes the ethylmalonyl-CoA (EMC) pathway for acetate assimilation but its H2 yield from acetate in the presence of l-glutamate has been reported to be low. In this study, deletion of ccr encoding crotonyl-CoA carboxylase/reductase, a key enzyme for the EMC pathway in R. sphaeroides, revealed that the EMC pathway is essential for H2 production from acetate and l-glutamate but not for the growth and acetate consumption in the presence of l-glutamate. We introduced a plasmid expressing aceBA from Rhodobacter capsulatus encoding two key enzymes for the glyoxylate bypass into R. sphaeroides, which resulted in a 64% increase in H2 production. However, compared with the wild-type strain expressing heterologous aceBA genes, the strain with aceBA introduced in the genetic background of an EMC pathway-disrupted mutant showed a lower H2 yield. These results indicate that a combination of the endogenous EMC pathway and a heterologously expressed glyoxylate bypass is beneficial for H2 production. In addition, introduction of the glyoxylate bypass into a polyhydroxybutyrate (PHB) biosynthesis-disrupted mutant resulted in a delay in the growth along with H2 production, although its H2 yield was comparable to that of the wild-type strain expressing heterologous aceBA genes. These results suggest that PHB production is important for fitness to the culture during H2 production from acetate and l-glutamate when both acetate-assimilating pathways are present.IMPORTANCE As an alternative to fossil fuel, H2 is a promising renewable energy source. Although photo-fermentative H2 production from acetate is key to developing an efficient process of bio-hydrogen production from biomass-derived sugars, H2 yields from acetate and l-glutamate by R. sphaeroides have been reported to be low. In this study, we observed that in addition to the endogenous EMC pathway, heterologous expression of the glyoxylate bypass in R. sphaeroides markedly increased H2 yields from acetate and l-glutamate. Therefore, this study provides a novel strategy for improving H2 yields from acetate in the presence of l-glutamate and contributes to a clear understanding of acetate metabolism in R. sphaeroides during photo-fermentative H2 production. PMID- 30413473 TI - Bioprospecting reveals class III omega-transaminases converting bulky ketones and environmentally relevant polyamines. AB - Amination of bulky ketones, particularly in (R)-configuration, is an attractive chemical conversion, however known omega-transaminases (omega-TAs) show insufficient performances. By applying two screening methods we discovered 10 amine transaminases from the class III omega-TAs family, 38% to 76% identical to homologues. We present examples of such enzymes preferring bulky ketones over keto acids and aldehydes with stringent (S)-selectivity. We also report representatives from the class III omega-TAs capable of converting (R) and (S) amines and bulky ketones, and one converting amines with longer alkyl substituents. The preference for bulky ketones was associated with the presence of a hairpin region proximal to the conserved Arg414 and residues conforming and close to it. The outward orientation of Arg414 additionally favored the conversion of (R)-amines. This configuration was also found to favor the utilization of putrescine as amine donor, so that class III omega-TAs with Arg414 in outward orientation may participate in vivo in the catabolism of putrescine. The positioning of the conserved Ser231 contributes also to the preference of amines with longer alkyl substituents. Optimal temperatures for activity ranged from 45 to 65 degrees C, and a few enzymes retained >= 50% of their activity in water-soluble solvents (up to 50% (v/v)). Hence, our results will pave the way to design, in the future, new class III omega-TAs converting bulky ketones and (R) amines for production of high value products, and screen those converting putrescine.IMPORTANCE Amine transaminases of the class III omega-TAs are key enzymes for modification of chemical building blocks, but finding those capable of converting bulky ketones and (R)-amines is still challenging. Here, by an extensive analysis of the substrate spectra of 10 class III omega-TAs, we identified a number of residues playing a role in determining the access and positioning of bulky ketones, bulky amines, and (R)- and (S)-amines as well as of environmentally relevant polyamines, particularly, putrescine. The results presented can significantly expand future opportunities for designing (R) specific class III omega-TAs to convert valuable bulky ketones and amines as well as deepening the knowledge into the polyamine catabolic pathways. PMID- 30413474 TI - The FlbA-regulated gene rpnR is involved in stress resistance and impacts protein secretion when Aspergillus niger is grown on xylose. AB - Proteins are secreted throughout the mycelium of Aspergillus niger except for the sporulating zone. A link between sporulation and repression of protein secretion was underlined by the finding that inactivation of the sporulation gene flbA results in mycelial colonies that secrete proteins throughout the colony. However, DeltaflbA hyphae also lyse and have thinner cell walls. This pleiotropic phenotype is associated with differential expression of 36 predicted transcription factor genes, of which rpnR was inactivated in this study. Sporulation, biomass, and secretome complexity were not affected in the deletion strain DeltarpnR of the fungus. In contrast, ribosomal subunit expression and protein secretion into the medium were reduced when A. niger was grown on xylose. Moreover, DeltarpnR showed decreased resistance to H2O2 and the proteotoxic stress-inducing agent dithiothreitol. Taken together, RpnR is involved in proteotoxic stress resistance and impacts protein secretion when A. niger is grown on xylose.IMPORTANCE Aspergillus niger secretes a high amount and diversity of industrially relevant enzymes into the culture medium. This makes this fungus a widely used industrial cell factory. For instance, carbohydrate-active enzymes of A. niger are used in biofuel production from lignocellulosic feedstock. These enzymes represent a major cost factor in this process. Higher production yields could substantially reduce these costs and therefore contribute to a more sustainable economy and less dependence on fossil fuels. Enzyme secretion is inhibited in A. niger by asexual reproduction. The sporulation protein FlbA is involved in this process by impacting expression of 36 predicted transcription factor genes. Here we show that one of these predicted transcriptional regulators, RpnR, regulates protein secretion and proteotoxic stress resistance. This gene is thus an interesting target to improve enzyme production in A. niger. PMID- 30413475 TI - Manganese oxide biomineralization provides protection against nitrite toxicity in a cell density dependent manner. AB - Manganese bio-mineralization is a widespread process among bacteria and fungi. To date there is no conclusive experimental evidence for, how and if this process impacts microbial fitness in the environment. Here we show how a model organism for manganese oxidation is growth-inhibited by nitrite, and that this inhibition is mitigated in presence of manganese. We show that such manganese-mediated mitigation of nitrite-inhibition is dependent on the culture inoculum size and that manganese oxide (MnOX) forms granular precipitates in the culture, rather than sheaths around individual cells. We provide evidence that MnOX protection involves both its ability to catalyze nitrite oxidation into (non-toxic) nitrate under physiological conditions, and its potential role in influencing processes involving reactive oxygen species (ROS). Taken together, these results demonstrate improved microbial fitness through MnOX deposition in an ecological setting, i.e. mitigation of nitrite toxicity, and point to a key role of MnOX in handling stresses arising from ROS.ImportanceWe present here a direct fitness benefit (i.e. growth-advantage) for manganese oxide bio-mineralization activity in Roseobacter sp AzwK-3b, a model organism used to study this process. We find that AzwK-3b in a laboratory culture experiment is growth-inhibited by nitrite in manganese free cultures, while the inhibition is considerably relieved by manganese supplementation and MnOX formation. We show that biogenic MnOX interacts directly with nitrite and possibly with reactive oxygen species, and find that its beneficial effects are established through formation of dispersed MnOx granules in a manner dependent on the population size. These experiments raise the possibility that manganese bio-mineralisation could confer protection against nitrite-toxicity to a population of cells. They open up new avenues of interrogating this process in other species, and provide possible routes to their biotechnological applications, including in metal recovery, biomaterials production, and in synthetic community engineering. PMID- 30413476 TI - Characterization of a novel endo-type xanthanase MiXen from xanthan-degrading Microbacterium sp. XT11. AB - Under general aqueous conditions, xanthan appears in an ordered conformation, which makes its backbone largely resistant to degradation by known cellulases. Therefore, the xanthan degradation mechanism is still unclear because of the lack of an efficient hydrolase. Herein, we report the catalytic properties of MiXen, a xanthan-degrading enzyme identified from the genus Microbacterium MiXen is a 952 amino-acid protein that is unique to strain XT11. Both the sequence and structural features suggested that MiXen probably belongs to a new branch of GH9 family and has a multi-modular structure, in which a catalytic (alpha/alpha)6 barrel is flanked by an N-terminal Ig-like domain and by a C-terminal domain that has very few homologues in sequence databases and functions as a carbohydrate binding module (CBM). Based on circular dichroism, shear-dependent viscosity, reducing sugar and gel permeation chromatography analysis, we demonstrated that recombinant MiXen could efficiently and randomly cleave glucosidic bonds within the highly ordered xanthan substrate. MiXen mutant free of the C-terminal CBM domain partially lost its xanthan-hydrolyzing ability because of decreased affinity towards xanthan, indicating the CBM domain assisted MiXen in hydrolyzing highly ordered xanthan via recognizing and binding to the substrate. Furthermore, side chain substituents and terminal mannosyl residue significantly influenced the activity of MiXen via the formation of more or less barriers to enzymolysis, respectively. Overall, the results of this study provide insight into the hydrolysis mechanism and enzymatic properties of a novel endo-type xanthanase that will benefit future applications.IMPORTANCEThis work characterized a novel endo-type xanthanase MiXen and elucidated that C-terminal carbohydrate-binding module of MiXen could drastically enhance the hydrolysis activity of the enzyme towards highly ordered xanthan. Both the sequence and structural analysis demonstrated that the catalytic domain and carbohydrate-binding module of MiXen belong to the novel branch of the GH9 family and CBMs, respectively. This xanthan 'cleaver' can help further reveal the enzymolysis mechanism of xanthan and provide an efficient tool for the production of molecular modified xanthan with new physicochemical and physiological functions. PMID- 30413477 TI - Transcriptome and comparative genomics analyses reveal new functional insights on key determinants of pathogenesis and interbacterial competition in Pectobacterium and Dickeya spp. AB - Soft-rot Enterobacteriaceae (SRE) typified by Pectobacterium and Dickeya genera are phytopathogenic bacteria inflicting soft-rot disease in crops worldwide. By combining genomic information from 100 SRE with whole-transcriptome datasets, we identified novel genomic and transcriptional associations amongst key pathogenicity themes in this group. Comparative genomics revealed solid linkage between the type I secretion system (T1SS) and the carotovoricin bacteriophage (Ctv) conserved in 96.7% of Pectobacterium genomes. Moreover, their co-activation during infection might indicate a novel functional association involving T1SS/Ctv. Another bacteriophage-borne genomic region mostly confined in less than 10% of Pectobacterium organisms was found, presumably comprising a novel lineage specific prophage in the genus. We also detected the transcriptional co regulation of a previously predicted toxin/immunity pair (WHH and SMI1_KNR4 families) along with type VI secretion system (T6SS) and hcp/vgrG genes suggesting a role in disease development as T6SS-dependent effectors. Further, we showed that another predicted T6SS-dependent endonuclease (AHH-family) exhibited toxicity in ectopic expression assays indicating antibacterial activity. Additionally, we report the striking conservation of group-4-capsule (GFC) cluster in 100 SRE strains which consistently features adjacently conserved serotype-specific gene-arrays comprising a previously unknown organization in GFC clusters. Also, extensive sequence variations found in gfcA orthologs suggest a serotype-specific role in the GfcABCD machinery.IMPORTANCE Despite the considerable loss inflicted on important crops yearly by Pectobacterium and Dickeya diseases, investigations on key virulence and interbacterial competition assets relying on extensive comparative genomics are still surprisingly lacking for these genera. Such approaches become more powerful overtime underpinned by the growing amount of genomic information in public databases. Particularly, our findings point to new functional associations amongst well known genomic themes enabling alternative means of neutralizing SRE diseases through disruption of pivotal virulence programs. By elucidating novel transcriptional and genomic associations, this study adds valuable information on virulence candidates that could be decisive in molecular applications in the near future. The utilization of 100 genomes of Pectobacterium and Dickeya strains in this study presents unprecedented scale for comparative analyses in these taxa, and provide novel insights on the biology of economically important plant pathogens. PMID- 30413478 TI - Rootstocks shape the rhizobiome: Rhizosphere and endosphere bacterial communities in the grafted tomato system. AB - Root-associated microbes are critical to plant health and performance, although understanding of the factors that structure these microbial communities and theory to predict microbial assemblages are still limited. Here we use a grafted tomato system to study the effects of rootstock genotypes and grafting in endosphere and rhizosphere microbiomes that were evaluated by sequencing 16S rRNA. We compared the microbiomes of nongrafted tomato cultivar BHN589, selfgrafted BHN589, and BHN589 grafted to Maxifort or RST-04-106 hybrid rootstocks. OTU-based bacterial diversity was greater in Maxifort compared to nongraft controls, whereas bacterial diversity in the controls (selfgraft and nongraft) and the other rootstock (RST-04-106) was similar. Grafting itself did not affect bacterial diversity; diversity in the selfgraft was similar to the nongraft. Bacterial diversity was higher in the rhizosphere than in the endosphere for all treatments. However, despite the lower overall diversity, there was a greater number of differentially abundant OTUs (DAOTUs) in the endosphere, with the greatest number of DAOTUs associated with Maxifort. In a PERMANOVA analysis, there was evidence for an effect of rootstock genotype on bacterial communities. The endosphere-rhizosphere compartment and study site explained a high percentage of the differences among bacterial communities. Further analyses identified OTUs responsive to rootstock genotypes in both the endosphere and the rhizosphere. Our findings highlight the effects of rootstocks on bacterial diversity and composition. The influence of rootstock and plant compartment on microbial communities indicates opportunities for the development of designer communities and microbiome-based breeding to improve future crop production.IMPORTANCE Understanding factors that control microbial communities is essential for designing and supporting microbiome-based agriculture. In this study, we used a grafted tomato system to study the effect of rootstock genotypes and grafting on bacterial communities colonizing the endosphere and the rhizosphere. Comparing the bacterial communities in control treatments (nongraft and selfgraft plants) with the hybrid rootstocks used by farmers, we evaluated the effect of rootstocks on overall bacterial diversity and composition. These findings indicate the potential for using plant genotype to indirectly select bacterial taxa. In addition, we identify taxa responsive to each rootstock treatments, which may represent candidate taxa useful for biocontrol and in biofertilizers. PMID- 30413479 TI - Focussed metabolism of beta-glucans by the soil Bacteroidetes Chitinophaga pinensis. AB - The genome and natural habitat of Chitinophaga pinensis suggest the ability to degrade a wide variety of carbohydrate-based biomass. Complementing our earlier investigations into the hydrolysis of some plant polysaccharides, we now show that C. pinensis can grow directly on spruce wood and fungal fruiting body. Growth was stronger on fungal material, although secreted enzyme activity was high in both cases, and all biomass-induced secretomes showed a predominance of beta-glucanase activities. We therefore conducted a screen of growth on and hydrolysis of beta-glucans isolated from different sources. Most non-crystalline beta-glucans supported good growth, with variable efficiency of polysaccharide deconstruction and oligosaccharide uptake, depending on the polysaccharide backbone linkage. In all cases, beta-glucan was the only type of polysaccharide that could be effectively hydrolysed by secreted enzymes. This contrasts with the secretion of a broad range of enzyme activities we observed during growth on complex heteroglycans. Our findings imply a role for C. pinensis in the turnover of multiple types of biomass, and suggest that the species may have two metabolic modes: a 'scavenging mode' where multiple different types of glycan may be degraded, and a more 'focussed mode' of beta-glucan metabolism. The significant accumulation of some types of beta-gluco-oligosaccharide in growth medium may be due to the lack of an appropriate transport mechanism, and we propose that this is due to the specificity of expressed Polysaccharide Utilisation Loci. We present a hypothetical model for beta-glucan metabolism by C. pinensis that suggests the potential for nutrient sharing among the microbial litter community.IMPORTANCE It is well known that the forest litter layer is inhabited by a complex microbial community of bacteria and fungi. However, while the importance of fungi in the turnover of natural biomass is well established, the role of their bacterial counterparts is less extensively studied. We show that Chitinophaga pinensis, a prominent member of an important bacterial genus, is capable of using both plant and fungal biomass as a nutrient source, but that it is particularly effective at deconstructing dead fungal material. The turnover of dead fungus is key in natural elemental cycles in the forest. We show that C. pinensis can perform extensive degradation of this material to support its own growth while also releasing sugars that may serve as nutrients for other microbial species. Our work adds detail to an increasingly complex picture of life among the environmental microbiota. PMID- 30413480 TI - Assessing transmission of antimicrobial resistant Escherichia coli in wild giraffe contact networks. AB - There is growing evidence that anthropogenic sources of antibiotics and antimicrobial resistant bacteria can spillover into natural ecosystems, raising questions about the role wild animals play in the emergence, maintenance, and dispersal of antibiotic resistance genes. In particular, we lack an understanding of how resistance genes circulate within wild animal populations, including whether specific host characteristics such as social associations promote inter host transmission of these genes. Here, we use social network analysis to explore the forces shaping population-level patterns of resistant Escherichia coli in wild giraffe (Giraffa camelopardalis) and assess the relative importance of social contact for the dissemination of resistant E. coli between giraffe. Of 195 giraffe sampled, only 5.1% harbored E. coli isolates resistant to one or more tested antibiotics. Whole-genome sequencing on a subset of resistant isolates revealed a number of acquired resistance genes with linkages to mobile genetic elements. However, we found no evidence that the spread of resistance genes among giraffe was facilitated by inter-host associations. Giraffe with lower social degree were more likely to harbor resistant E. coli, but this relationship was likely driven by a correlation between an individual's social connectedness and age. Indeed, resistant E. coli were most frequently detected in socially isolated neonates, indicating resistant E. coli may have a selective advantage in the neonatal gastrointestinal tract compared to other age classes. Taken together, these results suggest the maintenance of antimicrobial resistant bacteria in wild populations may, in part, be determined by host traits and microbial competition dynamics within the host.Importance Antimicrobial resistance represents a significant threat to human health, food security, and the global economy. To fully understand the evolution and dissemination of resistance genes, a complete picture of antimicrobial resistance in all biological compartments, including natural ecosystems, is required. The environment and wild animals may act as reservoirs for anthropogenically-derived resistance genes that could be transferrable to clinically relevant bacteria of humans and domestic animals. Our study investigates the possible transmission mechanisms for antimicrobial resistant bacteria within a wild animal population and, more broadly, contributes to our understanding of how resistance genes are spread and maintained in natural ecosystems. PMID- 30413481 TI - An Ovol2-Zeb1 transcriptional circuit regulates epithelial directional migration and proliferation. AB - Directional migration is inherently important for epithelial tissue regeneration and repair, but how it is precisely controlled and coordinated with cell proliferation is unclear. Here, we report that Ovol2, a transcriptional repressor that inhibits epithelial-to-mesenchymal transition (EMT), plays a crucial role in adult skin epithelial regeneration and repair. Ovol2-deficient mice show compromised wound healing characterized by aberrant epidermal cell migration and proliferation, as well as delayed anagen progression characterized by defects in hair follicle matrix cell proliferation and subsequent differentiation. Epidermal keratinocytes and bulge hair follicle stem cells (Bu-HFSCs) lacking Ovol2 fail to expand in culture and display molecular alterations consistent with enhanced EMT and reduced proliferation. Live imaging of wound explants and Bu-HFSCs reveals increased migration speed but reduced directionality, and post-mitotic cell cycle arrest. Remarkably, simultaneous deletion of Zeb1 encoding an EMT-promoting factor restores directional migration to Ovol2-deficient Bu-HFSCs. Taken together, our findings highlight the important function of an Ovol2-Zeb1 EMT regulatory circuit in controlling the directional migration of epithelial stem and progenitor cells to facilitate adult skin epithelial regeneration and repair. PMID- 30413482 TI - ChIP-Atlas: a data-mining suite powered by full integration of public ChIP-seq data. AB - We have fully integrated public chromatin chromatin immunoprecipitation sequencing (ChIP-seq) and DNase-seq data (n > 70,000) derived from six representative model organisms (human, mouse, rat, fruit fly, nematode, and budding yeast), and have devised a data-mining platform-designated ChIP-Atlas (http://chip-atlas.org). ChIP-Atlas is able to show alignment and peak-call results for all public ChIP-seq and DNase-seq data archived in the NCBI Sequence Read Archive (SRA), which encompasses data derived from GEO, ArrayExpress, DDBJ, ENCODE, Roadmap Epigenomics, and the scientific literature. All peak-call data are integrated to visualize multiple histone modifications and binding sites of transcriptional regulators (TRs) at given genomic loci. The integrated data can be further analyzed to show TR-gene and TR-TR interactions, as well as to examine enrichment of protein binding for given multiple genomic coordinates or gene names. ChIP-Atlas is superior to other platforms in terms of data number and functionality for data mining across thousands of ChIP-seq experiments, and it provides insight into gene regulatory networks and epigenetic mechanisms. PMID- 30413483 TI - beta-Catenin-RAS interaction serves as a molecular switch for RAS degradation via GSK3beta. AB - RAS proteins play critical roles in various cellular processes, including growth and transformation. RAS proteins are subjected to protein stability regulation via the Wnt/beta-catenin pathway, and glycogen synthase kinase 3 beta (GSK3beta) is a key player for the phosphorylation-dependent RAS degradation through proteasomes. GSK3beta-mediated RAS degradation does not occur in cells that express a nondegradable mutant (MT) beta-catenin. Here, we show that beta-catenin directly interacts with RAS at the alpha-interface region that contains the GSK3beta phosphorylation sites, threonine 144 and threonine 148 residues. Exposure of these sites by prior beta-catenin degradation is required for RAS degradation. The introduction of a peptide that blocks the beta-catenin-RAS interaction by binding to beta-catenin rescues the GSK3beta-mediated RAS degradation in colorectal cancer (CRC) cells that express MT beta-catenin. The coregulation of beta-catenin and RAS stabilities by the modulation of their interaction provides a mechanism for Wnt/beta-catenin and RAS-ERK pathway cross talk and the synergistic transformation of CRC by both APC and KRAS mutations. PMID- 30413484 TI - Outcomes following general anaesthesia in children with hypertrophic cardiomyopathy. AB - BACKGROUND: Children with hypertrophic cardiomyopathy (HCM) have historically been considered to be high-risk candidates for general anaesthesia (GA), but there is currently a paucity of evidence regarding the safety of anaesthesia and perioperative outcomes in this population. METHODS: Clinical features and outcomes of all paediatric patients (<18 years) with HCM undergoing GA between 2000 and 2016 were reviewed. RESULTS: 86 patients (median 12.4 years (IQR 6.5, 14.9)) underwent 164 separate GA procedures. Aetiology included non-syndromic disease (n=44, 56%), malformation syndromes (n=22, 26%), inborn error of metabolism (n=10, 12%) and neuromuscular disease (n=4, 5%). At the time of GA, mean maximal wall thickness (MWT) on echocardiography was 19 mm (SD+/-8 mm), 23 (14%) patients had severe left ventricular hypertrophy (MWT>30 mm) and 35 (21%) patients had a haemodynamically significant left ventricular outflow tract (LVOT) gradient (>50 mm Hg). The majority (n=143, 87%) had no perioperative complications. 20 (12%) patients had minor perioperative complications: bradycardia (n=4), hypotension (n=15) or transient ST segment changes (n=1). One (0.6% of GA procedures) patient experienced a cardiac arrest during anaesthetic induction with death occurring 3 days later. Clinical parameters (including age, MWT, LVOT gradient, systolic and diastolic dysfunction) were not associated with an increased risk of complications CONCLUSIONS: This is the largest published series to date of paediatric patients with HCM undergoing GA, which demonstrates that, in an expert centre, patients can be anaesthetised with a relatively low perianaesthetic mortality (0.6%) and prevalence of minor complications (12%). Future studies are required to systematically identify clinical features that may predict anaesthetic risk. PMID- 30413485 TI - Coronary artery aneurysms are more severe in infants than in older children with Kawasaki disease. AB - OBJECTIVE: We aimed to compare the severity of coronary artery abnormalities in Kawasaki disease between infants and older children. METHODS: We retrospectively reviewed and compared coronary artery dilation and aneurysm severity in infants <1 year of age with Kawasaki disease at our centre over a 10-year period with that observed in children >=1 year of age in the Pediatric Heart Network Trial of Pulse Steroid Therapy in Kawasaki Disease. Coronary artery abnormalities were defined by z-scores according to American Heart Association guidelines. RESULTS: Of the 93 infants identified during the study period, 80 were treated with intravenous gamma globulin within the first 10 days of illness and were included for comparison to 170 children >=1 year of age treated in the same time frame from the Pediatric Heart Network public database. The mean maximum z-score was significantly higher in infants compared with older children (3.37 vs 2.07, p<0.001). A higher incidence of medium and giant aneurysms was observed in infants compared with children >=1 year of age (11% vs 3% for medium aneurysms, p=0.015; 8% vs <1% for giant aneurysms, p=0.005). CONCLUSIONS: Infants with Kawasaki disease have more severe coronary artery dilation compared with older children, and a higher prevalence of medium and giant aneurysms. Because adverse outcomes are closely linked to the maximal coronary artery diameter in Kawasaki disease, patients diagnosed as infants require very close long-term monitoring for cardiac complications. PMID- 30413486 TI - Seasonality in clinical courses of Kawasaki disease. AB - OBJECTIVE: Epidemics of Kawasaki disease (KD) are well known; however, the seasonal variation in the clinical course of KD is uncertain. The aim of this study was to investigate the seasonality in the clinical course of KD. METHODS: This study included 744 patients who were admitted to six hospitals in Kitakyushu City for KD from 2010 to 2014. We divided the patients into two groups according to the average monthly temperature (warm and cold periods) and compared the clinical courses of KD. RESULTS: The clinical courses of 715 patients who were initially treated with intravenous immunoglobulin (IVIG) were investigated. The proportion of patients with resistance to the initial IVIG therapy was significantly higher during the warm period than during the cold period (p=0.016). There was no seasonality in the proportion of patients with coronary artery abnormalities. CONCLUSION: Seasonality was observed in the response to IVIG therapy of patients with KD. PMID- 30413487 TI - Which vasoactive drug should be first choice in paediatric septic shock? PMID- 30413488 TI - Early warning scores in paediatrics: an overview. AB - Paediatric Early Warning Scores (PEWS)are used in hospitalised patients to detect physiological deterioration and is being used increasingly throughout healthcare systems with a limited evidence based. There are two versions in general use that can lead to a clinical response, either by triggering an action or by reaching a 'threshold' when graduated responses may occur depending on the value of the score. Most evidence has come from research based on paediatric inpatients in specialist children's hospitals, although the range of research is expanding, taking into account other clinical areas such as paediatric intensive care unit, emergency department and the prehospital setting. Currrently, it is uncertain whether a unified system does deliver benefits in terms of outcomes or financial savings, but it may inform and improve patient communication. PEWS may be an additional tool in context of a patient's specific condition, and future work will include its validation for different conditions, different clinical settings, patient populations and organisational structure. The incorporation of PEWS within the electronic health records may form a keystone of the safe system framework and allow the development of consistent PEWS system to standardise practice. PMID- 30413489 TI - Economic consequences of preterm birth: a systematic review of the recent literature (2009-2017). AB - BACKGROUND: Despite extensive knowledge on the functional, neurodevelopmental, behavioural and educational sequelae of preterm birth, relatively little is known about its economic consequences. OBJECTIVE: To systematically review evidence around the economic consequences of preterm birth for the health services, for other sectors of the economy, for families and carers, and more broadly for society. METHODS: Updating previous reviews, systematic searches of Medline, EconLit, Web of Science, the Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Embase and Scopus were performed using broad search terms, covering the literature from 1 January 2009 to 28 June 2017. Studies reporting economic consequences, published in the English language and conducted in a developed country were included. Economic consequences are presented in a descriptive manner according to study time horizon, cost category and differential denominators (live births or survivors). RESULTS: Of 4384 unique articles retrieved, 43 articles met the inclusion criteria. Of these, 27 reported resource use or cost estimates associated with the initial period of hospitalisation, while 26 reported resource use or costs incurred following the initial hospital discharge, 10 of which also reported resource use or costs associated with the initial period of hospitalisation. Only two studies reported resource use or costs incurred throughout the childhood years. Initial hospitalisation costs varied between $576 972 (range $111 152-$576 972) per infant born at 24 weeks' gestation and $930 (range $930-$7114) per infant born at term (US$, 2015 prices). The review also revealed a consistent inverse association between gestational age at birth and economic costs regardless of date of publication, country of publication, underpinning study design, follow-up period, age of assessment or costing approach, and a paucity of evidence on non healthcare costs. Several categories of economic costs, such as additional costs borne by families as a result of modifications to their everyday activities, are largely overlooked by this body of literature. Moreover, the number and coverage of economic assessments have not increased in comparison with previous review periods. CONCLUSION: Evidence identified by this review can be used to inform clinical and budgetary service planning and act as data inputs into future economic evaluations of preventive or treatment interventions. Future research should focus particularly on valuing the economic consequences of preterm birth in adulthood. PMID- 30413490 TI - Utility of lung ultrasound scanning in neonatology. AB - The utility of point-of-care lung ultrasound in neonatology is rapidly expanding. This review summarises current evidence of a diagnostic, procedural and observational tool valuable in the management of newborns requiring intensive care. Approaching a patient, probe in-hand with focused clinical question is essential, and barriers to implication together with important research questions are explored. PMID- 30413491 TI - Does pulsatility index add value to newborn pulse oximetry screening for critical congenital heart disease? PMID- 30413492 TI - Cerebral palsy: not always what it seems. AB - Cerebral palsy (CP) is not a disease, but a neurological syndrome, a combination of signs and symptoms, some of which may occur in neurodegenerative or metabolic disorders, particularly those with an onset in the first 2 years of life. There are many different causes of the syndrome. All children with CP should undergo brain MRI, even with an identified antenatal or perinatal insult. Children with CP should be referred to a paediatric neurologist or a clinical geneticist, or both, if appropriate and particularly in the absence of a known perinatal cerebral insult, with brain MRI that is reported to be normal, a progression in, or new, signs or where there is a reported 'family history of CP'. Finally, a few of the CP syndromes may be readily treatable and potentially prevent irreversible neurological and cognitive impairment. PMID- 30413493 TI - Drug preparation and administration errors during simulated paediatric resuscitations. AB - INTRODUCTION: Very few studies have assessed drug preparation and administration errors during paediatric resuscitation. Current evidence suggests that medication errors in paediatrics are a serious problem. The aim of this study was to evaluate drug preparation and administration errors incurred during the simulated resuscitation of paediatric patients. METHODS: This was a prospective observational study performed in the emergency department of a tertiary-level hospital. Teams consisting of two emergency doctors were tasked with preparing and delivering medication during simulated emergency scenarios. Preparation processes were video recorded. All phials, syringes and administered volumes were collected and analysed to determine the accuracy of drug preparation and delivery. Deviations from intended volumes were calculated. MAIN RESULTS: A total of 96 dosages were recorded from 24 participants. Most errors were identified in the withdrawal of drug phase (prior to dilution) (13 of 96 doses had a >20% error), and the administration of medication phase (20 of 96 doses had a >20% error). Overall the median time taken to deliver each drug was 79 s (IQR 59, 100 s). The largest percentage errors were seen when a large syringe was used to withdraw or administer a small volume of medication. CONCLUSION: The study clearly demonstrated that there were significant errors in the preparation and administration of medication. Training in the preparation and administration of paediatric medications should be available for all emergency nurses and doctors. Correct syringe choice may reduce these errors-smaller syringes should be used for withdrawing or administering smaller volumes. PMID- 30413494 TI - What is the optimal management for the asymptomatic twin after diagnosis of late onset group B streptococcal disease? PMID- 30413495 TI - Perceived barriers to maternal and newborn health services delivery: a qualitative study of health workers and community members in low and middle income settings. AB - OBJECTIVES: In considering explanations for poor maternal and newborn health outcomes, many investigations have focused on the decision-making patterns and actions of expectant mothers and families, as opposed to exploring the 'supply side' (health service provider) barriers. Thus, we examined the health system factors impacting on access to and delivery of quality maternal and newborn healthcare in rural settings. DESIGN: A semistructured qualitative study using face-to-face in-depth interviews with health professionals, and focus group sessions with community members, in eight project sites in two districts of Upper West Region, Ghana, was employed. Participants were purposively selected to generate relevant data to help address the study objective. The survey was guided by WHO standard procedures and Ghana Health Ministry's operational work plan for maternal and newborn care. SETTING: Nadowli-Kaleo and Daffiama-Bussie-Issa districts in Upper West Region, Ghana. PARTICIPANTS: Two hundred and fifty-three participants were engaged in the study through convenient and purposive sampling: healthcare professionals (pharmacist, medical doctor, two district directors of health services, midwives, community health and enrolled nurses) (n=13) and community members comprising opinion leaders, youth leaders and adult non pregnant women (n=240 in 24 units of focus groups). RESULTS: Results show significant barriers affecting the quality and appropriateness of maternal and neonatal health services in the rural communities and the Nadowli District Hospital. The obstacles were inadequate medical equipment and essential medicines, infrastructural challenges, shortage of skilled staff, high informal costs of essential medicines and general limited capacities to provide care. CONCLUSION: Implementation of the birth preparedness and complication readiness strategy is in its infancy at the health facility level in the study areas. Increasing the resources at the health provider level is essential to achieving international targets for maternal and neonatal health outcomes and for bridging inequities in access to essential maternal and newborn healthcare. PMID- 30413496 TI - Association of coronary dominance with the severity of coronary artery disease: a cross-sectional study in Shaanxi Province, China. AB - OBJECTIVE: To investigate whether coronary artery dominance is associated with the severity of coronary artery disease (CAD). DESIGN: Cross-sectional study. SETTING: Single-centre. PARTICIPANTS: Between July 2015 and February 2017, 1654 patients who underwent coronary angiography (CAG) were recruited into this cross sectional study. MEASUREMENT AND METHODS: According to coronary dominance, patients were classified into left dominance (LD), right dominance (RD) and codominance (CD) based on the CAG results. Multiple linear regression analysis was performed to test the association between severity of CAD and coronary dominance. RESULTS: The total Gensini score was significantly higher in the RD group than in the left-CD group (42.3+/-33.6 vs 36.3+/-29.8; p=0.033). After adjusting for potential confounding factors, the results of multivariate linear regression showed that RD was associated with the severity of CAD (beta=6.699, 95% CI 1.193 to 12.205, p=0.017). CONCLUSIONS: The results suggest that right coronary dominance was associated with the severity of CAD. PMID- 30413497 TI - Impact and longevity of measles-associated immune suppression: a matched cohort study using data from the THIN general practice database in the UK. AB - OBJECTIVE: To test the hypothesis that measles infection increases the incidence of non-measles infectious diseases over a prolonged period of time. DESIGN: A population-based matched cohort study. DATA SOURCES: This study examined children aged 1-15 years in The Health Improvement Network UK general practice medical records database. Participants included 2228 patients diagnosed with measles between 1990 and 2014, which were matched on age, sex, general practitioner practice and calendar year with 19 930 children without measles. All controls had received at least one measles vaccination. Children with a history of immune compromising conditions or with immune-suppressive treatment were excluded. PRIMARY OUTCOME MEASURES: Incidence rate ratio (IRR) of infections, anti infective prescriptions and all-cause hospitalisations following measles in predetermined periods using multivariate analysis to adjust for confounding variables. RESULTS: In children with measles, the incidence rate for non-measles infectious disease was significantly increased in each time period assessed up to 5 years postmeasles: 43% in the first month (IRR: 1.43; 95% CI 1.22 to 1.68), 22% from month one to the first year (IRR: 1.22; 95% CI 1.14 to 1.31), 10% from year 1 to 2.5 years (IRR: 1.10; 95% CI 1.02 to 1.19) and 15% (IRR: 1.15; 95% CI 1.06 to 1.25) in years 2.5 to 5 years of follow-up. Children with measles were more than three times as likely to receive an anti-infective prescription in the first month and 15%-24% more likely between the first month and 5 years. The rate of hospitalisation in children with measles was increased only in the month following diagnosis but not thereafter (IRR: 2.83; 95% CI 1.72 to 4.67). CONCLUSION: Following measles, children had increased rates of diagnosed infections, requiring increased prescribing of antimicrobial therapies. This population-based matched cohort study supports the hypothesis that measles has a prolonged impact on host resistance to non-measles infectious diseases. PMID- 30413498 TI - Complaints from patients with functional neurological disorders: a cross sectional UK survey of why patients complain and the effect on the clinicians who look after them. AB - OBJECTIVE: To evaluate the nature of complaints from patients with functional neurological disorders and understand the reaction of UK neurology consultants to receiving complaints from this patient group. METHODS: A voluntary online retrospective survey was advertised to UK consultant neurologists. Questions asked about the nature of the complaint, how it was dealt with, how it affected their emotional well-being and attitude to work, and whether it influenced their clinical practice. Responses were anonymised. The frequency of responses and percentage of total responses were analysed. Respondents were also given opportunities to add personal comments. RESULTS: Responses from 58 clinicians were received. Patient disagreement with the diagnosis was a factor in 90% of complaints received. Only 77% of complaints were resolved within 6 months and 61% of clinicians received no feedback about the outcome. 31% of clinicians reported their most problematic complaint had an adverse effect on their mood. 67% of respondents changed their practice following the complaint with 59% investigating more frequently or due to perceived pressure from patients. CONCLUSIONS: Complaints from patients with functional neurological disorders appear to be primarily due to disagreement with the diagnosis. They are more difficult to resolve than other complaints, and clinicians who deal with them often become the 'second victim' in the process leading to potentially adverse effects on patient care. Strategies to tackle these issues are discussed. PMID- 30413499 TI - Characteristics and prognostic values of traditional pathological parameters and advanced molecular subtypes in women in Beijing with operable breast cancer: a retrospective analysis. AB - OBJECTIVES: This study investigated the characteristics and prognostic values of traditional pathological parameters and advanced molecular subtypes in women with operable breast cancer in Beijing. DESIGN: A retrospective study through case information enquiry or telephonic follow-up. SETTING: Beijing Friendship Hospital. PARTICIPANTS: 1042 patients with primary operable breast cancer between 2008 and 2012 were enrolled in the study. MEASURES: The characteristics and 5 year relapse rates according to the Nottingham Prognosis Index (NPI) and molecular subtypes were analysed. RESULTS: In 1042 patients, the percentages of high histological grade, N1+N2, T2+T4 were 7.3%, 24.2%, 46.9%, respectively. In patients with invasive breast cancer, the percentages of auxiliary staging, positive margins, vascular invasion and nerve infiltration were 65.0%, 2.8%, 10.5% and 1.1%, respectively. The missing percentages of auxiliary staging, margins, vascular tumour invasion and nerve infiltration were 14.2%, 31.4%, 46.5% and 97.4%, respectively. The percentages of ER-positive, PR-positive, HER2 positive and Ki-67 high expression were 64.3%, 43.8%, 18.8% and 62.7%, respectively. The percentages of luminal A, luminal B, HER2-overexpression and basal-like breast cancers were 10.5%, 54.2%, 8.2% and 11.2%, respectively. Luminal A, luminal B and basal-like breast cancer subtypes were more common in the >60 years group, the 41-60 years group and the 20-40 years group, respectively. The 5-year relapse rates according to NPI were as follows: 6.2% in the low recurrence risk group, 10.4% in the moderate recurrence risk group and 12.9% in the high recurrence risk group. The 5-year relapse rates according to molecular subtypes were as follows: luminal A 4.0%, luminal B 7.0%, HER2 overexpression14.2%, basal-like 15.6%. CONCLUSIONS: Reasonable analysis of traditional pathological parameters and advanced molecular subtypes in women with operable breast cancer in Beijing may be useful to guide precise treatment and predict prognosis. PMID- 30413500 TI - Exploring the phase for highest impact on radicality: a cross-sectional study of patient involvement in quality improvement in Swedish healthcare. AB - OBJECTIVES: Involving patients in quality improvement is often suggested as a critical step for improving healthcare processes. However, this comes with challenges related to resources, tokenism, validity and competence. Therefore, to optimise the use of available resources, there is a need to understand at what stage in the improvement cycle patient involvement is most beneficial. Thus, the purpose of this study was to identify the phase of an improvement cycle in which patient involvement had the highest impact on radicality of improvement. DESIGN: An exploratory cross-sectional survey was used. SETTING AND METHODS: A questionnaire was completed by 155 Swedish healthcare professionals (response rate 34%) who had trained and had experience in patient involvement in quality improvement. Based on their replies, the impact of patient involvement on radicality in various phases of the improvement cycle was modelled using the partial least squares method. RESULTS: Patient involvement in quality improvement might help to identify and realise innovative solutions; however, there is variation in the impact of patient involvement on perceived radicality depending on the phase in which patients become involved. The highest impact on radicality was observed in the phases of capture experiences and taking action, while a moderate impact was observed in the evaluate phase. The lowest impact was observed in the identify and prioritise phase. CONCLUSIONS: Involving patients in improvement projects can enhance the quality of care and help to identify radically new ways of delivering care. This study shows that it is possible to suggest at what point in an improvement cycle patient involvement has the highest impact, which will enable more efficient use of the resources available for patient involvement. PMID- 30413501 TI - Sex differences in the prevalence of neural tube defects and preventive effects of folic acid (FA) supplementation among five counties in northern China: results from a population-based birth defect surveillance programme. AB - OBJECTIVES: Sex differences in prevalence of neural tube defects (NTDs) have previously been recognised; however, the different susceptibility of men and women have not been examined in relation to the effects of folic acid (FA) supplementation. We hypothesised that FA may have a disproportionate effect that alters the sex-specific prevalence of NTDs. SETTING: Data from two time points, before (2003-2004) and after (2011-2016) the start of the supplementation programme, were obtained from a population-based birth defect surveillance programme among five counties in northern China. All live births (28 or more complete gestational weeks), all stillbirths of at least 20 weeks' gestational age and pregnancy terminations at any gestational age following the prenatal diagnosis of NTDs were included. PARTICIPANTS: A total of 25 249 and 83 996 births before and after the programme were included respectively. PRIMARY AND SECONDARY OUTCOME MEASURES: The prevalence of NTDs by sex and subtype, Male:female rate ratios and their 95% CI were calculated. RESULTS: Overall, NTDs were less prevalent among men than among women (rate ratio (RR) 0.92; 95% CI 0.90 to 0.94), so was anencephaly (RR 0.77; 95% CI 0.73 to 0.81) and encephalocele (RR 0.75; 95% CI 0.61 to 0.92), while spina bifida showed a male predominance (RR 1.10; 95% CI 1.05 to 1.15). The overall prevalence of NTDs decreased by 78/10 000 in men and 108.7/10 000 in women from 2003 to 2004 to 2011 to 2016. There was a significant sex difference in the magnitude of reduction, being greater in women than men, particularly for anencephaly. CONCLUSIONS: The prevalence of NTDs decreased in both sexes after the implementation of a massive FA supplementation programme. While female predominance was observed in open NTDs and total NTDs, they also had a greater rate of decrease in NTDs after the supplementation programme. PMID- 30413502 TI - Stillbirth among women in nine states in India: rate and risk factors in study of 886,505 women from the annual health survey. AB - OBJECTIVES: To assess the rate of stillbirth and associated risk factors across nine states in India. DESIGN: Secondary analysis of cross-sectional data from the Indian Annual Health Survey (2010-2013). SETTING: Nine states in India: Madhya Pradesh, Chhattisgarh, Rajasthan, Uttarakhand, Jharkhand, Odisha, Bihar, Assam and Uttar Pradesh. PARTICIPANTS: 886 505 women, aged 15-49 years. MAIN OUTCOME MEASURES: Stillbirth rate with 95% CI. Adjusted OR to examine the associations between stillbirth and (1) socioeconomic, behavioural and biodemographic risk factors and (2) complications in pregnancy (anaemia, eclampsia, other hypertensive disorders, antepartum and intrapartum haemorrhage, obstructed labour, breech presentation, abnormal fetal position). RESULTS: The overall rate of stillbirth was 10 per 1000 total births (95% CI 9.8 to 10.3). Indicators of socioeconomic deprivation were strongly associated with an increase in stillbirth: rural residence (adjusted OR (aOR) 1.27, 95% CI 1.16 to 1.39), female illiteracy (aOR 1.43, 95% CI 1.17 to 1.74), low socioeconomic status (aOR 2.42, 95% CI 1.82 to 3.21), schedule caste background (aOR 1.11, 95% CI 1.04 to 1.19) and woman not in paid employment (aOR 1.15, 95% CI 1.07 to 1.24). Women from minority religious groups were at higher risk than the Hindu majority (Muslim (aOR 1.33, 95% CI 1.25 to 1.43); Christian (aOR 1.42, 95% CI 1.19 to 1.70)). While a few women smoked (<1%), around 9% reported chewing tobacco, which was associated with an increased odds of stillbirth (aOR 1.11, 95% CI 1.02 to 1.21). Adverse pregnancy and birth characteristics were also associated with stillbirth: antenatal care visits <4 (aOR 1.08, 95% CI 1.01 to 1.15), maternal age <25 years (aOR 1.29, 95% CI 1.21 to 1.37) and >=35 years (aOR 1.16, 95% CI 1.04 to 1.29), multigravida (aOR 3.06, 95% CI 2.42 to 3.86), multiple pregnancy (aOR 1.77, 95% CI 1.47 to 2.15), assisted delivery (aOR 3.45, 95% CI 3.02 to 3.93), caesarean section (aOR 1.73, 95% CI 1.58 to 1.89), as were pregnancy complications (aOR 1.42, 95% CI 1.33 to 1.51). CONCLUSION: India is an emerging market economy experiencing a rapid health transition, yet these findings demonstrate the marked disparity in risk of stillbirth by women's socioeconomic status. Tobacco chewing and maternal and fetal complications were each found to be important modifiable risk factors. Targeting the 'at-risk' population identified here, improved recording of stillbirths and the introduction of local reviews would be important steps to reduce the high burden of stillbirths in India. PMID- 30413503 TI - Effectiveness of a free maternal healthcare programme under the National Health Insurance Scheme on skilled care: evidence from a cross-sectional study in two districts in Ghana. AB - OBJECTIVES: In her quest to reduce maternal mortality, Ghana introduced a free maternal healthcare programme under the National Health Insurance Scheme. This study aimed to evaluate if women registered with the insurance had a better chance of accessing maternal healthcare services in two districts in Ghana. SETTING: We conducted a cross-sectional quantitative study involving household interviews of all women of the reproductive age group (15-49 years) residing in Kintampo North Municipality and Kintampo South District in Ghana from May to July 2015. Logistics regression analysis at 95% CI was used to determine the independent associations between maternal health insurance and use of antenatal care, facility-based delivery and postnatal care services. PARTICIPANTS: Women who had children aged 3-12 months were selected to take part in the study. RESULTS: We observed that women with insurance are 39.5 times more likely to have a maximum of six antenatal care visits and 2.6 times more likely to have an average of four antenatal care visits than those without insurance. Additionally, they are 5.3 times more likely to have facility-based delivery than those without insurance. An association was also found between postnatal care use and insurance as women who do not have insurance are 12.0 (1/0.083) times more likely to receive postnatal care than those with insurance. CONCLUSIONS: Pregnant women who registered with health insurance had at least four antenatal care visits and delivered in a health facility. However majority of them did not go for postnatal care. PMID- 30413504 TI - HIV self-test performance among female sex workers in Kampala, Uganda: a cross sectional study. AB - OBJECTIVE: To evaluate HIV self-testing performance and results interpretation among female sex workers (FSWs) in Kampala, Uganda, who performed unassisted HIV self-testing. METHODS: In October 2016, 104 participants used an oral HIV self test while under observation by research assistants. Participants were not assisted on HIV self-test use prior to or during testing, and were only given the manufacturer's pictorial and written instructions to guide them. Research assistants recorded if participants completed and/or had difficulties with steps in the HIV self-testing process on a prespecified checklist. Randomly drawn, used HIV self-tests were interpreted by FSWs. We calculated the concordance between FSWs' interpretations of self-test results with those indicated in the manufacturer's instructions. RESULTS: Only 33% (34/104) of participants completed all of the key steps in the HIV self-testing process, and the majority (86%, 89/104) were observed having difficulties with at least one of these steps. Misinterpretation of HIV self-test results were common among FSWs: 23% (12/56) of FSWs interpreted HIV-negative self-test results as HIV positive and 8% (3/37) of FSWs interpreted HIV-positive self-test results as HIV negative. The concordance between FSWs' interpretations of self-test results and that indicated in the instructions was 73% (95% CI 56% to 86%) for HIV-positive self-tests and 68% (95% CI 54% to 80%) for HIV-negative self-tests. CONCLUSIONS: FSWs in Kampala, who performed unassisted HIV self-testing, skipped steps in the HIV self-testing process and had difficulties correctly interpreting self-test results. Training on use and interpretation of HIV self-tests may be necessary to prevent errors in the HIV self-testing process and to avoid the negative consequences of false positive and false-negative HIV self-test results among FSWs. TRIAL REGISTRATION NUMBER: NCT02846402. PMID- 30413505 TI - My life with lupus: contextual responses of African-American women with systemic lupus participating in a peer mentoring intervention to improve disease self management. AB - OBJECTIVE: The current article seeks to examine the ways in which African American women with systemic lupus erythematosus (SLE) describe their disease experience and how they cope with their disease. This qualitative study provides deeper insight into whether experiences of African-American women with SLE differ from previous qualitative study findings. METHODS: Qualitative data were gathered using interviews and a focus group, from participants in the Peer Approaches to Lupus Self-management (PALS) programme. Data were analysed for themes related to disease experience and how participants cope with their disease. Twenty-seven African-American women with SLE were recruited into the peer mentoring programme, of which 7 served as mentors and 20 served as mentees. A 12-week peer mentoring intervention delivered by phone and based on the Chronic Disease Self-Management and Arthritis Self-Management Programs. RESULTS: Three categories encompassing a total of 10 subcategories emerged from analyses: (A) interpersonal, familialandromantic relationships; (B) individual experiences of living with SLE; and (C) physician-patient relationships. CONCLUSION: We gained insight on several issues related to patient perspectives of African-American women with SLE, and the context surrounding their thoughts and feelings related to lupus, including their providers, families and other social support networks. Additional research efforts could explore and address the thematic domains and respective subthemes identified here. Although limited due to the preliminary nature of the study, this information can be used to create future evidence-based interventions to decrease the impact of SLE on African-American patients. PMID- 30413506 TI - Hospital postdischarge intervention trialled with family caregivers of older people in Western Australia: potential translation into practice. AB - : There is lack of a suitable assessment tool that can be used routinely and systematically by hospital staff to address family caregivers' (FCs') support needs. This paper describes a novel approach to identifying and addressing FCs' needs following hospital discharge of the older person receiving care. SETTING AND PARTICIPANTS: FC recruitment occurred on the patient's discharge from a tertiary hospital in Western Australia; 64 completed the study; 80% were female; mean age 63.2 years. INTERVENTION: The Further Enabling Care at Home (FECH) programme was delivered over the telephone by a specially trained nurse and included: support to facilitate understanding of the patient's discharge letter; caregiver support needs assessment and prioritisation of urgent needs; and collaborative guidance, from the nurse, regarding accessing supports. RESULTS: Sixty-four FCs completed the FECH programme. The top three support needs identified by the FCs were: knowing what to expect in the future (52%), knowing who to contact if they were concerned (52%) and practical help in the home (36%). The telephone-based outreach service worked well and was convenient for the nurse and the FCs, and saved on transport, time and money. Most of the FCs appreciated the systematic approach to identify and articulate their needs and were satisfied with the support they received, mainly navigation through the systems, problem solving, self-care strategies, explanation of illness, symptoms and medication and access to after-hours services. CONCLUSIONS: In order to guide services which may consider adopting this systematic approach to supporting FCs and integrating it into their routine practice, this evaluation of the FECH programme has described the processes implemented and highlighted the factors that hindered or facilitated these processes to engage caregivers with appropriate services in a timely manner. Positive feedback indicated that the programme was a useful addition to hospital discharge planning. TRIAL REGISTRATION NUMBER: ACTRN12614001174673; Results. PMID- 30413507 TI - Evaluation of a digital platform for osteoarthritis treatment: study protocol for a randomised clinical study. AB - INTRODUCTION: Despite favourable results from structured face-to-face treatment of osteoarthritis (OA) in Sweden through the Better management of patients with OsteoArthritis (BOA) initiative, only around 20% of people with knee or hip OA receive the primary treatment recommended by international guidelines (ie, information, exercise, weight management). In 2014, a digital treatment programme named Joint Academy was introduced in Sweden, based on the same concept as the face-to-face BOA programme. In line with BOA, Joint Academy follows national and international guidelines and best practice for OA treatment. Results from observational studies suggest that this digital treatment is a valuable alternative to the traditional treatment approach and can positively impact patients' function and pain. However, conclusions from such studies commonly suggest that more rigorous testing is necessary to ascertain the benefits of digital treatment delivery for people with OA. METHODS AND ANALYSIS: A randomised clinical trial will be performed, comparing regular face-to-face care according to BOA with the digital version, Joint Academy. A total of 270 participants with clinically diagnosed knee OA will be recruited at primary care centres and randomised to either standard treatment (BOA) for 3 months, or the experimental group (digital intervention programme). Both groups will receive educational sessions and exercises yet with a difference in programme deliverance. The objective of the trial is to evaluate the effectiveness of the online treatment programme, in comparison with BOA. The two treatment groups will be compared with respect to the number of repetitions of the 30 s chair stand test at 3, 6 and 12 months, using a mixed model repeated measures analysis of variance. ETHICS AND DISSEMINATION: Ethical approval has been attained from the Regional Board of Ethics in Lund, Sweden (Dnr 2017/719). Results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03328741. PMID- 30413508 TI - Observational retrospective study of US national utilisation patterns and live birth rates for various ovarian stimulation protocols for in vitro fertilisation. AB - OBJECTIVE: Alternative ovarian stimulation protocols for in vitro fertilisation (IVF) have grown in popularity. Yet, patient populations best suited for these protocols have not been defined. Our objective was, therefore, to determine national IVF utilisation patterns and live birth rates of various ovarian stimulation protocols. DESIGN: Retrospective cohort study. SETTING: Academic affiliated private fertility centre. PARTICIPANTS: Aggregate data published by Society for Assisted Reproductive Technology for autologous IVF cycles performed in the USA during 2014 and 2015 were analysed. IVF cycles were stratified based on ovarian stimulation protocol: 205 705 conventional stimulations, 4397 minimal stimulations, 2785 natural cycles and 514 in vitro maturation (IVM) cycles. Repeat cycles could not be determined in this analysis. OUTCOME MEASURES: Utilisation patterns and age-specific live birth rates for various ovarian stimulation protocols. RESULTS: With advancing female age, utilisation of conventional stimulation protocols decreased, while minimal stimulation and natural cycle IVF increased. Diminished ovarian reserve diagnoses were in all age groups less prevalent in patients undergoing conventional stimulation than with all other protocols. Live birth rates were highest with conventional stimulation at 42.4%, 33.1%, 22.1%, 11.7% and 3.9% for <35, 35-37, 38-40, 41-42 and >42 female age groups, respectively. The difference in live birth rates between conventional stimulation and other protocols widened with advancing age from 1.6 fold to 3.9-fold among women <35 years of age, reaching 4.4-fold to 6.6-fold among women >42 years of age. CONCLUSIONS: In comparison to conventional stimulation IVF-minimal stimulation, natural cycle IVF and IVM protocols offer lower but still acceptable live birth rates among young women. These alternative protocols are frequently used in older women and those with diminished ovarian reserve, despite their lower live birth rates. The reasons for this apparent incongruity warrant further careful exploration. PMID- 30413509 TI - Efficacy and safety of sodium-glucose cotransporter 2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) in patients with type 2 diabetes: a systematic review and network meta-analysis study protocol. AB - INTRODUCTION: Sodium-glucose cotransporter 2 inhibitors (SGLT-2is) and glucagon like peptide-1 receptor agonists (GLP-1RAs) are two classes of glucose-lowering drugs gaining popularity in the treatment of type 2 diabetes mellitus (T2DM). Current guidelines suggest patient-centred approaches when deciding between available hyperglycaemia drugs with no indication to which specific drug should be administered. Despite systematic reviews and meta-analyses being conducted within SGLT-2is and GLP-1RAs, differences across these classes of drugs have not been investigated. Therefore, this systematic review and network meta-analysis (NMA) will aim to compare the efficacy and safety profiles across and within SGLT 2is and GLP-1RAs. METHODS: PubMed, the Cochrane Central Register of Controlled Trials and ISI Web of Science will be searched from inception for published randomised controlled trials conducted in patients with T2DM, with at least two arms consisting of SGLT-2is, GLP-1RAs or control/placebo. Title and abstracts will be screened by two independent reviewers with conflicts resolved by a third. Data will be extracted by the primary researcher, a random sample will be checked by an independent reviewer. Risk of bias will be assessed using the Cochrane Risk of Bias Tool and overall quality of evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation approach.Study characteristics, participants baseline characteristics, mean change in cardiometabolic outcomes and number of adverse events will be extracted for each study. Primary outcome will be the mean change in glycated haemoglobin (HbA1c) (%, mmol/mol). Initial random-effects pairwise meta-analysis will be conducted for each unique treatment comparison where heterogeneity will be assessed. A Bayesian NMA approach will be adopted where random-effects generalised linear models will be fitted in WinBUGS. Sensitivity analysis will be conducted to assess choices of prior distributions and length of burn-in and sample. ETHICS AND DISSEMINATION: Ethics approval is not required for this study. Results from this study will be published in a peer-review journal. PROSPERO REGISTRATION NUMBER: CRD42018091306. PMID- 30413510 TI - Evidence into practice: protocol for a new mixed-methods approach to explore the relationship between trials evidence and clinical practice through systematic identification and analysis of articles citing randomised controlled trials. AB - INTRODUCTION: Randomised controlled trials (RCTs) provide high-quality evidence to inform practice. However, much routine care is not based on available RCT evidence. Understanding this disconnect may improve trial design, reporting and implementation. Published literature commenting on RCTs may yield relevant insights. This protocol presents a new approach examining how researchers understand, contextualise and use evidence from RCTs, through analysis of letters, editorials and discussion pieces citing individual RCTs. Surgical case studies will illustrate its ability to identify wide-ranging factors influencing application of trials evidence. METHODS AND ANALYSIS: In-depth study of published literature will explore written responses to RCTs. After purposefully selecting individual RCTs, we will systematically identify all citing articles covered in Web of Science and Scopus. Editorials, discussions and letters will be included. These are considered most likely to provide critiques and opinions about index RCTs. Original articles and reviews will be excluded. Clinical specialty, RCT design, outcomes and bibliographical data will be collected for RCTs and citing articles. Citing articles will be thematically analysed using the constant comparison technique to explore author understanding, contextualisation and relationship to clinical practice for the index trial. Coding will include generic issues relevant to all RCTs, such as sample size or blinding, and features specific to surgery, such as learning curve. Index trial quality will be examined using validated tools. Results will be combined to create a broad overview of the understanding and use of RCT evidence. ETHICS AND DISSEMINATION: This study involves secondary use of existing articles and does not require ethical approval. Pilot work will establish its feasibility and inform progression to larger scale utilisation across a broad range of RCTs. Findings will be published in a peer-reviewed journal and presented at surgical and methodological conferences. Results will guide future work on trial design to optimise implementation of results. PMID- 30413511 TI - Gut Feelings Questionnaire in daily practice: a feasibility study using a mixed methods approach in three European countries. AB - OBJECTIVES: The validated Gut Feelings Questionnaire (GFQ) is a 10-item questionnaire based on the definitions of the sense of alarm and the sense of reassurance. The purpose of the GFQ is to determine the presence or absence of gut feelings in the diagnostic reasoning of general practitioners (GPs).The aim was to test the GFQ on GPs, in real practice settings, to check whether any changes were needed to improve feasibility, and to calculate the prevalence of the GPs' sense of alarm and sense of reassurance in three different countries. SETTING: Primary care, six participating centres in Belgium, France and the Netherlands. PARTICIPANTS: We performed a think-aloud study with 24 experienced Dutch GPs, GP trainees and medical clerks who filled in the GFQ after diagnosing each of six case vignettes. We then performed a feasibility study in two phases, using a mixed-method approach, with 42 French and Dutch GPs in the first phase and then 10 Belgian, 10 Dutch and 10 French GPs in the second phase. All GPs filled in the GFQ after each of eight consultations with patients presenting new complaints and were subsequently interviewed about the use of the GFQ. OUTCOME MEASURES: GPs' experiences on using the GFQ in real practice, more specifically the average time needed for filling in the questionnaire.The prevalence of GPs' sense of alarm and sense of reassurance. RESULTS: The modified version of the GFQ, created without altering the sense of the validated items, was easy to use in daily practice. The prevalence of the GPs' sense of alarm occurred during 23% 31% of the included consultations. CONCLUSIONS: After a two-step study and several minor adaptations, the final version of the GFQ proved to be a feasible and practical tool to be used for prospective observational studies in daily practice. PMID- 30413512 TI - Educational disparities in perinatal health in Denmark in the first decade of the 21st century: a register-based cohort study. AB - OBJECTIVE: To investigate socioeconomic differences in six perinatal health outcomes in Denmark in the first decade of the 21st century. DESIGN: A population based cohort study. SETTING: Danish national registries. PARTICIPANTS: A total of 646 829 live born children and 3076 stillborn children (>=22+0 weeks of gestation) born in Denmark from 2000 to 2009. We excluded children with implausible relations between birth weight and gestational age (n=644), children without information on maternal country of origin (n=138) and implausible values of maternal year of birth (n=36). MAIN OUTCOME MEASURES: We investigated the following perinatal health outcomes: stillbirth, neonatal and postneonatal mortality, small-for-gestational age, preterm birth grated into moderate preterm, very preterm and extremely preterm, and congenital anomalies registered in the first year of life. RESULTS: Maternal educational level was inversely associated with all adverse perinatal outcomes. For all examined outcomes, the risk association displayed a clear gradient across the educational levels. The associations remained after adjustment for maternal age, maternal country of origin and maternal year of birth. Compared with mothers with vocational education, mothers with more than 15 years of education had an adjusted risk ratio for stillbirth of 0.64(95% CI 0.56 to 0.72). The corresponding adjusted risk ratios for neonatal mortality, postneonatal mortality, congenital anomalies, moderate preterm birth and small-for-gestational age were, respectively, 0.79(95% CI 0.67 to 0.93), 0.57(95% CI 0.42 to 0.78), 0.87(95% CI 0.83 to 0.91), 0.80(95% CI 0.77 to 0.83) and 0.83(95% CI 0.81 to 0.85). CONCLUSION: Substantial educational inequalities in perinatal health were still present in Denmark in the first decade of the 21st century. PMID- 30413513 TI - Conflict of interest disclosure slides at the European Society of Cardiology Congress 2016 in Rome: are they displayed long enough to assess their content? A cross-sectional study. AB - OBJECTIVES: To assess the duration of display of conflict of interest (COI) disclosure slides of presentations at the European Society of Cardiology (ESC) Congress 2016, and to identify factors associated with the duration of display of the disclosure slide. DESIGN: Cross-sectional observational study. OUTCOME MEASURES: Display duration of the COI disclosure slide and display duration per disclosure. RESULTS: Analysis of official video recordings of all oral presentations, viewed on the ESC website. 1673 oral presentations were analysed. In 706 presentations (42.2%), COIs were present on the disclosure slide. The median display duration of the disclosure slide was 2.49 s (minimum value: 0.16 s; IQR 1.47-4.08). In multivariable analysis, time spent on COI disclosures was positively related to the number of COIs (+0.11 s per extra COI), older estimated age of the speaker (+3.92 s for 75-85 years compared with <25 years), verbally commenting on disclosures (up to +8.25 s) and disclosures being of a non commercial nature (+2.83 s). In addition, speakers from Eastern, Southern and Western Europe, Africa+East Asia and Asia showed their disclosures significantly shorter than the reference group (Northern Europe). CONCLUSION: COI disclosure slides are often displayed too briefly to reasonably assess their content. Several factors appear to influence the duration of display of the COI disclosure slides, but none do so to the degree that the display duration becomes sufficiently long. PMID- 30413514 TI - 'People like you?': how people with hypertension make sense of future cardiovascular risk-a qualitative study. AB - OBJECTIVES: Cardiovascular disease (CVD) prevention guidelines recommend that patients' future CVD risk (as a percentage) is estimated and used to inform shared treatment decisions. We sought to understand the perspectives of patients with hypertension on their future risk of CVD. DESIGN: Qualitative, semistructured interviews and thematic analysis. PARTICIPANTS: People with hypertension who had not experienced a cardiovascular event recruited from primary care. SETTING: Participants were purposively sampled from two primary care practices in South London. Interviews were transcribed, and a thematic analysis was conducted. RESULTS: 24 people participated; participants were diverse in age, sex, ethnicity and socioeconomic status. Younger working-aged people were under-represented. Contrasting with probabilistic risk, many participants understood future CVD as binary and unknowable. Roughly half of participants avoided contemplating future CVD risk; for some, lifestyle change and medication obviated the need to think about CVD risk. Some participants identified with one portion of the probability fraction ('I'd be one of those ones.'). Comparison with peers (typically partners, siblings and friends of a similar age, including both 'healthy' and 'unhealthy' people) was most frequently used to describe risk, both among those who engaged with and avoided risk discussion. This contrasts with current risk scores, which describe probabilities in people with similar risk factors; many participants did not identify with such a group, and hence did not find these probabilities meaningful, even where correctly understood. CONCLUSIONS: Risk as typically calculated and communicated (eg, the risk of '100 people like you') may not be meaningful for patients who do not identify with the denominator. Comparing an individual's risk with their peers could be more meaningful. PMID- 30413515 TI - Assessing the impact of care pathways on potentially preventable complications and costs for spinal trauma patients: protocol for a data linkage study using cohort study and administrative data. AB - INTRODUCTION: Traumatic spinal cord injuries have significant consequences both for the injured individual and the healthcare system, usually resulting in lifelong disability. Evidence has shown that timely medical and surgical interventions can lead to better patient outcomes with implicit cost savings. Potentially preventable secondary complications are therefore indicators of the effectiveness of acute care following traumatic injury. The extent to which policy and clinical variation within the healthcare service impact on outcomes and acute care costs for patients with traumatic spinal cord injury (TSCI) in Australia is not well described. METHODS AND ANALYSIS: A comprehensive data set will be formed using record linkage to combine patient health and administrative records from seven minimum data collections (including costs), with an existing data set of patients with acute TSCI (Access to Care Study), for the time period June 2013 to June 2016. This person-level data set will be analysed to estimate the acute care treatment costs of TSCI in New South Wales, extrapolated nationally. Subgroup analyses will describe the associated costs of secondary complications and regression analysis will identify drivers of higher treatment costs. Mapping patient care and health service pathways of these patients will enable measurement of deviations from best practice care standards and cost effectiveness analyses of the different pathways. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the New South Wales Population and Health Services Research Ethics Committee. Dissemination strategies include peer reviewed publications in scientific journals and conference presentations to enable translation of study findings to clinical and policy audiences. PMID- 30413516 TI - Randomised controlled trial to assess the impact of a lifestyle intervention (ActWELL) in women invited to NHS breast screening. AB - INTRODUCTION: In Scotland, the incidence of breast cancer is predicted to rise significantly in the next few decades and while there are measures to support reductions in morbidity and mortality, the breast cancer community is currently exploring preventative opportunities including supporting weight management programmes in postmenopausal women. This study aims to assess the effectiveness and cost-effectiveness of a theory-based, community delivered, minimal contact, weight management (diet, physical activity and behaviour change techniques) programme (ActWELL) in women with a body mass index (BMI) >25 kg/m2 attending routine breast cancer screening appointments. METHODS AND ANALYSIS: The study will be a four-centre, 1:1 parallel group randomised controlled trial of a 12 month weight management intervention initiated in breast cancer screening centres, delivered by trained Breast Cancer Now lifestyle coaches in community settings. The intervention programme involves two intervention meetings with coaches plus (up to) nine telephone contacts over 12 months. The programme will focus on personalised diet (including alcoholic and sugary drinks) and physical activity habits. Behaviour change techniques include self-monitoring, goal setting, implementation intentions, action and coping plans. The study has a sample size of 414 women with a BMI >25 kg/m2 attending routine National Health Service breast cancer screening appointments. Measures will be taken at baseline, 12 weeks and at 12-month follow-up, complemented by qualitative interviews exploring perceived acceptability and impact on habitual behaviours. The two co primary outcomes are mean change in measured body weight and change in physical activity between groups to 12 months. Secondary outcomes are changes in eating habits, alcohol intake, sedentary time, quality of life, waist circumference, lipid, haemoglobin A1c and insulin profiles, blood pressure and cost effectiveness of the intervention. ETHICS AND DISSEMINATION: The protocol has been approved by East of Scotland Research Ethics Committee (17/ES/0073). All participants provide written informed consent. Dissemination will be through peer reviewed publication and conference presentations. TRIAL REGISTRATION NUMBER: ISRCTN11057518; Pre-results. PMID- 30413517 TI - Cohort profile of the Biomarkers of Acute Serious Illness in Children (BASIC) study: a prospective multicentre cohort study in critically ill children. AB - PURPOSE: Despite significant progress, challenges remain in the management of critically ill children, including early identification of infection and organ failure and robust early risk stratification to predict poor outcome. The Biomarkers of Acute Serious Illness in Children study aims to identify genetic and biological pathways underlying the development of critical illness in infections and organ failure and those leading to poor outcome (death or severe disability) in children requiring emergency intensive care. PARTICIPANTS: We recruited a prospective cohort of critically ill children undergoing emergency transport to four paediatric intensive care units (PICUs) in Southeast England between April 2014 and December 2016. FINDINGS TO DATE: During the study period, 1017 patients were recruited by the regional PICU transport team, and blood and urine samples were obtained at/around first contact with the patient by the transport team. Consent for participation in the study was deferred until after PICU admission and 674 parents/carers were consented. Further samples (blood, urine, stool and throat swabs) were collected after consent. Samples were processed and stored for genomic, transcriptomic, proteomic and metabolomic analyses. Demographic, clinical and laboratory data at first contact, during PICU stay and at discharge, were collected, as were detailed data regarding infectious or non-infectious aetiology. In addition, 115 families have completed 12-month validated follow-up questionnaires to assess quality of life and child behaviour.The first phase of sample analyses (transcriptomic profiling) is currently in progress. FUTURE PLANS: Stored samples will be analysed using genomic, proteomic and metabolic profiling. Advanced bioinformatics techniques will be used to identify biomarkers for early diagnosis of infection, identification of organ failure and risk stratification to predict poor outcome (death/severe disability). TRIAL REGISTRATION NUMBER: NCT03238040. PMID- 30413518 TI - Plagiarism in research: a survey of African medical journals. AB - OBJECTIVES: To examine whether regional biomedical journals in Africa had policies on plagiarism and procedures to detect it; and to measure the extent of plagiarism in their original research articles and reviews. DESIGN: Cross sectional survey. SETTING AND PARTICIPANTS: We selected journals with an editor in-chief in Africa, a publisher based in a low or middle income country and with author guidelines in English, and systematically searched the African Journals Online database. From each of the 100 journals identified, we randomly selected five original research articles or reviews published in 2016. OUTCOMES: For included journals, we examined the presence of plagiarism policies and whether they referred to text matching software. We submitted articles to Turnitin and measured the extent of plagiarism (copying of someone else's work) or redundancy (copying of one's own work) against a set of criteria we had developed and piloted. RESULTS: Of the 100 journals, 26 had a policy on plagiarism and 16 referred to text matching software. Of 495 articles, 313 (63%; 95% CI 58 to 68) had evidence of plagiarism: 17% (83) had at least four linked copied or more than six individual copied sentences; 19% (96) had three to six copied sentences; and the remainder had one or two copied sentences. Plagiarism was more common in the introduction and discussion, and uncommon in the results. CONCLUSION: Plagiarism is common in biomedical research articles and reviews published in Africa. While wholesale plagiarism was uncommon, moderate text plagiarism was extensive. This could rapidly be eliminated if journal editors implemented screening strategies, including text matching software. PMID- 30413519 TI - Smartphone problem-solving and behavioural activation therapy to reduce fear of recurrence among patients with breast cancer (SMartphone Intervention to LEssen fear of cancer recurrence: SMILE project): protocol for a randomised controlled trial. AB - INTRODUCTION: One of the most common distressing conditions experienced by breast cancer survivors is fear of cancer recurrence (FCR). There is, however, no standard intervention for ameliorating FCR. Our clinical experience and previous studies have suggested the potential benefits of problem-solving therapy (PST) and behavioural activation (BA). Given the huge number of cancer survivors and limited number of therapists to competently conduct PST and BA, we have developed PST and BA smartphone applications. This study aimed to evaluate the efficacy of the smartphone-based PST (Kaiketsu-App) and BA (Genki-App) apps in reducing FCR in patients with breast cancer. METHODS AND ANALYSIS: The SMartphone Intervention to LEssen fear of cancer recurrence project is an open-label, individually randomised, parallel-group trial. Allocation will be managed by a central server using a computer-generated random allocation sequence provided by an independent data centre. Participants will be randomised to smartphone-based intervention plus treatment as usual (TAU) or waitlist control with TAU alone. The primary endpoint of the study is the Japanese version of the Concerns About Recurrence Scale, which will be administered as an electronic patient-reported outcome on the patients' smartphone after 8 weeks. ETHICS AND DISSEMINATION: The present study is subject to the ethical guidelines for clinical studies published by Japan's Ministry of Education, Science and Technology and Ministry of Health, Labour and Welfare and the modified Act on the Protection of Personal Information as well as the ethical principles established for research on humans stipulated in the Declaration of Helsinki and further amendments thereto. The protocol was approved by the Institutional Review Board of Nagoya City University on 15 January 2018 (ID: 60-00-1171). TRIAL STATUS: The randomised trial, which commenced on 2 April 2018, currently enrols participants. The estimated end date for this study is in March 2020. TRIAL REGISTRATION NUMBER: UMIN000031140; Pre results. PMID- 30413520 TI - Establishing the prevalence of healthcare-associated infections in Australian hospitals: protocol for the Comprehensive Healthcare Associated Infection National Surveillance (CHAINS) study. AB - INTRODUCTION: A healthcare-associated infection (HAI) data point prevalence study (PPS) conducted in 1984 in Australian hospitals estimated the prevalence of HAI to be 6.3%. Since this time, there have been no further national estimates undertaken. In the absence of a coordinated national surveillance programme or regular PPS, there is a dearth of national HAI data to inform policy and practice priorities. METHODS AND ANALYSIS: A national HAI PPS study will be undertaken based on the European Centres for Disease Control method. Nineteen public acute hospitals will participate. A standardised algorithm will be used to detect HAIs in a two-stage cluster design, random sample of adult inpatients in acute wards and all intensive care unit patients. Data from each hospital will be collected by two trained members of the research team. We will estimate the prevalence of HAIs, invasive device use, single room placement and deployment of transmission based precautions. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Alfred Health Human Research Ethics Committee (HREC/17/Alfred/203) via the National Mutual Assessment. A separate approval was obtained from the Tasmanian Health and Medical Human Research Committee (H0016978) for participating Tasmanian hospitals. Findings will be disseminated in individualised participating hospital reports, peer-reviewed publications and conference presentations. PMID- 30413521 TI - Formative peer assessment in healthcare education programmes: protocol for a scoping review. AB - INTRODUCTION: In formative peer assessment, the students give and receive feedback from each other and expand their knowledge in a social context of interaction and collaboration. The ability to collaborate and communicate are essential parts of the healthcare professionals' competence and delivery of safe patient care. Thereby, it is of utmost importance to support students with activities fostering these competences during their healthcare education. The aim of the scoping review is to compile research on peer assessment presented in healthcare education programmes, focusing formative assessment. The result of the scoping review will form the basis for developing and conducting an intervention focusing collaborative learning and peer assessment in a healthcare education programme. METHODS AND ANALYSIS: The scoping review will be conducted by using the framework presented by Arksey & O'Malley and Levac et al. The primary research question is: How are formative peer assessment interventions delivered in healthcare education? The literature search will be conducted in the peer reviewed databases PubMed, Cumulative Index to Nursing and Allied Health Literature, Education Research Complete and Education Research Centre between September and December 2018. Additional search will be performed in Google Scholar, hand-searching of reference lists of included studies and Libsearch for identification of grey literature. Two researchers will independently screen title and abstract. Full-text articles will be screened by three researchers using a charting form. Studies meeting the inclusion criteria will be critically evaluated using the Critical Appraisal Skills Programme. A flow diagram will present the included and excluded studies. A narrative synthesis will be conducted by using thematic analysis as presented by Braun and Clarke. The findings will be presented under thematic headings using a summary table. To enhance validity, stakeholders from healthcare education programmes and healthcare institutions will be provided with an overview of the preliminary results. ETHICS AND DISSEMINATION: Research ethics approval is not required for the scoping review. PMID- 30413522 TI - Coproducing healthcare service improvement for people with common mental health disorders including psychotic experiences: a study protocol of a multiperspective qualitative study. AB - INTRODUCTION: Some people, who have common mental health disorders such as depression and anxiety, also have some psychotic experiences. These individuals may experience a treatment gap: their symptoms neither reach the increasingly high threshold for secondary care, nor do they receive full benefit from current interventions offered by the Improving Access to Psychological Therapies (IAPT) programme. The result may be poorer clinical and functional outcomes. A new talking therapy could potentially benefit this group. Informed by principles of coproduction, this study will seek the views of service users and staff to inform the design and development of such a therapy. METHODS AND ANALYSIS: Semistructured interviews will be conducted with IAPT service users, therapists and managers based in three different geographical areas in England. Our sample will include (1) approximately 15 service users who will be receiving therapy or will have completed therapy at the time of recruitment, (2) approximately 15 service users who initiated treatment but withdrew, (3) approximately 15 therapists each with at least 4-month experience in a step-3 IAPT setting and (4) three IAPT managers. Data analysis will be based on the constant comparative method. ETHICS AND DISSEMINATION: The study has been approved by the London Harrow Research Ethics Committee (reference: 18/LO/0642), and all National Health Service Trusts have granted permissions to conduct the study. Findings will be published in peer-reviewed academic journals, and presented at academic conferences. We will also produce a 'digest' summary of the findings, which will be accessible, visual and freely available. PMID- 30413523 TI - Frequent homologous recombination deficiency in high-grade endometrial carcinomas. AB - Purpose The elevated levels of somatic copy number alterations (SCNA) in a subset of high-risk endometrial cancers (EC) are suggestive of defects in pathways governing genome integrity. We sought to assess the prevalence of homologous recombination deficiency (HRD) in EC and its association with histopathological and molecular characteristics. Experimental Design Fresh tumor tissue was prospectively collected from 36 EC, and functional HRD was examined by the ability of replicating tumor cells to accumulate RAD51 protein at DNA double strand breaks (RAD51 foci) induced by ionizing radiation. Genomic alterations were determined by next generation sequencing and array comparative genomic hybridization/SNP array. The prevalence of BRCA-associated genomic scars-a surrogate marker for HRD-was determined in the TCGA EC cohort. Results Most EC included in the final analysis (n=25) were of non-endometrioid (52%), grade 3 (60%) histology and FIGO-stage I (72%). HRD was observed in 24% (n=6) of cases and was restricted to non-endometrioid EC (NEEC), with 46% of NEEC being HRD compared to none of the endometrioid EC (EEC, P=0.014). All but one of the HRD cases harboured either a pathogenic BRCA1 variant or high somatic copy number losses of HR genes. Analysis of TCGA cases supported these results, with BRCA associated genomic scars present in up to 48% (63/132) of NEEC vs. 12% (37/312) of EEC (P<0.001). Conclusions HRD occurs in EC, and is largely restricted to non endometrioid, TP53-mutant EC. Evaluation of HRD may help select patients that could benefit from treatments targeting this defect, including platinum compounds and PARP inhibitors. PMID- 30413524 TI - Predicting Outcome in Head and Neck Cancer: miRNAs with potentially big effects. AB - A five-microRNA signature for HPV negative head and neck squamous cell carcinoma (HNSCC) identifies patients at risk for inferior outcomes. Combining established clinical variables with this novel microRNA signature affords an opportunity to personalize and intensify treatment strategies in this high-risk patient population. PMID- 30413525 TI - Evaluation of Prophylactic Corticosteroid Eye Drop Use in the Management of Corneal Abnormalities Induced by the Antibody-Drug Conjugate Mirvetuximab Soravtansine. AB - PURPOSE: Reversible, low-grade ocular adverse events (AEs) are associated with administration of mirvetuximab soravtansine, a folate receptor alpha (FRalpha) targeted antibody-drug conjugate undergoing Phase III clinical evaluation in platinum-resistant ovarian cancer. This study investigated the underlying mechanisms of ocular toxicity and evaluated primary prophylactic use of corticosteroid eye drops in patients receiving mirvetuximab soravtansine. EXPERIMENTAL DESIGN: Target expression in the human eye was determined by immunohistochemistry. The ocular toxicity profile of mirvetuximab soravtansine was assessed preclinically using Dutch-Belted rabbits. In a Phase I clinical study, ovarian cancer patients were treated with 6 mg/kg mirvetuximab soravtansine intravenously once every 3 weeks, including one expansion cohort with corticosteroid eye drops administered daily for the first 10 days of each treatment cycle. RESULTS: FRalpha expression was absent from human corneal tissues. Ocular abnormalities in the rabbit eye appeared phenotypically consistent with off-target effects on the cornea. Forty patients were enrolled in the expansion cohort. Reversible grade 1 or 2 blurred vision and keratopathy occurred in 16 (40%) and 12 (30%) patients respectively; no grade 3/4 ocular events were observed. Compared to those patients who did not receive primary prophylaxis, corticosteroid eye drop use resulted in fewer dose reductions (5% versus 15%) and none discontinued due to ocular AEs. CONCLUSIONS: Preclinical modeling was predictive of the corneal-related symptoms seen in some patients dosed with mirvetuximab soravtansine. Primary prophylactic use of topical corticosteroid eye drops resulted in a trend towards symptomatic improvement and a reduction in ocular AE-related dose modifications in patients treated with mirvetuximab soravtansine. PMID- 30413526 TI - FDA Approval Summary: Axicabtagene Ciloleucel for Relapsed or Refractory Large B Cell Lymphoma. AB - In October 2017, the U.S. Food and Drug Administration granted regular approval to axicabtagene ciloleucel, a CD19-directed chimeric antigen receptor (CAR) T cell therapy, for treatment of adult patients with relapsed or refractory large B cell lymphoma after two or more lines of systemic therapy. Efficacy was based on complete remission (CR) rate and duration of response (DOR) in 101 adult patients with relapsed or refractory large B-cell lymphoma (median 3 prior systemic regimens) treated on a single-arm trial. Patients received a single infusion of axicabtagene ciloleucel, preceded by lymphodepleting chemotherapy with cyclophosphamide and fludarabine. The objective response rate per independent review committee was 72% (95% CI: 62, 81) with a CR rate of 51% (95% CI: 41, 62). With a median follow-up of 7.9 months, the median DOR was not reached in patients achieving CR (95% CI: 8.1 months, not estimable [NE]), whereas patients with partial remission had an estimated median DOR of 2.1 months (95% CI: 1.3, 5.3). Among 108 patients evaluated for safety, serious adverse reactions occurred in 52%. Cytokine release syndrome and neurologic toxicities occurred in 94% and 87% of patients, respectively, leading to implementation of a Risk Evaluation and Mitigation Strategy. PMID- 30413527 TI - The reciprocity between radiotherapy and cancer immunotherapy. AB - The clinical success of immune checkpoint inhibitors in treating metastatic and refractory cancers has generated significant interest in investigating their role in treating locally advanced diseases, thus requiring them to be combined with standard treatments in hope to produce synergistic antitumor responses. Radiotherapy in particular, has long been hypothesized to have actions complementary to those of immune checkpoint blockade, and a growing body of evidence indicates that cancer immunotherapy may also have radiosensitizing effects, which would provide unique benefit for locoregional treatments. Recent studies have demonstrated that when immune cells are activated by immunotherapeutics, they can reprogram the tumor microenvironment in ways that may potentially increase the radiosensitivity of the tumor. In this review, we highlight the evidence that supports reciprocal interactions between cancer immunotherapy and radiotherapy, where in addition to the traditional notion that radiation serves to enhance the activation of antitumor immunity, an alternative scenario also exists in which T-cell activation by cancer immunotherapy may sensitize tumors to radiation treatment through mechanisms that include normalization of the tumor vasculature and tissue hypoxia. We describe the empirical observations from preclinical models that support such effects and discuss their implications for future research and trial design. PMID- 30413528 TI - Correction: Regulation of ubiquitin-like with plant homeodomain and RING finger domain 1 (UHRF1) protein stability by heat shock protein 90 chaperone machinery. PMID- 30413531 TI - From Drosophila segmentation to human cancer therapy. AB - First described in Drosophila, Hedgehog signalling is a key regulator of embryonic development and tissue homeostasis and its dysfunction underlies a variety of human congenital anomalies and diseases. Although now recognised as a major target for cancer therapy as well as a mediator of directed stem cell differentiation, the unveiling of the function and mechanisms of Hedgehog signalling was driven largely by an interest in basic developmental biology rather than clinical need. Here, I describe how curiosity about embryonic patterning led to the identification of the family of Hedgehog signalling proteins and the pathway that transduces their activity, and ultimately to the development of drugs that block this pathway. PMID- 30413529 TI - Neurogenesis in the sea urchin embryo is initiated uniquely in three domains. AB - Many marine larvae begin feeding within a day of fertilization, thus requiring rapid development of a nervous system to coordinate feeding activities. Here, we examine the patterning and specification of early neurogenesis in sea urchin embryos. Lineage analysis indicates that neurons arise locally in three regions of the embryo. Perturbation analyses showed that when patterning is disrupted, neurogenesis in the three regions is differentially affected, indicating distinct patterning requirements for each neural domain. Six transcription factors that function during proneural specification were identified and studied in detail. Perturbations of these proneural transcription factors showed that specification occurs differently in each neural domain prior to the Delta-Notch restriction signal. Though gene regulatory network state changes beyond the proneural restriction are largely unresolved, the data here show that the three neural regions already differ from each other significantly early in specification. Future studies that define the larval nervous system in the sea urchin must therefore separately characterize the three populations of neurons that enable the larva to feed, to navigate, and to move food particles through the gut. PMID- 30413532 TI - The TRPC5 channel regulates angiogenesis and promotes recovery from ischemic injury in mice. AB - Ischemia-related diseases are a leading cause of death worldwide, and promoting therapeutic angiogenesis is key to effective recovery from hypoxia-ischemia. Given the limited success of angiogenic factors, such as vascular endothelial growth factor, in clinical trials, it is important to find more promising angiogenic targets. Here, using both cell- and tissue-based assays and a mouse model of injury-induced ischemia, we investigated the involvement of the transient receptor potential canonical 5 (TRPC5) ion channel in angiogenesis and the effects of a TRPC5 activator, the FDA-approved drug riluzole, on recovery from ischemic injury. We demonstrate that TRPC5 is involved in endothelial cell sprouting, angiogenesis and blood perfusion in an oxygen-induced retinopathy model and a hind-limb ischemia model. We found a potential regulatory link between nuclear factor of activated T cell isoform c3 and angiopoietin-1 that could provide the mechanistic basis for the angiogenic function of TRPC5. Importantly, treatment with riluzole, which can activate TRPC5 in endothelial cells, improved recovery from ischemia in mice. Our study reveals TRPC5 as a potential angiogenic target and suggests riluzole as a promising drug for managing ischemic diseases. PMID- 30413533 TI - Single nucleotide resolution analysis of nucleotide excision repair of ribosomal DNA in humans and mice. AB - The unique nucleolar environment, the repetitive nature of ribosomal DNA (rDNA), and especially the possible involvement of RNAPI in transcription-coupled repair (TCR) have made the study of repair of rDNA both interesting and challenging. TCR, the transcription-dependent, preferential excision repair of the template strand to the nontranscribed (coding) strand has been clearly demonstrated in genes transcribed by RNAPII. Whether TCR occurs in rDNA is unresolved. In the present work we have applied analytical methods to map repair events in rDNA using data generated by the newly developed XRseq procedure, which measures excision repair genome-wide with single nucleotide resolution. We find that in human and mouse cell lines rDNA is not subject to TCR of damage caused by UV or by cisplatin. PMID- 30413530 TI - Single cell transcriptome analysis of human, marmoset and mouse embryos reveals common and divergent features of preimplantation development. AB - The mouse embryo is the canonical model for mammalian preimplantation development. Recent advances in single cell profiling allow detailed analysis of embryogenesis in other eutherian species, including human, to distinguish conserved from divergent regulatory programs and signalling pathways in the rodent paradigm. Here, we identify and compare transcriptional features of human, marmoset and mouse embryos by single cell RNA-seq. Zygotic genome activation correlates with the presence of polycomb repressive complexes in all three species, while ribosome biogenesis emerges as a predominant attribute in primate embryos, supporting prolonged translation of maternally deposited RNAs. We find that transposable element expression signatures are species, stage and lineage specific. The pluripotency network in the primate epiblast lacks certain regulators that are operative in mouse, but encompasses WNT components and genes associated with trophoblast specification. Sequential activation of GATA6, SOX17 and GATA4 markers of primitive endoderm identity is conserved in primates. Unexpectedly, OTX2 is also associated with primitive endoderm specification in human and non-human primate blastocysts. Our cross-species analysis demarcates both conserved and primate-specific features of preimplantation development, and underscores the molecular adaptability of early mammalian embryogenesis. PMID- 30413535 TI - Benzolactam-related compounds promote apoptosis of HIV-infected human cells via protein kinase C-induced HIV latency reversal. AB - Latency-reversing agents (LRAs) are considered a potential strategy for curing cells of HIV-1 infection. Certain protein kinase C (PKC) activators have been previously reported to be LRAs because they can reverse HIV latency. In the present study, we examined the activities of a panel of benzolactam derivatives against cells latently infected with HIV. Using determination of p24 antigen in cell supernatants or altered intracellular GFP expression to measure HIV reactivation from latently infected cells along with a cytotoxicity assay, we found that some of the compounds exhibited latency-reversing activity, which was followed by enhanced release of HIV particles from the cells. One derivative, BL V8-310, displayed activity in ACH-2 and J-Lat cells latently infected with HIV at a concentration of 10 nM or higher, which was superior to the activity of another highly active PKC activator, prostratin. These results were confirmed with peripheral blood cells from HIV-infected patients. We also found that these drugs up-regulate the expression of caspase 3 and enhance apoptosis specifically in latently HIV-infected cells. Moreover, combining BL-V8-310 with a bromodomain containing 4 (BRD4) inhibitor, JQ1, not only enhanced HIV latency-reversing activity, but also reduced the effect on cytotoxic cytokine secretion from CD4+ T cells induced by BL-V8-310 alone. Our results suggest that BL-V8-310 and its related benzolactam derivatives are potential LRA lead compounds that are effective in reversing HIV latency and reducing viral reservoirs in HIV-positive individuals with few adverse effects. PMID- 30413534 TI - RNF12 catalyzes BRF1 ubiquitination and regulates RNA polymerase III-dependent transcription. AB - RNA polymerase III (Pol III) is responsible for the production of small non coding RNA species, including tRNAs and 5S rRNA. Pol III-dependent transcription is generally enhanced in transformed cells and tumors, but the underlying mechanisms remain not well understood. It has been demonstrated that the BRF1 subunit of TFIIIB is essential for the accurate initiation of Pol III-dependent transcription. However, it is not known whether BRF1 undergoes ubiquitin modification and whether BRF1 ubiquitination regulates Pol III-dependent transcription. Here, we show that RNF12, a RING domain-containing ubiquitin E3 ligase, physically interacts with BRF1. Via direct interaction, RNF12 catalyzes Lys27- and Lys33-linked polyubiquitination of BRF1. Furthermore, RNF12 is able to negatively regulate Pol III-dependent transcription and cell proliferation via BRF1. These findings uncover a novel mechanism for the regulation of BRF1 and reveal RNF12 as an important regulator of Pol III-dependent transcription. PMID- 30413536 TI - The Structure of PilA from Acinetobacter baumannii AB5075 suggests a mechanism for functional specialization in Acinetobacter type IV pili. AB - Type IV pili (T4P) are bacterial appendages composed of protein subunits, called pilins, non-covalently assembled into helical fibers. T4P are essential, in many bacterial species, for processes as diverse as twitching motility, natural competence, biofilm or microcolony formation, and host-cell adhesion. The genes encoding type IV pili are found universally in the Gram-negative, aerobic, non flagellated, and pathogenic coccobacillus Acinetobacter baumannii, but there is considerable variation in PilA, the major protein subunit, both in amino acid sequence and glycosylation patterns. Here we report the X-tray crystal structure of PilA from AB5075, a recently-characterized, highly-virulent isolate, at 1.9A resolution and compare it to homologues from A. baumannii strains ACICU and BIDMC57, which are C-terminally-glycosylated. These structural comparisons revealed that PilAAB5075 exhibits a distinctly electronegative surface chemistry. To understand the functional consequences of this change in surface electrostatics, we complemented a DeltapilA knockout strain with divergent pilA genes from ACICU, BIDMC57 and AB5075. The resulting transgenic strains showed differential twitching motility and biofilm formation while maintaining the ability to adhere to epithelial cells. PilAAB5075 and PilAACICU, while structurally similar, promote different characteristics, favoring twitching motility and biofilm formation respectively. These results support a model in which differences in pilus electrostatics affect the equilibrium of microcolony formation, which in turn alters the balance between motility and biofilm formation in Acinetobacter. PMID- 30413537 TI - NFAT5 up-regulates expression of the kidney-specific ubiquitin ligase gene Rnf183 under hypertonic conditions in inner-medullary collecting duct cells. AB - We previously reported that among the 37 RING finger protein (RNF) family members, RNF183 mRNA is specifically expressed in the kidney under normal conditions. However, the mechanism supporting its kidney-specific expression pattern remains unclear. In this study, we elucidated the mechanism of the transcriptional activation of murine Rnf183 in inner-medullary collecting duct cells. Experiments with anti-RNF183 antibody revealed that RNF183 is predominantly expressed in the renal medulla. Among the 37 RNF family members, Rnf183 mRNA expression was specifically increased in hypertonic conditions, a hallmark of the renal medulla. RNF183 up-regulation was consistent with the activation of nuclear factor of activated T cells 5 (NFAT5), a transcription factor essential for adaptation to hypertonic conditions. Accordingly, siRNA mediated knockdown of NFAT5 down-regulated RNF183 expression. Furthermore, the 3,466 to -3,136-bp region upstream of the mouse Rnf183 promoter containing the NFAT5-binding motif is conserved among mammals. A luciferase-based reporter vector containing the NFAT5-binding site was activated in response to hypertonic stress, but was inhibited by a mutation at the NFAT5-binding site. ChIP assays revealed that the binding of NFAT5 to this DNA site is enhanced by hypertonic stress. Of note, siRNA-mediated RNF183 knockdown increased hypertonicity-induced caspase-3 activation and decreased viability of mIMCD-3 cells. These results indicate that (i) RNF183 is predominantly expressed in the normal renal medulla, (ii) NFAT5 stimulates transcriptional activation of Rnf183 by binding to its cognate binding motif in the Rnf183 promoter, and (iii) RNF183 protects renal medullary cells from hypertonicity-induced apoptosis. PMID- 30413538 TI - Practice-based Research Network (PBRN) Engagement: 20+ Years and Counting. PMID- 30413539 TI - Slow Progress and Persistent Challenges for the Underrepresented Minority Family Physician. PMID- 30413540 TI - Board Certified Family Physician Workforce: Progress in Racial and Ethnic Diversity. AB - Diversification of the physician workforce has been a goal of Association of American Medical Colleges for several years and could improve access to primary care for under-served populations and address health disparities. We found that family physicians' demographics have become more diverse over time, but still do not reflect the national demographic composition. Increased collaboration with undergraduate universities to expand pipeline programs may help increase the diversity of students accepted to medical schools, which in turn should help diversify the family medicine workforce. PMID- 30413541 TI - Practitioner Participation in National Dental Practice-based Research Network (PBRN) Studies: 12-Year Results. AB - PURPOSE: This study examines practitioner participation over 12 years in the National Dental Practice-Based Research Network (PBRN) studies and practitioner meetings, average length of participation, and association of practitioner- and practice-level characteristics with participation. Little information exists about practitioners' long-term participation in PBRNs. METHODS: The network conducted a retrospective analysis of practitioner participation in 3 main network activities during 2005 to 2017. Practitioners who completed an enrollment questionnaire, practiced in the United States, and either attended a network meeting or received an invitation to complete a questionnaire or clinical study were included in the analysis. Practitioners (n = 3669) met inclusion criteria. The network implemented 38 studies (28 clinical and 10 questionnaire), 23 of which (15 clinical and 8 questionnaire) met the criteria for the current analysis. RESULTS: Overall, 86% (N = 3148) participated in at least 1 network activity during 2005 to 2017. Questionnaire studies had the highest rate with 81% (N = 2963) completing at least 1, 21% (N = 762) completed at least 1 clinical study and 19% (N = 700) attended at least 1 network meeting. Among 1578 practitioners enrolled in the first 5 years of the Network launch, 20% (N = 320) participated in multiple network activities over 5 to 9 years, and 14% (N = 238) for 10 to 12 years. Practitioner characteristics associated with participation varied depending on the activity assessed. CONCLUSION: The network engaged practitioners in its research activities with relatively high participation rates over a 12-year period. Strategies employed by the network to engage practitioners may serve as a model for PBRN networks for other allied health professions. PMID- 30413542 TI - Mailed Letter Versus Phone Call to Increase Uptake of Cancer Screening: A Pragmatic, Randomized Trial. AB - BACKGROUND: There is good evidence that cancer-specific patient outreach improves rates of cervical, breast, and colorectal cancer screening. However, it is unclear how primary care practices should implement integrated outreach for all 3 types of cancer screening. We aimed to understand whether integrated outreach using mailed letters or phone calls were more effective at increasing screening uptake in a primary care organization. METHOD: We conducted a pragmatic randomized trial comparing outreach by mailed letter or personalized phone call for patients overdue for cervical, breast, or colorectal cancer screening. The study was conducted at 6 clinics within an academic primary care organization in Toronto, Canada. Our primary outcome was an uptake of at least 1 screening test for which the patient was overdue. Our primary analysis was an intention-to treat, unadjusted comparison of proportions, using a chi2 test. We also compared costs per additional patient screened. All analyses were stratified by sex. RESULTS: A total of 3733 females and 1537 males were randomized to receive 1 of the interventions. Among women, 33.0% allocated to receive a reminder letter and 41.2% allocated to receive a reminder phone call received at least 1 screening test for which they were due (absolute difference, 8.1%; 95% CI, 5.1%-11.2%, P < .001). Among men, 24.8% allocated to receive a reminder letter and 28.8% allocated to a reminder phone call received screening for colorectal cancer (absolute difference, 4.1%; 95% CI, -0.4% to 8.5%, P = .073). For women and men, the letters cost approximately CaD $5.07 and CaD $7.16, respectively, for each completed screening test compared with CaD $8.71 and CaD $12.00 for the phone calls. CONCLUSIONS: Phone calls were more effective than mailed letters at increasing uptake for cervical, breast, and colorectal cancer screening among women. However, phone calls were more expensive than letters. Primary care practices should consider integrating phone call reminders into their practice, possibly as part of a targeted or staged approach to outreach for cancer screening. PMID- 30413543 TI - Interactive Mobile Doctor (iMD) to Promote Patient-Provider Discussion on Tobacco Use among Asian American Patients in Primary Care: A Pilot Study. AB - INTRODUCTION: This study examined the feasibility, acceptability, and efficacy of an interactive "Mobile Doctor" intervention (iMD) for Korean and Vietnamese American men, population groups with high smoking prevalence rates. METHODS: The iMD delivers 5As (Ask, Advise, Assess, Assist, and Arrange) via tailored in language video messages on a mobile tablet to Korean and Vietnamese male daily smokers right before a health care visit. A single-group trial was conducted with Korean- and Vietnamese-speaking patients at a federally qualified health center. Outcomes were assessed by self-reported surveys obtained postvisit and 3-month follow-up, and by examining electronic health record (EHR) progress notes from 3 consecutive primary care visits to evaluate impacts. RESULTS: Among 47 male daily smokers (87% participation rate), 98% were limited English proficient and 53% had no intent to quit smoking within 6 months. On average, iMD took 12.9 minutes to complete. All participants reported discussing smoking with their providers during the visit, and more than 90% thought iMD was at least somewhat helpful in their decision about quitting and in communicating with their providers. EHR documented 5As were significantly higher at the iMD visit for Assess (38.3%), Assist (59.6%), and Arrange (36.2%) compared with other visits without iMD. At 3 months, 51% made at least 1 24-hour quit attempt since the intervention. The self reported 7-day point prevalence abstinence was 19%. CONCLUSIONS: iMD is feasible and acceptable to Korean and Vietnamese male smokers, including those who were not intending to quit smoking. It is a promising tool for increasing patient provider discussion of tobacco use and possibly smoking cessation among Asian American male smokers. PMID- 30413544 TI - Opioid Overdose Hospitalizations among Medicare-Disability Beneficiaries. AB - INTRODUCTION: As the opioid epidemic progresses, a better understanding of those at elevated risk of opioid overdose is needed, particularly for populations whose growing risk may be overlooked. Medicare recipients under age 65 (Medicare disability beneficiaries [MDBs]) are one such population. We sought to analyze characteristics of opioid-overdose hospitalizations among MDBs and quantify the contribution of this population to opioid-overdose hospitalizations overall. METHODS: This retrospective cohort study included patients hospitalized for opioid overdose in the National/Nationwide Inpatient Sample from 1998 to 2013. The primary outcome measurements were number and characteristics of discharges, including patient sex, age, race, prescription opioid versus heroin overdose, and comorbidities. RESULTS: MDBs constituted 11.7% of US opioid overdose hospitalizations among those under 65 years of age in 1998; this proportion grew to 24.5% by 2013 (P < .0001). The proportion of female patients grew markedly among this cohort (P < .0001) and were disproportionately represented among MDBs (P < .0001). Prescription opioid overdose accounted for a larger proportion of opioid overdose hospitalizations among MDBs than among non-Medicare-insured patients under 65 years old (P < .0001). MDBs generally exhibited greater comorbidity burden versus non-Medicare-insured patients under age 65; however, chronic drug and alcohol abuse were less commonly documented among the Medicare cohort (P < .0001). CONCLUSIONS: MDBs constitute a substantial and growing proportion of opioid overdose hospitalizations in the United. To prevent opioid overdoses among MDBs, care must be taken to address the unique needs of this population. PMID- 30413545 TI - Disparities in Hypertension Control Across and Within Three Health Systems Participating in a Data-Sharing Collaborative. AB - INTRODUCTION: We aimed to standardize data collection from 3 health systems (HS1, HS2, HS3) participating in the San Francisco Bay Collaborative Research Network, and compare rates and predictors of uncontrolled blood pressure among hypertensive adults to identify opportunities for regional collaboration in quality improvement. METHODS: Retrospective cohort study using deidentified electronic health record data from all primary care patients with at least 1 visit in a 2-year period, using standard data definitions in a common data repository. Primary outcome was uncontrolled blood pressure at the most recent primary care visit. RESULTS: Of 169,793 adults aged 18 to 85 years, 53,133 (31.3%) had a diagnosis of hypertension. Of these, 18,751 (35%) had uncontrolled blood pressure at their last visit, with the proportion varying by system (29%, HS1; 31%, HS2; and 44%, HS3) and by clinical site within each system. In multivariate analyses, differences between health systems persisted, with HS2 and HS3 patients having a 1.15 times (95% CI, 1.11 to 1.19) and 1.46 times (95% CI, 1.42 to 1.50) greater relative risk of uncontrolled blood pressure compared with HS1. Across health systems, hypertensive patients were more likely to have uncontrolled blood pressure if they were uninsured, African Americans, current smokers, obese, or had fewer than 2 primary care visits during the 2-year measurement period. CONCLUSIONS: After controlling for standard individual predictors of hypertension control, significant and substantial differences in hypertension control persisted between health systems, possibly due to local quality improvement programs among other factors. There may be opportunities to share best practices and address common disparities across health systems. PMID- 30413546 TI - The Impact of the Affordable Care Act (ACA) Medicaid Expansion on Visit Rates for Diabetes in Safety Net Health Centers. AB - OBJECTIVE: To (1) compare clinic-level uninsured, Medicaid-insured, and privately insured visit rates within and between expansion and nonexpansion states before and after the Affordable Care Act (ACA) Medicaid expansion among the 3 cohorts of patient populations; and (2) assess whether there was a change in clinic-level overall, primary care visits, preventive care visits, and diabetes screening rates in expansion versus nonexpansion states from pre-ACA to post-ACA Medicaid expansion. METHODS: Electronic health record data on nonpregnant patients aged 19 to 64 years, with >=1 ambulatory visit between 01/01/2012 and 12/31/2015 (n = 483,912 in expansion states; n = 388,466 in nonexpansion states) from 198 primary care community health centers were analyzed. Using a difference-in-difference methodology, we assessed changes in visit rates pre-ACA versus post-ACA among a cohort of patients with diabetes, prediabetes, and no diabetes. RESULTS: Rates of uninsured visits decreased for all cohorts in expansion and nonexpansion states. For all cohorts, Medicaid-insured visit rates increased significantly more in expansion compared with nonexpansion states, especially among prediabetic patients (+71%). In nonexpansion states, privately insured visit rates more than tripled for the prediabetes cohort and doubled for the diabetes and no diabetes cohorts. Rates for glycosylated hemoglobin screenings increased in all groups, with the largest changes among no diabetes (rate ratio, 2.26; 95% CI, 1.97-2.56) and prediabetes cohorts (rate ratio, 2.00; 95% CI, 1.80-2.19) in expansion states. CONCLUSION: The ACA reduced uninsurance and increased access to preventive care for vulnerable patients, especially those with prediabetes. These findings are important to consider when making decisions regarding altering the ACA. PMID- 30413547 TI - Future Directions for Practice-Based Research Networks (PBRNs): A CERA Survey. AB - BACKGROUND: Thought leaders from family medicine and practice-based research networks (PBRNs) have put forth definitions and goals recommending future directions for PBRNs. Evidence demonstrating that PBRNs are acting in accordance with these trends supports future investment in PBRN infrastructure, funding, and training of clinician researchers. Our objective was to explore the alignment of PBRN research efforts with thought leader recommendations. METHODS: The 2017 Council of Academic Family Medicine Educational Research Alliance surveyed PBRN directors via emails to 126 respondents. This survey included 6 general background questions about PBRN characteristics. An additional 25 questions focused on current and future research directions, including the training of health care professionals about PBRN research. RESULTS: The survey response rate was 56/126 (44%). Physician faculty receive continuing medical education credit for PBRN training (reported by 12/56 of PBRN directors). PBRN provided continuing medical education for study participation (24/56), reviewing study results (7/56), attending a study results presentation (24/56), and attending study planning meetings (13/56). Practice-based research education of medical students and residents was reported at 11/56 and 14/56, respectively. Current PBRN research efforts were most frequent in the areas of community engagement, practice transformation, and quality improvement projects. CONCLUSION: PBRNs currently thrive on conducting research predominantly in quality improvement and practice transformation. However, the study findings suggest that moving forward, PBRNs should participate more in training the future generations of primary care researchers and to address health policy needs. PMID- 30413548 TI - The Complex Interpretation and Management of Zika Virus Test Results. AB - Zika virus disease provides the latest example of a critical nexus between public health and clinical practice. Interpreting Zika virus test results is complicated by the absence of a single testing approach with superior validity across contexts and populations. Molecular tests are highly specific, variably sensitive, and have a short window period. Serologic tests identify antibodies against Zika virus and are more likely than molecular tests to cross-react with other related viruses, reducing specificity. The type of test performed and timing relative to possible Zika virus exposure depend on public health guidance, testing algorithms, test availability, and capacity. Guidance from the Centers for Disease Control and Prevention and local health departments have changed throughout the course of the US epidemic based on prevalence, geography, and clinical concerns. Women with a low pretest probability of infection should be counseled against testing. Women with a high pretest probability of Zika virus infection should still receive enhanced prenatal monitoring and newborn evaluation, regardless of the test result. An appropriate interpretation of results depends on what tests are used, patient characteristics, and reasons for testing. Clinicians should take these factors into account in shared decision making discussions with pregnant women about Zika virus testing. PMID- 30413549 TI - Core Principles to Improve Primary Care Quality Management. AB - Quality management in American health care is in crisis. Performance measurement in its current form is costly, redundant, and labyrinthine. Increasingly, its contribution to achieving the Quadruple Aim is under close examination, especially in the domain of primary care services, where the burden of measurement is heaviest. This article assesses the state of quality management in primary care in the United States, particularly the 2015 Medicare Access and Children's Health Insurance Program Reauthorization Act, in comparative perspective, drawing lessons from the Quality and Outcomes Framework in the United Kingdom. The health care delivery function specific to primary care is pivotal to crossing the quality chasm, yet prior efforts to improve the quality of this function have failed more often than succeeded. These failures are the result of quality programs unguided by core principles of primary care. Quality management in primary care requires a more disciplined approach, adherent to 4 foundational principles: optimizing holistic patient and population health; harnessing the Quadruple Aim as a dynamic whole; applying measurements as tools for quality, not outcomes of quality; and prioritizing therapeutic relationships. These principles serve as the foundation for a bridge to high-functioning primary care that will lead American health care closer to the Quadruple Aim. PMID- 30413550 TI - The Association of Patient Satisfaction-Based Incentives with Primary Care Physician Opioid Prescribing. AB - PURPOSE: The opioid epidemic in the United States is an ongoing public health concern. Health care institutions use standardized patient satisfaction surveys to assess the patient experience and some offer incentives to their providers based on the results. We hypothesized that providers who report being incentivized based on patient satisfaction surveys are more likely to report an impact of such surveys on their opioid prescribing practices. METHODS: We developed a 23-item survey instrument to assess the self-perceived impact of patient satisfaction surveys on opioid prescribing practices in primary care and the potential impact of institutional incentives. The survey was emailed to all 1404 members of the Colorado Academy of Family Physicians. RESULTS: The response rate to the online survey was 10.4% (n = 146). Clinical indications for which responders prescribe opioids included acute pain (93%), cancer pain (85%), and chronic nonmalignant pain (72%). Among physicians using patient satisfaction surveys, incentivized physicians reported at least a slight impact on opioid prescribing 3 times more often than physicians who were not incentivized (36% vs 12%, P = .004). CONCLUSIONS: Efforts to improve patient satisfaction may have potentially untoward effects on providers' opioid prescribing behaviors. Our results suggest a need to further study the impact of provider incentive plans that are based on patient satisfaction scores. PMID- 30413551 TI - Academic Detailing for Postpartum Opioid Prescribing. AB - INTRODUCTION: Overprescribing opioid pain medications has become a major concern in our society due to the increasing rates of substance use disorders and the rate of accidental overdoses. The widespread availability of opioid medications suggests that patients are being prescribed opioids in amounts larger than they require for pain control. Efforts are now being made on a variety of fronts to decrease overprescribing. MATERIAL AND METHODS: A quality-improvement model was applied to address this concern at one medical center in women being discharged from the hospital following childbirth. The rates and amounts at which opioids were prescribed to this population before and after an academic detailing intervention were compared. RESULTS: The overall percentage of women who received prescriptions for opioid medications decreased from 100% to 93% in cesarean sections (P = .054) and 15% to 9% in vaginal deliveries (P = .03). The average prescription size decreased by 5 tablets (P < .0001). IMPLICATIONS: Simple quality-improvement methods may have a positive impact on opioid prescribing patterns, including decreasing the percentage of opioids postdelivery or the quantity of opioids per prescription. PMID- 30413552 TI - Recruiting Primary Care Practices for Research: Reflections and Reminders. AB - BACKGROUND: Recruiting primary care practices for research projects has always required carefully tended relationships, a compelling message, and good timing. Recruiting practices to participate in practice transformation research trials may take more and different efforts. We reflect on practice recruitment for a recently-concluded trial of a diabetes self-management support system in 2 states and 36 practices. METHODS: Iterative qualitative analysis of field notes, semistructured clinician and staff interviews, and meeting notes from a 2-state, cluster-randomized trial that aimed to improve self-management support for patients with type 2 diabetes mellitus. RESULTS: Although all 36 enrolled practices finished the study, fully recruiting practices early on took considerable effort, yielding 2 primary lessons: 1) practice-based research networks (PBRNs) must recruit more stakeholders at more levels, at the clinic, in the system, and across roles; and 2) practice recruitment is a process and may take longer than expected with unplanned turnover of key contacts. Adjusting our recruitment strategies required: helping with communication efforts in practices; aligning our study message according to stakeholders' interests; allowing for minor adaptations at the practice-level to align with critical practice workflows, staffing, and resources; re-engaging with clinical leadership over time; and identifying a "backup" champion due to turnover. CONCLUSIONS: When undertaking a pragmatic clinical trial requiring substantial practice change in a PBRN setting across a large number of practices, it is important that PBRN leaders develop a comprehensive strategy to identify and engage a broad group of stakeholders within each practice, understand their needs and priorities around research, and design and implement a structured communications strategy to maintain engagement throughout every phase of the project. PMID- 30413553 TI - Practice Rurality of Family Physicians Enrolled in a Practice Transformation Network. AB - The Transforming Clinical Practice Initiative prioritized the delivery of free practice transformation assistance by Practice Transformation Networks (PTNs) to small and rural practices that may otherwise lack the resources needed to succeed in Medicare's value-based payment (VBP) programs. We assessed the enrollment of rural practices in PTNs using 2016 TCPI enrollment data and American Board of Family Medicine recertification examination registration data from 2013 to 2016. PTNs enrolled a higher proportion of rural family medicine practices than are represented across the general workforce (P < .0001). We await more comprehensive data releases to fully understand enrollment to this important initiative. PMID- 30413554 TI - Re: Doctor-Patient Trust Among Chronic Pain Patients on Chronic Opioid Therapy after Opioid Risk Reduction Initiatives: A Survey. PMID- 30413555 TI - Author Index to Volume 31, 2018. PMID- 30413557 TI - Taking the blame: appropriate responses to medical error. AB - Medical errors are all too common. Ever since a report issued by the Institute of Medicine raised awareness of this unfortunate reality, an emerging theme has gained prominence in the literature on medical error. Fears of blame and punishment, it is often claimed, allow errors to remain undisclosed. Accordingly, modern healthcare must shift away from blame towards a culture of safety in order to effectively reduce the occurrence of error. Against this shift, I argue that it would serve the medical community well to retain notions of individual responsibility and blame in healthcare settings. In particular, expressions of moral emotions-such as guilt, regret and remorse-appear to play an important role in the process of disclosing harmful errors to patients and families. While such self-blaming responses can have negative psychological effects on the individual practitioner, those who take the blame are in the best position to offer apologies and show that mistakes are being taken seriously, thereby allowing harmed patients and families to move forward in the wake of medical error. PMID- 30413558 TI - Improving Emergency Department Care for Pediatric Victims of Sexual Abuse. AB - BACKGROUND AND OBJECTIVE: Evidence-based medical care of sexual abuse victims who present to the pediatric emergency department (PED) is necessary to facilitate forensic evidence collection and prevent pregnancy and sexually transmitted infections. Adherence to testing and treatment guidelines remains low in PEDs, despite recommendations from the American Academy of Pediatrics and Centers for Disease Control and Prevention. We aimed to increase the proportion of patient encounters at a PED for reported sexual abuse that receive algorithm-adherent care from 57% to 90% within 12 months. METHODS: Our team of PED and child abuse pediatricians outlined our theory for improvement, and multiple plan-do-study-act cycles were conducted to test interventions that were aimed at key drivers. Interventions included the construction of a best practice algorithm derived from published guidelines, targeted clinician education, and integration of an electronic order set. Our primary outcome was the proportion of patient encounters in which care adhered to algorithm recommendations. Data were abstracted from the records of all patient encounters evaluated in the PED for reported sexual abuse. RESULTS: We analyzed 657 visits between July 2015 and January 2018. The proportion of patient encounters with algorithm-adherent care improved from 57% to 87% during the study period. This improvement has been sustained for 13 months. Failure to test for hepatitis and syphilis constituted the majority of nonadherent care. CONCLUSIONS: Using improvement methodology, we successfully increased algorithm-adherent evaluation and management of patients presenting for sexual abuse. Targeted education and an electronic order set were associated with improved adherence to a novel care algorithm. PMID- 30413559 TI - Online Family Problem-solving Treatment for Pediatric Traumatic Brain Injury. AB - BACKGROUND AND OBJECTIVES: To determine whether online family problem-solving treatment (OFPST) is more effective in improving behavioral outcomes after pediatric traumatic brain injury with increasing time since injury. METHODS: This was an individual participant data meta-analysis of outcome data from 5 randomized controlled trials of OFPST conducted between 2003 and 2016. We included 359 children ages 5 to 18 years who were hospitalized for moderate-to severe traumatic brain injury 1 to 24 months earlier. Outcomes, assessed pre- and posttreatment, included parent-reported measures of externalizing, internalizing, and executive function behaviors and social competence. RESULTS: Participants included 231 boys and 128 girls with an average age at injury of 13.6 years. Time since injury and age at injury moderated OFPST efficacy. For earlier ages and short time since injury, control participants demonstrated better externalizing problem scores than those receiving OFPST (Cohen's d = 0.44; P = .008; n = 295), whereas at older ages and longer time since injury, children receiving OFPST had better scores (Cohen's d = -0.60; P = .002). Children receiving OFPST were rated as having better executive functioning relative to control participants at a later age at injury, with greater effects seen at longer (Cohen's d = -0.66; P = .009; n = 298) than shorter (Cohen's d = -0. 28; P = .028) time since injury. CONCLUSIONS: OFPST may be more beneficial for older children and when begun after the initial months postinjury. With these findings, we shed light on the optimal application of family problem-solving treatments within the first 2 years after injury. PMID- 30413561 TI - Novel initiator caspase reporters uncover previously unknown features of caspase activating cells. AB - The caspase-mediated regulation of many cellular processes, including apoptosis, justifies the substantial interest in understanding all of the biological features of these enzymes. To complement functional assays, it is crucial to identify caspase-activating cells in live tissues. Our work describes novel initiator caspase reporters that, for the first time, provide direct information concerning the initial steps of the caspase activation cascade in Drosophila tissues. One of our caspase sensors capitalises on the rapid subcellular localisation change of a fluorescent marker to uncover novel cellular apoptotic events relating to the actin-mediated positioning of the nucleus before cell delamination. The other construct benefits from caspase-induced nuclear translocation of a QF transcription factor. This feature enables the genetic manipulation of caspase-activating cells and reveals the spatiotemporal patterns of initiator caspase activity. Collectively, our sensors offer experimental opportunities not available by using previous reporters and have proven useful to illuminate previously unknown aspects of caspase-dependent processes in apoptotic and non-apoptotic cellular scenarios. PMID- 30413560 TI - The regulation of the homeostasis and regeneration of peripheral nerve is distinct from the CNS and independent of a stem cell population. AB - Peripheral nerves are highly regenerative in contrast to the poor regenerative capabilities of the CNS. Here we show that adult peripheral nerve is a more quiescent tissue than the CNS, yet all cell-types within a peripheral nerve proliferate efficiently following injury. Moreover, whereas oligodendrocytes are produced throughout life from a precursor pool, we find that the corresponding cell of the PNS, the myelinating Schwann cell (mSC) does not turnover in the adult. However, following injury, all mSCs can dedifferentiate to the proliferating progenitor-like SCs that orchestrate the regenerative response. Lineage analysis shows these newly-migratory, progenitor-like cells redifferentiate to form new tissue at the injury site, maintain their lineage but can switch to become a non-myelinating SC. In contrast, increased plasticity is observed during tumourigenesis. These findings show that peripheral nerves have a distinct mechanism for maintaining homeostasis and can regenerate without the need for an additional stem cell population. PMID- 30413562 TI - Proteomic Analysis of Baboon Cerebral Artery Reveals Potential Pathways of Damage by Prenatal Alcohol Exposure. AB - Alcohol is one of the most widely misused substances in the world. Alcohol consumption by pregnant women often results in an array of fetal developmental abnormalities, but the damage to the fetus by alcohol remains poorly understood. The limited knowledge regarding the molecular targets of alcohol in the developing fetus constitutes one of the major obstacles in developing effective pharmacological interventions that could prevent fetal damage after alcohol consumption by pregnant women. The fetal cerebral artery is emerging as an important mediator of fetal cerebral damage by maternal alcohol drinking. In the present work, we conduct proteomics analysis of cerebral (basilar) artery lysates of near-term fetal baboons to search for protein targets of fetal alcohol exposure. Our study demonstrates that 3 episodes of binge alcohol exposure during the second trimester-equivalent of human pregnancy are sufficient to render profound changes in fetal cerebral artery proteome. These changes were long lasting, as they were detected in near-term fetuses. In particular, the relative abundance of 238 proteins differed significantly between control and alcohol exposed fetuses. Enrichment analysis pointed at the group of metabolic activity proteins as a major class targeted by alcohol. Western blotting confirmed upregulation of the aldehyde dehydrogenase 6 family member A1 (ALDH6A1) in cerebral artery lysates from alcohol-exposed fetuses. This upregulation translated to greater ALDH activity of cerebral artery lysate of near-term fetuses following prenatal alcohol exposure when compared to controls. PMID- 30413563 TI - Restricting tobacco sales to only pharmacies combined with cessation advice: a modelling study of the future smoking prevalence, health and cost impacts. AB - OBJECTIVE: Restricting tobacco sales to pharmacies only, including the provision of cessation advice, has been suggested as a potential measure to hasten progress towards the tobacco endgame. We aimed to quantify the impacts of this hypothetical intervention package on future smoking prevalence, population health and health system costs for a country with an endgame goal: New Zealand (NZ). METHODS: We used two peer-reviewed simulation models: 1) a dynamic population forecasting model for smoking prevalence and 2) a closed cohort multi-state life table model for future health gains and costs by sex, age and ethnicity. Greater costs due to increased travel distances to purchase tobacco were treated as an increase in the price of tobacco. Annual cessation rates were multiplied with the effect size for brief opportunistic cessation advice on sustained smoking abstinence. RESULTS: The intervention package was associated with a reduction in future smoking prevalence, such that by 2025 prevalence was 17.3%/6.8% for Maori (Indigenous)/non-Maori compared to 20.5%/8.1% projected under no intervention. The measure was furthermore estimated to accrue 41 700 discounted quality adjusted life-years (QALYs) (95% uncertainty interval (UI): 33 500 to 51 600) over the remainder of the 2011 NZ population's lives. Of these QALYs gained, 74% were due to the provision of cessation advice over and above the limiting of sales to pharmacies. CONCLUSIONS: This work provides modelling-level evidence that the package of restricting tobacco sales to only pharmacies combined with cessation advice in these settings can accelerate progress towards the tobacco endgame, and achieve large population health benefits and cost-savings. PMID- 30413564 TI - RBP-Maps enables robust generation of splicing regulatory maps. AB - Alternative splicing of pre-messenger RNA transcripts enables the generation of multiple protein isoforms from the same gene locus, providing a major source of protein diversity in mammalian genomes. RNA binding proteins (RBPs) bind to RNA to control splice site choice and define which exons are included in the resulting mature RNA transcript. However, depending on where the RBPs bind relative to splice sites, they can activate or repress splice site usage. To explore this position-specific regulation, in vivo binding sites identified by methods such as cross-linking immunoprecipitation (CLIP) are integrated with alternative splicing events identified by RNA-seq or microarray. Merging these datasets enables the generation of a 'splicing map', where CLIP signal relative to a merged meta-exon provides a simple summary of the position-specific effect of binding on splicing regulation. Here, we provide RBP-maps, a software tool to simplify generation of these maps and enable researchers to rapidly query regulatory patterns of an RBP of interest. Further, we discuss various alternative approaches to generate such splicing maps, focusing on how decisions in construction (such as the use of peak versus read density, or whole-reads versus only single-nucleotide candidate crosslink positions) can affect the interpretation of these maps using example eCLIP data from the 150 RBPs profiled by the ENCODE consortium. PMID- 30413566 TI - Fixing the leaky bucket is not rocket science. PMID- 30413565 TI - Roles of specific aminoglycoside-ribosome interactions in the inhibition of translation. AB - Aminoglycosides containing a 2-deoxystreptamine core (AGs) represent a large family of antibiotics that target the ribosome. These compounds promote miscoding, inhibit translocation, and inhibit ribosome recycling. AG binding to helix h44 of the small subunit induces rearrangement of A-site nucleotides (nt) A1492 and A1493, which promotes a key open-to-closed conformational change of the subunit and thereby increases miscoding. Mechanisms by which AGs inhibit translocation and recycling remain less clear. Structural studies have revealed a secondary AG binding site in H69 of the large subunit, and it has been proposed that interaction at this site is crucial for inhibition of translocation and recycling. Here, we analyze ribosomes with mutations targeting either or both AG binding sites. Assaying translocation, we find that ablation of the h44 site increases the IC50 values for AGs dramatically, while removal of the H69 site increases these values modestly. This suggests that AG-h44 interaction is primarily responsible for inhibition, with H69 playing a minor role. Assaying recycling, we find that mutation of h44 has no effect on AG inhibition, consistent with a primary role for AG-H69 interaction. Collectively, these findings help clarify the roles of the two AG binding sites in mechanisms of inhibition by these compounds. PMID- 30413568 TI - News section PDF. PMID- 30413567 TI - What drives job satisfaction in the profession? PMID- 30413569 TI - BVA and Vet Record launch new online careers hub. PMID- 30413570 TI - More details needed on telemedicine trial. PMID- 30413571 TI - Owners urged to visit vet pre-Brexit. PMID- 30413574 TI - Export certificates to be signed by non-vets. PMID- 30413572 TI - New Roslin centre for animal health opens. PMID- 30413575 TI - Trial for lay TB testers will go ahead, says Defra. PMID- 30413577 TI - Protecting pigs against pandemic flu. PMID- 30413576 TI - Wildebeest and their muscle efficiency. AB - New research looks into how wildebeest manage travelling long distances in the searing heat. Georgina Mills reports. PMID- 30413578 TI - Data-driven dairy aims to maximise precision. PMID- 30413579 TI - Remembering the fallen. AB - This month marks the centenary of the end of the First World War. Here, Bruce Vivash Jones reflects on the War's impact on vets and war horses. PMID- 30413580 TI - Dog fighting: a role for veterinary professionals in tackling a harmful and illegal practice. PMID- 30413581 TI - Selected highlights from other journals. PMID- 30413582 TI - Mycobacterium in pets. PMID- 30413583 TI - Keeping snakes. PMID- 30413584 TI - Keeping snakes. PMID- 30413585 TI - Keeping snakes. PMID- 30413586 TI - Effectiveness of badger culls. PMID- 30413587 TI - Death notice. PMID- 30413588 TI - Offering better equine dentistry services. AB - Horse owner Anna Bowen describes why she uses a vet rather than an equine dentist for her horse's teeth. PMID- 30413590 TI - Sporting Achievement. PMID- 30413589 TI - Flying high in the poultry sector. AB - As a vet student, Kenny Nutting became hooked on working with poultry during his first week's EMS with St David's Poultry Team. Five years later, he is now on the board of directors of the practice. PMID- 30413591 TI - New Distance Learning Small Animal Medicine Programme. PMID- 30413592 TI - The influence of minimal misalignment on the repeatability of PET images examined by the repositioning of point sources. AB - Objective: We aimed to evaluate the influence of the minimal misalignment of the hot spot on the repeatability of PET images using the repositioning of point sources. Methods: Point sources with an inner-diameter of 1 mm were made with 1MUL of 18F solution. Seven point sources were placed on the x-axis in the field of-view. For fixed position imaging, PET data were acquired for 10 min 5 times serially. For variable position imaging, PET data were acquired for 10 minutes each with the point sources placed at 0 mm, +/-0.5 mm, and +/-1.0 mm in the x axis direction. The data were reconstructed using ordered-subsets expectation maximization (OSEM) and OSEM with point-spread function (OSEM+PSF) algorithms. The image matrix was 128*128, 200*200, 256*256, 400*400, and 512*512 pixels. The normalized maximum count (rMax), the variation of rMax (CVmax) and full width at half maximum (FWHM) were analyzed. Results: The hot spots on OSEM images far from the center became faint and broad, while those on the OSEM+PSF images became small and dense. Although the rMax was overestimated at the 5cm position on OSEM image, those at other positions were overestimated on OSEM+PSF images with a matrix size of >=256*256. The rMax showed a similar pattern in fixed and variable position images. The CVmax in fixed position OSEM images were <2%, irrespective of the matrix size. In contrast, the CVmax in variable position images were higher in comparison to fixed position images. The CVmax of the OSEM+PSF images were higher in comparison to OSEM images. The FWHM increased at positions far from the center on OSEM image, while that was stable at all positions on OSEM+PSF images. Conclusion: The repeatability of the small hot spot was affected by the minimal misalignment, especially on the OSEM+PSF images. Precise positioning is necessary if PET is to be used as a biomarker. Professions should recognize that the PSF correction deteriorates the repeatability of the small hot spot although it improves the spatial resolution of PET images. PMID- 30413593 TI - Assessing F-18 FDG uptake in the sentinel lymph node in breast cancer. AB - Objective: Fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) has limited value in early breast cancer. Sentinel lymph node (SLN) biopsy is the current procedure of choice to search for small metastatic deposits in the axillary lymph nodes in early breast cancer. In this retrospective study, we re-evaluated 18F-FDG PET/CT images after locating SLN(s) on PET/CT with the help of SLN single photon emission computed tomography/computed tomography (SPECT/CT) images and assessed 18F-FDG uptake particularly in the SLN(s). Our goal was to understand if combined evaluation of 18F-FDG PET/CT and SLN SPECT/CT could be a useful technique for detecting early lymph node metastasis in the axilla. Patients and Methods: 18F-FDG PET/CT images of newly diagnosed breast cancer patients who also had SLN scintigraphy (SPECT/CT) and biopsy result were analyzed to assess 18F-FDG uptake in the SLN(s). SLN(s) seen on SPECT/CT images were located on PET/CT images and its metabolic activity was assessed both visually and semiquantitaively using maximum standardized uptake value (SUVmax). 18F-FDG PET results were compared with histopathology result of SLN(s). Results: Twenty (20) patients among 130 met the inclusion criteria. SLN SPECT/CT images were very helpful for locating the SLN on 18F-FDG PET/CT images in all 20 patients. Histopathological analysis of SLN(s) demonstrated metastasis in 7 patients and no metastasis in 13. There was mild (visible) 18F-FDG uptake in the SLN(s) (SUVmax ranging from 1.2 to 4.1 and metastatic deposit size ranging from 6 to 8 mm) in 6 of 7 patients with SLN metastasis (85.7%). There was no or only faint 18F-FDG uptake in the SLN(s) (SUVmax less than 1) in 9 of 13 patients with no SLN metastasis (69.2%). ROC analysis indicated that cut-off point of SUVmax was 0.85 for differentiating SLN positive and SLN negative cases (sensitivity: 85.7% and specificity: 61.5 %, area under the curve: 0.747, P < 0.05). Conclusion: Combined evaluation of 18F-FDG PET/CT and SLN SPECT/CT images to assess 18F-FDG uptake particularly in the SLN(s) is a new image analysis technique to detect early metastatic disease in the axillary lymph nodes in breast cancer. Although, this technique does not seem to be feasible to use in routine practice mainly due to limitations of current PET/CT technology in detecting small amount of tumor, it is an interesting image analysis technique to know for possible future use. PMID- 30413594 TI - Encouraging Lifelong Learning: An Educator's Perspective on Teaching and Learning for the Nuclear Medicine Technologist. AB - The rapid influx of new technology and changing reimbursement and healthcare business models challenge nuclear medicine technology (NMT) educators to reexamine the effectiveness of traditional teaching methods. As a generation of technologists can attest, the skill sets and competencies taught today will not be the requirements of tomorrow. The question arises, "how can educators prepare students and the profession for future knowledge capacity?" The concept of lifelong learning (LLL) emerged in the 1970s as a response to the global paradigm shift from an industrial society to a knowledge society. Given the current healthcare climate and the dynamic nature of the NMT profession, the understanding and development of LLL assessment models may benefit both teacher and student learning. The article discusses the theoretical framework of LLL and social learning along with a sampling of teaching assessments. These assessments employ a problem-based-learning (PBL) approach that integrates the concepts of LLL into an accountability driven social organization. PMID- 30413595 TI - Accreditation and Assessment: The Basics for Nuclear Medicine Educators. AB - This article presents a high-level overview of accreditation and assessment in higher education.It is designed to provide nuclear medicine technology (NMT) educators with a foundational knowledge of accreditation and assessment. This foundation will help educators understand accreditation and assessment at the college/university and program levels by discussing key terminology and exploring the concept of a culture of assessment. PMID- 30413596 TI - Integrative leadership and its use in providing excellent patient care while overcoming hospital challenges. AB - Effective leadership in the healthcare setting is vital for delivering effective and efficient patient care while meeting organizational and departmental challenges. Hospitals face unique obstacles relating to regulation and accreditation, process inefficiencies, aging or difficult to treat patients, allocation of resources, and patient satisfaction. This article describes the characteristics of a leader, integrative leadership in the healthcare setting, and provides suggestions to engage coworkers in solving complex healthcare problems. PMID- 30413597 TI - In patients we trust. Reliability of self-reported weight and size in patients attending a nuclear medicine department. AB - Purpose: The aim of the study was to assess the reliability of self-reported weight and size of nuclear medicine patients in view of recommendation for the weight-dependent tracer application for imaging and therapy. Methods: A total of 824 patients (334m, 490f) were asked to report their weight and size prior imaging or therapy and their level of confidence. Subsequently, weight and size of each patient was measured and body mass index (BMI), body surface area (BSA) and lean body mass (LBM) were calculated. Differences between reported and true values were compared for statistically significant differences. Results: The average patient age was (60+/-14) years ((17-91) years). An over-or underestimation of weight of >=10% was observed in 3% of patients, size was overestimated by 1% by the patients. The BMI-calculation was affected by incorrect self-reported values. Conclusion: Most self-reported weights and sizes of nuclear medicine patients are accurate. However since over- and underestimation of weight and size leads to incorrect BMI, BSA and LBM values patient weights should be measured at least for patients receiving a weight adapted therapy or if quantification in PET/CT is needed. PMID- 30413598 TI - Technologist Approach to Global Dose Optimization. AB - Nuclear Medicine Technologists (NMTs) are specialized health professionals that cover a wide range of tasks from clinical routine (including image acquisition and processing, radiopharmaceutical dispensing and administration, patient care and radioprotection tasks) to leading clinical research in the field of Nuclear Medicine. As a fundamental concern in all radiation sciences applied to medicine, protection of individuals against the harmful effects of ionizing radiation must be constantly revised and applied by the professionals involved in medical exposures. The acknowledgement that NMTs play a prominent role in patient management and a number of procedural steps both in diagnostic and therapeutic nuclear medicine applications, carries the duty to be trained and knowledgeable on the topic of radiation protection and dose optimization. An overview on selected topics related to dose optimization is presented on this article, reflecting the similarities and particularities of dose reduction related principles, initiatives and practicalities from a global perspective. PMID- 30413599 TI - Comparison of Radioiodine uptake by Gamma Camera and Thyroid uptake probe-based methodologies and Diagnostic Radioiodine Scan in Differentiated thyroid carcinoma. AB - Aims and Objectives: The objective of the study was to make a quantitative comparison of 72-hrs neck uptake calculated by gamma camera-based and thyroid uptake probe-based methods after administration of low-dose (111-148 MBq) of 131I capsule in thyroid carcinoma follow-up patients who have already been treated with 131I. Methods: The study group consists of 46 patients, of whom 14 were male (average 47.5 yrs) and 32 were female (average 38 yrs). All patients already had undergone thyroidectomy followed by 131I treatment at least once and came to the institute after 6 months for follow-up. As per the institutional protocol the patients had their 131I neck uptake and whole-body scan at 72 hours, the uptake value evaluated by both uptake probe and camera-based method using medium-energy parallel-hole collimator. Result: Amongst a total of 46 patients, (i) neck uptake was negative in 24 patients by both probe-based (0.1% as cut-off as per institutional protocol) and camera-based methodologies and the scan, (ii) while positive in 10 patients by both the methods which was supported by scan finding.(iii) In further 10 cases thyroid uptake by probe-based uptake method showed (with 0.1% as cut-off) positive while camera-based uptake and scan finding were negative. In most of these cases scatter radiation contribution due to high non-target counts were found to be high. (iv) In two patients, thyroid uptake by probe-based method showed<0.1% where camera-based neck uptake and scan finding were positive for neck uptake. Thus, in 34 out of 46 patients (74%), both methods were found concordant, while in 12 out of 46 patients (26%), the uptakes were discordant with 0.1 % as the cut-off for probe-based uptake. Based upon the exploratory analysis of the results obtained, we propose camera-based neck uptake of 0.03% to be the cut-off for positive neck uptake. In the subgroup of patients with negative scan and systemic metastases in the vicinity of neck (n = 7), an uptake cutoff of 0.1% resulted in positive results in 85.7%. All patients had true negative results with camera-based cut-off of 0.03%. Based upon the analysis of these discordant results (between probe-based uptake method and scan), we further proposethe cut-off for positivity of the 131I uptake value by thyroid uptake probe-based method to be considered as 0.2% rather than 0.1% in orderto reduce false positivity with appropriate correlation with scan findings. Conclusion:Thus, in patients of thyroid carcinoma, camera-based uptake during 131I LDS canalso be reliableas conventional thyroid uptake probe-based method and can be used as a substitutein evaluating neck uptake calculation in patients with functioning metastases in the vicinity of neck or non-specific high physiological accumulation. PMID- 30413600 TI - Radiation Safety Certification: A Review. AB - It has become common for nuclear medicine technologists to assume the responsibilities, or even the role, of the radiation safety officer or associate radiation safety officer. Their responsibilities are primarily related to the radioactive materials license but increasingly can include additional safety responsibilities within the hospital. These include CT, MRI, and fluoroscopy safety. Many technologists reading this article may be interested in sitting for the radiation safety advanced certification examination by the Nuclear Medicine Technology Certification Board. A consultation of the content outline for that examination (found on the Nuclear Medicine Technology Certification Board website) is a good place to start. The content outline is quite extensive and cannot be covered within a single article. PMID- 30413601 TI - An Evaluation of Qualities of Nuclear Medicine Technology Programs and Graduates Leading to Employability. AB - Rationale: To evaluate the association between qualities of nuclear medicine technology (NMT) programs and graduates, and employability. Methods: We identified all NMT certification board applicants who passed the entry level NMT exam between 2012 and 2017. Certificants were e-mailed a survey with questions regarding graduate qualities, program qualities, and initial employment. Each quality was quantified. Age, gender, and desired employment within or outside the USA were also documented. An employability scale was created from the initial employment questions. Subjects were separated into four employability groups based on their employability score: poorly employable, marginally employable, satisfactorily employable, and optimally employable. An ANOVA test was performed on each quality using the four employability groups; a p-value less than 0.05 was considered significant. Results: 3,930 surveys were distributed; 884 certificants (22.5%) returned completed surveys. Six of the 10 qualities evaluated were significantly associated with employability: overall education (p<0.01), number of clinic hours (p<0.01), grade-point average (p<0.01), number of schools in a 100-mile radius (p<0.01),number of board attempts (p<0.01), and number of clinics (P = 0.04). The qualities that were not statistically significant were age, gender, employment location sought, board score, single vs. dual certification, program level of education, and number of graduates in the class. Conclusion: There are multiple graduate and program qualities which are predictive of employability of NMT graduates. PMID- 30413602 TI - Improving the spatial alignment in PET/CT using amplitude-based respiratory-gated PET and patient-specific breathing-instructed CT. AB - Appropriate attenuation correction is important for accurate quantification of standardized uptake values (SUVs) in positron emission tomography (PET). Patient respiratory motion can introduce a spatial mismatch between respiratory-gated PET and computed tomography (CT), reducing quantitative accuracy. In this study, the effect of a patient-specific breathing-instructed CT protocol on the spatial alignment between CT and amplitude-based optimal respiratory-gated PET images was investigated. Methods: 18F-fluorodeoxyglucose (FDG) PET/CT imaging was performed in 20 patients. In addition to the standard low-dose (LD) free-breathing CT, a breath-hold CT was acquired. The amplitude limits of the respiratory-gated PET were used to instruct patients to hold their breath during CT acquisition at a similar amplitude level. Spatial mismatch was quantified using the position differences between the lung-liver transition in PET and CT images, the distance between PET and CT lesions' centroids, and the amount of overlap as indicated by the Jaccard similarity coefficient (JSC). Furthermore, the effect on attenuation correction was quantified by measuring SUVs, metabolic tumor volume (MTVs) and total lesion glycolysis (TLGs) of lung lesions. Results: All patients found the breathing instructions feasible, however 4 patients had trouble complying to the instructions. In total, 18 patients were included. The average distance between the lung-liver transition between PET and CT was significantly reduced for breath hold CT (1.7+/-2.1 mm), compared to standard CT (5.6+/-7.3 mm) (P = 0.049). Furthermore, the mean distance between the lesions' centroids on PET and CT was significantly smaller when comparing breath-hold CT (3.6+/-2.0 mm) to standard CT (5.5+/-6.5 mm) (P = 0.040). Quantification of lung lesion SUV was significantly affected, with a higher SUVmean when breath-hold CT (6.3+/-3.9 g/cm3) is used for image reconstruction, compared to standard CT (6.1+/-3.8 g/cm3) (P = 0.044). Though MTV was not significantly different, TLG reached statistical significance. Conclusion: Optimal respiratory-gated PET in combination with patient-specific breathing-instructed CT results in an improved alignment between PET and CT images and shows an increased SUVmean and TLG. Even though the effects are small, a more accurate SUV and TLG determination is an important step towards a more stable PET quantification, which is relevant for radiotherapy planning and therapy response monitoring. PMID- 30413603 TI - Biodistribution and Dosimetry of Indigenous 131I-Rituximab in B-Cell Lymphoma: Pilot Study estimating patient specific dose comparing two different dosimetric methods. AB - BACKGROUND: Cost-containment through indigenous development and production and its subsequent examination in clinical settings would be a pivotal step for bringing radioimmunotherapy (RIT) agents to more widespread clinical practice in non-Hodgkin's lymphoma (NHL) patients, especially in developing countries. AIMS and OBJECTIVES: To examine the biodistribution and dosimetry of indigenously developed and radiolabeled 131I-Rituximab, using the monoclonal antibody of chimeric origin, in patients of B cell lymphoma for its potential use in RIT. MATERIALS and METHODS: This was a prospective study involving patients of B-cell NHL who underwent low dose diagnostic scan for the dosimetric and biodistribution studies. The study was presented and approved by the Institutional Scientific and Medical Ethics Committee and the product was approved by the regulatory body of DAE (Department of Atomic Energy) India, the Radiopharmaceutical Committee (RPC), for preliminary dosimetric studies. Patients with documented CD20 (Cluster Differentiation) positive NHL who were planned for and received Rituximab based chemotherapy under medical oncology supervision were recruited. Soon after the IV (Intravenous) Rituximab infusion (4-6 hrs), the small diagnostic dose of indigenously produced radioiodinated rituximab was administered by intravenous infusion. Serial planar (anterior and posterior) whole body gamma camera images were undertaken soon after the infusion (pre-void and post void) and thereafter on day 1, day 2, day 4 and day 6. All imaging were performed in Siemens Symbia dual head gamma camera equipped with 1.0 cm NaI (Tl) crystals and high-energy collimators. A 15 % energy window around 364 KeV, the dominant gamma-ray energy of 131I was applied. During each whole body gamma-scintigraphy, a source of 131I with known activity was used as the reference standard required for dosimetry calculations. RESULTS: A total of 13 patients have undergone assessment in this prospective study following the aforementioned study protocol. The calculated patient specific administered dose from the cumulative activity, that will give a whole-body radiation absorbed dose of 75cGy, using the MIRD (Medical Internal Radiation Dose) schema, ranged from 3095.42 to 6330.33 MBq(83.66 to 171.09 mCi), mean 3986.01+/-863.95 MBq(107.73+/-23.35 mCi) and median 3697.41 MBq(99.93 mCi). The mean residence time of this indigenous radiopharmaceutical was 69.54h. Within first 48 hours (2nd day) >=50% of the injected activity was cleared and by 144 hours (6th day) >=80% of the injected activity was cleared from the body in all patients. The patient-specific administered dose that would give a whole-body radiation absorbed dose of 75cGy, calculated by mean residence time and activity hours ranged from 2654.75 to 6210.45 MBq (71.75to 167.85 mCi) mean 3576.42+/ 927.59 MBq(96.66+/-25.07 mCi) and median 3421.02 MBq (92.46 mCi). With respect to organ-specific dosimetry, apart from blood pool (3.77Gy) and spleen (4.02Gy), the organs with decreasing order of mean radiation absorbed dose were lung (0.97Gy), liver (0.69Gy) and kidneys (0.7Gy) calculated for proposed therapeutic doses of the product. CONCLUSION: The indigenous product demonstrated kinetics similar in lines with that of approved commercially available radiopharmaceuticals, with advantage of less HAMA (Human Anti Mouse Antibody) response due to the pharmaceutical being a chimeric antibody rather than murine antibody and hence could be safely administered in clinical settings. In none of the organs there was dose limiting radiation exposure (>= 20Gy) at the proposed therapeutic doses of this indigenous 131I labeled rituximab product. PMID- 30413604 TI - Association between SCN1A Polymorphism rs3812718 and Valproic Acid Resistance in Epilepsy Children: A Case Control Study and Meta-analysis. AB - Resistance to valproic acid (VPA), a first-line antiepileptic drug (AED), is occurring at an alarming rate, particularly in children. Signal nucleotide polymorphisms are considered crucial in this process. Therefore, we investigated whether the SCN1A polymorphism rs3812718 could be associated with VPA resistance. A total of 231 children with epilepsy who were solely administered VPA were enrolled. DNA was extracted from the peripheral blood samples and was genotyped by the Mass Array method. Furthermore, a meta-analysis was conducted between the drug responsive and resistant patients who were exposed to voltage-gated sodium channels. Results revealed that the TT genotype was associated with a higher risk of developing drug resistance (OR = 2.636, 95% CI 1.08-6.433, P = 0.033). After adjusting for the risk factors, a significant difference was still observed between the responsive and resistant groups (OR = 2.861, 95% CI 1.141-7.174, P = 0.025). Moreover, the recessive model was associated with a decreased drug resistance (OR = 0.402, 95% CI 0.167-0.968, P = 0.042) after correcting the risk factors. Meta-analysis of nine studies revealed similar results. In conclusion, our results proved that the rs3812718 TT genotype was associated with a high risk of developing drug resistance, and the recessive model could decrease the risk of VPA resistance. PMID- 30413605 TI - Upregulated and interrelated expressions of GINS subunits predict poor prognosis in hepatocellular carcinoma. AB - The GINS complex is one of the core components of the eukaryotic replicative helicase CMG (Cdc45-MCM helicase-GINS) complex that serves as the replicative helicase unwinding duplex DNA ahead of moving replication fork during chromosome duplication. Many studies have highlighted the important functions among GINS subunits in various cancers. Nevertheless, the functions and prognostic roles of distinct GINS subunits in hepatocellular carcinoma (HCC) were largely unexplored. In this study, we reported the prognostic values of GINS subunits in HCC patients through analysis of several databases, including Oncomine, TCGA and Kaplan-Meier Plotter. We found that mRNA expressions of all GINS subunits were significantly upregulated in HCC tumor than in non-tumor liver tissues. Survival analysis revealed that elevated expression of individual GINS subunit predicts a poor overall survival (OS) in all HCC patients. When sorting the patients by gender, the correlation between elevated expression of individual GINS subunit and poor OS remains significant in male patient subgroup, but not in female patient subgroup. Additionally, we found that co-overexpression of all GINS subunits was significantly associated with a higher hazard ratio, suggesting the GINS complex may cooperate to promote HCC progression. Indeed, their expressions were highly correlated with each other in the same cohort and TRANSFAC analysis revealed that four transcription factors including C/EBPalpha, Oct-1, Sp1 and USF may serve as common transcription factors binding to the promoters of all four GINS subunits. Therefore, we propose that individual GINS subunit or GINS complex as a whole could be potential prognostic biomarkers for HCC. PMID- 30413606 TI - Functional annotation of extensively and divergently expressed miRNAs in suprachiasmatic nucleus of Clock ?19 mutant mice. AB - Circadian locomotor output cycles kaput protein (CLOCK) is a core transcription factor of complex integrated feedback loops in mammalian circadian clock. More genes have been reported to be regulated by CLOCK, however little is known about the role of CLOCK-mediated miRNAs. To dissect this, we used microarray analysis to measure miRNAs expression in suprachiasmatic nuclei (SCN) of wild type (WT) and Clock Delta19 mutant mice at two different time points. We found that miRNAs regulation in two time points was extensive (nearly 75% of the miRNAs expressed at each time point), and very little overlap, with only 6 miRNAs in common. Besides this, the predicted CLOCK regulated miRNAs at two time points participated in extremely diverse pathways. We validated nine miRNAs (miR-125a 3p, miR-144, miR-199a-5p, miR-199b*, miR-200a, miR-200b, miR-203, miR-449a and miR-96), which were involved in the same signaling pathway-hippo signaling pathway. The rhythms of these miRNAs showed a broad distribution of phase, amplitude and waveform in Clock mutation. And further analysis indicated that there may be three models of miRNAs-mediated circadian rhythms and hippo signaling pathway. MiRNAs, the small player, may play a hub role in connecting circadian rhythms and other pathways via its multiple target genes networks. PMID- 30413607 TI - An updated association between TNF-alpha -238G/A polymorphism and gastric cancer susceptibility in East Asians. AB - Polymorphisms in the tumor necrosis factor alpha (TNF-?C;) gene are emerging as key determinants of gastric diseases. The TNF-alpha-238G/A single-nucleotide polymorphism is the most extensively studied. However, this association is inconsistent among different populations. We therefore conducted an updated meta analysis to obtain a more precise estimate of the association of TNF-alpha-238G/A polymorphism with gastric cancer (GC) risk. A comprehensive search of PubMed, Embase, Chinese (CNKI and WanFang) databases was performed to identify relevant studies through May 5, 2018. Odds ratio (OR) and 95% confidence interval (CI) were used to assess the strength of the association. Fourteen studies were included in our meta-analysis involving 2,999 cases and 4,685 controls. There was no significant association between TNF-alpha -238G/A polymorphism and GC risk in the overall populations. In the subgroup analysis, we found that TNF-alpha 238G/A polymorphism was associated with the increased risk of GC among Asians, especially in Chinese, but not in Caucasians. Subgroup analysis by genotyping methods revealed increased risk for other methods. In conclusion, our present meta-analysis shows that TNF-alpha -238G/A polymorphism is associated with the risk of GC in East Asian individuals. PMID- 30413608 TI - An efficient method for FITC-labelling of proteins using tandem affinity purification. AB - Fluorescence-based assays are extremely diverse, sensitive and robust experimental methods for investigating the conformational changes, enzyme kinetics, dynamics and molecular interactions. A prerequisite for most of these experimental approaches is to label the protein of interest with one or more extrinsic fluorophores with desired photophysical properties. Fluorescein isothiocyanate (FITC), due to its high quantum efficiency and conjugate stability is most widely used fluorescence labelling reagent for such experimental approaches. However, the bottlenecks in this labelling reaction is requirement of high protein concentration, maintenance of protein stability during the labelling process as well as high background fluorescence due to ineffective removal of unreacted FITC, prior to fluorescence studies. Therefore, to overcome these inadequacies or limitations, we have modified the existing protocol by introducing tandem affinity purification (TAP) tags at the N- and C-termini of the target protein. Using this modified method, we have efficiently labelled target protein with significant decrease in precipitation, degradation and background fluorescence of unreacted FITC. This facile and rapid technique may also be used as a basis for labelling procedures with other fluorophores and hence has a broad application in spectroscopic studies. PMID- 30413609 TI - NDRG3 overexpression is associated with a poor prognosis in patients with hepatocellular carcinoma. AB - N-myc downstream-regulated gene 3 (NDRG3), an important member of the NDRG family, is involved in cell proliferation, differentiation, and other biological processes. This study analyzed NDRG3 expression in hepatocellular carcinoma (HCC) and explored the relationship between expression of NDRG3 in HCC patients and their clinicopathological characteristics. We performed quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) analysis and immunohistochemistry (IHC) analyses on HCC tissues to elucidate NDRG3 expression characteristics in HCC patients. Kaplan-Meier survival curve and Cox regression analyses were used to evaluate the prognoses of 102 patients with HCC. The results revealed that compared with non-tumor tissues, HCC tissues showed significantly higher NDRG3 expression. In addition, our analyses showed that NDRG3 expression was statistically associated with tumor size (p=0.048) and pathological grade (p=0.001). Survival analysis and Kaplan-Meier curves revealed that NDRG3 expression is an independent prognostic indicator for disease-free survival (p=0.002) and overall survival (p=0.005) in HCC patients. The data indicate that NDRG3 expression may be considered as an oncogenic biomarker and a novel predictor for HCC prognosis. PMID- 30413610 TI - Association of genetic polymorphisms of SelS with Type 2 diabetes in a Chinese population. AB - Background: Selenoprotein S (SelS) gene expression is positively correlated to triglyceride (TG) concentrations and is associated with diabetes in animal model. However, the relationship between genetic polymorphisms of SelS and Type 2 diabetes (T2DM) remains unclear. Methods: In the present study, we genotyped four single nucleotide polymorphisms (rs12910524, rs1384565, rs2101171, rs4965814) of SelS gene using TaqMan genotyping method in a case-control study (1947 T2DM patients and 1639 control subjects). Results: We found both rs1384565 CC genotype (12.1 compared with 6.6%, P<0.001) and C allele (35.2 compared with 24.4%, P<0.001) were more frequent in the T2DM patients than in the controls. Logistic regression analysis suggested after adjustment of other confounders, the difference remained significant between the two groups (CC compared with TT, P=0.002, OR = 1.884, 95% CI: 1.263-2.811; CT compared with TT, P<0.001, OR = 1.764, 95% CI: 1.412-2.204). Conclusion: The present study suggested that genetic polymorphisms of SelS were associated with T2DM in a Chinese population. PMID- 30413611 TI - Resetting the ligand binding site of placental protein 13/galectin-13 recovers its ability to bind lactose. AB - Placental protein-13 / galectin-13 (Gal-13) is highly expressed in placenta, where its lower expression is related to pre-eclampsia. Recently, the crystal structures of wild type Gal-13 and its variant R53H at high resolution were solved. The crystallographic and biochemical results showed that Gal-13 and R53H could not bind lactose. Here, we used site-directed mutagenesis to re-engineer the ligand binding site of wild type Gal-13, so that it could bind lactose. Of six newly engineered mutants, we were able to solve the crystal structures of three of them (R53HH57R; R53HR55NH57R, and R53HR55NH57R). All of these variants had the same two mutations (R53 to H, and H57 to R) and were able to bind lactose in the crystal, indicating that these mutations were sufficient for recovering the ability of Gal-13 to bind lactose. Moreover, the structures of R53H and R53HR55N show that these variants could co-crystallize with a molecule of Tris. Surprisingly, although these variants, as well as wild type Gal-13, could all induce hemagglutination, high concentrations of lactose could not inhibit agglutination, nor could they bind to lactose-modified Sepharose 6b beads. Overall, our results indicate that Gal-3 is not a normal galectin, which could not bind to beta-galactosides. Lastly, the distribution of EGFP-tagged wild type Gal-13 and its variants in HeLa cells showed that they are concentrated in the nucleus and could be co-localized within filamentary materials, possibly actin. PMID- 30413612 TI - Enhanced transfection of a macromolecular lignin-based DNA complex with low cellular toxicity. AB - Cationic polymers remain attractive tools for non-viral gene transfer. The effectiveness of these vectors rely on the ability to deliver plasmid DNA (pDNA) into the nucleus of cells. While we have previously demonstrated the potential of Lignin-PGEA-PEGMA as a non-viral gene delivery vector, alterations of cellular phenotype and cytotoxicity were observed post transfection. The present study aims to explore transfection conditions for high efficiency and low toxicity of the Lignin-PGEA-PEGMA based gene delivery system. Cellular toxicity was significantly reduced by using the centrifugation protocol, which enables rapid deposition of DNA complexes. Replacement of media post centrifugation resulted in minimal exposure of cells to excess polymers, which were toxic to cells. At an optimized DNA amount (500-750 ng) and molar ratios of nitrogen (N) in polymer to phosphate (P) in pDNA (N/P = 30-40), with the use of a novel transfection enhancer that facilitates endosomal escape and nuclear trafficking, the efficiency of gene delivery was increased significantly 24 h post transfection. The present study demonstrated an appropriately optimized protocol that enabled the utility of a novel cationic polymer blend with a mixture of fusogenic lipids and a histone deacetylate inhibitor in non-viral transfection, thereby providing an attractive alternative to costly commercial gene carriers. PMID- 30413613 TI - Decreased microRNA-182-5p helps alendronate promote osteoblast proliferation and differentiation in osteoporosis via the Rap1/MAPK pathway. AB - Osteoporosis (OP) is a serious health problem that contributes to osteoporotic structural damage and bone fragility. MicroRNAs (miRNAs) can exert important functions over bone endocrinology. Therefore, it is of substantial significance to clarify the expression and function of miRNAs in bone endocrine physiology and pathology to improve the potential therapeutic value for metabolism-related bone diseases. We explored the effect of microRNA-182-5p (miR-182-5p) on osteoblast proliferation and differentiation in OP rats after alendronate (ALN) treatment by targeting ADCY6 through the Rap1/mitogen-activated protein kinase (MAPK) signaling pathway. Rat models of OP were established to observe the effect of ALN on OP, and the expression of miR-182-5p, ADCY6 and the Rap1/MAPK signaling pathway-related genes was determined. To determine the roles of miR-182-5p and ADCY6 in OP after ALN treatment, the relationship between miR-182 and ADCY6 was initially verified. Osteoblasts were subsequently extracted and transfected with a miR-182-5p inhibitor, miR-182-5p mimic, si-ADCY6 and the MAPK signaling pathway inhibitor U0126. Cell proliferation, apoptosis and differentiation were also determined. ALN treatment was able to ease the symptoms of OP. miR-182-5p negatively targeted ADCY6 to inhibit the Rap1/MAPK signaling pathway. Cells transfected with miR-182 inhibitor decreased the expression of ALP, BGP and COL I, which indicated that the downregulation of miR-182-5p promoted cell differentiation and cell proliferation and inhibited cell apoptosis. In conclusion, this study shows that downregulated miR-182-5p promotes the proliferation and differentiation of osteoblasts in OP rats through Rap1/MAPK signaling pathway activation by upregulating ADCY6, which may represent a novel target for OP treatment. PMID- 30413614 TI - Association between three genetic variants in kallikrein 3 and prostate cancer risk. AB - BACKGROUND: Epidemiological studies have assessed the association between kallikrein 3 (KLK3) polymorphisms and prostate cancer (PCa) susceptibility. However, published data on this association are somewhat inconclusive. METHODS: Articles investigating the association between three KLK3 (rs1058205, rs2735839, and rs266882) variants and PCa susceptibility were searched from online databases, which included 35,838 patients and 36,369 control participants. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to demonstrate the strength of the association. We also utilized ELISA to detect serum expression of KLK3. In addition, in silico tools were adopted to evaluate the relationship of KLK3 expression and PCa survival time. RESULTS: The overall results indicated that polymorphism T>C of rs1058205 was associated with decreased risk of PCa (allele contrast: OR = 0.75, 95% CI = 0.64-0.88, P heterogeneity < 0.001; homozygote comparison: OR = 0.58, 95% CI = 0.42-0.81, P heterogeneity < 0.001), particularly in Caucasian population (allele contrast: OR = 0.77, 95% CI = 0.65 0.91, P heterogeneity < 0.001; homozygote comparison: OR = 0.58, 95% CI = 0.41 0.82, P heterogeneity < 0.001). No association was observed between the polymorphism A>G of rs2735839 and risk of PCa. In addition, no association was observed between polymorphism A>G of rs266882 and risk of PCa. Serum KLK3 levels in PCa patients carrying CC/CT genotypes were statistically lower than those carrying TT genotypes. Conclusion: This meta-analysis suggests that rs1058205 polymorphism of KLK3 is a risk factor for PCa development, polymorphism T>C of rs1058205 is associated with decreased susceptibility to PCa particularly in Caucasian population. PMID- 30413615 TI - Themis-associated phosphatase activity controls signaling in T cell development. AB - Thymocyte-expressed molecule involved in selection (Themis) has been shown to be important for T cell selection by setting the threshold for positive versus negative selection. Themis interacts with the protein tyrosine phosphatase (PTP) Src-homology domain containing phosphatase-1 (Shp1), a negative regulator of the T cell receptor (TCR) signaling cascade. However, how Themis regulates Shp1 is still not clear. Here, using a very sensitive phosphatase assay on ex vivo thymocytes, we have found that Themis enhances Shp1 phosphatase activity by increasing its phosphorylation. This positive regulation of Shp1 activity by Themis is found in thymocytes, but not in peripheral T cells. Shp1 activity is modulated by different affinity peptide MHC ligand binding in thymocytes. Themis is also associated with phosphatase activity, due to its constitutive interaction with Shp1. In the absence of Shp1 in thymocytes, Themis interacts with Shp2, which leads to almost normal thymic development in Shp1 conditional knockout (cKO) mice. Double deletion of both Themis and Shp1 leads to a thymic phenotype similar to that of Themis KO. These findings demonstrate unequivocally that Themis positively regulates Shp1 phosphatase activity in TCR-mediated signaling in developing thymocytes. PMID- 30413616 TI - Golgi-localized LOT regulates trans-Golgi network biogenesis and pollen tube growth. AB - The trans-Golgi network (TGN) is an essential tubular-vesicular organelle derived from the Golgi and functions as an independent sorting and trafficking hub within the cell. However, the molecular regulation of TGN biogenesis remains enigmatic. Here we identified an Arabidopsis mutant loss of TGN (lot) that is defective in TGN formation and sterile due to impaired pollen tube growth in the style. The mutation leads to overstacking of the Golgi cisternae and significant reduction in the number of TGNs and vesicles surrounding the Golgi in pollen, which is corroborated by the dispersed cytosolic distribution of TGN-localized proteins. Consistently, deposition of extracellular pectin and plasma membrane localization of kinases and phosphoinositide species are also impaired. Subcellular localization analysis suggests that LOT is localized on the periphery of the Golgi cisternae, but the mutation does not affect the localization of Golgi resident proteins. Furthermore, the yeast complementation result suggests that LOT could functionally act as a component of the guanine nucleotide exchange factor (GEF) complex of small Rab GTPase Ypt6. Taken together, these findings suggest that LOT is a critical player for TGN biogenesis in the plant lineage. PMID- 30413617 TI - Genome-wide RNA structurome reprogramming by acute heat shock globally regulates mRNA abundance. AB - The heat shock response is crucial for organism survival in natural environments. RNA structure is known to influence numerous processes related to gene expression, but there have been few studies on the global RNA structurome as it prevails in vivo. Moreover, how heat shock rapidly affects RNA structure genome wide in living systems remains unknown. We report here in vivo heat-regulated RNA structuromes. We applied Structure-seq chemical [dimethyl sulfate (DMS)] structure probing to rice (Oryza sativa L.) seedlings with and without 10 min of 42 degrees C heat shock and obtained structural data on >14,000 mRNAs. We show that RNA secondary structure broadly regulates gene expression in response to heat shock in this essential crop species. Our results indicate significant heat induced elevation of DMS reactivity in the global transcriptome, revealing RNA unfolding over this biological temperature range. Our parallel Ribo-seq analysis provides no evidence for a correlation between RNA unfolding and heat-induced changes in translation, in contrast to the paradigm established in prokaryotes, wherein melting of RNA thermometers promotes translation. Instead, we find that heat-induced DMS reactivity increases correlate with significant decreases in transcript abundance, as quantified from an RNA-seq time course, indicating that mRNA unfolding promotes transcript degradation. The mechanistic basis for this outcome appears to be mRNA unfolding at both 5' and 3'-UTRs that facilitates access to the RNA degradation machinery. Our results thus reveal unexpected paradigms governing RNA structural changes and the eukaryotic RNA life cycle. PMID- 30413618 TI - Quantitative constraints on autoxidation and dimer formation from direct probing of monoterpene-derived peroxy radical chemistry. AB - Organic peroxy radicals (RO2) are key intermediates in the atmospheric degradation of organic matter and fuel combustion, but to date, few direct studies of specific RO2 in complex reaction systems exist, leading to large gaps in our understanding of their fate. We show, using direct, speciated measurements of a suite of RO2 and gas-phase dimers from O3-initiated oxidation of alpha pinene, that ~150 gaseous dimers (C16-20H24-34O4-13) are primarily formed through RO2 cross-reactions, with a typical rate constant of 0.75-2 * 10-12 cm3 molecule 1 s-1 and a lower-limit dimer formation branching ratio of 4%. These findings imply a gaseous dimer yield that varies strongly with nitric oxide (NO) concentrations, of at least 0.2-2.5% by mole (0.5-6.6% by mass) for conditions typical of forested regions with low to moderate anthropogenic influence (i.e., <=50-parts per trillion NO). Given their very low volatility, the gaseous C16-20 dimers provide a potentially important organic medium for initial particle formation, and alone can explain 5-60% of alpha-pinene secondary organic aerosol mass yields measured at atmospherically relevant particle mass loadings. The responses of RO2, dimers, and highly oxygenated multifunctional compounds (HOM) to reacted alpha-pinene concentration and NO imply that an average ~20% of primary alpha-pinene RO2 from OH reaction and 10% from ozonolysis autoxidize at 3 10 s-1 and >=1 s-1, respectively, confirming both oxidation pathways produce HOM efficiently, even at higher NO concentrations typical of urban areas. Thus, gas phase dimer formation and RO2 autoxidation are ubiquitous sources of low volatility organic compounds capable of driving atmospheric particle formation and growth. PMID- 30413619 TI - Simplicial closure and higher-order link prediction. AB - Networks provide a powerful formalism for modeling complex systems by using a model of pairwise interactions. But much of the structure within these systems involves interactions that take place among more than two nodes at once-for example, communication within a group rather than person to person, collaboration among a team rather than a pair of coauthors, or biological interaction between a set of molecules rather than just two. Such higher-order interactions are ubiquitous, but their empirical study has received limited attention, and little is known about possible organizational principles of such structures. Here we study the temporal evolution of 19 datasets with explicit accounting for higher order interactions. We show that there is a rich variety of structure in our datasets but datasets from the same system types have consistent patterns of higher-order structure. Furthermore, we find that tie strength and edge density are competing positive indicators of higher-order organization, and these trends are consistent across interactions involving differing numbers of nodes. To systematically further the study of theories for such higher-order structures, we propose higher-order link prediction as a benchmark problem to assess models and algorithms that predict higher-order structure. We find a fundamental difference from traditional pairwise link prediction, with a greater role for local rather than long-range information in predicting the appearance of new interactions. PMID- 30413620 TI - Klotho controls the brain-immune system interface in the choroid plexus. AB - Located within the brain's ventricles, the choroid plexus produces cerebrospinal fluid and forms an important barrier between the central nervous system and the blood. For unknown reasons, the choroid plexus produces high levels of the protein klotho. Here, we show that these levels naturally decline with aging. Depleting klotho selectively from the choroid plexus via targeted viral vector induced knockout in Klotho flox/flox mice increased the expression of multiple proinflammatory factors and triggered macrophage infiltration of this structure in young mice, simulating changes in unmanipulated old mice. Wild-type mice infected with the same Cre recombinase-expressing virus did not show such alterations. Experimental depletion of klotho from the choroid plexus enhanced microglial activation in the hippocampus after peripheral injection of mice with lipopolysaccharide. In primary cultures, klotho suppressed thioredoxin interacting protein-dependent activation of the NLRP3 inflammasome in macrophages by enhancing fibroblast growth factor 23 signaling. We conclude that klotho functions as a gatekeeper at the interface between the brain and immune system in the choroid plexus. Klotho depletion in aging or disease may weaken this barrier and promote immune-mediated neuropathogenesis. PMID- 30413622 TI - Flavonols control pollen tube growth and integrity by regulating ROS homeostasis during high-temperature stress. AB - Plant reproduction requires long-distance growth of a pollen tube to fertilize the female gametophyte. Prior reports suggested that mutations altering synthesis of flavonoids, plant specialized metabolites that include flavonols and anthocyanins, impair pollen development in several species, but the mechanism by which flavonols enhanced fertility was not defined. Here, we used genetic approaches to demonstrate that flavonols enhanced pollen development by reducing the abundance of reactive oxygen species (ROS). We further showed that flavonols reduced high-temperature stress-induced ROS accumulation and inhibition of pollen tube growth. The anthocyanin reduced (are) tomato mutant had reduced flavonol accumulation in pollen grains and tubes. This mutant produced fewer pollen grains and had impaired pollen viability, germination, tube growth, and tube integrity, resulting in reduced seed set. Consistent with flavonols acting as ROS scavengers, are had elevated levels of ROS. The pollen viability, tube growth and integrity defects, and ROS accumulation in are were reversed by genetic complementation. Inhibition of ROS synthesis or scavenging of excess ROS with an exogenous antioxidant treatment also reversed the are phenotypes, indicating that flavonols function by reducing ROS levels. Heat stress resulted in increased ROS in pollen tubes and inhibited tube growth, with more pronounced effects in the are mutant that could be rescued by antioxidant treatment. These results are consistent with increased ROS inhibiting pollen tube growth and with flavonols preventing ROS from reaching damaging levels. These results reveal that flavonol metabolites regulate plant sexual reproduction at both normal and elevated temperatures by maintaining ROS homeostasis. PMID- 30413623 TI - Chromatin modifiers Mdm2 and RNF2 prevent RNA:DNA hybrids that impair DNA replication. AB - The p53-Mdm2 system is key to tumor suppression. We have recently reported that p53 as well as Mdm2 are capable of supporting DNA replication fork progression. On the other hand, we found that Mdm2 is a modifier of chromatin, modulating polycomb repressor complex (PRC)-driven histone modifications. Here we show that, similar to Mdm2 knockdown, the depletion of PRC members impairs DNA synthesis, as determined in fiber assays. In particular, the ubiquitin ligase and PRC1 component RNF2/Ring1B is required to support DNA replication, similar to Mdm2. Moreover, the Ring finger domain of Mdm2 is not only essential for its ubiquitin ligase activity, but also for proper DNA replication. Strikingly, Mdm2 overexpression can rescue RNF2 depletion with regard to DNA replication fork progression, and vice versa, strongly suggesting that the two ubiquitin ligases perform overlapping functions in this context. H2A overexpression also rescues fork progression upon depletion of Mdm2 or RNF2, but only when the ubiquitination sites K118/K119 are present. Depleting the H2A deubiquitinating enzyme BAP1 reduces the fork rate, suggesting that both ubiquitination and deubiquitination of H2A are required to support fork progression. The depletion of Mdm2 elicits the accumulation of RNA/DNA hybrids, suggesting R-loop formation as a mechanism of impaired DNA replication. Accordingly, RNase H overexpression or the inhibition of the transcription elongation kinase CDK9 each rescues DNA replication upon depletion of Mdm2 or RNF2. Taken together, our results suggest that chromatin modification by Mdm2 and PRC1 ensures smooth DNA replication through the avoidance of R-loop formation. PMID- 30413621 TI - Folding pathway of an Ig domain is conserved on and off the ribosome. AB - Proteins that fold cotranslationally may do so in a restricted configurational space, due to the volume occupied by the ribosome. How does this environment, coupled with the close proximity of the ribosome, affect the folding pathway of a protein? Previous studies have shown that the cotranslational folding process for many proteins, including small, single domains, is directly affected by the ribosome. Here, we investigate the cotranslational folding of an all-beta Ig domain, titin I27. Using an arrest peptide-based assay and structural studies by cryo-EM, we show that I27 folds in the mouth of the ribosome exit tunnel. Simulations that use a kinetic model for the force dependence of escape from arrest accurately predict the fraction of folded protein as a function of length. We used these simulations to probe the folding pathway on and off the ribosome. Our simulations-which also reproduce experiments on mutant forms of I27-show that I27 folds, while still sequestered in the mouth of the ribosome exit tunnel, by essentially the same pathway as free I27, with only subtle shifts of critical contacts from the C to the N terminus. PMID- 30413624 TI - Multiple prebiotic metals mediate translation. AB - Today, Mg2+ is an essential cofactor with diverse structural and functional roles in life's oldest macromolecular machine, the translation system. We tested whether ancient Earth conditions (low O2, high Fe2+, and high Mn2+) can revert the ribosome to a functional ancestral state. First, SHAPE (selective 2'-hydroxyl acylation analyzed by primer extension) was used to compare the effect of Mg2+, Fe2+, and Mn2+ on the tertiary structure of rRNA. Then, we used in vitro translation reactions to test whether Fe2+ or Mn2+ could mediate protein production, and quantified ribosomal metal content. We found that (i) Mg2+, Fe2+, and Mn2+ had strikingly similar effects on rRNA folding; (ii) Fe2+ and Mn2+ can replace Mg2+ as the dominant divalent cation during translation of mRNA to functional protein; and (iii) Fe and Mn associate extensively with the ribosome. Given that the translation system originated and matured when Fe2+ and Mn2+ were abundant, these findings suggest that Fe2+ and Mn2+ played a role in early ribosomal evolution. PMID- 30413625 TI - Remote optimization of an ultracold atoms experiment by experts and citizen scientists. AB - We introduce a remote interface to control and optimize the experimental production of Bose-Einstein condensates (BECs) and find improved solutions using two distinct implementations. First, a team of theoreticians used a remote version of their dressed chopped random basis optimization algorithm (RedCRAB), and second, a gamified interface allowed 600 citizen scientists from around the world to participate in real-time optimization. Quantitative studies of player search behavior demonstrated that they collectively engage in a combination of local and global searches. This form of multiagent adaptive search prevents premature convergence by the explorative behavior of low-performing players while high-performing players locally refine their solutions. In addition, many successful citizen science games have relied on a problem representation that directly engaged the visual or experiential intuition of the players. Here we demonstrate that citizen scientists can also be successful in an entirely abstract problem visualization. This is encouraging because a much wider range of challenges could potentially be opened to gamification in the future. PMID- 30413627 TI - Exploring the Potential of RET Kinase Inhibition for Irritable Bowel Syndrome: A Preclinical Investigation in Rodent Models of Colonic Hypersensitivity. AB - Abdominal pain represents a significant complaint in patients with irritable bowel syndrome (IBS). While the etiology of IBS is incompletely understood, prior exposure to gastrointestinal (GI) inflammation or psychological stress is frequently associated with the development of symptoms. Inflammation or stress induced expression of growth factors or cytokines may contribute to the pathophysiology of IBS. Here we aimed to investigate the therapeutic potential of inhibiting the receptor of glial cell line-derived neurotrophic factor (GDNF), rearranged during transfection (RET), in experimental models of inflammation and stress-induced visceral hypersensitivity resembling IBS sequelae. In RetCFP/+ mice, thoracic and lumbosacral dorsal root ganglia (DRG) were shown to express RET and co-localized with calcitonin gene-related peptide (CGRP). To understand the role of RET in visceral nociception, we employed GSK3179106 as a potent, selective, and gut-restricted RET kinase inhibitor. Colonic hyperalgesia quantified as exaggerated visceromotor response (VMR) to graded pressures (0-60 mmHg) of isobaric colorectal distention (CRD) was produced in multiple rat models induced by i) colonic irritation, ii) following acute colonic inflammation, iii) adulthood stress and iv) early life stress. In all the rat models, RET Inhibition with GSK3179106 attenuated the number of abdominal contractions induced by CRD. Our findings identify a role for RET in visceral nociception. Inhibition of RET kinase with a potent, selective, and gut-restricted small molecule may represent a novel therapeutic strategy for the treatment of IBS through the attenuation of post-inflammatory and stress-induced visceral hypersensitivity. PMID- 30413626 TI - Polygenic adaptation and convergent evolution on growth and cardiac genetic pathways in African and Asian rainforest hunter-gatherers. AB - Different human populations facing similar environmental challenges have sometimes evolved convergent biological adaptations, for example, hypoxia resistance at high altitudes and depigmented skin in northern latitudes on separate continents. The "pygmy" phenotype (small adult body size), characteristic of hunter-gatherer populations inhabiting both African and Asian tropical rainforests, is often highlighted as another case of convergent adaptation in humans. However, the degree to which phenotypic convergence in this polygenic trait is due to convergent versus population-specific genetic changes is unknown. To address this question, we analyzed high-coverage sequence data from the protein-coding portion of the genomes of two pairs of populations: Batwa rainforest hunter-gatherers and neighboring Bakiga agriculturalists from Uganda and Andamanese rainforest hunter-gatherers and Brahmin agriculturalists from India. We observed signatures of convergent positive selection between the rainforest hunter-gatherers across the set of genes with "growth factor binding" functions ([Formula: see text]). Unexpectedly, for the rainforest groups, we also observed convergent and population-specific signatures of positive selection in pathways related to cardiac development (e.g., "cardiac muscle tissue development"; [Formula: see text]). We hypothesize that the growth hormone subresponsiveness likely underlying the adult small body-size phenotype may have led to compensatory changes in cardiac pathways, in which this hormone also plays an essential role. Importantly, in the agriculturalist populations, we did not observe similar patterns of positive selection on sets of genes associated with growth or cardiac development, indicating our results most likely reflect a history of convergent adaptation to the similar ecology of rainforests rather than a more general evolutionary pattern. PMID- 30413628 TI - Towards Further Verification of Physiologically-Based Kidney Models: Predictability of the Effects of Urine-Flow and Urine-pH on Renal Clearance. AB - In vitro-in vivo extrapolation (IVIVE) of renal excretory clearance (CLR) using the physiologically-based kidney models can provide mechanistic insight into the interplay of multiple processes occurring in the renal tubule. However, the ability of these models to quantitatively capture the impact of perturbed conditions (e.g., urine flow/ urine pH changes) on CLR has not been fully evaluated. The current work aimed to assess the predictability of the effect of urine flow and urine pH on CLR and tubular drug concentrations (selected examples). Passive diffusion clearance across the nephron tubule membrane was scaled from in vitro Caco-2 permeability data by nephron tubular surface area to predict fraction reabsorbed and CLR of caffeine, chloramphenicol, creatinine, dextroamphetamine, nicotine, sulfamethoxazole and theophylline. CLR values predicted using mechanistic kidney model at urinary pH of 6.2 and 7.4 resulted in prediction bias of 2.87 and 3.62-fold, respectively. Model simulations captured urine flow dependent CLR, albeit with minor under-prediction of the observed magnitude of change. The relationship between drug solubility, urine flow and urine pH, illustrated in simulated intra-tubular concentrations of acyclovir and sulfamethoxazole, was in agreement with clinical data on tubular precipitation and crystal-induced acute kidney injury. This study represents the first systematic evaluation of the ability of the mechanistic kidney model to capture the impact of urine flow and urine pH on CLR and drug tubular concentrations with the aim to facilitate refinement of IVIVE-based mechanistic prediction of renal excretion. PMID- 30413630 TI - Cortical myoclonic tremor induced by fixation-off sensitivity: An unusual cause of insomnia. PMID- 30413629 TI - Neurologic phenotypes associated with COL4A1/2 mutations: Expanding the spectrum of disease. AB - OBJECTIVE: To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype-phenotype correlation. METHODS: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations. RESULTS: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across COL4A1 and a clear genotype-phenotype correlation did not emerge. CONCLUSION: COL4A1/COL4A2 mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying COL4A1/COL4A2 mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall. PMID- 30413631 TI - Safety, tolerability, and efficacy of fluoxetine as an antiviral for acute flaccid myelitis. AB - OBJECTIVE: To determine the safety, tolerability, and efficacy of fluoxetine for proven or presumptive enterovirus (EV) D68-associated acute flaccid myelitis (AFM). METHODS: A multicenter cohort study of US patients with AFM in 2015-2016 compared serious adverse events (SAEs), adverse effects, and outcomes between fluoxetine-treated patients and untreated controls. Fluoxetine was administered at the discretion of treating providers with data gathered retrospectively. The primary outcome was change in summative limb strength score (SLSS; sum of Medical Research Council strength in all 4 limbs, ranging from 20 [normal strength] to 0 [complete quadriparesis]) between initial examination and latest follow-up, with increased SLSS reflecting improvement and decreased SLSS reflecting worsened strength. RESULTS: Fifty-six patients with AFM from 12 centers met study criteria. Among 30 patients exposed to fluoxetine, no SAEs were reported and adverse effect rates were similar to unexposed patients (47% vs 65%, p = 0.16). The 28 patients treated with >1 dose of fluoxetine were more likely to have EV D68 identified (57.1% vs 14.3%, p < 0.001). Their SLSS was similar at initial examination (mean SLSS 12.9 vs 14.3, p = 0.31) but lower at nadir (mean SLSS 9.25 vs 12.82, p = 0.02) and latest follow-up (mean SLSS 12.5 vs 16.4, p = 0.005) compared with the 28 patients receiving 1 (n = 2) or no (n = 26) doses. In propensity-adjusted analysis, SLSS from initial examination to latest follow-up decreased by 0.2 (95% confidence interval [CI] -1.8 to +1.4) in fluoxetine treated patients and increased by 2.5 (95% CI +0.7 to +4.4) in untreated patients (p = 0.015). CONCLUSION: Fluoxetine was well-tolerated. Fluoxetine was preferentially given to patients with AFM with EV-D68 identified and more severe paralysis at nadir, who ultimately had poorer long-term outcomes. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with EV-D68 associated AFM, fluoxetine is well-tolerated and not associated with improved neurologic outcomes. PMID- 30413632 TI - Nationwide prevalence and incidence study of neuromyelitis optica spectrum disorder in Denmark. AB - OBJECTIVES: To estimate the nationwide population-based incidence, prevalence, and geographical distribution of neuromyelitis optica (NMO) spectrum disorder (NMOSD) in Denmark based on the 2015 International Panel for NMO Diagnosis (IPND) criteria. METHODS: We conducted a multicentre, historically prospective study. Data were sourced from the Danish National Patient Registry, the Danish Multiple Sclerosis Registry, departments of neurology, and laboratories providing aquaporin-4 antibody test. Cases were selected based on the 2006 Wingerchuk and the 2015 IPND criteria and were individually validated by an expert panel. RESULTS: We confirmed NMO in 30 cases (2006 criteria) and NMOSD in 56 cases (2015 IPND criteria) between 2007 and 2014. Defined by the 2006 criteria, the incidence of NMO was 0.029 per 100,000 person-years (95% confidence interval [CI] 0.014 0.051), and the prevalence (aged 16 years and older) was 0.566 per 100,000 (95% CI 0.370-0.830). Based on the 2015 IPND criteria, the incidence of NMOSD was 0.070 per 100,000 person-years (95% CI 0.046-0.102), and the prevalence (aged 16 years and older) was 1.09 per 100,000 (95% CI 0.808-1.440), without regional differences. CONCLUSIONS: Our estimates of incidence and prevalence are similar to other Caucasian population-based studies using the 2015 IPND criteria. We found no geographical clustering in Denmark. PMID- 30413634 TI - Papers from Japan: Catheter Implantation, and the Link Between Frailty and Mortality. PMID- 30413635 TI - Peritoneal Dialysis for Patients with End-Stage Renal Disease and Liver Cirrhosis. AB - End-stage renal disease patients with cirrhosis represent a therapeutic dilemma, with several difficulties associated with hemodialysis as a renal replacement therapy modality. Peritoneal dialysis is a feasible option for these patients, despite the confounders of associated infection risk, malnutrition, ascites management, and mechanical complications. This review covers the existing data on the outcomes and complications associated with the use of peritoneal dialysis in the cirrhotic patient. PMID- 30413633 TI - PCNT point mutations and familial intracranial aneurysms. AB - OBJECTIVE: To identify novel genes involved in the etiology of intracranial aneurysms (IAs) or subarachnoid hemorrhages (SAHs) using whole-exome sequencing. METHODS: We performed whole-exome sequencing in 13 individuals from 3 families with an autosomal dominant IA/SAH inheritance pattern to look for candidate genes for disease. In addition, we sequenced PCNT exon 38 in a further 161 idiopathic patients with IA/SAH to find additional carriers of potential pathogenic variants. RESULTS: We identified 2 different variants in exon 38 from the PCNT gene shared between affected members from 2 different families with either IA or SAH (p.R2728C and p.V2811L). One hundred sixty-four samples with either SAH or IA were Sanger sequenced for the PCNT exon 38. Five additional missense mutations were identified. We also found a second p.V2811L carrier in a family with a history of neurovascular diseases. CONCLUSION: The PCNT gene encodes a protein that is involved in the process of microtubule nucleation and organization in interphase and mitosis. Biallelic loss-of-function mutations in PCNT cause a form of primordial dwarfism (microcephalic osteodysplastic primordial dwarfism type II), and ~50% of these patients will develop neurovascular abnormalities, including IAs and SAHs. In addition, a complete Pcnt knockout mouse model (Pcnt /-) published previously showed general vascular abnormalities, including intracranial hemorrhage. The variants in our families lie in the highly conserved PCNT protein-protein interaction domain, making PCNT a highly plausible candidate gene in cerebrovascular disease. PMID- 30413636 TI - Challenges Facing Children on Chronic Peritoneal Dialysis in South Africa. PMID- 30413637 TI - Hemoperitoneum in a Peritoneal Dialysis Patient: Ruptured Ectopic Pregnancy. AB - Hemoperitoneum is a well-recognized complication in female peritoneal dialysis (PD) patients of childbearing age. Bloody effluent is commonly of minor nature, presenting during menstruation or midcycle, resolving after a few rapid exchanges without a need for further intervention. One must remain vigilant, however, and consider a broader differential diagnosis when hemoperitoneum is persistent or severe, as it indicates a serious and potentially life-threatening etiology. We report 2 episodes of hemoperitoneum in a PD patient occurring more than 1.5 years apart, with different underlying etiologies. The more dramatic second episode was due to a ruptured ectopic pregnancy, a condition which had not been reported as a cause of hemoperitoneum in dialysis patients to date and requires a high index of suspicion and prompt surgical intervention. PMID- 30413638 TI - Changing Dialysis Modality during Pregnancy: A Case Report. AB - Pregnancy in patients with end-stage renal disease is rare, with a paucity of management guidelines in the literature. Various hemodialysis (HD) and peritoneal dialysis (PD) protocols have been used to successfully manage pregnancy in this population; however, there is a growing body of evidence that the best maternal and fetal outcomes are associated with intensified, high-dose HD. The optimal timing of transition from PD to HD is not known for prevalent PD patients who become pregnant. We report the case of a 32-year-old aboriginal female who became pregnant while being treated with chronic PD. She was converted to intensive HD early in the second trimester and underwent a planned caesarian section at 36 weeks with excellent outcomes for mother and child. PMID- 30413639 TI - Gastric Electrical Stimulation Improves Symptoms of Diabetic Gastroparesis in Patients on Peritoneal Dialysis-2 Case Reports. AB - Diabetic gastroparesis (DGP), a delay in gastric emptying without obstruction to outflow as a complication of diabetes, typically develops after at least 10 years of diabetes. Cardinal symptoms include nausea, vomiting, early satiety, bloating, and upper abdominal pain. The aim of DGP treatment is to alleviate the severity and frequency of symptoms, improve the level of gastric emptying, ameliorate the patient's nutritional status and to optimize glycemic control. In the treatment of chronic drug-refractory nausea and vomiting secondary to DGP, gastric electrical stimulation (GES) such as Enterra Therapy System (Medtronic Inc., Minneapolis, MN, USA) can be considered. It is well established that diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) requiring renal replacement therapy. The exact prevalence of patients with severe DGP and ESRD is not known; however, finding a therapeutic approach to these patients, particularly those whose gastroparesis symptoms preclude them from undergoing kidney transplant procedure, represents a huge challenge. Our experience suggests that GES implantation can be an effective treatment modality for type 1 diabetic patients on peritoneal dialysis (PD) who are simultaneous pancreas-kidney transplantation candidates, by improving the severity and frequency of gastroparesis symptoms and eventually ensuring their optimal nutritional and fluid intake. PMID- 30413640 TI - Exit-Site Infection: A Comparison of Classification Systems. AB - In general, in peritoneal dialysis (PD) practice in hospitals, Twardowski and Prowant's exit-site classification system is used, while the International Society for Peritoneal Dialysis (ISPD) exit-site scoring system is practical to use in community visits with less experienced healthcare personnel. Nevertheless, when exit-site scoring is 3 points under the ISPD exit-site score system and it falls in the category of equivocal under the Twardowski and Prowant's exit-site classification, the physician should be vigilant about the possibility of developing peritonitis, and hence, patients need to be kept under periodic monitoring. PMID- 30413641 TI - Pharmacokinetics of 300 mg/d Intraperitoneal Daptomycin: New Insight from the DaptoDP Study. AB - The DaptoDP (NCT 2012-005699-33) study aimed to evaluate the pharmacokinetic parameters of daptomycin (DAP) in peritoneal dialysis-related peritonitis (PDRP) patients following intraperitoneal (IP) administration. The authors have already reported the findings on the 200-mg dosing and present here the follow-up results of the 300-mg dosing. The primary endpoint was a dialysate concentration of DAP above the effective concentration in situ during 6 hours of dwell time i.e., 16 mg/L. Secondary endpoints were to avoid the toxic threshold of 120 mg/L DAP and to be above 16 mg/L DAP for 2 hours in plasma. Pharmacokinetic parameters were evaluated on days 1 and 5. Safety data were evaluated on days 1 to 14 based on clinical and biological parameters. Daptomycin was administered in Nutrineal during 6 hours of dwell time for 14 days plus the usual antibiotic therapy in a separate dwell. Because the 200-mg dosing objectives were not reached, a higher DAP dose of 300 mg was tested in the next 3 patients. Effective dialysate and plasma concentrations were achieved at the 300-mg DAP dose with the plasma concentration well below the toxic threshold, even at steady state, during which the accumulation factor never exceeded 3. The optimal DAP dose of 300 mg daily by the IP route, as determined by the pharmacokinetic data, needs to be clinically confirmed prior to routine use. The peritoneal bioavailability of DAP supports using the IP route as an alternative to the intravenous route for peritonitis and systemic infections. PMID- 30413643 TI - Sustained Increase in Peritoneal Dialysis Prevalence through a Structured PD Initiation Service. PMID- 30413642 TI - More on Suprapubic Catheters and Peritoneal Dialysis. PMID- 30413644 TI - The transfer characteristics of hair cells encoding mechanical stimuli in the lateral line of zebrafish. AB - Hair cells transmit mechanical information by converting deflection of the hair bundle into synaptic release of glutamate. We have investigated this process in the lateral line of larval zebrafish (male and female) to understand how mechanical stimuli are encoded within a neuromast. Using multiphoton microscopy in vivo, we imaged synaptic release of glutamate using the reporter iGluSnFR and deflections of the cupula. We found that the neuromast is composed of a functionally diverse population of hair cells. Half the hair cells signalled cupula motion in both directions from rest, either by increasing glutamate release in response to a deflection in the positive direction or by reducing release in the negative direction. The relationship between cupula deflection and glutamate release demonstrated maximum sensitivity at displacements of just ~40 nm in the positive direction. The remaining hair cells only signalled motion in one direction and were less sensitive, extending the operating range of the neuromast beyond 1 MUm. Adaptation of the synaptic output was also heterogeneous, with some hair cells generating sustained glutamate release in response to a steady deflection of the cupula and others generating transient outputs. Finally, a distinct signal encoded a return of the cupula to rest: a large and transient burst of glutamate release from hair cells unresponsive to the initial stimulus. A population of hair cells with these different sensitivities, operating ranges and adaptive properties will allow the neuromast to encode weak stimuli while maintaining the dynamic range to signal the amplitude and duration of stronger deflections.SIGNIFICANCE STATEMENTHair cells transmit information about mechanical stimuli by converting very small deflections of their hair bundle into changes in the release of the neurotransmitter glutamate. We have measured this input-output relation in the live fish using a fluorescent protein and find that different hair cells vary in their mechanical sensitivity and the time-course of their response. These variations will allow the fish to sense the timing and duration of both very weak stimuli (~40 nm deflections) and strong stimuli (~1 MUm), underlying the ability of the fish to avoid predators and maintain its body position in flowing water. PMID- 30413645 TI - Histamine H1 receptor contributes to vestibular compensation. AB - Vestibular compensation is responsible for the spontaneous recovery of postural, locomotor and oculomotor dysfunctions in patients with peripheral vestibular lesion or posterior circulation stroke. Mechanism investigation of vestibular compensation is of great importance in both facilitating recovery of vestibular function and understanding the post-lesion functional plasticity in the adult central nervous system. Here, we report that postsynaptic histamine H1 receptor contributes greatly to facilitating vestibular compensation. The expression of H1 receptor is restrictedly increased in the ipsilesional rather than contralesional GABAergic projection neurons in the medial vestibular nucleus (MVN), one of the most important centers for vestibular compensation, in unilateral labyrinthectomized male rats. Furthermore, H1 receptor mediates an asymmetric excitation of the commissural GABAergic but not glutamatergic neurons in the ipsilesional MVN, which may help to rebalance bilateral vestibular systems and promote vestibular compensation. Selective blockage of H1 receptor in the MVN significantly retards the recovery of both static and dynamic vestibular symptoms following unilateral labyrinthectomy, and remarkably attenuates the facilitation of betahistine, whose effect has traditionally been attributed to its antagonistic action on the presynaptic H3 receptor, on vestibular compensation. These results reveal a previously unknown role for histamine H1 receptor in vestibular compensation and amelioration of vestibular motor deficits, as well as an involvement of H1 receptor in potential therapeutic effects of betahistine. The findings provide not only a new insight into the post-lesion neuronal circuit plasticity and functional recovery in the central nervous system, but also a novel potential therapeutic target for vestibular disorders.Significance statementVestibular disorders manifest postural imbalance, nystagmus and vertigo. Vestibular compensation is critical for facilitating recovery from vestibular disorders, and of great importance in understanding the post-lesion functional plasticity in the adult central nervous system. Here, we show that postsynaptic H1 receptor in the medial vestibular nucleus (MVN) contributes greatly to the recovery of both static and dynamic symptoms following unilateral vestibular lesion. H1 receptor selectively mediates the asymmetric activation of commissural inhibitory system in the ipsilesional MVN and actively promotes vestibular compensation. The findings provide not only a new insight into the post-lesion neuronal circuit plasticity and functional recovery of central nervous system, but also a novel potential therapeutic target for promoting vestibular compensation and ameliorating vestibular disorders. PMID- 30413646 TI - Neurochemical and behavioral dissections of decision-making in a rodent multi stage task. AB - Flexible decision-making in dynamic environments requires both retrospective appraisal of reinforced actions and prospective reasoning about the consequences of actions. These complementary reinforcement-learning systems can be characterized computationally with model-free and model-based algorithms, but how these processes interact at a neurobehavioral level in normal and pathological states is unknown. Here, we developed a translationally analogous multi-stage decision-making task to independently quantify model-free and model-based behavioral mechanisms in rats. We provide the first direct evidence that male rats, similar to humans, use both model-free and model-based learning when making value-based choices in the multi-stage decision-making task and provide novel analytic approaches for independently quantifying these reinforcement-learning strategies. Furthermore, we report that ex vivo dopamine tone in the ventral striatum and orbitofrontal cortex correlate with model-based, but not model-free, strategies indicating that the biological mechanisms mediating decision-making in the multi-stage task are conserved in rats and humans. This new multi-stage task provides a unique behavioral platform for conducting systems level analyses of decision-making in normal and pathological states.Significance statementDecision making is influenced by both a retrospective "model free" system and a prospective "model based" system in humans, but the biobehavioral mechanisms mediating these learning systems in normal and disease states are unknown. Here, we describe a translationally analogous multi-stage decision-making task to provide a behavioral platform for conducting neuroscience studies of decision making in rats. We provide the first evidence that choice behavior in rats is influenced by model-free and model-based systems and demonstrate that model based, but not model-free, learning is associated with cortico-striatal dopamine tone. This novel behavioral paradigm has the potential to yield critical insights into the mechanisms mediating decision-making alterations in mental disorders. PMID- 30413647 TI - Four unique interneuron populations reside in neocortical layer 1. AB - Sensory perception depends on neocortical computations that contextually adjust sensory signals in different internal and environmental contexts. Neocortical layer 1 (L1) is the main target of cortical and subcortical inputs that provide "top-down" information for context-dependent sensory processing. While L1 is devoid of excitatory cells, it contains the distal "tuft" dendrites of pyramidal cells (PCs) located in deeper layers. L1 also contains a poorly characterized population of GABAergic interneurons (L1 INs), which regulate the impact that different top down inputs have on PCs. A poor comprehension of L1 IN subtypes and how they impact PC activity has hampered our understanding of the mechanisms that underlie contextual modulation of sensory processing. We utilized novel genetic strategies in male and female mice combined with electrophysiological and morphological methods to help resolve differences that were unclear when using only electrophysiological and/or morphological approaches. We discovered that L1 contains four distinct populations of INs, each with a unique molecular profile, morphology, and electrophysiology, including a previously overlooked IN population (named here "canopy cells") representing 40% of L1 INs. In contrast to what is observed in other layers, most L1 neurons appear to be unique to the layer, highlighting the specialized character of the signal processing that takes place in L1. This new understanding of INs in L1, as well as the application of genetic methods based on the markers described here, will enable investigation of the cellular and circuit mechanisms of top-down processing in L1 with unprecedented detail.SIGNIFICANCE STATEMENTNeocortical layer 1 is the main target of cortico-cortical and subcortical projections that mediate top-down or context dependent sensory perception. However, this unique layer is often referred to as "enigmatic" because its neuronal composition has been difficult to determine. Using a combination of genetic, electrophysiological, and morphological approaches that helped resolve differences that were unclear when using a single approach, we were able to decipher the neuronal composition of layer 1. We identified markers that distinguish layer 1 neurons and found that the layer contains four populations of GABAergic interneurons, each with unique molecular profiles, morphologies, and electrophysiological properties. These findings provide a new framework for studying the circuit mechanisms underlying the processing of top-down inputs in neocortical layer 1. PMID- 30413648 TI - APOMAB(r) antibody drug conjugates targeting dead tumor cells are effective in vivo. AB - Antibody-drug conjugates (ADC) have revolutionized the field of cancer therapy. ADCs combine the high specificity of tumor-targeting monoclonal antibodies with potent cytotoxic drugs, which cannot be used alone because of their high toxicity. Up until now, all ADCs have either targeted cell membrane proteins on tumors or the tumor vasculature and microenvironment. Here, we investigate ADCs of APOMAB(r) (DAB4, or its chimeric derivative, chDAB4), which is a monoclonal antibody targeting the La/SSB protein which is only accessible for binding in dying or dead cancer cells. We show that DAB4-labeled dead cells are phagocytosed by macrophages, and that the apoptotic/necrotic areas within lung tumor xenografts are bound by DAB4 and are infiltrated with macrophages. We show that only APOMAB-ADCs with a cleavable linker and diffusible drug are effective in two lung cancer models, particularly when given after chemotherapy. These results are consistent with other recent studies showing that direct internalization of ADCs by target cells is not essential for ADC activity because the linker can be cleaved extracellularly or through other mechanisms. Rather than targeting a tumor cell type-specific antigen, DAB4-ADCs have the advantage of targeting a common trait in most solid tumors: an excess of post-apoptotic, necrotic cells either adjacent to hypoxic tumor regions or distributed more generally after cytotoxic therapy. Consequently, any antitumor effects are solely the result of bystander killing, either through internalization of the dead, ADC-bound tumor cells by macrophages or extracellular cleavage of the ADC in the tumor microenvironment. PMID- 30413649 TI - Pleiotropic Action of Novel Bruton's Tyrosine Kinase Inhibitor BGB-3111 in Mantle Cell Lymphoma. AB - Bruton's tyrosine kinase (BTK) is a key mediator of BCR-dependent cell growth signaling and a clinically effective therapeutic target in mantle cell lymphoma (MCL). The molecular impact of BTK inhibition remains unclear particularly in hematopoietic malignancies. We analyzed the molecular mechanisms of BTK inhibition with the novel inhibitor BGB-3111 (zanubrutinib) in MCL models. The efficacy of BGB-3111 was investigated using growth proliferation/cell viability and apoptosis assays in MCL cell lines and patient-derived xenograft (PDX) MCL cells. The activity and mechanisms of BGB-3111 were further confirmed using a cell line xenograft model, an MCL PDX mouse model, and a human phosphokinase profiler array and reverse phase protein array. Lastly, the mechanisms related to resistance to BTK inhibition were analyzed by creating cell lines with low levels of BTK using CRISPR/Cas 9 genome editing. We found that inhibition of BTK leads to suppression of tumor growth, which was mediated via potent suppression of Akt/mTOR, apoptosis, and metabolic stress. Moreover, targeted disruption of the BTK gene in MCL cells resulted in resistance to BTK inhibition and the emergence of novel survival mechanisms. Our studies suggest a general efficacy of BTK inhibition in MCL and potential drug resistance mechanism via alternative signaling pathways. PMID- 30413650 TI - miR-454-3p is an exosomal biomarker and functions as a tumor suppressor in glioma. AB - Glioma is the most common type of primary malignant brain tumor in adults. Our previous work discovered that plasma miR-454-3p may have some advantages in glioma prognosis, but the clinical significance and the regulatory mechanism of miR-454-3p in glioma have not been systematically investigated, especially regarding the relationship between circulating and tissue miR-454-3p. The expression level of miR-454-3p in glioma serum and tissues was analysed through quantitative real-time PCR (qRT-PCR). Cell-Counting Kit 8 (CCK-8), wound healing, transwell invasion, apoptosis and immunofluorescence assays were employed to assess the role of miR-454-3p in glioma cancer cells. ATG12 was selected as the target gene of miR-454-3p by bioinformatic analysis. The relationship between the ATG12 and miR-454-3p was further validated by luciferase reporter assays and western blot analysis. miR-454-3p was significantly downregulated in tumor tissues, while it was remarkably upregulated in exosomes from the same patients with glioma. The area under curve (AUC) of exosomal miR-454-3p for glioma diagnosis was 0.8663. The exosomal miR-454-3p was prominently lower in the post operative serums than that in the pre-operative serums. High miR-454-3p expression in exosomes or low miR-454-3p expression in tissue was associated with poor prognosis. Restored expression of miR-454-3p suppressed cell proliferation, migration, invasion and autophagy in glioma. ATG12 was validated as a direct target of miR-454-3p. The overexpression of ATG12 could partially reverse the effects induced by miR-454-3p suppression. Our data indicate that miR-454-3p may serve as an exosomal biomarker and may be developed into a novel treatment for glioma. PMID- 30413652 TI - Overexpression of acid-Ceramidase (ASAH1) Protects Retinal Cells (ARPE19) from Oxidative Stress. AB - Over 11 million people in the United States alone have some form of age-related macular degeneration (AMD). Oxidative stress, cell death, and the degeneration of retinal pigment epithelial (RPE) cells contributes to AMD pathology. Recent evidence suggests that Ceramide (Cer), a cellular sphingolipid mediator that acts as a second messenger to induce apoptosis, might play a role in RPE cell death. The lysosomal breakdown of Cer by acid Ceramidase (ASAH1, N-acylsphingosine amidohydrolase 1) into sphingosine is the major source for sphingosine 1 phosphate (S1P) production, which has an opposing role to Cer and provides cytoprotection. Here, we investigated the role of Cer in human RPE-derived ARPE19 cells under hydrogen peroxide-induced oxidative stress, and show that Cer and hexosyl-ceramide (Hex-Cer) levels increase in the oxidative-stressed ARPE19 cells, which can be prevented by over-expression of lysosomal ASAH1. This study demonstrates that oxidative stress generates sphingolipid death mediators in retinal cells and induction of ASAH1 could rescue retinal cells from oxidative stress by hydrolyzing excess ceramides. PMID- 30413651 TI - Differential mobility spectrometry as an orthogonal separation to LC-ESI-MS/MS for quantification of isomeric cerebrosides in plasma and cerebrospinal fluid. AB - Cerebrosides, including glucosylceramides (GlcCer) and galactosylceramides (GalCer), are important membrane components of animal cells with deficiencies resulting in devastating lysosomal storage disorders. Their quantification is essential for disease diagnosis and a better understanding of disease mechanisms. Simultaneous quantification of GlcCer and GalCer isomers is, however, particularly challenging due to their virtually identical structures. To address this challenge, we developed a new LC-MS-based method employing differential ion mobility spectrometry (DMS) capable of rapidly and reproducibly separating and quantifying isomeric cerebrosides in a single run. We show that this LC-ESI-DMS MS/MS method exhibits robust quantitative performance within an analyte concentration range of 2.8-355 nM. We further report simultaneous quantification of nine GlcCer (16:0, 18:0, 20:0, 22:0, 23:0, 24:1, 24:0, 25:0, and 26:0) and five GalCer (18:0, 20:0, 25:0, and 26:0) molecular species in human plasma, as well as six GalCer (18:0, 22:0, 23:0, 24:1, 24:0 and 25:0) and two GlcCer (24:1 and 24:0) in human cerebrospinal fluid. Our method expands the potential of the DMS technology in the field of glycosphingolipid (GSL) analysis for both biomarker discovery and drug screening by enabling the unambiguous assignment and quantification of cerebroside lipid species in biological samples. PMID- 30413653 TI - A comprehensive map of single base polymorphisms in the hypervariable LPA Kringle IV-2 copy number variation region. AB - Lipoprotein(a) concentrations are among the strongest genetic risk factors for cardiovascular disease and present pronounced inter-ethnic and inter-individual differences. About 90% of lipoprotein(a) variance is controlled by the LPA gene, which contains a 5.6 kb large copy number variation (KIV-2 repeat) that generates >40 protein isoforms. Variants within the KIV-2 region are not called in common sequencing projects, leaving up to 70% of the LPA coding region currently unaddressed. To allow a complete assessment of the variability in LPA, we developed a sequencing strategy for this region and report here the first map of genetic variation in the KIV-2 region, a comprehensively evaluated ultra-deep sequencing protocol and an easy-to-use variant analysis pipeline (https://github.com/genepi/lpa-pipeline). We sequenced 123 Central-European individuals and additionally reanalyzed public data of 2,504 individuals from 26 populations. We found dozens of loss-of-function and splice site mutations, as well as >100, partially even common, missense variants. Some coding variants were frequent in one population, but absent in others. This provides novel candidates to explain the large ethnic and individual differences in Lp(a) concentrations. Importantly, our approach and pipeline are applicable also to other similar copy number variable regions, allowing accessing regions, which are not captured by common genome sequencing. PMID- 30413654 TI - Integrating co-expression networks with GWAS to prioritize causal genes in maize. AB - Genome-wide association studies (GWAS) have identified loci linked to hundreds of traits in many different species. Yet, because linkage equilibrium implicates a broad region surrounding each identified locus, the causal genes often remain unknown. This problem is especially pronounced in non-human, non-model species where functional annotations are sparse and there is frequently little information available for prioritizing candidate genes. We developed a computational approach, Camoco, that integrates loci identified by GWAS with functional information derived from gene co-expression networks. Using Camoco, we prioritized candidate genes from a large-scale GWAS examining the accumulation of 17 different elements in maize seeds. Strikingly, we observed a strong dependence in the performance of our approach on the type of co-expression network used: expression variation across genetically diverse individuals in a relevant tissue context (in our case, roots) outperformed other alternatives. Two candidate genes identified by our approach were validated using mutants. Our study demonstrates that co-expression networks provide a powerful basis for prioritizing candidate causal genes from GWAS loci, but suggests that the success of such strategies can highly depend on the gene expression data context. Both the software and the lessons on integrating GWAS data with co-expression networks generalize to species beyond maize. PMID- 30413655 TI - Clubroot Disease Stimulates Early Steps of Phloem Differentiation and Recruits SWEET Sucrose Transporters within Developing Galls. AB - Successful biotrophic plant pathogens can divert host nutrition towards infection sites. Here we describe how the protist Plasmodiophora brassicae establishes a long-term feeding relationship with its host by stimulating phloem differentiation and phloem-specific expression of sugar transporters within developing galls. Development of galls in infected Arabidopsis thaliana plants is accompanied by stimulation of host BREVIS RADIX (BRX), COTYLEDON VASCULAR PATTERN 2 (CVP2) and OCTOPUS (OPS) gene expression leading to an increase in phloem complexity. We characterised how the arrest of this developmental reprogramming influences both the host and the invading pathogen. Furthermore, we found that infection leads to phloem-specific accumulation of SUGARS WILL EVENTUALLY BE EXPORTED TRANSPORTERS (SWEET11 and SWEET12) facilitating local distribution of sugars towards the pathogen. Utilising Fourier-transform infrared (FTIR) microspectroscopy to monitor spatial distribution of carbohydrates, we found that infection leads to the formation of a strong physiological sink at the site of infection. High resolution metabolic and structural imaging of sucrose distributions revealed that sweet11 sweet12 double mutants are impaired in sugar transport towards the pathogen, delaying disease progression. This work highlights the importance of precise regulation of sugar partitioning for plant pathogen interactions and the dependence of P. brassicae's performance on its capacity to induce a phloem sink at the feeding site. PMID- 30413656 TI - Role of 18F-FDG PET/CT in Cardiac Sarcoid Detection and Therapy Monitoring: Addition to the Expert Consensus. PMID- 30413657 TI - Immuno-PET of innate immune markers CD11b and IL-1beta detect inflammation in murine colitis. AB - Inflammatory bowel disease (IBD) is a chronic relapsing and remitting inflammatory disease of the gastrointestinal tract. The diagnosis and monitoring of IBD is reliant on endoscopy which is invasive and does not provide information regarding specific mediators. Symptom flare in IBD is associated with increased activation of innate immune pathways. Immuno-PET approaches have previously demonstrated the ability to detect colitis, however direct comparison of antibodies targeted to innate immune mediators and cells have not been evaluated. We aimed to compare immuno-PET of antibodies to IL-1beta and CD11b against standard 18F-FDG and MRI approaches to detect colonic inflammation. Methods: Colonic concentrations of IL-1beta and myeloperoxidase (MPO) were determined by ELISA and colonic infiltration by CD11b+ CD3- innate immune cells were determined by flow cytometry and compared between healthy and dextran sodium sulphate treated colitic mice. PET of 89Zr-labelled alpha-IL-1beta and alpha-CD11b, and 18F-FDG were compared by volume of interest and MRI by region of interest analysis. Imaging results were confirmed by ex vivo biodistribution analysis. Results: Colonic inflammation was associated with impaired colonic epithelial barrier permeability, an increase in colonic IL-1beta and MPO concentrations, and increased CD11b+ CD3- innate immune cell infiltration into the colon. 89Zr-alpha IL-1beta and 89Zr-alpha-CD11b immuno-PET detected colonic inflammation, as did 18F-FDG, and all PET tracers were more sensitive than MRI. While 18F-FDG volume of interests correlated with colitis severity and a strong trend was observed with 89Zr-alpha-IL-1beta, no correlation was observed for 89Zr-alpha-CD11b or MRI. 89Zr-alpha-IL-1beta was distributed mainly to the gastrointestinal tract, while 89Zr-alpha-CD11b was distributed in more tissue types. Conclusion: Immuno PET using antibodies directed to innate immune markers detected colonic inflammation, with 89Zr-alpha-IL-1beta providing a more tissue specific signal than 89Zr-alpha-CD11b. Development of these technologies for human subjects will potentially provide a less invasive approach than endoscopy for diagnosing and monitoring IBD. PMID- 30413658 TI - Metabolic subtyping of pheochromocytoma and paraganglioma by 18F-FDG pharmacokinetics using dynamic PET/CT scanning. AB - Background: Static single timeframe 18F-FDG PET/CT is useful for the localization and functional characterization of pheochromocytoma and paraganglioma (PPGL). 18F FDG-uptake varies between PPGLs with different genotypes and highest standardized uptake values (SUVs) are observed in case of succinate dehydrogenase (SDH) mutations, possibly related to enhanced aerobic glycolysis in tumor cells. The exact determinants of 18F-FDG accumulation in PPGL are unknown. We performed dynamic PET/CT scanning to assess in vivo 18F-FDG pharmacokinetics to investigate whether it has added value over static PET to distinguish different genotypes. Methods: Dynamic 18F-FDG PET/CT was performed in 13 sporadic PPGLs and 13 PPGLs from 11 patients with hereditary mutations in SDHA/B/D, von Hippel-Lindau (VHL), RET and neurofibromin 1 (NF1). Pharmacokinetic analysis was performed using a two tissue compartment tracer kinetic model. The derived transfer rate-constants for transmembranous glucose flux (K1 (in), k2 (out)) and intracellular phosphorylation (k3) along with the fractional blood volume (Vb) were analyzed using non-linear regression analysis. Glucose metabolic rate (MRglc) was calculated using Patlak linear regression analysis. Maximum SUVs (SUVmax) of the lesions were determined on additional static PET/CT. Results: Both MRglc and SUVmax for hereditary cluster 1 (SDHx, VHL) tumors were significantly higher than for hereditary cluster 2 (RET, NF1) (P<0.01) and sporadic tumors (P<0.01, P<0.05, respectively). Median k3 in cluster 1 was significantly higher than for sporadic tumors (P<0.01). Median Vb for cluster 1 was significantly higher than for cluster 2 tumors (P<0.01). No statistical significant differences in K1 and k2 were found between the groups. Cutoff values for k3 to distinguish between cluster 1 and other tumors were established at 0.015 min-1 (100% sensitivity, 15,8% specificity) and 0.636 min-1 (100% specificity, 85.7% sensitivity). MRglc significantly correlated with SUVmax (P = 0.001) and k3 (P = 0.002). Conclusion: In vivo metabolic tumor profiling in patients with PPGL can be achieved by assessing 18F-FDG pharmacokinetics using dynamic PET/CT scanning. Cluster 1 PPGLs can be reliably identified by a high 18F-FDG phosphorylation rate. PMID- 30413659 TI - Nuclear Medicine Board Review: Questions and Answers for Self-Assessment, 4th Edition. PMID- 30413660 TI - A Single Dose of 225Ac-RPS-074 Induces a Complete Tumor Response in a LNCaP Xenograft Model. AB - Promising biochemical responses to 225Ac-PSMA-617, even in patients that are refractory to beta-particle radiation, illustrate the potential of targeted alpha therapy (TAT) for the treatment of metastatic castrate-resistant prostate cancer. However, side effects such as xerostomia are severe and irreversible. In order to fully harness the potential of TAT, it is necessary to increase the therapeutic index of the targeted radioligands. One emerging strategy is to Increase clearance half-life through enhanced binding to serum albumin. We have evaluated the albumin-binding PSMA-targeting ligand RPS-074 in a LNCaP xenograft model to determine its potential value to the treatment of prostate cancer. Methods: 225Ac RPS-074 was evaluated in male BALB/c mice bearing LNCaP xenograft tumors. A biodistribution study was performed over 21 d to determine the dosimetry in tumors and normal tissue. The dose response was measured in groups of 7 mice using 37 kBq, 74 kBq, and 148 kBq 225Ac-RPS-074 and compared to positive and negative control groups. Mice were sacrificed when tumor volume exceeded 1500 mm3 Results: 225Ac-RPS-074 was labeled in >98% radiochemical yield and showed high (>10 %ID/g) and sustained accumulation in LNCaP tumors from 24 h to beyond 14 d. Signal in blood and highly vascularized tissues was evident over the first 24 h p.i., and cleared by 7 d. The tumor-to-kidney ratio was 4.3 +/- 0.7 at 24 h and 62.2 +/- 9.5 at 14 d. A single injection of 148 kBq induced a complete response in 6/7 tumors with no apparent toxic effects. Treatment with 74 kBq induced a partial response in 7/7 tumors, but from 42 d, 6/7 experienced significant regrowth. The 37 kBq group experienced a survival benefit relative to the negative control, but not compared to the positive control group. Conclusion: A single dose of 148 kBq 225Ac-RPS-074 induced a complete response in 86% of tumors, with tumor-to-normal tissue ratios that predict an improved therapeutic index. The use of the macropa chelator enabled quantitative radiolabeling and may facilitate the clinical translation of this promising targeted alpha therapeutic. PMID- 30413661 TI - F-18 FDG PET/CT for monitoring of ipilimumab therapy in patients with metastatic melanoma. AB - Immune checkpoint inhibitors (ICIs) are now commonly used to treat patients with metastatic malignant melanoma. While concerns have been raised that the inflammatory response induced by ICIs may limit the ability of 18F-FDG PET/CT to assess tumor response, systematic analyses on the use of 18F-FDG PET/CT in this setting are mostly lacking. Thus, we set out to evaluate the association between tumor response on 18F-FDG PET/CT and prognosis in patients with metastatic malignant melanoma treated with ipilimumab. Methods: We analyzed 60 consecutive patients with metastatic melanoma who underwent 18F-FDG PET/CT scans at both pre- and post-treatment to evaluate treatment response after completion of ipilimumab therapy. Tumor response was assessed by the change in the sum of SULpeak of up to 5 lesions according to PET Response Criteria in Solid Tumors (PERCIST5). New lesions on PET that appeared suspicious for metastases were considered progressive metabolic disease (PMD). Because immunotherapy may cause new inflammatory lesions that are detectable on 18F-FDG PET/CT, we also evaluated an immunotherapy-modified response classification (imPERCIST5). In this classification, new lesions do not define PMD per se; rather, PMD requires an increase in the sum of SULpeak by 30%. We then investigated whether the response classification could be simplified by only measuring SULpeak for the lesion with the highest FDG uptake on the baseline or follow-up scan (imPERCIST1). The correlation between tumor response according to these three definitions and overall survival (OS) was evaluated and compared to known prognostic factors. Results: In responders and non-responders, the two-year OS was 57% vs. 29% for imPERCIST1 (P = 0.011), and 66% vs. 29% for imPERCIST5 (P = 0.003). After multivariate analysis, imPERCIST5 remained prognostic (HR 3.853; 95% CI 1.498 9.911; P = 0.005). New sites of focal FDG uptake occurred more often in patients with PMD (n = 24) by imPERCIST5 than in those with SMD (n = 7) or PMR (n = 4). In patients with PMR, two of four isolated new lesions regressed spontaneously during follow-up. Conclusion: In patients with metastatic melanoma treated with ipilimumab, tumor response according to PERCIST was associated with OS. Our data suggest that PMD should not be defined by the appearance of new lesions, but rather by an increase in the sum of SULpeak. PMID- 30413662 TI - "As Long as You Ask": A Qualitative Study of Biobanking Consent-Oncology Patients' and Health Care Professionals' Attitudes, Motivations, and Experiences the B-PPAE Study. AB - INTRODUCTION: Consent to biobanking remains controversial, with little empirical data to guide policy and practice. This study aimed to explore the attitudes, motivations, and concerns of both oncology patients and health care professionals (HCPs) regarding biobanking. MATERIALS AND METHODS: Qualitative interviews were conducted with oncology patients and HCPs purposively selected from five Australian hospitals. Patients were invited to give biobanking consent as part of a clinical trial and/or for future research were eligible. HCPs were eligible if involved in consenting patients to biobanking or to donate specimens to clinical trials. RESULTS: Twenty-two patients participated, with head and neck (36%) and prostate (18%) the most common cancer diagnoses; all had consented to biobanking. Twenty-two HCPs participated, from across eight cancer streams and five disciplines. Themes identified were (a) biobanking is a "no brainer"; (b) altruism or scientific enquiry; (c) trust in clinicians, science, and institutions; (d) no consent-just do it; (e) respecting patient choice ("opt out"); (f) respectful timing of the request; (g) need for emotional/family support; (h) context of the biobanking request matters; and (i) factors for biobanking success. DISCUSSION: These findings reinforced previous findings regarding high public trust in, and support for, biobanking. An initial opt-in consent approach with the option of later opt-out was favored by patients to respect and recognize donor generosity, whereas HCPs preferred an upfront opt-out model. Factors impacting biobanking success included the context of the request for use in a trial or specific research question, pre-existing patient and HCP rapport, a local institution champion, and infrastructure. IMPLICATIONS FOR PRACTICE: Patients and health care professionals (HCPs) who experienced cancer biobanking consent were overwhelmingly supportive of biobanking. The motivations and approaches to seeking consent were largely mirrored between the groups. The findings of this study support the opt-in model of biobanking favored by patients; however, HCPs preferred an opt-out model. Both groups recognize the importance of making the request for biobanking at an appropriate time, preferably with emotional or family support, and respecting the timing of the request and privacy of the patient. Biobanking success can be promoted by hospital departments with a research focus by identifying an institutional biobanking champion and ensuring local infrastructure is available. PMID- 30413663 TI - SMAD4 Mutation in Small Cell Transformation of Epidermal Growth Factor Receptor Mutated Lung Adenocarcinoma. AB - The large screening of exons 18 to 21 of the epidermal growth factor receptor (EGFR) gene may lead to the discovery of rare, atypical molecular alterations for which the sensitivity to tyrosine kinase inhibitors (TKIs) remains uncertain. We are reporting a rare exon 18 EGFR mutation (p.E709_710 > D) that confers sensitivity to second-generation EGFR TKI (afatinib), lasting for 1 year. Tumor progression biopsy showed small cell lung cancer transformation, associated with a SMAD4 mutation. KEY POINTS: A rare exon 18 epidermal growth factor receptor mutation with sensitivity to afatinib is reported.Small cell transformation was observed at tumor progression.Acquisition of a SMAD4 mutation was observed at tumor progression. PMID- 30413664 TI - Protecting Patient Privacy in Narratives: The Lifespan-Brown Checklist for Appropriate Use of Patient Narratives. PMID- 30413665 TI - Immune Checkpoint Inhibitors and the Risk of Allograft Rejection: A Comprehensive Analysis on an Emerging Issue. AB - BACKGROUND: It is well known that the state of immune tolerance induced by broad immunosuppression to prevent allograft rejection leads to an increased risk of the development of cancer. One of the most promising new areas of cancer treatment has been the development of immune checkpoint inhibitors that target the cytotoxic T-lymphocyte-associated antigen 4 and programmed cell death protein 1/programmed death-ligand 1 (PD-L1) pathways. As a logical consequence, growing interest in these agents translated into their implementation in patients with transplant-related malignancies. Because of overlapping and perhaps mutually exclusive mechanisms of action of transplant immunosuppression and cancer immunomodulation, it is critical to examine these interactions. MATERIALS AND METHODS: We carried out a systematic search for review articles and case reports published between July 2014 and November 2017 using three engines: Usearch, PubMed, and Up-to-date. RESULTS: Overall, there were 20 cases with 12 allograft rejections. The rejection rate associated with nivolumab was 73% (8/11) and with pembrolizumab it was 100% (2/2). The use of ipilimumab did not lead to rejection in any instance (0/4, 0%). Of the two patients treated with the sequential use of ipilimumab/nivolumab, one lost his allograft, yielding a rejection rate of 50%. The sequential use of ipilimumab/pembrolizumab led to a rejection rate of 100% (1/1, 100%). CONCLUSION: The use of agents that act on the PD-L1 pathway are contraindicated in the face of solid organ allografts because of unacceptably high rates of irreversible allograft rejection. It appears that the use of ipilimumab may be tolerated as the mechanism is different from that of the PD-L1 agents. IMPLICATIONS FOR PRACTICE: Transplant rejection is a complex process that puts stress on patients and their families and can lead to tragic results. Significant advancements in the field of immunosuppression have led to the engenderment of agents devised to extend the survival of transplant recipients. The advent of immunomodulators in cancer therapy has been paradigm-shifting; however, because of their mechanism of action, their use must be carefully considered in patients with allografts and concomitant cancer. It appears that ipilimumab can be administered safely in these patients but that agents acting on the programmed death-ligand 1 pathway are contraindicated because of high rates of irreversible rejection. PMID- 30413666 TI - Capecitabine and Temozolomide as a Promising Therapy for Advanced Thymic Atypical Carcinoid. AB - BACKGROUND: Thymic atypical carcinoid (TAC) is a rare thymic neuroendocrine tumor that originates in the neuroendocrine system and lacks a standardized treatment. The combination of capecitabine (CAP) and temozolomide (TEM) is associated with an extremely high and long-lasting response rate in patients with metastatic pancreatic neuroendocrine tumors. However, there is little evidence showing that the CAPTEM regimen is effective for TAC. For patients with unresectable or metastatic atypical carcinoid of the thymus, few treatment options are available, and the treatment efficacy is not satisfactory. To explore the efficacy and safety of the CAPTEM regimen against TAC, we conducted a retrospective review. PATIENTS AND METHODS: A total of nine patients with advanced atypical carcinoid of the thymus in the China-Japan Friendship Hospital were treated with capecitabine (750 mg/m2 twice daily, days 1-14) and temozolomide (200 mg/m2 once daily, days 10-14) every 28 days between 2014 and 2018. The disease control rate (DCR), progression-free survival (PFS), and adverse effects after treatment were analyzed. The DCR was calculated by RECIST version 1.1. Progression-free survival was calculated by the Kaplan-Meier survival method. RESULTS: A total of nine patients (six male and three female) were included. The median age at CAPTEM initiation was 50 years (range, 26-58). The median number of CAPTEM cycles was 8 (range, 3-23). The DCR was 89% (8/9), with eight patients achieving stable disease. Only one patient (11%) showed progressive disease. The median PFS was 8 months. Because we applied vitamin B6 and ondansetron before administering the drugs, the side effects of this regimen were very small. Adverse reactions were all below grade 3 and included myelosuppression and digestive tract reaction. CONCLUSION: Our results suggest that the CAPTEM regimen may be effective and well tolerated for the treatment of TAC. More evidence is needed to validate the effectiveness of this regimen. IMPLICATIONS FOR PRACTICE: Capecitabine and temozolomide regimen is effective and well tolerated in patients with advanced thymic atypical carcinoid. PMID- 30413667 TI - Eribulin Mesylate as Third or Subsequent Line Chemotherapy for Elderly Patients with Locally Recurrent or Metastatic Breast Cancer: A Multicentric Observational Study of GIOGer (Italian Group of Geriatric Oncology)-ERIBE. AB - BACKGROUND: Metastatic breast cancer (MBC) is highly prevalent in middle-aged or elderly patients. Eribulin is a nontaxane microtubule inhibitor, approved for the treatment of pretreated MBC. This multicentric study (sponsored by GIOGer, Italian Group for Geriatric Oncology) was designed to assess the efficacy and tolerability of eribulin, according to parameters usually used in geriatric oncology. SUBJECTS, MATERIALS, AND METHODS: An observational study was conducted on 50 consecutive elderly patients with MBC. The primary endpoint was to evaluate the change in items score of comprehensive geriatric assessment (CGA) and health related quality of life (HRQL). Italian versions of the CGA and HRQL questionnaires were administered at baseline, before the third and fifth cycles, and then every three cycles until treatment discontinuation. Secondary endpoints were efficacy and safety. RESULTS: Overall, both EQ-5D scores and EQ-5D-3 L visual analogic scale did not significantly change from baseline; the percentage of subjects without problems doing usual activities tended to decrease during treatment (p for linear trend .018), and the percentage of patients with minor problems performing usual activities tended to increase (p for linear trend.012). Among CGA items, Instrumental Activities of Daily Living tended to decrease during treatment and Geriatric Depression Scale tended to increase. After 12 months follow-up, 24 patients (out of 47) showed clinical benefits; median progression-free survival was 4.49 months (2.10-10.33) and median OS was 7.31 months (3.70-14.03). The treatment was associated with mild toxicity. CONCLUSION: Eribulin treatment preserved quality of life and geriatric parameters included in the CGA, except for instrumental functioning and geriatric depression, in elderly patients with MBC. IMPLICATIONS FOR PRACTICE: A collaboration between oncologist and geriatric specialists is essential in the management of patients with metastatic breast cancer, who are frequently elderly or frail. The assessment of geriatric parameters in the decision-making process can contribute to direct toward the most appropriate therapeutic plan and preserve the quality of life of patients. Eribulin does not seem to affect quality of life or worsen the overall geriatric status; therefore, it can be considered a suitable option for elderly patients with metastatic breast cancer. PMID- 30413668 TI - Characterization of Comorbidities Limiting the Recruitment of Patients in Early Phase Clinical Trials. AB - BACKGROUND: Early phase clinical trials evaluate the safety and efficacy of new treatments. The exclusion/inclusion criteria in these trials are usually rigorous and may exclude many patients seen in clinical practice. Our objective was to study the comorbidities limiting the participation of patients with breast, colorectal, or lung cancer in clinical trials. MATERIALS AND METHODS: We queried ClinicalTrials.gov on December 31, 2016. We reviewed the eligibility criteria of 1,103 trials. Logistic regression analyses were completed, and exclusion was studied as a binary variable. RESULTS: Out of 1,103 trials, 70 trials (6%) excluded patients >75 years of age, and 45% made no reference to age. Eighty-six percent of trials placed restrictions on patients with history of prior malignancies. Regarding central nervous system (CNS) metastasis, 416 trials (38%) excluded all patients with CNS metastasis, and 373 (34%) only allowed asymptomatic CNS metastasis. Regarding chronic viral infections, 347 trials (31%) excluded all patients with human immunodeficiency virus, and 228 trials (21%) excluded all patients with hepatitis B or C infection. On univariate analysis, chemotherapy trials were more likely to exclude patients with CNS metastasis and history of other malignancies than targeted therapy trials. Multivariate analysis demonstrated that industry-sponsored trials had higher odds of excluding patients with compromised liver function. CONCLUSION: Many clinical trials excluded large segments of the population of patients with cancer. Frequent exclusion criteria included patients with CNS metastasis, history of prior malignancies, and chronic viral infections. The criteria for participation in some clinical trials may be overly restrictive and limit enrollment. IMPLICATIONS FOR PRACTICE: The results of this study revealed that most early phase clinic trials contain strict exclusion criteria, potentially excluding the patients who may be more likely to represent the population treated in clinical settings, leaving patients susceptible to unintended harm from inappropriate generalization of trial results. Careful liberalization of the inclusion/exclusion criteria in clinical trials will allow investigators to understand the benefits and drawbacks of the experimental drug for a broader population, and possibly improve recruitment of patients with cancer into clinical trials. PMID- 30413669 TI - First-in-Human Phase I Study of MBC-11, a Novel Bone-Targeted Cytarabine Etidronate Conjugate in Patients with Cancer-Induced Bone Disease. AB - LESSONS LEARNED: Results are consistent with MBC-11 targeting and treating cancer induced bone lesions by concentrating cytarabine and etidronate at the site of disease.MBC-11 was well tolerated, with an maximum tolerated dose of 5 mg/kg per day and myelosuppression as the principal toxicity.Treatment significantly reduced cancer cell activity in over half of bone lesions detected at baseline.MBC-11 pharmacokinetic and pharmacodynamic parameters are consistent with the novel drug design goals, and encouraging results warrant further clinical development. BACKGROUND: MBC-11 is a first-in-class conjugate of the bone-targeting bisphosphonate etidronate covalently linked to the antimetabolite cytarabine (araC). This first-in-human phase I dose escalation study assessed safety, tolerability, maximum tolerated dose (MTD), plasma pharmacokinetics, bone turnover, tumor biomarkers, and bone lesion activity by fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) imaging. METHODS: Fifteen patients with advanced solid cancers and cancer-induced bone disease (CIBD) were treated with 0.5-10 mg/kg per day of MBC-11 administered daily for 5 days of every 4 weeks for up to four cycles. RESULTS: Grade 1-2 myelosuppression, involving all lineages, was the principal toxicity. Two of three patients treated with 10 mg/kg experienced dose-limiting grade 4 neutropenia and thrombocytopenia (adverse event [AE] duration <=5 days); the MTD was 5 mg/kg. Four of five patients with pretreatment elevations of the bone resorption marker TRAP5b (tartrate resistant acid phosphatase-5b) had persistent decrements. Six of 13 patients who reported baseline pain noted a reduction after MBC-11. 18F-FDG-PET/CT imaging demonstrated partial metabolic responses in three patients and stable metabolic responses in three other patients. SUVmax (standard unit of emission normalized to total uptake) was reduced by at least 25% in 110 (52%) of 211 bone lesions. Significant activity was noted across all doses, and myelosuppression increased with dose. CONCLUSION: At MBC-11 doses that were well tolerated, substantial reductions in metabolic activity of bone-associated cancer cells provide a foundation for further disease-directed efficacy studies. PMID- 30413670 TI - The Transcription Factors PU.1 and IRF4 Determine Dendritic Cell-Specific Expression of RALDH2. AB - RALDH2 expressed in dendritic cells (DCs) plays a critical role in the development of regulatory T cells in mesenteric lymph nodes. Despite the importance of RALDH2 in intestinal immunity, little is known about the mechanism of DC-specific expression of RALDH2. In the current study, we focused on the hematopoietic cell-specific transcription factors PU.1 and IRF4 as the determinants of Aldh1a2 gene expression. The mRNA level of Aldh1a2, and subsequently the enzyme activity, were decreased by knockdown of PU.1 and IRF4 in bone marrow-derived DCs (BMDCs) of BALB/c mice. Chromatin immunoprecipitation assays showed that PU.1 and IRF4 bound to the Aldh1a2 gene ~2 kb upstream from the transcription start site in BMDCs. A reporter assay and an EMSA revealed that the Aldh1a2 promoter was synergistically transactivated by a heterodimer composed with PU.1 and IRF4 via the EICE motif at -1961/-1952 of the gene. The effect of small interfering RNAs for Spi1 and Irf4 and specific binding of PU.1 and IRF4 on the Aldh1a2 gene were also observed in DCs freshly isolated from spleen and mesenteric lymph nodes, respectively. GM-CSF stimulation upregulated the Aldh1a2 transcription in Flt3 ligand-generated BMDCs, in which the IRF4 expression and the PU.1 recruitment to the Aldh1a2 promoter were enhanced. We conclude that PU.1 and IRF4 are transactivators of the Aldh1a2 gene in vitro and ex vivo. PMID- 30413671 TI - Multiplexed FluoroSpot for the Analysis of Dengue Virus- and Zika Virus-Specific and Cross-Reactive Memory B Cells. AB - Dengue virus (DENV) and Zika virus (ZIKV) are mosquito-borne pathogens that have a significant impact on human health. Immune sera, mAbs, and memory B cells (MBCs) isolated from patients infected with one DENV type can be cross-reactive with the other three DENV serotypes and even more distantly related flaviviruses such as ZIKV. Conventional ELISPOTs effectively measure Ab-secreting B cells but because they are limited to the assessment of a single Ag at a time, it is challenging to distinguish serotype-specific and cross-reactive MBCs in the same well. We developed a novel multifunction FluoroSpot assay using fluorescently labeled DENV and ZIKV (FLVs) that measures the cross-reactivity of Abs secreted by single B cells. Conjugation efficiency and recognition of FLVs by virus specific Abs were confirmed by flow cytometry. Using a panel of DENV immune, ZIKV immune, and naive PBMC, FLVs were able to simultaneously detect DENV serotype specific, ZIKV-specific, DENV serotype cross-reactive, and DENV/ZIKV cross reactive Abs secreted by individual MBCs. Our findings indicate that the FLVs are sensitive and specific tools to detect specific and cross-reactive MBCs. These reagents will allow the assessment of the breadth as well as the durability of DENV/ZIKV B cell responses following vaccination or natural infection. This novel approach using FLVs in a FluoroSpot assay can be applied to other diseases such as influenza in which prior immunity with homosubtype- or heterosubtype-specific MBCs may influence subsequent infections. PMID- 30413673 TI - Storage of prescription veterinary medicines on UK dairy farms: a cross-sectional study. AB - Prescription veterinary medicine (PVM) use in the UK is an area of increasing focus for the veterinary profession. While many studies measure antimicrobial use on dairy farms, none report the quantity of antimicrobials stored on farms, nor the ways in which they are stored. The majority of PVM treatments occur in the absence of the prescribing veterinarian, yet there is an identifiable knowledge gap surrounding PVM use and farmer decision making. To provide an evidence base for future work on PVM use, data were collected from 27 dairy farms in England and Wales in Autumn 2016. The number of different PVMs stored on farms ranged from 9 to 35, with antimicrobials being the most common therapeutic group stored. Injectable antimicrobials comprised the greatest weight of active ingredient found, while intramammary antimicrobials were the most frequent unit of medicine stored. Antimicrobials classed by the European Medicines Agency as critically important to human health were present on most farms, and the presence of expired medicines and medicines not licensed for use in dairy cattle was also common. The medicine resources available to farmers are likely to influence their treatment decisions; therefore, evidence of the PVM stored on farms can help inform understanding of medicine use. PMID- 30413672 TI - Cutting Edge: Transcriptional Profiling Reveals Multifunctional and Cytotoxic Antiviral Responses of Zika Virus-Specific CD8+ T Cells. AB - Zika virus (ZIKV) constitutes an increasing public health problem. Previous studies have shown that CD8+ T cells play an important role in ZIKV-specific protective immunity. We have previously defined antigenic targets of the ZIKV specific CD8+ T cell response in humans. In this study, we characterized the quality and phenotypes of these responses by a combined use of flow cytometry and transcriptomic methods, using PBMCs from donors deriving from different geographical locations collected in the convalescent phase of infection. We show that ZIKV-specific CD8+ T cells are characterized by a polyfunctional IFN-gamma signature with upregulation of TNF-alpha, TNF receptors, and related activation markers, such as CD69, as well as a cytotoxic signature characterized by strong upregulation of GZMB and CRTAM. The signature is stable and not influenced by previous dengue virus exposure, geographical location, or time of sample collection postinfection. To our knowledge, this work elucidates the first in depth characterization of human CD8+ T cells responding to ZIKV infection. PMID- 30413674 TI - Grit score and its relationship to successful enrolment in specialist veterinary training. PMID- 30413675 TI - Equine piroplasmosis status in the UK: an assessment of laboratory diagnostic submissions and techniques. AB - Equine piroplasmosis (EP) has historically been of minor concern to UK equine practitioners, primarily due to a lack of competent tick vectors. However, increased detection of EP tick vector species in the UK has been reported recently. EP screening is not currently required for equine importation, and when combined with recent relaxations in movement regulations, there is an increased risk regarding disease incursion and establishment into the UK. This study evaluated the prevalence of EP by both serology and PCR among 1242 UK equine samples submitted for EP screening between February and December 2016 to the Animal and Plant Health Agency and the Animal Health Trust. Where information was available, 81.5 per cent of submissions were for the purpose of UK export testing, and less than 0.1 per cent for UK importation. Serological prevalence of EP was 8.0 per cent, and parasite DNA was found in 0.8 per cent of samples. A subsequent analysis of PCR sensitivity in archived clinical samples indicated that the proportion of PCR-positive animals is likely to be considerably higher. The authors conclude that the current threat imposed by UK carrier horses is not adequately monitored and further measures are required to improve national biosecurity and prevent endemic disease. PMID- 30413676 TI - Cross-sectional study on viraemia and shedding of porcine circovirus type 2 in a subclinically infected multiplier sow herd. AB - Vertical and horizontal transmission of porcine circovirus type 2 (PCV2) plays an important role for the spread of PCV2 within piglet-producing farms and following production steps. Further information is crucial to learn about the principles of PCV2 circulation among sows in piglet-producing farms to improve preventive healthcare concerning porcine circovirus diseases (PCVD) in downstream production steps. The present study was conducted as a cross-sectional study in a 400 sow multiplier herd in Germany with no PCV2 vaccination. Blood, faeces and saliva of the sows in all stages of production were tested for PCV2-DNA by real-time PCR. Results were analysed under respect of the parity and stage of production of the sows. PCV2-DNA in faeces or saliva was observed especially in young sows. Highest rates of viraemia in productive sows were found in the early stages of pregnancy. The results revealed that particularly gilts from the quarantine and rearing area and sows up to the second parity play a major role for the spread of PCV2 and thus for the maintenance of PCV2 infection in sow herds. Furthermore, the stage of production had a significant influence on the detection rate of PCV2-DNA in serum, saliva or faeces of the sows. PMID- 30413677 TI - Exploratory metagenomic analyses of periweaning failure-to-thrive syndrome affected pigs. AB - Modern pig farming is characterised by the emergence of several syndromes whose aetiology is unclear or has a multifactorial origin, including periweaning failure-to-thrive syndrome (PFTS). In fact, its specific aetiology remains elusive, although several causes have been investigated over time. The present study aimed to investigate the potential role of viral agents in PFTS-affected and healthy animals by evaluating the virome composition of different organs using a metagenomic approach. This analysis allowed demonstrating a higher abundance of Porcine parvovirus 6 (PPV6) in healthy subjects while Ungulate bocaparvovirus 2 (BoPV2), Ungulate protoparvovirus 1 (PPV) and Porcine circovirus 3 (PCV-3) were increased in pigs with PFTS. No differential abundance of RNA viruses was found between PFTS-affected and control pigs. Remarkably, this is the first molecular characterisation of PPV6 and BoPV2 in Spain and one of the few all around the world, supporting their apparent widespread circulation. Interestingly, PCV-3 has been recently identified in several clinical pathological conditions as well as in healthy pigs, while BoPV2 pathogenic potential is unknown. Although obtained results must be taken as preliminary, they open the door for further studies on the potential role of these viruses or their combination as predisposing factor/s for PFTS occurrence. PMID- 30413678 TI - A survey of dairy cow farmers in the United Kingdom: knowledge, attitudes and practices surrounding antimicrobial use and resistance. AB - Antimicrobial resistance (AMR) is among the most pressing challenges facing humanity. This survey of dairy cow farmers (n=372) was conducted to explore knowledge, attitudes and practices surrounding veterinary medicine use and to identify farmer-led solutions to reducing, replacing and refining antimicrobial use. Antimicrobials were the most commonly reported veterinary medicines used. Twenty-two per cent of the antibiotics used by dairy farmers contained a highest priority critically important active ingredient. Mastitis was rated as the most important health and welfare challenge and was the most common reason for medicine use. Frequency of veterinary contact was associated with a decrease in the use of antibiotic footbaths, more 'responsible' treatment choices and increased knowledge of AMR. Purchasing medicine from a vet practice rather than elsewhere was associated with an increased likelihood of disposing of waste milk responsibly. These findings highlight the important role of veterinarians in guiding responsible medicine use. Ninety per cent of participants stated that they were trying to reduce their antimicrobial use. Farmers suggested a wide array of alternative treatments and potential interventions for managing herd health. Findings from this project could be used to target education and training surrounding best practice, supporting the important role that farmers play in protecting public health. PMID- 30413679 TI - G protein subunit phosphorylation as a regulatory mechanism in heterotrimeric G protein signaling in mammals, yeast, and plants. AB - Heterotrimeric G proteins composed of Galpha, Gbeta, and Ggamma subunits are vital eukaryotic signaling elements that convey information from ligand-regulated G protein-coupled receptors (GPCRs) to cellular effectors. Heterotrimeric G protein-based signaling pathways are fundamental to human health [Biochimica et Biophysica Acta (2007) 1768, 994-1005] and are the target of >30% of pharmaceuticals in clinical use [Biotechnology Advances (2013) 31, 1676-1694; Nature Reviews Drug Discovery (2017) 16, 829-842]. This review focuses on phosphorylation of G protein subunits as a regulatory mechanism in mammals, budding yeast, and plants. This is a re-emerging field, as evidence for phosphoregulation of mammalian G protein subunits from biochemical studies in the early 1990s can now be complemented with contemporary phosphoproteomics and genetic approaches applied to a diversity of model systems. In addition, new evidence implicates a family of plant kinases, the receptor-like kinases, which are monophyletic with the interleukin-1 receptor-associated kinase/Pelle kinases of metazoans, as possible GPCRs that signal via subunit phosphorylation. We describe early and modern observations on G protein subunit phosphorylation and its functional consequences in these three classes of organisms, and suggest future research directions. PMID- 30413680 TI - A structural perspective of plant antimicrobial peptides. AB - Among the numerous strategies plants have developed to fend off enemy attack, antimicrobial peptides (AMPs) stand out as one of the most prominent defensive barriers that grant direct and durable resistance against a wide range of pests and pathogens. These small proteins are characterized by a compact structure and an overall positive charge. AMPs have an ancient origin and widespread occurrence in the plant kingdom but show an unusually high degree of variation in their amino acid sequences. Interestingly, there is a strikingly conserved topology among the plant AMP families, suggesting that the defensive properties of these peptides are not determined by their primary sequences but rather by their tridimensional structure. To explore and expand this idea, we here discuss the role of AMPs for plant defense from a structural perspective. We show how specific structural properties, such as length, charge, hydrophobicity, polar angle and conformation, are essential for plant AMPs to act as a chemical shield that hinders enemy attack. Knowledge on the topology of these peptides is facilitating the isolation, classification and even structural redesign of AMPs, thus allowing scientists to develop new peptides with multiple agronomical and pharmacological potential. PMID- 30413681 TI - A Survey of Current Prophylactic Treatment for Ophthalmia Neonatorum in Croatia and a Review of International Preventive Practices. AB - BACKGROUND Ophthalmia neonatorum, or neonatal conjunctivitis, is an acute infection that occurs within the first 28 days of life. This aim of this survey was to evaluate the current methods of preventive treatment for ophthalmia neonatorum in maternity hospitals in Croatia. MATERIAL AND METHODS The annual hospital birth rate in Croatia is approximately 40,000. A clinical survey was undertaken with data collected using questionnaires sent to all 32 maternity hospitals in Croatia. There was a 100% response rate to the questionnaires. RESULTS Preventive treatment for ophthalmia neonatorum was administrated to all newborns in 75% (24/32) of Croatian maternity hospitals. In 45.8% of maternity hospitals, (11/32) these procedures were performed within the first hour after birth. In 54.2% of maternity hospitals (13/32), preventive treatment for ophthalmia neonatorum was administrated to all newborns from one to three hours after birth. The main treatment agent was tobramycin (83.3%). Other topical prophylactic treatments included povidone-iodine (8.3%), erythromycin (4.2%), and silver nitrate (4.2%). In 25% of obstetric units, prophylaxis for ophthalmia neonatorum was not used routinely, but in cases of diagnosed neonatal conjunctivitis, antibiotic treatment with tobramycin was mainly used. CONCLUSIONS A survey of all 32 maternity hospitals in Croatia showed variation in the prevalence of preventive treatment for ophthalmia neonatorum and the methods used. These findings support the need to implement standardized preventive measures that both conform to international clinical guidelines and recognize treatment availability in Croatia, where topical povidone-iodine is currently preferred for the prevention of ophthalmia neonatorum. PMID- 30413682 TI - Diabetic Ketoacidosis and the Domino Effect. AB - BACKGROUND Severe hypertriglyceridemia is a well-known cause of acute pancreatitis. Mild elevations of triglyceride levels are common in patients presenting with diabetic ketoacidosis (DKA). Rarely, DKA can be accompanied by an elevation of serum triglyceride level severe enough to lead to AP. CASE REPORT We report one such case of a young diabetic male who presented with DKA that was complicated by hypertriglyceridemia-induced acute pancreatitis (HTGAP). We were able to treat the condition with a slightly prolonged infusion of intravenous (IV) regular insulin in an efficient and cost-effective manner with a good outcome. CONCLUSIONS From our experience, DKA-associated HTGAP can be rapidly, efficiently, and cost-effectively treated with IV regular insulin and close biochemical monitoring. A high index of suspicion for acute pancreatitis is necessary in patients with DKA, especially with co-existing hypertriglyceridemia; and all efforts should be made to diagnose it in a timely manner to prevent subsequent complications. PMID- 30413683 TI - Expression of Concern to IRE1a constitutes a negative feedback loop with BMP2 and acts as a novel mediator in modulating osteogenic differentiation. AB - The Editors-in-Chief are issuing an editorial expression of concern to alert readers that after publication of this article1 concerns have been raised with respect to the integrity of Figs 1c, 1e, 2b, 6b, and 7a. Chongqing Medical University is investigating these concerns and appropriate editorial action will be taken once the outcome of this investigation is known. The authors do not agree with this notice. PMID- 30413685 TI - Unusually complex phase of dense nitrogen at extreme conditions. AB - Nitrogen exhibits an exceptional polymorphism under extreme conditions, making it unique amongst the elemental diatomics and a valuable testing system for experiment-theory comparison. Despite attracting considerable attention, the structures of many high-pressure nitrogen phases still require unambiguous determination. Here, we report the structure of the elusive high-pressure high temperature polymorph iota-N2 at 56 GPa and ambient temperature, determined by single crystal X-ray diffraction, and investigate its properties using ab initio simulations. We find that iota-N2 is characterised by an extraordinarily large unit cell containing 48 N2 molecules. Geometry optimisation favours the experimentally determined structure and density functional theory calculations find iota-N2 to have the lowest enthalpy of the molecular nitrogen polymorphs that exist between 30 and 60 GPa. The results demonstrate that very complex structures, similar to those previously only observed in metallic elements, can become energetically favourable in molecular systems at extreme pressures and temperatures. PMID- 30413684 TI - Interpreting clinical trial data in multiple myeloma: translating findings to the real-world setting. AB - Substantial improvements in survival have been seen in multiple myeloma (MM) over recent years, associated with the introduction and widespread use of multiple novel agents and regimens, as well as the emerging treatment paradigm of continuous or long-term therapy. However, these therapies and approaches may have limitations in the community setting, associated with toxicity burden, patient burden, and other factors including cost. Consequently, despite improvements in efficacy in the rigorously controlled clinical trials setting, the same results are not always achieved in real-world practice. Furthermore, the large number of different treatment options and regimens under investigation in various MM settings precludes the feasibility of obtaining head-to-head clinical trial data, and there is a temptation to use cross-trial comparisons to evaluate data across regimens. However, multiple aspects, including patient-related, disease-related, and treatment-related factors, can influence clinical trial outcomes and lead to differences between studies that may confound direct comparisons between data. In this review, we explore the various factors requiring attention when evaluating clinical trial data across available agents/regimens, as well as other considerations that may impact the translation of these findings into everyday MM management. We also investigate discrepancies between clinical trial efficacy and real-world effectiveness through a literature review of non-clinical trial data in relapsed/refractory MM on novel agent-based regimens and evaluate these data in the context of phase 3 trial results for recently approved and commonly used regimens. We thereby demonstrate the complexity of interpreting data across clinical studies in MM, as well as between clinical studies and routine-care analyses, with the aim to help clinicians consider all the necessary issues when tailoring individual patients' treatment approaches. PMID- 30413686 TI - Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy. AB - Brain tumor patients commonly present with epileptic seizures. We show that tumor associated seizures are the consequence of impaired GABAergic inhibition due to an overall loss of peritumoral fast spiking interneurons (FSNs) concomitant with a significantly reduced firing rate of those that remain. The reduced firing is due to the degradation of perineuronal nets (PNNs) that surround FSNs. We show that PNNs decrease specific membrane capacitance of FSNs permitting them to fire action potentials at supra-physiological frequencies. Tumor-released proteolytic enzymes degrade PNNs, resulting in increased membrane capacitance, reduced firing, and hence decreased GABA release. These studies uncovered a hitherto unknown role of PNNs as an electrostatic insulator that reduces specific membrane capacitance, functionally akin to myelin sheaths around axons, thereby permitting FSNs to exceed physiological firing rates. Disruption of PNNs may similarly account for excitation-inhibition imbalances in other forms of epilepsy and PNN protection through proteolytic inhibition may provide therapeutic benefits. PMID- 30413687 TI - N2H4 as traceless mediator for homo- and cross- aryl coupling. AB - Transition-metal catalyzed couplings of aryl halides or arenes with aryl organometallics, as well as direct reductive coupling of two aryl halides, are the predominant methods to synthesize biaryls. However, stoichiometric amounts of metals are inevitably utilized in these reactions, either in the pre-generation of organometallic reagents or acting as reductant in situ, thus producing quantitative metal waste. Herein, we demonstrate that this longstanding challenge can be overcome with N2H4 as a metal surrogate. The fundamental innovation of this strategy is that N2 and H2 are generated as side products, which readily escape from the system after the reaction. The success of both homo- and cross coupling of various aryl electrophiles bearing a wide range of functional groups manifests the powerfulness and versatility of this strategy. Furthermore, both homo- and cross-couplings of a series of alkaloids, amino acids and steroids exemplify application of this protocol in the functionalization of biologically active molecules. PMID- 30413688 TI - High-resolution ultramicroscopy of the developing and adult nervous system in optically cleared Drosophila melanogaster. AB - The fruit fly, Drosophila melanogaster, is an important experimental model to address central questions in neuroscience at an organismic level. However, imaging of neural circuits in intact fruit flies is limited due to structural properties of the cuticle. Here we present a novel approach combining tissue clearing, ultramicroscopy, and data analysis that enables the visualisation of neuronal networks with single-cell resolution from the larval stage up to the adult Drosophila. FlyClear, the signal preserving clearing technique we developed, stabilises tissue integrity and fluorescence signal intensity for over a month and efficiently removes the overall pigmentation. An aspheric ultramicroscope set-up utilising an improved light-sheet generator allows us to visualise long-range connections of peripheral sensory and central neurons in the visual and olfactory system. High-resolution 3D reconstructions with isotropic resolution from entire GFP-expressing flies are obtained by applying image fusion from orthogonal directions. This methodological integration of novel chemical, optical, and computational techniques allows a major advance in the analysis of global neural circuit organisation. PMID- 30413690 TI - Selectively exciting quasi-normal modes in open disordered systems. AB - Transmission through disordered samples can be controlled by illuminating a sample with waveforms corresponding to the eigenchannels of the transmission matrix (TM). But can the TM be exploited to selectively excite quasi-normal modes and so control the spatial profile and dwell time inside the medium? We show in microwave and numerical studies that spectra of the TM can be analyzed into modal transmission matrices of rank unity. This makes it possible to enhance the energy within a sample by a factor equal to the number of channels. Limits to modal selectivity arise, however, from correlation in the speckle patterns of neighboring modes. In accord with an effective Hamiltonian model, the degree of modal speckle correlation grows with increasing modal spectral overlap and non orthogonality of the modes of non-Hermitian systems. This is observed when the coupling of a sample to its surroundings increases, as in the crossover from localized to diffusive waves. PMID- 30413691 TI - Broadband highly directive 3D nanophotonic lenses. AB - Controlling the directivity of emission and absorption at the nanoscale holds great promise for improving the performance of optoelectronic devices. Previously, directive structures have largely been centered in two categories nanoscale antennas, and classical lenses. Herein, we utilize an evolutionary algorithm to design 3D dielectric nanophotonic lens structures leveraging both the interference-based control of antennas and the broadband operation of lenses. By sculpting the dielectric environment around an emitter, these nanolenses achieve directivities of 101 for point-sources, and 67 for finite-source nanowire emitters; 3* greater than that of a traditional spherical lens with nearly constant performance over a 200 nm wavelength range. The nanolenses are experimentally fabricated on GaAs nanowires, and characterized via photoluminescence Fourier microscopy, with an observed beaming half-angle of 3.5 degrees and a measured directivity of 22. Simulations attribute the main limitation in the obtained directivity to imperfect alignment of the nanolens to the nanowire beneath. PMID- 30413689 TI - MAIT cells contribute to protection against lethal influenza infection in vivo. AB - Mucosal associated invariant T (MAIT) cells are evolutionarily-conserved, innate like lymphocytes which are abundant in human lungs and can contribute to protection against pulmonary bacterial infection. MAIT cells are also activated during human viral infections, yet it remains unknown whether MAIT cells play a significant protective or even detrimental role during viral infections in vivo. Using murine experimental challenge with two strains of influenza A virus, we show that MAIT cells accumulate and are activated early in infection, with upregulation of CD25, CD69 and Granzyme B, peaking at 5 days post-infection. Activation is modulated via cytokines independently of MR1. MAIT cell-deficient MR1-/- mice show enhanced weight loss and mortality to severe (H1N1) influenza. This is ameliorated by prior adoptive transfer of pulmonary MAIT cells in both immunocompetent and immunodeficient RAG2-/-gammaC-/- mice. Thus, MAIT cells contribute to protection during respiratory viral infections, and constitute a potential target for therapeutic manipulation. PMID- 30413692 TI - A model of temporal scaling correctly predicts that motor timing improves with speed. AB - Timing is fundamental to complex motor behaviors: from tying a knot to playing the piano. A general feature of motor timing is temporal scaling: the ability to produce motor patterns at different speeds. One theory of temporal processing proposes that the brain encodes time in dynamic patterns of neural activity (population clocks), here we first examine whether recurrent neural network (RNN) models can account for temporal scaling. Appropriately trained RNNs exhibit temporal scaling over a range similar to that of humans and capture a signature of motor timing, Weber's law, but predict that temporal precision improves at faster speeds. Human psychophysics experiments confirm this prediction: the variability of responses in absolute time are lower at faster speeds. These results establish that RNNs can account for temporal scaling and suggest a novel psychophysical principle: the Weber-Speed effect. PMID- 30413693 TI - Fossilization transforms vertebrate hard tissue proteins into N-heterocyclic polymers. AB - Vertebrate hard tissues consist of mineral crystallites within a proteinaceous scaffold that normally degrades post-mortem. Here we show, however, that decalcification of Mesozoic hard tissues preserved in oxidative settings releases brownish stained extracellular matrix, cells, blood vessels, and nerve projections. Raman Microspectroscopy shows that these fossil soft tissues are a product of diagenetic transformation to Advanced Glycoxidation and Lipoxidation End Products, a class of N-heterocyclic polymers generated via oxidative crosslinking of proteinaceous scaffolds. Hard tissues in reducing environments, in contrast, lack soft tissue preservation. Comparison of fossil soft tissues with modern and experimentally matured samples reveals how proteinaceous tissues undergo diagenesis and explains biases in their preservation in the rock record. This provides a target, focused on oxidative depositional environments, for finding cellular-to-subcellular soft tissue morphology in fossils and validates its use in phylogenetic and other evolutionary studies. PMID- 30413695 TI - Thermal transport crossover from crystalline to partial-crystalline partial liquid state. AB - Phase-change materials (crystalline at low temperatures and partial-crystalline partial-liquid state at high temperatures) are widely used as thermoelectric converters and battery electrodes. Here, we report the underlying mechanisms driving the thermal transport of the liquid component, and the thermal conductivity contributions from phonons, vibrations with extremely short mean free path, liquid and lattice-liquid interactions in phase-changed Li2S. In the crystalline state (T <= 1000 K), the temperature dependent thermal conductivity manifests two different behaviors, i.e., a typical trend of 1/T below 800 K and an even faster decrease between 800 and 1000 K. For the partial-crystalline partial-liquid Li2S when T >= 1100 K, the contributions of liquid and lattice liquid interactions increase significantly due to the fluidization of Li ions, and the vibrations with extremely short mean free path, presumably assimilated to diffusons, can contribute up to 46% of the total thermal conductivity at T = 1300 K. PMID- 30413694 TI - Transition path times of coupled folding and binding reveal the formation of an encounter complex. AB - The association of biomolecules is the elementary event of communication in biology. Most mechanistic information of how the interactions between binding partners form or break is, however, hidden in the transition paths, the very short parts of the molecular trajectories from the encounter of the two molecules to the formation of a stable complex. Here we use single-molecule spectroscopy to measure the transition path times for the association of two intrinsically disordered proteins that form a folded dimer upon binding. The results reveal the formation of a metastable encounter complex that is electrostatically favored and transits to the final bound state within tens of microseconds. Such measurements thus open a new window into the microscopic events governing biomolecular interactions. PMID- 30413696 TI - Active intermixing of indirect and direct neurons builds the striatal mosaic. AB - The striatum controls behaviors via the activity of direct and indirect pathway projection neurons (dSPN and iSPN) that are intermingled in all compartments. While such cellular mosaic ensures the balanced activity of the two pathways, its developmental origin and pattern remains largely unknown. Here, we show that both SPN populations are specified embryonically and intermix progressively through multidirectional iSPN migration. Using conditional mutant mice, we found that inactivation of the dSPN-specific transcription factor Ebf1 impairs selective dSPN properties, including axon pathfinding, while molecular and functional features of iSPN were preserved. Ebf1 mutation disrupted iSPN/dSPN intermixing, resulting in an uneven distribution. Such architectural defect was selective of the matrix compartment, highlighting that intermixing is a parallel process to compartment formation. Our study reveals while iSPN/dSPN specification is largely independent, their intermingling emerges from an active migration of iSPN, thereby providing a novel framework for the building of striatal architecture. PMID- 30413697 TI - A Chiron approach towards the stereoselective synthesis of polyfluorinated carbohydrates. AB - The replacement of hydroxyl groups by fluorine atoms on hexopyranose scaffolds may allow access to the discovery of new chemical entities possessing unique physical, chemical and ultimately even biological properties. The prospect of significant effects generated by such multiple and controlled substitutions encouraged us to develop diverse synthetic routes towards the stereoselective synthesis of polyfluorinated hexopyranoses, six of which are unprecedented. Hence, we report the synthesis of heavily fluorinated galactose, glucose, mannose, talose, allose, fucose, and galacturonic acid methyl ester using a Chiron approach from inexpensive levoglucosan. Structural analysis of single crystal X-ray diffractions and NMR studies confirm the conservation of favored 4C1 conformation for fluorinated carbohydrate analogs, while a slightly distorted conformation due to repulsive 1,3-diaxial F...F interaction is observed for the trifluorinated talose derivative. Finally, the relative stereochemistry of multi vicinal fluorine atoms has a strong effect on the lipophilicities (logP). PMID- 30413698 TI - Phenotype loss is associated with widespread divergence of the gene regulatory landscape in evolution. AB - Detecting the genomic changes underlying phenotypic changes between species is a main goal of evolutionary biology and genomics. Evolutionary theory predicts that changes in cis-regulatory elements are important for morphological changes. We combined genome sequencing, functional genomics and genome-wide comparative analyses to investigate regulatory elements in lineages that lost morphological traits. We first show that limb loss in snakes is associated with widespread divergence of limb regulatory elements. We next show that eye degeneration in subterranean mammals is associated with widespread divergence of eye regulatory elements. In both cases, sequence divergence results in an extensive loss of transcription factor binding sites. Importantly, diverged regulatory elements are associated with genes required for normal limb patterning or normal eye development and function, suggesting that regulatory divergence contributed to the loss of these phenotypes. Together, our results show that genome-wide decay of the phenotype-specific cis-regulatory landscape is a hallmark of lost morphological traits. PMID- 30413699 TI - Diffusion-limited association of disordered protein by non-native electrostatic interactions. AB - Intrinsically disordered proteins (IDPs) usually fold during binding to target proteins. In contrast to interactions between folded proteins, this additional folding step makes the binding process more complex. Understanding the mechanism of coupled binding and folding of IDPs requires analysis of binding pathways that involve formation of the transient complex (TC). However, experimental characterization of TC is challenging because it only appears for a very brief period during binding. Here, we use single-molecule fluorescence spectroscopy to investigate the mechanism of diffusion-limited association of an IDP. A large enhancement of the association rate is observed due to the stabilization of TC by non-native electrostatic interactions. Moreover, photon-by-photon analysis reveals that the lifetime of TC for IDP binding is at least two orders of magnitude longer than that for binding of two folded proteins. This result suggests the long lifetime of TC is generally required for folding of IDPs during binding processes. PMID- 30413700 TI - Evidence of depolarization and ellipticity of high harmonics driven by ultrashort bichromatic circularly polarized fields. AB - High harmonics generated by counter-rotating laser fields at the fundamental and second harmonic frequencies have raised important interest as a table-top source of circularly polarized ultrashort extreme-ultraviolet light. However, this emission has not yet been fully characterized: in particular it was assumed to be fully polarized, leading to an uncertainty on the effective harmonic ellipticity. Here we show, through simulations, that ultrashort driving fields and ultrafast medium ionization lead to a breaking of the dynamical symmetry of the interaction, and consequently to deviations from perfectly circular and fully polarized harmonics, already at the single-atom level. We perform the complete experimental characterization of the polarization state of high harmonics generated along that scheme, giving direct access to the ellipticity absolute value and sign, as well as the degree of polarization of individual harmonic orders. This study allows defining optimal generation conditions of fully circularly polarized harmonics for advanced studies of ultrafast dichroisms. PMID- 30413701 TI - Plant defences mediate interactions between herbivory and the direct foliar uptake of atmospheric reactive nitrogen. AB - Reactive nitrogen from human sources (e.g., nitrogen dioxide, NO2) is taken up by plant roots following deposition to soils, but can also be assimilated by leaves directly from the atmosphere. Leaf uptake should alter plant metabolism and overall nitrogen balance and indirectly influence plant consumers; however, these consequences remain poorly understood. Here we show that direct foliar assimilation of NO2 increases levels of nitrogen-based defensive metabolites in leaves and reduces herbivore consumption and growth. These results suggest that atmospheric reactive nitrogen could have cascading negative effects on communities of herbivorous insects. We further show that herbivory induces a decrease in foliar uptake, indicating that consumers could limit the ability of vegetation to act as a sink for nitrogen pollutants (e.g., smog from mobile emissions). Our study suggests that the interactions of foliar uptake, plant defence and herbivory could have significant implications for understanding the environmental consequences of reactive nitrogen. PMID- 30413702 TI - Chemical bonding origin of the unexpected isotropic physical properties in thermoelectric Mg3Sb2 and related materials. AB - The Mg3Sb2 structure is currently being intensely scrutinized due to its outstanding thermoelectric properties. Usually, it is described as a layered Zintl phase with a clear distinction between covalent [Mg2Sb2]2- layers and ionic Mg2+ layers. Based on the quantitative chemical bonding analysis, we unravel instead that Mg3Sb2 exhibits a nearly isotropic three-dimensional bonding network with the interlayer and intralayer bonds being mostly ionic and surprisingly similar, which results in the nearly isotropic structural and thermal properties. The isotropic three-dimensional bonding network is found to be broadly applicable to many Mg-containing compounds with the CaAl2Si2-type structure. Intriguingly, a parameter based on the electron density can be used as an indicator measuring the anisotropy of lattice thermal conductivity in Mg3Sb2-related structures. This work extends our understanding of structure and properties based on chemical bonding analysis, and it will guide the search for and design of materials with tailored anisotropic properties. PMID- 30413704 TI - Neodymium isotope evidence for glacial-interglacial variability of deepwater transit time in the Pacific Ocean. AB - There is evidence for greater carbon storage in the glacial deep Pacific, but it is uncertain whether it was caused by changes in ventilation, circulation, and biological productivity. The spatial epsilonNd evolution in the deep Pacific provides information on the deepwater transit time. Seven new foraminiferal epsilonNd records are presented to systematically constrain glacial to interglacial changes in deep Pacific overturning and two different epsilonNd evolution regimes occur spatially in the Pacific with reduced meridional epsilonNd gradients in glacials, suggesting a faster deep Pacific overturning circulation. This implies that greater glacial carbon storage due to sluggish circulation, that is believed to have occurred in the deep Atlantic, did not operate in a similar manner in the Pacific Ocean. Other mechanisms such as increased biological pump efficiency and poor high latitude air-sea exchange could be responsible for increased carbon storage in the glacial Pacific. PMID- 30413703 TI - Transcriptome-wide identification of transient RNA G-quadruplexes in human cells. AB - Guanine-rich RNA sequences can fold into four-stranded structures, termed G quadruplexes (G4-RNAs), whose biological roles are poorly understood, and in vivo existence is debated. To profile biologically relevant G4-RNA in the human transcriptome, we report here on G4RP-seq, which combines G4-RNA-specific precipitation (G4RP) with sequencing. This protocol comprises a chemical crosslinking step, followed by affinity capture with the G4-specific small molecule ligand/probe BioTASQ, and target identification by sequencing, allowing for capturing global snapshots of transiently folded G4-RNAs. We detect widespread G4-RNA targets within the transcriptome, indicative of transient G4 formation in living human cells. Using G4RP-seq, we also demonstrate that G4 stabilizing ligands (BRACO-19 and RHPS4) can change the G4 transcriptomic landscape, most notably in long non-coding RNAs. G4RP-seq thus provides a method for studying the G4-RNA landscape, as well as ways of considering the mechanisms underlying G4-RNA formation, and the activity of G4-stabilizing ligands. PMID- 30413705 TI - Oestrogen receptor alpha AF-1 and AF-2 domains have cell population-specific functions in the mammary epithelium. AB - Oestrogen receptor alpha (ERalpha) is a transcription factor with ligand independent and ligand-dependent activation functions (AF)-1 and -2. Oestrogens control postnatal mammary gland development acting on a subset of mammary epithelial cells (MECs), termed sensor cells, which are ERalpha-positive by immunohistochemistry (IHC) and secrete paracrine factors, which stimulate ERalpha negative responder cells. Here we show that deletion of AF-1 or AF-2 blocks pubertal ductal growth and subsequent development because both are required for expression of essential paracrine mediators. Thirty percent of the luminal cells are ERalpha-negative by IHC but express Esr1 transcripts. This low level ERalpha expression through AF-2 is essential for cell expansion during puberty and growth inhibitory during pregnancy. Cell-intrinsic ERalpha is not required for cell proliferation nor for secretory differentiation but controls transcript levels of cell motility and cell adhesion genes and a stem cell and epithelial mesenchymal transition (EMT) signature identifying ERalpha as a key regulator of mammary epithelial cell plasticity. PMID- 30413706 TI - The critical role of AMPK in driving Akt activation under stress, tumorigenesis and drug resistance. AB - PI3K/Akt signaling is activated in cancers and governs tumor initiation and progression, but how Akt is activated under diverse stresses is poorly understood. Here we identify AMPK as an essential regulator for Akt activation by various stresses. Surprisingly, AMPK is also activated by growth factor EGF through Ca2+/Calmodulin-dependent kinase and is essential for EGF-mediated Akt activation and biological functions. AMPK phosphorylates Skp2 at S256 and promotes the integrity and E3 ligase activity of Skp2 SCF complex leading to K63 linked ubiquitination and activation of Akt and subsequent oncogenic processes. Importantly, AMPK-mediated Skp2 S256 phosphorylation promotes breast cancer progression in mouse tumor models, correlates with Akt and AMPK activation in breast cancer patients, and predicts poor survival outcomes. Finally, targeting AMPK-mediated Skp2 S256 phosphorylation sensitizes cells to anti-EGF receptor targeted therapy. Our study sheds light on how stress and EGF induce Akt activation and new mechanisms for AMPK-mediated oncogenesis and drug resistance. PMID- 30413708 TI - A gas breathing hydrogen/air biofuel cell comprising a redox polymer/hydrogenase based bioanode. AB - Hydrogen is one of the most promising alternatives for fossil fuels. However, the power output of hydrogen/oxygen fuel cells is often restricted by mass transport limitations of the substrate. Here, we present a dual-gas breathing H2/air biofuel cell that overcomes these limitations. The cell is equipped with a hydrogen-oxidizing redox polymer/hydrogenase gas-breathing bioanode and an oxygen reducing bilirubin oxidase gas-breathing biocathode (operated in a direct electron transfer regime). The bioanode consists of a two layer system with a redox polymer-based adhesion layer and an active, redox polymer/hydrogenase top layer. The redox polymers protect the biocatalyst from high potentials and oxygen damage. The bioanodes show remarkable current densities of up to 8 mA cm-2. A maximum power density of 3.6 mW cm-2 at 0.7 V and an open circuit voltage of up to 1.13 V were achieved in biofuel cell tests, representing outstanding values for a device that is based on a redox polymer-based hydrogenase bioanode. PMID- 30413709 TI - Crystal structures of human ETB receptor provide mechanistic insight into receptor activation and partial activation. AB - Endothelin receptors (ETA and ETB) are class A GPCRs activated by vasoactive peptide endothelins, and are involved in blood pressure regulation. ETB-selective signalling induces vasorelaxation, and thus selective ETB agonists are expected to be utilized for improved anti-tumour drug delivery and neuroprotection. Here, we report the crystal structures of human ETB receptor in complex with ETB selective agonist, endothelin-3 and an ETB-selective endothelin analogue IRL1620. The structure of the endothelin-3-bound receptor reveals that the disruption of water-mediated interactions between W6.48 and D2.50 is critical for receptor activation, while these hydrogen-bonding interactions are partially preserved in the IRL1620-bound structure. Consistently, functional analysis reveals the partial agonistic effect of IRL1620. The current findings clarify the detailed molecular mechanism for the coupling between the orthosteric pocket and the G protein binding, and the partial agonistic effect of IRL1620, thus paving the way for the design of improved agonistic drugs targeting ETB. PMID- 30413710 TI - Mapping knowledge gaps in marine diversity reveals a latitudinal gradient of missing species richness. AB - A reliable description of any spatial pattern in species richness requires accurate knowledge about species geographical distribution. However, sampling bias may generate artefactual absences within species range and compromise our capacity to describe biodiversity patterns. Here, we analysed the spatial distribution of 35,000 marine species (varying from copepods to sharks) to identify missing occurrences (gaps) across their latitudinal range. We find a latitudinal gradient of species absence peaking near the equator, a pattern observed in both shallow and deep waters. The tropical gap in species distribution seems a consequence of reduced sampling effort at low latitudes. Overall, our results suggest that spatial gaps in species distribution are the main cause of the bimodal pattern of marine diversity. Therefore, only increasing sampling effort at low latitudes will reveal if the absence of species in the tropics, and the consequent dip in species richness, are artefacts of sampling bias or a natural phenomenon. PMID- 30413707 TI - Diet-induced adaptive thermogenesis requires neuropeptide FF receptor-2 signalling. AB - Excess caloric intake results in increased fat accumulation and an increase in energy expenditure via diet-induced adaptive thermogenesis; however, the underlying mechanisms controlling these processes are unclear. Here we identify the neuropeptide FF receptor-2 (NPFFR2) as a critical regulator of diet-induced thermogenesis and bone homoeostasis. Npffr2-/- mice exhibit a stronger bone phenotype and when fed a HFD display exacerbated obesity associated with a failure in activating brown adipose tissue (BAT) thermogenic response to energy excess, whereas the activation of cold-induced BAT thermogenesis is unaffected. NPFFR2 signalling is required to maintain basal arcuate nucleus NPY mRNA expression. Lack of NPFFR2 signalling leads to a decrease in BAT thermogenesis under HFD conditions with significantly lower UCP-1 and PGC-1alpha levels in the BAT. Together, these data demonstrate that NPFFR2 signalling promotes diet induced thermogenesis via a novel hypothalamic NPY-dependent circuitry thereby coupling energy homoeostasis with energy partitioning to adipose and bone tissue. PMID- 30413712 TI - The diamine cation is not a chemical example where density functional theory fails. PMID- 30413711 TI - A common genetic mechanism underlies morphological diversity in fruits and other plant organs. AB - Shapes of edible plant organs vary dramatically among and within crop plants. To explain and ultimately employ this variation towards crop improvement, we determined the genetic, molecular and cellular bases of fruit shape diversity in tomato. Through positional cloning, protein interaction studies, and genome editing, we report that OVATE Family Proteins and TONNEAU1 Recruiting Motif proteins regulate cell division patterns in ovary development to alter final fruit shape. The physical interactions between the members of these two families are necessary for dynamic relocalization of the protein complexes to different cellular compartments when expressed in tobacco leaf cells. Together with data from other domesticated crops and model plant species, the protein interaction studies provide possible mechanistic insights into the regulation of morphological variation in plants and a framework that may apply to organ growth in all plant species. PMID- 30413713 TI - Design and 22-step synthesis of highly potent D-ring modified and linker-equipped analogs of spongistatin 1. AB - Spongistatin 1 is among the most potent anti-proliferative agents ever discovered rendering it an attractive candidate for development as a payload for antibody drug conjugates and other targeted delivery approaches. Unfortunately, it is unavailable from natural sources and its size and complex stereostructure render chemical synthesis highly time- and resource-intensive. As a result, the design and synthesis of more acid-stable and linker functional group-equipped analogs that retain the low picomolar potency of the parent natural product requires more efficient and step-economical synthetic access. Using uniquely enabling direct complex fragment coupling crotyl- and alkallylsilylation reactions, we report a 22-step synthesis of a rationally designed D-ring modified analog of spongistatin 1 that is characterized by GI50 values in the low picomolar range, and a proof-of concept result that the C(15) acetate may be replaced with linker functional group-bearing esters with only minimal reductions in potency. PMID- 30413714 TI - Inflammation-induced Id2 promotes plasticity in regulatory T cells. AB - TH17 cells originating from regulatory T (Treg) cells upon loss of the Treg specific transcription factor Foxp3 accumulate in sites of inflammation and aggravate autoimmune diseases. Whether an active mechanism drives the generation of these pathogenic 'ex-Foxp3 TH17' cells, remains unclear. Here we show that pro inflammatory cytokines enhance the expression of transcription regulator Id2, which mediates cellular plasticity of Treg into ex-Foxp3 TH17 cells. Expression of Id2 in in vitro differentiated iTreg cells reduces the expression of Foxp3 by sequestration of the transcription activator E2A, leading to the induction of TH17-related cytokines. Treg-specific ectopic expression of Id2 in mice significantly reduces the Treg compartment and causes immune dysregulation. Cellular fate-mapping experiments reveal enhanced Treg plasticity compared to wild-type, resulting in exacerbated experimental autoimmune encephalomyelitis pathogenesis or enhanced anti-tumor immunity. Our findings suggest that controlling Id2 expression may provide a novel approach for effective Treg cell immunotherapies for both autoimmunity and cancer. PMID- 30413715 TI - Discovery of rare cells from voluminous single cell expression data. AB - Single cell messenger RNA sequencing (scRNA-seq) provides a window into transcriptional landscapes in complex tissues. The recent introduction of droplet based transcriptomics platforms has enabled the parallel screening of thousands of cells. Large-scale single cell transcriptomics is advantageous as it promises the discovery of a number of rare cell sub-populations. Existing algorithms to find rare cells scale unbearably slowly or terminate, as the sample size grows to the order of tens of thousands. We propose Finder of Rare Entities (FiRE), an algorithm that, in a matter of seconds, assigns a rareness score to every individual expression profile under study. We demonstrate how FiRE scores can help bioinformaticians focus the downstream analyses only on a fraction of expression profiles within ultra-large scRNA-seq data. When applied to a large scRNA-seq dataset of mouse brain cells, FiRE recovered a novel sub-type of the pars tuberalis lineage. PMID- 30413716 TI - Harnessing photoinduced electron transfer to optically determine protein sub nanoscale atomic distances. AB - Proteins possess a complex and dynamic structure, which is influenced by external signals and may change as they perform their biological functions. We present an optical approach, distance-encoding photoinduced electron transfer (DEPET), capable of the simultaneous study of protein structure and function. An alternative to FRET-based methods, DEPET is based on the quenching of small conjugated fluorophores by photoinduced electron transfer: a reaction that requires contact of the excited fluorophore with a suitable electron donor. This property allows DEPET to exhibit exceptional spatial and temporal resolution capabilities in the range pertinent to protein conformational change. We report the first implementation of DEPET on human large-conductance K+ (BK) channels under voltage clamp. We describe conformational rearrangements underpinning BK channel sensitivity to electrical excitation, in conducting channels expressed in living cells. Finally, we validate DEPET in synthetic peptide length standards, to evaluate its accuracy in measuring sub- and near-nanometer intramolecular distances. PMID- 30413717 TI - Spontaneous formation of nanoparticles on electrospun nanofibres. AB - We report the spontaneous formation of nanoparticles on smooth nanofibres in a single-step electrospinning process, as an inexpensive and scalable method for producing high-surface-area composites. Layers of nanofibres, containing the proton conducting electrolyte, caesium dihydrogen phosphate, are deposited uniformly over large area substrates from clear solutions of the electrolyte mixed with polymers. Under certain conditions, the normally smooth nanofibres develop caesium dihydrogen phosphate nanoparticles in large numbers on their external surface. The nanoparticles appear to originate from the electrolyte within the fibres, which is transported to the outer surface after the fibres are deposited, as evidenced by cross-sectional imaging of the electrospun fibres. The presence of nanoparticles on the fibre surface yields composites with increased surface area of exposed electrolyte, which ultimately enhances electrocatalytic performance. Indeed, solid acid fuel cells fabricated with electrodes from processed nanofibre-nanoparticle composites, produced higher cell voltage as compared to fuel cells fabricated with state-of-the-art electrodes. PMID- 30413718 TI - Targeting 17q23 amplicon to overcome the resistance to anti-HER2 therapy in HER2+ breast cancer. AB - Chromosome 17q23 amplification occurs in ~11% of human breast cancers. Enriched in HER2+ breast cancers, the 17q23 amplification is significantly correlated with poor clinical outcomes. In addition to the previously identified oncogene WIP1, we uncover an oncogenic microRNA gene, MIR21, in a majority of the WIP1 containing 17q23 amplicons. The 17q23 amplification results in aberrant expression of WIP1 and miR-21, which not only promotes breast tumorigenesis, but also leads to resistance to anti-HER2 therapies. Inhibiting WIP1 and miR-21 selectively inhibits the proliferation, survival and tumorigenic potential of the HER2+ breast cancer cells harboring 17q23 amplification. To overcome the resistance of trastuzumab-based therapies in vivo, we develop pH-sensitive nanoparticles for specific co-delivery of the WIP1 and miR-21 inhibitors into HER2+ breast tumors, leading to a profound reduction of tumor growth. These results demonstrate the great potential of the combined treatment of WIP1 and miR 21 inhibitors for the trastuzumab-resistant HER2+ breast cancers. PMID- 30413719 TI - Crystallographic and spectroscopic assignment of the proton transfer pathway in [FeFe]-hydrogenases. AB - The unmatched catalytic turnover rates of [FeFe]-hydrogenases require an exceptionally efficient proton-transfer (PT) pathway to shuttle protons as substrates or products between bulk water and catalytic center. For clostridial [FeFe]-hydrogenase CpI such a pathway has been proposed and analyzed, but mainly on a theoretical basis. Here, eleven enzyme variants of two different [FeFe] hydrogenases (CpI and HydA1) with substitutions in the presumptive PT-pathway are examined kinetically, spectroscopically, and crystallographically to provide solid experimental proof for its role in hydrogen-turnover. Targeting key residues of the PT-pathway by site directed mutagenesis significantly alters the pH-activity profile of these variants and in presence of H2 their cofactor is trapped in an intermediate state indicative of precluded proton-transfer. Furthermore, crystal structures coherently explain the individual levels of residual activity, demonstrating e.g. how trapped H2O molecules rescue the interrupted PT-pathway. These features provide conclusive evidence that the targeted positions are indeed vital for catalytic proton-transfer. PMID- 30413721 TI - The effect of non-thermal atmospheric plasma on the production and activity of recombinant phytase enzyme. AB - Atmospheric pressure cold plasma (ACP) is introduced as a useful tool in a variety of biological applications. Proteins are the most abundant macromolecules in living systems with a central role in all biological processes. These organic molecules are modified by ACP exposure that is responsible for many of ACP's biological effects. This study evaluated the effect of ACP on the production of recombinant phytase in yeast Pichia pastoris (P. pastoris) as well as the structure and function of the phytase enzyme. The results indicated that yeast cells treated with ACP, directly or indirectly, produced higher amounts of recombinant phytase, which was associated with the time of ACP treatment. The exposure of commercial phytase solution with ACP caused a significant increase in the enzyme activity (125%) after 4 hours. Evaluation of the phytase solution by far- and near-UV circular dichroism (CD) and fluorescence analysis indicated that this protein maintained its secondary structure when exposed to ACP while the tertiary structure was slightly unfolded. The effects of heat and H2O2 on the phytase structure and function were compared with the effect of ACP treatment. The modification of Cys, Tyr and Trp amino acids upon reactive oxygen/nitrogen spices was simulated using a molecular dynamics approach. RMSF and RMSD analysis suggested that this structural alteration occurs owing to changes made by reactive species in accessible amino acids. PMID- 30413720 TI - Leveraging heterogeneity across multiple datasets increases cell-mixture deconvolution accuracy and reduces biological and technical biases. AB - In silico quantification of cell proportions from mixed-cell transcriptomics data (deconvolution) requires a reference expression matrix, called basis matrix. We hypothesize that matrices created using only healthy samples from a single microarray platform would introduce biological and technical biases in deconvolution. We show presence of such biases in two existing matrices, IRIS and LM22, irrespective of deconvolution method. Here, we present immunoStates, a basis matrix built using 6160 samples with different disease states across 42 microarray platforms. We find that immunoStates significantly reduces biological and technical biases. Importantly, we find that different methods have virtually no or minimal effect once the basis matrix is chosen. We further show that cellular proportion estimates using immunoStates are consistently more correlated with measured proportions than IRIS and LM22, across all methods. Our results demonstrate the need and importance of incorporating biological and technical heterogeneity in a basis matrix for achieving consistently high accuracy. PMID- 30413722 TI - p.(Asp47Asn) and p.(Thr62Met): non deleterious LDL receptor missense variants functionally characterized in vitro. AB - Familial Hypercholesterolemia (FH) is a common genetic disorder caused most often by mutations in the Low Density Lipoprotein Receptor gene (LDLr) leading to high blood cholesterol levels, and ultimately to development of premature coronary heart disease. Genetic analysis and subsequent cascade screening in relatives allow diagnosis of FH at early stage, especially relevant to diagnose children. So far, more than 2300 LDLr variants have been described but only a minority of them have been functionally analysed to evaluate their pathogenicity in FH. Thus, identifying pathogenic mutations in LDLr is a long-standing challenge in the field. In this study, we investigated in vitro the activity p.(Asp47Asn) and p.(Thr62Met) LDLr variants, both in the LR1 region. We used CHO-ldlA7 transfected cells with plasmids carrying p.(Asp47Asn) or p.(Thr62Met) LDLr variants to analyse LDLr expression by FACS and immunoblotting, LDL binding and uptake was determined by FACS and analysis of mutation effects was assessed in silico. The in vitro activity assessment of p.(Asp47Asn) and p.(Thr62Met) LDLr variants shows a fully functional LDL binding and uptake activities. Therefore indicating that the three of them are non-pathogenic LDLr variants. These findings also emphasize the importance of in vitro functional LDLr activity studies to optimize the genetic diagnosis of FH avoiding the report of non-pathogenic variants and possible misdiagnose in relatives if cascade screening is carried out. PMID- 30413724 TI - Pretreatment Inflammation-Based Markers Predict Survival Outcomes in Patients with Early Stage Hepatocellular Carcinoma After Radiofrequency Ablation. AB - The prognostic significance of various systemic inflammation-based markers has been explored in different cancers after surgery. This study aimed to investigate whether these markers could predict outcomes in patients with early-stage hepatocellular carcinoma (HCC) undergoing radiofrequency ablation (RFA). One hundred eighteen patients with newly diagnosed HCC within the Milan criteria receiving RFA as initial therapy were retrospectively enrolled. Pretreatment inflammation-based markers including the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and prognostic nutritional index (PNI), together with other clinicopathologic parameters were collected. Cumulative overall survival (OS) and recurrence-free survival (RFS) were estimated by the Kaplan-Meier method and by multivariate analysis using Cox proportional hazard model. The 1-, 3-, and 5-year OS rates of patients were 90%, 67%, and 52%, respectively. Kaplan-Meier curves showed that baseline high NLR >= 2.5 (p = 0.006), low PNI < 40 (p = 0.005), history of end-stage renal disease (ESRD) (p = 0.005), non-Child-Pugh class A (p = 0.001) and elevated alpha-fetoprotein (AFP) >= 200 ng/mL (p = 0.005) significantly associated with the poor OS, whereas high PLR >= 100 did not. By multivariate analysis, high NLR >= 2.5 (hazard ratio (HR) 1.94; 95% confidence interval (CI), 1.05-3.59; p = 0.034), low PNI < 40 (HR 0.38; 95% CI, 0.20-0.72; p = 0.003), ESRD history (HR 3.60; 95% CI, 1.48-8.76; p = 0.005) and elevated AFP >= 200 ng/mL (HR 4.61; 95% CI, 1.75-12.13; p = 0.002) were independent factors. An elevated AFP level of >=200 ng/mL was the significant factor associated with intrahepatic new RFS by univariate and multivariate analyses. In conclusion, pretreatment NLR and PNI are simple and useful predictors for OS in patients with early-stage HCC after RFA. PMID- 30413723 TI - Ongoing human chromosome end extension revealed by analysis of BioNano and nanopore data. AB - The majority of human chromosome ends remain incompletely assembled due to their highly repetitive structure. In this study, we use BioNano data to anchor and extend chromosome ends from two European trios as well as two unrelated Asian genomes. At least 11 BioNano assembled chromosome ends are structurally divergent from the reference genome, including both missing sequence and extensions. These extensions are heritable and in some cases divergent between Asian and European samples. Six out of nine predicted extension sequences from NA12878 can be confirmed and filled by nanopore data. We identify two multi-kilobase sequence families both enriched more than 100-fold in extension sequence (p-values < 1e-5) whose origins can be traced to interstitial sequence on ancestral primate chromosome 7. Extensive sub-telomeric duplication of these families has occurred in the human lineage subsequent to divergence from chimpanzees. PMID- 30413725 TI - Lung fibroblasts express a miR-19a-19b-20a sub-cluster to suppress TGF-beta associated fibroblast activation in murine pulmonary fibrosis. AB - Lung fibroblasts play a pivotal role in pulmonary fibrosis, a devastating lung disease, by producing extracellular matrix. MicroRNAs (miRNAs) suppress numerous genes post-transcriptionally; however, the roles of miRNAs in activated fibroblasts in fibrotic lungs remain poorly understood. To elucidate these roles, we performed global miRNA-expression profiling of fibroblasts from bleomycin- and silica-induced fibrotic lungs and investigated the functions of miRNAs in activated lung fibroblasts. Clustering analysis of global miRNA-expression data identified miRNA signatures exhibiting increased expression during fibrosis progression. Among these signatures, we found that a miR-19a-19b-20a sub-cluster suppressed TGF-beta-induced activation of fibroblasts in vitro. Moreover, to elucidate whether fibroblast-specific intervention against the sub-cluster modulates pathogenic activation of fibroblasts in fibrotic lungs, we intratracheally transferred the sub-cluster-overexpressing fibroblasts into bleomycin-treated lungs. Global transcriptome analysis of the intratracheally transferred fibroblasts revealed that the sub-cluster not only downregulated expression of TGF-beta-associated pro-fibrotic genes, including Acta2, Col1a1, Ctgf, and Serpine1, but also upregulated expression of the anti-fibrotic genes Dcn, Igfbp5, and Mmp3 in activated lung fibroblasts. Collectively, these findings indicated that upregulation of the miR-19a-19b-20a sub-cluster expression in lung fibroblasts counteracted TGF-beta-associated pathogenic activation of fibroblasts in murine pulmonary fibrosis. PMID- 30413726 TI - Unlocking conserved and diverged metabolic characteristics in cassava carbon assimilation via comparative genomics approach. AB - Globally, cassava is an important source of starch, which is synthesized through carbon assimilation in cellular metabolism whereby harvested atmospheric carbon is assimilated into macromolecules. Although the carbon assimilation pathway is highly conserved across species, metabolic phenotypes could differ in composition, type, and quantity. To unravel the metabolic complexity and advantage of cassava over other starch crops, in terms of starch production, we investigated the carbon assimilation mechanisms in cassava through genome-based pathway reconstruction and comparative network analysis. First, MeRecon - the carbon assimilation pathway of cassava was reconstructed based upon six plant templates: Arabidopsis, rice, maize, castor bean, potato, and turnip. MeRecon, available at http://bml.sbi.kmutt.ac.th/MeRecon, comprises 259 reactions (199 EC numbers), 1,052 proteins (870 genes) and 259 metabolites in eight sub metabolisms. Analysis of MeRecon and the carbon assimilation pathways of the plant templates revealed the overall topology is highly conserved, but variations at sub metabolism level were found in relation to complexity underlying each biochemical reaction, such as numbers of responsible enzymatic proteins and their evolved functions, which likely explain the distinct metabolic phenotype. Thus, this study provides insights into the network characteristics and mechanisms that regulate the synthesis of metabolic phenotypes of cassava. PMID- 30413727 TI - The effect of drinking water pH on the human gut microbiota and glucose regulation: results of a randomized controlled cross-over intervention. AB - Studies in rodent models have shown that alterations in drinking water pH affect both the composition of the gut microbiota and host glucose regulation. To explore a potential impact of electrochemically reduced alkaline (pH ~ 9) versus neutral (pH ~ 7) drinking water (2 L/day) on human intestinal microbiota and host glucose metabolism we conducted a randomized, non-blinded, cross-over study (two 2-week intervention periods, separated by a 3-week wash-out) in 29 healthy, non smoking Danish men, aged 18 to 35 years, with a body mass index between 20.0 to 27.0 kg m-2. Volunteers were ineligible if they had previously had abdominal surgery, had not been weight stabile for at least two months, had received antibiotic treatment within 2 months, or had a habitual consumption of caloric or artificially sweetened beverages in excess of 1 L/week or an average intake of alcohol in excess of 7 units/week. Microbial DNA was extracted from faecal samples collected at four time points, before and after each intervention, and subjected to 16S rRNA gene amplicon sequencing (Illumina MiSeq, V4 region). Glycaemic regulation was evaluated by means of an oral glucose tolerance test.No differential effect of alkaline versus neutral drinking water was observed for the primary outcome, overall gut microbiota diversity as represented by Shannon's index. Similarly, neither a differential effect on microbiota richness or community structure was observed. Nor did we observe a differential effect on the abundance of individual operational taxonomic units (OTUs) or genera. However, analyses of within period effects revealed a significant (false discovery rate <=5%) increase in the relative abundance of 9 OTUs assigned to order Clostridiales, family Ruminococcaceae, genus Bacteroides, and species Prevotella copri, indicating a potential effect of quantitative or qualitative changes in habitual drinking habits. An increase in the concentration of plasma glucose at 30 minutes and the incremental area under the curve of plasma glucose from 0 30 and 0 120 minutes, respectively, was observed when comparing the alkaline to the neutral intervention. However, results did not withstand correction for multiplicity. In contrast to what has been reported in rodents, a change in drinking water pH had no impact on the composition of the gut microbiota or glucose regulation in young male adults. The study is registered at www.clinicaltrials.gov (NCT02917616). PMID- 30413729 TI - Implications of high rates of sexual recruitment in driving rapid reef recovery in Mo'orea, French Polynesia. AB - Coral abundance continues to decline on tropical reefs around the world, and this trend suggests that coral reefs may not persist beyond the current century. In contrast, this study describes the near-complete mortality of corals on the outer reef (10 m and 17 m depth) of the north shore of Mo'orea, French Polynesia, from 2005 to 2010, followed by unprecedented recovery from 2011 to 2017. Intense corallivory and a cyclone drove coral cover from 33-48% to <3% by 2010, but over the following seven years, recovery occurred through rapid population growth (up to 12% cover y-1) to 25-74% cover by 2017. The thirteen-year, U-shape trajectory of coral cover over time created by the loss and replacement of millions of corals through sexual reproduction underscores the potential for beneficial genetic responses to environmental conditions for at least one genus, Pocillopora. The high ecological resilience of this coral community appears to have been enhanced by variation among genera in the susceptibility to declining cover, and the capacity for population growth (i.e., response diversity). These results suggest that the outer coral communities of Mo'orea may be poised for genetic changes that could affect their capacity to persistence. PMID- 30413728 TI - Lysosomal and network alterations in human mucopolysaccharidosis type VII iPSC derived neurons. AB - Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by deficient beta-glucuronidase (beta-gluc) activity. Significantly reduced beta gluc activity leads to accumulation of glycosaminoglycans (GAGs) in many tissues, including the brain. Numerous combinations of mutations in GUSB (the gene that codes for beta-gluc) cause a range of neurological features that make disease prognosis and treatment challenging. Currently, there is little understanding of the molecular basis for MPS VII brain anomalies. To identify a neuronal phenotype that could be used to complement genetic analyses, we generated two iPSC clones derived from skin fibroblasts of an MPS VII patient. We found that MPS VII neurons exhibited reduced beta-gluc activity and showed previously established disease-associated phenotypes, including GAGs accumulation, expanded endocytic compartments, accumulation of lipofuscin granules, more autophagosomes, and altered lysosome function. Addition of recombinant beta-gluc to MPS VII neurons, which mimics enzyme replacement therapy, restored disease-associated phenotypes to levels similar to the healthy control. MPS VII neural cells cultured as 3D neurospheroids showed upregulated GFAP gene expression, which was associated with astrocyte reactivity, and downregulation of GABAergic neuron markers. Spontaneous calcium imaging analysis of MPS VII neurospheroids showed reduced neuronal activity and altered network connectivity in patient-derived neurospheroids compared to a healthy control. These results demonstrate the interplay between reduced beta-gluc activity, GAG accumulation and alterations in neuronal activity, and provide a human experimental model for elucidating the bases of MPS VII-associated cognitive defects. PMID- 30413730 TI - Effect of selected biocides on microbiologically influenced corrosion caused by Desulfovibrio ferrophilus IS5. AB - The marine bacterial strain Desulfovibrio ferrophilus IS5, known for its lithotrophic growth ability to use metallic iron as a sole electron donor and for causing corrosion of steel, was used in the current study. Four commonly used biocides in the oil and gas industry, namely tetrakis(hydroxymethyl) phosphonium sulfate (THPS), glutaraldehyde (GLUT), benzalkonium chloride (BAC), and GLUT/BAC were selected to study their efficacy in controlling carbon steel corrosion in the presence of this strain. Incubations containing strain IS5 and low carbon steel coupons were prepared in the presence and absence of the four biocides, and these were monitored using both electrochemical methods (electrochemical impedance spectroscopy, linear polarization resistance and potentiodynamic polarization) and surface analyses (scanning electron microscopy, confocal measurements, optical microscopy, and profilometry) to assess the biofilm/metal interactions. When THPS, BAC, and GLUT/BAC treatments were applied, minimal corrosion was measured by all methods. In contrast, severe pitting was observed in the presence of 50 ppm GLUT, similar to what was observed when D. ferrophilus IS5 was incubated in the absence of biocide, suggesting that GLUT alone may not be effective in controlling MIC in marine environments. This study also showed that the use of non-destructive electrochemical methods is effective for screening for real time biocide selection and monitoring of the impact of chemicals post-dosage in oil and gas operations. PMID- 30413732 TI - Thermochronological insights into reactivation of a continental shear zone in response to Equatorial Atlantic rifting (northern Ghana). AB - West Africa was subjected to deformation and exhumation in response to Gondwana break-up. The timing and extent of these events are recorded in the thermal history of the margin. This study reports new apatite fission track (AFT) data from Palaeoproterozoic basement along the primary NE-SW structural trend of the Bole-Nangodi shear zone in northwestern Ghana. The results display bimodality in AFT age (populations of ~210-180 Ma and ~115-105 Ma) and length distributions (populations of 12.2 +/- 1.6 and 13.1 +/- 1.4 um), supported by differences in apatite chemistry (U concentrations). The bimodal AFT results and associated QTQt thermal history models provide evidence for multiple cooling phases. Late Triassic - Early Jurassic cooling is interpreted to be related with thermal relaxation after the emplacement of the Central Atlantic Magmatic Province (CAMP). Early to middle Cretaceous cooling is thought to be associated with exhumation during the Cretaceous onset of rifting between West Africa and Brazil. Late Cretaceous - Cenozoic cooling can be related with exhumation of the Ivory Coast - Ghana margin and NNW-SSE shortening through western Africa. Furthermore, our data record differential exhumation of the crust with respect to the Bole Nangodi shear zone, preserving older (CAMP) cooling ages to the south and younger (rifting) cooling ages to the north of the shear zone, respectively. This suggests that the Palaeoproterozoic BN shear zone was reactivated during the Cretaceous as a result of deformation in the Equatorial Atlantic region of Africa. PMID- 30413731 TI - Functional eubacteria species along with trans-domain gut inhabitants favour dysgenic diversity in oxalate stone disease. AB - Analyses across all three domains of life are necessary to advance our understanding of taxonomic dysbiosis in human diseases. In the present study, we assessed gut microbiota (eubacteria, archaea, and eukaryotes) of recurrent oxalate kidney stone suffers to explore the extent of trans-domain and functional species dysbiosis inside the gut. Trans-domain taxonomic composition, active oxalate metabolizer and butyrate-producing diversity were explored by utilizing frc-, but-, and buk- functional gene amplicon analysis. Operational taxonomic units (OTUs) level analyses confound with the observation that dysbiosis in gut microbiota is not just limited to eubacteria species, but also to other domains like archaea and eukaryotes. We found that some of healthy eubacterial population retained together with Oxalobacter formigenes and Lactobacillus plantarum colonization in disease condition (p < 0.001 & FDR = 0.05). Interestingly, trans domain species diversity has been less shared and dysgenic taxa augmentation was found to be higher. Oxalate metabolizing bacterial species (OMBS) and butyrate producing eubacteria species were found to be decreased in Oxalobacter non colonizers; and Prevotella and Ruminococcus species which may contribute to oxalate metabolism and butyrate synthesis as well. Our study underscores fact that microbial dysbiosis is not limited to eubacteria only hence suggest the necessity of the trans-domain surveillance in metabolic diseases for intervention studies. PMID- 30413733 TI - Fibroblast growth factor-2, but not the adipose tissue-derived stromal cells secretome, inhibits TGF-beta1-induced differentiation of human cardiac fibroblasts into myofibroblasts. AB - Transforming growth factor-beta1 (TGF-beta1) is a potent inducer of fibroblast to myofibroblast differentiation and contributes to the pro-fibrotic microenvironment during cardiac remodeling. Fibroblast growth factor-2 (FGF-2) is a growth factor secreted by adipose tissue-derived stromal cells (ASC) which can antagonize TGF-beta1 signaling. We hypothesized that TGF-beta1-induced cardiac fibroblast to myofibroblast differentiation is abrogated by FGF-2 and ASC conditioned medium (ASC-CMed). Our experiments demonstrated that TGF-beta1 treatment-induced cardiac fibroblast differentiation into myofibroblasts, as evidenced by the formation of contractile stress fibers rich in alphaSMA. FGF-2 blocked the differentiation, as evidenced by the reduction in gene (TAGLN, p < 0.0001; ACTA2, p = 0.0056) and protein (alphaSMA, p = 0.0338) expression of mesenchymal markers and extracellular matrix components gene expression (COL1A1, p < 0.0001; COL3A1, p = 0.0029). ASC-CMed did not block myofibroblast differentiation. The treatment with FGF-2 increased matrix metalloproteinases gene expression (MMP1, p < 0.0001; MMP14, p = 0.0027) and decreased the expression of tissue inhibitor of metalloproteinase gene TIMP2 (p = 0.0023). ASC CMed did not influence these genes. The proliferation of TGF-beta1-induced human cardiac fibroblasts was restored by both FGF-2 (p = 0.0002) and ASC-CMed (p = 0.0121). The present study supports the anti-fibrotic effects of FGF-2 through the blockage of cardiac fibroblast differentiation into myofibroblasts. ASC-CMed, however, did not replicate the anti-fibrotic effects of FGF-2 in vitro. PMID- 30413734 TI - Multiple Human-Behaviour Indicators for Predicting Lung Cancer Mortality with Support Vector Machine. AB - Lung cancer is still one of the most common causes of death around the world, while there is overwhelming evidence that the environment and lifestyle factors are predominant causes of most sporadic cancers. However, when applying human behaviour indicators to the prediction of cancer mortality (CM), we are often caught in a dilemma with inadequate sample size. Thus, this study extracted 30 human-behaviour indicators of seven categories (air pollution, tobacco smoking & alcohol consumption, socioeconomic status, food structure, working culture, medical level, and demographic structure) from Organization for Economic Cooperation and Development Database and World Health Organization Mortality Database for 13 countries (1998-2013), and employed Support Vector Machine (SVM) to examine the weights of 30 indicators across the 13 countries and the power for predicting lung CM for the years between 2014-2016. The weights of different human-behaviour indicators indicate that every country has its own lung cancer killers, that is, the human-behaviour indicators are country specific; Moreover, SVM has an excellent power in predicting their lung CM. The average accuracy in prediction offered by SVM can be as high as 96.08% for the 13 countries tested between 2014 and 2016. PMID- 30413735 TI - Amyloid precursor protein-fragments-containing inclusions in cardiomyocytes with basophilic degeneration and its association with cerebral amyloid angiopathy and myocardial fibrosis. AB - Cardiomyopathies with intracellular inclusions are a distinct subset of cardiomyopathies whereas basophilic degeneration (BD) of the heart describes inclusions in cardiomyocytes of the aging heart, which have not yet been related to a specific disease condition or to a distinct type of protein inclusion. To address the question whether BD represents a specific pathological feature and whether it is linked to a distinct disease condition we studied 62 autopsy cases. BD inclusions exhibited an immunohistochemical staining pattern related to glycosylated, delta- or eta-secretase-derived N-terminal cleavage products of the amyloid precursor protein (sAPPdelta/eta) or shorter fragments of sAPPeta. BD aggregates were found in the myocardium of both ventricles and atria with highest amounts in the atria and lowest in the interventricular septum. The frequency of BD-lesions correlated with age, degree of myocardial fibrosis in individuals with arterial hypertension, and the severity of cerebral amyloid angiopathy (CAA). The intracytoplasmic deposition of N-terminal sAPPdelta/eta fragments in BD indicates a specific inclusion body pathology related to APP metabolism. The correlation with the severity of CAA, which is related to the APP-derived amyloid beta protein, supports this point of view and suggests a possible link between myocardial and cerebrovascular APP-related lesions. PMID- 30413736 TI - Touch engages visual spatial contextual processing. AB - The spatial context in which we view a visual stimulus strongly determines how we perceive the stimulus. In the visual tilt illusion, the perceived orientation of a visual grating is affected by the orientation signals in its surrounding context. Conceivably, the spatial context in which a visual grating is perceived can be defined by interactive multisensory information rather than visual signals alone. Here, we tested the hypothesis that tactile signals engage the neural mechanisms supporting visual contextual modulation. Because tactile signals also convey orientation information and touch can selectively interact with visual orientation perception, we predicted that tactile signals would modulate the visual tilt illusion. We applied a bias-free method to measure the tilt illusion while testing visual-only, tactile-only or visuo-tactile contextual surrounds. We found that a tactile context can influence visual tilt perception. Moreover, combining visual and tactile orientation information in the surround results in a larger tilt illusion relative to the illusion achieved with the visual-only surround. These results demonstrate that the visual tilt illusion is subject to multisensory influences and imply that non-visual signals access the neural circuits whose computations underlie the contextual modulation of vision. PMID- 30413737 TI - Genome Features and Biochemical Characteristics of a Robust, Fast Growing and Naturally Transformable Cyanobacterium Synechococcus elongatus PCC 11801 Isolated from India. AB - Cyanobacteria provide an interesting platform for biotechnological applications due to their efficient photoautotrophic growth, amenability to genetic engineering and the ability to grow on non-arable land. An ideal industrial strain of cyanobacteria would need to be fast growing and tolerant to high levels of temperature, light, carbon dioxide, salt and be naturally transformable. In this study, we report Synechococcus elongatus PCC 11801, a strain isolated from India that fulfills these requirements. The physiological and biochemical characteristics of PCC 11801 under carbon and light-limiting conditions were investigated. PCC 11801 shows a doubling time of 2.3 h, that is the fastest growth for any cyanobacteria reported so far under ambient CO2 conditions. Genome sequence of PCC 11801 shows genome identity of ~83% with its closest neighbors Synechococcus elongatus PCC 7942 and Synechococcus elongatus UTEX 2973. The unique attributes of PCC 11801 genome are discussed in light of the physiological characteristics that are needed in an industrial strain. The genome of PCC 11801 shows several genes that do not have homologs in neighbor strains PCC 7942 and UTEX 2973, some of which may be responsible for adaptation to various abiotic stresses. The remarkably fast growth rate of PCC 11801 coupled with its robustness and ease of genetic transformation makes it an ideal candidate for the photosynthetic production of fuels and chemicals. PMID- 30413738 TI - Embryonic Stem Cells Derived Kidney Organoids as Faithful Models to Target Programmed Nephrogenesis. AB - The kidney is a complex organ that is comprised of thousands of nephrons developing through reciprocal inductive interactions between metanephric mesenchyme (MM) and ureteric bud (UB). The MM undergoes mesenchymal to epithelial transition (MET) in response to the signaling from the UB. The secreted protein Wnt4, one of the Wnt family members, is critical for nephrogenesis as mouse Wnt4 /- mutants fail to form pretubular aggregates (PTA) and therefore lack functional nephrons. Here, we generated mouse embryonic stem cell (mESC) line lacking Wnt4 by applying the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated systems 9 (Cas9). We describe here, differentiation of the wild type and Wnt4 knockout mESCs into kidney progenitors, and such cells induced to undergo nephrogenesis by the mouse E11.5 UB mediated induction. The wild type three-dimensional (3D) self-organized organoids depict appropriately segmented nephron structures, while the Wnt4-deficient organoids fail to undergo the MET, as is the case in the phenotype of the Wnt4 knockout mouse model in vivo. In summary, we have established a platform that combine CRISPR/Cas9 and kidney organoid technologies to model kidney development in vitro and confirmed that mutant organoids are able to present similar actions as in the in vivo studies. PMID- 30413739 TI - The two phases of the Cambrian Explosion. AB - The dynamics of how metazoan phyla appeared and evolved - known as the Cambrian Explosion - remains elusive. We present a quantitative analysis of the temporal distribution (based on occurrence data of fossil species sampled in each time interval) of lophotrochozoan skeletal species (n = 430) from the terminal Ediacaran to Cambrian Stage 5 (~545 - ~505 Million years ago (Ma)) of the Siberian Platform, Russia. We use morphological traits to distinguish between stem and crown groups. Possible skeletal stem group lophophorates, brachiopods, and molluscs (n = 354) appear in the terminal Ediacaran (~542 Ma) and diversify during the early Cambrian Terreneuvian and again in Stage 2, but were devastated during the early Cambrian Stage 4 Sinsk extinction event (~513 Ma) never to recover previous diversity. Inferred crown group brachiopod and mollusc species (n = 76) do not appear until the Fortunian, ~537 Ma, radiate in the early Cambrian Stage 3 (~522 Ma), and with minimal loss of diversity at the Sinsk Event, continued to diversify into the Ordovician. The Sinsk Event also removed other probable stem groups, such as archaeocyath sponges. Notably, this diversification starts before, and extends across the Ediacaran/Cambrian boundary and the Basal Cambrian Carbon Isotope Excursion (BACE) interval (~541 to ~540 Ma), ascribed to a possible global perturbation of the carbon cycle. We therefore propose two phases of the Cambrian Explosion separated by the Sinsk extinction event, the first dominated by stem groups of phyla from the late Ediacaran, ~542 Ma, to early Cambrian stage 4, ~513 Ma, and the second marked by radiating bilaterian crown group species of phyla from ~513 Ma and extending to the Ordovician Radiation. PMID- 30413740 TI - A Research on Preparation and Application of the Monolithic Catalyst with Interconnecting Pore Structure. AB - In recent years, the monolithic material has been developed increasingly in the high performance liquid phase field, and it could also be applied in the field of catalyst, as a monolithic catalyst carrier, since it has a large specific surface area, and could be customized based on the mould. The monolithic catalyst is characterized with many advantages such as low bed pressure, high physical efficiency and small amplification effect. The most impotant part refers to the preparation of copper-based catalyst. The impregnation method is used to produce CuO-ZnO monolithic catalyst and CuO-ZnO-ZrO2 monolithic catalyst with the prepared monolithic silica-alumina carrier. The fixed bed microreactor is used to investigate the effect of copper-based catalyst on the process in which carbon dioxide is used to produce methanol through hydrogenation. The metal salt is added into the sol-gel process, which could form the M-O-Si bond, thus make the metal-containing catalytic material obtain good mechanical strength, and make it possible to be introduced into the acidic center generally. The metal-containing catalytic material carrier also has macropores and mesopores. The presence of large pores could make the molecular mass transfer more effective, while the presence of mesopores could increase the specific surface area of the material. In this paper, the experimental study has been conducted on the production of methanol through hydrogenation of CO2 under different catalysts, to mainly investigate the effect of catalysts with different catalytic performance on the reaction. PMID- 30413742 TI - High-throughput neutralization assay for multiple flaviviruses based on single round infectious particles using dengue virus type 1 reporter replicon. AB - Diseases caused by the genus Flavivirus, including dengue virus (DENV) and Zika virus (ZIKV), have a serious impact on public health worldwide. Due to serological cross-reactivity among flaviviruses, current enzyme-linked immunosorbent assay (ELISA) for IgM/G cannot reliably distinguish between infection by different flaviviruses. In this study, we developed a reporter-based neutralization assay using single-round infectious particles (SRIPs) derived from representative flaviviruses. SRIPs were generated by transfection of human embryonic kidney 293 T cells with a plasmid encoding premembrane and envelope (prME) proteins from DENV1-4, ZIKV, Japanese encephalitis virus, West Nile virus, yellow fever virus, Usutu virus, and tick-borne encephalitis virus, along with a plasmid carrying DENV1 replicon containing the luciferase gene and plasmid for expression of DENV1 capsid. Luciferase activity of SRIPs-infected cells was well correlated with number of infected cells, and each reporter SRIP was specifically neutralized by sera from mice immunized with each flavivirus antigen. Our high throughput reporter SRIP-based neutralization assay for multiple flaviviruses is a faster, safer, and less laborious diagnostic method than the conventional plaque reduction neutralization test to screen the cause of primary flavivirus infection. The assay may also contribute to the evaluation of vaccine efficacy and assist in routine surveillance and outbreak response to flaviviruses. PMID- 30413741 TI - Evoked Alpha Power is Reduced in Disconnected Consciousness During Sleep and Anesthesia. AB - Sleep and anesthesia entail alterations in conscious experience. Conscious experience may be absent (unconsciousness) or take the form of dreaming, a state in which sensory stimuli are not incorporated into conscious experience (disconnected consciousness). Recent work has identified features of cortical activity that distinguish conscious from unconscious states; however, less is known about how cortical activity differs between disconnected states and normal wakefulness. We employed transcranial magnetic stimulation-electroencephalography (TMS-EEG) over parietal regions across states of anesthesia and sleep to assess whether evoked oscillatory activity differed in disconnected states. We hypothesized that alpha activity, which may regulate perception of sensory stimuli, is altered in the disconnected states of rapid eye movement (REM) sleep and ketamine anesthesia. Compared to wakefulness, evoked alpha power (8-12 Hz) was decreased during disconnected consciousness. In contrast, in unconscious states of propofol anesthesia and non-REM (NREM) sleep, evoked low-gamma power (30-40 Hz) was decreased compared to wakefulness or states of disconnected consciousness. These findings were confirmed in subjects in which dream reports were obtained following serial awakenings from NREM sleep. By examining signatures of evoked cortical activity across conscious states, we identified novel evidence that suppression of evoked alpha activity may represent a promising marker of sensory disconnection. PMID- 30413743 TI - Targeting CD40 enhances antibody- and CD8-mediated protection against respiratory syncytial virus infection. AB - Respiratory Syncytial Virus (RSV) infects almost all children under the age of one and is the leading cause of hospitalization among infants. Despite several decades of research with dozens of candidate vaccines being vigorously evaluated in pre-clinical and clinical studies, there is no licensed vaccine available to date. Here, the RSV fusion protein (F) was fused with CD40 ligand and delivered by an adenoviral vector into BALB/c mice where the CD40 ligand serves two vital functions as a molecular adjuvant and an antigen-targeting molecule. In contrast to a formaldehyde-inactivated vaccine, the vectored vaccine effectively protected animals against RSV without inducing enhanced respiratory disease. This protection involved a robust induction of neutralizing antibodies and memory CD8 T cells, which were not observed in the inactivated vaccine group. Finally, the vectored vaccine was able to elicit long-lasting protection against RSV, one of the most challenging issues in RSV vaccine development. Further studies indicate that the long lasting protection elicited by the CD40 ligand targeted vaccine was mediated by increased levels of effector memory CD8 T cell 3 months post vaccination. PMID- 30413744 TI - Changes in canine serum N-glycosylation as a result of infection with the heartworm parasite Dirofilaria immitis. AB - Filariases are diseases caused by infection with filarial nematodes and transmitted by insect vectors. The filarial roundworm Dirofilaria immitis causes heartworm disease in dogs and other carnivores. D. immitis is closely related to Onchocerca volvulus, Wuchereria bancrofti and Brugia malayi, which cause onchocerciasis (river blindness) and lymphatic filariasis (elephantiasis) in humans and are neglected tropical diseases. Serum N-glycosylation is very sensitive to both pathological infections and changes in mammalian biology due to normal aging or lifestyle choices. Here, we report significant changes in the serum N-glycosylation profiles of dogs infected with D. immitis. Our data derive from analysis of serum from dogs with established patent infections and from a longitudinal infection study. Overall, galactosylation and core fucosylation increase, while sialylation decreases in infected dog sera. We also identify individual glycan structures that change significantly in their relative abundance during infection. Notably, the abundance of the most dominant N-glycan in canine serum (biantennary, disialylated A2G2S2) decreases by over 10 percentage points during the first 6 months of infection in each dog analyzed. This is the first longitudinal study linking changes in mammalian serum N-glycome to progression of a parasitic infection. PMID- 30413745 TI - Experimental screening studies on rabies virus transmission and oral rabies vaccination of the Greater Kudu (Tragelaphus strepsiceros). AB - Rabies in the Greater Kudu (Tragelaphus strepsiceros) in Namibia is unique and found in such magnitude as has not been reported elsewhere in southern Africa. Reasons as to why Kudus appear to be exceptionally susceptible to rabies still remain speculative at best. Because the current severe rabies endemic in Kudus continues to have an enormous negative impact on the Namibian agricultural sector, we set out to question existing dogmas regarding the epidemiology of the disease in a unique experimental setting. In addition, we explored effective measures to protect these antelopes. Although we were able to confirm high susceptibly of kudus for rabies and sporadic horizontal rabies virus transmission to contact animals, we contend that these observations cannot plausibly explain the rapid spread of the disease in Kudus over large territories. Since parenteral vaccination of free-roaming Kudus is virtually impossible, oral rabies vaccination using modified life virus vaccines with a high safety profile would be the ultimate solution to the problem. In a proof-of-concept study using a 3rd generation oral rabies virus vaccine construct (SPBN GASGAS) we found evidence that Kudus can be vaccinated by the oral route and protected against a subsequent rabies infection. In a second phase, more targeted studies need to be initiated by focusing on optimizing oral vaccine uptake and delivery. PMID- 30413746 TI - Ca2+ efflux via plasma membrane Ca2+-ATPase mediates chemotaxis in ascidian sperm. AB - When a spermatozoon shows chemotactic behavior, transient [Ca2+]i increases in the spermatozoon are induced by an attractant gradient. The [Ca2+]i increase triggers a series of stereotypic responses of flagellar waveforms that comprise turning and straight-swimming. However, the molecular mechanism of [Ca2+]i modulation controlled by the attractants is not well defined. Here, we examined receptive mechanisms for the sperm attractant, SAAF, in the ascidian, Ciona intestinalis, and identified a plasma membrane Ca2+-ATPase (PMCA) as a SAAF binding protein. PMCA is localized in sperm flagella membranes and seems to interact with SAAF through basic amino acids located in the second and third extracellular loops. ATPase activity of PMCA was enhanced by SAAF, and PMCA inhibitors, 5(6)-Carboxyeosin diacetate and Caloxin 2A1, inhibited chemotactic behavior of the sperm. Furthermore, Caloxin 2A1 seemed to inhibit efflux of [Ca2+]i in the sperm, and SAAF seemed to competitively reduce the effect of Caloxin 2A1. On the other hand, chemotactic behavior of the sperm was disordered not only at low-Ca2+, but also at high-Ca2+ conditions. Thus, PMCA is a potent candidate for the SAAF receptor, and direct control of Ca2+ efflux via PMCA is a fundamental mechanism to mediate chemotactic behavior in the ascidian spermatozoa. PMID- 30413747 TI - Genetic diversity and distribution dynamics of multidrug-resistant Mycobacterium tuberculosis isolates in Nepal. AB - Multidrug-resistant tuberculosis (MDR-TB) is an emerging public health problem in Nepal. Despite the implementation of a successful TB control program in Nepal, notifications of MDR-TB are increasing, yet the reasons are unknown. The objective of this study was to understand the genetic diversity and epidemiological characteristics of MDR-Mycobacterium tuberculosis (MTB) isolates in Nepal. We isolated and genotyped 498 MDR-MTB isolates collected from April 2009 to March 2013 and analyzed the patients' background information. Our results showed that the lineage 2 (Beijing family) was the most predominant lineage (n = 241; 48.4%), followed by lineage 3 (n = 153, 30.7%). Lineage 4 was the third most prevalent (n = 73, 14.5%) followed by lineage 1 (n = 32, 6.4%). The lineages were significantly associated with geographic region, ethnic group, age and sex of patients. The Beijing genotype was found to have an important role in transmitting MDR-TB in Nepal and was significantly associated with the eastern region, mongoloid ethnic group and younger age group. We conclude that early diagnosis and treatment including molecular-epidemiological surveillance of MDR TB cases will help to control transmission of MDR-TB in Nepal. PMID- 30413748 TI - Biotic resistance and vegetative propagule pressure co-regulate the invasion success of a marine clonal macrophyte. AB - Propagule pressure is considered a major driver of plant invasion success. Great propagule pressure would enable invasive species to colonize new areas overcoming the resistance of native species. Many highly invasive aquatic macrophytes regenerate from vegetative propagules, but few studies have experimentally investigated the importance of propagule pressure and biotic resistance, and their interaction, in determining invasion success. By manipulating both recipient habitat and the input of vegetative propagules of the invasive seaweed Caulerpa cylindracea in mesocosm, we examined whether higher propagule pressure would overcome the resistance of a native congeneric (Caulerpa prolifera) and influence its performance. With the native, C. cylindracea population frond number decreased irrespectively of pressure level. High propagule pressure did not increase stolon length and single plant size decreased due to the effects of intra- and interspecific competition. Native biomass decreased with increasing C. cylindracea propagule pressure. These results indicate that higher propagule pressure may fail in enhancing C. cylindracea invasion success in habitats colonized by the native species, and they suggest that biotic resistance and propagule pressure co-regulate the invasion process. These findings emphasize the need to preserve/restore native seaweed populations and may help to design effective management actions to prevent further C. cylindracea spread. PMID- 30413749 TI - Structure analysis and antiviral activity of CW-33 analogues against Japanese encephalitis virus. AB - Japanese encephalitis virus (JEV) is a member of neurotropic flaviviruses transmitted by mosquito bites, causing severe central nervous system disorders. Current JEV genotype III vaccines have a low protection against genotype I isolates in the risk zone. The lead compound CW-33, ethyl 2-(3',5' dimethylanilino)-4-oxo-4,5-dihydrofuran-3-carboxylate, demonstrates the antiviral activity against JEV with an IC50 values of 38.5 MUM for virus yield reduction (Int J Mol Sci 2016,17: E1386). This study synthesized fourteen CW-33 analogues containing a fluoro atom or one methoxy group at the C-2, C-3, or C-4 of anilino ring, and then evaluated for their antiviral activity and mechanism. Among 6 amalogues, CW-33A (ethyl 2-(2-fluoroanilino)-4-oxo- 4,5-dihydrofuran-3 carboxylate), and CW-33D (ethyl 2-(3-methoxyanilino)-4-oxo- 4,5-dihydrofuran-3 carboxylate exhibited antiviral potentials in viral cytopathic effect (CPE) inhibition. CW-33A significantly suppressed the viral protein expression, genome synthesis and intracellular JEV particle production, showing a higher inhibitory effect on JEV yield than CW-33 and CW-33D. The study demonstrated that a mono fluoro substitution on at the C-2 anilino ring of CW-33 improved the antiviral activity JEV, revealing the structure-activity relationship for developing novel agents against JEV infection. PMID- 30413750 TI - Host Directed Therapy for Chronic Tuberculosis via Intrapulmonary Delivery of Aerosolized Peptide Inhibitors Targeting the IL-10-STAT3 Pathway. AB - Here we demonstrate that aerosols of host directed therapies [HDT] administered during a chronic Mycobacterium tuberculosis (Mtb) infection have bactericidal effect. The pulmonary bacterial load of C57BL/6 mice chronically infected with Mtb was reduced by 1.7 and 0.6 log10CFU after two weeks of treatment via aerosol delivery with ST3-H2A2, [a selective peptide inhibitor of the STAT3 N-terminal domain] or IL10R1-7 [selective peptide inhibitor for the IL-10Ra] respectively and when compared to control mice treated with IL10R1-14 [peptide inhibitor used as negative control] or untreated mice infected with Mtb. Accordingly, when compared to control mice, the bactericidal capacity in mice was enhanced upon treatment with peptide inhibitors ST3-H2A2 and IL10R1-7 as evidenced by higher pulmonary activities of nitric oxide synthase, NADPH oxidase and lysozyme enzymes and decreased arginase enzyme activity. This therapy also modulated important checkpoints [Bcl2, Beclin-1, Atg 5, bax] in the apoptosis-autophagy pathways. Thus, even in the absence of antibiotics, targeting of the host pulmonary IL-10 STAT3 pathway can significantly reduce the Mtb bacilli load in the lungs, modulate the host own bactericidal capacity and apoptosis and autophagy pathways. Our approach here also allows targeting checkpoints of the lungs to determine their specific contribution in pulmonary immunity or pathogenesis. PMID- 30413751 TI - von Willebrand factor deficiency does not influence angiotensin II-induced abdominal aortic aneurysm formation in mice. AB - Abdominal aortic aneurysm (AAA) refers to a localized dilation of the abdominal aorta that exceeds the normal diameter by 50%. AAA pathophysiology is characterized by progressive inflammation, vessel wall destabilization and thrombus formation. Our aim was to investigate the potential involvement of von Willebrand factor (VWF), a thrombo-inflammatory plasma protein, in AAA pathophysiology using a dissection-based and angiotensin II infusion-induced AAA mouse model. AAA formation was induced in both wild-type and VWF-deficient mice by subcutaneous implantation of an osmotic pump, continuously releasing 1000 ng/kg/min angiotensin II. Survival was monitored, but no significant difference was observed between both groups. After 28 days, the suprarenal aortic segment of the surviving mice was harvested. Both AAA incidence and severity were similar in wild-type and VWF-deficient mice, indicating that AAA formation was not significantly influenced by the absence of VWF. Although VWF plasma levels increased after the infusion period, these increases were not correlated with AAA progression. Also detailed histological analyses of important AAA hallmarks, including elastic degradation, intramural thrombus formation and leukocyte infiltration, did not reveal differences between both groups. These data suggest that, at least in the angiotensin II infusion-induced AAA mouse model, the role of VWF in AAA pathophysiology is limited. PMID- 30413752 TI - Optimal positioning of storage systems in microgrids based on complex networks centrality measures. AB - We propose a criterion based on complex networks centrality metrics to identify the optimal position of Energy Storage Systems in power networks. To this aim we study the relation between centrality metrics and voltage fluctuations in power grids in presence of high penetration of renewable energy sources and storage systems. For testing purposes we consider two prototypical IEEE networks and we compute the correlation between node centrality (namely Eigenvector, Closeness, Pagerank, Betweenness) and voltage fluctuations in presence of intermittent renewable energy generators and intermittent loads measured from domestic users. We show that the topological characteristics of the power networks are able to identify the optimal positioning of active and reactive power compensators (such as energy storage systems) used to reduce voltage fluctuations according to the common quality of service standards. Results show that, among the different metrics, eigenvector centrality shows a statistically significant exponential correlation with the reduction of voltage fluctuations. This finding confirms the technical know-how for which storage systems are heuristically positioned far from supply reactive nodes. This also represents an advantage both in terms of computational time, and in terms of planning of wide resilient networks, where a careful positioning of storage systems is needed, especially in a scenario of interconnected microgrids where intermittent distributed energy sources (such as wind or solar) are fully deployed. PMID- 30413755 TI - CCAAT/Enhancer Binding Protein beta inhibits myogenic differentiation via ID3. AB - Myogenesis is regulated by the coordinated expression of muscle regulatory factors, a family of transcription factors that includes MYOD, MYF5, myogenin and MRF4. Muscle regulatory factors are basic helix-loop-helix transcription factors that heterodimerize with E proteins to bind the regulatory regions of target genes. Their activity can be inhibited by members of the Inhibitor of DNA binding and differentiation (ID) family, which bind E-proteins with high affinity, thereby preventing muscle regulatory factor-dependent transcriptional responses. CCAAT/Enhancer Binding protein beta (C/EBPbeta) is a transcription factor expressed in myogenic precursor cells that acts to inhibit myogenic differentiation, though the mechanism remains poorly understood. We identify Id3 as a novel C/EBPbeta target gene that inhibits myogenic differentiation. Overexpression of C/EBPbeta stimulates Id3 mRNA and protein expression, and is required for C/EBPbeta-mediated inhibition of myogenic differentiation. Misexpression of C/EBPbeta in myogenic precursors, such as in models of cancer cachexia, prevents the differentiation of myogenic precursors and we show that loss of Id3 rescues differentiation under these conditions, suggesting that the stimulation of Id3 expression by C/EBPbeta is an important mechanism by which C/EBPbeta inhibits myogenic differentiation. PMID- 30413754 TI - Divergent short-chain fatty acid production and succession of colonic microbiota arise in fermentation of variously-sized wheat bran fractions. AB - Though the physical structuring of insoluble dietary fiber sources may strongly impact their processing by microbiota in the colon, relatively little mechanistic information exists to explain how these aspects affect microbial fiber fermentation. Here, we hypothesized that wheat bran fractions varying in size would be fermented differently by gut microbiota, which would lead to size dependent differences in metabolic fate (as short-chain fatty acids; SCFAs) and community structure. To test this hypothesis, we performed an in vitro fermentation assay in which wheat bran particles from a single source were separated by sieving into five size fractions and inoculated with fecal microbiota from three healthy donors. SCFA production, measured by gas chromatography, uncovered size fraction-dependent relationships between total SCFAs produced as well as the molar ratios of acetate, propionate, and butyrate. 16S rRNA sequencing revealed that these size-dependent metabolic outcomes were accompanied by the development of divergent microbial community structures. We further linked these distinct results to subtle, size-dependent differences in chemical composition. These results suggest that physical context can drive differences in microbiota composition and function, that fiber-microbiota interaction studies should consider size as a variable, and that manipulating the size of insoluble fiber-containing particles might be used to control gut microbiome composition and metabolic output. PMID- 30413753 TI - The geranyl acetophenone tHGA attenuates human bronchial smooth muscle proliferation via inhibition of AKT phosphorylation. AB - Increased airway smooth muscle (ASM) mass is a prominent hallmark of airway remodeling in asthma. Inhaled corticosteroids and long-acting beta2-agonists remain the mainstay of asthma therapy, however are not curative and ineffective in attenuating airway remodeling. The geranyl acetophenone 2,4,6-trihydroxy-3 geranyl acetophenone (tHGA), an in-house synthetic non-steroidal compound, attenuates airway hyperresponsiveness and remodeling in murine models of asthma. The effect of tHGA upon human ASM proliferation, migration and survival in response to growth factors was assessed and its molecular target was determined. Following serum starvation and induction with growth factors, proliferation and migration of human bronchial smooth muscle cells (hBSMCs) treated with tHGA were significantly inhibited without any significant effects upon cell survival. tHGA caused arrest of hBSMC proliferation at the G1 phase of the cell cycle with downregulation of cell cycle proteins, cyclin D1 and diminished degradation of cyclin-dependent kinase inhibitor (CKI), p27Kip1. The inhibitory effect of tHGA was demonstrated to be related to its direct inhibition of AKT phosphorylation, as well as inhibition of JNK and STAT3 signal transduction. Our findings highlight the anti-remodeling potential of this drug lead in chronic airway disease. PMID- 30413757 TI - Structural and compositional study of precipitates in under-aged Cu-added Al-Mg Si alloy. AB - Atomic scale characterization of fine precipitates in an under-aged Cu added Al Mg-Si alloy was carried out by combination of atomically-resolved annular dark field scanning transmission electron microscopy and energy dispersive X-ray spectroscopy. Two types of precipitates were observed in the alloy. In the case of ordered beta" precipitates, beta" was proposed as Mg5-xAl2+xSi4 (x ~ 1) with solute Cu atoms replacing Al site of beta" precipitate. In the case of disordered precipitates, the precipitates were found to consist of beta" sub-unit cells, three-fold symmetric structure without Cu atoms, Cu containing structures termed as "Cu sub-unit cluster", and Q' sub-unit cells. Among these structures, the morphologies of three-fold symmetric structure without Cu atoms, Cu sub-unit cluster, and Q' sub-unit cell were almost the same, so that these structures should be the clusters of Q' phase. Since the areal density, length and diameter of precipitates were almost equal between Cu free Al-Mg-Si alloy and Cu added Al Mg-Si alloy, the increase of hardness by Cu addition should be due to the precipitation of Cu related precipitates, such as Cu sub-unit clusters and Q' sub unit cells. PMID- 30413756 TI - Water-repellent Hybrid Nanowire and Micro-scale Denticle Structures on Flexible Substrates of Effective Air Retention. AB - The air retention capability of a superhydrophobic surface plays the crucial role of drag reduction in an aqueous environment. Here, fabrication of water-repellent hybrid structural surfaces by synthesizing superhydrophobic nanowires with a high aspect ratio on micro-scale denticle structures to improve their air holding capacity in water is reported. The hybrid structure is realized by carrying out polymer molding of denticle structures on flexible substrates, hydrothermal growth of nanowires, and subsequent ultra-thin film coating. This technique is readily applicable to large areas, and the fabricated substrates are attachable onto curved surfaces. Our engineered, super water-repellent hybrid structures are found to effectively maintain air bubbles on their surfaces in a highly shear flow condition with a wall shear stress of up to 33.4 Pa, due to the combined effects of the micro-scale denticle structure, which reduces flow resistance, and the superhydrophobic, high-aspect-ratio nanowire structure, which enhances the capillary force to maintain the air bubbles. Our results show the importance of developing superhydrophobic structures of improved air retention capability. PMID- 30413759 TI - Whole-exome sequencing identifies two novel mutations in KCNQ4 in individuals with nonsyndromic hearing loss. AB - Mutations in potassium voltage-gated channel subfamily Q member 4 (KCNQ4) are etiologically linked to a type of nonsyndromic hearing loss, deafness nonsyndromic autosomal dominant 2 (DFNA2). We performed whole-exome sequencing for 98 families with hearing loss and found mutations in KCNQ4 in five families. In this study, we characterized two novel mutations in KCNQ4: a missense mutation (c.796G>T; p.Asp266Tyr) and an in-frame deletion mutation (c.259_267del; p.Val87_Asn89del). p.Asp266Tyr located in the channel pore region resulted in early onset and moderate hearing loss, whereas p.Val87_Asn89del located in the N terminal cytoplasmic region resulted in late onset and high frequency-specific hearing loss. When heterologously expressed in HEK 293 T cells, both mutant proteins did not show defects in protein trafficking to the plasma membrane or in interactions with wild-type (WT) KCNQ4 channels. Patch-clamp analysis demonstrated that both p.Asp266Tyr and p.Val87_Asn89del mutant channels lost conductance and were completely unresponsive to KCNQ activators, such as retigabine, zinc pyrithione, and ML213. Channels assembled from WT-p.Asp266Tyr concatemers, like those from WT-WT concatemers, exhibited conductance and responsiveness to KCNQ activators. However, channels assembled from WT p.Val87_Asn89del concatemers showed impaired conductance, suggesting that p.Val87_Asn89del caused complete loss-of-function with a strong dominant-negative effect on functional WT channels. Therefore, the main pathological mechanism may be related to loss of K+ channel activity, not defects in trafficking. PMID- 30413758 TI - Arabidopsis molybdenum cofactor sulfurase ABA3 contributes to anthocyanin accumulation and oxidative stress tolerance in ABA-dependent and independent ways. AB - Arabidopsis ABA3 is an enzyme involved in the synthesis of the sulfurated form of the molybdenum (Mo) cofactor (MoCo), which is required for the enzymatic activity of so-called Mo enzymes such as aldehyde oxidase (AO) and xanthine dehydrogenase (XDH). It has been reported that AO and XDH are essential for the biosynthesis of the bioactive compounds, ABA and allantoin, respectively. However, aba3 mutants often exhibit pleiotropic phenotypes that are not explained by defects in ABA and/or allantoin biosynthesis, leading us to hypothesize that ABA3 regulates additional metabolic pathways. To reveal the currently unidentified functions of ABA3 we compared transcriptome and metabolome of the Arabidopsis aba3 mutant with those of wild type and a typical ABA-deficient mutant aba2. We found that endogenous levels of anthocyanins, members of the flavonoid group, were significantly lower in the aba3 mutant than in the wild type or the aba2 mutant under oxidative stress. In contrast, mutants defective in the AO and XDH holoenzymes accumulated significantly higher levels of anthocyanins when compared with aba3 mutant under the same conditions. Our findings shed light on a key role of ABA3 in the ABA- and allantoin-independent accumulation of anthocyanins during stress responses. PMID- 30413760 TI - Ultrathin Air-Stable n-Type Organic Phototransistor Array for Conformal Optoelectronics. AB - Development of conformal n-channel organic phototransistor (OPT) array is urgent for future applications of organic complementary circuits in portable and wearable electronics and optoelectronics. In this work, the ultrathin conformal OPT array based on air-stable n-type PTCDI-C13H27 was fabricated. The OPT array shows excellent electrical and photoelectrical performance, good device uniformity, and remains stable in electron mobility by 83% after 90 days compared to the initial values. Eventhough mobility, on-state current, off-state current, and photocurrent of PTCDI-C13H27 thin film phototransistor show slight decrease with the decreased bending radius, the device still remains the stable photosensitivity as high as 104 when the device is freely adhered on the 2D surfaces and 3D hemispherical sphere, which is in a class with the highest photosensitivity for perylene diimide derivatives. These results present the promising application potential of our conformable air-stable n-type PTCDI-C13H27 OPTs as the photodetection system of curved artificial compound eyes in wearable and portable electronics and optoelectronics. PMID- 30413761 TI - The increasing variability of tropical cyclone lifetime maximum intensity. AB - This study investigates long-term changes in the variability of TC intensity of global tropical cyclones, a topic which has been relatively infrequently studied to date. Our study finds that the variability of global TC lifetime maximum intensity (LMI), as measured by the LMI standard deviation, increases during 1981 2016. The increasing trend in LMI variability is statistically significant for both the Northern and Southern Hemispheres, with three individual TC basins: the western North Pacific, the South Indian and the South Pacific also having statistically significant increases. This increasing trend primarily results from distinct changes in the relative percentages of TCs with different intensities. When comparing two periods: 1981-1998 and 1999-2016, the proportions of weak and strong TCs increase, whereas moderate TCs occur relatively less frequently. This bimodal pattern of observed LMI distribution change is further linked to opposite trends in the average intensities of TCs that undergo rapid intensification (RI) during their lifetime (RI TCs) and those that do not (non-RI TCs). The LMI distributions of RI and non-RI TCs migrate to higher and lower intensities, respectively. Our results demonstrate from an observational perspective that strong TCs have strengthened while weak TCs have weakened as the global climate has warmed since 1981. PMID- 30413763 TI - SATB family chromatin organizers as master regulators of tumor progression. AB - SATB (Special AT-rich binding protein) family proteins have emerged as key regulators that integrate higher-order chromatin organization with the regulation of gene expression. Studies over the past decade have elucidated the specific roles of SATB1 and SATB2, two closely related members of this family, in cancer progression. SATB family chromatin organizers play diverse and important roles in regulating the dynamic equilibrium of apoptosis, cell invasion, metastasis, proliferation, angiogenesis, and immune modulation. This review highlights cellular and molecular events governed by SATB1 influencing the structural organization of chromatin and interacting with several co-activators and co repressors of transcription towards tumor progression. SATB1 expression across tumor cell types generates cellular and molecular heterogeneity culminating in tumor relapse and metastasis. SATB1 exhibits dynamic expression within intratumoral cell types regulated by the tumor microenvironment, which culminates towards tumor progression. Recent studies suggested that cell-specific expression of SATB1 across tumor recruited dendritic cells (DC), cytotoxic T lymphocytes (CTL), T regulatory cells (Tregs) and tumor epithelial cells along with tumor microenvironment act as primary determinants of tumor progression and tumor inflammation. In contrast, SATB2 is differentially expressed in an array of cancer types and is involved in tumorigenesis. Survival analysis for patients across an array of cancer types correlated with expression of SATB family chromatin organizers suggested tissue-specific expression of SATB1 and SATB2 contributing to disease prognosis. In this context, it is pertinent to understand molecular players, cellular pathways, genetic and epigenetic mechanisms governed by cell types within tumors regulated by SATB proteins. We propose that patient survival analysis based on the expression profile of SATB chromatin organizers would facilitate their unequivocal establishment as prognostic markers and therapeutic targets for cancer therapy. PMID- 30413762 TI - Sympatric Ixodes-tick species: pattern of distribution and pathogen transmission within wild rodent populations. AB - The generalist tick Ixodes ricinus is the most important vector for tick-borne pathogens (TBP), including Borrelia burgdorferi sensu lato, in Europe. However, the involvement of other sympatric Ixodes ticks, such as the specialist vole tick I. trianguliceps, in the enzootic circulations of TBP remains unclear. We studied the distribution of I. ricinus and I. trianguliceps in Central Finland and estimated the TBP infection likelihood in the most common rodent host in relation with the abundance of the two tick species. Ixodes trianguliceps was encountered in all 16 study sites whereas I. ricinus was frequently observed only at a quarter of the study sites. The abundance of I. ricinus was positively associated with open water coverage and human population density around the study sites. Borrelia burgdorferi s. l.-infected rodents were found only in sites where I. ricinus was abundant, whereas the occurrence of other TBP was independent of I. ricinus presence. These results suggest that I. trianguliceps is not sufficient, at least alone, in maintaining the circulation of B. burgdorferi s. l. in wild hosts. In addition, anthropogenic factors might affect the distribution of I. ricinus ticks and, hence, their pathogens, thus shaping the landscape of tick borne disease risk for humans. PMID- 30413764 TI - The effect of dietary salt on blood pressure in individuals receiving chronic dialysis: a systematic review and meta-analysis of randomised controlled trials. AB - Dietary salt reduction in the general population lowers blood pressure and cardiovascular risk. Despite being widely recommended, there is limited evidence as to whether this is applicable to individuals with end-stage renal disease (ESRD) receiving dialysis. Therefore, we carried out a systematic review and meta analysis of randomised controlled trials (RCTs) investigating dietary salt reduction in individuals receiving dialysis. Studies were identified through search strategies for CENTRAL, MEDLINE, and EMBASE. Two authors independently assessed studies for eligibility with the inclusion criteria as follows: participants aged 18 years and over; a reduction in salt intake of at least 1 g/day over one week; no concomitant interventions during the study. The primary outcome was change in systolic and diastolic blood pressure. 848 reports were screened, from which 12 studies were selected for the systematic review. Four were RCTs (91 participants) that met the study inclusion criteria: three were conducted in haemodialysis patients and one in peritoneal dialysis patients; three were crossover trials and one was a parallel study. Dietary salt reduction was associated with an 8.4 mmHg reduction in systolic blood pressure (95% CI 4.8 12.0, Iota2 = 0%), and a 4.4 mmHg reduction in diastolic blood pressure (95% CI 2.2-6.6, Iota2 = 0%). In conclusion, few studies have investigated the role of dietary salt reduction in individuals with ESRD receiving dialysis, but these results suggest the importance of this intervention for lowering blood pressure in this group. PMID- 30413765 TI - Asexual reproduction and growth rate: independent and plastic life history traits in Neurospora crassa. AB - Trade-offs among traits influencing fitness are predicted by life history theory because resources allocated to one function are unavailable to another. Here we examine the relationship between two such traits, asexual reproduction and growth rate, in the filamentous fungus Neurospora crassa, where shared genetic and physiological factors and a source-sink energetic relationship between growth and reproduction may constrain the evolution of these traits. To test growth reproduction relationships in this species, we independently selected on mycelial growth rate or asexual spore production in a heterogeneous lab-derived population and evaluated the response of the non-selected traits. Combined with phenotypes for the 20 wild strains used to produce the heterogeneous population and the genome-wide genotypes of 468 strains, these data show that growth and reproduction are highly plastic in N. crassa and do not trade off either among wild strains or after laboratory selection in two environments. Rather, we find no predictable growth-reproduction relationship in the environments tested, indicating an effective absence of genetic constraint between these traits. Our results suggest that growth rate and asexual reproduction may not respond predictably to environmental change and suggest that reliance on a single trait as a proxy for fitness in fungal studies may be inadvisable. PMID- 30413766 TI - Analysis of the Genome and Metabolome of Marine Myxobacteria Reveals High Potential for Biosynthesis of Novel Specialized Metabolites. AB - Comparative genomic/metabolomic analysis is a powerful tool to disclose the potential of microbes for the biosynthesis of novel specialized metabolites. In the group of marine myxobacteria only a limited number of isolated species and sequenced genomes is so far available. However, the few compounds isolated thereof so far show interesting bioactivities and even novel chemical scaffolds; thereby indicating a huge potential for natural product discovery. In this study, all marine myxobacteria with accessible genome data (n = 5), including Haliangium ochraceum DSM 14365, Plesiocystis pacifica DSM 14875, Enhygromyxa salina DSM 15201 and the two newly sequenced species Enhygromyxa salina SWB005 and SWB007, were analyzed. All of these accessible genomes are large (~10 Mb), with a relatively small core genome and many unique coding sequences in each strain. Genome analysis revealed a high variety of biosynthetic gene clusters (BGCs) between the strains and several resistance models and essential core genes indicated the potential to biosynthesize antimicrobial molecules. Polyketides (PKs) and terpenes represented the majority of predicted specialized metabolite BGCs and contributed to the highest share between the strains. BGCs coding for non-ribosomal peptides (NRPs), PK/NRP hybrids and ribosomally synthesized and post-translationally modified peptides (RiPPs) were mostly strain specific. These results were in line with the metabolomic analysis, which revealed a high diversity of the chemical features between the strains. Only 6-11% of the metabolome was shared between all the investigated strains, which correlates to the small core genome of these bacteria (13-16% of each genome). In addition, the compound enhygrolide A, known from E. salina SWB005, was detected for the first time and structurally elucidated from Enhygromyxa salina SWB006. The here acquired data corroborate that these microorganisms represent a most promising source for the detection of novel specialized metabolites. PMID- 30413767 TI - Cardioprotective Effects of Curcumin-Nisin Based Poly Lactic Acid Nanoparticle on Myocardial Infarction in Guinea Pigs. AB - Myocardial infarction (MI) is the most prevalent cause of cardiovascular death. A possible way of preventing MI maybe by dietary supplements. The present study was thus designed to ascertain the cardio-protective effect of a formulated curcumin and nisin based poly lactic acid nanoparticle (CurNisNp) on isoproterenol (ISO) induced MI in guinea pigs. Animals were pretreated for 7 days as follows; Groups A and B animals were given 0.5 mL/kg of normal saline, group C metoprolol (2 mg/kg), groups D and E CurNisNp 10 and 21 mg/kg respectively (n = 5). MI was induced on the 7th day in groups B-E animals. On the 9th day electrocardiogram (ECG) was recorded, blood samples and tissue biopsies were collected for analyses. Toxicity studies on CurNisNp were carried out. MI induction caused atrial fibrillation which was prevented by pretreatment of metoprolol or CurNisNp. MI induction was also associated with increased expressions of cardiac troponin I (CTnI) and kidney injury molecule-1 (KIM-1) which were significantly reduced in guinea pig's pretreated with metoprolol or CurNisNp (P < 0.05). The LC50 of CurNisNp was 3258.2 MUg/mL. This study demonstrated that the formulated curcumin-nisin based nanoparticle confers a significant level of cardio protection in the guinea pig and is nontoxic. PMID- 30413768 TI - Leukocyte telomere length and risk of coronary heart disease and stroke mortality: prospective evidence from a Russian cohort. AB - Previous studies suggest that reduced leukocyte telomere length (LTL) is related to higher risk of mortality and several chronic conditions, including coronary heart disease (CHD) and stroke. However, the consistency of this association differs across populations. We investigated the relationship of LTL with CHD, stroke and all-cause mortality together with non-fatal CHD and stroke events in a Russian cohort with a mean age of 58 years at baseline. Data from 1,144 individuals in the Russian subset of the Health Alcohol and Psychosocial Factors in Eastern Europe (HAPIEE) cohort study were used. The associations between LTL at baseline and fatal/non-fatal outcomes during 12 years of follow-up were assessed using multivariable Cox regression models, which yielded adjusted hazard ratios (HR). Compared to individuals in the shortest tertile, those in the longest tertile of LTL had a 42% lower risk of death from all-causes (HR 0.58; 95% CI: 0.39-0.88) and 58% lower risk of death from CHD (HR 0.42; 95%CI: 0.19 0.97). Similar patterns of association were identified for non-fatal and combined fatal/non-fatal CHD and stroke events but the associations were weaker. Consistent with results of previous studies in Western populations, this cohort of elderly Russian adults found an inverse association between LTL and CHD and all-cause mortality. These findings reinforce the hypothesis that LTL may play (or be a marker of) an aetiological role in human health across diverse populations. PMID- 30413770 TI - From the archive. PMID- 30413771 TI - Monitoring Mechanical, Electronic, and Catalytic Trends in a Titanium Metal Organic Framework Under the Influence of Guest-Molecule Encapsulation Using Density Functional Theory. AB - In this study, we conduct a density functional theory investigation to study the mechanical stability of a titanium-based metal organic framework (MOF-901), which was hypothetically assumed to possess 2D characteristics. It is systematically found that the encapsulation of methanol enhances the mechanical stability of MOF 901 as the elastic tensors Cij of MOF-901?nMeOH are higher than the corresponding Cij quantities reported for solvent-free MOF-901. Moreover, the 2D characteristics of MOF-901 is confirmed by verifying the negative values of C33. At the same time, the band gap of MOF-901 is observed to be solvent-dependent. In its pure form, MOF-901 possesses a direct gap (Eg) of 2.07 eV, with the valence and conduction bands mainly constituted by electrons of 4-aminobenzoate linkers. Introducing methanol into MOF-901 causes distortion to the 4-aminobenzoate geometry, thereby induces electronic degeneracy to the conduction bands. Consequently, Eg is narrowed to 1.84 eV with 5.7 wt% MeOH or 1.63 eV with 11.4 wt% MeOH. Hence, it is possible to tailor the band gap of MOF-901 by controlling methanol guest, which only acquires van der Waals interaction to the framework. In addition, our theoretical prediction shows a Ti(IV) site can undergo electronic hopping to become Ti(III) under the effect of visible light (~440-443 nm). Then, Ti(III) is capable of breaking the C-Br bond in ethyl alpha bromophenylacetate spontaneously, which in turn activates the polymerization of methyl methacrylate with an energy barrier of 0.30 eV. PMID- 30413769 TI - R430: A potent inhibitor of DNA and RNA viruses. AB - Acyclovir (ACV) is an effective antiviral agent for treating lytic Herpes Simplex virus, type 1 (HSV-1) infections, and it has dramatically reduced the mortality rate of herpes simplex encephalitis. However, HSV-1 resistance to ACV and its derivatives is being increasingly documented, particularly among immunocompromised individuals. The burgeoning drug resistance compels the search for a new generation of more efficacious anti-herpetic drugs. We have previously shown that trans-dihydrolycoricidine (R430), a lycorane-type alkaloid derivative, effectively inhibits HSV-1 infections in cultured cells. We now report that R430 also inhibits ACV-resistant HSV-1 strains, accompanied by global inhibition of viral gene transcription and enrichment of H3K27me3 methylation on viral gene promoters. Furthermore, we demonstrate that R430 prevents HSV-1 reactivation from latency in an ex vivo rodent model. Finally, among a panel of DNA viruses and RNA viruses, R430 inhibited Zika virus with high therapeutic index. Its therapeutic index is comparable to standard antiviral drugs, though it has greater toxicity in non-neuronal cells than in neuronal cells. Synthesis of additional derivatives could enable more efficacious antivirals and the identification of active pharmacophores. PMID- 30413772 TI - Cryptic binding sites become accessible through surface reconstruction of the type I collagen fibril. AB - Collagen fibril interactions with cells and macromolecules in the extracellular matrix drive numerous cellular functions. Binding motifs for dozens of collagen binding proteins have been determined on fully exposed collagen triple helical monomers. However, when the monomers are assembled into the functional collagen fibril, many binding motifs become inaccessible, and yet critical cellular processes occur. Here, we have developed an early stage atomic model of the smallest repeating unit of the type I collagen fibril at the fibril surface that provides a novel framework to address questions about these functionally necessary yet seemingly obstructed interactions. We use an integrative approach by combining molecular dynamics (MD) simulations with atomic force microscopy (AFM) experiments and show that reconstruction of the collagen monomers within the complex fibril play a critical role in collagen interactions. In particular, the fibril surface shows three major conformational changes, which allow cryptic binding sites, including an integrin motif involved in platelet aggregation, to be exposed. The observed dynamics and reconstruction of the fibril surface promote its role as a "smart fibril" to keep certain binding sites cryptic, and to allow accessibility of recognition domains when appropriate. PMID- 30413773 TI - Geographical and temporal distribution of the residual clusters of human leptospirosis in China, 2005-2016. AB - Human leptospirosis outbreaks still persistently occur in part of China, indicating that leptospirosis remains an important zoonotic disease in the country. Spatiotemporal pattern of the high-risk leptospirosis cluster and the key characteristics of high-risk areas for leptospirosis across the country are still poorly understood. Using spatial analytical approaches, we analyzed 8,158 human leptospirosis cases notified during 2005-2016 across China to explore the geographical distribution of leptospirosis hotspots and to characterize demographical, ecological and socioeconomic conditions of high-risk counties for leptospirosis in China. During the period studied, leptospirosis incidence was geographically clustered with the highest rate observed in the south of the Province of Yunnan. The degree of spatial clustering decreased over time suggesting changes in local risk factors. However, we detected residual high-risk counties for leptospirosis including counties in the southwest, central, and southeast China. High-risk counties differed from low-risk counties in terms of its demographical, ecological and socioeconomic characteristics. In high-risk clusters, leptospirosis was predominantly observed on younger population, more males and farmers. Additionally, high-risk counties are characterized by larger rural and less developed areas, had less livestock density and crops production, and located at higher elevation with higher level of precipitation compare to low risk counties. In conclusion, leptospirosis distribution in China appears to be highly clustered to a discrete number of counties highlighting opportunities for elimination; hence, public health interventions should be effectively targeted to high-risk counties identified in this study. PMID- 30413774 TI - First observation of direct methane emission to the atmosphere from the subglacial domain of the Greenland Ice Sheet. AB - During a 2016 field expedition to the West Greenland Ice Sheet, a striking observation of significantly elevated CH4 concentrations of up to 15 times the background atmospheric concentration were measured directly in the air expelled with meltwater at a subglacial discharge point from the Greenland Ice Sheet. The range of hourly subglacial CH4 flux rate through the discharge point was estimated to be 3.1 to 134 g CH4 hr-1. These measurements are the first observations of direct emissions of CH4 from the subglacial environment under the Greenlandic Ice Sheet to the atmosphere and indicate a novel emission pathway of CH4 that is currently a non-quantified component of the Arctic CH4 budget. PMID- 30413775 TI - Non-coding RNAome of RPE cells under oxidative stress suggests unknown regulative aspects of Retinitis pigmentosa etiopathogenesis. AB - The discovery of thousands of non-coding RNAs has revolutionized molecular biology, being implicated in several biological processes and diseases. To clarify oxidative stress role on Retinitis pigmentosa, a very heterogeneous and inherited ocular disorder group characterized by progressive retinal degeneration, we realized a comparative transcriptome analysis of human retinal pigment epithelium cells, comparing two groups, one treated with oxLDL and one untreated, in four time points (1 h, 2 h, 4 h, 6 h). Data analysis foresaw a complex pipeline, starting from CLC Genomics Workbench, STAR and TopHat2/TopHat Fusion alignment comparisons, followed by transcriptomes assembly and expression quantification. We then filtered out non-coding RNAs and continued the computational analysis roadmap with specific tools and databases for long non coding RNAs (FEELnc), circular RNAs (CIRCexplorer, UROBORUS, CIRI, KNIFE, CircInteractome) and piwi-interacting RNAs (piRNABank, piRNA Cluster, piRBase, PILFER). Finally, all detected non-coding RNAs underwent pathway analysis by Cytoscape software. Eight-hundred and fifty-four non-coding RNAs, between long non-coding RNAs and PIWI-interacting, were differentially expressed throughout all considered time points, in treated and untreated samples. These non-coding RNAs target host genes involved in several biochemical pathways are related to compromised response to oxidative stress, visual functions, synaptic impairment of retinal neurotransmission, impairment of the interphotoreceptor matrix and blood - retina barrier, all leading to retinal cell death. These data suggest that non-coding RNAs could play a relevant role in Retinitis pigmentosa etiopathogenesis. PMID- 30413776 TI - Complete chloroplast genome sequence of Dryopteris fragrans (L.) Schott and the repeat structures against the thermal environment. AB - Dryopteris fragrans (L.) Schott is a fern growing on the surface of hot rocks and lava. It is exposed to sunlight directly and bears local hot environment. We sequenced the complete nucleotide sequence of its chloroplast (cp) genome. The cp genome was 151,978 bp in length, consisting of a large single-copy region (85,332 bp), a small single-copy region (31,947 bp) and a pair of inverted repeats (17,314 bp). The cp genome contained 112 genes and 345 RNA editing sites in protein-coding genes. Simple sequence repeats (SSRs) and long repeat structure pairs (30-55 bp) were identified. The number and percent of repeat structures are extremely high in ferns. Thermal denaturation experiments showed its cp genome to have numerous, dispersed and high GC percent repeat structures, which conferred the strongest thermal stability. This repeat-heavy genome may provide the molecular basis of how D. fragrans cp survives its hot environment. PMID- 30413777 TI - First in vitro evidence of modulated electro-hyperthermia treatment performance in combination with megavoltage radiation by clonogenic assay. AB - Modulated electro-hyperthermia (mEHT) is a form of hyperthermia used in the treatment of cancer. It is a variation that relies on a particular form of enhanced selectivity to enable more effective cancerous cell death yet maintaining the integrity of healthy non-cancerous cells. It is yet to successfully make the major step into the wider medical community despite several encouraging trials. In this study, we investigate mEHT from an in vitro perspective. We demonstrate a supra-additive effect on 9 L gliosarcoma cells when exposed to mEHT in combination with MV X-ray radiation. The supra-additive effect is hypothesized to be induced by the mEHT mechanism that in turn causes apoptosis, membrane damage and an increase in rate of cell growth. This proves to be extremely advantageous in the case of the aggressive 9 L cell line as it is known to be radioresistant. However, the universal success of this multimodal treatment does not appear to be positive for all cell lines and requires further research. Due to the fundamental approach taken in this research, our results also provide a new prospect for mEHT to be a tool for sterilizing otherwise radioresistant cancers. PMID- 30413778 TI - The Hsp70 Gene Family in Solanum tuberosum: Genome-Wide Identification, Phylogeny, and Expression Patterns. AB - Heat shock protein 70 (Hsp70) family members play important roles in protecting plants against abiotic stresses, including salt, drought, heat, and cold. In this study, 20 putative StHsp70 genes were identified in potato (Solanum tuberosum L.) through the integration of the gene structures, chromosome locations, phylogenetic relationships, and expression profiles. These StHsp70 genes were classified into five sub-families based on phylogenetic analysis. Chromosome mapping revealed that they were unevenly and unequally distributed on 10 of the 12 chromosomes. Furthermore, segmental and tandem duplication events contributed to the expansion of the StHsp70 genes. Phylogenetic tree of the HSP70 genes from potato and other plant species revealed multiple sub-families. These findings indicated a common ancestor which had generated diverse sub-families prior to a mono-dicot split. In addition, expression analysis using RNA-seq revealed that the majority of these genes were expressed in at least one of the tested tissue, and were induced by Phytophthora infestans. Then, based on qRT-PCR analysis, the results showed that the transcript levels of some of the StHsp70 genes could be remarkably induced by such abiotic and hormone stresses, which indicated their potential roles in mediating the responses of potato plants to both abiotic and biotic stress conditions. PMID- 30413781 TI - HIV and the liver. PMID- 30413779 TI - Mammalian Susceptibility to a Neonicotinoid Insecticide after Fetal and Early Postnatal Exposure. AB - Neonicotinoids have become the most widely used class of insecticides world-wide. Although numerous studies have documented neonicotinoid toxicity in bees and other insects, the effects of exposure during early development in mammals remain largely unexplored. We assessed the effects of the neonicotinoid imidacloprid (IMI) in adult male and female mice after in utero and early postnatal exposure. Pregnant mice were infused with IMI (0.5 mg/kg/day) from gestational day 4 to the end of nursing at postnatal day 21. The young adult offspring were studied in a series of biochemical and behavioral tests. To assess reproducibility, the behavioral analyses were conducted in three separate studies using multiple exposed litters. Exposure to IMI reduced fecundity, and in adult offspring, decreased body weight in male but not female pups. Offspring from IMI-treated mothers displayed lower triglycerides, elevated motor activity, enhanced social dominance, reduced depressive-like behavior, and a diminution in social aggression compared to vehicle treated controls. Low levels of IMI were detected in the brains and livers of the treated mothers, while trace levels were detected in some offspring. Our results demonstrate that transient exposure to a neonicotinoid over the early developmental period induces long-lasting changes in behavior and brain function in mice. PMID- 30413780 TI - Strong association between vertebral endplate defect and Modic change in the general population. AB - Modic change (MC) is considered an independent risk factor for low back pain (LBP) but its aetiology remains unclear. In this cross-sectional, large-scale population-based study we sought to characterise associations between endplate defect (ED) and MC in a population sample of broad age range. The study population consisted of 831 twin volunteers (including 4155 discs and 8310 endplates) from TwinsUK. Lumbar T2-weighted MR images were coded for ED and MC. Total endplate (TEP) score was calculated at each intervertebral disc while receiver operating curves (ROC) were calculated to define critical endplate values predictive of MC. MC was detected in 32.1% of the subjects, with a significantly higher prevalence at lower lumbar levels (3.5% at L1/2-L3/4 vs. 15.9% at L4/5-L5/S1, p < 0.001). TEP score was strongly and independently associated with MC at each lumbar level (risk estimates from 1.49 to 2.44; all p <= 0.001) after adjustment for age, sex, BMI and twin pairing. ROC analysis showed a TEP score cut-off of 6 above which there was a significantly higher prevalence of MC. In conclusion, ED were strongly associated with MC at every lumbar level. These findings support the hypothesis that endplate defect is a major initiating factor for the cascade of events that may include disc degeneration (DD) and MC. PMID- 30413782 TI - Modulation of acoustomechanical instability and bifurcation behavior of soft materials. AB - We demonstrate acoustically triggered giant deformation of soft materials, and reveal the snap-through instability and bifurcation behavior of soft materials in nonlinear deformation regime in response to combined loading of mechanical and acoustic radiation forces. Our theoretical results suggest that acoustomechanical instability and bifurcation can be readily modulated by varying either the mechanical or acoustic force. This modulation functionality arises from the sensitivity of acoustic wave propagation to nonlinear deformation of soft material, particularly to ratio of initial geometrical size of soft material to acoustic wavelength in the material. The tunable acoustomechanical instability and bifurcation behavior of soft materials enables innovative design of programmable mechanical metamaterials. PACS numbers: 43.35.+d, 43.25.+y, 46.70.De, 61.41.+e. PMID- 30413783 TI - Mutant p53-dependent mitochondrial metabolic alterations in a mesenchymal stem cell-based model of progressive malignancy. AB - It is well accepted that malignant transformation is associated with unique metabolism. Malignant transformation involves a variety of cellular pathways that are associated with initiation and progression of the malignant process that remain to be deciphered still. Here we used a mouse model of mutant p53 that presents a stepwise progressive transformation of adult Mesenchymal Stem Cells (MSCs). While the established parental p53Mut-MSCs induce tumors, the parental p53WT-MSCs that were established in parallel, did not. Furthermore, tumor lines derived from the parental p53Mut-MSCs (p53Mut-MSC-TLs), exhibited yet a more aggressive transformed phenotype, suggesting exacerbation in tumorigenesis. Metabolic tracing of these various cell types, indicated that while malignant transformation is echoed by a direct augmentation in glycolysis, the more aggressive p53Mut-MSC-TLs demonstrate increased mitochondrial oxidation that correlates with morphological changes in mitochondria mass and function. Finally, we show that these changes are p53Mut-dependent. Computational transcriptional analysis identified a mitochondrial gene signature specifically downregulated upon knock/out of p53Mut in MSC-TLs. Our results suggest that stem cells exhibiting different state of malignancy are also associated with a different quantitative and qualitative metabolic profile in a p53Mut-dependent manner. This may provide important insights for cancer prognosis and the use of specific metabolic inhibitors in a personalized designed cancer therapy. PMID- 30413784 TI - Species richness and taxonomic composition of trawl macrofauna of the North Pacific and its adjacent seas. AB - A checklist is presented of animal species obtained in 68,903 trawl tows during 459 research surveys performed by the Pacific Research Fisheries Center (TINRO Center) over an area measuring nearly 25 million km2 in the Chukchi and Bering seas, Sea of Okhotsk, Sea of Japan and North Pacific Ocean in 1977-2014 at depths of 5 to 2,200 m. The checklist comprises 949 fish species, 588 invertebrate species, and four cyclostome species (some specimens were identified only to genus or family level). For each species details are given on the type of trawl (benthic and/or pelagic) and basins where the species was found. Comprehensiveness of data, taxonomic composition of catches, dependence of species richness on the survey area, sample size, and habitat, are considered. Ratios of various taxonomic groups of trawl macrofauna in pelagic and benthic zones and in different basins are analysed. Basins are compared based on species composition. PMID- 30413785 TI - ROCK2, but not ROCK1 interacts with phosphorylated STAT3 and co-occupies TH17/TFH gene promoters in TH17-activated human T cells. AB - Rho-associated coiled-coil kinase (ROCK)2 targeting down-regulates autoimmune responses in animal models and patients, however the underlying molecular mechanism is still an enigma. We report that ROCK2 binds phosphorylated-STAT3 and its kinase activity controls the formation of ROCK2/STAT3/JAK2 complex and optimal STAT3 phosphorylation in human CD4+ T cells during T helper 17 (TH17) skewing. Moreover, chromatin-immunoprecipitation sequencing (ChIP-seq) analysis revealed that, genome-wide, about 70% of ROCK2 and STAT3 peaks overlapped and co localized to several key genes controlling TH17 and T follicular helper (TFH) cell functions. Specifically, the co-occupancy of ROCK2 and STAT3 on the Irf4 and Bcl6 genes was validated by ChIP-qPCR analysis. Furthermore, the binding of ROCK2 to both the Irf4 and Bcl6 promoters was attenuated by STAT3 silencing as well as by selective ROCK2 inhibitor. Thus, the present study demonstrated previously unidentified evidence that ROCK2-mediated signaling in the cytosol provides a positive feed-forward signal for nuclear ROCK2 to be recruited to the chromatin by STAT3 and potentially regulates TH17/TFH gene transcription. PMID- 30413786 TI - Energetics and Electronic Structure of Triangular Hexagonal Boron Nitride Nanoflakes. AB - We studied the energetics and electronic structures of hexagonal boron nitrogen (h-BN) nanoflakes with hydrogenated edges and triangular shapes with respect to the edge atom species. Our calculations clarified that the hydrogenated h-BN nanoflakes with a triangular shape prefer the N edges rather than B edges irrespective of the flake size. The electronic structure of hydrogenated h-BN nanoflakes depends on the edge atom species and their flake size. The energy gap between the lowest unoccupied (LU) and the highest occupied (HO) states of the nanoflakes with N edges is narrower than that of the nanoflakes with B edges and the band gap of h-BN. The nanoflakes possess peculiar non-bonding states around their HO and LU states for the N and B edges, respectively, which cause spin polarization under hole or electron doping, depending on the edge atom species. PMID- 30413787 TI - Computational characterization and control of electrical conductivity of nanowire composite network under mechanical deformation. AB - Quantitative models to predict the electrical performance of 1-D nanowire (NW) composite networks under external deformation such as bending and patterning are developed by Monte-Carlo based computations, and appropriate solutions are addressed to enhance the tolerance of the sheet resistance (Rs) of the NW networks under the deformation. In addition, several strategies are employed to improve further the robustness of the sheet resistance against the network deformation. In the case of bending, outstanding bending durability of a hybrid NW network coated on a 2-D sheet is confirmed with a numerical model, and a network of NWs aligned unidirectionally toward bend axis is introduced to alleviate the sheet resistance degradation. In the case of a narrowly patterned channel, the conductivity enhancement of a network of NWs aligned in parallel to the channel with reduced channel is validated, and a network made with two types of NWs with different lengths is suggested to enhance the tolerance of the electrical conductivity. The results offer useful design guidelines to the use of the 1-D NW percolation network for flexible transparent conducting electrodes. PMID- 30413789 TI - Cardol triene inhibits dengue infectivity by targeting kl loops and preventing envelope fusion. AB - Dengue virus causes a global burden that specific chemotherapy has not been established. A previous report suggested that anacardic acid inhibited hepatitis C virus infection. Here, we explored structure activity relationship of anacardic acid, cardanol, and cardol homologues with anti-DENV cellular infectivities. Cardol triene showed the highest therapeutic index at 29.07 with the CC50 and EC50 of 207.30 +/- 5.24 and 7.13 +/- 0.72 uM, respectively. Moreover, we observed that the more unsaturated the hydrocarbon tail, the higher the CC50s in all head groups. High CC50s were also found in HepG-2, THP-1, and HEK-293 cell lines where cardol triene CC50s were 140.27 +/- 8.44, 129.77 +/- 12.08, and 92.80 +/- 3.93 uM, respectively. Cardol triene expressed pan-dengue inhibition with the EC50s of 5.35 to 8.89 uM and kl loops of dengue envelope proteins were major targets. The strong binding energy at T48, E49, A50, P53, K128, V130, L135, M196, L198, Q200, W206, L207, I270, and L277 prevented cellular pH-dependent fusion. Zika virus kl loops were aligned in the closed position preventing cardol triene to bind and inhibit fusion and infectivity. This study showed for the first time that cardol triene had a potential for further development as anti-dengue inhibitors. PMID- 30413788 TI - Oral Pathobiont Activates Anti-Apoptotic Pathway, Promoting both Immune Suppression and Oncogenic Cell Proliferation. AB - Chronic periodontitis (CP) is a microbial dysbiotic disease linked to increased risk of oral squamous cell carcinomas (OSCCs). To address the underlying mechanisms, mouse and human cell infection models and human biopsy samples were employed. We show that the 'keystone' pathogen Porphyromonas gingivalis, disrupts immune surveillance by generating myeloid-derived dendritic suppressor cells (MDDSCs) from monocytes. MDDSCs inhibit CTLs and induce FOXP3 + Tregs through an anti-apoptotic pathway. This pathway, involving pAKT1, pFOXO1, FOXP3, IDO1 and BIM, is activated in humans with CP and in mice orally infected with Mfa1 expressing P. gingivalis strains. Mechanistically, activation of this pathway, demonstrating FOXP3 as a direct FOXO1-target gene, was demonstrated by ChIP-assay in human CP gingiva. Expression of oncogenic but not tumor suppressor markers is consistent with tumor cell proliferation demonstrated in OSCC-P. gingivalis cocultures. Importantly, FimA + P. gingivalis strain MFI invades OSCCs, inducing inflammatory/angiogenic/oncogenic proteins stimulating OSCCs proliferation through CXCR4. Inhibition of CXCR4 abolished Pg-MFI-induced OSCCs proliferation and reduced expression of oncogenic proteins SDF-1/CXCR4, plus pAKT1-pFOXO1. Conclusively, P. gingivalis, through Mfa1 and FimA fimbriae, promotes immunosuppression and oncogenic cell proliferation, respectively, through a two hit receptor-ligand process involving DC-SIGN+hi/CXCR4+hi, activating a pAKT+hipFOXO1+hiBIM-lowFOXP3+hi and IDO+hi- driven pathway, likely to impact the prognosis of oral cancers in patients with periodontitis. PMID- 30413790 TI - Ten-year experience of tricuspid valve replacement with the St. Jude medical valve. AB - Bioprosthetic valves for tricuspid valve replacement (TVR) have become increasingly popular in recent years, but mechanical valves remain valuable, particularly for the patients who want to avoid reoperation for bioprostheses malfunction. The aim of this study was to review our 10-year experience in adult patients who underwent TVR with the St. Jude Medical (SJM) valve. From 2005 to 2015, 265 TVRs with SJM valves were performed at our institution. The mean age at operation was 44.1 +/- 9.7 years, and 207 cases (78.1%) were female. The mean follow-up was 4.9 +/- 2.7 years. Preoperative atrial fibrillation was present in 199 cases (75.1%) and ascites in 26 (9.8%). Of all cases, 88.7% were characterized as New York Heart Association class III or IV. The hospital mortality was 6.4%. There were 9 deaths (3.8%) during late follow-up. The overall survival rates were 89.2% +/- 2.2% at 5 years and 86.6% +/- 2.9% at 10 years. The linearized rates of valve thrombosis and bleeding events were 0.8%/patient-year and 1.5%/patient-year, respectively. Three cases (1.3%) were reoperated due to prosthetic valve thrombosis. There was no reoperation for sperivalvular leakage and structural failure. The freedom from reoperation was 98.6% +/- 0.8% at 5 years and 98.6% +/- 0.8% at 10 years. The SJM valve in the tricuspid position is a reliable mechanical prosthesis with a low rate of valve thrombosis and reoperation. It is a reasonable choice for the patients who require mechanical valve replacement in the tricuspid position. PMID- 30413791 TI - Functional analysis of potential cleavage sites in the MERS-coronavirus spike protein. AB - The Middle East respiratory syndrome-related coronavirus (MERS-CoV) can cause severe disease and has pandemic potential. Therefore, development of antiviral strategies is an important task. The activation of the viral spike protein (S) by host cell proteases is essential for viral infectivity and the responsible enzymes are potential therapeutic targets. The cellular proteases furin, cathepsin L and TMPRSS2 can activate MERS-S and may cleave the S protein at two distinct sites, termed S1/S2 and S2'. Moreover, a potential cathepsin L cleavage site in MERS-S has been reported. However, the relative importance of these sites for MERS-S activation is incompletely understood. Here, we used mutagenic analysis and MERS-S-bearing vectors to study the contribution of specific cleavage sites to S protein-driven entry. We found that an intact S1/S2 site was only required for efficient entry into cells expressing endogenous TMPRSS2. In keeping with a previous study, pre-cleavage at the S1/S2 motif (RSVR) was important although not essential for subsequent MERS-S activation by TMPRSS2, and indirect evidence was obtained that this motif is processed by a protease depending on an intact RXXR motif, most likely furin. In contrast, the S2' site (RSAR) was required for robust viral entry into all cell lines tested and the integrity of one of the two arginines was sufficient for efficient entry. These findings suggest that cleavage at S2' is carried out by proteases recognizing a single arginine, most likely TMPRSS2 and cathepsin L. Finally, mutation of the proposed cathepsin L site did not impact viral entry and double mutation of S1/S2 and S2' site was compatible with cathepsin L- but not TMPRSS2-dependent host cell entry, indicating that cathepsin L can process the S protein at auxiliary sites. Collectively, our results indicate a rigid sequence requirement for S protein activation by TMPRSS2 but not cathepsin L. PMID- 30413793 TI - Active surveillance for prostate and thyroid cancers: evolution in clinical paradigms and lessons learned. AB - The adverse effects of overdiagnosis and overtreatment observed in men with clinically insignificant prostate cancers after the introduction of prostate specific antigen-based screening are now being observed in those with thyroid cancer, owing to the introduction of new imaging technologies. Thus, the evolving paradigm of active surveillance in prostate and thyroid cancers might be valuable in informing the development of future active surveillance protocols. The lessons learned from active surveillance and their implications include the need to minimize the use of broad, population-based screening programmes that do not incorporate patient education and the need for individualized or shared decision making, which can decrease the extent of overtreatment. Furthermore, from the experience in patients with prostate cancer, we have learned that consensus is required regarding the optimal selection of patients for active surveillance, using more-specific evidence-based methods for stratifying patients by risk. In this Review, we describe the epidemiology, pathology and screening guidelines for the management of patients with prostate and thyroid cancers; the evidence of overdiagnosis and overtreatment; and provide overviews of existing international active surveillance protocols. PMID- 30413792 TI - Evaluation of Insecticides induced hormesis on the demographic parameters of Myzus persicae and expression changes of metabolic resistance detoxification genes. AB - Insecticide induced-hormesis is a bi-phasic phenomenon generally characterized by low-dose induction and high-dose inhibition. It has been linked to insect pest outbreaks and insecticide resistance, which have importance in the integrated pest management (IPM). In this paper, hormesis effects of four insecticides on demographic parameters and expression of genes associated with metabolic resistance were evaluated in a field collected population of the green peach aphid, Myzus persicae Sulzer. The bioassay results showed that imidacloprid was more toxic than acetamiprid, deltamethrin and lambda-cyhalothrin. After exposure to sublethal doses of acetamiprid and imidacloprid for four generations, significant prolonged nymphal duration and increased fecundity were observed. Subsequently, mean generation time (T) and gross reproductive rate (GRR) was significantly increased. Moreover, expression of CYP6CY3 gene associated with resistance to neonicotinoids was increased significantly compared to the control. For pyrethriods, across generation exposure to sublethal doses of lambda cyhalothrin and deltamethrin prolonged the immature development duration. However, the expression of E4 gene in M. persicase was decreased by deltamethrin exposure but increased by lambda cyhalothrin. Based on results, demographic fitness parameters were effected by hormetic dose and accompanied with detoxifying genes alteration, hence, which would be evaluated in developing optimized insect pest management strategies. PMID- 30413794 TI - Transcriptomics in lung tissue upon respiratory syncytial virus infection reveals aging as important modulator of immune activation and matrix maintenance. AB - Aging poses an increased risk of severe infection by respiratory syncytial virus (RSV). The many different biological pathways comprising the response to infection in lungs that are influenced by aging are complex and remain to be defined more thoroughly. Towards finding new directions in research on aging, we aimed to define biological pathways in the acute response to RSV that are affected in the lungs by aging. We therefore profiled the full transcriptome of lung tissue of mice prior to and during RSV infection both at young and old age. In the absence of RSV, we found aging to downregulate genes that are involved in constitution of the extracellular matrix. Moreover, uninfected old mice showed elevated expression of pathways that resemble injury, metabolic aberrations, and disorders mediated by functions of the immune system that were induced at young age only by an exogenous trigger like RSV. Furthermore, infection by RSV mounted stronger activation of anti-viral type-I interferon pathways at old age. Despite such exaggerated anti-viral responses, old mice showed reduced control of virus. Altogether, our findings emphasize important roles in aging-related susceptibility to respiratory disease for extracellular matrix dysfunctions and dysregulated immune activation in lungs. PMID- 30413795 TI - Biomarker Phenotype for Early Diagnosis and Triage of Sepsis to the Pediatric Intensive Care Unit. AB - Early diagnosis and triage of sepsis improves outcomes. We aimed to identify biomarkers that may advance diagnosis and triage of pediatric sepsis. Serum and plasma samples were collected from young children (1-23 months old) with sepsis on presentation to the Pediatric Intensive Care Unit (PICU-sepsis, n = 46) or Pediatric Emergency Department (PED-sepsis, n = 58) and PED-non-sepsis patients (n = 19). Multivariate analysis was applied to distinguish between patient groups. Results were compared to our results for older children (2-17 years old). Common metabolites and protein-mediators were validated as potential biomarkers for a sepsis-triage model to differentiate PICU-sepsis from PED-sepsis in children age 1 month-17 years. Metabolomics in young children clearly separated the PICU-sepsis and PED-sepsis cohorts: sensitivity 0.71, specificity 0.93, and AUROC = 0.90 +/- 0.03. Adding protein-mediators to the model did not improve performance. The seven metabolites common to the young and older children were used to create the sepsis-triage model. Validation of the sepsis-triage model resulted in sensitivity: 0.83 +/- 0.02, specificity: 0.88 +/- 0.05 and AUROC 0.93 +/- 0.02. The metabolic-based biomarkers predicted which sepsis patients required care in a PICU versus those that could be safely cared for outside of a PICU. This has potential to inform appropriate triage of pediatric sepsis, particularly in EDs with less experience evaluating children. PMID- 30413796 TI - Use of human induced pluripotent stem cell-derived cardiomyocytes to assess drug cardiotoxicity. AB - Cardiotoxicity has historically been a major cause of drug removal from the pharmaceutical market. Several chemotherapeutic compounds have been noted for their propensities to induce dangerous cardiac-specific side effects such as arrhythmias or cardiomyocyte apoptosis. However, improved preclinical screening methodologies have enabled cardiotoxic compounds to be identified earlier in the drug development pipeline. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can be used to screen for drug-induced alterations in cardiac cellular contractility, electrophysiology, and viability. We previously established a novel 'cardiac safety index' (CSI) as a metric that can evaluate potential cardiotoxic drugs via high-throughput screening of hiPSC-CMs. This metric quantitatively examines drug-induced alterations in CM function, using several in vitro readouts, and normalizes the resulting toxicity values to the in vivo maximum drug blood plasma concentration seen in preclinical or clinical pharmacokinetic models. In this ~1-month-long protocol, we describe how to differentiate hiPSCs into hiPSC-CMs and subsequently implement contractility and cytotoxicity assays that can evaluate drug-induced cardiotoxicity in hiPSC-CMs. We also describe how to carry out the calculations needed to generate the CSI metric from these quantitative toxicity measurements. PMID- 30413797 TI - A soil-carrying lacewing larva in Early Cretaceous Lebanese amber. AB - Diverse organisms protect and camouflage themselves using varied materials from their environment. This adaptation and associated behaviours (debris-carrying) are well known in modern green lacewing larvae (Neuroptera: Chrysopidae), mostly due to the widespread use of these immature insects in pest control. However, the evolutionary history of this successful strategy and related morphological adaptations in the lineage are still far from being understood. Here we describe a novel green lacewing larva, Tyruschrysa melqart gen. et sp. nov., from Early Cretaceous Lebanese amber, carrying a preserved debris packet composed by soil particles entangled among specialised setae of extremely elongate tubular tubercles. The new morphotype has features related to the debris-carrying habit that are unknown from extant or extinct green lacewings, namely a high number of tubular tubercle pairs on the abdomen and tubular tubercle setae with mushroom shaped endings that acted as anchoring points for debris. The current finding expands the diversity of exogenous materials used by green lacewing larvae in deep time, and represents the earliest direct evidence of debris-carrying in the lineage described to date. The debris-carrying larval habit likely played a significant role during the initial phases of diversification of green lacewings. PMID- 30413799 TI - Response to "Ethical concerns regarding Danish genetic research". PMID- 30413798 TI - Behavioural responses to unexpected changes in reward quality. AB - Successive negative contrast (SNC) effects are changes in anticipatory or consummatory behaviour when animals unexpectedly receive a lower value reward than they have received previously. SNC effects are often assumed to reflect frustration and appear to be influenced by background affective state. However, alternative explanations of SNC, such as the functional-search hypothesis, do not necessarily imply an aversive affective state. We tested 18 dogs in a SNC paradigm using a patch foraging task. Dogs were tested in two conditions, once with the low value reward in all of five trials (unshifted) and once when reward value was altered between high and low (shifted). Following a reward downshift, subjects showed a SNC effect by switching significantly more often between patches compared to the unshifted condition. However, approach latency, foraging time and quantity consumed did not differ between conditions, suggesting non affective functional search behaviour rather than frustration. There was no relationship between strength of SNC and anxiety-related behaviours as measured in a novel object test and a personality questionnaire (C-BARQ). However, associations with the C-BARQ scores for Trainability and Stranger directed aggression suggest a possible link with behavioural flexibility and coping style. While reward quality clearly affects incentive motivation, the relationship between SNC, frustration and background affective state requires further exploration. PMID- 30413800 TI - CircDYM ameliorates depressive-like behavior by targeting miR-9 to regulate microglial activation via HSP90 ubiquitination. AB - Circular RNAs (circRNAs), highly expressed in the central nervous system, are involved in various regulatory processes and implicated in some pathophysiology. However, the potential role of circRNAs in psychiatric diseases, particularly major depressive disorder (MDD), remains largely unknown. Here, we demonstrated that circular RNA DYM (circDYM) levels were significantly decreased both in the peripheral blood of patients with MDD and in the two depressive-like mouse models: the chronic unpredictable stress (CUS) and lipopolysaccharide (LPS) models. Restoration of circDYM expression significantly attenuated depressive like behavior and inhibited microglial activation induced by CUS or LPS treatment. Further examination indicated that circDYM functions as an endogenous microRNA-9 (miR-9) sponge to inhibit miR-9 activity, which results in a downstream increase of target-HECT domain E3 ubiquitin protein ligase 1 (HECTD1) expression, an increase of HSP90 ubiquitination, and a consequent decrease of microglial activation. Taken together, the results of our study demonstrate the involvement of circDYM and its coupling mechanism in depression, providing translational evidence that circDYM may be a novel therapeutic target for depression. PMID- 30413801 TI - El Nino drives a widespread ulcerative skin disease outbreak in Galapagos marine fishes. AB - Climate change increases local climatic variation and unpredictability, which can alter ecological interactions and trigger wildlife disease outbreaks. Here we describe an unprecedented multi-species outbreak of wild fish disease driven by a climate perturbation. The 2015-16 El Nino generated a +2.5 degrees C sea surface temperature anomaly in the Galapagos Islands lasting six months. This coincided with a novel ulcerative skin disease affecting 18 teleost species from 13 different families. Disease signs included scale loss and hemorrhagic ulcerated patches of skin, fin deterioration, lethargy, and erratic behavior. A bacterial culture isolated from skin lesions of two of the affected fish species was identified by sequencing of the 16S rRNA gene as a Rahnella spp. Disease prevalence rates were linearly correlated with density in three fish species. In January 2016, disease prevalence reached 51.1% in the ring-tailed damselfish Stegastes beebei (n = 570) and 18.7% in the king angelfish Holacanthus passer (n = 318), corresponding to 78% and 86% decreases in their populations relative to a 4.5-year baseline, respectively. We hypothesize that this outbreak was precipitated by the persistent warm temperatures and lack of planktonic productivity that characterize extreme El Nino events, which are predicted to increase in frequency with global warming. PMID- 30413802 TI - Charcot Spine following chronic spinal cord injury: an analysis of 201 published cases. AB - STUDY DESIGN: Analysis of published cases OBJECTIVES: To identify and describe symptoms, radiologic findings, treatment strategies, and reoccurrence of Charcot spine in individuals with spinal cord injury (SCI). METHODS: This analysis included all English articles published prior to October 2017, describing Charcot spine after SCI as identified by multiple reviewers. Articles were excluded if Charcot spine was attributed to alternative conditions. Individual level data were available for 94% of reported cases. Outcomes included demographic factors, injury characteristics, clinical presentation, radiologic findings, management, and reoccurrence. RESULTS: Fifty included papers described 201 individuals with SCI who developed Charcot spine. 86% of individuals had paraplegia and 93% of individuals had a neurologically complete injury. Mean length of initial spinal fusion spanned 7.7 vertebral bodies (SD = 3.9). The most common presenting symptoms were back pain (56%), spinal deformity (48%), and crepitus (34%). Vertebral body destruction (83%), osteophytes (61%), and endplate destruction (57%) were commonly reported on radiographs. Reoccurrence of Charcot spine was described in 19% of cases after initial treatment. CONCLUSION: Charcot spine after SCI commonly presents with low back pain and radiologic evidence of vertebral body destruction. Cases have been described more often in individuals with paraplegia and neurologically complete injuries. Surgical management is often pursued. A high rate of reoccurrence of Charcot spine in individuals with SCI after initial treatment has been reported. PMID- 30413803 TI - Sepsis in mechanically ventilated patients with spinal cord injury: a retrospective analysis. AB - STUDY DESIGN: Retrospective analysis. OBJECTIVES: Sepsis, one of the most frequent and life-threatening complications on intensive care units (ICUs), is associated with a need for mechanical ventilation (MV) as well as adverse respiratory outcomes in hospitalized individuals. However, it has poorly been investigated in patients with spinal cord injury (SCI); a population at high risk for pulmonary and infectious complications. SETTING: Spinal Cord Injury Center, Heidelberg University Hospital. METHODS: Over a 5-year period, 182 individuals with SCI requiring MV during their ICU stay were analyzed. Data assessment included demographics, medical characteristics, focus and causative pathogen of sepsis, length of stay, weaning outcomes, and mortality. RESULTS: Sepsis was recorded in 28 patients (15%), containing a subgroup of individuals suffering from infectious SCI and co-occurring primary sepsis with Staphylococcus aureus as the predominant microorganism. In most individuals, sepsis was found as secondary complication, which was associated with pulmonary foci, Gram-negative bacteria, and high mortality. More than 80% of individuals with secondary sepsis required induction of MV due to respiratory failure. Furthermore, respiratory failure was found to be independent of sepsis focus, spectrum of causative pathogens, SCI etiology, or severity of injury. Subsequent weaning from the respirator was prolonged in more than 90% with a high proportion of weaning failure. CONCLUSIONS: Sepsis predominantly occurs as a secondary complication after SCI and is associated with detrimental outcomes. Although the lung is frequently affected as a failing organ, not all sepsis foci are pulmonary. Awareness of both actual sepsis focus and causative pathogen is central to initiate an adequate sepsis treatment. PMID- 30413804 TI - Survival after non-traumatic spinal cord injury: evidence from a population-based rehabilitation cohort in Switzerland. AB - STUDY DESIGN: Observational cohort study. OBJECTIVE: To investigate survival and life expectancy after NTSCI in Switzerland according to etiology. SETTING: Specialized rehabilitation centers in Switzerland. METHODS: Longitudinal data from the Swiss Spinal Cord Injury (SwiSCI) medical records study were used. Adjusted hazard ratios (HRs) and life expectancies were estimated using flexible parametric survival modeling. RESULTS: One thousand four hundred and fifty individuals were admitted to first rehabilitation for NTSCI between 1990 and 2011, contributing 6137 cumulative person-years at risk and 528 deaths. With reference to persons with a degenerative disc disorder, the HR for mortality in individuals with NTSCIs from infections was 1.42 (95% CI 0.99-2.04), while risk in those with NTSCIs from vascular disorders was 1.28 (95% CI 0.97-1.68). Mortality risk was most pronounced in individuals with NTSCIs from malignant neoplasms (HR 6.32, 95% CI 4.79-8.34). Exemplified for males with an attained age of 60 years, a malignant etiology was associated with 1.7 life years remaining (LYR), as compared to 10.1 LYR for non-malignant etiologies. Males with an attained age of 60 years and a degenerative disc etiology were estimated to have 12.9 LYR. CONCLUSIONS: This study contributes an evidence base for risk factors of mortality after NTSCI, reducing a considerable knowledge gap in survival after NTSCI. Survival and life expectancy estimates were highly differential between etiological groups, indicating a need for a heterogeneous clinical approach and dynamic health-care provisions for this growing population. PMID- 30413805 TI - Circulating tumor DNA in advanced prostate cancer: transitioning from discovery to a clinically implemented test. AB - The genomic landscape of metastatic castration-resistant prostate cancer (mCRPC) differs from that of the primary tumor and is dynamic during tumor progression. The real-time and repeated characterization of this process via conventional solid tumor biopsies is challenging. Alternatively, circulating cell-free DNA (cfDNA) containing circulating tumor DNA (ctDNA) can be obtained from patient plasma using minimally disruptive blood draws and is amenable to sequential analysis. ctDNA has high overlap with the genomic sequences of biopsies from metastases and has the advantage of being representative of multiple metastases. The availability of techniques with high sensitivity and specificity, such as next-generation sequencing (NGS) and digital PCR, has greatly contributed to the development of the cfDNA field and enabled the detection of genomic alterations at low ctDNA fractions. In mCRPC, a number of clinically relevant genomic alterations have been tracked in ctDNA, including androgen receptor (AR) aberrations, which have been shown to be associated with an adverse outcome to novel antiandrogen therapies, and alterations in homologous recombination repair (HRR) genes, which have been associated with a response to PARP inhibitors. Several clinical applications have been proposed for cfDNA analysis, including its use as a prognostic tool, as a predictive biomarker, to monitor tumor response and to identify novel mechanisms of resistance. To date, the cfDNA analysis has provided interesting results, but there is an urgent need for these findings to be confirmed in prospective clinical trials. PMID- 30413806 TI - Comparison of biparametric MRI to full multiparametric MRI for detection of clinically significant prostate cancer. AB - BACKGROUND: Multiparametric magnetic resonance imaging (MP-MRI) and MRI/ultrasound (US) fusion-guided biopsy are becoming more widely used techniques for prostate cancer (PCa) diagnosis and management. However, their widespread adoption and use, where available, are limited by cost and added time. These limitations could be minimized if a biparametric MRI (BP-MRI) focusing on T2 weighted and diffusion-weighted imaging is performed. Herein we report the cancer detection rate of BP-MRI compared with full MP-MRI. METHODS: Biopsy-naive and prior negative biopsy patients with clinical suspicion for PCa underwent MP-MRI with an imaging protocol incorporating narrow field-of-view T2-weighted, diffusion-weighted, and DCE pelvic MRI. Then patients underwent MRI/US fusion guided biopsy of target lesions between November 2013 and October 2017. The pathology results were compared to the positivity of the DCE sequence compared to the BP-MRI findings alone. RESULTS: There were 648 targeted lesions biopsied in 344 patients. We defined biparametric screen filter positivity as both T2 weighted and diffusion-weighted imaging positivity for the same lesion. The majority of target lesions (552/648, 85%) were screen filter positive. For those that were screen filter negative, a minority (14/96, 15%) had DCE-positive findings. Of these, 2/3 (67%) cancer-positive cases were seen on T2-weighted imaging. For those 82 that were screen filter negative and DCE negative, the DCE phase would not have added imaging suspicion. Only 3/82 (3.7%) were cancer positive; 2 with low risk, grade group 1 cancer and 1 with intraductal carcinoma, all identified on targeted T2-weighted MRI positivity. CONCLUSIONS: BP-MRI for the evaluation of PCa and for guiding MRI/US fusion-targeted biopsy has the advantages of reducing cost, time, and contrast exposure of MP-MRI by eliminating the DCE phase. These benefits are realized without forfeiting valuable diagnostic information, as shown by similar cancer detection rates of BP-MRI and MP-MRI in this study, particularly for clinically significant cases of PCa. PMID- 30413807 TI - Quantification of bone flare on 18F-NaF PET/CT in metastatic castration-resistant prostate cancer. AB - BACKGROUND: Bone flare has been observed on 99mTc-MDP bone scans of patients with metastatic castration-resistant prostate cancer (mCRPC). This exploratory study investigates bone flare in mCRPC patients receiving androgen receptor (AR) inhibitors using 18F-NaF PET/CT. METHODS: Twenty-nine mCRPC patients undergoing AR-inhibiting therapy (abiraterone, orteronel, enzalutamide) received NaF PET/CT scans at baseline, week 6, and week 12 of treatment. SUV metrics were extracted globally for each patient (SUV) and for each individual lesion (iSUV). Bone flare was defined as increasing SUV metrics or lesion number at week 6 followed by subsequent week 12 decrease. Differences in metrics across timepoints were compared using Wilcoxon tests. Cox proportional hazard regression was conducted between global metrics and progression-free survival (PFS). RESULTS: Total SUV was most sensitive for flare detection and was identified in 14/23 (61%) patients receiving CYP17A1-inhibitors (abiraterone, orteronel), and not identified in any of six patients receiving enzalutamide. The appearance of new lesions did not account for initial increases in SUV metrics. iSUV metrics followed patient-level trends: bone flare positive patients showed a median of 72% (range: 0-100%) of lesions with total iSUV flare. Increasing mean SUV at week 6 correlated with extended PFS (HR = 0.58, p = 0.02). CONCLUSION: NaF PET bone flare was present on 61% of mCRPC patients in the first 6 weeks of treatment with CYP17A1-inhibitors. Characterization provided in this study suggests favorable PFS in patients showing bone flare. This characterization of NaF flare is important for guiding treatment assessment schedules to better distinguish between patients showing bone flare and those truly progressing, and should be performed for all emerging mCRPC treatments and imaging agents. PMID- 30413808 TI - Small Mountainous Rivers Generate High-Frequency Internal Waves in Coastal Ocean. AB - High-frequency internal waves propagating offshore in small river plumes are regularly observed at satellite imagery in many world regions. In this work we describe a mechanism of generation of these internal waves by discharges of small and rapid rivers inflowing to coastal sea. Friction between river runoff at high velocity and the subjacent sea of one order of magnitude lower velocity causes abrupt deceleration of a freshened flow and increase of its depth, i.e., a hydraulic jump is formed. Transition from supercritical to subcritical flow conditions induces generation of high-frequency internal waves that propagate off a river mouth at a stratified layer between a buoyant river plume and subjacent ambient sea and influence turbulence and mixing at this layer. Basing on in situ and satellite data we estimated wavelengths, phase speeds, and frequencies of internal waves generated in small river plumes located off the northeastern coast of the Black Sea. This process is typical for many other world mountainous regions where numerous and closely spaced small and rapid rivers inflow to sea during high discharge periods and can strongly influence, first, structure and dynamics of river plumes and, second, physical, biological, and geochemical processes in adjacent coastal areas. PMID- 30413809 TI - Relationship of post-transplant thymopoiesis with CD4+FoxP3+ regulatory T cell recovery associated with freedom from chronic graft versus host disease. PMID- 30413810 TI - Pneumocystis jirovecii pneumonia prophylaxis in allogeneic hematopoietic cell transplant recipients: can we always follow the guidelines? AB - Pneumocystis jirovecii pneumonia (PCP) is a life-threatening disease in allogeneic hematopoietic cell transplantation (HCT) recipients. Trimethoprim sulfamethoxazole (TMP-SMX) is the preferred prophylaxis but has significant toxicity. We assessed 139 consecutive HCT patients for PCP prophylaxis in our center. According to our procedures, TMP-SMX should be given as first-line prophylaxis from engraftment. In case of intolerance, atovaquone (ATO) or aerosolized pentamidine may be given. Thirteen (9.3%) patients did not receive prophylaxis because they early died. Of the 126 prophylaxed patients, 113 (90%) received TMP-SMX and 13 (10%) received ATO as first-line regimen. However, only 51/113 (45%) patients received TMP-SMX as the sole prophylaxis: 60 patients were switched to ATO because of side effect. There were 18 PCP cases: 3 occurred before engraftment, 7 occurred under ATO, 3 occurred while prophylaxis was pending the resolution of side effects, and 5 occurred after stopping prophylaxis. No cases occurred under TMP-SMX while 7 (9.6%) cases occurred under first-(n = 13) or second (n = 60)-line ATO. There are many concerns about PCP prophylaxis after HCT: patients may develop PCP before engraftment or several months after stopping immunosuppressors, and half of them do not receive TMP-SMX all along the at-risk periods. New prophylactic drugs and strategies should be evaluated. PMID- 30413811 TI - Allogeneic stem cell transplantation for patients with relapsed or refractory T cell lymphoma: efficacy of lymphoma-directed conditioning against advanced disease. AB - Salvage chemotherapy induces disease remissions in patients with relapsed or refractory (r/r) T-cell lymphomas, but fails to provide lasting tumor control. We analyzed the outcome after peripheral blood stem and bone marrow transplantation (PBSCT, n = 80; BMT, n = 4) from matched related (MRD, n = 22) or matched and unmatched unrelated donors (MUD and MMD, n = 53 and n = 9, respectively) following conditioning with fludarabine, busulfan, and cyclophosphamide (FBC) for 84 consecutive patients with r/r T-cell malignancies. At start of conditioning LDH was elevated in 50% of cases, and residual tumor (PD, SD, PR) was detectable in 84% of patients. In total, 38% (95% CI 33-44) of the patients were alive and disease-free after a median observation time of 14.5 (range 1.8 to 114) months. Univariate and multivariate analyses identified low ECOG status, as well as occurrence of acute GvHD as favorable factors for outcome. Lymphoma-directed conditioning with fludarabin, busulfan and cyclophosphamid (FBC-12), and allogeneic stem cell transplantation resulted in long-term survival for a proportion of patients with r/r peripheral T-cell lymphoma, including those with PR and SD only after salvage therapy. PMID- 30413812 TI - Transplant-associated thrombotic microangiopathy: is the treatment more expensive than the disease? PMID- 30413813 TI - Head inversion technique to restore physiological conjunctival structure for surgical treatment of primary pterygium. AB - We describe a new surgical technique to treat primary pterygium, the head inversion technique, with its surgical outcomes. Seventy-five eyes of 75 consecutive patients with primary pterygium undergoing surgical treatment were included. The pterygium head and body were bluntly separated from the cornea and inverted onto the nasal conjunctival area. By injecting a balanced salt solution subconjunctivally, the conjunctiva was ballooned and smoothed. Two or three interrupted 8-0 virgin silk sutures were placed to secure the inverted conjunctiva in place. No adjunctive therapy was used during and after surgery. Postoperatively, one eye showed pterygium recurrence at 233 days, in which an unintended conjunctival hole was made during surgery. The Kaplan-Meier analysis showed that the recurrence rate at 1 year was 2.4%. In 43 eyes which were followed up for longer than 6 months, the vascular loop, which is characteristic of normal limbal structure, appeared on the nasal conjunctiva in 41 eyes (95.3%). The palisades of Vogt were found on the nasal limbus postoperatively in 13 eyes (30.2%). The pterygium head inversion technique was an effective treatment for primary pterygium. By separating the pterygium from the cornea and inverting the intact pterygium head onto the nasal conjunctival site, the conjunctiva restored near physiological status after surgery. PMID- 30413814 TI - Sensory nerve supports epithelial stem cell function in healing of corneal epithelium in mice: the role of trigeminal nerve transient receptor potential vanilloid 4. AB - In order to understand the pathobiology of neurotrophic keratopathy, we established a mouse model by coagulating the first branch of the trigeminal nerve (V1 nerve). In our model, the sensory nerve in the central cornea disappeared and remaining fibers were sparse in the peripheral limbal region. Impaired corneal epithelial healing in the mouse model was associated with suppression of both cell proliferation and expression of stem cell markers in peripheral/limbal epithelium as well as a reduction of transient receptor potential vanilloid 4 (TRPV4) expression in tissue. TRPV4 gene knockout also suppressed epithelial repair in mouse cornea, although it did not seem to directly modulate migration of epithelium. In a co-culture experiment, TRPV4-introduced KO trigeminal ganglion upregulated nerve growth factor (NGF) in cultured corneal epithelial cells, but ganglion with a control vector did not. TRPV4 gene introduction into a damaged V1 nerve rescues the impairment of epithelial healing in association with partial recovery of the stem/progenitor cell markers and upregulation of cell proliferation and of NGF expression in the peripheral/limbal epithelium. Gene transfer of TRPV4 did not accelerate the regeneration of nerve fibers. Sensory nerve TRPV4 is critical to maintain stemness of peripheral/limbal basal cells, and is one of the major mechanisms of homeostasis maintenance of corneal epithelium. PMID- 30413815 TI - Sex-associated preventive effects of low-dose aspirin on obesity and non alcoholic fatty liver disease in mouse offspring with over-nutrition in utero. AB - Aspirin has been found to diminish hypertriglyceridemia and hyperglycemia in both obese rodents and patients with type 2 diabetes mellitus. We aimed to test whether low-dose aspirin can prevent obesity and the progression of non-alcoholic fatty liver disease (NAFLD) in high-risk subjects. We used offspring mice with maternal over-nutrition as a high-risk model of obesity and NAFLD. The offspring were given postnatal HF-diet and diethylnitrosamine (DEN) to induce obesity and NAFLD, and were treated with or without a low dose of aspirin for 12 weeks (ASP or CTL groups). Aspirin treatment reduced body weight gain, reversed glucose intolerance, and depressed hepatic lipid accumulation in female, but not in male mice. Female mice displayed re-sensitized insulin/Akt signaling and overactivated AMPK signaling, with enhanced level of hepatic PPAR-gamma, Glut4, and Glut2, while male mice only enhanced hepatic PPAR-alpha and PPAR-gamma levels. The female ASP mice had inhibited p44/42 MAPK activity and enhanced Pten expression, while male displayed activated p38 MAPK signaling. Furthermore, the female but not the male ASP mice reduced Wnt-signaling activity via both the epigenetic regulation of Apc expression and the post-transcriptional regulation of beta catenin degradation. In summary, our study demonstrates a sex-associated effect of low-dose aspirin on obesity and NAFLD prevention in female but not in male mice. PMID- 30413816 TI - Choosing the Appropriate Endoscopic Armamentarium for Treatment of Anastomotic Leaks. PMID- 30413817 TI - Role of Early Endoscopically Centered Step-Up Interventions in Acute Necrotizing Pancreatitis. PMID- 30413818 TI - Secondary Haemophagocytic Syndrome and Overlapping Immune Reconstitution Syndrome: Life-Threatening Complications of Anti-Tnf-alpha Treatment for Crohn's Disease. PMID- 30413819 TI - Towards a Fuller Assessment of Gastric Motility in Patients With Upper GI Dyspepsia: Time to Accommodate! AB - There is increasing recognition of the importance of assessing patients with unexplained upper gastrointestinal symptoms for impaired gastric accommodation. New therapeutic approaches to treat impaired accommodation are being developed. This increasing interest in diagnosing and treating impaired gastric accommodation emphasizes the need to have a clinically available method to measure the gastric accommodation response. In this editorial, gastric accommodation is discussed along with the currently available methods for its assessment. We summarize our thoughts on what are the next steps needed to make a readily accessible method for assessing gastric accommodation more widely available. PMID- 30413820 TI - Eus-Guided Biliary Drainage in Patients With Distal Malignant Obstruction: A Work in Progress. PMID- 30413821 TI - Creating and Implementing a National Public Health Campaign: The American Cancer Society's and National Colorectal Cancer Roundtable's 80% by 2018 Initiative. PMID- 30413822 TI - High-grade Dysplasia in Resected Main-duct Intraductal Papillary Mucinous Neoplasm (MD-IPMN) is Associated with an Increased Risk of Subsequent Pancreatic Cancer. AB - BACKGROUND: There is lack of consensus on post-operative surveillance for resected non-invasive intraductal papillary neoplasms (IPMNs). In this study we explored risk factors for subsequent PC in patients with MD-IPMN undergoing partial pancreatectomy. METHODS: We searched the Mayo Clinic surgical pathology database for all cases of resected MD-IPMN between 1997 and 2014. Cases with histologically confirmed main pancreatic duct involvement either isolated or in a mixed pattern with branch-duct involvement were included. Outcomes of PC in the remnant pancreas, and death related to MD-IPMN were assessed with survival analyses (Kaplan-Meier and Cox regression). RESULTS: Among the 179 patients with resected MD-IPMN the incidence of concomitant PC and high-grade dysplasia (HGD) in the resected specimen was 23 and 14%, respectively. The mean duration of follow-up was 4.31 years (range 0.12-13.5 years). Excluding 28 subjects who either underwent initial total pancreatectomy or partial pancreatectomy with surgical margins positive for PC/HGD, the 5-year incidence of subsequent PC was 12%, including 60.6% and15.6% in those with initial PC and HGD, respectively. The 10-year incidence of PC was 21.2% overall, 60.6% for PC, 38.3% for HGD, and 3.0% for LGD. Risk of subsequent PC was significantly higher for those with initial PC compared with HGD (HR = 4.95, 95% CI: 1.63-15.03, p = 0.005 and for HGD compared with LGD (HR = 11.30, 95% CI: 1.55-82.26, p = 0.017). CONCLUSION: Patients with MD-IPMN with PC or HGD undergoing segmental pancreatectomy are at higher risk of subsequent PC and may benefit from post-operative surveillance. The post operative surveillance intervals in resected MD- IPMNs need to be tailored based on dysplasia grade. PMID- 30413823 TI - The next age of immunotherapy: optimisation, stratification and therapeutic synergies. AB - Cancer immunotherapy has entered a phase of broad application in the treatment of patients with haematologic and solid tumours. From first steps to standard of care, immunotherapy has established its utility and applicability across different cancer types. Now it must demonstrate its higher potential in more personalised and stratified approaches. PMID- 30413824 TI - PD-Loma: a cancer entity with a shared sensitivity to the PD-1/PD-L1 pathway blockade. AB - Clinical trials have now identified over 30 cancer histotypes with sensitivity to anti-PD-(L)1 therapies. It is the first time in oncology that a class of drugs has demonstrated such a wide spectrum of activity in monotherapy. This subgroup of cancers ('PD-Lomas') is driving the clinical research strategies for the next generation of combination immunotherapy. PMID- 30413825 TI - Teaching an old dog new tricks: next-generation CAR T cells. AB - Adoptive T cell therapy (ACT) refers to the therapeutic use of T cells. T cells genetically engineered to express chimeric antigen receptors (CAR) constitute the most clinically advanced form of ACT approved to date for the treatment of CD19 positive leukaemias and lymphomas. CARs are synthetic receptors that are able to confer antigen-binding and activating functions on T cells with the aim of therapeutically targeting cancer cells. Several factors are essential for CAR T cell therapy to be effective, such as recruitment, activation, expansion and persistence of bioengineered T cells at the tumour site. Despite the advances made in CAR T cell therapy, however, most tumour entities still escape immune detection and elimination. A number of strategies counteracting these problems will need to be addressed in order to render T cell therapy effective in more situations than currently possible. Non-haematological tumours are also the subject of active investigation, but ACT has so far shown only marginal success rates in these cases. New approaches are needed to enhance the ability of ACT to target solid tumours without increasing toxicity, by improving recognition, infiltration, and persistence within tumours, as well as an enhanced resistance to the suppressive tumour microenvironment. PMID- 30413826 TI - Immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) during tumour progression. AB - Under steady-state conditions, bone marrow-derived immature myeloid cells (IMC) differentiate into granulocytes, macrophages and dendritic cells (DCs). This differentiation is impaired under chronic inflammatory conditions, which are typical for tumour progression, leading to the accumulation of IMCs. These cells are capable of inducing strong immunosuppressive effects through the expression of various cytokines and immune regulatory molecules, inhibition of lymphocyte homing, stimulation of other immunosuppressive cells, depletion of metabolites critical for T cell functions, expression of ectoenzymes regulating adenosine metabolism, and the production of reactive species. IMCs are therefore designated as myeloid-derived suppressor cells (MDSCs), and have been shown to accumulate in tumour-bearing mice and cancer patients. MDSCs are considered to be a strong contributor to the immunosuppressive tumour microenvironment and thus an obstacle for many cancer immunotherapies. Consequently, numerous studies are focused on the characterisation of MDSC origin and their relationship to other myeloid cell populations, their immunosuppressive capacity, and possible ways to inhibit MDSC function with different approaches being evaluated in clinical trials. This review analyses the current state of knowledge on the origin and function of MDSCs in cancer, with a special emphasis on the immunosuppressive pathways pursued by MDSCs to inhibit T cell functions, resulting in tumour progression. In addition, we describe therapeutic strategies and clinical benefits of MDSC targeting in cancer. PMID- 30413827 TI - Cytokines in clinical cancer immunotherapy. AB - Cytokines are soluble proteins that mediate cell-to-cell communication. Based on the discovery of the potent anti-tumour activities of several pro-inflammatory cytokines in animal models, clinical research led to the approval of recombinant interferon-alpha and interleukin-2 for the treatment of several malignancies, even if efficacy was only modest. These early milestones in immunotherapy have been followed by the recent addition to clinical practice of antibodies that inhibit immune checkpoints, as well as chimeric antigen receptor T cells. A renewed interest in the anti-tumour properties of cytokines has led to an exponential increase in the number of clinical trials that explore the safety and efficacy of cytokine-based drugs, not only as single agents, but also in combination with other immunomodulatory drugs. These second-generation drugs under clinical development include known molecules with novel mechanisms of action, new targets, and fusion proteins that increase half-life and target cytokine activity to the tumour microenvironment or to the desired effector immune cells. In addition, the detrimental activity of immunosuppressive cytokines can be blocked by antagonistic antibodies, small molecules, cytokine traps or siRNAs. In this review, we provide an overview of the novel trends in the cytokine immunotherapy field that are yielding therapeutic agents for clinical trials. PMID- 30413828 TI - The clinical role of the TME in solid cancer. AB - The highly complex and heterogenous ecosystem of a tumour not only contains malignant cells, but also interacting cells from the host such as endothelial cells, stromal fibroblasts, and a variety of immune cells that control tumour growth and invasion. It is well established that anti-tumour immunity is a critical hurdle that must be overcome for tumours to initiate, grow and spread and that anti-tumour immunity can be modulated using current immunotherapies to achieve meaningful anti-tumour clinical responses. Pioneering studies in melanoma, ovarian and colorectal cancer have demonstrated that certain features of the tumour immune microenvironment (TME)-in particular, the degree of tumour infiltration by cytotoxic T cells-can predict a patient's clinical outcome. More recently, studies in renal cell cancer have highlighted the importance of assessing the phenotype of the infiltrating T cells to predict early relapse. Furthermore, intricate interactions with non-immune cellular players such as endothelial cells and fibroblasts modulate the clinical impact of immune cells in the TME. Here, we review the critical components of the TME in solid tumours and how they shape the immune cell contexture, and we summarise numerous studies evaluating its clinical significance from a prognostic and theranostic perspective. PMID- 30413829 TI - A variant of the glucose transporter gene SLC2A2 modifies the glycaemic response to metformin therapy in recently diagnosed type 2 diabetes. AB - AIMS/HYPOTHESIS: The aim of this study was to investigate the modifying effect of the glucose transporter (GLUT2) gene SLC2A2 (rs8192675) variant on the glycaemic response to metformin in individuals recently diagnosed with type 2 diabetes. METHODS: Individuals with type 2 diabetes (n = 508) from the prospective German Diabetes Study (age [mean +/- SD] 53 +/- 10 years; 65% male; BMI 32 +/- 6 kg/m2, metformin use 57%) underwent detailed metabolic characterisation (hyperinsulinaemic-euglycaemic clamp, IVGTT) during the first year after diagnosis. Participants provided self-reported data from the time of diagnosis. The change in fasting glucose was assessed in relation to SLC2A2 genotype and glucose-lowering treatment using two-way ANCOVA with gene*treatment interactions adjusted for age, sex, BMI and diabetes duration. RESULTS: The C variant allele of rs8192675 was associated with a higher prevalence of diabetes symptoms at diabetes diagnosis. In the metformin monotherapy group only, patients with a C allele showed a larger adjusted blood glucose reduction during the first year after diabetes diagnosis than patients with the TT genotype (6.3 mmol/l vs 3.9 mmol/l; genotype difference 2.4 mmol/l, p = 0.02; p value for genotype interaction [metformin monotherapy vs non-pharmacological therapy] <0.01). The greater decline in fasting glucose (CC/CT vs TT) in metformin monotherapy persisted after further adjusting for glucose values at diagnosis (genotype difference 1.0 mmol/l, p = 0.01; genotype*treatment interaction p = 0.06). CONCLUSIONS/INTERPRETATION: The variant rs8192675 in the SLC2A2 gene (C allele) is associated with an improved glucose response to metformin monotherapy during the first year after diagnosis in type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01055093. PMID- 30413830 TI - Stent Retriever Thrombectomy with Mindframe Capture LP in Isolated M2 Occlusions. AB - BACKGROUND AND PURPOSE: Mechanical thrombectomy is an effective recanalization technique in acute ischemic stroke patients with large vessel occlusions; however, it is unclear to what extent stent retriever thrombectomy may be applicable to occlusions of smaller peripheral cerebral vessels. The outcome of patients with isolated M2 occlusions treated with the Mindframe Capture low profile (LP) stent retriever was reviewed. MATERIAL AND METHODS: A retrospective review of prospectively collected data on all consecutive patients treated for isolated M2 occlusions between June 2013 and December 2017 using the Mindframe Capture LP was performed. Technical aspects of the recanalization procedure, recanalization rate, complication rate, and clinical outcome were analyzed. RESULTS: Mechanical thrombectomy with the Mindframe Capture LP was performed in 38 patients (median age 79 years) with an isolated M2 occlusion. The median National Institutes of Health Stroke Scale (NIHSS) score on admission was 7.5 (interquartile range, IQR 5-12) and successful reperfusion modified Thrombolysis in Cerebral Infarction (mTICI 2b or 3) was achieved in 28 patients (74%). A compensated/adjusted modified Rankin Scale (mRS) 0-2 at 3 months was observed in 65% when taking pre-stroke disability into account. Symptomatic intracranial hemorrhage (sICH) occurred in 1 patient (2.6%). Asymptomatic intracranial hemorrhage (aICH) was noted in 8 patients (21%) and a small subarachnoid hemorrhage (SAH) in the immediate vicinity of the target vessel was apparent in 8 patients (21%). CONCLUSION: The Mindframe Capture LP is a technically effective thrombectomy device for the treatment of isolated M2 occlusions. The lower profile of the device is advantageous when targeting peripheral intracranial occlusions. PMID- 30413831 TI - Further Development of Combined Techniques Using Stent Retrievers, Aspiration Catheters and BGC : The PROTECTPLUS Technique. AB - PURPOSE: First pass complete (mTICI 3) reperfusion must be regarded as the ultimate goal in mechanical thrombectomy (MT) in patients suffering from an emergent large vessel occlusion (ELVO). With this in mind a technical modification of the previously published PROTECT (PRoximal balloon Occlusion TogEther with direCt Thrombus aspiration during stent retriever thrombectomy) approach, the PROTECTPLUS technique was evaluated. Under proximal flow arrest using a balloon guide catheter (BGC), a stent retriever was only partially inserted into a large-bore aspiration catheter. This construction was subsequently retracted as a unit into the BGC with aspiration both at the aspiration catheter and at the BGC. METHODS: A case-control study was performed comparing the PROTECT technique with the PROTECTPLUS technique with respect to the technical and procedural parameters. Patients n = 165 (101 PROTECT, 64 PROTECTPLUS) with ELVO of either the terminus of the internal carotid artery or the proximal middle cerebral artery were included. RESULTS: Using the PROTECTPLUS resulted in a higher rate of first pass complete reperfusions (59.4% vs. 27.7%, p < 0.001) as compared with PROTECT. The PROTECTPLUS also led to shorter procedure times (21 min vs. 37 min, p = 0.001) and higher rates of overall complete reperfusion (73.5% vs. 49.5%, p = 0.014) compared to PROTECT. CONCLUSION: The PROTECTPLUS technique is a promising technical modification to further optimize endovascular stroke treatment. PMID- 30413832 TI - Sagittal skeletal correction using symphyseal miniplate anchorage systems : Success rates and complications. AB - OBJECTIVES: Aim of this study is to evaluate success rates and complications related with symphyseal miniplate anchorage systems used for treatment of Class 2 and Class 3 deformities. METHODS: A total of 58 miniplates applied to 29 growing patients were evaluated. The first group comprised 24 symphyseal miniplates applied to 12 patients and Forsus Fatigue Resistant Devices were attached to the head of the miniplates for mandibular advancement. The second group consisted of 34 symphyseal miniplates applied to 17 patients and intermaxillary elastics were applied between acrylic appliances placed on the maxillary dental arch and the symphyseal miniplates for maxillary protraction. Success rate and complications of the symphyseal plate-screw anchorage system were evaluated. RESULTS: The overall success rate of symphseal miniplates was 87.9%. Six miniplates showed severe mobility and 2 miniplates broke during orthodontic treatment. Infection, miniplate mobility and mucosal hypertrophy were statistically different between the two groups. CONCLUSIONS: Symphyseal miniplates were generally used as successful anchorage units in most patients. Infection, mobility, and mucosal hypertrophy occurred more frequently in Class 2 deformity correction. However, the success rates regarding the two treatment modalities were comparable. PMID- 30413833 TI - Combined stereotactic body radiotherapy and trans-arterial chemoembolization as initial treatment in BCLC stage B-C hepatocellular carcinoma. AB - PURPOSE: We retrospectively evaluated the efficacy and safety of stereotactic body radiotherapy (SBRT) combined with trans-arterial chemoembolization (TACE) as initial therapy in Barcelona Clinic Liver Cancer (BCLC) system stage B-C hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Seventy-two patients received a single dose of TACE followed by SBRT 4 weeks later. All patients had tumor sizes >=5 cm, at least 700 ml of disease-free liver, Child-Pugh (CP) score <= B7 and tumor nodules <=5. SBRT dose, ranging from 6 * 5-8 Gy or 5-10 * 4 Gy, was individualized according to normal tissue constraints. No subsequent scheduled treatment was delivered unless disease progression was observed. Local control (LC), overall survival (OS), progression-free survival (PFS), response rate (RR), and toxicity were evaluated. RESULTS: The patients' characteristics were: median age 60 years (range 28-87 years); CP score A/B (n = 68/4); BCLC stage B/C (n = 51/21); solitary/multifocal (n = 37/35); portal vein invasion (n = 18). The median tumor size and GTV were 11.2 cm (range 5.0-23.6 cm) and 751 cm3 (range 41-4009 cm3), respectively. The median equivalent dose in 2 Gy per fraction (EQD2, alpha/beta = 10) was 37.3 Gy2 (range, 28-72 Gy2). The median follow-up time was 16.8 months (range, 3-96 months). The objective RR was 68% and the 1-year LC rate was 93.6% (95% CI, 87.6-100%). The median OS was 19.8 months (95% CI, 11.6-30.6 months). SBRT-related grade 3 or higher adverse gastrointestinal events and treatment-related death occurred in three (2.8%) and one patient (1.4%) respectively. No patient developed classical radiation-induced liver injury. CONCLUSION: Our experience suggests that combined TACE and SBRT can be a safe and effective initial therapy for BCLC stage B-C HCC with appropriate patient selection. Further prospective trials are warranted. PMID- 30413834 TI - Unprecedented high catecholamine production causing hair pigmentation after urinary excretion in red deer. AB - Hormones have not been found in concentrations of orders of magnitude higher than nanograms per milliliter. Here, we report urine concentrations of a catecholamine (norepinephrine) ranging from 0.05 to 0.5 g/l, and concentrations of its metabolite DL-3,4-dihydroxyphenyl glycol (DOPEG) ranging from 1.0 to 44.5 g/l, in wild male red deer Cervus elaphus hispanicus after LC-MS analyses. The dark ventral patch of male red deer, a recently described sexually selected signal, contains high amounts of DOPEG (0.9-266.9 mg/l) stuck in the hairs, while DOPEG is not present in non-darkened hair. The formation of this dark patch is explained by the chemical structure of DOPEG, which is a catecholamine-derived o diphenol susceptible to be oxidized by air and form allomelanins, nitrogen-free pigments similar to cutaneous melanins; by its high concentration in urine; and by the urine spraying behavior of red deer by which urine is spread through the ventral body area. Accordingly, the size of the dark ventral patch was positively correlated with the concentration of DOPEG in urine, which was in turn correlated with DOPEG absorbed in ventral hair. These findings represent catecholamine concentrations about one million higher than those previously reported for any hormone in an organism. This may have favored the evolution of the dark ventral patch of red deer by transferring information on the fighting capacity to rivals and mates. Physiological limits for hormone production in animals are thus considerably higher than previously thought. These results also unveil a novel mechanism of pigmentation based on the self-application of urine over the fur. PMID- 30413835 TI - How toll-like receptors reveal monocyte plasticity: the cutting edge of antiinflammatory therapy. AB - Toll-like receptors (TLR)s are central in immune response by recognizing pathogen associated molecular patterns (PAMP)s. If they are essential to eliminate pathogens in earlier stages of infection, they also might play a role in homeostasis and tissue repair. TLR versatility parallels the plasticity of monocytes, which represent an heterogeneous population of immune cells. They are rapidly recruited to sites of infection and involved in clearance of pathogens and in tissue healing. This review underlines how TLRs have proved to be an interesting tool to study the properties of monocytes and why different therapeutic strategies exploring monocyte plasticity may be relevant in the context of chronic inflammatory disorders. PMID- 30413836 TI - Variations in Microbial Diversity and Metabolite Profiles of the Tropical Marine Sponge Xestospongia muta with Season and Depth. AB - Xestospongia muta is among the most emblematic sponge species inhabiting coral reefs of the Caribbean Sea. Besides being the largest sponge species growing in the Caribbean, it is also known to produce secondary metabolites. This study aimed to assess the effect of depth and season on the symbiotic bacterial dynamics and major metabolite profiles of specimens of X. muta thriving in a tropical marine biome (Portobelo Bay, Panama), which allow us to determine whether variability patterns are similar to those reported for subtropical latitudes. The bacterial assemblages were characterized using Illumina deep sequencing and metabolomic profiles using UHPLC-DAD-ELSD from five depths (ranging 9-28 m) across two seasons (spring and autumn). Diverse symbiotic communities, representing 24 phyla with a predominance of Proteobacteria and Chloroflexi, were found. Although several thousands of OTUs were determined, most of them belong to the rare biosphere and only 23 to a core community. There was a significant difference between the structure of the microbial communities in respect to season (autumn to spring), with a further significant difference between depths only in autumn. This was partially mirrored in the metabolome profile, where the overall metabolite composition did not differ between seasons, but a significant depth gradient was observed in autumn. At the phyla level, Cyanobacteria, Firmicutes, Actinobacteria, and Spirochaete showed a mild-moderate correlation with the metabolome profile. The metabolomic profiles were mainly characterized by known brominated polyunsaturated fatty acids. This work presents findings about the composition and dynamics of the microbial assemblages of X. muta expanding and confirming current knowledge about its remarkable diversity and geographic variability as observed in this tropical marine biome. PMID- 30413837 TI - Phase 1 study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell carcinoma. AB - mTOR inhibitors are frequently used in the treatment of metastatic renal cell cancer (mRCC). mTOR regulates cell growth, proliferation, angiogenesis, and survival, and additionally plays an important role in immune regulation. Since mTOR inhibitors were shown to benefit immunosuppressive regulatory T-cell (Treg) expansion, this might suppress antitumor immune responses. Metronomic cyclophosphamide (CTX) was shown to selectively deplete Tregs. This study was, therefore, designed to determine the optimal dosage and schedule of CTX when combined with everolimus to prevent this potentially detrimental Treg expansion. In this national multi-center phase I study, patients with mRCC progressive on first line anti-angiogenic therapy received 10 mg everolimus once daily and were enrolled into cohorts with different CTX dosages and schedules. Besides immune monitoring, adverse events and survival data were monitored. 40 patients, 39 evaluable, were treated with different doses and schedules of CTX. Combined with 10 mg everolimus once daily, the optimal Treg depleting dose and schedule of CTX was 50 mg CTX once daily. 23 (59%) patients experienced one or more treatment related >= grade 3 toxicity, mostly fatigue, laboratory abnormalities and pneumonitis. The majority of the patients achieved stable disease, two patients a partial response. Median PFS of all cohorts was 3.5 months. In conclusion, the optimal Treg depleting dose and schedule of CTX, when combined with everolimus, is 50 mg once daily. This combination leads to acceptable adverse events in comparison with everolimus alone. Currently, the here selected combination is being evaluated in a phase II clinical trial. TRIAL REGISTRATION: NCT01462214. PMID- 30413838 TI - ESNR-the next 50 years. PMID- 30413839 TI - Correction to: Treatment and mortality of Klebslella pneumoniae infections in critically ill patients: should we do and predict them better? AB - The original version of this article unfortunately contained a mistake. PMID- 30413840 TI - E-cigarette use is associated with other tobacco use among US adolescents. AB - OBJECTIVES: To examine whether tobacco initiation via e-cigarettes increases the likelihood of subsequent tobacco use among a large representative sample of US adolescents. METHODS: This study is a retrospective longitudinal analysis from a representative sample of US middle and high school students (n = 39,718) who completed the 2014 and 2015 National Youth Tobacco Survey. The adjusted odds ratios of lifetime and current use of tobacco use were estimated by logistic regression analysis while controlling for important socio-ecological factors associated with tobacco use. RESULTS: E-cigarette initiators were more likely to report current use of cigarettes (AOR 2.7; 1.9-4.0, p < 0.001), cigars (AOR 1.7; 1.2-2.4, p < 0.01), or smokeless tobacco (AOR 3.1; 2.2-5.4, p < 0.001), and lifetime use of the same products as well. Also, lifetime and current use of e cigarettes significantly increased the likelihood of cigarettes, cigars, and smokeless tobacco use. CONCLUSIONS: Initiation of tobacco via e-cigarette, lifetime, and current use of e-cigarettes are associated with higher odds of lifetime and current use of cigarettes, cigars, and smokeless tobacco. Collectively this suggests e-cigarettes may lead to an increased use of tobacco among adolescents. PMID- 30413842 TI - The dominant role of functional action representation in object recognition. AB - Action representation of manipulable objects has been found to be involved in object recognition. Recently, studies have indicated the existence of two distinct action systems: functional action specifying how to use an object and structural action concerning how to grasp an object. Despite evidence revealing the systems' anatomical and functional differences, few preceding studies have dissociated their respective roles in object recognition. The present study aimed to tease apart their roles in the recognition of manipulable objects with a priming paradigm. Specifically, we used static stimuli (photos, Experiments 1 and 2) and dynamic stimuli (video clips, Experiments 3 and 4) depicting functional and structural action hand gestures as primes and measured the magnitude of functional and structural action priming effect in object recognition. We found that static and dynamic priming stimuli induced a robust action priming effect only for functional action prime-target pairs. Naming latencies of the target objects were shorter when functional action representations of the prime and target were congruent than when they were incongruent. Moreover, as compared to static priming photos, dynamic priming stimuli induced a larger functional action priming effect. By contrast, neither static nor dynamic priming stimuli elicited a structural action priming effect. Behavioral data from our four experiments provide consistent evidence of the dominant role of functional action representation in the recognition of manipulable objects, suggesting that action knowledge regarding how to use rather than grasp an object is more likely an intrinsic component of objects' conceptual representation. PMID- 30413841 TI - Duration of new antidepressant use and factors associated with discontinuation among community-dwelling persons with Alzheimer's disease. AB - PURPOSE: To study how long antidepressants initiated after diagnoses of Alzheimer's disease (AD) were used and factors associated with discontinuation of use among persons with Alzheimer's disease (AD). In addition, differences in duration of use between the antidepressants groups were compared. METHODS: Register-based Medication use and Alzheimer's disease (MEDALZ) cohort included 70,718 community-dwelling people with AD who were diagnosed during the years 2005 2011. For this study, the new antidepressant users were included after 1-year washout period (N = 16,501; 68.6% females, mean age 80.9). The duration of antidepressant use was modeled with the PRE2DUP method. Factors associated with treatment discontinuation were assessed with Cox proportional hazard models and included age, gender, comorbid conditions and concomitant medications. RESULTS: Median duration of the new antidepressant use period was 309 days (IQR 93-830). For selective serotonin reuptake inhibitor (SSRI) use, the median duration was 331 days (IQR 101-829), for mirtazapine 202 days (IQR 52-635), and for serotonin and norepinephrine reuptake inhibitors (SNRIs) 134 days (IQR 37-522). After 1 year follow-up, 40.8% had discontinued antidepressant use, 54.6% after 2 years and 64.1% after 3 years. Factors associated with treatment discontinuation were age over 85, male gender, diabetes, and use of memantine, opioids, and antiepileptics whereas benzodiazepines and related drugs and antipsychotic use were inversely associated with discontinuation. CONCLUSIONS: Antidepressants are used for long-term among people with AD. Need and indication for antidepressant use should be assessed regularly as evidence on their efficacy for behavioral and psychological symptoms of dementia is limited. PMID- 30413843 TI - Cognitive resilience after prolonged task performance: an ERP investigation. AB - Deleterious consequences of cognitive fatigue might be avoided if people respond with increased effort to increased demands. In this study, we hypothesized that the effects of fatigue would be more pronounced in cognitive functions reflecting compensatory effort. Given that the P3a event-related potential is sensitive to the direction and amount of attention allocated to a stimulus array, we reasoned that compensatory effort would manifest in increased P3a amplitudes. Therefore, we compared P3a before (pre-test) and after (post-test) a 2 h long cognitively demanding (fatigue group, n = 18) or undemanding task (control group, n = 18). Two auditory tasks, a three-stimulus novelty oddball and a duration discrimination two-choice response task were presented to elicit P3a. In the fatigue group, we used the multi-attribute task battery as a fatigue-inducing task. This task draws on a broad array of attentional functions and imposed considerable workload. The control group watched mood-neutral documentary films. The fatigue manipulation was effective as subjective fatigue increased significantly in the fatigue group compared to controls. Contrary to expectations, however, fatigue failed to affect P3a in the post-test phase. Similar null effects were obtained for other neurobehavioral measures (P3b and behavioral performance). Results indicate that a moderate increase in subjective fatigue does not hinder cognitive functions profoundly. The lack of objective performance loss in the present study suggests that the cognitive system can be resilient against challenges instigated by demanding task performance. PMID- 30413844 TI - Shortening of Incision by "Pinch and Turn-Over Technique" in the Treatment of Axillary Osmidrosis. AB - BACKGROUND: The pinch and turn-over technique was developed to minimize the incision in the manual subdermal excision of apocrine glands in axillary osmidrosis for the best cure and fewest complications. METHODS: Through a 2-cm long incision, peripheral subdermal tissue was excised by the technique under direct vision using intravenous anesthesia and tumescent technique. Ninety-nine axillae in 50 patients including seven secondary cases were operated on from 2009 to 2018. Long-term follow-up (average 30.3 months) could be done on 40 patients with questionnaires consisting of four-point ordinal-scale questions regarding osmidrosis grade, hyperhidrosis grade and satisfaction. For systematic review regarding incision length, 220 articles from 1962 to 2018 were reviewed with the search terms "osmidrosis" or "bromhidrosis." RESULTS: Thirty-five and 30 of 40 respondents (87.5% and 75.0%) had excellent or good postoperative results in osmidrosis and hyperhidrosis grade. Postoperative improvement of osmidrosis grade (from 2.53 to 0.80) and hyperhidrosis grade (from 1.88 to 0.95) was statistically significant (p < 0.01). Thirty-four patients (85.0%) reported very satisfactory or satisfactory. Hematoma (2.0%), hyperpigmentation (5.0%), infection (5.0%) and noticeable scar (2.5%) were rare. Necrosis of flap margins was frequent (27.3%) but necessitated revision in two cases (2.0%). Among eleven articles found to describe incision length in pure manual subdermal excision, this technique provided the shortest incision compared with eight direct subdermal excision methods with an average incision length of 5.0 cm. CONCLUSIONS: This technique offers an open, direct and selective approach with a short incision. It could maintain the best efficiency while neutralizing negative side effects of conventional manual subdermal excision for axillary osmidrosis. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the table of contents or the online instructions to authors www.springer.com/00266 . PMID- 30413845 TI - Minimally invasive internal fixation of calcaneal fractures or subtalar joint arthrodesis using the Calcanail(r). AB - OBJECTIVE: A minimally invasive technique to prevent soft tissue problems using a calcaneal nail (Calcanail(r), FH Orthopedics, Heimsbrunn, France) for calcaneal fractures or in subtalar joint arthrodesis is described. INDICATIONS: Displaced extra-articular calcaneal fractures involving the tuberosity fragment and in displaced intra-articular calcaneal fractures with impression and/or displacement of the subtalar joint surface. Subtalar joint arthrodesis for posttraumatic subtalar osteoarthritis. CONTRAINDICATIONS: Severely displaced fractures type Sanders IV with the purpose of internal fixation; peripheral calcaneal fractures; general contraindications for operative treatment. SURGICAL TECHNIQUE: Minimally invasive reduction of calcaneal fractures using a special distractor and a graft pusher through a calcaneal working channel. Fixation performed via the insertion of the Calcanail(r) and the two locking screws, optional additional screws. Subtalar joint arthrodesis with a Calcanail(r) used with optional three locking screws to fix the talus and calcaneus creating an angular stable construct. POSTOPERATIVE MANAGEMENT: Mobilization and restricted weight-bearing for 6 weeks in the patient's own shoes after fracture fixation or in a walker after arthrodesis. RESULTS: Preliminary results of 69 cases from three surgical centers have already been published. From 2013-2017, the technique was used in 48 of our own patients (42 calcaneal fracture reduction and fixation; 6 for subtalar joint arthrodesis). Mean postoperative hospital stay was 7 days for fracture reduction without any need of additional operations. During follow-up, 6 implant removals and 2 secondary subtalar fusions were noticed. All 6 cases of subtalar joint arthrodesis were planned in posttraumatic subtalar osteoarthritis. PMID- 30413846 TI - [Diagnosis and treatment of aortic valve stenosis]. AB - Aortic valve stenosis (AS) is the most frequently observed valvular heart disease. Once it is symptomatic the mortality rapidly increases. The diagnostic gold standard is transthoracic echocardiography. By measuring the maximum transvalvular velocity, mean transaortic pressure gradient and aortic valve opening area, classification of the type of stenosis can be defined. A differentiation is made between high-gradient AS, low-flow low gradient AS with reduced ventricular ejection fraction (<50%) and the paradoxical low-flow low gradient AS with preserved ventricular function (>=50%). In some cases, additional diagnostic tools are necessary using dobutamine stress echocardiography, transesophageal echocardiography and cardiac computed tomography. The treatment follows an individualized approach. In cases of indications for valve replacement the multidisciplinary heart team takes into account the patient's age and individual risk for deciding whether an open surgical approach or transcatheter aortic valve implantation is indicated. PMID- 30413847 TI - [Frontiers in liver transplantation in indication and techniques]. AB - BACKGROUND: The frontiers in liver transplantation are intrinsically expansions of indications, e.g. hepatocellular carcinoma and (perihilar) cholangiocarcinoma, recipients with more severe concomitant diagnoses or "soft" contraindications and technically demanding reconstruction procedures of vascular structures (for portal vein thrombosis or aorto-hepatic conduits). In addition, an extension of the donor pool with suboptimal donor organs (old donors and steatotic livers) is of interest. METHODS: This article presents the current situation based on personal experiences in daily practice and an appropriate literature review. RESULTS: A significant reduction of 1-year patient survival has been reported in Germany. The percentage of so-called marginal donor organs is inversely proportional to the very low donation rate and parallel to the waiting list mortality. Simultaneously, the proportion of inpatients with multiple organ failure is rising. CONCLUSION: Results-oriented and controlled liver transplantation currently prohibits making inroads into the previously intrinsic frontiers. As long as the current circumstances do not change, a shift in the intrinsic frontiers of that which is surgically feasible will not be possible. The current situation forces the transplant surgeon to apply a more restrictive indications and organ acceptance policy. With this approach we can try to regain the previously excellent short- and long-term results of a 1-year survival of 90% and a 20-year survival of 50%. PMID- 30413849 TI - Green synthesis of silver nanoparticles from medicinal plants and evaluation of their antiviral potential against chikungunya virus. AB - The exploration of nanoscale materials for their therapeutic potential against emerging and re-emerging infections has been increased in recent years. Silver nanoparticles (AgNPs) are known to possess antimicrobial activities against different pathogens including viruses and provide an excellent opportunity to develop new antivirals. The present study focused on biological synthesis of AgNPs from Andrographis paniculata, Phyllanthus niruri, and Tinospora cordifolia and evaluation of their antiviral properties against chikungunya virus. Synthesized plants AgNPs were characterized to assess their formation, morphology, and stability. The cytotoxicity assays in Vero cells revealed that A. paniculata AgNPs were most cytotoxic with maximum non-toxic dose (MNTD) value of 31.25 MUg/mL followed by P. niruri (MNTD, 125 MUg/mL) and T. cordifolia AgNPs (MNTD, 250 MUg/mL). In vitro antiviral assay of AgNPs based on degree of inhibition of cytopathic effect (CPE) showed that A. paniculata AgNPs were most effective, followed by T. cordifolia and P. niruri AgNPs. The results of antiviral assay were confirmed by cell viability test using 3-(4, 5 dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) dye, which revealed that A. paniculata AgNPs inhibited the virus to a maximum extent. The cell viability of CHIKV-infected cells significantly increased from 25.69% to 80.76 and 66.8%, when treated with A. paniculata AgNPs at MNTD and 1/2MNTD, respectively. These results indicated that use of plants AgNPs as antiviral agents is feasible and could provide alternative treatment options against viral diseases which have no specific antiviral or vaccines available yet. PMID- 30413848 TI - Identification of patients with recent-onset psychosis in KwaZulu Natal, South Africa: a pilot study with traditional health practitioners and diagnostic instruments. AB - PURPOSE: There is considerable variation in epidemiology and clinical course of psychotic disorders across social and geographical contexts. To date, very little data are available from low- and middle-income countries. In sub-Saharan Africa, most people with psychoses remain undetected and untreated, partly due to lack of formal health care services. This study in rural South Africa aimed to investigate if it is possible to identify individuals with recent-onset psychosis in collaboration with traditional health practitioners (THPs). METHODS: We developed a strategy to engage with THPs. Fifty THPs agreed to collaborate and were asked to refer help-seeking clients with recent-onset psychosis to the study. At referral, the THPs rated probability of psychosis ("maybe disturbed" or "disturbed"). A two-step diagnostic procedure was conducted, including the self report Community Assessment of Psychic Experiences (CAPE) as screening instrument, and a semi-structured interview using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN). Accuracy of THP referrals, and test characteristics of the THP rating and the CAPE were calculated. RESULTS: 149 help seeking clients were referred by THPs, of which 44 (29.5%) received a SCAN DSM-IV diagnosis of psychotic disorder. The positive predictive value of a THP "disturbed" rating was 53.8%. Test characteristics of the CAPE were poor. CONCLUSION: THPs were open to identifying and referring individuals with possible psychosis. They recognized "being disturbed" as a condition for which collaboration with formal psychiatric services might be beneficial. By contrast, the CAPE performed poorly as a screening instrument. Collaboration with THPs is a promising approach to improve detection of individuals with recent-onset psychosis in rural South Africa. PMID- 30413851 TI - "More accurate correction using "patient-specific" cutting guides in opening wedge distal femur varization osteotomies. AB - PURPOSE: The distal femoral varization osteotomy (DFVO) by a lateral opening wedge osteotomy is an established intervention for patients suffering from lateral femoro-tibial osteoarthritis on a genu valgum deformity. In order to improve the accuracy of this correction, the use of a customized cutting guide (PSI) has been proposed as an alternative to conventional technique. The objective of our study was to compare the accuracy of post-operative alignment following DFVO in the coronal and sagittal plane using either a conventional abacus technique or PSI guide. METHOD: Twenty-one patients that underwent lateral opening wedge osteotomy from a technique using PSI based on 3D CT-scans were matched 1:1 to 21 patients operated on using a conventional technique (pre operative planning performed on standard radiographs). The accuracy of the correction was analyzed, comparing coronal and sagittal mechanical post-operative angles with pre-operative planning. RESULTS: With regard to alignment in the coronal plane (HKA correction), our study demonstrated a significant improvement in the accuracy of the correction obtained in the PSI group compared to the conventional group (0.43 +/- 0.50 vs 3.95 +/- 1.64 p < 0.001). In the sagittal plane (PDFA correction), we also found a significant improvement in correction accuracy in the PSI group (0.52 +/- 0.60 vs 3.10 +/- 1.83 p < 0.001). There was a significant decrease in operating time (delta 7.7 +/- 3.07 (1.5-13.9) (p = 0.0.161) and fluoroscopic images taken (6.9 +/- 0.54 (5.8-8) p < 0.001). CONCLUSION: Our results suggest that the use of PSI in DFVO improves the accuracy of correction in both the coronal and sagittal planes compared to conventional techniques. PMID- 30413850 TI - Novel osmotic stress control strategy for improved pneumocandin B0 production in Glarea lozoyensis combined with a mechanistic analysis at the transcriptome level. AB - Pneumocandin B0, the precursor of the antifungal drug caspofungin, is a secondary metabolite of the fungus Glarea lozoyensis. In this study, we investigated the effects of mannitol as the sole carbon source on pneumocandin B0 production by G. lozoyensis. The osmotic pressure is more important in enhancing pneumocandin B0 production than is the substrate concentration. Based on the kinetic analysis, an osmotic stress control fed-batch strategy was developed. This strategy led to a maximum pneumocandin B0 concentration of 2711 mg/L with a productivity of 9.05 mg/L/h, representing 34.67 and 6.47% improvements, respectively, over the best result achieved by the one-stage fermentation. Furthermore, G. lozoyensis accumulated glutamate and proline as compatible solutes to resist osmotic stress, and these amino acids also provided the precursors for the enhanced pneumocandin B0 production. Osmotic stress also activated ROS (reactive oxygen species) dependent signal transduction by upregulating the levels of related genes and increasing intracellular ROS levels by 20%. We also provided a possible mechanism for pneumocandin B0 accumulation based on signal transduction. These findings will improve our understanding of the regulatory mechanisms of pneumocandin B0 biosynthesis and may be applied to improve secondary metabolite production. PMID- 30413853 TI - [White matter alterations after chemotherapy and radiation]. AB - Nowadays chemotherapy and radiotherapy are fundamental therapy concepts in the guidelines of malignant tumors of the central nervous system. Both therapy concepts can cause neurological symptoms or white matter alterations can occur, which can be classified into acute, subacute and chronic. Both symptoms and white matter alterations during acute and subacute phases are in most cases completely reversible, whereas chronic white matter alterations can lead to severe neurological limitations and further impair the quality of life of cancer patients. PMID- 30413852 TI - Pharmacies for pain and trauma in ancient Greece. AB - PURPOSE: To summarize pharmacies for pain and trauma in ancient Greece, to present several pharmaceutical/therapeutical methods reported in myths and ancient texts, and to theorize on the medical explanation upon which these pharmacies were used. METHOD: A thorough literature search was undertaken in PubMed and Google Scholar as well as in physical books in libraries to summarize the pharmacies and pain practices used for trauma in ancient Greece. RESULTS: Archeological findings and historical texts have revealed that humans have always suffered from diseases and trauma that were initially managed and healed by priests and magicians. In early Greek antiquity, the term pharmacy was related to herbal inquiries, with the occupants called charmers and pharmacists. Additionally, apart from therapeutic methods, ancient Greeks acknowledged the importance of pain therapy and had invented certain remedies for both acute and chronic pain management. With observations and obtaining experience, they used plants, herbs, metals and soil as a therapeutic method, regardless of the cultural level of the population. They achieved sedation and central and peripheral analgesia with opium and cold, as well as relaxation of smooth muscle fibers and limiting secretions with atropina. CONCLUSION: History showed a lot of experience obtained from empirical testing of pain treatment in ancient people. Experience and reasoning constructed an explanatory account of diseases, therapies and health and have provided for the epistemology of medicine. PMID- 30413855 TI - The Relationship Between Pre-operative Left Ventricular Longitudinal Strain and Post-operative Length of Stay in Patients Undergoing Arterial Switch Operation Is Age Dependent. AB - INTRODUCTION: Post-operative length of stay (LOS) after the arterial switch operation (ASO) is variable. The association between pre-operative non-invasive measures of ventricular function and post-operative course has not been well established. The aims of this study were to (1) evaluate the relationship between pre-operative non-invasive measures of ventricular function and post-operative LOS and (2) evaluate the change in ventricular function after ASO. METHODS: Data were reviewed in consecutive ASO patients between 2010 and 2016. The primary outcome was post-operative LOS. Echocardiograms obtained during the pre-operative period and at the time of discharge were retrospectively analyzed using speckle tracking echocardiography. Pearson's correlation between patient-specific, pre operative, and echocardiographic data versus post-operative LOS was assessed. RESULTS: Fifty-two patients were included in analyses, 39 neonates and 13 infants. Left ventricular (LV) longitudinal strain correlated with post-operative LOS for infants age > 28 days (r = 0.62, p = 0.03), but not for neonates (r = 0.14, p = 0.40). Operative age (r = - 0.42, p = 0.003), weight at surgery (r = - 0.48, p <= 0.001), and cardiopulmonary bypass time (r = 0.30, p = 0.045) also correlated with post-operative LOS. Standard 2D measures of ventricular function did not correlate with post-operative LOS. LV ejection fraction and longitudinal strain worsened post-operatively. CONCLUSION: Higher pre-operative LV longitudinal strain (representing worse LV function) is associated with increased post-operative LOS after ASO in infants > 28 days, but not in neonates. LV ejection fraction and longitudinal strain worsened after ASO. Future studies should assess the utility of performing STE in risk stratifying patients prior to ASO. PMID- 30413854 TI - Effect of Long-Term Green Tea Polyphenol Supplementation on Bone Architecture, Turnover, and Mechanical Properties in Middle-Aged Ovariectomized Rats. AB - We investigated the effects of 6-month green tea polyphenols (GTP) supplementation on bone architecture, turnover, and mechanical properties in middle-aged ovariectomized (OVX) rats. Female rats were sham-operated (n = 39, 13/group) or OVX (n = 143, 13/group). Sham-control and OVX-control rats (n = 39) receiving no GTP were assigned for sample collection at baseline, 3, or 6 months. The remaining OVX rats (n = 104) were randomized to 0.15%, 0.5%, 1%, and 1.5% (g/dL) GTP for 3 or 6 months. Blood and bone samples were collected. Relative to the OVX-control group, GTP (1% and 1.5%) lowered serum procollagen type 1 N terminal propeptide at 3 and 6 months, C-terminal telopeptides of type I collagen at 3 months, and insulin-like growth factor-I at 6 months. GTP did not affect bone mineral content and density. At 6 months, no dose of GTP positively affected trabecular bone volume based on microCT, but a higher cortical thickness and improved biomechanical properties of the femur mid-diaphysis was observed in the 1.5% GTP-treated group. At 3 and 6 months, GTP (0.5%, 1%, and 1.5%) had lower rates of trabecular bone formation and resorption than the OVX-control group, but the inhibitory effects of GTP on periosteal and endocortical bone mineralization and formation at the tibial midshaft were only evident at 3 months. GTP at higher doses suppressed bone turnover in the trabecular and cortical bone of OVX rats and resulted in improved cortical bone structural and biomechanical properties, although it was not effective in preventing the ovariectomy-induced dramatic cancellous bone loss. PMID- 30413856 TI - Hormone therapy and osteoporosis in breast cancer survivors: assessment of risk and adherence to screening recommendations. AB - : The long-term impact of hormone therapy for breast cancer on risk of osteoporosis and the extent to which bone screening recommendations are implemented in daily practice remain unknown. We found that the aromatase inhibitor-induced risk of osteoporosis did not continue in the off-treatment follow-up. Adherence to screening recommendations was suboptimal. INTRODUCTION: A case-cohort study was undertaken to better understand the impact of hormone therapy on breast cancer patients' risk of osteoporosis, and to estimate the extent to which current bone mineral density screening recommendations are implemented in real-life daily practice. METHODS: This study is based on 1692 female breast cancer survivors recruited from "Leumit" healthcare fund, who were diagnosed with primary nonmetastatic invasive breast cancer between 2002 and 2012. A 20% random subcohort was sampled at baseline, and all osteoporosis cases were identified. Adjusted hazard ratios (HR) with 95% confidence intervals (CI) were estimated by weighted Cox proportional hazards models. RESULTS: Of 1692 breast cancer survivors, 312 developed osteoporosis during a median follow-up of 5 years. The crude cumulative incidence of osteoporosis accounting for death as a competing risk was 25.7% (95% CI, 21.9-29.5%). In multivariable analyses, osteoporosis was positively associated with the aromatase inhibitor (AI) sequential treatment after tamoxifen (HR, 3.14; 95% CI, 1.44-6.88; P = .004) but was more pronounced with AI use as upfront monotherapy (HR, 5.53; 95% CI, 1.46 20.88; P = .012). This effect did not continue in the off-treatment follow-up. In subgroup analysis by menopausal status, tamoxifen did not seem to confer a protective effect on bone health in postmenopausal patients. Adherence to screening recommendations in AI-treated postmenopausal women was suboptimal, particularly at baseline and after 48 months of continuous AI use. CONCLUSIONS: The natural, age-related reduction in bone density is exacerbated by breast cancer active AI treatment. Future research should focus on investigating screening adherence-related barriers/facilitators and effective strategies to bring practice in line with agreed standards. PMID- 30413857 TI - Ultrafast pediatric chest computed tomography: comparison of free-breathing vs. breath-hold imaging with and without anesthesia in young children. AB - BACKGROUND: General anesthesia (GA) or sedation has been used to obtain good quality motion-free breath-hold chest CT scans in young children; however pulmonary atelectasis is a common and problematic accompaniment that can confound diagnostic utility. Dual-source multidetector CT permits ultrafast high-pitch sub second examinations, minimizing motion artifact and potentially eliminating the need for a breath-hold. OBJECTIVE: The purpose of this study was to evaluate the feasibility of free-breathing ultrafast pediatric chest CT without GA and to compare it with breath-hold and non-breath-hold CT with GA. MATERIALS AND METHODS: Young (<=3 years old) pediatric outpatients scheduled for chest CT under GA were recruited into the study and scanned using one of three protocols: GA with intubation, lung recruitment and breath-hold; GA without breath-hold; and free-breathing CT without anesthesia. In all three protocols an ultrafast high pitch CT technique was used. We evaluated CT images for overall image quality, presence of atelectasis and motion artifacts. RESULTS: We included 101 scans in the study. However the GA non-breath-hold technique was discontinued after 15 scans, when it became clear that atelectasis was a major issue despite diligent attempts to mitigate it. This technique was therefore not included in statistical evaluation (86 remaining patients). Overall image quality was higher (P=0.001) and motion artifacts were fewer (P<.001) for scans using the GA with intubation and recruitment technique compared to scans in the non-GA free-breathing group. However no significant differences were observed regarding the presence of atelectasis between these groups. CONCLUSION: We demonstrated that although overall image quality was best and motion artifact least with a GA-breath-hold intubation and recruitment technique, free-breathing ultrafast pediatric chest CT without anesthesia provides sufficient image quality for diagnostic purposes and can be successfully performed both without and with contrast agent in young infants. PMID- 30413858 TI - Partial meniscectomy adversely affects return-to-sport outcome after anatomical double-bundle anterior cruciate ligament reconstruction. AB - PURPOSE: The purposes of this study were to determine whether the partial meniscectomy combined with ACL reconstruction affect the postoperative return-to sport and to identify if partial meniscectomy has an influence on the graft failure following an anatomical double-bundle ACL reconstruction case. METHODS: A retrospective cohort study including 426 primary double bundle ACL reconstruction cases. There were 206 males and 220 females, median age of 28.4 years, median BMI of 23.0, median preinjury Tegner score of 7.0 and median follow-up period after surgery of 24.0 months. Patients with less than 12 months of follow-up, revision surgery, multi-ligaments injury, previous contralateral knee ligaments injury and postoperative infection cases were excluded. Furthermore, patients who had meniscal repair were excluded in order to compare the outcomes between patients who had intact menisci and those who underwent partial meniscectomy. There were 227 patients with intact menisci (group A) and 199 patients with partial meniscectomy (group B). The median age was younger and the preoperative Tegner score was higher in group A. The patients in group B were subcategorized as the site of partial meniscectomy, including medial (group C), lateral (group D) and bicompartmental (group E) meniscectomy. There were 74, 94, and 31 patients in group C, D, and E, respectively. Return-to-sport (running and sport phase) and graft failure were included in our primary outcomes, and functional outcome as Lysholm knee scores was included in secondary outcome. RESULTS: The rate of return to running phase and sport phase were 91% (387/426) and 76% (303/399), the mean time taken to return to running and sport phase were 5.7 months and 11.1 months, respectively. There was significant difference in the returning to sport phase between group A and B (p = 0.01), and between group A and D/E subgroups (p = 0.007). There were fourteen graft failures (3.5%) in total. In addition, 9 and 5 graft failures in group A and B, respectively. Of the 5 graft failures in group B, 2 and 3 graft failures in group C and D, respectively. There was no significant difference of the graft failure ratio among the groups. CONCLUSION: Our study demonstrates that partial meniscectomy has an adverse effect on the return to sport phase following the anatomical double-bundle ACL reconstruction. Therefore, greater postoperative care would be needed to return to sport with partial meniscectomy in ACL reconstruction cases. On the contrary, partial meniscectomy is not considered to be the risk factor for graft failure at short term follow-up. LEVEL OF EVIDENCE: Case-control study, Level III. PMID- 30413859 TI - Increased ATFL-PTFL angle could be an indirect MRI sign in diagnosis of chronic ATFL injury. AB - PURPOSE: Magnetic resonance imaging (MRI) has relatively low accuracy in diagnosing chronic anterior talofibular ligament (ATFL) injury. This study's purpose was to evaluate the angle between the ATFL and posterior talofibular ligament (PTFL) as a new indirect MRI sign of chronic ATFL injury in patients with mechanical ankle instability (MAI). METHODS: This study included 200 participants: 105 patients with MAI and 95 patients seen at our institution for reasons unrelated to ankle instability. MR images of all 200 participants were reviewed. The ATFL-PTFL angle in the axial plane was measured and compared between groups. Receiver operating characteristic curves (ROC) were used to analyze ATFL-PTFL angles in participants with and without ATFL injury. The sensitivity and specificity of this method for diagnosing ATFL injury were calculated. RESULTS: The mean ATFL-PTFL angle was significantly larger among MAI patients than among control patients (81.5 degrees +/- 9.8 degrees vs 75.2 degrees +/- 8.9 degrees , respectively; P < 0.01). The area under the ROC was 0.789 (P < 0.01). The optimal cut-off point for diagnosing ATFL injury on the basis of the ATFL-PTFL angle was 79.0 degrees (sensitivity 0.89, specificity 0.67). CONCLUSION: The ATFL-PTFL angle was significantly larger among MAI patients than among those without MAI. Increased ATFL-PTFL angle offers a new indirect MRI sign for diagnosing chronic ATFL injury. The ATFL-PTFL angle can be used not only to improve the accuracy of diagnosis of chronic ATFL injury, but also to evaluate the restoration of normal ankle joint geometry after lateral ligament reconstruction. LEVEL OF EVIDENCE: III. PMID- 30413860 TI - Higher age, female gender, osteoarthritis and blood transfusion protect against periprosthetic joint infection in total hip or knee arthroplasties: a systematic review and meta-analysis. AB - PURPOSE: The goal of this systematic review and meta-analysis was to identify the main risk factors for periprosthetic joint infection (PJI) in patients undergoing total hip or knee arthroplasties. METHODS: A systematic review was conducted of the potential risk factors for PJI in total hip or total knee arthroplasty. Risk factors were compared and grouped according to demographics, comorbidities, behavior, infections, native joint diseases and other patient-related and procedure-related factors. Meta-analysis (random-effects models) was conducted using odds ratio (OR) and mean difference (MD). Risk of bias (ROBBINS-I) and strength of the evidence (GRADE) were assessed. RESULTS: The study included 37 studies (2,470,827 patients). Older age was a protective factor (MD = - 1.18). Male gender (OR 1.34), coagulopathy (3.05), congestive heart failure (2.36), diabetes mellitus (1.80), obesity (1.61), systemic neoplasia (1.57), chronic lung disease (1.52), and hypertension (1.21) increased the risk for PJI. Behavioral risk factors comprised alcohol abuse (2.95), immunosuppressive therapy (2.81), steroid therapies (1.88), and tobacco (1.82). Infectious risk factors included surgical site infections (6.14), postoperative urinary tract infections (2.85), and prior joint infections (2.15). Rheumatoid arthritis, posttraumatic native joint disease, high National Nosocomial Infections Surveillance (NNIS) system surgical patient index score, prior joint operation, American Society of Anesthesiologists score >= 3 and obesity were also significantly associated with higher risk of PJI. Osteoarthritis and blood transfusion were protective factors. CONCLUSIONS: The main risk factors for PJI in each category were male gender, coagulopathy, alcohol abuse, surgical site infection (highest score) and high NNIS system surgical patient index score. Protective factors were age, female gender in TKA, osteoarthritis and blood transfusion. Optimization of modifiable risk factors for PJI should be attempted in clinical practice. LEVEL OF EVIDENCE: II. PMID- 30413861 TI - National injury prevention measures in team sports should focus on knee, head, and severe upper limb injuries. AB - PURPOSE: To examine acute injuries in licensed floorball, football, handball, and ice hockey players in all ages nationwide in Sweden, and to identify the most common and severe injuries in each body location and recommend injury prevention measures. METHODS: Using national sport insurance data from years 2006-2015 was the incidence and proportion of acute injuries, and injuries leading to permanent medical impairment (PMI), calculated in the four team sports. The most common injury type and injured body part was identified, with a particular focus of the severe injuries. Comparison between sexes was made. RESULTS: In total, there were 92,162 registered injuries in all sports together. Knee injuries were most common, and also had the highest incidence of PMI, in all ball sports and in female ice hockey players. In male ice hockey, the most common injury was a dental and face injury, and PMI injuries were mostly in the shoulder. The most severe PMI injuries were rare and most often a face/eye injury in male floorball and ice hockey, a concussion in female ice hockey, and a knee injury in female floorball, and in both sexes in football and handball. CONCLUSIONS: To achieve the greatest impact in reducing the adverse effects of acute sport injuries nationwide in Sweden, preventive measures should focus on knee injuries in all the investigated team sports. The severe head/face and upper limb injuries also need attention. Protective equipment, neuromuscular training programs, rules enforcements, and fair-play interventions may reduce the incidence of injuries. PMID- 30413862 TI - [Transient loss of consciousness : Algorithm for the (differential) diagnosis of syncope at emergency department]. AB - Transient loss of consciousness (TLoC) is a common complaint leading to presentation at the emergency department. This comprises a heterogeneous group of disorders including cerebral events, metabolic disturbances, intoxication, psychogenic patterns or any form of syncope. While many causes are benign and self-limited not requiring extensive in-hospital evaluation, others are potentially severe. The optimal evaluation of patients with TLoC/syncope follows a risk-adapted diagnostic algorithm in order to exclude life-threatening conditions and to identify those with high risk for further deterioration like structural heart diseases requiring further diagnostic evaluation. Low-risk patients can be discharged without further extensive diagnostic work up. This article presents an algorithm for structured, evidence-based care of the syncope patient in accordance with the recently launched "2018 ESC guidelines for the diagnosis and management of syncope" in order to ensure that patients requiring hospitalization are managed appropriately and those with benign causes are discharged safely. The English version of this algorithm is available at the end of the article under "Supplementary Material". PMID- 30413863 TI - [Der Orthopade is not a publication supermarket of science]. PMID- 30413864 TI - [UroEvidence opens new call for applications]. PMID- 30413865 TI - Response to Comment on: "Estimating the Bioconcentration Factors of Hydrophobic Organic Chemicals from Biotransformation Rates Using Rainbow Trout Hepatocytes". PMID- 30413866 TI - Follow-up postoperative calls to reduce common postoperative complaints among urogynecology patients. AB - INTRODUCTION AND HYPOTHESIS: The purpose of our study was to identify the most common reasons why postoperative urogynecology patients called their surgeon within the first 6 weeks of surgery. We hypothesize that implementing a follow-up postoperative call (FPC) policy would decrease the number of patient-initiated calls within this postoperative period. METHODS: This is a prospective before-and after cohort study that was conducted in two phases. The initial phase identified the most common reasons why patients call within 6 weeks of their inpatient or outpatient urogynecological surgery. In the second phase, an intervention was implemented where each postoperative patient was called within 48 to 72 h of discharge: the intervention group. The primary outcome was the number of phone calls initiated by patients during the 6-week postoperative period. RESULTS: There were 226 patients in the control group and 233 patients in the intervention group. Significantly fewer calls were initiated by patients in the intervention group, both groups having a median of 1 call per person, range 0-8 in the control group and 0-10 in the intervention group (p = 0.04). The five most common complaints were as follows: pain (20.4%), medication management (17.4%), disability paperwork (15.5%), and laboratory results (11.5%). There was a significant reduction in calls concerning constipation, laboratory/pathology results, and disability insurance claims after implementing the FPC policy. CONCLUSIONS: The implementation of the FPC policy resulted in fewer patient initiated calls. As such, there were significant reductions in postoperative complaints of constipation, vaginal bleeding, incomplete bladder emptying, and inquiries into laboratory results and disability paperwork. PMID- 30413868 TI - Real-world use of sunitinib in Japanese patients with pancreatic neuroendocrine tumors: results from a post-marketing surveillance study. AB - BACKGROUND: Sunitinib is approved for the treatment of progressive, well differentiated pancreatic neuroendocrine tumors (pNETs) in patients with unresectable, locally advanced or metastatic disease. Safety and efficacy data in Japanese patients are limited. We report outcomes from a post-marketing surveillance study of sunitinib treatment in Japanese patients. METHODS: Sunitinib 37.5 mg once daily was orally administered in Japanese patients aged >= 15 years with pNETs. The primary endpoints included adverse events (AEs) occurring during the observation period of 168 days and objective response rate (ORR). RESULTS: Sunitinib was administered in 62 patients with pNETs. The median duration of treatment was 165 days. At 168 days from the start of treatment, 31 patients were still receiving sunitinib treatment and treatment continuation rate was 50.0%. Of the 31 patients who discontinued treatment, 18 (58.1%) discontinued because of AEs and 16 (51.6%) patients discontinued due to insufficient clinical effect. Of the 18 patients who discontinued due to AEs, 10 did so within 42 days of treatment initiation. The most common all-grade AEs were platelet count decreased (33.9%), diarrhea (29.0%), neutrophil count decreased (27.4%), hypertension (24.2%), and palmar-plantar erythrodysesthesia syndrome (24.2%). In the 51 patients eligible for the efficacy analysis, ORR was 13.7% (95% confidence interval, 5.7-26.3) and clinical benefit rate was 70.6%. CONCLUSIONS: There were no new safety concerns in real-world use of sunitinib in Japanese patients with pNETs. The short treatment duration likely led to low tumor response. Appropriate AEs management through dose interruption/reduction is essential for sunitinib treatment success in this patient population. PMID- 30413867 TI - Repair of colonic neovaginal stenosis using a biological graft in a male-to female transgender patient. AB - INTRODUCTION AND HYPOTHESIS: One in 2900 genotypical men report gender dysphoria, and many undergo gender confirmation surgery to match their physical phenotype to their identity. A variety of surgical techniques are used in male-to-female transgender patients, one of which is bowel vaginoplasty, and postoperative stenosis of the colonic neovagina is common. Extracellular matrix grafts have been used in vaginal reconstruction. with porcine urinary bladder matrix (UBM) acting as a scaffold for smooth-muscle tissue and matrix regeneration. The aim of this surgical video is to describe the use of a UBM biological graft in repair of introital stenosis due to recurrent granulation tissue in the colonic neovagina of a male-to-female transgender patient. METHODS: A 32-year-old male-to-female transgender patient with a history of rectosigmoid neovagina formation for genital gender confirmation surgery 12 months prior presented with genital granulation tissue and stenosis of her neovaginal introitus. Despite two surgical revisions, the patient developed recurrence of granulation tissue and obliteration of the neovaginal introitus, preventing sexual function of the neovagina. RESULTS: Reconstruction of the neovaginal introitus was performed using UBM. The patient noted improvement in comfort, hygiene, and quality of life following the procedure. This video describes our surgical technique and perioperative clinical findings. CONCLUSIONS: We report the novel use of UBM biological graft in the revision of a neovaginal introitus after former rectosigmoid vaginoplasty in a male-to-female transgender patient. PMID- 30413869 TI - Atrial fibrillation reduction by renal sympathetic denervation: 12 months' results of the AFFORD study. AB - AIM: The purpose of this pilot study was to assess whether renal sympathetic denervation (RDN) decreases atrial fibrillation (AF) burden in hypertensive patients with symptomatic AF at 6- and 12-month follow-up, as measured using an implantable cardiac monitor (ICM). METHODS AND RESULTS: A total of 20 patients with symptomatic paroxysmal or persistent AF (EHRA >= II) and primary hypertension with a mean office systolic blood pressure (BP) of > 140 mmHg were enrolled. After enrolment, an ICM was implanted 3 months pre-RDN to monitor AF burden. Quality of life (QOL) was assessed using the Atrial Fibrillation Effect on QualiTy-of-life (AFEQT) questionnaire. Mean age was 64 +/- 7 years and 55% were females. AF burden in min/day decreased from a median (IQR) of 1.39 (0-11) pre-RDN to 0.67 (0-31.6) at 6 months (p = 0.64) and to 0.94 (0-6.0) at 12 months (pre-RDN vs. 12 months; p = 0.03). QOL improved significantly at both 6 months (+ 11 +/- 15 points, p = 0.006) and 12 months (+ 10 +/- 19, p = 0.04) as compared to pre-RDN. Office BP decreased significantly at 12-month follow-up (- 20 +/- 19/- 7 +/- 10 mmHg), p < 0.01) as compared to pre-RDN. Ambulatory BP decreased - 7 +/- 16/- 3 +/- 9 mmHg (p > 0.05) at 12-month follow-up as compared to pre-RDN. CONCLUSION: This pilot study suggests that RDN might be able to decrease AF burden in min/day as measured using an ICM, with a positive effect on QOL. Large scale randomized trials are needed to prove the definite value of RDN in hypertensive patients with atrial fibrillation. PMID- 30413870 TI - [Optical coherence tomography angiography: Value for glaucoma diagnostics]. AB - BACKGROUND: Optical coherence tomography angiography (OCTA) is a novel noninvasive method which enables a quantitative evaluation of retinal and optic nerve head (ONH) perfusion. In this article, we discuss the principles of the application of OCTA and give a summary of the knowledge gained by using this method in glaucoma patients. METHODS: This article is based on a selective literature search and the analysis of own data. RESULTS: Quantitative OCTA parameters have a good reproducibility in glaucoma patients. Glaucoma patients show a reduced flow density (FD) in the ONH and in the area of the macula compared with a healthy control group. The FD parameters show a good diagnostic discriminatory power but are not superior to the structural parameters used in routine diagnostics. The reduced FD measured using OCTA correlates with the extent of functional and structural glaucoma damage. CONCLUSION: The OCTA is noninvasive, fast and reproducible. Initial results from studies on glaucoma patients show the high diagnostic potential of this method. The OCTA could become a part of clinical glaucoma management in the future. PMID- 30413871 TI - Adapting Urban Water Systems to Manage Scarcity in the 21st Century: The Case of Los Angeles. AB - Acute water shortages for large metropolitan regions are likely to become more frequent as climate changes impact historic precipitation levels and urban population grows. California and Los Angeles County have just experienced a severe four year drought followed by a year of high precipitation, and likely drought conditions again in Southern California. We show how the embedded preferences for distant sources, and their local manifestations, have created and/or exacerbated fluctuations in local water availability and suboptimal management. As a socio technical system, water management in the Los Angeles metropolitan region has created a kind of scarcity lock-in in years of low rainfall. We come to this through a decade of coupled research examining landscapes and water use, the development of the complex institutional water management infrastructure, hydrology and a systems network model. Such integrated research is a model for other regions to unpack and understand the actual water resources of a metropolitan region, how it is managed and potential ability to become more water self reliant if the institutions collaborate and manage the resource both parsimoniously, but also in an integrated and conjunctive manner. The Los Angeles County metropolitan region, we find, could transition to a nearly water self sufficient system. PMID- 30413872 TI - Short- and long-term outcomes of endoscopic submucosal dissection for early gastric cancer in the remnant stomach after gastrectomy. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) in the remnant stomach is a minimally invasive treatment. Few studies compared the technical difficulty of ESD involving the suture line and anastomosis, and information on long-term outcomes is insufficient. This study aimed to elucidate the short- and long-term outcomes of ESD for EGC in the remnant stomach. METHODS: We investigated patients who underwent ESD for EGC in the remnant stomach between September 2002 and March 2016. Clinicopathological data were retrieved to assess en bloc resection rates, complications, and long-term outcomes including overall survival and cause-specific survival. RESULTS: A total of 136 consecutive patients with 165 lesions resected by 157 ESD procedures were retrospectively evaluated. The en bloc resection rate was 95.5%. Complications included 16 intraoperative perforations (10.2%), 2 delayed perforations (1.3%), and 15 delayed bleeding (9.6%), which were successfully treated with endoscopy. The en bloc resection rate was significantly higher in the suture line group (100%) and the non-anastomosis or suture line group (98.8%) than in the anastomosis group (82.9%). However, the intraoperative perforation rate was significantly higher in the anastomosis group (31.4%) than in other groups. The 5-year overall and cause specific survival rates were 88.4% and 97.6%, respectively, during a median follow-up period of 50.7 months (interquartile range 30.8-91.3). CONCLUSIONS: The long-term outcomes of ESD for EGC in the remnant stomach were favorable. However, ESD involving the anastomosis was a technically demanding procedure due to the low en bloc resection rate and high perforation rate. PMID- 30413873 TI - Advanced assessment of serum Mac-2 binding protein glycosylation isomer in patients with biliary atresia. PMID- 30413874 TI - Response to the letter by Dr. Naoya Yamada, and Dr. Koichi Mizuta regarding our manuscript: "Mac-2 binding protein glycan isomer (M2BPGi) is a new serum biomarker for assessing liver fibrosis: more than a biomarker of liver fibrosis". PMID- 30413875 TI - Dupuytren's disease: limited fasciectomy, night splinting, and hand exercises long-term results. AB - BACKGROUND: Dupuytren's contracture (DC) is a fibroproliferative disorder of palmar fascia that causes flexion contractures of one or more digits. There is currently no gold standard operative and postoperative protocol for reducing recurrence rates. We propose a combination of surgical intervention, night splinting, and home hand exercises as a treatment protocol. METHODS: Thirty patients were included in our study, diagnosed with DC Tubiana grade II-IV. Our treatment protocol was limited fasciectomy followed by a 24-week night splint application, combined with home hand exercises for eight weeks. The outcomes were recurrence, QuickDASH score, extension or flexion deficit, and grip strength. The mean follow-up was 4.9 years (range 2-11 years). RESULTS: Recurrence of DC occurred in two patients (7%), who had discontinued the use of the splint within two months postoperatively. All other patients had complied with the postoperative protocol. The mean QuickDASH score improved from 61.5 (SD 2.1) to 8.6 (SD 2) postoperatively (p < 0.001). Grip strength did not differ significantly in the operated hands (37.9 kg, SD 1.3) when compared to the healthy hands (40.2 kg, SD 1.3, p = 0.035). The recurrence was not significantly correlated either with the Tubiana grade (p = 0.7), or with the patients' age (p = 0.27). CONCLUSIONS: This study shows that limited fasciectomy followed by a 24 week night splint application, combined with home hand exercises for at least eight weeks, is a viable protocol which reduces the rates of recurrence of DC. PMID- 30413876 TI - Secondary intraocular lens implantation: a large retrospective analysis. AB - PURPOSE: To investigate preoperative ocular risk factors and indications for secondary intraocular lens (IOL) implantation and compare postoperative complications, visual and refractive outcomes in a tertiary referral center. METHODS: Patients older than 14 years that underwent secondary IOL implantation and had a minimum follow-up of 3 months were enrolled in this retrospective case series. Preoperative ocular risk factors, indications for surgery, postoperative complications, and visual and refractive outcomes including prediction error (PE) and absolute error (AE) were evaluated. IOLs were fixated in following positions: anterior chamber (AC), retropupillary iris-claw (IC), sulcus, and capsular bag or sclera. RESULTS: One-hundred eighty-two eyes of 174 patients with mean follow-up of 17 +/- 13.6 months were evaluated. Leading cause for surgery was IOL dislocation (75%), followed by secondary aphakia (19%) and IOL opacifications (6%). Previous vitrectomy was the major preoperative ocular risk factor (43%). Mean corrected distance visual acuity improved from preoperative 0.68 +/- 0.55 to 0.42 +/- 0.31LogMAR by the last follow-up (p = 0.001). PE and AE differed highly depending on the indication for surgery (p = 0.041 and p = 0.008, respectively) and the IOL fixation (p = 0.011 and p = 0.028, respectively), with IC-IOLs showing the lowest PE and AE. Postoperative AC-hemorrhage occurred mainly after IC-IOLs (p = 0.003), and postoperative hypotony was significantly higher in eyes with previous uveitis (p = 0.026). CONCLUSIONS: Previous vitrectomy seems to be a major underreported risk factor in eyes that undergo secondary IOL implantation. Refractive outcomes depend on indication for surgery and fixation type, with retropupillary IC-IOLs providing the best refractive results, though not statistically significant compared to other IOL positions. PMID- 30413877 TI - Increasing temperature seasonality may overwhelm shifts in soil moisture to favor shrub over grass dominance in Colorado Plateau drylands. AB - Ecosystems in the southwestern U.S. are predicted to experience continued warming and drying trends of the early twenty-first century. Climate change can shift the balance between grass and woody plant abundance in these water-limited systems, which has large implications for biodiversity and ecosystem processes. However, variability in topo-edaphic conditions, notably soil texture and depth, confound efforts to quantify specific climatic controls over grass vs. shrub dominance. Here, we utilized weather records and a mechanistic soil water model to identify the timing and depth at which soil moisture related most strongly to the balance between grass and shrub dominance in the southern Colorado Plateau. Shrubs dominate where there is high soil moisture availability during winter, and where temperature is more seasonally variable, while grasses are favored where moisture is available during summer. Climate change projections indicate consistent increases in mean temperature and seasonal temperature variability for all sites, but predictions for summer and winter soil moisture vary across sites. Together, these changes in temperature and soil moisture are expected to shift the balance towards increasing shrub dominance across the region. These patterns are strongly driven by changes in temperature, which either enhance or overwhelm effects of changes in soil moisture across sites. This approach, which incorporates local, edaphic factors at sites protected from disturbance, improves understanding of climate change impacts on grass vs. shrub abundance and may be useful in other dryland regions with high edaphic and climatic heterogeneity. PMID- 30413878 TI - Seroprevalence of Toxoplasma gondii in one-humped camels (Camelus dromedarius) of Thal and Cholistan deserts, Punjab, Pakistan. AB - Toxoplasma (T.) gondii is an important zoonotic protozoan infecting humans and a wide range of animals. In this study, we determine the seroprevalence and risk factors associated with the seroprevalence of T. gondii in one-humped camels (Camelus dromedarius) in Pakistan. Camels are still an important mean of transportation in some desert areas in Pakistan. In addition, they are the main source of meat and milk for people in those regions; therefore, they have the potential to transmit T. gondii to humans. In order to estimate the seroprevalence of T. gondii, a total of 897 sera samples were collected from camels in the Thal (n = 359) and Cholistan (n = 440) deserts, along with other districts of Chakwal (n = 44) and Faisalabad (n = 54) Punjab, Pakistan, through convenient and snowball sampling techniques. These samples were then analyzed by an indirect enzyme-linked immune-sorbent assay (ELISA) for the presence of T. gondii-specific antibodies, using purified recombinant micronemal protein 3 (MIC3) as an antibody-catching antigen. Our results showed an overall seroprevalence of T. gondii as 40.1% (Thal = 45%; Cholistan = 35.9%; other districts = 33.7%). Risk factor analysis suggested that infection rate was higher in older animals (70.6%). In addition, female camels carried frequent infection (48.8%) than males (22.4%). What's more, female animals having abortion history showed even higher infection rate (75%) compared to pregnant (68.4%) and non pregnant (42.4%) animals. Our results reported high seroprevelance of T. gondii in camels in Pakistan which provided important information with respect to public health and disease controls. PMID- 30413879 TI - Local anesthetic spread into the paravertebral space with two types of quadratus lumborum blocks: a crossover volunteer study. AB - PURPOSE: Previous work showed that 20 mL of local anesthetic (LA) did not spread into the paravertebral space (PVS) via the intramuscular quadratus lumborum block (QLBi). If spread of LA into the PVS can be achieved by increasing the total LA volume, QLBi can be more effective. We hypothesized that a larger volume of LA for the QLBi would spread into the PVS. METHODS: This crossover volunteer study included five healthy men. For comparison, both the ultrasound-guided QLB type 2 (QLB2) and QLBi were employed on opposite sides of each volunteer, and the spread of LA solution (0.7 mL/kg) mixed with contrast media in the PVS was assessed 1 h after the first injection using magnetic resonance imaging. Sensory loss was evaluated by pinprick 90 min post-injection. Each volunteer underwent both QLB types, and the same procedures were administered on opposite sides 7 days after the first experiment. RESULTS: In total, 20 QLB blocks (10 QLB2 and 10 QLBi) were performed. LA did not spread into the PVS after the QLBi. The sensory block area included the lower abdomen after the QLB2, but not after the QLBi. The sensory block area did not extend to the upper abdominal region or the midline of the lower abdomen with either block method. CONCLUSION: LA administered by the QLB2 spreads into the PVS of T10-T12, resulting in lower and lateral abdominal sensory loss. In contrast, LA administered by the QLBi does not spread into the PVS and results in only lateral abdominal sensory loss. PMID- 30413880 TI - Thoracoscopic esophagectomy with total meso-esophageal excision reduces regional lymph node recurrence. AB - PURPOSE: We investigated the operative outcomes of thoracoscopic esophagectomy (TE) in the prone position, using the concept of total meso-esophageal excision for esophageal cancer. METHODS: The medical records of 140 consecutive patients with esophageal cancer who underwent radical esophagectomy by TE were reviewed retrospectively, and operative outcomes were compared between patients treated before (non-meso-esophagus; non-ME group) and after (ME group) the introduction of total meso-esophageal excision (ME). RESULTS: There were no significant differences between the groups in postoperative morbidity (non-ME group vs. ME group, 28.3% vs. 41.4%, p = 0.119), 30-day mortality (non-ME group vs. ME group, 0% vs. 1.1%; p = 0.433), and in-hospital mortality (non-ME group vs. ME group, 1.9% vs. 0%, p = 0.199). Although overall survival and relapse-free survival did not differ significantly between the groups, the overall recurrence rate was significantly lower in the ME group than the non-ME group (non-ME group vs. ME group, 43.4% vs. 23%, p = 0.011). In particular, the rate of regional lymph node recurrence in the mediastinum was lower in the ME group (non-ME group vs. ME group, 11.3% vs. 2.3%; p = 0.026). CONCLUSIONS: Our results suggest that the ME procedure might be one of the procedures that reduce regional lymph node recurrence in the mediastinum without any deterioration in short-term outcomes. PMID- 30413881 TI - Dietary branched-chain amino acids intake exhibited a different relationship with type 2 diabetes and obesity risk: a meta-analysis. AB - AIM: To assess whether oral branched-chain amino acids (BCAA) supplementation exerts influence on circulating BCAA and the significance of dietary BCAA in type 2 diabetes and obesity risk. METHOD: We searched PUBMED, EMBASE and Cochrane library through June 2018 to retrieve and screen published reports for inclusion in the meta-analysis after methodological assessment. Heterogeneity of studies was evaluated using I2 statistics, while sensitivity analysis and funnel plot were used to evaluate the potential effect of individual studies on the overall estimates and publication bias, respectively, using RevMan 5.3. RESULT: Eight articles on randomized clinical trial of oral BCAA supplementation, and seven articles on dietary BCAA intake and type 2 diabetes/obesity risks were eligible for inclusion in our meta-analyses. Mean difference and 95% confidence interval (CI) of circulating leucine was 39.65 (3.54, 75.76) umol/L, P = 0.03 post-BCAA supplementation. Also, OR and 95% CI for higher total BCAA intake and metabolic disorder risks were, 1.32 (1.14, 1.53), P = 0.0003-type 2 diabetes and 0.62 (0.47, 0.82), P = 0.0008-obesity. CONCLUSION: Oral BCAA supplementation exerts modest influence on circulating leucine profile and higher total BCAA intake is positively and contra-positively associated with type 2 diabetes and obesity risk, respectively. PMID- 30413882 TI - Expression of glucose transporters and morphometry in the intestine of Japanese quails after hatch. AB - The intestinal physiology and mechanisms involved in nutrient transport are not well established in quails (Coturnix coturnix japonica). The present study assessed the growth performance, morphological development, duodenal density and the expression of Sglt1 and Glut2 of female Japanese quails from 1 to 49 days of age. The three small intestine segments were sampled weekly from 1 to 49 days of age to evaluate villus height, crypt depth and villus: crypt ratio, and goblet cell counts. Scanning electronic microscopy was used to determine duodenal villus density, and real-time polymerase chain reaction (qPCR) was used to study the sodium/glucose cotransporter-1 Sglt1 and glucose transporter Glut2 in the jejunum. Villus height and crypt depth in the duodenum, jejunum and ileum increased with age until 42 and 49 days of age (P < 0.001), and regression analysis evidenced a quadratic effect (P < 0.0001), indicating increasing values to a maximum and then a decrease afterwards. Goblet cell counts increased (P < 0.001) in duodenum, jejunum and ileum from 1 to 42 days, decreasing at 49 days, which was also corroborated by the regression analysis. Villus density in the duodenum was greater in the first week, decreased with age and increased again at 42 days, probably due to the proximity with egg production onset. The expression of Sglt1 and Glut2 mRNA in the jejunum varied with age. In conclusion, the intestinal mucosa of female Japanese quail developed morphologically until 42days and functionally until earlier ages, indicating an adaptation to the exogenous diet during the first weeks of life. PMID- 30413883 TI - Recognizing critically ill children with a modified pediatric early warning score at the emergency department, a feasibility study. AB - Pediatric Early Warning Scores were developed to monitor clinical deterioration of children admitted to the hospital. Pediatric Early Warning Scores could also be useful in the Emergency Department to quickly identify critically ill patients so treatment can be started without delay. To determine if a newly designed, fast, and easy to use Modified Pediatric Early Warning Score can identify critically ill children in the Emergency Department. We conducted a retrospective observational study in the Emergency Department of an urban district hospital in Rotterdam, the Netherlands. Patients < 16 years attending the Emergency Department with an internal medical problem were included. Immediate intensive care unit admission was used as a measure for critically ill children. During the study period 2980 children attended the Emergency Department, ten (0.4%) of them required immediate intensive care unit admission. The Modified Pediatric Early Warning Score can identify critically ill children in the general pediatric Emergency Department population (area under the ROC curve 0.82). A sensitivity of 80% and specificity of 85% show potential to rule out critical illness in children visiting the Emergency Department when these results are validated in a larger population. A model containing both the Modified Pediatric Early Warning Score and the Manchester Triage System did not perform significantly better than the Manchester Triage System alone but did show a positive tendency in favor of the model containing the Modified Pediatric Early Warning Score and Manchester Triage System, area under the ROC curve 0.89 [95% CI 0.77-1.00] versus area under the ROC curve 0.82 [95% CI 0.68-0.95].Conclusions: In this feasibility study, the Modified Pediatric Early Warning Score could be a fast and easy to use tool to identify critically ill children in the general pediatric Emergency Department population. The effectiveness of the Modified Pediatric Early Warning Score may be optimized if combined with triage systems such as the Manchester Triage System. A larger prospective study is needed to confirm our results. What is known: * Pediatric Early Warning Scores can identify children who are in need for immediate intensive care unit admission at the Emergency Department. * Pediatric Early Warning Scores can be time-consuming, contain subjective parameters or parameters which are difficult to obtain in a reliable and standardized method. What is new: * We introduce a simplified, manageable and smartly designed Pediatric Early Warning Score on a pocket card based on an existing and previously investigated Pediatric Early Warning Score. * In this feasibility study the diagnostic performance of the Modified Pediatric Early Warning Score to predict immediate intensive care unit admission in the Emergency Department is in line with the original Pediatric Early Warning Scores but has to be validated on a larger scale. PMID- 30413884 TI - Immune response triggered by Trypanosoma cruzi infection strikes adipose tissue homeostasis altering lipid storage, enzyme profile and adipokine expression. AB - Adipose tissue is a target of Trypanosoma cruzi infection being a parasite reservoir during the chronic phase in mice and humans. Previously, we reported that acute Trypanosoma cruzi infection in mice is linked to a severe adipose tissue loss, probably triggered by inflammation, as well as by the parasite itself. Here, we evaluated how infection affects adipose tissue homeostasis, considering adipocyte anabolic and catabolic pathways, the immune-endocrine pattern and the possible repercussion upon adipogenesis. During in vivo infection, both lipolytic and lipogenic pathways are profoundly affected, since the expression of lipolytic enzymes and lipogenic enzymes was intensely downregulated. A similar pattern was observed in isolated adipocytes from infected animals and in 3T3-L1 adipocytes infected in vitro with Trypanosoma cruzi. Moreover, 3T3-L1 adipocytes exposed to plasmas derived from infected animals also tend to downregulate lipolytic enzyme expression which was less evident regarding lipogenic enzymes. Moreover, in vivo-infected adipose tissue reveals a pro-inflammatory profile, with increased leucocyte infiltration accompanied by TNF and IL-6 overexpression, and adiponectin downregulation. Strikingly, the nuclear factor PPAR-gamma is strongly decreased in adipocytes during in vivo infection. Attempts to favor PPAR-gamma-mediated actions in the adipose tissue of infected animals using agonists failed, indicating that inflammation or parasite-derived factors are strongly involved in PPAR-gamma inhibition. Here, we report that experimental acute Trypanosoma cruzi infection disrupts both adipocyte catabolic and anabolic metabolism secondary to PPAR-gamma robust downregulation, tipping the balance towards to an adverse status compatible with the adipose tissue atrophy and the acquisition of an inflammatory phenotype. PMID- 30413885 TI - Endothelial prostacyclin protects the kidney from ischemia-reperfusion injury. AB - Prostacyclin, or PGI2, is a product of PGI synthase (PGIS), down-stream of cyclooxygenase pathway. PGI2 has been demonstrated to play an important role in maintaining renal blood flow. Non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit cyclooxygenase are reported to increase the susceptibility of patients to acute kidney injury (AKI). This study explores the role of endothelium-derived prostacyclin in ischemia-reperfusion injury (I/RI). The renal PGIS expression and PGI2 production markedly increased following I/RI. Loss of one allele of PGIS gene or selective endothelial PGIS deletion (TEK-CRE PGISfl/fl mice) caused more severe renal damage following I/RI than control mice. Iloprost, a PGI2 analog, administered 30 min before the I/R surgery, markedly attenuated the renal damage in both control mice and TEK-CRE PGISfl/fl mice. Renal p-PKA expression significantly increased after I/RI in wild-type mice but not in the PGIS deletion mice, consistent with IP receptor mediating the protective effect. Further studies showed that PGIS deficiency was associated with reduced fluorescence microsphere accumulation in the kidney following I/R. Folic acid also induced marked kidney injury; however, endothelial PGIS deletion did not worsen kidney injury compared with wild-type mice. These studies indicate that PGIS-derived PGI2 can protect the kidney from acute injury caused by ischemia and reperfusion and PGIS/PGI2 is a potential intervention target for AKI. PMID- 30413886 TI - Screening of key candidate genes and pathways for osteocytes involved in the differential response to different types of mechanical stimulation using a bioinformatics analysis. AB - This study aimed to predict the key genes and pathways that are activated when different types of mechanical loading are applied to osteocytes. mRNA expression datasets (series number of GSE62128 and GSE42874) were obtained from Gene Expression Omnibus database (GEO). High gravity-treated osteocytic MLO-Y4 cell line samples from GSE62128 (Set1), and fluid flow-treated MLO-Y4 samples from GSE42874 (Set2) were employed. After identifying the differentially expressed genes (DEGs), functional enrichment was performed. The common DEGs between Set1 and Set2 were considered as key DEGs, then a protein-protein interaction (PPI) network was constructed using the minimal nodes from all of the DEGs in Set1 and Set2, which linked most of the key DEGs. Several open source software programs were employed to process and analyze the original data. The bioinformatic results and the biological meaning were validated by in vitro experiments. High gravity and fluid flow induced opposite expression trends in the key DEGs. The hypoxia related biological process and signaling pathway were the common functional enrichment terms among the DEGs from Set1, Set2 and the PPI network. The expression of almost all the key DEGs (Pdk1, Ccng2, Eno2, Egln1, Higd1a, Slc5a3 and Mxi1) were mechano-sensitive. Eno2 was identified as the hub gene in the PPI network. Eno2 knockdown results in expression changes of some other key DEGs (Pdk1, Mxi1 and Higd1a). Our findings indicated that the hypoxia response might have an important role in the differential responses of osteocytes to the different types of mechanical force. PMID- 30413887 TI - Conditional deletion of Bmp2 in cranial neural crest cells recapitulates Pierre Robin sequence in mice. AB - Bone morphogenetic protein (BMP) signaling plays a crucial role in the development of craniofacial organs. Mutations in numerous members of the BMP signaling pathway lead to several severe human syndromes, including Pierre Robin sequence (PRS) caused by heterozygous loss of BMP2. In this study, we generate mice carrying Bmp2-specific deletion in cranial neural crest cells using floxed Bmp2 and Wnt1-Cre alleles to mimic PRS in humans. Mutant mice exhibit severe PRS with a significantly reduced size of craniofacial bones, cleft palate, malformed tongue and micrognathia. Palate clefting is caused by the undescended tongue that prevents palatal shelf elevation. However, the tongue in Wnt1-Cre;Bmp2f/f mice does not exhibit altered rates of cell proliferation and apoptosis, suggesting contribution of extrinsic defects to the failure of tongue descent. Further studies revealed obvious reduction in cell proliferation and differentiation of osteogenic progenitors in the mandible of the mutants, attributing to the micrognathia phenotype. Our study illustrates the pathogenesis of PRS caused by Bmp2 mutation, highlights the crucial role of BMP2 in the development of craniofacial bones and emphasizes precise coordination in the morphogenesis of palate, tongue and mandible during embryonic development. PMID- 30413888 TI - Exploring the rearrangement of sensory intelligence in proteobacteria: insight of Pho regulon. AB - Pho regulon is a highly evolved and conserved mechanism across the microbes to fulfil their phosphate need. In this study, 52 proteobacteria genomes were analyzed for the presence of phosphorus acquisition genes, their pattern of arrangement and copy numbers. The diverse genetic architecture of the Pho regulon genes indicates the evolutionary challenge of nutrient limitation, particularly phosphorus, faced by bacteria in their environment. The incongruence between the Pho regulon proteins phylogeny and species phylogeny along with the presence of additional copies of pstS and pstB genes, having cross similarity with other genera, suggest the possibility of horizontal gene transfer event. The substitution rate analysis and multiple sequence alignment of the Pho regulon proteins were analyzed to gain additional insight into the evolution of the Pho regulon system. This comprehensive study confirms that genes perform the regulatory function (phoBR) were vertically inherited, whereas interestingly, genes whose product involved in direct interaction with the environment (pstS) acquired by horizontal gene transfer. The substantial amino acid substitutions in PstS most likely contribute to the successful adaptation of bacteria in different ecological condition dealing with different phosphorus availability. The findings decipher the intelligence of the bacteria which enable them to carry out the targeted alteration of genes to cope up with the environmental condition. PMID- 30413890 TI - Studying the chemical reactivity properties of the target tumor-environment tripeptides NGR (asparagine-glycine-arginine) and RGD (arginine-glycine-aspartic acid) in their interactions with tamoxifen through conceptual density functional theory. AB - Here, we report theoretical research into the interaction of the drug tamoxifen drug with tripeptides found in the tumor environment-specifically, asparagine glycine-arginine (NGR) and arginine-glycine-aspartic acid (RGD). Reactivity parameters of these tripeptides were calculated and their intrinsic reactivities and cross-reactivities were analyzed. The interactions of the tripeptides with the nanodiamond-tamoxifen (ND-TAM) complex where the nanodiamond acts as a nanocarrier were also examined theoretically. In addition, their intestinal absorption was predicted based on the polar surface area. The results showed that tamoxifen interacts with RGD, and this interaction remained after the addition of the nanodiamond. An analysis of the chemical hardnesses of the tripeptides was carried out to explore their possible use as synthetic vectors when joined to the nanodiamond. Results indicated that NGR is the most stable of the tripeptides and could be used for active targeting. All calculations were implemented using the conceptual framework of density functional theory. PMID- 30413891 TI - A new method for detecting individual trees in aerial LiDAR point clouds using absolute height maxima. AB - Data acquired from aerial laser scanner systems are increasingly used for detecting individual trees in operational inventories. In conventional analyses, tree detection is often performed on raster models that use local height maxima filters; an option that is likely to accumulate important errors. In order to reduce errors and improve the detection of individual trees, a new method is proposed that uses an Absolute Height Maxima (AHM) filter applied on the original point clouds obtained from Aerial Laser Scanning (ALS). ALS point clouds at a density of 2 to 4 points per square meter were acquired over forest stands in Hyrcanian forests. In the new method, false trees and commission errors were automatically found and excluded. To evaluate the efficiency of this new method, 121 sample trees in the field were located, with a DGPS and a mapping camera. The height and crown radius of the sample trees were also measured. The field surveyed variables were compared to the closest detected tree, with an overall detection accuracy of 75.2%. The initial results of this analysis allowed us to hypothesize that a higher detection of tree may be expected with larger densities. PMID- 30413893 TI - Cost-effectiveness of a home safety intervention to prevent falls in impaired elderly people living in the community. AB - PURPOSE: Among others, the German National Prevention Conference recently recommended the provision of preventive options for elderly to maintain their independent living. Because a home safety assessment and modification program (HSM) has shown to be effective in avoiding falls and risk of falling in elderly, the aim of this analysis was to evaluate the cost-effectiveness of HSM in patients aged >= 80 years who receive non-institutionalized long-term care. METHODS: In order to reflect quality-adjusted life years (QALYs) and costs resulting from HSM, a Markov-model with a time horizon of 20 years was performed from the perspective of the German statutory health insurance (SHI) and statutory long-term care insurance (LCI). The model assumed that HSM reduces fall-related hip fractures in accordance with the reduction of the rate of falls. Data was obtained from public databases and from various literature searches. The robustness of the results was assessed in deterministic and probabilistic sensitivity analyses. RESULTS: In women, the incremental cost-effectiveness ratio of HSM compared to no prevention was ?9580 per QALY, while in men, it was ?57,589. For the German SHI/LCI, in total, the provision of HSM to patients >= 80 years who receive non-institutionalized long-term care would result in annual costs of ?7.7 million. The results were robust in several sensitivity analyses. CONCLUSIONS: Provided that the rate of falls is a valid surrogate endpoint for the rate of fall-related hip fractures, HSM could be a promising approach for investments in preventive options targeting the reduction of fall-related fractures in elderly women. PMID- 30413889 TI - Recent advances and future trends of riboswitches: attractive regulatory tools. AB - Bacterial genomes contain a huge amount of different genes. These genes are spatiotemporally expressed to accomplish some required functions within the organism. Inside the cell, any step of gene expression may be modulated at four possible places such as transcription initiation, translation regulation, mRNA stability and protein stability. To achieve this, there is a necessity of strong regulators either natural or synthetic which can fine-tune gene expression regarding the required function. In recent years, riboswitches as metabolite responsive control elements residing in the untranslated regions of certain messenger RNAs, have been known to control gene expression at transcription or translation level. Importantly, these control elements do not prescribe the involvement of protein factors for metabolite binding. However, they own their particular properties to sense intramolecular metabolites (ligands). Herein, we highlighted current important bacterial riboswitches, their applications to support genetic control, ligand-binding domain mechanisms and current progress in synthetic riboswitches. PMID- 30413892 TI - Molecular identification of yeast, lactic and acetic acid bacteria species during spoilage of tchapalo, a traditional sorghum beer from Cote d'Ivoire. AB - Yeasts, lactic and acetic acid bacteria are responsible of microbial spoilage of alcoholic beverages. However species involved in deterioration of sorghum beer produced in Cote d'Ivoire has not been investigated. This study was carried out to identify species of yeast, LAB and AAB during spoilage of tchapalo in order to define the best strategy for beer preservative. Thus, a total of 210 yeasts, LAB and AAB were isolated from samples of tchapalo stored at ambient temperature and at 4 degrees C for 3 days. Based on PCR-RFLP of the ITS region and the sequencing of D1/D2 domain, yeast isolates were assigned to seven species (Saccharomyces cerevisiae, Candida tropicalis, Rhodotorula mucilaginosa, Trichosporon asahii, Kluyveromyces marxianus, Meyerozyma guilliermondii and Trichosporon coremiiforme). During the storage at ambient temperature and at 4 degrees C, S. cerevisiae was the predominant species (> 76%). Excepted R. mucilaginosa, occurrence of non-Saccharomyces species was sporadic. LAB species detected in fresh samples using molecular methods were Pediococcus acidilactici, Lactobacillus paracasei, Lb. curvatus, Lb. fermentum and Weisssella paramesenteroides. P. acidilactici was the dominant species (47.8%) followed by Lb. paracasei (17.5%). W. paramesenteroides and Lb. fermentum were not detected during the spoilage at ambient temperature while at 4 degrees C W. paramesenteroides and Lb. paracasei have not been detected. For AAB, the species found were Acetobacter pasteurianus sub paradoxus and Acetobacter cerevisiae. These species were common to all samples during spoilage and A. pasteurianus sub paradoxus was the most frequently detected. PMID- 30413894 TI - An impedimetric aptasensor for Shigella dysenteriae using a gold nanoparticle modified glassy carbon electrode. AB - This work describes an aptasensor for the foodborne pathogen Shigella dysenteriae (S. dysenteriae). A glassy carbon electrode (GCE) was modified with gold nanoparticles (AuNPs) by electrodeposition. Then, thiolated aptamer for S. dysenteriae detection was self-assembled on the surface of the modified GCE, and any free residual AuNPs were blocked with 6-mercapto-1-hexanol. The size, morphology, and distribution of the AuNPs were characterized by field emission scanning electron microscopy. Detection of S. dysenteriae was performed measurement of the charge transfer resistance (Rct) before and after addition of S. dysenteriae using hexacyanoferrate as an electrochemical probe. The interaction between the aptamer and outer-membrane proteins of S. dysenteriae lead to an increase in the Rct of the sensor. The assay has a linear dynamic range that extends from 101 to 106 CFU.mL-1 and a limit of detection of 100 CFU.mL-1. It can differentiate between alive S. dysenteriae and other pathogens. Dead S. dysenteriae cells do not have any effect on selectivity. Unpasteurized and pasteurized skim milk and some water samples were spiked with S. dysenteriae and then successfully examined by this method. The results were validated by real time PCR. The method is fast, low-cost, highly sensitive, and specific. Hence, it represents a valuable tool in food quality control. Graphical abstract Schematic presentation of a label free impedimetric aptasensor for Shigella dysenteriae using a glassy carbon electrode modified with gold nanoparticles (AuNPs) and 6 mercapto-1-hexanol (MCH). The limit of detection of this aptasensor is as low as 1 CFU.mL-1 for target bacteria. PMID- 30413895 TI - Nanostructured molybdenum oxide in a 3D metal organic framework and in a 2D polyoxometalate network for extraction of chlorinated benzenes prior to their quantification by GC-MS. AB - A three-dimensional metal organic framework (3D-MOF) and a two-dimensional polyoxometalate (2D-POM), both incorporating nanostructured molybdenum (VI) oxide, were synthesized and implemented for headspace needle trap extraction of traces of chlorobenzenes (CBs). The 3D-MOF of type {(Mo2O6)(4,4'-bpy)}n and the 2D-POM of type [4,4'-bpy][Mo7O22] were synthesized by a solvothermal process and characterized by FT-IR, powder X-ray diffraction, scanning electron microscopy, transmission electron microscopy, thermogravimetry, energy dispersive X-ray, elemental mapping and Brunner-Emmet-Teller adsorption analyses. The 3D-MOF proved to be superior. Following thermal desorption, the CBs (monochlorobenzene, 1,4 dichlorobenzene, 1,2-dichlorobenzene, 1,2,4-trichlorobenzene and 1,2,3,4 tetrachlorobenzene) were quantified by GC-MS. Under optimized conditions, the calibration plots are linear in the 1-1000 ng.L-1 concentration range, and the limits of detection range from 0.2 to 2 ng.L-1. The intra- and inter-day relative standard deviations for three replicates at levels of 10 and 200 ng.L-1 are in the range of 5-12% and 10-15%, respectively. The needle-to-needle reproducibility was also found to be in the range of 6-13%. The application of the method to the analysis of various spiked real water samples resulted in recoveries between 84 and 114%. Graphical abstract A comparison of extraction efficiency between 3D-MOF and 2D-POM, in which 3D-MOF is superior to isolate organic pollutants, due to possession of more 4,4'-bpy ligands and interaction sites. PMID- 30413897 TI - PDMS-free microfluidic cell culture with integrated gas supply through a porous membrane of anodized aluminum oxide. AB - Microfluidic cell cultures are often used in academic research but only rarely in pharmaceutical research because of unsuitable designs, inappropriate choice of materials or incompatibility with standard equipment. In particular, microfluidic cell cultures to control the gaseous microenvironment rely on PDMS despite its disadvantages. We present a novel concept for such a cell culture device that addresses these issues and is made out of hard materials instead of PDMS. Our device contains two microfluidic chambers that are separated by a porous membrane of anodized aluminum oxide. Because of the small pore sizes but high porosity, this design allows a gas supply from one chamber to the other while leakage of the medium is avoided. Furthermore, the cells can be cultured directly on the membrane which induces the same advantageous cell response as cultivation on very soft materials. Furthermore, the chip, made out of silicon and glass, is fabricated with clean-room technologies and thus allows mass production. The interfaces to the outer world are small reservoirs which are accessible with conventional pipettes so that the setup does not require any pump. The fabricated chip is characterized regarding its diffusion characteristics. HaCaT-cells are cultivated successfully up to 14 days inside the chip but can be also removed for further processes. The presented chip is a step to bring cell cultivation with controlled gas supply from academic to industrial applications. PMID- 30413896 TI - Colorimetric human papillomavirus DNA assay based on the retardation of avidin induced aggregation of gold nanoparticles. AB - A colorimetric assay for human papillomavirus (HPV) DNA was developed based on the retardation of the avidin-induced aggregation of gold nanoparticles (AuNPs) by HPV DNA. Positively charged avidin acts as a coagulant for AuNP aggregation. In the presence of the target DNA, however, the aggregation of AuNPs is retarded owing to electrosteric stabilization as a result of the hybridization of the target and probe DNA. In the absence of HPV DNA, the stabilization effect caused by the biotinylated probe DNA is weak, resulting in NP aggregation and a color change from red to purple. Aggregation may be easily observed with bare eyes or spectrophotometrically at about 560 nm. The visual detection limit is 1 nM. The assay was used for the determination of HPV DNA after polymerase chain reaction (PCR) amplification without any further purification. Graphical abstract Schematic presentation of the avidin-induced aggregation of unmodified gold nanoparticles (AuNPs) which leads to a color change from red to purple. In the presence of dsDNA, however, the aggregation is remarkably retarded. PMID- 30413898 TI - The antifungal agent of silver nanoparticles activated by diode laser as light source to reduce C. albicans biofilms: an in vitro study. AB - Candida albicans is a normal flora caused fungal infections and has the ability to form biofilms. The aim of this study was to improve the antifungal effect of silver nanoparticles (AgNPs) and the light source for reducing the biofilm survival of C. albicans. AgNPs were prepared by silver nitrate (AgNO3) and trisodium citrate (Na3C6H5O7). To determine the antifungal effect of treatments on C. albicans biofilm, samples were distributed into four groups; L + P+ was treatment with laser irradiation and AgNPs; L + P- was treatment with laser irradiation only; L - P+ was treatment with AgNPs only (control positive); L - P- was no treatment with laser irradiation or AgNPs (control negative). The growth of fungi had been monitored by measuring the optical density at 405 nm with ELISA reader. The particle size of AgNPs was measured by using (particle size analyzer) and the zeta potential of AgNPs was measured by using Malvern zetasizer. The PSA test showed that the particle size of AgNPs was distributed between 7.531 5559.644 nm. The zeta potentials were found lower than - 30 mV with pH of 7, 9 or 11. The reduction percentage was analyzed by ANOVA test. The highest reduction difference was given at a lower level irradiation because irradiation with a density energy of 6.13 +/- 0.002 J/cm2 resulted in the biofilm reduction of 7.07 +/- 0.23% for the sample without AgNPs compared to the sample with AgNPs that increased the biofilm reduction of 64.48 +/- 0.07%. The irradiation with a 450-nm light source had a significant fungicidal effect on C. albicans biofilm. The combination of light source and AgNPs provides an increase of biofilm reduction compared to the light source itself. PMID- 30413899 TI - Genetic determinants related to pharmacological induction of foetal haemoglobin in transfusion-dependent HbE-beta thalassaemia. AB - Thalassaemia are the most common inherited autosomal recessive single gene disorders characterized by chronic hereditary haemolytic anaemia due to the absence or reduced synthesis of one or more of the globin chains. Haemoglobin E beta thalassaemia is the genotype responsible for approximately one half of all severe beta-thalassaemia worldwide. This study proposes to evaluate the effect of various molecular parameters on the response of hydroxyurea. Hydroxyurea was started at an initial dose of 10 mg/kg of body weight/day on 110 transfusion dependent HbE-beta thalassaemia patients. HbF level was measured by HPLC analysis. beta-Thalassaemia mutations, XmnI and five other SNPs, and alpha-globin gene deletions and triplications were detected by ARMS-PCR, RFLP-PCR and Gap-PCR, respectively. Based on the factors for evaluating hydroxyurea-response, 42 patients were responders as they showed an increment of Hb from a mean baseline value of 6.45 g/dl (+/- 0.70) to 7.78 g/dl (+/- 0.72) post-therapy. Based on increase in HbF above the median value (14.72%) post-therapy, 78 patients were found to be responders. All the 78 responders showed mean decrease in transfusion of 74.26% (+/- 8.32) with a maximum decrease of 98.43%. There was a significant correlation between decrease in transfusion and increase in HbF level for all 78 responders. XmnI polymorphism showed the strongest association (p < 0.0001) with increase in HbF levels and Hb levels. Patients with alpha-globin gene deletions were better responders. It was concluded that hydroxyurea treatment is effective in transfusion-dependent HbE-beta thalassaemia patients and the response is best in patients having both XmnI polymorphism and alpha-deletion. PMID- 30413900 TI - Nivolumab as a safe and effective treatment in an HIV patient with refractory Hodgkin lymphoma. PMID- 30413901 TI - Systematic review and meta-analysis of the effect of iron chelation therapy on overall survival and disease progression in patients with lower-risk myelodysplastic syndromes. AB - The impact of iron chelation therapy (ICT) on overall survival (OS) and progression to acute myeloid leukemia (AML) in patients with iron overload and International Prognostic Scoring System low- or intermediate-risk myelodysplastic syndromes (MDS) is not well understood. We conducted a systematic review and meta analysis of published studies of ICT in patients with MDS to better elucidate these relationships. We searched PubMed, EMBASE, Cochrane databases, and the World Health Organization Clinical Trial Registry for studies reporting the impact of ICT on OS in patients with low- or intermediate-risk MDS. Studies were examined for demographics, effect measures, and potential bias risk. Fixed and random-effects models were used to calculate adjusted OS and adjusted hazards ratio (aHR) estimates, respectively, among the different studies. Nine observational studies (four prospective and five retrospective) were identified. For patients with MDS, ICT was associated with an overall lower risk of mortality compared with no ICT (aHR 0.42; 95% confidence interval (CI) 0.28-0.62; P < 0.01); however, there was significant heterogeneity across the studies. In studies reporting progression to AML, ICT was not associated with decreased risk of progression (odds ratio 0.68; 95% CI 0.31-1.43; P < 0.030). This systematic review and meta-analysis of nine nonrandomized trials demonstrated significant reduction in risk of mortality in patients with iron overload and low- or intermediate-risk MDS treated with ICT; however, a causal relationship cannot be established. Randomized, controlled trials are needed to more definitively evaluate the relationship between ICT and survival in patients with iron overload and low- or intermediate-risk MDS. PMID- 30413903 TI - Getting better temporal and spatial ecology data for threatened species: using lightweight GPS devices for small primate monitoring in the northern Andes of Colombia. AB - The use of GPS telemetry has been a reliable research tool for the study of primate biology in recent years. Although in the past technological restrictions limited its use mainly to large primates, recent improvements in battery size make it possible to use this technology for small species. We used GPS devices for monitoring two adult white-footed tamarins (Saguinus leucopus) from a free ranging group, and assessed its applicability for recording spatial and ecological data. GPS devices were operational for 66 and 85 days, recording 221 positions (36.6% acquisition rate; 73% of which were highly accurate) and 3195 activity values for both individuals. Depending on the estimation method, we calculated the home range size for the group to be 19.4 and 22.9 ha, which were within the range for the species in other localities. The animals were active each day for 11 h, with high activity during the early morning. The monkeys showed a constant and alternate use of four sleeping sites with a limited reuse of the same site on consecutive nights. These daily activity and sleeping site use patterns are similar to those reported for other Saguinus species. Based on the kind and quality of the data recorded, we consider GPS telemetry to be an efficient and advantageous method for tracking and obtaining ecological information from S. leucopus. In comparison to other data collection methods, GPS telemetry required fewer personnel and less time commitment to record data without compromising the accuracy of the spatial and activity information we obtained. PMID- 30413902 TI - Clinical impact of prognostic nutritional index in diffuse large B cell lymphoma. AB - We evaluated the association between the prognostic nutritional index (PNI) and the clinical features of diffuse large B cell lymphoma (DLBCL) and developed a novel prognostic model using a nomogram including the PNI and other biomarkers for cancer cachexia. A total of 228 DLBCL patients treated with first-line R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) were retrospectively reviewed. PNI was calculated as 10 * serum levels of albumin (g/dL) + 0.005 * absolute lymphocyte count (/mm3). Patients were categorized into low- and high-PNI groups based on a cut-off value of 40. The nomogram for predicting overall survival (OS) was constructed using a Cox regression model. PNI was positively correlated with skeletal muscle index, body mass index, and serum levels of albumin. The low-PNI group had a lower complete response rate (60.3% vs. 87.6%), increased treatment-related toxicity, and more frequent treatment discontinuation (43.5% vs. 8.8%) than the high-PNI group. The median OS was shorter in the low-PNI group than the high-PNI group (15.6 months vs. not reached; p < 0.001). Multivariate Cox regression analyses showed that PNI, sarcopenia, and the international prognostic index (IPI) were independent prognostic factors for OS. The nomogram developed using this regression model showed excellent discriminatory ability for predicting OS (c-index, 0.80) compared to the IPI alone (c-index, 0.75). Low PNI was associated with adverse clinical features of DLBCL. The proposed nomogram supports the clinical impact of cachexia on survival and may contribute to individualized therapy in DLBCL. PMID- 30413904 TI - Health risk assessment and source apportionment of polycyclic aromatic hydrocarbons associated with PM10 and road deposited dust in Ahvaz metropolis of Iran. AB - The objective of this study was to compare the characteristics of polycyclic aromatic hydrocarbons (PAHs) in PM10 and road dust samples, as well as to identify and quantify the contributions of each source profile using the positive matrix factorization (PMF) receptor model. Health risk assessment was carried out using toxic equivalency factors and incremental lifetime cancer risk (ILCR), which quantitatively estimate the exposure risk for age-specific groups. PM10 samples were collected on PTFE filters in the metropolitan area of Ahvaz. Road dust samples were also collected from all over the urban areas with different land uses. Total PAH concentrations in PM10 and road dust samples were 0.5-25.5 ng/m3 and 49.3-16,645 ug/kg, respectively. Pyrene was the highest PAH in the PM10 profile, whereas fluoranthene became the highest PAH in the road dust. Abundance of benzo[ghi]perylene at PM10 and road dust samples suggested a source indicator for traffic emissions. The results demonstrate that in 36.5% of samples, PM10 concentrations exceed the maximum concentration level recommended by EPA. A multiple linear regression model was used to estimate the influence of meteorological parameters (temperature, wind speed, and relative humidity) on buildup of PAHs. All of PAH species show higher concentrations during the cold and typical days rather than the dust event days and warm periods. PMF analysis showed that vehicular emissions (50.6%) and industrial activities (especially steel industries) (30.4%) were first two sources of PAHs bounded with PM10, followed by diesel emissions (11.6%) and air-soil exchange (7.4%). For road dust samples, three common sources were also identified: vehicular traffic (48%), industrial activities (42.3%), and petrogenic sources (9.7%), in line with that of diagnostic molecular ratios results. According to the results of health risk assessment model, the ILCR of exposure to PAHs associated with PM10 and road deposited dust was higher than the guidelines of USEPA, indicating high carcinogenic risk. PMID- 30413905 TI - Locally Used Antibiotics for Spinal Infection Prophylaxis and Their Effects on Epidural Fibrosis: an Experimental Laminectomy Study in Rats Using Rifamycin and Gentamycin. AB - The study aims to assess the effects of antibiotics (ABs), which are typically used in spinal infection prophylaxis, on the formation of epidural fibrosis (EF). Specifically, we investigated the effect of rifamycin and gentamycin on EF formation in laminectomized rats. Thirty-two rats were randomly and equally divided into four groups as follows: laminectomy and physiological saline (0.9% NaCl) solution (control); laminectomy and rifamycin; laminectomy and gentamicin; and laminectomy and a mixture of rifamycin and gentamicin. Laminectomy was performed on L1 and L2 vertebrae in all rats. One month after spinal surgery, spinal tissue samples surrounding the laminectomy were cut with a microtome and stained with hematoxylin-eosin and Masson's trichrome. The histopathological analysis included examining the extent of EF, fibroblast cell density, and cartilage and bone regeneration. Statistical analysis was performed using the IBM SPSS Statistics 22 program (SPSS IBM, Turkey). A value of p < 0.05 was considered statistically significant. EF value differences between the AB treatment groups and the control group were statistically significant (p = 0.030). Specifically, binary comparisons indicated that the EF value was significantly higher in the rifamycin group than that in the control group (p = 0.003; p < 0.05). Our study suggests that locally applied ABs, especially rifamycin, should be diluted before administration to the epidural space. PMID- 30413906 TI - The renin-angiotensin system in cardiovascular autonomic control: recent developments and clinical implications. AB - Complex and bidirectional interactions between the renin-angiotensin system (RAS) and autonomic nervous system have been well established for cardiovascular regulation under both physiological and pathophysiological conditions. Most research to date has focused on deleterious effects of components of the vasoconstrictor arm of the RAS on cardiovascular autonomic control, such as renin, angiotensin II, and aldosterone. The recent discovery of prorenin and the prorenin receptor have further increased our understanding of RAS interactions in autonomic brain regions. Therapies targeting these RAS components, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers, are commonly used for treatment of hypertension and cardiovascular diseases, with blood pressure-lowering effects attributed in part to sympathetic inhibition and parasympathetic facilitation. In addition, a vasodilatory arm of the RAS has emerged that includes angiotensin-(1-7), ACE2, and alamandine, and promotes beneficial effects on blood pressure in part by reducing sympathetic activity and improving arterial baroreceptor reflex function in animal models. The role of the vasodilatory arm of the RAS in cardiovascular autonomic regulation in clinical populations, however, has yet to be determined. This review will summarize recent developments in autonomic mechanisms involved in the effects of the RAS on cardiovascular regulation, with a focus on newly discovered pathways and therapeutic targets for this hormone system. PMID- 30413907 TI - Takotsubo syndrome in the Holy Bible. PMID- 30413908 TI - Modulation of cardiac autonomic control by resistance training in human participants. PMID- 30413909 TI - Letter by Garcia A, et al. regarding article "The clinical evaluation of the CADence device in the acoustic detection of coronary artery disease". PMID- 30413910 TI - Assessment of left atrial remodeling in paroxysmal atrial fibrillation with speckle tracking echocardiography: a study with an electrophysiological mapping system. AB - This study aimed to evaluate left atrial (LA) remodeling and fibrosis in paroxysmal atrial fibrillation (AF) using speckle tracking echocardiography (STE) based on the findings with radiofrequency catheter ablation (RFCA) so as to predict atrial remodeling prior to ablation. A total of 40 patients with paroxysmal AF were enrolled and divided into two groups based on LA bipolar voltage detected during RFCA: those with low-voltage zone (LVZ) (LV group, n = 19) and those without LVZ (non-LV group, n = 21). The segmental and global LA reservoir, conduit and contractile strain (epsilons, epsilone, epsilona) were analyzed using two-dimensional STE before RFCA. The segmental and global epsilons, epsilone, epsilona (%) decreased in the LV group. Especially, the epsilons in anteroseptal upper (18.32 +/- 7.94 vs. 31.61 +/- 9.39) and lower segments (16.60 +/- 7.23 vs. 29.23 +/- 9.81), posteroseptal upper (22.24 +/- 6.65 vs. 32.23 +/- 10.57) and lower segments (18.24 +/- 6.49 vs. 26.40 +/- 7.12), and the global epsilons (23.85 +/- 6.74 vs. 30.48 +/- 8.67) significantly decreased in the LV group than in the non-LV group (all P < 0.05). The epsilons <= 24.07 in the anteroseptal upper segment was an effective parameter to differentiate the LV group (sensitivity, 84%; specificity, 81%, P < 0.001). Besides, global epsilons tended to be an independent determinant of the LVZ (odds ratio 1.347, P = 0.046). STE enables a noninvasive method to evaluate LA remodeling prior ablation. PMID- 30413911 TI - Supporting Parents of a Child with Autism Spectrum Disorder: The French Awakening. AB - After being wrongfully blamed for their child's disturbances, French parents of a child with autism spectrum disorder (ASD) are now perceived as essential partners of care professionals. This shift in perspective has encouraged the development of parent training programs in the field of autism. In this paper, we present three programs currently implemented in France for parents of a child with ASD. We investigated their social validity, from the parents' perspective. All three programs showed good social validity: attendance rate was good and parents were satisfied. In France, like elsewhere, more parents should be given the opportunity to participate in such programs to help them deal with the specific challenges of raising a child with ASD. PMID- 30413912 TI - Comparative Analysis of the Adhesive Proteins of the Adult Stalked Goose Barnacle Pollicipes pollicipes (Cirripedia: Pedunculata). AB - Adhesion in barnacles is still poorly understood. The cement gland secretes an insoluble multi-protein complex, which adheres very strongly to a variety of substrates in the presence of water. This adhesion mechanism is bioinspiring for the engineering of new adhesive materials, but to replicate this adhesive system, the genes coding for the cement constitutive proteins must be identified and elucidated, and their products characterised. Here, the complete sequences of three cement protein (CP) genes (CP-100K, CP-52K, and CP-19K) isolated from the cement gland of the stalked barnacle Pollicipes pollicipes (order Scalpelliformes) were obtained using RACE PCR. The three genes were compared to the 23 other acorn barnacle CP genes so far sequenced (order Sessilia) to determine common and differential patterns and molecular properties, since the adhesives of both orders have visibly different characteristics. A shotgun proteomic analysis was performed on the cement, excreted at the membranous base of specimens, where the products of the three genes sequenced in the gland were identified, validating their function as CPs. A principal component analysis (PCA) was performed, to cluster CPs into groups with similar amino acid composition. This analysis uncovered three CP groups, each characterised by similar residue composition, features in secondary structure, and some biochemical properties, including isoelectric point and residue accessibility to solvents. The similarity among proteins in each defined group was low despite comparable amino acid composition. PCA can identify putative adhesive proteins from NGS transcriptomic data regardless of their low homology. This analysis did not highlight significant differences in residue composition between homologous acorn and stalked barnacle CPs. The characteristics responsible for the structural differences between the cement of stalked and acorn barnacles are described, and the presence of nanostructures, such as repetitive homologous domains and low complexity regions, and repetitive beta-sheets are discussed relatively to self-assembly and adhesion. PMID- 30413913 TI - Endoscopic sequestrectomy for skull base osteoradionecrosis in nasopharyngeal carcinoma patients: a 10-year experience. AB - BACKGROUND: Skull base osteoradionecrosis is a devastating post-irradiation complication in nasopharyngeal carcinoma patients. We conducted a retrospective analysis to assess the long-term survival and prognostic factors of patients with skull base osteoradionecrosis treated with endoscopic sequestrectomy. METHODS: We enrolled 59 nasopharyngeal carcinoma patients with skull base osteoradionecrosis who underwent endoscopic nasopharyngectomy. The clinical characteristics and outcome at the last follow-up visit were collected. The survival curve and univariate and multivariate survival analysis were analyzed by Kaplan-Meier and Cox proportional hazards model to analyze the potential prognostic factors of overall survival, including age, gender, number of radiation, number of operations, extension of disease (local or extensive), whether the ICA is exposed to the procedure (yes or no) and the hypha status (yes or no) at postoperative pathological examination. RESULTS: The predilection sites of skull base osteoradionecrosis in osteoradionecrosis patients are as follows: the base of the sphenoid bone and sphenoid sinus region, the clivus and petrous apex region including the internal carotid canal and the pterygoid process region (including its medial and lateral pterygoid plates). After surgery, clinical symptoms were alleviated in most patients to varying degrees. By the last follow-up visit, 26 patients had died. Most deaths (24) in the study occurred during the first 2 years. Most patients (24) died of sudden severe hemorrhage. The follow-up period ranged from 1 to 108 months, with a median of 27 months. The 2-year overall survival rate was 54.2%. Multivariate Cox regression analysis showed that the number of radiation (P = 0.026) and age (P = 0.002) were independent risk factors for the overall survival. CONCLUSIONS: Endoscopic sequestrectomy with minimal complications and clear vision is a valuable option for the therapy of skull base osteoradionecrosis in nasopharyngeal carcinoma patients. PMID- 30413915 TI - Distinguished Reviewers 2018. PMID- 30413914 TI - Genetic association of promoter in GRP78 gene with nasopharyngeal carcinoma in a Chinese population. AB - BACKGROUND: Emerging evidences were accumulated to support the view that GRP78 might be associated with multiple types of cancer. Given these, the aim of this study is to investigate the relationship between single nucleotide polymorphisms (SNPs) of GRP78 gene promoter and nasopharyngeal carcinoma (NPC). METHODS: Three SNPs (rs3216733, rs17840761 and rs17840762) in GRR78 promoter were estimated in 422 NPC patients and 452 controls. Genotyping was performed using SNaPshot SNP. Serum GRP78 level was performed by enzyme-linked immunosorbent assay (ELISA). Data were analyzed by SPSS 17.0 software. RESULTS: Significant association between rs3216733 polymorphism and NPC was observed (Cd vs. dd: OR = 0.57, 95% CI 0.43-0.76, P < 0.001; CC vs. dd: OR = 0.62, 95% CI 0.39-0.98, P = 0.043; Cd/CC vs. dd: OR = 0.58, 95% CI 0.44-0.76, P < 0.001; C vs. d OR = 0.70, 95% CI 0.57 0.86, P = 0.001). Additionally, we further found that expression were down regulated in serum of patients with NPC carrying rs3216733 CC genotype when compared to that of dd genotype (P < 0.001). CONCLUSION: The observations suggest that rs3216733 polymorphism in the GRP78 gene promoter may correlate with NPC susceptibility. PMID- 30413916 TI - Non-conservative Management of Placenta Accreta Spectrum in the Hybrid Operating Room: A Retrospective Cohort Study. AB - INTRODUCTION: Hysterectomy is the standard of care in placenta accreta spectrum (PAS). To reduce the risks of obstetric hemorrhage during surgery, endovascular interventions have been proposed. Our aim is to evaluate the feasibility and safety of the overall non-conservative management of PAS in the hybrid operating room (OR) to replace the classic two-step procedure (catheterization in the interventional radiology suite and transfer to conventional OR). MATERIALS AND METHODS: This is a retrospective study of series of patients with histopathologic confirmation of PAS treated in the hybrid OR at the same university hospital. We used for comparison our historical cohort managed with the standard two-step procedure. RESULTS: We included 110 patients, 80 in the conventional OR and 30 in the hybrid OR. There were no cases of major complications attributable to the endovascular procedures. In the two-step procedure, there were 10 (12.5%) intra arterial catheter displacements that required repositioning in the conventional OR under mobile C-arm fluoroscopy and no cases in the hybrid OR (p = 0.04). The mean operative time was 380 + 42 min in the conventional OR and 296 + 66 min in the hybrid OR (p = .00001). There were no differences in the gestational age at delivery, postoperative length of stay, or large-volume blood transfusion. There were no maternal deaths. CONCLUSIONS: The overall non-conservative management of PAS in the hybrid OR has shown to be feasible and safe in our series, offering potential advantages to replace the classic two-step procedure. More studies are needed to evaluate whether this strategy is cost-effective and whether it may improve maternal and perinatal outcomes. PMID- 30413917 TI - Penetrating Aortic Ulcer and Intramural Hematoma. AB - Acute aortic syndromes include a variety of overlapping clinical and anatomic diseases. Penetrating aortic ulcer (PAU), intramural hematoma (IMH) and aortic dissection can occur as isolated processes or can be found in association. All these entities are potentially life threatening, so prompt diagnosis and treatment is of paramount importance. PAU and IMH lesions in the Stanford Type A distribution often require urgent open surgical repair. Lesions in the Stanford Type B distribution may be managed medically in the absence of symptoms or progression; however, a low threshold for endovascular or surgical treatment should be maintained. This review summarizes the clinical presentation, epidemiology, diagnosis, indications for treatment and endovascular strategies in patients with PAU or IMH. PMID- 30413918 TI - Comparative Analysis of Intra-arterial Cone-Beam Versus Conventional Computed Tomography During Hepatic Arteriography for Transarterial Chemoembolization Planning. AB - PURPOSE: To compare the imaging characteristics of intra-arterial cone-beam computed tomography during hepatic arteriography (CBCTHA) versus intra-arterial computed tomography during hepatic arteriography (CTHA) for intraprocedural transarterial chemoembolization (TACE) planning. MATERIALS AND METHODS: This single-institution retrospective study included 144 patients (96 men, mean age 67.9 years; 48 women, mean age 62.3 years) who underwent 181 TACE sessions between January 2015 and July 2017. Intraprocedural CBCTHA (111 procedures) or CTHA (70 procedures) was performed for TACE planning. Reformatted maximum intensity projection CBCTHA and CTHA images were reviewed by two radiologists and classified using an ordinal scoring system (for tumor identification, tumor feeder vessel identification, and streaking artifact) and a binary scoring system (for the presence of breathing motion artifact and field of view encompassing the entire liver). Data were analyzed using an F test and a z-score test. RESULTS: There were no significant differences in demographic and tumor characteristics between the CBCTHA and CTHA patient cohorts. CTHA was superior to CBCTHA for tumor identification (P < .0001), tumor feeder vessel identification (P < .05), streaking artifact (P < .0001), and field of view encompassing the entire liver (P < .0001). There was a trend toward a lower frequency of breathing motion artifact with CTHA than with CBCTHA (1.4% vs. 10%; P = .057). CONCLUSION: CTHA provides improved clinical relevant imaging information compared to CBCTHA for intraprocedural TACE planning. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 30413919 TI - Tethered cord in children with anorectal malformations with emphasis on rectobladder neck fistula. AB - PURPOSE: To find the incidence of tethered cord (TC) in patients with anorectal malformations (ARM) and to determine the relationship between bowel/urinary control and TC in a subset of patients with rectobladder neck fistula (RBNF). METHODS: The database of a tertiary medical center was retrospectively collected for all patients treated for ARM from 1980 to 2012. All patients with TC and RBNF were identified. RESULTS: Among 790 patients, who underwent screening for TC, 285(36%) were diagnosed with TC. Eleven of 37 screened patients with RBNF were diagnosed with TC. The median follow-up period was 49 months (range 2-222 months). TC was diagnosed in 3/18(16.6%) patients with sacral ratio (SR) >= 0.7; 4/12(33.3%) with SR 0.41-0.69; and 4/7(57.1%) patients with SR 0-0.4. The association of TC in RBNF patients had a negative influence in the prognosis for bowel and urinary control. CONCLUSION: The incidence of TC among patients with ARM is 36%. Incidence of TC among patients with RBNF correlates with SR value and is higher with lower SR. Patients with RBNF and TC have dismal prognosis for bowel control, unrelated to their SR status. Many unresolved questions related to the management of ARM patients with asymptomatic TC still remain. PMID- 30413920 TI - The extent of pediatric orthopaedic research in low- and middle-income countries and the impact of academic collaboration on research quality: a scoping review. AB - INTRODUCTION: This review aims to (1) assess the breadth of pediatric orthopaedic research in low- and middle-income countries (LMICs) and (2) determine the impact of academic collaboration (an LMIC and a non-LMIC investigator) in published LMIC research. METHODS: Pediatric orthopaedic clinical studies conducted in LMICs from 2004 to 2014 were extracted from Embase, Cochrane, and Pubmed databases. Of 22,714 searched studies, 129 met inclusion criteria. RESULTS: 85% generated low quality evidence (level IV or lower). 21% were collaborative, and these were more likely than non-collaborative papers to generate level III evidence or higher (25% vs 13%, p = 0.141). DISCUSSION: Pediatric orthopaedic research produced by LMICs rarely achieves level I-III evidence, but collaborative studies are associated with higher levels of evidence. LEVEL OF EVIDENCE: N/A. PMID- 30413921 TI - Innervation of the entire internal anal sphincter in a mouse model of Hirschsprung's disease: a first report. AB - BACKGROUND: Impaired function of the internal anal sphincter (IAS) may be implicated in postoperative obstructed defecation (POD) that may complicate Hirschsprung's disease (HD) patients. While innervation of part of the IAS in HD has been reported, accurate details based on anatomic landmarks that can explain the clinical morbidity seen in POD are lacking, and there appear to be no studies that specifically document the innervation of the "entire" IAS in HD. We used endothelin receptor-B knockout mice to represent HD (HD-mice) and C57B6 wild mice as controls (C-mice) to investigate the innervation of the entire IAS to assess the pathophysiology of POD experimentally. METHODS: The end-point of the longitudinal muscle layer was used to define the border between the IAS and the circular muscle layer (CML). Specimens of anorectum from HD- and C-mice were immunostained with PGP 9.5 and S100 as general nerve markers, nNOS and VIP as parasympathetic nerve markers, TH as a sympathetic nerve marker, and calretinin as a reliable diagnostic marker for HD. Immunostained cells/fibers were quantified using ImageJ. RESULTS: On fluorescence microscopy, PGP 9.5, nNOS, and calretinin were significantly lower in the IAS of HD-mice than in C-mice (p < 0.05, respectively), while there were no significant differences between HD-mice and C-mice for S100, VIP, or TH. CONCLUSION: We are the first to confirm that the expression of histochemical markers of innervation is abnormal throughout the "entire" IAS in HD-mice. Application of this finding may be beneficial for preventing POD and requires further research. PMID- 30413922 TI - A Fluorescent Turn-On Carbazole-Rhodanine Based Sensor for Detection of Ag+ Ions and Application in Ag+ Ions Imaging in Cancer Cells. AB - Carbazole - Rhodanine conjugate is an effective fluorescent host for silver ions through fluorometric transformation from green to red color with a hyperchromic emission. An intramolecular charge transfer process derived from carbazole towards rhodanine favors interaction of thiocarbonyl S and carboxylic acid O of the rhodanine moiety towards Ag+ ion. Carbazole - rhodanine dyad accomplishes the lowest detection limit of 12.8 * 10-9 M and high quantum efficiency. A fluorescence reversibility of the probe with I- ion surges reutilization of sensor molecule as an Ag+ ion probe with minimal loss in the fluorescent efficiency. This fluorescent ligand is a biocompatible probe and is also a proficient candidate for fluorescent imaging of Ag+ ion in live cells. PMID- 30413923 TI - Presence of galactose in precultures induces lacS and leads to short lag phase in lactose-grown Lactococcus lactis cultures. AB - Lactose conversion by lactic acid bacteria is of high industrial relevance and consistent starter culture quality is of outmost importance. We observed that Lactococcus lactis using the high-affinity lactose-phosphotransferase system excreted galactose towards the end of the lactose consumption phase. The excreted galactose was re-consumed after lactose depletion. The lacS gene, known to encode a lactose permease with affinity for galactose, a putative galactose-lactose antiporter, was upregulated under the conditions studied. When transferring cells from anaerobic to respiration-permissive conditions, lactose-assimilating strains exhibited a long and non-reproducible lag phase. Through systematic preculture experiments, the presence of galactose in the precultures was correlated to short and reproducible lag phases in respiration-permissive main cultivations. For starter culture production, the presence of galactose during propagation of dairy strains can provide a physiological marker for short culture lag phase in lactose grown cultures. PMID- 30413924 TI - Evaluation of the performance of extreme patient-reported outcomes as surrogate markers for fibromyalgia in axial spondyloarthritis. AB - OBJECTIVES: The aim of the study is to evaluate the performance of extreme patient-reported outcomes (PRO) against definitions of fibromyalgia (FM) in patients with axial spondyloarthritis (axSpA). METHODS: Ancillary analysis of the Predict-SpA trial, an observational study of axSpA patients receiving TNF-alpha inhibitor, was performed. 'Extreme PRO' was defined as a score >= 8 on three out of the first five Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) questions (scored 0-10). FM was defined by the American College of Rheumatology (ACR) 1990 criteria and the Fibromyalgia Rapid Screening Test (FiRST). Performances of 'extreme PRO' for FM were evaluated by the sensitivity, specificity and positive likelihood ratio using the 1990 ACR criteria as gold standard. As secondary analysis, the FiRST was used as the external standard. RESULTS: The prevalence of 'extreme PRO' in this population was 28.8% at baseline and decreased to 9.9% at 12 weeks. 'Extreme PRO' had low sensitivity 12 weeks after TNF initiation (0.18, 95% confidence interval [CI] 0.10-0.27 vs 0.60, 95% CI 0.50-0.71, at baseline), but high specificity (0.92, 95% CI 0.89-0.94 vs 0.78, 95% 0.74-0.82, at baseline), using ACR 1990 criteria as gold standard. Performances when tested against FiRST at 12 weeks showed higher sensitivity (0.27, 95% CI 0.20-0.35) and specificity (0.96, 95% CI 0.94-0.98). CONCLUSION: The proposed extreme PRO definition showed great specificity for FM recognition in patients with axSpA, suggesting it could be used in observational studies when specific items for FM classification are not available. PMID- 30413925 TI - Bulgarian rheumatology: science and practice in a cost-constrained environment. AB - Our aim was to appraise publications from Bulgaria, to assess their global impact, and to describe features and challenges unique to the rheumatology practice in Bulgaria characterized by stringent cost constraints. The Scopus database was queried on 25th July 2018 and data on the number of published documents, their Hirsch-indices and citations number were extracted. Published Bulgarian guidelines for the management of rheumatic diseases and the presented data on Bulgarian Rheumatology Society were identified based on prior knowledge of the authors. From all the identified 1082 document the most extensively researched areas were rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), osteoporosis, and osteoarthritis (OA). For the last five years (from Jan 2013 to 25th July 2018) the number of publications was 293. We found that Bulgaria's international scientific collaboration in the field of rheumatology is focused on a handful of countries mainly from Europe. Although Bulgarian rheumatologists have access to costly biologic agents for treating their patients with rheumatic diseases, their funding may not be granted according to the current recommendations of European League against Rheumatism (EULAR) and national guidelines for the management of rheumatic diseases. Although the western world clearly dominates the production of scientific publications in rheumatology, Bulgarian rheumatology may present another perspective for diagnosis and management of patients with rheumatic diseases in a cost-stringent environment. Nevertheless, both rheumatology science and practice in Bulgaria still have a long way to go to take its deserved place among the other European countries. PMID- 30413926 TI - Risk of hospitalization for heart failure in rheumatoid arthritis patients treated with etanercept and abatacept. AB - To estimate biologic influence on heart failure (HF) risk in rheumatoid arthritis. Retrospective cohort (RECORD Study of Italian Society for Rheumatology) study on administrative healthcare databases. We identified 2527 patients treated with either etanercept (n = 1690) or abatacept (n = 837). HF incidence rate was higher in the abatacept cohort than in the etanercept cohort with a 2.38 (95% CI 1.08-5.27) crude competing risk HR (SHR) for abatacept of developing HF, not confirmed after adjustment for prespecified confounders (SHR 1.43; 95% CI 0.51-3.98). Abatacept, compared to etanercept, is prescribed to patients with a worse cardiovascular profile but does not increase the risk of developing HF, when confounding factors are accounted for. PMID- 30413927 TI - Nutritional interventions in elderly gastrointestinal cancer patients: the evidence from randomized controlled trials. AB - Literature concerning nutritional interventions in elderly patients with gastrointestinal cancer, with special reference to randomized clinical trials, has been critically reviewed. This segment of oncologic population was found to be penalized by a high prevalence of malnutrition and sarcopenia which translated in an increased rate of toxicity from chemotherapy, poor compliance with oncologic treatments, and, finally, with a poor prognosis. Attempts to reverse this condition included a potentiation of nutrients intake which should sequentially proceed through the use of dietary counseling and administration of standard or omega-3 fatty acid-enriched oral supplements to finally come to enteral or parenteral nutrition. Randomized clinical trials investigating the effects of simple dietary advice and use of standard oral supplements were disappointing as regards long-term compliance and results. Nutritional and clinical benefits were reported with the use of omega-3 fatty acid-enriched oral supplements and especially with long-term supplemental parenteral nutrition. Despite the general recommendation of the scientific community that emphasizes the use of the enteral route, whenever possible, for delivering the nutritional support, it appears from the literature that more consistent benefits can be achieved, especially in the long-term nutritional support, when an insufficient oral nutrition is partnered with intravenous nutrition. PMID- 30413928 TI - Laparoscopic approach for left-sided T4 colon cancer is a safe and feasible procedure, compared to open surgery. AB - BACKGROUND: A laparoscopic approach can be attempted for pathologic T4 (pT4) colon cancer. Our aim was to evaluate the clinico-oncologic outcomes following laparoscopic versus open surgery for right and left-sided pT4 colon cancer. METHODS: From a multicentric collaborative database, we enrolled 245 patients with right-sided colon cancer (RCC, 128 laparoscopy and 117 open) and 338 with left-sided colon cancer (LCC, 176 laparoscopy and 162 open). All patients underwent intended curative surgery for histologically proven T4 adenocarcinoma, between 2004 and 2013. The primary end-point of our analysis was the oncologic outcome, including the 5-year disease-free survival (5 year-DFS) and the 5-year overall survival (5 year-OS). The secondary end-points included the R0 resection rate and postoperative complications. RESULTS: Our study group included 224 T4N0 and 359 T4N+ tumors. The median follow-up was 53 months. For patients with RCC, the rate of postoperative morbidities was lower for the laparoscopy than that for the open surgery group (12.5 vs. 22.2%, p = 0.044). There was no difference in the R0 resection rate (94.5 vs. 96.6%, p = 0.425) between the groups. The 5 year DFS and 5 year-OS rates were lower for the laparoscopy than that in the open group (48.9% vs. 59.2%, p = 0.093; 60.0% vs. 70.0%, p = 0.284, respectively), but this difference was not statistically significant. Among patients with LCC, there were no differences in the rate of postoperative complication and R0 resection (15.3 vs. 21.0%, p = 0.307; 96.0 vs. 95.7%, p = 0.875, respectively). Both groups had comparable 5 year-DFS and 5 year-OS rates (62.7% vs. 61.1%, p = 0.552; 72.0% vs. 71.8%, p = 0.611, respectively). CONCLUSIONS: Laparoscopic surgery appears to be a safe procedure for patients with pT4 LCC, but requires careful consideration for patients with pT4 RCC. PMID- 30413929 TI - Short-term outcomes after elective colon cancer surgery: an observational study from the Norwegian registry for gastrointestinal and HPB surgery, NoRGast. AB - BACKGROUND: To describe the real burden of major complications after elective surgery for colon cancer in Norway, and to assess which predictors that are significantly associated with the short-term outcome. METHODS: An observational, multi-centre analysis of prospectively registered colon resections registered into the Norwegian Registry for Gastrointestinal Surgery, NoRGast, between January 2014 and December 2016. A propensity score-adjusted subgroup analysis for surgical access groups was attempted, with laparoscopic resections grouped as intention-to-treat. RESULTS: Out of 1812 resections, 14.0% of patients experienced a major complication within 30 days following surgery. The over-all reoperation rate was 8.7%, and rate of reoperation for anastomotic leak was 3.8%. Twenty patients (1.1%) died within 30 days after surgery. Higher age was not a significant predictor of major complications, including 30-day mortality. After correction for all co-variables, open access surgery was associated with higher rates of major complications (OR 1.67 (CI 1.22-2.29), p = 0.002), higher 30-day mortality (OR 4.39 (CI 1.19-16.13) p = 0.026) and longer length-of-stay (HR 0.58 (CI 0.52-0.65) p < 0.001). CONCLUSIONS: Our results indicate a low complication burden and high rate of uneventful patient journeys after elective surgery for colon cancer in Norway. Age was not associated with higher morbidity or mortality rates. Open access surgery was associated with an inferior short-term outcome. PMID- 30413930 TI - Endothelial Progenitor Cells Biology in Diabetes Mellitus and Peripheral Arterial Disease and their Therapeutic Potential. AB - Endothelial progenitors are a population of cells with the inherent capacity to differentiate into mature endothelial cells and proangiogenic paracrine action. These characteristics have led to extensive studies being performed and tested in the treatment of tissue ischemia. The natural course of diabetes mellitus (DM) results in multiple areas of vascular damage. Thus endothelial progenitor cells'(EPCs) beneficial potential is particularly desirable in diabetic patients. In this review, we summarize contemporary knowledge of EPC biology in DM. It has been shown that EPC functions are considerably impaired by DM. The presence of peripheral arterial disease (PAD) seems to further exacerbate the deficiencies of EPCs. However, studies examining EPC counts in PAD and DM observed disparate results, which can be due to a lack of consensus on precise EPC immunotype used in the different studies. Nevertheless, the results of EPC-based autologous cell therapy (ACT) are promising. In addition, EPCs have been shown to bean independent predictor of cardiovascular risk and diabetic foot ulcer healing. PMID- 30413931 TI - Type of delivery is not associated with maternal depression. AB - Although many women experience depressive symptoms during the first year after childbirth, the relationship between type of delivery and maternal depression is not clear. The purpose of this study is to evaluate relationship between type of delivery and maternal depression, between 6 to 16 months after childbirth. We performed a prospective cohort study of 558 low-socioeconomic status pregnant women without depression. All participants were recruited from primary care clinics of the public sector in three administrative districts in the Western area of the city of Sao Paulo, Brazil. Depressive symptoms were assessed using the Self-Report Questionnaire (SRQ-20). Type of delivery was classified as uncomplicated spontaneous vaginal delivery (UVD) (no episiotomy and no more than a first-degree perineal laceration), complicated vaginal delivery (CVD) (episiotomy or more than a second-degree perineal laceration), and cesarean delivery (CD). Data about type of delivery were extracted from medical charts. Crude and adjusted risk ratios with 95% confidence intervals were estimated using Poisson regression with robust variance estimates to examine the association between type of delivery with maternal depression. Among 482 women reassessed during 6 to 16 months after delivery, 18% had symptoms of depression. According to the type of delivery, 250 (51.8%), 85 (21.7%), and 147 (30.5%) were UVD, CVD, and CD, respectively. There was no association between type of delivery and maternal depression. In comparison with women submitted to uncomplicated vaginal, women who had a cesarean or perineal trauma/episiotomy did not show greater risk of maternal depression, in the medium to long term after delivery. PMID- 30413932 TI - A Higher Preoperative Glycemic Profile Is Associated with Rapid Gastric Emptying After Sleeve Gastrectomy for Obese Subjects. AB - BACKGROUND: Recent reports have shown that sleeve gastrectomy (SG) accelerates gastric emptying (GE), but the etiology remains unclear. This study aimed to investigate the factors affecting GE before and after SG. METHODS: We enrolled 35 normal weight healthy subjects and 23 obese patients receiving SG. The normal individuals and obese patients before and 3 months after SG received oatmeal based scintigraphy to measure GE. Gastrointestinal symptoms and circulating levels of peptide YY (PYY) were also measured. RESULTS: There were no differences in the GE parameters, including simple half-time at 3 h and percentage of gastric retention at 0.5, 1, 2, and 3 h between healthy controls and pre-SG obese subjects. SG led to accelerated GE, more gastrointestinal symptoms, and increased fasting PYY levels postoperatively. Based on our previously established normal GE values, 18 (78.3%) obese patients with rapid postoperative GE had higher levels of preoperative fasting glucose and glycated hemoglobin, and homeostasis model assessment of the insulin resistance index than those with normal postoperative GE. Twelve (52.2%) obese patients had preoperative diabetes mellitus (DM), and only four (17.4%) remained diabetic after SG. The post-SG gastric retention at 0.5 and 1 h was lower in patients with preoperative DM than in those without preoperative DM. Neither severity of gastrointestinal symptoms nor fasting PYY levels were associated with postoperative GE alterations. CONCLUSION: Most of the obese patients had accelerated GE after SG. A higher preoperative glycemic profile was associated with rapid post-SG GE. PMID- 30413933 TI - ID Proteins May Reduce Aggressiveness of Thyroid Tumors. AB - ID genes have an important function in the cell cycle, and ID proteins may help identify aggressive tumors, besides being considered promising therapeutic targets. However, their role in thyroid tumors is still poorly understood. We examined ID expression and their correlation with diagnostic and prognostic features aiming to find a clinical application in differentiated thyroid carcinoma (DTC) cases. mRNA levels of ID1, ID2, ID3, and ID4 genes were quantified and their expression was observed by immunohistochemistry in 194 thyroid samples including 68 goiters, 16 follicular adenomas, 75 classic papillary thyroid carcinomas, 18 follicular variants of papillary thyroid carcinoma, 5 follicular thyroid carcinomas, and 1 anaplastic thyroid cancer, besides 11 normal thyroid tissues. DTC patients were managed according to standard protocols and followed up for M = 28 +/- 16 months. ID2, ID3, and ID4 mRNA levels were higher in benign (2.0 +/- 1.9; 0.6 +/- 0.6; and 0.7 +/- 1.0 AU, respectively) than those in malignant nodules (0.30 +/- 0.62; 0.3 +/- 0.3; and 0.2 +/- 0.3 AU, respectively, p < 0.0001 for all three genes) and were associated with no extra thyroid invasion or metastasis at diagnosis. ID3 nuclear protein expression was higher in benign than that in malignant cells (5.2 +/- 0.9 vs 3.0 +/- 1.8 AU; p < 0.0001). On the contrary, the cytoplasmic expression of ID3 was higher in malignant than that in benign lesions (5.7 +/- 1.5 vs 4.0 +/- 1.4 AU; p < 0.0001). Our data indicate that ID genes are involved in thyroid tumorigenesis and suggest these genes act impeding the evolution of more aggressive phenotypes. The different patterns of their tissue expression may help identify malignancy and characterize thyroid lesion aggressiveness. PMID- 30413935 TI - Improved synergistic anticancer efficacy of quercetin in combination with PI-103, rottlerin, and G0 6983 against MCF-7 and RAW 264.7 cells. AB - Flavonoids have been chronicles of the history of a long way journey in the cure of physiological or pathophysiological conditions in various diseases including cancer. Our previous findings suggest the extensive mechanism of quercetin (QUE) mediated regression of cell survival, cell proliferation, oxidative stress, inflammation, and angiogenesis via modulating PI3K and PKC signaling in lymphoma as well as hepatocellular carcinoma. PI3K-PKC pathway is a key monitor of mammalian cells regulated by its different isoenzymes, which may exert similar or opposite cellular effects by differential coupling of signaling pathways. Put forward the invention of selective inhibitors against various isoenzymes is beneficial to reduce the burden of inclusive deleterious effects of drug for normal physiological process. Therefore, we hypothesized the improved anticancer efficacy of QUE in combination with isoenzyme inhibitors-rottlerin (ROT-PKCdelta inhibitor), G0 6983 (PKCalpha inhibitor), and PI-103 (p110alpha-class I PI3K inhibitor) in MCF-7 and RAW 264.7 cells. QUE significantly improves the cytotoxicity of ROT + G0 6983 ranged 30-55% and PI-103 ranged 24-63% after 24-48 h against MCF-7 cells. Additionally in the presence of QUE, the improved cytotoxicity of ROT + G0 6983 is observed to range 69-75% and PI-103 ranged 45 88% after 24-48 h in RAW 264.7 cells. This increment in cell deaths are positively correlated with enhanced morphological alteration observed in MCF-7 cells. Further, QUE significantly increases the attenuation of PKCalpha level approximately by 50% in combination with PI-103. Overall results of the current study suggested that QUE improves the synergistic anticancer efficacy in combination with PI-103, ROT, and G0 6983 in MCF-7 and RAW 264.7 cells. PMID- 30413936 TI - A Shared Neural Node for Multiple Innate Behaviors in Drosophila. PMID- 30413934 TI - Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease. AB - Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the epsilon4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 * 10-9), MINK1 (chromosome 17, meta-p = 1.98 * 10-7) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 * 10-7 and closest gene = MYBPC3, meta-p = 5.62 * 10-8). In a large 'AD-by-proxy' cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2. Expression of MBLAC1, SPI1, MINK1 and DDB2 was differentially altered within postmortem AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals. PMID- 30413938 TI - Frameless robot-assisted stereoelectroencephalography for refractory epilepsy in pediatric patients: accuracy, usefulness, and technical issues. AB - BACKGROUND: Stereoelectroencephalography (SEEG) is an effective technique to help to locate and to delimit the epileptogenic area and/or to define relationships with functional cortical areas. We intend to describe the surgical technique and verify the accuracy, safety, and effectiveness of robot-assisted SEEG in a newly created SEEG program in a pediatric center. We focus on the technical difficulties encountered at the early stages of this program. METHODS: We prospectively collected SEEG indication, intraoperative events, accuracy calculated by fusion of postoperative CT with preoperative planning, complications, and usefulness of SEEG in terms of answering preimplantation hypothesis. RESULTS: Fourteen patients between the ages of 5 and 18 years old (mean 10 years) with drug-resistant epilepsy were operated on between April 2016 and April 2018. One hundred sixty-four electrodes were implanted in total. The median entry point localization error (EPLE) was 1.57 mm (1-2.25 mm) and the median target point localization error (TPLE) was 1.77 mm (1.2-2.6 mm). We recorded seven intraoperative technical issues. Two patients suffered complications: meningitis without demonstrated germ in one patient and a right frontal hematoma in the other. In all cases, the SEEG was useful for the therapeutic decision-making. CONCLUSION: SEEG has been useful for decision-making in all our pediatric patients. The robotic arm is an accurate tool for the insertion of the deep electrodes. Nevertheless, it is an invasive technique not risk-free and many problems can appear at the beginning of a robotic arm-assisted SEEG program that must be taken into account beforehand. PMID- 30413939 TI - Transpalpebral approach in skull base surgery: how I do it. AB - BACKGROUND: Keyhole surgery has been actively developing in the last two decades. Modern neuroimaging, preoperative individual planning, and innovative neurosurgical equipment allow us to operate through mini craniotomy with minimization of approach-related complications. METHOD: Preoperative planning is very critical. After the patient positioning, skin incision, craniotomy, and dura incision are performed. Intradural lesion is reached with standard microneurosurgical technique. A watertight dura closure is important. CONCLUSION: Transpalpebral approach can be good alternative to traditional, extended fronto lateral craniotomies with excellent cosmetic and functional outcomes. Adequate selection of patients is important. PMID- 30413937 TI - A Critical Time-Window for the Selective Induction of Hippocampal Memory Consolidation by a Brief Episode of Slow-Wave Sleep. AB - Although extensively studied, the exact role of sleep in learning and memory is still not very clear. Sleep deprivation has been most frequently used to explore the effects of sleep on learning and memory, but the results from such studies are inevitably complicated by concurrent stress and distress. Furthermore, it is not clear whether there is a strict time-window between sleep and memory consolidation. In the present study we were able to induce time-locked slow-wave sleep (SWS) in mice by optogenetically stimulating GABAergic neurons in the parafacial zone (PZ), providing a direct approach to analyze the influences of SWS on learning and memory with precise time-windows. We found that SWS induced by light for 30 min immediately or 15 min after the training phase of the object in-place task significantly prolonged the memory from 30 min to 6 h. However, induction of SWS 30 min after the training phase did not improve memory, suggesting a critical time-window between the induction of a brief episode of SWS and learning for memory consolidation. Application of a gentle touch to the mice during light stimulation to prevent SWS induction also failed to improve memory, indicating the specific role of SWS, but not the activation of PZ GABAergic neurons itself, in memory consolidation. Similar influences of light-induced SWS on memory consolidation also occurred for Y-maze spatial memory and contextual fear memory, but not for cued fear memory. SWS induction immediately before the test phase had no effect on memory performance, indicating that SWS does not affect memory retrieval. Thus, by induction of a brief-episode SWS we have revealed a critical time window for the consolidation of hippocampus-dependent memory. PMID- 30413940 TI - The influence of histology on the response of brain metastases to gamma knife radiosurgery: a propensity score-matched study. AB - BACKGROUND: In terms of response to fractionated radiotherapy, metastatic brain tumors of certain origins are considered radioresistant. OBJECTIVE: To determine the influence of "radioresistant" histology on outcomes of brain metastases treated with radiosurgery. METHODS: Between 2001 and 2017, 121 patients with brain metastases from renal cell carcinoma (RCC) and 2151 from non-small cell lung cancer (NSCLC) were reviewed. Eighty-seven pairs were derived using propensity score matching. Local progression-free survival (PFS), progression patterns, distant PFS, and overall survival were investigated. RESULTS: The median follow-up period was 13.7 months (range, 1.6-78.4 months). A total of 536 lesions were treated using gamma knife radiosurgery (GKS), with a median dose of 20 Gy (range, 12-28 Gy). The actuarial local PFS rates in the RCC group were 91% and 89% at 6 and 12 months, respectively, and did not differ from the NSCLC group (97% and 83% at 6 and 12 months, respectively). Continuous progression, without response to GKS, was noted in seven of the eight progressed RCCs. However, six of the seven progressed NSCLCs showed transient shrinkage before progression. The median distant PFS was 9.3 months (95% CI, 6.3-12.2) in the RCC group and 8.0 months (95% CI, 5.5-10.4) in the NSCLC group. The median overall survival was 16.1 months (95% CI, 11.3-20.8) and 14.9 months (95% CI, 11.9-17.8) in RCC and NSCLC groups, respectively. CONCLUSION: Histological differences had no effect on local control in the single high-dose range used for radiosurgery. However, changes in tumor volume during progression varied across tumor histology. PMID- 30413941 TI - The survivorship of the link endo-rotational hinge total knee arthroplasty: 5-12 year follow-up of 100 patients. AB - INTRODUCTION: There is a paucity of survival data reporting the medium to long term outcome of the LINK(r) Endo-Model(r) rotational hinge total knee arthroplasty (ERH-TKA). Such information is essential when counselling patients and predictors of survival would help inform patients of their likely outcome. MATERIALS AND METHODS: A series of patients, who received an ERH-TKA, with a minimum follow-up of 5 years, were retrospectively identified from an established arthroplasty database. Data were collected from paper and electronic patient records. This included patient demographics, indication for surgery, complication rates and revision status. Our primary outcome of interest was joint implant survival. RESULTS: One hundred patients underwent an ERH-TKA over an 11-year period. There were 66 females and 34 males, with a mean age of 73.8 years and 67.6 years, respectively. Indications were classified into primary (n = 41), aseptic revision (n = 47) and two-stage infective revision (n = 12). The median follow-up was 8.2 (range 5-12) years. One-year implant survival amongst the cohort was 99%, falling to 95% at 5 years. Overall, there were eight revisions during the follow-up period. Considering only cases of aseptic failure, survival was 97% at 5 years and all failures occurred amongst revision cases. Implant failure was greater following revision arthroplasty but this was not statistically significant (p = 0.97). Cox regression analysis identified male sex to be the only independent predictor of failure (hazard ratio 1.75, 95% CI 1.04 31.82, p = 0.04) after adjusting for confounding variables. CONCLUSIONS: The ERH TKA has a good medium- to long-term survival rate but male patients are nearly twice as likely to undergo revision, compared to females, and should be made aware of this preoperatively. PMID- 30413942 TI - Dorsal buttress plate fixation for the treatment of fracture-dislocation of the fifth carpometacarpal joint with avulsion fracture of the hamate: a case report. AB - Fracture-dislocations of the fourth and fifth carpometacarpal (CMC) joints present a complex situation. Misdiagnosis and inadequate treatment may cause malunion and residual subluxation, which lead to painful arthritis and grip weakness. Open reduction along with internal fixation is the treatment of choice, but there is no consensus on an optimal treatment approach. We applied a novel surgical technique to treat a case of a fracture-dislocation of the fifth CMC joint with avulsion fracture of the hamate using a dorsal buttress plate between the hamate and the capitate. This method allowed for achieving rigid fixation without screw insertion across the bone fragments of the hamate. We could avoid the risk of unexpected fragmentation and unexpected damage to the volar neurovascular bundles around the hook of the hamate. Six months postoperatively, bone union was achieved and the reduction of the fourth and fifth CMC joints was maintained. Range of motion of the fourth and fifth CMC joints was almost equal to that on the contralateral side. Dorsal buttress plating between the hamate and the capitate could be an alternative technique for the treatment of fracture dislocation of the fifth CMC joint with avulsion fracture of the hamate. PMID- 30413943 TI - Development of the double level osteotomy in severe varus osteoarthritis showed good outcome by preventing oblique joint line. AB - INTRODUCTION: The purpose of the study was to describe the development of the surgical technique of double level osteotomy in patients with severe varus malalignment and to investigate the clinical and radiological outcome. It was hypothesized that good clinical results without a higher complication rate can be achieved by double level osteotomy to normalize joint angles and avoid joint line obliquity even in cases of progressed osteoarthritis. MATERIALS AND METHODS: Between 2011 and 2014, 33 patients (37 knees) undergoing double level osteotomies (open wedge HTO and closed wedge DFO) were included; of these, 24 patients (28 knees) were available in mean of 18 +/- 10 months for the follow-up examination. Indication was symptomatic varus malalignment and medial compartment osteoarthritis. Postoperatively, these patients were assigned to 20 kg partial weight-bearing using two crutches for 6 weeks followed by full weight-bearing. No braces or casts were used. Full weight-bearing long leg anteroposterior radiographs were obtained preoperatively, after 6 weeks and at the time of final follow-up. Mechanical tibiofemoral angle (mTFA), mechanical lateral distal femoral angle (mLDFA) and medial proximal tibia angle (MPTA) were measured. Clinical outcome was evaluated using Lequesne-, Lysholm-, Oxford-, and IKDC-score at the time of follow-up. RESULTS: The preoperative mTFA of - 11 +/- 3 degrees increased to 0 +/- 2 degrees at final follow-up. The difference between mTFA planning and final follow-up was - 2 +/- 3 degrees (p < 0.0006). At final follow up, MPTA and mLDFA were 89.2 +/- 2 degrees and 87 +/- 2 degrees , respectively. The Lysholm, Oxford, Lequesne, and IKDC scores were 88 +/- 13, 44 +/- 3, 2 +/- 2, and 77 +/- 12, respectively. CONCLUSIONS: This study showed that double level osteotomy for the patients with severe varus malalignment and medial compartment osteoarthritis normalises the alignment, joint-angles, avoids joint line obliquity, and leads to good clinical results, despite progressive osteoarthritis. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 30413944 TI - Social inequality in working life expectancy in Sweden. AB - BACKGROUND: In Sweden there is a socioeconomic divide between white and blue collar workers with respect to the risk for premature exit from working life. Disability pension has long represented a major reason behind early exits. OBJECTIVE: The present investigation aimed at studying the effect on socioeconomic groups of new guidelines issued by the Swedish government in 2006, limiting the possibilities for applicants to be granted pension on medical grounds. MATERIAL AND METHOD: The study was based on register data comprising the prevalence of disability pension and premature age pension in different occupations in the age group 55-64 years, comparing the years 2006 and 2011. RESULTS: It was found that in 2011 under the new guidelines, newly approved disability pensions had dropped by 70%. Women were affected more than men. The drop in disability pensions affected applicants within the two most prevalent diagnosis groups, mental disorders (a drop by 58%) and musculoskeletal disorders (a drop by 87%). In the same time period, the percentage in the age range 55-64 years choosing premature age pension more than doubled. An increase in the number of premature age pensions was more common in blue collar occupational groups than in white collar workers. Occupation had a higher impact on working life expectancy than country of birth. CONCLUSION: There are strong indications that many applicants, particularly blue collar workers, who had been unable to be granted disability pension under the new operational guidelines, instead choose premature retirement, a costly alternative for many individuals with already low pension benefits. The results indicate a tendency of passing on the societal costs of early labor market exits to various economic compensation arrangements, as well as to the individuals themselves. PMID- 30413945 TI - [Social inequality in reduced earning capacity among older employees : An analysis of routine data of the German statutory pension insurance]. AB - BACKGROUND: The efforts to extend working lives are accompanied by the question of whether it is possible for all employees to work longer for health reasons. Existing studies show for example that particularly workers in a lower socioeconomic position have a comparatively higher risk to prematurely retire. It is therefore likely that an increase of the state pension age puts particular pressure on such workers; however, studies on socioeconomic differences of disability retirement focusing on older workers in Germany are missing. OBJECTIVE: The aim of this study was to investigate whether social inequality exists for reduced earning capacity also for older workers. MATERIAL AND METHODS: The study relied on administrative data of the German pension insurance (DRV). Detailed information on the course of insurance was available for a random sample of all insured persons born in the years 1947 and 1961 (aged 59 and 45 years respectively at the beginning of the observational period; n = 160,688). Using Cox regressions (adjusted for working hours, national citizenship and location of workplace) associations between three socioeconomic features (education, occupation and income) and the risk of disability retirement in the observational period were investigated. The analysis was carried out separately for both cohorts (born 1947 and 1961) of younger and older employees and separately for men and women. RESULTS AND CONCLUSION: The results showed an increased risk of reduction in earning capacity even for older workers with a low socioeconomic position compared to those in a higher position. For men this is true for all three socioeconomic features investigated and both cohorts. For women the association was also observed with the exception of education and occupational position for those born in 1947. In the efforts to extend working lives, special attention should be paid to persons in lower socioeconomic positions in order to protect them from new disadvantages. PMID- 30413946 TI - The aminoglycoside geneticin permits translational readthrough of the CTNS W138X nonsense mutation in fibroblasts from patients with nephropathic cystinosis. AB - BACKGROUND: Cystinosis is an ultrarare disorder caused by mutations of the cystinosin (CTNS) gene, encoding a cystine-selective efflux channel in the lysosomes of all cells of the body. Oral therapy with cysteamine reduces intralysosomal cystine accumulation and slows organ deterioration but cannot reverse renal Fanconi syndrome nor prevent the eventual need for renal transplantation. A definitive therapeutic remains elusive. About 15% of cystinosis patients worldwide carry one or more nonsense mutations that halt translation of the CTNS protein. Aminoglycosides such as geneticin (G418) can bind to the mammalian ribosome, relax translational fidelity, and permit readthrough of premature termination codons to produce full-length protein. METHODS: To ascertain whether aminoglycosides permit readthrough of the most common CTNS nonsense mutation, W138X, we studied the effect of G418 on patient fibroblasts. RESULTS: G418 treatment induced translational readthrough of CTNSW138X constructs transfected into HEK293 cells and expression of full-length endogenous CTNS protein in homozygous W138X fibroblasts. CONCLUSIONS: Reduction in intracellular cystine indicates that the CTNS protein produced is functional as a cystine transporter. Interestingly, similar effects were seen even in W138X compound heterozygotes. These studies establish proof-of-principle for the potential of aminoglycosides to treat cystinosis and possibly other monogenic diseases caused by nonsense mutations. PMID- 30413947 TI - The effect of heparin hydrogel embedding on glutaraldehyde fixed bovine pericardial tissues: Mechanical behavior and anticalcification potential. AB - Heart valve diseases remain common in industrialized countries. Bioprosthetic heart valves, introduced as free of anticoagulation therapy alternatives to mechanical substitutes. Still they suffer from long term failure due to calcification. Different treatment methods introduced to inhibit calcification, have so far been limited in success. Glycosaminoglycans (GAGs) possess properties including high negative charge, anticoagulation and anti-inflammatory activity that make them a potential solution for calcification problem. In this study, heparin hydrogel was prepared and characterized both chemically and mechanically. After that, heparin hydrogel embedded bovine pericardial tissues, fixed with glutaraldehyde, were produced and tested for their mechanical behavior and anticalcifcation potential in vitro using the constant composition model. In the calcification experiments, tissues were divided into three groups: a) Controls without treatment, b) Hydrogel treated tissues and c) Tissues with raw heparin dissolved in the calcification solution. The results showed that embedding of tissue with hydrogel had no stiffening effect on its mechanical behavior. Calcification assessment showed a significant efficacy on inhibition of calcium phosphate deposition of hydrogel treated (second group) in comparison to untreated tissues (control, first group). Calcification inhibition potential was very similar in both the second and raw heparin (third group). Histological data confirmed the obtained results, suggesting that heparin treatment is a promising anticalcification agent. PMID- 30413948 TI - Analyzing the distinguishing factors that affect childhood obesity in South Korea. AB - Understanding obesity in children is crucial because it can lead to adulthood obesity and result in fatal chronic diseases. Distinctive factors associated with obesity in adults have been described, but distinctive factors related to children remain unclear. We analyzed the correlation between the percentage of body mass index and lifestyle habits by conducting surveys on physical, nutritional, and psychological factors, and we used annual physical examination data to compare different traits among elementary school students (n = 197) and middle school students (n = 461). Our study revealed that the computing hours in elementary school students with overweight and obesity were significantly correlated with the percentage of body mass index (r = 0.29 on school days and r = 0.35 on days off, all P < 0.05). No statistically significant difference was found (all P > 0.05) in the computing hours of middle school students with overweight and obesity. Childhood obesity can cause depression and reduce children's quality of life because of their distorted body perception. In conclusion, physical factors directly affecting childhood obesity and psychological and environmental factors surrounding a child should be considered. PMID- 30413949 TI - Interplay between diet and genetic susceptibility in obesity and related traits. AB - The incidence of obesity has been rapidly increasing, and this condition has become a major public health threat. A substantial shift in environmental factors and lifestyle, such as unhealthy diet, is among the major driving forces of the global obesity pandemic. Longitudinal studies and randomized intervention trials have shown that genetic susceptibility to obesity may interact with dietary factors in relation to the body mass index and risk of obesity. This review summarized data from recent longitudinal studies and intervention studies on variations and diets and discussed the challenges and future prospects related to this area and public health implications. PMID- 30413950 TI - Microstructural volumetric analysis of lateral ridge augmentation using differently conditioned tooth roots. AB - OBJECTIVES: Previous research revealed that autogenous tooth roots may be biologically equivalent to conventional bone grafts for lateral ridge augmentation. However, these analyses were limited to two dimensions, whereas healing is a volumetric process. The present study aimed at volumetrically assessing the microstructure following lateral ridge augmentation using extracted tooth roots. MATERIAL AND METHODS: The roots of differently conditioned maxillary premolars (i.e., healthy: PM-C; endodontically treated: PM-E; ligature-induced periodontitis: PM-P) and retromolar cortical autogenous bone (AB) blocks were used for lateral ridge augmentation at chronic-type defects in the lower quadrants of n = 16 foxhounds. At 12 weeks, titanium implants were inserted and left to heal for another 3 weeks. Tissue biopsies were scanned using microcomputed tomography (MUCT), and volumes of interest were separated at the buccal and oral aspects to measure bone volume per tissue volume (BV/TV), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp), and connectivity density (Conn.D). RESULTS: All groups investigated revealed comparable BV/TV, Tb.Th, Tb.Sp, and Conn.D values at either the augmented buccal or pristine oral aspects, respectively. A gradual but heterogeneous replacement of grafts was observed in all groups, but residual PM fragments were particularly noted in PM-C and PM-P groups. CONCLUSIONS: Differently conditioned PM and AB grafts were associated with a comparable bone microstructure within the grafted area. The duration of replacement resorption may vary considerably among the subjects. CLINICAL RELEVANCE: Autogenous tooth roots may serve as potential alternative to AB for localized alveolar ridge augmentation. PMID- 30413951 TI - Standardized assessment of the signal intensity increase on unenhanced T1 weighted images in the brain: the European Gadolinium Retention Evaluation Consortium (GREC) Task Force position statement. AB - After the initial report in 2014 on T1-weighted (T1w) hyperintensity of deep brain nuclei following serial injections of linear gadolinium-based contrast agents (GBCAs), a multitude of studies on the potential of the marketed GBCAs to cause T1w hyperintensity in the brain have been published. The vast majority of these studies found a signal intensity (SI) increase for linear GBCAs in the brain-first and foremost in the dentate nucleus-while no SI increase was found for macrocyclic GBCAs. However, the scientific debate about this finding is kept alive by the fact that SI differences do not unequivocally represent the amount of gadolinium retained. Since the study design of the SI measurement in various brain structures is relatively simple, MRI studies investigating gadolinium dependent T1w hyperintensity are currently conducted at multiple institutions worldwide. However, methodological mistakes may result in flawed conclusions. In this position statement, we assess the methodological basis of the published retrospective studies and define quality standards for future studies to give guidance to the scientific community and to help identify studies with potentially flawed methodology and misleading results. KEY POINTS: * A multitude of studies has been published on the potential of the marketed GBCAs to cause T1w hyperintensity in the brain. * The gadolinium-dependent T1w hyperintensity in the brain depends on patient's history, types of GBCAs used (i.e., linear vs. macrocyclic GBCAs) and MR imaging setup and protocols. * Quality standards for the design of future studies are needed to standardize methodology and avoid potentially misleading results from retrospective studies. PMID- 30413952 TI - Use of artificial neural networks to predict anterior communicating artery aneurysm rupture: possible methodological considerations. AB - KEY POINTS: Use of algorithms to generate synthetic cases might result in a misrepresentation of the entire population. Training an artificial neural network with a mix of real and synthetic data might lead to non-realistic prediction precision. PMID- 30413953 TI - Assessment of renal function before contrast media injection: right decisions based on inaccurate estimates. AB - OBJECTIVES: Information on renal function required before specified radiological examinations with contrast agents is usually obtained through prediction equations using serum creatinine and anthropometric data. The aim of our study was to demonstrate discrepancy between poor prediction and good diagnostic accuracy of glomerular filtration rate (GFR) estimated by prediction equations. METHODS: In 50 patients, reference GFR was measured as plasma clearance of 51 chromium labeled ethylene-diamine-tetraacetic-acid (51Cr-EDTA) and compared with GFR assayed by creatinine clearance (CC) and estimated by Cockcroft-Gault prediction equation (CG). For comparisons, CC and CG were considered as continuous, categorical, and binary variables. Accuracy of the reference GFR prediction was expressed in terms of prediction errors and diagnostic accuracy indices. RESULTS: As continuous variable, CG estimated individual values of GFR with large prediction error exceeding that of CC. As categorical variable, it classified the patient stage of chronic kidney disease (CKD) with medium diagnostic accuracy of 74% (CKD 3) and 62% (CKD 4). As binary variable, CG classified individual patient's GFR below 30 and 60 ml/min/1.73 m2 with good diagnostic accuracy of 80 and 94%, respectively. Performance of other prediction equations did not significantly differ from CG. CONCLUSIONS: Despite large variance and poor prediction accuracy of individual GFR estimates, most of them correctly classified individual patient's GFR below specified level. Results of prediction equations thus should be used and reported exclusively as binary variables, while numerical values of GFR, if required, should be measured by more accurate radionuclide or laboratory methods. KEY POINTS: * Radiological guidelines on contrast media require estimation of glomerular filtration rate to assess kidney function before specified contrast examinations. * Estimated glomerular filtration rate is obtained through prediction equations using serum creatinine and anthropometric data as predictors. * While numerical estimates of glomerular filtration rate are inaccurate (their prediction accuracy is poor), diagnostic accuracy of binary estimates (ability to classify patient's glomerular filtration rate below or above a specified level) is very good. PMID- 30413954 TI - Reply to "letter to the editor: use of artificial neural networks to predict anterior communicating artery aneurysm rupture: possible methodological issues". PMID- 30413955 TI - MRI radiomics analysis for predicting preoperative synchronous distant metastasis in patients with rectal cancer. AB - OBJECTIVES: To investigate the value of MRI radiomics based on T2-weighted (T2W) images in predicting preoperative synchronous distant metastasis (SDM) in patients with rectal cancer. METHODS: This retrospective study enrolled 177 patients with histopathology-confirmed rectal adenocarcinoma (123 patients in the training cohort and 54 in the validation cohort). A total of 385 radiomics features were extracted from pretreatment T2W images. Five steps, including univariate statistical tests and a random forest algorithm, were performed to select the best preforming features for predicting SDM. Multivariate logistic regression analysis was conducted to build the clinical and clinical-radiomics combined models in the training cohort. The predictive performance was validated by receiver operating characteristics curve (ROC) analysis and clinical utility implementing a nomogram and decision curve analysis. RESULTS: Fifty-nine patients (33.3%) were confirmed to have SDM. Six radiomics features and four clinical characteristics were selected for predicting SDM. The clinical-radiomics combined model performed better than the clinical model in both the training and validation datasets. A threshold of 0.44 yielded an area under the ROC (AUC) value of 0.827 (95% confidence interval (CI), 0.6963-0.9580), a sensitivity of 72.2%, a specificity of 94.4%, and an accuracy of 87.0% in the validation cohort for the combined model. A clinical-radiomics nomogram and decision curve analysis confirmed the clinical utility of the combined model. CONCLUSIONS: Our proposed clinical-radiomics combined model could be utilized as a noninvasive biomarker for identifying patients at high risk of SDM, which could aid in tailoring treatment strategies. KEY POINTS: * T2WI-based radiomics analysis helps predict synchronous distant metastasis (SDM) of rectal cancer. * The clinical-radiomics combined model could be utilized as a noninvasive biomarker for predicting SDM. * Personalized treatment can be carried out with greater confidence based on the risk stratification for SDM in rectal cancer. PMID- 30413956 TI - Image quality and diagnostic accuracy of coronary CT angiography derived from low dose dynamic CT myocardial perfusion: a feasibility study with comparison to invasive coronary angiography. AB - OBJECTIVES: To investigate the diagnostic performance of coronary CT angiography derived from dynamic CT myocardial perfusion imaging (CCTACT-MPI) by third generation dual-source CT with reference to invasive coronary angiography (ICA). MATERIALS AND METHODS: Patients with acute myocardial infarction and those who received successful reperfusion treatment were prospectively enrolled. Emergent ICA findings were used as the reference standard to assess the diagnostic performance of CCTACT-MPI for detection of significant coronary stenosis (diameter stenosis >= 50%). The radiation dose as well as image quality of CCTACT MPI was also assessed. RESULTS: Twenty-six patients with 352 segments were ultimately included for analysis. The mean radiation dose of CCTACT-MPI generated from dynamic CT-MPI was 3.2 +/- 1.1 mSv. Overall, 93.5% of total segments were interpretable (Likert score 2-4) whereas 6.5% segments were non-diagnostic (Likert score 1). Twenty-two patients with 84 segments were diagnosed by CCTACT MPI as having >= 50% stenosis presence, whereas 268 segments had no obstructive stenosis. Compared to ICA findings, the overall diagnostic accuracy of CCTACT-MPI of patient-based and vessel-based as well segment-based analysis was 92.3%, 83.6%, and 85.8% respectively. As shown by ROC analysis, the AUC of CCTACT-MPI for detection of >= 50% stenosis was 0.833 on a per-patient level, 0.843 on a per vessel level, and 0.822 on a per-segment level. CONCLUSIONS: CCTACT-MPI derived from dynamic CT-MPI was able to accurately diagnose obstructive coronary stenosis with reference to ICA. KEY POINTS: * CCTA derived from dynamic CT-MPI had a diagnostic image quality in 93.5% of total segments. * CCTA derived from dynamic CT-MPI was accurate in diagnosing obstructive CAD compared to ICA. * The mean radiation dose of dynamic CT-MPI for reconstruction of CCTA was 3.2 mSv. PMID- 30413957 TI - Whole-body MRI to assess bone involvement in prostate cancer and multiple myeloma: comparison of the diagnostic accuracies of the T1, short tau inversion recovery (STIR), and high b-values diffusion-weighted imaging (DWI) sequences. AB - PURPOSE: To compare the diagnostic accuracy of whole-body T1, short tau inversion recovery (STIR), high b-value diffusion-weighted imaging (DWI), and sequence combinations to detect bone involvement in prostate cancer (PCa) and multiple myeloma (MM) patients. MATERIALS AND METHODS: We included 50 consecutive patients with PCa at high risk for metastasis and 47 consecutive patients with a histologically confirmed diagnosis of MM who received whole-body MRI at two institutions from January to December 2015. Coronal T1, STIR, and reconstructed coronal high b-values DWI were obtained for all patients. Two musculoskeletal radiologists read individual sequences, pairs of sequences (T1-DWI, T1-STIR, and STIR-DWI), and all combined (T1-STIR-DWI) to detect bone involvement. Receiver operating characteristic curve analysis was used to assess diagnostic performance according to a "best valuable comparator" combining baseline and 6-month imaging and clinical and biological data. Interobserver agreement was calculated. RESULTS: Interobserver agreement for individual and combined MRI sequences was very good in the PCa group and ranged from good to very good in the MM group (0.76-1.00). In PCa patients, T1-DWI, T1-STIR, and T1-STIR-DWI showed the highest performance (sensitivity = 100% [95% CI = 90.5-100%], specificity = 100% [75.3 100%]). In MM patients, the highest performance was achieved by T1-STIR-DWI (sensitivity = 100% [88.4-100%], specificity = 94.1% [71.3-100%]). T1-STIR-DWI significantly outperformed all sequences (p < 0.05) except T1-DWI (p = 0.49). CONCLUSION: In PCa patients, a combination of either T1-DWI or T1-STIR sequences is not inferior to a combination of three sequences to detect bone metastases. In MM, T1-STIR-DWI and T1-DWI had the highest diagnostic performance for detecting bone involvement. KEY POINTS: * The sequences used in Whole Body MRI studies to detect bone involvement in prostate cancer and myeloma were evaluated. * In prostate cancer, any pairwise combinations of T1, STIR, and DWI have high diagnostic value. * In myeloma, the combinations T1-STIR-DWI or T1-DWI sequences should be used. PMID- 30413958 TI - Soft tissue sarcoma: adding diffusion-weighted imaging improves MR imaging evaluation of tumor margin infiltration. AB - PURPOSE: To determine the added value of diffusion-weighted imaging (DWI) to conventional magnetic resonance (MR) imaging in assessment of tumor margin infiltration in soft tissue sarcoma (STS) at 3T. MATERIALS AND METHODS: The institutional review board approved this retrospective study. Forty-five patients who underwent 3T MR imaging including DWI and were pathologically confirmed were included in this study. Two readers retrospectively scored conventional MR imaging alone. Then, they assessed a combination of conventional MR imaging and DWI. At pathology, margin infiltration was retrospectively reviewed by one pathologist blinded to MR findings. Areas under the curve (AUCs) of the receiver operating characteristic curve were obtained for diagnostic performance. Interobserver agreement for the scoring of margin infiltration of STS was assessed with kappa statistics. RESULTS: Among 45 cases of STS, 33 had infiltrative tumor margin at pathology. Sensitivity, specificity, and accuracy of each reader were 100%, 17%, and 78%; 97%, 25%, and 78% on conventional MR imaging alone and 94%, 67%, and 87%; 94%, 42%, and 80% on conventional MR imaging combined with DWI. AUCs of conventional MR imaging combined with DWI were significantly higher than those of conventional MR imaging alone: 0.890 vs 0.678 (p = .0123) and 0.846 vs 0.640 (p = .0305) for each reader. Interobserver agreements of conventional MR imaging alone and conventional MR imaging combined with DWI were moderate to substantial (kappa = 0.646, kappa = 0.496). CONCLUSION: The addition of DWI to conventional MR imaging may improve specificity for assessing tumor margin infiltration in STS at 3T. KEY POINTS: * DWI has added value for assessment of tumor margin infiltration in soft tissue sarcoma. * Addition of DWI to conventional MRI at 3T may improve specificity. * Addition of DWI to conventional MRI may help orthopedic surgeon determine the extent of the resection margin. PMID- 30413959 TI - Preoperative radiomic signature based on multiparametric magnetic resonance imaging for noninvasive evaluation of biological characteristics in rectal cancer. AB - OBJECTIVES: To develop and validate radiomic models in evaluating biological characteristics of rectal cancer based on multiparametric magnetic resonance imaging (MP-MRI). METHODS: This study consisted of 345 patients with rectal cancer who underwent MP-MRI. We focused on evaluating five postoperative confirmed characteristics: lymph node (LN) metastasis, tumor differentiation, fraction of Ki-67-positive tumor cells, human epidermal growth factor receptor 2 (HER-2), and KRAS-2 gene mutation status. Data from 197 patients were used to develop the biological characteristics evaluation models. Radiomic features were extracted from MP-MRI and then refined for reproducibility and redundancy. The refined features were investigated for usefulness in building radiomic signatures by using two feature-ranking methods (MRMR and WLCX) and three classifiers (RF, SVM, and LASSO). Multivariable logistic regression was used to build an integrated evaluation model combining radiomic signatures and clinical characteristics. The performance was evaluated using an independent validation dataset comprising 148 patients. RESULTS: The MRMR and LASSO regression produced the best-performing radiomic signatures for evaluating HER-2, LN metastasis, tumor differentiation, and KRAS-2 gene status, with AUC values of 0.696 (95% CI, 0.610-0.782), 0.677 (95% CI, 0.591-0.763), 0.720 (95% CI, 0.621-0.819), and 0.651 (95% CI, 0.539-0.763), respectively. The best-performing signatures for evaluating Ki-67 produced an AUC value of 0.699 (95% CI, 0.611-0.786), and it was developed by WLCX and RF algorithm. The integrated evaluation model incorporating radiomic signature and MRI-reported LN status had improved AUC of 0.697 (95% CI, 0.612-0.781). CONCLUSION: Radiomic signatures based on MP-MRI have potential to noninvasively evaluate the biological characteristics of rectal cancer. KEY POINTS: * Radiomic features were extracted from MP-MRI images of the rectal tumor. * The proposed radiomic signatures demonstrated discrimination ability in identifying the histopathological, immunohistochemical, and genetic characteristics of rectal cancer. * All MRI sequences were important and could provide complementary information in radiomic analysis. PMID- 30413961 TI - Obituary for professor Ian Isherwood. PMID- 30413960 TI - Detection of intralabyrinthine abnormalities using post-contrast delayed 3D-FLAIR MRI sequences in patients with acute vestibular syndrome. AB - PURPOSE: 3D-FLAIR sequences with delayed acquisition after contrast medium injection have demonstrated new insights into blood-labyrinthine barrier (BLB) abnormalities in various diseases. The aim of this study was to assess the BLB in patients referred with unilateral acute vestibular syndrome (UAVS). MATERIALS AND METHODS: In this retrospective multicenter imaging study, we performed 3D-FLAIR and steady-state free precession (SSFP) sequences 4 h after contrast medium administration in 26 healthy volunteers and in 30 patients with UAVS. Two radiologists, blinded to the clinical data, independently assessed the asymmetrical enhancement of the labyrinthine structures and the vestibular nerve on 3D-FLAIR sequences, and the signal of the labyrinthine structures on SSFP sequences. Inter-reader agreement tests were performed. RESULTS: An asymmetrical enhancement of the semicircular canals was observed in 26 out of 30 ears (86.6%, p < 0.001) and never observed in healthy subjects. An asymmetrical enhancement of the vestibular nerve was never observed in either patients or healthy subjects. An asymmetrical enhancement of the cochlea was observed on the 3D-FLAIR sequence in 6 out of 30 ears only in the patients' group (20%, p = 0.03) and always associated with an enhancement of at least one semicircular canal. A low signal on SSFP sequences was observed only in 11 out of 30 symptomatic ears (36.7%, p < 0.001), involving the utricle in 7 ears and the superior semicircular canal in 4 ears. CONCLUSION: Patients with typical UAVS presented with semicircular canal enhancement on MRI, while an asymmetrical enhancement of the vestibular nerve was not displayed. TRIAL REGISTRATION: NCT02529475 KEY POINTS: * Patients with typical vestibular neuronitis presented with semicircular canal enhancement on MRI in 87% of cases. * An enhancement of the vestibular nerve was never displayed. PMID- 30413962 TI - Psoas proximal insertion as a simple and reliable landmark for numbering lumbar vertebrae on MRI of the lumbar spine. AB - OBJECTIVE: To evaluate the value of psoas muscle proximal insertion for correct numbering of the lumbar vertebrae in MRI, in particular in case of lumbosacral transitional vertebra (LSTV). METHODS: Two radiologists assessed 477 MRI scans of the lumbar spine with a sagittal localizer sequence on the whole spine for numbering vertebrae caudally from C2. Proximal insertion of the psoas was determined as the most proximal vertebra with psoas over half of its body on coronal T2 STIR sequence. The last lumbar vertebra was named considering both its number and the presence or absence of LSTV according to Castellvi classification. These same parameters were also assessed on 207 PET-CT scans of another cohort including the whole spine. RESULTS: Proximal insertion of the psoas was L1 in 94.1% of cases: 98.5% in case of modal anatomy, 81.4% in case of LSTV, and 51.7% in case of missing or supernumerary lumbar vertebra without LSTV. There was no statistically significant difference between MRI and CT data. The inter-reader agreement for determination of psoas proximal insertion was excellent (kappa = 0.96). CONCLUSION: Proximal insertion of the psoas muscle is a helpful marker for correct numbering of the lumbar vertebrae in MRI and to detect a complete lumbosacral segmentation anomaly. KEY POINTS: * Proximal insertion of the psoas muscle can be easily identified on a coronal T2 STIR sequence. * Psoas proximal insertion on the spine almost always designates the first lumbar vertebra and is helpful to accurately number all lumbar vertebrae, especially in case of lumbosacral transitional vertebra. * Conversely, when psoas muscle does not insert five lumbar bodies above the apparent lumbosacral joint, the probability of variation in the number of lumbar vertebrae is high. PMID- 30413963 TI - Cavographic vs. cross-sectional measurement of the inferior vena cava diameter before filter placement: are we routinely oversizing? AB - OBJECTIVE: A megacava (vena cava with a diameter of 28 mm or greater) requires a particular filter to avoid migration. However, caval morphologies are variable. As the inferior vena cava (IVC) usually adopts a circular geometry after a filter is inserted, this study aims (a) to classify caval geometry and orientation; (b) to compare discrepancy between anterioposterior projective diameter (PD) and circumference-based calculated diameter (CD) measurements on cross-sectional computed tomography (CT) images; (c) if a discrepancy exists, determine how often it can affect IVC filter selection. METHODS: A total of 1503 patients were retrospectively reviewed. Caval morphology was classified. PD and CD were measured at infrarenal IVC. Differences between the PD and CD were assessed by the Wilcoxon signed-rank test or paired t test (if appropriate). The scatterplot of PD vs. CD was used to show whether one is consistently larger than the other. RESULTS: The PD was significantly larger than the CD (22.3 +/- 3.5 vs. 20.4 +/- 2.8, p < 0.001). The caval morphologies were divided into five types. Type 1 was oval IVC oriented left-anterior-oblique to the horizontal line with an angle (n = 999, 66.5%), type 2 was round IVC (n = 49, 3.3%), type 3 was oval IVC with a vertical long axis (n = 8, 0.5%), type 4 was oval IVC with a horizontal long axis (n = 75, 5.0%), and type 5 was irregularly shaped IVC (n = 372, 24.7%). CONCLUSION: Patients with round IVC are rare. Measurement of CD may be better to assess maximum IVC diameter compared with PD for the purpose of IVC filter placement. KEY POINTS: * Five types of IVC orientation are described in this paper: type 1 (n = 999, 66.5%), type 2 (n = 49, 3.3%), type 3 (n = 8, 0.5%), type 4 (n = 75, 5.0%), and type 5 (n = 372, 24.7%). * The incidence of megacava (vena cava with a diameter of 28 mm or greater) measured on anterioposterior projective imaging may be overestimated. * As an IVC will adopt a circular geometry following filter placement, circumference-based calculated diameter may be an appropriate approach for caval size determination. PMID- 30413964 TI - The efficacy of fluoroscopy-guided epidural blood patch in the treatment of spontaneous and iatrogenic cerebrospinal fluid leakage. AB - OBJECTIVE: To evaluate patient outcomes following fluoroscopy-guided epidural blood patch (FGEBP), factors affecting the outcome, and to identify the rate of fluoroscopy-guided lumbar punctures (FGLP) requiring FGEBP. METHODS: All FGLPs and FGEBPs between January 2014 and May 2017 were retrospectively evaluated. Information regarding patient characteristics, details of previous dural puncture (DP), details of the FGEBP, and FGEBP outcome were recorded. The outcome was classified into three categories as "complete response", "partial response", and "no response". Patients with "complete response" were compared to the combined group of "no response" and "partial response", classified as "incomplete response". Two-sample/Fisher's exact (continued/categorical variables) tests were used (p < 0.05). RESULTS: Sity-seven FGEBPs were performed in 63 patients (female/male, 36/27; mean age/BMI 38/28.2). Fifty-nine were referred following DP; 31 were performed by radiologists. The rate of FGLPs requiring FGEBP was 1.78% within 3.5 years. The mean DP-FGEBP interval was 4.8 days. "Complete response" was achieved in 56 (84.8%), "no response" was found following 4 (6%) procedures. Average applied blood volume was 16 cc (5-30 cc). No difference was found between "complete response" and "incomplete response" groups regarding age, sex, BMI, DP performer, DP level, DP fluoroscopy time, DP needle caliber/type, FGEBP level, FGEBP needle caliber/type, FGEBP fluoroscopy time, FGEBP performer, and applied blood volume (p > 0.05). Despite approaching significance, no statistically significant difference was found regarding the presence of previous DP (p = 0.06). CONCLUSIONS: The efficacy of FGEBP is high in a group of patients referred to radiology for treatment of CSF leakage with complete response in 84.8% of patients. KEY POINTS: * Fluoroscopy-guided epidural blood patch completely resolved symptoms in 85% of post-dural puncture headaches. * The success approaches 95% when including the patients with partial resolution of symptoms. * Epidural blood patch rate is found 1.8% following 1703 fluoroscopy guided lumbar punctures. PMID- 30413965 TI - Non-measurable infiltrative HCC: is post-contrast attenuation on CT a sign of tumor response? AB - OBJECTIVES: To evaluate the value of CT attenuation to assess the response to sorafenib in infiltrative/endovascular non-measurable advanced hepatocellular carcinoma (HCC). METHODS: From 2007 to 2014, patients with infiltrative HCC +/- tumor-in-vein (TIV) were retrospectively included. Attenuation of tumors and TIV were measured at baseline and follow-up on arterial and portal venous phase CT by two independent radiologists. Attenuation changes (overall and as per Choi criteria) and Child-Pugh score were correlated to overall survival. RESULTS: Forty patients were included (38 men, 95%). Attenuation of both the tumors and TIV was significantly lower in follow-up CT than on baseline CT (p = 0.002 (arterial), and p = 0.001 (portal) for tumor, and p = 0.004 (arterial) and p < 0.001 (porta) for TIV). Median attenuation of TIV was significantly lower than that of the tumor in follow-up images (p = 0.010). Median OS for the entire cohort was 4 +/- 1 months (95% CI: 2.1-5.9), with estimated OS rates at 6, 12, and 24 months of 43%, 29 and 12%, respectively. Baseline and follow-up CT attenuation in tumors and TVI were not correlated with survival. Survival was not significantly increased in patients with Choi criteria >15% CT HU decrease in the tumor and/or TIV during follow-up. Only Child-Pugh A (HR 4.9 (95%CI 2.3-10.7), p < 0.001) was identified as an independent factor of improved survival on multivariate analysis. CONCLUSION: Despite significant changes under sorafenib, tumor attenuation of infiltrative/endovascular non-measurable HCC may be of limited value to assess survival in this subgroup of patients with very poor prognosis. KEY POINTS: * Attenuation of both tumors and tumor-in-vein decreases after sorafenib. * Attenuation decrease is more marked in the tumor-in-vein than in the tumor. * Attenuation decrease is not associated with longer overall survival. PMID- 30413967 TI - A multi-year study following BACI design reveals no short-term impact of Bti on chironomids (Diptera) in a floodplain in Eastern Austria. AB - Short-term impacts of aerial application of Bacillus thuringiensis israelensis (Bti) on Culicidae and Chironomidae were investigated over several years in temporary waters of the Dyje and Morava floodplains in Eastern Austria. The sampling followed a Before-After-Control-Impact (BACI) approach with sampling dates immediately before and shortly after the application and was repeated for 3 years. To test for effects of the Bti treatment on the two Diptera families, linear mixed-effects models were used. Data analysis included the factors Before After and Control-Impact as fixed effects, while general temporal and spatial variables were random effects. One hundred sixteen taxa of chironomids were identified. Abundance varied between 2 and 1125 larvae per m2, while culicid densities reached values of several 100 ind. per liter. Total culicid abundance significantly decreased after the Bti treatment, whereas no significant effects were found on the abundance of total chironomids and dominant chironomid subfamilies, tribes, and genera, on relative proportions of chironomid feeding guilds, diversity, and species composition. Further studies from this area are needed to extend the investigation over a period of several weeks in order to reveal possible delayed effects of the larvicide application. PMID- 30413966 TI - Radiomics model of contrast-enhanced computed tomography for predicting the recurrence of acute pancreatitis. AB - OBJECTIVES: To predict the recurrence of acute pancreatitis (AP) by constructing a radiomics model of contrast-enhanced computed tomography (CECT) at AP first attack. METHODS: We retrospectively enrolled 389 first-attack AP patients (271 in the primary cohort and 118 in the validation cohort) from three tertiary referral centers; 126 and 55 patients endured recurrent attacks in each cohort. Four hundred twelve radiomics features were extracted from arterial and venous phase CECT images, and clinical characteristics were gathered to develop a clinical model. An optimal radiomics signature was chosen using a multivariable logistic regression or support vector machine. The radiomics model was developed and validated by incorporating the optimal radiomics signature and clinical characteristics. The performance of the radiomics model was assessed based on its calibration and classification metrics. RESULTS: The optimal radiomics signature was developed based on a multivariable logistic regression with 10 radiomics features. The classification accuracy of the radiomics model well predicted the recurrence of AP for both the primary and validation cohorts (87.1% and 89.0%, respectively). The area under the receiver operating characteristic curve (AUC) of the radiomics model was significantly better than that of the clinical model for both the primary (0.941 vs. 0.712, p = 0.000) and validation (0.929 vs. 0.671, p = 0.000) cohorts. Good calibration was observed for all the models (p > 0.05). CONCLUSIONS: The radiomics model based on CECT performed well in predicting AP recurrence. As a quantitative method, radiomics exhibits promising performance in terms of alerting recurrent patients to potential precautions. KEY POINTS: * The incidence of recurrence after an initial episode of acute pancreatitis is high, and quantitative methods for predicting recurrence are lacking. * The radiomics model based on contrast-enhanced computed tomography performed well in predicting the recurrence of acute pancreatitis. * As a quantitative method, radiomics exhibits promising performance in terms of alerting recurrent patients to the potential need to take precautions. PMID- 30413969 TI - Shwachman-Diamond Syndrome: Molecular Mechanisms and Current Perspectives. AB - Shwachman-Diamond syndrome (SDS) is a rare inherited disease mainly caused by mutations in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene. However, it has recently been reported that other genes, including DnaJ heat shock protein family (Hsp40) member C21 (DNAJC21), elongation factor-like 1 (EFL1) and signal recognition particle 54 (SRP54) are also associated with an SDS-like phenotype. Interestingly, SBDS, DNAJC21, EFL1 and SRP54 are involved in ribosome biogenesis: SBDS, through direct interaction with EFL1, promotes the release of the eukaryotic initiation factor 6 (eIF6) during ribosome maturation, DNAJC21 stabilizes the 80S ribosome, and SRP54 facilitates protein trafficking. These findings strengthen the postulate that SDS is a ribosomopathy. SDS is a multiple organ disease mainly characterized by bone marrow failure, bone malformations, pancreatic insufficiency and cognitive disorders. Almost 15-20% of patients with SDS present myelodysplastic syndrome with a high risk of acute myeloid leukemia (AML) transformation. Unfortunately, besides bone marrow transplantation, no gene based therapy for SDS has yet been developed. This review aims to recapitulate the recent findings on the molecular mechanisms of SDS underlying bone marrow failure, hematopoiesis and AML development and to draw a realistic picture of current perspectives. PMID- 30413970 TI - Clinical Practice Update 2018 Symposium of the Belgian Neurological Society 09th of June 2018. PMID- 30413968 TI - Molecular Imaging for Evaluation of Viable Testicular Cancer Nodal Metastases. AB - PURPOSE OF REVIEW: Determining the metastatic viability of suspicious retroperitoneal nodes in testicular cancer with conventional imaging is challenging. The aim of this report is to review recent evidence in the utilization of novel imaging modalities to assess viable testicular cancer nodal metastases. RECENT EVIDENCE: Testicular germ cell tumors (TCGTs) follow a predictable lymphatic metastatic spread to the retroperitoneum. Accordingly, retroperitoneal imaging is critical in staging, assessing treatment response, and evaluating for recurrence. Conventional computed tomography (CT) imaging is effective in diagnosing pathologically enlarged lymph nodes but lacks the molecular information to determine if suspicious nodes harbor viable tumor. Positron emission tomography (PET) with the metabolic radiotracer 2-deoxy-2 [18F]fluoro-D-glucose (18F-FDG or FDG) has been shown to be useful in determining the presence of or absence of viable tumor after chemotherapy for seminoma, but its role with non-seminomatous germ cell tumors (NSGCTs) and other clinical scenarios is limited. Patients with residual masses after chemotherapy for NSGCT present a difficult challenge because surgical resection carries a high degree of morbidity despite many patients only harboring fibrosis on final pathology. Current imaging modalities are unable to effectively differentiate fibrosis from viable tumor on preoperative imaging. Novel molecular imaging techniques present promising opportunities to improve diagnosis in these patients. Novel imaging platforms have potential to improve the ability to determine viable nodal metastases regardless of size and structure but confirmatory studies are currently lacking. PMID- 30413971 TI - Mental health in Parkinson's disease after receiving aquatic therapy: a clinical trial. AB - Depression is a major determinant of quality of life in individuals with Parkinson's disease. The aim of this study was to evaluate the effects of a program of Ai Chi aquatic therapy on pain, depression and quality of life in people with Parkinson's disease. Participants were randomized to receive dry land physiotherapy treatment (control group) or aquatic Ai Chi sessions in the pool (experimental group). The outcome measures used included the VAS pain scale, the Geriatric Depression Scale and the SF-36 quality of life scale. In the experimental group treated with aquatic therapy, significant differences were found in the pain, depression and quality of life variables post-treatment (p < 0.001). In the control group, improvements were only observed in the VAS pain scale, and these were less significant than the changes found in the experimental group (p = 0.006). The significant changes registered in the experimental group at the post-treatment assessment were maintained 1 month after completing the experimental intervention program. In conclusion, these findings indicate that physical exercise performed in water has positive effects on some of the factors that influence mood and quality of life in people with Parkinson's disease. PMID- 30413972 TI - Dental and medical practitioners' perception of community water fluoridation as a caries preventive measure. AB - AIM: To evaluate and compare the perceptions and concerns of dental and medical practitioners towards water fluoridation as a caries preventive measure. METHODS: A self-administered questionnaire comprising 21 questions was designed and validated to assess general knowledge and concerns of fluoride and community water fluoridation (CWF) as a dental caries preventive measure. The questions examined participant's perception regarding effectiveness, advantages, adverse effects, cost-benefit, and concerns pertinent to CWF. Dentists, general physicians and paediatricians were randomly recruited from public medical/dental centres, university clinics, and the private sector to complete the questionnaire. RESULTS: A total of 474 participants (74% response rate) completed the questionnaire (294 dentists and 180 medical practitioners). About 86% of the dentists and 78% of the medical practitioners agreed that CWF has a role in caries prevention. However, only a few of those would advise their patients to drink fluoridated water. There were some concerns about CWF, and the main concern in both groups was dental fluorosis. The level of awareness regarding CWF status in Kuwait amongst the two groups was low. However, the majority in both groups (77%) believed that the water supply should be optimally fluoridated. CONCLUSION: Dental and medical health care professionals agreed that water fluoridation can benefit the oral health of the individuals in the community, however, general knowledge about fluoride benefits, safety, risks and status of public water fluoridation was low. PMID- 30413975 TI - Graphene-Based Nanomaterials Toxicity in Fish. AB - Due to their unique physicochemical properties, graphene-based nanoparticles (GPNs) constitute one of the most promising types of nanomaterials used in biomedical research. GPNs have been used as polymeric conduits for nerve regeneration and carriers for targeted drug delivery and in the treatment of cancer via photothermal therapy. Moreover, they have been used as tracers to study the distribution of bioactive compounds used in healthcare. Due to their extensive use, GPN released into s environment would probably pose a threat to living organisms and ultimately to human health. Their accumulation in the aquatic environment creates problems to aquatic habitats as well as to food chains. Until now the potential toxic effects of GPN are not properly understood. Despite agglomeration and long persistence in the environment, GPNs are able to cross the cellular barriers successfully, entered into the cells, and are able to interact with almost all the cellular sites including the plasma membrane, cytoplasmic organelles, and nucleus. Their interaction with DNA creates more potential threats to both the genome and epigenome. In this brief review, we focused on fish, mainly zebrafish (Danio rerio), as a potential target animal of GPN toxicity in the aquatic ecosystem. PMID- 30413976 TI - Mercury (Hg), Lead (Pb), Cadmium (Cd), Selenium (Se), and Arsenic (As) in Liver, Kidney, and Feathers of Gulls: A Review. AB - Mercury (Hg), lead (Pb), cadmium (Cd), selenium (Se), and arsenic (As) are metals or metalloids of high concern because of their effects on the environment and, specially, their potential toxicity on the animals inhabiting there. Due to their relevance, these elements have been object of several biomonitoring studies in different animal species around the world. Birds are widespread and, as species, are able to supply specific and relevant information about the regions where they live, being useful as bioindicators, as long as they are not birds with a strong migratory character. The main goal of this review is to summarize data collected from different studies using seabirds, paying special attention to gulls, in order to be helpful for coming studies and regulatory affairs.Several tissues have been used to evaluate Hg, Cd, Pb, Se, and As concentrations in seabirds, being focused the present review in those analyzing the liver, kidneys, and feathers. The most frequently analyzed tissue for Hg was the liver, followed by feathers, and finally kidney. For Cd levels, most of the studies were carried out in the liver, followed by feathers and kidneys. Pb, Se, and As levels were determined to a lesser extent. Feathers should be taken carefully as indicator of accumulation of pollutants, since procedure during analysis may lead to controversial results.Some authors reported that interspecific differences in the exposure of elements are determined by multiple factors, including properties of the contaminant, species, feeding habits, migratory status, sex, and age.The present review provides a comprehensive overview of the analyzed elements' occurrence in different species of seabirds, including gulls. Therefore, it can be a useful database providing for Hg, Pb, Cd, Se, and As levels in different tissues of seabirds. PMID- 30413974 TI - An important step towards a prevascularized islet microencapsulation device: in vivo prevascularization by combination of mesenchymal stem cells on micropatterned membranes. AB - Extrahepatic transplantation of islets of Langerhans could aid in better survival of islets after transplantation. When islets are transfused into the liver 60-70% of them are lost immediately after transplantation. An important factor for a successful extrahepatic transplantation is a well-vascularized tissue surrounding the implant. There are many strategies known for enhancing vessel formation such as adding cells with endothelial potential, the combination with angiogenic factors and / or applying surface topography at the exposed surface of the device. Previously we developed porous, micropatterned membranes which can be applied as a lid for an islet encapsulation device and we showed that the surface topography induces human umbilical vein endothelial cell (HUVEC) alignment and interconnection. This was achieved without the addition of hydrogels, often used in angiogenesis assays. In this work, we went one step further towards clinical implementation of the device by combining this micropatterned lid with Mesenchymal Stem Cells (MSCs) to facilitate prevascularization in vivo. As for HUVECs, the micropatterned membranes induced MSC alignment and organization in vitro, an important contributor to vessel formation, whereas in vivo (subcutaneous rat model) they contributed to improved implant prevascularization. In fact, the combination of MSCs seeded on the micropatterned membrane induced the highest vessel formation score in 80% of the sections. PMID- 30413973 TI - Dietary Patterns, Physical Activity, Sleep, and Risk for Dementia and Cognitive Decline. AB - PURPOSE OF REVIEW: Diet, physical activity, and sleep are three major modifiable lifestyle factors. This selective review examines the evidence for strong and reliable associations between these three lifestyle factors and risk of dementia and cognitive decline, in an effort to assist clinicians with providing more informed answers to the common questions they face from patients. RECENT FINDINGS: Certain aspects of nutrition can decrease risk for dementia. Physical activity has also been associated with delayed or slower age-related cognitive decline. In addition, emerging evidence links sleep dysfunction and dementia, with amyloid deposition being a possible mediator. Data from further clinical trials are needed before more definitive conclusions can be drawn regarding the efficacy of these lifestyle interventions for lowering the risk of incident dementia and cognitive decline. Nevertheless, it is reasonable to make recommendations to our patients to adopt certain dietary changes and to engage in regular physical activity to improve cardiovascular risk factors for dementia. It is also reasonable to include questions on sleep during cognitive evaluations of the elderly, given the common co-occurrence of sleep dysfunction and cognitive impairment in the elderly population. PMID- 30413977 TI - The Toxicity of Nanoparticles to Organisms in Freshwater. AB - Nanotechnology is a rapidly growing industry yielding many benefits to society. However, aquatic environments are at risk as increasing amounts of nanoparticles (NPs) are contaminating waterbodies causing adverse effects on aquatic organisms. In this review, the impacts of environmental exposure to NPs, the influence of the physicochemical characteristics of NPs and the surrounding environment on toxicity and mechanisms of toxicity together with NP bioaccumulation and trophic transfer are assessed with a focus on their impacts on bacteria, algae and daphnids. We identify several gaps which need urgent attention in order to make sound decisions to protect the environment. These include uncertainty in both estimated and measured environmental concentrations of NPs for reliable risk assessment and for regulating the NP industry. In addition toxicity tests and risk assessment methodologies specific to NPs are still at the research and development stage. Also conflicting and inconsistent results on physicochemical characteristics and the fate and transport of NPs in the environment suggest the need for further research. Finally, improved understanding of the mechanisms of NP toxicity is crucial in risk assessment of NPs, since conventional toxicity tests may not reflect the risks associated with NPs. Behavioural effects may be more sensitive and would be efficient in certain situations compared with conventional toxicity tests due to low NP concentrations in field conditions. However, the development of such tests is still lacking, and further research is recommended. PMID- 30413978 TI - Water quality index for agricultural systems in Northwest Uruguay. AB - Agricultural systems have experienced rapid expansion and intensification in the last several decades. In Uruguay, since the beginning of 2000, the most common cropping systems have included soybeans. Currently, this crop is expanding towards lowlands traditionally occupied by rice in rotation with pastures. However, the environmental effects of agricultural intensification and diversification are not well known. Thus, some indices have been proposed to quantify the changes in agricultural production systems and assess water quality. The main goal of this study was to develop a water quality index (WQI) to assess the impacts of the diversification of rice production systems in northwest Uruguay. The study was carried out in an agricultural basin where other summer crops have been incorporated in the rice-pasture sequence. Agriculture intensification and crop diversification indices were calculated using information provided by farmers. Water samples were collected downstream of the production area before crop sowing and after crop harvest (2008-2009 to 2010-2011 and 2016-2017 to 2017-2018). Biochemical oxygen demand, nitrates, total phosphorus, fecal coliforms, and total suspended solids were the variables that mainly explained the effects of the agricultural activities on water quality. The proposed water quality index included these unweighted variables, which allowed for the pre-sowing and post-harvest to be differentiated, as well as the degree of diversification. Therefore, the proposed WQI constitutes a tool that can be used to evaluate the water quality in an agricultural basin. Likewise, it can be used to select agricultural sequences that generate the least possible impacts on the associated water resources. PMID- 30413979 TI - Characteristics and Follow-Up of 13 pedigrees with Gitelman syndrome. AB - CONTEXT: Gitelman syndrome (GS) is clinically heterogeneous. The genotype and phenotype correlation has not been well established. Though the long-term prognosis is considered to be favorable, hypokalemia is difficult to cure. OBJECTIVE: To analyze the clinical and genetic characteristics and treatment of all members of 13 GS pedigrees. METHODS: Thirteen pedigrees (86 members, 17 GS patients) were enrolled. Symptoms and management, laboratory findings, and genotype-phenotype associations among all the members were analyzed. RESULTS: The average ages at onset and diagnosis were 27.6 +/- 10.2 years and 37.9 +/- 11.6 years, respectively. Males were an average of 10 years younger and exhibited more profound hypokalemia than females. Eighteen mutations were detected. Two novel mutations (p.W939X, p.G212S) were predicted to be pathogenic by bioinformatic analysis. GS patients exhibited the lowest blood pressure, serum K+, Mg2+, and 24 h urinary Ca2+ levels. Although blood pressure, serum K+ and Mg2+ levels were normal in heterozygous carriers, 24-h urinary Na+ excretion was significantly increased. During follow-up, only 41.2% of patients reached a normal serum K+ level. Over 80% of patients achieved a normal Mg2+ level. Patients were taking 2 3 medications at higher doses than usual prescription to stabilize their K+ levels. Six patients were taking spironolactone simultaneously, but no significant elevation in the serum K+ level was observed. CONCLUSION: The phenotypic variability of GS and therapeutic strategies deserve further research to improve GS diagnosis and prognosis. Even heterozygous carriers exhibited increased 24-h Na+ urine excretion, which may make them more susceptible to diuretic-induced hypokalemia. PMID- 30413980 TI - Concordance with BRCA1/2 testing guidelines among women in The Health of Women (HOW) Study(r). AB - PURPOSE: To evaluate factors associated with compliance to the National Comprehensive Cancer Network (NCCN) guidelines for BRCA1/2 testing and identify groups who are at risk of under- and over-use of BRCA1/2 testing. METHODS: Data included 20,758 women from Dr. Susan Love Research Foundation's The Health of Women (HOW) Study(r). Multinomial logistic regression was used to examine the association of socioeconomic and demographic characteristics with whether the woman was over-, under-, or appropriately tested for BRCA1/2 mutations, per 2015 NCCN guidelines. RESULTS: 3894 women (18.8%) reported BRCA1/2 testing. 5628 (27.1%) women who met NCCN criteria for testing were not tested. Among women with a history of breast cancer, those without health insurance were more likely to be under-tested (OR 2.04, 95% CI 1.15-3.60) than those with managed care insurance, and higher education was associated with a lower likelihood of under-testing (Graduate/professional degree OR 0.71, 95% CI 0.55-0.91). CONCLUSION: Almost 30% of women were under-tested, indicating that many high-risk women who may benefit from genetic testing are currently being missed. Without appropriate testing, providers are unable to tailor screening recommendations to those carrying mutations who are at highest risk. Patient and healthcare provider education and outreach targeted to low-income and under-served populations may assist in reducing under-testing. PMID- 30413981 TI - Pseudoprogression of Melanoma Brain Metastases. AB - PURPOSE OF REVIEW: Immune checkpoint inhibitors are increasingly being used to treat melanoma brain metastases. One potential complication of immune checkpoint inhibitors is a phenomenon called pseudoprogression, in which a tumor transiently increases in size due to lymphocyte infiltration. This article reviews the characteristics of pseudoprogression and their clinical implications. RECENT FINDINGS: Pseudoprogression can be challenging to differentiate from true progression noted clinically or radiographically, thereby complicating management decisions and potentially confusing patients and their families. The transient tumor enlargement can also cause symptoms that mimic true tumor progression. Because the use of immunotherapy on melanoma brain metastases is a relatively new treatment paradigm, there is limited evidence to guide clinical decision-making and prognostication related to pseudoprogression. PMID- 30413982 TI - The relation between the age at diagnosis of problem behaviors related to aggression and distal outcomes in Swedish children. AB - Severe childhood aggressive behaviors are known to predict negative outcomes later in life; however, little is known about the effect of when in childhood aggression problems are diagnosed. While an earlier first diagnosis of problematic aggressive behavior might be associated with increased severity and, thus, worse outcomes, it is also possible that an earlier diagnosis affords an earlier start of treatment programs or indicates that greater attention is being paid to behavioral problems, thus resulting in attenuation of the severity of childhood aggression's impact on distal outcomes. The current study analyzed data from the population-based Swedish Data Registries, which include data on all children formally diagnosed by the Swedish medical system with a wide range of aggression problems between ages 8 and 18 (N = 5816) during the years 1987-2013, along with a matched control. Time-to-event analyses investigated whether the age at time of diagnosis affects later life outcomes while controlling for relevant confounders. Results show that for both boys and girls, those with a later diagnosis had lower average incomes (regression coefficient b = - 0.055, p < 0.005) and a higher probability of having a criminal record (odds ratio 1.126, p < 0.005) than children with earlier diagnoses. The effect on suicide attempts was not significant after correcting for multiple testing (odds ratio 1.264, p = 0.016). Grade score was not significantly affected. The results warrant further research concerning the potential advantage of earlier diagnoses, especially concerning generalizability beyond the Swedish population. PMID- 30413983 TI - Inverse remodelling algorithm identifies habitual manual activities of primates based on metacarpal bone architecture. AB - Previously, a micro-finite element (micro-FE)-based inverse remodelling method was presented in the literature that reconstructs the loading history of a bone based on its architecture alone. Despite promising preliminary results, it remains unclear whether this method is sensitive enough to detect differences of bone loading related to pathologies or habitual activities. The goal of this study was to test the sensitivity of the inverse remodelling method by predicting joint loading histories of metacarpal bones of species with similar anatomy but clearly distinct habitual hand use. Three groups of habitual hand use were defined using the most representative primate species: manipulation (human), suspensory locomotion (orangutan), and knuckle-walking locomotion (bonobo, chimpanzee, gorilla). Nine to ten micro-computed tomography scans of each species ([Formula: see text] in total) were used to create micro-FE models of the metacarpal head region. The most probable joint loading history was predicted by optimally scaling six load cases representing joint postures ranging from [Formula: see text] (extension) to [Formula: see text] (flexion). Predicted mean joint load directions were significantly different between knuckle-walking and non-knuckle-walking groups ([Formula: see text]) and in line with expected primary hand postures. Mean joint load magnitudes tended to be larger in species using their hands for locomotion compared to species using them for manipulation. In conclusion, this study shows that the micro-FE-based inverse remodelling method is sensitive enough to detect differences of joint loading related to habitual manual activities of primates and might, therefore, be useful for palaeoanthropologists to reconstruct the behaviour of extinct species and for biomedical applications such as detecting pathological joint loading. PMID- 30413984 TI - On the computation of in vivo transmural mean stress of patient-specific aortic wall. AB - It is well known that residual deformations/stresses alter the mechanical behavior of arteries, e.g., the pressure-diameter curves. In an effort to enable personalized analysis of the aortic wall stress, approaches have been developed to incorporate experimentally derived residual deformations into in vivo loaded geometries in finite element simulations using thick-walled models. Solid elements are typically used to account for "bending-like" residual deformations. Yet, the difficulty in obtaining patient-specific residual deformations and material properties has become one of the biggest challenges of these thick walled models. In thin-walled models, fortunately, static determinacy offers an appealing prospect that allows for the calculation of the thin-walled membrane stress without patient-specific material properties. The membrane stress can be computed using forward analysis by enforcing an extremely stiff material property as penalty treatment, which is referred to as the forward penalty approach. However, thin-walled membrane elements, which have zero bending stiffness, are incompatible with the residual deformations, and therefore, it is often stated as a limitation of thin-walled models. In this paper, by comparing the predicted stresses from thin-walled models and thick-walled models, we demonstrate that the transmural mean stress is approximately the same for the two models and can be readily obtained from in vivo clinical images without knowing the patient specific material properties and residual deformations. Computation of patient specific mean stress can be greatly simplified by using the forward penalty approach, which may be clinically valuable. PMID- 30413985 TI - Anisotropic stiffness and tensional homeostasis induce a natural anisotropy of volumetric growth and remodeling in soft biological tissues. AB - Growth in soft biological tissues in general results in anisotropic changes of the tissue geometry. It remains a key challenge in biomechanics to understand, quantify, and predict this anisotropy. In this paper, we demonstrate that anisotropic tissue stiffness and the well-known mechanism of tensional homeostasis induce a natural anisotropy of the geometric changes resulting from volumetric growth in soft biological tissues. As a rule of thumb, this natural anisotropy makes differential tissue volume elements dilate mainly in the direction(s) of lowest stiffness. This simple principle is shown to explain the experimentally observed growth behavior in a host of different soft biological tissues without relying on any additional heuristic assumptions or quantities (such as ad hoc defined growth tensors). PMID- 30413986 TI - The Male-Produced Aggregation-Sex Pheromone of the Cerambycid Beetle Plagionotus detritus ssp. detritus. AB - The number of longhorn beetles with confirmed aggregation-sex pheromones has increased rapidly in recent years. However, the species that have been studied most intensively are pests, whereas much less is known about the pheromones of longhorn beetles that are rare or threatened. We studied the cerambycid beetle Plagionotus detritus ssp. detritus with the goal of confirming the presence and composition of an aggregation-sex pheromone. This species has suffered widespread population decline due to habitat loss in Western Europe, and it is now considered threatened and near extinction in several countries. Beetles from a captive breeding program in Sweden were used for headspace sampling. Gas chromatography-mass spectrometry revealed that collections from males contained large quantities of two compounds, identified as (R)-3-hydroxy-2-hexanone (major component) and (S)-2-hydroxy-3-octanone (minor component), in addition to smaller quantities of 2,3-hexanedione and 2,3-octanedione. None of the compounds was present in collections from females. When tested singly in a field bioassay, racemic 3-hydroxy-2-hexanone and 2-hydroxy-3-octanone were not attractive to P. detritus, whereas a 5:1 blend elicited significant attraction. Both compounds are known as components of the pheromones of conspecific beetles, but, to our knowledge, this is the first cerambycid shown to use two compounds with different chain lengths, in which the positions of the hydroxyl and carbonyl functions are interchanged between the two. The pheromone has potential as an efficient tool to detect and monitor populations of P. detritus, and may also be useful in more complex studies on the ecology and conservation requirements of this species. PMID- 30413987 TI - Effects of polyploidization on the contents of photosynthetic pigments are largely population-specific. AB - The contents of photosynthetic pigments are an important indicator of many processes taking place in the plant body. Still, however, our knowledge of the effects of polyploidization, a major driver of speciation in vascular plants, on the contents of photosynthetic pigments is very sparse. We compared the contents of photosynthetic pigments among natural diploids, natural tetraploids, and synthetic tetraploids. The material originated from four natural mixed-cytotype populations of diploid and autotetraploid Vicia cracca (Fabaceae) occurring in the contact zone between the cytotypes in Central Europe and was cultivated under uniform conditions. We explored whether the contents of pigments are primarily driven by polyploidization or by subsequent evolution of the polyploid lineage and whether the patterns differ between populations. We also explored the relationship between pigment contents and plant performance. We found very few significant effects of the cytotype on the individual pigments but many significant interactions between the cytotype and the population. In pair-wise comparisons, many comparisons were not significant. The prevailing pattern among the significant once was that the contents of pigments were determined by polyploidization rather than by subsequent evolution of the polyploid lineage. The contents of the pigments turned out to be a useful predictor of plant performance not only at the time of material collection, but also at the end of the growing season. Further studies exploring differences in the contents of photosynthetic pigments in different cytotypes using replicated populations and assessing their relationship to plant performance are needed to assess the generality of our findings. PMID- 30413988 TI - Bi+ Visibility: Characteristics of Those Who Attempt to Make Their Bisexual+ Identity Visible and the Strategies They Use. AB - There are numerous forms of stigma that contribute to the de-legitimization and erasure of bisexual and other non-monosexual identities (collectively referred to as bisexual+ or bi+ identities). To reduce such stigma, efforts are needed to increase bi+ visibility. Little is known, however, about whether bisexual+ individuals attempt to attain greater bi+ visibility (i.e., make their bisexual+ identity visible to others) and, if so, how they do this. Using data from a mixed method (quantitative and qualitative) internet survey study of 397 individuals reporting attractions to more than one gender, we examined the proportion who attempted to attain greater bi+ visibility, the strategies they used to do so, and factors that distinguished those who made bi+ visibility attempts from those who did not. Results indicated that 58% made bi+ visibility attempts, with the most common being direct verbal communication (e.g., telling others) and visual displays (e.g., wearing bi/pride clothing, jewelry, tattoos). Less common attempts included indirect forms of communication, engagement in LGBT-related activities, and public behavioral displays. Those who made bi+ visibility attempts differed from those who did not on variables related to identity (e.g., centrality, self-affirmation, community connection) and internalized binegativity. Implications for understanding the reasons for and for not making bi+ visibility attempts, as well as the potential consequences of doing so, are discussed. PMID- 30413989 TI - Hybrid caffeic acid derivatives as monoamine oxidases inhibitors: synthesis, radical scavenging activity, molecular docking studies and in silico ADMET analysis. AB - BACKGROUND: Monoamine oxidase has been implicated in numerous neurological disorders. Although synthetic monoamine oxidase inhibitors (MAOI) have emerged with many side effects, the aspiration of natural based MAOI has greatly increased. As they exhibit fewer side effects and food interaction along with improved neuropharmacological profile. RESULTS: The in silico design of the caffeic acid derivatives led potent MAO inhibitors with remarkable antioxidant activity. The mechanistic insight of the compounds within the hMAO active site was achieved by molecular docking which led us to be more confident of the possible inhibition of MAO. CONCLUSIONS: The synthesized eugenol based ester of caffeic acid compound 7 exhibited MAO-A inhibition with IC50 values of 07.03 +/- 0.022 uM with good selectivity (SI = 0.291) towards MAO-A. Conversely, two anilides compounds 2 and 1, bearing chloro and nitro group at 2, 4 positions showed MAO-A inhibition with IC50 values of 08.51 +/- 0.017 uM and 08.87 +/- 0.005 uM, respectively. Only one compound 5 was found as a significant MAO-B inhibitor with the IC50 value of 10.80 +/- 0.024 uM. Moreover, compounds 1, 2, 4 and 9 have profoundly appeared as potent antioxidants as evaluated in duel assay by scavenging DPPH and H2O2. PMID- 30413990 TI - The life cycle and development characteristics of Dermacentor everestianus (Acari: Ixodidae) under field conditions in Qinghai-Tibet Plateau. AB - The tick Dermacentor everestianus mainly distributed in Tibet, China and Nepal, and can transmit some pathogens causing great damages in Qinghai-Tibet Plateau. This study investigated the life cycle and development characteristics of D. everestianus under field conditions. The average duration of the whole life cycle of D. everestianus was 124.4 days, with the host available in the field plot. Under natural conditions, the mean feeding, preoviposition and oviposition period of female ticks were 6.1, 17.9 and 21.2 days, respectively. The incubation time of eggs was the longest phase in the life cycle of the ticks (26 days on average). Moreover, the weight of engorged females was highly positively correlated with the number of the eggs that were laid (r = 0.81, P < 0.05). The reproductive efficiency index and reproductive fitness index in females were 7.3 and 5.9, respectively. The above findings suggest that the tick D. everestianus have evolved well adaptability to the highland areas. PMID- 30413991 TI - Who Benefits From a Defibrillator-Balancing the Risk of Sudden Versus Non-sudden Death. AB - PURPOSE OF REVIEW: Treatment with a defibrillator can reduce the risk of sudden death by terminating ventricular arrhythmias. The identification of patient groups in whom this function reduces overall mortality is challenging. In this review, we summarise the evidence for who benefits from a defibrillator. RECENT FINDINGS: Recent evidence suggests that contemporary pharmacologic and non defibrillator device therapies are altering the potential risks and benefits of a defibrillator. Who benefits from a defibrillator is determined by both the risk of sudden death and the competing risk of other, non-sudden causes of death. The balance of these risks is changing, which calls into question whether historic evidence for the use of defibrillators remains robust in the modern era. PMID- 30413992 TI - On the inverse energy transfer in rotating turbulence. AB - Rotating turbulence is an example of a three-dimensional system in which an inverse cascade of energy, from the small to the large scales, can be formed. While usually understood as a byproduct of the typical bidimensionalization of rotating flows, the role of the three-dimensional modes is not completely comprehended yet. In order to shed light on this issue, we performed direct numerical simulations of rotating turbulence where the 2D modes falling in the plane perpendicular to rotation are removed from the dynamical evolution. Our results show that while the two-dimensional modes are key to the formation of a stationary inverse cascade, the three-dimensional degrees of freedom play a non trivial role in bringing energy to the larger scales also. Furthermore, we show that this backwards transfer of energy is carried out by the homochiral channels of the three-dimensional modes. PMID- 30413993 TI - Assessment of a novel radiation reduction protocol for pediatric and adult congenital device implantation. AB - PURPOSE: Device implantation requires fluoroscopic guidance, which carries inherent risks of ionizing radiation. We evaluated the impact of a low-dose fluoroscopic protocol on radiation exposure during device implantation. METHODS: All patients who underwent pacemaker or ICD implantation with new transvenous leads from July 2011 to January 2018 were included. A novel ALARA protocol consisting of ultra-low frame rates (2-3 frames/s), low dose/frame (6-18 mGy/frame), and use of the "air-gap" technique in patients < 20 kg was employed. Demographics, procedural data, and radiation exposure levels were collected and analyzed. RESULTS: Thirty patients underwent device implantation without additional catheterization, electrophysiology study, or ablation procedure (median age 15 years; range 5-50) with a total of 43 leads placed. Forty-seven percent of patients had a primary rhythm disturbance, 33% had cardiomyopathy, and 20% had congenital heart disease. Fifty percent were pacemakers (53% dual chamber, 27% ventricle, 20% atrial) and 50% of devices implanted were ICDs (87% single-chamber). All implants were acutely successful with acceptable atrial and ventricular sensing and capture thresholds. The median fluoroscopy time was 11.5 min (inter-quartile range (IQR) 8.0-18.2), median air kerma dose 4.0 mGy (IQR 2.5 19.5), and median dose-area product 27.8 MUGy/m2 (IQR 17.1-106.5). Median implant procedure time was 133 min. One patient required revision secondary to device migration without lead derangement 2 days post-procedure. CONCLUSIONS: Use of a novel fluoroscopic protocol may help decrease radiation exposure to patients and staff without affecting efficacy or risk. These data may represent benchmarks against which future device implantation procedures can be compared. PMID- 30413994 TI - Defibrillation lessons commentary. PMID- 30413995 TI - Role of a serine protease gene (AccSp1) from Apis cerana cerana in abiotic stress responses and innate immunity. AB - Clip-domain serine proteases (Clip-SPs) mediate innate immunity and embryonic development in insects. However, the function of Clip-SPs in Apis cerana cerana is little known. Here, a Clip-SP gene, AccSp1, was identified. AccSp1 was mainly detected in third and sixth day instar larvae, dark-eyed pupae, and adults (1and 30 days post-emergence). In addition, AccSp1 was expressed at its highest level in the venom gland and epidermis than tentacle, abdomen, muscle, honey sac, head, leg, chest, hemolymph, rectum, and midgut. AccSp1 was induced by 4, 24, and 44 degrees C; H2O2; CdCl2; HgCl2; and pesticides (paraquat, pyridaben, and methomyl) and was inhibited by UV light and cyhalothrin treatments. When adults that had been pretreated with dsRNA 6 h prior (knocking AccSp1 down) were challenged with Bacillus bombysepticus for 18 h, the survival rate of bees greatly decreased, the activity of PO (phenoloxidase) was reduced, revealing that AccSp1 may play a critical role in assisting bees to survive the microbial infection and participate in regulating PO activity. The antioxidant enzymatic activities of catalase, peroxidase, and superoxide dismutase; the contents of hydrogen peroxide and malondialdehyde; and the ratio of NADP+/NADPH were all lower in samples containing dsRNA-AccSp1 interference than in control groups, but the content of carbonyl was not significantly different. These findings suggest the knockdown of AccSp1 may influence melanization so that the antioxidant enzyme activities and the harmful metabolites decreased. These results collectively suggest that AccSp1 plays critical roles in abiotic stresses responses and resistance to pathogens. PMID- 30413996 TI - Fibrin glue is a quick and effective treatment for primary and recurrent pilonidal sinus disease. AB - BACKGROUND: Pilonidal sinus disease (PSD) is a common, chronic inflammatory condition involving hair follicles within the natal cleft. It mainly affects young males and creates a significant health, social and economic burden. Traditional surgery is often radical resulting in pain, wound complications, long recovery times and poor cosmesis. The aim of our study was to evaluate fibrin glue as a primary treatment for PSD. METHODS: Fibrin glue procedures for a single surgeon at our institution were identified from operative coding databases and the logbook from January 2011 to January 2016. Patients had curettage of the sinus with fibrin glue obliteration. Recurrence data was collected retrospectively. RESULTS: One hundred and forty-six patients were identified; (115 (79%) males, mean age 30 (range 16-78 years). One hundred and forty-four (99%) were discharged the same day. Four (2.7%) were treated conservatively for wound discharge. Median operating time was 9 (range 4-28) min. There were 40 (27%) recurrences after one glue application. Median time to recurrence was 4 (range 0.25-36) months. Twenty-four (60%) of the recurrences had repeat glue treatment with 4 (16.6%) recurrences. After 2 rounds of treatment with glue alone, 126 out of 130 (96.9%) patients had healed. CONCLUSIONS: Fibrin glue application following curettage of the sinus is a quick and effective procedure for first and second line treatment of PSD. PMID- 30413997 TI - Ambulatory colectomy: fast-track management pushed to its limits? PMID- 30413998 TI - Can sidestream dark field (SDF) imaging identify subtle microvascular changes of the bowel during colorectal surgery? AB - BACKGROUND: Recognition of a non-viable bowel during colorectal surgery is a challenging task for surgeons. Identifying the turning point in serosal microcirculatory deterioration leading up to a non-viable bowel is crucial. The aim of the present study was to determine whether sidestream darkfield (SDF) imaging can detect subtle changes in serosal microcirculation of the sigmoid after vascular transection during colorectal surgery. METHODS: A prospective observational clinical study was performed at a single medical centre. All eligible participants underwent laparoscopic sigmoid resection and measurements were taken during the extra-abdominal phase. Microcirculation was measured at the transected bowel and 20 cm proximal to this point. Microcirculatory parameters such as Microvascular Flow Index (MFI), proportion of perfused vessels (PPV), perfused vessel density (PVD), total vessel density (TVD) and the Heterogeneity Index were determined. Data are presented as median (interquartile range) or mean +/- standard deviation. RESULTS: A total of 60 SDF images were acquired for 10 patients. Perfusion parameters and perfused vessel density were significantly lower at the transected bowel compared with the non-transected measurements [MFI 2.29 (1.96-2.63) vs 2.96 (2.73-3.00), p = 0.007; PPV 74% (55-83) vs 94% (86-97), p = 0.007; and PVD 7.61 +/- 2.99 mm/mm2 versus 10.67 +/- 1.48 mm/mm2, p = 0.009]. Total vessel density was similar between the measurement locations. CONCLUSIONS: SDF imaging can identify changes of the bowel serosal microcirculation. Significantly lower serosal microcirculatory parameters of the vascular transected bowel was seen compared with the non-transected bowel. The ability of SDF imaging to detect subtle differences holds promise for future research on microvascular cut-off values leading to a non-viable bowel. PMID- 30413999 TI - Immune regulation by protein ubiquitination: roles of the E3 ligases VHL and Itch. AB - Protein ubiquitination is an important means of post-translational modification which plays an essential role in the regulation of various aspects of leukocyte development and function. The specificity of ubiquitin tagging to a protein substrate is determined by E3 ubiquitin ligases via defined E3-substrate interactions. In this review, we will focus on two E3 ligases, VHL and Itch, to discuss the latest progress in understanding their roles in the differentiation and function of CD4+ T helper cell subsets, the stability of regulatory T cells, effector function of CD8+ T cells, as well as the development and maturation of innate lymphoid cells. The biological implications of these E3 ubiquitin ligases will be highlighted in the context of normal and dysregulated immune responses including the control of homeostasis, inflammation, auto-immune responses and anti-tumor immunity. Further elucidation of the ubiquitin system in immune cells will help in the design of new therapeutic interventions for human immunological diseases and cancer. PMID- 30414000 TI - Surgical trends of groin hernia repairs performed for recurrence in medicare patients. AB - BACKGROUND: The recurrence rate after groin hernia repair (GHR) has been estimated to be between 1-10% in adult patients. Neither national rates nor trends in recurrence over time have been reliably established for Medicare patients in the USA. MATERIALS: We evaluated patients undergoing GHR (inguinal = IHR; femoral = FHR) from 2011 to 2014 from the Medicare Provider Analysis and Review database. Patients were identified using ICD-9 diagnosis and ICD-9 and CPT procedure codes, stratified both by primary vs. recurrent hernia repair and by sex. One-tailed Cochran-Armitage tests evaluated trends over time and a generalized estimating equation model estimated factors associated with recurrent IHR or FHR. RESULTS: We identified 407,717 patients (87.0%, >= 65 years) who underwent an IHR and 11,578 (91.0%, >= 65 years) who underwent a FHR. The proportion of IHRs for recurrence decreased statistically from 14.3% in 2011 to 13.9% in 2014 (p < 0.01) in males and was increased, but not statistically so (7.0-7.4%) in females (p = 0.08). The proportion of FHRs for recurrence was decreased, but not statistically so (16.3-14.8%, p = 0.29) in males and increased in females (5.3-6.3%, p = 0.02). On multivariable analysis, males were more than twice as likely as females to undergo recurrent repair (IHR or FHR, both p < 0.01). CONCLUSIONS: Within the Medicare population, recurrence rates after groin hernia repairs were found to be higher than previously reported but have remained clinically stable over time. Establishing and reducing this rate is important for patient outcomes and expectations. PMID- 30414001 TI - Effects of Dietary Organic, Inorganic, and Nanoparticulate Zinc on Rainbow Trout, Oncorhynchus mykiss Larvae. AB - The present study was conducted to investigate the effects of different dietary zinc sources on growth performance, survival, and body composition of larval rainbow trout, Oncorhynchus mykiss. A total of 3240 larvae with an average weight of 82.3 +/- 11.6 mg were randomly divided into four groups by three replicates and were fed for 70 days. Organic zinc (Zn-proteinate, Bioplex Zn(r)), mineral zinc (ZnSO4), and nanoparticulate zinc (ZnO-NPs) were each added to the basal diet at 50-mg/kg diet. In all of the zinc-supplemented groups, final body weight (FBW) and weight gain (WG) increased significantly (P < 0.05) compared to the control at the termination of the feeding trial. There was no significant difference in specific growth rate (SGR) in experimental groups. Fish fed with mineral and nanoparticulate zinc, respectively, demonstrated the highest and lowest survival rates (P < 0.05) as compared to other experimental diets. Feed conversion ratio (FCR) significantly decreased (P < 0.05) in groups fed with organic and mineral zinc. There were no significant differences in protein, lipid, moisture, and ash content among fish fed the experimental diets. Fish fed mineral zinc showed the highest (P < 0.05) zinc content in the whole body than the other groups. The data of the present study confirm positive effects of the use of 50 mg kg-1 of zinc sources in early diet to enhance growth performance of rainbow trout larvae. PMID- 30414002 TI - Influence of Strontium on Vascular Endothelial Growth Factor and Fibroblast Growth Factor 2 Expression in Rat Chondrocytes Cultured In Vitro. AB - Strontium (Sr) can reduce cartilage degeneration and stimulate cartilage matrix formation. Angiogenesis plays a developmental role in chondrogenesis, and was stimulated by growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2). However, the direct influence of Sr on VEGF and FGF2 expressions in chondrocytes is not entirely clear. The objective of this study was to investigate the effects of different Sr concentrations on VEGF and FGF2 expressions in rat chondrocytes in vitro. Chondrocytes were isolated from Wistar rat articular by enzymatic digestion. As a Sr source, strontium chloride hexahydrate (SrCl2.6H2O) was added to the culture solution at final concentrations of 0, 0.5, 1.0, 2.0, 5.0, 20.0, and 100.0 MUg/mL. After 72 h of continuous culture, mRNA abundance and protein expression levels of VEGF and FGF2 in the chondrocytes were determined by real-time polymerase chain reaction (real time PCR) and Western blot, respectively. The results showed that VEGF and FGF2 expressions were dose-dependently elevated with Sr concentration in chondrocytes. The mRNA abundance and protein expression levels of VEGF were extremely significantly higher than those in the control group (P < 0.01) at 1.0 MUg/mL Sr treatment. For FGF2, there were markedly significant differences in mRNA and protein expression from control group (P < 0.01) when the Sr-treated concentration exceeded 5.0 MUg/mL and 20.0 MUg/mL, respectively. These results indicated that Sr might involve in the cartilage angiogenesis via regulating expression of VEGF and FGF2z. PMID- 30414003 TI - Total Bioavailable Organic Selenium in Fishmeal-Based Diet Influences Growth and Physiology of Juvenile Cobia Rachycentron canadum (Linnaeus, 1766). AB - The study examined the effects of supplemental organic selenium (Se) extracted from selenoyeast on the growth performance, glutathione peroxidase (GPx) activity, biochemical status and liver histochemistry of juvenile cobia Rachycentron canadum. Six experimental diets were prepared supplemented with Se with total concentration of 1.52 (Se-1.52), 1.93 (Se-1.93), 2.29 (Se-2.29), 2.71 (Se-2.71) and 3.14 (Se-3.14) mg/kg of total Se in the diets and a fishmeal-based control diet without Se supplementation containing 1.15 (Se-1.15) mg/kg of Se was used as control. Experimental diets were fed to the fish of six treatment groups in triplicate twice daily for 8 weeks. Juvenile cobia fed dietary Se of 1.93, 2.29 and 2.71 mg/kg showed increased final body weight (FBW), specific growth rate (SGR) and feed intake (FI) than the fish fed the control diet. Se accumulations in the muscle and liver tissue displayed a positive linear relationship with dietary Se levels. Se deficiency was apparent in fish fed the control diet and displayed reduced growth and feed efficiency. Red blood cell (RBC) counts were significantly (P < 0.05) higher in cobia fed dietary Se between 1.52 to 2.71 mg/kg than the fish fed 3.14-mg/kg Se diet. Glutathione peroxidase activity significantly (P < 0.05) declined in the group fed with control diet compared to fish fed Se-supplemental diet. Juvenile cobia fed the highest Se level (Se-3.14 mg/kg) showed toxic effects in the liver, including histopathological lesions in the liver. Based on the results obtained for FBW, SGR, tissue Se retention and haematological parameters, we conclude that optimal dietary Se requirement for juvenile cobia fed commercial diets is 2.32 mg/kg. PMID- 30414004 TI - GM1 Ameliorates Lead-Induced Cognitive Deficits and Brain Damage Through Activating the SIRT1/CREB/BDNF Pathway in the Developing Male Rat Hippocampus. AB - Developmental lead (Pb) exposure involves various serious consequences, especially leading to neurotoxicity. In this study, we examined the possible role of monosialoganglioside (GM1) in lead-induced nervous impairment in the developing rat. Newborn male Sprague-Dawley rat pups were exposed to lead from birth for 30 days and then subjected to GM1 administration (0.4, 2, or 10 mg/kg; i.p.) or 0.9% saline. The results showed that developmental lead exposure significantly impaired spatial learning and memory in the Morris water maze test, reduced GM1 content, induced oxidative stress, and weakened the antioxidative systems in the hippocampus. However, co-treatment with GM1 reversed these effects. Moreover, GM1 counteracted lead-induced apoptosis by decreasing the expression of Bax, cleaved caspase-3, and by increasing the level of Bcl-2 in a dose-dependent manner. Furthermore, we found that GM1 upregulated the expression of SIRT1, CREB phosphorylation, and BDNF, which underlie learning and memory in the lead-treated developing rat hippocampus. In conclusion, our study demonstrated that GM1 exerts a protective effect on lead-induced cognitive deficits via antioxidant activity, preventing apoptosis, and activating SIRT1/CREB/BDNF in the developing rat hippocampus, implying a novel potential assistant therapy for lead poisoning. PMID- 30414005 TI - Genetic engineering of T cells with chimeric antigen receptors for hematological malignancy immunotherapy. AB - The host immune system plays an instrumental role in the surveillance and elimination of tumors by recognizing and destroying cancer cells. In recent decades, studies have mainly focused on adoptive immunotherapy using engineered T cells for the treatment of malignant diseases. Through gene engraftment of the patient's own T cells with chimeric antigen receptor (CAR), they can recognize tumor specific antigens effectively and eradicate selectively targeted cells in an MHC-independent fashion. To date, CAR-T cell therapy has shown great clinical utility in patients with B-cell leukemias. Owing to different CAR designs and tumor complex microenvironments, genetically redirected T cells may generate diverse biological properties and thereby impact their long-term clinical performance and outcome. Meanwhile some unexpected toxicities that result from CAR-T cell application have been examined and limited the curative effects. Diverse important parameters are closely related with adoptively transferred cell behaviors, including CAR-T cells homing, CAR constitutive signaling, T cell differentiation and exhaustion. Thus, understanding CARs molecular design to improve infused cell efficacy and safety is crucial to clinicians and patients who are considering this novel cancer therapeutics. In this review, the developments in CAR-T cell therapy and the limitations and perspectives in optimizing this technology towards clinical application are discussed. PMID- 30414006 TI - Identification of a seed dormancy gene in soybean sheds light on crop domestication. PMID- 30414007 TI - New insights into nanomaterials combating bacteria: ROS and beyond. PMID- 30414008 TI - Vaccination of poultry successfully eliminated human infection with H7N9 virus in China. AB - The H7N9 viruses that emerged in China in 2013 were nonpathogenic in chickens but mutated to a highly pathogenic form in early 2017 and caused severe disease outbreaks in chickens. The H7N9 influenza viruses have caused five waves of human infection, with almost half of the total number of human cases (766 of 1,567) being reported in the fifth wave, raising concerns that even more human infections could occur in the sixth wave. In September 2017, an H5/H7 bivalent inactivated vaccine for chickens was introduced, and the H7N9 virus isolation rate in poultry dropped by 93.3% after vaccination. More importantly, only three H7N9 human cases were reported between October 1, 2017 and September 30, 2018, indicating that vaccination of poultry successfully eliminated human infection with H7N9 virus. These facts emphasize that active control of animal disease is extremely important for zoonosis control and human health protection. PMID- 30414010 TI - Palliative Care in Lung Cancer: When to Start. AB - PURPOSE OF REVIEW: Despite recent advances in the care of patients with advanced non-small cell lung cancer (NSCLC), significant morbidity and mortality remains. Symptoms caused by the cancer and its treatments can be profoundly debilitating. Palliative care aims to reduce this burden. In this review, we discuss the definition, purpose, benefits, and optimal timing of palliative care in advanced NSCLC. RECENT FINDINGS: Several studies evaluating the value of early palliative care for patients with advanced NSCLC and other advanced malignancies have identified benefits for patients, caregivers, and health systems. For patients with advanced NSCLC, introduction of palliative care early in the disease course improves quality of life and even overall survival. Early institution of palliative care should become standard of care for patients with advanced NSCLC. PMID- 30414009 TI - In vivo confirmation of altered hepatic glucose metabolism in patients with liver fibrosis/cirrhosis by 18F-FDG PET/CT. AB - OBJECTIVE: The aim of this study was to assess the value of 18F-FDG PET/CT for quantitative assessment of hepatic metabolism in patients with different stages of liver fibrosis/cirrhosis. MATERIALS AND METHODS: 18F-FDG PET/CT scans of 37 patients either with or without liver fibrosis/cirrhosis, classified according to the METAVIR score (F0-F4) obtained from histopathological analysis of liver specimen, were analyzed retrospectively and classified as follows: no liver fibrosis (F0, n = 6), mild liver fibrosis (F1, n = 11), advanced liver fibrosis (F2, n = 6), severe liver fibrosis (F3, n = 5), and liver cirrhosis (F4, n = 11). The liver-to-blood ratio (LBR, scan time corrected for a reference time of 75 min) was compared between patient groups. RESULTS: Patients with liver fibrosis or cirrhosis (>= F1; LBR 1.53 +/- 0.35) showed a significant higher LBR than patients with normal liver parenchyma (F0, 1.08 +/- 0.23; P = 0.004). In direct comparison, LBR increased up to the advanced stage of liver fibrosis (F2; 2.00 +/ 0.40) and decreased until liver cirrhosis is reached (F4, 1.32 +/- 0.14). CONCLUSION: Functional changes in liver parenchyma during liver fibrosis/cirrhosis affect hepatic glucose metabolism and significantly differ between stages of liver fibrosis/cirrhosis, classified according to the METAVIR scoring system, as demonstrated by LBR quantification by 18F-FDG PET/CT. PMID- 30414011 TI - Metric Transformations and the Filtered Monotonic Polynomial Item Response Model. AB - The [Formula: see text] metric in item response theory is often not the most useful metric for score reporting or interpretation. In this paper, I demonstrate that the filtered monotonic polynomial (FMP) item response model, a recently proposed nonparametric item response model (Liang & Browne in J Educ Behav Stat 40:5-34, 2015), can be used to specify item response models on metrics other than the [Formula: see text] metric. Specifically, I demonstrate that any item response function (IRF) defined within the FMP framework can be re-expressed as another FMP IRF by taking monotonic transformations of the latent trait. I derive the item parameter transformations that correspond to both linear and nonlinear transformations of the latent trait metric. These item parameter transformations can be used to define an item response model based on any monotonic transformation of the [Formula: see text] metric, so long as the metric transformation is approximated by a monotonic polynomial. I demonstrate this result by defining an item response model directly on the approximate true score metric and discuss the implications of metric transformations for applied testing situations. PMID- 30414012 TI - Potential widespread denitrosylation of brain proteins following prolonged restraint: proposed links between stress and central nervous system disease. AB - The biochemical pathways by which aberrant psychophysiological stress promotes neuronal damage and increases the risks for central nervous system diseases are not well understood. In light of previous findings that psychophysiological stress, modeled by animal restraint, can increase the activities and expression levels of nitric oxide synthase isoforms in multiple brain regions, we examined the effects of restraint, for up to 6 h, on levels of S-nitrosylated proteins and NOx (nitrite + nitrate), a marker for high-level nitric oxide generation, in the brains of rats. Results identify functionally-diverse protein targets of S nitrosylation in the brain, in vivo, and demonstrate the potential for widespread loss of protein nitrosothiols following prolonged restraint despite a concomitant increase in NOx levels. Since physiological levels of protein S-nitrosylation can protect neurons by maintaining redox homeostasis, by limiting excitatory neurotransmission, and by inhibiting apoptotic and inflammatory pathways, we propose that over-activation of protein denitrosylation pathways following sustained or repeated stress may facilitate neural damage and early stages of stress-related central nervous system disease. PMID- 30414014 TI - Application of a proton quantitative nuclear magnetic resonance spectroscopy method for the determination of actinodaphnine in Illigera aromatica and Illigera henryi. AB - Illigera aromatica S. Z. Huang et S. L. Mo and Illigera henryi W. W. Sm., belonging to the genus Illigera (Hernandiaceae), are used as herbal medicines for promoting blood circulation and treating tuberculosis. Actinodaphnine, the major bioactive alkaloid, plays an important role in the quality controls of the herbs. In the present study, a rapid, simple, accurate, and precise proton quantitative nuclear magnetic resonance (1H-qNMR) method was developed to determine the content of actinodaphnine in I. aromatica and I. henryi. DMSO-d6 enabled satisfactory separation of the signals to be integrated in 1H NMR spectrum. 1,4 Dinitrobenzene was selected as an internal standard. The limits of determination and quantitation were 0.005 and 0.038 mg/mL, respectively. This work implied that 1H-qNMR represents a feasible alternative to HPLC-based methods for quantitation of actinodaphnine in I. aromatica and I. henryi and is suitable for the quality control of I. aromatica and I. henryi. PMID- 30414015 TI - Comparison of the effects of pachymic acid, moronic acid and hydrocortisone on the polysome loading of RNAs in lipopolysaccharide-treated THP-1 macrophages. AB - We have proposed that analysis of ribosome-loaded mRNAs (i.e., the translatome) is useful for elucidation of pharmacological effects of phytocompounds in immune cells, regarding the involvement of post-transcriptional regulation mechanisms. In the present study, we compared the effects of pachymic acid from Poria cocos fungus and moronic acid from propolis with those of hydrocortisone on the translatomes of THP-1 macrophages exposed to bacterial lipopolysaccharide (LPS) to find clues to their biological effects. Polysome-associated RNAs collected from cells treated for 3 h with LPS plus each of the compounds were analyzed by DNA microarray followed by analyses of pathways/gene ontologies (GO). Upregulated mRNAs in enriched pathways that were found to contain AUUUA (AU)-rich motifs were checked by real-time PCR, and expression of candidate RNA-binding proteins stabilizing/destabilizing such AU-rich mRNAs was checked by Western blotting. The numbers of upregulated and downregulated genes (fold-changes +/- 2.0 versus vehicle-control) were, respectively, 209 and 125 for moronic acid, 23 and 2 for pachymic acid, and 214 and 59 for hydrocortisone treatment. Overlapping with hydrocortisone treatment for upregulation were 158 genes in moronic acid and 17 in pachymic acid treatment; of these, 16 overlapped within all treatments (C-X-C motif chemokine ligands, interferon-induced protein with tetratricopeptide repeats, etc.). Pathway analyses showed GO enrichments such as 'immune response', 'receptor binding', 'extracellular space' etc. The pachymic acid-upregulated mRNAs (highly overlapped with the other 2 treatments) showed the presence of signal peptides and AU-rich motifs, suggesting regulation by AU-rich element (ARE)-binding proteins. The expression of ARE-binding protein HuR/ELAV-1 was increased by the 3 compounds, and AUF1/hnRNP D was decreased by pachymic acid. These results suggested that pachymic acid and moronic acid effects may involve as yet unknown post-transcriptional modulation via ARE-binding proteins resembling that of glucocorticoids. PMID- 30414013 TI - Bladder Cancer Survivorship. AB - PURPOSE OF REVIEW: Bladder cancer (BC) is the second most common genitourinary malignancy, with a growing population of survivors globally. Over the past two decades, there has been a growing awareness of not only the oncologic, but also the quality of life ramifications of a BC diagnosis, treatment, and surveillance. In the current review, the literature surrounding the many domains that encompass bladder cancer survivorship is summarized and analyzed. RECENT FINDINGS: There have been ongoing efforts to decrease perioperative morbidity, particularly in patients undergoing radical cystectomy, with mixed results. There is a growing emphasis on the short and long-term health-related quality of life (HR-QoL) impacts of bladder cancer spanning the domains of physical and mental QoL related to urinary function, sexual function, and financial and psychological burden, with validated measures specific to BC patients. There continue to be disparities in oncologic outcomes by race and gender. The impact of BC is prolonged and there is an unmet need for long term support and survivorship resources to address this. There is a growing global population of bladder cancer patients, and their needs are complex and vary by stage, treatment, and certain demographic features. Outcome-centered perioperative strategies show potential to diminish treatment morbidity, and validated BC specific HR-QoL tools have helped to define the impact and burden of BC, but there continue to be large areas of unmet need that warrant greater study and intervention. PMID- 30414016 TI - Hormonal Regulation of Hippocampal Neurogenesis: Implications for Depression and Exercise. AB - Adult hippocampal neurogenesis exists in all mammalian species, including humans, and although there has been considerable research investigating the function and regulation of neurogenesis, there remain many open questions surrounding the complexity of this phenomenon. This stems partially from the fact that neurogenesis is a multistage process that involves proliferation, differentiation, migration, survival, and eventual integration of new cells into the existing hippocampal circuitry, each of which can be independently influenced. The function of adult neurogenesis in the hippocampus is related to stress regulation, behavioral efficacy of antidepressants, long-term spatial memory, forgetting, and pattern separation. Steroid hormones influence the regulation of hippocampal neurogenesis, stress regulation, and cognition and differently in males and females. In this chapter, we will briefly tap into the complex network of steroid hormone modulation of neurogenesis in the hippocampus with specific emphasis on stress, testosterone, and estrogen. We examine the possible role of neurogenesis in the etiology of depression and influencing treatment by examining the influence of both pharmacological (selective serotonin reuptake inhibitors, tricyclic antidepressants) treatments and non pharmacological (exercise) remedies. PMID- 30414017 TI - Insulin-Like Growth Factor-1 Alleviates Expression of Abeta1-40 and alpha-, beta , and gamma-Secretases in the Cortex and Hippocampus of APP/PS1 Double Transgenic Mice. AB - To examine the effect of subcutaneous injection of insulin-like growth factor-1 (IGF-1) on the expression of the amyloid protein (Abeta1-40), alpha-secretase (ADAM10), beta-secretase (BACE1), and gamma-secretase (PS1) in APP/PS1 double transgenic mice. APP/PS1 double transgenic mice and wild-type mice were divided into wild-type group, wild-type therapy group, transgenome group, and transgenic therapy group. Subcutaneous injection of IGF-1 (50 MUg/kg day) was administered once daily to the wild-type therapy group and transgenic therapy group for 8 weeks, respectively. The expression of the Abeta1-40 in the cortex and hippocampus was detected by immunohistochemistry 8 weeks after administration. The levels of Abeta1-40, DAM10, BACE1, and PS1 were analysed by Western blot. The expression of the Abeta1-40 in the cortex of the gene therapy group was significantly lower than that of the transgenome group (p < 0.05). In APP/PS1 double transgenic mice, BACE1 expression was markedly higher in both the hippocampus (p < 0.001, p = 0.00009) and the cortex (p = 0.001), compared to that of the wild-type mice. The treatment of IGF-1 markedly reduced ADAM10 expression in the hippocampus in both transgenic mice and wild-type mice (p < 0.05), whereas the treatment mainly decreased BACE1 expression in transgenic mice but not in the wild-type mice (p < 0.05). No significant differences in PS1 levels were detected in all groups. IGF decreased Abeta1-40 over-expression in the cortex and hippocampus and might inhibit the damage induced by Abeta1-40 in APP/PS1 double transgenic mice. Our study suggests that IGF-1 should inhibit Abeta production through alpha-secretase and beta-secretase but not gamma-secretase. PMID- 30414019 TI - Considerations on the Taxonomy of the Genus Arhuaco Adams and Bernard 1977, and its Relationships with the Genus Pronophila Doubleday [1849] (Nymphalidae, Satyrinae). AB - Arhuaco Adams & Bernard (1977) is one of the least known genera of Neotropical Satyrinae. It comprises two species and presents an unusual disjunct distribution, with A. ica Adams & Bernard (1977), endemic to the isolated Colombian Sierra Nevada de Santa Marta, and A. dryadina (Schaus 1913) found in the mountains of Costa Rica and Panama. Here, the female of A. dryadina is described, and a new generic diagnosis is presented. Affinities with other genera of the subtribe Pronophilina, in particular the potential closest relatives, such as Pronophila Doubleday (1849), are investigated based on morphological, molecular, ecological, and behavioral data. Results from molecular and morphological sources are incongruent. Molecular data indicate that Arhuaco is paraphyletic, with A. dryadina segregating within the Pronophila clade. Morphological data, by contrast, indicate a closer affinity between the two species currently placed in Arhuaco, favoring the monophyly of the genus, and show no consistent synapomorphies for Arhuaco + Pronophila. A vicariance biogeographical scenario is evaluated. PMID- 30414018 TI - Antennal Morphology and Localization of a Pheromone-Binding Protein of Lobesia botrana (Denis & Schiffermuller) (Lepidoptera: Tortricidae). AB - In the sensory system of insects, olfactory sensilla constitute important functional elements for discriminating odors. Therefore, we used light microscopy and scanning electron microscopy to investigate the morphology and distribution of sensilla in the antennae of Lobesia botrana (Denis & Schiffermuller). In addition, we studied the expression of the gene encoding for pheromone-binding protein 1 (LbotPBP1) by in situ hybridization. Lobesia botrana antennae are filiform and are subdivided into three segments: scape, pedicel, and flagellum. The number of flagellum and their overall length were significantly higher and longer in males than in females. Six morphological types of sensilla (trichodea, chaetica, coeloconica, auricillica, basiconica, and styloconica) were identified on the antennae of both sexes. Trichodea sensilla were the most abundant on the antennae of L. botrana, and three subtypes, discerned by their lengths, were observed. However, sensilla trichodea subtype III was only present in male antennae. Moreover, LbotPBP1 expression was restricted to this type of sensilla, thus confirming its olfactory role, specifically under the context of sexual pheromone perception. PMID- 30414020 TI - Brucella-associated cervical bursitis in cattle. AB - Bovine brucellosis poses a risk to human health and causes serious economic losses for the animal industry. This report describes the use of different diagnostic methods for the diagnosis of brucellosis in cattle affected by cervical bursitis from a slaughterhouse located in Sao Luis, Maranhao, Brazil. Serum samples from a total of 47 cattle with bursitis were collected and submitted to the Rose Bengal Test (RBT), and RBT-positive samples were further confirmed by the 2-mercaptoethanol (2-ME) assay. RBT indicated 85.1% (40/47) of positive samples, from which 78.7% (37/47) were confirmed by 2-ME. Immunohistochemistry detected Brucella spp. in 34.0% (16/47) of tissues with bursitis. PCR and/or bacterial isolation demonstrated that 63.8% (30/47) of samples were positive and morphologically compatible with Brucella sp. All colonies suggestive of Brucella sp. were confirmed by PCR. Isolates were further characterized by PCR Multiplex AMOS-ENHANCED, which indicated that the isolates corresponded to biovar 1, 2, 4 (43.33%). This study evidences an association between cervical bursitis and Brucella spp. infection in cattle, and that different biovars of Brucella circulate in bovine herds in Maranhao. PMID- 30414021 TI - Who's Buying What and How Much? Correlates of Purchase Behaviors From Medical Marijuana Dispensaries in Los Angeles, California. AB - Venue-based distribution of marijuana has become the normative model in the United States to obtain marijuana. This study examines one-time purchase behaviors at medical marijuana dispensaries (MMDs) to identify potential venue- and individual-level targets for prevention. We used a two-stage, venue-based sampling approach to randomly select patrons exiting 16 MMDs in Los Angeles, California during the spring of 2013. Patrons (N = 595) reported their discrete purchase behaviors during their most recent visit to the sampled MMD. We used hierarchical linear modeling to examine the amount spent on marijuana products, regressed on characteristics of the sampled dispensaries and their patrons. We used hierarchical generalized linear modeling to examine the likelihood of purchasing specific types of marijuana products and total grams of loose-leaf buds purchased. Patrons spent US$41.73 on average, with a range of $0-$330. We observed significant variation in purchase behaviors across MMDs and associations between venues located within high median income census tracts and a higher total amount spent and lower odds of purchasing only loose-leaf buds. The networked distance between a patron's home and the sampled MMD was positively associated with the total amount spent and total quantity of buds purchased. We also found significant relationships between medical conditions reported for use in three models: total amount spent, purchase of pre-rolled joints, and total grams of buds purchased. Policy makers may want to explore regulating the availability of specialty items that may be attractive to naive users, such as pre-rolled joints or edibles, or high-concentration products that may be sought out by regular, heavy users. PMID- 30414022 TI - Poultry biogas slurry can partially substitute for mineral fertilizers in hydroponic lettuce production. AB - Poultry biogas slurry, a by-product of the biogas production process, is rich in nutrients. However, improper handling increases the potential for serious environmental contamination and resource waste. The preparation of nutrient solutions for hydroponic lettuce production requires large amounts of mineral fertilizers, which provides an opportunity for poultry biogas slurry to enter the crop nutrient cycle. To assess the feasibility of the application of poultry biogas slurry, we used different proportions of biogas slurry and mineral fertilizers in a hydroponics experiment with lettuce. Four treatments were established: HS (half-strength Hoagland solution), BS (2.6% biogas slurry), BS + HS (1.3% biogas slurry + quarter-strength Hoagland solution), and BS + MF (2.6% biogas slurry + mineral fertilizers). The addition of poultry biogas slurry (BS + HS) did not have an adverse effect on lettuce growth, significantly increased the soluble sugar concentration, reduced the nitrate concentration, and the concentrations of heavy metals were still within the safety standards. In addition, the application of poultry biogas slurry could effectively reduce the production costs, energy consumption, and greenhouse gas emissions of hydroponically grown lettuce. Based on our study, poultry biogas slurry could replace 50% of the mineral fertilizer used in hydroponic lettuce production. The key is to control the electrical conductivity and replenish the nutrients that are lacking in the biogas slurry, especially magnesium. PMID- 30414023 TI - Distilled pyroligneous liquor obtained from Eucalyptus grandis and chitosan: physicochemical properties of the solution and films. AB - The pyroligneous liquor is a product obtained during the production of charcoal, with well-known antimicrobial activity. In this work, we characterized the physical chemistry properties of a formulation composed of distilled pyroligneous liquor (DPL), obtained from Eucalyptus grandis, and chitosan. A good interaction between the polymer and the solvent was observed. Auto-supported films were prepared with these systems and characterized with respect to their structure and photo-protection properties, water vapor permeability, and resistance to water and to thermal degradation. They present a semi-crystalline structure and are hygroscopic, but are stable under immersion for up to 7 days. The swelling degree in water is 300% in weight and the permeability to water vapor was between 30 and 45 g m-1 h-1 (for films with 80 to 10 MUm, respectively). The obtained films are able to efficiently block the incident UVB and UVC radiation; the molar absorptivity decreases exponentially with increasing wavelength and is stable up to 300 degrees C. These properties confer desirable properties to the films, obtained from these precursors of a renewable source, to be used as coatings. PMID- 30414024 TI - Influence of microalgae wastewater treatment culturing conditions on forward osmosis concentration process. AB - Forward osmosis is envisioned as a technology for microalgae concentration but fouling propensity during dewatering is currently a limiting factor that requires better understanding. The purpose of this study is to define the impact of microalgae culturing conditions on the downstream forward osmosis (FO) separation process-water recovery and microalgae harvesting. Chlorella vulgaris was cultivated in an outdoor lab-scale reactor fed with synthetic wastewater mimicking primary settled municipal influent under changing environmental conditions (temperature, solar radiation, nutrient balance) with varying hydraulic retention time. High efficiency of nutrient removal was achieved under all tested conditions but microalgae autoflocculation and lower rate of pollutant removal were observed with batches where culturing temperature (6.5-21 degrees C), solar irradiation rate (181 W/m2), and nitrogen/phosphorous ratio (2.9) were below the optimal range. Regarding FO concentration, high initial water fluxes (in the range of 18.2 to 19.5 L.m2.h-1) and water extraction rate (60.1-83.9%) were observed in all subsequent FO concentration tests. Significant membrane fouling (microalgae deposition on surface) associated with poor biomass recovery from the FO cell was found to be dependent on exopolymeric substance accumulation, which was a response to non-optimal environmental culturing conditions. PMID- 30414025 TI - Oxidative removal of recalcitrant organics in shale gas flowback fluid by the microwave-activated persulfate process. AB - Shale gas flowback fluid (SGF) is generated during shale gas extraction and typically contains a variety of toxic and refractory organic compounds. In this work, a microwave-activated persulfate process (MW-PS process) was developed to pretreat SGF. The major factors influencing the treatment efficiency of the MW-PS process (PS dose, initial pH, MW power, and reaction time) were optimized, and the synergetic effect (SE), degradation of recalcitrant matter, and energy consumption were systematically investigated. Results showed that the SE of the process reached a high index (i.e., 9.85), suggesting a significant synergetic effect of MW and PS. In addition, under the optimal MW-PS condition (PS dose of 2.5 g/L, MW power of 900 W, and initial pH of 2), chemical oxygen demand removal reached 66.40% in a short reaction time of 10 min. Other analyses demonstrated that benzene series compounds, organic acids, lipid substances, alkanes, antioxidants, and fluorescent dissolved organic matter in SGF were decomposed to smaller-molecule organic matter, suggesting that refractory and toxic organic matter was removed by the MW-PS treatment process. Overall, the results of this study showed that MW-PS technology is an effective and promising method to treat SGF once the operation parameters are optimized. PMID- 30414026 TI - Socio-geographic disparity in cardiorespiratory mortality burden attributable to ambient temperature in the United States. AB - Compared with relative risk, attributable fraction (AF) is more informative when assessing the mortality burden due to some environmental exposures (e.g., ambient temperature). Up to date, however, available AF-based evidence linking temperature with mortality has been very sparse regionally and nationally, even for the leading mortality types such as cardiorespiratory deaths. This study aimed to quantify national and regional burden of cardiorespiratory mortality (CRM) attributable to ambient temperature in the USA, and to explore potential socioeconomic and demographic sources of spatial heterogeneity between communities. Daily CRM and weather data during 1987-2000 for 106 urban communities across the mainland of USA were acquired from the publicly available National Morbidity, Mortality and Air Pollution Study (NMMAPS). We did the data analysis using a three-stage analytic approach. We first applied quasi-Poisson regression incorporated with distributed lag nonlinear model to estimate community-specific temperature-CRM associations, then pooled these associations at the regional and national level through a multivariate meta-analysis, and finally estimated the temperature-AF of CRM and performed subgroup analyses stratified by community-level characteristics. Both low and high temperatures increased short-term CRM risk, while temperature-CRM associations varied by regions. Nationally, the fraction of cardiorespiratory deaths caused by the total non-optimum, low, and high temperatures was 7.58% (95% empirical confidence interval, 6.68-8.31%), 7.15% (6.31-7.85%), and 0.43% (0.37-0.46%), respectively. Greater temperature-AF was identified in two northern regions (i.e., Industrial Midwest and North East) and communities with lower temperature and longitude, higher latitude, and moderate humidity. Additionally, higher vulnerability appeared in locations with higher urbanization level, more aging population, less White race, and lower socioeconomic status. Ambient temperature may be responsible for a large fraction of cardiorespiratory deaths. Also, temperature AF of CRM varied considerably by geographical and climatological factors, as well as community-level disparity in socioeconomic status. PMID- 30414027 TI - The environmental Kuznets curve by considering asymmetric oil price shocks: evidence from the top two. AB - This study is the first attempt to investigate the validity of the environmental Kuznets curve (EKC) hypothesis by considering the asymmetric oil price effects on the CO2 emission in the USA and China. The oil prices were incorporated as an indicator (proxy) of energy consumption in order to avoid potential endogeneity problems and allow exploring the asymmetric effects of the energy fluctuation on the CO2 release. The nonlinear autoregressive distributed lag (NARDL)-bound testing approach to cointegration of Shin et al. (2014) in the presence of structural break is used to identify both short-run and long-run dynamic relationships between real oil prices, per capita GDP, and per capita CO2 emissions over the period 1976-2013. The results indicate that the inverted U shaped EKC hypothesis is not supported in the short and long terms in both countries. Asymmetric findings suggest that positive and negative fluctuations in crude oil prices affect CO2 emissions differently in the USA and China. Unlike China, rising energy prices in the USA could be a contributing factor in the fight against pollution. More taxation of fossil energy and renewable energy subsidies are recommended for the American economy. However, the growth priority seems to outweigh the environmental issue for the Chinese economy. PMID- 30414028 TI - Harmful weed to prospective adsorbent: low-temperature-carbonized Ipomoea carnea stem carbon coated with aluminum oxyhydroxide nanoparticles for defluoridation. AB - Gainful utilization of stems of the pernicious weed, Ipomoea carnea, to prepare good quality carbon and its modification with aluminum oxyhydroxide (AlOOH) nanoparticles for efficient defluoridation from contaminated drinking water is discussed in this paper. Surface functional groups are enhanced by functionalization of the carbons under acid treatment which acted as anchor to the AlOOH nanoparticles. Formation of AlOOH particles over the carbon surface is confirmed from X-ray diffractometry analysis. The AlOOH-carbon nanocomposite showed higher fluoride removal capacity than the neat AlOOH nanoparticles with a maximum removal capacity in the range of 46.55-53.71 mg g-1. Reaction kinetics and isotherm studies showed that fluoride adsorption is quite feasible on the adsorbent surface. The column study showed the possibility of the adsorbent for large-scale applications. The adsorbent can be regenerated by a mild treatment with 0.1 N NaOH solutions. The adsorbent is highly capable for defluoridation from synthetic as well as fluoride-contaminated natural water and, thus, can be used as an alternative for commercial defluoridation adsorbents. The use of Ipomoea carnea for defluoridation can be a way of producing low-cost adsorbent material, and the use for such purposes may also be helpful to control the weed up to a good extent. PMID- 30414029 TI - Using nitrogen and oxygen isotopes to access sources and transformations of nitrogen in the Qinhe Basin, North China. AB - Nitrate pollution in water is a common environmental problem worldwide. The Qinhe Basin (QHB) faces with the risk of eutrophication. To clarify nitrate pollution of river water, water chemical data, water isotope values (deltaD and delta18O H2O), and dual nitrate isotope values (delta15N-NO3- and delta18O-NO3-) were used to discern sources and transformation mechanisms of nitrogen in the QHB. The nitrate concentrations of river water ranged from 0.71 to 20.81 mg L-1. The deltaD and delta18O-H2O values of river water varied from - 74 to -520/00 and from - 10.8 to - 7.20/00, with an average value of - 600/00 and - 8.20/00, respectively. The delta15N-NO3- and delta18O-NO3- values of nitrate ranged from - 6.7 to + 14.80/00 and from - 6.0 to + 5.60/00, with a mean value of + 4.60/00 and - 0.60/00, respectively. Assimilation by algae and the mixing of soil nitrogen, chemical fertilizer, sewage, and industrial wastewater could account for increasing delta15N-NO3- values. There was neither significantly positive nor negative correlation between delta15N-NO3- and delta18O-NO3- in river water, indicating that no obvious denitrification shifted isotopic values of nitrate in the QHB. Based on the dual isotopic values of nitrate and land use change in the watershed, it could be concluded that intensive nitrification dominated in the QHB, and dissolved nitrate was mainly derived from nitrification of ammonium in fertilizer, soil nitrogen, and domestic sewage. As the primary nitrate sources identified in the QHB, effective fertilization and afforestation can be taken to protect water resource from nitrate pollution. PMID- 30414030 TI - Monitoring polychlorinated dibenzo-p-dioxins/dibenzofurans and dioxin-like polychlorinated biphenyls in Africa since the implementation of the Stockholm Convention-an overview. AB - Polychlorinated dibenzo-p-dioxin (PCDDs), polychlorinated dibenzofurans (PCDF), and dioxin-like polychlorinated biphenyl (dl-PCB) are groups of toxic compounds released into the environment as unintentional by-products of combustion. They persist, bioaccumulate through the food chain, and cause adverse health effects. This review attempts to collate available information on the release of PCDD/Fs and dl-PCBs and other critical data relevant to their monitoring in Africa during the existence of the Stockholm Convention (SC). Much as the implementation of the SC may be lagging, literature showed that there has been encouraging efforts that have been made with respect to PCDDs/Fs and dl-PCBs monitoring in Africa. Results from a global monitoring study showed that PCDD/Fs released to air in Africa stood at 18-532 fg WHO98 TEQ/M3 while dl-PCBs were 7-278 fg WHO98 TEQ/m3. In human milk, the total concentration of PCDD/Fs, i.e., WHO 2005 TEQ LB has been reported to range from 0.5 ng/g fat to 12 ng/g fat. Fourteen laboratories in Africa participated in inter-laboratory assessments of persistent organic pollutants (POPs) with two specifically for PCDD/Fs analysis. This shows that some efforts are being made to boost capacity in Africa. Levels of PCDDs/Fs and dl-PCBs in clay consumed by pregnant women have been reported in Cameroon, Democratic Republic of Congo (DRC), Nigeria, Zimbabwe, Cote d'Ivoire, and Uganda with a maximum concentration of 103 pg TEQ/g. This finding was very significant since women are the most impacted through exposure to POPs, a fact that is acknowledged by the SC. PMID- 30414031 TI - Performance of a constructed wetland as an upstream intervention for stormwater runoff quality management. AB - In most developing countries, stormwater runoff has had significant impacts on aquatic environment by directly causing pollution of receiving water and reduction in treatment performance of wastewater treatment plants. With increasing encroachment on natural wetlands in Uganda, constructed wetlands offer a feasible option for the environment to cope up and buffer the impact of pollutants from the ever-increasing urban masses. This study investigated the performance efficiencies of three configurations (varied by the substrate used) of microcosm wetlands to remove physicochemical parameters from stormwater runoff in Uganda. The parameters monitored included chemical oxygen demand (COD), total suspended solids (TSS), total nitrogen (TN), and total phosphorus (TP). Hydraulic retention times (HRTs) of 2, 4, 6, and 8 days were studied. The mean concentrations of the physicochemical parameters in the runoff were 219.4 +/- 12.8 mg/L COD, 77.4 +/- 8.3 mg/L TSS, 9.0 +/- 0.4 mg/L TN, and 1.6 +/- 0.1 mg/L TP. Configuration A, vegetated with cattail (Typha latifolia) and bulrush (Scirpus lacustris), achieved maximum COD removal of 75.9% (HRT = 6 days), TN removal of 72.8% (HRT = 8 days), and TP removal of 62.8% (HRT = 8 days). Configuration C, the control, with no substrate, achieved the highest TSS removal of 75.6%. The results suggest that vegetated microcosm constructed wetlands can potentially be used to pre-treat stormwater within the catchment. However, an upstream sedimentation process unit is required to enhance their performance and to avoid premature clogging of the wetlands by TSS. The pre-treated stormwater reduces pollutant load into wastewater treatment plants and consequently better raw water quality for water treatment plants. PMID- 30414032 TI - Greenhouse gas emissions vary in response to different biochar amendments: an assessment based on two consecutive rice growth cycles. AB - The efficiency of biochar to mitigate greenhouse gas (GHG) emission from rice paddy soils is not consistent. Furthermore, which factor dominates this mitigation efficiency is not clear. In the present 2-year greenhouse experiment, the effects of biochars derived from two feedstocks (wheat straw and saw dust) and two pyrolysis temperatures (500 degrees C and 700 degrees C), and applied at two different rates (0.5 wt% and 3 wt%) on methane (CH4) and nitrous oxide (N2O) emissions, and the total global warming potential (GWPt), and GHG intensity (GHGI) were measured. The results showed that biochar applications did not alter GHG emission flux patterns in either rice cycle. In 2015, the N2O emissions were 24.6-71.2% lower under six biochar treatments than under the urea control treatment. Moreover, total CH4 emissions were mitigated by 13.3-92.6% and 27.7 53.5% under six and five biochar treatments in 2015 and 2016, respectively. Overall, lower GWPt and GHGI were observed under most of the biochar treatments compared with the urea control treatment in both rice cycles. The multivariate analysis of variance (MANOVA) results of the data from both years suggested that the biochar effects on reducing GHG emissions changed with either individual factors or their interactive effects. The responses of the GWPt and GHGI varied mainly with biochar application rate and pyrolysis temperature (P < 0.005); compared with that derived from a relatively low pyrolysis temperature and applied at a relatively low rate, biochar derived from a relatively high pyrolysis temperature and applied at a relatively high rate exerted relatively higher GWPt and GHGI mitigation efficiencies. The influence of the feedstock source was not as prominent as the application rate and pyrolysis temperature, which will expand the scope of biochar applications. PMID- 30414033 TI - ASO Author Reflections: Impact of Breast Cancer Screening Beyond Mortality Reductions. PMID- 30414034 TI - ASO Author Reflections: Long-Term Survival of Patients with Thin (T1) Cutaneous Melanomas. PMID- 30414035 TI - ASO Author Reflections: Metaplastic Breast Cancer-The Case for Doing Less and More. PMID- 30414036 TI - Robotic Repeat Right Hepatectomy for Recurrent Colorectal Liver Metastasis. AB - BACKGROUND: Repeat hepatectomy often is required for primary and metastatic tumors. The purpose of this video was to present a robotic repeat hepatectomy for recurrent colorectal metastasis after multiple previous open surgeries. PATIENT: A 64-year-old man underwent open left colectomy complicated by anastomotic leak. He was reoperated for colostomy, which was reverted. One year later, he underwent open metastasectomy. Recently, he presented a recurrence in the right liver, and a robotic right hepatectomy was indicated. TECHNIQUE: This approach used five trocars. The operation began with adhesiolysis. The next step was to dissect and divide the right hepatic artery and the right portal vein. A retrohepatic tunnel is created on the right side of the inferior vena cava for a modified liver hanging maneuver. The liver was pulled upwards and liver transection resumed towards the right hepatic vein. The liver was divided with bipolar forceps under continuous saline irrigation. The right hepatic duct was found inside the liver and was divided. Finally, the right hepatic vein was divided inside the liver parenchyma using a vascular stapler, and robotic right hepatectomy was completed. RESULTS: The operative time for docking was 10 min; adhesiolysis took 90 min while robotic right hepatectomy was completed in 240 min. The Pringle maneuver was not used. Estimated blood loss was 150 mL with no need for transfusion. Recovery was uneventful, and the patient was discharged on the fifth postoperative day. CONCLUSIONS: Robotic repeat hepatectomy is feasible and safe in experienced hands and may have some advantages over laparoscopic and open repeat liver resections. PMID- 30414037 TI - ASO Author Reflections: Salvage Surgery for Anal Cancer. PMID- 30414038 TI - Appendiceal Cancer Patient-Specific Tumor Organoid Model for Predicting Chemotherapy Efficacy Prior to Initiation of Treatment: A Feasibility Study. AB - INTRODUCTION: We have hypothesized that biofabrication of appendiceal tumor organoids allows for a more personalized clinical approach and facilitates research in a rare disease. METHODS: Appendiceal cancer specimens obtained during cytoreduction with hyperthermic intraperitoneal chemotherapy procedures (CRS/HIPEC) were dissociated and incorporated into an extracellular matrix-based hydrogel system as three-dimensional (3D), patient-specific tumor organoids. Cells were not sorted, preserving tumor heterogeneity, including stroma and immune cell components. Following establishment of organoid sets, chemotherapy drugs were screened in parallel. Live/dead staining and quantitative metabolism assays recorded which chemotherapies were most effective in killing cancer cells for a specific patient. Maintenance of cancer phenotypes were confirmed by using immunohistochemistry. RESULTS: Biospecimens from 12 patients were applied for organoid development between November 2016 and May 2018. Successful establishment rate of viable organoid sets was 75% (9/12). Average time from organoid development to chemotherapy testing was 7 days. These tumors included three high grade appendiceal (HGA) and nine low-grade appendiceal (LGA) primaries obtained from sites of peritoneal metastasis. All tumor organoids were tested with chemotherapeutic agents exhibited responses that were either similar to the patient response or within the variability of the expected clinical response. More specifically, HGA tumor organoids derived from different patients demonstrated variable chemotherapy tumor-killing responses, whereas LGA organoids tested with the same regimens showed no response to chemotherapy. One LGA set of organoids was immune-enhanced with cells from a patient-matched lymph node to demonstrate feasibility of a symbiotic 3D reconstruction of a patient matched tumor and immune system component. CONCLUSIONS: Development of 3D appendiceal tumor organoids is feasible even in low cellularity LGA tumors, allowing for individual patient tumors to remain viable for research and personalized drug screening. PMID- 30414039 TI - Can Patients with Multiple Breast Cancers in the Same Breast Avoid Mastectomy by Having Multiple Lumpectomies to Achieve Equivalent Rates of Local Breast Cancer Recurrence? Response to the Preliminary Alliance 11102 Trial Report. PMID- 30414040 TI - ASO Author Reflections: Surgery and Bevacizumab in Ovarian Cancer. PMID- 30414041 TI - Attributed social context and emotional content recruit frontal and limbic brain regions during virtual feedback processing. AB - In communication, who is communicating can be just as important as what is said. However, sender identity in virtual communication is often inferred rather than perceived. Therefore, the present research investigates the brain structures activated by sender identity attributions and evaluative feedback processing during virtual communication. In a functional magnetic resonance imaging (fMRI) study, 32 participants were told that they would receive personality feedback, either sent from another human participant or from a randomly acting computer. In reality, both conditions contained random but counterbalanced feedback, automatically delivered by approving or denying negative, neutral, or positive adjectives. Although physically identical, feedback attributed to the "human" sender activated multiple regions within a "social brain" network, including the superior frontal, medial prefrontal, and orbitofrontal cortex, anterior and posterior parts of the cingulate cortex, and the bilateral insula. Regardless of attributed sender, positive feedback increased responses in the striatum and bilateral amygdalae, while negative compared to neutral feedback elicited stronger insula and somatosensory responses. These results reveal the recruitment of an extensive mentalizing and social brain network by mere sender attributions and the activation of brain structures related to reward and punishment by verbal feedback, demonstrating its embodied processing. PMID- 30414042 TI - A CON-based NMR assignment strategy for pro-rich intrinsically disordered proteins with low signal dispersion: the C-terminal domain of histone H1.0 as a case study. AB - The C-terminal domain of histone H1.0 (C-H1.0) is involved in DNA binding and is a main determinant of the chromatin condensing properties of histone H1.0. Phosphorylation at the (S/T)-P-X-(K/R) motifs affects DNA binding and is crucial for regulation of C-H1.0 function. Since C-H1.0 is an intrinsically disordered domain, solution NMR is an excellent approach to characterize the effect of phosphorylation on the structural and dynamic properties of C-H1.0. However, its very repetitive, low-amino acid-diverse and Pro-rich sequence, together with the low signal dispersion observed at the 1H-15N HSQC spectra of both non- and tri phosphorylated C-H1.0 preclude the use of standard 1H-detected assignment strategies. We have achieved an essentially complete assignment of the heavy backbone atoms (15N, 13C' and 13Calpha), as well as 1HN and 13Cbeta nuclei, of non- and tri-phosphorylated C-H1.0 by applying a novel 13C-detected CON-based strategy. No C-H1.0 region with a clear secondary structure tendency was detected by chemical shift analyses, confirming at residue level that C-H1.0 is disordered in aqueous solution. Phosphorylation only affected the chemical shifts of phosphorylated Thr's, and their adjacent residues. Heteronuclear {1H}-15N NOEs were also essentially equal in the non- and tri-phosphorylated states. Hence, structural tendencies and dynamic properties of C-H1.0 free in aqueous solution are unmodified by phosphorylation. We propose that the assignment strategy used for C-H1.0, which is based on the acquisition of only a few 3D spectra, is an excellent choice for short-lived intrinsically disordered proteins with repetitive sequences. PMID- 30414044 TI - Correction to: Effects of Blood Flow Restriction Training on Muscular Strength and Hypertrophy in Older Individuals: A Systematic Review and Meta-Analysis. AB - Figures 2 and 3 were transposed. PMID- 30414043 TI - Emerging Scholar Best Article Award, 2018. PMID- 30414045 TI - Chronic vagal nerve stimulation exerts additional beneficial effects on the beta blocker-treated failing heart. AB - Vagal nerve stimulation (VNS) induces bradycardia in chronic heart failure (CHF). We hypothesized that beta-blocker would cover the beneficial effects of VNS on CHF if the anti-beta-adrenergic effect was the main VNS effect. This study investigated the effects of VNS on cardiac remodeling in rats with CHF treated with metoprolol. Two weeks after myocardial infarction, surviving rats were randomly assigned to groups of sham stimulation (SS), sham stimulation with metoprolol (SSM), or VNS with metoprolol (VSM). Compared to the SS group, heart rate was significantly reduced in the SSM and VSM groups. Hemodynamic assessments showed that VSM rats maintained better cardiac pump function and presented higher cardiac index and lower heart weight than SSM rats. VSM was also associated with lower plasma brain natriuretic peptide and norepinephrine levels than SSM. VSM but not SSM improved the 50-day survival rate compared with the SS group. The results suggest that VNS may exert its beneficial effects on the failing heart independently of its anti-beta-adrenergic mechanism. PMID- 30414046 TI - Emerging Strategies in the Treatment of Duchenne Muscular Dystrophy. AB - Duchenne muscular dystrophy (DMD) is a progressive X-linked degenerative muscle disease due to mutations in the DMD gene. Genetic confirmation has become standard in recent years. Improvements in the standard of care for DMD have led to improved survival. Novel treatments for DMD have focused on reducing the dystrophic mechanism of the muscle disease, modulating utrophin protein expression, and restoring dystrophin protein expression. Among the strategies to reduce the dystrophic mechanisms are 1) inhibiting inflammation, 2) promoting muscle growth and regeneration, 3) reducing fibrosis, and 4) facilitating mitochondrial function. The agents under investigation include a novel steroid, myostatin inhibitors, idebenone, an anti-CTGF antibody, a histone deacetylase inhibitor, and cardiosphere-derived cells. For utrophin modulation, AAV-mediated gene therapy with GALGT2 is currently being investigated to upregulate utrophin expression. Finally, the strategies for dystrophin protein restoration include 1) nonsense readthrough, 2) synthetic antisense oligonucleotides for exon skipping, and 3) AAV-mediated micro/minidystrophin gene delivery. With newer agents, we are witnessing the use of more advanced biotechnological methods. Although these potential breakthroughs provide significant promise, they may also raise new questions regarding treatment effect and safety. PMID- 30414047 TI - 2018 Colorado Alphaherpesvirus Latency Society Symposium. AB - Meeting Report on the 8th Annual Symposium of the Colorado Alphaherpesvirus Latency Society (CALS), held on May 16-19, 2018, in Vail, Colorado. PMID- 30414048 TI - Enhanced facilitation and diminished inhibition characterizes the pronociceptive endogenous pain modulatory balance of persons living with HIV and chronic pain. AB - Chronic pain in persons living with HIV (PLWH) may be related to alterations in endogenous pain modulatory processes (e.g., high facilitation and low inhibition of nociception) that promote exaggerated pain responses, known as hyperalgesia, and central nervous system (CNS) sensitization. This observational study examined differences in endogenous pain modulatory processes between 59 PLWH with chronic pain, 51 PLWH without chronic pain, and 50 controls without HIV or chronic pain. Quantitative sensory testing for temporal summation (TS) of mechanical and heat pain as well as conditioned pain modulation (CPM) were used to assess endogenous pain facilitatory and inhibitory processes, respectively. Associations among TS, CPM, and self-reported clinical pain severity were also examined in PLWH with chronic pain. Findings demonstrated significantly greater TS of mechanical and heat pain for PLWH with chronic pain compared to PLWH without chronic pain and controls. CPM effects were present in controls, but not in either PLWH with or without chronic pain. Among PLWH with chronic pain, greater TS of mechanical pain was significantly associated with greater average clinical pain severity. Results of this study suggest that enhanced facilitation and diminished inhibition characterizes the pronociceptive endogenous pain modulatory balance of persons living with HIV and chronic pain. PMID- 30414049 TI - Quantitative electroencephalography supports diagnosis of natalizumab-associated progressive multifocal leukoencephalopathy. AB - Long-term treatment of multiple sclerosis with natalizumab (NTZ) carries the risk of a devastating complication in the form of an encephalopathy caused by a reactivation of a latent John Cunningham virus infection (progressive multifocal leucoencephalopathy, PML). Early diagnosis is associated with considerably better prognosis. Quantitative EEG as an objective, rater-independent technique provides high sensitivity (88%) and specificity (82%) for the diagnosis of NTZ-PML. Combination of diagnostic modalities addressing static morphological (brain MRI) as well as functional (EEG) pathologic changes may improve risk management programmes. PMID- 30414050 TI - Influence of various intensities of 528 Hz sound-wave in production of testosterone in rat's brain and analysis of behavioral changes. AB - Testosterone is a nuclear androgen receptor ligand that controls multiple pathways in brain. In addition to the active biosynthesis of steroids in classic steroidogenic organs such as gonads, adrenals and placenta, testosterone also produced in astrocyte cells of brain. Testosterone and its level must be regulated in brain; because, it directly and indirectly affects memory and several key behavioral characteristics. The significance of sound waves on key enzymes that regulate levels of testosterone in brain has not been investigated. The aim of our study was to examine physical stress of such as sound on induction behavioral changes in animal models. According to the current study, sound waves with 528 Hz frequency in 100 dB intensity induce testosterone production in brain by enhancing StAR and SF-1 and reducing P450 aromatase gene expression. Frequency of 528 Hz also reduces total concentration of reactive oxidative species in brain tissue. Prolonged exposure to this sound wave showed reduction of anxiety related behaviors in rats. The results reveal that reduced anxiety is related to increased concentration of testosterone in brain. This study may lead to ascertain a possible therapy in which sounds may be utilized to reduce anxiety in individual. PMID- 30414051 TI - Cerebrolysin for the Treatment of Aneurysmal Subarachnoid Hemorrhage in Adults: A Retrospective Chart Review. AB - INTRODUCTION: Cerebrolysin is a neuroprotective drug used in the treatment of acute ischemic stroke. To our knowledge, this drug has never been evaluated in patients with aneurysmal subarachnoid hemorrhage (SAH). The aim of this study was to evaluate the effect of Cerebrolysin in patients with aneurysmal SAH. METHODS: Aneurysmal SAH patients who had their aneurysm obliterated at our institution from 2007 to 2016 were retrospectively studied. Patients received Cerebrolysin treatment or standard care only (control group). Subgroup analyses were performed according to Hunt and Hess grade (good grade <= 2, N = 216; poor grade >= 3, N = 246) and treatment procedure (clip or coil). RESULTS: In good-grade patients (N = 216), clinical outcomes and mortality did not differ significantly between the control and Cerebrolysin groups. In poor-grade patients (N = 246), the mortality rate was significantly lower in the Cerebrolysin group (8.7%) than in the control group (25.4%, p = 0.006). In patients who received microsurgical clipping (N = 328), the mortality rate was significantly lower in the Cerebrolysin group (7.3%) than in the control group (18.5%, p = 0.016). CONCLUSION: Cerebrolysin injection during the acute period of SAH appeared to reduce the mortality rate, especially in poor-grade patients. This study suggests the potential of Cerebrolysin for treating aneurysmal SAH. Further studies are needed to confirm our results. PMID- 30414052 TI - Bismuth-related acute neurotoxicity as stroke mimic: a case report. PMID- 30414053 TI - Mapping of QTL associated with seed longevity in durum wheat (Triticum durum Desf.). AB - Regeneration cycle of seeds kept at genebanks is determined by seed longevity. Information about longevity of species is important for storage periods, germination test intervals, and reproduction cycles. Seed longevity is different between species and depends on the storage conditions. It also differs between genotypes of a species providing the basis of genetic analyses of seed longevity. Studies in hexaploid wheat and barley have identified numerous quantitative trait locus (QTL) linked to the trait. Seed longevity in durum wheat, however, has not been attempted so far. Here, we present the first report of genetic analysis of grain longevity in durum wheat using a bi-parental mapping population composed of 114 recombinant inbred lines. QTL analysis identified three highly significant and one significant QTL for initial germination (on chromosomes 4B, 5A (2 QTL), and 6B), three significant QTL for germination after accelerated aging treatment (on chromosomes 5A and 7B (2 QTL)), and five significant QTL determining relative germination and distributed on chromosomes 3A, 3B, 5A, 6B, and 7B. This study confirms the results of previous investigations in bread wheat and provides a baseline for further research in durum wheat. PMID- 30414054 TI - Using extra systoles and the micro-fluid challenge to predict fluid responsiveness during cardiac surgery. AB - Fluid responsiveness prediction is difficult during cardiac surgery. The micro fluid challenge (micro-FC; rapid central infusion of 50 ml) and the extrasystolic method utilising post-extrasystolic preload increases may predict fluid responsiveness. Two study windows during coronary artery bypass graft surgery were defined, 1: After anaesthesia induction until surgical incision, 2: Left internal mammarian artery surgical preparation period. Each window consisted of 10-15 min observation for extrasystoles before a micro-FC was performed, after which a traditional fluid challenge (FC) was performed (5 ml/kg). Extrasystolic and micro-FC induced changes in hemodynamic variables were derived as predictors of fluid responsiveness defined as stroke volume increasing > 10% following FC. 61 patients were studied. Post-ectopic changes in pulse pressure (PP) predicted fluid responsiveness with receiver operating characteristic area (AUC) of 0.69 [CI 0.40;0.97] in the first study window and 0.64 [0.44;0.86] in the second window. Other post-ectopic predictors such as pre-ejection period (PEP) and systolic blood pressure (SBP) had similar or lower AUCs. Heart rate was 52.9 (SD +/-8.4) min- 1 and 53.6 (+/- 8.8) min- 1 in the two study windows. Micro-FC induced changes in PEP had AUC of 0.74 [0.57;0.90] in the first window and 0.60 [0.40;0.76] in the second window. Correcting micro-FC induced changes in PEP for the micro-FC induced changes in heart rate had AUCs of 0.84 [0.70;0.97] in the first window and 0.63 [0.47;0.79] in the second window. The investigated methods revealed insufficient validity during cardiac surgery. RR interval corrected changes during a micro-FC should be investigated further. Trial registration Clinicaltrials.gov: NCT03002129. PMID- 30414055 TI - A sticking sensation in the throat! PMID- 30414056 TI - Treatment of apixaban- and rivaroxaban-associated major bleeding using 4-factor prothrombin complex concentrate. AB - There is limited clinical experience with the use of coagulation concentrates to reverse the effect of direct oral anticoagulants. We assess the achievement of effective clinical hemostasis with the use of 4-factor prothrombin complex concentrate (PCC) in patients on apixaban or rivaroxaban presenting with major bleeding. A retrospective chart review was conducted at a tertiary referral medical center in the USA. We assess the achievement of clinical hemostasis using 4-factor PCC in patients on chronic apixaban or rivaroxaban therapy presenting with major bleeding. Clinical hemostasis was assessed by the International Society of Thrombosis and Hemostasis Scientific and Standardization Subcommittee criteria. A total of 29 patients are included in the study. The most common site of bleeding was intracranial hemorrhage (ICH) (72.4%), followed by gastrointestinal bleed (13.8%). Clinical hemostasis was achieved in 21 (72.4%) patients. Patients who did not achieve clinical hemostasis (27.6%) suffered from ICH, and all of them died during hospitalization except for two patients who were discharged with neurologic deterioration. One patient developed multiple brain infarctions after receiving 4-factor PCC. Sixteen patients (55.2%) were receiving concomitant medications that interact with apixaban and rivaroxaban and increase the risk of bleeding. Four-factor PCC appears to be effective in achieving clinical hemostasis in patients on apixaban or rivaroxaban presenting with major bleeding. It may be an alternative to patients who need anticoagulation reversal if the specific antidote, andexanet alfa, is not available. PMID- 30414058 TI - Isolation, Propagation, and Clonogenicity of Intestinal Stem Cells. AB - Intestinal stem cell research has greatly aided our understanding of the biology of intestinal self-renewal but has also shed light on the role of cancer stem cells (CSCs) in carcinogenesis, cancer growth, and dissemination. With new possibilities for CSC targeting, there is a need to have established techniques for quantifying (cancer) stem cell clonogenicity, particularly in organoid cultures. Here, we describe a detailed methodology for the isolation and expansion of mouse intestinal crypts from three different locations-the colon, proximal, and distal small intestine. In addition, we describe techniques that allow the measurement of stem cell clonogenicity and its manipulation using two approaches-organoid counting and immunohistochemistry. PMID- 30414057 TI - The Unique Spectrum of Mutations in Patients with Hereditary Tyrosinemia Type 1 in Different Regions of the Russian Federation. AB - BACKGROUND: Hereditary tyrosinemia (HT1) is an autosomal recessive disorder characterized by impaired tyrosine catabolism because of fumarylacetoacetate hydrolase deficiency. HT1 is caused by homozygous or compound heterozygous mutations in the FAH gene. The HT1 frequency worldwide is 1:100,000-1:120,000 live births. The frequency of HT1 in the Russian Federation is unknown. AIM: To estimate the spectrum of mutations in HT1 in several ethnic groups of the Russian Federation. MATERIALS AND METHODS: From 2004 to 2017, 43 patients were diagnosed with HT1. The analysis of amino acids and succinylacetone was performed using NeoGram Amino Acids and Acylcarnitines Tandem Mass Spectrometry Kit and a Sciex QTrap 3200 quadrupole tandem mass spectrometer. Bi-directional DNA sequence analysis was performed on PCR products using an ABI Prism 3500. RESULTS: In the Russian Federation, the most common mutation associated with HT1 (32.5% of all mutant alleles) is c.1025C>T (p.Pro342Leu), which is typical for the Chechen ethnic group. Patients of the Yakut, the Buryat, and the Nenets origins had a homozygous mutation c.1090G>C (p.Glu364Gln). High frequency of these ethnicity specific mutations is most likely due to the founder effect. In patients from Central Russia, the splicing site mutations c.554-1G>T and c.1062+5G>A were the most prevalent, which is similar to the data obtained in the Eastern and Central Europe countries. CONCLUSION: There are ethnic specificities in the spectrum of mutations in the FAH gene in HT1. The Chechen Republic has one of the highest prevalence of HT1 in the world. PMID- 30414059 TI - ASNC at 25. PMID- 30414060 TI - Heart rate and 123I-MIBG in heart failure with preserved ejection fraction: More variability and slower washout-A secret recipe for better survival. PMID- 30414061 TI - The Interplay Between Maladaptive Personality Traits and Mindfulness Deficits Among Adolescent Regular Gamblers: A Mediation Model. AB - Authors aimed to examine an explanatory model of risk that started with dysfunctional personality trait domains, passed through low levels of mindfulness, and culminated with problem gambling. For individuals with problem gambling, mindfulness may provide a significant avenue to prevent them from engaging in addictive behaviors and lead them to an improved sense of self control and emotion regulation. We employed a mediation analysis design assessing 326 Caucasian adolescent regular gamblers ranging in age from 15 to 17 years who were recruited in betting or bingo halls. Using the Personality Inventory for DSM 5-Brief Form (PID-5-BF)-Children, the South Oaks Gambling Screen, and the Child and Adolescent Mindfulness Measure, we examined the hypothesis that low levels of mindfulness partially mediate the relationship between dysfunctional personality trait domains and problem gambling. The findings underline the role that may play by the core skills of mindfulness. Indeed, results suggest how adolescents with personalities characterized by antagonism, disinhibition, and negative affectivity may tend toward a lack of awareness of self-related mental states and difficulty purposefully regulating attention and dealing with negative emotions that predispose them to gambling as a means of escape from uncomfortable feelings. PMID- 30414062 TI - Rethinking the doctor-patient relationship: toward a hermeneutically-informed epistemology of medical practice. AB - Although typically implicit, clinicians face an inherent conflict between their roles as medical healers and as providers of technical biomedicine (Scott et al. in Philos Ethics Humanit Med 4:11, 2009). This conflict arises from the tension between the physicalist model which still predominates in medical training and practice and the extra-physicalist dimensions of medical practice as epitomised in the concept of patient-centred care. More specifically, the problem is that, as grounded in a "borrowed" physicalist philosophy, the dominant "applied scientist" model exhibits a number of limitations which severely restrict its ability to underwrite the effective practice of care. Moreover, being structural in character, these problems cannot be resolved by piecemeal modifications of the existing model, nor by an appeal to evidence-based medicine (Miles in J Eval Clin Pract 15(6):887-890, 2009; Miles in Folia Med 55(1):5-24, 2013; Miles et al. in J Eval Clin Pract 14(5):621-649, 2008). Hence, the need for medical theorists to "partner with experts in the humanities to build a sui generis philosophy of medicine" (Whatley in J Eval Clin Pract 20(6):961-964, 2014, p. 961). In response, the present paper seeks to vindicate the merits of hermeneutically informed template in providing the requisite grounding. While capable of correcting for the limitations of the applied scientist model, a hermeneutically informed template is a "both/and" approach, which seeks to complement rather than exclude the physicalist dimension, and thereby aspires to reconcile technical mastery with patient-centred care, rather than eschew one in favour of the other. As such, it can provide a cogent philosophical template for current best practice, which does justice to the art as well as the science of medical care. PMID- 30414063 TI - The burden of cancer in Spain. AB - INTRODUCTION: Cancer imposes a huge financial burden in all developed countries. This study estimates the burden of cancer in Spain in 2015. METHODS: The most recent available epidemiological data on prevalence, incidence and mortality, and the economic data on direct (hospital, drugs, and primary care) and indirect (productivity) costs was used from the social perspective. RESULTS: Prevalence, incidence, and mortality were, respectively, 1240, 478, and 218 per 100,000 inhabitants. Mortality was higher for men, while disability rates were higher for women. Direct costs accounted for 4818 million euros and indirect costs were 640 million euros in 2015. Direct costs were almost completely borne by the hospital (94%). Total burden of cancer in Spain was 5458 million euros in 2015. CONCLUSIONS: In Spain, the costs of cancer were mainly borne by the hospital and these costs might increase in the future due to the expected increase in longevity. Further research would be needed to investigate whether it is possible to redistribute the economic burden of cancer. PMID- 30414064 TI - Efficacy of Tofacitinib for the Treatment of Psoriatic Arthritis: Pooled Analysis of Two Phase 3 Studies. AB - INTRODUCTION: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). This post hoc analysis assessed the efficacy of tofacitinib using pooled data from two phase 3 studies of patients with active PsA. METHODS: Data were pooled from OPAL Broaden (NCT01877668) and OPAL Beyond (NCT01882439). Patients had active PsA and either an inadequate response (IR) to >= 1 conventional synthetic disease-modifying antirheumatic drug (csDMARD) and were tumor necrosis factor inhibitor (TNFi)-naive (OPAL Broaden), or had IR to >= 1 TNFi (OPAL Beyond). Pooled data included tofacitinib 5 or 10 mg twice daily (BID; to month 6) and placebo (to month 3; patients then switched to tofacitinib 5 or 10 mg BID). Patients also received one background csDMARD. Endpoints included American College of Rheumatology (ACR)20 response and change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at month 3 (primary endpoints), ACR50/70 response, HAQ-DI response (decrease from baseline >= 0.35) and improvements in painful and swollen joint counts, psoriasis, enthesitis and dactylitis to month 6. RESULTS: A total of 710 patients were included (tofacitinib 5 mg BID: 238; tofacitinib 10 mg BID: 236; placebo: 236). Primary endpoints showed significant improvements at month 3 in patients receiving tofacitinib 5 or 10 mg BID vs. placebo. Significant improvements in HAQ DI response, painful and swollen joints, psoriasis, enthesitis and dactylitis vs. placebo were observed for both tofacitinib doses at month 3. Efficacy was maintained to month 6 (final pooled time point). CONCLUSIONS: In a pooled analysis of csDMARD-IR/TNFi-naive and TNFi-IR patients, tofacitinib was superior to placebo at month 3 across four PsA domains: peripheral arthritis, psoriasis, enthesitis and dactylitis. TRIAL REGISTRATION: OPAL Broaden (NCT01877668); OPAL Beyond (NCT01882439). FUNDING: Pfizer Inc. PMID- 30414065 TI - Antiretroviral treatment indications and adherence to the German-Austrian treatment initiation guidelines in the German ClinSurv HIV Cohort between 1999 and 2016. AB - PURPOSE: The aim of the study was to assess guideline adherence to combined antiretroviral therapy (ART) in the German ClinSurv HIV Cohort and the real-life impact of the Strategic Timing of Antiretroviral Therapy (START) study, to identify patients not treated as recommended by new guidelines. METHODS: We used data from the multicenter ClinSurv cohort of the Robert-Koch-Institute (RKI) between 1999 and 2016. Inclusion criteria were people living with HIV/AIDS, >= 18 years of age and cART naive at the first visit (FV). Adherence was defined as starting cART within 6 months of crossing the CD4+ T cell threshold as suggested by the German-Austrian treatment guidelines. Logistic regression was used to identify factors associated with non-adherence. RESULTS: 11,817 patients met the inclusion criteria. We observed an overall adherence rate of 60%, in patients with treatment indication who started cART timely between 2002 and 2015. Adherence rate increased constantly, demonstrating a potential increase in patients, with treatment indication, starting cART within 6 months of presentation from 55% in 2008 to 94% in 2015. Patients reporting injection drug use (OR 2.18, 95% CI 1.70-2.95) and patients between 18 years and 39 years of age at the time of their first visit (OR 2.89, 95% CI 1.35-6.18) were identified as risk groups associated with non-adherence. CONCLUSION: The majority of patients below the CD4+ T cell count threshold of applicable guidelines initiated treatment within 6 months. We observed a slowly diminishing proportion of patients not starting cART timely. Delayed treatment was more frequent in patients reporting injection drug use. PMID- 30414066 TI - Application of Group I Metal Adduction to the Separation of Steroids by Traveling Wave Ion Mobility Spectrometry. AB - Steroids represent an interesting class of small biomolecules due to their use as biomarkers and their status as scheduled drugs. Although the analysis of steroids is complicated by the potential for many isomers, ion mobility spectrometry (IMS) has previously shown promise for the rapid separation of steroid isomers. This work is aimed at the further development of IMS separation for the analysis of steroids. Here, traveling wave ion mobility spectrometry (TWIMS) was applied to the study of group I metal adducted steroids and their corresponding multimers for five sets of isomers. Each set of isomers had a minimum of one dimeric metal ion adduct that exhibited a resolution greater than one (i.e., approaching baseline resolution). Additionally, ion-neutral collision cross sections (CCSs) were measured using polyalanine as a calibrant, which may provide an additional metric contributing to analyte identification. Where possible, measured CCSs were compared to previously reported values. When measuring CCSs of steroid isomers using polyalanine as the calibrant, nitrogen CCS values were within 1.0% error for monomeric sodiated adducts and slightly higher for the dimeric sodiated adducts. Overall, TWIMS was found to successfully separate steroids as dimeric adducts of group I metals. Graphical Abstract ?. PMID- 30414067 TI - Free Radical-Initiated Peptide Sequencing Mass Spectrometry for Phosphopeptide Post-translational Modification Analysis. AB - Free radical-initiated peptide sequencing mass spectrometry (FRIPS MS) was employed to analyze a number of representative singly or doubly protonated phosphopeptides (phosphoserine and phosphotyrosine peptides) in positive ion mode. In contrast to collision-activated dissociation (CAD) results, a loss of a phosphate group occurred to a limited degree for both phosphoserine and phosphotyrosine peptides, and thus, localization of a phosphorylated site was readily achieved. Considering that FRIPS MS supplies a substantial amount of collisional energy to peptides, this result was quite unexpected because a labile phosphate group was conserved. Analysis of the resulting peptide fragments revealed the extensive production of a-, c-, x-, and z-type fragments (with some minor b- and y-type fragments), suggesting that radical-driven peptide fragmentation was the primary mechanism involved in the FRIPS MS of phosphopeptides. Results of this study clearly indicate that FRIPS MS is a promising tool for the characterization of post-translational modifications such as phosphorylation. Graphical Abstract ?. PMID- 30414068 TI - Serum Uric Acid Is Independently Associated with Coronary Calcification in an Asymptomatic Population. AB - Detecting early-stage atherosclerosis is an important step towards cardiovascular disease prevention. Coronary artery calcium (CAC) score is a sensitive and non invasive tool for detecting coronary atherosclerosis. Higher serum uric acid (SUA) levels are known to be associated with cardiovascular diseases. However, there is inconsistency regarding the independence of the association. The aim of our study was to assess the association of CAC and SUA in an asymptomatic population. CAC scans of 281 participants were analyzed in a voluntary screening program. A health questionnaire, physical examination, and laboratory tests were also performed. Participants with a history of cardiovascular disease were excluded from the analysis. 36.3% (n = 102) of the participants had no detectable CAC and 13.9% (n = 39) had a CAC score of > 300. SUA showed positive correlation with CAC score (0.175, p < 0.01). SUA was independently associated with Ca score > 300 (OR 5.17, p = 0.01) after the effects of conventional risk factors were eliminated. PMID- 30414069 TI - Induced Pluripotent Stem Cells in Disease Modelling and Regeneration. AB - The reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) has raised extreme hope among both scientists and society by means of development of personalized and regenerative medicine. The field of stem cell research has been accelerating with a drastic speed afterwards and many iPSC lines has been produced for understanding the mechanisms of many debilitating diseases which arise in a variety of organ systems. In this review article we try to focus on the current research regarding the use of iPSCs in both disease modeling and regeneration. PMID- 30414070 TI - Influence of Heart Rate, Age, and Gender on Heart Rate Variability in Adolescents and Young Adults. AB - Key autonomic functions are in continuous development during adolescence which can be assessed using the heart rate variability (HRV). However, the influence of different demographic and physiological factors on HRV indices has not been fully explored in adolescents. In this study we aimed to assess the effect of age, gender, and heart rate on HRV indices in two age groups of healthy adolescents (age ranges, 13-16 and 17-20 years) and two groups of healthy young adults (21-24 and 25-30 years). We addressed the issue using 5-min ECG recordings performed in the sitting position in 255 male and female participants. Time, frequency, and informational domains of HRV were calculated. Changes in HRV indices were assessed using a multiple linear regression model to adjust for the effects of heart rate, age, and gender. We found that heart rate produced more significant effects on HRV indices than age or gender. There was a progressive reduction in HRV with increasing age. Sympathetic influence increased with age and parasympathetic influence progressively decreased with age. The influence of gender was manifest only in younger adolescents and young adults. In conclusion, age, gender, and particularly heart rate have a substantial influence on HRV indices, which ought to be considered to avoid biases in the study of the autonomic nervous system development. The lack of the gender-related effects on HRV indices in late adolescence could be related to non-completely achieved maturity of the autonomic mechanisms, which deserves further exploration. PMID- 30414071 TI - After Hours: A Survey of Moonlighting Practices in Psychiatry Residents. AB - OBJECTIVE: The authors surveyed psychiatry residents to determine who participates in moonlighting and to understand their views and opinions on the necessity, importance, and educational value of moonlighting. METHODS: An electronic survey was distributed to psychiatry residents at 16 programs nationally. Descriptive characteristics were calculated. Logistic and linear regressions were performed to determine differences between those who moonlight and those who do not and to assess differences in measures of financial distress, quality of life, and work-life balance. RESULTS: A total of 173/624 (27.6%) residents participated. Within the subset allowed to moonlight, 50% (47/94) reported moonlighting during prior academic year, for an average of 17.4 +/- 8.6 hoursh per month. Within those eligible to moonlight, there were no differences in perceived financial distress, quality of life, work-life balance, and confidence between residents who moonlighted and those who did not. Among moonlighters, 10.6% moonlighted overnight before working the next day, and only 68.1% included moonlighting when recording duty hours. 45% reported no supervision available while moonlighting. CONCLUSIONS: In the study sample, 50% of psychiatry residents eligible to moonlight opted to do so. Though most programs have policies in place regarding moonlighting, programs may benefit from ensuring that residents are reporting moonlighting in duty hours and that supervision is available to those moonlighting. PMID- 30414072 TI - Requiring Buprenorphine Waivers for Psychiatry Residents. PMID- 30414073 TI - Serum and histological IgG4-negative type 1 autoimmune pancreatitis. AB - A 66-year-old man who was on oral medication for type 2 diabetes experienced a rapid decline in glycemic control (increase in glycosylated hemoglobin level from 7.7 to 10.2% over 3 months). Abdominal ultrasonography revealed a 20-mm hypoechoic mass in the pancreatic tail. Serum tumor marker carbohydrate antigen 19-9 and DUPAN2 levels were within the respective normal ranges; serum IgG4 level was also normal at 21.8 mg/dL. Abdominal contrast computed tomography revealed a 26-mm tumor in the pancreatic tail. Magnetic resonance cholangiopancreatography revealed disruption of the main pancreatic duct and dilation of the caudal pancreatic duct. Endoscopic ultrasonography revealed a near-round-shaped hypoechoic mass with interspersed hyperechoic areas. Endoscopic ultrasonography guided fine needle aspiration was performed using a 22-G needle, but no malignant findings were observed. There were no signs of sialadenitis, retroperitoneal fibrosis, nephropathy, or other conditions associated with IgG4-related diseases. Distal pancreatectomy was performed; a 23-mm white mass was resected from the pancreatic tail. A histopathological examination showed advanced inflammatory cell infiltration mainly involving lymphocytes/plasma cells along with storiform fibrosis and obliterative phlebitis. No more than five IgG4-positive cells were observed per high-power field. These were level 1 pathological findings, and a definitive diagnosis of type 1 autoimmune pancreatitis (AIP) was made according to the International Consensus Diagnostic Criteria. Type 1 AIP associated with normal serum IgG4 levels and absence of IgG4-positive cells on histological examination is a rare clinical entity, which is very difficult to distinguish from pancreatic cancer. Here we report such a case and present a review of the relevant literature. PMID- 30414074 TI - Determining Value in Health Technology Assessment: Stay the Course or Tack Away? AB - The economic evaluation of new health technologies to assess whether the value of the expected health benefits warrants the proposed additional costs has become an essential step in making novel interventions available to patients. This assessment of value is problematic because there exists no natural means to measure it. One approach is to assume that society wishes to maximize aggregate health, measured in terms of quality-adjusted life-years (QALYs). Commonly, a single 'cost-effectiveness' threshold is used to gauge whether the intervention is sufficiently efficient in doing so. This approach has come under fire for failing to account for societal values that favor treating more severe illness and ensuring equal access to resources, regardless of pre-existing conditions or capacity to benefit. Alternatives involving expansion of the measure of benefit or adjusting the threshold have been proposed and some have advocated tacking away from the cost per QALY entirely to implement therapeutic area-specific efficiency frontiers, multicriteria decision analysis or other approaches that keep the dimensions of benefit distinct and value them separately. In this paper, each of these alternative courses is considered, based on the experiences of the authors, with a view to clarifying their implications. PMID- 30414075 TI - To contemplate or not to contemplate evaluating a preliminary intervention proposal in an outpatient setting: the contemplation therapy group. AB - PURPOSE: The concept for the contemplation group intervention was derived from motivational interviewing (MI) to support people suffering from an eating disorder who are reluctant to engage with treatment. This evaluation focuses on the contemplation group run by the eating disorder services in the Cardiff and Vale area between 2012 and 2016 to investigate the outcomes for participants and implications for working with people suffering from an eating disorder who are ambivalent about change. METHOD: Quantitative measures were used to assess eating disorder symptomatology, motivation to change and location within the stages of change model. A brief qualitative evaluation of client experiences was also included. RESULTS: While dropout was high, a number of patients displayed increased readiness for treatment at the end of the group or even started to engage in change-focussed therapy. Participants who completed the group described it as challenging but helpful. CONCLUSIONS: This evaluation shows that explorative contemplation of their ambivalence towards their eating disorder and treatment was helpful for the participants of the group and supported them in achieving more clarity and decisiveness regarding whether to engage in treatment or not. Further research is needed to evaluate long-term outcomes for patients who feel ambivalent towards treatment, and to explore what interventions can be used to help them. EVIDENCE LEVEL: Level IV: Evidence obtained from multiple time series with or without the intervention. PMID- 30414076 TI - Psychometric properties of the modified Yale Food Addiction Scale Version 2.0 in an Italian non-clinical sample. AB - PURPOSE: To assess the dimensionality and psychometric properties of the modified Yale Food Addiction Scale 2.0 (mYFAS 2.0) in an Italian non-clinical sample. METHODS: 262 adults (184 women) were administered the Italian versions of the mYFAS 2.0, and questionnaires measuring binge eating severity, anxiety and depression symptoms, and emotional dysregulation. RESULTS: 15 individuals (5.7%) met the criteria for a diagnosis of food addiction according to the mYFAS 2.0. Bayesian confirmatory factor analysis supported a single-factor solution for the mYFAS 2.0. The mYFAS 2.0 had good internal consistency (Ordinal alpha = 0.91), and convergent validity with binge eating severity (r = 0.67, p < 0.001), both anxiety (r = 0.31, p < 0.001) and depressive (r = 0.35, p < 0.001) symptoms, and difficulties in emotion regulation (r = 0.35, p < 0.001). Finally, both discriminant validity with dietary restraint (Gamma = 0.11; p = 0.52) and incremental validity in predicting binge eating severity over emotion dysregulation and psychopathology (b = 0.52; t = 11.11; p < 0.001) were confirmed. CONCLUSIONS: The Italian mYFAS 2.0 has satisfactory psychometric properties and can be used as a brief instrument for the assessment of addictive eating behaviors when time constraints prevent the use of the original version. LEVEL OF EVIDENCE: Level V, cross-sectional descriptive study. PMID- 30414077 TI - Breakfast consumption pattern and its association with overweight and obesity among university students: a population-based study. AB - PURPOSE: To determine the association between breakfast consumption habit and overweight and obesity in a sample of Iranian university students. METHODS: A sample of 78,905 university students, aged 18 years or older, was recruited from 28 provinces in Iran to assess breakfast consumption pattern. Breakfast consumption habit was evaluated using a pre-tested questionnaire. Weight and height were measured using standard protocol and then body mass index (BMI) was calculated. Overweight (obesity included) and obesity were defined as BMI >= 25 and BMI >= 30 kg/m2, respectively. RESULTS: Mean age of participants was 21.50 +/ 4.01. After controlling for potential confounders, participants who ate breakfast > 4 days/week had 15% lower risk of overweight compared with those who ate < 1 day/week (OR: 0.85, 95% CI 0.78-0.92). Such significant association was also seen in female students (OR: 0.82, 95% CI 0.72-0.93); however, it was marginally significant in male ones (OR: 0.89, 95% CI 0.79-1.00). In addition, a significant inverse association was found between breakfast consumption and obesity (OR: 0.74, 95% CI 0.64-0.85) such that after adjusting for potential confounders, students who consumed breakfast > 4 days/week were 33% less likely to be obese compared with those who consumed it < 1 day/week (OR: 0.67, 95% CI 0.57-0.78). Such significant inverse association was also seen in either gender. CONCLUSIONS: Breakfast consumption was inversely associated with odds of overweight and obesity in university students. LEVEL OF EVIDENCE: Level V, cross sectional descriptive studies. PMID- 30414078 TI - Definition and diagnostic criteria for orthorexia nervosa: a narrative review of the literature. AB - AIM: In some cases, detrimental consequences on health are generated by self imposed dietary rules intended to promote health. The pursuit of an "extreme dietary purity" due to an exaggerated focus on food may lead to a disordered eating behavior called "orthorexia nervosa" (ON). ON raises a growing interest, but at present there is no universally shared definition of ON, the diagnostic criteria are under debate, and the psychometric instruments used in the literature revealed some flaws. This narrative review of the literature aims at assessing state of the art in ON definition, diagnostic criteria and related psychometric instruments and provides research propositions and framework for future analysis. METHODS: The authors collected articles through a search into Pubmed/Medline, Scopus, Embase and Google Scholar (last access on 07 August 2018), using "orthorexia", "orthorexia nervosa" and "obsessive healthy eating" as search terms, and filled three tables including narrative articles (English), clinical trials (English), and articles in languages different from English. The data extrapolated from the revised studies were collected and compared. In particular, for each study, the diagnostic criteria considered, the specific psychometric instrument used, the results and the conclusions of the survey were analyzed. RESULTS: The terms employed by the different authors to define ON were fixation, obsession and concern/preoccupation. Several adjectives emphasized these expressions (e.g. exaggerated/excessive, unhealthy, compulsive, pathological, rigid, extreme, maniacal). The suitable food and the diet were defined in different ways. Most of the papers did not set the diagnostic criteria. In some cases, an attempt to use DSM (edition IV or 5) criteria for anorexia nervosa, or avoidant/restrictive food intake disorder, or body dysmorphic disorder, was done. Specific diagnostic criteria proposed by the authors were used in few studies. All these studies indicated as primary diagnostic criteria: (a) obsessional or pathological preoccupation with healthy nutrition; (b) emotional consequences (e.g. distress, anxieties) of non-adherence to self-imposed nutritional rules; (c) psychosocial impairments in relevant areas of life as well as malnutrition and weight loss. The ORTO-15 and the Orthorexia Self-Test developed by Bratman were the most used psychometric tools. CONCLUSIONS: The present review synopsizes the literature on the definition of ON, proposed diagnostic criteria and psychometric instruments used to assess ON attitudes and behaviors. This work represents a necessary starting point to allow a further progression of the studies on the possible new syndrome and to overcome the criticisms that have affected both research and clinical activity until now. LEVEL OF EVIDENCE: Level V, narrative review. PMID- 30414079 TI - Unpacking the layers: a meta-ethnography of cancer survivors' loneliness. AB - PURPOSE: To review the empirical qualitative literature on cancer survivor's experiences with loneliness to inform assessments and interventions for improving cancer survivors' social well-being. METHODS: A rigorous systematic review of qualitative studies published in five databases between 1993 and 2016 was conducted. Three coders reviewed 285 titles and abstracts and, after applying a critical review process, 20 manuscripts were synthesized using meta-ethnography. RESULTS: The synthesis of the 20 studies provided a framework for understanding survivors' layers of loneliness at the level of the individual, their social support system, the healthcare system, and society. Internally, survivors described loneliness resulting from feelings of inauthenticity, of being alone in their cancer experience, and of lack of control. In their social networks, survivors attributed loneliness to others' avoidance, misperceptions of cancer, and others' failure to recognize the effects of cancer after active treatment. Unmet needs after treatment contributed to feelings of loneliness within the healthcare system. Further, societal stigma around cancer and pressures to experience growth after cancer created another layer of loneliness. The results suggest the need to move beyond an individual level perspective in assessing and treating loneliness in cancer survivors. CONCLUSIONS: This meta-ethnography presents an integrated framework of loneliness in cancer survivors as a multi layered experience. Implications for Cancer Survivors Conceptualizing loneliness from a systemic perspective adds missing pieces to the loneliness puzzle by encouraging assessment and intervention at interacting levels of functioning; considering how individuals respond to and are affected by their social systems can deepen our understanding of cancer survivorship. PMID- 30414080 TI - SOCS3 as a future target to treat metabolic disorders. AB - The suppressors of cytokine signaling (SOCS) are a group of eight proteins responsible for preventing excessive cytokine signaling. Among this protein family, SOCS3 has received special attention. SOCS3 expression is important to control certain allergy autoimmune diseases. Furthermore, SOCS3 expression is elevated in obesity and it is involved in the inhibition of leptin and insulin signaling, two important hormones involved in the control of energy metabolism. Therefore, increased SOCS3 expression in obese individuals is associated with several metabolic disorders, including reduced energy expenditure, increased food intake and adiposity, and insulin and leptin resistance. In addition, recent studies found that SOCS3 expression regulates energy and glucose homeostasis in several metabolic conditions, such as pregnancy, caloric restriction, and refeeding. Importantly, attenuation of SOCS3 expression in most cases improves leptin and insulin sensitivity, leading to beneficial metabolic effects. This review aims to discuss the role of SOCS3 in the control of blood glucose levels as well as in energy homeostasis. The development of pharmacological compounds to inhibit SOCS3 activity and/or expression may represent a promising therapeutic approach to treat type 2 diabetes mellitus, obesity, and other metabolic imbalances. PMID- 30414081 TI - On the association between abdominal aorta and basilar artery diameters: a population-based study in community-dwelling older adults. AB - INTRODUCTION: Information on the relationship between the diameters of the abdominal aorta (AA) and the basilar artery (BA) is limited. Using the Atahualpa Project cohort, we aimed to assess this association in Atahualpa residents aged >= 60 years. MATERIALS AND METHODS: Atahualpa residents aged >= 60 years underwent abdominal ultrasound and MRA of intracranial vessels. The independent association between both arterial diameters was estimated in a generalized linear model adjusted for demographics, cardiovascular risk factors, the presence of a fetal-type Circle of Willis, and severity of white matter hyperintensities. Fractional polynomials were fitted to model the relationship between AA and BA diameters. RESULTS: The mean age of 277 participants was 69.5 +/- 7.7 years (61% women). The mean AA diameter was 19.8 +/- 3.3 mm, and the mean BA diameter was 3.1 +/- 0.7 mm. The mean diameters of both arteries were significantly higher in men than in women. Locally weighted scatterplot smoothing showed a non-linear relationship between both arterial diameters. Fractional polynomial models showed that AA and BA diameters had a significant non-linear association in men (p = 0.005), but not in women (p = 0.315). When sex was excluded from a generalized linear model, the relationship between both arterial diameters became significant (p = 0.017). CONCLUSION: In this population of community-dwelling older adults, the relationship between AA and BA diameters was confined to men. The finding of a large AA diameter in men should prompt the investigation of the intracranial vasculature because of the possibility of BA ectasia. PMID- 30414082 TI - Pediatric musculoskeletal ultrasound: a pictorial essay. AB - Ultrasound (US) is the main imaging modality for the evaluation of pediatric patients with musculoskeletal diseases; particularly, it is an appropriate and reliable tool for diagnosis, follow-up and treatment of several musculoskeletal pathologies affecting the pediatric age. High-frequency (10-15 MHz) and high resolution probes provide very lofty quality images, allowing a detailed study of the pediatric musculoskeletal system. Among the well-known advantages of this technique-such as the absence of ionizing radiations, its low cost and wide availability-US can as well rely on some intrinsic characteristics of the pediatric musculoskeletal system that can improve its diagnostic capability. The unossified portions of the pediatric skeleton and the absence of a thickened adipose tissue allow US to be highly effective and reliable in the study of muscles, tendons and cartilage. Lower-frequency sectoral transducers can be required in the study of some joints such as the shoulder or the hip, as well as in the examination of deep soft-tissue lesions. Furthermore, both color and spectral Doppler play an important role in the examination of soft-tissue lesions and synovial phlogosis. In this pictorial essay the main pathological conditions of pediatric musculoskeletal system will be examined, such as painful hip, evolutionary hip dysplasia, osteochondrosis, trauma-related pathologies and juvenile idiopathic arthritis. PMID- 30414083 TI - Quantitative ultrasound of trapezius muscle involvement in myofascial pain: comparison of clinical and healthy population using texture analysis. AB - PURPOSE: Ultrasound is a non-invasive quantitative method to characterize sonographic textures of skeletal muscles. To date, there is no information available on the trapezius muscle. This study assessed the trapezius muscles of patients with myofascial pain compared with normal healthy participants. METHODS: The trapezius muscles of 15 healthy and 17 myofascial pain participants were assessed using B-mode ultrasound to obtain 120 images for healthy and 162 images from myofascial pain participants. Texture features such as blob area, count and local binary patterns (LBP) were calculated. Multi-feature classification and analysis were performed using principal component analysis (PCA) and MANOVA to determine whether there were statistical differences. RESULTS: We demonstrate the two principal components composed of a combination of LBP and blob parameters which explain 92.55% of the cumulative variance of our data set. In addition, blob characteristics were significantly different between healthy and myofascial pain participants. CONCLUSION: Our study provides evidence that texture analysis techniques can differentiate between healthy and myofascial pain affected trapezius muscles. Further research is necessary to evaluate the nature of these differences. PMID- 30414084 TI - Patient Power Revolution in Multiple Sclerosis: Navigating the New Frontier. AB - A debate on shared decision making in multiple sclerosis (MS) was led by a patient advocate and leading neurologists from the MS in the 21st Century Steering Group. Key themes and salient points which emerged from the debate and audience discussions are reported in this article. Arguments against shared decision making included the fact that physicians study and practice for years to reach their level of expertise, and that the level of understanding required to make these decisions may not be possible to communicate to patients within time limited consultations. Furthermore, unreliable online information, information overload or information with marketing bias may also cloud patients' judgements. Arguments for patient engagement focussed on how ownership of decisions can lead to improved adherence and outcomes, and a strengthening of the physician-patient relationship. Shared decision making requires educating patients to make informed decisions and to understand the risks and consequences of their choices. However, shared decision making may not be the correct option for every patient, and the level of involvement must be driven by the patient. To support patients' engagement and promote responsible management of their condition, physicians need to (1) foster and maintain a positive, ongoing relationship with their patients, and (2) provide patients with timely, accurate, and understandable information. There was broad agreement that the patient voice should be heard more in discussions around the future of MS care. MS in the 21st Century offers a model for patient involvement in partnership with MS healthcare specialists, and the steering group is currently considering these issues and developing tools and solutions to enhance patient-physician communication and relationships. Funding Merck KGaA, Darmstadt, Germany. PMID- 30414085 TI - Expression and Functional Relevance of Death-Associated Protein Kinase in Human Drug-Resistant Epileptic Brain: Focusing on the Neurovascular Interface. AB - Death-associated protein kinase (DAPK) is a key player in various cell death signaling pathways. Prolonged seizures induce neuronal stress; thus, we studied DAPK expression in resected brain tissues from patients with refractory epilepsy and the pathophysiological relevance of neurovascular DAPK. We used brain resections from temporal lobe epilepsy (TLE), tumor (BT), arteriovenous malformation (AVM), and autopsy, and isolated human endothelial cells (EPI-ECs) and glial cells (EPI-Astro) from epileptic brains compared to control brain endothelial cells (HBMECs) and astrocytes. DAPK and phosphorylated DAPK (p-DAPK) expression was evaluated by immunohistochemistry and western blot. Subcellular localization of DAPK in epileptic brain was explored; DAPK mRNA/protein levels in EPI-ECs/EPI-Astro were evaluated. We assessed DAPK localization with hypoxic inducible factor (HIF-1alpha) and vascular endothelial growth factor (VEGF) in epilepsy, BT, and AVM. We found DAPK overexpression across neurons, microcapillaries, and astrocytes in TLE vs controls; DAPK and p-DAPK levels significantly increased only in microsomal fractions of epileptic brain. DAPK mRNA remained unchanged, although increased DAPK and p-DAPK protein expression was observed in EPI-ECs. DAPK inhibition reduced p-DAPK, HIF-1alpha, and VEGF expression, but increased cytotoxicity and decreased cell viability in EPI-ECs and EPI-astro vs. controls. DAPK staining in TLE resembled BT and AVM, with predominant DAPK/p-DAPK expression in neurons and vasculature. Taken together, these findings suggest DAPK could be a potential molecular target in neuronal death and vascular changes in epilepsy. Increased brain endothelial and astrocytic DAPK in epilepsy, identified for the first time, may have relevance to angiogenesis, hypoxia, and cell survival in pathological conditions. PMID- 30414087 TI - Nootropic and Anti-Alzheimer's Actions of Medicinal Plants: Molecular Insight into Therapeutic Potential to Alleviate Alzheimer's Neuropathology. AB - Medicinal plants are the backbone of modern medicine. In recent times, there is a great urge to discover nootropic medicinal plants to reverse cognitive dysfunction owing to their less adverse effects. Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by the inevitable loss of cognitive function, memory and language impairment, and behavioral disturbances, which turn into gradually more severe. Alzheimer's has no current cure, but symptomatic treatments are available and research continues. The number of patients suffering from AD continues to rise and today, there is a worldwide effort under study to find better ways to alleviate Alzheimer's pathogenesis. In this review, the nootropic and anti-Alzheimer's potentials of 6 medicinal plants (i.e., Centella asiatica, Clitoria ternatea, Crocus sativus, Terminalia chebula, Withania somnifera, and Asparagus racemosus) were explored through literature review. This appraisal focused on available information about neuroprotective and anti-Alzheimer's use of these plants and their respective bioactive compounds/metabolites and associated effects in animal models and consequences of its use in human as well as proposed molecular mechanisms. This review progresses our existing knowledge to reveal the promising linkage of traditional medicine to halt AD pathogenesis. This analysis also avowed a new insight to search the promising anti-Alzheimer's drugs. PMID- 30414088 TI - Optimal Medical Therapy Prescribing Patterns and Disparities Identified in Patients with Acute Coronary Syndromes at an Academic Medical Center in an Area with High Coronary Heart Disease-Related Mortality. AB - BACKGROUND: Coronary heart disease (CHD)-related mortality is high in the southern United States. A five-drug pharmacotherapy regimen for acute coronary syndromes (ACS), defined as optimal medical therapy (OMT), can decrease CHD related mortality. Studies have indicated that OMT is prescribed 50-60% of the time. Assessment of prescribing could provide insight into the potential etiology of disparate mortality. OBJECTIVE: The aim was to evaluate prescribing of OMT at discharge in patients presenting with an ACS event at an academic medical center and identify patients at risk of not receiving OMT. METHODS: A single-center, retrospective cohort of patients with ACS diagnosis between July 2013 and July 2015 was investigated, and a multivariable regression analysis conducted to identify populations at risk of not receiving OMT. RESULTS: A total of 864 patients were identified by International Classification of Diseases, Ninth Revision (ICD-9) codes, with 533 excluded and 331 analyzed. OMT was prescribed in 69.79%. Patients >= 75 years of age [p = 0.003; odds ratio (OR) 0.30; 95% confidence interval (CI) 0.136-0.673], unstable angina presentation (p = 0.042; OR 0.55; 95% CI 0.307-0.977), and surgical management (p = 0.001; OR 0.22; 95% CI 0.095-0.519) were less likely to receive OMT. CONCLUSIONS: The percentage of patients prescribed OMT exceeded the reported global percentage of prescribed OMT. However, disparities exist among specific populations. PMID- 30414089 TI - Cognitive task modality influences postural control during quiet standing in healthy older adults. AB - BACKGROUND: The interstimulus interval of a cognitive task was found to have a limited effect on postural control in young adults, while visual cognitive tasks were found to improve stability compared to auditory tasks. It is of interest to investigate whether postural control in healthy older adults is sensitive to these types of cognitive task manipulations. AIMS: The objectives of the present experiment were to evaluate the impact of interstimulus interval and modality of a continuous cognitive task on postural control in healthy older adults. METHODS: Fifteen healthy older adults (70 +/- 3.2 years, 3 male) were asked to stand with feet together on a force platform while performing auditory and visual cognitive tasks performed with interstimulus intervals of 2 and 5 s. RESULTS: Visual tasks led to reductions in sway area and sway variability in the anterior-posterior direction compared to auditory tasks (ps <= 0.05). The interstimulus interval did not lead to a change in sway, except for a small change in the medial-lateral direction for the 2-s interval compared to the 5-s interval (p = 0.05). DISCUSSION AND CONCLUSIONS: Results suggest that the interstimulus interval had a very limited effect on postural sway. The modality of the cognitive task had a greater effect on postural sway, as visual cognitive tasks yielded smaller sway area and anterior-posterior sway variability than auditory conditions. Visual stimuli may have acted as an anchor, yielding reduced sway. PMID- 30414090 TI - Diagnostic methods for Helicobacter pylori infection: ideals, options, and limitations. AB - Helicobacter pylori (H. pylori) resides in the stomach, colonizes gastric epithelium, and causes several digestive system diseases. Several diagnostic methods utilizing invasive or non-invasive techniques with varying levels of sensitivity and specificity are developed to detect H. pylori infection. Selection of one or more diagnostic tests will depend on the clinical conditions, the experience of the clinician, cost, sensitivity, and specificity. Invasive methods require endoscopy with biopsies of gastric tissues for the histology, culture, and rapid urease test. Among non-invasive tests, urea breath test and fecal antigen tests are a quick diagnostic procedure with comparable accuracy to biopsy-based techniques and are methods of choice in the test and treatment setting. Other techniques such as serological methods to detect immunoglobulin G antibodies to H. pylori can show high accuracy as other non-invasive and invasive biopsies, but do not differentiate between current or past H. pylori infections. Polymerase chain reaction (PCR) is an emerging option that can be categorized as invasive and non-invasive tests. PCR method is beneficial to detect H. pylori from gastric biopsies without the need for the cultures. There is no other chronic gastrointestinal infection such as H. pylori with a set of comparable diagnostic methodologies. Despite the availability of multiple diagnostic methods, it remains unclear on the choice of any one method as the gold standard for detecting H. pylori infection, especially in epidemiological studies. In this work, we review the principal diagnostic methods used to detect H. pylori infection and their advantages and disadvantages, and applications in clinical practice. PMID- 30414091 TI - Comparison of three multiplex real-time PCR assays for detection of enteric viruses in patients with diarrhea. AB - In this study, the usability and performance of three commercially available multiplex real-time RT-PCR assays for the detection of major enteric viruses were investigated. In total, 481 fecal specimens were analyzed using the AllplexTM GI Virus Assay, the Rida(r)Gene Viral Stool Panel I, and the FTD Viral Gastroenteritis. The overall agreement between the assays was 99.9%. Despite convergent analytical performance, differences between the multiplex RT-PCR assays were apparent when considering their suitability for routine diagnostics. PMID- 30414092 TI - Evolution of haemostatic parameters and risk of bleeding during treatment with cefazolin. AB - In 2017, five cases of severe haemorrhages during treatment with cefazolin occurred in France. The aim of this study was to assess the risk of haemorrhage related to treatment with cefazolin by evaluating haemostatic parameters and bleeding events. A retrospective study was conducted from January 2016 to December 2017. Two populations were analysed: (i) overall population, which included all patients treated with cefazolin during this period and (ii) coagulation study population, which included all patients treated with cefazolin with available coagulation parameters (activated partial thromboplastin time (aPTT) and international normalised ratio (INR) at baseline and at the end of treatment or EoT). Values of either aPTT or INR at baseline and at EoT were compared. Cases of severe haemorrhages were reported and correlated with values of aPTT and INR. Overall, 132 patients received cefazolin and 59/132 (45%) were included in the coagulation study group. A significant increase of median aPTT was observed from baseline to EoT (39.5 and 44.3 sec; p = 0.004, respectively). Overall, severe haemorrhage occurred in 7/132 (5%) patients. Coagulation parameters were available in three of them, and no correlation was observed between bleeding events and aPTT increase. This study showed that bleeding is probably more frequent than ever reported before during cefazolin treatment. The significant increase of aPTT observed during cefazolin treatment was not correlated with risk of haemorrhage. Further studies are needed to explore the possible physio-pathological pathways behind the modification of haemostatic parameters and risk of haemorrhage. PMID- 30414094 TI - Brain T1rho mapping for grading and IDH1 gene mutation detection of gliomas: a preliminary study. AB - INTRODUCTION: The longitudinal relaxation time in the rotating frame (T1rho) has proved to be sensitive to metabolism and useful in application to neurodegenerative diseases. However, few literature exists on its utility in gliomas. Thus, this study was conducted to explore the performance of T1rho mapping in tumor grading and characterization of isocitrate dehydrogenase 1 (IDH1) gene mutation status of gliomas. METHODS: Fifty-seven patients with gliomas underwent brain MRI and quantitative measurements of T1rho and apparent diffusion coefficient (ADC) were recorded. Parameters were compared between high grade gliomas (HGG) and low-grade gliomas (LGG) and between IDH1 mutant and wildtype groups. RESULTS: HGG showed significantly higher T1rho values in both the solid and peritumoral edema areas compared with LGG (P < 0.001 and P = 0.005, respectively), whereas no significant differences in the two areas were found for ADC (both P > 0.05). Receiver operating characteristic (ROC) curve analysis showed that T1rho value in the solid area achieved the highest area under the ROC curve (AUC, 0.841) in grading with a sensitivity of 80.6% and a specificity of 81.0%. In the grade II/III glioma group, multivariate logistic regression showed that both tumor frontal lobe location (odds ratio [OR] 526.608; P = 0.045) and T1rho value of the peritumoral edema area (OR 0.863; P = 0.037) were significant predictors of IDH1 mutation. Using the combination, the diagnostic sensitivity and specificity for IDH1 mutated gliomas were 93.3% and 88.9%, respectively. CONCLUSIONS: Our study shows the feasibility of applying T1rho mapping in assessing the histologic grade and IDH1 mutation status of gliomas. PMID- 30414086 TI - Regional Amyloid-beta Load and White Matter Abnormalities Contribute to Hypometabolism in Alzheimer's Dementia. AB - We investigated the association between amyloid-beta deposition and white matter (WM) integrity as a determinant of brain glucose hypometabolism across the Alzheimer's disease (AD) spectrum. We assessed ninety-six subjects (27 cognitively normal, 49 mild cognitive impairment, and 20 AD dementia) who underwent [18F]FDG and [18F]Florbetapir positron emission tomography (PET) as well as magnetic resonance imaging (MRI) with diffusion tensor imaging. Among the regions with reduced fractional anisotropy (FA) in the AD group, we selected a voxel of interest in the angular bundle bilaterally for subsequent analyses. Using voxel-based interaction models at voxel level, we tested whether the regional hypometabolism is associated with FA in the angular bundle and regional amyloid-beta deposition. In the AD patients, [18F]FDG hypometabolism in the striatum, mesiobasal temporal, orbitofrontal, precuneus, and cingulate cortices were associated with the interaction between high levels of [18F]Florbetapir standard uptake value ratios (SUVR) in these regions and low FA in the angular bundle. We found that the interaction between, rather than the independent effects of, high levels of amyloid-beta deposition and WM integrity disruption determined limbic hypometabolism in patients with AD. This finding highlights a more integrative model for AD, where the interaction between partially independent processes determines the glucose hypometabolism. PMID- 30414095 TI - Comparative analysis of the diffusion kurtosis imaging and diffusion tensor imaging in grading gliomas, predicting tumour cell proliferation and IDH-1 gene mutation status. AB - INTRODUCTION: Few studies have applied diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI) for the comprehensive assessment of gliomas [tumour grade, isocitrate dehydrogenase-1 (IDH-1) mutation status and tumour proliferation rate (Ki-67)]. This study describes the efficacy of DKI and DTI to comprehensively evaluate gliomas, compares their results. METHODS: Fifty-two patients (18 females; median age, 47.5 years) with pathologically proved gliomas were prospectively included. All cases underwent DKI examination. DKI (mean kurtosis: MK, axial kurtosis: Ka, radial kurtosis: Kr) and DTI (mean diffusivity: MD, fractional anisotropy: FA) maps of each metric was derived. Three ROIs were manually drawn. RESULTS: MK, Ka, Kr and FA were significantly higher in HGGs than in LGGs, whereas MD was significantly lower in HGGs than in LGGs (P < 0.01). ROC analysis demonstrated that MK (specificity: 100% sensitivity: 79%) and Ka (specificity: 96% sensitivity: 82%) had the same and highest (AUC: 0.93) diagnostic value. Moreover, MK, Ka, and Kr were significantly higher in grade III than II gliomas (P ? 0.01). Further, DKI and DTI can significantly identify IDH-1 mutation status (P ? 0.03). Ka (sensitivity: 74%, specificity: 75%, AUC: 0.72) showed the highest diagnostic value. In addition, DKI metrics and MD showed significant correlations with Ki-67 (P ? 0.01) and Ka had the highest correlation coefficient (rs = 0.72). CONCLUSIONS: Compared with DTI, DKI has great advantages for the comprehensive assessment of gliomas. Ka might serve as a promising imaging index in predicting glioma grading, tumour cell proliferation rate and IDH-1 gene mutation status. PMID- 30414096 TI - The consistency of neuropathological diagnoses in patients undergoing surgery for suspected recurrence of glioblastoma. AB - PURPOSE: Clinical factors and neuro-imaging in patients with glioblastoma who appear to progress following standard chemoradiation are unable to reliably distinguish tumor progression from pseudo-progression. As a result, surgery is commonly recommended to establish a final diagnosis. However, studies evaluating the pathologists' agreement on pathologic diagnoses in this setting have not been previously evaluated. METHODS: A hypothetical clinical history coupled with images of histological sections from 13 patients with glioblastoma who underwent diagnostic surgery for suspected early recurrence were sent to 101 pathologists from 50 NCI-designated Cancer Centers. Pathologists were asked to provide a final diagnosis (active tumor, treatment effect, or unable to classify) and to report on percent active tumor, treatment effect, and degree of cellularity and degree of mitotic activity. RESULTS: Forty-eight pathologists (48%) from 30 centers responded. In three cases > 75% of pathologists diagnosed active tumor. In two cases > 75% diagnosed treatment effect. However, in the remaining eight cases the disparity in diagnoses was striking (maximum agreement on final diagnosis ranged from 36 to 68%). Overall, only marginal agreement was observed in the overall assessment of disease status [kappa score 0.228 (95% CI 0.22-0.24)]. CONCLUSIONS: Confidence in any clinical diagnostic assay requires that very similar results are obtained from identical specimens evaluated by sophisticated clinicians and institutions. The findings of this study illustrate that the diagnostic agreement between different cases of repeat resection for suspected recurrent glioblastoma can be variable. This raises concerns as pathological diagnoses are critical in directing standard and experimental care in this setting. PMID- 30414097 TI - A cancer tissue-specific FAM72 expression profile defines a novel glioblastoma multiform (GBM) gene-mutation signature. AB - INTRODUCTION: Glioblastoma multiform (GBM) is a neural stem cell (NSC)-derived malignant brain tumor with complex genetic alterations challenging clinical treatments. FAM72 is a NSC-specific protein comprised of four paralogous genes (FAM72 A-D) in the human genome, but its functional tumorigenic significance is unclear. METHODS: We conducted an in-depth expression and somatic mutation data analysis of FAM72 (A-D) in GBM using the comprehensive human clinical cancer study database cBioPortal [including The Cancer Genome Atlas (TCGA)]. RESULTS: We established a FAM72 transcription profile across TCGA correlated with the expression of the proliferative marker MKI67 and a tissue-specific gene-mutation signature represented by pivotal genes involved in driving the cell cycle. FAM72 paralogs are overexpressed in cancer cells, specifically correlating with the mitotic cell cycle genes ASPM, KIF14, KIF23, CENPE, CENPE, CEP55, SGO1, and BUB1, thereby contributing to centrosome and mitotic spindle formation. FAM72 expression correlation identifies a novel GBM-specific gene set (SCN9A, MXRA5, ADAM29, KDR, LRP1B, and PIK3C2G) in the de novo pathway of primary GBM predestined as viable targets for therapeutics. CONCLUSION: Our newly identified primary GBM-specific gene-mutation signature, along with FAM72, could thus provide a new basis for prognostic biomarkers for diagnostics of GBM and could serve as potential therapeutic targets. PMID- 30414098 TI - Mebendazole and radiation in combination increase survival through anticancer mechanisms in an intracranial rodent model of malignant meningioma. AB - PURPOSE: Meningiomas are a frequent tumor of the central nervous system. Although mostly benign, approximately 5% present as atypical or malignant tumors. Treatments for atypical meningiomas include gross total resection and radiotherapy, but about 33% of patients have recurrent tumors, sometimes as a higher grade. Recently, the brain penetrant anthelmintic drug, mebendazole, has shown promise as an anticancer agent in rodent models of glioblastoma and medulloblastoma. METHODS: The half maximal inhibitory concentration (IC50) effect on colony formation, cell proliferation, and caspase-3/7 markers of apoptosis of mebendazole with and without radiation was measured in vitro. Mice intracranially implanted with KT21MG1 human meningioma were administered mebendazole alone or in combination with radiation. Survival benefit was evaluated, while tumors were investigated by immunohistochemical staining for apoptosis, cell proliferation, and vascular density. RESULTS: In vitro experiments on meningioma cell lines showed the IC50 for mebendazole in the range of 0.26-0.42 uM. Mebendazole alone induced cytotoxicity, however the combination had a greater reduction in colony formation and resulted in higher levels of cleaved caspase-3. The in vivo study showed both, mebendazole alone and the combination, to have a survival benefit with an increase in apoptosis, and decreases in tumor cell and vascular proliferation. CONCLUSION: These preclinical findings indicate that mebendazole alone or in combination with radiation can be considered for the treatment of malignant meningioma. The mechanism of action for this combination may include an increase in apoptosis, a reduction in proliferation and angiogenesis, or a combination of these effects. PMID- 30414099 TI - Magmas inhibition as a potential treatment strategy in malignant glioma. AB - PURPOSE: Magmas (mitochondria-associated protein involved in granulocyte macrophage colony-stimulating factor signal transduction) is a nuclear gene that encodes the mitochondrial import inner membrane translocase subunit Tim16. Magmas is highly conserved, ubiquitously expressed in mammalian cells, and is essential for cell viability. Magmas expression levels are increased in prostate cancers and pituitary adenomas. Moreover, silencing Magmas by RNAi sensitizes pituitary adenoma cells to pro-apoptotic stimuli and induces a G0/G1 accumulation. The aim of this study was to examine whether inhibition of Magmas by small molecule inhibitors could be beneficial for the treatment of malignant gliomas. METHODS: We evaluated the expression of Magmas in patient-derived glioblastoma tissue samples and xenograft models. We studied the feasibility of a small molecule Magmas inhibitor (BT#9) as a therapeutic agent in stable human glioma cell lines and high-grade patient derived glioma stem-like cells. RESULTS: Magmas was overexpressed in tissue sections from glioma patients and xenografts. In vivo studies revealed that BT#9 could cross the blood-brain barrier in the animal model. Magmas inhibition by BT#9 in glioma cell lines significantly decreased cell proliferation, induced apoptosis along with vacuole formation, and blocked migration and invasion. In addition, BT#9 treatment decreased the respiratory function of glioma cells, supporting the role that Magmas serves as a reactive oxygen species regulator. CONCLUSIONS: This is the first study on the role of Magmas in glioma. Our findings suggest that Magmas plays a key role in glioma cell survival and targeting Magmas by small molecule inhibitors may be a therapeutic strategy in gliomas. PMID- 30414100 TI - Incidence of initial spinal metastasis in glioblastoma patients and the importance of spinal screening using MRI. AB - PURPOSE: Intracranial glioblastomas with simultaneous spinal lesions prior to chemoradiation therapy or craniotomy, defined as initial spinal metastasis, are not well understood. Herein, we investigated intracranial glioblastoma and demonstrated the importance of spinal screening using gadolinium enhanced spinal magnetic resonance imaging (Gd-MRI). METHODS: Consecutive adult patients with intracranial glioblastoma were treated between 2010 and 2014 and received spinal screening using Gd-MRI. Spinal screening was performed regardless of spine related symptoms, and patients presenting with and without initial spinal metastasis (spinal and non-spinal groups, respectively) were compared based on patient demographics, tumor characteristics, radiological and molecular features, and overall survival (OS). RESULTS: During the study period, 116 glioblastoma cases were treated and 87 of these (76%) underwent spinal screening. Among these patients, 11 (13%) were included in the spinal group, and 76 (87%) were included in the non-spinal group. All patients of the spinal group were free of symptoms related to spinal lesions. Compared with the non-spinal group, intracranial lesions of the spinal group presented higher incidences of intracranial dissemination and were located at subventricular zones (P = 0.0012 and 0.020, respectively). MIB-1 labeling index, molecular alterations such as IDH1 mutation, TERT promoter mutation, and immunoreactivity of ATRX and MGMT did not differ between two groups. OS was significantly shorter in the spinal group than in the non-spinal group (P = 0.0054). CONCLUSIONS: This study revealed a relatively high incidence of spinal metastasis. A subset of glioblastoma patients benefited from spinal screening, through which early detection of asymptomatic spinal metastasis was achieved. PMID- 30414101 TI - Retinal Vasculature Reactivity During Flicker Light Provocation, Cardiac Stress and Stroke Risk in Africans: The SABPA Study. AB - Structural and functional similarities exist between the retinal, cerebral and, as previously suggested, the coronary microvasculature. Retinal microvascular structure and functionality (in response to flicker-light-induced-provocation (FLIP)) may relate to coronary artery disease risk and possible stroke risk. We investigated associations between retinal vessel structure, functionality and cardiac stress markers (cardiac troponin T [cTnT], amino-terminal B-type natriuretic peptide [NT-proBNP]) to translate these retina-heart relationships to stroke risk. We included 317 African and Caucasian teachers' (aged 23-68 years), who participated in the Sympathetic Activity and Ambulatory Blood Pressure in Africans (SABPA) study. Fasting plasma and serum samples for cTnT and NT-proBNP were collected. Retinal vascular calibres were quantified from fundus images and dynamic retinal vessel calibre responses during FLIP. The University of California stroke risk score was applied to assess sub-clinical 10-year stroke risk. cTnT levels were similar in Africans and Caucasians, whereas NT-proBNP levels were lower in Africans. In Africans, a reduced arteriolar calibre and attenuated arteriolar dilation during FLIP was associated with higher cTnT (p < 0.01). Their larger retinal-venular calibre (p < 0.02) and attenuated arteriolar dilation during FLIP (p < 0.05) were associated with lower NT-proBNP. Again, exclusively in Africans, increased cardiac stress, wider venular calibres and retinal arteriovenous nicking predicted an increased 10-year stroke risk with odds ratios of 1.57 (95% CI, 1.34; 1.68, p = 0.031), 1.51 (95% CI, 1.26; 1.59, p = 0.002), 1.10 (95% CI, 0.94; 2.85, p = 0.002) and 1.06 (95% CI 0.83; 1.56, p = 0.052), respectively. None of these associations were evident in the Caucasian group. Investigating the retinal vasculature may serve as a tool to approximate sub-clinical coronary and cerebral microvasculature damage or dysfunction. These cardiac stress-retinal associations additionally predicted a greater stroke risk in the SABPA African cohort. Observable changes in the retinal vasculature may serve as markers for the identification and prediction of cardio-systemic and cerebral vascular morbidities and risks, thereby establishing a brain-heart link. Graphical Abstract Proposed series of events during which sustained high pressure and increased cardiac stress may alter retinal reactivity and link to increased stroke risk. PMID- 30414102 TI - Apoptotic role of marine sponge symbiont Bacillus subtilis NMK17 through the activation of caspase-3 in human breast cancer cell line. AB - The aim of the present study was to evaluate the diverse potential biological activity of partially purified crude extract (PPCEBS) of marine Bacillus subtilis NMK17 associated with marine sponge Clathria frondifera. Symbionts were isolated from a marine sponge, only the potential strain which exhibited apoptosis was sequenced using 16S rRNA and extract of the active strain was subjected to purification using HPLC. The potential pro-apoptotic role of PPCEBS was investigated in MCF-7 human breast cancer cell line for cytotoxicity by MTT assay, which showed dose-dependent cytotoxicity on 24 h of exposure. The apoptotic findings demonstrated that PPCEBS significantly induces apoptosis, which was characterised by apoptotic morphological changes. Further, an increased expression of the Caspase 3 and Bax whereas decreased Bcl-2 was confirmed by immunofluorescence and western blotting analysis in MCF-7 cell line, which revealed that PPCEBS has potent apoptosis-inducing property. Added to the desirable apoptotic activity, PPCEBS exhibited excellent antibacterial and antioxidant activities too. The pharmacological effect of the marine sponge associated bacteria from Gulf of Mannar India needs further attention in discovering new bioactive compounds. Our results suggested that the compounds present in the PPCEBS in marine bacterial B. subtilis NMK17 could be candidates for developing an apoptosis-specific drug with minimal toxicity. This study indicated that marine sponge-associated bacteria could be a good source to find the cytotoxic metabolites which would induce apoptosis and cause cancer cell death. Also, this study explores that marine natural products as a potential source of pharmaceuticals. PMID- 30414103 TI - Royal jelly mitigates cadmium-induced neuronal damage in mouse cortex. AB - This study aimed to evaluate the potential neuroprotective effect of royal jelly (RJ) against Cd-induced neuronal damage. Twenty-eight adult mice were placed equally into four groups. The control group received intraperitoneal (IP) injections of normal saline; the cadmium chloride (CdCl2) group was IP-injected 6.5 mg/kg (mg per kg of bodyweight) CdCl2; the RJ group was gavaged 85 mg/kg RJ; and the RJ + CdCl2 group was orally administered 85 mg/kg RJ 2 h before receiving IP-injections of 6.5 mg/kg CdCl2. All groups were treated for seven consecutive days and the mice were decapitated 24 h after the final dose. Cd accumulation was recorded in the cortical homogenates, accompanied by elevated levels of lipid peroxidation, nitric oxide, tumor necrosis factor-alpha, interleukin-1beta, and the pro-apoptotic mRNA Bax and caspase-3. Meanwhile, significantly decreased levels of detoxifying antioxidant enzymes including GSH-Px, GSH-R, SOD, and CAT, anti-apoptotic mRNA Bcl-2, and monoamines such as norepinephrine, dopamine, and serotonin were also observed, along with reduced gene expression of Nrf2 dependent antioxidants. Interestingly, in mice pretreated with RJ, the assessed parameters remained near normal levels. Our data provide evidence that RJ treatment has the potential to protect cortical neurons in Cd-intoxicated mice via its antioxidant, anti-inflammatory, anti-apoptotic, and neuromodulatory activity. PMID- 30414104 TI - Inherent anti-HIV activity of biocompatible anionic citrate-PEG-citrate dendrimer. AB - The development of new combinations to empower better protection against HIV infection is particularly important. Anionic polymers can block HIV infection. In the current study, first generation (G1) and second generation (G2) novel water soluble anionic citrate-PEG-citrate dendrimers were synthesized and characterized with Fourier-transform infrared spectroscopy (FTIR), nuclear magnetic resonance spectroscopy (NMR), and dynamic light scattering (DLS) methods. After the biocompatibility of the G2 dendrimer was determined, its antiviral activity was evaluated. This function may contribute to the peripheral groups of this dendrimer (carboxylate group). In order to measure the inhibitory effect of G2 on HIV infection, both pre-treatment (treated with G2 dendrimer before HIV infection) and co-treatment (simultaneously treated with G2 dendrimer and HIV infection) were used in vitro. The results showed the good synthesis of the G2 dendrimer, and the dendrimer showed antiviral properties (ICC50:0.4 mM) and low toxicity (CC50:0.6 mM) at high concentrations. A strong inhibitory effect was found when the co-treatment approach was used. This study achieved promising results which encourage the use of G2 dendrimers as anti-HIV agents. PMID- 30414105 TI - Acute severe mitral regurgitation with cardiogenic shock following balloon mitral valvuloplasty: echocardiographic findings and outcomes following surgery. AB - Acute severe mitral regurgitation (MR) is the commonest indication for emergency surgery following a balloon mitral valvuloplasty (BMV). It results in hemodynamic compromise with cardiogenic shock and or acute pulmonary edema. These patients deteriorate fast and often require respiratory and critical care support, followed by urgent mitral valve replacement (MVR). We analyzed the data of 1224 BMV procedures done over the 18-year period. We had 85 patients (6.9%) with acute severe MR and cardiogenic shock. The clinical profile, echocardiographic features and operative findings were studied. The echocardiography scores were compared for association with occurrence of MR. The immediate and long-term clinical outcomes of these acutely sick patients were studied. Of the 85 patients, 84 underwent MVR. Anterior mitral leaflet tear was observed in 65 (75%) cases, para commissural with annular tear in 8 (9.4%), Chordal injury in 7 (8%) and torn posterior leaflet in 5 (5.8%). We documented severe MR in 88 patients (7.1%), with 85 (6.9%) among them developing features of cardiogenic shock. None of the echocardiographic scoring systems were predictive of the occurrence of MR. The 30 day mortality was 4.7%. The mean clinical follow-up period after discharge was 9.3 +/- 0.9 years (range 2.2-17.8) with no late mortality. Acute severe MR had an incidence of 7% in this study. Injury to the anterior mitral leaflet was the commonest cause. The long-term outcomes were good with timely intervention and valve replacement surgery despite the fact that the majority (96%) presented with cardiogenic shock. None of the present valve scoring systems could predict the occurrence of severe MR. PMID- 30414106 TI - Arthropod Genome Sequencing and Assembly Strategies. AB - As in any endeavor, the strategy applied to a genome project can mean the difference between success and failure. This is especially important when limited funding often means only a single approach may be tried at a given time. Although the advance of all areas of genomics and transcriptomics in recent years has led to an embarrassment of riches, methods in the field have not quite reached the turn-key production status for all species, despite being closer than ever. Here I contrast and compare the technical approaches to genome projects in the hope of enabling strategy choices with higher probabilities of success. Finally, I review the new technologies that are not yet widely distributed which are revolutionizing the future of genomics. PMID- 30414107 TI - Genome Size Estimation and Quantitative Cytogenetics in Insects. AB - With care, it is possible using flow cytometry to create a precise and accurate estimate of the genome size of an insect that is useful for genomics, genetics, molecular/cell biology, or systematics. Genome size estimation is a useful first step in a complete genome sequencing project. The number of sequencing reads required to produce a given level of coverage depends directly upon the 1C amount of DNA per cell, while an even more critical need is an accurate 1C genome size estimate to compare against the final assembly. Here we present a detailed protocol to estimate genome size using flow cytometry. Published genome size estimates should be submitted to genomesize.com so that they are available to all. PMID- 30414108 TI - Isolation of High Molecular Weight DNA from Insects. AB - Isolation of high molecular weight (HMW) DNA from any organism can be daunting and populations of extremely small insects with hard exoskeletons are no exception. It can be challenging to isolate DNA that is clean enough to enzymatically label, digest or otherwise manipulate without sacrificing length. The method described here was originally developed to isolate HMW DNA for BAC library construction. More recently, it has proven reliable for long range optical mapping as well. PMID- 30414109 TI - Long Range Sequencing and Validation of Insect Genome Assemblies. AB - Advances in long read and long range sequencing technologies have enabled chromosome length resolution for de novo genome assemblies even in the absence of complementary resources such as physical maps. Herein, I introduce a few methods for quality control and discuss potential pitfalls when assembling insect genomes with long reads. PMID- 30414110 TI - Integrated Modeling of Structural Genes Using MCuNovo. AB - Correct modeling of protein-coding genes based on genome and cDNA data is a prerequisite for functional studies. Various programs such as MAKER, Cufflinks, Oases, and Trinity have been developed, each with advantages and drawbacks. Manual integration of different models for a single gene is cumbersome and becomes a daunting task for 14,000-18,000 genes in a typical holometabolous insect. We developed methods to evaluate the output of MAKER, Cufflinks, Oases and Trinity and select the best models to constitute the MCOT1.0 set for Manduca sexta, a biochemical model insect. To apply these methods in other organisms, we improved the algorithm (designated MCuNovo Gene Selector) and automated the data processing. In this chapter, we describe background information of algorithm development and how to prepare and run this program. PMID- 30414111 TI - Using BUSCO to Assess Insect Genomic Resources. AB - The increasing affordability of sequencing technologies offers many new and exciting opportunities to address a diverse array of biological questions. This is evidenced in entomological research by numerous genomics and transcriptomics studies that attempt to decipher the often complex relationships among different species or orders and to build "omics" resources to drive advancement of the molecular understanding of insect biology. Being able to gauge the quality of the sequencing data is of critical importance to understanding the potential limitations on the types of questions that these data can be reliably used to address. This chapter details the use of the Benchmarking Universal Single-Copy Orthologue (BUSCO) assessment tool to estimate the completeness of transcriptomes, genome assemblies, and annotated gene sets in terms of their expected gene content. PMID- 30414113 TI - Using Formaldehyde-Assisted Isolation of Regulatory Elements (FAIRE) to Identify Functional Regulatory DNA in Insect Genomes. AB - Differential regulation of gene expression determines cell-type-specific function, making identification of the cis-regulatory elements that control gene expression a central goal of developmental biology. In addition, changes in the sequence of cis-regulatory elements are thought to drive changes in gene expression patterns between species, making comparisons of cis-regulatory element usage important for evolutionary biology as well. Due to the number of extant species and the incredible morphological diversity that they exhibit, insects are favorite model organisms for both developmental and evolutionary biologists alike. However, identifying cis-regulatory elements in insect genomes is challenging. Here, I describe a method termed FAIRE-seq (Formaldehyde-Assisted Isolation of Regulatory Elements, followed by high-throughput sequencing) that can be used to identify functional DNA regulatory elements from developing insect tissues, genome-wide. PMID- 30414112 TI - The GFF3toolkit: QC and Merge Pipeline for Genome Annotation. AB - The GFF3toolkit ( https://github.com/NAL-i5K/GFF3toolkit ) supported by the i5k Workspace@NAL provides a suite of tools to handle gene annotations in GFF3 format from arthropod genome projects and their research communities. To improve GFF3 formatting of gene annotations, a quality control and merge procedure is proposed along with the GFF3toolkit. In particular, the toolkit provides functions to sort a GFF3 file, detect GFF3 format errors, merge two GFF3 files, and generate biological sequences from a GFF3 file. This chapter explains when and how to use the provided tools to obtain nonredundant arthropod gene sets in high quality. PMID- 30414114 TI - Using RAMPAGE to Identify and Annotate Promoters in Insect Genomes. AB - Application of Transcription Start Site (TSS) profiling technologies, coupled with large-scale next-generation sequencing (NGS) has yielded valuable insights into the location, structure, and activity of promoters across diverse metazoan model systems. In insects, TSS profiling has been used to characterize the promoter architecture of Drosophila melanogaster (Hoskins et al., Genome Res 21(2):182-192, 2011) and subsequently was employed to reveal widespread transposon-driven alternative promoter usage in the fruit fly (Batut et al., Genome Res 23:169-180, 2012).In this chapter we discuss the computational analysis of the experimental data derived from one of TSS profiling methods, RAMPAGE (RNA Annotation and Mapping of Promoters for Analysis of Gene Expression) that can be used for the precise, quantitative identification of promoters in insect genomes. We demonstrate this using the software tools GoRAMPAGE (Brendel and Raborn, GoRAMPAGE-A workflow for promoter detection by 5'-read mapping. https://github.com/BrendelGroup/GoRAMPAGE , 2016) and TSRchitect (Raborn and Brendel, TSRchitect: promoter identification from large-scale TSS profiling data. R Bioconductor package version 1.8.0 [Online]. Available: http://bioconductor.org/packages/release/bioc/html/TSRchitect.html , 2017), providing detailed instructions with the aim of taking the user from raw reads to processed results. PMID- 30414115 TI - CRM Discovery Beyond Model Insects. AB - Although the number of sequenced insect genomes numbers in the hundreds, little is known about gene regulatory sequences in any species other than the well studied Drosophila melanogaster. We provide here a detailed protocol for using SCRMshaw, a computational method for predicting cis-regulatory modules (CRMs, also "enhancers") in sequenced insect genomes. SCRMshaw is effective for CRM discovery throughout the range of holometabolous insects and potentially in even more diverged species, with true-positive prediction rates of 75% or better. Minimal requirements for using SCRMshaw are a genome sequence and training data in the form of known Drosophila CRMs; a comprehensive set of the latter can be obtained from the SCRMshaw download site. For basic applications, a user with only modest computational know-how can run SCRMshaw on a desktop computer. SCRMshaw can be run with a single, narrow set of training data to predict CRMs regulating a specific pattern of gene expression, or with multiple sets of training data covering a broad range of CRM activities to provide an initial rough regulatory annotation of a complete, newly-sequenced genome. PMID- 30414116 TI - Whole-Genome Bisulfite Sequencing for the Methylation Analysis of Insect Genomes. AB - DNA methylation is a conserved epigenetic modification of animal genomes, but genome methylation patterns appear surprisingly diverse in insects. Whole-genome bisulfite sequencing (WGBS) represents a sensitive and robust method for the characterization of genome-wide methylation patterns at single-base resolution. Here, we describe a step-by-step protocol for the generation and analysis of WGBS datasets using standard Illumina sequencing platforms. In comparison to whole genome sequencing, WGBS has additional caveats that require particular attention and are highlighted in this chapter. PMID- 30414117 TI - Bioinformatic Analysis of Methylation Patterns Using Bisulfite Sequencing Data. AB - Epigenetic factors, including DNA methylation, play a crucial role in the development, behavior, and stress response of insects yet the analysis of DNA methylation patterns remains quite challenging. This chapter will introduce the different technologies for DNA methylation analysis and present a general methodology for the analysis of DNA methylation patterns using the commonly used technology of bisulfite sequencing. The chapter will give a short overview of the sequencing technology itself and will primarily focus on presenting the bioinformatic and statistical analysis methodology of bisulfite sequencing data to study DNA methylation patterns. PMID- 30414118 TI - Physical Genome Mapping Using Fluorescence In Situ Hybridization with Mosquito Chromosomes. AB - The development of genomic resources and tools is an important step in designing novel approaches to genetic control of mosquitoes. Physical genome maps enhance the quality of the genome assemblies, improve gene annotation, and provide a better framework for comparative and population genomics studies in mosquitoes. In this chapter, we describe protocols for an important procedure in physical genome mapping-fluorescence in situ hybridization (FISH). We provide details on (1) dissection of salivary glands, ovaries, and imaginal discs for obtaining high quality polytene or mitotic chromosome preparations; (2) DNA-labeling procedures and extraction of repetitive DNA fractions; and (3) approaches to FISH on polytene and mitotic chromosomes. PMID- 30414119 TI - Target-Enriched Endosymbiont Sequencing (TEEseq): A New High-Throughput Sequencing Approach Applied to the Comprehensive Characterization of Endosymbionts. AB - Intracellular bacteria are ubiquitous in the insect world, with perhaps the best studied example being the alphaproteobacterium, Wolbachia. Like most endosymbionts, Wolbachia cannot be cultivated outside of its host cells, hindering traditional microbial characterization techniques. Furthermore, multiple Wolbachia strains can be present within a single host, and certain strains can be present in densities below the detection limit of current methods. To date, Wolbachia has most commonly been studied using polymerase chain reaction (PCR) amplification and Sanger DNA sequencing by targeting specific genes in the bacterium's genome. PCR amplification and Sanger sequencing of multiple Wolbachia strains requires analysis of individually cloned sequences, which is resource and labor intensive. To help mitigate these difficulties, we present a modified double digest restriction site associated DNA sequencing (ddRADseq) approach to target and sequence in parallel multiple genes by adding restriction enzyme recognition sites to gene-specific PCR primers. Adopting this strategy allows us to uniquely tag and sequence amplicons from multiple hosts simultaneously on an Illumina MiSeq platform. Our approach represents an efficient and cost-effective method to characterize multiple target genes in population surveys. PMID- 30414120 TI - Preparation and Use of a Yeast shRNA Delivery System for Gene Silencing in Mosquito Larvae. AB - The mosquito genome projects facilitated research in new facets of mosquito biology, including functional genetic studies in the dengue and Zika virus vector Aedes aegypti and the primary African malaria vector Anopheles gambiae. RNA interference (RNAi) has facilitated gene silencing experiments in both of these disease vector mosquito species and could one day be applied as a new method of vector control. Here, we describe a procedure for the genetic engineering of Saccharomyces cerevisiae (baker's yeast) that express short hairpin RNA (shRNA) corresponding to mosquito target genes of interest. Following cultivation, which facilitates inexpensive propagation of shRNA, the yeast is inactivated and prepared in a ready-to-use dry tablet formulation that is fed to mosquito larvae. Ingestion of the yeast tablets results in effective larval target gene silencing. This technically straightforward and affordable technique may be applicable to a wide variety of mosquito species and potentially to other arthropods that feed on yeast. PMID- 30414121 TI - Common Cell Lines Used to Study Bone Morphogenetic Proteins (BMPs). AB - Many research methods exist to elucidate the functions of BMPs during osteogenesis. This chapter briefly reviews common immortalized mesenchymal cell types used to measure the efficacy of osteogenic factors like BMP-2. Detailed information regarding media and culture conditions are provided. Parameters relevant to experimental reproducibility and cell line authentication are discussed. PMID- 30414122 TI - In Vitro and In Vivo Osteogenic Differentiation of Human Adipose-Derived Stromal Cells. AB - Adipose-derived stromal cells (ASCs) are a promising population of cells that may be useful for the regeneration of human tissue defects. ASCs are capable of forming bone tissue in vitro and in vivo. Further work is required to determine the optimal conditions that will allow human ASCs to regenerate tissue in clinically significant tissue defects. Here we present three experimental protocols that are indispensable for the study of ASC osteogenic activity. PMID- 30414123 TI - Cell-Based Gene Therapy System for Delivering BMPs. AB - The use of an adenoviral vector to transduce cells allows for certain secreted proteins or growth factors to be generated in vivo in eukaryotic cells with accurate posttranslational processing. The use of transduced cells eliminates viral toxicity, allows for targeted expression of the secreted factor at a specific site, and ensures that the therapy will be turned off when the cells are cleared by the organism. Here we describe the delivery system which utilizes cells transduced with a non-replicating adenovirus containing bone morphogenetic protein 2 (BMP-2) in the E1 region of the cassette. With this method of delivery, small amounts of the protein can incite de novo bone formation. PMID- 30414124 TI - Generation of Endogenous BMP Transcriptional Reporter Cells Through CRISPR/Cas9 Genome Editing. AB - Transcriptional reporter systems allow researchers to investigate the function and regulation of transcription factors. Conventional systems employ artificial cDNA overexpression vectors containing either a promoter fragment or specific nucleotide sequence repeats upstream of firefly luciferase or fluorescent reporters, such as green fluorescence protein (GFP) cDNA. These systems suffer mainly from the lack of chromatin context. Here, we describe the rapid generation of endogenous transcriptional reporter cells for the bone morphogenetic protein (BMP) pathway using CRISPR/Cas9 genome editing. In principle, our methodology can be applied to any cell line. The endogenous reporters will provide a robust system for the investigation of BMP transcriptional activity in the context of native chromatin landscape and facilitate chemical and genetic screens. PMID- 30414125 TI - High-Throughput, Biosensor-Based Approach to Examine Bone Morphogenetic Protein (BMP)-Receptor Interactions. AB - Binding of a BMP to its cognate cell surface receptors is the initiating step in the BMP signaling cascade. Thus, knowing which BMP-receptor complexes form is vital for understanding the physiological activities of a particular BMP. Here, we describe a surface plasmon resonance (SPR)-based, high-throughput approach that allows fast identification and evaluation of BMP-receptor complexes. Briefly, the extracellular, BMP-binding domains of receptors are produced as human IgG1-Fc-fusion proteins. The Fc moiety enables simple capture of the Fc receptor-fusion protein on the sensor chip, supports a highly reproducible, uniform approach of surface regeneration, and ensures full activity of the receptor moiety. BMPs are injected over the captured receptors at one concentration (approximately 60-100 nM), permitting stratification of high affinity, medium-affinity, and low-affinity binders. Using this concentration range, equilibrium dissociation constants for high-affinity and medium-affinity binders can be estimated with good accuracy and with great precision from the single injection binding curves. PMID- 30414126 TI - Mutagenesis and Imaging Studies of BMP Signaling Mechanisms in C. elegans. AB - C. elegans has played a central role in the elucidation of the TGFbeta pathway over the last two decades. This is due to the high conservation of the pathway components and the power of genetic and cell biological approaches applied toward understanding how the pathway signals. In Subheading 3, we detail approaches to study the BMP branch of the TGFbeta pathway in C. elegans. PMID- 30414127 TI - Gene Regulation of BMP Ligands in Drosophila. AB - Drosophila is a valuable system to study bone morphogenetic proteins (BMPs) due to the high functional conservation of the pathway and the molecular genetic tools available. Drosophila has three BMP ligands, decapentaplegic (BMP2/4), screw, and glass bottom boat (BMP5/6/7/8). Of these genes, the transcriptional regulation of decapentaplegic has been studied, and some of the enhancers directing its spatially specific gene expression have been described. These analyses have used many of the standard tools of molecular biology, but a valuable method of analysis often used in Drosophila is the creation of patches of mutant tissue at any stage and in any location by induced somatic recombination. The ability to create transgenic flies and manipulate the Drosophila genome with recombinases is well established. This method can be used to evaluate the requirements for specific transcription factors to act on enhancer elements in vivo, in stage- and tissue-specific manners. The yeast FLP/FRT recombination system facilitates experiments to interrogate loss- or gain of-function for transcription factor activity on known enhancers. This chapter will outline the necessary steps to create the tools needed and conduct somatic cell recombination experiments to interrogate the function of transcription factors on BMP enhancers. PMID- 30414128 TI - Using Amphioxus as a Basal Chordate Model to Study BMP Signaling Pathway. AB - The BMP signaling pathway has been shown to be involved in different aspects of embryonic development across diverse metazoan phyla. Comparative studies on the roles of the BMP signaling pathway provide crucial insights into the evolution of the animal body plans. In this chapter, we present the general workflow on how to investigate the roles of BMP signaling pathway during amphioxus embryonic development. As amphioxus are basal invertebrate chordates, studies on the BMP signaling pathway in amphioxus could elucidate the functional evolution of BMP pathway in the chordate group. Here, we describe methods for animal husbandry, spawning induction, and manipulation of the BMP signaling pathway during embryonic development through drug inhibitors and recombinant proteins. We also introduce an efficient method of using mesh baskets to handle amphioxus embryos for fluorescence immunostaining and multicolor fluorescence in situ hybridization and to assay the effects of manipulating BMP signaling pathway during amphioxus embryogenesis. PMID- 30414129 TI - Proteolytic Activation of Bmps: Analysis of Cleavage in Xenopus Oocytes and Embryos. AB - Bone morphogenetic proteins (Bmps) are synthesized as inactive precursors that are cleaved to generate active ligands, along with prodomain fragments that can modulate growth factor activity. Here we provide three protocols that can be used to examine the process of proteolytic activation of Bmps. The first protocol describes how to generate radiolabeled Bmp precursor proteins in Xenopus oocytes and then analyze the time course of precursor cleavage by recombinant enzymes in vitro. The second protocol details how to analyze cleavage of radiolabeled precursor proteins in Xenopus oocytes over time using pulse-chase analysis and autoradiography. This protocol can also be used to analyze folding and cleavage of radiolabeled precursor proteins at steady state. Finally, the third protocol details methods for isolating Bmp cleavage products from the blastocoele of Xenopus embryos and then analyzing them on immunoblots. PMID- 30414130 TI - Imaging and Quantification of P-Smad1/5 in Zebrafish Blastula and Gastrula Embryos. AB - Spatiotemporal patterns of morphogen activity drive differential gene expression with a high degree of precision within a developing embryo and reproducibly between embryos. Understanding the formation and function of a morphogen gradient during development requires quantitative measurement of morphogen activity throughout an individual embryo and also between embryos within a population. Quantification of morphogen gradients in to presents unique challenges in imaging and image processing to minimize error and maximize the quality of the data so it may be used in computational models of development and in statistically testing hypotheses. Here we present methods for the preparation, immunostaining, imaging, and quantification of a bone morphogenetic protein (BMP) activity gradient in individual zebrafish embryos as well as methods for acquiring population-level statistics after embryo grouping and alignment. This quantitative approach can be extended to other morphogen systems, and the computational codes can be adapted to other imaging contexts in zebrafish and other organisms. PMID- 30414131 TI - An Adult Zebrafish Model of Fibrodysplasia Ossificans Progressiva. AB - Fibrodysplasia ossificans progressiva (FOP) is a rare human skeletal disease caused by constitutively activating mutations in the gene ACVR1, which encodes a type I BMP/TGFbeta family member receptor. FOP is characterized by progressive heterotopic ossification (HO) of fibrous tissues, including skeletal muscle, tendons, and ligaments, as well as malformation of the big toes, vertebral fusions, and osteochondromas. Surgical interventions in patients often result in enhanced HO, which can exacerbate rather than improve diagnostic outcomes. As a result of these difficulties, a variety of animal models are needed to study human FOP. Here we describe the methods for creating and characterizing zebrafish conditionally expressing Acvr1lQ204D, the first adult zebrafish model for FOP. PMID- 30414132 TI - Generation and Identification of Genetically Modified Mice for BMP Receptors. AB - BMP signaling is critical in embryogenesis and in the development of numerous tissues. Many genetically modified (knockout and transgenic) mice have been established to study BMP function in development and disease. Mice with altered BMP receptor genes (including global knockout, conditional knockout, and conditional constitutively active transgenic mouse lines) have been particularly informative. In this chapter, we describe how the genetically modified mice were generated and introduce genotyping methods. These methods include regular PCR and genomic real-time PCR using specific primers based on different constructs in different mice strains. PMID- 30414133 TI - Phenotypic Analyses of Genetically Modified Mice for BMP Receptors. AB - BMPs play important roles in the development, disease, and regeneration of many tissues. Genetically modified mice with altered BMP receptor genes are particularly informative for clarifying the role of BMP signaling. In this chapter, we introduce several selected protocols for in vivo functional characterization of BMP receptors in genetically modified mice, including immunohistochemistry of BMP downstream signaling (P-Smad1/5/9 or others), histological analysis, whole-mount skeletal staining for cartilage and bone tissues, and whole-mount cartilage staining. PMID- 30414134 TI - Immunofluorescent Visualization of BMP Signaling Activation on Paraffin-Embedded Tissue Sections. AB - Immunohistochemistry allows the detection of the presence, localization, and activation of proteins in biological tissues by using the ability of antibodies to bind to specific antigens. Cellular signaling can be visualized using antibodies raised against phosphorylated proteins. Phosphorylated Smad1, Smad5, and Smad9 are the activated signaling molecules of the BMP pathway that transfer BMP signals from the cell surface to the nucleus. Here we describe the detection of phospho-Smad1/5/9 on paraformaldehyde-fixed and paraffin-embedded tissue sections by immunofluorescence. PMID- 30414135 TI - Spatial and Quantitative Detection of BMP Activity in Mouse Embryonic Limb Buds. AB - Modulation of bone morphogenetic protein (BMP) activity is essential to the progression of limb development in the mouse embryo. Genetic disruption of BMP signaling at various stages of limb development causes defects ranging from complete limb agenesis to oligodactyly, polydactyly, webbing, and chondrodysplasia. To probe the state of BMP signaling in early limb buds, we designed two sets of primers to measure both spatially and quantitatively the transcription of nine key genes indicative of canonical BMP activity. One set is used to generate digoxigenin (DIG)-labeled antisense RNA probes for whole-mount mRNA in situ hybridization, while the second set is used for SYBR(r) Green-based quantitative PCR on limb bud cDNA. Here we describe step-by-step protocols for both methods around this specific set of genes. PMID- 30414136 TI - Pharmacologic Strategies for Assaying BMP Signaling Function. AB - The bone morphogenetic protein (BMP) signaling pathway, a subset of the transforming growth factor beta (TGF-beta) signaling family, consists of structurally diverse receptors and ligands whose combinatorial specificity encodes autocrine, paracrine, and endocrine signals essential for regulating tissue growth, differentiation, and survival during embryonic patterning and postnatal tissue remodeling. Aberrant signaling of these receptors and ligands is implicated in a variety of inborn and acquired diseases. The roles of various receptors and their ligands can be explored using small molecule inhibitors of the BMP receptor kinases. Several BMP type I receptor kinase inhibitor tool compounds have been described that exhibit sufficient selectivity to discriminate BMP receptor signaling in vitro or in vivo, with various trade-offs in selectivity, potency, cell permeability, and pharmacokinetics. Several methods for assaying BMP function via pharmacologic inhibition are presented. Two in vitro methods, an In-Cell Western assay of BMP-mediated SMAD1/5/8 phosphorylation and an alkaline phosphatase osteogenic differentiation assay, represent efficient high-throughput methodologies for assaying pharmacologic inhibitors. Two in vivo methods are described for assaying the effects of BMP signaling inhibition in embryonic zebrafish and mouse development. Small molecule inhibitors of BMP receptor kinases represent an important complementary strategy to genetic gain- and loss-of-function and ligand-trap approaches for targeting this signaling system in biology and disease. PMID- 30414137 TI - Bone Morphogenetic Proteins (BMPs) and Bone Regeneration. AB - Many research methods exist to elucidate the role of BMP-2 during bone regeneration. This chapter briefly reviews important animal models used in these studies and provides details on the rat femur defect model. This animal model is frequently utilized to measure the efficacy of osteogenic factors like BMP-2. Detailed information about delivery methods, dose range, and dose duration used in BMP-2-related studies are provided. PMID- 30414138 TI - Heterotopic Ossification in Mouse Models of Fibrodysplasia Ossificans Progressiva. AB - Fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder of progressive extra-skeletal ossification, is the most disabling form of heterotopic ossification (HO) in humans. Most people with FOP carry an activating mutation in a BMP type I receptor gene, ACVR1 R206H, that promotes ectopic chondrogenesis and osteogenesis and in turn HO. Advances in elucidating the cellular and molecular events and mechanisms that lead to the ectopic bone formation are being made through the use of genetically engineered mouse models that recapitulate the human disease. We describe methods for inducing heterotopic ossification in a mouse model that conditionally expresses the Acvr1 R206H allele. PMID- 30414139 TI - Double-Humanized Mouse Model to Study Bone Morphogenetic Protein (BMP) Signaling in Tumor Xenografts. AB - The activation of the bone morphogenic protein (BMP) signaling pathway in cancer cells has been shown to enhance migration and tumor angiogenesis and promote survival. The BMP signaling pathway regulates benign cells in the tumor microenvironment and is a known regulator of immune cells. The development of BMP receptor inhibitors has allowed the study of tumor xenografts in mice. We describe a double-humanized mouse model with adoptively transferred human immune and human tumor cells that can be used to assess the effects of BMP inhibitors on these human cells in vivo. PMID- 30414140 TI - Introduction to FOXO Biology. AB - Forkhead box O (FOXO) proteins are a family of transcription factors with four members in mammals, namely FOXO1, FOXO3a, FOXO4, and FOXO6. FOXO factors, originally identified as downstream regulators of the insulin pathway, are known to bind to the promoters of a broad variety of target genes and control several processes of key importance for cellular homeostasis including cellular energy production, oxidative stress resistance, and cell viability and proliferation. Accordingly, deregulation of FOXO proteins has been shown to play an essential role in metabolic disorders, human longevity, and the suppression of tumors. As the activity of these transcription factors is controlled by posttranslational modifications, inactivation of FOXOs occurs mostly due to the overactivation of their upstream modifying enzymes providing a wealth of possibilities for restoring FOXO activity pharmaceutically. PMID- 30414141 TI - Characterization of MicroRNAs Regulating FOXO Expression. AB - MicroRNAs are critical post-transcriptional regulators of a majority of genes, of which the FOXO family of transcription factors is no exception. Here, we describe generalizable methods, including 3' UTR reporter assays and western blotting after microRNA manipulation, to test if a candidate miRNA (miR-182) directly targets a candidate (FOXO3) gene product. We also provide guidance on candidate miRNA selection and unbiased miRNA-target identification methods. PMID- 30414142 TI - Identification of Transcription Factor-Binding Sites in the Mouse FOXO1 Promoter. AB - One critical determinant of levels of gene expression is binding of transcription factors to cognate DNA sequences in promoter and enhancer regions of target genes. Transcription factors are DNA-binding proteins to which transcriptional co regulators are bound, ultimately resulting in histone modifications that change chromatin structure to regulate transcription. Examples of transcription factors include hormone-activated transcription factors such as the glucocorticoid receptor, transcription factors regulated by cell surface receptors such as FOXO1 and Smad2/Smad3, and many others. Promoter regions typically contain multiple, diverse transcription factor-binding sites. Binding sites for cell-type-specific transcription factors involved in cell fate determination such as Runx2, MyoD, or myogenin are frequently observed. Promoter regions are located within ~2 kb upstream of the transcriptional start site, whereas enhancers may be located at some distance from promoter sequences and exert long-range effects. Here, we will discuss classical and emerging technologies by which one can understand the role of binding of specific transcription factors in regulation of transcription of FOXO genes. PMID- 30414143 TI - Investigating Mechanisms that Control Ubiquitin-Mediated DAF-16/FOXO Protein Turnover. AB - Protein turnover of FOXO family transcription factors is regulated by the ubiquitin-proteasome system. A complex interplay of factors that covalently attach certain types of ubiquitin chains (E3-ubiquitin ligases), and enzymes that are able to remove ubiquitin conjugates (deubiquitylases), regulate the degradation of FOXO proteins by the proteasome. Here, we describe methods to characterize candidate E3-ubiquitin ligases and deubiquitylases as regulators of the FOXO ubiquitylation status. Our protocol can be utilized to purify and enrich a ubiquitylated FOXO pool from cultured cells under denaturing conditions, which inactivates cellular deubiquitylases and thereby protects ubiquitin conjugates on FOXO proteins. In addition, our method describes how ubiquitylated FOXO proteins can be renatured in a stepwise fashion to serve as substrates for in vitro deubiquitylation (DUB) assays. PMID- 30414144 TI - Phosphorylation of FOXO Proteins as a Key Mechanism to Regulate Their Activity. AB - Phosphorylation of FOXO transcription factors is one of the key mechanisms involved in the regulation of the activity, nucleo-cytosolic shuttling, and stability of this family of proteins. Here, we describe several experimental approaches allowing analysis of changes in the phosphorylation of these proteins upon exposure to different stimuli. PMID- 30414145 TI - Methodological Approach for the Evaluation of FOXO as a Positive Regulator of Antioxidant Genes. AB - All four FOXO isoforms have been shown to respond to changes in the cellular redox status of the cell, and regulate the expression of target genes that in turn can modulate the cellular oxidative status. However, the mechanisms involved are still controversial. It is clear though that redox regulation of FOXO factors occurs at different levels. The proteins themselves are redox-sensitive and their capacity to bind their target sites seems to be at least partially dependent on their oxidative status. Importantly, several of the cofactors that are known to regulate FOXO transcriptional activity are also sensitive to changes in the cellular redox status, in particular the deacetylase SirT1 is activated in response to reduced levels of reducing equivalents (increased NAD+/NADH+ ratio) and the coactivator PGC-1alpha is induced in response to increased cellular oxidative stress. Furthermore, nuclear localization of FOXO factors is also regulated by proteins that, like AKT, are themselves regulated directly or indirectly by the cellular levels of reactive oxygen and nitrogen species. In this technical review, we aim to update the current status of our knowledge of how to handle redox-regulated FOXO factor research in order to better understand FOXO biology. PMID- 30414146 TI - Characterization of FOXO Acetylation. AB - FOXO3 is a tumor suppressor that orchestrates the expression of genes that regulate cell cycle progression, apoptosis, metabolism, oxidative stress, and other important cellular processes. Its inactivation is closely associated with tumorigenesis and cancer progression. On the other hand, sirtuin proteins have been demonstrated to be able to deacetylate, thus causing FOXO3 inactivation at the posttranslational level. Therefore, targeting sirtuin proteins renders new avenues for breast cancer treatment. Here, we describe three procedures for studying FOXO3 posttranslational modifications controlled by sirtuin proteins in cancer cells. PMID- 30414147 TI - Transcriptional Activity of FOXO Transcription Factors Measured by Luciferase Assays. AB - The Forkhead box O (FOXO) family of transcription factors translates environmental cues into gene expression. FOXO factors are crucial for the maintenance of cell homeostasis, with important roles in cell fate decisions and differentiation. Identification of FOXO target genes requires strict validation by several methods. Luciferase-based reporters are a valuable starting point for determining the transcription-promoting capacity of potential FOXO-binding sites in candidate genes. Luciferase, an enzyme found in bioluminescent organisms catalyzes oxidation of luciferin to produce oxyluciferin together with light, which can be easily detected and measured with a luminometer. Due to their many advantages, transcriptional assays based on luciferase activity are widely used; they are easy, highly reproducible, and very sensitive. Continued improvements in luciferase-based vectors and measurement reagents confer considerable versatility. Luciferase-based reporters are also a reliable approach in the search for unknown components in the signaling pathways that control FOXO factor activity.We previously reported that FOXO transcription factors control expression of the enzyme diacylglycerol kinase alpha (DGKalpha) in T cells. DGKalpha consumes diacylglycerol, a lipid that activates several mitogenic pathways. Here, we describe the use of a luciferase-based promoter bearing the FOXO-binding sites of the DGKalpha gene to explore the relationship between the expression of this enzyme and stress conditions in NIH3T3 mouse fibroblasts. Our data support a role for FOXO factors in promoting high DGKalpha levels in conditions of growth factor deprivation. DGKalpha regulation by FOXO factors correlates with the reported alterations in DGKalpha expression during cell transformation and cancer progression. PMID- 30414148 TI - Monitoring the Transcriptional Activity of FOXO Transcription Factors by Analyzing their Target Genes. AB - FOXO proteins represent a subfamily of transcription factors that belong to the forkhead family. The study of FOXO target genes can be performed using Real-Time PCR (RT-PCR). The RT-PCR is a sensitive method that allows the detection and quantification of minute amounts of nucleic acids. In RT-PCR the accumulation of the amplicon is detected and measured as the reaction progresses. Here, we describe the application of RT-PCR technique to monitor the transcriptional activity of FOXO transcription factors. PMID- 30414149 TI - Using ChIP-Based Approaches to Characterize FOXO Recruitment to its Target Promoters. AB - Chromatin immunoprecipitation (ChIP) coupled to quantitative real-time PCR (ChIP qPCR) or Next-Generation Sequencing (ChIP-seq) enables us to study the dynamics of chromatin recruitment of transcription factors (TFs). The popular model system Caenorhabditis elegans has provided us with fundamental understanding of the role of Insulin/IGF-1-like signaling (IIS) in metabolism and aging. The FOXO TF DAF-16 is the major output of the pathway that regulates most of the phenotypes associated with the IIS pathway. Here, we describe a ChIP protocol to study FOXO recruitment dynamics in whole C. elegans extracts. We discuss detailed practical procedures, including optimization, growth, harvesting, formaldehyde fixation, sonication of worms, TF immunoprecipitation for further downstream processing using qPCR as well as NGS for the analysis of FOXO-bound DNA. PMID- 30414150 TI - RNAi-Mediated Silencing of FOXO Factors. AB - RNAi-mediated silencing of a particular gene is an important tool in the field of biology. Knocking down experiments has revealed the role of different proteins and their downstream targets. Here, we describe the procedure of silencing transcription factor of Forkhead box class "O" (FOXO) using shRNA. PMID- 30414151 TI - Immunofluorescence Analysis by Confocal Microscopy for Detecting Endogenous FOXO. AB - Cancer cells are known to inactivate tumor suppressor proteins by triggering their anomalous subcellular location. It has been well established that the aberrant location of FOXO proteins is linked to tumor formation, progression of the same, or resistance to anti-neoplastic treatment. Furthermore, the abnormal location of FOXO has also been considered a potential biomarker for diabetic complications or longevity in different organisms. Here, we describe the immunodetection of endogenous FOXO by confocal microscopy, which can be used as a chemical tool to quantify FOXO expression levels, its cellular location, and even its active/inactive forms with relevant antibodies. PMID- 30414152 TI - High-Throughput Image-Based Screening to Identify Chemical Compounds Capable of Activating FOXO. AB - FOXO proteins are transcription factors with important roles in the regulation of the expression of genes involved in cell growth, proliferation, differentiation, and longevity. FOXO proteins are active in the nucleus but, upon post translational modification they form a docking site for 14-3-3 proteins and are translocated to the cytoplasm where they are inactive.We make use of this regulatory mechanism of FOXO proteins to develop an image-based high-throughput screening platform to detect compounds that regulate FOXO3 subcellular localization. This system has proven a powerful tool to isolate inhibitors of proteins upstream of FOXO, such as PI3K inhibitors. PMID- 30414153 TI - Image-based Identification of Chemical Compounds Capable of Trapping FOXO in the Cell Nucleus. AB - Forkhead box O (FOXO) factors are tumor suppressor proteins commonly inactivated in human tumors. Furthermore, genetic variation within the FOXO3a gene is consistently associated with human longevity. FOXO proteins are usually inactivated by posttranslational modifications leading to cytoplasmic mislocalization. Therefore, the pharmacological activation by promoting nuclear localization of FOXOs is considered an attractive therapeutic approach to treat cancer and age-related diseases. We developed a cell-based imaging assay to screen for chemical agents capable of inhibiting the nuclear export and in turn trapping proteins that contain a nuclear export sequence including FOXO factors in the nucleus. The fluorescent signal of untreated assay cells localizes predominantly to the cytoplasm. Upon treatment with the nuclear export inhibitors the fluorescent-tagged reporter proteins appear as speckles in the nucleus. In a personalized medicine context, drugs capable of reactivating FOXO factors might be of enormous clinical value in human tumors in which these proteins are inactivated. Here, we describe the procedures for monitoring nuclear export which is suitable for high-throughput screening of compound collections. PMID- 30414154 TI - Quantifying Tissue-Specific Overexpression of FOXO in Drosophila via mRNA Fluorescence In Situ Hybridization Using Branched DNA Probe Technology. AB - While the highly conserved FOXO transcription factors have been studied in Drosophila melanogaster for decades, the ability to accurately control and measure their tissue-specific expression is often cumbersome due to a lack of reagents and to limited, nonhomogeneous samples. The need for quantitation within a distinct cell type is particularly important because transcription factors must be expressed in specific amounts to perform their functions properly. However, the inherent heterogeneity of many samples can make evaluating cell-specific FOXO and/or FOXO load difficult. Here, we describe an extremely sensitive fluorescence in situ hybridization (FISH) approach for visualizing and quantifying multiple mRNAs with single-cell resolution in adult Drosophila cardiomyocytes. The procedure relies upon branched DNA technology, which allows several fluorescent molecules to label an individual transcript, drastically increasing the signal-to noise ratio compared to other FISH assays. This protocol can be modified for use in various small animal models, tissue types, and for assorted nucleic acids. PMID- 30414155 TI - Genome-Wide Analysis for Identifying FOXO Protein-Binding Sites. AB - Forkhead box O (FOXO) proteins comprise a superfamily of transcription factors that play important roles in controlling various biological processes. Transcriptional control constitutes a crucial component in regulating complex biological processes. The identification of cis-regulatory elements is essential to understand the regulatory mechanism of gene expression. Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) is widely used to identify the cis-regulatory elements of transcription factors and other DNA-binding proteins on a genome-wide level. It is a powerful tool to analyze the regulatory networks underlying the biological processes. Here, we describe a detailed protocol for preparing ChIP-seq samples that are used for sequencing and subsequent data analyses. PMID- 30414156 TI - Mathematical Modeling of Nuclear Trafficking of FOXO Transcription Factors. AB - Nuclear cytoplasmic flux of Foxo transcription factors is paramount in cellular gene regulation. For example, excluding Foxo from skeletal muscle nuclei is necessary to avoid muscle wasting through elevated protein breakdown. Constructing a mathematical model of the signaling process leading to alteration of Foxo nuclear cytoplasm ratio is useful in predicting and interpreting such ratio changes. In this chapter we derive a general mathematical model for nuclear cytoplasmic flux. We apply this model to Foxo flux and take advantage of rapid phosphorylation approximation and conservation conditions to reduce the Foxo flux model. We constrain our model with data from mouse skeletal muscle with applied IGF. This procedure provides an example of what might be called the central approach of mathematical modeling: The cycling of a biological question through mathematical formulation and back to biological interpretation. PMID- 30414157 TI - Following Transcriptome to Uncover FOXO Biological Functions. AB - Two and half million red blood cells (RBC) are generated every second in a healthy adult. The process of RBC production known as erythropoiesis requires a meticulous synchrony between signaling processes and the activity of many transcription factor complexes. FOXO3 is a transcription factor that is responsive to signaling processes and essential for the erythroid proliferation and maturation, RBC formation, and lifespan. Here, we discuss how using an integrated computational and experimental systems biology approach new and unanticipated FOXO3 functions in terminal erythropoiesis were uncovered. These combinatory approaches identified FOXO3 as a key regulator of terminal erythropoiesis. As a result, a new mode of FOXO3 participation in erythroid transcription complex formation has been proposed. PMID- 30414158 TI - Hydra as Model to Determine the Role of FOXO in Longevity. AB - In non-senescent Hydra, continuously high activity of transcription factor FOXO contributes to continuous stem cell proliferation. Here, we describe how genetic manipulation of Hydra polyps using embryo-microinjection allows uncovering the role of FOXO in coordinating both stem cell proliferation and antimicrobial peptide0073 , effector molecules of the innate immune system, and regulators of the microbiome. PMID- 30414159 TI - Genetic Ablation of FOXO in Mice to Investigate Its Physiological Role. AB - Recent reports emphasized the role of FOXO family of transcription factors in nervous system homeostasis. Most studies employed primary neuronal cultures, established animal models for neuropathology, or invertebrate models. Demonstration of the normal and pathophysiological function of mammalian FOXO under complex in vivo conditions requires genetic study. Therefore, the conditional knockout mouse is an invaluable platform. Here, we describe the methods of establishing and analyzing nervous system-specific ablation of FOXO isoforms in mice. This chapter offers a detailed method to validate the deletion of Foxo genes in vivo and to study its role in the nervous system. Investigation of FOXO function by using the mouse system may advance our understanding of nervous system aging as well as neurodegenerative diseases. PMID- 30414160 TI - Analysis of FOXO3 Gene Polymorphisms Associated with Human Longevity. AB - Next-generation DNA sequencing has ushered in a new era of genotype-phenotype comparisons that have the potential to elucidate the genetic nature of complex traits. Since such methods rely on short sequence reads and since the human genome is composed largely of repetitive DNA elements larger than these read lengths many results cannot be mapped and are discarded, thus eliminating a large portion of the genome from analysis. Discerning associations in complex traits, such as longevity, will require either longer read lengths or methods to address these sequence complexities. Whole genome analysis, such as Genome Wide Association Studies (GWAS), also suffers from the repetitive nature of the human genome, as there exist many gaps in the availability of useable genetic markers, often in interesting regulatory regions. Methods are described here whereby some of these problems have been addressed by targeted DNA sequencing, full exploitation of available public databases, and a careful evaluation of genomic features where we use the FOXO3 gene as an example to identify functional variations and how they may relate to longevity. PMID- 30414161 TI - Analysis of FOXO3a Gene Polymorphism Associated with Asthma. AB - Single-nucleotide polymorphisms (SNP) represent genetic variation in a human population; 99.9% of the DNA sequence is identical and remaining 0.1% of DNA contains sequence variants. Around ten million SNPs are identified post human genome project. Identification of SNPs associated with disease phenotype has diagnostic potential and may predict drug response. Several technologies genotype thousands of SNPs simultaneously, for instance, genotyping arrays, gene-chip arrays, bead array technology, pyrosequencing, TaqMan approach, etc., however Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) remains a simplest, reliable, and cost effective method. In PCR-RFLP, a fragment that is to be analyzed for a mutation is amplified from genomic DNA using PCR, digested using appropriate restriction enzyme and then separated by gel electrophoresis. Sets of primer are used to amplify a fragment of interest and are designed in such a way that it flanks the polymorphic site and is located in such a way as to generate uneven sized fragments upon restriction endonuclease cleavage of the amplified PCR products. FOXO3a plays a key role in maintaining immunoregulation and is associated with several inflammatory diseases. Here, we report the PCR-RFLP protocol developed for detection of polymorphism in FOXO3a gene (rs13217795) by amplifying a 667 bp fragment followed by restriction endonuclease analysis using PagI to obtain RFLP patterns. PMID- 30414162 TI - Lung Ultrasound in the Assessment of Pulmonary Complications After Lung Transplantation. AB - INTRODUCTION: Lung ultrasound (LUS) has a high diagnostic accuracy for identifying frequent conditions in the post-operative phase after lung transplantation (LTx). This study aimed to investigate the feasibility and clinical ability of LUS to identify pulmonary complications such as pleural effusions and pneumonias in the early postoperative phase after LTx. METHODS: A prospective cohort study of lung transplant recipients who consecutively underwent single LTx (SLTx) or double LTx (DLTx) at the National Lung Transplantation Center in Denmark from May 1 to October 31, 2015 was conducted. LUS was performed at four time points corresponding to post-transplant day 3, and weeks 2, 6, and 12 (LUS #1 - 4) to detect and monitor variation in pathological LUS findings over time. Concurrent with LUS #4, a high-resolution computed tomography examination of the thorax (HRCT) was also performed. RESULTS: 14 patients (1 SLTx/13 DLTx, 7 (50 %) women, mean age: 50.4 years) who had undergone the four prespecified LUS examinations were included. Pleural effusion was the most common condition and most pronounced at post-LTx week 2. Findings consistent with pneumonia increased during week 2 and subsequently decreased. Corresponding to LUS #1, 2, 3, and 4, pleural effusion occurred in 85.7 %, 92.9 %, 85.7 %, and 78.6 %, and pneumonia in 21.4 %, 28.6 %, 14.3 %, and 14.3 %, respectively. HRCT findings at post-LTx week 12 were predominantly presented by unspecific ground glass opacities. CONCLUSION: In a post-LTx setting, LUS represents a clinical novelty as a feasible diagnostic and monitoring tool to identify pathological pulmonary complications in the early post-operative phase. PMID- 30414163 TI - [Uro mHealth: health apps in urology]. AB - The use of readily available mHealth apps on smartphones and tablets is increasing worldwide, including the field of urology. Access to knowledge, data collection and communication are thus simplified and accelerated. A wide range of health apps exists for the public, patients, health professionals and medical education. In particular, in the field of urology, several high quality mHealth contents have been created in recent years. Nevertheless, there is still need for improvement and development.The ubiquity of health apps might also bring particular risks. Healthcare professionals can use their private electronic devices when dealing with patients or patient data, and thus risk violations of patient and data protection rights.There are no universal quality standards or legal certification requirements for mHealth apps. Private (mostly commercial) app developers and providers possess quasi-proprietary rights concerning user data. Politics, scientific funding agencies and medical societies are therefore urgently needed to set standards and to promote and fund open-source key projects providing quality benchmarks within the field. PMID- 30414164 TI - Efficacy of a paclitaxel-eluting biliary metal stent with sodium caprate in malignant biliary obstruction: a prospective randomized comparative study. AB - BACKGROUNDS: The placement of a self-expandable metal stent (SEMS) is widely used in patients with unresectable malignant biliary obstructions, but SEMSs are susceptible to occlusion by tumor ingrowth or overgrowth. The efficacy and safety of a novel paclitaxel-eluting biliary metal stent incorporating sodium caprate (MSCPM-III) were compared prospectively with those of a covered metal stent (CMS) in patients with malignant biliary obstructions. METHODS: Patients with unresectable distal malignant biliary obstructions (n = 106) were prospectively enrolled in this study at multiple treatment centers. Stents were placed endoscopically: MSCPM-III in 54 patients and CMS in 51 patients. The patients received systemic chemotherapy regimens according to their disease characteristics. RESULTS: The two groups did not differ significantly in basic characteristics or mean follow-up period. Stent occlusion occurred in 14 patients who received MSCPM-III and in 11 patients who received CMS. Time to recurrent biliary obstruction (RBO) and survival time did not differ significantly between the two groups (P = 0.84 and P = 0.29, respectively). However, tumor size at 2 months after stent insertion was significantly decreased in patients in the MSCPM III group with bile duct cancers or those who experienced stent migration compared with the CMS group. Complications, including cholangitis and pancreatitis, were found to be acceptable in both groups. CONCLUSIONS: Although compared with a CMS the MSCPM-III did not significantly influence time to RBO or survival duration in patients with malignant biliary obstructions, MSCPM-III reduced tumor volume and was used safely in humans. PMID- 30414165 TI - Prevalence of Persistent Pain after Total Knee Arthroplasty and the Impact of Neuropathic Pain. AB - The present study aimed to define the prevalence of pain persisting after total knee arthroplasty (TKA) and determine the impact of neuropathic pain. Knee pain after TKA was evaluated in 154 patients (222 knees with osteoarthritis) using a numerical rating scale (NRS) and followed up for a mean of 4.7 years. The patients were classified according to whether they had no or mild pain (NRS <= 3), or moderate-to-severe pain (NRS > 3), and then assigned to groups with nociceptive, unclear, or neuropathic pain based on responses to painDETECT questionnaires. Risk factors for these types of pain were determined. The ratio of patients with moderate-to-severe pain was 28% (62 knees). Thirteen patients (21 knees; 9%) experienced unclear pain. Patients with moderate-to-severe or unclear pain had malalignment and lower Knee Society knee scores. In conclusion, a significant number of patients experienced moderate-to-severe and unclear pain after TKA. Moderate-to-severe pain was associated with unclear pain. PMID- 30414166 TI - Wound Closure in Flexion versus Extension following Total Knee Replacement: Outcomes and Complications. AB - Position of the knee may affect the range of movement (ROM) after a total knee replacement (TKR). It has been postulated that wound closure in extension may cause shortening of the extensor mechanism and increased tension on the soft tissues. The aim of this study was to determine effect of wound closure in TKR with the knee in flexion or extension on postoperative ROM and rehabilitation. A consecutive series of 121 patients underwent primary TKR between May 2011 and August 2012. Group A (60 patients) had wound closure in extension. Group B (61 patients) had wound closure in flexion. Baseline demographic data were compared age, body mass index, gender, American Society of Anesthetists status, length of stay, wound healing, and ROM. Oxford Knee Score (OKS) were assessed at 6 months, 1 year, and 2 years. Fifty-two males and 69 females with average age of 68 years (32-86) underwent TKR. There were no wound complications requiring surgical intervention. One patient in each group required manipulation under anesthesia for stiffness. There was no statistical difference in ROM and OKS at the last follow-up. There was no difference in outcomes following knee closure in flexion or extension. PMID- 30414167 TI - Evaluation of Femoral-Tibial Flexion Gap in Total Knee Arthroplasty with Everted or Lateralized Patella. AB - Intraoperative patellar position (eversion, lateralization, or in situ) influences the ligamentous balancing in knee flexion and thereby the correct positioning of the femoral component during total knee arthroplasty. The correct ligament balancing is crucial when, as in our experience, prostheses with medial pivot design are used. It was shown that the flexion gap in the normal knee is not rectangular and that the lateral compartment is significantly slacker than the medial. Therefore, to obtain a correct kinematics of a medial pivot anatomical prosthesis, it is essential to recreate an anatomical flexion gap slacker in the lateral compartment. We conducted a prospective study on a consecutive series of 87 total knee prostheses. The objective of this study is to evaluate the femoral external rotation angle in each patient with everted patella as well as with pure subluxated patella. The purpose of this study is to offer guidance about the optimal femoral rotation angle to achieve best outcomes of a knee replacement. The evaluation was done using an instrument developed by Medacta International (Switzerland) with our direct collaboration (Tensor, Medacta, Switzerland) and standardizing the basic conditions of each patient (knee 90 degrees flexed, medial transquadricipital surgical access, lateral displacement of the patella, tourniquet inflated at 250 mm Hg, spinal anesthesia). Each group was subdivided into subgroups according to gender, preoperative varus or valgus deformity, and patellar height. Our study advises against evaluating the flexion gap with everted patella due to high risk of underestimation of the lateral compartment laxity (differences up to + 3 degrees with pure subluxated patella compared with everted patella). PMID- 30414168 TI - A Total Knee Arthroplasty Is Stiffer When the Intraoperative Tibial Force Is Greater than the Native Knee. AB - We hypothesized that a total knee arthroplasty (TKA) with an intraoperative tibial force greater than the tibial force of the native knee has signs of stiffness as measured by loss of extension and flexion, and anterior translation of the tibia. Intraoperative forces in the medial and lateral tibial compartments were measured during passive motion in 71 patients treated with calipered kinematically aligned TKA. Maximum extension, flexion, and the anterior-posterior position of the tibia with respect to the distal femur at 90 degrees of flexion were measured. Measurements were repeated after exchanging to a 2 mm thicker insert. The sum of the average of the medial and lateral compartment forces at 0, 45, and 90 degrees of flexion represented the tibial force through a 90-degree motion arc. For the implanted insert, the tibial force averaged 28 +/- 17 lb, which is comparable to the 20 +/- 7 lb reported for the native knee. At 6 months, patients reported an average 40 point Oxford Knee and 15 point Western Ontario and McMaster Universities Osteoarthritis (WOMAC) score. For the 2 mm thicker insert, the tibial force averaged 50 +/- 28 lb. A 30 lb tibial force greater than native generated a 3-degree loss of extension, a 3-degree loss of flexion, and 3 mm anterior translation of the tibia. Because a TKA with a tibial force greater than native has signs of stiffness, a strategy for lowering this risk is to match the tibial force of the native knee when balancing a TKA as this restored high function. PMID- 30414169 TI - Demographic Trends and KRAS/BRAFV600E Mutations in Colorectal Cancer Patients of South China: a Single-site Report. AB - The incidence of colorectal cancer (CRC) is increasing in China. Here, we aimed to evaluate the latest demographic trends and KRAS/BRAF mutations status of Chinese CRC. 5546 CRC patients diagnosed from 2010 to 2017 were involved. KRAS exon 2 and BRAFV600E mutations were detected by Sanger sequencing and high resolution melting analysis or allelic-specific probe method. Gene mutation profiles and clinicopathologic characteristics of 5495 patients were analyzed. The joinpoint regression model was used to predict the demographic data in 2018. We found KRAS exon 2 and BRAFV600E mutation rates were 37.7% and 2.8% in CRC patients. Tumors with KRAS exon 2 mutations were more likely to be present in female and patients aged older than 75 years, right colon and have well differentiated histology. Tumors with BRAFV600E mutations were more likely to be present in the female, right colon and have poorly differentiated histology. From 2010 to 2017, the percentage of colon cancer and tubular adenocarcinoma in CRC increased substantially (from 39.3% to 51.8%, from 78.6% to 93.4%, respectively). The percentage of right colon cancer increased from 18.3% to 20.5%, which predictively may keep at 22.6% in 2018. The rise trends for patients with moderate differentiation tumor or KRAS exon 2 mutated tumor were apparent (from 50.3% to 78.6%, from 32.8% to 39.7%, respectively). In conclusion, in recent eight years, there is a shift to the colon, especially right colon in the incidence of Chinese CRC. Moreover tubular adenocarcinoma is becoming the primary histology type. This article is protected by copyright. All rights reserved. PMID- 30414171 TI - "It's Wrong to Exclude Girls From Something They Love." Adolescents' Attitudes About Sexism in Science, Technology, Engineering, and Math. AB - The current research examined adolescents' attitudes about sexism in fields related to science, technology, engineering, and math (STEM). The ethnically diverse sample (61% East Asian) was composed of 629 adolescents (Mage = 16.09) who attended a public school in the United States. Participants responded to closed- and open-ended questions about the prevalence and severity of sexism in STEM. We used latent profile analysis to classify participants into latent classes according to their responses. Of note, one latent class included participants who perceived sexism in STEM as a fairly common and very serious problem. Relative to the other classes, participants in this class were more likely to be girls and showed higher STEM value. Qualitative analyses illustrated that the participants in each class reasoned in fundamentally different ways about sexism in STEM. PMID- 30414170 TI - Newly developed anti-S100A8/A9 monoclonal antibody efficiently prevents lung tropic cancer metastasis. AB - The metastatic dissemination of cancer cells to remote areas of the body is the most problematic aspect in cancer patients. Among cancers, melanomas are notoriously difficult to treat due to their significantly high metastatic potential even during early stages. Hence, the establishment of advanced therapeutic approaches to regulate metastasis is required to overcome the melanoma disease. An accumulating mass of evidence has indicated a critical role of extracellular S100A8/A9 in melanoma distant metastasis. Lung S100A8/A9 is induced by melanoma cells from distant organs and it attracts these cells to its enriched lung environment since melanoma cells possess several receptors that sense the S100A8/A9 ligand. We hence aimed to develop a neutralizing antibody against S100A8/A9 that would efficiently block melanoma lung metastasis. Our protocol provided us with one prominent antibody, Ab45 that efficiently suppressed not only S100A8/A9-mediated melanoma mobility but also lung tropic melanoma metastasis in a mouse model. This prompted us to make chimeric Ab45, a chimera antibody consisting of mouse Ab45-Fab and human IgG2-Fc. Chimeric Ab45 also showed significant inhibition of the lung metastasis of melanoma. From these results, we have high hopes that the newly produced antibody will become a potential biological tool to block melanoma metastasis in future clinical settings. This article is protected by copyright. All rights reserved. PMID- 30414172 TI - Fragile X syndrome and connective tissue dysregulation. AB - Fragile X syndrome (FXS) is the most common cause of inherited intellectual disabilities and autism spectrum disorders, and it is an X-linked disorder in which there is a deficiency of the fragile X mental retardation 1 protein. This protein is crucial in regulating translation of mRNAs related to dendritic maturation and cognitive development. The phenotype of FXS is characterized by neurobehavioral alterations, social deficits, communication difficulties, and findings which suggest an alteration of connective tissue, especially in the ligaments and muscles, cardiovascular system and genitourinary system. Connective tissue connects and supports all other tissues of the body and is composed of cells and extracellular matrix (ECM). Several proteins have been involved in the connective tissue abnormalities associated with the FXS, such as matrix metalloproteinase 9, which plays an important role in the homeostasis of the ECM, being a potential therapeutic target for certain tetracycline antibiotics that have shown beneficial effects in FXS. Here, we review connective tissue problems described in FXS. PMID- 30414173 TI - Physical and chemical behaviour of Nabali Mohassan single-cultivar olive oil during prolonged storage. AB - BACKGROUND: The effect of storage time on the fluorescence emission intensity and physico-chemical properties of olive oil from the Palestinian cultivar Nabali Mohassan was studied. Olive oil samples stored up to 7 years were obtained from different olive orchards in Palestine, where prolonged storage is still in use. RESULTS: Due to oxidation, all fluorescent minor compounds (tocopherols, chlorophylls, pheophytins, and phenolic compounds) of olive oil significantly decreased as the storage time increased, whereas viscosity increased (p<0.05). Until one year of storage the physico-chemical properties of olive oil samples were within the limits of both Palestinian and European quality standards and minor compounds, although affected by a marked decrease compared to freshly produced oil, were still detectable. After 5 years, a 90% decrease of the fluorescence attributed to tocopherols occurred, and after 7 years phenolics reached a loss of 90%. CONCLUSION: The analysis of fluorescence, together with other physical measures, was a useful tool in monitoring oil aging. This is the first report on fluorescent minor compounds of oils obtained from Nabali Mohassan olive cultivar. A better knowledge of this single-cultivar oil could enhance the adoption of the best practices by producers, improving the whole production chain. This article is protected by copyright. All rights reserved. PMID- 30414174 TI - Critical observations that shaped our understanding of the function(s) of intracellular glycosylation (O-GlcNAc). AB - Almost 100 years after the first descriptions of proteins conjugated to carbohydrates (mucins), several studies suggested that glycoproteins were not restricted to the serum, extracellular matrix, cell surface, or endomembrane system. In the 1980s, key data emerged demonstrating that intracellular proteins were modified by monosaccharides of O-linked beta-N-acetylglucosamine (O-GlcNAc). Subsequently, this modification was identified on thousands of proteins that regulate cellular processes as diverse as protein aggregation, localization, post translational modifications, activity, and interactions. In this Review, we will highlight critical discoveries that shaped our understanding of the molecular events underpinning the impact of O-GlcNAc on protein function, the role that O GlcNAc plays in maintaining cellular homeostasis, and our understanding of the mechanisms that regulate O-GlcNAc-cycling. PMID- 30414175 TI - Triticum aestivum Ethanolic Extract Improves NAFLD in Mice Fed a Choline Deficient or High-Fat Diet. AB - BACKGROUND: Although nonalcoholic fatty liver disease (NAFLD) has become more prevalent with the rapid increase of obesity worldwide, no specific treatment has been developed. Several studies have shown that wheatgrass extract (Triticum aestivum [TA]) improves lipid metabolism. In this study, we evaluated the efficacy of GM-T (an ethanolic TA extract) in a murine NAFLD model. Mice were separated into 12 groups (n=10): two group of normal diet, choline-deficient diet (CDD) or high-fat diet (HFD) with vehicle, CCD or HFD with silymarin (400 mg kg-1 day-1 ), and CCD or HFD with GM-T (100, 200, or 400 mg kg-1 day-1 ). The study was performed for 8 weeks for the CDD groups and 12 weeks for the HFD groups. RESULTS: In the CDD-fed mice, GM-T improved serum liver enzyme activities and liver inflammation score compared with vehicle. In the HFD-fed mice, GM-T improved blood lipid profiles, liver inflammation score, steatosis score, and obesity compared with vehicle. CONCLUSION: The present study demonstrated that GM T effectively improved NAFLD in mice through a mechanism that improved insulin resistance and lipid metabolism, suggesting the possibility of a functional dietary supplement to improve liver health, overall metabolic syndrome, and obesity. This article is protected by copyright. All rights reserved. PMID- 30414176 TI - Deferral rate variability in blood donor eligibility assessment. AB - BACKGROUND: Both donors and the blood bank rely on the result of the donor health interview. However, survey data suggest that substantial variability in deferral rates among interviewers exist. We studied whether variability remained after adjusting for conditional factors. STUDY DESIGN AND METHODS: The data set included Dutch interview data on whole blood donor visits in 2015, where one of their visits was selected randomly. We applied logistic regression and multilevel regression analyses with the donor visit, with the interviewer representing the levels. We set up four models: 1) all reasons deferral, 2) low-hemoglobin-level deferral, 3) infectious disease risk deferral and 4) other medical reasons deferral. RESULTS: In total, 138,398 visits were included in the study, of which 60,534 (43.7%) related to male donors. The overall deferral rate for men was 7.91% and for women 12.25%. Deferral rates among interviewers ranged from as low as 1.19% up to 28.8%. Models 2 (low hemoglobin level) and particularly 4 (other medical reasons), for both men and women, showed significant intraclass correlation coefficients, implying considerable deferral rate variability among interviewers. Donor age, the number of previous visits, and the season had relatively large effects. However, explained variances of the logistic regression models were relatively low, ranging from 2.53% to 7.35%. CONCLUSION: Deferral appears to be a random process, while substantial variability was found among interviewer deferral rates, suggesting that some interviewers are more cautious than others. Our results suggest heuristic and subjective diagnosing to be prevalent. Steps should be taken to improve interview result validity. PMID- 30414177 TI - A case of Kindler syndrome in a young Indian female with exon deletion. PMID- 30414178 TI - Impact of phosphorus application on drought resistant responses of Eucalyptus grandis seedlings. AB - Eucalyptus grandis is the most widely planted tree species worldwide and can face severe drought during the initial months after planting because the root system is developing. A complete randomized design was used to study the effects of two water regimes (well-watered and water-stressed) and phosphorus (P) applications (with and without P) on the morphological and physio-biochemical responses of E. grandis. Drought had negative effects on the growth and metabolism of E. grandis, as indicated by changes in morphological traits, decreased net photosynthetic rates (Pn ), pigment concentrations, leaf relative water contents (LRWCs), nitrogenous compounds, over-production of reactive oxygen species (ROS), and higher lipid peroxidation. However, E. grandis showed effective drought tolerance strategies, such as reduced leaf area and transpiration rate (E), higher accumulation of soluble sugars and proline, and a strong antioxidative enzyme system. P fertilization had positive effects on well-watered seedlings due to improved growth and photosynthesis, which indicated the high P requirements during the initial E. grandis growth stage. In drought-stressed seedlings, P application had no effects on the morphological traits, but it significantly improved the LRWC, Pn , quantum efficiency of photosystem II (Fv /Fm ), chlorophyll pigments, nitrogenous compounds, and reduced lipid peroxidation. P fertilization improved E. grandis seedling growth under well-watered conditions but also ameliorated some leaf physiological traits under drought conditions. The effects of P fertilization are mainly due to the enhancement of plant N nutrition. Therefore, P can be used as a fertilizer to improve growth and production in the face of future climate change. This article is protected by copyright. All rights reserved. PMID- 30414179 TI - Standardized Nutrition Protocol for Very Low-Birth-Weight Infants Resulted in Less Use of Parenteral Nutrition and Associated Complications, Better Growth, and Lower Rates of Necrotizing Enterocolitis. AB - BACKGROUND: We assessed the impact of a standardized nutrition initiative for very low-birth-weight (VLBW) infants on their nutrition and clinical outcomes. METHODS: This was a prospective analysis of VLBW infants born before and after the initiation of a nutrition protocol. This protocol included trophic feeds, feeding advancement, fortification guidelines, parameters on the concentration of parenteral nutrition (PN), and the discontinuation of PN and central lines. Gastric residual monitoring was discontinued. Statistical analyses were performed with Fisher's exact and Student's t-tests. Primary outcome measures were days receiving PN, days made nil per os (NPO) after feeding initiation, necrotizing enterocolitis, and growth parameters. Secondary outcome measures were central line days, sepsis, blood transfusions, cholestasis, osteopenia, chronic lung disease, and retinopathy of prematurity. RESULTS: 136 VLBW infants were analyzed, including 77 in the preprotocol group and 59 in the postprotocol group. Infants postprotocol were found to have reduced PN days (26.1 versus [vs] 18.4, P < .01), fewer days made NPO after feeding initiation (7.2 vs 4.0, P = .02), NEC (7.8% vs 0%, P = 0.038), central-line days (26.5 vs 18.6, P < .01), cholestasis (16% vs 3%, P = .02), and blood transfusions (5.3 vs 3.1, P = .028). Growth, defined by change in z-score from birth to discharge, improved for weight (-1.3 vs -0.8, P < .01), length (-1.5 vs -1.0, P = .033), and head (-1.1 vs -0.6, P = .024). CONCLUSION: Initiation of a standardized nutrition initiative for VLBW infants significantly improved growth, reduced PN use, and improved patient outcomes. PMID- 30414180 TI - Reducing CIED lead dislodgements: Faithful alignment to small things. PMID- 30414181 TI - In silico model of the dilutional effects of conventional component therapy versus whole blood in the management of massively bleeding adult trauma patients. AB - BACKGROUND: There are multiple approaches to the blood product and fluid resuscitation of a bleeding trauma patient. An in silico model of different trauma resuscitation strategies was constructed to predict their effects on the volumes of the different body fluid compartments and on several important hemostatic factors. STUDY DESIGN AND METHODS: This multicompartment dynamic deterministic model comprised four interconnected modules (hemostatic, resuscitation, body fluid compartment, and dilutional coagulopathy). The model was divided into five resuscitation phases with simulations using six different resuscitation strategies: whole blood (WB) only, conventional component therapy (CCT) only or 10 units of WB followed by CCT, with either 1 L of crystalloid or 1.5 units of WB or red blood cells in the prehospital phase. RESULTS: At the end of the simulations using 1 L of crystalloid fluids in the prehospital resuscitation phase, the use of WB led to a 1.4 g/dL higher hemoglobin concentration, 32 mg/dL higher fibrinogen concentration, and 0.9 L lower total extracellular fluid volume compared to CCT. Prehospital blood product transfusion in place of crystalloid resulted in higher hemoglobin and fibrinogen concentrations and a lower international normalized ratio throughout the resuscitation regardless of the resuscitation strategy used. Throughout both the prehospital crystalloid and prehospital blood product transfusion simulations, the hemoglobin and fibrinogen concentrations and platelet counts were higher, and the international normalized ratio was lower, when WB was used compared to CCT. CONCLUSIONS: This model predicted improved hemostatic factor levels and a smaller total extracellular fluid volume volume when WB was transfused instead of CCT to bleeding trauma patients. PMID- 30414182 TI - Physical inactivity-induced insulin resistance: could alterations to the vasculature be to blame? PMID- 30414183 TI - Gene exchange between two divergent species of the fungal human pathogen, Coccidioides. AB - The fungal genus Coccidioides is composed of two species, Coccidioides immitis and Coccidioides posadasii. These two species are the causal agents of coccidioidomycosis, a pulmonary disease also known as valley fever. The two species are thought to have shared genetic material due to gene exchange in spite of their long divergence. To quantify the magnitude of shared ancestry between them, we analyzed the genomes of a population sample from each species. Next, we inferred what is the expected size of shared haplotypes that might be inherited from the last common ancestor of the two species and find a cutoff to find what haplotypes have conclusively been exchanged between species. Finally, we precisely identified the breakpoints of the haplotypes that have crossed the species boundary and measure the allele frequency of each introgression in this sample. We find that introgressions are not uniformly distributed across the genome. Most, but not all, of the introgressions segregate at low frequency. Our results show that divergent species can share alleles, that species boundaries can be porous, and highlight the need for a systematic exploration of gene exchange in fungal species. PMID- 30414184 TI - Disappearance of a pre-excitation immediately after the initiation of rapid atrial pacing: What is the mechanism? PMID- 30414185 TI - The role of nervous system in adaptive response of bone to mechanical loading. AB - Bone tissue is remodeled through the catabolic function of the osteoclasts and the anabolic function of the osteoblasts. The process of bone homeostasis and metabolism has been identified to be co-ordinated with several local and systemic factors, of which mechanical stimulation acts as an important regulator. Very recent studies have shown a mutual effect between bone and other organs, which means bone influences the activity of other organs and is also influenced by other organs and systems of the body, especially the nervous system. With the discovery of neuropeptide (calcitonin gene-related peptide, vasoactive intestinal peptide, substance P, and neuropeptide Y) and neurotransmitter in bone and the adrenergic receptor observed in osteoclasts and osteoblasts, the function of peripheral nervous system including sympathetic and sensor nerves in bone resorption and its reaction to on osteoclasts and osteoblasts under mechanical stimulus cannot be ignored. Taken together, bone tissue is not only the mechanical transmitter, but as well the receptor of neural system under mechanical loading. This review aims to summarize the relationship among bone, nervous system, and mechanotransduction. PMID- 30414186 TI - Lysosome and proteasome pathways are distributed in laticifers of Euphorbia helioscopia L. AB - At present, the lysosome pathway (LP) and proteasome pathway (PP) are known as major clearance systems in eukaryotic cells. The laticifer, a secretory tissue, degrades some cytoplasm during development. In this study, we investigated the distribution of LP and PP in non-articulated laticifers of Euphorbia helioscopia L. Electron microscopy revealed that, plastids, mitochondria and some cyotsol were degraded in the late development laticifers, where there were numerous vesicles originated from dicytosomes. Accordingly, some key proteins in LP and PP were detected in E. helioscopia latex using isobaric tags for relative and absolute quantitation (iTRAQ) proteomics. Further immunohistochemistry analysis revealed that the clathrin heavy chain (CHC) belonging to LP and the ubiquitin mediated proteasome degradation increases gradually as the laticifer develops. Immuno-electron microscopy revealed that the cysteine proteinase (CP), CHC and AP 2 complex subunit beta-1 (AP2B1) belonging to LP were mainly distributed in vesicles deriving from dicytosomes, which we called lysosome-like vesicles. Ubiquitin was widely distributed in the cytosol, and proteasome activity was significantly reduced when various concentrations of the inhibitor MG132 were added to the latex total protein. We hypothesize that LP and PP are distributed in E. helioscopia laticifers; and it was speculated that LP and PP might be involved in the degradation of organelles and some cytoplasmic matrix in E. helioscopia laticifers. This article is protected by copyright. All rights reserved. PMID- 30414187 TI - Glioblastoma endothelium drives bevacizumab-induced infiltrative growth via modulation of PLXDC1. AB - Bevacizumab, a VEGF-targeting monoclonal antibody, may trigger an infiltrative growth pattern in glioblastoma. We investigated this pattern using both a human specimen and rat models. In the human specimen, a substantial fraction of infiltrating tumor cells were located along perivascular spaces in close relationship with endothelial cells. Brain xenografts of U87MG cells treated with bevacizumab were smaller than controls (p=0.0055; Student-t test), however, bands of tumor cells spread through the brain farther than controls (p<0.001; Student-t test). Infiltrating tumor cells showed tropism for vascular structures and propensity to form tubules and niches with endothelial cells. Molecularly, bevacizumab triggered an epithelial to mesenchymal transition with over expression of the receptor Plexin Domain Containing 1 (PLXDC1). These results were validated using brain xenografts of patient-derived glioma stem-like cells. Enforced expression of PLXDC1 in U87MG cells promoted brain infiltration along perivascular spaces. Importantly, PLXDC1 inhibition prevented perivascular infiltration and significantly increased the survival of bevacizumab-treated rats. This study indicates that bevacizumab-induced brain infiltration is driven by vascular endothelium and depends on PLXDC1 activation of tumor cells. This article is protected by copyright. All rights reserved. PMID- 30414188 TI - Multidermatomal zosteriform lichen planus pigmentosus-a unique presentation. PMID- 30414189 TI - Hypopyon pustules of Sneddon-Wilkenson disease. PMID- 30414190 TI - Electrical pulse stimulation induces differential responses in insulin action in myotubes from severely obese individuals. AB - KEY POINTS: Exercise/exercise training can enhance insulin sensitivity through adaptations in skeletal muscle, the primary site of insulin-mediated glucose disposal; however, in humans the range of improvement can vary substantially. The purpose of this study was to determine if obesity influences the magnitude of the exercise response in relation to improving insulin sensitivity in human skeletal muscle. Electrical pulse stimulation (EPS; 24 h) of primary human skeletal muscle myotubes improved insulin action in tissue from both lean and severely obese individuals, but responses to EPS were blunted with obesity. EPS improved insulin signal transduction in myotubes from lean but not severely obese subjects and increased AMP accumulation and AMPK Thr172 phosphorylation, but to a lesser degree in myotubes from the severely obese. These data reveal that myotubes of severely obese individuals enhance insulin action and stimulate exercise responsive molecules with contraction, but in a manner and magnitude that differs from lean subjects. ABSTRACT: Exercise/muscle contraction can enhance whole-body insulin sensitivity; however, in humans the range of improvements can vary substantially. In order, to determine if obesity influences the magnitude of the exercise response, this study compared the effects of electrical pulse stimulation (EPS)-induced contractile activity upon primary myotubes derived from lean and severely obese (BMI >= 40 kg/m2 ) women. Prior to muscle contraction, insulin action was compromised in myotubes from the severely obese as was evident from reduced insulin-stimulated glycogen synthesis, glucose oxidation, glucose uptake, insulin signal transduction (IRS1, Akt, TBC1D4), and insulin-stimulated GLUT4 translocation. EPS (24 h) increased AMP, IMP, AMPK Thr172 phosphorylation, PGC1alpha content, and insulin action in myotubes of both the lean and severely obese subjects. However, despite normalizing indices of insulin action to levels seen in the lean control (non-EPS) condition, responses to EPS were blunted with obesity. EPS improved insulin signal transduction in myotubes from lean but not severely obese subjects and EPS increased AMP accumulation and AMPK Thr172 phosphorylation, but to a lesser degree in myotubes from the severely obese. These data reveal that myotubes of severely obese individuals enhance insulin action and stimulate exercise-responsive molecules with contraction, but in a manner and magnitude that differs from lean subjects. PMID- 30414191 TI - Biosynthesis of DDMP saponins in soybean is regulated by a distinct UDP glycosyltransferase. AB - 2,3-Dihydro-2,5-dihydroxy-6-methyl-4H-pyran-4-one (DDMP) saponins are one of the major saponin groups that are widely distributed in legumes such as pea, barrel medic, chickpea, and soybean. The steps involved in DDMP saponin biosynthesis remain uncharacterized at the molecular level. We isolated two recessive mutants that lack DDMP saponins from an ethyl methanesulfonate-induced mutant population of soybean cultivar Pungsannamul. Segregation analysis showed that the production of DDMP saponins is controlled by a single locus, named Sg-9. The locus was physically mapped to a 130-kb region on chromosome 16. Nucleotide sequence analysis of candidate genes in the region revealed that each mutant has a single nucleotide polymorphism in the Glyma.16G033700 encoding a UDP-glycosyltransferase UGT73B4. Enzyme assays and mass spectrum-coupled chromatographic analysis reveals that the Sg-9 protein has glycosyltransferase activity, converting sapogenins and group B saponins to glycosylated products, and that mutant proteins had only partial activities. The tissue-specific expression profile of Sg-9 matches the accumulation pattern of DDMP saponins. This is the first report on a new gene and its function in the biosynthesis of DDMP saponins. Our findings indicate that Sg 9 encodes a putative DDMP-transferase that plays a critical role in the biosynthesis of DDMP saponins. This article is protected by copyright. All rights reserved. PMID- 30414192 TI - Effect of Cognitive Style on Topographical Learning Across Life Span: Insights From Normal Development. AB - Notwithstanding its well-established role on high-demanding spatial navigation tasks during adulthood, the effect of field dependence-independence during the acquisition of spatial navigation skills is almost unknown. This study assessed for the first time the effect of field dependence-independence on topographical learning (TL) across the life span: 195 individuals, including 54 healthy young adults (age-range = 20-30), 46 teenagers (age-range = 11-14), and 95 children (age-range = 6-9) participated in this study. Field dependence-independence interacted with age in predicting TL. Also during childhood higher field independence was associated with better performances but not later in the life, that is, during adolescence and adulthood. This result suggests that field dependence-independence may have a role in fostering the acquisition of TL. PMID- 30414193 TI - Immune globulin potency in the 21st century: views from the patient community. PMID- 30414194 TI - The histological spectrum of Talimogene laherparepvec (TVEC) injections neutrophilic and chronic granulomatous dermatitis. AB - We read with interest the case series by Everett et al. (1) describing chronic granulomatous dermatitis at sites of Talimogene laherparepvec (TVEC) injections for advanced melanoma. This article is protected by copyright. All rights reserved. PMID- 30414195 TI - Enhanced sampling method in molecular simulations using genetic algorithm for biomolecular systems. AB - We propose a molecular simulation method using genetic algorithm (GA) for biomolecular systems to obtain ensemble averages efficiently. In this method, we incorporate the genetic crossover, which is one of the operations of GA, to any simulation method such as conventional molecular dynamics (MD), Monte Carlo, and other simulation methods. The genetic crossover proposes candidate conformations by exchanging parts of conformations of a target molecule between a pair of conformations during the simulation. If the candidate conformations are accepted, the simulation resumes from the accepted ones. While conventional simulations are based on local update of conformations, the genetic crossover introduces global update of conformations. As an example of the present approach, we incorporated genetic crossover to MD simulations. We tested the validity of the method by calculating ensemble averages and the sampling efficiency by using two kinds of peptides, ALA3 and (AAQAA)3 . The results show that for ALA3 system, the distribution probabilities of backbone dihedral angles are in good agreement with those of the conventional MD and replica-exchange MD simulations. In the case of (AAQAA)3 system, our method showed lower structural correlation of alpha-helix structures than the other two methods and more flexibility in the backbone psi angles than the conventional MD simulation. These results suggest that our method gives more efficient conformational sampling than conventional simulation methods based on local update of conformations. (c) 2018 Wiley Periodicals, Inc. PMID- 30414196 TI - ANGIOTROPISM IN RECURRENT CUTANEOUS SQUAMOUS CELL CARCINOMA: IMPLICATIONS FOR REGIONAL TUMOR RECURRENCE AND EXTRAVASCULAR MIGRATORY SPREAD. AB - Extravascular migratory metastasis is a form of cancer metastasis in which tumor cells spread by tracking along the abluminal aspect of vessel walls without breaking the vascular endothelial lining or intraluminal invasion. This phenomenon has been extensively described in melanoma and is being increasingly recognized in other neoplasms. Various modalities of treatment, including radiation-, chemo-, targeted- and immune- therapies may potentially induce angiotropic behavior in neoplastic cells. Although there is a risk for tumor recurrence and metastasis, angiotropism may be under-recognized and is rarely reported. Here, we report a case of recurrent poorly-differentiated acantholytic squamous cell carcinoma of the scalp with extensive perineural invasion, previously treated with multiple therapies. There was multifocal extravascular cuffing of neoplastic cells around and focally involving the walls of small to medium caliber blood vessels within and surrounding the tumor, without obvious tumor intravasation. In addition, small subtle nests of neoplastic keratinocytes were noted along the abluminal aspect of a large caliber deep dermal blood vessel in an enface margin, away from the main tumor mass. Such involvement can be difficult to identify; and thus, may be missed particularly during intra operative frozen section evaluation, leading to false negative margins and is therefore, a diagnostic pitfall. This article is protected by copyright. All rights reserved. PMID- 30414197 TI - Theoretical study of lanthanide-based in vivo luminescent probes for detecting hydrogen peroxide. AB - The 4f-4f emissions from lanthanide trication (Ln3+ ) complexes are widely used in bioimaging probes. The emission intensity from Ln3+ depends on the surroundings, and thus, the design of appropriate photo-antenna ligands is indispensable. In this study, we focus on two probes for detecting hydrogen peroxide, for which emission intensities from Tb3+ are enhanced chemo-selectively by the H2 O2 -mediated oxidation of ligands. To understand the mechanism, the Gibbs free energy profiles of the ground and excited states related to emission and quenching are computed by combining our approximation-called the energy shift method-and density functional theory. The different emission intensities are mainly attributed to different activation barriers for excitation energy transfer from the ligand-centered triplet (T1) to the Tb3+ -centered excited state. Additionally, quenching from T1 to the ground state via intersystem crossing was inhibited by intramolecular hydrogen bonds only in the highly emissive Tb3+ complexes. (c) 2018 Wiley Periodicals, Inc. PMID- 30414198 TI - Reproducibility of the durometer and myoton devices for skin stiffness measurement in healthy subjects. AB - BACKGROUND: Clinical assessment of skin stiffness is unreliable in many applications. The durometer, an industrial device to measure hardness, has previously been applied in scleroderma. The Myoton is a noninvasive handheld device for assessing soft tissue biomechanical parameters. MATERIALS AND METHODS: We evaluated the reproducibility of both devices in six healthy subjects in the volar forearm, dorsal forearm, upper arm, shin, and calf bilaterally. The intraclass correlation coefficient (ICC) was used as a measure of reproducibility among three observers. RESULTS: The interobserver intraclass correlation coefficient (ICC) of overall stiffness for the Myoton was 0.74 [95% confidence interval (CI) 0.45-1.00] and 0.71 [0.39-1.00] for the durometer. Coefficient of variation (CV) for the Myoton was 6.4% [range 1.3-12.1] and 7.6% [range 4.4-13.8] for the durometer. Myoton and durometer values had a Pearson correlation of 0.69. The intraobserver Myoton ICC was 0.89 [0.74-1.00] and CV 3.1% [range 1.6-5.0]. The 95% confidence minimal detectable change by the Myoton for a single observer is 32.4 N/m, which is 7.6% of the average subject's overall stiffness. CONCLUSION: The Myoton demonstrated high reproducibility, particularly in the overall stiffness parameter, and merits further investigation to assess disease progression and treatment efficacy. PMID- 30414199 TI - Commentary: The New International Guideline for diagnosis and management of PCOS was worth the effort. PMID- 30414200 TI - Influence of midwifery presence in United States centers on labor care and outcomes of low-risk parous women: A Consortium on Safe Labor study. AB - BACKGROUND: Sixty percent of United States births are to multiparous women. Hospital-level policies and culture may influence intrapartum care and birth outcomes for this large population, yet have been poorly explored using a large, diverse sample. We sought to use national United States data to analyze the association between midwifery presence in maternity care teams and the birth processes and outcomes of low-risk parous women. METHODS: We conducted a retrospective cohort study using Consortium on Safe Labor data from low-risk parous women in either interprofessional care (n = 12 125) or noninterprofessional care centers (n = 8996). Unadjusted, adjusted (age, race, health insurance type), propensity-adjusted, and propensity-matched logistic regression models were used to assess processes and outcomes. RESULTS: There was concordance in outcome differences across regression models. With propensity score matching, women at interprofessional centers, compared with women at noninterprofessional centers, were 85% less likely to have labor induced (risk ratio [RR] 0.15; 95% CI 0.14-0.17). The risk for primary cesarean birth among low risk parous women was 36% lower at interprofessional centers (RR 0.64; 95% CI 00.52-0.79), whereas the likelihood of vaginal birth after cesarean for this population was 31% higher (RR 1.31; 95% CI 1.10-1.56). There were no significant differences in neonatal outcomes. CONCLUSIONS: Parous women have significantly higher rates of vaginal birth, including vaginal birth after cesarean, and lower likelihood of labor induction when cared for in centers with midwives. Our findings are consistent with smaller analyses of midwifery practice and support integrated, team-based models of perinatal care to improve maternal outcomes. PMID- 30414201 TI - Constraint structure optimization to a specific minimum using ionization energy. AB - A structure optimization method with ionization energy constraint is developed to explore structures with specific ionization energy. The Levine-Coe-Martinez penalty function (J Phys Chem B 2008, 112, 405) was adopted, and the penalty function includes a predefined core-ionization energy and inner-shell ionization energy. For an SN 2 reaction, isomerization of a platinum complex, a proton transfer reaction, and carbon monoxide adsorption on a palladium cluster, the present method was tested, and the targeted energy minima were obtained as designated by the input ionization energy. The shape of the objective function, the parameters in the penalty function, and structural changes during the optimization process were discussed. An automated parameter setting and possible problems are discussed for future direction. (c) 2018 Wiley Periodicals, Inc. PMID- 30414202 TI - Resonance Energy Transfer in a Genetically Engineered Polypeptide Results in Unanticipated Fluorescence Intensity. AB - When beta-sheet forming polypeptides bearing tryptophan residues along one edge were irradiated at 280 nm, the tryptophan absorbance maximum, the fluorescence intensity of the C-terminal acceptor chromophore, N-(7-dimethylamino-4-methyl coumarin (DACM), increased proportionally with an increasing number of donor tryptophans. The fluorescence intensity increased even as the length of the beta sheet edge approached 256 A, well beyond the Forster radius for the tryptophan acceptor chromophore pair. The folding of the peptides under investigation was verified by circular dichroism (CD) and deep UV resonance Raman experiments. Control experiments showed that the enhancement of DACM fluorescence occurred concomitantly with peptide folding. In control experiments, the DACM fluorescence intensity of the solutions of tryptophan and DACM did not show any enhancement of DACM fluorescence with increasing tryptophan concentrations. Formation of fibrillar aggregates of the substrate peptides prepared for the fluorescence studies was undetectable by thioflavin T(ThT) fluorescence. PMID- 30414203 TI - Topical treatment with a cathepsin G inhibitor, beta-keto-phosphonic acid, blocks ultraviolet irradiation-induced basement membrane damage in hairless mouse skin. AB - BACKGROUND: Ultraviolet light (UV) exposure contributes various effects to skin including damage of the basement membrane. Cathepsin G (CTSG) belongs to serine protease family and its upregulation is involved in wrinkle formation by chronic UV irradiation. However, the effect of CTSG on the basement membrane damage in skin remains unclear. PURPOSE: To investigate the effects of topical treatment with a CTSG inhibitor, beta-keto-phosphonic acid (KPA), on basement membrane damage in chronically UV-irradiated hairless mouse skin. METHODS: The dorsal skin of hairless mice was exposed to UV 3 times/week for 8 weeks. KPA was applied immediately after each session of UV irradiation. The basement membrane components, CTSG expression, and neutrophils infiltration were analyzed by immunofluorescence staining. The basement membrane structures were visualized by transmission electron microscope. CTSG and MMP-13 protein levels were analyzed by Western blotting. Assessment of wrinkle formation was examined using a skin replica assay. RESULTS: KPA prevented UV irradiation-induced decrease of type VII collagen, laminin 332 and perlecan at the basement membrane zone and prevented UV induced breakage of lamina densa and UV-induced shortening of hemidesmosome. KPA prevented UV-induced CTSG and MMP-13 expressions in chronically UV-irradiated hairless mice. Increase of neutrophils infiltration by UV irradiation and UV induced wrinkle formation were also prevented by KPA. CONCLUSION: Our present study showed the possible involvement of CTSG in UV-induced basement membrane damage in skin through topical treatment with a cathepsin G inhibitor, KPA. Thus, inhibition of CTSG may be a useful strategy for the prevention of UV-induced basement membrane damage and photoaging. This article is protected by copyright. All rights reserved. PMID- 30414204 TI - Martini coarse-grained model for polyethylenimine. AB - As a polycation with diverse applications in biomedical and environmental engineering, polyethylenimine (PEI) can be synthesized with varying degrees of branching, polymerization, and can exist in different protonation states. There have been some interests in molecular modeling of PEI at all-atom or coarse grained (CG) levels, but present CG models are limited to linear PEIs. Here we present the methodology to systematically categorize bond lengths, bond angles and dihedral angles, which allows us to model branched PEIs. The CG model was developed under the Martini scheme based on eight ~600 Da PEIs, with four different degree of branching at two different protonation states. Comparison of the CG model with all-atom simulations shows good agreement for both local (distributions for bonded interactions) and global (end-to-end distance, radius of gyration) properties, with and without salt. Compatibility of the PEI model with other CG bio-molecules developed under the Martini scheme will allow for large-scale simulations of many PEI-enabled processes. (c) 2018 Wiley Periodicals, Inc. PMID- 30414205 TI - Effects of pre-treatments on bulk stable isotope ratios in fish samples: A cautionary note for studies comparisons. AB - RATIONALE: Stable isotope analysis (SIA) has revolutionized ecological studies over the past thirty years. One of the major fields where SIA is applied in the marine environment, is related to the definition of ecosystem structure and function. With marine top predators such as sharks, SIA is a method of choice because tissue samples can be collected without the sacrifice of the animal. In elasmobranch research, the influence of molecules such as urea, trimethylamine oxide and lipids must be considered when using stable isotopes as ecological markers. Currently, a range of pre-treatments are used to chemically remove these molecules prior to S;I analyses. METHODS: This study investigated the impact of 11 commonly used pre-treatments on carbon and nitrogen contents and C:N atomic ratio, as well as carbon and nitrogen SI ratios in elasmobranch tissues and its prey, measured by isotope ratio mass spectrometry. Three tissues were tested: blood and muscle of the ragged-tooth shark Carcharias taurus, and muscle of one teleost species, the Cape knifejaw Oplegnathus conwayi. RESULTS: Compared with untreated samples, no trend or generalization could be highlighted with the influence of pre-treatments being species-, tissues- and chemical element dependent. For the delta13 C and delta15 N values, differences among pre treatments were as high as 3 0/00, therefore potentially leading to erroneous ecological interpretation. CONCLUSION: The chemical properties of molecules (e.g. urea, lipids) combined with the polarity of solutions (e.g. water, solvents) explained a large part these observations. This study highlights that pre treatments need to be considered especially when comparing carbon and nitrogen stable isotope ratios between studies. The results of this study provide a call to all stable isotope researchers to make a concerted effort to standardize pre treatment methods. This is crucial as global reviews are becoming increasingly more informative. PMID- 30414206 TI - Cor triatriatum dexter with right ventricular hypoplasia: Role of multimodality imaging in decision making. AB - Cor Triatriatum Dexter (CTD) is a rare congenital anomaly involving the systemic venous valves. Failure of regression of the right-sided sinus venosus valve leads to abnormal septation of the right atrium and a variety of right atrial and tricuspid valve obstructive lesions. The presentation can be varied ranging from asymptomatic to persistent neonatal cyanosis. We describe a late diagnosis of CTD in a 10-month-old male with persistent hypoxia despite balloon valvuloplasty for mild pulmonic valve stenosis with a large secundum atrial septal defect and a mildly hypoplastic right ventricle. PMID- 30414207 TI - Long noncoding RNA THRIL contributes in lipopolysaccharide-induced HK-2 cells injury by sponging miR-34a. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with unknown etiology. Nowadays, several long noncoding RNAs (lncRNAs) have been reported as molecular alterations involved in SLE. This study aimed to reveal the function of TNF-related and HNRNPL-related immunoregulatory lncRNA (THRIL) in SLE. Human epithelial HK-2 cells were exposed to lipopolysaccharide (LPS) to mimic an in vitro SLE model. Then, the functions of THRIL, miR-34a, and monocyte chemoattractant protein-1 (MCP-1), as well as their correlations were detected. LncRNA THRIL was highly expressed in the LPS-stimulated cells, and THRIL overexpression aggravated LPS-induced cell damage as cell viability was decreased, and apoptosis and the release of proinflammatory cytokines were increased. THRIL worked as a sponge of microRNA-34a (miR-34a) and it could directly target MCP-1. Furthermore, MCP-1-activated JNK and Wnt/beta-catenin signaling pathways. In conclusion, this study suggested that lncRNA THRIL might be a key regulator participating in LPS-induced injury in HK-2 cells. THRIL overexpression aggravated LPS-induced injury possibly via sponging miR-34a, and thus preventing MCP-1 from degradation by miR-34a. The THRIL/miR-34a/MCP-1 axis might play critical roles in SLE. PMID- 30414208 TI - Perspectives on the future of Mass Spectrometry. PMID- 30414209 TI - Abacavir Hypersensitivity Reaction Reporting Rates During a Decade of HLA-B*5701 Screening as a Risk Mitigation Measure. AB - INTRODUCTION: HLA-B*5701 screening identifies patients at increased risk for abacavir (ABC) hypersensitivity reaction (HSR). Screening was adopted in GlaxoSmithKline and ViiV Healthcare clinical trials in 2007 and HIV treatment guidelines in 2008. Company meta-analyses of trials pre-HLA-B*5701 screening reported HSR rates of 4% to 8%. We analyzed the effectiveness of HLA-B*5701 screening on reducing HSR rates using clinical trial, observational (OPERA) cohort, and spontaneous reporting data. METHODS: A meta-analysis examined 12 trials in 3063 HLA-B*5701-negative patients receiving an ABC-containing regimen from April 9, 2007 to September 22, 2015. Potential cases were identified using pre-specified MedDRA preferred terms (drug hypersensitivity, hypersensitivity, anaphylactic reaction, anaphylaxis) and adjudicated against a Company ABC HSR case definition. Investigator-diagnosed cases were identified and rates were calculated. In the OPERA cohort, 9619 patients initiating their first ABC containing regimen from January 1, 1999 to January 1, 2016 were identified. Patients were observed from regimen start until the earliest-following censoring event: ABC discontinuation, loss to follow-up, death, or study end (July 31, 2016). OPERA physicians evaluated events against OPERA definitions for definite/probable cases of ABC HSR; rates were calculated pre- and post-2008. The Company case definition was used to identify spontaneously reported cases for four marketed ABC-containing products; reporting rates were calculated using estimated exposure from sales data, through December 31, 2016. RESULTS: Suspected ABC HSR rates were 1.3% or less in the meta-analysis. In the OPERA cohort, the rate was 0.4% among patients initiating ABC post-2008 versus 1.3% pre-2008 (p<0.0001). Spontaneous reporting rates were low post-2008 (54 to 22 cases per 100,000 patient-years exposure [PYE]) versus pre-2008 (618 to 55 cases per 100,000 PYE). CONCLUSIONS: Clinically suspected ABC HSR rates were 1.3% or less in HLA-B*5701-negative patients. Recognizing their limitations, data from the OPERA cohort and spontaneous reporting indicate that HLA-B*5701 screening has reduced reporting rates of suspected HSR in clinical practice. Where screening for HLA-B*5701 is standard care, patients should be confirmed negative for this allele before starting ABC treatment. This article is protected by copyright. All rights reserved. PMID- 30414210 TI - Intersubject specific absorption rate variability analysis through construction of 23 realistic body models for prostate imaging at 7T. AB - PURPOSE: For ultrahigh field (UHF) MRI, the expected local specific absorption rate (SAR) distribution is usually calculated by numerical simulations using a limited number of generic body models and adding a safety margin to take into account intersubject variability. Assessment of this variability with a large model database would be desirable. In this study, a procedure to create such a database with accurate subject-specific models is presented. Using 23 models, intersubject variability is investigated for prostate imaging at 7T with an 8 channel fractionated dipole antenna array with 16 receive loops. METHOD: From Dixon images of a volunteer acquired at 1.5T with a mockup array in place, an accurate dielectric model is built. Following this procedure, 23 subject-specific models for local SAR assessment at 7T were created enabling an extensive analysis of the intersubject B1 + and peak local SAR variability. RESULTS: For the investigated setup, the maximum possible peak local SAR ranges from 2.6 to 4.6 W/kg for 8 * 1 W input power. The expected peak local SAR values represent a Gaussian distribution CONCLUSION: The presented procedure allows for the creation of a customized model database. The results provide valuable insights into B1 + and local SAR variability. Recommended power thresholds per channel are 3.1 W with phase shimming on prostate or 2.6 W for multidimensional pulses. PMID- 30414211 TI - Pharmacokinetics and tissue distribution study of bisabolangelone from Angelicae Pubescentis Radix in rat using LC-MS/MS. AB - A sensitive and accurate LC-MS/MS method was established for quantifying bisabolangelone in rat plasma and tissues. Bisabolangelone was isolated and purified from Angelicae Pubescentis Radix. The pharmacokinetic and tissue distribution of bisabolangelone after administration to rat was performed by LC MS/MS. Separation was carried out on a C8 (4.6 * 100 mm, 1.8 MUm) column. The MS/MS transitions of bisabolangelone and tussilagone (internal standard) were set at m/z 249.1 -> 109.1 and m/z 391.4 -> 217.4, respectively. The lower limit of quantification in plasma and other tissues ranged from 1 to 4 ng/mL. The biosamples were prepared using protein precipitation method with acetonitrile. The recovery was >92%. The results showed that values of maximum concentrations and area under the curve depended linearly on the studied doses (2.5, 5 and 7.5 mg/kg body weight). The other ingredients in Angelicae Pubescentis Radix extract possibly reduce the absorption of bisabolangelone in rat. Tissue distribution revealed that bisabolangelone was widely distributed in vivo. The highest and lowest concentrations of bisabolangelone were found in the stomach and in the brain, respectively. It was concluded that the newly established HPLC-MS/MS method was suitable to describe the pharmacokinetic characteristics of bisabolangelone in rat after administration. PMID- 30414212 TI - Evaluation of [18 F]2FP3 in pigs and non-human primates. AB - So far, no suitable 5-HT7 R radioligand exists for clinical positron emission tomography (PET) imaging. [18 F]2FP3 was first tested in vivo in cats, and the results were promising for further evaluations. Here, we evaluate the radioligand in pigs and non-human primates (NHPs). Furthermore, we investigate species differences in 5-HT7 R binding with [3 H]SB-269970 autoradiography in post-mortem pig, NHP, and human brain tissue. Specific binding of [18 F]2FP3 was investigated by intravenous administration of the 5-HT7 R specific antagonist SB-269970. [3 H]SB-269970 autoradiography was performed as previously described. [18 F]2FP3 was synthesized in an overall yield of 35% to 45%. High brain uptake of the tracer was found in both pigs and NHPs; however, pretreatment with SB-269970 only resulted in decreased binding of 20% in the thalamus, a 5-HT7 R-rich region. Autoradiography on post-mortem pig, NHP, and human tissues revealed that specific binding of [3 H]SB-269970 was comparable in the thalamus of pig and NHP. Despite the high uptake of [18 F]2FP3 in both species, the binding could only be blocked to a limited degree with the 5-HT7 R antagonists. We speculate that the affinity of the radioligand is too low for imaging the 5-HT7 Rs in vivo and that part of the PET signal arises from targets other than the 5-HT7 R. PMID- 30414213 TI - Successful and safe long-term treatment of cerebral aspergillosis with high-dose voriconazole guided by therapeutic drug monitoring. AB - We report the case of a patient who had cerebral aspergillosis after otorhinolaryngologic surgery and who was successfully and safely treated with high-dose voriconazole (200 mg q6h) for more than 1 year thanks to a TDM-guided approach coupled with pharmacological review and with genotyping of CYP2C19 polymorphisms. The findings support the idea that personalized medicine based on TDM coupled with the need of avoiding drug-drug interactions may be helpful for maximizing the net benefit (probability of efficacy vs. probability of adverse events) of voriconazole in the management of long-term treatment of cerebral aspergillosis. PMID- 30414214 TI - Preparation, optimization, and pharmacokinetic study of nanoliposomes loaded with triacylglycerol-bound punicic acid for increased antihepatotoxic activity. AB - Hit, Lead & Candidate Discovery Punicic acid of pomegranate oil (PAP) has gained heightened interest due to several health benefits, such as anticarcinogenic, antidiabetic, and antiatherosclerotic properties. However, these bioactivities have been hampered by chemical instability, poor water solubility, rapid metabolism, and low bioavailability of PAP. Therefore, this study was aimed at optimizing the liposomal formulation of Triacylglycerol-bound punicic acid with its regioisomers (TPAR) for improved oral bioavailability and increased hepatoprotection through antioxidation and anti-inflammation. Herein, the optimized TPAR nanoliposome (TPAR-NL) was developed using thin-film dispersion method and subsequently characterized with appropriate indices. The optimized TPAR-NL produced fairly stable spherical nanoparticles (? 200 nm) with encapsulation efficiency (%EE) of 85.77%, as well as enhanced in vitro release and improved oral bioavailability. The TPAR-NL exhibited profound antihepatotoxic effect in mice pretreated with carbon tetrachloride (CCl4 ) via reduction of serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels compared with free TPAR. The TPAR-loaded liposome also significantly reduced oxidative stress by increasing superoxide dismutase and glutathione levels while lowering malonaldehyde concentration compared with the free TPAR. The TPAR-LNF further exhibited remarkable anti-inflammatory activity compared with the free drug via inhibition of interleukin-6 and tumor necrosis factor alpha generation. Thus, the developed nanoliposomes potentiated the antihepatotoxic activity of TPAR via antioxidation and anti-inflammation. PMID- 30414215 TI - ABC-ABC-Type meso-meso Directly Linked Porphyrin Dimer. AB - Covalently linked porphyrin oligomers are attractive molecules because of their extended pi-conjugated systems. Among various porphyrin oligomers, meso-meso directly linked porphyrin oligomers exhibit unique photophysical properties due to their strong exciton couplings derived from alternative orthogonal geometry of the porphyrins. Although their structural and electronic properties can be greatly altered by substituents at meso-positions, it is still difficult to introduce different substituents at the meso-positions. Thus, it is a challenge to develop general synthetic methodologies for functional porphyrin dimers and oligomers with different substituents at the specific meso-positions. Herein, we established the general synthetic strategy for meso-ABC-ABC-type meso-meso directly linked porphyrin dimers via stepwise functionalization starting from the building block, 10,15,20-meso-free 5-substituted porphyrin. We successfully prepared the meso-ABC-ABC-type meso-meso linked donor-pi-acceptor-type porphyrin dimer, which exhibited the highest power conversion efficiency (7.91%) ever reported for dye-sensitized solar cells based on dimeric orthogonal donor-pi acceptor-type organic sensitizers. We believe that our synthetic strategy provides a useful guidance for the rational design of functional porphyrin dimers and oligomers toward diverse applications. PMID- 30414216 TI - Comparative evaluation of decellularized porcine liver matrices crosslinked with different chemical and natural crosslinking agents. AB - The natural liver extracellular matrix (ECM) achieved by decellularization holds great potential in the fields of tissue engineering and regenerative medicine. Additionally, the use of crosslinking agents on the ECM to stabilize its ultrastructure and enhance scaffold durability is gaining interest in tissue engineering. The objective of this study was to compare the scaffold properties of porcine liver ECM crosslinked with different agents (glutaraldehyde, genipin, and quercetin) to find the best strategy for producing a decellularized matrix with optimal and stable characteristics for transplantation and regeneration. The properties examined include mechanical properties, material stability, immunogenicity, and angiogenic capacity. Scaffolds were implanted into the greater omentum of rats, and their abilities to induce immune cell subpopulation invasion and neovascularization were evaluated. The results show that genipin crosslinking of decellularized liver matrices increased the mechanical and proangiogenic properties and reduced the inflammatory response in vivo. PMID- 30414217 TI - Massively parallelization strategy for material simulation using high-dimensional neural network potential. AB - The potential energy surface (PES) calculation is the bottleneck for modern material simulation. The high-dimensional neural network (HDNN) technique emerged recently appears to be a problem solver for fast and accurate PES computation. The major cost of the HDNN lies at the computation of the structural descriptors that capture the geometrical environment of atoms. Here, we introduce a massive parallelization strategy optimized for our recently developed power-type structural descriptor. The method involves three-levels: from the top to the bottom the parallelization is over atoms first, then, over structural descriptors and finally over the n-body functions. We illustrate the parallelization method in a boron crystal system and show that the parallelization efficiency is maximally 100%, 58%, and 34% at each level. (c) 2018 Wiley Periodicals, Inc. PMID- 30414218 TI - Prognostic factors for breast cancer patients with T1-2 tumor and 1-3 positive axillary nodes treated using total mastectomy without radiotherapy. AB - Prospective randomized trials have demonstrated that postmastectomy radiotherapy (PMRT) improves not only locoregional recurrence-free survival, but also overall survival for node-positive breast cancer patients. Subset analyses in previous trials have shown that improvement of overall survival with PMRT is not always demonstrated for patients with 1-3 positive nodes. Indications for PMRT are still marginal for patients with pathological invasion 5 cm in diameter and 1-3 positive nodes. The aim of this study was to clarify poor prognostic factors for breast cancer patients with pathological invasion size 5 cm and 1-3 positive nodes. Participants comprised 428 breast cancer patients with T1-2 tumor and 1-3 positive axillary nodes (pT1-2 N1) treated using total mastectomy without radiotherapy. Correlations between clinicopathological characteristics and 10 year Kaplan-Meier estimates of locoregional recurrence-free survival, disease free survival, and overall survival were retrospectively analyzed. Median follow up was 98 months. Locoregional recurrence was observed in 20 patients (4.7%), and distant recurrence was observed in 70 patients (16.4%). Disease-free survival rate was 80.8%, and overall survival rate within the study period was 90%. Multivariate analysis demonstrated that favorable prognostic factors for locoregional recurrence-free survival were the presence of chemotherapy and positive hormone receptor status, and for disease-free survival were presence of chemotherapy, pT1 tumor, and single positive node. Physicians may consider these favorable prognostic factors in decision to eliminate PMRT from patients with the borderline indications. PMID- 30414220 TI - Nitrogen-doped Carbon-CoOx Nanohybrids: A Precious Metal Free Cathode that Exceeds 1.0 W cm-2 Peak Power and 100 h Life in Anion-Exchange Membrane Fuel Cells. AB - Efficient and durable nonprecious metal electrocatalysts for the oxygen reduction (ORR) are highly desirable for several electrochemical devices, including anion exchange membrane fuel cells (AEMFCs). Here, a 2D planar electrocatalyst with CoOx embedded in nitrogen-doped graphitic carbon (N-C-CoOx ) was created through the direct pyrolysis of a metal-organic complex with a NaCl template. The N-C CoOx catalyst showed high ORR activity, indicated by excellent half-wave (0.84 V vs. RHE) and onset (1.01 V vs. RHE) potentials. This high intrinsic activity was also observed in operating AEMFCs where the kinetic current was 100 mA cm-2 at 0.85 V. When paired with a radiation-grafted ETFE powder ionomer, the N-C-CoOx AEMFC cathode was able to achieve extremely high peak power density (1.05 W cm-2 ) and mass transport limited current (3 A cm-2 ) for a precious metal free electrode. The N-C-CoOx cathode also showed good stability over 100 hours of operation with a voltage decay of only 15 % at 600 mA cm-2 under H2 /air (CO2 free) reacting gas feeds. The N-C-CoOx cathode catalyst was also paired with a very low loading PtRu/C anode catalyst, to create AEMFCs with a total PGM loading of only 0.10 mgPt-Ru cm-2 capable of achieving 7.4 W mg-1 PGM as well as supporting a current of 0.7 A cm-2 at 0.6 V with H2 /air (CO2 free)-creating a cell that was able to meet the 2019 U.S. Department of Energy initial performance target of 0.6 V at 0.6 A cm-2 under H2 /air with a PGM loading <0.125 mg cm-2 with AEMFCs for the first time. PMID- 30414219 TI - Feasibility, acceptability, and safety of the Recapture Life videoconferencing intervention for adolescent and young adult cancer survivors. AB - OBJECTIVE: Online psychological therapies provide a way to connect adolescent and young adult (AYA) cancer survivors to evidence-based support. We aimed to establish the feasibility, acceptability, and safety of Recapture life, a six session group-based online cognitive-behavioural intervention, led by a facilitator, for AYAs in the early post-treatment period. METHODS: A randomised controlled trial compared Recapture Life to an online peer-support group control and a waitlist control. Participants could nominate a support person. Acceptability was assessed using study opt-in and retention rates, participant reported benefits/burdens of participation, and group facilitator burden. We also assessed the feasibility (eg, frequency/impact of technological difficulties) and psychological safety (ie, occurrence of clinically concerning distress) of the program. RESULTS: Sixty-one participants took part (45 AYAs, 51.1% female; 19 support people). The opt-in rate was 30%, the enrolment rate was 87%, and 75% of participants took part in >=5/6 sessions. AYAs reported high benefit and low burden of participation. Overall, 95 online group sessions were conducted; few required rescheduling by group facilitators (3%), but many took place outside of office hours (~90 hours). It took 40 days on average to create online groups, but established weekly sessions commenced quickly (M = 4.0 minutes). Technological difficulties were common but had a low impact on intervention delivery. Although 54% of AYAs returned a clinically concerning distress screen at some point, none reflected acute mental health risks. CONCLUSIONS: The data largely indicate that Recapture Life is an acceptable, feasible, and safe model of evidence-based psychological support for AYAs during early survivorship, which nevertheless experienced common challenges in online/AYA intervention delivery. PMID- 30414222 TI - Maternal discourse continuity and infants' actions organize 12-month-olds' language exposure during object play. AB - Infant language learning depends on the distribution of co-occurrences within language- between words and other words-and between language content and events in the world. Yet infant-directed speech (IDS) is not limited to words that refer to perceivable objects and actions. Rather, caregivers' utterances contain a range of syntactic forms and expressions with diverse attentional, regulatory, social, and referential functions. We conducted a distributional analysis of linguistic content types at the utterance level, and demonstrate that a wide range of content types in maternal speech can be distinguished by their distributions in sequences of utterances and by their patterns of co-occurrence with infants' actions. We observed free-play sessions of 38 12-month-old infants and their mothers, annotated maternal utterances for ten content types, and coded infants' gaze target and object handling. Results show that all content types tended to repeat in consecutive utterances, whereas preferred transitions between different content types reflected sequences from attention-capturing to directing and then descriptive utterances. Specific content types were associated with infants' engagement with objects (declaratives, descriptions, object names), with disengagement from objects (talk about attention, infant's name), and with infants' gaze at the mother (affirmations). We discuss how structured discourse might facilitate language acquisition by making speech input more predictable and/or by providing clues about high-level form-function mappings. This article is protected by copyright. All rights reserved. PMID- 30414221 TI - Management of papillary lesions without atypia of the breast diagnosed on needle biopsy. AB - BACKGROUND: Current surgical practice often leads to excision of all papillary lesions of the breast diagnosed on percutaneous biopsy. This study aims to identify a subset of patients with papillary lesions who may be able to avoid surgery. METHODS: Between January 2000 and December 2015, 157 cases of papillary lesions with complete surgical excision pathology results were reviewed retrospectively to compare the clinical, imaging and pathology features. Of these, 50 patients with benign papillary lesions without atypia and 19 patients with benign papillary lesions with atypia on needle biopsy were analysed to determine the rate of upgrade to malignancy after surgery. RESULTS: Of the 50 patients with benign papillary lesions without atypia on biopsy, two (4%) were upgraded to low grade ductal carcinoma in situ after surgical excision. Both these patients had suspicious features on imaging. Of the 19 patients with papillary lesions with atypia diagnosed on needle biopsy, eight (42%) were upgraded to malignancy after surgery. The differences between benign, atypical and malignant papillary lesions were further compared. Malignant lesions were more suspicious radiologically (P = 0.001), more likely to have architectural distortion (P = 0.001), more peripherally located (P = 0.001) and were larger in size (P = 0.01). Patients diagnosed with malignant lesions were also older (P = 0.001). CONCLUSION: Younger patients diagnosed with small central benign papillary lesions without atypia on needle biopsy, and without suspicious imaging, may be managed conservatively with surveillance. PMID- 30414223 TI - Follow the leader: followership and its relevance for surgeons. PMID- 30414224 TI - Emphysematous pyelonephritis in renal allograft related to antibody-mediated rejection: A case report and literature review. AB - Emphysematous pyelonephritis (EPN) is a rare condition which can rapidly progress to sepsis and multiple organ failure with high mortality. We experienced a rare case of EPN in a renal allograft related to antibody-mediated rejection (AMR). The patient received a deceased donor kidney transplant due to end-stage renal disease secondary to diabetes mellitus. Cross-match test was negative but she had remote history of anti-HLA-A2 antibody corresponding with the donor HLA. Surgery concluded without any major events. Anti-thymoglobulin was given perioperatively for induction. She was compliant with her immunosuppressive medications making urine of 2 L/d with serum creatinine of 1.9 mg/dL at discharge on post-operative day (POD) 6. She did well until POD 14 when she presented to the clinic with features of sepsis, pain over the transplanted kidney area and decline in urine volume with elevated serum creatinine. CT revealed extensive gas throughout the transplanted kidney. Renal scan revealed non-functional transplant kidney with no arterial flow. Based on these findings, a decision to perform transplant nephrectomy was made. At laparotomy, the kidney was completely necrotic. Pathology showed non-viable kidney parenchyma with the tubules lacking neutrophilic casts suggestive of ischemic necrosis. Donor-specific antibody (DSA) returned positive with high intensity anti-HLA-A2 antibody. This is the first case of early EPN in allograft considered to have occurred as a result of thrombotic ischemia secondary to AMR. This case suggests consideration of perioperative anti-B-cell and/or anti-plasma cell therapies for historical DSA and strict post-operative follow-up in immunologically high-risk recipients to detect early signs of rejection and avoid deleterious outcomes. PMID- 30414225 TI - Randomized controlled trial of probiotic use for post-colonoscopy symptoms. AB - BACKGROUND: Symptoms of bloating, discomfort and altered bowel function persist post-colonoscopy in up to 20% of patients. A previous randomized controlled trial of probiotics for post-colonoscopy symptoms has demonstrated a reduction in duration of pain with the use of probiotics. This was performed with air insufflation and the question was asked whether the effect would persist with the use of carbon dioxide to insufflate the colon. METHODS: Eligible patients were recruited and randomized to receive either probiotic or placebo capsules post colonoscopy. A questionnaire was completed documenting the presence of pre procedural and post-procedural symptoms for the following 2 weeks. The results were entered into a database and processed by an independent statistician. The primary outcome was mean pain score and incidence of bloating over the first 7 days and at 14 days post procedure. The secondary outcome was the time to return of normal bowel function. RESULTS: Two hundred and forty participants were recruited and randomized (120 probiotic and 120 placebo). Data were available for 75 patients in the probiotic and 75 in the placebo group. There was no significant difference between groups in post-procedural discomfort, bloating nor time to return of normal bowel function. Subgroup analysis of the patients with preexisting symptoms showed a reduction in incidence of bloating with the use of probiotics. CONCLUSION: There may be a role for the use of probiotics in the subgroup of patients with preexisting symptoms; however, routine use of probiotics to ameliorate post-procedural symptoms of carbon dioxide insufflation colonoscopy cannot be advocated. PMID- 30414226 TI - Presenting signs and patient co-variables in Gaucher disease: outcome of the Gaucher Early Diagnosis Consensus (GED-C) Delphi initiative. AB - BACKGROUND: Gaucher disease (GD) presents with a range of signs and symptoms. Physicians can fail to recognize the early stages of GD owing to a lack of disease awareness, which can lead to significant diagnostic delays and sometimes irreversible but avoidable morbidities. AIMS: The Gaucher Earlier Diagnosis Consensus (GED-C) initiative aimed to identify signs and co-variables considered most indicative of early type 1 and type 3 GD, to help non-specialists identify 'at-risk' patients who may benefit from diagnostic testing. METHODS: An anonymous, three-round Delphi consensus process was deployed among a global panel of 22 specialists in GD (median experience 17.5 years, collectively managing almost 3000 patients). The rounds entailed data gathering, then importance ranking and establishment of consensus, using 5-point Likert scales and scoring thresholds defined a priori. RESULTS: For type 1 disease, seven major signs (splenomegaly, thrombocytopenia, bone-related manifestations, anaemia, hyperferritinaemia, hepatomegaly, and gammopathy) and two major co-variables (family history of GD and Ashkenazi-Jewish ancestry) were identified. For type 3 disease, nine major signs (splenomegaly, oculomotor disturbances, thrombocytopenia, epilepsy, anaemia, hepatomegaly, bone pain, motor disturbances, and kyphosis) and one major co-variable (family history of Gaucher disease) were identified. Lack of disease awareness, overlooking mild early signs, and failure to consider GD as a diagnostic differential were considered major barriers to early diagnosis. CONCLUSIONS: The signs and co-variables identified in the GED-C initiative as potentially indicative of early GD will help to guide non specialists and raise their index of suspicion in identifying patients potentially suitable for diagnostic testing for GD. This article is protected by copyright. All rights reserved. PMID- 30414227 TI - Emergency presentations of acute biliary pain: changing patterns of management in a tertiary institute. AB - BACKGROUND: Acute biliary pain is the most common presentation of gallstone disease. Untreated patients risk recurrent pain, cholecystitis, obstructive jaundice, pancreatitis and multiple hospital presentations. We examine the outcome of implementing a policy to offer laparoscopic cholecystectomy on index presentation to patients with biliary colic in a tertiary hospital in Australia. METHODS: This is a retrospective cohort study of adult patients presenting to the emergency department (ED) with biliary pain during three 12-month periods. Outcomes in Group A, 3 years prior to policy implementation, were compared with groups 2 and 7 years post implementation (Groups B and C). Primary outcomes were representations to ED, admission rate and time to cholecystectomy. RESULTS: A total of 584 patients presented with biliary colic during the three study periods. Of these, 391 underwent cholecystectomy with three Strasberg Type A bile leaks and no bile duct injuries. The policy increased admission rates (A = 15.8%, B = 62.9%, C = 29.5%, P < 0.001) and surgery on index presentation (A = 12.0%, B = 60.7%, C = 27.4%, P < 0.001). There was a decline in time to cholecystectomy (days) (A = 143, B = 15, C = 31, P < 0.001), post-operative length of stay (days) (A = 3.6, B = 3.2, C = 2.0, P < 0.05) and representation rates to ED (A = 42.1%, B = 7.1%, C = 19.9%, P < 0.001). There was a decline in policy adherence in the later cohort. CONCLUSION: Index hospital admission and cholecystectomy for biliary colic decrease patient representations, time to surgery, post-operative stay and complications of gallstone disease. This study demonstrates the impact of the policy with initial improvement, the dangers of policy attrition and the need for continued reinforcement. PMID- 30414228 TI - Development of sleep patterns in children with obese and normal-weight parents. AB - AIM: To study the sleep development and sleep characteristics in children at different obesity risks, based on parental weight, and also to explore their weekday-weekend sleep variations and associated family factors. METHODS: A total of 145 children participating in a longitudinal obesity prevention project were included, of which 37 had normal-weight parents (low obesity risk), and 108 had overweight/obese parents (high obesity risk). Sleep diaries at ages 1 and 2 years were used to study sleep development in children at different obesity risks. Objectively assessed sleep using an accelerometer at 2 years of age was used to analyse weekday-weekend sleep variations. RESULTS: There was no difference in sleep development from age 1 to age 2 among children at different obesity risks, but more children in the high-risk group had prolonged sleep onset latency and low sleep efficiency. At 2 years of age, children in the high-risk group had more weekday-weekend variation in sleep offset (mean difference 18 min, 95% confidence interval (CI) 4-33 min), midpoint of sleep (mean difference 14 min, 95% CI 3-25 min) and nap onset (mean difference 42 min, 95% CI 10-74 min) than children in the low-risk group, after adjusting for other family factors. However, no difference could be detected between groups in weekday-weekend variation in sleep duration. CONCLUSIONS: Unfavourable sleep characteristics, as well as more variation in sleep schedules, have been observed in children at high obesity risk. While the differences were relatively small, they may reflect the unfavourable sleep hygiene in families at high obesity risk. PMID- 30414229 TI - HIF-1alpha promotes bone marrow stromal cell migration to the injury site and enhances functional recovery after spinal cord injury in rats. AB - INTRODUCTION: Spinal cord injury (SCI) is a severe worldwide health problem, and efficacious strategies to properly repair SCI have not yet been developed. Recently, use of gene and cell therapy as alternative treatments for SCI have been proposed as safe and promising strategies. AIMS: This study investigated the therapeutic effects and underlying mechanisms of hypoxia-inducible factor-1alpha carried in recombinant adenovirus (Adv-HIF-1alpha) administered immediately following spinal cord injury (SCI) in adult rats. RESULT: Adv-HIF-1alpha-treated animals showed better functional recovery and smaller cavity volume than those in the vehicle-treated control group. Both the numbers of green fluorescent protein labeled bone marrow stromal cells (GFP-BMSCs) and cells double-positive for GFP and a cell lineage marker (NeuN) in the injured spinal cord were larger in the Adv-HIF-1alpha-treated group. The expression levels of neurotrophins such as neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) were also higher in the Adv-HIF-1alpha-treated group. CONCLUSION: Adv-HIF-1alpha improves functional recovery in rats with SCI, and the underlying mechanism may be related to the mobilization of BMSCs to the injured area and higher expression levels of NT-3 and BDNF. PMID- 30414230 TI - Low risk of invasive lobular carcinoma of the breast in carriers of BRCA1 (hereditary breast and ovarian cancer) and TP53 (Li-Fraumeni syndrome) germline mutations. AB - BACKGROUND: Invasive lobular carcinoma (ILC) of the breast has epidemiological, molecular and clinical specificities, and should likely be considered a unique entity. As for genetic susceptibility, CDH1 germline mutations predispose exclusively to ILC. Data are however scarce regarding ILC in women with BRCA1/2 (Hereditary Breast and Ovarian Cancer) and TP53 (Li-Fraumeni syndrome) germline mutations. METHODS: We included all breast cancers from female patients tested at our institute between 1992 and 2016 (n = 3469) for which pathology data were available. ILC proportion comparison according to mutational status was performed by a chi-squared test. The impact of susceptibility genes on ILC proportion was investigated by univariate logistic regression with wild-type patients as reference. RESULTS AND DISCUSSION: There were 265 (7.64%) ILC: 2/342 (0.58%) in BRCA1 patients, 24/238 (10%) in BRCA2 patients, 1/57 (1.75%) in TP53 patients and 238/2832 (8.4%) in non-carriers. The majority of breast cancers in all groups were invasive ductal and ductal in situ carcinomas. The difference in ILC proportion was highly significant (P < 0.001). Compared to wild-type patients, BRCA1 was associated with a lower ILC proportion (OR 0.064 [95% CI 0.016;0.259], P < 0.0001). BRCA2 OR was 1.222 [95%CI 0.785;1.902] (P = 0.374), TP53 OR was 0.195 [95%CI 0.027;1.412] (P = 0.105). ILC are therefore underrepresented in BRCA1 and TP53 mutation carriers. Formal significance (P = 0.05) was not reached for TP53, but statistical power was only 38%. Based on ILC incidence in the general population, we make the hypothesis that BRCA1 and TP53 do not predispose to ILC, as the few occurrences of ILC in mutation carriers could be attributed to chance and not to germline mutations. Our observations will be useful to clinical cancer geneticists managing patients with ILC, as a BRCA1 or TP53 mutation in these patients would be unlikely. Genetic counseling should be adapted accordingly. PMID- 30414231 TI - Evaluating hemodialysis patient's nutritional status: Body Mass Index or Body Cell Mass Index? AB - OBJECTIVE: Evaluate which of two combinations of parameters based on ISRNM recommendations could better identify patients with Protein Energy Wasting (PEW) and to compare the relationship of these two combinations with other clinical and body composition parameters. DESIGN AND METHODS: This was a multicenter longitudinal study with 24 months of follow-up. The PEW patients were characterized by: Group A (GA ) - normalized Protein Catabolic Rate (nPCR) < 1.0 g/Kg/day, albumin < 3.8 g/dL and Body Cell Mass Index (BCMI) < 6.4 Kg/m2 (n=203); Group B (GB ) - nPCR < 1.0 g/Kg/day, albumin < 3.8 g/dL and Body Mass Index (BMI) <23 Kg/m2 (n=109). All the patients who did not meet these requirements were considered "well-nourished" (GA : n=1818; GB : n=3292). RESULTS: When compared to the well-nourished patients, PEW patients in the GA presented higher age, Kt/V, C reactive protein, relative overhydration, fat tissue index (FTI); lower creatinine, albumin, nPCR, PTH, hemoglobin, phosphorus, calcium X phosphorus product, potassium, dry weight, BMI, BCMI, lean tissue index, %IDWG . In the GB well-nourished patients FTI was significantly higher. In Cox analysis, the combination with BCMI was a strong independent predictor of mortality in these patients (HR: 1.48; CI: 1.00-2.19; p=0.048), even after adjustment. Although GB combination seemed to be also a predictor of death (HR: 2.67; CI: 1.92-3.71; p<0.001), when adjusted, the association remained no longer significant. CONCLUSION: A new combination of parameters including protein intake, albumin and BCMI demonstrated significant associations with other nutrition and inflammation parameters as well as with mortality. This article is protected by copyright. All rights reserved. PMID- 30414232 TI - Isolated bone marrow metastases of colorectal adenocarcinoma. PMID- 30414233 TI - Management of in-transit melanoma metastases: a review. AB - In-transit metastases (ITM) of cutaneous melanoma are locoregional recurrences confined to the superficial lymphatics that occur in 3.4-6.2% of patients diagnosed with melanoma. ITM are a heterogeneous disease that poses a therapeutic dilemma. Patients may have a prolonged disease trajectory involving multiple or repeat treatment modalities for frequent recurrences. The management of ITM has evolved without the development of a standardized protocol. Owing to the variability of the disease course there are few dedicated clinical trials, with a number of key trials in stage III melanoma excluding ITM patients. Thus, there is a paucity of quality data on the efficacy of the treatment modalities available for ITM and even fewer studies directly comparing modalities. At present the mainstay of ITM treatment is surgical resection, with intralesional therapies, isolated limb infusion and radiotherapy utilized as second-line measures. The developing role of targeted therapies and immunotherapy has yet to be explored completely in these patients. This review addresses the evidence base of the efficacy of the various treatment modalities available and those factors that have impacted their clinical uptake. PMID- 30414234 TI - A narrative review of proteinuria and albuminuria as clinical biomarkers in children. AB - Proteinuria is an important biomarker commonly used to detect and manage kidney disease in children. There are now a variety of methods available to measure urinary protein loss, and physicians are faced with several contrasting strategies: 24-h or timed collection versus spot samples (first-morning or random), measurement of total urinary protein versus selective measurement of urinary albumin, unadjusted urine protein concentration versus protein-to creatinine ratio and the use of dipstick versus laboratory-based methods. In this review, we will discuss the advantages and disadvantages of these different approaches. We will then summarise the evidence base for proteinuria as a clinical biomarker in different settings, including discussion of the current and potential role of measuring low-level albuminuria. Finally, we will highlight gaps in the literature and opportunities for further research into proteinuria among children. PMID- 30414235 TI - Digital droplet polymerase chain reaction analysis of common viruses in the aqueous humour of patients with Posner-Schlossman syndrome in Chinese population. AB - BACKGROUND: To compare the detection results consistency of quantitative polymerase chain reaction (qPCR) and digital droplet polymerase chain reaction (ddPCR), and determine the value of ddPCR for viral detection in the aqueous humour. METHODS: A total of 130 aqueous humour samples were collected, including 60 patients with Posner-Schlossman syndrome (PSS) in case group and 70 elderly patients with senile cataract in control group. The target nucleic acid fragments of human cytomegalovirus (HCMV), herpes simplex virus, Epstein-Barr virus and varicella zoster virus in aqueous humour were analysed by qPCR and ddPCR, respectively, for the diagnosis and curative effect monitoring of pathogen induced PSS. Samples with inconsistent results were verified by next-generation sequencing. RESULTS: There were 27 and 20 HCMV-positive cases detected in the case group by ddPCR and qPCR, respectively. ddPCR increased the sensitivity for the HCMV virus detection from 400 to 100 copies/mL. No other pathogens were found in this study. The results of ddPCR were consistent with that of next generation sequencing. The mean (SD) of Lg (HCMV copies/mL) detected by ddPCR and qPCR were 1.66 (1.92) and 1.10 (1.61), respectively (P < 0.001). Compared with qPCR, results of ddPCR showed better consistency with validity of clinical treatment. All patients with ddPCR-positive results had good validity on antiviral therapy, exhibiting anterior chamber inflammation remission, resolution of corneal oedema and good IOP control within 1 month. CONCLUSIONS: HCMV was the leading cause of pathogen-induced PSS in the Chinese population. ddPCR was a promising tool for early detection, accurate diagnosis and therapeutic validity monitoring of pathogen-induced PSS. The high sensitivity of ddPCR could avoid repeated anterior chamber tap. PMID- 30414236 TI - When Causality Shapes the Experience of Time: Evidence for Temporal Binding in Young Children. AB - It is well-established that the temporal proximity of two events is a fundamental cue to causality. Recent research with adults has shown that this relation is bidirectional: events that are believed to be causally related are perceived as occurring closer together in time-the so-called temporal binding effect. Here we examined the developmental origins of temporal binding. Participants predicted when an event that was either caused by a button press, or preceded by a non causal signal, would occur. We demonstrate for the first time that children as young as four years are susceptible to temporal binding. Binding occurred both when the button press was executed via intentional action, and when a machine caused it. These results suggest binding is a fundamental, early developing property of perception and grounded in causal knowledge. This article is protected by copyright. All rights reserved. PMID- 30414237 TI - Visual and ocular morbidity in severe open-globe injuries presenting to a regional eye centre in New Zealand. AB - IMPORTANCE: Open-globe injuries (OGI) are a leading cause of monocular blindness world-wide with considerable cost to the individual and society. BACKGROUND: To characterize the epidemiology, severity and outcomes of OGI treated at a major ophthalmology centre in New Zealand. DESIGN: Retrospective study. PARTICIPANTS: A total of 385 eyes of 381 patients over a 10-year period. METHODS: Eligible patients were identified using diagnosis and surgery codes on hospital discharge summaries. Clinical notes were reviewed to determine patient demographics, injury details, treatments and outcomes. MAIN OUTCOME MEASURES: Complications of injury, visual acuity at 3 months and final follow-up, and final status of the eye. RESULTS: The estimated annual incidence of OGI was 2.8 per 100 000. Working-age males predominated but age at injury ranged from 9 months to 90 years. Maori and Pacific peoples were over-represented. Injuries were severe with 58.7% presenting with vision of hand movements or worse. Penetrating injuries (56.4%) were most common, followed by globe ruptures (35.6%). Major complications included retinal detachment (15.8%), enucleation/evisceration (9.1%), phthisis bulbi (9.9%), endophthalmitis (2.6%) and sympathetic ophthalmia (0.26%). Despite the injury severity, 46% of eyes achieved final BCVA of >=6/12. The Ocular Trauma Score (OTS) was a useful prognostic tool for stratifying severity of injury and predicting visual outcome (Fisher's exact test P < 0.001). CONCLUSIONS AND RELEVANCE: The incidence and severity of OGI in NZ are comparable to global statistics. Surgical repair can effectively recover vision, predicted well by the OTS. We identified at-risk groups to target with education and prevention strategies. PMID- 30414238 TI - Chemical Synthesis of Magnetically Hard and Strong Rare Earth Metal Based Nanomagnets. AB - We report a general chemical approach to synthesize strongly ferromagnetic rare earth metal (REM) based SmCo and SmFeN nanoparticles (NPs) with ultra-large coercivity. The synthesis started with the preparation of hexagonal CoO+Sm2 O3 (denoted as SmCo-O) multipods via decomposition of Sm(acac)3 and Co(acac)3 in oleylamine. These multipods were further reduced with Ca at 850 degrees C to form SmCo5 NPs with sizes tunable from 50 to 200 nm. The 200 nm SmCo5 NPs were dispersed in ethanol, and magnetically aligned in polyethylene glycol (PEG) matrix, yielding a PEG-SmCo5 NP composite with the room temperature coercivity (Hc ) of 49.2 kOe, the largest Hc among all ferromagnetic NPs ever reported, and saturated magnetic moment (Ms ) of 88.7 emu g-1 , the highest value reported for SmCo5 NPs. The method was extended to synthesize other ferromagnetic NPs of Sm2 Co17 , and, for the first time, of Sm2 Fe17 N3 NPs with Hc over 15 kOe and Ms reaching 127.9 emu g-1 . These REM based NPs are important magnetic building blocks for fabrication of high-performance permanent magnets, flexible magnets, and printable magnetic inks for energy and sensing applications. PMID- 30414239 TI - Discovery of cancer cell proliferation inhibitors from Salviae miltiorrhizae radix et rhizoma by a trace peak enrichment approach. AB - Salviae miltiorrhizae radix et rhizoma is a traditional herbal medicine with anti cancer activities. In this work, a trace peak enrichment approach combined with a cell proliferation assay was applied for screening cancer cell proliferation inhibitors from the extract of S. miltiorrhiza. A set of 123 peak fractions were prepared, and by comprehensive screening, 21 tanshinones were screened out as cancer cell proliferation inhibitors and their structures were tentatively identified by liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry analysis. The inhibitory activities of nine available screened tanshinones were validated, with their IC50 values ranging from 0.63 to 28.40 MUM, indicating their activities strongly inhibit the proliferation of cancer cells. This study presents tanshinones that are potential cancer cell proliferation inhibitors and may explain the anti-cancer activity of S. miltiorrhiza. PMID- 30414241 TI - Carotid artery stenosis, diabetes mellitus, and TCD4+ lymphocyte subpopulations. PMID- 30414240 TI - Reduction in Albuminuria With Dapagliflozin Cannot Be Predicted by Baseline Clinical Characteristics or Changes in Most Other Risk Markers. AB - The sodium glucose co-transporter 2 inhibitor dapagliflozin has been shown to decrease urinary albumin:creatinine ratio (UACR). This effect, however, varies among individual patients. In this study, we assessed the baseline characteristics and concurrent changes in other cardiovascular risk markers that might be associated with UACR response to dapagliflozin. A pooled analysis of 11 phase 3 randomized, controlled clinical trials was performed. UACR change from baseline after 24 weeks treatment with dapagliflozin 10 mg/day in 531 patients with type 2 diabetes and UACR >=30 mg/g at baseline was determined. UACR response was defined as >30% reduction from baseline at 24-weeks, whereas UACR non response was defined as <=30% reduction at 24-weeks. A total of 288 (54%) patients were classified as responders and 243 (46%) as non-responders. At 24 weeks, the UACR adjusted mean change from baseline was -71.2% and 25.9% in responders and non-responders, respectively. Baseline characteristics were similar between both groups. Changes in HbA1c and body weight were comparable across groups. Responders showed a numerically larger reduction in eGFR and SBP versus non-responders. UACR reduction to dapagliflozin is an individual characteristic that cannot be predicted by baseline clinical features or changes in metabolic parameters. Whether UACR response would improve long-term renal and cardiovascular outcomes remains to be determined. This article is protected by copyright. All rights reserved. PMID- 30414242 TI - Misconceptions and persistence: resources for targeting student alternative conceptions in biotechnology. AB - Conceptual understanding and reasoning of nonscience major students enrolled in a course on biotechnology were evaluated before and after instruction. The instrument for analysis of student understanding was the Biotechnology Instrument for Knowledge Elicitation (BIKE). The BIKE targets 11 key concepts, as determined by experts in the field. A statistically significant score improvement was observed in each of the 11 concept areas after completion of the course, Biotechnology in Society (N = 117). Student responses to both the pretest and posttest were highly informative and revealed several common misconceptions that could have been overlooked in a closed form testing scenario. These alternative conceptions and recommended clarifications have been presented here. Our goal in documenting and distributing these is to better equip educators in biology and biochemistry to anticipate student preconceptions, design targeted interventions, and improve student conceptual reasoning in topics pertaining to biology and biotechnology. (c) 2018 International Union of Biochemistry and Molecular Biology, 46(6):602-611, 2018. PMID- 30414243 TI - Multicenter investigation of the reliability and validity of the Live Donor Assessment Tool as an enhancement to the psychosocial evaluation of living donors. AB - The Live Donor Assessment Tool (LDAT) is the first psychosocial assessment tool developed to standardize live donor psychosocial evaluations. A multi-center study was conducted to explore reliability and validity of the LDAT and determine its ability to enhance the psychosocial evaluation beyond its center of origin. Four transplant programs participated, each with their own team of evaluators and unique demographics. Liver and kidney living donors (LDs) undergoing both standard psychosocial evaluation and LDAT from June 2015 to September 2016 were studied. LDAT inter-rater reliability, associations between LDAT scores and psychosocial evaluation outcome, and psychosocial outcomes post-donation were tested. 386 LD evaluations were compared and had a mean LDAT score of 67.34+/ 7.57. In 140 LDs with 2 LDATs by different observers, the inter-rater scores correlated (r=0.63). LDAT scores at each center and overall stratified to the conventional grouping of psychosocial risk level. LDAT scores of 131 subjects who proceeded with donation were expectedly lower in LDs requiring post-donation counseling (t=-2.78, p=0.01). The LDAT had good reliability between raters and predicted outcome of the psychosocial evaluation across centers. It can be used to standardize language among clinicians to communicate psychosocial risk of LD candidates, and assist teams when anticipating post-donation psychosocial needs. This article is protected by copyright. All rights reserved. PMID- 30414244 TI - Aligning Developmental and Processing Accounts of Implicit and Statistical Learning. AB - A long-standing question in child language research concerns how children achieve mature syntactic knowledge in the face of a complex linguistic environment. A widely accepted view is that this process involves extracting distributional regularities from the environment in a manner that is incidental and happens, for the most part, without the learner's awareness. In this way, the debate speaks to two associated but separate literatures in language acquisition: statistical learning and implicit learning. Both fields have explored this issue in some depth but, at present, neither the results from the infant studies used by the statistical learning literature nor the artificial grammar learning tasks studies from the implicit learning literature can be used to fully explain how children's syntax becomes adult-like. In this work, we consider an alternative explanation that children use error-based learning to become mature syntax users. We discuss this proposal in the light of the behavioral findings from structural priming studies and the computational findings from Chang, Dell, and Bock's () dual-path model, which incorporates properties from both statistical and implicit learning, and offers an explanation for syntax learning and structural priming using a common error-based learning mechanism. We then turn our attention to future directions for the field, here suggesting how structural priming might inform the statistical learning and implicit learning literature on the nature of the learning mechanism. PMID- 30414245 TI - Efficacy of two plant extracts against acne vulgaris: Initial results of microbiological tests and cell culture studies. AB - BACKGROUND: Acne vulgaris is a common skin disease characterized by increased sebum production, inflammation, and colonization of Propionibacterium acnes (P. acnes) on pilosebaceous follicles. AIMS: To determine the efficacy of two different plant extracts against P. acnes and to analyze the gene expression levels of IL-1alpha, SRD5A1, and TNFalpha in HaCaT cells treated with these plant extracts. METHODS: Anti-acne extract 1 (AE1) consisted of Juglans regia (walnut husk), Myrtus communis (myrtle leaves), Matricaria chamomilla (chamomilla flowers), Urtica dioica (stinging nettle leaves), and Rosa damascena (rose flowers). Anti-acne extract 2 (AE2) contained Brassica oleracea var. botrytis (broccoli) and B. oleracea var. italica (cauliflower). The antimicrobial activities of the extracts were tested on two different P. acnes strains: the reference strain of P. acnes (ATCC 51277) and the clinical isolate from a patient. The minimum inhibitory concentration (MIC) of the extracts was determined using the broth dilution method. Human keratinocyte cells were used for in vitro tests. Gene expression analyses were performed with RT-qPCR. RESULTS: The MIC values of the extracts were below 1/2048 ug/mL. In the gene expression analysis, AE1 increased the expression level of TNFalpha (1.1719, P < 0.0001), suppressed the expression level of IL-1alpha, SRD5A1 (0.0588, P = 0.0231; 0.3081, P = 0.0351), respectively. AE2 suppressed gene expression level of IL-1alpha, SRD5A1, TNFalpha (0.3815, P = 0.0254; 0.3418, P = 0.0271; 0.1997, P = 0.0623). CONCLUSIONS: Both herbal extracts demonstrated strong antibacterial and anti-inflammatory activity in this preliminary trial. In conclusion, the topical application of these botanical extracts can be good candidates for local acne treatment. PMID- 30414246 TI - Regio/Stereoselective Glycosylation of Diol and Polyol Acceptors in Efficient Synthesis of Neu5Ac-alpha-2,3-LacNPhth Trisaccharide. AB - A concise approach to a Neu5Ac-alpha-2,3-LacNPhth trisaccharide derivative was developed. First, the regio/stereoselective glycosylation between glycoside donors and glucoNPhth diol acceptors was investigated. It was found that the regioselectivity depends not only on the steric hindrance of the C2-NPhth group and the C6-OH protecting group of the glucosamine acceptors, but also on the leaving group and protecting group of the glycoside donors. Under optimized conditions, LacNPhth derivatives were synthesized in up to 92 % yield through a regio/stereoselective glycosylation between peracetylated-alpha-galactopyranosyl trichloroacetimidate and p-methoxyphenyl 6-O-tert-butyldiphenylsilyl-2-deoxy-2 phthalimido-beta-d-glucopyranoside, avoiding the formation of glycosylated orthoesters and anomeric aglycon transfer. Then, the LacNPhth derivative was deacylated and then protected on the primary position by TBDPS to form a LacNPhth polyol acceptor. Finally, the Neu5Ac-alpha-2,3-LacNPhth derivative was synthesized in 48 % yield through the regio/stereoselective glycosylation between the LacNPhth polyol acceptor and a sialyl phosphite donor. Starting from d glucosamine hydrochloride, the target Neu5Ac-alpha-2,3-LacNPhth derivative was synthesized in a total yield of 18.5 % over only 10 steps. PMID- 30414247 TI - Synthesis of g-C3N4 Nanosheets Using Highly Condensed Lamellar Crystalline Melamine-Cyanuric Acid Supramolecular Complex for Enhanced Solar Hydrogen Generation. AB - Highly condensed lamellar melamine-cyanuric acid supramolecular (MCS) complex was synthesized in autoclave at high pressure as a precursor for synthesizing g-C3N4 nanosheets. Due to the distinctive properties of the prepared MCS complex, the efficient g-C3N4 nanosheets photocatalyst can be obtained by heating treatment of this MCS complex under argon followed by calcination in air at 400 oC. The resulting nanosheets with in-plan nanoholes showed an extremely high specific surface area (~270 m2 g-1) and significantly enhanced light absorption in the visible region. This phenomenon is observed for the first time for carbon nitride nanosheets. The light enhancement results from the sizeable conjugated system of tri-s-triazine units in the carbon nitride framework coupling with structural defects by the presence of oxygen-containing groups being induced during the synthesis. Consequently, the obtained carbon nitride nanosheets exhibited excellent performance for hydrogen generation under full sunlight and especially, under visible light. Its quantum efficiency (QE) is 20.9% at 420 nm, one of the highest values for carbon nitride materials; even at 590 nm, the QE is 3.5%. To the best of our knowledge, the integrated QE of this material in the visible region (420 to 600 nm) is approximately 1% - the highest one compared to all other the carbon nitride nanosheet materials reported previously. PMID- 30414248 TI - Organ-mounted robot localization via function approximation. AB - BACKGROUND: Organ-mounted robots adhere to the surface of a mobile organ as a platform for minimally invasive interventions, providing passive compensation of physiological motion. This approach is beneficial during surgery on the beating heart. Accurate localization in such applications requires accounting for the heartbeat and respiratory motion. Previous work has described methods for modeling quasi-periodic motion of a point and registering to a static preoperative map. The existing techniques, while accurate, require several respiratory cycles to converge. METHODS: This paper presents a general localization technique for this application, involving function approximation using radial basis function (RBF) interpolation. RESULTS: In an experiment in the porcine model in vivo, the technique yields mean localization accuracy of 1.25 mm with a 95% confidence interval of 0.22 mm. CONCLUSIONS: The RBF approximation provides accurate estimates of robot location instantaneously. PMID- 30414249 TI - Quantitative FRET measurement based on spectral unmixing of donor, acceptor and spontaneous excitation-emission spectra. AB - The spontaneous excitation-emission (ExEm) spectrum is introduced to the quantitative mExEm-spFRET methodology we recently developed as a spectral unmixing component for quantitative FRET measurement, named as SPEES-FRET method. The spectral fingerprints of both donor and acceptor were measured in HepG2 cells with low autofluorescence separately expressing donor and acceptor, and the spontaneous spectral fingerprint of HEK293 cells with strong autofluoresence was measured from blank cells. SPEES-FRET was performed on improved spectrometer microscope system to measure the FRET efficiency (E) and concentration ratio (RC ) of acceptor to donor vales of FRET tandem plasmids in HEK293 cells, and obtained stable and consistent results with the expected values. Moreover, SPEES FERT always obtained stable results for the bright and dim cells coexpressing Cerulean and Venus or CFP-Bax and YFP-Bax, and the E values between CFP-Bax and YFP-Bax were 0.02 for healthy cells and 0.14 for the staurosporine (STS)-treated apoptotic cells. Collectively, SPEES-FRET has very strong robustness against cellular autofluorescence, and thus is applicable to quantitative evaluation on the protein-protein interaction in living cells with strong autofluoresence. This article is protected by copyright. All rights reserved. PMID- 30414250 TI - Actin Microridges. AB - Microridges are highly distinctive "fingerprint"-patterned structures situated on the outer surface of superficial layer cells of the epithelium. An F-actin-based cytoskeleton is the underlying core structural component of microridges. The basis for much of what is known about microridges has been provided by in vivo and in vitro fish epithelial systems. Nonetheless the microridge literature is quite small, especially when compared with other actin-based cellular structures such as those involved in cell motility. A PubMed search of the terms "Microridges" yields 261 citations from the mid-1970s to the writing of this review. "Microplicae," an alternative name for microridges, and "Actin Microridges" search terms give 204 and 8 references, respectively, in the same time period. By comparison a search of "Lamellipodia" over the same time period yields over 6,400 citations for this important motility structure while a search of the associated "filopodia" results in close to 7,300 articles. Despite the near-ubiquity of microridges in epithelia across species the study of these structures has clearly been neglected. In-depth analysis of microridge molecular composition is very limited while their function remains unclear. This review draws upon information derived from studies of fish as well as mammalian species to provide a more comprehensive view of these structures. The wide-spread distribution of these structures between species and various tissues indicate the microridges have important and common functions in healthy organisms. Conversely, disease conditions may show alterations in microridge structure and function and thus warrant further investigation. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30414251 TI - The whither of bacteriophytochrome-based near-infrared fluorescent proteins: Insights from two-photon absorption spectroscopy. AB - We present one- and two-photon-absorption fluorescence spectroscopic analysis of biliverdin-chromophore-based single-domain near-infrared fluorescent proteins (iRFPs). This article is protected by copyright. All rights reserved. PMID- 30414252 TI - The effectiveness of 4DCT in children and adults: A pooled analysis. AB - BACKGROUND: While four-dimensional computed tomography (4DCT) is extensively used in adults, reluctance remains to use 4DCT in children. Day-to-day (interfractional) variability and irregular respiration (intrafractional variability) have shown to be limiting factors of 4DCT effectiveness in adults. In order to evaluate 4DCT applicability in children, the purpose of this study is to quantify inter- and intrafractional variability of respiratory motion in children and adults. The pooled analysis enables a solid comparison to reveal if 4DCT application for planning purposes in children could be valid. METHODS/MATERIALS: We retrospectively included 90 patients (45 children and 45 adults), for whom the diaphragm was visible on abdominal/thoracic free-breathing cone beam CTs (480 pediatric, 524 adult CBCTs). For each CBCT, the cranial-caudal position of end-exhale and end-inhale positions of the right diaphragm dome were manually selected in the projection images. The difference in position between both phases defines the amplitude. Cycle time equaled inspiratory plus expiratory time. We analyzed the variability of the inter- and intrafractional respiratory induced diaphragm motion. RESULTS: Ranges of respiratory motion characteristics were large in both children and adults (amplitude: 4-17 vs 5-24 mm, cycle time 2.1-3.9 vs 2.7-6.5 s). The mean amplitude was slightly smaller in children than in adults (10.7 vs 12.3 mm; P = 0.06). Interfractional amplitude variability was statistically significantly smaller in children than in adults (1.4 vs 2.2 mm; P = 0.00). Mean cycle time was statistically significantly shorter in children (2.9 vs 3.6 s; P = 0.00). Additionally, intrafractional cycle time variability was statistically significantly smaller in children (0.5 vs 0.7 s; P = 0.00). CONCLUSIONS: Overall variability is smaller in children than in adults, indicating that respiratory motion is more regular in children than in adults. This implies that a single pretreatment 4DCT could be a good representation of daily respiratory motion in children and will be at least equally beneficial for planning purposes as it is in adults. PMID- 30414253 TI - Integrating Incomplete Information With Imperfect Advice. AB - When our own knowledge is limited, we often turn to others for information. However, social learning does not guarantee accurate learning or better decisions: Other people's knowledge can be as limited as our own, and their advice is not always helpful. This study examines how human learners put two "imperfect" heads together to make utility-maximizing decisions. Participants played a card game where they chose to "stay" with a card of known value or "switch" to an unknown card, given an advisor's advice to stay or switch. Participants used advice strategically based on which cards the advisor could see (Experiment 1), how helpful the advisor was (Experiment 2), and what strategy the advisor used to select advice (Experiment 3). Overall, participants benefited even from imperfect advice based on incomplete information. Participants' responses were consistent with a Bayesian model that jointly infers how the advisor selects advice and the value of the advisor's card, compared to an alternative model that weights advice based on the advisor's accuracy. By reasoning about others' minds, human learners can make the best of even noisy, impoverished social information. PMID- 30414254 TI - Two Dimensional Correlation Analysis of Raman microspectroscopy of subcellular interactions of drugs in vitro. AB - Two dimensional correlation analysis is explored to data mine the time evolution of the characteristic Raman microspectroscopic signatures of the subcellular responses of the nucleoli of human lung cancer cells to the uptake of doxorubicin. A simulated dataset of experimental control spectra, perturbed with systematically time-dependent spectral changes, constituted by a short term response which represents the initial binding of the drug in the nucleolus, followed by a longer term response of the organelle metabolism, is used to validate the analysis protocol. Applying two dimensional correlation analysis, the in phase, synchronous correlation co-efficients are seen to contain contributions of both response profiles, whereas they can be independently extracted from the out of phase, asynchronous correlation co-efficients. The methodology is applied to experimental data of the uptake of doxorubicin in human lung cell lines to differentiate the signatures of chemical binding and subsequent cellular response. This article is protected by copyright. All rights reserved. PMID- 30414255 TI - Efficacy of bevacizumab for posttraumatic choroidal neovascularization. PMID- 30414256 TI - Associations of cytokine concentrations in aqueous humour with retinal vascular abnormalities and exudation in Coats' disease. AB - PURPOSE: To investigate the associations of cytokine concentrations in aqueous humour with the severity of retinal vascular abnormalities, exudation and fibrosis in patients with Coats' disease. METHODS: Aqueous humour samples were collected in 23 paediatric patients (23 eyes) with Coats' disease and six age matched control patients (six eyes) with congenital cataract in this cross sectional, case-control study. Through Cytometric Bead Array technology, six angiogenic, inflammatory and fibrotic cytokines were measured for their concentrations in aqueous humour. Ophthalmologic characteristics including retinal vessel abnormalities, exudation and fibrosis of Coats' disease were also clinically evaluated for analysis. RESULTS: The aqueous levels of vascular endothelial growth factor (VEGF) (p = 0.006) and monocyte chemoattractant protein 1 (MCP-1) (p < 0.001) were significantly higher in the Coats' disease group than in the control group. The concentrations of angiogenin were peaked in eyes with first-grade vessels tortuosity (p < 0.001), and also positively correlated with the severity of retinal capillary abnormalities (r = 0.910, p < 0.001). The concentrations of MCP-1 (r = 0.966, p < 0.001) and VEGF (r = 0. 765, p = 0.002) were significantly correlated with the extent of retinal exudation. The aqueous humour transforming growth factor-beta (TGFbeta) concentrations were higher in eyes with retinal fibrosis than in non-fibrotic eyes with Coats' disease (p = 0.004). CONCLUSION: In Coats' disease, angiogenin may act as a potential biomarker for retinal vascular abnormalities. The concentrations of VEGF and MCP 1 may positively correlate with the severity of retinal exudation. PMID- 30414257 TI - European Association for the Study of Diabetes 2018. PMID- 30414258 TI - Novel biopesticide based on Erinnyis ello betabaculovirus: characterization and preliminary field evaluation to control Erinnyis ello in rubber plantations. AB - BACKGROUND: The hornworn Erinnyis ello is the major pest of natural rubber crops in Colombia, mainly controlled using toxic chemical insecticides. The use of E. ello Betabaculovirus is an environmentally sustainable alternative for its control. The aim of the present work was to characterize a prototype biopesticide formulation and evaluate its efficacy under different conditions. RESULTS: Quality control evaluations of formulated biopesticide revealed that all the parameters evaluated were under permissible level. The Lethal Concentrations LC50 and LC90 of the biopesticide were 4.3x103 and 5.5x104 Occlusion bodies.mL-1 , respectively. Biopesticide efficacies against second and fourth instar larvae under greenhouse conditions were higher than 80%. Evaluation of two application rates in a clonal garden resulted in 84% and 88% efficacy, comparable to obtained with the chemical. The biopesticide in a commercial plantation showed efficacies among 74% and 82%. Biopesticide post-application persistence was estimated at least in one week under field natural conditions. Results allowed to select the lowest evaluated dose (1x1011 OBs.ha-1 ) as the basis for further field evaluations. CONCLUSION: Formulated ErelGV showed high efficacy to control the hornworm in rubber crops and high potential to be included in Integrated Pest Management programs, thereby could be an interesting alternative to replace agrochemicals. This article is protected by copyright. All rights reserved. PMID- 30414259 TI - Multispectral photoacoustic imaging of cancer with broadband CuS nanoparticles covering both NIR-I and NIR-II biological windows. AB - In this study, CuS nanoparticles with optical absorption covering both near infrared I (NIR-I) and NIR-II biological windows were prepared and served as the contrast agents for multispectral photoacoustic imaging. The physiological parameters including concentrations of deoxyhemoglobin and oxyhemoglobin as well as the water content in the tumor location were quantified based on the multispectral photoacoustic reconstruction method. More importantly, the concentration of CuS nanoparticles /drugs accumulated in the tumor was also recovered after intravenously injection, which are essential for image-guided cancer theranostics. In addition, phantom and in vivo experimental tests were performed to inspect and compare the imaging depth and SNR between the two NIR biological windows. Interestingly, we discovered that a higher SNR was obtained in the NIR-II window than that in the NIR-I window. Meanwhile, the multispectral imaging results also demonstrated that the imaging contrast and penetration depth in the NIR-II window were also significantly improved as compared to those from the NIR-I window. This article is protected by copyright. All rights reserved. PMID- 30414261 TI - Optical Versus Virtual Microscope for Medical Education: A Systematic Review. AB - Many technological innovations have changed the traditional practice of medical education and clinical practice. Whole slide imaging (WSI) technology provided an unique way of viewing conventional glass slides in histology and pathology laboratories. The WSI technology digitalized glass slide images and made them readily accessible via the Internet using tablets or computers. Users utilized the pan-and-zoom function to view digital images of slides, also referred to as the virtual microscope (VM), simulating use of an optical microscope (OM). Several articles have reported various outcomes on the utility of VM in teaching laboratories. Recently, the Royal College of Physicians and Surgeons of Canada certification examinations for anatomical pathologists ha completely adopted VM for the national licensing examination. To better inform medical educators, there is an urgent need for more structured reviews to draw evidence-based conclusions on the effectiveness of VM and learner's perceptions, in comparison to OM. The current study provides a descriptive summary of published outcomes using the systematic review approach. In conclusion, medical students' performance was improved with adoption of VM into the curriculum and recognized as a preferred learning modality, compared to OM. On the contrary, resident learners' performance was comparable between using OM and VM, with OM being the favored slide-viewing modality. PMID- 30414260 TI - Hypoglycaemia as a function of HbA1c in type 2 diabetes: Insulin glargine 300 U/mL in a patient-level pooled analysis of EDITION 1, 2 and 3. AB - Basal insulin therapy often involves a compromise between achieving glycaemic targets and avoiding hypoglycaemia, dependent on how intensively insulin is titrated. In the phase 3a EDITION 1, 2 and 3 studies, insulin glargine 300 U/mL (Gla-300) provided equivalent glycaemic control to insulin glargine 100 U/mL (Gla 100) with less hypoglycaemia in people with type 2 diabetes mellitus (T2DM). The current study evaluated the rates of confirmed (<=3.9 mmol/L [<=70 mg/dL]) or severe hypoglycaemia over 6 months of treatment with Gla-300 or Gla-100 in these EDITION studies, as a function of HbA1c . Analysis was performed on patient-level data pooled from the three EDITION studies, and annualized hypoglycaemia rate as a function of HbA1c at month 6 was fitted using a negative binomial regression model. People treated with Gla-300 experienced a consistently lower rate of confirmed (<=3.9 mmol/L [<=70 mg/dL]) or severe hypoglycaemia versus those treated with Gla-100, regardless of HbA1c at month 6. The results suggest that treatment with Gla-300 versus Gla-100 could allow people with T2DM to achieve equivalent glycaemic control with less hypoglycaemia. This article is protected by copyright. All rights reserved. PMID- 30414262 TI - Comparison of survival rate and crestal bone loss of narrow diameter dental implants versus regular dental implants: A systematic review and meta-analysis. AB - The aim of the present study was to establish survival rates, as well as crestal bone loss (CBL) of narrow diameter implants (NDI), compared to regular diameter implants (RDI). The current review followed the Enhancing the QUAlity and Transparency Of health Research guidelines and Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. We searched main databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane Oral Health Group Trials Register) for articles addressing the focused question up to and including May 2018. Meta-analyses were conducted for CBL and survival rates. Qualitatively, three clinical studies showed comparable CBL and survival rates between NDI and RDI at follow up. Only one study showed increased CBL around NDI compared to RDI. The overall weighted mean difference (WMD) for CBL (WMD = .06, 95% confidence interval [CI] = -.38-.51, P=.76) and risk difference for survival rate (risk difference = .88, 95% CI = .22-3.50, P=.85) were not significant between the NDI and RDI groups at follow up. NDI and RDI showed comparable CBL and survival rates. However, the findings of the present study should be interpreted with caution due to significant heterogeneity and the low number of included studies. Further randomized, controlled trials should be performed in order to obtain strong conclusions. PMID- 30414263 TI - EGFR confers radioresistance in human oropharyngeal carcinoma by activating endoplasmic reticulum stress signaling PERK-eIF2alpha-GRP94 and IRE1alpha-XBP1 GRP78. AB - The activation of epidermal growth factor receptor (EGFR) is associated with radioresistance in malignant tumors. Specifically, radiation can destroy endoplasmic reticulum (ER) homeostasis to induce ER stress (ERS). However, the effect of EGFR-mediated regulation of ERS signaling pathway on radiosensitivity has not yet been reported. The present study showed that silencing EGFR increased radiosensitivity of both radiosensitive and radioresistant oropharyngeal squamous cell carcinoma (OSCC) cells by inhibiting ER stress signaling (PERK-eIF2alpha GRP94 and IRE1alpha-XBP1-GRP78). This effect was abolished by pretreatment with EGF, however. In addition, knockdown of EGFR in OSCC cells inhibited DNA double stand break repair and autophagy while increased radiation-induced apoptosis. Conversely, activating ERS inhibited the aforementioned functions. Furthermore, EGF increased ER stress-independent ERK and AKT signaling upon irradiation of OSCC cells. Immunohistochemical analysis of 80 tissue samples from OSCC patients showed that co-expression of EGFR and PERK was associated with poor prognosis. It thus appears EGFR confers radioresistance in OSCC by activating ER stress signaling. These results suggested that the cooperative effects of radiotherapy and EGFR-targeted inhibitor therapy can be further improved by inhibiting PERK eIF2alpha-GRP94 and IRE1alpha-GRP78 in non-response oropharyngeal carcinoma patients. PMID- 30414265 TI - Regenology: Time for a New Specialty? PMID- 30414264 TI - Analysis of bacteriological pollution and the detection of antibiotic resistance genes of prevailing bacteria emanating from pig farm seepage. AB - Management and disposal of pig farm seepage constitute a serious environmental challenge, and seepage discharge from agricultural waste-water is considered to be one of the greatest contributors of organic substances, bacterial pathogens, and antibiotic resistance genes into the environment. The objectives of this study were to assess the level of bacteriological pollution and to identify the resident antibiotic-resistant genes of culturable bacteria from a studied pig farm seepage. Enumeration of the viable bacterial cell of plated bacteria suspensions (10-1 to 10-8 cfu/mL) was performed; also, identification of pure bacterial colonies was done using an API 20E bacterial identification kit. CLSI guidelines for antimicrobial susceptibility testing were adopted to determine the antibiotic susceptibility/resistance of the cultured bacterial isolates. Identification of resident-resistant genes was done using molecular biology procedures. The results on viable cells in seepage samples ranged from 4.30 * 102 to 1.29 * 109 cfu/mL. Pseudomonas luteola, Enterococcus vulneris, Salmonella choleraesuis spp arizonae, Escherichia coli, Enterobacter cloacae, Proteus mirabillis etc. were isolated from the pig farm soil samples. Almost all of the cultured isolates were resistant to Penicillin G, Vancomycin, Oxytetracycline, Spectinomycin, and Lincomycin. The most frequent resistant genes detected in the isolates were Van A, Van B, InuA, aph (3")-llla, blaTEM, Otr A, and Otr B. It was inferred from the study that Pig farm seepage has the ability to cause bacterial pollution that may negatively impact the natural environment, by introducing bacteria pathogens that harbor antibiotic-resistant genes. PMID- 30414266 TI - Active Learning of the Floor of Mouth Anatomy with Ultrasound. AB - More emphasis is now being placed on active learning in medical education. Ultrasound is an active learning tool that can be used to supplement didactic instruction. This study describes a self-guided activity for learning floor of mouth ultrasound. Thirty-three first year medical students learned floor of mouth scan technique and ultrasound anatomy through a brief PowerPoint module. They subsequently performed the scan on a standardized patient. Each student was asked to label the floor of mouth muscles on the image he or she acquired. After the activity, the students were given a quiz on anatomic relationships of the floor of mouth. Perceptions about the activity were collected through a survey. All 33 students obtained a floor of mouth image within a three minute time limit. Twenty four (73%) students were able to completely and accurately label the image in time. The mean score on the muscle relationships quiz was 93%. Overall perceptions were very positive with most students expressing a "high" or "very high" level of interest in incorporating similar self-guided activities within the curriculum. This study showed that it is feasible for students to learn scan technique and recognize relevant ultrasound anatomy in an independent fashion through a brief active learning module. Furthermore, the students found the activity enjoyable. The implication is that similar activities could be developed which would provide additional ways to incorporate active learning strategies. PMID- 30414267 TI - Effects of Erythromycin on the Proliferation and Apoptosis of Cultured Nasal Polyp-Derived Cells and the Extracellular Signal-Regulated Kinase (ERK)/Mitogen Activated Protein Kinase (MAPK) Signaling Pathway. AB - BACKGROUND Erythromycin and its derivatives have been used to treat nasal polyposis and reduce inflammation, but the mechanism of action remains unclear. The extracellular signal-regulated kinase (ERK) and mitogen-activated protein kinase (MAPK) pathway proteins are expressed in nasal polyps. The aim of this study was to investigate the effects of erythromycin on cell proliferation, apoptosis, and the expression of p-MEK1 and p-ERK1 on cultured nasal polyp derived cells. MATERIAL AND METHODS Nasal polyp-derived cells (n=32) and control cells from normal inferior turbinate tissue (n=32) were divided into four groups: the control group; the erythromycin-treated (100 MUM) group; the selumetinib treated (2 nM) group; and the erythromycin + selumetinib-treated group. Western blot was used to detect p-MEK1 and p-ERK1 proteins. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect mRNA expression of BCL-2 and BAX. Flow cytometry detected expression of Ki-67 and cell apoptosis. Cell apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Spectrophotometry assessed caspase-3 activity. RESULTS The expression of Ki-67 was significantly increased, and cell apoptosis was significantly reduced in untreated nasal polyp-derived cells compared with controls. Erythromycin treatment significantly decreased cell proliferation and the expression of p-MEK1 and p-ERK1, and increased apoptosis in nasal polyp derived cells compared with control cells. Selumetinib treatment had a synergistic effect with erythromycin to reduce the expression of p-MEK1 and p ERK1, reduce cell proliferation, and increase cell apoptosis. CONCLUSIONS In cultured cells derived from nasal polyps, erythromycin treatment reduced cell proliferation and increased apoptosis by inhibiting the activation of the ERK/MAPK signaling pathway. PMID- 30414268 TI - The influence of nuclear interactions on ionization chamber perturbation factors in proton beams: FLUKA simulations supported by a Fano test. AB - PURPOSE: In all recent protocols for the reference dosimetry of clinical proton beams ionization chamber perturbation factors are assumed to be unity. In this work, such factors were computed using the FLUKA Monte Carlo code for three ionization chamber types, with particular attention to the influence of nuclear interactions. METHODS: The accuracy of the transport algorithms implemented in FLUKA was first evaluated by performing a Fano cavity test. Ionization chamber perturbation factors were computed for the PTW-34001 Roos(r) and the PTW-34070 and PTW-34073 Bragg peak(r) chambers for proton beams of 60 to 250 MeV using the same transport parameters that were needed to pass the Fano test. RESULTS: FLUKA was found to pass the Fano test within 0.15%. Ionization chamber simulation results show that the presence of the air cavity and the wall results in dose perturbations of the order of 0.6% and 0.8%, respectively. The perturbation factors are shown to be energy dependent and nuclear interactions must be taken into account for accurate calculation of the ionization chamber's response. CONCLUSION: Ionization chamber perturbations can amount to 1% in high-energy proton beams and therefore need to be considered in dosimetry procedures. This article is protected by copyright. All rights reserved. PMID- 30414269 TI - Interventions for infantile haemangiomas of the skin: abridged Cochrane systematic review including GRADE assessments. AB - Infantile haemangiomas (IH) are soft swellings of the skin that occur in 3-10% of infants. When haemangiomas occur in high-risk areas or when complications develop, active intervention is necessary. This is an update of a Cochrane Review assessing the interventions for the management of IH in children. We searched for randomized controlled trials in CENTRAL, MEDLINE, Embase, LILACS, AMED, PsycINFO, CINAHL and six trials registers to February 2017. We included 28 trials (1728 participants) assessing 12 interventions. We downgraded evidence from high to moderate/low for issues related to risk of bias and imprecision. Oral propranolol (3 mg/kg/day) probably improves clinician-assessed clearance compared to placebo (risk ratio (RR) 16.61, 95% confidence interval (CI) 4.22 to 65.34; moderate quality of evidence (QoE)); we found no evidence of a difference in terms of serious adverse events (RR 1.05, 95% CI 0.33 to 3.39; low QoE). We found the chance of reduction of redness may be improved with topical timolol maleate (0.5% gel applied twice daily) when compared to placebo (RR 8.11, 95% CI 1.09 to 60.09; low QoE). We found no instances of bradycardia or hypotension for this comparison. Our key results indicate that oral propranolol and topical timolol maleate are more beneficial than placebo in terms of clearance or other measures of resolution, or both, without an increase in harms. This article is protected by copyright. All rights reserved. PMID- 30414271 TI - Assessing the ability of human endothelial cells derived from induced pluripotent stem cells to form functional microvasculature in vivo. AB - Forming functional blood vessel networks is a major clinical challenge in the fields of tissue engineering and therapeutic angiogenesis. Cell-based strategies to promote neovascularization have been widely explored, but cell sourcing remains a significant limitation. Induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) are a promising, potentially autologous, alternative cell source. However, it is unclear whether iPSC-ECs form the same robust microvasculature in vivo documented for other EC sources. In this study, we utilized a well-established in vivo model, in which endothelial cells (iPSC-EC or HUVEC) were co-injected with normal human lung fibroblasts (NHLFs) and a fibrin matrix into the dorsal flank of SCID mice to assess their ability to form functional microvasculature. Qualitatively, iPSC-ECs were capable of vessel formation and perfusion and demonstrated similar vessel morphologies to HUVECs. However, quantitatively, iPSC-ECs exhibited a two-fold reduction in vessel density and a three-fold reduction in the number of perfused vessels compared to HUVECs. Further analysis revealed the presence of COL-IV and aSMA were significantly lower around iPSC-EC/NHLF vasculature than in HUVEC/NHLF implants, suggesting reduced vessel maturity. Collectively, these results demonstrate the need for increased iPSC-EC maturation for clinical translation to be realized. This article is protected by copyright. All rights reserved. PMID- 30414270 TI - Malpresentation in low- and middle-income countries: associations with perinatal and maternal outcomes in the Global Network. AB - INTRODUCTION: Uncertainty exists regarding the impact of malpresentation on pregnancy outcomes and the optimal mode of delivery in low- and middle-income countries. We sought to compare outcomes between cephalic and non-cephalic pregnancies. MATERIAL AND METHODS: Using the NICHD Global Network's prospective, population-based registry of pregnancy outcomes from 2010-2016, we studied outcomes in 436,112 singleton pregnancies. Robust Poisson regressions were used to estimate the risk of adverse outcomes associated with malpresentation. We examined rates of cesarean delivery for malpresentation and compared outcomes between cesarean and vaginal delivery by region. RESULTS: Across all regions, stillbirth and neonatal mortality rates were higher among deliveries with malpresentation. In adjusted analysis, malpresentation was significantly associated with stillbirth (adjusted relative risk (aRR) 4.0, 95% confidence interval (CI); 3.7 to 4.5) and neonatal mortality (aRR 2.3, 95% CI; 2.1 to 2.6). Women with deliveries complicated by malpresentation had higher rates of morbidity and mortality. Rates of cesarean delivery for malpresentation ranged from 27% to 87% among regions. Compared to cesarean, vaginal delivery for malpresentation was associated with increased maternal risk, especially postpartum hemorrhage (aRR 5.0, 95% CI; 3.6 to 7.1). CONCLUSIONS: In a cohort of deliveries in low- and middle-income countries, malpresentation was associated with increased perinatal and maternal risk. Further research is needed to determine the best management of these pregnancies. This article is protected by copyright. All rights reserved. PMID- 30414272 TI - A novel calibration method incorporating non-linear optimization and ball-bearing markers for cone-beam CT with a parameterized trajectory. AB - PURPOSE: Cone-beam (CB) CT is a powerful non-invasive imaging modality, and is widely used in many applications. Accurate geometric parameters are essential for high-quality image reconstruction. Usually, a CBCT system with higher spatial resolution, particularly on the order of microns or nanometers, will be more sensitive to the parametric accuracy. Here we propose a novel calibration method combining a simple phantom containing ball bearing markers and an advanced optimization procedure. This method can be applied to CBCT with reproducible geometry and frame-to-frame invariant geometric parameters. METHODS: Our proposed simplex-simulated annealing procedure minimizes the cost function that associates the geometrical parameters with the degree to which the back-projections of the ball bearings in projections from various viewing angles converge, and the global minimum of the cost function corresponds to the actual geometric parameters. Specifically, six geometric parameters can be directly obtained by minimizing the cost function, and the last parameter, the distance from source to rotation axis (SRD), can be obtained using prior knowledge of the phantom - the spacing between the two ball bearings. RESULTS: Numerical simulation was performed to validate that the proposed method with various noise levels. With the proposed method, the mean errors and standard deviations can be reduced to ~ 10% and less than 1=3 of a competing benchmark method in the case of strong Gaussian noise (sigma = 200% of the pixel size) and large tilt angle (tilt angle = -4 degrees ). The calibration experiments with micro-CT and high-resolution CT scanners demonstrate that the proposed method recovers imaging parameters accurately, leading to superior image quality. CONCLUSION: The proposed method can obtain accurate geometric parameters of a CBCT system with a circular trajectory. While in the case of micro-CT the proposed method has a performance comparable to the competing method, for high-resolution CT, which is more sensitive to geometric calibration, the proposed method demonstrates higher calibration accuracy and more robustness than the benchmark algorithm. This article is protected by copyright. All rights reserved. PMID- 30414273 TI - Growth Kinetics and Mathematical Modeling of Synechocystis sp. PCC 6803 Under Flashing Light. AB - In photobioreactors and natural systems, microalgae are subjected to rapidly changing light intensities (LI) due to light attenuation and mixing. A controlled way to study the effect of rapidly changing LI is to subject cultures to flashing light. In this study, series of flashing-light experiments were conducted using Synechocystis sp. PCC6803 with constant overall average LI of ~84 MUmol m-2 s-1 , and relative times in the light and dark varied. The results were also compared to simulated results using a mathematical model including an absorbed pool of light energy, photoacclimation, and photoinhibition. With equal time in light and dark, the specific growth rate (MU) systematically decreased with increasing light duration, and u decreased further when the ratio of light to dark was decreased. The model captured both trends with the mechanistic explanation that when the light duration was very short, the changes in the pool of absorbed LI were smoothed out across the light and dark periods, whereas longer durations caused the biomass to experience discrete light and dark conditions that lead to reduced light absorption, more energy loss to non-photochemical quenching, and more photodamage. These growth effects were accentuated as the ratio of light to dark decreased. This article is protected by copyright. All rights reserved. PMID- 30414274 TI - Psoriasis in a cohort of patients with common variable immunodeficiency. AB - Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency in adults. CVID is characterized by reduced serum levels of IgG, IgA, and/or IgM, recurrent bacterial infections, autoimmune and inflammatory diseases and malignancies. According to literature, autoimmune diseases occur in 20-30% of CVID patients. Dermatological involvement has occasionally been reported in CVID and includes alopecia totalis, lichen planus, and vitiligo. Data regarding the frequency and features of psoriasis in CVID are scant. This article is protected by copyright. All rights reserved. PMID- 30414275 TI - Cosmetic benefit of a biomimetic lamellar cream formulation on barrier function or the appearance of fine lines and wrinkles in randomised proof-of-concept clinical studies. AB - OBJECTIVE: Two studies were designed to evaluate the potential cosmetic benefit of a biomimetic, niacinamide-containing moisturising cream for the first time in humans. METHODS: In both studies, healthy women were randomised to use two treatments, one for the left side of the body and one for the right, from three options: the test cream, a positive control or no treatment (use of standard cleanser only). Treatments were applied twice daily for 4 weeks to the face and forearms (Study 1) or the face only (Study 2). Instrumental and clinical skin assessments were performed by trained technicians. Study 1 involved tape stripping and a 5-day no-treatment ('regression') period at the end of the 4 weeks. Independent lay graders were asked to grade the skin texture of subjects in Study 2 from high-resolution photographs. RESULTS: In Study 1 (n=66), the test cream significantly decreased trans-epidermal water loss (TEWL) values on the forearm, and in the cheek area of the face, relative to baseline and compared to no treatment, and increased skin Corneometer values. The improvements were partially retained during a subsequent 5-day period of no treatment. Increases in TEWL values on skin subjected to tape stripping were significantly lower after 4 weeks of using the test cream compared to no treatment. In Study 2 (n=72 subjects with visible signs of ageing), there was a favourable trend in the change from baseline of a skin roughness parameter, Ra , for the test cream compared to no treatment. There were statistically significant improvements in the Fitzpatrick wrinkle score compared to no treatment, decreases in TEWL and increased Corneometer values and Cutometer values (R5 elasticity parameter). Grading of high-resolution images failed to detect improvement in skin texture (defined as pores, smoothness, and unevenness) for the test cream versus no treatment. No treatment-related serious or severe adverse events were reported. CONCLUSION: Twice daily application of the test cream over 4 weeks had beneficial effects on skin barrier function, moisturisation, wrinkle dimensions and elasticity compared to no treatment. These studies provide proof-of-concept evidence and highlight the cosmetic benefit of the biomimetic lamellar cream formulation. STUDY REGISTRATION: NCT03216265, NCT03180645. This article is protected by copyright. All rights reserved. PMID- 30414276 TI - MRI-guided Transurethral Insonation of Silica-shell Phase-shift Emulsions in the Prostate with an Advanced Navigation Platform. AB - PURPOSE: In this study, the efficacy of transurethral insonation of silica-shell ultrasound-triggered phase-shift emulsions (sUPEs) doped with MR contrast was evaluated. The influence of sUPEs on MR imaging assessment of the ablation zone was also investigated. METHODS: sUPEs were doped with a magnetic resonance (MR) contrast agent, Gd2 O3 , to assess ultrasound transition. Injections of saline (sham), saline and sUPEs alone, and saline and sUPEs with Optison microbubbles were performed under guidance of a prototype interventional MRI navigation platform in a healthy canine prostate. Treatment arms were evaluated for differences in lesion size, T1 -contrast, and temperature. In addition, non perfused areas (NPAs) on dynamic contrast-enhanced (DCE) MRI, 55 degrees C isotherms, and areas of 240 cumulative equivalent minutes at 43 degrees C (CEM43 ) dose or greater computed from MR thermometry were measured and correlated with ablated areas indicated by histology. RESULTS: For treatment arms including sUPEs, the computed correlation coefficients between the histological ablation zone and the NPA, 55 degrees C isotherm, and 240 CEM43 area ranged from 0.96 0.99, 0.98-0.99, and 0.91-0.99, respectively. In the absence of sUPEs, the computed correlation coefficients between the histological ablation zone and the NPA, 55 degrees C isotherm, and 240 CEM43 area were 0.69, 0.54, and 0.50, respectively. Across all treatment arms, the areas of thermal tissue damage and NPAs were not significantly different (p = 0.47). Areas denoted by 55 degrees C isotherms and 240 CEM43 dose boundaries were significantly larger than the areas of thermal damage, again for all treatment arms (p = 0.009 and 0.003, respectively). No significant differences in lesion size, T1 -contrast, or temperature were observed between any of the treatment arms (p > 0.0167). Lesions exhibiting thermal fixation on histological analysis were present in 6 of 9 insnonations involving sUPE injections and 1 of 5 insonations involving saline sham injections. Significantly larger areas (p = 0.002), higher temperatures (p = 0.004), and more frequent ring patterns of restricted diffusion on ex vivo diffusion-weighted imaging (p = 0.005) were apparent in lesions with thermal fixation. CONCLUSIONS: T1 contrast suggesting sUPE transition was not evident in sUPE treatment arms. The use of MR imaging metrics to predict prostate ablation was not diminished by the presence of sUPEs. Lesions generated in the presence of sUPEs exhibited more frequent thermal fixation, though there were no significant changes in the ablation areas when comparing arms with and without sUPEs. Thermal fixation corresponded to some qualitative imaging features. This article is protected by copyright. All rights reserved. PMID- 30414277 TI - Polhemus EM tracked Micro Sensor for CT-guided interventions. AB - PURPOSE: Electromagnetic (EM) tracking is a key technology in image-guided therapy. A new EM Micro Sensor was presented by Polhemus Inc.; it is the first to enable localization of medical instruments through their trackers. Different field generators (FGs) are available by Polhemus, one being almost as small as a sugar cube. As accuracy and robustness of tracking are known challenges to using EM trackers in clinical environments, the goal of this study was a standardized assessment of the Micro Sensor in both a laboratory (lab) and a computed tomography (CT) environment. METHODS: The Micro Sensor was assessed by means of Hummel et al.'s standardized protocol; it was assessed in conjunction with a Polhemus Liberty tracker and three FGs - with edge lengths of 1 (TX1), 2 (TX2), and 4 (TX4) inches. Precision as well as positional and rotational accuracy were determined in a lab and a CT suite. Distortions by four different metallic cylinders and tracking of two typical medical instruments - a hypodermic needle and a flexible endoscope - were also tested. RESULTS: A jitter of 0.02 mm or less was found for all FGs in the different environments, except for the TX2 FG for which no valid data could be obtained in the CT. Errors of 5 cm distance measurements were 0.6 mm or less for all FGs in the lab. While the distance errors of the TX1 FG were only slightly increased up to 1.6 mm in the CT, those of the TX4 FG were found to be up to around 10% of the measured distance (5.4 mm on average). The mean orientation error was found to be 0.9 degrees /0.5 degrees /0.1 degrees for the TX4/TX2/TX1 FG in the lab. In the CT environment, rotation errors were in the same range: less than 1.2 degrees /0.1 degrees for the TX4/TX1 FG. Deviation under the presence of metallic cylinders stayed below 1 mm in most cases. Precision and orientational accuracy do not seem to be affected by instrument tracking and stayed in the same range as for the other measurements whereas distance errors were slightly increased up to 1.7 mm. CONCLUSION: This study shows that accurate tracking of medical instruments is possible with the new Micro Sensor; it demonstrated a jitter of 0.01 mm or less, position errors below 2 mm, and rotation errors of less than 0.3 degrees . As with other EM trackers, errors increase when large tracking volumes with ranges of up to 50 cm are required in clinical environments. For smaller tracking volumes with ranges of up to 15 cm, a high accuracy and robustness was found. This is interesting especially for the TX1 FG which can easily be placed in close vicinity to the region of interest. PMID- 30414278 TI - Effect of zein additive on perfume evaporation. AB - OBJECTIVE: Zein is known to have filmogen properties. We wanted to show if a zein film containing eugenol (eugenol as model) would retain the fragrances, slow their evaporation and therefore produce a long lasting perception of perfume. METHODS: We added corn zein to eugenol in a hydro-alcoholic solution to form a film in vitro and at the surface of the human skin. We have studied the trapping and release of eugenol from zein film by GC/MS. Also we labeled eugenol with deuterium to image specifically its distribution in the zein film using Secondary Ion Mass Spectrometry technique (NanoSIMS 50). Finally, we applied the zein/D eugenol formulation onto skin to image the eugenol location on and in skin by SIMS. RESULTS: We showed that eugenol evaporation from zein film can be divided in three periods. The first period (<= 2 hours) corresponds to the simultaneous solvent and eugenol evaporation occurring during film formation. The second period corresponds to the continuous and slow eugenol evaporation during a few hours (about 10 hours) but not to its completion. The third period (at least up to 48 hours) results from the trapping of eugenol in zein film. After 24 or 48 hours, trapped eugenol can be released and evaporated under mechanical deformations of the film. Moreover we showed that zein addition does not favor the eugenol penetration into viable epidermis which may cause allergenic cutaneous reaction. CONCLUSION: The zein additive is safe to use, doesn't impact the olfactory perception, allows a better perception of the fragrance (long lasting effect) in a more protective way and can be used in perfume. This article is protected by copyright. All rights reserved. PMID- 30414279 TI - You can't get CMV from a blood transfusion: 2017 Emily Cooley award lecture. PMID- 30414280 TI - The analysis of human leukocyte antigen-G level in patients with endometrial cancer by Western blot technique. AB - PROBLEM: Aberrant expression of human leukocyte antigen-G (HLA-G) in various malignancies has been shown to participate in tumour development by suppressing immune regulation within the tumour microenvironment. The detection of HLA-G has reportedly been correlated with certain clinicopathological parameters in several neoplasms. Both the soluble and membranous forms of HLA-G are biologically active, and therefore, we aimed to evaluate the HLA-G level by Western blot technique. METHOD OF STUDY: The total amount of HLA-G protein was analyzed in the primary tumour in 113 tissue samples derived from patients with endometrial cancer. The HLA-G protein level was measured by Western Blot technique and was analyzed with respect to the clinicopathological parameters. RESULTS: Human leukocyte antigen-G protein levels were statistically significantly higher in the cancerous tissues derived from the women with advanced endometrial cancer than those from women with early stage disease. Moreover, we showed that endometrial cancer patients with lymph node metastases had statistically significantly higher HLA-G levels in the primary uterine tumour. CONCLUSION: The aberrant expression of HLA-G antigens by malignant cells could be one of the strategies tumour cells use to escape immune surveillance. The presence of HLA-G within the cancer nest and its microenvironment would seem to be linked to disease progression. PMID- 30414281 TI - Trifluoromethylation of Allenes: An Expedient Access to alpha-Trifluoromethylated Enones at Room Temperature. AB - A silver(I) catalyzed regioselective trifluoromethylation of allenes using Langlois salt NaOSOCF3 is demonstrated. This transformation enables direct expedient access to alpha-trifluoromethylated acroleins which are valuable synthons for a number of pharmaceuticals and agrochemicals containing vinyl-CF3 moieties. Versatility of this trifluoromethylation method has been established with good yield and excellent regioselectivity. Preliminary experiments and computational studies were carried out to elucidate the mechanistic insight of this protocol. PMID- 30414282 TI - Inhibition of dentin matrix-bound cysteine cathepsins by potassium fluoride. AB - Matrix metalloproteinases (MMPs) and cysteine cathepsins (CCs) can break down unprotected type I collagen fibrils in dentin matrix. This study investigated the use of potassium fluoride (KF) as a potential inhibitor of MMPs and CCs in dentin. Demineralized dentin beams were divided into groups (n = 10 in each group) and incubated in artificial saliva (AS, control), either alone or with one of seven concentrations of KF (6-238 mM fluoride) for 1, 7, and 21 d. After 21 d, all groups were further aged in AS for 6 months. Total MMP activity was screened using the colorimetric MMP assay. The activities of MMP-2 and MMP-9 were investigated using gelatin zymography. At the end of each incubation, changes in loss of dry mass and CC-mediated or total dissolution of collagen peptides were measured via precision weighing, C-terminal crosslinked telopeptide of type I collagen (CTX), and hydroxyproline (HYP) assays. The beams were examined using scanning electron microscopy. After 21 d, total MMP activities, dry mass loss, and CTX release for the groups exposed to 179 and 238 mM fluoride were significantly lower compared with the control group. After 6 months, all groups showed similar total MMP activity, dry mass loss, and HYP release, and CTX levels were significantly lower when the fluoride concentration was >=24 mM. Calcium fluoride (CaF2 )-like precipitates were observed over the beams. In summary, KF significantly inhibited the catalytic activity of dentin matrix-bound CCs but did not seem to be effective for MMP-mediated activity. PMID- 30414283 TI - Strikingly high levels of heterozygosity despite 20 years of inbreeding in a clonal honey bee. AB - Inbreeding (the mating between closely related individuals) often has detrimental effects that are associated with loss of heterozygosity at overdominant loci, and the expression of deleterious recessive alleles. However, determining which loci are detrimental when homozygous, and the extent of their phenotypic effects, remains poorly understood. Here, we utilise a unique inbred population of clonal (thelytokous) honey bees, Apis mellifera capensis, to determine which loci reduce individual fitness when homozygous. This asexual population arose from a single worker ancestor approximately 20 years ago, and has persisted for at least 100 generations. Thelytokous parthenogenesis results in a 1/3 of loss of heterozygosity with each generation. Yet, this population retains heterozygosity throughout its genome due to selection against homozygotes. Deep sequencing of one bee from each of the three known sub-lineages of the population revealed that 3,766 of 10,884 genes (34%) have retained heterozygosity across all sub-lineages, suggesting that these genes have heterozygote advantage. The maintenance of heterozygosity in the same genes and genomic regions in all three sub-lineages suggests that nearly every chromosome carries genes that show sufficient heterozygote advantage to be selectively detrimental when homozygous. This article is protected by copyright. All rights reserved. PMID- 30414284 TI - Egg OIT in clinical practice (SEICAP II): Maintenance patterns and desensitization state after normalizing the diet. AB - BACKGROUND: It is unknown which are the most suitable maintenance-pattern and egg consumption to maintain the desensitization state after ending the oral immunotherapy (OIT). This multicentre-randomized-controlled trial compared two maintenance OIT patterns with pasteurized-egg-white (PEW), evaluating the egg consumption effect on the desensitization state after ending the OIT. METHODS: One-hundred-one children with confirmed egg allergy were randomized: 25 to an egg free diet (CG) and 76 to an OIT year with PEW and two maintenance patterns, 38 patients daily 3.3g proteins (AG) and 38 every two days (BG). PEW challenge (DBPCFC), adverse reactions and immune markers were assessed at baseline, at the end of the OIT and 6 and 12 months later on ad libitum egg-consumption (T0, T12, T18, T24). A questionnaire evaluated the egg-consumption at T18. RESULTS: At T12, 64/76 (84.21%) OIT patients had reached total desensitization (32 AG, 32 BG) vs. 4/25 (16.00%) CG who passed the PEW-DBPCFC. Thirty patients (93.75%) AG vs. 25 (78.12%) BG completed an OIT year. At T18, 27/29 (93.1%) AG vs. 20/24 (83.3%) BG passed the PEW-DBPCFC, 96% consuming at least two egg-servings/week. At T24, 97.43% OIT patients passed the challenge. Most patients had adverse-reactions, more frequent in the BG patients; frequency and severity of reactions decreased through the study. PEW skin-prick-test weal and sIgE antibody serum levels similarly decreased in AG or BG, but AG patients had greater increase of PEW sIgG4 (p<.05). CONCLUSIONS: Daily OIT maintenance achieves better adherence, effectiveness and safety. Two egg-servings/week ensure maintained desensitization after the end of an OIT year. This article is protected by copyright. All rights reserved. PMID- 30414285 TI - Comprehensive strategy to reduce the incidence of lead dislodgement for cardiac implantable electronic devices. AB - BACKGROUND: Lead dislodgement (LD) is a well-recognized complication during implantation of cardiac implantable electronic devices (CIEDs). An intraprocedural protocol, referred to as reduction of LD protocol, was developed to reduce the risk of LD. METHODS: The protocol involved (1) inserting a straight stylet down the right atrial lead and applying forward pressure while monitoring for fluoroscopic stability, (2) visualizing all leads during deep inspiration to determine if there is adequate lead redundancy, and (3) having the patient take a deep breath and cough while pacing just at capture threshold to assess for loss of capture in each lead. Any intraprocedural change in the parameters fulfilling the predefined criteria for inadequate lead implantation prompted lead repositioning. Data regarding demographic factors, clinical characteristics, and incidence of LD in the first 30 days after implant was obtained from intramural CIED database. The preintervention (control) group spanned 27 months and consisted of a total of 4,294 leads while the postintervention (intervention) group spanned 17 months and consisted of 2,361 leads implanted. RESULTS: There was no significant difference in the demographic factors and clinical characteristics in the two groups. Protocol compliance was > 90%. There were 44 occurrences of LD (1.02%) before and 10 (0.4%) after implementation of the protocol. The protocol significantly reduced the incidence of LD during the 30 days after implant (P = 0.014). No clinical characteristic predicted the risk of LD. CONCLUSION: Intraprocedural maneuvers performed to assess the adequacy of lead implantation results in reduced risk of LD. PMID- 30414286 TI - Comparison of the Cervex-Brush alone to Cytobrush plus Cervex-Brush for detection of cervical dysplasia in women with a transformation zone type 3. AB - INTRODUCTION: Twenty percent of colposcopic assessments are inadequate due to a type 3 transformation zone (TZ3). In the absence of colposcopic or histological assessment, subsequent management is guided by the referral screening test. In the UK routine cervical screening is completed by a Cervex-Brush alone. This study examines the effectiveness of a cytobrush in addition to a standard Cervex Brush when used in TZ3 assessment. METHODOLOGY: An 18 month diagnostic accuracy study in a single NHS Trust. Women with a TZ3 booked for LLETZ with a referral cytology of high risk HPV and squamous dyskaryosis were recruited. Immediately prior to LLETZ a Cervex-Brush plus Cytobrush liquid-based cytology sample was taken. Presence of endocervical cells were compared. Predictability of CIN2+ was by blind standardised reporting of the LLETZ histology. RESULTS: One hundred and five women were recruited from a total eligible population of 153 cases (68.8%). Endocervical cell yield was increased with the Cervex-Brush plus Cytobrush when compared to the Cervex-Brush alone (99.1% vs 79.1%, p<0.001). Irrespective of cytological grade, age or parity, there was no difference in predictability of CIN2+ between sampling methods CONCLUSIONS: When compared to Cervex-Brush sampling alone, the addition of a Cytobrush improves endocervical sampling but does not improve cytological predictability of CIN2+ in women with a TZ3. These data suggest that women who will reliably attend for cytological follow-up can be safely referred to primary care for a Cervex-Brush alone. This article is protected by copyright. All rights reserved. PMID- 30414287 TI - Clinicopathological analysis of oral diffuse large B-cell lymphoma, NOS: A systematic review. AB - BACKGROUND: Diffuse large B-cell lymphoma, NOS (DLBCL NOS) is the commonest extranodal non-Hodgkin lymphoma diagnosed in the oral and maxillofacial region. However, few studies are currently available and its prognostic determinants remain undefined. PURPOSE: To analyse the available data on oral DLBCL NOS and to describe its clinicopathological features, identifying potential prognostic factors. METHODS: An electronic systematic search was performed using multiple databases with a specific search strategy in April 2018. All reports describing DLBCL NOS involving the oral cavity and jaw bones with sufficient clinicopathological information were assessed. RESULTS: Sixty-three publications were included in the study, comprising 122 cases. Oral DLBCL NOS was found predominantly in elderly males (61.5%), and most often presented as an asymptomatic swelling of the gingiva. Patients commonly were HIV-negative (36.1%), with few reports describing EBV-positive cases (four cases/3.3%). Only eight cases presented B symptoms and most cases were classified as stage I or II (48.4%). CHOP therapy was the main treatment option (24.5%) and the overall 5 year survival rate achieved 83%. Males and advanced Ann Arbor stage patients presented significantly lower survival rates in the univariate analysis, but no significance was found in the multivariate model. CONCLUSION: Oral DLBCL NOS is an aggressive malignancy, but with a high survival rate. PMID- 30414288 TI - Executive function subdomains are associated with poststroke functional outcome and permanent institutionalization. AB - BACKGROUND: Impairment of executive functions (EFs) is a common cognitive symptom poststroke and affects independence in daily activities. Previous studies have often relied on brief cognitive tests not fully considering the wide spectrum of EF subdomains. We used a detailed assessment of EFs to examine which of the subdomains and tests have the strongest predictive value on poststroke functional outcome and institutionalization in long-term follow-up. METHODS: A subsample of 62 patients from the Helsinki Stroke Aging Memory Study was evaluated with a battery of 7 neuropsychological EF tests 3 months poststroke and compared to 39 healthy control subjects. Functional impairment was evaluated with the modified Rankin Scale (mRS) and Instrumental Activities of Daily Living Scale (IADL) at 3 months, and with mRS at 15 months poststroke. Institutionalization was reviewed from the national registers of permanent hospital admissions in up to 21-year follow-up. RESULTS: The stroke group performed poorer than the control group in multiple EFs tests. Tests of inhibition, set shifting, initiation, strategy formation, and processing speed were associated with mRS and IADL in stroke paitients. EF subdomain scores of inhibition, set shifting and processing speed were associated with functional outcome. In addition, inhibition was associated with the risk for earlier institutionalization. CONCLUSIONS: EF was strongly associated with poststroke functional impairment. In follow-up, poor inhibition was related to earlier permanent institutionalization. Results suggest the prognostic value of EFs subdomains after stroke. This article is protected by copyright. All rights reserved. PMID- 30414289 TI - Association of Serum Galectin-3 with Risks of Death and Vascular Events in Acute Ischemic Stroke Patients: the Role of Hyperglycemia. AB - OBJECTIVE: Whether the association between galectin-3 and stroke outcome is modified by fasting plasma glucose (FPG) is unknown. We aimed to evaluate the prognostic effect of galectin-3 among ischemic stroke patients stratified by FPG. METHODS: 3082 ischemic stroke patients were included in this study and serum galectin-3 was tested at baseline. The primary outcome was a composite outcome of death and vascular events, and secondary outcomes were death, stroke recurrence and vascular events within one-year after stroke. RESULTS: Increased galectin-3 was significantly associated with the primary outcome, stroke recurrence and vascular events in the patients with hyperglycemia but not in those with normoglycemia (P for interaction < 0.05 for all). The multivariate adjusted hazard ratios (95% confidence intervals) were 1.72(1.05-2.84), 2.64(1.14-6012) and 2.68(1.33-5.38) for the primary outcome, stroke recurrence and vascular events, respectively. A linear association between galectin-3 and primary outcome was observed in hyperglycemic patients (P for linearity=0.007). CONCLUSION: Increased galectin-3 was associated with the primary outcome, stroke recurrence and vascular events within one-year after stroke in the patients with hyperglycemia, suggesting that galectin-3 may be an important prognostic factor for ischemic stroke patients with hyperglycemia. This article is protected by copyright. All rights reserved. PMID- 30414290 TI - RiSLnet: Rapid Identification of Smart Mutant Libraries using Protein Structure Network. Application to thermal stability enhancement. AB - A key point of protein stability engineering is to identify specific target residues whose mutations can stabilize the protein structure without negatively affecting the function or activity of the protein. Here, we propose a method, called RiSLnet (Rapid identification of Smart mutant Library using residue network), to identify such residues by combining network analysis for protein residue interactions, identification of conserved residues, and evaluation of relative solvent accessibility. To validate its performance, the method was applied to four proteins, i.e. T4 lysozyme, ribonuclease H, barnase, and cold shock protein B. Our method predicted beneficial mutations in thermal stability with ca. 62% average accuracy when the thermal stability of the mutants was compared to the ones in the Protherm database. It was further applied to lysine decarboxylase (CadA) to experimentally confirm its accuracy and effectiveness. RiSLnet identified mutations increasing the thermal stability of CadA with the accuracy of ca. 60% and significantly reduced the number of candidate residues (~99%) for mutation. Finally, combinatorial mutations designed by RiSLnet and in silico saturation mutagenesis yielded a thermally stable triple mutant with the half-life (T1/2 ) of 114.9 min at 58 degrees C, which is approximately two-fold higher than that of the wild-type. This article is protected by copyright. All rights reserved. PMID- 30414291 TI - The association between blood donor sex and age and transfusion recipient mortality: an exploratory analysis. AB - BACKGROUND: There is recent support for long-term adverse effects of donor recipient sex-mismatched red blood cell (RBC) transfusion, but short-term impact is unknown. A retrospective exploratory analysis was performed using data from a research database. METHODS: Adults admitted to hospitals in one Canadian center who received RBCs (2008-2014 [3 sites]; 2012-2014 [1 site]) were eligible. Patient data were extracted from a research database and donor data from the blood supplier. Cox regression models were used, with control of risk and confounding variables as covariates or using stratification. Exposure was defined by mutually exclusive categories. The outcome was in-hospital mortality. RESULTS: A total of 25,219 adults received 97,886 RBCs. Diagnoses included cardiovascular (28.8%), neoplastic (15.6%), traumatic (15.4%), or gastrointestinal (10.5%); 56.3% of transfused RBCs were male donors, and median donor age was 45 years (interquartile range, 30-54). Female patients exposed to male RBCs experienced a higher risk of in-hospital death (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.02-1.69; p = 0.038) compared to exclusive female RBC exposure. Exposure to RBCs from donors aged 45 years or younger was associated with a higher in-hospital death (HR, 1.21; 95% CI, 1.02-1.44; p = 0.026) compared to exclusive RBC exposure to donors older than 45 years. Donor-recipient sex mismatched RBC exposure (vs. exclusively sex-matched) and RBC exposure from donors aged 45 years or younger (vs. exclusively RBCs from donors >45) were associated with increased mortality: sex-mismatched (HR, 1.23; (95% CI, 1.04 1.45; p = 0.017); donors aged 45 years or younger (HR, 1.21; (95% CI, 1.02-1.43; p = 0.031). CONCLUSION: Donor-recipient sex-matched RBC transfusions and transfusions from older donors may benefit patients. PMID- 30414292 TI - Interleukin-37 inhibits osteoclastogenesis and alleviates inflammatory bone destruction. AB - Excessive osteoclast formation is one of the important pathological features of inflammatory bone destruction. Interleukin-37 (IL-37) is an anti-inflammatory agent that is present throughout the body, but it displays low physiological retention. In our study, high levels of the IL-37 protein were detected in clinical specimens from patients with bone infections. However, the impact of IL 37 on osteoclast formation remains unclear. Next, IL-37 alleviated the inflammatory bone destruction in the mouse in vivo. We used receptor activator of nuclear factor-kappaB ligand and lipopolysaccharide to trigger osteoclastogenesis under physiological and pathological conditions to observe the role of IL-37 in this process and explore the potential mechanism of this phenomenon. In both induction models, IL-37 exerted inhibitory effects on osteoclast differentiation and bone resorption. Furthermore, IL-37 decreased the phosphorylation of inhibitor of kappaBalpha and p65 and the expression of nuclear factor of activated T cells c1, while the dimerization inhibitor of myeloid differentiation factor 88 reversed the effects. These data provide evidence that IL-37 modulates osteoclastogenesis and a theoretical basis for the clinical application of IL-37 as a treatment for bone loss-related diseases. PMID- 30414293 TI - Identification of the first Crocodylus siamensis cathelicidin gene and RN15 peptide derived from cathelin domain exhibiting antibacterial activity. AB - Cathelicidins are effector molecules of vertebrate immunity that play vital roles against microbial invasion. They are widely identified in mammals, but few have been reported in Crocodilians, which are considered to be species with a powerful immune system. In the present study, we identified and characterized a novel cathelicidin from the blood of the Siamese crocodile, Crocodylus siamensis. A cDNA sequence (501 base pair) encoded a predicted 166-residue prepropeptide of C. siamensis cathelicidin (Cs-CATH), which comprised a 21-residue signal peptide, a 109-residue cathelin domain, and a 36-residue mature cathelicidin peptide. Multiple sequence alignment and phylogenetic analysis demonstrated that Cs-CATH shared a high degree of similarity with other crocodilian cathelicidins. Joint consideration of elastase cleavage site, physicochemical properties, and predicted secondary structure demonstrated that RN15 peptide is a candidate antimicrobial peptide derived from Cs-CATH. The synthetic RN15 peptide demonstrates antimicrobial activity against Gram-positive and Gram-negative bacteria. Scanning electron microscopy illustrated RN15-peptide-induced bacteria cells exhibited morphological change. Besides, RN15 peptide demonstrates low hemolytic activity against human erythrocytes and low cytotoxic activity against normal human dermal fibroblasts. This is the first cathelicidin identified from C. siamensis, and it is highlighted that its derived peptide from cathelin domain promises potent novel peptide antibiotics templates. PMID- 30414294 TI - Spiropyran-based Nanocarrier: A New Zn2+-Responsive Delivery System with Real Time Intracellular Sensing Capabilities. AB - A new spiropyran-based stimuli-responsive delivery system is presented that encapsulates and then releases an extraneous compound in response to elevated levels of Zn2+, a critical factor in cell apoptosis. A C12-alkyl substituent on the spiropyran promotes self-assembly into a micelle-like nanocarrier in aqueous media, with nanoprecipitation and encapsulation of added payload. Zn2+ binding occurs to an appended bis(2-pyridylmethyl)amine group at biologically relevant micromolar concentration. This leads to switching of the spiropyran (SP) isomer to the strongly fluorescent ring opened merocyanine-Zn2+ (MC-Zn2+) complex, with associated expansion of the nanocarriers to release the encapsulated payload. Payload release is demonstrated in solution and in HEK293 cells by encapsulation of a blue fluorophore, 7-hydroxycoumarin, and monitoring its release using fluorescence spectroscopy and microscopy. Furthermore, we demonstrate the use of the nanocarriers to deliver a caspase inhibitor, Azure B, into apoptotic cells in response to an elevated Zn2+ concentration. This then inhibits intracellular caspase activity, as evidenced by confocal microscopy and in real-time by time lapsed microscopy. Finally, the nanocarriers are shown to release an encapsulated proteasome inhibitor (5) in Zn2+-treated breast carcinoma cell line models. This then inhibits intracellular proteasome and induces cytotoxicity to the carcinoma cells. PMID- 30414295 TI - An unusual case of Nocardia cyriacigeorgica presenting with spinal abscesses in a renal transplant recipient and a review of the literature. AB - Nocardia species represent a well-recognized yet uncommon cause of opportunistic infections in humans. It most frequently presents as a pulmonary infection with or without central nervous system involvement. It is a very rare cause of spinal abscesses, with only 26 cases reported in the literature. Here we report a 49 year-old man with a history of renal transplantation who presented with low back pain and was diagnosed with epidural and paraspinal abscesses due to Nocardia cyriacigeorgica that was successfully treated with antimicrobial therapy alone. In addition to the case reported here, we also conducted a systematic review of the existing literature regarding spinal abscesses due to Nocardia species and examined the success of the various treatments utilized. PMID- 30414296 TI - Mixed hemimicelle magnetic dispersive solid-phase extraction using carbon-coated magnetic nanoparticles for the determination of tramadol in urine samples. AB - Ionic liquid carbon-coated magnetic nanoparticles were successfully applied as an adsorbent in a mixed hemimicelle magnetic dispersive solid-phase extraction method for the determination of tramadol from urine samples coupled with high performance liquid chromatography with UV-vis detection. The significant parameters affect the extraction efficiency including type and amount of adsorbent, sample volume, pH, ionic strength, type and amount of elution solvent, time of extraction and desorption, time of ionic liquid loading on the adsorbent and stirring rate were studied and optimized. The proposed method provided a fast, straightforward, environmentally friendly and adsorbent recyclable approach for tramadol analysis. The linear range for the tramadol determination was from 100 to 1500 ng/mL. Precisions and accuracies were within 6%. The applicability of the proposed method in clinical trial was tried successfully on determination of tramadol in addicted subjects under tramadol therapy. The mean percent recovery of the patient samples was 94%. The results proved that the proposed method could be applied in clinical and forensic laboratories for determination of tramadol from biological urine samples. PMID- 30414297 TI - Increased rate of acute caesarean sections in women with epilepsy: Results from Oppland Perinatal Database in Norway. AB - BACKGROUND: Studies in women with epilepsy (WWE) regarding pregnancy and labour complications have disclosed contradictory results. Our purpose was to investigate whether WWE have a higher risk of acute caesarean section (CS) or pregnancy complications than women without epilepsy or women with other chronic diseases, and if we found a higher risk, explore potential explanations. METHODS: The study used prospectively registered obstetric data from Oppland Perinatal Database in the period 2001 - 2011, containing information on 18 244 births, including 110 singleton pregnancies in mothers with validated epilepsy. Data regarding epilepsy were collected retrospectively from medical records. RESULTS: Epilepsy was a significant risk factor for acute CS, breech presentation and low birth weight in offspring (respectively OR 1.93 (95% CI 1.2-3.1), OR 2.29 (95% CI 1.2-4.6), and OR 2.10 (95% CI 1.0-4.2). In multivariate logistic regression analysis, antiepileptic drug-exposure was an independent risk factor for acute CS (OR 2.00, 95% CI 1.06-3.77) and polytherapy was a significant risk factor for breech presentation (OR 5.37, 95% CI 1.13-25.57). Seizure frequency during pregnancy had no influence on the complication rate. CONCLUSION: We found that women with epilepsy using AEDs during pregnancy have increased rate of acute CS, breech presentation and low birth weight, and that seizure frequency during pregnancy did not influence the complication rate. This article is protected by copyright. All rights reserved. PMID- 30414298 TI - Dual Antiplatelet Therapy Reduced Stroke Risk in High-risk Transient Ischemic Attack Patients Assessed by ABCD3-I Score. AB - BACKGROUND: Several clinical trials demonstrated that dual antiplatelet therapy benefited TIA patients with an ABCD2 score >=4. The present study aims to investigate whether the ABCD3-I score could be a more appropriate tool for TIA patients' selection to use dual antiplatelet therapy in real-world experience. METHODS: We derived data from the TIA database of the First Affiliated Hospital of Zhengzhou University. The predictive outcome was ischemic stroke at 90-day. The additive interaction effect was presented by the attributable proportion due to interaction (AP). The Kaplan-Meier curves were plotted to present cumulative stroke rates in different risk categories with monotherapy and dual antiplatelet therapy. Cox proportional hazards regression was used to determine risk factors associated with stroke. RESULTS: Among 785 patients, the mean (SD) age was 56.95 (12.73) years, 77 patients (9.8%) had an ischemic stroke at 90-day. A percentage of 55.8 patients (AP, 95%confidence interval [CI], 20.8%-90.9%) were attributed to additive interaction of ABCD3-I score and antiplatelet therapy. The Kaplan Meier curves showed a significant difference between patients with monotherapy and dual antiplatelet therapy in high-risk TIA patients (p= 0.021). Dual antiplatelet therapy reduced 90-day stroke risk in high-risk TIA patients assessed by ABCD3-I score independently (adjusted hazard ratio [HR] =0.43, 95%CI, 0.20-0.92, p= 0.031). The benefit did not exist in the low- and median-risk patients by ABCD3-I score, patients with ABCD2 >=4, or <4. CONCLUSIONS: High-risk TIA patients assessed by ABCD3-I score received the most pronounced clinical benefit from early use of dual antiplatelet therapy in the real-clinical experience. This article is protected by copyright. All rights reserved. PMID- 30414299 TI - Clinical course of multiple sclerosis and labor-force absenteeism: a longitudinal population-based study. AB - BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is a chronic neurological disease associated with substantial disability and morbidity. The objective of our study was to assess long-term consequences of MS clinical course on sick leave and disability pension. METHODS: Patients with relapse-remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS) were identified through the Swedish Multiple Sclerosis Registry. We calculated the mean annual prevalence and number of sick leave and disability pension days by clinical course, age, and year pre and post diagnosis, and compared outcomes using Welch's t-tests and analysis-of-variance models, mixed-effects regression, and survival analysis. RESULTS: The sample included 5,371 patients (4,568 with RRMS, 390 with SPMS, and 413 with PPMS). The mean annual number of days with sick leave and disability pension ranged from 101 one year after diagnosis to 164 after 11 years for patients with RRMS. Corresponding estimates for PPMS were 188 and 311 days. Higher levels of absenteeism were observed in patients with PPMS versus RRMS seven years before diagnosis for sick leave (p<0.025) and 10 years for disability pension (p<0.034). Differences between SPMS and PPMS were minor. CONCLUSIONS: Patients with RRMS have substantially lower levels of sick leave and disability pension over time compared with their counterparts with SPMS and PPMS, while labour-force absenteeism is similar for patients with SPMS and PPMS. These findings contribute to the understanding of the impact of MS on socio-economic outcomes and help inform the discussion on the clinical classification of different courses of the disease. This article is protected by copyright. All rights reserved. PMID- 30414300 TI - Sapienza Global Bedside Evaluation of Swallowing after Stroke: the GLOBE-3S study. AB - BACKGROUND AND PURPOSE: Dysphagia occurs in up to 50% of all patients with acute stroke. There is debate regarding which is the most effective screening tool in identifying aspiration in patients with acute stroke. We assessed the accuracy of the Sapienza Global Bedside Evaluation of Swallowing after Stroke (GLOBE-3S), which combines the Toronto Bedside Swallowing Screening Test (TOR-BSST(c)) with oxygen desaturation and laryngeal elevation measurement during swallowing. METHODS: We prospectively enrolled consecutive patients with stroke within 72 h of symptom onset. All patients with stroke firstly underwent a standard neurological examination, then the GLOBE-3S evaluation and finally the fiberoptic endoscopic evaluation of swallowing (FEES). Two different assessors, a neurologist and a speech pathologist, blind to both the clinical data and each other's evaluation, administered the GLOBE-3S and FEES examination. We assessed the accuracy of the GLOBE-3S in detecting post-stroke swallow impairment with aspiration using the FEES as the standard. RESULTS: We enrolled 50 patients with acute stroke, 28 of whom (56%) had swallowing impairment with aspiration at FEES evaluation. A total of 33 patients (66%) failed the GLOBE-3S evaluation. The GLOBE-3S reached a sensitivity of 100% and a specificity of 77.3% (negative predictive value, 100%; positive likelihood ratio, 4.34). The median time required for the GLOBE-3S to be performed was 297 s. CONCLUSIONS: GLOBE-3S is quick to perform at the bedside and can accurately identify aspiration in patients with acute stroke. By including the measurement of laryngeal elevation and monitoring of oxygen desaturation, it could represent a highly sensitive instrument to avoid the misdiagnosis of silent aspirators. PMID- 30414301 TI - Comparing Two Classification Schemes for Seizures and Epilepsy in Rural China. AB - BACKGROUND: The International League Against Epilepsy (ILAE) updated the classifications of seizures and epilepsies in 2017. We compared the 2017 classifications with the 1980's classifications in rural China. METHODS: People with epilepsy were recruited from rural areas in China receiving treatment under the National Epilepsy Control Programme. Their seizures and epileptic syndrome were classified using the 1980's ILAE classification system and then re classified according the 2017 system. Differences in seizure, epilepsy and aetiology classifications were identified. RESULTS: A total of 597 individuals (58% males, aged 6-78 years) were included. Among them 535 (90%) had a single seizure type, 57 (9.55%) had two types, and five (0.84%) had three. There was complete agreement between the 1981 and 2017 classifications for the 525 individuals with focal seizures. Seizures originally classified as generalised in 10 of 65 individuals were re- classified as unknown in the 2017 classifications. Compared to the 1980's classifications, the proportion of individuals with unknown seizures and unknown epilepsy increased from 1.2% (7/597) to 2.8% (17/597, p=0.002), and unknown aetiology increased from 32% (189/597: 182 cryptogenic and seven unclassified) to 39% (230/597; p<0.001) in the 2017 classifications. CONCLUSIONS: The 1980's and 2017 classifications had 100% agreement in classifying focal seizures and epilepsy in rural China. A small but significant proportion of generalised seizures and epilepsy and aetiologies classified in the old classifications were re-classified to unknown in the new classifications. These results highlight the need for improvement in clinical evaluation of people with epilepsy in resource-poor settings. This article is protected by copyright. All rights reserved. PMID- 30414303 TI - Live Donor Liver Transplantation Using Selected Grafts with Two Bile Ducts compared to One Bile Duct Does Not Impact on Patient Outcome. AB - We read with great interest the article from the Toronto group showing similar results with grafts with one or more bile ducts in living donor liver transplantation (LDLT). (1) However, one should take this message cautiously as intuitively a graft with one duct is preferred by most surgeons. Some previous studies have demonstrated that multiple bile ducts were significant independent risk factor for development of biliary complications with no difference in patient survival when compared with single duct in pediatric LT. This article is protected by copyright. All rights reserved. PMID- 30414302 TI - Hemorrhagic transformation after stroke: Interrater and intrarater agreement. AB - BACKGROUND: Hemorrhagic transformation (HT) is a complication of stroke that can occur spontaneously or after treatment. We aimed to assess the interrater and intrarater reliability of HT diagnosis. METHODS: Studies assessing the reliability of the European Cooperative Acute Stroke Study (ECASS) classification of HT or of the presence (yes/no) of HT were systematically reviewed. Eighteen raters independently examined 30 post-thrombectomy computed tomography scans selected from the Aspiration versus Stentriever (ASTER) trial. They were asked whether there was HT (yes/no), what the ECASS classification of the particular scan (0/HI1/HI2/PH1/PH2) was, and whether they would prescribe an antiplatelet agent if it was otherwise indicated. Agreement was measured with Fleiss' and Cohen's kappa statistics. RESULTS: The systematic review yielded 4 studies involving few (<=3) raters with heterogeneous results. In our 18-rater study, agreement for the presence of HT was moderate (kappa=0.55, 95%CI [0.41-0.68]). Agreement for ECASS classification was only fair for all 5 categories, but agreement improved to substantial (k=0.72, 95%CI [0.69-0.75]) after dichotomizing ECASS into 0/HI1/HI2/PH1 versus PH2. The interrater agreement for the decision to reintroduce antiplatelet therapy was moderate for all raters, but substantial among vascular neurologists (kappa=0.70 [0.57-0.84]). CONCLUSION: The ECASS classification may involve too many categories and the diagnosis of HT may not be easily replicable, except in the presence of a large parenchymal hematoma. This article is protected by copyright. All rights reserved. PMID- 30414305 TI - Domestication and crop evolution of wheat and barley: Genes, genomics, and future directions. AB - Wheat and barley are two of the founder crops of the agricultural revolution that took place 10,000 years ago in the Fertile Crescent and both crops remain among the world's most important crops. Domestication of these crops from their wild ancestors required the evolution of traits useful to humans, rather than survival in their natural environment. Of these traits, grain retention and threshability, yield improvement, changes to photoperiod sensitivity and nutritional value are most pronounced between wild and domesticated forms. Knowledge about the geographical origins of these crops and the genes responsible for domestication traits largely pre-dates the era of next-generation sequencing, although sequencing will lead to new insights. Molecular markers were initially used to calculate distance (relatedness), genetic diversity and to generate genetic maps which were useful in cloning major domestication genes. Both crops are characterized by large, complex genomes which were long thought to be beyond the scope of whole-genome sequencing. However, advances in sequencing technologies have improved the state of genomic resources for both wheat and barley. The availability of reference genomes for wheat and some of its progenitors, as well as for barley, sets the stage for answering unresolved questions in domestication genomics of wheat and barley. PMID- 30414304 TI - Next-generation amplicon TRB locus sequencing can overcome limitations of flow cytometric Vbeta expression analysis and confirms clonality in all T-cell prolymphocytic leukemia cases. AB - T-cell receptor (TCR) beta repertoire analysis can distinguish monoclonal from polyclonal T-cell proliferations and crucially aid in the diagnosis of T-cell malignancies. TCR repertoire can be assessed either by flow cytometry (FCM), or by molecular genetic techniques. We compared the results of parallel analyses of Vbeta expression by FCM and TRB rearrangements by DNA-based next-generation sequencing (NGS) in 80 diagnostic peripheral blood samples of patients with T cell prolymphocytic leukemia (T-PLL) for (1) the diagnosis of clonality and (2) the assessment of dominant Vbeta usage. FCM-based analysis of the surface expression was performed using the IOTest Beta Mark kit. The NGS-based analysis employed the multiplex Biomed-2 VB-JB primers. In all the samples, one or two clonal TRB rearrangements were detected by NGS. Although a dominant Vbeta domain usage was detected by FCM in only 41/80 (51%) samples, clonality was suspected in all of them. In a total of 12 cases, the FCM missed the clone detected by NGS, despite theoretical coverage by the antibodies, the functionality of the rearrangement, and the expression of TCRalphabeta on the cell surface. Partly overlapping with those cases, FCM discovered predominant Vbeta usage in the T-PLL population that differed from the one detected by NGS in 10 cases. Overall, the concordant NGS and FCM results were obtained on 61/80 (76%) of samples. We conclude that NGS-based TRB analysis can overcome certain limitations of FCM based analysis by the identification of both productive and nonproductive rearrangements and by covering the whole Vbeta spectrum. Currently available FCM analysis of Vbeta expression lacks this breadth but has advantages, such as parallel immunophenotyping and a more accurate quantification of the Vbeta usage. (c) 2018 International Society for Advancement of Cytometry. PMID- 30414306 TI - GRAIN LENGTH AND AWN 1 negatively regulates grain size in rice. AB - Grain size is an important factor determining yield in rice. Here, we identified a recessive mutant gene, grain length and awn 1 (gla1), which caused a significant increase in grain length and weight, and was associated with long awns. The gla1 mutation was mapped to a single-nucleotide polymorphism in a gene encoding a cytoplasmically-localized mitogen-activated protein kinase (MAPK) phosphatase. Overexpression of GLA1 caused a decrease in grain length, and the GLA1 protein interacted with OsMAPK6. These results suggest that GLA1 may serve as a negative regulator of the OsMAPKK4-OsMAPK6 cascade, controlling grain size via the dephosphorylation of OsMAPK6. PMID- 30414307 TI - Sediment deposition from eroding peatlands alters headwater invertebrate biodiversity. AB - Land use and climate change are driving widespread modifications to the biodiverse and functionally unique headwaters of rivers. In temperate and boreal regions, many headwaters drain peatlands where land management and climate change can cause significant soil erosion and peat deposition in rivers. However, effects of peat deposition in river ecosystems remain poorly understood. We provide two lines of evidence-derived from sediment deposition gradients in experimental mesocosms (0-7.5 g/m2 ) and headwaters (0.82-9.67 g/m2 )-for the adverse impact of peat deposition on invertebrate community biodiversity. We found a consistent negative effect of sediment deposition across both the experiment and survey; at the community level, decreases in density (1956 to 56 individuals per m2 in headwaters; mean 823 +/- 129 (SE) to 288 +/- 115 individuals per m2 in mesocosms) and richness (mean 12 +/- 1 to 6 +/- 2 taxa in mesocosms) were observed. Sedimentation increased beta diversity amongst experimental replicates and headwaters, reflecting increasing stochasticity amongst tolerant groups in sedimented habitats. With increasing sedimentation, the density of the most common species, Leuctra inermis, declined from 290 +/- 60 to 70 +/- 30 individuals/m2 on average in mesocosms and >800 individuals/m2 to 0 in the field survey. Traits analysis of mesocosm assemblages suggested biodiversity loss was driven by decreasing abundance of invertebrates with trait combinations sensitive to sedimentation (longer life cycles, active aquatic dispersal of larvae, fixed aquatic eggs, shredding feeding habit). Functional diversity metrics reinforced the idea of more stochastic community assembly under higher sedimentation rates. While mesocosm assemblages showed some compositional differences to surveyed headwaters, ecological responses were consistent across these spatial scales. Our results suggest short-term, small-scale stressor experiments can inform understanding of "real-world" peatland river ecosystems. As climate change and land-use change are expected to enhance peatland erosion, significant alterations to invertebrate biodiversity can be expected where these eroded soils are deposited in rivers. PMID- 30414309 TI - Regulating a key mitotic regulator, Polo-like Kinase 1 (PLK1). AB - During cell division, duplicated genetic material is separated into two distinct daughter cells. This process is essential for initial tissue formation during development and to maintain tissue integrity throughout an organism's lifetime. To ensure the efficacy and efficiency of this process, the cell employs a variety of regulatory and signaling proteins that function as mitotic regulators and checkpoint proteins. One vital mitotic regulator is polo-like kinase 1, or PLK1, a highly conserved member of the polo-like kinase family. Unique from its paralogues, it functions specifically during mitosis as a regulator of cell division. PLK1 is spatially and temporally enriched at 3 distinct sub-cellular locales; the mitotic centrosomes, kinetochores, and the cytokinetic midbody. These localization patterns allow PLK1 to phosphorylate specific downstream targets to regulate mitosis. In this review, we will explore how polo-like kinases were originally discovered and diverged into the 5 paralogues (PLK1-5) in mammals. We will then focus specifically on the most conserved, PLK1, where we will discuss what is known about how its activity is modulated, its role during the cell cycle, and new, innovative tools that have been developed to examine its function and interactions in cells. This article is protected by copyright. All rights reserved. PMID- 30414308 TI - Identification of a variant associated with early-onset diabetes in the intron of the insulin gene with exome sequencing. AB - Whole-exome sequencing is a new technology. We used it to explore the gene responsible for early-onset diabetes as a result of impaired insulin secretion in a family. In the INS gene, we identified the heterozygous c.188-31G>A mutation in the proband - a 43-year-old woman. The mutation was also identified in her two daughters with diabetes, but not in her son or her parents, all of whom did not have diabetes. The substitution was located 31 bp proximal to exon 3 in intron 2. It was predicted to create an ectopic splice site leading to inserting 29 nucleotides of intron 2 as an exonic sequence in the transcript. The mutation has been reported in White families, and the present case is the first report in an Asian person. The present results would help in understanding the role of the mutation in developing diabetes. PMID- 30414311 TI - Imaging Brain Tissue Slices with Terahertz Near-Field Microscopy. AB - Photoconductive antenna microprobe (PCAM)-based terahertz (THz) near-field imaging technique is promising for biomedical detection due to its excellent biocompatibility and high resolution yet it is limited by its imaging speed and the difficulty in the control of the PCAM tip-sample separation. In this work, we successfully realized imaging of mouse brain tissue slices using an improved home built PCAM-based THz near-field microscope. In this system, the imaging speed was enhanced by designing and applying a voice coil motor-based delay-line. The tip sample separation control was implemented by developing an image analysis-based technique. Compared with conventional PCAM-based THz near-field systems, our improved system is 100 times faster in imaging speed and the tip-sample separation can be controlled to a few micrometers (e.g., 3 MUm), satisfying the requirements of THz near-field imaging of biological samples. It took about ~30 min (not the tens of hours it took to acquire the same kind of image previously) to collect a THz near-field image of brain tissue slices of BALb/c mice (500 MUm * 500 MUm) with pixel size of 20 MUm * 20 MUm. The results show that the mouse brain slices can be properly imaged and different regions in the slices (i.e., the corpus callosum region and the cerebrum region) can be identified unambiguously. Evidently, the work demonstrated here provides not only a convincing example but a useful technique for imaging biological samples with THz near-field microscopy. This article is protected by copyright. All rights reserved. PMID- 30414310 TI - Emergence of novel recombination lineage 3 of porcine reproductive and respiratory syndrome viruses in Southern China. AB - Lineage 3 of porcine reproductive and respiratory syndrome viruses, which belong to North America type 2, has a long epidemic history in China. The novel lineage 3 viruses constantly emerging in recent years are characterized by a high detection rate and significant pathogenicity. In this study, we investigated the prevalence of lineage 3 in southern China and selected two isolated strains for genome and virulence analyses. A cross-sectional epidemiology investigation indicated that the prevalence of lineage 3 antigens was 35.68% (95% CI: 27.6 44.3%) among 227 samples collected from over 100 infected farms from January 2016 to July 2017 in southern China. Two novel isolates of lineage 3 were selected. After 20 passages, Marc-145 cells were not susceptible to those viruses. Full length genome analysis indicated that the two strains share 95.2% homology with each other and 95.7%-96.2% with highly pathogenic porcine reproductive and respiratory syndrome viruses (HP-PRRSVs; JXA1-like strain, lineage 8.7). Phylogenetic and molecular evolutionary results showed that for the two isolates, HP-PRRSV provides most of the ORF1 gene. Animal experiment revealed discrepancies in virulence between the strains. Although challenge resulted in 100% morbidity, the isolate carrying most of the HP-PRRSV ORF1 caused severe clinical symptoms and 40% mortality, whereas the other isolate containing part of the ORF1 gene caused no mortality. Overall, these findings suggest that lineage 3 viruses might be commonly circulating in most of southern China. Frequent recombination events within HP-PRRSVs of this lineage with changing virulence could represent potential threats to the pig industry. PMID- 30414312 TI - nanoDSF as screening tool for enzyme libraries and biotechnology development. AB - Enzymes are attractive tools for synthetic applications. To be viable for industrial use, enzymes need sufficient stability towards the desired reaction conditions such as high substrate and cosolvent concentration, non-neutral pH and elevated temperatures. Thermal stability is an attractive feature not only because it allows for protein purification by thermal treatment and higher process temperatures but also due to the associated higher stability against other destabilising factors. Therefore, high-throughput screening (HTS) methods are desirable for the identification of thermostable biocatalysts by discovery from nature or by protein engineering but current methods have low throughput and require time-demanding purification of protein samples. We found that nanoscale differential scanning fluorimetry (nanoDSF) is a valuable tool to rapidly and reliably determine melting points of native proteins. To avoid intrinsic problems posed by crude protein extracts, hypotonic extraction of overexpressed protein from bacterial host cells resulted in higher sample quality and accurate manual determination of several hundred melting temperatures per day. We have probed the use of nanoDSF for HTS of a phylogenetically diverse aldolase library to identify novel thermostable enzymes from metagenomic sources and for the rapid measurements of variants from saturation mutagenesis. The feasibility of nanoDSF for the screening of synthetic reaction conditions was proved by studies of cosolvent tolerance, which showed protein melting temperature to decrease linearly with increasing cosolvent concentration for all combinations of six enzymes and eight water-miscible cosolvents investigated, and of substrate affinity, which showed stabilisation of hexokinase by sugars in the absence of ATP cofactor. ENZYMES: Alcohol dehydrogenase (NADP+ ) (EC 1.1.1.2), transketolase (EC 2.2.1.1), hexokinase (EC 2.7.1.1), 2-deoxyribose-5-phosphate aldolase (EC 4.1.2.4), fructose-6-phosphate aldolase (EC 4.1.2.n). PMID- 30414313 TI - Solitary fibrous tumors of the pleura: A single center experience at National Cancer Center, China. AB - BACKGROUND: This study explored the clinicopathological features, predictive factors of malignancy, effectiveness of video assisted thoracic surgery (VATS), and prognosis of solitary fibrous tumor of the pleura (SFTP). METHODS: A single center retrospective study of the data of 82 patients with SFTP who were surgically treated in our department between January 2003 and December 2015 was conducted. RESULTS: A total of 82 SFTPs (70 benign, 12 malignant) were included and all patients underwent complete en bloc resection. SFTPs originated from the visceral pleura in 47 (57%) and the parietal pleura in 35 (43%) patients. In our cohort, malignant tumors were often symptomatically large, and the patients with malignant SFTPs (mSFTPs) often had a family history of neoplasms. Patients in the VATS group (n = 22) had tumors with significantly smaller diameters, required a shorter surgical duration and shorter hospital stay, and experienced less intraoperative blood loss and less postoperative chest tube drainage compared to the thoracotomy group (n = 60). No tumor recurrence was found in benign SFTP (bSFTP) patients. The long term survival and disease-free survival rates of mSFTP patients were 76% and 53%, respectively. CONCLUSION: Larger tumor diameter and a family history of neoplasm may be predictive factors for mSFTP; however, this conclusion needs to be verified in large cohort. VATS is safe and reliable for treating selected SFTP patients. Local recurrence is associated with mSFTP patient death, thus close follow-up of such patients is crucial. PMID- 30414314 TI - Mitochondrial DNA haplogroups and age at onset of Machado-Joseph disease/Spinocerebellar ataxia type 3: a study in patients from multiple populations. AB - BACKGROUND: Mitochondrial dysfunction has been implicated in the pathogenesis of several neurodegenerative disorders, namely of Machado-Joseph disease, an autosomal dominant late-onset polyglutamine ataxia that results from an unstable expansion of a CAG tract in the ATXN3 gene. The size of the CAG tract only partially explains age at onset, highlighting the existence of disease modifiers. Mitochondrial DNA haplogroups have been associated with clinical presentation in other polyglutamine disorders, constituting potential modifiers of Machado-Joseph disease phenotype. METHODS: To investigate if mtDNA haplogroups contribute to age at onset of Machado-Joseph disease, a cross-sectional study, using 235 unrelated patients from Portugal, Brazil, India and Japan was performed. mtDNA haplogroups were obtained after sequencing the mtDNA hypervariable region I. Patients were classified in 15 phylogenetically related haplogroup clusters. RESULTS: Age at onset was significantly different among populations, implying the existence of another non-CAG factors, which seem to be population-specific. In the Portuguese population, patients classified as JT haplogroup presented the earliest onset (estimated onset of 34.6 years). W and X haplogroups seem to have a protective effect, causing a delay in onset (estimated onset of 47 years). No significant association between haplogroup clusters and age at onset was detected in the other populations or when all patients were pooled. Although JT haplogroup has already been implicated in other neurodegenerative disorders, no previous reports of an association between haplogroups W and X and disease were found. CONCLUSIONS: These findings suggest that JT, W and X haplogroups seem to modify age at onset in Machado-Joseph disease; replication studies should be performed in European populations, where the frequency of the candidate modifiers is similar. This article is protected by copyright. All rights reserved. PMID- 30414315 TI - Safety and efficacy of autologous hematopoietic stem cell transplantation following natalizumab discontinuation in aggressive Multiple Sclerosis. AB - BACKGROUND: Natalizumab (NTZ) is a highly effective treatment for relapsing remitting multiple sclerosis (RRMS), but its withdrawal is often followed by disease reactivation or rebound, even if other disease-modifying treatments (DMTs) are administered. In this study, for the first time, safety and efficacy of autologous hematopoietic stem cell transplantation (aHSCT) performed following NTZ discontinuation was retrospectively compared with conventional DMTs. METHODS: Patients with RRMS treated with NTZ and who discontinued the drug after at least six administrations and with at least six months of follow-up were included. Patients underwent aHSCT after a minimum period of six months following NTZ withdrawal, receiving in the meanwhile cyclophosphamide or corticosteroids, or received other DMTs approved for MS (control group) after an adequate wash-out period. Both hematological and neurological follow-up were assessed according to standard policies. RESULTS: Fifty-two patients were included, 11 who received aHSCT and 41 DMTs. Baseline clinical and demographic characteristics were similar between the two groups. No fatality or life-threatening complications, including Progressive Multifocal Leukoencephalopathy, were observed. At three years following NTZ discontinuation no evidence of disease activity was reported in 54.5% of the patients in the aHSCT group compared to 11.5% of those in the DMT group (p=0.0212); disease reactivation in the aHSCT patients was observed only during wash-out/bridging therapy and after aHSCT 100% of the cases were free from disease activity. CONCLUSION: These data suggest that an aggressive therapy should be established after NTZ with the shortest possible wash-out period. AHSCT after six months from NTZ withdrawal seems safe. This article is protected by copyright. All rights reserved. PMID- 30414316 TI - Human herpesvirus 6 encephalitis in patients administered mycophenolate mofetil as prophylaxis for graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. AB - BACKGROUND: Human herpesvirus 6 (HHV-6) encephalitis is a known life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo HSCT). However, few studies have focused on the occurrence of HHV-6 encephalitis in patients receiving mycophenolate mofetil (MMF) combined with a calcineurin inhibitor as prophylaxis for graft-versus-host disease (GVHD). This study aimed to investigate the impact of MMF administered for GVHD prophylaxis in the occurrence of HHV-6 encephalitis after allo-HSCT and the characteristics of this condition. METHODS AND RESULTS: We retrospectively analyzed 73 patients who underwent allo-HSCT (83 transplants) at our hospital between April 2010 and December 2015. MMF (2-3 g/d) was administered along with a calcineurin inhibitor. Seven patients (8.0%) developed encephalitis due to HHV-6. The median period from allo-HSCT to the onset of HHV-6 encephalitis was 23 days (range, 17-98 days). The cumulative incidence of HHV-6 encephalitis on day 100 after treatment was 12% and 6% in patients who underwent cord blood transplantation (CBT) and non-CBT (ie, bone marrow transplantation and peripheral blood stem cell transplantation), respectively (P = 0.344). Neurological symptoms of encephalitis were more severe in non-CBT cases than those in CBT cases. All patients diagnosed with HHV-6 encephalitis were treated with ganciclovir or foscarnet. None of the enrolled patients died from HHV-6 encephalitis. CONCLUSIONS: Mycophenolate mofetil may have the potential to increase the frequency of severe HHV-6 encephalitis in patients undergoing CBT and non-CBT. Thus, MMF should be administered with caution, and patients should be monitored closely for HHV-6 encephalitis even those who did not undergo CBT. PMID- 30414317 TI - Energy efficient physiologic coupling of gait and respiration is altered in chronic obstructive pulmonary disease. AB - AIMS: Coupling between walking and breathing in humans is well established. In healthy systems, the ability to couple and uncouple leads to energy economization. It is unknown if physiologic efficiency is susceptible to alteration particularly in individuals with airflow obstruction. The aim of this research to determine if coupling was compromised in a disease characterized by abnormal airflow and dyspnea, and if this was associated with reduced energy efficiency. METHODS: As a model of airflow obstruction, 17 chronic obstructive pulmonary disease (COPD) patients and 23 control subjects were included and walked on a treadmill for six-minutes at three speeds (preferred speed and +/-20% preferred speed) while energy expenditure, breathing, and walking were recorded. Rating of perceived exertion was recorded at the end of each walking trial. The most commonly used frequency ratio (i.e. strides:breath) and cross recurrence quantification analysis were used to quantify coupling. Linear regression models were used to determine associations. RESULTS: Less complex frequency ratios, simpler ratios, (i.e. 1:1 and 3:2) accompanied with stronger coupling were moderately associated with increased energy expenditure in COPD subjects. This was found for all three speeds. CONCLUSION: The novel finding was that increased energy expenditure was associated with stronger and less complex coupling. Increased effort is needed when utilizing a frequency ratio of 1:1 or 3:2. The more stable the coupling, the more effort it takes to walk. In contrast to the complex energy efficient coupling of controls, those with airflow obstruction manifested simpler and stronger coupling associated with reduced energy efficiency. This article is protected by copyright. All rights reserved. PMID- 30414318 TI - Membrane topologies of PEX13 and PEX14 provide new insights on the mechanism of protein import into peroxisomes. AB - PEX13 and PEX14 are two core components of the so-called peroxisomal docking/translocation module, the transmembrane hydrophilic channel through which newly synthesized peroxisomal proteins are translocated into the organelle matrix. The two proteins interact with each other and with PEX5, the peroxisomal matrix protein shuttling receptor, through relatively well characterized domains. However, the topologies of these membrane proteins are still poorly defined. Here, we subjected proteoliposomes containing PEX13 or PEX14 and purified rat liver peroxisomes to protease-protection assays and analyzed the protected protein fragments by mass spectrometry, Edman degradation and western blotting using antibodies directed to specific domains of the proteins. Our results indicate that PEX14 is a bona fide intrinsic membrane protein with a Nin -Cout topology, and that PEX13 adopts a Nout -Cin topology, thus exposing its carboxy terminal Src homology 3 [SH3] domain into the organelle matrix. These results reconcile several enigmatic findings previously reported on PEX13 and PEX14 and provide new insights into the organization of the peroxisomal protein import machinery. ENZYMES: Trypsin, EC3.4.21.4; Proteinase K, EC3.4.21.64; Tobacco etch virus protease, EC3.4.22.44. PMID- 30414319 TI - Regulation of Tip60-dependent p53 acetylation in cell fate decision. AB - The acetylation of p53 plays an essential role in regulating its transcriptional activity. Nevertheless, how p53 acetylation is modulated in cell fate decision is less understood. We developed a network model to reveal how Tip60-dependent p53 acetylation is regulated to modulate cellular outcome. We proposed that p53 is progressively activated and exhibits distinct dynamics depending on the severity of DNA damage. For mild damage, p53 is primarily activated to trigger cell cycle arrest by transactivating p21, with its concentration showing pulses. For severe damage, p53 is acetylated at Lysine 120 (K120) by Tip60 to trigger apoptosis by inducing PUMA, and its concentration increases to high levels. Several p53 centered feedback loops coordinate to regulate its acetylation status, ensuring a robust decision on cell fate. PMID- 30414320 TI - Effects of treadmill training on microvascular remodeling in the rat following spinal cord injury. AB - INTRODUCTION: The morphological characteristics of skeletal muscles innervated caudal to a spinal cord injury (SCI) undergo dramatic phenotypic and microvascular changes. METHOD: Female Sprague Dawley rats received a severe contusion at thoracic level 9/10, and were randomly assigned to locomotor training (TR), epidural stimulation (ES) or a combination of the treatment groups (CB). Fibre type composition and capillary distribution were assessed in phenotypically distinct compartments of the tibialis anterior. RESULTS: SCI induced a shift in Type II fibre phenotype from oxidative to glycolytic (P<0.05) as well as capillary loss within the oxidative core and glycolytic cortex; the CB treatment best maintained capillary supply within both compartments. DISCUSSION: The angiogenic response of CB training improved capillary distribution across the muscle, becoming spatially more homogeneous and decreasing mean capillary supply area, potentially improving oxygenation. There is an important role for weight bearing training in maintaining the oxidative phenotype of muscle following SCI. This article is protected by copyright. All rights reserved. PMID- 30414321 TI - Effect of gellan gum on functional properties of low-fat chicken meat batters. AB - The effects of substituting pork back-fat with addition of gellan gum and water on gel characteristics, rheological property, water mobility, and distribution of chicken meat batters were studied. The addition of gellan gum significantly affected the cooking yield, color, texture, and rheological property of chicken meat batters (p < .05). The cooking yield and textural properties were not significantly different (p > .05) when gellan gum was added with 0, 0.2, and 0.4%. When the level of gellan gum reached 0.6%, the cooked chicken meat batters had significantly lower L* value, cooking yield, hardness, springiness, cohesiveness, and chewiness values (p < .05). The initial storage modulus (G') of chicken batters was significantly decreased (p < .05) with increasing gellan gum. During the heating, an increase in denaturation temperature of the myosin head and tail were observed in chicken batters with added gellan gum. The G' of chicken batters with 0, 0.2, and 0.4% gellan gum were not significant difference (p > .05) at 80C, but the G' of chicken batters with 0.6% gellan gum was significantly decreased (p < .05). LF-NMR revealed that T21 and T22 were significantly increased (p < .05) with increasing the water and gellan gum content while P21 and P22 were not significantly different (p > .05) in the chicken batters with 0, 0.2, and 0.4% gellan gum. A significant decrease was observed (p < .05) in the chicken batter with 0.6% gellan gum. Overall, added 0.2 and 0.4% gellan gum to chicken meat batters could reduce pork back-fat. PRACTICAL APPLICATIONS: Emulsion-type meat products contain a high level of fat, saturated fatty acids, and cholesterol, which have a potential negative effect on consumers health. However, animal fat plays an important role in the textural properties and water-holding capacity of meat products. One of great challenges in meat processing is how to find a fat substitute to produce low-fat meat products which have overall acceptable quality. This study showed that the addition of gellan gum influenced the textural properties of chicken batters and changed the dynamic rheological behavior. The addition of 0.2 and 0.4% gellan gum kept a stable cooking yield and textural properties of cooked chicken batters and also reduced the pork back-fat. LF-NMR could reflect the cooking yield and gel properties of the chicken batters. Gellan gum may be used to replace pork back-fat to produce low-fat chicken meat batters having overall acceptability in meat industry for meeting consumer demand. PMID- 30414322 TI - Clinical and electrodiagnostic features of non-traumatic sciatic neuropathy. AB - INTRODUCTION: We sought to characterize etiologies and features of sciatic neuropathy unrelated to penetrating nerve trauma. METHODS: A retrospective review of 109 patients with electrodiagnostically confirmed sciatic neuropathies. RESULTS: Hip replacement surgery represented the most common (34.9%) etiology, while inflammatory sciatic neuropathy was seen in 7.3%. Electrodiagnostic testing revealed an axonal neuropathy in 95.4% and a demyelinating neuropathy in 4.6%. Predominant involvement of the peroneal division was seen in 39.4% and tibial in 5.5%. Nine of 31 (29.0%) patients who had MRI or neuromuscular ultrasound study showed abnormalities within the sciatic nerve. At the final visit, 46.4% of patients required assistance for ambulation. Young age, lack of severe initial weakness, and presence of tibial compound muscle action potential or sural sensory nerve action potential were predictors of favorable outcome. DISCUSSION: Sciatic neuropathies are usually axonal on electrodiagnostic testing, affect preferentially the peroneal division, and are commonly associated with incomplete recovery. This article is protected by copyright. All rights reserved. PMID- 30414323 TI - Relationships between neuronal birthdates and tonotopic positions in the mouse cochlear nucleus. AB - Tonotopy is a key anatomical feature of the vertebrate auditory system, but little is known about the mechanisms underlying its development. Since date of birth of a neuron correlates with tonotopic position in the cochlea, we investigated if it also correlates with tonotopic position in the cochlear nucleus (CN). In the cochlea, spiral ganglion neurons are organized in a basal to apical progression along the length of the cochlea based on birthdates, with neurons in the base (responding to high-frequency sounds) born early around mouse embryonic day (E) 9.5-10.5, and those in the apex (responding to low-frequency sounds) born late around E12.5-13.5. Using a low-dose thymidine analog incorporation assay, we examine whether CN neurons are arranged in a spatial gradient according to their birthdates. Most CN neurons are born between E10.5 and E13.5, with a peak at E12.5. A second wave of neuron birth was observed in the dorsal cochlear nucleus (DCN) beginning on E14.5 and lasts until E18.5. Large excitatory neurons were born in the first wave, and small local circuit neurons were born in the second. No spatial gradient of cell birth was observed in the DCN. In contrast, neurons in the anteroventral cochlear nucleus (AVCN) were found to be arranged in a dorsal to ventral progression according to their birthdates, which are aligned with the tonotopic axis. Most of these AVCN neurons are endbulb innervated bushy cells. The correlation between birthdate and tonotopic position suggests testable mechanisms for specification of tonotopic position. PMID- 30414324 TI - Health Maintenance for Adults with Neuromuscular Diseases on Immunosuppression. AB - Immunosuppressants are commonly used in the treatment of neuromuscular diseases. The use of these medications requires health maintenance screening and monitoring for multiple potential sides effects, which may be best conducted when the prescribing physician and primary care physician work in tandem. Clinical practice guidelines, recommendations from professional organizations, prescription drug labeling, and expert opinion were reviewed and combined to provide recommendations for health maintenance for eight different immunosuppressants. Recommendations are provided for vaccinations, infection prophylaxis, laboratory monitoring, bone density screening, cancer screening, and other considerations. While studies in individuals with neuromuscular diseases are sparse, knowledge gained from the use of immunosuppressants in other conditions is applied in this review to provide recommendations to be used during the treatment of neuromuscular diseases in adults. This article is protected by copyright. All rights reserved. PMID- 30414325 TI - A Phenomenological Study on the Experience of Syrian Asylum-Seekers and Refugees in the United States. AB - Violence in Syria has displaced an unprecedented number of people from their homes. While couple/family therapy (C/MFT) scholars have explored migration experiences, particularly among refugees, there is still limited research using a bioecological framework. This exploratory study examined the experiences of Syrian asylum-seekers and refugees living in the United States using a qualitative phenomenological approach. Twelve Syrians (n = 8 men, n = 4 women) between 20 and 52 years of age (M = 35.8, SD = 10.7) were interviewed about their experiences across three stages of resettlement: (1) pre-resettlement, (2) resettlement/migration, and (3) post-resettlement. Findings suggest that the effects of conflict-induced displacement and resettlement permeate across multiple ecologies. These range from the individual and his or her interpersonal relationships to their larger community and society. C/MFTs should account for contextual factors while becoming familiar with the sociopolitical impact of displacement and resettlement in their clinical work with this population. PMID- 30414326 TI - Needle Electromyography and Histopathologic Correlation in Myopathies. AB - INTRODUCTION: Needle electromyography (EMG) findings help confirm myopathy and may indicate specific pathologic changes on muscle biopsy. METHODS: Retrospective chart review of 218 consecutive patients referred for muscle biopsy. Presence of specific needle EMG findings was correlated to pathologic findings of inflammation, necrosis, splitting, and vacuolar changes. Sensitivity, specificity, and positive and negative predictive values of specific EMG findings for pathologic changes were calculated. RESULTS: Short duration motor unit potentials (MUPs) were sensitive (83-94%), but not specific (34-49%) for pathologic changes. Fibrillation potentials were 65-74% sensitive and 58-81% specific for inflammation, necrosis, splitting, or vacuolar changes. The absence of fibrillation potentials had high negative predictive value (82-93%) for inflammation, splitting, or vacuolar changes. DISCUSSION: Fibrillation potentials and short duration MUP predict pathologic changes of muscle fiber necrosis, splitting, and/or vacuolar changes (as seen with inflammatory myopathies and muscular dystrophies). Absence of fibrillation potentials suggests other myopathologic changes (e.g. congenital myopathy). This article is protected by copyright. All rights reserved. PMID- 30414327 TI - Relationships Among Emerging Adult Psychological Problems, Maltreatment, and Parental Psychopathology: Moderation by Parent-Child Relationship Quality. AB - Current research supports clear relationships between parental psychopathology, parental maltreatment, and emerging adult child psychopathology. Less research has examined how the role of the parent-child relationship influences these existing associations. The current study tested two models that examined the moderating effect of parent-child relationship quality on parental psychopathology and emerging adult mental health as well as the effect on parental maltreatment and emerging adult mental health. It was expected that high parent-child relationship quality would buffer against the negative effects of parental psychopathology and maltreatment while enhancing the effects of functional parenting characteristics. Participants included 1,452 emerging adults, predominantly Caucasian (73.3%) college students who completed surveys on their mental health, recent experienced maltreatment, and their parents' mental health problems. Results suggested lowest rates of mental health problems for emerging adults were associated with higher parent-child relationship quality and lower parental psychological problems, whereas negative outcomes were associated with higher parental psychopathology, regardless of parent-child relationship quality. Additionally, physical maltreatment was associated with lower rates of mental health concerns in the context of higher mother-daughter relationship quality. Results emphasize the continuing impact of the parent-child relationship, particularly the mother-daughter relationship, on emerging adults' mental health. Moreover, the current study demonstrates the continuing influence of parents on their emerging adult children. PMID- 30414328 TI - The SnRK1-eIFiso4G1 signaling relay regulates the translation of specific mRNAs in Arabidopsis under submergence. AB - Cellular responses to oxygen deprivation are essential for survival during energy crises in plants and animals. Hypoxia caused by submergence results in reprogramming of translation dynamic in plants, but the molecular mechanisms are not well understood. Here we show that Arabidopsis Snf1-related protein kinase 1 (SnRK1) phosphorylates the translation initiation factor eIFiso4G to regulate translation dynamic under submergence. In Arabidopsis, there are two eIFiso4G genes, eIFiso4G1 and eIFiso4G2, which belong to the eIF4G family. Both eIFiso4Gs were phosphorylated by SnRK1 under submergence. Interestingly, the eIFiso4G1 knockout mutant, but not the eIFiso4G2 mutant, became more sensitive to submergence, implying that eIFiso4G1 is involved in regulating submergence tolerance in Arabidopsis. Comparison of RNA sequences in the polysome fraction and the RNAs immunoprecipited by eIFiso4G1 from Col-0 and the SnRK1 and eIFiso4G1 mutants revealed that lack of eIFiso4G1 phosphorylation disrupts the translation of specific mRNAs under submergence. Taken together, our findings suggest that the SnRK1-eIFiso4G1 relay controls the translation of an array of genes under hypoxia, including core hypoxia response genes and genes related to stress response and biosynthetic process. This article is protected by copyright. All rights reserved. PMID- 30414329 TI - A Danish register-based study on involuntary treatment in anorexia nervosa. AB - OBJECTIVE: Involuntary treatment is controversial and widely debated, but remains a significant component of treatment for severe anorexia nervosa. Given how little is known about this topic, we describe the frequency of various involuntary measures in a national cohort of all patients diagnosed with anorexia nervosa. In a subsample of patients, we explored predictors of the first involuntary measure recorded. METHOD: Descriptive statistics and Cox proportional hazard analyses were conducted using the national registers of Denmark covering the total population. Data from the National Patient Register and the Psychiatric Central Research Register including all psychiatric visits from 1969 onwards were merged with data from the National Register on Coercion covering 1999 onward. Involuntary measures registered between 2000 and 2013 were analyzed. RESULTS: A total of 4,727 patients with a diagnosis of anorexia nervosa representing 16,592 admissions were included. Eighteen percent experienced at least one involuntary measure. A variety of measures were used with tube feeding being the most frequent followed by mechanical restraint, involuntary medication, physical restraint, constant observation, and sedative medication. A subsample of 2% of AN patients had more than 100 involuntary measures recorded. The first recorded involuntary measure was predicted by most but not all psychiatric comorbidities, especially schizophrenia, autism spectrum, and personality disorders, older age at first diagnosis, and previous admissions. DISCUSSION: It is important to develop a more granular understanding of patients at risk of requiring involuntary treatment and to determine how best to treat them effectively with minimal use of involuntary measures. PMID- 30414330 TI - Interplay between age-based competitive asymmetries within the brood and direct competition between inbred and outbred offspring in a burying beetle. AB - Theory suggests that intraspecific competition associated with direct competition between inbred and outbred individuals should be an important determinant of the severity of inbreeding depression. The reason is that, if outbred individuals are stronger competitors than inbred ones, direct competition should have a disproportionate effect on the fitness of inbred individuals. However, an individual's competitive ability is not only determined by its inbreeding status but also by competitive asymmetries that are independent of an individual's inbreeding status. When this is the case, such competitive asymmetries may shape the outcome of direct competition between inbred and outbred individuals. Here, we investigate the interface between age-based competitive asymmetries within broods and direct competition between inbred and outbred offspring in the burying beetle Nicrophorus vespilloides. We found that inbred offspring had lower survival than outbred ones confirming that there was inbreeding depression. Furthermore, seniors (older larvae) grew to a larger size and had higher survival than juniors (younger larvae), confirming that there were age-based competitive asymmetries. Nevertheless, there was no evidence that direct competition between inbred and outbred larvae exacerbated inbreeding depression, no evidence that inbreeding depression was more severe in juniors and no evidence that inbred juniors suffered disproportionately due to competition from outbred seniors. Our results suggest that direct competition between inbred and outbred individuals does not necessarily exacerbate inbreeding depression and that inbred individuals are not always more sensitive to poor and stressful conditions than outbred ones. PMID- 30414331 TI - The Impact of Tacrolimus Exposure on Extrarenal Adverse Effects in Adult Renal Transplant Recipients. AB - AIMS: Tacrolimus has been associated with notable extrarenal adverse effects (AEs), which are unpredictable and impact patient morbidity. The association between model-predicted tacrolimus exposure metrics and standardized extrarenal AEs in stable renal transplant recipients was investigated and a limited sampling strategy (LSS) was developed to predict steady-state tacrolimus area under the curve over 12-hour dosing period (AUCss,0-12hr ). METHODS: All recipients receiving tacrolimus and mycophenolic acid >=6 months completed a 12-hour cross sectional observational pharmacokinetic-pharmacodynamic study. Patients were evaluated for the presence of individual and composite gastrointestinal, neurological, and aesthetic AEs during the study visit. The associations between AEs and tacrolimus exposure metrics generated from a published population pharmacokinetic model were investigated using a logistic regression analysis in NONMEM 7.3. A LSS was determined using a Bayesian estimation method with the same patients. RESULTS: Dose-normalized tacrolimus AUCss,0-12hr and apparent clearance (CL/F) were independently associated with diarrhea, dyspepsia, insomnia, and neurologic AE ratio. Dose-normalized tacrolimus maximum concentration (CMAX ) was significantly correlated with skin changes and acne. No AE associations were found with trough concentrations. Samples collected at 0-2, 0-1-4 and 0-1-2-4 hours provided a precise and unbiased prediction of tacrolimus AUC (root mean squared prediction error [RMSE] < 10%), which was not well characterized using trough concentrations only (RMSE > 15%). CONCLUSIONS: Several AEs (i.e., diarrhea, dyspepsia, insomnia, and neurologic AE ratio) were associated with tacrolimus dose normalized AUCss,0-12hr , and clearance. Skin changes and acne were associated with dose-normalized CMAX concentrations. To facilitate clinical implementation, a LSS was developed to predict AUCss,0-12hr values using sparse patient data to efficiently assess projected immunosuppressive exposure and potentially minimize AE manifestations. PMID- 30414332 TI - A case review of a patient experience of photopheresis using a peripherally inserted central catheter. AB - Extracorporeal photopheresis (ECP) is a cell based immunomodulatory therapy in which the patient is attached intravenously to a cell separating machine. During ECP a patient's blood is collected via either a central venous access device (CVAD) or a peripherally inserted 16G arterial venous fistula needle in either one or both antecubital fossa. However, patients presenting for ECP with GVHD repeatedly present a challenge to the ECP team due to poor venous access resulting from previous therapies and skin changes. The use of peripherally inserted central venous catheters (PICCs) offers an alternative route of vascular access for this cohort of patients. Here we present a case report of a patient successfully treated with ECP following the insertion of a PICC line. PMID- 30414333 TI - Current understanding and perioperative management of pediatric pulmonary hypertension. AB - Pediatric pulmonary hypertension (PH) is a complex disease with multiple, diverse etiologies affecting the premature neonate to the young adult. Pediatric pulmonary arterial hypertension (PAH), whether idiopathic or associated with congenital heart disease, is the most commonly discussed form of pediatric PH, as it is progressive and lethal. However, neonatal forms of PH are vastly more frequent, and while most cases are transient, the risk of morbidity and mortality in this group deserves recognition. PH due to left heart disease is another subset increasingly recognized as an important cause of pediatric PH. One aspect of pediatric PH is very clear: anesthetizing the child with PH is associated with a significantly heightened risk of morbidity and mortality. It is therefore imperative that anesthesiologists who care for children with PH have a firm understanding of the pathophysiology of the various forms of pediatric PH, the impact of anesthesia and sedation in the setting of PH, and anesthesiologists' role as perioperative experts from preoperative planning to postoperative disposition. This review summarizes the current understanding of pediatric PH physiology, preoperative risk stratification, anesthetic risk, and intraoperative considerations relevant to the underlying pathophysiology of various forms of pediatric PH. This article is protected by copyright. All rights reserved. PMID- 30414335 TI - Usefulness of platelet to lymphocyte ratio for predicting recurrence of atrial fibrillation after direct current cardioversion. AB - OBJECTIVE: Atrial fibrillation (AF) is the most common cardiac rhythm disorder with the associated risks of stroke and mortality. The usefulness of platelet to lymphocyte ratio (PLR), a recently described inflammatory marker, in predicting adverse cardiovascular events has been demonstrated in several studies. In the current study, we investigated the role of PLR in predicting recurrence after successful electrical cardioversion (ECV) in patients with non-valvular persistent AF. METHODS: A total of 287 patients with non-valvular persistent AF achieving restoration of the sinus rhythm after successful ECV were included in this study. At study entry, complete blood count, routine biochemistry tests, and transthoracic echocardiography (TTE) were performed routinely in all subjects. Patients were followed up for 6 months following the procedure and comparisons were performed between patients who recurred and who maintained the sinus rhythm (SR). RESULTS: At 6 months of follow-up, AF recurred in 108 patients, corresponding to a recurrence rate of 39%. Mean PLR values in the "AF recurrence group" (mean age 57.4 +/- 12.0 years, 47.6% [n = 80] female) and in "SR maintenance" group (mean age 65.0 +/- 9.4 years, 55.6% [n = 60] female) were 184.8 +/- 44.2 and 103.3 +/- 44.2, respectively, with a significant difference between the two groups (p < 0.001). In multiple regression analyses, PLR emerged as a risk factor associated with AF recurrence during the 6-month follow-up period after successful ECV (odds ratio [OR]: 3.029 (1.013-9.055 95% confidence interval [CI]), p = 0.047). When a cutoff value of 147 was used, the sensitivity and specificity of PLR for predicting AF recurrence were 83.3% and 84.5%, respectively. CONCLUSION: Elevated PLR is a marker of increased inflammation and may serve as a practical and inexpensive predictor for recurrence during 6 months of follow-up in patients with non-valvular persistent AF who had restoration of the sinus rhythm after successful ECV. PMID- 30414334 TI - Protist Diversity and Seasonal Dynamics in Skagerrak Plankton Communities as Revealed by Metabarcoding and Microscopy. AB - Protist community composition and seasonal dynamics are of major importance for the production of higher trophic levels, such as zooplankton and fish. Our aim was to reveal how the protist community in the Skagerrak changes through the seasons by combining high-throughput sequencing and microscopy of plankton collected monthly over two years. The V4 region of the 18S rRNA gene was amplified by eukaryote universal primers from the total RNA/cDNA. We found a strong seasonal variation in protist composition and proportional abundances, and a difference between two depths within the euphotic zone. Highest protist richness was found in late summer-early autumn, and lowest in winter. Temperature was the abiotic factor explaining most of the variation in diversity. Dinoflagellates was the most abundant and diverse group followed by ciliates and diatoms. We found about 70 new taxa recorded for the first time in the Skagerrak. The seasonal pattern in relative read abundance of major phytoplankton groups was well in accordance with microscopical biovolumes. This is the first metabarcoding study of the protist plankton community of all taxonomic groups and through seasons in the Skagerrak, which may serve as a baseline for future surveys to reveal effects of climate and environmental changes. PMID- 30414336 TI - Interneuronal gap junctions increase synchrony and robustness of hippocampal ripple oscillations. AB - Sharp wave-ripples (SWRs) are important for memory consolidation. Their signature in the hippocampal extracellular field potential can be decomposed into a ~100 ms long sharp wave superimposed by ~200 Hz ripple oscillations. How ripple oscillations are generated is currently not well understood. A promising model for the genesis of ripple oscillations is based on recurrent interneuronal networks (INT-INT). According to this hypothesis, the INT-INT network in CA1 receives a burst of excitation from CA3 that generates the sharp wave, and recurrent inhibition leads to an ultrafast synchronization of the CA1 network causing the ripple oscillations; fast-spiking parvalbumin-positive basket cells (PV+ BCs) may constitute the ripple-generating interneuronal network. PV+ BCs are also coupled by gap junctions (GJs) but the function of GJs for ripple oscillations has not been quantified. Using simulations of CA1 hippocampal networks of PV+ BCs, we show that GJs promote synchrony beyond a level that could be obtained by only inhibition. GJs also increase the neuronal firing rate of the interneuronal ensemble, while they affect the ripple frequency only mildly. The promoting effect of GJs on ripple oscillations depends on fast GJ transmission ( ? 0.5 ms), which requires proximal GJ coupling ( ? 100 MUm from soma), but is robust to variability in the delay and the amplitude of GJ coupling. PMID- 30414337 TI - Allergy alerts - the incidence of parentally reported allergies in children presenting for general anaesthesia. AB - BACKGROUND AND AIM: Pediatric patients increasingly report allergies, including allergies to food and medications. We sought to determine the incidence and, nature of parent-reported allergies in children presenting for surgery and its significance for anaesthetists. METHOD: We prospectively collected data on admissions through our surgical admission unit over a two-month period at a pediatric tertiary care teaching hospital. Data collected included patient demographics, history of atopy, with more comprehensive information collected if an allergy was reported. A clinical immunologist and an anaesthetist reviewed the documentation of all patients reporting an allergy. RESULTS: We reviewed 1001 pediatric patients, 158 (15.8%) patients with parent-reported allergies; to medications/drugs (n=73), food (n=66), environmental allergens (dust/grasses, n=35), tapes/dressings (n=27), latex (n=4) and venom (e.g. bee, wasp, n=9). 41 patients reported antibiotic allergies, with Beta-lactam antibiotics being the most common, with the majority presenting with rash alone (57%). 10 patients reported allergies to non-steroidal anti-inflammatory drugs (NSAID) and 8 to opioids. 24 patients reported egg and/or peanut allergy. Only 3/1001 (0.3%) patients were deemed to have evidence of likely IgE mediated drug allergy. Of the reported allergies, only 60 (38.2%) had been investigated prior, most likely to be followed up were food (53%) and environmental allergies (44.4%). Only 4/73 (5.5%) reported medication allergies had further follow up. Just 4 patients (0.4% of the entire cohort) had drug sensitivities/allergies that were likely to majorly alter anaesthesia practice. CONCLUSION: Only the minority of parent reported allergies in paediatric surgical patients were specialist confirmed and likely to be clinically relevant. Self-reported food allergy is commonly specialist verified, reactions to medications were generally not. Over-reporting of allergies is increasingly common and limits clinician choice of medications. Better education of patients and their families and more timely verification or dismissal of parent-reported reactions is urgently needed. This article is protected by copyright. All rights reserved. PMID- 30414338 TI - Climate change does not affect seafood quality of a common targeted fish. AB - Climate change can affect marine and estuarine fish via alterations to their distributions, abundances, sizes, physiology and ecological interactions, threatening the provision of ecosystem goods and services. While we have an emerging understanding of such ecological impacts to fish, we know little about the potential influence of climate change on the provision of nutritional seafood to sustain human populations. In particular, the quantity, quality and/or taste of seafood may be altered by future environmental changes with implications for the economic viability of fisheries. In an orthogonal mesocosm experiment, we tested the influence of near-future ocean warming and acidification on the growth, health and seafood quality of a recreationally and economically important fish, yellowfin bream (Acanthopagrus australis). The growth of yellowfin bream significantly increased under near-future temperature conditions (but not acidification), with little change in health (blood glucose and haematocrit) or tissue biochemistry and nutritional properties (fatty acids, lipids, macro-and micronutrients, moisture, ash, and total N). Yellowfin bream appear to be highly resilient to predicted near-future ocean climate change, which might be facilitated by their broad spatio-temporal distribution across habitats and broad diet. Moreover, an increase in growth, but little change in tissue quality, suggests that near-future ocean conditions will benefit fisheries and fishers that target yellowfin bream. The data reiterate the inherent resilience of yellowfin bream as an evolutionary consequence of their euryhaline status in often environmentally challenging habitats, and imply their sustainable and viable fisheries into the future.We contend that widely-distributed species that span large geographic areas and habitats can be "climate-winners" by being resilient to negative direct impacts of near-future oceanic and estuarine climate change. This article is protected by copyright. All rights reserved. PMID- 30414339 TI - Visible Light Photocatalysis of the Ketyl Radical Coupling Reaction. AB - Ketyl radical coupling reactions for the construction of diversely functionalised alcohols have been continuously developed for many decades. Based on the widespread application of photocatalysis that is often complementary to the traditional methods, ketyl radical coupling reactions glow the new vigor. This Minireview aims to briefly and concisely summarise the methodologies which construct ketyl radical intermediates through visible light photocatalysis over the past 10 years. The ketyl-radical-generation activators are grouped in Lewis acids, Bronsted acids, in situ-generated Bronsted acids, and others. PMID- 30414341 TI - Down-regulation of lncRNA XIST ameliorates podocytes apoptosis in membranous nephropathy via miR-217/TLR4 pathway. AB - NEW FINDINGS: What is the central question of this study? Up-regulation of lncRNA XIST in injured podocytes and membranous nephropathy has been noted, but its implication in membranous nephropathy pathogenesis has not been elucidated in detail. What is the main finding and its importance? We demonstrated that XIST was up-regulated in kidney tissue of membranous nephropathy and in injured podocytes. Down-regulation of XIST inhibited podocytes apoptosis. XIST negatively regulated miR-217, and miR-217 controlled TLR4. XIST modulated TLR4 through miR 217 and inhibition of XIST suppressed podocytes apoptosis induced by Angiotensin II via miR-217. ABSTRACT: Background Membranous nephropathy is often characterized by glomerular podocyte injury. Up-regulation of lncRNA XIST has been verified in membranous nephropathy and in injured podocytes; hence the role of XIST in podocyte injury and membranous nephropathy was explored. Methods QRT PCR and western blot were performed to detect the expression XIST, miR-217, and TLR4 protein respectively. Podocyte apoptosis was evaluated with flow cytometry. Interaction between XIST and miR-217 was analyzed by RIP and RNA pull-down assay, respectively. Dual luciferase reporter assay was used to exam the interplay between miR-217 and TLR4. Results LncRNA XIST and Ang II up-regulation, kidney and podocyte injury were indicated in kidney tissue of patients with membranous nephropathy. Increase of XIST and apoptosis were induced by Ang II in podocytes. Down-regulation of XIST inverted podocytes apoptosis induced by Ang II. MiR-217 was negatively regulated by XIST. MiR-217 controlled TLR4 by targeting its 3' UTR. XIST modulated TLR4 through miR-217 and inhibition of XIST inverted podocytes apoptosis induced by Ang II via regulating miR-217. Conclusion Down regulation of XIST ameliorates podocytes apoptosis via the miR-217/TLR4 pathway, which may improve membranous nephropathy. This article is protected by copyright. All rights reserved. PMID- 30414340 TI - Regional and network properties of white matter function in Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder with dysfunction in cortices as well as white matter (WM) tracts. While the changes to WM structure have been extensively investigated in PD, the nature of the functional changes to WM remains unknown. In this study, the regional activity and functional connectivity of WM were compared between PD patients (n = 57) and matched healthy controls (n = 52), based on multimodel magnetic resonance imaging data sets. By tract-based spatial statistical analyses of regional activity, patients showed decreased structural-functional coupling in the left corticospinal tract compared to controls. This tract also displayed abnormally increased functional connectivity within the left post-central gyrus and left putamen in PD patients. At the network level, the WM functional network showed small-worldness in both controls and PD patients, yet it was abnormally increased in the latter group. Based on the features of the WM functional connectome, previously un-evaluated individuals could be classified with fair accuracy (73%) and area under the curve of the receiver operating characteristics (75%). These neuroimaging findings provide direct evidence for WM functional changes in PD, which is crucial to understand the functional role of fiber tracts in the pathology of neural circuits. PMID- 30414342 TI - Intestinal immune dysregulation driven by dysbiosis promotes barrier disruption and bacterial translocation in rats with cirrhosis. AB - In cirrhosis, intestinal dysbiosis, intestinal barrier impairment and systemic immune system abnormalities lead to gut bacterial translocation (GBT) and bacterial infection. However, intestinal immune system dysfunction and its contribution to barrier damage are poorly understood. This study correlates immune system dysregulation in the intestines of rats at different stages of CCl4 -induced cirrhosis with barrier function and pathogenic microbiota. The following variables were addressed in the small intestine: intraepithelial and lamina propria lymphocyte (IEL, LPL) activation status and cytokine production (flow cytometry), cytokine mRNA and protein expression (real-time quantitative PCR (qPCR) and immunofluorescence), microbiota composition of ileum content (16SrDNA massive sequencing), permeability (fecal albumin loss) and epithelial junctions (immunohistochemistry and immunofluorescence). The intestinal mucosa in cirrhotic rats showed a proinflammatory pattern of immune dysregulation in IEL and LPL, which featured the expansion of activated lymphocytes, switch to a Th1 regulatory pattern and Th17 reduction. In cirrhotic rats with ascites, this state was associated with epithelial junction protein disruption, fecal albumin loss, and GBT. Direct correlations (p<0.01) were observed between elevated IFNgamma expressing T cytotoxic LPL and fecal albumin, and between inflammatory taxa abundance and IFNgamma-producing immune cells in the ileum. Bowel decontamination led to redistributed microbiota composition, reduced proinflammatory activation of mucosal immune cells, normalized fecal albumin levels and diminished GBT, but there were no modifications in Th17 depletion. Conclusion: The intestinal mucosa of rats with cirrhosis acquires a proinflammatory profile of immune dysregulation that parallels the severity of cirrhosis. This impaired intestinal immune response is driven by gut dysbiosis and leads to disrupted barrier function, promoting GBT. This article is protected by copyright. All rights reserved. PMID- 30414343 TI - Convergent evolution of locomotor morphology but not performance in Gymnotiform swimmers. AB - Convergent evolution of a novel locomotor strategy implies that a fitness benefit may be associated with the new gait. Opportunities to study this phenomenon are often constrained by a lack of transitional taxa, but teleost fishes offer examples of extant species across such evolutionary shifts in gait. For instance, one species from Osteoglossiformes and the entire order of Gymnotiformes independently evolved a novel gait, gymnotiform locomotion, where thrust is produced by the undulation of an elongate anal fin. Here, we investigate whether this convergence in gait is also associated with similarities in shape, burst swimming abilities, and/or steady-swimming energetics. Specifically, we measured body and fin morphology of fish within Gymnotiformes and Osteoglossiformes, along with closely related Siluriformes and Cypriniformes, to examine the link between gymnotiform locomotion and morphology in a phylogenetic context. Second, we tested the burst swimming capabilities and oxygen consumption during endurance swimming of a subset of the same gymnotiform, osteoglossiform, and cypriniform species, including 'transitional' Osteoglossiformes that exhibit intermediate gaits, to determine whether the evolution of this specialized gait is associated with a change in either of these performance metrics. Our results suggest that convergence on the gymnotiform gait is associated with morphological convergence, but does not constrain a fish's maximum sprinting speeds or their energetic demands during steady swimming. PMID- 30414344 TI - Emergency Medical Services Administration of Systemic Corticosteroids for Pediatric Asthma: A Statewide Study of Emergency Department Outcomes. AB - BACKGROUND: For children with an asthma exacerbation, systemic corticosteroids (CS) administered in the emergency department (ED) decrease hospital admission rates and ED length-of-stay (LOS).1-4 Time-dependent effects favor earlier CS administration, ideally within the first hour of ED arrival.2,3 Only one pediatric study has examined if earlier, EMS administration of CS improves patient outcomes.5 That study found decreased hospital admission rates and ED LOS after adding dexamethasone to intravenous (IV) methylprednisolone as options for pediatric asthma. However, the study was of a single EMS agency and overall EMS CS use was low (<20%).5 To date, no large study has examined pediatric asthma outcomes after EMS treatment. This study's objective was to examine a statewide population of pediatric asthma patients to determine the effects of EMS administration of CS on ED outcomes. This article is protected by copyright. All rights reserved. PMID- 30414345 TI - The Advancement of Pediatric Anesthesia Pharmacology: David Ryan Cook (Scions, Serendipity, and Six Degrees of Separation). AB - Dr. David Ryan Cook, Professor Emeritus of Anesthesiology and Pharmacology at the University of Pittsburgh and Chief of Anesthesiology at Children's Hospital of Pittsburgh (1977-1999), is a pioneer in the field of pediatric anesthesiology and pharmacology. Dr. Cook contributed significantly to the understanding of pharmacologic differences among infants, children, and adults. His work as a clinician-scientist, educator, and mentor defined the pharmacology of many of the anesthetic agents we continue to use today. He brought science to the art of anesthesia and enhanced the safety of pediatric perioperative care. Based on a 2017 interview with Dr. Cook, this article outlines the development of his career and his contributions to the field of anesthesiology and pharmacology. This article is protected by copyright. All rights reserved. PMID- 30414346 TI - Multi-gene panel sequencing of established and candidate melanoma susceptibility genes in a large cohort of Dutch non-CDKN2A/CDK4 melanoma families. AB - Germline mutations in the major melanoma susceptibility gene CDKN2A explain genetic predisposition in only 10-40% of melanoma-prone families. In this study we comprehensively characterized 488 melanoma cases from 451 non-CDKN2A/CDK4 families for mutations in 30 established and candidate melanoma susceptibility genes using a custom-designed targeted gene panel approach. We identified (likely) pathogenic variants in established melanoma susceptibility genes in 18 families (n=3 BAP1, n=15 MITF p.E318K; diagnostic yield 4.0%). Among the three identified BAP1-families, there were no reported diagnoses of uveal melanoma or malignant mesothelioma. We additionally identified two potentially deleterious missense variants in the telomere maintenance genes ACD and TERF2IP, but none in the POT1 gene. MC1R risk variants were strongly enriched in our familial melanoma cohort compared to healthy controls (R variants: OR 3.67, 95% CI 2.88-4.68, p<0.001). Several variants of interest were also identified in candidate melanoma susceptibility genes, in particular rare (pathogenic) variants in the albinism gene OCA2 were repeatedly found. We conclude that multi-gene panel testing for familial melanoma is appropriate considering the additional 4% diagnostic yield in non-CDKN2A/CDK4 families. Our study shows that BAP1 and MITF are important genes to be included in such a diagnostic test. This article is protected by copyright. All rights reserved. PMID- 30414348 TI - Measuring testosterone and testosterone replacement therapy in men receiving androgen deprivation therapy for prostate cancer: A survey of UK uro-oncologists' opinions and practice. AB - AIM: To explore the practice and attitudes of uro-oncologists in the UK regarding monitoring testosterone levels and the use of testosterone replacement therapy (TRT) in their prostate cancer patients treated with androgen deprivation therapy (ADT). METHODS: An expert-devised online questionnaire was completed by the members of the British Uro-oncology Group (BUG). RESULTS: Of 160 uro-oncologists invited, 84 completed the questionnaire. Before initiating ADT in patients with non-metastatic prostate cancer, only 45% of respondents measured testosterone levels and 61% did not measure testosterone at all during ADT in the adjuvant or neoadjuvant setting. However, in men with metastatic prostate cancer, 71% of the uro-oncologists measured testosterone before starting ADT and the majority continued testing during treatment. Approximately two-thirds of respondents did not prescribe TRT for their patients who were in remission following neo(adjuvant) ADT and who had castration levels of testosterone. DISCUSSION: Among UK uro-oncologists, the measurement of testosterone levels before and during ADT was not typically part of routine practice in the management of patients with prostate cancer. However, testosterone levels were checked more frequently for patients with metastatic disease than disease at an earlier stage. Testing could be conducted in parallel with PSA measurement as testosterone levels are linked to biochemical failure. The majority of specialists participating in the survey did not prescribe TRT for their patients in remission following ADT. CONCLUSION: Uro-oncologists in the UK do not generally measure testosterone as part of their patient management and they remain cautious about the possible benefits of TRT in men with prostate cancer. PMID- 30414347 TI - Global soil nitrous oxide emissions since the pre-industrial era estimated by an ensemble of Terrestrial Biosphere Models: Magnitude, attribution and uncertainty. AB - Our understanding and quantification of global soil nitrous oxide (N2 O) emissions and the underlying processes remain largely uncertain. Here we assessed the effects of multiple anthropogenic and natural factors, including nitrogen fertilizer (N) application, atmospheric N deposition, manure N application, land cover change, climate change and rising atmospheric CO2 concentration, on global soil N2 O emissions for the period 1861-2016 using a standard simulation protocol with seven process-based terrestrial biosphere models. Results suggest global soil N2 O emissions have increased from 6.3 +/- 1.1 Tg N2 O-N yr-1 in the pre industrial period (the 1860s) to 10.0 +/- 2.0 Tg N2 O-N yr-1 in the recent decade (2007-2016). Cropland soil emissions increased from 0.3 Tg N2 O-N yr-1 to 3.3 Tg N2 O-N yr-1 over the same period, accounting for 82% of the total increase. Regionally, China, South Asia and Southeast Asia underwent rapid increases in cropland N2 O emissions since the 1970s. However, US cropland N2 O emissions had been relatively flat in magnitude since the 1980s, and EU cropland N2 O emissions appear to have decreased by 14%. Soil N2 O emissions from predominantly natural ecosystems accounted for 67% of the global soil emissions in the recent decade but showed only a relatively small increase of 0.7 +/- 0.5 Tg N2 O-N yr-1 (11%) since the 1860s. In the recent decade, N fertilizer application, N deposition, manure N application and climate change contributed 54%, 26%, 15% and 24%, respectively, to the total increase. Rising atmospheric CO2 concentration reduced soil N2 O emissions by 10% through the enhanced plant N uptake, while land cover change played a minor role. Our estimation here does not account for indirect emissions from soils and the directed emissions from excreta of grazing livestock. To address uncertainties in estimating regional and global soil N2 O emissions, this study recommends several critical strategies for improving the process-based simulations. This article is protected by copyright. All rights reserved. PMID- 30414349 TI - HLA-DR/DQ Molecular Mismatch: A prognostic biomarker for primary alloimmunity. AB - Alloimmune risk stratification in renal transplantation has lacked the necessary prognostic biomarkers to personalize recipient care or optimize clinical trials. HLA molecular mismatch improves precision compared to traditional antigen mismatch but has not been studied in detail at the individual molecule level. This study evaluated 664 renal transplant recipients and correlated HLA-DR/DQ single molecule eplet mismatch with serologic, histologic, and clinical outcomes. Compared to traditional HLA-DR/DQ whole antigen mismatch HLA-DR/DQ single molecule eplet mismatch improved the correlation with de novo donor-specific antibody (dnDSA) development (AUC 0.54 versus 0.84) and allowed recipients to be stratified into low, intermediate, and high alloimmune risk categories. These risk categories were significantly correlated with primary alloimmune events including Banff >=1A T-cell mediated rejection (p=0.0006), HLA-DR/DQ dnDSA development (p<0.0001), antibody-mediated rejection (p<0.0001), as well as all cause graft loss (p=0.0012) and each of these correlations persisted in multivariate models. Thus, HLA-DR/DQ single molecule eplet mismatch may represent a precise, reproducible, and widely available prognostic biomarker that can be applied to tailor immunosuppression or design clinical trials based on individual patient risk. This article is protected by copyright. All rights reserved. PMID- 30414350 TI - Antitumor Platinum(II) Complexes with 1,10-phenanthroline and Hydrophilic Alkoxyacetates as Ligands. AB - Four platinum complexes, formulated as [Pt(phen)(OCOCH2OR)2] (phen = 1,10 phenanthroline, R = Me, Et, iPr, or tBu), have been synthesized and well characterized by elemental analysis, IR, 1H-NMR, 13C-NMR and ESI-MS spectroscopy. Replacing chloride groups of the precursor Pt(phen)Cl2 with alkoxyacetate anions greatly improved the aqueous solubility and cytotoxicity of the resulting platinum complexes. The in vitro antitumor study revealed that complexes 1-3 were active in vitro towards four human tumor cell lines, especially complex 1 which exhibited prominent in vitro cytotoxic activity against HCT-116 comparable to cisplatin and oxaliplatin. Flow cytometry assay indicated that representative complexes 1 and 2 exerted cytotoxicity on HCT-116 cell line through inducing cell apoptosis and blocking cell cycle progression in the S or G2/M phases. The interaction of representative complexes with pET28a plasmid DNA was tested by agarose gel electrophoresis, which demonstrated that complexes 1 and 2 were capable of distorting plasmid DNA mainly by covalent binding and degradation effect. PMID- 30414351 TI - Shigella effector IpaH4.5 targets 19S regulatory particle subunit RPN13 in the 26S proteasome to dampen cytotoxic T lymphocyte activation. AB - Subversion of antigen-specific immune responses by intracellular pathogens is pivotal for successful colonisation. Bacterial pathogens, including Shigella, deliver effectors into host cells via the type III secretion system (T3SS) in order to manipulate host innate and adaptive immune responses, thereby promoting infection. However, the strategy for subverting antigen-specific immunity is not well understood. Here, we show that Shigella flexneri invasion plasmid antigen H (IpaH) 4.5, a member of the E3 ubiquitin ligase effector family, targets the proteasome regulatory particle non-ATPase 13 (RPN13) and induces its degradation via the ubiquitin-proteasome system (UPS). IpaH4.5-mediated RPN13 degradation causes dysfunction of the 19S regulatory particle (RP) in the 26S proteasome, inhibiting guidance of ubiquitinated proteins to the proteolytically active 20S core particle (CP) of 26S proteasome and thereby suppressing proteasome-catalysed peptide splicing. This, in turn, reduces antigen cross-presentation to CD8+ T cells via major histocompatibility complex (MHC) class I in vitro. In RPN13 knockout mouse embryonic fibroblasts (MEFs), loss of RPN13 suppressed CD8+ T cell priming during Shigella infection. Our results uncover the unique tactics employed by Shigella to dampen the antigen-specific cytotoxic T lymphocyte (CTL) response. PMID- 30414352 TI - Antimicrobial stewardship intervention for the clinical pathways improves antimicrobial prophylaxis in surgical or non-surgical invasive therapies. AB - BACKGROUND: The standard duration of administration of antimicrobial prophylaxis in surgery and non-surgical invasive therapy was shortened according to the promotion of appropriate use. Here, we conducted an intervention to optimise antimicrobial prophylaxis by revising all relevant clinical pathways based on the most recent guidelines. METHODS: We conducted a single-centre, prospective cohort study in patients who received antimicrobial prophylaxis to evaluate outcomes following revision of the clinical pathways for antimicrobial prophylaxis. Antibiotic consumption and the duration of antibiotic administration were compared before and after revising the clinical pathways. RESULTS: Thirty-five of 171 clinical pathways were considered inappropriate for antimicrobial use and were optimised. After this revision, the duration of antibiotic administration was significantly shortened (before revision: 3 [1-5] days vs after revision: 2 [1-3] days, median [interquartile range], P < 0.001). The rate of discontinuation of antibiotics within 48 h after surgery or non-surgical invasive therapy was significantly higher after the revision (62.4% vs 81.8%, P < 0.001). In contrast, the incidence of surgical site infection (SSI) was not significantly different before and after the revision (5.7% vs 4.3%, P = 0.177). A multivariate Cox proportional analysis indicated that revision of the clinical pathways was one of the prognostic factors associated with the discontinuation of antibiotics within 48 h after surgery or non-surgical invasive therapy (hazard ratio, 0.69; 95% confidence interval, 0.63-0.76, P < 0.001). CONCLUSIONS: Our findings suggest that revising all relevant clinical pathways was highly effective in reducing antibiotic consumption and shortening the antibiotic administration period without increasing the incidence of SSIs. PMID- 30414353 TI - Screening of Hyperlipidemia among Patients with Rheumatoid Arthritis in the United States. AB - OBJECTIVE: To determine the proportion of primary lipid screening among patients with rheumatoid arthritis (RA) and compare it with patients with diabetes mellitus (DM) and patients with neither RA nor DM. To determine whether primary lipid screening varied according to the healthcare provider (rheumatologist vs. non-rheumatologist). METHODS: We analyzed claims data from United States' private and public health plans from 2006-2010. Eligibility requirements included: 1) continuous medical and pharmacy coverage for >=12 months (baseline period), and 2) >2 physician diagnoses and relevant medications to define 4 disease categories: RA, DM, RA and DM, or neither condition. Among the 330,695 eligible participants, we calculated the proportion with a lipid profile ordered during the 2 years following baseline. Time-varying Cox proportional hazard models were used to determine the probability of hyperlipidemia screening in participants with RA according to provider specialty. RESULTS: Over half the patients were 41 71 years old. Among patients with RA (n=12,182), DM (n=62,834), RA and DM (n=1,082), and neither condition (n=167,811), the proportion screened for hyperlipidemia was 37%, 60%, 55%, and 41%, respectively. Patients with RA who visited a rheumatologist and a non-rheumatology clinician during follow-up had a 55% (95% CI [1.36, 1.78]) higher screening probability than those who only visited a rheumatologist. CONCLUSION: Primary lipid screening was suboptimal among RA patients. It was also lower than patients with DM and minimally different from the general population. Screening was higher for RA patients receiving care from both a rheumatologist and a non-rheumatologist (e.g. primary care physician). This article is protected by copyright. All rights reserved. PMID- 30414354 TI - A 49-Year-Old Man with Debilitating Aches and Pains and a Mysterious Culprit. AB - The patient reported pain that started insidiously in his feet and gradually progressed proximally from the lower extremities to the pelvis, spine and chest. He described it as dull and aching, constant and exacerbated by minimal movement and even inspiration. He complained of frequent severe muscle spasms, cramps, progressive weakness and difficulty with ambulation leading to the use of a wheelchair. He also reported being diagnosed with multiple non-traumatic rib fractures. He had seen multiple physicians in the past for his condition and was given a multitude of treatments without effect. Non-steroidal anti-inflammatory medications provided minimal relief. He had been treated with sulfasalazine 2 gm po daily, golimumab 50 mg subcutaneously once monthly for 6 months then etanercept 50 mg subcutaneously once weekly for 6 months for "presumed spondyloarthritis" with no effect. He was diagnosed with fibromyalgia by other physicians and was prescribed pregabalin without improvement. He denied using any other medications. This article is protected by copyright. All rights reserved. PMID- 30414355 TI - Process development for an inducible rituximab-expressing Chinese hamster ovary cell line. AB - Inducible mammalian expression systems are becoming increasingly available and are not only useful for the production of cytotoxic/cytostatic products, but also confer the unique ability to uncouple the growth and production phases. In this work, we have specifically investigated how the cell culture state at the time of induction influences the cumate-inducible expression of recombinant rituximab by a GS-CHO cell line. To this end, cells grown in batch and fed-batch cultures were induced at increasing cell densities (1 to 10 * 10 6 cells/mL). In batch, the cell specific productivity and the product yield were found to reduce with increasing cell density at induction. A dynamic feeding strategy using a concentrated nutrient solution applied prior and postinduction allowed to significantly increase the integral of viable cells and led to a 3-fold increase in the volumetric productivity (1.2 g/L). The highest product yields were achieved for intermediate cell densities at induction, as cultures induced during the late exponential phase (10 * 10 6 cells/mL) were associated with a shortened production phase. The final glycosylation patterns remained however similar, irrespective of the cell density at induction. The kinetics of growth and production in a 2 L bioreactor were largely comparable to shake flasks for a similar cell density at induction. The degree of galactosylation was found to decrease over time, but the final glycan distribution at harvest was consistent to that of the shake flasks cultures. Taken together, our results provide useful insights for the rational development of fed-batch cell culture processes involving inducible CHO cells. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 2018. PMID- 30414356 TI - Comparison of Electrocardiographic Biomarkers for Differentiating Drug-induced Single vs. Multiple Cardiac Ion Channel Block. AB - Since introduction of the ICH proarrhythmia guidelines in 2005, no new marketed drugs have been associated with unacceptable risk of TdP. Although cardiac safety improved, these guidelines had the unintended consequence of eliminating potentially beneficial drugs from pipelines early in development. More recently, it has been shown that a QTc prolonging drug may be safe if it impacts multiple ion channels vs. only hERG and that this effect can be discriminated using QT subintervals. We compared the predictive power of four ECG repolarization metrics to discriminate single vs. multichannel block: a) traditional 10-sec signal averaged triplicates, and b) three metrics that employed increasing density of automatically measured beat-to-beat (btb) intervals. Predictive power was evaluated using logistic regression and quantified with receiver operating characteristic area under the curve. Compared to the traditional 10-sec signal averaged triplicates, the reduction in classification error ranged from two to six with increasing density of btb measurements. This article is protected by copyright. All rights reserved. PMID- 30414357 TI - Pharmacokinetic and pharmacodynamic considerations in the design of therapeutic antibodies. AB - The design and development of therapeutic monoclonal antibodies through optimizing their pharmacokinetic (PK) and pharmacodynamic (PD) properties is crucial to improve efficacy while minimizing adverse events. Many of these properties are interdependent, which highlights the inherent challenges in therapeutic antibody design, where improving one antibody property can sometimes lead to changes in others. Here, we discuss optimization approaches for PK/PD properties of therapeutic mAbs. This article is protected by copyright. All rights reserved. PMID- 30414358 TI - Circulating Oxidized Low-Density Lipoprotein is a Strong Risk Factor for the Early Stage of Coronary Heart Disease. AB - This study aimed to detect the circulating oxidized low-density lipoprotein (ox LDL) levels of controls and patients with stable angina pectoris (SAP), unstable angina pectoris (UAP), and acute myocardial infarction (AMI) and also to investigate the correlation with the severity of coronary heart disease (CHD). Plasma levels of circulating ox-LDL-4E6, malondialdehyde (MDA), high-sensitivity C-reactive protein (hs-CRP), total cholesterol, high-density lipoprotein cholesterol, LDL cholesterol, apoprotein A, apoprotein B, and lipoprotein (a) (Lp(a)) were measured in 99 participants who underwent coronary angiography. The plasma ox-LDL level was significantly higher in patients with CHD than in controls (P = 0.000). However, it was lower in the UAP and AMI groups than in the SAP group (P = 0.000). The lipid peroxide level (MDA) showed a significant difference among all groups (P = 0.000). It increased significantly in patients with CHD. The Lp(a) and hs-CRP levels were significantly higher in patients with CHD (P = 0.000 and 0.000, respectively). No difference in Lp(a) was found among the SAP, UAP, and AMI groups (P = 0.296). In patients with CHD, the plasma ox-LDL correlated negatively with hs-CRP (P = 0.011), and serum MDA correlated positively with hs-CRP (P = 0.004). The plasma ox-LDL could be used as a strong risk factor for the early stage but not the advanced stage of CHD. Hs-CRP may bound and transfer ox-LDL to macrophages. (c) 2018 IUBMB Life, 2018. PMID- 30414359 TI - Olfaction and Colour Vision: What Can They Tell Us about Parkinson's Disease? AB - Parkinson's disease is a neurodegenerative disorder with the pathological accumulation of alpha synuclein in the brain and peripheral nerve tissue. Early stages of synucleinopathies, often present clinically with rapid eye movement (REM) sleep disorder (RBD). Clinical markers that indicate early progression from RBD to manifest synucleinopathies include abnormal dopamine transporter (DAT) imaging, motor and non-motor symptoms. Despite the high diagnostic strength of DAT imaging and motor abnormalities, they are not the earliest biomarkers. Non motor signs of neurodegeneration such as colour vision and olfaction abnormalities are detectable by clinical examination as early as 20 years before disease onset. Detailed analysis of olfactory and colour vision dysfunction can provide valuable information regarding brain pathologies, further specifying clinical phenotypes, and giving clues to underlying pathophysiological mechanisms in Parkinson's disease and related disorders. PMID- 30414360 TI - Anorectal Malignant Melanoma: Retrospective Analysis of Six Patients and Review of the Literature. AB - Malignant melanomas are rare aggressive tumours originating from the pigment producing melanocytes. In our study, a review of the literature and a retrospective analysis of patients undergoing surgery at our clinic due to anorectal malignant melanoma were performed. The information of 6 patients undergoing surgery in our clinic due to anorectal malignant melanoma between January 2010 and January 2018 was retrieved retrospectively. The patients were assessed regarding demographic data, physical examination and imaging findings, the surgical method performed, postoperative complication, histopathological findings, oncological treatment and follow-up results. Four of the patients were female and 2 were male and the mean age was 61.6 (46-83) years. Two patients (33%) had liver metastases at the time of initial presentation. Abdominoperineal resection (APR) was performed in all patients 3 with laparoscopic method. The mean length of hospital stay was recorded to be 6.5 +/- 1 days (5-12 days). Adjuvant chemotherapy and radiotherapy were administered in all patients. Also, interferon treatment was administered in one patient additionally. During the follow-up, 4 patients died due to extensive metastatic disease determined approximately in the 13th month. Two patients with regular follow-up are well and free of disease and their mean postoperative lifetime has been determined to be 12.5 months (6-26 months). Anorectal malignant melanomas (ARMM) are rare but aggressive tumours. The treatment should be focused on minimizing morbidity and maximizing the quality of life and function while removing the gross tumour. PMID- 30414361 TI - Minimally Invasive Fibrin Sealant Application in Pilonidal Sinus: A Comparative Study. AB - The aim of this study was to compare the filling of the pilonidal sinus tract with fibrin sealant (FS) against tract excision and primary closure (PC) as the primary procedure. Details of all patients who underwent treatment for a symptomatic first episode of pilonidal sinus disease between January 2011 and December 2015 were prospectively recorded in a custom database. Patients underwent PC (n=17) or FS (n=17) according to patient preference. Prior surgical treatment and ongoing infection precluded entry. Patients were treated with antibiotics if presenting with infection. Outcomes measured were recurrence, further procedures, outpatient attendances and length of follow-up to resolution. 34 consecutive patients [FS vs. PC: male n=15 vs. 12 p=0.398; mean age 29 (SEM 12) vs. 30 (SEM 15) p=0.849] were included. Treated preoperative infections were similar FS (n=5) vs. PC (n=12) (p=0.038, chi-squared test). FS cohort had more sinuses FS median (range) 2 (1-4) vs. PC 1 (1-3) (p=0.046). Postoperative outcomes: recurrence rate FS (n=5) vs. PC (n=4) (p=0.629); infection rate FS (n=1) vs. PC (n=8) (p=0.045); total number of operations required FS 1 (1-2) vs. PC 1 (1-4) (p=0.19); total number of outpatient attendance FS 2 (1-7) vs. PC 3 (1 16) (p=0.629); follow-up FS 129 days +/- 33 vs. PC 136 +/- 51 (p=0.914). Fibrin sealant is not inferior to excision followed by primary closure. PMID- 30414362 TI - The Effect of Concurrent Tetanus-diphtheria Vaccination on the Antibody Response to Rabies Vaccine: A Preliminary Study. AB - The number of studies in the literature investigating the effect of tetanus vaccination on rabies prophylaxis is rather limited. In this study, we aimed to investigate the effect of concurrent tetanus-diphtheria (Td) vaccination on the antibody response to rabies vaccine. The data of consecutive 80 patients who presented to Sakarya University Training and Research Hospital, Department of Emergency due to rabies suspected exposure between 15 October 2012 and 12 June 2013 were enrolled to this study. Postexposure rabies prophylaxis had been given to all cases, however concurrent tetanus vaccination had been administered to some of them according to their need. Cases were divided into two parts according to their receipt of tetanus prophylaxis as rabies only group (group R, n=37), and rabies and tetanus-diphtheria group (group R+Td, n=43). Rabies antibody levels were tested in sera of the cases at first and postvaccination 21st day. The median antibody levels of each group were measured and compared with each other statistically. In our study, postvaccination 21st day antibody level of group R was 0.68 IU/ml (IQR: 0.79), while the same for group R+Td was 0.52 IU/ml (IQR: 0.48) (p=0.022). Concurrent administration of Td vaccine was found to have a significant negative effect on the antibody response to rabies vaccine. Our results should be confirmed with further studies including more cases. PMID- 30414363 TI - Cervicomedullary Ganglioglioma in a Child - A Case Report. AB - Ganglioglioma is a benign slow-growing neoplasm that most frequently occurs at the supratentorial region. Nevertheless, there are occasional reports of ganglioglioma occurring in the brainstem and spinal cord. Here we report a rare case of the craniocervical ganglioglioma. A 3.5-year-old male, presented with severe progressive quadriparesis, gait disturbance, and sphincter deficit. Physical examination demonstrated the quadriparesis, associated with positive Hoffman, Babinski, and clonus signs, and increased respond of deep tendon reflexes. Magnetic resonance imaging (MRI) demonstrated an ill-defined mass within medulla and upper cervical spinal cord, which was hypo to iso signal on T1, heterogeneous iso to hypersignal on T2 and demonstrated marked bright enhancement on T1 with gadolinium (Gad) injection. On surgery, the mass had a soft texture, ill-defined border, and grey to brown appearance. According to the frozen section report, and due to the absence of the tumour-neural parenchymal interference, only decompression of the tumour and expansile duraplasty were performed. The histopathology revealed ganglioglioma. On last follow-up 14 months after surgery, the patient was asymptomatic and neurological status was improved. The craniocervical MRI demonstrated the tumour that did not grow. Although it is rare, the ganglioglioma should be in the differentiated diagnoses of tumours with compatible clinical and radiologic features even in the unusual locations, especially in the pediatric and young patients. Safety surgical resection should be considered in these patients, whenever possible. In the case of partial resection, that is common in the tumours located within functionally critical structures, long close follow-up rather than radiation therapy is required. PMID- 30414365 TI - Rheumatology in Portugal: 70 years improving the future for rheumatic patients. PMID- 30414364 TI - Effect of baseline renal and hepatic function on the incidence of adverse drug events: the Japan Adverse Drug Events study. AB - Background The impact of renal and hepatic dysfunction on the morbidity and mortality of inpatients with adverse drug events (ADEs) is uncertain in daily clinical practice. The objective of this study was to investigate the effect of renal and hepatic function on ADEs and inpatients' morbidity and mortality. Methods The Japan Adverse Drug Events (JADE) study was a prospective cohort study carried out at three tertiary-care teaching hospitals in Japan. Participants were consecutive inpatients (n=3459) aged 15 years or older. We evaluated the effect of renal and hepatic function on the occurrence of ADEs, and assessed how they affected length of hospital stay (LOS) and in-hospital mortality. We used the estimated glomerular filtration rate to quantify renal function and categorized patients into three groups (normal, >=60 mL/min/1.73 mm; moderate, >=30 and <60 mL/min/1.73 mm; severe, <30 mL/min/1.73 mm). We defined patients as having hepatic dysfunction when at least one data point (total bilirubin, aspartate aminotransferase, alanine aminotransferase, or gamma glutamyltransferase) was beyond a cutoff value. Results We analyzed the laboratory data of 2508 patients. There was a significant difference in the occurrence of ADEs among the three GFR categories (normal, 20%; moderate, 26%; severe, 22%; p=0.02). More ADEs occurred in patients with hepatic dysfunction (25% vs. 20%, p=0.01). LOS was significantly longer in those with ADEs stratified either by renal or by hepatic dysfunction (p<0.0001). ADEs were independently associated with in-hospital mortality, adjusting for renal and hepatic function (p<0.0001). Conclusions Inpatients' organ dysfunction increased ADEs, and ADEs were associated with both LOS and in hospital mortality independently, irrespective of renal and hepatic function. PMID- 30414366 TI - Ozone therapy for low back pain. A systematic review. AB - BACKGROUND: Low back pain associated with lumbar disc herniation is common in the general population, with evident repercussion in quality of life and a significant economic burden. Patients refractory to conservative treatment seek additional treatment and minimally invasive interventions were proposed as valid options. Ozone therapy has been suggested as an alternative due to its potential analgesic and anti-inflammatory effect. OBJECTIVE: This systematic review aims to investigate the effectiveness and safety of ozone therapy for low back pain in patients with lumbar disc herniation. MATERIAL AND METHODS: A systematic search was performed in Pubmed and Scopus, followed by a three-step selection process. Data was processed by 2 independent reviewers and information was gathered based in pre-defined variables. Only articles performed in humans; original and English written; on treatment with ozone; comparing the result of ozone therapy (experimental group) with another non-ozone intervention (control group); and on patients with lumbar pain and disc hernia, were included. RESULTS: From 439 references retrieved after duplicates removal, inclusion and exclusion criteria were applied, and 7 studies were included in the final revision. One article compared treatment with ozone versus placebo, one ozone and global postural re education versus global postural re-education alone, two the combination of ozone with steroid versus steroid alone, two ozone versus steroid and one ozone versus micro-discectomy. All but the study comparing ozone application with micro discectomy, showed similar or better results in the experimental group. Only three studies evaluated the presence of side effects. In two papers no complication was reported, and in the other, a low percentage of adverse effects was observed, not significantly different between the two study groups. CONCLUSIONS: Only a small number of poor quality studies on ozone effect in low back pain and disc herniation were available for inclusion in our review. Nevertheless, these reported an improvement in pain and functional scores with its application. Complications, mostly minor, but potentially serious are underreported. Additional studies with adequate and consistent methodologies are needed before the role of ozone can be established in the management of low back pain. PMID- 30414367 TI - Non-pharmacological and non-surgical interventions to manage patients with knee osteoarthritis: An umbrella review. AB - Objective - Update the last known umbrella review and summarize the available high-quality evidence from systematic reviews on the effectiveness of non pharmacological and non-surgical interventions for patients with knee OA. Methods - The systematic reviews were identified thought electronic databases such as, MEDLINE, Embase, Physiotherapy Evidence Database (PEDro), The Cochrane Library, SciELo, Science Direct, Google Scholar, Research Gate and B-ON. The studies selection respected the following terms to guide the search strategy using the P (humans with knee osteoarthritis) I (non-pharmacological and non-surgical treatments) C (pharmacological, surgical, placebo, no intervention, or other non pharmacological/ non-surgical conservative treatments) O (pain, functional status, stiffness, inflammation, quality of life and patient global assessment) model. Results - Following the PRISMA statement, 41 systematic reviews were found on the electronic databases that could be included in the umbrella review. After methodical analysis (R-AMSTAR), only 35 had sufficient quality to be included. There is gold evidence that Standard Exercise programs can reduce pain and improve physical function in patients with knee OA. Additionally, there is silver evidence for Acupuncture, Aquatic Exercise, Electroacupuncture, Interferential Current, Kinesio Taping, Manual Therapy, Moxibustion, Pulsed Electromagnetic Fields, Tai Chi, Ultrasound, Yoga, and Whole-Body Vibration. For other interventions, the quality of evidence is low or did not show sufficient efficacy from the systematic reviews to support their use. Conclusion - Comparing to last known umbrella review, similar results were achieved on Acupuncture and Exercise interventions to improve the patients' pain, stiffness, function and quality of life, but it was found different results regarding the utilization of Transcutaneous Electrical Nerve Stimulation and Low-Level Laser Therapy as they do not improved the patients' pain and physical function. PMID- 30414368 TI - Bone biopsy: an ally in the management of fragility fractures in chronic kidney disease. AB - Patients with chronic kidney disease (CKD) have an increased susceptibility to fracture and this risk gradually rises as renal disease progresses. Chronic Kidney Disease-Mineral and Bone Disorder (CKD- MBD) encompasses the mineral, bone, hormonal and calcific cardiovascular abnormalities that develop in these patients. Renal osteodystrophy (ROD) corresponds to the histopathologic description of bone lesions associated with CKD-MBD. Fragility fracture approach in CKD stages 1-3a may be similar to that of the general population. However, in stages 3b-5, osteoporosis cannot be established by the World Health Organization (WHO) criteria based on bone mineral density (BMD) or the presence of fragility fractures, because low BMD and fractures can also occur in the different forms of ROD. The gold standard for the diagnosis and classification of ROD is tetracycline double-labelled transiliac bone biopsy, with bone histology and histomorphometric analysis. By informing on bone turnover, mineralization and volume, it is a valuable tool that may help guide the management of CKD patients with fragility fractures, as therapeutic measures are distinct depending if the patient has osteoporosis or one of the forms of ROD. For patients with stages 1-3 CKD, without biochemical abnormalities suggestive of CKD-MBD, who sustained low trauma fractures, any therapeutic approved for use in osteoporosis could be used. However, there is little evidence for the efficacy and safety of conventional anti-osteoporotic agents in patients with more advanced CKD stages, so currently the approach is opinion-based and must be patient-tailored depending on the presence or absence of ROD. PMID- 30414369 TI - Non-invasive Oxygen-Ozone therapy in treating digital ulcers of patients with systemic sclerosis. AB - BACKGROUND: Digital ulcers (DUs) in Systemic sclerosis (SSc) result from recurrent Raynaud's phenomenon (RP) and microtrauma with high impact on quality of life. Medical use of ozone (triatomic oxygen) was initiated in the 19th century. Ozone has multiple therapeutic effects in wound healing due to the property of releasing nascent oxygen, which has been shown to stimulate antioxidant enzymes. We aimed to assess the effects of ozone therapy on the healing of scleroderma DUs and determine levels of expression of vascular endothelial growth factor (VEGF), and endothelin-1 type A receptor (ETAR) autoantibodies in the wounds after treatment. SUBJECTS AND METHODS: Fifty SSc female patients with DUs, were randomized into ozone group (I) (n=25) treated by calcium channel blockers plus oxygen-ozone treatment and control group (II) (n=25) treated by calcium channel blockers only. Ozone group received noninvasive oxygen-ozone treatments for 30 minutes per day for 20 days using the ozone generator device. Therapeutic effects were graded into 4 levels according to Zhang and other researchers. The wounds sizes were measured at baseline and day 20, respectively. Expressions of VEGF and ETAR autoantibodies proteins were determined by immune-histochemical examination. RESULTS: Demographics and clinical characteristics of the 2 groups showed no significant differences. At day 20, the effective healing rate was significantly higher in group (I) than in group (II), where it represented 96% (24/25) in ozone group versus 44% (11/25) in control group, and (?? = 0.007). After treatment, the wound sizes in both groups were significantly smaller than before treatment. In group (I), the wound size reduction was significantly more than in group (II) (0.75 +/- 0.30 versus 2.44 +/ 0.80 mm), (?? = 0.00). At day 20, VEGF was significantly higher in ozone group (I), than in control group (II), (83.96+/-9.68) versus (67.92+/-6.55), (?? = 0.00) while, ETAR was significantly lower in ozone group (I), than in control group (II), (3.14+/-1.12 versus 4.59+/-1.24), (?? = 0.00). CONCLUSION: Ozone therapy may be beneficial tool in the treatment of DUs in SSc patients, where it promotes the wound healing through a potential induction of VEGF and down regulation of ETAR at sites of the ulcers. PMID- 30414370 TI - Whole peripheral blood miR-146a and miR-155 expression levels in Systemic lupus erythematosus patients. AB - Objective: To evaluate the diagnostic value of peripheral blood microribonucleic acid (miRNA, miR)-146a and miR-155 expression in systemic lupus erythematosus (SLE). Methods: Expression levels of miR-155 and miR-146a in whole peripheral blood samples from 40 SLE patients and 32 healthy controls (HCs) were determined by quantitative reverse transcription-polymerase chain reaction qRT-PCR (SYBR Green technology) and 2-??Ct method was used for analysis. SPSS v20 was used for receiver operating characteristic (ROC) curve and Spearman correlation analysis. Results: Whole peripheral blood expression levels of miR-146a and miR-155 were overexpressed in 62.5% and 50%, respectively, of the SLE patients compared to HCs. The ROC curve analysis showed that the expression levels of miR-146a could discriminate SLE patients from HCs with area under the curve (AUC)=0.711 (95% CI: 0.585/0.837, p=0.002, with 82.5% sensitivity and 56.2% specificity. The diagnostic accuracy of miR-155 was lower with AUC=0.691 (95% CI: 0.566/0.817, p=0.005, with 77.5% sensitivity and 50.0% specificity. The diagnostic accuracy did improve when combination of the studied miRNAs was used in multimarker ROC curve analysis (AUC=0.716, 95% CI: 0.590/0.842, p=0.002, 82.5% sensitivity and 56.2% specificity). miR-146a and miR-155 showed correlation with the diagnosis (rs=0.363 and 0.330, respectively) and the age of the patients (rs =0.239 and 0.366, respectively), and miR-155 showed correlation with the presence of secondary Raynaud syndrome (Spearman correlation coefficient=0.250) Conclusions: Our data showed that the expression levels of miR-146a and miR-155 in PB could be used as diagnostic biomarkers for SLE patients but larger study is needed to confirm these results. Key words: peripheral blood, miRNA, expression, systemic lupus erythematosus, biomarker. PMID- 30414371 TI - Immunoglobulin G4-related disease with recurrent uveitis and kidney tumor mimicking childhood polyarteritis nodosa: a rare case report. AB - INTRODUCTION: Immunoglobulin G4-related disease (IgG4-RD) is an condition rarely reported in children. Additionally, IgG4-RD may rarely mimic vasculitis in adults and may infrequently present with uveitis. In our service, 6,198 patients were followed-up and only one (0.0001%) of them had IgG4-RD. To our knowledge, the present IgG4-RD case was the first mimicking childhood polyarteritis nodosa (c PAN) with recurrent uveitis and kidney tumor. CASE REPORT: We describe herein a 7 year-old boy that presented intermittent fever. He developed arthralgia, weight loss, myalgia, skin lesions and recurrent uveitis. Skin biopsy revealed necrotizing vasculitis in medium/small sized vessels associated with septal panniculitis suggesting cPAN. Prednisone and azathioprine were administered with improvement. At 11 years, he had persistent fever and abdominal angiotomography revealed a large tumor in left kidney and he was then submitted to nephrectomy. The renal histopathology showed lymphoplasmacytic and histiocytic proliferation with extensive areas of fibrosis, and lymphomonocitic phlebitis with presence of IgG4 in 43 plasmocyte cells, suggesting IgG4-RD. DISCUSSION: we present herein a unique case of a male pediatric patient with IgG4-RD with rare ocular, cutaneous and renal manifestations. PMID- 30414372 TI - Pulmonary involvement in neonatal lupus: a challenging diagnosis - case report and literature review. AB - INTRODUCTION: Pulmonary involvement is relatively frequent in adult and juvenile patients with Systemic Lupus Erythematosus (SLE), but its occurrence in newborns with Neonatal Lupus Erythematosus (NLE) is exceedingly rare. CASE REPORT: A mother with SLE and positive anti-SSA/Ro and anti-SSB/La delivered a preterm newborn with third-degree heart block and positive anti-SSA/Ro confirmed postnatally. A temporary pacemaker was placed at D3 and a definitive pacemaker only at D15 due to sepsis with concurrent mild respiratory failure. Despite adequate antibiotic therapy, negative cultures and decreasing inflammatory parameters, at D17 severe respiratory failure ensued, requiring mechanical ventilation. Chest x-ray showed symmetrical interstitial infiltrates. Acute Lupus Pneumonitis (ALP) and Pulmonary Embolism were suspected and the chest angio-CT revealed diffuse ground glass opacities. After 3 methylprednisolone pulses he improved rapidly. DISCUSSION: The diagnosis of ALP in NLE, mostly one of exclusion, is a challenge. A high degree of suspicion and a multidisciplinary approach to these patients are fundamental in order not to delay establishing a diagnosis. Although few reports in the literature, early aggressive treatments are probably crucial for a favorable outcome without long-term sequelae. PMID- 30414373 TI - Neonatal Lupus Erythematosus in a newborn with Citrullinemia. AB - A 24-day-old female newborn presented with multiple annular erythematous plaques with a targetoid shape, on the forehead, neck and upper trunk, that had begun ten days earlier. She had been diagnosed with citrullinemia type 1 in the first week of life and arginine supplementation was initiated. Her personal and family history was otherwise unremarkable. Laboratory tests showed high levels of anti La/SSB and anti-Ro/SSA in both mother and baby. The patient was diagnosed with Neonatal lupus erythematosus on the basis of the clinical, histopathological and laboratorial findings. Neonatal lupus is a rare immune-mediated disease that results from transplacental transfer of maternal IgG antinuclear antibodies. The disease can affect different organs, mainly the skin and heart. Although the skin lesions are usually characteristic, they pose a diagnostic challenge in the absence of maternal history. PMID- 30414374 TI - Iloprost infusion through elastomeric pump for the outpatient treatment of severe Raynaud's phenomenon and digital ulcers - a single centre experience. AB - Raynaud's phenomenon (RP) and digital ulcers (DU) are the main clinical features of vasculopathy that occurs in several systemic rheumatic diseases. Intravenous iloprost is recommended for the treatment of severe RP and DU in patients with systemic sclerosis and portable devices for iloprost infusion have been recently designed, allowing outpatient treatment. This new alternative for drug administration not only avoids absenteeism, with the patient having the opportunity to continue his own family and work life, but also reduces the costs associated with hospitalization. We describe our protocol and report our experience with 12 patients, for a total of 25 infusions, who have received domiciliary iloprost through elastomeric pump. Patients could easily manage the device and the treatment outcomes were promising, with all patients having DU healing, without any special safety concerns. PMID- 30414375 TI - Presence of anti-Porphyromonas gingivalis-peptidylarginine deiminase antibodies in serum from juvenile systemic lupus erythematosus patients AB - The presence of a biofilm-associated gingival inflammation in patients having juvenile systemic lupus erythematosus (jSLE) might function as a reservoir of anaerobic Gram-negative bacteria such as Porphyromonas gingivalis. Porphyromonas gingivalis also express functional endogenous peptidylarginine deiminase (PAD) enzymes, which catalyzes a citrullination reaction that can lead to formation of citrullinated peptides. We analyzed 30 patients with jSLE (16.2+/-1.5 years-old) and 29 healthy controls (15.4+/-2.3 years old jSLE was diagnosed according to the criteria of the American College of Rheumatology. The individuals underwent a full-mouth periodontal examination and were diagnosed with biofilm-associated gingival inflammation. Blood samples were taken and serum levels anti-PPAD IgG were determined by ELISA, and the results were expressed in arbitrary units (AU). The presence of Porphyromonas gingivalis was confirmed using the checkerboard DNA DNA hybridization. Porphyromonas gingivalis was detected in both groups without any significant difference between them (p=0.58). The median levels of anti-PPAD were 0.54 AU (0.40 - 0.77) in juvenile SLE patients and 0.48 AU (0.26 - 0.97) in the control group (p=0.95). This is the first study to report the presence of anti-PPAD antibodies in serum from jSLEpatient. PMID- 30414376 TI - Seronegative cat scratch disease in a patient with systemic lupus erythematosus. PMID- 30414377 TI - Agreement and Repeatability of Two Biometers to Measure Anterior Segment Components: Refractive Error Effect. AB - BACKGROUND To assess the repeatability and agreement between a new high resolution optical coherence tomographer (OCT) and a Scheimpflug topographer. MATERIAL AND METHODS Sixty phakic and healthy participants were measured in this study, and one eye per participant was analyzed. Depending on their refractive error, each participant was allocated into a myopic, hyperopic, or emmetropic group. The Cirrus HD-OCT 5000 (Carl Zeiss Meditec, Jena, Germany), and the Sirius Scheimpflug topographer (Costruzione Strumenti Oftalmici, Florence, Italy) were used to take all measurements. RESULTS The repeatability of these instruments to measure the anterior chamber depth, angle-to-angle, thinnest pachymetry, and both nasal and temporal angles was smaller than 0.15 mm, 0.40 mm, 10 um, and 10 degrees, respectively. However, the repeatability of the Scheimpflug instrument to measure the apex pachymetry was about 15 um, and for the OCT, it was about 4 um for all groups. On average, the Sirius Scheimpflug instrument measured shallower anterior chamber depth (about 0.10 mm), shorter angle-to-angle (about 0.5 mm), thinner corneas (approximately 10 um), and narrower angles (around 5 degrees) for all refractive groups. CONCLUSIONS The repeatability of the Cirrus OCT and Sirius Scheimpflug instrument was good and independent of the refractive error. Nevertheless, to judge whether these instruments could be used interchangeable, clinical criteria are needed. PMID- 30414378 TI - Histamine Receptors and Cancer Pharmacology: An Update. AB - In the present review we will discuss the recent advances in the understanding of the role of histamine and histamine receptors in cancer biology. The controversial role of the histaminergic system in different neoplasias including gastric, colorectal, oesophageal, oral, pancreatic, liver, lung, skin, blood and breast cancers will be reviewed. The expression of histamine receptor subtypes, with special emphasis in histamine H4 receptor (H4R), in different cell lines and human tumours, the signal transduction pathways and the associated biological responses as well as the in vivo treatment of experimental tumours with pharmacological ligands will be described. The presented evidence demonstrates that histamine regulates cancer-associated biological processes during cancer development in multiple cell types, including neoplastic cells and cells of tumour microenvironment. The outcome will depend on tumour cell type, histamine receptors expression, signal transduction associated to those receptors, tumour microenvironment and histamine metabolism, supporting the complexity of cancer disease. Findings show the pivotal role of H4R in the development and progression of many types of cancers, and considering its immunomodulatory properties, H4R arises as the most promising molecular therapeutic target for cancer treatment within histamine receptor family. Furthermore, H4R is differentially expressed in tumours compared with normal tissues and in most cancer types in which data was available, H4R expression is associated to clinicopathological characteristics, suggesting that H4R might represent a novel cancer biomarker. PMID- 30414379 TI - Isolation and Culture of Microglia. AB - Microglia represent 5-10% of cells in the central nervous system and contribute to the development, homeostasis, injury, and repair of neural tissues. As the tissue-resident macrophages of the central nervous system, microglia execute core innate immune functions such as detection of pathogens/damage, cytokine secretion, and phagocytosis. However, additional properties that are specific to microglia and their neural environment are beginning to be appreciated. This article describes approaches for purification of microglia by fluorescence activated cell sorting using microglia-specific surface markers and for enrichment of microglia by magnetic sorting and immunopanning. Detailed information about culturing primary microglia at various developmental stages is also provided. Throughout, we focus on special considerations for handling microglia and compare the relative strengths or disadvantages of different protocols. (c) 2018 by John Wiley & Sons, Inc. PMID- 30414380 TI - Th1 type immune responses to Porphyromonas gingivalis antigens exacerbate Angiotensin II dependent hypertension and vascular dysfunction. AB - BACKGROUND AND PURPOSE: Emerging evidence indicates that hypertension is mediated by immune mechanisms. We hypothesized that exposure to Porphyromonas gingivalis antigens, commonly encountered in periodontal disease, can enhance immune activation in hypertension and exacerbate blood pressure elevation, vascular inflammation and vascular dysfunction. EXPERIMENTAL APPROACH: Th1 immune response were elicited through immunizations using Porphyromonas gingivalis lysate antigens (10ug) conjugated with aluminium oxide (50ug) and IL-12 (1ug). The hypertension and vascular endothelial dysfunction evoked by sub-pressor doses of Angiotensin II (0.25mg/kg/day) were studied and vascular inflammation was quantified by flow cytometry and real time polymerase chain reaction. KEY RESULTS: Systemic T cell activation, characteristic for hypertension, was exacerbated by P. gingivalis antigen stimulations. This translated into increased aortic vascular inflammation with enhanced leukocytes, in particular, T cell and macrophage infiltration. Expression of the Th1 cytokines, Interferon-gamma and Tumour Necrosis Factor-alpha and the transcription factor TBX21 was increased in aortas of P. gingivalis/Interleukin-12/aluminium oxide immunized mice, while IL-4 and TGF-beta were unchanged. These immune changes in mice with induced T helper type 1 immune responses were associated with enhanced blood pressure elevation and endothelial dysfunction compared to control mice in response to two weeks infusion of a sub-pressor dose of Angiotensin II. CONCLUSION AND IMPLICATIONS: These studies support the concept that Th1 immune responses induced by bacterial antigens such as P. gingivalis can increase sensitivity to sub-pressor pro hypertensive insults such as low dose Angiotensin II, therefore providing a mechanistic link between chronic infection such as periodontitis and hypertension. PMID- 30414381 TI - Mitochondrial protective effect of neferine through the modulation of Nrf2 signalling in ischemic stroke. AB - BACKGROUND AND PURPOSE: Ischemic stroke is a leading cause of death and long-term disability. Promising neuroprotective compounds are urgently needed to overcome the clinical therapeutic limitations. Neuroprotective agents are limited to single-target agents, which further limited their clinical effectiveness. Due to the brain particular energy requirements, the energy microenvironment, centred in the mitochondria, is a new research hotspot in the complex pathology of ischemic stroke. Here, we studied the effects of neferine (Nef), a bis-benzylisoquinoline alkaloid extracted from the seed embryo of Nelumbo Nucifera Gaertn, on ischemic stroke and its underlying mitochondrial protective mechanisms. EXPERIMENTAL APPROACHES: Permanent middle cerebral artery occlusion (pMCAO)-induced focal cerebral ischemia rats and tert-butyl hydroperoxide (t-BHP)-injured PC12 cells were used to investigate the neuroprotective effects, particularly regarding energy microenvironment regulation by mitochondria and the mechanism of Nef in vivo and in vitro. KEY RESULTS: Nef protected t-BHP-injured PC12 cells in vitro and ameliorated neurological score, infarct volume, regional cerebral blood flow, cerebral microstructure and oxidant-related enzyme deficits in pMCAO rat in vivo. Nef also prevented mitochondrial dysfunction both in vivo and in vitro. The underlying mechanism of mitochondrial protective effect of Nef might be attributed to the increased translocation of Nrf2 to nucleus. Furthermore, the translocation of Nrf2 to nucleus was also decreased by p62 knockdown. CONCLUSIONS AND IMPLICATIONS: The data in this study demonstrated that Nef might have therapeutic potential for ischemic stroke and may exert its protective role through mitochondrial protection. In addition, this protection might be attributed to the modulation of Nrf2 signalling. PMID- 30414382 TI - Growth of E. coli on Solid Media. AB - We provide protocols for titering and isolating bacterial colonies from single cells by serial dilutions, for streaking agar plates, and for spreading suspensions of cells on plates. Support protocols describe replica plating and methods for storing strains as agar stabs and frozen stocks. (c) 2018 by John Wiley & Sons, Inc. PMID- 30414383 TI - SIRT1 represses PKC-zeta activity via regulating interplay of acetylation and phosphorylation in cardiac hypertrophy. AB - BACKGROUND AND PURPOSE: Activation of protein kinase C-zeta (PKC-zeta) is closely linked to the pathogenesis of cardiac hypertrophy. PKC-zeta can be activated by certain lipid metabolites such as phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and ceramide. However, its endogenous negative regulators are not well defined. Here, the role of Sirtuin 1 (SIRT1)-PKC-zeta signaling axis and the underlying molecular mechanisms were investigated in cardiac hypertrophy. EXPERIMENTAL APPROACH: Cellular hypertrophy was monitored by measuring cell surface area and the mRNA levels of hypertrophic biomarkers. Interaction between SIRT1 and PKC-zeta was investigated by co-immunoprecipitation and confocal immunofluorescence microscopy. SIRT1 activation was enhanced by resveratrol (RSV) treatment or Ad-SIRT1 transfection. Cardiac hypertrophy model was established by abdominal aortic constriction (AAC) surgery or induced by isoprenaline in vivo. KEY RESULTS: Overexpression of PKC-zeta led to cardiac hypertrophy and increased activity of nuclear factor-kappaB (NF-kappaB), extracellular regulated protein kinases 1/2 (ERK1/2) and extracellular regulated protein kinases 5 (ERK5), which could be ameliorated by SIRT1 overexpression. Enhancement of SIRT1 activity suppressed acetylation of PKC-zeta, hindered its binding to phosphoinositide dependent kinase-1 (PDK-1) and inhibited PKC-zeta phosphorylation in cardiac hypertrophy. Consequently, PKC-zeta's downstream pathways were suppressed in cardiac hypertrophy. This regulation loop suggests a new role for SIRT1 in mediation of cardiac hypertrophy. CONCLUSIONS AND IMPLICATIONS: SIRT1 is an endogenous negative regulator for PKC-zeta and mediates its activity via regulating the acetylation and phosphorylation in the pathogenesis of cardiac hypertrophy. Targeting SIRT1-PKC-zeta signaling axis may suggest a novel therapeutic approach against cardiac hypertrophy. PMID- 30414384 TI - Reducing overestimation of the treatment effect by interim analysis when designing clinical trials. AB - WHAT IS KNOWN AND OBJECTIVE: Several researchers in the statistical and medical communities have noted the overestimation of the treatment effect when a trial is stopped early in the interim analysis for efficacy; however, methods to reduce this overestimation are rarely used because the overestimation mechanisms are not well understood by many in clinical trial practice. A trial design that leads to less overestimation is needed. METHODS: A computer simulation of hypothetical clinical trials is used to visually explain why the overestimation occurs. A quantitative evaluation of the magnitude of the overestimation is made according to the characteristics of the trial design, such as the total number of events, number of events in the interim analysis, proportion of the number of events to total events and the type of alpha-spending function. RESULTS AND DISCUSSION: When the total number of events was more than or equal to 300 and the proportion of the interim events was larger than 50%, the overestimation was acceptable. Moreover, even if the total number of events was 150, the overestimation was sufficiently small when the proportion of the interim events was >70% and a Pocock type alpha-spending function was used. The overestimation decreased when the total number of events and the proportion of the number of events in the interim analysis increased. In addition, the overestimation of the Pocock type alpha-spending function was smaller in comparison with that of the O'Brien Fleming type, which is widely accepted for confirmatory trials. WHAT IS NEW AND CONCLUSION: We recommend setting the proportion of events in the interim analysis at 50% when the O'Brien-Fleming type alpha-spending function is used in confirmatory trials to reduce the risk of overestimation. In contrast, the Pocock type boundary could be used in explanatory trials. PMID- 30414385 TI - Visualizing Secretory Cargo Transport in Budding Yeast. AB - Budding yeast is an excellent model organism for studying the dynamics of the Golgi apparatus. To characterize Golgi function, it is important to visualize secretory cargo as it traverses the secretory pathway. We describe a recently developed approach that generates fluorescent protein aggregates in the lumen of the yeast endoplasmic reticulum and allows the fluorescent cargo to be solubilized for transport through the Golgi by addition of a small-molecule ligand. We further describe how to generate a yeast strain expressing the regulatable secretory cargo, and we provide protocols for visualizing the cargo by 4D confocal microscopy and immunoblotting. (c) 2018 by John Wiley & Sons, Inc. PMID- 30414386 TI - Generating Model Integrated Evidence for Generic Drug Development and Assessment. AB - Quantitative methods and modeling (QMM) covers a broad spectrum of toolsets of which physiologically-based models and quantitative clinical pharmacology are most critical for generic drugs. QMM has been increasingly applied by the U.S. Food and Drug Administration (FDA) to facilitating generic drug development and review, and has played a critical role in the modernization of bioequivalence (BE) assessment, especially for locally acting drug products, complex products of other types, and modified-release solid oral dosage forms. QMM has aided the development of novel BE methods, in vitro only BE approaches, and risk-based evaluations. The future of QMM is model-integrated evidence or Virtual BE studies that can potentially provide pivotal information for generic drug approval. In summary, QMM is indispensable in modernizing generic drug development, BE assessment, and regulatory decision makings. Regulatory examples demonstrate how QMM can be utilized in modernizing generic drug development, addressing challenges in BE assessment, and supporting regulatory decision-making. This article is protected by copyright. All rights reserved. PMID- 30414387 TI - Pharmacokinetic-pharmacodynamic modelling of platelet response to ticagrelor in stable coronary artery disease and prior myocardial infarction patients. AB - AIM: To characterize ticagrelor exposure-response relationship for platelet inhibition in patients with stable coronary artery disease (CAD) and a history of myocardial infarction (MI), using non-linear mixed effects modelling and simulation. METHODS: Platelet function data were integrated with plasma concentration data of ticagrelor and its active metabolite AR-C1249010XX in a population pharmacokinetic and pharmacodynamic (PK/PD) model, based on two clinical studies. In the ONSET/OFFSET study, PK and platelet function were assessed in 123 CAD patients receiving placebo, ticagrelor (180 mg followed by 90 mg twice daily) or clopidogrel (600 mg followed by 75 mg once daily). In the PEGASUS-TIMI 54 platelet function substudy, PK and platelet function were assessed during maintenance dosing in 180 prior MI patients receiving placebo, ticagrelor 60 mg or ticagrelor 90 mg twice daily. RESULTS: Platelet inhibition by ticagrelor was described by a sigmoidal Emax model. On average, half maximal inhibition was reached at ticagrelor concentrations of 116 (RSE: 5.3%) nmol/L. Simulations showed that near maximal platelet inhibition is achieved with both ticagrelor 60 and 90 mg twice daily. At simulated lower doses, platelet inhibition is overall reduced, more variable between patients, and show greater peak-to-trough variability. Ticagrelor antiplatelet response was similar between the studied patient populations. CONCLUSIONS: In patients with stable CAD or a history of MI, near maximal platelet inhibition is achieved with both ticagrelor 60 and 90 mg twice daily. At modeled doses below 60mg, the response is overall reduced, more variable between patients, and patients will display greater peak to-trough variability. PMID- 30414388 TI - Determination of antioxidant potential of Acacia nilotica leaf extract in oxidative stress response system of Saccharomyces cerevisiae. PMID- 30414389 TI - Non-mitotic effect of albendazole triggers apoptosis of human leukemia cells via SIRT3/ROS/p38 MAPK/TTP axis-mediated TNF-alpha upregulation. AB - Albendazole (ABZ) is a microtubule-targeting anthelmintic that acts against a variety of human cancer cells, but the dependence of its cytotoxicity on non mitotic effect remains elusive. Thus, we aimed to explore the mechanistic pathway underlying the cytotoxicity of ABZ in human leukemia U937 cells. ABZ-induced apoptosis of U937 cells was characterized by mitochondrial ROS generation, p38 MAPK activation, TNF-alpha upregulation and activation of the death receptor mediated pathway. Meanwhile, ABZ induced tubulin depolymerization and G2/M cell cycle arrest. ABZ-induced SIRT3 degradation elicited ROS-mediated p38 MAPK activation, leading to pyruvate kinase M2-mediated tristetraprolin (TTP) degradation. Inhibition of TTP-mediated TNF-alpha mRNA decay elicited TNF-alpha upregulation in ABZ-treated cells. Either the overexpression of SIRT3 or abolishment of ROS/p38 MAPK activation suppressed TNF-alpha upregulation and rescued the viability of ABZ-treated cells. In contrast to the inhibition of ROS/p38 MAPK pathway, SIRT3 overexpression attenuated tubulin depolymerization and G2/M arrest in ABZ-treated cells. Treatment with a SIRT3 inhibitor induced TNF-alpha upregulation and cell death without the induction of G2/M arrest in U937 cells. Taken together, our data indicate that ABZ-induced SIRT3 downregulation promotes its microtubule-destabilizing effect, and that the non mitotic effect of ABZ largely triggers apoptosis of U937 cells via SIRT3/ROS/p38 MAPK/TTP axis-mediated TNF-alpha upregulation. Notably, the same pathway is involved in the ABZ-induced death of HL-60 cells. PMID- 30414390 TI - Endothelial cell transient receptor potential channel C5 (TRPC5) is essential for endothelium-dependent contraction in mouse carotid arteries. AB - Augmented endothelium-dependent contractions (EDC) contributes to endothelial dysfunction and vascular disease progression. An early signal in EDC is cytosolic [Ca2+]i rise in endothelial cells, which stimulates the production of contractile prostanoids, leading to vascular contraction. In this study, the molecular identity of Ca2+-permeable channels in endothelial cells and its function were investigated. Vascular tension was measured by wire myograph. EDCs were elicited by acetylcholine (ACH) in the presence of NG-nitro-l-arginine methyl ester (L NAME). [Ca2+]i was measured using a Ca2+-sensitive fluorescence dye. Enzyme Immunoassay (EIA) was used for prostaglandin measurement. Immunohistochemical staining found the expression of transient receptor potential channel C5 (TRPC5) in endothelial and smooth muscle cells of mouse carotid arteries. ACH-induced EDC in male mouse carotid arteries was found to be substantially reduced in TRPC5 knockout (KO) mice than in wild-type (WT) mice. TRPC5 inhibitors clemizole and ML204 also reduced the EDC. Furthermore, ACH-induced Ca2+ entry in endothelial cells was lower in TRPC5 KO mice than in WT mice. Moreover, the EDC was abolished by a cyclooxygenase-2 (COX-2) inhibitor NS-398, but not affected by a COX-1 inhibitor valeryl salicylate (VAS). Enzyme immunoassay results showed that TRPC5 stimulated the COX-2-linked production of prostaglandin F2alpha (PGF2alpha), prostaglandin E2 (PGE2), and prostaglandin D2 (PGD2). Exogeneous PGF2alpha, PGE2, and PGD2 could induce contractions in carotid arteries. Our present study demonstrated that TRPC5 in endothelial cells contributes to EDC by stimulating the production of COX-2-linked prostanoids. The finding extends our knowledge about EDC. PMID- 30414391 TI - The Processing of Xenografts Will Result in Different Clinical Responses. AB - PURPOSE: Clinicians might decide to use a xenograft to reconstruct an osseous defect. Xenografts are processed differently depending on the manufacturer. The purpose of this article is to review the processing methods and clinical ramifications of these processing methods on the behavior of xenografts. MATERIALS AND METHODS: Differences in surface morphology of xenografts based on processing, xenografts used for sinus augmentation, onlay grafting using particulate xenografts, and available clinical trials are reviewed. RESULTS: When used for grafting the extraction socket or preserving or reconstructing the ridge contour, xenografts can result in different resorption rates over time. CONCLUSION: Based on the available information gleaned from the literature, clinical recommendations are included for specific clinical applications. PMID- 30414392 TI - Exodontia for the Patient With a Left Ventricular Assist Device. PMID- 30414393 TI - Conservative Treatment of a Periapical Cementoblastoma: A Case Report. AB - Cementoblastoma is a rare benign odontogenic neoplasm of ectomesenchymal origin, accounting for fewer than 6% of all odontogenic tumors. Although the tumor characteristics are well known, the standard practice to treat this lesion is surgical excision and extraction of the affected tooth, with few reported cases using a tooth-conservative treatment approach. This report presents the case of a 33-year-old woman with cementoblastoma who underwent conservative treatment to preserve her tooth in the oral cavity. Endodontic treatment of the tooth was performed; 30 days later, the lesion was removed with the apical third of the root of the tooth. After 7 years of follow-up, no recurrence was observed, and the tooth retains its masticatory function. In certain cases of cementoblastoma, the affected tooth can be kept in the oral cavity instead of being extracted, thereby preserving the oral health of patients. PMID- 30414394 TI - Two-stage screening for preterm preeclampsia at 11-13 weeks' gestation. AB - BACKGROUND: Screening for preeclampsia (PE) at 11-13 weeks' gestation by a combination of maternal factors, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and serum placental growth factor (PlGF) (triple test) can predict about 90% of PE, with delivery at <32 weeks (early-PE), and 75% of PE with delivery at <37 weeks (preterm-PE), at a screen positive rate (SPR) of 10%. In pregnancies identified as being at high-risk for PE by such screening, administration of aspirin (150 mg/day from 11-14 weeks' gestation to 36 weeks) reduces the rate of early-PE by about 90% and preterm-PE by about 60%. Recording of maternal history and blood pressure are part of routine prenatal care but measurement of UtA-PI and PlGF require additional costs. OBJECTIVE: To explore the possibility of carrying out first-stage screening in the whole population by maternal factors alone or a combination of maternal factors, MAP and UtA-PI or maternal factors, MAP and PlGF and proceeding to second-stage screening by the triple test only for a subgroup of the population selected on the basis of the risk derived from first-stage screening. STUDY DESIGN: The data for this study were derived from prospective non-intervention screening for PE at 11+0 - 13+6 weeks' gestation in 61,174 singleton pregnancies. Patient-specific risks of delivery with PE at <37 and <32 weeks' gestation were calculated using the competing risks model to combine the prior distribution of the gestational age at delivery with PE, obtained from maternal characteristics and medical history, with various combinations of multiple of the median (MoM) values of MAP, UtA-PI and PlGF. We estimated the detection rate (DR) of preterm-PE and early-PE at overall SPR of 10%, 15% and 20%, from a policy in which first-stage screening of the whole population is carried out by some of the components of the triple test and second-stage screening by the full triple test on women selected on the basis of results from first-stage screening. RESULTS: If the method of first-stage screening is maternal factors, then measurements of MAP, UtA-PI and PlGF can be reserved for only 70% of the population achieving similar DR and SPR as with screening the whole population with the triple test. In the case of first-stage screening by maternal factors, MAP and UtA-PI, then measurement of PlGF can be reserved for only 30-40% of the population and if first-stage screening is by maternal factors, MAP and PlGF, measurement of UtA-PI can be reserved for only 20 30% of the population. Empirical results were consistent with model-based performance. CONCLUSIONS: Two-stage screening and biomarker testing for only part of the population will have financial benefits over conducting the test for the entire population. PMID- 30414395 TI - Human and computational models of atopic dermatitis: a review and perspectives by an expert panel of the International Eczema Council. AB - Atopic dermatitis (AD) is a prevalent disease worldwide associated with systemic co-morbidities, representing a significant burden on individuals, their families and society. Therapeutic options for AD remain limited, in part due to lack of well-characterised animal models. To better define pathophysiological mechanisms and to identify novel therapeutic targets and biomarkers that predict therapeutic response, there has been increasing interest in developing experimental approaches to study the pathogenesis of human AD in vivo, in vitro, and in silico. This review critically appraises a range of models including: genetic mutations relevant to AD; experimental challenge of human skin in vivo; tissue culture models; integration of "omic" datasets; and the development of predictive computational models. Whilst no one individual model recapitulates the complex AD pathophysiology, our review highlights insights gained into key elements of cutaneous biology, molecular pathways and therapeutic target identification through each approach. Recent developments in computational analysis, including the application of machine learning and a systems approach to data integration and predictive modelling, highlight the applicability of these methods to AD subclassification (endotyping), therapy development and precision medicine. Such predictive modelling will highlight knowledge gaps, further inform refinement of biological models, and support new experimental and systems approaches to AD. PMID- 30414396 TI - Stories about HPV vaccine in social media, traditional media, and conversations. AB - How stories from media and social interactions shape parents' HPV vaccination decisions is poorly understood. We sought to characterize parents' exposure to such stories, as well as associations between story exposure and vaccination behavior. Study participants were 1263 parents of U.S. adolescents who had not yet completed the HPV vaccine series. In 2017, these parents completed an online survey about whether they had heard stories of people who were harmed by HPV vaccine or who got diseases HPV vaccine could have prevented. Almost half of parents had heard HPV vaccine stories, which were about vaccine harms only (19%), vaccine preventable diseases only (11%), or both (15%). Stories of harms more often came from social and traditional media; stories of preventable diseases more often came from conversations (all p < 0.01). Parents who heard only stories about harms were less likely than those who heard no stories to have initiated HPV vaccination (23% vs. 33%, aOR:0.48; 95% CI:0.33:0.69). They were more likely to have delayed (79% vs. 66%, aOR:2.00; 95% CI:1.09:3.71) or refused (72% vs. 24%, aOR:8.87; 95% CI:4.09:19.25) HPV vaccination. Exposure to both stories about harms and preventable diseases was similarly associated with initiation, delay and refusal. Exposure to only stories about preventable diseases was not associated with initiation, delay or refusal. In conclusion, stories of HPV vaccine harms may be associated more strongly with vaccination behavior than stories of HPV vaccine preventable diseases. Communication campaigns should consider strategies to elevate stories of preventable diseases in social and traditional media. PMID- 30414397 TI - Glaucoma Specialist Detection of Optical Coherence Tomography Suspicious Rim Tissue in Glaucoma and Glaucoma Suspect Eyes. AB - PURPOSE: To assess glaucoma specialists' detection of optic nerve head (ONH) rim tissue that is thin by optical coherence tomography (OCT) criteria. DESIGN: Reliability analysis METHODS: 5 clinicians marked the disc margin (DM) and rim margin (RM) on stereo-photos of 151 glaucoma or glaucoma suspect eyes obtained within 3 months of OCT imaging. The photo and OCT infrared image for each eye were colocalized and regionalized into twelve sectors relative to the axis between Bruch's membrane opening (BMO) centroid and the fovea. For each clinician, the distance from BMO centroid to their DM (DM radius) and RM (RM radius) was used to generate sectoral rim width (RW) (DM radius - RM radius) and cup-to-disc ratio (CDR) (RM radius / DM radius) estimates. OCT minimum rim width (MRW) was determined by sector. Among all eyes, for each OCT MRW suspicious sector (< 5% of OCT normative data base), we determined each clinician's detection (clinician CDR >= 0.7). RESULTS: Clinicians most commonly failed to detect OCT suspicious rim tissue in the nasal sectors. Among 502 sectors with suspicious OCT MRW all 5 clinicians rated CDR >= 0.7 in only 29.5% and all 5 clinicians rated CDR < 0.7 in 21%. OCT suspicious rim thickness was most common (32% of eyes) in the nasal and inferior sectors. MRW vs clinician RW discordance was greatest nasally, while BMO vs clinician DM discordance was greatest temporally. CONCLUSIONS: Clinicians most commonly failed to detect OCT suspicious rim thickness nasally where suspicious rim tissues were also most common. PMID- 30414398 TI - Transcranial Direct Current Stimulation in Pediatric Motor Disorders: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To systematically examine the safety and effectiveness of transcranial direct current stimulation (tDCS) interventions in pediatric motor disorders. DATA SOURCES: PubMed, EMBASE, Cochrane, CINAHL, Web of Science, and ProQuest databases were searched from inception to August 2018. STUDY SELECTION: tDCS randomized controlled trials (RCTs), observational studies, conference proceedings and dissertations in pediatric motor disorders were included. Two authors independently screened articles based on predefined inclusion criteria. DATA EXTRACTION: Data related to participant demographics, intervention, and outcomes were extracted by two authors. Quality assessment was independently performed by two authors. DATA SYNTHESIS: Twenty-three studies involving a total of 391 participants were included. There was no difference in drop-out rates between active (1/144) and sham (1/144) tDCS groups, risk difference 0.0, 95% CI [-.05, .04]. Across studies, the most common adverse effects in the active group were tingling (17.2%), discomfort (8.02%), itching (6.79%), and skin redness (4%). Across 3 studies in children with cerebral palsy, tDCS significantly improved gait velocity (MD = .23; 95% CI [0.13, 0.34], p < .0005), stride length (MD = 0.10; 95% CI [0.05, 0.15], p< .0005), and cadence (MD = 15.7; 95% CI [9.72, 21.68], p< .0005). Mixed effects were found on balance, upper-extremity function, and overflow movements in dystonia. CONCLUSION: Based on the studies reviewed, tDCS is a safe technique in pediatric motor disorders and may improve some gait measures and involuntary movements. Research to date in pediatric motor disorders shows limited effectiveness in improving balance and upper-extremity function. tDCS may serve as a potential adjunct to pediatric rehabilitation; to better understand if tDCS is beneficial for pediatric motor disorders, more well designed RCTs are needed. PMID- 30414399 TI - Structured, aerobic exercise reduces fat mass and is partially compensated through energy intake but not energy expenditure in women. AB - BACKGROUND: Exercise-induced weight loss is often less than expected and highly variable in men and women. Behavioural compensation for the exercise-induced energy deficit could be through energy intake (EI), non-exercise physical activity (NEPA) or sedentary behaviour (SB). We investigated this issue in women. METHODS: Twenty-four overweight [body mass index (BMI) M = 27.9 kg/m2, SD = 2.7] women [age M = 33.1 years, SD = 11.7] completed 12-weeks of supervised exercise (5*500kcal per week) in a non-randomised, pre-post intervention study. Body mass (BM), waist circumference (WC), body composition, resting metabolic rate (RMR), total daily EI, individual meals, appetite sensations and appetite-related peptides were measured at baseline (week 0) and post-intervention (week 12). Free living physical activity (PA) and SB were measured (SenseWear) at baseline, week 1 and 10 of the exercise intervention, and at post-intervention (week 13). RESULTS: Following the 12-week exercise intervention BM [p = .04], BMI [p = .035], WC [p < .001] and fat mass (FM) [p = .003] were significantly reduced, and fat-free mass (FFM) significantly increased [p = .003]. Total [p = .028], ad libitum [p = .03] and snack box EI [p = .048] were significantly increased and this was accompanied by an increase in hunger [p = .01] and a decrease in fullness [p = .03] before meals. The peptides did not explain changes in appetite [p > .05]. There was no compensatory reduction in NEPA [p > .05] and no increase in SB, rather there was a decrease in SB during the exercise intervention [p = .03]. CONCLUSIONS: Twelve-weeks of supervised aerobic exercise resulted in a significant reduction in FM and an increase in FFM. Exercise increased hunger and EI which only partially compensated for the increase in energy expenditure. There was no evidence for a compensatory reduction in NEPA or an increase in SB. Dietary intervention, as an adjunct to exercise, may offset the compensatory increase in EI and result in a greater reduction in BM. TRIAL REGISTRATION: Our trial was retrospectively registered on the International Standard Randomised Controlled Trials Registry (ISRCTN78021668, 27th September 2016) and can be found here: https://doi.org/10.1186/ISRCTN78021668. PMID- 30414400 TI - How fitting is F.I.T.T.?: A perspective on a transition from the sole use of frequency, intensity, time, and type in exercise prescription. AB - The prevalence of physical inactivity continues to rise despite there being sufficient evidence to indicate the appropriate dosage of exercise to mitigate risk for many non-communicable diseases. This rise in physical inactivity is unlikely related to exercise prescription knowledge, but rather in the way exercise is prescribed. Current exercise prescription guidelines are characterized by the FITT Principle: Frequency, Intensity, Time, and Type. In order to target this physical inactivity epidemic, many have focused on the manipulation FITT components. However, perhaps this is not where the focus needs to lie - at least not as FITT is currently defined. Instead, we propose a change may be needed to the way exercise is prescribed - inclusion of measurement of enjoyment. This measurement of enjoyment is crucial to better inform exercise prescription, and may be the missing piece to overcome these high rates of physical inactivity. PMID- 30414401 TI - LncRNA SNHG1 alleviates OGD induced injury in BMEC via miR-338/HIF-1alpha axis. AB - BACKGROUND: Brain microvascular endothelial cell (BMEC) is an important therapeutic target for the inhibition of brain vascular dysfunction in ischemic stroke. Expression of long non-coding RNA SNHG1 is reportedly upregulated in BMEC after OGD. The present study aims to investigate the potential roles of SNHG1 in OGD-induced injury in BMEC. METHODS: Mice primary brain microvascular endothelial cells (BMEC) were cultured under "normal" or "oxygen/glucose-deprived" (OGD) conditions. The expression of SNHG1 and miR-338 after OGD were examined by qPCR. shRNA against SNHG1 were used to knockdown SNHG1 in BMEC. MiR-338-3p mimic and inhibitor were used to change the expression of miR-338 in BMEC. The relationship between SNHG1 and miR-338, and the relationship between miR-338 and HIF-1alpha were clarified using RNA pull-down and luciferase reporter gene assays, respectively. RESULTS: SNHG1 and miR-338 were upregulated in OGD induced BMEC. SNHG1 silence aggravated OGD-induced cell apoptosis by down-regulating Bcl-2, HIF 1alpha and VEGF-A, and upregulating caspase 3 activity and Bax. MiR-338 was upregulated in SNHG1-silenced BMEC. RNA pull-down assays showed that SNHG1 could be directly bound by miR-338. In addition, miR-338 overexpression reduced cell viability in OGD while miR-338 inhibition protected BMEC against OGD-induced injury. Furthermore, luciferase reporter assay showed that HIF-1alpha was a direct target of miR-338. CONCLUSIONS: SNHG1 exerted protective effects against OGD induced injury via sponging miR-338, thus upregulating HIF-1alpha/VEGF-A in BMEC. PMID- 30414402 TI - Rapid subtyping of pathogenic and nonpathogenic Vibrio parahaemolyticus by fourier transform infrared spectroscopy with chemometric analysis. AB - Vibrio parahaemolyticus which naturally inhabits marine and estuarine environment represents pathogenic strains (virulence genes tdh or trh positive) and non pathogenic strains (virulence genes negative). In this study, a rapid method for subtyping pathogenic and non-pathogenic V. parahaemolyticus was established using fourier transform infrared (FTIR) spectroscopy with chemometric analysis. This method targeted three strains of genotypes of V. parahaemolyticus including tdh positive, trh positive and virulence gene-negative (nonpathogenic) V. parahaemolyticus. The FTIR absorption spectra between 1800 and 900 cm-1 highlighted the most distinctive variations and were the most useful for characterizing the three bacteria. The successful differentiation and identification of the three bacteria could be accomplished in less than 1 h by FTIR using principal component analysis (PCA), or another cluster model of hierarchical cluster analysis (HCA). The method was verified by analyzing spiked V. parahaemolyticus fish samples. Furthermore, all of ten clinical isolates of V. parahaemolyticus were identified as tdh-positive, none of the clinical isolates were trh-positive, and all of ten environmental isolates were identified as non pathogenic by the subtyping method, which were confirmed by PCR assays. All data demonstrated that the newly established subtyping method by FTIR is practical, time-saving, labor-saving, specific and cost-effective, especially suitable for the basic laboratories of CDC and port quarantine departments to perform suiveillance and epidemiological traceability of pathogenic V. parahaemolyticus. PMID- 30414403 TI - WSV181 inhibits JAK/STAT signaling and promotes viral replication in Drosophila. AB - The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway plays a critical role in host defense against viral infections. Here, we report the use of the Drosophila model system to investigate the modulation of the JAK/STAT pathway by the white spot syndrome virus (WSSV) protein WSV181. WSV181 overexpression in transgenic flies resulted in the downregulation of STAT92E and STAT92E-targeted genes. This result indicates that WSV181 can suppress JAK/STAT signaling by controlling STAT92E expression. An infection experiment was carried out on transgenic Drosophila infected with Drosophila C virus and on Litopenaeus vannamei injected with recombinant WSV181 and WSSV. The increased viral load and suppressed transcript levels of JAK/STAT pathway components indicate that WSV181 can promote viral proliferation by inhibiting the JAK/STAT pathway. This study provided evidence for the role of WSV181 in viral replication and revealed a new mechanism through which WSSV evades host immunity to maintain persistent infection. PMID- 30414404 TI - Activation of CCL20 and its receptor CCR6 promotes endometrium preparation for implantation and placenta development during the early pregnancy period in pigs. AB - The success of implantation and placentation during early pregnancy depends on the intrauterine environment of diverse histotrophs, including nutrients, growth factors, cytokines, and chemokines. Here, we determined the functional role and signal transduction of CC-motif chemokine 20 (CCL20) in the porcine endometrium during pregnancy. The expression of CCL20 and its receptor CCR6 was abundant in the glandular epithelium (GE) and luminal epithelium (LE) of the porcine endometrium during early pregnancy. Administration of CCL20 to porcine endometrial LE cells increased cellular proliferation with strong PCNA expression by activation of PI3K and MAPK signaling. Blocking PI3K and MAPK decreased the CCL20-mediated elevated proliferation of pLE cells. Moreover, the proliferation of pLE cells was enhanced by inhibiting the LPS-induced cytokines and tunicamycin induced endoplasmic reticulum (ER) stress response proteins. Overall, these results suggest that CCL20 may improve the endometrial receptivity through inducing proliferative signal transduction in the porcine endometrium during the early gestational period. PMID- 30414405 TI - Cocaine and cocaine expectancy increase growth hormone, ghrelin, GLP-1, IGF-1, adiponectin, and corticosterone while decreasing leptin, insulin, GIP, and prolactin. AB - The dopamine system-essential for mood and movement-can be activated in two ways: by excitatory inputs that cause burst firing and stamp-in learning or by slow excitatory or inhibitory inputs-like leptin, insulin, ghrelin, or corticosterone that decrease or increase single-spike (pacemaker) firing rate and that modulate motivation. In the present study we monitored blood samples taken prior to and during intravenous cocaine or saline self-administration in rats. During cocaine taking, growth hormone and acetylated ghrelin increased 10-fold; glucagon-like peptide-1 (GLP-1) doubled; non-acetylated ghrelin, insulin-like growth factor-1 (IGF-1), and corticosterone increased by 50% and adiponectin increased by 17%. In the same blood samples, leptin, insulin, gastric inhibitory polypeptide (GIP), and prolactin decreased by 40-70%. On the first day of testing under extinction conditions-where the animals earned unexpected saline instead of cocaine-5-fold increases were seen for growth hormone and acetylated ghrelin and equal changes in amplitude and latency-were seen in each of the other cases except for IGF-1 (which increased at a slower rate). Single-spike firing affects the tonic activation level of the dopamine system, involving very different controls than those that drive burst firing; thus, the present data suggest interesting new targets for medications that might be used in the early stages of drug abstinence. PMID- 30414406 TI - Cooperative DNA Binding of the Plasmid Partitioning Protein TubR from the Bacillus cereus pXO1 Plasmid. AB - Tubulin/FtsZ-like GTPase TubZ is responsible for maintaining the stability of pXO1-like plasmids in virulent Bacilli. TubZ forms a filament in a GTP-dependent manner, and like other partitioning systems of low-copy-number plasmids, it requires the centromere-binding protein TubR that connects the plasmid to the TubZ filament. Systems regulating TubZ partitioning have been identified in Clostridium prophages as well as virulent Bacillus species, in which TubZ facilitates partitioning by binding and towing the segrosome: the nucleoprotein complex composed of TubR and the centromere. However, the molecular mechanisms of segrosome assembly and the transient on-off interactions between the segrosome and the TubZ filament remain poorly understood. Here, we determined the crystal structure of TubR from Bacillus cereus at 2.0-A resolution and investigated the DNA-binding ability of TubR using hydroxyl radical footprinting and electrophoretic mobility shift assays. The TubR dimer possesses 2-fold symmetry and binds to a 15-bp palindromic consensus sequence in the tubRZ promoter region. Continuous TubR-binding sites overlap each other, which enables efficient binding of TubR in a cooperative manner. Interestingly, the segrosome adopts an extended DNA-protein filament structure and likely gains conformational flexibility by introducing non-consensus residues into the palindromes in an asymmetric manner. Together, our experimental results and structural model indicate that the unique centromere recognition mechanism of TubR allows transient complex formation between the segrosome and the dynamic polymer of TubZ. PMID- 30414407 TI - HIV-1 Protease Uses Bi-Specific S2/S2' Subsites to Optimize Cleavage of Two Classes of Target Sites. AB - Retroviral proteases (PRs) have a unique specificity that allows cleavage of sites with or without a P1' proline. A P1' proline is required at the MA/CA cleavage site due to its role in a post-cleavage conformational change in the capsid protein. However, the HIV-1 PR prefers to have large hydrophobic amino acids flanking the scissile bond, suggesting that PR recognizes two different classes of substrate sequences. We analyzed the cleavage rate of over 150 combinations of six different HIV-1 cleavage sites to explore rate determinants of cleavage. We found that cleavage rates are strongly influenced by the two amino acids flanking the amino acids at the scissile bond (P2-P1/P1'-P2'), with two complementary sets of rules. When P1' is proline, the P2 side chain interacts with a polar region in the S2 subsite of the PR, while the P2' amino acid interacts with a hydrophobic region of the S2' subsite. When P1' is not proline, the orientations of the P2 and P2' side chains with respect to the scissile bond are reversed; P2 residues interact with a hydrophobic face of the S2 subsite, while the P2' amino acid usually engages hydrophilic amino acids in the S2' subsite. These results reveal that the HIV-1 PR has evolved bi-functional S2 and S2' subsites to accommodate the steric effects imposed by a P1' proline on the orientation of P2 and P2' substrate side chains. These results also suggest a new strategy for inhibitor design to engage the multiple specificities in these subsites. PMID- 30414408 TI - Corrigendum to "Anti-androgenic therapy with finasteride improves cardiac function, attenuates remodeling and reverts pathologic gene-expression after myocardial infarction in mice" Journal of Molecular and Cellular Cardiology 122 (2018) 114-124. PMID- 30414409 TI - The Accumulation of Heparan Sulfate S-Domains in Kidney Transthyretin Deposits Accelerates Fibril Formation and Promotes Cytotoxicity. AB - The highly sulfated domains of heparan sulfate (HS), also called HS S-domains, are made up of repeated trisulfated disaccharide units [iduronic acid (2S) glucosamine (NS, 6S)-] and are selectively remodeled by extracellular endoglucosamine 6-sulfatases (Sulfs). Although HS S-domains are critical for signal transduction of several growth factors, their roles in amyloidoses are not yet fully understood. Here, we found HS S-domains in the kidney of a patient with transthyretin amyloidosis (ATTR amyloidosis). In in vitro assays with cells stably expressing human Sulfs, heparin, a structural analog of HS S-domains, promoted aggregation of TTR in an HS S-domain-dependent manner. Interactions of cells with TTR fibrils and cytotoxicity of these fibrils also depended on HS S domains at the cell surface. Furthermore, glypican-5 (GPC5), encoded by the susceptibility gene for nephrotic syndrome GPC5, was found to be accumulated in the ATTR amyloidosis kidney. Our study thus provides a novel insight into the pathological roles of HS S-domains in amyloidoses, and we propose that enzymatic remodeling of HS chains by Sulfs may offer an effective approach to inhibiting formation and cytotoxicity of amyloid fibrils. PMID- 30414410 TI - Pseudoxanthoma Elasticum as a Paradigm of Heritable Ectopic Mineralization Disorders: Pathomechanisms and Treatment Development. AB - Ectopic mineralization is a global problem and leading cause of morbidity and mortality. The pathomechanisms of ectopic mineralization are poorly understood. Recent studies on heritable ectopic mineralization disorders with defined gene defects have been helpful in elucidation of the mechanisms of ectopic mineralization in general. The prototype of such disorders is pseudoxanthoma elasticum (PXE), a late-onset, slowly progressing disorder with multi-system clinical manifestations. Other conditions include generalized arterial calcification of infancy (GACI) characterized by severe, early-onset mineralization of the cardiovascular system often with early postnatal demise. In addition, arterial calcification due to CD73 deficiency (ACDC) occurs late in life mostly affecting arteries in the lower extremities in elderly individuals. These three conditions, PXE, GACI, and ACDC, caused by mutations in ABCC6, ENPP1, and NT5E, are characterized by reduced levels of inorganic pyrophosphate (PPi) in plasma. Since PPi is a powerful anti-mineralization factor, it has been postulated that reduced PPi is a major determinant for ectopic mineralization in PXE, GACI, and ACDC. These and related observations on complementary mechanisms of ectopic mineralization have resulted in development of potential treatment modalities for PXE, including administration of bisphosphonates, stable PPi analogs with anti-mineralization activity. It is conceivable that efficient treatments may soon become available for heritable ectopic mineralization disorders with application to common calcification disorders. PMID- 30414411 TI - Nur77: Key Functions and Therapeutic Prospects in Inflammation-Related Lung Diseases. AB - The transcription factor nuclear receptor 77 (Nur77) belongs to the NR4A subfamily of nuclear hormone receptors. It features an atypical ligand-binding site that precludes canonical ligand binding, leading to the designation "orphan nuclear receptor." However, recent studies show that small molecules can interact with the receptor and modulate its activity by inducing a conformational change in the Nur77 ligand-binding site. Nur77 expression and activation are rapidly induced by a wide range of physiological and pathological stimuli. Once expressed, Nur77 initiates transcriptional activity and modulates expression of its target genes. Both in vitro and in vivo evidence shows that Nur77 dampens the immune response to pro-inflammatory stimuli such as tumor necrosis factor-alpha, toll-like receptor ligands, and oxidized lipids, primarily by suppressing NF kappaB signaling. Although studies focusing on Nur77's role in lung pathophysiology are currently incomplete, available data support its involvement in the pathogenesis of several lung diseases including asthma, acute lung injury, and pulmonary fibrosis, and thus suggest a therapeutic potential for Nur77 activation in these diseases. This review addresses the mechanisms that control Nur77 expression and activity as well as its known roles in inflammation-related lung diseases. Evidence regarding the therapeutic potential of Nur77-targeting molecules will also be presented. Although current knowledge is limited, additional rigorous research followed by clinical studies may firmly identify Nur77 as a pharmacological target for inflammation-related lung diseases. PMID- 30414412 TI - Cytochrome c6 is the main respiratory and photosynthetic soluble electron donor in heterocysts of the cyanobacterium Anabaena sp. PCC 7120. AB - Cytochrome c6 is a soluble electron carrier, present in all known cyanobacteria, that has been replaced by plastocyanin in plants. Despite their high structural differences, both proteins have been reported to be isofunctional in cyanobacteria and green algae, acting as alternative electron carriers from the cytochrome b6-f complex to photosystem I or terminal oxidases. We have investigated the subcellular localization of both cytochrome c6 and plastocyanin in the heterocyst-forming cyanobacterium Anabaena sp. PCC 7120 grown in the presence of combined nitrogen and under diazotrophic conditions. Our studies conclude that cytochrome c6 is expressed at significant levels in heterocysts, even in the presence of copper, condition in which it is strongly repressed in vegetative cells. However, the copper-dependent regulation of plastocyanin is not altered in heterocysts. In addition, in heterocysts, cytochrome c6 has shown to be the main soluble electron carrier to cytochrome c oxidase-2 in respiration. A cytochrome c6 deletion mutant is unable to grow under diazotrophic conditions in the presence of copper, suggesting that cytochrome c6 plays an essential role in the physiology of heterocysts that cannot be covered by plastocyanin. PMID- 30414413 TI - Role of the PB-loop in ApcE and Phycobilisome Core Function in Cyanobacterium Synechocystis sp. PCC 6803. AB - The phycobilisome (PBS) is a giant highly-structured pigment-protein antenna of cyanobacteria and red algae. PBS is composed of the phycobiliproteins and several linker polypeptides. The large core-membrane linker protein (LCM or ApcE) influences many features and functions of PBS and consists of several domains including the chromophorylated PB-domain. Being homologous to the phycobiliprotein alpha-subunits this domain includes a so-called PB-loop insertion whose functions are still unknown. We have created the photoautotrophic mutant strain of the cyanobacterium Synechocystis sp. PCC 6803 with lacking PB loop. Using various spectral techniques we have demonstrated that this mutation does not destroy the PBS integrity and the internal PBS excitation energy transfer pathways. At the same time, the deletion of the PB-loop leads to the decrease of connectivity between the PBS and thylakoid membrane and to the compensatory increase of the relative photosystem II content. Mutation provokes the violation of the thylakoid membranes arrangement, the inability to perform state transitions, and diminishing of the OCP-dependent non-photochemical PBS quenching. In essence, even such a minute mutation of the PBS polypeptide component, like the PB-loop deletion, becomes important for the concerted function of the photosynthetic apparatus. PMID- 30414414 TI - Functional investigation of an universally conserved leucine residue in subunit a of ATP synthase targeted by the pathogenic m.9176 T>G mutation. AB - Protons are transported from the mitochondrial matrix to the intermembrane space of mitochondria during the transfer of electrons to oxygen and shuttled back to the matrix by the a subunit and a ring of identical c subunits across the membrane domain (FO) of ATP synthase, which is coupled to ATP synthesis. A mutation (m.9176 T > G) of the mitochondrial ATP6 gene that replaces an universally conserved leucine residue into arginine at amino acid position 217 of human subunit a (aL217R) has been associated to NARP (Neuropathy, Ataxia and Retinitis Pigmentosa) and MILS (Maternally Inherited Leigh's Syndrome) diseases. We previously showed that an equivalent thereof in Saccharomyces cerevisiae (aL237R) severely impairs subunit a assembly/stability and decreases by >90% the rate of mitochondrial ATP synthesis. Herein we identified three spontaneous first site intragenic suppressors (aR237M, aR237T and aR237S) that fully restore ATP synthase assembly. However, mitochondrial ATP synthesis rate was only partially recovered (40-50% vs wild type yeast). In light of recently described high resolution yeast ATP synthase structures, the detrimental consequences of the aL237R change can be explained by steric and electrostatic hindrance with the universally conserved subunit a arginine residue (aR176) that is essential to FO activity. aL237 together with three other nearby hydrophobic residues have been proposed to prevent ion shortage between two physically separated hydrophilic pockets within the FO. Our results suggest that aL237 favors subunit c-ring rotation by optimizing electrostatic interaction between aR176 and an acidic residue in subunit c (cE59) known to be essential also to the activity of FO. PMID- 30414415 TI - Anti-melanogenesis of novel kojic acid derivatives in B16F10 cells and zebrafish. AB - Novel kojic acid derivatives (KADs) with the potential ability to inhibit tyrosinase were synthesized and were further identified by Q-Exactive, IR and NMR. Among these compounds, KAD2 showed the best inhibitory effects on diphenolase activity and monophenolase activity, with IC50 of 7.50 MUM and 20.51 MUM, respectively. The anti-melanogenic activity of KAD2 was further confirmed by assessing the inhibition of melanin content and intracellular tyrosinase activity in B16F10 cells and zebrafish model. It demonstrated that KAD2 suppressed the expression of microphthalmia-associated transcription factor (MITF), tyrosinase (TYR), tyrosinase related protein-1 and 2 (TRP-1 and TRP-2) in a concentration dependent manner. Furthermore, KAD2 dose-dependently suppressed the expression of the phosphorylation of protein kinase A (PKA) and cAMP-response element binding protein (CREB) and rescued the phosphorylation of Akt. Additionally, KAD2 could inhibit body pigmentation in zebrafish. Taken together, our findings elucidated that KAD2 has significant anti-melanogenic activity via CREB and Akt pathway mediated suppression the expression of MITF and TYR family proteins in B16F10 cells. It could provide new insight into the development of novel anti melanogenic agents to apply in the fields of food sciences, agriculture, cosmetics and medicine. PMID- 30414416 TI - Purification, modeling and structural insights of calmodulin-binding receptor like cytoplasmic kinase 2 from Oroxylum Indicum. AB - Calmodulin binding receptor like cytoplasmic kinase 2 (CRCK2) belongs to the family of receptor like kinases (RLKs) which is mainly implicated in pathways associated with the stress responses in plants. The protein from the stem of Oroxylum indicum was isolated and purified using anion-exchange followed by gel filtration chromatography. The purity of protein was checked using SDS-PAGE, which showed a single band of 50 kDa. The purified protein was identified as CRCK2 using MALDI-TOF. Using I-TASSER, a bioinformatics tools, the model of protein was constructed and its secondary structure was predicted using VADAR. The secondary structure content was also determined by far-UV CD, which indicated that the CRCK2 is mainly beta-sheet dominating protein (43% beta-sheet). The secondary structural content predication from computational method is in close agreement with the result obtained by CD spectropolarimeter. This study validates I-TASSER model for determination of structure of a protein. Moreover, stability of CRCK2 was monitored against heat- and guanidinium chloride (GdmCl)-induced denaturation by using circular dichroism (CD) and fluorescence spectroscopy. Denaturation curve analysis gave values of 2.88 +/- 0.12 kcal mol-1and 4.11 +/- 0.09 M for ? degrees GD (Gibbs free energy change at 25 degrees C) and Cm (midpoint of denaturation), respectively. It has been observed that purified CRCK2 is quite stable protein against both heat-induced as well as GdmCl-induced denaturation. This is very first report of purification and biophysical characterization of CRCK2 protein from medicinal plant O. indicum. PMID- 30414417 TI - In vitro biocompatibility study of a water-rinsed biomimetic silk porous scaffold with olfactory ensheathing cells. AB - Olfactory ensheathing cells (OECs) are one of the most promising candidates for cell-based therapy in repairing spinal cord injury (SCI). However, the conventional method of transplanting OECs, orthotopically or intrathecally, leads to a low rate of cell replacement and limited utilization due to the impediments of chemical and physical barriers after SCI. In this study, we fabricated a three dimensional (3-D) silk fibroin (SF) scaffold with a novel water-rinsing process. Compared to traditional methanol-treated scaffolds (MTS) and ethanol-treated scaffolds (ETS), the present water-rinsed scaffold (WRS) had a biomimetic nanofibrous structure and softer mechanical properties and was shown to be more biocompatible with OECs. The in vitro study showed that the 3-D SF scaffolds supported OEC adhesion and spreading and that the OECs had a normal cell phenotype. A quantitative study using the CCK8 assay revealed that OEC proliferation on the WRS was higher than that on the MTS and ETS. Moreover, a significantly higher level of GDNF was detected when the OECs were cultured on the WRS. Collectively, these results suggested that the 3-D biomimetic SF porous scaffolds not only provide suitable microenvironments for governing OEC behaviour but also serve as a promising transplantation strategy for OECs to repair SCI. PMID- 30414418 TI - Punica granatum sarcotesta lectin (PgTeL) impairs growth, structure, viability, aggregation, and biofilm formation ability of Staphylococcus aureus clinical isolates. AB - In this work, we evaluated the ability of Punica granatum sarcotesta lectin (PgTeL) to impair the growth and viability of the Staphylococcus aureus clinical isolates 8325-4 (non-resistant) and LAC USA300 (MRSA strain). The effects of this lectin on aggregating, hemolytic activity, biofilm-forming ability, and expression of virulence genes (hla, rnaIII, and spa) were also investigated. PgTeL showed antibacterial activity against 8325-4 and LAC USA300 strains by interfering with both the growth (MIC50 of 6.25 and 12.5 MUg/mL, respectively) and survival (MBC values of 25.0 and 50.0 MUg/mL, respectively). Culture growth started only at the ninth (8325-4) and tenth (LAC USA300) hour in the presence of PgTeL at MIC50, while growth was detected since the first hour in the control. The lectin caused markedly altered cell morphology in both the strains. Although, at the MIC50, PgTeL caused structural alterations, most cells were still viable, while at the MBC it promoted cell injury and death. PgTeL showed anti-aggregation effect and exhibited antibiofilm activity against both the isolates. However, the lectin did not interfere with the hemolytic activity of LAC USA300 and with the expression of hla, rnaIII, and spa genes. In conclusion, PgTeL is a lectin with multiple inhibitory effects on S. aureus clinical isolates. PMID- 30414419 TI - The use of ACE INDEL polymorphism as a biomarker of coronary artery disease (CAD) in humans with Mediterranean-style diet. AB - The ACE INDEL gene polymorphisms are strongly associated with CAD. Therefore, the present study was undertaken to investigate the relationship between ACE INDEL polymorphism and CAD in Turkish Cypriots whose are expected to have Mediterranean style diet. 273 Turkish Cypriot descent volunteer subjects (186 controls and 87 CAD patients) participated in this study. Genotyping for the ACE INDEL polymorphism was performed by PCR-RFLP analysis. Biochemical parameters except the glucose and triglyceride lipid level were all within normal limits. Glucose level was found significant (p = 0.019) and triglyceride level was observed at the borderline for significance (p = 0.050) in participants according to WHO guidelines. With the respect to the genotype and allele distributions of ACE INDEL, the results showed statistically significant in CAD patients (p = 0.034) and not significant (p = 0.190) in controls. Haplotype analysis showed that D allele was more frequent in patients compared to controls. Thus, there is a statistically significant association with CAD disease with DD genotypes (p = 0.030) in Turkish Cypriot population. The results indicated that ACE INDEL polymorphism is an important predictor of coronary artery disease in Turkish Cypriots. Although 47% of the studied Turkish Cypriot population carry the D allele (p = 0.07), protocols should be developed for prevention strategies immediately. PMID- 30414420 TI - Genome-wide analysis of purple acid phosphatase (PAP) family proteins in Jatropha curcas L. AB - Purple acid phosphatase (PAP) family genes play a crucial role in the phosphorus (P) foraging and recycling. There are 25 putative Jatropha curcas PAP genes (JcrPAP) were identified and classified into three groups based on their molecular weights. Subcellular localization prediction indicated that most of the JcrPAPs were localized to secretory pathway. Several PAPs possess signal peptide motifs and varied numbers of N-glycosylation and transmembrane helix motifs. JcrPAP proteins have 3-5 active pocket sites comprising 1 to 11 binding residues which interact with different ligands such as iron (Fe), N-acetyl l-d-Glucosamine (NAG), zinc (Zn) and manganese (Mn). The core structure of the predicted JcrPap28 was similar to the Ipomoea batatas Pap protein. Most of the JcrPAP genes showed higher expression in the root tissues compared to stem and leaf tissues. Several JcrPAP genes were upregulated under low phosphorus conditions. JcrPAP genes such as JcrPap26b, JcrPap27b, and JcrPap28 have shown multifold induction in low phosphorus treated plants which suggest that these genes might be involved in phosphorus metabolism. The present study provided the structural variations and expression regulation of JcrPAP genes in the economically viable biodiesel crop and it would be helpful for the crop improvement under phosphorus limiting conditions. PMID- 30414421 TI - Control of beta-sitosterol biosynthesis under light and watering in desert plant Calotropis procera. AB - Most scientific studies on Calotropis procera refer to the plant as an important source of pharmaceutical compounds and its valuable benefits in medicine. One of the most important substances in this plant is the potential immunostimulant beta sitosterol (BS) that acts in improving human health. This study focused on the effects of lighting before and after irrigation on the BS accumulation pathway namely steroid biosynthesis. Studying the enzymes in BS biosynthetic pathway indicated the upregulation at dawn and predusk of the SMT2 and SMO2 genes encoding sterol methyltransferase 2 and methylsterol monooxygenase, two key enzymes in BS accumulation in C. procera. The results almost indicated no regulation at the different time points of the CYP710A gene encoding sterol 22 desaturase, an enzyme that acts in depleting beta-sitosterol towards the biosynthesis of stigmasterol. RNA-Seq data was validated via quantitative RT-PCR and results were positive. The data of ultra-performance liquid chromatography tandem mass spectrometry analysis with regard to BS accumulation also aligned with those of RNA-Seq analysis. We focused on the effects of light before and after watering on BS accumulation in C. procera. Our results show that BS accumulation is high at dawn in both dehydrated and well-watered condition. While, the BS was dramatically decrease at midday in well-watered plants. This increase/decrease in BS content is correlated with rates of expression of SMT 2 gene. This gene is a key convertor between the different branches in the cardiac glycoside biosynthesis. Accordingly, it could be suggested that BS (or one of the descendent product) may play an important role in C. procera tolerance to drought/light intensity conditions. PMID- 30414422 TI - 1,25-Dihydroxyvitamin D3 induces formation of neutrophil extracellular trap-like structures and modulates the transcription of genes whose products are neutrophil extracellular trap-associated proteins: A pilot study. AB - Neutrophils are components of the innate immune system that participate in controlling infectious diseases through microbicidal mechanisms such as phagocytosis, degranulation and the release of neutrophil extracellular traps (NETs). NETs are DNA structures that are released through the decondensation and spreading of chromatin and the adherence of various proteins, including neutrophil elastase (NE), myeloperoxidase (MPO) and peptidyl arginine deiminase 4 (PDA4). Since NETs recovered after treatment of activated polymorphonuclear neutrophils can enhance IL-1beta and IFN-alpha production by LPS-activated macrophages, they are thought to be keys to the host's defenses and inflammation. 1,25(OH)2D3 has been shown to play an important role in modulating neutrophils activation and in preventing infections. Therefore, the aim of this study was to assess the effect of 1,25(OH)2D3 in modulating induction of the release of NETs and in regulating the transcription of genes whose products in human neutrophils are NETs-associated proteins, TLRs and interferon. We observed that 1,25(OH)2D3 induced production of NETs-like structures while also upregulating NE/PAD4/COX 3/GAPDH mRNA levels. Additionally, we found an increase in TLR7 and type I interferon (IFN) mRNA levels as a result of neutrophil activation by 1,25(OH)2D3. Since the transcription of genes whose products constitute NETs-associated proteins are differentially-regulated by 1,25(OH)2D3, we proposed that this might restrict the spread of pathogens, such as virus, by inducing NETs, the expression of TLR7 and secretion of IFN-alpha. Our results suggest the potential importance of this hormone in preventing infections by inducing NETs formation. PMID- 30414423 TI - Measurement of midnight ACTH levels is useful for the evaluation of midnight cortisol levels. AB - OBJECTIVE: Elevated midnight cortisol levels induced by non-suppressed ACTH levels may lead to false-positive results for hypercortisolism in patients with adrenal incidentaloma. We investigated whether plasma ACTH-associated high midnight serum cortisol levels are correlated with other endocrinological findings with respect to hypothalamic-pituitaryadrenal function or hypercortisolism status. METHODS: Two-hundred-forty-six patients with adrenocortical adenoma were evaluated via measurements of midnight ACTH and cortisol levels, a 1-mg dexamethasone suppression test (DST), and a cosyntropin releasing hormone (CRH) stimulation test. Patients were divided into four groups according to their midnight plasma ACTH levels. RESULTS: The groups with higher midnight ACTH levels had significantly higher basal ACTH levels. A positive relationship was observed between midnight serum cortisol and serum cortisol in the 1-mg DST for all groups; stronger associations were observed in the group with lower midnight ACTH. In the CRH test, peak, delta, and sigma ACTH had significant inverse relationships with midnight cortisol levels in the lowest and second lowest midnight ACTH groups. Patients with midnight cortisol levels >3.5 MUg/dL were further divided into two groups according to whether their midnight plasma ACTH levels were below or above 10.0 pg/mL. There were significantly fewer patients with hypercortisolism in the higher ACTH group; midnight serum cortisol levels were associated with hypercortisolism only in the lower ACTH group. CONCLUSION: We demonstrated that midnight ACTH-associated cortisol values were not correlated with other endocrinological findings or hypercortisolism state. Measurement of midnight ACTH levels is important, and careful evaluation is needed for patients with higher midnight ACTH levels. PMID- 30414424 TI - Two new 4-methylidene containing steroids, craterol A and B, from the New Zealand two sponge association between Stelletta crater and Desmacella dendyi. AB - NMR-directed investigation of the two sponge association between Stelletta crater and Desmacella dendyi has resulted in the isolation of two new members of the rare 4-methylidene class of sterols. Craterol A (1) and B (2) represent the first examples of natural products reported from the species S. crater. The isolation of these compounds challenges the role of 4-methylidene sterols as chemotaxonomic markers for the sponge genus Theonella. PMID- 30414425 TI - Sex-based differences in resting MAPK, androgen, and glucocorticoid receptor phosphorylation in human skeletal muscle. AB - PURPOSE: To determine if there is differential expression and phosphorylation of the androgen receptor (AR), glucocorticoid receptor (GR), and mitogen-activated protein kinases (MAPK) in skeletal muscle at rest between males and females. METHODS: Ten college-aged males (mean +/- SD; age = 22 +/- 2.4 yrs, ht = 175 +/- 7 cm, body mass = 84.1 +/- 11.8 kg) and ten females (mean +/- SD; age = 20 +/- 0.9 yrs; ht = 169 +/- 7 cm; body mass = 67.1 +/- 8.7 kg) reported to the laboratory following an overnight fast. Resting muscle biopsies were collected from the vastus lateralis and analyzed for total and phosphorylated GR (ser134, ser211, and ser226), total and phosphorylated AR (ser81, ser213, ser515, ser650), and total and phosphorylated MAPK (ERK, JNK, p38) via western blotting. A phosphorylation index (PI) was calculated to determine phosphorylated receptor expression after accounting for differences in total receptor content. RESULTS: Males had more total AR compared to females (+42 +/- 4%; p < 0.001). Females had higher phosphorylation of ARser81 (+87 +/- 11%; p = 0.001) and ser515 (+55 +/- 13%; p = 0.019). However, when the phosphorylated ratios were corrected for differences in total AR expression (i.e. our PI), the overall phosphorylation at these sites were similar between sexes (ser515, males = 100% vs females 92%; ser81, males = 100% vs females = 107%). pGRser134 was higher in males compared to females (+50 +/- 15%; p = 0.016). Phospho-p38 was higher in females compared to males (+5050 +/- 16%; p < 0.001). CONCLUSION: At rest, ARs and GRs are differentially phosphorylated at some, but not all sites when comparing males and females. Differential regulation of phosphorylated AR, GR, and p38 between males and females may have implications for the degree of muscle adaptations observed following resistance or endurance training. PMID- 30414426 TI - Loss of pigment epithelium-derived factor leads to ovarian oxidative damage accompanied by diminished ovarian reserve in mice. AB - AIMS: This study aims to investigate the pathophysiological role and mechanism of pigment epithelium-derived factor (PEDF) deletion in ovarian damage. METHODS: Female PEDF-knockout mice and their wild-type littermates were used in this study. Relevant tests were performed at 8-10 weeks or 32 weeks of age. KEY FINDINGS: Compared to the wild-type mice, the PEDF-knockout mice showed diminished ovarian reserve (DOR), worse ovum quality after injection to induce controlled ovarian stimulation, increased serum follicle stimulating hormone (FSH) level and an follicle stimulating hormone/luteinizing hormone (FSH/LH) ratio. Moreover, severe ovarian oxidative damage was found in ovaries of PEDF knockout mice that mainly manifested as an accumulation of reactive oxygen species (ROS), NF-E2-related factor 2 (Nrf2) pathway activation, significantly upregulated expression of ROS-generating genes. Correspondingly, the PEDF knockout mice exhibited lipid metabolism disorder and insulin resistance, which mainly manifested as obesity, abdominal fat accumulation, adipocyte enlargement, severe ectopic fat deposition, dyslipidemia, changes in adipokine levels, hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired insulin tolerance and significantly declined protein kinase B (Akt) phosphorylation levels. SIGNIFICANCE: Loss of PEDF leads to ovarian oxidative damage accompanied by DOR in mice, this is related to PEDF deficiency induced severe insulin resistance and lipid metabolism disorder. Therefore, PEDF may be a potential target for the treatment of diseases related to ovarian oxidative damage. PMID- 30414427 TI - Intestinal luminal content from high-fat-fed prediabetic mice changes epithelial barrier function in vitro. AB - AIMS: Evidence suggests that administration of a high-fat diet (HFD) results in changes in the intestinal lumen environment. Gut dysbiosis associated with intestinal barrier disruption may be involved in type 2 diabetes mellitus (T2DM) development through increased intestinal permeability, which would trigger an inflammatory response leading to peripheral insulin resistance state and ultimately T2DM. In this study, we investigated the effect of the intestinal luminal content isolated from control or HFD-fed prediabetic mice upon the tight junction (TJ)-mediated epithelial barrier in Caco-2 and MDCK epithelial cell lines. METHODS/KEY FINDINGS: Exposure to small intestine luminal content (SI) isolated from HFD-fed prediabetic mice induced a more significant decrease in transepithelial electrical resistance (TEER), associated with higher paracellular flux in Caco-2 and MDCK cells after 6 h and 4 h respectively, as compared to the SI obtained from control mice. Such changes were accompanied by a significant decrease in TJ content of claudins, occludin, and ZO-1, indicative of disruption of the TJ barrier. Meanwhile, large intestine luminal content from control (Ctrl LI) and prediabetic (HFD-LI) animals did not change TEER significantly, however, paracellular flux was significantly increased after 24 h, accompanied by a decrease in ZO-1 (after HFD-LI exposure) in Caco-2 and significant changes in the junctional distribution of claudins-1, -2, occludin and ZO-1 proteins in MDCK, particularly after HFD-LI exposure. SIGNIFICANCE: Luminal components of intestinal content, altered by HFD exposure, induce impairment of the TJ structure and function in vitro, corroborating the idea of a role of the intestinal paracellular barrier in the obesity-related T2DM pathogenesis. PMID- 30414428 TI - Antinociceptive and anti-inflammatory effect of Naringenin in different nociceptive and inflammatory mice models. AB - Inflammation is the vital defensive response triggered by our immune system against an infection or deleterious stimuli. This response in due course affects its own biological system leading to serious diseases like arteriosclerosis, osteoporosis, pancreatitis, cancer etc. Currently, researchers focused on utilizing phytochemicals as anti-inflammatory drugs since the drugs presently available in the market causes serious side effects and are less potent. Flavonoids are polyphenols which imparts colours to the plants and fruits. These flavonoids serve as phytonutrients to plants and they also possess antioxidant, anti-inflammatory and anti-cancer properties. Naringenin is one such flavonoid classified under flavones groups present in citrus fruits and vegetables. The present study is aimed to identify and confirm the antinociceptive and anti inflammatory efficacy of Naringenin in different mice models. The antinociceptive effect of Naringenin was analyzed by both thermal induced and chemical induced nociceptive mice models. Carrageenan-induced paw edema test was performed to detect the anti-inflammatory effect of Naringenin and it is confirmed by analyzing the leukocyte infiltration in peritoneal cavity. Air pouch model test is performed to estimate the inhibitory property of Naringenin against proinflammatory cytokines. The potency of drug Naringenin was confirmed by treating along with opioid inhibitors naloxone and the results compared with standard drugs. To assess the muscle relaxant property of Naringenin open field test was performed. The overall results of Naringenin in different nociceptive and inflammatory mice models suggest that, Naringenin is a potent anti inflammatory drug which relieves pain effectively and can be used in pain management therapy. PMID- 30414429 TI - Trigonelline therapy confers neuroprotection by reduced glutathione mediated myeloperoxidase expression in animal model of ischemic stroke. AB - AIM: Stroke is devastating with a limited choice of intervention. Many pharmacological entities are available but none of them have evolved successfully in counteracting the multifaceted molecular alterations following stroke. Myeloperoxidase (MPO) has been reported to play an important role in neuroinflammation following neurodegenerative diseases. Therefore, using it as a therapeutic target may be a strategy to confer neuroprotection in stroke. Trigonelline (TG), a plant alkaloid has shown neuroprotective effects in the past. Here we explore its neuroprotective effects and its role in glutathione mediated MPO inhibition in ischemic stroke. METHODS: An in silico study was performed to confirm effective TG and MPO interaction. An in vitro evaluation of toxicity with biochemical estimations was performed. Further, in vivo studies were undertaken where rats were treated with 25, 50 and 100 mg/kg TG or standard MPO inhibitingdrug4-Aminobenzoic hydrazide (4-ABH) at 60 min prior, post immediate and an hour post 90 min of middle cerebral artery occlusion (MCAo) followed by 24 h reperfusion. Rats were evaluated for neurodeficit and motor function tests. Brains were further harvested for infarct size evaluation, biochemical analysis, and western blot experiments. KEY FINDINGS: TG at 100 mg/kg dose i.p. administered immediately post ischemia confers neuroprotection by reducing cerebral infarct with improvement in motor and neurodeficit scores. Furthermore, elevated nitrite and MDA levels were also found to be reduced in brain regions in the treated group. TG also potentiated intrinsic antioxidant status and markedly inhibited reduced glutathione mediated myeloperoxidase expression in the cortical brain region. SIGNIFICANCE: TG confers neuroprotection by reduced glutathione mediated myeloperoxidase inhibition in ischemic stroke. PMID- 30414430 TI - Contribution of sulfate-reducing bacteria to homeostasis disruption during intestinal inflammation. AB - Alteration in microbial populations and metabolism are key events associated with disruption of intestinal homeostasis and immune tolerance during intestinal inflammation. A substantial imbalance in bacterial populations in the intestine and their relationships with the host have been observed in patients with inflammatory bowel disease (IBD), believed to be part of an intricate mechanism of triggering and progression of intestinal inflammation. Because elevated numbers of sulfate-reducing bacteria (SRB) have been found in the intestines of patients with IBD, the study of their interaction with intestinal cells and their potential involvement in IBD has been the focus of investigation to better understand the intestinal pathology during IBD, as well as to find new ways to treat the disease. SRB not only directly interact with intestinal epithelial cells during intestinal inflammation but may also promote intestinal damage through generation of hydrogen sulfide at high levels. Herein we review the literature to discuss the various aspects of SRB interaction with host intestinal tissue, focusing on their interaction with intestinal epithelial and immune cells during intestinal inflammation. PMID- 30414431 TI - Metformin alleviates hyperglycemia-induced apoptosis and differentiation suppression in osteoblasts through inhibiting the TLR4 signaling pathway. AB - AIMS: Metformin was found to protect against hyperglycemia-induced injury in osteoblasts, but the cellular mechanisms involved remain unclear. Therefore, the aim of this study was to determine the effect of metformin on hyperglycemia induced apoptosis and differentiation suppression in osteoblasts and to explore its relationships with the TLR4 signaling pathway. MAIN METHODS: A mouse osteoblast cell line, MC3T3-E1, and a diabetic rat model were used to survey the protective effects of metformin on hyperglycemia-induced injury. TLR4 expression was altered using small interfering (si)RNA and lentivirus-mediated TLR4 overexpression. LPS was used as a specific TLR4 activator, and CLI-095 was used as a TLR4 inhibitor. KEY FINDINGS: Metformin improved osteoblast differentiation, reduced apoptosis in hyperglycemic osteoblasts, and inhibited TLR4, MyD88 and NF kappaB expression in a dose-dependent manner. Down-regulating the expression or inhibiting the activity of TLR4 enhanced these protective effects of metformin on osteoblast differentiation, cell viability and cell apoptosis in hyperglycemic conditions, whereas up-regulating the expression or activating the activity of TLR4 had the opposite effects. Activating NF-kappaB suppressed the protective effects of metformin, while inhibiting NF-kappaB activity had the opposite effects. Metformin increased ALP and OCN secretion, enhanced BMP-2 expression, improved bone mineral density (BMD), and decreased TLR4, MyD88 and NF-kappaB levels in the femur tissues of diabetic rats. SIGNIFICANCE: Taken together our experimentation support the hypothesis that metformin may alleviate hyperglycemia induced apoptosis and differentiation suppression in osteoblasts by inhibiting the TLR4/MyD88/NF-kappaB signaling pathway. PMID- 30414432 TI - Energy and metabolic pathways in trefoil factor family member 2 (Tff2) KO mice beyond the protection from high-fat diet-induced obesity. AB - AIMS: Trefoil factor family member 2 (TFF2) is a small gut peptide. We have previously shown that Tff2 knock out (KO) mice are protected from high-fat (HF) diet-induced obesity (De Giorgio et al., 2013a). Thus, exploring Tff2 KO-related pathways of mice at the genomic, proteinic and biochemical levels would allow us to elucidate the processes behind this protection from obesity. MAIN METHODS: To explore the metabolic and energetic effects related to Tff2 deficiency, we used sampled blood from the previous study to measure levels of free fatty acids, glucose, glycerol and triglycerides in serum. Expression levels of selected genes and proteins related to energy metabolism in the skeletal muscle, liver and adipose tissue were also studied. KEY FINDINGS: Following the 12-wk challenging of Tff2 KO and WT mice with both HF and low-fat diet, Tff2 KO mice had lower levels of serum glucose, triglycerides and glycerol. Importantly, western blotting and Q_RT-PCR revealed that the expression levels of selected genes and proteins are toward less fat storage and increased energy expenditure by enhancing lipid and glucose utilization via oxidative phosphorylation. SIGNIFICANCE: We mapped a part of the metabolic and biochemical pathways of lipids and glucose involving the adipose tissue, liver, skeletal muscle and sympathetic nervous system that protect Tff2 KO mice from the HF diet-induced obesity. Our data highlight Tff2-related pathways as potential targets for obesity therapies. PMID- 30414433 TI - Evaluation of serum pannexin-1 as a prognostic biomarker for traumatic brain injury. AB - BACKGROUND: Pannexin-1 is a type of hexameric plasma membrane channel-forming proteins, and plays a significant role in brain injury. We investigated the potential prognostic value of pannexin-1 in traumatic brain injury. METHODS: A single peripheral blood sample in 112 patients with severe traumatic brain injury and 112 controls was prospectively collected for subsequent measurement of serum pannexin-1. Clinical follow-up was performed at 6 months. An unfavorable outcome was defined as Glasgow Outcome Scale score of 1-3. RESULTS: The patients showed markedly higher serum pannexin-1 concentrations than the controls. Among the patients, pannexin-1 concentrations were significantly and negatively correlated with Glasgow coma scale scores. On receiver operating characteristic curve analysis, the predictive value in terms of area under the curve was substantially high for serum pannexin-1 as a predictor for both 6-month mortality and unfavorable outcome. Regression analyses confirmed that there was an increased risk of either 6-month mortality, overall survival or unfavorable outcome associated with serum pannexin-1 concentrations after adjusting for possible confounders. CONCLUSIONS: Serum pannexin-1 may represent a potential prognostic biomarker for head trauma. PMID- 30414434 TI - Chemiluminescence immunoassay for sensing lipoprotein-associated phospholipase A2 in cardiovascular risk evaluation. AB - BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a novel inflammatory biomarker, which is useful as an adjunct identification tool for cardiovascular disease. However, the important limitation of the conventional enzyme-linked immunosorbent assay (PLAC ELISA) for Lp-PLA2 assay is its relatively low sensitivity and time consuming. A method to measure the Lp-PLA2 simply, rapidly and sensitively is essential for predicting cardiovascular events in clinic. METHODS: We took advantage of magnetic separation integrated with chemiluminescence to detect Lp-PLA2. The concentration of Lp-PLA2 was measured through a one-step process by mixing antibody labelled magnetic beads, antigen and antibody at one time. RESULTS: Our method realized the sample to answer within 17 min. The detection limit and measurement range were 0.18 ng/ml and 0.18 1350 ng/ml, respectively. The specificity assay showed that no appreciable interference was observed for the substances of bilirubin, triglyceride, hemoglobin, rheumatoid factor and human anti-mouse antibody up to the concentrations of 40 mg/dl, 1000 mg/dl, 2000 mg/dl, 1500 IU/ml and 30 ng/ml, separately. We also tested 122 clinical samples using our method, presenting good overall correlations (R2 = 0.979) to the PLAC ELISA. It is worth mentioning that, our method was faster, had a wider range of measurement and higher sensitivity compared with the PLAC ELISA. CONCLUSIONS: The Lp-PLA2 assay is straightforward, sensitive and precise, which is highly suitable to further explore the clinical performance of Lp-PLA2 in studies of cardiovascular risk management. PMID- 30414435 TI - NIST calibration alignment is essential when selecting a laboratory reference method for evaluating POC Blood Glucose Monitoring Systems. PMID- 30414436 TI - Acute kidney injury as a rare manifestation of pediatric sarcoidosis: A case report and systematic literature review. AB - BACKGROUND: Sarcoidosis is a chronic noncaseating granulomatous disease with an unknown etiology that can affect multiple organs. Renal involvement in pediatric onset adult-type sarcoidosis is rare, and only a few cases have been reported. We present a case of a Chinese patient with pediatric-onset adult-type sarcoidosis with renal involvement, and a literature review was performed. METHODS: The PubMed database was searched for publications, and relevant clinical data were extracted and presented. RESULTS: We identified 22 pediatric-onset adult-type sarcoidosis cases with renal involvement. Acute kidney injury was the major clinical presentation. Granulomatous interstitial nephritis was the predominant histopathological feature. All patients were treated with corticosteroids and immunosuppressive agents, and most achieved improved outcome. CONCLUSIONS: Sarcoidosis should be considered in children with acute kidney injury of an unknown etiology. A final diagnosis is established through a combination of the clinical and laboratory characteristics, radiological presentation, and histological features of noncaseating granulomas. A therapeutic schedule should be decided after a systemic assessment. PMID- 30414437 TI - Comparison of serum human epididymis protein 4 and CA125 on endometrial cancer detection: A meta-analysis. AB - BACKGROUND: Endometrial cancer (EC) is common type of gynecologic malignancy affecting a large number of females around the world. While most early stage cases are well managed with a relatively benign prognosis, the late stage cases have poor survival. Among the many biomarkers identified, serum human epididymis protein 4 (HE4) and CA125 are most promising surrogates for EC detection. METHODS: We performed a meta-analysis to estimate the diagnostic accuracy of HE4 and CA125 and compared their performance. A literature research was performed in Medline, Cochrane Literature Library and CNKI. After filtering, twelve studies evaluating the diagnostic value of serum HE4, alone or in comparison with CA125, were included. The total sample size was 1106 patients and 1480 controls. Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR) were calculated and summary receiver operating characteristic (SROC) curves were plotted to assess the diagnostic accuracy. RESULTS: The pooled estimates for HE4 were sensitivity: 0.71 (95%CI 0.56-0.82), specificity: 0.87 (95%CI 0.80-0.92), and area under ROC curve: 0.88 (0.85-0.91), compared to 0.35 (95% CI 0.25-0.46), 0.83 (95% CI 0.71-0.91), and 0.58 (95% CI 0.54-0.63), respectively, of CA125. Subgroup analysis demonstrated a better performance of HE4 in Caucasian population, compared to Chinese population. CONCLUSION: This analysis suggested that when stage and histological type are not specifically considered, serum HE4 is generally a better tool than CA125 in EC diagnosis by its significantly higher sensitivity than CA125. PMID- 30414438 TI - Factors related to depressive symptoms in older adult patients with type 2 Diabetes Mellitus. AB - BACKGROUND: The association of type 2 Diabetes Mellitus (DM2) with depressive symptoms may affect the quality of life of older adults and increase their risk of morbidity and deterioration in functional activities. This study aimed to investigate the variables related to depressive symptoms in older adult patients with DM2. METHODS: This cross-sectional, descriptive, analytical study included 102 older adult patients with DM2, treated in northeastern Brazil. We evaluated demographic, clinical, and functional variables [Timed Up and Go (TUG) test, a scale to assess performance (WHO Disability Assessment Schedule), and psycho cognitive variables (using the Mini Mental State Examination (MMSE) and Geriatric Depression Scale (GDS)). RESULTS: There was a significant correlation between the GDS and body mass index (p = 0.04, rho = 0.20) and intensity of pain (p = 0.09, rho = 0.26); and scores on the MMSE (p = 0.01, rho = -0.25); WHODAS (p < 0.001, rho = 0.61); TUG test (p = 0.016, rho = 0.25), and TUG dual task (p = 0.029, rho = 0.23). CONCLUSION: Depressive symptoms in older adult patients with DM2 were associated with being female, being single, being illiterate, having poor overall health, using a walking aid, having higher body mass index, having a greater intensity of dizziness, exhibiting functional impairment, and having gait and cognition deficits. PMID- 30414439 TI - Population-level transition of capsular polysaccharide types among sequence type 1 group B Streptococcus isolates with reduced penicillin susceptibility during their long-term hospital epidemic. AB - Over a 35-month period, group B Streptococcus isolates with reduced penicillin susceptibility (PRGBS) were detected from elderly patients at a regional hospital, accompanying population-level transition of PRGBS serotypes. Seventy seven non-duplicate PRGBS recovered from 73 patients were analyzed to infer their genetic relatedness. Serotype III PRGBS predominated (16 serotype III/1 serotype Ib) in the first nine months (period I), then 3 serotype Ib isolates appeared transiently for the next three months (period II), which was replaced predominantly by serotype Ia (20 serotype Ia/1 serotype III/1 nontypeable) for nine months (period III). In the last 14 months (period IV), besides 25 serotype Ia, 10 serotype III isolates were also identified. Serotypes III and Ia isolates, belonging to ST1 shared G329V, G398A, V405A, and G429D in penicillin-binding protein2X. Of three strains subjected to whole-genome sequencing, serotype III strain SU12 (period I) had the higher degrees of genomic similarity with serotype Ia strain SU97 (period III) rather than serotype Ib strain SU67 (period II) based on average nucleotide identity and single nucleotide polymorphisms analyses. Analysis of the cps gene clusters and the upstream and downstream flanking sequences revealed that disruption of hyaluronidase gene located upstream of cpsY by insertion of an IS1548 was found in strain SU12, whereas DeltaISSag8 was inserted between tRNA-Arg and rpsA genes located downstream of cpsL for strain SU97. Interestingly, most of serotype III PRGBS re-emerged in phase IV had this tRNA-Arg-DeltaISSag8-rpsA region. Capsular switching and nosocomial transmission may possibly contribute to population-level serotype replacement among ST1 PRGBS isolates. PMID- 30414440 TI - Omalizumab lowers asthma exacerbations, oral corticosteroid intake and blood eosinophils: Results of a 5-YEAR single-centre observational study. AB - Omalizumab is a humanized monoclonal antibody which binds to human immunoglobulins E (IgE), thus preventing their interactions with both high affinity and low affinity IgE receptors. Therefore, omalizumab is currently recommended for add-on biological therapy of uncontrolled allergic asthma, mainly characterized by type 2 airway eosinophilic inflammation. Because omalizumab has been the first, and for a long time the only available monoclonal antibody for add-on treatment of type 2 asthma, some long-term studies have been published which provide a clear evidence of the therapeutic effectiveness of the anti-IgE pharmacological strategy. Within this context, the present single-centre observational study refers to 15 patients with severe allergic asthma, treated with omalizumab for at least 5 years at the Respiratory Unit of "Magna Graecia" University Hospital located in Catanzaro, Italy. In these asthmatic subjects we observed significant increases in asthma control test (ACT) score, with respect to baseline (14.60 +/- 2.97), after 1 year (19.20 +/- 2.98; p < 0.0001) and 5 years (21.67 +/- 2.38; p < 0.0001) of add-on treatment with omalizumab. More importantly, omalizumab significantly lowered the number of annual asthma exacerbations (baseline: 3.66 +/- 2.01) after 1 year (0.83 +/- 1.14; p < 0.0001) and 5 years (0.63 +/- 0.99; p < 0.0001), respectively. This excellent therapeutic outcome made it possible to drastically decrease the daily oral intake of prednisone (baseline: 22.50 +/- 5.17 mg) after 1 year (1.83 +/- 4.06 mg; p < 0.0001), as well as after 5 years (1.66 +/- 3.61 mg; p < 0.0001). With regard to lung function, omalizumab significantly and persistently enhanced FEV1 (baseline: 1636 +/- 628.4 mL) after 1 year (2000 +/- 679.7 mL; p < 0.05) and 5 years (1929 +/- 564.8 mL; p < 0.05), respectively. Such relevant clinical and functional improvements were associated with reductions of blood eosinophil counts (baseline: 646.0 +/- 458.9 cells/MUl), already detectable after 1 year (512.7 +/- 327.8 cells/MUl; not significant), which reached the threshold of statistical significance after 5 years (326.0 +/- 171.8 cells/MUl; p < 0.05). Therefore, these real-life data referring to our single-centre observational investigation further corroborate the long-term therapeutic ability of omalizumab to improve several clinical, functional and haematological signatures of severe type 2 asthma. PMID- 30414441 TI - Medicines in the forest: ethnobotany of wild medicinal plants in the pharmacopeia of the Wichi people of Salta province (Argentina). AB - ETHNOPHARMACOLOGICAL RELEVANCE: This article presents the results of a study on wild plant pharmacopeia and medical ethnobotany of the Wichi people of the South American Gran Chaco region, where native forest still persist. Few previous works on the former subjects exist, with only partial information. Traditionally, shamans are in charge of healing serious diseases and wild plants are used for treating minor problems. Some ethnobotanists believe that much of the present pharmacopeia of native peoples of the Gran Chaco comes from the Criollos (local non-native people) and that medicinal plants and uses would have been much fewer in the past. AIMS OF THE STUDY: The study aims to: a) document the wild medicinal plants used by the Wichis and the associated ethnobotanical knowledge, b) discuss the use of medicinal plants in the current sanitary, epidemiological and ethnomedical context of the Wichis, and c) analyse the similarities between the medicinal plants and uses of the Wichis and those reported for the Criollos of the study area, for the We'enhayek (Wichis of Bolivia) and for other indigenous peoples of the Gran Chaco. All of them will help to answer a general research question: are medicinal wild plants of the Wichis present pharmacopoeia long dated or are they relatively new adquisitions? MATERIALS AND METHODS: Original data were obtained between 2005 and 2017 from 51 informants through open and semi structured interviews, participant observation, "walks-through-the-forest" technique and gathering of plant vouchers. Consensus of Use (CU) per species, use, ailment and use-category were calculated. Species and uses of the Wichis and those reported for other groups of the region were compared confronting the data, a similarity index (Sorensen) was calculated and a cluster anaylsis was carried out. An interpretative analysis of the results was performed. RESULTS: Original data consist of 408 applications for which 115 plants of 48 botanical families are used for treating 68 ailments or symptoms. Species are mainly used for treating prevalent health disorders in Wichi epidemiological context (skin and digestive disorders, fever, respiratory affections) and feminine issues. CONCLUSIONS: The similarity of the current Wichi pharmacopoeia with the other ethnic groups of the region seem to respond more to a geographical proximity than to cultural affinity. Much (but not all) of their pharmacopoeia seem to be novel, resulting from a permanent seek for solutions to both old and new health problems in the native forests. Many medicinal plants, but not specific uses, seem to come from the neighbouring Criollos, whilst traditional remedies seem to be simultaneosly preserved. Hence, I propose that the ethnobotanical "diversification hypothesis", slightly modified, applies in the case of wild medicinal plants of the Wichis, as new wild medicines are being added to the old ones to fill therapeutic vacancies that for several sociocultural and historical reasons appear in their traditional pharmacopoeia. Altogether, results provide novel information of interest for ethnopharmacology, medical ethnobotany and related disciplines, expand the knowledge of Wichi pharmacopoeia and contitute a baseline for future diachronic and cross-cultural studies in the Gran Chaco region. PMID- 30414442 TI - Longitudinal association between inflammatory markers and specific symptoms of depression in a prospective birth cohort. AB - BACKGROUND: Low-grade inflammation is associated with depression, but studies of specific symptoms are relatively scarce. Association between inflammatory markers and specific symptoms may provide insights into potential mechanism of inflammation-related depression. Using longitudinal data, we have tested whether childhood serum interleukin 6 (IL-6) and C-reactive protein (CRP) levels are associated with specific depressive symptoms in early adulthood. METHODS: In the ALSPAC birth cohort, serum IL-6 and CRP levels were assessed at age 9 years and 19 depressive symptoms were assessed at age 18 years. We used modified Poisson generalised linear regression with robust error variance to estimate the risk ratio (RR) and 95% confidence interval (95% CI) for each depressive symptom. In addition, we used confirmatory factor analysis to create two continuous latent variables representing somatic/neurovegetative and psychological dimension scores. Structural equation modelling was used to test the associations between IL-6 and these dimension scores. RESULTS: Based on data from 2731 participants, IL-6 was associated with diurnal mood variation, concentration difficulties, fatigue and sleep disturbances. The adjusted RRs for these symptoms at age 18 years for participants in top, compared with bottom, third of IL-6 at age 9 years were 1.75 (95% CI, 1.13-2.69) for diurnal mood variation, 1.50 (95% CI, 1.11 2.02) for concentration difficulties, 1.31 (95% CI, 1.12-1.54) for fatigue, and 1.24 (95% CI, 1.01-1.52) for sleep disturbances. At dimension level, IL-6 was associated with both somatic/neurovegetative (beta = 0.059, SE = 0.024, P = 0.013) and psychological (beta = 0.056, SE = 0.023, P = 0.016) scores. CONCLUSIONS: Inflammation is associated with specific symptoms of depression. Associations with so-called somatic/neurovegetative symptoms of depression such as fatigue, sleep disturbances and diurnal mood variation indicate that these symptoms could be useful treatment targets and markers of treatment response in clinical trials of anti-inflammatory treatment for depression. PMID- 30414443 TI - A backbone for reverse-translation: Evidence for neuroinflammation in patients with low back pain. PMID- 30414444 TI - Structural studies and biological evaluation of T30695 variants modified with single chiral glycerol-T reveal the importance of LEDGF/p75 for the aptamer anti HIV-integrase activities. AB - Some G-quadruplex (GQ) forming aptamers, such as T30695, exhibit particularly promising properties among the potential anti-HIV drugs. T30695 G-quadruplex binds to HIV-1 integrase (IN) and inhibits its activity during 3'-end processing at nanomolar concentrations. Herein we report a study concerning six T30695-GQ variants, in which the R or S chiral glycerol T, singly replaced the thymine residues at the T30695 G-quadruplex loops. CD melting, EMSA and HMRS experiments provided information about the thermal stability and the stoichiometry of T30695 GQ variants, whereas CD and 1H NMR studies were performed to evaluate the effects of the modifications on T30695-GQ topology. Furthermore, LEDGF/p75 dependent and independent integration assays were carried out to evaluate how T loop modifications impact T30695-GQ biological activities. The obtained results showed that LEDGF/p75 adversely affects the potencies of T30695 and its variants. The IN inhibitory activities of the modified aptamers also depended on the position and on the chirality (R or S) of glycerol T loop in the GQ, mostly regardless of the G-quadruplex stabilities. In view of our and literature data, we suggest that the allosteric modulation of IN tetramer conformations by LEDGF/p75 alters the interactions between the aptamers and the enzyme. Therefore, the new T30695 variants could be suitable tools in studies aimed to clarify the HIV-1 IN tetramers allostery and its role in the integration activity. PMID- 30414445 TI - Streptococcus gordonii induces bone resorption by increasing osteoclast differentiation and reducing osteoblast differentiation. AB - Streptococcus gordonii is commonly found in the periapical endodontic lesions of patients with apical periodontitis, a condition characterized by inflammation and periapical bone loss. Since bone metabolism is controlled by osteoclastic bone resorption and osteoblastic bone formation, we investigated the effects of S. gordonii on the differentiation and function of osteoclasts and osteoblasts. For the determination of bone resorption activity in vivo, collagen sheets soaked with heat-killed S. gordonii were implanted on mouse calvaria, and the calvarial bones were scanned by micro-computed tomography. Mouse bone marrow-derived macrophages (BMMs) were stimulated with M-CSF and RANKL for 2 days and then differentiated into osteoclasts in the presence or absence of heat-killed S. gordonii. Tartrate-resistant acid phosphatase staining was performed to determine osteoclast differentiation. Primary osteoblast precursors were differentiated into osteoblasts with ascorbic acid and beta-glycerophosphate in the presence or absence of heat-killed S. gordonii. Alkaline phosphatase staining and alizarin red S staining were conducted to determine osteoblast differentiation. Western blotting was performed to examine the expression of transcription factors including c-Fos, NFATc1, and Runx2. Heat-killed S. gordonii induced bone destruction in a mouse calvarial implantation model. The differentiation of RANKL primed BMMs into osteoclasts was enhanced in the presence of heat-killed S. gordonii. Heat-killed S. gordonii increased the expression of c-Fos and NFATc1, which are essential transcription factors for osteoclast differentiation. On the other hand, heat-killed S. gordonii inhibited osteoblast differentiation and reduced the expression of Runx2, an essential transcription factor for osteoblast differentiation. S. gordonii exerts bone resorptive activity by increasing osteoclast differentiation and reducing osteoblast differentiation, which may be involved in periapical bone resorption. PMID- 30414446 TI - Clinical use of an immune monitoring panel in liver transplant recipients: A prospective, observational study. AB - Immunosuppressive therapy greatly contributed to making liver transplantation the standard treatment for end-stage liver diseases. However, it remains difficult to predict and measure the efficacy of pharmacological immunosuppression. Therefore, we used a panel of standardized, commonly available, biomarkers with the aim to describe their changes in the first 3 weeks after the transplant procedure and assess if they may help therapeutic drug monitoring in better tailoring the dose of the immunosuppressive drugs. We prospectively studied 72 consecutive patients from the day of liver transplant (post-operative day #0) until the post-operative day #21. Leukocytes, neutrophils, lymphocytes (CD4+, CD8+), natural killer cells, monocytes, immunoglobulins and tacrolimus serum levels were measured on peripheral blood (at day 0, 3, 7, 14, 21 after surgery). Patients who developed infections showed significantly higher CD64+ monocytes on post operative day #7. IgG levels were lower on post operative day #3 among patients who later developed infections. We also found that a sharp decrease in IgA from post operative day #0 to 3 (-226 mg/dL in the ROC curve analysis) strongly correlates with the onset of infections among HCV- patients. No specific markers of rejection emerged from the tested panel of markers. Our results show that some early changes in peripheral blood white cells and immunoglobulins may predict the onset of infections and may be useful in modulating the immunosuppressive therapy. However, a panel of commonly available, standardized biomarkers do not support in improving therapeutic drug monitoring ability to individualize immunosuppressive drugs dosing. PMID- 30414447 TI - Incidence of Aortitis in Surgical Specimens of the Ascending Aorta Clinical Implications at Follow-Up. AB - The objectives of this study are too evaluate the incidence of aortitis on a surgical population, establish any relationship with systemic diseases, verify early and late surgical results and provide clinical and radiological follow-up to determine factors potentially predicting progression of the disease and influencing late outcome. From 2009 to 2017, 237 patients underwent elective operations on the ascending aorta. Segments of the excised tissues were routinely sent for histologic evaluation, providing adequate data in 178 (75%) for a clinical and pathologic correlation. Patients with aortitis (Group 1) (n = 26) were compared with 152 with atherosclerotic or degenerative disease (Group 2). Incidence of aortitis was 15%, being clinically isolated in 73%. In 24 patients (92%), a giant cell aortitis was found. Actuarial survival at 3 years is 88% in Group 1 and 98% in Group 2 and 74% and 98% at 5 years, respectively (P = 0.016). A control angio-computed tomography revealed an increased descending aorta diameter in 2 out of 14 late survivors. A positron emission tomography showed presence of arteritis in other vascular segments in 3 patients. Clinically isolated aortitis is extremely frequent in patients with inflammatory aortic disease. The diagnosis is often difficult and may be supported by routine pathologic evaluation of surgical explants and by multimodality imaging. The latter should be employed to allow adequate patient follow-up and to disclose potential recurrences in untreated aortic segments. PMID- 30414449 TI - Identification of gene products that control lipid droplet size in yeast using a high-throughput quantitative image analysis. AB - Lipid droplets (LDs) are important organelles involved in energy storage and expenditure. LD dynamics has been investigated using genome-wide image screening methods in yeast and other model organisms. For most studies, genes were identified using two-dimensional images with LD enlargement as readout. Due to imaging limitation, reduction of LD size is seldom explored. Here, we aim to set up a screen that specifically utilizes reduced LD size as the readout. To achieve this, a novel yeast screen is set up to quantitatively and systematically identify genes that regulate LD size through a three-dimensional imaging-based approach. Cidea which promotes LD fusion and growth in mammalian cells was overexpressed in a yeast knockout library to induce large LD formation. Next, an automated, high-throughput image analysis method that monitors LD size was utilized. With this screen, we identified twelve genes that reduced LD size when deleted. The effects of eight of these genes on LD size were further validated in fld1 null strain background. In addition, six genes were previously identified as LD-regulating genes. To conclude, this methodology represents a promising strategy to screen for players in LD size control in both yeast and mammalian cells to aid in the investigation of LD-associated metabolic diseases. PMID- 30414448 TI - Design of ChooseWell 365: Randomized controlled trial of an automated, personalized worksite intervention to promote healthy food choices and prevent weight gain. AB - BACKGROUND/AIMS: Behavioral nudges in the food environment increase healthy choices, but it is unknown if they improve diet and health. The ChooseWell 365 study will determine if an automated, personalized worksite intervention to nudge healthier choices improves overall diet and cardiometabolic health. DESIGN: Randomized controlled trial of 602 hospital employees who regularly use on-site cafeterias and pay with an employee ID. INTERVENTION: The intervention combines an environmental strategy (traffic-light labeling) with objective feedback and personalized nudges (health/lifestyle tips, social norms, incentives) to promote healthy food choices. The ChooseWell 365 software platform automatically generates personalized emails and letters that integrate employees' weight goals with health, lifestyle, and cafeteria purchasing data. Over one year, the intervention group receives two weekly emails. One provides a log of daily purchases; the second provides personalized health/lifestyle tips. The intervention group receives monthly mailed letters with social norm comparisons and financial incentives for healthier purchases. The one-year intervention will be completed in February 2019; all follow-up will be completed March 2020. OUTCOMES: Weight, cardiometabolic risk factors, and dietary intake at one and two year follow-up. Other outcomes include worksite food purchases by study participants and other non-participant employees who are socially connected (inferred from purchasing data) to participants. CONCLUSIONS: ChooseWell 365 tests a novel strategy to deliver a scalable worksite prevention program that is integrated into the workday. The intervention is personalized but automated and therefore does not require costlier individual counseling. In the future, this program could be applied broadly in other worksite settings. PMID- 30414450 TI - Structural stability of human butyrylcholinesterase under high hydrostatic pressure. AB - Human butyrylcholinesterase is a nonspecific enzyme of clinical, pharmacological and toxicological significance. Although the enzyme is relatively stable, its activity is affected by numerous factors, including pressure. In this work, hydrostatic pressure dependence of the intrinsic tryptophan fluorescence in native and salted human butyrylcholinesterase was studied up to the maximum pressure at ambient temperature of about 1200 MPa. A correlated large shift toward long wavelengths and broadening observed at pressures between 200 and 700 MPa was interpreted as due to high pressure-induced denaturation of the protein, leading to an enhanced exposure of tryptophan residues into polar solvent environment. This transient process in native butyrylcholinesterase presumably involves conformational changes of the enzyme at both tertiary and secondary structure levels. Pressure-induced mixing of emitting local indole electronic transitions with quenching charge transfer states likely describes the accompanying fluorescence quenching that reveals different course from spectral changes. All the pressure-induced changes turned irreversible after passing a mid point pressure of about 400 +/- 50 MPa. Addition of either 0.1 M ammonium sulphate (a kosmotropic salt) or 0.1 M lithium thiocyanate (a chaotropic salt) to native enzyme similarly destabilized its structure. PMID- 30414451 TI - A roadmap for important centers of growth in the pediatric skeleton to consider during radiation therapy and associated clinical correlates of radiation-induced growth toxicity. AB - With the increasing use of advanced radiation techniques such as intensity modulated radiation therapy, stereotactic radiation therapy, and proton therapy, radiation oncologists now have the tools to mitigate radiation-associated toxicities. This is of utmost importance in the treatment of a pediatric patient. To best utilize these advanced techniques to mitigate radiation-induced growth abnormalities, the radiation oncologist should be equipped with a nuanced understanding of the anatomy of centers of growth. This article aims to enable the radiation oncologist to better understand, predict, and minimize the radiation-mediated toxicities on growth. We review the process of bone development and radiation-induced growth abnormalities and provide an atlas for contouring important growth plates to guide radiation treatment planning. A more detailed recognition of important centers of growth may improve future treatment outcomes in children receiving radiation therapy. PMID- 30414452 TI - Surgical Mentorship of John Homans by Harvey Cushing: The Untold Story. PMID- 30414453 TI - Outcomes after Pancreatectomy with Routine Pasireotide Usage. AB - BACKGROUND: Morbidity following pancreatectomy is commonly due to leakage of exocrine secretions resulting in abscess or pancreatic fistula (PF). Previously, we authored a double-blind randomized controlled trial demonstrating perioperative pasireotide administration lowers abscess or PF formation by over 50%. Accordingly, we adopted pasireotide usage as standard practice following pancreatectomy in October 2014 and hypothesized a similar PF/abscess rate reduction would be observed. STUDY DESIGN: A prospectively maintained database was queried for all patients who underwent pancreatectomy between October 2014 and July 2017. Pasireotide was administered preoperatively and twice daily for 7 days postoperatively or until discharge. The primary outcome was clinically relevant PF/abscess requiring procedural intervention, identical to the prior trial outcome. Logistic regression was utilized to compare outcomes to the placebo arm of the prior randomized trial and to control known PF risk factors. RESULTS: During the 34-month study period, 652 patients underwent pancreatectomy (211 distal pancreatectomy, 441 pancreaticoduodenectomy). Compared to the historical placebo group (N=148), the observational group had an increased prevalence of higher ASA scores (69% vs. 54%, p<0.001) and high-risk cases (small duct and soft gland, 47% vs. 36%, p=0.030). The primary outcome occurred in 13.3% of patients receiving pasireotide versus 20.9% in the placebo arm of the prior trial (OR 0.58 [95% C.I. 0.37-0.92], p=0.020). Biliary leakage was lower in those receiving pasireotide (0.6% versus 3.4%, p=0.014) while other morbidity was unchanged. No subpopulation was identified more likely to benefit from pasireotide. CONCLUSIONS: At our center, adoption of pasireotide has allowed us to achieve a clinically significant abscess or pancreatic leak rate of 13.3%, approximating the effect observed in the randomized trial of pasireotide during routine surgical practice. PMID- 30414454 TI - Quorum-sensing systems trigger catalase expression to reverse the oxyR deletion mediated VBNC state in Salmonella typhimurium. AB - OxyR is an important regulatory protein that plays a key role in anti oxygenation, and its deletion causes a special VBNC (Viable But Non-Culturable) state in many bacteria including Salmonella typhimurium. The S. typhimurium in the VBNC state can grow in LB broth but cannot grow on an LB plate unless its concentration is sufficiently high. However, the mechanism that reverses this state is not clear. In this study, conditioned media containing autoinducer collected from the wild type strain can restore the growth of low concentrations of the oxyR mutant strain on LB plates, and S. typhimurium collected from the plate has higher catalase activity than that from the broth, suggesting that a quorum-sensing system can trigger catalase expression to resuscitate the organism from the VBNC state independent of the OxyR regulon. We discovered a novel catalase (STM14_2049, Cat) whose expression is strictly concentration-dependent. The purified Cat protein has obvious catalase activity in vitro and in vivo and can restore the growth of the low concentration oxyR mutant strain. Thus, we believed Cat plays a role in VBNC resuscitation process. By understanding this mechanism, we can further understand the antioxidation and quorum-sensing systems in Salmonella typhimurium. PMID- 30414455 TI - Optimizing the interventricular interval in biventricular pacing: When and how. PMID- 30414456 TI - Statins in atrial fibrillation prevention: A closed chapter?: Invited commentary for the Hellenic Journal of Cardiology on: Sai et al. "Atorvastatin Prevents Postoperative Atrial Fibrillation for Patients undergoing Cardiac Surgery". PMID- 30414457 TI - Altered resting-state dynamics in autism spectrum disorder: Causal to the social impairment? AB - Autism spectrum disorder (ASD) is characterized by profound impairments in social abilities and by restricted interests and repetitive behaviors. Much work in the past decade has been dedicated to understanding the brain-bases of ASD, and in the context of resting-state functional connectivity fMRI in high-functioning adolescents and adults, the field has established a set of reliable findings: decreased cortico-cortical interactions among brain regions thought to be engaged in social processing, along with a simultaneous increase in thalamo-cortical and striato-cortical interactions. However, few studies have attempted to manipulate these altered patterns, leading to the question of whether such patterns are actually causally involved in producing the corresponding behavioral impairments. We discuss a few such recent attempts in the domains of fMRI neurofeedback and overt social interaction during scanning, and we conclude that the evidence of causal involvement is somewhat mixed. We highlight the potential role of the thalamus and striatum in ASD and emphasize the need for studies that directly compare scanning during multiple cognitive states in addition to the resting state. PMID- 30414458 TI - Intracellular antigen processing by ERAP2: Molecular mechanism and roles in health and disease. AB - Endoplasmic Reticulum Aminopeptidase 2 (ERAP2) is an intracellular enzyme localized in the ER that has been shown to play roles in the generation of peptides that serve as ligands for MHC class I (MHC-1) molecules. Although ERAP2 has been primarily described as an accessory and complementary enzyme to the homologous ERAP1, several lines of evidence during the last few years suggest that it can play distinct and important roles in processing antigenic peptides and influencing cellular cytotoxic immune responses. Such emerging evidence has been shaping ERAP2 as a potentially tractable target for regulating select autoimmune and anti-cancer responses for therapeutic purposes. Here, we review the state-of-the-art knowledge on the role of ERAP2 in antigen processing, its structure and molecular mechanism, influence on shaping MHC-I-bound immunopeptidomes and its involvement in disease pathogenesis. PMID- 30414459 TI - Maternal HLA-G*01:01:01:04 protects from anti-HLA-class II immunization in pregnant women. AB - Factors determining anti-HLA immunization are poorly understood, although anti HLA immunization following pregnancy is well described. The HLA-G molecule has been extensively described for its implication in immunological tolerance, especially during pregnancy. Transplant studies show an association between HLA-G haplotypes and alloimmunization. Our aim was to investigate the association of HLA-G haplotypes with anti-HLA class I and II immunization in a cohort of women having experienced one or more pregnancies and with no transfusion history. Maternal blood samples (n=270) collected at delivery and formerly screened for anti-HLA antibodies, HLA-A and HLA-B antigens, were screened by NGS for HLA-G gene polymorphism. Univariate analysis further confirmed that the number of pregnancies was significantly associated with anti-HLA class I immunization, whereas no other variable remained significant after Bonferroni correction. Our results showed however that anti-HLA class II immunization was associated with the number of children whereas the HLA-G*01:01:01:04 allele was protective against this immunization. PMID- 30414460 TI - Outcomes Following Implantable Cardioverter-Defibrillator Generator Replacement in Patients with Recovered Left Ventricular Systolic Function: the National Cardiovascular Data Registry. AB - BACKGROUND: Some patients with heart failure (HF) experience recovery of left ventricular (LV) systolic function by the end of their ICD generator battery life. Outcomes following generator replacement in this setting are poorly understood. OBJECTIVES: We sought to describe outcomes following implantable cardioverter-defibrillator (ICD) generator replacement associated with recovery of LV systolic function. METHODS: We evaluated 26,197 Medicare beneficiaries enrolled in the NCDR ICD Registry who underwent primary-prevention ICD generator replacement between 2006-2009, stratified by LV ejection fraction (LVEF): reduced (LVEF<=35%), partially-recovered (LVEF>35% and<=50%), and recovered (LVEF>50%). RESULTS: At the time of generator replacement, 7.3% of patients had recovered and 17.5% had partially-recovered LVEF. Periprocedural events were rare (<1%) among all patients. Among reduced LVEF patients, the incidence of HF readmission and mortality at three years were 27.5% and 32.7%, respectively. In comparison, HF readmission and mortality were lower for patients with partially-recovered LVEF [readmission: 15.9%, hazard ratio (HR)=0.66 (95%CI 0.61-0.72); mortality: 23.0%, HR=0.82 (95%CI 0.76-0.87)] and recovered LVEF [readmission: 12.2%, HR=0.55 (95%CI 0.48-0.63); mortality: 18.2%, HR=0.72 (95%CI 0.64-0.80)]. CONCLUSIONS: Patients with partially-recovered and recovered LVEF have lower risks of mid-term adverse outcomes compared to those with reduced LVEF following ICD generator replacement. Approximately three in four patients continue to have reduced LVEF at the time of generator replacement and are at high risk for HF readmission and mortality. These data highlight the prognostic associations of LVEF in patients undergoing generator replacement, and the clinical encounter for generator replacement as an opportunity to identify those at increased risk for adverse outcomes. PMID- 30414461 TI - Lower sarcoplasmic reticulum Ca2+ threshold for triggering afterdepolarizations in diabetic rat hearts. AB - BACKGROUND: Type-2 diabetes (T2D) increases the arrhythmias risk through incompletely elucidated mechanisms. Ventricular arrhythmias could be initiated by delayed afterdepolarizations (DADs) resulting from elevated spontaneous sarcoplasmic reticulum (SR) Ca2+ release (SR Ca2+ leak). OBJECTIVE: To test the role of DADs and SR Ca2+ leak in triggering arrhythmias in T2D hearts. METHODS: We compared rats with late-onset T2D that display pancreatic and cardiac phenotypes similar to those in humans with T2D (HIP rats) and their non-diabetic littermates (WT). RESULTS: HIP rats showed higher propensity for premature ventricular complexes and ventricular tachyarrhythmias while HIP myocytes displayed more frequent DADs and had lower SR Ca2+ content compared to the WT. However, the threshold SR Ca2+ at which depolarizing transient inward currents (Itis) are generated was also significantly decreased in HIP myocytes and was below the actual SR Ca2+ load, which explains the increased DAD incidence despite reduced Ca2+ in SR. In agreement with these findings, Ca2+ spark frequency was augmented in myocytes from HIP vs. WT rats, which suggests activation of ryanodine receptors (RyR) in HIP hearts. Indeed, RyR phosphorylation (by CaMKII and PKA) and oxidation are enhanced in HIP hearts, while there is no RyR O GlcNAcylation in either HIP or control hearts. CaMKII inhibition dissipated the difference in Ca2+ spark frequency between HIP and WT myocytes. CONCLUSIONS: The threshold SR Ca2+ for generating depolarizing Itis is lower in T2D due to RyR activation following hyperphosphorylation and oxidation, which favors the occurrence of DADs despite low SR Ca2+ loads. PMID- 30414462 TI - Distinct mechanisms underlying local antinociceptive and pronociceptive effects of natural alkylamides from Acmella oleracea compared to synthetic isobutylalkyl amide. AB - Acmella oleracea (jambu), is used as ingredient for food and in folk medicine to relief toothache. Jambu edible flowers are rich in alkylamides, mainly spilanthol, which are responsible to evoke chemesthetic sensations. This study aimed to investigate the local effects promoted by the intraplantar injection of the hexanic fraction (HF) rich in alkylamides from jambu flowers and compare to synthetic isobutylalkyl amide (IBA). Swiss male mice were intraplantarly administrated with HF and IBA (0.1-30 MUg/20 MUL), and the underlying mechanisms associated to the antinociceptive (0.1 MUg) and pronociceptive (30 MUg) effects were evaluated in chemical and sensorial tests. HF and IBA at 0.1 MUg promoted analgesia in neurogenic and inflammatory phases of formalin test, against glutamate-induced nociception and independent of the activation of endogenous opioidergic system and dependent of TRPV1 modulation, whereas only HF reduced both nociception and mast cell degranulation in hindpaw induced by compound 48/80. However, both potentiated the TRPA1-mediated nociception. In contrast, HF and IBA (30 MUg)-evoked nociceptive behaviors were reduced by the activation of opioidergic system, by TRPA1 antagonist and TRP nociceptive fibers desensitization. In addition, 30 MUg IBA-evoked nociception by activation of TRPV1, and 30 MUg HF by mast cell degranulation. Furthermore, on the contrary of IBA, HF elevated both mechanical and thermal paw threshold. Altogether, these results indicate that alkylamides could elicited dual effects, adding new evidences and mechanisms for these opposite actions in different doses. Although further research is needed, we confirmed that alkylamides displays local analgesic and/or anesthetic effects. PMID- 30414463 TI - Glatiramer acetate persists at the injection site and draining lymph nodes via electrostatically-induced aggregation. AB - Glatiramer acetate (GA) is widely prescribed for the treatment of relapsing remitting multiple sclerosis, however, the mechanism of action is still not fully understood. We investigated the structural properties of GA and examined alterations to the drug upon injection into the subcutaneous space. First, a variety of biophysical characterization techniques were employed to characterize GA in solution. GA was found to exist as alpha helices in solution with a hydrodynamic radius of ~3 nm in size. To simulate GA behavior at the site of injection, GA was injected into a solution of 1.5 MDa hyaluronic acid (HA). Visible aggregates were observed immediately upon injection and subsequent testing indicated aggregation was driven by electrostatic interactions between the positively-charged GA and negatively-charged HA. In vivo testing confirmed GA formed spherical particles in the nano- to micrometer size range, suggesting this mechanism contributes to persistence at the injection site and in draining lymph nodes. The aggregates were found to associate with glycosaminoglycans, suggesting an electrostatic mechanism of induced aggregation like the simulated injection. These novel observations may help explain the complex immunomodulatory mechanisms of GA and adverse injection site reactions seen in patients. PMID- 30414464 TI - Clay nanoparticles co-deliver three antigens to promote potent immune responses against pathogenic Escherichia coli. AB - Currently, there are few strategies for controlling pathogenic bacteria, especially the pathotypes of Escherichia coli which are an emerging threat to public health worldwide. Here, multivalent vaccine formulations are reported for control of pathogenic E. coli. The formulations utilised clay nanoparticles, either layered double hydroxides (LDH) or hectorite (HEC), to complex with a cocktail of three recombinant antigens, intimin beta (IB), proprietary antigen 1 (PAg1) and proprietary antigen 2 (PAg2). Acting as nano-adjuvants, LDH and HEC were able to stimulate strong, durable and balanced immune responses in mice. Moreover, LDH-IB-PAg1-PAg2 and HEC-IB-PAg1-PAg2 immunised mice developed potent mucosal immune responses and efficiently prevented adherence of enterohemorrhagic E. coli serotype O26 to mammalian cells. Notably, the multi-faceted immune responses elicited by the clay nanoparticle formulations were significantly higher than those induced by a QuilA formulation, without antigenic competition observed for the first time. The results of this study suggest that LDH and HEC offer considerable promise as effective multivalent vaccine carriers against important pathogens such as enteropathogenic E. coli. PMID- 30414465 TI - Radiofrequency ablation of a middle cardiac vein inserted accessory pathway resulting in posterolateral coronary artery occlusion: A case report. AB - INTRODUCTION: Posteroseptal accessory pathways account for 34.5% of the total. Of these, 36% are located within the coronary sinus (CS). Its ablation requires technical alternatives to avoid damage to surrounding tissues, especially branches of the right coronary artery. CASE REPORT: A 22-year-old man was referred for re-do ablation of an accessory left septal-septal (PSE) pathway. Inside the CS, a precocity of 25 ms was found in the region of the median cardiac vein (VCM) (Fig. 2, panel A). Radiofrequency (RF) was administered with a non irrigated bidirectional catheter within this vessel with resolution of the pre excitation after 5 seconds. Immediately after, the patient presented chest pain and revealed a ST segment elevation of 1 mm in the inferior leads of ECG. Coronary angiography showed occlusion of the middle third of the posterior ventricular branch of the right coronary artery, with no signs of thrombus or dissection. Arterial angioplasty was performed with a bare metal stent, followed by TIMI III distal flow. Retrograde aortic mapping was performed and a precocity of 20 ms was found in the PSE region. The RF was applied followed by loss of pre excitation after 1.5 seconds of application. CONCLUSION: This case demonstrates the risks involving delivering radiofrequency within the coronary sinus. We discuss some strategy that could help electrophysiologists in similar cases. PMID- 30414467 TI - Review of 400 Consecutive Oral Food Challenges to Almond. AB - BACKGROUND: Diagnosis of almond allergy is complicated by a high rate of false positive test results. Accurate diagnosis of almond allergy is critical as almond is a source of nutrition and milk products for children with other food allergies. OBJECTIVES: We reviewed the outpatient almond oral food challenges (OFCs) performed at our institution to analyze the pass rate and identify variables that predict OFC outcome. METHODS: We reviewed all almond OFCs performed at our pediatric, university-based outpatient practice between October 2015 and July 2017. OFC details, including dosing, reactions, and treatments, as well as demographic, clinical, and laboratory data were compiled. Statistical analysis was performed using the Fisher's exact and student t-tests. RESULTS: We identified 400 patients who underwent consecutive almond OFCs. Of these, 375 passed (93.8%, median sIgE 1.41 kUA/L, mean SPT wheal 3.23 mm), 16 failed (4.0%, sIgE 2.54 kUA/L, SPT 5.0 mm), and 9 were indeterminate (2.3%, sIgE 3.33 kUA/L, SPT 5.0 mm). Among children who reacted, pruritus was the most common symptom. Only two children had reactions that required epinephrine. There was no difference in demographics or allergic comorbidities between those who passed and failed. CONCLUSIONS: Among patients in our cohort, the probability of passing an almond OFC was 94%. Although higher almond sIgE level and SPT wheal size correlated with OFC failure, the pass rate remained >95% for patients with sIgE up to 10 kUA/L and SPT wheal size up to 5 mm. Among the patients who had a reaction to almond, anaphylaxis was uncommon. Our data support that performing outpatient OFCs to almond is safe for select patients. PMID- 30414466 TI - RIFM fragrance ingredient safety assessment, benzeneacetaldehyde, 3,4-dimethyl-, CAS Registry Number 68844-97-3. PMID- 30414468 TI - Immunology of the ancestral differences in eosinophilic esophagitis. PMID- 30414469 TI - Dietary polyphenols and their roles in fat browning. AB - Discovery of the presence of brown adipose tissue (BAT) in newborn babies and adult humans, especially constitutively active brown fat or inducible beige fat, has led to the investigation of strategies employing BAT aimed at the development of novel therapeutic avenues for combating obesity and diabetes. Such antiobesity therapeutic tools include pharmaceutical and nutraceutical dietary polyphenols. Although there have been emerging notable advances in knowledge of and an increased amount of research related to brown and beige adipocyte developmental lineages and transcriptional regulators, current knowledge regarding whether and how food factors and environmental modifiers of BAT influence thermogenesis has not been extensively investigated. Therefore, in this review, we summarized recent updates on the exploration of dietary polyphenols while paying attention to the activation of BAT and thermogenesis. Specifically, we summarized findings pertaining to BAT metabolism, white adipose tissue (WAT) browning and thermogenic function of polyphenols (e.g., flavan-3-ols, green tea catechins, resveratrol, capsaicin/capsinoids, curcumin, thymol, chrysin, quercetin and berberine) that may foster a relatively safe and effective therapeutic option to improve metabolic health. We also deciphered the underlying proposed mechanisms through which these dietary polyphenols facilitate BAT activity and WAT browning. Characterization of thermogenic dietary factors may offer novel insight enabling revision of nutritional intervention strategies aimed at obesity and diabetes prevention and management. Moreover, identification of polyphenolic dietary factors among plant-derived natural compounds may provide information that facilitates nutritional intervention strategies against obesity, diabetes and metabolic syndrome. PMID- 30414470 TI - Detection of ribonucleoside modifications by liquid chromatography coupled with mass spectrometry. AB - A small set of ribonucleoside modifications have been found in different regions of mRNA including the open reading frame. Accurate detection of these specific modifications is critical to understanding their modulatory roles in facilitating mRNA maturation, translation and degradation. While transcriptome-wide next generation sequencing (NGS) techniques could provide exhaustive information about the sites of one specific or class of modifications at a time, recent investigations strongly indicate cautionary interpretation due to the appearance of false positives. Therefore, it is suggested that NGS-based modification data can only be treated as predicted sites and their existence need to be validated by orthogonal methods. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is an analytical technique that can yield accurate and reproducible information about the qualitative and quantitative characteristics of ribonucleoside modifications. Here, we review the recent advancements in LC-MS/MS technology that could help in securing accurate, gold-standard quality information about the resident post-transcriptional modifications of mRNA. PMID- 30414471 TI - Increasing the participation of medical students in surgical research: The Italian case and the role of research collaboratives. PMID- 30414472 TI - Integrated Bioinformatical Analysis for Identificating the Therapeutic Targets of Aspirin in Small Cell Lung Cancer. AB - PURPOSE: We explored the mechanism of aspirin in SCLC by dissecting many publicly available databases. METHODS AND RESULTS: Firstly, 11 direct protein targets (DPTs) of aspirin were identified by DrugBank 5.0. Then protein-protein interaction (PPI) network and signaling pathways of aspirin DPTs were analyzed. We found that aspirin was linked with many kinds of cancer, and the most significant one is SCLC. Next, we classified the mutation of 4 aspirin DPTs in SCLC (IKBKB, NFKBIA, PTGS2 and TP53) using cBio Portal. Further, we identified top 50 overexpressed genes of SCLC by Oncomine, and the interconnected genes with the 4 aspirin DPTs in SCLC (IKBKB, NFKBIA, PTGS2 and TP53) by STRING. Lastly, we figured out 5 consistently genes as potential therapeutic targets of aspirin in SCLC. CONCLUSION: The integrated bioinformatical analysis could improve our understanding of the underlying molecular mechanism about how aspirin working in SCLC. Integrated bioinformatical analysis may be considered as a new paradigm for guiding future studies about interaction in drugs and diseases. PMID- 30414473 TI - Lifetime trajectory simulation of chronic disease progression and comorbidity development. AB - INTRODUCTION: Comorbidity is common in elderly patients and it imposes heavy burden on both individual and the whole healthcare system. This study aims to gain insights of comorbidity development by simulating the lifetime trajectory of disease progression from single chronic disease to comorbidity. METHODS: Eight health states spanning from no chronic condition to comorbidity are considered in this study. Disease progression network is constructed based on the seven-year retrospective data of around 700,000 residents living in Singapore central region. Microsimulation is applied to simulate the process of aging and disease progression of a synthetic new-born cohort for the entire lifetime. RESULTS: Among the 40 unique trajectories observed from the simulation, the top 10 trajectories covers 60% of the cohort. Timespan of most trajectories from birth to death is 80 years. Most people progress to at risk at late 30s, develop the first chronic condition at 50s or 60s, and then progress to complications at 70s. It is also observed that the earlier one person develops chronic conditions, the more life-year-lost is incurred. DISCUSSION: The lifetime disease progression trajectory constructed for each person in the cohort describes how a person starts healthy, becomes at risk, then progresses to one or more chronic conditions, and finally deteriorates to various complications over the years. This study may help us have a better understanding of chronic disease progression and comorbidity development, hence add values to chronic disease prevention and management. PMID- 30414474 TI - A Smartwatch-Based Framework for Real-Time and Online Assessment and Mobility Monitoring. AB - Smartphone and smartwatch technology is changing the transmission and monitoring landscape for patients and research participants to communicate their healthcare information in real time. Flexible, bidirectional and real-time control of communication allows development of a rich set of healthcare applications that can provide interactivity with the participant and adapt dynamically to their changing environment. Additionally, smartwatches have a variety of sensors suitable for collecting physical activity and location data. The combination of all these features makes it possible to transmit the collected data to a remote server, and thus, to monitor physical activity and potentially social activity in real time. As smartwatches exhibit high user acceptability and increasing popularity, they are ideal devices for monitoring activities for extended periods of time to investigate the physical activity patterns in free-living condition and their relationship with the seemingly random occurring illnesses, which have remained a challenge in the current literature. Therefore, the purpose of this study was to develop a smartwatch-based framework for real-time and online assessment and mobility monitoring (ROAMM). The proposed ROAMM framework will include a smartwatch application and server. The smartwatch application will be used to collect and preprocess data. The server will be used to store and retrieve data, remote monitor, and for other administrative purposes. With the integration of sensor-based and user-reported data collection, the ROAMM framework allows for data visualization and summary statistics in real-time. PMID- 30414475 TI - A Method for Harmonization of Clinical Abbreviation and Acronym Sense Inventories. AB - BACKGROUND: Previous research has developed methods to construct acronym sense inventories from a single institutional corpus. Although beneficial, a sense inventory constructed from a single institutional corpus is not generalizable, because acronyms from different geographic regions and medical specialties vary greatly. OBJECTIVE: Develop an automated method to harmonize sense inventories from different regions and specialties towards the development of a comprehensive inventory. METHODS: The method involves integrating multiple source sense inventories into one centralized inventory and cross-mapping redundant entries to establish synonymy. To evaluate our method, we integrated 8 well-known source inventories into one comprehensive inventory (or metathesaurus). For both the metathesaurus and its sources, we evaluated the coverage of acronyms and their senses on a corpus of 1 million clinical notes. The corpus came from a different institution, region, and specialty than the source inventories. RESULTS: In the evaluation using clinical notes, the metathesaurus demonstrated an acronym (short form) micro-coverage of 94.3%, representing a substantial increase over the two next largest source inventories, the UMLS LRABR (74.8%) and ADAM (68.0%). The metathesaurus demonstrated a sense (long form) micro-coverage of 99.6%, again a substantial increase compared to the UMLS LRABR (82.5%) and ADAM (55.4%). CONCLUSIONS: Given the high coverage, harmonizing acronym sense inventories is a promising methodology to improve their comprehensiveness. Our method is automated, leverages the extensive resources already devoted to developing institution-specific inventories in the United States, and may help generalize sense inventories to institutions who lack the resources to develop them. Future work should address quality issues in source inventories and explore additional approaches to establishing synonymy. PMID- 30414476 TI - Toxicological study of doxorubicin-loaded PLGA nanoparticles for the treatment of glioblastoma. AB - Doxorubicin loaded in poloxamer 188-coated PLGA nanoparticles (Dox-NP + P188) was shown to produce a high antitumor effect against the experimental orthotopic 101.8 glioblastoma in rats upon intravenous administration. The objective of the present study was to evaluate the acute and chronic toxicity of this nanoformulation. The parent drug was used as a reference formulation. Acute toxicity of doxorubicin-loaded nanoparticles in mice and rats was similar to that of free doxorubicin. The chronic toxicity study was conducted in Chinchilla rabbits; the treatment regimen consisted of 30 daily intravenous injections using two dosage levels: 0.22 mg/kg/day and 0.15 mg/kg/day. The study included assessment of the body weight, hematological parameters, blood biochemical parameters, urinalysis, and pathomorphological evaluation of the internal organs. The results of the study demonstrated that the hematological, cardiac, and testicular toxicity of doxorubicin could be reduced by binding the drug to PLGA nanoparticles. Coating of PLGA nanoparticles with poloxamer 188 contributed to the reduction of cardiotoxicity. Functional and morphological abnormalities caused by the nanoparticulate doxorubicin were dose-dependent and reversible. Altogether these results provide evidence that the PLGA-based nanoformulation not only might enable the broadening of the spectrum of doxorubicin activity but also an improvement of its safety profile. PMID- 30414477 TI - Prolonged release from orodispersible films by incorporation of diclofenac-loaded micropellets. AB - Prolonged drug release provided by multiple-unit dosage forms is highly beneficial to enhance the compliance and safety of the pharmacotherapy even for patients with swallowing deficiencies. To facilitate the intake for these patients, multiple-unit tablets and capsules have to be crushed or opened. An attempt to overcome these issues has been made by the introduction of orodispersible films (ODFs), which rapidly disintegrate within the oral cavity and facilitate the intake of oral solid dosage forms. The aim of this study was to develop a rapidly disintegrating ODF with prolonged release properties by incorporation of small-sized micropellets (MPs). MPs with a drug load of 70% were produced by wet extrusion and spheronization using Vivapur(r) MCG as pelletizing aid and diclofenac sodium (DS) as model drug. MPs were film-coated with an Eudragit(r) RS/RL coating and incorporated into the ODF-forming hypromellose solution. ODFs were produced by solvent casting technique. Disintegration times were determined using the PharmaTest(r) disintegration tester equipped with sample holders for ODFs. Dissolution studies were performed for MPs and ODFs. X ray micro-computed tomography was used to visualize internal and external surface structures of MPs before and after release studies. MP-loaded ODFs show fast disintegration within 30 s, whereby film-coated MPs remain intact. Uncoated MPs are disintegrating thus revealing immediate DS release. In comparison, DS release was prolonged for film-coated MPs and corresponding ODFs. Incorporation of different amounts of MPs had no effect on the dissolution, but on mechanical properties of ODFs, which decrease with increasing amounts of MPs. The production of rapidly disintegrating ODFs with prolonged release properties for DS, representing a freely water-soluble drug, was feasible. PMID- 30414478 TI - Injectability as a function of viscosity and dosing materials for subcutaneous administration. AB - Injectability is a term related to the ease of parenteral administration of a dosing solution, and includes dose preparation, dose administration, ergonomics related to these procedures, pain of injection, and other adverse events at the injection site. This article focuses on force measurements related to injectability, namely: force to expel syringe contents (expulsion force - a mimic for in vivo injection force), needle-penetration force, and needle-bending force, and these results are supplemented by expulsion time measurements with 18 participants, as well as injections in a porcine model. Based on the expulsion time measurements, where 80 N injection force was found to be difficult for most people, we consider the maximum acceptable injection force to be 40 N, and recommend targeting no more than 20 N, especially if the configuration may be used in an autoinjector or similar device. The injectability of antisense oligonucleotide solutions was assessed to determine optimal dosing materials (among those evaluated) for a variety of solution viscosities. Dosing materials varied in syringe inner diameter, needle inner diameter, needle length, and needle wall thickness: standard-wall vs. thin-wall. In general, short (6-8 mm) thin-wall needles are recommended as a way to improve patient perception and comfort during subcutaneous dose administration. PMID- 30414479 TI - Integrative meta-analysis of publically available microarray datasets of several epithelial cell lines identifies biological processes affected by silver nanoparticles exposure. AB - The present study aimed to identify differentially expressed genes (DEGs) under silver nanoparticle (AgNPs) treatment. We used a meta-analysis approach to integrate four publicly available microarray datasets, containing control and epithelium samples treated by either AgNPs- or Ag ions. The Fisher's method combined p-values of studies. Post hoc analyses including protein-protein interaction (PPI) and the overrepresentation test were conducted. Analytical results identified 1652 DEGs associated with AgNPs exposure. The most significant up-regulated genes, including MT1H, MT1X, and MT2A were metallothionein family members. The most significant down-regulated gene, TM4SF5, is a novel biomarker for AgNPs exposure. The PPI network analysis revealed that a member of the heat shock protein family, HSP90AA1, is the top up-regulated "hub" gene. Up-regulation of heat shock proteins and metallothionein genes is part of a cellular response to oxidative stress induced by AgNPs treatment. Interestingly, AgNPs may interact negatively with blood coagulation and amino acid metabolism systems. PMID- 30414480 TI - Oxidative stress induced by camptothecin and hydroxyl-camptothecin in IOZCAS-Spex II cells of Spodoptera exigua Hubner. AB - Camptothecin (CPT) and its derivatives show potential insecticidal activities against various insect species due to target at DNA-Topoisomerase I complex and induce apoptosis death of insect cells. Oxidative stress resulted from excessive production of reactive oxygen species (ROS) has been proved to be an important component of the mechanism of pesticide toxicity. The aim of the present study was to investigate whether CPTs promote the increasing of intracellular oxidative stress by enhancing accumulation of intracellular ROS in IOZCAS-Spex-II cells derived from Spodoptera exigua Hubner. Results demonstrated that there was a significant increase in the level of intracellular ROS accompanied by markedly increased DNA damage, lipid peroxidation and protein carbonylation after exposing to CPT and hydroxyl-camptothecin (HCPT) in IOZCAS-Spex-II cells. These results documented ROS generation induced by CPT and HCPT played an essential role in toxicity and mode of action of CPTs against insects. This research will throw new light on the critical roles of oxidative stress in CPTs- induced toxicity against insects, as well as on the exploration of using CPTs as a kind of insecticide with unique mode of action in the future. PMID- 30414481 TI - Influence of cadmium on oxidative stress and NADH oscillations in mussel mitochondria. AB - Biological organisms evolved to take advantage of recurring environmental factors which enabled them to assimilate and process metabolic energy for survival. Mitochondria display non-linear oscillations in NADH levels (i.e. wave behavior) that result from the balance between NADH production (aerobic glycolysis) and oxidation for ATP synthesis. The purpose of this study was to examine the effects of cadmium (Cd) on mitochondrial NADH oscillations in quagga mussels Dreissena bugensis exposed to 50 and 100 MUg/L CdCl2 for 7 days at 15 degrees C. Metallothionein (MT) levels, thioredoxin reductase (TrxR) activity and NADH oxidation rate were also determined, as were oscillations in NADH and the formation of dissipative structures (turbidity), in isolated mitochondria suspensions. The results show that exposure to Cd readily induced MT levels at both concentrations tested and that TrxR and NADH oxidase activity was induced at 100 MUg/L Cd only. In control mussels, NADH levels oscillated in mitochondria suspensions with a natural period of 2 to 2.5 min for up to 40 min. Exposure to Cd increased the complexity of the frequency profile of NADH oscillations and reduced the amplitudes of the natural signal with a period of 2 to 2.5 min. The formation of dissipative structures decreased in response to a Cd concentration of 100 MUg/L but increased at a level of 50 MUg/L. The amplitudes at the natural frequency were significantly correlated with NADH oxidase activity (r = -0.91) and with the formation of dissipative structures (r = -0.59). We conclude that Cd could alter the natural frequency in oscillations of NADH in mitochondria, thereby contributing to an increase in NADH oxidation rate and disruption of the spatial organization of mitochondria in suspension. In conclusion, changes in the wave behavior of NADH in mitochondria are proposed as a novel biomarker of toxicity in aquatic organisms. PMID- 30414482 TI - Effects of replacing fish meal with soybean meal on growth performance, feed utilization and physiological status of juvenile obscure puffer, Takifugu obscurus. AB - An 8-week feeding trial was conducted to evaluate the growth performance, feed utilization and physiological status of obscure puffer, Takifugu obscurus (13.03 +/- 0.14 g) fed diets in which fish meal (FM) was replaced with various levels of dehulled and defatted soybean meal (SBM): 0% (SBM0), 15% (SBM15), 30% (SBM30), 45% (SBM45), 60% (SBM60) and 75% (SBM75). No significant differences were observed in weight gain and specific growth rate (SGR) of fish when FM replacement level was lower than 30%, and the broken-line model of SGR showed the maximum replacement level was 40%. Fish fed the SBM-containing diets had a lower red blood cell value compared to the control. The hemoglobin and methemoglobin values showed a declining tendency as dietary SBM level increased. Plasma triacylglycerol, cholesterol and low-density lipoprotein cholesterol levels also showed a decreasing trend that was associated with the reduced crude lipid content of whole body as dietary SBM level increased. The activities of alanine aminotransferase and aspartate aminotransferase in fish fed the SBM-containing diets were all higher than those fed the control diet while glutathione peroxidase and catalase activities were lower than the control group. Results indicated that up to 40% FM protein, based on the broken-line analysis of SGR, can be replaced with SBM in diet for obscure puffer juveniles with supplemental lysine, methionine and taurine. PMID- 30414483 TI - Biomaterials and glia: Progress on designs to modulate neuroinflammation. AB - Microglia are multi-functional cells that play a vital role in establishing and maintaining the function of the nervous system and determining the fate of neurons following injury or neuropathology. The roles of microglia are diverse and essential to the capacity of the nervous system to recover from injury, however sustained inflammation can limit recovery and drive chronic disease processes such as neurodegenerative disorders. When assessing implantable therapeutic devices in the central nervous system, an improved lifetime of the implant is considered achievable through the attenuation of microglial inflammation. Consequently, there is a tremendous underexplored potential in biomaterial and engineered design to modulate neuroinflammation for therapeutic benefit. Several strategies for improving device compatibility reviewed here include: biocompatible coatings, improved designs in finer and flexible shapes to reduce tissue shear-related scarring, and loading of anti-inflammatory drugs. Studies about microglial cell cultures in 3D hydrogels and nanoscaffolds to assess various injuries and disorders are also discussed. A variety of other microglia-targeting treatments are also reviewed, including nanoparticulate systems, cellular backpacks, and gold plinths, with the intention of delivering anti-inflammatory drugs by targeting the phagocytic nature of microglia. Overall, this review highlights recent advances in biomaterials targeting microglia and inflammatory function with the potential for improving implant rejection and biocompatibility studies. STATEMENT OF SIGNIFICANCE: Microglia are the resident immune cells of the central nervous system, and thus play a central role in the neuroinflammatory response against conditions than span acute injuries, neuropsychiatric disorders, and neurodegenerative disorders. This review article presents a summary of biomaterials research that target microglia and other glial cells in order to attenuate neuroinflammation, including but not limited to: design of mechanically compliant and biocompatible stimulation electrodes, hydrogels for high-throughput 3D modelling of nervous tissue, and uptake of nanoparticle drug delivery systems. The goal of this paper is to identify strengths and gaps in the relevant literature, and to promote further consideration of microglia behaviour and neuroinflammation in biomaterial design. PMID- 30414484 TI - Freeze-Casting Porous Chitosan Ureteral Stents for Improved Drainage. AB - As a new strategy for improved urinary drainage in parallel to the potential for additional functions such as drug release and self-removal, highly porous chitosan stents are manufactured by radial, bi-directional freeze-casting. Inserting the porous stent in a silicone tube to emulate its placement in the ureter shows that it is shape conforming and remains safely positioned in place, also during flow tests, including those performed in a peristaltic pump. Cyclic compression tests on fully-hydrated porous stents reveal high stent resilience and close to full elastic recovery upon unloading. The drainage performance of the chitosan stent is evaluated, using effective viscosity in addition to volumetric flow and flux; the porous stent's performance is compared to that of the straight portion of a commercial 8 Fr double-J stent which possesses, in its otherwise solid tube wall, regularly spaced holes along its length. Both the porous and the 8 Fr stent show higher effective viscosities when tested in the silicone tube. The performance of the porous stent improves considerably more (47.5%) than that of the 8 Fr stent (30.6%) upon removal from the tube, illustrating the effectiveness of the radially aligned porosity for drainage. We conclude that the newly-developed porous chitosan ureteral stent merits further in vitro and in vivo assessment of its promise as an alternative and complement to currently available medical devices. PMID- 30414485 TI - Mammary fibroblasts remodel fibrillar collagen microstructure in a biomimetic nanocomposite hydrogel. AB - Architecture and microstructure of type I collagen fibers constitute central regulators of tumor invasion with aligned fibers providing a route for migration of stromal and cancer cells. Several different aspects of fibrillar collagen, such as stiffness, density, thickness, and pore size, may regulate migration of cancer cells, but determining effects of any one parameter requires clear decoupling of physical properties of collagen networks. The objective of this work is to develop and apply an in vitro three-dimensional (3D) tumor-extra cellular matrix (ECM) model with tunable physical parameters to define how stromal fibroblasts modulate collagen microstructure to control migration of breast cancer cells. We incorporated two different types of polyhedral oligomeric silsesquioxane (POSS) nano-molecules into a collagen/alginate matrix to induce different mechanisms of gelling. The resultant biomimetic, nanocomposite hydrogels show different collagen fibrillar microstructures while maintaining constant overall matrix stiffness, density, and porosimetry. Spheroids of human mammary fibroblasts embedded in these 3D matrices remodel the collagen network to varying extents based on differences in underlying matrix microstructures. The remodeled collagen matrix shows oriented, thicker fibrillar tracks, facilitating invasion of tumor cells. By decoupling effects of matrix stiffness and architecture, our nanocomposite hydrogels serve as robust platforms to investigate how biophysical properties of tumor environments control key processes regulating tumor progression in breast cancer and other malignancies. STATEMENT OF SIGNIFICANCE: Our manuscript demonstrates a new type of nanocomposite hydrogel with two different gelling mechanisms, produced by incorporating two types of polyhedral oligomeric silsesquioxane (POSS) nano molecules into a collagen/alginate matrix. The resultant biomimetic hydrogels show different fibrillar collagen microstructures while maintaining constant overall matrix stiffness, density, and porosimetry. These gels allow us to uncouple effects of matrix stiffness versus architecture on migration and invasion of breast cancer cells and stromal fibroblasts. Upon embedding spheroids of human mammary fibroblasts (HMFs) and dissociated 231 breast cancer cells, we showed that HMFs remodeled the collagen network to differing extents dependent on starting matrix microstructures in each hydrogel. The remodeled collagen matrix showed aligned collagen fibers perpendicular to the surface of a spheroid with migrating HMFs following these fibers as occurs in tumors in vivo. To our knowledge, this is the first study showing significant different fibrillar collagen microstructures with constant collagen density and gel stiffness. This study establishes a new type of nanocomposite 3D hydrogels for studies of biophysical and cellular interactions in engineered tumor environments. PMID- 30414486 TI - Construction of a biodegradable, versatile nanocarrier for optional combination cancer therapy. AB - A novel biodegradable versatile nanocarrier (FA-CM) was fabricated based on the self-assembly of delaminated CoAl-layered double hydroxides (LDHs) and manganese dioxide (MnO2) for optional combination cancer therapy. Biodegradation, versatility, targeting, bioimaging, in vitro cytotoxicity and in vivo antitumor efficacy were evaluated. The results showed that FA-CM could not only be effectively degraded into Co2+, Al3+ and Mn2+ to overcome the long-term toxic side effects, but also successfully load any positive-charged, negative-charged, hydrophilic, and hydrophobic drug, meeting the critical requirement of versatile nanocarrier. Meanwhile, the presence of FA led to the higher uptake efficiency, cytotoxicity, and excellent fluorescence imaging of FA-CM toward cancerous cells. In particular, FA-CM exhibited glutathione and pH dual-response drug release, avoiding any premature leakage and side effects. The applicability of the FA-CM was determined by co-loading hydrophilic (doxorubicin (DOX)) and hydrophobic drug (paclitaxel (PTX)) for synergistic combination chemotherapy. In vitro cytotoxicity evaluation and a xenograft tumor model of hepatoma showed that this combination exhibited more efficient anticancer effects compared with either free drug alone or the corresponding cocktail solutions. Especially, the ratios of DOX and PTX loaded on FA-CM could be tuned as needed. A powerful approach is provided for the design and preparation of a biodegradable versatile nanocarrier with targeted ability and excellent biocompatibility, which can be potentially applied in clinical practice and medical imaging. STATEMENT OF SIGNIFICANCE: Drug delivery nanocarriers that can transport an effective dosage of drug molecules to targeted cells and tissues have been extensively designed to overcome the adverse side effects and low effectiveness of conventional chemotherapy. However, lack of biodegradability and versatility existing in majority of nanocarriers limit their further clinical applications. Thus, constructing a novel biodegradable versatile nanocarrier that can carry various types of drugs, is in urgent need and more suitable for commercial production and clinical use. In this study, we developed a novel biodegradable versatile nanocarrier (FA-CM) based on the self-assembly of delaminated CoAl-layered double hydroxides (LDHs) and manganese dioxide (MnO2) for optional combination cancer therapy. This work provides a new strategy for constructing versatile biodegradable platform for targeted drug delivery, which would have broad applications in cancer theranostics. PMID- 30414487 TI - Isocyanate-terminated urethane-based dental adhesive bridges dentinal matrix collagen with adhesive resin. AB - Commercially available dental adhesives fail to chemically unite the demineralized collagen matrix with resinous materials within the resin-dentin interface. Sub-micron separations between the collagen fibrils and polymerized resin provide the backdrop for bond deterioration. Here, novel isocyanate terminated urethane methacrylate precursors (UMP) were synthesized with the capacity to bond chemically to dentin collagen via covalent and hydrogen bonds. Collagen grafted with UMP also copolymerized with other methacrylate resin monomers, thereby producing a monoblock of chemically-linked biocomposite. The viscosity, degree of conversion and biocompatibility of UMP are comparable with commercially available resin monomers. An experimental adhesive containing 40% UMP demonstrated co-polymerization capability, good infiltration capacity and achieved higher immediate bond strength to dentin than the control commercially available adhesive. Improvement of dentin bonding by incorporation of UMP into dentin adhesives justifies future evaluation of the potential of these UMP-based adhesives in extending the longevity of resin-dentin bonds. STATEMENT OF SIGNIFICANCE: Composite-adhesive restorations have become an indispensable treatment modality in contemporary restorative dentistry. While the inability of these adhesives to bond chemically with collagen undermines the bond quality. This study describes a novel isocyanate-terminated urethane multi methacrylate precursors (UMP) which can bridge dentinal matrix collagen with adhesive resin by covalent and hydrogen bonds. Furthermore, an experimental UMP-based adhesive shows better co-polymerization capability, good infiltration capacity and higher immediate bond strength than the putatively effective adhesive Single Bond 2. The new chemical bonding mechanism based on UMP would theoretically produce more stable bonding interface that are more resistant to degradation. PMID- 30414488 TI - Suicide-gene transfection of tumor-tropic placental stem cells employing ultrasound-responsive nanoparticles. AB - A Trojan-horse strategy for cancer therapy employing tumor-tropic mesenchymal stem cells transfected with a non-viral nanovector is here presented. In this sense, ultrasound-responsive mesoporous silica nanoparticles were coated with a polycation (using two different molecular weights), providing them with gene transfection capabilities that were evaluated using two different plasmids. First, the expression of Green Fluorescent Protein was analyzed in Decidua derived Mesenchymal Stem Cells after incubation with the silica nanoparticles. The most successful nanoparticle was then employed to induce the expression of two suicide genes: cytosine deaminase and uracil phosphoribosyl transferase, which allow the cells to convert a non-toxic pro-drug (5-fluorocytosine) into a toxic drug (5-Fluorouridine monophosphate). The effect of the production of the toxic final product was also evaluated in a cancer cell line (NMU cells) co cultured with the transfected vehicle cells, Decidua-derived Mesenchymal Stem Cells. STATEMENT OF SIGNIFICANCE: Cell-mediated cancer therapy has recently attracted great interest. Tumor-homing cells can exert anticancer effects through innate capacities, via transfection with a therapeutic gene or acting as vehicles of therapeutic nanoparticles. In this work, an ultrasound-responsive mesoporous silica nanoparticle (capable of carrying an anticancer drug) is engineered to act as a non-viral transfection agent for tumor-tropic human placental mesenchymal stem cells. The successful transfection of the vehicle cells is evaluated employing different expression plasmids. After transfection with two suicide genes, the vehicle cells are capable of converting a non-toxic pro-drug into a highly toxic molecule, which can also kill surrounding cancer cells in an in vitro co-culture model. This work opens the gate for a plethora of strategies in which both genes and drug-loaded nanoparticles can be transported towards tumor tissues by easily available human mesenchymal stem cells. PMID- 30414489 TI - Effects of dietary blackberry syrup supplement on growth performance, antioxidant, and immunological responses, and resistance of Nile tilapia, Oreochromis niloticus to Plesiomonas shigelloides. AB - The present study investigated the effects of dietary blackberry syrup on growth performance, haematological, non-specific immune and spleen gene expression responses of Nile tilapia, Oreochromis niloticus. Five experimental groups of fish with mean weights of 26.75 +/- 2.67 g were used in the study; three of them were fed with blackberry syrup incorporated diets (7.5 g kg-1- BBRY7.5, 15 g kg-1 BBRY15, 30 g kg-1- BBRY30), whereas an additive free basal diet served as the control. Additionally, the fifth group was an antibiotic medicated diet (0.02 g kg-1- ABTC), prepared with the florfenicol. Dietary blackberry syrup especially at 15 g kg-1 significantly increased growth performance, respiratory burst activity, potential killing activity, phagocytic activity, phagocytic index, lysozyme activity, myeloperoxidase activity, total immunoglobulin levels, serum SOD activity and serum CAT activity (p < 0.05). Furthermore, dietary blackberry syrup increased the expression levels of immune [heat shock protein 70 (HSP70), interleukin 1, beta (IL-1beta), tumor necrosis factor (TNF-alpha), interferon gamma (IFN-gamma), immunoglobulin M (IgM)] and antioxidant [glutathione peroxidase (GPx)] related genes in the spleen of fish fed with especially 15 g kg 1 blackberry syrup (p < 0.05). At the end of the 20-day challenge period the survival rates were significantly higher in the BBRY15 and ABTC groups compared to all other treatment groups (p < 0.05). As a result, feeding Nile tilapia with a diet containing 15 g kg-1 blackberry syrup over a period of 90 days might be adequate to improve growth performance, fish immune parameters, antioxidant status, as well as survival rate against P. shigelloides, similar to antibiotic treatment. Hence, blackberry syrup can be used as an antibiotics replacer for controlling P. shigelloides in tilapia feed. PMID- 30414490 TI - alpha-Phellandrene enhances the immune response and resistance against Vibrio alginolyticus in white shrimp (Litopenaeus vannamei). AB - Innate immunity and resistance against Vibrio alginolyticus in white shrimp, Litopenaeus vannamei, that received alpha-phellandrene were examined. The results indicated that the percent survival of shrimp receiving 4, 8, and 12 MUg g-1 alpha-phellandrene was significantly higher than that of control shrimp after 72 h (p < 0.05). In a separate experiment, the phenoloxidase (PO), respiratory bursts, superoxide dismutase (SOD), and phagocytic and lysozyme activity of L. vannamei receiving 8 and 12 MUg g-1 alpha-phellandrene were significantly higher than those of the other groups upon challenge with V. alginolyticus at 24-60, 36 60, 12-60, 12-72 and 48-72 h, respectively. However, no significant differences in the total haemocyte counts (THC) of L. vannamei receiving any dose of alpha phellandrene and of control shrimp were observed at 12-72 h. The expression (mRNA transcripts) of the immune genes prophenoloxidase (proPO), LPS- and beta-1,3 glucan-binding protein (LGBP) and peroxinectin (PE) of shrimp receiving alpha phellandrene at 8 and 12 MUg g-1 significantly increased after challenge with V. alginolyticus for 72 h (p < 0.05). We conclude that the immune ability and resistance against V. alginolyticus infection increased in L. vannamei receiving >4 MUg g-1 alpha-phellandrene. These results indicated that alpha-phellandrene plays an important role in the innate immunity of white shrimp. PMID- 30414491 TI - The proliferation and clonal migration of B cells in the systemic and mucosal tissues of channel catfish suggests there is an interconnected mucosal immune system. AB - IgM transcripts from different mucosal and systemic tissues from a single adult channel catfish have been evaluated. Arrayed heavy chain cDNA libraries from each of these different mucosal and systemic tissues were separately constructed, hybridized with VH family specific probes and a variety of approaches were used to define their structural relationships. Baseline hybridization studies indicated that the tissue libraries had different VH expression patterns, and sequencing studies indicated this was not simply due to varying proportions of the same B cell population. In the systemic tissues of PBL, spleen, and anterior kidney >95% of the sequenced clones in the arrayed libraries represented different heavy chain rearrangements. Diversity was also found in the mucosal libraries of skin, gill lamellae, and two non-adjoining regions of the intestine, but additional populations were identified which indicated localized clonal expansion. Various clonal sets were characterized in detail, and their genealogies indicated somatic mutation accompanied localized clonal expansion with some members undergoing additional mutations and expansion after migration to different mucosal sites. PCR analyses indicated these mucosal clonal sets were more abundant within different mucosal tissues rather than in the systemic tissues. These studies indicate that the mucosal immune system in fish can express B cell transcripts differently from those found systemically. These studies further indicate that the mucosal immune system is interconnected with clonal B cells migrating between different mucosal tissues, results which yield new insight into immune diversity in early vertebrate phylogeny. PMID- 30414492 TI - Imaging and therapeutic applications of persistent luminescence nanomaterials. AB - The development of probes for biomolecular imaging and diagnostics is a very active research area. Among the different imaging modalities, optics emerged since it is a noninvasive and cheap imaging technique allowing real time imaging. In vitro, this technique is very useful however in vivo, fluorescence suffers from low signal-to-noise ratio due to tissue autofluorescence under constant excitation. To address this limitation, novel types of optical nanoprobes are actually being developed and among them, persistent luminescence nanoparticles (PLNPs), with long lasting near-infrared (NIR) luminescence capability, allows doing optical imaging without constant excitation and so without autofluorescence. This review will begin by introducing the physical phenomenon associated to the long luminescence decay of such nanoprobes, from minutes to hours after ceasing the excitation. Then we will show how this property can be used to develop in vivo imaging probes and also more recently nanotheranostic agents. Finally, preliminary data on their biocompatibility will be mentioned and we will conclude by envisioning on the future applications and improvements of such nanomaterials. PMID- 30414493 TI - Recent insights in magnetic hyperthermia: From the "hot-spot" effect for local delivery to combined magneto-photo-thermia using magneto-plasmonic hybrids. AB - Magnetic hyperthermia which exploits the heat generated by magnetic nanoparticles (MNPs) when exposed to an alternative magnetic field (AMF) is now in clinical trials for the treatment of cancers. However, this thermal therapy requires a high amount of MNPs in the tumor to be efficient. On the contrary the hot spot local effect refers to the use of specific temperature profile at the vicinity of nanoparticles for heating with minor to no long-range effect. This magneto thermal effect can be exploited as a relevant external stimulus to temporally and spatially trigger drug release. In this review, we focus on recent advances in magnetic hyperthermia. Indirect experimental proofs of the local temperature increase are first discussed leading to a good estimation of the temperature at the surface (from 0.5 to 6 nm) of superparamagnetic NPs. Then we highlight recent studies illustrating the hot-spot effect for drug-release. Finally, we present another recent strategy to enhance the efficacity of thermal treatment by combining photothermal therapy with magnetic hyperthermia mediated by magneto plasmonic nanoplatforms. PMID- 30414494 TI - Electric field-responsive nanoparticles and electric fields: physical, chemical, biological mechanisms and therapeutic prospects. AB - Electric fields are among physical stimuli that have revolutionized therapy. Occurring endogenously or exogenously, the electric field can be used as a trigger for controlled drug release from electroresponsive drug delivery systems, can stimulate wound healing and cell proliferation, may enhance endocytosis or guide stem cell differentiation. Electric field pulses may be applied to induce cell fusion, can increase the penetration of therapeutic agents into cells, or can be applied as a standalone therapy to ablate tumors. This review describes the main therapeutic trends and overviews the main physical, chemical and biological mechanisms underlying the actions of electric fields. Overall, the electric field can be used in therapeutic approaches in several ways. The electric field can act on drug carriers, cells and tissues. Understanding the multiple effects of this powerful tool will help harnessing its full therapeutic potential in an efficient and safe way. PMID- 30414495 TI - Approaches to physical stimulation of metallic nanoparticles for glioblastoma treatment. AB - Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor. Despite new knowledges on the genetic characteristics, conventional therapy for GBM, tumor resection followed by radiotherapy and chemotherapy using temozolomide is limited in efficacy due to high rate of recurrence. GBM is indeed one of the most complex and difficult cancer to treat mainly due to its highly invasive properties and the standard treatments are thus rarely curative. Major challenges in the treatment of GBM are the limitation of irreversible brain damage, the infiltrative part of the tumor which is the ultimate cause of recurrence, the difficulty of identifying tumor margins and disseminated tumor cells, and the transport across the blood-brain barrier in order to obtain a sufficient therapeutic effect for pharmalogical agents. Considering these limitations, this review explores the in vivo potential of metal-based nanoparticles for hyperthermia, radiotherapy and photodynamic therapy. This article describes and clearly outlines the recent in vivo advances using innovative therapeutic metallic nanoparticles such as iron oxide, silver, gadolinium and gold nanoparticles. PMID- 30414496 TI - Successful development of oral SEDDS: screening of excipients from the industrial point of view. AB - Oral administration is the most accepted and favored route as various side effects such as fear, pain and risk of infections can be avoided resulting in a comparatively high patient compliance. However, from the industrial point of view the development of oral delivery systems is still challenging as various drugs are poorly soluble as well as slightly permeable leading to low bioavailability. As self-emulsifying drug delivery systems are able to incorporate both hydrophobic and hydrophilic drugs, these carrier systems have received more and more attention within the last years. Based on the broad range of currently available excipients, this review provides a kind of guideline for the selection of excipients useful to improve bioavailability of the drug on the one hand. As the regulatory status of potential excipients are highly important to introduce the formulation on the market, the review is focused on the other hand on excipients listed in the IIG database of the FDA by taking their corresponding maximum concentration into account. Furthermore, the issue of oral sensation and taste masking is discussed useful for the development of intraoral SEDDS. PMID- 30414497 TI - Betulin silver nanoparticles qualify as efficient antimelanoma agents in in vitro and in vivo studies. AB - The current study was purported to assess the: (i) in vitro toxicity of betulin silver nanoparticles (AgNPs-B), bare and capped with polyethylene glycol (PEG), on two murine melanoma cell lines (B164A5 and B16Ova) and on healthy cell lines (keratinocytes and melanocytes), and (ii) in vivo antitumor efficacy of PEGylated AgNPs-B in an experimental melanoma model. Bare and PEG-capped AgNPs-B were synthesized by a chemical reduction method resulting in stable and non-aggregated spherical AgNPs-B and PEG-AgNPs-B, of narrow size distributions and mean hydrodynamic diameters of 25 nm and 75 nm, respectively. In vitro assessments were achieved by MTT and Annexin V-FITC assays and in vivo evaluation involved non-invasive techniques for the surveillance of the physiological skin parameters changes and histopathological examination of the harvested organs. The in vitro results revealed selective cytotoxicity against melanoma cells, at low doses that are nontoxic to normal cells; higher doses were associated with the loss of selectivity and toxicity for healthy cells. PEGylated formulation of betulin exerted a dose-dependent pro-apoptotic effect, more obvious in the case of B164A5 cells. Histopathological analysis suggested that PEGylated AgNPs-B developed relevant in vivo effects as antimelanoma agents by decreasing the tumor volume and inhibiting the development of secondary tumors. PMID- 30414498 TI - siRNA-mediated protein knockdown in precision-cut lung slices. AB - Small interfering RNA (siRNA) can induce RNA interference, which leads to the knockdown of messenger RNA (mRNA) and protein. As a result, siRNA is often used in vitro and in vivo to unravel the function of genes and as a therapeutic agent to disrupt excessive expression of disease-related genes. However, there is a large gap between in vitro and in vivo models in terms of simplicity, flexibility, throughput, and translatability. This gap could be bridged by using precision-cut tissue slices, which represent viable explants prepared from animal or human tissue that can be cultured ex vivo. Previously, we demonstrated that self-deliverable siRNA (Accell siRNA) induced significant mRNA knockdown in lung slices. The goal of this study, however, was to investigate whether Accell siRNA also induced protein knockdown in murine lung slices. Slices were incubated for up to 96 h with no siRNA (untransfected), non-targeting siRNA (control), or gene targeting siRNA (Gapdh, Ppib, Serpinh1, and Bcl2l1). Overall, untransfected and transfected slices remained viable during an incubation of 96 h. In addition, gene-targeting siRNAs induced not only significant and specific mRNA knockdown but also protein knockdown. Finally, protein knockdown of fibrogenesis-related targets (Ppib, Serpinh1, and Bcl2l1) was shown to influence fibrogenesis on mRNA level, thereby demonstrating this model its utility in functional genomics and translational research. PMID- 30414499 TI - Evaluation of chemometric approaches for polymorphs quantification in tablets using near-infrared hyperspectral images. AB - Near-Infrared hyperspectral image (HSI-NIR) is a useful technique for pharmaceutical research and industry alike. It can provide important surface information such as the polymorphs quantification and its distribution over the tablet. Several chemometric tools are applied for this purpose, with MCR-ALS and PLS regression being the most common approaches. In this work, a detailed comparison between these two approaches are performed. Beyond a "simple" regression comparison, a comparison of the score images (local quantification) was also evaluated. The system under study is tablets with ternary mixtures of Mebendazol (MBZ) polymorphs, microcrystalline cellulose and magnesium stearate. PLS models, in general, gave lower RMSEP (below 1.7% w/w for the three MBZ polymorphs) than the corresponding MCR-ALS predictions. Analyzing the distributions of the scores in the images of each sample shows clear differences between the PLS and MCR-ALS models. The MCR-ALS gave more chemical meaningful distribution maps for all polymorphs, even though the PLS accurately predicts the average concentration across the image. The problem is that the PLS models used the main spectral regions to quantify each MBZ polymorph, but at the same time undermines the minor spectroscopic changes caused by the different polymorphs. Although this may seem as a minor deviation from the truth, the results clearly show that this deviation is detrimental for the analysis of the spatial distribution of the analytes. These results indicate that the optimal multivariate model for multivariate images depend on the goal of the analysis: global quantification or a distribution analysis. PMID- 30414500 TI - Mature counterfactual reasoning in 4- and 5-year-olds. AB - Counterfactual reasoning is a hallmark of the human imagination. Recently, researchers have argued that children do not display genuine counterfactual reasoning until they can reason about events that are overdetermined and consider the removal of one of multiple causes that lead to the same outcome. This ability has been shown to emerge between 6 and 12 years of age. In 3 experiments, we used an overdetermined physical causation task to investigate preschoolers' ability to reason counterfactually. In Experiment 1a, preschoolers (N = 96) were presented with a "blicket-detector" machine. Children saw both overdetermined (2 causal blocks on a box) and single-cause trials (1 causal and 1 non-causal block) and were asked what would have happened if one of the two blocks had not been placed on the box. Four-year-olds' performance was above chance on both trial types, and 5-year-olds' performance was at ceiling, whereas 3-year-olds did not perform above chance on any trial types. These findings were replicated in Experiment 1b with 4- and 5-year-olds (N = 40) using more complex question wording. In Experiment 2 (N = 40, 4- and 5-year-olds), we introduced a temporal delay between the placement of the first and second block to test the robustness of children's counterfactual reasoning. Even on this more difficult version of the task, performance was significantly above chance. Given a clear and novel causal structure, preschoolers display adult-like counterfactual reasoning. PMID- 30414501 TI - Atmin modulates Pkhd1 expression and may mediate Autosomal Recessive Polycystic Kidney Disease (ARPKD) through altered non-canonical Wnt/Planar Cell Polarity (PCP) signalling. AB - Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a genetic disorder with an incidence of ~1:20,000 that manifests in a wide range of renal and liver disease severity in human patients and can lead to perinatal mortality. ARPKD is caused by mutations in PKHD1, which encodes the large membrane protein, Fibrocystin, required for normal branching morphogenesis of the ureteric bud during embryonic renal development. The variation in ARPKD phenotype suggests that in addition to PKHD1 mutations, other genes may play a role, acting as modifiers of disease severity. One such pathway involves non-canonical Wnt/Planar Cell Polarity (PCP) signalling that has been associated with other cystic kidney diseases, but has not been investigated in ARPKD. Analysis of the AtminGpg6 mouse showed kidney, liver and lung abnormalities, suggesting it as a novel mouse tool for the study of ARPKD. Further, modulation of Atmin affected Pkhd1 mRNA levels, altered non-canonical Wnt/PCP signalling and impacted cellular proliferation and adhesion, although Atmin does not bind directly to the C-terminus of Fibrocystin. Differences in ATMIN and VANGL2 expression were observed between normal human paediatric kidneys and age-matched ARPKD kidneys. Significant increases in ATMIN, WNT5A, VANGL2 and SCRIBBLE were seen in human ARPKD versus normal kidneys; no substantial differences were seen in DAAM2 or NPHP2. A striking increase in E cadherin was also detected in ARPKD kidneys. This work indicates a novel role for non-canonical Wnt/PCP signalling in ARPKD and suggests ATMIN as a modulator of PKHD1. PMID- 30414502 TI - SCUBE1-enhanced bone morphogenetic protein signaling protects against renal ischemia-reperfusion injury. AB - We previously reported that the membrane-bound SCUBE1 (signal peptide-CUB epithelial growth factor domain-containing protein 1) forms a complex with bone morphogenetic protein 2 (BMP2) ligand and its receptors, thus acting as a BMP co receptor to augment BMP signal activity. However, whether SCUBE1 can bind to and facilitate signaling activity of BMP7, a renal protective molecule for ischemia reperfusion (I/R) insult, and contribute to the proliferation and repair of renal tubular cells after I/R remains largely unknown. In this study, we first showed that I/R-induced SCUBE1 was expressed in proximal tubular cells, which coincided with the expression of renoprotective BMP7. Molecular and biochemical analyses revealed that SCUBE1 directly binds to BMP7 and its receptors, functioning as a BMP co-receptor to promote BMP7 signaling. Furthermore, we used a new Scube1 deletion (Delta2) mouse strain to further elucidate the renal pathophysiological function of SCUBE1 after I/R injury. As compared with wild-type littermates, Delta2 mice showed severe renal histopathologic features (extensive loss of brush border, tubular necrosis, and tubular dilation) and increased inflammation (neutrophil infiltrate and induction of monocyte chemoattractant protein-1, tumor necrosis factor-alpha and interleukin-6) during the resolution of I/R damage. They also showed reduced BMP signaling (phosphorylated Smad1/5/8) along with decreased proliferation and increased apoptosis of renal tubular cells. Importantly, lentivirus-mediated overexpression of SCUBE1 enhanced BMP signaling and conferred a concomitant survival outcome for Delta2 proximal tubular epithelial cells after hypoxia-reoxygenation treatment. The protective BMP7 signaling may be facilitated by stress-inducible SCUBE1 after renal I/R, which suggests potential targeted approaches for acute kidney injury. PMID- 30414503 TI - Enhanced antifouling and antimicrobial thin film nanocomposite membranes with incorporation of Palygorskite/titanium dioxide hybrid material. AB - Palygorskite (Pal) is a kind of low-cost and environment-friendly natural nanoclay material with tubular structure and excellent hydrophilicity. TiO2 nanoparticles, especially anatase phase, have prominent photocatalytic bactericidal and organic pollutant decomposition activities. In this work, Pal and Pal/TiO2 nanocomposite were successfully embedded in the polyamide (PA) selective layer of the reverse osmosis (RO) membranes via interfacial polymerization. The tubular structure of Pal possesses a cross-sectional area of 0.37 * 0.63 nm2, which facilitates the selective transport of water molecules through PA layers. The water flux of Pal incorporated TFN membrane increases to approximately 40 l.m-2.h-1 at 16 bar, which is 1.6-fold higher than the reference TFC membrane. Meanwhile, the NaCl rejection is maintained at approximately 98%. Although the Pal/TiO2 incorporated TFN membrane exhibited slightly lower flux (1.4-fold higher than TFC), the embedded Pal/TiO2 contributed to the antifouling and photocatalytic bactericidal capacities and the salt rejection maintained at an acceptable level of 98%, which are greatly desired in the membrane desalination and water reclamation processes. PMID- 30414504 TI - Optimized bimetallic nickel-iron phosphides with rich defects as enhanced electrocatalysts for oxygen evolution reaction. AB - Exploring low-cost and outstanding bimetallic phosphides to substitute noble metals as electrocatalysts for oxygen evolution reaction (OER) in alkaline media is essential for renewable energy technologies. Herein, bimetallic nickel-iron phosphides nanoparticles (P-NiFe-800 NPs) with rich defects have been synthesized through gas annealing at 800 degrees C and phosphorization using uniform nickel iron nanocubes (NiFe NCs) as precursor. At optimized calcination temperature, the obtained P-NiFe-800 NPs are composed of uniform nanoparticles with the rough surface, which suggests the larger surface area and more exposed rich active sites than other samples for OER. The introduction of P element to binary nickel iron metals can optimize the crystalline and electronic structures of NiFe NCs and thus enhance electrocatalytic properties. Owing to the distinct morphological structure and synergistic effect between nickel-iron and phosphorus, P-NiFe-800 NPs demonstrate superior electrocatalytic activities for OER with lower overpotential of 270.1 mV to achieve a current density of 10 mA cm-2, smaller Tafel slope of 39 mV dec-1, lower electrochemical impedance spectroscopy (EIS) value, bigger determined double-layer capacitance (Cdl) of 2130 uF cm-2 and prominent stability than NiFe NCs, NiFe-600 NPs, NiFe-700 NPs, NiFe-800 NPs, NiFe 900 NPs, P-NiFe NCs, P-NiFe-600 NPs, P-NiFe-700 NPs and P-NiFe-900 NPs. The optimized phosphorization is helpful for fabricating the bimetallic phosphides as efficient catalysts for OER. PMID- 30414505 TI - Central venous catheter-related venous thrombosis in children with end-stage renal disease undergoing hemodialysis. AB - Despite the high rate of central venous catheter (CVC)-related venous thromboembolic (VTE) complications and long-term sequelae, CVCs remain a vital component of patient care in children with complex underlying diseases. In this review, we focus on CVC-related VTE in children with end-stage renal disease (ESRD) undergoing hemodialysis, a population in whom the provision of renal replacement therapy is a lifelong undertaking. Occlusion of the CVC and thrombosis underlie most instances of access malfunction and failure in children on chronic hemodialysis. Frequent CVC replacements are required, resulting in increased risk of central vein thrombosis and stenosis, precluding adequate hemodialysis in years to come. As recurrent CVC malfunction may constitute the sole sign of CVC-related VTE, a high index of suspicion is required for its investigation and the consequent institution of anticoagulation treatment, attempting to salvage the CVC and minimize recurrent line exchanges and venous cannulations and their sequelae. Hemodialysis access planning should take into account potentially modifiable prothrombotic risk factors in order to preserve vascular access. Effective strategies for maintenance of catheter patency and survival are needed for the conservation of future hemodialysis access. Further investigation aiming for identification of predictors of CVC-related VTE in children undergoing hemodialysis will aid in the design and application of much needed multicenter prospective studies examining the benefit and the safety of thromboprophylaxis. PMID- 30414506 TI - Pharmaceutical Policy Reforms to Regulate Drug Prices in Asia Pacific Region: The Case of Australia, China, India, Malaysia, New Zealand, and South Korea. AB - Medicine price directly affects affordability and access to medicines particularly in countries where a major portion of pharmaceutical spending is through out-of-pocket payment, such as in the Asia Pacific region. We have undertaken a detailed appraisal of the pharmaceutical policy reforms to regulate drug prices in 3 developed (Australia, New Zealand, and South Korea) and 3 emerging (China, India, and Malaysia) economies of the Asia Pacific region. Despite continuous efforts by the authorities in adopting a wide range of reformatory pharmaceutical pricing policies to ensure affordability of medicines, these policies may not be optimal where drug prices were not lowered as expected (eg, in Korea). On the contrary, considerable price reductions of various pharmaceuticals have been observed in New Zealand and India because of the reform in pharmaceutical pricing policy. This review of pharmaceutical pricing reforms reinforces the need for constant monitoring by policy makers in Asia Pacific countries to regulate drug prices and to undertake reform in pharmaceutical pricing policies when necessary to ensure affordability and access to medicines. PMID- 30414507 TI - A study for the mechanism of sensory disorder in restless legs syndrome based on magnetoencephalography. AB - In spite of the relatively high incidence rate, the etiology and pathogenesis of restless legs syndrome (RLS) are still unclear. Long-term drug treatments fail to achieve satisfying curative effects, which is reflected by rebound and augmentation of related symptoms. An electrophysiological endophenotype experiment was done to investigate the mechanism of somatosensory disorder among RLS patients. Together with 15 normal subjects as the control group, with comparable ages and genders to the RLS patients, 15 primitive RLS patients were scanned by Magnetoencephalography (MEG) under natural conditions; furthermore, the somatosensory evoked magnetic field (SEF) with single and paired stimuli, was also measured. Compared to the control group, the SEF intensities of RLS patients' lower limbs were higher, and the paired-pulse depression (PPD) for SEF in RLS patients was attenuated. It was also revealed by time-frequency analysis of somatosensory induced oscillation (SIO) in RLS patients, that 93.3% of somatosensory induced Alpha (8-12 Hz) oscillations were successfully elicited, while 0% somatosensory induced Gamma (30-55 Hz) oscillations were elicited; which was significantly different from the control group. Additionally, in RLS patients exhibit increased excitability of the sensorimotor cortex, a remarkable abnormality existing in early somatosensory gating control (GC) and an attenuated inhibitory interneuron network, which consequently results in a compensatory mechanism through which RLS patients increase their attention-driven lower limb sensory gating control via somatosensory-induced Alpha (8-12 Hz) oscillation. This hyperexcitability, partially due to an electrocortical disinhibition, may have an important therapeutical implication, and become an important target of neuromodulatory interventions. PMID- 30414508 TI - Role of STIM1/ORAI1-mediated store-operated Ca2+ entry in skeletal muscle physiology and disease. AB - Store-operated Ca2+ entry (SOCE) is a Ca2+ entry mechanism activated by depletion of intracellular Ca2+ stores. In skeletal muscle, SOCE is mediated by an interaction between stromal-interacting molecule-1 (STIM1), the Ca2+ sensor of the sarcoplasmic reticulum, and ORAI1, the Ca2+-release-activated-Ca2+ (CRAC) channel located in the transverse tubule membrane. This review focuses on the molecular mechanisms and physiological role of SOCE in skeletal muscle, as well as how alterations in STIM1/ORAI1-mediated SOCE contribute to muscle disease. Recent evidence indicates that SOCE plays an important role in both muscle development/growth and fatigue. The importance of SOCE in muscle is further underscored by the discovery that loss- and gain-of-function mutations in STIM1 and ORAI1 result in an eclectic array of disorders with clinical myopathy as central defining component. Despite differences in clinical phenotype, all STIM1/ORAI1 gain-of-function mutations-linked myopathies are characterized by the abnormal accumulation of intracellular membranes, known as tubular aggregates. Finally, dysfunctional STIM1/ORAI1-mediated SOCE also contributes to the pathogenesis of muscular dystrophy, malignant hyperthermia, and sarcopenia. The picture to emerge is that tight regulation of STIM1/ORAI1-dependent Ca2+ signaling is critical for optimal skeletal muscle development/function such that either aberrant increases or decreases in SOCE activity result in muscle dysfunction. PMID- 30414509 TI - Estrogen depletion alters mineralization regulation mechanisms in an ovariectomized monkey animal model. AB - Ovariectomized animal models have been extensively used in osteoporosis research due to the resulting loss of bone mass. The purpose of the present study was to test the hypothesis that estrogen depletion alters mineralization regulation mechanisms in an ovariectomized monkey animal model. To achieve this we used Raman microspectroscopy to analyze humeri from monkeys that were either SHAM operated or ovariectomized (N = 10 for each group). Measurements were made as a function of tissue age and cortical surface (periosteal, osteonal, endosteal) based on the presence of calcein fluorescent double labels. In the present work we focused on osteoid seams (defined as a surface with evident calcein labels, 1 MUm distance away from the mineralizing front, and for which the Raman spectra showed the presence of organic matrix but not mineral), as well as the youngest mineralized tissue between the second fluorescent label and the mineralizing front, 1 MUm inwards from the front with the phosphate mineral peak evident in the Raman spectra (TA1). The spectroscopically determined parameters of interest were the relative glycosaminoglycan (GAG) and pyridinoline (Pyd) contents in the osteoid, and the mineral content in TA1. At all three cortical surfaces, significant correlations were evident in the SHAM-operated animals between osteoid GAG (negative) and Pyd content, and mineral content, unlike the OVX animals. These results suggest that in addition to the well-established effects on turnover rates and bone mass, estrogen depletion alters the regulation of mineralization by GAGs and Pyd. PMID- 30414511 TI - Examining the role of imageability and regularity in word reading accuracy and learning efficiency among first and second graders at risk for reading disabilities. AB - This study explored word reading accuracy and word learning efficiency in first- and second-grade students (N = 125). In two experiments, students participated in a short training exposing them to words that varied on orthographic regularity and imageability. In Experiment 1 the form of word feedback was manipulated (phonemic vs. whole word), whereas in Experiment 2 pretraining exposure was manipulated (training on meaning vs. imageability). Crossed random effects models were used to explore child- and item-level predictors related to number of exposures to mastery, posttest word reading performance, and maintenance performance after 1 week. Results from Experiment 1 indicate that imageability plays a role in irregular word learning. Results from Experiment 2 suggest that students who received imageability training required fewer exposures to reach mastery. There was a significant interaction between initial word reading skill and condition, with students with low word reading skills requiring fewer exposures for mastery if they were in the imageability condition. Overall, these findings suggest that word imageability significantly affects both word reading accuracy and rate of word learning. PMID- 30414510 TI - Deletion of nicotinic acetylcholine receptor alpha9 in mice resulted in altered bone structure. AB - Alterations in bone strength and structure were found in knockout (KO) mouse strains with deletion of several acetylcholine receptors. Interestingly, the expression of the nicotinic acetylcholine receptors (nAChR) subunit alpha10 was down-regulated in osteogenic differentiated mesenchymal stem cells of patients with osteoporosis whereas the expression of subunit alpha9 was not altered. Since nAChR subunits alpha9 and alpha10 are often combined in a functional receptor, we analyzed here the bone of adult female KO mice with single deletion of either nAChR alpha9 (alpha9KO) or alpha10 (alpha10KO). Biomechanical testing showed a significant decrease of bending stiffness and maximal breaking force in alpha9KO compared to their corresponding wild type mice. Furthermore, an increase in trabecular pattern factor (Tb.Pf) and structure model index (SMI) was detected by MUCT in alpha9KO indicating reduced bone mass. On the mRNA level a decrease of Collagen 1alpha1 and Connexin-43 was measured by real-time RT-PCR in alpha9KO while no alteration of osteoclast markers was detected in either mouse strain. Using electron microcopy we observed an increase in the number of osteocytes that showed signs of degeneration and cell death in the alpha9KO compared to their wild type mice, while alpha10KO showed no differences. In conclusion, we demonstrate alterations in bone strength, structure and bio-marker expression in alpha9KO mice which imply the induction of osteocyte degeneration. Thus, our data suggest that nAChR containing the alpha9 subunit might be involved in the homeostasis of osteocytes and therefore in bone mass regulation. PMID- 30414512 TI - Shoulder tendon characteristics in disabled swimmers in high functional classes - Preliminary report. AB - OBJECTIVE: To characterize disabled swimmers in comparison to an able-bodied swimmers for (1) supraspinatus tendon thickness, (2) subacromial space and (3) occupation ratio. DESIGN: Cross-Sectional Study. SETTING: Research laboratory. PARTICIPANTS: Disabled swimmers with upper (DSw-Upper) (n = 8) and lower (DSw Lower) (n = 7) extremity disorders. The DSw-Upper were classified in sports class S7-S8, while DSw-Lower in S9-S10. The control group had 15 able-bodied swimmers. MAIN OUTCOME MEASURES: Ultrasound images of (1) supraspinatus tendon in short axis and long axis, (2) subacromial space, and (3) occupation ratio. RESULTS: A thicker supraspinatus tendon in short axis was observed in DSw-Upper versus C-Sw (p = 0.012) and DSw-Upper versus DSw-Lower (p = 0.018); and in long axis for DSw Upper versus CSw (p = 0.0001), and DSw-Upper versus DSw-Lower (p = 0.002). There was a greater occupation ratio in DSw-Upper versus DSw-Lower in short axis (p = 0.013) and long axis (p = 0.035). CONCLUSIONS: The present study showed a thicker supraspinatus tendon and greater occupation ratio with the tendon occupying more of the subacromial space that may predispose upper extremity disabled swimmers to tendon disorders such as subacromial impingement syndrome. Ultrasound examination can be used to assess shoulder tendon characteristics and the relationship to the subacromial space, to determine potential for injury and training load monitoring. PMID- 30414513 TI - Manganese alters expression of proteins involved in the oxidative stress of Meyerozyma guilliermondii. AB - Organisms, in general, respond to environmental stress by altering their pattern of protein expression (proteome), as an alternative to growing in stressful conditions. A strain of Meyerozyma guilliermondii resistant to manganese was isolated from a sample of water collected from mine drainage in southeastern Minas Gerais (Brazil), and demonstrated manganese detoxification capacity. Protein extracts containing the soluble fractions were obtained after growth of the strain in the absence and presence of MnSO4. Tryptic peptides recovered from samples were analyzed by liquid chromatography coupled to mass spectrometry (LC MS/MS). Shotgun/bottom-up analyses of the soluble fractions revealed a total of 1257 identified molecules. Treatment with Mn did not affect the growth of yeast but induced changes in the protein profile, with 117 proteins expressed in the absence of Mn and 69 expressed only in its presence. Most of these are annotated as related to DNA repair, oxidoreductase activity, and remodeling of gene expression. This is the first proteomic report of M. guilliermondii, with promising characteristics for Mn bioremediation, and the first of the genus Meyerozyma. This proteomic characterization may help in the understanding of molecular regulatory mechanisms associated with tolerance to excess Mn, and the potential use of biomass in bioremediation processes. SIGNIFICANCE: Environmental pollution by heavy metals such as manganese (Mn2+) has increased as it is a by product of the mining industry and a potential environmental contaminant. Many studies have explored the use of bacteria for manganese bioremediation, but yeasts have emerged as a promising alternative, displaying faster growth and greater removal efficiency. Previous works of our laboratory showed that Meyerozyma guilliermondii, a non-pathogenic haploid yeast (ascomycete), has excellent removal and accumulation capacity of Mn2+, potentially useful in bioremediation. Nowadays efforts have been devoted to understanding the physiology of metal hyperaccumulation to gain insights into the molecular basis of hyperaccumulation. To obtain a comprehensive understanding of the molecular mechanism of Mn2+ hyperaccumulation in M. guilliermondii, proteomic approaches were employed yielding the first compositional proteomic map of total soluble proteins and their differential expression in the presence of Mn2+. We believe our findings are of biotechnological interest concerning the utilization of M. guilliermondii for bioremediation purposes. PMID- 30414514 TI - Unraveling the molecular mechanism of the response to changing ambient phosphorus in the dinoflagellate Alexandrium catenella with quantitative proteomics. AB - Phosphorus (P) is a key macronutrient limiting cell growth and bloom formation of marine dinoflagellates. Physiological responses to changing ambient P have been investigated in dinoflagellates; however, the molecular mechanisms behind these responses remain limited. Here, we compared the protein expression profiles of a marine dinoflagellate Alexandrium catenella grown in inorganic P-replete, P deficient, and inorganic- and organic-P resupplied conditions using an iTRAQ based quantitative proteomic approach. P deficiency inhibited cell growth and enhanced alkaline phosphatase activity (APA) but had no effect on photosynthetic efficiency. After P resupply, the P-deficient cells recovered growth rapidly and APA decreased. Proteins involved in sphingolipid metabolism, organic P utilization, starch and sucrose metabolism, and photosynthesis were up-regulated in the P-deficient cells, while proteins associated with protein synthesis, nutrient assimilation and energy metabolism were down-regulated. The responses of the P-deficient A. catenella to the resupply of organic and inorganic P presented significant differences: more biological processes were enhanced in the organic P resupplied cells than those in the inorganic P-resupplied cells; A. catenella might directly utilize G-6-P for nucleic acid synthesis through the pentose phosphate pathway. Our results indicate that A. catenella has evolved diverse adaptive strategies to ambient P deficiency and specific mechanisms to utilize dissolved organic P, which might be an important reason resulting in A. catenella bloom in the low inorganic P environment. BIOLOGICAL SIGNIFICANCE: The ability of marine dinoflagellates to utilize different phosphorus (P) species and adapt to ambient P deficiency determines their success in the ocean. In this study, we investigated the response mechanisms of a dinoflagellate Alexandrium catenella to ambient P deficiency, and resupply of inorganic- and organic-P at the proteome level. Our results indicated that A. catenella initiated multiple adaptive strategies to ambient P deficiency, e.g. utilizing nonphospholipids and glycosphingolipids instead of phospholipids, enhancing expression of acid phosphatase to utilize organic P, and reallocating intracellular energy. Proteome responses of the P-deficient A. catenella to resupply of inorganic- and organic-P differed significantly, indicating different utilization pathways of inorganic and organic P, A. catenella might directly utilize low molecular weight organic P, such as G-6-P as both P and carbon sources. PMID- 30414515 TI - Proteomics and Penicillium chrysogenum: Unveiling the secrets behind penicillin production. AB - Discovery, industrial production and clinical applications of penicillin, together with scientific findings on penicillin biosynthesis and its complex regulation, are model milestones of the historical evolution of the most recognized 'magic bullet' against microbial infections available in the worldwide market. Thousands of tons of penicillin produced nowadays are the result of a huge number of technical, industrial and scientific tackled and solved challenges. This combination of, sometimes unsuspected, findings has given Proteomics the chance to support the understanding of the physiology of the high producing fungal strains and the development of enhanced mutants by means of inverse engineering. Thus, this review, which is part of the special issue entitled "A Tribute to J. Proteomics on its 10th Anniversary", describes how Proteomics has contributed to characterize different aspects related to penicillin production in Penicillium chrosogenum. It covers from global proteome characterizations (intracellular, extracellular and microbodies) to proteome-wide comparative analyses between different penicillin-producing mutant strains and conditions, paying special attention to the methodologies used, as well as to the most important outcomes. As a result, a guide of Proteomics approaches applied to the characterization of penicillin production by P. chrysogenum is detailed in the birthday of the Fleming's most relevant finding. SIGNIFICANCE: Although the discovery of penicillin is celebrating the 90th birthday and its clinical application is worldwide recognized, in fact, semisynthetic penicillins are still one of the most prescribed antibiotics, only the arrival of the post-genomic era during the first decade of the 21st century, and more precisely the Proteomics approaches, have contributed to unveil the industrial secrets behind penicillin production. This review provides relevant information, based on proteomics studies, about the molecular mechanisms responsible for increased penicillin titres, and therefore, may represent a clear model of inverse engineering in microorganisms. PMID- 30414516 TI - Proteome characterization in various biological fluids of Trypanosoma brucei gambiense-infected subjects. AB - Human African trypanosomiasis (HAT) is a neglected tropical disease that is endemic in sub-Saharan Africa. Control of the disease has been recently improved by better screening and treatment strategies, and the disease is on the WHO list of possible elimination. However, some physiopathological aspects of the disease transmission and progression remain unclear. We propose a new proteomic approach to identify new targets and thus possible new biomarkers of the disease. We also focused our attention on fluids classically associated with HAT (serum and cerebrospinal fluid (CSF)) and on the more easily accessible biological fluids urine and saliva. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) established the proteomic profile of patients with early and late stage disease. The serum, CSF, urine and saliva of 3 uninfected controls, 3 early stage patients and 4 late stage patients were analyzed. Among proteins identified, in CSF, urine and saliva, respectively, 37, 8 and 24 proteins were differentially expressed and showed particular interest with regards to their function. The most promising proteins (Neogenin, Neuroserpin, secretogranin 2 in CSF; moesin in urine and intelectin 2 in saliva) were quantified by enzyme-linked immunosorbent assay in a confirmatory cohort of 14 uninfected controls, 23 patients with early stage disease and 43 patients with late stage disease. The potential of two proteins, neuroserpin and moesin, with the latter present in urine, were further characterized. Our results showed the potential of proteomic analysis to discover new biomarkers and provide the basis of the establishment of a new proteomic catalogue applied to HAT-infected subjects and controls. SIGNIFICANCE: Sleeping sickness, also called Human African Trypanosomiasis (HAT), is a parasitic infection caused by a parasitic protozoan, Trypanosoma brucei gambiense or T. b. rhodesiense which are transmitted via an infected tsetse fly: Glossina. For both, the haemolymphatic stage (or first stage) signs and symptoms are intermittent fever, lymphadenopathy, hepatosplenomegaly, headaches, pruritus, and for T. b. rhodesiense infection a chancre is often formed at the bite site. Meningoencephalitic stage (or second stage) occurs when parasites invade the CNS, it is characterised by neurological signs and symptoms such as altered gait, tremors, neuropathy, somnolence which can lead to coma and death if untreated. first stage of the disease is characterizing by fevers, headaches, itchiness, and joint pains and progressive lethargy corresponding to the second stage with confusion, poor coordination, numbness and trouble sleeping. Actually, diagnosing HAT requires specialized expertise and significant resources such as well equipped health centers and qualified staff. Such resources are lacking in many endemic areas that are often in rural locales, so many individuals with HAT die before the diagnosis is established. In this study, we analysed by mass spectrometry the entire proteome of serum, CSF, urine and saliva samples from infected and non-infected Angolan individuals to define new biomarkers of the disease. This work of proteomics analysis is a preliminary stage to the characterization of the whole proteome, of these 4 biological fluids, of HAT patients. We have identified 69 new biomarkers. Five of them have been thoroughly investigated by ELISA quantification. Neuroserpine and Moesin are respectively promising new biomarkers in CSF and urine's patient for a better diagnosis. PMID- 30414517 TI - A green approach to fabricating nacre-inspired nanocoating for super-efficiently fire-safe polymers via one-step self-assembly. AB - Developing a high efficient, environmental-friendly and universal fire-safe strategy for combustible polymers is crucial but challengeable. Inspired by nacre, we developed a super-efficiently fire-safe nanocoating based on carboxymethyl chitosan (CCS) and modified montmorillonite (MMT) via one-step self assembly. The nanocoating possessed well-arranged nacre-like hierarchical microstructure, exhibiting high transparency and specific nacre-like iridescence. More importantly, the nanocoating endowed many large-scale polymer substrates, such as polyester film, cotton fabric and polyurethane foam, with super-efficient fire-safety by dip-coating or spray-coating. All the coated substrates were self extinguished in the burning tests. Meanwhile, their heat release and smoke production were decreased remarkably. Most notably, the peak heat release rate, total heat release, peak smoke production rate and total smoke production of polyurethane foam were decreased by 84.1%, 89.4%, 84.4% and 95.2%, respectively. Additionally, no organic solvent, halogen and phosphorus element were involved, which was environmental-friendly. Our findings provide a super-efficient, economical, universal and green fabrication strategy for fire-safe polymers. PMID- 30414518 TI - Noncellular Modification of Acellular Nerve Allografts for Peripheral Nerve Reconstruction: A Systematic Critical Review of the Animal Literature. AB - BACKGROUND: Acellular nerve allografts (ANAs) have been established as promising alternatives to autologous nerve grafts, which represent the reference standard. Our research group recently performed a systematic review of reported cell-based enriching methods for recellularization of ANAs. Recellularization results in consistent improvement of peripheral neuroregeneration compared with plain ANAs. We systematically reviewed the effects on nerve regeneration when ANA enrichment was obtained through biological, chemical, and physical modification instead of cells. METHODS: The PubMed, ScienceDirect, Medline, and Scopus databases were searched for reports of noncellular modification of ANAs, reported from January 2007 to December 2017. The inclusion criteria were English language, noncellular enrichment of ANAs in peripheral nerve regeneration, an in vivo study design, and postgrafting neuroregenerative outcomes assessment. The exclusion criteria were the central nervous system as the site of ANA application, nerve conduits, xenografts, case series, case reports, and reviews. RESULTS: Only animal studies were found to be eligible. We included 16 studies, which were analyzed regarding the animal model, decellularization method, graft-enriching mode, and neuroregenerative tests performed. CONCLUSIONS: Noncellular-based stimulation of ANAs demonstrated positive effects on recovery of nerve function compared with nerve grafting compared with plain ANAs. The neuroregenerative effect of autografting still appeared superior to ANAs, even with noncellular enrichment of ANAs. However, we found that in a few studies, modified ANAs closely approached or even outperformed autografts. Future research should include more preclinical investigations of this promising tool and clinical translation to increase the level of evidence available in the challenging field of peripheral nerve reconstruction. PMID- 30414519 TI - Retrieval of a Distally Migrated Coil With Direct Aspiration Technique During A Temporary Bridging Device Embolization of a Wide Neck Supraophthalmic Aneurysm. PMID- 30414520 TI - An epidermoid cyst of the cerebellopontine angle presenting with the contralateral trigeminal neuralgia : An extremely rare case and the review of literature. AB - An epidermoid cyst is a rare tumor of the cerebellopontine angle region. It usually presents with ipsilateral compressive symptoms. The contralateral trigeminal neuralgia is an unusual presentation in such cases. We did not find such case reports in the literature. Here, we report a case of 62 years old female having right cerebellopontine angle epidermoid cyst presenting with right hearing impairment and the contralateral trigeminal neuralgia. The possible mechanism leading to the contralateral trigeminal neuralgia is discussed here along with the diagnosis and the management of the case. PMID- 30414521 TI - Differential Diagnosis and Treatment Modality of Parasellar Plasmacytoma: Clinical Series and Literature Review. AB - BACKGROUND: Parasellar plasmacytomas are rare tumors arising from the sellar region that should be considered in differential diagnosis for lesions involving the sella and clivus. Prior to surgical pathologic examination, parasellar plasmacytomas are often misdiagnosed as invasive pituitary adenomas or chordomas due to the similarity of clinical presentation and imaging findings. METHODS: We retrospectively reviewed 5 patients with parasellar plasmacytoma who underwent endonasal endoscopic tumor resection in Beijing Tiantan Hospital between January 2008 and January 2018. Their clinical symptoms and radiological features, as well as treatment modalities and outcomes, were summarized. RESULTS: A total of 5 patients (3 men and 2 women; median age at diagnosis, 54 years; range, 47-61 years) with parasellar plasmacytoma were enrolled in this clinical series. The presenting symptoms mainly included diplopia, headache, and blurred vision. All patients were treated with endonasal endoscopic surgery combined with adjuvant therapy, and, after undergoing postoperative radiotherapy, complete remissions were achieved on a median follow-up time of 41 months (range, 15-120 months). CONCLUSIONS: The differential diagnosis of parasellar plasmacytoma with pituitary adenoma and chordoma should include a thorough endocrine workup, neurological examination, and radiological assessment. Our study supports radiotherapy as the main treatment of choice for parasellar plasmacytoma, given its typical feature of relatively high radiosensitivity. Tumor resection through the endonasal endoscopic approach in combination with adjuvant radiotherapy may be the optimal initial treatment strategy in long-term control of the lesion and alleviation of neurological symptoms. PMID- 30414522 TI - Noninfectious Fever in Aneurysmal Subarachnoid Hemorrhage: Association with Cerebral Vasospasm and Clinical Outcome. AB - OBJECTIVE: The purpose of this study was to evaluate the association between noninfectious fever onset and radiographic vasospasm, delayed ischemic neurologic deficit (DIND), delayed cerebral infarction (DCI), and clinical outcome in patients with aneurysmal subarachnoid hemorrhage. METHODS: We evaluated 44 patients for the association between noninfectious fever (greater than 101.5 degrees F) and the development of radiographic vasospasm by digital subtraction angiography (DSA) and transcranial Doppler (TCD), DIND, DCI, and modified Rankin scale outcome score at 6 months to 2 years. Multivariate logistic regression analyses were performed to account for patient age, sex, admission Hunt and Hess grade, and Fisher grade. TCD was additionally used for temporal analysis. RESULTS: Noninfectious fever was significantly associated with radiographic vasospasm using both DSA (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.2 4.5; P = 0.02) and TCD (OR, 2.4; 95% CI, 1.2-5.6; P = 0.02), but it was not associated with DIND, DCI, or outcome. The maximum cross correlation between TCD velocity and temperature occurred for temperatures taken 1 day prior to TCD velocity measurement. A quadratic mixed-effects model demonstrated that TCD velocity was significantly associated with temperature from 1 day prior to TCD velocity measurement (beta = 13.5; 95% CI, 0.83-8.79, P = 0.01), posthemorrhage day (beta = 20.1; 95% CI, 2.14-7.52; P < 0.001), and (posthemorrhage day)2 (beta = -0.72; 95% CI, -0.26 to -0.11; P < 0.001). CONCLUSIONS: Noninfectious fever was associated with the development of radiographic vasospasm but not with DIND, DCI, or clinical outcome. Furthermore, there is a temporal association between the onset of noninfectious fever and radiographic vasospasm by 1 day. Fever independent of patient's infectious profile may be an early marker for the development of radiographic vasospasm. PMID- 30414523 TI - Serum Biomarkers and Clinical Outcomes in Traumatic Spinal Cord Injury: Prospective Cohort Study. AB - BACKGROUND: A plethora of reactive cellular responses emerge immediately after a traumatic spinal cord injury (SCI) and may influence the patient's outcomes. We investigated whether serum concentrations of neuron-specific enolase, interleukin 6, glial-derived neurotrophic factor, and neurotrophic growth factor reflect the acute-phase responses to different etiologies of SCI and may serve as predictive biomarkers of neurologic and functional outcomes. METHODS: Fifty-two patients were admitted to the intensive care unit after SCI due to traffic accidents, falls, and firearm wounds and had blood samples collected within 48 hours and 7 days after SCI. Thirty-six healthy subjects with no history of SCI were included as controls. Neurologic and functional status was evaluated on the basis of American Spinal Injury Association and Functional Independence Measure scores over a period of 48 hours and 6 months after SCI. RESULTS: Serum NSE increased significantly 48 hours and 7 days after SCI compared with controls, while interleukin-6 increased only at 48 hours. In contrast, the neurotrophic growth factor level significantly decreased 48 hours and 7 days after SCI. Serum glial derived neurotrophic factor level did not differ from control at any time point. Also, there was no significant difference in biomarker concentrations between the etiologies of SCI or the level of spinal injury. There were no correlations between biomarker levels at 48 hours with neurologic or functional outcomes 7 days and 6 months after SCI. CONCLUSIONS: Our results suggest expansive axonal damage coupled with an acute proinflammatory response after SCI. However, in our study biomarker concentration did not correlate with short- or long-term prognosis, such as survival rate or sensory and motor function. PMID- 30414525 TI - Analysis of Cost and 30-Day Outcomes in Single-Level Transforaminal Lumbar Interbody Fusion and Less Invasive, Stand-Alone Lateral Transpsoas Interbody Fusion. AB - BACKGROUND: A comparative evaluation of operative costs between single-level transforaminal interbody fusion (TLIF) and stand-alone lateral transpsoas interbody fusion (LIF) has not yet been done. We analyzed the costs, operative parameters, and early outcomes of single-level stand-alone LIF versus single level TLIF. METHODS: Ten patients who underwent single-level TLIF and 10 patients who underwent single-level stand-alone LIF were included in the analysis. Total, variable, and fixed costs from perioperative data were available from a single institution. In addition, patient demographics, length of hospital stay, and 30 day outcomes and readmission rates were reviewed. RESULTS: Total cost, variable cost, and fixed costs were significantly lower in the LIF group, and there was no difference in outcomes. CONCLUSIONS: Single-level stand-alone LIF may prove to be more cost-effective and provide cost savings with analogous 30-day outcomes compared with single-level TLIF procedures. PMID- 30414524 TI - Minimally invasive versus traditional open transforaminal lumbar interbody fusion for the treatment of single-level spondylolisthesis grades 1 and 2: a systematic review and meta-analysis. AB - OBJECTIVE: The purpose of the present study is to compare the clinical efficacy and safety between minimally invasive and traditional open transforaminal lumbar interbody fusion in the treatment of single-level spondylolisthesis grades 1 and 2. STUDY DESIGN: Systematic review and meta-analysis. METHODS: A comprehensive literature retrieval was performed in three electronic databases(Pubmed, Embase and Cochrane library). Randomized or non-randomized controlled studies published from January 2000 to April 2018 which compared minimally invasive transforaminal lumbar interbody fusion(MIS-TLIF) with traditional open transforaminal lumbar interbody fusion(TO-TLIF) for treating single-level spondylolisthesis grades 1 and 2 were achieved. Quality of included studies were evaluated by the modified Jadad scale. Data were extracted according to the predefined clinical outcome measures, including preoperative and postoperative back pain VAS(VAS-BP) and Oswestry Disability Index(ODI) score; operation time and estimated intraoperative blood loss; length of hospitalization; the complication, reoperation and fusion rate. RESULTS: Six studies(n=394 patients) were finally included. Two of them were randomized controlled trials(RCTs) and the remaining four were prospective or retrospective cohort studies. The pooled data revealed that both techniques had similar preoperative and last follow-up VAS-BP, complication rate, reoperation rate, and fusion rate. However, with the exception of more operation time, MIS-TLIF was associated with less intraoperative blood loss, shorter hospital stay, and better long-term functional outcome when compared with TO TLIF. CONCLUSIONS: Based on the available evidence, MIS-TLIF appears to be an more efficacious and safe technique with reduced tissue trauma, quicker postoperative recovery and better long-term functional outcome for the treatment of single-level spondylolisthesis grades 1 and 2. PMID- 30414526 TI - Comparison of Percutaneous Kyphoplasty Versus Modified Percutaneous Kyphoplasty for Treatment of Osteoporotic Vertebral Compression Fractures. AB - BACKGROUND: Although percutaneous kyphoplasty (PKP) is performed to restore the vertebral body height and kyphosis in osteoporotic vertebral compression fractures (OVCFs), the regained height may be lost on balloon deflation. This study compares PKP with modified percutaneous kyphoplasty (MPKP) in terms of the clinical outcomes in treating OVCFs. METHODS: Between May 2014 and March 2016, 76 patients with OVCFs were randomly assigned to 2 groups according to the procedure chosen: the PKP group (n = 36) and MPKP group (n = 40). Perioperative parameters, radiologic data, and other clinical parameters were compared between the groups. RESULTS: Of the 76 patients, 68 were followed-up for an average of 16 months. Both groups showed similar degrees of postoperative improvement on the visual analog scale, without any significant intergroup difference. However, the MPKP group showed greater improvement in vertebral body height and recovery of the Cobb angle compared with the PKP group. Additionally, the volume of bone cement and operative time were significantly higher in the MPKP group than in the PKP group, whereas the Oswestry Disability Index at the last follow-up was significantly lower in the MPKP group than in the PKP group. The cement leakage ratio and incidence of recurrent vertebral fractures did not differ significantly between the groups. CONCLUSIONS: MPKP prevents the loss of vertebral height observed with PKP during balloon deflation in addition to providing greater height, Cobb angle recovery, and quality of life compared with PKP in cases of OVCF. PMID- 30414527 TI - Computer-aided detection of fasciculations and other movements in muscle with ultrasound: Development and clinical application. AB - OBJECTIVE: To develop an automated algorithm for detecting fasciculations and other movements in muscle ultrasound videos. Fasciculation detection in muscle ultrasound is routinely performed online by observing the live videos. However, human observation limits the objective information gained. Automated detection of movement is expected to improved sensitivity and specificity and increase reliability. METHODS: We used 42 ultrasound videos from 11 neuromuscular patients for an iterative learning process between human observers and automated computer analysis, to identify muscle ultrasound movements. Two different datasets were selected from this, one to develop the algorithm and one to validate it. The outcome was compared to manual movement identification by clinicians. The algorithm also quantifies specific parameters of different movement types, to enable automated differentiation of events. RESULTS: The algorithm reliably detected fasciculations. With algorithm guidance, observers found more fasciculations compared to visual analysis alone, and prescreening the videos with the algorithm saved clinicians significant time compared to reviewing full video sequences. All videos also contained other movements, especially contraction pseudotremor, which confused human interpretation in some. CONCLUSIONS: Automated movement detection is a feasible and attractive method to screen for fasciculations in muscle ultrasound videos. SIGNIFICANCE: Our findings affirm the potential clinical usefulness of automated movement analysis in muscle ultrasound. PMID- 30414528 TI - Survival with nal-IRI (liposomal irinotecan) plus 5-fluorouracil and leucovorin versus 5-fluorouracil and leucovorin in per-protocol and non-per-protocol populations of NAPOLI-1: Expanded analysis of a global phase 3 trial. AB - BACKGROUND: In the phase 3 randomised NAPOLI-1 clinical study, a 45% increase in median overall survival (OS) was shown with liposomal irinotecan, 5-fluorouracil and leucovorin (nal-IRI+5-FU/LV) versus 5-FU/LV in patients with metastatic pancreatic cancer progressing after gemcitabine-based therapy. Here, we report data from a pre-specified, expanded analysis of outcomes in the per-protocol (PP) population. MATERIALS AND METHODS: The PP population comprised patients receiving >=80% of planned treatment during the first 6 weeks, with no major protocol violations. A post-hoc analysis of the non-PP population was also performed. RESULTS: For PP patients, median OS was 8.9 (95% confidence interval: 6.4-10.5) months with nal-IRI+5-FU/LV (n = 66) vs 5.1 (4.0-7.2) months with 5-FU/LV (n = 71; unstratified hazard ratio [HR] 0.57, p = 0.011). For non-PP patients, it was 4.4 (3.3-5.3) months with nal-IRI+5-FU/LV (n = 51) vs 2.8 (1.7-3.2) months with 5 FU/LV (n = 48; unstratified HR 0.64, p = 0.0648). CONCLUSION: A statistically significant survival advantage was observed with nal-IRI+5-FU/LV vs 5-FU/LV in the PP patient population. PMID- 30414529 TI - Cesarean section in Australian women with epilepsy. AB - The literature suggests that cesarean delivery or birth is carried out more often in pregnant women with epilepsy (WWE) than in pregnant women in the general population. Data were utilized from the Australian Pregnancy Register (APR) for Women on Antiepileptic Medication to investigate this issue in Australia. Over almost two decades, the mean CS rate in 1900 APR women was 39.2%, but was only 29.9% in women in the general population (relative risk (R.R.) = 1.31, 95% confidence interval (C.I.) 1.24, 1.39). Rates for forceps and suction-assisted delivery were similar in the two datasets. The 9.3% excess CS rate was almost entirely accounted for by operations carried out prior to the onset of labor. The rates for CS during labor were very similar. Only 11.0% of the WWE knew the indication for their prelabor CS, whereas 69.8% knew why theirs had been carried out during labor (odds ratio (O.R.) = 0.054; 99% C.I. 0.032, 0.089). Slightly older mothers and increased proportions of primipara probably made small contributions to the increased prelabor CS rate in the Australian WWE, but most of the excess could not be accounted for in the Register data. Australian obstetricians may have tended to regard prelabor CS as a preferable course of action in managing delivery in WWE, even in the absence of other indications. PMID- 30414530 TI - FOXA2 gene mutation in a patient with congenital complex pituitary hormone deficiency. AB - We report a patient with congenital complex pituitary hormone deficiency (CPHD) with intestinal malrotation and anal atresia. We identified a de novo heterozygous mutation, c.664T > G (p.Cys222Gly), in the FOXA2 gene in this individual. This missense mutation had the potential to affect the DNA binding properties of the FOXA2 protein based on a protein structure prediction. Since a CPHD patient with another missense mutation and one other case with an entire gene deletion have also been reported, we speculated that a haploinsufficiency of the FOXA2 gene might be a genetic etiology for this disorder. Phenotypic similarities and differences among these three cases are also discussed. PMID- 30414531 TI - Identification of a somatic mutation in the RHEB gene through high depth and ultra-high depth next generation sequencing in a patient with Hemimegalencephaly and drug resistant Epilepsy. AB - Malformations of cortical development are a frequent cause of drug-resistant Epilepsy and developmental delay. Hemimegalencephaly is a Malformation of cortical development characterized by enlargement of all or a part of one cerebral hemisphere. Germline and somatic mutation in genes belonging to the Mammalian Target of Rapamycin (mTOR) pathway has been identified in patients suffering from epilepsy secondary to Hemimegalencephaly and focal cortical dysplasia. We present here a patient suffering from severe neonatal Epilepsy since 3 h of life secondary to Hemimegalencephaly, requiring an anatomic hemispherectomy surgical procedure for seizure control, where by means of next generation sequencing at an ultra-high depth coverage, we were able to identify a novel somatic mutation in the RHEB gene (NM_005614: c.119A > T: p. Glu40Val). The histopathological diagnosis was Cortical Dysplasia type IIB determined by the presence of dysmorphic neurons of variable size with nuclear alteration and balloon cells in the context of Hemimegalencephaly, which are similar to that have been demonstrated in hyperactivating RHEB models. This is the first report of a somatic mutation in RHEB gene in a patient suffering from Epilepsy secondary to Hemimegalencephaly. It highlights different current topics in the fields of genetics of Malformations of cortical development: a-somatic mosaicism is not uncommon in these neurodevelopmental disorders; b-the molecular diagnostic approach should involve the use of state-of-the-art methods and the sampling of different tissues; c-new findings might facilitate therapeutics discoveries while providing an improved understanding of normal brain development. PMID- 30414532 TI - What have we been trying to do and have we been any good at it? A history of measuring the success of genetic counseling. AB - Genetic counseling as a formal clinical service was defined in 1947, though the first study of its effectiveness was not published until 1966. This history can be broadly divided in to 3 periods: 1) 1947-1980, when the focus was primarily on prevention of disability, 2) 1981-1995, when the rationales for counseling began to shift and the first studies on the psychosocial effects of genetic counseling started to appear, albeit still largely focused on reproduction, and 3) 1996 - Present, when genetic counselors increased their presence in oncology, cardiology, and other non-reproductive areas of genetic counseling. Changes in outcome measures of genetic counseling have been intertwined with technological advances in genetic testing, better and more sophisticated outcome measures, the growing professional independence and clinical positions of genetic counselors, and the influence of social scientists particularly from behavioral psychology. Despite advances, assessment of the effectiveness of genetic counseling continues is complicated by a lack of widespread agreement about the most appropriate outcome measures as well as research design problems. Broadly speaking though, genetic counseling tends to improve information recall, improve psychological well-being, and is generally well-regarded by patients. PMID- 30414533 TI - Barriers to rejecting junk food sponsorship in sport-a formative evaluation using concept mapping. AB - OBJECTIVES: Energy-dense, nutrient-poor food and drink ('junk food') brands sponsoring sport is a growing public health concern. This study explored sports administrators' perceptions of the barriers to rejecting junk food sponsorship. STUDY DESIGN: This study used concept mapping. METHODS: The Concept Systems Global MAXTM web platform was used to collect and analyse data from 29 sports administrators across all levels of sport in Victoria, Australia. RESULTS: Brainstorming generated 33 barriers to rejecting junk food sponsorship. After the barriers were synthesised and edited, participants sorted and rated 32 barriers. Multidimensional scaling and hierarchical cluster analysis identified a four cluster solution: community attitudes and values (seven barriers); junk food is the easy sell (retail; five barriers); financial viability (16 barriers); and organisational capability (policy and governance; four barriers). The financial viability barriers were rated the most important (mean = 3.65 of 5) and the hardest to overcome (1.42). The organisational capability (policy and governance) barriers were rated the least important (2.14) and the easiest to overcome (3.20). CONCLUSIONS: Sports administrators clearly perceive that rejecting junk food sponsorship could place significant financial strain on their organisations. There appears to be considerable scope to build the capacity of sporting organisations to rejecting junk food sponsorship. Despite the literature indicating that most parents think junk food companies are not suitable sponsors, sports administrators perceive that there is a broad public acceptance of junk food sponsorship in sport. The fact that sports administrators perceive a link between junk food sponsorship and the lack of healthy options at club canteens and venue food outlets adds an additional, not previously identified, level of complexity to the junk food sponsorship in sport debate. PMID- 30414535 TI - Linking phytoplankton pigment composition and optical properties: A framework for developing remote-sensing metrics for monitoring cyanobacteria. AB - This study has been performed in the framework of a research program aiming to develop a low-cost aerial sensor for the monitoring of cyanobacteria in freshwater ecosystems that could be used for early detection. Several empirical and mechanistic remote-sensing tools have been already developed and tested at large scales and have proven useful in monitoring cyanobacterial blooms. However, the effectiveness of these tools for early detection is hard to assess because such work requires the detection of low concentrations of characteristic pigments amid complex ecosystems exhibiting several confounding factors (turbidity, blooms of other species, etc.). We developed a framework for performing high-throughput measurements of the absorbance and reflectance of small volumes (~ = 20 mL) of controlled mixtures of phytoplankton species and studied the potential of this framework to validate remote-sensing proxies of cyanobacteria concentration. The absorption and reflectance spectra of single and multiple cultures carried a specific signal that allowed for the quantitative analysis of culture mixes. This specific signal was shown to be related to known pigment absorbance spectra. The concentrations of chlorophyll-a and -b, phycocyanin and phycoerythrin could be obtained from direct absorbance measurements and were correlated with the concentration obtained after pigment extraction (R2 >= 0.96 for all pigments). A systematic test of every possible two-band and three-band normalized difference between optical indices was then performed, and the coincidental correlation with chlorophyll-b (absent in cyanobacteria) was used as an indicator of non specificity. Two-band indices were shown to suffer from non-specificity issues and could not yield strong and specific relationships with phycocyanin or phycoerythrin (maximum R2 < 0.5). On the other hand, the three-band modified normalized difference indices yielded strong specific relationships (R2 > 0.8). PMID- 30414536 TI - Using upstream oxidants to minimize surface biofouling and improve hydraulic performance in GAC biofilters. AB - The combination of biological growth and particle loading can adversely affect hydraulic performance in drinking water biofilters. In this study, upstream oxidant addition was used to distribute biologically-derived filter clogging in granular activated carbon (GAC) biofilters. Oxidant penetration was assessed during pilot-scale operation and backwashing of dual media (GAC/sand) and multimedia (GAC/anthracite/sand) biofilters. Influent chlorine (HOCl), monochloramine (NH2Cl), and hydrogen peroxide (H2O2) residuals were optimized to react with the GAC surface in the upper portion of the filter media bed (depth < 0.5 m) to attenuate biomass development. As the oxidant residual was quenched by surface-mediated reaction with the filter media, biomass growth was promoted deeper in the filter bed (depth > 0.5 m). The oxidant-induced effects on biomass and hydraulic performance were monitored through measurements of adenosine triphosphate (ATP) and head loss accumulation at different media depths. Addition of oxidants (e.g., 0.6 mg Cl2/L HOCl) could decrease terminal head loss by 20% in dual media filters and 40% in multimedia filters. These hydraulic benefits were achieved without significantly affecting removal of assimilable organic carbon (AOC), total organic carbon (TOC), turbidity, and particle counts. Oxidant type, residual concentration, media type, media age, and media depth influenced the passage of oxidant residuals and distribution of filter biomass. When oxidants were added during backwashing, oxidant residual was quenched through the bed depth from a combination of reactions with GAC media and biofilm degradation. This attenuation of residual oxidant may prevent the oxidant residual from penetrating the entire bed depth, potentially compromising backwashing objectives. PMID- 30414534 TI - Increased SOD2 in the diaphragm contributes to exercise-induced protection against ventilator-induced diaphragm dysfunction. AB - Mechanical ventilation (MV) is a life-saving intervention for many critically ill patients. Unfortunately, prolonged MV results in rapid diaphragmatic atrophy and contractile dysfunction, collectively termed ventilator-induced diaphragm dysfunction (VIDD). Recent evidence reveals that endurance exercise training, performed prior to MV, protects the diaphragm against VIDD. While the mechanism(s) responsible for this exercise-induced protection against VIDD remain unknown, increased diaphragm antioxidant expression may be required. To investigate the role that increased antioxidants play in this protection, we tested the hypothesis that elevated levels of the mitochondrial antioxidant enzyme superoxide dismutase 2 (SOD2) is required to achieve exercise-induced protection against VIDD. Cause and effect was investigated in two ways. First, we prevented the exercise-induced increase in diaphragmatic SOD2 via delivery of an antisense oligonucleotide targeted against SOD2 post-exercise. Second, using transgene overexpression of SOD2, we determined the effects of increased SOD2 in the diaphragm independent of exercise training. Results from these experiments revealed that prevention of the exercise-induced increases in diaphragmatic SOD2 results in a loss of exercise-mediated protection against MV-induced diaphragm atrophy and a partial loss of protection against MV-induced diaphragmatic contractile dysfunction. In contrast, transgenic overexpression of SOD2 in the diaphragm, independent of exercise, did not protect against MV-induced diaphragmatic atrophy and provided only partial protection against MV-induced diaphragmatic contractile dysfunction. Collectively, these results demonstrate that increased diaphragmatic levels of SOD2 are essential to achieve the full benefit of exercise-induced protection against VIDD. PMID- 30414537 TI - Removal of polar organic micropollutants by pilot-scale reverse osmosis drinking water treatment. AB - The robustness of reverse osmosis (RO) against polar organic micropollutants (MPs) was investigated in pilot-scale drinking water treatment. Experiments were carried in hypoxic conditions to treat a raw anaerobic riverbank filtrate spiked with a mixture of thirty model compounds. The chemicals were selected from scientific literature data based on their relevance for the quality of freshwater systems, RO permeate and drinking water. MPs passage and the influence of permeate flux were evaluated with a typical low-pressure RO membrane and quantified by liquid chromatography coupled to high-resolution mass spectrometry. A strong inverse correlation between size and passage of neutral hydrophilic compounds was observed. This correlation was weaker for moderately hydrophobic MPs. Anionic MPs displayed nearly no passage due to electrostatic repulsion with the negatively charged membrane surface, whereas breakthrough of small cationic MPs could be observed. The passage figures observed for the investigated set of MPs ranged from less than 1%-25%. Statistical analysis was performed to evaluate the relationship between physicochemical properties and passage. The effects of permeate flux were more pronounced for small neutral MPs, which displayed a higher passage after a pressure drop. PMID- 30414539 TI - Methamphetamine use and cognitive function: A systematic review of neuroimaging research. AB - BACKGROUND: Long-term use of MA has been associated with cognitive dysfunction in several domains. Neuroimaging studies have also reported structural, metabolic, and functional changes in MA users. However, no systematic review has been conducted on those studies in MA users that combined neuroimaging and cognitive tasks. METHODS: This article systematically reviews correlation between brain imaging measures and cognitive performance in subjects with current and previous history of MA use. Findings are categorized based on cognitive domain. RESULTS: MA users performed more poorly than controls in all cognitive domains (psychomotor, working memory, attention, cognitive control, and decision- making) and a positive correlation has been repeatedly observed between performance and brain measures (regional volume/density, blood flow, glucose metabolism, FA value, NAA level, and activation) in MA users. Performance in cognitive control was consistently reported to show relationship with brain measures in the PFC and ACC, while decision- making consistently showed correlation with brain measures in the PFC, ACC, and striatum. CONCLUSIONS: There is solid evidence for brain- behavior relationship in cognitive functioning in MA users, particularly in cognitive control and decision-making. More research with correlation analysis between brain-behavior and MA use parameters is strongly encouraged. PMID- 30414538 TI - Neuroendocrine Key Regulator Gene Expression in Merkel Cell Carcinoma. AB - Merkel cell carcinoma (MCC) is a highly aggressive non-melanoma skin cancer of the elderly which is associated with the Merkel cell polyomavirus (MCPyV). MCC reveals a trilinear differentiation characterized by neuroendocrine, epithelial and pre/pro B-cell lymphocytic gene expression disguising the cellular origin of MCC. Here we investigated the expression of the neuroendocrine key regulators RE1 silencing transcription factor (REST), neurogenic differentiation 1 (NeuroD1) and the Achaete-scute homolog 1 (ASCL1) in MCC. All MCCs were devoid of REST and were positive for NeuroD1 expression. Only one MCC tissue revealed focal ASCL1 expression. This was confirmed in MCPyV-positive MCC cell lines. Of interest, MCPyV-negative cell lines did express REST. The introduction of REST expression in REST-negative, MCPyV-positive MCC cells downregulated the neuroendocrine gene expression. The lack of the neuroendocrine master regulator ASCL1 in almost all tested MCCs points to an important role of the absence of the negative regulator REST towards the MCC neuroendocrine phenotype. This is underlined by the expression of the REST-regulated microRNAs miR-9/9* in REST-negative MCC cell lines. These data might provide the basis for the understanding of neuroendocrine gene expression profile which is expected to help to elucidate the cellular origin of MCC. PMID- 30414540 TI - A comprehensive evaluation of omega-3 fatty acid supplementation in cystic fibrosis patients using lipidomics. AB - The evaluation of the benefits of omega-3 fatty acid supplementation in humans requires the identification and characterization of suitable biomarkers of its incorporation in the body. The reference method for the evaluation of omega-3, gas chromatography, is difficult to apply in clinical practice because of its low throughput and does not provide information about the incorporation of specific fatty acids in lipid species and the potential effects of supplementation on lipid classes. We used a quantitative lipidomic approach to follow the incorporation of omega-3 fatty acids into plasma lipids in cystic fibrosis patients (n=50) from a randomized controlled clinical trial after the supplementation of seaweed oil enriched with docosahexaenoic acid (DHA). Lipidomic analysis accurately showed the distribution of fatty acids in different lipid classes after omega-3 supplementation, and the performance in determining the compliance to supplementation was similar to that of gas chromatography coupled to mass spectrometry. Twelve months after fatty acid supplementation, DHA was predominantly incorporated into highly unsaturated cholesteryl esters (110.9+/-16.2 vs. 278.6+/-32.6 MUM, mean+/-S.E.M.) and phosphatidylcholine (142.4+/-11.9 vs. 272.9+/-21.4 MUM) and, to a lesser extent, into phosphatidylethanolamine (9.4+/-0.8 vs. 15.5+/-1.5 MUM) and triglycerides (0.4+/ 0.04 vs. 1.1+/-0.12 MUM). In addition, a technique was developed for the fast measurement of the DHA/arachidonic acid ratio to simplify the follow-up of nutritional intervention with DHA-enriched foods. We conclude that lipidomics is a suitable approach for monitoring the incorporation of omega-3 fatty acids in nutritional studies. PMID- 30414541 TI - Functional mapping and effective connectivity of the human operculum. AB - The operculum, defined as the cortex adjacent to the insula, is a large structure encompassing three lobes, with a recognized role in a variety of neurologic and psychiatric conditions. Its complex functions include sensory, motor, autonomic and cognitive processing. In humans, these are extended with the addition of language. These functions are implemented by highly specialized neuronal populations and their widespread connections, which our study aims at mapping in detail. We studied a group of 31 patients that were explored with intracranial electrodes during the pre-surgical workup for drug-resistant epilepsy. We have selected the subset of contacts implanted in non-epileptogenic opercular cortex and we analyzed the neurophysiological and behavioral responses to direct electrical stimulation. The functional mapping was performed by applying 1 Hz and 50 Hz electrical stimulation on 252 contact pairs and recording the threshold for evoking clinical effects. The effective connectivity was assessed using cortico cortical evoked potentials elicited by single-pulse electrical stimulation in a subset of 19 patients. The locations of the effects grouped in twelve distinct semiological classes were analyzed. The most frequent effects evoked by stimulation of the frontal operculum were language related (29%). The Rolandic area produced most often oropharyngeal symptoms (47%), the parietal operculum produced somatosensory effects (67%), while the temporal evoked auditory (58%) semiology. The connectivity pattern was complex, with these structures having widespread ipsilateral and contralateral projections. The local connections between the opercular subregions and with the insula, as well as with more distant areas like the cingulate gyrus, were distinguished by strength and between-subjects consistency. In conclusion, we demonstrate specific opercular functionality, distinct from the one of the insular cortex. The study is complemented by a literature review on the opercular functional connectome in human and non-human primates. PMID- 30414542 TI - Persistent endocrine-disrupting chemicals found in human follicular fluid stimulate the proliferation of granulosa tumor spheroids via GPR30 and IGF1R but not via the classic estrogen receptors. AB - Epidemiological studies have found that women have detectable levels of organic pollutants such as hexachlorobenzene (HCB), 2,2-dichlorodiphenyldichloroethylene (p,p'-DDE), polychlorinated biphenyl 153 (PCB153), perfluorooctanoate (PFOA), and perfluorooctane sulfonate (PFOS) in their follicular fluid. Thus, these compounds may directly affect the function of granulosa cells within the ovary and may promote granulosa cell tumor (GCT) progression. Two human GCT cell lines, COV434 and KGN, have been used as in vitro model systems to represent juvenile (JGCT) and adult (AGCT) GCT subtypes, respectively. In this study, we found that basal expression of estrogen receptor 1 (ESR1), estrogen receptor 2 (ESR2), and insulin like growth factor 1 receptor (IGF1R) was higher in the AGCT subtype than in the JGCT subtype. All of the compounds acted as mitogenic factors at low nanomolar concentrations in the JGCT and AGCT forms of GCT. Interestingly, PFOA, PFOS, and HCB stimulated cell proliferation through IGF1R, whereas p,p'-DDE acted through GPR30. Moreover, a mixture of the five compounds also significantly stimulated granulosa cell proliferation; however, the observed effect was lower than predicted. Interestingly, the proliferative effect of a mixture of these compounds was dependent on IGF1R and GPR30 but independent of the classic estrogen receptors. Taken together, our results demonstrate for the first time that mixtures of persistent organic pollutants present in follicular fluids may induce granulosa tumor progression through IGF1R and GPR30 by acting as mitogenic factors in granulosa cells. PMID- 30414543 TI - From micro to macro-contaminants: The impact of low-energy titanium dioxide photocatalysis followed by filtration on the mitigation of drinking water organics. AB - This study evaluated strategies targeting macro- and micro-organic contaminant mitigation using low-energy titanium dioxide photocatalysis. Energy inputs of 1, 2, and 5 kWh m-3 resulted in incomplete oxidation of macro-organic natural organic matter, signified by greater reductions of UV254 and specific ultraviolet UV absorbance (SUVA) in comparison to dissolved organic carbon (DOC). The rate of UV254 removal was 3 orders of magnitude greater than the rate of DOC degradation. Incomplete oxidation improved operation of downstream filtration processes. Photocatalysis at 2 kWh m-3 increased the bed life of downstream granular activated carbon (GAC) filtration by 340% relative to direct filtration pretreatment. Likewise, photocatalysis operated ahead of microfiltration decreased fouling, resulting in longer filter run times. Using 2 kWh m-3 photocatalysis increased filter run time by 36 times in comparison to direct filtration. Furthermore, levels of DOC and UV254 in the membrane permeate improved (with no change in removal across the membrane) using low-energy photocatalysis pretreatments. While high-energy UV inputs provided high levels of removal of the estrogenic micro-organics estrone (E1), 17beta-estradiol (E2), estriol (E3), and 17alpha-ethynlestradiol (EE2), low-energy photocatalysis did not enhance removal of estrogens beyond levels achieved by photolysis alone. In the cases of E1 and E3, the addition of TiO2 as a photocatalyst reduced degradation rates of estrogens compared to UV photolysis. Overall, process electrical energy per order magnitude reductions (EEOs) greatly improved using photocatalysis, versus photolysis, for the macro-organics DOC, UV254, and SUVA; however, energy required for removal of estrogens was similar between photolysis and photocatalysis. PMID- 30414544 TI - An overview of the uses of high performance size exclusion chromatography (HPSEC) in the characterization of natural organic matter (NOM) in potable water, and ion exchange applications. AB - Natural organic matter (NOM) constitutes the terrestrial and aquatic sources of organic plant like material found in water bodies. As of recently, an ever increasing amount of effort is being put towards developing better ways of unraveling the heterogeneous nature of NOM. This is important as NOM is responsible for a wide variety of both direct and indirect effects: ranging from aesthetic concerns related to taste and odor, to issues related to disinfection by-product formation and metal mobility. A better understanding of NOM can also provide a better appreciation for treatment design; lending a further understanding of potable water treatment impacts on specific fractions and constituents of NOM. The use of high performance size-exclusion chromatography has shown a growing promise in its various applications for NOM characterization, through the ability to partition ultraviolet absorbing moieties into ill-defined groups of humic acids, hydrolysates of humics, and low molecular weight acids. HPSEC also has the ability of simultaneously measuring absorbance in the UV visible range (200-350 nm); further providing a spectroscopic fingerprint that is simply unavailable using surrogate measurements of NOM, such as total organic carbon (TOC), ultraviolet absorbance at 254 nm (UV254), excitation-emission matrices (EEM), and specific ultraviolet absorbance at 254 nm (SUVA254). This review mainly focuses on the use of HPSEC in the characterization of NOM in a potable water setting, with an additional focus on strong-base ion-exchangers specifically targeted for NOM constituents. PMID- 30414545 TI - Surface coating of UF membranes to improve antifouling properties: A comparison study between cellulose nanocrystals (CNCs) and cellulose nanofibrils (CNFs). AB - The inherent properties of hydrophilicity and environmental preferability of cellulose nanocrystals (CNCs) and cellulose nanofibers (CNFs) make them great candidates for application in water-treatment membranes. In this study, the antifouling properties of CNCs and CNFs, modified ultrafiltration (UF) membranes, were directly compared. A facile modification method was conducted by coating CNCs and CNFs on the surface of polyethersulfone (PES) membranes to prepare CNC coating membranes and the CNF-coating membranes. Membrane surface morphology was characterized by atomic force microscopy (AFM), and the results showed that the CNF-coating membranes exhibited greater surface roughness than the CNC-coating membranes. Pure water flux measurements demonstrated that the flux of the CNC coating membranes was slightly lower than that of the CNF-coating membranes. Antifouling properties were evaluated and compared for the two types of membranes by filtration of NOM foulant models, humic acid (HA) and bovine serum albumin (BSA). The results showed that the antifouling properties of the modified membranes were enhanced through the coating of either CNCs or CNFs to a control PES membrane. The CNC-coating membranes outperformed the CNF-coating membranes in alleviating both reversible fouling and irreversible fouling caused by HA and BSA. In addition, the antifouling performance of the coating membranes was enhanced with increased coating content. PMID- 30414546 TI - Removal of hexavalent chromium by biochar supported nZVI composite: Batch and fixed-bed column evaluations, mechanisms, and secondary contamination prevention. AB - Conversion of carcinogenic Cr(VI) to less toxic Cr(III) has long been regarded as the most efficient and effective method to remediate Cr(VI)-contaminated water. However, the widely used reducing agents such as nano zero-valent iron (nZVI) and its derivatives often have low stability and their applications in water treatment may introduce secondary contaminations. To shed light on these, nZVI was loaded on sludge derived biochar to produce nZVI-BC composite for Cr(VI) removal. Batch experiments showed that Cr(VI) adsorption on nZVI-BC was endothermic and highly pH dependent. The adsorption kinetic and isotherm data were described by the pseudo second-order kinetic model and the Langmuir isotherm model, respectively. The removal of Cr(VI) by nZVI-BC was mainly through reduction-adsorption. After the experiment, nZVI-BC was transformed into a stable magnetic adsorbent that can be magnetically separated from aqueous phase during first circle application. In fix-bed columns, nZVI-BC also effectively removed Cr(VI) under various operation conditions and the Thomas and Yoon-Nelson models described the experimental breakthrough curves well. The post-adsorption nZVI-BC was re-pyrolyzed, which stabilized and reduced the bioavailability of Cr in the biochar. Re-pyrolysis thus can be used as an effective technology to reduce the environmental risks of post-adsorbent biochar for safe disposal. PMID- 30414547 TI - Isomeric derivatives of triazoles as new toxic decomposition products of 1,1 dimethylhydrazine. AB - Unsymmetrical dimethylhydrazine (UDMH) is a rocket propellant for carrier rockets and missiles. UDMH is environmentally hostile compound, which easily forms a variety of toxic products of oxidative transformation. The liquidation of unused UDMH from retired launch sites is performed by the complete burning of UDMH containing wastes. Due cyclicity of the burning equipment the UDMH-containing wastes are subject of prolonged storage in contact with atmospheric oxygen and thus contains a complicated mixture of UDMH degradation products. High performance liquid chromatography (HPLC), high resolution mass spectrometry (HRMS) and NMR were used for the isolation on characterization of new highly polar and potentially toxic UDMH transformation products in the mixture. Two series of unreported isomers with high ionization cross section in electrospray ionization were isolated by repeated preparative HPLC. The structures of the isomers were established by tandem HRMS and NMR. The cytotoxicity of the isolated compounds has been preliminarily studied and found to be similar to UDMH or higher. PMID- 30414548 TI - The atmospheric transport and pattern of Medium chain chlorinated paraffins at Shergyla Mountain on the Tibetan Plateau of China. AB - Large amounts of short chain and medium chain chlorinated paraffins (SCCPs and MCCPs) are released into the environment during production and usage. However, compared to SCCPs, there is a significant lack of attention for MCCPs. In this work, 83 air samples, collected between 2012 and 2015 from the Tibetan Plateau, were analyzed to investigate the airborne levels and distributions of MCCPs, further to evaluate their potential long-range transport behavior on the alpine area. The total air MCCP concentrations at Shergyla Mountain and Lhasa were between 50 and 690 pg/m3 and 800-6700 pg/m3, respectively. At Shergyla Mountain, MCCP concentrations in the air appeared an increasing trend with altitude, which indicated that MCCPs could potentially possess the ability of "mountain cold trapping". C14 and C15 congener groups were the dominant homologue groups. The mountain contamination potential (MCP) of different congener groups is closely related to their equilibrium partitioning coefficients between octanol and air (KOA), and water and air (KWA). Increasing MCCPs levels might be a potential threat to the environment and human exposure. PMID- 30414549 TI - Effect of calcination on structure and photocatalytic property of N-TiO2/g C3N4@diatomite hybrid photocatalyst for improving reduction of Cr(VI). AB - The N-TiO2/g-C3N4@diatomite (NTCD) composite has been prepared through a simple impregnation method, using titanium tetrachloride as precursor and urea as nitrogen-carbon source. Then the effects of calcination temperature on structure, surface property and photocatalytic activity of the catalysts were investigated. And XRD, TEM, XPS, FTIR and UV-vis diffuse adsorption spectroscopy were used to characterize the obtained powders. The photocatalytic activity of the NTCD was evaluated through the reduction of aqueous Cr (VI) under visible light irradiation (lambda > 400 nm). The results demonstrated that the nano-TiO2 particles ranging from 15 to 30 nm in the crystal of anatase are well deposited on the surface of diatomite in the NTCD-500 which calcined at 500 degrees C for 2 h. Furthermore, the g-C3N4 with the lay thickness of 0.92 nm was attached to the surface of nano-TiO2. The N-doped TiO2 and g-C3N4 doped catalysts could co enhance response in the visible light region and reduce band gap of NTCD-500 (Eg = 3.07 eV). And the NTCD-500 sample exhibited nearly 100% removal rate within 5 h for photocatalytic reduction of Cr (VI) which was higher activity than P25, crude TiO2@diatomite and g-C3N4@diatomite. PMID- 30414550 TI - Formation kinetics of disinfection byproducts in algal-laden water during chlorination: A new insight into evaluating disinfection formation risk. AB - It is necessary and important to investigate the formation of disinfection byproducts (DBPs) in water treatment systems for the management of disinfection formation risk. In the present study, the formation potential of trichloromethane (TCM) and haloacetic acids in different algal metabolites were compared, and the formation kinetics of these DBPs were investigated. The results indicated that DBP formation potential, the traditional index widely used to evaluate the disinfection formation risk, can represent neither the total precursors of DBPs nor the possible generated amounts of DBPs in drinking water systems. Kinetic analyses showed that the formation of DBPs could be well described by a classical second-order reaction kinetic model and that the actual concentrations of DBPs during chlorination were predictable with the model. The formation of DBPs in drinking water treatment systems was highly dependent on the total precursors of DBPs in water and the formation rate of DBPs with chlorine; the latter is usually underestimated in previous studies. Because of their high reactivity, TCM in hydrophilic extracellular organic matter and trichloroacetic acid in all algal metabolites should be serious considerations in the management of disinfection formation risk. PMID- 30414551 TI - Residential and school greenspace and academic performance: Evidence from the GINIplus and LISA longitudinal studies of German adolescents. AB - BACKGROUND: Few studies have reported the association between greenspace and academic performance at school level. We examined associations between both residential and school greenspace and individual school grades in German adolescents. METHODS: German and maths grades from the latest school certificate, residential and school greenspace, and covariates were available for 1351 10 and 15 years old Munich children and 1078 Wesel children from two German birth cohorts - GINIplus and LISA. Residential and school greenspace was assessed by the Normalized Difference Vegetation Index (NDVI), tree cover, and (in Munich only) proportion of agricultural land, forest, and urban green space in 500-m and 1000-m circular buffers. Longitudinal associations between each exposure-outcome pair were assessed by logistic mixed effects models with person and school as random intercepts and adjusted for potential confounders. RESULTS: No associations were observed between any of the greenspace variables and grades in Wesel children. Several statistically significant associations were observed with German and maths grades in Munich children, however associations were inconsistent across sensitivity analyses. CONCLUSIONS: There is no evidence of an association of higher greenspace at residence, school or combined with improved academic performance in German adolescents from the GINIplus and LISA longitudinal studies. PMID- 30414552 TI - Increased zonulin is associated with hyperactivity and social dysfunctions in children with attention deficit hyperactivity disorder. AB - BACKGROUND: In attention deficit hyperactivity disorder (ADHD), deteriorations of brain gut axis has been shown in previous studies. One area where the most important challenges are seen in ADHD is social functioning. Zonulin is a protein found in the intestinal intraepithelial component; it has been shown that the level of zonulin increases when intestinal permeability is impaired. Changes in intestinal function were shown in ADHD. Zonulin has been shown to be associated with social impairment in children with autism spectrum disorder. In this study, it was aimed to evaluate the relationship between the ADHD symptoms and zonulin in children with ADHD. Secondarily relation of zonulin and difficulties in social functioning was examined in these children. METHODS: Forty children diagnosed with ADHD and forty-one healthy children similar age and gender to ADHD group and their mothers were included in the study. Children without any chronic systemic immunological or infectious diseases were included in the case and control group. The ADHD symptoms were scored by the DuPaul ADHD scale and the social functioning of the children was assessed by the Social Responsiveness Scale (SRS). Serum zonulin levels were analyzed by enzyme-linked immunosorbent assay. RESULTS: Children with ADHD had higher serum zonulin levels and were more impaired in social functioning compared to controls. The level of zonulin was independently predicted with hyperactivity symptoms and SRS scores in regression analysis. CONCLUSION: In this sample of children with ADHD, elevated zonulin levels were associated with increased symptoms of hyperactivity and impairment of social functioning. PMID- 30414553 TI - DNA transfer: DNA acquired by gloves during casework examinations. AB - As loss and/or contamination of DNA evidence can have major negative implications, it is incumbent on forensic practitioners to minimise this risk. DNA transfer during examination of items, even when wearing gloves, is a potential risk. Here we observe a number of laboratory based biological evidence recovery personnel performing a range of examinations to help evaluate the risks. Assessments are made of; what is touched by each glove and in which sequence; the number, duration and types of contacts made by each glove with the item under examination, tools used and any other surfaces; when the gloves are replaced; as well as DNA profiles of samples taken of the worn gloves at time of replacement against those relating to the item under examination, the examiner and other staff members. Observations show that many different surface areas are touched by gloves during examinations. Differences were observed among examiners in what they touched and when they changed gloves. DNA was retrieved from the outer surfaces of the majority of gloves examined. In many instances the case associated person of interest was observed within the profile generated. So too were profiles of the examiner or other staff members, predominantly from the first and last gloves used during the examination, which were associated with removing the exhibit from its packaging and repackaging it. Several of the observed contacts made by the gloves were deemed high contamination risk events. This study is one of the first to investigate DNA transfer during actual casework examinations, increases our awareness of potential DNA contamination risks during the examination of exhibits, and highlights the need to consider improvements in procedures and/or training of those involved with forensic examinations. PMID- 30414554 TI - Do bipolar disorder soft signs impact outcomes following Transcranial Magnetic Stimulation (TMS) therapy for depression? AB - BACKGROUND: Transcranial Magnetic Stimulation (TMS) is not currently FDA approved for depressed patients with bipolar disorder (BD), but many unipolar depressed patients presenting for TMS have soft signs of bipolarity. It is not known whether or not these soft signs portend differential outcomes. OBJECTIVE: To investigate the relationship between BD soft signs and TMS treatment outcomes in a naturalistic treatment setting. METHODS: We conducted a retrospective chart review of MDD patients (n = 105) treated with TMS. BD diathesis was defined by responses to a modified version of the Mood Disorder Questionnaire and family history. RESULTS: TMS response rates for the group with BD diathesis and the group without were equivalent using two self-report depression severity scales. Remission rate was significantly lower for the bipolar soft signs group (13.5% versus 30.2%; p = 0.04) on one scale. This result does not hold when corrected for multiple comparisons. We did not observe switch to mania. LIMITATIONS: These data are limited to patients diagnosed with unipolar depression with "soft" bipolar features defined by subthreshold symptoms. The results cannot be extrapolated to patients with a full bipolar diagnosis. CONCLUSION: Bipolar diathesis in MDD is not a safety concern but may lead to somewhat lower remission rates when considering TMS treatment. PMID- 30414555 TI - The synergic relationship of social anxiety, depressive symptoms and waist circumference in adolescents: Mediation analysis. AB - BACKGROUND: It is not well established whether depression leads to weight loss or weight gain, or whether a relationship exists among depression, social anxiety, and weight status. The aim of this study was to evaluate the synergic association among social anxiety, depressive symptoms, and waist circumference (WC) during adolescence and examine whether depression mediated the relationship between social anxiety and WC. METHODS: A cross-sectional study was performed with 1296 adolescents from a northeastern district in Brazil. It was used the Social Anxiety Scale for Adolescents (SAS-A) to evaluate symptoms of social anxiety and the Depression Scale of the Center for Epidemiologic Studies (CES-D) for symptoms of depression. Structural equation modeling was used to determine whether depression, social anxiety, and WC were synergically associated. Analysis was adjusted for sex, age, height, and mother's educational level. RESULTS: Symptoms of social anxiety were directly associated with symptoms of depression and WC, whereas symptoms of depression were not associated with WC. LIMITATIONS: This is a cross-sectional study, and so we cannot infer causality in the interpretation of results. CONCLUSION: Social anxiety was found to be associated with depressive symptoms and WC. General medical doctors and health practitioners who observe overweight adolescents with any symptoms of anxiety might consider a thorough evaluation of the patient's mental health. PMID- 30414556 TI - Roles for globus pallidus externa revealed in a computational model of action selection in the basal ganglia. AB - The basal ganglia are considered vital to action selection - a hypothesis supported by several biologically plausible computational models. Of the several subnuclei of the basal ganglia, the globus pallidus externa (GPe) has been thought of largely as a relay nucleus, and its intrinsic connectivity has not been incorporated in significant detail, in any model thus far. Here, we incorporate newly revealed subgroups of neurons within the GPe into an existing computational model of the basal ganglia, and investigate their role in action selection. Three main results ensued. First, using previously used metrics for selection, the new extended connectivity improved the action selection performance of the model. Second, low frequency theta oscillations were observed in the subpopulation of the GPe (the TA or 'arkypallidal' neurons) which project exclusively to the striatum. These oscillations were suppressed by increased dopamine activity - revealing a possible link with symptoms of Parkinson's disease. Third, a new phenomenon was observed in which the usual monotonic relationship between input to the basal ganglia and its output within an action 'channel' was, under some circumstances, reversed. Thus, at high levels of input, further increase of this input to the channel could cause an increase of the corresponding output rather than the more usually observed decrease. Moreover, this phenomenon was associated with the prevention of multiple channel selection, thereby assisting in optimal action selection. Examination of the mechanistic origin of our results showed the so-called 'prototypical' GPe neurons to be the principal subpopulation influencing action selection. They control the striatum via the arkypallidal neurons and are also able to regulate the output nuclei directly. Taken together, our results highlight the role of the GPe as a major control hub of the basal ganglia, and provide a mechanistic account for its control function. PMID- 30414557 TI - Improved regression model to predict an impact of SOD1 mutations on ALS patients survival time based on analysis of hydrogen bond stability. AB - Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterised by the inevitable degeneration of central and peripheral motor neurons. Aggregation of mutant SOD1 is one of the molecular mechanisms underlying the onset of the disease. There are a number of regression models designed to predict the survival of patients based on an analysis of experimental data on thermostability, heterodimerisation energy, and changes in the hydrophobicity of SOD1 mutants. Previously, we proposed regression models linking the change in the stability of hydrogen bonds in mutant SOD1 calculated using molecular dynamics and elastic networks with patients survival time. In this study, these models were improved in terms of accuracy of survival time prediction by taking into account the variance of survival time values relative to the mean, the number of patients carrying each specific mutation, and the use of random forest regression as a regression method. The accuracy of the previous models was roughly 5.2 years while the accuracy of the new ones are up to 4 years. The model is also superior to those published by other authors. It was found that the hydrogen bonds important for prediction of survival time are formed by residues at positions located in the regions of the protein responsible for aggregation as well as in structural and functionally important sites. PMID- 30414558 TI - Reversible flocculation of nanoparticles by a carbamate surfactant. AB - Fatty alkyldiamine readily reacts with CO2 in aqueous solution at pH 12 to reversibly form surface active carbamate species. The carbamate can be reverted to the amine by exposure to N2 and heat. In this work, a carbamate-based surfactant (Y12-carbamate) has been used to disperse and stabilize hydrophobic nanoparticles. This state could be regarded as the "on" state of a series of cycle. The nanoparticles were then flocculated when the carbamate groups were cleaved by exposure to N2 and heating, corresponding to the "off" state. In a subsequent cycle, the nanoparticles were re-dispersed by exposure to CO2, while the pH remained at 12. This cycle of re-dispersion and flocculation could be repeated two times without impairing the particle size. However, further cycles increased the particle size, indicating that all particles could not be completely re-dispersed. In addition, we also investigated the effect of pH on the colloidal stability with sodium Y12-carbamate, by measuring particle size and electrophoretic mobility. The results showed that pH strongly influenced the stability of the nanoparticles. Sodium Y12-carbamate stabilized the particles with a negative electrophoretic mobility at pH well above pKa whereas at pH close to pKa of Y12-amine (pKa = 9.0), the particles quickly flocculated, as a result of an ion-pair formation between Y12-ammonium and Y12-carbamate. PMID- 30414559 TI - Plasmonic microgels of Au nanorods: Self-assembly and applications in chemophotothermo-synergistic cancer therapy. AB - Plasmonic microgels (PMgels) of the self-assembled gold nanorods (Au NRs) with side-by-side piles in ionic liquid microgels were prepared. Transmission electron microscopy (TEM) images revealed unique self-growth and self-arrangement of Au NRs in the microgel systems. The fabrication of PMgels occurs through co assembling Au NRs and an ionic liquid microgel system, therefore differs from the fabrication of conventional plasmonic hybrid nanocomposites. These PMgels showed strong absorption in the near-infrared window and enhanced photothermal conversion efficiency, up to 52.8%, compared to the Au NRs (22%) as a result of the ordering and dense packing of Au NRs in the microgels. When the PMgels were exposed to a near-IR laser, the doxorubicin hydrochloride (Dox) released from PMgels and the resulting thermal effect can immensely inhibit tumor growth both in vitro and in vivo. The tests demonstrated that no tumor metastasis occurred. This platform of the PMgels with the laser-controlled delivery system could provide chemo-photothermal synergistic therapy for a wide spectrum of diseases. PMID- 30414560 TI - TiF4 and NaF varnishes induce low levels of apoptosis in murine and human fibroblasts through mitochondrial Bcl-2 family and death receptor signalling. AB - OBJECTIVES: This study evaluated the level and mechanism of apoptosis in human gingival fibroblasts (HGF) and murine fibroblasts (NIH/3T3) treated with a titanium tetrafluoride (TiF4) varnish compared those treated with a sodium fluoride (NaF) varnish. METHODS: Cells were treated with a TiF4, NaF (both 2.45%F) or placebo varnish for 6 h and were then examined using the TUNEL method. The activities of caspase-3, -8 and -9 were assessed. cDNA for Bax, Bad, Bcl-2 and Fas-L was amplified by quantitative PCR. Bax, Bcl-2 and Fas-L were further detected by western blot analysis. RESULTS: Both fluorides similarly increased the percentage of apoptosis, while they failed to activate caspases. The Bax/Bcl 2 gene expression ratio was not altered by either fluoride treatment regardless of the type of cell. NaF varnish increased the amplification of the Fas-L gene in NIH/3T3 and HGF cells, while treatment with the TiF4 varnish resulted in a lower Bad/Bcl-2 expression ratio compared to that of the control for NIH/3T3 cells, but not for HGF cells. No effect of the fluorides was detected in the protein analysis. CONCLUSIONS: NaF and TiF4, at the studied conditions, similarly induce a low level of apoptosis, with consequent modest activation of the Bcl-2 and Fas l-dependent signalling pathways. Generally, HGF cells are more susceptible to the fluoride effect than NIH/3T3 cells. PMID- 30414561 TI - Developmental exposure to environmentally relevant concentrations of bifenthrin alters transcription of mTOR and ryanodine receptor-dependent signaling molecules and impairs predator avoidance behavior across early life stages in inland silversides (Menidia beryllina). AB - Altered transcription of calcium-dependent signaling cascades involving the ryanodine receptor (RyR) and mechanistic target of rapamycin (mTOR) in response to environmental exposures have been described in model vertebrates, including zebrafish, while the relevance for wild fishes remains unknown. To address this knowledge gap, we exposed the euryhaline model species Menidia beryllina (inland silversides) to the insecticide bifenthrin, a known modulator of calcium signaling. The main objectives of this study were to determine: (1) whether exposure of developing silversides to environmentally relevant concentrations of bifenthrin alters their behavior; and (2) whether behavioral changes correlate with altered expression of genes involved in RyR and mTOR-dependent signaling pathways. At six hours post fertilization (hpf), inland silversides were exposed to bifenthrin at 3, 27 and 122 ng/L until 7 days post fertilization (dpf, larvae hatched at 6dpf), followed by a 14-day recovery period in uncontaminated water. Transcriptional responses were measured at 5, 7 and 21 dpf; locomotor behavior following external stimuli and response to an olfactory predator cue were assessed at 7 and 21 dpf. Bifenthrin elicited significant non-monotonic transcriptional responses in the majority of genes examined at 5 dpf and at 21 dpf. Bifenthrin also significantly altered predator avoidance behavior via olfactory mechanisms with main effects identified for animals exposed to 3 and 27 ng/L. Behavioral effects were not detected in response to visual stimuli during acute exposure, but were significant in the predator-cue assessment following the recovery period, suggesting delayed and long-term effects of early developmental exposures to bifenthrin. Our findings demonstrate that at picomolar (pM) concentrations, which are often not represented in ecotoxicological studies, bifenthrin perturbs early development of inland silversides. These developmental impacts are manifested behaviorally at later life stages, specifically as altered patterns of predator avoidance behavior, which have been correlated with population decline. Collectively, these data suggest that bifenthrin may be negatively impacting wild fish populations. PMID- 30414562 TI - Efficacy of blue LED in microbial inactivation: Effect of photosensitization and process parameters. AB - Efficacy of blue (462 +/- 3 nm) Light emitting diode (LED) illumination to inactivate the foodborne pathogens like Escherichia coli and Staphylococcus aureus in the presence of exogenous photosensitizer (curcumin) was studied in vitro. The effect of temperature, concentration of photosensitizer and incubation time with photosensitizer for microbial inactivation was investigated and sublethal injury of cells was determined. Mechanism of inactivation by the combination of photosensitizer and blue light was also examined. A maximum reduction of 5.94 +/- 0.22 and 5.91 +/- 0.20 log CFU/ml was obtained for E. coli and S. aureus, respectively, when treated with photosensitizer (20 MUM) at 13 J/cm2 of blue light. There was no significant change in the inactivation of these pathogens both at 9 degrees C and 27 degrees C in the presence of photosensitizer. Even, the incubation with the photosensitizer didn't show any significant difference on the inactivation of these food-borne pathogens. Sublethal injury (>90% injury) was also observed for the cells treated with photosensitizer and blue light simultaneously. Confocal laser scanning microscopy analysis revealed that membrane integrity was disturbed due to photodynamic activity of curcumin in both the bacteria. Further, both cells produced intracellular reactive oxygen species by the action of photosensitizer and blue light. Scanning electron microscopy of E. coli and S. aureus cells treated with photosensitizer and blue light showed morphological changes in the cell wall compared to untreated group. The study indicated that photodynamic inactivation of foodborne pathogens using LED-based photosensitization can be explored as a potential technique for food safety. PMID- 30414563 TI - The coexistence of recurrent cerebral tumefactive demyelinating lesions with longitudinally extensive transverse myelitis and demyelinating neuropathy. AB - Combined central and peripheral demyelination (CCPD) is a rare chronic inflammatory disorder of the nervous system. In this article, we report on a CCPD patient with a very unusual pattern of central demyelination, comprising recurrent cerebral tumefactive demyelinating lesions (three times, each one in a new area of the brain) and one episode of longitudinally extensive transverse myelitis. This patient could not be classified as having multiple sclerosis, or neuromyelitis optica spectrum disorder, or any other well-known inflammatory disorder of the central nervous system, associated with demyelinating neuropathy. A diagnosis of idiopathic inflammatory demyelinating disorder (IIDD) was made while waiting for more knowledge concerning the diseases currently characterized as IIDD. PMID- 30414564 TI - Two strongly linked single nucleotide polymorphisms (Q320P and V397I) in GDF9 gene are associated with litter size in cashmere goats. AB - Growth differentiation factor 9 (GDF9) gene is an effective intra-ovarian regulator; it plays a crucial role in early folliculogenesis in female mammals. The non synonymous mutations: g.3905A > C (also known as p.Gln320Pro/Q320P) and g.4135G > A (also know as p.Val397Ile/V397I), are two well-known and controversial single nucleotide polymorphisms (SNPs) within GDF9 gene in goats with different prolificacy, and so far, there were no studies on linkage between Q320P and V397I. Therefore, the aim of this work was to study whether Q320P and V397I mutations have a significant effect on litter size, in Shaanbei white cashmere goats (SBWC, n = 1511), and to explore the specific relationship between these two SNPs. The results showed that both of Q320P and V397I mutations exhibited three genotypes; the minor allele frequencies (MAF) of the SNPs were 0.286 and 0.477, respectively; and these two SNPs were in strong linkage disequilibrium (D' = 0.976, r2 = 0.348) in the studied goats. Moreover, association analyses revealed that Q320P was significantly associated with the first-born litter size in goats irrespective of the sample size (n = 1511; P = 0.008), while V397I significantly affected litter size until the sample size crossed 1300 (P = 0.015). Meanwhile, the diplotypes PP-II and QP-VI were observed to have a superior effect on litter size (P = 3.78 * 10-5) to that of the haplotypes (P = 1.12 * 10-7). Thus, the findings led us to assume that Q320P mutation was the major SNP affecting goat litter size. These findings can provide useful DNA markers for selecting superior individuals in marker-assisted selection (MAS) for breeding in relation to fecundity in goats. PMID- 30414566 TI - Contrast-enhanced ultrasonography of maternal and fetal blood flows in pregnant bitches. AB - We evaluated the potential usefulness of CEUS to assess fetal-maternal circulation during pregnancy in dogs. Nine bitches were examined at 23, 30, and 45 days of gestation using an ultrasound machine (LOGIQ E9) and SonoVue(r) contrast media as echo-signal enhancer. Qualitative and quantitative evaluation of contrast enhancement patterns of uterine artery and utero/placental vessels were performed on recorded images. Independently of the gestational periods, the qualitative evaluation showed the initial wash-in phase from the first appearance of the uterine artery to the rapid distribution in embryonic vesicles or placenta to the progressive washout, whilst there was no enhancement of either embryos or fetuses in any bitch. Independent of gestational age, parameters derived from quantitative analysis of time intensity-curves of contrast enhancement (peak intensity, time to peak, rise time, washout) did not vary between proximal placenta, distal placenta, and uterine artery. With the progression of gestation, AUC values did not change in both proximal and distal placenta, but in the uterine artery it was lower (P <= 0.05) at day 30 than at day 23 (464.8 +/- 16.1 vs.596.4 +/- 28.1, respectively). In conclusion, CEUS appears to safely permit evaluation of the maternal and fetal vessels in the first two third of gestation, without any clinically relevant adverse effects. Further studies in a larger number of bitches in different stages of pregnancy are needed to establish standard parameters for normal pregnancies that can be used to detect abnormalities of pregnancy. PMID- 30414565 TI - Effects of an intravaginal GnRH analogue administration on rabbit reproductive parameters and welfare. AB - On commercial farms, rabbit does are subjected to a reproductive rhythm that does not account for their welfare or physiology, leading to reduced longevity and consequently high annual replacement. The European Food Safety Authority (EFSA) recommends limited and infrequent use of hormone treatments, and suggests replacement with alternative methods that do not threaten animal welfare when possible. In the present study, we aimed to determine whether the GnRH analogue lecirelin acetate could be administered by inclusion in the seminal dose during insemination. Twenty 9-month-old does (Grigio del Monferrato, autochthonous Italian breed),each having two previous deliveries, were individually housed and divided into two groups at artificial insemination. The control group received 0.2 mL of intramuscular lecirelin (Dalmarelin, Fatro(r), Italy) prior to insemination. The intravaginal group was inseminated with a seminal dose that included 0.3 mL Dalmarelin. The experiment was performed for six consecutive reproductive cycles at 42-day intervals, and included a total of 120 inseminations. Prior to each insemination, the heterospermic pooled semen samples were assessed for sperm motility and morphology. Each ejaculate was divided into two samples, with and without lecirelin addition. Compared to the control group, the does with intravaginal Dalmarelin administration showed equal or greater sexual receptivity, which resulted in a higher fertility rate over increasing cycles. The seminal dose volume was very low, possibly explaining the better results in the intravaginal group, which received a similar amount of hormone (0.3 mL/doe) as the control group (0.2 mL/doe). The negative performance of the control group may have also been due to anti-GnRH formation, and the more stressful method of ovulation induction. The number of live-born kits did not significantly differ between groups. Progressive motility was significantly positively correlated with motility characteristics, including VAP, VSL, ALH, BCF, STR, and LIN. Overall, our present findings supported that the incorporation of GnRH in a seminal dose could be used for ovulation induction in rabbit does. Further studies should identify the optimal dose of GnRH for intravaginal administration, taking into account that the intravaginal absorption capacity is about 10 times smaller than the intramuscular absorption capacity. PMID- 30414567 TI - Effects of different doses of eugenol on plasma cortisol levels and the quality of fresh and frozen-thawed sperm in South American catfish (Rhamdia quelen). AB - The production of captive fish is only possible through artificial reproduction, but manipulation is a known stressor stimulus. Thus, the objective of the present study was to evaluate the effects of different eugenol concentrations (0, 30, 40, 50 and 60 mg/L) during reproductive management of Rhamdia quelen. Seventy-five mature male R. quelen were randomly distributed among the five treatments, and blood samples were collected at the time of semen collection to measure plasma cortisol. The following parameters were evaluated in the fresh semen samples: motility, motility duration, concentration and fertilization rate. The following parameters were evaluated in the frozen semen samples: motility, motility duration, morphology, membrane integrity, DNA integrity and mitochondrial functionality. The animals anesthetized with eugenol at concentrations of 40 and 50 mg/L had lower levels of plasma cortisol (88.4 and 83.3 ng/mL, respectively) than the control (147.1 ng/mL). For fresh semen, the control treatment presented the highest rate and time of motility but differed (P < 0.05) only from the animals treated with 60 mg/L eugenol. For the cryopreserved semen the highest rates and motility time were observed in the control treatment and in the animals anesthetized with 40 mg/L eugenol, differing (P < 0.05) from anesthetized animals with 50 and 60 mg/L. Mitochondrial functionality was higher in fish anesthetized with 30 mg/L eugenol differing only for animals anesthetized with 60 mg/L. There was no difference between treatments for sperm concentration and fertilization rate of fresh semen. There were no differences (P > 0.05) between treatments in the parameters of membrane integrity, DNA integrity and% of normal spermatozoa after thawing of the cryopreserved semen samples. The use of 30, 40 and 50 mg/L eugenol maintained the seminal quality of the fresh semen, and the quality of the thawed semen was maintained with 30 and 40 mg/L eugenol. These results show that stress reduction can be reconciled with reproductive management without compromising reproductive performance. PMID- 30414568 TI - Angpt2 Induces Mesangial Cell Apoptosis through the MicroRNA-33-5p-SOCS5 Loop in Diabetic Nephropathy. AB - Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Mesangial cell (MC) loss is correlated with worsening renal function in DN. Disturbance of angiopoietin (Angpt)/Tie ligand-receptor system causes inflammation and abnormal angiogenesis. This association between elevated circulating Angpt2 and poor renal outcome has been in DN patients. However, the pathogenic role of Angpt2 in the MCs remains unknown. We found serum Angpt2 levels were elevated in type 2 diabetes mellitus (DM) patients and db/db mice, which correlated with albuminuria. Angpt2 synergistically induced MC apoptosis under high glucose (HG), and miR-33-5p regulated Angpt2-inducing MC apoptosis treated with HG. Loss of miR-33-5p increased suppressor of cytokine signaling 5 (SOCS5), leading to the inhibition of Janus kinase 1 and signal transducer and activator of transcription 3 signaling transduction. Elevated expression of SOCS5 was found in the MCs in kidney sections of both db/db mice and type 2 DM patients. Decreased miR-33-5p levels were found in the urine of db/db mice and type 2 DM patients, and miR-33-55p levels negatively correlated with albuminuria. Angpt2 leads to MC apoptosis via the miR-33-5p-SOCS5 loop in DN. miR-33-5p is predictive of kidney injury in DN. These findings may provide future applications in predicting renal dysfunction and the therapeutic potential of DN. PMID- 30414571 TI - GiPlot: An interactive cloud-based tool for visualizing and interpreting large spectral data sets. AB - Latest advances in technology and the growing amount of experimental and business data have increased the number of users accessing on-line tools dedicated to quickly visualize and analyse large data sets. This paper describes the development and functionality of a new interactive cloud computing based plotting tool (GiPlot - Google-based Interactive Plot) easy-to-use for universal data. It has interactive features that facilitate data share and interpretation, and selection of specific data suitable for further uses and detailed studies. It also allows quick and step-by-step visualizations of the impact of various experimental conditions on spectral data sets. For a detailed illustration of the features of this interactive plotting tool, we have used mainly spectral data for a given solute dissolved in mixed solvents and for changes in the absorption and/or fluorescence properties of a solute solution in the presence of different chemical stimuli. The most important features and functionalities of this new tool have also been summarized and suggestively highlighted through a short collection of video tutorials containing many examples, developed by the authors of this paper as a support for both the tool and this paper. PMID- 30414570 TI - Enhancement of growth and salt tolerance of rice seedlings by ACC deaminase producing Burkholderia sp. MTCC 12259. AB - Increasing soil salinity is often associated with accelerated ethylene production in plants, leading to overall growth reduction. The salt-tolerant 1 aminocyclopropane-1-carboxylic acid (ACC) deaminase-producing PGPR may alleviate salt stress by reducing the production of stress ethylene. In this study, a salt tolerant ACC deaminase-producing strain named P50 was isolated from a coastal rice field in Odisha, India, which enhanced the growth of rice seedlings under salt stress. The P50 strain was identified as Burkholderia sp. based on phenotypic characteristics, MALDI-TOF MS data for ribosomal proteins and 16S rDNA sequence-based homology. Various PGP traits of strain P50 were characterized, among which the ACC deaminase activity was optimized at different physical conditions and confirmed by enzyme assay, as well as FTIR. The IAA, EPS and proline production of this strain were estimated under increasing NaCl concentrations essential for plant growth promotion under salt stress. Finally, the P50 strain was utilized in a gnotobiotic assay using rice seedlings (cv. Swarnamasuri) under saline stress. Seedlings treated with the P50 strain showed improvement in various morphological and biochemical characteristics, ROS scavenging antioxidant enzymatic activities, and reduced amounts of stress ethylene compared to non-inoculated strains under salinity. In addition, isolation of the ACC deaminase mutant of this strain was not found to reduce stress ethylene, confirming that the P50 strain was associated with a reduction in stress ethylene. Strain P50 was also found to colonize the root surfaces of rice seedlings associated with the plant-microbe interaction process. Thus, as an effective salt-tolerant PGPR, strain P50 can be utilized in salt-affected agricultural fields to improve plant growth in a sustainable manner. PMID- 30414572 TI - Construction of pure worm-like AuAg nanochains for ultrasensitive SERS detection of pesticide residues on apple surfaces. AB - Ultrasensitive detection of pesticide residues on agricultural products using surface-enhanced Raman spectroscopy (SERS) is of significant interest in food security. Herein, worm-like AuAg nanochains with highly interconnected ultrafine (~6.2 nm) bimetallic particles were developed as an excellent SERS nanosensor via laser-assisted strategy. The SERS detection limit of thiram molecules on apple surfaces is about 10-7 M (0.03 ppm), which is about 200 times lower than the maximal residue limit (MRL, 7 ppm) in fruit prescribed by the U.S. Environmental Protection Agency (EPA). Importantly, the established excellent linear relationships between the SERS intensities and thiram concentrations can sensitively monitor the slight variation of pesticide residues in agriculture. PMID- 30414569 TI - A Simplified System to Express Circularized Inhibitors of miRNA for Stable and Potent Suppression of miRNA Functions. AB - MicroRNAs (miRNAs) are an evolutionarily conserved class of small regulatory noncoding RNAs, binding to complementary target mRNAs and resulting in mRNA translational inhibition or degradation, and they play an important role in regulating many aspects of physiologic and pathologic processes in mammalian cells. Thus, efficient manipulations of miRNA functions may be exploited as promising therapeutics for human diseases. Two commonly used strategies to inhibit miRNA functions include direct transfection of chemically synthesized miRNA inhibitors and delivery of a gene vector that instructs intracellular transcription of miRNA inhibitors. While most miRNA inhibitors are based on antisense molecules to bind and sequester miRNAs from their natural targets, it is challenging to achieve effective and stable miRNA inhibition. Here we develop a user-friendly system to express circular inhibitors of miRNA (CimiRs) by exploiting the noncanonical head-to-tail backsplicing mechanism for generating endogenous circular RNA sponges. In our proof-of-principle experiments, we demonstrate that the circular forms of the hsa-miR223-binding site of human beta arrestin1 (ARRB1) 3' UTR sponge RNA (BUTR), the bulged anti-miR223 (cirBulg223) and bulged anti-miR21 (cirBulg21), exhibit more potent suppression of miRNA functions than their linear counterparts. Therefore, the engineered CimiR expression system should be a valuable tool to target miRNAs for basic and translational research. PMID- 30414573 TI - Effect of intermolecular interaction on excited-state properties of thermally activated delayed fluorescence molecules in solid phase: A QM/MM study. AB - Recently, thermally activated delayed fluorescence (TADF) molecules have attracted great attention since nearly 100% exciton usage efficiency was obtained in TADF molecules. Most TADF molecules used in organic light-emitting diodes are in aggregation state, so it is necessary to make out the intermolecular interaction on their photophysical properties. In this work, the excited-state properties of the molecule AI-Cz in solid phase are theoretically studied by the combined quantum mechanics and molecular mechanics (QM/MM) method. Our results show that geometry changes between the ground state (S0) and the first singlet excited state (S1) are limited due to the intermolecular pi-pi and CH-pi interactions. The energy gap between S1 and the first triplet excited state is broadened and the transition properties of excited states are changed. Moreover, the Huang-Rhys factors and the reorganization energy between S0 and S1 are decreased in solid phase, because the vibration modes and rotations are hindered by intermolecular interaction. The non-radiative rate has a large decrease in solid phase which improves the light-emitting performance of the molecule. Our calculation provides a reasonable explanation for experimental measurements and highlights the effect of intermolecular interaction on excited-states properties of TADF molecules. PMID- 30414574 TI - Interaction of a dimeric carbocyanine dye aggregate with bovine serum albumin in non-aggregated and aggregated forms. AB - The interaction of fluorescent dyes with serum proteins has garnered significant interest owing to potential for non-covalent labeling and imaging applications. In this work, dimeric benzothiazole-based trimethine cyanine dyes are synthesized and their interaction with bovine serum albumin studied. The dimeric cyanine dyes mainly exist as H-dimers and H-aggregates in aqueous solution. A combination of absorbance, fluorescence, circular dichroism spectroscopy and atomic force and fluorescence microscopy indicate the formation of dye-BSA complexes. Binding of one of the dimeric dyes on BSA with a Ka of 1.49*105M-1 results in disruption of dye self-aggregates and unfolding of the dyes into the monomeric or open conformation. Fluorescence enhancement experienced by the dimeric dyes upon interaction with BSA is superior to that registered by Thioflavin T. Surfactant SDS has been used to further tune the self-aggregation of the dimeric dye resulting in a 200-fold fluorescence enhancement in presence of BSA. Interaction of a dimeric dye with BSA under conditions favoring protein aggregation is found to result in faster dye binding and the resulting fluorescence enhancement is easily visualized by fluorescence microscopy. The interaction of a dimeric cyanine dye aggregate with BSA is promising for non-covalent labeling applications in sharp contrast to the monomeric dye counterpart. PMID- 30414575 TI - Interpretation of the binding interaction between bupropion hydrochloride with human serum albumin: A collective spectroscopic and computational approach. AB - Bupropion hydrochloride (BPH) an antidepressant and widely used to treat addiction of nicotine. The actual protein existing in blood plasma for the vehicle of exogenous and endogenous substances is human serum albumin i.e. HSA. The interaction of BPH with HSA was examined by molecular docking, multiple spectroscopy's such as fluorescence (emission, synchronous and three dimensional), UV-vis (ultraviolet-visible), FT-IR (Fourier transform infrared) and CD (circular dichroism) at physiological pH 7.40 at 286, 296 and 306 K. BPH was particularly bind to HSA through forces called hydrogen bonds and vander Waals at site I (IIA) which was confirmed from negative values of thermodynamics calculated by van't Hoff equation and docking studies in addition to site marker analysis. This interaction was spontaneous and exothermic process. Secondary structure including conformation of HSA changes after interaction with BPH was revealed from CD and FT-IR (Fourier self-deconvolution to curve fitting), UV-vis, 3D and synchronous florescence techniques. Forster's theory (non-radiation energy transfer) was applied to calculate the distance from tryptophan of HSA to BPH. This interaction involves static quenching (Stern-Volmer and Modified Stern Volmer equations) with larger binding constant values were in the range 105 confirming that strong interaction was exists between BPH and HSA. The interference of bio-active Mg2+, Cu2+, Zn2+, Ca2+ and Fe2+ metal ions on this interaction was also analysed. PMID- 30414576 TI - Novel insights on the vibronic transitions in free base meso-tetrapyridyl porphyrin. AB - We present novel results on the free base 5,10,15,20-meso-tetra(pyridyl)-21H,23H porphyrin (H2TPyP). This molecule presents complex electronic and vibrational properties and despite the vast literature reporting the transitions observed in its absorption and fluorescence spectra, a more accurate interpretation has been kept elusive. In particular, we show that the molecule's Q-band develops into many electronic and vibronic transitions, whose the well-known "four orbital model" finds it difficult to reconcile. Using distinct spectroscopy techniques, we conclude that both Qx- and Qy-bands comprise, in fact, two quasi-degenerated electronic states together with their respective vibronic progressions each. The analysis of the Huang-Rhys factors and complementary time- and polarization resolved measurements reinforce the need for the proposed Q-band multi features remodeling. PMID- 30414577 TI - Natural decay of archaeological oak wood versus artificial degradation processes An FT-IR spectroscopy and X-ray diffraction study. AB - Wood has been extensively used as a material for different applications over the years, therefore the understanding of different degradation processes in various environments is of great importance. In this study, the infrared spectroscopy, X ray diffraction and chemometric methods were used to evaluate and compare the structure of archaeological and artificially degraded oak wood. The results clearly show that modifications in the structure of archaeological wood are related to the position of the material in the log (sapwood and heartwood), thus the extent of wood degradation. To identify the possible factors influencing these effects, the control wood samples were exposed to artificial white rot biodegradation with Coriolus (Trametes) versicolor and to alkali treatment (with NaOH solution). Due to the structural similarities between biodegraded wood and control or archaeological samples, this type of decay is likely to occur during natural ageing along with degradation produced by other environmental factors. Further, no real similarity was identified between the alkali treated wood and archaeological samples, indicating that such degradation does not affect wood under natural conditions. PMID- 30414578 TI - Selection of cyanobacteria over green algae in a photo-sequencing batch bioreactor fed with wastewater. AB - In this work, a strategy based on photo-sequencing batch operation was used to select cyanobacteria over unsettled green algae in a wastewater treatment system, evaluating for the first time the effect of hydraulic regimes on nutritional dynamics and microorganisms' competition. During 30 days of operation, an initial microalgae mixed consortia dominated by the green microalgae Scenedesmus sp. was cultivated in two different photo-sequencing batch reactors operated at hydraulic retention time (HRT) of 6 days (PSBR6) and 4 days (PSBR4) at a theoretical solids retention time (SRT) of 10 d. Both reactors were compared with a semi-continuous reactor (SC10) operated at 10 d of HRT and 10 days of SRT (used as a control). The results indicated that PSBR6 and PSBR4 decreased Scenedesmus sp. population by 88% and 48%, respectively. However, only PSBR6 provided suitable conditions to select cyanobacteria from an initial green algae dominated culture. These conditions included volumetric loads of 11.72 mg TN L-1 d-1, 2.04 mg TP L-1 d-1 and 53.31 mg TOC L-1 d-1. The remaining nutrients in the culture led also to a phosphorus limiting N:P ratio (34:1) that improved the increase of cyanobacteria from an initial 2% until 70% of the total population. In addition, PSBR6 reached a biomass production of 0.12 g L-1 d-1, while removing TN, TP and TOC by 58%, 83% and 85%, respectively. Conversely, the application of higher nutrients loads caused by lower HRT (PSBR4) led to an increase of only 13% of cyanobacteria while SC10 remained with the same biomass composition during all the experimental time. Thus, this study showed that the dominance of cyanobacteria in microalgal-based wastewater treatment systems can be controlled by the operational and nutritional conditions. This knowledge could contribute to control microalgae contamination from up-scaling cyanobacterial biomass production in wastewater treatment systems. PMID- 30414579 TI - Secondary organic aerosol of PM2.5 in a mountainous forest area in southeastern China: Molecular compositions and tracers implication. AB - Secondary organic aerosol (SOA) plays an important role in global climate change and air quality. PM2.5 (particles with aerodynamic diameters <=2.5 MUm) samples were collected at a mountainous forest site (Mt. Wuyi) in southeastern China between November 2015 and July 2016. Fourteen PM2.5-bound SOA tracers, including isoprene, alpha/beta-pinene, beta-caryophyllene, and toluene, were measured using the gas-chromatography-mass-spectrometry method. The total concentrations of the isoprene, alpha/beta-pinene, beta-caryophyllene, and toluene SOA tracers were 45.28 +/- 65.52, 30.66 +/- 24.44, 5.99 +/- 7.25, and 0.62 +/- 0.72 ng m-3, respectively. The isoprene SOA tracers exhibited the highest concentration (145.97 +/- 53.78 ng m-3) and accounted for 76 +/- 9% of the total concentration of SOA tracers in summer. In fall-winter, the mass fraction of 2-methylglyceric acid was significantly enhanced because of the lower temperature and higher NOx level. As later-generation products of alpha/beta-pinene tracers, high proportions of 3-hydroxyglutaric acid and 3-methyl-1,2,3 butanetricarboxylic acid were observed on Mt. Wuyi, suggesting that the aerosols were highly oxidized. Biomass burning events affected by local and regional sources were identified by analyzing typical SOA tracers. Significant positive correlation (R2 = 0.74) was found between the beta-caryophyllene tracer and levoglucosan. The average concentration of secondary organic carbon (SOC) as estimated from SOA tracers was 1.46 MUgC m-3. The isoprene SOC accounted for 70% of the total SOC in summer, whereas the beta-caryophyllene SOC was the predominant component in winter. Meanwhile, the estimated toluene SOC accounted for 11.6% of the total SOC during the study period. The study helps understanding the characteristics and the formation of SOA in a mountainous forest area of southeastern China. PMID- 30414580 TI - Spatial avoidance, inhibition of recolonization and population isolation in zebrafish (Danio rerio) caused by copper exposure under a non-forced approach. AB - Aquatic ecosystems receive run-off and discharges from different sources that lead to the accumulation of contaminants such as copper. Besides producing lethal and sub-lethal effects, copper has shown to be aversive to zebrafish (Danio rerio) by triggering avoidance response. The primary aim of the present study was to evaluate how a copper gradient could affect the spatial distribution of D. rerio by triggering avoidance, preventing recolonization and isolating populations. Secondly, to what extent the food availability in a previously avoided environment could make it a less aversive environment was assessed. A non forced, multi-compartmented exposure system with a copper gradient (0-300 MUg.L 1), through which fish could move, was used for the avoidance and recolonization assays. To test the effect of copper on population isolation, two uncontaminated connected zones were separated by a chemical barrier with a copper concentration of 90 MUg.L-1 (a concentration producing an avoidance of 50% - AC50). Zebrafish avoided copper and the 2 h-AC50 was 90.8 MUg.L-1. The recolonization was in accordance with avoidance and the relationship ACx/RC100-x (RC: recolonization concentration) was around 2.5. When food was provided in the highest copper concentration, the recolonization pattern was altered, although the distribution of the fish was not statistically different from the scenario without food. The chemical barrier formed by copper (90 MUg.L-1) impaired the migratory potential of the fish population by 41.3%; when food was provided in the last compartment, no statistically significant trend of fish moving towards that concentration was observed. Copper might act as an environmental disruptor by triggering spatial avoidance, preventing recolonization and isolating populations in zebrafish. The present study allows simultaneously including three ecological concepts to ecotoxicological studies that have received little attention: habitat selection, recolonization and habitat chemical fragmentation. PMID- 30414581 TI - Evaluation of long-term estuarine vegetation changes through Landsat imagery. AB - Salt marshes support estuarine biodiversity and provide ecosystem services; however, their general decay is being observed worldwide, in large part due to land reclamation. Accordingly, there is a growing concern about salt marsh preservation status having in mind the promotion of effective management decisions towards their conservation and restoration. Satellite imagery offers the opportunity to monitor land surface dynamics, constituting a fundamental information source for wetland monitoring. This study analyses spatial and temporal vegetation changes within Ria de Aveiro coastal lagoon between 1984 and 2017, by processing and analyzing TM and ETM+ Landsat imagery. A database consisting of 264 cloud-free images was collected and analyzed. The Normalized Difference Water Index was computed using the remote surface reflectance and was then used to distinguish land from water and to estimate the flooded lagoon area. Moreover, the tidal state was determined for each image from a tidal elevation record monitored at the lagoon entrance. Subsequently, four vegetation indices (VI) were computed and their spatial variability in the lagoon area uncovered by water was assessed. Spatially averaged spectral indices were also statistically analyzed and seasonal variations and interannual trends evaluated. Results show that the intertidal area increased, and VI values decreased indicating a possible reduction in the Chlorophyll content and suggesting that the new intertidal regions are mostly covered by mud. The spatially averaged VI values show seasonal patterns, with peaks in spring and summer, coinciding with high biomass productivity periods. The largest flooded area and VI modifications occurred after 1999, suggesting that changes are associated with dredging activities performed in the main lagoon channels. This study reinforced the potential of Landsat archives to monitor coastal wetlands, highlighting their importance for coastal managers of threatened systems, and therefore helping to define management strategies about the ecological conservation of estuarine systems. PMID- 30414582 TI - Financing agricultural drought risk through ex-ante cash transfers. AB - Despite advances in drought early warning systems, forecast information is rarely used for triggering and financing early actions, such as cash transfer. Scaling up cash transfer pay-outs, and overcoming the barriers to actions based on forecasts, requires an understanding of costs resulting from False Alarms, and the potential benefits associated with appropriate early interventions. On this study, we evaluate the potential cost-effectiveness of cash transfer responses, comparing the relative costs of ex-ante cash transfers during the maize growing season to ex-post cash transfers after harvesting in Kenya. For that, we developed a forecast model using Fast-and Frugal Trees that unravels early warning relationships between climate variability, vegetation coverage, and maize yields at multiple lead times. Results indicate that our models correctly forecast low maize yield events 85% of the time across the districts studied, some already six months before harvesting. The models' performance improves towards the end of the growing season driven by a decrease of 29% in the probability of False Alarms. Overall, we show that timely cash transfers ex-ante to a disaster can often be more cost-effective than investing in ex-post expenditures. Our findings suggest that early response can yield significant cost savings, and can potentially increase the effectiveness of existing cash transfer systems. PMID- 30414583 TI - The variation of vegetation greenness and underlying mechanisms in Guangdong province of China during 2001-2013 based on MODIS data. AB - This study explored the spatiotemporal variation of vegetation greenness and the mechanisms underlying this variation in the subtropical region of Guangdong in China during 2001-2013 to obtain a better understanding of vegetation response to climate and land use/cover changes in warm-humid regions. Satellite-based vegetation indices, land use/cover data and observed weather records during 2001 2013 were used. Univariate and multivariate linear regressions were conducted to quantify the trends and variations in vegetation greenness and the relationships with climate and land use/cover changes. The results indicated that the annual mean greenness trended upward significantly in eastern and western Guangdong and downward significantly in northern Guangdong. The patterns of significant positive or negative relationships between vegetation greenness and climatic factors were observed at the sub-regional scale. In addition, our results showed that (i) vegetation greenness in Guangdong was more sensitive to changes in temperature than in precipitation, (ii) spring temperature had an important time lag effect on seasonal mean greenness in the following summer and autumn, and (iii) winter greenness depended largely on vegetation growth in the previous autumn. Furthermore, the conversion of grasslands and croplands to evergreen forests resulting from afforestation increased the vegetation greenness in eastern and western Guangdong. Overall, our results suggest that afforestation plays a dominant role in increasing vegetation cover/greenness in Guangdong whereas the effects of land use/cover change on vegetation growth are subject to climatic conditions. Thus, a better understanding of terrestrial vegetation dynamics requires considering both climate and land use/cover changes. PMID- 30414584 TI - Association between polyfluoroalkyl chemical concentrations and leucocyte telomere length in US adults. AB - Exposure to some environmental chemicals is reportedly associated with the leucocyte telomere length (LTL), but the effects of the non-occupational exposure to polyfluoroalkyl chemical (PFCs) on the LTL are not well understood. Using data from 773 participants in the National Health and Nutrition Examination Survey (NHANES) conducted in 1999-2000, we analysed the association between blood PFC concentrations and LTL. Coefficients (betas) and 95% confidence intervals (CIs) for the blood PFC concentrations in association with the LTL were estimated using multivariate linear regression models after adjustment for age, gender, race, body mass index (BMI), poverty income ratio, educational level, white blood cell count, C-reactive protein and other PFCs. The results identified a strong positive association between the blood perfluorooctane sulfonic acid (PFOS) concentration and LTL in adults, and no associations were found between the LTL and other PFCs. In the linear regression models, each increment of one standard deviation (SD) in the base-10-logarithm-transformed PFOS concentration was associated with a 21-bp increase in the LTL in the fully adjusted model (P = 0.033). Moreover, serum PFOS was associated with the LTL mainly in females and individuals aged 40-50, as demonstrated by stratified analyses. These results provide epidemiological evidence showing that environment-related levels of serum PFOS are positively associated with the LTL in adults. PMID- 30414585 TI - Dramatic hydrodynamic and sedimentary responses in Galveston Bay and adjacent inner shelf to Hurricane Harvey. AB - Hurricane Harvey, one of the worst hurricanes that hit the United States in recent history, poured record-breaking rainfall across the Houston metropolitan area. Based on a comprehensive set of data from various sources, we examined the dramatic responses in hydrodynamic and sedimentary processes of Galveston Bay to this extreme event. Using a freshwater fraction method that circumvents the uncertainties in surface runoff and groundwater discharge, the freshwater load into the bay during Harvey and the following month was estimated to be 11.1 * 109 m3, about 3 times the bay volume, which had completely refreshed the entire bay. Harvey also delivered 9.86 * 107 metric tons of sediment into the bay, equivalent to 18 years of average annual sediment load. At a site inside the San Jacinto Estuary, acute bed erosion of 48 cm followed by deposition of 22 cm of new sediment was observed from the sediment cores. Slow salinity recovery (~2 month) and a thick flood deposit (~10.5 cm average over the entire bay) had likely impacted the ecosystem in the bay and the adjacent inner shelf. Estuaries with similar bathymetric and geometric characteristics, i.e., shallow bathymetry with narrow outlets, are expected to experience similar dramatic estuarine responses while extreme precipitation events are expected to occur more frequently under the warming climate. PMID- 30414586 TI - Can a carbon emission trading scheme generate the Porter effect? Evidence from pilot areas in China. AB - "Kyoto Protocol" states that carbon market is one of three private emission reduction instruments. Since 2013 China implemented carbon emission trading scheme (ETS) in seven provinces or cities. The purpose of this paper is to investigate whether the implementation of ETS can result in the Porter effect. Based on the Porter hypothesis theory, this study employs the difference-in difference (DID) method and the improved DEA model to analyze whether ETS can bring economic dividend and environmental dividend. The empirical results specify that in the short term, ETS can significantly reduce carbon emissions in the pilot provinces, but fail to increase GDP. Therefore, ETS does not realize the Porter effect in the short term. Nevertheless, in terms of the empirical results we can find ETS plays a significant role in emission reduction. In the long term, ETS can stimulate sustainable economic dividend and environmental dividend, and achieve the Porter effect. From the test results, we can find ETS has good economic and emission reduction functions. ETS achieves the Porter effect in the long term but not in the short term. In order to achieve the Porter effect from ETS successfully, a sound carbon emission trading scheme must be established to ensure efficient carbon emission trading market. PMID- 30414587 TI - Characterizing petroleum hydrocarbons deposited on road surfaces in urban environments. AB - Petroleum hydrocarbons are a toxic pollutant group, primarily including volatile organic compounds (VOC), semi-volatile organic compounds (SVOC) and non-volatile organic compounds (NVOC). These pollutants can be accumulated on urban roads during dry periods and then washed-off by stormwater runoff in rainy days. Unlike heavy metals and polycyclic aromatic hydrocarbons, petroleum hydrocarbons have not received an equal attention in the field of stormwater pollutant processes. This paper investigated characteristics of VOC, SVOC and NVOC pollutant loads deposited on urban roads and their influential factors using a forward stepwise regression and PROMETHEE-GAIA analysis techniques. The results indicate that the loads deposited on urban roads were NVOC > SVOC > VOC. It is also noted that the degrees of factors in influencing petroleum hydrocarbons deposited on urban roads did not equal and their order was total solids > land use type > vehicular traffic > roughness of road surfaces. The research results also showed that petroleum hydrocarbons on urban road surfaces tend to be source limiting rather than transport limiting. These outcomes can contribute to petroleum hydrocarbons polluted stormwater management, such as treatment system design and stormwater modelling approach improvement. PMID- 30414588 TI - Removal of epoxiconazole and pyraclostrobin from highly contaminated effluent (grams per liter level): Comparison between ozone and solar still decontamination using real field conditions. AB - Brazilian environmental legislation obliges the aeroagriculture operators to treat the effluents generated after aircraft washing. This effluent commonly contains high levels of pesticides (g L-1) with potential to produce point source pollution. In the present study, we evaluated the efficiency of two systems on the removal of the fungicides epoxiconazole and pyraclostrobin from these effluents. The first system is based on ozonation and is currently suggested by regulatory authority. The second system is based on a pyramid-shaped solar still. The pesticides removal was monitored using liquid chromatography mass spectrometry to determine the mass quantity of both molecules throughout the treatment. After treatment with ozone treatment, the total mass of epoxiconazole decreased by 73% and pyraclostrobin decreased by 90.8%. The solar distillation system removed epoxiconazole and pyraclostrobin by >99.995 and 99.99%, respectively. The both systems proved to be efficient in the treatment of effluent containing residues of the fungicide Opera(r), a formulation containing epoxiconazole and pyraclostrobin. The solar distillation system showed a higher degree of removal and presents the advantage of operating without energy sources, reagents or consumables. PMID- 30414589 TI - Prevalence and distribution of antibiotic resistance in marine fish farming areas in Hainan, China. AB - Antibiotic resistance represents a global health crisis for humans, animals, and for the environment. Transmission of antibiotic resistance through environmental pathways is a cause of concern. In this study, quantitative PCR and culture dependent bacteriological methods were used to detect the abundance of antibiotic resistance genes (ARGs) and the quantity of culturable heterotrophic antibiotic resistant bacteria (ARB) in marine fish farming areas. The results indicated that sul and tet family genes were widely distributed in marine fish farming areas of Hainan during both rearing and harvesting periods. Specifically, sul1 and tetB were the most dominant ARGs. The total abundance of ARGs increased significantly from the rearing to the harvesting period. A total of 715 ARB strains were classified into 24 genera, within these genera Vibrio, Acinetobacter, Pseudoalteromonas, and Alteromonas are opportunistic pathogens. High bacterial resistance rate to oxytetracycline (OT) was observed. The numbers of OT- and enrofloxacin-resistant bacteria dropped significantly from rearing the period to the harvesting. The co-occurrence pattern showed that Ruegeria and tetB could be indicators of ARB and ARGs, respectively, which were found in the same module. Redundancy analysis indicated that salinity was positively correlated with the most dominant ARB, and was negatively correlated with the most dominant ARGs. These findings demonstrated the prevalence and persistence of ARGs and ARB in marine fish farming areas in China. PMID- 30414590 TI - Exploring Multi-Use potentials in the Euro-Mediterranean sea space. AB - European seas are experiencing rapid development. The anthropogenic demand for marine resources and space exerts the need for novel concepts for sustainable resource exploitation and smart space allocation. Multi-Use (MU) is an emerging concept to overcome spatial claims and support Blue Growth, however its actual potentials and current status of implementation in different sea basins is to a large extent unexplored. An analytical framework using a mixed method approach is proposed for the identification and analysis of MU potentialities in eight EU countries of the Euro-Mediterranean sea basin. The paper addresses opportunities and challenges of ten existing and potential MU combinations driven by three maritime sectors: tourism, renewable energy and Oil & Gas industry. Opportunities and challenges for MU development were presented in terms of drivers, added values, barriers and impacts. Results show that highest potential for MU development are related to tourism-driven MU combinations (e.g. pescatourism), but also emerging MU potentials exist related to Floating Offshore Wind energy and aquaculture (Gulf of Lion) and the re-use of Oil & Gas decommissioned platforms (Northern-Central Adriatic Sea). Findings were discussed for their geospatial distribution and their policy, socio-economic, technical and environmental boundary conditions. Recommendations on actions to foster MU development in the Euro-Mediterranean sea space are provided. PMID- 30414591 TI - Organic loading rate (OLR) regulation for enhancement of aerobic sludge granulation: Role of key microorganism and their function. AB - According to unique growth characteristics of various environmental microorganism specially with different substrates and their levels, aerobic sludge granulation are studied under different operation mode of influent organic loading rate (OLR), and the EPS component, sludge surface characters and functional microbes are analyzed to achieve a novel process for stable sludge granulation. Results showed that activated sludge cultivated under gradient influent OLR decreasing from 5.5 to 3.5 kgCOD m-3 d-1 achieved complete granulation with average size of 438 MUm and exopolysaccharide (PS) to protein (PN) ratio over 2.0. Meanwhile, these granules had excellent flocculability and hydrophobicity with Zeta potential and contact angle of -15 mV and 110 degrees , respectively. Principal component analysis (PCA) illustrated that microbes with function of EPS secretion enriched with decreased OLR regulation for their suitable specific growth characteristics, then promoted other microbes aggregation and sludge granulation along with the improvement of cellular surface characters and microbial niche. PMID- 30414592 TI - Medical-surgical readmissions in patients with co-occurring serious mental illness: A systematic review and meta-analysis. AB - OBJECTIVE: To estimate the relationship between comorbid serious mental illness (SMI) diagnosis and 30-day medical-surgical readmissions. METHODS: In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) we searched five databases (2012 to 2017) to identify relevant articles on the relationship between SMI diagnosis and readmissions. We used the National Institute of Health's Quality Appraisal Tool for Observational Cohort and Cross Sectional Studies guidelines to appraise studies and assess risk of bias. Data were narratively synthesized and a pooled random effects unadjusted odds ratio was estimated using meta-analysis. Heterogeneity was investigated using subgroup analysis and meta-regression. RESULTS: Our search yielded 424 articles after removing duplicates. Nine met inclusion criteria. All studies were retrospective observational cohort studies. The meta-analysis showed that people with SMI have greater odds of readmission than people without SMI (pooled OR 1.38, CI 1.23 1.56, I2 = 98.6%). There was heterogeneity in patient cohorts, study methodology, and definition of SMI. No significant possibility of publication bias was detected (Classic fail-safe N = 3480). CONCLUSION: There is a meaningful relationship between SMI diagnosis and medical-surgical readmissions. Given the prevalence of SMI in patients hospitalized for medical-surgical problems and the heterogeneity of evidence, further research on sources of variation in outcomes is critically needed. PMID- 30414593 TI - Hypothalamic-pituitary-adrenal axis feedback sensitivity in different states of back pain. AB - Pain normally signals a threat to bodily integrity and causes emotional distress. Acute pain serves a protective function, yet, when pain turns chronic, the protective function is lost. A chain of psychophysiological alterations including changes in the stress regulation system, apparent in dysfunctional activity and responsivity of the hypothalamic-pituitary-adrenal (HPA) axis, might be an important factor in this context. Moreover, maladaptive responses may be complicated by affective comorbid symptoms such as anxiety and depression, and alter nociceptive processing. However, the relationship among pain chronicity, stress regulation, and contributing components of comorbid symptomatology as well as somatosensory profiles has rarely been examined. In the present study, we obtained diurnal cortisol profiles at baseline and feedback regulation (following a dexamethasone suppression test (DST)) in subacute (SABP) and chronic (CBP) back pain patients and healthy control individuals (HC). We also assessed anxiety, depression and chronic stress levels and used quantitative sensory testing (QST) to detect sensory abnormalities. We found a hyper-suppression of cortisol following DST and thus enhanced negative stress feedback sensitivity in SABP compared to both CBP and HC. In SABP, DST-related cortisol levels were negatively associated with pain intensity, mediated by cold pain thresholds and anxiety. These data support a stress model of pain chronicity and suggest that stress responses might be indicators of individual vulnerability in the transition period of subacute pain. PMID- 30414594 TI - Accelerated DNA methylation age and the use of antihypertensive medication among older adults. AB - The discrepancy of DNA methylation age (DNAmAge) with chronological age (termed as age acceleration, AA) has been identified to be associated with many aging related health outcomes including hypertension. Since taking antihypertensive medication (AHM) could prevent aging-related diseases caused by hypertension, we hypothesized that using AHM could also reduce the AA. We examined this hypothesis among 546 males aged 55-85 years by exploring the associations of AHM use with AA and its change rate (DeltaAA) in two visits with a median follow-up of 3.86 years. Horvath DNAmAge was derived from DNA methylation profiles measured by Illumina HumanMethylation450 BeadChip and information on AHM use was collected by physician interview. A general decreasing pattern of AA was observed between the two visits. After the fully adjusting for potential covariates including hypertension, any AHM use showed a cross-sectional significant association with higher AA at each visit, as well as a longitudinal association with increased DeltaAA between visits. Particularly, relative to participants who never took any AHM, individuals with continuous AHM use had a higher DeltaAA of 0.6 year/chronological year. This finding underlines that DNAmAge and AA may not be able to capture the preventive effects of AHMs that reduce cardiovascular risks and mortality. PMID- 30414595 TI - Inflammatory markers and mediators in heart disease. PMID- 30414596 TI - PhotoAgeClock: deep learning algorithms for development of non-invasive visual biomarkers of aging. AB - Aging biomarkers are the qualitative and quantitative indicators of the aging processes of the human body. Estimation of biological age is important for assessing the physiological state of an organism. The advent of machine learning lead to the development of the many age predictors commonly referred to as the "aging clocks" varying in biological relevance, ease of use, cost, actionability, interpretability, and applications. Here we present and investigate a novel non invasive class of visual photographic biomarkers of aging. We developed a simple and accurate predictor of chronological age using just the anonymized images of eye corners called the PhotoAgeClock. Deep neural networks were trained on 8414 anonymized high-resolution images of eye corners labeled with the correct chronological age. For people within the age range of 20 to 80 in a specific population, the model was able to achieve a mean absolute error of 2.3 years and 95% Pearson and Spearman correlation. PMID- 30414597 TI - Underdosing of Surfactant for Preterm Babies with Respiratory Distress Syndrome in Clinical Practice: A Retrospective Cohort Study. AB - OBJECTIVE: To evaluate the initial doses of surfactant administered to preterm infants with respiratory distress syndrome. STUDY DESIGN: This is a retrospective cohort study of 206 preterm infants admitted in four level III neonatal intensive care units of acute tertiary care hospitals in Spain between 2013 and 2015. RESULTS: The mean initial dose of surfactant was 173.9 (37.3) mg/kg, and 47.5% of infants received a dose of 200 mg/kg +/- 10% (180-220 mg/kg), 47% less than 180 mg/kg (-10%), and 5.4% more than 220 mg/kg (+10%). Very preterm infants (<28 weeks) received higher initial doses than more mature infants, but in all cases, the mean doses were below the recommended 200 mg/kg (by 9.2% in gestational age 23-28 weeks, by 15.9% in 29-32 weeks, and by 24.3% in >32 weeks). CONCLUSION: Administration of surfactant below the prescribed dose is a frequent error in clinical practice. Inadvertently rounding down doses seems a plausible explanation. PMID- 30414598 TI - Comparing Postpartum Visit Attendance with a Scheduled 2- to 3-Week or 6-Week Visit after Delivery. AB - OBJECTIVE: To evaluate whether scheduling a 2- to 3-week versus 6-week postpartum visit results in higher visit attendance. STUDY DESIGN: We conducted a secondary analysis of a quasi-experimental before-after study to compare postpartum visit attendance after changing routine scheduling of visits from 6 weeks to 2 to 3 weeks after delivery. Secondary outcomes include patient satisfaction and breastfeeding continuation at 3 and 6 months postpartum. We collected postpartum visit information through a chart review and conducted telephonic interviews at 3 and 6 months postpartum to assess satisfaction with visit timing and breastfeeding status. We performed multivariable analyses to assess predictors of visit attendance. RESULTS: Women scheduled at 2 to 3 weeks postpartum demonstrated higher visit attendance (90.2%; 95% confidence interval [CI]: 86.6-93.9%) compared with 6 weeks (81.6%; 95% CI: 76.3-86.2%; p < 0.01). Predictors for visit attendance include postpartum visit timing, age, education, parity, prior miscarriage, and high-risk index pregnancy in multivariate analysis. Scheduling at 2 to 3 weeks postpartum increased visit completion in women who were younger and had lower educational attainment, high-risk index pregnancy, and no prior miscarriages. We found no differences in patient satisfaction or breastfeeding continuation at 3 and 6 months postpartum related to postpartum visit timing. CONCLUSION: Scheduling a 2- to 3-week postpartum visit is associated with higher attendance. PMID- 30414599 TI - First-Trimester Uterine Artery Doppler for the Prediction of Preeclampsia in Nulliparous Women: The Great Obstetrical Syndrome Study. AB - OBJECTIVE: This study aimed to estimate the performance of first-trimester uterine artery (UtA) pulsatility index (PI) for the prediction of preeclampsia (PE). METHODS: We conducted a prospective cohort study of nulliparous women with singleton gestation at 11 0/7-13 6/7 weeks. UtA-Doppler's was performed on both UtAs and the mean UtA-PI was reported in multiple of median (MoM) adjusted for gestational age. Using receiver operating characteristic curves and their area under the curves (AUC); we calculated the performance of UtA-PI for the prediction of PE. Proportional hazard models were used to develop prediction models combining UtA-PI and maternal characteristics. RESULTS: Out of 4,676 participants with completed follow-up, 232 (4.9%) developed PE, including 202 (4.3%) term and 30 (0.6%) preterm PE. Mean UtA-PI decreased with gestational age between 11 and 13 6/7 weeks (p < 0.001). First-trimester UtA-PI was associated with preterm (AUC: 0.69; 95% CI [confidence interval]: 0.57-0.80) but not with term (AUC: 0.52; 95% CI: 0.48-0.56) PE. UtA-PI combined with maternal characteristics could predict 45% of preterm PE at a false positive rate of 10%. CONCLUSION: First-trimester UtA-PI decreases with gestational age between 11 and 13 6/7 weeks and is associated with the risk of preterm but not term PE. PMID- 30414600 TI - Evaluating Fundal Dominant Contractions on Spatiotemporal Electrohysterography as a Marker for Effective Labor Contractions. AB - OBJECTIVE: To evaluate if fundal (F) dominance of the electrohysterogram is associated with vaginal delivery and lack of F dominance is associated with cesarean for labor dystocia. STUDY DESIGN: We conducted a prospective cohort study of nulliparous women in spontaneous labor at >=36 weeks. Clinicians were blinded to electrohysterography data which were in addition to standard cardiotocography. All contractions in the hour preceding diagnosis of complete cervical dilation (for women delivering vaginally) or the hour preceding the decision for cesarean were analyzed. RESULTS: Of 224 patients, 167 had evaluable data. The proportion of F dominant contractions was not different for women undergoing cesarean for labor dystocia (n = 11) compared with all others (n = 156)-88.7 +/- 10.2 versus 86.0 +/- 11.4%; p = 0.44. Results were similar when comparing the cesarean for labor dystocia group to those undergoing cesarean for other indications (n = 10) and vaginal deliveries (n = 146)-88.7 +/- 10.2 versus 86.5 +/- 10.0 versus 85.9 +/- 11.5%; p = 0.74. CONCLUSION: We were unable to confirm our earlier finding that F dominance of the electrohysterogram is associated with vaginal delivery and lack of F dominance is associated with cesarean for dystocia. PMID- 30414601 TI - Longitudinal Measurements of Resting Energy Expenditure by Indirect Calorimetry in Healthy Term Infants during the First 2 Months of Life. AB - OBJECTIVE: To determine longitudinal measurements of resting energy expenditure (REE) by indirect calorimetry (IC) in healthy term infants during the first 2 months of life. STUDY DESIGN: An outpatient prospective pilot study was performed in healthy term infants to estimate REE by measuring expired gas fractions of oxygen (O2) and carbon dioxide (CO2) with IC in a respiratory and metabolic steady state. RESULTS: A total of 30 measurements were performed. Fourteen subjects completed measurements at both 1 and 2 months of life, and two subjects had only measurements made at 1 month of life. Mean REE values were 64.1 +/- 12.7 and 58.4 +/- 14.3 kcal/kg/d at 1 and 2 months of age, respectively. Mean O2 consumption and CO2 production measurements were 9.3 +/- 2.0 and 7.7 +/- 1.2 mL/kg/min and 8.1 +/- 2.2 and 6.4 +/- 1.1 mL/kg/min at 1 and 2 months of age, respectively. CONCLUSION: This pilot study demonstrates longitudinal measurements of REE by IC in healthy term infants during the first 2 months of life. We also demonstrate that, overall, there is consistency in REE values in this population, with a likely decrease in individual longitudinal measurements over the first 2 months of life. PMID- 30414602 TI - Gender Differences in Academic Rank and NIH Funding among Academic Maternal-Fetal Medicine Physicians in the United States. AB - OBJECTIVE: This article evaluates gender differences in academic rank and National Institutes of Health (NIH) funding among academic maternal-fetal medicine (MFM) physicians. STUDY DESIGN: This was a cross-sectional study of board-certified academic MFM physicians. Physicians were identified in July 2017 from the MFM fellowship Web sites. Academic rank and receipt of any NIH funding were compared by gender. Data on potential confounders were collected, including years since board certification, region of practice, additional degrees, number of publications, and h-index. RESULTS: We identified 659 MFM physicians at 72 institutions, 312 (47.3%) male and 347 (52.7%) female. There were 246 (37.3%) full, 163 (24.7%) associate, and 250 (37.9%) assistant professors. Among the 154 (23.4%) MFM physicians with NIH funding, 89 (57.8%) were male and 65 (42.2%) were female (p = 0.003). Adjusting for potential confounders, male MFM physicians were twice as likely to hold a higher academic rank than female MFM physicians (adjusted odds ratio [aOR], 2.04 [95% confidence interval, 1.39-2.94], p < 0.001). There was no difference in NIH funding between male and female MFM physicians (aOR, 1.23 [0.79-1.92], p = 0.36). CONCLUSION: Compared with female academic MFM physicians, male academic MFM physicians were twice as likely to hold a higher academic rank but were no more likely to receive NIH funding. PMID- 30414603 TI - Assessing Maternal and Fetal Risks Associated with Prolonged Induction of Labor. AB - OBJECTIVE: To assess whether prolonged induction of labor was associated with increased maternal or neonatal morbidity. STUDY DESIGN: We performed a retrospective cohort study of women undergoing induction of labor at a single institution. We included women with singletons >= 36 weeks with initial cervical dilation <=4 cm. Prolonged induction of labor was defined as lasting > 36 hours from the time of initial method to delivery. A 2-to-1 propensity score-matched analysis was performed between women with and those without prolonged induction of labor. Maternal outcomes were cesarean delivery, chorioamnionitis, endometritis, postpartum hemorrhage, severe perineal laceration, and length of postpartum admission. Neonatal outcomes included Apgar scores, umbilical artery pH, and neonatal intensive care admission. RESULTS: Among 2,021 women, 407 (20.1%) had a prolonged induction. In unadjusted analyses, prolonged induction of labor was associated with increased cesarean delivery and chorioamnionitis. After 2-to-1 propensity score matching, there were 267 women with prolonged induction and 424 controls. Women with prolonged induction of labor had higher rates of cesarean delivery (35.6 vs. 16%, p < 0.001), chorioamnionitis (14.2 vs. 4.7%, p < 0.001), endometritis (6.4 vs. 1.9%, p = 0.002), and postpartum hemorrhage (18.8 vs. 11.9%, p = 0.008). There were no significant differences in neonatal outcomes. CONCLUSION: Overall length of induction impacts maternal outcome. PMID- 30414604 TI - Manipulation under Anesthesia: Does Polyethylene Thickness Matter? AB - Total knee arthroplasty (TKA) has been established as the most effective treatment for end-stage, symptomatic osteoarthritis of the knee. However, improper polyethylene size selection has been proposed to predispose patients to postoperative stiffness following TKA. The aim of this study is to evaluate if there is a correlation between the use of the thinnest tibial implant thickness and implant manufacturer with the likelihood of undergoing manipulation under anesthesia (MUA). A retrospective review of unilateral TKAs performed between January 2012 and November 2015 was performed. Each knee implant system was normalized by total tibial component thickness for each individual implant system (metal back plus polyethylene) and reaggregated to assess the difference in MUA rates when comparing the thinnest tibial component thickness against the next two sizes. Subset analysis was performed comparing the thinnest tibial component thickness for each individual implant system versus (1) all other tibial component sizes and (2) tibial components one and two sizes larger. A total of 2,728 patients were retrospectively evaluated, of which 71 (2.60%) underwent MUA. Combined tibial component thickness ranged from 8 to 21 mm. When aggregated together to compare the MUA rate between the thinnest liner and the next two sizes, no statistically significant difference was observed (p = 1). Subset analysis demonstrated inconsistent significant differences in MUA rates. Our results suggest that the polyethylene liner thickness alone is not a predictor of postoperative knee stiffness necessitating MUA. When selecting a polyethylene liner, a proper fit maximizing flexion/extension stability is the most crucial factor. PMID- 30414605 TI - What Kinds of Posterior Cruciate Ligament Bundles Are Preserved in Cruciate Retaining Total Knee Arthroplasty? A Three-Dimensional Morphology Study. AB - In this study, the effects of tibial bone cutting on the attachment area of the posterior cruciate ligament (PCL), including both the anterolateral bundle (ALB) and posteromedial bundle (PMB), in cruciate-retaining total knee arthroplasty (CR TKA) were simulated using a three-dimensional (3D) model of the tibial reconstruction. A total of 40 knees with medial osteoarthritis in patients scheduled for TKA were evaluated. Following surface registration of 3D computed tomography (CT) and 3D magnetic resonance imaging (MRI) models of the tibia with the PCL, the area of PCL attachment was calculated. Tibial bone cutting in the 3D CT model was simulated at 8 and 10 mm distal to the center of the lateral articular surfaces of the tibia and with posterior tibial slope angles of 0, 7, and 10 degrees. The percentages of the ALB and PMB tibial attachment areas that remained after cutting at 8 mm were, respectively, 21.8 +/- 19.7% and 86.3 +/- 17.7% with 0 degrees, 9.5 +/- 10.4% and 64.1 +/- 23.6% with 7 degrees, and 8.1 +/ 6.7% and 51 +/- 25.3% with 10 degrees. These results suggest that only half of the PCL attachment area was left after the bone cut simulation. Complete preservation of the ALB and PMB attachment areas requires appropriate selection of surgical procedures and devices. PMID- 30414606 TI - Cognitive Training for Robotic Arm-Assisted Unicompartmental Knee Arthroplasty through a Surgical Simulation Mobile Application. AB - Advances in mobile device technology combined with the implementation of surgical simulation have led to the development of novel applications (apps) as a potential learning tool for surgical trainees. Touch Surgery (TS) (Kinosis Limited, London, United Kingdom) is a mobile-based app that combines cognitive task analysis with a virtual reality medium to familiarize the user with a surgical procedure through interactive rehearsal. The purpose of this study was to compare the educational efficacy of the TS app with a traditional paper-based learning program in performing a robotic arm-assisted unicompartmental knee arthroplasty. Twelve participants (four interns, four residents, four adult reconstructive fellows) were randomized to a paper-based technique guide or learning modules from the Mako Partial Knee (Stryker, Mahwah, NJ) TS app. Trainees were subjected to a baseline pretest. After preparing with the allocated training tool, participants completed an immediate posttest followed by a retention test administered 3 weeks later. The TS simulation group demonstrated greater improvement (22% score increase; p = 0.001) in posttest assessment compared with the control group (10% score increase; p = 0. 09). The TS simulation group demonstrated better information recall compared with the control group based on the score differential following the 3-week retention test. This randomized comparative study demonstrated that the TS app was better than traditional paper-based learning for both immediate posttest performance and long term information recall of the Mako robotic arm-assisted unicompartmental knee arthroplasty. Surgical simulation apps may be an effective learning tool for surgical trainees. PMID- 30414607 TI - Prediction of hemodynamic fluctuations after induction of general anesthesia using propofol in non-cardiac surgery: a retrospective cohort study. AB - BACKGROUND: Although propofol is a common anesthetic agent for the induction of general anesthesia, hemodynamic fluctuations are occasionally prominent during induction/intubation. The aims of this study were to determine the influential factors on enhanced hemodynamic fluctuation and to establish a prediction formula to quickly determine the dose of propofol to protect against hemodynamic fluctuations. METHODS: This retrospective cohort study patients (n = 2097) were 18 years or older. They underwent general anesthesia induction using propofol and orotracheal intubation for non-cardiac surgery at Kyushu University Hospital during April 2015 to March 2016. Preoperative patient clinical information was collected from anesthesia preoperative evaluation records. Intraoperative data were obtained from computerized anesthesia records. If patients' post-induction mean arterial blood pressure (MAP) decreased or increased 30% or more from their pre-induction MAP, they were determined to have enhanced hemodynamic fluctuations. Unconditional logistic regression was used to assess the adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Structural equation modeling (SEM) was conducted to simultaneously examine the direct and indirect effect (path coefficient = r) of potential variables. RESULTS: In the SEM analysis, age was significantly associated with enhanced hemodynamic fluctuations (adjusted odds ratio = 1.008, 95% CI = 1.001-1.015, P = 0.03). Age (path coefficient (r) = - 0.0113, 95% CI = - 0.0126-0.010, P < 0.001), American Society of Anesthesiologists physical status (ASA-PS) (r = - 0.0788, 95% CI = - 0.1431 0.0145, P = 0.02), sex (r = 0.057, 95% CI = 0.0149-0.9906, P = 0.01), and fentanyl dose (r = 0.1087, 95% CI = 0.0707-0.1467, P < 0.001) influenced the dose of propofol in induction. The prediction formula of "Propofol dose (mg) = [2.374 0.0113 * age (year) - 0.0788 (if ASA-PS 3 or 4) + 0.057 (if female) + 0.1087 * fentanyl dose (MUg/kg)] * body weight (kg)" was derived. CONCLUSIONS: Age was associated with hemodynamic fluctuations in induction. Although the prediction formula is considered to be acceptable, future studies validating whether it can decrease patients' risk of enhanced hemodynamic fluctuations in clinical situations are necessary. PMID- 30414609 TI - Efficacy of continuous in-wound infusion of levobupivacaine and ketorolac for post-caesarean section analgesia: a prospective, randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: In-wound catheters for infusion of local anaesthetic for post caesarean section analgesia are well tolerated in parturients. Few studies have examined continuous in-wound infusion of a combination of local anaesthetic and non-steroidal anti-inflammatory drug for post-caesarean section analgesia. This single centre study evaluated post-operative analgesic efficacy and piritramide sparing effects of continuous in-wound infusion of either local anaesthetic or non-steroidal anti-inflammatory agent, or the combination of both, versus saline placebo, when added to systemic analgesia with paracetamol. METHODS: After National Ethical Board approval, 59 pregnant women scheduled for non-emergency caesarean section were included in this prospective, randomised, double-blind, placebo-controlled study. The parturients received spinal anaesthesia with levobupivacaine and fentanyl. Post-operative analgesia to 48 h included paracetamol 1000 mg intravenously every 6 h, with the studied agents as in-wound infusions. Rescue analgesia with piritramide was available as needed, titrated to 2 mg intravenously. Four groups were compared, using a subcutaneous multi-holed catheter connected to an elastomeric pump running at 5 mL/h over 48 h. The different in-wound infusions were: levobupivacaine 0.25% alone; ketorolac tromethamine 0.08% alone; levobupivacaine 0.25% plus ketorolac tromethamine 0.08%; or saline placebo. The primary outcome was total rescue piritramide used at 24 h and 48 h post-operatively, under maintained optimal post-caesarean section analgesia. RESULTS: Compared to placebo in-wound infusions, ketorolac alone and levobupivacaine plus ketorolac in-wound infusions both significantly reduced post-operative piritramide consumption at 24 h (p = 0.003; p < 0.001, respectively) and 48 h (p = 0.001; p < 0.001). Compared to levobupivacaine, levobupivacaine plus ketorolac significantly reduced post-operative piritramide consumption at 24 h (p = 0.015) and 48 h (p = 0.021). For levobupivacaine versus ketorolac, no significant differences were seen for post-operative piritramide consumption at 24 h and 48 h (p = 0.141; p = 0.054). CONCLUSION: Continuous in wound infusion with levobupivacaine plus ketorolac provides greater opioid sparing effects than continuous in-wound infusion with levobupivacaine alone. TRIAL REGISTRATION: German Clinical Trials Register: retrospectively registered on 30 July, 2014, DRKS 00006559 . PMID- 30414608 TI - High flow nasal therapy in perioperative medicine: from operating room to general ward. AB - BACKGROUND: High flow nasal therapy (HFNT) is a technique in which humidified and heated gas is delivered to the airways through the nose via small nasal prongs at flows that are higher than the rates generally applied during conventional oxygen therapy. The delivered high flow rates combine mixtures of air and oxygen and enable different inspired oxygen fractions ranging from 0.21 to 1. HFNT is increasingly used in critically ill adult patients, especially hypoxemic patients in different clinical settings. MAIN BODY: Noninvasive ventilation delivers positive pressure (end-expiratory and inspiratory pressures or continuous positive airway pressure) via different external interfaces. In contrast, HFNT produces different physiological effects that are only partially linked to the generation of expiratory positive airway pressure. HFNT and noninvasive ventilation (NIV) are interesting non-invasive supports in perioperative medicine. HFNT exhibits some advantages compared to NIV because HFNT is easier to apply and requires a lower nursing workload. Tolerance of HFNT remains a matter of intense debate, and it may be related to selected parameters. Patients receiving HFNT and their respiratory patterns should be closely monitored to avoid delays in intubation despite correct oxygenation parameters. CONCLUSION: HFNT seems to be an interesting noninvasive support in perioperative medicine. The present review provides anesthesiologists with an overview of current evidence and practical advice on the application of HFNT in perioperative medicine in adult patients. PMID- 30414610 TI - Periprosthetic infection is the major indication for TKA revision - experiences from a university referral arthroplasty center. AB - BACKGROUND: We hypothesized, that periprosthetic joint infection (PJI) accounts for the major proportion of first (primary) and repeated (secondary) Total Knee Arthroplasty revisions at our university referral arthroplasty center. METHODS: One thousand one hundred forty-three revisions, performed between 2008 and 2016 were grouped into primary (55%) and secondary (45%) revisions. The rate of revision indications was calculated and indications were categorized by time after index operation. The odds ratios of the indications for primary versus secondary revision were calculated. RESULTS: In the primary revision group PJI accounted for 22.3%, instability for 20.0%, aseptic loosening for 14.9% and retropatellar arthrosis for 14.2%. PJI (25.6%) was the most common indication up to 1 year after implantation, retropatellar arthrosis (26.8%) 1-3 years and aseptic loosening (25.6%) more than 3 years after implantation. In the secondary revision group PJI accounted for 39.7%, aseptic loosening for 16.2% and instability for 13.2%. PJI was the most common indication at any time of revision with 43.8% up to one, 35.4% 1-3 years and 39.4% more the 3 years after index operation. The odds ratios in repeated revision were 2.32 times higher (p = 0.000) for PJI. For instability and retropatellar arthrosis the odds ratios were 0.60 times (p = 0.006) and 0.22 times (p = 0.000) lower. CONCLUSIONS: PJI is the most common indication for secondary TKA revision and within one year after primary TKA. Aseptical failures such as instability, retropatellar arthrosis and aseptical loosening are the predominant reasons for revision more than one year after primary TKA. PMID- 30414611 TI - Identification of key genes and miRNAs markers of papillary thyroid cancer. AB - OBJECTIVE: In this study, crucial genes and microRNAs (miRNAs) associated with the progression, staging, and prognosis of papillary thyroid cancer (PTC) were identified. METHODS: Four PTC datasets, including our own mRNA-sequencing (mRNA seq) dataset and three public datasets downloaded from Gene Expression Omnibus and The Cancer Genome Atlas, were used to analyze differentially expressed genes (DEGs) and miRNAs (DEMs) between PTC tumor tissues and paired normal tissues (control). Gene ontology (GO) terms and pathways associated with these DEGs were identified, and protein-protein interactions (PPIs) were analyzed. Additionally, an miRNA-mRNA regulatory network was constructed and the functions of DEMs were explored. Finally, miRNAs/mRNAs associated with tumor staging and prognosis were identified. The expression levels of several key genes and miRNAs were validated by qRT-PCR. RESULTS: Numerous DEGs and DEMs were identified between tumor and control groups in four datasets. The DEGs were significantly enriched in cell adhesion and cancer-related GO terms and pathways. In the constructed PPI network, ITGA2, FN1, ICAM1, TIMP1 and CDH2 were hub proteins. In the miRNA-mRNA negative regulatory networks, miR-204-5p regulated the largest number of target genes, such as TNFRSF12A. miR-146b, miR-204, miR-7-2, and FN1 were associated with tumor stage in PTC, and TNFRSF12A and CLDN1 were related to prognosis. CONCLUSIONS: Our results suggested the important roles of ITGA2, FN1, ICAM1, TIMP1 and CDH2 in the progression of PTC. miR-204-5p, miR-7-2, and miR-146b are potential biomarkers for PTC staging and FN1, CLDN1, and TNFRSF12A may serve as markers of prognosis in PTC. PMID- 30414612 TI - Integrative analysis of single-cell expression data reveals distinct regulatory states in bidirectional promoters. AB - BACKGROUND: Bidirectional promoters (BPs) are prevalent in eukaryotic genomes. However, it is poorly understood how the cell integrates different epigenomic information, such as transcription factor (TF) binding and chromatin marks, to drive gene expression at BPs. Single-cell sequencing technologies are revolutionizing the field of genome biology. Therefore, this study focuses on the integration of single-cell RNA-seq data with bulk ChIP-seq and other epigenetics data, for which single-cell technologies are not yet established, in the context of BPs. RESULTS: We performed integrative analyses of novel human single-cell RNA seq (scRNA-seq) data with bulk ChIP-seq and other epigenetics data. scRNA-seq data revealed distinct transcription states of BPs that were previously not recognized. We find associations between these transcription states to distinct patterns in structural gene features, DNA accessibility, histone modification, DNA methylation and TF binding profiles. CONCLUSIONS: Our results suggest that a complex interplay of all of these elements is required to achieve BP-specific transcriptional output in this specialized promoter configuration. Further, our study implies that novel statistical methods can be developed to deconvolute masked subpopulations of cells measured with different bulk epigenomic assays using scRNA-seq data. PMID- 30414613 TI - Systematic review of single-incision versus conventional multiport laparoscopic surgery for sigmoid colon and rectal cancer. AB - OBJECTIVES: To explore whether single-incision laparoscopic surgery (SILS) has the better short-term clinical and pathological outcomes than conventional multiport laparoscopic surgery (CLS) for sigmoid colon and rectal cancer. METHODS: A literature investigation of MEDLINE, PubMed, Ovid, Embase, Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure (CNKI), Chinese Biological Medicine (CBM), and Wanfang databases for relevant researches was performed. Fixed effects and random effects models were used to calculate the corresponding outcomes. Standardized mean difference and risk ratio were calculated for continuous and dichotomous variables separately. RESULTS: Nine clinical controlled trials were composed of two randomized clinical trials and seven non-randomized clinical trials with a total of 829 patients. Two hundred ninety-nine (36.1%) patients underwent SILS, and 530 (63.9%) patients underwent CLS. The meta-analysis showed that SILS had more lymph node resection (SMD - 0.25, 95% CI - 0.50 to - 0.002) and less defecation time (SMD - 0.46, 95% CI - 0.75 to - 0.17), exhaust time (SMD - 0.46, 95% CI - 0.75 to - 0.18), and hospital stay (SMD - 0.30, 95% CI - 0.45 to - 0.15 than CLS. SILS was also accompanied with shorter incision length (SMD - 2.46, 95% CI - 4.02 to - 0.90), less pain score (SMD - 0.56, 95% CI - 0.91 to - 0.21), and lower complication rate (RR 0.66, 95% CI 0.47 to 0.91). Blood loss, operative time, distal margin, conversion rate, anastomotic fistula, readmission, local recurrence, and distant metastasis showed no statistical differences in two groups. In all subgroup analysis, SILS also had advantages of incision length, operative time, defecation time, exhaust time, and hospitalization time than CLS. CONCLUSION: SILS could be a more safe and reliable surgical technique than CLS for sigmoid colon and rectal cancer. However, further high-quality studies between these two techniques need to be further developed. PMID- 30414614 TI - Contributions of symptomatic osteoarthritis and physical function to incident cardiovascular disease. AB - BACKGROUND: Osteoarthritis (OA) is associated with worsening physical function and a high prevalence of comorbid health conditions. In particular, cardiovascular disease (CVD) risk is higher in individuals with OA than the general population. Limitations in physical function may be one pathway to the development of CVD among individuals with OA. This study evaluated associations of symptomatic knee OA (sxKOA), baseline physical function and worsening of function over time with self-reported incident CVD in a community-based cohort. METHODS: Our sample consisted of individuals from the Johnston County Osteoarthritis Project who did not report having CVD at baseline. Variables used to evaluate physical function were the Health Assessment Questionnaire (HAQ), time to complete 5 chair stands, and the 8-ft walk. Worsening function for these variables was defined based on previous literature and cutoffs from our sample. Logistic regression analyses examined associations of sxKOA, baseline function and worsening of function over time with self-reported incident CVD, unadjusted and adjusted for relevant demographic and clinical characteristics. RESULTS: Among 1709 participants included in these analyses, the mean age was 59.5 +/- 9.5 years, 63.6% were women, 15% had sxKOA, and the follow up time was 5.9 +/- 1.2 years. About a third of participants reported worsening HAQ score, about two fifths had worsened chair stand time, half had worsened walking speed during the 8-ft walk, and 16% self-reported incident CVD. In unadjusted analyses, sxKOA, baseline function, and worsening function were all associated with self-reported incident CVD. In multivariable models including all of these variables, sxKOA was not associated with incident CVD, but worsening function was significantly associated with increased CVD risk, for all three functional measures: HAQ odds ratio (OR) = 2.49 (95% confidence interval (CI) 1.90-3.25), chair stands OR = 1.58 (95% CI 1.20-2.08), 8-ft walk OR = 1.53 (95%CI 1.15-2.04). These associations for worsening function remained in models additionally adjusted for demographic and clinical characteristics related to CVD risk. CONCLUSIONS: The association between symptomatic knee osteoarthritis and cardiovascular disease risk was explained by measures of physical function. This highlights the importance of physical activity and other strategies to prevent functional loss among individuals with symptomatic knee osteoarthritis. PMID- 30414615 TI - The effect of statin treatment on circulating coenzyme Q10 concentrations: an updated meta-analysis of randomized controlled trials. AB - BACKGROUND: The effect of statin treatment on circulating coenzyme Q10 (CoQ10) has been studied in numerous randomized controlled trails (RCTs). However, whether statin treatment decreases circulating CoQ10 is still controversial. METHODS: PubMed, EMBASE, and the Cochrane Library were searched to identify RCTs to investigate the effect of statin treatment on circulating CoQ10. We calculated the pooled standard mean difference (SMD) using a fixed effect model or random effect model to assess the effect of statin treatment on circulating CoQ10. The methodological quality of the studies was determined according to the Cochrane Handbook. Publication bias was evaluated by a funnel plot, the Egger regression test, and the Begg-Mazumdar correlation test. RESULTS: Twelve RCTs with a total of 1776 participants were evaluated. Compared with placebo, statin treatment resulted in a reduction of circulating CoQ10 (SMD, - 2.12; 95% CI, - 3.40 to - 0.84; p = 0.001), which was not associated with the duration of statin treatment (Exp, 1.00; 95% CI, 0.97 to 1.03; p = 0.994). Subgroup analysis demonstrated that both lipophilic statins (SMD, - 1.91; 95% CI, - 3.62 to 0.2; p = 0.017) and hydrophilic statins (SMD, - 2.36; 95% CI, - 4.30 to - 0.42; p = 0.028) decreased circulating CoQ10, and no obvious difference was observed between the two groups (SMD, - 0.20; 95% CI, - 0.208 to 0.618; p = 0.320). In addition, both low-middle intensity statins (SMD, - 2.403; 95% CI, - 3.992 to - 0.813; p < 0.001) and high intensity statins (SMD, - 1.727; 95% CI, - 2.746 to - 0.709; p < 0.001) decreased circulating CoQ10. Meta-regression showed that the effect of statin on decreasing circulating CoQ10 was not closely associated with the duration of statin treatment (Exp, 1.00; 95% CI, 0.97 to 1.03; p = 0.994). CONCLUSIONS: Statin treatment decreased circulating CoQ10 but was not associated with the statin solution, intensity, or treatment time. The findings of this study provide a potential mechanism for statin-associated muscle symptoms (SAMS) and suggest that CoQ10 supplementation may be a promising complementary approach for SAMS. PMID- 30414616 TI - Enhanced biosynthesis of arbutin by engineering shikimate pathway in Pseudomonas chlororaphis P3. AB - BACKGROUND: Arbutin is a plant-derived glycoside with potential antioxidant, antibacterial and anti-inflammatory activities. Currently, it is mainly produced by plant extraction or enzymatic processes, which suffers from expensive processing cost and low product yield. Metabolic engineering of microbes is an increasingly powerful method for the high-level production of valuable biologicals. Since Pseudomonas chlororaphis has been widely engineered as a phenazine-producing platform organism due to its well-characterized genetics and physiology, and faster growth rate using glycerol as a renewable carbon source, it can also be engineered as the cell factory using strong shikimate pathway on the basis of synthetic biology. RESULTS: In this work, a plasmid-free biosynthetic pathway was constructed in P. chlororaphis P3 for elevated biosynthesis of arbutin from sustainable carbon sources. The arbutin biosynthetic pathway was expressed under the native promoter Pphz using chromosomal integration. Instead of being plasmid and inducer dependent, the metabolic engineering approach used to fine-tune the biosynthetic pathway significantly enhanced the arbutin production with a 22.4-fold increase. On the basis of medium factor optimization and mixed fed-batch fermentation of glucose and 4 hydroxybenzoic acid, the engineered P. chlororaphis P3-Ar5 strain led to the highest arbutin production of 6.79 g/L with the productivity of 0.094 g/L/h, with a 54-fold improvement over the initial strain. CONCLUSIONS: The results suggested that the construction of plasmid-free synthetic pathway displays a high potential for improved biosynthesis of arbutin and other shikimate pathway derived biologicals in P. chlororaphis. PMID- 30414617 TI - Treatment of osteoarthritis of the elbow with open or arthroscopic debridement: a narrative review. AB - BACKGROUND: Elbow osteoarthritis (OA) is a common disabling condition because of pain and loss of motion. Open and arthroscopic debridement are the preferred treatment, however there is no consensus on which treatment modality is suited to which category of patient or stage of disease. The objective of this study was to narratively review the literature for a more comprehensive understanding of its treatment options and associated outcomes, trying to provide a better treatment plan. METHODS: The PubMed database, EMBASE, Cochrane Library, and Google Scholar were searched, using the keywords (elbow [title/abstract] and osteoarthritis [title/abstract] and (surgery or open or arthroscop* or debridement or ulnohumeral arthroplasty) including all possible studies with a set of inclusion and exclusion criteria. RESULTS: A total of 229 studies were identified. Twenty one articles published between 1994 and 2016 satisfied the inclusion and exclusion criteria including 651 elbows in 639 patients. After comparison, mean postoperative improvement in (ROM) was 28.6 degrees and 23.3 degrees ,Mayo elbow performance score/index(MEPS/MEPI) 31 and 26.8 and the total complication rate was 37(11.5%), and 18(5.5%) for open and arthroscopic procedure. CONCLUSIONS: This narrative review could not provide an insight on which surgical procedure is superior to the other due to the poor orthopedics literature. However, from the data we obtained the open and arthroscopic debridement procedures seem to be safe and effective in the treatment of elbow OA. The optimal surgical intervention for the treatment of symptomatic elbow OA should be determined depending on patients' conditions. PMID- 30414619 TI - Selective impairment of attentional set shifting in adults with ADHD. AB - BACKGROUND: Task switch protocols are frequently used in the assessment of cognitive control, both in clinical and non-clinical populations. These protocols frequently confound task switch and attentional set shift. The current study investigated the ability of adult ADHD patients to shift attentional set in the context of switching tasks. METHOD: We tested 38 adults with ADHD and 39 control adults with an extensive diagnostic battery and a task switch protocol without proactive interference. The experiment combined orthogonally task-switch vs. repetition, and attentional set shift vs. no shift. Each experimental stimulus had global and local features (Hierarchical/"Navon" stimuli), associated with corresponding attentional sets. RESULTS: ADHD patients were slower than controls in task switch trials with a simultaneous shift of attention between global/local attentional sets. This also correlated significantly with diagnostic scales for ADHD symptoms. The patients had more variable reaction times, but when the attentional set was kept constant neither were they significantly slower nor showed higher task switch costs. CONCLUSION: ADHD is associated with a deficit in flexible deployment of attention to varying sources of stimulus information. PMID- 30414618 TI - Biomass from microalgae: the potential of domestication towards sustainable biofactories. AB - Interest in bulk biomass from microalgae, for the extraction of high-value nutraceuticals, bio-products, animal feed and as a source of renewable fuels, is high. Advantages of microalgal vs. plant biomass production include higher yield, use of non-arable land, recovery of nutrients from wastewater, efficient carbon capture and faster development of new domesticated strains. Moreover, adaptation to a wide range of environmental conditions evolved a great genetic diversity within this polyphyletic group, making microalgae a rich source of interesting and useful metabolites. Microalgae have the potential to satisfy many global demands; however, realization of this potential requires a decrease of the current production costs. Average productivity of the most common industrial strains is far lower than maximal theoretical estimations, suggesting that identification of factors limiting biomass yield and removing bottlenecks are pivotal in domestication strategies aimed to make algal-derived bio-products profitable on the industrial scale. In particular, the light-to-biomass conversion efficiency represents a major constraint to finally fill the gap between theoretical and industrial productivity. In this respect, recent results suggest that significant yield enhancement is feasible. Full realization of this potential requires further advances in cultivation techniques, together with genetic manipulation of both algal physiology and metabolic networks, to maximize the efficiency with which solar energy is converted into biomass and bio products. In this review, we draft the molecular events of photosynthesis which regulate the conversion of light into biomass, and discuss how these can be targeted to enhance productivity through mutagenesis, strain selection or genetic engineering. We outline major successes reached, and promising strategies to achieving significant contributions to future microalgae-based biotechnology. PMID- 30414620 TI - Aircraft noise and self-assessed mental health around a regional urban airport: a population based record linkage study. AB - BACKGROUND: Limited evidence suggests that residential exposure to aircraft noise negatively influences population mental health around large airports, but it is not known whether the same is true for smaller airports. We investigated whether residential exposure to aircraft noise near a regional urban airport was associated with risk of chronic self-assessed mental ill health. METHODS: This is a cross-sectional study of 198,532 people aged 18 years and over living in Belfast, United Kingdom, enumerated at the 2011 Census. Residential exposure to aircraft noise (LAeq,16h) was assessed by linking Census records with modelled noise contours surrounding George Best Belfast City Airport (c.42,000 annual aircraft movements). Associations between noise and mental ill health were estimated using multiple logistic regression adjusting for demographic characteristics, socio-economic status and comorbidity. RESULTS: Prevalence of self-assessed mental ill health was greater in high noise (>=57 dB) compared to low noise (< 54 dB) areas (12.4% vs. 9.7%). We found no association between aircraft noise and risk of mental ill health after adjustment for socio-economic status (high vs. low noise odds ratio: 1.03 CI: 0.93, 1.14). DISCUSSION: Associations between aircraft noise and mental health have been reported near large airports at similar average noise levels to those observed here. Our findings indicate that the noise environment around this smaller airport (with fewer flights and no night flights) has little influence on population mental health. PMID- 30414621 TI - Integrated treatment for autonomic paraneoplastic syndrome improves performance status in a patient with small lung cell carcinoma: a case report. AB - BACKGROUND: Paraneoplastic neurological syndromes (PNS) are rare disorders associated with cancer and are believed to be immune mediated. Patients with autonomic PNS suffer from variable combinations of parasympathetic and sympathetic failure. Autonomic PNS are usually associated with other PNS, such as encephalomyelitis and sensory neuropathy; however, autonomic symptoms may rarely manifest as PNS symptoms. Autonomic symptoms, therefore, may be overlooked in patients with cancer. CASE PRESENTATION: We described a 65-year-old Japanese man who was diagnosed with autonomic PNS due to small-cell lung carcinoma (SCLC) with Eastern Cooperative Oncology Group (ECOG) performance status 3, who suffered from orthostatic hypotension, and urinary retention needing a urethral balloon. Laboratory studies showed decreased levels of noradrenaline, and were positive for anti-ganglionic acetylcholine receptor antibody, type 1 antineuronal nuclear antibody, and sry-like high mobility group box 1 antibody. Nerve conduction evaluations and 123I-metaiodobenzylguanidine myocardial scintigraphy showed no abnormalities. Abdominal contrast-enhanced computed tomography revealed marked colonic distention. The patient's autonomic symptoms resolved following integrated treatment (symptomatic treatment, immunotherapy, and additional chemotherapy) enabling the patient to walk, remove the urethral balloon, and endure further chemotherapy. ECOG performance status remained at 1, 10 months after admission. CONCLUSIONS: Integrated treatment for autonomic PNS may improve autonomic symptoms and ECOG performance status of patients with cancer. PMID- 30414622 TI - Tropical summer induces DNA fragmentation in boar spermatozoa: implications for evaluating seasonal infertility. AB - Summer infertility continues to undermine pig productivity, costing the pig industry millions in annual losses. The boar's inefficient capacity to sweat, non pendulous scrotum and the extensive use of European breeds in tropical conditions, can make the boar particularly vulnerable to the effects of heat stress; however, the link between summer heat stress and boar sperm DNA damage has not yet been demonstrated. Semen from five Large White boars was collected and evaluated during the early dry, late dry and peak wet seasons to determine the effect of seasonal heat stress on the quality and DNA integrity of boar spermatozoa. DNA damage in spermatozoa during the peak wet was 16-fold greater than during the early dry and nearly 9-fold greater than during the late dry season. Sperm concentration was 1.6-fold lower in the peak wet than early dry whereas no difference was found across several motility parameters as determined by computer-assisted sperm analysis. These results demonstrate that tropical summer (peak wet season) induces DNA damage and reduces concentration without depressing motility in boar spermatozoa, suggesting that traditional methods of evaluating sperm motility may not detect inherently compromised spermatozoa. Boar management strategies (such as antioxidant supplementation) need to be developed to specifically mitigate this problem. PMID- 30414623 TI - Expression and regulation of high mobility group AT-hook 1 (HMGA1) during ovulation and luteinisation in rat ovary. AB - High mobility group AT-hook 1 (HMGA1) is able to regulate gene expression and function as a tumour suppressor. The spatiotemporal expression pattern of HMGA1 was investigated in this study. Immature female rats (22-23 days old) were treated with 10 IU, s.c., pregnant mare's serum gonadotrophin to stimulate follicular development, followed 48 h later by injection with 5 IU, s.c., human chorionic gonadotrophin (hCG). Whole ovaries or granulosa cells were collected at various times after hCG administration (n = 3 per time point). Real-time polymerase chain reaction and western blot analysis revealed that HMGA1 was highly stimulated in the ovary by 4-12 h after hCG treatment. In situ hybridisation analysis demonstrated that Hmga1 mRNA expression was induced in granulosa cells between 8 and 12 h after hCG treatment. There was negligible Hmga1 mRNA signal observed in newly forming corpora lutea. In addition, the data indicated that both the protein kinase (PK) A and PKC pathways regulated Hmga1 expression in rat granulosa cells. In rat granulosa cell cultures, upregulation of Hmga1 was dependent on new protein synthesis because Hmga1 was inhibited by cycloheximide. Furthermore, Hmga1 mRNA expression in rat granulosa cell cultures was inhibited by AG1478, whereas NS398 and RU486 had no effect, suggesting that Hmga1 expression was regulated, in part, by the epidermal growth factor pathway. In summary, the findings of this study suggest that induction of Hmga1 may be important for theca and granulosa cell differentiation into luteal cells. PMID- 30414624 TI - Opossum milk IgG is from maternal circulation and timing of transfer correlates with neonatal immune development. AB - Marsupials, with short gestation times, have more complex and changing patterns of milk composition than eutherians. Maternal immunoglobulins (Ig) that confer immunity on offspring are among the components that change during marsupial lactation. In the present study we quantified the abundance of mammary transcripts encoding Ig heavy chains and their corresponding transporters in the laboratory opossum Monodelphis domestica. IgA transcripts were the most abundant in opossum mammary and, with IgM, increased in abundance linearly from birth to weaning. Similarly, the Fc receptor for IgA, the poly-Ig receptor, also increased in abundance throughout lactation. There were few transcripts for IgG or IgE within the opossum mammaries. This is in contrast with reports for Australian marsupial species. Transcripts for the Neonatal Fc Receptor (FcRN), which transports IgG, were detected throughout lactation, and opossum milk is known to contain IgG. Therefore, milk IgG is likely to be taken from the maternal circulation, rather than resulting from local production. There is a parallel increase in FcRN in the newborn gut that declines around the time when neonates have matured to the point where they can make their own IgG. These results are consistent with a transfer of maternal Ig that is coordinated with the development of the neonatal immune system. PMID- 30414625 TI - The Importance of Continual Learning in a Rapidly Changing Health Care Environment. PMID- 30414626 TI - Central arteriovenous anastomosis for the treatment of patients with uncontrolled hypertension and paroxysmal AF. AB - A central iliac arteriovenous anastomosis, the 'coupler' (ROX Medical, California, USA) results in a significant reduction in blood pressure in hypertensive patients. This study assessed the change in AF burden following coupler implantation in patients with paroxysmal AF (PAF) and hypertension. Good blood pressure control using the coupler results in a significant reduction in AF burden. PMID- 30414627 TI - Bi-allelic POLR3A Loss-of-Function Variants Cause Autosomal-Recessive Wiedemann Rautenstrauch Syndrome. AB - Wiedemann-Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome, is a rare disorder of unknown etiology. It has been proposed to be autosomal-recessive and is characterized by variable clinical features, such as intrauterine growth restriction and poor postnatal weight gain, characteristic facial features (triangular appearance to the face, convex nasal profile or pinched nose, and small mouth), widened fontanelles, pseudohydrocephalus, prominent scalp veins, lipodystrophy, and teeth abnormalities. A previous report described a single WRS patient with bi-allelic truncating and splicing variants in POLR3A. Here we present seven additional infants, children, and adults with WRS and bi-allelic truncating and/or splicing variants in POLR3A. POLR3A, the largest subunit of RNA polymerase III, is a DNA-directed RNA polymerase that transcribes many small noncoding RNAs that regulate transcription, RNA processing, and translation. Bi-allelic missense variants in POLR3A have been associated with phenotypes distinct from WRS: hypogonadotropic hypogonadism and hypomyelinating leukodystrophy with or without oligodontia. Our findings confirm the association of bi-allelic POLR3A variants with WRS, expand the clinical phenotype of WRS, and suggest specific POLR3A genotypes associated with WRS and hypomyelinating leukodystrophy. PMID- 30414628 TI - Impairments of auditory-verbal short-term memory: Do selective deficits of the input phonological buffer exist? AB - The existence of the functional syndrome of auditory-verbal short-term storage impairment was used as strong supporting evidence for the presence of a phonological buffer in the first version of the Baddeley-Hitch working memory model. In later versions the syndrome corresponded to the selective impairment of the phonological input buffer. The present paper considers whether the correspondence between the functional syndrome, represented by 20 published cases, and a Baddeley-Hitch model component is still of value to memory theory. The following potential problems for the theoretical utility of the correspondence are considered: 1. The apparent rarity of examples of the syndrome: are they outliers? 2. Is short-term memory not merely the activation of long-term memory traces? 3. Could the syndrome be due to failed interaction between perceptual and motor speech processing? 4. Do some aspects of the syndrome not fit the Baddeley-Hitch model predictions? 5. Has the Baddeley-Hitch model not been replaced by more powerful connectionist models? 6. Could the syndrome arise from weakened speech perception processes? It is argued that there are difficulties for each of these possibilities. It is held that the correspondence retains its value. PMID- 30414629 TI - Thirteen-Year Outcomes in Very Preterm Children Associated with Diffuse Excessive High Signal Intensity on Neonatal Magnetic Resonance Imaging. AB - OBJECTIVE: To investigate the association between white matter diffuse excessive high signal intensity (DEHSI) on neonatal magnetic resonance imaging in very preterm infants and neurobehavioral outcomes at the age of 13 years. STUDY DESIGN: Magnetic resonance images of very preterm children (<30 weeks gestational age or <1250 g birth weight) were evaluated at term-equivalent age with DEHSI classified into 5 grades. Additionally, visibility of the posterior periventricular crossroads was assessed. General intelligence, memory, attention, executive function, motor abilities, and behavior were examined in 125 children at age 13 years and related to DEHSI grades using linear regression. RESULTS: DEHSI was detected in 93% of infants; 21% grade 1, 22% grade 2, 32% grade 3, and 18% grade 4. Neurobehavioral outcomes were similar for all DEHSI groups. There was weak evidence that higher DEHSI grades related to higher verbal IQ and attention and that lower DEHSI grades related to better planning ability. Adjustment for gestational age, birth weight standard score, and sex further weakened these effects. Only 12 children had invisible posterior crossroads and showed slightly poorer outcomes at 13 years of age. CONCLUSIONS: There was little evidence that neonatal DEHSI serves as a sensitive biomarker for later impairment. Further investigation on the importance of invisible posterior periventricular crossroads in larger samples is needed. PMID- 30414630 TI - Regimes of Complex Lipid Bilayer Phases Induced by Cholesterol Concentration in MD Simulation. AB - Cholesterol is essential to the formation of phase-separated lipid domains in membranes. Lipid domains can exist in different thermodynamic phases depending on the molecular composition and play significant roles in determining structure and function of membrane proteins. We investigate the role of cholesterol in the structure and dynamics of ternary lipid mixtures displaying phase separation using molecular dynamics simulations, employing a physiologically relevant span of cholesterol concentration. We find that cholesterol can induce formation of three regimes of phase behavior: 1) miscible liquid-disordered bulk, 2) phase separated, domain-registered coexistence of liquid-disordered and liquid-ordered domains, and 3) phase-separated, domain-antiregistered coexistence of liquid disordered and newly identified nanoscopic gel domains composed of cholesterol threads we name "cholesterolic gel" domains. These findings are validated and discussed in the context of current experimental knowledge, models of cholesterol spatial distributions, and models of ternary lipid-mixture phase separation. PMID- 30414632 TI - Fetal Heart Monitoring. PMID- 30414631 TI - The effect of respiration-driven flow waveforms on hemodynamic metrics used in Fontan surgical planning. AB - OBJECTIVE: Poor total cavopulmonary connection (TCPC) hemodynamics have been hypothesized to be associated with long-term complications in Fontan patients. Image-based Fontan surgical planning has shown great potential as a clinical tool because it can pre-operatively evaluate patient-specific hemodynamics. Current surgical planning paradigms commonly utilize cardiac-gated phase contrast magnetic resonance (MR) imaging to acquire vessel flows. These acquisitions are often taken under breath-held (BH) conditions and ignore the effect of respiration on blood flow waveforms. This study investigates the effect of respiration-driven flow waveforms on patient-specific hemodynamics using real time MR acquisitions. METHODS: Patient-specific TCPCs were reconstructed from cardiovascular MR images. Real-time phase contrast MR images were acquired under both free-breathing (FB) and breath-held conditions for 9 patients. Numerical simulations were employed to assess flow structures and hemodynamics used in Fontan surgical planning including hepatic flow distribution (HFD) and indexed power loss (iPL), which were then compared between FB and BH conditions. RESULTS: Differences in TCPC flow structures between FB and BH conditions were observed throughout the respiratory cycle. However, the average differences (BH - FB values for each patient, which are then averaged) in iPL and HFD between these conditions were 0.002 +/- 0.011 (p = 0.40) and 1 +/- 3% (p = 0.28), respectively, indicating no significant difference in clinically important hemodynamic metrics. CONCLUSIONS: Respiration affects blood flow waveforms and flow structures, but might not significantly influence the values of iPL or HFD. Therefore, breath held MR acquisition can be adequate for Fontan surgical planning when focusing on iPL and HFD. PMID- 30414633 TI - Care of the Severely Injured Orthopedic Trauma Patient: Considerations for Initial Management, Operative Timing, and Ongoing Resuscitation. PMID- 30414634 TI - Neurocognitive Impact of Anesthesia in Children. PMID- 30414635 TI - Update on Modalities and Techniques for Labor Epidural Analgesia and Anesthesia. PMID- 30414636 TI - Transversus Abdominis Plane Blocks. PMID- 30414637 TI - Cardiac Dysrhythmias: Understanding Mechanisms, Drug Treatments, and Novel Therapies. PMID- 30414638 TI - Perioperative Management of Pulmonary Hypertension and Right Ventricular Failure During Noncardiac Surgery. PMID- 30414639 TI - Patient Satisfaction in Anesthesia: Implementation, Relevance, and Identification of Meaningful Measures. PMID- 30414640 TI - Trends in Anesthesia-Related Liability and Lessons Learned. PMID- 30414641 TI - Emergency Preparedness and Mass Casualty Considerations for Anesthesiologists. PMID- 30414643 TI - Updates in the Management of Postoperative Nausea and Vomiting. PMID- 30414642 TI - Optimal Perioperative Blood Pressure Management. PMID- 30414644 TI - Left Ventricular Assist Devices and Noncardiac Surgery. PMID- 30414645 TI - Anesthesiology at the Cutting Edge. PMID- 30414646 TI - Maxillofacial prosthetic rehabilitation: A survey on the quality of life. AB - STATEMENT OF PROBLEM: Maxillofacial prostheses, especially those supported by endosseous implants, are regarded as a viable, secure treatment for the reconstruction of facial defects to restore quality of life. The long-term quality of life of patients treated with facial prostheses with different retentive systems is unclear. PURPOSE: The purpose of this clinical study was to assess the long-term quality of life of patients treated with facial prostheses with different retentive systems over a 14-year period at a Dutch oral and maxillofacial surgery unit. MATERIAL AND METHODS: A total of 66 patients with facial prostheses were inventoried and categorized based on anatomic location and type of retention. A 62-item questionnaire was designed to survey the daily prosthetic use, care, quality, durability, longevity, and reliability of retention. Furthermore, issues relating to general satisfaction, self-image, and socialization frequency were addressed. RESULTS: Completed validated questionnaires were returned by 52 patients. Of the prosthetic replacements, 23% (n=12) were orbital, 33% (n=17) nasal, and 44% (n=23) auricular prostheses. The survey showed that a prosthetic reconstruction led to high satisfaction scores with regard to wearing comfort, anatomic fit, color, and anatomic form. A significant difference was shown for implant-retained facial prostheses, which provided enhanced retention and increased ease of placement and removal (Fisher exact test P=.01 and P=.04). Patients with nasal prostheses were less satisfied with the junction of their prostheses to the surrounding soft tissue and more aware of others noticing their prosthetic rehabilitation. Patients with auricular defects were less embarrassed (P=.01) by their prostheses. Although auricular prostheses were less frequently cleaned (P=.01), no significant difference was found in minor soft tissue complications between different anatomic locations and the various retentive systems. CONCLUSIONS: Implant-retained prostheses have advantages over adhesive-retained prostheses in terms of ease of handling. However, improvements in prosthetic material properties, including color stability and durability, are needed to increase the longevity of facial prostheses. PMID- 30414647 TI - Effect of the number of splinted abutments on the accuracy of zirconia copings. AB - STATEMENT OF PROBLEM: Splinting periodontally or structurally compromised abutments is a common procedure. However, studies that investigated the effect of splinting on the accuracy of zirconia copings are lacking. PURPOSE: The purpose of this in vitro study was to evaluate the magnitude of marginal and internal gaps of zirconia copings based on the number of splinted abutments and digital scan technique. MATERIAL AND METHODS: Four maxillary acrylic resin incisors were prepared for ceramic restorations. Epoxy resin master models were fabricated by duplicating the acrylic resin model. An intraoral scanner was used to build 40 digital models (direct digital scan group [DD]); an additional 40 digital models were constructed by scanning 40 maxillary definitive casts using a laboratory scanner (indirect digital scan group [ID]). During computer-aided design, the DD and ID groups were subdivided into 4 groups; single unit (group SU); 2-unit splinted (group 2S); 3-unit splinted (group 3S), and 4-unit splinted (group 4S). Zirconia copings were then fabricated. Using the replica technique, marginal, axial, and occlusal gaps were measured and statistically evaluated (alpha=.05). RESULTS: In DD, group 4S exhibited larger marginal gaps than groups SU, 2S, and 3S (P<.001). In ID, group SU exhibited smaller marginal and occlusal gaps than group 4S (P<.001). Group 4S exhibited significantly greater axial gaps than groups SU, 2S, and 3S (P<.001). CONCLUSIONS: As the number of splinting units increased, the magnitude of the marginal gap tended to increase; however, the differences were less than 5 MUm, which is clinically insignificant. Axial gaps in the ID group demonstrated a significant difference (>35 MUm) among the groups. PMID- 30414648 TI - Risky business this public health. PMID- 30414649 TI - Imaging in Foot and Ankle Instability. AB - This article reviews the imaging aspects relevant to ligamentous instabilities of the foot and ankle with a focus on MRI and ultrasound imaging. A pictorial review of the anatomy of the medial and lateral ankle ligaments, syndesmosis, spring ligament, Lisfranc complex, hallux sesamoid complex, and lesser toe plantar plate as seen on MRI is presented. Selected cases of ligamentous pathology relevant to foot and ankle instability are presented. The value of imaging in the assessment of foot and ankle instability is reviewed. PMID- 30414650 TI - Acute Lateral Ankle Instability. AB - Acute injuries to the lateral ankle complex remain common and account for 20% to 25% of musculoskeletal injuries. Initial assessment should use the Ottawa ankle rules, and grading should take into account degree of mechanical instability. Nonoperative measures are preferable for all grades of injury; however, mechanical instability is a predictor for resprains. Functional treatment after a short period of relative immobilization gives satisfactory results, and residual chronic ankle instability can be managed by repair or reconstruction. Delayed physical examination in elite athletes, along with 3T MRI, may be helpful in making a case for early surgical stabilization. PMID- 30414651 TI - Chronic Lateral Ankle Instability: Open Surgical Management. AB - Open surgical reconstruction for chronic lateral ankle instability is a proven and effective means of providing renewed stability. Ankle arthroscopy is recommended before reconstruction to address intra-articular pathology. The open procedure discussed is well researched and proven to restore stability and the ability to return to sport and daily activity. Anatomic shortening with reattachment into a bony trough allows return to full motion, reliable stability, and return to an active lifestyle without sacrificing any tendons or requiring a tenodesis. The authors' aggressive rehabilitation protocol is provided; the approach to athletes/patients with ligament laxity or cavovarus alignment is also addressed. PMID- 30414652 TI - Arthroscopic Treatment of Ankle Instability: Brostrom. AB - Over the last 10 years, significant advances have been made and successful techniques have now been developed that effectively treat ankle instability via the arthroscope.Currently arthroscopic lateral ligament repair techniques can be grouped into "arthroscopic-assisted techniques," "all-arthroscopic techniques," and "all-inside techniques." Recent studies have proven these arthroscopic techniques to be a simple, safe, and biomechanically equivalent, stable alternative to open Brostrom Gould lateral ligament reconstruction. PMID- 30414653 TI - Arthroscopic Treatment of Ankle Instability - Allograft/Autograft Reconstruction. AB - Inversion ankle sprains represent one of the most common traumatic injuries in the active sports population. Although most respond well to conservative treatment, some hide important lesions. Lateral ankle ligament injuries occur in more than 80% of all ankle sprains, with one-third of these developing chronic ankle instability (CAI). Lateral ankle ligament repair or reconstruction procedures aim to restore normal ankle anatomy and function in patients with CAI. Arthroscopic reconstruction techniques allow the surgeon to reach surgery objectives with minimal soft tissue injury. When the indications and surgical steps are respected, this arthroscopic technique seems to be safe and reproducible. PMID- 30414654 TI - Percutaneous Ankle Reconstruction of Lateral Ligaments. AB - Chronic ankle instability following ankle sprains causes pain and functional problems such as recurrent giving way. Within the 3 ligaments of the lateral ligament complex, 80% of patients tear the anterior talofibular ligament (ATFL), whereas the other 20% of patients tear the ATFL and calcaneofibular ligament (CFL). Rarely, the posterior talofibular ligament is involved. An incidence of 10% to 30% of patients will fail conservative treatment and result in chronic ankle instability that may require surgical treatment. To date, numerous open surgical procedures for anatomic repair or reconstruction of ATFL and/or CFL provide good clinical results. PMID- 30414655 TI - Malalignment and Lateral Ankle Instability: Causes of Failure from the Varus Tibia to the Cavovarus Foot. AB - A lower leg or hindfoot varus malalignment is a frequently encountered but underestimated cause of chronic ankle instability and ankle arthritis in the long term. When evaluating patients with ankle instability, a high index of clinical suspicion for tibia and hindfoot malalignment and subsequent biomechanics should be maintained. Management of lateral ankle instability in the presence of varus malalignment must comprise a generous indication for accurate hindfoot realignment. In young and active patients, realignment should be combined with formal lateral ligamentous repair. PMID- 30414656 TI - Revision of Surgical Lateral Ankle Ligament Stabilization. AB - Ankle sprains continue to be among the most common musculoskeletal injuries, most of which never require surgical treatment. Surgical treatment has traditionally been successful for those patients whose symptoms do not improve with nonoperative care. However, recurrent instability, although rare, can occur early or late after a stabilization procedure, as the result of an acute traumatic event or chronic repetitive minor injury. A complete workup of patients with recurrent ankle instability should be completed before revision surgery and should include evaluation for generalized joint hypermobility as well as anatomic variations, such as hindfoot varus, first ray plantarflexion, and midfoot cavus. PMID- 30414657 TI - Acute and Chronic Syndesmotic Injury: The Authors' Approach to Treatment. AB - Ankle injuries are a common traumatic injury. Rupture to the syndesmosis may occur as a result of these injuries. Strategies for the treatment of both acute and chronic syndesmotic repair are reviewed in detail. Significance of Chaput, Wagstaffe, and posterior malleolus fractures on syndesmotic stability are reviewed. Treatment considerations for total ankle arthroplasty are discussed, and correction of coronal plane deformity as a result of late syndesmotic injury at the time of ankle arthroplasty is outlined. PMID- 30414658 TI - Medial Ankle Instability: The Deltoid Dilemma. AB - Diagnosis and treatment of medial ankle instability (MAI) are still controversial and poorly discussed in literature. The purpose of this review is to highlight different clinical presentations of MAI and develop a guide for its management. The deltoid ligament complex is injured more commonly than expected, because deltoid ligament injuries may either be isolated or occur in combination with other lesions, such as lateral ankle ligament injury, posterior tibial tendon insufficiency, osteochondral lesion, and others. The presence of a pes planovalgus deformity in a patient without posterior tibial tendon insufficiency may indicate MAI. PMID- 30414659 TI - Spring Ligament Instability. AB - The crucial role of the spring ligament complex within the pathologic process that leads to flatfoot deformity has evolved recently. There has been improvement in the anatomic knowledge of the spring ligament and understanding of its complex relationship to the deltoid complex and outstanding advances in biomechanics concepts related to the spring ligament. Optimization of flatfoot treatment strategies are focused on a renewed interest in the spring ligament and medial soft tissue reconstruction in concert with bony correction to obtain an adequate reduction of the talonavicular deformity and restoration of the medial longitudinal arch. PMID- 30414660 TI - Low-Energy Lisfranc Injuries in an Athletic Population: A Comprehensive Review of the Literature and the Role of Minimally Invasive Techniques in Their Management. AB - Tarsometatarsal (TMT) joint complex injuries can be caused by either direct or indirect injuries. The Lisfranc joint represents approximately 0.2% of all fractures. Up to 20% of these injuries are misdiagnosed or missed on initial radiographic assessment; therefore, a high index of suspicion is needed to accurately diagnose TMT joint injuries and avoid the late sequelae of substantial midfoot arthrosis, pain, decreased function, and loss of quality of life. This review discusses the anatomy, diagnosis, and management of athletic Lisfranc injuries, including a description of the preferred minimally invasive surgical techniques used by the senior author of this article. PMID- 30414661 TI - Turf Toe Injury - Current Concepts and an Updated Review of Literature. AB - Turf toe injuries can be a disabling if not recognized and treated early. A high index of suspicion, based on the mechanism of injury and appropriate imaging, helps in the timely diagnosis. These injuries are frequently known to occur on artificial playing surfaces, because of the increased traction at the shoe surface interface. Stress and instability testing are key components to assess the need for surgical intervention. Accurate timely diagnosis and treatment can allow full return to physical activities for most athletes, back to their pre injury level. PMID- 30414662 TI - Plantar Plate Injury and Angular Toe Deformity. AB - Lesser toe plantar plate injuries at the metatarsophalangeal (MTP) joint are a common source of metatarsalgia. The second MTP joint is the most commonly affected digit. The fibrocartilaginous plantar plate is the most important static stabilizer of the MTP joint; high loading with weight bearing can lead to attritional plantar plate injuries. Chronic pain with weight bearing is the common presentation of lesser toe instability. Untreated plantar plate instability can lead to hammer toe and mallet toe deformities. Combined Weil osteotomy and plantar plate repair yields favorable pain relief and angular deformity correction for patients who fail conservative treatment. PMID- 30414663 TI - Preface. PMID- 30414664 TI - Modeling Parental Influence on Teenagers' Food Consumption: An Analysis Using the Family Life, Activity, Sun, Health, and Eating (FLASHE) Survey. AB - OBJECTIVE: To investigate (1) how perceived parental control, perceived parental modeling, and parent-teen co-decision making are associated with teenagers' consumption of fruits and vegetables as well as sugary drinks and less healthful food; and (2) whether self-efficacy mediates this relationship. DESIGN: Cross sectional survey. PARTICIPANTS: A total of 1,657 adolescents aged 12-17years. MAIN OUTCOME MEASURE(S): Perceived parental control, perceived parental modeling, parent-teen co-decision making, self-efficacy, and consumption of fruits and vegetables as well as sugary drinks and less healthful food. ANALYSIS: Ordinary least-squares regressions and mediation analyses. RESULTS: After controlling for teenagers' self-efficacy, perceived parental control was not significantly associated with teenagers' fruit and vegetable consumption but it was negatively related to teenagers' consumption of sugary drinks and less nutrient-dense food. Perceived parental modeling had a positive correlation to teenagers' fruit and vegetable consumption and a negative relationship to their consumption of sugary drinks and less healthful food. Parent-teen co-decision making regarding teenagers' food consumption emerged as a positive predictor for teenagers' fruit and vegetable consumption but not for that of sugary drinks and foods with little nutritional value after controlling for self-efficacy. CONCLUSIONS AND IMPLICATIONS: Findings from this study demonstrated that perceived parental behaviors were related to teenagers' nutrition intakes. Not exerting too much control and having teenagers participate in the decision-making process could help teenagers eat more healthily. Furthermore, providing a positive role model for teenagers can be an effective strategy to encourage teenagers to eat better. PMID- 30414665 TI - Welcome and Invitation to the 2019 Annual Conference. PMID- 30414666 TI - Physical Activity and Nutrition Education Programs. PMID- 30414667 TI - Communicating and Assessing Physical Activity: Outcomes From Cognitive Interviews With Low-Income Adults. AB - OBJECTIVE: This investigation sought to identify the physical activity (PA) terms and concepts that are best understood by low-income adults. DESIGN: This was a cross-sectional study using semistructured cognitive interviews that employed retrospective verbal probing techniques. SETTING: Interviews were conducted in Expanded Food and Nutrition Education Program (EFNEP) sites in New Jersey, Tennessee, and Washington. PARTICIPANTS: A convenience sample of 57 adults participating in or eligible for participation in EFNEP. PHENOMENON OF INTEREST: Participants' interpretations and conceptualizations of PA concepts and terms. ANALYSIS: Template and constant comparative analysis. RESULTS: Participants interpreted many PA terms and concepts in unintended ways. Exercise was the term that came closest to conveying moderate to vigorous PA. Terms used to describe muscle-strengthening activities were mostly understood. Intentional engagement in extra activities was difficult for participants to conceptualize despite multiple tested wordings; making small changes to be active came closest to conveying this concept. Participants' comprehension of the PA terms differed by their PA and literacy levels. CONCLUSIONS AND IMPLICATIONS: Nutrition educators should be mindful of the terminologies they used in communicating messages and assessing PA behaviors to EFNEP participants or similar populations. PMID- 30414668 TI - Optimized robust control for industrial unstable process via the mirror-mapping method. AB - In this work, a novel optimized robust control algorithm, based on the mirror mapping method, is proposed for a class of industrial unstable process with time delay. The optimizing criterion is to minimize the sensitivity function to enhance its robustness. The controllers are designed based on the Pade approximated mirror-mapping process with a stable form, other than the original unstable system. The developed algorithm could release the internal stability constraints to the unstable plant. By using the graphical stability criterion, a systematic methodology is derived to obtain the exact stabilizing region, where the sole design parameter is related to the stability degree of the closed-loop system. The proposed algorithm is with characteristics of concise and efficient design. Three experiments has been employed to illustrate that the control effects can achieve the satisfied performance in aspects of disturbance rejection and robustness. PMID- 30414669 TI - Formation-containment control of networked Euler-Lagrange systems: An event triggered framework. AB - To improve the concurrency of leaders' formation and followers' containment, a difficult problem of designing the formation controller and the containment controller simultaneously should be addressed for networked systems. Motivated by this, this paper presents an even-triggered control framework for networked Euler Lagrange systems to achieve formation-containment control even in the presence of uncertain parameters. An event-triggered formation controller is firstly designed for leaders to achieve the desired configuration. An event-triggered containment control law is then developed to guarantee that all the followers can converge to the convex hull formed by leaders. The key feature of the containment control law is that it does not necessitate any relative velocity information with respect to neighbor followers. Each controller's gains are adaptively tuned using only local information. The parametric uncertainties are accommodated by using the adaptive updating law. Zeno behaviors of the triggering time sequences are also excluded. As a result, the communication burden of formation-containment system can be reduced. Numerical simulation is finally presented to verify the effectiveness of the proposed event-triggered formation-containment control framework. PMID- 30414670 TI - UDE-based chattering-free sliding mode control for systems with mismatched uncertainties. AB - The sliding mode control (SMC) approach has been extensively studied and applied owing to its excellent performance and inherent robustness. However, it could hardly address the mismatched uncertainties because of its structural limitation. In this paper, a chattering-free sliding mode control approach based on an uncertainty and disturbance estimator (UDE) is proposed for a class of nonlinear systems with mismatched uncertainties. The UDE is designed for the estimation of both matched and mismatched uncertainties, which only requires the spectrum of the lumped uncertainties. With the compensation of the estimated uncertainties, an adaptive sliding mode surface is constructed. To attenuate the chattering phenomenon, a UDE-based control law is developed by eliminating the discontinuous switching control term. Moreover, the closed-loop stability of the proposed control scheme is proved based on the Lyapunov theory. Simulation results on a magnetic levitation (MagLev) system are presented to illustrate the effectiveness of the proposed control scheme, which achieves strong robustness, chattering reduction and zero steady tracking error. PMID- 30414671 TI - Frequency frame approach on loop shaping of first order plus time delay systems using fractional order PI controller. AB - This study proposes an analytical design method of fractional order proportional integral (FOPI) controllers for first order plus time delay (FOPTD) systems. Suggested technique obtains the general computation equations of controllers for such systems. These equations are used to tune controller parameters to meet specified frequency and phase properties to satisfy the stability of whole system. It is found that the designed controllers not only make the system stable, but also have positive effect on the performance and robustness of the system. Main contribution of the paper lays on this thought. There proposed a concept, "frequency frame" which encloses the curves between phase and gain crossover frequencies in Bode plot. Robustness of the control system can be improved by expanding or constricting the edges of this frame and flattening the curves inside the frame. Thus, any case that leads the system to instability can be avoided. Analytically derived equations are tested with proper examples and the results are shown illustratively. Advantages and disadvantages of the method are comparatively given. PMID- 30414672 TI - Identification of a rare homozygous c.790C>T variation in the TFB2M gene in Korean patients with autism spectrum disorder. AB - Mitochondrial dysfunction and subsequent enhanced oxidative stress is implicated in the pathogenesis of autism spectrum disorder (ASD). Mitochondrial transcription factor B2 (TFB2M) is an essential protein in mitochondrial gene expression. No reports have described TFB2M mutations and variations involved in any human diseases. We identified a rare homozygous c.790C>T (His264Tyr) variation in TFB2M gene in two Korean siblings with ASD by whole-exome sequencing. The roles of the TFB2M variation in the pathogenesis of ASD were investigated. Patient fibroblasts revealed increased transcription of mitochondrial genes and mitochondrial function in terms of ATP, membrane potential, oxygen consumption, and reactive oxygen species (ROS). Overexpression of the TFB2M variant in primary-cultured fibroblasts demonstrated significantly increased transcription of mitochondrial genes and mitochondrial function compared with overexpression of wild-type TFB2M. Molecular dynamics simulation of the TFB2M variant protein suggested an increase in the rigidity of the hinge region, which may cause alterations in loading and/or unloading of TFB2M on target DNA. Our results suggest that augmentation of mitochondrial gene expression and subsequent enhancement of mitochondrial function may be associated with the pathogenesis of ASD in Korean patients. PMID- 30414673 TI - Inhibitory effect of celastrol on adipogenic differentiation of human adipose derived stem cells. AB - Control of adipogenesis in mesenchymal stem cells (MSCs) offers enormous potential for management of obesity- and aging-related diseases. Celastrol, the traditional Chinese medicine extracted from Tripterygium wilfordi, exhibits anti obesity effects in in vitro and in vivo murine models. This study describes how celastrol affects multilineage differentiation potential of human adipose-derived stem cells (hADSCs). We performed in vitro adipogenic differentiation of hADSCs and investigated how celastrol-induced lipid accumulation and expression of adipocyte differentiation markers varied with dose, duration, and donor age. In addition, we assessed the effect of celastrol on osteogenic and chondrogenic differentiation of hADSCs. During adipogenic induction of hADSCs, the inhibitory effect of celastrol on lipid accumulation and adipogenesis depended on dose, duration, time of administration, and individual donor. Inhibition was mediated by proliferator-activated receptor-gamma (PPARG) and CCAAT/enhancer-binding protein alpha (CEBPA). Celastrol also suppressed differentiation of hADSCs into the osteogenic and chondrogenic lineages. Celastrol plays a regulatory role in multilineage differentiation of human MSCs. Our findings provide important insights regarding management of obesity and stem cell therapy. PMID- 30414674 TI - History of Minimally Invasive Surgical Oncology. AB - Introduction of the fiberoptic light-source and CCD chip camera resulted in the rapid growth of minimally invasive surgical procedures. In surgical oncology, the change came slowly owing to concerns about adhering to oncological principals while learning to use new technology. Pioneers in minimally invasive colorectal surgery proved that minimally invasive resection for cancer was oncologically noninferior to traditional surgery. Early adopters treating esophageal and gastric cancer established that a minimally invasive approach was feasible with lower morbidity and equivalent oncologic outcomes. These results provide a basis for the extension of minimally invasive surgical techniques to other types of cancer surgery. PMID- 30414675 TI - Transluminal Cancer Surgery. AB - Transluminal surgery, also known as natural orifices endoluminal surgery, can be considered the most minimally invasive approach of gaining access to an organ. Although some approaches, such as transgastric or transvaginal cholecystectomy, have remained experimental, peroral endoscopic myotomy to treat achalasia and transanal total mesorectal excision to treat low rectal cancer have become accepted, safe, and feasible approaches by trained surgeons for selected patients. This article recapitulates the development of transluminal surgery from its experimental beginnings to the validated procedure it has become today. PMID- 30414676 TI - Training for Minimally Invasive Cancer Surgery. AB - The surgical oncologist of the future requires training in minimally invasive techniques. Increasing constraints on time and resources have led to a new emphasis on finding innovative ways to teach these surgical skills inside and outside the operating room. The goal of producing technically gifted minimally invasive surgical (MIS) oncologists requires robust, educationally sound training curricula. This article describes how MIS oncology training occurs at present with an outline of educational ideals training programs can strive for, provides two examples of successful MIS oncology programs to highlight effective strategies for moving forward, and introduces three new developments on the horizon. PMID- 30414677 TI - Robotic Head and Neck Surgery. AB - Robotic head and neck surgery applies minimally invasive principles to unique anatomy and natural orifices for surgical access. Expanding from a tradition of minimally invasive endoscopic otolaryngology procedures, surgical robotics has transformed head and neck surgery. However, surgeons are faced with significant challenges, and anatomic constraints impede visualization and constrain surgical maneuvers. Transoral robotic surgery (TORS) has been developed over the past decade with favorable oncologic and functional outcomes, changing the way head and neck surgeons approach both malignant and benign diseases. As new robotic platforms emerge, access will continue to improve and push the boundaries of minimally invasive approaches. PMID- 30414678 TI - Minimally Invasive Approaches to Pediatric Solid Tumors. AB - Over the last decade, driven in part by the favorable adult experience and a crescendoing number of case series and retrospective reports in the pediatric surgical literature, minimally invasive surgical (MIS) approaches are increasingly used as adjunctive or definitive surgical treatments for an ever expanding list of pediatric tumors. Although most current treatment protocols lack surgical guidelines regarding the use of MIS, this growing body of MIS literature provides a framework for the development of multicenter trial groups, prospective registries, and further centralization of subspecialist services. This article highlights the current available data on MIS approaches to a variety of pediatric malignancies. PMID- 30414679 TI - Endoscopic Management of Pancreatic Cancer. AB - The role of endoscopy in the care of patients with pancreatic cancer continues to evolve. The early diagnosis of pancreatic cancer has been difficult. Endoscopic ultrasound examination should be used to examine pancreatic lesions because it can characterize lesions and sample tissue. Endoscopic retrograde cholangiopancreatography is essential in managing biliary obstructions. Endoscopic ultrasound can assist in gaining access to difficult biliary trees. Endoscopic placement of luminal stents can be used for palliative purposes. Postoperative issues such as strictures and anastomotic ulcers can generally be managed endoscopically. Injectable therapy and drug-eluting stent placements are potential areas for use in the future. PMID- 30414680 TI - Virtual and Augmented Reality in Oncologic Liver Surgery. AB - Virtual reality (VR) and augmented reality (AR) in complex surgery are evolving technologies enabling improved preoperative planning and intraoperative navigation. The basis of these technologies is a computer-based generation of a patient-specific 3-dimensional model from Digital Imaging and Communications in Medicine (DICOM) data. This article provides a state-of-the- art overview on the clinical use of this technology with a specific focus on hepatic surgery. Although VR and AR are still in an evolving stage with only some clinical application today, these technologies have the potential to become a key factor in improving preoperative and intraoperative decision making. PMID- 30414681 TI - Fluorescence Imaging for Minimally Invasive Cancer Surgery. AB - This article demonstrates surgical techniques of intraoperative fluorescence imaging using indocyanine green, focusing on its application in minimally invasive hepatobiliary and pancreatic surgery. In this area, indocyanine green fluorescence imaging has been applied to liver cancer identification, fluorescence cholangiography, delineation of hepatic segments, and fluorescence angiography and perfusion assessment. The development of target-specific fluorophores and advances in imaging technology will allow real-time intraoperative fluorescence imaging to develop into an essential intraoperative navigation tool. This property may contribute to enhancing both accuracy and safety of minimally invasive surgery. PMID- 30414682 TI - Minimally Invasive Staging Surgery for Cancer. AB - Staging laparoscopy (SL) is used to assess for radiographically occult metastatic disease and local resectability in selected patients with gastrointestinal malignancies. SL may avoid nontherapeutic laparotomy in patients with unresectable cancer and is associated with shorter length of hospital stay and time to receipt of systemic therapy compared with nontherapeutic laparotomy. With improvements in preoperative imaging, careful patient selection for SL is imperative. SL and peritoneal washings should be considered for patients with distal gastroesophageal and locally advanced gastric cancer before planned neoadjuvant chemotherapy or resection. SL should be considered in selected high risk patients with hepatopancreatobiliary malignancies. PMID- 30414683 TI - Minimally Invasive Surgery for Palliation. AB - Palliative care is the multidisciplinary focus on patient symptoms and quality of life. The emphasis of minimally invasive surgery on reduced pain and faster recovery aligns well with the goals of palliative care. Minimally invasive approaches can be safely and effectively used to address several common complications of solid organ malignancies as well as the complications of cytotoxic therapy. A patient-centered, minimally invasive approach will not only help alleviate disabling symptoms and improve patient quality of life but will also minimize the pain and adverse effects of the intervention itself. PMID- 30414684 TI - Robotic Developments in Cancer Surgery. AB - Indications for robotic surgery have been rapidly expanding since the first introduction of the robotic surgical system in the US market in 2000. As the robotic systems have become more sophisticated over the past decades, there has been an expansion in indications. Many new tools have been added with the aim of optimizing outcomes after oncologic surgery. Complex abdominal cancers are increasingly operated on using robot-assisted laparoscopy and with acceptable outcomes. In this article, the authors discuss robotic developments, from the past and the future, with an emphasis on cancer surgery. PMID- 30414685 TI - Minimally Invasive Oncologic Surgery. PMID- 30414686 TI - Minimally Invasive Oncologic Surgery, Part I. PMID- 30414687 TI - Vacuum bell treatment of pectus excavatum: An early North American experience. AB - PURPOSE: Conservative treatment of pectus excavatum with a vacuum bell device may be an attractive alternative to surgical repair. We describe an early North American experience with this device. METHODS: Prospectively maintained chest wall clinic registries from two institutions were reviewed to identify pectus excavatum patients <=21 years treated with the vacuum bell from 2013 to 2017. Multivariate linear regression was used to compare mean improvements in deformity depth and Haller Index between groups of patients based on age and usage metrics (hours/day and days/week). RESULTS: Thirty-one patients with a median age of 14 years received treatment with the device. Mean follow-up duration was 18 months. Median depth and Haller Index at treatment onset were 2.3 cm and 3.9, respectively. Improvements in deformity-depth were superior with device usage >2 h/day (p < 0.01) and daily use (p < 0.01). After adjusting for compliance, younger age of treatment onset was associated with greater improvement in Haller Index but not deformity depth. CONCLUSION: Our prospective early North American experience found the vacuum bell to be a potential alternative to surgical treatment for pectus excavatum. Longer usage periods in a daily frequency are associated with best results. TYPE OF STUDY: Treatment study; case series with no comparison group. LEVEL OF EVIDENCE: Level IV. PMID- 30414688 TI - Outcomes in omphalocele correlate with size of defect. AB - BACKGROUND: Omphaloceles can be some of the more challenging cases managed by pediatric surgeons. Single center studies have not been meaningful in delineating outcomes due to the length of time required to accumulate a large enough series with historical changes in management negating the results. The purpose of this study was to evaluate factors impacting the morbidity and mortality of neonates with omphaloceles. METHODS: A multicenter, retrospective observational study was performed for live born neonates with omphalocele between 2005 and 2013 at nine centers in the United States. Maternal and neonatal data were collected for each case. In-hospital management and outcomes were also reported and compared between neonates with small and large omphaloceles. RESULTS: Two hundred seventy-four neonates with omphalocele were identified. The majority were delivered by cesarean section with a median gestational age of 37 weeks. Overall survival to hospital discharge was 81%. The presence of an associated anomaly was common, with cardiac abnormalities being the most frequent. Large omphaloceles had a significantly longer hospital and ICU length of stay, time on ventilator, number of tracheostomies, time on total parenteral nutrition, and time to full feeds, compared to small omphaloceles. Birth weight and defect size were independent predictors of survival. CONCLUSION: This is the largest contemporary study of neonates with omphalocele. Increased defect size is an independent predictor of neonatal morbidity and mortality. LEVEL OF EVIDENCE: Level II. PMID- 30414689 TI - Evaluation of a water-soluble contrast protocol for nonoperative management of pediatric adhesive small bowel obstruction. AB - BACKGROUND/PURPOSE: We examined outcomes before and after implementing an enteral water-soluble contrast protocol for management of pediatric adhesive small bowel obstruction (ASBO). METHODS: Medical records were reviewed retrospectively for all children admitted with ASBO between November 2010 and June 2017. Those admitted between November 2010 and October 2013 received nasogastric decompression with decision for surgery determined by surgeon judgment (preprotocol). Patients admitted after October 2013 (postprotocol) received water soluble contrast early after admission, were monitored with serial examinations and radiographs, and underwent surgery if contrast was not visualized in the cecum by 24 h. Group outcomes were compared. RESULTS: Twenty-six patients experienced 29 admissions preprotocol, and 11 patients experienced 12 admissions postprotocol. Thirteen (45%) patients admitted preprotocol underwent surgery, versus 2 (17%) postprotocol patients (p = 0.04). Contrast study diagnostic sensitivity as a predictor for ASBO resolution was 100%, with 90% specificity. Median overall hospital LOS trended shorter in the postprotocol group, though was not statistically significant (6.2 days (preprotocol) vs 3.6 days (postprotocol) p = 0.12). Pre- vs. postprotocol net operating cost per admission yielded a savings of $8885.42. CONCLUSIONS: Administration of water-soluble contrast after hospitalization for pediatric ASBO may play a dual diagnostic and therapeutic role in management with decreases in surgical intervention, LOS, and cost. TYPE OF STUDY: Retrospective comparative study. LEVEL OF EVIDENCE: Level III. PMID- 30414690 TI - Pediatric firearm injuries in Los Angeles County: Younger children are more likely to be the victims of unintentional firearm injury. AB - BACKGROUND: Firearm injuries are now the third leading cause of death in children. Understanding the circumstances surrounding pediatric firearm injuries will allow for targeted injury prevention efforts. We hypothesized that younger children are more likely to be victims of unintentional firearm injury. METHODS: A multicenter, retrospective review of patients <18 years old who sustained firearm injuries in Los Angeles County from 2006 to 2015 was performed. Unintentional injuries were defined as accidental firearm discharge without violent intent. Intentional injuries were defined as firearm discharge with intent to injure (including suicide). RESULTS: After review of 304 pediatric firearm injuries, 206 had sufficient narrative to determine intent with 10% of injuries classified as unintentional. Unintentional injuries were more common in younger children, more frequently caused by a firearm from within the home, and more likely to involve friend/family (all p < 0.05). Intentional injuries were associated with more injuries and accounted for all deaths in our study cohort. CONCLUSIONS: In pediatric firearm injury, younger children are more susceptible to unintentional injuries, but intentional injuries are more common overall. Future interventions need to target both intentional violence in older children and unintentional firearm injury in young children if the frequency is to be reduced. TYPE OF STUDY: Epidemiologic study. LEVEL OF EVIDENCE: Level III. PMID- 30414691 TI - Outcomes following two-stage surgical approaches in the treatment of pediatric ulcerative colitis. AB - INTRODUCTION: Surgery for the treatment of ulcerative colitis (UC) can be performed in one-, two-, or three-stage procedures [1]. The more traditional approach is a total proctocolectomy and creation of an ileo pouch-anal anastomosis and diverting stoma at the initial operation, followed by ileostomy closure several weeks later (TIPPA) [1]. An alternative is an initial subtotal colectomy and end ileostomy [2]. In this alternative approach (NIPAA), a completion proctectomy and definitive ileo pouch-anal anastomosis can be performed without a diverting stoma. We hypothesize that functional outcomes following a NIPAA approach when performed in children, in our experience, are likely similar or improved when compared to those treated by TIPAA. METHODS: After IRB approval, a review of patients who underwent a two-stage Laparoscopic IPAA from 2004 to 2017 occurred. Data included demographics, diagnosis, surgical intervention time to full diet, level of continence, use of antidiarrheals and complications. RESULTS: N = 41 (NIPAA = 14, TIPAA = 27). After establishment of bowel continuity, no significant differences in appetite recovery, continence, or complications were noted. The number of antidiarrheals prescribed were significantly higher in the TIPAA group (p = 0.01). Thirteen patients (31.7%) had pouchitis: 4 NIPAA and 9 TIPAA (p = NS). Of the 41 patients, 11 required subsequent surgery; 2 patients (18.2%) received NIPAA and 9 (81.8%) received TIPAA (p = 0.20). Two TIPAA patients received a diverting ileostomy owing to chronic anal pain and failure to achieve continence. CONCLUSION: This study suggests children with medically refractory UC treated by NIPAA or TIPAA have similar outcomes. Minimal differences in overall outcome were noted following either approach. However, NIPAA may reduce reliance on antidiarrheals to achieve satisfactory defecation outcomes. LEVEL OF EVIDENCE: III Retrospective comparative study. PMID- 30414692 TI - Room for "quality" improvement? Validating National Surgical Quality Improvement Program-Pediatric (NSQIP-P) appendectomy data. AB - INTRODUCTION: Accurate data are essential for the validity of clinical registries. This study aimed to validate NSQIP-P data, assess representativeness, and evaluate risk-adjusted predictive ability at a single institution. METHODS: A prospective appendectomy-specific pediatric surgery research database (RD) maintained by clinical researchers was compared to the NSQIP-P data for appendectomies performed in 2016 at a tertiary children's hospital. NSQIP-P sampled data collected by trained surgical clinical reviewers (SCRs) were compared to matched RD patients. Both datasets used NSQIP-P definitions. Using chi2, datasets were compared by patient demographics, disease severity (simple vs. complicated), and outcomes. RESULTS: 458 appendectomies for acute appendicitis were performed in 2016, of which 250 (55%) were abstracted by SCRs and matched to RD patients. Patient demographics were similar between datasets. Disease severity (NSQIP-P:50% complicated vs RD:31% complicated) and composite morbidity (NSQIP-P:6.0% vs RD:14.4%) were significantly different (both p < 0.01). Demographics and outcomes were similar between matched (n = 250) and unsampled patients in the RD (n = 208). NSQIP-P's risk-adjusted predicted morbidity was significantly lower than morbidity observed in all (n = 458) RD patients (NSQIP-P:9.9% vs RD:14.2%, p < 0.01). CONCLUSIONS: Though constituting a representative sample, NSQIP-P appendectomy data were inconsistent with department data. Discrepancies appear to be the result of underreporting of outcome variables and disease misclassification. TYPE OF STUDY: Retrospective comparative review. LEVEL OF EVIDENCE: Level III. PMID- 30414693 TI - The protective effects of fecal microbiota transplantation in an experimental model of necrotizing enterocolitis. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is a serious disease that affects premature neonates, causing high mortality. In the search for new options of treatment it was investigated whether fecal microbiota transplantation (FMT) decreased the inflammatory response during NEC development in experimental model. METHODS: Wistar rats were used and divided as follows: naive, control (NEC induction), FMT-before (transplantation of microbiota before insult) and FMT after (microbiota transplantation after insult). The microbiota transplantation was performed by administering a feces solution obtained from an adult donor rat. The induction of enterocolitis involves feeding by artificial formula, hypothermia, hypoxia and endotoxin administration. MPO activity, TNF-alpha, IL 1beta and IL-6 levels, oxidative and nitrosative damage and the grade of intestinal mucosa lesion were analyzed. RESULTS: The control group had a significant increase of inflammatory and oxidative parameters when compared to naive animals. Both FMT-before and after decreased all inflammatory and oxidative damage parameters when compared to control group. This was also true to the intestinal mucosa damage. CONCLUSION: FMT administered just before or after NEC induction improved gut and systemic inflammation, and gut oxidative damage and intestinal injury. PMID- 30414694 TI - Open tunneled central line insertion in children - External or internal jugular vein? PMID- 30414695 TI - Alginate microparticles loaded with basic fibroblast growth factor induce tissue coverage in a rat model of myelomeningocele. AB - BACKGROUND/PURPOSE: We sought to develop a minimally invasive intra-amniotic therapy for prenatal treatment of myelomeningocele (MMC) in an established rat model. METHODS: Time-dated pregnant rats were gavage-fed retinoic acid to induce MMC. Groups received intraamniotic injections at E17.5 with alginate particles loaded with fluorescent dye, basic fibroblast growth factor (Alg-HSA-bFGF), fluorescently tagged albumin (Alginate-BSA-TR), free bFGF, blank alginate particles (Alg-Blank), or PBS. Groups were analyzed at 3 h for specific particle binding or at term (E21) to determine MMC coverage. RESULTS: Alginate microparticles demonstrated robust binding to the MMC defect 3 h after injection. Of those specimens analyzed at E21, 150 of 239 fetuses (62.8%) were viable. Moreover, 18 of 61 (30%) treated with Alg-HSA-bFGF showed evidence of soft tissue coverage compared to 0 of 24 noninjected (P = 0.0021), 0 of 13 PBS (P = 0.0297), and 0 of 42 free bFGF (P = P < 0.0001). Scaffolds of aggregated particles associated with disordered keratinized tissue were observed covering the defect in 2 of 18 (11%) Alg-BSA-TR and 3 of 19 (16%) Alg-Blank specimens. CONCLUSIONS: Injection of microparticles loaded with bFGF resulted in significant soft tissue coverage of the MMC defect compared to controls. Alginate microparticles without growth factors might result in scaffold development over the fetal MMC. TYPE OF STUDY: Basic science. LEVEL OF EVIDENCE: N/A. PMID- 30414696 TI - Distinct prognostic roles of S100 mRNA expression in gastric cancer. AB - BACKGROUND: The S100 protein family is implicated in tumor invasion and metastasis, but its prognostic roles in gastric cancer (GC) has not been elucidated. MATERIALS AND METHODS: In the current study, Kaplan-Meier plotter (KM plotter) database integrated the expression data and survival information of 1065 GC patients were downloaded from the Gene Expression Omnibus (GEO) (GSE22377, GSE14210 and GSE51105) that published by the three major cancer centers (Berlin, Bethesda and Melbourne). Then this database was used to explore the prognostic values of mRNA expression of each individual S100 in GC patients. We further assessed the prognostic value of S100 in different Lauren classifications, clinicopathological features and clinical treatment of gastric cancer. RESULTS: Expression of 12 members of the S100 family correlated with overall survival (OS) for all GC patients. Increased expression of S100A3, S100A5, S100A7, S100A7A, S100A11, S100A13, S100Z and S100 G were found to be strongly associated with worse survival, while S100A8, S100A9, S100B and S100 P were correlated with better prognosis in all GC patients. Further assessment of prognostic values of S100 in gastric cancer with different clinical features indicated that different S100 members may interact with different signaling pathways and exerted different functions in gastric cancer development. CONCLUSIONS: Although the results should be further testified in clinical studies, our findings offer new insights into the contribution of S100 members to GC progression and might promote development of S100 targeted reagents for treating GC. PMID- 30414697 TI - Distribution, bioaccumulation and trophic transfer of trace metals in the food web of Chaohu Lake, Anhui, China. AB - Chaohu Lake is one of the five largest freshwater lakes in China situated in Anhui Province. Water, sediment and aquatic organisms were collected from Chaohu Lake. Trace metals were measured to investigate their bioaccumulation pattern and trophic transfer in the food web as well as potential health risk assessment through fish consumption. Trophic interactions were investigated by stable nitrogen isotope. Linear regression of log metal concentration versus delta15N was used to determine whether there is biomagnification or biodilution. Results showed that concentrations of trace metals in water were rather low except Hg, some of which surpassed the scope of quality standard. Trace metals in sediment exceeded background values nevertheless within the range for the protection of aquatic life. Therein, geochemical fractionation showed that Cd would pose a considerable potential ecological risk. Trace metals were higher in plankton except for Cu and Zn was higher in shrimp due to metabolic needs. Decreasing trend was observed in Pb, Cr, Cd, As and Hg levels with increasing trophic level whereas increasing trend was observed in Zn. Trace metals in fish were lower than legislation thresholds except for Cr in two samples that exceeded the threshold value. Nonetheless, total target hazard quotient values and target cancer risk were lower than unit and within acceptable range, indicating there was no health risk for inhabitants from trace metals through fish consumption. PMID- 30414698 TI - A Whole-genome CRISPR Screen Identifies a Role of MSH2 in Cisplatin-mediated Cell Death in Muscle-invasive Bladder Cancer. AB - BACKGROUND: The response to first-line, platinum-based treatment of muscle invasive bladder cancer has not improved in 3 decades. OBJECTIVE: To identify genes that influence cisplatin resistance in bladder cancer. DESIGN, SETTING, AND PARTICIPANTS: We performed a whole-genome CRISPR screen in a bladder cancer cell line to identify genes that mediate resistance to cisplatin. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Targeted validation was performed in two bladder cancer cell lines. The top gene candidate was validated in a publicly available bladder cancer dataset. RESULTS AND LIMITATIONS: From the CRISPR screen, we identified MSH2 as the most significantly enriched gene and mismatch repair as the most significantly enriched pathway that promoted resistance to cisplatin. Bladder cancer cells with knockdown of MSH2 showed a reduction in cisplatin-mediated apoptosis. MSH2 loss did not impact the sensitivity to other chemotherapies, including the cisplatin analog oxaliplatin. Bladder tumors with low MSH2 protein levels, quantified using reverse-phase protein array, showed poorer survival when treated with cisplatin- or carboplatin-based therapy; these results require future validation using immunohistochemistry. Additionally, results are retrospective from patients with primarily high-grade tumors; thus, validation in a controlled clinical trial is needed. CONCLUSIONS: We generated in vitro evidence that bladder cancer cell lines depleted of MSH2 are more resistant to cisplatin. We additionally found an association between low MSH2 in bladder tumors and poorer patient survival when treated with platinum-based chemotherapy. If successfully validated prospectively, MSH2 protein level could assist in the selection of patients for chemotherapy. PATIENT SUMMARY: We report the first evidence that MSH2 protein level may contribute to chemotherapy resistance observed in muscle-invasive bladder cancer. MSH2 has potential as a biomarker predictive of response to platinum-based therapy. PMID- 30414699 TI - Verbal long-term memory is enhanced by retrieval practice but impaired by prefrontal direct current stimulation. AB - Retrieval practice involves repeatedly testing a student during the learning experience, reliably conferring learning advantages relative to repeated study. Transcranial direct current stimulation (tDCS) of the left dorsolateral prefrontal cortex (dlPFC) has also been shown to confer learning advantages for verbal memory, though research is equivocal. The present study examined the effects of retrieval versus study practice with or without left dlPFC tDCS on verbal episodic memory. Participants (N = 150) experienced either retrieval practice or study practice, and active anodal, active cathodal, or sham tDCS while encoding word lists, and then returned two days later for a final recall test. Three primary patterns emerged: first, during encoding, tDCS did not influence recall rates in the retrieval practice group. Second, during final recall, participants in the retrieval practice groups recalled more than those in the study practice groups. Finally, during final recall, anodal tDCS decreased recall relative to sham and cathodal stimulation, suggesting that it interfered with developing highly detailed memories that could be relied upon for subsequent recollection. Data support existing research demonstrating the effectiveness of retrieval practice as a learning strategy, but also suggest that anodal dlPFC stimulation can induce long-term negative impacts on verbal episodic memory retrieval. PMID- 30414700 TI - Invention Versus Gold Standard: A Hands-On Research Pearl on Study Design and Statistical Concerns. AB - This article points out what is important to consider when planning to perform and analyze a commonly seen study involving a comparison of an innovation with something established. A hands-on guide on how to perform this type of research trial and how to choose proper statistical methods is given. PMID- 30414701 TI - Fibromuscular Dysplasia of Coronary and Brachial Artery. PMID- 30414702 TI - Determining the Optimal Systolic Blood Pressure for Hypertensive Patients: A Network Meta-analysis. AB - BACKGROUND: There is clinical trial evidence that lowering systolic blood pressure (SBP) to < 120 mm Hg is beneficial, and this has influenced the latest American guideline on hypertension. We therefore used network meta-analysis to study the association between SBP and cardiovascular outcomes. METHODS: We searched for randomized controlled trials targeting different blood pressure levels that reported cardiovascular events. The mean achieved SBP in each trial was classified into 5 groups (110-119, 120-129, 130-139, 140-149, and 150-159 mm Hg). The primary variables of cardiovascular mortality, stroke, and myocardial infarction were assessed using frequentist and Bayesian approaches. RESULTS: Fourteen trials with altogether 44,015 patients were included. Stroke and major adverse cardiovascular events were reduced when lowering SBP to 120-129 mm Hg compared with 130-139 mm Hg (odds ratio [OR] 0.83, 95% confidence interval [CI] 0.69-0.99 and OR 0.84, 95% CI 0.73-0.96), 140-149 mm Hg (OR 0.73, 95% CI 0.55 0.97 and OR 0.74, 95% CI 0.60-0.90), and 150-159 mm Hg (OR 0.43, 95% CI 0.26-0.71 and OR 0.41, 95% CI 0.30-0.57), respectively. More intensive control to < 120 mm Hg further reduced stroke (OR 0.58, 95% CI 0.38-0.87; OR 0.51, 95% CI 0.32-0.81; and OR 0.30, 95% CI 0.16-0.56). In contrast, SBP >= 150 mm Hg increased myocardial infarction and cardiovascular mortality compared with 120-129 mm Hg (OR 1.73, 95% CI 1.06-2.82 and OR 2.18, 95% CI 1.32-3.59) and 130-139 mm Hg (OR 1.53, 95% CI 1.01-2.32 and OR 1.71, 95% CI 1.11-2.61). No significant relationship between SBP and all-cause mortality was found. CONCLUSIONS: SBP < 130 mm Hg is associated with a lower risk of stroke and major adverse cardiovascular events. Further lowering to < 120 mm Hg can be considered to reduce stroke risk if the therapy is tolerated. Long-term SBP should not exceed 150 mm Hg because of the increased risk of myocardial infarction and cardiac deaths. PMID- 30414703 TI - LAMB3 is associated with disease progression and cisplatin cytotoxic sensitivity in head and neck squamous cell carcinoma. AB - OBJECTIVES: Laminin subunit beta-3 (LAMB3) is a major component of the basement membrane zone. In our study, we investigated the role of LAMB3 in head and neck squamous cell carcinoma (HNSCC) progression and its clinical implication as a prognostic biomarker. MATERIALS AND METHODS: A retrospective analysis of 100 patients with HNSCC who had undergone curative surgery from 1999 to 2011 was performed. We evaluated LAMB3 expression by immunohistochemistry and its associations with clinicopathological characteristics and survival. For functional in vitro analyses, cell proliferation, migration, and invasion and western blot assays were performed following LAMB3 suppression. In addition, the role of LAMB3 in cisplatin-induced cytotoxicity was clarified by measuring cell proliferation. RESULTS: LAMB3 expression was up-regulated in HNSCC cell lines and patient tissues. High LAMB3 expression was significantly associated with positive lymph node metastasis (odds ratio: 6.316; P < 0.001) and poor prognosis in patients with HNSCC. LAMB3 suppression reduced cell migration/invasion via down regulation of epithelial-to-mesenchymal transition-associated proteins (Vimentin and Slug). Moreover, LAMB3 suppression increased cisplatin cytotoxicity in HNSCC cells. CONCLUSION: Our findings indicate that LAMB3 may be used as a prognostic biomarker in HNSCC and support that LAMB3 silencing could induce the sensitivity of anti-cancer drugs such as cisplatin. PMID- 30414704 TI - The impact of radiological retroperitoneal lymphadenopathy on survival after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases. AB - OBJECTIVES: To investigate the impact of retroperitoneal lymphadenopathy (RPLP) on pre-operative CT scan on overall survival (OS) and disease-free survival (DFS) after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS HIPEC) for peritoneal metastases (PM) of colorectal cancer. BACKGROUND: In patients with PM enlarged retroperitoneal lymph nodes (RPLP) are usually considered extra-regional lymph node metastases and therefore these patients may be excluded from CRS-HIPEC. This is a clinical dilemma since it is often hard to obtain histology from these nodes. METHODS: In this multicenter, retrospective study all consecutive patients with colorectal PM treated with CRS-HIPEC between 2004 and 2013 were included. The preoperative CT-scan was re-analyzed for the presence of RPLP based on the radiological appearance of enlarged lymph nodes. Outcomes were OS and DFS. Kaplan-Meier methods and Cox regression modeling were used to analyze the impact of RPLP on OS and DFS. RESULTS: In 25 of 401 patients (6.1%) RPLP was observed on the preoperative CT-scan. Patient, tumor and surgical characteristics did not statistically significantly differ between groups with and without RPLP. After a median follow-up of 46 months, the one-, three- and five-year survival was 80%, 59%, 38% and 90%, 50%, 36% in the group with and without RPLP respectively. Median OS (47 vs. 35 months, logrank: p = 0.70) and median DFS (14 vs. 15 months, logrank: p = 0.81) did not statistically significantly differ between groups. In multivariable analysis, RPLP did not significantly influence survival. CONCLUSION: Enlarged retroperitoneal lymph nodes on a pre-operative CT-scan should not automatically exclude patients from CRS-HIPEC. PMID- 30414705 TI - High prevalence of chronic kidney disease in patients with multiple endocrine neoplasia type 1 and improved kidney function after parathyroidectomy. AB - BACKGROUND: Because chronic kidney disease is an important comorbidity associated with primary hyperparathyroidism, we sought to evaluate the prevalence of chronic kidney disease and effects of parathyroidectomy on kidney function in patients with multiple endocrine neoplasia type 1-associated primary hyperparathyroidism. METHODS: We performed a retrospective analysis of 112 patients with multiple endocrine neoplasia type 1-associated primary hyperparathyroidism who had at least 1 operation for primary hyperparathyroidism at 2 tertiary referral centers. The preoperative and postoperative estimated glomerular filtration rates were compared. The prevalence of chronic kidney disease stage 3 or worse (estimated glomerular filtration rates less than 60 mL/min/1.73m2) in this cohort was compared to the rates in the US population reported by the Centers for Disease Control and Prevention. RESULTS: The median age at the time of parathyroidectomy was 36.5 years (range: 12-76 years). A total of 99 patients had biochemical remission. The rate of chronic kidney disease stage 3 or worse in patients with multiple endocrine neoplasia type 1-associated primary hyperparathyroidism was greater than that observed in the US population for ages 20-39 and 40-59 (5% [n = 2/44] vs 0.39% [n = 18/4565], P = .015 and 10% [n = 4/40] vs 2.31% (n = 89/3848), P = .015, respectively). We observed improved estimated glomerular filtration rates in those with chronic kidney disease stage 3 or worse postoperatively (48 vs 57 mL/min/1.73m2, P = .047). A successful parathyroidectomy normalized all 24 hour urine calcium excretion. CONCLUSION: An indication for early parathyroidectomy should include estimated glomerular filtration rates less than 60mL/min/1.73m2 in patients with multiple endocrine neoplasia type 1-associated primary hyperparathyroidism. PMID- 30414706 TI - Validation of day 1 drain fluid amylase level for prediction of clinically relevant fistula after distal pancreatectomy using the NSQIP database. AB - BACKGROUND: The role of postoperative day 1 drain fluid amylase level in predicting clinically relevant postoperative pancreatic fistula is under investigation. In a previous multicenter study conducted on 338 patients undergoing distal pancreatectomy, day 1 drain fluid amylase level has been correlated to the development of a clinically relevant pancreatic fistula and an amylase value of 2,000 U/L was found to be most predictive of the development of clinically relevant postoperative pancreatic fistula. Our objective was to validate the previously established cutoff level for drain fluid amylase on postoperative day 1 after distal pancreatectomy as a predictor for clinically relevant postoperative pancreatic fistula using a different patient population from the National Surgery Quality Improvement Program database. METHODS: We studied all patients undergoing distal pancreatectomy from the National Surgery Quality Improvement Program pancreatectomy specific participant use file from 2014 to 2016. We applied the day 1 drain fluid amylase level of 2,000 U/L cutoff to divide patients into 2 groups and compared clinical outcomes in both groups. Among patients with a day 1 drain fluid amylase level < 2,000 U/L, we compared the patient characteristics of those who developed a clinically relevant postoperative pancreatic fistula to those who did not. Finally, to independently validate the previously defined day 1 drain fluid amylase level, we proceeded to determine the optimal cutoff value of day 1 drain fluid amylase level, which can be used as a predictor for the development of clinically relevant postoperative pancreatic fistula after distal pancreatectomy using a receiving operating characteristic curve. RESULTS: A total of 1,007 patients underwent distal pancreatectomy. The mean day 1 drain fluid amylase level was 4,290.04 +/- 8,492.35 U/L. Clinically relevant postoperative pancreatic fistula occurred in 203 patients (20.2%). Using bivariate analysis, patients with day 1 drain fluid amylase level >= 2,000 U/L were more likely to develop clinically relevant postoperative pancreatic fistula (32.5% vs 11.25%, P < .0001), to have a higher mean number of days before drain removal (8.83 vs 5.59, P < .0001), to have a drain 30 days postoperatively (12.59% vs 3.63%, P < .0001), and to undergo percutaneous drainage (13.75% vs 9.69%, P = .04). Among patients with a day 1 drain fluid amylase level < 2,000 U/L, 11% of patients went on to develop a clinically relevant postoperative pancreatic fistula. Analysis of this subgroup of patients did not identify any discernable preoperative characteristics that were predictive of this complication. Application of maximal Youden index calculated the day 1 drain fluid amylase level value at 2,000 U/L with a sensitivity of 67.98% and a specificity of 63.81% for clinically relevant postoperative pancreatic fistula, with a positive predictive value of 32.17%, a negative predictive value of 88.75%, and a Youden index of 0.32. CONCLUSION: Using a different population of patients and a different data set as well as an independent analysis, we successfully validated a day 1 drain fluid amylase level of 2,000 U/L as striking the best balance in terms of sensitivity and specificity for the detection of clinically relevant postoperative pancreatic fistula. The identified cutoff might be employed in the design of a trial of early drain removal in patients undergoing distal pancreatectomy. PMID- 30414707 TI - An acute encephalopathy with reduced diffusion in BRAF-associated cardio-facio cutaneous syndrome. AB - BACKGROUND: Cardio-facio-cutaneous syndrome (CFCS) is a rare genetic disorder characterized by cardiovascular anomalies, dysmorphic faces, ectodermal abnormalities and developmental delays. Mutations in BRAF and other RAS-MAPK pathway-associated genes are commonly identified in patients with CFCS. While this molecular pathway is known to be associated with neuro-inflammatory conditions, only one case with CFCS has been reported thus far to develop acute encephalopathy in childhood. CASE REPORT: A 3-year-old boy with dysmorphic features and mild psychomotor delay developed acute encephalopathy. After a 45 min long, generalized seizure, the magnetic resonance imaging revealed that the restricted diffusion signals spread to the bilateral subcortical white matters on day 1 of illness. Despite the 14 days of intensive care, the acute symptoms of encephalopathy left him intractable epilepsy and severe neurocognitive impairments. The whole-exome sequencing analysis identified a de novo heterozygous mutation of BRAF (NM_004333:p.Thr241Met) in this case. CONCLUSION: The present case suggests that the hyperactive condition of ERK signals might augment the development of acute encephalopathy and post-encephalopathic epilepsy in childhood. PMID- 30414708 TI - Age estimation in 5-16-year-old children by measurement of open apices: North German formula. AB - The aims of this study were to test the accuracy of Cameriere et al.'s European formula on a sample of North German children based on dental age (DA) for chronological age (CA) assessment and to adapt the formula used, in case of regional peculiarities of this group of children. Orthopantomograms of 1000 children (444 males and 556 females) aged 5-16years were used. The roots of seven left mandibular teeth were evaluated. The number of teeth with complete root development (N zero (0)) was counted. Teeth with incomplete root development were examined and the distance between the inner sides of the open apex was measured and normalized by dividing it by the tooth length to avoid error due to magnification. Cameriere et al.'s European formula underestimated the mean CA of boys by 0.56+/-1.04years and of girls by -0.32+/-0.96. The results of the regression analysis showed that sex (g), the sum of normalized open apices (s), number of teeth with closed apices (N0) and the first-order interaction between the normalized apex width of the canine (x3) and N0 contributed significantly to the fit. All previously mentioned factors were included in the regression model, yielding to the following formula: DA=9.829+0.632 N0-1.037s+0.686g-1.582N0*x3, where g is a variable: 1 for males and 0 for females. The adapted formula explained 84.1% of the total deviance, with a median age of 0.070 years and 1.185 years interquartile range, (IQR). PMID- 30414709 TI - New Perspectives in Oxygen Therapy Titration: Is Automatic Titration the Future? AB - Oxygen therapy, like all technology-based treatments, is continuously evolving. There are no doubts as to its effectiveness in the treatment of acute and respiratory failure in different clinical scenarios. However, the dosing guidelines for oxygen therapy are not as strict as for other treatments. The use of higher than necessary flows over excessively long periods, derived from the clinician's perception of it as a 'life-saving treatment with few side effects', has led to a rather liberal use of this intervention, despite evidence that overuse and suboptimal adjustment can be harmful. The titration of oxygen therapy, which is traditionally performed manually, has been shown to be beneficial. Recently, new devices have been developed that automatically adjust oxygen flow rates to the needs of each patient, in order to maintain stable oxygen saturation levels. These closed-loop oxygen supply systems can potentially reduce medical error, improve morbidity and mortality, and reduce care costs. Familiarizing the medical community with these technological advances will improve awareness of the risks of the inappropriate use of oxygen therapy. The aim of this paper is to provide an update of recent developments in oxygen therapy titration. PMID- 30414710 TI - Clinical Interest of Circulating Tumor DNA in Oncology. AB - Genetic alterations in tumors, as predictor of response to targeted-therapies or as prognostic markers, are clinically relevant to determine adequate therapeutic management. Tumor biopsy is currently the golden standard for somatic alterations assessment, but this approach is invasive and does not consider tumor heterogeneity. In various body fluids like plasma, somatic mutations have been identified. Circulating tumor DNA (ctDNA) holds promises in tumor burden monitoring or malignancies early detection. Since allele frequencies of circulating somatic mutations are low, highly sensitive novel assays have been developed to allow the investigation of the tumor genome, leading to the emergence of the "liquid biopsy" concept. Despite these technological advances, other assays for identifying intratumor and intermetastases heterogeneity need to be developed. Before being applied to clinic, ctDNA analyses need to be harmonized and validated with well-powered, well-designed studies. One of the primary prerequisite to incorporation of ctDNA analysis in the follow-up strategy of malignancies is the checking of the concordance with golden standard detection methods, imaging, circulating proteins and biopsy. This review focuses on the clinical interest of ctDNA in solid tumors and hematological malignancies. PMID- 30414711 TI - Making epilepsy a national priority in African countries. PMID- 30414712 TI - Percutaneous electrical stimulation for overactive bladder in children: a pilot study. AB - PURPOSE: The purpose of this was to evaluate the efficacy (tolerance and safety) of once-a-week parasacral percutaneous electrical nerve stimulation (PENS) to treat overactive bladder (OAB) in children. MATERIALS AND METHODS: This is a prospective case series of children aged 4-14 years who underwent PENS for OAB. Acupuncture needles were used bilaterally and symmetrically at S3 for sacral nerve stimulation (Figure). Eighteen children with pure OAB underwent PENS weekly for 20 weeks. Frequency was 10 Hz. Intensity varied up to a maximum of 10 mA, as tolerated by the participant, but without reaching the motor threshold. Pulse width was 600 MUs Patients' voiding history was assessed before treatment using a structured questionnaire. The dysfunctional voiding scoring system (DVSS) was used before and after treatment to quantify symptoms of lower urinary tract dysfunction. A visual analog scale (VAS) was used to evaluate treatment outcome. RESULTS: Seven boys and eleven girls (mean age, 7.82 +/- 2.45 years) were included. According to the VAS, symptoms were resolved in 66% of patients. Urinary urgency, present in all children at baseline, was resolved in 84% (P = 0.001). The proportion of patients with involuntary loss of urine without urgency decreased from 77% before treatment to 27% (P = 0.04). Urge incontinence resolved in 13 of 16 patients after treatment (P = 0.001). Only one of the 12 children with frequent urination at baseline reported this complaint after treatment (P = 0.04). All cases of recurrent urinary tract infection were resolved (P = 0.001). Regarding nocturnal enuresis, treatment was successful in 9 of 14 children (P = 0.004). DISCUSSION: The theory behind this new method is that when skin impedance is overcome through the use of acupuncture needles and greater proximity is attained between the tip of the electrode and the sacral nerves, a more effective stimulus is achieved, with enough energy to provide the same benefits as parasacral transcutaneous electrical nerve stimulation with the advantage that treatment can be given only once a week. CONCLUSIONS: Percutaneous electrical nerve stimulation seems to be an effective and safe treatment for OAB over the short term. Furthers studies with a control group are needed. PMID- 30414713 TI - Commentary to 'Assessment of pediatric bowel and bladder dysfunction: a critical appraisal of the literature'. PMID- 30414714 TI - Helicobacter pylori and portal hypertensive gastropathy. PMID- 30414715 TI - Individualized 3D-printed templates for high-dose-rate interstitial multicathether brachytherapy in patients with breast cancer. AB - PURPOSE: High-dose-rate, multicatheter interstitial brachytherapy is technically complex and operator-dependent, requiring lengthy training and specialized skills. Furthermore, until the advent of contouring on computerized tomography (CT) images, difficulties existed in locating the target volume precisely. The present article reports the results of a study that aimed at producing and validating a 3D-printed template to aid in target volume localization for multicatheter interstitial brachytherapy in patients with breast cancer. METHODS AND MATERIALS: Thirteen patients, candidates for accelerated partial breast irradiation or boost, were enrolled in the study. The target volume was defined on CT slices, and a template with empty spaces corresponding to the target volume projection on the patient's skin was produced by a 3D printer. The procedure was compared with the standard method followed in our center (1) visually, by assessing overlap between the target volume projections on the patient's skin, (2) by X-ray findings, and (3) by intraclass correlation coefficient. RESULTS: Visual assessment and X-ray findings showed the 3D-printed target volume always fell within the standard volume in all 13 patients. The intraclass correlation coefficient indicated moderate agreement for both the medial and the lateral skin projections. CONCLUSIONS: The 3-D printed templates constitute a quick, easy, and reliable method to localize the target volume for high-dose-rate interstitial multicathether brachytherapy in patients with breast cancer and can safely be used in clinical practice. PMID- 30414716 TI - Anti-inflammatory and analgesic activity of Habbe Gule Aakh, A polyherbal Unani formulation in animal models. AB - BACKGROUND: Habbe Gule Aakh is extensively used in Unani medicine for anti inflammatory and analgesic activity. OBJECTIVE: To evaluate anti-inflammatory and analgesic effects of Habbe Gule Aakh on Wistar rats and Swiss mice of either sex. MATERIALS AND METHODS: The study was carried out in Wistar rats for anti inflammatory activity while Swiss mice were used for analgesic activity. In both the tests animals were divided into five groups of six animals each which served as control, standard and test groups A, B and C. For anti-inflammatory activity, method reported by Amman was followed. For analgesic activity, Koster's protocol was adapted. RESULTS: Significant (P < 0.01) reduction in the paw volume was noted in all the test groups but less than the standard drug. Mean writhes of group B and C reduced significantly (P < 0.01) demonstrating analgesic effect. CONCLUSION: The study validated the claim of Unani medicine of use of Habbe Gule Aakh in inflammation and pain. Further, phytochemical studies are needed to know the exact mechanism of action of this formulation. PMID- 30414717 TI - Antenatal hydration in POTS - could technology help? PMID- 30414718 TI - Anesthetic management of parturients with Arnold Chiari malformation-I: a multicenter retrospective study. AB - BACKGROUND: Consensus regarding the safest mode of delivery and anesthetic management for parturients with Arnold Chiari malformation-I (ACM-I) remains controversial. This study assessed their anesthetic management and reported anesthetic complications during hospitalization for delivery. METHODS: This was a multicenter, retrospective, cohort study of patients with ACM-I undergoing vaginal or cesarean delivery. Data were obtained from the electronic databases of four United States academic institutions using International Classification of Diseases (ICD) codes from 2007-2017 at three sites and 2004-2017 at one site. The primary outcome was anesthetic complications. RESULTS: Data were analyzed for 185 deliveries in 148 patients. Diagnosis of ACM-I was made prior to delivery in 147 (80%) cases. Pre-delivery neurosurgical consultation for management of ACM-I was performed in 53 (36%) patients. Pre-existing symptoms were recorded for 89 (48%) of the deliveries. Vaginal deliveries occurred in 80 (43%) cases, and 62 women (78%) received neuraxial labor analgesia. Cesarean delivery was performed in 105 (57%) cases, of which 70 women (67%) had neuraxial anesthesia and 34 (32%) received general anesthesia. Post-dural puncture headache was reported in three (2%) patients who had neuraxial anesthesia, and in two (12%) patients with syringomyelia. There was one reported case of aspiration pneumonia with general anesthesia (3%). CONCLUSIONS: The findings suggest that anesthetic complications occur infrequently in patients with ACM-I regardless of the anesthetic management. Although institutional preference in anesthetic and obstetric care appears to drive patient management, the findings suggest that an individualized approach has favorable outcomes in this population. PMID- 30414719 TI - Endovascular Denervation: A New Approach for Cancer Pain Relief? AB - PURPOSE: To evaluate the effects of endovascular denervation (EDN) on abdominal cancer pain relief. MATERIALS AND METHODS: From April 2017 to February 2018, 7 cancer patients (2 males and 5 females) were enrolled in this study. The diagnoses of the patients included 3 pancreatic cancer, 2 cervical carcinoma, 1 cholangiocarcinoma, and 1 esophageal cancer with retroperitoneum lymph nodes invasion. Denervation was carried out at the abdominal aorta close to the origin of celiac artery and superior mesenteric artery with the use of a multielectrode radiofrequency ablation catheter with settings of time 120 seconds and temperature 60 degrees C. The primary end point was improvement in pain scores. The secondary end points included change in quality of life, intake of narcotics, and the safety of EDN. RESULTS: All of the patients experienced pain relief. The pain scores as measured by means of visual analog scores at 1, 2, 4, 8, and 12 weeks after the procedure were significantly lower than before the operation (P < .001). A > 4 score reduction was observed in all cases. A significant reduction in narcotics use within 3 months after the operation was also seen. The quality of life scores of the patients improved significantly (P < .005) with better sleep. No severe treatment-related adverse events or major complications were observed. CONCLUSIONS: EDN is a safe and effective means to alleviate pain caused by cancer and may serve as a new approach for cancer pain relief and palliative care. PMID- 30414720 TI - Prevalence, course and psychosis-predictive value of negative symptoms in 22q11.2 deletion syndrome. AB - BACKGROUND: The 22q11.2 deletion syndrome (22q11DS) is one of the highest known risk factors for schizophrenia and recent findings have highlighted the clinical relevance of ultra-high risk (UHR) criteria in this population. However, studies in other at-risk populations have shown that the presence of negative symptoms (NS) is also of clinical relevance in predicting transition to psychosis. The present study examined in detail the presence and course of NS in 22q11DS, as well as their value in predicting transition to psychosis. METHODS: A total of 111 participants aged between 8 and 33 years were assessed with the Structured Interview for Psychosis-Risk Syndromes (SIPS). A follow-up assessment was available for 89 individuals. RESULTS: Core NS of at least moderate severity were present in 50.5% of the sample and were more severe in individuals meeting UHR criteria. They predominantly remained stable over time and their emergence between baseline and follow-up assessment was associated with significant functional decline. Some NS were significant predictors of conversion to psychosis and the emergence/persistence of psychosis risk. CONCLUSIONS: Altogether, these findings highlight that NS are core manifestations of psychosis in individuals with 22q11DS that strongly impact global functioning. The presence of NS should be a primary target of early therapeutic intervention in this population. PMID- 30414721 TI - Inflammatory biomarkers in psychosis and clinical high risk populations. AB - BACKGROUND: Immunological, nutritional, and microbial factors have been implicated in the pathophysiology of schizophrenia, but the interrelationship among measures is understudied. In particular, an increase in the levels of the pro-inflammatory cytokine interleukin-6 (IL-6) is associated with all phases of the illness, and may be associated with other inflammatory markers. Vitamin D is a modulator of the immune system, and LPS antibodies are an indirect measure of gut barrier function. In this study we investigated potential contributing inflammatory mechanisms for IL-6 elevation. METHODS: We compared the levels of vitamin D, C-reactive protein (CRP), antibodies to lipopolysaccharide (LPS), and IL-6 in children, adolescents and young adults with psychosis (n = 47), individuals at clinical high risk for psychosis (n = 17) and unaffected comparison controls (n = 33). Participants were diagnosed by a psychiatrist, using a structured interview, the MINI-Neuropsychiatric Interview. 25(OH)D was measured in serum using chemiluminescent micro particle immunoassay, and anti-LPS antibodies, CRP and IL-6 levels were measured by ELISA. RESULTS: IL-6 and C reactive protein levels were significantly elevated in the psychosis group relative to the unaffected control subjects. In the psychosis group, levels of IL 6 correlated positively with IgA anti-LPS antibodies and negatively correlated with vitamin D. CONCLUSIONS: Our findings show a significant correlation between IL-6, anti-LPS antibodies and vitamin D deficiency in psychosis, suggesting the existence of multiple potential pathways related to IL-6 elevation in psychosis, and therefore multiple potential strategies for risk mitigation. Collectively these findings support hypotheses regarding interrelated inflammatory contributions to the pathophysiology of psychosis. PMID- 30414722 TI - Addressing the Value of Gene Therapy and Enhancing Patient Access to Transformative Treatments. AB - Although high upfront costs for the high value of gene therapy have resulted in concerns about sufficient reimbursement to allow patient access to these therapies, the significant benefits of gene therapies will not be realized unless patients have access to them. Stakeholders are discussing these issues, and the payment models being developed for the newly approved gene therapies provide an early indication of the flexibility that will be needed from treatment manufacturers, payers, and policy makers to optimize patient access. Maximizing patient access to effective gene therapies is one integral part of the overall mission of the American Society of Gene and Cell Therapy, along with maximizing the quality of therapies and minimizing their costs. PMID- 30414723 TI - Microorganisms isolated at admission and treatment outcome in sputum smear positive pulmonary tuberculosis. AB - Cured or completed cases in newly diagnosed sputum smear-positive pulmonary tuberculosis (TB) is 47.7% in Japan in 2016. Aging of TB patients and their underlying conditions could affect treatment outcome. We analyzed the association between the isolation of microorganisms from sputum at admission and the 180-day mortality rate of the sputum smear-positive pulmonary TB patients in Chiba-East Hospital in Japan. Total subjects were 761 (median age: 63 years). Sputum test for microorganisms was conducted in 708 patients. Microorganisms other than the normal oral flora were isolated in 128 cases (18.1%). Details of the isolated microorganisms were as follows: methicillin-resistant Staphylococcus aureus 23 cases, Klebsiella pneumoniae 17 cases, Pseudomonas aeruginosa 16 cases. Mortality was significantly elevated in the patients with those microorganisms than the others (39.8% vs. 10.2%) (P < 0.01). Fifty-one of 128 patients with those microorganisms died, and 10 of them died of infectious disease, which is the most frequent cause of deaths. The factors associated with the isolation of those microorganisms were as follows: respiratory failure (adjusted odds ratio (aOR):2.5 [95% confidence interval (CI) 1.3-4.7]), performance status 3 or 4 (aOR:2.9 [95% CI 1.6-5.4]), serum albumin <3.0 mg/dL (aOR:2.1 [95% CI 1.3-3.6], age of 65 years or older (aOR:2.0 [95% CI 1.2-3.4]). Those strains were isolated from one of sixth patients. Patients with those microorganisms did not always develop infectious diseases; however, treatment outcomes were poor, with higher mortality. The isolations of microorganisms were associated with various underlying conditions, leading to death. Thus, attention should be paid to TB patients with the above factors. PMID- 30414724 TI - Is the Munich dysphagia Test-Parkinson's disease (MDT-PD) a valid screening tool for patients at risk for aspiration? AB - BACKGROUND: Dysphagia is common in Parkinson's disease (PD) and leads to pneumonia, malnutrition, and reduced quality of life. For detecting dysphagia exposed PD patients, the Munich dysphagia test-Parkinson's disease (MDT-PD) is a patient self-reported tool that has been developed specifically for PD patients. The MDT-PD is available in both German and English. This study aimed to ascertain whether the MDT-PD can detect aspiration in PD patients and, therefore, serve as a suitable screening tool. METHODS: In a controlled, cross-sectional, observational study, a total of 119 PD outpatients were examined clinically and were evaluated by the MDT-PD and the one swallowing question (NMS-3) from the nonmotor symptom questionnaire for Parkinson's disease (NMSQuest). The results of the MDT-PD and the NMS-3 were compared to the penetration-aspiration scale (PAS) rating defined by flexible endoscopic evaluation of swallowing (FEES). KEY RESULTS: Half of the patients with aspiration as determined using FEES were not detected by the MDT-PD and NMS-3 self-reported tools. The proportion of false positive patients was high with both tools. The sensitivity of the MDT-PD to detect patients who are at risk for aspiration is insufficient (0.37) and not superior to applying the dysphagia screening question from the NMSQuest (0.5). CONCLUSION: This study reveals that the MDT-PD is not suitable for detecting aspiration in PD patients and, therefore, cannot be considered as a screening tool for aspiration. However, at present, there is no alternative validated screening tool that can reliably detect aspiration in PD patients. A readjustment of the MDT-PD is urgently needed. PMID- 30414725 TI - [Additional non-contraceptive effects of contraception: CNGOF Contraception Guidelines]. AB - Hormonal and intrauterine contraceptive methods provide women with highly efficient protection against undesired pregnancy. Additional non-contraceptive effects are now well documented. Combined hormonal contraceptives use, either through the oral transdermal and vaginal route, allow a reduction in menorrhagia, dysmenorrhea, functional ovarian cysts, benign breast and uterine disease, endometriosis-related pain and recurrence. A reduction in ovarian cancer risks, including in women with BRCA syndrome, endometrial and colon cancer is documented. This effect is prolonged for years after contraception discontinuation. Non-contraceptive benefits of progestin-only contraceptives are less documented. Use of the levonorgestrel IUD is associated with a reduction in menorrhagia, dysmenorrhea including in case of endometriosis. Copper IUD use is associated with a decrease in cervix and endometrial cancer risk. PMID- 30414726 TI - Achyranthes bidentata polypeptide k improves long-term neurological outcomes through reducing downstream microvascular thrombosis in experimental ischemic stroke. AB - Achyranthes bidentata Bl. (A. bidentata) occupies an important position in traditional Chinese medicine owing to the property of promoting the circulation of blood and removing stasis. Achyranthes bidentata polypeptide k (ABPPk) is one of the active components isolated from A. bidentata.We previously demonstrated that ABPPk has potent neuroprotective effects against neuronal apoptosis both in vitro and in vivo, but the roles and mechanisms of ABPPk on long-term functional recovery after ischemic stroke remain unknown. In the current study, we investigated the neuroprotective effects of ABPPk on filament transient middle cerebral artery occlusion (tMCAO) rats and found that ABPPk reduced the infarct volume and maintained the neuronal integrity in the ischemic penumbra. Moreover, we found that ABPPk might reduce the formation of downstream microthrombus through preventing ischemic-induced oxidative damage of brain endothelial cells and activation of tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1), and NF-kappaB. ABPPk also inhibited polymorphonuclearleukocytes(PMNs) infiltration and matrix metalloproteinase-2/-9 (MMP-2/-9) activation in the ischemic penumbra. Morris water maze, foot fault test, and modified neurological severity score were assessed for a period of 6 weeks following tMCAO. ABPPk improved long-term recognition abilities and neurological outcomes after stroke compared with saline-treated rats. Taken together, these results suggested that ABPPk is beneficial to the improvement of long-term outcomes after transient cerebral ischemia injury and can be used as a potential neuroprotective agent. PMID- 30414727 TI - Effect of tau-pathology on charged multivesicular body protein 2b (CHMP2B). AB - Charged multivesicular body protein 2b (CHMP2B) is a subunit of the endosomal sorting complex required for transport (ESCRT)-III that mediates scission of budded membranes. Neurons with CHMP2B-positive granulovacuolar inclusions in the cytoplasm are much more frequent in hippocampi of cases with Alzheimer's disease when compared with controls. We analyzed immunolabeled brain sections from tau transgenic mice, APP-transgenic mice, non-transgenic mice, and human hippocampi to investigate the relation between CHMP2B and tau and plaque pathology that are major histopathological features of Alzheimer's disease. Neurons undergoing granulovacuolar degeneration (GVD) were found in human hippocampi and old tau trangenic mice but not in the APP-transgenic strains. 57% of neurons with GVD displayed GVD-granules double-labeled for CHMP2B and the GVD-marker casein kinase 1delta in 24 months-old tau-transgenic mice and 5.7% of neurons with tau hyper phosphorylated at Thr212 and Ser214 (immunoreactive with antibody AT100) displayed CHMP2B-positive GVD-granules, in human hippocampi it was 100% and 46% respectively. The number of neurons with GVD-inclusions increased in tau transgenic mice with the number of AT100-positive neurons, suggesting a link between tau-pathology and GVD. GVD-granules in human hippocampi also displayed immunoreactivity for Vps4a, another protein component of ESCRT-III. In cases with aging-related tau astrogliopathy (ARTAG), astrocytes containing hyper phosphorylated tau immunoreactive with antibody AT8 displayed strong CHMP2B immunoreactivity. The results suggest dysregulation of CHMP2B together with tau pathology and possibly a disturbance of the regulation of vesicular compartments. The absence of combined Abeta- and tau-associated pathology in the transgenic mice may account for the difference in CHMP2B-immunoreactivity between the transgenic mice and human hippocampus. PMID- 30414728 TI - MIonSite: Ligand-specific prediction of metal ion-binding sites via enhanced AdaBoost algorithm with protein sequence information. AB - Accurately targeting metal ion-binding sites solely from protein sequences is valuable for both basic experimental biology and drug discovery studies. Although considerable progress has been made, metal ion-binding site prediction is still a challenging problem due to the small size and high versatility of the metal ions. In this paper, we develop a ligand-specific predictor called MIonSite for predicting metal ion-binding sites from protein sequences. MIonSite first employs protein evolutionary information, predicted secondary structure, predicted solvent accessibility, and conservation information calculated by Jensen-Shannon Divergence score to extract the discriminative feature of each residue. An enhanced AdaBoost algorithm is then designed to cope with the serious imbalance problem buried in the metal ion-binding site prediction, where the number of non binding sites is far more than that of metal ion-binding sites. A new gold standard benchmark dataset, consisting of training and independent validation subsets of Zn2+, Ca2+, Mg2+, Mn2+, Fe3+, Cu2+, Fe2+, Co2+, Na+, K+, Cd2+, and Ni2+, is constructed to evaluate the proposed MIonSite with other existing predictors. Experimental results demonstrate that the proposed MIonSite achieves high prediction performance and outperforms other state-of-the-art sequence-based predictors. The standalone program of MIonSite and corresponding datasets can be freely downloaded at https://github.com/LiangQiaoGu/MIonSite.git for academic use. PMID- 30414729 TI - Cardioprotective effects of physical exercise on redox biology in mice exposed to hand-rolled cornhusk cigarette smoke. AB - The present study sought to evaluate the effects of physical training on histological parameters and oxidative stress in the myocardium of mice chronically exposed to hand-rolled cornhusk cigarette (HRCC) smoke. Male Swiss mice (60 days old, 30-35 g) were either exposed to ambient air or passively exposed to the smoke of 12 cigarettes daily over 3 sessions (4 cigarettes per session) for 60 consecutive days with or without physical training for 8 weeks. Forty-eight hours after the last training session, the heart was surgically removed for histological analysis and measurement of oxidative stress parameters. Histological imaging revealed cell disruption, with poorly defined nuclei, in the mice exposed to HRCC smoke, but not in the control group. However, mice exposed to HRCC smoke with physical training displayed signs of tissue repair and improved tissue integrity. Biochemical analysis revealed decreased production of superoxide, 2',7'-dichlorofluorescein (DCF), and nitrite, as well as decreased protein carbonylation, in the physical training groups, likely due to the exercise-induced increase in glutathione peroxidase (GPX) activity and glutathione (GSH) content. Taken together, our results suggest that physical exercise exerts cardioprotective effects by modulating the redox responses in animals exposed to HRCC smoke. PMID- 30414730 TI - 79-Year-Old Man With Shortness of Breath and Fevers. PMID- 30414731 TI - 35-Year-Old Man With Episodic Fever and Cough. PMID- 30414732 TI - Supraventricular Arrhythmias: Clinical Framework and Common Scenarios for the Internist. AB - Supraventricular arrhythmias can cause uncomfortable symptoms for patients. Often, the first point of contact is in the primary care setting, and thus, it is imperative for the general internist to have a clinical framework in place to recognize this cluster of cardiac arrhythmias, be familiar with immediate and long-term management of supraventricular tachycardias, and understand when cardiac electrophysiologic consultation is necessary. The electrocardiographic characteristics can have subtle but important clues to the diagnosis and initial management. An understanding of the mechanisms of these arrhythmias is essential to provide proper therapy to the patient. In addition, there are common practice strategies that should be emphasized to avoid common misperceptions that could pose risk to the patient. In this review, we provide a framework to more easily recognize and classify these arrhythmias. We also illustrate the mechanism for these arrhythmias to provide an understanding of the interventions generally used. PMID- 30414733 TI - Health Literacy and 1-Year Mortality: Mechanisms of Association in Adults Hospitalized for Cardiovascular Disease. AB - OBJECTIVE: To test theorized patient-level mediators in the causal pathway between health literacy (HL) and 1-year mortality in adults with cardiovascular disease (CVD). PATIENTS AND METHODS: A total of 3000 adults treated at Vanderbilt University Hospital from October 11, 2011, through December 18, 2015, for acute coronary syndrome or acute decompensated heart failure (ADHF) participated in the Vanderbilt Inpatient Cohort Study. Participants completed a bedside-administered survey and consented to health record review and longitudinal follow-up. Multivariable mediation models examined the direct and indirect effects of HL (a latent variable with 4 indicators) with 1-year mortality after discharge (dichotomous). Hypothesized mediators included social support, health competence, health behavior, comorbidity index, type of CVD diagnosis, and previous-year hospitalizations. RESULTS: Of the 2977 patients discharged from the hospital (60% male; mean age, 61 years; 83% non-Hispanic white, 37% admitted for ADHF), 17% to 23% had inadequate HL depending on the measure, and 10% (n=304) died within 1 year. The total effect of lower HL on 1-year mortality (adjusted odds ratio [AOR]=1.31; 95% CI, 1.01-1.69) was decomposed into an indirect effect (AOR=1.50; 95% CI, 1.35-1.67) via the mediators and a nonsignificant direct effect (AOR=0.87; 95% CI, 0.66-1.14). Each SD decrease in HL was associated with an absolute 3.2 percentage point increase in the probability of 1-year mortality via mediators admitted for ADHF, comorbidities, health behavior, health competence, and previous-year hospitalizations (listed by contribution to indirect effect). CONCLUSION: Patient-level factors link low HL and mortality. Health competence and health behavior are modifiable mediators that could be targeted by interventions post hospitalization for CVD. PMID- 30414734 TI - Advances in the Treatment of Sickle Cell Disease. AB - Sickle cell disease (SCD) is a monogenic disorder that afflicts approximately 100,000 Americans and millions of people worldwide. It is characterized by hemolytic anemia, vaso-occlusive crises, relentless end-organ injury, and premature death. Currently, red blood cell transfusion and hydroxyurea are the major disease-modifying therapies available for SCD. Hematopoetic stem cell transplant is curative, but barriers to treatment are substantial and include a lack of suitable donors, immunologic transplant rejection, long-term adverse effects, prognostic uncertainty, and poor end-organ function, which is especially problematic for older patients. Gene therapy to correct the betas point mutation is under investigation as another curative modality. Deeper insights into the pathophysiology of SCD have led to the development of novel agents that target cellular adhesion, inflammation, oxidant injury, platelets and/or coagulation, vascular tone, and hemoglobin polymerization. These agents are in preclinical and clinical trials. One such agent, L-glutamine, decreases red blood cell oxidant injury and is recently US Food and Drug Administration approved to prevent acute pain episodes of SCD in patients 5 years of age or older. The purpose of this review is to describe the currently established therapies, barriers to curative therapies, and novel therapeutic agents that can target sickle cell hemoglobin polymerization and/or its downstream sequelae. A PubMed search was conducted for articles published up to May 15, 2018, using the search terms sickle cell disease, novel treatments, hematopoietic stem cell transplantation, and gene therapy. Studies cited include case series, retrospective studies, prospective clinical trials, meta-analyses, online abstracts, and original reviews. PMID- 30414735 TI - Prognosis assessment by pathologist: Is the detection of intratumoural tertiary lymphoid structures a reliable tool? PMID- 30414736 TI - Breastfeeding and NAFLD from the maternal side of the mother-infant dyad. PMID- 30414737 TI - Hepatic encephalopathy: Another brick in the wall. PMID- 30414738 TI - Prognostic factors impacting survival in early stage uterine carcinosarcoma. AB - OBJECTIVE: Evaluate the impact of clinicopathologic characteristics and adjuvant treatment on survival outcomes in early stage uterine carcinosarcoma patients. METHODS: We performed a retrospective cohort study of women with stage I or II uterine carcinosarcoma at our institution between March 1990 and June 2016. All pathology had been reviewed and confirmed by gynecologic pathologists. Data were extracted from the electronic medical record. Descriptive and comparative statistics were used to compare clinicopathologic characteristics. Univariable and multivariable analyses were performed for survival outcomes. RESULTS: 140 patients were identified. Median age was 67 years (range: 36-91). Median follow up was 39.1 months (2.9-297.4). The majority of patients had stage IA (67%) versus stage IB (21%) or stage II (11%) disease. The majority of patients (63%) received adjuvant treatment: vaginal brachytherapy only (14%); whole pelvic radiation therapy only (16%); chemotherapy only (n = 13, 9%); combination chemotherapy and vaginal brachytherapy (15%); combination chemotherapy and whole pelvic radiation (9%). 52 patients (37%) received no adjuvant therapy. Median overall survival (OS) was 48.0 months (95% CI 32.7-80.9). On multivariable analysis for OS, advancing age (HR 1.05, 95% CI 1.03-1.08, p < 0.001), higher stage (stage IB: HR 1.64, 95% CI 0.91-2.95, p = 0.10; stage II: HR 3.04, 95% CI 1.51-6.13, p = 0.002), and the presence of a rhabdomyosarcoma component (HR 1.66, 95% CI 1.02-2.70, p = 0.04) were significantly associated with worse OS. CONCLUSIONS: Advancing age, stage, and the presence of a rhabdomyosarcoma component were all associated with worse OS in patients with early stage uterine carcinosarcoma. New treatment algorithms should incorporate factors aside from stage alone. PMID- 30414739 TI - Cyclin D1 silencing impairs DNA double strand break repair, sensitizes BRCA1 wildtype ovarian cancer cells to olaparib. AB - OBJECTIVE: Poly(ADP-ribose) polymerase inhibitors (PARPi) are active in cancer cells that have impaired repair of DNA by the homologous recombination (HR) pathway. Strategies that disrupt HR may sensitize HR-proficient tumors to PARP inhibition. As a component of the core cell cycle machinery, cyclin D1 has unexpected function in DNA repair, suggesting that targeting cyclin D1 may represent a plausible strategy for expanding the utility of PARPi in ovarian cancer. METHODS: BRCA1 wildtype ovarian cancer cells (A2780 and SKOV3) were treated with a combination of CCND1 siRNA and olaparib in vitro. Cell viability was assessed by MTT. The effects of the combined treatment on DNA damage repair and cell cycle progression were examined to dissect molecular mechanisms. In vivo studies were performed in an orthotopic ovarian cancer mouse model. Animals were treated with a combination of lentivirus-mediated CCND1 shRNA and olaparib or olaparib plus scrambled shRNA. Molecular downstream effects were examined by immunohistochemistry. RESULTS: Silencing of cyclin D1 sensitized ovarian cancer cells to olaparib through interfering with RAD51 accumulation and inducing cell cycle G0/G1 arrest. Treatment of lentivirus-mediated CCND1-shRNA in nude mice statistically significantly augmented the olaparib response (mean tumor weight +/ SD, CCND1-shRNA plus olaparib vs scrambled shRNA plus olaparib: 0.172 +/- 0.070 g vs 0.324 +/- 0.044 g, P< 0.05). CONCLUSIONS: Silencing of cyclin D1 combined with olaparib may lead to substantial benefit for ovarian cancer management by mimicking a BRCAness phenotype, and induction of G0/G1 cell cycle arrest. PMID- 30414740 TI - Prediction of short-term surgical complications in women undergoing pelvic exenteration for gynecological malignancies. AB - OBJECTIVE: Pelvic exenteration (PE) is an extensive surgery associated with high rates of postoperative morbidity and mortality. The absence of well-defined preoperative selection criteria to identify patients eligible for PE prompted the assessment of pre-operative predictors of 30-day major surgical complications. METHODS: Demographics and surgical characteristics of patients undergoing PE for gynecologic cancer in a single institution between 01/2004-12/2016 were reviewed. Postoperative complications within 30 days following surgery were graded using the Accordion grading system. Logistic regression was used to analyze potential risk factors for severe postoperative complications. RESULTS: A total of 138 patients were included in the cohort. Forty-five patients underwent total PE, 52 anterior PE, and 41 posterior PE. Among the 137 patients with follow-up, a severe postoperative complication was experienced by 37 patients (27.0%) and 3 patients (2.2%) experienced death within 90 days. The most frequent grade 3 complications were complications of urinary reconstruction (n = 15), wound dehiscence (n = 9), and abdominal abscess requiring intervention with drain or return to the operating room (n = 6). On multivariable analysis, independent predictors of severe postoperative complications were anterior or total PE (adjusted odds ratio (aOR): 11.66, 95% CI 2.56-53.18), pre-operative hemoglobin <=10 mg/dl (aOR 2.70, 95% CI 1.02-7.14) and presence of 3+ comorbidities (aOR: 2.76, 95% CI 1.07-7.10). CONCLUSIONS: Major complications after exenteration are common. Surgical complexity and patient selection play a considerable role in predicting complications. These data can be used to better risk stratify patients undergoing PE. PMID- 30414741 TI - Effects of bilateral salpingo-oophorectomy on menopausal symptoms and sexual functioning among women with a BRCA1 or BRCA2 mutation. AB - INTRODUCTION: Prophylactic bilateral salpingo-oophorectomy (BSO) is recommended at an early age to BRCA mutation carriers to prevent ovarian cancer. It is critical to evaluate the impact of BSO on non-cancer outcomes, including quality of life (QOL), menopausal symptoms and sexual functioning. METHODS: BRCA mutation carriers who elected to undergo a BSO completed three questionnaires prior to surgery and then again approximately one and three years following surgery which included: 1) medical history questionnaire, 2) Menopause-Specific Quality of Life Intervention questionnaire and 3) Sexual Activity Questionnaire. The change in quality of life, menopausal symptoms and sexual functioning before and after oophorectomy was determined using a paired t-test and stratified by menopausal status at surgery. RESULTS: We included 140 BRCA mutation carriers with an average follow-up of 3.5 years following BSO. Among 93 women who were premenopausal, oophorectomy was associated with an increase in menopausal symptoms (vasomotor, physical) (P < 0.001) and a decline in sexual functioning (discomfort, pleasure) (P <= 0.0001), but had no impact on overall QOL (P = 0.31). HRT mitigated, but did not eliminate the adverse effects. Women who were postmenopausal at surgery (n = 47) experienced an increase in physical symptoms (P = 0.03) and a decline in sexual functioning (discomfort) (P = 0.004) and in overall QOL (P = 0.04). CONCLUSIONS: This study demonstrates that 3.5 years after oophorectomy, BRCA mutation carriers experience a significant worsening of menopausal symptoms and a decline in sexual functioning, particularly among those who underwent surgery prior to natural menopause. The use of HRT mitigated some but not all the effects. Overall, women who were premenopausal at surgery did not experience a decline in their QOL. PMID- 30414742 TI - Acute ischemic stroke in a trauma cohort: Incidence and diagnostic challenges. AB - INTRODUCTION: Diagnosis of acute ischemic stroke is critical for acute intervention. Its diagnosis may be obscured in trauma patients due to confounding injuries. We report its incidence in trauma patients following their presentation at our institution. METHODS: Electronic charts of all acute trauma patients presenting to a designated level 1 trauma center emergency department between September 2012-November 2015 were screened and included in the study if they had a discharge diagnosis of acute ischemic stroke. Patient data were reviewed to identify the presence of neurologic deficit on initial triage, imaging type obtained (intracranial or extracranial) and time to diagnosis of stroke. RESULTS: Of 192 trauma patients screened, 11 were found to have acute ischemic stroke (5.7%). Patients were generally young (median age, 49 years) and predominantly males (n = 8). Presentation after vehicular crash was most frequent (n = 8 or 73%). Patients had predominantly skeletal injuries (n = 8 or 73%). Initial workup involved vascular imaging below the neck (n = 9), while only one had intracranial vascular imaging. When patients underwent cervicocranial vascular imaging, 64% (n = 7) had findings explaining the etiology of their stroke. None of the patients was diagnosed with acute ischemic stroke on admission. Its diagnosis was delayed by an average 1.8 days following presentation. CONCLUSIONS: Acute ischemic stroke in trauma patients was a frequent diagnosis albeit with delay. Routine craniocervical vascular imaging at the time of presentation could potentially facilitate early diagnosis. A prospective study with routine craniocervical vascular imaging in trauma patients will be needed to further explore this hypothesis. PMID- 30414743 TI - Comparison of phenobarbital-adjunct versus benzodiazepine-only approach for alcohol withdrawal syndrome in the emergency department. AB - OBJECTIVES: To compare a phenobarbital-adjunct versus benzodiazepine-only approach for the management of alcohol withdrawal syndrome in the emergency department (ED) with regard to the need for intensive care unit (ICU) admission, severity of symptoms on ED discharge, and complications. METHODS: This was a retrospective cohort study conducted in two academic EDs in the United States. Adult patients seen in the ED with a diagnosis of alcohol withdrawal syndrome were included. Patients were categorized into two groups based on whether phenobarbital was administered in the ED: 1) phenobarbital group (with or without benzodiazepines) or 2) non-phenobarbital group. The primary outcome measure was the need for ICU admission. Secondary outcomes included Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) scores at ED discharge, and complications. Complications were a composite of death, need for intubation, hypotension or vasopressor use, seizures, and hospital acquired pneumonia. RESULTS: The study cohort included 209 patients (phenobarbital = 97, non phenobarbital = 112). The mean (standard deviation) age was 49 (12) years and 85% (n = 178) were male. A similar proportion of patients in the phenobarbital (14%, n = 14) and non-phenobarbital (11%, n = 12) groups required ICU admission (p = 0.529). The median CIWA-Ar score on ED discharge was 7 (IQR 4-12) points in the phenobarbital group and 7 (IQR 4-14) points in the non-phenobarbital group (p = 0.752). The occurrence of complications was also similar in the phenobarbital (9%, n = 9) and non-phenobarbital groups (11%, n = 10). CONCLUSION: Adjunctive phenobarbital use in the ED for alcohol withdrawal syndrome did not result in decreased ICU admission, severity of symptoms, or complications. PMID- 30414744 TI - Acute liver failure: A review for emergency physicians. AB - INTRODUCTION: Acute liver failure (ALF) remains a high-risk clinical presentation, and many patients require emergency department (ED) management for complications and stabilization. OBJECTIVE: This narrative review provides an evidence-based summary of the current data for the emergency medicine evaluation and management of ALF. DISCUSSION: While ALF remains a rare clinical presentation, surveillance data suggest an overall incidence between 1 and 6 cases per million people every year, accounting for 6% of liver-related deaths and 7% of orthotopic liver transplants (OLT) in the U.S. The definition of ALF includes neurologic dysfunction, an international normalized ratio >= 1.5, no prior evidence of liver disease, and a disease course of <=26 weeks, and can be further divided into hyperacute, acute, and subacute presentations. There are many underlying etiologies, including acetaminophen toxicity, drug induced liver injury, and hepatitis. Emergency physicians will be faced with several complications, including encephalopathy, coagulopathy, infectious processes, renal injury, and hemodynamic instability. Critical patients should be evaluated in the resuscitation bay, and consultation with the transplant team for appropriate patients improves patient outcomes. This review provides several guiding principles for management of acute complications. Using a pathophysiological-guided approach to the management of ALF associated complications is essential to optimizing patient care. CONCLUSIONS: ALF remains a rare clinical presentation, but has significant morbidity and mortality. Physicians must rapidly diagnose these patients while evaluating for other diseases and complications. Early consultation with a transplantation center is imperative, as is identifying the underlying etiology and initiating symptomatic care. PMID- 30414745 TI - A case of breastfeeding ketoacidosis: A rare but important diagnosis for emergency physicians to recognize. AB - We report a case of lactation ketoacidosis in a 22-year-old female who was breastfeeding two infants while dieting. She appeared non-toxic, but had a serum bicarbonate of 7meq/L, a pH of 7.07, and moderate serum ketones. She responded well to simple carbohydrate replenishment and brief cessation of breastfeeding. Emergency Physicians should be aware of this entity so as to avoid unnecessary morbidity and to begin prompt treatment. PMID- 30414746 TI - Who is the principal offender? PMID- 30414747 TI - OCT/atherectomy/pathology studies open new perspectives for in vivo characterization of plaque composition. PMID- 30414748 TI - Incidence and predictors of stroke in patients discharged with the diagnosis of acute coronary syndrome. AB - BACKGROUND: Stroke is one the most feared cardiovascular disease due to its high risk of disability and its incidence after an acute coronary syndrome (ACS) is not uncommon. METHODS: Retrospective study of all consecutive patients admitted for an ACS in two hospitals. Competing risk regression, taking all-cause mortality as a competing event, was used for the assessment of stroke incidence. RESULTS: We included 8771 patients, AF prevalence 12.4%. AF patients were older and presented higher prevalence of cardiovascular risk factors, previous cardiovascular disease, and lower glomerular filtration rate. Less than half of AF patients were receiving oral anticoagulation before admission. In-hospital mortality was 5.1% and it was more than two-fold higher in AF patients (10.2% vs. 4.4%; p < 0.01). Relevant differences on medical treatments were observed at discharge and oral anticoagulation was roughly <50% in AF patients. During a median follow-up was 58.7 months, 313 patients experienced at least one stroke (incidence 3.8%, 95% CI 3.4-4.2,) and it was 2-fold higher in patients with AF: 7.8% vs. 3.3% (p < 0.01). Median time to first stroke was 33.0 (30.1) months and it was shorter for AF patients compared to non-AF patients (28.2 +/- 22.3 vs. 34.6 +/- 31.1; p < 0.01). The adjusted competing risk regression identified AF, previous stroke and CHA2DS2-VASc score = 2 or >=3 as independent predictors of stroke; CHA2DS2-VASc score = 2 was associated to higher risk of stroke only in AF patients. CONCLUSIONS: The long-term incidence of stroke after an ACS was 3.8%, 7.8% in AF-patients and 3.3% in patients without any diagnosis of AF. PMID- 30414749 TI - Resuscitation for out-of-hospital cardiac arrest in adults with congenital heart disease. AB - AIMS: Adult congenital heart disease (ACHD) patients are at increased risk of sudden cardiac death and out-of-hospital cardiac arrest (OHCA). Currently, insufficient data exist on outcome, causes and circumstances of OHCA of ACHD patients resuscitated for OHCA. We investigate these parameters in ACHD patients in comparison to OHCA in the general population. METHODS AND RESULTS: We identified ACHD patients with OHCA by linking data from a Dutch nationwide registry of ACHD patients (CONCOR, n = 15,727), and ARREST, a cohort of OHCA cases (n = 17,868). 62 ACHD patients with OHCA were identified. Ventricular septal defect (n = 11), bicuspid aortic valve (n = 10) and atrial septal defect (n = 8) were the most common diagnoses. We included OHCA cases from the general population as controls. ACHD patients were younger than controls (n = 11,624) at the time of OHCA (47 (SD +/- 17) years vs. 66 (SD +/- 15) years, respectively, p < 0.001), and more often had a shockable initial rhythm (67% vs 40%, respectively, p < 0.001). A cardiac cause of OHCA was identified in 76% of ACHD patients, with only 7% due to myocardial infarction or ischemia. Survival was better in ACHD patients than in controls (44% vs. 19%, p < 0.001), but this difference disappeared after correction for age, gender, witnessed arrest, bystander resuscitation, public location and shockable rhythm. CONCLUSIONS: OHCA in ACHD patients occurs at young age, is rarely caused by ischemia and occurs mainly in patients with simple congenital defects. Risk stratification efforts should therefore not be restricted to ACHD patients with severe congenital defects. PMID- 30414750 TI - Response to letter from dr Altmayer regarding publication "Sequential treatment with sildenafil and riociguat in patients with persistent or inoperable chronic thromboembolic pulmonary hypertension improves functional class and pulmonary hemodynamics". PMID- 30414751 TI - Funding sources and costs to deliver cardiac rehabilitation around the globe: Drivers and barriers. AB - BACKGROUND: Cardiac rehabilitation (CR) reach is minimal globally, primarily due to financial factors. This study characterized CR funding sources, cost to patients to participate, cost to programs to serve patients, and the drivers of these costs. METHODS: In this cross-sectional study, an online survey was administered to CR programs globally. Cardiac associations and local champions facilitated program identification. Costs in each country were reported using purchasing power parity (PPP). Results were compared by World Bank country income classification using generalized linear mixed models. RESULTS: 111/203 (54.68%) countries in the world offer CR, of which data were collected in 93 (83.78% country response rate; N = 1082 surveys, 32.0% program response rate). CR was most-often publicly funded (more in high-income countries [HICs]; p < .001), but in 60.20% of countries patients paid some or all of the cost. Funding source impacted capacity (p = .004), number of patients per exercise session (p < .001), personnel (p = .037), and functional capacity testing (p = .039). The median cost to serve 1 patient was $945.91PPP globally. In low and middle-income countries (LMICs), exercise equipment and stress testing were perceived as the most expensive delivery elements, with front-line personnel costs perceived as costlier in HICs (p = .003). Modifiable factors associated with higher costs included CR team composition (p = .001), stress testing (p = .002) and telemetry monitoring in HICs (p = .01), and not offering alternative models in LMICs (p = .02). CONCLUSIONS: Too many patients are paying out-of-pocket for CR, and more public funding is needed. Lower-cost delivery approaches are imperative, and include walk tests, task-shifting, and intensity monitoring via perceived exertion. PMID- 30414752 TI - The Core of Parents' Main Concerns When Having a Child With Cataract and Its Clinical Implications. AB - PURPOSE: To investigate the main concerns associated with being a parent of a child with cataract and how the parents deal with these concerns. DESIGN AND METHOD: Twenty-three parents; 6 mothers, 5 fathers and 6 couples with a child with cataract were included in this study. The parents included some with a personal experience of cataract and some without. Data was collected through 17 in-depth interviews, which were recorded and transcribed verbatim for analysis by the method of Grounded Theory developed by Charmaz. RESULTS: The Grounded Theory describes the parents' efforts to balance the child's inability and ability in order to maintain their social functioning and lead a normal life through a process comprising four main categories; Mastering, Collaborating, Facilitating, and Adapting. This process makes the path of transition evident, starting when the child is diagnosed and continuing for several years during her/his growth and development. CONCLUSION: The core of parent-child interaction is mastering the balance between the child's disability and ability in order to achieve the best possible outcome, visually and habitually. The interactions changes through a process towards adjustment and acceptance. All the parents emphasized that you do what you have to do to achieve a successful visual outcome of the child. CLINICAL IMPLICATIONS: The model provides a comprehensive understanding of parental self management that can be used by a case manager, preferable a nurse, to pilot the parents through the process. PMID- 30414753 TI - Evidence for the Validity of the Children's Attraction to Physical Activity (CAPA) Scale in Iranian Preschool Children. AB - PURPOSE: The escalating trend of overweight and obesity is a major global health challenge and needs particular attention. There are a number of reasons for this increase, but the dominant one appears to be the pandemic of physical inactivity. It is now clear that children's attraction to physical activity is an important promising factor in children's physical activity involvement. In this study, we aimed to cross-validate the long version of children's attraction to physical activity (CAPA) scale in Iranian preschool children. DESIGN AND METHODS: Evidence for the validity of the scale was based on face validity, content validity, and internal consistency. The scale was translated into Persian and underwent forward translation, synthesis of the translation and backward translation. Face and content validity were subsequently assessed on individuals and expert panels. A sample of 30 preschool children (5-6 years of age) were randomly selected from three kindergartens. Children were interviewed by their kindergarten teachers. RESULTS: Internal consistency for each of the five subscales of the CAPA scale was evaluated through Cronbach's alpha. The internal consistency was acceptable for most of the subscales when negative statements were excluded from the analyses. CONCLUSIONS: The results supported the use of modified version of Persian-language long CAPA scale for Iranian preschool children, with the deletion of negatively worded items. PRACTICE IMPLICATIONS: Health care professionals may use the CAPA when assessing the attraction of children toward physical activity and its potential involvement in childhood obesity. PMID- 30414754 TI - Predictive factors for survival of oligometastatic colorectal cancer treated with Stereotactic body radiation therapy. AB - BACKGROUND AND PURPOSE: Colorectal cancer (CRC) represents one of the major leading causes of death from cancer. Aim of the present study was to analyze outcome of oligometastatic CRC patients treated with stereotactic body radiation therapy (SBRT), and to evaluate predictive factors of survival. MATERIALS AND METHODS: We included patients with maximum 5 metastases. Previous/concomitant systemic treatments were allowed. End points of the present study were the outcome in terms of Local control of treated metastases (LC), progression free survival (PFS), and overall survival (OS). RESULTS: 437 metastases were treated in 270 patients. Lung was site of metastases in 48.5% of cases, followed by liver (36.4%). Systemic treatment was administered before SBRT in 199 patients (73.7%). Median follow-up time was 23 months (3-98.7). Rates of LC at 1, 3 and 5 years were 95%, 73% and 73%, respectively. Time from diagnosis of metastases to SBRT was the only factor predictive of LC (HR 1.62, p = 0.023). Median PFS was 8.6 months. Rates of OS at 1, 3 and 5 years were 88.5%, 56.6%, and 37.2%, respectively. Lesion greater than 30 mm (HR 1.82, p = 0.030), presence of non lung metastases (HR 1.67, p = 0.020), the use of systemic treatment before SBRT (HR 1.82, p = 0.023), and progression of treated metastases (HR 1.80, p = 0.007), were all predictive of worse OS. CONCLUSIONS: Stereotactic body radiation therapy represents an effective approach in the management of oligometastatic CRC. Control of treated oligometastases seems to be a strong positive predictive factor for both PFS and OS. PMID- 30414755 TI - Persistent reduction in global longitudinal strain in the longer term after radiation therapy in patients with breast cancer. AB - BACKGROUND: More than 80% of breast cancer patients receive radiotherapy (RT). However, RT can lead to cardiotoxicity, which usually develops insidiously over years, making diagnosis difficult. It is also unknown whether early identification of at-risk patients might improve long-term outcome. We have previously described subclinical alterations, detected by two-dimensional speckle tracking strain echocardiography, in left ventricular (LV) function immediately following RT in breast cancer. HYPOTHESIS: Subclinical myocardial alterations in LV function consequent to RT cardiotoxicity, observed early, persist at 12 months. METHODS: 40 chemotherapy naive women with left-sided breast cancer, treated with surgery and adjuvant breast RT, were prospectively recruited from two tertiary hospitals. Transthoracic echocardiography was performed at baseline (pre-RT), 6 weeks post-RT, and 12 months post-RT. RESULTS: An increase in LV end diastolic and end systolic volumes was seen from baseline, consistent with persistent LV remodelling; however, due to the increase in both systolic and diastolic volumes over time, no change in LV ejection fraction (EF) was observed. Global longitudinal strain (GLS) and S' velocity remained significantly lower at 12 months post-RT. GLS dropped by >10% in 16 patients and by >20% in 4 patients compared to baseline. CONCLUSIONS: Subclinical cardiac dysfunction using strain analysis, evident early, persists one year after RT, despite unchanged conventional indices such as LVEF. Persistent GLS reduction may be of particular importance in breast cancer patients receiving concomitant chemotherapy. Longer term prospective studies are required to determine if reductions in strain post RT are associated with future adverse cardiovascular events. PMID- 30414756 TI - Delineation guideline for the para-aortic lymph node region in cervical cancer - Clarification letter. PMID- 30414757 TI - Early outcomes of breast cancer patients treated with post-mastectomy uniform scanning proton therapy. AB - BACKGROUND: Postmastectomy proton radiotherapy improves normal tissue sparing in comparison to photon-based approaches. Several studies have reported dosimetry comparison and tolerable acute toxicity profile with limited follow-up. We report our institutional experience of postmastectomy proton radiation including clinical efficacy and toxicities. METHODS: From December 2013 to February 2015, 42 consecutive patients who received mastectomy for non-metastatic breast cancer were treated with adjuvant chest wall and regional nodal proton therapy at a single proton center. 3D conformal uniform scanning with en face matching fields was used. RESULTS: The median follow-up among patients was 35 months (range 1-55 months). There was one local failure, zero regional nodal failure, and six distant failures. The 3-year rate of locoregional disease-free survival was 96.3%, metastasis-free survival was 84.1%, and overall survival was 97.2%. The only local failure event occurred on the chest wall within the radiation field, approximately 2.5 years after the completion of radiation. Skin dermatitis, fatigue, and esophagitis were the most common acute toxicity. All patients developed grade 1 or 2 acute skin toxicity and there was no grade 3 or 4 acute skin toxicity. Proton radiation is able to achieve excellent target coverage with median PTV V95 over 95% and heart sparing with median mean heart dose less than 1 Gy (RBE). CONCLUSION: With close to three years of median follow-up, post mastectomy proton radiation has shown excellent locoregional control rates and favorable toxicity profile. Long-term adverse effect of heart-sparing radiation will require longer follow-up time and randomized clinical trials. PMID- 30414758 TI - Epoetin receptor status may alter the outcomes in head and neck cancers treated with radiotherapy and darbepoetin-alpha. PMID- 30414759 TI - Patterns of proton therapy use in pediatric cancer management in 2016: An international survey. AB - PURPOSE: To facilitate the initiation of observational studies on late effects of proton therapy in pediatric patients, we report on current patterns of proton therapy use worldwide in patients aged less than 22 years. MATERIALS & METHODS: Fifty-four proton centers treating pediatric patients in 2016 in 11 countries were invited to respond to a survey about the number of patients treated during that year by age group, intent of treatment, delivery technique and tumor types. RESULTS: Among the 40 participating centers (participation rate: 74%), a total of 1,860 patients were treated in 2016 (North America: 1205, Europe: 432, Asia: 223). The numbers of patients per center ranged from 1 to 206 (median: 29). Twenty-four percent of the patients were <5 years of age, and 50% <10 years. More than 30 pediatric tumor types were identified, mainly treated with curative intent: 48% were CNS, 25% extra-cranial sarcomas, 7% neuroblastoma, and 5% hematopoietic tumors. About half of the patients were treated with pencil beam scanning. Treatment patterns were broadly similar across the three continents. CONCLUSION: To our knowledge, this survey provides the first worldwide assessment of proton therapy use for pediatric cancer management. Since previous estimates in the United States and Europe, CNS tumors remain the cancer types most commonly treated with protons in 2016. However, the proportion of extra-cranial tumors is growing worldwide. The typically low numbers of patients treated in each center indicate the need for international research collaborations to assess long-term outcomes of proton therapy in pediatric patients. PMID- 30414760 TI - Disseminated neoplasia in cultured Crassostrea gasar oysters from northeast Brazil. AB - Disseminated neoplasia (DN) is a disease that affects bivalves worldwide and can lead to mass mortalities. In the present study, a pathological survey conducted from December 2011 to August 2012 in Crassostrea gasar, an oyster of commercial interest in northeast Brazil, revealed the occurrence of DN in oysters reared in the Mamanguape estuary, Paraiba State, Brazil. The present work describes the pathological and functional aspects of the disease in C. gasar by light microscopy (haemolymph cell monolayer and histological section) and flow cytometry analyses. The prevalence of the disease was low (7.1% of 182 oysters examined). Enlarged (neoplastic) cells showed reniform, ovoid or circular-shaped nuclei, with prominent nucleoli and predominantly short filipodia. They were found in the haemolymph and infiltrated the connective tissues of different organs, including the digestive system, gills and gonads, as well as in the sinuses and vessels. Three levels of progression of DN in tissues were observed, light (61.5%), moderate (15.4%) and advanced (23.1%). The viability of neoplastic cells circulating in the haemolymph (97.4%) was similar to that in the haemocytes (95.7%). The neoplastic cells showed low phagocytic ability (3.9%) compared with that of haemocytes (42.4%). Conversely, reactive oxygen species production (679 A.U.) and the total haemocyte count (3.9 * 106 cells mL-1) were higher in the affected oysters than in unaffected oysters (268 A.U. and 1.5 * 106 cells mL-1, respectively). The low prevalence and primarily mild intensity found in the sampled oysters does not preclude an impact at the population level. A timely survey of DN is thus recommended in order to assess the severity and impact of this disease in wild and cultured populations of C. gasar oysters. PMID- 30414761 TI - See 1-simulate 10,000-do 1; teach 1. PMID- 30414762 TI - Pathology of valved venous homografts used as right ventricle-to-pulmonary artery conduits in congenital heart disease surgery. AB - OBJECTIVES: Although valved venous homografts (VVHs) are used for establishing right ventricle-to-pulmonary artery continuity in some complex heart defects, the tissue changes that occur in situ have not been described. We review the gross and microscopic changes observed in explanted VVH conduits and their effects on functionality. METHODS: In total, 20 explanted VVH conduits were evaluated for valve integrity, presence of thrombus, and stenosis. Hematoxylin and eosin- and trichrome-stained sections were reviewed for neointima formation, wall remodeling, inflammation, and calcification. Regurgitation and narrowing were assessed on pre-explant echocardiogram, and angiographic video clips were correlated with tissue findings. The source of the proliferating cells within the conduits was investigated by fluorescent in situ hybridization. RESULTS: Thirteen male and 7 female infants underwent VVH implantation either as part of a composite Sano shunt (65%) or to establish right ventricle-to-pulmonary artery continuity in biventricular hearts (35%). The median duration of conduits in situ was 140 days (range: 98-340 days). Conduits were predominantly explanted for staged conversion to bidirectional Glenn (60%) and conduit upsizing (20%). The valves remained intact and functional in 75% of cases. Occlusive thrombosis was absent in all. Wall thickening due to neointima formation and wall remodeling was uniformly present and appeared to be driven by smooth muscle actin-expressing cells, which by fluorescent in situ hybridization are predominantly of recipient origin. Minimal calcification and mild adventitial chronic inflammation were present. CONCLUSIONS: Vein wall thickening is a uniform finding and can cause stenosis. The valves remain functional in most, and vein walls undergo remodeling with only minimal inflammation and calcification. PMID- 30414763 TI - Post-thoracotomy pain and nerve protection: Back to the drawing board? PMID- 30414764 TI - True, true, or unrelated? Fluoroquinolones and aortic disease. PMID- 30414765 TI - Open versus clamp-on distal anastomosis techniques in acute type A aortic dissection: The ship has already left the port. PMID- 30414766 TI - Coarctation, aneurysm, carotid agenesis, oh my! Complex arch anatomy requires thoughtful operative planning for safe repair. PMID- 30414767 TI - Ligating the left atrial appendage in atrial fibrillation: What additional evidence do surgeons need? PMID- 30414768 TI - A glimpse into the future for transcatheter mitral valve replacement in mitral annular calcification. PMID- 30414769 TI - Dance with me to the end of love: Serotonin and the carcinoid heart. PMID- 30414770 TI - Characteristics and longer-term outcomes of paravalvular leak after aortic and mitral valve surgery. AB - BACKGROUND: Paravalvular leak (PVL) is often seen after aortic (AV) and mitral valve (MV) surgery, either due to infection or valve dehiscence. We sought to describe predictors of longer-term outcomes in patients who developed PVL after AV and MV surgery and were considered eligible for reoperative cardiac surgery (RCS). METHODS: We studied 495 such patients (65 +/- 14 years, 65% men, 47% with MV PVL) who presented at our center between January 2003 and December 2011. Patients with severe mitral/aortic stenosis, patients with less than mild PVL, and those with prohibitive risk precluding RCS were excluded. Society of Thoracic Surgeons (STS) score was calculated. Primary endpoint was mortality. RESULTS: At baseline, mean STS score and left ventricular ejection fraction were 5.8 +/- 4% and 52 +/- 12%, respectively. In total, 105 (21%) had infective PVL and 72% had moderate or greater PVL. At a median of 8 days, 351 (71%) patients underwent RCS to repair PVL (3% in-hospital postoperative mortality), and at 6.6 +/- 4 years, 230 (47%) patients died. On multivariable Cox survival analysis, greater STS score (hazard ratio or HR 1.35), mitral versus aortic PVL (HR 1.66), infectious etiology (HR 2.05), and greater right ventricular systolic pressure (HR 1.09) were associated with greater longer-term mortality, whereas surgery (HR 0.58) was associated with improved longer-term survival (all P < .05). CONCLUSIONS: Patients who develop mild or greater PVL after AV/MV surgery have a high rate of longer-term mortality, despite excellent perioperative outcomes. Greater STS score, right ventricular systolic pressure, infectious etiology, and MV (vs AV) involvement were all independently associated with long-term mortality, whereas RCS for PVL closure was associated with improved longer-term survival. PMID- 30414771 TI - "Crossing the quality chasm" in cardiothoracic surgical education. PMID- 30414772 TI - In vitro comparison of the hemocompatibility of two centrifugal left ventricular assist devices. AB - OBJECTIVES: Shear stress from left ventricular assist devices induces von Willebrand factor degradation and platelet dysfunction, leading to nonsurgical bleeding. We characterized the hemostatic changes induced by 2 centrifugal left ventricular assist devices, the HeartMate 3 (Abbott Inc, Chicago, Ill) and the EVAHEART (Evaheart Inc, Houston, Tex), for comparison. METHODS: Whole blood from 8 healthy volunteers was used ex vivo. Blood from the same donor was used for 6 hours of circulation in a miniature mock-loop system consisting of 2 identical extracorporeal circuits to compare the following experimental settings: (1) optimal revolutions per minute (rpm) for the HeartMate 3 (n = 4; 5000 rpm) and the EVAHEART (n = 4; 2500 rpm) and (2) equal rpm (3000 rpm for the HeartMate 3 and EVAHEART, n = 4 vs n = 4). For both settings, blood flow was adjusted to 1 mock-loop filling volume per minute (HeartMate 3 = 82 mL/min, EVAHEART = 100 mL/min). A panel of coagulation markers was analyzed to investigate hemostatic changes. RESULTS: The free plasma hemoglobin concentration was significantly lower in the EVAHEART compared with the HeartMate 3 after 6 hours of mock-loop circulation under both settings (optimal: 37 +/- 31 vs 503 +/- 173 mg/dL, P < .0001; equal: 27 +/- 4 vs 139 +/- 135 mg/dL, P = .024). Loss of von Willebrand factor high-molecular-weight multimers occurred in both left ventricular assist devices and settings, but the von Willebrand factor:activity/von Willebrand factor:antigen ratio after 6 hours was significantly lower in optimal settings for the HeartMate 3 (P = .009). The thrombin-antithrombin complex level was significantly lower with the EVAHEART for both settings (P < .0001). CONCLUSIONS: The EVAHEART left ventricular assist device caused less hemolysis, resulted in lower coagulation activation, and provided better preservation of von Willebrand factor functional activity compared with the HeartMate 3 device. These findings prove that left ventricular assist device design plays a major role in minimizing blood damage during left ventricular assist device support. PMID- 30414773 TI - Have mitral valve simulators made it to reality? PMID- 30414774 TI - To be or not to be: The guidelines are the question. PMID- 30414775 TI - Does valve choice matter in patients receiving hemodialysis? PMID- 30414776 TI - This side up. PMID- 30414777 TI - Continued pursuit of evidence-based indications and the optimal operation for pediatric valve-sparing aortic root replacement. PMID- 30414778 TI - Are we throwing the baby out with the bath water: Redux. PMID- 30414779 TI - Accelerated onset of chronic wasting disease in elk (Cervus canadensis) vaccinated with a PrPSc-specific vaccine and housed in a prion contaminated environment. AB - Chronic wasting disease (CWD) is a fatal prion disease affecting multiple cervid species. Effective management tools for this disease, particularly in free ranging populations, are currently limited. We evaluated a novel CWD vaccine in elk (Cervus canadensis) naturally exposed to CWD through a prion-contaminated environment. The vaccine targets a YYR disease-specific epitope to induce antibody responses specific to the misfolded (PrPSc) conformation. Female elk calves (n = 41) were captured from western Wyoming and transported to the Thorne Williams Wildlife Research Center where CWD has been documented since 1979. Elk were held in contaminated pens for 14 to 20 days before being alternately assigned to either a vaccine (n = 21) or control group (n = 20). Vaccinated animals initially received two vaccinations approximately 42 days apart and annual vaccinations thereafter. Vaccination induced elevated YYR-specific antibody titers in all animals. Elk were genotyped for the prion protein gene at codon 132, monitored for clinical signs of CWD through daily observation, for disease status through periodic biopsy of rrectoanal mucosa-associated lympoid tissue (RAMALT), and monitored for YYR-specific serum antibody titres. Mean survival of vaccinated elk with the 132MM genotype (n = 15) was significantly shorter (800 days) than unvaccinated elk (n = 13) of the same genotype (1062 days; p = 0.003). Mean days until positive RAMALT biopsy for 132MM vaccinated elk (6 7 8) were significantly shorter than unvaccinated 132MM elk (990; p = 0.012). There was, however, no significant difference in survival between vaccinated (n = 4) and control (n = 5) elk with the 132ML genotype (p = 0.35) or in timing of positive RAMALT biopsies of 132ML elk (p = 0.66). There was no strong (p = 0.17) correlation between YYR-specific antibody titers and survival time. Determining the mechanism by which this vaccine accelerates onset of CWD will be important to direct further CWD vaccine research. PMID- 30414780 TI - Improving immunization data quality in Peru and Mexico: Two case studies highlighting challenges and lessons learned. AB - INTRODUCTION: The Global Vaccine Action Plan and the Regional Immunization Action Plan of the Americas call for countries to improve immunization data quality. Immunization information systems, particularly electronic immunization registries (EIRs), can help to facilitate program management and increase coverage. However, little is known about efforts to develop and implement such systems in low- and middle-income countries. We present the experiences of Mexico and Peru in implementing EIRs. METHODS: We conducted case studies of an EIR in Mexico and of a population registry in Peru. Information was gathered from technical documents, stakeholder focus groups, site visits, and semi-structured interviews of national stakeholders. We organized findings into narratives that emphasized challenges and lessons learned. RESULTS: Mexico built one of the world's first EIRs, incorporating novel features such as local-level tracking of patients; however, insufficient resources and poor data registration practices led to the system's discontinuation. Peru created an information system to improve affiliation to social programs, including the immunization program and quality of demographic data. Mexico's experience highlights lessons in failed sustainability of an EIR and a laudable effort to reform a country's information system. Peru's demonstrates that attempts to improve health and other data may strengthen health systems, including immunization data. Major challenges in information system implementation and sustainability in Peru and Mexico related to funding, clear governance structures, and resistance among health workers. DISCUSSION: These case studies reinforce the need for countries to ensure adequate funding, plans for sustainability, and health worker capacity-building activities before implementing EIRs. They also suggest new approaches to implementation, including economic incentives for sub-national administrative levels and opportunities to link efforts to improve immunization data with other health and political priorities. More information on best practices is needed to ensure the successful adoption and sustainability of immunization registries in low- and middle-income countries. PMID- 30414781 TI - Preparing for safety monitoring after rotavirus vaccine introduction - Assessment of baseline epidemiology of intussusception among children <2 years of age in four Asian countries. AB - Intussusception is the invagination of one segment of the bowel into a distal segment, characterized by symptoms of bloody stool, vomiting, and abdominal pain. Previous studies have found regional differences in incidence but the etiology of most intussusception cases is unknown. Rotavirus vaccines were associated with a slightly of increased risk of intussusception in post-licensure evaluations in high- and middle-income countries, but not in low income African countries. To describe the baseline epidemiology of intussusception in young children prior to rotavirus vaccine implementation, active sentinel hospital surveillance for intussusception in children < 2 years of age was conducted in 4 low income Asian countries (Bangladesh, Nepal, Pakistan and Vietnam). Over a 24-month period, 15 sites enrolled 1,415 intussusception cases, of which 70% were enrolled in Vietnam. Overall, 61% of cases were male and 1% (n = 16) died, ranging from 8% in Pakistan to 0% in Vietnam. The median age of cases enrolled ranged from 6 months in Bangladesh and Pakistan to 12 months in Vietnam. The proportion of cases receiving surgical management was 100% in Bangladesh, 88% in Pakistan, 61% in Nepal, and 1% in Vietnam. The high proportion of males and median age of cases around 6 months of age found in this regional surveillance network are consistent with previous descriptions of the epidemiology of intussusception in these countries and elsewhere. Differences in management and the fatality rate of cases between the countries likely reflect differences in access to healthcare and availability of diagnostic modalities. These baseline data will be useful for post-rotavirus vaccine introduction safety monitoring. PMID- 30414782 TI - Immunogenicity and safety of the 4CMenB and MenACWY-CRM meningococcal vaccines administered concomitantly in infants: A phase 3b, randomized controlled trial. AB - BACKGROUND: Invasive meningococcal disease has its highest incidence in infants. Co-administration of serogroup B (4CMenB) and quadrivalent conjugate (MenACWY CRM) vaccines could protect against 5 clinically-relevant meningococcal serogroups. METHODS: This phase 3b, open, multicenter study (NCT02106390), conducted in Mexico and Argentina, enrolled and randomized (1:1:1) 750 healthy infants to receive either 4CMenB co-administered with MenACWY-CRM (4CMenB/MenACWY group), 4CMenB (4CMenB group), or MenACWY-CRM alone (MenACWY group) at ages 3, 5, 7 and 13 months. Non-inferiority of immune responses of co-administration to single administration of vaccines was assessed at 1 month post-booster dose (primary objective). Immunogenicity was evaluated pre- and 1 month post-primary and booster vaccinations using human serum bactericidal assay (hSBA). Safety was assessed. RESULTS: At 1 month post-booster vaccination, between-group hSBA geometric mean titer (GMT) ratios ranged from 0.89 to 1.03 for serogroup B strains (group 4CMenB/MenACWY over 4CMenB), and from 1.05 to 2.48 for ACWY serogroups (group 4CMenB/MenACWY over MenACWY). The lower limit of the 2-sided 95% confidence intervals for all GMT ratios was >0.5; the primary objective was demonstrated. Across all groups and serogroup B strains, 68-100% and 87-100% of children had hSBA titers >=5 at 1 month post-primary and booster vaccination, respectively. For serogroups ACWY, >=96% (post-primary vaccination) and >=98% (post-booster vaccination) of children in all groups had hSBA titers >=4. Post booster vaccination, GMTs increased >=5.99-fold from pre-booster values for each strain/serogroup. Solicited adverse events (AEs) were more frequent in groups 4CMenB/MenACWY and 4CMenB than in MenACWY; incidence of all other AEs was similar between groups. Serious AEs were reported for 6, 13, and 11 participants in groups 4CMenB/MenACWY, 4CMenB, and MenACWY, respectively; 1 (group 4CMenB) was considered vaccine-related. CONCLUSION: Immune responses elicited by co administration of 4CMenB and MenACWY-CRM was non-inferior to single immunization. Co-administration of vaccines was immunogenic and well tolerated in infants. ClinicalTrials.gov: NCT02106390. PMID- 30414783 TI - LACE-Bio: Validation of Predictive and/or Prognostic Immunohistochemistry/Histochemistry-based Biomarkers in Resected Non-small-cell Lung Cancer. AB - BACKGROUND: Complete resection of non-small-cell lung cancer (NSCLC) offers the potential for cure after surgery and adjuvant chemotherapy. Patients may not benefit and may experience severe toxicity. There are no validated molecular tools to allow better patient selection. MATERIALS AND METHODS: The LACE-Bio (LACE [Lung Adjuvant Cisplatin Evaluation]) project includes 4 trials (International Adjuvant Lung Cancer Trial [IALT], Adjuvant Navelbine International Trialist Association [ANITA], JBR10, and Cancer and Leukemia Group B (CALGB)-9633). Immunohistochemistry biomarkers shown in one trial to have a prognostic/predictive effect on overall survival were tested. RESULTS: The majority of the promising biomarkers could not be validated; the prognostic effect of tumor infiltrating lymphocytes and beta-tubulin was confirmed. Potential causes include tissue fixation, storage, the use of tissue microarrays, and varying reagent/antibody batches. CONCLUSIONS: Immunohistochemistry assays from single trials may be misleading and require validation before being used for patient selection. LACE-Bio-2 is evaluating potential genomic biomarkers that may allow more precise selection of patients with NSCLC for adjuvant chemotherapy in NSCLC. PMID- 30414784 TI - Development and Implementation of a Diabetic Ketoacidosis Protocol for Adults With Type 1 and Type 2 Diabetes at a Tertiary Care Multicampus Hospital. AB - OBJECTIVES: Diabetic ketoacidosis (DKA) is associated with significant morbidity and mortality. Using standardized protocols for DKA management improves outcomes and is recommended in Diabetes Canada's clinical practice guidelines. Audits of DKA care at our institution revealed inconsistent management. We developed, piloted and evaluated a standardized DKA protocol adapted into preprinted order sets for use in the emergency department and the acute monitoring area. METHODS: The protocol was developed by an expert committee on the basis of Diabetes Canada's clinical practice guidelines, a literature review and an environmental survey. A before-and-after analysis was used. Uptake of the DKA protocol and clinical outcomes were monitored through statistical process control. RESULTS: Patients admitted postprotocol (n=55, mean age 37.9 years [SD 17.5 years], 62% male, 85% type 1 diabetes) were compared to those admitted preprotocol (n=55, mean age 43.3 years [SD 17.5 years], 53% male, 67.2% type 1 diabetes). Postimplementation, 87% of patients were managed according to the protocol. Postprotocol ordering of appropriate laboratory investigations increased, appropriate intravenous (IV) fluid resuscitation improved, continuation of IV insulin until anion gap closure increased, mean time to anion gap closure decreased and mean length of stay was reduced. Of those surveyed, 85% of nurses and 74% of physicians felt that the protocol improved patient care, and 75% of patients rated their DKA management as being satisfactory. CONCLUSIONS: Successful implementation of a standardized preprinted protocol for DKA management significantly improved best practices for DKA management and was valued by treating clinicians. PMID- 30414785 TI - Effect of Aerobic and Resistance Exercise on Glycemic Control in Adults With Type 1 Diabetes. AB - OBJECTIVES: Physical exercise is recommended for individuals with type 1 diabetes, yet the effects of exercise on glycemic control are not well established. We evaluated the impact of different modes of exercise on glycemic control in people with type 1 diabetes. METHODS: In a 3-week randomized crossover trial, 10 adults with type 1 diabetes (4 men and 6 women, aged 33+/-6 years; duration of diabetes, 18+/-10 years; glycated hemoglobin level, 7.4%+/-1%) were assigned to 3 weeks of intervention: aerobic exercise (treadmill at 60% of maximum volume of oxygen utilization), resistance training (8 to 12 repetitions of 5 upper and lower body exercises at 60% to 80% of 1 repetition maximum) or no exercise (control). During each exercise week, participants completed 2 monitored 45 min exercise sessions. For each week of the study, we analyzed participants' insulin pump data, sensor glucose data and meal intake using a custom smart-phone application. The primary outcome was the percentage of time in range (glucose >3.9 mmol/L and <=10 mmol/L) for the 24 h after each bout of exercise or rest during the control week. The study was registered on ClinicalTrials.gov (NCT:02687893). RESULTS: Aerobic exercise caused a mean glucose reduction during exercise of 3.94+/-2.67 mmol/L, whereas the reduction during resistance training was 1.33+/-1.78 mmol/L (p=0.007). The mean percentage time in range for the 24 h after resistance training was significantly greater than that during the control period (70% vs. 56%, p=0.013) but not after aerobic exercise (60%). CONCLUSIONS: The results indicate that when various confounders are considered, resistance training could improve glycemic control in this population. PMID- 30414786 TI - Tibial tunnel widening following anterior cruciate ligament reconstruction: A retrospective seven-year study evaluating the effects of initial graft tensioning and graft selection. AB - PURPOSE: To investigate tibial tunnel widening in ACL reconstruction patients over seven years to establish the effects of initial graft tension on tibial widening and clinical outcomes when using both patellar tendon (BTB) and hamstring tendon (HS) grafts. METHODS: Ninety patients, who were reconstructed with BTB or HS autografts, were randomized using one of two initial graft tension protocols; 1) tensioned to restore normal anteroposterior laxity ("low-tension"; n = 46) and 2) tensioned to over-constrain anteroposterior (AP) laxity by two millimeters ("high-tension"; n = 44). Seventy patients had post-surgical data with 45 available for review at seven years. Tunnel widening was assessed via radiographs at one-, three-, and seven-year follow-up. Patient-reported outcomes were compared. RESULTS: The mean +/- 95% confidence intervals of the initial diameters for the BTB autografts were 10.3 +/- 0.5 mm (Low-tension) and 10.2 +/- 0.6 mm (High-tension) with final diameters of 10.8 +/- 0.6 mm (Low-tension) and 9.9 +/- 0.6 mm (High-tension). The initial diameters for HS autografts were 8.1 +/- 0.9 mm (Low-tension) and 8.4 +/- 0.7 mm (High-tension) with final diameters of 11.5 +/- 1.1 mm (Low-tension) and 11.1 +/- 0.9 mm (High-tension). For subjects with HS autografts, mean tunnel diameters significantly changed over time (p < .001); no significant changes were observed in BTB autografts (p = .29). Change in diameter of the HS autograft group remained significantly greater than the BTB group at all time points for both tension groups (p < .05). No differences in patient-reported outcomes were found between tension groups or graft types. CONCLUSIONS: Patients who underwent ACL-R with HS autograft exhibited tibial tunnel widening over seven years. Patients with BTB autografts did not experience widening, regardless of initial graft tension. Patient-reported outcomes were equivalent. PMID- 30414787 TI - No association between positive intraoperative allograft cultures and infection rates after reconstructive knee ligament surgery. AB - BACKGROUND: Several reports of severe infections associated with allograft tissue in knee reconstructive surgery have led many surgeons to consider routine intraoperative culture of allograft tissue before implantation. Thus, the purpose of this study was to determine the prevalence of positive soft tissue allograft cultures in reconstructive knee surgery, and evaluate its association with surgical site infection. METHODS: Retrospective study of 202 patients who underwent knee reconstructive ligament surgeries, including revisions, between January 2013 and July 2017. Intraoperative culture results were obtained and the report of a surgical site infection during follow-up was recorded. Patients without cultures were excluded. A priori power analysis was performed. The association between positive culture results and development of surgical site infection was evaluated using Fisher's Exact test (P < 0.05). RESULTS: A total of 300 allografts were implanted in 202 patients. Mean average follow-up was 32.9 +/ 12.5 (range 13 to 57.9) months. Sixteen patients had positive intraoperative allograft cultures (7.9%). The most frequently isolated organism was Bacillus species (six cultures); none of these patients presented with clinical signs of infection. Nine patients developed surgical site infections and were treated with oral antibiotics, and one patient developed septic arthritis that required surgical debridement of the implanted graft; all of these patients had a negative soft tissue allograft culture. No significant association was found between a positive culture and surgical site infection (P = 0.43). CONCLUSION: There was no apparent association between positive intraoperative irradiated soft tissue allograft cultures and surgical site infection in reconstructive knee surgery. PMID- 30414788 TI - Quantitative and qualitative assessment of frontal plane knee motion in males and females: A reliability and validity study. AB - BACKGROUND: The aim was to determine reliability and validity of frontal plane projection angle (FPPA) and visual assessments (VA) in both males and females. METHODS: Fifty-four participants (30 females) performed lateral step-downs while kinematics were recorded by two-dimensional and three-dimensional analyses. Two raters viewed the videos, extracted images, and measured the FPPA (quantitative). Using the videos, the raters also categorized (qualitative VA) each participant's motion as demonstrating dynamic valgus (>10 degrees valgus), dynamic varus (>10 degrees varus), or no change. Reliability was assessed for FPPA and VA using intraclass correlation coefficients and Kappa, respectively. Validity was determined by comparing the FPPA to three-dimensional measures (Pearson correlations) and comparing the VA to both FPPA and standard reference 3D kinematics (Kappa). RESULTS: FPPA showed good-excellent reliability (ICC = 0.850 0.998). VA showed minimal-moderate reliability (kappa = 0.370-0.766). The FPPA showed large correlations (r = -0.514-0.531) with hip adduction in both sexes but only a moderate relationship with knee abduction in males (r = 0.427-0.445). VA showed no-weak (kappa = 0.153-0.475) and weak-moderate (kappa = 0.455-0.698) agreement compared to FPPA and no-weak (kappa = -0.300-0.183) and no-minimal (kappa = -0.078-0.027) disagreement compared to the reference standard 3D kinematics in males and females, respectively. CONCLUSION: The quantitative FPPA is more reliable and valid than qualitative VA of frontal knee plane motion. PMID- 30414789 TI - The relationship between anteroposterior stability and medial-lateral stability of the bi-cruciate stabilized total knee arthroplasty. AB - BACKGROUND: Acquisition of appropriate anteroposterior (AP) stability depends on the prosthetic design and intraoperative soft tissue handling. A bi-cruciate stabilized (BCS) total knee arthroplasty (TKA) has a two cam-post mechanism, which substitutes for the anterior cruciate ligament and posterior cruciate ligament (PCL). Therefore, appropriate AP stability is expected. Because the PCL is sacrificed during BCS TKA, medial stability and lateral stability are thought to be important factors to determine AP stability. However, no previous study has reported AP stability after BCS TKA and the relationship between AP and medial lateral stability. METHODS: AP stability was measured using a navigation system intraoperatively and the KT 2000 device postoperatively. Intraoperative joint laxity of the medial and lateral compartments was evaluated separately using a compartment-specific ligament tensioner. The relationship between AP stability and medial-lateral laxity was assessed. RESULTS: Intraoperative AP translation at 30 degrees and 90 degrees knee flexion angles was 7.7 +/- 3.1 mm and 5.9 +/- 2.0 mm, respectively. Postoperative AP translation at 30 degrees was 5.9 +/- 1.7 mm. AP translation correlated positively with medial joint laxity at 30 degrees (R = 0.29) and 90 degrees (R = 0.40). The intraoperative and postoperative AP translations at 30 degrees flexion had a positive relationship (R = 0.61). CONCLUSION: AP stability of the BCS TKA had a positive relationship with intraoperative medial stability. Therefore, surgical soft tissue handling focusing on medial stability is also appropriate for AP stability of BCS TKA. Additionally, intraoperative AP translation turned out to be a predictive indicator for postoperative knee AP stability at 30 degrees flexion. PMID- 30414790 TI - Response to Macchi et al. "Letter to the Editor 'Histopathological study of the infrapatellar fat pad in the rat model of patellar tendinopathy: A basic study'". PMID- 30414791 TI - Comparison of medial and lateral posterior femoral condyle articular cartilage wear patterns. AB - BACKGROUND: While degenerative changes to the articular cartilage of the anterior and distal portions of the femoral condyles have been well studied in the literature, the changes that occur on the posterior femoral condyle are not as clear. The purpose of this study was to assess the difference in articular cartilage thickness between the medial and lateral posterior femoral condyles in knees undergoing unicompartmental knee arthroplasty. METHODS: A retrospective review of prospectively gathered data on 107 consecutive patients undergoing unicompartmental knee arthroplasty performed by a single surgeon was performed. The remaining articular cartilage thickness after resection of the posterior femoral condyle was measured and simple analysis conducted to compare cartilage thickness between medial and lateral posterior femoral condyles. RESULTS: Ninety two medial unicompartmental arthroplasties and 15 lateral unicompartmental arthroplasties were performed during the 16 month study period. The majority of lateral UKA patients were female and had lower BMI than medial UKA patients. The articular cartilage thickness on the medial posterior femoral condyle was 3 mm +/ 1 mm (mean +/- standard deviation) and 1 mm +/- 1 mm on the lateral side (p value <0.001). CONCLUSIONS: There is a significant difference in articular cartilage thickness between the medial and lateral posterior femoral condyles in patients undergoing unicompartmental knee arthroplasty. This coincides with a potentially inherently different pattern of articular cartilage degeneration between the medial and lateral compartments of the knee and has implications on implant designs and resurfacing techniques about the knee. PMID- 30414792 TI - Prevalence of excessive lateral pressure syndrome in varus osteoarthritic candidates for high tibial osteotomy. AB - BACKGROUND: This study aimed to determine the prevalence of excessive lateral pressure syndrome (ELPS) in potential candidates for high tibial osteotomy (HTO) using single-photon emission computed tomography-computed tomography (SPECT-CT). We also sought to identify risk factors related to the presence of ELPS. METHODS: This retrospective study included 150 patients (216 knees) who were candidates for HTO from an initial screening of 3579 patients (7158 knees). There were 183 female and 33 male knees with a mean age of 58 years. The presence of ELPS was defined as a grade 3 uptake on the SPECT-CT at the lateral PF joint. To determine the risk factors related to the ELPS, multivariate regression analysis was performed with independent demographic and radiographic variables. RESULTS: Increased uptake on the lateral side of the PF joints was detected in 120 knees (56% of total subjects). Of these, 34 (16%) knees presented with a grade 3 uptake, which indicated the presence of ELPS. No single risk factor had significant associations with the presence of ELPS. CONCLUSIONS: A considerable number of the knees that were candidates for HTO had ELPS. Nonetheless, we did not find any risk factor related to the presence of ELPS. These results suggest that surgeons should be cautious when diagnosing concomitant ELPS despite acceptable radiographic findings from patellofemoral joints when performing HTO. PMID- 30414793 TI - Meniscal repair in patients age 40 years and older: A systematic review of 11 studies and 148 patients. AB - PURPOSE: The purpose of this review is to evaluate published outcomes for reported failure rates following meniscus repair in patients age 40 years or older. METHODS: A systematic search was performed, and 225 meniscus repair outcome studies on adults were identified in the English literature. Included studies reported either individual patient data with at least one patient age >=40 years or summary data with all patients' age >=40 years. Failure rates were determined based on previously reported risk factors (regardless of age) including concomitant anterior cruciate ligament (ACL) reconstruction (ACLR), tear location, and tear pattern. RESULTS: Meniscus repair outcomes for 148 patients from 11 studies were included (125 inside-out repairs and 23 all-inside repairs). The overall failure rate was 10% (15/148) and ranged from 0 to 23% in individual studies with more than one patient age >=40 years. One comparative study of patients over versus under age 40 years was identified, with no difference in failure rates between groups. Most tears were peripheral tears with avascular extension (nine-percent overall failure rate) or without avascular extension (nine-percent failure rate). Among studies that reported tear pattern, overall failure rates for vertical-longitudinal or bucket handle tears were nine percent and complex and/or horizontal tears were 23%. Repairs with concomitant ACL reconstruction had a five-percent overall failure rate versus 15% in ACL intact patients. CONCLUSION: Meniscus repair failure rates in patients age 40 years and older are comparable to rates quoted for younger patients. LEVEL OF EVIDENCE: Level IV. Systematic review of Level III and IV studies. PMID- 30414794 TI - The biomechanical and morphological characteristics of the ligamentum mucosum and its potential role in anterior knee pain. AB - BACKGROUND: The ligamentum mucosum is composed of dense regular connective tissue and traverses from the distal femur to the infrapatellar fat pad. While the gross and histologic morphology has been studied, there is currently no evidence concerning the biomechanical properties of the ligamentum mucosum and the potential of anterior knee pain. The purpose of this study was to determine the anatomical, mechanical and histological properties of the ligamentum mucosum. METHODS: Dissections were performed on cadaveric knee specimens (N = 18) and histological analysis (n = 6) was performed to define the anatomical characteristics of the ligamentum mucosum using standard hematoxylin and eosin (H&E), Masson's trichrome, and immunohistochemical methods. Biomechanical testing (n = 5) was conducted to determine the tensile properties of the ligamentum mucosum. The peak load at failure, stiffness, and strain were analyzed. RESULTS: Sixty-four percent of the knees had a ligamentum mucosum and the histological analysis confirmed it to be composed of dense regular connective tissue. Small peripheral nerves were identified in the junction between the ligamentum mucosum and the fat pad. The average (SD) peak force of failure, stiffness, and strain were 31.9 N (19.0), 5.1 N/mm (3.59), and 0.83 (0.14), respectively. CONCLUSIONS: The tensile strength and stiffness of the ligamentum mucosum is considerably less than the primary stabilizers of the knee joint. Based on these findings, it is improbable that the ligamentum mucosum has a meaningful effect on the kinematics of the extensor mechanism; perturbations of the tissue and the connected infrapatellar fat pad could potentially play a role in the pathogenesis of anterior knee pain. PMID- 30414795 TI - Epigenetic Changes in Airway Smooth Muscle as a Driver of Airway Inflammation and Remodeling in Asthma. AB - Epigenetic changes are heritable changes in gene expression, without changing the DNA sequence. Epigenetic processes provide a critical link between environmental insults to the airway and functional changes that determine how airway cells respond to future stimuli. There are three primary epigenetic processes: histone modifications, DNA modification, and noncoding RNAs. Airway smooth muscle has several important roles in the development and maintenance of the pathologic processes occurring in asthma, including inflammation, remodeling, and contraction/hyperresponsiveness. In this review, we describe the evidence for the role of epigenetic changes in driving these processes in airway smooth muscle cells in asthma, with a particular focus on histone modifications. We also discuss how existing therapies may target some of these changes and how epigenetic processes provide targets for the development of novel asthma therapeutics. Epigenetic marks may also provide a biomarker to assess phenotype and treatment responses. PMID- 30414796 TI - Development of an in-situ hybridization assay using riboprobes for detection of viral haemorrhagic septicemia virus (VHSV) mRNAs in a cell culture model. AB - An in situ hybridization (RNA-ISH) assay has been developed and optimized to detect viral haemorrhagic septicemia virus (VHSV), an OIE listed piscine rhabdovirus, in infected fish cells using fathead minnow (FHM) as a model cell line. Two antisense riboprobes (RNA probes) targeting viral transcripts from a fragment of nucleoprotein (N) and glycoprotein (G) genes were generated by reverse transcription polymerase chain reaction (RT-PCR) using VHSV specific primers followed by a transcription reaction in the presence of digoxigenin dUTP. The synthesized RNA probes were able to detect viral mRNAs in formalin fixed VHSV infected FHM cells at different time points post inoculation (pi). To correlate the signal intensity, a time dependent quantitation of the viral mRNA transcript and infectivity titer was done by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and 50% tissue culture infectivity dose (TCID50), respectively, from the infected cells and culture supernatants. Further, we compared the diagnostic sensitivity of ISH assay with immunocytochemistry (ICC). Both the riboprobes used in the ISH assay detected VHSV as early as 6 hpi in the FHM cells inoculated with a multiplicity of infection (moi) of 2. Also, the signal detection in ISH was at an early stage in comparison to ICC, wherein, signal was first detected at 12 hpi. Our results clearly highlight that current ISH assay can be of value as a diagnostic tool to localize and detect VHSV in conjunction with conventional virus isolation in cell culture. PMID- 30414797 TI - Effect of intravascular cooling on microvascular obstruction (MVO) in conscious patients with ST-elevation myocardial infarction undergoing primary PCI: Results from the COOL AMI EU pilot study. AB - OBJECTIVE: COOL AMI EU pilot was a multi-center, randomized controlled trial to assess feasibility and safety of rapid intravascular therapeutic hypothermia (TH) in conscious patients with anterior ST-elevation myocardial infarction (STEMI) undergoing primary PCI (PPCI). We report the effect of hypothermia upon microvascular obstruction (MVO). METHODS: Conscious patients with anterior STEMI and symptom duration <6 h were recruited and randomized to PPCI + TH or PPCI alone. TH was induced using the ZOLL(r) ProteusTM intravascular temperature management system and rapid infusion of 1 L of cold normal saline, with a target temperature of 32 degrees C. MVO was measured by cardiac magnetic resonance (CMR) at 4 to 6 days post-MI. MVO larger than 3.9% of LV was considered as extensive MVO. RESULTS: 50 patients were randomized; mean age was 58 years, and 86% were men. At reperfusion, mean intravascular temperature for the TH group was 33.6 +/- 1 degrees C. The presence of MVO was high and not different in both groups (74% vs. 77%, p = 0.79). The proportion of patients with extensive MVO was 11% in the TH group and 23% in the control group (OR 0.4 95%CI 0.07-2.35, p = 0.30). Patients with extensive MVO showed reduced EF at 4-6 days (34% versus 43%, p = 0.01). The percentage of patients with EF <35% at 30 days was 6% in the TH group versus 24% in the control group (p = 0.19). CONCLUSION: In the COOL-AMI Pilot Trial, the presence of MVO in both test groups was high and extensive MVO was related with reduced LVEF. The efficacy of therapeutic hypothermia (TH) in MVO reduction should be tested in a pivotal trial. PMID- 30414798 TI - The Pt-Cr everolimus-eluting stent with bioabsorbable polymer in the treatment of patients with acute coronary syndromes. Results from the SYNERGY ACS registry. AB - OBJECTIVES: We investigated the safety and efficacy of the bioabsorbable polymer coated, everolimus-eluting coronary stent (SYNERGY) stent in a real-world study population with acute coronary syndromes (ACS). BACKGROUND: A number of clinical trials support the overall efficacy and safety of the SYNERGY stent. However, a recent trial (TIDES-ACS) in the context of ACS reported worrying figures of infarction and definite/probable stent thrombosis in the SYNERGY control arm. METHODS: This is a multicenter registry (10 centers) including consecutive patients with ACS (unstable angina, non-ST elevated myocardial infarction, ST elevated myocardial infarction) who underwent percutaneous revascularization with the implantation of SYNERGY stent. The primary endpoint was the composite of cardiac death, myocardial infarction and target lesion revascularization at 12 months. RESULTS: A total of 1008 patients were included with age 65.4 +/- 14.8 years, 23.8% females and a 24.5% diabetics. Regarding presentation, a 15.2% with unstable angina, 43% with non-ST elevated myocardial infarction and 41.8% with ST elevated myocardial infarction. Primary outcome was met in 3% (7% in SYNERGY TIDES-ACS arm, P superiority <0.01 and 6.3% in OPTIMAX TIDES-ACS arm, P superiority <0.01). Cardiac death was 1.3% (1.6%, p = 0.8 and 0.5%, P superiority =0.1 respectively). Myocardial infarction was 1.6% (4.6%, p < 0.01 and 1.8%, P superiority = 0.9 respectively). Target lesion revascularization was 1% (3.4%, p < 0.01 and 5.4%, P superiority <0.01 respectively). Definite or probable thrombosis was 0.9% (2.8%, p <= 0.01 and 1.1%, P superiority = 0.8 respectively). CONCLUSIONS: The results of this registry show a very good safety and efficacy profile at 12 months for the SYNERGY stent in patients with ACS. SUMMARY: A recent trial (TIDES-ACS) in the context of acute coronary syndromes (ACS) reported worrying figures of infarction and definite/probable stent thrombosis in the SYNERGY stent control arm. We investigated the safety of SYNERGY stent in a real-world study population with ACS applying the same inclusion/exclusion criteria as used in the TIDES-ACS trial. Primary endpoint was the composite of cardiac death, myocardial infarction and TLR at 12 months. A total of 1008 patients have been included. Primary outcome was met in 3% (7% in SYNERGY TIDES ACS arm, P superiority <0.01 and 6.3% in OPTIMAX TIDES-ACS arm, P superiority <0.01). PMID- 30414799 TI - Diminished brain responses to second-language words are linked with native language literacy skills in dyslexia. AB - Dyslexia is characterized by poor reading skills, yet often also difficulties in second-language learning. The differences between native- and second-language speech processing and the establishment of new brain representations for spoken second language in dyslexia are not, however, well understood. We used recordings of the mismatch negativity component of event-related potential to determine possible differences between the activation of long-term memory representations for spoken native- and second-language word forms in Finnish-speaking 9-11-year old children with or without dyslexia, studying English as their second language in school. In addition, we sought to investigate whether the bottleneck of dyslexic readers' second-language learning lies at the level of word representations or smaller units and whether the amplitude of mismatch negativity is correlated with native-language literacy and related skills. We found that the activation of brain representations for familiar second-language words, but not for second-language speech sounds or native-language words, was weaker in children with dyslexia than in typical readers. Source localization revealed that dyslexia was associated with weak activation of the right temporal cortex, which has been previously linked with word-form learning. Importantly, the amplitude of the mismatch negativity for familiar second-language words correlated with native language literacy and rapid naming scores, suggesting a close link between second language processing and these skills. PMID- 30414800 TI - Erythropoietin modulates macrophages but not post-ischemic acute kidney injury in mice. AB - BACKGROUND/PURPOSE: Substantial progress was made in acute kidney injury (AKI) over the past 10 years, but no therapeutic interventions have been shown to prevent AKI or accelerate functional recovery after injury. A large number of preclinical studies supports the use of recombinant human erythropoietin (rHuEPO) to prevent AKI, but the clinical trial data are inconclusive. To address concerns about preclinical study design and reporting in AKI, we here presented our rigorous experiments on the use of rHuEPO in a mouse model simulating the most common post-ischemic AKI in patients. METHODS: Use of saline vehicle or rHuEPO (100 or 1000 U/KgBW) in mice subjected to AKI induced by ischemia-reperfusion injury of left kidney 2 weeks after right nephrectomy (NX + IRI). RESULTS: NX + IRI resulted in a reproducible AKI model. Use of rHuEPO as a pretreatment or posttreatment did not affect AKI severity, functional recovery, and mouse survival regardless of gender, injury severity, or doses of rHuEPO. Administering rHuEPO with 1000 U/KgBW did increase hematocrit and modulate AKI kidney macrophages by Nos2 downregulation and Ccl17 upregulation. Active expression of erythropoietin receptor (EPOR) was not identified in renal cells by lineage tracing study, whereas expression of colony-stimulating factor 2 receptor beta (CSF2Rbeta) was identified in kidney macrophages and upregulated after AKI. Both EPOR and CSF2Rbeta were identified in cultured bone marrow derived macrophages, possibly mediated the robust inhibition of cytokine-induced phenotype switching by rHuEPO. CONCLUSION: Use of rHuEPO can modulate macrophage function but not the post-ischemic AKI severity, functional recovery and survival in mice. PMID- 30414801 TI - Systematic Review and Meta-Analysis of Iliofemoral Stenting for Post-thrombotic Syndrome. AB - OBJECTIVE: Stent placements are considered as a treatment for post-thrombotic syndrome (PTS) with iliofemoral obstruction, but the application of these iliofemoral venous stents has also caused a lot of controversy. The purpose of this systematic review and meta-analysis was to summarise the efficacy and safety of venous stents in PTS with obstruction in iliofemoral venous segments. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register for Controlled Trials databases and key references were searched up to 15 January 2018. The main relevant outcomes included technical success, peri-operative complications, symptom resolution, a change of symptom scores, and long-term patency of the stents. RESULTS: Overall, 504 limbs of 489 patients from seven studies were included in this study. A GRADE assessment showed the quality of the evidence was "very low" for 11 relevant outcomes. The technical success rate was 95%. The pooled rate of complications including 30 day thrombotic event, per-operative venous injury, and back pain was 3.4%, 18.14%, and 52%, respectively. The rates of ulcer healing, pain and oedema relief were 75.66%, 52%, and 42%, respectively. The primary, assisted primary and secondary patency rates were 83.36%, 90.59%, and 94.32%, respectively, at 12 months and 67.98%, 82.26%, and 86.10%, respectively, at 36 months. CONCLUSIONS: Endovenous stenting has the potential to be effective and has a low risk of peri-operative complications. The quality of evidence to support this treatment is very low. Endovenous iliofemoral stenting should be considered a treatment option for PTS with iliofemoral obstruction. PMID- 30414803 TI - A Step Towards Equitable Access: Understanding the Use of Fertility Services by Immigrant Women in Toronto. AB - OBJECTIVE: The authors sought to study whether there is differential access to fertility services for immigrant women in a single-payer system. METHODS: A cross sectional quantitative survey was administered to 265 patients over 3 months. All participants were female patients in heterosexual relationships at a university affiliated hospital-based fertility clinic in a large metropolitan city. Data on sociodemographic characteristics, reproductive history, and experience accessing fertility services were collected. Statistical analysis, including chi-square and ANOVA regression, was completed using JMP software. RESULTS: The response rate of the survey was 86.6%. A total of 265 women participated, 124 (47%) immigrants and 141(53%) non-immigrants. Immigrants more commonly left questions unanswered. Long term immigrants had a significantly longer average duration of infertility than non-immigrant women (47 months vs. 34 months; P = 0.04). There was a trend towards a delay in seeing a health care provider among long-term immigrants. The most commonly reported reasons for delaying fertility care were "not knowing there was a problem" and "treatments being too expensive." Although participants across all groups relied on their primary care provider to supply information on fertility services, a greater percentage (17%) of recent immigrants than non immigrant participants (7%) used the Internet to obtain information. CONCLUSION: Immigrant women addressed their fertility needs even when they had fewer resources and less social stability than did non-immigrant women. However, they experienced a delay in receiving specialized care for infertility. Immigrant women also appeared less comfortable disclosing personal information in a health care setting. PMID- 30414802 TI - Optimal Antiplatelet Therapy in Moderate to Severe Asymptomatic and Symptomatic Carotid Stenosis: A Comprehensive Review of the Literature. AB - OBJECTIVES: Carotid stenosis patients are at risk of vascular events despite antiplatelet therapy. Data on prescribed antiplatelet regimens have not been comprehensively collated from trials to guide optimal therapy in this population. METHODS: This review was conducted in line with the current Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Medline, Ovid, Embase, Web of Science, and Google Scholar from 1988 to 2018 were searched using the search terms "carotid stenosis", "asymptomatic", "symptomatic", "antiplatelet", and "anti-platelet" to identify randomised trials in patients with asymptomatic or symptomatic extracranial moderate-severe carotid stenosis on any form of antiplatelet therapy in which vascular events and pre specified composite outcome events were reported. RESULTS: Twenty-five studies were judged eligible for inclusion. Data from one randomised controlled trial showed no significant difference in benefit with aspirin versus placebo in asymptomatic carotid stenosis, but it is still reasonable to recommend aspirin (81-325 mg daily) for prevention of vascular events in these patients. Low to medium dose aspirin (81-325 mg daily) is superior to higher doses (>650 mg daily) at preventing recurrent vascular events in patients undergoing endarterectomy. Data from endovascular treatment (EVT) trials support peri-procedural treatment of asymptomatic and symptomatic patients with 81-325 mg of aspirin daily. The use of peri-procedural aspirin-clopidogrel in patients undergoing EVT is based on one pilot trial, but appears safe. Short-term aspirin-dipyridamole or aspirin clopidogrel treatments are equally effective at reducing micro-embolic signals on transcranial Doppler ultrasound in patients with >=50% symptomatic carotid stenosis. There is insufficient evidence to recommend routine aspirin-clopidogrel combination therapy to reduce the risk of recurrent clinical ischaemic events in patients with symptomatic moderate-severe carotid stenosis. CONCLUSIONS: This comprehensive review outlines an evidence based approach to antiplatelet therapy in carotid stenosis patients. Future trials should randomise such patients to receive different antiplatelet regimens to assess their efficacy and safety and to optimise peri-procedural and long-term preventive treatment in this patient cohort. PMID- 30414804 TI - Brachial Plexus Birth Injury in Elective Versus Emergent Caesarean Section: A Cohort Study. AB - OBJECTIVE: Although Caesarean section (CS) is protective for brachial plexus birth injury (BPBI), the incidence is not zero. A trial of labour with unfavourable intrauterine positioning is hypothesized to result in excessive force on the brachial plexus. The purpose of this study was to determine the risk of BPBI in emergent CS versus elective CS. METHODS: This was a retrospective cohort study. The authors used a nationwide demographic sample of all infants born in Canada from 2004 to 2012. BPBI diagnoses, risk factors, and national incidence data were obtained from the Canadian Institute for Health Information Discharge Abstract Database and Hospital Morbidity Database. The primary outcome was risk of BPBI in emergent CS versus elective CS. RESULTS: BPBI incidence was 1.24 per 1000 live births. Known biases may have underestimated the incidence. CS (elective and emergent) was protective for BPBI as compared with vaginal delivery (OR 0.15; 95% CI 0.13-0.18, P < 0.0001). Emergent CS was a moderately strong risk factor for BPBI versus elective CS (OR 3.14; 95% CI 1.79-5.10, P = 0.0001). CONCLUSION: Emergent CS is a moderate risk factor for BPBI compared with elective CS. Intrauterine positioning with a trial of labour may provide an antenatal etiology in these distinct cases. PMID- 30414806 TI - Conflict Among Colleagues: Health Care Providers Feel Undertrained and Unprepared to Manage Inevitable Workplace Conflict. AB - OBJECTIVE: In the health care sector, intercollegial conflict is inevitable. Such conflict may have an adverse effect on employee turnover, workplace morale, and patient safety and care. Conversely, skillful management of conflict may result in beneficial change and improvement. Improved conflict management (CM)/dispute resolution (DR) knowledge for health care professionals (HCPs) has been shown to reduce the negative impacts of conflict. This study aimed to determine whether HCPs feel equipped to manage collegial workplace conflict and whether they feel there is a need for CM training. METHODS: An electronic survey was developed to determine the attitudes, experience, and background training HCPs have had with CM, as well as whether respondents felt they needed CM/DR training. The survey was emailed to 660 HCPs in 2013 at Sunnybrook Health Sciences Centre, Toronto, Ontario. RESULTS: The response rate was 46% (303 of 660). Of 303 respondents, 128 (42%) reported previous formal training in CM/DR, but only 80 of 303 (26%) felt adequately trained to manage conflict and resolve disputes in the workplace, with 59% believing they need more conflict training. Among respondents, 76% wanted to see these skills incorporated into their own career training opportunities, but only 34% were aware of courses available to improve their CM/DR skills, and 50% stated they would be interested in taking such courses; 79% wanted to see these skills incorporated into medical school curricula. CONCLUSION: This needs assessment survey found that most HCPs did not believe that they have adequate training to manage workplace conflict comfortably, and they felt more training is needed in CM/DR. PMID- 30414805 TI - A Review of the Effects of Physical Therapy on Self-Esteem in Postpartum Women With Lumbopelvic Dysfunction. AB - This study sought to determine the impact of physical therapy for lumbopelvic dysfunction on self-esteem in postpartum women. Systematic searches were carried out in CINAHL, Embase, PsycINFO, Medline (OVID), Cochrane, and Web of Science by a health sciences librarian using various combinations of subject headings and key words. A dual review process was used first to assess titles and abstracts and then to examine the full text. Conflicts were resolved through discussion or a third reviewer as needed. Dual data extraction was completed using a standardized collection form. Pairs of reviewers met to discuss conflicts. Data quality was assessed using the Cochrane Collaboration's Risk of Bias Tool, the Joanna Briggs Critical Appraisal Tool, and the Critical Appraisal Skills Programme Checklist. Thirteen articles were included in the review. None of the articles assessed self-esteem specifically; however, each article assessed aspects of self-esteem (self-concept, self-efficacy, self-worth, depression, quality of life, general well-being, or physical function). All articles reported improvements in the selected outcome measures compared with baseline; two studies that compared two different physical therapy interventions found no significant differences between the interventions. To our knowledge, there is no literature explicitly evaluating self-esteem in postpartum women following physical therapy intervention for lumbopelvic dysfunction. Low self-esteem is shown to predict depression and anxiety; therefore, interventions that increase self-esteem may be useful in reducing the risk of depression. PMID- 30414807 TI - Recurrent Chronic Intervillositis: The Diagnostic Challenge - A Case Report and Review of the Literature. AB - BACKGROUND: Chronic intervillositis (CI) is a rare placental condition involving diffuse infiltration of intervillous spaces by CD68- or CD45-positive maternal mononuclear inflammatory cells. Because no validated clinical or biochemical markers are specific to CI, the diagnosis is purely histopathological and is made postpartum. CASE: This report describes a case of recurrent CI associated with adverse complications in two successive pregnancies. Both pregnancies were complicated by intrauterine growth restriction. Coexistent massive perivillous fibrin deposition was present in the first placenta. This case highlights the importance of CI in explaining and predicting adverse perinatal outcomes. CONCLUSION: CI is associated with adverse pregnancy outcomes and a high risk of recurrence, and it can coexist with massive perivillous fibrin deposition. Pathologists must ensure that the significance of these diagnoses is adequately conveyed to clinicians, to optimize management of subsequent pregnancies. PMID- 30414808 TI - SMART coils for intracranial aneurysm embolization: Follow-up outcomes. AB - The SMART coil (Penumbra Inc., Alameda, CA, USA) is a new microcoil designed to enhance deliverability. Although prior studies have described its perioperative safety and efficacy, the follow-up outcomes after embolization of intracranial aneurysms using SMART coils have not been reported. Therefore, the aim of this retrospective cohort study is to assess the angiographic outcomes at interim follow-up after aneurysm embolization with SMART coils. We reviewed data from consecutive patients with intracranial aneurysms who underwent endovascular treatment using SMART coils between June 2016 and August 2017. Baseline data and follow-up angiographic outcomes using the modified Raymond-Roy classification (MRRC) were recorded. The study cohort comprised 33 patients with 34 aneurysms who underwent SMART coil embolization and had sufficient follow-up data. The mean age was 57 years, and 82% were female. The mean aneurysm maximum diameter and neck width were 6.1 +/- 2.2 mm and 3.2 +/- 1.2 mm, respectively, and 14.7% of aneurysms were ruptured. The overall complication rate was 12%. Initial mean coil packing density was 26%, and the initial MRRC was I, II, IIIa, and IIIb in 24%, 26%, 35%, and 15%, respectively. At last follow-up (mean duration 7.7 +/- 3.2 months), the MRRC was I, II, IIIa, and IIIb in 62%, 26%, 3%, and 9%, respectively. The retreatment rate was 14.7%. The SMART coil is efficacious for the treatment of appropriately selected aneurysms, with an acceptable risk profile. The majority of residual aneurysms after the initial embolization procedure will progress to complete or near-complete occlusion at interim follow up. PMID- 30414809 TI - Thrombectomy in stroke of unknown onset, wake up stroke and late presentations: Australian experience from 2 comprehensive stroke centres. AB - Two recent randomized controlled trials (RCTs) showed selected patients treated with endovascular thrombectomy (EVT) more than 6 h from acute ischemic stroke (AIS) onset had significant improvement in functional outcome at 90 days compared with standard care alone. Our aim is to determine the outcome and predictors of good outcome in AIS patients undergoing EVT with unknown-onset, or late presentation, stroke after 6 h from time last seen well, or witnessed stroke onset, at two Australian comprehensive stroke centres. A retrospective analysis of functional outcome and mortality at 90-days from a prospective cohort of 56 consecutive patients with unknown-onset, or late presentation, stroke with large vessel occlusion (LVO) in the anterior cerebral circulation undergoing EVT over a 15-month period (2016-2017). We evaluated factors which correlated with good functional outcome defined as a 90-day modified Rankin scale (mRS) 0-2. Recanalization times and symptomatic intracranial haemorrhage (sICH) rates were also examined. A good functional outcome was achieved in 35 patients (62%). Eight patients died (14%). Median time-to-recanalization was 7.6 h. SICH occurred in four patients (7%). Factors which predicted good 90-day functional outcome included baseline National Institutes of Health Stroke Scale (NIHSS) < 16, 24 h NIHSS < 10, baseline Alberta Stroke Program Early CT Score (ASPECTS) >= 8, pre procedural CT perfusion imaging and LVO lesion location. This study shows good 'real world' outcomes, comparable to published RCTs, in patients with unknown onset, or late presentation, stroke treated with EVT more than 6 h from stroke onset. PMID- 30414810 TI - Results of TachoSil(r) associated with fibrin glue as dural sealant in a series of patients with spinal intradural tumors surgery. Technical note with a review of the literature. AB - A major problem of surgery for intradural spinal tumors (IST) is the occurrence in the post-operative period of a cerebrospinal fluid (CSF) leak. To the best of our knowledge, here we report on the largest series of IST patients in whom the TachoSil(r) associated to fibrin glue was used as dural sealant in this kind of surgery. Moreover, we extensively reviewed the literature reporting the results of TachoSil(r) in spine surgery. The data of 35 consecutive surgically treated IST patients were reviewed. In all cases TachoSil(r) associated with fibrin glue was used as dural sealant. Mean age was 58.14 +/- 15.56 years and mean follow-up (FU) was 23.20 +/- 9.76 months. The Modified McCormick Scale (MMS) was used to assess the functional status of patients pre-operatively and at latest FU. All article dealing with the use of TachoSil(r) in spine surgery were included in the literature review. A CSF collection (treated conservatively with needle aspiration and bed rest with no consequence) was observed only in 1 out of 35 cases. No wound infection nor adverse reaction to the TachoSil(r) occurred during the FU. At latest FU we observed an improvement of MMS grade in 23 patients (65.71%) and a stable functional status in 12 cases (34.28%). According to our experience and the literature review using the TachoSil(r) after dural closure is safe and effective in IST surgery. Better standardized studies are needed to establish the usefulness of TachoSil(r) for incidental dural tear in degenerative spine surgery. PMID- 30414811 TI - Risk factors for ischemic stroke post bone fracture. AB - Stroke is one of the most devastating complications after bone fracture. However, due to the rarity of the complication, the risk factor for post fracture stroke remains unknown. We retrospectively reviewed 2914 fractured adults referred to the first affiliated hospital of Xi'an Jiaotong University, a regional referral center of China, from January 2008 to May 2013. As a result, among the 2914 patients, 13 of them had newly onset stroke within a median of 4 days after bone fractures (ranging from 1 to 25 days). The overall prevalence of post fracture stroke was 0.446%. The post fracture stroke prevalence in patients older than 68 years old was 3.542%. Compared to patients with vertebral (0.124%) and femur (0.619%) fractures, patients with hip fractures had a higher prevalence of post fracture stroke (2.320%) (P < 0.001). Univariate analysis showed that hyperlipidemia, history of prior fracture, more comorbidities, higher CHADS2 score and higher neutrophil counts at admission were more often observed among patients who had post fracture stroke (P < 0.05). With the multiple logistic regression analysis, we identified that history of prior fracture was an independent risk factor for post fracture ischemic stroke (OR = 6.417, 95% CI = 1.581-26.051, P = 0.009). Our study illustrates that the history of prior fracture is associated with a 6.4-fold increase in the risk of post fracture ischemic stroke. PMID- 30414812 TI - Hospital costs associated with inpatient versus outpatient awake craniotomy for resection of brain tumors. AB - BACKGROUND: With increasing fiscal restraints on health care systems, procedural cost-effectiveness has become an important metric for evaluating surgical procedures. While outpatient craniotomy has been shown to be safe and effective, the economic implications of this procedure has yet to be examined. Here, we present the first cost analysis comparing inpatient versus outpatient awake craniotomy for tumor resection/biopsy. METHODS: We conducted a retrospective chart review on consecutive patients undergoing awake craniotomy for tumor resection/biopsy at a publicly funded tertiary care center from Sept 2014 to Aug 2015. Patient demographics, comorbidities and surgical factors were recorded. Direct and indirect costs for each patient visit were calculated based on institutional records. RESULTS: A total of 50 consecutive patients undergoing awake craniotomy for tumor resection were included in this study (29 outpatients, 21 inpatients). Rates of complications and 30-day readmission were similar between groups. The total costs associated with inpatient surgery were nearly double that of outpatient surgery ($10649 versus $5242, P < 0.001). In-patient surgery resulted in a nearly 6-fold increase in unit/bed costs compared to out patient surgery ($4142 versus $758, P < 0.001). There were no differences in the costs incurred from the operating room, laboratory, or anesthesia departments. CONCLUSIONS: Costs associated with outpatient craniotomy are nearly half compared to inpatient craniotomy and this is largely driven by reductions in bed resource utilization and allied health services. Outpatient neurosurgery for tumor resection is therefore a safe and feasible option for appropriately selected patients and confers an overall cost reduction. PMID- 30414813 TI - Percutaneous kyphoplasty for osteoporotic vertebral compression fractures via unilateral versus bilateral approach: A meta-analysis. AB - The objective of the research was to compare the efficacy of lateral and bilateral PKP approaches for OVCFs. A comprehensive literature search was performed from the PubMed, Cochrane Library and Embase between January 2008 and May 2017. The clinical efficacy of the two approaches was evaluated by comparing perioperative outcomes (operation time, the volume of injected cement, X-ray exposure times and mean radiation dose), clinical outcomes (kyphotic angle reduction, restoration rate, visual analogue scale [VAS], Oswestry Disability Index [ODI] and SF-36), and operation-related complications (cement leakage and adjacent vertebral fracture). Data was analyzed using Review Manger 5.3.A total of 791 patients from 10 studies were included in our meta-analysis. The pooled results showed significant difference in operation time (weighted mean difference [WMD] -19.67, 95% confidence interval [CI] [-25.20 to -14.14]; P < 0.001); volume of injected cement (WMD -2.03, 95%CI [-2.63 to -1.42]; P < 0.001); mean radiation dose in patients (WMD -1.06 95CI [-1.23 to -0.90]; P < 0.001); and the rate of cement leakage (WMD 0.58 95CI [0.38-0.90]; P = 0.01) between these two approaches. However, the pooled results revealed no significant difference in X ray exposure times, kyphotic angle reduction, restoration rate, VAS, ODI, SF-36 and adjacent vertebral fracture. Our study presented that patients with OVCFs could obtain similar satisfactory clinical results via both unilateral and bilateral PKP approaches. Considering less operation time, less cement volume, lower mean radiation dose of patients, a lower rate of cement leakage and less surgery-related costs, we suggest that a unilateral PKP approach is advantageous. PMID- 30414814 TI - Question 2: When is actigraphy useful for the diagnosis and treatment of sleep problems? PMID- 30414815 TI - Changing respiratory expectations with the new disease trajectory of nusinersen treated spinal muscular atrophy [SMA] type 1. AB - Spinal muscular atrophy [SMA] is the most common genetic cause of childhood mortality, primarily from the most severe form SMA type 1. It is a severe, progressive motor neurone disease, affecting the lower brainstem nuclei and the spinal cord. There is a graded level of severity with SMA children from a practical viewpoint described as "Non-sitters", "Sitters" and less commonly, "Ambulant" correlating with SMA Type 0/Type 1, Type 2 and Type 3 respectively. Children with SMA Type 0 have a severe neonatal form whilst those with SMA Type 1 develop hypoventilation, pulmonary aspiration, recurrent lower respiratory tract infections, dysphagia and failure to thrive before usually succumbing to respiratory failure and death before the age of 2 years. The recent introduction of the antisense oligonucleotide nusinersen into clinical practice in certain countries, following limited trials of less than two years duration, has altered the treatment landscape and improved the outlook considerably for SMN1 related SMA. Approximately 70% of infants appear to have a clinically significant response to nusinersen with improved motor function. It appears the earlier the treatment is initiated the better the response. There are other rarer genetic forms of SMA that are not treated with nusinersen. Clinical expectations will change although it is unclear as yet what the extent of response will mean in terms of screening initiatives [e.g., newborn screening], "preventative strategies" to maintain respiratory wellbeing, timing of introduction of respiratory supports, and prolonged life expectancy for the subcategory of children with treated SMA type 1. This article provides a review of the strategies available for supporting children with respiratory complications of SMA, with a particular emphasis on SMA Type 1. PMID- 30414816 TI - Spinal muscular atrophy: A modifiable disease emerges. PMID- 30414818 TI - Initiation, Continuation, Switching, and Withdrawal of Heart Failure Medical Therapies During Hospitalization. AB - Patients with worsening heart failure with reduced ejection fraction (HFrEF) spend a large proportion of time in the hospital and other health care facilities. The benefits of guideline-directed medical therapy (GDMT) in the outpatient setting have been shown in large randomized controlled trials. However, the decision to initiate, continue, switch, or withdraw HFrEF medications in the inpatient setting is often based on multiple factors and subject to significant variability across providers. Based on available data, in well-selected, treatment-naive patients who are hemodynamically stable and clinically euvolemic after stabilization during hospitalization for HF, elements of GDMT can be safely initiated. Inpatient continuation of GDMT for HFrEF appears safe and well-tolerated in most hemodynamically stable patients. Hospitalization is also a potential time for switching from an angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker to sacubitril/valsartan therapy in eligible patients, and is the subject of ongoing study. Therapy withdrawal or need for dose reduction is rarely required, but if needed identifies a particularly at-risk group of patients with progressive HF. If recurrent intolerance to neurohormonal blockers is observed, these patients should be evaluated for advanced HF therapies. There is an enduring need for using the teachable moment of HFrEF hospitalization for optimal initiation, continuation, and switching of GDMT to improve post-discharge patient outcomes and the quality of chronic HFrEF care. PMID- 30414819 TI - Frequency of Transition From Stage A to Stage B Heart Failure After Initiating Potentially Cardiotoxic Chemotherapy. AB - OBJECTIVES: This study sought to determine the prevalence of American Heart Association/American College of Cardiology Foundation (AHA/ACCF) heart failure (HF) stages after potentially cardiotoxic chemotherapy was initiated. BACKGROUND: For individuals receiving potentially cardiotoxic chemotherapy, the frequency of transitioning from Stage A to more advanced HF stages is not well described. METHODS: In 143 Stage A HF patients with breast cancer, lymphoma and leukemia, renal cell carcinoma, or sarcoma prior to and then at 3, 6, and 12 to 24 months after potentially cardiotoxic chemotherapy was initiated, we obtained blinded cardiac magnetic resonance measurements of left ventricular ejection fraction (LVEF). RESULTS: Three months after potentially cardiotoxic chemotherapy was initiated, 18.9% of patients transitioned from Stage A to Stage B HF. A total of 83% and 80% of patients with Stage A HF at 3 months, respectively, exhibited Stage A HF at 6 and 12 to 24 months; 68% and 56% of those with Stage B HF at 3 months, respectively, exhibited Stage B HF at 6 and 12 to 24 months (p < 0.0001 and p = 0.026, respectively). CONCLUSIONS: Transitioning from Stage A to Stage B or remaining in Stage A HF 3 months after potentially cardiotoxic chemotherapy was initiated relates to longer-term (6 to 24 months post-treatment) assessments of HF stage. PMID- 30414820 TI - "To B or Not to B"...That Is the Question: Whether We Can Identify Those at Risk for Cardiac Dysfunction During Cancer Therapy. PMID- 30414817 TI - ESCMID generic competencies in antimicrobial prescribing and stewardship: towards a European consensus. AB - OBJECTIVE: To develop a consensus-based set of generic competencies in antimicrobial prescribing and stewardship for European prescribers through a structured consensus procedure. METHODS: The RAND-modified Delphi procedure comprised two online questionnaire rounds, a face-to-face meeting between rounds, and a final review. Our departure point was a set of competencies agreed previously by consensus among a UK multi-disciplinary panel, and which had been subsequently revised through consultation with ESCMID Study Group representatives. The 46 draft competency points were reviewed by an expert panel consisting of specialists in infectious diseases and clinical microbiology, and pharmacists. Each proposed competency was assessed using a nine-point Likert scale, for relevance as a minimum standard for all independent prescribers in all European countries. RESULTS: A total of 65 expert panel members participated, from 24 European countries (one to six experts per country). There was very high satisfaction (98%) with the final competencies set, which included 35 competency points, in three sections: core concepts in microbiology, pathogenesis and diagnosing infections (11 points); antimicrobial prescribing (20 points); and antimicrobial stewardship (4 points). CONCLUSIONS: The consensus achieved enabled the production of generic antimicrobial prescribing and stewardship competencies for all European independent prescribers, and of possible global utility. These can be used for training and can be further adapted to the needs of specific professional groups. PMID- 30414821 TI - Using a Decision Support Algorithm for Referrals to Post-Acute Care. AB - OBJECTIVES: Although hospital clinicians strive to effectively refer patients who require post-acute care (PAC), their discharge planning processes often vary greatly, and typically are not evidence-based. DESIGN: Quasi-experimental study employing pre-/postdesign. Aimed at improving patient-centered discharge processes, we examined the effects of the Discharge Referral Expert System for Care Transitions (DIRECT) algorithm that provides clinical decision support (CDS) regarding which patients to refer to PAC and to what level of care (home care or facility). SETTING AND PARTICIPANTS: Conducted in 2 hospitals, DIRECT data elements were collected in the pre-period (control) but discharging clinicians were blinded to the advice and provided usual discharge care. During the postperiod (intervention), referral advice was provided within 24 hours of admission to clinicians, and updated twice daily. Propensity modeling was used to account for differences between the pre-/post patient cohorts. MEASURES: Outcomes compared between the control and the intervention periods included PAC referral rates, patient characteristics, and same-, 7-, 14-, and 30-day readmissions or emergency department visits. RESULTS: Although 24%-25% more patients were recommended for PAC referral by DIRECT algorithm advice, the proportion of patients receiving referrals for PAC did not significantly differ between the control (3302) and intervention (5006) periods. However, the characteristics of patients referred for PAC services differed significantly and inpatient readmission rates decreased significantly across all time intervals when clinicians had DIRECT CDS compared with without. There were no differences observed in return emergency department visits. Largest effects were observed when clinicians agreed with the algorithm to refer (yes/yes). CONCLUSIONS/IMPLICATIONS: Our findings suggest the value of timely, automated, discharge CDS for clinicians to optimize PAC referral for those most likely to benefit. Although overall referral rates did not change with CDS, the algorithm may have identified those patients most in need, resulting in significantly lower inpatient readmission rates. PMID- 30414822 TI - Effects of Resistance Training on Functional Strength and Muscle Mass in 70-Year Old Individuals With Pre-sarcopenia: A Randomized Controlled Trial. AB - OBJECTIVE: Sarcopenia has been defined as age-related loss of muscle mass and function. The aim of this randomized controlled trial was to examine the effects of a 10-week instructor-led resistance training program on functional strength and body composition in men and women aged 70 years with pre-sarcopenia. DESIGN, SETTING, AND PARTICIPANTS: Participants were randomized to either 10 weeks of a physical training regimen including optional nutritional supplementation (n = 36) or to a control group (n = 34) (ClinicalTrials.gov, no. NCT03297632). The main outcome was changes in the Short Physical Performance Battery (SPPB) score. Secondary outcomes included the Timed Up and Go test, chair sit-stand time, lean body mass, and fat mass. RESULTS: The intervention had no significant effect on SPPB in the total cohort (P = .18), when comparing changes in the intervention group with the control group. However, those given the intervention in the male subcohort increased 0.5 +/- 0.4 (mean +/- standard error for the difference) points in SPPB during follow-up (P = .02) compared to male controls. With respect to secondary outcomes, the intervention group decreased 0.9 +/- 0.6 seconds in chair sit-stand time compared to controls (P = .01). Furthermore, the intervention resulted in significantly greater improvements for the training group than control group in all measures of body composition (P <= .01 for all). For example, lean body mass increased by a mean of 1147 +/- 282 g (P < .001), and total fat mass decreased by a mean of 553 +/- 225 g (P = .003), favoring the intervention group. CONCLUSION/IMPLICATIONS: The main finding of this intervention study is that an easy-to-use, functional resistance training program was effective in maintaining functional strength and increasing muscle mass in older adults with pre-sarcopenia. PMID- 30414823 TI - Three repeated sessions of transcranial random noise stimulation (tRNS) leads to long-term effects on reaction time in the Go/No Go task. AB - OBJECTIVE: We aimed to investigate whether the number of sessions delivered within one day influences the acute and long-term effects of transcranial random noise stimulation (tRNS) applied over the dorsolateral prefrontal cortex (DLPFC) on inhibitory control. METHODS: Thirty-six healthy participants were randomly assigned to receive either (i) 3 active (3A), (ii) 1 active and 2 sham (1A2S) or (iii) 3 sham (3S) tRNS sessions. The 3 tRNS were delivered consecutively in the same half-day separated by 30min with the anode over the right and the cathode over the left DLPFC. The effects of tRNS on inhibitory control were assessed 5 times using a Go/No Go task: at baseline (T0), after one tRNS session (T1), after the 3 sessions (T3), 1 (D1) and 8 (D8) days after. RESULTS: As compared to sham, active tRNS did not acutely modulate accuracy in the Go/No Go task but decreased reaction times at Go trials. At D1, participants who received at least one active tRNS sessions (3A and 1A2S groups) were faster than those who received 3 sessions of sham. At D8, only the participants who received 3 active tRNS sessions were faster to successfully respond to Go trials as compared to sham. DISCUSSION: Three active tRNS sessions induced longer effects on reaction times than a single session of active tRNS, compared to sham. These findings suggested that delivering repeated tRNS sessions on the same day induces more sustained effects than delivering a single session. PMID- 30414824 TI - Using EEG-based brain computer interface and neurofeedback targeting sensorimotor rhythms to improve motor skills: Theoretical background, applications and prospects. AB - Many Brain Computer Interface (BCI) and neurofeedback studies have investigated the impact of sensorimotor rhythm (SMR) self-regulation training procedures on motor skills enhancement in healthy subjects and patients with motor disabilities. This critical review aims first to introduce the different definitions of SMR EEG target in BCI/Neurofeedback studies and to summarize the background from neurophysiological and neuroplasticity studies that led to SMR being considered as reliable and valid EEG targets to improve motor skills through BCI/neurofeedback procedures. The second objective of this review is to introduce the main findings regarding SMR BCI/neurofeedback in healthy subjects. Third, the main findings regarding BCI/neurofeedback efficiency in patients with hypokinetic activities (in particular, motor deficit following stroke) as well as in patients with hyperkinetic activities (in particular, Attention Deficit Hyperactivity Disorder, ADHD) will be introduced. Due to a range of limitations, a clear association between SMR BCI/neurofeedback training and enhanced motor skills has yet to be established. However, SMR BCI/neurofeedback appears promising, and highlights many important challenges for clinical neurophysiology with regards to therapeutic approaches using BCI/neurofeedback. PMID- 30414825 TI - Analysis of magnetic resonance imaging-confirmed soft tissue injury pattern in simple elbow dislocations. AB - BACKGROUND: The elbow is the second most commonly dislocated joint. Stability depends on the degree of soft tissue injury, with 2 proposed patterns, one starting laterally and the other medially. The purpose of this study was to describe the injured structures observed in magnetic resonance images (MRIs) in a prospective cohort of simple elbow dislocations. METHODS: We evaluated 17 consecutive cases of simple elbow dislocations. Two musculoskeletal radiologists assessed the initial x-ray images and MRIs performed for all elbows. Radiologists evaluated the following soft tissue structures: medial collateral ligament complex (MCL), flexor-pronator muscle mass origin, anterior capsule (AC), posterior capsule, lateral collateral ligament complex (LCL), and extensor muscle mass origin. The radiologists were blinded to the study hypothesis. RESULTS: The initial radiographs in 16 patients showed the dislocation was posterolateral in 12, posterior in 3, and posteromedial in 1. We observed complete AC tear in 12 patients, MCL in 10, and LCL in 9. The inter-rater reliability for the radiologists was 0.70 (substantial) for MRI. CONCLUSIONS: In our series after simple elbow dislocation, complete AC tears were most common, followed by MCL and LCL tears. No single mechanism-related soft tissue injury pattern of simple elbow dislocation was observed, and different grades of soft tissue injury exist. PMID- 30414826 TI - Effect of temperature on saccharification and oligosaccharide production efficiency in koji amazake. AB - Koji amazake, prepared from rice koji, is a traditional Japanese sweet beverage. The main source of sweetness is glucose derived from rice starch following digestion by enzymes of Aspergillus oryzae during saccharification. The temperature of this process was empirically determined as 45 degrees C-60 degrees C, but no studies have systematically investigated the effect of temperature on saccharification efficiency. We addressed this in the present study by evaluating saccharification efficiency at various temperatures. We found that glucose content was the highest at 50 degrees C (100%) and was reduced at temperatures of 40 degrees C (66.4%), 60 degrees C (91.9%), and 70 degrees C (76.6%). We previously reported that 12 types of oligosaccharides are present in koji amazake; the levels of eight of these, namely nigerose, kojibiose, trehalose, isomaltose, gentiobiose, raffinose, panose, and isomaltotriose, were the highest at 50 degrees C-60 degrees C, whereas sophorose production was maximal at 70 degrees C. Based on these findings, we initially performed saccharification at 50 degrees C and then switched the temperature to 70 degrees C. The maximum amount of each saccharide including sophorose that was produced was close to the values obtained at these two temperatures. Thus, oligosaccharide composition of koji amazake is dependent on saccharification temperature. These findings provide useful information for improving the consumer appeal of koji amazake by enhancing oligosaccharide content. PMID- 30414827 TI - Phlebotomy tube interference with nuclear magnetic resonance (NMR) lipoprotein subclass analysis. AB - BACKGROUND: Lipoprotein subclass analysis by nuclear magnetic resonance (NMR) can be used in risk assessment of atherosclerotic cardiovascular disease (ASCVD). There is little information in the literature regarding phlebotomy tube interferences with NMR testing. METHODS: Pooled human serum was exposed to phlebotomy tubes manufactured by Becton Dickinson (BD), Greiner Bio-One, or Sarstedt. Serum was analyzed on the Axinon lipoFIT by NMR assay and by conventional lipid assays performed on a Roche Cobas 8000 system. The effect of incomplete fill volume was also assessed. RESULTS: Analytical interference in NMR lipoprotein subclass results was observed across many different tube types. The 5 mL Greiner Bio-One Z Serum Sep Clot Activator tube correlated the best with non gel containing serum tubes from BD and Greiner Bio-One. BD Serum Separator Tubes (SSTs) displayed strong interferences across several NMR analytes that were enhanced with decreased tube fill volumes. Interferences were also observed with different sizes of Greiner Bio-One Z Serum Sep Clot Activator tubes. Interference was generally not observed with conventional lipid testing, although minor interference was found for some tubes with lipoprotein(a) [Lp(a)]. CONCLUSIONS: NMR lipoprotein subclass analysis should be standardized by both tube type and tube size to prevent risk of analytical interference. PMID- 30414828 TI - Hybrid palliation as a bridge to biventricular repair in critical aortic stenosis with coarctation. AB - Optimal management- balloon dilation versus surgical valvotomy- of neonatal critical aortic stenosis (AS) remains controversial. We describe a term neonate with critical AS and coarctation, severe left ventricular (LV) dysfunction with endocardial fibro-elastosis palliated with surgical valvotomy and hybrid as a bridge to early biventricular repair. Initial repair consisted of commissurotomy to create bicuspid morphology with placement of bilateral pulmonary artery bands and maintenance of ductal patency with prostaglandin. LV function improved over two weeks allowing for repeat surgical valvotomy and coarctation repair. Patient was discharged two weeks post-operatively with low normal LV function, mild aortic stenosis/regurgitation. PMID- 30414829 TI - Upper mini-sternotomy for pulmonary valve repair. AB - Pulmonary valve repair in an adolescent via upper mini-sternotomy is reported. Several tips to enhance proper display of the valve in the surgical field are depicted. PMID- 30414830 TI - Patient Experience After Cardiac Surgery: Identifying Areas for Improvement. AB - BACKGROUND: Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) is a publicly reported survey of patient experience with in-hospital care. We reviewed institutional HCAHPS survey data to assess our patients' experience after cardiac surgery and identify targets for practice improvement. METHODS: We reviewed data from patients undergoing the most common cardiac operations, with dismissal from October 1, 2012, through September 30, 2015. We used top-box methodology to combine survey results into 9 domains, including the global (composite) hospital rating, dichotomized as high vs low. Multivariable logistic regression analysis was used to evaluate the independent associations of variables with low global ratings. Key driver analysis using domain means and Spearman correlation between the global rating and the 8 other domains identified targets for quality improvement. RESULTS: Among 1,315 surveyed patients, a low global hospital rating was independently associated with low perceived overall health (fair or poor vs excellent; odds ratio [OR], 5.4; P=.001), younger age (18 59 vs >=70 years; OR, 1.6; P=.048), prolonged length of stay (OR, 1.6; P=.02), and robotic mitral valve (MV) repair (robotic vs open repair; OR, 2.4; P=.045). Patients undergoing transcatheter aortic valve replacement (TAVR) reported global ratings similar to that of patients with open aortic valve operations (OR, 0.9; P=.64). Key drivers of patient experience were care transitions and communication regarding medications. CONCLUSIONS: The primary targets of improvement for our institution are care transitions and communications regarding medications. The less-invasive procedures (robotic MV repair, TAVR) were not independently associated with higher patient-experience scores. PMID- 30414831 TI - Ventricular Pseudoaneurysms after Perventricular Closure of Ventricular Septal Defect. AB - Perventricular ventricular septal defect closure has become an accepted method for treatment of some muscular and perimembranous ventricular septal defects. We report the case of a child who developed left ventricular pseudoaneurysms after perventricular closure of a ventricular septal defect performed at 3 months of age. At 18 months, the ventricular pseudoaneurysms were closed surgically. Ventricular trauma from guide wire use during device placement was thought to be the etiology. The potential for injury to the left ventricular free wall should be borne in mind and sought with serial imaging during and after perventricular septal defect closure. PMID- 30414832 TI - Double burden of disease: A global health challenge. PMID- 30414833 TI - Risk Prediction Model for Major Adverse Outcome in Proximal Thoracic Aortic Surgery. AB - BACKGROUND: Proximal thoracic aortic surgery utilizing hypothermic circulatory arrest (HCA) carries risks of mortality and major morbidity; however, these risks are not the same for every patient. The goal of the current study was to establish a risk prediction model for risk-stratifying patients undergoing proximal thoracic aortic surgery with HCA for degenerative pathology, so as to facilitate preoperative physician-patient counseling. METHODS: A retrospective analysis was conducted on 489 patients who underwent proximal thoracic aortic surgery with HCA for degenerative pathology between 07/2005 - 08/2014 at a single referral institution; patients with acute dissection (n=139) were excluded. Multivariable logistic regression was used to build a risk prediction model and identify preoperative predictors of major adverse outcome - the composite endpoint of 30-day/in-hospital mortality, stroke, acute renal failure, prolonged ventilation, or discharge to a location other than home. The results were validated using an independent cohort of 120 patients operated on from 09/2014 to 09/2016. RESULTS: Multivariable analysis identified age (p=0.0002, odds ratio [OR] 2.01), total arch replacement (p<=0.0001, OR 6.75), and procedure status (p=0.0028, OR 2.73 for urgent; OR 43.58 for emergent) as independent predictors associated with major adverse outcome. The calibration curve for probability of major adverse outcome showed excellent agreement between the model and observations. The concordance index was 0.93 in external validation. CONCLUSIONS: The current study identified risk factors for major adverse outcome after proximal thoracic aortic surgery with HCA for degenerative pathology. The proposed simple, accurate model can quantify risk and facilitate physician patient counseling prior to possible surgical intervention. PMID- 30414834 TI - A secondary structure within a human piRNA modulates its functionality. AB - The piwi-interacting RNAs (piRNAs) are small non-coding RNAs, mostly 24-32 nucleotides in length. The piRNAs are not known to have any conserved secondary structure or sequence motifs. Using bioinformatics analysis, we discovered the presence of putative G-quadruplex (GQ) forming sequences in human piRNAs. We studied human piR-48164/piR-GQ containing a potential GQ forming sequence and using biochemical and biophysical techniques confirmed its ability to form a GQ. Using EMSA, we discovered that the formation of GQ structure led to inhibition of the piRNA binding to the HIWI-PAZ domain as well as the complementary base pairing to a target RNA. The inability of the piR-GQ to interact with the PIWI protein might be detrimental to the function of the piRNA. To investigate if the formation of a GQ structure in piRNA prevents its target gene silencing in vivo, we used a reporter assay. The piR-GQ failed to inhibit the reporter gene expression while a mutated version that lacked the ability to form GQ inhibited reporter gene expression indicating that the presence of GQ in piRNA is detrimental to its function. These studies unraveled the dependence of a piRNA's functionality on an RNA secondary structure and added a new layer of regulation to their function. PMID- 30414835 TI - Role of adenomatous polyposis coli (APC) gene mutations in the pathogenesis of colorectal cancer; current status and perspectives. AB - Colorectal cancer (CRC) is one of the most common forms of solid tumors in the world with high rates of mortality and morbidity. Most cases of CRCs are initiated by inactivating mutations in a tumor suppressor gene, adenomatous polyposis coli (APC), leading to constitutive activation of the Wnt signaling pathway. This review summarizes the roles of somatic and germline mutations of the APC gene in hereditary as well as sporadic forms of CRC. We also discuss the diagnostic and prognostic value of the APC gene in the pathogenesis of CRC for a better understanding of CRC disease. PMID- 30414836 TI - Time dependent HPLC analysis of the product ratio of enzymatically reduced prodrug CB1954 by a modified and immobilised nitroreductase. AB - Directed enzyme prodrug therapy is a chemotherapy strategy that utilises prodrug activating enzymes to activate prodrugs at the tumour location, thus reducing off target effects. The most commonly investigated enzyme for use with the CB1954 prodrug is the NfnB nitroreductase from E. coli. Literature states that CB1954 is reduced by NfnB at the 2- or 4-position at a 1:1 ratio; deviation from this ratio has been observed in the literature, but not further investigated. The kinetic parameters for the genetically-modified enzymes; NfnB-his, NfnB-cys and AuNP-NfnB cys were assessed and HPLC analysis was used to determine the hydroxylamine product ratios formed when reacted with CB1954. Time-dependent HPLC studies were carried out to assess how this ratio changes over time. It was shown that the hydroxylamine ratio formed by the reduction of CB1954 by a nitroreductase changes over time and that this change in ratio relates directly to the kinetics of the reaction. Thus, the hydroxylamine ratio measured using HPLC at a given time point was not a true indication of the preference of the nitroreductase enzymes during catalysis. These results question how nitroreductases are evaluated in terms of the hydroxylamine ratio and it is suspected that this phenomenon may also apply to other enzyme/prodrug combinations. PMID- 30414837 TI - Amelioration of UV radiation-induced photoaging by a combinational sunscreen formulation via aversion of oxidative collagen degradation and promotion of TGF beta-Smad-mediated collagen production. AB - The presence of 40-50% more UV radiation in high altitude areas renders the plethora of sunscreen products available in the market virtually ineffective. In this light of event, four US FDA approved UV filters were combined with melatonin and pumpkin seed oil to produce a broad spectrum sunscreen cream, which is envisaged to provide optimum sunprotection along with enhanced antioxidant activity. The objective of this study is to evaluate the protective effect of the sunscreen cream against UV radiation-induced skin photoaging in adult Wistar albino rats and identify its possible underlying mechanism. Wistar rats were exposed to broad spectrum UV radiation for 28 days. The test group received the sunscreen formulation dermally every day prior to UV radiation. The effects of the formulation against UV induced symptoms; viz. skin thickness and edema, in vivo antioxidant activities, inflammatory cytokines, collagen content, histopathological examination and expression of specific genes established the protective activity of the formulation. The test formulation was able to mitigate the harmful effects of UV radiation by increasing in vivo SOD, GSH-Px, CAT and collagen levels; decreasing skin edema, skin thickness and cytokines like IL-6, IL-1beta, TNF-alpha and TGF-beta1. UV radiation induced changes in histological architecture and arrangement of collagen and elastin fibers were also prevented by the test formulation. Finally, the formulation was able to regulate the expression of COL3A1, COX-2, bFGF, VEGF-C, Smad2, Smad4, Smad7 genes which induced significant photoprotective activity. The sunscreen formulation ameliorated UV induced photoaging by preventing oxidative collagen degradation and augmentation of TGF-beta-Smad-mediated collagen production. PMID- 30414838 TI - A novel chemical lysis method for maximum release of DNA from difficult-to-lyse bacteria. AB - Molecular detection of microorganisms requires releasing DNA from cells. However, since certain microbial organisms are refractory to lysis by chemical or enzymatic methods, mechanical lysis by bead-beating is typically employed to disrupt difficult-to-lyse microbes. A newly developed chemical lysis method called sporeLYSE enables release of DNA from difficult-to-lyse microbes without bead-beating. The sporeLYSE method was compared to bead-beating and an alkaline/detergent lysis solution for releasing DNA from microbes grown in vitro, including surrogates of Category A bioterrorism agents. sporeLYSE released 83% to 100% of DNA from Mycobacterium smegmatis, Francisella philomiragia, Yersinia enterocolitica, Bacillus thuringiensis, Pseudomonas aeruginosa, Moraxella catarrhalis and Klebsiella pneumoniae. qPCR results indicated that sporeLYSE extracted an equal or greater amount of DNA than either bead-beating or alkaline/detergent lysis from Gram-positive and Gram-negative bacteria. When sporeLYSE was used to extract DNA from saliva and sputum spiked with M. smegmatis and M. tuberculosis, respectively, the qPCR Ct values were 4-8 cycles lower than those for extractions via alkaline/detergent lysis and heat. Mean Ct values for sporesLYSE extractions from spores of Clostridium difficile and C. botulinum were approximately two cycles lower than those of MagNA Pure DNA extractions. Our results suggest that sporeLYSE is an easy-to-use liquid reagent that can efficiently release large amounts of DNA from a variety of bacteria, including spores. PMID- 30414839 TI - Protective effects of alpinetin on lipopolysaccharide/d-Galactosamine-induced liver injury through inhibiting inflammatory and oxidative responses. AB - Alpinetin, a type of novel plant flavonoid derived from Alpinia katsumadai Hayata, has been reported to have anti-inflammatory effects. The aim of this investigation was designed to reveal the protective effects of alpinetin on Lipopolysaccharide (LPS)/d-galactosamine (D-Gal)-induced liver injury in mice. Alpinetin (12.5, 25, 50 mg/kg) were given 1 h before LPS and D-Gal treatment. 12 h after LPS and D-Gal treatment, the liver tissues and serum were collected. Our results showed that alpinetin treatment improved liver histology, indicating a marked decrease of inflammatory cell infiltration and restore hepatic lobular architecture. Alpinetin also inhibited liver myeloperoxidase (MPO) activity and malondialdehyde (MDA) level. Furthermore, LPS/D-Gal-induced tumor necrosis factor alpha (TNF-alpha) and Interleukin-1beta (IL-1beta) production were dose dependently inhibited by alpinetin. Alpinetin also attenuated LPS/D-Gal-induced expression of phospho-NF-kappaB p65 and phospho-IkappaBalpha. In addition, alpinetin was found to increase the expression of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). In conclusion, these findings suggested that alpinetin inhibited liver injury through inhibiting NF-kappaB and activating the Nrf2 signaling pathway. PMID- 30414840 TI - Temporary autonomic modulation with botulinum toxin type A to reduce atrial fibrillation after cardiac surgery. AB - BACKGROUND: Postoperative atrial fibrillation (POAF) frequently complicates cardiac surgery and is associated with worse outcomes. The cardiac autonomic nervous system is implicated in the pathogenesis of POAF. OBJECTIVE: The purpose of this study was to determine the efficacy and safety of selective cardiac autonomic modulation in preventing POAF. METHODS: In this randomized, double blind, placebo-controlled trial, adults undergoing cardiac surgery were randomized 1:1 to intraoperative injection of 250 units onabotulinumtoxinA (botulinum toxin type A [BoNTA]) or placebo into epicardial fat pads. The study was powered to detect a 40% reduction in relative risk of POAF. Time to first episode of in-hospital POAF was the primary outcome, evaluated in patients receiving injection. Additionally, incidence of POAF, length of stay (LOS), and adverse events were examined. RESULTS: The trial assigned 145 patients to injection, 15 of whom were dropped before treatment, leaving 130 patients for analysis. Overall, 36.5% (23/63) of BoNTA-treated patients developed POAF compared with 47.8% (32/67) of placebo-treated patients. The time-to-event analysis revealed a hazard ratio of 0.69 (95% confidence interval 0.41-1.19; P = .18) for the BoNTA vs placebo arm. There were no significant differences in postoperative hospital LOS (median [interquartile range] 6.0 [3.4] vs 6.2 [3.7] days; P = .51) or adverse events prolonging LOS (27/63 [42.9%] vs 30/67 [44.8%]; P = .83) in patients receiving BoNTA vs placebo. CONCLUSION: Epicardial injection of onabotulinumtoxinA was without discernible adverse effects, but we failed to detect a significant difference in risk of POAF. Future large-scale studies of epicardial onabotulinumtoxinA injection as a potential POAF prevention strategy should be designed to study smaller, but clinically meaningful, treatment effects. PMID- 30414841 TI - Long-term suppression of atrial fibrillation by botulinum toxin injection into epicardial fat pads in patients undergoing cardiac surgery: Three-year follow-up of a randomized study. AB - BACKGROUND: Botulinum toxin (BTX) injections into epicardial fat pads in patients undergoing coronary artery bypass grafting (CABG) has resulted in suppression of atrial fibrillation (AF) during the early postoperative period through 1-year of follow-up in a pilot program. OBJECTIVE: The purpose of this study was to report 3-year AF patterns by the use of implantable cardiac monitors (ICMs). METHODS: Sixty patients with a history of paroxysmal AF and indications for CABG were randomized 1:1 to either BTX or placebo injections into 4 posterior epicardial fat pads. All patients received an ICM with regular follow-up for 3 years after surgery. The primary end point of the extended follow-up period was incidence of any atrial tachyarrhythmia after 30 days of procedure until 36 months on no antiarrhythmic drugs. The secondary end points included clinical events and AF burden. RESULTS: At the end of 36 months, the incidence of any atrial tachyarrhythmia was 23.3% in the BTX group vs 50% in the placebo group (hazard ratio 0.36; 95% confidence interval 0.14-0.88; P = .02). AF burden at 12, 24, and 36 months was significantly lower in the BTX group than in the placebo group: 0.22% vs 1.88% (P = .003), 1.6% vs 9.5% (P < .001), and 1.3% vs 6.9% (P = .007), respectively. In the BTX group, 2 patients (7%) were hospitalized during follow up compared with 10 (33%) in the placebo group (P = .02). CONCLUSION: Injection of BTX into epicardial fat pads in patients undergoing CABG resulted in a sustained and substantial reduction in atrial tachyarrhythmia incidence and burden during 3-year follow-up, accompanied by reduction in hospitalizations. PMID- 30414842 TI - Paeoniflorin in experimental BALB/c mansoniasis: A novel anti-angiogenic therapy. AB - Chronic hepatic schistosomiasis causes portal hypertension, fibrosis and lethal hepatosplenic complications. Previous studies focused mainly on schistosomicidal drugs and neglected the therapeutic approaches against the vascular complications after portal hypertension. Investigating a novel anti-angiogenic therapy is an urgent. The current study is to evaluate the performance of Paeoniflorin (PAE) as an anti-angiogenic therapy, being a powerful anti-fibrotic, compared to artemether (ART) and praziqantel (PZQ) in schistosomiasis mansoni BALB/c mice. Thirty two laboratory bred male BALB/c Swiss albino mice. The mice were classified into four groups (8 mice each), control infected (CI), PZQ (300 mg/kg/12 h), ART (0.1 ml/mg/d) and PAE (50 mg/kg/d) treated groups for one month. All mice groups were sacrificed 15 weeks post infection for assessment of the drugs' efficacy by parasitological, histopathological and immunohistochemical studies. Our results in PAE group showed marked reduction in the mean egg count/gram stool, worm burden, egg count/gram liver tissue, granuloma diameter and pro-angiogenic factors as vascular endothelial growth factor (VEGF), Proliferating cell nuclear antigen (PCNA), alpha-smooth muscle actin (alpha-SMA) and CD34; conversely, there was an augmentation of the tissue inhibitor metalloproteinases-2 (TIMP-2) as an anti-angiogenic expression that was exceeded ART and PZQ treated groups compared to CI group (p?0.001). Conclusively, PAE has an anti-angiogenic impact with no vascular proliferative activity or recanalization, no micro-vessel density (MVD) changes, granuloma resolution and fibrosis regression. PAE is predicted to be a potential therapy for chronic hepatic diseases associated with fibrosis and angiogenesis, hopeful in protecting from advanced serious complications; cancer and metastasis. PMID- 30414843 TI - Isolation and growth inhibition potential of entomopathogenic nematodes against three public health important mosquito vectors. AB - The prevalence of mosquito vector borne diseases and the resistance of mosquitoes to conventional pesticides have been of important public concern to the mosquito endemic countries. Present study was conducted to identify the native bio larvicidal potential of the entomopathogenic nematodes; Steinernema siamkayai (KPR-4) Heterohabditis indica (KPR-8), Steinernema glaseri and Steinernema abbasi. The isolated nematodes were subsequently cultured and evaluated their larvicidal potential against the larvae of Aedes aegypti, Anopheles stephensi and Culex quinquefasciatus. Among the tested four different nematode species, the S. abassi exerted the highest mortality against A. aegypti (97.33%), the H. indica (KPR-8) against A. stephensi (97.33%) and the S. siamkayai (KPR-4) against C. quinquefasciatus (98.67%). The maximal mosquito-larvicidal property of EPNs was found with the LC50 and LC90 values (IJs/larvae): S. abbasi = 12.47 & 54.35 on A. aegypti; H. indica KPR-8 = 19.88 & 66.81 on A. stephensi and S. siamkayai KPR-4 = 16.69 & 58.97 on C. quinquefasciatus, respectively. The presently generated data on the molecular and larvicidal characteristics of the entomopathogenic nematodes form an important baseline data that upon further research would lead to the development of eco-friendly mosquito-control agent. PMID- 30414844 TI - Requirement of Pitx2 for skeletal muscle homeostasis. AB - Skeletal muscle is generated by the successive incorporation of primary (embryonic), secondary (fetal), and tertiary (adult) fibers into muscle. Conditional excision of Pitx2 function by an MCKCre driver resulted in animals with histological and ultrastructural defects in P30 muscles and fibers, respectively. Mutant muscle showed severe reduction in mitochondria and FoxO3 mediated mitophagy. Both oxidative and glycolytic energy metabolism were reduced. Conditional excision was limited to fetal muscle fibers after the G1-G0 transition and resulted in altered MHC, Rac1, MEF2a, and alpha-tubulin expression within these fibers. The onset of excision, monitored by a nuclear reporter gene, was observed as early as E16. Muscle at this stage was already severely malformed, but appeared to recover by P30 by the expansion of adjoining larger fibers. Our studies demonstrate that the homeodomain transcription factor Pitx2 has a postmitotic role in maintaining skeletal muscle integrity and energy homeostasis in fetal muscle fibers. PMID- 30414845 TI - MMP7 sensitivity of mutant ECM proteins: An indicator of melanoma survival rates and T-cell infiltration. AB - OBJECTIVE: To assess the potential impact of mutant ECM amino acids (AA) on melanoma-related matrix metalloproteinase-7 (MMP7) activity. DESIGN AND METHODS: We applied a novel scripted algorithm, based on the MEROPS database, to reveal mutant-dependent sensitivity changes across the cancer genome atlas, melanoma dataset. RESULTS: This approach revealed a strong bias in favor of mutant AA dependent protease sensitivity increases. Thus, melanoma specimens with relatively few mutations had only MMP7 mutant sensitive, ECM peptides. As mutations increased, melanoma specimens included mutant AA representing mostly increased sensitivity and a small but increasing number of mutant AA representing decreased MMP7 sensitivity. There was no detection of melanoma specimens with only decreases in MMP7 sensitivity. Furthermore, melanoma specimens with exclusively increased sensitivity and thereby only a few overall mutations represented reduced T-cell infiltrates and worse outcomes. CONCLUSIONS: Overall, the results indicated that changes in MMP7 sensitivity, attributable to mutant AA, have the potential of identifying patients with distinct survival outcomes as well as patients with cancer specimen immune activity. PMID- 30414846 TI - Limitations of the Hoffmann method for establishing reference intervals using clinical laboratory data. AB - OBJECTIVE: To examine the effect of different limits of acceptability on the Hoffmann method for selecting "healthy" populations from laboratory test data. METHODS: Thyroid stimulating hormone (TSH) and free thyroxine (FT4) were measured in Shunyi Maternal and Children's Hospital of Beijing Children's Hospital. The sample size of participants of TSH and FT4 for reference intervals (RIs) establishment was 10,864 and 10,799, respectively. RIs were calculated by Hoffmann method with different acceptable deviations (alpha value). The validation data was collected prospectively and the out-of-range (OOR) values were calculated to examine the applicability of RIs with different acceptable deviations. The sample size for RIs validation was 880 and 867, respectively. The RIs were considered as valid when OOR was <10%. RESULTS: alpha value was set at different levels for establishing the RIs of TSH and FT4. It was shown that the larger alpha value, the wider the RI. The RIs calculated by the Hoffmann method, under the default alpha value of 0.05, were much narrower than the previous findings. The OOR of both TSH and FT4 were far more from 10% when the alpha value was 0.05. In this simulation, the OOR of TSH and FT4 was not <10% until the alpha value was set as 0.55 and 0.80, respectively. The established RIs were valid for both training dataset and validation dataset. CONCLUSIONS: It can be somewhat subjective to define the acceptable deviation when selecting "normal" reference individuals. The default value of acceptable deviation may not be applicable in some cases. It is necessary to determine the acceptable deviation based on the certain condition, instead of using the default value directly. PMID- 30414847 TI - Roles of alpha-methyl trans-cyclopropane groups in behavior of mixed mycolic acid monolayers. AB - Mixed Langmuir films of type 1 alpha-(alpha-) and keto-mycolic acids (MAs) were investigated to understand the roles of alpha-methyl trans-cyclopropane containing keto-MA in determining the physical and chemical properties of the monolayers. Surface pressure (pi) vs. mean molecular area (A) isotherms were measured at constant mole fractions defined as the ratio of the keto-MA molarity to the total molarity of alpha-MA and keto-MA (Xketo) at 25 degrees C and 37 degrees C. A and the elastic modulus (E) of the mixed monolayer were compared for different Xketo at fixed pi values. In keto-MA rich monolayers, A values were much larger than values of the combined areas of alpha-MA and keto-MA, while the E values were close to those of solid keto-MA monolayers. A and E were also plotted against the mole fraction of alpha-methyl trans-cyclopropane containing keto-MA, which showed that the alpha-methyl trans-cyclopropane group stabilized the W-form conformation of mycolic acids in monolayers, and rendered them solid state. Furthermore, a comparison of the experimental results and the alpha-methyl trans-cyclopropane content in cell-wall MAs from various strains indicated that the ratio of trans-cyclopropane content was important in determining the nature of the mixed MA layer. PMID- 30414848 TI - The lipid environment of Escherichia coli Aquaporin Z. AB - In this study, we have investigated the lipids surrounding AqpZ, and the effects of a destabilizing mutation W14A (Schmidt and Sturgis, 2017) on lipid protein interactions. In a first approach, we used Styrene Maleic Acid copolymer to prepare AqpZ containing nanodiscs, and these were analyzed for their lipid content, investigating both the lipid head-group and acyl-chain compositions. These results were complemented by native mass spectrometry of purified AqpZ in the presence of lipids, to give insights of variations in lipid binding at the surface of AqpZ. In an effort to gain molecular insights, to aid interpretation of these results, we performed a series of coarse grained molecular dynamics simulations of AqpZ, in mixed lipid membranes, and correlated our observations with the experimental measurements. These various results are then integrated to give a clearer picture of the lipid environment of AqpZ, both in the native membrane, and in lipid nanodiscs. We conclude that AqpZ contains a lipid binding site, at the interface between the monomers of the tetramer, that is specific for cardiolipin. Almost all the cardiolipin, in AqpZ containing nanodiscs, is probably associated with this site. The SMA 3:1 nanodiscs we obtained contain a rather high proportion of lipid, and in the case of nanodiscs containing AqpZ cardiolipin is depleted. This is possibly because, in the membrane, there is little cardiolipin not associated with binding sites on the surface of the different membrane proteins. Surprisingly, we see no evidence for lipid sorting based on acyl chain length, even in the presence of a large hydrophobic mismatch, suggesting that conformational restrictions are energetically less costly than lipid sorting. PMID- 30414849 TI - TFEB protects nucleus pulposus cells against apoptosis and senescence via restoring autophagic flux. AB - OBJECTIVE: Excessive apoptosis and senescence of nucleus pulposus (NP) cells are major pathological changes in intervertebral disc degeneration (IVDD) development; previous studies demonstrated pharmacologically or genetically stimulation of autophagy may inhibit apoptosis and senescence in NP cells. Transcription factor EB (TFEB) is a master regulator of autophagic flux via initiating autophagy-related genes and lysosomal biogenesis. This study was performed to confirm whether TFEB was involved in IVDD development and its mechanism. METHODS: TFEB activity was detected in NP tissues in puncture-induced rat IVDD model by immunofluorescence as well as in tert-Butyl hydroperoxide (TBHP), the reactive oxygen species (ROS) donor to induce oxidative stress, treated NP cells by western blot. After TFEB overexpression in NP cells with lentivirus transfection, autophagic flux, apoptosis and senescence percentage were assessed. In in vivo study, the lentivirus-normal control (LV-NC) or lentivirus-TFEB (LV-TFEB) were injected into the center space of the NP tissue, after 4 or 8 weeks, Magnetic resonance imaging (MRI), X ray, Hematoxylin-Eosin (HE) and Safranin O staining were used to evaluate IVDD grades. RESULTS: The nuclear localization of TFEB declined in degenerated rat NP tissue as well as in TBHP treated NP cells. Applying lentivirus to transfect NP cells, TFEB overexpression restored the TBHP-induced autophagic flux blockage and protected NP cells against apoptosis and senescence; these protections of TFEB are diminished by chloroquine-medicated autophagy inhibition. Furthermore, TFEB overexpression ameliorates the puncture-induced IVDD development in rats. CONCLUSIONS: Experimental IVDD inhibited the TFEB activity. TFEB overexpression suppressed TBHP-induced apoptosis and senescence via autophagic flux stimulation in NP cell and alleviates puncture-induced IVDD development in vivo. PMID- 30414851 TI - Post-transcriptional pseudouridylation in mRNA as well as in some major types of noncoding RNAs. AB - Pseudouridylation is a post-transcriptional isomerization reaction that converts a uridine to a pseudouridine (Psi) within an RNA chain. Psi has chemical properties that are distinct from that of uridine and any other known nucleotides. Experimental data accumulated thus far have indicated that Psi is present in many different types of RNAs, including coding and noncoding RNAs. Psi is particularly concentrated in rRNA and spliceosomal snRNAs, and plays an important role in protein translation and pre-mRNA splicing, respectively. Psi has also been found in mRNA, but its function there remains essentially unknown. In this review, we discuss the mechanisms and functions of RNA pseudouridylation, focusing on rRNA, snRNA and mRNA. We also discuss the methods, which have been developed to detect Psis in RNAs. This article is part of a Special Issue entitled: mRNA modifications in gene expression control edited by Dr. Soller Matthias and Dr. Fray Rupert. PMID- 30414850 TI - Joint attention is intact even when visuospatial working memory is occupied. AB - The gaze of another modulates and shifts an observer's spatial attention toward this gaze direction. This phenomenon is termed joint attention. Although previous studies found joint attention was induced during a spatial working memory task, it remains an open question whether spatial working memory interferes with joint attention. To address this question, we conducted a dual task paradigm consisting of gaze cuing and spatial working memory tasks. The gaze cuing task requires that participants respond to the location of an abrupt onset of a target while ignoring the gaze of a facial image located at the center of the display. In the spatial working memory task, participants memorized two or three locations of small dots and judged whether these locations changed in the probe screen. In the dual task condition, while participants were maintaining spatial information of the spatial working memory task, they performed the gaze cuing task. In Experiment 1, maintaining spatial information did not impair the magnitude of joint attention. In Experiment 2, we increased load of spatial working memory task, and still observed results similar to Experiment 1. In Experiment 3, we replicated the findings in Experiment 1 when an identification task was conducted. In addition, we measured electrooculographic signals to investigate eye movements of participants during the task. The study provides that joint attention is intact even if spatial working memory is occupied. PMID- 30414853 TI - Multiple measures of impulsivity, eating behaviours and adiposity in 7-11-year olds. AB - Previous research suggests that the relationship between the multiple aspects of children's impulsivity, eating behaviour and adiposity may depend on measures used. Fifty 7-11-year-olds (28 female, 22 male) completed four impulsivity tasks (Go/No-Go, Door Opening, Circle Drawing, Delay Discounting), consumed a snack, reported on their eating, and were weighed and measured. Parents completed measures of child impulsivity and eating behaviour. Impulsivity and adiposity were positively correlated. Lower rates of delay discounting were associated with lower snack intake. Ability to inhibit a pre-potent response was related to dietary restraint and snack intake. Findings suggest a complex, multifaceted relationship between impulsivity, eating and adiposity, which are measure and respondent dependent. PMID- 30414852 TI - EP300-HDAC1-SWI/SNF functional unit defines transcription of some DNA repair enzymes during differentiation of human macrophages. AB - Differentiation of human macrophages predisposes these cells to numerous tasks, i.e. killing invading pathogens, and this entails the need for enhanced intracellular defences against stress, including conditions that may increase DNA damage. Our study shows that expression of DNA repair enzymes, such as PARP1, BRCA1 and XRCC1, are activated during macrophage development by the SWI/SNF chromatin remodelling complex, which serves as a histone acetylation sensor. It recognises and displaces epigenetically marked nucleosomes, thereby enabling transcription. Acetylation is controlled both in monocytes and macrophages by the co-operation of EP300 and HDAC1 activities. Differentiation modulates the activities of individual components of EP300-HDAC1-SWI/SNF functional unit and entails recruitment of PBAF to gene promoters. In monocytes, histone-deacetylated promoters of repressed PARP1, BRCA1 and XRCC1 respond only to HDAC inhibition, with an opening of the chromatin structure by BRM, whereas in macrophages both EP300 and HDAC1 contribute to the fine-tuning of nucleosomal acetylation, with HDAC1 remaining active and the balance of EP300 and HDAC1 activities controlling nucleosome eviction by BRG1-containing SWI/SNF. Since EP300-HDAC1-SWI/SNF operates at the level of gene promoters characterized simultaneously by the presence of E2F binding site(s) and CpG island(s), this allows cells to adjust PARP1, BRCA1 and XRCC1 transcription to the differentiation mode and to restart cell cycle progression. Thus, mutual interdependence between acetylase and deacetylase activities defines the acetylation-dependent code for regulation of histone density and gene transcription by SWI/SNF, notably on gene promoters of DNA repair enzymes. PMID- 30414854 TI - Eosinophil progenitor levels correlate with tissue pathology in pediatric eosinophilic esophagitis. AB - Blood eosinophil progenitors (EoPs) correlate with tissue pathology during active eosinophilic esophagitis (EoE), providing additional evidence for blood EoP levels as a biomarker for disease activity and suggesting a role for EoPs in EoE pathogenesis. PMID- 30414855 TI - Efficacy and safety of histamine H4 receptor antagonist ZPL-3893787 in atopic dermatitis. AB - BACKGROUND: Histamine 4 (H4) receptor antagonists are potential novel treatments for inflammatory skin diseases including atopic dermatitis (AD). OBJECTIVE: To study the efficacy and safety of ZPL-3893787 (selective H4 receptor antagonist) in moderate/severe AD. METHODS: A randomised, double-blind, placebo-controlled, parallel-group study was conducted to evaluate ZPL-3893787 (30mg) once daily oral therapy in adult patients with moderate/severe AD. Patients were randomized (2:1), to ZPL-3893787 (n=65) or placebo (n=33) for 8 weeks. Patients had a history of AD for >12 months, Eczema Area and Severity Index (EASI) of >=12 and <=48, Investigator's Global Assessment (IGA) >=3, pruritus score of >=5 (0-10 scale) and AD of >=10% body surface area (BSA). Efficacy parameters included EASI, IGA, SCORing Atopic Dermatitis (SCORAD), and pruritus assessment. RESULTS: Treatment with oral ZPL-3893787 showed a 50% reduction in EASI score compared to 27% for placebo. The placebo-adjusted reduction in EASI score at Week 8 was 5.1; 1-sided p=0.01. Clear or almost-clear IGA scores were 18.5% with ZPL-3893787 vs placebo 9.1%. SCORAD exhibited 41% reduction with ZPL-3893787 vs 26% placebo (placebo-adjusted reduction of 10.0; p=0.004). There was a 3-point reduction (scale 1-10) in pruritus with ZPL-389, but there was a similar reduction with placebo, resulting in a non-significant difference (p=0.249). Patient reported pruritus subscore obtained from SCORAD was reduced with ZPL-3893787 compared to placebo at Week 8 (non-significant). ZPL-3893787 was well tolerated. CONCLUSION: These results showed for the first time that ZPL-3893787 improved inflammatory skin lesions in patients with AD, confirming H4 receptor antagonism as a novel therapeutic option. PMID- 30414856 TI - New delivery forms of nasal corticosteroids. PMID- 30414857 TI - Novel locus for atopic dermatitis in African Americans and replication in European Americans. AB - The present study provides the first genetic locus associated with AD in African Americans. PMID- 30414858 TI - Innate immune crosstalk in asthmatic airways: innate lymphoid cells coordinate the polarization of lung macrophage. AB - BACKGROUND: Recent studies have emphasized the role of innate lymphoid cells (ILCs) in the development of asthma. The involvement of group 2 ILCs (ILC2s) in asthma is well studied, however, the participation of other types of ILCs in the development of asthma remains unclear. OBJECTIVE: This study aims to understand the role of various ILCs in the patients with asthma, especially their effect on the polarization of macrophages. METHODS: Each subset of ILCs and macrophages in induced sputum from 51 steroid-naive asthma patients and 18 healthy donors analyzed by flow cytometry. To determine whether the polarization of macrophages could be regulated by ILCs, alveolar macrophages (AM) were sorted; and co cultured with each subset of ILCs. RESULTS: In addition to ILC2s, ILC1s and ILC3s were increased in the induced sputum from asthmatics when compared with the healthy controls. The dominance of macrophages in induced sputum was more prominent in asthmatics than healthy controls. A positive correlation between ILC2s and M2 macrophages and that of ILC1s/ILC3s and M1 macrophages observed. Co culture of ILC2s with AMs induced the expression of M2 macrophage-related genes, whereas co-culture of ILC1s and ILC3s with AMs induced the expression of M1 macrophage-related genes via cytokine secretion as well as cell-cell contact. According to the inflammatory signature, patients with eosinophilic asthma have more ILC2s and M2 macrophages while those with non-eosinophilic asthma present are M1 macrophages dominant profile. CONCLUSION: A different subset of ILCs regulates the polarization of macrophages, contributing to developing the distinct phenotype of asthma. PMID- 30414859 TI - Identification of inhibitory mechanisms in pseudo-allergy involving Mrgprb2/MRGPRX2-mediated mast cell activation. AB - Ceramide-CD300f binding inhibits mouse Mrgprb2 (human MrgprX2)-mediated mast cell activation, thereby suppressing pseudo-allergic reactions. CD300f could be a therapeutic target against IgE-independent pseudo-allergy as well as IgE dependent allergy. PMID- 30414860 TI - Peak Flow Variability In Childhood And Body Mass Index In Adult Life. AB - Peak flow variability in childhood is a significant and independent predictor of subsequent body mass index increase up to age 26. Shared developmental and genetic factors may explain, at least in part, the association between these two phenotypes. PMID- 30414861 TI - Engineering of structural variants of the major peanut allergens Ara h 2 and Ara h 6 for allergen-specific immunotherapy. AB - Applying a novel way to design hypoallergens, we produced variants of the major peanut allergens Ara h 2 and Ara h 6 with significantly reduced IgE-binding and basophil activation capacities and preserved T-cell stimulatory activity. PMID- 30414862 TI - Targeting the crosstalk between cytokine-induced killer cells and myeloid-derived suppressor cells in hepatocellular carcinoma. AB - BACKGROUND: Cytokine-induced killer (CIK) cell-based immunotherapy is effective as adjuvant therapy in early stage hepatocellular carcinoma (HCC) but lacks efficacy in advanced HCC. We investigated immune suppressor mechanisms focuing on CIKs and myeloid-derived suppressor cells (MDSCs). METHODS: MDSCs were quantified by flow cytometry and quantitative real-time PCR. Cytokines were detected by cytokine array. An LDH cytotoxicity assay was performed in the presence or absence of MDSCs to study CIK function against HCC cells in vitro. An FDA approved PDE5 inhibitor, tadalafil, was used to target MDSCs in vitro and in vivo. Two different murine HCC cell lines were tested in subcutaneous and orthotopic tumor models in C57BL/6 and BALB/c mice. The anti-tumor effects of human CIKs and MDSCs were also tested in vitro. RESULTS: Adoptive cell transfer of CIKs into tumor bearing mice induced inflammatory mediators (e.g., CX3CL1, IL 13) in the tumor microenvironment and an increase of tumor infiltrating MDSCs leading to impaired anti-tumor activity in two different HCC tumor models. MDSCs efficiently suppressed the cytotoxic activity of CIKs in vitro. In contrast, treatment with a PDE5 inhibitor reversed the MDSC suppressor function via ARG1 and iNOS blockade and systemic treatment with a PDE5 inhibitor prevented MDSC accumulation in the tumor microenvironment upon CIK cell therapy and increased its anti-tumor efficacy. Similar results were observed when human CIKs were tested in vitro in the presence of CD14+HLA-DR-/low MDSCs. Treatment of MDSCs with a PDE5 inhibitor suppressed MDSCs suppressor function and enhanced CIK activity against human HCC cell lines in vitro. CONCLUSION: Our results suggest that targeting MDSCs is an efficient strategy to enhance the antitumor efficacy of CIKs for the treatment of patients with HCC. Lay Summary CIK cells are a mixture of immune cells given to eliminate cancer cells. However, not all patients respond to this treatment. Here we show in two different liver cancer models that MDSCs are increased in response to CIK cell therapy and subsequently may be targeted with medication to provide an additional therapeutic benefit. PMID- 30414863 TI - Non-Alcoholic Fatty Liver Disease-A Global Public Health Perspective. AB - As the epidemics of obesity and type 2 diabetes mellitus increase worldwide, the prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing proportionately. The subtype of NAFLD which can be characterized as non-alcoholic steatohepatitis (NASH) is a potentially progressive liver disease that can lead to cirrhosis, hepatocellular carcinoma, liver transplantation, and death; it is associated with extrahepatic manifestations such as chronic kidney disease cardiovascular disease and sleep apnea. NAFLD and NASH are also associated with a large economic burden and poor health-related quality of life. Despite this important burden, we are only beginning to understand its mechanisms of pathogenesis and the contribution of environmental and genetic factors to the risk of developing a progressive course. Research is underway to identify appropriate non-invasive diagnostic methods and effective treatments. Although the risk of liver related mortality is increased in NAFLD patients with liver fibrosis stages 3 or 4 , the leading cause of death is cardiovascular disease. Given the rapidly growing global burden of NAFLD and NASH, efforts must continue to find accurate non-invasive diagnostic and prognostic biomarkers, to develop effective treatments for individuals with advanced NASH as well as prevention methods for individuals at high risk for NAFLD and progressive liver disease. PMID- 30414864 TI - Effect of NGM282, a FGF19 analogue, in Primary Sclerosing Cholangitis: a Multicentre, Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial. AB - BACKGROUND AND AIMS: Primary Sclerosing Cholangitis (PSC) is an inflammatory, cholestatic and progressively fibrotic liver disease devoid of effective medical intervention. NGM282, an engineered, non-tumorigenic FGF19 analogue, potently regulates CYP7A1-mediated bile acid homeostasis. We assessed the activity and safety of NGM282 in patients with PSC. METHODS: In this double-blind, placebo controlled phase 2 trial, patients who had PSC confirmed by cholangiography or biopsy and an elevated alkaline phosphatase (ALP) >1.5xULN were randomly assigned 1:1:1 to receive NGM282 1 mg, 3 mg or placebo once daily for 12 weeks. The primary outcome was the change in ALP from baseline to week 12. Secondary and exploratory outcomes included changes in serum biomarkers of bile acid metabolism and fibrosis. Efficacy analysis was by intention-to-treat. RESULTS: 62 patients were randomized to receive NGM282 1 mg (n=21), NGM282 3 mg (n=21) or placebo (n=20). At 12 weeks, there were no significant differences in the mean change from baseline in ALP between the NGM282 and placebo groups, and therefore, the primary endpoint was not met. However, NGM282 significantly reduced levels of 7alpha-hydroxy-4-cholesten-3-one (a marker of hepatic CYP7A1 activity, LS mean differences -6.2 ng/mL [95% CI -10.7 to -1.7; P=0.008] and -9.4 ng/mL [-14.0 to 4.9; P<0.001] in the NGM282 1 mg and 3 mg groups, respectively, compared with placebo) and bile acids. Importantly, fibrosis biomarkers that predict transplant free survival, including Enhanced Liver Fibrosis score and Pro-C3, were significantly improved following NGM282 treatment. Most adverse events were mild to moderate in severity, with gastrointestinal symptoms more frequent in the NGM282 treatment groups. CONCLUSIONS: In patients with PSC, NGM282 potently inhibited bile acid synthesis and decreased fibrosis markers, without significantly affecting ALP levels. LAY SUMMARY: We present for the first time, the clinical and laboratory effects of a first-in-class, engineered analogue of the endocrine hormone FGF19 in patients with PSC. By incorporating non-invasive markers of fibrosis, beyond standard liver injury markers, we show that NGM282 impacted on fibrosis turnover and hepatic inflammation without changing alkaline phosphatase. Our findings demonstrate the complexities of using highly potent rational agents in PSC, and furthermore challenge the dogma about what the appropriate endpoints should be for trials in PSC. PMID- 30414865 TI - Randomized evaluation of trial acceptability by INcentive (RETAIN): Study protocol for two embedded randomized controlled trials. AB - INTRODUCTION: The most common and conceptually sound ethical concerns with financial incentives for research participation are that they may (1) represent undue inducements by blunting peoples' perceptions of research risks, thereby preventing fully informed consent; or (2) represent unjust inducements by encouraging enrollment preferentially among the poor. Neither of these concerns has been shown to manifest in studies testing the effects of incentives on decisions to participate in hypothetical randomized clinical trials (RCTs), but neither has been assessed in real RCTs. METHODS AND ANALYSES: We are conducting randomized trials of real incentives embedded within two parent RCTs. In each of two trials conducted in parallel, we are randomizing 576 participants to one of three incentive groups. Following preliminary determination of patients' eligibility in the parent RCT, we assess patients' research attitudes, demographic characteristics, perceived research risks, time spent reviewing consent documents, ability to distinguish research from patient care, and comprehension of key trial features. These quantitative assessments will be supplemented by semi-structured interviews for a selected group of participants that more deeply explore patients' motivations for trial participation. The trials are each designed to have adequate power to rule out undue and unjust inducement. We are also exploring potential benefits of incentives, including possible increased attention to research risks and cost-effectiveness. PMID- 30414866 TI - Structural characterization and pharmaceutical properties of three novel cocrystals of ethenzamide with aliphatic dicarboxylic acids. AB - Ethenzamide (ET) was screened in cocrystallization experiments with pharmaceutically acceptable coformer molecules to discover materials of improved physicochemical properties, that is, higher solubility and better stability. Three novel cocrystals of ethenzamide with glutaric, malonic and maleic acids were obtained by neat grinding and slow evaporation from solution. The purpose of the study was to notice the changes in the geometry and interactions of ET molecule in crystalline phase introduced by different acid and relate them to physicochemical properties of pure ethenzamide. Therefore, the crystal structure of the cocrystals was determined by single-crystal X-ray diffraction analysis. The powder samples were characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, 13C and 15N solid-state nuclear magnetic resonance spectroscopy. Spectroscopic studies were supported by gauge including projector augmented wave (GIPAW) calculations of chemical shielding constants. The high stability of cocrystals during direct compression was proved. The solubility in simulated gastric fluids for studied cocrystals appeared to be approximately 1.6 times-fold higher than ethenzamide. The dissolution rates of all ethenzamide cocrystals were not faster than the pure drug, but after 240 minutes more drug was released. PMID- 30414867 TI - Development a subcellular semi-mechanism based pharmacokinetic/pharmacodynamic model to characterize paclitaxel effects delivered by polymeric micelles. AB - A transit compartment model was widely and successfully applied to characterize the complex time course of cancer chemotherapeutic effects in vivo or in vitro. However the underlying mechanisms were not quantitatively depicted. This study aimed to develop a semi-mechanism based cellular pharmacokinetic/pharmacodynamic (PK/PD) model to characterize paclitaxel (PTX) effect delivered by PLGA-PEG micelles which was based on analysis of drug subcellular distribution, the tubulin assembly level, the cell cycle shift and the resulting cytotoxicity. Human breast cancer cell line MCF-7 was exposed to PTX at the concentration of 20 and 40 ng/mL. The in vitro pharmacokinetics of micelle-entrapped PTX was described by a three-compartment model composed of membrane/organelle, nucleus and cytoskeleton. A hypothetical effect compartment was employed to characterize the distribution delay. The time course of tubulin polymerization stimulation was fitted by the indirect response model. The relationship between tubulin polymerization and G2/M cell population was described by a linear model, and the promoting effect of G2/M arrest on the cytotoxicity was characterized by the Emax model. The proposed model captured the data successfully and described the cellular mechanism of anti-mitotic drug nanoparticles quantitatively. The methodology and the resulting model could be a supplement for traditional in vivo studies. PMID- 30414868 TI - Determining Maximum Sublimation Rate for a Production Lyophilizer: Computational Modeling and Comparison with Ice Slab Tests. AB - Equipment capability is an important factor in scale up and technology transfer for lyophilized pharmaceutical products. Experimental determination of equipment capability limits, such as the maximum sublimation rate at a given chamber pressure, is time intensive for production lyophilizers. Here we present computational fluid dynamics modeling of equipment capability and compare it with experimental data for Minimum Controllable Pressure ice slab sublimation tests in a 23 m2 shelf area freeze-dryer. It is found that the vapor flow in the production scale is characterized by turbulent effects at high sublimation rates. For the considered freeze-dryer configuration, the onset of turbulence occurs at a sublimation rate of 17 kg/hr and leads to an increase in the Minimum Controllable Pressure by 3-4 mTorr for the flow rates up to 40 kg/hr. Variations in the shelf and duct orientations as well as the valve stroke distance and their effect on the equipment limit and pressure uniformity are also discussed. The Minimum Controllable Pressure measured experimentally agreed within 5% with CFD results. For high vapor sublimation rates at final stages of ice slab testing, the condenser load affects the product chamber pressure control. Estimate of condenser pressure changes due to ice accumulation has been included. PMID- 30414869 TI - Application of optical flow algorithms to laser speckle imaging. AB - Since of its introduction in 1980s, laser speckle imaging has become a powerful tool in flow imaging. Its high performance and low cost made it one of the preferable imaging methods. Initially, speckle contrast measurements were the main algorithm for analyzing laser speckle images in biological flows. Speckle contrast measurements, also referred as Laser Speckle Contrast Imaging (LSCI), use statistical properties of speckle patterns to create mapped image of the blood vessels. In this communication, a new method named Laser Speckle Optical Flow Imaging (LSOFI) is introduced. This method uses the optical flow algorithms to calculate the apparent motion of laser speckle patterns. The differences in the apparent motion of speckle patterns are used to identify the blood vessels from surrounding tissue. LSOFI has better spatial and temporal resolution compared to LSCI. This higher spatial resolution enables LSOFI to be used for autonomous blood vessels detection. Furthermore, Graphics Processing Unit (GPU) based LSOFI can be used for quasi real time imaging. PMID- 30414870 TI - Differences in skin blood flow oscillations between the plantar and dorsal foot in people with diabetes mellitus and peripheral neuropathy. AB - BACKGROUND: Understanding the differences in skin blood flow (SBF) on the plantar and dorsal foot in people with diabetes mellitus (DM) may help to assess the influence of diabetes and neuropathy on microvascular dysfunction and risks of diabetic foot ulcers in this population. However, there is no study comparing SBF oscillations between the plantar and dorsal foot in people with DM and peripheral neuropathy (PN). OBJECTIVE: The objective of this study was to compare SBF oscillations between the plantar and dorsal foot in people with DM and PN and investigate the underlying mechanisms responsible for the differences. METHODS: 18 people with Type 2 DM and PN and 8 healthy controls were recruited. Laser Doppler flowmetry (LDF) was used to measure SBF on the plantar and dorsal foot for 10 min when the subject was in the supine position. Wavelet analysis was used to quantify the relative amplitude of the characteristic frequency components of SBF oscillations. Sample entropy analysis was used to quantify the regularity degree of SBF oscillations. RESULTS: People with DM and PN had a higher SBF on the plantar foot compared to the dorsal foot. The relative wavelet amplitudes of metabolic and myogenic frequency components on the plantar foot were respectively higher and lower compared to the dorsal foot. Sample entropy analysis showed that SBF on the plantar foot had a higher degree of regularity compared to the dorsal foot. CONCLUSIONS: In people with DM and PN, higher SBF on the plantar foot is attributed to the metabolic and myogenic controls, and SBF on the plantar foot exhibits a higher degree of regularity compared to the dorsal foot. People with DM and PN also had higher plantar and dorsal SBF compared to the healthy controls. This study provides evidence to document differences in SBF of the plantar and dorsal foot in people with DM and PN. PMID- 30414871 TI - Synergistic effect of aripiprazole and escitalopram in increasing serotonin but not norepinephrine neurotransmission in the rat hippocampus. AB - In addition to schizophrenia and bipolar disorder, aripiprazole is approved as an adjunct for major depressive disorder (MDD). Adding aripiprazole to the 5-HT reuptake inhibitor escitalopram reverses the inhibitory action of escitalopram on firing activity of rat 5-HT, norepinephrine (NE) and DA neurons. This study investigated how aripiprazole, escitalopram and their combination affect the net effect of 5-HT and NE neurotransmission in the rat hippocampus. Electrophysiological recordings of hippocampus CA3 pyramidal neurons were conducted in anesthetized Sprague-Dawley rats after 2- and 14-day administration regimens. Aripiprazole and escitalopram (2 and 5 mg/kg/day, respectively) were delivered alone or in combination through subcutaneous injections and implanted osmotic minipumps, respectively. Overall neurotransmission of 5-HT and NE were assessed by determining possible enhancements in tonic activation of 5-HT1A receptors and alpha1- and alpha2-adrenoceptors. This was achieved by assessing increases of firing rate of pyramidal neurons due to disinhibition induced by injections of antagonists for these three types of receptors. While neither 2- and 14-day administration of escitalopram nor aripiprazole significantly altered firing rate of pyramidal neurons following injection of 5-HT1A antagonist WAY100635, their combination for 14 days significantly increased this parameter. Fourteen days of the same drug regimens did not change firing following injection of the alpha1- and alpha2-adrenoceptor antagonists prazosin and idazoxan, respectively. A synergy between aripiprazole and escitalopram was thus documented by an increase in the tonic activation of 5-HT1A receptors after 14 days of administration that may account, at least in part, for the benefits of this strategy in MDD. PMID- 30414872 TI - From Pretending to Truly Being OK: A Journey From Illness to Health With Postinfection Irritable Bowel Syndrome: The Patient's Perspective. PMID- 30414873 TI - Modeling vaccination decision making process in a finite population. AB - Vaccination is considered as one of the most crucial methods in controlling the spread of infectious diseases. However, it is difficult to predict the expected vaccine coverage level because it depends on human behaviors. We consider deterministic and stochastic models to simulate how individuals choose strategies in the scenario of vaccination. In an infinite population, a system of replicator equations is formulated and the expected level is calculated. Decision making processes in both an unstructured finite population and a structured finite population are discussed. Expected vaccine coverage levels are calculated and analyzed. In a structured finite population, passive decision making process and initiative decision making process are defined. It is also analytically and numerically proved that the passive decision making process can predict a higher vaccine coverage level than the process of initiative decision making. PMID- 30414874 TI - Misinterpretation risks of global stochastic optimisation of kinetic models revealed by multiple optimisation runs. AB - One of use cases for metabolic network optimisation of biotechnologically applied microorganisms is the in silico design of new strains with an improved distribution of metabolic fluxes. Global stochastic optimisation methods (genetic algorithms, evolutionary programing, particle swarm and others) can optimise complicated nonlinear kinetic models and are friendly for unexperienced user: they can return optimisation results with default method settings (population size, number of generations and others) and without adaptation of the model. Drawbacks of these methods (stochastic behaviour, undefined duration of optimisation, possible stagnation and no guaranty of reaching optima) cause optimisation result misinterpretation risks considering the very diverse educational background of the systems biology and synthetic biology research community. Different methods implemented in the COPASI software package are tested in this study to determine their ability to find feasible solutions and assess the convergence speed to the best value of the objective function. Special attention is paid to the potential misinterpretation of results. Optimisation methods are tested with additional constraints that can be introduced to ensure the biological feasibility of the resulting optimised design: (1) total enzyme activity constraint (called also amino acid pool constraint) to limit the sum of enzyme concentrations and (2) homeostatic constraint limiting steady state metabolite concentration corridor around the steady state concentrations of metabolites in the original model. Impact of additional constraints on the performance of optimisation methods and misinterpretation risks is analysed. PMID- 30414875 TI - Acemosin- a cytotoxic 20-norsteroid from Asparagus racemosus. AB - A novel cytotoxic 20-norsteroid with twenty-six carbon atoms named acemosin (1) was isolated and structural characterized together with two known compounds, asparacosin A (2) and stigmasterol (3) from the roots of Asparagus racemosus. Their structures were elucidated by a combination of 2D NMR, HR-MS and X-ray crystallographic analyses. Acemosin (1) possesses an unprecedented carbon skeleton, where the methyl group at C-20 is absent. Acemosin shows moderate cytotoxicity against HepG2 cancer cell line with its IC50 value of 87.3 MUg/mL. PMID- 30414876 TI - Xanthone-derived polyketides from the Thai mangrove endophytic fungus Phomopsis sp. xy21. AB - Six new xanthone-derived polyketides, named phomoxanthones F-K (1-6), along with three known ones, were isolated from Phomopsis sp. xy21, which was isolated as an endophytic fungus from the Thai mangrove Xylocarpus granatum. Phomoxanthone F (1) represents the first xanthone-derived polyketide containing a 10a-decarboxylated benzopyranone nucleus that was substituted by a 4-methyldihydrofuran-2(3H)-one moiety at C10a. Phomoxanthones G (2) and H (3) are highly oxidized xanthone derived polyketides containing a novel 5-methyl-6-oxabicyclo[3.2.1]octane motif. This is the first report of a C6-O-C12 bridge in xanthone-derived polyketides. Additionally, a plausible biogenetic pathway for these xanthone-derived polyketides is proposed. PMID- 30414877 TI - Meroterpenoids isolated from Arnebia euchroma (Royle) Johnst. and their cytotoxic activity in human hepatocellular carcinoma cells. AB - Six previously undescribed naturally occurring meroterpenoids (2, 5-9) together with seven known meroterpenoids (1, 3, 4, 10-13) were isolated from the root plant of Arnebia euchroma. Their structures and absolute configurations were determined by extensive 1D (1H NMR, 13C NMR) and 2D NMR (1H1H COSY, DEPT, HMQC, HMBC, NOESY) spectroscopic methods, spectroscopy high resolution mass spectrometry, as well as DFT and MM2 force-field calculations. Meroterpenoids 1 13 were evaluated for their cytotoxicities against human liver cancer cell lines SMMC-7721, HepG2, QGY-7703 and HepG2/ADM. Meroterpenoid 5 exhibited the most potent activity with IC50 values of 6.40 +/- 0.51, 3.86 +/- 0.28, 3.43 +/- 0.27 and 11.31 +/- 0.67 MUM, respectively. Meroterpenoid 4 exhibited significant growth inhibitory effects against HepG2/ADM with IC50 at 18.77 +/- 1.23 MUM, and meroterpenoid 8 with IC50 at 5.41 +/- 0.51 and 6.18 +/- 0.47 MUM against HepG2 and QGY-7703, respectively. These were more potent than the positive drug, Cisplatin. PMID- 30414878 TI - Withanolides and aromatic glycosides isolated from Nicandra physaloides and their anti-inflammatory activity. AB - Two new withanolides (1-2) together with five known ones (3-7), and three known aromatic glycosides (8-10) were isolated from the dried stems and leaves of Nicandra physaloides, an edible and medicinal plant. Their structures were identified by extensive spectroscopic analyses or comparison with literature data. The absolute configuration of 2 was assigned via X-ray crystallography. Compound 1 with a spiroketal moiety is relatively unusual in withanolides. Aromatic glycosides (8-10) showed potent inhibitory activity against LPS-induced nitric oxide production in RAW 264.7 macrophages, with IC50 values from 4.69 to 16.12 MUM. PMID- 30414879 TI - Membrane-binding domains in autophagy. AB - Autophagy is an intracellular degradation system conserved among eukaryotes that mediates the degradation of various biomolecules and organelles. During autophagy, a double membrane-bound organelle termed an autophagosome is synthesized de novo and delivers targets from the cytoplasm to the lysosomes for degradation. Autophagosome formation involves complex and dynamic membrane rearrangements, which are regulated by dozens of autophagy-related (Atg) proteins. In this review, we summarize our current knowledge of membrane-binding domains and motifs in Atg proteins and discuss their roles in autophagy. PMID- 30414880 TI - The Impact of Ghrelin on the Survival and Efficacy of Dopaminergic Fetal Grafts in the 6-OHDA-Lesioned Rat. AB - Ghrelin is a peptide produced in the gut with a wide range of physiological functions. Recent studies have suggested it may have potential as a neuroprotective agent in models of Parkinson's disease, reducing the impact of toxic challenges on the survival of nigral dopaminergic neurons. The presence of the ghrelin receptor (GHSR1a) on the dopaminergic neurons of the substantia nigra raises the possibility that a potential application for this property of ghrelin may be as an adjunctive neuroprotective agent to enhance and support the survival and integration of dopaminergic cells transplanted into the striatum. Thus far, inconsistent outcomes in clinical trials for fetal cell transplantation have been linked to low rates of cell survival which we hypothesize could be ameliorated by the presence of ghrelin. To explore this, we confirmed the expression of the GHSR1a and related enzymes on e14 ventral mesencephalon. To determine a functional effect, five groups of female Sprague-Dawley rats received a unilateral 6-OHDA lesion to the medial forebrain bundle and four received an intrastriatal graft of e14 ventral mesencephalic cells. Grafted rats received saline; acyl-ghrelin (10 ug/kg); acyl-ghrelin (50 ug/kg) or the ghrelin agonist JMV-2894 (160 ug/kg) i.p. for 8 weeks. An effect of ghrelin at low dose on hippocampal neurogenesis indicated blood-brain barrier penetrance and attainment of biologically relevant levels but neither acyl-ghrelin nor JMV-2894 improved graft survival or efficacy. PMID- 30414881 TI - A Quantitative Meta-analysis of Neuroimaging Studies of Pragmatic Language Comprehension: In Search of a Universal Neural Substrate. AB - Pragmatics may be defined as the ability to communicate by expressing and recognizing intentions. The objective of this meta-analysis was to identify neural substrates for comprehension of pragmatic content in general, as well as the differences between pragmatic forms, and to describe if there is differential recruitment of brain areas according to natural language. This meta-analysis included 48 functional magnetic resonance imaging studies that reported pragmatic versus literal language contrasts. The pragmatic forms were speech acts, metaphors, idioms, and irony. Effect Size-Signed Differential Mapping software was used to calculate the mean for all contrasts as well as for each pragmatic form, and make comparisons among all forms. Due to variations in pragmatic content configuration such as natural language, stimulus modality, and writing systems, these variations were also analyzed with subgroups' analyses. The analyses found a highly reproducible bilateral fronto-temporal and medial prefrontal cortex network for pragmatic comprehension. Each pragmatic form showed a specific convergence pattern within this bilateral network. Natural language analyses showed that fronto-temporal regions were recruited by Germanic languages, while only left frontal areas were recruited by Romance languages, and right medial prefrontal cortex by Japanese. In conclusion, pragmatic language comprehension involves classical language areas in bilateral perisylvian regions, along with the medial prefrontal cortex, an area involved in social cognition. Together, these areas could represent the "pragmatic language network". Nonetheless, when proposing a universal neural substrate for all forms of pragmatic language, the diversity among studies in terms of pragmatic form, and configuration, must be taken into consideration. PMID- 30414882 TI - Psychophysiological response of air mobile protection teams in an air accident manoeuvre. AB - Different extreme contexts elicit a stress response on human body, specifically on combat produces an increase of sympathetic nervous system and a direct effect on the organic response. This research aimed to study the psychophysiological response of an air security force in a simulated air accident in a hostile area and its subsequent subterfuge to a safe area. We analyzed 13 soldiers (32.4 +/- 8.0 years) from an air security force unit of the Spanish Air Force who were divided into three teams to conduct the manoeuvre. We analyzed before and after the manoeuvre psychological well-being scale, personal views survey, recovery stress questionnaire (REST-52 Sport); heart rate variability, visual analogue scale, rated of perceived exertion, spirometry, hydration and hand strength were analyzed during the four days of the manoeuvre: This produced a significantly (p < .05) increase in sympathetic modulation, hand strength, dehydration status, general and specific stress from RESTQ-52. With this data we can conclude that an air accident manoeuvre of three nights and four days causes in the air mobile protection team a high sympathetic nervous system modulation, increases on muscle strength manifestations and stress and a dehydration status. PMID- 30414883 TI - Heart rate variability and emotion regulation among individuals with obesity and loss of control eating. AB - Autonomic nervous system functioning, measured with heart rate variability (HRV), is associated with emotion regulation and likely contributes to binge eating. This study examined the link between HRV and binge eating severity and analyzed changes in HRV as a marker of emotion regulation in individuals with binge eating. Participants (n = 28) with obesity and loss of control eating reported overeating and loss of control episodes and completed an HRV assessment at rest and during a mental stressor. At rest, lower time-domain HRV was linked to more severe loss of control (SDNN B = -0.18, p = 0.03). Frequency-domain HRV was associated with more severe overeating (LFn B = 14.92, p = 0.03; HFn B = -14.81, p = 0.04). Frequency-domain HRV differed between resting and stressed conditions (p's < 0.001). Findings contribute to understanding emotion regulation in binge eating and guide future research and novel intervention development. PMID- 30414884 TI - Long-term behavioural effects of maternal obesity in C57BL/6J mice. AB - Diet is increasingly being recognised as an important contributor to mental health. A diet high in sugar and polyunsaturated fatty acids can have negative consequences for disease symptoms and outcomes in schizophrenia patients. There is also evidence that particular diets can have beneficial, therapeutic-like properties for human brain disorders. Additionally, dietary choices of mothers have been found to affect cognitive domains and anxiety behaviour of offspring. Here we investigated the effects of maternal high fat diet (HFD) on a variety of behavioural domains in offspring and also consider behaviours, which are schizophrenia-relevant. Female C57BL/6 J mice were fed HFD (N = 13) or chow (N = 11) from 6 weeks prior to mating, during gestation and lactation. The male offspring of these mothers were weaned onto chow on PND24 and underwent testing for a range of behavioural outcomes starting at 38 weeks of age. Offspring of HFD mothers were significantly heavier compared to those of control mothers from weaning and throughout the duration of the experiment. Offspring of HFD mothers had significantly improved sensorimotor gating compared to offspring of control mothers but showed no altered behavioural response in tests for cognition, sociability, locomotion or exploration. Which HFD-induced factor is responsible for the effects, e.g. altered maternal nursing behaviour, altered gestational physiology, or others warrants further investigation. PMID- 30414885 TI - The odour of human milk: Its chemical variability and detection by newborns. AB - Human milk odour has for long elicited research interest with regard to its function in breastfeeding initiation. The present review aims to provide an overview of the behavioural effects of human milk odour in the human neonate, considering different types of response measures in a feeding or non-feeding context. Further, an overview of the current knowledge of odorant composition and factors influencing milk odour is provided by summarizing results from analytical studies using olfactometry, and addressing changes in milk odour due to storage, lactational stage, and maternal dietary intake of odorous substances. We finally highlight some issues for future research. PMID- 30414886 TI - Can disbudding of calves (one versus four weeks of age) induce chronic pain? AB - BACKGROUND: Calf disbudding is a welfare-relevant invasive husbandry procedure. While it is widely recognized that disbudding elicits acute pain, its chronic consequences are currently unknown. OBJECTIVES: Primary aim of this study was to investigate whether disbudding leads to chronic pain in calves; secondary aim was to evaluate the influence of age at disbudding (1 week versus 4 weeks). METHODS: Thirty-four Holstein bull calves, enrolled in a prospective, controlled, randomized trial, underwent either early disbudding (ED) or late disbudding (LD) or sham treatment (control) at 1 and 4 weeks of age. Pain scoring and quantitative sensory tests (von Frey filaments and algometry) were performed at regular intervals up to 105 days of life; neurophysiological determination of nociceptive reflex thresholds and conditioned pain modulation (CPM) up to 90 days. Data was analyzed with the Brunner and Langer model followed by post-hoc test, with level of significance set at 0.05. RESULTS: Thirty-one calves completed the data collection. Signs of chronic sensitization were observed in 38% of disbudded calves (4 in ED and 4 in LD). Pain scores (until 105 days) and allodynia scores (until 60 days) were significantly higher while pressure thresholds (until 105 days) were significantly lower in both groups ED and LD compared to control. Late disbudded calves showed impairment of trigeminal CPM. Lower laser-evoked trigeminal reflex thresholds were found in clinically painful calves compared to control. CONCLUSIONS: The sequelae of disbudding can extend beyond the acute post-procedural phase. Chronic trigeminal sensitization, independently from the age at disbudding can affect individual calves. PMID- 30414887 TI - The effects of the urocortins on the hypothalamic-pituitary-adrenal axis - similarities and discordancies between rats and mice. AB - The urocortins (Ucn I, Ucn II and Ucn III) are structural analogues of corticotropin-releasing factor (CRF). The aim of our present experiments was to compare the effects of the urocortins on the hypothalamic-pituitary-adrenal (HPA) axis in rats and mice, including the hypothalamic adrenocorticotropic hormone (ACTH) secretagogues, such as CRF and arginine vasopressin (AVP). Therefore, male CFLP mice and male Wistar rats were injected intracerebroventricularly (icv) with 0.5, 1, 2 and 5 MUg/2 MUl of Ucn I, Ucn II or Ucn III. After 30 min the animals were decapitated, and then, hypothalamic CRF and AVP concentrations and plasma ACTH and corticosterone (CORT) levels were measured. All measurements were performed by enzyme-linked immunosorbent assays (ELISA), except that of the plasma CORT level, which was determined by chemofluorescent assay. Ucn I increased significantly the hypothalamic CRF and AVP concentrations in both rats and mice. Ucn II and Ucn III influenced significantly only the hypothalamic CRF concentration in rats, without affecting the hypothalamic AVP concentration. In contrast, Ucn II and Ucn III increased significantly only the hypothalamic AVP concentration in mice, without affecting the hypothalamic CRF concentration. The hypothalamic changes were reflected more or less accurately by changes of the plasma ACTH and CORT levels. The present experiments demonstrate that the urocortins regulate the HPA axis centrally via modulation of the hypothalamic ACTH secretagogues and that there are some similarities and discordancies between rats and mice regarding this regulation. PMID- 30414888 TI - Preface. PMID- 30414889 TI - Program Director Perceptions of Usefulness of the Accreditation Council for Graduate Medical Education Milestones System for Urology Resident Evaluation. AB - OBJECTIVES: To assess the application and perceived usefulness of the Accreditation Council for Graduation Medical Education (ACGME) Milestones system for resident evaluation among urology program directors (PDs). MATERIALS AND METHODS: We conducted an online survey of 133 urology PDs. The survey addressed several domains: (1) demographic information, (2) logistics and implementation of the faculty Clinical Competency Committee (CCC) meetings, and (3) perceived overall effectiveness and usefulness of the Milestones assessments. RESULTS: Eighty-eight responses were obtained (66% response rate). A total of 42/88 programs (48%) described the Milestones as very or somewhat unhelpful in resident evaluation, with a comparable proportion (44%) responding Milestones assessments never or almost never accurately distinguished between residents. Respondents felt higher scores on all domains of the Milestones were completely or somewhat uncorrelated to higher in-service exam scores (58%), with a smaller fraction (49%) deeming they were not predictive of board passage rates. Overall, 30% of respondents answered neutrally as to whether they felt the Milestones format has led to better resident formative feedback, and 35% were neutral as to the implications of this system toward promoting professional development. CONCLUSIONS: The ACGME Milestones system for resident evaluation was initiated to create a uniform competency-based assessment system; however, a sizable proportion of urology PDs in our cohort did not find the Milestones system helpful or accurate in assessing residents or predicting future successes. Given the Milestones system is still in its infancy, the utility of this system within urology has yet to be fully assessed. PMID- 30414890 TI - The Association of the Mayo Adhesive Probability (MAP) Score With Total Operative Time in Patients Undergoing Hand-assisted Laparoscopic Donor Nephrectomy. AB - OBJECTIVE: To assess whether donor kidney Mayo Adhesive probability (MAP) score is associated with (total operative time) ORT in patients undergoing hand assisted laparoscopic donor nephrectomy (HALDN). METHODS: Three hundred and thirty-one patients undergoing HALDN were reviewed. Donor kidney MAP scores were recorded based on preoperative computed tomography or magnetic resonance imaging. Single variable and multiple variable regression analysis were used to evaluate the correlation between MAP score and ORT. RESULTS: Three hundred and thirty-one patients underwent HALDN between January 2007 and April 2017. Median body mass index was 26.4 kg/m2 (interquartile range 23.4, 29.5) and median age at time of surgery was 45 years (interquartile range 37, 53). Two hundred and thirty-one patients had donor kidney MAP = 0. Hundred patients had donor kidney MAP >0. Mean ORT was 163 minutes for females with MAP = 0 and 166 minutes for females with MAP >0. Median ORT was 180 minutes for males with MAP =0 and 191 minutes for males with MAP >0. Donor kidney MAP score > 0 was significantly correlated with longer ORT (increase of 24.4 minutes, P = .001) in single variable analysis. In multivariable analysis, this correlation was only significant for males (increase of 28.9 minutes, P = .013). CONCLUSION: MAP score > 0 is associated with longer ORT for males undergoing HALDN. PMID- 30414891 TI - The novel exchange protein activated by cyclic AMP 1 (EPAC1) agonist, I942, regulates inflammatory gene expression in human umbilical vascular endothelial cells (HUVECs). AB - Exchange protein activated by cyclic AMP (EPAC1) suppresses multiple inflammatory actions in vascular endothelial cells (VECs), partly due to its ability to induce expression of the suppressor of cytokine signalling 3 (SOCS3) gene, the protein product of which inhibits interleukin 6 (IL6) signalling through the JAK/STAT3 pathway. Here, for the first time, we use the non-cyclic nucleotide EPAC1 agonist, I942, to determine its actions on cellular EPAC1 activity and cyclic AMP regulated gene expression in VECs. We demonstrate that I942 promotes EPAC1 and Rap1 activation in HEK293T cells and induces SOCS3 expression and suppresses IL6 stimulated JAK/STAT3 signalling in HUVECs. SOCS3 induction by I942 in HUVECs was blocked by the EPAC1 antagonist, ESI-09, and EPAC1 siRNA, but not by the broad spectrum protein kinase A (PKA) inhibitor, H89, indicating that I942 regulates SOCS3 gene expression through EPAC1. RNA sequencing was carried out to further identify I942-regulated genes in HUVECs. This identified 425 I942-regulated genes that were also regulated by the EPAC1-selective cyclic AMP analogue, 007, and the cyclic AMP-elevating agents, forskolin and rolipram (F/R). The majority of genes identified were suppressed by I942, 007 and F/R treatment and many were involved in the control of key vascular functions, including the gene for the cell adhesion molecule, VCAM1. I942 and 007 also inhibited IL6-induced expression of VCAM1 at the protein level and blocked VCAM1-dependent monocyte adhesion to HUVECs. Overall, I942 represents the first non-cyclic nucleotide EPAC1 agonist in cells with the ability to suppress IL6 signalling and inflammatory gene expression in VECs. PMID- 30414892 TI - Decrease in 14-3-3eta protein levels is correlated with improvement in disease activity in patients with rheumatoid arthritis treated with Tofacitinib. AB - 14-3-3eta protein is a proinflammatory mediator that may represent a novel diagnostic and prognostic biomarker for rheumatoid arthritis (RA). We assessed the correlation between changes in serum 14-3-3eta levels and changes in clinical disease activity measures in RA patients treated with Tofacitinib (TOF). Paired serum samples from 35 patients with RA were obtained at baseline and 5 months after the initiation of treatment with TOF. The levels of 14-3-3eta were measured by JOINT stat 14-3-3eta ELISA test kits (Augurex Life Sciences Corp.). The cut off was defined as 0.19 ng/ml. 14-3-3eta positivity was found in 57% of the patients at baseline and in 37% of the patients after 5 months of treatment. Mean +/- SD baseline 14-3-3eta levels [4.92 +/- 8.86 ng/ml] were significantly higher (p < 0.005) than 14-3-3eta levels following treatment [1.97 +/- 4.59 ng/ml]. A statistically significant improvement (p < 0.001) of CDAI, SDAI, DAS4ESR and DAS4CRP was achieved after 5 month of treatment. Decrease in 14-3-3eta protein levels was highly correlated with improvement in DAS4ESR (r = 0.50, p < 0.01), DAS4CRP (r = 0.46, p < 0.01) and ESR (r = 0.36, p = 0.03) and moderately correlated with improvement in CDAI (r = 0.32, p = 0.065) and SDAI (r = 0.33, p = 0.051). The correlation between decrease in 14-3-3eta levels and improvement in DAS4ESR remained significant in a partial correlation analysis controlling for ESR (r = 0.39, p = 0.02). This study demonstrates that in RA patients who were treated with TOF, decrease in 14-3-3eta levels is correlated with improvement in clinical disease activity parameters. The 14-3-3eta protein may serve as an objective biomarker for monitoring of TOF therapy response. PMID- 30414893 TI - Negative regulation of angiogenesis by novel micro RNAs. AB - Angiopoietin-1 (Ang-1) is a ligand of Tie-2 receptors that promotes survival, migration, and differentiation of endothelial cells (ECs). Recent studies have identified several microRNA (miRNA) families that either promote or inhibit angiogenesis. To date, the nature and functional importance of miRNAs in Ang-1 induced angiogenesis are unknown. Microarray screening of known miRNAs in human umbilical vein endothelial cells (HUVECs) revealed that the expressions of miR 103b, miR-330-5p, miR-557, miR-575, miR-1287-5p, and miR-1468-5p significantly decrease following exposure to Ang-1 for 24 h. Exposure to the angiogenesis factors angiopoietin-2 (Ang-2), vascular endothelial growth factor, fibroblast growth factor 2, and transforming growth factor beta also inhibits miR-103b expression, but exerts varying effects on the other miRNAs. By overexpressing miR 103b, miR-330-5p, miR-557, miR-575, miR-1287-5p, and miR-1468-5p with selective mimics, we demonstrated that the pro-survival effects of Ang-1 are eliminated, Caspase-3 activity increases, and cell migration, proliferation, and capillary like tube formation decreases. Conversely, transfection with selective miRNA inhibitors increases cell survival, inhibits Caspase-3 activity, and stimulates migration, proliferation and tube formation. miRNet miRNA-target gene network analyses revealed that miR-103, miR-330-5p, miR-557, miR-575, miR-1287-5p, and miR-1468-5p directly interact with 47, 95, 165, 108, 49, and 16 gene targets, respectively. Since many of these genes are positive regulators of angiogenic processes, we conclude that these miRNAs function as anti-angiogenic miRNAs and that their downregulation may be essential for Ang-1-induced angiogenesis to occur. PMID- 30414894 TI - Zebrafish fatty acids receptor Gpr84 enhances macrophage phagocytosis. AB - GPR84 was identified as a receptor for medium-chain fatty acids with carbon chain lengths of 9-14. It has previously been reported that lipopolysaccharide (LPS) induces significantly up-regulation of zebrafish gpr84, and zebrafish gpr84 overexpression markedly increased the LPS-stimulated production of the cytokine IL-12. Here we expanded on these studies to further investigate the roles of zebrafish Gpr84 in immune reaction. Flow cytometric assay was used to assess the effects of zebrafish Gpr84 on the phagocytosis of bacteria by macrophages. It was found that overexpression of zebrafish gpr84 significantly increased both the phagocytic ability (PA) and phagocytic index (PI) values of the macrophages engulfing the bacteria, suggesting that zebrafish Gpr84 was able to promote the phagocytosis of bacteria by the macrophages. The data proves the direct effect of Gpr84 in immune reaction. PMID- 30414895 TI - Effect of immunostimulatory feed supplements on the development of acquired immunity in rainbow trout (Oncorhynchus mykiss). AB - Immunostimulatory feed supplements are an increasingly common feature of aquaculture management and their benefit has been confirmed for a wide area of products. However, these investigations have often focused on the benefit of these supplements on the innate immune system. In the current project, we investigated a mixture of two commercial feed supplements (Biotronic(r) Top 3 and Levabon(r) Aquagrow E) with a known protective effect against bacterial infections. The effect of the supplemented diet on antibody titters of Oncorhynchus mykiss vaccinated against Yersinia ruckeri was determined by ELISA. Furthermore, an infection trial was performed to confirm the effect of the supplements on the survival of the fish. Finally, their effects on the growth parameters of the fish were also determined. The results from this study found no significant effect on the general antibody titters. However, when considering only the titters of specific anti-Y ruckeri antibodies, the supplemented feed was associated with an improved response to the vaccine, significantly better than in the fish that had received the control feed. PMID- 30414896 TI - Establishment of rapid detection method and surveillance of budgerigar fledgling disease virus using a TaqMan Real-Time PCR. AB - Budgerigar fledgling disease virus (BFDV) infection causes sudden death, abdominal distention, and feather abnormality in psittacine birds. In this study, we developed a TaqMan Real-time PCR assay to detect BFDV by targeting a conserved region in VP1 gene. The detection limit of the assay was 30 DNA gene copies, 1000 times more sensitive than conventional PCR. The coefficients of variation were less than 1.09% in either intra- or inter-assays, indicating high reproducibility. By using this method, the prevalence of BFDV in China was evaluated. 56 feces samples were collected from four psittacine birds breeding facilities in China. The results showed 28 out of 56 samples were positive for BFDV in Real-Time PCR assay, while only 19 samples were positive in PCR assay. Three facilities were positive for BFDV with positive rates from 60% to 87.5%. Further sequence analysis of VP1 genes from the positive samples indicated that VP1 genes fell into two different lineages in phylogenetic tree, suggesting that different genotypes BFDV are co-circulating in China. PMID- 30414897 TI - Treg cells depletion is a mechanism that drives microvascular dysfunction in mice with established hypertension. AB - BACKGROUND: Microvascular dysfunction is a major complication in hypertensive patients. We previously reported that CD4+CD25+ T regulatory cells (Treg) play an important preventive role in hypertension-induced vascular dysfunction. However, whether Treg cells therapy and autophagy inhibition could rescue Treg cells survival and microvascular function in established hypertension is an important question that remained unanswered. METHODS & RESULTS: Here we showed that Treg cells from mice model of established hypertension displayed an enhanced apoptotic rate, which was rescued with Treg cells transfer and autophagy inhibition. We also showed increased autophagy in mesenteric resistance artery (MRA) in mice with established hypertension. Importantly, the inhibition of autophagy or one single transfer of Treg cells into mice with established hypertension improved the microvascular function independently of high blood pressure. The protection involves the modulation of interleukin-10 (IL-10), inflammation, endoplasmic reticulum (ER) stress, oxidative stress, Akt, and eNOS. CONCLUSIONS: The present study suggests that Treg cells survival is regulated by autophagy. Also, Treg cells as a cellular therapy aimed at rescuing the microvascular function through an autophagy-dependent mechanism and independently of arterial blood pressure lowering effects. Because our mouse model of established hypertension mimics the clinical situation, our results have the potential for new therapeutic approaches that involve the manipulation of Treg cells and autophagy to overcome established hypertension-induced cardiovascular complications. PMID- 30414898 TI - Development of novel zero-order release budesonide tablets for the treatment of ileo-colonic inflammatory bowel disease and comparison with formulations currently used in clinical practice. AB - Up to 50% of Crohn's disease and ulcerative colitis patients suffer from ileo colonic inflammation. Topically delivered budesonide is an effective treatment but in vitro as well as clinical data suggest that oral formulations currently used in clinical practice are not optimal to treat the ileo-colon. The aim of this in vitro study was to develop ileo-colonic-targeted zero-order sustained release tablets containing 3 mg or 9 mg budesonide. Targeted delivery was achieved by coating the tablets with the ColoPulse technology (ColoPulse 3 mg or ColoPulse 9 mg, respectively). Tablets were tested in a 10-h gastrointestinal simulation system for site-specific release, zero-order release kinetics (R2 >= 0.950), release rate, and completeness of release (>=80%). Release profiles of the novel formulations were compared with Entocort, Budenofalk, and Cortiment (budesonide MMX). ColoPulse 3 mg and 9 mg were targeted to the simulated ileo colon, budesonide release was complete and in a sustained zero-order manner, and both formulations complied with a 6-month accelerated stability study. None of the formulations currently used in clinical practice targeted the ileo-colon. These in vitro results are discussed in light of clinical data. ColoPulse 3 mg and 9 mg are novel interesting formulations for the treatment of the entire ileo colon in inflammatory bowel disease. PMID- 30414899 TI - Selection of the suitable polymer for supercritical fluid assisted preparation of carvedilol solid dispersions. AB - Solid dispersions production is one of the substantial approaches for improvement of poor drug solubility. Additionally, supercritical fluid assisted method for preparation of solid dispersions can offer many advantages in comparison to the conventional melting or solvent-evaporation methods. Miscibility analysis provides valuable guidance for selection of the most appropriate polymeric carrier for dispersion of the drug of interest. In addition to the increased drug release rate, solid dispersions should have proper mechanical attributes in order to be successfully formulated in the final solid dosage form such as tablet. Therefore, several pharmaceutical grade polymers have been selected for development of BCS Class II drug carvedilol (CARV) solid dispersions. They were compared based on behavior in supercritical CO2 and affinity towards CARV calculated from the miscibility analysis. By utilization of the supercritical CO2 assisted method, solid dispersions of CARV with the selected (co)polymers (polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), Soluplus(r) and Eudragit(r)) were obtained. Properties of the prepared CARV-polymer dispersions were observed by the polarizing and scanning electron microscopy and analyzed by differential scanning calorimetry and Fourier transform infrared spectroscopy. CARV was additionally characterized by X-ray powder diffraction. Furthermore, in vitro dissolution studies and dynamic compaction analysis were performed on the selected samples of solid dispersions. Among the studied polymers, PVP and HPMC have been identified as polymers with the highest affinity towards CARV, based on the calculated deltap values. This has been also confirmed with the highest dissolution efficiency of CARV-PVP and CARV-HPMC solid dispersions. Solid state characterization indicated that CARV was dispersed either molecularly, or in the amorphous form, depending on interactions with each polymer. Determination of CARV-PVP and CARV-HPMC mechanical properties revealed that CARV-PVP solid dispersion has superior compactibility and tabletability. Therefore, CARV-PVP solid dispersion has been highlighted as the most appropriate for the further development of tablets as the final dosage form. Presented study provides an example for efficient approach for development of poorly soluble drug solid dispersion with satisfactory tableting properties. PMID- 30414900 TI - Ginger polysaccharides induced cell cycle arrest and apoptosis in human hepatocellular carcinoma HepG2 cells. AB - In this study, ginger polysaccharide (GP) was obtained from ginger by enzymatic method, its chemical properties and antitumor activity were investigated. The results indicated that the composition and proportion of GP were l-rhamnose, d arabinose, d-mannose, d-glucose and d-galactose in a molar ratio of 3.64:5.37:3.04:61.03:26.91, GP had the characteristic absorption peak of polysaccharide. Congo red experiment showed that GP had a triple helix structure, which could have anti-tumor effect. Furthermore, MTT assay, cell morphology observation, nuclear morphology observation and reactive oxygen species observation demonstrated that GP had significant antitumor effect. Flow cytometry suggested that GP could promote apoptosis and arrest cells in G0-G1 phase. Real time fluorescence quantification and Western blot revealed that GP could up regulate the expression of Bax, Fas, FasL, caspase-3, p21 and p53, and down regulate the expression of Bcl-2. These studies suggested that GP would be used as an antitumor drug in foods to promote the development of functional foods. PMID- 30414901 TI - Formulation and characterization of hydrogel based on pectin and brea gum. AB - A hydrogel is a three-dimensional network formed by flexible chains of polymers that absorb considerable amounts of water. The objectives of this work were to formulate hydrogels from pectin and brea gum and to study their functional properties. Brea gum solutions present positive charge below pH = 3.5. Pectin has anionic character due to uronic acids. Hydrogels were formulated from pectin and brea gum solutions. DSC and FTIR confirmed the existence of strong interaction between both polymers. Rheological and texture profiles indicated that hydrogels behaved as a strong gels. Swelling and erosion were dependent on the pH values of the medium. The release of a dye molecule from the hydrogel was controlled by a Fickian diffusion mechanism. The capability of these hydrogels to respond to the changes in pH of the medium and to modify dye release, could be valuable for medical, food and industrial uses. PMID- 30414902 TI - Overexpression of G2 and S phase-expressed-1 contributes to cell proliferation, migration, and invasion via regulating p53/FoxM1/CCNB1 pathway and predicts poor prognosis in bladder cancer. AB - Bladder cancer is one of the most common urogenital tumors worldwide. The specific function and molecular mechanism of GTSE1 in bladder cancer remain unknown. In the present study, real-time quantitative polymerase chain reaction and Western blotting were used to identify GTSE1 expression in bladder cancer tissues and cells, and immunohistochemical assays were conducted to investigate GTSE1 expression in tissue microarray. Regression analyses explored the relationship between GTSE1 expression and pathological characteristics. A series of functional tests were performed to observe the effects of GTSE1 knockdown or overexpression, and the related mechanism was also performed. GTSE1 expression was significantly higher in bladder cancer tissues; overexpression of GTSE1 was positively associated with disease recurrence history, lymph node invasion, and progression. Patients with higher GTSE1 expression were more likely to experience shorter survival time, and GTSE1 expression served as a prognostic factor for the disease progression. Knockdown of GTSE1 obviously suppressed the proliferation, migration, and invasion capacity whereas increasing GTSE1 led to the opposite trend, which suggested that GTSE1 could serve as a potential therapeutic target for bladder cancer. GTSE1 overexpression in bladder cancer might participate in the regulation of FoxM1/CCNB1 expression via the induction of the transfer of p53 to cytoplasm. PMID- 30414903 TI - Characterization of water status and water soluble pectin from peaches under the combined drying processing. AB - Characterization of water status and water soluble pectin (WSP) from peach were evaluated after different stage of combined drying in which osmotic dehydration (OD) was considered as the pre-treatment prior to instant controlled pressure drop (DIC) - assisted infrared radiation drying (IRD) (IR-DIC). Results showed that the contents of free water and immobilized water decreased to 0 g after the combined drying. The content of bound water increased after IRD treatment. The residual PME activity in peach slices was 153.3-179.6% after OD treatment, while, the PG were totally inactivated after IRD. The degree of esterification (DE), WSP content and average molar mass (Mw) decreased significantly (from 75.00 to 43.74, from 156.00 to 74.91 mg/g AIR and from 2.28 to 0.49 * 105 Da, respectively) after the combined drying. The neutral sugar of WSP was mainly composed by galactose, arabinose and rhamnose, whose contents decreased after the combined drying. However, OD treatment would slow down the degradation. There was a low peak at 1740 cm-1 in FT-IR spectrum observed for WSP after IRD and DIC treatment, which might illustrate the degradation of WSP during the combined drying. PMID- 30414904 TI - Pectin extraction from Helianthus annuus (sunflower) heads using RSM and ANN modelling by a genetic algorithm approach. AB - In this work, Response Surface Methodology (RSM) and Artificial Neural Network coupled with genetic algorithm (ANN-GA) have been used to develop a model and optimise the conditions for the extraction of pectin from sunflower heads. Input parameters were extraction time (10-20 min), temperature (40-60 degrees C), frequency (30-60 Hz), solid/liquid ratio (S/L) (1:20-1:40 g/mL) while pectin yield (PY%) was the output. Results showed that ANN-GA had a higher prediction efficiency than RSM. Using ANN as the fitness function, a maximum pectin yield of 29.1 +/- 0.07% was searched by genetic algorithm at the time of 10 min, temperature of 59.9 degrees C, frequency of 30 Hz, and solid liquid ratio of 1:29.9 g/mL while the experimental value was found to be 29.5 +/- 0.7%. Extracted pectin was characterised by FTIR and 13C NMR. Thus, ANN coupled GA has proved to be the effective method for the optimization of process parameters for pectin extraction from sunflower heads. PMID- 30414905 TI - Multi-fingerprint profiling combined with chemometric methods for investigating the quality of Astragalus polysaccharides. AB - It is a challenge to ascertain the quality of polysaccharides due to their complex chemical structure; therefore, multi-fingerprint profiling was used to investigate the quality of Astragalus polysaccharides (APS) harvested from Inner Mongolia (NM) and Gansu (GS) with the help of chemometric analysis. Additionally, FT-IR and 1H NMR were applied to characterize the chemical structure of the harvested APS. The spectral fingerprinting results indicated that APS had reduced similarity when they were from different origins. Further, PCA showed that NM and GS could be distinguished and that the main differences from the loading plots were in the absorption intensity of carbonyls and H1 signals of Galp and beta glucose. Moreover, UPLC/Q-TOF-MS fingerprints were established based on the monosaccharide composition of the APS. The concentration of monosaccharides and results of cluster analysis indicated that GlcA might be an indicator that can be used to distinguish NM and GS. Overall, this multiple fingerprint method was stable, comprehensive and valid for monitoring APS quality. PMID- 30414906 TI - Chitosan-based nanocomposite matrices: Development and characterization. AB - Chitosan-based nanocomposites have a significant industrial impact related to the possibility to design and create new materials and structures. Cellulose nanocrystals (CNC) can be extracted from microcrystalline cellulose (MCC) by controlled acid hydrolysis with H2SO4. This work was focused on: to study the microstructure of CNC isolated from MCC after different hydrolysis times; to develop nanocomposites chitosan-based films; to characterize their structural and thermo-mechanical properties; to analyze the spectral differences among samples by means of ATR-FTIR in combination with principal component analysis (PCA) and square partial minimums model (PLS). It is worth noting that the selected condition for isolate the CNC from MCC was the acid treatment for 2 h, evidenced by size measurements. This fact was supported by transmission electron microscope (TEM) and dynamic light scattering (DLS). In this regard, SEM studies of films showed an assembly process between the nanocelluloses and the CH matrix. The incorporation of CNC into the films resulted in strong interactions between the filler and the matrix demonstrating the affinity between the phases and modifying the mechanical profiles. In summary, CNC was found to be a satisfactory reinforcing agent in biodegradable nanocomposite chitosan-based packaging and are promising as a means to develop tailor-made materials. PMID- 30414907 TI - TWEAK/Fn14 Interaction Confers Aggressive Properties to Cutaneous Squamous Cell Carcinoma. AB - Recent studies showed that tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (Fn14) signaling participates in the progression of internal malignancies. However, its role in the biological properties of cutaneous squamous cell carcinoma (SCC) remains unclear. This study was designed to explore the effect of TWEAK/Fn14 activation on cutaneous SCC as well as the relevant mechanism. The expression of TWEAK and Fn14 was determined in tissue samples of patients with cutaneous SCC. Human primary keratinocytes and SCC cell lines were cultured in vitro, receiving stimulation of TWEAK. The xenografts of SCC were generated subcutaneously in BALB/c nude mice. The results showed that both TWEAK and Fn14 were highly expressed in human cutaneous SCC. Moreover, TWEAK/Fn14 activation promoted the proliferation, migration, and invasion of cultured SCC cells. Interestingly, TNF receptor type 2 (TNFR2) was upregulated in cultured SCC cells, and the transfection of TNFR2 siRNA abrogated the effect of TWEAK on these cells. Finally, the favorable effect of TWEAK/Fn14 signals was confirmed in BALB/c nude mice with SCC xenografts. In conclusion, TWEAK/Fn14 signals contribute to the progression of cutaneous SCC, possibly involving the TNF-alpha-independent TNFR2 signal transduction. PMID- 30414908 TI - A preclinical model for studying herpes simplex virus infection. AB - Herpes simplex virus (HSV) infections can cause considerable morbidity. Currently, nucleoside analogues such as acyclovir are widely used for treatment. However, HSV infections resistant to these drugs are a clinical problem among immunocompromised patients. To provide more efficient therapy and to counteract resistance, a different class of antiviral compounds has been developed. Pritelivir, a helicase primase inhibitor, represents a promising candidate for improved therapy. Here, we established a HSV-1 infection model on microneedle pretreated human skin ex vivo. We identified HSV-1-specific histological changes (e.g. cytopathic effects, multinucleated giant cells), down regulation of nectin 1, nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cell (NF-kappaB; p65), interferon regulatory factor 3 (IRF3), and signaling of the interferon-inducible protein MxA. Accordingly, this model was used to test the potency of pritelivir compared to the standard drug acyclovir. We discovered that both drugs had a comparable efficacy to inhibit HSV-1 replication, suggesting that pritelivir could be an alternative therapeutic agent for patients infected with acyclovir resistant strains. To our knowledge, we present a previously unreported ex vivo HSV-1 infection model with abdominal human skin to test antiviral drugs thus bridging the gap between in vitro and in vivo drug screening and providing a valuable preclinical platform for HSV research. PMID- 30414909 TI - Are bacteria infectious pathogens in hidradenitis suppurativa (HS)? Debate at the Symposium for Hidradenitis Suppurativa Advances meeting (November 2017). AB - In November 2017, a formal debate on the role of bacteria in the pathogenesis of hidradenitis suppurativa (HS) was held at the 2nd Symposium on Hidradenitis Suppurativa Advances (SHSA) in Detroit, MI. In this report, we present both sides of the argument as debated at the SHSA meeting, and then discuss the potential role of bacteria as classic infectious pathogens versus an alternative pathogenic role as activators of dysregulated commensal bacterial-host interactions. While there was consensus that bacteria play a role in pathogenesis, and thus are pathogenic, there was a compelling discussion about whether bacteria in HS incite an infectious disease as we classically understand it, or whether bacteria might play a different role in HS pathogenesis. PMID- 30414910 TI - Altered Notch signaling in Dowling-Degos disease: Additional mutations in POGLUT1 and further insights into disease pathogenesis. PMID- 30414911 TI - Racial/ethnic differences in incidence and persistence of childhood atopic dermatitis. AB - Although previous studies have explored racial/ethnic differences in incident atopic dermatitis (AD) in childhood, few studies have examined risk factors associated with AD persistence. As such, we sought to examine differences in incidence and persistence of childhood AD by race/ethnicity accounting for socio demographic characteristics and perinatal vitamin D levels. Using data from Project Viva, a prospective pre-birth cohort in eastern Massachusetts, we studied 1,437 mother-child pairs with known AD status to examine the associations of race/ethnicity with maternally-reported child AD. We used multivariable logistic regression, adjusting for socio-demographic factors and maternal plasma vitamin D, to estimate adjusted odds ratios (aOR) of AD incidence at early childhood and persistence at mid-childhood. Compared to non-Hispanic whites, non-Hispanic blacks (aOR 2.71, 95% CI: 1.75, 4.19) and other non-Hispanics (aOR 1.80, 95% CI: 1.16, 2.80) were more likely to have incident AD. Non-Hispanic blacks (aOR 6.26, 95% CI: 2.32, 16.88) and Hispanics (aOR 6.42, 95% CI: 1.93, 21.41) with early childhood AD were more likely to have persistent AD. In conclusion, compared to non-Hispanic whites, AD incidence and persistence is higher among certain non white racial/ethnic subgroups. Further research is warranted to identify environmental, socioeconomic, and genetic factors that may be responsible for the observed differences. PMID- 30414912 TI - Oxygen-guided radiation therapy. AB - BACKGROUND: It has been known for over a hundred years that tumor hypoxia, a near universal characteristic of solid tumors, decreases the curative effectiveness of radiation therapy. However, to date, there are no reports that demonstrate an improvement in radiation effectiveness in a mammalian tumor based on tumor hypoxia localization and local hypoxia treatment. METHODS: For radiation targeting of hypoxic subregions in a mouse fibrosarcoma, we used oxygen images obtained using electron paramagnetic resonance (EPR) pO2 imaging combined with 3D printed radiation blocks. This achieved conformal radiation delivery to all hypoxic areas in FSa fibrosarcomas in mice. RESULTS: We demonstrate that the treatment delivering a radiation boost to hypoxic volumes has a significant (p=0.04) doubling of tumor control relative to boosts to well-oxygenated volumes. Additional dose to well oxygenated tumor regions minimally increases tumor control beyond the 15% control dose to the entire tumor. If we can identify portions of the tumor that are more resistant to radiation it may be possible to reduce the dose to more sensitive tumor volumes without significant compromise in tumor control. CONCLUSION: This work demonstrates in a single intact mammalian tumor type that tumor hypoxia is a local tumor phenomenon whose treatment can be enhanced by local radiation. Despite enormous clinical effort to overcome hypoxic radiation resistance, this is the first such demonstration, even in preclinical models, of targeting additional radiation to hypoxic tumor to improve therapeutic ratio. PMID- 30414913 TI - Early life stress and voluntary alcohol consumption in relation to Maoa methylation in male rats. AB - Early life stress (ELS) or alcohol consumption can influence DNA methylation and affect gene expression. The monoamine oxidase A (Maoa) encodes the enzyme that metabolizes monoaminergic neurotransmitters crucial for the stress response, alcohol reward, and reinforcement. Previously, we reported lower Maoa expression in the nucleus accumbens and dorsal striatum of male rats exposed to ELS during the first three postnatal weeks, and to voluntary alcohol consumption in adulthood, compared with controls. The present study continued to investigate the effect of ELS and alcohol consumption on Maoa methylation, and its relation to Maoa expression in these animals. We selected candidate CpGs after performing next-generation bisulfite sequencing of the Maoa promoter, intron 1-5, exons 5 and 6, together comprised of 107 CpGs, in a subgroup of rats. Pyrosequencing was used to analyse the methylation of ten candidate CpGs in the promoter and intron 1 in the entire sample. ELS and alcohol displayed an interaction effect on CpG specific methylation in the dorsal striatum. CpG-specific methylation correlated with Maoa expression, corticosterone levels, and alcohol consumption in a brain region-specific manner. CpG-specific methylation in the Maoa promoter was a potential moderator of the interaction of ELS with alcohol consumption on Maoa expression in the NAc. However, the findings were sparse, did not survive correction for multiple testing, and the magnitude of differences in methylation levels was small. In conclusion, CpG-specific Maoa methylation in the promoter and intron 1 may associate with ELS, alcohol consumption and Maoa expression in reward-related brain regions. PMID- 30414914 TI - Engineering stilbene metabolic pathways in microbial cells. AB - Numerous in vitro and in vivo studies on biological activities of phytostilbenes have brought to the fore the remarkable properties of these compounds and their derivatives, making them a top storyline in natural product research fields. However, getting stilbenes in sufficient amounts for routine biological activity studies and make them available for pharmaceutical and/or nutraceutical industry applications, is hampered by the difficulty to source them through synthetic chemistry-based pathways or extraction from the native plants. Hence, microbial cell cultures have rapidly became potent workhorse factories for stilbene production. In this review, we present the combined efforts made during the past 15 years to engineer stilbene metabolic pathways in microbial cells, mainly the Saccharomyces cerevisiae baker yeast, the Escherichia coli and the Corynebacterium glutamicum bacteria. Rationalized approaches to the heterologous expression of the partial or the entire stilbene biosynthetic routes are presented to allow the identification and/or bypassing of the major bottlenecks in the endogenous microbial cell metabolism as well as potential regulations of the genes involved in these metabolic pathways. The contributions of bioinformatics to synthetic biology are developed to highlight their tremendous help in predicting which target genes are likely to be up-regulated or deleted for controlling the dynamics of precursor flows in the tailored microbial cells. Further insight is given to the metabolic engineering of microbial cells with "decorating" enzymes, such as methyl and glycosyltransferases or hydroxylases, which can act sequentially on the stilbene core structure. Altogether, the cellular optimization of stilbene biosynthetic pathways integrating more and more complex constructs up to twelve genetic modifications has led to stilbene titers ranging from hundreds of milligrams to the gram-scale yields from various carbon sources. Through this review, the microbial production of stilbenes is analyzed, stressing both the engineering dynamic regulation of biosynthetic pathways and the endogenous control of stilbene precursors. PMID- 30414915 TI - Initiation of sex change and gonadal gene expression in black sea bass (Centropristis striata) exposed to exemestane, an aromatase inhibitor. AB - Many teleost fishes exhibit sequential hermaphroditism, where male or female gonads develop first and later undergo sex change. Model sex change species are characterized by social hierarchies and coloration changes, which enable experimental manipulations to better understand these processes. However, other species such as the protogynous black sea bass (Centropristis striata) do not exhibit these characteristics and instead receive research attention due to their importance in fisheries or aquaculture. Black sea bass social structure is unknown, which makes sex change sampling difficult, and few molecular resources are available. The purpose of the present study was to induce sex change using exemestane, an aromatase inhibitor, and assess gonadal gene expression using sex markers (amh, zpc2) and genes involved in steroidogenesis (cyp19a1a, cyp11b), estrogen signaling (esr1, esr2b), and apoptosis or atresia (aen, casp9, fabp11, parg, pdcd4, rif1). Overall, dietary exemestane treatment was effective, and most exposed females exhibited early histological signs of sex change and significantly higher rates of ovarian atresia relative to control females. Genes associated with atresia did not reflect this, however, as expression patterns in sex changing gonads were overall similar to those of ovaries, likely due to a whole ovary dilution effect of the RNA. Still, small but insignificant expression decreases during early sex change were detected for ovary-related genes (aen, casp9, fabp11, zpc2) and anti-apoptotic factors (parg, rif1). Exemestane treatment did not impact spermatogenesis or testicular gene expression, but testes were generally characterized by elevated steroidogenic enzyme and estrogen receptor mRNAs. Further research will be needed to understand these processes in black sea bass, using isolated ovarian follicles and multiple stages of sex change. PMID- 30414916 TI - Weaning European glass eels (Anguilla anguilla) with plant protein-based diets and its effects on intestinal maturation. AB - Weaning glass eels with compound diets (36% proteins, 16% lipids) differing in their fishmeal (FM) level (50, 75 and 100% FM replaced by a blend of plant proteins, PP) was compared to a group fed cod roe. Weaning lasted for 20 days and then, eels were fed compound diets for 70 days, whereas the other group was only fed cod roe (90 days). Diets were tested with four replicates and evaluated in terms of growth, survival, glass eels metamorphosis into elvers, oxidative stress status and activity of digestive enzymes. Although glass eels are traditionally fed with fish roe and progressively weaned onto compound diets, results revealed that this strategy should not be prolonged for a long time, since feeding glass eels with cod roe for 90 days negatively affected their growth (2 times lower than fish fed compound diets), delayed their metamorphosis, as well as the maturation of their digestive function as the ratio of alkaline phosphatase and leucine-alanine peptidase indicated. Weaning glass eels onto compound diets differing in their FM levels did not affect their growth, metamorphic stage nor the activity of pancreatic enzymes (total alkaline proteases, trypsin, bile salt activated lipase and alpha-amylase), although 75% FM replacement by PP sources delayed the level of intestinal maturation in eels. In comparison to glass eels fed the 100% FM diet, survival was negatively affected in groups fed diets with 50 and 75% FM replacement by PP ingredients, which indicated that further improvement is needed in diet formulation for this stage of development. PMID- 30414917 TI - Correction. PMID- 30414918 TI - Prognostic Factors, Treatment, and Survival in Cutaneous Pleomorphic Sarcoma. AB - BACKGROUND: Limited information exists on the influence of demographics, tumor characteristics, and treatment on survival in cutaneous pleomorphic sarcoma (CPS). OBJECTIVE: To describe incidence rates and prognostic factors affecting survival in CPS. METHODS: National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) data (1972-2013) was analyzed for 2423 patients diagnosed with CPS. RESULTS: Age-adjusted incidence rate was 0.152 cases per 100,000 person years and was 4.5-fold higher in males than females. Male gender, white race, and increasing age over 40 were significantly associated with decreased overall survival. Head and neck tumors, tumors over 15mm, and with grade III or IV histology had significantly decreased survival. Surgical excision had a survival benefit compared no treatment. Radiation therapy did not provide a survival benefit. Patients with localized disease had the greatest survival followed by regional and distant disease. LIMITATIONS: SEER data may not be reflective of all CPS patients. Recurrences, restaging, or additional non-mortality events over time are not tracked. CONCLUSIONS: and Relevance: Tumor size, grade, gender, age at diagnosis, and race appear to influence survival as prognostic factors in CPS. Surgical tumor extirpation provides a survival benefit over no treatment whereas primary or adjuvant radiation does not provide a survival benefit. PMID- 30414919 TI - Multidrug-resistant Clostridium difficile ribotypes 078 and 014/5-FLI01 in piglets from Costa Rica. AB - Though an overlap of Clostridium difficile PCR ribotypes (RT) in humans and animals has been noted -particularly in piglets-information regarding C. difficile isolates from swine is scarce in Latin America. A characterization of 10 C. difficile isolates obtained from this origin in Costa Rica revealed the presence of the RT078 (n = 4) and RT014/5-FLI01 (n = 6) ribotypes. Unlike two previous reports from the region, all isolates were multidrug resistant (MDR). According to a minimum spanning tree (MST) analysis, our RT078 isolates formed a clonal complex with some German RT078 isolates and the already noted overlap of RT078 strains in humans and animals. This unanticipated high level of genetic relatedness confirms the transcontinental spread and geographically unlimited clustering of RT078. PMID- 30414920 TI - Hyphae fragments from A. fumigatus sensitize lung cells to silica particles (Min U-Sil): Increased release of IL-1beta. AB - Exposure to particulate matter (PM), such as mineral particles and biological particles/components may be linked to aggravation of respiratory diseases, including asthma. Here we report that exposure to Aspergillus fumigatus hyphae fragments (AFH) and lipopolysaccharide (LPS) induced both mRNA synthesis and release of pro-inflammatory interleukin-1 beta (IL-1beta) in both human THP-1 monocytes (THP-1 Mo) and phorbol 12-myristate 13-acetate (PMA)-differentiated THP 1 monocytes (THP-1 macrophages; THP-1 Ma); while Min-U-Sil alone enhanced the release of IL-1beta only in THP-1 Ma. Co-exposure to LPS or AFH with Min-U-Sil caused a synergistic release of IL-1beta when compared to single exposures. In contrast, Min-U-Sil did not markedly change LPS- and AFH-induced release of tumor necrosis factor alpha (TNF-alpha). The combined exposures did not increase the LPS- and AFH-induced expression of IL-1beta mRNA. Notably, the AFH- and LPS induced IL-1beta responses with and without co-exposure to Min-U-Sil in THP-1 Mo were found to be caspase-dependent as shown by inhibition with zYVAD-fmk. Furthermore, co-exposure with AFH and Min-U-Sil resulted in similar synergistic releases of IL-1beta in primary human airway macrophages (AM; sputum), peripheral blood monocyte-derived macrophages (MDM) and in the human bronchial epithelial cell line (BEAS-2B). In conclusion, AFH induce both the synthesis and release of IL-1beta. However, Min-U-Sil further enhanced the cleavage of the induced pro-IL 1beta. PMID- 30414921 TI - The Min Oscillator Defines Sites of Asymmetric Cell Division in Cyanobacteria during Stress Recovery. AB - When resources are abundant, many rod-shaped bacteria reproduce through precise, symmetric divisions. However, realistic environments entail fluctuations between restrictive and permissive growth conditions. Here, we use time-lapse microscopy to study the division of the cyanobacterium Synechococcus elongatus as illumination intensity varies. We find that dim conditions produce elongated cells whose divisions follow a simple rule: cells shorter than ~8 MUm divide symmetrically, but above this length divisions become asymmetric, typically producing a short ~3-MUm daughter. We show that this division strategy is implemented by the Min system, which generates multi-node patterns and traveling waves in longer cells that favor the production of a short daughter. Mathematical modeling reveals that the feedback loops that create oscillatory Min patterns are needed to implement these generalized cell division rules. Thus, the Min system, which enforces symmetric divisions in short cells, acts to strongly suppress mid cell divisions when S. elongatus cells are long. PMID- 30414922 TI - Modeling and Predicting the Activities of Trans-Acting Splicing Factors with Machine Learning. AB - Alternative splicing (AS) is generally regulated by trans-splicing factors that specifically bind to cis-elements in pre-mRNAs. The human genome encodes ~1,500 RNA binding proteins (RBPs) that potentially regulate AS, yet their functions remain largely unknown. To explore their potential activities, we fused the putative functional domains of RBPs to a sequence-specific RNA-binding domain and systemically analyzed how these engineered factors affect splicing. We discovered that ~80% of low-complexity domains in endogenous RBPs displayed distinct context dependent activities in regulating splicing, indicating that AS is under more extensive regulation than previously expected. We developed a machine learning approach to classify and predict the activities of RBPs based on their sequence compositions and further validated this model using endogenous RBPs and synthetic polypeptides. These results represent a systematic inspection, modeling, prediction, and validation of how RBP sequences affect their activities in controlling splicing, paving the way for de novo engineering of artificial splicing factors. PMID- 30414923 TI - Gain of CTCF-Anchored Chromatin Loops Marks the Exit from Naive Pluripotency. AB - The genome of pluripotent stem cells adopts a unique three-dimensional architecture featuring weakly condensed heterochromatin and large nucleosome-free regions. Yet, it is unknown whether structural loops and contact domains display characteristics that distinguish embryonic stem cells (ESCs) from differentiated cell types. We used genome-wide chromosome conformation capture and super resolution imaging to determine nuclear organization in mouse ESC and neural stem cell (NSC) derivatives. We found that loss of pluripotency is accompanied by widespread gain of structural loops. This general architectural change correlates with enhanced binding of CTCF and cohesins and more pronounced insulation of contacts across chromatin boundaries in lineage-committed cells. Reprogramming NSCs to pluripotency restores the unique features of ESC domain topology. Domains defined by the anchors of loops established upon differentiation are enriched for developmental genes. Chromatin loop formation is a pervasive structural alteration to the genome that accompanies exit from pluripotency and delineates the spatial segregation of developmentally regulated genes. PMID- 30414924 TI - Fluorometric Quantification of Single-Cell Velocities to Investigate Cancer Metastasis. AB - Hematogenous metastasis is a multistep, selectin-regulated process whose mechanisms remain poorly understood. To investigate this biological pathway of cancer dissemination and better understand circulating cancer cells, we developed a high-throughput methodology that integrates organ-on-chip-like microfluidic and photoconvertible protein technologies. Our approach can ascribe single-cell velocity as a traceable cell property for off-chip analysis of the direct relationships between cell molecular profiles and adhesive phenotypes in the context of physiologically relevant fluid flow. We interrogate how natively expressed selectin ligands relate to colon cancer cell rolling frequencies and velocities and provide context for previously reported disparities in in vitro and in vivo models of selectin-mediated adhesion and metastasis. This integrated methodology represents a versatile approach for the development of anti metastatic therapeutics as well as to generate and test mechanistic hypotheses regarding spatiotemporal processes that occur over timescales of seconds to hours with single-cell resolution. PMID- 30414926 TI - Light-adaptive state transitions in the Ross Sea haptophyte Phaeocystis antarctica and in dinoflagellate cells hosting kleptoplasts derived from it. AB - Light state transitions (STs) is a reversible physiological process that oxygenic photosynthetic organisms use in order to minimize imbalances in the electronic excitation delivery to the reaction centers of Photosystems I and II, and thus to optimize photosynthesis. STs have been studied extensively in plants, green algae, red algae and cyanobacteria, but sparsely in algae with secondary red algal plastids, such as diatoms and haptophytes, despite their immense ecological significance. In the present work, we examine whether the haptophyte alga Phaeocystis antarctica, and dinoflagellate cells that host kleptoplasts derived from P. antarctica, both endemic in the Ross Sea, Antarctica, are capable of light adaptive STs. In these organisms, Chl a fluorescence can be excited either by direct light absorption, or indirectly by electronic excitation (EE) transfer from ultraviolet light absorbing mycosporine-like amino acids (MAAs) to Chl a (Stamatakis et al., Biochim. Biophys. Acta 1858 [2017] 189-195). Here we show that, on adaptation to PS II-selective light, dark-adapted P. antarctica cells shift from light state 1 (ST1; more EE ending up in PS II) to light state 2 (ST2; more EE ending up in PS I), as revealed by the spectral distribution of directly excited Chl a fluorescence and by changes in the macro-organization of pigment protein complexes evidenced by circular dichroism (CD) spectroscopy. In contrast, no STs are clearly detected in the case of the kleptoplast-hosting dinoflagellate cells, and in the case of indirectly excited Chls a, via MAAs, in P. antarctica cells. PMID- 30414925 TI - Integration of Tumor Genomic Data with Cell Lines Using Multi-dimensional Network Modules Improves Cancer Pharmacogenomics. AB - Leveraging insights from genomic studies of patient tumors is limited by the discordance between these tumors and the cell line models used for functional studies. We integrate omics datasets using functional networks to identify gene modules reflecting variation between tumors and show that the structure of these modules can be evaluated in cell lines to discover clinically relevant biomarkers of therapeutic responses. Applied to breast cancer, we identify 219 gene modules that capture recurrent alterations and subtype patients and quantitate various cell types within the tumor microenvironment. Comparison of modules between tumors and cell lines reveals that many modules composed primarily of gene expression and methylation are poorly preserved. In contrast, preserved modules are highly predictive of drug responses in a manner that is robust and clinically relevant. This work addresses a fundamental challenge in pharmacogenomics that can only be overcome by the joint analysis of patient and cell line data. PMID- 30414927 TI - Uncoupling mechanism and redox regulation of mitochondrial uncoupling protein 1 (UCP1). AB - Brown adipose tissue (BAT) and brown in white (brite) adipose tissue, termed also beige adipose tissue, are major sites of mammalian nonshivering thermogenesis. Mitochondrial uncoupling protein 1 (UCP1), specific for these tissues, is the key factor for heat production. Recent molecular aspects of UCP1 structure provide irrefutable support for the fatty acid cycling model of coupling, i.e. when UCP1 expels fatty acid anions in a uniport mode from the matrix, while uncoupling. Protonophoretic function is ensured by return of the protonated fatty acid to the matrix independent of UCP1. This mechanism is advantageous for mitochondrial uncoupling and compatible with heat production in a pro-thermogenic environment, such as BAT. It must still be verified whether posttranslational modification of UCP1, such as sulfenylation of Cys253, linked to redox activity, promotes UCP1 activity. BAT biogenesis and UCP1 expression, has also been linked to the pro oxidant state of mitochondria, further endorsing a redox signalling link promoting an establishment of pro-thermogenic state. We discuss circumstances under which promotion of superoxide formation exceeds its attenuation by uncoupling in mitochondria and throughout point out areas of future research into UCP1 function. PMID- 30414928 TI - Structure-dynamic and functional relationships in a Li+-transporting sodium calcium exchanger mutant. AB - The cell membrane (NCX) and mitochondrial (NCLX) Na+/Ca2+ exchangers control Ca2+ homeostasis. Eleven (out of twelve) ion-coordinating residues are highly conserved among eukaryotic and prokaryotic NCXs, whereas in NCLX, nine (out of twelve) ion-coordinating residues are different. Consequently, NCXs exhibit high selectivity for Na+ and Ca2+, whereas NCLX can exchange Ca2+ with either Na+ or Li+. However, the underlying molecular mechanisms and physiological relevance remain unresolved. Here, we analyzed the NCX_Mj-derived mutant NCLX_Mj (with nine substituted residues) imitating the ion selectivity of NCLX. Site-directed fluorescent labeling and ion flux assays revealed the nearly symmetric accessibility of ions to the extracellular and cytosolic vestibules in NCLX_Mj (Kint = 0.8-1.4), whereas the extracellular vestibule is predominantly accessible to ions (Kint = 0.1-0.2) in NCX_Mj. HDX-MS (hydrogen-deuterium exchange mass spectrometry) identified symmetrically rigidified core helix segments in NCLX_Mj, whereas the matching structural elements are asymmetrically rigidified in NCX_Mj. The HDX-MS analyses of ion-induced conformational changes and the mutational effects on ion fluxes revealed that the "Ca2+-site" (SCa) of NCLX_Mj binds Na+, Li+, or Ca2+, whereas one or more additional Na+/Li+ sites of NCLX_Mj are incompatible with the Na+ sites (Sext and Sint) of NCX_Mj. Thus, the replacement of ion-coordinating residues in NCLX_Mj alters not only the ion selectivity of NCLX_Mj, but also the capacity and affinity for Na+/Li+ (but not for Ca2+) binding, bidirectional ion-accessibility, the response of the ion-exchange to membrane potential changes, and more. These structure-controlled functional features could be relevant for differential contributions of NCX and NCLX to Ca2+ homeostasis in distinct sub-cellular compartments. PMID- 30414929 TI - Energy transfer dynamics in a red-shifted violaxanthin-chlorophyll a light harvesting complex. AB - Photosynthetic eukaryotes whose cells harbor plastids originating from secondary endosymbiosis of a red alga include species of major ecological and economic importance. Since utilization of solar energy relies on the efficient light harvesting, one of the critical factors for the success of the red lineage in a range of environments is to be found in the adaptability of the light-harvesting machinery, formed by the proteins of the light-harvesting complex (LHC) family. A number of species are known to employ mainly a unique class of LHC containing red shifted chlorophyll a (Chl a) forms absorbing above 690 nm. This appears to be an adaptation to shaded habitats. Here we present a detailed investigation of excitation energy flow in the red-shifted light-harvesting antenna of eustigmatophyte Trachydiscus minutus using time-resolved fluorescence and ultrafast transient absorption measurements. The main carotenoid in the complex is violaxanthin, hence this LHC is labeled the red-violaxanthin-Chl a protein, rVCP. Both the carotenoid-to-Chl a energy transfer and excitation dynamics within the Chl a manifold were studied and compared to the related antenna complex, VCP, that lacks the red-Chl a. Two spectrally defined carotenoid pools were identified in the red antenna, contributing to energy transfer to Chl a, mostly via S2 and hot S1 states. Also, Chl a triplet quenching by carotenoids is documented. Two separate pools of red-shifted Chl a were resolved, one is likely formed by excitonically coupled Chl a molecules. The structural implications of these observations are discussed. PMID- 30414930 TI - Spectral microscopic imaging of heterocysts and vegetative cells in two filamentous cyanobacteria based on spontaneous Raman scattering and photoluminescence by 976 nm excitation. AB - Photosynthetic pigment-protein complexes are highly concentrated in thylakoid membranes of chloroplasts and cyanobacteria that emit strong autofluorescence (mainly 600-800 nm). In Raman scattering microscopy that enables imaging of pigment concentrations of thylakoid membranes, near infrared laser excitation at 1064 nm or visible laser excitation at 488-532 nm has been often employed in order to avoid the autofluorescence. Here we explored a new approach to Raman imaging of thylakoid membranes by using excitation wavelength of 976 nm. Two types of differentiated cells, heterocysts and vegetative cells, in two diazotrophic filamentous cyanobacteria, Anabaena variabilis, and Rivularia M-261, were characterized. Relative Raman scattering intensities of phycobilisomes of the heterocyst in comparison with the nearest vegetative cells of Rivularia remained at a significantly higher level than those of A. variabilis. It was also found that the 976 nm excitation induces photoluminescence around 1017-1175 nm from the two cyanobacteria, green alga (Parachlorella kessleri) and plant (Arabidopsis thaliana). We propose that this photoluminescence can be used as an index of concentration of chlorophyll a that has relatively small Raman scattering cross-sections. The Rivularia heterocysts that we analyzed were clearly classified into at least two subgroups based on the Chla-associated photoluminescence and carotenoid Raman bands, indicating two physiologically distinct states in the development or aging of the terminal heterocyst. PMID- 30414931 TI - Atomistic insights into cardiolipin binding sites of cytochrome c oxidase. AB - Mitochondrial cytochrome c oxidase couples the reduction of oxygen to proton pumping. Despite an overall good understanding of its molecular mechanism, the role of cardiolipin in protein function is not understood. Here, we have studied the cardiolipin-protein interactions in a dynamic context by means of atomistic molecular dynamics simulations performed on the entire structure of monomeric and dimeric forms of the enzyme. Several microseconds of simulation data reveal that the crystallographic cardiolipin molecules that glue two monomers together bind weakly in hybrid and single-component lipid bilayers and dissociate rapidly. Atomistic simulations performed in the absence of tightly bound cardiolipin molecules strongly perturb the structural integrity of subunits III and VIIa, thereby highlighting an indispensable nature of lipid-protein interactions in enzyme function such as proton uptake and oxygen channeling. Our results demonstrate the strength of molecular simulations in providing direct atomic description of lipid-protein processes that are difficult to achieve experimentally. PMID- 30414932 TI - Measuring the functionality of the mitochondrial pumping complexes with multi wavelength spectroscopy. AB - The proton pumps of the mitochondrial electron transport chain (ETC) convert redox energy into the proton motive force (DeltaP), which is subsequently used by the ATP synthase to regenerate ATP. The limited available redox free energy requires the proton pumps to operate close to equilibrium in order to maintain a high DeltaP, which in turn is needed to maintain a high phosphorylation potential. Current biochemical assays measure complex activities far from equilibrium and so shed little light on their function under physiological conditions. Here we combine absorption spectroscopy of the ETC hemes, NADH fluorescence spectroscopy and oxygen consumption to simultaneously measure the redox potential of the intermediate redox pools, the components of DeltaP and the electron flux in RAW 264.7 mouse macrophages. We confirm that complex I and III operate near equilibrium and quantify the linear relationship between flux and disequilibrium as a metric of their function under physiological conditions. In addition, we quantify the dependence of complex IV turnover on DeltaP and the redox potential of cytochrome c to determine the complex IV driving force and find that the turnover is proportional to this driving force. This form of quantification is a more relevant metric of ETC function than standard biochemical assays and can be used to study the effect of mutations in either mitochondrial or nuclear genome affecting mitochondrial function, post translation changes, different subunit isoforms, as well as the effect of pharmaceuticals on ETC function. PMID- 30414934 TI - Regulated chloroplast transcription termination. AB - Transcription termination by the RNA polymerase (RNAP) is a fundamental step of gene expression that involves the release of the nascent transcript and dissociation of the RNAP from the DNA template. However, the functional importance of termination extends beyond the mere definition of the gene borders. Chloroplasts originate from cyanobacteria and possess their own gene expression system. Plastids have a unique hybrid transcription system consisting of two different types of RNAPs of dissimilar phylogenetic origin together with several additional nuclear encoded components. Although the basic components involved in chloroplast transcription have been identified, little attention has been paid to the chloroplast transcription termination. Recent identification and functional characterization of novel factors in regulating transcription termination in Arabidopsis chloroplasts via genetic and biochemical approaches have provided insights into the mechanisms and significance of transcription termination in chloroplast gene expression. This review provides an overview of the current knowledge of the transcription termination in chloroplasts. PMID- 30414933 TI - Engineering of B800 bacteriochlorophyll binding site specificity in the Rhodobacter sphaeroides LH2 antenna. AB - The light-harvesting 2 complex (LH2) of the purple phototrophic bacterium Rhodobacter sphaeroides is a highly efficient, light-harvesting antenna that allows growth under a wide-range of light intensities. In order to expand the spectral range of this antenna complex, we first used a series of competition assays to measure the capacity of the non-native pigments 3-acetyl chlorophyll (Chl) a, Chl d, Chl f or bacteriochlorophyll (BChl) b to replace native BChl a in the B800 binding site of LH2. We then adjusted the B800 site and systematically assessed the binding of non-native pigments. We find that Arg-10 of the LH2 beta polypeptide plays a crucial role in binding specificity, by providing a hydrogen bond to the 3-acetyl group of native and non-native pigments. Reconstituted LH2 complexes harbouring the series of (B)Chls were examined by transient absorption and steady-state fluorescence spectroscopies. Although slowed 10-fold to ~6 ps, energy transfer from Chl a to B850 BChl a remained highly efficient. We measured faster energy-transfer time constants for Chl d (3.5 ps) and Chl f (2.7 ps), which have red-shifted absorption maxima compared to Chl a. BChl b, red-shifted from the native BChl a, gave extremely rapid (<=0.1 ps) transfer. These results show that modified LH2 complexes, combined with engineered (B)Chl biosynthesis pathways in vivo, have potential for retaining high efficiency whilst acquiring increased spectral range. PMID- 30414935 TI - Constitutive androstane receptor weakens the induction of panaxytriol on CYP3A4 by repressing the activation of pregnane X receptor. AB - Nuclear receptors pregnane X receptor (PXR; NR1I2) and constitutive androstane receptor (CAR; NR1I3) play a vital role in regulating CYP3A4. Our previous studies have demonstrated that panaxytriol (PXT) upregulates the expression of CYP3A4 via the PXR regulatory pathway. This study aimed to explore how CAR mediates the regulation of CYP3A4 in the presence of PXT using HepG2 cell, hCAR overexpressing HepG2 cell and hCAR-silenced HepG2 cell models. In HepG2 cells, PXT induced the expression of CYP3A4 in a concentration-dependent manner (10-80 MUM) and the high concentration of PXT (80 MUM) upregulated the expression of CAR. The concentrations of PXT (10-40 MUM) had no impact on the expression of CAR, but could significantly induce the expression of CYP2B6 target gene by activating CAR. The dual-luciferase reporter gene assay also showed that CAR mediated CYP3A4 luciferase activity can be promoted by 80 MUM of PXT (1.54-fold), while 5, 10, 20, and 40 MUM of PXT had no influence on CAR-mediated CYP3A4 luciferase activity. In hCAR-overexpressing HepG2 cells, PXT concentrations (10 40 MUM) that significantly induced PXR and CYP3A4 in HepG2 cells had no impact on the expression of CYP3A4, CAR and PXR, whereas a high concentration of PXT (80 uM) could weakly induce the mRNA and protein levels of CAR and CYP3A4. Moreover, the expression of PXR and CYP3A4 in hCAR-silenced HepG2 cells was markedly elevated compared with the blank control or with normal HepG2 cells treated with 10-80 MUM of PXT. In conclusion, CAR significantly weakens the ability of PXT to induce CYP3A4 expression by repressing the activation of PXR. There may be a cross-talk mechanism between PXR and CAR on the regulation of CYP3A4 in the presence of PXT. Additionally, a high concentration of PXT (80 MUM) induced CYP3A4 via the CAR regulatory pathway. PMID- 30414936 TI - From bench to bedside, via desktop. Recent advances in the application of cutting edge in silico tools in the research of drugs targeting bromodomain modules. AB - The discipline of drug discovery has greatly benefited by computational tools and in silico algorithms aiming at rationalization of many related processes, from the stage of early hit identification to the preclinical phases of drug candidate validation. The various methodologies referred to as molecular modeling tools span a broad spectrum of applications, from straightforward approaches such as virtual screening of compound libraries to more advanced techniques involving the precise estimation of free energy upon binding of the candidate drug to its macromolecular target. To this end, we report an overview of specific studies where implementation of such sophisticated modeling algorithms has shown to be indispensable for addressing challenging systems and biological questions otherwise difficult to answer. We focus our attention on the emerging field of bromodomain inhibitors. Bromodomains are small modules involved in epigenetic signaling and currently comprise high-priority targets for developing both drug candidates and chemical probes for basic biomedical research. We attempt a critical presentation of selected cases utilizing cutting-edge in silico methodologies, with our main emphasis being on absolute or relative free energy simulations, on implementation of quantum-mechanics level calculations and on characterization of solvent thermodynamics. We discuss the advantages and strengths as well as the drawbacks and weaknesses of computational tools utilized in those works and we attempt to comment on specific issues related to their integration into the regular medicinal chemistry practice. Our conclusion is that while such methods indeed represent highly promising resources for further advancing the discipline, their application is not always trivial. PMID- 30414937 TI - Dormant, quiescent, tolerant and persister cells: four synonyms for the same target in cancer. AB - Although many drugs/treatments are now available for most diseases, too often, resistance to these treatments impedes complete therapeutic success. Acquired resistance is a major problem in many pathologies but it is an acute one in cancers and infections. This is probably because these diseases often require long durations of treatment, which ascribe to the selection of resistant cells. However, the actual mechanisms implicated in the selection process are still under debate. It is becoming increasingly clear that resistance is associated with the heterogeneity of cancer cells or micro-organisms and that multiple mechanisms underlie the emergence of drug-resistant subpopulations. Recently, it has been suggested that a subpopulation of drug tolerant cells present in cancer populations and called "persisters" play a major role in this resistance. Recent studies have shown that microorganisms share similar properties. Still, how persister/tolerant cells intervene in the development of resistance is not completely elucidated but seems to be related to epigenetic changes in treated cells and the capacity of persisters to modulate and/or highjack their microenvironment. Due to the complexity of this process, the input from mathematicians, as well as new methods of bioinformatics and statistics, is necessary to fully comprehend the acquisition of resistance/tolerance deriving from and leading to the heterogeneous cell populations. The present review will give a brief overview of the most recent data available on drug tolerant cells in cancers and their similarities with microorganisms. PMID- 30414938 TI - Donepezil improves neuropathy through activation of AMPK signalling pathway in streptozotocin-induced diabetic mice. AB - Diabetic neuropathy (DN) is a common complication of diabetes mellitus and is associated with structural changes in the nerves. However, the molecular basis for DN is poorly understood. Adenosine monophosphate activated protein kinase (AMPK) has been shown to regulate the activity of some kinases including protein kinase B (AKT), mitogen-activated protein kinases (MAPK) and mammalian target of rapamycin complex 1 (mTORC1) that represent important signalling pathways modulating the function of peripheral nociceptive neuron. Donepezil can activate AMPK and exerts neuroprotective effects. In this study, streptozotocin (45 mg/kg for 5 Day, i.p.) was used to induce experimental DN. After confirmation of development of neuropathy, mice were randomly distributed into five groups: Group 1; negative control group received saline (0.9%NaCl), Group 2; diabetic mice received saline, Group (3-5); diabetic mice received daily donepezil (1, 2 or 4 mg/kg, p.o.) respectively for 20 days. Mice were then sacrificed under anesthesia then their sciatic nerve and spinal cord were dissected out and processed for biochemical and histopathological studies. Diabetic mice revealed severe histological abnormalities including degenerated neurons in the spinal cord and swollen myelin sheath with inflammatory edema observed in sciatic nerves. In addition, diabetic mice showed reduced expression of p-AMPK in sciatic nerves with consequent activation of AKT/MAPK/4EBP1. A significant upregulation of the N Methyl-d-aspartate (NMDA) receptors in both cervical and lumbar regions of spinal cord of diabetic mice was also demonstrated. Donepezil, an AMPK activator, blocked the phosphorylation of AKT/MAPK/4EBP1, down regulate the expression of NMDA receptors and reversed hyperalgesia developed in diabetic mice. Therefore, Donepezil could be a potential pharmacological agent for management of DN. PMID- 30414939 TI - Acyl-CoA synthetase-4 is implicated in drug resistance in breast cancer cell lines involving the regulation of energy-dependent transporter expression. AB - Acyl-CoA synthetase-4 (ACSL4) is an enzyme implicated in estrogen receptor alpha (ERalpha) negative regulation and hormone therapy resistance in breast cancer. In addition, ACSL4 has been associated to certain types of hormone resistance in prostate cancer. Chemotherapeutic treatment of disseminated breast cancer is usually faced with therapy resistance associated to ATP-binding cassette (ABC) transporter expression, which detect and eject anti-cancer drugs from cells. In this context, the aim of the present work was to study the role of ACSL4 in anti cancer drug resistance and the involvement of ABC transporters in the underlying mechanisms. To this end, we used MCF-7 Tet-Off/ACSL4 and MDA-MB-231 mock cells, which overexpress ACSL4, and control line MCF-7 Tet-Off empty vector, MDA-MB-231 shRNA ACSL4 and MDA-MB-231 wild type cells. Assays were conducted on cell viability (MTT), cell proliferation (BrdU), drug efflux (flow cytometry), ACSL4 responsive drug resistance ABC transporter genes (RNA-Seq), transporter mRNA expression, protein levels and signaling pathway participation (real-time PCR and Western blot). Higher survival rates upon chemotherapeutic treatment were obtained in MCF-7 Tet-Off/ACSL4 and MDA-MB-231 mock cells, an effect counteracted by doxycycline- or shRNA-induced ACSL4 inhibition, respectively. A synergic effect of ACSL4 inhibitor triacsin C and chemotherapeutic drugs was observed on the inhibition of MDA-MB-231 wild type cell proliferation. MCF-7 Tet-Off/ACSL4 cells showed greater doxorubicin, Hoechst 33342 and calcein AM efflux. In contrast, MDA-MB-231 shRNA ACSL4 cells evidenced inhibition of chemotherapeutic drug efflux. ABCG2, ABCC4, and ABCC8 were identified as ACSL4-responsive drug resistance genes whose expression was increased in MCF-7 Tet-Off/ACSL4 cells but inhibited in MDA-MB-231 shRNA ACSL4 cells. Further cell survival assays in the presence of Ko 143 and Ceefourin 1, inhibitors of ABCG2 and ABCC4, respectively, upon chemotherapeutic treatment showed greater participation of ABCG2 in anti cancer drug resistance in cells overexpressing ACSL4. In addition, ACSL4 inhibition and chemotherapeutic treatment combined with rapamycin-induced mTOR inhibition synergically inhibited proliferation and reduced ABCG2 expression in cells overexpressing ACSL4. In sum, ACSL4 may be regarded as a novel therapeutic target regulating the expression of transporters involved in anticancer drug resistance through the mTOR pathway to restore drug sensitivity in tumors with poor prognosis for disease-free and overall survival. PMID- 30414940 TI - Serine residues in the alpha4 nicotinic acetylcholine receptor subunit regulate surface alpha4beta2* receptor expression and clustering. AB - BACKGROUND AND PURPOSE: Chronic nicotine exposure upregulates alpha4beta2* nicotinic acetylcholine receptors (nAChRs) in the brain. The goal of this study was to examine the role of three serine residues in the large cytoplasmic loop of the alpha4 subunit on alpha4beta2* upregulation in neurons. EXPERIMENTAL APPROACH: Serine residues S336, S470 and S530 in mouse alpha4 were mutated to alanine and then re-expressed in primary neurons from cortex, hippocampus and subcortex of alpha4 KO mice. Mutant and wild type alpha4 expressing neurons were treated with nicotine (0.1, 1 and 10 MUM) and assessed for alpha4beta2* upregulation. KEY RESULTS: alpha4beta2* nAChRs expressing S336A or S470A mutants were deficient at cell surface upregulation in both subcortex and hippocampal neurons. S530A alpha4beta2* mutants exhibited aberrant surface upregulation in subcortical neurons. None of the mutants affected surface upregulation in cortical neurons or upregulation of total alpha4beta2* binding sites in any region. Further, dense domains or clusters of alpha4beta2* nAChRs were observed in the neuronal surface. The impact of nicotine exposure on the intensity, area, and density of these clusters was dependent upon individual mutations. CONCLUSIONS AND IMPLICATIONS: Effects of alpha4 nAChR mutants on surface upregulation varied among brain regions, suggesting that the cellular mechanism of alpha4beta2* upregulation is complex and involves cellular identity. We also report for the first time that alpha4beta2* nAChRs form clusters on the neuronal surface and that nicotine treatment alters the characteristics of the clusters in an alpha4 mutant-dependent manner. This finding adds a previously unknown layer of complexity to the effects of nicotine on alpha4beta2* expression and function. PMID- 30414941 TI - Poly(ADP-ribosylated) proteins in beta-amyloid peptide-stimulated microglial cells. AB - Amyloid-treated microglia prime and sustain neuroinflammatory processes in the central nervous system activating different signalling pathways inside the cells. Since a key role for PARP-1 has been demonstrated in inflammation and in neurodegeneration, we investigated PARylated proteins in resting and in beta amyloid peptide treated BV2 microglial cells. A total of 1158 proteins were identified by mass spectrometry with 117 specifically modified in the amyloid treated cells. Intervention of PARylation on the proteome of microglia showed to be widespread in different cellular districts and to affect various cellular pathways, highlighting the role of this dynamic post-translational modification in cellular regulation. Ubiquitination is one of the more enriched pathways, encompassing PARylated proteins like NEDD4, an E3 ubiquitine ligase and USP10, a de-ubiquitinase, both associated with intracellular responses induced by beta amyloid peptide challenge. PARylation of NEDD4 may be involved in the recruiting of this protein to the plasma membrane where it regulates the endocytosis of AMPA receptors, whereas USP10 may be responsible for the increase of p53 levels in amyloid stimulated microglia. Unfolded protein response and Endoplasmic Reticulum Stress pathways, strictly correlated with the Ubiquitination process, also showed enrichment in PARylated proteins. PARylation may thus represent one of the molecular switches responsible for the transition of microglia towards the inflammatory microglia phenotype, a pivotal player in brain diseases including neurodegenerative processes. The establishment of trials with PARP inhibitors to test their efficacy in the containment of neurodegenerative diseases may be envisaged. PMID- 30414942 TI - Evaluation of the Prognostic Significance of TNM Staging Guidelines in Lung Carcinoid Tumors. AB - BACKGROUND: The Tumor Lymph Node and Metastasis (TNM) classification for lung cancer, originally designed for non-small cell lung carcinoma, is applied to staging of bronchopulmonary carcinoid tumors. The validity of the 8th Edition staging system for carcinoid tumors has not been assessed. In this study, we evaluated its prognostic accuracy using data from a large national population based cancer registry. PATIENTS AND METHODS: Patients with typical and atypical bronchopulmonary carcinoids, diagnosed between 2000 and 2013, were identified from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) registry. We used competing risks analysis to compare 10-year disease specific survival (DSS) across stages. RESULTS: Overall, 4,645 patients with bronchopulmonary carcinoid tumors were identified. Worsening DSS with increasing TNM status and stage was demonstrated across both typical and atypical carcinoids, with overlaps between adjacent subcategories. The combined stages (I vs II, II vs III, III vs IV) showed greater separation in DSS despite persistent overlaps between groups. For typical carcinoids, we found decreased DSS for stage II, stage III, and stage IV with HR 3.8 (95% CI: 2.6-5.6), HR 4.3 (95% CI: 3.0 6.1), and HR 9.0 (95% CI: 6.1-13.1), respectively, compared to stage I. CONCLUSION: The combined stage categories of the 8th Edition TNM staging system provide useful information on outcomes for typical and atypical carcinoids. However, persistent overlaps in combined stage and subcategories of the staging system limit the usefulness of the TNM staging system, particularly in intermediate stages. These limitations suggest the need for further future study and refinement. PMID- 30414943 TI - Cardiorespiratory fitness and development of abdominal obesity. AB - Both, cardiorespiratory fitness and abdominal obesity are independently associated with developing cardiovascular disease and its risk factors. However, the relationship between both attributes is unclear. We examine the relationship between cardiorespiratory fitness and the risk of developing abdominal obesity, and secondarily, other adiposity measures. Retrospective observational study of a cohort of 1284 sedentary patients, who had participated in a clinical trial of physical activity promotion carried out in Spain (2003-2007). At baseline, they were free of cardiovascular disease, hypertension, diabetes, dyslipidemia and/or abdominal obesity, with an indirect VO2max measurement, were 19-80 years old, 62% women, and had completed the two year follow-up. The exposure factor was cardiorespiratory fitness categorized as high, moderate or low, according to tertiles of VO2max values. The main outcome measure was the risk of developing abdominal obesity, as defined by waist circumference >102 (men) and >88 (women) cm. Secondary outcomes were the risk of developing: general obesity, excess body fat, and their combination ("defined" obesity). At two years, 10.5% of the participants had developed abdominal obesity: 6.1% in the high cardiorespiratory fitness tertile, 9.7% in the moderate tertile (adjusted odds ratio, 1.20; 95% confidence interval 0.68-2.10), and 15.7% in the low tertile (adjusted odds ratio, 2.29; 95% confidence interval 1.34-3.91). Moreover, 2.2% of participants in the high cardiorespiratory fitness tertile developed "defined" obesity as did 5.4% in the low tertile (adjusted odds ratio, 2.90; 95% confidence interval 1.15 7.29). Low cardiorespiratory fitness levels are associated with a higher risk of developing abdominal and "defined" obesity. PMID- 30414944 TI - Risk factors for severe complications of colonoscopy in screening programs. AB - Severe complications (SC) in colonoscopy represent the most important adverse effect of colorectal cancer screening programs (CRCSP). The objective is to evaluate the risk factors for SC in colonoscopy indicated after a positive fecal occult blood test in population-based CRCSP. The SC (n = 161) identified from 48,730 diagnostic colonoscopies performed in a cohort of all the women and men invited from 2000 to 2012 in 6 CRCSP in Spain. A total of 318 controls were selected, matched for age, sex and period when the colonoscopy was performed. Conditional logistic regression models were estimated. The analysis was performed separately in groups: immediate-SC (same day of the colonoscopy); late-SC (between 1 and 30 days after); perforation; and bleeding events. SC occurred in 3.300/00 of colonoscopies. Prior colon disease showed a higher risk of SC (OR = 4.87). Regular antiplatelet treatment conferred a higher risk of overall SC (OR = 2.80) and late-SC (OR = 9.26), as did regular anticoagulant therapy (OR = 3.47, OR = 7.36). A history of pelvic-surgery or abdominal-radiotherapy was a risk factor for overall SC (OR = 5.03), immediate-SC (OR = 8.49), late-SC (OR = 4.65) and perforation (OR = 21.59). A finding of adenoma or cancer also showed a higher risk of overall SC (OR = 8.71), immediate-SC (OR = 12.67), late-SC (OR = 4.08), perforation (OR = 4.69) and bleeding (OR = 17.02). The risk of SC doesn't vary depending on the type of preparation or type of anesthesia. Knowing the clinical history of patients such as regular previous medication and history of surgery or radiotherapy, as well as the severity of the findings during the colonoscopy process could help to focus prevention measures in order to minimize SC in CRCSP. PMID- 30414945 TI - Orthognathic Surgery Has a Significant Positive Effect on Perceived Personality Traits and Perceived Emotional Expressions in Long Face Patients. AB - PURPOSE: Crowdsourcing is increasingly being used in medical research to obtain the opinion and perception of laypeople. We hypothesized that a layperson's perception of a patient with long face dentofacial deformity is more favorable after orthognathic surgery than before surgery regarding perceived personality traits and emotional facial expressions. MATERIALS AND METHODS: We implemented a survey, distributed through Amazon.com's Mechanical Turk crowdsourcing platform, to compare 6 perceived personality traits and 6 perceived emotional traits before and after (>6 months) orthognathic surgery in patients through standardized photographs (3 facial views). The sample was composed of 20 patients randomly selected from our long face dentofacial deformity database, treated by 1 surgeon, all having undergone bimaxillary and chin orthognathic surgery. The outcome variable was change in each of the 12 perceived personality and emotional traits studied. Descriptive and bivariate statistics were computed. P < .05 was considered significant. RESULTS: A total of 500 respondents (raters) completed the survey in less than 10 hours. The respondents were mostly men (60%), aged 25 to 34 years (57%), white (71%), and college graduates (53%) with an annual income between $20,000 and $50,000 (48%). After jaw reconstruction and completion of orthodontic treatment, long face patients as a group were perceived to be significantly more trustworthy, more friendly, more intelligent, more attractive, and more dominant and also perceived as happier and less angry, sad, afraid, or disgusted than they were before surgery (P < .05). CONCLUSIONS: We confirmed that laypersons consistently report positive changes in a long face patient's perceived personality traits and perceived emotional expressions after bimaxillary and chin orthognathic surgery. PMID- 30414946 TI - G protein-coupled receptor 30 mediates meiosis resumption and gap junction communications downregulation in goat cumulus-oocyte complexes by 17beta estradiol. AB - Estrogen plays a critical role in the regulation of gap junctions between oocytes and granulosa cells in mammalian ovaries. G protein-coupled receptor 30 (GPR30) was identified as a membrane estrogen receptor, mediating rapid, nongenomic signaling events that might be responsible for the regulation of oocyte meiosis resumption and gap junction intercellular communications (GJICs). The present study aimed to determine the expression and localization of GPR30 and its role in oocyte meiotic progression and GJICs in goat cumulus-oocyte complexes (COCs). Immunofluorescence experiments revealed that GPR30 was primarily located in the plasma membrane of cumulus cells and oocytes in goats. 17beta-estradiol could promote oocyte meiotic progression, which was blocked by G15 (a selective GPR30 antagonist) but not ICI182780 (a nuclear estrogen receptor inhibitor) in the early stage of in vitro culture. The effect of 17beta-estradiol on the GJICs was quantified by lucifer yellow (LY) microinjection and calcein-AM fluorescent dye diffusion. 17beta-estradiol treatment of goat COCs resulted in rapid downregulation of GJICs. The transfer of calcein from cumulus cells to oocytes could be significantly inhibited by carbenoxolone (a known gap junction blocker), 17beta-estradiol or G1 (a GPR30 agonist), and this inhibition could be reversed by G15 but not ICI182780, indicating that GPR30 mediates the effect of 17beta estradiol on the rapid downregulation of GJICs. 17beta-estradiol also stimulated the serine 368 phosphorylation of connexin 43 (Cx43) when COCs were in vitro cultured for 4 h, 6 h, and 8 h. More importantly, 17beta-estradiol or G1 could separately promote the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK 1/2) and Cx43 significantly when COCs were cultured for 4 h. Furthermore, both ERK1/2 and Cx43 phosphorylation could be inhibited by G15 and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor AG1478 or by the ERK1/2 inhibitor PD98059, indicating that EGFR-ERK1/2 signaling was involved in these events. These results supported the hypothesis that GPR30 mediated 17beta-estradiol-stimulated meiotic resumption and GJIC reduction in goat COCs. Thus, the present study provides novel insights into elucidating the mechanisms for steroid hormone action in the regulation of oocyte maturation. PMID- 30414947 TI - The C-type lectin-like receptor Nkrp1b: Structural proteomics reveals features affecting protein conformation and interactions. AB - The cytotoxicity of mouse natural killer (NK) cells in response to pathological changes in target cells is regulated via the Nkrp1b receptor. Here, we characterized the Nkrp1b structure and structural features (stalk, loop, and oligomerization state) that affect its interactions. To study the Nkrp1b protein structure and the functional importance of its stalk, two Nkrp1b protein variants differing by the presence of the stalk were prepared. These variants were studied using a combination of structural mass spectrometry approaches with computational modeling to derive structural models. In addition, information about biological activity and localization in mammalian cells was acquired using scanning microscopy techniques and western blotting. Based on these methods, we obtained the structure of Nkrp1b ectodomain in its monomeric and dimeric conformations, identified the dimerization interface, and determined disulfide connections within the molecule. We found that Nkrp1b occurs as a mixture of monomers and homodimers, both in vitro and in vivo. SIGNIFICANCE: Despite the long-standing assumption that Nkrp1 proteins are homodimers connected by disulfide bonds in the stalk region, our data showed that both Nkrp1b protein variants form monomers and homodimers irrespective of the presence of the stalk. We demonstrated that the stalk is not crucial for protein dimerization or ligand binding and that Nkrp1b interacts with its natural ligands only in its monomeric conformation; therefore, dimers may have another regulatory function. Using a unique combination of computational, biochemical, and biological methods, we revealed the structural conformation and behavior of Nkrp1b in its native state. In addition, it is a first report utilizing the intermolecular chemical cross-linking of light- and heavy-labeled protein chains together with ion mobility-mass spectrometry to design the structural models of protein homodimers. PMID- 30414948 TI - Association between maternal pre-pregnancy body mass index, gestational weight gain, and offspring atopic dermatitis: a prospective cohort study. AB - BACKGROUND: Maternal weight status may contribute to the development of atopic disorders in children. OBJECTIVE: The objective of this study was to assess associations of maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) with risk of atopic dermatitis in children METHODS: Maternal pre-pregnancy BMI and GWG were assessed by questionnaire through the Growing Up Today Study (GUTS), a prospective cohort study of U.S. children. Mothers reported whether GUTS participants had ever been diagnosed with atopic dermatitis by a clinician in either 1997 or 1999, when GUTS participants were between 10-17 years old. We used multivariable logistic regression to estimate the association of BMI and GWG with atopic dermatitis in offspring (expressed as odds ratios (OR) with 95% confidence intervals). RESULTS: Among 13,269 GUTS participants, 2,058 (16%) had childhood atopic dermatitis. Higher maternal pre-pregnancy BMI was not associated with atopic dermatitis (p trend = 0.48). By contrast, GWG was associated with increased atopic dermatitis risk (p trend = 0.005). Compared to children of mothers who gained 25-34 lb, children of mothers who gained 35-44 lb (OR 1.11,0.98-1.26) and >=45 lbs (OR 1.23,1.05-1.43) had an increased risk of atopic dermatitis. These associations appeared stronger with pre-pregnancy BMI >25 (GWG 35-44 lb: OR 1.20,0.84-1.69; GWG >=45 lb: OR 1.57,1.07-2.31), but the statstical interaction between BMI and GWG was not significant. CONCLUSION: In this study, increased GWG was associated with increased risk of atopic dermatitis in offspring. This supports existing evidence that prenatal exposures contribute to the development of atopic disorders. PMID- 30414949 TI - Characterization of the thymus in Lrp4 myasthenia gravis: Four cases. AB - Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction. Most patients have pathogenic autoantibodies against the acetylcholine receptor (AChR). In the last years a novel subpopulation of MG patients has been described that harbors antibodies against low-density lipoprotein receptor-related protein 4 (Lrp4), another postsynaptic neuromuscular antigen. In early-onset AChR MG (EOMG), the thymus plays an important role in immunopathogenesis, and early thymectomy is beneficial. It is still unknown if the thymus plays any role in Lrp4-MG. In this pilot study, we compared thymus samples from four patients with Lrp4-MG (one pre-treated with immunosuppressive drugs), four non-MG controls and five EOMG patients (not pretreated with immunosuppressive drugs). Immunohistochemistry of the Lrp4-MG thymi revealed normal architecture, with normal numbers and distribution of B-cells, lymphoid follicles and Hassall's corpuscles. Primary CD23+ lymphoid follicles were similarly infrequent in Lrp4-MG and control thymic sections. In none of the control or Lrp4-MG thymi did we find secondary follicles with CD10+ germinal centers. These were evident in 2 of the 5 EOMG thymi, where primary lymphoid follicles were also more frequent on average, thus showing considerable heterogeneity between patients. Even if characteristic pathological thymic changes were not observed in the Lrp4 subgroup, we cannot exclude a role for the thymus in Lrp4-MG pathogenesis, since one Lrp4-MG patient went into clinical remission after thymectomy alone (at one year follow-up) and one more improved after thymectomy in combination with immunosuppressive therapy. PMID- 30414950 TI - Strategies for brain-targeting liposomal delivery of small hydrophobic molecules in the treatment of neurodegenerative diseases. AB - Neurodegenerative diseases (NDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), threaten the health of an ever-growing number of older people worldwide; so far, there are no effective cures. Significant efforts have been devoted to developing new drugs for NDs in recent years, and some small molecules have been shown to be promising in preclinical studies. However, the major challenge for brain-targeting drugs is how to efficiently deliver the drugs across the blood-brain barrier (BBB) to desired targets. To address this issue, liposomal delivery systems have proved to be ideal carriers for neuroprotective small molecules. Here, we summarize recent advances in the brain-targeting liposomal delivery of small hydrophobic molecules (SHMs) and propose strategies for developing liposomal SHMs as disease-modifying neurotherapeutics for NDs. PMID- 30414951 TI - Malignant transformation of canine oral papillomavirus (CPV1)-associated papillomas in dogs: An emerging concern? AB - Canine oral papillomavirus (CPV1, also known as COPV), the most common cause of non-neoplastic papillomas, has not been shown to cause squamous cell carcinomas (SCC). Furthermore, malignant transformation of benign papillomas to SCC has only been reported in a single group of dogs with severe combined immunodeficiency infected with CPV2. Here, we report a series of 7 dogs with benign CPV1 associated papillomas with histologic evidence of CPV1 causing malignant transformation to carcinoma in situ and ultimately SCC. Expression of p53 and p16 proteins in CPV1-infected cells within the benign papillomas and lesions that progressed into SCC also supported an association between papillomavirus and malignant transformation. Moreover, our retrospective analysis indicated that while there have been increased numbers of viral papillomas with malignant transformation, the number of annually diagnosed canine viral papillomas has remained constant over the past decade in our laboratory. We speculate that either an altered host immunity from increased usage of immunosuppressive drugs or changing environmental factors, e.g. increase exposure to UV radiation, may cause an increased oncogenic potential of this "low-risk" virus. This study aims to raise awareness of the malignant potential of CPV1 and to encourage further investigations into the cause of this suspected change in its oncogenic potential. PMID- 30414953 TI - Comparison of partial replacement of fishmeal with soybean meal and EnzoMeal on growth performance of Asian seabass Lates calcarifer. AB - This study explored the impact of fishmeal replacement by commercial soybean meal (SM) and EnzoMeal (EZM) on Asian seabass Lates calcarifer growth performance using six diets. The six diets comprised two sources of plant proteins with three levels each, including 300 g kg-1 soybean meal (SM30), 300 g kg-1 EnzoMeal (EZM30), 400 g kg-1 soybean meal (SM40), 400 g kg-1 EnzoMeal (EZM40), 500 g kg-1 soybean meal (SM50), and 500 g kg-1 EnzoMeal (EZM50). The soybean level was shown to significantly affect the final fish weight, weight gain, specific growth rate (SGR), survival, feed intake, feed conversion ratio (FCR), and apparent digestibility coefficient (ADC). Further, the plant meal type significantly affected the final weight, weight gain, feed intake, ADC, and body lipid content. The highest final weight was observed in the SM30 group, and the lowest final weight was in the EZM50 group. Fish fed EZM had lower body weight than those fed soybean meal at the same inclusion level. However, once the fish had adapted to the EZM diet the fish weight variation was low. At the 300 g kg-1 and 400 g kg-1 inclusion levels the fish fed EZM showed significantly higher ADC than those fed soybean. The pepsin activity of fish fed EZM at 300 g kg-1 and 400 g kg-1 was higher than those fed soybean meal at the same levels. The enterocyte height in the hindgut of fish fed SM40 and SM50 was significantly higher than those fed EZM40 and EZM50, respectively. This study indicates that EZM could be a potential source of plant protein to replace fishmeal in fish feed as it contains high protein and low anti-nutritional factors. However, the major endpoint measurements on fish performance suggest that low feed intake constrains further EZM inclusion beyond 300 g kg-1 in the diet. PMID- 30414952 TI - Chronic psychological stress impairs germinal center response by repressing miR 155. AB - Germinal centers (GC) are vital to adaptive immunity. BCL6 and miR-155 are implicated in control of GC reaction and lymphomagenesis. FBXO11 causes BCL6 degradation through ubiquitination in B-cell lymphomas. Chronic psychological stress is known to drive immunosuppression. Corticosterone (CORT) is an adrenal hormone expressed in response to stress and can similarly impair immune functions. However, whether GC formation is disrupted by chronic psychological stress and its molecular mechanism remain to be elucidated. To address this issue, we established a GC formation model in vivo, and a GC B cell differentiation model in vitro. Comparing Naive B cells to GC B cells in vivo and in vitro, the differences of BCL6 and FBXO11 mRNA do not match the changes at the protein level and miR-155 levels that were observed. Next we demonstrated that CORT increase, induced by chronic psychological stress, reduced GC response, IgG1 antibody production and miR-155 level in vivo. The effect of chronic psychological stress can be blocked by a glucocorticoid receptor (GR) antagonist. Similarly, impaired GC B cell generation and isotope class switching were observed. Furthermore, we found that miR-155 and BCL6 expression were downregulated, but FBXO11 expression was upregulated in GC B cells treated with CORT in vitro. In addition, we demonstrated that miR-155 directly down-regulated FBXO11 expression by binding to its 3-untranslated region. The subsequent overexpression of miR-155 significantly blocked the stress-induced impairment of GC response, due to changes in FBXO11 and BCL6 expression, as well as increased apoptosis in B cells both in vivo and in vitro. Our findings suggest perturbation of GC reaction may play a role in chronic psychological stress-induced immunosuppression through a glucocorticoid pathway, and miR-155-mediated post transcriptional regulation of FBXO11 and BCL6 expression may contribute to the impaired GC response. PMID- 30414954 TI - Modulation of luminal L-alanine transport in proximal tubular cells of frog kidney induced by low micromolar Cd2+ concentration. AB - The kidneys are recognized as a major target of cadmium-induced toxicity. However, all mechanisms that are involved in the early stages of cadmium nephrotoxicity, particularly considering low micromolar concentrations of cadmium ions (Cd2+) are still unknown. Therefore, the aim of this study was to investigate the effects of peritubular acute exposure to micromolar Cd2+ concentration (2.3 MUmol/L) on the rapid depolarization and the rate of slow repolarization of peritubular membrane potential difference (PD), induced by luminal application of L-alanine in proximal tubular cells of frog kidney. The results showed that the luminal application of L-alanine rapidly depolarized the peritubular membrane PD of -42.00 +/- 11.68 mV by 23.89 +/- 4.15 mV with an average rate of slow repolarization of 5.64 +/- 0.81 mV/min. Additionally, peritubular acute exposure to Cd2+ induced change in rapid depolarization of peritubular membrane PD of -53.33 +/- 13.01 mV by 18.78 +/- 3.31 mV (P < 0.01) after luminal application of L-alanine. Also, peritubular acute exposure to Cd2+ led to statistically significant decrease in the rate of slow repolarization of peritubular membrane PD (3.53 +/- 0.35 mV/min; P < 0.05). In conclusion, these results suggest that peritubular acute exposure to low micromolar Cd2+ concentration decreased the rapid depolarization and the rate of slow repolarization of peritubular membrane PD induced by luminal application of L alanine. This is followed by reduced luminal sodium-coupled transport of L alanine and this change may be one of the possible mechanisms involved in the early stages of Cd2+-induced nephrotoxicity. PMID- 30414955 TI - Adoptive Immunotherapy with Cord Blood for the Treatment of Refractory Acute Myelogenous Leukemia: Feasibility, Safety, and Preliminary Outcomes. AB - Adoptive immunotherapy has shown efficacy in patients with relapsed/refractory acute myelogenous leukemia (AML). We conducted a prospective evaluation of cord blood (CB)-based adoptive cell therapy following salvage chemotherapy in patients with AML or myelodysplastic syndrome (MDS) and describe the safety and early outcomes of this approach. To enhance the antileukemic effect, we selected CB units (CBUs) with a shared inherited paternal antigen (IPA) and/or noninherited maternal antigen (NIMA) match with the recipients. Furthermore, the CBUs had total nucleated cell (TNC) dose <2.5 * 107/kg and were at least 4/6 HLA-matched with the patients; a higher allele-level match was preferred. Heavily pretreated adult patients with AML/MDS were enrolled. CBU searches were performed for 50 patients. CBUs with shared IPA targets were identified for all, and CBUs with NIMA matches were found for 80%. Twenty-one patients underwent treatment (AML, primary induction failure, n = 8; refractory relapse, n = 10, including 7 recipients of previous allogeneic HSCT; blast crisis chronic myelogenous leukemia, n = 1; MDS, n = 2). Most received combination chemotherapy; those not fit for intensive treatment received a hypomethylating agent. Response was defined as <10% residual blasts in hypocellular bone marrow at approximately 2 weeks after treatment. Ten of the 19 evaluable patients responded, including 5 of the 7 recipients of previous transplant. Response was seen in 4 of 4 patients with full CBU-derived chimerism, 2 of 2 of those with partial, low-level chimerism and 4 of 12 of the recipients with no detectable CBU chimerism. The most common adverse events were infections (bacterial, n = 5; viral, n = 2; fungal, n = 5). Grade IV acute graft-versus-host disease (GVHD) developed in 2 patients with full CBU chimerism; 2 other patients had grade 1 skin GVHD. A total of 11 patients died, 7 from disease recurrence and 4 from infections (1 early death; the other 3 in remission at the time of death). Overall, 12 patients proceeded to allogeneic HSCT; of those, 7 had responded to treatment, 3 had not (and had received additional therapy), and 2 had persistent minimal residual disease. In conclusion, the use of CB as adoptive immunotherapy in combination with salvage chemotherapy for patients with refractory AML/MDS is feasible, can induce disease control, can serve as a bridge to allogeneic HSCT, and has an acceptable incidence of adverse events. Alloreactivity was enhanced through the selection of CBUs targeting a shared IPA and/or NIMA match with the patients. CBUs with lower cell doses, already available in the CB bank and unlikely to be adequate grafts for adult transplants, can be used for cell therapy within a short time frame. PMID- 30414956 TI - Quality of Care in the Treatment of Localized Intermediate and High Risk Prostate Cancer at Minority Serving Hospitals. AB - PURPOSE: To investigate quality of care at minority-serving hospitals (MSH) compared to other institutions for men with localized intermediate and high-risk prostate cancer (PCa). METHODS: We identified 536,539 men aged >=40 years presenting with localized intermediate and high-risk PCa in the United States between 2004-2015 using the National Cancer Database (NCDB). Institutions were ranked according to the proportion of Black and Hispanic patients treated at a given institution, and the top decile institutions were defined as MSH. We used multivariable analyses to characterize the association between MSH and three endpoints: receipt of definitive treatment, time to definitive treatment, and receipt of androgen deprivation therapy in young (<=65 years) and healthy (no comorbidity) men treated with external beam radiation therapy. RESULTS: 162 and 1168 hospitals were defined as MSH and non-MSH, respectively. In multivariable analyses, MSH was associated with decreased odds of receiving definitive treatment (Adjusted Odds Ratio [AOR] 0.73 95%-CI: 0.62-0.85, p<0.001). The adjusted mean time to treatment was significantly longer in MSHs compared to non MSHs (4.9days, standard error 2.2; p=0.024). Among young and healthy men, there was no association between treatment at MSH and receipt of androgen deprivation therapy in conjunction with external beam radiation (AOR 0.90; 95%-CI: 0.75-1.09, p=0.291). CONCLUSION: Treatment at MSH was associated with lower odds of receiving definitive therapy and longer time to definitive therapy for localized intermediate- and high-risk PCa, despite adjustment for race. This suggests that some of the racial disparities in PCa may be explained by the sites at which racial/ethnic minorities receive care. PMID- 30414957 TI - Clinical, pathologic, and oncologic findings of radical prostatectomy patients with extraprostatic extension diagnosed on pre-operative prostate biopsy. AB - PURPOSE: Prostatic adenocarcinoma (PCa) with extraprostatic extension (EPE) detected on prostate needle biopsy (PNB) is an uncommon finding. We aimed to describe the clinical and pathologic findings in a large cohort of PCa patients treated with radical prostatectomy (RP) who had EPE identified on PNB. MATERIALS AND METHODS: Using our institutional pathology database, we identified 83 PCa cases with EPE on PNB between 2000-2018 who underwent treatment with RP and had clinical follow-up information. Clinical and pathologic outcomes were examined. RESULTS: Sixty-five percent (54/83) of patients presented with clinical stage >=T2 disease. On biopsy, 60% (50/83) of patients had grade group (GG) 4-5, and 81% (66/83) had perineural invasion. EPE was confirmed in the RP specimen in 98% (81/83) of cases. At RP, 59% (49/83) had positive surgical margins, 45% (37/83) had seminal vesicle invasion, and 37% (30/83) had lymph node involvement. Median length of follow-up after RP was 2 years. Overall, 45% (34/76) of patients received post-operative radiation at a median of 1 year after RP; 11% (8/73) received chemotherapy at a median of 2 years after RP. The 3-year biochemical recurrence (BCR)-free survival rate was 48.4% (95% CI 0.345-0.610), and the 3 year metastasis-free survival rate was 75.2% (95% CI 0.603-0.851). CONCLUSIONS: Patients with EPE detected on PNB almost always have extraprostatic disease and markedly adverse pathology at RP. Many experience BCR, and most will require multi-modal therapy. These data can be useful in counseling such patients with regards to management approach and expected outcomes after surgery. PMID- 30414958 TI - Cannabinoid type 2 (CB2) receptor system modulates paclitaxel-induced microglial dysregulation and central sensitization in rats. AB - Paclitaxel induces microglial activation and production of proinflammatory mediators in the dorsal horn, which contribute to the development and maintenance of central sensitization and pain behavior. MDA7, 1-((3-benzyl-3-methyl-2,3 dihydro-1-benzofuran-6-yl)carbonyl) piperidine is a novel highly selective CB2 agonist. We tested the hypothesis that activation of CB2 receptor by MDA7 modulates microglial dysregulation, suppresses the overexpression of brain derived neurotrophic factor (BDNF) in microglia in the dorsal horn, and attenuates the central sensitization and pain behavior induced by paclitaxel. Groups of rats randomly received saline or 1.0 mg/kg of paclitaxel daily i.p. for 4 consecutive days for a total cumulative dose of 4 mg/kg. MDA7 15 mg/kg i.p. or vehicle were administered 15 min before administering paclitaxel for 4 days and then continued for another 10 days. Behavioral and molecular studies were performed. Paclitaxel induced the expression of CB2 receptors and production of IL-6 in microglia in the dorsal horn. MDA7 attenuated the expression of IL-6 and promoted the expression of IL-10. Paclitaxel induced epigenetic upregulation of IRF8 and P2X purinoceptor 4 (P2 * 4) in microglia and subsequently increased the expression of alpha isoform of calcium/calmodulin-dependent protein kinase II (CaMKIIalpha), transcriptional factors p-CREB and DeltaFosB, leading to the overproduction of BDNF in microglia. Paclitaxel also upregulated the expression of glutamate receptor subunits GluR1 and NR2B, decreased the expression of K+-Cl- cotransporter (KCC2), and induced mechanical allodynia in rats. All of the aforementioned molecular changes were attenuated by MDA7. Our data show that MDA7 attenuated paclitaxel-induced molecular and behavioral changes in rats. Perspectives: This study provides evidence that paclitaxel induced microglia dysregulation and epigenetically upregulated the microglial expression of BDNF, which led to sensitization of dorsal horn neurons and mechanical allodynia in rats. The CB2 agonist MDA7 alleviated these pathological processes. MDA7 represents an innovative therapeutic approach for treatment of chemotherapy induced neuropathy. PMID- 30414959 TI - Tobacco Heating System 2.2 has a limited impact on DNA methylation of candidate enhancers in mouse lung compared with cigarette smoke. AB - Cigarette smoke (CS) exposure has been shown to correlate with changes in DNA methylation levels, however, the impact of CS on DNA methylation at genome-wide scale is missing. Here, we used whole-genome bisulfite sequencing to assess the effects of CS extract and aerosol from the Tobacco Heating System (THS) 2.2, a candidate modified risk tobacco product, on DNA methylation in lung and liver tissues from apolipoprotein E-deficient mice during an eight-month period of exposure. We found that in lung tissue, CS mainly induced hypermethylation of candidate enhancers at late time points, while promoters were less affected. This effect was strongly reduced upon cessation or switching to THS 2.2. By contrast, chronic exposure to THS 2.2 had a limited effect on DNA methylation at both promoters and enhancers. We also identified members of the Ets and Fox families of transcription factors as potential players in the epigenetic response to CS exposure in lung tissue. In contrast to the lung, DNA methylation in the liver was largely insensitive to all investigated exposures. In summary, our investigations indicate that CS-related DNA methylation alterations are tissue specific, occur mainly at enhancers and are strongly reduced upon smoking cessation or switching to THS2.2. PMID- 30414960 TI - Differential effects of metformin glycinate and hydrochloride in glucose production, AMPK phosphorylation and insulin sensitivity in hepatocytes from non diabetic and diabetic mice. AB - The liver is a main target tissue of the biguanide metformin which activates AMP activated protein kinase (AMPK). We previously reported that administration of metformin glycinate showed a greater decrease of glycated hemoglobin A1c than a placebo in patients with type 2 diabetes mellitus (T2DM). In this study, we compared the effects of metformin hydrochloride, the oral antidiabetic drug of first choice, with those of metformin glycinate in hepatocytes from non-diabetic and diabetic mice and humans. Both formulations were equally potent regard to the reduction of basal and glucagon-induced glucose production and mRNA levels of gluconeogenic enzymes (Pck1 and G6pc) in hepatocytes from C57/Bl6 mice and humans. On the contrary, phosphorylation of AMPK and its substrate acetyl CoA carboxylase (ACC) was faster in hepatocytes treated with metformin glycinate. Likewise, we found stronger reduction in hepatocytes from obese/diabetic db/db mice of glucagon-induced glucose output and more sustained AMPK phosphorylation after treatment with metformin glycinate. Importantly, insulin sensitization regarding phosphorylation of AKT (Ser473) was enhanced in hepatocytes from db/db mice or humans pretreated with metformin glycinate. In conclusion, our data indicate that metformin glycinate may be an alternative therapy against insulin resistance during obesity and/or T2DM. PMID- 30414961 TI - RIFM fragrance ingredient safety assessment, guaiyl acetate, CAS Registry Number 134-28-1. PMID- 30414962 TI - The Antibody Light-Chain Linker Regulates Domain Orientation and Amyloidogenicity. AB - The antibody light chain (LC) consists of two domains and is essential for antigen binding in mature immunoglobulins. The two domains are connected by a highly conserved linker that comprises the structurally important Arg108 residue. In antibody light chain (AL) amyloidosis, a severe protein amyloid disease, the LC and its N-terminal variable domain (VL) convert to fibrils deposited in the tissues causing organ failure. Understanding the factors shaping the architecture of the LC is important for basic science, biotechnology and for deciphering the principles that lead to fibril formation. In this study, we examined the structure and properties of LC variants with a mutated or extended linker. We show that under destabilizing conditions, the linker modulates the amyloidogenicity of the LC. The fibril formation propensity of LC linker variants and their susceptibility to proteolysis directly correlate implying an interplay between the two LC domains. Using NMR and residual dipolar coupling-based simulations, we found that the linker residue Arg108 is a key factor regulating the relative orientation of the VL and CL domains, keeping them in a bent and dense, but still flexible conformation. Thus, inter-domain contacts and the relative orientation of VL and CL to each other are of major importance for maintaining the structural integrity of the full-length LC. PMID- 30414963 TI - RNA-Mediated Dimerization of the Human Deoxycytidine Deaminase APOBEC3H Influences Enzyme Activity and Interaction with Nucleic Acids. AB - Human APOBEC3H is a single-stranded (ss)DNA deoxycytidine deaminase that inhibits replication of retroelements and HIV-1 in CD4+ T cells. When aberrantly expressed in lung or breast tissue, APOBEC3H can contribute to cancer mutagenesis. These different activities are carried out by different haplotypes of APOBEC3H. Here we studied APOBEC3H haplotype II, which is able to restrict HIV-1 replication and retroelements. We determined how the dimerization mechanism, which is mediated by a double-stranded RNA molecule, influenced interactions with and activity on ssDNA. The data demonstrate that the cellular RNA bound by APOBEC3H does not completely inhibit enzyme activity, in contrast to other APOBEC family members. Despite degradation of the cellular RNA, an approximately 12-nt RNA remains bound to the enzyme, even in the presence of ssDNA. The RNA-mediated dimer is disrupted by mutating W115 on loop 7 or R175 and R176 on helix 6, but this also disrupts protein stability. In contrast, mutation of Y112 and Y113 on loop 7 also destabilizes RNA-mediated dimerization but results in a stable enzyme. Mutants unable to bind cellular RNA are unable to bind RNA oligonucleotides, oligomerize, and deaminate ssDNA in vitro, but ssDNA binding is retained. Comparison of A3H wild type and Y112A/Y113A by fluorescence polarization, single-molecule optical tweezer, and atomic force microscopy experiments demonstrates that RNA-mediated dimerization alters the interactions of A3H with ssDNA and other RNA molecules. Altogether, the biochemical analysis demonstrates that RNA binding is integral to APOBEC3H function. PMID- 30414964 TI - Controlling Liquid-Liquid Phase Separation of Cold-Adapted Crystallin Proteins from the Antarctic Toothfish. AB - Liquid-liquid phase separation (LLPS) of proteins is important to a variety of biological processes both functional and deleterious, including the formation of membraneless organelles, molecular condensations that sequester or release molecules in response to stimuli, and the early stages of disease-related protein aggregation. In the protein-rich, crowded environment of the eye lens, LLPS manifests as cold cataract. We characterize the LLPS behavior of six structural gamma-crystallins from the eye lens of the Antarctic toothfish Dissostichus mawsoni, whose intact lenses resist cold cataract in subzero waters. Phase separation of these proteins is not strongly correlated with thermal stability, aggregation propensity, or cross-species chaperone protection from heat denaturation. Instead, LLPS is driven by protein-protein interactions involving charged residues. The critical temperature of the phase transition can be tuned over a wide temperature range by selective substitution of surface residues, suggesting general principles for controlling this phenomenon, even in compactly folded proteins. PMID- 30414965 TI - Biochemical Studies Provide Insights into the Necessity for Multiple Arabidopsis thaliana Protein-Only RNase P Isoenzymes. AB - RNase P catalyzes removal of the 5' leader from precursor tRNAs (pre-tRNAs) in all three domains of life. Some eukaryotic cells contain multiple forms of the protein-only RNase P (PRORP) variant, prompting efforts to unravel this seeming redundancy. Previous studies concluded that there were only modest differences in the processing of typical pre-tRNAs by the three isoforms in Arabidopsis thaliana [AtPRORP1 (organellar), AtPRORP2 and AtPRORP3 (nuclear)]. Here, we investigated if different physical attributes of the three isoforms might engender payoffs under specific conditions. Our temperature-activity profiling studies revealed that AtPRORPs display substrate-identity dependent behavior at elevated temperatures (37-45 degrees C), with the organellar variant outperforming the nuclear counterparts. Echoing these findings, molecular dynamics simulations revealed that AtPRORP2 relative to AtPRORP1 samples a wider conformational ensemble that deviates from the crystal structure. Results from our biochemical studies and molecular dynamics simulations support the idea that AtPRORPs have overlapping but not necessarily redundant attributes and inspire new perspectives on the suitability of each variant to perform its function(s) in a specific cellular locale. PMID- 30414966 TI - Contacts in Death: The Role of the ER-Mitochondria Axis in Acetic Acid-Induced Apoptosis in Yeast. AB - Endoplasmic reticulum-mitochondria contact sites have been a subject of increasing scientific interest since the discovery that these structures are disrupted in several pathologies. Due to the emerging data that correlate endoplasmic reticulum-mitochondria contact sites function with known events of the apoptotic program, we aimed to dissect this interplay using our well established model of acetic acid-induced apoptosis in Saccharomyces cerevisiae. Until recently, the only known tethering complex between ER and mitochondria in this organism was the ER-mitochondria encounter structure (ERMES). Following our results from a screening designed to identify genes whose deletion rendered cells with an altered sensitivity to acetic acid, we hypothesized that the ERMES complex could be involved in cell death mediated by this stressor. Herein we demonstrate that single ablation of the ERMES components Mdm10p, Mdm12p and Mdm34p increases the resistance of S. cerevisiae to acetic acid-induced apoptosis, which is associated with a prominent delay in the appearance of several apoptotic markers. Moreover, abrogation of Mdm10p or Mdm34p abolished cytochrome c release from mitochondria. Since these two proteins are embedded in the mitochondrial outer membrane, we propose that the ERMES complex plays a part in cytochrome c release, a key event of the apoptotic cascade. In all, these findings will aid in targeted therapies for diseases where apoptosis is disrupted, as well as assist in the development of acetic acid-resistant strains for industrial processes. PMID- 30414967 TI - A Membrane Protein Complex Docking Benchmark. AB - We report the first membrane protein-protein docking benchmark consisting of 37 targets of diverse functions and folds. The structures were chosen based on a set of parameters such as the availability of unbound structures, the modeling difficulty and their uniqueness. They have been cleaned and consistently numbered to facilitate their use in docking. Using this benchmark, we establish the baseline performance of HADDOCK, without any specific optimization for membrane proteins, for two scenarios: true interface-driven docking and ab initio docking. Despite the fact that HADDOCK has been developed for soluble complexes, it shows promising docking performance for membrane systems, but there is clearly room for further optimization. The resulting set of docking decoys, together with analysis scripts, is made freely available. These can serve as a basis for the optimization of membrane complex-specific scoring functions. PMID- 30414968 TI - An efficient constitutive expression system for Anti-CEACAM5 nanobody production in the yeast Pichia pastoris. AB - Nanobodies offer multiple advantages over conventional antibodies in terms of size, stability, solubility, immunogenicity, and production costs, with improved tumor uptake and blood clearance. Additionally, the recombinant expression of nanobodies is robust in various expression systems, such as Escherichia coli, Saccharomyces cerevisiae and Pichia pastoris. P. pastoris is the most widely used microorganism for nanobody production, but all or almost all expression vectors developed for this system are based on the regulated promoter of the alcohol oxidase 1 gene (AOX1) that requires methanol for full induction. In this study, a constitutive anti-CEACAM5 nanobody expression system was constructed under the control of a glyceraldehyde-3-phosphate dehydrogenase promoter (GAP) promoter. The effects of different carbon sources and pH on nanobody expression were evaluated in shaking flask cultures. After 96 h of constitutive expression in shaking flask, a yield of 51.71 mg/L was obtained. In addition, this constitutive expression system produced nanobodies at equivalent yield and affinity to that produced by methanol-induced expression. The results of this study indicated that the use of a constitutive expression system is a promising alternative for the production of nanobodies applied for cancer diagnosis and therapy. PMID- 30414969 TI - Recombinant expression, purification and bioactivity characterization of extracellular domain of human tumor necrosis factor receptor 1. AB - The interaction between TNF-alpha with TNFR1 triggers important signaling pathways inducing diverse cellular phenomena including inflammation, apoptosis, etc., and is involved in the pathogenesis and progression of numerous autoimmune diseases. The extracellular domain (ECD) of TNFR has been successfully used to clinically treat such TNF-associated diseases. However, large-scale production of these biological material via eukaryotic cell expression systems is usually costly owing to the culture medium and complicated growth conditions. This study aimed to extract pure soluble human TNFR1-ECD and investigate its biological activity, using a prokaryotic expression system. Recombinant vector pMCSG7-TNFR1 ECD was constructed via ligation-independent cloning. The His-tag fusion protein was expressed in E. coli and localized in inclusion bodies. Recombinant TNFR1-ECD was refolded and purified via nickel-affinity chromatography, tag cleavage, followed by cation-exchange chromatography or size-exclusion chromatography. A purity of over 95% and a yield of 9.3 mg protein per liter of bacterial culture media was obtained. The purified protein showed significant affinity of 2.15 nM towards human TNF-alpha and inhibited TNF-alpha-mediated cytotoxicity in L929 cells, with an ED50 of 0.10 MUg/ml. It formed a self-associated oligomer with a KD of 1.15 MUM, detected via microscale thermophoresis. We thus established a highly efficient approach to construct, express, and purify the recombinant protein of human TNFR1-ECD from a prokaryotic system. The antagonistic bioactivities in vitro indicate this protein as a prospective molecules for drug research against autoimmune diseases characterized by TNF-alpha overexpression. PMID- 30414970 TI - Abdominal pumping involvement in the liquid feeding of honeybee. AB - Honeybee drinking is facilitated by a "mop-like" tongue, which helps honeybees suck in the sucrose solution from the environment. However, the liquid-transport mechanism from the pharynx to the crop, especially the natural link between abdominal pumping and dipping behavior on the sucrose solution intake, remains obscure. A significant increase in abdominal pumping frequency is observed when honeybees drink the sucrose solution. Abdominal pumping exhibits a function other than respiration. This second function assists in driving the sucrose solution from the pharynx to the crop. We combine the experimental measurements using high speed video and X-ray phase contrast imaging with theoretical modeling to investigate the effect of abdominal pumping in liquid feeding of honeybee. Experimental results show that a honeybee performs abdominal pumping in the abdomen at a faster rhythm during sucrose solution feeding than during other physiological activities. In addition, the period of abdominal pumping is in concordance with that of dipping cycles. Theoretical analysis demonstrates that the abdomen, which is comparable with a micro pump, changes its volume rhythmically. Such expansion reduces pressure in the abdomen, which also reduces pressure in the crop and helps propel the sucrose solution from the pharynx to the crop. Abdominal pumping can help honeybees improve their feeding efficiency and save foraging time. This research work reveals a specific feeding mechanism of insects fed on sucrose solution and opens a new way for the design of microfluidic pump. PMID- 30414971 TI - Effects of corneal preservation conditions on human corneal endothelial cell culture. AB - The purpose of this study was to investigate the growth capacity of human corneal endothelial cells (HCEnCs) isolated from old donor corneas preserved in 4 different storage conditions. The following conditions were evaluated, A) cold storage (CS) (Optisol GS) for 7 days at 4 degrees C [n = 6]; B) organ culture (OC) (Cornea Max) for 7 days at 31 degrees C [n = 6]; C) OC for 28 days at 31 degrees C [n = 6] and; D) CS for 7 days at 4 degrees C followed by OC for 28 days at 31 degrees C [n = 6]. Following preservation, the Descemet membrane endothelium complex was peeled and digested using Collagenase-Type1 and was subsequently trypsinized before being plated into 2 wells (from each cornea) of an 8-well chamber slide. Media was refreshed every alternate day. The confluence rate (%) was assessed, and overall viability was determined using Hoechst, Ethidium Homodimer and CalceinAM staining. HCEnC-associated markers ZO-1, Na+/K+ ATPase, CD166 (Tag1A3), PRDX-6 (Tag2A12) and proliferative marker Ki-67 were used to analyse the cultures established from each condition. Donor tissues preserved in hypothermia (condition A) resulted in 9.3% +/- 4.0% trypan-blue positive cells (TBPCs) hence lower number of HCEnCs was plated. <1% TBPCs were observed in conditions B, C and D. Indicatively, confluence in conditions A, B, C and D was 14.0%, 24.8%, 23.4% and 25.4% respectively (p = 0.9836) at day 1. By day 9, HCEnCs established from all conditions became confluent except cells from condition A (94.2% confluence). All HCEnCs in the 4 conditions were viable and expressed HCEnC-associated markers. In conclusion, OC system has advantages over hypothermic media for the preservation of older donor corneas rejected for corneal transplant and deemed suitable for corneal endothelial cell expansion, with lower TBPCs before peeling and longer period of tissue preservation over hypothermic storage system. PMID- 30414972 TI - Physiological pressure enhances the formation of tight junctions in engineered and native corneal endothelium. AB - Cells and tissues are influenced by environmental conditions. In vivo, the corneal endothelium is subjected to hydrostatic intraocular pressure (IOP) and to the hydrokinetic pressure of the moving aqueous humor in the anterior chamber. In this paper, we used a corneal bioreactor to recreate the IOP condition and investigated the effect of the in vivo hydrodynamic environment of corneal endothelial cells on the formation of tight junctions. Native ex vivo corneas and engineered corneal endothelia subjected to pressure showed an increase in ZO-1 expression at the cell periphery. Pressure also improved the corneal transparency of engineered and native corneas. Corneal thickness was accordingly reduced from 926 +/- 70 MUm to 651 +/- 70 MUm for the engineered corneal endothelium and from 847 +/- 27 MUm to 571 +/- 23 MUm for the native endothelium. These results suggest that the hydrodynamic pressure of the anterior chamber is important for the cell junction integrity of the corneal endothelium. PMID- 30414973 TI - Kappa opioid receptors mediate yohimbine-induced increases in impulsivity in the 5-choice serial reaction time task. AB - Dynorphin (DYN), and its receptor, the kappa opioid receptor (KOR) are involved in drug seeking and relapse but the mechanisms are poorly understood. One hypothesis is that DYN/KOR activation promotes drug seeking through increased impulsivity, because many stimuli that induce DYN release increase impulsivity. Here, we systematically compare the effects of drugs that activate DYN/KOR on performance on the 5-choice serial reaction time task (5-CSRTT), a test of sustained attention and impulsivity. In Experiment 1, we determined the effects of U50,488 (0, 2.5, 5 mg/kg), yohimbine (0, 1.25, 2.5 mg/kg), and nicotine (0, 0.15, 0.3 mg/kg) on 5-CSRTT performance. In Experiment 2, we determined the effects of alcohol (0, 0.5, 1.0, 1.5 g/kg) on 5-CSRTT performance before and after voluntary, intermittent alcohol exposure. In Experiment 3, we determined the potential role of KOR in the pro-impulsive effects of yohimbine (1.25 mg/kg) and nicotine (0.3 mg/kg) by the prior administration of the KOR antagonist nor BNI (10 mg/kg). Premature responding, the primary measure of impulsivity, was reduced by U50,488 and alcohol, but these drugs had a general suppressive effect. Yohimbine and nicotine increased premature responding. Yohimbine-, but not nicotine-induced increases in premature responding were blocked by nor-BNI, suggesting that impulsivity induced by yohimbine is KOR dependent. This may suggests a potential role for KOR-mediated increases in impulsivity in yohimbine induced reinstatement. PMID- 30414974 TI - Deep brain stimulation targets for treating depression. AB - Deep brain stimulation (DBS) is a new therapeutic approach for treatment resistant depression (TRD). There is a preliminary evidence of the efficacy and safety of DBS for TRD in the subgenual anterior cingulate cortex, the ventral capsule/ventral striatum, the nucleus accumbens, the lateral habenula, the inferior thalamic peduncle, the medial forebrain bundle, and the bed nucleus of the stria terminalis. Optimal stimulation targets, however, have not yet been determined. Here we provide updated knowledge substantiating the suitability of each of the current and potential future DBS targets for treating depression. In this review, we discuss the future outlook for DBS treatment of depression in light of the fact that antidepressant effects of DBS can be achieved using different targets. PMID- 30414975 TI - (Pro)renin/renin receptor expression during normal and preeclamptic pregnancy in rats. AB - AIMS: Pregnancy is a physiological stage with profound cardiovascular changes leading to hypotension. Preeclampsia (PE) reverts these normal changes inducing hypertension. Renin-angiotensin system (RAS) has been related in PE genesis. It has been reported a novel receptor in the system, the Prorenin/Renin receptor (PRR), with several roles in renal and cardiovascular illnesses. It is not known, however, if PRR changes its expression or is activated during normal or PE complicated pregnancy on tissues intimately related to hypertension. So, the aim of this work was to describe PRR expression during normal and hypertensive pregnancy in rats. METHODS: We used a subrenal aortic coarctation (SRAC) model in rats. Atria, septum and ventricular heart tissue, aorta and renal tissue samples were homogenized and immunoblotted using anti-PRR and anti-PLZF antibodies. We also measured gene expression by RT-PCR. KEY FINDINGS: Hypertension and proteinuria were observed in SRAC-pregnant rats. In pregnant, non-SRAC rats, PRR showed a higher expression of both, gene and protein compared to non-pregnant rats in heart, aorta and kidney tissues. PE induces a very high expression of PRR in cardiac tissues and, on the contrary, decreases PRR expression in both, aorta and kidney. PLZF, a marker of PRR function, was augmented only in aorta and kidney in non-SRAC pregnant rats. In SRAC-pregnant rats, PLZF increment disappeared. SIGNIFICANCE: These findings indicate that PRR expression changes differently during pregnancy and PE in tissues related to cardiovascular functions and suggest a probable participation of the receptor during normal and preeclamptic pregnancy in the rat. PMID- 30414976 TI - Andrographolide enhances redox status of liver cells by regulating microRNA expression. AB - Andrographis paniculata Nees and its principal compound andrographolide are well known for exerting beneficial effects by modulating signaling pathways in different biological systems. Our earlier studies have demonstrated the ability of andrographolide as well as andrographolide enriched extracts to activate Nrf2/HO-1 pathway through adenosine A2a receptor. Present study investigated ability of andrographolide to regulate Nrf2 induced antioxidant defense systems by miRNAs using HepG2 cells. Andrographolide strongly induced Nrf2 which in turn modulated enzymes of glutathione and thioredoxin antioxidant systems. It also regulated crucial transcription factors viz. hepatocyte nuclear factor alpha (HNF4A) and tumor suppressor protein 53 (p53). Downregulation of HNF4A by andrographolide led to decrease in miRNAs regulating Heme oxygenase-1 (miR-377) and glutathione cysteine ligase (miR-433). Upregulation of p53 on the other hand led to increase in miRNAs regulating thioredoxin interacting protein (miR-17, miR 224) and glutathione peroxidase (miR-181a). Involvement of p53 and HNF4A in modulation of these miRNAs was confirmed by chromatin immunoprecipitation assay. Overall, the work reveals that andrographolide through modulation of p53 and HNF4A, regulates miRNAs leading to upregulation of HO-1, glutathione and thioredoxin systems. Andrographolide thus, can play a beneficial role in modulating antioxidant defense in oxidative stress induced diseases such as diabetes, ageing etc. PMID- 30414977 TI - Changing pattern of prevalence and genetic diversity of rotavirus, norovirus, astrovirus, and bocavirus associated with childhood diarrhea in Asian Russia, 2009-2012. AB - This hospital-based surveillance study was carried out in Novosibirsk, Asian Russia from September 2009 to December 2012. Stool samples from 5486 children with diarrhea and from 339 healthy controls were screened for rotavirus, norovirus, astrovirus, and bocavirus by RT-PCR. At least one enteric virus was found in 2075 (37.8%) cases with diarrhea and 8 (2.4%) controls. In the diarrhea cases, rotavirus was the most commonly detected virus (24.9%), followed by norovirus (13.4%), astrovirus (2.8%) and bocavirus (1.1%). Mixed viral infections were identified in 4.3% cases. The prevalence of enteric viruses varied every season. Rotavirus infection was distributed in a typical seasonal pattern with a significant annual increase from November to May, while infections caused by other viruses showed no apparent seasonality. The most common rotavirus was G4P[8] (56%), followed by G1P[8] (20.1%), G3P[8] (5.5%), G9P[8], G2P[4] (each 1.3%), six unusual (1.2%), and five mixed strains (0.5%). Norovirus GII.3 (66.5%) was predominant, followed by GII.4 (27.3%), GII.6 (3.7%), GII.1 (1.6%), and four rare genotypes (totally, 0.9%). Re-infection with noroviruses of different genotypes was observed in four children. The classic human astrovirus belonged to HAstV-1 (82%), HAstV-5 (8%), HAstV-4 (4.7%), HAstV-3 (4%) and HAstV-2 (1.3%). Consecutive episodes of HAstV-1 and HAstV-4 infections were detected in one child with an 8-month interval. Bocavirus strains were genotyped as HBoV2 (56.5%), HBoV1 (38.7%), HBoV4 (3.2%) and HBoV3 (1.6%). In the controls, norovirus strains belonged to GII.4 (n = 4), GII.1, GII.3, and GII.6, and HBoV2 strain were detected. Most of the detected virus isolates were characterized by a partial sequencing of the genomes. The genotype distribution of most common enteric viruses found in the Asian part of Russia did not differ considerably from their distribution in European Russia in 2009-2012. PMID- 30414978 TI - Smooth muscle cell differentiation from rabbit amniotic cells. AB - Amniotic fluid (AF) is the liquid layer that provides mechanical support and allows movement of the fetus during embryogenesis. Mesenchymal stem cells (MSCs), which have differentiation capacity, are also found in AF-derived cells at a low ratio. Smooth muscle cells (SMCs) play an important role in organ function and are frequently used in tissue engineering. We examined the differentiation of AF derived MSCs (AMSCs) into SMCs. AMSCs were sorted from cultured amniotic cells and differentiated into SMCs using differentiation agents, including platelet derived growth factor BB (PDGF-BB) and tumor growth factor beta (TGF-beta). Characterization of differentiated SMCs was confirmed morphologically, molecularly (via quantitative polymerase chain reaction [qPCR] and immunocytochemistry [ICC]), and functionally (using a contractile assay and fluo 4 calcium signaling assay). Poly(lactide-co-glycolide) (PLGA) scaffolds were fabricated, and the attachment capacity of AMSCs was assessed via scanning electron microscopy. AMSCs were successfully differentiated into SMCs. Our results indicate that AMSCs change their morphology and exhibit increased expression of ACTA2 and MYH11, which was confirmed via qPCR and ICC. Furthermore, functional experiments revealed that differentiated SMCs had both contraction ability and increased Ca2 concentration in the cytoplasm. Finally, PLGA scaffolds were prepared and AMSCs were successfully planted onto the scaffolds. The AMSCs fully differentiated into functional SMCs, and the PLGA polymer is a suitable scaffold material for AMSCs. With further clinical trials, AF-derived MSC-based SMC engineering may become a highly efficient treatment option. PMID- 30414979 TI - MicroRNA-sequencing data analyzing melanoma development and progression. AB - MicroRNAs (miRNAs) deregulated in melanoma are of growing importance in cancer research. We aimed to define the miRNAome of melanoma cell lines and primary melanocytes by RNA-Seq using identical cell lines as in a published miRNA expression study based on cDNA arrays. We identified 79 miRNAs, which are significantly deregulated during melanoma development. In addition, we could also determine 29 miRNAs being involved in melanoma progression. Interestingly, not all characterized miRNAs derived from cDNA array analyses of our and other groups could be found to be differentially expressed using RNA-Seq analyses, however, new miRNAs, formerly not associated with melanoma, were found to be strongly regulated. PMID- 30414981 TI - Molecular biomarkers of Graves' ophthalmopathy. AB - Graves' ophthalmopathy (GO), a complication of Graves' disease (GD), is typified by orbital inflammation, ocular tissue expansion and remodeling and, ultimately, fibrosis. Orbital fibroblasts are key effectors of GO pathogenesis exhibiting exaggerated inflammatory and fibroproliferative responses to cytokines released by infiltrating immune cells. Activated orbital fibroblasts also produce inflammatory mediators that contribute to disease progression, facilitate the orbital trafficking of monocytes and macrophages, promote differentiation of matrix-producing myofibroblasts and stimulate accumulation of a hyaluronan-rich stroma, which leads to orbital tissue edema and fibrosis. Proteomic and transcriptome profiling of the genomic response of ocular and non-ocular fibroblasts to INF-gamma and TGF-beta1 focused on identification of translationally-relevant therapeutic candidates. Induction of plasminogen activator inhibitor-1 (PAI-1, SERPINE1), a clade E member of the serine protease inhibitor (SERPIN) gene family and a prominent regulator of the pericellular proteolytic microenvironment, was one of the most highly up-regulated proteins in INF-gamma- or TGF-beta1-stimulated GO fibroblasts as well as in severe active GD compared to patients without thyroid disease. PAI-1 has multifunctional roles in inflammatory and fibrotic processes that impact tissue remodeling, immune cell trafficking and survival as well as signaling through several receptor systems. This review focuses on the pathophysiology of the GO fibroblast and possible targets for effective drug therapy. PMID- 30414980 TI - Molecular evaluation of BRAF gene mutation in thyroid tumors: Significant association with papillary tumors and extra thyroidal extension indicating its role as a biomarker of aggressive disease. AB - BACKGROUND: Somatic mutation of the BRAF gene is one to be the most commonly known genetic change in thyroid tumors especially papillary thyroid cancers. The T1799A activating point mutation is detected in >98% of the thyroid tumors, and result in substitution of amino acid valine at position 600 to glutamic acid. METHOD: In this study, we evaluated BRAF mutation in 95 Indian thyroid tumors by pyrosequencing assay. RESULTS: Overall, 36 cases (38%) showed presence of BRAF V600E mutation, while none of the cases showed V600 K mutation. BRAF mutation was found predominantly in female patients in comparison to males (38.4% vs. 36.4%, p = .86). Likewise, smaller sized tumors (<=2.0 cm) showed increased frequency of BRAF mutation as compared to larger sized tumors which were greater than equal to 2 cm (46% vs. 34.4%, p = .64). Furthermore, the frequency of BRAF mutations was significantly higher in conventional PTC tumor type in comparison to non conventional and other than PTC tumor type (56% vs. 35% vs. 4%, p = .0007). Notably, a significant correlation between presence of BRAF mutation and extra thyroidal extension was noted. Nevertheless, presence of BRAF mutation was neither associated with capsular/vascular invasion, nor with tumor necrosis. CONCLUSIONS: Pyrosequencing assay was found to be highly sensitive and accurate method for detecting BRAF point mutations. The frequency and distribution pattern of BRAF mutations is similar to global reports. Furthermore, association of BRAF mutation with extra thyroidal extension indicates its aggressive nature and thus can provide insights into the progression of thyroid tumors from less aggressive to poorly differentiated subtype. PMID- 30414982 TI - Auditory predictions shape the neural responses to stimulus repetition and sensory change. AB - Perception is a highly active process relying on the continuous formulation of predictive inferences using short-term sensory memory templates, which are recursively adjusted based on new input. According to this idea, earlier studies have shown that novel stimuli preceded by a higher number of repetitions yield greater novelty responses, indexed by larger mismatch negativity (MMN). However, it is not clear whether this MMN memory trace effect is driven by more adapted responses to prior stimulation or rather by a heightened processing of the unexpected deviant, and only few studies have so far attempted to characterize the functional neuroanatomy of these effects. Here we implemented a modified version of the auditory frequency oddball paradigm that enables modeling the responses to both repeated standard and deviant stimuli. Fifteen subjects underwent functional magnetic resonance imaging (fMRI) while their attention was diverted from auditory stimulation. We found that deviants with longer stimulus history of standard repetitions yielded a more robust and widespread activation in the bilateral auditory cortex. Standard tones repetition yielded a pattern of response entangling both suppression and enhancement effects depending on the predictability of upcoming stimuli. We also observed that regularity encoding and deviance detection mapped onto spatially segregated cortical subfields. Our data provide a better understanding of the neural representations underlying auditory repetition and deviance detection effects, and further support that perception operates through the principles of Bayesian predictive coding. PMID- 30414983 TI - Sensorimotor network segregation declines with age and is linked to GABA and to sensorimotor performance. AB - Aging is typically associated with declines in sensorimotor performance. Previous studies have linked some age-related behavioral declines to reductions in network segregation. For example, compared to young adults, older adults typically exhibit weaker functional connectivity within the same functional network but stronger functional connectivity between different networks. Based on previous animal studies, we hypothesized that such reductions of network segregation are linked to age-related reductions in the brain's major inhibitory transmitter, gamma aminobutyric acid (GABA). To investigate this hypothesis, we conducted graph theoretical analyses of resting state functional MRI data to measure sensorimotor network segregation in both young and old adults. We also used magnetic resonance spectroscopy to measure GABA levels in the sensorimotor cortex and collected a battery of sensorimotor behavioral measures. We report four main findings. First, relative to young adults, old adults exhibit both less segregated sensorimotor brain networks and reduced sensorimotor GABA levels. Second, less segregated networks are associated with lower GABA levels. Third, less segregated networks and lower GABA levels are associated with worse sensorimotor performance. Fourth, network segregation mediates the relationship between GABA and performance. These findings link age-related differences in network segregation to age-related differences in GABA levels and sensorimotor performance. More broadly, they suggest a neurochemical substrate of age-related dedifferentiation at the level of large-scale brain networks. PMID- 30414984 TI - Optimising neonatal fMRI data analysis: Design and validation of an extended dHCP preprocessing pipeline to characterise noxious-evoked brain activity in infants. AB - The infant brain is unlike the adult brain, with considerable differences in morphological, neurodynamic, and haemodynamic features. As the majority of current MRI analysis tools were designed for use in adults, a primary objective of the Developing Human Connectome Project (dHCP) is to develop optimised methodological pipelines for the analysis of neonatal structural, resting state, and diffusion MRI data. Here, in an independent neonatal dataset we have extended and optimised the dHCP fMRI preprocessing pipeline for the analysis of stimulus response fMRI data. We describe and validate this extended dHCP fMRI preprocessing pipeline to analyse changes in brain activity evoked following an acute noxious stimulus applied to the infant's foot. We compare the results obtained from this extended dHCP pipeline to results obtained from a typical FSL FEAT-based analysis pipeline, evaluating the pipelines' outputs using a wide range of tests. We demonstrate that a substantial increase in spatial specificity and sensitivity to signal can be attained with a bespoke neonatal preprocessing pipeline through optimised motion and distortion correction, ICA-based denoising, and haemodynamic modelling. The improved sensitivity and specificity, made possible with this extended dHCP pipeline, will be paramount in making further progress in our understanding of the development of sensory processing in the infant brain. PMID- 30414985 TI - Chemotherapy in elderly patients with pancreatic cancer: Efficacy, feasibility and future perspectives. AB - By 2030 70% of newly diagnosed pancreatic ductal adenocarcinoma (PDAC) will occur in older adults. Elderly patients, defined by the World Health Organization (WHO) as people older than 65 years, represent a heterogeneous group with different biological and functional characteristics that need personalized anticancer treatments. Since older patients are under-represented in randomized phase III trials, their management is mostly extrapolated from studies performed in younger patients, without robust evidence-based recommendations. However, data from retrospective studies and case-control series show that elderly may benefit from chemotherapy in both the adjuvant and advanced disease settings. Although with discordant results, gemcitabine-based treatment and dose-adapted fluorouracil combination regimens seem to be effective and well tolerated in this subset of patients. A proper balance of potential treatment benefits and side effects represent the crucial point for managing elderly patients with PDAC. Therefore an appropriate patient selection is essential to maximize the therapeutic benefit in the older population: randomized studies aiming to better standardizing fitness parameters and implementing the routine use of comprehensive geriatric assessments are strongly warranted. In this light, the detection of molecular prognostic markers able to detect patients who may benefit more from oncological treatments should be a primary endpoint of age-focused clinical trials. Altogether, the field of geriatric oncology will expand in the next years, and the clinical management of elderly patients affected by PDAC will become a major public health issue. PMID- 30414986 TI - Post-neoadjuvant strategies in breast cancer: From risk assessment to treatment escalation. AB - The post-neoadjuvant setting in early breast cancer represents an attractive scenario for adjuvant clinical trials, offering the opportunity to test new drugs or combinations in high-risk patients who did not achieve pathologic complete response after primary treatment. No standard therapies are routinely proposed to patients with residual disease after neoadjuvant chemotherapy and few trials have explored this setting. To date, only one randomized phase III study showed the benefit of additional capecitabine after neoadjuvant chemotherapy, and international guidelines recommend at least to consider its use, particularly for triple negative breast cancer. Therefore, the management of these patients is still a clinical challenge, with limited data supporting the use of an additional adjuvant non-cross-resistant chemotherapy. Escalation strategies are currently under evaluation, with new agents proposed as supplementary post-neoadjuvant treatment (e.g. platinum salts, capecitabine, poly ADP-ribose polymerase inhibitors, immune checkpoint inhibitors, cyclin-dependent kinase 4/6 inhibitors). Based on these premises, selection criteria are critical to identify patients who may benefit from post-neoadjuvant therapies, through the validation of prognostic and predictive biomarkers for a reliable risk assessment and estimation of benefit. The present review summarizes the efforts in introducing new therapeutic options for patients with breast cancer and residual disease after neoadjuvant treatment, with a particular focus on the ongoing clinical trials and useful biomarkers for risk stratification. PMID- 30414988 TI - Added value of plasma metabolomics to describe maternal effects in rat maternal and prenatal toxicity studies. AB - For regulatory purposes prenatal developmental toxicity (OECD No. 414) studies are routinely performed in our laboratories. The suitability of metabolomics as technology to identify maternal toxicity in such studies was investigated. Plasma was sampled from pregnant, non-fasted rats on gestation day 20 before cesarean section. Metabolite profiling was performed by gas- and liquid-chromatography tandem mass spectrometry techniques. The sensitivity of routinely examined maternal toxicity parameters (OECD No. 414) was compared to those of metabolome analysis. Evaluating 44 studies, the metabolome-derived NOEL was more sensitive in 45% of the cases in detecting maternal toxicity than the maternal NOAEL. Metabolome patterns indicative for liver effects and 4-hydroxyphenylpyruvate dioxygenase (HPPD) enzyme-inhibition were established in pregnant rats based on regulated metabolites using reference compounds. The HPPD inhibition and liver toxicity patterns in pregnant rats were reasonably comparable to the ones established in non-pregnant, fasted rats. Metabolomics is a useful tool for an improved and mechanism-based identification of maternal toxicity in maternal and prenatal toxicity studies. The data suggest that the current classical maternal toxicity parameters may underestimate the extent of effects of compounds on the dams. PMID- 30414987 TI - The regulation of positive and negative emotions through instructed causal attributions in lifetime depression - A functional magnetic resonance imaging study. AB - Adequate emotional control is essential for mental health. Deficiencies in emotion regulation are evident in many psychiatric disorders, including depression. Patients with depression show, for instance, disrupted neural emotion regulation in cognitive regulation regions such as lateral and medial prefrontal cortices. Since depressed individuals tend to attribute positive events to external circumstances and negative events to themselves, modifying this non-self serving attributional style may represent a promising regulation strategy. Spontaneous causal attributions are generally processed in medial brain structures, particularly the precuneus. However, so far no study has investigated neural correlates of instructed causal attributions (e.g. instructing a person to intentionally relate positive events to the self) and their potential to regulate emotions. The current study therefore aimed to examine how instructed causal attributions of positive and negative events affect the emotional experience of depressed individuals as well as its neural bases. For this purpose pictures of sad and happy faces were presented to 26 patients with a lifetime major depression (MDD) and 26 healthy controls (HC) during fMRI. Participants should respond naturally ("view") or imagine that the person on the picture was sad/happy because of them ("internal attribution") or because something else happened ("external attribution"). Trait attributional style and depressive symptoms were assessed with questionnaires to examine potential influential factors on emotion regulation ability. Results revealed that patients compared to controls show a non-self-serving trait attributional style (i.e. more external attributions of positive events and more internal attributions of negative events). Intriguingly, when instructed to apply specific causal attributions during the emotion regulation task, patients and controls were similarly able to regulate positive and negative emotions. Regulating emotions through instructed attributions (internal/external attribution>view) generally engaged the precuneus, which was correlated with patients' trait attributional style (i.e. more precuneus activation during external>view was linked to a general tendency to relate positive events to external sources). Up-regulating happiness through internal (compared to external) attributions recruited the parahippocampal gyrus only in controls. The down-regulation of sadness (external>internal attribution), in contrast, engaged the superior frontal gyrus only in patients. Superior frontal gyrus activation thereby correlated with depression severity, which implies a greater need of cognitive resources for a successful regulation in more severely depressed. Patients and controls did not differ in activation in brain regions related to cognitive emotion regulation or attribution. However, results point to a disturbed processing of positive emotions in depression. Interestingly, increased precuneus resting-state connectivity with emotion regulation brain regions (inferior parietal lobule, middle frontal gyrus) was linked to healthier attributions (i.e. external attributions of negative events) in patients and controls. Adequate neural communication between these regions therefore seem to facilitate an adaptive trait attributional style. Findings of this study emphasize that despite patients' dysfunctional trait attributional style, explicitly applying causal attributions effectively regulates emotions. Future research should examine the efficacy of instructed attributions in reducing negative affect and anhedonia in depressed patients, for instance by means of attribution trainings during psychotherapy. PMID- 30414989 TI - Deferasirox selectively induces cell death in the clinically relevant population of leukemic CD34+CD38- cells through iron chelation, induction of ROS, and inhibition of HIF1alpha expression. AB - Despite a high remission rate after therapy, only 40-50% of acute myeloid leukemia (AML) patients survive 5 years after diagnosis. The main cause of treatment failure is thought to be insufficient eradication of CD34+CD38- AML cells. In order to induce preferential cell death in CD34+CD38- AML cells, two separate events may be necessary: (1) inhibition of survival signals such as nuclear factor kappa-beta (NF-kappaB) and (2) induction of stress responses such as the oxidative stress response. Therefore, regimens that mediate both effects may be favorable. Deferasirox is a rationally designed oral iron chelator mainly used to reduce chronic iron overload in patients who receive long-term blood transfusions. Our study revealed that clinically relevant concentrations of deferasirox are cytotoxic in vitro to AML progenitor cells, but even more potent against the more primitive CD34+CD38- cell population. In addition, we found that deferasirox exerts its effect, at least in part, by inhibiting the NF kappaB/hypoxia-induced factor 1-alpha (HIF1alpha) pathway and by elevating reactive oxygen species levels. We believe that, pending further characterization, deferasirox can be considered as a potential therapeutic agent for eradicating CD34+CD38- AML cells. PMID- 30414990 TI - Development of doxorubicin hydrochloride loaded pH-sensitive liposomes: Investigation on the impact of chemical nature of lipids and liposome composition on pH-sensitivity. AB - This study investigates the impact of the chemical nature of lipids and additive on the formulation and properties of pH sensitive liposomes. The objective is to understand the respective role of the formulation parameters on the liposome properties in order to optimize the conditions for efficient encapsulation of doxorubicin (DOX). These liposomes should be stable at physiological pH, and disrupt in slightly acidic media such as the tumor microenvironment to release their DOX load. The major challenge for encapsulating DOX in pH sensitive liposomes lies in the fact that this drug is soluble at low pH (when the pH sensitive liposomes are not stable), but the DOX aqueous solubility decreases in the pH conditions corresponding to the stability of the pH-sensitive liposomes. The study of pH-sensitivity of liposomes was conducted using carboxyfluorescein (CF) encapsulated in high concentration, i.e. quenched, and following the dye dequenching as sensor of the liposome integrity. We studied the impact of (i) the chemical nature of lipids (dioleoyl phosphatidyl ethanolamine (DOPE), palmitoyl oleoyl phosphatidyl ethanolamine (POPE) and dimyristoyl phosphatidyl ethanolamine (DMPE)) and (ii) the lipid/stabilizing agent ratio (alpha-tocopheryl succinate), on the pH sensitivity of the liposomes. Optimized liposome formulations were then selected for the encapsulation of DOX by an active loading procedure, i.e. driven by a difference in pH inside and outside the liposomes. Numerous experimental conditions were explored, in function of the pH gradient and liposome composition, which allowed identifying critical parameters for the efficient DOX encapsulation in pH-sensitive liposomes. PMID- 30414991 TI - Selective blocking laminoplasty in cervical laminectomy and fusion to prevent postoperative C5 palsy. AB - BACKGROUND CONTEXT: Cervical laminectomy and fusion (CLF) is a common surgical option for multilevel cord compression. Postoperative C5 palsy occurrence after CLF has been a vexing problem for spine physicians. The posterior shift of the cord following laminectomy has been implicated as a major factor for postoperative C5 palsy, but attempts by spine surgeons to mitigate excessive shift while providing sufficient decompression have not been well reported. PURPOSE: To compare the incidence of postoperative C5 palsy after performing selective blocking laminoplasty concurrently with CLF to those of conventional CLF. STUDY DESIGN: A retrospective comparative study of prospectively collected data. PATIENT SAMPLE: Of 116 cervical myelopathy patients with degenerative cervical myelopathy, ossification of the posterior longitudinal ligament, and multilevel disc herniation, 93 patients (69 in group A [CLF group] and 24 in group B [selective blocking laminoplasty with CLF, CLF-S group]) were included in the study. OUTCOME MEASURES: The primary outcome measure was the occurrence of postoperative C5 palsy. Secondary end points included (1) clinical outcomes based on pain intensity, neck disability index (NDI), Japanese Orthopaedic Association (JOA) score, (2) radiologic outcomes including cervical alignment and fusion rate at 1 year and hardware complications, and (3) perioperative data (hospital stay, blood loss, and operative times). METHODS: We compared the occurrence of postoperative C5 palsy, as well as clinical, radiologic, and surgical outcomes, between the two groups at 1-year follow-up. RESULTS: The patients in both groups were statistically similar between the groups with respect to demographic characteristics such as age, sex, smoking status, body mass index, preoperative pathology, surgical segments, and the degree of the cervical lordosis. Postoperative C5 palsy developed in 9 of 61 patients (14%) in group A and in 0 of 24 patients (0%) in group B (CLF-S group) (p=.03). Postoperative neck pain, NDI, and JOA improvement were not significantly different between the two groups (p=.93, 0.90, and 0.79, respectively). Perioperative data did not differ significantly between the two groups. CONCLUSIONS: This study showed that performing selective blocking laminoplasty might lead to reducing the incidence of postoperative C5 palsy in CLF surgery. PMID- 30414992 TI - Optimal Satellite Rod Constructs to Mitigate Rod Failure Following Pedicle Subtraction Osteotomy (PSO): A Finite Element Study. AB - BACKGROUND CONTEXT: Pedicle subtraction osteotomy (PSO) is a challenging restoration technique for sagittal imbalance and is associated with significant complications. One of the major complications is rod fracture and there exists a need for a biomechanical assessment of this complication for various instrumentation configurations. PURPOSE: To evaluate and compare the global range of motion (ROM), rod stress distribution and the forces on the pedicle subtraction site in various instrumentation configurations using finite element analysis (FEA). STUDY DESIGN/SETTING: A computational biomechanical analysis METHODS: A previously validated osseoligamentous three-dimensional spinopelvic finite element model (T10-pelvis) was used to develop a 30 degrees PSO at the L3 level. In addition to the standard bilateral cobalt chromium primary rod instrumentation of the PSO model, various multi-rod configurations including constructs with medially, laterally and posteriorly affixed satellite rods and the short-rod technique were assessed in spinal physiological motions. T10-S1 global ROM, maximum von Mises stress on the rods and at the PSO level, factor of safety (yield stress of the rod material/maximum actual stress in the rod) and the load acting across the PSO site were compared between various instrumentation configurations. The higher the factor of safety the lesser the chances of rod failure. RESULTS: Among all multi-rod constructs, posteriorly affixed satellite rod construct showed the greatest motion reduction compared to the standard bilateral rod configuration followed by medially and laterally affixed satellite rod constructs. Compared to the standard bilateral rod configuration, recessed short-rod technique resulted in 4-49% reduction in T10-S1 ROM recorded in extension and lateral bending motions, respectively, while the axial rotation motion increased by approximately 31%. Considering the maximum stress values on the rods, the recessed short-rod technique showed the greatest factor of safety (FOS=4.1) followed by posteriorly (FOS=3.9), medially (FOS=3), laterally affixed satellite rod constructs (FOS=2.8), and finally the standard bilateral rod construct (FOS=2.7). By adding satellite rods, the maximum von Mises stress at the PSO level of the rods also reduced significantly and at this level resulted in the greatest factor of safety in the posteriorly affixed satellite rod construct. Compared to the standard bilateral rod construct, the load magnitude acting on the osteotomy site decreased by 11%, 16%, and 37% in the laterally, medially, and posteriorly affixed satellite rod constructs, respectively, and did not change with the short-rod technique. CONCLUSIONS: Adding satellite rods increases the rigidity of the construct, which results in an increase in the stability and the reduction of the global range of motion. Additionally, having satellite rods reduces the stress on the primary rods at the PSO level and shifts the stresses from this PSO region to areas adjacent to the side-by-side connectors. The data suggests a significant benefit in supplementing medial over lateral satellite rods at the PSO by reducing stress on the primary rods. Except the recessed short-rod technique, all other multi-rod constructs decrease the magnitude of the load acting across the osteotomy region, which could cause a delayed or non-union at the PSO site. CLINICAL SIGNIFICANCE: The study evaluates the mechanical performance of various satellite rod instrumentation configurations following PSO to predict the risk factors for rod fracture and thereby mitigate the rate of clinically relevant failures. PMID- 30414993 TI - The role of insulin-like growth factor 1 in ALS cell and mouse models: A mitochondrial protector. AB - Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disorder, but little is known about the exact causes and pathophysiology of this disease. In transgenic mouse models of ALS, mitochondrial abnormalities develop during the disease and might contribute to the progression of ALS. Gene therapy was recently shown to induce beneficial effects. For example, the delivery of human insulin like growth factor-1 (hIGF-1) by self-complementary adeno-associated virus (AAV) vectors has been shown to prolong the lifespan of ALS transgenic mice. However, the function of IGF-1 in mitochondria has not been systematically studied in ALS models. In this study, scAAV9-hIGF-1 was intramuscularly injected into transgenic SOD1G93A mice and administered to cell lines expressing the ~25-kDa C-terminal fragment of transactive response DNA-binding protein (TDP-25). The mitochondrial electrical transmembrane potential was hyperpolarized, and electron microscopy findings revealed that the abnormal mitochondria were transformed. Moreover, the intrinsic mitochondrial apoptotic process was modified through the upregulation of anti-apoptotic proteins (B-cell lymphoma-extra large (Bcl-xl) and B-cell lymphoma-2 (Bcl-2)), the downregulation of pro-apoptotic proteins (Bcl-2 associated x protein (Bax) and Bcl-2 homologous antagonist killer (Bak)) and a reduction in mitochondrial cytochrome c release. Mitophagy was also increased after scAAV9-hIGF-1 treatment, as evidenced by a decrease in the p62 level and an increase in the LC3-II level. Furthermore, the clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) system was used to delete the IGF-1 gene in SOD1G93A model mice via an intrathecal injection of scAAV9-sgRNA-IGF1-Cas9 to confirm these findings. The protective effect of IGF-1 on the mitochondria decreased after genetic deletion. These novel findings demonstrate that IGF-1 strongly protects mitochondria from apoptosis and upregulates mitophagy in mouse and cell models of ALS. Therefore, therapies that specifically protect mitochondrial function might be promising strategies for treating ALS. PMID- 30414994 TI - Visual mismatch negativity and representational momentum: Their possible involvement in the same automatic prediction. AB - To maintain real-time interaction with a dynamically changing visual object, the brain is thought to automatically predict the next state of the object based on the pattern of its preceding changes. A behavioral phenomenon known as representational momentum (RM: forward displacement of the remembered final state of an object along its preceding change pattern) and an electrophysiological phenomenon known as visual mismatch negativity (VMMN: an event-related brain potential component that is elicited when an object suddenly deviates from its preceding change pattern) have each indicated the existence of such automatic predictive processes. However, there has been no direct investigation of whether or not these phenomena are involved in the same predictive processes. To address this issue, the present study examined the correlation between RM and VMMN by using a hybrid paradigm in which both phenomena can be measured for the rotation of a bar. The results showed that the magnitudes of RM and VMMN were positively correlated; participants who exhibited greater RM along the regular rotation of a bar tended to show greater VMMN in response to sudden reversal embedded in the regular rotation of a bar. This result provides empirical support for the hypothesis that RM and VMMN may be involved in the same automatic predictive processes. Due to the methodological limitations of a correlation analysis, this hypothesis has to be carefully tested in future studies that examine the relationship between RM and VMMN from multiple perspectives. PMID- 30414995 TI - Long-term adherence to growth hormone therapy in a large health maintenance organization cohort. AB - OBJECTIVE: Adherence to treatment regimen is a key factor in the success of Growth Hormone (GH) therapy. Our objective was to assess the long time adherence to treatment in a large cohort of patients. DESIGN: It is a retrospective study. The data was collected from a single central computerized data center well maintained and checked for quality. All patient aged 1-16 years, treated with GH during 2006-2015 for >2 years, who were insured by "Clalit" Health Maintenance Organization. Adherence was measured by the number of months of pharmacy purchased GH annually: good (11-12), moderate (7-10), and poor (<7) months per year. RESULTS: 2263 patients (59% males) were treated for >2 years. Mean age at treatment initiation was 8.3 +/- 3.6 years, 74% were secular Jews, 6.8% ultra religious Jews and 18.9% of Arab origin. Only 30% of patients had good adherence to GH therapy. Patients who started treatment before age 8 years had poorest adherence rate. No association was found between adherence to GH therapy and gender or socioeconomic status. In a multivariate analysis (gender, age groups, ethnicity and clinic SES) we found the ultra-religious population had higher risk for non adherence (OR 2.16, CI 95% 1.46-3.19). The poorest adherence by age was in the youngest patients. In patients treated for >5 years (n = 668), adherence rate declined slightly over the years. CONCLUSIONS: Long term adherence to GH therapy is suboptimal. Measures for improving adherence especially among younger and ultra- religious patients are needed. PMID- 30414996 TI - Surgical, Clinical, and Functional Outcomes in Patients with Rectosigmoid Endometriosis in the Grey Zone: 13-Year Long-term Follow-up. AB - OBJECTIVES: To date, there is no consensus regarding the choice between radical (segmental resection) or conservative (shaving, discoid excision) surgical management for rectosigmoid endometriosis (RSE), in particular for patients with preoperative intermediate risk of bowel segmental resection (the grey zone). The objective was to compare long-term surgical, clinical, and functional outcomes between conservative and radical surgery in patients with RSE and preoperative intermediate risk of segmental resection. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Endometriosis tertiary level referral center, Sant'Orsola Academic Hospital, Bologna, Italy. PATIENTS: Three hundred and ninety-two patients with RSE presented for complete macroscopic surgical excision between January 2004 and January 2017. INTERVENTION: Assessment of laparoscopic bowel shaving, discoid or segmental resection for the treatment of RSE. MEASUREMENTS AND MAIN RESULTS: Patients were divided into three groups according to surgical technique: shaving (297/392, 75.8%), discoid excision (33/392, 8.4%) and segmental resection (62/392, 15.8%). Preoperative characteristics, surgical data, short- and long-term complications, rate of proven and suspected recurrence were assessed. The segmental resection group showed more short-term complications compared with the discoid group and shaving group (17.7% vs 9.1% vs 5.4%, respectively; p = .004). Median follow-up time was 43 months (range, 12-163). Suspected and proven RSE recurrence rates showed no statistically significant difference among the three groups. There were no significant differences concerning the rate of de novo chronic constipation and urinary retention. CONCLUSION: Conservative surgery is preferred to radical surgery in patients with RSE in the grey zone risk category because it results in similar suspected and proven RSE recurrence rates and is associated with less short-term complications. PMID- 30414997 TI - Low Grade Appendiceal Mucinous Neoplasm Diagnosed During Exploratory Laparoscopy for a Presumed Pelvic Mass. AB - STUDY OBJECTIVE: To demonstrate a surgical video of laparoscopic management of an appendiceal mass preoperatively misdiagnosed as a pelvic mass DESIGN: A step-by step explanation of the diagnosis and laparoscopic management of an appendiceal mass using an instructive video (Canadian Task Force Classification III). SETTING: A teaching hospital in New Haven CT, USA. PATIENT: 53-year old multiparous peri-menopausal patient underwent work-up for pelvic pain. Pelvic imaging revealed a 72 * 35 * 28mm cystic structure abutting the uterine fundus with thin partial septum but no mural nodules or concomitant pelvic lymphadenopathy. INTERVENTION: Exploratory laparoscopy showed unremarkable pelvic anatomy. After the entire small bowel was run, the cystic structure abutting the uterine fundus was deemed to be an appendiceal mass. The observed convergence of the three taeniae coli at the junction of the cecum with the cystic mass confirmed the diagnosis. For laparoscopic resection, the umbilical fold port site was extended to 12mm to introduce the Endo GIA stapler. The appendiceal mass was stabilized in view with a laparoscopic grasper and the stapler was articulated to fit the base of the appendix without narrowing the lumen of the cecum. The specimens were removed through the umbilical port site in a laparoscopic bag without spillage. MAIN RESULTS: Pathology returned low grade appendiceal mucinous neoplasm with no evidence of invasion. Patient was managed appropriately with laparoscopic appendectomy and discharged home on the day of surgery. CONCLUSION: Appendiceal masses should be considered in the differential diagnosis of a presumed pelvic mass. For low-grade appendiceal mucinous neoplasms that are diagnosed intra-operatively, laparoscopic resection without spillage or rupture is a feasible and appropriate approach for treatment (1,2,3). PMID- 30414998 TI - Barbed Suture Versus Conventional Suture for Vaginal Cuff Closure in Total Laparoscopic Hysterectomy: A Randomized Controlled Clinical Trial. AB - STUDY OBJECTIVE: To determine the surgical time, suture time, presence of postoperative dyspareunia, and complications that occur after closing the vaginal cuff with a barbed suture compared with conventional suture. DESIGN: A randomized, controlled clinical trial (Canadian Task Force classification I). SETTING: Private gynecological clinic in Medellin, Colombia. PATIENTS: 150 women who underwent total laparoscopic hysterectomy for benign pathology. INTERVENTIONS: The patients underwent total laparoscopic hysterectomy with intracorporeal closure of the vaginal cuff and were randomized to two groups, one using a barbed suture (V-LocTM 90; Medtronic/Covidien; New Haven, CT). and the other using polyglactin 910 (coated VICRYL suture; Ethicon/Johnson & Johnson; New Brunswick, NJ). MEASUREMENTS AND MAIN RESULTS: The total operative time, closing time of the vaginal vault, presence of complications in the cuff, and incidence of postoperative dyspareunia were recorded. The patients were evaluated at a postoperative office visit 2 weeks after the procedure and at 24 weeks, a telephone interview was conducted. Seventy-five patients were included in the barbed suture group, and 75 patients in the polyglactin 910 group. The average time to complete the suture of the vaginal cuff was 12.01 minutes (+/- 5.37 standard deviation [SD]) for the barbed suture group versus 13.49 minutes (+/- 6.48) in the polyglactin 910 group (-0.44 to 3.4 95% confidence interval [CI]; p = .130). Blood loss was 31.56 (+/- 22.93) mL in the barbed suture group versus 30.82 (+/- 21.75) mL in the polyglactin 910 group (-7.95 to 6.47 95% CI; p = .840). The frequency of postoperative events such as hematoma, cellulitis, cuff dehiscence, fever, emergency consultation, and hospitalization was not statistically significant between groups. No statistically significant difference was found regarding deep dyspareunia at 24 postoperative weeks. CONCLUSION: No differences were found in surgical time or frequency of adverse events when comparing patients following vaginal cuff closure with barbed suture versus polyglactin 910. PMID- 30414999 TI - Surgical Management and Prevention of Ovarian Remnant. AB - STUDY OBJECTIVE: To provide surgeons with surgical techniques necessary for management and prevention of ovarian remnant syndrome. DESIGN: Instructional video (Canadian Task Force classification III). SETTING: Academic medical center. INTERVENTION: Surgical dissection and retroperitoneal anatomy. MEASUREMENTS AND MAIN RESULTS: Ovarian remnant syndrome occurs when residual ovarian tissue inadvertently remains in situ after salpingo-oophorectomy [1-4]. It can result in pelvic pain and pelvic mass [1-4]. Risk factors include endometriosis, adhesive disease, pelvic inflammatory disease, and prior pelvic surgery [1-4]. Ovarian remnant can also occur as a result of ovarian stroma extending up to 1.4 cm into the infundibulopelvic ligament beyond the visible margin [5]. Medical management and radiotherapy are treatment options but do not provide the definitive management that surgery affords [1-4]. Surgery also avoids missing a potential malignancy within the remnant tissue [1-4]. This video demonstrates the surgical techniques necessary to treat and prevent this condition, including key retroperitoneal anatomy. Mayo Clinic Institutional Review Board approval was not required for this video article. CONCLUSION: Both treatment and prevention of ovarian remnant syndrome follow the same basic surgical principles, including high ligation of the infundibulopelvic ligament, retroperitoneal dissection, and excision of all peritoneum and tissue adherent to the ovary. PMID- 30415000 TI - Visuospatial word search task only effective at disrupting declarative memory when prediction error is present during retrieval. AB - Prediction error is recognized as a necessary boundary condition for memory reactivation and reconsolidation. Furthermore, behavioral manipulations (e.g., visuospatial interference tasks, like Tetris) have been shown to be effective at disrupting reactivated memory. In the present study, participants created a memory with positive valence by viewing an uplifting video of a young boy who built an arcade out of cardboard boxes. Two weeks later, memory for the video was reactivated with a prediction error (i.e., new information was added) or without a prediction error (i.e., no new information was added). Following memory reactivation, participants completed a novel visuospatial interference task (i.e., a complex word search) or a control task (i.e., sitting quietly). One week following reactivation, participants completed two memory tests (i.e., free recall and recognition). Results showed that the visuospatial interference task was effective in reducing free recall, but only in the group that received a prediction error during retrieval. No other significant differences were observed, including on the recognition test. These results expand the literature on reconsolidation by showing that destabilization of memory with a positive emotional valence requires a prediction error and that a novel visuospatial interference task (i.e., complex word search) is an effective behavioral manipulation for decreasing free recall. PMID- 30415001 TI - Impact of Piperacillin/Tazobactam on Nephrotoxicity in Patients with Gram negative Bacteremia. AB - Piperacillin/tazobactam has been associated with nephrotoxicity in patients receiving vancomycin. Its impact on nephrotoxicity in patients with gram-negative bacteremia (GNB) is unclear. This study aims to evaluate piperacillin/tazobactam's impact on nephrotoxicity in patients with GNB. Our retrospective cohort included patients >=18 years of age who received >=48 hours of therapy for bacteremia due to Escherichia coli, Pseudomonas aeruginosa, Enterobacter sp., Klebsiella sp., Acinetobacter sp., or Stenotrophomonas maltophila from 1/1/2008-8/31/2011. Patients with a baseline serum creatinine (SCr) >=3.5 mg/dL, polymicrobial infection, or recurrent bacteremia were excluded. Nephrotoxicity was defined as a >=0.5 mg/dL increase in SCr or >=50% increase from baseline for >=2 consecutive days. Any variable demonstrating a 10% change in the exposure effect was kept in the final model. All variables biologically reasonable causes of nephrotoxicity were also considered for inclusion. The median age of the cohort (n = 292) was 76 years and 38% had a cancer diagnosis. ICU residence was also common (22%) upon the identification of the GNB. There was no difference in nephrotoxicity incidence based on days of piperacillin/tazobactam received (0d: 13.6%, 1-2d: 14.7%, 3-4d: 6.9%, 5+d: 16.7%; p = 0.71). In the multivariable analysis, baseline SCr, total body weight, and vasopressor use were independently associated with nephrotoxicity. Duration of piperacillin/tazobactam therapy was not associated with nephrotoxicity in the multivariable (1-2d: OR 0.91, 95% CI 0.39-2.12; 3-4d: OR 0.48, 95%CI 0.10-2.46; 5+d: OR 0.57, 95%CI 0.11-3.02) analysis. In our cohort of patients with bacteremia, the duration of piperacillin/tazobactam was not associated with nephrotoxicity. PMID- 30415002 TI - Ceftolozane/tazobactam for the treatment of serious P. aeruginosa infections: a multicenter nationwide clinical experience. AB - To describe the largest clinical experience using ceftolozane-tazobactam (C/T) for treatment of different type of Pseudomonas aeruginosa infections. A retrospective study was performed at 22 hospitals in Italy from June 2016 to March 2018. All adult patients treated with at least 4 days of C/T were enrolled. A successful clinical outcome was defined as complete resolution of clinical signs and symptoms related to P. aeruginosa infection and lack of microbiological evidence of infection. C/T treatment was documented in 101 patients with diverse infections, including nosocomial pneumonia (31.7%), acute bacterial skin and skin structure infections (30.8%), complicated UTI (13.8%), complicated IAI (12.8%), bone infections (8.9%) and primary bacteraemia (7.9%). Almost half of P.aeruginosa strains were XDR (51%), with 78% of the isolates resistant to at least one carbapenem. C/T was used as first-line therapy in 39 patients (34.6%). When used as second or later line, the most common reasons for discontinuation of previous antibiotics were in vitro resistance of P.aeuruginosa strain and clinical failure of previous therapy. Concomitant antibiotics was reported in 35% of patients. C/T doses were 1.5 grams/8h in 70 patients (69.3%) and 3 grams/8h in 31 patients (30.7%); the median duration of C/T therapy was 14 days. The overall clinical success was 83.2%. Significant lower success rates were observed in patients with sepsis or those receiving continuous renal replacement therapy. Mild adverse events were reported in only three patients. C/T demonstrated a favourable safety and tolerability profile regardless of the type of infection. Clinicians should be aware of the risk of clinical failure with C/T therapy in septic patients receiving continuous renal replacement therapy. PMID- 30415004 TI - Stability of cefiderocol against clinically significant broad-spectrum oxacillinases. PMID- 30415003 TI - Groups of coevolving positions provide drug resistance to Mycobacterium tuberculosis: a study using targets of first-line antituberculosis drugs. AB - BACKGROUND: Drug resistance has been associated with point mutations in the coding regions, which lead to an altered protein sequence and structure. Such changes have been seen as isolated events which occur at various positions in a sequence. However, we hypothesize that it is not a single mutation at a specific position instead a group of positions which coevolve in a correlated fashion to increase the fitness of target protein against a drug. METHODS: Scientific literature was searched to identify drug resistance genes relevant to the current first-line multidrug regimen (Isoniazid, Rifampicin, Ethambutol, and Pyrazinamide), used to treat tuberculosis caused by Mycobacterium tuberculosis. We screened the selected protein sequences of M. tuberculosis drug resistance genes using a bioinformatics approach to detect the groups of coevolving positions. Moreover, attempts were made to map the identified coevolving positions on already known mutations. The coevolving amino acids detected were also mapped on the secondary structure and active site residues. FINDINGS: The groups of coevolving amino acids present at important structural and functional positions were successfully detected in the targets of first-line antituberculosis drugs. The algorithmically characterized genetic mutations and the lineage-specific SNPs detected earlier in drug resistance genes of M. tuberculosis complex genomes were also found in the identified coevolving groups. Mapping of coevolving positions to secondary structure of proteins clearly indicates the preference of amino acid residues in helix to coevolve. Moreover, the active site residues of some candidate proteins were also found in coevolving groups. INTERPRETATION: The coevolving groups detected in this study will be useful to get new insight on the molecular and evolutionary basis of drug resistance. Apart from this, the present work provides an important first step towards finding solutions of multidrug resistance problem through coevolution analysis of proteins which in-turn help to develop new drug regimen against pathogens including M. tuberculosis. PMID- 30415005 TI - Inhibition of miR-423-5p suppressed prostate cancer through targeting GRIM-19. AB - OBJECTIVE: To determine the effect of miR-423-5p on the progression of prostate cancer (PC). METHODS: miR-423-5p and GRIM-19 expressions were detected by qRT-PCR and western blot. PC cell proliferation was measured by MTT assay. PC cell apoptosis was detected by flow cytometry. Dual luciferase reporter assay was used to confirm the interaction between miR-423-5p and GRIM-19. RESULTS: Compared with normal prostate tissues and prostate epithelial cell HPrEC, miR-423-5p was up regulated in human PC tissues and PC3 cells, whereas GRIM-19 expression was decreased. Inhibition of miR-423-5p suppressed PC3 cell proliferation, promoted PC3 cell apoptosis, and decreased anti-apoptosis protein BCL-2 expression. GRIM 19 was a target of miR-423-5p, and GRIM-19 was negatively regulated by miR-423-5p in PC3 cells. In addition, miR-423-5p knockdown inhibited the proliferation and promoted the apoptosis of PC3 cells through GRIM-19. In vivo experiments showed that miR-423-5p inhibitor administration reduced tumor volume, down-regulated miR 423-5p and GRIM-19 expressions in PC tissues of nude mice. CONCLUSION: Inhibition of miR-423-5p suppressed PC through targeting GRIM-19. PMID- 30415006 TI - Overexpression of long non coding RNA CA3-AS1 suppresses proliferation, invasion and promotes apoptosis via miRNA-93/PTEN axis in colorectal cancer. AB - AIMS: In previous studies, dysregulated lncRNAs in colorectal cancer were screened using RNA-sequencing by Atsushi Yamada. In these dysregulated lncRNAs, a long non coding RNA named CA3-AS1 attracted our attention due to its high conservation and fold change, which was downregulated in colorectal cancer. In this study, we aimed to investigate the function and mechanism of lncRNA CA3-AS1 in colorectal cancer. METHODS: RT-PCR was used to detect CA3-AS1, miR-93, PTEN mRNA expression. Apoptosis, proliferation, and invasion were examined by western blotting, CCK8, transwell assay to evaluate the function of RPL34-AS1. RESULTS: We found that lncRNA CA3-AS1 mainly located in cytoplasm, and overexpression of lncRNA CA3-AS1 inhibits cell proliferation, invasion and promotes cell apoptosis. Our results revealed that miR-93 could directly bind to CA3-AS1, and verified the oncogenic role of miR-93. Furthermore, we found that miR-93 played its role through regulating PTEN, the tumor-suppressor gene, which was inversely correlated with miR-93. CONCLUSION: Based on the investigation, lncRNA CA3-AS1 inhibited the proliferation, invasion and apoptosis, which could be blocked by overexpression of miR-93. In summary, our study demonstrated that CA3-AS1/miR 93/PTEN axis may play an important role in the regulation of colorectal cancer progression, which provides new insights for clinical treatment. PMID- 30415007 TI - Combined treatment of ABT199 and irinotecan suppresses KRAS-mutant lung cancer cells. AB - Lung cancer has become the most prevalent neoplasm throughout the world with 1,2 million deaths per year. Molecular genetic analyses have suggested that KRAS mutation is much more frequency in NSCLC. Significant challenges are to develop selective pharmacological inhibitors for RAS mutation to treat cancers driven. In our study, we used the combinatorial strategy to target oncogene addiction for RAS-mutant cells and the data showed that ABT199 and irinotecan leads to RAS mutant lung cancer cell growth inhibition and enhanced apoptosis in vitro and in vivo. Furthermore, PI3K/AKT signaling was down-regulated by the combination in KRAS-mutant lung cancer cells. Importantly, the effects of ABT199 and irinotecan combination are synergistic on the RAS-mutant lung cancer cells. Therefore, the combination suggests a strong synergy in vivo and a potential avenue for therapeutic treatment of KRAS-mutant cancers which are otherwise difficult targeted by small molecules. PMID- 30415008 TI - Expression profile analysis identifies the long non-coding RNA landscape and the potential carcinogenic functions of LINC00668 in laryngeal squamous cell carcinoma. AB - In order to explore the differentially expressed long non-coding RNAs (lncRNAs) in laryngeal squamous cell carcinoma (LSCC), the GSE84957 lncRNA expression profile was included in the present study through data mining in the National Center for Biotechnology Information/Gene Expression Omnibus (NCBI/GEO). Then, the differentially expressed genes (DEGs) of LSCC (1646 lncRNAs and 2713 mRNAs, fold change >= 2, P <= 0.05) were identified from the GSE84957 dataset using bioinformatics analysis. Of the 10 selected differentially expressed lncRNAs, the expression of 7 lncRNAs were verified by qRT-PCR method. Then, LINC00668, a potential carcinogenic lncRNA, was screened out by narrowing down the screening criteria (fold change >= 4, P <= 0.01). Furthermore, correlation analysis demonstrated that expression levels of LINC00668 were associated with age, pathological differentiation degree, T stage, clinical stage and cervical lymph node metastasis. Moreover, a series of bioinformatics tools and in vitro experiments proved that knockdown of LINC00668 inhibited the proliferation, migration and invasion ability of LSCC cells. The present study identified the lncRNAs landscape of LSCC through data mining and bioinformatics analysis, and verified oncogenic LINC00668, which may play important roles in promoting LSCC cells proliferation, migration and invasion. PMID- 30415009 TI - Expression and prognosis analyses of forkhead box A (FOXA) family in human lung cancer. AB - Despite advances in early diagnosis and treatment, cancer still remains the major reason of mortality worldwide. The forkhead box A (FOXA) family is reported to participate in diverse human diseases. However, little is known about their expression and prognostic values in human lung cancer. Herein, we conducted a detailed cancer vs. normal analysis. The mRNA expression levels of FOXA family in numerous kind of cancers, including lung cancer, were analyzed using the Oncomine and GEPIA database. We observed that the mRNA expression levels of FOXA1, and FOXA3 were all increased while FOXA2 were decreased in most cancers compared with normal tissues, especially in lung cancer. Moreover, the expression levels of FOXA1, and FOXA3 are also highly expressed, while FOXA2 were decreased in almost all cancer cell lines, particularly in lung cancer cell lines, analyzing by Cancer Cell Line Encyclopedia (CCLE) and EMBL-EBI databases. Furthermore, the LinkedOmics database was used to evaluate the prognostic values, indicating that higher expression of FOXA1, FOXA3 indicated a poor overall survival (OS), while increased FOXA2 revealed a better OS in lung cancer. To conclusion, FOXA family showed significant expression differences between cancer and normal tissues, especially lung cancer, and FOXA1, FOXA3 could be promising prognostic biomarkers for lung cancer. PMID- 30415010 TI - In-depth study of lin-28 suggests selectively conserved let-7 independent mechanism in Drosophila. AB - Lin-28 is a conserved RNA-binding protein that is involved in a wide range of developmental processes and pathogenesis. At the molecular level, Lin-28 blocks the maturation of let-7 and regulates translation of certain mRNA targets. In Drosophila, Lin-28 is reported to play a role in oogenesis, muscle formation, and the symmetric division of adult intestinal stem cells. In this study, we characterized Drosophila Lin-28 through a detailed examination of its temporal and spatial expression. Lin-28 is specifically expressed in embryonic nervous and cardiac systems. However, loss or gain of lin-28 function does not cause any abnormality during embryonic development. Instead, the ubiquitous overexpression of Lin-28 leads to lethality from late larval stage to pupal stage, and eye specific overexpression causes severe cell loss. The ectopic expression of human Lin28A has the same effect as Drosophila Lin-28, indicating functional conservation in Lin-28 orthologs. We also examined the effect of Lin-28 on let-7 biogenesis through the mutant and overexpression analysis. Lin-28 does not block the production of let-7 in Drosophila, which suggests the let-7 independent pathway as a molecular mechanism of Lin-28. PMID- 30415011 TI - Dmrt1 directly regulates the transcription of the testis-biased Sox9b gene in Nile tilapia (Oreochromis niloticus). AB - The Nile tilapia Sox9b gene is characterized as a homolog of the mammalian Sox9 gene, which exhibits testis-biased expression and is involved in testis development. However, the transcriptional regulation of the Sox9b gene is poorly understood. In this study, we demonstrated that the male sex differentiation gene doublesex and mab-3 related transcription factor 1 (Dmrt1) was predominantly expressed in the Nile tilapia testis and that Dmrt1 knockdown in the Nile tilapia decreased the expression of the Sox9b gene in the testis. An in silico analysis predicted that the proximal promoter of the Nile tilapia Sox9b gene had two potential cis-regulatory elements (CREs) for the Dmrt1 transcription factor. Together, a luciferase reporter analysis and site-directed mutagenesis revealed that Dmrt1 increased the transcriptional activity of the Nile tilapia Sox9b promoter via a specific CRE near the translation start site. A chromatin immunoprecipitation (ChIP) analysis and an electrophoretic mobility shift assay (EMSA) confirmed that Dmrt1 could directly bind to this specific CRE for Dmrt1 in the Nile tilapia Sox9b promoter. Taken together, our results demonstrate that the male sex-differentiation factor Dmrt1 positively regulates the transcription of the Nile tilapia Sox9b gene by directly binding to a specific CRE within the Sox9b promoter. PMID- 30415012 TI - Accommodative esotropia and Brown syndrome in a girl with recessive geleophysic dysplasia. PMID- 30415013 TI - Use of Heart Failure Exacerbating Medications Among Adults with Heart Failure. PMID- 30415014 TI - Improvement in Biventricular Cardiac Function Following Ambulatory Counterpulsation. AB - BACKGROUND: The NuPulseCV intravascular ventricular assist system (iVAS), which consists of a durable pump placed through the subclavian artery, provides extended duration ambulatory counterpulsation. This study investigated the effect of iVAS on biventricular cardiac function. METHODS AND RESULTS: We reviewed all heart failure patients who received iVAS implantation as a bridge to transplantation or a bridge to candidacy since April 2016 as part of the iVAS first-in-human and subsequent Feasibility study. We compared data of transthoracic echocardiography performed just before implantation (without iVAS support) and again at 30 days or just before explantation (on iVAS support). Eighteen patients (58.8 +/- 7.4 years old and 15 males) received iVAS support for 53 +/- 43 days. Fourteen patients were bridged to cardiac replacement therapy after 35 +/- 19 days and the remaining 4 patients have been supported for 118 +/- 41 days. There were no deaths during iVAS support. At 30 days, there was a significant improvement in left ventricular ejection fraction (16.5 +/- 11.9% vs. 24.4 +/- 12.8%; p=0.007) and marked reduction in left atrial size (62.7 +/- 35.7 vs. 33.8 +/- 17.2 mL/m2; p<0.001). Right ventricular fractional area change improved dramatically (25.4 +/- 12.9% vs. 42.1 +/- 12.4%; p<0.001). All other right ventricular and right atrial parameters improved significantly as well (size, tricuspid annular plane systolic excursion, and velocity of tricuspid annular systolic motion). CONCLUSIONS: Improvement in biventricular cardiac function was observed following 30 days of iVAS support. Further studies should examine the use of this technology as a bridge to recovery. PMID- 30415015 TI - Physical blood-brain barrier disruption induced by focused ultrasound does not overcome the transporter-mediated efflux of erlotinib. AB - Overcoming the efflux mediated by ATP-binding cassette (ABC) transporters at the blood-brain barrier (BBB) remains a challenge for the delivery of small molecule tyrosine kinase inhibitors (TKIs) such as erlotinib to the brain. Inhibition of ABCB1 and ABCG2 at the mouse BBB improved the BBB permeation of erlotinib but could not be achieved in humans. BBB disruption induced by focused ultrasound (FUS) was investigated as a strategy to overcome the efflux transport of erlotinib in vivo. In rats, FUS combined with microbubbles allowed for a large and spatially controlled disruption of the BBB in the left hemisphere. ABCB1/ABCG2 inhibition was performed using elacridar (10 mg/kg i.v). The brain kinetics of erlotinib was studied using 11C-erlotinib Positron Emission Tomography (PET) imaging in 5 groups (n = 4-5 rats per group) including a baseline group, immediately after sonication (FUS), 48 h after FUS (FUS + 48 h), elacridar (ELA) and their combination (FUS + ELA). BBB integrity was assessed using the Evan's Blue (EB) extravasation test. Brain exposure to 11C-erlotinib was measured as the area under the curve (AUC) of the brain kinetics (% injected dose (%ID) versus time (min)) in volumes corresponding to the disrupted (left) and the intact (right) hemispheres, respectively. EB extravasation highlighted BBB disruption in the left hemisphere of animals of the FUS and FUS + ELA groups but not in the control and ELA groups. EB extravasation was not observed 48 h after FUS suggesting recovery of BBB integrity. Compared with the control group (AUCBaseline = 1.4 +/- 0.5%ID.min), physical BBB disruption did not impact the brain kinetics of 11C-erlotinib in the left hemisphere (p > .05) either immediately (AUCFUS = 1.2 +/- 0.1%ID.min) or 48 h after FUS (AUCFUS+48h = 1.1 +/- 0.3%ID.min). Elacridar similarly increased 11C-erlotinib brain exposure to the left hemisphere in the absence (AUCELA = 2.2 +/- 0.5%ID.min, p < .001) and in the presence of BBB disruption (AUCFUS+ELA = 2.1 +/- 0.5%ID.min, p < .001). AUCleft was never significantly different from AUCright (p > .05), in any of the tested conditions. BBB integrity is not the rate limiting step for erlotinib delivery to the brain which is mainly governed by ABC-mediated efflux. Efflux transport of erlotinib persisted despite BBB disruption. PMID- 30415016 TI - Predicting drug delivery efficiency into tumor tissues through molecular simulation of transport in complex vascular networks. AB - Efficient delivery of anticancer drugs into tumor tissues at maximally effective and minimally toxic concentrations is vital for therapeutic success. At present, no method exists that can predict the spatial and temporal distribution of drugs into a target tissue after administration of a specific dose. This prevents accurate estimation of optimal dosage regimens for cancer therapy. Here we present a new method that predicts quantitatively the time-dependent spatial distribution of drugs in tumor tissues at sub-micrometer resolution. This is achieved by modeling the diffusive flow of individual drug molecules through the three-dimensional network of blood-vessels that vascularize the tumor, and into surrounding tissues, using molecular mechanics techniques. By evaluating delivery into tumors supplied by a series of blood-vessel networks with varying degrees of complexity, we show that the optimal dose depends critically on the precise vascular structure. Finally, we apply our method to calculate the optimal dosage of the cancer drug doxil into a section of a mouse ovarian tumor, and demonstrate the enhanced delivery of liposomally administered doxorubicin when compared to free doxorubicin. Comparison with experimental data and a multiple-compartment model show that the model accurately recapitulates known pharmacokinetics and drug-load predictions. In addition, it provides, for the first time, a detailed picture of the spatial dependence of drug uptake into tissues surrounding tumor vasculatures. This approach is fundamentally different to current continuum models, and reveals that the target tumor vascular topology is as important for therapeutic success as the transport properties of the drug delivery platform itself. This sets the stage for revisiting drug dosage calculations. PMID- 30415017 TI - Differential nickel-induced responses of olfactory sensory neuron populations in zebrafish. AB - The olfactory epithelium of fish includes three main types of olfactory sensory neurons (OSNs). Whereas ciliated (cOSNs) and microvillous olfactory sensory neurons (mOSNs) are common to all vertebrates, a third, smaller group, the crypt cells, is exclusive for fish. Dissolved pollutants reach OSNs, thus resulting in impairment of the olfactory function with possible neurobehavioral damages, and nickel represents a diffuse olfactory toxicant. We studied the effects of three sublethal Ni2+ concentrations on the different OSN populations of zebrafish that is a widely used biological model. We applied image analysis with cell count and quantification of histochemically-detected markers of the different types of OSNs. The present study shows clear evidence of a differential responses of OSN populations to treatments. Densitometric values for Galpha olf, a marker of cOSNs, decreased compared to control and showed a concentration-dependent effect in the ventral half of the olfactory rosette. The densitometric analysis of TRPC2, a marker of mOSNs, revealed a statistically significant reduction compared to control, smaller than the decrease for Galpha olf and without concentration dependent effects. After exposure, olfactory epithelium stained with anti calretinin, a marker of c- and mOSNs, revealed a decrease in thickness while the sensory area appeared unchanged. The thickness reduction together with increased densitometric values for HuC/D, a marker of mature and immature neurons, suggests that the decrements in Galpha olf and TRPC2 immunostaining may depend on cell death. However, reductions in the number of apical processes and of antigen expression could be a further explanation. We hypothesize that cOSNs are more sensitive than mOSNs to Ni2+ exposure. Difference between subpopulations of OSNs or differences in water flux throughout the olfactory cavity could account for the greater susceptibility of the OSNs located in the ventral half of the olfactory rosette. Cell count of anti-TrkA immunopositive cells reveals that Ni2+ exposure does not affect crypt cells. The results of this immunohistochemical study are not in line with those obtained by electro-olfactogram. PMID- 30415018 TI - Amphiphilic nanoparticle delivery enhances the anticancer efficacy of a TLR7 ligand via local immune activation. AB - Although immunotherapy shows great promise for the long-term control of cancer, many tumors still fail to respond to treatment. To improve the outcome, the delivery of immunostimulants to the lymph nodes draining the tumor, where the antitumor immune response is initiated, is key. Efforts to use nanoparticles as carriers for cancer immunotherapy have generally required targeting agents and chemical modification of the drug, and have unfortunately resulted in low delivery and therapeutic efficiency. Here, we report on the efficacy of gold nanoparticles with approximately 5 nm hydrodynamic diameter coated with a mixture of 1-octanethiol and 11-mercaptoundecanesulfonic acid for the delivery of an immunostimulatory TLR7 ligand to tumor-draining lymph nodes. The drug was loaded without modification through nonspecific adsorption into the ligand shell of the nanoparticles, taking advantage of their amphiphilic nature. After loading, nanoparticles retained their stability in solution without significant premature release of the drug, and the drug cargo was immunologically active. Upon subcutaneous injection into tumor-bearing mice, the drug-loaded particles were rapidly transported to the tumor-draining lymph nodes. There, they induced a local immune activation and fostered a cytotoxic T-cell response that was specific for the tumor. Importantly, the particle-delivered TLR7 ligand blocked the growth of large established tumors and significantly prolonged survival compared to the free form of the drug. Thus, we demonstrate for the first time that nanoparticle delivery of a TLR7 immunostimulant to the tumor-draining lymph nodes enhances antitumor immunity and improves the outcome of cancer immunotherapy. PMID- 30415019 TI - Vascularized 3D printed scaffolds for promoting bone regeneration. AB - 3D printed scaffolds hold promising perspective for bone tissue regeneration. Inspired by process of bone development stage, 3D printed scaffolds with rapid internal vascularization ability and robust osteoinduction bioactivity will be an ideal bone substitute for clinical use. Here, we fabricated a 3D printed biodegradable scaffold that can control release deferoxamine, via surface aminolysis and layer-by-layer assembly technique, which is essential for angiogenesis and osteogenesis and match to bone development and reconstruction. Our in vitro studies show that the scaffold significantly accelerates the vascular pattern formation of human umbilical endothelial cells, boosts the mineralized matrix production, and the expression of osteogenesis-related genes during osteogenic differentiation of mesenchymal stem cells. In vivo results show that deferoxamine promotes the vascular ingrowth and enhances the bone regeneration at the defect site in a rat large bone defect model. Moreover, this 3D-printed scaffold has excellent biocompatibility that is suitable for mesenchymal stem cells grow and differentiate and possess the appropriate mechanical property that is similar to natural cancellous bone. In summary, this 3D-printed scaffold holds huge potential for clinical translation in the treatment of segmental bone defect, due to its flexibility, economical friendly and practicality. PMID- 30415020 TI - Predictors of plantar fasciitis in Thai novice conscripts after 10-week military training: A prospective study. AB - OBJECTIVE: To identify the individual, anatomical, and biomechanical predictors of plantar fasciitis among novice conscripts. DESIGN: A prospective cohort study. SETTING: Military training camp in Bangkok, Thailand. PARTICIPANTS: One hundred thirteen novice conscripts without lower extremity pain prior to the commencement of military training. MAIN OUTCOME MEASURE(S): Individual, anatomical, and biomechanical variables were assessed in all participants at baseline. The primary criterion variable was the presence or absence of plantar fasciitis. RESULTS: After 10 weeks of training, 113 participants were classified as having (n = 71) and not having (n = 42) plantar fasciitis. The results indicated that the conscripts with poorer quality of movement and lesser femoral anteversion angle tended to exhibit plantar fasciitis (odds ratio = 1.996 and 0.720, respectively). Regarding individual components, the conscripts with higher body mass index and higher stress level had increased risk of plantar fasciitis (odds ratio = 1.238 and 1.110, respectively). Moreover, the conscripts with a higher level of physical exercise before military training had a reduced risk of presenting with plantar fasciitis (odds ratio = 0.242). CONCLUSIONS: Multiple predictors-especially individual characteristics and the abnormalities from the proximal region (other than foot and ankle)-contributed to the development of plantar fasciitis among Thai novice conscripts. PMID- 30415021 TI - Synthesis, and anti-proliferative, Pim-1 kinase inhibitors and molecular docking of thiophenes derived from estrone. AB - Heterocyclization of steroids were reported to give biologically active products where ring D modification occured. Estrone (1) was used as a template to develop new heterocyclic compounds. Ring D modification of 1 through its reaction with cyanoacetylhydrazine and elemental sulfur gave the thiophene derivative 3. The latter compound reacted with acetophenone derivatives 4a-c to give the hydrazide hydrazone derivatives 5a-c, respectively. In addition, compound 3 formed thiazole derivatives through its first reaction with phenylisothiocyanate to give the thiourea derivative 9 followed by the reaction of the later with alpha halocarbonyl compounds. In the present work a series of novel estrone derivatives were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase, and six typical cancer cell lines (A549, H460, HT-29, MKN 45, U87MG and SMMC-7721). The most promising compounds 5b, 5c, 11a, 13c, 15b, 15c, 15d, 17a and 17b were further investigated against the five tyrosine kinases c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR. Compounds 5b, 15d, 17a and 17b were selected to examine their Pim-1 kinase inhibition activity where compounds 15d and 17b showed high activities. Molecular docking of some of the most potent compounds was demonstrated. PMID- 30415022 TI - Genetic diversity and hybrid formation in Central European club-mosses (Diphasiastrum, Lycopodiaceae) - New insights from cp microsatellites, two nuclear markers and AFLP. AB - In Europe, the genus Diphasiastrum (Lycopodiophyta) forms a reticulate network of six diploid taxa, including three parent species (D. alpinum, D. complanatum and D. tristachyum) and three hybrids (D. * issleri, D. * oellgaardii and D. * zeilleri). It was not clear if the hybrids arose once or repeatedly, if they have reproductive competence and if backcrossing occurs. We addressed these questions by analysing 209 accessions for chloroplast microsatellites (cp), two nuclear markers (introns of the RPB and LFY genes) and AFLP. For D. complanatum we show a sexual life cycle with alternation of generations: the gametophytic DNA amount is half of that of the sporophyte. With the exception of a single accession all hybrids display one of the two parental cp haplotypes; their frequencies do not differ significantly from a 1:1 ratio. Genotypes of nuclear markers are species specific, displaying 2/4/1 (RPB) and 1/8/1 alleles (LFY) for the three parents mentioned above; all hybrids have one allele from each parent. All three hybrid taxa apparently represent independent F1 crosses. Hybridisation occurs bidirectional; no evidence for recent backcrossing was found. Asexual reproduction via agamospory is at least rare, since AFLP showed all hybrid plants to be different. PMID- 30415023 TI - Integrating phylogenomics, phylogenetics, morphometrics, relative genome size and ecological niche modelling disentangles the diversification of Eurasian Euphorbia seguieriana s. l. (Euphorbiaceae). AB - Next generation sequencing has revolutionised biology. Restriction-associated DNA sequencing (RADseq) has primarily been used to study infraspecific relationships but has also been applied in multi-species phylogenomic analyses. In this study, we used a combination of phylogenomic (with RADseq data) and phylogenetic (with sequences of the nuclear internal transcribed spacer, ITS) methods to explore relationships within the taxonomically intricate Euphorbia seguieriana s. l., one of the most widespread Euphorbia taxa inhabiting zonal and extrazonal steppes from Iberia to Central Asia. In the inferred phylogenies the southeastern Balkan and Anatolian populations were clearly separated, supporting the distinction of E. niciciana from E. seguieriana at the species level. Within E. seguieriana, the populations from the Caucasus, Iran, and easternmost Anatolia were sister to all other populations based on RADseq, making necessary the description of a new, morphologically divergent subspecies, E. seguieriana subsp. armeniaca. Conversely, additional studies are needed to understand the status of the E. seguieriana subsp. hohenackeri, which is sympatric with E. seguieriana subsp. armeniaca. Niche analyses indicated that differences in the climatic niche between E. niciciana and E. seguieriana are relatively small compared with the climatic differences between the regions over which they are distributed. Contrary to previous believes, E. niciciana and E. seguieriana are allopatric and have likely diverged during the Pleistocene in two different glacial refugia as suggested by distribution modelling. Euphorbia niciciana nowadays has a Submediterranean distribution, occupying habitats that are slightly warmer, moister, and less seasonal in temperature but more seasonal in precipitation than E. seguieriana, a characteristic species of continental steppes. Using flow cytometry, we demonstrate that the relative genome sizes of E. niciciana and E. seguieriana differ significantly. Additionally, multivariate morphometric analyses of 56 morphological characters indicated clear morphological divergence of the two species. Importantly, we also provide a revised taxonomic treatment including formal nomenclatural changes, an identification key and species descriptions. Our study demonstrates that an integrative approach, combining modern phylogenomic methods with traditional phylogenetic, cytogenetic, environmental and morphological analyses can result in satisfactorily resolved relationships in intricate groups of closely related species. Finally, phylogenetic inference using ITS sequences is still a useful tool for resolving relationships among the taxa at the species level, but the phylogenomic approach based on RADseq data certainly provides better resolution both among and within species. PMID- 30415024 TI - The contribution of the instrumented Timed-Up-and-Go test to detect falls and fear of falling in people with multiple sclerosis. AB - Fear of falling (FoF) and actual falling typifies two common complaints in people with MS (PwMS). The objective of our study was to examine the Instrumented Timed Up-and-Go test (ITUG) in relation to falls and FoF in PwMS. This case-control study comprised 75 participants; 50 PwMS (33 women), aged 44.2 (S.D = 7.2) and 25 healthy subjects (18 women) aged 44.4 (S.D = 8.6). The ITUG test was evaluated by the APDM Mobility lab (Portland, OR, USA) and was completed under two task conditions, normal and while performing a cognitive test (ITUG-cog). FoF was evaluated by the FES-I questionnaire. PwMS were divided into subgroups of fallers and non-fallers based on their fall history. Total duration to complete the ITUG and ITUG-cog was higher in the PwMS group compared to the healthy controls. Total duration to complete the ITUG-cog was higher compared to the normal ITUG in both groups. However, non-significant differences were found for the condition x group factor. The total duration to complete the ITUG was increased in the MS fallers compared to the non-fallers. No other differences in ITUG measures were found between MS subgroups. According to the regression analysis, the sit-to-stand phase explained 22.7% of the variance relating to FoF in PwMS (R2 = 0.227). The study provides new insights into the TUG test in PwMS. The sit-to-stand transition appears to be a major component associated with FoF. Furthermore, the cognitive-motor interference in conjunction with the ITUG is probably not unique in PwMS. PMID- 30415025 TI - Coexistence of Multiple Sclerosis and Alzheimer's disease: A review. AB - BACKGROUND: People with multiple sclerosis (MS) are living longer than ever and will likely face the same age-related diseases as other seniors; however, there is strikingly little information on the coexistence of MS with many common diseases of aging. In particular, little appears to be known about the coexistence of MS with Alzheimer's disease (AD), the most common form of dementia. METHODS: In this review, we explore what is known about the coexistence of MS and AD, including a focused literature search to identify any reports of individuals with both MS and AD (PubMed, to May 2017). We also discuss the wider epidemiology, diagnosis, and pathophysiology of MS and AD. RESULTS: In total, we found 24 individuals with pathological features of both MS and AD described as case series or reports (published between 1976-2014), but no epidemiological or population-based studies, aside from one conference proceeding (2011). Comorbid MS and AD was reported in a broad range of MS disease courses including relapsing remitting, primary progressive, secondary progressive and so-called 'benign.' Despite the clear diagnostic challenges involved, these individual case reports provide evidence that AD and MS can coexist in the same person. CONCLUSION: In summary, we highlight a major knowledge gap in our understanding of two potentially common neurological conditions. With the ageing population, and an estimated 2.3 million people living with MS and 46 million with AD or other dementias worldwide, it will become increasingly important to recognize and understand how to manage individuals with these complex comorbid conditions. PMID- 30415026 TI - Modelling the effects of multiple stressors on respiration and microbial biomass in the hyporheic zone using decision trees. AB - Integrity of freshwater surface- and groundwater ecosystems and their ecological and qualitative status greatly depends on ecological processes taking place in streambed sediments overgrown by biofilm, in the hyporheic zone (HZ). Little is known about the interactions and effects of multiple stressors on biologically driven processes in the HZ. In this study, machine learning (ML) tools were used to provide evidence-based information on how stressors and ecologically important environmental factors interact and drive ecological processes and microbial biomass. The ML technique of decision trees using the J48 algorithm was applied to build models from a data set of 342 samples collected over three seasons at 24 sites within the catchments of five gravel-bed rivers in north-central Slovenia. Catchment-scale land use data and reach-scale environmental features indicating the HZ morphology and physical and chemical characteristics of water were used as predictive variables, while respiration (R) and microbial respiratory electron transport system activity (ETSA) were used as response variables indicating ecological processes and total protein content (TPC) indicating microbial biomass. Separate models were built for two HZ depths: 5-15 cm and 20-40 cm. The models with R as a response variable have the highest predictive performance (67 89%) showing that R is a good indicator of complex environmental gradients. The ETSA and TPC models were less accurate (42-67%) but still provide valuable ecological information. The best model show that temperature when combined with selected water quality elements is an important predictor of R at depth of 5-15 cm. The ETSA and TPC models show the combined effects of temperature, catchment land use and selected water quality elements on both response variables. Overall, this study provides new knowledge on how ecological processes occurring in the HZ respond to catchment and reach-scale variables, and provides evidence-based information about complex interactions between temperature, catchment land use and water quality. These interactions are highly dependent on the selection of the response variable, i.e., each response variable is influenced by a specific combination of predictive environmental variables. PMID- 30415027 TI - Minimizing atheromatous emboli during arch surgery with a sequential debranching procedure. PMID- 30415028 TI - Root Reimplantation with Leaflet Repair. AB - Reimplantation of the aortic valve is a procedure well recognized for its safety, excellent success in preserving the leaflets without a composite valve graft, and long-term durability. Unanswered questions are whether the procedure should be used for bicuspid valves and, if so, which ones, and also the role of leaflet repair. In our experience with just under 2,000 aortic valve repairs, we found that use of a root procedure, particularly root reimplantation, resulted in excellent long-term durability. Just as with mitral valve repairs that include an anular ring, it appears that for aortic valve repairs, bracing the root is important. We have found that leaflet repair during a reimplantation procedure is not detrimental to long-term durability. PMID- 30415029 TI - A Glimpse Into the Heart: Innovative Cardioscope Captures Stunning Views of a Heart in Motion. PMID- 30415030 TI - Accumulation and transformation of heavy metals in surface sediments from the Yangtze River estuary to the East China Sea shelf. AB - The concentration and speciation of heavy metals (Cu, Co, Ni, Zn, Cr, Pb and Cd) were studied in surface sediment from the Yangtze River(YR)to the East China Sea (ECS) shelf. The results showed that high contents of metals were found in the YR estuary (YRE) and in the nearshore muddy area, while lower concentrations were found in the YR channel and the ECS shelf. However, after standardization, the total content of most heavy metals from the YR showed little change or slightly increased during the transport process from the river to the estuary but decreased significantly outside the estuary, especially in the sediments of the ECS shelf. The residual fraction is the dominant fraction for all the metals, while the oxidizable and reducible fractions are the most important forms of the nonlithogenic fractions. The total amount of heavy metals from the YR to the continental shelf is mainly affected by the filtration of the estuary and the barrier impacts of the coastal current in the ECS. The environmental physicochemical conditions that vary significantly in the turbidity zone greatly influence the associated forms of metals. The metals in the acid-soluble fraction are mostly affected by the pH change in the sediment and the discharge of human activities, while the reducible fraction is significantly affected by the bottom water DO. The oxidizable fraction was affected by oxidation-reduction potential (ORP), primary productivity, as well as OM content. Therefore, with changes in the physicochemical conditions of the environment, the metals have undergone significant changes in their speciation from the YR to the ECS shelf. Various complex effects in the estuary area have not only a large filtration effect on the total amount of metals but also a major impact on the geochemical forms of the metals. PMID- 30415031 TI - Abundance and distribution of microplastics in the surface sediments from the northern Bering and Chukchi Seas. AB - Worldwide the seafloor has been recognized as a major sink for microplastics. However, currently nothing is known about the sediment microplastic pollution in the North Pacific sector of the Arctic Ocean. Here, we present the first record of microplastic contamination in the surface sediment from the northern Bering and Chukchi Seas. The microplastics were extracted by the density separation method from collected samples. Each particle was identified using the microscopic Fourier transform infrared spectroscopy (MUFTIR). The abundances of microplastics in sediments from all sites ranged from not detected (ND) to 68.78 items/kg dry weight (DW) of sediment. The highest level of microplastic contamination in the sediment was detected from the Chukchi Sea. A negative correlation between microplastic abundance and water depth was observed. Polypropylene (PP) accounted for the largest proportion (51.5%) of the identified microplastic particles, followed by polyethylene terephthalate (PET) (35.2%) and rayon (13.3%). Fibers constituted the most common shape of plastic particles. The range of polymer types, physical shapes and spatial distribution characteristics of the microplastics suggest that water masses from the Pacific and local coastal inputs are possible sources for the microplastics found in the study area. In overall, our results highlight the global distribution of these anthropogenic pollutants and the importance of management action to reduce marine debris worldwide. PMID- 30415032 TI - High-throughput transcriptomics: Insights into the pathways involved in (nano) nickel toxicity in a key invertebrate test species. AB - Nickel nanoparticles (NiNPs) have an estimated production of ca. 20 tons per year in the US. Nickel has been risk-assessed for long in Europe, but not NiNPs, hence the concern for the environment. In the present study, we focused on investigating the mechanisms of toxicity of NiNPs and the comparison to NiNO3. The high-throughput microarray for the soil ecotox model Enchytraeus crypticus (Oligochaeta) was used. To anchor gene to phenotype effect level, organisms were exposed to reproduction effect concentrations EC20 and EC50, for 3 and 7 days. Results showed commonly affected pathways between NiNPs and NiNO3, including increase in proteolysis, apoptosis and inflammatory response, and interference with the nervous system. Mechanisms unique to NiNO3 were also observed (e.g. glutathione synthesis). No specific mechanisms for NiNPs were found, which could indicate that longer exposure period (>7 days) is required to capture the peak response to NiNPs. A mechanisms scheme is assembled, showing both common and unique mechanisms to NiNO3 and NiNPs, providing an important framework for further, more targeted, studies. PMID- 30415033 TI - Potential for mitigating global agricultural ammonia emission: A meta-analysis. AB - Ammonia (NH3) emission from agricultural sources has contributed significantly to air pollution, soil acidification, water eutrophication, biodiversity loss, and declining human health. Although there are numerous strategies for reducing NH3 emission from agricultural systems, the effectiveness of these measures is highly variable. Furthermore, the integrated assessment of measures to reduce NH3 emission both from livestock production and cropping systems based on animal and crop type is lacking. Therefore, we conducted a global meta-analysis and integrated assessment of measures to reduce NH3 emission from agricultural systems. Most of the studied mitigation strategies were effective in reducing NH3 emission. In the livestock production system, dietary additive, urease inhibitor (UI), manure acidification and deep manure placement have the highest mitigation potential relative to other mitigation strategies, with reduction ranges of 35.1 54.2%, 24.3-68.7%, 88.8-95.0%, and 93.8-99.7%, respectively, relative to the control, while manure storage management could significantly reduce NH3 emission by 70.0-82.1%. In the cropping system, fertilizer source, use of enhanced efficiency fertilizers, and method of field application are most effective for reducingNH3 emission. The use of ammonium nitrate, controlled release fertilizer (CRF), and deep placement of fertilizers could reduce NH3 emission by 88.3, 56.8, and 48.0%, respectively. Choosing a proper fertilizer is critical for decreasing NH3 emission from cropping systems. We conclude that carefully planned and adopted strategies suited for local conditions are promising for minimizing NH3 emission from agricultural systems on a global scale, while possible effects of those mitigation measures on the emission of greenhouse gases should be studied in the future. PMID- 30415034 TI - Association between urinary concentration of phthalate metabolites and impaired renal function in Shanghai adults. AB - BACKGROUND: Exposure to phthalates is reported to be associated with increased incidence of microalbuminuria and low-grade albuminuria in children and adolescents. However, this phenomenon of phthalate-related nephrotoxicity is unknown in adults. METHODS: Urine samples of 1663 adults from the 2012 Shanghai Food Consumption Survey (SHFCS) were measured for 10 metabolites of 6 phthalates and for renal function parameters. Their associations were explored by linear and logistic regression models. RESULTS: Multivariate linear regression analysis showed that all three renal function parameters (albumin-to-creatinine ratio (ACR), beta2-microglobulin (B2M), and N-acetyl-beta-d-glucosaminidase (NAG)) are positively associated with six metabolites, including mono-benzylphthalate (MBzP), mono-2-ethylhexylphthalate (MEHP), mono-2-ethyl-5-oxohexyphthalate (MEOHP), mono-2-ethyl-5-hydroxyhexylphthalate (MEHHP), mono-2-ethyl-5 carboxypentylphthalate (MECPP), and mono-2-carboxymethyl-hexyl phthalate (MCMHP) (P < 0.05). Logistic analysis showed that the prevalence of hyperALBuria, hyperB2Muria, hyperNAGuria, or potentially impaired renal function (PIRF) were positively associated with urinary levels of MBzP, MEOHP, and MECPP, respectively (P < 0.05). Co-exposure to identified risk metabolites monoethylphthalate (MEP), MBzP, MEHP, MEOHP, MECPP, MEHHP, and MCMHP increased the risk of having impaired renal function. CONCLUSION: Certain metabolites of phthalates, including bis (2 ethylhexyl) phthalate (DEHP) and benzyle butyl phthalate (BBzP), were associated with impaired renal function in Shanghai adults. PMID- 30415035 TI - Vertical mixing with return irrigation water the cause of arsenic enrichment in groundwater of district Larkana Sindh, Pakistan. AB - Stable isotopes ratios (0/00) of Hydrogen (delta2H) and Oxygen (delta18O) were used to trace the groundwater recharge mechanism and geochemistry of arsenic (As) contamination in groundwater from four selected sites (Larkana, Naudero, Ghari Khuda Buksh and Dokri) of Larkana district. The stable isotope values of delta2H and delta18O range from 70.780/00 to -56.010/00 and from -10.920/00 to -7.350/00, relative to Vienna Standard for Mean Ocean Water (VSMOW) respectively, in all groundwater samples, thus indicating the recharge source of groundwater from high salinity older water. The concentrations of As in all groundwater samples were ranged from 2 MUg/L to 318 MUg/L, with 67% of samples exhibited As levels exceeding than that of World Health Organization (WHO) permissible limit 10 MUg/L and 42% of samples expressed the As level exceeding than that of the National Environmental Quality Standard (NEQS) 50 MUg/L. The leaching and vertical mixing with return irrigation water are probably the main processes controlling the enrichment of As in groundwater of Larkana, Naudero, Ghari Khuda Buksh and Dokri. The weathering of minerals mostly controlled the overall groundwater chemistry; rock-water interactions and silicate weathering generated yielded solutions that were saturated in calcite and dolomite in two areas while halite dissolution is prominent with high As area. PMID- 30415037 TI - Bioavailability and effects of microplastics on marine zooplankton: A review. AB - Microplastics are abundant and widespread in the marine environment. They are a contaminant of global environmental and economic concern. Due to their small size a wide range of marine species, including zooplankton can ingest them. Research has shown that microplastics are readily ingested by several zooplankton taxa, with associated negative impacts on biological processes. Zooplankton is a crucial food source for many secondary consumers, consequently this represents a route whereby microplastic could enter the food web and transfer up the trophic levels. In this review we aim to: 1) evaluate the current knowledge base regarding microplastic ingestion by zooplankton in both the laboratory and the field; and 2) summarise the factors which contribute to the bioavailability of microplastics to zooplankton. Current literature shows that microplastic ingestion has been recorded in 39 zooplankton species from 28 taxonomic orders including holo- and meroplanktonic species. The majority of studies occurred under laboratory conditions and negative effects were reported in ten studies (45%) demonstrating effects on feeding behaviour, growth, development, reproduction and lifespan. In contrast, three studies (14%) reported no negative effects from microplastic ingestion. Several physical and biological factors can influence the bioavailability of microplastics to zooplankton, such as size, shape, age and abundance. We identified that microplastics used in experiments are often different to those quantified in the marine environment, particularly in terms of concentration, shape, type and age. We therefore suggest that future research should include microplastics that are more representative of those found in the marine environment at relevant concentrations. Additionally, investigating the effects of microplastic ingestion on a broader range of zooplankton species and life stages, will help to answer key knowledge gaps regarding the effect of microplastic on recruitment, species populations and ultimately broader economic consequences such as impacts on shell- and finfish stocks. PMID- 30415036 TI - Association between urinary polycyclic aromatic hydrocarbon metabolites and dyslipidemias in the Chinese general population: A cross-sectional study. AB - BACKGROUND: Exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with metabolic diseases. However, relationships between PAH exposures and dyslipidemias have not been well addressed. OBJECTIVES: To investigate associations between urinary PAH metabolite concentrations and dyslipidemias in the general population. METHODS: Twelve urinary PAH metabolites and four serum lipid profiles were measured in 3640 Chinese adults from the Wuhan-Zhuhai cohort. Dyslipidemias, including hyper-total cholesterol (HyperTC), hyper-triglyceride (HyperTG), hyper-low density lipoprotein cholesterol (HyperLDL-C), and hypo-high density lipoprotein cholesterol (HypoHDL-C) were classified according to the levels of serum lipids. Multiple logistic regression models were used to estimate the associations between urinary PAH metabolites and the prevalence of dyslipidemias. The effects of PAH exposure routes on dyslipidemias were further estimated by stratified analysis. RESULTS: We found positive exposure-response relationships between urinary PAH metabolites and the prevalence of dyslipidemias. Compared with the lowest tertile of urinary PAH metabolites, increased risk of HyperTC were observed in those in the highest tertiles; The odds ratios (ORs) and 95% confidence intervals were 1.23 (1.03, 1.47), 1.44 (1.21, 1.71), 1.19 (1.01, 1.42), and 1.43 (1.20, 1.71) for 1-OHNa, 9-OHFlu, 1 OHPh, and 4-OHPh, respectively. Participants in the highest tertiles of 1-OHNa and 2-OHFlu had higher risk for HyperLDL-C, and the ORs were 1.21 (1.01, 1.45) and 1.18 (0.98, 1.42), respectively. Among smokers, only urinary 1-OHNa was associated with increased risk of HyperTC (1.36, 1.08-1.73) and HyperLDL-C (1.33, 1.01-1.74). While the increasing urinary levels of 9-OHFlu, 1-OHPh, and 4-OHPh were significantly associated with increased risk of HyperTC among non-smokers. In addition, the associations between urinary PAH metabolites and dyslipidemias were more pronounced among non-smokers who are cooked for themselves and had long term traffic exposure. CONCLUSION: Elevated urinary PAH metabolites were associated with increased risks of HyperTC and HyperLDL-C. The source of PAH exposure could modify PAH species that affect dyslipidemias. PMID- 30415038 TI - Gelatin Paste as an alternative cost-effective hemostatic agent in cranial surgery: Doing More with Less. AB - OBJECTIVE: To present an alternative cost-effective hemostatic agent (HA) for cranial surgery, describing the technique to produce it. MATERIAL AND METHODS: This HA has been used in three reference centers over the last year during 230 procedures including different types of pathology such as skull base, oncology, vascular and trauma, either for endoscopic or open approaches. This agent was made from a low-cost and worldwide available gelatin foam, mixed with saline solution in 2 syringes, connected by a three-way stopcock, making a useful hemostatic paste. RESULTS: The cost was 16 and 28 times less, compared with Surgiflotm (Ethicon, Johnson and Johnson, N.J., U.S.A.) and Flosealtm (Baxter International, Inc., Deerfield IL) respectively. The median time to prepare the mix was 3 minutes. It was very effective for venous and low-flow bleeding. CONCLUSIONS: The presented technique offers a reliable and cost-effective way of achieving hemostasis in cranial surgery and thus allowing hospitals with limited resources to perform advanced procedures in a safer way. PMID- 30415039 TI - Study of Simple Immunohistochemical Cytocolorimetric Assay Application for More Accurate Assessment of Prognosis in Patients with Pituitary Adenomas. AB - BACKGROUND: Immunohistochemistry is a basic diagnostic technique. Immunohistochemical examination results reflect mainly qualitative and less quantitative characteristics of proteomic status of cells. A combined approach with complex quantitative evaluation of marker expression using colorimetric analysis and computer technologies can expand the diagnostic capabilities of immunohistochemistry. We studied such an approach developed by using expression of the proliferative marker Ki-67 in pituitary adenomas. METHODS: A retrospective, blind, randomized, comparative study was performed of Ki-67 expression activity in pituitary adenomas using the traditional Ki-67 labeling index and a simple immunohistochemical cytocolorimetric analysis developed by us with immunohistochemical cytocolorimetric index (ICI) estimation as predictors of relapse, assessing the relationships of these indicators with the time before relapse. RESULTS: Mean Ki-67 labeling index was 3.87% +/- 0.29% in the relapse free group and 4.01% +/- 0.29% in the relapse group; the difference was not statistically significant. The average Ki-67 ICI was 24.16% +/- 0.51% in the relapse-free group and 30.68% +/- 0.64% in the relapse group; the difference was statistically significant. The correlation coefficient of ICI values and time before relapse was -0.302, indicating the presence of a weak negative correlation. CONCLUSIONS: We successfully tested an ICI estimation method developed by us to assess Ki-67 expression in pituitary adenomas. The ICI technique can be used both as a prognostic factor for relapse and, in combination with other modern proteomic and genetic methods, as the basis for creation of new multimodal analyzing systems for functional state assessment of cells and tissues. PMID- 30415040 TI - Surgical rescue retrieval of a filter protection device in carotid artery stenting with stent deformation: case report and literature review. AB - BACKGROUND: Despite the development of neuroendovascular treatment, device related complications requiring surgical procedures remain. We report a case requiring surgical retrieval of a filter protection device in carotid artery stenting (CAS) with an open-cell stent, due to stent deformation, and review past reports on CAS in which surgical retrieval of devices was required. CASE DESCRIPTION: An 82-year-old man underwent CAS for symptomatic right internal carotid artery stenosis with severe calcification and tortuosity. Immediately after placement of the open-cell stent, stent deformation was detected and the filter protection device could not be retrieved. All noninvasive device retrieval attempts failed, and the device was ultimately retrieved surgically. After surgery, right cerebral infarction progressed increased, but no permanent deficit was observed. CONCLUSIONS: As the treatment of cerebrovascular disease shifts from surgical to endovascular approaches, surgeons must be familiar with devices and techniques to manage complications of neuroendovascular treatment. PMID- 30415041 TI - The history of and controversy over Kambin's Triangle: A historical analysis of the lumbar transforaminal corridor for endoscopic and surgical approaches. AB - The transforaminal corridor in the lumbar spine allows access to the traversing and exiting nerve roots, the thecal sac, and the intervertebral disc space. Surgeons performing midline and minimally invasive approaches for lumbar interbody fusion access the disc space within the boundaries created by the exiting root of a segment and the traversing root after a complete facetectomy, and removal of the pars interarticularis and lamina. Endoscopic surgeons and interventional pain management physicians approach the lumbar segment through a similar corridor, but with the bony anatomy intact. Although the boundaries of the corridor may seem the same, the angle of the trajectory and the bone work between the two differ. The overlap between these two distinct access corridors has led to an openhanded application of the term Kambin's Triangle. Initially described for endoscopic approaches to the lumbar spine for microdiscectomy, this "working triangle" has been grafted into the transforaminal lumbar interbody fusion literature. Given the similarities between these corridors, it is understandable how the lines of this nomenclature have blurred. The result has been an interchangeable application of the term Kambin's triangle for a variety of procedures in the spine literature. The objective of the current work is to add clarity to the various lumbar transforaminal corridors. The term "Kambin's triangle" should be limited to percutaneous access to the disc space for endoscopic procedures in the intact spine and should not be applied to TLIFs after laminectomy and facetectomy. Instead, the term "expanded transforaminal corridor" should be applied. PMID- 30415042 TI - The Incremental Value of Magnetic Resonance Neurography for the Neurosurgeon: Review of the Literature. AB - INTRODUCTION: Magnetic Resonance Neurography (MRN) is a newer imaging technique that is increasingly utilized for detailed visualization of peripheral nerves not reliably achieved with conventional imaging modalities. While MRN has been previously characterized in the literature, few studies have assessed its utility to neurosurgery, where there is potentially substantial impact particularly with pre-operative assessment. In this article, we performed a retrospective review of cases in which MRN was used utilized for clinical evaluation and surgical decision making. METHODS AND RESULTS: MRN, clinical assessment and operative decision making was retrospectively assessed in 206 consecutive patients at our institution between 2015-2018. MRN was determined to lead to a change in diagnosis or surgical decision making in 44 patients (21.4% - 27 female, 17 male). These were classified into six major diagnostic categories: Trauma, Post surgical evaluation, Compressive/Degenerative conditions, Tumors, Neuritis/Inflammation and Other neurogenic lesions. Nine representative cases were selected from these categories to highlight the range of Neurosurgical pathologies where MRN was useful in diagnostic assessment and surgical decision making. CONCLUSIONS: MRN is an underutilized resource with great potential value in the diagnoses, surgical planning and postoperative assessment of various Neurosurgical conditions. These present incremental utility to the Neurosurgeon as well as socioeconomic benefit in the detection of potentially surgically treatable lesions. PMID- 30415043 TI - Diagnosis and Treatment of Isolated Cerebral Mucormycosis: Patient-Level Data Meta-Analysis and Mayo Clinic Experience. AB - Isolated cerebral mucormycosis is a rare and serious infection associated with intravenous drug abuse We provide a comprehensive meta-analysis of reported cases in the literature and an unpublished case from our institution. We searched PubMed/Medline, EMBASE, Scopus, Cochrane Databases, and our institution's electronic health records from inception through March 31, 2018. Cases were considered isolated (only affecting the cerebrum, cerebellum, or brainstem) if documentation existed for the absence of other primary sources of infection. Continuous variables were summarized using median and interquartile range (IQR) and categorical variables using frequency with proportion. Relationships between variables were tested using the Wilcoxon rank sum and Pearson chi2 tests. A total of 130 manuscripts (141 patients) met eligibility requirements and were screened; 68 patients were included in the analyses. The median (IQR) age was 28 (24-38) years, 57% of patients were men. Most patients had a history of IVDA (82%), and 20% were HIV positive. Lesion location was mostly supratentorial (91%), particularly in the basal ganglia (71.2%). Cultures were positive in 38% of cases, Rhizopus being the most common organism (59%). The mortality rate was 65%. Survivors were significantly more likely to have received amphotericin B (92% vs 43%, P<.001) or to have undergone stereotactic aspiration (58% vs 25%, P=.01). Isolated cerebral mucormycosis has a pooled mortality rate of 65%. The presence of lesions in the basal ganglia, rapidly progressing symptoms, and a history of IVDA should raise suspicion for early initiation of amphotericin B and stereotactic aspiration. PMID- 30415044 TI - Analysis of complications after a cranioplasty with a customized 3D titanium-mesh plate. AB - OBJECTIVE: To report the outcomes of cranioplasty (CP) with a customized 3dimensional(3D) titanium-mesh plate and identify the relationship between various clinical variables and complications after CP. MATERIALS AND METHODS: A total of 20 patients who underwent surgery with customized 3D titanium-mesh plates and were followed-up for more than 6 months from January 2015 to December 2017 were enrolled. Complications related to CP were retrospectively reviewed. Patients were divided into two groups (no complication group and complication group), and various clinical variables related to complications were compared between the two groups. In addition, we performed the correlation analysis to identify the clinical variable significantly correlated with the complications after CP with a customized 3D titanium-mesh plate. RESULTS: Eleven out of 20 patients developed complications, such as extrusion, intracranial infection, severe operation site pain, and wound dehiscence. Among the various clinical variables, only the presence of ventriculo-peritoneal shunt (V-P shunt) system was significantly correlated with the overall complication (odds ratio, 14.00; p value = 0.032; 95% confidence interval 1.56-222.92). CONCLUSION: While a customized 3D titanium-mesh plate is associated with a lower risk of intracranial infection, the rate of post-operative complications, including mainly cosmetic problems, such as forehead mesh extrusion and dehiscence, was high at 55%, and V P shunt system was significantly correlated with the overall complication rate after CP with a customized 3D titanium-mesh plate. PMID- 30415045 TI - Surgical Outcomes and Prognostic Factors for Metastatic Spine Hepatocellular Carcinoma. AB - BACKGROUND: We evaluated the surgical outcomes of metastatic spine hepatocellular carcinoma (HCC) and determined the factors that might influence the outcomes of metastatic HCC of the spine. METHODS: From 2010 to 2017, 72 patients with HCC derived metastatic spine tumors were treated in our department. For each patient, we recorded the pre- and postoperative visual analog scale score, Frankel grade, perioperative complications, and mortality. Univariate and multivariate analyses were used to explore a range of factors that might influence postoperative survival. RESULTS: The mean postoperative survival was 10.8 +/- 5.4 months. The concordance rate between a Tokuhashi score of 0-8 and a life expectancy of <6 months was only 19.2%. The mean postoperative survival for patients undergoing excisional surgery was 14.7 +/- 6.5 months, and the mean survival of those receiving palliative surgery was 8.5 +/- 2.6 months. Pain had significantly improved in both patient groups (P < 0.001). Paralysis did not change significantly in the excisional surgery group (P = 0.641) or palliative surgery group (P = 0.912). Univariate analysis showed that the preoperative Frankel score, Tomita score, Tokuhashi score, blood loss, multilevel metastases, and operative type were independent prognostic factors for postoperative survival time. Multivariate analysis showed that operation type was an independent factor for prognosis, just as were the Tomita score and Tokuhashi score. CONCLUSIONS: Our results have challenged previously reported estimates of the life expectancy correlating with the Tokuhashi score. Our results showed that excisional surgery resulted in better clinical outcomes compared with palliative surgery. PMID- 30415046 TI - Spinal Cord Stimulation in Adult Tethered Cord Syndrome: Case Report and Review of the Literature. AB - Spinal cord stimulation (SCS) is an evidence - based treatment for chronic neuropathic pain, however there is a dearth of evidence investigating this modality in patients with tethered cord syndrome (TCS). We present a case of 55 year old woman with history of lipo-myelomeningocele repair and multiple detethering surgeries who presented with chronic low back and leg pain accompanied by progressive gait dysfunction. After a successful trial, she underwent SCS paddle lead placement that resulted in decrease of her visual analog scale (VAS) for pain from 9/10 to 0-2/10 as well as daily opioid intake from 90-199mg Morphine Equivalents Doses (MED) to 40-60mg MED. On last follow-up she reported 70-85% relief of her low back and leg pain, better ambulation, and improved quality of life. The literature review identified 2 other case reports of SCS in TCS with similar improvement in pain alleviation. PMID- 30415047 TI - Covered stent to salvage iatrogenic vertebral artery injury with un-controlled bleeding in the OR setting. AB - BACKGROUND: Iatrogenic vertebral artery injury is an uncommon but well recognized complication during cervical spine surgery. Intraoperative surgical repair is extremely challenging and options for endovascular repair are limited due to lack of proper equipment in the operating room setting. CASE DESCRIPTION: a 53 year old female who presented with myleopathy underwent anterior cervical discectomy and fusion of C3-7. A significant laceration injury of left vertebral artery was encountered during surgery, which was salvaged by intraoperative, endovascular repair with a covered stent under portable fluoroscopy guidance. The salvage and repair led to the rest of the surgery to be finished as planned preoperatively without any consequences. CONCLUSIONS: Vertebral artery injury is an uncommon but severe complication of cervical spine surgery. For the uncontrolled bleeding, intraoperative endovascular repair with portable fluoroscopy is warranted and possible. Covered stent can seal the laceration and stop the bleeding completely which enables completion of the surgery. PMID- 30415048 TI - Synovial Cyst as A Marker for Lumbar Instability: a systematic review and meta analysis. AB - BACKGROUND: The pathogenesis of synovial cysts is largely unknown; however, they are increasingly thought of as markers of spinal facet instability and are typically associated with degenerative spondylosis. In this article, we specifically investigate the incidence of concomitant synovial cyst with underlying degenerative spondylolisthesis. METHODS: A literature search was performed using 4 online databases to assess the association between lumbar synovial cysts and degenerative spinal pathologies. Meta-analyses were performed on the prevalence rates of coexisting degenerative spinal pathologies and treatment modalities. A random-effects model was used to calculate means and 95% confidence intervals. RESULTS: A total of 17 studies encompassing 824 cases met the inclusion criteria. The pooled prevalence rates of concurrent spondylolisthesis, facet arthropathy, and degenerative disc disease at the same level of synovial cysts were 42.5% [39.0%, 46.1%], 89.3% [79.0%, 94.8%], and 48.8% [43.8%, 53.9%], respectively. Among these, patients with coexisting spondylolisthesis were more likely to undergo spinal fusion surgery (versus laminectomy alone) as well as reoperation than patients without spondylolisthesis with the pooled odds ratio of 11.5 [4.5, 29.1, p<0.0001] and 2.0 [0.9, 4.2, p = 0.088], respectively. CONCLUSIONS: Patients with a combination of synovial cysts and degenerative spondylolisthesis are more likely to undergo spinal fusion surgery vs. laminectomy alone, compared to patients with synovial cysts and no preoperative spondylolisthesis. Furthermore, patients with synovial cysts and spondylolisthesis are more likely to require an additional fusion surgery. This review lends credence to the argument that synovial cyst herniations may be a manifestation of an unstable spinal level. PMID- 30415049 TI - Utility of a single fenestrated mini-clip in the management of small cerebral aneurysm: Technical report of two cases. AB - BACKGROUND: Fenestrated mini-clips were developed as an effective tool for dog ear-shaped remnants of aneurysms. However, the special property of these clips may have other applications. Here, we report two cases of ruptured small aneurysm and suggest the alternative utility of a single application of a fenestrated mini clip. CASE DESCRIPTION: A 77-year-old woman was admitted to our hospital with subarachnoid hemorrhage (SAH) due to anterior communicating aneurysm. The aneurysm was treated with surgical clipping via a right pterional approach. Because dissection of tight adhesion between the aneurysm and ipsilateral A2 might cause intraoperative bleeding, the angled fenestrated mini-clip was applied across the ipsilateral A2 without dissection of adhesion and obliterated the aneurysm without complications. In another case, a 60-year-old man presented with SAH due to ruptured vertebral artery (VA)-posterior inferior cerebellar artery (PICA) aneurysm and was treated with surgical clipping via a far-lateral approach. Because aneurysm visualization was impeded by PICA even after mobilization of the PICA and VA, a fenestrated standard-clip was applied across the PICA. However, this clip impeded visualization of the aneurysm and could not be opened in the tight surgical field. In contrast, subsequent application of a fenestrated mini-clip allowed better visualization of the aneurysm, even in a tight field, and resulted in successful obliteration of the aneurysm. CONCLUSION: Single application of fenestrated mini-clips may be suitable in cases of small aneurysms with thin walls adhering to branch vessels or where visualization of the aneurysm is impeded by the parent artery. PMID- 30415050 TI - Awake Craniotomy for the Removal of a Left Insular Cavernous Malformation. AB - The insula plays a crucial role in speech planning due to its connections with cortical and sub-cortical areas. Surgical management of cavernous malformation (CM) of the insula consist in total resection of the lesion and the surrounding gliosis to avoid or reduce seizures. When located in the dominant hemisphere an awake craniotomy with intraoperative mapping reduce the risk of functional damage. The insula is covered by the operculum and gets relationship with the middle cerebral artery and its branches that run along its lateral surface. Therefore, high expertise is required to manage the exposure of the insula and its complex anatomy. This video demonstrates the surgical management of a large left insular CM. A 29-years-old female with multiple CM and seven years of partial seizures and recent onset of short memory loss. Neuroimaging showed a large left insular and planum polare CM with important mass effect and hemorrhage signs. The patient consented to surgery and an awake pretemporal craniotomy was carried out with continuous motor evoked potential monitoring. No language function was localized in the superior temporal gyrus, therefore cortisectomy of the middle portion was performed to expand the operative corridor. The vessel manipulation during wide opening of the sylvian fissure increased the risk of postoperative vasospasm and blood drain into the surgical field. The CM was exposed and completely removed without functional damage. The patient recovered from surgery without complications and no seizures occurred at 2-months follow up. Postoperative imaging showed complete removal of the CM. PMID- 30415051 TI - Patient-Oriented Aesthetic Outcome After Lumbar Spine Surgery: A 1-Year Follow-Up Prospective Observational Study Comparing Minimally Invasive and Standard Open Procedures. AB - BACKGROUND: Despite recent treatment developments, back pain and related disabilities still represent a challenge for practitioners. Among the available surgical techniques, many different features and outcomes have been investigated; however, aesthetic result was missing among them. The present investigation was designed to prospectively compare patient-oriented aesthetic results after minimally invasive surgery (MIS) and standard open surgery (SOS) for the lumbar spine. METHODS: This was a prospective observational study with 1-year follow-up. Patients who underwent SOS were assigned to group 1 and MIS to group 2. Patient oriented aesthetic result evaluation was collected using a dedicated visual aesthetic analogue scale. The Vancouver Scar Scale was used to exclude objective underlying influencing factors. The Oswestry Disability Index and a 10-point itemized visual analogue scale for back pain were administered to assess the clinical and functional status. Follow-up data were collected before discharge at 1, 6, and 12 months. Statistical analysis was conducted, and P < 0.05 was considered as significant. RESULTS: We enrolled 74 patients, 44 in group 1 and 30 in group 2. The 2 groups were homogeneous for demographic and clinical data. No clinical or functional differences were measured at the end of follow-up. Visual aesthetic analogue scale reported greater mean values in group 1 at every follow up time. CONCLUSIONS: Patients seem to prefer the aesthetic result from a single midline incision after SOS compared with MIS. The use of specific techniques could be considered if there is scientific evidence reporting greater aesthetic outcome, having similar clinical and functional ones. PMID- 30415052 TI - Case Report: Phantom Sensation - An Underreported Sensory Outcome Following Intercostal-to-Musculocutaneous Nerve Transfer. AB - BACKGROUND: Intercostal-to-musculocutaneous (ICN-MCN) nerve transfer is commonly performed in patients with brachial plexus avulsion injuries. As techniques have improved since its inception in 1963, most patients now experience some level of motor function improvement of their affected arm. While motor outcomes are well described, there is a paucity of literature describing sensory outcomes. It is thus difficult to gauge surgical success with respect to sensory function, and there is a necessity to share clear expectations with patients regarding intended or unintended post-operative sensation. CASE DESCRIPTION: In this case report, we describe an unintended sensory outcome of this procedure. Three years after the operation, our patient experiences a "phantom sensation" on his chest when he is touched on the lateral forearm in the distribution of the lateral antebrachial cutaneous nerve. This outcome can be explained with review of the anatomy before and after the operation. The persistence of this adverse outcome suggests limitations in sensory cortical neuroplasticity. CONCLUSIONS: It is important to be aware of potential sensory complications in ICN-MCN nerve transfer. While this complication is known, it is often overlooked and underreported. Complications such as this should be emphasized in order to set expectations for patients and guide evaluation of sensory outcomes in future study. PMID- 30415053 TI - Cervical hyperextension deformity following sagittal balance correction in a patient with Congenital Limb Girdle Myopathy: Surgical technique and review of the literature. AB - BACKGROUND: There is no gold standard surgical treatment for cervical hyperextension deformity especially in case of muscular dystrophy. Special considerations and caution should be taken as they carry high risk of early mortality and spinal cord injury. Only a few case reports are available in the literature. CASE DESCRIPTION: We report a case of surgical correction of an iatrogenic cervical hyperextension deformity following sagittal balance correction in a patient with congenital limb girdle myopathy. Patient was successfully treated by posterior cervical release and fusion after verification of the range of motion (ROM), the reducibility of the deformity and the absence of any positional spinal cord compression with dynamic radiographic examination and preoperative MRI in the desired post-operative position. CONCLUSIONS: We suggest posterior cervical release and fusion in case of a radiologically and clinically reducible cervical hyperextension deformity under both motor and sensory spinal evoked potential monitoring. In cases of long-standing rigid non reducible cervical hyperextension, laminectomy and concomitant duroplasty could be considered. PMID- 30415054 TI - Severe Lumbar Intervertebral Disc Degeneration Is Associated with Modic Changes and Fatty Infiltration in the Paraspinal Muscles at all Lumbar Levels, Except for L1-L2: A Cross-Sectional Analysis of 50 Symptomatic Women and 50 Age-Matched Symptomatic Men. AB - BACKGROUND: Low back pain is a common public health problem associated with lumbar intervertebral disc degeneration. It is still unclear, however, whether intervertebral disc degeneration is an isolated process or accompanied by other degenerative events. We analyzed whether disc degeneration was associated with vertebral end-plate changes and fatty infiltration in the paraspinal muscles. We also aimed to identify whether the severity of disc degeneration influenced this association. METHODS: Intervertebral disc degeneration, vertebral end-plate changes, and fatty infiltration in the multifidus, erector spinae, and psoas muscles at all lumbar intervertebral disc levels were evaluated on lumbar spine magnetic resonance images of 50 symptomatic women and 50 age-matched symptomatic men. RESULTS: The women had greater lumbar intervertebral disc degeneration scores at L4-L5 and L5-S1 and in total. The women had more fatty infiltration in the multifidus and erector spinae muscles at L4-L5 and L5-S1. The men had more fatty infiltration in the psoas muscle at L5-S1. Patients with severe intervertebral disc degeneration were more likely to have increased fatty infiltration in the multifidus and erector spinae muscles. The rate of vertebral end-plate changes was also greater in the patients with severe intervertebral disc degeneration. CONCLUSIONS: Severe disc degeneration in the lumbar spine is closely associated with Modic changes and fatty infiltration in the multifidus and erector spinae muscles. We suggest that disc degeneration is not an isolated event but, rather, a continuum of events that could more clearly be shown in future prospective, large sample-size studies. PMID- 30415055 TI - A comparison of cervical disc arthroplasty and anterior cervical discectomy and fusion in patients with two-level cervical degenerative disc disease: 5-year follow-up results. AB - OBJECTIVE: Present the long-term clinical and radiographic comparison between the Prestige-LP cervical disc replacement and the Zero-p spacer cervical disc fusion in treatment of patients with symptomatic two-level cervical degenerative disease. METHODS: 36 patients in the ACDF group and 24 patients in the CDA group were analyzed before surgery and at 1 week, 3, 6, 12, 24 and 60 months after surgery. Clinical assessments included Japanese Orthopedic Assessment (JOA), Visual Analog Scale (VAS), and Neck Disability Index (NDI) scores. Radiographic assessments included cervical lordosis (CL), range of motion (ROM) of the total cervical spine, functional spinal unit (FSU), superior and inferior adjacent segments. Complications including heterotopic ossification (HO) and adjacent segment degeneration (ASD) at 5-year follow-up were collected as well. RESULTS: Mean follow-up period was 65.6 months. Both ACDF and CDA groups showed significant clinical improvements in terms of JOA, VAS and NDI (P?.05), but there was no significant difference between groups at the last follow-up period. A significant increase of cervical lordosis (CL) was observed in the CDA group after surgery while significant difference was not observed between groups. ROM of the total cervical spine and FSU were maintained during the follow-up and significant decrease was observed in ACDF group after surgery (P?.05). The ROM of the superior adjacent segment did not show any difference while the ROM of the inferior adjacent segment in the ACDF group was observed a significant increase at 6 months and 1 year after surgery and a significant decrease at the last follow-up period. A total of 8 (33.3%) patients in the CDA group were observed an occurrence of HO. ASD was observed in 2 (8.3%) patients underwent CDA surgery and 8 (22.2%) patients underwent ACDF surgery. CONCLUSION: Both the use of the Prestige-LP and Zero-P spacer implantations are safe and effective. At 5 years after surgery, CDA with Prestige-LP is superior in terms of ROM of the total cervical spine, FSU and inferior adjacent segment. It also has a relatively low ASD occurrence rate. This procedure may be a suitable choice for the treatment of contiguous two-level CDDD. PMID- 30415057 TI - Pharmacological study of anti-inflammatory activity of aqueous extracts of Mikania glomerata (Spreng.) and Mikania laevigata (Sch. Bip. ex Baker). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Mikania glomerata Spreng. (MG) and Mikania laevigata Sch. Bip. ex Baker (ML), popularly known as guaco, are medicinal plants similar in morphology, chemical composition and medicinal uses. Both species are often used and sold without distinction; however, it is believed that their chemical composition is different. AIM: Thus, the aim of this study is to investigate if the aqueous extract of MG and ML present similar anti-inflammatory activity to the point of being used interchangeably. MATERIAL AND METHODS: Different doses of both extracts and coumarin were given to rats in different experimental models to assess the anti-inflammatory activity between these two species. For this, the animals were submitted to paw edema, pleurisy and degranulation of peritoneal mast cell and the extracts were also characterized by Ultra High Efficiency Liquid Chromatography coupled to Mass Spectrometry (UHPLC MS). RESULTS: The chromatographic method showed that ML presents ten times more coumarin than MG. Oral administration of MG, ML and coumarin inhibited paw edema induced by carrageenan (400 mg/kg, 55% inhibition; 400 mg/kg, 57% inhibition; 75 mg/kg, 38% inhibition; p < 0.05, respectively). MG, ML and coumarin treatment also inhibited the edema induced by compound 48/80 (400 mg/kg, 56% inhibition; 400 mg/kg, 69% inhibition; 75 mg/kg, 40% inhibition; p < 0.05, respectively). MG, ML and coumarin did not prevent mast cell degranulation and the consequent histamine release in Wistar rat peritoneal mast cells induced by compound 48/80. MG did not inhibit cell infiltration in pleurisy nor the highest dose tested, while ML decreased the leukocyte migration (200 and 400 mg/kg, 23% and 30% inhibition; p < 0.001, respectively) and, to a lesser extent, coumarin also reduced cell infiltration (10, 50 and 75 mg/kg; 15%, 16% and 17% inhibition; p < 0.001, respectively). CONCLUSION: The variation of the results of the anti inflammatory activity found in M. glomerata and M. laevigata demonstrates that these two species should not be used interchangeably. Coumarin, as already proven, has anti-inflammatory action however, we have suggested that it probably is not the only component responsible for this therapeutic effect in the extracts. PMID- 30415056 TI - The Differences between Intracranial Mesenchymal Chondrosarcoma and Conventional Chondrosarcoma in Clinical Features and Outcomes. AB - OBJECTIVE: The goal of this study is to report the differences in clinical feature and outcomes between intracranial MCS (mesenchymal chondrosarcoma) and CCS (conventional chondrosarcoma). METHODS: Clinical data of patients with primary intracranial MCS and CCS were retrospectively extracted and analyzed to compare the differences between each other. RESULTS: Seventy-four patients with intracranial chondrosarcoma (61 cases with MCS and 13 cases with CCS) were included. When compared with patients with CCS, those with MCS presented a younger mean age (21.1-year old vs 34.5-year old,p<0.001), a poor mean preoperative KPS (Karnofsky Performance Scale) (64.6 vs 77.8, p=0.014). When compared with CCS, MCS was less likely located in skull base (38.5% vs 96.7%, p<0.001) and had a larger tumor volume (87.8cm3 vs 26.7cm3, p<0.001). The rates of gross total resection (GTR) in MCS subgroup and CCS subgroup were 41.1% (25) and 46.2% (6), respectively; and the rates of adjuvant radiotherapy postoperatively were 44.2%(27) and 46.2%(6), respectively. After a mean follow-up of 41.7 months, 1-year, 3-year, and 5-year overall survival (OS) and progression free survival (PFS) of MCS were significantly shorter than that of CCS. Multivariate analysis revealed that the tumor pathology and the extent of surgery were independent predictors for tumor recurrence. CONCLUSIONS: Clinical features of MCS are quite different from that of CCS. The current management of intracranial MCS referring to CCS could not yield satisfactory outcomes enough. The treatment strategy of MCS should be aggressive and individualized. PMID- 30415058 TI - Actinidia Chinensis Planch Root Extract Attenuates Proliferation and Metastasis of Hepatocellular Carcinoma by Inhibiting Epithelial-Mesenchymal Transition. AB - ETHNO-PHARMACOLOGICAL RELEVANCE: Numerous studies have demonstrated the potent anticancer activity of various Chinese herbs. Actinidia Chinensis Planch root (acRoots), a traditional Chinese medicine, functions as an antitumor and detoxifying agent and plays a role in diuresis and hemostasis. Treatment with acRoots confers strong inhibition of tumor growth in various forms of cancer. Here, we evaluated the anticancer activity and molecular mechanisms of Actinidia Chinensis Planch root extract (acRoots) on hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Our previous study used mRNA chip analyses to identify the genes regulated by acRoots. Further analyses of the altered genes identified a key regulator of genes in response to acRoots. Here, the effects of acRoots on HCC cell proliferation, migration, invasion, and apoptosis were evaluated by cell counting, Transwell and apoptosis assays. In addition, the in vivo anti-HCC effects of acRoots were investigated using an HCC animal model. The expression of a key regulator of genes in response to acRoots was analyzed using quantitative polymerase chain reaction and western blotting. RESULTS: Treatment with acRoots (10mg/mL) had no cytotoxicity in L02 cells and had a positive effect on L02 cell viability; however, it significantly inhibited HCC cell proliferation. Treatment with acRoots downregulated DLX2 gene expression in HCC cells, and high DLX2 expression was associated with advanced stage and poor prognosis in patients with HCC. Treatment with acRoots inhibited proliferation, invasion and migration, clonality, and the epithelial-to-mesenchymal transition, and promoted the apoptosis of HCC cells by downregulating DLX2 expression. HCC cells with higher DLX2 expression were more sensitive to acRoots. CONCLUSIONS: acRoots inhibited the malignant biological behavior of HCC cells via regulation of the epithelial mesenchymal transition (EMT) by DLX2. PMID- 30415059 TI - Mycetia cauliflora methanol extract exerts anti-inflammatory activity by directly targeting PDK1 in the NF-kappaB pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Mycetia cauliflora Reinw. (Rubiaceae) has been used as a traditional remedy to ameliorate clinical signs of inflammatory diseases, including pain, inflammation, ulcers, and wounds. Among the Mycetia subfamilies, the molecular and cellular mechanisms of Mycetia longifolia (Rubiaceae) have been studied. However, those of Mycetia cauliflora are not clearly understood. Comprehensive investigation of this plant is necessary to evaluate its potential for ethnopharmacological use. MATERIALS: and methods: The activities of Mycetia cauliflora methanol extract (Mc-ME) on the secretion of inflammatory mediators, the mRNA expression of proinflammatory cytokines, and identification of its molecular targets were elucidated using lipopolysaccharide (LPS)-induced macrophage-like cells. Moreover, the suppressive actions of Mc-ME were examined in an LPS-induced peritonitis mouse model. RESULTS: At nontoxic concentrations, Mc-ME downregulated the release of nitric oxide (NO), the mRNA expression of inducible nitric oxide synthase (iNOS), and the mRNA expression of interleukin (IL)-1beta from LPS-activated RAW264.7 cells. This extract also inhibited the nuclear translocation of p65 and p50 and the phosphorylation of IkappaBalpha, IKK, and AKT. Western blot analysis and in vitro kinase assays confirmed that phosphoinositide-dependent kinase-1 (PDK1) is the direct immunopharmacological target of Mc-ME effect. In addition, Mc-ME significantly reduced inflammatory signs in an animal model of acute peritonitis. These effects were associated with decreased NO production and decreased AKT phosphorylation. CONCLUSION: Our results suggest that Mc-ME displays anti-inflammatory actions in LPS-treated macrophage-like cells and in an animal model of acute inflammatory disease. These actions are preferentially managed by targeting PDK1 in the nuclear factor (NF)-kappaB signaling pathway. PMID- 30415060 TI - Chemical characterization and evaluation of gastric antiulcer properties of the hydroethanolic extract of the stem bark of Virola elongata (Benth.) Warb. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Virola elongata is a tree species belonging to the Myristicaceae family, distributed in the North and Midwest regions of Brazil, in the phytogeographic domain of the Amazon. The aqueous infusion or the hydroethanolic macerate of the stem bark of V. elongata are used in Brazilian and Ecuadorian indigenous folk medicine for several ethnopharmacological purposes, principally, in the treatment of stomach pain, indigestions, and gastric ulcers. This study was aimed to investigate the gastroprotective activity of this plant in order to support its popular use with scientific evidence. MATERIALS AND METHODS: The stem bark hydroethanolic extract of the plant (HEVe) was prepared by maceration. Its qualitative and quantitative phytochemical constituents were investigated by classical colorimetric techniques, HPLC, and electrospray ionization-multiple stage fragmentation (ESI-MSn). The gastroprotective and antiulcer activity of HEVe at doses of 100, 300 and 900 mg/kg p.o. were tested using three acute (acidified ethanol, piroxicam, and in-water-restrain stress), and one chronic (acetic acid) animal ulcer models. The probable mode of action of the HEVe was evaluated by analyzing gastric acid secretion, mucus content, nitric oxide effect, and its antioxidant properties (on catalase, myeloperoxidase, and GSH content) in experimental rodents. The direct extract's activity on the growth of Helicobacter pylori was also investigated. RESULTS: Total phenolic content in the HEVe was of 146.20 +/- 1.07 mg, being flavonoids about 50% (71.79 +/- 0.70 mg) of it. Comparative HPLC fingerprint analysis revealed the presence of known phenolic antiulcer compounds, such as gallic acid, catechin, and rutin. Also, methanol/water fractionation and ESI-MSn analysis of the HEVe reveals the presence of quinic acid, 3,3',4-trihydroxystilbene, juruenolid D, one catechin dimer, one C-glycosyl flavonoid, one polyketide and two neolignans as the major components of the extract. The HEVe attenuated gastric ulceration in all the different models of acute gastric ulcer, by enhancing gastroprotection through its antioxidant properties in vivo, and reducing also considerably the gastric secretion and total acidity. The HEVe also presented healing properties against the induced chronic ulceration process. On the other hand, the HEVe did not exhibit direct activity against H. pylori. CONCLUSION: The HEVe exhibited significant gastroprotective/antiulcer effects and contain a relative high proportion of phenolic compounds, especially flavonoids, that could likely account, at least in part, for its pharmacological properties. The results justify its traditional usage and provided scientific evidence for its potential as a new herbal medicine to treat gastric ulcers. PMID- 30415061 TI - Acetylcholinesterase Inhibitor from Anthocleista vogelii Leaf Extracts. AB - BACKGROUND: Anthocleista vogelii (Planch) is used in folk medicine in conditions related to inflammation and oxidative stress. AIM OF STUDY: The leaf extracts were investigated for their bioactive constituents in our quest for novel compounds for the management of neurodegenerative diseases. MATERIALS AND METHODS: Anthocleista vogelii crude leaf extract obtained from 80% methanol was successively partitioned with n-hexane, dichloromethane (DCM), ethyl acetate (EtOAc) and n-butanol. This gave four solvent fractions of the crude extract. These fractions and isolated compound were subjected to acetylcholinesterase (AChE) inhibitory activity test using the microplate assay method. The structure of the isolated compound was determined using spectroscopic methods (1D and 2D NMR and MS). RESULTS: The results of the acetylcholinesterase inhibitory assay revealed that n-buOH and ethyl acetate fractions had the best activity with IC50 of 564.58 +/- 1.08 and 727.63 +/- 76.71ug/mL respectively. Activity directed fractionation of each of these fractions led to the isolation of the same compound identified as a C-glucosylflavone; isovitexin-7-O-methyl ether (swertisin). This rare C-glucosylflavone co-exist as two rotamers and exhibited duplication of NMR signals. It is reported from this plant for the first time. Swertisin displayed better acetylcholinesterase inhibitory activity with IC50 of 32.09 +/- 0.11ug/mL than physostigmine (eserine) with IC50 of 56.09 +/- 0.01ug/mL used as a standard. CONCLUSIONS: This study reports isolation and characetrization of a rare C-glycosylflavone; isovitexin-7-O-methyl ether (swertisin). Isolated compound exhibited duplication of NMR signals and better acetylcholinesterase inhibitory activity than eserine used as a standard. The activity exhibited by this compound suggests that it could be useful in the management of neurodegenerative diseases. PMID- 30415062 TI - Aqueous extract of Dipsacus asperoides suppresses lipopolysaccharide-stimulated inflammatory responses by inhibiting the ERK1/2 signaling pathway in RAW 264.7 macrophages. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Dipsaci Radix, which is the dried root of Dipsacus asperoides C. Y. Cheng and T. M. Ai (Dipsacaceae), is used to treat back pain and blood stasis syndrome in Korean traditional medicine. AIM OF THE STUDY: To understand the mechanisms responsible for the pharmacological activities of D. asperoides, we investigated the inhibitory effect of D. asperoides on lipopolysaccharide (LPS)-induced inflammation in mouse macrophages RAW 264.7 cells. MATERIALS AND METHODS: Aqueous extract of D. asperoides (AEDA) was prepared by boiling D. asperoides in water and then administered to LPS treated RAW 264.7 cells. Cell viabilities were measured using an MTT assay, and protein levels were determined by western blotting. The ROS scavenging activity of AEDA was measured using a DCFH-DA assay and levels of nitric oxide (NO) were determined using a NO assay. The nuclear translocations of NF-kappaB and Nrf2 were investigated immunocytochemically, and pro-inflammatory cytokines in supernatant were evaluated by ELISA. RESULTS: Treatment with AEDA suppressed the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX 2) in LPS-stimulated RAW 264.7 macrophages. AEDA also reduced ROS, pro inflammatory cytokine (IL-6 and IL-1beta) levels, and iNOS-derived NO and COX-2 derived prostaglandin E2 release to medium, and suppressed the phosphorylation and degradation of IkappaB and the activation of NF-kappaB in macrophages. Furthermore, treatment with AEDA inhibited the ERK1/2 pathway but not the JNK or p38 MAPK pathways. In addition, AEDA significantly promoted Nrf2 translocation from cytoplasm to nucleus and up-regulated the expression of HO-1. CONCLUSION: These results suggest that AEDA has anti-inflammatory and anti-oxidative effects through the inhibition of NF-kappaB and ERK1/2 and the activation of Nrf2/HO-1 in macrophages. PMID- 30415064 TI - Dynamic control of hydrogel crosslinking via sortase-mediated reversible transpeptidation. AB - Cell-laden hydrogels whose crosslinking density can be dynamically and reversibly tuned are highly sought-after for studying pathophysiological cellular fate processes, including embryogenesis, fibrosis, and tumorigenesis. Special efforts have focused on controlling network crosslinking in poly(ethylene glycol) (PEG) based hydrogels to evaluate the impact of matrix mechanics on cell proliferation, morphogenesis, and differentiation. In this study, we sought to design dynamic PEG-peptide hydrogels that permit cyclic/reversible stiffening and softening. This was achieved by utilizing reversible enzymatic reactions that afford specificity, biorthogonality, and predictable reaction kinetics. To that end, we prepared PEG-peptide conjugates to enable sortase A (SrtA) induced tunable hydrogel crosslinking independent of macromer contents. Uniquely, these hydrogels can be completely degraded by the same enzymatic reactions and the degradation rate can be tuned from hours to days. We further synthesized SrtA-sensitive peptide linker (i.e., KCLPRTGCK) for crosslinking with 8-arm PEG-norbornene (PEG8NB) via thiol-norbornene photocrosslinking. These hydrogels afford diverse softening paradigms through control of network structures during crosslinking or by adjusting enzymatic parameters during on-demand softening. Importantly, user controlled hydrogel softening promoted spreading of human mesenchymal stem cells (hMSCs) in 3D. Finally, we designed a bis-cysteine-bearing linear peptide flanked with SrtA substrates at the peptide's N- and C-termini (i.e., NH2-GGGCKGGGKCLPRTG CONH2) to enable cyclic/reversible hydrogel stiffening/softening. We show that matrix stiffening and softening play a crucial role in growth and chemoresistance in pancreatic cancer cells. These results represent the first dynamic hydrogel platform that affords cyclic gel stiffening/softening based on reversible enzymatic reactions. More importantly, the chemical motifs that affords such reversible crosslinking were built-in on the linear peptide crosslinker without any post-synthesis modification. STATEMENT OF SIGNIFICANCE: Cell-laden 'dynamic' hydrogels are typically designed to enable externally stimulated stiffening or softening of the hydrogel network. However, no enzymatic reaction has been used to reversibly control matrix crosslinking. The application of SrtA-mediated transpeptidation in crosslinking and post-gelation modification of biomimetic hydrogels is innovative because of the specificity of the reaction and reversible tunability of crosslinking kinetics. While SrtA has been previously used to crosslink and fully degrade hydrogels, matrix softening and reversible stiffening of cell-laden hydrogels has not been reported. By designing simple peptide substrates, this unique enzymatic reaction can be employed to form a primary network, to gradually soften hydrogels, or to reversibly stiffen hydrogels. As a result, this dynamic hydrogel platform can be used to answer important matrix related biological questions that are otherwise difficult to address. PMID- 30415065 TI - Glass-ceramics for cancer treatment: So close, or yet so far? AB - After years of research on the ability of glass-ceramics in bone regeneration, this family of biomaterials has shown revolutionary potentials in a couple of emerging applications such as cancer treatment. Although glass-ceramics have not yet reached their actual potential in cancer therapy, the relevant research activity is significantly growing in this field. It has been projected that this idea and the advent of magnetic bioactive glass-ceramics and mesoporous bioactive glasses could result in major future developments in the field of cancer. Undoubtedly, this strategy needs further developments to better answer the critical questions essential for clinical usage. This review aims to address the existing research developments on glass-ceramics for cancer treatment, starting with the current status and moving to future advances. STATEMENT OF SIGNIFICANCE: Although glass-ceramics have not yet reached their potential in cancer therapy, research activity is significantly growing. It has been speculated that this idea and the advent of modern glass-ceramics could result in significant future advances. Undoubtedly, this strategy needs further investigations and many critical questions have to be answered before it can be successfully applied for cancer treatment. This paper reviews the current state-of-the-art, starting with current products and moving onto recent developments in this field. According to our knowledge, there is a lack of a systematic review on the importance and developments of magnetic bioactive glass-ceramics and mesoporous bioactive glasses for cancer treatment, and it is expected that this review will be of interest to those working in this area. PMID- 30415066 TI - Reduced expression of the lncRNA NRON is a potential hallmark of the CMV amplified CD8+ T cell accumulations commonly seen in older humans. AB - The characteristic accumulation of late-stage differentiated CD8+ T cells is enhanced by lifelong latent cytomegalovirus (CMV) persistence, which makes it challenging to screen for subclinical biomarkers of immune aging in the elderly. We systematically identified predominantly preformed, long, noncoding RNAs (lncRNAs) as integrative biomarkers of CD8+ T cell aging in 14 elderly CMV carriers over 80 years of age. After sorting the CD28nullCD8+ T cell subset and its CD28bearingCD8+ counterpart in five nonagenarians, we profiled the differential expression of lncRNAs and genes in CD28nullCD8+ T cells via array detection. We focused on 11 differentially expressed antisense lncRNAs and cross referenced them with previously identified age-accumulated lncRNAs to create a set of candidates in CD28nullCD8+T cells. We performed intracellular validation on the age-accumulated candidate lncRNAs paired with their antisense target genes using quantitative polymerase chain reaction (qPCR). Simultaneously, we sorted the CMVpp65-specific CD8+ T cell subset and its counterpart from participant cells with the HLA-A-*0201 genotype. The validated age-accumulated lncRNAs in CD28nullCD8+ T cells were intracellularly cross-validated in CMVpp65CD8+ T cells. Finally, we identified the immunity-related gene(s) that acted as potential target(s) to the cross-validated age-accumulated lncRNA(s), using bioinformatics techniques. The potential regulation of the final identified lncRNA-gene pair(s) was simultaneously predicted in two pathway-integrated networks. We concluded that expression of an age-accumulated lncRNA (NRON) was decreased, whereas that of its immunity-related target gene (NFAT) was increased, in both CD28nullCD8+ T cells and CMVpp65CD8+ T cells of elderly individuals with persistent CMV infection. The identification of NRON as a potential biomarker suggests that NRON contributes to CMV-enhanced CD28nullCD8+ T cell aging by modulating phosphorylation and/or IL-4-dependent NFAT signaling. PMID- 30415063 TI - Attenuation of CD47-SIRPalpha Signal in Cholangiocarcinoma Potentiates Tumor Associated Macrophage-Mediated Phagocytosis and Suppresses Intrahepatic Metastasis. AB - The involvement of chronic inflammation in cholangiocarcinoma (CCA) progression is well established. Cluster of differentiation 47 (CD47) is mutually expressed in various cancers and serves as a protective signal for phagocytic elimination. CD47 signaling blockage is a recent treatment strategy; however, little is known regarding CD47 in CCA. Therefore, the potential use of CD47 targeting in CCA was focused. CD47 was highly expressed in CCA compared to hepatocellular carcinoma (HCC). Disturbance of CD47-signal regulatory protein-alpha (SIRPalpha) interaction by blocking antibodies promoted the macrophage phagocytosis. The therapeutic potential of anti-CD47 therapy was demonstrated in liver metastatic model; alleviation of cancer colonization together with dense macrophage infiltrations was observed. The usefulness of anti-CD47 was emphasized by its universal facilitating macrophage activities. Moreover, increased production of inflammatory cytokines, such as IL-6 and IL-10, in macrophage exposed to CCA conditioned media suggested that CCA alters macrophages toward cancer promotion. Taken together, interfering of CD47-SIRPalpha interaction promotes macrophage phagocytosis in all macrophage subtypes and consequently suppresses CCA growth and metastasis. The unique overexpression of CD47 in CCA but not HCC offers an exceptional opportunity for a targeted therapy. CD47 is therefore a novel target for CCA treatment. PMID- 30415067 TI - Brain signatures associated with swallowing efficiency in older people. AB - Swallowing is a complex movement consisting of the sequential and orderly activation of the swallowing muscles. Neuroimaging evidence has revealed a complex cortical and subcortical representation of voluntary swallowing. The repetitive saliva swallowing test (RSST) is a convenient and simple method for assessing swallowing performance in older people. It remains unclear whether individual differences in swallowing performance are associated with variations in structural brain signatures. We aimed to investigate the association between swallowing efficiency (SWE, measured by the RSST) and gray matter volume (GMV) in healthy older adults. Forty healthy older adults (52-82 years old, 28 female) underwent T1-weighted magnetic resonance imaging (MRI) and clinical assessments of SWE, stimulated/unstimulated salivary flow rate, masticatory cycle, and walking speed. GMV was quantified using a voxel-based morphometry (VBM) approach based on the MRI data. SWE was significantly negatively correlated with age. The association between SWE and hand grip strength, but not the other clinical metrics, was statistically significant. The GMV of the left posterior cerebellum (from cerebellum crus to lobule VIII) was significantly positively correlated with SWE, as evidenced by the results of whole-brain and cerebellum-specific VBM analyses. SWE was significantly positively correlated with the cerebellar volume in the region-of-interest analyses based on automated segmentation. In healthy older adults, swallowing efficiency was positively correlated with cerebellar GMV. The findings suggested that in older people, structural variations of the brain may play a key role in individual differences in swallowing performance. PMID- 30415068 TI - Alterations of hippocampal neurogenesis during development of Alzheimer's disease like pathology in OXYS rats. AB - Neurogenesis is the key mechanism of neuronal plasticity in the adult mammalian brain. Alterations of neurogenesis happen concurrently with (and contribute to) development and progression of numerous neuropathological conditions including Alzheimer's disease (AD). Being the most common type of dementia, AD is studied extensively; however, the data concerning changes in neurogenesis in the pathogenesis of this disease are inconsistent. Here, using OXYS rats as a suitable model of the most common (sporadic) form of AD, we examined neurogenesis in the hippocampal dentate gyrus in early ontogenesis prior to appearance of any signs of neurodegeneration and during development and progression of AD-like pathology. We demonstrated retardation of hippocampal development in OXYS rats at an early age; this problem may contribute to the emergence of AD signs late in life. Manifestation and progression of AD-like pathology are accompanied by transcriptome changes affecting genes involved in neurogenesis in the hippocampus. These genes are associated with the extracellular matrix and angiogenesis; this observation points to alteration of a cellular microenvironment. This change along with an increased TrkA/p75NTR ratio of nerve growth factor receptors in the hippocampus may contribute to increased density of immature neurons that we observed at the progressive stage of AD-like pathology in OXYS rats. These changes may be considered a compensatory reaction intended to slow down AD-associated neurodegeneration at the progressive stage of the disease. Collectively, these data suggest that alterations of neurogenesis may not only accompany the course of Alzheimer's disease but also play a causative role in this disorder. PMID- 30415070 TI - Neuron-specific overexpression of core clock genes improves stress-resistance and extends lifespan of Drosophila melanogaster. AB - Gene expression is much altered in aging. We observed age-dependent decline of core clock genes' expression in the whole body of the fruit fly. We hypothesized that inducible overexpression of clock genes (cry, per, tim, cyc and Clk) in the nervous system can improve healthspan of D. melanogaster. We studied the lifespan of transgenic Drosophila and showed life extension for cry, per, cyc and tim genes. It was also the significant positive changes in the stress-resistance of flies overexpressing core clock genes in conditions of hyperthermia, hyperoxia, starvation and persistent lighting. The overexpression of per and cry restore circadian rhythms of locomotor activity. The results presented support the hypotheses that the compensation of circadian oscillator genes expression can improve the healthspan in Drosophila melanogaster. PMID- 30415069 TI - Effects of ovarian hormones and estrogen receptor alpha on physical activity and skeletal muscle fatigue in female mice. AB - : Menopause is associated with declines in physical activity and skeletal muscle strength. Physical activity is also reduced in rodents after ovariectomy (OVX) and whole-body estrogen receptor alpha (ERalpha) knockout. However, it is unclear if the effects are estradiol (E2) specific. Thus, the overall purpose of this study was to investigate the effects of the ovarian hormones, E2 and progesterone (P4), and skeletal muscle ERalpha (skmERalpha) on physical activity and skeletal muscle contractility in female mice. METHODS: Study 1: Forty female C57Bl/6J mice were given free access to running wheels for 2 weeks to assess baseline running and randomized into 4 treatment groups: OVX, OVX + E2, OVX + P4, OVX + E2 + P4. All mice underwent OVX, returned to wheels for 2 weeks, received hormone pellet implants and returned to running wheels for 6 weeks, after which soleus muscle contractility testing was completed. Study 2: Thirty-two skeletal muscle specific ERalpha knock-out (skmERalphaKO) mice and wildtype (WT) littermates were randomized into 4 groups: skmERalphaKO-Run, skmERalphaWT-Run, skmERalphaKO-Sed, and skmERalphaWT-Sed. Run mice were given free access to wheels for 20 wk and sedentary (Sed) mice maintained normal cage activities. At the end point, muscle contractility was tested. RESULTS: Study 1: OVX + E2 + P4 group ran greater distances than both the OVX and OVX + P4 groups (p <= 0.009). After fatiguing contractions, soleus muscles of the OVX + E2 + P4 group maintained greater submaximal force than those of other groups (p = 0.023). Immediately after the fatiguing contractions, OVX + E2 + P4 muscles had greater maximal force production than the OVX + E2 group (p = 0.027). Study 2: There were no differences in running distance between skmERalphaWT and skmERalphaKO mice (p = 0.240). Soleus muscles of skmERalphaKO mice were more fatigable (p < 0.001) and did not recover force as well as skmERalphaWT mice (p < 0.001). In vivo isometric, concentric and eccentric torque was decreased in skmERalphaKO mice compared to skmERalphaWT mice (p <= 0.029). CONCLUSIONS: Combined treatment of E2 + P4 in OVX mice restored physical activity, predominantly driven by E2, and protected soleus muscles against fatigue. Muscle of skmERalphaKO mice was weak regardless of physical activity. Although 20 wk of wheel running partially prevented force loss during fatigue in skmERalphaKO mice, force production during recovery remained low, indicating that estradiol functions through ERalpha in skeletal muscle. PMID- 30415071 TI - Carbonization and ball milling on the enhancement of Pb(II) adsorption by wheat straw: Competitive effects of ion exchange and precipitation. AB - Straw biomass is a promising adsorbent for the removal of heavy metals. To improve its Pb(II) adsorption capacity and elucidate competition of adsorption mechanisms (e.g., ion exchange and precipitation), the Pb(II) adsorption mechanisms for wheat straw (WS-CK), wheat straw-biochar (WS-BC), and ball-milled wheat straw-biochar (WS-BC + BM) samples were investigated in detail by EDX, XRD, and FTIR. The results implied that the Pb(II) adsorption capacities at an adsorbent dosage of 0.2 g/L onto WS-CK, WS-BC, and WS-BC + BM were 46.33, 119.55, and 134.68 mg/g, respectively. This indicates that carbonization and ball milling are efficient techniques for improving the adsorption capacity of Pb(II) onto wheat straw, as WS-BC and WS-BC + BM exhibited adsorption capacities comparable to other commonly used bioadsorbents. Carbonization contributed significantly to precipitation (e.g., PbCO3 and Pb3(CO3)2(OH)2). Furthermore, competition existed between ion exchange and precipitation during the Pb(II) adsorption process. With relative lower adsorbent dosages, carbonization and ball milling enhanced ion exchange capacity. PMID- 30415072 TI - Enhancing the production of light olefins and aromatics from catalytic fast pyrolysis of cellulose in a dual-catalyst fixed bed reactor. AB - In this study, the effects of a macroporous catalyst (CaO), mesoporous catalyst (MCM-41), and microporous catalysts (ZSM-5 and SAPO-34) on the production of light olefins and aromatics from cellulose catalytic fast pyrolysis were investigated in a dual-catalyst fixed bed reactor. Further the fractional catalytic pyrolysis of MCM-41 or CaO with ZSM-5 or SAPO-34 was explored. The results showed that ZSM-5 was the most efficient catalyst for the formation of light olefins and aromatics followed by MCM-41, CaO and SAPO-34, and no aromatics were found with SAPO-34 only. Moreover, 15% CaO combined 85% ZSM-5 produced the highest yield of light olefins (5.59%) and aromatic (13.42%). The addition of CaO and MCM-41 promoted the selectivity of C2H4 and decreased the production of naphthalene. PMID- 30415073 TI - Lactic acid production from glucose and xylose using the lactogenic Escherichia coli strain JU15: Experiments and techno-economic results. AB - In this work, d-lactic acid production was evaluated from a simulated hydrolysate of corn stover (32 g/L xylose, 42 g/L glucose) with the metabolically engineered Escherichia coli strain JU15. Based on the experimental results, a technical and economic analysis of the entire process was performed using the Aspen Plus software. As a result, it was possible to show that the strain can efficiently produce lactic acid from both sugars, reaching a final concentration of 40 g/L and a yield of 0.6 g lactic acid/g sugars. The process is economically viable at higher scales of 1000 tons/day. The cost distribution is influenced by the scale of the process; on a larger scale, the cost of raw materials represents a higher percentage of total cost than it does on smaller scales. The use of a metabolically engineered strain allows a better use of the sugars obtained from agroindustrial residues. PMID- 30415074 TI - Is SBRT Boost Feasible for PET Positive Lymph Nodes for Cervical Cancer?: Evaluation using Tumor Control Probability (TCP) and QUANTEC Criteria. AB - BACKGROUND: and Purpose: To examine the feasibility of SBRT as an EBRT boost to PET positive Lymph Nodes (PET(+) LN) in cervical cancer patients and evaluate overall tumor control probability (TCP) increase. METHODS AND MATERIALS: Ten patients with cervical cancer and (PET(+) LN) metastasis who received EBRT (45Gy) followed by a 3D conformal radiotherapy (3DCRT) boost (5.4-9Gy) and tandem-and ovoid HDR brachytherapy (16-30Gy) were retrospectively enrolled in this study. SBRT plans were generated using 21Gy, 24Gy, or 30Gy as a replacement for 3DCRT boost. EQD2 dose maps were made using an alpha/beta value of 10 for PET(+) LNs and 3 for OARs. TCP values were calculated using a logistic TCP model where two input parameters (D50 and Gamma50=2) were modeled by two clinical outcomes, our institution and the literature. OAR sparing was evaluated using QUANTEC dose limits. RESULTS: Thirty percent of 10 patients receiving conventional boost, experienced recurrence. The TCP of SBRT schemes were 88+/-7% (97+/-2%) (21Gy), 96+/-1% (99+/-0%) (24Gy), and 99+/-1% (100+/-0%) (30Gy), while the conventional LN boost TCP value was 25+/-11% (58+/-15%) when TCP input parameters were based on published clinical outcome data for lymph node SBRT treatments (institutional outcome data). The tumor coverage dose (D90) of the SBRT boost plans were on average 32.34Gyalphabeta=10(21Gy), 37.78Gyalphabeta=10(24Gy), and 55.54Gyalphabeta=10(30Gy) higher than the conventional LN boost plan. The QUANTEC OAR dose constraints were met for the bladder, rectum, and bowel in all cases for the SBRT LN 21Gy group, and in 90% and 70% of cases in the SBRT LN 24Gy and SBRT LN 30Gy groups, respectively. CONCLUSION: An SBRT boost dose of 30Gy can be delivered without compromising QAUANTEC OAR limits. The use of SBRT increases TCP values regardless of input parameters. PMID- 30415075 TI - Impact of Multi-Institutional Prospective Peer Review on Target and Organ-At-Risk Delineation in Radiation Therapy. AB - PURPOSE: Peer review is an essential component of quality assurance programs in radiation oncology. The purpose of this work was to assess if peer reviewers recommend expansion or reduction of planning target volumes (PTVs) and organs-at risk (OARs) in prospective multidisciplinary daily contour rounds. METHODS AND MATERIALS: The peer group evaluated appropriateness of PTVs and OARs for each case according to evidence-based departmental directives. We reviewed 7645 cases presented between September 2013 and March 2017. We isolated recommendations for PTV/OAR modification and classified each as expansion, reduction, both, or indeterminate. Recommendations were analyzed by technique, site, and physician experience. RESULTS: Eight junior and 7 senior radiation oncologists were included. PTV or OAR modifications were recommended for 750 of 7645 prescriptions (9.7%). The peer group recommended PTV modifications for 534 prescriptions (7.0%). There were 309 expansions (57.9%), 115 reductions (21.5%), 15 both (2.8%), and 95 indeterminate (17.8%). Reasons for PTV expansions included increased nodal coverage and inadequate margins due to motion. The peer group recommended OAR modifications for 216 prescriptions (2.8%). There were 102 expansions (47.2%), 23 reductions (10.6%), 2 both (0.9%), and 89 indeterminate (41.2%). Reasons for OAR expansions included missing critical structures and inadequate extent as per departmental standardization. Head-and-neck represented the largest percentage of PTV recommendations (28.8%). Intensity-modulated radiation therapy (IMRT) plans received the most PTV and OAR recommendations (66.8% and 74.5% respectively). The recommendation rate for senior and junior faculty was 43% and 28% respectively. CONCLUSIONS: Peer review resulted in PTV or OAR change recommendations for approximately 10% of cases. Expansions of PTV were recommended over 2.5 times more frequently than reductions and over 3 times more frequently than OAR expansions. This general trend was observed for treatment technique, site, and physician experience. Prospective peer review could yield systematically larger volumes which could impact multi-center clinical trials. PMID- 30415076 TI - Pulsed Doppler fetal atrioventricular interval measurement: Assessment of a new image scoring method. AB - OBJECTIVES: We propose an image scoring method to improve the quality and the reproducibility of measurement of the AV interval before establishing reference tables of the measurements and studies on the prevention and treatment of first degree AV block especially if the first child has been diagnosed AV block. METHOD: Prospective study from May 2015 to June 2016. Sonographers were asked to measure AV interval with pulsed Doppler in a five-chamber view in standard second trimester screening before and after having received our image scoring method. Images were scored by 2 blinded reviewers. RESULTS: The intra-class correlation coefficient (ICC) between the two reviewers for the overall score was 0.91. On average, the measurement quality increased by 2.5 points/10 (95% CI 1.0-4.0). In the second set of images, after the scoring method was given, the score stared at 6.50 for the first image, with a significant improvement of 0.18 (p = 0.016) per subsequent image comparing to a non significant improvement for the first set of image. There was a significant improvement in intra-observer reliability, ICC: 0.680 [95% CI 0.606-0.854] versus 0.458 [95% CI 0.140-0.651]. CONCLUSION: The use of this scoring method is simple, reproducible and improves image quality and reproducibility of AV interval measurement in a five-chamber view. PMID- 30415077 TI - Presence of small screens in bedrooms is associated with shorter sleep duration and later bedtimes in children with obesity. AB - BACKGROUND: The presence of small screens in the sleep environment has been associated with shorter sleep duration and later bedtimes in children of normal weight, but the role these devices play in the sleep environment of overweight children is unclear. OBJECTIVE: To examine the association of small screen presence in the sleep environment with sleep behaviors among school-age children with obesity. METHODS: We surveyed 526 parents of children ages 6-12 years old with a body mass index (BMI) >= 95th percentile who were participating in a randomized trial to treat childhood obesity. Twelve months after enrollment, parents were asked how frequently their child slept with or near a small screen (defined as a cellphone, smartphone, or texting/chat-capable device). We used multivariable linear regression to examine associations of the presence of small screens with sleep duration, waketime, and bedtime. RESULTS: Compared to children who rarely/never slept with a small screen in their bedroom, children who did so one day or more per week had shorter sleep durations and later bedtimes. After adjusting for TV presence in the bedroom, small screen presence was still associated with shorter sleep duration (-9.9 minutes; p=0.02) and later weekday (8.8 minutes; p=0.03) and weekend (12.0 minutes; p=0.03) bedtimes. CONCLUSION: Children with obesity and a small screen present in their sleep environment have shorter sleep durations and later bedtimes than children who rarely/never sleep with a small screen. Pediatricians should consider inquiring about small screens in the bedroom when counseling on healthy sleep and weight management habits. PMID- 30415078 TI - Development and pilot testing of a coping kit for parents of hospitalized children. AB - OBJECTIVE: Serious pediatric illness places great stress on families. Parents who learn coping skills may better manage these stressors. This study sought to develop and refine a stress coping intervention for parents of hospitalized children, assess the intervention acceptability among these parents, and gather preliminary data on stress, negative and positive affect, anxiety, depression, and self-efficacy. METHODS: We conducted an observational study in 2 phases, enrolling parents of children who were inpatients with serious illness, 10 in Phase 1 and 40 in Phase 2. All parents completed at baseline measures of stress and psychological well-being and were introduced to the Coping Kit for Parents. Follow-up interviews were conducted at one week (all parents) and one month (Phase 2 parents only) regarding the acceptability of the intervention. RESULTS: At baseline, parents reported that stressful situations were frequent (mean=30.6, SD=6.8) and difficult (mean=26.2, SD=7.1), and revealed elevated levels of negative affect (mean=27.3, SD=7.7), depression (mean=8.5, SD=3.7) and anxiety (mean=11.3, SD=3.1), and moderate levels of self-efficacy related to their child's illness (mean=3.3, SD=0.5). The majority of parents used the kit regularly and on a scale of 1 to 7 agreed that the kit was helpful (mean=6.0, SD=0.9), interesting (mean=5.7, SD=1.3), practical (mean=5.7, SD=1.4), enjoyable (mean=6.0, SD=1.3), and they would recommend it to other parents (mean=6.4, SD=0.9). CONCLUSIONS: The Coping Kit for Parents is an acceptable stress management intervention that could be made available to parents of children with serious illness at pediatric hospitals with minimal staff training or time commitment. PMID- 30415079 TI - Admit v. Discharge-A Cost Analysis of Infants 29-60 Days Old with Febrile Urinary Tract Infection at Low Risk for Bacteremia. AB - BACKGROUND AND OBJECTIVES: Ninety percent of infants 29-60 days old presenting to the emergency department (ED) with fever and urinary tract infection are admitted due to fear of concomitant bacteremia. Many of these infants are at low risk for bacteremia and can be safely discharged with no heightened risk of adverse events. This study sought to estimate the potential savings from outpatient management of low-risk infants. METHODS: A comparative cost analysis was performed using bacteremia probability estimates from a previously published prediction model. We estimated costs using a national pediatric database coupled with retrospective chart review of infants who presented to our ED between 2011 2015. RESULTS: The relative cost savings for the discharge strategy was $80,333 ($19,127 vs. $99,460; 80% savings) for each patient with bacteremia and $257,073 per 100 patients overall. Similar savings were found for charges-$304,949 ($71,421 vs $376,371; 80%) for each patient with bacteremia and $975,838 per 100 patients. Our institutional reimbursements provided an estimated savings of $148,924 ($73,280 vs. $222,204; 67%) and $476,533 per 100 patients overall. CONCLUSIONS: The relative cost savings from discharging rather than admitting low risk infants with febrile UTI were significant, even accounting for expenditures associated with the return emergency room visit of initially discharged bacteremic patients. These savings are achievable without an increase in adverse events. Similar outcomes were demonstrated for hospital charges and reimbursements, which further strengthens these results. This study emphasizes how risk stratification in clinical decision-making can lead to substantial cost savings without compromising patient outcomes. PMID- 30415080 TI - Response to Anastasio et al. - Severe imported falciparum malaria - Clinical and drug supply challenges. PMID- 30415081 TI - Bacterial respiratory carriage in French Hajj pilgrims and the effect of pneumococcal vaccine and other individual preventive measures: A prospective cohort survey. AB - BACKGROUND: Viral respiratory tract infections are known to be common in Hajj pilgrims while the role of bacteria is less studied. METHODS: Clinical follow-up, adherence to preventive measures and PCR-based pharyngeal bacterial carriage pre- and post-Hajj, were assessed in a cohort of 119 French Hajj pilgrims. RESULTS: 55% had an indication for pneumococcal vaccination. Occurrence of respiratory symptoms was 76.5%, with cough (70.6%) and sore throat (44.5%) being the most frequent; fever was reported by 38.7% pilgrims and 42.0% took antibiotics. Respiratory symptoms, fever and antibiotic intake were significantly more frequent in pilgrims with indication for vaccination against pneumococcal infection. The prevalence of S. pneumoniae carriage (1.8% pre-, 9.8% post-Hajj), H. influenzae carriage (0.9%, 45.4%) and K. pneumoniae (2.8%, 9.8%) significantly increased post-Hajj. Pilgrims vaccinated with conjugate pneumococcal vaccine were seven time less likely to present S. pneumoniae carriage post-Hajj compared to those not vaccinated (3.2% vs. 18.0%, OR = 0.15; 95% CI [0.03-0.74], p = 0.02). CONCLUSIONS: Pilgrims at risk for pneumococcal disease are more likely to suffer from febrile respiratory symptoms at the Hajj despite being immunized against pneumococcal disease and despite lowered S. pneumoniae carriage and should be targeted for reinforced prevention against respiratory infections. PMID- 30415082 TI - Rationale and design for a cluster randomized quality-improvement trial to increase the uptake of evidence-based therapies for patients at high cardiovascular risk: The BRIDGE-Cardiovascular Prevention trial. AB - BACKGROUND: Translating evidence into clinical practice in the management of high cardiovascular risk patients is challenging. Few quality improvement interventions have rigorously evaluated their impact on both patient care and clinical outcomes. OBJECTIVES: The main objectives are to evaluate the impact of a multifaceted educational intervention on adherence to local guidelines for the prescription of statins, antiplatelets and angiotensin converting enzyme inhibitors or angiotensin II receptor blockers for high cardiovascular risk patients, as well as on the incidence of major cardiovascular events. DESIGN: We designed a pragmatic two arm cluster randomized trial involving 40 clusters. Clusters are randomized to receive a multifaceted quality improvement intervention or to routine practice (control). The multifaceted intervention includes: reminders, care algorithms, training of a case manager, audit and feedback reports, and distribution of educational materials to health care providers. The primary endpoint is the adherence to combined evidence-based therapies (statins, antiplatelet therapy and angiotensin converting enzyme inhibitors or angiotensin receptor blockers) at 12 months after the intervention period in patients without contra-indications for these medications. All analyses follow the intention-to-treat principle and take the cluster design into account using linear mixed logistic regression modeling. SUMMARY: If proven effective, this multifaceted intervention would have wide utility as a means of promoting optimal usage of evidence-based interventions for the management of high cardiovascular risk patients. PMID- 30415083 TI - An international cluster-randomized quality improvement trial to increase the adherence to evidence-based therapies for acute ischemic stroke and transient ischemic attack patients: Rationale and design of the BRIDGE STROKE Trial. AB - BACKGROUND: Translating evidence into clinical practice in the management of acute ischemic stroke (AIS) and transient ischemic attack (TIA) is challenging especially in low- and middle-income countries. OBJECTIVES: The aim of this study is to assess the effect of a multifaceted quality improvement intervention on adherence to evidence-based therapies for AIS and TIA patients care. DESIGN: We designed a pragmatic, 2-arm cluster-randomized trial involving 36 clusters and 1624 patients from Brazil, Argentina, and Peru. Hospitals are randomized to receive a multifaceted quality improvement intervention (intervention group) or to routine care (control group). The BRIDGE Stroke multifaceted quality improvement intervention includes case management, reminders, health care providers' educational materials (including treatment algorithms), interactive workshops, and audit and feedback reports. Primary outcome is a composite adherence score to AIS and TIA performance measures. Secondary outcomes include an "all or none" composite end point to performance measures, the individual components of the composite end points, and clinical outcomes at 90 days following admission (stroke recurrence, death, and disability measured by the modified Rankin scale). SUMMARY: The BRIDGE Stroke Trial is an international pragmatic evaluation of a multifaceted quality improvement intervention. If effective, this intervention could be potentially extended widely to improve the quality of care and outcomes of patients with AIS or TIA. PMID- 30415084 TI - Blood pressure differences between home monitoring and daytime ambulatory values and their reproducibility in treated hypertensive stroke and TIA patients. AB - BACKGROUND: Guidelines recommend ambulatory or home blood pressure monitoring to improve hypertension diagnosis and monitoring. Both these methods are ascribed the same threshold values, but whether they produce similar results has not been established in certain patient groups. METHODS: Adults with mild/moderate stroke or transient ischemic attack (N = 80) completed 2 sets of ambulatory and home blood pressure monitoring. Systolic and diastolic blood pressure values from contemporaneous measurements were compared, and the limits of agreement were assessed. Exploratory analyses for predictive factors of any difference were conducted. RESULTS: Daytime ambulatory blood pressure values were consistently lower than home values, the mean difference in systolic blood pressure for initial ambulatory versus first home monitoring was -6.6 +/- 13.5 mm Hg (P<=.001), and final ambulatory versus second home monitoring was -7.1 +/- 11.0mm Hg (P<=.001). Mean diastolic blood pressure differences were -2.1 +/- 8.5mm Hg (P=.03) and -2.0 +/- 7.2mm Hg (P=.02). Limits of agreement for systolic blood pressure were -33.0 to 19.9mm Hg and -28.7 to 14.5mm Hg for the 2 comparisons and for DBP were -18.8 to 14.5mm Hg and -16.1 to 12.2mm Hg, respectively. The individual mean change in systolic blood pressure difference was 11.0 +/- 8.3mm Hg across the 2 comparisons. No predictive factors for these differences were identified. CONCLUSIONS: Daytime ambulatory systolic and diastolic blood pressure values were significantly lower than home monitored values at both time points. Differences between the 2 methods were not reproducible for individuals. Using the same threshold value for both out-of-office measurement methods may not be appropriate in patients with cerebrovascular disease. PMID- 30415085 TI - Signaling lymphocyte activation molecule family in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease characterized by a breakdown in immune tolerance leading to the development of auto-reactive lymphocytes and autoantibodies. Recent findings have provided new insight on the role of the signaling lymphocytic activation molecule family (SLAMF) receptors, a group of nine co-regulatory molecules involved in the activation of hematopoietic cells, and their downstream protein SLAM-associated protein (SAP), into the pathogenesis of SLE. This review summarizes the current knowledge on SLAMF in human SLE immunopathogenesis, and the importance of SLAMF molecules as new therapeutic targets. PMID- 30415086 TI - Natural and modified IL-2 for the treatment of cancer and autoimmune diseases. AB - Interleukin-2 (IL-2) is a pleiotropic cytokine required for both effector lymphocyte proliferation/differentiation and regulatory T cell expansion/survival. Ability to receive IL-2 signals is defined by the affinity to distinct IL-2-receptor-complexes expressed on each subset of cells. While IL-2 targets anti-tumor cytotoxic lymphocytes (CTLs) for the treatment of patients with melanoma or renal cell carcinoma, IL-2 directed at regulatory T (Treg) cells could have potential therapeutic value in several immune-related diseases including chronic graft-versus-host disease (cGVHD), type 1 diabetes (T1D) and systemic lupus erythematosus (SLE). A variety of IL-2 alteration has been made to deliver IL-2 to the proper target, including mutant IL-2, IL-2-fusion proteins and anti-IL-2 antibodies. Experimental and clinical trials using IL-2 are expanding to diverse group of diseases including solid organ transplantation. Although the sustainability and efficiency of IL-2-responding cells in controlling disease activity are still not fully understood, the results of clinical trials will provide a basis of the most effective regimen for each disease. PMID- 30415087 TI - Inhibition as a potential resolution to the attentional capture debate. AB - Physically salient stimuli, such as uniquely colored objects, seem to have an inherent power to capture our attention, but formal research on this topic has produced conflicting results and theories. Here, we review evidence that the attentional capture debate can be resolved by positing a new suppressive process. This suppressive process can occur before attentional shifting to prevent salient items from attracting attention. In the current article, we review converging evidence that salient items are suppressed to avoid attentional capture comes from studies of psychophysics, eye movements, single-unit recordings, and event related potentials (ERPs). Crucially, the ability to inhibit salient distractors seems to be learned as participants gain experience with the simple features of the to-be-ignored stimuli. PMID- 30415088 TI - Comparison of OnabotulinumtoxinA versus sacral neuromodulation for refractory urinary urge incontinence: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND & AIM: Both intradetrusor OnabotulinumtoxinA (BTX) and Sacral neuromodulation (SNM) as third-line therapies for urgency urinary incontinence (UUI) are increasingly being utilized. However, there are differences in preference between patients and medical personnel in clinical practice. This meta analysis was designed to compare BTX versus SNM in treatment of UUI. METHODS: We searched the Cochrane Library, PubMed, EMBASE and Web of Science from January 1, 1992 to April 22, 2018. Mean differences (MDs) and risk ratio (RR) with its 95% confidence intervals (CIs) were estimated to compare the outcomes of the groups. All the MDs were after subtracting OnabotulinumtoxinA data from Sacral neuromodulation data. RRs were acquired from comparing OnabotulinumtoxinA data to Sacral neuromodulation data. Two reviewers assessed trial quality and extracted data independently. All statistical analyses were performed using standard statistical procedures provided in Review Manager 5.2. This work has been reported in line with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and AMSTAR (Assessing the methodological quality of systematic reviews) Guidelines. RESULTS: Seven randomized controlled trials and two retrospective studies (N = 1649 participants) were identified for the present analysis. In change from baseline in UUI episodes (UUIE) per day, comparing BTX groups with SNM groups, the effects were observed through 1, 2, 4, 5 and 6 month, with pooled MDs of -0.62, -0.55, -0.38, -1.02 and -0.50 respectively. In UUIE reduction post treatment, the pooled RRs of complete UUIE reductions through 4 and 6 months respectively were 5.13 and 6.63. Significant results were observed through overall times in more than 75% UUIE reduction. No significance was found in more than 50% UUIE reduction. Significant results were observed in urinary tract infection. More treatment satisfaction were found in BTX groups than that in SNM groups (RR 1.14, 95% CI 1.01-1.29; P = 0.004). CONCLUSIONS: Generally, BTX seems superior to SNM in treatment of UUI but inferior regarding safety. Patients receiving BTX experienced a higher treatment satisfaction. PMID- 30415089 TI - Trans-anal or trans-abdominal total mesorectal excision? A systematic review and meta-analysis of recent comparative studies on perioperative outcomes and pathological result. AB - BACKGROUND: Trans-anal total mesorectal resection (TaTME) is a novel approach for rectal cancer. However, the perioperative and pathological outcomes of this procedure remain controversial. METHOD: A systematic literature search was performed using PubMed, Embase, Wanfang (China) and the Cochrane Library databases without restriction to regions or languages. We included 17 trials comparing TaTME with Laparoscopic TME (LaTME) for meta-analysis (MA). Fixed and random-effect models were used to measure the pooled estimates. RESULTS: A total of 17 trials including 1346 patients were eligible for this MA. Pooled perioperative data using TaTME was associated with a significant reduction in estimated blood loss (WMD: 41.40, CI: 76.83 to -5.97; p = 0.02), hospital stay (WMD: 1.27, CI: 2.32 to -0.23; p = 0.02), conversion (OR: 0.28 CI: 0.15-0.52; p < 0.0001), readmission rates (OR: 0.42, CI: 0.25-0.69; p = 0.0007) and overall postoperative complications (OR: 0.73, CI: 0.56-0.95; p = 0.02). TaTME did not compromise surgical duration (WMD: 11.61, CI: 26.62-3.41; p = 0.13) or enhance complications including anastomotic leakage, ileus, urinary dysfunction, wound infection and pelvic abscess. Concerning pathological outcomes, the TaTME group demonstrated longer circumferential resection margins (CRM) (WMD: 0.91, CI: 0.58 1.24; p < 0.00001) and reduced CRM involvement (OR: 0.47, CI: 0.29-0.75; p = 0.002), whilst the distal resection margin (DRM) quality of the mesorectum and harvested lymph node were comparable. CONCLUSION: TaTME achieves similar surgical outcomes to LaTME, with the added advantage of a safe CRMs, reduced blood loss, shorter hospital stay, lower conversion and readmission rates, and lower postoperative morbidity. Long-term oncological and functional data are now required to confirm these findings. PMID- 30415090 TI - Management of distal radius fracture: A comparison of actual and theoretical treatments. AB - PURPOSE: The objective of this study was to explore whether there were any differences between the theoretical operative treatment of distal radius fractures according to AAOS guideline on basis of measurement of radiographs and the treatment they actually received in our institution. METHODS: From April 2015 to February 2018, a total of 693 patients with 697 fresh close adult distal radius fractures were evaluated retrospectively. Fractures were respectively grouped into categories by AAOS criterion and actually treatment. After gleaning demographic information and measuring radiographic items, all results were put into a database. Single factors analysis, Chi-square test and further logistic regression analysis were performed to determine correlations between actual and theoretical treatments. RESULTS: In all 240 fractures fulfilled at least one AAOS criterion for surgery, only 61 fractures actually received operation. And in the conservative group recommended by AAOS, 52 of 457 fractures actually were proceeded with surgery. There were slight correlation between AAOS guideline and actually operation (Phi = 0.181). From multivariable logistic regression analysis, Only one of three AAOS criterion was proved probable indicator of clinic treatment. Three factors, namely age, intra-articular step-off as well as with other fractures, were proved probable actually surgery indications (P < 0.05). CONCLUSIONS: AAOS surgery criteria of distal radius fractures were partially instructive, but not so precise predictors for actually operation. In the clinic, the choice of operative treatment correlated with multiple factors. PMID- 30415092 TI - Public-private partnerships for e-government in developing countries: An early stage assessment framework. AB - Although public-private partnerships (PPP) and electronic government (e government) have proven to be fruitful mechanisms for economic development and emerging economies seem to recognize their importance, consistent methods for analyzing the early planning stages of e-government portfolios are lacking. The present work utilized a comprehensive literature review to understand the evaluation criteria for PPP projects throughout the early-stage planning process. A qualitative meta-synthesis was employed to identify critical factors for PPP and e-government, with a particular focus on developing countries, PPP, and e government criteria. Our research presents a framework named "PPP4e-Gov" (public private partnerships for e-government). The framework compares risk and value factors of e-government PPP projects and adopts a weighted scoring model that estimates the risks that should be considered in a project and how much value a given e-government initiative may generate if the PPP option is chosen. As an illustration of how the framework may be used, the paper interviewed ten practitioners in Costa Rica who tried out PPP4e-Gov and showcased how to plan their e-government initiatives. PMID- 30415091 TI - Dysexecutive disorders and their diagnosis: A position paper. AB - Although executive function disorders are among the most prevalent cognitive impairments a consensus on diagnostic criteria has yet to be reached. With a view to harmonizing these criteria, the present position paper (i) focuses on the main dysexecutive disorders, (ii) examines recent approaches in both the behavioral and cognitive domains, (iii) defines diagnostic boundaries for frontal syndrome, (iv) reports on the frequency and profile of the executive function disorders observed in the main brain diseases, and (v) proposes an operationalization of diagnostic criteria. Future work must define the executive processes involved in human adaptive behavior, characterize their impairment in brain diseases, and improve the management of these conditions (including remediation strategies and rehabilitation). PMID- 30415093 TI - High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers - authors' response. PMID- 30415094 TI - Sudden unexpected death in the young - Value of massive parallel sequencing in postmortem genetic analyses. AB - Cases of sudden cardiac death (SCD) in young and apparently healthy individuals represent a devastating event in affected families. Hereditary arrhythmia syndromes, which include primary electrical heart disorders as well as cardiomyopathies, are known to contribute to a significant number of these sudden death cases. We performed postmortem genetic analyses in young sudden death cases (aged <45years) by means of a defined gene panel using massive parallel sequencing (MPS). The data were evaluated bioinformatically and detected sequence variants were assessed using common databases and applying in silico prediction tools. In this study, we identified variants with likely pathogenic effect in 6 of 9 sudden unexpected death (SUD) cases. Due to the detection of numerous unknown and unclassified variants, interpretation of the results proved to be challenging. However, by means of an appropriate evaluation of the findings, MPS represents an important tool to support the forensic investigation and implies great progress for relatives of young SCD victims facilitating adequate risk stratification and genetic counseling. PMID- 30415095 TI - The effects of household corrosive substances on silver amalgam and porcelain fused-to-metal restorations and non-restored teeth. AB - This study examines the effects of household corrosive products on 105 restored (silver amalgam and porcelain-fused-to metal) and non-restored teeth. Five household products were utilized, including hydrochloric acid, sulfuric acid and detergent. Teeth were radiographed before and after exposure and were submerged for 120 or 264h. Documentation included weight, mesiodistal and buccolingual crown measurements, ordinal scores, and photography at specific hours of exposure. Results indicate that 81.9% of the teeth could be positively matched by radiographs. Hydrochloric acid had the most destructive effects mainly to non restored and silver amalgam teeth followed by sulfuric acid. Porcelain samples were more resistant to the effects of acid and conferred protection to the underlying teeth. Acid type, acid concentration and the restoration type are statistically significant contributors to alterations and in radiographic matching. Household corrosive substances may affect the morphology of teeth, and in some cases completely destroy teeth, which could conceal identifications. PMID- 30415096 TI - Sexual size dimorphism in three species of forensically important blowflies (Diptera: Calliphoridae) and its implications for postmortem interval estimation. AB - Forensic entomologists rely on insects present in human remains to establish a minimum postmortem interval (PMImin). Blowflies have been widely used in these estimates because they lay eggs on the victim's body shortly after death and, within hours, larvae hatch and grow at predictable rates. Hence, isomegalen diagrams based on larval size and local temperature are considered good models to estimate PMImin. Still, most professional do not account for size sexual dimorphism in blowflies, which add uncertainty to predictive models by two mechanisms: (1) males and females might grow up to different sizes, and; (2) males and females might grow at different rates. In this study, we investigate sexual dimorphism and biases on the prediction of adult size in three species of blowflies (Lucilia sericata, Calliphora vicina and Calliphora vomitoria) reared under different larval densities. Estimated size range, stablished with and without sex discrimination, showed that females were larger than males in the three species. The ultimate size of adult stage, however, was more difficult to predict. C. vicina and C. vomitoria decrease as density raises but at different rates, and even males and females of the same species react differently to density increase. Adult size of L. sericata, in contrast, shows a slight increase with density. Except for C. vomitoria females, estimated size ranges are lower when species are divided by sex. Our results show that sex is an important factor to consider in PMImin estimates. Scenarios for all three species shorten their estimated size ranges when compared to databases with no sex identification. Therefore, computing data by sex raises accuracy in size based predictive models. PMID- 30415097 TI - Micro-CT for saw mark analysis on human bone. AB - In toolmark analysis, microscopy techniques, such as micro-CT, are used to visualise and measure toolmarks left on bones by a tool. In dismemberment cases, properties such as the width of the saw mark can provide cues to which tool was used by the culprit. The aim of the current study was to establish whether; (i) micro-CT is an appropriate imaging technique for saw mark analysis, (ii) toolmarks statistically differ when created with different tools, (iii) toolmark width can predict tool blade width, and (iv) toolmarks differ if created under different methodological conditions. Across two experiments, 270 saw marks were created using eight tools with either a controlled or free saw action on either fleshed or defleshed human long bone. Toolmarks were micro-CT scanned and seven toolmark properties were categorised or measured by two independent raters. The current study found that; (i) micro-CT was found to be a powerful and reliable imaging method for the visualisation and measurement of saw mark properties, (ii) toolmark properties differed significantly within and between various methodological conditions (p<.001) when created by eight different tools, (iii) a regression model developed using toolmark widths from Experiment 2 overall predicted 94% of tool widths in Experiment 1, and iv) methodological factors such as tissue presence and saw action significantly and inconsistently influenced toolmark properties for different tools. The study further validates the use of mirco-CT for saw mark analysis and demonstrates the potential of using toolmark properties to determine the tool used in cases of dismemberment. Given the effects that methodological factors such as tissue presence can have on toolmark properties, future studies should use experimental set ups with fleshed human tissue and use a free saw action. PMID- 30415098 TI - Detergent-modified catalytic and enzymomimetic activity of silver and palladium nanoparticles biotemplated by Pyrococcus furiosus ferritin. AB - Palladium and silver nanoparticles (NPs) anchored at the outer surface of ferritin form stable suspension of non-coated particles that possess several catalytic and enzymomimetic activities. These activities are strongly affected by detergents that significantly influence the reaction efficiency and specificity. Reductive dehalogenation of various azo dye substrates shows strong differences in reactivity for each substrate-detergent pair. Reductive dehalogenation is negatively influenced by cationic detergents while catalytic depropargylation is severely impaired by polyethylene oxide containing detergents that is an important finding in respect to potential biorthogonal applications. Moreover, Suzuki-Miyaura reaction is promoted by polyethylene oxide containing detergents but some of them also facilitate dehalogenation. Enzymomimetic peroxidase activity of silver NPs can be detected only in presence of sodium dodecyl sulfate (SDS) while peroxidase activity of palladium NPs is enhanced by SDS and sodium deoxycholate. PMID- 30415099 TI - Racial/ethnic differences in the utilization of chemotherapy among stage I-III breast cancer patients, stratified by subtype: Findings from ten National Program of Cancer Registries states. AB - BACKGROUND: The study aimed to examine racial/ethnic differences in chemotherapy utilization by breast cancer subtype. METHODS: Data on female non-Hispanic white (NHW), non-Hispanic black (NHB), and Hispanic stage I-III breast cancer patients diagnosed in 2011 were obtained from a project to enhance population-based National Program of Cancer Registry data for Comparative Effectiveness Research. Hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) were used to classify subtypes: HR+/HER2-; HR+/HER2+; HR-/HER2-; and HR-/HER2 + . We used multivariable logistic regression models to examine the association of race/ethnicity with three outcomes: chemotherapy (yes, no), neo-adjuvant chemotherapy (yes, no), and delayed chemotherapy (yes, no). Covariates included patient demographics, tumor characteristics, Charlson Comorbidity Index, other cancer treatment, and participating states/areas. RESULTS: The study included 25,535 patients (72.1% NHW, 13.7% NHB, and 14.2% Hispanics). NHB with HR+/HER2- (adjusted odds ratio [aOR] 1.22, 95% CI 1.04-1.42) and Hispanics with HR-/HER2- (aOR 1.62, 95% CI 1.15-2.28) were more likely to receive chemotherapy than their NHW counterparts. Both NHB and Hispanics were more likely to receive delayed chemotherapy than NHW, and the pattern was consistent across each subtype. No racial/ethnic differences were found in the receipt of neo-adjuvant chemotherapy. CONCLUSIONS: Compared to NHW with the same subtype, NHB with HR+/HER2- and Hispanics with HR-/HER2- have higher odds of using chemotherapy; however, they are more likely to receive delayed chemotherapy, regardless of subtype. Whether the increased chemotherapy use among NHB with HR+/HER2- indicates overtreatment needs further investigation. Interventions to improve the timely chemotherapy among NHB and Hispanics are warranted. PMID- 30415100 TI - The impact of temperature on metal mixture stress: Sublethal effects on the freshwater isopod Asellus aquaticus. AB - Chemical and natural factors have been demonstrated to interact and potentially change the toxicity of the individual stressors. Yet, while there exists a multitude of papers studying the temperature-dependent toxicity of single chemicals, little research exists on the impact of temperature on chemical mixtures. This paper investigates the effect of temperature on environmentally relevant mixtures of Cd, Cu and Pb. We linked the effects on respiration, growth, feeding rate and activity of Asellus aquaticus to the free ion activities, as a measure for the bioavailability of the metals, and the body concentrations. We observed interactions of temperature and metal body concentrations on all sublethal endpoints, except activity. Mixture effects on accumulation and feeding rate were observed as well and even an interaction between metal body burden, mixture and temperature treatment was revealed for the feeding rate of Pb exposed isopods. This research adds to a growing body of evidence that the current chemical-based monitoring is insufficient to estimate chemical toxicity in aquatic ecosystems and must, therefore, be complemented with effect-based tools. PMID- 30415101 TI - Co-delivery of paclitaxel and cisplatin in poly(2-oxazoline) polymeric micelles: Implications for drug loading, release, pharmacokinetics and outcome of ovarian and breast cancer treatments. AB - Concurrent delivery of multiple drugs using nanoformulations can improve outcomes of cancer treatments. Here we demonstrate that this approach can be used to improve the paclitaxel (PTX) and alkylated cisplatin prodrug combination therapy of ovarian and breast cancer. The drugs are co-loaded in the polymeric micelle system based on amphiphilic block copolymer poly(2-methyl-2-oxazoline-block-2 butyl-2-oxazoline-block-2-methyl-2-oxazoline) (P(MeOx-b-BuOx-b-MeOx). A broad range of drug mixing ratios and exceptionally high two-drug loading of over 50 wt.% drug in a stable micellar solution is demonstrated. The drugs co-loading in the micelles result in a slowed-down release to serum, improved pharmacokinetics and increased tumor distribution for both drugs. A superior anti-tumor activity of co-loaded PTX/CP drug micelles compared to single drug micelles or their mixture was demonstrated in cisplatin-resistant human ovarian carcinoma A2780/CisR xenograft tumor and multidrug resistant breast cancer LCC-6-MDR orthotopic tumor models. The improved tumor delivery of co-loaded drugs was related to decreased drug release rates as confirmed by simulation for micelle, serum and tumor compartments in a three-compartmental model. Overall, the results provide support for the use of PTX and cisplatin co-loaded micelles as a strategy for improved chemotherapy of ovarian and breast cancer and potential for the clinical translation. PMID- 30415102 TI - Thermo-triggered ultrafast self-healing of microporous coating for on-demand encapsulation of biomacromolecules. AB - Medical coatings cooperated with biomacromolecules can regulate biological events and tissue responses, thus increasing medical implant longevity and providing improved and/or new therapeutic functions. In particular, medical coatings, which can load the correct species and doses of biomacromolecules according to individual diagnoses, will significantly optimize treatment effects and satisfy the rising clinical need of "precision medicine". Herein, we report on a dynamic microporous coating with an ultrafast self-healing property to fulfill the "load and-play" concept for "precision medicine". A structure-switchable coating based on poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) triblock copolymer network is constructed. The coating can be switched to microporous morphology via a water swelling and freeze-drying process. Then, through a mild thermo-trigger as low as 40 degrees C, this spongy coating can undergo self-healing to switch back to a pore-free structure within minutes to even 5 s. Based on this dynamic coating, we suggest a simple and versatile method to encapsulate biomacromolecules for surface-mediated delivery. The ultrafast self-healing of the microporous structure enables uniform incorporation of biomacromolecules with an easily achieved high loading of albumin of 16.3 MUg/cm2 within 1 min. More importantly, controllable encapsulation can be realized by simple control of the concentration of the loading solution. We further demonstrate that the encapsulated biomacromolecules retained their bioactivity. This work may benefit clinicians with flexibility to provide personalized medical coatings for individual patients during treatment. PMID- 30415103 TI - Phylogeny and Classification of Novel Diversity in Sainouroidea (Cercozoa, Rhizaria) Sheds Light on a Highly Diverse and Divergent Clade. AB - Sainouroidea is a molecularly diverse clade of cercozoan flagellates and amoebae in the eukaryotic supergroup Rhizaria. Previous 18S rDNA environmental sequencing of globally collected fecal and soil samples revealed great diversity and high sequence divergence in the Sainouroidea. However, a very limited amount of this diversity has been observed or described. The two described genera of amoebae in this clade are Guttulinopsis, which displays aggregative multicellularity, and Rosculus, which does not. Although the identity of Guttulinopsis is straightforward due to the multicellular fruiting bodies they form, the same is not true for Rosculus, and the actual identity of the original isolate is unclear. Here we isolated amoebae with morphologies like that of Guttulinopsis and Rosculus from many environments and analyzed them using 18S rDNA sequencing, light microscopy, and transmission electron microscopy. We define a molecular species concept for Sainouroidea that resulted in the description of 4 novel genera and 12 novel species of naked amoebae. Aggregative fruiting is restricted to the genus Guttulinopsis, but other than this there is little morphological variation amongst these taxa. Taken together, simple identification of these amoebae is problematic and potentially unresolvable without the 18S rDNA sequence. PMID- 30415105 TI - Is there an association between pregnant women's experience of violence and their partner's drinking? A Swedish population-based study. AB - OBJECTIVE: Pregnancy is a time of heightened vulnerability for women, especially for experiencing violence in their close and intimate relationships. Alcohol misuse by a male intimate partner is a known contributor to increased risk and severity of intimate partner violence generally, however less is known about the relationship between partner drinking patterns and women's experience of violence in their relationship, and particularly in early pregnancy. This study aimed to explore these associations in a large, population-based sample of Swedish expectant parents. DESIGN, SETTING AND PARTICIPANTS: Data for this cross sectional study were drawn from 11 461 couples (22 922 participants) enrolled in Salut, a child health promotion programme in Vasterbotten County Council, Sweden. Data were collected at women's antenatal care visits during the first trimester of pregnancy. MEASUREMENTS: Questionnaires included male partners' self-reported drinking patterns using AUDIT (Alcohol Use Disorders Identification Test) and pregnant women's reports of violence. Descriptive and logistic regression analyses were undertaken to examine prevalence of reported violence and association with partner drinking patterns. FINDINGS: There was a strong association between male partner alcohol misuse and the odds of pregnant women experiencing violence in general, experiencing violence since becoming pregnant, and fear for their own safety at the time of enrolment in ANC. The odds of having experienced being controlled or physically hurt in a relationship, or having ever experienced sexual violence, were higher with more serious alcohol misuse by the male partner. Most striking was that women whose partners reported hazardous drinking or alcohol dependence had nearly nine times higher odds of experiencing being physically hurt by a partner since becoming pregnant, compared to women whose partners reported non-harmful alcohol use (OR 8.50, CI 2.39-30.17, p = 0.001). Fearing for current safety was also strongly linked to more severe alcohol use by their current male partner (OR 7.65, CI 1.02-57.24, p = 0.048). KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: This study contributes population level evidence that the risk for women of experiencing violence in general or in early pregnancy is exacerbated when a male partner drinks in harmful ways. Health professionals and those supporting pregnant women should pay attention to the role of risk factors such as partner alcohol use. Ensuring the health of pregnant women and safety in their relationships is important for maternal, foetal and infant health and family functioning. PMID- 30415104 TI - Addressing transition to motherhood, guideline adherence by midwives in prenatal booking visits: Findings from video recordings. AB - OBJECTIVE: To assess if and how primary care midwives adhere to the guideline by addressing transition to motherhood at the first prenatal booking visit and to what extent there was a difference in addressing transition to motherhood between nulliparous and multiparous women. DESIGN: Cross-sectional observational study of video-recorded prenatal booking visits. SETTING AND PARTICIPANTS: 126 video recordings of prenatal booking visits with 18 primary care midwives in the Netherlands taking place between August 2010 and April 2011. MEASUREMENTS: Five observers assessed dichotomously if midwives addressed seven topics of transition to motherhood according to the Dutch guideline prenatal midwifery care from the Royal Dutch Organization of Midwives and used six communication techniques. Frequencies and percentages of addressing each topic and communication technique were calculated. Differences between nulliparous and multiparous women were examined with Chi-Square tests or Fischer Exact tests, were appropriate. The agreement between the five observers was quantified using Fleiss' Kappa. FINDINGS: During all visits at least one of the seven topics of transition to motherhood was addressed. The topics mother-to-infant bonding and support were addressed respectively in 2% and 16% of the visits. In almost all visits the topics desirability of the pregnancy, experience with the ultrasound examination or abdominal palpation or hearing the foetal heartbeat and practical preparation were addressed. Open questions for addressing transition to motherhood were used in 6% of the prenatal booking visits. Dutch midwives addressed transition to motherhood mostly by giving information (100%) and by using closed-ended questions (94%) and following woman's initiative (90%). Nulliparous women brought up transition to motherhood on their own initiative more often than multiparous women (97% versus 84%). For the topics 'desirability of the pregnancy 'and' practical preparations' and for conversation techniques 'giving information' and 'closed-ended questions', 100% agreement was achieved. However, the topic 'Support' had poor agreement (kappa = 0.19). KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Although during every visit the transition of motherhood was addressed, the topics mother-to-infant bonding and support should get more attention. Midwives should improve adherence to the guideline by addressing transition to motherhood and by using more open questions. Furthermore, they should focus on taking the initiative to address the transition to motherhood in multiparous women themselves. PMID- 30415106 TI - Palliative treatment of germ cell cancer. AB - Most patients with metastatic germ-cell cancer (GCC) can be cured by cisplatin based combination chemotherapy. Yet, about 10-15% of metastatic GCC patients will eventually die of their disease. This narrative review focuses on treatment options when cure is no longer realistic. PMID- 30415107 TI - Effects of personal and task constraints on limb coordination during walking: A systematic review and meta-analysis. AB - BACKGROUND: In human behaviour, emergence of movement patterns is shaped by different, interacting constraints and consequently, individuals with motor disorders usually display distinctive lower limb coordination modes. OBJECTIVES: To review existing evidence on the effects of motor disorders and different task constraints on emergent coordination patterns during walking, and to examine the clinical significance of task constraints on gait coordination in people with motor disorders. METHODS: The search included CINHAL Plus, MEDLINE, HSNAE, SPORTDiscus, Scopus, Pubmed and AMED. We included studies that compared intra limb and inter-limb coordination during gait between individuals with a motor disorder and able-bodied individuals, and under different task constraints. Two reviewers independently examined the quality of studies by using the Newcastle Ottawa Scale-cohort study. FINDINGS: From the search results, we identified 1416 articles that studied gait patterns and further analysis resulted in 33 articles for systematic review and 18 articles for meta-analysis-1, and 10 articles for meta-analysis-2. In total, the gait patterns of 539 patients and 358 able-bodied participants were analysed in the sampled studies. Results of the meta-analysis for group comparisons revealed a low effect size for group differences (ES = 0.24), and a moderate effect size for task interventions (ES = -0.53), on limb coordination during gait. INTERPRETATION: Findings demonstrated that motor disorders can be considered as an individual constraint, significantly altering gait patterns. These findings suggest that gait should be interpreted as functional adaptation to changing personal constraints, rather than as an abnormality. Results imply that designing gait interventions, through modifying locomotion tasks, can facilitate the emergent re-organisation of inter-limb coordination patterns during rehabilitation. PMID- 30415108 TI - Synthesis, recognition and sensing properties of dipyrrolylmethane-based anion receptors. AB - Two tweezer-like anion receptors 2,2'-bis(2-cyano-2-phenylvinyl)-5,5'-dimethyl dipyrromethane (1) and 2,2'-bis[2-cyano-2-(4-nitrophenyl)vinyl]-5,5'-dimethyl dipyrromethane (2) were synthesized in good yields, via a facile condensation of diformyldipyrromethane and the appropriate phenylacetonitrile. Anion recognition properties of these receptors were studied in detail in DMSO solution, by means of UV-vis and 1H NMR titration techniques. The obtained results indicated that receptor 2 containing a terminal nitro group exhibited the strong and selective binding to biologically important fluoride and dihydrogenphosphate ions over other anions. In addition, the binding strength of receptor 2 with fluoride was enhanced by a factor of 18, relative to receptor 1 lacking the nitro group. Remarkably, the presence or absence of nitro group within receptor compounds also had a great influence on the anion-binding selectivity. In particular, a distinct color change of DMSO solution of receptor 2 was observed only upon addition of fluoride, showing the potential of 2 acting as an effective colorimetric sensor for the detection of fluoride anion. PMID- 30415109 TI - Modeling and simulation for the evaluation of dose adaptation rules of intravenous lacosamide in children. AB - A combined adult and pediatric population pharmacokinetic model including covariate effects was developed; simulations were subsequently performed to guide intravenous pediatric dosing adaptations. Two pharmacokinetic trials with sparse blood sampling were conducted in children with epilepsy and two trials in healthy adults with serial blood sampling. Lacosamide plasma concentration-time data were available from 43 healthy adults (18-45 years of age; body weight 50-101 kg; n = 1735 concentration vs time records), and from 79 children with epilepsy (6 months 17 years of age; body weight 6-76 kg; n = 402 concentration vs time records), with 14, 22, 25 and 18 participants in age groups <2 years, 2 to <6 years, 6 to <12 years and 12 to <18 years, respectively. A two-compartment population pharmacokinetic model was developed using nonlinear mixed effects modeling. Plasma clearance was scaled using a fixed allometric exponent on body weight, while central volume of distribution used a freely estimated allometric exponent. The model-based pharmacokinetic predictions suggested that there is no need to adapt the recommendations regarding intravenous infusion durations in children compared with adults. PMID- 30415110 TI - Cost Effectiveness of Combination Therapy Versus Monotherapy in Benign Prostatic Hyperplasia: A Colombian Experience. AB - OBJECTIVES: To estimate the incremental cost effectiveness ratio of pharmacological treatment for benign prostatic hyperplasia from the payer's perspective. METHODS: The cost effectiveness of 5 mg finasteride, 0.5 mg dutasteride, 10 mg alfuzosin, 10 mg terazosin, 0.4 mg tamsulosin, 4 mg doxazosin, and the combination therapy of 5 mg finasteride and 8 mg doxazosin was evaluated using a Markov model over a 30-year period. The costs were estimated using national tariffs and were reported in US dollars. Cost and effectiveness outcomes were discounted at a rate of 5% per year. Men (aged >=40 years) with moderate to severe lower urinary tract symptoms and uncomplicated benign prostatic hyperplasia were included in the analysis. Outcomes included costs and quality adjusted life-years. A probabilistic sensitivity analysis was performed on important parameters with Monte-Carlo simulation. RESULTS: Finasteride alone or in combination with doxazosin dominated all alpha-blockers. After excluding dominated alternatives, the incremental cost-utility ratio for combination therapy was $377 per quality-adjusted life-year, being a cost-effective alternative using the threshold of $15 000. Model results were robust to changes in costs, utility weights, and probabilities. Acceptability curves consistently demonstrated that the combination therapy was most likely cost-effective. CONCLUSIONS: The combination of finasteride and doxazosin is cost-effective compared with dutasteride, tamsulosin, terazosin, and alfuzosin in patients with benign prostatic hyperplasia with moderate or severe symptoms who are older than 40 years. PMID- 30415111 TI - Virus-associated carcinomas of the head & neck: Update from the 2017 WHO classification. AB - Virus-associated carcinomas of the head and neck represent an unusual confluence of infections spread by viral transmission and cellular dysregulation resulting in carcinogenesis. While much remains to be elucidated about the exact progression from infection to cancer, a basic framework of viral biology can complement the pathologist's understanding of morphology. This context informs the pathologist's everyday practice, including selecting ancillary studies, communicating prognostically relevant findings, and participating in treatment planning. By comparing and contrasting the salient features of human papillomavirus-associated oropharyngeal carcinoma and Epstein-Barr virus associated nasopharyngeal carcinoma, this review summarizes recent evidence to guide current practice. PMID- 30415112 TI - Semen collection by electro-stimulation in a variety of bird orders. AB - It is unquestinable that artificial insemination (AI) offers many benefits to avian conservation programs, but a serious impediment towards implementing AI for wild species is the development of effective techniques to consistently collect good quality ejaculates. Thus, we aimed to examine the success rate of electro stimulation (ES) in collecting semen from 49 unconditioned males from orders Piciformes, Strigiformes, Accipitriformes, Cathartiformes, Galiformes, Anseriformes and Psittaciformes at different times of the year. Sixty out of 299 ES attempts provided ejaculates with sperm, but collection success rates varied widely (0-50%) depending on the species. Except for swans whose greater results were registered during spring-summer, males from most orders responded better to ES during winter-spring, suggesting seasonal variations on semen collection success rates. Overall, ES enabled successful semen collection from males of unproven and proven fertility under mixed pairing conditions. However, the highest success rate occurred in paired males with fertile clutches (40.6%) followed by unpaired males (22.1%), paired males without clutches (13.9%), and paired males with infertile clutches (6.8%). Behavioral responses of male birds to electrical impulses were also recorded to assess any discomfort during semen collection. Furthermore, macroscopic and microscopic analysis provided ejaculate parameters from several species, even from orders that hitherto have never been assessed for semen collection, which may serve as a starting point in the future. Altogether, these findings demonstrate the feasibility of ES in collecting semen from unpaired, unconditioned and non-imprinted males from a variety of bird orders. In the medium to long term, the use of this technique in both captive and free-ranging populations offers new perspectives to ensure genetic diversity in avian conservation programs. PMID- 30415113 TI - Hepatic metabolomics reveals that liver injury increases PCB 126-induced oxidative stress and metabolic dysfunction. AB - The deleterious effects of PCB 126 are complex, and the role of the liver in modifying toxic insult is not well understood. We utilized metabolomics approaches to compare liver metabolites significantly affected by PCB 126 in control mice and a diet induced liver injury mouse model. In this 14-week study, mice were fed either an amino acid supplemented control diet (CD) or a methionine choline deficient diet (MCD) which promoted nonalcoholic steatohepatitis (NASH) and were subsequently exposed to PCB 126. The liver metabolome was profiled by a global metabolomic analysis using LC-MS. There were clear differences between PCB 126 exposed and control mice in the hepatic metabolomic profiles (216 and 266 metabolites were altered in CD-fed and MCD-fed mice respectively after PCB 126 exposure). PCB 126 modulated glycerophospholipid metabolism, glutathione metabolism, and CoA biosynthesis pathways irrespective of diet; indicating that the disturbance in lipid metabolism and thiol metabolites are general markers of PCB 126 exposure irrespective of liver health. Additionally, metabolites associated with oxidative stress and mitochondrial dysfunction were greatly elevated in PCB 126 exposed mice with compromised livers (e.g., 4-hydroxy-nonenal glutathione, oxylipids, uric acid, and acylcarnitines). Moreover, PCB 126 exposure downregulated redox genes, and the effect was more pronounced in liver injury mice. In conclusion, this study demonstrates that PCB 126 could induce oxidative stress and metabolic dysfunction, and pre-existing liver injury can markedly modify PCB 126-induced metabolic changes. Using metabolic profiling, this study suggests mechanism of enhanced PCB 126 toxicity under liver injury settings. PMID- 30415115 TI - The aqueous solubility of common organic groundwater contaminants as a function of temperature between 5 and 70 degrees C. AB - High-temperature thermal energy storage in shallow aquifers can potentially increase ambient groundwater temperatures up to 70 degrees C or even more. Since an increase in temperature is expected to influence contaminant mass flux into groundwater monitoring the spreading of organic contaminants located in the subsurface is crucial. In numerous former studies, the NAPL solubility, one major parameter controlling mass flux on field scale, was measured at temperatures up to 70 degrees C for a broad spectrum of organic substances. However, quantitative calculations of solubilities as a function of temperature considering a compiled database are largely missing. Aiming to examine the reliability of existing solubility-temperature relationships, to describe them functionally and further to identify knowledge gaps, previously published data on solubilities of 42 different organic groundwater contaminants were evaluated in this study. By using a common temperature regression function, the calculated solubility curves from compiled solubility data for 5-70 degrees C show relative changes between a few percent (CHCs and BTEX) and up to 2000% (PAHs). As published temperature-dependent solubilities for chlorinated ethylenes are contradictory in parts, solubilities of tetrachloroethylene, trichloroethylene, 1,2-cis-dichloroethylene and 1,2-trans-dichloroethylene were additionally investigated in more detail using batch experiments between 5 and 70 degrees C. The results show distinctive solubility minima at medium temperatures (20-40 degrees C) with concentrations decreasing from 5 degrees C to the minimum by 10 20%. The measured and calculated temperature-dependent solubilities enable a more reliable assessment of thermal energy storage at contaminated sites, of existing thermal remediation approaches and of combinations of underground heat storage with groundwater remediation. PMID- 30415114 TI - Effects of lead, mercury, aluminium and manganese co-exposure on the serum BDNF concentration of pre-school children in Taizhou, China. AB - Previous studies have shown that toxic metal exposure can have adverse effects on the nervous system of children, but the toxicology of metal co-exposure on neurodevelopment remains to be clarified. Brain derived neurotrophic factor (BDNF) plays an important role in nervous system development, but the possible effects of metal co-exposure on the serum BDNF concentrations of children remain unknown. A total of 561 children living in Taizhou City, China were recruited to participate in our cross-sectional multicenter survey. We measured their blood Pb, Hg, Al and Mn levels and serum BDNF concentrations as well as determined their associations in the total and within sex subgroups. The geometric means of the blood Pb, Hg, Al and Mn levels in all the participants were 67.18 MUg/L, 1.01 MUg/L, 52.03 MUg/L and 18.26 MUg/L, respectively. The serum BDNF concentration in children was 19.45 ng/mL. After adjusting for confounders, the blood Pb levels were significantly negatively associated with the serum BDNF concentrations in all the subjects and boys but not in girls. In addition, a significantly negative interaction between blood Pb and blood Hg and a positive interaction between blood Pb and blood Al on serum BDNF concentrations were also observed in boys but not in girls. Our findings highlight the toxic effects of metal co-exposure on serum BDNF levels in pre-school children and indicate that these effects might differ by gender, which suggest that special attention should be paid to the sex specific effects of metal exposure. PMID- 30415116 TI - Genotoxicity assay and potential byproduct identification during different UV based water treatment processes. AB - Formation of genotoxic byproducts during different ultraviolet (UV) -related water/wastewater treatment processes (including medium pressure (MP) UV oxidation, LP UV oxidation, chlorination, biological activated carbon (BAC) treatment, H2O2 oxidation, and two or more combined processes) was investigated by Ames fluctuation test using Salmonella strains TA98 and TA100 with and without rat liver enzyme extract S9. Byproducts responsible for genotoxicity were identified. The results showed that MP UV can induce mutagenicity and LP UV treatment does not induce mutagenicity. H2O2 oxidation could degrade part of genotoxic compounds. Compared with chlorination, BAC treatment is more effective in removing genotoxicity. Mutagenicity was found mostly in samples tested with TA100 instead of TA98, especially with TA100 without S9, indicating that guanosine and/or cytosine adducts contribute to mutation or toxicological effects in MP UV treated samples. Potential genotoxic byproducts were selected, most of which were nitrogenous organic compounds with more than 10 carbon atoms. Nitrosamines and histidine were excluded from potential genotoxic candidates. The results could contribute to evaluation of mutagenicity of various UV-based water treatment processes. PMID- 30415117 TI - Bioaccumulation and cycling of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) in three mangrove reserves of south China. AB - Total 22 organochlorine pesticides (OCPs) compounds and 31 polychlorinated biphenyls (PCBs) congeners in mangrove sediments and tissues (leaf, branch, root and fruit) of nine species from three Mangrove Reserves of China were studied. The mean concentrations of total DDTs, HCHs, OCPs and PCBs in sediments were 2.84, 0.06, 3.84 and 0.17 ng g-1 dw, while those in tissues were 1.85, 0.22, 9.43 and 1.61 ng g-1 dw, respectively. The elevated OCPs and PCBs levels in mangrove leaves may be caused by atmospheric sedimentation. The biota sediment accumulation factor (BSAF) values of both OCPs (mean: 3.4) and PCBs (mean: 9.9) are generally larger than one, implying mangroves' bioaccumulation and their ability to intercept pollutants. The BSAFs of PCBs in mangrove tissues were negatively correlated with the PCB congener's octanol-water partition coefficients (KOW, R = 0.58, n = 31, p < 0.001), suggesting that lower chlorinated CB congeners are more bioaccumulative in mangroves. In order to better understanding the fate of these organochlorine compounds, the cycling (including the standing accumulation, the annual absorption, the annual net retention, the annual return, and the turnover period) of OCPs and PCBs in the Mangrove Reserves were estimated, and the results indicated that mangroves are playing important roles in retaining OCPs and PCBs. PMID- 30415118 TI - Efficient extraction of estrogen receptor-active compounds from environmental surface water via a receptor-mimic adsorbent, a hydrophilic PEG-based molecularly imprinted polymer. AB - We report an efficient screening procedure for the selective detection of compounds that are actively bound to estrogen receptor (ER) from environmental water samples using a receptor-mimic adsorbent prepared by a molecularly imprinted polymer (MIP). To mimic the recognition ability of ER, we improved the typical MIP preparation procedure using a hydrophilic matrix with a polyethylene glycol (PEG)-based crosslinker and a hydrophobic monomer to imitate the hydrophobic pocket of ER. An optimized MIP prepared with methacrylic acid as an additional functional monomer and estriol (E3), an analogue of 17beta-estradiol (E2), exhibited highly selective adsorption for ER-active compounds such as E2 and E3, with significant suppression of non-specific hydrophobic adsorption. The prepared MIP was then applied to the screening of ER-active compounds in sewage samples. The fraction concentrated by the MIP was evaluated by in vitro bioassay using the yeast two-hybrid (Y2H) method and liquid chromatography-quadrupole time of-flight mass spectrometry (LC-Q-TOFMS). Compared to an authentic adsorbent, styrene-divinylbenzene (SDB)-based resin, the fraction concentrated by the MIP had 120% ER activity in the Y2H assay, and only 25% peak volume was detected in LC-Q-TOFMS. Furthermore, a few ER-active compounds were identified only from the fraction concentrated by the MIP, although they could not be determined in the fraction concentrated by the SDB-based resin due to ion suppression along with high levels of hydrophobic compounds. These results indicated that the newly developed MIP effectively captured ER-active compounds and while allowing most non-ER-active compounds to pass through. PMID- 30415119 TI - Transport and retention behavior of carbonaceous colloids in natural aqueous medium: Impact of water chemistry. AB - Carbon based materials are emerging as a sustainable alternative to their metal oxide counterparts. However, their transport behavior under natural aqueous environment is poorly understood. This study investigated the transport and retention profiles of carbon nanoparticles (CNPs) and graphene oxide quantum dots (GOQDs) through column experiments in saturated porous media. CNPs and GOQDs (30 mg/L) were dispersed in natural river water (RW) and passed through the column at a flow rate of 1 mL/min, which mimicking the natural water flow rate. After every 10 min, the column effluents were collected and the mass recovery and retention profiles were monitored. Results indicated that the transport of both carbonaceous colloids was predominantly controlled by surface potential and ionic composition of natural water. The CNPs with its high surface potential (-40 mV) exhibited more column transport and was less susceptible to solution pH (5.6-6.8) variation as compared to GOQDs (-24 mV). The results showed that, monovalent salt (NaCl) was one of the dominating factors for the retention and transport of carbonaceous colloids compared to divalent salt (CaCl2). Furthermore, the presence of natural organic matter (NOM) increased the transport of both carbonaceous colloids and thereby decreases the tendency for column retention. PMID- 30415120 TI - Investigation on degradation behavior of dissolved effluent organic matter, organic micro-pollutants and bio-toxicity reduction from secondary effluent treated by ozonation. AB - The environmental risk of secondary effluent has caused increasing attention in recent years, the negative effect of dissolved effluent organic matters (dEfOM) and organic micro-pollutants (OMPs) was a hot research point. In this research, the degradation behavior of dEfOM and fourteen OMPs in the ozonation was revealed using spectroscopic and chromatographic tools. Ozonation was effective for reducing UV254, but had limited effect in dissolved organic carbon reduction. The dEfOM with shorter absorption wavelength was preferentially removed in the ozonation (230 nm > 240 nm > 254 nm) and high molecular weight humics was largely reduced by the ozonation. Soluble microbial by-products were more reactive with ozone than humic acid as reflected by the fluorescence. Degradation behavior of the OMPs was identified based on their elimination kinetics and molecular structures and a simplified classification method was proposed. The group I OMPs (logkO3>5) showed high removal efficiency with 1 mg/L of ozone, while the removal of group II OMPs (1< logkO3<5) was largely dependent on the ozone dose. The CC bond, deprotonated amidogen, phenolic, aniline and anisole groups in these OMPs structures were the main reaction sites with ozone. The group III OMPs without active groups in the molecules showed slight removal in the ozonation. Moreover, genotoxicity and estrogenic activity were simultaneously analyzed for further evaluation on the risk of the effluent. The genotoxicity and estrogenic activity of the secondary effluent were 73.46 MUg 4-NQO/L and 519.86 ng E2/L, respectively and an ozone dose of 10 mg/L could reduce the bio-toxicity to the detection limit. PMID- 30415121 TI - A systematic ab initio optimization of monohydrates of HCl*HNO3*H2SO4 aggregates. AB - Hydrates of HCl, HNO3 and H2SO4 involved in polar stratospheric clouds capture the attention of researchers due to the mixtures composed with them. The molecular aggregates generated with these strong acids show different behaviors, geometries and nucleation reactions at atmospheric temperatures. Here is presented a systematic ab initio optimization study of monohydrates of HCl*HNO3*H2SO4 using the Density Functional Theory, by means of geometry optimizations carried out with B3LYP hybrid method and aug-cc-pVTZ basis set, a high level of theory, within Gaussian 09 program. This systematic optimization procedure consists to situate systematically the H2O molecule around the cluster in study, on the favorable positions to develop higher quantity of hydrogen bonds as possible, in order to obtain major quantity of different electronic structures of these monohydrates. Applying this systematic optimization methodology over previously optimized complexes of HCl, HNO3 and H2SO4, the present theoretical approach provides thirty-two different optimized electronic structures of monohydrates that were yielded from seven initial groups of (HCl*HNO3*H2SO4) complex, placing the H2O in eight positions around them. Moreover, their Infrared spectra have been predicted for all (HCl*HNO3*H2SO4)-monohydrates achieved. Likewise, It is shown the outcomes of the electronic energies, relative Gibbs free energies, Infrared spectra, the wavenumbers of hydrogen bonds, inter monomeric parameters, electronic structures of (HCl*HNO3*H2SO4)-monohydrates. These monohydrates could be considered precursors of the atmospheric heterogeneous nucleation reactions. These results can be useful to experimentalists of Catalysis, Astrophysics, Corrosion of metals and ceramics, aromatic compounds reactions, even environmental pollution and industrial smog. PMID- 30415122 TI - Targeting the NF-kappaB/IkappaBalpha complex via fragment-based E-Pharmacophore virtual screening and binary QSAR models. AB - Nuclear factor-kappaB (NF-kappaB) transcription factors represent a conserved family of proteins that regulate not only immune cells, but also heart cells, glial cells and neurons, playing a fundamental role in various cellular processes. Due to its dysregulation in certain cancer types as well as in chronic inflammation and autoimmune diseases, it has recently been appreciated as an important therapeutic target. The aim of this study was to investigate the binding pocket of NF-kappaB (p50/p65) heterodimer complex in association with NF kappaB inhibitor IkappaBalpha to identify potent ligands via fragment-based e pharmacophore screening. The ZINC Clean Fragments (~2 million) and the Schrodinger's medically relevant Glide fragments library (~670) were used to create the e-pharmacophore models at the potential binding site which was validated by site mapping. Glide/HTVS docking was conducted followed by re docking of the top 20% fragments by Glide/SP and Glide/XP protocols. The top 85000 Glide XP-docked fragments were used to generate the e-pharmacophore hypotheses. The Otava small molecule library (~260000 drug-like molecules) and 85 known NF-kappaB inhibitors were additionally screened against the derived e pharmacophore models. The top-1000 high-scored molecules, which were well aligned to the e-pharmacophore models, from the Otava small molecule library, were then docked into the binding pocket. Finally, the selected 88 hit molecules and the 85 known inhibitors were analyzed by the MetaCore/MetaDrugTM platform, which uses developed binary QSAR models for therapeutic activity prediction as well as pharmacokinetic and toxicity profile predictions of screening molecules. Ligand selection criteria led to the refinement of 3 potent hit molecules using molecular dynamics (MD) simulations to better investigate their structural and dynamical profiles. The selected hit molecules had a low toxicity and a significant therapeutic potential for heart failure, antiviral activity, asthma and depression, all conditions in which NF-kappaB plays a critical role. These hit ligands were also structurally stable at the NF-kappaB/IkappaBalpha complex as per the MD simulations and MM/GBSA analysis. Two of these ligands (Otava IDs: 1426436 and 6248112) showed stronger binding and therefore are hypothesized to be more potent. The identification of new potent NF-kappaB/IkappaBalpha inhibitors may thus present a novel therapy for inflammation-mediated conditions as well as cancer, facilitating more efficient research, and leading the way to future drug development efforts. PMID- 30415123 TI - Positive mental health moderates the association between suicide ideation and suicide attempts. AB - BACKGROUND: Positive mental health (PMH) has been shown to confer resilience against suicide ideation. However, it is unclear, whether PMH also buffers the relationship between suicide ideation and suicide attempts. The current study aimed to determine whether PMH moderates the association between lifetime suicide ideation and lifetime suicide attempts. METHODS: A total of 199 psychiatric inpatients with lifetime suicide attempts (female: n = 109; age: M = 37.56, SD = 14.38, range: 18-81) were interviewed on lifetime suicide ideation/behavior and completed a measure on PMH. RESULTS: PMH moderated the impact of lifetime suicide ideation on lifetime suicide attempts: For those individuals who reported high levels of PMH, the rate of lifetime suicide attempts was reduced even when experiencing frequent episodes of lifetime suicide ideation. LIMITATIONS: Given the cross-sectional nature of the data, conclusions on causality should be handled carefully. CONCLUSION: PMH seems to confer resilience and should be taken into account, when assessing individuals for suicide risk. PMID- 30415124 TI - Patterns of self-harm methods over time and the association with methods used at repeat episodes of non-fatal self-harm and suicide: A systematic review. AB - BACKGROUND: The risk of self-harm repetition and suicide may be influenced by self-harm method choice. However, there are mixed findings regarding whether there is a discernible pattern in self-harm methods over successive episodes of non-fatal self-harm, and if so, how these may be associated with self-harm repetition and/or suicide. METHODS: A systematic review of five electronic databases was undertaken until 31 May 2018 to identify cohort studies on patterns of self-harm methods and their association with methods used either at repeat self-harm episodes and/or suicide. RESULTS: 15 studies were included reporting data on of 127,371 participants. Over an average follow-up period of 2.8 years, one-third (33.3%) switched methods between episodes of self-harm, most commonly from self-injury to self-poisoning. For suicide, almost one-half (42.1%) switched methods over an average follow-up period of 11.2 years. LIMITATIONS: Studies were characterised by a moderate study quality. Studies tended to group all methods into self-injury and/or self-poisoning with little consideration as to the diverse range of self-harm methods included within these broad categories and the likely differences in potential lethality between these methods. Few investigated the role of alcohol and/or drug dependence and mental illness on self-harm method choice. CONCLUSIONS: Given the frequency of method switching observed, and the lack of discernible patterns over time, all patients should be routinely assessed for risk and needs irrespective of the method used at the index episode of non fatal self-harm. PMID- 30415125 TI - Maltreatment, attachment, and substance use in adolescence: Direct and indirect pathways. AB - Past research indicates that maltreatment increases risk for adolescent substance use; however, research is limited on how attachment between adolescents and their parents influences this relationship. The present study examined psychological and physical maltreatment, attachment avoidance and attachment anxiety, and substance use (i.e., cigarettes, alcohol, marijuana, and 'other drugs') among adolescents between the ages of 12 and 18 (N = 737; 59.3% female; Mage = 14.69, SD = 1.46). Psychological maltreatment was significantly related to cigarettes, alcohol, and marijuana use, and physical maltreatment was related to cigarette and marijuana use. Exposure to both forms of maltreatment was also associated with increased attachment avoidance and attachment anxiety, but only attachment avoidance predicted substance use. Indirect paths indicated that attachment avoidance mediated the relationship between psychological maltreatment and cigarette (B = 0.14, CI [0.001, 0.314]) and alcohol use (B = 0.09, CI [0.011, 0.188]). Attachment avoidance also mediated the relationship between physical maltreatment and cigarette (B = 0.15, CI [0.031, 0.311]) and alcohol use (B = 0.09, CI [0.027, 0.185]). No significant mediated effects for attachment anxiety emerged. Attachment avoidance may increase risk for substance use because youth have a lower rate of disclosing their activities to their parents, and do not seek or accept their guidance. Instead, they may turn to peers who also engage in substance use as a source of support. Interventions designed to increase parent teen attachment security and decrease attachment avoidance may be particularly useful in reducing risk for substance use. PMID- 30415126 TI - Cortical atrophy pattern-based subtyping predicts prognosis of amnestic MCI: an individual-level analysis. AB - We categorized patients with amnestic mild cognitive impairment (aMCI) based on cortical atrophy patterns and evaluated whether the prognosis differed across the subtypes. Furthermore, we developed a classifier that learns the cortical atrophy pattern and predicts subtypes at an individual level. A total of 662 patients with aMCI were clustered into 3 subtypes based on cortical atrophy patterns. Of these, 467 patients were followed up for more than 12 months, and the median follow-up duration was 43 months. To predict individual-level subtype, we used a machine learning-based classifier with a 10-fold cross-validation scheme. Patients with aMCI were clustered into 3 subtypes: medial temporal atrophy, minimal atrophy (Min), and parietotemporal atrophy (PT) subtypes. The PT subtype had higher prevalence of APOE epsilon4 carriers, amyloid PET positivity, and greater risk of dementia conversion than the Min subtype. The accuracy for binary classification was 89.3% (MT vs. Rest), 92.6% (PT vs. Rest), and 86.6% (Min vs. Rest). When we used ensemble model of 3 binary classifiers, the accuracy for predicting the aMCI subtype at an individual level was 89.6%. Patients with aMCI with the PT subtype were more likely to have underlying Alzheimer's disease pathology and showed the worst prognosis. Our classifier may be useful for predicting the prognosis of individual aMCI patients. PMID- 30415128 TI - Mesenteric vascular and nerve sparing surgery in laparoscopic segmental intestinal resection for deep infiltrating endometriosis. AB - OBJECTIVE(S): To investigate Mesenteric vascular and nerve Sparing Surgery (MSS) as surgical laparoscopic technique to perform segmental intestinal resection for deep infiltrating endometriosis (DIE). STUDY DESIGN: Prospective cohort study between January 2013 and December 2016. Consecutive patients with suspected intestinal DIE underwent clinical and imaging evaluation to confirm intestinal involvement. Indications for radical surgery and surgical technique (intestinal resection versus shaving) were consistent with Abrao algorithm. Surgeons aimed to perform MSS in all the consecutive patients that required intestinal resection. MSS consists in mesenteric artery, branching arteries, and surrounding nerve fibers preservation by dissecting mesentery adherent to the intestinal wall. Data about history, preoperative and post-operative evaluation, surgery and complications were recorded. Symptoms were evaluated before and 30-60 days after surgery with numeric rating scale for pain. Constipation was evaluated with the Constipation Assessment Scale (CAS). Patients with diagnosis of irritable bowel syndrome, inflammatory bowel diseases, diverticulitis, and previous segmental intestinal resection were excluded. RESULTS: Sixty-two out of 75 (82.7%) consecutive women with intestinal endometriosis underwent laparoscopic segmental intestinal resection performed with MSS. Major complications that required repeated operation occurred in 4 cases (6.5%). Anastomotic leakage occurred in only 1 case (1.6%). Dysmenorrhea (p < .001; r = -0.86), dyspareunia (p < .001; r = -0.80), dyschezia (p < .001; r = -0.86) and dysuria (p < .001; r = -0.56) were significantly improved after surgery. After an average of 33.1 months from surgery, severe constipation was reported only by two patients (3.6%) (CAS: 13 16). The median time from surgery to intestinal function recovery (flatus or stool passage) was one day. Logistic regression analysis showed constipation related to the distance from anal verge and time since surgery. CONCLUSION(S): MSS in laparoscopic intestinal resection for DIE may be reproducible, safe and effective. MSS could be combined with pelvic nerve-sparing surgery as an effective approach to improve intestinal symptoms after radical surgery for DIE that requires segmental intestinal resection. PMID- 30415129 TI - Screening and management of the small for gestational age fetus in the UK: A survey of practice. AB - BACKGROUND: Antenatal detection of the small for gestational (SGA) fetus has become an important indicator of quality of antenatal care in the UK. This has been driven by a desire to reduce stillbirth in this at risk group. METHODS: We conducted a postal survey of 187 NHS consultant units within the UK to determine what the current practice for the detection and subsequent management of the suspected SGA fetus was following the guidance from the Royal College of Obstetricians and Gynaecologists (RCOG) in 2013. RESULTS: The survey was performed in 3 rounds between 2016 and 2017 with a response rate of 65%. 85% of units assessed risk factors for SGA at booking. 81% of units used a customized symphysis fundal height (SFH) chart to screen for SGA with 95% of them using a cut off of <10th centile to refer for ultrasound assessment. When ultrasound is used to detect SGA, 80% of units used estimated fetal weight (EFW), with 89% of these using a cut off of <10th centile to diagnose SGA. Umbilical artery (UA) Doppler monitoring was undertaken in 97% of management and 94% delivered after 37 weeks. Only 24% of units had a dedicated fetal growth clinic, whilst 48% of units were able to offer computerised CTG to monitor the SGA fetus. CONCLUSIONS: Overall there is consistency in the screening methods for SGA (customised SFH charts) and identification of suspected SGA (SFH <10th centile, EFW <10th centile, UA monitoring and induction of labour at term). There was a low uptake of computerized CTG to monitor SGA babies and a low number of specialised fetal growth clinics. PMID- 30415127 TI - Strong and specific associations between cardiovascular risk factors and white matter micro- and macrostructure in healthy aging. AB - Cardiovascular health declines with age, increasing the risk of hypertension and elevated heart rate in middle and old age. Here, we used multivariate techniques to investigate the associations between cardiovascular health (diastolic blood pressure, systolic blood pressure, and heart rate) and white matter macrostructure (lesion volume and number) and microstructure (as measured by diffusion-weighted imaging) in the cross-sectional, population-based Cam-CAN cohort (N = 667, aged 18-88). We found that cardiovascular health and age made approximately similar contributions to white matter health and explained up to 56% of variance therein. Lower diastolic blood pressure, higher systolic blood pressure, and higher heart rate were each strongly, and independently, associated with white matter abnormalities on all indices. Body mass and exercise were associated with white matter health, both directly and indirectly via cardiovascular health. These results highlight the importance of cardiovascular risk factors for white matter health across the adult lifespan and suggest that systolic blood pressure, diastolic blood pressure, and heart rate affect white matter health via separate mechanisms. PMID- 30415130 TI - Variable infectivity and conserved engagement in cell-to-cell viral transfer by HIV-1 Env from Clade B transmitted founder clones. AB - HIV-1 transmission is usually initiated by a single viral strain called transmitted/ founder (T/F) virus. In in vitro models, HIV-1 can efficiently spread via cell-free and virological synapse (VS)-mediated cell-to-cell infection. Both modes of infection require the viral glycoprotein Envelope (Env). The efficiency with which T/F Envs initiate VS and mediate cell-to-cell infection has not been well characterized. Here we tested a panel of isogenic HIV-1 molecular clones that carry different Clade B T/F Envs. We found that despite variable infectivity among different Env clones in the two modes of infection, T/F Envs generally mediated efficient VS formation and subsequent cell-to-cell transfer. In contrast, in vitro infectivity of the T/F Env clones was more variable and strongly correlated with intrinsic fusogenicity of various Envs. We speculate that the conservation of cell-to-cell transfer by T/F Env is indicative of a biologically important function of Env. PMID- 30415132 TI - Local contour symmetry facilitates scene categorization. AB - People are able to rapidly categorize briefly flashed images of real-world environments, even when they are reduced to line drawings. This setting allows for the study of time-limited perceptual grouping processes in the human visual system that are applicable to line drawings. Previous work (Wilder, Dickinson, Jepson, & Walther, 2018) showed that standard local features of individual contours, or junctions between contours, do not account for this rapid classification ability but, rather, the relative placement of these contours appeared to be important. Here we provide strong support for this observation by demonstrating that local ribbon symmetry between neighboring pairs of contours facilitates the categorization of complex real-world environments. To this end, we introduce a novel computational approach, based on the medial axis transform, for measuring the degree of local ribbon symmetry in a line drawing. We use this measure to separate the contour pixels for a given scene into the most ribbon symmetric half and the least ribbon symmetric half. We then show human observers the resulting half-images in a rapid-categorization experiment. Our results demonstrate that local ribbon symmetry facilitates the categorization of complex real-world environments. This is the first study of the role of local symmetry in inter-contour grouping for human scene classification. We conclude that local ribbon symmetry appears to play an important role in jump-starting the grouping of image content into meaningful units, even in flashed presentations. PMID- 30415131 TI - Core gene insertion in hepatitis B virus genotype G functions at both the encoded amino acid sequence and RNA structure levels to stimulate core protein expression. AB - Hepatitis B virus genotype G possesses a 36-nucleotide (nt) insertion at the 5' end of core gene, adding 12 residues to core protein. The insertion markedly increased core protein level irrespective of viral genotype, with the effect reproducible using CMV-core gene construct. Here we used such expression constructs and transient transfection experiments in Huh7 cells to identify the structural bases. The insertion is predicted to create a stem-loop structure 14nt downstream of core gene AUG. A + 1 or + 2 frameshift into the 36nt mitigated enhancement of core protein level. Point mutations to disrupt or restore the stem loop had opposite effects on core protein expression. Shifting the translation initiation site downstream or further upstream of the stem-loop rendered it inhibitory or no longer stimulatory of core protein expression. Therefore, both the reading frame and a properly positioned stem-loop structure contribute to marked increase in core protein expression by the 36-nt insertion. PMID- 30415133 TI - How bilinguals perceive speech depends on which language they think they're hearing. AB - Bilinguals understand when the communication context calls for speaking a particular language and can switch from speaking one language to speaking the other based on such conceptual knowledge. There is disagreement regarding whether conceptually-based language selection is also possible in the listening modality. For example, can bilingual listeners perceptually adjust to changes in pronunciation across languages based on their conceptual understanding of which language they're currently hearing? We asked French- and Spanish-English bilinguals to identify nonsense monosyllables as beginning with /b/ or /p/, speech categories that French and Spanish speakers pronounce differently than English speakers. We conceptually cued each bilingual group to one of their two languages or the other by explicitly instructing them that the speech items were word onsets in that language, uttered by a native speaker thereof. Both groups adjusted their /b-p/ identification boundary as a function of this conceptual cue to the language context. These results support a bilingual model permitting conceptually-based language selection on both the speaking and listening end of a communicative exchange. PMID- 30415134 TI - Semiological characteristics of patients with psychogenic nonepileptic seizures: Gender-related differences. AB - Psychogenic nonepileptic seizures (PNES) are more prevalent among women, and diagnosis may sometimes be delayed by as much as seven years. Understanding the effect of gender on the presentation of a PNES may assist with diagnosis based on semiological details in the clinical setting. Although video-EEG monitoring (VEM) is the gold standard for diagnosing PNES, determining gender-related seizure semiology through careful history may prevent diagnostic delay while waiting for VEM. The aim of this study was to investigate gender-related differences in the semiology of PNES. Patients, all aged at least 16 years, diagnosed with PNES following VEM between December 2005 and November 2016 were included in this study. All patients' medical records and video-EEG-documented PNES were reviewed, and the presence or absence of semiological signs was recorded for each documented attack. Demographic features and semiological signs of PNES were compared between female and male patients. Forty-one patients (31 females, 10 males) aged 27.2 +/- 12.2 years (range: 16-65) were included in the study. Mean age at onset of PNES was higher for female patients than males, at 24.3 +/- 11.5 versus 17.5 +/- 3.2 years (p = 0.005). The median duration of PNES was longer for female patients than males, at 10 min (range: 5 s-120 min) versus 2 min (range: 10 s-60 min) (p = 0.016). The most common symptom was forced eye closure in both genders. No significant gender-specific differences were observed in terms of the type or semiology of PNES. Although there are no major gender-related differences in PNES semiology, our findings highlight the importance of greater caution, especially in male patients, when diagnosing PNES, remembering that onset may also occur at young ages and that a short seizure duration does not exclude PNES. PMID- 30415135 TI - Cortical excitability and seizure control influence attention performance in patients with idiopathic generalized epilepsies (IGEs). AB - We recently found that higher cortical excitability is associated with poorer attention performance in healthy adults. While patients with idiopathic generalized epilepsies (IGEs), previously termed genetic generalized epilepsies, are known to demonstrate increased cortical excitability and cognitive deficits, a relationship between these variables in IGEs has not been investigated. Therefore, we aimed to characterize the effects of cortical excitability and seizure control on cognitive performance in IGEs. We studied 30 patients with IGEs (16 patients with controlled IGEs (cIGEs) and 14 patients with treatment resistant IGEs (trIGEs)) and 24 healthy controls (HCs). Transcranial magnetic stimulation (TMS) was used to measure cortical excitability, including long interval intracortical inhibition (LICI). Attention was assessed with the Digit Span Forwards, Digit Span Backwards, Trails A, and Flanker tasks. Executive functioning was assessed using Trails B, Stroop Color and Word, and the Wisconsin Card Sorting Task. Two-way multivariate analyses of variance (MANOVAs) were conducted to assess the influences of seizure control (HCs vs. cIGEs vs. trIGEs) and cortical excitability (inhibitory vs. excitatory) on composite measures of attention and executive functions. Attention performance was significantly affected by cortical excitability and seizure control. Participants with primarily excitatory LICI responses, indicating higher cortical excitability, performed worse than inhibitory responders on composite attention (Wilks' lambda = 0.748, F(4, 44) = 3.72, p = 0.011). While participants with cIGEs and trIGEs did not significantly differ in attention performance, participants with trIGEs performed worse on the Digit Forwards (False Discovery Rate (FDR)p < 0.001), Digit Backwards (FDRp = 0.015), and Flanker (FDRp = 0.0075) tasks compared with HCs. These results provide support for the relationship between cortical excitability and attention dysfunction in IGEs. Further investigation is needed to determine whether there is a causal relationship between these variables and whether intracortical gamma-aminobutyric acid (GABA)B networks may be targeted to improve attention deficits in clinical populations with decreased LICI. Findings also suggest that additional research directly comparing cognition in patients with cIGEs and trIGEs is warranted. PMID- 30415136 TI - Revisiting the public awareness, attitudes, and understanding towards epilepsy among Singapore residents. AB - A survey to assess the familiarity, attitudes, and knowledge about epilepsy was done using a questionnaire identical to the one used in 1999. Two hundred forty six people participated in our survey in 2017 as compared with 214 in the 1999 survey. In terms of familiarity about epilepsy, 76% had heard or read about epilepsy, 55.7% had witnessed a seizure, and 35.8% knew someone with epilepsy (85%, 56%, and 36% respectively in 1999). Forty point five percent were not familiar with or did not know what to do if they witnessed a seizure (44% in 1999); 25.6% would put something in the mouth of a person having a seizure (32% in 1999). In terms of attitudes towards epilepsy, 14.6% would object to their children associating with one with epilepsy while 19.9% would object to their children marrying a person with epilepsy (13% and 36% respectively in 1999). Only 43.1% would employ a person with epilepsy while 68.3% would employ if seizures do not interfere with the job (42 and 66% respectively in 1999). In terms of knowledge of seizures and epilepsy, 66.3% associated epileptic attack with convulsion (68% in 1999). Only 37.5% were aware of nonconvulsive forms of epilepsy (25% in 1999). Twenty-six point eight percent did not know what treatment to recommend to relatives/friends with epilepsy while 60.6% recommend western medicine (22% and 60% respectively in 1999). CONCLUSION: The awareness, attitudes, and understanding towards epilepsy does not seem to show any significant difference when compared with that in 1999. Reluctance to marry and employ a person with epilepsy persists. The awareness about first aid of a patient having a seizure, attitudes towards marrying a person with epilepsy, and the understanding of cause of epilepsy have shown some positive changes over 17 years. PMID- 30415137 TI - Validation of the Chinese version of the Hamilton Rating Scale for Depression in adults with epilepsy. AB - OBJECTIVE: This study aimed to validate the Chinese version of the 17-item Hamilton Rating Scale for Depression (C-HRSD-17) for use in adult patients with epilepsy (PWE). METHODS: A consecutive sample of Chinese adult PWE from a tertiary hospital was examined using the C-HRSD-17 and the Mini International Neuropsychiatric Interview (MINI) Plus Chinese Version 5.0.0. RESULTS: A total of 191 PWE completed the assessment of depression. According to the MINI, thirty patients (15.7%) had current major depressive disorder (MDD). The Cronbach's alpha coefficient for the C-HRSD-17 was 0.832. Receiver operating characteristic (ROC) analysis showed an area under the curve (AUC) of 0.983 (95% CI = 0.968 0.998). With a cutoff score of 9, the C-HRSD-17 demonstrated the best psychometric properties, with a sensitivity of 96.7%, a specificity of 93.8%, a positive predictive value (PPV) of 74.4%, and a negative predictive value (NPV) of 99.3%. CONCLUSION: The C-HRSD-17 proved to be a valid and reliable assessment tool, with a cutoff score of 9 for screening of current MDD in Chinese adult PWE. PMID- 30415138 TI - Development of the transition-age program (TAP): Review of a pilot psychosocial multidisciplinary transition program in a Level 4 epilepsy center. AB - Approximately 50% of patients diagnosed with epilepsy in childhood will need treatment in adulthood. Transition from pediatric to adult epilepsy care is challenging, and an unsuccessful transition can have detrimental effects. Researchers emphasize the importance of addressing possible barriers to transition in a multidisciplinary setting. In this paper, we describe a transition program implemented in a Level 4 epilepsy center in the Midwest. This program involves a psychosocial multidisciplinary team including a pediatric neuropsychologist, pediatric psychologist, and social worker who meet jointly with patient and his/her caregiver(s) before and after the transition. The pretransition visit involves assessment of transition readiness, screening for neurobehavioral comorbidities, provision of education regarding epilepsy care during the transition period, goal-setting, and development of a portable summary. The posttransition visit revisits goals and provides additional individualized recommendations and/or referrals for intervention as clinically indicated. The goal of this program is to facilitate a smooth transition from pediatric to adult providers to ensure optimal epilepsy care and quality of life. PMID- 30415139 TI - Naringin in a combined therapy with phenytoin on pentylenetetrazole-induced kindling in rats. AB - Phenytoin (Dilantin) is an orally active, use-dependent voltage-gated sodium channel inhibitor and is a potent, economical, and widely used anticonvulsant agent. The objective of the present study was to investigate the effect of the combined treatment of naringin (40 mg/kg and 80 mg/kg) and phenytoin on prevention of seizure attacks, development of kindling, oxidative stress, cognitive impairment, and neurochemicals in the frontal cortex, temporal cortex, and hippocampus, and morphological changes in the hippocampus. Treatment with the high dose of naringin (80 mg/kg) along with phenytoin has shown to offer protection against seizures, development of kindling, and cognition enhancement through Y-maze test and improved % conditioned avoidance response (% CAR) through pole climbing test in pentylenetetrazole (PTZ)-induced kindling model. It has also been shown to improve neurochemical balance by elevating levels of Gamma amino butyric acid (GABA) and dopamine, decreasing levels of glutamate, oxidative biomarker (malondialdehyde (MDA)), and increasing levels of antioxidants (glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and total thiol and offered neuroprotection in the hippocampus. So, coadministration of naringin with phenytoin offers a potential treatment option for drug-resistant epilepsy and associated comorbidities. Interpretable research on flavonoids will support the clinical evidence for the recommendation of flavonoids as supplements with antiepileptic drugs (AEDs) for curtailing pharmacoresistant epilepsy and AED associated comorbidities. PMID- 30415140 TI - Hydrogen bonding between ethynyl aromates and triethylamine: IR spectroscopic and computational study. AB - Ethynylpyridines (EPs) and ethynylbenzene (EB) are multifunctional systems able to participate in hydrogen-bonded complexes as both donors and acceptors of the H atom. Their structures and stabilities are mainly a function of the hydrogen bonding properties of the partner in the complex and the surroundings in which the complexation occurs. In this paper, IR spectroscopy and quantum chemical calculations are employed to characterize hydrogen-bonded complexes of 2- and 3 EP and EB with triethylamine (TEA) in tetrachloroethene (C2Cl4) solution. The formation of CH?N hydrogen bonds is experimentally confirmed by the appearance of TEA concentration-dependent signals in the IR spectra of the EPs and EB. Along with the signals due to unassociated CH and CC oscillators (2-EP: 3308 cm-1 and 2120 cm-1; 3-EP: 3308 cm-1 and 2116 cm-1; EB: 3313 cm-1 and 2113 cm-1) weak, red shifted signals arise at ~3215 +/- 5 cm-1 and ~2105 +/- 5 cm-1 which are assigned to the stretching vibrations of hydrogen-bonded CH? and CC? oscillators, respectively. This result is at variance with those of previous investigations of EB and TEA in the gas phase. In the 2-EP?TEA complex these bands remain at the same position with increasing TEA concentration. However, in the 3-EP?TEA and EB?TEA complexes the CH? stretching band demonstrates a slightly reduced red shift as the TEA concentration increases, whereas the CC? stretching band absorbs at the same wavenumber in the investigated TEA concentration range. The results of B3LYP-D3 calculations indicate that complexes with more or less linear CH?N intermolecular hydrogen bonds are more stable than other, dispersion-driven complexes. Complexes with the Cs symmetrical TEA conformer are predicted to have larger binding energy than those formed with the C3 and C1 symmetrical conformers. The predicted IR spectral shifts are slightly different for complexes with the three different TEA conformers. Association constants of hydrogen-bonded complexes at 26 degrees C are estimated to be ~0.1 mol-1 dm3. PMID- 30415141 TI - Can information increase the understanding and uptake of insurance? Lessons from a randomized experiment in rural Burkina Faso. AB - Community Based Health Insurance Schemes are often confronted to very low uptake. We analyze the impact of a randomized information package on the understanding and adoption of Community Based Health Insurance in Burkina Faso. The sample consists of about 2000 households in the rural community of Ziniare which we interviewed several times between 2013 and 2016. In contrast to previous studies in the literature, we assess the effects of an intensive information intervention combining tools and repeated interaction instead of only a single event of information provisioning. The information package combines three tools to present different types of information - a brochure presenting factual information, a video presenting a hypothetical health episode and a personalized phone call reminder. The brochure and video are delivered through home visits by specially trained agents. Despite the repeated interaction and the comprehensiveness of the information package, we find only modest improvements in the understanding of insurance principles following our intervention. Investigating treatment heterogeneity, we observe an increase in understanding in poorer households and in households with literate heads. Given the small improvements in insurance knowledge we do not see a significant effect on insurance uptake either. We conclude that information is not enough to increase insurance uptake and discuss the role of other factors that might matter including the political context in which our experiment was implemented. PMID- 30415142 TI - Pharmacokinetic study of sirolimus ophthalmic formulations by consecutive sampling and liquid chromatography-tandem mass spectrometry. AB - Sirolimus is regarded as one of the most effective immunosuppressants receiving extensive attention over the years, for which the ocular application needs further development in clinical keratoplasty. In order to study the transcorneal absorption effect of ophthalmic administration, there was a need to study the pharmacokinetics of drugs in aqueous humor. In this work, a validated and reliable HPLC-ESI-MS/MS method was established to study the pharmacokinetics of sirolimus nanoformulations in rabbit aqueous humor. The analysis conditions were as follows. Ascomycin was chosen as internal standard. After a simple precipitation extraction procedure, the aqueous humor samples were separated on a XBridge C18 column (4.6 mm * 150 mm, 3.5 MUm, Waters Co., USA) with a mobile phase comprised of water (0.1% formic acid and 5 mM ammonium formate) and methanol (0.1% formic acid) at the ratio of 10:90 (v/v). The mass analysis was achieved by positive ionization with multiple reaction monitoring (MRM) mode. The highest response ion pairs m/z at 931.5->864.5 were chosen for sirolimus. The validated results showed that the calibration range was 0.3-100.6 ng/mL with r = 0.9997 (n = 6). The R.S.D. values of the intra- and inter-day precision were less than 11% and the average accuracy values were between 94.73%-100.20%. Besides, for reducing the consumption of rabbits and the variation of the data, we designed a consecutive sampling method in pharmacokinetic study, with only seven rabbits consumed for each formulation. In conclusion, the developed analysis method was more reliable and practical than previously reported experiments. Meanwhile, the validated method was successfully applied to study the pharmacokinetics of sirolimus micelle and sirolimus nanosuspension after ophthalmic administration. PMID- 30415143 TI - MiRNA-27a sensitizes breast cancer cells to treatment with Selective Estrogen Receptor Modulators. AB - BACKGROUND: MicroRNA-27a (miR-27a) is a small non-coding RNA, shown to play a role in multiple cancers, including the regulation of ERalpha expression in breast cancer. Most ERalpha positive tumors are treated with Selective Estrogen Receptor Modulators (SERMs) and thus the role of miR-27a expression in response to SERM treatment is of interest. METHODS: Tamoxifen resistant cells were generated by molecular evolution with six cycles of tamoxifen treatment. MCF7 and T47D luminal A breast cancer cell lines were either treated with miR-27a mimics, or ER-signaling was modulated ectopically. The changes were analyzed with RT qPCR, western blotting and transcriptional activity ERE-reporter assays. Moreover, the response to SERM treatments (tamoxifen, endoxifen and toremifen) was investigated by cell viability and apoptosis measurements. An in silico analysis of survival data from the METABRIC study was performed in order to assess the prognostic value of miR-27a for response to SERM treatment. RESULTS: Tamoxifen-resistant cells showed decreased expression of ERalpha and miR-27a. The overexpression of miR-27a increased the levels of ERalpha, while modulation of ERalpha decreased miR-27a expression. High miR-27a expression increased the sensitivity of MCF7 and T47D cells to SERM treatments and re-sensitized the cells to tamoxifen. Patient survival of luminal A breast cancer patients that underwent endocrine therapies was better in groups with high miR-27a expression. CONCLUSION: MiR-27a sensitizes luminal A breast cancer cells to SERM treatments based on a positive feedback loop with ERalpha. An increased overall-survival of ER-positive breast cancer patients that underwent endocrine treatments and displayed high miR-27a levels was found. PMID- 30415144 TI - Validation of selected (n,2n) dosimetry reactions in IRDFF-1.05 library. AB - Spectrum-averaged cross sections (SACS) have been measured in the reference 252Cf(sf) neutron field for the following high-threshold (n,2n) neutron dosimetry reactions since they are especially important due to the high threshold which allows validation of upper parts of prompt fission neutron spectrum. This work includes 59Co(n,2n)58Co, 197Au(n,2n)196Au, 169Tm(n,2n)168Tm, 55Mn(n,2n)54Mn, 93Nb(n,2n)92 mNb and 89Y(n,2n)88Y and for the 59Co(n,p)59Fe threshold reactions. SACS were inferred from experimentally determined reaction rates by gamma spectrometry using a semiconductor high-purity germanium detector to measure irradiated samples. Measured reaction rates agree within quoted uncertainties with those calculated from the IRDFF-1.05 library, except for the reaction 55Mn(n,2n)54Mn, for which the measured value is underestimated by 16%. For this reaction the ENDF-B/VII.1 evaluation agrees with measured reaction rate within uncertainties. PMID- 30415146 TI - Studying drug-drug interaction through chromatographic analysis of two mixtures offering antimicrobial synergism. AB - Micellar mobile phase was utilized for the separation and quantification of two antimicrobial mixtures with some analgesics that were found to augment their antimicrobial activity, namely; cefotaxime sodium (CFX) with ibuprofen (IBU) and naproxen (NPX) (mixture Iota), and azithromycin dihydrate (AZT) with diclofenac sodium (DIC) (mixture IotaIota). Both mixtures were analyzed using a C18 column operated at 50 degrees C using a mobile phase composed of sodium dodecyl sulphate (SDS), an organic modifier; (1-propanol or acetonitrile), and 0.3% triethylamine (TEA), adjusting pH to the required value with 2 M orthro phosphoric acid, accompanied with UV detection. The proposed method was subjected to full validation procedure and was applied to determine the concentration of the studied antibiotics in homogenized liver, kidney and heart rat tissue samples, with or without the co-administered non steroidal anti-inflammatory drugs. PMID- 30415145 TI - Study on physico-mechanical and gamma-ray shielding characteristics of new ternary nanocomposites. AB - In this study, a series of "Epoxy-Clay-PbO" nanocomposites under the name of ECPNCs were prepared by the molding method, and their physico-mechanical properties were investigated by different techniques. Focus of the work, was on the shielding ability of the ECPNCs for the gamma rays, emitted from Ir-192, Cs 137 and Co-60 with a wide range of energy. Scanning electron microscopy, and X ray diffractometry demonstrated that clay platelets were fully exfoliated, and the PbO particles were homogenously distributed in the polymeric matrix. Thermo gravimetric analysis and standard tensile tests revealed that PbO content has an "increasing/decreasing" effect on "thermal stability/mechanical strength" of the nanocomposites. Gamma shielding experiments showed that efficacy of ECPNCs containing 30 wt% PbO was 47% better than that of concrete. Experimental attenuation data were confirmed by theoretical calculations, so that the maximum difference between them was 14.1%. Furthermore, a correlation was developed between PbO content of the ECPNCs and their mass attenuation coefficient for all gamma sources. PMID- 30415147 TI - Czech 23-month-olds use gender agreement to anticipate upcoming nouns. AB - Children acquiring Dutch, French, and Spanish can use gender of articles to facilitate the processing of upcoming nouns. The current study examined whether a similar effect can be found for bound gender-marking agreement morphemes in Czech, a language without obligatory articles. The experiment was designed so that the anticipatory effects of gender-marking morphemes before the head noun onset could be observed. In a preferential looking experiment, 33 children (aged 21-24 months) were shown picture pairs that could be labeled with masculine and feminine nouns. They heard a phrase comprising a demonstrative, an adjective, and a noun, where the first two elements were inflected for gender. The inflections were either correct (matching the noun gender) or incorrect (mismatched). Children were also given offline receptive grammar and vocabulary tasks. The group of children as a whole did not show significant differences in looking behavior between the experimental conditions. When split by the grammar task, the high-scoring children showed significant differences between looks toward the target noun in the matched and mismatched conditions even before the onset of the target noun. No significant difference was observed in the low-scoring group and in the groups split by vocabulary. Results suggest that knowledge of the gender system is just emerging before the second birthday and that more advanced children can use gender information encoded in bound morphemes to actively anticipate the upcoming nouns. PMID- 30415148 TI - Crime but not punishment? Children are more lenient toward rule-breaking when the "spirit of the law" is unbroken. AB - Even early in development, children understand how rules work, and they harshly evaluate rule violators. Furthermore, we know that adults make nuanced evaluations about rule violations; in many situations, they believe that it can be acceptable to violate the technical language of a rule (the "letter of a rule") if doing so does not violate the reason why the rule was created (the "spirit of the rule"). Distinguishing between the letter and spirit of a rule is critical for a developed normative understanding. We investigated whether and when children begin to believe that it is less wrong to violate the letter of a rule if one does not violate the rule's spirit. Participants (N = 246 4- to 10 year-olds) were asked to evaluate a rule-breaker who either violated the letter of a rule but not the spirit or violated both the letter and spirit of a rule. We found that by 4 years of age, children acknowledged that the rule had technically been broken in both cases, but their evaluations of the rule-breaker were much more lenient in the case where the spirit of the rule remained intact. We also found that children are increasingly more lenient in the case where the spirit of the rule remains intact case as they age, and they are increasingly harsher in the case where the spirit is violated. We discuss how these studies provide insight into early normative reasoning, including implications for future research on social cognitive development, rule learning, and legislative intent. PMID- 30415149 TI - Nurse anesthetists' evaluations of anesthesiologists' operating room performance are sensitive to anesthesiologists' years of postgraduate practice. AB - STUDY OBJECTIVE: The first aim of this study was to test whether a 7 item evaluation scale developed by our department's certified registered nurse anesthetists (CRNAs) was psychometrically reliable. The second aim was to test whether anesthesiologists' performance changed with their years of postgraduate experience. DESIGN, SETTING, MEASUREMENTS: Sixty-two University of Iowa CRNAs evaluated 81 anesthesiologists during one weekend. Anesthesiologists' scores were adjusted for CRNA rater leniency. Anesthesiologists' scores were tested for sensitivity to CRNA-anesthesiologist case-specific variables. Scores also were tested against anesthesiologists' years of postgraduate experience. The latter association was tested for sensitivity to case-specific variables, anesthesiologists' clinical supervision scores provided by residents, and anesthesiologist clinical assignment variables. MAIN RESULTS: The 7 items demonstrated a single-factor structure, allowing calculation of mean score over the 7 items. Individual anesthesiologist scores were reliable when scores were provided by at least 10 different CRNAs. Anesthesiologists' scores (mean 3.34 [SD 0.41]) were not affected by the interval since last CRNA-anesthesiologist interaction, number of interactions, or case-specific variables. There was a negative association between leniency-adjusted anesthesiologist scores and years of anesthesiologist postgraduate practice (coefficient -0.20 per decade, t = 19.39, P < 0.0001). The association remained robust when accounting for case specific variables, resident clinical supervision scores, and overall clinical assignment variables. CONCLUSIONS: Anesthesiologists' operating room performance can be evaluated reliably by non-physician anesthesia providers (CRNAs). The evaluation process can be done reliably and validly using an assessment scale consisting of only a few (<10) items and with evaluations by only a few individuals (>=10 CRNA raters). There is no indication evaluations provided by CRNAs were significantly influenced by the interval between interaction and evaluation, number of interactions, or other case-specific variables. From CRNAs' perspectives, on average, as anesthesiologists gain experience, anesthesiologists' behaviors in the operating room change, providing CRNAs with less direct assistance in patient care. PMID- 30415150 TI - Anesthetic challenges and outcomes for procedures in the intraoperative magnetic resonance imaging suite: A systematic review. AB - BACKGROUND AND OBJECTIVE: Hybrid operating room suites with intraoperative magnetic resonance imaging enable image guided surgery in a fully functional operating room environment. While this environment creates challenges to anesthetic care, the effects on anesthetic adverse events and outcomes are largely unknown. This systematic scoping review aims to map the existing knowledge about anesthetic care in advanced imaging hybrid operating rooms. METHODS: A broad-based literature search was performed using the PubMed (Medline), Embase, Cochrane Library, Web of Science, and Google Scholar databases. References published in English between January 1994 and August 2017 were included. Quality of evidence was assessed using the GRADE guidelines. RESULTS: Forty-seven manuscripts were eligible for data collection. Adverse events were heterogeneously defined across 17 manuscripts and occurred in 0 to 100% (quality of evidence mostly very low). Monitoring difficulty was reported in 4 manuscripts of very low data quality. Interference between the magnet and the electrocardiogram was investigated in 2 manuscripts (quality of evidence low and very low, respectively). None of the reported events appeared to result in long term patient harm. Author recommendations or a narrative review of the literature were provided in 40 manuscripts. Common safety concerns included lower equipment reliability, inaccessibility of the patient and airway, and the relative isolation of the suite (in relationship to other anesthesia care areas). Most authors also emphasized the importance of safety checklists, protocols, and provider training. DISCUSSION: While intraoperative magnetic resonance imaging hybrid operating rooms are increasingly utilized, the existing literature does not allow estimating adverse event rates in this location. Prospective studies quantifying the effect of the environment on anesthesia outcomes are lacking. Despite this, there is a broad consensus regarding the anesthetic and safety concerns. More research is needed to inform practice standards and training requirements for this challenging environment. PMID- 30415151 TI - Resting frontal EEG asymmetry in adolescents with major depression: Impact of disease state and comorbid anxiety disorder. AB - OBJECTIVE: Greater relative right- than left-frontal cortical activity has been frequently found in adults with major depression (MD). As the few studies in adolescents with MD have been inconclusive, the aim of this study was to assess frontal alpha asymmetry (FAA) in an adolescent sample with MD whilst taking into account possible confounding variables such as disease state and comorbid anxiety disorder. METHODS: An 8-minute resting frontal EEG was assessed in 34 healthy controls (HCs), 16 adolescents with MD in remission without comorbid anxiety disorder (rMDa-), 22 adolescents with acute depression without comorbid anxiety disorder (MDa-), and 23 adolescents with acute depression and comorbid anxiety disorder (MDa+). Alpha power was analyzed over corresponding frontal Regions of Interests. RESULTS: Compared to HCs, MDa+ adolescents demonstrated more left- than right-sided EEG alpha power, indicating greater right-than left-frontal cortical activity. No other group differences emerged. CONCLUSIONS: The results suggest that greater relative right-frontal cortical activity in adolescent MD is not a result of disease state but can be attributed to comorbid anxiety disorder. SIGNIFICANCE: Results suggest that FAA is not linked to adolescent depression per se and highlight the importance of considering comorbid disorders when examining asymmetry patterns in adolescent MD. PMID- 30415152 TI - A SERS microfluidic platform for targeting multiple soluble immune checkpoints. AB - Immune checkpoint blockade therapies are promising next generation immunotherapeutic treatments for cancer. Whilst sequential solid biopsies are an invaluable source of prognostic information, they are not feasible for monitoring therapeutic outcomes over time. Monitoring soluble immune checkpoint markers expression in body fluids could potentially be a better alternative. Current methods (e.g. ELISA) for detecting immune-checkpoint proteins mostly rely on the use of monoclonal antibodies which are expensive and time-consuming to manufacture and isolate. Herein, we report an integrated surface enhanced Raman scattering (SERS)-microfluidics device for the detection of immune checkpoint proteins which involves the use of i) nano yeast single chain variable fragment (scFv) as a promising alternative to monoclonal antibodies providing high stability at relative low-cost and simplicity for production, ii) graphene oxide functionalised surface to reduces the bio functionalization steps, thus avoiding the general paradigm of biotin-streptavidin chemistry and iii) a microfluidic platform enabling alternating current electrohydrodynamics (ac-EHD) induced nanomixing to enhance the target scFv binding and minimize the non-specific interactions. Specific and multiplex detection of immune checkpoint biomarkers is achieved by SERS based spectral encoding. Using this platform, we successfully demonstrated the detection of clinically relevant soluble immune checkpoints PD 1, PD-L1 and LAG-3 from as low as 100 fg/mL of analytes spiked in human serum. PMID- 30415153 TI - A novel electrochemical immunosensor for highly sensitive detection of prostate specific antigen using 3D open-structured PtCu nanoframes for signal amplification. AB - Herein, a novel electrochemical ultrasensitive immunosensor was designed for detecting prostate-specific antigen (PSA) with three-dimensional (3D) PtCu hollow nanoframes (PtCu HNFs) as signal amplification. The highly opened PtCu HNFs were synthesized by a one-pot solvothermal method with cetyltrimethylammonium chloride (CTAC) and trishydroxymethyl aminomethane (Tris) as co-structuring directors. The architectures enlarged the loading of prostate specific antibodies (Ab) and efficiently catalyzed hydrogen peroxide (H2O2) reaction, ultimately amplifying the signals. And polylysine was used to disperse PtCu HNFs, improve the biocompatibility and bind the Ab on the electrode surface. The fabricated immunosensor exhibited lower detection limit (0.003 ng mL-1, S/N = 3), and wider linear range (0.01-100.0 ng mL-1), along with the improved reproducibility, selectivity and stability for the assay of PSA. Thus, it is a desirable platform for PSA detection in clinical diagnosis and practical applications. PMID- 30415154 TI - Disposable stainless steel-based electrochemical microsensor for in vivo determination of indole-3-acetic acid in soybean seedlings. AB - In vivo detecting of plants signal molecules is of great importance for the precision farming, crop management and plant phenotyping. In this work, for in vivo detecting indole-3-acetic acid (IAA), one of phytohormones, fine stainless steel (SS) wire was used as electrode material. Highly ordered nanopores, popcorn like Au nanostructures, Pt nanoparticles and reduced graphene oxide (ERGO) nanocomposite films, and polymerized ST film (PST) were fabricated on the SS microelectrode in turn for improving the detection effect. Using the as-prepared SS microelectrode as working electrode, two untreated SS wires as reference electrode and counter electrode respectively, a disposable electrochemical microsensor for IAA were developed. The microsensor exhibited excellent selectivity and high sensitivity with low detection limit (LOD) of 43 pg mL-1. The limit of quantity (LOQ) is 143 pg mL-1. The RSD was 7% for 12 different PST/Pt-ERGO/Au/a-SS microsensors in presence of 100 ug mL-1 IAA. Using this microsensor, IAA of the stem of soybean seedlings was detected in vivo under salt stress. Our result was also confirmed by ultra-performance liquid chromatography mass spectrum (UPLC-MS). This is the first report for the in vivo detection of IAA in plants using SS-based electrochemical microsensor. Our sensor provides an excellent sensing platform for detecting IAA in plants in vivo. PMID- 30415155 TI - A rapid real-time quantification in hybrid paper-polymer centrifugal optical devices. AB - The research progress in the centrifugal microfluidic platform provides great opportunities for simple and effective analytical measurements in a variety of areas including biomedical engineering. In this study, we propose an optical reader that can measure the transmittance in a very sensitive and rapid manner on a hybrid paper-polymer centrifugal disc platform. This device enables real-time monitoring of multiple samples by measuring the absorbance of the light transmitted through the paper integrated on the disc between the light emitting diode (LED) and the photodiode (PD) regardless of the ambient light condition. To confirm its efficiency, we analyzed one of the blood's important indicators, glucose in a successful manner within 10 s without any additional complex image analysis. In addition, we discussed the results by comparing with the reflectance based methods and with those of the previously reported studies by introducing a figure of merit to evaluate the performance of the assay. PMID- 30415156 TI - An ultrasensitive electrochemical impedance-based biosensor using insect odorant receptors to detect odorants. AB - Herein, we present that insect odorant receptors reconstituted into the lipid bilayers of liposomes can be successfully immobilized onto a gold surface and selectively and sensitively detect odorant molecules. The odorant receptors (OrXs) Or10a, Or22a, and Or71a from the common fruit fly, Drosophila melanogaster, were recombinantly expressed, purified and integrated into nano liposomes (100-200 nm). These liposomes were covalently attached to the self assembled monolayers (SAMs) of a 6-mercaptohexanoic acid (MHA)-modified gold surface. X-ray Photo Electron Spectroscopy (XPS) and Quartz Crystal Microbalance with Dissipation (QCM-D) measurements confirmed the successful modification of the gold surface and immobilization of liposomes. Atomic Force Microscopy (AFM) revealed that the liposomes were covalently attached to the surface without any disruption of vesicles. The liposomes tethered to the gold sensor surface were then treated with a range of known ligands of various concentrations. We demonstrated by Electrochemical Impedance Spectroscopy (EIS) that an OrX/liposome EIS sensor can sensitively and selectively detect its known ligand to femtomolar concentrations by detecting a change in electrical signal upon binding. Our study is the first step towards using purified insect odorant receptors alone in biosensors to enable the development of novel ultrasensitive volatile sensors for medical diagnostic, air quality, food safety and border security applications. PMID- 30415157 TI - Epicardial adipose tissue feeding and overfeeding the heart. AB - Epicardial adipose tissue is a particular visceral fat depot with unique anatomic, biomolecular, and genetic features. Epicardial fat displays both physiological and pathological properties. Epicardial fat expresses genes and secretes cytokines actively involved in the thermogenesis and regulation of lipid and glucose metabolism of the adjacent myocardium. A disequilibrium between epicardial fat feeding and overfeeding the myocardium with free fatty acids leads to intramyocardial fat infiltration causing organ damage and clinical consequences. The upregulation of epicardial fat proinflammatory and lipogenic genes contributes to the fat build up in the proximal coronary arteries. Epicardial fat is a measurable and modifiable risk factor that can serve as a novel and additional tool for cardiovascular risk stratification. Pharmacologically targeting epicardial fat with drugs such as glucagon peptide like 1 analogs or sodium glucose transport 2 inhibitors reduces the epicardial fat burden and induces beneficial cardiometabolic effects. Assessment and manipulation of epicardial fat transcriptome might open new avenues in the prevention of cardiometabolic diseases. PMID- 30415158 TI - Update on glucose in critical care. AB - The aim of this review is to summarize recent developments on the mechanisms involved in stress hyperglycemia associated with critical illness. Different aspects of the consequences of stress hyperglycemia as well as the therapeutic approaches tested so far are discussed: the physiological regulations of blood glucose, the mechanisms underlying stress hyperglycemia, the clinical associations, and the results of the prospective trials and meta-analyses to be taken into consideration when interpreting the available data. Current recommendations, challenges, and technological hopes for the future are be discussed. PMID- 30415159 TI - Coffee and tea consumption and the risk for subarachnoid hemorrhage: A meta analysis. AB - OBJECTIVES: Reports on the association between coffee or tea consumption and subarachnoid hemorrhage (SAH) risk are inconsistent. The aim of this study was to determine if an association exists between consumption of coffee or tea and the risk for SAH. METHODS: A random-effects model was used to estimate the summary relative risks (RRs) and 95% confidence intervals (CIs). Heterogeneity among studies was assessed using the statistics Cochran's Q and I2. Seven studies on coffee consumption and five on tea consumption were included in the meta analysis. RESULTS: The pooled RRs of SAH for the highest versus the lowest categories of coffee and tea consumption were 1.31 (95% CI, 0.84-2.05) and 0.83 (95% CI, 0.65-1.08), respectively. There was evidence of heterogeneity among studies of coffee consumption (Pheterogeneity = 0.002, I2 = 71.7%) but not among studies of tea consumption (Pheterogeneity = 0.34, I2 = 11.3%). Omitting one study that substantially contributed to the heterogeneity among studies of coffee consumption yielded a pooled RR of 1.51 (95% CI, 1.10-2.06). Dose-response analysis showed that the summary RRs of SAH for an increase of one cup of coffee and tea consumption per day were 1.00 (95% CI, 0.96-1.04) and 0.97 (95% CI, 0.85 1.11), respectively. There was no evidence of publication bias. CONCLUSION: Our meta-analysis of current evidence does not support an association between the consumption of coffee or tea and SAH risk. Further studies with prospective designs that control for important confounders and provide sufficient data for dose-response analysis are warranted. PMID- 30415160 TI - Probiotic and synbiotic therapy in the critically ill: State of the art. AB - Recent medical history has largely viewed our bacterial symbionts as pathogens to be eradicated rather than as essential partners in optimal health. However, one of the most exciting scientific advances in recent years has been the realization that commensal microorganisms (our microbiome) play vital roles in human physiology in nutrition, vitamin synthesis, drug metabolism, protection against infection, and recovery from illness. Recent data show that loss of "health promoting" microbes and overgrowth of pathogenic bacteria (dysbiosis) in patients in the intensive care unit (ICU) appears to contribute to nosocomial infections, sepsis, and poor outcomes. Dysbiosis results from many factors, including ubiquitous antibiotic use and altered nutrition delivery in illness. Despite modern antibiotic therapy, infections and mortality from often multidrug resistant organisms are increasing. This raises the question of whether restoration of a healthy microbiome via probiotics or synbiotics (probiotic and prebiotic combinations) to intervene on ubiquitous ICU dysbiosis would be an optimal intervention in critical illness to prevent infection and to improve recovery. This review will discuss recent innovative experimental data illuminating mechanistic pathways by which probiotics and synbiotics may provide clinical benefit. Furthermore, a review of recent clinical data demonstrating that probiotics and synbiotics can reduce complications in ICU and other populations will be undertaken. Overall, growing data for probiotic and symbiotic therapy reveal a need for definitive clinical trials of these therapies, as recently performed in healthy neonates. Future studies should target administration of probiotics and synbiotics with known mechanistic benefits to improve patient outcomes. Optimally, future probiotic and symbiotic studies will be conducted using microbiome signatures to characterize actual ICU dysbiosis and determine, and perhaps even personalize, ideal probiotic and symbiotic therapies. PMID- 30415161 TI - Abdominal obesity in normal weight versus overweight and obese hemodialysis patients: Associations with nutrition, inflammation, muscle strength, and quality of life. AB - OBJECTIVE: The biological basis of abdominal obesity leading to more severe outcomes in patients with normal body mass index (BMI) on maintenance hemodialysis (MHD) is unclear. The aim of this study was to compare the properties of abdominal obesity in different BMI categories of patients on MHD. METHODS: We performed a cross-sectional study of 188 MHD patients (52.7% women; mean age, 69.4 +/- 11.5 y) with abdominal obesity in different BMI groups using criteria from the World Health Organization. Appetite and dietary intake, body composition, handgrip strength, malnutrition inflammation score (MIS), inflammatory biomarkers, adipokines, and health-related quality-of-life (QoL) questionnaires were studied. RESULTS: According to multivariable analyses, abdominally obese patients with normal BMIs consumed less protein per day (P = 0.04); had lower measurements of surrogates of lean (P < 0.001) and fat mass (P < 0.001); and had higher total cholesterol, tumor necrosis factor-alpha (P < 0.05), and ratios of adiponectin to leptin (P = 0.003) than overweight and obese patients with abdominal obesity. Multivariable analyses showed no differences in handgrip strength among the study groups.The abdominally obese study participants with normal weight had significantly lower scores in role physical (P = 0.003) and pain (P = 0.04) scales after multivariable adjustments. CONCLUSIONS: Normal weight MHD patients with abdominal obesity exhibited a more proatherogenic profile in terms of inflammatory markers and adipokine expression, lower body composition reserves, and lower physical ability than patients with abdominal obesity with overweight and obesity. This at least partially explains the abdominal obesity paradox in the MHD population in which worse clinical outcomes are seen in abdominally obese patients with normal BMIs, as opposed to overweight and obese patients who are also abdominally obese. PMID- 30415162 TI - HDV evolution-will viral resistance be an issue in HDV infection? AB - Hepatitis D virus (HDV) is a hepatotropic subviral infectious agent, obligate satellite of the Hepatitis B virus (HBV) and is highly related to viroids. HDV affects around 5% of the 257 million chronic HBV-carriers worldwide, leading to the most severe form of chronic viral hepatitis. Interferon alpha is the only approved treatment for chronic hepatitis D, albeit with low response rates (around 20%-30%). New antiviral strategies are currently under study. Due to the high viral evolution rates (10-3 to 10-4 substitutions/site/year) HDV forms an extremely complex viral population (quasispecies) that can be studied by Next Generation Sequencing. Therefore, although specific viral resistance in HDV infection has not been reported, it cannot be completely discarded. PMID- 30415163 TI - A novel all-trans retinoic acid derivative inhibits proliferation and induces apoptosis of myelodysplastic syndromes cell line SKM-1 cells via up-regulating p53. AB - Myelodysplastic syndromes (MDS) are a varied set of hematologic neoplasms and a high risk of progression to acute myeloid leukemia (AML). 4-Amino-2 trifluoromethyl-phenyl retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative, play an important role in various types of cancer cells as a tumor inhibitor. However, little is known concerning its antitumor effect on MDS. The cell viability and the percentage of apoptotic cells were used to measure MTT, Flow Cytometry and Hoechst 33342/PI staining. In addition, real-time quantitative RT-PCR (qRT-PCR) and western blotting were used to analyzed the expression of p53, as well as the levels of BNIP3, apoptosis proteins of Caspase-3, BAX and BCL 2. After SKM-1 cells were incubated with DAC, ATRA and ATPR, the viability of the SKM-1 cells was inhibited in a dose- and time-dependent manner. Both Hoechst staining and flow cytometry showed the apoptosis of SKM-1 cells was increased. Moreover, SKM-1 cells treated with ATPR unveiled elevated mRNA and protein levels of p53, BNIP3, BAX and Caspase-3 expression and decreased BCL-2 expression. However, silencing p53 suppressed the pro-apoptosis function of ATPR. Consequently, these data provide the first evidence for ATPR increased apoptosis in SKM-1 cells by p53 that is mutually dependent on and obligatorily linked to BNIP3 gene activation. PMID- 30415164 TI - Aloperine suppresses allergic airway inflammation through NF-kappaB, MAPK, and Nrf2/HO-1 signaling pathways in mice. AB - To explore the effects of aloperine (ALO) on allergic airway inflammation, we investigated whether its mechanism is related with NF-kappaB, MAPK, and Nrf2/HO-1 signaling pathways. Histochemical staining and inflammatory cell count were used to observe lung histopathological changes in mice. ELISA was used to detect the content of inflammatory cytokines and IgE in the mouse bronchoalveolar lavage fluid (BALF). Airway hyperresponsiveness (AHR) to inhale methacholine was measured by the plethysmography in conscious mice. Immunohistochemical method was used to detect the expression levels of Nrf2 and HO-1 in lung tissues. The key proteins of MAPK, NF-kappaB, and Nrf2/HO-1 in lung tissues were quantitatively analyzed by Western blot. Finally, the in vitro effect of ALO on the production of pro-inflammatory mediators and cytokines by lipopolysaccharide-stimulated RAW 264.7 cells was also evaluated. In the ovalbumin (OVA)-induced asthma mouse model, ALO reduced the exudation and infiltration of inflammatory cells and suppressed goblet cell hyperplasia. ALO-treated asthmatic mice also decreased the protein levels of interleukin (IL)-4, IL-5, IL-13, IFN-gamma, and IgE in BALF and attenuated AHR. Furthermore, ALO inhibited the expression of key proteins of MAPK and NF-kappaB pathways, and increased the expression of Nrf2/HO-1 in OVA challenged mice. Additional in vitro study has shown that ALO abrogates the macrophage production of inducible nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-alpha, IL-6, and IL-1beta. Taken together, ALO attenuated allergic airway inflammation through regulating NF-kappaB, MAPK, and Nrf2/HO-1 signaling pathways. The results suggest the utility of ALO as an anti inflammatory agent for the treatment of asthma. PMID- 30415166 TI - Pyranopyrazoles as efficient antimicrobial agents: Green, one pot and multicomponent approach. AB - Innovative therapeutic heterocycles having precisely thiadiazolyl-pyranopyrazole fragments were prepared by using the ecofriendly synthetic route. Entire compounds formed in quantitative yields. All the composites tested for their antimicrobial effectiveness against four microbial, two beneficial fungi's and accurately measured the minimum inhibitory concentrations (MIC and MBC/MFC), along with some initial structure activity relationships (SARs) also discussed. From the biological outcomes, the motif 6f provided an outstanding activity against all six pathogens. The possible presence of a nitro substituent on this composite may undoubtedly enhance the activity. In addition, amalgams 6d, 6g and 6l displayed promising antimicrobial results. This may be justified to the presence of electron capture group attached to the benzene ring, while the combinations 6j and 6k were zero effect towards all bacterial strains. The other compounds were excellent to low antimicrobial efficiency. The intriguing point was observed that all the active compounds had in common immense antibacterial effectiveness on Gram-negative bacteria than Gram-positive one and more antifungal activity on A. niger compare to other fungus. All things considered and suggested that this outstanding green synthetic approach is used to develop biological active compounds. On top of that, biological results confirmed that these biologically energetic motifs suitable for additional preclinical examine with the aim of standing novel innovative drugs. PMID- 30415165 TI - ARC regulates programmed necrosis and myocardial ischemia/reperfusion injury through the inhibition of mPTP opening. AB - Necrosis is a key factor in myocardial injury during cardiac pathological processes, such as myocardial infarction (MI), ischemia/reperfusion (I/R) injury and heart failure. Increasing evidence suggests that several aspects of necrosis are programmed and tightly regulated, so targeting the necrosis process has become a new trend for myocardial protection. Multiple cellular signaling pathways have been implicated in necrotic cell death, such as the death receptor mediated extrinsic and mitochondrial intrinsic pathways. However, the precise mechanisms underlying myocardial necrosis remain unclear. In this study, we showed that apoptosis repressor with caspase recruitment domain (ARC) participated in the mitochondrial intrinsic pathway and inhibited myocardial necrosis by preventing the opening of the mitochondrial permeability transition pore (mPTP). ARC attenuated necrotic cell death triggered by exposure to 500 MUM hydrogen peroxide (H2O2) in the cardiomyocyte cell line H9c2. In mice, ARC ameliorated myocardial necrosis, reduced the myocardial infarct size and improved long-term heart function during I/R injury. Mechanistically, it has been shown that the inhibition of necrosis by ARC was dependent on its mitochondrial localization and that ARC prevented the opening of mPTP by targeting CypD, the main regulator of mPTP. In addition, ARC expression was negatively regulated by the transcription factor p53 at the transcriptional level during the necrosis process. These findings identified the novel role of ARC in myocardial necrosis and delineated the p53-ARC-CypD/mPTP necrosis pathway during ischemia- and oxidative stress-induced myocardial damage, which can provide a new strategy for cardiac protection. PMID- 30415167 TI - Abiotic factors determine functional outcomes of microbial inoculation of soils from a metal contaminated brownfield. AB - Whole community microbial inoculation can improve soil function in contaminated environments. Here we conducted a case study to investigate whether biotic factors (inoculum) or abiotic factors (soil base) have more impact on the extracellular enzymatic activities in a whole community microbial inoculation. To this end, we cross-inoculated microbial communities between two heavy metal contaminated soils, with high and low extracellular enzyme activities, respectively. We measured extracellular phosphatase activity, a proxy for soil function, after self- and cross-inoculation of microbial communities into sterilized soils, and all activities were normalized to non-inoculated controls. We found that inoculation increased phosphatase activity in the soils. For soils treated with different inocula, we found significant differences in the microbial community compositions but no significant differences in the extracellular phosphatase activities normalized to their respective sterilized, non-inoculated controls (4.7 +/- 1.8 and 3.3 +/- 0.5 for soils inoculated with microbial communities from 146 to 43, respectively). On the other hand, normalized phosphatase activities between the two soil bases were significantly different (4.1 +/- 0.12 and 1.9 +/- 0.12 for soil bases 146 and 43, respectively) regardless of the source of the inoculum that did not vary between soil bases. The results indicate that the abiotic properties of the soils were a significant predictor for phosphatase activity but not for the end-point composition of the microbial community. The findings suggest that targeted microbial inocula from metal contaminated soils can increase phosphatase activity, and likely soil functioning in general, but the degree to which this happens depends on the abiotic environment, in this case, metal contamination. PMID- 30415168 TI - Disentangling the effects of the aqueous matrix on the potential toxicity of liquid pig manure in sub-tropical soils under semi-field conditions. AB - Inadequate application of liquid pig manure (LPM) may pose risks to the soil due to the potential contaminants that exists, as well as by the large water input that can originate excessive moisture. By using Terrestrial Model Ecosystems, this study aimed to evaluate the effect of application of LPM (82% moisture) using the application rates of 20, 50 and 150 m3 ha-1 and also of the corresponding amount of water to understand the origin of effects on the soil fauna of two sub-tropical soils. In general, the results obtained for the two soil types indicated that LPM (150 m3 ha-1) changed the composition of soil fauna, with an increase in the abundance of insect larvae and dipterans, but a decrease in the number of earthworms and enchytraeids. Microbial biomass, soil respiration and the nutrients Mg, K and P increased with the amount of LPM supplied to the soil. When analysing the effects of adding large volumes of water via the LPM, results showed that application did not originate significant effects on the parameters measured. The differences obtained when comparing both treatments were mainly attributed to the organic load brought by the LPM and not to the amount of water without LPM. PMID- 30415169 TI - Bibliographic and visualized analysis of geopolymer research and its application in heavy metal immobilization: A review. AB - Geopolymer (GP) is a novel aluminosilicate inorganic polymer, and it possesses excellent characteristics in application of various fields, and its advantages have attracted worldwide attention. Based on the Citespace software, the bibliometric analysis combined with the visualization analysis on GP was summarized on the publications that extracted from Web of Science (WOS) from 1990 to 2017. The analysis results demonstrate that the research on GP develops rapidly in the last years, and the GP have already possessed a degree of application value in several engineering fields. This research shows a multidisciplinary amalgamation tendency in contents and methods. Additionally, the main application in pollution treatment of GP is heavy metal immobilization. The immobilization effects of GP for heavy metal are mainly depended on physical encapsulation, adsorption effect, chemical bonding, substitution for Al3+ and other effects. And these effects are simultaneous action on heavy metal immobilization under different conditions. Furthermore, the majority of GP are based on the fly ash and metakaolin, and the most frequently used leaching method is the Toxicity Characteristic Leaching Procedure (TCLP). Moreover, there are also several problems need to be solved before GP can be widely applied in heavy metal treatment. Overall, GP have possessed a great potential research and application value in the present stage, especially in the aspect of heavy metal immobilization. PMID- 30415170 TI - Drum composting of nitrogen-rich Hydrilla Verticillata with carbon-rich agents: Effects on composting physics and kinetics. AB - Composting of the Hydrilla verticillata, an invasive aquatic weed, signifies aquatic waste management as a safe and hygienic method that produces a nutrient rich end product, i.e., compost. However, its higher moisture content, higher N losses, and lower degradation rate have shown negative impacts on the composting process. Therefore the primary objective of this study was to assess the composting physics and the degradation kinetics after addition of three different carbon-rich agents with Hydrilla verticillata. To pursue this objective, three carbon-rich agents (viz. dry leaves in Run A, grass clippings in Run B and wood chips in Run C) each were mixed (10% w/w) to the optimized control mixture of Hydrilla verticillata, cow dung and sawdust (8:1:1) as reported in the earlier study. The composting experiments were performed in 550L rotary drum composter for 20 days to evaluate variation in physical, chemical, nutritional properties as well as degradation kinetics. The Run A and Run B were the only two mixtures that attained the temperature (55-70 degrees C) that indicates standard sterilization capacity in both with maximum moisture reduction (17%) and total Kjeldahl N increment (48%) in the latter. Organic matter losses throughout the process followed a first-order kinetic equation in all the Run (A-C) and control with the higher loss in Run B whereas least in control. Nevertheless, the addition of all carbon-rich agents is found to be beneficial to improve composting physics. Amongst all Runs (A-C), Run B achieved maximum reduction in the initial value of bulk density (64%) and increment in the initial value of free air space (20%). The study also concluded that all the carbon-rich agents have produced compost with the nutritional concentration suitable for agricultural proposes. PMID- 30415171 TI - The reuse of waste glass for enhancement of heavy metals immobilization during the introduction of galvanized sludge in brick manufacturing. AB - The mixing of galvanized sludge in fired clay brick manufacturing has been regarded as an alternative approach for the consumption of galvanized sludge. Decreasing the surface area and porosity of fired brick definitely lowers the risk of heavy metal release. In this study, a novel method is proposed to reduce the surface area and porosity of bricks and promote heavy metal immobilization by adding waste glass. The introduction of waste glass enhanced the physical and mechanical performances of fired clay bricks and resulted in an increase in bulk density and compressive strength and a decrease in water absorption. Microstructure analysis showed that the texture of the bricks turned from porous to smooth and homogeneous due to the introduction of waste glass. Porosity analysis showed that surface area and pore volume of fired brick were substantially reduced. When the added waste glass amount exceeded 15 wt%, the heavy metal concentrations that leached from bricks containing 10 wt% galvanized sludge fired at 950 degrees C met the regulatory requirement. These results demonstrate that waste glass can be reused to enhance the stabilization/solidification of heavy metals, during the mixing of hazardous waste in bricks and ceramics manufacturing process. PMID- 30415172 TI - Organizing forestry governance: Cadre training in China's multi-level governance regime. AB - Extant literature has examined cadre training within the context of the Chinese party-state's adaptive capacities, focusing on training delivered through party schools and administration academies. This article offers a different perspective, analyzing professional training as a steering mechanism in China's multi-level governance regime. Using China's State Forestry Administration (SFA) as a case study, the article explores the structure of training programs within the administration, the types of training offered to forestry cadres, and the role of training in the implementation of policies to promote sustainable forest management. It shows that training pursues different objectives, one of which is to facilitate and contribute to policy implementation. The SFA categorizes trainees into a number of centrally-defined, standardized groups and determines what kind of knowledge and skills each group of trainees are expected to acquire via training. Finally, it shows that training is used as a means to organize governance in China. PMID- 30415173 TI - Externalizing and self-medicating: Heterogeneity among repeat DUI offenders. AB - AIM: Despite significant reductions in Driving Under the Influence (DUI) in the United States during recent decades, DUI continues to be a major public health threat. The current study investigated the intersection of two domains known to influence DUI: criminal history and psychiatric comorbidity. METHODS: DUI recidivists (N = 743) attending a court-mandated two-week inpatient DUI program completed a computerized mental health assessment as part of their intake to that program. Participants' criminal records were obtained 4-5 years after program attendance. FINDINGS: This study identified three primary repeat DUI offender subtypes with distinct patterns of criminal behavior and psychiatric comorbidity: (Type I) those whose DUI emerges from a pattern of drinking to cope with mood and anxiety problems, (Type II) those whose DUI emerges as part of a larger pattern of externalizing and criminal behavior, and (Type III) those whose DUI offenses reflect more acute triggers and isolated episodes of excessive drinking. CONCLUSION: These findings suggest that current treatment models used in DUI programs are inadequate to address the heterogeneity in the population of DUI recidivists and that earlier and more comprehensive screening would allow for better targeting of resources to DUI offender subtypes. PMID- 30415174 TI - Automatic nodule detection for lung cancer in CT images: A review. AB - Automatic lung nodule detection has great significance for treating lung cancer and increasing patient survival. This work summarizes a critical review of recent techniques for automatic lung nodule detection in computed tomography images. This review indicates the current tendency and obtained progress as well as future challenges in this field. This research covered the databases including Web of Science, PubMed, and the Press, including IEEE Xplore and Science Direct, up to May 2018. Each part of the paper is summarized carefully in terms of the method and validation results for better comparison. Based on the results, some techniques show better performance for lung nodule detection. However, researchers should pay attention to the existing challenges, such as high sensitivity with a low false positive rate, large and different patient databases, developing or optimizing the detection technique of various types of lung nodules with different sizes, shapes, textures and locations, combining electronic medical records and picture archiving and communication systems, building efficient feature sets for better classification and promoting the cooperation and communication between academic institutions and medical organizations. We believe that automatic computer-aided detection systems will be developed with strong robustness, high efficiency and security assurance. This review will be helpful for professional researchers and radiologists to further learn about the latest techniques in computer-aided detection systems. PMID- 30415175 TI - Association between olanzapine treatment and brain cortical thickness and gray/white matter contrast is moderated by cholesterol in psychotic disorders. AB - Altered cortical brain morphology is observed in psychotic disorders. Despite the importance of lipid homeostasis for healthy brain functioning, knowledge about its role in cortical alterations in psychosis is limited. In a sample of patients with psychotic disorders, we investigated the relationship between treatment with olanzapine (OLZ), and cortical thickness and gray/white matter intensity contrast, and the association between these measures and serum lipid levels. We included 33 OLZ users, 19 unmedicated psychotic patients and 76 healthy controls (HC). Data on serum lipids and cortical measures based on MR brain images processed with FreeSurfer were analyzed with General Linear Models. We found that intensity contrast was similar in OLZ users as compared to HC and that the cortex (frontal, orbitofrontal, medial temporal) was thinner in OLZ users (p < 0.05, Bonferroni corrected). An OLZ-specific HDL interaction effect was further found for the pericentral cortical thickness measure (p < 0.05, Bonferroni corrected). Additionally, nominally significant findings indicated similar OLZ-specific interaction effects for cortical thickness in several regions, and an OLZ specific interaction with LDL for occipital lobe contrast (p < 0.05, uncorrected). Our findings may suggest a drug-related lipid-effect on brain myelination. Experimental studies and replications in different study samples are needed to clarify these complex relationships further. PMID- 30415176 TI - Electrophysiological correlates of visual backward masking in patients with first episode psychosis. AB - Visual backward masking is strongly impaired in patients with schizophrenia. Masking deficits have been proposed as potential endophenotypes of schizophrenia. Masking performance deficits manifest as strongly reduced amplitudes in the electroencephalogram (EEG). In order to fulfill the criteria of an endophenotype, masking deficits should not vary substantially across time and should be present at the first psychotic event. To verify whether these conditions are met for visual backward masking, we tested patients with first episode psychosis (n = 21) in a longitudinal study. Patients were tested with visual backward masking and EEG three times every six months over a period of one year. We found that the EEG amplitudes of patients with first episode psychosis were higher as compared to those of patients with schizophrenia but lower as compared to those of unaffected controls. More interestingly, we found that the EEG amplitudes of patients with first episode psychosis remained stable over the course of one year. Since chronic schizophrenia patients have strongly reduced amplitudes, we speculate that the neural correlates of masking deficits (EEG amplitudes) continue to decrease as the disease progresses. PMID- 30415177 TI - Vape shop location and marketing in the context of the Food and Drug Administration regulation. AB - OBJECTIVES: A range of electronic nicotine delivery systems (ENDSs; e.g. e cigarettes, e-hookahs) have emerged in the US market, with rapid increases in use. While ENDSs may facilitate harm reduction in smokers, they may represent risks to health and addiction in the nicotine naive. Vape shops account for a substantial proportion of ENDS sales/distribution. STUDY DESIGN: Brief summary of the relevant literature. METHODS: This communication provides a brief summary of relevant literature derived from traditional tobacco retail and point-of-sale marketing and synthesizes issues regarding how the Food and Drug Administration regulation might impact the ENDS market, specifically the vape shop industry, a nuanced tobacco retail environment. RESULTS: This literature indicates that tobacco retailers are disproportionately located near vulnerable populations (e.g. the socio-economically disadvantaged, racial/ethnic minorities, and young adults) and may use stronger promotional activities to target these populations. Research extending this literature to ENDSs and ENDS retailers, such as vape shops, is limited. Regulatory efforts, spatial access, and exposure to marketing and advertising are macrolevel factors that have a significant impact on the individual-level tobacco use. CONCLUSIONS: Future research should examine multilevel factors (e.g. policies, community context, and marketing) and extend this literature to the ENDS market, particularly vape shops, which is especially relevant during the rapidly changing regulatory environment. PMID- 30415178 TI - The hydrophobic surface state of talc as influenced by aluminum substitution in the tetrahedral layer. AB - Talc is both an important industrial mineral product recovered by flotation, and also in other cases, a gangue mineral of concern in the flotation of certain sulfide ores, such as the PGM ores from South Africa and from the United States. The talc face surface is naturally hydrophobic with a water sessile drop contact angle of nearly 80 degrees , which accounts for its flotation recovery in one case, and its contamination of sulfide mineral concentrates in other instances. Due to the presence of impurities in the talc structure the surface properties change. One such effect is the presence of aluminum, which can replace silicon in the silica tetrahedral layer of the talc structure. This results in a charge imbalance on the face surface because Si+4 is replaced by Al+3. Sessile drop contact angle and bubble attachment time measurements were made, and these results were compared to the results from molecular dynamics simulations (MDS). The extent of aluminum substitution in the silica tetrahedral layer was considered, and the sessile drop contact angle was found to decrease with increased aluminum content, decreasing from about 80 degrees for no substitution (talc) to 0 degrees for extensive substitution (phlogopite). The water film was found to be stable at the surface of highly aluminum substituted crystals due to the interaction between water molecules and the increased polarity of the surface state. This stable water film restricts the air bubble from attaching to such face surfaces. However, in the absence of aluminum substitution, no interactions between the water molecules and the face surface were observed and the air bubble readily attached to the face surface. This study provides additional understanding of how aluminum substitution in the tetrahedral layer affects the fundamental surface properties of talc, paving the way for the design of improved reagents for talc flotation as an industrial mineral product, and for talc depression in the recovery of sulfide mineral concentrates. PMID- 30415179 TI - Vitamin K deficiency in critical ill patients; a prospective observational study. AB - BACKGROUND: Vitamin K is a cofactor for proteins involved in cardiovascular health, bone metabolism and cancer. Measuring uncarboxylated prothrombin, also termed as "protein induced by vitamin K absence or antagonism for factor II (PIVKA-II)", has been used to assess vitamin K status. High levels may indicate vitamin K deficiency. The aim of this study was to measure PIVKA-II and prothrombin time (PT-INR) in intensive care (ICU) patients and correlate vitamin K status with mortality. METHODS: Ninety-five patients admitted to the ICU had blood samples taken near admission and every third day. In addition to PIVKA-II and PT-INR, critical-care severity scores were computed. RESULTS: The median baseline PIVKA-II was 4.97 MUg/L compared to the upper reference of 2.0 MUg/L. PIVKA-II further increased at days 3 and 6, (median 7.88 MUg/L, p = .047 and median 8.14 MUg/L, p = .011) predominantly in cardiac arrest patients (median 21.4 MUg/L, day 3). CONCLUSION: Intensive care patients have increased PIVKA-II levels at admission, which increases during the ICU stay, especially in cardiac arrest patients. There were no correlations between PIVKA-II and PT-INR, SOFA score or mortality. Further studies are needed to determine why PIVKA-II increases and whether high PIVKA-II levels in ICU patients affect long-term mortality or morbidity. PMID- 30415180 TI - The use of the PSH-AM in patients with diffuse axonal injury and autonomic dysregulation: A cohort study and review. AB - PURPOSE: 1) To determine the clinical expression and consequences of autonomic dysregulation in patients with diffuse axonal injury (DAI), and 2) to study the use of the "paroxysmal sympathetic hyperactivity assessment measure" (PSH-AM). METHODS: Patients clinically diagnosed with autonomic dysregulation were selected from a cohort involving 116 patients with DAI. We studied the incidence of autonomic features, treatment, and outcome. In addition a systematic review was performed. RESULTS: Autonomic dysregulation was diagnosed in 19 of 116 (16.4%). Lower age (OR 0.95) and higher DAI grade (OR 7.2) were risk factors for autonomic dysregulation. Autonomic dysregulation was associated with an unfavourable outcome (OR 5.6) and a longer ICU and hospital stay. On the PSH-AM 57.9% (n = 11) scored a probable paroxysmal sympathetic hyperactivity (PSH), 36.8% (n = 7) scored possible, and 5.2% (n = 1) scored unlikely. The review yielded 30 articles. The incidence of autonomic dysregulation after TBI varied from 7.7 32.6% (mean 13.5%). TBI patients with autonomic dysregulation had a longer ICU stay and poorer outcome. CONCLUSION: Patients with DAI and autonomic dysregulation had a longer ICU stay and a poorer outcome compared to patients without autonomic dysregulation. The PSH-AM is a potential valuable tool to determine the likelihood of autonomic dysregulation. PMID- 30415181 TI - Vasopressin vs noradrenaline: Have we found the perfect recipe to improve outcome in septic shock? AB - PURPOSE: The metabolic and circulatory disturbances in patients with septic shock results in a high mortality rate. There is a lack of high-level evidence on the optimal approach. We present a meta-analysis elucidating the outcomes of regimes with only noradrenaline versus a combination of noradrenaline and vasopressin in managing septic shock. METHODS: A literature search of studies comparing the use of noradrenaline and vasopressin in septic shock was conducted, using MEDLINE and EMBASE databases. The primary outcome evaluated was mortality rate. Subgroup analysis of secondary measures was also conducted using Review Manager 5.3 software. RESULTS: Four RCTs of 1039 patients were included. There is good evidence supporting a comparable mortality rate (RR: 0.92, 95% CI: 0.78, 1.08, p = .32, I2 = 0%), and moderate evidence supporting an equivalent length of ICU stay (MD: 0.14, 95% CI: -1.37, 1.65, p = .86, I2 = 46%) and occurrence of adverse events (RR: 1.19, 95% CI: 0.83, 1.70, p = .35, I2 = 13%) between the two cohorts. CONCLUSION: The two regimes have equivalent outcomes, but vasopressin has a role in selected patients experiencing less severe septic shock beyond a 36-h period. Further work will make definitive clinical recommendations for optimal strategy of vasopressin or noradrenaline usage. PMID- 30415182 TI - Calcineurin-inhibitor induced pain syndrome - Magnetic resonance imaging and scintigraphic findings illustrated through two cases. AB - Calcineurin-inhibitor induced pain syndrome (CIPS) is a condition characterized by lower extremity pain in patients receiving tacrolimus or cyclosporine therapy following organ transplantation. Through two cases, we demonstrate key imaging findings in CIPS with bone scintigraphy and magnetic resonance imaging (MRI), which are those of increased scintigraphic activity and marrow edema in the lower extremities, respectively. CIPS is an important condition that has characteristic imaging findings, but is unfortunately underappreciated in the radiology literature. To our knowledge, this is the first article in the radiology literature presenting two cases of CIPS, as well as the first to present both scintigraphic and MRI findings in this condition. PMID- 30415183 TI - Identification of a correlation between the sonographic appearance and molecular subtype of invasive breast cancer: A review of 311 cases. AB - PURPOSE: To identify the ultrasound and clinical features related to the different molecular subtypes of invasive breast cancer. METHODS: Sonographic and clinical data of 311 surgically confirmed breast cancer cases were retrospectively reviewed and compared based on various subtypes. RESULTS: Luminal A (LA) breast cancers were associated with a low histologic grade, spiculated margins, an echogenic rim and posterior acoustic attenuation. The human epidermal growth factor receptor 2-positive (HER2+) subtype was characterized by a high grade, indistinct and spiculated margins, enhanced posterior acoustics, calcifications, and vascularity. Triple negative breast cancers (TNBCs) were more likely to present with a high tumor grade, circumscribed and microlobulated margins, and the absence of an echogenic rim and calcifications; to be markedly hypoechoic; and to have posterior acoustic enhancement and hypovascularity. Luminal B (LB) cancers were more likely to be associated with an indistinct margin and relative vascularity. CONCLUSION: Our study demonstrated that the sonographic and clinical features of breast cancer were significantly correlated with the molecular subtype. The imaging findings of the different subtypes and their biological implications may provide additional auxiliary information for clinical diagnosis, systemic treatment and prognosis prediction. PMID- 30415184 TI - A quantitative image analysis using MRI for diagnosis of biliary atresia. AB - PURPOSE: Biliary atresia is a life-threatening disease that needs early diagnosis and management. Recently, MRI images have been used for the diagnosis of biliary atresia with improved accuracy of diagnosis when other imaging modalities such as ultrasonography are equivocal. This study aimed to evaluate the juxta-hilar extrahepatic biliary tree using MRI images to determine a quantitative value for diagnosing biliary atresia. MATERIALS AND METHODS: This retrospective study was approved by the Ethical Committee at Mackey Memorial Hospital (IRB Number: 15MMHIS149e). Between January 2010 and December 2015, twenty-five patients with surgically confirmed biliary atresia were enrolled (age 18-65 days). Another 25 patients with clinically or surgically diagnosed idiopathic neonatal hepatitis (age 6-64 days) and 20 patients with non-hepatobiliary disease (age 6-65 days) were considered control group and normal subjects, respectively. The diameter of the enlarged, T2-hyperintense structure was measured using MRI images by two radiologists both blinded. The cut-off value for a biliary atresia diagnosis was obtained by area under the curve analysis. RESULTS: The diameter of the T2 hyperintense structure at porta hepatis in biliary atresia (4.79 +/- 1.14 mm) is larger than in idiopathic neonatal hepatitis (1.72 +/- 0.42 mm) or in non hepatobiliary disease (1.72 +/- 0.35 mm) (p < 0.05). The optimum cut-off value for diagnosing biliary atresia was 3.1 mm with 98% sensitivity and 98% specificity. CONCLUSION: The value of the enlarged, T2-hyperintense structure measured on MRI images was significantly increased in biliary atresia and may be useful in diagnosing biliary atresia. PMID- 30415185 TI - Do you know what I'm thinking? Temporal and spatial brain activity during a theory-of-mind task in children with autism. AB - The social impairments observed in children with autism spectrum disorder are thought to arise in part from deficits in theory of mind, the ability to understand other people's thoughts and feelings. To determine the temporal spatial dynamics of brain activity underlying these atypical theory-of-mind processes, we used magnetoencephalography to characterize the sequence of functional brain patterns (i.e. when and where) related to theory-of-mind reasoning in 19 high-functioning children with autism compared to 22 age- and sex matched typically-developing children aged 8-12 during a false-belief (theory-of mind) task. While task performance did not differ between the two groups, children with autism showed reduced activation in the left temporoparietal junction between 300-375 and 425-500 ms, as well as increased activation in the right inferior frontal gyrus from 325 to 375 ms compared to controls. The overlap in decreased temporoparietal junction activity and increased right inferior frontal gyrus activation from 325 to 375 ms suggests that in children with autism, the right inferior frontal gyrus may compensate for deficits in the temporoparietal junction, a neural theory-of-mind network hub. As the right inferior frontal gyrus is involved in inhibitory control, this finding suggests that children with autism rely on executive functions to bolster their false belief understanding. PMID- 30415186 TI - Autoregulation and repair in microtubule homeostasis. AB - Even in the face of damaging insults, most cells maintain stability over time through multiple homeostatic pathways, including maintenance of the microtubule cytoskeleton that is fundamental to numerous cellular processes. The dynamic instability-perpetual growth and shrinkage-is the best-known microtubule regulatory pathway, which allows rapid rebuilding of the microtubule cytoskeleton in response to internal or external cues. Much less investigated is homeostatic regulation through availability of alpha-beta tubulin heterodimers-microtubules' main building blocks-which influences total mass and dynamic behavior of microtubules. Finally, the most recently discovered is microtubule homeostasis through self-repair, where new GTP-bound tubulin heterodimers replace the lost ones in the microtubule lattice. In this review we try to integrate our current knowledge on how dynamic instability, regulation of tubulin mass, and self-repair work together to achieve microtubule homeostasis. PMID- 30415187 TI - Microtubule lattice plasticity. AB - In classical microtubule dynamic instability, the dynamics of the built polymer depend only on the nucleotide state of its individual tubulin molecules. Recent work is overturning this view, pointing instead towards lattice plasticity, in which the fine-structure and mechanics of the microtubule lattice are emergent properties that depend not only on the nucleotide state of each tubulin, but also on the nucleotide states of its neighbours, on its and their isotypes, and on interacting proteins, drugs, local mechanical strain, post translational modifications, packing defects and solvent conditions. In lattice plasticity models, the microtubule is an allosteric molecular collective that integrates multiple mechanochemical inputs and responds adaptively by adjusting its conformation, stiffness and dynamics. PMID- 30415188 TI - Environmental characteristics of early childhood education and care, daily movement behaviours and adiposity in toddlers: A multilevel mediation analysis from the GET UP! Study. AB - STUDY OBJECTIVE: This study aimed to examine the direct effects of environmental characteristics of early childhood education and care (ECEC) centres on adiposity, and the indirect effects through daily movement behaviours (physical activity, sedentary time and naps). METHODS: 274 children (average age 19.73 +/- 4.15 months) from 27 ECEC centres participated in this study. Environmental characteristics of ECEC centres were rated using the Infant/Toddler Environment Rating Scale-revised edition (ITERS-R). Daily movement behaviours were assessed using 24-h accelerometry. Body mass index z-scores were used to indicate adiposity. RESULTS: There were no significant direct effects or indirect effects of environmental characteristics on toddlers' adiposity through daily movement behaviours. However, the environmental characteristics of "personal care routine" (B=0.72, p = 0.041) and "activity" (B = 0.87, p < 0.050) were positively associated with the percentage of time these toddlers spent in moderate-to vigorous physical activity (MVPA). "Listening and talking" was also positively associated withnap(s) durations (B = 4.08 p = 0.001). CONCLUSION: The relationships between environmental characteristics of ECEC centres and adiposity in toddlers, as well as, the mediating roles of daily movement behaviours still need confirmation by future longitudinal and experimental studies with long follow-up periods. At the same time, a broader spectrum of environmental characteristics of these settings needs to be examined with toddlers' adiposity in future studies; other potential mediators may also need to be taken into considerations. PMID- 30415189 TI - Pinellia pedatisecta lectin exerts a proinflammatory activity correlated with ROS MAPKs/NF-kappaB pathways and the NLRP3 inflammasome in RAW264.7 cells accompanied by cell pyroptosis. AB - Pinellia pedatisecta, a widely used herb in Chinese medicine, has proinflammatory toxicity related to its Pinellia pedatisecta lectin (PPL), but the mechanism is still unknown. However, for safer use, it is necessary to clarify its proinflammatory mechanism. Herein, we studied the mechanism in RAW264.7 cells. PPL decreased the mitochondrial membrane potential (MMP) and increased the outflow of calcium, accompanied by the overproduction of reactive oxygen species (ROS), which resulted in the activation of the MAPK and NF-kappaB pathways and the release of IL-1beta. The maturation of IL-1beta relied on caspase-1 p20, the active caspase-1, as demonstrated by adding caspase-1 inhibitor. While caspase-1 was associated with the activation of the NLRP3 inflammasome, we further found that the stimulation of PPL also contributed to the activation. In addition, TXNIP was downregulated, whereas NLRP3/caspase-1 p20/ASC was upregulated, and there was binding of TXNIP with NLRP3. There was also binding of NLRP3 with ASC and caspase-1. Further, we found that N-acetylcysteine (NAC), an ROS scavenger, could inhibit the PPL-stimulated activation of these pathways and the release of IL-1beta. Moreover, PPL led to cell pyroptosis with pyknotic nuclei and plasma membrane rupture, which could be inhibited by NAC. All of these findings demonstrated an important role of ROS in the inflammation caused by PPL. Taken together, our data provide new mechanistic insights into the possible endogenous signaling pathways involved in the inflammation of RAW264.7 cells, stimulated by PPL. PMID- 30415190 TI - Serum immunoglobulin G provides early risk prediction in immunoglobulin A nephropathy. AB - BACKGROUND: Immunoglobulin A (IgA) nephropathy (IgAN) is a common primary glomerular disease that potentially leads to renal failure, risk prediction of declining kidney function is crucial for early clinical management. Immunoglobulin G (IgG) is an important constituent of the immune system and serves as the preferred therapeutic target in human autoimmune diseases. However, its role in the progression of IgAN is unclear. METHODS: From May 2009 to April 2014, 455 patients diagnosed with IgAN at the Second Xiangya Hospital were enrolled in this study; the median follow-up was 42.2 months. All subjects were divided into four groups according to IgG level quartiles. The study endpoint was end-stage renal disease (ESRD) or an irreversible 50% estimated glomerular filtration rate (eGFR) reduction. Clinical data and pathological features of renal biopsy specimens were collected. RESULTS: Among IgAN patients, serum IgG levels were directly correlated with the levels of serum albumin and serum IgA but reversely correlated with body weight, systolic blood pressure, and serum creatinine and cholesterol levels. According to stratified analysis of serum IgG, the proportions of composite renal endpoints among the enrolled IgAN patients in the serum IgG concentration subgroups 1 (<7.86), 2 (7.86-10.30), 3 (10.31-12.70), and 4 (>12.71 g/l) were 9.6%, 9.2%, 3.7%, and 3.7% respectively. Importantly, cumulative renal survival rates were significantly higher in the patients with increased serum IgG (p = 0.0114). Serum IgG was also predictive of renal survival, with an HR of 0.745 (95% CI, 0.614 to 0.905, p = 0.003) after adjusting for significant factors in the univariate Cox regression and an HR of 0.871 (95% CI, 0.780 to 0.973, p = 0.014) adjusting for traditional risk factors of IgAN. CONCLUSION: These findings demonstrate that a decreased serum IgG level at the time of renal biopsy is independently associated with a poor renal outcome in IgAN patients. PMID- 30415191 TI - Different socioeconomic backgrounds between hazardous drinking and heavy episodic drinking: Prevalence by sociodemographic factors in a Japanese general sample. AB - BACKGROUND: Hazardous drinking (HD) and heavy episodic drinking (HED) constitute different types of alcohol-related harm. The socioeconomic status (SES) background of various alcohol consumption behaviors is not clear. The purpose of this study was to clarify existing SES differences between HD and HED. METHODS: The 2013 national survey regarding alcohol use among Japanese adults was utilized. The results from 1193 men and 1503 women aged 20-64 years were included in the analysis. Education attainment, household income, marital status, working status, and occupation were adopted as SES determinants. Binomial logistic regression analysis was conducted to estimate the odds ratios (ORs) of HD and HED for each SES group. RESULTS: ORs (95% confidence intervals) of HD were higher among persons with less education among both men [1.61 (1.18-2.20)] and women [1.78 (1.19-2.67)]. The OR of HED in men was significantly higher among those who belonged to high household income, were married, and managers or professionals. The OR of HED among women was higher in persons who were employed, as compared with those who engaged in housework. There were no correlations between HED and educational background. CONCLUSIONS: This study showed that in Japan, a lower educational background for both men and women was associated with a higher risk for HD, while higher current SES for men and working women were associated with a higher risk for HED. It is necessary to recognize the SES differences between HD and HED to achieve a policy to reduce alcohol-related harm. PMID- 30415192 TI - Dental age estimation in Malaysian adults based on volumetric analysis of pulp/tooth ratio using CBCT data. AB - Forensic odontology plays an important role in human identification and dental age estimation is an integral part of this process. The aim of the study was to investigate the association between chronological age and pulp/tooth volume ratio in a Malaysian population (Malays and Chinese) from cone-beam computed tomography (CBCT) scans, enhanced with Mimics software. Three hundred CBCT scans of 153 males and 147 females, aged between 16 and 65 years were divided into 5 age groups. Volumetric analysis of the pulp/tooth ratio was performed in maxillary left canines, maxillary right canines and maxillary right central incisors. Simple linear regression and Pearson correlation analysis indicated the strongest coefficient of correlation (R) values for maxillary right central incisors (0.83) followed by maxillary right canines (0.74) and maxillary left canines (0.73). Fisher's Z test indicated that dental age estimation is gender independent. The derived regression equations were further validated on an independent group of 126 teeth. The results indicated mean absolute error (MAE) values of 6.48 and 8.58 years for maxillary right central incisors and maxillary canines respectively. It was also noticed that MAE values were higher among the age groups ranging from 46 to 65 years. This study showed that a volumetric change in the pulp cavity with age is a valuable assessment method for dental age estimation among Malaysian population. PMID- 30415193 TI - Quantification of secondary dentin formation based on the analysis of MDCT scans and dental OPGs in a contemporary Malaysian population. PMID- 30415194 TI - Na+/K+-ATPase, acetylcholinesterase and glutathione S-transferase activities as new markers of postmortem interval in Swiss mice. AB - Determining precisely the postmortem interval (PMI) is a key parameter for forensic researches, given that various physical, biochemical and metabolic changes begin to occur in the body after death. In the present study, the Na+/K+ ATPase, glutathione S-transferase (GST) and acetylcholinesterase (AChE) activities were evaluated. For this, male adult Swiss mice were killed by isoflurane inhalation anesthesia and divided into four groups according to time of death (0, 6, 24 and 48 h). The brain, liver, kidney and skeletal muscle tissues were removed. Our results revealed that at the time of 6 h, there was a decrease on Na+/K+-ATPase and GST activities in the brain and liver tissues, respectively. In addition, at this time point, an increase on renal GST activity was verified. At the time of 24 h, an increase on the cerebral AChE and renal GST activities was observed, while the cerebral Na+/K+-ATPase activity was decreased. Forty-eight hours after death, cerebral Na+/K+-ATPase and renal GST activities remained decreased and increased, respectively. In addition, no alteration was observed on the GST activity in the skeletal muscle and brain (in PMIs evaluated). The present study revealed that the brain and kidney (at the times of 24 and 48 h) were the tissues that suffered the most changes in almost all the enzymes evaluated. Our results demonstrated that enzyme activity assessments are reliable, easy-to-perform and low-cost determinations, and could be promising postmortem markers. PMID- 30415195 TI - Spectrum of mutations of familial hypercholesterolemia in the 22 Arab countries. AB - BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is an inherited genetic disorder of lipid metabolism characterized by a high serum LDL-cholesterol profile and xanthoma formation, and FH increases the risk of premature atherosclerosis and cardiovascular disease (CVD). Mutations in the low-density lipoprotein (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin 9 (PCSK9), and LDLRAP1 genes have been associated with FH. Although FH is a major risk for CVD, the disease prevalence and its underlying molecular basis in the 22 Arab countries are still understudied. This study aimed to analyze all peer-reviewed studies related to the prevalence of FH and its causative mutations in the 22 Arab countries. METHODS: We searched five literature databases (Scopus, Science Direct, Web of Science, PubMed, and Google Scholar) from inception until June 2018, using all possible search terms to capture all of the genetic and prevalence data related to Arab patients with FH. RESULTS: A total of 5,484 titles and abstracts were identified; 51 studies met our inclusion criteria for the final systematic review. Fifty-one mutations in Arab patients with FH were identified in only eight Arab countries; 47 were identified in the LDLR gene, two in the PCSK9 gene, and two in LDLRAP1 gene. Twenty mutations in the LDLR gene were distinctive to Arab patients. A few studies reported prevalence estimates, ranging from 0.4% to 6.8%. CONCLUSIONS: This is the first systematic review to dissect the up-to-date status of the genetic epidemiology of Arab patients with FH. It seems that FH is underdiagnosed and that its prevalence is understudied due to the dearth of published information about Arab patients with FH. Therefore, there is a need for well controlled genetic epidemiological studies on Arab patients with FH. PMID- 30415196 TI - Psychiatry and developmental psychopathology: Unifying themes and future directions. AB - In the past 35 years, developmental psychopathology has grown into a flourishing discipline that shares a scientific agenda with contemporary psychiatry. In this editorial, which introduces the special issue, we describe the history of developmental psychopathology, including core principles that bridge allied disciplines. These include (1) emphasis on interdisciplinary research, (2) elucidation of multicausal pathways to seemingly single disorders (phenocopies), (3) description of divergent multifinal outcomes from common etiological start points (pathoplasticity), and (4) research conducted across multiple levels of analysis spanning genes to environments. Next, we discuss neurodevelopmental models of psychopathology, and provide selected examples. We emphasize differential neuromaturation of subcortical and cortical neural networks and connectivity, and how both acute and protracted environmental insults can compromise neural structure and function. To date, developmental psychopathology has placed greater emphasis than psychiatry on neuromaturational models of mental illness. However, this gap is closing rapidly as advances in technology render etiopathophysiologies of psychopathology more interrogable. We end with suggestions for future interdisciplinary research, including the need to evaluate measurement invariance across development, and to construct more valid assessment methods where indicated. PMID- 30415197 TI - Reduced willingness to invest effort in schizophrenia with high negative symptoms regardless of reward stimulus presentation and reward value. AB - BACKGROUND: Negative symptoms in schizophrenia, which are related to poor functioning, are thought to be grounded on aberrant functioning in the reward system. We aimed to disentangle how negative symptoms and two cognitive aspects of goal-directed behavior, mental representation of reward and reward value, affect willingness to invest effort to attain a reward in schizophrenia. AIMS AND PROCEDURES: To this purpose, 43 schizophrenia patients and 35 healthy controls were assessed for negative symptoms and general functioning, and completed an effort-based reward task. Patients were split in high and low negative symptoms scorers. A series of ANOVA tests were conducted in order to test the effects of group controlling for representation of reward (Task 1) and balance between reward value and effort (Task 2) on will to invest effort to attain a reward. MAIN FINDINGS: Schizophrenia patients with high negative symptoms chose to invest lower amounts of effort for a reward compared both to low negative symptoms patients and to controls in both tasks. Neither mental representation of reward (Task 1) nor reward value (Task 2) did differentially affect will to invest effort between-groups. CONCLUSIONS: These findings suggest that the lower willingness to invest effort observed in schizophrenia patients with high negative symptoms may not be related to cognitive aspects of goal-oriented behavior. PMID- 30415198 TI - Child sex moderates the relationship between cortisol stress reactivity and symptoms over time. AB - BACKGROUND: Past work suggests that individual differences in stress reactivity have implications for the development of psychopathology; in particular, females' stress reactivity appears more closely tied to internalizing symptoms than males' reactivity. Conversely, males who are under-reactive to threat may be at risk for externalizing problems. However, little is known about when such differences may emerge, although this knowledge could have implications for early prevention. METHODS: Cortisol reactivity to a laboratory stressor was assessed in 409 three year-old children (201 boys), along with parent-reported children's internalizing (anxiety and depression) and externalizing (oppositional-defiant and attention problems and hyperactivity) symptoms. Parent-reported symptoms were re-collected at child ages 5 (N = 379) and 8 (N = 364). Multilevel modelling was used to investigate whether the relationship between cortisol reactivity and symptoms differed between boys and girls over time. RESULTS: Girls with lower cortisol reactivity showed a negative association between depressive symptoms and time, while girls with higher reactivity showed no such association. No interaction between sex and cortisol reactivity was found for anxious symptoms. Boys with higher cortisol reactivity showed a negative association between symptoms and time, while boys with lower cortisol reactivity showed no such association. Time and ADHD symptoms were unrelated for boys, regardless of their cortisol reactivity. CONCLUSIONS: Findings suggest that the implications of stress reactivity indexed via cortisol vary for boys and girls, as well as for different symptom manifestations. PMID- 30415199 TI - Social cognition in schizophrenia: The role of mentalizing in moral dilemma decision-making. AB - BACKGROUND: Patients with schizophrenia have difficulties in several aspects of social cognition, e.g. emotion recognition and mentalizing. It is yet unclear if patients also show deficits in moral decision-making and whether the two aspects interact. Deficits in moral decision-making abilities might put patients in disadvantageous positions in every-day interactions. METHOD: Twenty-five patients with schizophrenia and twenty-five matched healthy controls participated in six moral dilemma tasks, a standard moral competency test and two mentalizing tasks. In addition, we assessed psychopathology and empathy abilities. In a brief intervention patients were asked to empathize with characters in the moral dilemmas. We expected that the decisions made by patients with schizophrenia would be more out-come-oriented, i.e. utilitarian, as compared to those made by healthy controls. RESULTS: Patients and healthy controls did not decide significantly differently on the moral dilemmas and patients showed normal moral competencies. Deficits in mentalizing in patients were replicated. Only in a regression analysis, however, we were able to show that PANSS positive scores and the Comic Strip task scores contributed to the moral decisions. Empathy training did not have an altering influence on decision-making. DISCUSSION: Although an overlap between social cognition and moral decision-making networks has been proposed, deficits in moral decision-making and explicit associations with mentalizing were not present in patients. Psychopathology together with mentalizing abilities, however, contributed to decision-making in patients. Our findings suggest that in schizophrenia some aspects, e.g. mentalizing, are more strongly impaired while other aspects, e.g. moral decision-making, are preserved. Further research is needed to elucidate the different aspects forming social cognition and their mutual contributions, specifically in schizophrenia. PMID- 30415200 TI - Response to: 'Will SPAR be useful in the usual patients with scleroderma?' by Chattopadhyay et al. PMID- 30415201 TI - Biomarkers: to be or not to be. PMID- 30415202 TI - Response to e-letter: 'Tocilizumab in patients with adult-onset Still's disease refractory to glucocorticoid treatment' by Lee. PMID- 30415203 TI - Impact of heart disease on maternal, fetal and neonatal outcomes in a low resource setting. AB - BACKGROUND: The burden of pre-existing cardiovascular disease and the contribution to adverse pregnancy outcomes are not robustly quantified, particularly in low-income countries. We aimed to determine both the prevalence of maternal heart disease through active case finding and its attributable risk to adverse pregnancy outcomes. METHODS: We conducted a 24-month prospective longitudinal investigation in three Ugandan health centres, using echocardiography for active case finding during antenatal care. Women with and without heart disease were followed to 6 weeks post partum to determine pregnancy outcomes. Prevalence of heart disease was calculated. Per cent attributable risk estimates were generated for maternal, fetal and neonatal mortality. RESULTS: Screening echocardiography was performed in 3506 women. The prevalence of heart disease was 17 per 1000 women (95% CI 13 to 21); 15 per 1000 was rheumatic heart disease. Only 3.4% of women (2/58) had prior diagnosis. Cardiovascular complications occurred in 51% of women with heart disease, most commonly heart failure. Per cent attributable risk of heart disease on maternal mortality was 88.6% in the exposed population and 10.8% in the overall population. Population attributable risk of heart disease on fetal death was 1.1% and 6.0% for neonatal mortality CONCLUSIONS: Occult maternal heart disease may be responsible for a substantial proportion of adverse pregnancy outcomes in low-resource settings. Rheumatic heart disease is, by far, the most common condition, urging global prioritisation of this neglected cardiovascular disease. PMID- 30415204 TI - Long-term outcome after atrial correction for transposition of the great arteries. AB - OBJECTIVE: This study assessed adult survival and morbidity patterns in patients who underwent atrial correction according to Mustard or Senning for transposition of the great arteries (TGA). METHODS: In 76 adult patients with TGA (59% male) after atrial correction, long-term survival and morbidity were investigated in three periods: early (<15 years postoperatively), midterm (15-30 years postoperatively) and late (>30 years postoperatively). RESULTS: The Mustard technique was performed in 41 (54%) patients, and the Senning technique was performed in 35 (46%) patients aged 3.1 (IQR: 2.1-3.8) and 1.0 (IQR: 0.6-3.1; p<0.01) years, respectively. Adult survival was 82% at 39.7 (IQR: 35.9-42.4) years postoperatively and exceeded 50 years in four patients. Supraventricular tachycardia (SVT) occurred in 51% of patients. The incidences of ventricular arrhythmia (0%, 8% and 13%; p<0.01), heart failure (0%, 5% and 19%; p<0.01) and surgical reinterventions (0%, 5% and 11%; p=0.01) increased from early to late follow-up. At last follow-up, RV function was depressed in 31 (46%) patients, and New York Heart Association functional class was >=2 in 34 (48%) patients. Bradyarrhythmia, SVT and ventricular arrhythmia were associated with depressed RV function (OR: 4.47, 95% CI 1.50 to 13.28, p<0.01; OR: 3.74, 95% CI 1.26 to 11.14, p=0.02; OR: 14.40, 95% CI 2.80 to 74.07, p<0.01, respectively) and worse functional capacity (OR: 2.10, 95% CI 0.75 to 5.82, p=0.16; OR: 2.87, 95% CI 1.06 to 7.81, p=0.04; OR: 8.47, 95% CI 1.70 to 42.10, p<0.01, respectively). CONCLUSIONS: In adult patients with TGA, survival was 82% at 39.7 (IQR: 35.9 42.4) years after atrial correction. Morbidity was high and included SVT as most frequent adverse event. Ventricular arrhythmias, heart failure and surgical reinterventions were common during late follow-up. Adverse events were associated with depressed right ventricle function and reduced functional class. PMID- 30415205 TI - A career in cardiology: why? PMID- 30415206 TI - Epidemiology of pericardial diseases in Africa: a systematic scoping review. AB - OBJECTIVES: This scoping review sought to summarise available data on the prevalence, aetiology, diagnosis, treatment and outcome of pericardial disease in Africa. METHODS: We searched PubMed, Scopus and African Journals Online from 1 January 1967 to 30 July 2017 to identify all studies published on the prevalence, aetiologies, diagnosis, treatment and outcomes of pericardial diseases in adults residing in Africa. RESULTS: 36 studies were included. The prevalence of pericardial diseases varies widely according to the population of interest: about 1.1% among people with cardiac complaints, between 3.3% and 6.8% among two large cohorts of patients with heart failure and up to 46.5% in an HIV-infected population with cardiac symptoms. Tuberculosis is the most frequent cause of pericardial diseases in both HIV-uninfected and HIV-infected populations. Patients with tuberculous pericarditis present mostly with effusive pericarditis (79.5%), effusive constrictive pericarditis (15.1%) and myopericarditis (13%); a large proportion of them (up to 20%) present in cardiac tamponade. The aetiological diagnosis of pericardial diseases is challenging in African resource limited settings, especially for tuberculous pericarditis for which the diagnosis is not definite in many cases. The outcome of these diseases remains poor, with mortality rates between 18% and 25% despite seemingly appropriate treatment approaches. Mortality is highest among patients with tuberculous pericarditis especially those coinfected with HIV. CONCLUSION: Pericardial diseases are a significant cause of morbidity and mortality in Africa, especially in HIV infected individuals. Tuberculosis is the most frequent cause of pericardial diseases, and it is associated with poor outcomes. PMID- 30415207 TI - Challenges in outlier surgeon assessment in the era of public reporting. AB - OBJECTIVE: To assess the effect of various evaluation and reporting strategies in determining outlier surgeons, defined by having worse-than-expected mortality after cardiac surgery. METHODS: Our study included 33 394 isolated coronary artery bypass graft (CABG) procedures performed by 136 surgeons and 12 172 surgical aortic valve replacement (SAVR) procedures performed by 113 surgeons between 2010 and 2014. Three current methodologies based on the framework of comparing observed and expected (O/E ratio) mortality, with different distributional assumptions, were examined. We further assessed the consistency of outliers detected by these three methods and the impact of using different time windows and aggregating data of CABG and SAVR procedures. RESULTS: The three methods were consistent and detected same outliers, with the least conservative method detecting additional outliers (outliers detected for methods 1, 2 and 3: CABG 3 (2.2%), 2 (1.5%) and 8 (5.9%); SAVR 1 (0.9%), 0 (0.0%) and 11 (9.7%)). When numbers of cases recorded were low and events were rare, the two more conservative methods were unlikely to detect outliers unless the O/E ratios were extremely high. However, these two methods were more consistent in detecting the same surgeons as outliers across different time windows for assessment. Of the surgeons who performed both CABG and SAVR, none was an outlier for both procedures when assessed separately. Aggregating data from CABG and SAVR may lead to results to be dominated by the procedure that had a higher caseload. CONCLUSIONS: The choices of outlier assessment method, time window for assessment and data aggregation have an intertwined impact on detecting outlier surgeons, often representing different value assumptions toward patient protection and provider penalty. It is desirable to use different methods as sensitivity analyses, avoid aggregating procedures and avoid rare-event endpoints if possible. PMID- 30415208 TI - Cardiac biomarkers predict mortality in emergency patients presenting with atrial fibrillation. AB - OBJECTIVES: To assess the predictive value of N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitive troponin T (hs-TnT) serum levels for mid term mortality in patients presenting with symptomatic atrial fibrillation (AF) to an emergency department. METHODS: Non-interventional cohort/follow-up study, including consecutive patients presenting to a tertiary care university emergency department due to symptomatic AF between 2012 and 2016. Multivariable Cox proportional hazard regression models were used to estimate the mortality rates and hazards per 100 patient-years (pry) for NT-proBNP and hs-TnT serum levels in quintiles. RESULTS: 2574 episodes of 1754 patients (age 68 (IQR 58-75) years, female gender 1199 (44%), CHA2DS2-VASc 3 (IQR 1-4)) were recorded. Following the exclusion of incomplete datasets, 1780 episodes were available for analysis. 162 patients deceased during the mid-term follow-up (median 23 (IQR 4-38) months); the mortality rate was 4.72/100 pry. Hazard for death increased with every quintile of NT-proBNP by 1.53 (HR; 95% CI 1.27 to 1.83; p<0.001) and by 1.31 (HR; 95% CI 1.10 to 1.55; p=0.002) with every quintile of hs-TnT in multivariate Cox regression analysis. No interaction between NT-proBNP and hs-TnT levels could be observed. CONCLUSION: Elevated NT-proBNP and hs-TnT levels are independently associated with increased mid-term mortality in patients presenting to an emergency department due to symptomatic AF. TRIAL REGISTRATION NUMBER: NCT03272620; Results. PMID- 30415209 TI - Constitutional mismatch repair deficiency as a differential diagnosis of neurofibromatosis type 1: consensus guidelines for testing a child without malignancy. AB - Constitutional mismatch repair deficiency (CMMRD) is a rare childhood cancer predisposition syndrome caused by biallelic germline mutations in one of four mismatch-repair genes. Besides very high tumour risks, CMMRD phenotypes are often characterised by the presence of signs reminiscent of neurofibromatosis type 1 (NF1). Because NF1 signs may be present prior to tumour onset, CMMRD is a legitimate differential diagnosis in an otherwise healthy child suspected to have NF1/Legius syndrome without a detectable underlying NF1/SPRED1 germline mutation. However, no guidelines indicate when to counsel and test for CMMRD in this setting. Assuming that CMMRD is rare in these patients and that expected benefits of identifying CMMRD prior to tumour onset should outweigh potential harms associated with CMMRD counselling and testing in this setting, we aimed at elaborating a strategy to preselect, among children suspected to have NF1/Legius syndrome without a causative NF1/SPRED1 mutation and no overt malignancy, those children who have a higher probability of having CMMRD. At an interdisciplinary workshop, we discussed estimations of the frequency of CMMRD as a differential diagnosis of NF1 and potential benefits and harms of CMMRD counselling and testing in a healthy child with no malignancy. Preselection criteria and strategies for counselling and testing were developed and reviewed in two rounds of critical revisions. Existing diagnostic CMMRD criteria were adapted to serve as a guideline as to when to consider CMMRD as differential diagnosis of NF1/Legius syndrome. In addition, counselling and testing strategies are suggested to minimise potential harms. PMID- 30415210 TI - Reclassification of BRCA1 and BRCA2 variants of uncertain significance: a multifactorial analysis of multicentre prospective cohort. AB - BACKGROUND: BRCA1 and BRCA2 (BRCA1/2) variants classified ambiguously as variants of uncertain significance (VUS) are a major challenge for clinical genetic testing in breast cancer; their relevance to the cancer risk is unclear and the association with the response to specific BRCA1/2-targeted agents is uncertain. To minimise the proportion of VUS in BRCA1/2, we performed the multifactorial likelihood analysis and validated this method using an independent cohort of patients with breast cancer. METHODS: We used a data set of 2115 patients with breast cancer from the nationwide multicentre prospective Korean Hereditary Breast Cancer study. In total, 83 BRCA1/2 VUSs (BRCA1, n=26; BRCA2, n=57) were analysed. The multifactorial probability was estimated by combining the prior probability with the overall likelihood ratio derived from co-occurrence of each VUS with pathogenic variants, personal and family history, and tumour characteristics. The classification was compared with the interpretation according to the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG/AMP) guidelines. An external validation was conducted using independent data set of 810 patients. RESULTS: We were able to redefine 38 VUSs (BRCA1, n=10; BRCA2, n=28). The revised classification was highly correlated with the ACMG/AMP guideline-based interpretation (BRCA1, p for trend=0.015; BRCA2, p=0.001). Our approach reduced the proportion of VUS from 19% (154/810) to 8.9% (72/810) in the retrospective validation data set. CONCLUSION: The classification in this study would minimise the 'uncertainty' in clinical interpretation, and this validated multifactorial model can be used for the reliable annotation of BRCA1/2 VUSs. PMID- 30415211 TI - Characterising the phenotype and mode of inheritance of patients with inherited peripheral neuropathies carrying MME mutations. AB - BACKGROUND: Mutations in the metalloendopeptidase (MME) gene were initially identified as a cause of autosomal recessive Charcot-Marie-Tooth disease type 2 (CMT2). Subsequently, variants in MME were linked to other late-onset autosomal dominant polyneuropathies. Thus, our goal was to define the phenotype and mode of inheritance of patients carrying changes in MME. METHODS: We screened 197 index cases with a hereditary neuropathy of the CMT type or distal hereditary motor neuropathy (dHMN) and 10 probands with familial amyotrophic lateral sclerosis (fALS) using a custom panel of 119 genes. In addition to the index case subjects, we also studied other clinically and/or genetically affected and unaffected family members. RESULTS: We found 17 variants in MME in a total of 20 index cases, with biallelic MME mutations detected in 13 cases from nine families (three in homozygosis and six in compound heterozygosis) and heterozygous variants found in 11 families. All patients with biallelic variants had a similar phenotype, consistent with late-onset axonal neuropathy. Conversely, the phenotype of patients carrying heterozygous mutations was highly variable [CMT type 1 (CMT1), CMT2, dHMN and fALS] and mutations did not segregate with the disease. CONCLUSION: MME mutations that segregate in an autosomal recessive pattern are associated with a late-onset CMT2 phenotype, yet we could not demonstrate that MME variants in heterozygosis cause neuropathy. Our data highlight the importance of establishing an accurate genetic diagnosis in patients carrying MME mutations, especially with a view to genetic counselling. PMID- 30415213 TI - History of military psychology. AB - Military psychology is a specialist discipline within applied psychology. It entails the application of psychological science to military operations, systems and personnel. The specialty was formally founded during World War I in the UK and the USA, and it was integral to many early concepts and interventions for psychological and neuropsychological trauma. It also established a fundamental basis for the psychological assessment and selection of military personnel. During and after World War II, military psychology continued to make significant contributions to aviation psychology, cognitive testing, rehabilitation psychology and many models of psychotherapy. Military psychology now consists of several subspecialties, including clinical, research and occupational psychology, with the latter often referred to in the USA as industrial/organisational psychology. This article will provide an overview of the origins, history and current composition of military psychology in the UK, with select international illustrations also being offered. PMID- 30415212 TI - Novel homozygous CFAP69 mutations in humans and mice cause severe asthenoteratospermia with multiple morphological abnormalities of the sperm flagella. AB - BACKGROUND: Male infertility is a major issue of human reproduction health. Asthenoteratospermia can impair sperm motility and cause male infertility. Asthenoteratospermia with multiple morphological abnormalities of the flagella (MMAF) presents abnormal spermatozoa with absent, bent, coiled, short and/or irregular-calibre flagella. Previous studies on MMAF reported that genetic defects in cilia-related genes (eg, AKAP4, DNAH1, CFAP43, CFAP44 and CFAP69) are the major cause of MMAF. However, the known MMAF-associated genes are only responsible for approximately 30% to 50% of human cases. We further investigated the cases with MMAF in search of additional genes mutated in this condition. METHODS AND RESULTS: We conducted whole exome sequencing in a male individual with MMAF from a consanguineous Han Chinese family. Sanger sequencing was also conducted in additional individuals with MMAF. Intriguingly, a homozygous frameshift mutation (p.Leu357Hisfs*11) was identified in the gene encoding CFAP69 (cilia and flagella-associated protein 69), which is highly expressed in testis. The subsequent Sanger sequencing of the CFAP69 coding regions among 34 additional individuals with MMAF revealed a case with homozygous nonsense mutation (p.Trp216*) of CFAP69. Both of these CFAP69 loss-of-function mutations were not present in the human population genome data archived in the 1000 Genomes Project and ExAC databases, nor in 875 individuals of two Han Chinese control populations. Furthermore, we generated the knockout model in mouse orthologue Cfap69 using the CRISPR-Cas9 technology. Remarkably, male Cfap69-knockout mice manifested with MMAF phenotypes. CONCLUSION: Our experimental findings elucidate that homozygous loss-of-function mutations in CFAP69 can lead to asthenoteratospermia with MMAF in humans and mice. PMID- 30415214 TI - Development of alcohol treatment for UK military personnel. AB - The consumption of alcohol in the UK Armed Forces (AF) as 'an agent to assist cohesion and informal operational debriefing' is a social and psychological conceptualisation that has some empirical support. Indisputable data exist to suggest that high levels of alcohol misuse and related problems are prevalent among UK AF. Recent research indicates that the overall level of hazardous alcohol consumption remains high in the UK military, with little evidence of reduced consumption over time. Meanwhile, risky drinking in the general population appears to be decreasing. This paper describes work to develop a key aspect of an integrated care pathway for UK military personnel at all levels of alcohol risk. The project focuses on the development of an evidence-based treatment response across primary care and mental health services that will link with preventative initiatives. Specialist (substance misuse) input from the Defence Clinical Psychology Service across and within Departments of Community Mental Health lends an overarching perspective to a major healthcare and organisational concern for the UK AF. Work towards a consistent treatment pathway for alcohol misuse is also benefiting from collaboration between the Ministry of Defence and Public Health England. PMID- 30415215 TI - Peacekeepers suffered combat-related injuries in Mali: a retrospective, descriptive study. AB - PURPOSE: To describe the combat-related injuries cured by Chinese Level 2 medical treatment facility (CHN L2) in Mali from 1 March 2016 to 1 March 2018, including type of weapon, mortality, nature of injuries, degree and location of injuries and surgical procedures. METHODS : A retrospective, descriptive study of 176 injured cases that met the terrorist attacks was conducted. The medical data were collected by an electronic database system. All collected data were entered into an Excel spreadsheet for calculation. RESULTS: We found that improvised explosive devices (114/176, 65%) were the most commonly used weapons of attack in Mali. 68.75% of the injuries (121/176) were classified as 'minor injuries according to Abbreviated Injury Scale score. As one patient may suffer multiple injuries, each location and nature of injuries was counted separately. Surface injuries were the top (116/197, 58.88%), followed by orthopaedic injuries (52/197, 26.39%) and internal injuries (29/197, 14.72%). The extremities were the most frequently injured body parts (144/197, 73.09%). We operated 175 surgeries to deal with the 176 combat-related injuries, which accounted for 40.05% of all 437 surgeries. The surgical debridement to remove fragments of explosive was the most frequently performed surgery. We also admitted 20 cases (18/176, 34%) into intensive care unit and transferred 40 cases to Level 3 medical facility. CONCLUSION: Peacekeepers taking protective measures for head and trunk frequently got surface injuries. And their unprotected extremities often got injured. The fragment removal was the top surgery and the damage control surgery was the highly technical nature surgery we performed. Chinese military should offer advanced surgical training course to military surgeons who carry out overseas operations. PMID- 30415216 TI - Passive-dynamic ankle-foot orthosis improves medium-term clinical outcomes after severe lower extremity trauma. AB - INTRODUCTION: Individuals with delayed below-knee amputation have previously reported superior clinical outcomes compared with lower limb reconstruction. The UK military have since introduced a passive-dynamic ankle-foot orthosis (PDAFO) into its rehabilitation care pathway to improve limb salvage outcomes. The aims were to determine if wearing a PDAFO improves medium-term clinical outcomes and what influence does multidisciplinary team (MDT) rehabilitation have after PDAFO fitting? Also, what longitudinal changes in clinical outcomes occur with MDT rehabilitation and how do these results compare with patients with previous lower extremity trauma discharged prior to PDAFO availability? METHODS: We retrospectively evaluated levels of mobility, activities of daily living, anxiety, depression and pain in a heterogeneous group of 23 injured UK servicemen 34+/-11 months after PDAFO provision. We also retrospectively analysed 16 patients across four time points (pre-PDAFO provision, first, second and final inpatient admissions post-PDAFO provision) using identical outcome measures, plus the 6 min walk test. RESULTS: Outcomes were compared with previous below-knee limb salvage and amputees. Before PDAFO, 74% were able to walk and 4% were able to run independently. At follow-up, this increased to 91% and 57%, respectively. Mean depression and anxiety scores remained stable over time (p>0.05). After 3 weeks, all patients could walk independently (pre-PDAFO=31%). Mean 6 min walk distance significantly increased from 440+/-75 m (pre-PDAFO) to 533+/-68 m at last admission (p=0.003). The ability to run increased from 6% to 44% after one admission. CONCLUSIONS: All functional and most psychosocial outcomes in PDAFO users were superior to previous limb salvage and comparable to previous below knee amputees. The PDAFO facilitated favourable short-term and medium-term changes in all clinical outcome measurements. PMID- 30415217 TI - Neuropsychology and clinical health psychology in the UK Ministry of Defence. AB - Neuropsychological testing has been used in a wide range of applications across military settings, including the selection of personnel to engage in covert operations, battlefield assessment and rehabilitation following blast exposure, traumatic brain injury, other neurological conditions and assessments of malingering. Over recent decades, military psychologists have helped to shape the advances in assessing and remediating the psychological sequela that is associated with operationally related neurological and other physical injuries. This paper will present an overview of some of the neuropsychological and related services within the UK Armed Forces, which are provided to service personnel with traumatic brain and other physical injuries. PMID- 30415218 TI - Neuroergonomic and psychometric evaluation of full-face crew oxygen masks respiratory tolerance: a proof-of-concept study. AB - INTRODUCTION: Preventing in-flight hypoxia in pilots is typically achieved by wearing oxygen masks. These masks must be as comfortable as possible to allow prolonged and repeated use. The consequences of mask-induced facial contact pressure have been extensively studied, but little is known about mask-induced breathing discomfort. Because breathlessness is a strong distractor and engages cerebral resources, it could negatively impact flying performances. METHODS: Seventeen volunteers (age 20-32) rated respiratory discomfort while breathing with no mask and with two models of quick-donning full-face crew oxygen masks with regulators (mask A, mask B). Electroencephalographic recordings were performed to detect a putative respiratory-related cortical activation in response to inspiratory constraint (experiment 1, n=10). Oxygen consumption was measured using indirect calorimetry (experiment 2, n=10). RESULTS: With mask B, mild respiratory discomfort was reported significantly more frequently than with no mask or mask A (experiment 1: median respiratory discomfort on visual analogue scale 0.9 cm (0.5-1.4), experiment 1; experiment 2: 2 cm (1.7-2.9)). Respiratory-related cortical activation was present in 1/10 subjects with no mask, 1/10 with mask A and 6/10 with mask B (significantly more frequently with mask B). Breathing pattern, sigh frequency and oxygen consumption were not different. CONCLUSIONS: In a laboratory setting, breathing through high-end aeronautical full-face crew oxygen masks can induce mild breathing discomfort and activate respiratory-related cortical networks. Whether or not this can occur in real-life conditions and have operational consequences remains to be investigated. Meanwhile, respiratory psychometric and neuroergonomic approaches could be worth integrating to masks development and evaluation processes. PMID- 30415219 TI - Defence Anaesthesia transition from the Tri-Service Anaesthetic Apparatus to the Diamedica Portable Anaesthesia Machine 02. AB - Defence Anaesthesia is changing its draw-over anaesthetic capability from the Tri Service Anaesthetic Apparatus (TSAA) to the Diamedica Portable Anaesthesia Machine 02 (DPA02). The DPA02 will provide a portable, robust, lightweight and simple method for delivering draw-over volatile anaesthesia with the option of positive pressure ventilation through manual or mechanical operation for paediatric and adult patients. The UK Defence Medical Services uses a modified configuration of the DPA02; this paper seeks to explain the rationale for the differing configurations and illustrates alternative assemblies to support integration with other Defence Anaesthesia equipment. High-fidelity simulation training using the DPA02 will continue to be delivered on the Defence Anaesthesia Simulation Course (DASC). Conformite Europeenne accreditation of DPA02 supports future UK live patient training in centres of excellence supervised by subject matter experts; this was not possible with the TSAA. This article is intended to be a key reference for all members of the Defence Anaesthesia team. Alongside other resources, it will be given as precourse learning prior to attending the DASC and the Military Operational Surgical Training. This article will also be issued with all Defence DPA02 units, supporting ease of access for review during future clinical exercises (including validation), prior to supervised live training and on operational deployments. PMID- 30415220 TI - Adopting a multidisciplinary approach to maximising performance during military visual search tasks. AB - During the conflicts in Afghanistan and Iraq, many UK military personnel were killed or injured by improvised explosive devices (IEDs). Insurgents sought to develop new ways of concealing and detonating IEDs, and UK forces invested significantly in finding new ways of detecting and avoiding them. Between 2010 and 2014 the UK's Defence Science and Technology Laboratory's Human and Social Sciences Group (HSSG) was asked to investigate the factors that might affect the performance of these specialist search teams and identify ways to improve effectiveness and maximise safety through training, human factors advice on equipment design, and recommendations on changes to tactics techniques and procedures. This paper provides a short summary of some of the research conducted that underpinned the advice and recommendations that were provided. The research conducted by the HSSG, in collaboration with the industry and the academia, helped ensure that search teams had the best possible training, advice and equipment. PMID- 30415221 TI - Changes in calcium channel proteins according to magnesium sulfate administration in placentas from pregnancies with pre-eclampsia or fetal growth restriction. AB - We aimed to evaluate the changes in plasma membrane Ca2+-ATPase (PMCA) and sarcoendoplasmic reticulum CA2+-ATPase (SERCA-2) according to the antepartal magnesium sulfate (MgSO4) administration in the placentas from pregnancies with pre-eclampsia (PE) or fetal growth restriction (FGR). Pregnant women were classified as follows: (group 1) pregnancies without PE or FGR (n=16), (group 2) pregnancies with PE or FGR but without MgSO4 administration (n=14), and (group 3) pregnancies with PE or FGR and with MgSO4 administration (n=28). We observed the localization of PMCA and SERCA-2 in placentas and compared its expression among 3 groups. And we observed its expression in BeWo cells following treatment with MgSO4 and CoCl2 PMCA staining was more observed in the basal membrane, whereas SERCA-2 staining was observed predominantly under the microvillous membrane. SERCA-2 expression was significantly increased in group 3 compared with that in group 1. Considering the gestational age at delivery, PMCA expression was increased in group 2 and group 3 compared with that in group 1 after 36 weeks of gestation. SERCA-2 was increased in group 3, but not in group 2 compared with that in group 1 after 36 weeks of gestation. In BeWo cells, MgSO4 treatment increased PMCA and SERCA-2 expression. PMCA expression was influenced by gestational age at delivery, and SERCA-2 expression was increased in the presence of PE and antepartal MgSO4 administration. This indicates that antepartal MgSO4 administration has a greater influence on SERCA-2 than PMCA. PMID- 30415222 TI - The occurrence of neointimal hyperplasia after flow-diverter implantation is associated with cardiovascular risks factors and the stent design. AB - BACKGROUND: Neo-intimal hyperplasia (NIH) is frequently observed after flow diverter stent (FDS) implantation. Although mostly asymptomatic, this vascular response can sometimes lead to delayed ischemic strokes. This study intended to evaluate the factors potentially influencing the rates of NIH following FDS treatment. MATERIAL AND METHODS: All aneurysm treatments performed with a Pipeline embolization device (PED) or a SILK stent from May 2011 to May 2015 were collected in a prospectively maintained database. Patient demographics, clinical, and angiographic outcomes including both digital subtraction angiography and C arm cone-beam CT were registered. Two blind reviewers rated the presence of NIH on a binary scale (present/absent). RESULTS: From 148 patients, 63 datasets were available for analysis. Inter-reader agreement was excellent (Kappa=0.88). NIH was positively correlated with smoking, dyslipidemia, and high blood pressure, but not with aneurysm characteristics. At early follow-up (<12 months), NIH was more frequently associated with the use of the SILK stent (68%) rather than the PED (38%): P<0.02. At long-term follow-up, the NIH rate in the total population dropped from 55% to 26% with no more significant difference between the two stents. The complete occlusion rate as seen in early follow-up was higher in the SILK group with 76% vs 65% but without statistical significance (P=0.4). CONCLUSION: NIH is a dual-vessel reaction after FDS implant. When planning a treatment in locations at risk of ischemic complications if severe NIH would occur, then the stent design should be considered. However, minimal NIH might also be needed as it is involved in aneurysm healing. Before treatment patients should be recommended best medical management of their cardiovascular risks factors to prevent an excessive NIH reaction. PMID- 30415223 TI - Influence of ASPECTS and endovascular thrombectomy in acute ischemic stroke: a meta-analysis. AB - BACKGROUND: Prompt revascularization of the ischemic penumbra following an acute ischemic event (AIS) has established benefit within the literature. However, use of the semi-quantitative Alberta Stroke Program Early CT Score (ASPECTS) to evaluate patient suitability for revascularization has been inconsistent in patient risk stratification and selection. OBJECTIVE: To conduct a meta-analysis to evaluate the available evidence for a clinically valid ASPECTS threshold in assessment of suitability for revascularization following AIS. METHODS: Two independent reviewers searched Medline (Ovid) and Cochrane Central Register of Systematic Reviews databases for studies appraising outcomes of endovascular thrombectomy (EVT) in relation to a variably-defined preoperative ASPECTS. RESULTS: A total of 13 articles were included. The pooled good outcome proportion after EVT was 41.4% (95% CI 36.4% to 46.6%; p<0.001), with subjective study specific definitions of favorable and unfavorable subgroup outcomes of 49.7% (95% CI 44.2% to 55.3%; I2=76.5%; p<0.001) and 33.2% (95% CI 28.5% to 38.3%; I2=33.16%), respectively. Objective trichotomization into low (0-4), intermediate (5-7), and high (8-10) subgroups yielded pooled good outcome proportions of 17.1% (95% CI 6.8% to 36.8%; I2=64.24%; p=0.039), 35.7% (95% CI 30.5% to 41.3%; I2=23.11%; p=0.245), and 49.7% (95% CI 44.2% to 55.3%; I2=76.5%; p<0.001) for low, intermediate, and high ASPECTS, respectively. CONCLUSIONS: A subjectively favorable ASPECTS is associated with significantly better outcomes after EVT than an unfavorable ASPECTS, regardless of the cut-off used. EVT is unlikely to be useful in patients with an objectively low ASPECTS and is likely to be useful for those with high ASPECTS; findings in patients with intermediate ASPECTS were equivocal. PMID- 30415224 TI - Effects of music therapy on anxiety and physiologic parameters in angiography: a systematic review and meta-analysis. AB - BACKGROUND: Given the anxiety patients experience during angiography, evidence supporting the efficacy of music therapy during these angiographic procedures is potentially of clinical value. OBJECTIVE: To analyze the existing literature forthe use of music therapy during cerebral, coronary, and peripheral angiography to determine whether it improves patient anxiety levels, heart rate, and blood pressure during the procedure. METHODS: PubMed, Embase, and Scopus were searched to identify studies of interest. Inclusion criteria included studies reporting using music therapy in either cerebral, coronary, or peripheral angiography. Studies focused on a pediatric population; animal studies and case reports were excluded. Participant demographics, interventions, and outcomes were collected by two study authors. Bias and study quality of randomized controlled trials (RCTs) were assessed using the Cochrane Risk of Bias Tool. Separate meta-analyses of the RCTs were performed to compare State Trait Anxiety Inventory (STAI), heart rate (HR), and systolic and diastolic blood pressure (SBP and DBP) in the music intervention group versus control group. Heterogeneity was determined by calculating I2 values, and a random-effects model was used when heterogeneity exceeded 50%. RESULTS: The preprocedure to postprocedure improvement in STAI was significantly greater in the experimental group than the control group (p=0.004), while the decrease in HR, SBP, and DBP was not significant. CONCLUSIONS: Recorded music and/or music therapy in angiography significantly decreases patients' anxiety levels, while it has little to no effect on HR and BP. This meta-analysis is limited by the relatively few RCTs published on this subject. PROSPERO REGISTRATION NUMBER: CRD42018099103. PMID- 30415225 TI - A systematic review and meta-analysis of observational evidence for the use of bailout self-expandable stents following failed anterior circulation stroke thrombectomy. AB - BACKGROUND: The crucial role of thrombectomy in the management of emergent large vessel occlusive stroke is not disputed but there is a technical failure rate in a significant minority of patients whose outcomes are often poor. Our objective was to perform a systematic review and meta-analysis to assess the safety and efficacy of permanent self-expandable stent deployment as a bailout procedure in cases of failed anterior circulation thrombectomy. METHODS: Two independent reviewers searched the Pubmed (Medline) database for studies reporting outcomes following failed endovascular thrombectomy with subsequent rescue therapy employing self-expandable stents. RESULTS: Eight studies (one prospective, seven retrospective) originating from Europe, Asia, and America comprising 160 patients met the inclusion criteria. Estimated baseline National Institutes of Health Stroke Scale score was 17.1 (95% CI 15.7 to 18.4). Following failed thrombetcomy and stent deployment, the rate of favorable outcome (modified Rankin Scale score 0-2) was 43% (95% CI 34% to 53%). Pooled mortality was 21% (95% CI 13% to 33%). Successful recanalization (Thrombolysis in Cerebral Infarction (TICI) 2b-3 or Thrombolysis in Myocardial Infarction (TIMI) 2-3) was 71% (95% CI 63% to 77%). Symptomatic intracerebral hemorrhage was seen in 12% (95% CI 7% to 18%). The Solitaire stent (Medtronic) was the most commonly deployed stent following failed thrombectomy attempts (66%; 95% CI 31% to 89%). Pre- or post-stent angioplasty was performed in 39%of patients (95% CI 29% to 48%). Glycoprotein IIb/IIIa inhibitors were used in 89% (95% CI 71% to 97%). 95% of patients received postprocedural antiplatelet therapy. CONCLUSION: A rescue stent procedure seems reasonable as a last resort following failed thrombectomy but currently the level of evidence is limited. Prospective registries may aid in guiding future recommendations. PMID- 30415226 TI - Prevalence of large vessel occlusion in patients presenting with acute ischemic stroke: a 10-year systematic review of the literature. AB - BACKGROUND: Accurate assessment of the prevalence of large vessel occlusion (LVO) in patients presenting with acute ischemic stroke (AIS) is critical for optimal resource allocation in neurovascular intervention. OBJECTIVE: To perform a systematic review of the literature in order to identify the proportion of patients with AIS presenting with LVO on image analysis. METHODS: A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in order to identify studies reporting LVO rates for patients presenting with AIS. Studies that included patients younger than 18 years, were non-clinical, or did not report LVO rates in the context of a consecutive AIS series were excluded. Characteristics regarding presentation, diagnosis, and LVO classification were recorded for each paper. RESULTS: Sixteen studies, spanning a total of 11 763 patients assessed for stroke, were included in the qualitative synthesis. The majority (10/16) of articles reported LVO rates exceeding 30% in patients presenting with AIS. There was substantial variability in the LVO definitions used, with nine unique classification schemes among the 16 studies. The mean prevalence of LVO was 31.1% across all studies, and 29.3% when weighted by the number of patients included in each study. CONCLUSIONS: Despite the wide variability in LVO classification, the majority of studies in the last 10 years report a high prevalence of LVO in patients presenting with AIS. These rates of LVO may have implications for the volume of patients with AIS who may benefit from endovascular therapy. PMID- 30415227 TI - Machine learning improves prediction of delayed cerebral ischemia in patients with subarachnoid hemorrhage. AB - BACKGROUND AND PURPOSE: Delayed cerebral ischemia (DCI) is a severe complication in patients with aneurysmal subarachnoid hemorrhage. Several associated predictors have been previously identified. However, their predictive value is generally low. We hypothesize that Machine Learning (ML) algorithms for the prediction of DCI using a combination of clinical and image data lead to higher predictive accuracy than previously applied logistic regressions. MATERIALS AND METHODS: Clinical and baseline CT image data from 317 patients with aneurysmal subarachnoid hemorrhage were included. Three types of analysis were performed to predict DCI. First, the prognostic value of known predictors was assessed with logistic regression models. Second, ML models were created using all clinical variables. Third, image features were extracted from the CT images using an auto encoder and combined with clinical data to create ML models. Accuracy was evaluated based on the area under the curve (AUC), sensitivity and specificity with 95% CI. RESULTS: The best AUC of the logistic regression models for known predictors was 0.63 (95% CI 0.62 to 0.63). For the ML algorithms with clinical data there was a small but statistically significant improvement in the AUC to 0.68 (95% CI 0.65 to 0.69). Notably, aneurysm width and height were included in many of the ML models. The AUC was highest for ML models that also included image features: 0.74 (95% CI 0.72 to 0.75). CONCLUSION: ML algorithms significantly improve the prediction of DCI in patients with aneurysmal subarachnoid hemorrhage, particularly when image features are also included. Our experiments suggest that aneurysm characteristics are also associated with the development of DCI. PMID- 30415228 TI - Downstream vascular changes after flow-diverting device deployment in a rabbit model. AB - BACKGROUND: Flow diverters (FDs) are increasingly used in the treatment of intracranial aneurysms, and carry the risk of thromboembolic complications, even in patients treated with dual antiplatelet therapy. The effect of FDs on the downstream vascular is unknown. The aim of the study was to investigate vascular wall pulse wave velocity (PWV) and contractility changes following FD treatment in a rabbit model. METHODS: FDs (Pipeline Embolic Device, Medtronic Inc., Irvine, California, USA) were implanted in the aorta of normal rabbits and sham-operated aorta were used as controls (n=6 per group). Pulse wave imaging with ultra-fast ultrasound at 1600 frames per second (Vantage, Verasonics, Inc., Kirkland, WA) was performed in the vessel wall distal to FD prior to device implantation and at 8- week follow-up to measure the PWV. Force contraction vascular reactivity studies were conducted in the aortic rings using an organ bath. RESULTS: The difference in mean PWV in the follow-up compared with pre-implantation was significantly higher in the distal vessels compared with sham controls (1.18 m/s [SD=0.54] vs. 0.37 m/s [SD=1.09], P=0.03). Conversely, the aortic segments distal to the FD exhibited a 55% increase in vascular contractility compared with proximal segments (P=0.002). We observed a significant positive correlation between mean PWV and mean vascular contractility. CONCLUSION: Implantation of FD was associated with increased PWV and vascular contractility, suggesting that FD implantation causes changes to the vascular wall. Further studies are needed to understand the clinical implication of changes in vascular PWV and contractility. PMID- 30415229 TI - Percutaneous transluminal angioplasty using the novel drug-coated balloon catheter SeQuent Please NEO for the treatment of symptomatic intracranial severe stenosis: feasibility and safety study. AB - OBJECTIVES: Intracranial arteriosclerotic disease is a relevant cause of ischemic stroke worldwide with a high recurrence rate despite best medical treatment. Following the SAMMPRIS trial, endovascular treatment has remained a second-line therapy. Meanwhile, there has been significant advances in device technology. SeQuent Please NEO is a novel polymer-free, drug-coated (paclitaxel/iopromide) balloon (DCB) primarily designed for cardiology. Because of its high flexibility and pushability, it may also be suitable for intracranial use. The aim of this study was to assess the feasibility and safety of SeQuent Please NEO DCB in symptomatic intracranial severe stenosis. METHODS: A single-center retrospective cohort study of patients with symptomatic intracranial severe stenosis treated with SeQuent Please NEO DCB was performed at a tertiary stroke center. RESULTS: Ten patients (all men, median age 73 years (IQR 69-77)) were included. Median pre treatment stenosis grade was 78% (IQR 75-80%) with four internal carotid artery, two mid-basilar artery, and four vertebral artery lesions. Median post-treatment stenosis grade was 50% (IQR 45-53%). Successful angioplasty was achieved in all cases without technical failure. There were no cases of peri-procedural reocclusion and no deaths at median follow-up of 3 months (IQR 2-3). CONCLUSION: In this pilot study, SeQuent Please NEO DCB was feasible and safe in the treatment of symptomatic intracranial severe stenosis. It might represent a promising alternative to medical treatment in selected cases. PMID- 30415230 TI - Preliminary experience with the use of low profile visualized intraluminal support device in basilar artery for aneurysm treatment. AB - BACKGROUND: The low profile visualized intraluminal support (LVIS) device is being increasingly used for the treatment of intracranial aneurysms. Its application in the basilar artery (BA) has not yet been reported. OBJECTIVE: To evaluate the safety and early efficacy of the LVIS device for the treatment of BA aneurysms. METHODS: A prospectively maintained database was retrospectively reviewed for all patients with BA aneurysms treated by LVIS stents at our institution. Angiographic results were evaluated using the modified Raymond-Roy classification (mRRC). RESULTS: 23 patients (mean age 52.8 years) with a BA aneurysm that was treated by LVIS stent implantation, with (n=21) or without (n=2) adjunctive coiling, were included in our study. 7 aneurysms were treated in the setting of subarachnoid hemorrhage (SAH). 10 aneurysms were located at the basilar tip, 10 at the basilar trunk, and 3 at the superior cerebellar artery. Procedure related complications developed in three patients (13%), including two perforator infarction and one worsening mass effect. Complications resulted in permanent morbidity (4%) in one case. One fatality was related to severe poor grade SAH. At a mean follow-up of 6.9 months, 13 of the 20 patients were mRRC I closure, 3 were mRRC II closure with an improvement from class IIIa, 3 were observed to be recanalized from class IIIa to IIIb, and 1 with stenting only was still patent similar to the immediate angiography. CONCLUSION: The LVIS stent represents a feasible and safe option for endovascular embolization of BA aneurysms. Although recanalization may occur after LVIS treatment, the mid term complete occlusion rate was acceptable. PMID- 30415231 TI - Early detection of lung cancer in a population at high risk due to occupation and smoking. AB - OBJECTIVE: The US National Comprehensive Cancer Network (NCCN) recommends two pathways for eligibility for Early Lung Cancer Detection (ELCD) programmes. Option 2 includes individuals with occupational exposures to lung carcinogens, in combination with a lesser requirement on smoking. Our objective was to determine if this algorithm resulted in a similar prevalence of lung cancer as has been found using smoking risk alone, and if so to present an approach for lung cancer screening in high-risk worker populations. METHODS: We enrolled 1260 former workers meeting NCCN criteria, with modifications to account for occupational exposures in an ELCD programme. RESULTS: At baseline, 1.6% had a lung cancer diagnosed, a rate similar to the National Lung Cancer Screening Trial (NLST). Among NLST participants, 59% were current smokers at the time of baseline scan or had quit smoking fewer than 15 years prior to baseline; all had a minimum of 30 pack-years of smoking. Among our population, only 24.5% were current smokers and 40.1% of our participants had smoked fewer than 30 pack-years; only 43.5% would meet entry criteria for the NLST. The most likely explanation for the high prevalence of screen-detected lung cancers in the face of a reduced risk from smoking is the addition of occupational risk factors for lung cancer. CONCLUSION: Occupational exposures to lung carcinogens should be incorporated into criteria used for ELCD programmes, using the algorithm developed by NCCN or with an individualised risk assessment; current risk assessment tools can be modified to incorporate occupational risk. PMID- 30415232 TI - Epidemiology of silicosis: reports from the SWORD scheme in the UK from 1996 to 2017. AB - OBJECTIVE: To document the demographic risk factors of workers reported to have silicosis in the UK. METHODS: All cases of silicosis reported to the Surveillance of Work-related and Occupational Respiratory Disease (SWORD) scheme between January 1996 and December 2017 were classified into one of eight industry categories, and one of five age groups. In addition, to investigate whether there had been any temporal change, mean age and range at diagnosis was plotted for each year. From 2006, data were also available relating to the date of onset of symptoms, allowing a comparison between workers with and without respiratory symptoms. RESULTS: For the period between 1996 and 2017, there were 216 cases of silicosis reported. The mean (range) age of those reported was 61 years (23-89), with the majority (98%) being male. Across all industries, 65% of cases were diagnosed in individuals of working age (<65 for men and <60 for women). Silicosis was reported in young workers across all industry groups, with around one in six of all silicosis cases affecting workers under the age of 46 years. There was no clear trend in age of diagnosis with time. Between 2006 and 2017, 81% of 108 workers with silicosis were reported to be symptomatic. CONCLUSIONS: Silicosis remains an important health problem in the UK affecting workers of all ages across a wide range of industries traditionally associated with silica exposure. PMID- 30415233 TI - Identifying optimal candidates for early TIPS among patients with cirrhosis and acute variceal bleeding: a multicentre observational study. AB - OBJECTIVES: Early placement of transjugular intrahepatic portosystemic shunt (TIPS) has been shown to improve survival in high-risk patients (Child-Pugh B plus active bleeding at endoscopy or Child-Pugh C 10-13) with cirrhosis and acute variceal bleeding (AVB). However, early TIPS criteria may overestimate the mortality risk in a significant proportion of patients, and the survival benefit conferred by early TIPS in such patients has been questioned. Alternative criteria have been proposed to refine the criteria used to identify candidates for early TIPS. Nevertheless, the true survival benefit provided (or not) by early TIPS compared with standard treatment in the different risk categories has not been investigated in specifically designed comparative studies. DESIGN: We collected data on 1425 consecutive patients with cirrhosis and AVB who were admitted to 12 university hospitals in China between December 2010 and June 2016. Of these, 206 patients received early TIPS, and 1219 patients received standard treatment. The Fine and Gray competing risk regression model was used to compare the outcomes between the two groups that were stratified based on the currently available risk stratification systems after adjusting for liver disease severity and other potential confounders. RESULTS: Overall, early TIPS was associated with an 80% relative risk reduction (RRR) in mortality at 6 weeks (adjusted HR=0.20; 95% CI: 0.10 to 044; p<0.001) and 51% RRR at 1 year (adjusted HR=0.49, 95% CI: 0.32 to 0.73; p<0.001) compared with standard treatment. In stratification analyses, the RRRs in mortality did not significantly differ among the risk categories. However, the absolute risk reductions (ARRs) of mortality were more pronounced in high-risk patients. The ARRs at 6 weeks were -2.1%, -10.2% and 32.4% in Model for End-stage Liver Disease (MELD) <=11, 12-18 and >=19 patients and were -1.5%, -9.1% and -23.2% in Child-Pugh A, B and C patients, respectively (interaction tests, p<0.001 for both criteria). The ARRs for mortality at 1 year were -1.7%, -5.4% and -32.7% in MELD <=11, 12-18 and >=19 patients, respectively, and -3.6%, -5.2% and -20.3% in Child-Pugh A, B and C patients, respectively (interaction tests, p<0.001 for both criteria). After adjusting for liver disease severity and other potential confounders, a survival benefit was observed in MELD >=19 or Child-Pugh C patients but not in MELD <=11 or Child-Pugh A patients. In MELD 12-18 patients, a survival benefit was observed within 6 weeks but not at 1 year. In Child-Pugh B patients, a survival benefit was observed in those with active bleeding but not those without active bleeding. However, the evaluation of active bleeding was associated with a high interobserver variability. Furthermore, early TIPS was associated with a significantly reduced incidence of failure to control bleeding or rebleeding and new or worsening ascites, without increasing the risk of overt hepatic encephalopathy. CONCLUSIONS: Early TIPS was associated with improved survival in patients with MELD >=19 or Child-Pugh C cirrhosis but not in patients with MELD <=11 or Child-Pugh A cirrhosis. For MELD 12-18 or Child-Pugh B patients, future studies addressing optimal selection criteria for early TIPS remain highly warranted. PMID- 30415235 TI - Pharmacogenetic considerations of anticoagulant medication. AB - Predicting the clinical consequences of anticoagulant therapy by identifying gene variants could help in the risk assessment of thrombosis or bleeding before and after surgery and may result in choosing more beneficial therapy. This work provides an overview of pharmacogenetic data of commonly used anticoagulant medication. The review focuses on polymorphisms influencing the efficacy and safety of the parenteral and oral anticoagulants. There is evidence that heparin resistance and heparin-induced thrombocytopenia could be genetically determined but it does not mean that the risk of bleeding or thromboembolism is related to mutations in general. CYP2C9 and VKORC1 polymorphisms are essential determinants in the genotype-guided dosing of warfarin and may distinguish patients who would benefit from switching to direct oral anticoagulants (DOACs). Further multi ethnic studies associating genes of enzymes metabolizing DOACs with primary clinical endpoints are necessary. Pharmacogenetics-based dosing of anticoagulant medication should point towards the subpopulation of patients. PMID- 30415234 TI - Stromal protein betaig-h3 reprogrammes tumour microenvironment in pancreatic cancer. AB - OBJECTIVE: Pancreatic cancer is associated with an abundant stromal reaction leading to immune escape and tumour growth. This massive stroma drives the immune escape in the tumour. We aimed to study the impact of betaig-h3 stromal protein in the modulation of the antitumoural immune response in pancreatic cancer. DESIGN: We performed studies with p48-Cre;Kras G12D, pdx1-Cre;KrasG12D;Ink4a/Arf fl/fl, pdx1-Cre;KrasG12D; p53R172H mice and tumour tissues from patients with pancreatic ductal adenocarcinoma (PDA). Some transgenic mice were given injections of anti-betaig-h3, anti-CD8, anti-PD1 depleting antibodies. Tumour growth as well as modifications in the activation of local immune cells were analysed by flow cytometry, immunohistochemistry and immunofluorescence. Tissue stiffness was measured by atomic force microscopy. RESULTS: We identified betaig h3 stromal-derived protein as a key actor of the immune paracrine interaction mechanism that drives pancreatic cancer. We found that betaig-h3 is highly produced by cancer-associated fibroblasts in the stroma of human and mouse. This protein acts directly on tumour-specific CD8+ T cells and F4/80 macrophages. Depleting betaig-h3 in vivo reduced tumour growth by enhancing the number of activated CD8+ T cell within the tumour and subsequent apoptotic tumour cells. Furthermore, we found that targeting betaig-h3 in established lesions released the tissue tension and functionally reprogrammed F4/80 macrophages in the tumour microenvironment. CONCLUSIONS: Our data indicate that targeting stromal extracellular matrix protein betaig-h3 improves the antitumoural response and consequently reduces tumour weight. Our findings present betaig-h3 as a novel immunological target in pancreatic cancer. PMID- 30415236 TI - Antithrombotic medications and their impact on fibrin clot structure and function. AB - Fibrin constitutes a major protein component of intravascular thrombi in all locations. Fibrin formation and its functions are essential for physiological hemostasis and the pathologic thrombosis. Formation of dense fibrin networks which are relatively resistant to lysis is observed in patients with venous or arterial thromboembolism, including myocardial infarction, ischemic stroke and venous thromboembolism. Measures of clot characteristics, in particular clot permeability and clot lysis time, may predict arterial and venous recurrent thromboembolic events. Medications, including vitamin K antagonists (VKA), direct oral anticoagulants (DOAC), and parenteral direct or indirect thrombin or activated factor X inhibitors increase clot permeability, reflecting fibrin network density, in association with enhanced efficiency of fibrinolysis. These effects are only in part related to decreased thrombin generation. There is evidence that aspirin can also favorably alter fibrin clot properties probably through acetylation of fibrinogen. No such effects were observed for P2Y12 inhibitors. Of note, plasma fibrin clot permeability has been shown to predict adverse clinical outcomes in patients receiving oral anticoagulants, which might have practical implications. The current review summarizes data on effects of antithrombotic agents on fibrin clot phenotype in cardiovascular disease. PMID- 30415237 TI - Antioxidant protection against cosmic radiation-induced oxidative stress at commercial flight altitude. AB - It is proposed that at the commercial flight altitude the cosmic radiation affects the human body and induces the oxidative stress. This review presents data to support this idea and also cumulates the information to provide the basis for antioxidant supplementation in persons that travel by plane at high altitudes. The conclusion is that the heterogeneity of cosmic radiation can produce different effects on human body through different mechanisms and the prophylactic treatment with antioxidants can reduce the oxidative stress generated by the radiation exposure. PMID- 30415238 TI - Effect of thiol antioxidants on lipopolysaccharide-induced cyclooxygenase-2 expression in pulmonary epithelial cells. AB - Cyclooxygenase-2 (COX-2) plays an important role in pulmonary inflammatory response, and its expression is regulated by several transcription factors including nuclear factor kappa-B (NF-kappaB), activator protein-1 (AP-1), and signal transducer and activator of transcription-3 (STAT-3), which are activated by oxidative stress. Glutathione (GSH) and N-acetyl cysteine (NAC) are thiol antioxidants that scavenge reactive oxygen species (ROS). The present study investigated whether lipopolysaccharide (LPS) induces COX-2 expression through ROS generation and the activation of oxidant-sensitive transcription factors such as NF-kappaB, AP-1, and STAT-3 in pulmonary epithelial A549 cells. The cells were pretreated with GSH or NAC for 1 hour prior to LPS stimulation. Intracellular ROS levels, DNA-binding activities of NF-kappaB, AP-1, and STAT-3, and mRNA and protein levels of COX-2 were determined. Our results showed that LPS increased ROS levels that peaked at 2 hours. LPS activated NF-kappaB, AP-1, and STAT-3 and induced the expression of COX-2 in A549 cells in a time-dependent manner. Pretreatment of thiol antioxidants GSH and NAC reduced ROS levels and attenuated the increase in ROS, the activation of NF-kappaB, AP-1, and STAT-3, and the expression of COX-2 in LPS-treated A549 cells. In conclusion, GSH and NAC suppress COX-2 expression by reducing ROS levels and inhibiting the activation of NF-kappaB, AP-1, and STAT-3 in pulmonary epithelial A549 cells exposed to LPS. Pretreatment with thiol antioxidants GSH and NAC may be beneficial for the treatment of pulmonary inflammation associated with oxidative stress. PMID- 30415239 TI - Changes in the vasoactive effects of nitric oxide, hydrogen sulfide and the structure of the rat thoracic aorta: the role of age and essential hypertension. AB - Several studies have already confirmed the specific vasomotor effect of hydrogen sulfide (H2S) and its interaction with the nitric oxide (NO) system in normotensive rats, but results in spontaneously hypertensive rats (SHRs) are limited. the aim of this study was to describe the age- and blood pressure dependent effects of endogenous NO and exogenous Na2S and their interaction in vasomotor responses of the thoracic aorta (TA) in normotensive Wistar rats and SHRs. the systolic blood pressure (sBP), vasoactivity, NO-synthase (NOS) expression and activity, cystathionine gamma-lyase (CSE) expression, and geometry of the isolated TA were evaluated at 4 and 16 weeks of age. Although hypertrophy of the heart was observed in young and adult SHRs, the sBP was increased only in adulthood. the contractile responses were decreased in young as in adult SHRs with the key participation of the endogenous NO system. however, the hypotrophy in the young and the hypertrophy (mainly at the expense of extracellular matrix) in the adult SHRs were found in the TA. While unchanged in young SHRs, in adult SHRs, partially impaired endothelial function was confirmed. Nevertheless, the NO dependent component of acetylcholine-induced relaxation was higher in both young and adult SHRs. Consistently, even though there was an age-dependent decrease in NOS activity in both strains, NOS activity was higher in both young and adult SHRs compared to age-matched normotensive rats. Application of exogenous Na2S evoked a concentration-dependent dual vasoactive effect of TAs in both strains, regardless of age. Increased sensitivity in favor of vasorelaxant responses of Na2S in prehypertensive SHRs, and an enhanced maximal vasorelaxation in adult SHR was observed. the acute NO inhibition generally increased the relaxant phase of Na2S responses; nevertheless, the development of hypertension potentiated this effect. the TA of the SHRs is endowed with a unique inherent predisposition of vasoactive mechanisms, which serve as compensatory processes during the developed stage of hypertension: the NO component and H2S signaling pathways are implicated. the decreased contractility seems to be a deleterious effect. the increased participation of the H2S system on vasorelaxation after acute NO inhibition could be considered a reserved mechanism in case of endogenous NO deficiency. PMID- 30415240 TI - The role of purinergic P2Y12 receptor blockers on the angiogenic properties of endothelial cells: an in vitro study. AB - Pharmacotherapy with agents that inhibit platelet function has proven to be effective in the treatment of acute coronary syndrome. Proper re-endothelization after angioplasty prevents adverse cardiovascular events. Therefore, in this in vitro study we examined how antiplatelet P2Y12 receptor blockers can affect endothelial cells' angiogenic properties. Endothelial cells were exposed to ticagrelor, prasugrel and clopidogrel in their highest concentrations obtained in serum after the treatment with loading and clinical doses. Further, the viability, apoptosis, and necrosis were tested and the following angiogenic properties such as proliferation, migration, invasiveness, tube formation, wound healing and the production of angiogenic mediators (bFGF, PDGF, MMP-2, Ang-2, TIMP-1). The results of this study showed that P2Y12 receptor blockers in the tested concentrations are safe for endothelial cells. They neither induced necrosis or apoptosis nor changed the endothelial cell viability, migration, invasiveness, tube formation, wound healing, the production of VEGF or its receptors. However, they reduced cell proliferation. It was shown that out of these three drugs, ticagrelor in its loading concentration had the most potent angiogenic property. It reduced cell proliferation and changed the production of angiogenic (bFGF, MMP-2) and angiostatic mediators (Ang-2). In conclusion, P2Y12 receptor blockers in the concentrations obtained in the serum during standard therapy reduced endothelial cell proliferation. Despite this slight antimitogenic effect, they did not change endothelial cell tube formation or wound healing. Out of the three tested drugs, ticagrelor had the most potent angiogenic effect in vitro, but not strong enough to disturb tube formation and wound healing. PMID- 30415241 TI - Beneficial anti-inflammatory effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker in the treatment of dextran sulfate sodium induced colitis in mice. AB - The renin-angiotensin system (RAS) in the intestine is involved in the regulation of inflammation, apoptosis and tissue fibrosis in experimental models of colitis; the inhibition of local RAS by pharmacologic interventions has been claimed to prevent and alleviate colitis. In this study, we compared the benefits of an angiotensin-converting enzyme (ACE) inhibitor, enalapril, an angiotensin receptor blocker, losartan and their combination in dextran sodium sulfate (DSS)-induced colitis in mice by assessing the histopathological and macroscopic changes in the colon, and by measuring the expression of the pro-inflammatory interleukin 1beta (IL-1beta) and tumor necrosis factor alpha (Tnf-alpha) genes. We also examined the consequences of these interventions on colonic angiotensin-converting enzyme protein and its ectodomain shedding as well as gene expression of RAS components, Agt and Ace, and corticosterone synthesis and its components, Lrh-1 and Cyp11b1. Both enalapril and losartan alleviated colitis by reducing the inflammatory cell infiltrate in colon. In addition, enalapril downregulated the pro-inflammatory IL 1beta expression whereas losartan treatment resulted in lower macroscopic scores, but the effects of the medications were not synergistic when the drugs were combined. ACE-ectodomain shedding was enhanced in the distal colon in DSS colitis. We found no evidence that ACE inhibition or angiotensin receptor blockade altered intestinal RAS or corticosterone synthesis. We conclude that some of the benefits of ACE inhibition and angiotensin receptor blockade might differ in the treatment of colitis, but their combination is unlikely to confer additional benefits. PMID- 30415242 TI - Clinicopathologic charcterization of sorafenib-induced endoplasmic reticulum stress in human liver cancer cells. AB - Sorafenib (Sor) is clinical standard therapy for advanced hepatocellular carcinoma (HCC). However, detailed molecular mechanism behind Sor-exerted pharmacological effect remains unknown. In this study, sera samples, staged hepatic cancer tissues from Sor-treated patients with advanced HCC were harvested for a group of biochemical tests and immunoassays. Compared to non-treated control, blood contents of alanine transaminase (ALT), aspartate transaminase (AST), alphafetoprotein (AFP), fibroblast growth factor 21 (FGF21) were decreased in Sor-treated HCC patients, while the level of interleukin 10 (IL-10) were increased. As well, reduced triglyceride (TG), total cholesterol (T-CHOL), interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha) levels in sera were checked in Sor-treated HCC patients. In comparison with non-treated cancer sections, Sor-treated HCC cells showed decreased positive cells of proliferative marker for proliferating cell nuclear antigen (PCNA) and metastasized biomarker for cytokeratin 19 (CK19). In addition, elevated immunofluorescence-labeled cells of endoplasmic reticulum (ER)-stress markers of activating transcription factor 6 (ATF6), eukaryotic initiation factor 2alpha kinase (eIF2alpha), glucose-regulated protein (GRP-78), X-box binding protein 1 (XBP1) were observed in Sor-treated HCC livers. Further, validated data from Western blot assay exhibited that hepatocellular expressions of ATF6, eIF2alpha, GRP78, XBP1 in Sor-treated HCC liver cells were up-regulated. Briefly, our present clinicopathologic findings indicate that Sor-induced ER stress may be responsible for therapeutic mechanism against advanced HCC. In addition, induction of intracellular ER stress functions as a promising strategy for treating advanced HCC. PMID- 30415243 TI - Increased Weight Gain During the Long Interdialytic Period Is Associated with Minor Effects on Blood Pressure Control in Clinically Stable In-Centre Haemodialysis Patients. AB - BACKGROUND/AIMS: Three-day-a-week chronic haemodialysis (cHD) involves 1 long (72 h) and 2 short (48 h) inter-dialytic periods (IDPs). We aimed to determine whether BP control following the long IDP is inferior to the short IDPs. METHODS: All pre- and post-dialysis BP and weight measurements over a 4-week period were retrospectively analyzed among 135 clinically stable cHD patients at 2 academic centres with comparisons between measurements recorded following short and long IDPs. Subsequently, 23 clinically stable cHD patients underwent 24-h ambulatory blood pressure monitoring (ABPM) during the final day/night cycle of the long IDP and 1 short IDP within the same week. RESULTS: In combined and separate analyses of the 2 retrospective cohorts, pre-dialysis BP parameters were not different following long and short IDPs despite greater inter-dialytic weight gain (IDWG) during the long IDP. Subgroup analyses of the total cohort showed no evidence for inferior BP control during the long IDP among those with high %IDWG. In the ABPM study, nocturnal hypertension and loss of nocturnal dipping were frequent. Furthermore, daytime systolic blood pressure (SBP) and pulse pressure were modestly higher during the last day/night cycle of the long compared with short IDP. CONCLUSION: In stable cHD patients, the greater IDWG that occurred during the long IDP was not associated with overtly inferior BP control as reflected in pre-dialysis BP measurements. However, modestly higher daytime SBP was evident towards the end of the long IDP by 24 h ABPM. Thus, while fluid gain has well documented associations with hypertension and adverse cardiovascular outcomes, the excess IDWG that occurs during the long IDP exerts relatively minor effects on BP control in patients on well-established dialysis regimens that are better identified by ambulatory monitoring. PMID- 30415244 TI - miR-142-5p Improves Neural Differentiation and Proliferation of Adipose-Derived Stem Cells. AB - BACKGROUND/AIMS: MiRNAs may regulate neurogenic differentiation of adipose derived stem cells (ADSCs). In this study, we hypothesized that the miR-142-5p can repress the expression of RhoA/ROCK1 pathway on the neurogenesis of ADSCs. METHODS: Deregulated miRNA during neurogenic differentiation of ADSCs were identified. The expression of neuron-specific enolase (NSE) and beta III tubulin (Neuron-specific class III beta-tubulin) were detected as the markers of neurogenic differentiation by immunostaining and western blot. The targeting of miR-142-5p on RhoA and ROCK1 was verified by dual luciferase assay, qRT-PCR and western blot. The roles of miR-142-5p and the RhoA/ROCK1 signaling pathway were explored by using functional experiments including cell viability and colony formation assays. RESULTS: MiR-142-5p is significantly upregulated during neurogenic differentiation of ADSCs. Knockdown of endogenous miR-142-5p hampered neurogenic differentiation. MiR-142-5p could directly target RhoA and ROCK1 mRNA and repress their expressions, through which it increased the proportion of differentiated cells with positive NSE and beta III tubulin. RhoA/ROCK1 signaling pathway is involved in miR-142-5p effect on the process of neurogenic differentiation of ADSCs. CONCLUSION: Our results demonstrate that miR-142-5p functions as a growth promotive miRNA and plays an important role in neurogenic differentiation by targeting RhoA/ROCK1 in ADSCs. PMID- 30415245 TI - PFKFB4 Promotes Breast Cancer Metastasis via Induction of Hyaluronan Production in a p38-Dependent Manner. AB - BACKGROUND/AIMS: The bi-functional enzyme 6-phosphofructo-2-kinase/fructose-2, 6 biphosphatase-4 (PFKFB4) is highly expressed in many types of cancer and its requirement for tumor survival has been demonstrated in glioma, lung, and prostate cancers. However, whether PFKFB4 plays a role in the tumor metastasis remains uncertain. This study explores the role of PFKFB4 in tumor metastasis and its underlying mechanisms in breast cancer cells. METHODS: The expression of PFKFB4 was first analyzed using the Cancer Genome Atlas (TCGA) dataset, and confirmed by immunohistochemical staining of tissue microarray and breast cancer tissues from patient samples. Gain- and loss-of- function approaches were used to investigate the effects of PFKFB4 on breast cancer cell migration in vitro. Orthotopic xenograft model and experimental metastasis model were used to assess the effects of PFKFB4 on breast cancer cell metastasis in vivo. ELISA and immunofluorescence staining were used to examine HA production. Quantitative RT PCR and western blotting were used to explore the mRNA and protein levels of HAS2, respectively. RESULTS: We found that PFKFB4 enhances the migration/invasiveness of breast cancer cells in vitro as well as in vivo. Notably, the effects of PFKFB4 on migration are mediated by induction of HAS2 expression and HA production. Moreover, PFKFB4-induced HAS2 up-regulation depends upon the activation of p38 signaling. CONCLUSION: PFKFB4 promotes the metastasis of breast cancer cells via induction of HAS2 expression and HA production in a p38-dependent manner. Therefore, the PFKFB4/p38/HAS2 signaling pathway may serve as a potential therapeutic target for metastatic breast cancer. PMID- 30415247 TI - Niacin Inhibits Apoptosis and Rescues Premature Ovarian Failure. AB - BACKGROUND/AIMS: Over 99% of mouse and human ovarian follicles will undergo specialized cell death including atresia and apoptosis. Reduction of apoptosis may help reduce infertility and maintain the reproductive ability in women. METHODS: 3-day B6D2F1 mice were used to culture small follicle and ovary tissue with niacin and 18-day mice were intraperitoneal injected with niacin to determine its effect on follicle development. Then establish 8-weeks POF animal model with cytoxan (CTX) or radiation. Treatment group was given 0.1 mL of 100 mM niacin by an intraperitoneal injection twice before ovulation. The ovaries were collected and the follicles were counted and categorized, and ovarian histologic sections were stained for TUNEL. Ovarian function was then evaluated by monitoring ovulation. Microarray analyses, Western blot, immunofluorescence and real-time quantitative PCR were used to assess the mechanism of ovarian injury and repair. RESULTS: We found that niacin promotes follicle growth in the immature oocyte and it increased the levels of a germ-line cell marker DDX4, and a cell proliferation marker PCNA in the ovary. Addition of niacin to the cell culture reduced oocyte apoptosis in vitro. Administration of niacin to treat premature ovarian failure (POF) in mouse models showed inhibition of follicular apoptosis under harmful conditions, such as radiation and chemotherapy damage, by markedly reducing cumulus cell apoptosis. Additionally, the number of developing follicles increased after administration of niacin. CONCLUSION: Niacin may have an important function in treating POF by reducing apoptosis in clinical applications. PMID- 30415246 TI - Canopy Homolog 2 Expression Predicts Poor Prognosis in Hepatocellular Carcinoma with Tumor Hemorrhage. AB - BACKGROUND/AIMS: Canopy homolog 2 (CNPY2) is a signature gene highly associated with tumor progression, including hepatocellular carcinoma (HCC). The presence of tumor hemorrhage (TH) implies a fast-growing and worse tumor microenvironment. We examined a possible association between CNPY2 levels and TH and evaluated their prognostic values in patients with HCC. METHODS: CNPY2 mRNA and protein levels were respectively determined in two independent cohorts of HCC specimens using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry of tissue microarrays. Kaplan-Meier survival and Cox regression analyses were executed to evaluate the prognosis of HCC. CNPY2 knockout HCC cell lines were established by the CRISPR/Cas9 gene editing system, and the functional role of CNPY2 in HCC cell proliferation and growth was examined in vitro and in vivo. RESULTS: qRT-PCR showed that CNPY2 expression was significantly higher in HCC tumor tissue than in adjacent non-tumor tissue. Immunohistochemistry of HCC tissue microarrays demonstrated that CNPY2 expression was significantly correlated with TH and clinicopathological features indicating worse HCC progression. The prognostic value of CNPY2 expression and TH was validated by Cox proportional hazards analyses. Furthermore, CNPY2 knockout resulted in the significant suppression of MHCC97H cell proliferation, tumor growth, and hemorrhage. Bioinformatics analysis revealed that CNPY2 was closely associated with the expression levels of 6 positive impact genes in HCC, namely, ROMO1, BOLA2, HSF1, ATG4B, ATF4, and DENR, which are implicated in the regulation of the tumor microenvironment. CONCLUSION: CNPY2 is an oncogene that plays a critical role in the progression of HCC with TH. CNPY2 could be exploited as a novel prognostic marker and potential target for therapeutic intervention in HCC. PMID- 30415248 TI - Comparative Analyses of the Transcriptome and Proteome of Comte de Paris and Smooth Cayenne to Improve the Understanding of Ethephon-Induced Floral Transition in Pineapple. AB - BACKGROUND/AIMS: Ethylene is usually used to induce floral transition in pineapple. However, its successful induction in plants categorized as Cayenne is difficult or completely ineffective, and information concerned is limited. The present study was undertaken to investigate the molecular mechanisms underlying this obstacle. METHODS: Transcriptome and proteome comparative analyses were performed to explore the important regulation and pathway variations after ethephon induction in the induction-easy 'Comte de Paris' (CP) and induction-hard 'Smooth Cayenne' (SC) cultivars via RNA-seq (RNA-sequencing) and iTRAQ (isobaric tags for relative and absolute quantification). RESULTS: CP and SC exhibited basic differences at the transcriptomic and proteomic levels before ethephon treatment, including the expression of genes and proteins related to ethylene signal transduction. After ethephon induction, the expression of genes and proteins involved in plant ethylene signal transduction and carbohydrate metabolism responded more strongly in CP than in SC. The expression of the floral meristem identity (FMI) genes AG, TFL and FT exhibited greater changes in CP, and more transcription factors responded in SC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that many differentially expressed genes (DEGs) in CP were annotated to terms and pathways involved in photoperiodism and shared components involved in carbohydrate metabolism and plant hormone signal transduction. CONCLUSION: These findings contribute to the understanding of the molecular mechanism underlying the variation between CP and SC in response to ethephon-mediated floral induction. PMID- 30415249 TI - A Rodent Model of Anxiety: The Effect of Perinatal Immune Challenges on Gastrointestinal Inflammation and Integrity. AB - OBJECTIVES: Gastrointestinal (GI) inflammation and GI integrity deficits are common comorbidities of neuropsychiatric disorders. Ongoing research suggests that these aberrations may be contributing to heightened immune signals that have the potential to disrupt neuronal homeostasis and exacerbate behavioural deficits. The current study aimed to determine whether the well-characterized animal model of neuropsychopathology, the maternal immune activation (MIA) model, produced GI inflammation and integrity disruptions in association with anxiety like behaviour. METHODS: Pregnant Wistar rats were exposed to the viral mimetic polyriboinosinic:polyribocytidilic acid (polyI:C) on gestational days (GD) 10 and 19. Evidence of ANS activation, GI inflammation, and GI barrier integrity was assessed in both neonatal (postnatal day, P7) and adult (P84) offspring. Anxiety like behaviour was assessed at P100. RESULTS: Neonatal MIA offspring exhibited an altered intestinal inflammatory profile and evidence of an increase in lymphoid aggregates. MIA neonates also displayed disruptions to GI barrier tight junction protein mRNA. In addition, adult MIA offspring exhibited an increase in anxiety like behaviours. CONCLUSION: These results indicate that the MIA rat model, which is well documented to produce behavioural, neurochemical, and neuroanatomical abnormalities, also produces GI inflammation and integrity disruptions. We suggest that this model may be a useful tool to elucidate biological pathways associated with neuropsychiatric disorders. PMID- 30415250 TI - Prenatal Growth in Fetuses with Isolated Cyanotic and Non-Cyanotic Congenital Heart Defects. AB - BACKGROUND: Fetal growth may vary significantly in different congenital heart defects (CHDs). OBJECTIVES: To investigate prenatal growth of CHD fetuses and its correlation with classifications based upon expected oxygen delivery to the fetal brain or structural findings. METHODS: Seventy-nine euploid fetuses with isolated CHD were recruited prospectively and categorized by the expected oxygen supply to the brain (low, intermediate, and high) or by the expected arterial mixing considering two categories (cyanotic or non-cyanotic). Biometry and Doppler were recorded, and Z-scores (Zs) calculated. Growth changes at different time points were analyzed and compared with 150 controls. RESULTS: A total of 664 exams were performed on 229 fetuses. Median head circumference (HC) Zs were lower in all CHD fetuses from the second trimester onwards and in cyanotic CHD fetuses from the first onwards, with associated smaller abdominal circumference (AC) in the third trimester (first-trimester biparietal diameter Zs cyanotic: -1.3 [-2.36; -0.98], non-cyanotic -0.72 [-1.25; -0.6], p = 0.044, second-trimester HC Zs cyanotic: 1.47 [-2.3; -0.84]; non-cyanotic -0.45 [-0.83; -0.02], p < 0.0001; AC Zs cyanotic 0.0 [-0.44; 0.86]; non-cyanotic 0.65 [0.31; 1], p = 0.0006). Birth-weight centiles were smaller in CHDs (particularly in cyanotic) with no differences between categories of brain oxygen delivery. CONCLUSIONS: Fetuses with cyanotic CHD have fetal growth restriction, impaired head growth, yet normal posterior fossa dimensions and fetal-placental Doppler. PMID- 30415251 TI - MicroRNA-323a-3p Promotes Pressure Overload-Induced Cardiac Fibrosis by Targeting TIMP3. AB - BACKGROUND/AIMS: Cardiac fibrosis is a major cause of diverse cardiovascular diseases. MicroRNAs have recently been proven a novel class of regulators of cardiac fibrosis. In this study, we sought to investigate the role of miR-323a-3p and its mechanisms in regulating cardiac fibrosis. METHODS: The transverse aortic constriction (TAC) mice model was induced and neonatal cardiac fibroblasts (CFs) were cultured. MTT (3- [4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide) assay was used to detect the cell viability. Echocardiography was used to evaluate cardiac function. Masson's Trichrome stain was used to evaluate the development of fibrosis. Luciferase activity assay was performed to confirm the miRNA's binding site. Real-time PCR and Western blot were used to evaluate the level of mRNA and protein. RESULTS: MiR-323a-3p was found up-regulated in myocardial tissues subjected to TAC and in CFs cultured with Angiotensin II (Ang II). Overexpression of miR-323a-3p significantly increased the mRNA levels of collagen I, collagen III, MMP2 and MMP9, while inhibition of miR-323a-3p prevented the proliferation, collagen production and the protein level of transforming growth factor (TGF-beta) in rat neonatal CFs. Strikingly, injection of antagomiR-323a-3p elevated cardiac function and inhibited the expression of TGF-beta in the TAC mice. TIMP3 was a direct target of miR-323a-3p, as the overexpression of miR-323a-3p decreased the protein and mRNA levels of TIMP3. In the CFs with pre-treatment of Ang II, siRNA-TIMP abolished the effects of AMO 323a-3p on the inhibition of the proliferation of CFs, the down-regulation of collagen I and collagen III, and the expression of TGF-beta. CONCLUSION: Our findings provide evidence that miR-323a-3p promotes cardiac fibrosis via miR-323a 3p-TIMP3-TGF-beta pathway. miR-323a-3p may be a new marker for cardiac fibrosis progression and that inhibition of miR-323a-3p may be a promising therapeutic target for the treatment of cardiac fibrosis. PMID- 30415252 TI - Identification of Novel LncRNA Biomarkers and Construction of LncRNA-Related Networks in Han Chinese Patients with Ischemic Stroke. AB - BACKGROUND/AIMS: Long non-coding RNAs (lncRNAs) are potential biomarkers of tumors, cardiac disease, and cerebral disease because of their interaction with coding RNAs. This work focused on ischemic stroke (IS) and aimed to identify novel lncRNA biomarkers and construct lncRNA-related networks in IS. METHODS: Differentially expressed lncRNAs were identified using Arraystar Human LncRNA Microarray v4.0, and validated with qRT-PCR. A lncRNA-mRNA co-expression network and a lncRNA-miRNA-mRNA regulatory network were constructed. Functional and pathway analyses were then performed. RESULTS: In total, 560 up-regulated and 690 down-regulated differentially expressed lncRNAs were found (P < 0.05, false discovery rate < 0.05, absolute fold change >= 2). qRT-PCR results confirmed that lncRNA-ENST00000568297, lncRNA-ENST00000568243, and lncRNA-NR_046084 exhibited significant differential expression between IS and controls (all P < 0.05). Areas under the curves (AUCs) for these lncRNAs were 0.733, 0.743, and 0.690, respectively, and the combined AUC was 0.843. A coding-noncoding co-expression (CNC) network was constructed based on Pearson's correlation coefficient. A specific lncRNA-miRNA-mRNA regulatory network of ENST00000568297, ENST00000568243, and NR_046084 was also constructed. Functional annotation of the up- and down-regulated mRNAs was performed. Pathway analysis enriched IS-related pathways with mRNAs in the lncRNA-miRNA-mRNA regulatory network. CONCLUSION: LncRNA and mRNA expression profiles in human peripheral blood were altered after IS. ENST00000568297, ENST00000568243, and NR_046084 were identified as novel potential diagnostic biomarkers of IS. Analysis of the CNC network and lncRNA miRNA-mRNA regulatory network suggested that lncRNAs may participate in IS pathophysiology by regulating pivotal miRNAs, mRNAs, or IS-related pathways. PMID- 30415253 TI - Intraoperative Optical Coherence Tomography-Guided Membrane Peeling for Surgery of Macular Pucker: Advantages and Limitations. AB - PURPOSE: Epiretinal membranes (ERMs) are a disorder leading to progressive vision loss and metamorphopsia. The gold standard in therapy is vitrectomy with membrane peeling. The aim of this study was to assess whether the use of intraoperative optical coherence tomography (iOCT), which allows tomographic visualization of the membrane during peeling, enables peeling without staining. METHODS: This prospective study included 30 eyes of 30 patients with idiopathic ERMs scheduled for surgery. Pars plana vitrectomy with iOCT was performed in all cases, whereas staining of ERMs was only performed if needed. Internal limiting membrane (ILM) peeling was performed in case of wrinkled retinal surface after peeling of ERMs. RESULTS: In 63% (n = 19) eyes the ERM could be peeled successfully without use of staining. Nevertheless, in 89% (n = 17) of patients having had ERM peeling without dye, staining of the ILM was performed afterwards for peeling the ILM. Best corrected visual acuity improved in 80% (n = 24) and remained unchanged in 7% (n = 2) 3 months after surgery. There were no significant differences in postoperative results between patients with and without staining for ERM peeling. CONCLUSIONS: Use of iOCT helps to complete ERM peeling in a majority of cases without use of a chromovitrectomy dye, but as iOCT fails to visualize the ILM, chromovitrectomy still facilitates macular surgery in a majority of cases. PMID- 30415254 TI - Low Skeletal Muscle Mass Predicts Incident Dipstick Albuminuria in Korean Adults without Chronic Kidney Disease: A Prospective Cohort Study. AB - BACKGROUND: Previous cross-sectional studies have shown that low muscle mass is associated with albuminuria in the general population. However, the longitudinal association of low muscle mass with the development of albuminuria is not well known at this time. METHODS: We evaluated 48,101 individuals without chronic kidney disease (CKD) who underwent 2 health check-ups in 2012 and 2016. Participants' skeletal muscle masses were measured using a bioelectrical impedance analyzer and compared via a skeletal muscle mass index (SMI; SMI [%] = total skeletal muscle mass [kg]/body weight [kg] * 100). Urine albumin was determined by dipstick semi-quantitative analysis and incident albuminuria was defined as >=1+ dipstick albumin at the time of the second check-up. We used logistic regression analysis to determine the relationship between skeletal muscle mass and incident albuminuria. RESULTS: The study participants were divided into quartiles according to baseline SMI. After 4 years, 305 cases of incident albuminuria were observed. The cumulative incidences of albuminuria were 0.78, 0.66, 0.62, and 0.47% for the first through fourth quartiles of SMI respectively. Multivariable logistic analysis revealed that the ORs (95% CIs) for incident albuminuria were 1.63 (1.05-2.55) in the first quartile compared with those in the fourth quartile and 1.40 (1.05-1.88) in the participants with sarcopenia versus those without sarcopenia. CONCLUSIONS: Low skeletal muscle mass was independently associated with the development of dipstick albuminuria after 4 years in Korean adults without CKD. Further research is needed to verify the role of low muscle mass in the development of albuminuria and renal injury. PMID- 30415255 TI - Mini-Percutaneous Nephrolithotomy with Ureter Catheter: A Safe and Effective form of mPCNL Offers Better Quality of Life. AB - OBJECTIVE: To compare outcomes and postoperative quality of life (QoL) among patients with kidney stone who received mini-percutaneous nephrolithotomy (mPCNL), partial tubeless mPCNL or mPCNL with ureter catheter in a prospective randomized clinical trial. METHODS: From May 2017 to December 2017, 60 patients with kidney stone who underwent mPCNL were randomized into 3 groups: Group I (mPCNL), Group II (partial tubeless mPCNL), Group III (mPCNL with ureter catheter). We evaluated perioperative characteristics, stone clearance, analgesic requirements and QoL by using the Wisconsin Stone QOL questionnaire. RESULTS: The age, gender, stone diameter, body mass index, length of operation, drop in hemoglobin and stone-free rates for the 3 groups were similar among these groups. However, the postoperative visual analog scale and the analgesic requirement in Group II were significantly the lowest (p < 0.05). According to Wisconsin Stone QOL questionnaire, compared to Group I, statistical significant difference in the QoL was seen in Group II and III, indicating a meaningful and immediate improvement in the postoperative QoL following mPCNL. CONCLUSION: Compared with standard and partial tubeless mPCNL, mPCNL with ureter catheter is a safe and useful form of mPCNL, which can offer better QoL and is more cost effective. PMID- 30415256 TI - Pro-Angiogenic Role of LncRNA HULC in Microvascular Endothelial Cells via Sequestrating miR-124. AB - BACKGROUND/AIMS: HULC is a multifunctional lncRNA that has pro-angiogenic function in various cancers. The present study was designed to see the role of lncRNA HULC in normal endothelial cells angiogenesis. METHODS: Cell viability, apoptosis, migration, tube formation and expression levels of angiogenesis related proteins were respectively assessed in human microvascular endothelial HMEC-1 cells after lncRNA HULC was silenced by shRNA transfection. Cross regulation between lncRNA HULC and miR-124, and between miR-124 and MCL-1 were detected by qRT-PCR, sequence analysis, and luciferase reporter assay. RESULTS: Silence of lncRNA HULC significantly reduced viability, migration, tube formation and protein levels of VEGF, VEGFR2, CD144 and eNOS in HMEC-1 cells. Meanwhile, silence of lncRNA HULC induced apoptosis in HMEC-1 cells, as Bcl-2 was down regulated, Bax was up-regulated, and caspase-3 and -9 were cleaved. miR-124 expression was negatively regulated by lncRNA HULC, and HULC worked as a molecular sponge for miR-124, in having miR-124 exhausted. Besides, MCL-1 was a target gene of miR-124. Rescue assay results showed that the effects of lncRNA HULC silence on HMEC-1 cells growth, migration and angiogenesis were abolished by miR-124 suppression. Similarly, the effects of miR-124 on HMEC-1 cells were abolished by MCL-1 overexpression. Furthermore, MCL-1 activated PI3K/AKT and JAK/STAT signaling pathways. CONCLUSION: These findings suggest a pro-angiogenic role of lncRNA HULC in endothelial cells. The pro-angiogenic actions of lncRNA HULC may be through sponging miR-124, preventing MCL-1 from degradation by miR 124. PMID- 30415257 TI - Impact of GADD34 on Apoptosis of Tonsillar Mononuclear Cells from IgA Nephropathy Patients by Regulating Eif2alpha Phosphorylation. AB - BACKGROUND/AIMS: Tonsillectomy may be an important method to achieve a long-term remission of IgAN, but patients' physical status may limit their access to this surgery. We proposed an encouraging solution through inhibiting GADD34 expression in order to promote tonsillar mononuclear cells (TMCs) apoptosis and reduce nephropathic IgA secretion. METHODS: A total of 12 IgAN and 9 non-IgAN patients were involved from March 2015 to May 2016. After TMCs were extracted by density gradient centrifugation and stimulated by inactivated hemolytic streptococcus, the mRNA and protein expression of GADD34, GRP78, CHOP, Bcl-2, Bcl-XL, AID, Ialpha-Calpha, and cleaved caspase-3 were examined by fluorescent RT-PCR and Western blotting. Guanabenz treatment and siRNA interference were applied to downregulate GADD34 in tonsillar mononuclear cells from IgAN patients, and P eIF2alpha expression was examined by Western Blotting. Cell apoptosis was evaluated by Annexin V FITC/PI flowcytometry, and IgA secretion in cultural supernatant was inspected by enzyme linked immunosorbent assay. RESULTS: After stimulation, the expression of GADD34 was significantly increased in IgAN patients (P< 0.05). Cell apoptosis was mitigated and IgA secretion level was elevated (P< 0.05). To be noticed, CHOP expression had no significant difference between two groups. After guanabenz treatment and siRNA interference, a prolonged elevation of P-eIF2alpha expression was observed. Cell apoptosis was reinforced and IgA secretion level was decreased (P< 0.05). CONCLUSION: GADD34 may be a potential therapeutic target for IgAN treatment due to its effect on cell apoptosis. PMID- 30415258 TI - Analysis of Prestenting on Outcomes of Flexible Ureteroscopy for Upper Urinary Urolithiasis: A Historical Control Study. AB - OBJECTIVES: The aim of this study is to explore the efficacy and safety of flexible ureteroscopy (fURS) with prestenting (PS) for patients and a newly starting department. METHOD: The data of patients who underwent fURS for calculi with nonprestenting (NPS) after a clinical practice change was compared with PS patients before. RESULT: In all, 199 patients met the inclusion criteria. There was no significant difference for both groups in basic demography except that the NPS group included more proximal ureteral stone. Subgroup analysis was then used by a different site. There was no significance in sheath success (4/100 vs. 1/99, p = 0.369). Stone free rate (SFR) and success rate between PS and NPS group showed significant difference in total (96.94 vs. 89.58%, p = 0.048, 96.97 vs. 85.00%, p = 0.005 respectively). Better SFR and success rate were found only for the renal stones in subgroup analysis (97.67 vs. 80.49%, p = 0.014, 97.67 vs. 74.42%, p = 0.003 respectively). Operative time was significantly longer based on stenting status (45.969 +/- 19.4732 vs. 30.553 +/- 8.9645 min, p = 0.01) and there was no difference in subgroup analysis. More complications were found in the NPS group, but no severe complications were encountered. CONCLUSION: Intentional PS is a feasible try for an amateur fURS surgeon or a newly started department in order to gain a better outcome and lower complications in the whole time. It improves the outcomes when additional small surgery is not the trouble. PMID- 30415259 TI - Ganoderic Acid A Protects Rat H9c2 Cardiomyocytes from Hypoxia-Induced Injury via Up-Regulating miR-182-5p. AB - BACKGROUND/AIMS: Ganoderic acid A (GAA) isolated from Ganoderma lucidum, shows various benefit activities, such as anti-tumor activity, anti-HIV activity and hepatoprotective activity. However, the potential effects of GAA on hypoxia induced injury of cardiomyocytes are still unclear. In this study, we aimed to reveal the effects of GAA on hypoxic-induced H9c2 cell injury, as well as potential underlying molecular mechanisms. METHODS: Rat H9c2 cardiomyocytes were cultured in hypoxia condition with different doses of GAA. Cell viability and apoptosis were detected by CCK-8 assay and flow cytometry, respectively. qRT-PCR was performed to assess the expression levels of microRNA-182-5p (miR-182-5p) and phosphatase and tensin homologue (PTEN). Cell transfection was conducted to change the expression levels of miR-182-5p and PTEN in H9c2 cells. Finally, protein levels of key factors involved in cell proliferation, cell apoptosis and PTEN/PI3K/AKT pathway were evaluated using western blotting. RESULTS: Hypoxia treatment significantly induced H9c2 cell viability loss and apoptosis. GAA incubation remarkably protected H9c2 cells from hypoxia-induced viability loss, proliferation inhibition and apoptosis. In addition, GAA obviously enhanced the expression level of miR-182-5p in H9c2 cells. Suppression of miR-182-5p notably alleviated the protective effects of GAA on hypoxia-treated H9c2 cells. Furthermore, miR-182-5p negatively regulated the mRNA and protein levels of PTEN in H9c2 cells. GAA attenuated hypoxia-induced inactivation of PI3K/AKT pathway in H9c2 cells by up-regulating miR-182-5p and then down-regulating PTEN. CONCLUSION: GAA protected rat H9c2 cardiomyocytes from hypoxia-induced injury might via up regulating miR-182-5p, down-regulating PTEN and then activating PI3K/AKT signaling pathway. PMID- 30415260 TI - High Concentration of Aspirin Induces Apoptosis in Rat Tendon Stem Cells via Inhibition of the Wnt/beta-Catenin Pathway. AB - BACKGROUND/AIMS: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in clinical practice to relieve fever and pain. Aspirin, as a representative NSAID, has been widely used in the treatment of tendinopathy. Some reports have demonstrated that aspirin can induce apoptosis in cancer cells. However, evidence regarding aspirin treatment for tendinopathy, especially the effect of this treatment on tendon stem cells (TSCs), is lacking. Understanding the effect of aspirin on tendinopathy may provide a basis for the rational use of NSAIDs in clinical practice. The aim of our study was to determine whether aspirin induces apoptosis in rat TSCs via the Wnt/beta-catenin pathway. METHODS: First, we used flow cytometry and fluorescence to detect TSC apoptosis. Protein expression of the apoptosis-related caspase-3 pathway was investigated via western blot analysis. Next, we used western blotting to determine the effect of aspirin on the Wnt/beta-catenin pathway. We used immunostaining to detect the levels of Bcl2, cleaved caspase-3, and P-beta-catenin in the Achilles tendon. Finally, we used flow cytometry, fluorescence, and western blotting to investigate the aspirin-induced apoptosis of TSCs via the Wnt/beta-catenin pathway. RESULTS: Aspirin induced morphological apoptosis in rat TSCs via the mitochondrial/caspase 3 pathway and induced cellular apoptosis in the Achilles tendon. Apoptosis was partly reversed after adding the Wnt signaling activator Wnt3a and lithium chloride (LiCl, a GSK-3beta inhibitor). Aspirin administration led to a dose dependent increase in COX-2 expression. Apoptosis was promoted after adding the COX-2 inhibitor NS398. CONCLUSION: The Wnt/beta-catenin pathway plays a vital role in aspirin-induced apoptosis by regulating mitochondrial/caspase-3 function. Elevating COX-2 levels may protect cells against apoptosis. More importantly, the results remind us to consider the apoptotic effect of aspirin on TSCs and tendon cells when aspirin is administered to treat tendinopathy. The relationship between the positive and negative effects of aspirin remains a subject for future study. PMID- 30415261 TI - Brain and Body Size Relations among Spotted Hyenas (Crocuta crocuta). AB - The relationship between brain size and body size across species "from mouse to elephant" is described by a function of positive slope. Almost uniformly, the relationship between brain size and body size within a species has a positive slope, though this is less steep than across species. The spotted hyena, Crocuta crocuta, differs from most other mammals in a number of ways including the fact that, on average, adult females weigh more than adult males and occasionally display greater body lengths. Brains of 5 female and 4 male hyenas were weighed in the field near Moyale in Northern Kenya, and body weights and body lengths were obtained from the same animals. When our analyses of brain/body relationships in these animals revealed an unanticipated negative relationship between brain size and body length, we extended our measurements to include intracranial volume in 19 skulls (8 females and 11 males) from the collection at the Museum of Vertebrate Zoology, University of California Berkeley; body weights and lengths were also available. A third dataset was formed by measuring intracranial volumes in 60 spotted hyena skulls (27 females and 33 males) in the Natural History Museum, London, UK; body lengths and intracranial volumes were available. Brain/body size slopes, in general, were not significantly different from zero except in 3 cases: brain weight/body length for Moyale males alone and males and females together, and cranial volume/body weight for Museum of Vertebrate Zoology males and females together. Although most of the slopes were not significantly different from zero, they were all negative, and a statistical test which combined probabilities from the 3 datasets supports the conclusion that there is a negative relationship between brain size and body size in spotted hyenas. Possible explanations for the negative slopes are discussed, including costs and benefits of large brains and large bodies and physiological mechanisms. PMID- 30415262 TI - Triclosan Suppresses Testicular Steroidogenesis via the miR-6321/JNK/ Nur77 Cascade. AB - BACKGROUND/AIMS: Triclosan (TCS), a broad-spectrum antibacterial and antifungal compound and an endocrine disruptor, has anti-androgenic properties and could adversely affect male reproduction and fertility. METHODS: To elucidate the underlying roles of miRNAs and the MAPK pathway in TCS-mediated repression of testicular steroidogenesis, Sprague-Dawley male rats were dosed daily with TCS for 31 days, and TM3 cells were exposed to TCS for 24 h after the pretreatments with the activator of JNK, Nur77 siRNA, or recombinant lentivirus vector for Nur77. Tissues and/or cells were analyzed by several techniques including transmission electron microscopy, lentivirus production, overexpression, gene silencing, luciferase reporter assay, chromatin immunoprecipitation, western blot, and real-time PCR. RESULTS: TCS caused histopathologic alterations in the testis and reduced plasma LH and testicular testosterone. TCS induced miR-6321 expression, which in turn depressed its target gene, Map3k1. The inhibition of Map3k1 subsequently inactivated its downstream JNK/c-Jun pathway. ChIP and qPCR assays confirmed that c-Jun directly bound to the Nur77 DNA promoter regions to regulate Nur77 expression. The knockdown and overexpression of Nur77 demonstrated that the JNK/c-Jun-mediated decline in the transcription and translation of Nur77 resulted in the depression of steroidogenic proteins including SRB1, StAR, and 3beta-HSD. Intriguingly, the protein expressions of 5alpha-Reductases (SRD5A1 and SRD5A2) were also downregulated after TCS exposure. CONCLUSION: Taken together, the miR-6321/Map3k1-regulated JNK/c-Jun/ Nur77 cascade contributes to TCS-caused suppression of testicular steroidogenesis, and the decrease in 5alpha-Reductase expressions may be the compensatory mechanism. PMID- 30415263 TI - HOXA-AS2 Promotes Proliferation and Induces Epithelial-Mesenchymal Transition via the miR-520c-3p/GPC3 Axis in Hepatocellular Carcinoma. AB - BACKGROUND/AIMS: Previous studies have demonstrated that long non-coding RNAs (lncRNAs) may play critical roles in cancer biology, including Hepatocellular carcinoma (HCC). The HOXA cluster antisense RNA2 (HOXA-AS2) lncRNA plays an important role in carcinogenesis, however, the underlying role of HOXA-AS2 in HCC remains unknown. The present study examined the effects of HOXA-AS2 on the progression of HCC, and explored the underlying molecular mechanisms. METHODS: Quantitative real-time PCR was used to detect HOXA-AS2 expression in HCC tissues and cell lines. Furthermore, the effects of HOXA-AS2 silencing and overexpression on cell proliferation, cell cycle, apoptosis, migration, and invasion were assessed in HCC in vitro and in vivo. Furthermore, bioinformatics online programs predicted and luciferase reporter assay were used to validate the association of HOXA-AS2 and miR-520c-3p in HCC cells. RESULTS: We observed that HOXA-AS2 was up regulated in HCC tissues and cell lines. In vitro experiments revealed that HOXA AS2 knockdown significantly inhibited HCC cells proliferation by causing G1 arrest and promoting apoptosis, whereas HOXA-AS2 overexpression promoted cell growth. Further functional assays indicated that HOXA-AS2 significantly promoted HCC cell migration and invasion by promoting EMT. Bioinformatics online programs predicted that HOXA-AS2 sponge miR-520c-3p at 3'-UTR with complementary binding sites, which was validated using luciferase reporter assay. HOXA-AS2 could negatively regulate the expression of miR-520c-3p in HCC cells. MiR-520c-3p was down-regulated and inversely correlated with HOXA-AS2 expression in HCC tissues. miR-520c-3p suppressed cell proliferation, invasion and migration in HCC cells, and enforced expression of miR-520c-3p attenuated the oncogenic effects of HOXA AS2 in HCC cells. By bioinformatic analysis and dual-luciferase reporter assay, we found that miR-223-3p directly targeted the 3'-untranslated region (UTR) of Glypican-3 (GPC3), one of the key players in HCC. GPC3 was up-regulated in HCC tissues, and was negatively correlated with miR-520c-3p expression and positively correlated with HOXA-AS2 expression. CONCLUSION: In summary, our results suggested that the HOXA-AS2/miR-520c-3p/GPC3 axis may play an important role in the regulation of PTC progression, which could serve as a biomarker and therapeutic target for HCC. PMID- 30415264 TI - Urine Bacteria-Derived Extracellular Vesicles and Allergic Airway Diseases in Children. AB - BACKGROUND: Microbiota and human allergic airway diseases have been proven to be interrelated. Bacteria-derived extracellular vesicle (EV)s are known to play important roles in interbacterial and human-bacteria communications, but their relationship with allergies has not been examined yet. Urine EVs were investigated to determine whether they could be used as biomarkers for monitoring allergic airway diseases in children. METHODS: Subjects were 4 groups of chronic rhinitis (CR), allergic rhinitis (AR), atopic asthma (AS) and healthy controls. Single voided urine samples were collected. Urine EVs were isolated and their DNA was extracted for 16S-rDNA pyrosequencing. RESULTS: A total of 118 children participated in this study; 27, 39, 19, and 33 were in the CR, AR, AS, and control group, respectively. The AR had a significantly high Chao-1 index than that of controls. Principal component analysis revealed dysbiosis in the CR, AR, and AS compared to the controls. One phylum and 19 families and genera were significantly enriched or depleted in the disease groups compared to the controls; the Actinobacteria phylum and the Sphingomonadaceae family were more abundant in the AS and CR, the Comamonadaceae family, the Propionibacteraceae family, Propionibacterium and Enhydrobacter were more enriched in the CR, and the Methylobacteriaceae family and Methylobacterium were more abundant in each disease group, while the Enterobacteriaceae family was depleted in each disease group. CONCLUSIONS: CR, AR, and AS had a distinct composition of urine EVs. Urine EVs could be an indicator for assessing allergic airway diseases in children. PMID- 30415265 TI - Evolution of Endolymph Secretion and Endolymphatic Potential Generation in the Vertebrate Inner Ear. AB - The ear of extant vertebrates reflects multiple independent evolutionary trajectories. Examples include the middle ear or the unique specializations of the mammalian cochlea. Another striking difference between vertebrate inner ears concerns the differences in the magnitude of the endolymphatic potential. This differs both between the vestibular and auditory part of the inner ear as well as between the auditory periphery in different vertebrates. Here we provide a comparison of the cellular and molecular mechanisms in different endorgans across vertebrates. We begin with the lateral line and vestibular systems, as they likely represent plesiomorphic conditions, then review the situation in different vertebrate auditory endorgans. All three systems harbor hair cells bathed in a high (K+) environment. Superficial lateral line neuromasts are bathed in an electrogenically maintained high (K+) microenvironment provided by the complex gelatinous cupula. This is associated with a positive endocupular potential. Whether this is a special or a universal feature of lateral line and possibly vestibular cupulae remains to be discovered. The vestibular system represents a closed system with an endolymph that is characterized by an enhanced (K+) relative to the perilymph. Yet only in land vertebrates does (K+) exceed (Na+). The endolymphatic potential ranges from +1 to +11 mV, albeit we note intriguing reports of substantially higher potentials of up to +70 mV in the cupula of ampullae of the semicircular canals. Similarly, in the auditory system, a high (K+) is observed. However, in contrast to the vestibular system, the positive endolymphatic potential varies more substantially between vertebrates, ranging from near zero mV to approximately +100 mV. The tissues generating endolymph in the inner ear show considerable differences in cell types and location. So-called dark cells and the possibly homologous ionocytes in fish appear to be the common elements, but there is always at least one additional cell type present. To inspire research in this field, we propose a classification for these cell types and discuss potential evolutionary relationships. Their molecular repertoire is largely unknown and provides further fertile ground for future investigation. Finally, we propose that the ultimate selective pressure for an increased endolymphatic potential, as observed in mammals and to a lesser extent in birds, is specifically to maintain the AC component of the hair-cell receptor potential at high frequencies. In summary, we identify intriguing questions for future directions of research into the molecular and cellular basis of the endolymph in the different compartments of the inner ear. The answers will provide important insights into evolutionary and developmental processes in a sensory organ essential to many species, including humans. PMID- 30415266 TI - Nephrological Care Extended to Immigrants. PMID- 30415267 TI - Silencing the FOLR2 Gene Inhibits Cell Proliferation and Increases Apoptosis in the NCI-H1650 Non-Small Cell Lung Cancer Cell Line via Inhibition of AKT/Mammalian Target of Rapamycin (mTOR)/Ribosomal Protein S6 Kinase 1 (S6K1) Signaling. AB - BACKGROUND The FOLR2 gene encodes folate receptor-beta (FR-beta), which is expressed by tumor-associated macrophages. The effects of FOLR2 gene expression in non-small cell lung cancer (NSCLC) remains unknown. This study aimed to investigate the effects of FOLR2 gene expression and gene silencing in human NSCLC cell lines and normal human bronchial epithelial (HBE) cells in vitro. MATERIAL AND METHODS Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were performed to detect the expression of the FOLR2 gene, cell cycle and apoptosis-associated genes in normal HBE cells and the NSCLC cell lines, A549, NCI-H1299, NCI-H1650, and NCI-H460. Using small interfering RNA (siRNA), or silencing RNA, FOLR2 gene silencing was performed for NCI-H1650 cells. Cell counting kit-8 (CCK-8) was used to measure cell viability. Cell cycle and apoptosis were determined using flow cytometry. Western blot evaluated the expression of Akt, mTOR, and S6K1 signaling. RESULTS Expression of the FOLR2 gene was increased in NSCLC cells compared with normal HBE cells. Silencing of the expression of the FOLR2 gene in NCI-H1650 cells reduced cell viability, increased cell apoptosis, and arrested cells in the G1 phase of the cell cycle, decreased the expression of cyclin D1, upregulated expression of cell cycle inhibitors, p21 and p27, upregulated the expression of Bax/Bcl-2, and inhibited phosphorylation of AKT, mTOR, and S6K1. CONCLUSIONS Silencing of the FOLR2 gene inhibited phosphorylation of AKT, mTOR, and S6K1, inhibited cell proliferation and increased apoptosis in the NCI-H1650 human NSCLC cell line. PMID- 30415268 TI - A Propensity Score-Matched Analysis for Non-Intubated Thoracic Surgery. AB - BACKGROUND Most observations of non-intubated anesthesia under spontaneous breathing are small-cohort, non-homogeneous surgery types and lack an intubation control. We therefore retrospectively compared the perioperative conditions and postoperative recovery of non-intubated video-assisted thoracoscopic surgery (NIVATS group) and intubated VATS (IVATS group) with a propensity score-matching analysis. MATERIAL AND METHODS We case-matched 119 patients in the NIVATS group with patients in the IVATS group by a propensity score-matched analysis. All of them underwent lobectomy. RESULTS In the NIVATS group, operative and anesthesia times were significantly shorter (P<0.01). NIVATS showed a faster and more stable recovery in the PACU, postoperative awaking and post-anesthesia care unit (PACU) stay times was shorter (P<0.01), and use of sedatives and analgesics was lower (P<0.05). The incidence of pulmonary exudation, atelectasis, and pleural effusion were higher (P<0.05). Although intraoperative SpO2 was lower and PETCO2 was higher in the NIVATS group (P<0.01), postoperative PaCO2 and SaO2 in both groups were similar (P>0.05). Postoperative counts of leukocytes and neutrophils and hemoglobin levels also had no difference between the 2 groups (P>0.05). CONCLUSIONS NIVATS has a more rapid and stable recovery in the PACU, and has no significant influence on oxygenation, but is more likely to cause postoperative radiologic complications. PMID- 30415269 TI - IC-2 Suppresses Proliferation and Induces Apoptosis of Bladder Cancer Cells via the Wnt/beta-Catenin Pathway. AB - BACKGROUND The Wnt/beta-catenin signaling pathway participates in many important tumorigeneses processes, including bladder cancer. The inhibition of abnormal activation of Wnt pathways might provide a new approach to tumor treatment. In the present study, we investigated the role of IC-2, a novel Wnt pathways small molecular inhibitor, in bladder cancer tumorigenesis. MATERIAL AND METHODS Bladder cancer cells were treated with various concentrations of IC-2 (0-5 MUM) in vitro. The proliferation ability was measured using colony formation assay and apoptosis was measured using flow cytometry analysis. The protein expression was detected using Western blot analysis. Xenograft in vivo assay was performed to assess tumor growth. RESULTS IC-2 suppressed the proliferation and aggravated the apoptosis of bladder cancer cells in dose-dependent and time-dependent manners in vitro. Moreover, high concentrations of IC-2 inhibited the Wnt pathway-related protein expression levels, including beta-catenin, Cyclin D1, and TCF4. In vivo, administration of IC-2 in xenograft mice decreased the beta-catenin expression and reduced the tumor volume. CONCLUSIONS Our results validate the tumor inhibition effect of IC-2 on bladder cancer in vivo and in vitro, providing a novel therapeutic strategy for bladder cancer. PMID- 30415270 TI - The lonely passion of the "people". AB - This paper explores the psychological sources of support for a leader, and unwavering belief in the illusions he promotes, which persists despite confrontation with reality. Lonely passion is an oxymoron. It is passion because of the intensity of the supporters' longing which is partially shaped by fear and loss. Their passion is lonely because they appear to be left empty with their love unrequited, having given their selves up and only having an illusion in return. It explores the effects of socio-economic disruption in creating or contributing to the development of a "social character" and threatening the integrity of the self. It explores the characteristics of the leader, including methods of manipulation, in eliciting passionate devotion. It uses Ferenczi's Confusion of Tongues situation as a model for understanding the relationship between leader and follower. The idealization of the leader as a power to be feared and a savior from the imagined threats he has created, and the dynamics of identification, masochism and victimization are invoked. The only remedy for the toxicity of the situation is empathy, which is understood in a historical as well as psychological context. PMID- 30415272 TI - Heme oxygenase-1 ameliorates hypoxia/reoxygenation via suppressing apoptosis and enhancing autophagy and cell proliferation though Sirt3 signaling pathway in H9c2 cells. AB - Cardiomyocyte infarction could lead to high morbidity and mortality worldwide. Recent studies demonstrated that Heme oxygenase-1 (HO-1) could exert cardiac protective effect and arouse attention. However, the detailed mechanism is still unclear. Our study provided evidences of the protective effect of HO-1 overexpression on cardiomyocytes against hypoxia/reoxygenation (H/R). We divided the treatment into four groups: the control group, H/R group, H/R+HO-1 group, and H/R+Null group. Immunofluorescent study was utilized to label the BrdU-positive and LC3-positive cells. Flow cytometry and TUNEL assay were used to examine the cell apoptosis. Protein levels of Bax, Bcl-2, Sirt3, beclin-1, LC3-I, and LC3-II were both measured using western blotting. The results indicated that HO-1 overexpression decreased the cell apoptosis and enhanced the cell proliferation. The level of Sirt3 and autophagy were also increased in H/R+HO-1 group compared with H/R group. However, ZnPP, a HO-1 inhibitor, and SiRNA of Sirt3 are both reversed the decrease of cell apoptosis of HO-1 overexpression. Moreover, ZnPP also decreased the expression of Sirt3 in HO-1 overexpression treatment group. In summary, HO-1 overexpression protects cardiomyocytes against H/R injury via ameliorating cell apoptosis and enhancing cell proliferation and autophagy through Sirt3 signaling pathway. PMID- 30415271 TI - Characterizing sources of variability in zebrafish embryo screening protocols. AB - There is a need for fast, efficient, and cost-effective hazard identification and characterization of chemical hazards. This need is generating increased interest in the use of zebrafish embryos as both a screening tool and an alternative to mammalian test methods. A Collaborative Workshop on Aquatic Models and 21st Century Toxicology identified the lack of appropriate and consistent testing protocols as a challenge to the broader application of the zebrafish embryo model. The National Toxicology Program established the Systematic Evaluation of the Application of Zebrafish in Toxicology (SEAZIT) initiative to address the lack of consistent testing guidelines and identify sources of variability for zebrafish-based assays. This report summarizes initial SEAZIT information gathering efforts. Investigators in academic, government, and industry laboratories that routinely use zebrafish embryos for chemical toxicity testing were asked about their husbandry practices and standard protocols. Information was collected about protocol components including zebrafish strains, feed, system water, disease surveillance, embryo exposure conditions, and endpoints. Literature was reviewed to assess issues raised by the investigators. Interviews revealed substantial variability across design parameters, data collected, and analysis procedures. The presence of the chorion and renewal of exposure media (static versus static-renewal) were identified as design parameters that could potentially influence study outcomes and should be investigated further with studies to determine chemical uptake from treatment solution into embryos. The information gathered in this effort provides a basis for future SEAZIT activities to promote more consistent practices among researchers using zebrafish embryos for toxicity evaluation. PMID- 30415273 TI - Arsenic trioxide ameliorates murine colon inflammation through inflammatory cell enzymatic modulation. AB - Arsenic trioxide (As2O3) is a trending subject in recent therapy approaches despite its described toxicity. In this work, we have investigated the use of arsenic trioxide in a murine model of chemically induced inflammatory bowel disease "colitis." Male mice were randomly separated into four different groups. Controls received vehicle, arsenic group had a daily injection of As2O3 (2.5 mg/kg, i.p.) for 2 days. Colitis was induced through intra-rectal instillation of 4% (v/v) solution of acetic acid in the second day. The treatment group (As2O3 + acetic acid) received the same treatment as the two previous groups. Twenty-four hours after colitis challenge, animals were sacrificed and organs (colons, livers, and kidneys) were taken for analysis. Disease-related macroscopic and microscopic symptoms, as well as histologic observations, showed a high index in the colitis group, which was greatly reduced by the As2O3 pretreatment. Similarly, colon length was reduced during colon inflammation, which was prevented in the presence of As2O3. Inflammatory cells and oxidative stress markers significantly increased during inflammation accompanied by a considerable reduction of antioxidants. As2O3 treatment managed to reverse these observations to normal levels. Mitochondrial implication was observed through mPTP opening phenomena and semi-quantitative cell death estimation. Low-dose As2O3 use as a mean of preventing the acute phase of colitis can be seen as an interesting approach which counts as a great addition to IBD available treatments. PMID- 30415275 TI - A reply to Henningfield, Fant & Wang (2018): regulatory action to control kratom is long overdue. PMID- 30415274 TI - Growth pattern of temporal bone pneumatization: a computed tomography study with consecutive age groups. AB - PURPOSE: To investigate the growth pattern of temporal bone pneumatization (TBP) in consecutive age groups from birth to 18 years old using 3D air-density reconstruction of high-resolution CT (HRCT). METHODS: A total of 570 patients under 18 years old who performed temporal bone HRCT and with no structural abnormalities on both sides were included. Nineteen groups were created to represent consecutive ages, with 15 males and 15 females in each group. Volume rendering of air density was performed using a segmentation threshold of - 200 HU to obtain TBP volume of each side. The differences in TBP between the sides, sexes, and ages were statistically analyzed. RESULTS: The mean volume of TBP was measured as 1.17 +/- 0.44 ml in patients less than 1 year old and 6.81 +/- 1.93 ml as adult size. High consistencies of TBP volume between different sides or sexes were found in most of age groups. Significant differences were shown between sides only in 9- and 11-year-old female groups (p9 = 0.031, p11 = 0.016) while between sexes only in 6- and 16-year-old groups (p6 = 0.001, p16 = 0.043), although the volume was larger in all the male groups older than 6 years. The curve drawn by the mean volume in consecutive age groups showed that TBP continued to grow linearly in both males and females until they reached 14 years old. The corresponding linear regression equations were as follows: ym = 1.553 + 0.370x, (x <= 14 years, R2 = 0.596); yf = 1.561 + 0.304x, (x <= 14 years, R2 = 0.565). CONCLUSION: The TBP volume shows a linear growth pattern from birth until reaching adult size after 14 years old. PMID- 30415276 TI - Combined ?9-tetrahydrocannabinol and moderate alcohol administration: effects on ingestive behaviors in adolescent male rats. AB - RATIONALE: Whereas co-use of alcohol and marijuana is prevalent in adolescents, the effects of such drug co-exposure on ingestive and cognitive behaviors remain largely unexplored. We hypothesized that co-exposure to alcohol and ?9 tetrahydrocannabinol (THC), the main psychoactive constitute of marijuana, alters feeding behavior and cognition differently from either drug alone. METHODS: Male rats received daily THC (3-20 mg/kg/day) or oil vehicle through subcutaneous injection or consumption of a cookie with access to saccharin or saccharin sweetened alcohol during adolescence (P30-45). Barnes maze and sucrose preference tests were applied to assess spatial memory and behavioral flexibility and abstinence-related anhedonia, respectively. RESULTS: Subcutaneous THC did not affect alcohol intake but dose-dependently increased acute (3 h) chow intake and reduced weight gain. Moderate alcohol consumption reduced the acute hyperphagic effect of subcutaneous THC. By contrast, oral THC at a dose > 5 mg/kg robustly reduced alcohol intake without affecting 3-h chow intake. At this dose, some rats stopped consuming the THC-laced cookies. Furthermore, oral THC reduced weight gain, and co-exposure to alcohol alleviated this effect. Chronic subcutaneous, but not oral, THC reduced sucrose intake during abstinence. Neither treatment impaired cognitive behaviors in the Barnes maze. CONCLUSION: Moderate alcohol and THC consumption can interact to elicit unique outcomes on ingestive behaviors and energy balance. Importantly, this study established a novel model of voluntary alcohol and THC consumption for studying mechanisms underlying the consequences of adolescent onset co-use of the two drugs. PMID- 30415277 TI - No effect of attentional bias modification training in methamphetamine users receiving residential treatment. AB - RATIONALE: Attentional bias toward drug-related stimuli is a feature of drug addiction that is linked to craving and drug-seeking behavior. OBJECTIVES/METHOD: An attentional bias modification (ABM) program was tested in 42 methamphetamine dependent clients (DSM-IV criteria) receiving residential treatment for their drug use. Participants were randomly assigned to one of two groups (N = 21 each), receiving 12 sessions of either computerized ABM training (designed to train attention away from methamphetamine stimuli 100% of the time) or an attentional control condition (designed to train attention away from methamphetamine stimuli 50% of the time). Outcome measures included attentional bias to methamphetamine related stimuli on a probe detection task, self-reported craving, and preferences to view methamphetamine-related images on a Simulated Drug Choice Task. A subset of participants (N = 17) also underwent fMRI in a cue-induced craving paradigm. RESULTS: Poor split-half reliability was observed for the probe detection task. Using this task, attentional bias toward methamphetamine-related stimuli was greater after training than at baseline, irrespective of group (p = 0.037). Spontaneous and cue-induced methamphetamine craving diminished with time (ps < 0.01), but ABM training did not influence these effects (group by time interactions, ps > 0.05). ABM training did not influence selection of methamphetamine-related pictures in the Simulated Drug Choice task (p > 0.05). In the fMRI assessment, cue-induced activation in the ventromedial prefrontal cortex was reduced over time, without an effect of ABM training. CONCLUSIONS: ABM training did not improve several clinically relevant variables in treatment seeking methamphetamine users. Additional research is needed to improve the measurement of attentional bias. PMID- 30415278 TI - Mechanisms of fear learning and extinction: synaptic plasticity-fear memory connection. AB - RATIONALE: The ability to memorize threat-associated cues and subsequently react to them, exhibiting escape or avoidance responses, is an essential, often life saving behavioral mechanism that can be experimentally studied using the fear (threat) conditioning training paradigm. Presently, there is substantial evidence supporting the Synaptic Plasticity-Memory (SPM) hypothesis in relation to the mechanisms underlying the acquisition, retention, and extinction of conditioned fear memory. OBJECTIVES: The purpose of this review article is to summarize findings supporting the SPM hypothesis in the context of conditioned fear control, applying the set of criteria and tests which were proposed as necessary to causally link lasting changes in synaptic transmission in corresponding neural circuits to fear memory acquisition and extinction with an emphasis on their pharmacological diversity. RESULTS: The mechanisms of synaptic plasticity in fear circuits exhibit complex pharmacological profiles and satisfy all four SPM criteria-detectability, anterograde alteration, retrograde alteration, and mimicry. CONCLUSION: The reviewed findings, accumulated over the last two decades, provide support for both necessity and sufficiency of synaptic plasticity in fear circuits for fear memory acquisition and retention, and, in part, for fear extinction, with the latter requiring additional experimental work. PMID- 30415279 TI - Neonatal exposure to propofol affects interneuron development in the piriform cortex and causes neurobehavioral deficits in adult mice. AB - RATIONALE: Animal studies have shown that early postnatal propofol administration is involved in neurobehavioral alterations in adults. However, the underlying mechanism is not clear. METHODS: We used c-Fos immunohistochemistry to identify activated neurons in brain regions of neonatal mice under propofol exposure and performed behavioral tests to observe the long-term consequences. RESULTS: Exposure to propofol (30g or 60 mg/kg) on P7 produced significant c-Fos expression in the deep layers of the piriform cortex on P8. Double immunofluorescence of c-Fos with interneuron markers in the piriform cortex revealed that c-Fos was specifically induced in calbindin (CB)-positive interneurons. Repeated propofol exposure from P7 to P9 induced behavioral deficits in adult mice, such as olfactory function deficit in a buried food test, decreased sociability in a three-chambered choice task, and impaired recognitive ability of learning and memory in novel object recognition tests. However, locomotor activity in the open-field test was not generally affected. Propofol treatment also significantly decreased the number of CB-positive interneurons in the piriform cortex of mice on P21 and adulthood. CONCLUSIONS: These results suggest that CB-positive interneurons in the piriform cortex are vulnerable to propofol exposure during the neonatal period, and these neurons are involved in the damage effects of propofol on behavior changes. These data provide a new target of propofol neurotoxicity and may elucidate the mechanism of neurobehavioral deficits in adulthood. PMID- 30415280 TI - Prognostic impact of combining whole-body PET/CT and brain PET/MR in patients with lung adenocarcinoma and brain metastases. AB - PURPOSE: The role of brain FDG-PET in patients with lung cancer and brain metastases remains unclear. Here, we sought to determine the prognostic significance of whole-body PET/CT plus brain PET/MR in predicting the time to neurological progression (nTTP) and overall survival (OS) in this patient group. METHODS: Of 802 patients with non-small cell lung cancer who underwent primary staging by a single-day protocol of whole-body PET/CT plus brain PET/MR, 72 cases with adenocarcinoma and brain metastases were enrolled for a prognostic analysis of OS. On the basis of the available follow-up brain status, only 52 patients were eligible for prognostic analysis of nTTP. Metastatic brain tumors were identified on post-contrast MR imaging, and the tumor-to-brain ratio (TBR) was measured on PET images. RESULTS: Multivariate analysis revealed that FDG-PET findings and eligibility for initial treatment with targeted therapy were significant independent predictors of nTTP and OS. A new index, termed the molecular imaging prognostic (MIP) score, was proposed to define three disease classes. MIP scores were significant predictors of both nTTP and OS (P < 0.001). Pre-existing prognostic indices such as Lung-molGPA scores were significant predictors of OS but did not predict nTTP. CONCLUSIONS: When staging is performed with whole-body PET/CT plus brain PET/MR, our new prognostic index may be helpful to stratify the outcomes of patients with lung adenocarcinoma and brain metastases. The superior prognostic power of this index for nTTP might be used to select appropriate patients for intracranial control and thereby achieve better quality of life. PMID- 30415282 TI - Towards new frontiers in neuroendocrinology: A tribute to Peter H. Seeburg. PMID- 30415281 TI - In silico assessment of new progesterone receptor inhibitors using molecular dynamics: a new insight into breast cancer treatment. AB - Nowadays, breast cancer is one of the most widespread malignancies in women, and the second leading cause of cancer death among women. The progesterone receptor (PR) is one of the treatment targets in breast cancer, and can be blocked with selective progesterone receptor modulators (SPRMs). Since administration of chemical drugs can cause serious side effects, and patients, especially those undergoing long-term treatment, can suffer harmful consequences, there is an urgent need to discover novel potent drugs. Large-scale structural diversity is a feature of natural compounds. Accordingly, in the present study, we selected a library of 20,000 natural compounds from the ZINC database, and screened them against the PR for binding affinity and efficacy. In addition, we evaluated the pharmacodynamics and ADMET properties of the compounds and performed molecular docking. Moreover, molecular dynamics (MD) simulation was carried out in order to examine the stability of the protein. In addition, principal component analysis (PCA) was performed to study the motions of the protein. Finally, the MMPBSA method was applied in order to estimate the binding free energy. Our docking results reveal that compounds ZINC00936598, ZINC00869973 and ZINC01020370 have the highest binding energy into the PR binding site, comparable with that of Levonorgestrel (positive control). Moreover, RMSD, RMSF, Rg and H-bond analysis demonstrate that the lead compounds preserve stability in complex with PR during simulation. Our PCA analysis results were in accordance with MD results and the binding free energies support the docking results. This study paves the way for discovery of novel drugs from natural sources and with optimal efficacy, targeting the PR. Graphical Abstract The binding mode of new progesterone receptor inhibitors. PMID- 30415283 TI - Endogenous opioid signalling in the brain during pregnancy and lactation. AB - During pregnancy, the regulation of several neuroendocrine systems is altered to support the pregnancy and facilitate the transition to motherhood. These adaptations are organised by the mother's brain and include those that serve to optimise foetal growth, protect the foetus(es) from adverse prenatal programming by maternal stress, facilitate timely parturition and ensure the offspring are nourished and cared for after birth. Although pregnancy hormones are important in inducing and maintaining many of these adaptations, their effects are often mediated via interactions with neuropeptide systems in the brain. In particular, endogenous opioids in the maternal brain play key roles in altered regulation of the stress axis, the oxytocin system, the prolactin system and the neural circuits controlling maternal behaviour. Together, these adaptations maximise the likelihood of a successful pregnancy outcome. PMID- 30415284 TI - Orange, yellow and blue luminescent carbon dots controlled by surface state for multicolor cellular imaging, light emission and illumination. AB - Three kinds of carbon dots (CDs) with different photoluminescence (PL) (blue, yellow or orange) were synthesized by microwave heating. They display wavelength independent excitation wavelengths (in the range from 444 to 574 nm), similar average particle size (from 3.7 to 4.2 nm), and fluorescence lifetimes (from 2.7 to 3.1 ns). Color and quantum yields (from 8 to 45% in ethanol) are related to the oxidation degree and the number of N-functional groups on their surface. The CDs are shown to be viable nanoprobes for multicolor imaging of cells. Three composite phosphors were obtained by coating the various CDs on starch particle. The resulting nanomaterials emit solid-state fluorescence with a quantum yield of >=16%. They were used to fabricate luminescent blocks and light-emitting diodes with controllable color temperature. Graphical abstract (a) The synthesis process of the three carbon dots (CDs). The application in cell imaging (b), starch/CD phosphors (c), starch/CD phosphors-based luminescent blocks (d) and light emitting diodes (e). (lambdaex: excitation wavelength). PMID- 30415286 TI - Surgical options and trends in treating rectal prolapse: long-term results in a 19-year follow-up study. AB - PURPOSE: Many different operations have been proposed for treating rectal prolapse, with varying recurrence rates and functional outcome. The main purpose of this study was to assess long-term results of surgery for prolapse of the rectum. METHODS: We carried out a retrospective study to evaluate changing trends in surgical strategies and outcome in all patients treated in our hospital over 19 years. RESULTS: Ninety-three patients were operated and 30 (32%) experienced recurrence of external prolapse during a median (range) follow-up time of 82 (2 231) months. There were 37 reoperations for recurrence, bringing the total number of operations to 130. From 1998 to 2010, laparoscopic posterior suture rectopexy was the preferred abdominal procedure with Delorme's operation as the perineal alternative. Observed recurrence rates were 15/49 (31%) and 8/15 (53%) during a median observation time of 84 and 9 months, respectively. From 2011 to 2017, these procedures were replaced by ventral mesh rectopexy and Altemeier's rectosigmoidectomy. The observed recurrence rate for ventral mesh rectopexy was 3/22 (14%) during a median observation time of 29 months. The 30-day mortality rate was 3% and complication rate 14%. CONCLUSIONS: The recurrence rates were high after all procedures, with no significant difference between posterior suture rectopexy and ventral mesh rectopexy, but the short observation time for the latter procedure is a limitation of the study. Both procedures had low complication rates, and ventral mesh rectopexy had no mortality. PMID- 30415287 TI - Safety and efficacy of subtotal or total parathyroidectomy for patients with secondary or tertiary hyperparathyroidism in four academic centers in the Netherlands. AB - PURPOSE: Hyperparathyroidism (HPT) is a common abnormality in patients with end stage renal disease (ESRD). Since the introduction of cinacalcet in 2004, a shift from surgery toward predominantly medical treatment has occurred. Surgery is thought to be associated with more complications than oral medication. The aim of this retrospective study was to evaluate 30-day outcomes and effectiveness of parathyroidectomy (PTx) in ESRD patients in the Netherlands. METHODS: A national database containing data from four academic medical centers in the Netherlands of patients with ESRD-related HPT, who had undergone PTx and kidney transplantation between 1994 and 2015, was established. Primary endpoints were 30-day mortality and complication rate. Secondary endpoints were biochemical measurements. RESULTS: We identified 187 HPT patients undergoing PTx, with a median age of 46 years. Median preoperative PTH level was 866 pg/mL (interquartile range [IQR] 407 1547 pg/mL). At 3 months, the median PTH drop from baseline was 93% (IQR, 71-98%) to a median of 61 pg/mL (IQR, 23-148 pg/mL, p < 0.001). Over the 25-year inclusion period, 13 patients (7.0%) required re-exploration for persistent or recurrent disease. Thirty-day mortality and complication rate were 0.0% and 7.9% respectively. Median serum calcium levels improved significantly postoperatively from 2.6 (2.4-2.8) mmol/L to 2.3 (2.1-2.5) mmol/L (p < 0.001). CONCLUSIONS: PTx is a safe and effective procedure in the frail ESRD population. These data show that there should be no reluctance for surgical intervention and when indicated, nephrologists can safely refer these patients for PTx. PMID- 30415285 TI - Overview of the SAMPL6 host-guest binding affinity prediction challenge. AB - Accurately predicting the binding affinities of small organic molecules to biological macromolecules can greatly accelerate drug discovery by reducing the number of compounds that must be synthesized to realize desired potency and selectivity goals. Unfortunately, the process of assessing the accuracy of current computational approaches to affinity prediction against binding data to biological macromolecules is frustrated by several challenges, such as slow conformational dynamics, multiple titratable groups, and the lack of high-quality blinded datasets. Over the last several SAMPL blind challenge exercises, host guest systems have emerged as a practical and effective way to circumvent these challenges in assessing the predictive performance of current-generation quantitative modeling tools, while still providing systems capable of possessing tight binding affinities. Here, we present an overview of the SAMPL6 host-guest binding affinity prediction challenge, which featured three supramolecular hosts: octa-acid (OA), the closely related tetra-endo-methyl-octa-acid (TEMOA), and cucurbit[8]uril (CB8), along with 21 small organic guest molecules. A total of 119 entries were received from ten participating groups employing a variety of methods that spanned from electronic structure and movable type calculations in implicit solvent to alchemical and potential of mean force strategies using empirical force fields with explicit solvent models. While empirical models tended to obtain better performance than first-principle methods, it was not possible to identify a single approach that consistently provided superior results across all host-guest systems and statistical metrics. Moreover, the accuracy of the methodologies generally displayed a substantial dependence on the system considered, emphasizing the need for host diversity in blind evaluations. Several entries exploited previous experimental measurements of similar host guest systems in an effort to improve their physical-based predictions via some manner of rudimentary machine learning; while this strategy succeeded in reducing systematic errors, it did not correspond to an improvement in statistical correlation. Comparison to previous rounds of the host-guest binding free energy challenge highlights an overall improvement in the correlation obtained by the affinity predictions for OA and TEMOA systems, but a surprising lack of improvement regarding root mean square error over the past several challenge rounds. The data suggests that further refinement of force field parameters, as well as improved treatment of chemical effects (e.g., buffer salt conditions, protonation states), may be required to further enhance predictive accuracy. PMID- 30415288 TI - Evaluation of a clinical preventive treatment using Er,Cr:YSGG (2780 nm) laser on the susceptibility of enamel to erosive challenge. AB - The purpose of this in vitro study was to evaluate the effect of a clinical preventive treatment using Er,Cr:YSGG laser irradiation on bovine enamel susceptibility after erosive challenge. Twelve sound bovine incisors were used and twenty-four enamel specimens were prepared in total. Two experimental groups (n = 12) were assigned as follows: Group 1 was the control group and in Group 2, the enamel specimens were irradiated with an Er,Cr:YSGG (2780 nm) laser system for 20 s, with average output power of 0.25 W, pulse repetition rate at 20 Hz without water or air flow and the pulse duration was fixed at 140 MUsec. The tip diameter was 600 MUm, the tip to tissue distance was 1 mm, the speed of handpiece movement was 2 mm/s, the power density was 88.34 W/cm2, and the fluence was 31.25 J/cm2. The specimens were submitted to erosive challenge using a common soft drink. Surface microhardness changes, surface roughness changes, and surface loss were evaluated after erosive challenge. The data were statistically analyzed using one-way ANOVA and Tukey's post-hoc test at a level of significance a = 0.05. Er,Cr:YSGG laser-treated enamel exhibited significantly less decrease in surface microhardness and significant less surface loss compared to control enamel after the erosive challenge (p < 0.05). The experimental groups did not show significant differences in surface roughness increase after the erosive challenge (p > 0.05). Er,Cr:YSGG laser treatment may be promising for the limitation of enamel erosive tooth wear induced by excessive consumption of soft drinks. Clinical studies are needed to clarify whether this protective effect is clinically significant. PMID- 30415289 TI - Selective loss of photosystem I and formation of tubular thylakoids in heterotrophically grown red alga Cyanidioschyzon merolae. AB - We previously found that glycerol is required for heterotrophic growth in the unicellular red alga Cyanidioschyzon merolae. Here, we analyzed heterotrophically grown cells in more detail. Sugars or other organic substances did not support the growth in the dark. The growth rate was 0.4 divisions day-1 in the presence of 400 mM glycerol, in contrast with 0.5 divisions day-1 in the phototrophic growth. The growth continued until the sixth division. Unlimited heterotrophic growth was possible in the medium containing DCMU and glycerol in the light. Light-activated heterotrophic culture in which cells were irradiated by intermittent light also continued without an apparent limit. In the heterotrophic culture in the dark, chlorophyll content drastically decreased, as a result of inability of dark chlorophyll synthesis. Photosynthetic activity gradually decreased over 10 days, and finally lost after 19 days. Low-temperature fluorescence measurement and immunoblot analysis showed that this decline in photosynthetic activity was mainly due to the loss of Photosystem I, while the levels of Photosystem II and phycobilisomes were maintained. Accumulated triacylglycerol was lost during the heterotrophic growth, while keeping the overall lipid composition. Observation by transmission electron microscopy revealed that a part of thylakoid membranes turned into pentagonal tubular structures, on which five rows of phycobilisomes were aligned. This might be a structure that compactly conserve phycobilisomes and Photosystem II in an inactive state, probably as a stock of carbon and nitrogen. These results suggest that C. merolae has a unique strategy of heterotrophic growth, distinct from those found in other red algae. PMID- 30415290 TI - Cognitive-perceptual load modulates hand selection in left-handers to a greater extent than in right-handers. AB - Previous studies have proposed that selecting which hand to use for a reaching task appears to be modulated by a factor described as "task difficulty," defined by either the requirement for spatial precision or movement sequences. However, we previously reported that analysis of the movement costs associated with even simple movements plays a major role in hand selection. We further demonstrated, in right-handers, that cognitive-perceptual loading modulates hand selection by interfering with the analysis of such costs. It has been reported that left handers tend to show less dominant hand bias in selecting which hand to use during reaching. We, therefore, hypothesized that hand selection would be less affected by cognitive-perceptual loading in left-handers than in right-handers. We employed a visual search task that presented different levels of difficulty (cognitive-perceptual load), as established in previous studies. Our findings indicate that left-handed participants tend to show greater modulation of hand selection by cognitive-perceptual loading than right-handers. Left-handers showed lower dominant hand reaction times than right-handers, and greater high-cost movements that reached to extremes of the contralateral workspace under the most difficult task conditions. We previously showed in this task that midline crossing has high-energy and time costs and that they occur more frequently under cognitively demanding conditions. The current study revealed that midline crossing was associated with the lowest reaction times, in both handedness groups. The fact that left-handers showed lower dominant hand reaction times, and a greater number of high-cost cross-midline reaches under the most cognitively demanding conditions suggests that these actions were erroneous. PMID- 30415291 TI - Recent advances in the discovery and combinatorial biosynthesis of microbial 14 membered macrolides and macrolactones. AB - Macrolides, especially 14-membered macrolides, are a valuable group of antibiotics that originate from various microorganisms. In addition to their antibacterial activity, newly discovered 14-membered macrolides exhibit other therapeutic potentials, such as anti-proliferative and anti-protistal activities. Combinatorial biosynthetic approaches will allow us to create structurally diversified macrolide analogs, which are especially important during the emerging post-antibiotic era. This review focuses on recent advances in the discovery of new 14-membered macrolides (also including macrolactones) from microorganisms and the current status of combinatorial biosynthetic approaches, including polyketide synthase (PKS) and post-PKS tailoring pathways, and metabolic engineering for improved production together with heterologous production of 14-membered macrolides. PMID- 30415292 TI - Microbial platforms to produce commercially vital carotenoids at industrial scale: an updated review of critical issues. AB - Carotenoids are a diverse group of isoprenoid pigments that play crucial roles in plants, animals, and microorganisms, including body pigmentation, bio communication, precursors for vitamin A, and potent antioxidant activities. With their potent antioxidant activities, carotenoids are emerging as molecules of vital importance in protecting against chronic degenerative disease, such as aging, cancer, cataract, cardiovascular, and neurodegenerative diseases. Due to countless functions in the cellular system, carotenoids are extensively used in dietary supplements, food colorants, aquaculture and poultry feed, nutraceuticals, and cosmetics. Moreover, the emerging demand for carotenoids in these vast areas has triggered their industrial-scale production. Currently, 80% 90% of carotenoids are produced synthetically by chemical synthesis. However, the demand for naturally produced carotenoids is increasing due to the health concern of synthetic counterparts. This article presents a review of the industrial production of carotenoids utilizing a number of diverse microbes, including microalgae, bacteria, and fungi, some of which have been genetically engineered to improve production titers. PMID- 30415293 TI - Bone loss in the affected forearm in patients with breast cancer-related lymphedema: a controlled study. AB - PURPOSE: We aimed to investigate the association between lymphedema and bone mass density (BMD) of affected and unaffected forearms in patients with breast cancer related lymphedema (BCRL). We also explored whether there was a relationship between any disability and BMD on the affected side. METHODS: We evaluated 111 patients (53.75 +/- 9.07) with unilateral lymphedema (group 1) and 61 patients (50.90 +/- 12.44) without lymphedema (group 2) after breast cancer surgery. BMD was performed by dual-energy x-ray absorptiometry (DXA) in lumbar spine, femoral neck, and distal forearm on both sides. Functional situation was assessed by the Disabilities of the Arm, Shoulder and Hand (QuickDASH) questionnaire. RESULTS: The total Z score (p = 0.018), T score (p = 0.005), and BMD value (p = 0.014) were lower in the affected forearm than the unaffected forearm in group 1. There was no difference between the affected or unaffected sides in the total Z score (p = 0.394), T score (p = 0.518), and BMD value (p = 0.629) in group 2. The DXA measurements in terms of the total forearm Z, T scores, and BMD value on the affected side were statistically significantly different between the groups. There was no difference between groups in the femur neck and lumbar total Z and T scores. There was also a positive correlation between the QuickDASH scores and lymphedema stage (r = 0.469, p = 0.001) and the duration without treatment of lymphedema (r = 0.298, p = 0.02) in group 1. CONCLUSION: We recommend early diagnosis and treatment of lymphedema for the protection of upper extremity disability and localized osteoporosis in patients with BCRL. PMID- 30415294 TI - Hypoxic expression of NLRP3 and VEGF in cultured retinal pigment epithelial cells: contribution of P2Y2 receptor signaling. AB - Retinal hypoxia is a major condition of the chronic inflammatory disease age related macular degeneration. Extracellular ATP is a danger signal which is known to activate the NLRP3 inflammasome in various cell systems. We investigated in cultured human retinal pigment epithelial (RPE) cells whether hypoxia alters the expression of inflammasome-associated genes and whether purinergic receptor signaling contributes to the hypoxic expression of key inflammatory (NLRP3) and angiogenic factor (VEGF) genes. Hypoxia and chemical hypoxia were induced by a 0.2%-O2 atmosphere and addition of CoCl2, respectively. Gene expression was determined with real-time RT-PCR. Cytosolic NLRP3 and (pro-) IL-1beta levels, and the extracellular VEGF level, were evaluated with Western blot and ELISA analyses. Cell culture in 0.2% O2 induced expression of NLRP3 and pro-IL-1beta genes but not of the pro-IL-18 gene. Hypoxia also increased the cytosolic levels of NLRP3 and (pro-) IL-1beta proteins. Inflammasome activation by lysosomal destabilization decreased the cell viability under hypoxic, but not control conditions. In addition to activation of IL-1 receptors, purinergic receptor signaling mediated by a pannexin-dependent release of ATP and a release of adenosine, and activation of P2Y2 and adenosine A1 receptors, was required for the full hypoxic expression of the NLRP3 gene. P2Y2 (but not A1) receptor signaling also contributed to the hypoxic expression and secretion of VEGF. The data indicate that hypoxia induces priming and activation of the NLRP3 inflammasome in cultured RPE cells. The hypoxic NLRP3 and VEGF gene expression and the secretion of VEGF are in part mediated by P2Y2 receptor signaling. PMID- 30415296 TI - Reproduction and mortality rates in ecologically distinct species of murid rodents. AB - The trade-off between reproduction and somatic maintenance is one of the most studied concepts of modern evolutionary ecology. This theory predicts a negative relationship between maximum species longevity and total reproductive output. However, studies performed on natural animal populations have found contradictory results, probably due to the unlikelihood of wild animals gaining both maximum longevity and maximum potential fecundity. A comparison of the mortality rates and reproductive output of four ecologically distinct rodent species of Cricetidae family that were maintained in the laboratory in controlled conditions revealed the different life-history tactics of subterranean social mole voles and three related aboveground species: hydrophilic water voles, arid dwarf hamsters and steppe lemmings. Regardless of the relatively higher mortality rates at early ages in mole voles, this species has considerably higher maximum species longevity and smaller litter sizes that do not depend on calendar age, whereas in dwarf hamsters and water voles clear negative correlations between female age and litter size were detected. Steppe lemmings, as a semi-social arid species, shared some life-history tactics with both mole voles and aboveground non-social rodents. PMID- 30415295 TI - Uropygial gland size: a marker of phenotypic quality that shows no senescence in a long-lived seabird. AB - Studies of senescence in the wild have traditionally focused on traits like survival or fecundity. Although efforts to measure other salient phenotypic traits and markers of relevant physiological processes are rapidly increasing, traits related to self-maintenance remain understudied in the context of aging. Uropygial or preen gland is a holocrine gland, exclusive to birds, directly linked to self-maintenance of the quality of plumage. We measured the size of uropygial glands of common gulls (Larus canus) in a cross sectional manner in order to test whether it shows the similar age-related decline as reproductive traits previously recorded in this species. Gulls with larger glands started breeding earlier in the season, indicating that gland size is a marker of individual phenotypic quality. We found a senescent decline in the onset of breeding and the size of white wing patches, a sexually dimorphic ornamental trait, while in contrast, preen gland increased with advancing age. This finding supports the view of life-history theory that in long-lived species whose lifetime reproductive success depends heavily on lifespan, self-maintenance is prioritized over reproduction. Altogether our results support the concept that senescence in the wild can be asynchronous for traits related to maintenance versus reproduction. PMID- 30415297 TI - Qualitative and Quantitative Assessment of Patient and Carer Experience of Chemotherapy (Docetaxel) in Combination with Androgen Deprivation Therapy (ADT) for the Treatment of Metastatic Hormone-Sensitive Prostate Cancer (mHSPC). AB - INTRODUCTION: Recent studies suggest that docetaxel plus androgen deprivation therapy can prolong survival among men with metastatic hormone-sensitive prostate cancer (mHSPC). However, as a cytotoxic therapy, there is a need to understand the experiences of men with mHSPC receiving docetaxel and their carers in a real world setting. METHODS: During phase 1, semi-structured qualitative interviews were conducted with men with mHSPC (n = 31) and their carers (n = 14) in Europe to elicit in-depth data concerning their experiences with docetaxel. Eighteen men were also asked to record their experiences in a diary for 7 days. During phase 2, men with mHSPC (n = 161) and carers of men with mHSPC (n = 135) completed an online survey comprising self-report questionnaires including the Cancer Therapy Satisfaction Questionnaire, Brief Fatigue Inventory, Functional Assessment of Cancer Therapy-Prostate, EuroQol-5-Dimensions and the Burden Scale for Family Caregivers (carers only). RESULTS: At the outset of therapy, men reported a willingness to take docetaxel to prolong their life, despite being fearful of the potential side effects and impacts on their daily lives. Patient and carer experiences were generally consistent with pre-treatment expectations. However, variations in individual experiences and their ability to tolerate side effects were evident. Fatigue emerged as a prominent symptom with the majority (n = 98, 60.9%) of men reporting experiencing moderate-severe fatigue in the past 24 h. Participant ratings of fatigue were strongly correlated with health-related quality of life (r = - 0.82). Nausea, diarrhoea and sore mouth were also among the most bothersome symptoms for participants. CONCLUSIONS: Findings from this study highlight that real-world experience of docetaxel may differ from that observed in clinical trials and that care must be taken to ensure that treatment options are tailored to the needs of individual patients to promote not only how long patients survive but also the quality of that survival. FUNDING: Janssen. PMID- 30415298 TI - Effects of Tiotropium Combined with Theophylline on Stable COPD Patients of Group B, D and its Impact on Small Airway Function: A Randomized Controlled Trial. AB - INTRODUCTION: Tiotropium bromide has been widely used in clinical practice, while theophylline is another treatment option for chronic obstructive pulmonary disease (COPD). However, only a few relevant studies have investigated the long term outcomes and efficacy of both in patients with COPD. We evaluated the effects of tiotropium and low-dose theophylline on stable COPD patients of groups B and D. METHODS: Eligible participants (n = 170) were randomized and received either tiotropium 18 ug once daily with theophylline 100 mg twice daily (Group I) or tiotropium 18 ug once daily (Group II) for 6 months. COPD assessment test (CAT), modified Medical Research Council (mMRC) dyspnea scores and pulmonary function tests were measured before randomization and during the treatment. RESULTS: After 6 months of treatment, the CAT scores in both groups decreased significantly (11.41 +/- 3.56 and 11.08 +/- 3.05, p < 0.0001). The changes of CAT (p = 0.028) and mMRC scores (p = 0.049) between the two groups differed after 1 month of treatment. In Group I, forced expiratory flow after 25% of the FVC% predicted (MEF25% pred) was significantly improved after 3 months (4.84 +/- 8.73%, p < 0.0001) and 6 months (6.21 +/- 8.65%, p < 0.0001). There was a significant difference in small airway function tests (MEF50% pred, MEF25% pred, and MMEF% pred) between the two groups after 6 month of treatment (p = 0.003, p < 0.0001, and p = 0.021, respectively). CONCLUSIONS: Tiotropium combined with low dose theophylline significantly improved the symptoms and general health of patients with stable COPD of groups B and D after 6 months of follow-up. Additionally, this therapy also improved the indicators of small airway function. TRIAL REGISTRATION: Chinese Clinical Trial Registry (Registry ID: ChiCTR1800019027). PMID- 30415299 TI - 2018 Scientific Referees. PMID- 30415300 TI - Applying DoTS adverse drug reactions classification to reports from hospital stimulated reporting. PMID- 30415301 TI - Differential diagnosis of pulmonary enteric adenocarcinoma and metastatic colorectal carcinoma with the assistance of next-generation sequencing and immunohistochemistry. AB - PURPOSE: Pulmonary enteric adenocarcinoma (PEAC), defined as tumors with an enteric component exceeding 50% and a histological morphology similar to colorectal cancer (CRC) and metastatic colorectal carcinoma (MCC), is an extremely rare primary lung adenocarcinoma, which was recently recognized by World Health Organization (WHO). Adenocarcinomas with intestinal differentiation have also been described in other anatomic sites, including paranasal sinuses, extrahepatic biliary tree, uterine and cervix, ovary. The morphologic spectrum and immunohistochemical profiles of PEAC overlap with those of colonic adenocarcinomas, the diagnosis of PEAC remains challenging. Currently, colonoscopy has to be performed to confirm the diagnosis, resulting in low compliance due to its invasiveness. Due to the rareness of PEAC, its molecular signature has not been comprehensively examined. METHODS: In this study, we investigated the molecular signatures associated with PEAC and its histological counterparts, CRC and MCC using capture-based targeted sequencing. RESULTS: We revealed that 12/13 (92.31%) PEAC patients harbored mutations in well-established driver genes for non-small cell lung cancer and none of them had mutations unique to CRC. Furthermore, 13/15 (86.7%) of MCC harbored mutations that are frequently seen in CRC. CONCLUSION: Collectively, our study showed that PEAC, exhibiting a similar mutational profile with NSCLC, showed a distinctive signature from CRC and MCC. Furthermore, we derived a classification model, intergrading both IHC markers and genetic signature, to accurately diagnose PEAC. PMID- 30415302 TI - Glioma stem cells reconstruct similar immunoinflammatory microenvironment in different transplant sites and induce malignant transformation of tumor microenvironment cells. AB - PURPOSE: This study aimed to examine whether the different tumor-transplanted sites could construct a similar immunoinflammatory microenvironment and to investigate the interactions between tumor microenvironment cells. METHODS: The red fluorescent protein-SU3 (SU3-RFP) or SU3 glioma stem cells (GSC) were inoculated into the brain, liver, abdominal cavity, and subcutis of green fluorescent protein (GFP)-nude mice. The tumor tissues were taken to observe the tissue cell distribution. The single cell suspension of tumor tissues was prepared and cultured, while the SU3-RFP cells were co-cultured with the cells from GFP-transgenic mice. The RFP+, GFP+, and RFP+/GFP+ cells were traced by fluorescence microscope, and their protein expressions were determined by Western blot analysis. The markers of immunoinflammatory cells, including F4/80, CD11b, CD11c, CD80, CD47, and SIRP-alpha, were determined by RT-PCR and immunocytochemistry assays, respectively. RESULTS: The xenograft models of all transplant sites were inducible, and the red tumor cells of tumor tissues were encircled by a great quantity of host-derived green cells, including immunoinflammatory cells with CD80, F4/80, CD11b, and CD11c expressions, which might generate the cell colonies and possess the pseudopodia. Additionally, the interactions between red tumor cells and green immunoinflammatory cells, including cell fusion process and yellow fusion cell formation, were observed in cultured cells. The fusion cells-derived B4 cells with expressions of CD47 and SIRP-alpha proteins had the strong proliferation ability and tumorigenic effect. CONCLUSIONS: The similar tumor immunoinflammatory microenvironment was constructed by GSC in different transplant sites, and the cell fusion indicated a malignant transformation of the tumor microenvironment cells. PMID- 30415303 TI - Reply to the letter regarding NADPH oxidase inhibitor. PMID- 30415304 TI - Supraorbital keyhole versus pterional craniotomies for ruptured anterior communicating artery aneurysms: a propensity score-matched analysis. AB - The safety and efficacy of the supraorbital keyhole approach for aneurysm surgery have not been well researched through a high-quality controlled study. The objective of the study was to compare the safety and efficacy of the supraorbital and pterional approaches for ruptured anterior communicating aneurysm (AComAn). A total of 140 patients, with 70 patients in each group, were enrolled after 1:1 propensity score matching. Clinical variables, postoperative complications, and long-term outcomes were retrospectively compared. Baseline characteristics were equivalent between the two groups. Significantly shorter operative time and less intraoperative blood loss were observed in the supraorbital group compared to the pterional group (141.9 min vs. 184.5 min, P < 0.001; 160.4 ml vs. 250.7 ml, P = 0.008). The incidence of intraoperative aneurysm rupture was similar between the groups (20% vs. 18.6%, P = 0.830). The rate of procedural complications involving subdural hematoma and intracranial infection was lower in patients treated through the supraorbital (10.0%) vs. the pterional approach (32.9%, P < 0.001), but no significant difference was observed for the incidence of ischemic events (15.7% vs. 18.6%, P = 0.654). Within a median 33.4-month (range, 11-67 months) follow-up, a similar proportion of patients achieved a favorable outcome (Glasgow Outcome Scale IV or V) across the two groups (83.6% vs. 80.0%, P = 0.285), while better cosmetic results were observed in the supraorbital group (94.0%) vs. the pterional group (86.2%, P = 0.129). According to our results, we recommend the keyhole approach for AComAn surgery for neurosurgeons who have gained sufficient experience with this technique due to its advantages over the pterional approach. PMID- 30415305 TI - Impact of connectivity between the pars triangularis and orbitalis on identifying the frontal language area in patients with dominant frontal gliomas. AB - We have previously revealed that identification of the frontal language area (FLA) can be difficult in patients with dominant frontal glioma involving the pars triangularis (PT). The present study added new cases and performed additional analyses. We noticed a new finding that the presence of extension to the pars orbitalis (POr) was associated with negative response to the FLA. The aim of the present study was to evaluate the impact of PT involvement with extension to the POr on the failure to identify the FLA. From 2000 to 2017, awake craniotomy was performed on 470 patients. Of these patients, the present study included 148 consecutive patients with frontal glioma on the dominant side. We evaluated whether tumors involved the PT or extended to the POr. Thirty one of 148 patients showed involvement of the PT, and we examined the detailed characteristics of these 31 patients. The rate of negative response for the FLA was 61% in patients with involvement of the PT. In 31 patients with frontal glioma involving the PT, univariate analyses showed significant correlation between extension to the POr and failure to identify the FLA (P = 0.0070). Similarly, multivariate analysis showed only extension to the POr correlated significantly with failure to identify the FLA (P = 0.0129). We found new evidence that extension to the POr which impacts connectivity between the PT and POr correlated significantly with negative response to the FLA of patients with dominant frontal glioma. PMID- 30415306 TI - Non-infectious causes that increase early and mid-to-late pregnancy loss rates in a crossbreed dairy herd. AB - High reproductive performance is an element factor for profitability in dairy herds; although, pregnancy loss of non-infectious nature during early and mid-to late embryonic period is increasing in dairy cattle. Based on that, the present study aimed to determine the incidence of pregnancy loss before and after 60 days of insemination, and to identify some non-infectious causes that could enhance it. The herd was composed by 600 crossbred dairy cows and those with a corpus luteum (CL) were treated with prostaglandinF2alpha, then inseminated, on the other hand, those without a CL were submitted to a timed artificial insemination protocol (TAI). Pregnancy losses rates were analyzed by logistic regression by SAS, and differences were considered significant when P < 0.05. The overall pregnancy loss and mid-to-late pregnancy loss were not affected by animal category (P > 0.05); although, early pregnancy loss was higher in cows than in heifers (11.90 vs. 3.39%). The early pregnancy loss was higher in those cows that calved on spring/summer when compared to those calved on fall/winter (9.22% vs. 16.11%), moreover, those inseminated during spring/summer tended to have higher early pregnancy loss when compared to those inseminated on fall/winter (13.35% vs. 8.57%). In conclusion, when some of non-infectious causes were evaluated, it was observed that cows that calved on spring/summer had higher pregnancy loss. At this point, strategies should be developing to minimize pregnancy loss in dairy herds, as it could be considered an important reproductive problem. PMID- 30415307 TI - Assessment of Awareness about Antibiotic Resistance and Practices Followed by Veterinarians for Judicious Prescription of Antibiotics: An Exploratory Study in Eastern Haryana Region of India. AB - The rise of antibiotic resistance and its global outreach has recently become a subject of increasing importance in veterinary research with an objective to reduce the load of antibiotic resistance in dairy farming practices. The present study was designed to analyze antibiotic prescriptions by veterinarians and to evaluate the appropriateness of prescribing behavior in consistent with prudent use of antibiotics. A total of 48 veterinarians were selected randomly from government Veterinary hospitals constituting a total of 48 veterinarians as respondents. The study revealed that most of prescriptions corresponded sound to prudent use of antibiotic and its treatment guidelines. To assess their awareness about antibiotic resistance and its related veterinary practices, an exclusively Awareness Index of antibiotic resistance was developed. It was observed that antibiotics were prescribed in initial encounter of diagnosis; thus, antibiotic conservation practices were found lacking. The ethical awareness of veterinarians was found lacking to establish valid veterinary-client relationship and ensure active involvement of stakeholders. This study largely looks into this angle by unearthing the drug prescribing behavior in order to shape the interdisciplinary research on this biological and profoundly social issue. PMID- 30415308 TI - Monitoring the urban green spaces and landscape fragmentation using remote sensing: a case study in Osmaniye, Turkey. AB - Urban green spaces play a significant role in management of physical activity, psychological well-being, and public health of urban residents. With the expansion of urban areas in Turkey during the past decades, urban green spaces have been fragmented and dispersed causing impairment and environmental degradation. The purpose of this study is to model urban green space distribution by focusing on the landscape fragmentation in city of Osmaniye using remote sensing and geographic information system technology. Normalized difference vegetation index (NDVI) and urban landscape ratio (ULR) were used to assess the proximity and spatial arrangement of urban green spaces within the neighbor landscapes to quantify the urban land use effect. The geospatial analysis results showed that increase in total built-up area and population has significantly decreased the urban green space cover because of high levels of landscape fragmentation in urban city center. Also, due to high levels of landscape fragmentation, approximately 45% of the Osmaniye city is estimated to become urbanized by 2030. This study demonstrated the benefits of directional vegetation index application with geospatial analyses in characterizing the environmental quality for planning and management of urban green spaces. This approach could be used for determining the future urban land development scenarios correlating with regional planning procedures. PMID- 30415309 TI - Rapid kVp switching dual-energy CT in the assessment of urolithiasis in patients with large body habitus: preliminary observations on image quality and stone characterization. AB - PURPOSE: The purpose of this study was to investigate the image quality (IQ) considerations of rapid kVp switching dual-energy CT (rsDECT) in the assessment of urolithiasis in patients with large body habitus and to evaluate whether it allows stone characterization. MATERIALS AND METHODS: In this IRB-approved, HIPAA compliant retrospective study, 93 consecutive patients (M/F = 72/21, mean age 56.9 years, range 23-83 years) with large body habitus (> 90 kg/198 lbs) who underwent dual-energy (DE) stone protocol CT on a rapid kVp switching DECT scanner between January 2013 and December 2016 were included. Scan acquisition protocol included an initial unenhanced single-energy CT (SECT) scan of KUB followed by targeted DECT in the region of stones. Two readers evaluated both CT data sets (axial 5 mm 120 kVp/140 kVp QC/70 keV monoenergetic, material density water/iodine images and coronal/sagittal 3 mm images) for the assessment of image quality (Scores: 1-4) and characterization of stone composition (reference standard: crystallography). RESULTS: One hundred and five CT examinations were performed in 93 patients (mean body weight 105.12 +/- 13.53 kg, range 91-154 kg), and a total of 321 urinary tract calculi (mean size-4.8 +/- 3.2 mm, range 1.2-22 mm) were detected. Both SECT and targeted monoenergetic images were of acceptable image quality (mean IQ: 3.77 and 3.83, kappa 0.79 and 0.87 respectively). Material density water and iodine images had lower IQ scores (mean IQ: 2.97 and 3.09 respectively) with image quality deterioration due to severe photon starvation/streak artifacts in 20% (21/105) and 17% (18/105) scans, respectively. Characterization of stone composition into uric acid/non-uric acid stones was achieved in 93.14% (299/321) of calculi (mean size: 4.99 +/- 3.3 mm, range 1.2-22 mm), while 7% (22/321) stones could not be characterized (mean size 3.03 +/- 1.16 mm, range 1.6-6.4 mm) (p < 0.001). Most common reason for non-characterization was image quality deterioration of the material density iodine images due to severe photon starvation artifacts. On multivariate regression, stone size and patient weight were predictors of stone composition determination on DECT (p < 0.05). The transverse diameter had a weak negative correlation with stone composition determination, but it was not statistically significant. Stone characterization into uric acid vs. non-uric acid stones was accurate in 95% (n = 38/40) of stones in comparison with crystallography. CONCLUSION: In patients with large body habitus, rsDECT allowed characterization of most calculi (93%) despite image quality deterioration due to photon starvation/streak artifacts in up to 20% of material density images. Stone size and patient weight were predictors of stone composition determination on DECT, and small calculi in very large patients may not be characterized. PMID- 30415310 TI - The phosphodiesterase 5 inhibitor sildenafil decreases the proinflammatory chemokine IL-8 in diabetic cardiomyopathy: in vivo and in vitro evidence. AB - PURPOSE: Interleukin (IL)-8 is a proinflammatory C-X-C chemokine involved in inflammation underling cardiac diseases, primary or in comorbid condition, such diabetic cardiomyopathy (DCM). The phosphodiesterase type 5 inhibitor sildenafil can ameliorate cardiac conditions by counteracting inflammation. The study aim is to evaluate the effect of sildenafil on serum IL-8 in DCM subjects vs. placebo, and on IL-8 release in human endothelial cells (Hfaec) and peripheral blood mononuclear cells (PBMC) under inflammatory stimuli. METHODS: IL-8 was quantified: in sera of (30) DCM subjects before (baseline) and after sildenafil (100 mg/day, 3-months) vs. (16) placebo and (15) healthy subjects, by multiplatform array; in supernatants from inflammation-challenged cells after sildenafil (1 uM), by ELISA. RESULTS: Baseline IL-8 was higher in DCM vs. healthy subjects (149.14 +/- 46.89 vs. 16.17 +/- 5.38 pg/ml, p < 0.01). Sildenafil, not placebo, significantly reduced serum IL-8 (23.7 +/- 5.9 pg/ml, p < 0.05 vs. baseline). Receiver operating characteristic (ROC) curve for IL-8 was 0.945 (95% confidence interval of 0.772 to 1.0, p < 0.01), showing good capacity of discriminating the response in terms of drug-induced IL-8 decrease (sensitivity of 0.93, specificity of 0.90). Sildenafil significantly decreased IL-8 protein release by inflammation-induced Hfaec and PBMC and downregulated IL-8 mRNA in PBMC, without affecting cell number or PDE5 expression. CONCLUSION: Sildenafil might be suggested as potential novel pharmacological tool to control DCM progression through IL-8 targeting at systemic and cellular level. PMID- 30415311 TI - Long-Term Efficacy and Safety of Hizentra(r) in Patients with Primary Immunodeficiency in Japan, Europe, and the United States: a Review of 7 Phase 3 Trials. AB - Many patients with primary immunodeficiency (PID) require immunoglobulin G (IgG) replacement therapy, delivered as intravenous IgG (IVIG) or subcutaneous IgG (SCIG). We aim to identify trends in efficacy and safety that would not be evident in individual studies of small patient numbers. Seven open-label, Phase 3, prospective, multicenter studies of the efficacy and safety of Hizentra(r) (a SCIG), conducted in Japan, Europe, and the US were summarized. Overall, 125 unique patients received 15,013 weekly infusions during a total observation period of 250.9 patient-years. Mean weekly doses of Hizentra(r) were 83.22-221.3 mg/kg body weight; infusion rates per patient (total body rate) were 25.2-49.3 mL/h across studies. The rates of infections and serious bacterial infections were 3.10 and 0.03 events per patient/year, respectively. Annualized rates of days hospitalized due to infection, out of work/school, and prophylactic antibiotic use were 0.95, 5.14, and 36.78 per patient, respectively. For the equivalent monthly dose, weekly Hizentra(r) SCIG administration resulted in expectedly-increased serum IgG trough levels in patients switching from IVIG, and maintained levels in patients switching from previous SCIG. Adverse events (AEs) totaled 5039 (events/infusion 0.094-0.773), almost all of which were mild/moderate. Three thousand one hundred ninety-seven were considered treatment related, the most common of which were injection site reactions (2919 events; 0.001-0.592 AEs per infusion). Systemic AEs were very uncommon. The results from these seven studies indicate that Hizentra(r) therapy was both efficacious and well tolerated during long-term treatment. This is particularly important in patients with PID, who may require lifelong IgG replacement therapy. PMID- 30415312 TI - Identification of pathogenic bacteria in human blood using IgG-modified Fe3O4 magnetic beads as a sorbent and MALDI-TOF MS for profiling. AB - A method is described for fast identification of bacteria by combining (a) the enrichment of bacterial cells by using magnetite (Fe3O4) magnetic beads modified with human IgG (IgG@Fe3O4) and (b) MALDI-TOF MS analysis. IgG has affinity to protein A, protein G, protein L and glycans on the surface of bacterial cells, and IgG@Fe3O4. It therefore is applicable to the preconcentration of a range of bacterial species. The feasibility of the method has been demonstrated by collecting six species of pathogenic bacteria (Gram-positives: Staphylococcus aureus and Kocuria rosea; Gram-negatives: Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter cloacae and Pseudomonas aeruginosa). Bacteria with concentrations as low as 10 CFU.mL-1 in spiked water samples were extracted by this sorbent with recovery rates of >50%. After enrichment, bacteria on the IgG@Fe3O4 sorbent were further identified by MALDI-TOF MS. Bacteria in concentrations as low as 105 CFU in 100 MUL of human whole blood can be identified by the method. Compared to other blood culture based tests, the culture time is shortened by 40% (from ~10 h to ~6 h), and the plate culture procedure (overnight) is avoided. After short blood culture, the enrichment and identification can be finished in one hour. The IgG@Fe3O4 is of practical value in clinical diagnosis and may be combined with other identification methods, e.g. PCR, Raman spectroscopy, infrared spectroscopy, etc. Graphical abstract A non targeted, fast and sensitive assay for bacterial identification from human blood has been developed based on the enrichment of bacteria by IgG@Fe3O4 and identification by MALDI-TOF MS. PMID- 30415313 TI - The quality of life in extracorporeal life support survivors: single-center experience of a long-term follow-up. AB - OBJECTIVE: To evaluate the health-related quality of life on a very long-term follow-up in patients treated with extracorporeal membrane oxygenation (ECMO) during neonatal and pediatric age. DESIGN: Prospective follow-up study. SETTING: Pediatric Intensive Care Unit of a tertiary-care University-Hospital. PATIENTS: Out of 20 neonates and 21 children treated with ECMO in our center, 24 patients underwent short-term neurological follow-up. Twenty of them underwent long-term neurological follow-up. INTERVENTION: Short-term follow-up was performed at 18 months and consisted in clinical evaluation, electroencephalography, and neuroimaging. Long-term follow-up was performed in 2017, at the mean period 19.72 years from ECMO (median 20.75, range 11.50-24.08) and consisted in a standardized questionnaires self-evaluation (PedsQL 4.0 Generic Core Scale) of health-related quality of life and an interviewed about the presence of organ morbidity, school level, or work position. MEASUREMENTS AND MAIN RESULTS: Sixty-one percent (25/41) of the patients survived within 30 days after ECMO treatment. Short-term follow up was performed in 24 patients (1 patient but died before the evaluation): 21 patients (87%) showed a normal neurological status, and 3 developed severe disability. Long-term follow-up was performed in 20 long-term survivors (3 patients were not possible to be contacted and considered lost to follow-up): mean age of patients at long-term follow-up was 21.23 (median 20.96, range 13.33 35.58) years; 90% (18/20) of them have no disability with a complete normal quality of life and 95% have no cognitive impairment. CONCLUSIONS: ECMO represents a life-saving treatment for infants and children with respiratory and/or heart failure; survivors show a good quality of life comparable to healthy peers. PMID- 30415314 TI - Establishment of a normative database and evaluation of the test-retest repeatability of the Spaeth/Richman contrast sensitivity test. AB - PURPOSE: To evaluate the test-retest repeatability of a computer-based contrast sensitivity (CS) test, the Spaeth/Richman contrast sensitivity (SPARCS) test, and to determine the effects of age and lens status on CS in normal eyes. STUDY DESIGN: Prospective cross-sectional study. METHODS: The participants were assessed by use of the SPARCS test in each eye 3 times. The first 2 sessions were supervised, while the third was unsupervised. CS was determined for 5 areas of vision (central, superotemporal, superonasal, inferotemporal, and inferonasal) and combined to provide a total score. The test-retest repeatability was determined using Bland-Altman analysis and the intraclass correlation coefficient (ICC). RESULTS: The total SPARCS scores (maximum possible score = 100) ranged from 86.37 (+/-1.09) (for those aged 20 to 29 years) to 70.71 (+/-2.64) (for those aged 80 to 87 years). Individuals aged between 10 and 87 years with a normal eye examination (n = 205) were enrolled. When the SPARCS scores for the first 2 sessions were compared, the ICC was 0.79, and the repeated tests were fairly equivalent (mean difference = -0.29, P = .491). The test-retest 95% limits of agreement (95% LoA) ranged from -11.07 to +11.35. When the supervised sessions were compared with the unsupervised session, the ICC was 0.80, and there was slight improvement in the CS scores during the unsupervised session (mean difference = -1.15, P = .0001). The test-retest 95% LoA ranged from -9.18 to +10.60. The CS declined with advanced age and increased cataract severity (P <0.0001). CONCLUSION: Strong agreement was found between repeated SPARCS scores. Older age and increased lens opacity were associated with decline in CS in 5 areas of the visual field. The SPARCS test provides reliable and reproducible assessment of CS in normal eyes. PMID- 30415315 TI - Knowledge and Practices of Cervical Cancer and Its Prevention Among Malawian Women. AB - Malawi has the highest incidence of cervical cancer in the world. Due to various challenges the country faces in terms of cervical cancer control, women have a poor chance to survive this disease. The purpose of our study was to describe the knowledge and practices of cervical cancer and its screening as well as the educational preferences of women living in a rural community in the Chiradzulu District. We conducted a survey among women between the ages 30 and 45, used convenience sampling, a calculated sample size (n = 282) and structured interviews to collect the data. A questionnaire adapted from a previous study served as data collection instrument. The data were analysed in Microsoft Excel and chi-square (p < .05) was used to investigate the relationships between the variables. Content analyses analysed the open-ended questions. The mean age of the sample was 36.1 (SD +/- 5.1) and the highest percentage (37.4%; n = 98) belonged to the Yao ethnic group. The majority attended primary school (66.0%; n = 173), were married (74.4%; n = 195) and depended on a small business as source of income (55.7%; n = 146). Most of the women (93.4%; n = 247) had heard of cervical cancer and the visual inspection with acetic acid (VIA) screening programme (67.9%; n = 178) but only 22.9% (n = 60) indicated they had been screened. Lack of knowledge of the screening programme was the most common reason for not being screened. Having a demonstration of the VIA procedure was the most popular educational method (92.0%; n = 241) which gives a fresh approach to educational programmes aimed at preventing cervical cancer. PMID- 30415316 TI - Regions of multistationarity in cascades of Goldbeter-Koshland loops. AB - We consider cascades of enzymatic Goldbeter-Koshland loops (Goldbeter and Koshland in Proc Natl Acad Sci 78(11):6840-6844, 1981) with any number n of layers, for which there exist two layers involving the same phosphatase. Even if the number of variables and the number of conservation laws grow linearly with n, we find explicit regions in reaction rate constant and total conservation constant space for which the associated mass-action kinetics dynamical system is multistationary. Our computations are based on the theoretical results of our companion paper (Bihan, Dickenstein and Giaroli 2018, preprint: arXiv:1807.05157 ) which are inspired by results in real algebraic geometry by Bihan et al. (SIAM J Appl Algebra Geom, 2018). PMID- 30415317 TI - The development of interferon-based gene therapy for BCG unresponsive bladder cancer: from bench to bedside. AB - BACKGROUND AND PURPOSE: BCG unresponsive bladder cancer is an inherently resistant disease state for which the preferred treatment is radical cystectomy. To date, no effective intravesical therapies exist for patients who possess these resistant tumors. For this reason, many research groups are actively investigating/testing novel therapeutic agents to aid in bladder preservation for this patient population. This review article describes our 15-year experience developing and testing IFN-based gene therapy. METHODS: A comprehensive review was performed of all studies pertaining to IFN-based gene therapy for non-muscle invasive bladder cancer from 2003 to 2018. RESULTS AND CONCLUSIONS: Over the past two decades, gene therapy has evolved into a powerful tool in our fight against cancer. After overcoming the initial barriers associated with gene delivery to the bladder, we have made significant strides forward in developing this novel therapeutic strategy for the treatment of this inherently resistant disease state. Our results to date are very encouraging; however, much work lies ahead to better understand and optimize this novel approach for treating non-muscle invasive bladder. PMID- 30415319 TI - Relationship between cerebral microbleeds and white matter MR hyperintensities in systemic lupus erythematosus: a retrospective observational study. AB - PURPOSE: White matter hyperintensities (WMH) and cerebral microbleeds (CMBs) are known to be associated with small vessel diseases (SVD) and neuroinflammation. The purpose was to investigate the relationship between CMBs and WMH in patients with systemic lupus erythematosus (SLE). METHODS: Thirty-one SLE patients with WMH and 27 SLE patients with normal brain MRI were compared. The presence, location, and grading of CMBs were assessed using susceptibility-weighted images. WMH volume was quantitatively measured. Clinical characteristics and serologic markers were compared. We also performed two separate subgroup analyses after (1) dividing WMH into inflammatory lesion vs. SVD subgroups and (2) dividing WMH into those with vs. without CMB subgroups. RESULTS: The WMH group showed more frequent CMBs than the normal MR group (p < 0.001). The WMH group showed higher SLE disease activity index, longer disease duration, and a higher incidence of antiphospholipid syndrome than the normal MR group (p = 0.02, 0.04, and 0.04, respectively). There was a moderate correlation between WMH volume and CMB grading (r = 0.49, p = 0.006). Within the WMH group, the inflammatory lesion subgroup showed more frequent CMBs and larger WMH volume than the SVD subgroup (p < 0.001 and 0.02, respectively). The WMH with CMB subgroup had larger WMH volume than the WMH without CMB subgroup (p = 0.004). CONCLUSION: In patients with SLE, CMBs could be related to large-volume WMH and inflammatory lesions. CMBs along with severe WMH could be used as an imaging biomarker of vasculitis in patients with SLE. PMID- 30415318 TI - Updates in the Diagnosis and Treatment of Paraneoplastic Neurologic Syndromes. AB - The disorders of the central nervous system associated with cancer by remote immune-mediated mechanisms are a heterogeneous group. These disorders encompass the classic paraneoplastic disorders and the recently recognized autoimmune encephalitis associated with antibodies against neuronal cell surface or synaptic proteins that occur with or without cancer association. In the last decade, the new surge of interest in neuronal diseases associated with anti-neuronal antibodies led to the rapid discovery of new forms of disease that have different manifestations and were not previously suspected to be immune mediated. The recognition of these syndromes is important because it may lead to early detection of an underlying malignancy and prompt initiation of treatment, improving chances for a better outcome. PMID- 30415320 TI - Outpatient Psychotherapy for Adults with High-Functioning Autism Spectrum Condition: Utilization, Treatment Satisfaction, and Preferred Modifications. AB - Many adults with autism spectrum condition (ASC) desire outpatient psychotherapy (PT). This study compared reasons for seeking PT, experiences with PT, and modifications preferred with respect to PT of individuals with ASC to non autistic individuals with depression (MDD). Furthermore, factors predictive for treatment satisfaction were identified in individuals with ASC. A total of 262 adults with ASC without intellectual impairment and 304 non-autistic controls with MDD were surveyed. In this pilot study both groups predominantly sought treatment for depressiveness. A low level of expertise with autism was the main reason for being declined by therapists and a contributing factor to the overall treatment dissatisfaction of patients with ASC. ASC patients desire adjustments such as written communication, and clearly structured sessions. PMID- 30415322 TI - Total mercury status in an urban water body, Mithi River, Mumbai and analysis of the relation between total mercury and other pollution parameters. AB - Mercury is a heavy metal which has garnered attention recently in India. Minamata Convention on mercury was established on October 2013 and was joined by India on September 30, 2014. India is seen as a major mercury pollution source after China according to many studies in the past. Various mercury pollution sites that are currently recognized in India are Kodai Lake, Kodaikanal, Tamil Nadu, and Thane Creek, Mumbai. Since 1992, chlor-alkali plants have been regulated to eliminate mercury cell process of manufacturing. Also, medical and health care facilities are discarding mercury-containing equipment and processes. Various anthropogenic sources of mercury to the atmosphere include combustion of fossil fuels, processing and mining of primary metal ores, cement manufacturing units, chlor alkali plants, and use of mercury in various products like paints, electric switches, and relays. The hazard associated with mercury pollution becomes extremely serious when we consider its ability to be transported over long-range distances. Various atmospheric transport models suggest India and other Asian countries to be a major source of long-range transport of mercury to North America. Considering the hazards of mercury and its widespread presence in our life, a study on mercury pollution in an urban water body is conducted. This study deals with Mithi River located in Mumbai Metropolitan Region (19.0760 degrees N, 72.8777 degrees E) to study the total mercury in water and derive its relationship with other pollution parameters. PMID- 30415324 TI - Feasibility of FreeStyle Libre Flash Glucose Monitoring System in pregnant woman affected by type 1 diabetes. PMID- 30415323 TI - Intraoperative neuromonitoring of anterior root muscle response during hip surgery under spinal anesthesia. AB - The aim of this study was to evaluate the anterior root muscle (ARM) response monitorability during total hip arthroplasty (THA) under spinal anesthesia. A total of 20 adults (64.6 +/- 13.87 years old) were monitored using ARM response and free-run electromyography during THA. To elicit the ARM response from muscles, percutaneous stimulation of the lumbosacral roots was performed by self adhesive electrodes placed over the skin of the projection of the first and third lumbar interspinous space (anode) and over the abdominal skin of the umbilicus (cathode). Latency and amplitude values of the ARM response were recorded from both sides (non-operated and operated) and from five muscles as follows: rectus femoris (RF), vastus lateralis (VL), biceps femoris long-head (BF), Tibialis Anterior (TA) and gastrocnemius. The most recorded ARM response in a muscle was the TA (n = 38); the least recorded AMR response in a muscle was the BF (n = 33). The mean stimulus intensities for the non-operated and the operated sides were 462.5 +/- 112.8 V and 520.0 +/- 172.3 V (p = 0.834), respectively. The mean latencies and amplitude values of the ARM response from muscles were as follows: 8.8 +/- 1.4 ms; 98.8 +/- 114.5 uV for RF; 9.8 +/- 2.1 ms; 119.1 +/- 122.23 uV for VL; 9.5 +/- 1.6 ms; 39.6 +/- 30.3 uV for BF; 15.1 +/- 1.9 ms; 146.6 +/- 150.9 uV for TA; 15.6 +/- 2.4 ms; 81.0 +/- 99.9 uV for Gastrocnemius. The present study demonstrates that the ARM response could easily and safely be obtained during THA under spinal anesthesia. This non-invasive technique may have a potential to detect early neurological deficit in patients who need complex hip surgery under spinal anesthesia. PMID- 30415325 TI - Repurposing Macromolecule Delivery Tools for Plant Genetic Modification in the Era of Precision Genome Engineering. AB - Efficient delivery of macromolecules into plant cells and tissues is important for both basic research and biotechnology product applications. In transgenic research, the goal is to deliver DNA molecules into regenerable cells and stably integrate them into the genome. Over the past 40 years, many macromolecule delivery methods have been studied. To generate transgenic plants, particle bombardment and Agrobacterium-mediated transformation are the methods of choice for DNA delivery. The rapid advance of genome editing technologies has generated new requirements on large biomolecule delivery and at the same time reinvigorated the development of new transformation technologies. Many of the gene delivery options that have been studied before are now being repurposed for delivering genome editing machinery for various applications. This article reviews the major progress in the development of tools for large biomolecule delivery into plant cells in the new era of precision genome engineering. PMID- 30415326 TI - The Use of an Automated Platform to Assemble Multigenic Constructs for Plant Transformation. AB - Compared to traditional means, modern DNA assembly methods allow cloning of large, multigenic vectors for plant transformation in rapid fashion. These methods are often robust and efficient and can assemble multiple DNA fragments into a single vector in one reaction. Here we describe the use of an automated DNA assembly platform for the generation of complex, multigenic T-DNA binary vectors using a hierarchical Golden Gate cloning strategy. These DNA constructs contained diverse DNA elements for the expression of multiple genes for trait stacking in the crop of interest. This platform streamlines the DNA assembly and validation process through high-efficiency cloning methods, integrated automation equipment, and increased throughput. The implementation of this platform removes bottlenecks for routine molecular biology and opens new possibilities for downstream experimental idea testing. PMID- 30415327 TI - Ensifer-Mediated Transformation (EMT) of Rice (Monocot) and Oilseed Rape (Dicot). AB - Ensifer adhaerens OV14 underpins the successful crop transformation protocol, termed Ensifer-mediated transformation (EMT). The adaptability and efficiency of EMT technology to successfully transform both monocot and dicots have been previously reported. To facilitate community users' transition to EMT, the modified rice and oilseed rape plants generated in this work were developed using EMT protocols that were grounded in standard Agrobacterium-mediated transformation (AMT) processes. Therefore, this chapter describes simple yet crucial steps involved in transferring the use of EMT of rice and oilseed rape for generation of fertile and independent transgenic lines. PMID- 30415321 TI - Regulatory B and T lymphocytes in multiple sclerosis: friends or foes? AB - Current clinical experience with immunomodulatory agents and monoclonal antibodies in principle has established the benefit of depleting lymphocytic populations in relapsing-remitting multiple sclerosis (RRMS). B and T cells may exert multiple pro-inflammatory actions, but also possess regulatory functions making their role in RRMS pathogenesis much more complex. There is no clear correlation of Tregs and Bregs with clinical features of the disease. Herein, we discuss the emerging data on regulatory T and B cell subset distributions in MS and their roles in the pathophysiology of MS and its murine model, experimental autoimmune encephalomyelitis (EAE). In addition, we summarize the immunomodulatory properties of certain MS therapeutic agents through their effect on such regulatory cell subsets and their relevance to clinical outcomes. PMID- 30415328 TI - Setaria viridis as a Model Plant for Functional Genomic Studies in C4 Crops. AB - Setaria viridis is an emerging model for C4 species, and it is an important model to validate some genes for further C4 crop transformation, such as sugarcane, maize, and wheat. Here, we describe two protocols for stable transformation of S. viridis mediated by Agrobacterium tumefaciens with three different reporter genes and two selectable markers. Routine transformation efficiency reaching 29% was achieved using embryogenic callus in S. viridis (accession A10.1). Alternatively, we developed a transformation method by floral dip with 0.6% efficiency. The developed protocols could be useful for genetic and genomics studies of important food-feed-fiber-fuel C4 crops. PMID- 30415329 TI - Transient Transformation Using Particle Bombardment for Gene Expression Analysis. AB - Transient transformation or transient expression results in rapid and fleeting gene expression. This approach is often used as a first-tier screening tool for evaluation of components that affect gene expression. Here, we describe the use of particle bombardment of lima bean cotyledons with constructs containing the green fluorescent protein (gfp) coding region for evaluation of promoter components that influence gene expression. Although this approach is conceptually quite simple, this lima bean transient expression system may not work well, if our methods and notes are not carefully read and followed. Our laboratory has successfully optimized this method over the past 10 years, resulting in a transient expression system, which works like no other that we have seen. PMID- 30415330 TI - Maize Transformation Using the Morphogenic Genes Baby Boom and Wuschel2. AB - Despite the fact that maize transformation has been available for over 25 years, the technology has remained too specialized, labor-intensive, and inefficient to be useful for the majority of academic labs. Compounding this problem, future demands in maize genome engineering will likely require a step change beyond what researchers view as "traditional" maize transformation methods. Recently, we published on our use of constitutively expressed morphogenic transcription factors Baby Boom (Bbm) and Wuschel2 (Wus2) to improve maize transformation, which requires CRE-mediated excision before regeneration of healthy, fertile T0 plants. Moving beyond this first-generation system, we have developed a new expression system for Bbm and Wus2, using a non-constitutive maize phospholipid transferase protein promoter (Pltp pro) driving Bbm expression and a maize auxin inducible promoter (Axig1 pro) for WUS2 expression. Using this combination of expression cassettes, abundant somatic embryos rapidly form on the scutella of Agrobacterium-transformed zygotic immature embryos. These somatic embryos are uniformly transformed and can be directly germinated into plants without a callus phase. Transformed plants are sent to the greenhouse in as little as 1 month, and these T0 plants match the seed-derived phenotype for the inbred and are fertile. T1 seeds germinate normally and have a uniformly wild-type inbred phenotype. This new system represents a rapid, user-friendly transformation process that can potentially facilitate high-throughput production of transgenic T0 plants in B73, Mo17, and the recently developed Fast-Flowering Mini-Maize. PMID- 30415331 TI - Efficient and Fast Production of Transgenic Rice Plants by Agrobacterium-Mediated Transformation. AB - Genetic transformation plays a key role in deciphering regulation of agronomic traits at molecular level in rice, a model monocot cereal crop. Here we describe an efficient and fast protocol for producing transgenic japonica rice plants using the Agrobacterium-mediated transformation method. The protocol simplifies medium compositions and transformation steps and can be easily followed by a lab technician with little tissue culture experience. Using this protocol, we have transformed thousands of gene constructs in the past 10 years and edited hundreds of genes with the CRISPR-Cas9 system recently. PMID- 30415332 TI - Protocol for Agrobacterium-Mediated Transformation and Transgenic Plant Production of Switchgrass. AB - Switchgrass (Panicum virgatum L.) is one of the most important bioenergy crops for lignocellulose ethanol production. Molecular breeding provides a powerful tool to supplement conventional switchgrass breeding by introducing or editing genes of interest. In this chapter, we describe Agrobacterium tumefaciens mediated transformation protocols for lowland tetraploid switchgrass cultivar Alamo. PMID- 30415333 TI - Biolistic Transformation of Wheat. AB - Biolistic transformation of wheat is one of the most commonly used methods for gene function study and trait discovery. It has been widely adapted as a fundamental platform to generate wheat plants with new traits and has become a powerful tool for facilitating the crop improvement. In this chapter, we present a complete and straightforward protocol for wheat transformation via biolistic bombardment system. Although wheat is still one of the hardest plant species to transform, this protocol offers an optimized and efficient system to produce transgenic plants. To demonstrate the application of this protocol, in this chapter we describe an example of obtaining transgenic wheat by the co bombardment of two plasmids, containing a green fluorescent protein gene and a glufosinate herbicide selection gene, respectively. In addition, procedures for the screening and testing of putative transgenic plants are described. This protocol has been successfully applied to generate stable transgenic bread wheat (Triticum aestivum) in both spring and winter varieties. PMID- 30415334 TI - Mesophyll Protoplasts and PEG-Mediated Transfections: Transient Assays and Generation of Stable Transgenic Canola Plants. AB - Plant protoplasts are derived by controlled enzymatic digestion that removes the plant cell wall without damaging the cell membrane. Protoplasts represent a true single-cell system and are useful for various biochemical and physiological studies. Protoplasts from several agriculturally important crop species can be regenerated into a fertile whole plant, extending the utility of protoplasts from transient expression assays to the generation of stable transformation events. Here we describe procedures for transient and stable transformation of leaf mesophyll protoplasts obtained from axenic shoot cultures of canola (Brassica napus). Key steps including enzymatic digestion for protoplast release, density gradient-based protoplast purification, PEG-mediated transfection, bead-type culturing (sea-plaque agarose and sodium alginate), and the recovery of putative transgenic canola plants are described. This method has been used for double stranded DNA break-mediated genome editing and for the routine generation of stable transgenic canola events at commercial scale. PMID- 30415335 TI - A Unified Agrobacterium-Mediated Transformation Protocol for Alfalfa (Medicago sativa L.) and Medicago truncatula. AB - Simplification of transformation procedures greatly improves work efficiency. In this chapter, we introduce a unified Agrobacterium-mediated transformation protocol that is used for both alfalfa (Medicago sativa L., Regen SY4D) and Medicago truncatula (ecotype R108). Whole trifoliates or leaflets are used as explants. Sonication is applied to enhance Agrobacterium infection and cytokinins are added to the medium to facilitate shoot regeneration. More than 90% transformation efficiency is achieved for alfalfa, while the relatively lower efficiency of up to 60% is obtained for M. truncatula, which depends on different selectable markers in the gene constructs. Transgenic plants are produced within 4-8 months with average timeline of 6 months. Using this unified protocol, the same types of media are used for both species which results in significant saving in time and resources. PMID- 30415336 TI - Poplar Transformation. AB - First publications of successful Agrobacterium-mediated transformation of tobacco were published more than 30 years ago. Protocols for Agrobacterium-based transformation as well as biolistic bombardment and PEG transformation of protoplasts are available for more than 150 plant species from various plant families. Also for many Populus species and hybrids, adapted transformation protocols have been published. The standard protocol for Agrobacterium-mediated transformation of different Populus genotypes is the leaf-disc method. Here, we first describe the transfer of genes into poplar by using the Agrobacterium-based leaf disc methods. In addition, alternative basic transformation methods, namely, biolistic bombardment and PEG transformation of protoplasts, are also described. Further, we present improved poplar transformation protocols by simplifying the transformation procedure and optimizing tissue preparation and plant regeneration. PMID- 30415337 TI - The Genetic Transformation of Sweet Orange (Citrus sinensis L. Osbeck) for Enhanced Resistance to Citrus Canker. AB - Developing disease resistance is one of the most important components of any plant breeding program. Citrus traditional breeding methods (bud sport selection, crossbreeding, and other breeding channels) are a laborious task and often hampered by long juvenility, a high degree of heterozygosity, polyembryony, self incompatibility, and abortion of reproductive organs. An interesting alternative to the classical breeding approach is the use of genetic transformation, which provides the means for adding a single agronomic trait to a plant without otherwise altering its phenotype. Agrobacterium tumefaciens-mediated transformation has been carried out with numerous hybrids and citrus species. This technique allowed us to introduce the Bs2 gene in Citrus, as well as to increase citrus canker resistance in transgenic Bs2 gene-expressing lines. PMID- 30415339 TI - Agrobacterium-Mediated Transformation of Solanum tuberosum L., Potato. AB - Potato is considered the fourth most important food crop in the world, and the most important non-cereal crop. Potato is transformed using Agrobacterium tumefaciens with relative ease. Several improvements have been made in the last 20 years with respect to tissue culture, transformation, and regeneration of potato. This chapter describes a reliable and efficient potato transformation system using internodal explants. Plasmid preparation, Agrobacterium transformation, potato transformation, regeneration, and recovery are described in detail, as well as molecular characterization of resulting putative transgenic plants. PMID- 30415338 TI - Genetic Modification of Grapevine Embryogenic Cultures. AB - Precision breeding is an approach to grapevine genetic improvement that transfers only specific traits among sexually compatible species via the relatively stable mitotic cell division pathway in order to avoid the significant disruption imposed upon conventional breeding by meiosis. Factors enabling precision breeding include the availability of the Vitis genome sequence combined with highly optimized gene insertion and plant regeneration protocols. A protocol for the production of grapevine embryogenic cultures and their genetic transformation is described. Embryogenic cultures are produced from either leaf or floral explants. Somatic embryos at the cotyledonary stage of development are used for Agrobacterium-mediated transformation. Following co-cultivation with Agrobacterium containing the genes of interest, modified embryos are selected on the basis of anthocyanin pigmentation and antibiotic resistance. Somatic embryos are then germinated to produce modified plants that are hardened and transferred to a greenhouse. The presence of the genes of interest is confirmed by PCR. PMID- 30415340 TI - Agrobacterium tumefaciens-Mediated Transformation of Tomato. AB - Tomato is both an important food crop and serves as a model plant species that is used for various research investigations including understanding gene function. Transformation is commonly utilized to facilitate these investigations in combination with all the extensive genetic and genomic resources available for tomato. The transformation protocol routinely used in our laboratory has been applied to many different tomato genotypes and relies on Agrobacterium tumefaciens infection of young cotyledon sections. We have used vector systems for overexpression, RNA interference for gene silencing, and CRISPR/Cas9 for genome editing. Vectors used to design gene constructs contained selectable marker genes that conferred resistance to kanamycin, hygromycin, and the herbicide component, bialaphos. The protocol we follow for Agrobacterium-mediated transformation of both cultivated and wild species of tomato is detailed in this chapter. PMID- 30415341 TI - DNA Break Repair in Plants and Its Application for Genome Engineering. AB - Genome engineering is a biotechnological approach to precisely modify the genetic code of a given organism in order to change the context of an existing sequence or to create new genetic resources, e.g., for obtaining improved traits or performance. Efficient targeted genome alterations are mainly based on the induction of DNA double-strand breaks (DSBs) or adjacent single-strand breaks (SSBs). Naturally, all organisms continuously have to deal with DNA-damaging factors challenging the genetic integrity, and therefore a wide range of DNA repair mechanisms have evolved. A profound understanding of the different repair pathways is a prerequisite to control and enhance targeted gene modifications. DSB repair can take place by nonhomologous end joining (NHEJ) or homology dependent repair (HDR). As the main outcome of NHEJ-mediated repair is accompanied by small insertions and deletions, it is applicable to specifically knock out genes or to rearrange linkage groups or whole chromosomes. The basic requirement for HDR is the presence of a homologous template; thus this process can be exploited for targeted integration of ectopic sequences into the plant genome. The development of different types of artificial site-specific nucleases allows for targeted DSB induction in the plant genome. Such synthetic nucleases have been used for both qualitatively studying DSB repair in vivo with respect to mechanistic differences and quantitatively in order to determine the role of key factors for NHEJ and HR, respectively. The conclusions drawn from these studies allow for a better understanding of genome evolution and help identifying synergistic or antagonistic genetic interactions while supporting biotechnological applications for transiently modifying the plant DNA repair machinery in favor of targeted genome engineering. PMID- 30415342 TI - Gene Stacking in Plants Through the Application of Site-Specific Recombination and Nuclease Activity. AB - Biotechnology methods for inserting genes one by one or as a block of fragment into plant genomes are needed to introduce valuable traits into crop varieties. Insertion of multiple genes into a single site, called as molecular stacking, is important to allow co-inheritance of the genes into the progeny. Generally, two approaches are available for creating gene stacks: nuclease-induced targeted gene integration into native sites and recombinase-mediated gene integration into the engineered sites. The recombinase application is attractive as several recombinases show high efficiency and precision in plant genomes. This chapter describes a gene stacking method based on the use of Cre-lox site-specific recombination system to integrate genes into the engineered sites and nucleases to delete selection genes leading to stacking of traits into a single genomic site. High efficiency and precision, and undetectable off-target effects of Cre lox in a number of plant species, make it an attractive tool for complex applications such as gene stacking. PMID- 30415343 TI - CRISPR/Cas9 for Mutagenesis in Rice. AB - CRISPR/Cas9 (clustered regularly interspaced short palindromic repeat/CRISPR associated protein 9) provides a workhorse for genome editing biotechnology. CRISPR/Cas9 tailored for enabling genome editing has been extensively interrogated and widely utilized for precise genomic alterations in eukaryotic organisms including in plant species. The technology holds the great promise to better understand gene functions, elucidate networks, and improve the performance of crop plants such as increasing grain yields, improving nutritional content, and better combating the biotic and abiotic stresses. Various methods or protocols specific for different plant species have been established. Here, we present a CRISPR/Cas9-mediated genome editing protocol in rice, including detailed information about single-guide RNA design, vector construction, plant transformation, and mutant screening processes. PMID- 30415344 TI - Plant Biotechnology Applications of Zinc Finger Technology. AB - With ever-increasing genomic information combined with modern tools for genome modification, we are entering a new era of plant biotechnology. One major tool used for genome modification is the zinc finger nuclease (ZFN). Here, we discuss how ZFNs have proven useful in many genome modification applications. In order to remove the function of a gene or genes, targeted mutagenesis using ZFNs has been readily demonstrated creating numerous gene knockouts, and gene deletion has been demonstrated with removal of gene segments both native and transgenic up to 9 Mb. Applications for gain of function have also been demonstrated. Precision gene editing using ZFNs has resulted in the development of herbicide tolerance, and numerous forms of targeted gene addition have been exhibited. In addition to genome modification, this chapter also describes the use of zinc finger protein transcription factors (ZFP-TFs) for gene regulation in order to provide useful modification of gene expression resulting in altered phenotypes. PMID- 30415345 TI - Overview of Biotechnology-Derived Herbicide Tolerance and Insect Resistance Traits in Plant Agriculture. AB - Biotechnology has been central for the acceleration of crop improvement over the last two decades. Since 1994, when the first commercial biotechnology-derived tomato crop was commercialized, the cultivated area for genetically modified crops has reached 185.1 million hactares worldwide. Both the number of crops and the number of traits developed using biotechnology have accounted for this increase. Among the most impactful biotechnology-derived traits are insect resistance and herbicide tolerance, which have greatly contributed to the worldwide increase in agricultural productivity and stabilization of food security. In this chapter, we provide an overview of the history of the biotechnology-derived input traits, the existing genetically engineered commercial crop products carrying insect resistance and herbicide tolerance traits, as well as a perspective on how new technologies could further impact the development of new traits in crops. With the projection of the world population to increase to 9.8 billion by the year 2050 and reduction in available farmland, one of the biggest challenges will be to provide sustainable nourishment to the projected population. Biotechnology will continue to be the key enabler for development of insect resistance and herbicide tolerance traits to overcome that imminent challenge. PMID- 30415346 TI - Developing Transgenic Agronomic Traits for Crops: Targets, Methods, and Challenges. AB - The last two decades have witnessed a surge of investment by the agricultural biotechnology industry in the development of transgenic agronomic traits. These are traits that improve yield performance by modifying endogenous physiological processes such as energy capture, nutrient utilization, and stress tolerance. In this chapter we provide a foundation for understanding these fundamental processes and then outline approaches that have been taken to use this knowledge for yield improvement. We characterize the current status of product development pipelines in the industry and illustrate the trait discovery process with three important examples-bacterial cold-shock proteins, alanine aminotransferase, and auxin-regulated genes. The challenges with developing and commercializing an agronomic trait product are discussed. PMID- 30415347 TI - Transgenic and Genome Editing Approaches for Modifying Plant Oils. AB - Vegetable oils are important for human and animal nutrition and as renewable resources for chemical feedstocks. We provide an overview of transgenic and genome editing approaches for modifying plant oils, describing useful model and crop systems and different strategies for transgenic modifications. We also describe new genome editing approaches that are beginning to be applied to oilseed plants and crops. These approaches are illustrated with examples for modifying the nutritional quality of vegetable oils by altering fatty acid desaturation, producing non-native fatty acids in oilseeds, and enhancing the overall accumulation of oil in seeds and leaves. PMID- 30415348 TI - Molecular Analysis for Characterizing Transgenic Events. AB - To develop a commercial trait product, a large number of transgenic events are often produced to obtain the event with desired level of expression. It is crucial to develop efficient and sensitive molecular characterization methods to advance events with stable transgene expression, free of vector backbone sequences and without major changes to the native genome caused by transgene insertion. Here, we discuss a variety of analytical tools, including quantitative PCR (qPCR), Southern blot analysis, and various sequencing technologies, which have been widely used to determine the insert copy number, presence/absence of vector backbone sequences, integrity of the T-DNA, and genomic location of the T DNA insertion. Moreover, since the discovery of RNA interference in 1998 (Fire et al., Nature 391:806-811, 1998), RNAi has emerged as another powerful tool in in the development of a new transgenic trait for insect control. RNAi creates a double-stranded RNA duplex as the active molecule which forms a strong secondary structure, resulting in challenges for detection. In addition to molecular analysis at the DNA level, this chapter describes detection methods of the active molecules (i.e., double-stranded RNA) for RNAi-based traits. PMID- 30415349 TI - Detection of Transgenic Proteins by Immunoassays. AB - Rapid development and global cultivation of genetically modified (GM) crops necessitated the use of analytical tools that detect GM crops throughout the product life cycle. Antibody-based immunoassays such as enzyme-linked immunosorbent assays (ELISA) are instrumental in detecting protein expression in transgenic plants. These analytical tools are used throughout development, regulatory registration, commercialization, and stewardship of biotech products. Here we describe the Cry1F ELISA analytical method protocol, data generation and review, and troubleshooting of technical challenges. PMID- 30415350 TI - Systematic Evaluation of Field Crop Performance Using Modern Phenotyping Tools and Techniques. AB - The genetic improvement of field crops through plant breeding and genetic modification is highly dependent on understanding, measuring, selecting, and manipulating phenotypes. Most phenotypes result from the complex interaction of a crop's genetics with the environment and management practices in which that crop is grown. Linking gene to phenotype in field environments to create superior crop varieties can therefore be challenging, particularly for genetically complex traits that are difficult to measure. This chapter is designed to help readers overcome these difficulties by describing tools and techniques used in successful crop improvement programs. It provides methodologies that can be broadly applied across numerous situations irrespective of field crop, environment, modest financial resources, or other factors. The chapter's focus is primarily on small- and large-scale, replicated, research plot-based screening trials since these trials are crucial, ubiquitous, and costly for both public- and private-sector crop improvement programs. To ease the understanding of the protocols discussed, this chapter's materials and methods section is composed of ten subsections, with each subsection covering a critical portion of the field crop phenotyping process: regulatory, environmental, and safety considerations; trait identification and prioritization; environment characterization; field site selection; experimental design; field design, preparation, and management; crop and soil measurements; environmental monitoring; in-field data recording; and data management and analysis. PMID- 30415351 TI - MPBPK-TMDD models for mAbs: alternative models, comparison, and identifiability issues. AB - The aim of the present study was to evaluate model identifiability when minimal physiologically-based pharmacokinetic (mPBPK) models are integrated with target mediated drug disposition (TMDD) models in the tissue compartment. Three quasi steady-state (QSS) approximations of TMDD dynamics were explored: on (a) antibody target complex, (b) free target, and (c) free antibody concentrations in tissue. The effects of the QSS approximations were assessed via simulations, taking as reference the mPBPK-TMDD model with no simplifications. Approximation (a) did not affect model-derived concentrations, while with the inclusion of approximation (b) or (c), target concentration profiles alone, or both drug and target concentration profiles respectively deviated from the reference model profiles. A local sensitivity analysis was performed, highlighting the potential importance of sampling in the terminal pharmacokinetic phase and of collecting target concentration data. The a priori and a posteriori identifiability of the mPBPK TMDD models were investigated under different experimental scenarios and designs. The reference model and QSS approximation (a) on antibody-target complex were both found to be a priori identifiable in all scenarios, while under the further inclusion of QSS approximation (b) target concentration data were needed for a priori identifiability to be preserved. The property could not be assessed for the model including all three QSS approximations. A posteriori identifiability issues were detected for all models, although improvement was observed when appropriate sampling and dose range were selected. In conclusion, this work provides a theoretical framework for the assessment of key properties of mathematical models before their experimental application. Attention should be paid when applying integrated mPBPK-TMDD models, as identifiability issues do exist, especially when rich study designs are not feasible. PMID- 30415352 TI - Cardiac effects of CPAP treatment in patients with obstructive sleep apnea and atrial fibrillation. AB - PURPOSE: Obstructive sleep apnea (OSA) has been recognized as an independent risk factor for the development and progression of atrial fibrillation (AF). We aimed to investigate the changes in heart rate and atrial and ventricular ectopy after continuous positive airway pressure (CPAP) treatment in patients with OSA and AF. METHODS: Consecutive patients with AF underwent ambulatory sleep monitoring, and OSA was defined as an Apnea-Hypopnea-Index (AHI) >= 5/h. Treated patients completed in-laboratory CPAP titration study. A 24-h ECG Holter was performed at baseline and at 3 and 6 months after CPAP treatment. RESULTS: One hundred patients (70% males) with AF were included in the final analysis. OSA was diagnosed in 85% of patients. There were no significant changes in mean 24-h heart rate in patients with paroxysmal or permanent AF at 3 and 6 months of treatment compared to baseline. In patients with paroxysmal AF (n = 29), atrial and ventricular ectopy counts/24 h significantly decreased at 3 months compared to baseline (median (IQR) 351 (2049) to 57 (182), P = 0.002; 68 (105) to 16 (133), P = 0.01 respectively). At 6 months follow-up, the atrial ectopy count/24 h significantly decreased in patients with paroxysmal AF compared to baseline (median (IQR) 351 (2049) to 31 (113), P = 0.016, n = 14). In patients with permanent AF (n = 15), there was a significant reduction in ventricular ectopy count/24 h at 3 months compared to baseline (median (IQR) 100 (1116) to 33 (418), P = 0.02). CONCLUSIONS: There is a significant decrease in atrial and ventricular ectopy count/24 h in patients with AF and OSA at 3 and 6 months of CPAP treatment compared to baseline. PMID- 30415353 TI - Surface Molecularly Imprinted Carbon Dots Based Core-Shell Material for Selective Fluorescence Sensing of Ketoprofen. AB - In this work, we report an environment friendly core-shell material based on Carbon Dot core and Molecularly Imprinted Polymer shell as sensor for highly selective fluorescence detection of ketoprofen. The Carbon Dots (CDs) were prepared by a hydrothermal method and the polymer layer around the CDs core was synthesised by sol-gel polymerisation. The prepared material was characterized by Fluorescence Spectroscopy, FT-IR Spectroscopy and Transmission Electron Spectroscopy (TEM). Fluorescence from the Carbon Dots- Molecularly Imprinted Polymer (CDs-MIP) was found to quench selectively in the presence of ketoprofen and quenching effect was found to be greater than for Non-Imprinted Polymer (CDs NIP) which indicated the potential of CDs-MIP as a fluorescence sensing material for ketoprofen. The imprinting factor was obtained to be 2.35. Under optimized conditions, a linear response was obtained in the concentration range from 0.039 to 3.9 MUM with a detection limit of 0.01 MUM. The correlation coefficient was 0.999. The developed sensor was applied to determination of ketoprofen in human serum and urine samples with good recoveries ranging from 96 to 104% indicating successful application of the proposed sensor in biological fluids. PMID- 30415354 TI - Impact of Bariatric Surgery on the Pharmacokinetics Parameters of Amoxicillin. AB - BACKGROUND: Bariatric surgery leads to several anatomo-physiological modifications that may affect pharmacokinetic parameters and consequently alter the therapeutic effect of drugs, such as antibiotics. The pharmacokinetics of oral amoxicillin after Roux-en-Y gastric bypass (RYGB) surgery is unknown. OBJECTIVES: The objective of this study was to evaluate the impact of bariatric surgery on the pharmacokinetics of amoxicillin. METHODS: This study was performed as a randomized, open-label, single-dose clinical trial, with two periods of treatment, in which obese subjects (n = 8) received an amoxicillin 500 mg capsule orally before and 2 months after the RYGB surgery. The amoxicillin plasma concentration was determined by liquid chromatography coupled to mass spectrometry (LC-MS/MS). RESULTS: After the surgery, the mean weight loss was 17.03 +/- 5.51 kg, and mean body mass index (BMI) decreased from 46.21 +/- 2.82 to 38.82 +/- 3.32 kg/m2. The mean amoxicillin area under the plasma concentration versus time curve from time zero to the time of the last quantifiable concentration (AUC0-tlast) increased significantly (3.5-fold); the maximum plasma concentration (Cmax) increased 2.8-fold after the bariatric surgery. No correlation was found between amoxicillin absorption, BMI, and weight loss percentage. CONCLUSION: The alterations observed in the amoxicillin pharmacokinetics suggest that obese subjects included in this trial had a substantially increase in amoxicillin systemic exposure after RYGB surgery. However, despite this increase, its exposure was lower than the values reported for non-obese volunteers. TRIAL REGISTRATION: Identifiers: NCT03588273. PMID- 30415355 TI - An In Vitro Model for Conditioning Lesion Effect. AB - Axons of a peripheral nerve grow faster after an axotomy if it attains a prior injury a few days earlier. This is called conditioning lesion effect (CLE) and very much valued since it may provide new insights into neuron biology and axonal regeneration. There are established in vivo experimental paradigms to study CLE, however, there is a need to have an in vitro conditioning technique where CLE occurs in a maximally controlled environment. Mouse primary sensory neurons were isolated from lumbar 4-5 dorsal root ganglia and incubated at 37 degrees C on a silicon-coated watch glass that prevents cell attachment. After this conditioning period they were transferred to laminin coated culture dishes. Similar cultures were set up with freshly isolated neurons from control animals and from the animals that received a sciatic nerve cut 3 days earlier. All preparations were placed on a live cell imaging microscopy providing physiological conditions and photographed for 48 h. Axonal regeneration and neuronal survival was assessed. During the conditioning incubation period neurons remained in suspended aggregates and did not grow axons. The regeneration rate of the in vitro conditioned neurons was much higher than the in vivo conditioned and control preparations during the first day of normal incubation. However, higher regeneration rates were compromised by progressive substantial neuronal death in both types of conditioned cultures but not in the control preparations. By using neutralizing antibodies, we demonstrated that activity of endogenous leukemia inhibitory factor is essential for induction of CLE in this model. PMID- 30415356 TI - Letter to the Editor Regarding: A Comprehensive Review on Copemyl(r). PMID- 30415357 TI - Patient and Physician Perspectives in a Case of Severe Traumatic Brain Injury. AB - Traumatic brain injury is a challenge for general practitioners and specialists worldwide due to the heterogeneous clinical picture, secondary injuries and complex treatment including surgery, medication, intensive care, nutrition and rehabilitation. This case report is about a TBI patient with a score of four on the Glasgow Coma Scale when she was transferred from the primary hospital to our center. Her condition, treatment options and expectations were discussed with the relatives. The patient was subjected to surgery and received pharmacologic intervention including a neurotrophic drug and extensive rehabilitation measures including occupational therapy. Considering the patient's remarkable recovery, a combination of multiple treatment approaches seems promising in patients with severe traumatic brain injury. PMID- 30415358 TI - Authors' Response to the Letter to the Editor Regarding: A Comprehensive Review on Copemyl(r). PMID- 30415359 TI - Helicobacter pylori Infection: New Facts in Clinical Management. AB - PURPOSE: The global prevalence of Helicobacter pylori remains high in spite of its significant downwards trajectory in many regions. The clinical management of H. pylori infection merits guidance to meet ongoing challenges on whom and how to test, prevent, and cure related diseases. RECENT FINDINGS: Several international guidelines and consensus reports have updated the management strategies for cure of the H. pylori infection. The definition of H. pylori gastritis as an infectious disease independent of whether or not presenting with clinical manifestations and symptoms has broadened the use of the test and treat strategy. Patients on selected long-term medications, such as aspirin, other anti-platelet agents, NSAIDs, and PPIs should be considered for H. pylori test and treat. Important progress is made with initiatives in primary and secondary gastric cancer prevention. Uncertainties persist in the interpretation of the role of H. pylori in association with extragastric diseases. Selection of therapies needs to address individual antibiotic resistance and regional surveillance of resistance for the adoption of an effective treatment algorithm. CONCLUSION: Clinical aspects of H. pylori infection have evolved over time and the therapeutic management requires continuous adaptation. A vaccine is still a non-fulfilled promise. The future will tell us more about the role of H. pylori in interactions with the gut microbiome. PMID- 30415360 TI - Assessment of soil buffer capacity on nutrients and pharmaceuticals in nature based solution applications. AB - The ability of a soil to sustain infiltration rates and to attenuate pollutants is critical for the design and operation of Managed Aquifer Recharge/Soil Aquifer Treatment and phyto-treatment schemes, also referred to as "Blue Infrastructures". We investigated the buffering capacity of a sediment sample and a peat soil sample for nutrients and selected pharmaceutical compounds and its evolution under continuous infiltration of secondary treated wastewater (TWW) in column experiments. Samples were obtained from two blue infrastructures, the Sant'Alessio Induced River Bank Filtration plant and the San Niccolo large-scale phyto-treatment plant in Italy, and were mainly different in their organic carbon contents (0.9 and 48%, respectively). In the column experiments, a constant infiltration rate of about 0.5 L/d was maintained for 6 months. After 4 months of operation, diclofenac and carbamazepine were spiked into the TWW to evaluate their fate. Water quality was monitored by periodic water sampling from the column inflow, at sampling ports along the column length, and at the outflow. Hydraulic conductivity (K) was also monitored. The hydraulic conductivity of the Sant'Alessio sediment decreased by a factor of 10 during the first 10 days of infiltration and then stabilized, while for the San Niccolo K (initially lower) remained constant for 50 days until it decreased following a change of the redox condition in the column. The different redox conditions, due to the two different soils tested, influenced also the concentration and mobility of PO43-, Fe, Mn, and NPOC, and the speciation of the redox sensitive elements (nitrogen and sulfur). NOPC and phosphate were enriched during the filtration through San Niccolo peat soil (from 2 to 4 times, respectively), while they were buffered by the Sant'Alessio sediment (from 0.2 to 0.4 times, respectively). Diclofenac removal (69% and below 20% for San Niccolo and Sant'Alessio, respectively) was related to sorption and degradation processes and it was lower than the removal of carbamazepine in both soils (76 and 35%). The buffer capacity differences between the two soils were higher for diclofenac (62%) than carbamazepine (35%). Nevertheless, since no apparent degradation of carbamazepine was detected in both soils, its persistence in the soil may have a larger impact in case of desorption, posing contamination risk to groundwater. The results highlight the importance of the soils or sediments to be used as medium in such nature-based solutions for their operations. They also offer an approach to, e.g., tailor man made soil layers in infiltration basins. We strongly suggest that soil characteristics and test duration are carefully considered in designing these infrastructures, when nature-based processes are the choice for dealing with reuse of treated wastewater management issues. PMID- 30415361 TI - The remediation potential and kinetics of cadmium in the green alga Cladophora rupestris. AB - This study determined the subcellular distribution, chemical forms, and effects of metal homeostasis of excess Cd in Cladophora rupestris. Biosorption data were analyzed with Langmuir and Freundlich adsorption models and kinetic equations. Results showed that C. rupestris can accumulate Cd. Cd mainly localized in the cell wall and debris (42.8-68.2%) of C. rupestris, followed by the soluble fraction (22.1-38.4%) observed in C. rupestris. A large quantity of Cd ions existed as insoluble CdHPO4 complexed with organic acids, Cd(H2PO4)2, Cd phosphate complexes (FHAC) (43.2-56.0%), and pectate and protein-integrated Cd (FNaCl) (30.8-43.2%). The adsorption data were well fitted by the Freundlich model (R2 = 0.933) and could be described by the pseudo-second-order reaction rate (R2 = 0.997) and Elovich (R2 = 0.972) equations. Related parameters indicated that Cd adsorption by C. rupestris is a heterogeneous diffusion. Cd promoted Ca and Zn uptake by C. rupestris. Cu, Fe, Mn, and Mg adsorption was promoted by low Cd concentrations and inhibited by high Cd concentrations. Results suggested that cell wall sequestration, vacuolar compartmentalization, and chemical morphological transformation are important mechanisms of Cd stress tolerance by C. rupestris. This study suggests that C. rupestris has bioremediation potential of Cd. PMID- 30415363 TI - Pb2+ adsorption by a compost obtained from the treatment of tobacco from smuggled cigarettes and industrial sewage sludge. AB - The adsorption of Pb2+ by a compost obtained from the treatment of tobacco from smuggled cigarettes (SCT) and industrial sewage sludge (ISS) was investigated. The Pb2+ adsorption process was evaluated as function of different concentrations of adsorbent and adsorbate, pH variations, and contact time. Fourier transformed infrared spectroscopy (FTIR) and energy dispersive X-ray spectrometry (EDX) were adopted to obtain information regarding structural changes and a better understanding of the adsorption mechanism. The adsorbent maximum adsorption capacity for Pb2+, calculated using the Sips equation, was 21.454 mg/g with 3 g/L adsorbent at pH 5. The adsorption kinetics best adjustment was obtained using the pseudo-second-order model with a time of 240 min to reach the adsorption equilibrium. FTIR and EDX results suggest that Pb2+ might have bonded to phenolic, carboxylic, hydroxyl, and amine groups; they also show formation of organometallic complexes and cationic exchange between the compost and the solution. The study confirmed that the compost evaluated can be used as a potential adsorbent in environments contaminated with Pb2+. PMID- 30415362 TI - Determining the effects of aeration intensity and reactor height to diameter (H/D) ratio on granule stability based on bubble behavior analysis. AB - Aerobic granular sludge was considered as a leading wastewater technology in the next century. However, the loss of granule stability limited the application of this promising biotechnology. Increasing aeration intensity and height to diameter (H/D) ratio were conventional strategies to enhance granule stability. In this study, hydraulic effects of aeration intensity and H/D ratio were explored basing on bubble behavior analysis. However, results revealed that due to viscous resistance, increasing aeration intensity and H/D ratio had limited effects on enhancing hydraulic shear stress, not to mention the extra operation and construction cost. A deflector component was further applied to regulate hydraulic shear stress on large granules under low aeration intensity and H/D ratio. Hydraulic shear stress of large granules was constantly around 3.0 times higher than that in the conventional reactor, resulting in higher percentage of granules within optimal size range (81.95 +/- 5.13%). A high abundance of denitrifying bacteria was observed in reactors, which led to high TN removal efficiency of 88.6 +/- 3.8%. PMID- 30415364 TI - Highly dispersed core-shell iron nanoparticles decorating onto graphene nanosheets for superior Zn(II) wastewater treatment. AB - This study reports the preparation of highly dispersed nanoscale zerovalent iron (nZVI) with core-shell structure decorated onto graphene nanosheets (Gr-NS) to form nZVI-Gr-NS composite. Meanwhile, its excellent performance for concentrated Zn(II) wastewater treatment is also studied. The adsorption of Zn(II) onto nZVI Gr-NS is well simulated by the pseudo-second-order model, which indicates the adsorption is the rate-controlling step. Moreover, the adsorption isotherms of Zn(II) on the nZVI-Gr-NS can fit well with the Langmuir model. The negative thermodynamic parameters (?GO, ?HO, ?SO) calculated from the temperature dependent isotherms indicate that the sorption reaction of Zn(II) is an exothermic and spontaneous process. The high saturation magnetization (37.4 emu g 1) of the nZVI-Gr-NS makes separation of nZVI-Gr-NS-bound Zn(II) easily and quickly from aqueous solution. Most importantly, nZVI-Gr-NS composites not only remove Zn(II) but also spontaneously remove As, Se, and Cu ions from real smelting wastewater samples. This study provides a good solution for heavy metal removal in real wastewater. PMID- 30415365 TI - Structural decomposition analysis of embodied carbon in trade in the middle reaches of the Yangtze River. AB - The middle reaches of the Yangtze River are the first demonstration zone for low carbon urbanization in the midwest regions of China, and the division of carbon emission reduction responsibility is an important aspect of construction of ecological civilization. In this paper, the embodied carbon emissions in trade are estimated by using an input-output model in the middle reaches of the Yangtze River, and then a structural decomposition analysis (SDA) model is further applied to conduct decomposition analysis on factors of embodied carbon changes. Our primary findings show the following: (1) Production-based CO2 emissions from Hubei and Hunan are higher than consumption-based CO2 emissions. There are situations in Jiangxi and Anhui where production-based CO2 emissions are both higher and lower than consumption-based CO2 emissions. However, inter-regional trade implied carbon is dominated by net inflows. Moreover, the inter-regional embodied carbon emissions in trade mainly flow out to relatively developed regions, such as Jiangsu and Shanghai. The inflow of embodied carbon in trade comes mainly from relatively backward economic development areas, such as Shaanxi and Inner Mongolia. (2) From the perspective of industry, industries in Jiangxi and Anhui are dominated by net inflow, whereas industries in Hunan and Hubei are dominated by net outflow. Meanwhile, industry in the middle reaches of the Yangtze River displays a high carbon-locked phenomenon. Specifically, the high carbon-locked outflow industries are mainly concentrated in the transportation and warehousing industry, agriculture, and the chemical industry, and the outflow provinces flow out mainly to Jiangsu, Guangdong, and other economically developed regions; high carbon-locked inflows are concentrated in metal smelting and rolling processing, food manufacturing and tobacco processing, and construction, and the provinces are mainly Hebei, Henan, and Inner Mongolia, where economic development is lacking. (3) Furthermore, the results of SDA decomposition indicate that scale effect is generally the most important factor leading to embodied carbon outflow. Meanwhile, the energy carbon emission effect, the energy intensity effect, and the structural effect are important factors-the inter industry association effect mainly promotes the embodied carbon outflow. Consequently, based on the distinction between production and consumer responsibility, and from the perspective of scale effect and structural effect, the related policy suggests that consumers should be held responsible. PMID- 30415366 TI - Heavy-metal concentrations in feathers of cinereous vulture (Aegypius monachus L.) as an endangered species in Turkey. AB - The aim of this study is to find out the certain heavy-metal levels in the feathers of cinereous vulture (Aegypius monachus L.), which is a threatened species. The feathers of the cinereous vultures were collected from the breeding areas in Sundiken and Turkmenbaba Mountains. To avoid misleading results, vanes and calamuses of the rectrices were evaluated separately in terms of their As, Cd, Cr, Cu, Hg, Ni, Pb and Zn contents. ICP-OES was used to analyse the metal levels in feathers which belonged to 43 different individuals. All of the heavy metal concentrations except for Cu were higher in vanes than in calamuses. The mean levels of Cd (0.254 +/- 1.589 MUg/g d.w. in the calamus and 0.334 +/- 0.156 MUg/g d.w. in the vane), Cr (6.536 +/- 6.378 MUg/g d.w. in the vane), Ni (11.886 +/- 10.891 MUg/g d.w. in the vane) and Pb (5.671 +/- 3.884 MUg/g d.w. in the vane) exceeded the threshold values for the birds. As a result, we recommend further studies to understand the effects of the heavy metals on the population of the species. PMID- 30415367 TI - A more fine-grained measure towards animal welfare: a study with regards to gender differences in Spanish students. AB - The environmental issue is nowadays taking more importance in the environmental awareness all around the world, and in this field, animal consideration is more and more spread. A highlighted part in globalisation is the animal welfare awareness. This article presents a study comparing attitudes towards animals among secondary and university students in reference to gender. It was carried out on 1394 Spanish participants from 11 to 26 years. The instrument used in the study is the reviewed version of the Animal Welfare Attitude Scale which was renamed as "Animal Welfare Attitude-Revised Scale" (AWA-R Scale), with a Cronbach alpha reliability value of 0.85. It is subdivided into four components namely C1: animal abuse for pleasure or due to ignorance; C2: leisure with animals; C3: farm animals; and C4: animal abandonment. These components have been deeply detailed by a confirmatory factor analysis (CFA), which highly contributes to define the position of participants for the different dimensions of animal welfare. It is concluded that significant differences exist between males' and females' attitudes in all components of the AWA-R Scale. It is also suggested that two social characteristics-people's attitudes towards animals and towards environmental protection-are, at the very least, coexistent and may indeed be interdependent. These differences between gender in matters of socialisation could thus be reflected in environmental attitudes, and also in others related to them, i.e. animal welfare attitudes. PMID- 30415368 TI - Vertical distribution of fluorine in farmland soil profiles around phosphorous chemical industry factories. AB - High concentration of fluorine (F) in agricultural soils has got significant attention considering its impacts on human health, but little information was available about F distribution in farmland soil profiles around phosphorous chemical industry factories. In present study, farmland soil profiles and relevant medium samples were collected from farmlands around a main phosphorous chemical base in southwest China. At 0-100-cm profiles, concentrations of soil total F (Ft, 400.9-1612.0 mg kg-1) and water soluble F (Fw, 3.4-26.0 mg kg-1) decreased with profile depth in industrial areas. Industrial activities enhanced F concentration in soil mainly at 0-40-cm profiles. No disparity for both Ft and Fw distributions in paddy-dry land rotation field and dry land indicates short term land utilization could not affect the F distribution in soil profiles. Correlation analysis showed soil organic matter and wind direction were important factors influencing the distribution of F in soil profiles. The shutdown of factory and government control of industrial emissions effectively decreased the ambient air F (Fa) concentrations in industrial areas. In where Fa and dustfall F concentrations were high, high soil Ft, Fw, and crop edible part F concentrations were found. PMID- 30415369 TI - Adsorption and desorption cycles of reactive blue BF-5G dye in a bone char fixed bed column. AB - In the textile industry, the amount of dye unfixed in fabrics is discarded with wastewaters. Effluents of this nature can be treated efficiently by adsorption on activated bone char, but the reuse of adsorbent is necessary for the technique to be economically feasible. Therefore, the objective of this work was to study the process of desorption of BF-5G blue dye from a bone char fixed-bed column. Solutions of sodium chloride, acetic acid and ethyl alcohol were tested as regenerating agents. Due to the hydrophobicity effect of organic solvent molecules, the highest desorption capacity was observed for ethyl alcohol solution, and the fixed bed was reused after six cycles of adsorption. The other solutions did not promote significant desorption. The results showed that adsorption of the dye involved irreversible interactions between adsorbate molecules and bone char. However, the use of acetic acid solution resulted in the neutralisation of some of the adsorbent surface charges, allowing the fixed bed to operate for a longer time in the second cycle than in the first. PMID- 30415370 TI - Improving one-dimensional pollution dispersion modeling in rivers using ANFIS and ANN-based GA optimized models. AB - Simulation and prediction of the pollution transport is one of the major problems in environmental and rivers engineering studies. The numerical tools have been used in simulation of the concentration profile transmission for description of river water quality. The one-dimensional advection-dispersion equation (ADE) is used in applied water quality modeling and requires the accurate estimation of longitudinal dispersion coefficient (Dx). This paper develops a hybrid numerical intelligence model for dispersion modeling in open-channel flows. The main contribution of this paper is to improve the results of 1D numerical simulation of pollutant transport in steady flows by estimation of dispersion coefficient (Dx) based on artificial intelligence models and subset selection of maximum dissimilarity (SSMD). The developed hybrid model uses an intelligence module based on optimized adaptive neuro fuzzy inference system (ANFIS) and artificial neural networks (ANNs) for longitudinal dispersion estimation, in which their structures are optimized by genetic algorithm (GA). Intelligence estimates of Dx by ANN, ANFIS, ANFIS-GA, ANN-GA, multiple linear regression (MLR), and empirical equation are compared with observed values of Dx available in 505 river section, and the ANFIS-GA, as the most accurate, is incorporated and integrated with developed 1D-ADE numerical module. The numerical solution of 1D-ADE is done using physically influenced scheme (PIS) for face flux estimation in finite volume method. The performance of hybrid models PIS-ANFIS-GA, PIS-ANFIS, and PIS empirical is compared using the R2, RMSE, MAE, and NSE values in comparison with analytical solution and measured concentration hydrographs. The results revealed that the hybrid numerical-intelligence model is more accurate than the other classical methods for sediment/pollutant dispersion prediction in open-channel flows. The developed hybrid numerical-intelligence model can accurately simulate the dispersion processes in rivers and is a novel step in applicability of ANFIS GA and ANN-GA models. Graphical abstract ?. PMID- 30415373 TI - A Case of Acute Pemphigus Vulgaris Relapses Associated with Cocaine Use and Review of the Literature. AB - Pemphigus is a bullous autoimmune disease that affects the skin and mucous membranes. It is very difficult to establish the etiology and the triggering factors that influence reactivations in pemphigus vulgaris (PV). The case of a 33 year-old male with chronic history of intranasal cocaine consumption is presented in this report. We present the clinical case of the patient, followed for a total of 86 weeks, with ten relapses secondary to probable cocaine use. The patient was admitted to the emergency department after presenting polymorphic dermatosis characterized by blisters, vesicles, and excoriations extending from the oral cavity to the thorax, and to the inguinal and genital regions, affecting approximately 35 % of the body surface area with a score of 56 on the Pemphigus Skin Disorder Index. Skin biopsies were compatible with PV diagnosis. The patient had clinical improvement with a combination of methylprednisolone 500 mg intravenously (IV) and cyclophosphamide 500 mg IV every 15 days, along with prednisone 50 mg orally (PO) q24 h and mycophenolic acid 500 mg PO q6 h. Persistent cocaine use is highly likely to be the factor triggering lesion reactivation and responsible for the torpid evolution. We cannot definitively conclude whether the change from azathioprine to mycophenolic acid after the tenth relapse was the adjuvant medication responsible for the end of the consolidation phase and complete remission on therapy. This case study could potentially serve as a guide for management of patients who continuously persist with cocaine use, leading to a clinical picture refractory to multiple therapeutic schemes. PMID- 30415372 TI - Seasonal variations in cardiac implantable electronic device infections. AB - Infections of cardiac implantable electronic devices (CIEDs) have increased over the past decade. However, the impact of the climate on CIED infections is unknown. To determine whether there is a seasonal variation in CIED infections. In this single-center observational study, retrospective analysis of prospectively collected data was performed. Timone Hospital in Marseille (south east France) is a tertiary care institution and the regional reference center for management of CIED infections. All consecutive patients with CIED extractions for infectious reasons were included over a 12-year period. We noted the mean temperature ( degrees C), precipitation (mm) and the incidence of CIED infections over this period. Among 612 patients [mean (standard deviation) age, 72.4 (13.0) years; 74.0% male], 238 had endocarditis alone (38.9%), 249 had pocket infection alone (40.7%), and 125 had both (20.4%). We found bacterial documentation in 428 patients (70.0%), commensal in 245 (40.0%). The incidence of CIED infections was positively associated with high temperature (regression coefficient = 0.075; P = 0.01) and precipitation (regression coefficient = 0.022; P < 0.01). Seasonal variation was specific of pocket infections, whether they were associated with endocarditis or not. Subgroups with infection seasonality were: women, elderly people (> 75 years), late CIED infection and skin commensal bacterial infections. We found a seasonal variation in pocket infections, whether associated with endocarditis or not. Infections were associated with elevated temperatures and precipitation. Therefore, specific prevention strategy should be discussed in high-risk patients. PMID- 30415374 TI - Anterior controllable antedisplacement fusion as a choice for 28 patients of cervical ossification of the posterior longitudinal ligament with dura ossification: the risk of cerebrospinal fluid leakage compared with anterior cervical corpectomy and fusion. AB - PURPOSE: To compare the incidence rate of cerebrospinal fluid (CSF) leakage between anterior controllable antedisplacement fusion (ACAF) and anterior cervical corpectomy and fusion (ACCF) in the treatment of ossification of the posterior longitudinal ligament (OPLL) with dura ossification (DO). METHODS: In the period from June 2015 to June 2017, ACAF and ACCF were performed on patients with OPLL with DO. Double-layer sign was observed on axial bone window of CT images. The operation duration, blood loss, and hospital stay were measured. Radiologic assessment included occupying rate, type and extent of OPLL, decompression width, postoperative area of the spinal canal, and anteroposterior diameter of the spinal cord. The JOA scoring system was used to evaluate the neurological status. Surgery-related complications such as CSF leakage and spinal cord or nerve injury were all recorded. RESULTS: There were 28 patients in ACAF group and 31 in ACCF group. On cross-sectional CT, decompression width and postoperative spinal canal area were both significantly larger in the ACAF group than that in the ACCF group (P < 0.01). The anteroposterior diameter of the spinal cord was significantly larger in the ACAF group (P < 0.05). Mean JOA score was better in the ACAF group (P < 0.05). In the ACCF group, seven (22.6%) patients had CSF leakage. However, only one (3.6%) presented with CSF leakage in the ACAF group. The difference of incidence rate of CSF leakage was significant (P < 0.01). CONCLUSIONS: ACAF, which can significantly reduce CSF leakage and achieve good neurological recovery, is a good option to treat cervical OPLL with DO. These slides can be retrieved under Electronic Supplementary Material. PMID- 30415375 TI - Mitochondrial dynamics and metastasis. AB - Changes in cellular metabolism are now a recognized hallmark of cancer. Although this process is ripe with therapeutic potential in the clinic, its complexity and extraordinary plasticity have systematically defied dogmas and oversimplifications. Perhaps, best exemplifying this intricacy is the role of mitochondria in cancer, which in just a few years has gone from largely unnoticed to pivotal disease driver. The underlying mechanisms are only beginning to emerge. However, there is now clear evidence linking the dynamic nature of mitochondria to the machinery of tumor cell motility and metastatic spreading. These studies may open fresh therapeutic options for patients with disseminated cancer, currently an incurable and mostly lethal condition. PMID- 30415376 TI - Awareness and Knowledge of Human Papilloma Virus and Cervical Cancer in Women with High Pap Uptake. AB - This cross-sectional study explored knowledge, awareness, and health practices surrounding cervical cancer prevention and screening. Patients (n = 129) were recruited from three community clinics of underserved populations in Dallas, Texas. Women between ages 18-65 were surveyed using a self-administered questionnaire to evaluate their knowledge, awareness, and attitudes related to pap tests, human papilloma virus (HPV), HPV vaccines, and cervical cancer. Most women reported having a pap test in the past 3-5 years (86.6%). Over half knew that there was an increased risk of cervical cancer with an HPV infection, abnormal pap test, or both (52%). However, less than half of women knew the purpose of a pap test (40%), the purpose of the HPV vaccine (48%), or the transmission mode of HPV (25%). Over half of participants first heard about a pap test from a doctor (60%), about one quarter from their mother (24%), and less than a quarter from others (16%). More than half of women were aware of HPV (55%), while less than half were aware of the HPV vaccine (48%). Overall, we found that while most women had a high uptake of pap tests, they had low knowledge of the purpose of a pap test, the HPV vaccine, and transmission mode of HPV. They also had low awareness of HPV and the HPV vaccine. Given that almost all cases of cervical cancer are due to HPV infection, future studies should aim to further explore the gap between knowledge and awareness of HPV and pap uptake. PMID- 30415377 TI - Children's Pain and Distress at a Public Influenza Vaccination Clinic: A Parent Survey and Public Observation Study. AB - Immunizations are a necessary but distressing and painful procedure that most infants and children regularly undergo. Each year, a tertiary pediatric hospital in Canada holds an influenza vaccination clinic for all staff and their families. Evidence-based interventions to reduce pain and distress in babies and children are used. Despite this, infants and children continue to be distressed throughout the vaccination procedure. The objectives of this study were to: (1) measure the prevalence of distress among infants and children before, during, and after vaccine administration at the clinic, and (2) evaluate parents' perception of their child(ren)'s distress before, during, and after vaccine administration and the effectiveness of pain management interventions used during the clinic. A cross-sectional design of naturalistic observation and parent surveys was used and data was analyzed using descriptive statistics. A total of 283 children between 6 months and 18 years were vaccinated at the clinic, with 52% observed to be distressed before, during, or after the procedure. There were 115 parents of 206 children that completed the survey; 47% of these parents perceived that their children were distressed before, during, or after vaccination, and 42% perceived that the pain treatments used for their child(ren) were very effective. The results of this study will continue to inform interventions for needle-related pain and distress management, as well as improvements for future public vaccination clinics. PMID- 30415378 TI - Learning in the absence of overt practice: a novel (previously unseen) stimulus can trigger retrieval of an unpracticed response. AB - Skilled performance is traditionally thought to develop via overt practice. Recent research has demonstrated that merely instructed stimulus-response (S-R) bindings can influence later performance and readily transfer across response modalities. In the present study, we extended this to include instructed category response (C-R) associations. That is, we investigated whether merely instructed C R bindings can trigger an unpracticed response (in a different modality) on perception of a novel (previously unseen) stimulus. In a learning-test design, participants had to classify stimuli by comparing them to perceptual category templates (Experiment 1) or semantic category descriptions (Experiment 2) presented prior to each block. During learning blocks, participants had to respond manually, respond vocally, or listen passively to the correct response being spoken. A manual response was always required at test. In test blocks, the categories could either be novel or repeated from the learning block, whereas half of the stimuli were always novel and half were always repeated from the learning block. Because stimulus and category repetitions were manipulated orthogonally, it was possible to directly compare the relative contribution of S R and C-R associations to performance. In Experiment 1, test performance was enhanced by repeating the C-R bindings independently of the stimulus. In Experiment 2, there was also evidence of an S-R repetition benefit independent of the classification. Critically, instructed associations formed in one response modality were robust to changes in the required response, even when no overt response was required during training, indicating the need to update the traditional view of associative learning. PMID- 30415379 TI - Effect of Congenital Heart Disease Status on Trends in Pediatric Infective Endocarditis Hospitalizations in the United States Between 2000 and 2012. AB - The purpose of this study was to create national estimates for the incidence of pediatric infective endocarditis (IE) in the United States and to determine if these changed after the implementation of the 2007 American Heart Association IE guidelines. It also sought to determine the effect of congenital heart disease (CHD) status on outcomes in IE. Hospital discharges with the diagnosis of IE in patients < 18 years old from the Kids' Inpatient Database were identified from the years 2000, 2003, 2006, 2009, and 2012. Discharges were grouped into Pre- and Post-2007 groups to facilitate analysis surrounding the implementation of the guidelines in 2007. Patients were categorized by age, underlying CHD, and etiologic organism. Descriptive comparisons and changes in categorical variables were made between groups. Average annual IE hospitalization rates before and after the 2007 guidelines were 10.8 and 9.3 per 1,000,000 children, respectively. The proportion of IE patients with CHD was stable between time periods, (45% vs. 47%, p = 0.50). Mortality was higher in the Post-2007 time period for CHD patients than non-CHD patients (11.1% vs. 2.4%, respectively; p < 0.001), while there was no difference noted during the Pre-2007 time period (6.5% vs. 6.6%, respectively; p = 0.95). Streptococcus was more common among CHD patients than non-CHD patients (27% vs. 17%), while Staphylococcus was more common among non CHD patients than CHD patients (34% vs. 24%, p < 0.001). Even though the incidence of IE was stable over time, mortality was higher in CHD patients after the implementation of the 2007 AHA IE prophylaxis guidelines. PMID- 30415380 TI - Ventricular Arterial Coupling: A Novel Echocardiographic Risk Factor for Disease Progression in Pediatric Dilated Cardiomyopathy. AB - In adult heart failure (HF) patients, a higher ventricular arterial (VA) coupling ratio measured non-invasively is associated with worse HF prognosis and response to treatment. There are no data regarding the relationship of VA coupling to outcome in pediatric dilated cardiomyopathy (DCM) patients. We investigated the association of VA coupling ratio with worse outcome (mechanical circulatory support, transplant, or death) in 48 children with DCM and 97 age-gender matched controls. Mean age at presentation was 9 +/- 7 years; DCM patients had a higher arterial elastance (3.8 +/- 1.7 vs 2.7 +/- 0.7 respectively p = 0.001), a lower LV elastance (1.1 +/- 0.65 vs 4.5 +/- 1.4, respectively p = 0.001) and higher VA coupling ratio (5.0 +/- 3.9 vs 0.34 +/- 0.14, respectively p = 0.001). Outcome events occurred in 27/48 (56%) patients. Patients with an outcome event had a higher NYHA class (p = 0.001), lower LV elastance (0.8 +/- 0.47 vs 1.6 +/- 0.57, respectively p = 0.001), higher arterial elastance (4.5 +/- 1.8 vs 2.9 +/- 1.1, respectively p = 0.002), and a higher VA coupling ratio (7.1 +/- 3.8 vs 2.2 +/- 1.5, respectively p = 0.001) compared to those without. In a multivariate CART analysis, VA coupling was the top and only discriminator of poor outcome. In conclusion, a higher VA coupling ratio is associated with worse outcome in pediatric patients with DCM. VA coupling is promising as a bedside analysis tool that may provide insight into the mechanisms of HF in pediatric DCM and identify potential targets for therapy. PMID- 30415381 TI - Birth Location of Infants with Critical Congenital Heart Disease in California. AB - The American Academy of Pediatrics classifies neonatal intensive care units (NICUs) from level I to IV based on the acuity of care each unit can provide. Birth in a higher level center is associated with lower morbidity and mortality in high-risk populations. Congenital heart disease accounts for 25-50% of infant mortality related to birth defects in the U.S., but recent data are lacking on where infants with critical congenital heart disease (CCHD) are born. We used a linked dataset from the Office of Statewide Health Planning and Development to access ICD-9 diagnosis codes for all infants born in California from 2008 to 2012. We compared infants with CCHD to the general population, identified where infants with CCHD were born based on NICU level of care, and predicted level IV birth among infants with CCHD using logistic regression techniques. From 2008 to 2012, 6325 infants with CCHD were born in California, with 23.7% of infants with CCHD born at a level IV NICU compared to 8.4% of the general population. Level IV birth for infants with CCHD was associated with lower gestational age, higher maternal age and education, the presence of other congenital anomalies, and the diagnosis of a single ventricle lesion. More infants with CCHD are born in a level IV NICU compared to the general population. Future studies are needed to determine if birth in a lower level of care center impacts outcomes for infants with CCHD. PMID- 30415382 TI - Z-Score Reference Ranges for Fetal Heart Functional Measurements in a Large Brazilian Pregnant Women Sample. AB - The objective of this study was to determine the reference values for fetal heart functional measurements at 24 and 34 weeks of gestation and to develop Z-score equations for all measurements. A single-center, prospective, cross-sectional study with normal fetuses between 24 and 34 weeks of gestation was performed. All pregnant women underwent a comprehensive fetal Doppler echocardiogram with anatomical and functional analysis. Measurements of left and right cardiac output, combined cardiac output, mitral and tricuspid valve flow, inferior vena cava flow, and pulmonary vein flow were performed. The Shapiro-Wilk test and histogram evaluation were performed on all variables. Linear regression was used to assess the relationships between measurements and gestational age. A total of 612 pregnant women with singleton and normal fetuses were included. We assessed the reference values and percentiles of cardiac function as a function of gestational age. The variables that were not normally distributed were subjected to logarithmic or square root transformation. Eleven Z-score equations were developed, with equations for left and right ventricle output and combined cardiac output that were dependent on gestational age and with other equations that were independent of gestational age. The present study produced a large database, allowing the demonstration of reference values and percentiles as well as the development of Z-score equations to facilitate the echocardiographic evaluation of fetal heart function. PMID- 30415383 TI - Transcriptome-based mining and expression profiling of Pythium responsive transcription factors in Zingiber sp. AB - Transcription factors (TFs) fine-tune the host defense transcriptome in response to pathogen invasions. No information is available on Zingiber zerumbet (Zz) TFs involved in defense response against Pythium myriotylum. Here, we provide a global identification, characterization, and temporal expression profiling of Zz TFs following an incompatible interaction with P. myriotylum using a transcriptome sequencing approach. We identified a total of 903 TFs belonging to 96 families based on their conserved domains. Evolutionary analysis clustered the Zz TFs according to their phylogenetic affinity, providing glimpses of their functional diversities. High throughput expression array analysis highlighted a complex interplay between activating and repressing transcription factors in fine tuning Zz defense response against P. myriotylum. The high differential modulation of TFs involved in cell wall fortification, lignin biosynthesis, and SA/JA hormone crosstalk allows us to envisage that this mechanism plays a central role in restricting P. myriotylum proliferation in Zz. This study lays a solid foundation and provides valuable resources for the investigation of the evolutionary history and biological functions of Zz TF genes involved in defense response. PMID- 30415384 TI - Single-centre experience on genotypic and phenotypic features of southern Brazilian patients with McArdle disease. AB - McArdle disease (MD) is a metabolic myopathy caused by deficiency of the myophosphorylase enzyme. The aim of our study was to analyse a series of MD patients in Brazil and the correlation between clinical findings, laboratory data, electromyography, muscle biopsy and genetic features. The PYGM gene was analysed by PCR/RLFP and Sanger sequencing. The sample included 12 patients, aged 18-57 years, from unrelated families. Exercise intolerance was present in all cases. Serum creatine kinase levels at rest were increased in all patients. Forearm ischaemic exercise testing in five patients revealed no increase in venous lactate. Needle electromyography presented 'myopathic pattern' in six patients. Muscle biopsy showed vacuolar myopathy in 10 patients and deficiency of myophosphorylase enzyme in all patients. The genetic analysis showed p.R50X as the most common mutation (allelic frequency: 56.25%), other known mutations (p.Y574X, p.G205S, p.W798R, IVS14 + 1G > A and IVS19-1G > A) and a new mutation (p.Asn168Lysfs*15) were also identified. Several features of the disorder were similar to the vast majority of patients worldwide. The genetic findings of this study revealed a range of mutations that are quite similar to the European cohort. The discovery of one novel mutation increases the genotypic heterogeneity of PYGM gene. PMID- 30415385 TI - Hotspots of small strokes in glioma surgery: an overlooked risk? AB - BACKGROUND: Small deep infarcts constitute a well-known risk of motor and speech deficit in insulo-opercular glioma surgery. However, the risk of cognitive deterioration in relation to stroke occurrence in so-called silent areas is poorly known. In this paper, we propose to build a distribution map of small deep infarcts in glioma surgery, and to analyze patients' cognitive outcome in relation to stroke occurrence. METHODS: We retrospectively studied a consecutive series of patients operated on for a diffuse glioma between June 2011and June 2017. Patients with lower-grade glioma were cognitively assessed, both before and 4 months after surgery. Areas of decreased apparent diffusion coefficient (ADC) on the immediate postoperative MRI were segmented. All images were registered in the MNI reference by ANTS algorithm, allowing to build a distribution map of the strokes. Stroke occurrence was correlated with the postoperative changes in semantic fluency score in the lower-grade glioma cohort. RESULTS: One hundred fifteen patients were included. Areas of reduced ADC were observed in 27 out of 54 (50%) patients with a lower-grade glioma, and 25 out of 61 (41%) patients with a glioblastoma. Median volume was 1.6 cc. The distribution map revealed five clusters of deep strokes, corresponding respectively to callosal, prefrontal, insulo-opercular, parietal, and temporal tumor locations. No motor nor speech long-term deficits were caused by these strokes. Cognitive evaluations at 4 months showed that the presence of small infarcts correlated with a slight decrease of semantic fluency scores. CONCLUSION: Deep small infarcts are commonly found after glioma surgery, but their actual impact in terms of patients' quality of life remains to be demonstrated. Further studies are needed to better evaluate the cognitive consequences-if any-for each of the described hotspots and to identify risk factors other than the surgery-induced damage of microvessels. PMID- 30415386 TI - Risk factors for growth of conservatively managed unruptured intracranial aneurysms. AB - PURPOSE: Unruptured intracranial aneurysms (UIAs) occur in 2-3% of the adult population, but, once discovered, do not always require treatment. Untreated patients are usually followed with serial imaging to identify interval growth. In this study, we assessed the risk and risk factors for growth in a homogenous series of patients with conservatively managed UIAs. METHODS: Data from consecutive patients without history of subarachnoid hemorrhage and a conservatively managed UIA were retrospectively reviewed and only patients with at least 2 years of radiological follow-up were included in our study. We evaluated patients for the incidence of UIA growth, as well as analyzed risk factors for UIA growth. RESULTS: In 349 patients and 385 conservatively managed UIAs with 2210 patient-years of radiological follow-up, the risk of growth was 2.9% per aneurysm-year. Size (diameter greater than 5 mm), location (basilar artery apex), and weight loss (decrease in BMI over follow-up period) were all significantly associated with increased risk of UIA growth. There was a greater risk of UIA growth during the first 3 years of follow-up (7.5% per aneurysm-year) compared to the remaining years (2.7% per aneurysm-year). CONCLUSIONS: Conservatively managed UIAs in patients without prior history of SAH have a 2.9% risk of growth per aneurysm-year. UIAs greater than 5 mm in diameter, those located at the basilar artery apex, or patients who experience a decrease in BMI are more likely to grow and warrant closer follow-up. The risk of aneurysm growth is increased in the few years after diagnosis and decreases afterward. PMID- 30415387 TI - Tendon morphology and mechanical properties assessed by ultrasound show change early in recovery and potential prognostic ability for 6-month outcomes. AB - PURPOSE: Optimizing tendon structural recovery during the first 12 weeks after Achilles tendon rupture is a prime target to improve patient outcomes, but a comprehensive understanding of biomarkers is needed to track early healing. The purpose of this study was to observe healing of tendon structure over time using ultrasound-based, tendon-specific measures and to identify relationships between tendon structural characteristics and clinical measures of gait and strength. METHODS: Twenty-seven participants (21 males, mean (SD) age 39 (11) years) were assessed at 4, 8, 12, and 24 weeks after injury or surgery using ultrasound imaging techniques. Gait analysis and strength testing were added at the later time points. RESULTS: Ruptured tendons had significantly lower dynamic shear modulus (p < 0.001), greater tendon cross-sectional area (p < 0.001), and greater length (p < 0.001) than the uninjured side. Dynamic shear modulus, cross sectional area, and length were found to increase over time (p < 0.01). Tendon structure at 4 weeks post-injury [cross-sectional area symmetry (r = 0.737, p = 0.002) and dynamic shear modulus (r = 0.518, p = 0.040)] related to stance phase walking symmetry at 24 weeks. CONCLUSIONS: Tendon structure assessed by ultrasound imaging changes over the first 24 weeks of healing after Achilles tendon rupture, suggesting it could be used as a biomarker to track tendon healing early in recovery. Additionally, tendon structure within the first 12 weeks relates to later walking gait and heel-rise symmetry, which may indicate that tendon structure could have prognostic value in the care of these patients. This study's clinical relevance is in its support for using ultrasound imaging to assess early patient healing and prognosticate later patient outcomes after Achilles tendon rupture. LEVEL OF EVIDENCE: Level 2, prospective cohort prognostic study. PMID- 30415388 TI - Lower limb alignment becomes more varus and hyperextended from supine to bipedal stance in asymptomatic, osteoarthritic and prosthetic neutral or varus knees. AB - PURPOSE: Knee alignment is a fundamental measurement in the assessment, monitoring and surgical management of patients with osteoarthritis. There is a lack of data regarding how static tibiofemoral alignment varies between supine and standing conditions. This study aimed to quantify the relationship between supine and standing lower limb alignment in asymptomatic, osteoarthritic (OA) and prosthetic (TKA) knees. METHODS: A non-invasive position capture system was used to assess knee alignment for 30 asymptomatic controls and 31 patients with OA both before and after TKA. Coronal and sagittal mechanical femorotibial angles were measured supine with the lower limb in extension and in bipedal stance. Changes between conditions were analysed using paired ttests. Vector plots of ankle centre displacement relative to the knee centre from supine to standing were produced to allow three-dimensional visualisation. RESULTS: All groups showed a trend towards varus and extension when going from supine to standing. Mean change for asymptomatic knees was 1.2 degrees more varus (p = 0.001) and 3.8 degrees more extended (p < 0.001). For OA knees this was 1.1 degrees more varus (p = 0.009) and 5.9 degrees more extended (p < 0.001) and TKA knees 1.9 degrees more varus (p < 0.001) and 5.6 degrees more extended (p < 0.001). CONCLUSION: The observed consistent changes in lower limb alignment between supine and standing positions across knee types suggests the soft tissue envelope restraining the knee may have a greater influence on dynamic alignment changes than the underlying bony deformity. This highlights the importance of quantifying soft tissue behaviour when planning, performing and evaluating alignment dependent surgical interventions of the knee. When routinely assessing any type of knee, clinicians should be aware that subtle consistent alignment changes occur under weightbearing conditions and tailor their treatments accordingly. LEVEL OF EVIDENCE: II. PMID- 30415389 TI - Genetic and antigenic dynamics of influenza A viruses of swine on pig farms in Thailand. AB - Surveillance studies of influenza A virus of swine (IAV-S) have accumulated information regarding IAVs-S circulating in Thailand, but how IAVs-S evolve within a farm remains unclear. In the present study, we isolated 82 A(H1N1)pdm09 and 87 H3N2 viruses from four farms from 2011 through 2017. We then phylogenetically and antigenically analyzed the isolates to elucidate their evolution within each farm. Phylogenetic analysis demonstrated multiple introductions of A(H1N1)pdm09 viruses that resembled epidemic A(H1N1)pdm09 strains in humans in Thailand, and they reassorted with H3N2 viruses as well as other A(H1N1)pdm09 viruses. Antigenic analysis revealed that the viruses had acquired antigenic diversity either by accumulating substitutions in the hemagglutinin protein or through the introduction of IAV-S strains with different antigenicity. Our results, obtained through continuous longitudinal surveillance, revealed that IAV-S can be maintained on a pig farm over several years through the generation of antigenic diversity due to the accumulation of mutations, introduction of new strains, and reassortment events. PMID- 30415390 TI - No detection of CD4-independent human immunodeficiency virus 1 envelope glycoproteins in brain tissue of patients with or without neurological complications. AB - Macrophage (mac)-tropic human immnunodeficiency virus type 1 (HIV-1) and simian immnunodeficiency virus (SIV) in brain are associated with neurological disease. Mac-tropic HIV-1 evolves enhanced CD4 interactions that enable macrophage infection via CD4, which is in low abundance. In contrast, mac-tropic SIV is associated with CD4-independent infection via direct CCR5 binding. Recently, mac tropic simian-human immunodeficiency virus (SHIV) from macaque brain was also reported to infect cells via CCR5 without CD4. Since SHIV envelope proteins (Envs) are derived from HIV-1, we tested more than 100 HIV-1 clade B Envs for infection of CD4-negative, CCR5+ Cf2Th/CCR5 cells. However, no infection was detected. Our data suggest that there are differences in the evolution of mac tropism in SIV and SHIV compared to HIV-1 clade B due to enhanced interactions with CCR5 and CD4, respectively. PMID- 30415391 TI - Discovery of three RNA viruses using ant transcriptomic datasets. AB - Three novel RNA viruses, named Formica fusca virus 1 (GenBank accession no. MH477287), Lasius neglectus virus 2 (MH477288) and Myrmica scabrinodis virus 2 (MH477289), were discovered in ants collected in Cambridge, UK. The proposed virus names were given based on the hosts in which they were identified. The genome sequences were obtained using de novo transcriptome assembly of high throughput RNA sequencing reads and confirmed by Sanger sequencing. Phylogenetic analysis showed that Formica fusca virus 1 grouped within the family Nyamiviridae, Lasius neglectus virus 2 grouped within the family Rhabdoviridae and Myrmica scabrinodis virus 2 belongs to the family Dicistroviridae. All three viruses are highly divergent from previously sequenced viruses. PMID- 30415392 TI - A novel T-cell epitope in the transmembrane region of the hepatitis B virus envelope protein responds upon dendritic cell expansion. AB - Restoring antiviral immunity is a promising immunotherapeutic approach to the treatment of chronic hepatitis B virus (HBV) infection. Dendritic cells play a crucial role in triggering antiviral immunity. In this study, we identified immunodominant epitopes prevalent in CD8+ T cell responses. We characterized the hierarchy of HBV epitopes targeted by CD8+ T cells following autologous monocyte derived dendritic cell (moDC) expansion in HBV-infected subjects with distinct disease stages: treatment-naive (TN group, n = 168), treatment with complete virological response (TR group, n = 72), and resolved HBV infection (RS group, n = 28). T cell responses against 32 HBV epitopes were measured upon moDC expansion. Several subdominant epitopes that triggered HBV-specific CD8+ T cell responses were identified. These epitopes' responses varied in individuals with different disease stages. Moreover, the most immunodominant and immunoprevalent epitope included the envelope residues 256-270 (Env256-270), corresponding to amino acid residues 93-107 in the small HBV surface protein (SHBs) across three patient groups. The frequency of Env256-270-specific interferon-gamma-producing T cells was the highest in the RS group and the lowest in the TN group. In addition, individuals with HLA-A*02:03/02:06/02:07 were capable of responding to Env256-270. Env256-270-specific CD8+ T cells tolerated amino acid variations within the epitope detected in HBV genotypes B and C. This suggests that Env256 270 in SHBs is crucial in HBV-specific T cell immunity following autologous moDC expansion. It might be a potential target epitope for dendritic-cell-based immunotherapy for CHB patients with complete viral suppression by long-term NAs treatment. PMID- 30415393 TI - Modified DWI-FLAIR mismatch guided thrombolysis in unknown onset stroke. AB - DWI-FLAIR mismatch has been recently proven to identify patients with unknown onset stroke (UOS) eligible for thrombolysis. However, this concept may exclude patients from thrombolysis who may eventually benefit as well. We aimed to examine the feasibility, safety and potential efficacy of thrombolysis in wake-up stroke (WUS) and UOS patients using a modified DWI-FLAIR mismatch allowing for partial FLAIR positivity. WUS/UOS patients fulfilling the modified DWI-FLAIR mismatch and treated with intravenous thrombolysis (IVT) were compared to propensity score matched WUS/UOS patients excluded from IVT due to FLAIR positivity. The primary endpoint was a symptomatic intracranial hemorrhage (SICH), the secondary endpoints were improvement of >= 4 in NIHSS score and mRS score at 3 months. 64 IVT-treated patients (median NIHSS 9) and 64 controls (median NIHSS 8) entered the analysis (p = 0.2). No significant difference in SICH was found between the IVT group and the controls (3.1% vs. 1.6%, p = 0.9). An improvement of >= 4 NIHSS points was more frequent in IVT patients as compared to controls (40.6% vs. 18.8%, p = 0.01). 23.4% of IVT patients achieved a mRS score of 0-1 at 3 months as compared to 18.8% of the controls (p = 0.8). SICH, improvement of NIHSS >= 4 and mRS 0-1 at 3 months were comparable in thrombolyzed patients with negative FLAIR images versus those thrombolyzed with partial positive FLAIR images (3% vs. 3%, p = 0.9; 40% vs. 41%, p = 0.9; 19% vs. 22%, p = 0.8). Our study signalizes that thrombolysis may be feasible in selected WUS/UOS patients with partial FLAIR signal positivity. PMID- 30415394 TI - An Eimeria acervulina OTU protease exhibits linkage-specific deubiquitinase activity. AB - Ubiquitination is an important post-translational modification process that regulates many cellular processes. Proteins can be modified at single or multiple lysine residues by a single ubiquitin protein or by ubiquitin oligomers. It is important to note that the type of ubiquitin chains determines the functional outcome of the modification. Ubiquitin or ubiquitin chains can be removed by deubiquitinases (DUBs). In our previous study, the Eimeria tenella ovarian tumour (Et-OTU) DUB was shown to regulate the telomerase activity of E. tenella and affect E. tenella proliferation. The amino acid sequences of Et-OTU (GenBank: XP_013229759.1) and Eimeria acervulina (E. acervulina) ovarian tumour (Ea-OTUD3) DUB (XP_013250378.1) are 74% identical. Although Et-OTU may regulate E. tenella telomerase activity, whether Ea-OTUD3 affects E. acervulina growth and reproduction remains unclear. We show here that Ea-OTUD3 belongs to the OTU domain class of cysteine protease deubiquitinating enzymes. Ea-OTUD3 is highly linkage-specific, cleaving K48 (Lys48)-, K63-, and K6-linked diubiquitin but not K29-, K33-, and K11-linked diubiquitin. The precise linkage preference of Ea OTUD3 among these three nonlinear diubiquitin chains is K6 > K48 > K63. Recombinant Ea-OTUD3, but not its catalytic-site mutant Ea-OTUD3 (C247A), exhibits activity against diubiquitin. Ea-OTUD3 removes ubiquitin from the K48-, but to a lesser extent from the K63-linked ubiquitinated E. acervulina proteins of the modified target protein, thereby exhibiting the characteristics of deubiquitinase. This study reveals that the Ea-OTUD3 is a novel functional deubiquitinating enzyme. Furthermore, the Ea-OTUD3 protein may regulate the stability of some K48-linked ubiquitinated E. acervulina proteins. PMID- 30415395 TI - Evaluation of an automated magnetic bead-based DNA extraction and real-time PCR in fecal samples as a pre-screening test for detection of Echinococcus multilocularis and Echinococcus canadensis in coyotes. AB - Efficient and sensitive diagnostic tools are essential for the study of the eco epidemiology of Echinococcus species. We evaluated an automated magnetic bead based DNA extraction commercial kit followed by qPCR (MB-qPCR), for the detection of Echinococcus multilocularis and Echinococcus canadensis in coyote (Canis latrans) fecal samples. The diagnostic sensitivity was determined by validating the method against the scraping, filtration, and counting technique (SFCT) for samples collected in Canada. From the 60 samples tested, 27 out of 31 SFCT positives samples for Echinococcus cestodes were positive in the MB-qPCR for E. multilocularis, with a sensitivity of 87.1% (95% CI 70.2 to 96.4%). Two samples were also positive for E. canadensis in the MB-qPCR and confirmed by morphological identification of adult worms. The agreement of the MB-qPCR and the SFCT was statistically significant with a kappa value of 0.67 (95% CI 0.48-0.85; p value < 0.001). The magnetic bead-based DNA extraction followed by qPCR proved to have a sensitivity comparable to the SFCT to detect E. multilocularis. Although the diagnostic sensitivity for E. canadensis was not estimated, MB-qPCR identified E. canadensis cases previously overlooked when using SFCT. We propose a combination of molecular and morphological identification using the MB-qPCR and the SFCT to detect both parasites, allowing for a more efficient large-scale surveillance, and detecting co-infections of Echinococcus species that can be difficult to identify when only based on morphology. PMID- 30415396 TI - Potential exposure to metals and health risks of metal intake from Tieguanyin tea production in Anxi, China. AB - The metal content of Tieguanyin tea from Anxi, Southeast China, was studied. Leaching experiments were designed based on the local tea-drinking habits, and tea infusions were prepared using three types of water and two methods of soaking tea. Twelve metals (Cd, As, Cr, Pb, Se, Sb, Ag, Tl, Cu, Zn, Be, and Ba) were measured by inductively coupled plasma mass spectrometry (ICP-MS), and a human health risk assessment was performed. The results showed that the quality of water used for steeping tea has a direct effect on the leaching concentrations of metals in the tea infusion and this effect can be reduced by using pure water or commercially available drinking water. Further, the two tea-soaking methods used by local residents can reduce the metal intake. The health risk assessment determined that the carcinogenic risk values of Cr, As, and Pb (Cr > Pb > As) were within an acceptable range (10-7-10-4); therefore, the concentrations of these metals in tea infusions do not pose substantial carcinogenic risk to tea drinkers. The results also indicate that the high concentrations of Tl in the tea infusions pose a substantial noncarcinogenic risk and may result from the dissolution characteristics of Tl and the water quality. PMID- 30415397 TI - Delayed massive hemothorax due to a diaphragmatic laceration caused by lower rib fractures. AB - A delayed hemothorax requiring surgical treatment is considered a rare minor thoracic injury. We experienced four cases of delayed massive hemothorax due to a diaphragmatic laceration caused by lower rib fractures. A computed tomography scan on admission revealed multiple rib fractures in all patients, and at least one fractured lower rib was severely displaced, which injured the diaphragm. The duration between the injury and the diagnosis were 14 h-30 days. Emergency surgical treatment was performed, and intraoperative findings revealed a diaphragmatic laceration with oozing due to injury caused by the edge of a fractured rib. After the operation, all patients were successfully discharged. PMID- 30415398 TI - Transthoracic ultrasound in children. PMID- 30415399 TI - Migration of calcium deposit over the biceps brachii muscle, a rare complication of calcific tendinopathy: Ultrasound image and treatment. AB - Calcific tendinopathy is characterized by the deposition of calcium, mostly hydroxyapatite crystals, in tendons. Women are more frequently affected than men, with prevalence in the fourth and fifth decades of life. This condition has been reported between 2.5 and 7.5% of healthy shoulders in adults, but other tendons may also be affected. A complication of this condition is the migration of calcium deposits from tendons, usually the supraspinatus, into the subacromial subdeltoid bursa. We reported a rare complication of calcific tendinopathy, that is, calcium deposits migrated from the long head of the biceps tendon over the proximal tract of the biceps brachii muscle. PMID- 30415400 TI - Relapsing paralytic ileus in multiple sclerosis requiring surgery: a video case report. PMID- 30415401 TI - A novel autosomal recessive orthostatic hypotension syndrome: and other updates on recent autonomic research. PMID- 30415402 TI - Is GH nadir during OGTT a reliable test for diagnosis of acromegaly in patients with abnormal glucose metabolism? AB - PURPOSE: The growth hormone (GH) nadir during oral glucose tolerance test (OGTT) is the gold standard diagnostic test for acromegaly. The utility of OGTT-GH suppression test in patients with abnormal glucose metabolism (AGM) has not been well established. In this study, we compared the GH nadir during OGTT in patients evaluated for acromegaly in the presence and absence of AGM. METHODS: This is a retrospective cohort study of patients with acromegaly (G1, n = 40) and a group in whom acromegaly was not confirmed (G2, n = 53) who had OGTT-GH suppression test during 2000-2012, using a monoclonal GH immunoenzymatic assay. The patients were categorized as having normal glucose metabolism (NGM) or AGM. GH nadir during OGTT in each group were compared. RESULTS: In G1 and G2, 17 and 19 patients had AGM, respectively. Among 17 patients with diabetes, median HbA1C was 7% (range 5.7-9.6%). All except one patient had HbA1C< 8%. There was no difference in the GH nadir in patients with or without AGM within G1 (p = 0.15) and G2 (p = 0.43). All G1 patients with AGM had GH nadir > 0.4 ug/L. Four G1 patients with NGM had GH nadir<0.4 ug/L. All G2 patients had GH nadir < 0.4 ug/L, except one with NGM and GH nadir of 0.4 ug/L. CONCLUSION: Using highly sensitive GH assay, a GH nadir >= 0.4 ug/L during the OGTT-GH suppression test may be used for diagnosis of acromegaly in patients with AGM in the absence of poorly controlled diabetes. PMID- 30415403 TI - Tunable superamphiphobic surfaces: a platform for naked-eye ATP detection. AB - A superamphiphobic surface composed of two different size ranges of TiO2 nanoparticles was simply fabricated through spraying the perfluorosilane coated TiO2 nanoparticles suspension dispersing in ethanol. The surface chemistry was finely regulated through gradient UV irradiation-induced organic compound degradation to fabricate surface with gradient solid surface energy or wettability. The fabricated surface shows good droplet sorting ability, which can successfully discriminate ethanol droplets with different concentrations. As a proof-of-concept, the biosensor application of this surface was demonstrated by using it for naked-eye ATP detection. Liquid droplets with different concentrations of ATP after ATP-dependent rolling circle amplification (RCA) can be effectively sorted by the surface. This developed biosensor methodology based on droplet sorting ability of the fabricated surface is energy-efficient and economical which is promising for biosensors, point-of-care testing, and biochemical assays. Graphical abstract ?. PMID- 30415404 TI - Piotr Konieczka, Jacek Namiesnik: Quality assurance and quality control in the analytical chemical laboratory: a practical approach, 2nd ed. PMID- 30415406 TI - Autoimmune Enteropathy: An Updated Review with Special Focus on Stem Cell Transplant Therapy. AB - Autoimmune enteropathy (AIE) is a complex disease affecting both children and adults. Although associated with significant morbidity and mortality, the pathophysiology of the disease and its treatment have not been well characterized. This study aims to review the medical literature available on this rare but clinically significant ailment, to help establish a better understanding of its pathophysiology and enumerate the available diagnostic and treatment modalities. A literature search was conducted on PubMed using key terms related to autoimmune enteropathy and intractable diarrhea, with no restrictions on the date of publication or language. We found a total of 98 reports of AIE published in the form of case reports and case series. The evidence reviewed suggests that AIE is a multifaceted disorder that requires a high index of suspicion in the appropriate clinical setting to be able to make an early diagnosis. Current evidence supports the use of supportive care to correct nutritional and metabolic deficiencies, and immunosuppressives and immunomodulators as directed therapies. Hematopoietic stem cell transplant is an aggressive, but successful curative modality for patients with AIE as part of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Cumulative clinical experience with management of AIE has allowed improved outcomes in transplanted and non-transplanted AIE patients even though morbidity and mortality with are still high in patients with this condition. More research is needed to further define the role of new therapies for AIE, and a central registry with participation of multiple institutions might help share and standardize care of patients with this rare but serious condition. PMID- 30415405 TI - A tridecaptin-based fluorescent probe for differential staining of Gram-negative bacteria. AB - The traditional Gram-staining method, which was invented more than a century ago for differentiating bacteria as Gram positive or Gram negative, is still widely practiced in microbiology. However, Gram staining suffers from several problems which can affect the accuracy of the diagnosis. Here, we report a new Gram negative-specific fluorescent probe, which is based on a narrow-spectrum antibiotic, tridecaptin A1, and allows selective staining of Gram-negative bacteria in different fixed bacterial samples. Solid-phase peptide synthesis was used to prepare the tridecaptin A1-fluorophore conjugate with a single structure. Labeling selectivity of the probe toward Gram-negative bacteria was confirmed by testing against a panel of bacterial species. By combining the use of a previously reported Gram-positive-specific fluorescent probe, we then further showed the capability of the new probe in differential labeling of a number of complex bacterial samples, which included a mouse gut microbiota cultured in vitro, as well as microbiotas collected from the human oral cavity, soil, and crude oil. High labeling selectivity and coverage were observed in most samples. This method offers a new Gram-negative-specific probe with a defined structure, which allows facile fluorescence-based differentiation of Gram-positive and Gram negative bacteria for further microbial studies. PMID- 30415407 TI - Short-Term Symptomatic Relief in Gastroesophageal Reflux Disease: A Comparative Study of Esomeprazole and Vonoprazan. AB - BACKGROUND AND AIM: Proton pump inhibitors and vonoprazan (a potassium competitive acid blocker) are recommended as first-line treatments for gastroesophageal reflux disease (GERD). However, few reports have investigated the onset of action of these agents for GERD symptom relief. The present study compared the symptom relief of esomeprazole with that of vonoprazan via monitoring self-reported GERD symptoms after treatment initiation. METHODS: This was a prospective, multicenter, randomized, open-label, parallel group, comparative clinical study between esomeprazole (20 mg/day) and vonoprazan (20 mg/day) administered for 4 weeks to patients with GERD symptoms. Patients who had scores >= 8 on the Gastroesophageal Reflux Disease Questionnaire (GerdQ) were defined as having GERD and enrolled in this study. Sixty patients were randomly assigned to either the esomeprazole group (n = 30) or the vonoprazan group (n = 30). Treatment response rates in each drug group were evaluated according to the GerdQ. The Frequency Scale for the Symptoms of GERD (FSSG) scores from the 1st day after treatment initiation and the Global Overall Symptom (GOS) scale scores during treatment were also evaluated. RESULTS: At 4 weeks, the treatment response rates for symptom relief according to the GerdQ were 88.0% in the esomeprazole group and 81.8% in the vonoprazan group. The GOS scales, which reflect the impact of GERD symptoms, were similar for both groups. The FSSG scores decreased from the 1st to the 14th day in both groups. CONCLUSIONS: There were no substantial differences in the symptom relief between the two groups at any time point in this short-term study. PMID- 30415408 TI - Malignant Transformation of Ectopic Pancreas. AB - Malignant transformation of ectopic pancreas tissue is a diagnostic challenge as clinical symptoms and radiographic features of these tumors are non-specific. Given the rarity of these lesions, it is usually neither suspected nor included in the diagnostic workup of different tumors. We conducted a comprehensive literature review regarding malignancy arising from ectopic pancreas for a better understanding of its frequency, clinicopathological features, and prognosis. A literature search was performed in three major databases: PubMed, Cochrane, and Web of Science. Fifty-four well-documented cases of malignant ectopic pancreas were identified in the published literature. Our analysis provided the following observations: (1) there was a slight predominance of males over females; (2) most patients with malignant transformation of ectopic pancreas were middle-aged; (3) most commonly, the tumor was located in the stomach; (4) most tumors were adenocarcinomas; (5) most frequently, the malignancy arose within a type I heterotopia according to Heinrich classification; (6) macroscopically, a subepithelial-like appearance was most frequently observed; and (7) improved prognosis for ectopic pancreatic malignancies in comparison with reported survival data for orthotopic pancreatic cancer. Even if the majority of cases of ectopic pancreas are incidental findings and malignant transformation is a rare event, pancreatic heterotopy should be considered as a source of potentially malignant lesions. PMID- 30415409 TI - Unusual presentation of recurrent papillary thyroid microcarcinoma with neck muscles and skin dissemination. PMID- 30415410 TI - Modulation of K+ channel N-type inactivation by sulfhydration through hydrogen sulfide and polysulfides. AB - Fast N-type inactivation of voltage-gated K+ (Kv) channels is important in fine tuning of cellular excitability. To serve diverse cellular needs, N-type inactivation is regulated by numerous mechanisms. Here, we address how reactive sulfur species-the gaseous messenger H2S and polysulfides-affect N-type inactivation of the mammalian Kv channels Kv1.4 and Kv3.4. In both channels, the H2S donor NaHS slowed down inactivation with varying potency depending on the "aging" of NaHS solution. Polysulfides were > 1000 times more effective than NaHS with the potency increasing with the number of sulfur atoms (Na2S2 < Na2S3 < Na2S4). In Kv1.4, C13 in the N-terminal ball domain mediates the slowing of inactivation. In recombinant protein exposed to NaHS or Na2S4, a sulfur atom is incorporated at C13 in the protein. In Kv3.4, the N terminus harbors two cysteine residues (C6, C24), and C6 is of primary importance for channel regulation by H2S and polysulfides, with a minor contribution from C24. To fully eliminate the dependence of N-type inactivation on sulfhydration, both cysteine residues must be removed (C6S:C24S). Sulfhydration of a single cysteine residue in the ball-and chain domain modulates the speed of inactivation but does not remove it entirely. In both Kv1.4 and Kv3.4, polysulfides affected the N-terminal cysteine residues when assayed in the whole-cell configuration; on-cell recordings confirmed that polysulfides also modulate K+ channel inactivation with undisturbed cytosol. These findings have collectively identified reactive sulfur species as potent modulators of N-type inactivation in mammalian Kv channels. PMID- 30415411 TI - Allelic nomenclature for the duplicated MHC class II DQ genes in sheep. AB - The principal MHC class II molecules involved in the presentation of peptides to the antigen specific receptors on CD4+ T cells genes in sheep are derived from DR and DQ genes. Allelic nomenclature systems for the DRB1 and its partner DRA loci are available for Ovid's; however, no official nomenclature is available for the DQ genes which creates ambiguity within the research community. Ovine MHC haplotypes include at least two pairs of DQA and DQB genes, termed DQA1, DQB1 and DQA2, DQB2 and both sets are polymorphic and both seem to be functional. In a number of haplotypes, the DQA1 locus appears to be absent (DQA1-null) and is replaced by a second locus termed DQA2-like. Here, we identify families of alleles based on sequence similarity and phylogenetic clustering which correspond to each of the DQA and DQB genes identified in previous genomic and transcript analyses of homozygous animals. Using such criteria to cluster sequences, we have named 82 full-length and partial cDNA transcripts derived from domestic sheep (Ovis aries) which correspond to alleles at the Ovar-DQA1, DQA2, DQA2-like, DQB1, DQB2 and DQB2-like genes and provide associated sequence resources available to the research community through the IPD-MHC Database. This sets the basis for naming and annotation of DQ genes within the ovine MHC and may be used as a template for DQ genes in other ruminant species which will ultimately support research in livestock infectious disease. PMID- 30415412 TI - A novel preoperative scoring system for the indication of unicompartmental knee arthroplasty, as predictor of clinical outcome and satisfaction. AB - INTRODUCTION: Proper patient selection is a crucial factor for the outcome of the unicompartmental knee arthroplasty (UKA). However, there is still not a clear consensus on which patients could benefit the utmost from a UKA. The purpose of this prospective study was to introduce a novel, preoperative, predictive score (Unicompartmental Indication Score, UIS) to aid proper patient selection in UKA. MATERIALS AND METHODS: A total of 152 patients with an average age of 68 years and a mean follow-up of 27 months were evaluated preoperatively with the UIS and postoperative at every follow-up. Correlation analysis was applied to identify potential relationships between the UIS, functional outcomes, pain relief, patient satisfaction, and range of motion. The ROC analysis was used to identify the best cutoff value of the UIS, which would have predicted an optimal outcome following UKA. RESULTS: The majority of the patients (91%) were satisfied with the operation, with 61% reporting excellent and 30% good satisfaction. The UIS was positively correlated to the postoperative Knee Society Score (KSS) for both pain (r = 0.26, p < 0.001) and function (r = 0.31, p < 0.001). The UIS was also positively correlated to the patient satisfaction (p = 0.46, p < 0.001) and maximum postoperative flexion (r = 0.25, p < 0.001). The ROC analysis provided an ideal cutoff for UIS at 25 points (sensitivity: 75%, sensibility: 93%, area under the curve: 86%). At a mean follow-up of 27 months (range 24-37), we observed three revisions in 152 consecutive UKA with a mean UIS of 27 points (range 20 30). CONCLUSIONS: The newly introduced UIS score might be a reliable preoperative scoring system to predict patients with excellent satisfaction, functional outcome, pain relief and possibly implant survivorship following UKA, and therefore, could help the proper patient selection and decision-making in UKA. LEVEL-OF-EVIDENCE: Prospective study, II. PMID- 30415413 TI - Fixation of a modular curved revision stem with a taper of 2 degrees in the femur. AB - INTRODUCTION: Modular revision stems with a short distal component can prevent the bypassing of the femoral isthmus and hereby theoretically have advantages concerning risk of periprosthetic fractures, breakage of the junction and a technically easier revision procedure. MATERIALS AND METHODS: Radiological evaluation of 202 stem revision operations with the modular curved revision stem "Revitan Curved" with a 2 degrees taper was carried out after a mean follow-up period of 7.44 +/- 2.09 years (3-13 years) to investigate whether short-stem combinations are effective in Paprosky 2 and 3A defects with respect to rate of subsidence and loosening. RESULTS: Sixty of 62 endofemoral (96.8%) and 137 of 140 transfemoral implantations (97.9%) involved the short, 140 mm distal component. Significant subsidence was seen in 3.3% of cases following endofemoral implantation and in 2.1% of cases following transfemoral implantation. Neither aseptic loosening nor periprosthetic fracture were observed. CONCLUSION: The use of combinations of short modular components leads to reproducibly good outcomes in femoral revision with respect to subsidence and loosening. PMID- 30415414 TI - A novel method using bone peg fixation for acute osteochondral fracture of the talus: a surgical technique. AB - INTRODUCTION: The osteochondral fracture of the talus is an uncommon condition, therefore, there are controversies for the optimal treatment. We report a novel surgical technique of bone peg fixation for osteochondral fracture of the talus. MATERIALS AND METHODS: We report two cases that underwent bone peg fixation for the acute osteochondral fractures of talus. Clinical and radiographic evaluations were performed at the last follow-up. RESULTS: At the last follow-up, mean ROM of ankle joint was 50 degrees (range 45 degrees -55 degrees ). Additionally, mean VAS and AOFAS score were 0 and 100 at the last follow-up, respectively. All patients obtained bone union without complication at the last follow-up radiographs. CONCLUSIONS: This case study shows good clinical and radiographic results with autologous bone peg fixation in patients with acute osteochondral fractures of the talus. LEVEL OF EVIDENCE: V, expert opinion. PMID- 30415415 TI - The minimalinvasive direct anterior approach in aseptic cup revision hip arthroplasty: a mid-term follow-up. AB - INTRODUCTION: The minimally invasive direct anterior approach (DAA) is an established approach for primary total hip arthroplasty (THA). The complication rates in hip revision arthroplasty are much higher in comparison with primary THA. A right positioning of the implants and a soft tissue, especially the abductors spearing approach, is important to get good functional results and low complication rates. The aim of this study was to show the clinical and radiological outcome of isolated revision hip arthroplasty of the cup by using the DAA. MATERIALS AND METHODS: Aseptic cup revisions were carried out in 48 patients using the DAA. A decision to exchange the stem was made intraoperatively in seven cases. Complications, radiological and functional outcome were assessed. All of the data were collected retrospectively. The mean follow-up period was 65 months. RESULTS: In most of the cases the standard DAA was used. A proximal extension was nescessary in 15 patients (31%). The mean cup inclination angle after revision was 44 degrees (min. 25 degrees , max. 62 degrees ). Six implants (12.5%) were located outside of the Lewinnek safe zone. The centers of rotation of the revision implants were a mean of 0.6 cm superior (min. 0, max. 2.2 cm) and 0.5 cm lateral (min. 0.2 cm, max 1.2 cm) in comparison with the center of rotation in the healthy hip on the contralateral side. Harris Hip Score improved significantly from 50 to 91 (P = 0.03). Complications noted consisted of two periprosthetic infections (4.2%), one aseptic cup loosening (2.1%), two hematomas requiring revision (4.2%), and one case each of femoral nerve injury, lower-leg venous thrombosis, and pneumonia. No dislocations were observed and there were no cases of heterotopic ossification based on the Brooker classification. No persistent damage of the nervus cutaneus femoris lateralis was found at the follow-up examinations. CONCLUSIONS: The DAA represents a feasible option in hip revision arthroplasty. Anatomic reconstruction of the cup is reproducibly possible. Good medium-term results can also be achieved. Particularly in relation to dislocation, the complication rates are low. Due to the learning curve, the DAA should only be used in hip revision arthroplasty by those with sufficient experience in primary THA. Adequate data regarding stem revisions through the DAA are not available at the moment. PMID- 30415416 TI - Evaluation of image quality and radiation dose saving comparing knowledge model based iterative reconstruction on 80-kV CT pulmonary angiography (CTPA) with hybrid iterative reconstruction on 100-kV CT. AB - OBJECTIVES: To evaluate dose reduction and image quality of 80-kV CT pulmonary angiography (CTPA) reconstructed with knowledge model-based iterative reconstruction (IMR), and compared with 100-kV CTPA with hybrid iterative reconstruction (iDose4). MATERIALS AND METHODS: One hundred and fifty-one patients were prospectively investigated for pulmonary embolism; a study group of 76 patients underwent low-kV setting (80 kV, automated mAs) CTPA study, while a control group of 75 patients underwent standard CTPA protocol (100 kV; automated mAs); all patients were examined on 256 MDCT scanner (Philips iCTelite). Study group images were reconstructed using IMR while the control group ones with iDose4. CTDIvol, DLP, and ED were evaluated. Region of interests placed in the main pulmonary vessels evaluated vascular enhancement (HU); signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated. RESULTS: Compared to iDose4-CTPA, low-kV IMR-CTPA presented lower CTDIvol (6.41 +/- 0.84 vs 9.68 +/- 3.5 mGy) and DLP (248.24 +/- 3.2 vs 352.4 +/- 3.59 mGy * cm), with ED of 3.48 +/- 1.2 vs 4.93 +/- 1.8 mSv. Moreover, IMR-CTPA showed higher values of attenuation (670.91 +/- 9.09 HU vs 292.61 +/- 15.5 HU) and a significantly higher SNR (p < 0.0001) and CNR (p < 0.0001).The subjective image quality of low-kV IMR-CTPA was also higher compared with iDose4-CTPA (p < 0.0001). CONCLUSIONS: Low-dose CTPA (80 kV and automated mAs modulation) reconstructed with IMR represents a feasible protocol for the diagnosis of pulmonary embolism in the emergency setting, achieving high image quality with low noise, and a significant dose reduction within adequate reconstruction times(<= 120 s). PMID- 30415417 TI - Health-related quality of life assessment among people living with HIV in Rio de Janeiro, Brazil: a cross-sectional study. AB - PURPOSE: To assess health-related quality of life (HRQoL) and its associated factors among people living with HIV/AIDS (PLWHA) in Rio de Janeiro, Brazil. METHODS: A cross-sectional study including PLWHA receiving usual HIV-care at Instituto Nacional de Infectologia Evandro Chagas (INI/Fiocruz) was conducted between 2014 and 2016 in Rio de Janeiro, Brazil. The EQ-5D-3L assessed HRQoL; PHQ 2 and ASSIST were used for screening depression and substance use, respectively. Clinical variables were obtained from the INI/Fiocruz cohort database, and structured questions evaluated intimate partner violence, sexual abstinence and relationship status. Data were analysed using multivariable Tobit regression model. RESULTS: A total of 1480 PLWHA were included: 64.7% were male at birth (38.4% men who have sex with men [MSM], 24.3% heterosexual men and 2% transgender women [TGW]); median age was 43.1 years, and 95.8% were receiving antiretroviral therapy. The median EQ-5D-3L utility score was 0.801. Results showed that the following factors: MSM and women; older age; lower educational level; no engagement in a relationship; depression screening positive; polysubstance use; and, detectable viral load were independently associated with worse HRQoL. CONCLUSIONS: PLWHA under care at INI/Fiocruz presented good HRQoL. Polysubstance use, depression and lower educational level were among the factors negatively associated with HRQoL. This was the first time that the EQ-5D-3L utility scores were calculated for a considerable number of PLWHA in Brazil, which is a fundamental piece of information for future cost-effectiveness analysis. PMID- 30415418 TI - Caffeine exposure and acute kidney injury in premature infants with necrotizing enterocolitis and spontaneous intestinal perforation. AB - BACKGROUND: Acute kidney injury (AKI) is common in preterm infants, but specific therapies remain scarce. Recent studies have demonstrated an association between caffeine exposure and less frequent AKI in the first 7-10 days after birth. We hypothesized that patients with necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) would provide a better natural model of AKI to evaluate this association. METHODS: We reviewed all premature patients diagnosed with NEC or SIP at our institution from 2008 to 2014. AKI was defined by change in serum creatinine using the neonatal Kidney Disease: Improving Global Outcomes definition. Caffeine was prescribed for apnea of prematurity and caffeine exposure was determined by chart review. RESULTS: A total of 146 patients with NEC/SIP were reviewed. Of these, 119 (81.5%) received caffeine, and 91 (62.3%) developed AKI. AKI occurred less frequently in patients who received caffeine than in those who did not (55.5% vs. 92.6%; odds ratio (OR) 0.10; 95% confidence interval (CI) 0.02-0.44). This association persisted in multivariable models after adjustment for potential confounders (adjusted OR 0.08; 95% CI 0.01-0.42; number needed to be exposed to caffeine to prevent one case of AKI = 2.6). Although baseline serum creatinine did not differ by caffeine exposure, patients receiving caffeine had lower peak creatinine (median 1.0 mg/dl vs. 1.5 mg/dl; p = 0.008) and absolute creatinine change (median 0.42 mg/dl vs. 0.68 mg/dl; p = 0.003) than those who did not. CONCLUSIONS: Caffeine exposure in preterm infants with NEC/SIP is associated with decreased incidence and severity of AKI. PMID- 30415419 TI - Correlation between endocapillary proliferative and nephrotic-range proteinuria in children with Henoch-Schonlein purpura nephritis. AB - BACKGROUND: The endocapillary proliferative (EP) lesion is not included in the International Study of Kidney Disease in Children (ISKDC) pathological classification of Henoch-Schonlein purpura nephritis (HSPN). The main objective of the study was to determine the pathological importance of EP in the development of proteinuria in children with Henoch-Schonlein purpura nephritis (HSPN). METHODS: The pathological features of 148 HSPN children with nephrotic range proteinuria were investigated retrospectively. Urinary IgG, transferrin, and albumin levels were measured by immunonephelometry. The correlations between EP lesion and 24-h proteinuria, urinary IgG, urinary transferrin, and urinary albumin were analyzed. Renal biopsy specimens were immunohistochemically stained for nephrin and podocalyxin. RESULTS: Of the total 581 cases of children with HSPN who underwent renal biopsy, 148 cases (25.5%) presented with nephrotic-range proteinuria. The pathological types of HSPN with nephrotic-range proteinuria were categorized as IIb, IIIa, IIIb, IIIb with diffuse EP, IVb, pure focal EP type, and pure diffuse EP type. Among these types, pure diffuse EP type accounted for 7.4%. The levels of 24-h proteinuria and urinary albumin were the highest in pure diffuse EP type among all pathological types, and the percentage of EP correlated with 24-h proteinuria and urinary albumin levels. 24-h proteinuria was significantly higher in pure diffuse EP type relative to HSPN IIb type, and significantly higher in IIIb with EP, compared with HSPN IIIb. Nephrin, but not podocalyxin, was downregulated in EP segment. CONCLUSIONS: EP is an independent pathogenic factor in HSPN with nephrotic-range proteinuria. Downregulation of nephrin in EP segment is a potential molecular mechanism of nephrotic-range proteinuria. Albumin is the major urinary protein component in HSPN with EP. PMID- 30415420 TI - Can childhood obesity influence later chronic kidney disease? AB - Childhood overweight and obesity affects more and more children. Whilst associations of childhood overweight with later outcomes such as hypertension, diabetes and cardiovascular disease have been well documented, less is known about the association of childhood overweight and obesity with kidney disease. We review the existing evidence for the association of childhood obesity with markers of childhood and adult kidney disease. Whilst there is some evidence for an association, studies have not been able to distinguish between childhood being a sensitive time to develop later kidney problems, or whether observed associations of childhood obesity with poor outcomes are driven by greater lifelong exposure to obesity. PMID- 30415421 TI - Clinical and patient-reported outcomes after image-guided intra-articular therapeutic hip injections for osteoarthritis-related hip pain: a retrospective study. AB - OBJECTIVE: To evaluate change in patient-reported outcomes following image-guided intra-articular therapeutic steroid hip injections for pain and assess correlations of outcomes with patient- and injection-specific factors. MATERIALS AND METHODS: We retrospectively reviewed consecutive patients treated for hip pain who completed outcomes assessments from October 2011 to September 2017 at an outpatient orthopedic surgery clinic. Only patients with radiographic hip osteoarthritis (Tonnis grade >= 1) who underwent steroid hip injections were included. Outcomes assessments included EuroQol-5 domain (EQ5D), EQ5D-visual analog scale (VAS), and hip disability and osteoarthritis outcome score (HOOS), obtained before and within 1-6 months post-injection. Among 113 patients who completed surveys, the mean age was 59 years (+/-13.7 years), including 77 women (68%) and 36 men (32%). Time to repeat injection or arthroplasty was recorded. Exact Wilcoxon signed rank test assessed score differences and Spearman correlation, Kruskal-Wallis, and Mann-Whitney tests assessed correlations. RESULTS: Of 113 patients, 34 had outcomes measured at <8 weeks and 79 at >=8 weeks. There was no significant change among any of the patients, short- or long term follow-up subgroups in EQ5D (p = 0.450, 0.770, 0.493 respectively), EQ5D-VAS (p = 0.581, 0.915, 0.455), average-HOOS (p = 0.478, 0.696, 0.443) or total-HOOS (p = 0.380, 0.517, 0.423) scores. Forty-nine patients underwent hip arthroplasty within 1 year. Positive correlation was found between days from injection to surgery and change in EQ5D (r = 0.29, p = 0.025), average-HOOS (r = 0.33, p = 0.019), and total-HOOS (r = 0.37, p = 0.008). CONCLUSION: We demonstrated no significant change in patient-reported outcomes measured at short- and long-term intervals up to 6 months after therapeutic steroid hip injections. PMID- 30415422 TI - An enzymatic ratiometric fluorescence assay for 6-mercaptopurine by using MoS2 quantum dots. AB - A ratiometric fluorescence method is described for the determination of the anticancer drug 6-mercaptopurine (6-MP). The method is based on the use of fluorescent MoS2 quantum dots (MQDs) and of the enzyme horseradish peroxidase (HRP). In the absence of 6-MP, HRP catalyzes the oxidation of o-phenylenediamine (OPD) by H2O2 to form 2,3-diaminophenazine (DAP). This leads to quenching of the violet fluorescence of MQDs (measured at excitation/emission wavelengths of 360/415 nm), while the strong yellow fluorescence of DAP (peaking at 560 nm) becomes increasingly strong. In the presence of 6-MP, however, it will be preferentially oxidized by the HRP/H2O2 system to form a disulfide dimer. Hence, less H2O2 is available for the oxidation of OPD and less DAP will be formed. This results in the recovery of the violet fluorescence and a decrease of the yellow fluorescence. The ratio of the two signals can be used to quantify either H2O2 or 6-MP. Linear responses are observed for H2O2 in 0.5-140 MUM concentration range, and for 6-MP in the 0.5-70 MUM concentration range, with detection limits of 0.1 MUM and 0.29 MUM, respectively. The method was applied to the determination of 6 MP in spiked human urine and gave satisfactory results. Graphical Abstract Schematic of an enzymatic fluorometric method for determination of 6 mercaptopurine (6-MP). It is based on the presence of 6-MP that can inhibit the HRP-catalyzed oxidation of o-phenylenediamine (OPD) to form 2,3-diaminophenazine (DAP). Hence, the fluorescence resonance energy transfer (FRET) between DAP and MoS2 quantum dots (MQDs) is suppressed. PMID- 30415425 TI - Secondary Arterial Hypertension: From Routine Clinical Practice to Evidence in Patients with Adrenal Tumor. AB - Prevalence of arterial hypertension is up to 30-40% in epidemiological studies, it increases with aging and affects the cardiovascular risk. Essential form of hypertension is the most frequent; however, 5-10% of patients are affected by a specific and potentially reversible cause of increased blood pressure levels, called secondary hypertension. In general, all patients with young onset-age (< 40-50 years) or resistant hypertension should be screened for secondary forms. Among them, primary aldosteronism, Cushing's Syndrome and pheochromocytoma are the most common cause of endocrine hypertension associated with an autonomous secretion of adrenal hormones, often secondary to a tumor (either mono- or bi lateral, or not always in the adrenals). Their diagnosis could be challenging, especially in patients with hypertension as the first (and/or isolated) clinical manifestation. Moreover, they are all rare form of hypertension, therefore a correct screening with a sensitive test is mandatory, to refer quickly the patients to an Endocrine Unit. In this short review we pinpoint our attention to these adrenal-related secondary form of hypertension, describing in a concise way their first-line screening procedures. PMID- 30415426 TI - Changes in bacterial diversity and catabolic gene abundance during the removal of dimethylphenol isomers in laboratory-scale constructed wetlands. AB - Constructed wetlands (CWs) are well-established wastewater treatment technologies and applied for bioremediation of contaminated water. Despite the optimal performance of CWs, the understanding of the bacterial processes in the rhizosphere, where mainly microbial degradation processes take place, is still limited. In the present study, laboratory-scale CWs planted with Juncus effusus and running under controlled conditions were studied in order to evaluate removal efficiency of dimethylphenols (DMPs), also in comparison to an unplanted bed. Next to removal rates, the bacterial community structure, diversity, and distribution, their correlation with physiochemical parameters, and abundance of the phenol hydroxylase gene were determined. As a result, better removal performance of DMP isomers (3,4-, 3,5-, and 2,6-DMP added as singles compounds or in mixtures) and ammonium loads, together with a higher diversity index, bacterial number, and phenol hydroxylase gene abundance in Juncus effusus CW in comparison with the non-planted CW, indicates a clear rhizosphere effect in the experimental CWs. An enhancement in the DMP removal and the recovery of the phenol hydroxylase gene were found during the fed with the DMP mixture. In addition, the shift of bacterial community in CWs was found to be DMP isomer dependent. Positive correlations were found between the bacteria harboring the phenol hydroxylase gene and communities present with 3,4-DMP and 3,5-DMP isomers, but not with the community developed with 2,6-DMP. These results indicate that CWs are highly dynamic ecosystems with rapid changes in bacterial communities harboring functional catabolic genes. PMID- 30415427 TI - Two-hundred-liter scale fermentation, purification of recombinant human fibroblast growth factor-21, and its anti-diabetic effects on ob/ob mice. AB - Fibroblast growth factor-21 (FGF-21) is a potential cytokine for type II diabetes mellitus. This study aimed to optimize recombinant human FGF-21 (rhFGF-21) production in Escherichia coli BL21 (DE3) employing high cell density fermentation at a 200-L scale and pilot-scale purification. FGF-21 was eventually expressed in E. coli BL21 (DE3) using human FGF-21 synthetic DNA sequence via the introduction of vector pET-3c; the product is used as seed strain during the fermentation of rhFGF-21. Fermentation of rhFGF-21 was performed in a 30-L and 200-L fermenters. rhFGF-21 was primarily expressed in the form of inclusion bodies after IPTG induction. At the 200-L scale, the bacterial production and expression levels of rhFGF-21 were 38.8 +/- 0.6 g/L and 30.9 +/- 0.7%, respectively. Additionally, the high purification (98%) of rhFGF-21 was tested with HPLC analysis and reducing & non-reducing SDS-PAGE analysis. The final yield of purified rhFGF-21 was 71.1 +/- 13.9 mg/L. The activity of rhFGF-21 stock solution reached at 68.67 +/- 8.74 IU/mg. Blood glucose controlling and insulin sensitization were improved with treatment of rhFGF-21 in type II diabetic ob/ob mice. Our results showed that the relatively stable and time-saving pilot-scale production process was successfully established, providing an efficient and cost effective strategy for large-scale and industrial production of rhFGF-21. PMID- 30415424 TI - Detecting significant genotype-phenotype association rules in bipolar disorder: market research meets complex genetics. AB - BACKGROUND: Disentangling the etiology of common, complex diseases is a major challenge in genetic research. For bipolar disorder (BD), several genome-wide association studies (GWAS) have been performed. Similar to other complex disorders, major breakthroughs in explaining the high heritability of BD through GWAS have remained elusive. To overcome this dilemma, genetic research into BD, has embraced a variety of strategies such as the formation of large consortia to increase sample size and sequencing approaches. Here we advocate a complementary approach making use of already existing GWAS data: a novel data mining procedure to identify yet undetected genotype-phenotype relationships. We adapted association rule mining, a data mining technique traditionally used in retail market research, to identify frequent and characteristic genotype patterns showing strong associations to phenotype clusters. We applied this strategy to three independent GWAS datasets from 2835 phenotypically characterized patients with BD. In a discovery step, 20,882 candidate association rules were extracted. RESULTS: Two of these rules-one associated with eating disorder and the other with anxiety-remained significant in an independent dataset after robust correction for multiple testing. Both showed considerable effect sizes (odds ratio ~ 3.4 and 3.0, respectively) and support previously reported molecular biological findings. CONCLUSION: Our approach detected novel specific genotype phenotype relationships in BD that were missed by standard analyses like GWAS. While we developed and applied our method within the context of BD gene discovery, it may facilitate identifying highly specific genotype-phenotype relationships in subsets of genome-wide data sets of other complex phenotype with similar epidemiological properties and challenges to gene discovery efforts. PMID- 30415428 TI - Complete nitrification: insights into the ecophysiology of comammox Nitrospira. AB - Nitrification, the oxidation of ammonia via nitrite to nitrate, has been considered to be a stepwise process mediated by two distinct functional groups of microorganisms. The identification of complete nitrifying Nitrospira challenged not only the paradigm of labor division in nitrification, it also raises fundamental questions regarding the environmental distribution, diversity, and ecological significance of complete nitrifiers compared to canonical nitrifying microorganisms. Recent genomic and physiological surveys identified factors controlling their ecology and niche specialization, which thus potentially regulate abundances and population dynamics of the different nitrifying guilds. This review summarizes the recently obtained insights into metabolic differences of the known nitrifiers and discusses these in light of potential functional adaptation and niche differentiation between canonical and complete nitrifiers. PMID- 30415429 TI - Cash Transfers, Young Women's Economic Well-Being, and HIV Risk: Evidence from HPTN 068. AB - Despite the large interest in economic interventions to reduce HIV risk, little research has been done to show whether there are economic gains of these interventions for younger women and what intermediary role economic resources play in changing participants' sexual behavior. This paper contributes to this gap by examining the impacts of a conditional cash transfer (CCT) for young women in South Africa on young women's economic resources and the extent to which they play a role in young women's health and behavior. We used data from HIV Prevention Trials Network 068 study, which provided transfers to young women (in addition to their parents) conditional on the young woman attending at least 80% of school days in the previous month. We found that the CCT increased young women's economic wellbeing in terms of having savings, spending money, being unindebted, and food secure. We also investigated heterogeneous effects of the program by household economic status at baseline because the program was not specifically poverty targeted and found that the results were driven by young women from the poorest families. From these results, we examined heterogeneity by baseline poverty for other outcomes related to HIV risk including sexual behavior and psychosocial well-being. We found psychosocial well-being benefits in young women from the poorest families and that economic wellbeing gains explained much these impacts. PMID- 30415430 TI - Maternal Motivation to Take Preventive Therapy in Antepartum and Postpartum Among HIV-Positive Pregnant Women in South Africa: A Choice Experiment. AB - HIV-positive pregnant women who are initiated on lifelong antiretroviral therapy (ART) and isoniazid preventive therapy (IPT) have lower adherence rates after delivery. We quantified maternal motivation to take preventive therapy before and after delivery among pregnant women newly diagnosed with HIV. We enrolled pregnant women (>= 18 years) with a recent HIV diagnosis (< 6 months) at 14 public primary health clinics in Matlosana, South Africa and followed them in the postpartum period. Participants received eight choice tasks comparing two mutually exclusive sub-sets of seven possible benefits related to preventive therapy identified through literature reviews and key informant interviews. Data was analyzed using conditional logit regression in the antepartum versus postpartum periods. Coefficients are reported with 95% confidence intervals (CI). Sixty-five women completed surveys both at enrollment and in the postpartum period. All women were already on ART, while 21 (32%) were receiving IPT at enrollment. The mean CD4 count was 436 (+/- 246) cells/mm3. In the antepartum period, preventing HIV transmission to partners was the most important benefit (coefficients (beta) = 0.87, 95% CI 0.64, 1.11), followed by keeping healthy for family (beta = 0.75, 95% CI 0.52, 0.97). Such prioritization significantly decreased in the postpartum period (p < 0.001). Compared to other motivators, keeping a high CD4 count was least prioritized in the antepartum period (beta = 0.19, 95% CI - 0.04, 0.43) but was most prioritized in the postpartum period (beta = 0.39, 95% CI 0.21, 0.57). These results highlight that messages on family might be particularly salient in the antepartum period, and keeping CD4 count high in the postpartum period. Understanding maternal motivation may help to design targeted health promotion messages to HIV-positive women around the time of delivery. PMID- 30415431 TI - Rectal Douching Practices Associated with Anal Intercourse: Implications for the Development of a Behaviorally Congruent HIV-Prevention Rectal Microbicide Douche. AB - Tenofovir administration via rectal douching results in higher rectal-mucosa drug concentration than oral administration. Many who engage in receptive anal intercourse (RAI) use cleansing rectal douches. To inform development of a behaviorally-congruent tenofovir douche, 4751 individuals >= 18 years-old, born male, from all US states/territories, who engaged in anal intercourse responded to an online survey. Of those who reported RAI in the prior 3 months, 80% douched beforehand, 82% within 1 h, mean 2.9 consecutive applications; 27% douched afterwards, 83% within 1 h, mean 1.7 consecutive applications. Among multidose users, 78% applied doses within 2 min, and 76% retained liquid < 1 min. Most used tap water (89%) in an enema bottle (50%) or rubber bulb (43%), and douched for cleanliness (97%), to avoid smelling bad (65%), and to enhance pleasure (24%). 98% reported high likelihood of using an HIV-prevention douche. An ideal product will protect within a user's typical number of applications, within 1 h, and be dissolvable in tap water. PMID- 30415432 TI - Understanding the Time Needed to Link to Care and Start ART in Seven HPTN 071 (PopART) Study Communities in Zambia and South Africa. AB - To achieve UNAIDS 90:90:90 targets at population-level, knowledge of HIV status must be followed by timely linkage to care, initiation and maintenance of antiretroviral therapy (ART) for all people living with HIV (PLHIV). Interpreting quantitative patterns using qualitative data, we investigate time taken to link to care and initiate ART amongst individuals aware of their HIV-status in high HIV-prevalence urban communities in the HPTN 071 (PopART) study, a community randomised trial of a combination HIV prevention package, including universal testing and treatment, in 21 communities in Zambia and South Africa. Data are drawn from the seven intervention communities where immediate ART irrespective if CD4 count was offered from the trial-start in 2014. Median time from HIV diagnosis to ART initiation reduced after 2 years of delivering the intervention from 10 to 6 months in both countries but varied by gender and community of residence. Social and health system realities impact decisions made by PLHIV about ART initiation. PMID- 30415433 TI - Correction to: Sam68 Promotes Invasion, Migration, and Proliferation of Fibroblast-like Synoviocytes by Enhancing the NF-kappaB/P65 Pathway in Rheumatoid Arthritis. AB - Unfortunately the author name, Rongqing Qin, was wrongly spelt as Rongqin Qin in the original version. It has been updated and the complete corrected author group is given below. PMID- 30415434 TI - Frequency-induced morphology alterations in microconfined biological cells. AB - Low-intensity therapeutic ultrasound has demonstrated an impetus in bone signaling and tissue healing for decades now. Though this technology is clinically well proven, still there are breaches in studies to understand the fundamental principle of how osteoblast tissue regenerates physiologically at the cellular level with ultrasound interaction as a form of acoustic wave stimuli. Through this article, we illustrate an analysis for cytomechanical changes of cell membrane periphery as a basic first physical principle for facilitating late downstream biochemical pathways. With the help of in situ single-cell direct analysis in a microfluidic confinement, we demonstrate that alteration of low intensity pulse ultrasound (LIPUS) frequency would physically perturb cell membrane and establish inherent cell oscillation. We experimentally demonstrate here that, at LIPUS resonance near 1.7 MHz (during 1-3 MHz alteration), cell membrane area would expand to 6.85 +/- 0.7% during ultrasound exposure while it contracts 44.68 +/- 0.8% in post actuation. Conversely, cell cross-sectional area change (%) from its previous morphology during and after switching off LIPUS was reversibly different before and after resonance. For instance, at 1.5 MHz, LIPUS exposure produced 1.44 +/- 0.5% expansion while in contrast 2 MHz instigates 1.6 +/- 0.3% contraction. We conclude that alteration of LIPUS frequency from 1-3 MHz keeping other ultrasound parameters like exposure time, pulse repetition frequency (PRF), etc., constant, if applied to a microconfined biological single living cell, would perturb physical structure reversibly based on the system resonance during and post exposure ultrasound pulsing. We envision, in the near future, our results would constitute the foundation of mechanistic effects of low intensity therapeutic ultrasound and its allied potential in medical applications. Graphical Abstract Frequency Dependent Characterization of Area Strain in Cell Membrane by Microfluidic Based Single Cell Analysis. PMID- 30415435 TI - Malignant ascites occurs most often in patients with high-grade serous papillary ovarian cancer at initial diagnosis: a retrospective analysis of 191 women treated at Bayreuth Hospital, 2006-2015. AB - BACKGROUND: Malignant ascites often develops in patients with ovarian cancer, but there is a lack of more detailed characterization of the different histological subtypes. METHODS: Ascites specimens from patients with ovarian cancer who were treated at Bayreuth Hospital from 2006 to 2015, with follow-up until December 2016, were reevaluated retrospectively. RESULTS: A total of 191 women (mean age 64 years, range 48-79) were included, of whom 180 (94.2%) had carcinoma, three (1.6%) had malignant mixed mullerian tumors (MMMTs), four (2.1%) had sex cord stromal tumors (SCSTs), three (1.6%) had germ cell tumors (GCTs), and one (0.5%) had a sarcoma. The carcinoma group comprised 134 (70.1%) patients with high-grade serous papillary ovarian cancer, 17 (8.9%) with low-grade serous papillary ovarian cancer, 10 (5.3%) with mucinous carcinomas, nine (4.7%) with endometrioid carcinomas, six (3.1%) with clear cell carcinomas, and four (2.1%) with neuroendocrine tumors. The latter group consisted of two patients with mixed neuroendocrine-nonneuroendocrine tumors (MiNENs), one with only a small cell carcinoma (SCCO), and one with a mucinous carcinoid. The noncarcinomatous group of eight patients (4.2%) included three (1.6%) with Sertoli-Leydig cell tumor and mature cystic teratoma (MCT), one (0.5%) with a granulosa cell tumor, and one with a leiomyosarcoma. A statistically significant difference in the proportion of patients with malignant ascites was observed, at 17.7% (3/17) in those with low-grade serous papillary ovarian cancer and 91.8% (123/134) in those with high grade serous papillary ovarian carcinomas. In both patients with MiNEN, the glandular tumor cell component was found in the ascites. Tumor cells were found in the ascitic fluid in 50% (5/10) of patients with mucinous ovarian carcinomas, 16.7% (1/6) of those with clear cell carcinomas, and 33.3% (1/3) of those with MMMTs. The two patients (2/3; 66.7%) with neoplastic squamous cell components in MCT and the only patient with a granulosa cell tumor in the SCST group (1/4; 25%) had malignant cell populations in the ascites, whereas patients with endometrioid cell carcinoma and leiomyosarcoma lacked tumor cells in the ascites. The malignant ascites was detected at the initial diagnosis in all 138 (100%) patients with ovarian neoplasms. CONCLUSIONS: High-grade serous papillary ovarian cancer was the main histological subtype most frequently found in ascites fluid in this series. The significant difference (P < 0.00001) in the malignancy rate in comparison with low-grade serous papillary carcinoma confirms the histological distinction between the two entities. Initial evidence of ovarian cancer in ascites fluid allows correct primary diagnosis in cytology specimens and is important for staging and prognosis. PMID- 30415437 TI - Direct hyperbilirubinemia in newborns with gastroschisis. AB - BACKGROUND: Patients with gastroschisis and prolonged total (or partial) parenteral nutrition (PN) commonly develop direct hyperbilirubinemia (DH). OBJECTIVE: To quantify the prevalence and severity of DH in newborns with gastroschisis and characterize the diagnostic work-up for DH in this patient population. DESIGN/METHODS: Retrospective chart review of patients born with gastroschisis between 2005 and 2015 for the first 6 months of life. RESULTS: 29 patients were identified with gastroschisis. Mean gestational age and birthweight were 36.4 (+/- 1.8) weeks and 2.5 (+/- 0.6) kg. 41% were treated with primary reduction versus staged closure. Peak total and direct bilirubin (DB) levels were 10.17 +/- 6.21 mg/dL and 5.58 +/- 3.94 mg/dL, respectively. 23 patients (79.3%) were diagnosed with DH and 78.2% underwent additional work-up for hyperbilirubinemia consisting of imaging and laboratory studies, none of which revealed a cause for DH other than the presumed PN-associated cholestasis. In all patients, DB began to decline within 1-10 days of initiation of enteral feeds. CONCLUSION(S): DH is common in patients with gastroschisis and is unlikely to be associated with pathology aside from PN. Additional work-up may lead to unnecessary resource utilization. LEVELS OF EVIDENCE: Case series with no comparison group, Level IV. PMID- 30415438 TI - Post-operative paralysis and elective ventilation reduces anastomotic complications in esophageal atresia: a systematic review and meta-analysis. AB - AIM OF STUDY: The repair of esophageal atresia (EA) carries an increased risk of anastomotic leak and stricture formation, especially in patients with anastomotic tension. To minimize this risk, pediatric surgeons perform elective post operative muscle paralysis, positive-pressure ventilation, and head flexion (PVF) to reduce movement and tension at the anastomosis. We systematically reviewed and analyzed the effect of post-operative PVF on reducing anastomotic complications. METHODS: Embase, MEDLINE, Web of Science, and PubMed databases were used to conduct searches. Articles reporting pediatric EA undergoing primary anastomosis, anastomotic complications, and comparisons between patients who received post operative PVF to those who did not were included. Odds ratios (OR) for all post operative anastomotic complications were calculated using random effects modelling. MAIN RESULTS: Three of the 2268 papers retrieved met inclusion criteria (all retrospective cohort studies). There were no randomized controlled trials. Post-operative PVF showed a significant reduction in anastomotic leak (OR 0.07; 95% CI 0.01-0.35) when compared to no PVF. Stricture formation was not statistically different between groups. Potential sources of bias include patient allocation. CONCLUSIONS: Based on available data, our analysis indicates PVF may reduce anastomotic post-operative leak. To confirm these results, a prospective study with clearer definitions of treatment allocation should be performed. PMID- 30415440 TI - The improvement of biocompatibility of adhesives : The effects of resveratrol on biocompatibility and dentin micro-tensile bond strengths of self-etch adhesives. AB - OBJECTIVE: The aim of this in vitro study is to evaluate the effects of resveratrol (RES) addition on the cytotoxicity and microtensile bond strength (MUTBS) of different adhesives. MATERIALS AND METHODS: Five self-etching adhesives (G-aenial Bond-GC, Optibond All in One-Kerr, Gluma Self Etch-Kulzer, Clearfil S3 Bond-Kuraray, and Nova Compo-B Plus-Imicryl) were tested. They were applied to L-929 cell culture by the extract method. In the test groups, 0.5 MUM RES (Sigma-Aldrich) was added into the medium. Cell viability was assessed by MTT assay after 24 h. Human extracted third molars were used for MUTBS test (n = 7). The adhesives with or without 0.5 MUM RES addition were applied on dentin surfaces. A composite build-up was constructed. Then, the specimens were sectioned into multiple beams with the non-trimming version of the microtensile test and subjected to microtensile forces. Statistical analysis was performed using ANOVA and post hoc Tukey test (p ? 0.05). RESULTS: The extracts of all adhesives decreased the cell viability. However, RES addition increased the cell viability in all groups (p ? 0.05). RES addition did not cause any decrease in MUTBS values of the adhesives compared to baseline. Optibond All in One showed the highest MUTBS after RES addition. It was followed by Clerafil S3 Bond and Nova Compo-B Plus. No difference was determined between the Optibond All in One and Clearfil S3 Bond. There was difference between Optibond All in One and Nova Compo-B Plus (p ? 0.05). CONCLUSION: RES addition may improve the biocompatibility without causing negative influence on MUTBS of the adhesives. CLINICAL RELEVANCE: RES addition has clinical applicable potential to overcome the adverse biocompatibility of adhesives. PMID- 30415439 TI - CIGB-814, an altered peptide ligand derived from human heat-shock protein 60, decreases anti-cyclic citrullinated peptides antibodies in patients with rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic T cell-mediated autoimmune disease. Serum autoantibodies against cyclic citrullinated peptides (anti-CCP) are significant markers for diagnosis and prognosis of this disease. Induction of immune tolerance as therapeutic approach for RA constitutes a current research focal point. In this sense, we carried out a phase I clinical trial in RA patients with a new therapeutic candidate (called CIGB-814); which induced mechanisms associated with restoration of peripheral tolerance in preclinical studies. CIGB 814 is an altered peptide ligand (APL), derived from a CD4+ T cell epitope of human heat-shock protein 60 (HSP60), an autoantigen involved in the pathogenesis of RA. Twenty patients with moderate disease activity were included in this open label trial. Sequential dose-escalation of 1, 2.5 and 5 mg of CIGB-814 was studied. Consecutive groups of six, five, and nine patients received a subcutaneous dose weekly of the peptide during the first month and one dose monthly during the next 5 months. The peptide was well tolerated and reduced disease activity. Here, we reported the quantification of anti-CCP antibodies during the treatment with this APL and in the follow-up stage. Anti-CCP antibodies were quantified in the plasma from patients by a commercial enzyme immunoassay at baseline (T0) and at weeks 28 and 48. Results showed that CIGB-814 induced a significant reduction of anti-CCP antibodies. In addition, this decrease correlated with clinical improvement in patients assessed by Disease Activity Score in 28 joints (DAS28) criteria. These findings reinforce the therapeutic potential of CIGB-814. PMID- 30415441 TI - Macrophage behavior and interplay with gingival fibroblasts cultured on six commercially available titanium, zirconium, and titanium-zirconium dental implants. AB - OBJECTIVES: The host-material interface has been a crucial relationship dictating the successful integration of biomaterials, including dental implants. The aim of the present study was to first investigate how macrophages behaved on various dental implant surfaces and thereafter to investigate their effect on soft tissue cells. MATERIALS AND METHODS: Macrophage adhesion, proliferation, and polarization towards either an M1 or M2 phenotype were investigated on six implant surfaces fabricated from pure titanium (Ti), pure zirconium (ZLA), and a titanium-zirconium (Ti-Zi) alloy of various surface topographies/chemistries. Thereafter, conditioned media (CM) collected from macrophages seeded on these various implant surfaces was cultured with murine gingival fibroblasts and investigated for their ability to promote collagen synthesis. RESULTS: Macrophages attached and proliferated in similar levels on all implant surfaces; however, the modSLA hydrophilic surfaces tended to decrease the pro-inflammatory response by lowering the gene expression of TNF-alpha, IL-1, and IL-6 and promoting tissue resolution through the expression of an M2-macrophage cytokine IL-10. Thereafter, CM from macrophages were seeded with gingival fibroblasts on each implant surface. In general, CM from macrophages significantly promoted gingival fibroblast cell attachment on all implant surfaces at either 4 or 8 h and, most notably, significantly promoted fibronectin and TGF-beta gene expression on both Ti and Ti-Zi hydrophilic surfaces. CONCLUSIONS AND CLINICAL RELEVANCE: The present study found that implant surface topography and chemistry substantially impacted macrophage behavior. Most notably, modifications via hydrophilicity to both the pure Ti and Ti-Zi were shown to favor the secretion of macrophage pro-resolution markers and favored subsequent gingival fibroblast cell behavior when cultured with CM, whereas surface composition (Ti vs ZLA vs Ti-Zi) had little effect on macrophage polarization or gingival fibroblast behavior. This finding suggests that surface hydrophilicity would improve the soft tissue integration of dental implants, irrespective of material composition. PMID- 30415436 TI - Can environment or allergy explain international variation in prevalence of wheeze in childhood? AB - Asthma prevalence in children varies substantially around the world, but the contribution of known risk factors to this international variation is uncertain. The International Study of Asthma and Allergies in Childhood (ISAAC) Phase Two studied 8-12 year old children in 30 centres worldwide with parent-completed symptom and risk factor questionnaires and aeroallergen skin prick testing. We used multilevel logistic regression modelling to investigate the effect of adjustment for individual and ecological risk factors on the between-centre variation in prevalence of recent wheeze. Adjustment for single individual-level risk factors changed the centre-level variation from a reduction of up to 8.4% (and 8.5% for atopy) to an increase of up to 6.8%. Modelling the 11 most influential environmental factors among all children simultaneously, the centre level variation changed little overall (2.4% increase). Modelling only factors that decreased the variance, the 6 most influential factors (synthetic and feather quilt, mother's smoking, heating stoves, dampness and foam pillows) in combination resulted in a 21% reduction in variance. Ecological (centre-level) risk factors generally explained higher proportions of the variation than did individual risk factors. Single environmental factors and aeroallergen sensitisation measured at the individual (child) level did not explain much of the between-centre variation in wheeze prevalence. PMID- 30415442 TI - Preliminary study on the effect of nucleolin specific aptamer-miRNA let-7d chimera on Janus kinase-2 expression level and activity in gastric cancer (MKN 45) cells. AB - Recently, much attention has been focused on the use of miRNAs in cancer treatment. The role of proto-oncogene Janus kinase-2 (JAK-2) in proliferation and survival of gastric cancer has been previously documented. The aim of this study was to evaluate the effect of a chimera consisted of nucleolin specific aptamer (NCL-Apt) and miRNA let-7d on JAK2 expression level and activity in gastric cancer cells. NCL-Apt-miRNA let-7d chimera was prepared by two methods. Gastric cancer (MKN-45) cell line and control cell line of human dermal fibroblast (HDF) were treated with the chimera and the changes in JAK2 expression and activity were determined using real-time PCR and ELISA techniques, respectively. In MKN-45 cells, the chimera caused significant decrease in JAK2 expression level and activity compared to the aptamer alone and miRNA mimic negative control. Nevertheless, transfected miRNA let-7d showed remarkable reduction in the expression level of JAK2 in comparison with control state in both MKN-45 and HDF, confirmed unspecific effect of let-7d on normal and cancerous cells. With regard to the synergic effect of this chimera on JAK2 activity, it might be viewed as a therapeutic candidate in gastric cancer. However, further studies are warranted to prove it. PMID- 30415443 TI - Assessment of genetic variation among wild Alpinia nigra (Zingiberaceae) population: an approach based on molecular phylogeny. AB - Genetic structure was evaluated among wild Alpinia nigra (Gaertn.) B.L. Burtt, populations. The information of genetic relatedness was developed using random amplified polymorphic DNA (RAPD), inter-simple sequence repeat (ISSR) and barcoding loci (plastid and mitochondrial). The order (high to low) of Shannon's information index (I) and Nei's gene diversity (h) from the populations was: "IIT Guwahati" > "Amingaon" > "Saraighat". Genetic diversity decreased and genetic differentiation increased among the three populations. We observed no isolation by distance thus lower amount of gene flow was observed. Narrow range of genetic distance among the three populations and appearance of two distinct clusters strengthened the geographical isolation in dendrogram and principal component analysis. No mutation among the three populations was observed for seven plastid loci and two mitochondrial tested suggesting the taxonomic homogeneity. The phylogeny based on nine barcoding loci supported our observation that individuals of IIT Guwahati were partially isolated from the outside populations. Our study will provide a backbone for developing strategies to resist habitat fragmentation of Zingiberaceous plants. PMID- 30415444 TI - The effects of IAM38 blocking or CD4 blocking on the binding of exogenous DNA in rabbit sperm. AB - The binding of exogenous DNA to sperm is a key process for sperm-mediated gene transfer; however, the underlying molecular mechanisms have yet to be elucidated. In the present study, we aimed to identify the DNA binding proteins (DBPs) in rabbit sperm and to gain further understanding of the molecular mechanism of sperm and exogenous DNA interaction. Native polyacrylamide gel electrophoresis was used for separating free sperm proteins and complexes of DNA fragment/sperm proteins. A distinct band was found after Coomassie blue staining, and seven potential proteins were identified by mass spectrometry analysis. An analysis of the physical/chemical properties of the seven proteins revealed that the sperm inner acrosomal membrane protein IAM38 (IAM38) matched the features of the DBPs. Western blotting analysis showed that the IAM38 and CD4 were present in the sperm but not in the seminal plasma. Blocking of the IAM38 impaired the DNA-binding capacity of the sperm. Blocking the CD4 decreased the DNA-uptake capacity of the sperm but did not influence the DNA-binding capacity of the sperm. Moreover, the EGFP-positive embryos and EGFP-positive blastocysts were also decreased after IAM38 blocking or CD4 blocking in comparison with the control group. In conclusion, our results imply that foreign DNA first binds to the transmembrane IAM38 of the sperm plasma membrane and then forms the complex of DNA/IAM38/CD4 with CD4 to complete the transportation of exogenous DNA into the nucleus of sperm. PMID- 30415445 TI - Spatiotemporal Expression Changes of PACAP and Its Receptors in Retinal Ganglion Cells After Optic Nerve Crush. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) has been demonstrated to play a crucial part in protecting retinal ganglion cells (RGCs) from apoptosis in various retinal injury animal models. PACAP has two basic groups of receptors: PACAP receptor type 1 (PAC1R) and vasoactive intestinal polypeptide/PACAP receptors (VPAC1R and VPAC2R). However, few studies illustrated the spatial and temporal expression changes of endogenous PACAP and its receptors in a rodent optic nerve crush (ONC) model. In this study, a significant upregulation of PACAP and PAC1R in the retina after ONC was observed in both protein and RNA levels. The peak level of PACAP and PAC1R expression could be found on the fifth day following ONC. In addition, immunofluorescent labeling indicated that PACAP and PAC1R were localized mainly in RGCs. On the contrary, VPAC1R and VPAC2R were hardly detected in the retina. Collectively, the spatiotemporal expression of PACAP and its high-affinity receptor PAC1R were remarkably changed after ONC, and mainly expressed in the ganglion cell layer of the retina. This suggested that the upregulation of PACAP and PAC1R may play a vital role in RGC death after ONC. PMID- 30415447 TI - Microbial treatment: the potential application for Parkinson's disease. AB - Alterations in the composition of the intestinal flora are associated with the pathophysiology of Parkinson's disease (PD). More importantly, the possible cause effect links between gut flora and PD pathogenesis have been identified using PD animal models. Recent studies have found that probiotics improve the symptoms associated with constipation in PD patients. In addition, fecal microbiota transplantation (FMT) was recently shown to provide a protective effect against 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in mice. Effective microbial therapy for PD includes probiotics and FMT. Therefore, microbial therapy may be a useful and novel approach for treatment of PD. In this review, I discuss the use of microbial treatment in PD. PMID- 30415448 TI - Lack of association between dopamine transporter loss and non-motor symptoms in patients with Parkinson's disease: a detailed PET analysis of 12 striatal subregions. AB - INTRODUCTION: Patients with Parkinson's disease (PD) present a variety of non motor symptoms. However, it remains unclear whether dopamine depletion is related to non-motor symptoms, and which non-motor symptoms are significantly dependent on dopaminergic deficit. METHODS: Forty-one patients with PD who underwent positron emission tomography imaging of dopamine transporters (DATs) were recruited for this study. The striatum was divided into 12 subregions, and DAT activity, as striatal dopaminergic concentration, was calculated in each subregion. In addition to measuring motor symptoms using the Unified Parkinson's Disease Rating Scale-part III (UPDRS-III), various non-motor symptoms were assessed using the Montreal cognitive assessment, frontal assessment battery, Beck depression inventory (BDI), Beck anxiety inventory, PD sleep scale (PDSS), PD fatigue scale, and non-motor symptoms scale (NMSS) for PD. RESULTS: For simple linear regression analyses, dopaminergic depletion in all striatal subregions was negatively correlated with the UPDRS-III score. The most relevant non-motor symptom assessment related to dopaminergic loss in the 12 subregions was NMSS, followed by BDI and PDSS. However, following multiple linear regression analyses, dopaminergic depletion in the 12 striatal subregions was not related with any of the non-motor symptoms. Conversely, dopaminergic deficit in the right anterior and posterior putamen was associated with the UPDRS-III score. CONCLUSIONS: Striatal dopaminergic depletion was not significantly correlated with any of the various non-motor symptoms in PD. Our findings suggest that non-dopaminergic systems are significantly implicated in the pathogenesis of non-motor symptoms in patients with PD. PMID- 30415450 TI - Epidemiological, Clinical and Outcome Aspects of Patients with Cryptococcosis Caused by Cryptococcus gattii from a Non-endemic Area of Brazil. AB - Cryptococcosis by Cryptococcus gattii occurs mainly in immunocompetent hosts, however, during the last decades, a growing number of cases in immunocompromised individuals have been noticed around the world. This report presents epidemiological, clinical and outcome aspects of patients with cryptococcosis caused by this species from a non-endemic area in Brazil. Of 278 Cryptococcus spp. clinical isolates recovered during the same period, 267 (96%) were molecularly identified as Cryptococcus neoformans VNI genotype and 11 (4%) as C. gattii VGII genotype by URA-5 RFLP. Of the 11 C. gattii patients, eight were male, mean age of 47.5 years. Of these, four were HIV-infected, one was kidney transplanted, one presented low CD4+ T cells values of unknown cause, another presented chronic liver disease meanwhile the remaining four were apparently immunocompetent. Disseminated disease and cryptococcal meningitis were present in four patients each. Most patients received amphotericin B plus fluconazole. Seven out of the 11 patients cured and four died before or during the therapy. The increased number of individuals with cryptococcosis by this species during the last decades needs to be carefully evaluated specially those who are HIV infected. Nevertheless, Cryptococcus species differentiation is currently relevant in order to better know their relation with geographical, clinical host preference and outcome particularities. PMID- 30415449 TI - Assessment of 16S rRNA gene primers for studying bacterial community structure and function of aging flue-cured tobaccos. AB - Selection of optimal primer pairs in 16S rRNA gene sequencing is a pivotal issue in microorganism diversity analysis. However, limited effort has been put into investigation of specific primer sets for analysis of the bacterial diversity of aging flue-cured tobaccos (AFTs), as well as prediction of the function of the bacterial community. In this study, the performance of four primer pairs in determining bacterial community structure based on 16S rRNA gene sequences in AFTs was assessed, and the functions of genes were predicted using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). Results revealed that the primer set 799F-1193R covering the amplification region V5V6V7 gave a more accurate picture of the bacterial community structure of AFTs, with lower co-amplification levels of chloroplast and mitochondrial genes, and more genera covered than when using the other primers. In addition, functional gene prediction suggested that the microbiome of AFTs was involved in kinds of interested pathways. A high abundance of functional genes involved in nitrogen metabolism was detected in AFTs, reflecting a high level of bacteria involved in degrading harmful nitrogen compounds and generating nitrogenous nutrients for others. Additionally, the functional genes involved in biosynthesis of valuable metabolites and degradation of toxic compounds provided information that the AFTs possess a huge library of microorganisms and genes that could be applied to further studies. All of these findings provide a significance reference for researchers working on the bacterial diversity assessment of tobacco-related samples. PMID- 30415446 TI - The Role of MicroRNAs in Patients with Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a serious neurodegenerative disease that affects motor neurons and leads to death within 2 to 3 years after the first symptoms manifest. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression in fundamental cellular processes and, post transcriptionally, the translation levels of target mRNA transcripts. We searched PubMed for studies that examined miRNAs in ALS patients and attempted to group the results in order to find the strongest miRNA candidate for servings as an ALS biomarker. The studies on humans so far have been diverse, yielding considerably heterogeneous results, as they were performed on a wide variety of tissues and subjects. Among the miRNAs that were found consistently deregulated are miR-206, miR-133, miR-149, and miR-338-3p. Additively, the deregulation of some specific miRNAs seems to compose a miRNA expression profile that is specific for ALS. More research is required in order for the scientific community to reach a consensus. PMID- 30415451 TI - Patient-reported outcomes with golimumab in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: non-interventional study GO-NICE in Germany. AB - The TNF inhibitor golimumab (GLM) is a treatment option in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). The GO-NICE study assessed patient-reported outcomes (PRO) in patients newly treated with monthly GLM 50 mg subcutaneously (SC) under real-life conditions in Germany. A prospective non-interventional study with 24-month observation per patient was conducted at 158 sites. Available for analysis were 1,458 patients, 474 with rheumatoid arthritis (RA: 54.9 +/- 13.4 years, 72.8% females, 60.4% biologic-naive), 501 with psoriatic arthritis (PsA: 50.5 +/- 12.1 years, 54.1% females; 47.5% biologic-naive), and 483 with ankylosing spondylitis (AS: 43.6 +/- 12.3 years, 66.5% males; 58.4% biologic-naive). A total of 664 patients completed follow-up to month 24. An improvement of QoL by EuroQoL EQ-5D 3L was seen after 6 months and was maintained over 24 months. The patients' health state today (EQ visual analog scale) improved statistically significantly (p < 0.0001 vs. BL) from 51.0 at baseline (BL) to 63.4 (RA), from 48.4 to 64.3 (PsA) and from 46.8 to 66.5 (AS). Functional ability (FFbH) improved significantly (p < 0.003 vs. BL) from BL 68.2 to 76.1 points (RA), from 69.0 to 76.8 points (PsA), and from 69.0 to 78.5 points (AS). The mean FACIT-Fatigue score increased significantly (p < 0.0001 vs. BL) from BL 32.4 to 38.3 points (RA), from 30.0 to 35.9 points (PsA), and from 29.9 to 37.9 points after 24 months (AS); p < 0.0001 vs. BL each. On treatment with GLM SC once monthly, significant improvements in patient-reported QoL parameters were noted in a very similar manner in all three diseases.Trial registration ClinTrials.gov Identifier: NCT01313858. Registered March 14, 2011; https://clinicaltrials.gov/ct2/show/record/NCT01313858 . PMID- 30415452 TI - Self-reported disease severity in women with systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE), pathology with net feminine predominance, is one of the most complex autoimmune diseases and has major impact on patients' life. The aim is to identify patient and disease-related factors associated with self-perceived disease severity in female SLE patients. This cross-sectional study enrolled 73 women fulfilling the 2012 Systemic Lupus International Collaborating Clinic (SLICC) criteria. SLE disease activity was assessed by the Systemic Lupus Activity Measure (SLAM) score and overall damage by the SLICC/American College of Rheumatology (ACR) index. Patients' general characteristics, associated conditions as well as SLE specific clinical involvements and therapeutic principles were also noted. Fatigue was assessed by FACIT-fatigue scale. Self-perceived disease severity was assessed using numerical rating scales (1-10 NRSs), to evaluate the disease severity at inclusion (1-10 NRS now) and worst severity anytime during disease history (1-10 NRS worst ever). In regard to worst ever lupus severity, 54.8% of patients responded with 9 or 10, while none with 1 or 2 even if only 22.9% of the patients responded with 7 or more for disease severity at inclusion (1-10 NRS now). Women with higher 1-10 NRS now answers had also higher 1-10 NRS worst ever, SLAM, SLICC, and FACIT-fatigue scores. They associated more frequently anxiety/depression diagnosis, antiphospholipid syndrome, joint involvement as well as treatments with corticosteroids. Self-reported disease severity worst ever, anxiety/depression diagnosis, fatigue, and the daily dose of corticosteroids were independently associated with patients' perception on lupus severity at inclusion: OR (95% CI), 2.13 (1.15-3.94) p = 0.017, 6.67 (1.11-39.97) p = 0.038, 1.10 (1.02-1.19) p = 0.018, and 1.11 (1.02-1.21) p = 0.020, respectively. The vast majority of patients identified severe and very severe events during their disease history, results that raise awareness of burden concerning lupus occurrence in women's life. Self-perceived lupus severity is multifactorial, influenced also by factors less considered in the SLE management like fatigue and the depression/anxiety disorders, but also by the previous patient's experience. PMID- 30415453 TI - Translation, cross-cultural adaptation and validation of the Osteoarthritis Quality of Life (OAQoL) questionnaire for use in Portugal. AB - Osteoarthritis (OA) is the most prevalent rheumatic disease and is a leading cause of decreased quality of life (QoL). The OA Quality of Life questionnaire (OAQoL) is an OA-specific patient-reported outcome measures. The aim of this study was to translate and validate the original UK English version of the Osteoarthritis Quality of Life (OAQoL) questionnaire into European Portuguese. The translation of the questionnaire was carried out according to a dual panel methodology (bilingual panel followed by lay panel). This was followed by cognitive debriefing interviews (CDIs) with OA patients to assess comprehension and relevance of the translated questionnaire. Finally, a validation survey was conducted to assess its psychometric properties. The Portuguese OAQoL, a comparator scale (the Nottingham Health Profile-NHP) as well as questions relating to demographic and disease information were administered to OA patients. A sub-sample of patients also completed the Portuguese OAQoL two weeks later, to assess test-retest reliability. The internal consistency, construct validity and known group validity (according to perceived OA severity) of the scale was also assessed. Both the bilingual and lay panels consisted of five individuals and no major difficulties relating to the translation process were identified. A total of ten patients with OA participated in the CDIs. The mean time to complete the questionnaire was 5 min. These interviews revealed that the Portuguese version of the OAQoL was clear, relevant and easy to complete. Finally, 53 OA patients (44 females; mean age of 67.6 years) completed the validation survey. Cronbach's alpha coefficient was 0.87, demonstrating high internal consistency. Test-retest reliability, assessed by Spearman's rank correlation coefficient, was 0.86. Moderate correlations were found with the majority of the NHP sections, providing evidence of construct validity. Significant differences in OAQoL scores were found between patients who differed according to their perceived OA severity, providing evidence of known group validity. The Portuguese version of the OAQoL is a valid and reliable questionnaire that can be used to assess QoL in OA, both in clinical practice and for research purposes. PMID- 30415454 TI - Advances in Retinal Imaging and Applications in Diabetic Retinopathy Screening: A Review. AB - Rising prevalence of diabetes worldwide has necessitated the implementation of population-based diabetic retinopathy (DR) screening programs that can perform retinal imaging and interpretation for extremely large patient cohorts in a rapid and sensitive manner while minimizing inappropriate referrals to retina specialists. While most current screening programs employ mydriatic or nonmydriatic color fundus photography and trained image graders to identify referable DR, new imaging modalities offer significant improvements in diagnostic accuracy, throughput, and affordability. Smartphone-based fundus photography, macular optical coherence tomography, ultrawide-field imaging, and artificial intelligence-based image reading address limitations of current approaches and will likely become necessary as DR becomes more prevalent. Here we review current trends in imaging for DR screening and emerging technologies that show potential for improving upon current screening approaches. PMID- 30415456 TI - Imaging tryptophan uptake with positron emission tomography in glioblastoma patients treated with indoximod. AB - INTRODUCTION: Glioblastoma (GBM) is the most frequent and aggressive primary tumor of the central nervous system, accounting for over 50% of all primary malignant gliomas arising in the adult brain. Even after surgical resection, adjuvant radiotherapy (RT) and temozolomide (TMZ) chemotherapy, as well as tumor treating fields, the median survival is only 15-20 months. We have identified a pathogenic mechanism that contributes to the tumor-induced immunosuppression in the form of increased indoleamine 2,3 dioxygenase 1 (IDO1) expression; an enzyme that metabolizes the essential amino acid, tryptophan (Trp), into kynurenine (Kyn). However, real-time measurements of IDO1 activity has yet to become mainstream in clinical protocols for assessing IDO1 activity in GBM patients. METHODS: Pre-treatment and on-treatment alpha-[11C]-methyl-L-Trp (AMT) positron emission tomography (PET) with co-registered MRI was performed on patients with recurrent GBM treated with the IDO1 pathway inhibitor indoximod (D1-MT) and TMZ. RESULTS: Regional intratumoral variability of AMT within enhancing and non enhancing tumor was noted at baseline. On treatment imaging revealed decreased regional uptake suggesting IDO1 pathway modulation with treatment. CONCLUSIONS: Here, we have validated the ability to use PET of the Trp probe, AMT, for use in visualizing and quantifying intratumoral Trp uptake in GBM patients treated with an IDO1 pathway inhibitor. These data serve as rationale to utilize AMT-PET imaging in the future evaluation of GBM patients treated with IDO1 enzyme inhibitors. PMID- 30415458 TI - Clinical evaluation of CT radiation dose in whole-body 18F-FDG PET/CT in relation to scout imaging direction and arm position. AB - OBJECTIVE: Radiation exposure in CT is modulated by automatic exposure control (AEC) mainly based on scout images. We evaluated CT radiation dose in whole-body PET/CT in relation to scout imaging direction and arm position, and investigated the behavior of AEC. METHODS: Eighty adult patients who underwent whole-body 18F FDG PET/CT were divided into groups A, B, C, and D. The posteroanterior scout image alone (PA scout) was used for AEC-based dose modulation in groups A and B, while the posteroanterior and lateral scout images (PA + Lat scout) were used in groups C and D. Patients in groups A and C were imaged with their arms beside the head, while those in groups B and D were imaged with their arms at the sides of the trunk. Dose-length product provided by the scanner was recorded. The tube current value, a determinant of radiation dose, for each slice was plotted against slice location to produce a tube current modulation curve. The scan range was divided into seven anatomical regions, and regional tube current was defined as average tube current for each region. Effective dose was calculated for each region and then summed together. RESULTS: Regional tube current was higher in the body trunk and proximal thigh using the PA scout than using the PA + Lat scout, resulting in higher dose-length product and effective dose using the PA scout. A marked dose increase was shown in the shoulder especially using the PA scout. Spike-like high current at the top of the head was often observed in tube current modulation curves using the PA scout but not using the PA + Lat scout. Raising the arms increased tube current in the head and neck and decreased it in the chest and abdomen. Although dose-length product did not differ significantly depending on arm position, raising the arms decreased effective dose significantly. CONCLUSIONS: AEC-based CT dose modulation in whole-body PET/CT is affected by scout imaging direction and arm position, which should be considered to determine an optimal imaging protocol for whole-body PET/CT. PMID- 30415457 TI - Identification and detection sensitivity of Microcystis aeruginosa from mixed and field samples using MALDI-TOF MS. AB - To verify the applicability of identifying Microcystis aeruginosa by matrix assisted laser desorption-ionization-time-of-flight mass spectrometry (MALDI-TOF MS), mixed and field samples were employed to study the sensitivity and the analysis power, respectively. Series diluted samples and artificially mixed samples by the M. aeruginosa NIES-843 strain were designed to verify the sensitivity. The lowest detection limit was 1.955 * 106 cells in pure samples, while for mixed samples, the lowest detection limit and ratio of NIES-843 strain were 2.88 * 106 cells and 33.7%, respectively. The results provided a reference for the reasonable volume of the water sample in which the M. aeruginosa could be detected. Ribosomal protein biomarkers for identifying M. aeruginosa which were successfully detected from the field samples in Taihu Lake, indicated that the identification of M. aeruginosa by MALDI-TOF MS could be applied in field samples. Furthermore, different genetic types of M. aeruginosa strains were also detected at different locations in Taihu Lake, which revealed the diversity of M. aeruginosa and the detection power of MALDI-TOF MS at the strain level for the field samples. The sensitivity and detection power in the analysis of M. aeruginosa by the MALDI-TOF MS demonstrated the applicability of this method in routine environmental monitoring. PMID- 30415459 TI - Pharmacogenetics of Membrane Transporters of Tacrolimus in Solid Organ Transplantation. AB - Membrane transporters play an essential role in the pharmacokinetics of drugs as they mediate exchanges between biological compartments. Tacrolimus is characterized by wide interpatient variability in terms of its pharmacokinetics that may in part be due to genetic factors. The pharmacogenetics of drug transporters is therefore a promising area to explore in the clinical pharmacology of tacrolimus. The aim of this review is to provide an overview of currently available data regarding the pharmacogenetics of membrane transporters that may be involved in the interindividual variability of the response to tacrolimus. Several genetic variants in genes coding for influx or efflux membrane transporters (e.g. ABCB1, ABCC2, ABCC8, SLC30A8, SLCO1B1/3, SLC28A1, SLC22A11, and SLC28A3) have been associated with tacrolimus pharmacokinetics variability or the occurrence of toxicity; however, there is still a degree of controversy as to the impact of these variants in vivo and further investigations are needed to confirm these results in larger cohorts and to validate the relevance of such genetic biomarkers for personalization of immunosuppressive therapy in solid organ transplantations. The relationship between transporter polymorphisms and the intracellular concentration of tacrolimus should also be further investigated. Finally, the main challenge could be elucidation of the interplay of biological mechanisms underlying genetic variations that alter the drug concentration or its clinical effect. PMID- 30415460 TI - An integrated molecular modeling approach for the tryptase monomer-curcuminoid recognition analysis: conformational and bioenergetic features. AB - Human mast cell tryptase has been shown as an activating enzyme in matrix degradation process. The previous study suggest that tryptase either alone or in joining with activation of metalloproteinases, can associate in extra cellular matrix damage and the possible destruction of the basement membrane resulting in photoaging. Therefore the inhibition of tryptase activity is one of the most important therapeutic strategies against the photoaging. Curcumin has been shown to be a potential agent for preventing and/or treating the photoaging induced by UV radiation. However, the protective effect of curcumin against the photoaging through the tryptase inhibition is still inadequately understood. In this work, computational methods to characterize the structural framework and define the atomistic details of the determinants for the tryptase inhibition mechanism by curcuminoids were performed. By molecular docking, three putative binding models able to efficiently bind all curcuminoids were identified. Analysis of molecular dynamics simulations revealed that cyclocurcumin, curcumin glucuronide, and curcumin, the most effective inhibitors from the three models, modified significant tryptase monomer rigidity by binding in all the possible sites. The result of these binding events is the suppression of the functional enzymatic motions involving the binding of substrates to the catalytic site. On the basis of this finding may thus be beneficial for the development of new natural inhibitors for the therapeutic remedy of photoaging, targeting and modulating the activity of tryptase. PMID- 30415461 TI - Fractionation of Protein Hydrolysates of Fish Waste Using Membrane Ultrafiltration: Investigation of Antibacterial and Antioxidant Activities. AB - In this study, yellowfin tuna (Thunnus albacores) viscera were hydrolyzed with protamex to obtain hydrolysate that is separated by a membrane ultrafiltration into four molecular size fractions (< 3, 3-10, 10-30, and 30 kDa <). Antibacterial and antioxidant properties of the resulting hydrolysates and membrane fractions were characterized, and results showed that the lowermost molecular weight fraction (< 3 kDa) had significantly the highest (P < 0.05) percentage of bacteria inhibition against Gram-positive (Listeria and Staphylococcus) and Gram-negative (E. coli and Pseudomonas) pathogenic and fish spoilage-associated microorganisms and scavenging activity against DPPH and ABTS radical and ferric reducing antioxidant power among the fractionated enzymatic hydrolysates. These results suggest that the protein hydrolysate derived from yellowfin tuna by-products and its peptide fractions could be used as an antimicrobial and antioxidant ingredient in both nutraceutical applications and functional food. PMID- 30415462 TI - Pain Intensity Factors Changing Breakthrough Pain Prevalence in Patients with Advanced Cancer: A Secondary Analysis of a Cross-Sectional Observational International Study. AB - INTRODUCTION: Different definitions of breakthrough pain (BTP) influence the observed BTP prevalence. This study examined BTP prevalence variability due to use of different cutoffs for controlled background pain, different assessment periods for background pain, and difference between worst and average pain intensity (PI). METHODS: Cancer patients from the EPCRC-CSA study who reported flare-ups of pain past 24 h were potential BTP cases. BTP prevalence was calculated for different cutoffs for background PI on numeric rating scales (NRS 0-10) for the past week, past 48 and past 24 h period. Furthermore, BTP cases were categorized based on the difference between maximum and average PI past 24 h (range, 0 to > 2 points, NRS 0-10). RESULTS: Of 696 respondents, 302 patients (43.4%) reported pain flares the past 24 h. The BTP prevalence when using a defined background PI <= 4 for the past week was 19.8%. This number varied for different defined cutoffs for background PI. Actual background PI and BTP prevalence also varied between the assessment periods "past week", "past 48 h", and "past 24 h" (PI 4.0, 3.6, and 3.4; BTP prevalence 19.8, 22.7, and 24.9% for background PI <= 4). For patients with background PI <= 4 past week, 105 had a difference between maximum and average PI >= one point and 48 had a difference > two points. CONCLUSIONS: The reported BTP prevalence is dependent on the cutoff for background PI in the BTP definition, population background PI during the assessment period, and defined cutoff for the difference between worst and average PI. FUNDING: NTNU, Norwegian University of Science and Technology. PMID- 30415463 TI - Intra-operative diagnosis of periprosthetic joint infection can rely on frozen sections in patients without synovial fluid analyses. AB - BACKGROUND: The purpose of this study was to determine whether frozen sections can increase diagnostic values of serological tests for the assessment of periprosthetic joint infection (PJI) in patients without synovial fluid analyses. METHODS: A retrospective review of 128 revision arthroplasties (79 hips and 49 knees) from January 2016 to December 2017 was performed. Diagnosis of PJI was based on the Musculoskeletal Infection Society criteria for infection. Three diagnostic models for PJI, with model 1 including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), model 2 including model 1 plus frozen sections > 5 polymorphonuclear neutrophil (PMN)s per high-power field (HPF), and model 3 including model 1 plus frozen sections > 10 PMNs per HPF, were developed. Then receiver operating characteristic (ROC) curves were generated, and the areas under the ROC curves (AUCs) were compared. RESULTS: The AUC of model 1, model 2, and model 3 was 79.40% [95% confidence interval (CI), 69.84 to 86.64%], 89.30% (95% CI, 82.93 to 93.92%), and 85.52% (95% CI, 78.44 to 91.4%), respectively. The AUC of model 1 was significantly lower than that of model 2 (p = 0.002) and model 3 (p = 0.039). Although the result was not significant (p = 0.132), there was a trend toward a higher AUC of model 2 than model 3. CONCLUSIONS: This study reveals that intra-operative frozen sections significantly increased the performance of serum ESR and CRP in the diagnosis of PJI. The combination of serological tests and frozen sections for the assessment of PJI may be reliable in patients without synovial fluid analyses. PMID- 30415464 TI - Proximal femoral replacement in non-oncologic patients undergoing revision total hip arthroplasty. AB - PURPOSE: Proximal femoral replacements (PFRs) have been recently utilized in complex revision arthroplasties where proximal femoral bone is compromised. The purpose of this study is to evaluate the clinical outcomes, complications, and survivorship of PFRs as a salvage treatment for severe bone loss after non oncologic revision total hip arthroplasty. METHODS: This is a retrospective review of all patients who underwent femoral revision surgery using a single design PFR between 2004 and 2013 at our institution. Forty patients (41 hips) were included with a mean age of 64 years (29-90). According to Paprosky classification, 15 femurs had type IIIB defect, and 26 had type IV defect. Patients were followed for a mean of five years (2-10). The average length of reconstruction was 150 mm (81-261). A Kaplan-Meier analysis was used to determine the survival of the PFR. RESULTS: A total of nine patients (9 PFRs, 22%) were re operated upon. Three re-operations were for infection, two for dislocation, two for aseptic loosening, and two for periprosthetic fracture. The survivorship at five years was 95.1% for revision of the femoral stem for aseptic loosening. We did not find length of the segmental reconstruction or the indication for revision, to be a risk factor for implant failure or re-revision. CONCLUSIONS: Proximal femoral replacements have shown an acceptable survivorship in non oncologic revision hip arthroplasties for severe proximal femoral bone loss. The frequent use of constrained liners may decrease the risk of dislocation due to the loss of the abductor mechanism encountered in these complex reconstructions. PMID- 30415465 TI - Autogenic mesenchymal stem cells for intervertebral disc regeneration. AB - PURPOSE: A systematic review of the literature was conducted to clarify the outcomes of autologous mesenchymal stem cells (MSC) injections for the regeneration of the intervertebral disc (IVD). METHODS: The following databases were accessed: PubMed, Medline, CINAHL, Cochrane, Embase and Google Scholar bibliographic databases. Articles including previous or planned surgical interventions were excluded. Only articles reporting percutaneous autologous MSC injection to regenerate IVD in humans were included. We referred to the Coleman Methodology Score for the methodological quality assessment. The statistical analysis was performed using Review Manager Software 5.3. RESULTS: After the databases search and cross-references of the bibliographies, seven studies were included in the present work. The funnel plot detected low risk of publication bias. The Coleman Methodology Score reported a good result, scoring 61.07 points. A total of 98 patients were enrolled, with 122 treated levels. All the patients underwent conservative therapies prior to injection. A remarkable improvement in the quality of life were reported after the treatment. The average Oswestry Disability Index (ODI) improved from "severe disability" to "minimal disability" at one year follow-up. The visual analogue scale (VAS) showed an improvement of ca. 30% at one year follow-up. Only one case of herniated nucleus pulposus was reported. No other adverse events at the aspiration or injection site were observed. CONCLUSIONS: This systematic review of the literature proved MSC injection to be a safe and feasible option for intervertebral disc regeneration in the early-degeneration stage patients. Irrespective of the source of the MSCs, an overall clinical and radiological improvement of the patients has been evidenced, as indeed a very low complication rate during the follow-up. PMID- 30415466 TI - Photoelectrochemical determination of the activity of protein kinase A by using g C3N4 and CdS quantum dots. AB - A sensitive and selective photoelectrochemical (PEC) method is described for the detection of protein kinase A (PKA) activity based on the use of graphite-like carbon nitride (g-C3N4) and the CdS quantum dots (QDs). Firstly, a complex was synthesized from g-C3N4 and gold nanoparticles (AuNPs). It was employed as both the PEC-active material and as a support for immobilization of peptides. The latter were assembled on an ITO electrode modified with g-C3N4-AuNPs and subsequently phosphorylated by PKA in the presence of adenosine 5'-[gamma thio]triphosphate (ATP-S). Finally, CdS quantum dots (QDs) were introduced on the ITO in order to increase the PEC response of g-C3N4 based on the Cd-S binding between the QDs and thiol groups. Under the optimal conditions and a typical working voltage of -0.3 V, the method has a dynamic range that extends from 0.05 to 50 unit.mL-1, with a 0.017 unit.mL-1 lower detection limit. The method was successfully applied to the quantification of the inhibitory effect of ellagic acid on the activity of PKA, and to monitor enzyme activity in cell lysates. Graphical abstract Schematic of a sensitive and selective photoelectrochemical biosensor for the detection of protein kinase A activity. It is based on the use of graphite-like carbon nitride and CdS quantum dots. PMID- 30415467 TI - Somatic offloading during sperm maturation: shining light on the extragenomic paternal dowry. PMID- 30415468 TI - Limited relationships between reactive oxygen species levels in culture media and zygote and embryo development. AB - PURPOSE: Reactive oxygen species (ROS) are thought to play a critical role in the success of IVF. The relationships between oxidative stress parameters in culture media and IVF outcomes have not been extensively investigated. The objective of this study is to examine the relationships between early human embryonic parameters and levels of ROS in culture media. METHODS: This prospective study was conducted with 2633 spent culture media collected from patients undergoing conventional IVF (n = 101) and intracytoplasmic sperm injection (ICSI) (n = 60). Both fertilization and early culture were performed in universal IVF medium and G series medium. ROS levels were measured by chemiluminescence assays using luminol as the probe on days 1, 3, and 5 and determined the relationships of ROS levels with zygote condition, embryo quality, and clinical pregnancy rate. RESULTS: ROS levels per embryo in culture media on the corresponding days 1, 3, and 5 showed significant correlations between each pair in the total cohort. Similar results were observed in the IVF and ICSI groups, but day 1 and day 3 ROS levels were significantly higher in culture media of IVF than of ICSI embryos. ROS levels in culture medium were not significantly associated with embryo quality, blastocyst formation, or arrest. ROS levels on day 1 were similar in media of normally fertilized zygotes, unfertilized oocytes, and polyspermic zygotes and were not associated with delayed embryonic development, high fragmentation, blastocyst formation, or arrest after prolonged culture. ROS levels in media were not associated with the likelihood of conception. CONCLUSIONS: ROS levels in culture media may not be an effective indicator of embryo selection for IVF. PMID- 30415469 TI - Semen parameters on the day of oocyte retrieval predict low fertilization during conventional insemination IVF cycles. AB - PURPOSE: Poor fertilization during conventional IVF is difficult to predict in the absence of abnormal semen parameters; large-scale studies are lacking. The purpose of this study is to evaluate factors associated with low fertilization rates in conventional insemination IVF cycles. METHODS: A retrospective cohort study evaluating demographic, reproductive evaluation, and IVF cycle characteristics to identify predictors of low fertilization (defined as 2PN/MII <= 30% per cycle). Participants were included if they were undergoing their first IVF cycle utilizing fresh autologous oocytes and conventional insemination with male partner's sperm (with normal pretreatment semen analysis). They were randomly divided into a training set and a validation set; validation modeling with logistic regression and binary distribution was utilized to identify covariates associated with low fertilization. RESULTS: Postprocessing sperm concentration of less than 40 million/ml and postprocessing sperm motility < 50% on the day of retrieval were the strongest predictors of low fertilization in the training dataset. Next, in the validation set, cycles with either low postprocessing concentration (<= 40 million/ml) or low postprocessing progressive motility (<= 50%) were 2.9-times (95% CI 1.4, 6.2) more likely to have low fertilization than cycles without either risk factor. Furthermore, cycles with low postprocessing concentration and progressive motility were 13.4 times (95% CI 4.01, 45.06) more likely to have low fertilization than cycles without either risk factor. CONCLUSIONS: Postprocessing concentration and progressive motility on the day of oocyte retrieval are predictive of low fertilization in conventional IVF cycles with normal pretreatment diagnostic semen analysis parameters. PMID- 30415470 TI - WWP2 Is One Promising Novel Oncogene. AB - WWP2 is an E3 ubiquitin ligase and plays an important role in regulation of many cellular biological activities through ubiquitination and degradation of its substrates. Recently accumulating evidences indicate that WWP2 plays a crucial part in the pathogenesis in different types of tumors. In this report, the role of this gene especially in tumorigenesis was reviewed. WWP2 is dysregulated in various of tumors, and it promotes carcinogenesis mainly through PTEN/Akt signaling pathway. WWP2 also participates in anti-cancer agents' sensitivity, indicating WWP2 may be a novel target for cancer treatment. WWP2 is one promising novel oncogene. PMID- 30415471 TI - Case control study found that primary language disorders were associated to screen exposure at 3.5-6.5 years of age. AB - AIM: We explored the associations between childhood exposure to screens, including televisions, computers, game consoles, tablets and smartphones, and primary language disorders. METHODS: This multi-centre case-control study comprised 167 children aged 3.5-6.5 years, who were born in 2010-2012 and diagnosed with primary language disorders, and 109 matched controls without language disorders. Questionnaires were completed by their parents who were recruited by 16 family doctors and 27 speech and language therapists in the Ille et-Vilaine region of France. The data were analysed using a multivariate logistic regression model and presented as adjusted odds ratios (aOR) and 95% confidence intervals (95% CI). RESULTS: We found that cases (44.3%) and controls (22.0%) exposed to screens in the morning before nursery or primary school were three times more likely to develop primary language disorders (aOR 3.40, 95% CI 1.60 7.23). When this risk was combined with rarely or never discussing screen content with their parents (aOR 2.14, 95% CI 1.01-4.54) they were six times more likely to have language problems (aOR 5.86, 95% CI 1.44-23.95). CONCLUSION: Being exposed to screens in the morning before school, and rarely or never discussing screen content with parents, meant children were six times more likely to develop primary language disorders. This article is protected by copyright. All rights reserved. PMID- 30415473 TI - Relationship between timing of trial randomization, protocol completion, and clinical outcomes among patients hospitalized for heart failure: from the ASTRONAUT trial. PMID- 30415472 TI - Upregulation of mtSSB by interleukin-6 promotes cell growth through mitochondrial biogenesis-mediated telomerase activation in colorectal cancer. AB - It is now widely accepted that mitochondrial biogenesis is inhibited in most cancer cells. Interestingly, one of the possible exceptions is colorectal cancer (CRC), in which the content of mitochondria has been found to be higher than in normal colon mucosa. However, to date, the causes and effects of this phenomenon are still unclear. In the present study, we systematically investigated the functional role of mitochondrial single-strand DNA binding protein (mtSSB), a key molecule in the regulation of mitochondrial DNA (mtDNA) replication, in the mitochondrial biogenesis and CRC cell growth. Our results demonstrated that mtSSB was frequently upregulated in CRC tissues and that upregulated mtSSB was associated with poor prognosis in CRC patients. Furthermore, overexpression of mtSSB promoted CRC cell growth in vitro by regulating cell proliferation. The in vivo assay confirmed these results, indicating that the forced expression of mtSSB significantly increases the growth capacity of xenograft tumors. Mechanistically, the survival advantage conferred by mtSSB was primarily caused by increased mitochondrial biogenesis and subsequent ROS production, which induced telomerase reverse transcriptase (TERT) expression and telomere elongation via Akt/mTOR pathway in CRC cells. In addition, FOXP1, a member of the forkhead box family, was identified as a new transcription factor for mtSSB. Moreover, our results also demonstrate that proinflammatory IL-6/STAT3 signaling facilitates mtSSB expression and CRC cell proliferation via inducing FOXP1 expression. Collectively, our findings demonstrate that mtSSB induced by inflammation plays a critical role in the regulation of mitochondrial biogenesis, telomerase activation, and subsequent CRC proliferation, providing a strong evidence for mtSSB as drug target in CRC treatment. PMID- 30415474 TI - Mapping GABA and glutamate inputs to gonadotrophin-releasing hormone neurones in male and female mice. AB - Gonadotrophin-releasing hormone (GnRH) neurone function is dependent upon gonadal steroid hormone feedback, which is communicated in large part through an afferent neuronal network. The classical neurotransmitters GABA and glutamate are important regulators of GnRH neurone activity and are implicated in mediating feedback signals. In the present study, we aimed to determine whether GABAergic or glutamatergic input to GnRH neurones differs between males and females and/or exhibits morphological plasticity in response to steroid hormone feedback in females. Tissue collected from GnRH-green fluorescent protein (GFP) male and female mice in dioestrus underwent immunofluorescence labelling of GFP and either the vesicular GABA transporter (VGAT) or the vesicular glutamate transporter 2 (VGLUT2). No differences in the densities or absolute numbers of VGAT immunoreactive (-IR) or VGLUT2-IR puncta apposed to GnRH neurones were identified between males and females. The most significant input from either neurotransmitter was to the proximal dendritic region and 80% of VGAT-IR puncta apposed to GnRH neurones co-localised with synaptophysin. Putative inputs were also assessed in ovariectomised (OVX) female mice treated with negative (OVX+E) or positive (OVX+E+E) feedback levels of oestrogen, and OVX+E+E mice were killed during the expected GnRH/luteinising hormone surge. No differences in VGLUT2-IR contacts to GnRH neurones were identified between animals under the negative feedback influence of oestrogen (OVX+E) or the positive influence of oestrogen (OVX+E+E), regardless of cFos activation status. By contrast, a significant elevation in putative GABAergic inputs to GnRH neurones at the time of the preovulatory surge was found in the cFos-negative subset of GnRH neurones, both at the level of the soma and at the proximal dendrite. Taken together, these data suggest that, although GABAergic and glutamatergic innervation of GnRH neurones is not sexually differentiated, cyclic fluctuations in steroid hormone feedback over the female oestrous cycle result in plastic changes in GABAergic inputs to a subpopulation of GnRH neurones. PMID- 30415475 TI - Low structural complexity of non-native grassland habitat exposes prey to higher predation. AB - The structural complexity of vegetation can have profound effects on the hunting efficiency of predators, thereby affecting their intake rate of prey. While studies have shown that vegetation complexity can play an important role in managing unwanted impacts of predators, it is less clear how structural complexity of invasive vegetation affects the vulnerability of terrestrial prey. Short non-native pasture species, for example, bred for agricultural production are highly invasive and pervade grassland ecosystems worldwide. They generally have low structural complexity compared with taller native vegetation they often displace. We conducted controlled experiments to test whether non-native pastures expose fauna to greater predation risk. Survival of invertebrates (tethered locusts) subject to predation by invasive mammalian insectivores (European hedgehogs) in non-native pasture (0.10 per 24 hrs; 95% CI, 0.08-0.13) was less than half that in structurally complex native perennial tussock (bunch) grass (0.24; 95% binomial CI, 0.18-0.31). A significant positive relationship was apparent between structural complexity (grass dry stem density) surrounding each locust and their survival. In a second experiment, survival of locusts placed solely in tussock increased with decreasing locust density in tussock, presumably reflecting fewer resource-rich patches that predators could focus on. These results demonstrate that invasion by structurally simple non-native vegetation exposes prey to greater risk of predation. This is concerning from a global nature conservation perspective given that conversion of nearly half of the world's temperate grasslands to agriculture includes a range of invasive, structurally simple non-native plant species. Minimising invasion, and maintaining and restoring complex habitat structure may be a useful conservation option for reducing unwanted predation. This article is protected by copyright. All rights reserved. PMID- 30415476 TI - The ultrasound characteristics of regions identified as suspicious by magnetic resonance imaging (MRI) predict the likelihood of clinically significant cancer on MRI-ultrasound fusion-targeted biopsy. AB - OBJECTIVE: To determine whether the presence of an ultrasound hypoechoic region at the site of a region of interest (ROI) on magnetic resonance imaging (MRI) results in improved prostate cancer (PCa) detection and predicts clinically significant PCa on MRI-ultrasonography fusion-targeted prostate biopsy (MRF-TB). MATERIALS AND METHODS: Between July 2011 and June 2017, 1058 men who underwent MRF-TB, with or without systematic biopsy, by a single surgeon were prospectively entered into an institutional review board-approved database. Each MRI ROI was identified and scored for suspicion by a single radiologist, and was prospectively evaluated for presence of a hypoechoic region at the site by the surgeon and graded as 0, 1 or 2, representing none, a poorly demarcated ROI-HyR, or a well demarcated ROI-HyR, respectively. The interaction of MRI suspicion score (mSS) and ultrasonography grade (USG), and the prediction of cancer detection rate by USG, were evaluated through univariate and multivariate analysis. RESULTS: For 672 men, the overall and Gleason score (GS) >=7 cancer detection rates were 61.2% and 39.6%, respectively. The cancer detection rates for USGs 0, 1 and 2 were 46.2%, 58.6% and 76.0% (P < 0.001) for any cancer, and 18.7%, 35.2% and 61.1% (P < 0.001) for GS >=7 cancer, respectively. For MRF-TB only, the GS >=7 cancer detection rates for USG 0, 1 and 2 were 12.8%, 25.7% and 52.0%, respectively (P < 0.001). On univariate analysis, in men with mSS 2-4, USG was predictive of GS >=7 cancer detection rate. Multivariable regression analysis showed that USG, prostate-specific antigen density and mSS were predictive of GS >=7 PCa on MRF-TB. CONCLUSIONS: Ultrasonography findings at the site of an MRI ROI independently predict the likelihood of GS >=7 PCa, as men with a well demarcated ROI-HyR at the time of MRF-TB have a higher risk than men without. PMID- 30415477 TI - Optimization of Ultrasound-Assisted Extraction of Monoterpene Glycoside from Oil Peony Seed Cake. AB - Ultrasound-assisted extraction (UAE) of total monoterpene glycosides extract (TMGE) from oil peony seed cakes was investigated. The extraction yield was optimized using response surface methodology (RSM). The chemical constituents of the monoterpene glycosides extract were isolated by repeated column chromatography, and the contents of the main isolated monoterpene glycosides in the oil peony seed cakes were determined by HPLC. The optimum conditions were as follows: a liquid-to-solid ratio of 27 mL/g, ultrasonic extraction time of 16 min, ultrasonic extraction temperature of 26 degrees C, and ethanol concentration of 67%. Under these conditions, the extraction yield of TMGE was 10.24%. Twenty monoterpene glycosides were isolated from the oil peony seed cakes, and compounds 11-12, 16 and 20 showed strong inhibitory activities on NO production. TMGE from oil peony seed cakes can also to be used as promising immunosuppressive drug due to its high content of monoterpene glycosides and immune-inhibitory activity. PRACTICAL AAPPLICATION: The peony seed oil was authorized as a new food by the Ministry of Health of the People's Republic of China. Peony seed cake is one of the most important by-products in the preparation of peony seed oil, and accounts for approximately 40% of the total mass of the peony seed. Total monoterpene glycosides are the main active ingredient of oil peony seed cake. This research has optimized the extraction conditions of total monoterpene glycoside from seeds cake of Paeonia ostii, which will provide useful reference information for further studies, and offer related industries with helpful guidance in practice. PMID- 30415478 TI - Antihistamine-resistant chronic spontaneous urticaria: 1-year data from the AWARE study. AB - BACKGROUND: Previous reports indicate that patients with chronic spontaneous urticaria (CSU) are undertreated and that physicians show poor adherence to guideline recommendations. Awareness of CSU has improved in recent years, but it remains unclear if this has improved the management of these patients in clinical practice. OBJECTIVE: To describe disease burden, quality of life (QoL), and treatment patterns of patients with H1 -antihistamine-refractory CSU in Germany. METHOD: AWARE (A World-wide Antihistamine-Refractory chronic urticaria patient Evaluation) is a global prospective, non-interventional study of chronic urticaria in the real-world setting, supported by the manufacturer of omalizumab. Patients (18-75 years) were included who had H1 -antihistamine-refractory CSU for >=2 months. Disease characteristics, pharmacological treatments, and QoL (dermatology life quality index [DLQI], chronic urticaria QoL questionnaire, and angioedema QoL questionnaire) are reported for patients enrolled in Germany. RESULTS: After 1 year in AWARE, CSU remained uncontrolled (urticaria control test [UCT] score <12) in 432 of 1032 (42.2%) patients. QoL impairment remained high after one year, with 28.2% of patients reporting that CSU had a moderate/very large/extremely large effect on the DLQI. Most patients did not receive guideline recommended treatments at the end of the one-year observation period. Changes in treatments were most evident at the first patient visit, with an increase in patients receiving omalizumab vs. prior therapy from 8.5% to 21.4%, and a decrease in those receiving no treatment from 29.9% to 12.8%. These changes were associated with reduced hives, angioedema, UCT scores, and QoL scores at Month 3, but only modest improvements thereafter. Of 528 patients with uncontrolled CSU and who were eligible for treatment escalation, only 3% received up-dosing of H1 antihistamines and only 5% were initiated on omalizumab during one year of treatment. CONCLUSIONS & CLINICAL RELEVANCE: This study highlights a significant discrepancy between recommendations for managing CSU in international guidelines, and in real-world clinical practice in Germany. This article is protected by copyright. All rights reserved. PMID- 30415479 TI - The US Biosimilar Market: Stunted Growth and Possible Reforms. AB - In 2010, Congress created an abbreviated application pathway for biosimilars, versions of approved biologics made by different manufacturers. However, as of November 1, 2018, the Food and Drug Administration had approved only 13 biosimilars under this pathway, of which just 6 were available for patients to use. We review the history of US regulation of biologics and identify manufacturing, regulatory, and marketing issues that have limited biosimilar market entry and uptake, concluding with recommendations for reform. This article is protected by copyright. All rights reserved. PMID- 30415480 TI - Interplay of central and peripheral circadian clocks in energy metabolism regulation. AB - Metabolic health founds on a homeostatic balance that has to integrate the daily changes of rest/activity and feeding/fasting cycles. A network of endogenous 24 hour circadian clocks helps to anticipate daily recurring events and adjust physiology and behavioural functions accordingly. Circadian clocks are self sustained cellular oscillators based on a set of clock genes/proteins organised in interlocked transcriptional-translational feedback loops. The body's clocks need to be regularly reset and synchronised with each other to achieve coherent rhythmic output signals. This synchronisation is achieved by interplay of a master clock, which resides in the suprachiasmatic nucleus, and peripheral tissue clocks. This clock network is reset by time signals such as the light/dark cycle, food intake and activity. The balanced interplay of clocks is easily disturbed in modern society by shiftwork or high-energy diets, which may further promote the development of metabolic disorders. In this review, we summarise the current model of central-peripheral clock interaction in metabolic health. Different established mouse models for central or peripheral clock disruption and their metabolic phenotypes are compared and the possible relevance of clock network interaction for the development of therapeutic approaches in humans is discussed. PMID- 30415481 TI - Protective stabilization of mitochondrial permeability transition and mitochondrial oxidation during mitochondrial Ca2+ stress by melatonin's cascade metabolites C3-OHM and AFMK in RBA1 astrocytes. AB - Cyclic 3-hydroxymelatonin (C3-OHM) and N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) are two major cascade metabolites of melatonin. We previously showed melatonin provides multiple levels of mitochondria-targeted protection beyond as a mitochondrial antioxidant during ionomycin-induced mitochondrial Ca2+ (mCa2+ ) stress in RBA1 astrocytes. Using noninvasive laser scanning fluorescence coupled time-lapse digital imaging microscopy, this study investigated whether C3-OHM and AFMK also provide mitochondrial levels of protection during ionomycin-induced mCa2+ stress in RBA1 astrocytes. Interestingly, precise temporal and spatial dynamic live mitochondrial images revealed that C3-OHM and AFMK prevented specifically mCa2+ -mediated mitochondrial reactive oxygen species (mROS) formation and hence mROS-mediated depolarization of mitochondrial membrane potential (?Psim ) and permanent lethal opening of the MPT (p-MPT). The antioxidative effects of AFMK, however, were less potent than that of C3-OHM. Whether C3-OHM and AFMK targeted directly the MPT was investigated under a condition of "oxidation free-Ca2+ stress" using a classic antioxidant vitamin E to remove mCa2+ -mediated mROS stress and the potential antioxidative effects of C3-OHM and AFMK. Intriguingly, two compounds still effectively postponed "oxidation free-Ca2+ stress"-mediated depolarization of ?Psim and p-MPT. Measurements using a MPT pore-specific indicator Calcein further identified that C3-OHM and AFMK, rather than inhibiting, stabilized the MPT in its transient protective opening mode (t-MPT), a critical mechanism to reduce overloaded mROS and mCa2+ . These multiple layers of mitochondrial protection provided by C3-OHM and AFMK thus crucially allow melatonin to extend its metabolic cascades of mitochondrial protection during mROS- and mCa2+ -mediated MPT-associated apoptotic stresses and may provide therapeutic benefits against astrocyte mediated neurodegeneration in the CNS. PMID- 30415482 TI - A novel GNRHR gene mutation causing Congenital Hypogonadotropic Hypogonadism (CHH) in a Brazilian Kindred. AB - Congenital Hypogonadotropic Hypogonadism (CHH) is a challenging inherited endocrine disorder characterized by absent or incomplete pubertal development and infertility due to low action/secretion of the hypothalamic gonadotrophin releasing hormone (GnRH). Given a growing list of gene mutations accounting for CHH, application of massively parallel sequencing has become an excellent molecular diagnosis approach since it has enabled simultaneous evaluation of many genes. The study proposes the use of Whole Exome Sequencing (WES) to identify causative and modifying mutations based on a phenotype-genotype CHH analysis by in-house exome pipeline. Based on 44 known genes related to CHH in humans, we were able to identify a novel homozygous GNRHR p.Thr269Met mutant, which segregates with CHH kindred and was predicted to be deleterious by in silico analysis. A functional study measuring intracellular inositol phosphate (IP) when stimulated with GnRH on COS-7 cells confirmed that the p.Thr269Met GnRHR mutant performed greatly diminished IP accumulation relative to the transfected wild type GnRHR. Additionally, the proband carries three heterozygous variants in CCDC141 and one homozygous in SEMA3A gene, but their effects in modifying the phenotype are uncertain. Since they do not segregate with reproductive phenotype in family members, we advocate they do not contribute to CHH oligogenicity. WES proved to be useful for CHH molecular diagnosis and reinforced its benefit for identifying heterogeneous genetic disorders. Our findings expand the GnRHR mutation spectrum and phenotype-genotype correlation in CHH. This article is protected by copyright. All rights reserved. PMID- 30415483 TI - Lung cancer after lung transplantation: An analysis of 25 years of experience in a single institution. AB - BACKGROUND: The aim of our study was to describe the lung cancer characteristics in lung transplant recipients at our institution. METHODS: Between January 1, 1992, and August 15, 2017, 463 patients underwent lung transplantation. RESULTS: We found a total of 19 lung cancers (4.10%). Eight patients had lung cancer in the explanted lung, 8 in the native remaining lung, and 3 in the transplanted lung. Histopathological findings were: adenocarcinoma in 10, SCC in 8 patients, and 1 was undetermined. Among lung cancers in the explanted lungs, there were 6 stage I, 1 stage III, 1 stage IV. Among patients with a lung cancer in the remaining native lung, 3 had early stage disease and 5 had stage IV disease. Among lung cancers in the transplanted lung, there were: 1 stage I, 1 stage II and 1 stage IV. Overall median survival in lung transplant recipients without lung cancer was 8.77 +/- 0.74 years compared to 6.19 +/- 1.4 years in recipients with lung cancer. CONCLUSION: Lung cancer following lung transplantation was uncommon. Early stage lung cancer discovered in the explanted lungs had no impact on survival. Lung cancer occurring in the transplanted or in the native remaining lung had a poor prognosis. PMID- 30415484 TI - Traffic-related air pollution induces non-allergic eosinophilic airway inflammation and cough hypersensitivity in guinea pigs. AB - BACKGROUND: The pathogenesis and pathophysiology of eosinophilia-related chronic cough such as non-asthmatic eosinophilic bronchitis and cough variant asthma are still not clear. OBJECTIVE: This study is to examine the potential role of traffic-related air pollution (TRAP) in eosinophilic inflammation and cough responses. METHODS: Non-sensitized guinea pigs were exposed to TRAP in an urban traffic tunnel or kept in a filtered air environment for 7 or 14 days. Reflexive cough was measured using citric acid and allyl isothiocyanate (AITC) challenges, respectively. Spontaneous cough counting was determined using audio recording and a waveform analysis. Airway inflammation was evaluated using differential cells in bronchoalveolar lavage fluid (BALF) and lung histopathology. To further elucidate the relationship between airway inflammation and cough hypersensitivity, a subgroup of those exposed for 14 days received a dexamethasone treatment. RESULTS: Compared to reflexive cough count (mean (95% confidence interval) in 10 min) provoked by the AITC challenge for the unexposed animals (3.1 (1.7-4.5)), those were increased significantly following both the 7 day (12.0 (6.8-17.2), p<0.01) and the 14-day (12.0 (6.4-17.6), p<0.01) TRAP exposure. The effect provoked by the citric acid challenge was more profound following the 14-day exposure (26.0 (19.5-32.5) vs. 3.8 (1.5-6.0) for the control, p<0.001). TRAP exposures enhanced spontaneous cough events, caused a significant increase of eosinophils and neutrophils in BALF, and resulted in a dramatic eosinophilic infiltration in submucosal layer of trachea and bronchus, which can be inhibited significantly by dexamethasone treatment. CONCLUSIONS & CLINICAL RELEVANCE: TRAP exposures induced cough hypersensitivity and non allergic eosinophilic inflammation of airways in guinea pigs. This study highlights the potential mechanisms of eosinophilia-related chronic cough that can be induced by traffic-related air pollution. This article is protected by copyright. All rights reserved. PMID- 30415485 TI - The role of sensorimotor experience in the development of mimicry in infancy. AB - During social interactions we often have an automatic and unconscious tendency to copy or 'mimic' others' actions. The dominant view on the neural basis of mimicry appeals to an automatic coupling between perception and action. It has been suggested that this coupling is formed through associative learning during correlated sensorimotor experience. Although studies with adult participants have provided support for this hypothesis, little is known about the role of sensorimotor experience in supporting the development of perceptual-motor couplings, and consequently mimicry behaviour, in infancy. Here we investigated whether the extent to which an observed action elicits mimicry depends on the opportunity an infant has had to develop perceptual-motor couplings for this action through correlated sensorimotor experience. We found that mothers' tendency to imitate their 4-month-olds' facial expressions during a parent-child interaction session was related to infants' facial mimicry as measured by electromyography. Maternal facial imitation was not related to infants' mimicry of hand actions, and instead we found preliminary evidence that infants' tendency to look at their own hands may be related to their tendency to mimic hand actions. These results are consistent with the idea that mimicry is supported by perceptual-motor couplings that are formed through correlated sensorimotor experience obtained by observing one's own actions and imitative social partners. PMID- 30415486 TI - Tracking seasonal rhythms of plants in diverse ecosystems with digital camera imagery. AB - Global change is shifting the seasonality of vegetation in ecosystems around the globe. High-frequency digital camera imagery, and vegetation indices derived from that imagery, is facilitating better tracking of phenological responses to environmental variation. This method, commonly referred to as the "phenocam" approach, is well-suited to several specific applications, including: close-up observation of individual organisms; long-term canopy-level monitoring at individual sites; automated regional-to-continental scale observatory networks; and tracking responses to experimental treatments. Several camera networks are already well-established, and some camera records are a more than a decade long. These data can be used to identify the environmental controls on phenology in different ecosystems, which will contribute to the development of improved prognostic phenology models. This article is protected by copyright. All rights reserved. PMID- 30415488 TI - Trans-lineage polymorphism and non-bifurcating diversification of the genus Picea. AB - Non-bifurcating divergence caused by introgressive hybridization is continuously reported for groups of closely related species. In this study, we aimed to construct genome-scale classification of deep lineages of the conifer genus Picea, establish their phylogenetic relationships and test the bifurcating hypothesis between deeply branching lineages based on genomic data. We sequenced the transcriptomes of 35 individuals of 27 taxa covering all main lineages of the genus. Four major lineages, comprising three to 12 taxa each, largely consistent with morphological evidence, were recovered across the coalescent and integrated nuclear phylogeny. However, many of the individual gene trees recovered contradict one another. Moreover, the well-supported coalescent tree here inferred differs from previous studies based on various DNA markers, with respect to topology and inter-lineage relationships. We identified the shared polymorphisms between four major lineages. ABBA-BABA tests confirmed the inter lineage gene flow and thus violated the bifurcating divergence model. Gene flow occurred more frequently between lineages distributed in the same continent than those disjunct between continents. Our results indicate that introgression and non-bifurcating diversification apply, even between deeply branching lineages of the conifer genus Picea. This article is protected by copyright. All rights reserved. PMID- 30415487 TI - Klebsiella pneumoniae disassembles host microtubules in lung epithelial cells. AB - Klebsiella pneumoniae raises significant concerns to the health care industry as these microbes are the source of widespread contamination of medical equipment, cause pneumonia as well as other multiorgan metastatic infections and have gained multidrug resistance. Despite soaring mortality rates, the host cell alterations occurring during these infections remain poorly understood. Here, we show that during in vitro and in vivo K. pneumoniae infections of lung epithelia, microtubules are severed and then eliminated. This destruction does not require direct association of K. pneumoniae with the host cells, as microtubules are disassembled in cells that are distant from the infecting bacteria. This microtubule dismantling is dependent on the K. pneumoniae (Kp) gene ytfL as non pathogenic Escherichia coli expressing Kp ytfL disassemble microtubules in the absence of K. pneumoniae itself. Our data points to the host katanin catalytic subunit A like 1 protein (KATNAL1) and the katanin regulatory subunit B1 protein (KATNB1) as the gatekeepers to the microtubule severing event as both proteins localise specifically to microtubule cut sites. Infected cells that had either of these proteins knocked out maintained intact microtubules. Taken together, we have identified a novel mechanism that a bacterial pathogen has exploited to cause microtubule destruction within the host epithelia. PMID- 30415489 TI - Chronic liver injury drives non-traditional intrahepatic fibrin(ogen) cross linking via tissue transglutaminase. AB - INTRODUCTION: Intravascular fibrin clots and extravascular fibrin deposits are often implicated in the progression of liver fibrosis. However, evidence supporting a pathological role of fibrin in hepatic fibrosis is indirect and based largely on studies using anticoagulant drugs that inhibit activation of the coagulation protease thrombin, which has other downstream targets that promote fibrosis. Therefore, the goal of this study was to determine the precise role of fibrin deposits in experimental hepatic fibrosis. METHODS: Liver fibrosis was induced in mice expressing mutant fibrinogen insensitive to thrombin-mediated proteolysis (i.e., locked in the monomeric form), termed FibAEK mice, and Factor XIII A2 subunit-deficient mice (FXIII-/- ). Female wild-type mice, FXIII-/- mice, and homozygous FibAEK mice were challenged with carbon tetrachloride (CCl4 ), twice weekly for 4 or 6 weeks (1 ml/kg, ip). RESULTS: Hepatic injury and fibrosis induced by CCl4 challenge were unaffected by FXIII deficiency or inhibition of thrombin-catalyzed fibrin polymer formation (in FibAEK mice). Surprisingly, hepatic deposition of cross-linked fibrin(ogen) was not reduced in CCl4 challenged FXIII-/- mice or FibAEK mice compared to wild-type mice. Rather, deposition of cross-linked hepatic fibrin(ogen) following CCl4 challenge was dramatically reduced in tissue transglutaminase-deficient mice (TGM2-/- mice). However, the reduction in cross-linked fibrin(ogen) in TGM2-/- mice did not affect CCl4 -induced liver fibrosis. CONCLUSIONS: These results indicate that neither traditional fibrin clots, formed by the thrombin:FXIIIa pathway, nor atypical TGM2-cross-linked fibrin(ogen) contribute to experimental CCl4 -induced liver fibrosis. Collectively, the results indicate that liver fibrosis occurs independently of intrahepatic fibrin(ogen) deposition. This article is protected by copyright. All rights reserved. PMID- 30415490 TI - The impact of currently licensed therapies on viral and immune responses in Chronic Hepatitis B: considerations for future novel therapeutics. AB - Despite the availability of a preventative vaccine, chronic hepatitis B (CHB) remains a global healthcare challenge with the risk of disease progression due to cirrhosis and hepatocellular carcinoma. Although current treatment strategies, Interferon and nucleos(t)ide analogues have contributed to reducing morbidity and mortality related to CHB, these therapies are limited in providing functional cure. The treatment paradigm in CHB is rapidly evolving with a number of new agents in the developmental pipeline. However, until novel agents with functional cure capability are available in the clinical setting, there is a pressing need to optimise currently licensed therapies. Here we discuss current agents used alone and/or in combination strategies along with the impact of these therapies on viral and immune responses. Novel treatment strategies are outlined and the potential role of current therapies in the employment of pipeline agents is discussed. This article is protected by copyright. All rights reserved. PMID- 30415491 TI - Arabidopsis ANAC092 regulates auxin-mediated root development by binding to the ARF8 and PIN4 promoters. AB - Auxin is an important plant hormone that is essential for growth and development due to its effects on organogenesis, morphogenesis, tropisms, and apical dominance. The functional diversity of auxin highlights the importance of its biosynthesis, transport, and associated responses. In this study, we show that a NAC transcription factor, ANAC092 (also named AtNAC2 and ORESARA1), known to positively regulate leaf senescence and contribute to abiotic stress responses, also affects primary root development. Plants overexpressing ANAC092 had altered root meristem lengths and shorter primary roots compared with the wild-type control. Additionally, expression of the proANAC092::GUS was strongly induced by indole-3-acetic acid. Quantitative real-time RT-PCR (qRT-PCR) analysis revealed that the YUCCA2, PIN, and ARF expression levels were downregulated in ANAC092 overexpressing plants. Moreover, yeast one-hybrid and chromatin immunoprecipitation assays confirmed that ANAC092 binds to the promoters of AUXIN RESPONSE FACTOR 8 (ARF8) and PIN-FORMED 4 (PIN4). Furthermore, a dual-luciferase assay indicated that ANAC092 decreases ARF8 and PIN4 promoter activities. We also applied a CRISPR/Cas9 system to mutate ANAC092. The roots of three of the analyzed mutants were longer than normal. Collectively, our findings indicate that ANAC092 negatively affects root development by controlling the auxin pathway. PMID- 30415492 TI - Regulation of osteoblasts by alkaline phosphatase in ankylosing spondylitis. AB - AIM: Ankylosing spondylitis (AS) is characterized by excessive spinal ankylosis and bone formation. Alkaline phosphatase (ALP) activity is reported to be high in AS, but little is known about the molecular relationship between ALP and AS. The aims of this study were to investigate the relevance of ALP to AS and the role of ALP in the regulation of osteoblast differentiation in AS. METHODS: High throughput data with accession numbers GSE73754 and GSE41038 were downloaded from the Gene Expression Omnibus. We retrospectively collected and compared the ALP levels of male patients with AS to those of sex- and age-matched healthy controls (HC) and rheumatoid arthritis (RA) patients. Total serum ALP and ALP activity were measured in the AS and RA groups. ALP gene expression and intracellular ALP activity were analyzed in microarray data from primary diseases control (Ct) and AS-bone-derived cells (BdCs) and in vitro experiments. Furthermore, the effect of ALP inhibitor was examined in both primary Ct- and AS-BdCs under osteoblast differentiation. Regulation of runt-related transcription factor 2 (RUNX2) by ALP was also analyzed. RESULTS: Alkaline phosphatase level was higher in AS compared with RA and HC and was associated with radiograph progression. ALP expression was also enriched in the bone tissue of AS patients. Furthermore, AS-BdCs exhibited increasing ALP activity, leading to accelerated osteoblastic activity and differentiation. Intriguingly, inhibition of ALP reduced RUNX2 expression, a master transcriptional factor in osteoblasts, and differentiation status of both primary Ct- and AS-BdCs. Treatment of ALP activator or inhibitor modulated RUNX2 protein level and RUNX2 regulated ALP promoter activity, indicating a reciprocal ALP-RUNX2 positive feedback to regulate osteoblast differentiation. CONCLUSION: Alkaline phosphatase was highly expressed in AS patients, may be involved in the ankylosis of AS, and represents a possible therapeutic target for ankylosis. PMID- 30415493 TI - Reconstruction of the Replaced Right Hepatic Artery Using Donor Iliac Arterial Y Graft in Orthotopic Liver Transplantation: A Single Center Experience Over 1700 Transplants. AB - Variations in the donor hepatic arterial anatomy can potentially present difficulties when completing the hepatic arterial reconstruction in orthotopic liver transplantation (OLT). It has previously been reported that in roughly 20% of the population, variations in hepatic arterial anatomy are present with the most common being type III or replaced right hepatic artery (RRH) arising from the superior mesenteric artery (SMA) (1,2,3). Of the many anomalies encountered, our focus in the current letter is on the reconstruction of the replaced right hepatic artery (Type III). This article is protected by copyright. All rights reserved. PMID- 30415494 TI - Return of secondary findings in genomic sequencing: Military implications. AB - BACKGROUND: Genomic sequencing has become a widely used tool in clinical and research settings in both civilian and military healthcare systems. METHODS: In this paper, we consider potential military-specific implications of returning genomic sequencing secondary findings to ensure the proper protections, policies, and processes are in place for the use of this information. RESULTS: We specifically use two examples to highlight potential military implications of the return of secondary findings. CONCLUSION: Clinicians and researchers are strongly encouraged to consider the military implications of the return of results for informed consent of service members or their families undergoing clinical or research genomic sequencing. PMID- 30415495 TI - Whole exome sequencing identifies novel predisposing genes in neural tube defects. AB - BACKGROUND: Neural tube defects (NTD) are among the most common defects affecting 1:1000 births. They are caused by a failure of neural tube closure during development. Their clinical presentation is diverse and dependent on the site and severity of the original defect on the embryonic axis. The etiology of NTD is multifactorial involving environmental factors and genetic variants that remain largely unknown. METHODS: We have conducted a whole exome sequencing (WES) study in five new NTD families and pooled the results with WES data from three NTD families and 43 trios that were previously investigated by our group. We analyzed the data using biased candidate gene and unbiased gene burden approaches. RESULTS: We identified four novel loss-of-function variants in three genes, MTHFR, DLC1, and ITGB1, previously associated with NTD. Notably, DLC1 carried two protein truncating variants in two independent cases. We also demonstrated an enrichment of variants in MYO1E involved in cytoskeletal remodeling. This enrichment reached borderline significance in a replication cohort supporting the association of this new candidate gene to NTD. CONCLUSION: These data provide some key insights into the pathogenic mechanisms of human NTD and demonstrate the power of next-generation sequencing in deciphering the genetics of this complex trait. PMID- 30415496 TI - Global knowledge gaps in the prevention and control of bovine viral diarrhoea (BVD) virus. AB - The significant economic impacts of bovine viral diarrhoea (BVD) virus have prompted many countries worldwide to embark on regional or national BVD eradication programmes. Unlike other infectious diseases, BVD control is highly feasible in cattle production systems because the pathogenesis is well understood and there are effective tools to break the disease transmission cycle at the farm and industry levels. Coordinated control approaches typically involve directly testing populations for virus or serological screening of cattle herds to identify those with recent exposure to BVD, testing individual animals within affected herds to identify and eliminate persistently infected (PI) cattle, and implementing biosecurity measures such as double-fencing shared farm boundaries, vaccinating susceptible breeding cattle, improving visitor and equipment hygiene practices, and maintaining closed herds to prevent further disease transmission. As highlighted by the recent DISCONTOOLS review conducted by a panel of internationally recognized experts, knowledge gaps in the control measures are primarily centred around the practical application of existing tools rather than the need for creation of new tools. Further research is required to: (a) determine the most cost effective and socially acceptable means of applying BVD control measures in different cattle production systems; (b) identify the most effective ways to build widespread support for implementing BVD control measures from the bottom-up through farmer engagement and from the top-down through national policy; and (c) to develop strategies to prevent the reintroduction of BVD into disease-free regions by managing the risks associated with the movements of animals, personnel and equipment. Stronger collaboration between epidemiologists, economists and social scientists will be essential for progressing efforts to eradicate BVD from more countries worldwide. PMID- 30415497 TI - Systems Model-Guided Rice Yield Improvements Based on Genes Controlling Source, Sink and Flow. AB - A large number of genes related to source, sink and flow have been identified after decades of research in plant genetics. Unfortunately, these genes have not been effectively utilized in modern crop breeding. This perspective paper aims to examine the reasons behind such a phenomenon and propose a strategy to resolve this situation. Specifically, we first systematically survey the currently cloned genes related to source, sink and flow; then we discuss three factors hindering effective application of these identified genes, which include the lack of effective methods to identify limiting or critical steps in a signaling network, the misplacement of emphasis on properties, at the leaf, instead of the whole canopy level, and the non-linear complex interaction between source, sink and flow. Finally, we propose the development of systems models of source, sink and flow, together with detailed simulation of interactions between them and their surrounding environments, to guide effective use the identified elements in modern rice breeding. These systems models will contribute directly to the definition of crop ideotype and also identification of critical features and parameters that limit the yield potential in current cultivars. PMID- 30415498 TI - Elderly onset of early rheumatoid arthritis is a risk factor for bone erosions, refractory to treatment: KURAMA cohort. AB - AIM: Age at disease onset has been implicated as an indicator of disease activity and severity in rheumatoid arthritis (RA). This study aimed to investigate how old age at disease onset affects patient treatment and prognosis in early RA. METHODS: Data from the Kyoto University Rheumatoid Arthritis Management Alliance (KURAMA) cohort was analyzed. From 2011 to 2015, a total of 2182 patients with RA were enrolled in the cohort; 239 patients were newly diagnosed with RA and were followed up for 2 years. The patients were divided into the following two groups: the young-onset RA (YORA) which included patients <60 years old (n = 117) and elderly-onset RA (EORA) which comprised patients >=60 years old (n = 122). The clinical and laboratory data were compared at baseline, at 1 year, and at 2 years after onset. RESULTS: Disease activity was higher in EORA than in YORA at baseline. Although disease activity was equivalent between EORA and YORA at 1 or 2 years, more EORA patients had bone erosions at baseline and at 2 years. More than 25% of the anti-citrullinated protein autoantibody (ACPA)-positive EORA patients without erosions at baseline had bone erosions even if they attained clinical remission at 1 or 2 years, while ~10% of YORA patients had erosions. CONCLUSION: Bone erosions were more frequently found in EORA. Clinical remission at 1 or 2 years was not enough to protect bone erosions in the ACPA-positive EORA patients. Optimal treatment strategies preventing radiological damage should be considered for EORA. PMID- 30415499 TI - Human Cardiac Organoids for Disease Modeling. AB - Human cardiac drug discovery and disease modeling face challenges in recapitulating cellular complexity and animal-to-human translation due to the limitations of conventional 2D cell culture and animal models. The development of human cardiac organoid technologies could help in stimulating and maintaining differentiated cell functions for extended periods of time. By closely mimicking in vivo organ functions in vitro they could thereby help in overcoming the obstacles mentioned above. By constructing human cardiac organoids from pluripotent stem cell-derived cells, derived from patients with specific known geno- and phenotypes, more complex and robust in vitro tools have recently become available for disease modeling. In this review we will describe the relevance and importance of evolving organoid platforms in disease biology. We further provide examples of cardiac organoid platforms which may lead the way towards future personalized medicine and drug discovery. This article is protected by copyright. All rights reserved. PMID- 30415500 TI - Assessment of Radiofrequency Ablation Efficacy for Hepatocellular Carcinoma by Histology and Pre-transplant Radiology. AB - Radiofrequency ablation (RFA) represents a potentially curative option for hepatocellular carcinoma (HCC) in the early stages. This study aims at evaluating the histologic response after RFA of small HCCs arising in cirrhosis. Data from 78 patients with de-novo HCCs, treated with RFA and subsequently transplanted were reviewed. The last radiological assessment before liver transplantation (LT) was used for comparison between Modified Response Evaluation Criteria in Solid Tumors (mRECIST) and histological findings. A total of 125 de-novo HCCs (median diameter: 20mm) were treated with RFA only in 92 sessions. Ninety-eight nodules did not show local recurrence during follow-up (78.4%), the remaining were retreated, except one because of subsequent LT. On explanted livers, complete pathological response (CPR) was observed in 61.6%, being 76.9% when <2cm, 55.0% when 2-3cm and 30.8% when >3cm. Tumors near to hepatic vessels had CPR in 50% of cases versus 69.3% for tumors distant from vessels (p=0.039). Of the 125 HCCs, 114 had available radiological assessment within a median of 3 months before LT. mRECIST complete was observed in 77.2% of nodules before LT. The k-Cohen was 0.48 (moderate agreement). The overall accuracy was of 78.1%. A total of 18 complications were recorded, only one graded as major. CONCLUSIONS: RFA can provide high CPR for HCC, especially in smaller tumors distant from hepatic veins or portal branches. The agreement between mRECIST and histology is only moderate. Further refinements in radiological assessment are essential to accurately assess the true effectiveness of RFA. This article is protected by copyright. All rights reserved. PMID- 30415501 TI - Dividing neutrophils in subsets, reveals a significant role for activated neutrophils in the development of airway hyperreactivity. AB - BACKGROUND: Previous research has emphasized the importance of eosinophils in allergic asthma, while paying less attention to neutrophils. The known functionality of neutrophils in the inflammatory process has recently changed and knowledge about subsets of neutrophils, as characterized by their expression of CD16 and CD62L, has surfaced. Their specific roles in asthma are still unknown. OBJECTIVE: To study the functional differences between subsets of neutrophils by characterising the impact of individual subsets on airway smooth muscle reactivity. METHODS: The direct effect of neutrophils on airway hyper responsiveness was assessed by co-culturing different subsets of neutrophils (produced by LPS in vitro stimulation) with human isolated small airways or murine tracheae with subsequent evaluation of smooth muscle reactivity to bradykinin in myographs. Supernatants and tissue were saved for ELISA and immunohistochemistry. RESULTS: The CD16high CD62Ldim neutrophils were found to enhance the response to bradykinin in both human isolated small airways and murine tracheae. No such effects were obtained for the other subsets. The response is due to an upregulation of bradykinin receptor 2 through release of TNFalpha from the neutrophil. CONCLUSIONS & CLINICAL RELEVANCE: The present study introduces a new concept regarding the role of neutrophils and defines a novel direct link between a specific activated neutrophil subset and airway smooth muscle, establishing neutrophils as important players in the development of asthmatic airway hyperactivity. This article is protected by copyright. All rights reserved. PMID- 30415502 TI - Predicting the initial spread of novel Asian origin influenza A viruses in the continental United States by wild waterfowl. AB - Using data on waterfowl band recoveries, we identified spatially-explicit hotspots of concentrated waterfowl movement to predict occurrence and spatial spread of a novel influenza A virus (clade 2.3.4.4) introduced from Asia by waterfowl from an initial outbreak in North America in November 2014. In response to the outbreak, the hotspots of waterfowl movement were used to help guide sampling for clade 2.3.4.4 viruses in waterfowl as an early warning for the U.S. poultry industry during the outbreak. After surveillance sampling of waterfowl, we tested whether there was greater detection of clade 2.3.4.4 viruses inside hotspots. We found that hotspots defined using kernel density estimates of waterfowl band recoveries worked well in predicting areas with higher prevalence of the viruses in waterfowl. This approach exemplifies the value of ecological knowledge in predicting risk to agricultural security. This article is protected by copyright. All rights reserved. PMID- 30415503 TI - Basal cell enumeration does not predict malignancy in canine perianal gland tumor cytology. AB - BACKGROUND: Perianal (hepatoid) gland tumors are common in dogs, and the distinction between the benign and malignant forms is clinically important. Cytology of these tumors typically contains many large hepatoid cells and fewer small basal cells. OBJECTIVES: The objective of this study was to determine whether the proportion of the smaller basaloid reserve cells in cytologic samples from perianal tumors correlates with malignancy. METHODS: Eighty-three cases of cytologically diagnosed perianal gland tumors with corresponding histopathologic sections were identified from two separate institutions and included six (7.2%) malignant tumors and 77 (92.8%) benign tumors. The proportion of basal cells from each sample was evaluated. RESULTS: No difference between these groups was found, although the study was sufficiently powered to detect an approximately 1.5-fold change in basal cell proportion. CONCLUSIONS: This report found no evidence that the proportion of basal cells in canine perianal tumor cytology is an indication of the potential for malignancy. We, therefore, do not recommend citing this feature in cytologic reports or when communicating with clinicians. PMID- 30415504 TI - HSD17B13 is a Hepatic Retinol Dehydrogenase Associated with Histological Features of Non-Alcoholic Fatty Liver Disease. AB - Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. A single nucleotide polymorphism (SNPs), rs6834314, was associated with serum liver enzymes in the general population, presumably reflecting liver fat or injury. We studied rs6834314 and its nearest gene, HSD17B13 (17-beta hydroxysteroid dehydrogenase 13) to identify associations with histological features of NAFLD, and to characterize the functional role of HSD17B13 in NAFLD pathogenesis. The minor allele of rs6834314 was significantly associated with increased steatosis, but decreased inflammation, ballooning, Mallory-Denk bodies, and liver enzyme levels in 768 adult Caucasians with biopsy-proven NAFLD, and with cirrhosis in the general population. We found two plausible causative variants in the HSD17B13 gene. rs72613567, a splice-site SNP in high linkage with rs6834314 (r2 =0.94) generates novel splice variants and shows a similar pattern of association with NAFLD histology. Its minor allele generates simultaneous expression of exon 6-skipping and G-nucleotide insertion variants. Another SNP, rs62305723 (encoding a P260S mutation) is significantly associated with decreased ballooning and inflammation. Hepatic expression of HSD17B13 is 5.9-fold higher (p=0.003) in patients with NAFLD. HSD17B13 is targeted to lipid droplets, requiring the conserved AA22-28 sequence and AA71-106 region. The protein has a retinol dehydrogenase (RDH) activity, with enzymatic activity dependent on lipid droplet targeting and co-factor binding site. The exon 6-deletion, G-insertion, and newly-described naturally-occurring P260S mutation, all confer loss of enzymatic activity. In conclusion, we demonstrate the association of variants in HSD17B13 with specific features of NAFLD histology, and identify the enzyme as a lipid droplet-associated RDH. Our data suggest that HSD17B13 plays a role in NAFLD through its enzymatic activity. This article is protected by copyright. All rights reserved. PMID- 30415505 TI - Mutational load, inbreeding depression and heterosis in subdivided populations. AB - This paper examines the extent to which empirical estimates of inbreeding depression and inter-population heterosis in subdivided populations, as well as the effects of local population size on mean fitness, can be explained in terms of current estimates of mutation rates, and the distribution of selection coefficients against deleterious mutations provided by population genomics data. Using population genetics models, numerical predictions of the genetic load, inbreeding depression and heterosis were obtained for a broad range of selection coefficients and mutation rates. The models allowed for the possibility of very high mutation rates per nucleotide site, as is sometimes observed for epiallelic mutations in plants. There was fairly good quantitative agreement between the theoretical predictions and empirical estimates of heterosis and the effects of population size on genetic load, on the assumption that the deleterious mutation rate per individual per generation is approximately one, but there was less good agreement for inbreeding depression. Weak selection, of the order of magnitude suggested by population genomic data, is required to explain the observed patterns. Possible caveats concerning the applicability of the models are discussed. This article is protected by copyright. All rights reserved. PMID- 30415506 TI - Prevalence of underlying gastrointestinal malignancies in iron-deficient heart failure. AB - AIMS: Anaemia and iron deficiency (ferritin level < 100 or 100-300 MUg/L with transferrin saturation < 20%) are prevalent in heart failure. Mechanistically, iron deficiency is linked to poor intestinal uptake, increased intestinal loss, and chronic inflammation. However, the prevalence of underlying gastrointestinal malignancies is not established in iron-deficient heart failure with or without anaemia. METHODS AND RESULTS: Patients followed up in a single-centre, heart failure database with baseline registration of haemoglobin and iron status were retrospectively evaluated. The proportion of patients undergoing upper and lower gastrointestinal endoscopy between inclusion and censoring was determined. Afterwards, the prevalence of biopsy that confirmed intestinal malignancies in relation to baseline iron and haemoglobin status was determined. Anaemia was defined as a haemoglobin level <12 g/dL, and iron deficiency according to the aforementioned criteria. Of the 1197 patients in the database, 699 (59%) patients underwent full endoscopic workup over a mean follow-up of 50 +/- 27 months. A total of 50 intestinal malignancies were identified (n = 42, 84%, in iron deficient vs. n = 8, 16%, non-iron-deficient patients; P < 0.001). The prevalence of intestinal malignancies was non-statistically different in iron-deficient patients with anaemia (n = 12/129, 9.3%) or without anaemia (n = 30/287, 10.5%; P = 0.551). The prevalence was much lower in patients without iron deficiency with anaemia (n = 5/83, 6%) or without anaemia (n = 3/200, 1.5%). In patients with iron deficiency but without anaemia (a group in which the role of endoscopic workup is less established), ferritin levels carried an inverse diagnostic capacity in detecting patients with an underlying malignancy (area under the curve = 0.741, P < 0.001). A ferritin level < 56 MUg/L had the best acuity, detecting malignancies with a sensitivity of 80% and a specificity of 71%. CONCLUSIONS: Endoscopic evaluation is warranted in heart failure patients with iron-deficient anaemia given the high prevalence of underlying intestinal malignancies, as advised by gastroenterology guidelines. However, additional research is needed assessing the best approach to patients with iron deficiency without anaemia, given the high occurrence of intestinal malignancies in these patients. A lower ferritin level could potentially help stratify the need for an endoscopic workup in these patients. PMID- 30415507 TI - Supervised versus autonomous exercise training in breast cancer patients: A multicenter randomized clinical trial. AB - BACKGROUND: There is a well-known correlation between obesity, sedentary lifestyle, and breast cancer incidence and outcome. The Arbeitsgemeinschaft Medikamentose Tumortherapie (AGMT) exercise study was a multicenter, randomized clinical trial and assessed the feasibility and efficacy of physical training in 50 breast cancer patients undergoing aromatase inhibitor treatment. METHODS: Postmenopausal, estrogen receptor-positive breast cancer patients under aromatase inhibitor treatment were randomized 1:1 to counseling and unsupervised training for 48 weeks (unsupervised arm) or counseling and a sequential training (supervised arm) with a supervised phase (24 weeks) followed by unsupervised physical training (further 24 weeks). Primary endpoint was the individual maximum power output on a cycle ergometer after 24 weeks of exercise. A key secondary endpoint was the feasibility of achieving 12 METh/week (metabolic equivalent of task hours per week). RESULTS: Twenty-three patients (92%) in the unsupervised arm and 19 patients (76%) in the supervised arm with early-stage breast cancer completed the study. After 24 weeks, the supervised arm achieved a significantly higher maximum output in watt (mean 132 +/- standard deviation [SD] 34; 95% confidence interval [CI] 117-147) compared to baseline (107 +/- 25; 95%CI 97-117; P = 0.012) with a numerically higher output than the unsupervised arm (week 24 115 +/- 25; 95%CI 105-125; P = 0.059). Significantly higher METh/week was reported in the supervised arm compared to the unsupervised arm during the whole study period (week 1-24 unsupervised: 18.3 (7.6-58.3); supervised: 28.5 (6.7 40.1); P = 0.043; week 25-48; P = 0.041)). CONCLUSION: This trial indicates that patients in an exercise program achieve higher fitness levels during supervised than unsupervised training. PMID- 30415508 TI - Prevalence of human papillomavirus in oral rinse samples from healthy individuals in northern Thailand. AB - BACKGROUND: The incidence of oral cancers associated with human papillomavirus (HPV) has been increasing in recent years. Therefore, it is necessary to elucidate HPV prevalence in oral cells and exposure to risk factors in various age groups. METHODS: Oral rinse samples from healthy individuals in northern Thailand were investigated for HPV prevalence and genotyped using the polymerase chain reaction (GP5+/6+ primers) and DNA sequencing of the PCR products. RESULTS: Samples were collected from 594 participants between 4 and 60 years of age. HPV was detected in 3.7% of samples. The prevalence of HPV-positive cases was 8.6% in the 31-50 age group. HPV prevalence increased with age and was the highest (9.2%) in the 41-50 age group, but decreased (to 3%) in the 51-60 age group. Risk factors significantly associated with HPV-positive cases included alcohol consumption, coffee drinking, sexual activity, and having children. HPV 16 and 18 were common genotypes, especially in the 31-50 age group, and were associated with having sexual activity (odds ratio 19.0 [95% CI: 2.5-142.5]). At follow-up of some individuals in the 4-10 age group, a 9-year-old child was found to be positive for HPV18. CONCLUSIONS: These results suggest that HPV can be acquired at a young age and the prevalence peaks in the middle age class among healthy individuals in northern Thailand, especially in the 31-50 age group. PMID- 30415510 TI - Commentary on paracetamol in preterm infants. PMID- 30415509 TI - Variability of blood eosinophils in patients in a clinic for severe asthma. AB - BACKGROUND: Blood eosinophils are used to determine eligibility for agents targeting IL-5 in patients with uncontrolled asthma. However, little is known about the variability of blood eosinophil measures in these patients before treatment initiation. OBJECTIVE: To characterize variability and patterns of variability of blood eosinophil levels in a real-world clinic for severe asthmatics. METHODS: Retrospective review of blood eosinophils measured over a 5 year period in patients enrolled in an urban clinic. Repeated measures of blood eosinophil levels in individuals were evaluated and cluster analysis was performed to characterize patients by eosinophil patterns. Clinical characteristics associated with eosinophil levels and patterns of variability were analyzed. RESULTS: Patients treated in the Bellevue Hospital Asthma Clinic within a 3-month period were identified (n = 219). Blood eosinophil measures were obtained over the previous 5 years. Only 6% (n= 13) of patients had levels that were consistently above 300 cells/MUL. Nearly 50% (n = 104) had eosinophil levels that traversed the threshold of 300 cells/MUL. In contrast, 102 (46%) had levels that never reached the threshold of 300 cells/MUL. Cluster analyses revealed three clusters with differing patterns of levels and variability. There was a suggestion of decreased clinical control and increased atopy in the cluster with the greatest variability in blood eosinophil measures. CONCLUSION: In an urban clinic for patients referred for uncontrolled asthma, blood measures of eosinophils were variable and showed differing patterns of variability. These data reinforce the need to perform repeated eosinophil blood measures for appropriate designation for therapeutic intervention. This article is protected by copyright. All rights reserved. PMID- 30415511 TI - Correcting Cherenkov light attenuation in tissue using spatial frequency domain imaging for quantitative surface dosimetry during whole breast radiation therapy. AB - Imaging Cherenkov emission during radiotherapy permits real-time visualization of external beam delivery on superficial tissue. This signal is linear with absorbed dose in homogeneous media, indicating potential for quantitative dosimetry. In humans, the inherent heterogeneity of tissue optical properties (primarily from blood and skin pigment) distorts the linearity between detected Cherenkov signal and absorbed dose. We examine the potential to correct for superficial vasculature using spatial frequency domain imaging (SFDI) to map tissue optical properties for large fields of view. In phantoms, applying intensity corrections to simulate blood vessels improves Cherenkov image (CI) negative contrast by 24% for a vessel 1.9-mm-in diameter. In human trials, SFDI and CI are acquired for women undergoing whole breast radiotherapy. Applied corrections reduce heterogeneity due to vasculature within the sampling limits of the SFDI from a 22% difference as compared to the treatment plan, down to 6% in one region and from 14% down to 4% in another region. The optimal use for this combined imaging system approach is to correct for small heterogeneities such as superficial blood vessels or for interpatient variations in blood/melanin content such that the corrected CI more closely represents the surface dose delivered. PMID- 30415512 TI - Anaemia in Sri Lanka: the missing pieces PMID- 30415513 TI - Response of the National Institute of Infectious Diseases, Sri Lanka to an unexpected dengue epidemic in 2017 PMID- 30415514 TI - Behavioral, familial and comorbid illness risk factors of colorectal cancer: a case control study AB - Introduction: Though colorectal cancer is a disease of public health importance, there is little evidence about risk factors of colorectal cancer in South Asians. Objectives: We aimed to determine the behavioral, familial and comorbid illness risk factors for colorectal cancer among Sri Lankan adults. Methods: We conducted this study among 325 participants (65 incident colorectal cancer cases, 130 hospital and 130 community controls) in five major health care institutions and communities in areas with high incidence in Sri Lanka. Behavioral, genetic and comorbid risk factors were assessed through an interviewer administered questionnaire. Risk factors were evaluated using bivariate and multivariate logistic regression. Results: Adjusted logistic regression showed that frequent consumption of red meat (OR 3.06, 95% CI 1.26-7.43) and deep fried food (OR 2.54, 95% CI 1.22-5.39), hypertension >= 10 years (OR 3.3, 95% CI 1.3-8.6), colorectal cancer (OR 4.91, 95% CI 1.70-14.18) and other cancers (OR 3.0, 95% CI 1.14-7.81) among first degree relatives and age >50 years (OR 2.6, 95% CI 1.1 to 5.9) were significant risk factors compared to hospital controls. Frequent consumption of deep fried food (OR 4.2, 95% CI 1.7-10.1), being an ever smoker (OR 3.2, 95% CI 1.1-9.3), a current or former drinker (OR 5.4, 95% CI 1.1-27.8) and hypertension >= 10 (OR 5.1, 95% CI 1.7-15.6) were risk factors compared to community controls. Conclusion: The behavioral, familial and comorbid illness risk factors identified should be considered in designing preventive strategies and identifying high-risk individuals for screening for colorectal cancer. PMID- 30415515 TI - The -31 G/C promoter gene polymorphism of surviving in Turkish colorectal cancers patients AB - Introduction: Survivin (also known as birc5) is the first protein discovered among the apoptosis-regulating gene family referred to as inhibitor of apoptosis proteins (IAPs). It is expressed and controlled during cellular differentiation and development in human beings. Survivin expression has been shown in a number of cancers and has been associated with cancer development. Objective: In our study, we compared with blood samples as our control and normal- tumoural tissue samples, which obtained from the same tissue of 100 cases diagnosed with colorectal cancer, at Department of Pathology, Istanbul University. Methods: The present study employed PCR-RFLP to identify the -31 G/C polymorphism in the promoter region of the survivin gene. Distribution of the survivin polymorphism was compared between control and tumoural tissue samples using the chi-square test. Results: Comparison of all samples revealed that there was significant difference in distribution of survivin promoter -31G/C between control group and tumour and normal tissue of the patient group (p<0.05). When genotypes of the control and tumour tissues were compared according to gender, there was no statistically significant difference in the distribution of survivin promoter 31G/C in females p=0.420 or males p=0.309. Conclusion: A significant difference was seen in distribution of C allele in tumour tissue compared to normal tissue. PMID- 30415516 TI - Prevalence of BK virus among renal transplant recipients in a tertiary care hospital in Sri Lanka AB - Introduction: BK virus nephropathy (BKVN) is an important cause of graft failure in post renal transplant patients. Detection of BK virus replication early enables prevention of BK virus nephropathy. Understanding BK virus epidemiology in post renal transplant patients will be useful in implementing a routine screening programme. Objectives: Objectives were to determine the prevalence of BK virus viruria and viraemia among post renal transplant patients within the first two years of transplantation. Methodology: A hospital-based, descriptive cross-sectional study was conducted on 136 clinic and in-ward patients. Plasma and urine were tested for BK virus DNA using real time PCR. Serum creatinine done within two weeks of data collection was recorded. Results: The prevalence of BK virus viruria was 53.67% and viraemia was 11%. Viraemia >1000 copies/ml was associated with abnormal serum creatinine and higher median serum creatinine. No similar association was observed with viruria. Among patients with normal serum creatinine, virus was not detected in urine in 48.9% and plasma in 92.7%. Conclusion: The prevalence of BK virus is high in this study population. Significant viraemia was associated with elevated serum creatinine. Viruria or viraemia was not detected among a large number of patients with normal serum creatinine. PMID- 30415517 TI - Clinico-pathological characteristics and outcome of upper urinary tract urothelial carcinoma presenting to a tertiary care urology unit in Sri Lanka AB - Introduction: Upper urinary tract urothelial cancers account for 5% of urothelial tumours. In the West, the majority affect the pelvicalyceal system, with pyelocalyceal to ureteric ratio of 3:1. This study aims to describe the clinico-pathological features and outcome of upper urinary tract urothelial cancer treated surgically in a tertiary care unit in Sri Lanka. Methods: A retrospective analysis of all patients who underwent nephroureterectomy for upper urinary tract urothelial cancer at the Urology Unit at National Hospital of Sri Lanka between January1997 and December 2016 was carried out. Results: There were 43 patients. Male: female=1.87. Median age was 65 years (range:42-83). Macroscopic haematuria was the commonest presentation (n=29; 67.4%). Median duration of symptoms was 3 months (range 0.5-6). In the majority (n=20;46.5%) the tumour was confined to the ureter. Thirty-three (75.6%) were papillary tumours. Twenty-one had non-muscle invasive tumours (pTa: n=6(14%), pT1: n=15(34.9%) and others had invasive cancers (pT2: n=11(25.6%), pT3: n=7(16.3%) and pT4: n=4(9.3%)). Majority were low grade tumours (n=23;53.5%). Twelve (27.9%) had preceding urothelial bladder cancer. Nineteen (44.2%) were lost to follow up after surgery. Median follow up duration of the rest was 40 months (range:4 224months). Of them, 9(20.9%) developed metachronous bladder tumours. Nine had recurrence free survival of >=5years and 15 had overall survival of >=5 years. Of them, 4 patients survived >=10 years. Older age (p=0.015) and presence of necrosis(p=0.05) were the only clinico-pathological parameters predictive of tumour recurrence. Conclusions: A relatively higher number females and high number of ureteric tumours were noted compared to similar studies from Asia. PMID- 30415518 TI - Clinical characteristics and outcomes of hepatocellular carcinoma: results from prospective study, from a tertiary referral center in ?Sri Lanka AB - Introduction: Hepatocellular carcinoma is increasing globally. Compared to global patterns, hepatitis B and C are rare in Sri Lanka whilst non-alcoholic fatty liver disease (NAFLD) and alcohol are the commonest causes of hepatocellular carcinoma. Objectives: To determine the characteristics of a cohort of Sri Lankan patients with hepatocellular carcinoma of non-viral aetiology. Methods: Details of 550 consecutive patients with hepatocellular carcinoma referred from 2012 to 2017 were collected prospectively. Demographic data, clinical and biochemical details, aetiology, comorbidities, tumor characteristics and type of treatment offered were retrospectively analyzed. Results: Median age was 62.9 years (range 12 - 88) with male preponderance (n = 473; 86%). Overall median BMI was 35.8 kgm 2. Majority (n=309; 56 %) had NAFLD induced cirrhosis, second commonest cause was alcohol (n=203;36.9 %). Tumour was single nodular 233(42.4%) and diffusely infiltrating 92(16.7%). Diagnostic rise in serum alpha-fetoprotein (over 200 micrograms) was seen in 30.2%. Venous invasion was present in 28.5% [portal vein 136 (24.7%), hepatic vein 9 (1.6%) and cava 12(2.2%)]. Extra hepatic tumor spread was seen in 6.9% [lungs 20(3.6%), bones 4(0.7%), peritoneal 6 (1.1%) and metastases at other sites 8 (1.45%)]. Curative surgery was offered in 78(14.2%). Tumour embolization was done in 192(34.9%), radio frequency ablation 34(6.2%), alcohol injection 42(7.6%) and 204(37.1%) patients were offered palliative care. Overall median survival was 20.6 months. Conclusions: In a large Sri Lankan cohort, most hepatocellular carcinomas were due to cryptogenic cirrhosis and it was aggressive at presentation. Screening of high-risk NAFLD patients needs to be considered and further palliative care needs to be improved. PMID- 30415519 TI - Skeletal fluorosis in Vavuniya District: an observational study AB - Background: The WHO recommended safe upper limit for fluoride in drinking water is 1.5 mg/l. Groundwater sources in many parts of Sri Lanka often exceed this limit. The high fluoride content of groundwater and high environmental temperatures in Vavuniya District predispose to pre-skeletal fluorosis and skeletal fluorosis in adults. Objectives: To identify residents of Vavuniya District with clinical features of pre-skeletal and skeletal fluorosis; to describe their clinical, biochemical and radiographic features; to determine the fluoride content of blood and urine in individuals with established diagnoses, and of their drinking water. Methods: In 98 volunteers we detected 60 with clinical features of pre-skeletal and skeletal fluorosis. Clinical examination, biochemical and radiographic investigations were performed. Forty four with confounding factors were excluded. The balance 16 had radiographic investigation for fluoride bone disease, and assessment of clinical features for pre-skeletal fluorosis. The radiographic criteria of skeletal fluorosis were trabecular haziness, osteosclerosis, osteophytes, cortical thickening and ligamentous or muscle attachment ossification. All 16 had "spot" samples of 15 ml of venous blood taken for biochemical tests and fluoride estimation; and 30 ml of urine, and water from 16 dug wells for fluoride. Results: The 16 selected (11 males) had BMI between 20.6 and 31.9 kg/m2, and were between 22 and 84 years (x = 59.9 + 20.4). They used water from domestic dug wells for drinking. All had adequate renal function. All serum and urine samples had raised fluoride levels way above the reference ranges for serum (0.02 - 0.18 mg/l) and urine (0.6 - 2.0 mg/l). The 16 water samples showed a mean fluoride content of 2.90 +0.93 mg/l. Interpretation: In a cohort of 60 individuals in Vavuniya with symptoms suggestive of skeletal fluoride toxicity, 6 had skeletal fluorosis, 10 had pre skeletal fluorosis, and groundwater sources had fluoride levels much higher than WHO recommended upper limit for drinking water. Residents in Vavuniya are predisposed to pre-skeletal and skeletal fluorosis. All 16 had been misdiagnosed as various types of arthritis. PMID- 30415521 TI - Rare presentation of Guillain-Barre syndrome with complete heart block and neuropathic chest pain mimicking acute coronary syndrome: a case report PMID- 30415520 TI - Impact of tuberculosis and long term benefits of anti-retroviral treatment in patients with HIV in Sri Lanka AB - Introduction: Although prevalence of HIV infection in Sri Lanka is low, there is a gradual increase in incidence. Effective anti-retroviral treatment (ART) controls the virus, improves immunity and reduces transmission of HIV greatly. Objective: We studied the impact of tuberculosis and response to ART in a cohort of patients with HIV in Sri Lanka. Methodology: A retrospective study of all patients with HIV followed up at the ART clinic at National Institute of Infectious Diseases, Angoda, Sri Lanka was carried out. Their socio-demographic data, clinical presentations, anti-retroviral treatment and clinical, immunological and virological response were analysed. Results: Study included 72 patients. Mean age was 47.19 (SD-10.354) years. Male to female ratio was 1:0.8. Forty nine (68%) patients were diagnosed with HIV after presenting with an opportunistic infection. Of these, 25 had tuberculosis (TB). Another 5 developed TB later. Fifty two (72.2%) had CD4 cell counts<200/MUl which included 45(62.5%) who had CD4<100/MUl. Twenty six (36.1%) patients were bed ridden and a further 6 (8.3%) were physically dependent at the time of diagnosis. Mean duration of ART was 82.4 months. With ART, CD4 cell counts and mobility improved. In 38 (52.8%) CD4 counts increased to more than 500/MUl. Viral load became undetectable in 62 (86.1%). Sixty nine (95.8%) became completely physically independent. Conclusion: TB is a common co-infection in patients with HIV in Sri Lanka. Though many patients with HIV presented with poor immunological and physical status, ART markedly improved these outcomes and reduced the viral load which results in prevention of spread of HIV. Therefore, ART should be supported and encouraged PMID- 30415522 TI - Initial experience and outcomes of peroral endoscopic myotomy for the treatment of oesophageal achalasia in a tertiary care centre PMID- 30415523 TI - Does Rapid Eye Movement Sleep Aggravate Obstructive Sleep Apnea? AB - Objectives: To investigate the apnea-hypopnea index (AHI) according to the sleep stage in more detail after control of posture. Methods: Patients who underwent nocturnal polysomnography between December 2007 and July 2018 were retrospectively evaluated. Inclusion criteria were as follows: age >18 years, sleep efficacy >80%, and patients who underwent polysomnography only in the supine position (100% of the time). Patients were classified into different groups according to the methods: the first, rapid eye movement (REM)-dominant group (AHIREM/AHINREM >2), non-rapid eye movement (NREM)-dominant group (AHINREM/AHIREM >2), and non-dominant group; and the second, light sleep group (AHIN1N2>AHISWS) and slow wave sleep (SWS) group (AHISWS>AHIN1N2). Results: A total of 234 patients (mean age, 47.4+/-13.9 years) were included in the study. There were 108 patients (46.2%) in the REM-dominant group, 88 (37.6%) in the non dominant group, and 38 (16.2%) in the NREM-dominant group. The AHI was significantly higher in the NREM-dominant group than in the REM-dominant group (32.9+/-22.9 events/hr vs. 18.3+/-9.5 events/hr, respectively). There were improvements in the AHI from stage 1 to SWS in NREM sleep with the highest level in REM sleep. A higher AHISWS than AHIN1N2 was found in 16 of 234 patients (6.8%); however, there were no significant predictors of these unexpected results except AHI. Conclusion: Our results demonstrated the highest AHI during REM sleep stage in total participants after control of posture. However, there were 16.2% of patients showed NREM-dominant pattern (AHINREM/AHIREM >2) and 6.8% of patients showed higher AHISWS than AHIN1N2. Therefore, each group might have a different pathophysiology of obstructive sleep apnea (OSA), and we need to consider this point when we treat the patients with OSA. PMID- 30415524 TI - Pathogenesis of human norovirus genogroup II genotype 4 in post-weaning gnotobiotic pigs. AB - Norovirus is the most common cause of acute gastroenteritis. Its pathogenesis is poorly understood owing to the difficulty of establishing viral infection in animal models. Here, post-weaning gnotobiotic pigs were infected with human norovirus genogroup II genotype 4 (HuNoV GII.4) to investigate the pathogenesis and replication of the virus. Three groups of four pigs were infected with 1*105, 1*106, or 1*107 genomic equivalent (GE) copies of HuNoV GII.4. Four pigs were used as negative controls. Blood and rectal swab samples were collected after viral infection, and gross legions were examined after necropsy. Diarrhea was induced in 25% and 75% of pigs infected with 1*106 and 1*107 GE copies, respectively. Viral shedding was detected in 50%, 75%, and 50% of pigs infected with 1*105, 1*106, and 1*107 GE copies, respectively. Viremia was detected in 25% of pigs infected with either 1*106 or 1*107 GE copies. When gross lesions of gastroenteritis were investigated, the ileum walls of the infected pigs were thinner than those of the controls. Villi atrophy and inflammatory cell infiltration were identified in the ileum of each infected pig. Viral capsid was identified in the jejunum, ileum, colon, spleen, and mesenteric lymph node. Virus replication was newly verified in the spleen and mesenteric lymph nodes by detection of negative-sense viral RNA. In conclusion, HuNoV GII.4 could induce acute gastroenteritis and replicate in the extra-intestinal lymphoid tissues in post-weaning gnotobiotic pigs. Therefore, such pigs would be a suitable animal model for studying the pathogenesis and replication of HuNoV. PMID- 30415525 TI - Gold nanoparticles conjugation enhances antiacanthamoebic properties of Nystatin, Fluconazole and Amphotericin B. AB - Parasitic infections have remained a significant burden on human and animal health. In part, this is due to lack of clinically-approved novel antimicrobials and a lack of interest by the pharmaceutical industry. An alternative approach is to modify existing clinically-approved drugs for efficient drugs delivery formulations to ensure minimum inhibitory concentration is achieved at the target site. Nanotechnology offers the potential to enhance the therapeutic efficacy of drugs through modification of nanoparticles with ligands. Amphotericin B, Nystatin, and Fluconazole are clinically available drugs in the treatment of amoebal and fungal infections. These drugs were conjugated with gold nanoparticles. To characterize these Gold-conjugated drugs atomic force microscopy, ultraviolet-visible spectrophotometry, Fourier transform infrared spectroscopy were performed. These drugs and their gold nanoconjugates were examined for antimicrobial activity against the protist pathogen, Acanthamoeba castellanii of the T4 genotype. Moreover, host cell cytotoxicity assays were accomplished. Cytotoxicity of these drugs and drug conjugated gold nanoparticles was also determined by lactate dehydrogenase assay. Gold nanoparticles conjugation resulted in enhanced bioactivity of all three drugs with Amphotericin B producing most significant effects against Acanthamoeba castellanii (P<0.05). In contrast, bare gold nanoparticles did not exhibit significant antimicrobial potency. Furthermore, amoebae treated with drugs-conjugated gold nanoparticles showed reduced cytotoxicity against HeLa cells. In this report, we demonstrated the use of nanotechnology to modify existing clinically-approved drugs and enhancing their efficacy against pathogenic amoebae. Given the lack of development of novel drugs, this is a viable approach in the treatment of neglected diseases. PMID- 30415526 TI - Characterization of Gel16 as a cytochrome P450 in geldanamycin biosynthesis and in-silico analysis for endogenous electron transport system. AB - Geldanamycin and its derivatives, inhibitor of heat shock protein 90, are considered as potent anticancer drug, and their biosynthetic pathway has not yet been fully elucidated. The key step of conversion of 4,5-dihydrogeldanamycin to geldanamycin was expected to catalyse by a P450 monooxygenase, Gel16. The adequate bioconversions by cytochrome P450 mostly rely upon its interaction with redox partners. Several numbers of ferredoxin and ferredoxin reductase are available in a genome of organism, but only few suitable partners can operate in full efficiency. In this study we have expressed cytochrome P450 gel16 in Escherichia coli and performed the in-vitro assay using 4,5-dihydrogeldanamycin as a substrate. We demonstrated that in-silico method can be applicable for the efficient mining of convenient endogenous redox partners (9 ferredoxins and 6 ferredoxin reductases) against CYP Gel16 from Streptomyces hygroscopicus. The distances about ligand FDX4-FDR6 were found to be 9.384 A. Similarly the binding energy between Gel16-FDX4 and FDX4-FDR6 were -611.88 kcal/mol and -834.48 kcal/mol, respectively, suggesting the lowest distance and binding energy rather than other redox partners. These findings suggested that the best redox partners of Gel16 could be NADPH?FDR6?FDX4?Gel16. PMID- 30415527 TI - Immunomodulatory properties of Lactobacillus plantarum NC8 expressing an anti CD11c single-chain Fv fragment. AB - As a member of lactic acid bacteria species, Lactobacillus plantarum (L. plantarum) has been used extensively for vaccine delivery previously. Considering to the critical role of dendritic cells in stimulating host immune response, in this study, we constructed a novel CD11c targeting L. plantarum strain with surface displayed the variable fragments of anti-CD11c single chain antibody (scFv-CD11c). The newly designed L. plantarum strain, named 409-aCD11c, could adhere and invade more efficiently to bone marrow-derived DCs (BMDCs) in vitro due to the specific interaction between scFv-CD11c and CD11c located on the surface of BMDCs. After incubation with BMDCs, the 409-aCD11c strain harboring an eukaryotic vector pValac-GFP could lead to more efficient expression of GFP compared with wild type strains shown by flow cytometry analysis, indicating the enhanced translocation of pValac-GFP from L. plantarum to BMDCs. Similar results were also observed in vivo study, which showed that the oral administration resulted in efficient expression of GFP in both Peyer's patch (PP) and mesenteric lymph nodes (MLNs) within 7 days after the last administration. In addition, the CD11c targeting strain significantly promoted the differentiation and maturation of DCs, the differentiation of IL-4+ and IL-17A+ T helper (Th) cells in MLNs, as well as production of B220+ IgA+ B cells in the PP. In conclusion, this study developed a novel DC-targeting L. plantarum strain which could increase the ability to deliver eukaryotic expression plasmid to host cells, indicating a promising approach for vaccine study. PMID- 30415528 TI - Combined lowering effects of rosuvastatin and L. acidophilus on cholesterol levels in rat. AB - Statins are a class of lipid lowering drugs commonly used in the prevention of cardiovascular diseases. However, statin therapy present many limitations, which lead to an increased interest in non-drug therapies, such as probiotics, to improve blood cholesterol levels. Indeed, probiotic strains such as Lactobacillus acidophilus have been found to improve blood lipid profiles, especially in reducing total cholesterol and LDL-C levels. In this study, we established a high cholesterol rat model and studied the effect of Lactobacillus acidophilus administration alone or in conjunction with rosuvastatin. We were able to show that indeed Lactobacillus exerts a cholesterol-lowering effect. Additionally, we observed that when administered together, rosuvastin and Lactobacillus exert a combined cholesterol-lowering effect. Altogether, our data advocate for the possibility of establishing probiotics as non-drug supplements for the treatment of hypercholesterolemia. PMID- 30415529 TI - Phenazine and 1-undecene producing Pseudomonas chlororaphis subsp. aurantiaca strain KNU17Pc1 for growth promotion and disease suppression in Korean maize cultivars. AB - In this study, strain KNU17Pc1 was tested for its antifungal activity against Rhizoctonia solani AG-1(IA), which causes banded leaf and sheath blight (BLSB) of maize. KNU17Pc1 was tested further for its broad-spectrum antifungal activity and in vitro plant growth promoting (PGP) traits. In addition, the in vivo effects of KNU17Pc1 on reduction of BLSB severity and seedling growth promotion of two maize cultivars under greenhouse conditions were investigated. On the basis of multilocus sequence analysis (MLSA), KNU17Pc1 was confirmed as P. chlororaphis subsp. aurantiaca. The study revealed that KNU17Pc1 had strong in vitro antifungal activity and was effective toward all in vitro PGP traits except phosphate solubilization. In this study, for the first time, a strain of P. chlororaphis against Colletotrichum dematium, Colletotrichum gloeosporioides, Fusarium oxysporum f.sp. melonis, Fusarium subglutinans and Stemphylium lycopersici has been reported. Further biochemical studies showed that KNU17Pc1 was able to produce both types of phenazine derivatives, PCA and 2-OH-PCA. In addition, solid phase microextraction-gas chromatography-mass spectrometry (SPME GC-MS) analysis identified 13 volatile organic compounds (VOCs) in the TSB culture of KNU17Pc1, 1-undecene being the most abundant volatile. Moreover, for the first time, Octamethylcyclotetrasiloxan (D4), dimethyl disulfide, 2-methyl 1,3-butadiene and 1-undecene were detected in P. chlororaphis. Furthermore, this study reported for the first time the effectivenes of P. chlororaphis to control BLSB of maize. Hence, further studies are necessary to test effectiveness of KNU17Pc1 under different environmental conditions so that it will be exploited further for biocontrol and plant growth promotion. PMID- 30415530 TI - The inhibition of melanogenesis via the PKA and ERK signaling pathways by Chlamydomonas reinhardtii extract in B16F10 melanoma cells and artificial human skin equivalents. AB - Abnormal melanin synthesis results in several hyperpigmentary disorders such as freckles, melanoderma, age spots, and other hyperpigmentation syndromes. In this study, we investigated the anti-melanogenic effects of an extract from the microalgae Chlamydomonas reinhardtii (CE) and potential mechanisms responsible for its inhibitory effect in B16F10, normal human epidermal melanocyte cells, and human skin-equivalent models. The CE extract showed significant dose-dependent inhibitory effects on alpha-melanocyte-stimulating hormone-induced melanin synthesis in cells. Additionally, the CE extract exhibited suppressive effects on the mRNA and protein expression of microphthalmia-associated transcription factor, tyrosinase, tyrosinase-related protein-1, and tyrosinase-related protein 2. The CE extract also inhibited the phosphorylation of protein kinase A and extracellular signal-related kinase, which function as upstream regulators of melanogenesis. Using a three-dimensional reconstructed pigmented epidermis model, the CE-mediated anti-pigmentation effects were confirmed by Fontana-Masson staining and melanin content assays. Taken together, CE extract can be used as an anti-pigmentation agent. PMID- 30415531 TI - Lipoteichoic acid isolated from Lactobacillus plantarum maintains inflammatory homeostasis through regulation of Th1- and Th2-induced cytokines. AB - Lipoteichoic acid isolated from Lactobacillus plantarum K8 (pLTA) alleviates lipopolysaccharide (LPS)-induced excessive inflammation through inhibition of TNF alpha and interleukin (IL)-6. In addition, pLTA increases the survival rate of mice in a septic shock model. In the current study, we have found that pLTA contributes to homeostasis through regulation of pro- and anti-inflammatory cytokine production. In detail, pLTA decreased the production of IL-10 by phorbol 12-myristate-13-acetate (PMA)-differentiated THP-1 cells stimulated with prostaglandin E2 (PGE-2) and LPS. However, TNF-alpha production which was inhibited by PGE-2+LPS increased by pLTA treatment. The regulatory effects of IL 10 and TNF-alpha induced by PGE-2 and LPS in PMA-differentiated THP-1 cells were mediated by pLTA, but not by other LTAs isolated from either Staphylococcus aureus (aLTA) and L. sakei (sLTA). Further studies revealed that pLTA-mediated IL 10 inhibition and TNF-alpha induction in PGE-2+LPS-stimulated PMA-differentiated THP-1 cells were mediated by dephosphorylation of p38 and phosphorylation of c Jun N-terminal kinase (JNK), respectively. Reduction of pLTA-mediated IIL-10 inhibited the metastasis of breast cancer cells (MDA-MB-231), which was induced by IL-10 or conditioned media prepared from PGE-2+LPS-stimulated PMA differentiated THP-1 cells. Taken together, our data suggest that pLTA contributes to inflammatory homeostasis through induction of repressed pro inflammatory cytokine as well as inhibition of excessive anti-inflammatory cytokine. PMID- 30415532 TI - Tentacles For Tinies: The Many Arms of the Crocheted Octopus PMID- 30415533 TI - Recent advances in multidimensional separation for proteome analysis. AB - Due to high peak capacity and separation efficiency, multidimensional separation strategies have become an established tool in qualitative and quantitative analysis of proteomes. The recent technological developments in multidimensional separation strategies mainly focus on the improvement of separation resolution (peak capacity), analysis throughput and sensitivity. The aim of this review is to provide these informative resources, which might be helpful to those in proteomics community who are interested in improving MDLC performance or using them for novel proteomic applications. This review will summarize the recent advances of such techniques, and highlight their important biological applications in proteomic study over the past 2 years. PMID- 30415534 TI - Honey Norisoprenoids Attract Bumble Bee, Bombus terrestris, in New Zealand Mountain Beech Forests. AB - Three varieties of honey of different dominant floral origin were found to attract social Hymenoptera, including the large earth bumble bee, Bombus terrestris, in a New Zealand mountain beech forest. This study was undertaken to identify volatile organic compounds that induce the attraction of bumble bees to honeybee ( Apis mellifera) honey. We analyzed the chemical composition of the volatile organic compounds produced in three distinct varieties of honey (i.e., manuka, honeydew, and clover honey). The composition of the chemical profile of the three honey varieties differed in the quality and in the ratio of compounds in the headspace. o-Methoxyacetophenone was the main compound in the headspace of all three honey varieties. Among the 40 compounds identified in the headspace in the three varieties, only seven shared compounds (i.e., benzaldehyde, benzyl alcohol, phenylacetaldehyde, 2-phenylethanol, isophorone, 4-oxoisophorone, and o methoxyacetophenone) were present in the headspace of the three honey varieties. The relative attractiveness of various blends of the seven common compounds found in the three honey varieties was tested for the attraction to bumble bees in a mountain beech forest. A binary blend of isophorone and 4-oxoisophorone at a ratio of 90:10 was the most attractive blend for both bumble bee workers and queens. A small number of honey bee workers were also attracted to the former binary blend. Our study represents the first identification of a honey-derived attractant for bumble bees and honey bees. The potential application of our finding for monitoring of bumble bees or to enhance crop pollination and help to tackle the current concern of a global pollination crisis is discussed. PMID- 30415535 TI - Fast Equivalency Estimation of Unknown Enzyme Inhibitors in Situ the Effect Directed Fingerprint, Shown for Bacillus Lipopeptide Extracts. AB - The hyphenation of high-performance thin-layer chromatography (HPTLC) with enzyme inhibition assays followed by high-resolution mass spectrometry (HRMS) represents a targeted profiling of complex natural samples required in the development of new natural pharmaceuticals, functional foods, and cosmetics. This direct combination of a chromatogram with an enzymatic assay substantially extents the understanding of inhibitor properties in vitro. For the first time, a straightforward workflow was established for estimating the equivalency of unknown inhibitors directly in the autogram. Exemplarily, lipopeptides produced as secondary metabolites by five different Bacillus strains were analyzed by HPTLC hyphenated with the tyrosinase and acetylcholinesterase (AChE) assays. Lipopeptides that showed an inhibition were characterized by HPTLC-HRMS. Among the many reports about the biological properties of lipopeptides, their enzyme inhibitory properties are new. The most intense inhibitors were identified as surfactin and iturin A according to reference substances and exact masses. Three further inhibitors were supposedly assigned as fengycin, iturin C, and surfactin methyl ester according to their exact masses. The inhibitory activities of surfactin and iturin A were quantitatively compared with kojic acid and piperine, as references for common natural inhibitors. Their equivalently calculated tyrosinase inhibition showed that 1 MUg kojic acid was equal to 1.8 MUg and 3.2 MUg of iturin A and surfactin standards, respectively; regarding to AChE inhibition, 1 MUg piperine was equal to 1.7 MUg and 0.6 MUg of iturin A and surfactin, respectively. Further unknown enzyme inhibitors found in the sample were exemplarily calculated as surfactin, iturin A, kojic acid, and piperine equivalents to estimate their importance. PMID- 30415536 TI - Solvent-Free Photoresponsive Artificial Muscles Rapidly Driven by Molecular Machines. AB - We prepared photoresponsive actuators as both hydrogels and dry gels consisting of 4-arm poly(ethylene glycol) (PEG) cross-linked by a [c2]daisy chain, which is a double-threaded [2]rotaxane dimer with alpha-cyclodextrin (alphaCD) and stilbene. The obtained gels showed fast and large deformation triggered by UV irradiation in both wet and dry states. The UV/vis spectroscopy results, NMR measurements and tensile tests on the gels revealed that the actuation is driven by photoisomerization of the stilbene unit in the [c2]daisy chain. The responsiveness of these gels depends on the molecular weight of the 4-arm PEG. These results suggest that alphaCD recognizes trans-stilbene prior to UV irradiation to maintain the length of the PEG chain in the polymer network and that photoisomerization allows alphaCD to leave the cis-stilbene moiety and move onto the PEG chain because the association constant of alphaCD with cis-stilbene is quite low. Thus, the sliding motion of the alphaCD unit shrinks the [c2]daisy chain, leading to the contraction of the gels. In both wet and dry states, these actuations are repeatable through reversible photoisomerization of the stilbene moiety using different wavelengths of UV-light irradiation and can be used to perform bending and lifting actions (for 15 times heavier weight compared to the dry gel). PMID- 30415538 TI - Conjugation of Oxidized Betanidin and Gomphrenin Pigments from Basella alba L. Fruits with Glutathione. AB - Formation of glutathionic conjugates with quinonoid forms generated through oxidation of betanidin and gomphrenin obtained from fruits of Basella alba L. was studied by high-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry (HPLC-DAD-ESI-MS/MS) and ion-trap time-of-flight high resolution mass spectrometry (LCMS-IT-TOF). The conjugates were studied for the aim of trapping the formed quinonoids by glutathione which would indicate a presence of specific quinonoid structures in reaction products of the pigments with 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) cation radicals. The structure of betanidin conjugate, which was formed with high efficiency, was established by NMR analysis. In the case of gomphrenin conjugate, its structure was tentatively indicated as analogous to betanidin conjugate by MS n fragmentation paths. In contrast, no detectable glutathionic conjugate of betanin quinonoid (quinone methide) was present in similar betanin reaction mixtures. As a result of additional experiments performed during oxidation of gomphrenin by ABTS cation radicals in the absence of glutathione, except for decarboxylated and dehydrogenated gomphrenin derivatives, generation of betanidin and its derivatives was observed which indicated that the subsequent dopachromic intermediate rearrangement affected hydrolysis of the glucosidic bond. This is in contrast to betanin which is not deglucosylated in the same conditions during the oxidation. The obtained results shed some light on the oxidation pathways of various glycosylated betacyanins with gomphrenin being presumably the most potent antioxidant ascertained in this group of pigments. PMID- 30415537 TI - Dose-Dependent Increases in Liver Cholesterol but Not Plasma Cholesterol from Consumption of One to Five Whole Eggs and No Effects from Egg Whites on Liver or Plasma Cholesterol in Hamsters. AB - The dose-dependent effect of egg consumption on plasma cholesterol in humans remains inconclusive. It is unknown if egg white consumed in a normal amount can reduce plasma cholesterol. We used hamsters as a model to (i) investigate the dose-dependent effect of consuming zero to five whole eggs on plasma total cholesterol (TC) and (ii) examine if egg white, equivalent to one to five eggs, possessed any reducing effects on plasma TC. In experiment 1, hamsters were divided into six groups ( n = 8 each) and fed either a control diet or one of five experimental diets supplemented with whole-egg powder equivalent to one to five eggs per 2000 kcal. Results showed that supplementation with one egg increased plasma TC by 25% compared with that of the control (226 +/- 16 versus 282 +/- 56 mg/dL, p < 0.05), whereas supplementation with two to five eggs did not significantly produce any additional effects on plasma cholesterol. However, supplementation with one to five eggs in diets caused a dose-dependent accumulation of cholesterol in the liver from 21.5 +/- 4.4 to 71.3 +/- 7.3 mg/g ( p < 0.01). In the second experiment, hamsters were divided into six groups and fed either a high-cholesterol control diet or one of five experimental diets supplemented with egg-white powder from one to five eggs. Results showed that egg white powder affected neither plasma nor liver cholesterol levels. The egg-white powder did not affect fecal sterol excretion, suggesting it had no effect on cholesterol absorption. It was therefore concluded that consumption of two to five eggs did not significantly produce any additional effects on plasma cholesterol, whereas egg white did not possess a plasma-cholesterol-lowering activity if it was consumed at amounts similar to those in a normal human diet. PMID- 30415539 TI - Selective CO2 Reduction Catalyzed by Single Cobalt Sites on Carbon Nitride under Visible-Light Irradiation. AB - Framework nitrogen atoms of carbon nitride (C3N4) can coordinate with and activate metal sites for catalysis. In this study, C3N4 was employed to harvest visible light and activate Co2+ sites, without the use of additional ligands, in photochemical CO2 reduction. Photocatalysts containing single Co2+ sites on C3N4 were prepared by a simple deposition method and demonstrated excellent activity and product selectivity toward CO formation. A turnover number of more than 200 was obtained for CO production using the synthesized photocatalyst under visible light irradiation. Inactive cobalt oxides formed at relatively high cobalt loadings but did not alter product selectivity. Further studies with X-ray absorption spectroscopy confirmed the presence of single Co2+ sites on C3N4 and their important role in achieving selective CO2 reduction. PMID- 30415540 TI - Synthesis of Myrocin G, the Putative Active Form of the Myrocin Antitumor Antibiotics. AB - The antiproliferative antimicrobial fungal metabolites known as the myrocins have been proposed to cross-link DNA by double nucleotide addition. However, the nature of the DNA-reactive species is ambiguous, as myrocins have been isolated as functionally distinct 5-hydroxy-gamma-lactone and diosphenol isomers. Based on literature precedent, we hypothesized that the diosphenol 7 (assigned here the trivial name myrocin G) is the biologically active form of the representative isolate (+)-myrocin C (1). To probe this, we developed a short enantioselective route to 7. A powerful fragment-coupling reaction that forms the central ring of the target in 38% yield and in a single step was developed. In support of our hypothesis, 7 was efficiently transformed to the bis(sulfide) 6, a product previously isolated from reactions of 1 with excess benzenethiol. This work provides the first direct access to the diosphenol 7, sets the stage for elucidating the mode of interaction of the myrocins with DNA, and provides a foundation for the synthesis of other pimarane diterpenes. PMID- 30415541 TI - Analytical Model of the Free Energy of Alchemical Molecular Binding. AB - We present a parametrized analytic statistical model of the thermodynamics of alchemical molecular binding within the solvent potential of mean force formalism. The model describes the free energy profiles of linear single decoupling alchemical binding free energy calculations accurately. The parameters of the model, which are physically motivated, are derived by maximum likelihood inference from data obtained from alchemical molecular simulations. The validity of the model has been assessed on a set of host-guest complexes. The model faithfully reproduces both the binding free energy profiles and the probability densities of the perturbation energy as a function of the alchemical progress parameter. The model offers a rationalization for the characteristic shape of binding free energy profiles. The parameters obtained from the model are potentially useful descriptors of the association equilibrium of molecular complexes. Potential applications of the model for the classification of molecular complexes and the design of alchemical molecular simulations are envisioned. PMID- 30415542 TI - Anthocyanins Extracted from Aronia melanocarpa Protect SH-SY5Y Cells against Amyloid-beta (1-42)-Induced Apoptosis by Regulating Ca2+ Homeostasis and Inhibiting Mitochondrial Dysfunction. AB - We investigated the cytoprotective effects of anthocyanins in Aronia melanocarpa against apoptosis induced by Abeta1-42, a key mediator of AD pathophysiology. We measured intracellular calcium with a colorimetric kit, cellular apoptosis with DAPI, intracellular ROS with the fluorescent marker 2,3-dimethoxy-1,4 naphthoquinone, mitochondrial membrane potential with JC-1, and ATP with a colorimetric kit. Gene transcription and protein expression levels of calmodulin, cytochrome c, caspase-9, cleaved caspase-3, Bcl-2, and Bax were analyzed by RT PCR and Western blotting. The results showed that pretreatment with anthocyanins significantly inhibited Abeta1-42-induced apoptosis, decreased intracellular calcium and ROS, and increased ATP and mitochondrial membrane potential. RT-PCR and Western blotting revealed that anthocyanins upregulated the gene transcription and protein expression of calmodulin and Bcl-2 and downregulated those of cytochrome c, caspase-9, cleaved caspase-3, and Bax. A. melanocarpa anthocyanins protected SH-SY5Y cells against Abeta1-42-induced apoptosis by regulating Ca2+ homeostasis and apoptosis-related genes and inhibiting mitochondrial dysfunction. PMID- 30415543 TI - A Photoswitchable Heteroditopic Ion-Pair Receptor. AB - Designing light-switchable heteroditopic receptors is challenging because it necessitates simultaneous (de)activation of two separate binding sites. Herein, we present the first photoswitchable heteroditopic ion-pair receptor in which both cation and anion binding sites are simultaneously and reversibly switched OFF and ON by a single photoswitch. Our receptor is simple, low molecular weight, and readily synthesized from commercially available precursors. Single-crystal X ray structures and NMR spectroscopic titrations support ion-pair binding to the receptor both in the solid state and in solution, with strong positive cooperativity between the cation and anion binding. The receptor can be completely switched OFF by UV light-triggered photoisomerization of an acylhydrazone C?N double bond and remains kinetically stable in the deactivated form due to an intramolecular hydrogen bond. Its re-activation could be achieved by light irradiation or, more effectively, by fast acid-catalyzed back isomerization. Our simple photoswitchable ion-pair receptor may serve as a blueprint for the design of new generations of switchable receptors, transporters, soft materials, and self-assembled systems, where incorporation of a functional heteroditopic ON/OFF photoswitch has been challenging up to now. PMID- 30415545 TI - Unravelling the Effect of p,p'-Dichlorodiphenyldichloroethylene (DDE) in Hypertension of Wistar Rats. AB - Hypertension is a multifactorial disease with limited knowledge of the involved mechanisms. p,p'-DDE ( p,p'-dichlorodiphenyldichloroethylene) is a pollutant commonly found in tissues that interferes with endocrine signaling. This study aimed to evaluate the mechanism of hypertension triggered by p,p'-DDE exposure in the presence or absence of a HF (high-fat) diet in rats. The renin-angiotensin system (RAS) was evaluated by qPCR in liver and adipose tissue (AT), and a transcriptome analysis comparing visceral AT of HF diet and HF/DDE groups was performed. HF diet influenced RAS, but the p,p'-DDE effect was more evident in liver than in AT (interaction between the diet and p,p'-DDE treatment affected aldosterone receptor and angiotensin converting enzyme 2 expression in liver, p < 0.05, two-way ANOVA). p,p'-DDE induced a decrease in the expression of genes involved in the retinoid acid biosynthesis pathway (Crabp1; -2.07-fold; p = 0.018), eNOS activation (Nos1; -1.64-fold; p = 0.012), and regulation and urea cycle (Ass1; -2.07-fold; p = 0.02). This study suggested that p,p'-DDE may play a fundamental role in the pathogenesis of hypertension, not exclusively in RAS but also by induction of hyperuricemia and increased oxidative stress, which may lead to endoplasmic reticulum stress and vascular injury. PMID- 30415544 TI - Attenuation by Tetrahydrocurcumin of Adiposity and Hepatic Steatosis in Mice with High-Fat-Diet-Induced Obesity. AB - Diet-induced obesity is strongly associated with nonalcoholic fatty-liver disease (NAFLD) and insulin resistance. We aimed to investigate the in vivo therapeutic value of tetrahydrocurcumin (THC) intervention in high-fat-diet (HFD)-induced obesity and hepatic steatosis. C57BL/6 mice were fed an HFD for 10 weeks, and then they received 20 or 100 mg/kg THC along with the HFD for another 10 weeks. Mice fed an HFD for 20 weeks experienced obesity, hepatic steatosis, hyperlipidemia, and insulin resistance. Tetrahydrocurcumin (THC) intervention for 10 weeks significantly reduced adiposity (epididymal-fat weights of 6.6 +/- 0.4 g for the HFD-only group and 5.3 +/- 0.8 and 5.6 +/- 0.7 g for the HFD with 20 mg/kg THC and HFD with 100 mg/kg THC groups, respectively; p < 0.05) via downregulation of adipogenic factors. Inflammatory macrophage infiltration and polarization were decreased by THC in mouse epididymal adipose tissues. In the liver, THC markedly alleviated steatosis by approximately 28-37% ( p < 0.05) via the downregulation of lipogenesis, the activation of AMP-activated protein kinase (AMPK), and the increase of fatty acid oxidation. Elevated blood glucose and insulin resistance were also improved by THC, which might be caused by regulation of the hepatic insulin signaling cascade, gene transcription involved in glucose metabolism, and reduced macrophage infiltration in the liver and adipose tissue. Our results demonstrated the beneficial effects of THC-mediated intervention against obesity and NAFLD as well as other metabolic syndromes, revealing a novel therapeutic use of THC in obese populations. PMID- 30415546 TI - Effect of Formulation and Processing Parameters on the Size of mPEG- b-p(HPMA-Bz) Polymeric Micelles. AB - Micelles composed of block copolymers of poly(ethylene glycol)- b-poly( N-2 benzoyloxypropyl methacrylamide) (mPEG- b-p(HPMA-Bz)) have shown great promise as drug-delivery carriers due to their excellent stability and high loading capacity. In the present study, parameters influencing micelle size were investigated to tailor sizes in the range of 25-100 nm. Micelles were prepared by a nanoprecipitation method, and their size was modulated by the block copolymer properties such as molecular weight, their hydrophilic-to-hydrophobic ratio, homopolymer content, as well as formulation and processing parameters. It was shown that the micelles have a core-shell structure using a combination of dynamic light scattering and transmission electron microscopy analysis. By varying the degree of polymerization of the hydrophobic block ( NB) between 68 and 10, at a fixed hydrophilic block mPEG5k ( NA = 114), it was shown that the hydrophobic core of the micelle was collapsed following the power law of ( NB * Nagg)1/3. Further, the calculated brush height was similar for all the micelles examined (10 nm), indicating that crew-cut micelles were made. Both addition of homopolymer and preparation of micelles at lower concentrations or lower rates of addition of the organic solvent to the aqueous phase increased the size of micelles due to partitioning of the hydrophobic homopolymer chains to the core of the micelles and lower nucleation rates, respectively. Furthermore, it was shown that by using different solvents, the size of the micelles substantially changed. The use of acetone, acetonitrile, ethanol, tetrahydrofuran, and dioxane resulted in micelles in the size range of 45-60 nm after removal of the organic solvents. The use of dimethylformamide and dimethylsulfoxide led to markedly larger sizes of 75 and 180 nm, respectively. In conclusion, the results show that by modulating polymer properties and processing conditions, micelles with tailorable sizes can be obtained. PMID- 30415547 TI - Adsorption and Crystallization of Particles at the Air-Water Interface Induced by Minute Amounts of Surfactant. AB - Controlling the organization of particles at liquid-gas interfaces usually relies on multiphasic preparations and external applied forces. Here, we show that micromolar amounts of a conventional cationic surfactant induce, in a single step, both adsorption and crystallization of various types of nanometer- to micrometer-sized anionic particles at the air-water interface, without any additional phase involved or external forces other than gravity. Contrary to conventional surfactant-induced particle adsorption through neutralization and hydrophobization at a surfactant concentration close to the critical micellar concentration (CMC), we show that in our explored concentration regime (CMC/1000 CMC/100), particles adsorb with a low contact angle and maintain most of their charge, leading to the formation of two-dimensional assemblies with different structures, depending on surfactant ( Cs) and particle ( Cp) concentrations. At low Cs and Cp, particles are repulsive and form disordered assemblies. Increasing Cp in this regime increases the number of adsorbed particles, leading to the formation of mm-sized, highly ordered polycrystalline assemblies because of the long-range attraction mediated by the collective deformation of the interface. Increasing Cs decreases the particle repulsion and therefore the interparticle distance within the monocrystalline domains. A further increase in Cs (~CMC/10) leads to a progressive neutralization of particles accompanied by the formation of disordered structures, ranging from densely packed amorphous ones to loosely packed gels. These results emphasize a new role of the surfactant to mediate both adsorption and crystallization of particles at liquid-gas interfaces and provide a practical manner to prepare two-dimensional ordered colloidal assemblies in a remarkably robust and convenient manner. PMID- 30415548 TI - Small Surface, Big Effects, and Big Challenges: Toward Understanding Enzymatic Activity at the Inorganic Nanoparticle-Substrate Interface. AB - Enzymes are important biomarkers for molecular diagnostics and targets for the action of drugs. In turn, inorganic nanoparticles (NPs) are of interest as materials for biological assays, biosensors, cellular and in vivo imaging probes, and vectors for drug delivery and theranostics. So how does an enzyme interact with a NP, and what are the outcomes of multivalent conjugation of its substrate to a NP? This invited feature article addresses the current state of the art in answering this question. Using gold nanoparticles (Au NPs) and semiconductor quantum dots (QDs) as illustrative materials, we discuss aspects of enzyme structure-function and the properties of NP interfaces and surface chemistry that determine enzyme-NP interactions. These aspects render the substrate-on-NP configurations far more complex and heterogeneous than the conventional turnover of discrete substrate molecules in bulk solution. Special attention is also given to the limitations of a standard kinetic analysis of the enzymatic turnover of these configurations, the need for a well-defined model of turnover, and whether a "hopping" model can account for behaviors such as the apparent acceleration of enzyme activity. A detailed and predictive understanding of how enzymes turn over multivalent NP-substrate conjugates will require a convergence of many concepts and tools from biochemistry, materials, and interface science. In turn, this understanding will help to enable rational, optimized, and value-added designs of NP bioconjugates for biomedical and clinical applications. PMID- 30415549 TI - Detection of Aliphatically Bridged Multi-Core Polycyclic Aromatic Hydrocarbons in Sooting Flames with Atmospheric-Sampling High-Resolution Tandem Mass Spectrometry. AB - This paper provides experimental evidence for the chemical structures of aliphatically substituted and bridged polycyclic aromatic hydrocarbon (PAH) species in gas-physe combustion environments. The identification of these single- and multicore aromatic species, which have been hypothesized to be important in PAH growth and soot nucleation, was made possible through a combination of sampling gaseous constituents from an atmospheric pressure inverse coflow diffusion flame of ethylene and high-resolution tandem mass spectrometry (MS-MS). In these experiments, the flame-sampled components were ionized using a continuous VUV lamp at 10.0 eV and the ions were subsequently fragmented through collisions with Ar atoms in a collision-induced dissociation (CID) process. The resulting fragment ions, which were separated using a reflectron time-of-flight mass spectrometer, were used to extract structural information about the sampled aromatic compounds. The high-resolution mass spectra revealed the presence of alkylated single-core aromatic compounds and the fragment ions that were observed correspond to the loss of saturated and unsaturated units containing up to a total of 6 carbon atoms. Furthermore, the aromatic structures that form the foundational building blocks of the larger PAHs were identified to be smaller single-ring and pericondensed aromatic species with repetitive structural features. For demonstrative purposes, details are provided for the CID of molecular ions at masses 202 and 434. Insights into the role of the aliphatically substituted and bridged aromatics in the reaction network of PAH growth chemistry were obtained from spatially resolved measurements of the flame. The experimental results are consistent with a growth mechanism in which alkylated aromatics are oxidized to form pericondensed ring structures or react and recombine with other aromatics to form larger, potentially three-dimensional, aliphatically bridged multicore aromatic hydrocarbons. PMID- 30415550 TI - Millimeter-Sized Two-Dimensional Molecular Crystalline Semiconductors with Precisely Defined Molecular Layers via Interfacial-Interaction-Modulated Self Assembly. AB - The newly emerging field in organic electronics is to control the molecule substrate interface properties at a two-dimensional (2D) limit via interfacial interactions, which paves the way for driving the molecular assembly for highly ordered 2D molecular crystalline films with precise molecular layers and large area uniformity. Here, by exploiting molecule-substrate van der Waals (vdW) interactions, we demonstrate thermally induced self-assembly of 2D organic crystalline films exhibiting well-defined molecular layer number over a millimeter-sized area. The organic field-effect transistors (OFETs) with bilayer films show excellent electrical performance with a maximum mobility of 12.8 cm2 V 1 s-1. Moreover, we find that the monolayer films can act as interfacial molecular templates to construct heterojunctions with well-balanced ambipolar transport behaviors. The capability of thermally induced self-assembly of 2D molecular crystalline films with controllable molecular layers and scale-up coverage opens up a way for realizing complicated electronic applications, such as lateral heterojunctions and superlattices. PMID- 30415551 TI - Intra-familial Transmission of Chronic Hepatitis B Infection: A Large Population Based Cohort Study in Northern Iran. AB - AIM: The aim of this study was to investigate the intra-familial transmission of chronic hepatitis B (CHB) in Golestan province, that has the highest prevalence of CHB in Iran. METHODS: The Golestan Cohort Study (GCS) is a population-based prospective study of 50045 individuals, 40 years or older, initially set-up to study upper GI cancers in Northern Iran. In 2008, a baseline measurement of hepatitis B surface antigen (HBsAg) on the stored serum of all GCS participants identified 3505 HBsAg+ individuals. In 2011, we assessed HBV serological markers in 2590 initially HBsAg+ individuals and their first-degree relatives including spouses (1454) and children (3934). RESULTS: The median (IQR) age of spouses and children were 52 (12) and 25 (12) years respectively. Out of 5388 family members, 2393 (44.5%) had no HBV markers, indicating susceptibility to infection. Of these, 378 (15.8%) were fully-vaccinated children with no apparent response to primary immunization. HBsAg was positive in 2.2% (n = 33) of spouses and 8.2% (n = 325) of children (overall rate of 6.6%). HBcAb was positive in 761 (52.3%) and 914 (23%) spouses and children, respectively. The rate of spontaneous loss of HBsAg (HBsAg-, HBsAb+ and HbcAb+) was 41.3% and 13.9% in spouses and children, respectively. A higher rate of HBsAg+ children (10.2%) was found in families in which the mother was positive for HBsAg compared with families where the father was positive for HBsAg (6.3%) (P < 0.001). When both parents were positive for HBsAg, the rate of HBsAg positivity was high (23.5%, P < 0.001). Despite high virus exposure rates between spouses (52.6 %), the prevalence of HBsAg positivity among them was very low (2.3 %). CONCLUSION: Sexual and parent-to-child transmission are important routes of CHB spread in this population from northern Iran despite the fact that 24 years have passed since the beginning of hepatitis B vaccination in infants. Low percentage of HBsAg positivity in spouses is related to high HBsAg clearance rate among them. PMID- 30415552 TI - The Association Between Major Dietary Patterns and Pregnancy-related Complications. AB - BACKGROUND: Most pregnancy-related complications are associated with increased risks of adverse outcomes for mother and her infant. Although, relations between diet and pregnancy's complications indicate that there may be some benefits of nutritional factors to prevent such disorders, there are rare studies regarding the associations of dietary patterns and mentioned complications. So, the aim of the present study was to determine the relationship between dietary patterns and risk of pregnancy-related complications. METHODS: The current prospective observational study was based on the data collected from 812 pregnant women. Dietary data was collected using a validated semi-quantitative food frequency questionnaire. RESULTS: Three major dietary patterns identified according to the results from the factor loading matrix were: (i) 'western dietary pattern'; (ii) 'traditional dietary pattern'; (iii) 'healthy dietary pattern'. Overall, this study demonstrated a marginal significant inverse association between high adherence to healthy dietary pattern and chance of having pre-eclampsia. Also, a high chance of pre-eclampsia was observed among women with the most adherence to western dietary pattern. CONCLUSION: We found that dietary patterns might be associated with the risk of pregnancy-related complications. Further studies are required to confirm these findings. PMID- 30415553 TI - The Effects of Folic Acid Supplementation on Recurrence and Metabolic Status in Endometrial Hyperplasia: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - BACKGROUND: Data on the effects of folic acid supplementation on clinical symptoms and metabolic profiles of patients with endometrial hyperplasia (EH) are limited. This investigation was performed to evaluate the effects of folic acid supplementation on clinical symptoms and metabolic status of patients with EH. METHODS: This randomized, double-blind, placebo-controlled trial was conducted among 60 women diagnosed with EH. Diagnosis of EH was made based on biopsy results. Participants were randomly allocated to 2 groups to take 5 mg/d folic acid supplements (n = 30) or placebo (n = 30) for 12 weeks. RESULTS: After the 12 week intervention, folic acid supplementation significantly decreased fasting plasma glucose (beta -3.99 mg/ dL; 95% CI, -7.39, -0.59; P = 0.02), serum insulin levels (beta -2.82 uIU/mL; 95% CI, -4.86, -0.77; P = 0.008), homeostasis model assessment for insulin resistance (beta -0.68; 95% CI, -1.20, -0.17; P = 0.009), triglycerides (beta -16.47 mg/dL; 95% CI, -28.72, -4.22; P = 0.009) and very-low density lipoprotein (VLDL) cholesterol (beta -3.29 mg/dL; 95% CI, -5.74, -0.84; P = 0.009), and significantly increased the quantitative insulin sensitivity check index (beta 0.01; 95% CI, 0.004, 0.03; P = 0.01) compared with the placebo. Additionally, folic acid intake resulted in a significant reduction in serum high sensitivity C-reactive protein (hs-CRP) (beta -0.36 mg/L; 95% CI, -0.52, -0.21; P < 0.001) compared with the placebo. Folic acid supplementation did not affect other metabolic parameters. CONCLUSION: In conclusion, we found that folic acid administration for 12 weeks to subjects with EH improved glycemic control, triglycerides, VLDL-cholesterol and hs-CRP levels, but did not influence recurrence and other metabolic profiles. PMID- 30415554 TI - The Prediction of Obstructive Sleep Apnea Using Data Mining Approaches. AB - BACKGROUND: Obstructive sleep apnea (OSA) which is the most common sleep disorder breathing (SDB), imposes heavy costs on health and economy. The aim of this study was to provide models based on data mining approaches (C5.0 decision tree and logistic regression model [LRM]) and choose a top model for predicting OSA without polysomnography (PSG) devices that is a standard method for diagnosis of this disease, to identify patients with this syndrome payment. METHODS: In this cross sectional study, data was extracted from the medical records of 333 patients with sleep disorders who were referred to sleep disorders research center of Kermanshah University of Medical Sciences during the years 2012-2016. All patients underwent one night PSG. A stepwise LRM was fitted and its performance was compared with C5.0 decision tree with use of the criteria of accuracy, sensitivity and specificity. RESULTS: For C5.0 decision tree, accuracy was obtained 0.757 with 95% confidence interval (0.661, 0.838), sensitivity was 0.66 and specificity was 0.809. For LRM, these items were obtained 0.737 (0.639, 0.820), 0.693 and 0.78 respectively. CONCLUSION: C5.0 decision tree showed better performance than LRM in diagnosis of OSA. So this model can be considered as an alternative approach for PSG. PMID- 30415555 TI - A Mobile Application for Managing Diabetic Patients' Nutrition: A Food Recommender System. AB - BACKGROUND: As a prevalent metabolic disease, diabetes has different side effects and causes a wide range of co morbidity with a high rate of mortality. There is a need for certain interventions to manage this disease. Iranians usually have three main meals a day. Considering the special needs of diabetic patients and the possibility of hypoglycemia between the main meals, it is essential for these patients to eat something as a snack. Considering these conditions and the society's orientation towards modern technologies such as smart phones, designing mobile-based nutrition recommender systems can be helpful. METHODS: The snack recommender system is a knowledge-based smart phone application. This study has focused on the development of a recommender system that combines artificial intelligence techniques and makes up a knowledge base according to the guidelines posed by the American Diabetes Association (ADA). The snack menu was recommended in accordance with the patient's favorites and conditions. The accuracy of the recommended menu was assessed in 2 steps. First, it was compared with the diet prescribed by three nutrition specialists. In the second step, system's suggested menu was evaluated by the data from 30 diabetic patients using a valid questionnaire. RESULTS: The results of evaluating the snack recommender system by nutritionists showed that this system is capable of recommending various snacks according to the season (accuracy of 100%) and personal interests (accuracy of 90%) to diabetic patients. According to health nutritionists, the snacks suggested by this system are matched with Iranian culture. Moreover, the results revealed that a higher body mass index (BMI) makes the recommender system less sensitive to personal interests to suggest what is basically beneficial for one's health. CONCLUSION: This study was a pioneering research to develop a more comprehensive dietary recommender system for diabetic patients which includes main meals as well. Patients found the system useful and were satisfied with the application. This system is believed to be able to help diabetic patients to take more healthy diet which leads to a better lifestyle. PMID- 30415556 TI - Ante-mortem Diagnosis of Human Rabies Cases Using SYBR Green Real-Time PCR. AB - BACKGROUND: Rabies, as the most important zoonotic disease, is transmitted through a bite or scratch by an infected domestic or wild carnivores and bats or contact of open wound with infected saliva. The fluorescent antibody test (FAT) is the "gold standard" diagnostic method for suspected brain samples. For close monitoring of unknown encephalitis, rabies surveillance, and also the limitations for post-mortem diagnosis of rabies in human and performing fast prophylactic measures for other individuals in contact with rabid patients, ante-mortem diagnosis based on molecular methods such as real-time polymerase chain reaction (PCR) seems to be more reliable. In this study, we detected 2 positive rabid cases using SYBR Green real-time PCR for the first time in Iran. METHODS: In this study, 3 saliva samples at intervals up to 6 hours were collected from any of the nine suspected patients with nonspecific symptoms between March 2016 and March 2017. Total RNA extraction, cDNA synthesis and real-time PCR were performed along with confirmed negative and positive controls. Then, we tracked the patients for follow-up and understanding of their status. On brain samples of patients who died, FAT and MIT (mouse inoculation test) were performed to obtain definitive results. RESULTS: In this study, the patients were 4 females and 5 males, between 8 and 80 years old from different geographical areas of Iran. The ante-mortem saliva samples of 2 out of nine patients who died were positive by SYBR Green real-time PCR. Positive results of FAT test on these samples confirmed the presence of rabies virus infection in their brains and also the ante-mortem diagnosis results. CONCLUSION: The results of this study suggest that SYBR Green real-time PCR technique on saliva sample can be used as an applicable method for ante-mortem diagnosis of rabies to avoid infection of other people such as the treating medical staff or family members of the patient. PMID- 30415557 TI - tRNA Methyltransferase Defects and Intellectual Disability. AB - In all organisms, transfer RNA (tRNA) molecules are required to undergo post transcriptional modifications at different levels in order to convert into mature tRNAs. These modifications are critical for many aspects of tRNA function and structure, such as translational efficiency, flexibility, codon-anticodon interaction, stability, and fidelity. Up to now, over 100 modified nucleosides have been identified in tRNAs from all domains of life. Post-transcriptional modifications include different chemical processes such as methylation, deamination, or acetylation, with methylation reactions as the most common. tRNA methyltransferases are a family of enzymes involved in the post-transcriptional methylation of tRNA bases. Recent studies have reported different human diseases resulting from defects in tRNA methyltransferase activity, including cancer, diabetes and neurological disorders such as intellectual disability (ID). In this article, we focused on biological function and characterization of tRNA methyltransferases associated with ID in order to explain how functional disruption of tRNA methyltransferases could lead to ID phenotype. PMID- 30415558 TI - Social Challenges of Mothers with Blindness in Iranian Setting. PMID- 30415559 TI - Missed Links in the Determination of Challenges of Urban Family Physician Program. PMID- 30415560 TI - Response to the Letter to the Editor. PMID- 30415561 TI - Hemoglobin A1c Cut-off to Diagnose Diabetes in Iranian Population. PMID- 30415562 TI - Mirza Ali Hamedani: An Influential Physician in the Qajar Period, Iran. AB - The knowledge of medicine underwent a revolution in the Qajar period, especially during the reign of Naser al-Din Shah Qajar (1831-1896 AD). The dispatch of students to Europe, establishment of Dar ul-Funun, Hafez al-Seheh Assembly, and clinics, entrance of European teachers and physicians to Iran, approval of medical rules by the parliament, introduction of a new therapeutic style, and translation of medical textbooks into Persian were some of the changes that occurred during this period. As a result, modern medicine influenced the Iranian Islamic traditional medicine. An educated Iranian physician, Mirza Ali Doctor Hamedani was one of the physicians of this period, who traveled to France, studied the European medicine and considerably contributed to the evolution of the modern medicine along the traditional medicine. The present manuscript describes the scientific personality and contributions of this physician to the science of medicine. PMID- 30415563 TI - Melatonin Improves Mood Status and Quality of Life and Decreases Cortisol Levels in Fibromyalgia. AB - BACKGROUND:: Mood disturbances are implicated in the pathogenesis of fibromyalgia. The aim of this study was to assess the effect of different doses of melatonin on quality of life, mood status, pain, anxiety, and urinary cortisol levels in patients with fibromyalgia. METHODS:: After a 10-day baseline period for the collection of data about participants' initial status, participants took different doses of melatonin for 10 consecutive days each, with placebo given during the 10 days either before or between melatonin doses. Participants' moods, quality of life, and pain levels were assessed using the Fibromyalgia Impact Questionnaire (FIQ), a Numerical Pain Scale (NPS), the State-Trait Anxiety Test (STAI), a Visual Analog Scale (VAS), and the Short Form-36 Health Survey (SF-36). Urinary cortisol levels were measured using enzyme-linked immunoassay. RESULTS:: Doses of 9, 12, and 15 mg of melatonin were associated with decreases in the total score of the FIQ, NPS scores, and urinary cortisol levels. The State Anxiety subscale of the STAI improved after the 12 mg dose. The scores on the VAS improved after the 9 mg dose. The dimensions evaluated in the SF-36 questionnaire improved after the 9 mg dose. CONCLUSION:: Melatonin improved mood, anxiety levels, and quality of life while decreasing cortisol levels in patients with fibromyalgia. PMID- 30415564 TI - Relationship continuity and person-centred care in how spouses make sense of challenging care needs. AB - OBJECTIVES: Some spouses providing care for a partner with dementia experience continuity in the relationship: Despite the changes that have occurred, the person with dementia and the relationship are felt to be essentially the same as they were before the dementia. Others experience discontinuity: The person and the relationship feel very different. Previous qualitative research has suggested that continuity may be linked with the delivery of more person-centred care. Using a mixed-methods approach, the present study aimed to provide a more robust test of this claim. METHOD: Twenty-six spousal carers completed the Birmingham Relationship Continuity Measure and the Caregiver Hassles Scale, and took part in an interview about their response to challenging care needs. Attributions about the causes of those needs were extracted from the interviews and coded. Codes referred either to dementia as a cause, or to a range of other causes that reflected a more person-centred focus. A measure of person-centred care was obtained by calculating the percentage of the total number of attributions that fell into these more person-centred categories. RESULTS: Consistent with the hypothesis that continuity and person-centred care are linked, those who reported greater continuity reported a significantly higher percentage of person-centred attributions. CONCLUSIONS: Person-centred care is important for the well-being of those giving and those receiving the care. Little is currently known about how to support families to be more person-centred. The possibility of supporting person centred care through enhancing the experience of continuity merits investigation. PMID- 30415566 TI - Primary vascular prevention: The end of the road for aspirin? PMID- 30415565 TI - The Impact of Timing of Tympanostomy Tube Placement on Sequelae in Children With Cleft Palate. AB - OBJECTIVE:: To describe the impact of timing of tympanostomy tube insertion on the number of tubes received and complications in children with routine tube placement. DESIGN:: Retrospective case series. SETTING:: Tertiary care children's hospital. PARTICIPANTS:: Records from a consecutive sample of 401 children with cleft palate were reviewed. Sixty-five patients with isolated cleft palate and 82 patients with cleft lip and palate had follow-up until 5 years of age and were included. INTERVENTIONS:: Tympanostomy tubes. MAIN OUTCOME MEASURE(S):: Number of tubes received and tube-related complications. The hypothesis was formulated prior to data collection. RESULTS:: Males comprised 55.8% of included patients, and tubes were placed in 98.6% of patients at a median age of 6.5 months. Effusion was documented at first tube placement for 96.5% of patients. Most (67.4%) patients required replacement of tubes, and 10.6% required long-term tubes. Complications included otorrhea (71.0%), myringosclerosis (35.2%), granulation (22.8%), perforation (17.9%), retained tubes (5.5%), and cholesteatoma (1.4%). Cleft lip and palate ( P < .001) and otorrhea ( P = .023) were associated with tube placement before palatoplasty. Patients with tube placement before palatoplasty ( P = .033), genetic disorders ( P = .007), failed newborn hearing screen ( P = .012), otorrhea ( P < .001), and granulation ( P < .001) received more tubes. CONCLUSIONS:: Nearly universal effusion in patients with cleft palate supports the need for routine tube placement. The potential for otorrhea and requiring more tubes should be weighed against the risks associated with prolonged effusion when considering tube placement before palatoplasty. PMID- 30415567 TI - [Use of noninvasive ventilation in critically ill patients]. AB - INTRODUCTION: The use of noninvasive ventilation has increased worldwide. Its mortality reducing benefit has been shown in several different conditions compared to invasive ventilation. Common counterarguments against the technique are its increased technical and caregiver requirements and increased mortality associated with treatment failure. AIM: The aim of our work was to describe our experiences with noninvasive ventilation in the intensive care unit. METHOD: We reviewed patient data from the Respiratory Intensive Care unit of Semmelweis University operated from 2014 to 2016. Statistical analysis was performed by Mann Whitney U test and Z-test; odds ratio was calculated with chi-square test. RESULTS: Out of the 301 patients analyzed, 147 received noninvasive ventilation. Noninvasive failure rate was 24.5%. The highest failure rate was associated with immunodeficiency associated pneumonia, interstitial lung disease and pneumonia (71.4%, 33.3% and 31.6%), while noninvasive ventilation was the most successful in cardiogenic pulmonary edema and hypercapnic respiratory failure (0 and 16.7% failure rate). Treatment failure was associated with significantly higher mortality (33.3%) compared to patients initially ventilated invasively (24.5%) and patients successfully treated with noninvasive ventilation (3.6%), resulting in a 2.65-fold mortality increase in invasively ventilated patients (OR = 2.65, 95% CI = 1.305-5.374, p = 0.009), and a 13.33-fold mortality increase in noninvasive failure patients (OR = 13.33; 95% CI 3.278-54.238; p<0.001). Outcome scores did not predict noninvasive failure. CONCLUSION: Noninvasive ventilation is a widely used, effective treatment mode which can improve the outcome in certain diseases compared to invasive ventilation. Noninvasive ventilation in incorrect indications could, however, lead to increased failure rates and mortality. Orv Hetil. 2018; 159(45): 1831-1837. PMID- 30415568 TI - [Dirofilariasis in the head and neck region. Case report]. AB - Dirofilariasis refers to an infection caused by a specific parasitic roundworm. Dirofilaria repens - transmitted by mosquito bites - accounts for most human cases. The parasite forms a subcutaneous mass called cutaneous dirofilariasis near the original site of intrusion. The incidence of human infections shows an increasing tendency. We report a case of a 35-year-old woman presenting with three-week history of a painful swelling in the temporal region. The initial diagnostic work-up revealed a roundworm embedded in the subcutaneous fat tissue and temporal muscle. Differential diagnosis included erysipelas, herpes zoster, temporal arteritis. The final diagnosis of helminthiasis was established by ultrasound examination. A multidisciplinary consultation including infectious diseases specialist suggested surgical removal of the lesion. The microbiological examination of the specimen confirmed the presence of a female Dirofilaria repens. Orv Hetil. 2018; 159(45): 1844-1847. PMID- 30415569 TI - [Miscellaneous]. PMID- 30415571 TI - [ECG pearl: the Brugada sign. Case report]. AB - An Asian patient was admitted with palpitation. The ECG showed coved-shaped type Brugada pattern with QRS-fragmentations. Early recognition and risk stratification are the most important issues in Brugada syndrome. Orv Hetil. 2018; 159(45): 1848-1850. PMID- 30415570 TI - [Comparative functional outcome of reverse shoulder prostheses implanted on degenerative and oncological indications]. AB - INTRODUCTION: Several methods (bone graft, endoprosthesis) are used to reconstruct proximal humerus resections due to primary and metastatic tumours. One of the new procedures is the replacement of the joint surfaces and the removed proximal humerus end with reverse shoulder prosthesis, optionally supplemented with bone implantation (composite procedure) in the hope of achieving better shoulder function. AIM: The aim of this study was to compare the shoulder function of the patient group operated by the above procedure with reverse prosthesis to a patient group operated by indication of degenerative shoulder disease (rotator cuff arthropathy). METHOD: The study involved 23 patients (13 men, 10 women) who were operated between 2012 and 2016 in our institution. Among them, 15 had rotator cuff arthropathy indication of reverse prosthesis, while in 8 cases, resection of the humerus and prosthesis implantation were performed due to tumour lesions. The average age of our patients was 62.5 years (17-82) and the average follow-up was 23.5 months (5-57). We performed physical examination, X-ray pictures on their operated arm, and data were recorded and analysed based on functional score systems. RESULTS: The level of postoperative pain was almost the same in the two groups, but only the rotator cuff arthropathy group needed pain medications. In line with our expectations, we received slightly lower values by each of the three scoring systems in case of tumorous patients. The tumorous patients were satisfied with the results achieved. CONCLUSIONS: Following proximal humerus resections, reversed prosthesis implantation with occasional bone allografts is a reliable method of reconstruction, which approaches available functions and reliability as compared to non-tumour-indicating patients. Orv Hetil. 2018; 159(45): 1838-1843. PMID- 30415572 TI - [Non-alcoholic fatty liver disease - a summary and update based on the EASL-EASD EASO Clinical Practice Guidelines of 2016]. AB - The non-alcoholic fatty liver disease (NAFLD) as a common metabolic disease affects nearly one third of the population in the developed countries. The significance of the NAFLD is due to its spectrum disease (simple steatosis -> NASH [non-alcoholic steatohepatitis] +/- fibrosis -> cirrhosis -> HCC [hepatocellular carcinome]) character; its association with obesity, type 2 diabetes mellitus (T2DM), dyslipidaemia, metabolic syndrome, insulin resistance; and its complications both as a consequence of the direct progression of the liver disease and also related to the additional target organ damage due to the progression of the metabolic disease (cardiovascular, renal). The clinical practice guideline jointly authored by 3 European professional societies (EASL EASD-EASO) in 2016 offers a gap-filling, more united diagnostic, therapeutical and follow-up algorithm for the management of NAFLD. The authors of this article could only aim at highlighting the most important considerations and cite a few important literatures that became available only after the publication of the original article. Orv Hetil. 2018; 159(45): 1815-1830. PMID- 30415573 TI - A new cytochalasin derivative from the mangrove-derived endophytic fungus Xylaria sp. HNWSW-2. AB - A new cytochalasin derivative xylarisin B (1), together with four known compounds astropyrone (2), guaidiol (3), xylaropyrone B (4), and xylaropyrone C (5), were isolated from the fermentation broth of Xylaria sp. HNWSW-2. Their structures were elucidated by spectroscopic data. Among them, compounds 2 and 3 at a concentration of 50 MUg/ml showed weak inhibitory activity against AChE with inhibition rates of 10.4 and 12.9%, respectively. In addition, compound 2 also exhibited inhibitory activity against alpha-glycosidase with inhibition rate of 77.0% at a concentration of 0.25 mg/ml.[Formula: see text]. PMID- 30415574 TI - Re-engineering and synthesis of cytotoxic 2,3:7,8-di(alkylenedioxy)-extended analogs of quaternary sanguinarine chloride. AB - A method was developed to synthesize 2,3:7,8-di(alkylenedioxy)-extended analogs of quaternary sanguinarine chloride. 1-Bromo-2-bromomethyl-3,4-alkylenedioxy benzenes and 6,7-alkylenedioxynaphthalen-1-amines were synthesized first. Reactions to construct the target compounds with these two series of synthons involved alterations on a published method for synthesizing 2,3,7,8 tetraoxygenated derivatives of benzo[c]phenanthridinium, substituting benzyl bromides for benzoic aldehydes, prolonging the radical annulation time, and conducting N-methylation with formic acid and NaBH4. All the target compounds showed the same or better in vitro growth inhibitory activities against cancer cell lines compared with the positive compound. The structure activity relationship relevant to cytotoxicity and lipophilicity of the target compounds was produced. PMID- 30415575 TI - Can a temporary increase in corticosteroid dosage reduce asthma exacerbations? PMID- 30415576 TI - Functional outcome of total hip arthroplasty after a previous hip arthroscopy: a retrospective comparative cohort study. AB - BACKGROUND:: Despite patients demonstrating significant short-term clinical improvement from a hip arthroscopy (HA), a number of patients progress to significant osteoarthritis of the hip requiring total hip arthroplasty (THA). This study aims to evaluate if there is any difference in the functional outcome of patients undergoing THA after a previous hip arthroscopy compared to patients undergoing THA for primary osteoarthritis of the hip. METHODS:: Between 2010 and 2013, in a group of 414 patients who underwent hip arthroscopy, we identified 18 patients who underwent a subsequent uncemented THA. These formed the study group. During the same period, 625 patients underwent an uncemented THA performed for primary OA, of which 63 patients were matched to the study group for age, follow up and implants used. These formed the control group. Pre-op and post-op Oxford Hip Scores (OHS) were recorded for all patients. RESULTS:: A mean follow-up of 26.5 and 26.3 months was observed in the study and control groups respectively. The median (interquartile ranges) preoperative OHS were 14 (8.25, 17.0) and 18.5 (13.25, 24.75) in the 2 groups. Corresponding postoperative scores were 40 (31.25, 45) and 46 (43, 48). Median difference between the preoperative and postoperative OHS was 27 (19, 31) and 25 (18.25, 31). Adjusting for the pre treatment scores, the postoperative scores in the study arm were significantly lower than for the control arm with an estimate (SE) of -0.464 ( p = 0.012). Post hoc power analysis showed that the study was sufficiently powered to detect a meaningful difference in scores. CONCLUSION:: Total hip arthroplasty after hip arthroscopy leads to satisfactory functional outcomes. However, the functional outcome in this group is significantly worse than in a matched cohort of patients undergoing THA for osteoarthritis. There was no difference in the rate of complications between the 2 groups. PMID- 30415577 TI - The serum albumin threshold for increased perioperative complications after total hip arthroplasty is 3.0 g/dL. AB - INTRODUCTION:: Low serum albumin is associated with higher perioperative complications following total hip arthroplasty (THA). The distinct threshold for a significant rise in perioperative complications has not been defined for THA. The purpose of this study was to define the threshold at which perioperative complications rise after THA. METHODS:: We analysed the American College of Surgeons NSQIP database from 2006 to 2013. Our study cohort included unilateral primary THA with reported preoperative albumin levels. Patients were stratified by albumin level. We analysed mortality and 6 composite complication variables (any complication, any complication without transfusion, wound infection, systemic infection, cardiac/pulmonary complications, and any major complication). All data analysis was executed in STATA statistical software. Multivariable logistic regression analysis was used to adjust for odds ratios. RESULTS:: The final cohort included 24,586 patients who were stratified based upon serum albumin levels. Odds ratios after multivariable regression adjustment for age, gender, race, body mass index, ASA classification, and Charlson Comorbidity Index indicated a trend to elevated odds of complication for all composite complications (3 of which were statistically significant) when serum albumin level was <3.0 g/dL. CONCLUSION:: Low serum albumin is associated with increased perioperative complications following THA. The threshold associated with an increase in major perioperative complications appears to be an albumin level of <3.0 g/dL. With attempts to correct modifiable risk factors prior to surgery, the threshold value at which perioperative complications increase is important to define. PMID- 30415578 TI - Chemical constituents from the whole herb of Hemiphragma heterophyllum. AB - Phytochemical investigation on Hemiphragma heterophyllum led to the isolation of two new compounds, heterophyllumin A (1) and heterophylliol (3), along with nine known compounds, (-)-sibiricumin A (2), iridolactone (4), jatamanin A (5), dihydrocatalpolgenin (6), 25-hydroperoxycycloart-23-en-3beta-ol (7), 24 methylenecycloartanol (8), (+)-pinoresinol (9), hexadec-(4Z)-enoic acid (10), and 9,12, 15-octadecatrienoic acid (11). Their structures were elucidated on the basis of detailed spectroscopic analyses and by comparison with literature data. Further, the structure of compound 3 was unambiguously confirmed by single crystal X-ray analysis. Some of those compounds showed moderate activity in the alpha-glucosidase inhibition assay. [Formula: see text]. PMID- 30415579 TI - (-)-Calcaridine B, a new chiral aminoimidazole-containing alkaloid from the marine sponge Leucetta chagosensis. AB - LC-DAD/MS-based dereplication of organic extract of a calcareous sponge Leucetta chagosensis afforded one new chiral aminoimidazole-containing alkaloid, (-) calcaridine B (1), along with one achiral imidazole analog leucettamine E (2) as well as one known imidazole derivative (2E, 9E)-pyronaamidine-9-(N-methylimine) (3). Their structures were elucidated on the basis of NMR spectroscopic analyses, and comparing with the literature. The cytotoxic activities of all isolates were evaluated against three human cancer cell lines, and compounds 1 and 3 exhibited mild cytotoxicities toward the MCF-7 cell line with IC50 values of 25.3-24.2 MUM, respectively. PMID- 30415580 TI - 7-year results of primary total hip arthroplasty with the uncemented Avenir stem. AB - AIMS:: The aim of the present study was to evaluate the 7-year functional outcome and radiographic results of primary total hip arthroplasties (THAs) performed with the uncemented Avenir stem. PATIENTS AND METHODS:: Between January 2006 and October 2008, 100 consecutive primary hips in 92 patients were enrolled at 2 centres. The mean age at operation was 58.5 years (27-87 years). Mini-incision (50%) and standard approaches (50%) were used to implant 22 standard and 78 lateralised stems. RESULTS:: The 7-year Kaplan-Meier survival rate was 98.9% (95% CI, 92.9-99.8) with stem revision for any reason as endpoint. No stem related complications occurred. 1 stem revision was due to deep infection at 51 months post-op. We had 4 acetabular revisions. The mean Harris Hip Score (HHS) at 7 years follow-up was 93.1 points (60-100). Radiographic analysis showed 2 patients had non-progressive radiolucent lines and no patient had any signs of stem subsidence or loosening. CONCLUSION:: The 7-year implant survival and the functional outcomes for THA performed with the study device are excellent and were in line with those documented for comparable contemporary uncemented fully HA-coated stems. Longer term follow-up of this consecutive series needs to be performed. PMID- 30415581 TI - Efficacy of phospholipidated curcumin in nonalcoholic fatty liver disease: a clinical study. AB - Curcumin is a safe and dietary phytochemical that can improve different pathophysiologic features of non-alcoholic fatty liver disease (NAFLD). Here, we investigated the efficacy of phospholipidated curcumin supplementation in NAFLD patients. In this single-arm study, 36 patients were recruited. Each patient received three capsules a day (each containing 500 mg of phospholipidated curcumin [overall content of curcuminoids per capsule: 100 mg]) for a period of 8 weeks. The results indicated that phospholipidated curcumin supplementation reduced NAFLD severity and ameliorated ultrasonographic and biochemical measures (including liver transaminases and lipid profile) associated with disease progression. PMID- 30415582 TI - Small, but mighty? Searching for human microproteins and their potential for understanding health and disease. PMID- 30415583 TI - Multi-sector perspectives on learning for interprofessional practice: lessons for higher education and organisational culture. AB - In order to build the evidence base for interprofessional education and practice, it is important to establish how the concepts and theories are understood by higher education providers, policy-makers, managers, and practitioners. Using an interdisciplinary research approach, and facilitated by the use of visual images, we undertook a discourse analysis of interviews and discussions around definitions, competencies, and cultures of learning for interprofessional practice in the context of child health and social care in Scotland. Challenges to interprofessional practice were seen as generated within professional hierarchies and the complicatedness of working with chronic or multisystem disease. In order to work collaboratively, individual practitioners should understand the boundaries of their own knowledge and skills and demonstrate the capacity for interpersonal communication (within and between professions), as well as problem-solving and dealing with uncertainty. While there was agreement on these as key learning needs for collaborative working, the term interprofessional education was rarely used in practice by the interviewees and there was perception of a gap between university and workplace settings in supporting learning for interprofessional practice. It is recommended that educational frameworks acknowledge that the interprofessional learning journey is influenced by context and organisational culture. PMID- 30415584 TI - Disease-modifying Drugs in Osteoarthritis: Current Understanding and Future Therapeutics. AB - INTRODUCTION: Osteoarthritis (OA) is a leading cause of pain and disability among adults with a current prevalence of around 15% and a predicted prevalence of 35% in 2030 for symptomatic OA. It is increasingly recognized as a heterogeneous multi-faceted joint disease with multi-tissue involvement of varying severity. Current therapeutic regimens for OA are only partially effective and often have significant associated toxicities. There are no disease-modifying drugs approved by the regulatory bodies. Areas covered: We reviewed the opportunities within key OA pathogenetic mechanism: cartilage catabolism/anabolism, pathological remodelling of subchondral bone and synovial inflammation to identify targeted disease-modifying osteoarthritis drugs (DMOADs), based on compounds currently in Phase II and III stages of clinical development in which x-ray and/or MRI was used as the structural outcome with/without symptomatic outcomes according to regulatory requirements. Expert opinion: Given the heterogeneity of the OA disease process and complex overlapping among these phenotypes, a "one size fits all" approach used in most clinical trials would unlikely be practical and equally effective in all patients, as well as in all anatomical OA sites. On the other hand, it is a challenge to develop a targeted drug with high activity, specificity, potency, and bioavailability in the absence of toxicity for long term use in this chronic disease of predominantly older adults. Further research and insight into evaluation methods for drug-targeted identification of early OA and specific characterization of phenotypes, improvement of methodological designs, and development/refinement of sensitive imaging and biomarkers will help pave the way to the successful discovery of disease-modifying drugs and the optimal administration strategies in clinical practice. PMID- 30415585 TI - Sonopermeation to improve drug delivery to tumors: from fundamental understanding to clinical translation. AB - INTRODUCTION: Ultrasound in combination with microbubbles can make cells and tissues more accessible for drugs, thereby achieving improved therapeutic outcomes. In this review, we introduce the term 'sonopermeation', covering mechanisms such as pore formation (traditional sonoporation), as well as the opening of intercellular junctions, stimulated endocytosis/transcytosis, improved blood vessel perfusion and changes in the (tumor) microenvironment. Sonopermeation has gained a lot of interest in recent years, especially for delivering drugs through the otherwise impermeable blood-brain barrier, but also to tumors. Areas covered: In this review, we summarize various in vitro assays and in vivo setups that have been employed to unravel the fundamental mechanisms involved in ultrasound-enhanced drug delivery, as well as clinical trials that are ongoing in patients with brain, pancreatic, liver and breast cancer. We summarize the basic principles of sonopermeation, describe recent findings obtained in (pre-) clinical trials, and discuss future directions. Expert Opinion: We suggest that an improved mechanistic understanding, and microbubbles and ultrasound equipment specialized for drug delivery (and not for imaging) are key aspects to create more effective treatment regimens by sonopermeation. Real time feedback and tools to predict therapeutic outcome and which tumors/patients will benefit from sonopermeation-based interventions will be important to promote clinical translation. PMID- 30415586 TI - Peripheral auditory dysfunction secondary to traumatic brain injury: a systematic review of literature. AB - PRIMARY OBJECTIVE: To understand the effects of non-blast-related TBI on peripheral auditory function in adults, as measured through basic and advanced audiological assessments. BACKGROUND: Despite numerous studies demonstrating hearing loss post TBI there has been no systematic investigation of the prevalence, nature and severity of peripheral hearing loss. DATA IDENTIFICATION: An English-language systematic search using MEDLINE, CINAHL, PsychINFO, PubMed and hand-searching of reference lists was conducted from 1 January 1990 to 31 October 2016. STUDY SELECTION: After independent review by the authors, 20 of 281 originally identified articles were retained. DATA EXTRACTION: Audiological findings were extracted and synthesized across studies. RESULTS: Using the Oxford Centre for Evidence Based Medicine levels of evidence (2009), 3b was the highest level of evidence within the review. Sensorineural hearing loss was the most consistent auditory deficit reported post TBI. CONCLUSION: The range and frequency of auditory dysfunction in patients with TBI remain unclear. Future research should focus on understanding the nature, frequency and change of auditory deficits over time following TBI. Knowledge in this area will provide crucial information for clinicians and facilitate the development of diagnostic and best practice guidelines which currently are lacking for the management of this patient population. PMID- 30415587 TI - Ma Huang Tang ameliorates bronchial asthma symptoms through the TLR9 pathway. AB - CONTEXT: Ma Huang Tang (MHT) has been used to treat influenza, fever, bronchial asthma, etc. as a traditional Chinese medication. However, the anti-inflammation mechanism of MHT remains unclear. OBJECTIVE: The study identifies the possible mechanisms of MHT on ovalbumin (OVA)-induced acute bronchial asthma in mice. MATERIALS AND METHODS: First, an asthma-related protein-protein interaction (PPI) network was constructed. And then, the acute bronchial asthma mice models were established by exposing to aerosolized 1% ovalbumin for 30 min/day for 1 week, and the mice were administered 2.0, 4.0, or 8.0 g/kg of MHT daily. To evaluate therapeutic effect, sensitization time, abdominal breathing time, eosinophils in bronchoalveolar lavage fluid, and tissue and trachea pathology were examined. Related genes were measured using RNA sequencing (RNA-seq). The expression levels of TLR9 in lung and trachea tissues were determined by immunohistochemical staining. RESULTS: MHT had a LD50 = 19.2 g/kg against asthma, while MHT at high doses (8 g/kg) effectively extended the sensitization time and abdominal breathing time and alleviated OVA-induced eosinophilic airway inflammation and mitigated pathological changes. The RNA-seq assay showed that the high-dose MHT resulted in a significant decrease in the levels of TLR9, TRAF6, TAB2, etc. in the lung tissue. Immunohistochemical assay confirmed the down-regulated of TLR9. Molecular docking revealed that six MHT compounds potentially mediated the TLR9 signaling pathway. DISCUSSION AND CONCLUSIONS: MHT could mitigate the pathological changes of acute asthma-like syndrome through inhibition of the TLR9 pathway. Results of this study may provide a reference for the development of a novel therapy for patients with allergic asthma. PMID- 30415588 TI - Cost-effectiveness Analysis and Safety of Erythromycin 4%Gel and 4% Chlorhexidine Scrub for Pitted Keratolysis Treatment. AB - BACKGROUND: Studies of Pitted keratolysis (PK) treatment are limited. OBJECTIVES: To study cost-effectiveness and to compare the safety of 4% chlorhexidine scrub with 4% erythromycin gel, for PK infections. Materials and methods This cohort study was conducted on naval rating cadets with a clinical diagnosis of PK at Chumpol Naval Rating School, Thailand in 2016. Participants were randomly treated with either 4% erythromycin gel or 4% chlorhexidine scrub for 4 weeks. The clinical examinations were evaluated at the baseline and at 1 and 2 months after treatment. A decision-tree model was used to evaluate the costs, resource utilization and outcomes as quality-adjusted life-years (QALYs). Results Of 344 naval rating cadets, 125 (36.3%) were diagnosed with PK. Sixty-four were treated with erythromycin. Approximately 80% of participants had complete resolution Foot odor were significantly improved at 2 months (p < 0.001) for both groups. No adverse effects were reported. Total cost for 4 weeks' treatment with the erythromycin gel and chlorhexidine scrub was US$ 77.34, US$ 51.9, respectively. Chlorhexidine treatment and erythromycin gel had 0.1526 and 0.1425 QALYs, respectively. Conclusion treatment of PK with either 4% chlorhexidine scrub or 4% erythromycin gel had similar outcomes. However, using chlorhexidine scrub was more cost-effective. PMID- 30415589 TI - Through the resident lens: examining knowledge and attitudes about midwifery among physician trainees. AB - Interprofessional collaboration optimizes maternal-newborn outcomes and satisfaction with care. Since 2002, midwives have provided an increasing proportion of maternity care in British Columbia (BC). Midwives often collaborate with and/or refer to physicians; but no study to date has explored Canadian medical trainees' exposure to, knowledge of, and attitudes towards midwifery practice. We designed an online cross-sectional questionnaire that included a scale to measure attitudes towards midwifery (13 items) and residents' knowledge of midwifery (94 items across 5 domains). A multi-disciplinary expert panel rated each item for importance, relevance, and clarity. The survey was distributed to family medicine (n = 338) and obstetric (n = 40) residents in BC. We analyzed responses from 114 residents. Residents with more favourable exposures to midwifery during their education had significantly more positive attitudes towards midwives (rs = 0.32, p = 0.007). We also found a significant positive correlation between residents' attitudes towards midwifery and four of five knowledge domains: scope of practice (rs = 0.41, p < 0.001); content of education (rs = 0.30, p = 0.002), equipment midwives carry to home births (rs = 0.30, p = 0.004) and tests that midwives can order (rs = 0.39, p < 0.001). The most unfavourable exposures were observing interprofessional conversations (66.2%), and providing inpatient consultations for midwives (61.4%). Findings suggest increased interprofessional education may foster improved midwife-physician collaboration. Abbreviations: BC - British Columbia; UBC - University of British Columbia. PMID- 30415590 TI - New abietane diterpenoid glucosides from underground parts of Isodon taliensis. AB - Two new abietane diterpenoid glucosides, talienosides A and B (1 and 2), along with four known compounds (3 - 6), were isolated from the ethyl acetate soluble portion of 70% acetone extract of the underground parts of Isodon taliensis. Their structures were elucidated based on the analyses of extensive spectroscopic data and physicochemical properties. The two new compounds were tested for their bioactivities against malaria and diabetes by beta-hematin formation inhibition and alpha-glycosidase inhibition experiments, respectively. However, only 2 showed weak beta-hematin formation inhibitory activity. [Formula: see text]. PMID- 30415591 TI - Identifying intangible assets in interprofessional healthcare organizations: feasibility of an asset inventory. AB - Healthcare systems increasingly use business models that focus on tangible assets such as finances and facilities. Yet intangible assets, such as values, relationships and human capital, remain critical for understanding the worth of interprofessional healthcare education and collaboration. We implemented a novel interprofessional collaborative pilot exercise to explore the feasibility and usefulness of an Asset Inventory-using KJ methodology and an appreciative inquiry perspective-to identify and better understand intangible assets and their value in interprofessional healthcare education/training organizations, for planning, and as a first step toward informing strategic decision-making. Twenty-eight faculty physicians, nurses, psychosocial and family faculty, educators, health services researchers and administrative staff participated. Participants identified intangible assets in five categories: Philosophy/Mission, Practice/Practical Strategies, Human Capital, Scholarship/Research Productivity, and Partnerships. Participants reported a greater understanding of intangible assets, and increased enthusiasm, organizational confidence, and stakeholder ownership for healthcare education programs. While this study is preliminary, the Asset Inventory may prove useful to enhance understanding of the importance of intangible assets within interprofessional healthcare education/training organizations, to inform planning and decision-making, to identify and foster interprofessional collaborative capacity across clinical and training settings, and to leverage intangible assets in today's rapidly changing business-focused healthcare systems. PMID- 30415592 TI - Can we predict and prevent emergency department visits for postpartum hypertensive complications in patients with hypertensive disorders in pregnancy? AB - BACKGROUND: Hypertensive disorders of pregnancy are major causes of maternal mortality and morbidity, and postpartum hypertensive complications have significant implications on maternal health and public health care system. Antepartum community care programs for hypertension are in place at major centres of Canada, however such a program for postpartum are usually lacking, and could be a cost-effective solution to reduce postpartum hypertensive complications. OBJECTIVES: To assess the proportion of women who present to the emergency department (ED) or outpatient clinics for postpartum hypertensive (PPHTN) complications up to 6 weeks postpartum, among pregnancies complicated by antenatal hypertensive disorders in Calgary, Canada. Secondary objectives were to identify risk factors for PPHTN complications, and to perform a cost-benefit analysis to support postpartum community care program (PCCP) as a way to decrease ED and clinic visits for PPHTN complications, and thus has a favourable economic impact on the public health care system. STUDY DESIGN: Retrospective cohort study using administrative databases, followed by chart review of ED visits to confirm diagnoses and estimate cost of visits and admissions. The participants were women followed by the Calgary Antenatal Community Care Program (ACCP) for hypertensive disorders, from 2014 to 2015, inclusive. The primary outcome was ED or clinic visit associated with an outpatient database record of hypertensive disorder diagnosis, within 42 days postpartum. RESULTS: Among 319 deliveries included in the study, 30 women (9.4, 95%CI 6.2-12.6%) visited ED or clinics for PPHTN. We identified multiple antihypertensive medication use and abnormal postpartum gestational hypertension labs as risk factors for ED visit among these women (Table 1). We estimate a CAD$152 per antenatal hypertensive patient cost benefit for PCCP. CONCLUSION: The proposed PCCP appears to have an economic benefit to health care system with decrease in ED and clinic visits. Further studies with greater sample size could strengthen the findings in this study. PMID- 30415594 TI - VITAL Signs for Dietary Supplementation to Prevent Cancer and Heart Disease. PMID- 30415593 TI - Ocrelizumab reduces progression of upper extremity impairment in patients with primary progressive multiple sclerosis: Findings from the phase III randomized ORATORIO trial. AB - BACKGROUND:: Upper extremity (UE) impairment is common with primary progressive multiple sclerosis (PPMS). OBJECTIVE:: This exploratory analysis examined the effects of ocrelizumab on confirmed progression (CP) and confirmed improvement (CI) in UE impairment in patients from ORATORIO. METHODS:: Patients with PPMS received ocrelizumab 600 mg or placebo every 24 weeks for ?120 weeks. The Nine Hole Peg Test (9HPT) was administered at baseline (BL) and every 12 weeks thereafter. Prespecified exploratory endpoints included change in 9HPT time and proportion of patients with CP of ?20% in 9HPT. Analysis populations included intention-to-treat (ITT) patients and subgroups stratified by BL 9HPT time and Expanded Disability Status Scale. Post hoc analyses included the proportion of patients achieving more severe thresholds of CP and the proportion achieving CI in 9HPT. RESULTS:: Among ITT patients, ocrelizumab significantly reduced the change in 9HPT time over 120 weeks, the risk of CP of ?20% in 9HPT time for both hands and the risk of more severe 9HPT progression versus placebo. Numerical trends also favoured ocrelizumab versus placebo with respect to achieving CI. Consistent directional trends were observed in subgroup analyses. CONCLUSION:: Ocrelizumab reduces the risk of UE disability progression and may increase the possibility of improvement versus placebo in PPMS. PMID- 30415595 TI - Nurses' Knowledge and Attitudes Toward Complementary and Alternative Medicine for Adult Patients With Cancer in Bandung, West Java, Indonesia: A Qualitative Study. AB - The aim of this study was to explore nurses' knowledge and attitudes toward the use of complementary and alternative medicine (CAM) among cancer patients in a palliative care setting. A descriptive qualitative approach was used in this study. Semistructured interviews were conducted with 10 nurses recruited using purposive sampling. The data were analyzed using an inductive semantic approach. Thematic analysis identified that nurses possess limited knowledge of CAM. Nurses were skeptical toward CAM and less confident to recommend its use. Four main themes (and two subthemes) emerged: Understanding of CAM, Hesitative Attitudes, Personal Experience, and Preferences in Learning about CAM. There is a need to integrate CAM topics into nursing education programs in order to develop nurses' knowledge and build positive attitudes toward CAM use. Sufficient knowledge and positive attitudes toward CAM would support safety and quality of care in management of patients with cancer who use or are contemplating using CAM. PMID- 30415596 TI - Untreated depression and non-medical use of prescription pain relievers: findings from the National Survey on Drug Use and Health 2008-2014. AB - OBJECTIVES: Despite growing concerns for non-medical use of prescription pain relievers (NMUPPRs), little is known about the role of comorbid, untreated depressive disorders. METHODS: We examined past year rates of NMUPPRs and major depressive episode (MDE), using data between 2008 and 2014 from the National Survey on Drug Use and Health for both youths (12-17 years) and adults (18 or older). Prevalence estimates with 95% confidence intervals were computed. Stratified analyses and generalized linear models were run to examine the association between NMUPPRs and MDE, controlling for treatments received for mental health and/or substance misuse. In order to explore whether MDE effect might change by treatment received, a model with an interaction term including MDE and treatment was fit. RESULTS: Among respondents, about 9% (youths) and 7% (adults) reported past year MDE and about 6% (youths), and 4% (adults) NMUPPRs. About 1.2% (youths) and 0.7% (adults) reported both MDE and NMUPPRs. Those with past year MDE were more likely to report NMUPPRs (RR, 95%CI: 2.60, 2.42-2.80, and 2.64, 2.47-2.82, for youths and adults). Considering the any treatment/MDE interaction on NMUPPRs, MDE risk ratio for subjects who received some treatment (youths: adjusted risk ratio (ARR) = 1.15; adults: ARR = 1.25) was about 70-80% as compared with their untreated counterpart (youths: ARR = 1.57; adults: ARR = 1.54). The likelihood of reporting NMUPPRs amongst respondents who did not receive any treatment was higher for those with past year MDE (main effect: youths ARR = 1.57, p < 0.001; adults ARR = 1.54, p < 0.001). CONCLUSION: Unrecognized and untreated depressive disorders should be considered for prevention, treatment, and policy implications in order to tackle NMUPPRs epidemic. PMID- 30415597 TI - Tackling mixed messages: Practitioner reflections on working with adolescents with atypical anorexia and their families. AB - The treatment of atypical anorexia nervosa (AN) poses new research and practice challenges for the field of eating disorders. The objective of this study was to describe frontline practitioners' perceptions of differences between adolescents living with atypical versus typical AN, as well as the intervention challenges they experience when working with these adolescents and their families. We followed the principles of fundamental qualitative description and recruited a purposeful sample of practitioners treating adolescent eating disorders to complete a one-on-one semi-structured interview. Conventional content analysis and the constant comparison technique were used for data analysis. A total of 23 practitioners from four countries participated in this study. Practitioners described that adolescents with atypical AN present with higher pre-morbid weights and rates of weight-based teasing compared to their AN peers. Clinical challenges perceived by practitioners to be specific to working with adolescents with atypical AN included: addressing conflicting messages about eating disorders and weight loss, empathizing with a justified fear of weight gain, and increased risk for parental and therapist collusion with the eating disorder. Findings have implications for delivering interventions to adolescents seeking care for atypical AN. PMID- 30415598 TI - Treatment modalities for hip and knee osteoarthritis: A systematic review of safety. AB - Current guidelines on the management of hip and knee osteoarthritis (OA) do not compare safety of treatment modalities. We therefore systematically reviewed 20 studies investigating mortality and serious complications of both medical and surgical treatments for hip and knee OA using PubMed, Scopus, Web of Knowledge and Google Scholar. Mortality was the highest for naproxen (hazard ratio (HR) = 3 (1.9, 4.6)) and lowest for total hip replacement (relative risk (RR) = 0.7 (0.7, 0.7)). Highest gastrointestinal complications were reported for diclofenac (odds ratio (OR) = 4.77 (3.94, 5.76)) and lowest for total knee replacement (HR = 0.6 (0.49, 0.75)). Ibuprofen had the highest renal complications (OR = 2.32 (1.45, 3.71)), whereas celecoxib had the highest cardiovascular risk (OR = 2.26 (1, 5.1)) and lowest was for tramadol (RR = 1.1 (0.87, 1.4)). Results show that medical management of hip and knee OA, particularly with non-steroidal anti inflammatory drugs, may carry higher mortality compared to surgery. Careful consideration should be given to medical management taking into account known co morbidities. PMID- 30415599 TI - 'I would describe myself as a deformed troll': Using interpretative phenomenological analysis to explore body image struggles among palliative care patients. AB - BACKGROUND:: Illness adjustment is a widely studied area in the palliative care context. However, research focussing on how altered body image can affect men and women in palliative care is limited and unclear. AIM:: To explore the links between palliative care patients' affected sense of self, altered body image and terminal illness adjustment. DESIGN:: Semi-structured interviews were conducted, and the Interpretative Phenomenological Analysis approach was used to analyse patients' experiences. SETTING/PARTICIPANTS:: English-speaking, adult palliative care outpatients were interviewed at a local community hospice in the United Kingdom. The mean age was 55 years (ranging from 35-65 years). RESULTS:: Analysis of accounts indicated three superordinate themes: (1) 'Not being me': self discrepancy, (2) existing in the landscape of loss, (3) living and thriving in the landscape of loss. The most disturbing issues, such as appearance-focussed struggles and low body-confidence, were stemming from participants' frustration over their lack of control and their attachment to their former self-image. CONCLUSIONS:: The patients' insights demonstrated that body image distress was prevalent among all respondents regardless of gender or diagnosis. A spiral model is described showing how discrepancy-based processing (i.e. 'not being me') and rigid attachment to former self can have harmful consequences on palliative patients' abilities to cope. In order to facilitate adjustment to a self-identity crisis resulting from a terminal diagnosis, it is necessary for professionals to recognise and address body image changes among palliative care outpatients. PMID- 30415600 TI - Motif discovery in biological network using expansion tree. AB - Networks are powerful representation of topological features in biological systems like protein interaction and gene regulation. In order to understand the design principles of such complex networks, the concept of network motifs emerged. Network motifs are recurrent patterns with statistical significance that can be seen as basic building blocks of complex networks. Identification of network motifs leads to many important applications, such as understanding the modularity and the large-scale structure of biological networks, classification of networks into super-families, protein function annotation, etc. However, identification of network motifs is challenging as it involves graph isomorphism which is computationally hard. Though this problem has been studied extensively in the literature using different computational approaches, we are far from satisfactory results. Motivated by the challenges involved in this field, an efficient and scalable network Motif Discovery algorithm based on Expansion Tree (MODET) is proposed. Pattern growth approach is used in this proposed motif centric algorithm. Each node of the expansion tree represents a non-isomorphic pattern. The embeddings corresponding to a child node of the expansion tree are obtained from the embeddings of the parent node through vertex addition and edge addition. Further, the proposed algorithm does not involve any graph isomorphism check and the time complexities of these processes are [Formula: see text] and [Formula: see text], respectively. The proposed algorithm has been tested on Protein-Protein Interaction (PPI) network obtained from the MINT database. The computational efficiency of the proposed algorithm outperforms most of the existing network motif discovery algorithms. PMID- 30415601 TI - Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure. AB - BACKGROUND: Acute decompensated heart failure accounts for more than 1 million hospitalizations in the United States annually. Whether the initiation of sacubitril-valsartan therapy is safe and effective among patients who are hospitalized for acute decompensated heart failure is unknown. METHODS: We enrolled patients with heart failure with reduced ejection fraction who were hospitalized for acute decompensated heart failure at 129 sites in the United States. After hemodynamic stabilization, patients were randomly assigned to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or enalapril (target dose, 10 mg twice daily). The primary efficacy outcome was the time-averaged proportional change in the N-terminal pro B-type natriuretic peptide (NT-proBNP) concentration from baseline through weeks 4 and 8. Key safety outcomes were the rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema. RESULTS: Of the 881 patients who underwent randomization, 440 were assigned to receive sacubitril valsartan and 441 to receive enalapril. The time-averaged reduction in the NT proBNP concentration was significantly greater in the sacubitril-valsartan group than in the enalapril group; the ratio of the geometric mean of values obtained at weeks 4 and 8 to the baseline value was 0.53 in the sacubitril-valsartan group as compared with 0.75 in the enalapril group (percent change, -46.7% vs. -25.3%; ratio of change with sacubitril-valsartan vs. enalapril, 0.71; 95% confidence interval [CI], 0.63 to 0.81; P<0.001). The greater reduction in the NT-proBNP concentration with sacubitril-valsartan than with enalapril was evident as early as week 1 (ratio of change, 0.76; 95% CI, 0.69 to 0.85). The rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema did not differ significantly between the two groups. CONCLUSIONS: Among patients with heart failure with reduced ejection fraction who were hospitalized for acute decompensated heart failure, the initiation of sacubitril-valsartan therapy led to a greater reduction in the NT-proBNP concentration than enalapril therapy. Rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema did not differ significantly between the two groups. (Funded by Novartis; PIONEER-HF ClinicalTrials.gov number, NCT02554890 .). PMID- 30415602 TI - Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. AB - BACKGROUND: The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined. METHODS: We randomly assigned patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease to receive either dapagliflozin or placebo. The primary safety outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Secondary efficacy outcomes were a renal composite (>=40% decrease in estimated glomerular filtration rate to <60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes) and death from any cause. RESULTS: We evaluated 17,160 patients, including 10,186 without atherosclerotic cardiovascular disease, who were followed for a median of 4.2 years. In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE (upper boundary of the 95% confidence interval [CI], <1.3; P<0.001 for noninferiority). In the two primary efficacy analyses, dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; hazard ratio, 0.93; 95% CI, 0.84 to 1.03; P=0.17) but did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; hazard ratio, 0.83; 95% CI, 0.73 to 0.95; P=0.005), which reflected a lower rate of hospitalization for heart failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88); there was no between-group difference in cardiovascular death (hazard ratio, 0.98; 95% CI, 0.82 to 1.17). A renal event occurred in 4.3% in the dapagliflozin group and in 5.6% in the placebo group (hazard ratio, 0.76; 95% CI, 0.67 to 0.87), and death from any cause occurred in 6.2% and 6.6%, respectively (hazard ratio, 0.93; 95% CI, 0.82 to 1.04). Diabetic ketoacidosis was more common with dapagliflozin than with placebo (0.3% vs. 0.1%, P=0.02), as was the rate of genital infections that led to discontinuation of the regimen or that were considered to be serious adverse events (0.9% vs. 0.1%, P<0.001). CONCLUSIONS: In patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, treatment with dapagliflozin did not result in a higher or lower rate of MACE than placebo but did result in a lower rate of cardiovascular death or hospitalization for heart failure, a finding that reflects a lower rate of hospitalization for heart failure. (Funded by AstraZeneca; DECLARE-TIMI 58 ClinicalTrials.gov number, NCT01730534 .). PMID- 30415603 TI - Outcomes of expedited rotator cuff surgery in injured workers: Impact of pathology on readiness for return to work. AB - OBJECTIVES:: The objectives of this study were to (1) examine the overall recovery and satisfaction following an expedited rotator cuff (RC) decompression or repair at 3-6 months and (2) explore group differences (repair vs. decompression) in demographics, clinical, disability, and psychosocial factors. METHODS:: This was a prospective longitudinal study of injured workers whose surgery was expedited. The outcome measures were Quick disabilities of the arm, shoulder, and hand ( QuickDASH), the Hospital Anxiety and Depression Scale (HADS), the readiness for return to work (RRTW) scale, and satisfaction with surgery and overall recovery. RESULTS:: Of 118 patients participated in the study, 106 patients, age: 51 (9), 71 males (67%) completed the study. Sixty-four (60%) patients underwent a RC repair and 42 (40%) had RC decompression. Patients improved on average in QuickDASH ( p = 0.004), anxiety ( p = 0.003), and depression scores ( p = 0.004). The majority of patients (75%) were satisfied with surgery. In the decompression group, the pre-contemplation (PC) stage of the RRTW which documents the absence of desire or planning for return to work in the non-working sample ( r = 0.81, p = 0.008) and the uncertain maintenance (UM) stage of the RRTW which explores the worker's struggle to stay at work in the working sample correlated with physical disability as measured by the QuickDASH scores ( r = 0.62, p = 0.0001). In the repair group, the above domains correlated with the depression HADS scores (PC: r = 0.64, p = 0.001 and UM: r = 0.57, p < 0.0001). CONCLUSION:: Expedited RC surgery improved physical disability and mental well-being and was associated with a relatively high satisfaction at a maximum of 6 months. The poorer report of readiness for return to work was associated with higher physical disability in the decompression group and higher report of depression in the repair group. These differential associations may emphasize the importance of physical versus psychological management in patients with different levels of pathology. PMID- 30415604 TI - Risk assessment of endocrine disrupting phthalates and hormonal alterations in children and adolescents. AB - Risk assessment and hormone evaluation were carried out for di(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP), endocrine disrupting chemicals (EDCs), in 302 Korean children (n = 223) and adolescents (n = 79) (< age 19). Urinary and serum concentrations of DEHP, MEHP (mono(2-ethylhexyl) phthalate), DBP, MBP (monobutyl phthalate), and PA (phthalic acid, a common final metabolite of phthalates) were detected in children and adolescents. Daily exposure levels were estimated to be 16.45 +/- 36.50 MUg/kg b.w./day for DEHP, which is one-third of the tolerable daily intake (TDI) value (50 MUg/kg b.w./day), but 14 out of 302 participants had a hazard index (HI = intake/TDI) value >1. The mean daily exposure level of DBP was 1.23 +/- 1.45 MUg/kg b.w./day, which is one-eighth of the TDI value (10 MUg/kg b.w./day), but 1 out of 302 participants had a HI value > 1. Positive correlations were observed between serum DBP or MEHP, and serum estradiol (E2) and/or luteinizing hormone (LH) in prepubescent children. In addition, serum MBP levels were found to be negatively correlated with serum triiodothyronine (T3) or thyroxine (T4) in male participants, and serum DEHP levels with serum thyroid stimulating hormone (TSH) in female adolescents. Low density lipoprotein (LDL) levels were positively correlated with serum PA levels in children and adolescents. DEHP, DBP or its metabolites may be associated with altered hormone levels in children and adolescents. Data suggest that exposure levels of DEHP and DBP in Korean children need to be reduced to levels below TDI to protect them from EDC-mediated toxicities. Abbreviations: DBP: dibutyl phthalate; DEHP: di(2-ethylhexyl) phthalate; E2: estradiol; EDC: endocrine disrupting chemical; EFSA: European Food Safety Authority; FSH: follicle stimulating hormone; HDL: high density lipoprotein; HI: hazard index; LDL: low density lipoprotein; LH: luteinizing hormone; MEHP: mono(2-ethylhexyl) phthalate; MBP: monobutyl phthalate; PA: phthalic acid; PPAR: peroxisome proliferator activated receptor gamma; PVC: polyvinyl chloride; T3: triiodothyronine; T4: thyroxine; TDI: tolerable daily intake; TG: triglyceride; TSH: thyroid stimulating hormone; UPLC/MS/MS: Ultra Performance Liquid Chromatography/Tandem Mass Spectrometry; WWF: World Wildlife Fund. PMID- 30415605 TI - Salvage Pulmonary Operations Following Stereotactic Body Radiotherapy for Small Primary and Metastatic Lung Tumors: Evaluation of the Operative Procedures. AB - Stereotactic body radiotherapy is an alternative treatment option for small sized, primary lung cancers and pulmonary metastatic diseases. In the case of local relapse after stereotactic body radiotherapy, salvage pulmonary resection is considered cautiously. However, no study has described the difficulty of the salvage operations. This study aimed to assess the difficulty associated with salvage operative procedures. Eight patients who developed local relapse after stereotactic body radiotherapy and had undergone salvage pulmonary operations were enrolled in this study (stereotactic body radiotherapy group). Additionally, 439 patients who underwent video-assisted thoracoscopic lobectomy without previous stereotactic body radiotherapy were enrolled as the standard operative control group (non-stereotactic body radiotherapy group). In the stereotactic body radiotherapy group, 1 of the 8 patients had undergone lobectomy with composite resection of the third and fourth ribs. Of the 8 patients, 6 had undergone video-assisted thoracoscopic lobectomy and 1 had been inoperable because of rapid tumor progression. The operation time and the incision length of the utility port were apt to be longer in the stereotactic body radiotherapy group than in the non-stereotactic body radiotherapy group. On the contrary, the duration of drain placement and the length of hospital stay after the operation were not different. Thus, the salvage pulmonary operations were performed in the usual video-assisted thoracoscopic lobectomy approach, but slightly complicated than the standard video-assisted thoracoscopic lobectomy. Although to decide the indication of salvage operation might be difficult, it could be a feasible treatment option in local relapse after stereotactic body radiotherapy. PMID- 30415606 TI - Take three, test one: a cross-sectional study to evaluate the molecular detection of Chlamydia trachomatis and Neisseria gonorrhoeae in pooled pharyngeal, anorectal and urine samples versus single-site testing among men who have sex with men in Belgium. AB - OBJECTIVES: To investigate the efficacy of performing a pooling strategy of triple-anatomical site samples (pharyngeal, anorectal and urine samples) for simultaneous Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) nucleic acid amplification detection. METHODS: A total of 117 specimen sets (pharyngeal, anorectal and urine) were collected from 98 men between 2014 and 2016. Double sampling of pharyngeal, anorectal and urine samples allowed for pooled and unpooled analyses using a multiplex Abbott Real Time CT/NG assay, together with confirmatory PCR testing in case of CT/NG positivity. Clinical and demographic data were analyzed. RESULTS: The positivity rate for the triple-site pooled testing for CT and NG was 8.5% (10/117) and 6.8%, (8/117), respectively, compared to the single-site testing total positivity rate, which was 9.4% (11/117) and 4.3% (5/117) for CT and NG, respectively. Pooled analysis missed one CT-positive urine sample and one CT-positive anorectal sample could not be confirmed. In addition, less PCR inhibition was reported for the pooled sample (PS) testing and ERV-3 qPCR testing revealed ineffective sampling of self-collected anorectal swabs in two cases. No pharyngeal samples were positive for CT, nor were any urine samples positive for NG. CONCLUSION: This small study showed that PS testing is a possible testing strategy for screening high-risk men who have sex with men attending pre-exposure prophylaxis (PrEP) clinics. However, due to the low positivity rate of CT/NG in this study, larger evaluations are needed to confirm the effectiveness of CT/NG screening with multiple-site PS nucleic acid amplification test (NAAT) screening practices. PMID- 30415607 TI - Preparation and application of alpha-Fe2O3@MIL-101(Cr)@TiO2 based on metal organic framework for photocatalytic degradation of paraquat. AB - In this study, a new magnetic alpha-Fe2O3@MIL-101(Cr)@TiO2 photocatalyst was successfully synthesized. The material synthesized had been fully characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, energy dispersive X-ray spectroscopy, vibrating sample magnetometry, transmission electron microscopy, and Brunauer-Emmett-Teller isotherm methods. The X-ray diffraction analysis corroborates that nanoparticles are polycrystalline with rhombohedral and tetragonal crystal structures for Fe2O3 and TiO2, respectively. In addition, the photocatalytic degradation of the herbicide paraquat in the presence of alpha-Fe2O3@MIL-101(Cr)@TiO2 under ultraviolet (UV) irradiation was studied. The effect of experimental parameters such as the initial concentration of catalyst, the pH, and the initial paraquat was investigated. The optimal conditions were achieved for concentration of catalyst 0.2 g L-1, pH 7, and concentration of paraquat 20 mg L-1. The photocatalytic degradation efficiency was 88.39% after 15 min with alpha-Fe2O3@MIL-101(Cr)@TiO2 under UV irradiation. The pseudo-second-order kinetic model for photocatalytic degradation of paraquat was obtained. The catalysts could be recovered and reused without any loss of efficiency for five times in the consequent reactions. To the best of our knowledge, this is the first report on the photocatalytic degradation of paraquat using new alpha-Fe2O3@MIL-101(Cr)@TiO2 photocatalyst under UV irradiation condition. PMID- 30415608 TI - Systematic fast-track transition from oncological treatment to dyadic specialized palliative home care: DOMUS - a randomized clinical trial. AB - BACKGROUND:: The focus of specialized palliative care is to improve quality of life for patients with incurable cancer and their relatives including an increased opportunity to make their own choice of place of care and death. AIM:: To investigate whether a systematic fast-track transition from oncological treatment to specialized palliative care at home for patients with incurable cancer reinforced with a psychological dyadic intervention could result in more time spent at home and death at home. Secondary aims were to investigate effects on quality of life, symptomatology and survival. DESIGN:: A prospective, single centre, randomized controlled trial ( Clinicaltrials.gov : NCT01885637). SETTING/PARTICIPANTS:: In all, 340 patients with incurable cancer and no or limited antineoplastic treatment options. RESULTS:: No statistically significant difference was found regarding number of deaths (4%, p = 0.460) and time spent at home (3%, p = 0.491). The secondary outcomes indicated that the intervention resulted in improved quality of life (-11.6 +/- 25.5, p = 0.005, effect size = 0.44, 95% confidence interval = -0.77; -0.11), social functioning (-15.8 +/- 31.4, p = 0.001, effect size = -0.50, 95% confidence interval = -0.84; -0.17) and emotional functioning (-9.1 +/- 21.2, p = 0.039, effect size = -0.43, 95% confidence interval = -0.76; -0.10) after 6 months. A linear mixed-effect regression model confirmed a possible effect on emotional and social functioning at 6 months. Regarding survival, no differences were found between groups ( p = 0.605). No adverse effects were seen as consequence of the intervention. CONCLUSIONS:: The main findings indicated that the intervention had no effect on time spent at home or place of death. However, the intervention resulted in a weak improvement of quality of life, social functioning and emotional functioning after 6 months. PMID- 30415609 TI - Fermented foods, the gut and mental health: a mechanistic overview with implications for depression and anxiety. AB - Mental disorders including depression and anxiety are often comorbid with gut problems, suggesting a bidirectional relationship between mental health and gut function. Several mechanisms might explain this comorbidity, such as inflammation and immune activation; intestinal permeability; perturbations in the hypothalamic pituitary-adrenal axis; neurotransmitter/neuropeptide dysregulation; dietary deficiencies; and disturbed gut microbiome composition. The potential of modulating the microbiome-gut-brain axis, and subsequently mental health, through the use of functional foods, is an emerging and novel topic of interest. Fermented foods are considered functional foods due to their putative health benefits. The process of microbial fermentation converts food substrates into more nutritionally and functionally rich products, resulting in functional microorganisms (probiotics), substrates that enhance proliferation of beneficial bacteria in the gut (prebiotics), and bioactive components (biogenics). These functional ingredients act biologically in the gastrointestinal tract and have the ability to modify the gut microbiota, influence translocation of endotoxins and subsequent immune activation, and promote host nutrition. This narrative review explores the theoretical potential of the functional components present in fermented foods to alter gut physiology and to impact the biological mechanisms thought to underpin depression and anxiety. Pre-clinical studies indicate the benefits of fermented foods in relieving perturbed gut function and for animal models of depression and anxiety. However, in humans, the literature relating to the relevance of fermented food for treating or preventing depression and anxiety is sparse, heterogeneous and has significant limitations. This review identifies a critical research gap for further evaluation of fermented foods in the management of depression anxiety in humans. PMID- 30415611 TI - Effective quality systems: implementation in Australian public hospitals. AB - PURPOSE: The purpose of this paper is to review the implementation of seven components of quality systems (QSs) linked with quality improvement in a sample of Australian hospitals. DESIGN/METHODOLOGY/APPROACH: The authors completed a systematic review to identify QS components associated with measureable quality improvement. Using mixed methods, the authors then reviewed the current state of these QS components in a sample of eight Australian hospitals. FINDINGS: The literature review identified seven essential QS components. Both the self evaluation and focus group data suggested that none of the hospitals had all of these seven components in place, and that there were some implementation issues with those components that were in use. Although board and senior executives could point to a large number of quality and safety documents that they felt were supporting a vision and framework for safe, high-quality care, middle managers and clinical staff described the QSs as compliance driven and largely irrelevant to their daily pursuit of safe, high-quality care. The authors also found little specific training in quality improvement for staff, lack of useful data for clinicians on the quality of care they provide and confusion about how organisational QSs work. PRACTICAL IMPLICATIONS: This study provides a clearer picture of why QSs are not yet achieving the results that boards and executives want to achieve, and that patients require. ORIGINALITY/VALUE: This is the first study to explore the implementation of QSs in hospitals in-depth from the perspective of hospital staff, linking the findings to the implementation of QS component identified in the literature. PMID- 30415610 TI - Low-Dose Methotrexate for the Prevention of Atherosclerotic Events. AB - BACKGROUND: Inflammation is causally related to atherothrombosis. Treatment with canakinumab, a monoclonal antibody that inhibits inflammation by neutralizing interleukin-1beta, resulted in a lower rate of cardiovascular events than placebo in a previous randomized trial. We sought to determine whether an alternative approach to inflammation inhibition with low-dose methotrexate might provide similar benefit. METHODS: We conducted a randomized, double-blind trial of low dose methotrexate (at a target dose of 15 to 20 mg weekly) or matching placebo in 4786 patients with previous myocardial infarction or multivessel coronary disease who additionally had either type 2 diabetes or the metabolic syndrome. All participants received 1 mg of folate daily. The primary end point at the onset of the trial was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Near the conclusion of the trial, but before unblinding, hospitalization for unstable angina that led to urgent revascularization was added to the primary end point. RESULTS: The trial was stopped after a median follow-up of 2.3 years. Methotrexate did not result in lower interleukin-1beta, interleukin-6, or C-reactive protein levels than placebo. The final primary end point occurred in 201 patients in the methotrexate group and in 207 in the placebo group (incidence rate, 4.13 vs. 4.31 per 100 person-years; hazard ratio, 0.96; 95% confidence interval [CI], 0.79 to 1.16). The original primary end point occurred in 170 patients in the methotrexate group and in 167 in the placebo group (incidence rate, 3.46 vs. 3.43 per 100 person-years; hazard ratio, 1.01; 95% CI, 0.82 to 1.25). Methotrexate was associated with elevations in liver enzyme levels, reductions in leukocyte counts and hematocrit levels, and a higher incidence of non-basal-cell skin cancers than placebo. CONCLUSIONS: Among patients with stable atherosclerosis, low-dose methotrexate did not reduce levels of interleukin-1beta, interleukin-6, or C-reactive protein and did not result in fewer cardiovascular events than placebo. (Funded by the National Heart, Lung, and Blood Institute; CIRT ClinicalTrials.gov number, NCT01594333 .). PMID- 30415612 TI - Managing the essential medicines stock at rural healthcare systems in India. AB - PURPOSE: The purpose of this paper is to eliminate the medicine stock-out problem by building an optimum medicine stock in rural healthcare centers in India. DESIGN/METHODOLOGY/APPROACH: Data associated with inflow and outflow of a specific medicine (folic acid tablets) arer collected from all consecutive supply chain stages during the survey. While conducting the survey, it is found that several medicines are out of stock owing to uncertain lead time and demand. Integrating with quantity discount and min-max ( s, S) inventory policy, two models are developed using system dynamics: one is Model 1 with constant lead time and uncertain demand, and the other is Model 2 with both uncertain lead time and demand. FINDINGS: Both models are simulated for a period of one year on Stella 9.1 platform. The results are compared with actual data, and the comparison shows significant improvement of the medicine stock at all downstream stages, while maintaining a certain safety stock. Further, Model 2 suggests a larger stock than Model 1 at each point of time. PRACTICAL IMPLICATIONS: Despite numerous issues, the stocks of medicine in rural healthcare systems can be improved as suggested by the models. The models depict the behavior of inventory stock at each stage of the supply chain and act as a function of time that could be used in the form of a prediction tool for the policymakers. ORIGINALITY/VALUE: This paper is one of the first papers that had developed the model of the medicine supply chain in rural parts of a developing country. It provides a generic framework for the stock assessment and improvement throughout the supply chain. PMID- 30415613 TI - Factors associated with participation and completion of a survey-based study. AB - PURPOSE: The Healthy Work Place (HWP) study investigated methods to improve clinicians' dissatisfaction and burnout. The purpose of this paper is to identify factors that influenced study enrollment and completion and assess effects of initial clinic site enrollment rates on clinician outcomes, including satisfaction, burnout, stress and intent to leave practice. DESIGN/METHODOLOGY/APPROACH: In total, 144 primary care clinicians (general internists, family physicians, nurse practitioners and physician assistants) at 14 primary care clinics were analyzed. FINDINGS: In total, 72 clinicians enrolled in the study and completed the first survey (50 percent enrollment rate). Of these, 10 did not complete the second survey (86 percent completion rate). Gender, type, burnout, stress and intervention did not significantly affect survey completion. Hence, widespread agreement about most moral/ethical issues (72 percent vs 22 percent; p=0.0060) and general agreement on treatment methods (81 percent vs 50 percent; p=0.0490) were reported by providers that completed both surveys as opposed to just the initial survey. Providers with high initial clinic site enrollment rates (=50 percent providers) obtained better outcomes, including improvements in or no worsening of satisfaction (odds ratio (OR)=19.16; p=0.0217) and burnout (OR=6.24; p=0.0418). SOCIAL IMPLICATIONS: More providers experiencing workplace agreement completed the initial and final surveys, and providers at sites with higher initial enrollment rates obtained better outcomes including a higher rate of improvement or no worsening of job satisfaction and burnout. ORIGINALITY/VALUE: There is limited research on clinicians' workplace and other factors that influence their participation in survey-based studies. The findings help us to understand how these factors may affect quality of data collecting and outcome. Thus, the study provides us insight for improvement of quality in primary care. PMID- 30415614 TI - Intravenous fluid delivery time improvement: application of cross-docking system. AB - PURPOSE: The cost of pharmaceutical supply chain due to drug waste is one of the current major issues in health care. Drug waste associated with intravenous (IV) fluid form of medication is one of the crucial issues for many pharmacies. The purpose of this paper is to apply a cross-docking model to minimize the IV delivery lead time to reduce drug waste by scheduling staff in a local hospital's inpatient pharmacy. DESIGN/METHODOLOGY/APPROACH: A mixed integer linear programming model is applied to the IV delivery system of a hospital. The parameters are selected based on the observations made in the inpatient pharmacy. FINDINGS: The result implies that cross-docking approach can be effectively applied to IV delivery system. In fact, the cross-docking optimization model employed in this case study reduces the IV delivery completion time of the inpatient pharmacy by 41 percent. RESEARCH LIMITATIONS/IMPLICATIONS: The scope of this research is limited to the activities performed after IV preparation. PRACTICAL IMPLICATIONS: The application of cross-docking system in staff scheduling will be beneficial for health care organizations that aim to minimize medication waste. ORIGINALITY/VALUE: The prime value of this study lies in the introduction of a cross-docking concept in an internal hospital ordering process. Cross-docking models are widely used in general supply chain systems; however, their application for specific activities inside hospitals is the novelty of this study, which can fill the research gap in terms of drug waste management within the inpatient pharmacy. PMID- 30415615 TI - Surgical audit: are we not closing the loop? AB - PURPOSE: A clinical audit is a key component of the clinical governance framework. The rate of audit completion in general surgery has not been investigated. The purpose of this paper is to assess the rates of audit activity and completion and explore the barriers to successful audit completion. DESIGN/METHODOLOGY/APPROACH: This was a multi-centre study evaluating current surgical audit practice. A standardised audit proforma was designed. All clinical audits in general surgery during a two-year period were identified and retrospectively reviewed. Data held by the audit departments were collated, and individual audit teams were contacted to verify the data accuracy. Audit teams failing to complete the full audit cycle with a re-audit were asked to explain the underlying reasons behind this. FINDINGS: Of the six trusts approached, two refused to participate, and one failed to initiate the project. A total of 39 audits were registered across three surgical directorates. Only 15 out of 39 audits completed at least one audit cycle, with 4 deemed of no value to re-audit. Only seven audits were completed to re-audit. Achieving a publication or a presentation was the most cited reason for not completing the audit loop. ORIGINALITY/VALUE: This study demonstrates that the poor rates of audit completion rate found in other areas of clinical medicine pervade general surgery. Improved completion of an audit is essential and strategies to achieve this are urgently needed. PMID- 30415616 TI - A strategic and good governance perspective on handling patient complaints. AB - PURPOSE: The patient complaint is one of the main procedures of exercising patient's rights in the Finnish health care system. Such complaints typically concern the quality of care and/or patient safety. The purpose of this paper is to examine the types of patient complaints received by a specialized medical care organization and the kinds of responses given by the organization's personnel. The organization's strategy and good governance principles provide the framework for understanding the organization's action. DESIGN/METHODOLOGY/APPROACH: This study's data comprise patient complaints and the responses from personnel of a specialized medical care organization from the start of 2012 to the end of January 2014. The data were analyzed through qualitative data analysis. FINDINGS: The results show many unwanted grievances, but also reveal the procedures employed to improve health care processes. The results are related to patients' care experiences, provision of information, personnel's professional skills and the approach to patient complaints handling. The integrative result of the analysis was to find consensus between the patients' expectations and personnel's evaluation of patients' needs. ORIGINALITY/VALUE: Few prior studies have examined patient complaints related to both strategy and good governance. Patient complaints were found to have several confluences with an organization's strategic goals, objectives and good governance principles. The study recommends further research on personnel procedures for patient complaints handling, with a view to influencing strategic planning and implementation of strategies of organizations. PMID- 30415617 TI - Health care complaint journeys for system comparison. AB - PURPOSE: The "patient journey" technique is one that has been used by health care providers to investigate the strengths and weaknesses of their service delivery. The purpose of this paper is to discuss the experience of adapting this approach for use in an atypical context - the comparison of two systems for managing health care complaints and notifications. It highlights a number of relevant considerations and provides suggestions for similar studies. DESIGN/METHODOLOGY/APPROACH: The design and methods of the study are described, with commentary on the success of key aspects and challenges encountered. To enable comparison between the two systems, this study had a "paired" design, in which examples were selected from each system so that they matched on basic, prescribed, criteria. Data about each matter's journey were then collected from administrative records. FINDINGS: While, overall, the technique provided rich data on the processes of the systems under investigation, the type of data collected (related to administrative/communicative events) and the study's comparative purpose required consideration and management of a number of issues. These included the implications of using administrative records and the impact of differences between the systems on the paired design. ORIGINALITY/VALUE: This paper describes an attempt to apply the "journey" approach in a context that is uncommon in two ways: first, in its focus on regulatory processes (complaint/notification handling), rather than care provision to an individual patient; and second, in its objective of comparing two different systems. It is hoped this account will assist in further development of this technique. PMID- 30415618 TI - Identification of factors influencing the rise of cesarean sections rates in Pakistan, using MCDM. AB - PURPOSE: The rate of cesarean sections has been rapidly increased in the last few decades in all the developing as well as developed countries. The rate of cesarean sections determined by the World Health Organization has been crossed by many countries, like Brazil, India, China, USA, Australia, etc. Similarly, this rate has also increased in Pakistan. The purpose of this paper is to explore and identify the factors that are responsible for the rising rate of cesarean sections in Pakistan. DESIGN/METHODOLOGY/APPROACH: These factors are categorized under medical and non-medical factors. The medical factors include the obesity of mother, age of mother, weight of the baby, umbilical cord prolapse, fetal distress, abnormal presentation, dystocia and failure to progress. The non medical factors include financial incentives of doctors, time convenience for doctors, high tolerance to surgery, patient's preference toward cesarean section, private hospitals, public hospitals, income status of patients, rural areas, urban areas and the education of patients. To identify the critical factors, data have been collected and a multi-criteria decision-making technique, called Decision Making Trial and Evaluation Laboratory, is used. FINDINGS: The result shows that the medical factors that are responsible for the rise in the rate of cesarean sections are umbilical cord prolapse, age of mother and obesity of mother. On the other hand, the non-medical factors that are the reasons for the increase in cesarean sections are the large number of private hospitals and the unethical acts of the doctors in these hospitals, preference of patients, and either the unavailability of doctors or poor conditions of hospitals in rural areas. ORIGINALITY/VALUE: Cesarean section is an important surgical intervention and is considered to be very essential in the cases of existing as well as potential medical problems to the mother or the baby. Cesarean section is also performed for non-medical reasons. In Pakistan, the number of private hospitals has increased and these hospitals provide good health care. However, these hospitals do not work under the rules and regulations set by the government. The doctors in private hospitals perform unnecessary cesarean sections in order to fulfill the demands of private hospital's owners. In addition to this, it is also found that, nowadays, most women prefer to give birth through cesarean section in order to eliminate the pain of normal vaginal delivery. PMID- 30415619 TI - Registered nurses' knowledge and care practices regarding patients with dysphagia in Saudi Arabia. AB - PURPOSE: The purpose of this paper is to assess the knowledge and practices of nursing staff caring for patients with dysphagia to determine any needs for further education programmes. DESIGN/METHODOLOGY/APPROACH: A self-administered questionnaire with close-ended questions was completed by nurses at a tertiary hospital in Saudi Arabia to measure the depth of their dysphagia knowledge. FINDINGS: From 316 potential participants, a sample of 174 nurses completed the questionnaire. The results revealed that the participants had partial theoretical and practical knowledge about nursing care for patients with dysphagia. Of interest, 78 per cent of the nurses reported that they had received less than 1 h of training in dysphagia, and only 4 per cent were aware of speech and language pathologists' role in dysphagia management. PRACTICAL IMPLICATIONS: As the medical professionals who have the most contact with the patients, nurses have a central role in the care of patients with dysphagia. This study provides information that will guide strategies for in-service nurse education dysphagia programmes. ORIGINALITY/VALUE: The estimated Saudi prevalence of dysphagia is high due to increased incidence of medical conditions commonly associated with dysphagia, such as stroke, cerebral palsy and traumatic brain injuries from traffic accidents. Nurses play a pivotal role in caring for these patients. However, little is known about the level of care patients with dysphagia require in Saudi hospital settings. PMID- 30415620 TI - Effect of Lean Six Sigma on quality performance in Malaysian hospitals. AB - PURPOSE: The purpose of this paper is to investigate the effects of Lean Six Sigma (LSS) and workforce management on the quality performance of Malaysian hospitals. This paper also investigates the direct and indirect relationships between top management commitment and quality performance of the healthcare organisations in Malaysia. DESIGN/METHODOLOGY/APPROACH: This study applied stratified random sampling to collect data from 15 different hospitals in Peninsular Malaysia. The self-administered survey questionnaires were distributed among 673 hospital staff (i.e. doctors, nurses, pharmacists, and medical laboratory technologists) to obtain 335 useful responses with a 49.47 per cent valid response rate. The research data were analysed based on confirmatory factor analysis and structural equation modelling by using AMOS version 23 software. FINDINGS: The research findings indicated that LSS and workforce management have a significant impact on quality performance of the Malaysian hospitals, whereas senior management commitment was found to have an insignificant relationship with quality performance. The research findings indicate that senior management commitment has no direct significant relationship with quality performance, but it has an indirect significant relationship with quality performance through the mediating effects of LSS and workforce management. RESEARCH LIMITATIONS/IMPLICATIONS: This research focussed solely on healthcare organisations in Malaysia and thus the results might not be applicable for other countries as well as other service organisations. ORIGINALITY/VALUE: This research provides theoretical, methodological, and practical contributions for the LSS approach and the research findings are expected to provide guidelines to enhance the level of quality performance in healthcare organisations in Malaysia as well as other countries. PMID- 30415621 TI - Development of the Persian patient satisfaction questionnaire. AB - PURPOSE: The purpose of this paper is to explore the validity and reliability of the Persian version of the patient satisfaction questionnaire (PVPSQ). The study addressed the communication skills section of the PSQ specifically. DESIGN/METHODOLOGY/APPROACH: This cross-sectional study was conducted in 2015 to determine the validity and reliability of the Persian version of the patient satisfaction questionnaire (PSQ). In total, 538 patients (ten in pilot, 488 in tests, 40 in retest), 14 experts and 198 residents participated. The items' impact score, content validity index, and content validity ratio were calculated. Construct validity and reliability of the scale were examined with exploratory factor analysis, Cronbach's alpha, and the Intraclass correlation coefficient (ICC), respectively. FINDINGS: The questionnaire demonstrated a content validity index=0.94, content validity ratio=0.84, impact score=4.61, Cronbach's alpha=0.93 and ICC=0.513 ( p<0.00). A single factor was found in the eigenvalue distribution of the PSQ that predicted approximately 93 percent of the variance. PRACTICAL IMPLICATIONS: The results of this study will permit researchers in all Persian speaking countries to use a valid and reliable Persian version of the PSQ to evaluate patients' satisfaction with residents' communication skills. ORIGINALITY/VALUE: There were a few Persian questionnaires to assess patient satisfaction with physicians' communication skills, but their psychometric properties had not been reported until the time of this study. By using the PVPSQ, both researchers at Iranian universities of medical sciences and researchers in other Persian-speaking countries can assess residents' communication skills from the patient's perspective more reliably. PMID- 30415622 TI - Improving hospital food menu quality: an experimental approach. AB - PURPOSE: The purpose of this paper is to examine whether the negative impressions consumers hold toward institutional food can be remedied by subtle changes in menu descriptions. While an expectancy-disconfirmation explanation would suggest this, a negativity bias explanation would suggest otherwise. DESIGN/METHODOLOGY/APPROACH: The authors test the research question using an experimental 2 * 2 full factorial design, with data collected from 100 university students. FINDINGS: The results show that when hospital menus are made somewhat fancier in their description, consumers evaluate the food as more attractive and menu variation to be greater. This implies that the judgments are more likely to be based on an expectancy-disconfirmation process that on being subject to negativity bias. RESEARCH LIMITATIONS/IMPLICATIONS: The authors study perceived attractiveness and menu variation, but future research should include taste perceptions and consumption volume. PRACTICAL IMPLICATIONS: Institution managers could improve consumer perceptions of how attractive the food being served is, and the perceived variation in their menus, by subtly changing the course descriptions to become fancier. However, as such, a strategy based on an expectancy-disconfirmation process, institution managers should beware not to sweeten the pill too much, i.e., making promises they cannot keep may backfire if one makes the menus too fancy compared to what is delivered. ORIGINALITY/VALUE: The authors extend current knowledge on menu label effects by addressing them for food suppliers, which are inherently associated with low food quality. The authors also show that when managers apply such strategies, the effect is due to a disconfirmation process rather than a negativity bias. PMID- 30415623 TI - Investigating health information systems-induced errors. AB - PURPOSE: The purpose of this paper is to present a review of health information system (HIS)-induced errors and its management. This paper concludes that the occurrence of errors is inevitable but it can be minimised with preventive measures. The review of classifications can be used to evaluate medical errors related to HISs using a socio-technical approach. The evaluation could provide an understanding of errors as a learning process in managing medical errors. DESIGN/METHODOLOGY/APPROACH: A literature review was performed on issues, sources, management and approaches to HISs-induced errors. A critical review of selected models was performed in order to identify medical error dimensions and elements based on human, process, technology and organisation factors. FINDINGS: Various error classifications have resulted in the difficulty to understand the overall error incidents. Most classifications are based on clinical processes and settings. Medical errors are attributed to human, process, technology and organisation factors that influenced and need to be aligned with each other. Although most medical errors are caused by humans, they also originate from other latent factors such as poor system design and training. Existing evaluation models emphasise different aspects of medical errors and could be combined into a comprehensive evaluation model. RESEARCH LIMITATIONS/IMPLICATIONS: Overview of the issues and discourses in HIS-induced errors could divulge its complexity and enable its causal analysis. PRACTICAL IMPLICATIONS: This paper helps in understanding various types of HIS-induced errors and promising prevention and management approaches that call for further studies and improvement leading to good practices that help prevent medical errors. ORIGINALITY/VALUE: Classification of HIS-induced errors and its management, which incorporates a socio-technical and multi-disciplinary approach, could guide researchers and practitioners to conduct a holistic and systematic evaluation. PMID- 30415624 TI - Iatrogenic emergency medicine procedure complications and associated trouble shooting strategies. AB - PURPOSE: The purpose of this paper is to provide a consolidated reference for the acute management of selected iatrogenic procedural injuries occurring in the emergency department (ED). DESIGN/METHODOLOGY/APPROACH: A literature search was performed utilizing PubMed, Scopus, Web of Science and Google Scholar for studies through March of 2017 investigating search terms "iatrogenic procedure complications," "error management" and "procedure complications," in addition to the search terms reflecting case reports involving the eight below listed procedure complications. FINDINGS: This may be particularly helpful to academic faculty who supervise physicians in training who present a higher risk to cause such injuries. ORIGINALITY/VALUE: Emergent procedures performed in the ED present a higher risk for iatrogenic injury than in more controlled settings. Many physicians are taught error-avoidance rather than how to handle errors when learning procedures. There is currently very limited literature on the error management of iatrogenic procedure complications in the ED. PMID- 30415625 TI - Effects of job resources factors on nurses job performance (mediating role of work engagement). AB - PURPOSE: The purpose of this paper is to examine the mediating role of work engagement (vigor and dedication) between job resources (job characteristics, supervisor and co-worker support, participation in decision making and job security) and job performance (task and contextual) rated by the supervisor. DESIGN/METHODOLOGY/APPROACH: A sample of 364 nurses and their supervisors was used. Structural equation modeling with Amos 17 was used to obtain a model fit with path significance of work engagement as the mediator between job resources and job performance. FINDINGS: The results found support for the proposed conceptual claim and confirm that work engagement with a two-factor model (vigor and dedication) mediates the relationship between job resources (job characteristics, supervisor and co-worker support, participation in decision making and job security) and with a multidimensional construct of job performance (task and contextual performance) rated by the supervisor. PRACTICAL IMPLICATIONS: The findings of this research will help human resource managers and professionals to further develop the working environment, provide job security and opportunities for employees to participate in decision making in a way that enhances employee work engagement, which, ultimately, improves employee job performance. ORIGINALITY/VALUE: Past studies have not previously tested the two factor model of work engagement (vigor and dedication) as the mediating variable between job resources (job characteristics, supervisor and co-worker support, participation in decision making and job security) and job performance rated by the supervisor. PMID- 30415626 TI - Patients' satisfaction as a dimension of quality: a survey on outpatients' care in Dubai. AB - PURPOSE: The last few years have seen a stronger emphasis on patient-centred care within the international healthcare setting. Patient-centred care is clearly perceived to be important to optimise the satisfaction and well-being of patients. The purpose of this paper is to review current patient-centred practices for outpatients in both private clinics and public hospitals in Dubai. Such a comparison contributes to the identification of best management practices as a means of enhancing healthcare delivery. DESIGN/METHODOLOGY/APPROACH: This study is based on an independent survey consisting of self-administered questionnaires, in which patients were asked to rate several aspects of private clinics or government hospitals in Dubai. The questionnaire used has been drawn from the Consumer Assessment of Healthcare Providers and Systems Clinician and Group Survey, Version 3.0. Responses from 420 patients form a data set that is analysed quantitatively. FINDINGS: In total, 420 respondents took part in this survey. The results of the survey show that there is a considerable difference between the expectation levels of patients from government hospitals and patients from private clinics. Patients from government hospitals consistently show that time is a critical aspect of the service received, with 68 per cent of the respondents reporting this issue. Additionally, poor customer care, as reported by 14 per cent of the respondents, is also a critical issue. Timely service and appointments are among the main factors that contribute to patient satisfaction. Patients in private clinics, instead, particularly value clear explanations from doctors and nurses - this is corroborated by the fact that 11 per cent of the respondents reported appreciation of this type of service. PRACTICAL IMPLICATIONS: This paper draws attention to a patient-centric perspective of healthcare, and highlights the importance of educating patients through clear explanations. ORIGINALITY/VALUE: Little evidence exists on the standards of healthcare in Dubai. The authors explore this area and present direct evidence on quality standard implementation, identify implementation shortcomings and make recommendations for future research and practice. PMID- 30415627 TI - Environmental impact reduction as a new dimension for quality measurement of healthcare services. AB - PURPOSE: The purpose of this paper is to provide a detailed accounting of energy and materials consumed during magnetic resonance imaging (MRI). DESIGN/METHODOLOGY/APPROACH: The first and second stages of ISO standard (ISO 14040:2006 and ISO 14044:2006) were followed to develop life cycle inventory (LCI). The LCI data collection took the form of observations, time studies, real time metered power consumption, review of imaging department scheduling records and review of technical manuals and literature. FINDINGS: The carbon footprint of the entire MRI service on a per-patient basis was measured at 22.4 kg CO2eq. The in-hospital energy use (process energy) for performing MRI is 29 kWh per patient for the MRI machine, ancillary devices and light fixtures, while the out-of hospital energy consumption is approximately 260 percent greater than the process energy, measured at 75 kWh per patient related to fuel for generation and transmission of electricity for the hospital, plus energy to manufacture disposable, consumable and reusable products. The actual MRI and standby energy that produces the MRI images is only about 38 percent of the total life cycle energy. RESEARCH LIMITATIONS/IMPLICATIONS: The focus on methods and proof-of concept meant that only one facility and one type of imaging device technology were used to reach the conclusions. Based on the similar studies related to other imaging devices, the provided transparent data can be generalized to other healthcare facilities with few adjustments to utilization ratios, the share of the exam types, and the standby power of the facilities' imaging devices. PRACTICAL IMPLICATIONS: The transparent detailed life cycle approach allows the data from this study to be used by healthcare administrators to explore the hidden public health impact of the radiology department and to set goals for carbon footprint reductions of healthcare organizations by focusing on alternative imaging modalities. Moreover, the presented approach in quantifying healthcare services' environmental impact can be replicated to provide measurable data on departmental quality improvement initiatives and to be used in hospitals' quality management systems. ORIGINALITY/VALUE: No other research has been published on the life cycle assessment of MRI. The share of outside hospital indirect environmental impact of MRI services is a previously undocumented impact of the physician's order for an internal image. PMID- 30415628 TI - Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. AB - BACKGROUND: Patients with elevated triglyceride levels are at increased risk for ischemic events. Icosapent ethyl, a highly purified eicosapentaenoic acid ethyl ester, lowers triglyceride levels, but data are needed to determine its effects on ischemic events. METHODS: We performed a multicenter, randomized, double blind, placebo-controlled trial involving patients with established cardiovascular disease or with diabetes and other risk factors, who had been receiving statin therapy and who had a fasting triglyceride level of 135 to 499 mg per deciliter (1.52 to 5.63 mmol per liter) and a low-density lipoprotein cholesterol level of 41 to 100 mg per deciliter (1.06 to 2.59 mmol per liter). The patients were randomly assigned to receive 2 g of icosapent ethyl twice daily (total daily dose, 4 g) or placebo. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. The key secondary end point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. RESULTS: A total of 8179 patients were enrolled (70.7% for secondary prevention of cardiovascular events) and were followed for a median of 4.9 years. A primary end-point event occurred in 17.2% of the patients in the icosapent ethyl group, as compared with 22.0% of the patients in the placebo group (hazard ratio, 0.75; 95% confidence interval [CI], 0.68 to 0.83; P<0.001); the corresponding rates of the key secondary end point were 11.2% and 14.8% (hazard ratio, 0.74; 95% CI, 0.65 to 0.83; P<0.001). The rates of additional ischemic end points, as assessed according to a prespecified hierarchical schema, were significantly lower in the icosapent ethyl group than in the placebo group, including the rate of cardiovascular death (4.3% vs. 5.2%; hazard ratio, 0.80; 95% CI, 0.66 to 0.98; P=0.03). A larger percentage of patients in the icosapent ethyl group than in the placebo group were hospitalized for atrial fibrillation or flutter (3.1% vs. 2.1%, P=0.004). Serious bleeding events occurred in 2.7% of the patients in the icosapent ethyl group and in 2.1% in the placebo group (P=0.06). CONCLUSIONS: Among patients with elevated triglyceride levels despite the use of statins, the risk of ischemic events, including cardiovascular death, was significantly lower among those who received 2 g of icosapent ethyl twice daily than among those who received placebo. (Funded by Amarin Pharma; REDUCE-IT ClinicalTrials.gov number, NCT01492361 .). PMID- 30415629 TI - Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. AB - BACKGROUND: It is unclear whether supplementation with vitamin D reduces the risk of cancer or cardiovascular disease, and data from randomized trials are limited. METHODS: We conducted a nationwide, randomized, placebo-controlled trial, with a two-by-two factorial design, of vitamin D3 (cholecalciferol) at a dose of 2000 IU per day and marine n-3 (also called omega-3) fatty acids at a dose of 1 g per day for the prevention of cancer and cardiovascular disease among men 50 years of age or older and women 55 years of age or older in the United States. Primary end points were invasive cancer of any type and major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes). Secondary end points included site-specific cancers, death from cancer, and additional cardiovascular events. This article reports the results of the comparison of vitamin D with placebo. RESULTS: A total of 25,871 participants, including 5106 black participants, underwent randomization. Supplementation with vitamin D was not associated with a lower risk of either of the primary end points. During a median follow-up of 5.3 years, cancer was diagnosed in 1617 participants (793 in the vitamin D group and 824 in the placebo group; hazard ratio, 0.96; 95% confidence interval [CI], 0.88 to 1.06; P=0.47). A major cardiovascular event occurred in 805 participants (396 in the vitamin D group and 409 in the placebo group; hazard ratio, 0.97; 95% CI, 0.85 to 1.12; P=0.69). In the analyses of secondary end points, the hazard ratios were as follows: for death from cancer (341 deaths), 0.83 (95% CI, 0.67 to 1.02); for breast cancer, 1.02 (95% CI, 0.79 to 1.31); for prostate cancer, 0.88 (95% CI, 0.72 to 1.07); for colorectal cancer, 1.09 (95% CI, 0.73 to 1.62); for the expanded composite end point of major cardiovascular events plus coronary revascularization, 0.96 (95% CI, 0.86 to 1.08); for myocardial infarction, 0.96 (95% CI, 0.78 to 1.19); for stroke, 0.95 (95% CI, 0.76 to 1.20); and for death from cardiovascular causes, 1.11 (95% CI, 0.88 to 1.40). In the analysis of death from any cause (978 deaths), the hazard ratio was 0.99 (95% CI, 0.87 to 1.12). No excess risks of hypercalcemia or other adverse events were identified. CONCLUSIONS: Supplementation with vitamin D did not result in a lower incidence of invasive cancer or cardiovascular events than placebo. (Funded by the National Institutes of Health and others; VITAL ClinicalTrials.gov number, NCT01169259 .). PMID- 30415630 TI - Social Rewards: From Basic Social Building Blocks to Complex Social Behavior. AB - Humans are social creatures, engaging almost constantly in social behaviors that serve ultimate social goals, such as forming strong bonds with one another. However, most social behaviors provide only incremental progress toward an ultimate goal. Instead, the drive to engage in any individual social act may derive from its proximal value rather than its ultimate goal. Thus, this proximal value forms the foundation on which the complexities of human sociality are built. We describe two complementary approaches for using proximal social rewards to understand social behaviors and their ultimate goals: (a) decontextualizing social rewards-paring down complex social interactions can help identify which basic building blocks remain valuable even in minimalistic contexts-and (b) recontextualizing social rewards-reintroducing motivational and contextual factors into the study of social experience can help identify how proximal rewards serve their ultimate function. We discuss how this dual-approach framework can inform future research by bridging basic social building blocks and real-world social goals. PMID- 30415631 TI - Identifying Suitable Brain Regions and Trial Size Segmentation for Positive/Negative Emotion Recognition. AB - The development of suitable EEG-based emotion recognition systems has become a main target in the last decades for Brain Computer Interface applications (BCI). However, there are scarce algorithms and procedures for real-time classification of emotions. The present study aims to investigate the feasibility of real-time emotion recognition implementation by the selection of parameters such as the appropriate time window segmentation and target bandwidths and cortical regions. We recorded the EEG-neural activity of 24 participants while they were looking and listening to an audiovisual database composed of positive and negative emotional video clips. We tested 12 different temporal window sizes, 6 ranges of frequency bands and 60 electrodes located along the entire scalp. Our results showed a correct classification of 86.96% for positive stimuli. The correct classification for negative stimuli was a little bit less (80.88%). The best time window size, from the tested 1[Formula: see text]s to 12[Formula: see text]s segments, was 12[Formula: see text]s. Although more studies are still needed, these preliminary results provide a reliable way to develop accurate EEG-based emotion classification. PMID- 30415632 TI - Instance-Based Representation Using Multiple Kernel Learning for Predicting Conversion to Alzheimer Disease. AB - The early detection of Alzheimer's disease and quantification of its progression poses multiple difficulties for machine learning algorithms. Two of the most relevant issues are related to missing data and results interpretability. To deal with both issues, we introduce a methodology to predict conversion of mild cognitive impairment patients to Alzheimer's from structural brain MRI volumes. First, we use morphological measures of each brain structure to build an instance based feature mapping that copes with missed follow-up visits. Then, the extracted multiple feature mappings are combined into a single representation through the convex combination of reproducing kernels. The weighting parameters per structure are tuned based on the maximization of the centered-kernel alignment criterion. We evaluate the proposed methodology on a couple of well known classification machines employing the ADNI database devoted to assessing the combined prognostic value of several AD biomarkers. The obtained experimental results show that our proposed method of Instance-based representation using multiple kernel learning enables detecting mild cognitive impairment as well as predicting conversion to Alzheimers disease within three years from the initial screening. Besides, the brain structures with larger combination weights are directly related to memory and cognitive functions. PMID- 30415633 TI - Coupled Oscillators Model of Hyperexcitable Neuroglial Networks. AB - Glial populations within neuronal networks of the brain have recently gained much interest in the context of hyperexcitability and epilepsy. In this paper, we present an oscillator-based neuroglial model capable of generating Spontaneous Electrical Discharges (SEDs) in hyperexcitable conditions. The network is composed of 16 coupled Cognitive Rhythm Generators (CRGs), which are oscillator based mathematical constructs previously described by our research team. CRGs are well-suited for modeling assemblies of excitable cells, and in this network, each represents one of the following populations: excitatory pyramidal cells, inhibitory interneurons, astrocytes, and microglia. We investigated various pathways leading to hyperexcitability, and our results suggest an important role for astrocytes and microglia in the generation of SEDs of various durations. Analysis of the resultant SEDs revealed two underlying duration distributions with differing properties. Particularly, short and long SEDs are associated with deterministic and random underlying processes, respectively. The mesoscale of this model makes it well-suited for (a) the elucidation of glia-related hypotheses in hyperexcitable conditions, (b) use as a testing platform for neuromodulation purposes, and (c) a hardware implementation for closed-loop neuromodulation. PMID- 30415634 TI - Determination of fragrance allergens and their dermal sensitization quantitative risk assessment (QRA) in 107 spray perfumes. AB - Cutaneous allergy occurs primarily as a result of using cosmetic, household, and laundry products available on the market that contain fragrances. The aim of this study was to develop a rapid and specific high-performance liquid chromatography with ultraviolet detection (HPLC-UV) method for quantification of 25 fragrance allergens (amyl cinnamyl alcohol, benzyl alcohol, benzyl benzoate, benzyl cinnamate, benzyl salicylate, citronellol, cinnamyl alcohol, citral, coumarin, eugenol, farnesol, geraniol, hydroxycitronellal, HICC (4-(4-hydroxy-4 methylpentyl)-3-cyclohexene-1-carboaldehyde), isoeugenol, isoeugenyl acetate, lilial (butyl phenyl methyl propional), limonene, linalool, methyl 2-octynoate, etc.). In addition, an exposure-based quantitative risk assessment (QRA) was performed to determine safe levels of fragrance ingredients in 107 perfumes. In 76 women's and 31 men's fragrances, 25 allergens were identified at concentrations ranging from undetectable (N.D.) to 8,997.68 mg/kg, and from N.D. to 17,352.34 mg/kg, respectively. An exposure-based sensitization QRA revealed that the ratios of acceptable exposure level (AEL) to consumer exposure level (CEL) of fragrance ingredients were greater than 1, suggesting an absence of skin sensitizing potential. However, the maximum level used in the exposure scenario was determined by the product purpose and application type, and AEL/CEL ratios of lilial, HICC, citral, isoeugenol, and methyl 2-octynoate analyzed in women's perfume were 0.53, 0.67 0.19, 0.13, and 0.57, respectively. As the ratios of AEL:CEL of these fragrance ingredients were below 1, the utilization of these potential skin sensitizers is not considered safe. Our findings indicate that the sensitization risk of allergens with AEL:CEL ratios below 1 detected in fragrances needs to be reduced to the appropriate human safety level for risk management. PMID- 30415636 TI - The Prevalence of Military Sexual Trauma: A Meta-Analysis. AB - Due to methodological heterogeneity, the exact prevalence of military sexual trauma (MST) is unknown. To elucidate our understanding of the pervasiveness of this important social issue, a meta-analysis was conducted. A computerized database search in PsycINFO, PubMed, and PILOTS revealed 584 unique citations for review. Of these identified studies, 69 met the inclusion criteria for the meta analysis. The results revealed that 15.7% of military personnel and veterans report MST (3.9% of men, 38.4% of women) when the measure includes both harassment and assault. Additionally, 13.9% report MST (1.9% of men, 23.6% of women) when the measure assesses only assault and 31.2% report MST (8.9% of men, 52.5% of women) when the measure assesses only harassment. Regardless of the type of victimization incident (i.e., harassment or assault), women evidenced significantly larger prevalence rates compared to men. Self-report measure and interviews were associated with higher prevalence rates than the review of veterans affair (VA) medical records when measuring both harassment and assault and only harassment. No significant differences were observed among prevalence rates based on VA, non-VA, or both VA and non-VA recruitment. Ultimately, the findings suggest that MST is a pervasive problem, among both men and women in the military, highlighting the importance of this line of research. PMID- 30415637 TI - Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. AB - BACKGROUND: Higher intake of marine n-3 (also called omega-3) fatty acids has been associated with reduced risks of cardiovascular disease and cancer in several observational studies. Whether supplementation with n-3 fatty acids has such effects in general populations at usual risk for these end points is unclear. METHODS: We conducted a randomized, placebo-controlled trial, with a two by-two factorial design, of vitamin D3 (at a dose of 2000 IU per day) and marine n-3 fatty acids (at a dose of 1 g per day) in the primary prevention of cardiovascular disease and cancer among men 50 years of age or older and women 55 years of age or older in the United States. Primary end points were major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes) and invasive cancer of any type. Secondary end points included individual components of the composite cardiovascular end point, the composite end point plus coronary revascularization (expanded composite of cardiovascular events), site-specific cancers, and death from cancer. Safety was also assessed. This article reports the results of the comparison of n-3 fatty acids with placebo. RESULTS: A total of 25,871 participants, including 5106 black participants, underwent randomization. During a median follow-up of 5.3 years, a major cardiovascular event occurred in 386 participants in the n-3 group and in 419 in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P=0.24). Invasive cancer was diagnosed in 820 participants in the n-3 group and in 797 in the placebo group (hazard ratio, 1.03; 95% CI, 0.93 to 1.13; P=0.56). In the analyses of key secondary end points, the hazard ratios were as follows: for the expanded composite end point of cardiovascular events, 0.93 (95% CI, 0.82 to 1.04); for total myocardial infarction, 0.72 (95% CI, 0.59 to 0.90); for total stroke, 1.04 (95% CI, 0.83 to 1.31); for death from cardiovascular causes, 0.96 (95% CI, 0.76 to 1.21); and for death from cancer (341 deaths from cancer), 0.97 (95% CI, 0.79 to 1.20). In the analysis of death from any cause (978 deaths overall), the hazard ratio was 1.02 (95% CI, 0.90 to 1.15). No excess risks of bleeding or other serious adverse events were observed. CONCLUSIONS: Supplementation with n-3 fatty acids did not result in a lower incidence of major cardiovascular events or cancer than placebo. (Funded by the National Institutes of Health and others; VITAL ClinicalTrials.gov number, NCT01169259 .). PMID- 30415638 TI - Congenital intrahepatic portocaval shunts and hypoglycemia due to secondary hyperinsulinism: a case report and review of the literature. AB - BACKGROUND: Congenital portosystemic shunts present with various associated complications, such as other congenital malformations, hyperammonemia, or hepatopulmonary syndrome. Few cases of associated hypoglycemia have been reported so far and our case, to the best of our knowledge, describes the most severe extent of hypoglycemia. CASE PRESENTATION: We describe the case of a newborn Arab boy with two intrahepatic portosystemic shunts, resulting in severe and persistent hypoglycemia, due to which one of the shunts was closed by interventional radiology whereas the other shunt had already closed spontaneously. CONCLUSIONS: Because he showed elevated levels for insulin and prolonged high insulin levels in an oral glucose tolerance test, our case supports the theory that portocaval shunts cause a reduced hepatic insulin reduction due to the high blood volume bypassing the liver. This case provides further insights into glucose regulation mechanisms of the liver and we suggest a consistent screening for hypoglycemia in patients with congenital portosystemic shunts. PMID- 30415639 TI - The annual, temporal and spatial pattern of Setaria tundra outbreaks in Finnish reindeer: a mechanistic transmission model approach. AB - BACKGROUND: In northern Finland (Lapland), reindeer are reared as semi domesticated animals. The region has a short summer season of 2-3 months, yet reindeer are infected with the mosquito-borne filarioid parasite Setaria tundra. The infection causes peritonitis and perihepatitis, which cause significant economic losses due to reduced body weight of infected animals. The objective of this study was to: (i) describe the spatial and temporal pattern of outbreaks in three different areas across Finnish Lapland; and (ii) construct a temperature driven mechanistic transmission model to quantify the potential role of temperature on intensity of S. tundra transmission in reindeer. METHODS: We developed a temperature-driven transmission model able to predict the number of S. tundra potentially transmitted from an infectious reindeer. We applied the model to the years 2004-2015, and compared the predictions to the proportion of reindeer whose livers were condemned due to S. tundra infection at the time of slaughter. RESULTS: The mean proportion of liver condemnation increased in reindeer slaughtered in late autumn/winter compared to earlier dates. The outbreaks were geographically clustered each year but there were no fixed foci where outbreaks occurred. Larger outbreaks were recorded in the southern regions of reindeer-herding areas compared to the central or northern parts of Lapland. Our model showed that temperatures never allowed for transmission of more than a single generation of S. tundra each season. In southern (Kuusamo) and central (Sodankyla) Lapland, our model predicted an increasing trend from 1979 to 2015 for both the duration of the effective transmission period of S. tundra (P < 0.001) and for the potential number of L3 S. tundra larvae being transmitted from an infectious reindeer (P < 0.001). CONCLUSIONS: The effective transmission period for S. tundra in reindeer is very short in Lapland, but it increased over the period studied. Only one generation of S. tundra can be transmitted in one season among reindeer in Lapland. Increasing temperatures may facilitate a range expansion and increasing duration of effective transmission period for S. tundra. PMID- 30415640 TI - The 2018 Nobel Prize in medicine goes to cancer immunotherapy (editorial for BMC cancer). PMID- 30415641 TI - Selective serotonin reuptake inhibitor use during early pregnancy and congenital malformations: a systematic review and meta-analysis of cohort studies of more than 9 million births. AB - BACKGROUND: In 2005, the FDA cautioned that exposure to paroxetine, a selective serotonin reuptake inhibitor (SSRI), during the first trimester of pregnancy may increase the risk of cardiac malformations. Since then, the association between maternal use of SSRIs during pregnancy and congenital malformations in infants has been the subject of much discussion and controversy. The aim of this study is to systematically review the associations between SSRIs use during early pregnancy and the risk of congenital malformations, with particular attention to the potential confounding by indication. METHODS: The study protocol was registered with PROSPERO (CRD42018088358). Cohort studies on congenital malformations in infants born to mothers with first-trimester exposure to SSRIs were identified via PubMed, Embase, Web of Science, and the Cochrane Library databases through 17 January 2018. Random-effects models were used to calculate summary relative risks (RRs). RESULTS: Twenty-nine cohort studies including 9,085,954 births were identified. Overall, use of SSRIs was associated with an increased risk of overall major congenital anomalies (MCAs, RR 1.11, 95% CI 1.03 to 1.19) and congenital heart defects (CHD, RR 1.24, 95% CI 1.11 to 1.37). No significantly increased risk was observed when restricted to women with a psychiatric diagnosis (MCAs, RR 1.04, 95% CI 0.95 to 1.13; CHD, RR 1.06, 95% CI 0.90 to 1.26). Similar significant associations were observed using maternal citalopram exposure (MCAs, RR 1.20, 95% CI 1.09 to 1.31; CHD, RR 1.24, 95% CI 1.02 to 1.51), fluoxetine (MCAs, RR 1.17, 95% CI 1.07 to 1.28; CHD, 1.30, 95% CI 1.12 to 1.53), and paroxetine (MCAs, RR 1.18, 95% CI 1.05 to 1.32; CHD, RR 1.17, 95% CI 0.97 to 1.41) and analyses restricted to using women with a psychiatric diagnosis were not statistically significant. Sertraline was associated with septal defects (RR 2.69, 95% CI 1.76 to 4.10), atrial septal defects (RR 2.07, 95% CI 1.26 to 3.39), and respiratory system defects (RR 2.65, 95% CI 1.32 to 5.32). CONCLUSIONS: The evidence suggests a generally small risk of congenital malformations and argues against a substantial teratogenic effect of SSRIs. Caution is advisable in making decisions about whether to continue or stop treatment with SSRIs during pregnancy. PMID- 30415642 TI - Quantitative myocardial first-pass cardiovascular magnetic resonance perfusion imaging using hyperpolarized [1-13C] pyruvate. AB - BACKGROUND: The feasibility of absolute myocardial blood flow quantification and suitability of hyperpolarized [1-13C] pyruvate as contrast agent for first-pass cardiovascular magnetic resonance (CMR) perfusion measurements are investigated with simulations and demonstrated in vivo in a swine model. METHODS: A versatile simulation framework for hyperpolarized CMR subject to physical, physiological and technical constraints was developed and applied to investigate experimental conditions for accurate perfusion CMR with hyperpolarized [1-13C] pyruvate. Absolute and semi-quantitative perfusion indices were analyzed with respect to experimental parameter variations and different signal-to-noise ratio (SNR) levels. Absolute myocardial blood flow quantification was implemented with an iterative deconvolution approach based on Fermi functions. To demonstrate in vivo feasibility, velocity-selective excitation with an echo-planar imaging readout was used to acquire dynamic myocardial stress perfusion images in four healthy swine. Arterial input functions were extracted from an additional image slice with conventional excitation that was acquired within the same heartbeat. RESULTS: Simulations suggest that obtainable SNR and B0 inhomogeneity in vivo are sufficient for the determination of absolute and semi-quantitative perfusion with <=25% error. It is shown that for expected metabolic conversion rates, metabolic conversion of pyruvate can be neglected over the short duration of acquisition in first-pass perfusion CMR. In vivo measurements suggest that absolute myocardial blood flow quantification using hyperpolarized [1-13C] pyruvate is feasible with an intra-myocardial variability comparable to semi-quantitative perfusion indices. CONCLUSION: The feasibility of quantitative hyperpolarized first-pass perfusion CMR using [1-13C] pyruvate has been investigated in simulations and demonstrated in swine. Using an approved and metabolically active compound is envisioned to increase the value of hyperpolarized perfusion CMR in patients. PMID- 30415643 TI - Short-term changes in nightlife attendance and patron intoxication following alcohol restrictions in Queensland, Australia. AB - BACKGROUND: This study aims to explore short-term changes following the introduction of alcohol restrictions (most notably 2 am to 3 am last drinks). We examined patterns of nightlife attendance, intoxication, and alcohol use among patrons shortly before and after restrictions were introduced in Fortitude Valley, Brisbane: the largest night-time entertainment precinct of Queensland. METHODS: Street-intercept patron interviews were conducted in Fortitude Valley in June (n = 497) and July (n = 562) 2016. A pre-post design was used to assess changes in time spent out drinking/partying prior to the interview, time of arrival in the precinct, pre-drinking, and blood alcohol concentration (BAC). RESULTS: Regression models indicated that after the policy introduction, the proportion of people arriving at Fortitude Valley before 10:00 pm increased (OR = 1.38; 95% CI = 1.04, 1.82). Participants reported going out, on average, one hour earlier after the intervention (beta = - 0.17; 95% CI = 0.11, 0.22). There was a decrease (RRR = 0.58; 95% CI = 0.43, 0.79) in the proportion of participants who had a high level of intoxication (BAC >=0.10 g/dL) post-intervention. No other significant differences were found. CONCLUSIONS: Earlier cessation of alcohol sales and stopping the sale of rapid intoxication drinks after midnight was associated with people arriving in Fortitude Valley earlier. Though legislative loopholes allowed some venues to continue trading to 5 am, the proportion of people in the precinct who were highly intoxicated decreased after the restriction. Further measurement will be required to determine whether the reduction has persisted. PMID- 30415645 TI - Effects of partial replacement of soybean meal with other protein sources in diets of lactating cows. AB - The protein nutrition of dairy cows is of great importance because of its direct influence on milk production, reproductive efficiency, and feeding cost. Eight first-lactation Holstein cows were randomly assigned to two contemporary 4 * 4 Latin squares in a 2 * 2 factorial design to evaluate the effects of replacing soybean meal with yeast-derived microbial protein (YMP) as a protein source (0% or 1.5% of dry matter (DM)) and its combination with slow-release urea (SRU; 0% or 0.75% of DM) on DM intake and milk production and composition, as well as blood parameters and nitrogen balance. Each experimental period lasted 28 days, with 21 days of adaptation and 7 days of data collection. The diets were formulated to attend the nutritional recommendations of the National Research Council and consisted of 49% forage (47% corn silage and 2% Tifton hay) and 51% concentrate, with 16.8% CP and 1.6 Mcal net energy for lactation/kg DM. For diets without YMP, the inclusion of SRU decreased DM intake, milk production as well as N intake and balance, but did not affect efficiency of production, milk composition or most of blood parameters. On the contrary, for diets with YMP, DM intake and milk production were increased by inclusion of SRU, while minor effects were observed for milk efficiency and composition, blood parameters as well as N intake, excretion and balance. When diets with SRU were compared, the inclusion of YMP increased DM intake, 4% fat-corrected milk, and N intake and balance (P<0.05), with no differences in milk production (kg/day), milk energy, efficiency of milk production or most of the blood parameters. For diets without SRU, YMP inclusion decreased DM intake, milk production, milk energy, N intake, fecal N and N balance (P<0.05), with no effects on milk efficiency and composition, or most of blood parameters. In conclusion, the use of YMP, SRU or both as partial substitutes of soybean meal in the diet of lactating cows has no negative effects on productivity parameters. PMID- 30415646 TI - Efficacy of a written prayer technique on the anxiety of mothers of children with cancer. AB - OBJECTIVE: To investigate the effect of a written prayer technique on the anxiety of mothers of children with cancer. METHOD: This clinical trial recruited 90 mothers of children with cancer admitted to the Medical Centre of Tehran. Using a convenience sampling method, we randomly assigned the participants to two groups: control (n = 45) and intervention (n = 45). Data were collected through the Spielberger's anxiety scale and a demographic questionnaire. Maternal anxiety was measured before the intervention, immediately after the three-day intervention, and five weeks after the intervention. We used a writing technique in the intervention and control groups for 20 minutes over three consecutive days. In the intervention group, participants wrote down their sincere desires and wishes that they demanded from God without any worry or stress. The control group spent 20 minutes writing their normal daily schedules; for example, feeding their children or changing their children's clothes. During the three consecutive days of intervention, we asked both groups not to worry about grammar or spelling errors. Finally, the data were analyzed using descriptive and analytical statistical methods.ResultA statistically significant difference was observed between the two groups (intervention and control mean, 34.9 +/- 9.9 and 47.9 +/- 16.2, respectively) relative to anxiety after the intervention (p < 0.001). After five weeks, the intervention group continued to exhibit significantly reduced anxiety compared with the control group (intervention and control mean, 34.7 +/- 9.6 and 48.5 +/- 16.4; p < 0.001).Significance of resultsThe written prayer technique appears to be an effective, efficient, cost-effective, and practical method for reducing anxiety in mothers of children with cancer. PMID- 30415647 TI - Improvement of General Disaster Preparedness Belief Scale Based on Health Belief Model. AB - : IntroductionThe Health Belief Model (HBM) can be used as a guide in enhancing the peoples' awareness, improving the motivation, and providing tools that address beliefs and attitudes toward general disaster preparedness (GDP). METHODS: The aim of this study was to improve and re-test all psychometric properties of the published General Disaster Preparedness Belief (GDPB) scale based on HBM carried out in the general population. This scale development study measured by 58 items was prepared under the same structure of the developed GDPB scale that measured 31 items before. This expanded scale was applied to 973 individuals. Firstly, the data from application of the expanded scale was examined under Exploratory Factor Analysis (EFA). Then, the estimations obtained from Confirmatory Factor Analysis (CFA) for the expanded scale with 45 items were compared with the estimations obtained from the previous scale with 31 items. RESULTS: The EFA lead to the removal of 13 items and the retention of 45 items. The items which the factor loadings were below 0.30 and which gave the factor loadings for more dimension were excluded from the data set. A model measured six dimensions with 45 items was hypothesized: six items under perceived susceptibility, four items under perceived severity, six items under perceived benefits, 14 items under perceived barriers, five items under cues to action, and 10 items under self-efficacy. For CFA results, all estimations for factor loadings were significant. The scale with 45 items obtained in this study fit because Comparative Fit Index (CFI), Goodness of Fit Index (GFI), and Adjusted Goodness of Fit Index (AGFI) were over 0.95. CONCLUSION: These results suggest that the scale with 45 items shows improvement in the scale with 31 items. This study indicates that the GDPB scale with 45 items based on HBM has acceptable validity and reliability. This tool can be used in disaster preparedness surveys.Inal E, Dogan N. Improvement of General Disaster Preparedness Belief scale based on Health Belief Model. PMID- 30415644 TI - Sport, doping and male fertility. AB - It is universally accepted that lifestyle interventions are the first step towards a good overall, reproductive and sexual health. Cessation of unhealthy habits, such as tobacco, alcohol and drug use, poor nutrition and sedentary behavior, is suggested in order to preserve/improve fertility in humans. However, the possible risks of physical exercise per se or sports on male fertility are less known. Being "fit" does not only improve the sense of well-being, but also has beneficial effects on general health: in fact physical exercise is by all means a low-cost, high-efficacy method for preventing or treating several conditions, ranging from purely physical (diabetes and obesity) to psychological (depression and anxiety), highly influencing male reproduction. If male sexual and reproductive health could be positively affected by a proper physical activity, inadequate bouts of strength - both excessive intensity and duration of exercise training - are more likely to have detrimental effects. In addition, the illicit use of prohibited drugs (i.e. doping) has reached pandemic proportions, and their actions, unfortunately very often underestimated by both amateur and professional athletes, are known to disrupt at different levels and throughout various mechanisms the male hypothalamic-pituitary-gonadal axis, resulting in hypogonadism and infertility. PMID- 30415648 TI - Bias-contingent attention bias modification and attention control training in treatment of PTSD: a randomized control trial. AB - BACKGROUND: Randomized control trials (RCTs) comparing attention control training (ACT) and attention bias modification (ABM) in posttraumatic stress disorder (PTSD) have shown mixed results. The current RCT extends the extant literature by comparing the efficacy of ACT and a novel bias-contingent-ABM (BC-ABM), in which direction of training is contingent upon the direction of pre-treatment attention bias (AB), in a sample of civilian patients with PTSD. METHODS: Fifty treatment seeking civilian patients with PTSD were randomly assigned to either ACT or BC ABM. Clinician and self-report measures of PTSD and depression, as well as AB and attention bias variability (ABV), were acquired pre- and post-treatment. RESULTS: ACT yielded greater reductions in PTSD and depressive symptoms on both clinician rated and self-reported measures compared with BC-ABM. The BC-ABM condition successfully shifted ABs in the intended training direction. In the ACT group, there was no significant change in ABV or AB from pre- to post-treatment. CONCLUSIONS: The current RCT extends previous results in being the first to apply ABM that is contingent upon AB at pre-treatment. This personalized BC-ABM approach is associated with significant reductions in symptoms. However, ACT produces even greater reductions, thereby emerging as a promising treatment for PTSD. PMID- 30415649 TI - Risk and coaggregation of major psychiatric disorders among first-degree relatives of patients with bipolar disorder: a nationwide population-based study. AB - BACKGROUND: Bipolar disorder is a highly heritable mental illness that transmits intergeneratively. Previous studies supported that first-degree relatives (FDRs), such as parents, offspring, and siblings, of patients with bipolar disorder, had a higher risk of bipolar disorder. However, whether FDRs of bipolar patients have an increased risk of schizophrenia, major depressive disorder (MDD), autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD) remains unclear. METHODS: Among the entire population in Taiwan, 87 639 patients with bipolar disorder and 188 290 FDRs of patients with bipolar disorder were identified in our study. The relative risks (RRs) of major psychiatric disorders were assessed among FDRs of patients with bipolar disorder. RESULTS: FDRs of patients with bipolar disorder were more likely to have a higher risk of major psychiatric disorders, including bipolar disorder (RR 6.12, 95% confidence interval (CI) 5.95-6.30), MDD (RR 2.89, 95% CI 2.82-2.96), schizophrenia (RR 2.64, 95% CI 2.55-2.73), ADHD (RR 2.21, 95% CI 2.13-2.30), and ASD (RR 2.10, 95% CI 1.92-2.29), than the total population did. These increased risks for major psychiatric disorders were consistent across different familial kinships, such as parents, offspring, siblings, and twins. A dose-dependent relationship was also found between risk of each major psychiatric disorder and numbers of bipolar patients. CONCLUSIONS: Our study was the first study to support the familial coaggregation of bipolar disorder with other major psychiatric disorders, including schizophrenia, MDD, ADHD, and ASD, in a Taiwanese (non-Caucasian) population. Given the elevated risks of major psychiatric disorders, the public health government should pay more attention to the mental health of FDRs of patients with bipolar disorder. PMID- 30415650 TI - Pharmacokinetic and bioequivalence study of sugar-coated and film-coated eperisone tablets in healthy subjects: A randomized, open-label, three-way, reference-replicated crossover study?. AB - OBJECTIVE: Eperisone hydrochloride is used in the treatment of musculoskeletal disorders as a muscle relaxant via blocking of calcium channels. In this study, we aimed to investigate the within-subject variability (CVwR) of reference eperisone formulation for highly-variable drugs and to perform bioequivalence study of two oral formulations (sugar- and film-coated tablets) of eperisone hydrochloride 50 mg in healthy subjects by reference-replicated crossover study. MATERIALS AND METHODS: 36 healthy Korean male subjects were recruited, and 33 subjects completed the study. A randomized, single-dose, open-label, three-way, three-sequence, reference formulation-replicated, crossover bioequivalence study was conducted to determine the bioequivalence of eperisone. Blood samples were collected before dosing and at 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours after dosing. The plasma concentration of eperisone was determined using liquid chromatography-tandem mass spectrometry. RESULTS: The CVwR of eperisone reference product was 33.17% for AUCt and 50.21% for Cmax. The acceptance limit for Cmax was scaled to 0.6984 - 1.4319 according to CVwR. The 90% confidence intervals for the test/reference geometric mean ratio were 0.8275 - 1.1692 for AUCt and 0.7587 - 1.1652 for Cmax, which were within the accepted bioequivalence limits. Single oral doses of eperisone hydrochloride 50 mg were generally well tolerated in healthy adult subjects in this study. CONCLUSION: The newly developed film-coated tablet can be interchanged with the original sugar-coated tablet of eperisone. In addition, the reference scaling methods are more effective and economical than the classical method for assessing BE of HVDs.?. PMID- 30415651 TI - Argyrophilic grain disease presenting as behavioral frontotemporal dementia. AB - Argyrophilic grain disease (AgD) is a frequent late-onset 4R tauopathy of old age characterized by the presence of profuse spindle-shaped argyrophilic grains (AGs). It is a neurodegenerative disorder that is clinically characterized by a slow progressive amnestic mild cognitive impairment similar to Alzheimer's disease. In rare instances, it is characterized as a behavioral-variant frontotemporal dementia (bv-FTD). In this study, we report a case with typical clinical and neuroimaging features of bv-FTD, who had autopsy findings consistent with a definitive diagnosis of AgD. We suggest that AgD might be included in the differential diagnosis of patients presenting with bv-FTD.?. PMID- 30415652 TI - Acute esophageal necrosis (black esophagus) complicating calcific uremic arteriolopathy?. AB - The current case report describes a chronic hemodialysis patient presenting with painful penile ulceration that was clinically and histologically proven to be related to calcific uremic arteriolopathy. The patient subsequently developed severe upper gastrointestinal bleeding that was both endoscopically and histologically shown to be due to acute esophageal necrosis (AEN), also known as necrotizing esophagitis and "black esophagus". AEN is a rare condition characterized by diffuse necrosis of the esophageal mucosa. The condition is diagnosed endoscopically with demonstration of circumferential mucosal necrosis involving the distal esophagus that can extend proximally. Mortality rates for both calcific uremic ateriolopathy and acute esophageal necrosis are high. Management of both conditions is reviewed. The patient recovered from the acute illness, but expired 6 months later due to progressive failure to thrive. To our knowledge, AEN has not previously been described secondary to calcific uremic arteriolopathy.?. PMID- 30415653 TI - Rate and risk factors for AKI after CT scans in a cancer cohort?. AB - AIMS: The proinflammatory milieu in cancer patients may expose them to increased risk for acute kidney injury (AKI) after IV contrast (CON). The aims of this study were to determine: (1) the rates of AKI after CON and noncontrast (NC) CT scans in cancer inpatients, (2) if rates differed among cancer subtypes, and (3) whether recent chemotherapy, comorbid conditions, or nephrotoxins increase AKI after CON. MATERIALS AND METHODS: Retrospective data was collected on adults who had received a CON or NC CT from January 1, 2012 to December 30, 2014. AKI was defined as a > 1.5* increased baseline creatinine. Data was analyzed using Rao Scott chi2-test, propensity score matching, and logistic regressions. RESULTS: A total of 7,512 CT scans were performed in 4,456 patients (4,958 NC, 2,554 CON). The rate for AKI with CON was 7.3% and 11.4% (p < 0.001) with NC imaging. The risk of AKI increased with lower baseline eGFR: for eGFR <= 29 mL/min/1.73m2, OR = 1.83 (p = 0.0002); for eGFR 30 - 59 mL/min/1.73m2, OR = 1.5 compared to eGFR >= 60 mL/min/1.73m2 (p < 0.0001). AKI rates were higher when any chemotherapy was given within 60 days of CT (OR = 1.22, p < 0.02), with congestive heart failure (OR 1.51, p = 0.0006), and history of AKI (OR 3.89, p < 0.0001). In 1:1 propensity score matched samples, the OR for AKI after CON was 0.87 (p = 0.23) compared to NC. CONCLUSION: In cancer patients, eGFR below 59 mL/min/1.73m2 were associated with increased rate of AKI, independent of contrast exposure. Congestive heart failure and prior AKI were also associated with increased rates of AKI.?. PMID- 30415655 TI - Usability and Acceptability of Everhealthier Women, a Mobile Application to Enhance Informed Health Choices. AB - OBJECTIVE: To explore women's use and acceptance of Everhealthier Women, a mobile health (mHealth) application (app) designed to provide women with easy access to preventive health information and to promote adherence to life-saving clinical screenings and disease prevention behaviors. DESIGN: Qualitative descriptive study. SETTING: A Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) office in a large Northeastern U.S. city. PARTICIPANTS: Fifteen low-income women ages 18 to 30 years who used WIC services. METHODS: Participants completed a baseline survey regarding their use of technology to obtain health information. Next, they received an introductory session to Everhealthier Women on a mobile device by a study staff member and individually explored the app. Afterward, they completed a questionnaire in the waiting room to assess their initial views on the acceptability and usefulness of the app. Participants were then contacted over a period of 3 weeks to elicit feedback about their app use through a series of open-ended questions. Descriptive statistics were calculated, and content analysis was performed. RESULTS: Fourteen of the 15 participants reported using the Internet to search for health information in the past. Seven participants had used mHealth apps, and 14 believed that Everhealthier Women was easy to navigate and beneficial for women of all ages. They reported being more likely to use the app if it was recommended by a friend or health care provider. The app was mainly used to search for health information and set appointment reminders. CONCLUSION: mHealth apps can be powerful public health tools; however, evidence should inform their development. Research about specific apps, such as Everhealthier Women, advances our knowledge about the benefits of mHealth and implementation challenges and could inform stakeholders of the optimal level of investment in new technologies. Consideration of financial, time, and personal constraints is needed to evaluate the use of mHealth apps by economically disadvantaged populations. PMID- 30415654 TI - Solid-State NMR Identification of Intermolecular Interactions in Amelogenin Bound to Hydroxyapatite. AB - Biomineralization processes govern the formation of hierarchical hard tissues such as bone and teeth in living organisms, and mimicking these processes could lead to the design of new materials with specialized properties. However, such advances require structural characterization of the proteins guiding biomineral formation to understand and mimic their impact. In their "active" form, biomineralization proteins are bound to a solid surface, severely limiting our ability to use many conventional structure characterization techniques. Here, solid-state NMR spectroscopy was applied to study the intermolecular interactions of amelogenin, the most abundant protein present during the early stages of enamel formation, in self-assembled oligomers bound to hydroxyapatite. Intermolecular dipolar couplings were identified that support amelogenin dimer formation stabilized by residues toward the C-termini. These dipolar interactions were corroborated by molecular dynamics simulations. A beta-sheet structure was identified in multiple regions of the protein, which is otherwise intrinsically disordered in the absence of hydroxyapatite. To our knowledge, this is the first intermolecular protein-protein interaction reported for a biomineralization protein, representing an advancement in understanding enamel development and a new general strategy toward investigating biomineralization proteins. PMID- 30415656 TI - Drug delivery systems for programmed and on-demand release. AB - With the advancement in medical science and understanding the importance of biodistribution and pharmacokinetics of therapeutic agents, modern drug delivery research strives to utilize novel materials and fabrication technologies for the preparation of robust drug delivery systems to combat acute and chronic diseases. Compared to traditional drug carriers, which could only control the release of the agents in a monotonic manner, the new drug carriers are able to provide a precise control over the release time and the quantity of drug introduced into the patient's body. To achieve this goal, scientists have introduced "programmed" and "on-demand" approaches. The former provides delivery systems with a sophisticated architecture to precisely tune the release rate for a definite time period, while the latter includes systems directly controlled by an operator/practitioner, perhaps with a remote device triggering/affecting the implanted or injected drug carrier. Ideally, such devices can determine flexible release pattern and intensify the efficacy of a therapy via controlling time, duration, dosage, and location of drug release in a predictable, repeatable, and reliable manner. This review sheds light on the past and current techniques available for fabricating and remotely controlling drug delivery systems and addresses the application of new technologies (e.g. 3D printing) in this field. PMID- 30415657 TI - Local Auxin Biosynthesis Is a Key Regulator of Plant Development. AB - Auxin is a major phytohormone that controls numerous aspects of plant development and coordinates plant responses to the environment. Morphogenic gradients of auxin govern cell fate decisions and underlie plant phenotypic plasticity. Polar auxin transport plays a central role in auxin maxima generation. The discovery of the exquisite spatiotemporal expression patterns of auxin biosynthesis genes of the WEI8/TAR and YUC families suggested that local auxin production may contribute to the formation of auxin maxima. Herein, we systematically addressed the role of local auxin biosynthesis in plant development and responses to the stress phytohormone ethylene by manipulating spatiotemporal patterns of WEI8. Our study revealed that local auxin biosynthesis and transport act synergistically and are individually dispensable for root meristem maintenance. In contrast, flower fertility and root responses to ethylene require local auxin production that cannot be fully compensated for by transport in the generation of morphogenic auxin maxima. PMID- 30415658 TI - Low-Dose Radiation Conditioning Enables CAR T Cells to Mitigate Antigen Escape. AB - CD19 chimeric antigen receptors (CARs) have demonstrated great efficacy against a range of B cell malignancies. However, antigen escape and, more generally, heterogeneous antigen expression pose a challenge to applying CAR therapy to a wide range of cancers. We find that low-dose radiation sensitizes tumor cells to immune rejection by locally activated CAR T cells. In a model of pancreatic adenocarcinoma heterogeneously expressing sialyl Lewis-A (sLeA), we show that not only sLeA+ but also sLeA- tumor cells exposed to low-dose radiation become susceptible to CAR therapy, reducing antigen-negative tumor relapse. RNA sequencing analysis of low-dose radiation-exposed tumors reveals the transcriptional signature of cells highly sensitive to TRAIL-mediated death. We find that sLeA-targeted CAR T cells produce TRAIL upon engaging sLeA+ tumor cells, and eliminate sLeA- tumor cells previously exposed to systemic or local low-dose radiation in a TRAIL-dependent manner. These findings enhance the prospects for successfully applying CAR therapy to heterogeneous solid tumors. Local radiation is integral to many tumors' standard of care and can be easily implemented as a CAR conditioning regimen. PMID- 30415660 TI - Modern orthopaedic trauma care in Italy. PMID- 30415659 TI - Long Noncoding RNA lncMUMA Reverses Established Skeletal Muscle Atrophy following Mechanical Unloading. AB - Reversing established muscle atrophy following mechanical unloading is of great clinical challenge. Long noncoding RNAs (lncRNAs) have been demonstrated to play important roles in myogenesis. Here we identified a lncRNA (mechanical unloading induced muscle atrophy-related lncRNA [lncMUMA]) enriched in muscle, which was the most downregulated lncRNA during muscle atrophy development in hindlimb suspension (HLS) mice. The in vitro and in vivo data demonstrated that the decreased expression levels of lncMUMA closely associated with a reduction of myogenesis during mechanical unloading. Mechanistically, lncMUMA promoted myogenic differentiation by functioning as a miR-762 sponge to regulate the core myogenic regulator MyoD in vitro. The enforced expression of lncMUMA relieved the decreases in MyoD protein and muscle mass in miR-762 knockin mice. Therapeutically, the enforced expression of lncMUMA improved the in vitro myogenic differentiation of myoblasts under microgravity simulation, prevented the muscle atrophy development, and reversed the established muscle atrophy in HLS mice. These findings identify lncMUMA as an anabolic regulator to reverse established muscle atrophy following mechanical unloading. PMID- 30415661 TI - Post-traumatic ossifications of the rectus femoris: Arthroscopic treatment and clinical outcome after 2 years. AB - : Injuries of the rectus femoris tendon origin could result in a chronic tendinopathy, leading to groin pain and loss of function. Conservative treatment with analgesics and physical therapy is the gold standard, but in some cases excessive bone formation after avulsion injuries, can lead to a post-traumatic heterotopic ossification (PHO) and may benefit from surgical removal. METHODS: Outcome was evaluated in 16 top soccer players (age 24-43 years) affected by calcification of the proximal rectus who underwent arthroscopic excision (6-12 and 24 months). X-ray and 3D CT was collected for all patients. Hip disability and Osteoarthritis Outcome Score, Oxford Hip Score, Modified Harris Hip Score, together with visual analog scales (VAS) for pain, sport activity level (SAL), and activities of daily living (ADL) were used to evaluate clinical outcome. TECHNICAL PROCEDURE: after central compartment examination and treatment was accomplished, attention was focused to the ossification of the rectus femoris. A complete exposure of the ossification was achieved; when possible attention was taken in detaching the minimum amount of fibers of the direct head of the rectus femoris from its insertion site. During the entire procedure, both dynamic direct visualization and fluoroscopic evaluation of the amount of resection were performed. RESULTS: Clinical outcome was excellent; the percentage of return to pre-injury level sport was 68.75 % (11 athletes), with significant statistical improvement of MHHS, OHS and all 3 VAS subscales in all patients at 2 years follow-up. CONCLUSION: Arthroscopic removal using conventional hip arthroscopic portals represent both effective and safe procedure to adequately treat post traumatic ossification of the rectus femoris. PMID- 30415662 TI - Free flap and kickstand external fixator in foot and ankle soft tissue reconstruction. The versatility of a microsurgical-friendly application of an orthopedic device. AB - INTRODUCTION: Foot and ankle are prone to injuries and often require free flap for complex soft tissue reconstruction due to the insufficiency of local soft tissue. Lower limb reconstruction can be commonly compromised by venous insufficiency, and the elevation of the limb represents a critical component of the postoperative care. This study aims to explore the versatility of combining free soft tissue flap reconstruction for complex foot and ankle defect with a temporary Kickstands External Fixator (KEF) placement. MATERIALS AND METHODS: A retrospective analysis was performed on 14 patients with unilateral foot or ankle complex soft tissue defects (post-traumatic, soft tissue infection and osteomyelitis, chronic skin ulcer, sarcoma), treated with free flap and KEF placement. Patients' demographics, etiology of injury, type of reconstruction, duration of KEF, complications related to the flap and the KEF placement were recorded. RESULTS: The mean age of patients was 52.57-year-old (range 35-68). The average follow up was 15.5 months (range: 3-25). An anterolateral thigh (ALT) flap was performed in 12 patients; 2 patients received composite forearm free flap plus flexor carpalis radial for Achilles tendon reconstruction. The average time for KEF removal was 378 weeks. All flaps survived, though partial necrosis was observed in 1 case. No complication at the flap donor site or related to the KEF placement was observed. No equinus deformity was reported. CONCLUSION: The KEF placement when performing a complex soft tissue free flap reconstruction of foot and ankle could be an effective method to guarantee limb elevation, avoid pressure on the flap especially in posterior reconstructions, avoid heel pressure ulcer formation and equinus deformity. PMID- 30415663 TI - Treatment of fractures of the tibial plateau (Schatzker VI) with external fixators versus plate osteosynthesis. AB - INTRODUCTION: The purpose of this study was to determine the effectiveness of circular external fixation (CEF) as a definitive treatment option for patients with complex tibial plateau fractures (Schatzker VI) compared with the outcomes of a fixed angle locking plates' group. METHODS: Level III evidence. Retrospective, comparative study in a Level I Trauma Center. Fourteen patients treated with CEF (Group A) were compared to fourteen patients treated with minimal invasive angle locking plates (Group B). The mean time from fractures to surgery was 19 days for Group A with a mean ISS of 24 and 7 days for Group B with a mean ISS of 14. The main outcome measures were clinical and radiographic. RESULTS: Complete union was obtained in Group A at an average of 22 weeks and at 17 weeks in Group B. Two patients developed non-union, one in each group. Normal alignment was observed in both groups, no statistical differences were observed in Paley's anatomical posterior proximal tibial angle (aPPTA) and mechanical medial proximal tibial angle (mMPTA) between two groups. Results based on the Association for the Study and Application of the Method of Ilizarov criteria for Group A: 71% excellent and 29% good as far as bone outcomes are concerned and as 57% excellent, 37% good, and 7% fair for functional outcomes. CONCLUSIONS: Definitive fixation with circular external fixator is effective in complex Schatzker VI tibial plateau fractures. Advantages include maintaining the frame till union, reduced risk of infection, early mobilization, restoration of the normal lower extremity alignment, versatility, and improved union rate in patients with multiple traumatic injuries, infection, and soft tissue injuries. PMID- 30415665 TI - Predicting the failure in distal femur fractures. AB - INTRODUCTION: The incidence of nonunion after fractures of the distal femur is up to 6%. The distal femoral nonunion is a disabling disease that needs complex steps in his treatment. Aim of our study is to find predicting factors of non unions. MATERIALS AND METHODS: We retrospectively analyzed 116 cases of distal femoral fractures and 20 cases of non-unions. In both surgeries we analyzed: accuracy of reduction, stability of fixation, hardware used, residual medial or lateral bone defect, use of autologous or heterologous bone grafts. RESULTS: Malreduction, particularly axial defect, associated with unbalanced fixation, and a medial cortical bone defect of greater or lesser extent were found to be the major risk factors of nonunion. Addressing both the mechanical and the biological environment was associated with successful non union treatment. CONCLUSION: The main principles for solving a distal femoral nonunion are new better reduction, correction of the medial bone defect and biological support with bone grafting. From the mechanical side the association of a medial strut graft or a medial column plate could be very useful in the treatment of these non-unions. PMID- 30415664 TI - Unlocked versus dynamic and static distal locked femoral nails in stable and unstable intertrochanteric fractures. A prospective study. AB - INTRODUCTION: Few clinical studies have analyzed the utility of distal interlocking screws in stable and unstable intertrochanteric fractures treated with intramedullary devices. We performed a prospective analysis comparing short unlocked versus short dynamic and short static distal locked intramedullary nails. MATERIALS AND METHODS: Nine level-II trauma centres were involved in the study. 240 patients over the age of 65 with a stable (AO/OTA 31-A1) or unstable intertrochanteric fracture (AO/OTA 31-A2) were prospectively investigated. The same type of nail was used in every patient. Patients were randomly divided into 3 groups according to the type of distal locking used. Intra-operative variables were examined and patients were followed clinically and radiographically at 1, 3, 6, 12 months postoperatively. All complications were recorded. RESULTS: A total of 212 patients completed 1 year of follow-up visits. In the Unlocking Group (UG) the operation time, blood loss, fluoroscopy time, total length of incision were significantly decreased compared to both the Dynamic Group (DG) and the Static Group (SG) (p < 0.05). Conversely, no reliable differences in intraoperative variables were noted between the Dynamic Group and the Static Group (p > 0.05). In terms of time of fracture union we found no differences among the three Groups (p > 0.05). Moreover, no cases of limb shortening >1 cm or varus collapse were detected in any group. The 3 Groups were similar in terms of HHS, SF-12 and Barthel index results at 1-year follow-up (p > 0.05). Finally, no significant differences were demonstrated across the three Groups in terms of major complications. CONCLUSIONS: This clinical study further confirms the hypothesis that short intramedullary nails do not need to be locked for stable and unstable intertrochanteric fractures. PMID- 30415667 TI - The fake unlocked femoral nail: A configuration to avoid in stable pertrochanteric femur fractures. AB - BACKGROUND: Intramedullary unlocked nailing is a safe and used treatment for stable pertrocantheric fractures. Due to the femoral anterior bow of the shaft or a wrong entry point, the distal tip of the nail can be impinging the anterior cortex. This type of situation can compromise the function of the nail, leading to nonunion of the fracture, and cut-out. The aim of this study was to assess the relationship between nail impingement of the anterior cortex of the femur and cut out and nonunion incidence in patients with pertrochanteric stable fracture treated with an IM nail in an unlocked configuration. MATERIAL AND METHODS: A retrospective study based on medical records and imaging from the archives of our Level I academic medical center was conducted. The study included patients with proximal femoral fractures treated with short cephalomedullary nails between January 2012 and May 2015. The data collected were analyzed to a possible correlation with the healing time and occurrence of nonunion and cut-out. RESULTS: The study population counted 429 cases. Applying the inclusion criteria the final series was composed of 169 patients: 112 females (66.73%) and 57 males (33.27%), with a mean age of 81.23 years (range: 67-93 years). Distal tip impingement was observed in 22 cases (13.02%). In total 16 (9.47%) postoperative complications were recorded: 8 non-union and 7 cut-outs. Consolidation was registered in 153 cases and the fracture healing time averaged 14.4 +/- 3.8 weeks (range, 11-24 weeks). The cortical impingement was correlated with nonunion and cut-out (p < 0.001) Logistic regression analysis revealed jamming sign significantly affected the fracture healing time (p < 0.001). CONCLUSION: The occurrence of cut-out and nonunion after cephalomedullary nailing of stable pertrochanteric fractures appear to be correlated to the presence of the cortical impingement. For this reason, the fake unlocked femoral nail with the cortical impingement is a configuration to avoid in stable pertrochanteric femur fractures. PMID- 30415666 TI - The impact of magnetic resonance imaging in the diagnostic and classification process of osteoporotic vertebral fractures. AB - INTRODUCTION: Standard radiographs are still considered as the gold standard for the early assessment of thoraco-lumbar osteoporotic vertebral fractures (OVFs), although several studies demonstrated superior accuracy of magnetic resonance imaging (MRI) in the diagnostic process of OVFs. The aim of this study was to quantify the misdiagnosis rate of OVFs and analyse the impact of MRI on early diagnosis and classification, compared to standard radiographs alone. MATERIALS AND METHODS: A total of 173 patients were enrolled in this study. All participants were 55 years of age or older (60 years for men) and complained acute back pain with suspected thoracolumbar OVFs without history of high-energy trauma. Diagnosis of OVF was initially performed on standard radiographs obtained in the emergency room. Then, all the patients underwent MRI scan with short-tau inversion recovery (STIR) sequencing within 7 days. We compared the level and number of fractures identified on standard radiographs with the MRI scan results. The discordance between radiographic and MRI diagnosis was quantified. Fractures were classified according to AO Spine Classification. RESULTS: Mean age of the study participant was 74.2 years (range 55-92). They were 100 males and 73 females. MRI modified initial diagnosis in 52% (90/173) of our patients: in 43.9% of patients MRI identified one or more new thoracolumbar fracture. In 14 cases (8.1%) MRI disproved the evidence of any thoracolumbar fracture, even those recognized at plain X-rays. Bone bruise was detected by MRI in 19 vertebral bodies in 8 patients (4.6%) at levels that were classified as unremarkable on X ray alone. In addition, 63 patients (36.4%) presented a total of 93 old fractures. The classification of fracture pattern after MRI changed in 28.90% of the patients (changes mostly involved AO type A1 patterns). CONCLUSIONS: Underdiagnosis of osteoporotic vertebral fractures is a common problem due to a lack of radiographic detection. Our results showed that the extensive use of MRI imaging allows better accuracy in the diagnostic process and in the classification assessment, compared to conventional radiographs. Further investigation should provide additional information about the impact of early MRI on treatment and management of elderly patients with suspected OVFs, including the decision to hospitalize or not, and how it could affect clinical outcome and social costs. PMID- 30415668 TI - Re-fractures after periprosthetic femoral fracture: A difficult to treat growing evidence. AB - INTRODUCTION: Periprosthetic fractures are increasing. The treatment is mostly surgical, but it has a high complication rate. Re-fracture and non-union with implant failure are the more frequent complications. Those complications are difficult to treat and can lead to severe disability. The purpose of this study is to determine the clinical results of periprosthetic femoral re-fracture treatment. MATERIALS AND METHODS: Twenty patients were treated for femoral re fractures (17 women, 3 men). The mean age and follow-up are 75.7 years (46-95) and 6.15 years (0.4-15) respectively. The diagnosis of new periprosthetic fracture according to Vancouver classification were: 3 type A, 5 type B1, 1 type B2, 2 B3, 8 type C; 1 Lewis-Rorabeck type II. Patients were followed-up clinically, with a Harris Hip Score, and radiologically at 2, 4, 6, 12 months, and then annually. RESULTS: All patients healed except for two cases in which an infection occurred. Two cases, treated with plate osteosynthesis, had a malunion in varus. Six patients died for unrelated reasons after fracture healing. One patient was excluded because of a follow-up shorter than 12 months. In 16 cases (84%) a Trendelenburg gait or the use of aids for walking has been necessary. At final follow-up the mean HHS was 65 (range 45-82). Fractures treatment differed depending on the type of the fracture, prosthesis stability and bone loss. Tension band wiring, long plate fixation, revision with a long stem with cables or a sandwich technique (two plates or one plate plus one strut graft) have been performed according to fracture type. CONCLUSIONS: Re-fractures and non-union with implant failure are common after periprosthetic fracture treatment. Infection and malunion are the main complications of their treatment. Residual limping with the necessity of aids even after fracture healing is often present. The choice of a correct surgical strategy is essential to minimize the risk of new complications and ensure the highest possibility to heal. The most important factor is to achieve a good stability, a reasonable vital environment and don't leave new areas of lower resistance uncovered. Poor functional outcome has to be expected especially in refracture after a revision surgery. PMID- 30415669 TI - Intercondylar eminence fracture treated by resorbable magnesium screws osteosynthesis: A case series. AB - INTRODUCTION: Tibial spine avulsion fractures are mostly a paediatric injury which appropriate treatment is currently debated in literature. The choice between conservative and surgical treatment is based on the radiographic classification of Meyers-McKeever. The most diffused surgical techniques involve either internal fixation devices (screws) or bone tunnels fixation with resorbable sutures. Today, a third option is represented by resorbable magnesium screws which could combine the best features of the two classical systems. Objective of this study is to investigate the efficacy of these new devices in the surgical treatment of tibial spine avulsions. MATERIALS AND METHODS: Since 2014 we have seen seven patients with tibial eminence fracture. Patients underwent clinical and radiological examination (MRI, CT scan) before surgery. Only 3 patients that presented with a grade III or IV lesion were treated surgically with internal fixation with magnesium resorbable screws. In post operative follow-up, functional recovery was evaluated at 1, 2, 4, 6 and 12 months, clinically and by X-ray. Lysholm and IKDC scores were submitted at 1, 2, 6 and 12 months. MRI was repeated at 6 and 12 months. RESULTS: All three surgical patients showed progressive clinical and functional improvement during the follow up period. The first case showed a quicker overall recovery rate, which might be due to the lower grade of the lesion. Radiographs and MRI evaluation showed regular healing of the injury. The devices appeared completely resorbed at the 6 months follow-up and replaced by newly formed bone at the 12 months follow-up. CONCLUSIONS: The treatment of tibial spine avulsion fractures with arthroscopic reduction and internal fixation (ARIF) technique by magnesium resorbable screws seems to result in an excellent functional recovery without complications related to fixation devices, which were completely resorbed after 6 months and replaced by newly formed bone after 12 months. This new method could be considered as an alternative option to classic techniques by non resorbable fixation devices or bone tunnel fixation. Further studies are needed in order to evaluate the efficacy of these new devices in a wider group of patients. PMID- 30415670 TI - Intramedullary nailing of tibial shaft fractures in the semi-extended position using a suprapatellar approach: A retrospective case series. AB - Tibial shaft fractures are extremely common injuries. High rate of union, acceptable alignment in all planes, and a low complication rate have been reported when diaphyseal fractures are treated by intramedullary nailing. However, knee pain after tibial nailing has historically been problematic. While the exact aetiology of the knee pain is still unknown, surgical approach relative to the patellar tendon, nerve transection, violation of the fat pad or joint capsule as well as nail diameter and implant prominence have been claimed as possible causes. Therefore, establishing an appropriate starting point remains a crucial step in the surgical procedure. Recently, suprapatellar nailing in the semi-extended position has been suggested as a safe and effective surgical technique. Literature is lacking on this topic, therefore the present article discusses clinical outcomes of 25 patients treated by suprapatellar nailing at 2 years follow up and a literature review. PMID- 30415671 TI - Periprosthetic acetabular fractures: A New classification proposal. AB - INTRODUCTION: Acetabulum periprosthetic fractures are rare, but are increasing, due to increase in high-energy trauma and a decrease in mortality index. Reconstruction of an acetabular fracture, in the presence of hip arthroplasty can be very complex and represents a real challenge for orthopedic surgeon. Aim of this multicentric study is to classify periprosthetic acetabulum fractures and to propose a treatment algorithm. MATERIALS AND METHODS: 24 cases of acetabular periprosthetic fracture were treated surgically from 01.01.2010 to 31.04.2017 in three different hospitals; 4 males and 20 females, average age 76 years (range 56 90 years). TREATMENT: 4 cases treated conservatively, 8 cases ORIF, 2 cases treated with acetabular ring and screws, 9 cases ORIF and acetabular cup revision, 1 implant removal without revision. RESULTS: All cases were reviewed at minimum 12 months follow-up. In 22 cases, there was no need for new surgical procedures and radiographically all implants appeared stable and with good bone integration. In a case of a type 1b fracture, a dislocation of prosthetic implant was observed after 3 months. In a case prosthesis was explanted and it was not possible to perform a revision. DISCUSSION AND CONCLUSIONS: Fracture classification systems must facilitate communication between surgeons and encourage documentation and research. However, they should also have prognostic value, so from them should come directly a treatment algorithm. In our experience, most important factors as prognostic and therapeutic predictors were: implant stability and timing of fracture: intraoperative or postoperative. In postoperative fractures CT is mandatory to evaluate cup mobilization and fracture patterns. Our classification proposal is simple and easy to remember for daily use. From it is derived a simple treatment plan. PMID- 30415672 TI - Acetabular fractures: Is it possible to regain the same patient's related quality of life before trauma? AB - INTRODUCTION: acetabular fractures are difficult to treat with often an unsatisfactory results for patients. The aim of this study is to investigate about the health-related quality-of-life outcome of patients with a traumatic acetabular fracture, as recorded at least 24 months after their surgery. METHODS: a cohort of patients underwent a dedicated acetabular surgical reconstruction for a pelvic trauma between November 2011 and May 2016, were enrolled to investigate, at least two years after injury, their midterm quality of life; SF-36 and LiSat 11 were used. RESULTS: 35 patients were enrolled but only 28 patients were revisited, 20 males (714%) and 8 females (286%) with a mean age of 43 years (19 73). The most common cause was motor vehicle accident (655%). Lower score after trauma are reported in both tests, SF-36 and LiSat 11, for all items. DISCUSSION: comparing the SF-36 score in the Italian normative sample with our SF-36 score before the trauma there is no statistically significant difference (p = 0.1661) underlining how the patients before the trauma were healthy and in good health. Both scores, SF-36 and LiSat-11, before and after trauma are statistically different with respectively p = 0,0002 and p = 0,049 which proves the lower quality of life after trauma in comparison to their life before trauma. CONCLUSIONS: Although the treatment protocols of acetabular fractures have greatly improved over the years, these continue to have disabling consequences that hardly allow to recover a good quality of life two years after the trauma. PMID- 30415673 TI - Treatment of pathologic fractures of the proximal femur. AB - BACKGROUND: Metastatic lesions to the proximal femur occur frequently and require special consideration due to the high risk of pathologic fractures. Type of surgery might influence patient survival considering the growing concept of oligometastases. In fact, the use of modular tumor megaprosthesis is increasing in the last decades compared to intramedullary nailing. Aim of this study was to evaluate oncological and functional results of treatment in patients with pathologic or impending fracture of the proximal femur, with patient survival being the primary, complications the secondary, and functional results the tertiary endpoint. METHODS: Between 2016 and 2017, 40 patients with pathologic fracture (29 cases) or impending fracture according to the Mirels score (11 cases) of the proximal femur, were treated in our Institute and prospectively collected. There were 29 females (72.5%) and 11 males (27.5%), with a mean age at diagnosis of the metastasis of 63.6 years (range 35 to 92 years). Patients were treated due to bone metastases (commonly develop from breast cancer) or hematologic malignancies. Considering number of lesions, 17 patients had less than three bone metastases. Surgical procedures included intramedullary nailing (7 patients), conventional endoprosthesis (4 patients) and modular endoprosthetic replacement (29 patients). Adjuvant treatments included chemotherapy (13 cases), radiation therapy (8 cases) or both (15 cases), and selective arterial embolization (6 pre-op). Oncological results were evaluated considering the survival of patients. Functional results were assessed as pain intensity in VAS score and MSTS score. RESULTS: The mean follow-up of patients was 10.2 months (range 6-26.3 years). At the latest evaluation, 23 patients were alive with disease, 3 patients were alive without evidence of disease and 14 patients were dead with disease. There was a significant better survival in patients treated with PFR compared to IMN and EPR groups (p = 0.0080). No differences in term of survival were found comparing impending vs actual pathological fracture and oligo vs multiple metastases. After surgery, all patients experienced improvement in quality of life resulting from reduction in pain. Mean MSTS score was 22.4. The overall complications rate was 22.5%. The most frequent complication was dislocation followed by wound dehiscence and deep infections. CONCLUSION: Modular tumour prosthesis for proximal femur replacement provides good functional outcome, relative low incidence of complications and higher life quality in the medium term. Oncologic results were influenced by type of surgery, biased by the correct indications for resection and nailing. Preoperative general health condition, life expectancy and ambulatory capacity may influence treatment strategy. With the numbers available, the patients with actual pathologic or impending fracture of the proximal femur treated with resection had a significantly higher survival, especially those with metastases from renal carcinoma or multiple myeloma. PMID- 30415674 TI - Elastic stable intramedullary nailing (ESIN) in paediatric femur and tibia shaft fractures: Comparison between titanium and stainless steel nails. AB - INTRODUCTION: Elastic stable intramedullary nailing (ESIN) is currently considered the gold standard in surgical treatment of femur and tibial shaft fractures in school age paediatric patients. Although elastic intramedullary nails are available in both titanium (Ti) and stainless steel (SS) alloy, titanium nails are most commonly used. Nevertheless, there is still contrasting evidence as to whether the use of Ti nails can offer better outcomes in terms of fracture healing and stability over SS nails. The aim of this study was to compare outcomes and complications of Ti and SS ESIN for femur and tibia shaft fractures in a population of school age paediatric patients. MATERIALS AND METHODS: All consecutive patients who underwent ESIN for femoral or tibial shaft fracture from June 2012 to May 2015 at our centre were retrospectively reviewed. Standard demographic data were collected. Pre-operative and post-operative X-rays were reviewed, complications were collected from patients charts. Patients were divided in two groups, titanium nails (Ti group) and stainless steel nails (SS group) and outcomes compared between the two. RESULTS: A total of 34 patients were included (17 patients Ti group, 17 patients SS group) with a total of 14 femur and 21 tibia fractures. Average age at surgery was 9.4 +/- 2.5 years in Ti group and 10.4 +/- 2.4 years in SS group (p = 0.21). The average time to bone healing was 3 months in Ti group, and 2.8 months in SS group (p = 0.63). At final follow-up (12 months), no patient showed a coronal plane or sagittal plane deformity >10 degrees and >15 degrees , respectively. Complication rate was similar between the two groups (24% Ti group, 22% SS group). CONCLUSIONS: We did not observe any significant difference in terms of bone healing, fracture mechanical stability, return to full activity, and complication rate between Ti and SS ESIN for paediatric femoral and tibial shaft fractures. While Ti nails remain a better choice for patients with metal allergy, SS nails may offer safe, effective, and cheaper alternative to Ti nails in school age femur and tibial shaft fractures. PMID- 30415675 TI - Does the presence of posterior comminution modify the treatment and prognosis in capitellar and trochlear fractures? Study performed on 45 consecutive patients. AB - INTRODUCTION: Only few case series of capitellar and trochlear fractures have been reported. Some of them assume that the presence of a posterior comminution (type B according to Dubberley classification) can represent a negative risk factor for treatment and prognosis respect to the type A cases (without posterior comminution). Nevertheless, how this parameter impacts the treatment and the prognosis has never been quantified before. MATERIALS AND METHODS: All the capitellar and trochlear fractures treated from 2007 to 2015 have been retrospectively reviewed. The presence of posterior comminution on a pre operative CT-scan was correlated to the surgical technique, to the timing of initiation of rehabilitation and to clinical outcomes. RESULTS: 45 Consecutive patients have been selected, 17 not presenting a posterior comminution (type A), and 28 with posterior comminution (type B). In all the type A fractures a lateral approach (Kocher o Kocher extensile) was used and the fragment fixation was always performed using only screws. Elbow replacement or olecranon osteotomy were performed only to treat type B fractures. Augmented fixations, using plates and k wires, or prosthetic replacement have been used only in type B fractures. The post-operative immobilization was significantly inferior for type A fracture. Better results have been obtained in type A fractures: mean MEPI score was 86 in type A and 73 in type B, the range of motion was significatively higher in type A both in flexion-extension and in pronation-supination. In type B fractures a significant higher number of complications have been observed (64% vs 29%) along with more reoperations. DISCUSSION: The study has confirmed that, even without considering the extension of the fracture on the coronal plane, the presence of posterior comminution represents an evident negative risk factor, influencing the surgical approach and treatment, the fixation technique, the post-operative rehabilitation, the clinical outcomes, the complications and re-operation rates. CONCLUSIONS: The analysis of the present case series shows how the treatment and the outcomes can be significantly anticipated based on the presence or absence of posterior comminution. Patients with type A fracture are more likely treated with a Kocher approach, screw fixation, an early rehabilitation is performed. In type A fractures better outcomes and low complications rate are expected. PMID- 30415678 TI - ? PMID- 30415676 TI - Balloon-assisted reduction, pin fixation and tricalcium phosphate augmentation for calcaneal fracture: A retrospective analysis of 42 patients. AB - INTRODUCTION: The treatment of intra-articular calcaneal fractures is still complex and controversial. Although open reduction and internal fixation (ORIF) is favored by many authors, several percutaneous techniques have been introduced to reduce complications and to obtain satisfactory clinical and radiological results. Among these percutaneous treatments, balloon reduction and bone graft augmentation is gaining an increasing popularity. MATERIALS AND METHODS: We retrospectively examined a series of 42 patients treated operatively with a minimally invasive reduction technique using an inflatable bone tamp filled with tricalcium phosphate (calcaneoplasty) for Sander's type II, III and IV calcaneal fractures between 2010 and 2015. Conventional X-rays and CT scan were performed pre-operatively, at 3 and 12 months post-operatively and at the last-follow-up. The American Orthopaedic Foot and Ankle Society (AOFAS) score and the Maryland Foot Score (MFS) were used for clinical evaluation. Bohler's angle and the Score Analysis of Verona (SAVE) were calculated to assess bone reduction. RESULTS: All 42 patients were available for clinical and radiographic follow-up at an average of 665 months (range 38-92). At the last follow-up the mean AOFAS score was 82.1 (good) and the mean MFS was 80.8 (good). The mean Bohler's angle improved from 1.29 degrees pre-operatively to 27.8 degrees at the last follow-up. The SAVE highlighted good and excellent results in 30 (72%) patients. There were only 3 (7.1%) cases of superficial skin infection with only 6 (14.2%) patients complaining of residual pain. No cases of adverse reaction or deep infection were observed. CONCLUSIONS: Calcaneoplasty appears to be a valid option of treatment for calcaneal fractures and a reliable alternative to ORIF. This technique allows stable fracture reduction and early weight-bearing combined with good clinical and radiological results and few complications. PMID- 30415679 TI - ? PMID- 30415680 TI - [Restraint in geriatric care, an overview]. AB - Restraint is a deprivation of liberty which in certain, clearly codified situations is a necessary part of the care process. The multidisciplinary objective evaluation of the risk/benefit ratio must take into consideration the person's dignity. The situation is often encountered in geriatric care where the fundamental principles are the maintaining of autonomy or the functional improvement of the patient or resident. PMID- 30415681 TI - [Restraint in geriatric care, pharmacological and non-pharmacological approaches]. AB - Restraint in geriatric care is not a trivial act. It must be regulated, performed in accordance with best practice guidelines and respect patients' fundamental rights. It requires initial evaluation as well as daily re-evaluation. An alternative must always be considered by the whole team, which should be mindful of its responsibility and its sense of ethics. PMID- 30415682 TI - [The use and consequences of physical restraint in geriatric care]. AB - The use of physical restraint with the elderly remains a much-debated topic. Its use remains criticised and is also something of a paradox given its practice in this kind of facilities. All health professionals may use it in their daily practice, in a wide variety of situations. PMID- 30415683 TI - [Restraint in geriatric care and caregivers' self-examination]. AB - The practice of restraint in geriatric care leads caregivers to examine their own practice. It is a matter of respecting the elderly patient while assuring their safety and being true to one's professional values. Reflecting on the issue collectively as a team is a potential strategy for providing the best possible response. This article analyses some examples at Grenoble-Alpes University hospital. PMID- 30415684 TI - [Philosophical reflection on restraint]. AB - The caregiver is very much involved in implementing restraint. This act, which is not trivial, lies at the crossroads of the notion of dignity, respect, violence, consent. Restraint can be considered through the prism of philosophy questioning our own humanity. PMID- 30415685 TI - [Restraint in nursing homes, the psychologist's point of view]. AB - With regard to restraint, the caregiving teams are confronted on a daily basis with various issues which reveal a clash between the respect of a person's rights and dignity and the need to protect and provide a safe environment. The triangular relationship between the resident, their family and the multidisciplinary caregiving team can result in the construction of a response to this dilemma between liberty and safety. PMID- 30415686 TI - [Communication technologies, time pressure and the right to disconnect]. AB - Essential tools in the constant race against time endured by companies, communication technologies also bring with them a new time pressure, emergency situations and information overload which can lead to new types of disorders, stress and sometimes burnout. One of the ways to escape these negative consequences is to implement sustainable practices within the telecommunications environment, in particular through the creation of a time buffer zone and the opportunity to partially disconnect. PMID- 30415687 TI - [Educating patients with chronic conditions cared for at home, a nursing initiative in Marseille]. AB - Drawing on her hospital expertise in pulmonology, a currently private practice nurse describes her work supporting patients with chronic obstructive pulmonary disease in their home. In collaboration with hospital- and community-based teams, she uses a support tool to formalise therapeutic education sessions. PMID- 30415688 TI - [Initial management of foot wounds]. AB - Foot wounds are frequent and not usually serious. The first caregiver to provide treatment must decide on the most appropriate action to take, sometimes in inadequate places. We present an analysis of the management of these traumas to highlight the key stages of the evaluation and initial treatment of the wound while placing the patient on a coherent and efficient clinical pathway. PMID- 30415689 TI - [Pain assessment: a duty in daily practice]. AB - An analysis of pain management was carried out on a general medicine ward. A task force was thereby created in order to identify the issues surrounding this management and suggest improvements. Collaboration between the different participants resulted in actions involving all of the professionals working on the ward. The evaluation of the effectiveness of these actions is envisaged, as a conclusion to two years of fruitful learning. PMID- 30415690 TI - [Raising awareness of organised breast cancer screening]. AB - Student nurses in eastern France have organised, in collaboration with local nonprofit organisations, awareness raising actions to promote breast cancer screening. Working very closely with female populations, undertaking highly personal questioning, diverging representations and beliefs were some of the difficulties these students had to manage as part of these preventive and educational care missions. PMID- 30415691 TI - A baby immunisation clinic in primary care. AB - Eliza is a practice nurse in a large general practice in England. Today she is running a baby immunisation clinic. Amanda, a first time mother, is bringing Lisa, her 8 week old baby for her primary course of immunisations. Lisa has previously been examined by the doctor and had her 6 week routine check-up. She is a healthy baby, born at term and there are no contra indications to the immunisation programme. PMID- 30415692 TI - ? PMID- 30415693 TI - ? PMID- 30415694 TI - ? PMID- 30415695 TI - ? PMID- 30415696 TI - Reply to "Are decision support systems accurately guide physicians caring patients with advanced disease?" PMID- 30415697 TI - Early anomaly detection in smart home: A causal association rule-based approach. AB - As the world's population grows older, an increasing number of people are facing health issues. For the elderly, living alone can be difficult and dangerous. Consequently, smart homes are becoming increasingly popular. A sensor-rich environment can be exploited for healthcare applications, in particular, anomaly detection (AD). The literature review for this paper showed that few works consider environmental factors to detect anomalies. Instead, the focus is on user activity and checking whether it is abnormal, i.e., does not conform to expected behavior. Furthermore, reducing the number of anomalies using early detection is a major issue in many applications. In this context, anomaly-cause discovery may be helpful in recommending actions that may prevent risk. In this paper, we present a novel approach for detecting the risk of anomalies occurring in the environment regarding user activities. The method relies on anomaly-cause extraction from a given dataset using causal association rules mining. These anomaly causes are utilized afterward for real-time analysis to detect the risk of anomalies using the Markov logic network machine learning method. The detected risk allows the method to recommend suitable actions to perform in order to avoid the occurrence of an actual anomaly. The proposed approach is implemented, tested, and evaluated for each contribution using real data obtained from an intelligent environment platform and real data from a clinical datasets. Experimental results prove our approach to be efficient in terms of recognition rate. PMID- 30415698 TI - The Diverged Trypanosome MICOS Complex as a Hub for Mitochondrial Cristae Shaping and Protein Import. AB - The mitochondrial contact site and cristae organization system (MICOS) is a multiprotein complex responsible for cristae formation. Even though cristae are found in all mitochondria capable of oxidative phosphorylation, only Mic10 and Mic60 appear to be conserved throughout eukaryotes. The remaining 4 or 5 known MICOS subunits are specific to the supergroup Opisthokonta, which includes yeast and mammals that are the only organisms in which this complex has been analyzed experimentally. We have isolated the MICOS from Trypanosoma brucei, a member of the supergroup Excavata that is profoundly diverged from opisthokonts. We show that it is required for the maintenance of the unique discoidal cristae that typify excavates, such as euglenids and kinetoplastids, the latter of which include trypanosomes. The trypanosome MICOS consists of 9 subunits, most of which are essential for normal growth. Unlike in opisthokonts, it contains two distinct Mic10 orthologs and an unconventional putative Mic60 that lacks a mitofilin domain. Interestingly, one of the essential trypanosomatid-specific MICOS subunits called TbMic20 is a thioredoxin-like protein that appears to be involved in import of intermembrane space proteins, including respiratory chain complex assembly factors. This result points to trypanosome MICOS coordinating cristae shaping and population of its membrane with proteins involved in respiration, the latter via the catalytic activity of TbMic20. Thus, trypanosome MICOS allows us to define which of its features are conserved in all eukaryotes and decipher those that represent lineage-specific adaptations. PMID- 30415699 TI - Self-Assembly of the RZZ Complex into Filaments Drives Kinetochore Expansion in the Absence of Microtubule Attachment. AB - The kinetochore is a dynamic multi-protein assembly that forms on each sister chromatid and interacts with microtubules of the mitotic spindle to drive chromosome segregation. In animals, kinetochores without attached microtubules expand their outermost layer into crescent and ring shapes to promote microtubule capture and spindle assembly checkpoint (SAC) signaling. Kinetochore expansion is an example of protein co-polymerization, but the mechanism is not understood. Here, we present evidence that kinetochore expansion is driven by oligomerization of the Rod-Zw10-Zwilch (RZZ) complex, an outer kinetochore component that recruits the motor dynein and the SAC proteins Mad1-Mad2. Depletion of ROD in human cells suppresses kinetochore expansion, as does depletion of Spindly, the adaptor that connects RZZ to dynein, although dynein itself is dispensable. Expansion is also suppressed by mutating ZWILCH residues implicated in Spindly binding. Conversely, supplying cells with excess ROD facilitates kinetochore expansion under otherwise prohibitive conditions. Using the C. elegans early embryo, we demonstrate that ROD-1 has a concentration-dependent propensity for oligomerizing into micrometer-scale filaments, and we identify the ROD-1 beta propeller as a key regulator of self-assembly. Finally, we show that a minimal ROD-1-Zw10 complex efficiently oligomerizes into filaments in vitro. Our results suggest that RZZ's capacity for oligomerization is harnessed by kinetochores to assemble the expanded outermost domain, in which RZZ filaments serve as recruitment platforms for SAC components and microtubule-binding proteins. Thus, we propose that reversible RZZ self-assembly into filaments underlies the adaptive change in kinetochore size that contributes to chromosome segregation fidelity. PMID- 30415700 TI - Distinct Roles of RZZ and Bub1-KNL1 in Mitotic Checkpoint Signaling and Kinetochore Expansion. AB - The Mad1-Mad2 heterodimer is the catalytic hub of the spindle assembly checkpoint (SAC), which controls M phase progression through a multi-subunit anaphase inhibitor, the mitotic checkpoint complex (MCC) [1, 2]. During interphase, Mad1 Mad2 generates MCC at nuclear pores [3]. After nuclear envelope breakdown (NEBD), kinetochore-associated Mad1-Mad2 catalyzes MCC assembly until all chromosomes achieve bipolar attachment [1, 2]. Mad1-Mad2 and other factors are also incorporated into the fibrous corona, a phospho-dependent expansion of the outer kinetochore that precedes microtubule attachment [4-6]. The factor(s) involved in targeting Mad1-Mad2 to kinetochores in higher eukaryotes remain controversial [7 12], and the specific phosphorylation event(s) that trigger corona formation remain elusive [5, 13]. We used genome editing to eliminate Bub1, KNL1, and the Rod-Zw10-Zwilch (RZZ) complex in human cells. We show that RZZ's sole role in SAC activation is to tether Mad1-Mad2 to kinetochores. Separately, Mps1 kinase triggers fibrous corona formation by phosphorylating two N-terminal sites on Rod. In contrast, Bub1 and KNL1 activate kinetochore-bound Mad1-Mad2 to produce a "wait anaphase" signal but are not required for corona formation. We also show that clonal lines isolated after BUB1 disruption recover Bub1 expression and SAC function through nonsense-associated alternative splicing (NAS). Our study reveals a fundamental division of labor in the mammalian SAC and highlights a transcriptional response to nonsense mutations that can reduce or eliminate penetrance in genome editing experiments. PMID- 30415701 TI - Genetic Interactions between the Aurora Kinases Reveal New Requirements for AURKB and AURKC during Oocyte Meiosis. AB - Errors in chromosome segregation during female meiosis I occur frequently, and aneuploid embryos account for 1/3 of all miscarriages in humans [1]. Unlike mitotic cells that require two Aurora kinase (AURK) homologs to help prevent aneuploidy (AURKA and AURKB), mammalian germ cells also require a third (AURKC) [2, 3]. AURKA is the spindle-pole-associated homolog, and AURKB/C are the chromosome-localized homologs. In mitosis, AURKB has essential roles as the catalytic subunit of the chromosomal passenger complex (CPC), regulating chromosome alignment, kinetochore-microtubule attachments, cohesion, the spindle assembly checkpoint, and cytokinesis [4, 5]. In mouse oocyte meiosis, AURKC takes over as the predominant CPC kinase [6], although the requirement for AURKB remains elusive [7]. In the absence of AURKC, AURKB compensates, making defining potential non-overlapping functions difficult [6, 8]. To investigate the role(s) of AURKB and AURKC in oocytes, we analyzed oocyte-specific Aurkb and Aurkc single and double-knockout (KO) mice. Surprisingly, we find that double KO female mice are fertile. We demonstrate that, in the absence of AURKC, AURKA localizes to chromosomes in a CPC-dependent manner. These data suggest that AURKC prevents AURKA from localizing to chromosomes by competing for CPC binding. This competition is important for adequate spindle length to support meiosis I. We also describe a unique requirement for AURKB to negatively regulate AURKC to prevent aneuploidy. Together, our work reveals oocyte-specific roles for the AURKs in regulating each other's localization and activity. This inter-kinase regulation is critical to support wild-type levels of fecundity in female mice. PMID- 30415702 TI - Aristaless Controls Butterfly Wing Color Variation Used in Mimicry and Mate Choice. AB - Neotropical Heliconius butterflies display a diversity of warningly colored wing patterns, which serve roles in both Mullerian mimicry and mate choice behavior. Wing pattern diversity in Heliconius is controlled by a small number of unlinked, Mendelian "switch" loci [1]. One of these, termed the K locus, switches between yellow and white color patterns, important mimicry signals as well as mating cues [2-4]. Furthermore, mate preference behavior is tightly linked to this locus [4]. K controls the distribution of white versus yellow scales on the wing, with a dominant white allele and a recessive yellow allele. Here, we combine fine-scale genetic mapping, genome-wide association studies, gene expression analyses, population and comparative genomics, and genome editing with CRISPR/Cas9 to characterize the molecular basis of the K locus in Heliconius and to infer its evolutionary history. We show that white versus yellow color variation in Heliconius cydno is due to alternate haplotypes at a putative cis-regulatory element (CRE) downstream of a tandem duplication of the homeodomain transcription factor aristaless. Aristaless1 (al1) and aristaless2 (al2) are differentially regulated between white and yellow wings throughout development with elevated expression of al1 in developing white wings, suggesting a role in repressing pigmentation. Consistent with this, knockout of al1 causes white wings to become yellow. The evolution of wing color in this group has been marked by retention of the ancestral yellow color in many lineages, a single origin of white coloration in H. cydno, and subsequent introgression of white color from H. cydno into H. melpomene. PMID- 30415703 TI - Stimulus-Driven Cortical Hyperexcitability in Individuals with Charles Bonnet Hallucinations. AB - Throughout the lifespan, the cerebral cortex adapts its structure and function in response to changing sensory input [1, 2]. Whilst such changes are typically adaptive, they can be maladaptive when they follow damage to the peripheral nervous system, including phantom limb pain and tinnitus [3, 4]. An intriguing example occurs in individuals with acquired ocular pathologies-most commonly age related macular degeneration (MD) [5]-who lose their foveal vision but retain intact acuity in the peripheral visual field. Up to 40% of ocular pathology patients develop long-term hallucinations involving flashes of light, shapes, or geometric patterns and/or complex hallucinations, including faces, animals, or entire scenes, a condition known as Charles Bonnet Syndrome (CBS) [6, 7, 8]. Though CBS was first described over 250 years ago [9, 10], the neural basis for the hallucinations remains unclear, with no satisfactory explanation as to why some individuals develop hallucinations, while many do not. An influential but untested hypothesis for the visual hallucinations in CBS is that retinal deafferentation causes hyperexcitability in early visual cortex. To assess this, we investigated electrophysiological responses to peripheral visual field stimulation in MD patients with and without hallucinations and in matched controls without ocular pathology. Participants performed a concurrent attention task within intact portions of their peripheral visual field, while ignoring flickering checkerboards that drove periodic electrophysiological responses. CBS individuals showed strikingly elevated visual cortical responses to peripheral field stimulation compared with patients without hallucinations and controls, providing direct support for the hypothesis of visual cortical hyperexcitability in CBS. PMID- 30415706 TI - Silent Learning. AB - We introduce the concept of "silent learning"-the capacity to learn despite neuronal cell-firing being largely absent. This idea emerged from thinking about dendritic computation [1, 2] and examining whether the encoding, expression, and retrieval of hippocampal-dependent memory could be dissociated using the intrahippocampal infusion of pharmacological compounds. We observed that very modest enhancement of GABAergic inhibition with low-dose muscimol blocked both cell-firing and the retrieval of an already-formed memory but left induction of long-term potentiation (LTP) and new spatial memory encoding intact (silent learning). In contrast, blockade of hippocampal NMDA receptors by intrahippocampal D-AP5 impaired both the induction of LTP and encoding but had no effect on memory retrieval. Blockade of AMPA receptors by CNQX impaired excitatory synaptic transmission and cell-firing and both memory encoding and retrieval. Thus, in keeping with the synaptic plasticity and memory hypothesis [3], the hippocampal network can mediate new memory encoding when LTP induction is intact even under conditions in which somatic cell-firing is blocked. PMID- 30415707 TI - Re: The relationships among physical activity, sedentary behaviour, obesity and quitting behaviours within a cohort of smokers in California. PMID- 30415705 TI - Purging of Strongly Deleterious Mutations Explains Long-Term Persistence and Absence of Inbreeding Depression in Island Foxes. AB - The recovery and persistence of rare and endangered species are often threatened by genetic factors, such as the accumulation of deleterious mutations, loss of adaptive potential, and inbreeding depression [1]. Island foxes (Urocyon littoralis), the dwarfed descendants of mainland gray foxes (Urocyon cinereoargenteus), have inhabited California's Channel Islands for >9,000 years [2-4]. Previous genomic analyses revealed that island foxes have exceptionally low levels of diversity and elevated levels of putatively deleterious variation [5]. Nonetheless, all six populations have persisted for thousands of generations, and several populations rebounded rapidly after recent severe bottlenecks [6, 7]. Here, we combine morphological and genomic data with population-genetic simulations to determine the mechanism underlying the enigmatic persistence of these foxes. First, through analysis of genomes from 1929 to 2009, we show that island foxes have remained at small population sizes with low diversity for many generations. Second, we present morphological data indicating an absence of inbreeding depression in island foxes, confirming that they are not afflicted with congenital defects common to other small and inbred populations. Lastly, our population-genetic simulations suggest that long-term small population size results in a reduced burden of strongly deleterious recessive alleles, providing a mechanism for the absence of inbreeding depression in island foxes. Importantly, the island fox illustrates a scenario in which genetic restoration through human-assisted gene flow could be a counterproductive or even harmful conservation strategy. Our study sheds light on the puzzle of island fox persistence, a unique success story that provides a model for the preservation of small populations. PMID- 30415704 TI - Effective Glucose Uptake by Human Astrocytes Requires Its Sequestration in the Endoplasmic Reticulum by Glucose-6-Phosphatase-beta. AB - After its uptake into the cytosol, intracellular glucose is phosphorylated to glucose-6-phosphate (G6P), trapping it within the cell and preparing it for metabolism. In glucose-exporting tissues, like liver, G6P is transported into the ER, where it is dephosphorylated by G6Pase-alpha. The glucose is then returned to the cytosol for export [1, 2]. Defects in these pathways cause glycogen storage diseases [1]. G6Pase-beta, an isozyme of G6Pase-alpha, is widely expressed [3, 4]. Its role in cells that do not export glucose is unclear, although mutations in G6Pase-beta cause severe and widespread abnormalities [5-7]. Astrocytes, the most abundant cells in the brain, provide metabolic support to neurons, facilitated by astrocytic endfeet that contact blood capillaries or neurons [8 12]. Perivascular endfeet are the main site of glucose uptake by astrocytes [13], but in human brain they may be several millimeters away from the perineuronal processes [14]. We show that cultured human fetal astrocytes express G6Pase-beta, but not G6Pase-alpha. ER-targeted glucose sensors [15, 16] reveal that G6Pase beta allows the ER of human astrocytes to accumulate glucose by importing G6P from the cytosol. Glucose uptake by astrocytes, ATP production, and Ca2+ accumulation by the ER are attenuated after knockdown of G6Pase-beta using lentivirus-delivered shRNA and substantially rescued by expression of G6Pase alpha. We suggest that G6Pase-beta activity allows effective uptake of glucose by astrocytes, and we speculate that it allows the ER to function as an intracellular "highway" delivering glucose from perivascular endfeet to the perisynaptic processes. PMID- 30415708 TI - Re: Letter to the Editor of Public Health in response to 'The relationships among physical activity, sedentary behaviour, obesity, and quitting behaviours within a cohort of smokers in California'. PMID- 30415709 TI - Generating amorphous target margins in radiation therapy to promote maximal target coverage with minimal target size. AB - BACKGROUND AND SIGNIFICANCE: This work provides proof-of-principle for two versions of a heuristic approach that automatically creates amorphous radiation therapy planning target volume (PTV) margins considering local effects of tumor shape and motion to ensure adequate voxel coverage with while striving to minimize PTV size. The resulting target thereby promotes disease control while minimizing the risk of normal tissue toxicity. METHODS: This work describes the mixed-PDF algorithm and the independent-PDF algorithm which generate amorphous margins around a radiation therapy target by incorporating user-defined models of target motion. Both algorithms were applied to example targets - one circular and one "cashew-shaped." Target motion was modeled by four probability density functions applied to the target quadrants. The spatially variant motion model illustrates the application of the algorithms even with tissue deformation. Performance of the margins was evaluated in silico with respect to voxelized target coverage and PTV size, and was compared to conventional techniques: a threshold-based probabilistic technique and an (an)isotropic expansion technique. To demonstrate the algorithm's clinical utility, a lung cancer patient was analyzed retrospectively. For this case, 4D CT measurements were combined with setup uncertainty to compare the PTV from the mixed-PDF algorithm with a PTV equivalent to the one used clinically. RESULTS: For both targets, the mixed-PDF algorithm performed best, followed by the independent-PDF algorithm, the threshold algorithm, and lastly, the (an)isotropic algorithm. Superior coverage was always achieved by the amorphous margin algorithms for a given PTV size. Alternatively, the margin required for a particular level of coverage was always smaller (8-15%) when created with the amorphous algorithms. For the lung cancer patient, the mixed-PDF algorithm resulted in a PTV that was 13% smaller than the clinical PTV while still achieving >=99.9% coverage. CONCLUSIONS: The amorphous margin algorithms are better suited for the local effects of target shape and positional uncertainties than conventional margins. As a result, they provide superior target coverage with smaller PTVs, ensuring dose delivered to the target while decreasing the risk of normal tissue toxicity. PMID- 30415710 TI - Classification of auditory selective attention using spatial coherence and modular attention index. AB - BACKGROUND AND OBJECTIVE: Brain-Computer Interfaces (BCIs) based on auditory selective attention have been receiving much attention because i) they are useful for completely paralyzed users since they do not require muscular effort or gaze and ii) focusing attention is a natural human ability. Several techniques - such as recently developed Spatial Coherence (SC) - have been proposed in order to optimize the BCI procedure. Thus, this work aims at investigating and comparing two strategies based on spatial coherence detection: contralateral and modular classifiers. The latter is a new method using modular attention index. The new classifier was developed to implement an auditory BCI where a volunteer makes binary choices using selective attention under the amplitude-modulated tones stimulation. METHODS: Contralateral and modular classifiers were applied to the electroencephalogram (EEG) recorded from 144 subjects under the BCI protocol. The best set of parameters (carriers of the stimulus, channels and trials of signal) for this BCI was investigated taking into consideration the hit rate and the information transfer rate. RESULTS: The best result obtained using the modular classifier was a hit rate of 91.67% and information transfer rate of 6.74 bits/min using 0.5 kHz/4.0 kHz as stimuli and three windows (5.10 sec of EEG signal). These results were obtained with five electrodes (C3, P3, F8, P4, O2) using exhaustive search to identify regions with greater coherence. CONCLUSION: The modular classifier - using electroencephalogram channels from the central, frontal, occipital and parietal areas - improves the performance of auditory BCIs based on selective attention. PMID- 30415711 TI - Application of multiscale Poincare short-time computation versus multiscale entropy in analyzing fingertip photoplethysmogram amplitudes to differentiate diabetic from non-diabetic subjects. AB - BACKGROUND AND OBJECTIVES: Multiscale Poincare (MSP) plots have recently been introduced to facilitate the visualization of time series of physiological signals. This study aimed at investigating the feasibility of MSP application in distinguishing subjects with and without diabetes. METHODS: Using photoplethysmogram (PPG) waveform amplitudes acquired from unilateral fingertip of non-diabetic (n = 34) and diabetic (n = 30) subjects, MSP indices (MSPI) of the two groups were compared using 1000, 500, 250, 100 data points. Data from Poincare index (short-term variability/long-term variability [i.e. SD1/SD2] ratio, SSR) and multiscale entropy (MSE) were also obtained with the four corresponding data points for comparison. RESULTS: SSR and MSPI were both negatively related to glycated hemoglobin (HbA1c) and fasting blood sugar levels. Significant negative correlation was also noted between MSPI and pulse pressure. When only 500 and 250 data points were included, significant elevations in the non-diabetic group were only noted in MSPI (both p < 0.01). Furthermore, MSPI was significantly higher in non-diabetic than that in diabetic subjects on all scales (i.e., 1-10) but not using MSE when utilizing 1000 data points. CONCLUSIONS: The results demonstrated enhanced sensitivity of MSP in differentiating between non diabetic and diabetic subjects compared to SSR and MSE, highlighting the feasibility of MSP application in biomedical data analysis to reduce computational time and enhance sensitivity. PMID- 30415712 TI - An improved support vector machine-based diabetic readmission prediction. AB - BACKGROUND AND OBJECTIVE: In healthcare systems, the cost of unplanned readmission accounts for a large proportion of total hospital payment. Hospital specific readmission rate becomes a critical issue around the world. Quantification and early identification of unplanned readmission risks will improve the quality of care during hospitalization and reduce the occurrence of readmission. In clinical practice, medical workers generally use LACE score method to evaluate patient readmission risks, but this method usually performs poorly. With this in mind, this study presents a novel method combining support vector machine and genetic algorithm to build the risk prediction model, which simultaneously involves feature selection and the processing of imbalanced data. This model aims to provide decision support for clinicians during the discharge management of patients with diabetes. METHOD: The experiments were conducted from a set of 8756 medical records with 50 different features about diabetic readmission. After preprocessing the data, an effective SMOTE-based method was proposed to solve the imbalance data problem. Further, in order to improve prediction performance, a hybrid feature selection mechanism was devised to select the important features. Subsequently, an improved support vector machine based (SVM-based) method was developed and the genetic algorithm was used to tune the sensitive parameter of the algorithm. Finally, the five-fold cross-validation method was applied to compare the performance of proposed method with other methods (LACE score, logistic regression, naive bayes, decision tree and feed forward neural networks). RESULTS: Experimental results indicate that the proposed SVM-based method achieves an accuracy of 81.02%, a sensitivity of 82.89%, a specificity of 79.23%, and outperforms other popular algorithms in identifying diabetic patients who may be readmitted. CONCLUSIONS: Our research can improve the performance of clinic decision support systems for diabetic readmission, by which the readmission possibility as well as the waste of medical resources can be reduced. PMID- 30415713 TI - Towards an efficient and Energy-Aware mobile big health data architecture. AB - BACKGROUND AND OBJECTIVES: Mobile and ubiquitous devices are everywhere, generating an exorbitant amount of data. New generations of healthcare systems are using mobile devices to continuously collect large amounts of different types of data from patients with chronic diseases. The challenge with such Mobile Big Data in general, is how to meet the growing performance demands of the mobile resources handling these tasks, while simultaneously minimizing their consumption. METHODS: This research proposes a scalable architecture for processing Mobile Big Data. The architecture is developed around three new algorithms for the effective use of resources in performing mobile data processing and analytics: mobile resources optimization, mobile analytics customization, and mobile offloading. The mobile resources optimization algorithm monitors resources and automatically switches off unused network connections and application services whenever resources are limited. The mobile analytics customization algorithm attempts to save energy by customizing the analytics processes through the implementation of some data-aware schemes. Finally, the mobile offloading algorithm uses some heuristics to intelligently decide whether to process data locally, or delegate it to a cloud back-end server. RESULTS: The three algorithms mentioned above are tested using Android-based mobile devices on real Electroencephalography (EEG) data streams retrieved from sensors and an online data bank. Results show that the three combined algorithms proved their effectiveness in optimizing the resources of mobile devices in handling, processing, and analyzing EEG data. CONCLUSION: We developed an energy-efficient model for Mobile Big Data which addressed key limitations in mobile device processing and analytics and reduced execution time and limited battery resources. This was supported with the development of three new algorithms for the effective use of resources, energy saving, parallel processing and analytics customization. PMID- 30415714 TI - Global optimal constrained ICA and its application in extraction of movement related cortical potentials from single-trial EEG signals. AB - BACKGROUND AND OBJECTIVE: The constrained ICA (cICA) is a recent approach which can extract the desired source signal by using prior information. cICA employs gradient-based algorithms to optimize non convex objective functions and therefore global optimum solution is not guaranteed. In this study, we propose the Global optimal constrained ICA (GocICA) algorithm for solving the conventional cICA problems. Due to the importance of movement related cortical potentials (MRCPs) for neurorehabilitation and developing a suitable mechanism for detection of movement intention, single-trial MRCP extraction is presented as an application of GocICA. METHODS: In order to evaluate the performance of the proposed technique, two kinds of datasets including simulated and real EEG data have been utilized in this paper. The GocICA method has been implemented based on the most popular meta-heuristic optimization algorithms such as Genetic Algorithm (GA), Particle Swarm Optimization (PSO) and Charged System Search (CSS) where the results have been compared with those of conventional cICA and two ICA-based methods (JADE and Infomax). RESULTS: It was found that GocICA enhanced the extracted MRCP from multi-channel EEG better than both conventional cICA and ICA based methods and also outperformed them in single-trial MRCP detection with higher true positive rates (TPRs) and lower false positive rates (FPRs). Moreover, CSS-cICA resulted in the greatest TPR (91.2232 +/- 3.4708) and the lowest FPR (8.7465 +/- 3.7705) for single-trial MRCP detection from real EEG data and the greatest signal-to-noise ratio (SNR) (39.2818) and the lowest mean square error (MSE) and individual performance index (IPI) (41.8230 and 0.0012, respectively) for single-trial MRCP extraction from simulated EEG data. CONCLUSIONS: These results confirm the superiority of GocICA with respect to conventional cICA that is due to the ability of meta-heuristic optimization algorithms to escape from local optimal point. As such, GocICA is a promising new algorithm for single-trial MRCP detection which can be used for detecting other types of event related cortical potentials (ERPs) such as P300 and also for EEG artifact removal. PMID- 30415715 TI - Trends and characteristics of global medical informatics conferences from 2007 to 2017: A bibliometric comparison of conference publications from Chinese, American, European and the Global Conferences. AB - BACKGROUND: As the second-largest economy in the world, China has invested considerable financial and policy support into hospital informatization since health care reform in 2010. However, the results and experience of such investments have not been compared with relevant research and applications in the United States and Europe. OBJECTIVES: From the perspective of professional conference proceedings, we comparatively analyzed the current situations, characteristics, hotspots, and trends of medical informatics (MI) development in China, the United States and Europe to help Chinese MI researchers and practitioners summarize their experiences and determine gaps compared to their American and European peers. We also aimed to educate foreign peers about the special contributions of the China MI circle and facilitate multilevel international cooperation. METHODS: English conference proceedings of the American Medical Informatics Association (AMIA) Annual Symposium (USA), Medical Informatics Europe (MIE, Europe) and World Conference on Medical Informatics (MEDINFO, Global) from 2007 to 2017 were searched within Scopus and Pubmed. Proceedings of Chinese MI conferences (CMIAAS, CHINC, CHITEC, CPMI) (China) were searched within Chinese databases CQVIP, CNKI and WanFang during the same period. The datasets were preprocessed via a Natural Language Processing (NLP) package on Python and were qualitatively and quantitatively analyzed via bibliometric methods. RESULTS: Overall, 2285, 1601, 1930 and 5431 papers were publicized from the AMIA Symposium (USA), MIE (Europe), MEDINFO (Global) and Chinese MI conferences (China) between 2007 and 2017, respectively, with an H-index of 32, 19, 19 and 3, respectively. The AMIA Symposium, MIE and MEDINFO received submissions from 43, 68 and 80 countries (or regions), respectively, but Chinese MI conferences (CMIAAS, CHINC, CHITEC, CPMI) only received submissions from 3 foreign countries. Author affiliations were quite similar among the AMIA Symposium, MIE and MEDINFO, as 67%, 75% and 70% of authors came from universities/colleges, respectively; 18%, 10% and 11% came from medical institutions, respectively; and 7%, 8% and 10% came from institutes, respectively. In contrast, the majority (54%) of authors in Chinese MI conferences came from medical institutions followed by universities/colleges (17%) and institutes (10%). Of the top 5 authors with the most publications in AMIA Symposium, MIE and MEDINFO, 14/15 of them had medical backgrounds, but only one author from the Chinese MI conferences majored in medicine. Electronic medical records (EMR) were included in the top 10 high-frequency keywords by all four conference groups, but the amount of time that this keyword appeared differed in 2009, 2011, 2012 and 2013, respectively. CONCLUSIONS: The MI annual conferences are all different among China, the United States and Europe. China lags in the theoretical and discipline bases but has made considerable investments in the past 10 years. China should fully use its second-mover advantage and application advantages and utilize international experiences and cooperation to make stronger contributions to global MI development. PMID- 30415716 TI - Fusion based Glioma brain tumor detection and segmentation using ANFIS classification. AB - The detection of tumor regions in Glioma brain image is a challenging task due to its low sensitive boundary pixels. In this paper, Non-Sub sampled Contourlet Transform (NSCT) is used to enhance the brain image and then texture features are extracted from the enhanced brain image. These extracted features are trained and classified using Adaptive Neuro Fuzzy Inference System (ANFIS) approach to classify the brain image into normal and Glioma brain image. Then, the tumor regions in Glioma brain image is segmented using morphological functions. The proposed Glioma brain tumor detection methodology is applied on the Brain Tumor image Segmentation challenge (BRATS) open access dataset in order to evaluate the performance. PMID- 30415717 TI - Fully Automatic Brain Tumor Segmentation using End-To-End Incremental Deep Neural Networks in MRI images. AB - BACKGROUND AND OBJECTIVE: Nowadays, getting an efficient Brain Tumor Segmentation in Multi-Sequence MR images as soon as possible, gives an early clinical diagnosis, treatment and follow-up. The aim of this study is to develop a new deep learning model for the segmentation of brain tumors. The proposed models are used to segment the brain tumors of Glioblastomas (with both high and low grade). Glioblastomas have four properties: different sizes, shapes, contrasts, in addition, Glioblastomas appear anywhere in the brain. METHODS: In this paper, we propose three end-to-end Incremental Deep Convolutional Neural Networks models for fully automatic Brain Tumor Segmentation. Our proposed models are different from the other CNNs-based models that follow the technique of trial and error process which does not use any guided approach to get the suitable hyper parameters. Moreover, we adopt the technique of Ensemble Learning to design a more efficient model. For solving the problem of training CNNs model, we propose a new training strategy which takes into account the most influencing hyper parameters by bounding and setting a roof to these hyper-parameters to accelerate the training. RESULTS: Our experiment results reported on BRATS-2017 dataset. The proposed deep learning models achieve the state-of-the-art performance without any post-processing operations. Indeed, our models achieve in average 0.88 Dice score over the complete region. Moreover, the efficient design with the advantage of GPU implementation, allows our three deep learning models to achieve brain segmentation results in average 20.87 s. CONCLUSIONS: The proposed deep learning models are effective for the segmentation of brain tumors and allow to obtain high accurate results. Moreover, the proposed models could help the physician experts to reduce the time of diagnostic. PMID- 30415718 TI - Diagnosis of urinary tract infection based on artificial intelligence methods. AB - BACKGROUND AND OBJECTIVE: Urinary tract infection (UTI) is a common disease affecting the vast majority of people. UTI involves a simple infection caused by urinary tract inflammation as well as a complicated infection that may be caused by an inflammation of other urinary tract organs. Since all of these infections have similar symptoms, it is difficult to identify the cause of primary infection. Therefore, it is not easy to diagnose a UTI with routine examination procedures. Invasive methods that require surgery could be necessary. This study aims to develop an artificial intelligence model to support the diagnosis of UTI with complex symptoms. METHODS: Firstly, routine examination data and definitive diagnosis results for 59 UTI patients gathered and composed as a UTI dataset. Three classification models namely; decision tree (DT), support vector machine (SVM), random forest (RF) and artificial neural network (ANN), which are widely used in medical diagnosis systems, were created to model the definitive diagnosis results using the composed UTI dataset. Accuracy, specificity and sensitivity statistical measurements were used to determine the performance of created models. RESULTS: DT, SVM, RF and ANN models have 93.22%, 96.61%, 96.61%, 98.30% accuracy, 95.55%, 97.77%, 95.55%, 97.77% sensitivity and 85.71%, 92.85%, 100%, 100% specificy results, respectively. CONCLUSIONS: ANN has the highest accuracy result of 98.3% for UTI diagnosis within the proposed models. Although several symptoms, laboratory findings, and ultrasound results are needed for clinical UTI diagnosis, this ANN model only needs pollacuria, suprapubic pain symptoms and erythrocyte to get the same diagnosis with such accuracy. This proposed model is a successful medical decision support system for UTI with complex symptoms. Usage of this artificial intelligence method has its advantages of lower diagnosis cost, lower diagnosis time and there is no need for invasive methods. PMID- 30415719 TI - Accurate liver vessel segmentation via active contour model with dense vessel candidates. AB - BACKGROUND AND OBJECTIVE: The purpose of this paper is to propose a fully automated liver vessel segmentation algorithm including portal vein and hepatic vein on contrast enhanced CTA images. METHODS: First, points of a vessel candidate region are extracted from 3-dimensional (3D) CTA image. To generate accurate points, we reduce 3D segmentation problem to 2D problem by generating multiple maximum intensity (MI) images. After the segmentation of MI images, we back-project pixels to the original 3D domain. We call these voxels as vessel candidates (VCs). A large set of MI images can produce very dense and accurate VCs. Finally, for the accurate segmentation of a vessel region, we propose a newly designed active contour model (ACM) that uses the original image, vessel probability map from dense VCs, and the good prior of an initial contour. RESULTS: We used 55 abdominal CTAs for a parameter study and a quantitative evaluation. We evaluated the performance of the proposed method comparing with other state-of-the-art ACMs for vascular images applied directly to the original data. The result showed that our method successfully segmented vascular structure 25%-122% more accurately than other methods without any extra false positive detection. CONCLUSION: Our model can generate a smooth and accurate boundary of the vessel object and easily extract thin and weak peripheral branch vessels. The proposed approach can automatically segment a liver vessel without any manual interaction. The detailed result can aid further anatomical studies. PMID- 30415720 TI - Cascaded classifiers and stacking methods for classification of pulmonary nodule characteristics. AB - BACKGROUND AND OBJECTIVES: Detection and classification of pulmonary nodules are critical tasks in medical image analysis. The Lung Image Database Consortium (LIDC) database is a widely used resource for small pulmonary nodule classification research. This dataset is comprised of nodule characteristic evaluations and CT scans of patients. Although these characteristics are utilized in several studies, they can be used to improve classification performance. METHODS: Numerous methods have been proposed to classify malignancy, but there are not many studies that facilitate nodule characteristics in classification steps. In this study, we use information on nodule characteristics and propose cascaded classification schemes. A group of hand-crafted features and deep features are used to define the nodules. In the first step of the classifier, the nodule characteristics are classified based on individual base classifiers. In the second step, the results of the first level classifier are combined for use in malignancy classification. In addition, stacking methods are applied to improve the performance of the cascaded classifiers. RESULTS: The results confirmed that combining deep and hand-crafted features contribute to classification performance with an 8% improvement in average classification accuracy, 9% improvement in sensitivity, and 3% in specificity. Deep features from a nodule bounding area are more descriptive than the exact nodule region. The best performing cascaded classifier featured a classification accuracy of 84.70%, sensitivity of 67.37%, and specificity of 95.46%. First level stacking demonstrated similar results on classification accuracy and specificity but sensitivity was measured at 75.59%. Stacking on both levels provided the best classification accuracy and specificity with scores of 86.98% and 96.06%, respectively. When the malignancy ratings were grouped, stacking on both levels demonstrated better performance than other methods with a classification accuracy of 88.80%, sensitivity of 88.41%, and specificity of 94.12%. CONCLUSIONS: Information on cascading characteristics with image features is beneficial for the classification of the malignancy ratings. Stacking approaches on both levels demonstrate better classification accuracy, but in the context of sensitivity, first level stacking performs better. Grouping the malignancy ratings results in better classification outcomes as in the case of similar studies in the literature. PMID- 30415721 TI - Nutrition delivery, workload and performance in a model-based ICU glycaemic control system. AB - BACKGROUND AND OBJECTIVE: Hyperglycaemia is commonplace in the adult intensive care unit (ICU), and has been associated with increased morbidity and mortality. Effective glycaemic control (GC) can reduce morbidity and mortality, but has proven difficult. STAR is a model-based GC protocol that uniquely maintains normoglycaemia by changing both insulin and nutrition interventions, and has been proven effective in controlling blood glucose (BG) in the ICU. However, most ICU GC protocols only change insulin interventions, making the variable nutrition aspect of STAR less clinically desirable. This paper compares the performance of STAR modulating only insulin, with three simpler alternative nutrition protocols in clinically evaluated virtual trials. METHODS: Alternative nutrition protocols are fixed nutrition rate (100% caloric goal), CB (Cahill et al. best) stepped nutrition rate (60%, 80% and 100% caloric goal for the first 3 days of GC, and 100% thereafter) and SLQ (STAR lower quartile) stepped nutrition rate (65%, 75% and 85% caloric goal for the first 3 days of GC, and 85% thereafter). Each nutrition protocol is simulated with the STAR insulin protocol on a 221 patient virtual cohort, and GC performance, safety and total intervention workload are assessed. RESULTS: All alternative nutrition protocols considerably reduced total intervention workload (14.6-19.8%) due to reduced numbers of nutrition changes. However, only the stepped nutrition protocols achieved similar GC performance to the current variable nutrition protocol. Of the two stepped nutrition protocols, the SLQ nutrition protocol also improved GC safety, almost halving the number of severe hypoglycaemic cases (5 vs. 9, P = 0.42). CONCLUSIONS: Overall, the SLQ nutrition protocol was the best alternative to the current variable nutrition protocol, but either stepped nutrition protocol could be adapted by STAR to reduce workload and make it more clinically acceptable, while maintaining its proven performance and safety. PMID- 30415722 TI - Automated detection and classification of liver fibrosis stages using contourlet transform and nonlinear features. AB - BACKGROUND AND OBJECTIVE: Liver fibrosis is a type of chronic liver injury that is characterized by an excessive deposition of extracellular matrix protein. Early detection of liver fibrosis may prevent further growth toward liver cirrhosis and hepatocellular carcinoma. In the past, the only method to assess liver fibrosis was through biopsy, but this examination is invasive, expensive, prone to sampling errors, and may cause complications such as bleeding. Ultrasound-based elastography is a promising tool to measure tissue elasticity in real time; however, this technology requires an upgrade of the ultrasound system and software. In this study, a novel computer-aided diagnosis tool is proposed to automatically detect and classify the various stages of liver fibrosis based upon conventional B-mode ultrasound images. METHODS: The proposed method uses a 2D contourlet transform and a set of texture features that are efficiently extracted from the transformed image. Then, the combination of a kernel discriminant analysis (KDA)-based feature reduction technique and analysis of variance (ANOVA) based feature ranking technique was used, and the images were then classified into various stages of liver fibrosis. RESULTS: Our 2D contourlet transform and texture feature analysis approach achieved a 91.46% accuracy using only four features input to the probabilistic neural network classifier, to classify the five stages of liver fibrosis. It also achieved a 92.16% sensitivity and 88.92% specificity for the same model. The evaluation was done on a database of 762 ultrasound images belonging to five different stages of liver fibrosis. CONCLUSIONS: The findings suggest that the proposed method can be useful to automatically detect and classify liver fibrosis, which would greatly assist clinicians in making an accurate diagnosis. PMID- 30415723 TI - A semi-supervised deep learning method based on stacked sparse auto-encoder for cancer prediction using RNA-seq data. AB - BACKGROUND AND OBJECTIVE: Cancer has become a complex health problem due to its high mortality. Over the past few decades, with the rapid development of the high throughput sequencing technology and the application of various machine learning methods, remarkable progress in cancer research has been made based on gene expression data. At the same time, a growing amount of high-dimensional data has been generated, such as RNA-seq data, which calls for superior machine learning methods able to deal with mass data effectively in order to make accurate treatment decision. METHODS: In this paper, we present a semi-supervised deep learning strategy, the stacked sparse auto-encoder (SSAE) based classification, for cancer prediction using RNA-seq data. The proposed SSAE based method employs the greedy layer-wise pre-training and a sparsity penalty term to help capture and extract important information from the high-dimensional data and then classify the samples. RESULTS: We tested the proposed SSAE model on three public RNA-seq data sets of three types of cancers and compared the prediction performance with several commonly-used classification methods. The results indicate that our approach outperforms the other methods for all the three cancer data sets in various metrics. CONCLUSIONS: The proposed SSAE based semi supervised deep learning model shows its promising ability to process high dimensional gene expression data and is proved to be effective and accurate for cancer prediction. PMID- 30415724 TI - Artificial Intelligence in Clinical Implications. PMID- 30415725 TI - Establishment of trauma care system based on local conditions: Un imperative trend. PMID- 30415726 TI - Dreams Are the Foundation of the Future-But Dreams Realized Are the Foundation of Success. PMID- 30415727 TI - Transformational-taking time to care. PMID- 30415728 TI - Response to Walters' Article Regarding Raising Awareness for Sepsis. PMID- 30415729 TI - Avoid Insulin-Related Adverse Events When Treating Hyperkalemia: Could Impaired Awareness of Hypoglycemia Play a Role? PMID- 30415730 TI - Response to Waszak Article about Education Provided by Nurses to ED Patients Who Are Prescribed Opioid Analgesics. PMID- 30415731 TI - Florida One Step Closer. PMID- 30415732 TI - When Patients Backslide Into Their Back Story: Can Emotional Intelligence Help Emergency Nurses? PMID- 30415733 TI - First- and Second-Order Problem Solving: When Rework and Workarounds Become an Opportunity for Improving Safety. PMID- 30415734 TI - Emergency Nursing Review Questions: November 2018. PMID- 30415735 TI - Change Ahead: Construction in the Emergency Department. PMID- 30415736 TI - A Different Spin to Emergency Nursing: Spain, Part 2. PMID- 30415737 TI - Autism Emergency Care Success: Plan, Collaborate, and Accommodate. PMID- 30415738 TI - What Is Cannabinoid Hyperemesis Syndrome? PMID- 30415739 TI - Erratum in "Dexmedetomidine for Treatment of Refractory Heroin Withdrawal". PMID- 30415740 TI - Cervical Collar Placement Algorithm for Triage Nurses. PMID- 30415741 TI - Placental characteristics in monochorionic twins with selective intrauterine growth restriction in relation to the umbilical artery Doppler classification. AB - INTRODUCTION: The objective of this study was to evaluate the placental characteristics of monochorionic twin pregnancies with selective intrauterine growth restriction (sIUGR) classified according to the Gratacos classification based on umbilical artery Doppler measurements. METHODS: All consecutive placentas from monochorionic twin pregnancies with sIUGR, (defined as a birthweight discordance > 25% and/or an estimated fetal weight in one twin <10th centile) examined between May 2002 and February 2018 were included in the study. Each placenta was injected with colored dye to study the angioarchitecture. Primary outcomes were placental share discordance and diameter of the arterio arterial anastomoses in relation to the umbilical artery Doppler types of sIUGR (Gratacos classification). RESULTS: Of the 83 sIUGR twins included, 27 were classified as Gratacos type I, 24 as type II and 32 as type III. The median gestational age at delivery was 34.3 weeks for type I, compared to 31.2 weeks and 31.6 weeks for type II and type III respectively. A trend towards a higher placental share discordance in type III sIUGR was observed. The median arterio arterial diameter was 1.7 mm (0.8-2.6) in type I, 1.7 mm (1.2-2.2) in type II and 2.8 (2.0-3.5) mm in type III (p < 0.01). DISCUSSION: Type III sIUGR placentas appear to be characterized by a larger diameter of the arterio-arterial anastomoses and a larger placental share discordance compared to type I and II sIUGR. The insights in the placental architecture of sIUGR placentas may offer new views on the pathophysiology of the disease. PMID- 30415742 TI - Serum podocalyxin for early detection of preeclampsia at 11-13 weeks of gestation. AB - Podocalyxin is expressed on endothelial surface throughout the body and is likely released into the circulation during pregnancy in association with vessel remodeling. We have recently reported that serum podocalyxin is significantly increased in preeclampsia at disease presentation. In this study we investigated whether serum podocalyxin is altered prior to clinical presentation of preeclampsia. At 11-13 weeks of gestation, serum podocalyxin was significantly elevated in women who subsequently developed preeclampsia. Multi-factorial analysis suggests that combination of serum podocalyxin with the long isoform of HtrA3 and mean arterial pressure, may provide effective detection of late-onset preeclampsia at 11-13 weeks of pregnancy. PMID- 30415743 TI - Immunohistochemical expression of the nicotinic acetylcholine receptor (nAChR) subunits in the human placenta, and effects of cigarette smoking and preeclampsia. AB - INTRODUCTION: Cigarette smoking (CS) and preeclampsia (PE), regulate the expression of nicotinic acetylcholine receptor (nAChR) subunits in the placenta, yet no data exist at the histological level. METHODS: Using immunohistochemistry of formalin fixed and paraffin embedded placental tissue, this study quantified the expression of nine nAChR subunits (alpha2, alpha3, alpha4, alpha5, alpha7, alpha9, beta1, beta2, delta) and compared the expression amongst four groups of non-smoker non-PE (controls, n = 8), smokers (n = 8), PE (n = 8), and those who were smokers with PE (smoke + PE, n = 4). Quantification was of the percentage of villi with positive cells stained (% villi with +ve), percentage of positive stained cells per villous (% +ve cells/villous), percentage of positive cells in the decidua (%+ve Decidua), and intensity of staining in the outer villous trophoblast layer. RESULTS: Changes were restricted to the villi (as opposed to the decidua), and were specific to the alpha9 (smoke + PE), beta1 (smokers), and beta2 (PE) subunits when compared to controls. CS seemed to have a protective effect for the beta2 subunit and an additive effect for the alpha9 and beta1 subunits within the villous core/stroma cells and not the trophoblast layer. DISCUSSION: These findings support that both CS and PE affect nAChRs in the placenta, but that this is restricted to the villi. PMID- 30415744 TI - Approach for differentiating trophoblast cell lineage from human induced pluripotent stem cells with retinoic acid in the absence of bone morphogenetic protein 4. AB - INTRODUCTION: Placental transport is the first step in chemotherapeutic safety evaluations during pregnancy. However, a well-established in vitro model is not available. We previously reported that a trophoblast layer model using differentiating choriocarcinoma JEG-3 cells (DJEGs) can be used for placental drug transport studies. However, it was necessary to increase the similarities between the syncytiotrophoblast, the main layer of the placental barrier, and the in vitro evaluation model in order for the model to be useful for placental drug transport evaluations. We focused on in vivo similarities of differentiating induced pluripotent stem cells (iPSCs). iPSCs can achieve a syncytiotrophoblast like form and secrete human chorionic gonadotropin (hCG) following bone morphogenetic protein 4 (BMP4) treatment. However, BMP4-treated iPSCs can differentiate into several cell types. In the placental transport model, a dense syncytiotrophoblast cell layer is necessary for appropriate differentiation. METHODS: The conditions permitting differentiation of iPSCs into syncytiotrophoblasts with retinoic acid (RA) treatment without BMP4 were investigated. The presence of syncytiotrophoblast-like cells was confirmed by measurement of mRNA expression levels of breast cancer resistance protein (BCRP) and paternally expressed 10 (PEG10) in syncytiotrophoblasts. In addition, immunofluorescence imaging of cytokeratin 7 (CK7) induced in trophoblasts was performed. RESULTS: and Discussion: RA-induced iPSCs exhibited these syncytiotrophoblast-like features and hCG secretion was maintained for at least 28 days after treatment with RA (500 nM) without BMP4. These results suggest that RA-induced iPSCs are a suitable in vitro syncytiotrophoblast model that can be used as an indicator of drug placental transport for pharmacotherapy during pregnancy. PMID- 30415745 TI - Immunomodulatory effects of human amniotic epithelial cells on naive CD4+ T cells from women with unexplained recurrent spontaneous abortion. AB - INTRODUCTION: Immune imbalance at the maternal-fetal interface plays a fundamental role in the pathogenesis of unexplained recurrent spontaneous abortion (URSA). Human amniotic epithelial cells (hAECs) possess pregnancy friendly immunomodulatory effects. Here, we investigated how function of naive CD4+ T cells from URSA patients is affected by hAECs. METHODS: Phenotypic characteristics of hAECs were determined by flow cytometry and their effect on proliferation of allogeneic peripheral blood mononuclear cells (PBMCs) was evaluated by a BrdU cell proliferation assay. Naive CD4+ T cells were isolated from 25 URSA patients and 5 healthy women and co-cultured with hAECs. Immunomodulatory effects of hAECs on cytokines profile, proliferation of stimulated CD4+ T cells and induction of regulatory T cells (Tregs) were assessed by ELISA and flow cytometry, respectively. Functional competency of Tregs was evaluated in an allogeneic mixed lymphocyte reaction (MLR) system. RESULTS: hAECs did not elicit allogeneic proliferative responses of PBMCs, inhibited proliferation of naive CD4+ T cells, induced production of Th2 and suppressed production of Th1 and Th17 cytokines. hAECs showed the ability to induce differentiation of Tregs and production of transforming growth factor-beta1 (TGF beta1) and interleukin-10 (IL-10). This ability was found to be superior in control subjects compared to URSA patients. Indeed, Tregs generated in the presence of hAECs expressed higher levels of CTLA-4 compared to Tregs generated in their absence and restrained the proliferation of autologus PBMCs in MLR system. CONCLUSION: Based on these findings, hAECs can be considered as one potential candidate in immunotherapy of patients with URSA. PMID- 30415746 TI - Endogenous carbon monoxide production by menadione. AB - INTRODUCTION: Smokers have a significantly decreased risk of pre-eclampsia (PE), possibly attributed to an increase in blood carbon monoxide (CO) concentrations. At physiological concentrations, CO has been demonstrated to have placental vasodilatory and anti-inflammatory properties. Increasing endogenous CO production may have therapeutic potential to either prevent or treat PE. Menadione (MD), synthetic vitamin K3, increases CO in rat microsomes. Our objective was to investigate MD's ability to increase endogenous CO concentrations in pregnancy. METHODS: Three experiments were completed. First, in vitro CO production was measured using isolated GD15 placentas. Second, non pregnant normotensive mice received no, 1.5, 4.0 or 6.5 g/L MD for 7 days. Lastly, pregnant normotensive mice received either no or 6.5 g/L MD in water from GD10.5 to GD17.5. Consumption was measured as average daily water intake per gram of body weight. Maternal and fetal CO levels in the blood and tissue were quantified using headspace gas chromatography. RESULTS: MD significantly increased CO production in isolated GD15 placentas. In both pregnant and non pregnant experiments, splenic CO, hepatic CO, and splenic mass were higher in treated mice compared to controls (all p < 0.05). Maternal %COHb and Hb in treated dams were not significantly different compared to controls. The fetal:placental mass ratio was significantly lower in the treatment group (p = 0.002). DISCUSSION: Placental CO production was observed in GD15 placentas after co-incubation with MD. MD administration increased CO in the liver and spleens of pregnant mice. Further investigation into different doses of MD is required to identify one without demonstrable fetal/placental effects. PMID- 30415747 TI - GBD 2017: a fragile world. PMID- 30415749 TI - The association of cardiorespiratory fitness, body mass index, and age with testosterone levels at screening of healthy men undergoing preventive medical examinations: The Cooper Center Longitudinal Study. AB - BACKGROUND: Currently, exogenous hormone replacement is used in many men with hypogonadism without clear organic cause. This study examines the contribution of modifiable health behaviors, i.e., physical activity and weight control, to the maintenance of testosterone levels with aging. METHODS: In a cross-sectional study of 2994 healthy men aged 50-79 years examined at a preventive medicine clinic from January 2012 to March 2016, screening morning total testosterone levels were measured and categorized as low (<250 ng/dL), low normal (250-399 ng/dL), and normal (>400 ng/dL). Cardiorespiratory fitness (fitness) was estimated from a maximal exercise treadmill test. Multiple logistic regression models were used to test the associations between low testosterone levels and age, body mass index (BMI), and fitness. FINDINGS: Mean testosterone levels were in the normal range for each age group (50-59, 60-69, and 70-79). There was a similar prevalence of low testosterone in each age group (11.3%, 10%, and 10.5%, respectively). The prevalence of low testosterone was positively associated with BMI and negatively associated with fitness but was not associated with age. INTERPRETATION: This study found no evidence that low testosterone is an inevitable consequence of aging. Maintenance of healthy weight and fitness may help maintain normal testosterone levels. PMID- 30415750 TI - Linking the menopause rating scale to the International classification of functioning, disability and health - A first step towards the implementation of the EMAS menopause health care model. AB - OBJECTIVES: To link the Menopause Rating Scale (MRS-II) to the International Classification of Functioning, Disability and Health (ICF) and present a clinical application of an ICF-based tool. STUDY DESIGN: The MRS-II was linked to the corresponding ICF category. The linked items were used to generate an ICF Categorical Profile. To broadly examine its feasibility in clinical practice, qualitative interviews with three patients were performed. MAIN OUTCOME MEASURES: Corresponding items of the MRS-II in the ICF. Perception of the ICF Categorical Profile from patients' perspective. RESULTS: A total of 44 concepts from the MRS II were identified that could be linked to 24 different ICF categories, which all belonged to the component Body Functions. From patients' perspective, filling in the ICF Categorical Profile helped to structure their goals but did not improve the overview of symptoms. CONCLUSIONS: The ICF Categorical Profile could be a valuable tool in menopause healthcare; however, it is necessary to adapt the ICF for this specific use. An ICF Core Set needs to be developed in order to accomplish the goal of the European Menopause and Andropause Society and implement its Healthy Menopause Health Care Model in daily practice. PMID- 30415751 TI - Feasibility, safety, acceptability, and functional outcomes of playing Nintendo Wii Fit PlusTM for frail older adults: A randomized feasibility clinical trial. AB - BACKGROUND: Recently, interactive video games (IVGs) have been used as a health care intervention that provides both exercise and cognitive stimulation. Several studies have shown that IVGs can improve postural control, gait, cognition, and functional independence in elderly people and patients with neurological disease. However, there is a lack of evidence about the effects of IVGs on frail and pre frail elderly people. The aim of this study was to evaluate the feasibility, safety, and acceptability of playing Nintendo Wii Fit PlusTM (NWFP) interactive video games, and the functional outcomes (postural control, gait, cognition, mood, and fear of falling) in frail and pre-frail older adults. METHODS: This study is a randomized controlled, parallel-group, feasibility trial. Participants were frail and pre-frail older adults randomly assigned to the experimental group (EG, n = 15) or control group (CG, n = 15). Participants in the EG performed 14 training sessions, lasting 50 min each, twice a week. In each training session, participants played five of 10 selected games, with two attempts at each game. Participants in the CG received general advice regarding the importance of physical activity. All participants were assessed on three occasions by a blinded physical therapist: before and after intervention, and 30 days after the end of the intervention (follow-up). We assessed the feasibility (score of participants in the games), acceptability (game satisfaction questionnaire), safety (adverse events during training sessions), and functional outcomes: (1) postural control (Mini-BESTest); (2) gait (Functional Gait Assessment); (3) cognition (Montreal Cognitive Assessment); (4) mood (GDS-15); and (5) fear of falling (FES-I). RESULTS: Participants in the EG improved their scores in all 10 games, reported that they understood and enjoyed the tasks of the games, and presented few adverse events during the practice. There was a significant improvement in the Mini-BESTest and Functional Gait Assessment in the EG when compared with the CG (p < 0.05). CONCLUSION: The use of NWFP was feasible, acceptable, and safe for frail older adults and improved their postural control and gait. There were no effects on cognition, mood, or fear of falling. This trial was registered in the Brazilian Registry of Clinical Trials (RBR-823rst) on 11 June 2016. PMID- 30415752 TI - Therapeutic options for aromatase inhibitor-associated arthralgia in breast cancer survivors: A systematic review of systematic reviews, evidence mapping, and network meta-analysis. AB - Aromatase inhibitor-associated arthralgia (AIA) is a common problem in breast cancer survivors and is associated with noncompliance with aromatase inhibitor therapy. The aim of this research was to assess the current evidence for the various therapeutic options available for AIA. We searched the PubMed, EMBASE, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects for systematic reviews of trials investigating treatments for AIA to June 2018. Eligible systematic reviews were subjected to evidence mapping and the randomized controlled trials included in the systematic reviews were hand searched for a network meta-analysis. Six systematic reviews were included in the evidence mapping. Acupuncture was the most common treatment modality studied (four randomized controlled trials), and pharmacological interventions, aerobic exercise, Nordic walking, omega-3 fatty acids, and vitamin D were assessed less frequently. In view of the limitations in the overall confidence level for each review, the evidence for acupuncture as an effective treatment for AIA was considered low. Second, data from 6 randomized controlled trials were included in the network meta-analysis. When compared with a waiting list control, acupuncture (mean difference [MD] -2.00, 95% confidence interval [CI] -3.16, -0.84), aerobic exercise (MD -0.80, 95% CI -1.33, -0.016), and omega-3 fatty acids (MD -2.10, 95% CI -3.23, -0.97) significantly improved pain severity scores. Network meta analysis of adverse events was not possible because of poor reporting. Acupuncture is presently the most widely investigated intervention but is recommended for AIA with low overall confidence based on the current evidence. PMID- 30415753 TI - Factors associated with prevalent and incident foot pain: data from the Tasmanian Older Adult Cohort Study. AB - OBJECTIVES: To describe factors associated with prevalent and incident foot pain in a population-based cohort of older adults (n = 1092). STUDY DESIGN: Longitudinal observational study. MAIN OUTCOME MEASURES: Prevalent foot pain, incident foot pain after 5 years. METHODS: Potential correlates included demographic factors, anthropometry, leg strength, metabolic factors, steps per day (using pedometer), pain at 6 other sites, and psychological wellbeing. Data were analysed using log binomial models. RESULTS: Participants were aged 50-80 years (mean 63 years), 49% male, mean body mass index (BMI) 27.8 +/- 4.7 at baseline. The prevalence of foot pain at baseline was 38% and the incidence of new pain over 5 years was 20%. BMI, pain at other sites (neck, hands, knees, pain at three or more sites), and poorer psychological wellbeing were independently associated with baseline foot pain. Baseline BMI and pain in the neck, hands, and knees were independently associated with incident foot pain; but change in weight or BMI, total number of painful joints and psychological wellbeing were not. Self reported diabetes and cigarette smoking were not associated with prevalent or incident foot pain. CONCLUSIONS: This study demonstrates that greater body weight and joint pain at multiple sites were consistently associated with prevalent foot pain and predict incident foot pain. Addressing excess body mass and taking a global approach to the treatment of pain may reduce the prevalence and incidence of foot pain in older adults. PMID- 30415754 TI - Risk of asthma onset after natural and surgical menopause: Results from the French E3N cohort. AB - BACKGROUND: The gender switch in asthma incidence around puberty has been put forward to suggest a role of sex hormones in asthma. However, there are limited and inconsistent findings on change in asthma incidence with menopause. We aimed to investigate the associations between menopause and asthma incidence, and interactions with overweight/obesity. METHODS: Asthma incidence was assessed in 67,872 women free of asthma at baseline (aged 41-68 years) and regularly followed up as a part of the French E3N cohort. Adjusted hazard ratios (aHR) were derived from Cox models considering age as the time-scale, menopausal status as a time varying covariate and taking into account menopausal treatment. RESULTS: During 843,243 person-years of follow-up, 1205 new-onset asthma cases were identified. Compared with pre-menopause, surgical menopause was associated with an increased risk of asthma onset (aHR = 1.33 [95%CI 1.01-1.75]) but no association was observed for natural menopause (aHR = 1.05 [0.84-1.32]). In women with natural menopause, a further analysis separating the transition through menopause and the later post-menopausal period did not show any change in asthma incidence with menopause in the total sample or in normal-weight women alone. However, in overweight/obese women, peri-menopausal and post-menopausal women had an increased risk of developing asthma compared with pre-menopausal women of the same age (aHR = 1.91 [1.00-3.66] and aHR = 2.08 [1.07-4.06] respectively). CONCLUSION: Surgical menopause was associated with an increased risk of asthma onset. For natural menopause, no change in asthma incidence was observed in normal-weight women. However, overweight/obese women had an increased risk of developing asthma after natural menopause. PMID- 30415755 TI - Understanding driving anxiety in older adults. AB - BACKGROUND/OBJECTIVES: Driving anxiety is a heterogeneous experience that can impact on everyday activities. Little is known about whether older adults experience driving anxiety and, if so, what impact it has on their health, functioning, and quality of life. This is particularly important given the ageing population and driving patterns of older drivers. The present study examines the extent of self-reported driving anxiety in older adult drivers. DESIGN: Population survey of community-dwelling older drivers. SETTING: New Zealand. PARTICIPANTS: 1170 adults aged 65 and over. MEASUREMENTS: Self-reported ratings of driving anxiety. RESULTS: 62.3% of participants reported no driving anxiety, 27.0% reported mild driving anxiety and 10.7% endorsed more moderate to extreme levels of driving anxiety, which is higher than has been identified with adults aged 55-72. Women were significantly more often (p < .01) represented in the groups of mildly and moderately anxious drivers, and those who were moderately to extremely anxious were more likely to be aged 70+ (p < .04). Those with moderate to severe driving anxiety tended to drive less often, for shorter distances, and to use alternative modes of transport more often than those with mild or no driving anxiety. CONCLUSION: Driving anxiety is experienced by many older adults, with quite a large proportion reporting high levels of driving anxiety and associated differences in driving patterns. Further research is needed to better understand why older drivers experience driving anxiety, and how it impacts health and wellbeing as well as driving self-regulation and cessation. PMID- 30415756 TI - Medical cannabis use in older patients: Update on medical knowledge. AB - BACKGROUND: There is increasing scientific data suggesting that cannabis is beneficial for a large range of medical conditions. Physicians need up-to-date medical knowledge (i.e., indications, dose and safety properties) before prescribing cannabis for older patients, who are, a priori, more prone to its adverse effects than younger patients. A mini-review was conducted to examine the evidence on medical cannabis use in older patients. METHODS: An English and French systematic Medline (PubMed) search, from January 1, 2001 to October 15, 2018, was conducted using the MeSH terms "Cannabis"[Mesh] OR "Marijuana Abuse"[Mesh] OR "Medical Marijuana"[Mesh] OR "Marijuana Smoking"[Mesh] combined with the MeSH terms ("Aged"[Mesh]) OR "Aged, 80 and over"[Mesh]. A total of 451 abstracts were identified and full relevant articles were retrieved and analysed. RESULTS: Even with a growing body of data showing positive effects of medical cannabis use, mixed results have been reported. Most clinical studies have had small samples and there are few randomized controlled trials. This lack of evidence on the positive clinical effects of medical cannabis use is especially marked for older patients, few of whom have been examined. CONCLUSIONS: There is a lack of consistent data on the clinical effects of medical cannabis use in older patients to guide cannabis prescription for this group of patients. PMID- 30415757 TI - Olive oil consumption and human health: A narrative review. AB - The potential health benefits of olive oil consumption, particularly within the context of the Mediterranean diet, have been extensively investigated. However, its specific health benefits remain to be confirmed. The aim of the present work is to review the scientific evidence regarding the specific impact of olive oil consumption on human health, including the prevention of cardiovascular disease, cancers, and diabetes mellitus. Ten related meta-analyses were reviewed to this effect. Olive oil consumption was found to be beneficial for several chronic non communicable diseases (e.g. including cardiovascular disease, breast cancer and type 2 diabetes), whereas there were contradictory findings regarding its impact on several biomarkers. In conclusion, the aggregated evidence supports the assertion that olive oil consumption is beneficial for human health, and particularly for the prevention of cardiovascular diseases, breast cancer, and type 2 diabetes mellitus. PMID- 30415758 TI - Gout - An update of aetiology, genetics, co-morbidities and management. AB - Gout is an increasingly common chronic disorder of urate crystal deposition that manifests as flares of acute inflammatory arthritis. Hyperuricaemia is a prerequisite and a fifth of both men and woman are hyperuricaemic. The prevalence of gout is much lower than the prevalence of hyperuricaemia for reasons that are not currently clear. Gout is more common in men than women prior to menopause due to the uricosuric effects of oestrogen, but after menopause the incidence of gout rises substantially in women. Co-morbidities are an important issue in gout, with cardiovascular disease, diabetes mellitus, obesity and chronic kidney disease all common in patients with gout. Environmental factors like diet affect the incidence of gout but there is little evidence to support an emphasis on diet in treating established gout. The diagnosis of gout is often made without the use of joint aspiration and validated diagnostic rules are available for both primary and secondary care as well as classification criteria for research use. The overarching principle of the management of gout with pharmacotherapy is the need to reduce serum urate levels to below a target of 0.30 mmol/L or 0.36 mmol/L depending on whether it is tophaceous or non-tophaceous respectively. The use of allopurinol has been researched extensively and newer strategies for safer effective dosing are now recommended. Newer agents have been introduced for the treatment of gout, including febuxostat and lesinurad. A number of important questions in the field are under current investigation. PMID- 30415759 TI - Foot problems as a risk factor for falls in community-dwelling older people: A systematic review and meta-analysis. AB - BACKGROUND: Foot problems are common in older people. The objective of this systematic review was to determine whether foot problems increase the risk of falling in community-dwelling older people. METHODS: Electronic databases were searched from inception to May 2018. To be eligible for inclusion, papers needed to (i) include community-dwelling older participants, (ii) document falls either retrospectively or prospectively, and (iii) document or assess the presence of foot problems. Screening and data extraction were performed by two independent assessors, with disagreements resolved by consensus. RESULTS: A total of 146 papers were screened by title and abstract, and nine met the inclusion criteria. An additional six eligible papers were identified by searching the reference lists of included papers, resulting in a total of 15 papers. Quantitative synthesis indicated that older people who fell were more likely to have foot pain, hallux valgus, lesser toe deformity, plantar fasciitis, reduced ankle dorsiflexion range of motion, reduced toe plantarflexion strength, impaired tactile sensitivity and increased plantar pressures when walking. Meta-analysis indicated that fallers were more likely to have foot pain (pooled odds ratio [OR] 1.95, 95% CI 1.38-2.76, p < 0.001), hallux valgus (pooled OR 1.89, 95% CI 1.19 3.00, p = 0.007) and lesser toe deformity (pooled OR 1.67, 95% CI 1.07-2.59, p = 0.020). CONCLUSION: Foot problems, particularly foot pain, hallux valgus and lesser toe deformity, are associated with falls in older people. Documentation of foot problems and referral to foot care specialists should therefore be a routine component of falls risk assessment and prevention. PMID- 30415760 TI - The Archetypes of Medicine: A Job Description for the 21st Century. AB - Medicine is facing an identity crisis, one that might find resolution by revisiting a past rich in multifaceted individuals who transcended the strict definition of 'doctor', excelled in other fields of human endeavor, and showed us different ways of being physicians. This paper reviews 12 archetypes that have been part of the profession since its inception, but that, as of late, might have been forgotten. Our goal is to elicit discussion and introspection, with the premise that being a physician ought to be something larger than being a mere technician. If our premise is accepted, then the next step would be to identify those personal traits that made those archetypes possible, so that we can start both recruiting for them and then nurturing them during training. PMID- 30415761 TI - The buffering effect of social support on the relationship between discrimination and psychological distress among church-going African-American adults. AB - Discrimination is a pervasive stressor among African-American adults. Social support is an important protective factor for psychological distress, especially among minority populations. Although a number of studies have examined social support in relation to discrimination, little research has examined how social support may serve as an important protective factor against both physical and psychological symptoms related to overall psychological distress within this group. The current study examined social support as a moderator of the relationship between discrimination and overall psychological distress as measured by the Brief Symptom Inventory among a community sample of 122 African American church-going adults. Results indicated that social support buffered the associations of discrimination and overall psychological distress (p < 0.0001) in expected directions. Findings highlight the importance of cultivating strong social relationships to attenuate the effects of this social determinant on mental health disparities among this group. PMID- 30415762 TI - Regulation of host cell pyroptosis and cytokines production by Mycobacterium tuberculosis effector PPE60 requires LUBAC mediated NF-kappaB signaling. AB - Tuberculosis, caused by Mycobacterium tuberculosis infection, remains a global public health threat. The success of M. tuberculosis largely contributes to its manipulation of host cell fate. The role of M. tuberculosis PE/PPE family effectors in the host destiny was intensively explored. In this study, the role of PPE60 (Rv3478) was characterized by using Rv3478 recombinant M. smegmatis. PPE60 can promote host cell pyroptosis via caspases/NLRP3/gasdermin. The production of pro-inflammatory cytokines, such as IL-1beta, IL-6, IL-12p40 and TNF-alpha was altered by PPE60. We found that LUBAC was involved in PPE60 elicited NF-kappaB signaling by using Linear Ubiquitin Chain Assembly Complex (LUBAC)-specific inhibitor gliotoxin. The PPE60 recombinant M. smegmatis survival rate within macrophages is increased, as well as elevated resistance to stresses such as low pH, surface stresses and antibiotics exposure. For a first time it is firstly reported that M. tuberculosis effector PPE60 can modulate the host cell fate via LUBAC-mediated NF-kappaB signaling. PMID- 30415763 TI - Erratum of "Laryngeal electromyography in dysphonic patients with incomplete glottic closure". PMID- 30415764 TI - CRISPR diagnostics: Underappreciated uses in perinatology. AB - CRISPR-based therapeutics have the potential to revolutionize the treatment of hereditary diseases, but current efforts to translate research to the bedside face significant technical, regulatory, and ethical hurdles. In this article, we discuss an underappreciated application of CRISPR: diagnostic testing, and argue that: (1) CRISPR diagnostics are poised to disrupt diagnostic practices including perinatal screening and (2) since CRISPR diagnostics pose minimal technical, regulatory and ethical hurdles (unlike CRISPR therapeutic uses) they are likely to be clinically relevant before CRISPR-based therapies, and thus warrant medical community's attention. PMID- 30415765 TI - Contrast-enhanced ultrasound (CEUS) nephrostogram: utility and accuracy as an alternative to fluoroscopic imaging of the urinary tract. AB - AIM: To establish the feasibility and accuracy of contrast-enhanced ultrasound (CEUS) nephrostogram in comparison to the reference standard, fluoroscopic nephrostogram, in providing alternative imaging of the urinary tract post nephrostomy insertion. MATERIALS AND METHODS: This prospective study was approved by the institutional and national ethics committee. All patients for whom a fluoroscopic nephrostogram was requested were included. Fluoroscopic and CEUS nephrostograms were performed within 24 hours. Image analysis (nephrostomy position, opacification of pelvicalyceal system, ureter, and bladder) was performed by two reviewers, and the diagnostic accuracy of the CEUS nephrostograms was compared to fluoroscopic nephrostograms. RESULTS: Sixty-two nephrostograms were performed in 48 patients from June 2011 to April 2016, (male: 25/48, 52.1%; mean age 65 years, range 28-90 years). Indications for nephrostomy were: malignancy (29/62; 46.8%), benign ureteric stricture (14/62; 22.6%), urinary diversion (8/62; 12.9%), renal calculus (5/62; 8.1%), haematoma (3/62; 4.8%) or pelvi-ureteric junction obstruction (3/62; 4.8%). Two nephrostomies were identified as displaced by both techniques. The pelvicalyceal system was visualised in 60/60 (100%) examinations in both fluoroscopic and CEUS nephrostograms. The entire ureter was visualised in 30/60 (50%) with CEUS compared to 32/60 (53.3%) fluoroscopically. The distal ureter was the least well visualised segment for both techniques with no significant difference (p=0.815). Both CEUS and fluoroscopy could be used to correctly identify complications including entero-ureteric fistula or urine leak. Fluoroscopic nephrostogram demonstrated drainage into the bladder in 33/60 (55%), CEUS confirmed drainage in 34/60 (56.7%) cases (p=0.317). CONCLUSIONS: CEUS nephrostogram can determine the correct positioning of a nephrostomy and assess drainage into the bladder with statistically comparable results to fluoroscopy. PMID- 30415766 TI - Utility of arterial spin labelling MRI for discriminating atypical high-grade glioma from primary central nervous system lymphoma. AB - AIM: To evaluate the ability of arterial spin labelling (ASL) magnetic resonance imaging (MRI) in differentiating primary central nervous system lymphoma (PCNSL) from atypical high-grade glioma (HGG), as well as exploring the underlying pathological mechanisms. METHODS AND MATERIALS: Twenty-three patients with PCNSL and 17 patients with atypical HGG who underwent ASL-MRI were identified retrospectively. Absolute cerebral blood flow (aCBF) and normalised cerebral blood flow (nCBF) values were obtained, and were compared between PCNSL and atypical HGG using the Mann-Whitney U-test. The performance in discriminating between PCNSL and atypical HGG was evaluated using receiver-operating characteristics analysis and area-under-the-curve (AUC) values for aCBF and nCBF. The correlation between microvessel density (MVD) and aCBF was determined by Spearman's correlation analysis. RESULTS: Atypical HGG demonstrated significantly higher aCBF, nCBF, and MVD values than PCNSL (p<0.05). The diagnostic accuracy of discriminating PCNSL from atypical HGG showed AUC=0.877 (95% confidence interval [CI] 0.735-0.959) for aCBF, and AUC=0.836 (95% confidence interval [CI] 0.685 0.934) for nCBF. There was a moderate positive correlation between aCBF values of region of interest (ROI >30 mm2) in the enhanced area and MVD values (rho=0.579, p=0.0001), and a strong positive correlation between aCBF values MVD based on "point-to-point biopsy" (rho=0.83, p=0.0029). Interobserver agreements for aCBF and nCBF were excellent (ICC >0.75). CONCLUSIONS: ASL perfusion MRI is a useful imaging technique for the discrimination between atypical HGG and PCNSL, which may be determined by the difference of MVD between them. PMID- 30415768 TI - Re: Circulating Extracellular Vesicles in Human Disease. PMID- 30415769 TI - Re: Acute Kidney Injury After Partial Nephrectomy in Solitary Kidneys: Impact on Long-term Stability of Renal Function. PMID- 30415767 TI - A technique for measuring anisotropy in atrial conduction to estimate conduction velocity and atrial fibre direction. AB - BACKGROUND: Cardiac conduction properties exhibit large variability, and affect patient-specific arrhythmia mechanisms. However, it is challenging to clinically measure conduction velocity (CV), anisotropy and fibre direction. Our aim is to develop a technique to estimate conduction anisotropy and fibre direction from clinically available electrical recordings. METHODS: We developed and validated automated algorithms for estimating cardiac CV anisotropy, from any distribution of recording locations on the atrial surface. The first algorithm is for elliptical wavefront fitting to a single activation map (method 1), which works well close to the pacing location, but decreases in accuracy further from the pacing location (due to spatial heterogeneity in the conductivity and fibre fields). As such, we developed a second methodology for measuring local conduction anisotropy, using data from two or three activation maps (method 2: ellipse fitting to wavefront propagation velocity vectors from multiple activation maps). RESULTS: Ellipse fitting to CV vectors from two activation maps (method 2) leads to an improved estimation of longitudinal and transverse CV compared to method 1, but fibre direction estimation is still relatively poor. Using three activation maps with method 2 provides accurate estimation, with approximately 70% of atrial fibres estimated within 20?. We applied the technique to clinical activation maps to demonstrate the presence of heterogeneous conduction anisotropy, and then tested the effects of this conduction anisotropy on predicted arrhythmia dynamics using computational simulation. CONCLUSIONS: We have developed novel algorithms for calculating CV and measuring the direction dependency of atrial activation to estimate atrial fibre direction, without the need for specialised pacing protocols, using clinically available electrical recordings. PMID- 30415770 TI - Re: A Randomized, Double-blind, Placebo-controlled Trial of Certolizumab Pegol in Women with Refractory Interstitial Cystitis/Bladder Pain Syndrome. PMID- 30415771 TI - Re: Clinical Outcomes of the Upper Urinary Tract after Ureteral Clipping for Treatment of Low Functioning or Nonfunctioning Renal Moieties. PMID- 30415772 TI - Sesaminol diglucoside, a water-soluble lignan from sesame seeds induces brown fat thermogenesis in mice. AB - Brown adipose tissue (BAT) is the site of non-shivering thermogenesis in mammals, wherein energy is dissipated as heat. We observed that aqueous extract of black sesame seed triggers an increase in the expression of Uncoupling Protein 1 (UCP1) in brown adipocytes from mice. The active component from the extract was purified and identified to be sesaminol diglucoside (SDG). SDG treatment decreased mass of white fat pads and serum glucose levels and increased UCP1 levels in BAT thereby protecting mice against high fat induced weight gain. Further in silico and in vitro studies revealed that these effects are due to the agonist like behaviour of SDG towards beta 3 adrenergic receptors (beta3-AR). Together, our results suggest that SDG induces BAT mediated thermogenesis through beta3-AR and protects mice against diet-induced obesity. PMID- 30415773 TI - The roles of hypoxia-inducible Factor-1 and iron regulatory protein 1 in iron uptake induced by acute hypoxia. AB - BACKGROUND INFORMATION: Divalent metal transporter 1 (DMT1) and transferrin receptor (TfR1) are vital proteins for cellular iron uptake. These proteins have hypoxia-responsive elements (HREs) in their 5'-regulatory region, and they are regulated by hypoxia-inducible factor 1alpha (HIF-1alpha) transcriptionally under hypoxic condition. Besides, iron regulatory protein 1 (IRP1) regulates DMT1 and TfR1 by binding to iron-responsive elements (IREs) present in their mRNAs to control cellular iron homeostasis. RESULTS: Here, we explored the effect of acute hypoxia on iron uptake. Ferrous iron uptake was elevated by DMT1(+IRE) and TfR1 under acute hypoxia. The luciferase activity analysis revealed that the functional HREs of DMT1 and TfR1 were increased. However, their IREs-dependent luciferase activities were reduced simultaneously. The mRNA stability of TfR1 and DMT1(+IRE) was suppressed under acute hypoxia. The mRNA levels of TfR1 and DMT1(+IRE) were restrain by silencing IRP1. In sharp contrast, HIF-1alpha overexpression enhanced the mRNA levels of TfR1 and DMT1(+IRE), which reversed the inhibition of IRP1 on both. HIF-1alpha konckdown suppressed the hypoxia induced increase expression of TfR1 and DMT1(+IRE), whereas both proteins had little change when further decreased the IRP1 expression under hypoxia. Hypoxia upregulated the protein expression of Ferrtin-L in a time-dependent manner, yet there was no different when IRP1 silencing or overexperssion under hypoxia. The lactate dehydrogenase (LDH) release induced by hypoxia was increased by TfR1 siRNA silence. CONCLUSIONS: We propose that HIF-1/HRE system might play a principal part in hypoxia induced iron uptake. PMID- 30415774 TI - Bovine lactoferrin reverses programming of epithelial-to-mesenchymal transition to mesenchymal-to-epithelial transition in oral squamous cell carcinoma. AB - Epithelial-to-mesenchymal transition (EMT) is a biological process of invasion and metastasis in cancers, including in oral squamous cell carcinoma (OSCC). However, an effective anticancer drug that directly targets EMT has not yet been discovered. Therefore, we aimed to investigate the repressive effects of bovine lactoferrin (bLF) on EMT to achieve mesenchymal-to-epithelial transition (MET) in OSCC. OSCC cell lines, HOC313 (EMT-induced) and SCCVII (without EMT induction), were treated with bLF. The effects of bLF on EMT in OSCC were identified histologically by haematoxylin and eosin staining and observed morphologically and immunohistochemically using an anti-E-cadherin antibody. Expression levels of E-cadherin and vimentin were investigated using RT-PCR and western blotting. Immuno-expression of E-cadherin was examined in vivo in tumour tissues of C3H/HeN mice, transplanted with SCCVII cells, with or without bLF administration. We found that bLF changed the spindle-like mesenchymal cells to cuboidal-like epithelial cells and enhanced the affinity of membrane-bound E-cadherin in HOC313 cells. The transformation of EMT-MET in HOC313 cells was confirmed by the upregulation of E-cadherin and suppression of vimentin. Moreover, bLF suppressed TWIST expression through downregulation of ERK1/2 phosphorylation. Additionally, the inhibition tumour cell infiltration and increase in E-cadherin expression were observed in xenografts of the mice orally administered with bLF. Thus, based on the results from in vitro and in vivo studies, we concluded that bLF caused the restoration of epithelial properties through MET. Importantly, this finding is novel and is the first report indicating that bLF inhibited EMT and induced MET in OSCC, suggesting that bLF may provide a novel therapeutic strategy in OSCC. PMID- 30415775 TI - Spontaneous oscillation of the ciliary beat frequency regulated by release of Ca2+ from intracellular stores in mouse nasal epithelia. AB - Ciliary beating frequency (CBF) was investigated in ciliated nasal epithelial cells (cMNECs) isolated from mice using video microscopy equipped with a high speed camera. In cMNECs, a spontaneous CBF oscillation was observed. The CBF oscillation was abolished by BAPTA-AM but not by Ca2+-free solution. The addition of thapsigargin, which depletes Ca2+ from internal stores, also abolished CBF oscillation. Moreover, the intracellular Ca2+ concentration [Ca2+]i, spontaneously oscillated even with the Ca2+-free solution. Moreover, 2APB (an inhibitor of the IP3 receptor) abolished CBF oscillation in cMNECs. Overall, these findings suggest that the CBF oscillation in cMNECs is triggered by the release of Ca2+ from the IP3-sensitive internal stores. Moreover, IBMX, an inhibitor of phosphodiesterase, did not affect CBF oscillation in cMNECs, although it slightly increased CBF. These results suggest that CBF oscillations were induced by [Ca2+]i oscillation controlled via the release of Ca2+ from IP3 sensitive stores, rather than via cAMP accumulation. CBF oscillation possibly plays a crucial role in maintaining an efficient mucociliary clearance in the nasal epithelia. PMID- 30415776 TI - Vimentin intermediate filaments function as a physical barrier during intracellular trafficking of caveolin-1. AB - Both the cytoskeletal intermediate filaments (IFs) and cytoplasmic caveolae contribute to active processes such as cell migration, morphogenesis and vesicular trafficking, but the interplay between these two systems has remained elusive. Here, we find that vimentin and nestin IFs interact with caveolae central component caveolin-1 (CAV-1) and importantly, restrain the intracellular trafficking of CAV-1 positive vesicles by serving as a physical barrier. Consequently, CAV-1 vesicles show less density and mobility in vimentin IFs enriched region, which is a substrate stiffness independent process. Moreover, depletion of vimentin IFs releases the slow movement proportion of CAV-1 positive vesicles and thus increases their cytoplasmic dynamics, whereas the expression of caveolae-associated protein CAV-1, CAV-2 and cavin-1 were unaffected. Collectively, these results reveal a negative role of IFs in regulating the trafficking of intracellular CAV-1 vesicles in live cells. PMID- 30415777 TI - Detection of N-glycolylneuraminic acid biomarkers in sera from patients with ovarian cancer using an engineered N-glycolylneuraminic acid-specific lectin SubB2M. AB - N-glycolylneuraminic acid (Neu5Gc)-containing glycans are a prominent form of aberrant glycosylation found in human tumor cells and have been proposed as cancer biomarkers. The B subunit of the subtilase cytotoxin (SubB) produced by Shiga toxigenic Escherichia coli recognises Neu5Gc containing glycans. We have previously engineered this lectin, SubB2M, for greater specificity and enhanced recognition of Neu5Gc-containing glycans. Here we further explore the utility of SubB2M to detect Neu5Gc tumor biomarkers in sera from patients with ovarian cancer. Using surface plasmon resonance (SPR) we show that SubB2M can detect the established ovarian cancer biomarker, CA125, in a highly sensitive and specific fashion in the context of human serum. These studies established conditions for screening serum samples from patients with ovarian cancer for Neu5Gc glycans. We found that serum from patients with all stages of ovarian cancer had significantly elevated mean levels of Neu5Gc glycans compared to normal controls. Serum from patients with late stage disease (stages IIIC, IV) had uniformly elevated levels of Neu5Gc glycans. Detection of Neu5Gc-glycans using SubB2M has the potential to be used as a diagnostic ovarian cancer biomarker, as well as a tool for monitoring treatment and disease progression in late stage disease. PMID- 30415778 TI - Study on the degradation rule of calcitonin in vitro in patients with medullary thyroid carcinoma. AB - BACKGROUND: It was found that calcitonin in vitro can degrade rapidly whether in refrigeration or at room temperature, which increases the difficulty of accurate detecting of calcitonin greatly. This study was designed to solve this problem. METHODS: Serum samples with increased calcitonin from patients with medullary thyroid carcinoma were collected and divided into refrigeration and room temperature group. Analyze the degradation rule of calcitonin in the two groups according to the time of blood draw (T0), the time of sample detection (Tx), and the concentration (y) measured at Tx. RESULTS: The degradation rate of calcitonin was significantly different between the two storage conditions. The degradation has plateau stage and its concentration is associated with the original concentration. The degradation rule of the two groups can be expressed by the formula: y = -aln(x) + b. In the formula, b/a are constants associated with storage condition and gender. "x" is the time interval between blood draw and detection, that is, x = Tx - T0. CONCLUSIONS: The significance of the presence of immunoreactive isoforms and fragments of calcitonin with different stability in patients with medullary thyroid carcinoma is unclear. To make the inspection report more accurate and reliable, maybe the inspection personnel should report both the instrumental and corrected result, and also indicate the correction formula on the inspection report. PMID- 30415779 TI - Effects of molecular crowding on a bimolecular group I ribozyme and its derivative that self-assembles to form ribozyme oligomers. AB - In the RNA world, enrichment of self-replicating RNAs would have been beneficial to their survival, amplification, and evolution. Self-assembly of RNAs may be a strategy by which they enrich themselves. We examined the effects of molecular crowding on the activity of a bimolecular group I ribozyme and its derivative that self-assembles to form ribozyme oligomers. In a comparative activity assay using PEG as a molecular crowder, PEG rescued mutations in the parent bimolecular ribozyme more effectively than those in the oligomeric form. PMID- 30415780 TI - CircNUP214 sponges miR-145 to promote the expression of ZEB2 in thyroid cancer cells. AB - Circular (circ)RNAs have been implicated in cancer development. However, few studies have examined the role of circRNAs in papillary thyroid cancer (PTC). In this study we found that circNUP214 was upregulated in clinical PTC specimens relative to adjacent normal tissue. In vitro analyses showed that circNUP214 knockdown suppressed PTC cell proliferation, invasion, migration, and tumorigenesis. A luciferase reporter assay confirmed that circNUP214 binds to miR 145, which directly targets zinc finger E-box binding homeobox (ZEB)2. Thus, circNUP214 may play an oncogenic role in PTC by acting as a sponge for miR-145, leading to upregulation of ZEB2. These results provide evidence for a new regulatory mechanism in PTC development involving circNUP214, which can serve as a potential therapeutic target in PTC treatment. PMID- 30415781 TI - The transcriptome of the marine calanoid copepod Temora longicornis under heat stress and recovery. AB - Understanding the impacts of global change in zooplankton communities is crucial, as alterations in the zooplankton communities can affect entire marine ecosystems. Despite the economic and ecological importance of the calanoid copepod Temora longicornis in the Belgian part of the North Sea, molecular data is still very limited for this species. Using HiSeq Illumina sequencing, we sequenced the whole transcriptome of T. longicornis, after being exposed to realistic temperatures of 14 and 17 degrees C. After both an acute (1 day) and a more sustained (5 days) thermal exposure to 17 degrees C, we investigated gene expression differences with animals exposed to 14 degrees C, which may be critical for the thermal acclimation and resilience of this copepod species. We also studied the possibility of a short term stress recovery of a heat shock. A total of 179,569 transcripts were yielded, of which 44,985 putative ORF transcripts were identified. These transcripts were subsequently annotated into roughly 22,000 genes based on known sequences using Gene Ontology (GO) and KEGG databases. Temora only showed a mild response to both the temperature and the duration of the exposure. We found that the expression of 27 transcripts varied significantly with an increase in temperature of 3 degrees C, of which eight transcripts were differentially expressed after acute exposure only. Gene set enrichment analysis revealed that, overall, T. longicornis was more impacted by a sustained thermal exposure, rather than an immediate (acute) exposure, with two times as many enriched GO terms in the sustained treatment. We also identified several general stress responses independent of exposure time, such as modified protein synthesis, energy mobilisation, cuticle and chaperone proteins. Finally, we highlighted candidate genes of a possible recovery from heat exposure, identifying similar terms as those enriched in the heat treatments, i.e. related to for example energy metabolism, cuticle genes and extracellular matrix. The data presented in this study provides the first transcriptome available for T. longicornis which can be used for future genomic studies. PMID- 30415782 TI - Exceptional experiences reported by scientists and engineers. AB - CONTEXT: Throughout history people have reported exceptional experiences that appear to transcend the everyday boundaries of space and time, such as perceiving someone's thoughts from a distance. Because such experiences are associated with superstition, and some violate currently accepted materialist conventions, one might assume that scientists and engineers would be much less likely to report instances of these experiences than the general population. OBJECTIVES: To evaluate 1) the prevalence of exceptional human experiences (EHEs), 2) the level of paranormal belief, 3) the relationship between them, and 4) potential predictors of EHEs in three groups. PARTICIPANTS: Potential volunteers were randomly selected to receive invitations for an anonymous survey. MAIN MEASURES: Data were collected on 25 different types of EHEs, demographics, religious or spiritual affiliations, paranormal beliefs, mental health, and personality traits. Group differences were analyzed with chi-square tests and analysis of variance, and predictors were evaluated with a general linear model. RESULTS: 94.0% of the general population (n = 283), 93.2% of scientists and engineers (n = 175), and 99.3% of enthusiasts (n = 441) endorsed at least one EHE (X2(2) = 21.1, p < 0.0005). Paranormal belief was highest in EHE enthusiasts, followed by scientists and the general population (F(2,769) = 116.2, p < 0.0005). Belief was positively correlated with experience (r = 0.61, p < 0.0005). An exploratory general linear model showed that variables such as mental health, personality, impact and family history predict the endorsement and frequency of EHEs. This study indicates that EHEs occur frequently in both the general population and in scientists and engineers. PMID- 30415783 TI - Oxytocin receptor gene methylation in male and female PTSD patients and trauma exposed controls. AB - Oxytocin receptor gene (OXTR) DNA-methylation levels have been associated with trauma-exposure, mood- and anxiety disorders, and social processes relevant to posttraumatic stress disorder (PTSD). We hypothesized that OXTR methylation may play a role in the neurobiological underpinnings of PTSD. In the current study, we compared OXTR methylation between PTSD patients (n = 31, 14 females) and trauma-exposed controls (n = 36, 19 females). Additionally, the association between OXTR methylation and PTSD symptom severity and amygdala reactivity to an emotional faces task was assessed, as a neural hallmark of PTSD. DNA-methylation was investigated in the CpG island located at exon 3 of the OXTR, previously associated with OXTR expression. We observed a significant interaction between PTSD-status, sex and CpG-position on methylation levels. Post-hoc testing revealed that methylation levels at two specific CpG-sites were significantly higher in PTSD females compared to female trauma-exposed controls and PTSD males (CpGs Chr3:8809437, Chr3:8809413). No significant differences in methylation were observed between male PTSD patients and controls. Furthermore, within PTSD females, methylation in these CpG-sites was positively associated with anhedonia symptoms and with left amygdala responses to negative emotional faces, although this was no longer significant after stringent correction for multiple comparisons. Though the modest size of the current sample is an important limitation, we are the first to report on OXTR methylation in PTSD, replicating previously observed (sex-specific) associations of OXTR methylation with other psychiatric disorders. PMID- 30415785 TI - Anal Cancer: Putting Health-Related Quality of Life at the Forefront. PMID- 30415784 TI - Hypofractionated Concomitant Chemoradiation in Inoperable Locally Advanced Non small Cell Lung Cancer: A Report on 100 Patients and a Systematic Review. AB - AIMS: Concomitant chemoradiation is the standard of care in patients with inoperable non-small cell lung cancer. The purpose of this study was to analyse the survival outcome and toxicity data of using hypofractionated chemoradiation. MATERIALS AND METHODS: One hundred patients were treated from June 2011 to November 2016. Treatment consisted of 55 Gy in 20 daily fractions concurrently with split-dose cisplatin vinorelbine chemotherapy over 4 weeks followed by two cycles of cisplatin vinorelbine only. Survival was estimated using Kaplan-Meier and Cox regression was carried out for known prognostic factors. A systematic search of literature was conducted using Medline, Embase and Cochrane databases and relevant references included. RESULTS: In total, 97% of patients completed radiotherapy and 73% of patients completed all four cycles of chemotherapy. One patient died of a cardiac event during consolidative chemotherapy. There were two cases of grade 4 toxicities (one sepsis, one renal impairment). Grade 3 toxicities included nausea/vomiting (17%), oesophagitis (15%), infection with neutropenia (12%) and pneumonitis (4%). Clinical benefit was seen in 86%. Two year progression-free survival and overall survival rates were 49% and 58%, respectively. The median progression-free survival and overall survival were 23.4 and 43.4 months, respectively. The only significant prognostic factor was the number of chemotherapy cycles received (P = 0.02). The systematic review identified 13 relevant studies; a variety of regimens were assessed with variable reporting of outcomes and toxicity but with overall an improvement in survival over time. CONCLUSION: Our experience compared with the original phase II trial showed improved treatment completion rates and survival with acceptable morbidity. With appropriate patient selection this regimen is an effective treatment option for locally advanced non-small cell lung cancer. This study helps to benchmark efficacy and toxicity rates while considering the addition of new agents to hypofractionated concurrent chemoradiotherapy. The agreement of a standard regimen for assessment in future trials would be beneficial. PMID- 30415786 TI - Implementing statistical methods for generalizing randomized trial findings to a target population. AB - Randomized trials are considered the gold standard for assessing the causal effects of a drug or intervention in a study population, and their results are often utilized in the formulation of health policy. However, there is growing concern that results from trials do not necessarily generalize well to their respective target populations, in which policies are enacted, due to substantial demographic differences between study and target populations. In trials related to substance use disorders (SUDs), especially, strict exclusion criteria make it challenging to obtain study samples that are fully "representative" of the populations that policymakers may wish to generalize their results to. In this paper, we provide an overview of post-trial statistical methods for assessing and improving upon the generalizability of a randomized trial to a well-defined target population. We then illustrate the different methods using a randomized trial related to methamphetamine dependence and a target population of substance abuse treatment seekers, and provide software to implement the methods in R using the "generalize" package. We discuss several practical considerations for researchers who wish to utilize these tools, such as the importance of acquiring population-level data to represent the target population of interest, and the challenges of data harmonization. PMID- 30415787 TI - Isokinetic assessment of trunk muscles in facioscapulohumeral muscular dystrophy type 1 patients. AB - Facioscapulohumeral muscular dystrophy type 1 is the third most common inherited myopathy. Its severity is proportionate to the loss of microsatellite D4Z4 repetitions, which are below 10. Patients suffer from weakness in facial muscles, shoulder girdles and ankle dorsiflexors. Trunk impairment is reported in few studies. To assess correlation between D4Z4 number of repetitions in facioscapulohumeral muscular dystrophy type 1 patients and trunk extensors and flexors isokinetic peak torque, 48 patients with southern Blot confirmed facioscapulohumeral muscular dystrophy type 1 were enrolled to perform clinical evaluation (Ricci's Clinical Severity Scoring, Berg Balance Scale, Functional Reach Test, timed up-and-go test, six-minute walk test, functional independence measure) and trunk isokinetic assessment. Trunk extensors and flexors isokinetic peak torque at 60 degrees /sec were significantly correlated with number of D4Z4 microsatellite repetitions, sex, weight and age-independent (r = 0.391 [0.121; 0.662], p < 0.006 and r = 0.334 [0.028; 0.641], p < 0.033, respectively). Ricci's Clinical Severity Scoring was significantly correlated to trunk extensors isokinetic peak torque at 60 degrees /sec, sex and weight-independent (r = -0.743 [-0.938; -0.548], p < 0.0001). This study demonstrates moderate correlation between pathologic compression of D4Z4 microsatellite array and trunk extensors isokinetic strength among facioscapulohumeral muscular dystrophy type I patients. PMID- 30415788 TI - Severe limb-girdle muscular dystrophy 2A in two young siblings from Guinea-Bissau associated with a novel null homozygous mutation in CAPN3 gene. AB - Limb-girdle muscular dystrophy 2A (LGMD2A) or calpainopathy is the most common type of LGMD worldwide, representing about 30-40% of all described cases. Nevertheless, its prevalence in sub-Saharan African countries is unknown. We report two young siblings from Guinea-Bissau with recessive calpainopathy due to novel null homozygous c.1702Gdup mutation in CAPN3 gene. Their phenotype was quite aggressive concerning limb-girdle atrophy and muscle weakness as well as respiratory involvement. The proband needed nocturnal non-invasive ventilation at the age of 32, and his 33-year-old affected sister succumbed to an acute respiratory arrest after an intercurrent infection. This is the first description of calpainopathy in the sub-Saharian African region. Although there is no consistent genotype-phenotype correlation in calpainopathy, the new null homozygous mutation found in the CAPN3 gene may be associated with the particularly severe phenotype observed in our patients. PMID- 30415789 TI - Music, rhythm, rehabilitation and the brain: From pleasure to synchronization of biological rhythms. PMID- 30415748 TI - Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. AB - BACKGROUND: How long one lives, how many years of life are spent in good and poor health, and how the population's state of health and leading causes of disability change over time all have implications for policy, planning, and provision of services. We comparatively assessed the patterns and trends of healthy life expectancy (HALE), which quantifies the number of years of life expected to be lived in good health, and the complementary measure of disability-adjusted life years (DALYs), a composite measure of disease burden capturing both premature mortality and prevalence and severity of ill health, for 359 diseases and injuries for 195 countries and territories over the past 28 years. METHODS: We used data for age-specific mortality rates, years of life lost (YLLs) due to premature mortality, and years lived with disability (YLDs) from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 to calculate HALE and DALYs from 1990 to 2017. We calculated HALE using age-specific mortality rates and YLDs per capita for each location, age, sex, and year. We calculated DALYs for 359 causes as the sum of YLLs and YLDs. We assessed how observed HALE and DALYs differed by country and sex from expected trends based on Socio demographic Index (SDI). We also analysed HALE by decomposing years of life gained into years spent in good health and in poor health, between 1990 and 2017, and extra years lived by females compared with males. FINDINGS: Globally, from 1990 to 2017, life expectancy at birth increased by 7.4 years (95% uncertainty interval 7.1-7.8), from 65.6 years (65.3-65.8) in 1990 to 73.0 years (72.7-73.3) in 2017. The increase in years of life varied from 5.1 years (5.0-5.3) in high SDI countries to 12.0 years (11.3-12.8) in low SDI countries. Of the additional years of life expected at birth, 26.3% (20.1-33.1) were expected to be spent in poor health in high SDI countries compared with 11.7% (8.8-15.1) in low-middle SDI countries. HALE at birth increased by 6.3 years (5.9-6.7), from 57.0 years (54.6-59.1) in 1990 to 63.3 years (60.5-65.7) in 2017. The increase varied from 3.8 years (3.4-4.1) in high SDI countries to 10.5 years (9.8-11.2) in low SDI countries. Even larger variations in HALE than these were observed between countries, ranging from 1.0 year (0.4-1.7) in Saint Vincent and the Grenadines (62.4 years [59.9-64.7] in 1990 to 63.5 years [60.9-65.8] in 2017) to 23.7 years (21.9-25.6) in Eritrea (30.7 years [28.9-32.2] in 1990 to 54.4 years [51.5-57.1] in 2017). In most countries, the increase in HALE was smaller than the increase in overall life expectancy, indicating more years lived in poor health. In 180 of 195 countries and territories, females were expected to live longer than males in 2017, with extra years lived varying from 1.4 years (0.6-2.3) in Algeria to 11.9 years (10.9-12.9) in Ukraine. Of the extra years gained, the proportion spent in poor health varied largely across countries, with less than 20% of additional years spent in poor health in Bosnia and Herzegovina, Burundi, and Slovakia, whereas in Bahrain all the extra years were spent in poor health. In 2017, the highest estimate of HALE at birth was in Singapore for both females (75.8 years [72.4-78.7]) and males (72.6 years [69.8-75.0]) and the lowest estimates were in Central African Republic (47.0 years [43.7-50.2] for females and 42.8 years [40.1 45.6] for males). Globally, in 2017, the five leading causes of DALYs were neonatal disorders, ischaemic heart disease, stroke, lower respiratory infections, and chronic obstructive pulmonary disease. Between 1990 and 2017, age standardised DALY rates decreased by 41.3% (38.8-43.5) for communicable diseases and by 49.8% (47.9-51.6) for neonatal disorders. For non-communicable diseases, global DALYs increased by 40.1% (36.8-43.0), although age-standardised DALY rates decreased by 18.1% (16.0-20.2). INTERPRETATION: With increasing life expectancy in most countries, the question of whether the additional years of life gained are spent in good health or poor health has been increasingly relevant because of the potential policy implications, such as health-care provisions and extending retirement ages. In some locations, a large proportion of those additional years are spent in poor health. Large inequalities in HALE and disease burden exist across countries in different SDI quintiles and between sexes. The burden of disabling conditions has serious implications for health system planning and health-related expenditures. Despite the progress made in reducing the burden of communicable diseases and neonatal disorders in low SDI countries, the speed of this progress could be increased by scaling up proven interventions. The global trends among non-communicable diseases indicate that more effort is needed to maximise HALE, such as risk prevention and attention to upstream determinants of health. FUNDING: Bill & Melinda Gates Foundation. PMID- 30415790 TI - Name That Nephrogram: Asymmetric Renal Enhancement in the Acute Care Setting. AB - Disorders of the kidney and urinary collecting system are common encountered in the acute care setting. Computed tomography has progressively replaced intravenous pyelography for the evaluation of most urinary tract pathology including acute flank pain, suspected malignancy, congenital abnormalities, anatomical variants, and inflammatory/vascular conditions through evaluation of the "nephrogram" produced by intravenous contrast material filtering through the kidneys. In this review, we describe the most common types of abnormal nephrograms seen on renal computed tomography, and highlight the salient features and conditions associated with them, in addition to a pictorial review with specific and interesting related cases. The types of abnormal nephrograms reviewed are absent, unilateral delayed, striated, spotted, and persistent. PMID- 30415791 TI - Solitary fibrous tumor in the pelvis: An infrequent entity. PMID- 30415792 TI - Major ambulatory surgery for the treatment of breast cancer: Factors conditioning conversion to conventional hospitalization. AB - INTRODUCTION: The main step in curative treatment for breast cancer is surgery. Its use in an ambulatory setting can contribute towards more efficient healthcare, providing additional benefits for patients. In this study, we analyze the results obtained with this treatment method and identify factors related with conversion to hospitalization. METHODS: Results were analyzed from the 206 surgeries performed for breast cancer in 2016, using three different methods: day surgery, overnight ambulatory (23h) and conventional hospitalization. The ambulatory success and conversion rates were calculated for the global sample and stratified, distinguishing between conservative surgery, mastectomy and axillary surgery. A univariate analysis was performed to identify the factors involved in conversion. RESULTS: For the global sample, the ambulatory surgery rate was 61.2%, 16.5% conversions and a success rate of 83.4%. For conservative surgery, ambulatory, success and conversion rates were 78.8%, 88.6 and 11.4%, respectively. For mastectomies, the ambulatory rate was 28.6%, with 62.9% success and 37.1% conversions. The 11 axillary surgeries were performed as day surgeries. Factors associated with conversion were mastectomy vs. vs. conservative surgery and the appearance of postoperative complications. CONCLUSIONS: Ambulatory surgery for the surgical treatment of breast cancer should be standard care. Optimized results require adequate patient selection and the performance of surgical technique that needs to be as careful and as conservative as possible. PMID- 30415793 TI - The Acute Care Surgery model in the world, and the need for and implementation of trauma and emergency surgery units in Spain. AB - The Acute Care Surgery model groups trauma and emergency surgery with surgical critical care. Conceived and extended during the last 2 decades throughout North America, the magnitude and clinical idiosyncrasy of emergency general surgery have determined that this model has been expanded to other parts of the world. In our country, this has led to the introduction and implementation of the so-called trauma and emergency surgery units, with common objectives as those previously published for the original model: to decrease the rates of emergency surgery at night, to allow surgeons linked to elective surgery to develop their activity in their own disciplines during the daily schedule, and to become the perfect link and reference for the continuity of care. This review summarizes how the original model was born and how it expanded throughout the world, providing evidence in terms of results and a description of the current situation in our country. PMID- 30415794 TI - Altered regulation of serum lysosomal acid hydrolase activities in Parkinson's disease: A potential peripheral biomarker? AB - INTRODUCTION: Recent studies have indicated that lysosomal dysfunction contributes to the development of idiopathic Parkinson's disease (PD). It is uncertain whether dysregulation of serum lysosomal acid hydrolase activity exists in sporadic PD patients compared with normal controls (NCs) and parkinsonian syndrome (PS) patients. METHODS: Sporadic PD patients without GBA1 mutations (n = 68) were matched with normal controls (n = 45), and parkinsonian syndrome patients (n = 32) in terms of family history, age, and sex. We measured the activities of lysosomal enzymes, alpha-galactosidase, beta-galactosidase, and beta-hexosaminidase and examined the possible correlations between lysosomal acid hydrolase activities with age in NCs, PD, and PS patients. RESULTS: beta Galactosidase activity was significantly higher in the PD and PS than in the NC group (P < 0.001). The beta-galactosidase to alpha-galactosidase and beta hexosaminidase to beta-galactosidase activity ratios were more useful for distinguishing PD and PS patients from NCs (P < 0.0001). Furthermore, alpha galactosidase activity was significantly higher in PS patients than both PD and NC groups (p = 0.04). beta-Galactosidase and alpha-galactosidase activities exhibited a statistically significant negative correlation with age in NCs, and beta-hexosaminidase activity showed a positive correlation with age in PS. However, PD patients did not show any of these correlations. CONCLUSION: Our results suggest the presence of an unknown regulatory mechanism(s) of serum acid hydrolase activities with aging in the normal population and abnormalities in their regulation in PD and PS patients. However, the pattern of dysregulation in these two groups is different. Thus, serum lysosomal acid hydrolase activity can be used as a peripheral biomarker for PD. PMID- 30415795 TI - Relation of CHA2DS2VASC Score With Hemorrhagic Stroke and Mortality in Patients Undergoing Fibrinolytic Therapy for ST Elevation Myocardial Infarction. AB - Hemorrhagic stroke (HS) is a feared complication of Fibrinolytic therapy (FT). Risk assessment scores may help in risk stratification to reduce this complication. Patients (admissions) >=18 years with a primary diagnosis of ST elevation myocardial infarction (STEMI) who received systemic thrombolysis were extracted from Nationwide Inpatient Sample database and stratified and compared based on CHA2DS2VASC score 0 to 3, 4 to 6, and 7 to 9 as low, intermediate and high risk, respectively. The primary outcomes of interest were HS and mortality. We performed logistic regression analysis with a composite of HS and mortality as the primary end point. Of the 917,307 admissions with a primary diagnosis of STEMI, 39,579 (4.3%) underwent FT. The median score was 3 (interquartile range 1 to 5). The rate of HS significantly increased in the risk category compared with the low and intermediate groups (0.5% and 0.6% vs 4.1%; p <0.001). Mortality increased with increasing risk category (3.8% vs 10.5% vs 20.7%; p <0.001). Compared with the low-risk group patients in the intermediate (odds ratio 2.11 95% confidence interval [CI] 1.56 to 2.85; p <0.001) and high risk groups (odds ratio 3.47 95% CI 1.68 to 7.2; p <0.001) were more likely to experience the composite end point of HS or inpatient mortality. CHA2DS2VASC score performed better at predicting mortality (area under curve 0.67, 95% CI 0.64 to 0.7; p = 0.014) than HS (area under curve 0.6 95% CI 0.52 to 0.69; p = 0.021). In conclusion, patients with high CHA2DS2VASC score (7 to 9) are at a higher risk of hemorrhagic stroke and death after FT for STEMI. CHA2DS2VASC score performed better at predicting mortality than hemorrhagic stroke in this cohort. PMID- 30415796 TI - Timing of Noninvasive Studies in Patients With Secondary Takotsubo Syndrome. PMID- 30415797 TI - Comparison between general, spinal, epidural, and combined spinal-epidural anesthesia for cesarean delivery: a network meta-analysis. AB - BACKGROUND: This study is a network meta-analysis to compare maternal and fetal outcomes associated with four different anesthetic techniques for cesarean delivery. METHODS: An arm-based, random-effect frequentist network meta-analysis was performed. A random effect model was selected considering deviance information criteria. Randomized trials reporting the following outcomes were included: Apgar score at 1- or 5-min; umbilical arterial and venous pH; umbilical arterial pH <7.2; and neonatal score at 2-4 hours. Loop-specific heterogeneity was evaluated by risk of odds ratio and tau2. Quality of evidence was assessed using the GRADE approach. RESULTS: Data from 46 randomized trials including 3689 women contributed to the study. There were significant differences in Apgar score <=6 at 1 min between spinal versus general anesthesia (odds ratio 0.27, 95% confidence interval [CI] 0.13 to 0.55: moderate quality evidence) and Apgar scores at 1- and 5-min, favoring spinal anesthesia. Umbilical venous pH associated with epidural anesthesia was significantly higher than that with general anesthesia (mean difference 0.010, 95% CI 0.001 to 0.020: moderate quality evidence) or spinal anesthesia. Spinal anesthesia was ranked best for Apgar score <=6 at 1-min (SUCRA=89.8), Apgar score at 1-min (SUCRA=80.4) and 5 min (SUCRA=90.5). Epidural anesthesia was ranked highest for umbilical venous pH (SUCRA=87.4) and neonatal score (SUCRA=79.3). CONCLUSIONS: Spinal and epidural anesthesia were ranked high regarding Apgar scores and epidural anesthesia was ranked high regarding umbilical venous pH, but the results were based on small heterogeneous studies with high or unclear risks of bias. PMID- 30415798 TI - Anaesthetic management for caesarean section of a parturient with a known difficult airway and closed spinal dysraphism. AB - Many anaesthetists consider patients with existing neurological deficits, untreated spinal pathology or those having undergone major spinal intervention to be precluded from undergoing neuraxial anaesthesia. While this is partly rooted in fears of litigation there is also a lack of consensus of the best practice in the anaesthetic management of these patients. We present our management of a parturient who attended our institution, having a number of anaesthetic complexities including a known difficult airway, spinal fusion and persistent spinal cord tethering. She successfully underwent delivery under neuraxial blockade for the delivery of her fourth child. We believe that by undergoing a thorough multidisciplinary clinical evaluation, including the extensive use of neuroimaging and ultrasound, it may be possible to plan and perform safe neuraxial anaesthesia. PMID- 30415799 TI - Obstetric anesthesia management of the patient with cardiac disease. AB - Cardiovascular disease is the leading cause of maternal mortality in much of the developed world. Risk stratification models can predict which patients are at greatest risk for maternal or fetal morbidity or mortality. Particular cardiac diseases hold significant risk of mortality during pregnancy including pulmonary hypertension, aortic aneurysm, left-ventricular outflow tract obstruction, and severe cardiomyopathy. High-risk patients should deliver at high-resource hospitals under the care of experts in cardiology, obstetrics, perinatology, neonatology and anesthesiology. The obstetric anesthesiologist should formulate delivery plans for cardiac monitoring, labor analgesia, cesarean anesthesia, postpartum monitoring, as well as plans for obstetric or cardiac emergencies. Carefully coordinated multidisciplinary care of pregnant women with cardiac disease can result in successful outcomes. PMID- 30415800 TI - Pharmacist prescribing: An overnight success, decades in the making. PMID- 30415801 TI - Elusive eradication: Challenges facing the worldwide eradication of polio. PMID- 30415802 TI - Baricitinib, Tildrakizumab-asmn, and Elagolix sodium. PMID- 30415803 TI - Repeat Intravenous Ketamine Dosing in Children Undergoing Emergency Department Procedural Sedation. AB - BACKGROUND: Patients undergoing procedural sedation with intravenous ketamine often receive repeat doses to maintain dissociation; however, data between doses are lacking. OBJECTIVES: The purpose of this study was to characterize the frequency, time interval, and dosages of ketamine received by children undergoing procedural sedation and to explore the effects of age and body mass index on these parameters. METHODS: This was a retrospective study of patients 1 to 18 years of age undergoing procedural sedation with intravenous ketamine in a pediatric emergency department between October 2016 and June 2017. Total repeat ketamine dosages were standardized to a 1-h sedation. RESULTS: Four hundred nineteen patients were included in the analysis. The median sedation time was 33.0 minutes (interquartile range [IQR] 25.0-45.0). Three hundred sixty-three patients (86.6%) received at least 1 repeat ketamine dose. The median time between doses was 7.0 minutes (IQR 5.0-12.0). Children <6 years of age, compared with older children, received higher hourly doses of ketamine in mg/kg/h (2.8 [IQR 1.8-3.9] vs. 1.8 [IQR 1.2-2.6], pc < 0.01). Children <3 years of age, compared with older children, received the highest hourly dose of ketamine in mg/kg/h (3.7 [IQR 2.3-5.0] vs. 1.9 [IQR 1.4-2.8], pc < 0.01). Ketamine repeat and hourly dosing does not appear to be significantly different in children of differing body mass index classes. CONCLUSIONS: Patients undergoing ketamine sedation often receive repeat doses to maintain dissociation. Patients <3 years of age received the highest total repeat ketamine dosages. PMID- 30415804 TI - Knowledge, perception, performance, and attitude regarding hand hygiene and related factors among infection control nurses in South Korea: A cross-sectional study. AB - BACKGROUND: We assessed the current status of knowledge, perception, attitude, and role model regarding hand hygiene (HH) among infection control nurses (ICNs) and identified the factors influencing these variables. METHODS: A structured questionnaire was adapted from a World Health Organization survey. Data were collected from November 8, 2017, to February 2, 2018. RESULTS: ICNs showed the following scores (mean +/- SD): knowledge (19.5 +/- 2.3), perception (69.9 +/- 8.9), attitude (46.9 +/- 5.8), and role model (39.2 +/- 6.0). HH performance of health care workers (HCWs) was 75.2 +/- 15.5. Mean HH performance scores of HCWs (P = .007) differed significantly according to infection control experience (3 groups: <=12 months, 13-24 months, >24 months). Perception, attitude, and role model scores showed positive correlations with each other (P < .01). The regression model for HH performance of HCWs was calculated as follows: Y1 = 31.638 + 0.067X1 (perception of ICNs) + 0.133X2 (attitude of ICNs) + 0.825X3 (role model of ICNs) (P < .001; adjusted R2 = 0.115). DISCUSSION: Perception, attitude, and role model scores of ICNs were significant predictors of HH performance of HCWs. CONCLUSIONS: Specialized well-structured HH education programs should be developed for ICNs that will help improve HH performance of HCWs. PMID- 30415805 TI - Observation of stethoscope sanitation practices in an emergency department setting. AB - BACKGROUND: Stethoscopes harbor pathogens that can be transferred to patients when proper sanitary measures are not taken. Our aim was to assess medical provider stethoscope cleaning and hand hygiene in an emergency department setting. METHODS: The frequency and methods of stethoscope cleaning during and after provider-patient encounters were observed anonymously in an emergency department of the VA San Diego Healthcare System. RESULTS: Among the total of 426 encounters, 115 (26.9%) involved the use of a personal stethoscope. In 15 of these 115 encounters (13.0%), the provider placed a glove over the stethoscope before patient contact. In 13 of these 115 encounters (11.3%), the provider cleaned the stethoscope with an alcohol swab after patient interaction. Stethoscope hygiene with water and a hand towel before patient interaction was observed in 5 of these 115 encounters (4.3%). Hand sanitizer use or handwashing was observed in 213 of the 426 encounters (50.0%) before patient interaction. Gloves were used before patient interaction in 206 of these 426 encounters (48.4%). Hand sanitizer or handwashing was used in 332 of the 426 encounters (77.9%) after patient interaction. CONCLUSIONS: Rates of stethoscope and hand hygiene performance were lower than expected. Further investigation of stethoscope contamination and the associated risk of nosocomial infection are needed. Perhaps clearer guidelines on proper stethoscope cleaning would reduce this risk. PMID- 30415807 TI - Neurosurgery in viral encephalitis: Application of decompressive craniectomy in medical diseases. PMID- 30415808 TI - Testing a Conceptual Model for Men's Sexual Desire Referring to Automatic Thoughts, Emotions, Sexual Function, and Sexism. AB - INTRODUCTION: Literature lacks biopsychosocial models of men's sexuality. Regarding sexual desire, Carvalho and Nobre (J Sex Med 2011;8:754-763.) presented a cognitive-affective model including age, medical factors, dyadic adjustment, psychopathology, restrictive attitudes toward sexual activity, erection concerns, lack of erotic thoughts (LET), sadness, and shame as predictors. In particular, automatic thoughts were highlighted as the main predictors of sexual desire in men. AIM: To test a conceptual model (confronting full and partial mediation) considering the interrelated role of automatic thoughts, emotional factors, sexual function, and sexism in influencing the levels of men's sexual desire. METHODS: Selected variables were the best predictors of men's sexual desire in a previous study on 450 heterosexual Italian men (age 31.36 +/- 10.73 years). Path diagrams were built including "orgasmic function," "LET," "erection concerns thoughts" (ECT), "hostile sexism," and "positive affect" as predictors of sexual desire. The 2 versions of the model were designed as a "partial" and a "full mediation" from automatic thoughts toward desire. ECT and LET were selected as main predictors, with direct paths going from ECT to positive affect and sexual desire, and from LET to positive affect, orgasmic function, and sexual desire. Direct paths were also drawn from emotions and orgasm to sexual desire. Moreover, in the partial mediation model, part of ECT and LET effect was mediated by emotions and orgasm, and part directly influenced sexual desire. Hostile sexism and sociodemographic variables were considered as exogenous variables influencing sexual desire. Path analyses were performed through structural equation modeling approach. MAIN OUTCOME MEASURE: Results from 4 standardized questionnaires and sociodemographic information were considered for this study: International Index of Erectile Function, Positive and Negative Affect Schedule, Ambivalent Sexism Inventory, and Sexual Modes Questionnaire. RESULTS: Results showed a satisfactory data fit for both versions, but the partial mediation model was retained (chi2 = 35.312, degree of freedom = 34, P = .406; goodness of fit = .987; normed fit index = .945; comparative fit index = .998; root mean square error of approximation = .009 [95% CI .000-.036]). All the endogenous paths and hostile sexism were found to be significant. CLINICAL IMPLICATIONS: The model selected could suggest the need to operate under an biopsychosocial approach, considering cognitive, emotional, and sexual aspects all together to elicit an effective arise of sexual desire level. STRENGTH & LIMITATIONS: The study can claim a good methodology and the proposal of an interesting model, even if the results should be carefully interpreted due to the use of no representative sample, self-report measures, and the limited number of variables involved. CONCLUSION: Our findings suggest that cognitive, emotional, sexual functioning, and cultural variables interplay affecting men's sexual interest. Nimbi FM, Tripodi F, Rossi R, et al. Testing a Conceptual Model for Men's Sexual Desire Referring to Automatic Thoughts, Emotions, Sexual Function, and Sexism. J Sex Med 2018;15:1518-1526. PMID- 30415809 TI - Hepatocyte Nuclear Factor-4alpha P2 Promoter Variants Are Associated With the Risk of Metabolic Syndrome and Testosterone Deficiency in Aging Taiwanese Men. AB - BACKGROUND: Hepatocyte nuclear factor-4alpha (HNF4A) can influence the risk of insulin resistance that is postulated to be an important link between metabolic syndrome (MetS) and testosterone deficiency (TD) in men. AIM: To investigate the relationship between single-nucleotide polymorphisms (SNPs) of HNF4A and the risk of developing MetS and TD in a population of aging Taiwanese men. METHODS: A free health screening of men over 40 years of age was conducted in a medical center in Kaohsiung City, Taiwan. All participants underwent a physical examination, answered a questionnaire on demographics and medical history, completed the Androgen Deficiency in The Aging Male questionnaire to assess clinical symptoms of TD, and provided 20-mL whole blood samples for biochemical, hormonal, and genetic evaluation. MAIN OUTCOME MEASURE: 3 common SNPs (rs11574736, rs1884613, and rs2144908) of HNF4A were selected and identified using a TaqMan 5' allelic discrimination assay. RESULTS: 559 men were enrolled for this study (mean age, 55.8+/- 4.9 years). Prevalence of TD was significantly higher (P = .031) in subjects with MetS (16.8%) than those without MetS (10.1%). In SNP rs1884613 of HNF4A, subjects with the C allele carried a 1.31- and 1.50-times higher risk of developing MetS and TD, respectively, compared to those with the G allele, after adjusting for potential covariates. In addition, subjects with the CC genotype were exposed to a 1.91- and 2.20-times higher risk of developing MetS and TD, respectively, compared to those with the GG genotype. CLINICAL IMPLICATIONS: Our findings may point to the importance of the role played by insulin resistance in the link between MetS and TD. STRENGTH & LIMITATIONS: Our current work is the first report with adequate sample size to evaluate the role of genetic variants of HNF4A on the risk of both MetS and TD in men. The limitations included subjects enrolled from a free health screening and single measurement of serum testosterone levels. CONCLUSION: The rs1884613 SNP marker of HNF4A is significantly associated with an increased risk for developing both MetS and TD in aging Taiwanese men. Further population-based studies utilizing larger samples of different ethnicities may be needed to confirm these preliminary results. Liu C-C, Lee Y-C, Hung S-P. Hepatocyte Nuclear Factor-4alpha P2 Promoter Variants Are Associated With the Risk of Metabolic Syndrome and Testosterone Deficiency in Aging Taiwanese Men. J Sex Med 2018;15:1527-1536. PMID- 30415810 TI - Androgen Receptor Polymorphism and Female Sexual Function and Desire. AB - INTRODUCTION: The effect of testosterone depends on the exposure of and the sensitivity of the androgen receptor (AR). It has been shown that a cytosine adenine-guanine (CAG) trinucleotide repeat polymorphism in the AR gene has an impact on AR functional capacity in men. However, large studies are lacking on the impact of this polymorphism on female sexual function. AIM: To determine whether the CAG repeat length was associated with different aspects of women's sexual function and dysfunction, including desire, arousal, lubrication, orgasm, satisfaction, sexual pain, and sexually related personal distress. METHODS: This cross-sectional study included 529 healthy women, aged 19-65 years. Participants completed a questionnaire to provide demographic and sexual data. The CAG repeat length was analyzed in a blood sample. The correlations between CAG repeat lengths and different aspects of sexual function were calculated. Independent Student t-tests were performed to evaluate differences in the mean number of CAG repeats in the short and long allele and of the biallelic mean length determined by simple calculation and X-inactivation analysis, respectively, between women with sexual problems and women without sexual problems. P values <.05 were considered statistically significant. MAIN OUTCOME MEASURE: We used the Female Sexual Function Index, with 6 subdomains, to distinguish between women without and women with impaired sexual function; low sexual desire; impaired arousal, lubrication, or orgasm; diminished satisfaction; or pain during sex. The Female Sexual Distress Scale was used to measure sexually related personal distress. RESULTS: Overall, we found that increasing numbers of CAG repeats were correlated to increased sexual function. We found that women with problems achieving orgasm had a significantly lower number of CAG repeats than women that reported no problems reaching orgasm. We found no associations between CAG repeat lengths and other aspects of female sexual dysfunction, including hypoactive sexual desire disorder. CLINICAL IMPLICATIONS: The results could indicate an impact of the AR on women's sexual function, including the ability to reach orgasm. STRENGTH & LIMITATIONS: This is a large study using validated sexual questionnaires. A limitation is the cross-sectional design. Owing to the study design, this study is explorative and hypothesis generating. CONCLUSION: In this large cross sectional study, we demonstrated that CAG repeat length is positively correlated to sexual function and that women with a reduced ability to reach orgasm had smaller numbers of CAG repeats in the AR gene than women with no orgasmic problems. These findings indicated that androgens and ARs might play a role in women's sexual function. Wahlin-Jacobsen S, Flanagan JN, Pedersen AT, Kristensen E, Arver S, Giraldi A. Androgen Receptor Polymorphism and Female Sexual Function and Desire. J Sex Med 2018;15:1537-1546. PMID- 30415806 TI - Military-related risk factors for dementia. AB - INTRODUCTION: In recent years, there has been growing discussion to better understand the pathophysiological mechanisms of traumatic brain injury and post traumatic stress disorder and how they may be linked to an increased risk of neurodegenerative diseases including Alzheimer's disease in veterans. METHODS: Building on that discussion, and subsequent to a special issue of Alzheimer's & Dementia published in June 2014, which focused on military risk factors, the Alzheimer's Association convened a continued discussion of the scientific community on December 1, 2016. RESULTS: During this meeting, participants presented and evaluated progress made since 2012 and identified outstanding knowledge gaps regarding factors that may impact veterans' risk for later life dementia. DISCUSSION: The following is a summary of the invited presentations and moderated discussions of both the review of scientific understanding and identification of gaps to inform further investigations. PMID- 30415811 TI - Novel Concept Enabling an Old Idea: A Flexible Electrode Array to Treat Neurogenic Erectile Dysfunction. AB - INTRODUCTION: Many studies have shown that electrostimulation of the cavernosal nerve can induce and maintain penile erection. Based on these discoveries, neurostimulation to activate the erectile response has been considered a potential solution to treat erectile dysfunction (ED). However, despite recognized potential, this technology has not been further developed. The barrier is the complex anatomy of the human cavernous nerve, which challenges the intraoperative identification of the cavernosal nerves for electrode placement. AIM: To overcome this major barrier, we proposed a practical solution: a 2 dimensional flexible electrode array that can cover the entire plexus area, ensuring that at least 1 of the electrodes will be in optimal contact with the cavernosal nerve, without the need of intraoperative identification. The present study aims to evaluate this concept intraoperatively. METHODS: 24 patients enrolled for open radical prostatectomy were recruited. During the surgical procedures, the electrode array was positioned on the pelvic plexus (on the prostatic apex or pelvic wall) and electrical stimulation was applied to induce penile erection. Penile erectile response was assessed by (i) visual change of penile tumescence and (ii) by a penile plethysmograph system. MAIN OUTCOME MEASURE: Ability and success rate of evoking penile response were measured by applying electrical stimulation using the developed electrode array. RESULTS: Electrical stimulation produced immediate penile response in all cases when tested before (on prostatic apex) or after prostate removal (on pelvic wall). Clear visual penile engorgement was observed in 75% of the cases, whereas 25% showed minimal to moderate penile tumescence. As expected, patients with lower International Index of Erectile Function-5 score presented a reduced response, whereas stimulation before prostate removal showed greater response than following removal. Interestingly, erectile response was potentiated by bilateral stimulation (circumference increase [mm]: 2.7 +/- 1.02 vs. 8.2 +/- 1.9, P = .01). CLINICAL IMPLICATIONS: These data bring sufficient proof of concept of a conceivable novel medical implant for the treatment of ED caused by mechanical nerve injury, such as prostatectomy and spinal cord injury. STRENGTH & LIMITATIONS: This is the first approach that can ensure the optimal site stimulation of the erectogenic neuronal path within the lower pelvic area and overcome the major barrier of individual anatomic variability. However, because this study was performed intraoperatively in an acute scenario, further studies are needed to evaluate its chronic efficacy for clinical practice. CONCLUSION: The flexible electrode array concept can ensure the electrostimulation of erectogenic neuronal path when positioned on the prostate apex or pelvic floor. Skoufias S, Sturny M, Fraga-Silva R, et al. Novel concept enabling an old idea: A flexible electrode array to treat neurogenic erectile dysfunction. J Sex Med 2018;15:1558-1569. PMID- 30415812 TI - Concurrent Assessment of Penile Blood Flow and Circumference as Indicators of Male Sexual Arousal. AB - INTRODUCTION: The current study aims to validate a new imaging tool to assess men's sexual psychophysiological responding: laser Doppler imaging (LDI), which directly measures subcutaneous genital blood flow. In this study, we concurrently assessed genital sexual arousal in a sample of men using the LDI and the current gold standard of male sexual psychophysiology, the penile strain gauge (PSG). AIM: To (i) assess the validity of the LDI as a measure of male sexual arousal, (ii) evaluate the relationship between the LDI and PSG, and (iii) compare sexual concordance produced by the LDI and PSG. METHODS: A total of 25 male participants (Mage = 24.28 years, SD = 6.10, range 18-37) watched 4 experimental films (ie, anxiety-provoking, humorous, erotic, neutral nature content) while their sexual arousal was assessed. Genital sexual arousal was assessed using the LDI (blood perfusion) and PSG (penile tumescence) concurrently. Subjective sexual arousal was assessed using continuous and discrete self-reported measures. MAIN OUTCOME MEASURE: Results demonstrate the validity of the LDI as an imaging-based measure of male genital arousal, and one that is comparable to the PSG. RESULTS: Significant increases in genital blood flow assessed via the LDI were observed for erotic, but not anxiety-provoking, humorous, or neutral films (F[1.65, 39.57] = 18.23, P < .001, etap2 = .43). A moderate, positive correlation between genital arousal measured via the LDI and PSG concurrently was observed (r = .40), despite considerable across-participant variability. In the current sample, the LDI and PSG both produced strong sexual concordance estimates (r = .51 and r = .46, respectively). When all LDI and PSG concordance estimates were correlated, a moderate relationship was revealed (r = .37). CLINICAL IMPLICATIONS: As a new imaging tool for male sexual psychophysiological arousal, the LDI holds promise for improving our understanding of issues related to men's sexual health. STRENGTH & LIMITATIONS: Movement artifacts produced by penile engorgement were a limitation to the LDI as an imaging technique. Further, the LDI used in the current study was a discrete measure of arousal, whereas the PSG was continuous; future research would benefit by using continuous measurement capabilities of contemporary LDI systems. CONCLUSION: As a valid measure of genital sexual arousal in men, the LDI holds promise as a tool that can be used to explore more nuanced questions about human sexuality, including cross-gender comparisons and real-time exploration of genital arousal patterns. Bossio JA, Singh M, Pukall CF. Concurrent assessment of penile blood flow and circumference as indicators of male sexual arousal. J Sex Med 2018;15:1570-1578. PMID- 30415813 TI - The Risk of Sexual Dysfunction and Effectiveness of Treatment of Benign Prostatic Hyperplasia With Severe Lower Urinary Tract Dysfunction With Combination of Dutasteride and Solifenacin. AB - INTRODUCTION: Correction of benign prostatic hyperplasia (BPH) with lower urinary tract (LUT) symptoms (LUTS) is treated with drugs of different pharmacological classes having side effects including suppression of sexual function. AIM: To assess the effect of simultaneous intake of dutasteride and solifenacin on the reversibility of severe LUTS and sexual function in men with BPH. METHODS: Patients from group A took dutasteride 0.5 mg/d, those from group V took dutasteride 0.5 mg/d and solifenacin 10 mg/d, and those from group S took dutasteride 0.5 mg/d and solifenacin 20 mg/d. The duration of the observation was 6 months. The sexual function was rated with the International Index of Erectile Function questionnaire and Men's Sexual Health Questionnaire-ejaculatory dysfunction. The functional status of LUT was rated with International Prostate Symptom Score, overactive bladder questionnaire-awareness tool, diary voiding, and uroflowmetry. MAIN OUTCOME MEASURE: The state of sexual function and function of the LUT in men improved. RESULTS: The erectile function in all men, having participated in the study, did not change [group A, 9.8 (1.6)/9.4 (3.8), P >= .05; group B, 10.1 (2.1)/10.5 (3.7), P >= .05; group C, 9.7 (1.5)/9.5 (2.6), P >= .05]. The ejaculator function significantly decreased in all groups. According to International Prostate Symptom Score, obstruction diminished in this group [incomplete emptying, 3.7 (0.7)/1.5 (0.3), P <= .05; intermittence, 3.5 (1.0)/3.5 (1.0), P <= .05; weak stream, 3.8 (0.6)/1.5 (0.4), P <= .05; straining, 3.4 (0.5)/0.7 (0.7), P <= .05] as did hyperactivity [urgency, 2.8 (0.7)/0.9 (0.7), P <= .05; nocturia, 2.8 (0.6)/1.2 (0.4), P <= .05]. All numbers in the manuscript are given in points unless otherwise stated. The values in parentheses are SD (unless otherwise specified). CLINICAL IMPLICATIONS: The information that a high dose of solifenacin administered concomitantly with dutasteride may contribute to increase in sexual satisfaction and preservation of erectile function at the baseline level can be useful and used by sexologists, urologists, and family doctors. STRENGTH & LIMITATIONS: The combination of dutasteride 0.5 mg/d and solifenacin 10 mg/d saves erectile function and improves sexual satisfaction. At the same time, the symptoms of obstruction and hyperactivity disappear or are reduced in most patients. Nevertheless, we did not study late results of the combined therapy. CONCLUSION: Suggested combination does not impact on erectile function but decreases ejaculator function; however, it does not affect a general high rating of sexual function by patients. Thus, overall sexual function in men with BPH and severe LUTS is not impaired by prolonged intake of double dosage of solifenacin combined with dutasteride. The combination of dutasteride and solifenacin is effective and safe to treat BPH and severe LUTS. Kosilov K, Kuzina I, Kuznetsov V, et al. The Risk of Sexual Dysfunction and Effectiveness of Treatment of Benign Prostatic Hyperplasia With Severe Lower Urinary Tract Dysfunction With Combination of Dutasteride and Solifenacin. J Sex Med 2018;15:1579-1590. PMID- 30415814 TI - Prevalence and Risk Factors for Sexual Problems and Distress in Chinese Unmarried Young Women: An Observational Study. AB - INTRODUCTION: Research conducted in the West has shown that sexual function and distress was common in white women from younger to older adulthood; however, little research attention to date has been given to Chinese young women. AIM: Our primary aim is to assess the prevalence and factors associated with sexual problems and distress in Chinese unmarried young women. METHODS: Between November 2015 and June 2017, 431 young women who visited 3 sexual health clinics completed an anonymous questionnaire detailing their demographics, sexual behavior, current sexual relationship, sexual function, and sexual distress. Descriptive bivariate analysis and logistic regression analyses were performed. MAIN OUTCOME MEASURES: Sexual function and distress were assessed by the Female Sexual Function Index (FSFI) and Female Sexual Distress Scale-Revised (FSDS-R), respectively. RESULTS: Overall, 76 young women (17.6%) obtained total FSFI score <=23.45 (Chinese cut off), 47 of whom scored 11 or above for FSDS-R. Individual domain and total FSFI scores were significantly correlated with FSDS-R score (P < .001). Based on domain scores, 35.5%, 18.8%, 12.8%, and 10.7% of them were at risk for orgasmic, pain, arousal, and desire problems, respectively. Arousal and lubrication problems were strongly associated with distress. Sexual problems were associated with not initiating sex (odds ratio [OR] 2.50, P = .001), often had sexual fantasy (OR 0.55, P = .036), and willingness for vaginal sex (OR 0.49, P < .001). Sexual distress was associated with having life stressors (OR 1.88, P = .012) and willingness for vaginal sex (OR 0.61, P = .003). Self-perception of body being unattractive to boyfriend (OR 3.33, P = .015), not initiating sex (OR 3.21, P = .001), willingness for vaginal sex (OR 0.39, P < .001), and no life stressors (OR 0.46, P = .036) were associated with both sexual problem and distress. CLINICAL IMPLICATIONS: Physicians should be alerted to sexual problems in young women and encourage those with distress to seek help. STRENGTHS & LIMITATIONS: Using validated psychometric tools to assess sexual problems and distress provides reference for future comparison. Admission and recall biases are unavoidable in observational questionnaire study. Depression was not evaluated and might bias the estimation of distress. CONCLUSION: About 11% of Chinese young women had sexual problems and were distressed (ie, sexual dysfunction). They were characterized by having a self-perception that their body was unattractive to their boyfriend, not initiating sex, unwilling for vaginal sex, and having life stressors. Lo SS-T, Kok W-m. Prevalence and Risk Factors for Sexual Problems and Distress in Chinese Unmarried Young Women: An Observational Study. J Sex Med 2018;15:1620-1628. PMID- 30415815 TI - Impact of Camera Deviation on Penile Curvature Assessment Using 2D Pictures. AB - BACKGROUND: An accurate curvature assessment (CA) is required in the decision making process for patients with Peyronie's disease. In-office CA following induced erection is the gold standard for CA, although penile photography is commonly used due to its convenience. Camera deviations during 2D image acquisition might affect CA accuracy. AIM: To investigate the impact of camera angle deviations on CA. METHODS: 2D pictures were taken from 5 models with a known uniplanar curvature (40 degrees , 45 degrees , 60 degrees , 90 degrees , and 120 degrees ). The model was kept on a fixed point and the camera was rotated around it. Pictures were taken with every 10 degrees increase in camera deviation from the optimal position. The camera rotated to a maximum of 90 degrees deviation in both the vertical and horizontal planes. The pictures were analyzed by 2 different urologists using a goniometer. The expected apparent curvature (AC) and the corresponding picture assessment error (PAE = AC - real model curvature) were also calculated for each picture using trigonometry principles. MAIN OUTCOME MEASURE: Assessing PAE magnitude and patterns was our primary outcome. Secondary outcomes were intraobserver, interobserver, and observer-AC intraclass correlation coefficient (ICC). RESULTS: 100 pictures were analyzed. Intraobserver reliability was high (ICC = 0.99) for both urologists. Interobserver and observer-AC correlation were also high (ICC = 0.996 and ICC = 0.992, respectively). When the camera rotated in the horizontal axis, the PAE underestimated the curvature for models with curvatures smaller than 90 degrees and overestimated the reading of the 120 degrees model. When the camera rotated in the vertical axis, PAE had an inverse effect. The PAE showed a tendency to increase exponentially with higher deviation, reaching almost 100% for a deviation of 80 degrees . Nevertheless, analyzing its magnitude regardless of the curvature, PAE was always <5% for camera deviations of 0-20 degrees . CLINICAL IMPLICATIONS: If using picture-based CA, clinicians should attempt to take a picture perpendicular to the curvature plane for the most accurate measurement in degrees. Many clinicians request that patients take 3 pictures in a standard fashion (craniocaudal, lateral, and frontal), and if this technique is to be used, an extra picture is recommended. STRENGTH & LIMITATIONS: In our controlled environment, we were able to isolate CA errors due to camera angles from other confounders such as erection hardness. As a consequence, however, our results cannot be easily generalized. CONCLUSION: PAE due to non-optimal camera position is a complex phenomenon that affects CA depending on the rotation axis and the degree of penile curvature. Nevertheless, PAE is always <5% for camera deviations of 0-20 degrees . Nascimento B, Cerqueira I, Miranda EP, et al. Impact of Camera Deviation on Penile Curvature Assessment Using 2D Pictures. J Sex Med 2018;15:1638-1644. PMID- 30415816 TI - Ixekizumab Improved Patient-Reported Genital Psoriasis Symptoms and Impact of Symptoms on Sexual Activity vs Placebo in a Randomized, Double-Blind Study. AB - INTRODUCTION: Genital psoriasis (GenPs) is common and distressing for patients, but is often not discussed with physicians, and no previous clinical trials have assessed the effects of biologics specifically on GenPs and its associated symptoms. AIM: To report results for novel patient-reported outcomes (PROs) for the assessment of symptoms and the sexual impact of GenPs before and after treatment in the IXORA-Q study. METHODS: IXORA-Q (NCT02718898) was a phase III, randomized, double-blind, placebo-controlled study of ixekizumab (80 mg/2 weeks after 160-mg initial dose) vs placebo for GenPs. Men and women >=18 years old with moderate-to-severe GenPs and body surface area (BSA) >=1% were assessed through 12 weeks. MAIN OUTCOME MEASURE: GenPs symptoms were assessed using the 8 item Genital Psoriasis Symptoms Scale (GPSS), Genital Psoriasis Sexual Frequency Questionnaire (GenPs-SFQ), and Genital Psoriasis Sexual Impact Scale (GPSIS) (validation data presented in the supplemental materials), and the Dermatology Life Quality Index (DLQI) item 9. RESULTS: For patients receiving ixekizumab (N = 75) vs placebo (N = 74), statistically significant improvement in GenPs symptoms were seen from week 1 onward (GPSS total and individual items, all P < .005). Sexual activity avoidance owing to GenPs symptoms (GPSIS) decreased significantly with ixekizumab from week 4 onward (all P <.005), whereas impact of sexual activity on GenPs improved significantly with ixekizumab at weeks 2-8 (all P < 0.05). Ixekizumab resulted in significant improvement vs placebo by week 1 onward in limitations on frequency of sexual activity owing to GenPs (GenPs-SFQ item 2). Sexual difficulties caused by skin (DLQI item 9) decreased significantly with ixekizumab from week 2 onward (all P < .001). CLINICAL IMPLICATIONS: Both GenPs symptoms and impact on sexual activity improved rapidly and significantly with ixekizumab vs placebo through 12 weeks in patients with moderate-to-severe GenPs and BSA >=1%. STRENGTH & LIMITATIONS: To our knowledge, this is the first phase III, randomized, placebo-controlled, double-blinded clinical trial to evaluate the effect of any treatment on the symptoms and sexual impact related to GenPs. The study did not include an active comparator owing to the lack of any well established treatment for moderate-to-severe GenPs, and the period assessed herein was of relatively short duration. CONCLUSION: These validated PRO measures may aid in future clinical studies of GenPs and in facilitating discussions of GenPs symptoms and their impact between patients and clinicians. Yosipovitch G, Foley P, Ryan C. Ixekizumab improved patient-reported genital psoriasis symptoms and impact of symptoms on sexual activity vs placebo in a randomized, double blind study. J Sex Med 2018;15:1645-1652. PMID- 30415817 TI - Impact of Pelvic Radiation Therapy on Inflatable Penile Prosthesis Reoperation Rates. AB - INTRODUCTION: Considering that radiation therapy (RT) compromises soft tissue microvasculature, impairs wound healing, and causes cavernosal fibrosis, inflatable penile prosthesis (IPP) outcomes may be adversely affected in men treated with RT. AIM: To compare IPP outcomes among those who had undergone prior RT vs a cohort who underwent radical prostatectomy (RP) before insertion of IPP. METHODS: The Surveillance, Epidemiology, and End Results (SEER)-Medicare Database was queried for men with prostate cancer (PCa) who underwent RT (n = 83,277) or RP (n = 32,608) with subsequent IPP insertion between 2002 and 2013. Men who had undergone both RT and RP were excluded from the analysis. MAIN OUTCOME MEASURE: The primary outcome was reoperation, defined by removal, revision, or replacement of the IPP. RESULTS: We identified 350 men who received an IPP following RT and 653 who received an IPP following RP. Men who underwent RT were older (P < .01) and had more comorbidities (P < .01). There were no significant differences in overall reoperation rates at 90 days (P = .78), 1 year (P = .52), or 3 years (P = .48). Time-to-event analysis demonstrated that RT was not associated with an increased likelihood of overall reoperation (hazard ratio [HR] 1.46, 95% confidence interval [CI] 0.94-2.29, P = .09). There was no association between time from RT to IPP and overall reoperation rates. CLINICAL IMPLICATIONS: Prior RT for the treatment of PCa does not impact the revision or removal rates of IPPs as compared with a cohort of non-radiated patients who underwent RP. STRENGTH & LIMITATIONS: The strength includes the analysis of outcomes among a contemporary, nationwide cohort with robust follow-up. Using diagnosis and procedure codes, we were thoroughly able to capture reoperations. Limitations include the lack of specific indications for reoperation and inability to control for surgeon experience or technique. CONCLUSION: IPP is a safe and effective treatment of erectile dysfunction that should be offered to men with a history of pelvic radiation who have failed medical therapy. Golan R, Patel NA, Sun T, et al. Impact of pelvic radiation therapy on inflatable penile prosthesis reoperation rates. J Sex Med 2018;15:1653-1658. PMID- 30415818 TI - Editorial Comment on "Self-Reported Vaginal Laxity-Prevalence, Impact, and Associated Symptoms in Women Attending a Urogynecology Cinic". PMID- 30415819 TI - Response to Letter to the Editor "Conservation efforts risk poisoning endangered New Zealand kea". PMID- 30415820 TI - [Being diagnosed with COPD: A qualitative study of real life experience]. AB - INTRODUCTION: This qualitative study aimed to explore the real life experience of the patients with chronic obstructive pulmonary disease (COPD) at the time they receive the diagnosis. METHODS: Data were collected using face to face interviews in general practice as well as focus groups in a pulmonary rehabilitation centre. RESULTS: Thirty-four patients participated in the study. Most of them were made aware of their disease by a pulmonologist during hospitalisation for an acute exacerbation. Several terms were used to name the disease including emphysema, asthma, chronic bronchitis and COPD (acronym often not explained). At the time of the announcement, patients expressed responses which included for some a sense of stupefaction associated with anxiety and for others guilt and an attitude of denial. If the need for smoking cessation was mentioned by doctors, a lack of information at the time of the announcement was general. The chronic and potentially serious aspects of COPD were not understood or rarely mentioned. CONCLUSION: The announcement of the disease did not always appear to have been of good quality. Ideally, the diagnosis of COPD should be conveyed to people after its identification in a dedicated consultation, combined with better information and a proposal for psychological support. PMID- 30415821 TI - Spinal fractures in patients with diffuse idiopathic skeletal hyperostosis: Clinical characteristics by fracture level. AB - BACKGROUND: Diffuse idiopathic skeletal hyperostosis (DISH) makes the spine prone to unstable fractures with neurological deterioration. This study was conducted to assess clinical and radiographic features of spinal fractures in DISH by the level of spinal injury, and to evaluate the optimal treatment for each level. METHODS: A multicenter retrospective study over a 5-year period, including 46 patients (35 males; 11 females) with a mean age of 77.2 +/- 9.7 years at the time of injury. By fracture level, there were 7 cervical (15.2%), 25 thoracic (54.3%), and 14 lumbar (30.4%) fractures. We recorded the cause of injury, whether diagnosis was delayed, and neurological status by Frankel grade. Ossification and fracture patterns were assessed by CT-multi-planar reconstruction (MPR). RESULTS: Neurological status immediately after the cervical-spine injury was C (28.6%) or E (71.4%); after thoracic injury, C (12.0%) or E (88.0%); and after lumbar injury, D (21.4%) or E (78.6%). Inability to walk at admission was more frequent in patients with a spinal-cord injury above the lumbar level (P = .033). Vertebral-body fractures were observed in 14.3% of the cervical injuries, 80.0% of the thoracic injuries, and 50.0% of the lumbar injuries (P = .004). Most patients with a cervical fracture had a disc-level fracture (85.7%). Posterior column ankylosis was observed in 14.3% of the cervical-fracture group, 72.0% of the thoracic-fracture group, and 78.6% of the lumbar-fracture group (P = .008). CONCLUSION: Ossification and fracture patterns in patients with DISH varied distinctly by the level of spinal injury. Intervertebral-disc fractures were frequently observed in the cervical spine. Delayed diagnosis, vertebral-body fracture, and posterior-column ankylosis were observed in the thoracolumbar spine. This study recommends 3 above and 3 below fusion, to avoid instrumentation failure in the fixation of spinal fracture in patients with DISH. PMID- 30415822 TI - Japanese version of the international PROMs "Vail Hip Score": Reliability, validity, and responsiveness according to the COSMIN checklist. AB - BACKGROUND: This study aimed to develop a Japanese version of the international PROMs "Vail Hip Score (Vail10)" and to establish its reliability, validity, and responsiveness with COSMIN check-list. METHODS: The study was conducted from March 2016 to October 2017 and included 46 patients totaling 47 joints. Disorders included 30 cases of FAI (55%), 13 cases of DDH (28%), and 4 others (8%). We administered an identical set of PROMs (5 measures: Japanese-version iHOT12 (pilot draft), Japanese-version Vail10, Japanese-version Oxford Hip Score, JHEQ, and SF36) twice in these subjects. We determined interclass correlation coefficients for the first and second round [ICC(1,2)], as well as the Cronbach alpha coefficient for patient responses to each of the 10 items in Vail10. In addition, we determined Spearman rank correlation coefficients of Vail10, OHS, JHEQ, satisfaction VAS, the 8 subscales of SF36, and the 3 QOL summary scores. RESULTS: ICC for the total score of all 10 items in Vail10 was 0.96. Cronbach alpha coefficient was 0.96. Bland-Altman plot analysis showed a solid agreement. Regarding the validity, Spearman rank correlation coefficients, only satisfaction VAS, and SF36 subscales of PF and BP had r > 0.45 (p < 0.01 in both administration rounds). The SDC (1.32) was smaller than the MIC (8.14). CONCLUSIONS: After developing the Japanese version of Vail10, we examined its Reliability, validity, and responsiveness by administering the measure to patients with acetabular labral tear. Correlations were strong and demonstrated the efficacy of the Japanese version of Vail10. PMID- 30415823 TI - Revision total hip arthroplasty with metal on metal bearing for ceramic bearing fractures. AB - BACKGROUND: Due to concern of potential metallosis caused by residual microscopic ceramic particles, metal-on-metal (MoM) bearing is deemed undesirable in revision total hip arthroplasty (THA) for ceramic bearing fracture. We determined whether MoM bearing is suitable to be used in revision THA for ceramic fractures and also evaluated whether this treatment increases serum iron levels compared with MoM bearing revision THA for polyethylene failure. METHODS: Between 2006 and 2012, 22 patients underwent revision surgery using MoM bearing (28 mm femoral head in 18 hips and 32 mm in 4 hips) for ceramic bearing fracture and followed average 52.1 months. We assessed radiological parameter and functional outcome using Harris hip score (HHS) and WOMAC score. Also, serum cobalt (Co) and chromium (Cr) blood tests were performed and compared with the result obtained from age, sex- and follow-up duration-matched patients with MoM revision THA for failed polyethylene bearing. RESULTS: The mean HHS improved from 60.6 preoperatively to 90.3 at final follow-up. There were no changes in cup position, progression of osteolytic lesions, and measurable wear of MoM bearing articulation at final follow-up radiographs. There was one case of recurrent dislocation after surgery, which was treated with greater trochanter distal advancement and one case of deep infection, which underwent two-stage revision. Mean serum Co level (1.7 vs. 1.4 MUg/dl; p = 0.211) and Cr level (0.70 vs. 1.01 MUg/dl; p = 0.327) showed no significant difference. CONCLUSIONS: MoM articulation with liner cementation into the acetabular cup along with total synovectomy can be chosen in revision surgery for ceramic fracture with good midterm follow-up. However, the use of MoM bearing is indicated when the stem and metal shell can be retained and ceramic on ceramic or ceramic on polyethylene bearing cannot be selected. Also long-term outcome needs to be further evaluated. PMID- 30415824 TI - Development of torsadogenic risk assessment using human induced pluripotent stem cell-derived cardiomyocytes: Japan iPS Cardiac Safety Assessment (JiCSA) update. AB - Cardiac safety assessment is challenging because a better understanding of torsadogenic mechanisms beyond hERG blockade and QT interval prolongation is necessary for patient safety. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a new human cell-based platform to assess cardiac safety in non-clinical testing during drug development. The multi electrode array (MEA) platform is a promising electrophysiological technology to assess QT interval prolongation and proarrhythmic potential of drug candidates using hiPSC-CMs. The Japan iPS Cardiac Safety Assessment (JiCSA) has established an MEA protocol to evaluate the applicability of hiPSC-CMs for assessing the torsadogenic potential of compounds and completed a large-scale validation study using 60 compounds. During our study, an international multi-site study of hiPSC CMs was performed by the Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative using 28 compounds. We have comparatively analyzed our JiCSA datasets with those of CiPA using the CiPA logistical and ordinal linear regression model. Regardless of the protocol differences, the evaluation results of the 28 compounds were very similar and highly predictable for torsadogenic risks. Thus, an MEA-based approach using hiPSC-CMs would be a standard testing method to evaluate proarrhythmic potentials. This review paper would provide new insights into the hiPSC-CMs/MEA method required for its regulatory use. PMID- 30415825 TI - SBF-1 preferentially inhibits growth of highly malignant human liposarcoma cells. AB - Frequent local recurrence and metastasis are generally involved in human liposarcoma, but the management is a challenge. There is an urgent need for improved effective therapy. In the present study, we reported that SBF-1, a steroidal glycoside, inhibited the growth of cultured highly malignant human liposarcoma SW872-S cells in vitro and in vivo. SBF-1 down-regulated the phosphorylation of protein kinase B (AKT) and thus reduced cell adhesion to fibronectin and laminin. Then we found that SBF-1 inhibited the expression of oxysterol binding protein (OSBP) in SW872-S cells, indicating that OSBP may be involved in malignant liposarcoma cell survival. Cancer cell growth and AKT phosphorylation were inhibited significantly upon knockdown of OSBP in SW872-S cells in vitro. Taken together, these results suggest that SBF-1 causes an apparent loss of OSBP function in SW872-S cells, resulting in growth inhibition. Based on our findings, OSBP serves as a potential therapeutic target for human liposarcoma. PMID- 30415826 TI - Implications of changing trekker demographics on travel health in the Annapurna region. AB - OBJECTIVE: The objective is to investigate trekkers' changing demographics, travel patterns and experience of illness in the Annapurna region. STUDY DESIGN: A mixed method study comprising a cross-sectional survey was carried out with trekkers who had completed trekking in the Annapurna region. METHODS: Interviews were carried out with trekkers using a standardised questionnaire from September to December (main trekking season) 2014 and 2016. The interview format included trekkers' demographic characteristics, travel patterns, preparation and logistics and experiences of illness and treatment. RESULTS: The demographic composition of trekkers had changed. Chinese and Nepalese trekkers were the most dominant groups along with other international trekkers from 16 different countries. In terms of the trekking pattern, the Chinese and the Nepalese trekkers spent a median of 7 days each in the trek and trekked to a median altitude of 3500 m, while other international trekkers spent a median of 10 days and trekked to a median altitude of 4000 m. In general, trekkers' food habits and travel patterns were good. They undertook some health preparation by using the Internet, consulting friends and travel guidebooks and consulting a doctor, pharmacist and other healthcare providers and brought medicines accordingly. However, 25% of trekkers, most commonly Chinese, Korean and Nepalese, came without any health preparation and with no medicines. Thirty percent of the trekkers became sick during the trek with common illnesses such as diarrhoea, vomiting, the common cold, headache, fever and altitude-related symptoms. CONCLUSIONS: Trekkers' demographic composition has changed from that found in previous studies, and this was reflected in their trekking pattern. Trekkers' health preparations for high altitude trekking were still inadequate, especially among the newer groups such as the Nepalese, Chinese and Korean trekkers. Issues such as trekkers' health preparation and practice, eating patterns, the length of trek and altitude and health and safety provision need further improvement, especially in the context of these changing trekker demographics. PMID- 30415827 TI - Environmentally Mediated Social Dilemmas. AB - By consuming and producing environmental resources, organisms inevitably change their habitats. The consequences of such environmental modifications can be detrimental or beneficial not only to the focal organism but also to other organisms sharing the same environment. Social evolution theory has been very influential in studying how social interactions mediated by public 'goods' or 'bads' evolve by emphasizing the role of spatial structure. The environmental dimensions driving these interactions, however, are typically abstracted away. We propose here a new, environment-mediated taxonomy of social behaviors where organisms are categorized by their production or consumption of environmental factors that can help or harm others in the environment. We discuss microbial examples of our classification and highlight the importance of environmental intermediates more generally. PMID- 30415828 TI - A newly developed transaortic axial flow ventricular assist device: Early clinical experience. PMID- 30415829 TI - Predictive factors of infectious complications in the postoperative of percutaneous nephrolithotomy. AB - OBJECTIVE: Infectious complications (IC) following percutaneous nephrolithotomy surgery (PCNL) can be life-threatening. Our objective was to analyse preoperative predictors of IC in PCNL. MATERIALS AND METHODS: A total of 203 patients who underwent PCNL were included in a prospective study between January 2013 and February 2016. A postoperative IC was defined as urinary infection/pyelonephritis, systemic inflammatory response syndrome or sepsis. The variables analysed were age, gender, number, size(cm) and side of stone; Hounsfield units,diabetes (insulin dependent or not), preoperative culture, isolated bacteria, multitract, bodymass index and surgical time (min). A multivariate forward stepwise (logistic regression) was performed. RESULTS: IC occurred in 30 patients (14.8%): 9 (4.4%) had urinary infection, 14 (6.9%) systemic inflammatory response syndrome and 7 (3.5%) sepsis. In addition, 13 (43.3%) had negative preoperative urine culture, 15 (50%) positive and in 2 (6.7%) was not available. On the logistic regression analysis, stone size (cm), insulin dependent diabetes and female sex were independently associated with increased risk of IC (odds ratio [OR] 1.03, 14.6 and 7.8, respectively; P=.0001). CONCLUSIONS: Patients with large stone burdens, insulin diabetes condition and female gender, should be counselled properly regarding postoperative infection risks and closely followed up to diagnose IC (specially sepsis) soon enough. Negative preoperative urine culture seems not reliable enough to exclude an infectious complication according to our results. PMID- 30415830 TI - Comorbidity of chronic back pain and depression in Germany: Results from the GEDA study, 2009 and 2010. AB - BACKGROUND: Depression and chronic back pain are two common disabling diseases. Studies suggest an association of both conditions. We aimed to determine sex- and age-specific prevalences of depression, chronic back pain and the combination of both. Furthermore, influencing factors and resulting consequences were analyzed. METHODS: Data was derived by pooling two representative cross-sectional telephone surveys "German Health Update (GEDA)" 2009 and 2010 including 43,312 adults. Self reported physician-diagnosed chronic somatic diseases including diagnosed depression and chronic back pain in the past 12 months were assessed. Age- and sex-specific prevalence was calculated. Logistic regression was used to examine their association and identify influencing factors. Sick days, missed workdays and doctor visits were compared for single disease vs. comorbidity. RESULTS: 12 month prevalence for diagnosed depression was 6.7 %, chronic back pain was 21.1 % and the comorbidity of both was 3.0 %. An association of depression and chronic back pain was found for both sexes and all age groups. The characteristics "female sex", "being 50-64 years of age", "low socioeconomic status" and "low social support" increased the likelihood of comorbid depression and chronic back pain. Comorbid depression and chronic back pain increased the number of sick days, missed workdays and doctor visits significantly. CONCLUSION: The results show a strong association of depression and chronic back pain. The direction of association cannot be determined due to the cross-sectional design of the study. Identifying patients at risk for comorbid depression and chronic back pain early on might improve treatment and reduce the economic impact. PMID- 30415831 TI - Multiple Cardiac Papillary Fibroelastomas - Are They Really Rare or Underdiagnosed? PMID- 30415832 TI - Inpatient Versus Outpatient Arthroplasty: A Single-Surgeon, Matched Cohort Analysis of 90-Day Complications. AB - BACKGROUND: Although some prior work supports the safety of same-day arthroplasty performed in a hospital, concerns remain when these procedures are performed in a free-standing ambulatory surgery center. The purpose of this study is to compare 90-day complication rates between matched cohorts that underwent inpatient vs outpatient arthroplasty at an ambulatory surgery center. METHODS: A single surgeon cohort of 243 consecutive patients who underwent outpatient arthroplasty was matched with 243 inpatients who had the same procedure. One-to-one nearest neighbor matching with respect to gender, age, American Society of Anesthesiologists Score, and body mass index was utilized. The 486 primary arthroplasties included 178 unicondylar knees (36.6%), 146 total hips (30.0%), 92 total knees (18.9%), and 70 hip resurfacings (14.5%). Ninety-day outcomes including reoperation, readmission, unplanned clinic or emergency department visits, and major and minor complications were compared using a 2-sample proportions test. RESULTS: The 2 cohorts were similar in distribution of demographic variables, demonstrating successful matching. The inpatient and outpatient cohorts both had readmission rates of 2.1% (P = 1.0). With the number of subjects studied, there were no statistically significant differences in rates of major complications (2.1% vs 2.5%, P = 1.0), minor complications (7.0% vs 7.8%, P = .86), reoperations (0.4% vs 2.1%, P = .22), emergency department visits (1.6% vs 2.5%, P = .52), or unplanned clinic visits (3.3% vs 5.8%, P = .19). CONCLUSION: This study suggests that arthroplasty procedures can be performed safely in an ambulatory surgery center among appropriately selected patients without an increased risk of complications. PMID- 30415833 TI - Perioperative high-dose-rate brachytherapy in locally advanced and recurrent gynecological cancer: Final results of a Phase II trial. PMID- 30415834 TI - An Amygdala-Hippocampus Subnetwork that Encodes Variation in Human Mood. AB - Human brain networks that encode variation in mood on naturalistic timescales remain largely unexplored. Here we combine multi-site, semi-chronic, intracranial electroencephalography recordings from the human limbic system with machine learning methods to discover a brain subnetwork that correlates with variation in individual subjects' self-reported mood over days. First we defined the subnetworks that influence intrinsic brain dynamics by identifying regions that showed coordinated changes in spectral coherence. The most common subnetwork, found in 13 of 21 subjects, was characterized by beta-frequency coherence (13-30 Hz) between the amygdala and hippocampus. Increased variability of this subnetwork correlated with worsening mood across these 13 subjects. Moreover, these subjects had significantly higher trait anxiety than the 8 of 21 for whom this amygdala-hippocampus subnetwork was absent. These results demonstrate an approach for extracting network-behavior relationships from complex datasets, and they reveal a conserved subnetwork associated with a psychological trait that significantly influences intrinsic brain dynamics and encodes fluctuations in mood. PMID- 30415836 TI - Positional Stability and Membrane Occupancy Define Skin Fibroblast Homeostasis In Vivo. AB - Fibroblasts are an essential cellular and structural component of our organs. Despite several advances, the critical behaviors that fibroblasts utilize to maintain their homeostasis in vivo have remained unclear. Here, by tracking the same skin fibroblasts in live mice, we show that fibroblast position is stable over time and that this stability is maintained despite the loss of neighboring fibroblasts. In contrast, fibroblast membranes are dynamic during homeostasis and extend to fill the space of lost neighboring fibroblasts in a Rac1-dependent manner. Positional stability is sustained during aging despite a progressive accumulation of gaps in fibroblast nuclei organization, while membrane occupancy continues to be maintained. This work defines positional stability and cell occupancy as key principles of skin fibroblast homeostasis in vivo, throughout the lifespan of mice, and identifies membrane extension in the absence of migration as the core cellular mechanism to carry out these principles. PMID- 30415835 TI - EMC Is Required to Initiate Accurate Membrane Protein Topogenesis. AB - Mammals encode ~5,000 integral membrane proteins that need to be inserted in a defined topology at the endoplasmic reticulum (ER) membrane by mechanisms that are incompletely understood. Here, we found that efficient biogenesis of beta1 adrenergic receptor (beta1AR) and other G protein-coupled receptors (GPCRs) requires the conserved ER membrane protein complex (EMC). Reconstitution studies of beta1AR biogenesis narrowed the EMC requirement to the co-translational insertion of the first transmembrane domain (TMD). Without EMC, a proportion of TMD1 inserted in an inverted orientation or failed altogether. Purified EMC and SRP receptor were sufficient for correctly oriented TMD1 insertion, while the Sec61 translocon was necessary for insertion of the next TMD. Enforcing TMD1 topology with an N-terminal signal peptide bypassed the EMC requirement for insertion in vitro and restored efficient biogenesis of multiple GPCRs in EMC knockout cells. Thus, EMC inserts TMDs co-translationally and cooperates with the Sec61 translocon to ensure accurate topogenesis of many membrane proteins. PMID- 30415838 TI - Tempo and Mode of Genome Evolution in the Budding Yeast Subphylum. AB - Budding yeasts (subphylum Saccharomycotina) are found in every biome and are as genetically diverse as plants or animals. To understand budding yeast evolution, we analyzed the genomes of 332 yeast species, including 220 newly sequenced ones, which represent nearly one-third of all known budding yeast diversity. Here, we establish a robust genus-level phylogeny comprising 12 major clades, infer the timescale of diversification from the Devonian period to the present, quantify horizontal gene transfer (HGT), and reconstruct the evolution of 45 metabolic traits and the metabolic toolkit of the budding yeast common ancestor (BYCA). We infer that BYCA was metabolically complex and chronicle the tempo and mode of genomic and phenotypic evolution across the subphylum, which is characterized by very low HGT levels and widespread losses of traits and the genes that control them. More generally, our results argue that reductive evolution is a major mode of evolutionary diversification. PMID- 30415839 TI - Scalable, Continuous Evolution of Genes at Mutation Rates above Genomic Error Thresholds. AB - Directed evolution is a powerful approach for engineering biomolecules and understanding adaptation. However, experimental strategies for directed evolution are notoriously labor intensive and low throughput, limiting access to demanding functions, multiple functions in parallel, and the study of molecular evolution in replicate. We report OrthoRep, an orthogonal DNA polymerase-plasmid pair in yeast that stably mutates ~100,000-fold faster than the host genome in vivo, exceeding the error threshold of genomic replication that causes single generation extinction. User-defined genes in OrthoRep continuously and rapidly evolve through serial passaging, a highly straightforward and scalable process. Using OrthoRep, we evolved drug-resistant malarial dihydrofolate reductases (DHFRs) in 90 independent replicates. We uncovered a more complex fitness landscape than previously realized, including common adaptive trajectories constrained by epistasis, rare outcomes that avoid a frequent early adaptive mutation, and a suboptimal fitness peak that occasionally traps evolving populations. OrthoRep enables a new paradigm of routine, high-throughput evolution of biomolecular and cellular function. PMID- 30415840 TI - Identity Noise and Adipogenic Traits Characterize Dermal Fibroblast Aging. AB - During aging, stromal functions are thought to be impaired, but little is known whether this stems from changes of fibroblasts. Using population- and single-cell transcriptomics, as well as long-term lineage tracing, we studied whether murine dermal fibroblasts are altered during physiological aging under different dietary regimes that affect longevity. We show that the identity of old fibroblasts becomes undefined, with the fibroblast states present in young skin no longer clearly demarcated. In addition, old fibroblasts not only reduce the expression of genes involved in the formation of the extracellular matrix, but also gain adipogenic traits, paradoxically becoming more similar to neonatal pro-adipogenic fibroblasts. These alterations are sensitive to systemic metabolic changes: long term caloric restriction reversibly prevents them, whereas a high-fat diet potentiates them. Our results therefore highlight loss of cell identity and the acquisition of adipogenic traits as a mechanism underlying cellular aging, which is influenced by systemic metabolism. PMID- 30415837 TI - Reconstructing the Deep Population History of Central and South America. AB - We report genome-wide ancient DNA from 49 individuals forming four parallel time transects in Belize, Brazil, the Central Andes, and the Southern Cone, each dating to at least ~9,000 years ago. The common ancestral population radiated rapidly from just one of the two early branches that contributed to Native Americans today. We document two previously unappreciated streams of gene flow between North and South America. One affected the Central Andes by ~4,200 years ago, while the other explains an affinity between the oldest North American genome associated with the Clovis culture and the oldest Central and South Americans from Chile, Brazil, and Belize. However, this was not the primary source for later South Americans, as the other ancient individuals derive from lineages without specific affinity to the Clovis-associated genome, suggesting a population replacement that began at least 9,000 years ago and was followed by substantial population continuity in multiple regions. PMID- 30415841 TI - Structural Basis for Cholesterol Transport-like Activity of the Hedgehog Receptor Patched. AB - Hedgehog protein signals mediate tissue patterning and maintenance by binding to and inactivating their common receptor Patched, a 12-transmembrane protein that otherwise would suppress the activity of the 7-transmembrane protein Smoothened. Loss of Patched function, the most common cause of basal cell carcinoma, permits unregulated activation of Smoothened and of the Hedgehog pathway. A cryo-EM structure of the Patched protein reveals striking transmembrane domain similarities to prokaryotic RND transporters. A central hydrophobic conduit with cholesterol-like contents courses through the extracellular domain and resembles that used by other RND proteins to transport substrates, suggesting Patched activity in cholesterol transport. Cholesterol activity in the inner leaflet of the plasma membrane is reduced by PTCH1 expression but rapidly restored by Hedgehog stimulation, suggesting that PTCH1 regulates Smoothened by controlling cholesterol availability. PMID- 30415842 TI - Short communication: Evaluation of the efficacy of novel disbudding methods for dairy calves. AB - The objectives of this study were to (1) evaluate whether cryoablation or the administration of clove oil was as efficacious as cautery disbudding at preventing horn growth, and (2) evaluate whether the efficacy of cautery disbudding is affected by removing or leaving the horn bud tissue intact after disbudding of dairy calves. At approximately 4 d of age (4.0 +/- 0.88 d of age, mean +/- SD), 265 dairy heifer calves from 3 dairy farms (farm 1: n = 129 calves; farm 2: n = 109 calves; farm 3: n = 27 calves) were disbudded. Each calf had 1 of 4 treatments randomly assigned to each horn bud: (1) clove oil (0.5 mL) administered subcutaneously under the horn bud (CLOV, n = 135 buds); (2) a liquid nitrogen-filled probe applied to the horn bud area for 30 s (CRYO, n = 134 buds); (3) cautery disbudding using an electric hot-iron and the horn bud removed (BUDOFF, n = 130); or (4) cautery disbudding and the horn bud tissue left intact (BUDON, n = 131). Calves were assessed for signs of infection at the disbudding site frequently within the first month after disbudding. At approximately 6 mo of age (6 +/- 2.2 mo, mean +/- SD) calves were assessed for scur or horn growth. The disbudding procedures were considered successful if no scur or horn development was observed. Within the first month, 12% of disbudding wounds showed some indication of infection, such as pus, exudate, or swelling; of the infected buds, 52% were associated with the BUDON treatment, 27% with CLOV, 25% with BUDOFF, and 2% with CRYO treatments. At 6 mo of age, BUDOFF was the most effective method of preventing horn growth and CRYO was the least efficacious [mean percentage of success: BUDOFF: 100% (95% CI: 97.7-100.0); CRYO: 1% (95% CI: 0.2-5.3)]. Injecting clove oil under the horn bud was 87% (95% CI: 80.6-92.5) successful. Not removing the horn bud tissue after cautery disbudding reduced the efficacy of this method by 9% [91% success (95% CI: 83.8-95.7)]; moreover, this method was associated with more infection at the site of disbudding. It appears as though the clove oil treatment could be used as an alternative to cautery disbudding of dairy calves; however, further research is needed to evaluate the tissue damage and associated pain caused by clove oil and to refine this technique (i.e., administration methods to improve efficacy) before it could be considered an alternative to cautery. PMID- 30415843 TI - Use of a stochastic simulation model to estimate the cost per case of digital dermatitis, sole ulcer, and white line disease by parity group and incidence timing. AB - A farm-level stochastic simulation model was modified to estimate the cost per case of 3 foot disorders (digital dermatitis, sole ulcer, and white line disease) by parity group and incidence timing. Disorder expenditures considered within the model included therapeutics, outside labor, and on-farm labor. Disorder losses considered within the model included discarded milk, reduced milk production, extended days open, an increased risk of culling, an increased risk of death (natural or euthanized), and disease recurrence. All estimates of expenditures and losses were defined using data from previously published research in stochastic distributions. Stochastic simulation was used to account for variation within the farm model; 1,000 iterations were run. Sensitivity of foot disorder costs to selected market prices (milk price, feed price, replacement heifer price, and slaughter price) and herd-specific performance variables (pregnancy rate) were analyzed. Using our model assumptions, the cost per disorder case over all combinations of parity group and incidence timing, regardless of incidence likelihood, was lowest for digital dermatitis ($64 +/- 24; mean +/- standard deviation), followed by white line disease ($152 +/- 26) and sole ulcer ($178 +/- 29). Disorder costs were greater in multiparous versus primiparous cows and were always highest at the beginning of lactation. The greatest contributing cost categories were decreased milk production, an increased risk of culling, and disease recurrence. The contribution of cost categories to the total cost of disorder varied by disorder type, parity group, and incidence timing. For all disorders, the cost per case increased as milk price or replacement heifer price increased and decreased as feed price, pregnancy rate, or slaughter price increased. Understanding how foot disorder costs change according to cow-specific conditions (i.e., disorder type, parity group, and days in milk at incidence) and herd-specific conditions (i.e., market prices and performance variables) can help improve on-farm decisions about treatment and prevention of foot disorders. PMID- 30415844 TI - Short communication: Activity of nisin, lipid bilayer fragments and cationic nisin-lipid nanoparticles against multidrug-resistant Staphylococcus spp. isolated from bovine mastitis. AB - Staphylococci are the main etiological agents of bovine mastitis. Bacteriocins and nanoparticles have emerged as promising alternatives for the future development of antimicrobial agents. This study evaluated the activity of the bacteriocin nisin and bicelles of the synthetic cationic lipid dioctadecyldimethylammonium bromide, alone and in combination, against multidrug resistant Staphylococcus spp. strains isolated from bovine mastitis. In summary, cationic nisin/dioctadecyldimethylammonium bromide nanoparticles are shown to be a promising alternative for the control of mastitis caused by multidrug-resistant Staphylococcus spp. PMID- 30415845 TI - Risk factors for antimicrobial use in veal calves and the association with mortality. AB - The intensive use of antimicrobials in the veal industry is heavily criticized, but drivers for antimicrobial usage (AMU) are still poorly understood. The industry fears that a drastic reduction in AMU would increase mortality, creating an unacceptable welfare issue. The objectives of the present study were to identify risk factors for AMU and to explore the relationship between AMU and mortality. A retrospective cohort study was performed on the antimicrobial registration data from the largest Belgian veterinary veal practice. The data set contained 295 production cycles from 78 farms, representing 146,014 calves and 8 veal companies (also called integrations). The average AMU was 32.3 defined daily dose animal per year [defined daily dose animal per year, standard deviation: 11.04], of which 76.2% was administered orally and 23.8% parentally. The AMU remained stable between 2014 and 2016 with only a slight, but significant increase in total AMU between 2015 (31.0 defined daily dose animal per year, standard deviation: 10.5) and 2016 (35.1, 10.8). Use of almost all antimicrobial classes decreased over 2014 to 2016; however, use of long-acting macrolides, doxycycline, and aminosides increased significantly. Analysis identified breed (higher use in beef calves compared with dairy and crossbreeds), month of arrival (lower use when arrived in April or May compared with winter months), and veal company as risk factors. The veal company not only significantly affected total AMU, but also affected the majority of the antimicrobial classes. Additionally, breed differences were present for oxytetracycline, colistin, and classic macrolides, and a month effect was present for doxycycline only. These data illustrate that this veterinary practice realized a reduction of 46% in total AMU and of 96% in critically important antibiotics (fluoroquinolones, cephalosporins of the third and fourth generation) compared with the Belgian benchmark from 2007 to 2009. Replacement of critically important drugs by an increased use of long acting macrolides is worrisome. Mortality risk was very low compared with benchmarks referenced internationally and did not increase with decreasing AMU. Use of trimethoprim-sulfonamides was a risk factor, whereas use of oxytetracycline was a protective factor for mortality. The absence of a relationship with mortality at the current levels of AMU suggests that a further rational reduction is possible. Attention should be paid to consider different AMU benchmarks for different breeds and to include the veal company as a target for antibiotic awareness campaigns. PMID- 30415846 TI - Lactobacillus casei expressing methylglyoxal synthase causes browning and heterocyclic amine formation in Parmesan cheese extract. AB - Undesired browning of Parmesan cheese can occur during the latter period of ripening and cold storage despite the relative absence of reducing sugars and high temperatures typically associated with Maillard browning. Highly reactive alpha-dicarbonyls such as methylglyoxal (MG) are products and accelerants of Maillard browning chemistry and can result from the microbial metabolism of sugars and AA by lactic acid bacteria. We demonstrate the effects of microbially produced MG in a model Parmesan cheese extract using a strain of Lactobacillus casei 12A engineered for inducible overexpression of MG synthase (mgsA) from Thermoanaerobacterium thermosaccharolyticum HG-8. Maximum induction of plasmid born mgsA led to 1.6 mM MG formation in Parmesan cheese extract and its distinct discoloration. The accumulation of heterocyclic amines including beta-carboline derivatives arising from mgsA expression were determined by mass spectrometry. Potential MG-contributing reaction mechanisms for the formation of heterocyclic amines are proposed. These findings implicate nonstarter lactic acid bacteria may cause browning and influence nutritional aspects of Parmesan by enzymatic conversion of triosephosphates to MG. Moreover, these findings indicate that the microbial production of MG can lead to the formation of late-stage Maillard reaction products such as melanoidin and beta-carbolines, effectively circumventing the thermal requirement of the early- and intermediate- stage Maillard reaction. Therefore, the identification and control of offending microbiota may prevent late-stage browning of Parmesan. The gene mgsA may serve as a genetic biomarker for cheeses with a propensity to undergo MG-mediated browning. PMID- 30415847 TI - Short communication: Meta-analysis of dairy cows fed conventional sorghum or corn silages compared with brown midrib sorghum silage. AB - A meta-analysis was conducted to compare the effects of feeding dairy cows conventional sorghum silage (CSS) or conventional corn silage (CCS) compared with brown midrib sorghum silage (BMRSS) diets on dry matter intake (DMI), milk production, and milk composition. Data from 9 published articles (1984 to 2015) were used to contrast diets with CSS (7 means comparisons; 104 cows) or CCS (13 means comparisons; 204 cows) versus BMRSS diets. Statistical analysis was performed using fixed or random effects models with the Metafor package of R (https://www.R-project.org). The degree of heterogeneity was measured with the I2 statistic, and publication bias was determined with funnel plots and Egger's regression test. Other sources of heterogeneity of response were analyzed through meta-regression. Estimated effect size was calculated for DMI, milk production, and milk composition. No evidence of publication bias was observed for any variable tested. The highest degree of heterogeneity (I2 = 41.5 and 72.6%) was observed for DMI among dependent variables tested in both comparisons, indicating that intake responses to silage type are rather inconsistent; in contrast, milk production had the lowest degree of heterogeneity (I2 = 0%), supporting the idea that the responses of this variable to silage type were very consistent across studies. Compared with BMRSS diets, cows fed CSS diets exhibited decreased milk production (1.64 kg/d), milk fat concentration (0.09%), milk fat yield (0.08 kg/d), milk protein yield (0.04 kg/d), and milk lactose yield (0.16 kg/d) and tended to decrease DMI (0.83 kg/d). Compared with CCS diets, cows fed BMRSS diets increased milk fat concentration (0.10%), but decreased milk protein concentration (0.06%) and tended to increase lactose yield (0.08 kg/d). Meta regression indicated that days in milk affected DMI and milk production when CSS diets were compared with BMRSS diets, and DMI when CCS diets were compared with BMRSS diets. Additionally, the inclusion rate of silage in the diet and dietary neutral detergent fiber affected yields of milk fat and lactose, respectively, when CCS and BMRSS diets were compared. Overall, lactation performance improved when cows were fed diets formulated with BMRSS compared with CSS, but performance was not different for cows fed BMRSS and CCS diets. However, the small sample size may have influenced these results by increasing the margin of the error and, concurrently, the power of the meta-analysis. Results of this analysis suggest that additional research is needed to explore the effects of days in milk and the inclusion rates of silages in the diets when comparing BMRSS with CSS or CCS. PMID- 30415848 TI - Differences between performance of F1 crossbreds and Holsteins at different production levels. AB - Crossbreeding in dairy cattle has recently become of increased interest. However, farmers in Scandinavian countries are reluctant to implement crossbreeding in their herds, and one reason is the common opinion that only herds at a poor level of management can benefit from crossbreeding. The Danish Cattle Database (SEGES, Aarhus, Denmark) provided data on 14 traits regarding milk yield, udder health, fertility traits, stillbirth, and survival. The data were collected from 103,307 pure Holstein cows and 14,832 F1 crosses (Holstein dam and Nordic Red sire). The cows were born between 2008 and 2014 and originated from 424 herds that contributed data from at least 5 purebreds and 5 crossbreds across the years. We split the animals into 3 production levels: high, average, and low according to the herd's average production (kg) of 305-d fat plus protein in the given birth year of the cow. We estimated least squares means of breed group (purebred and crossbred) performance within each production level. Crossbred performance in 305 d fat yield in first-parity cows was greater than that of Holstein across all herd production levels; the gain was greater in high- (9 kg more than Holstein) and average-producing herds (7 kg more than Holstein) than in low-producing herds (3 kg more than Holstein). Regardless of production level or parity, crossbreds did not outperform Holstein in terms of 305-d protein yield (0 to 8 kg less). Crossbreds had relatively better udder health than Holstein in both first and second parity (up to 15% less mastitis) within any of the production levels. In terms of fertility, stillbirth, and survival, crossbreds performed better than purebreds, and improved performance was independent of herd production level. We conclude that differences in performance between F1 crossbreds and Holstein are independent of production level. PMID- 30415849 TI - Symposium review: The relevance of bovine milk phospholipids in human nutrition Evidence of the effect on infant gut and brain development. AB - This paper reflects the concepts reviewed during the presentation in the Joint MILK/Lactation Biology Symposium at the ADSA 2018 Annual Meeting. Our intention is to update the concepts and advances in the area of research regarding milk phospholipids or polar lipid fraction as part of a dairy ingredient used today in nutritional studies that focus on gut health as well as brain development of infants. Although processing advances have allowed the production of novel ingredients rich in milk fat globule membrane (MFGM) components, mostly monitored by phospholipid concentration and presence of membrane proteins, there is wide variability in their composition and structure. Furthermore, we aimed to include in the phospholipid fraction of milk nanovesicles designated as milk exosomes, which are secreted into milk by different secretion mechanisms than those of the fat globules but are also made up of a unique mixture of polar lipids. We consider imperative the study of polar lipid-derived structures from milk regarding composition and structure to gain insights into their biological effect in human health. Nevertheless, and tolerating the differences in composition and concentration of their components, studies supplementing the diet of infants with polar lipids (i.e., MFGM components) have shown significant advances in several areas of human health and well-being. Here we present a summary of the important components of MFGM and milk exosomes as well as an overview of the effects on gut health and brain and cognitive development when added to the diet of infants. PMID- 30415850 TI - Short communication: Antimicrobial resistance and virulence genes of Enterococcus faecalis isolated from subclinical bovine mastitis cases in China. AB - This study aimed to investigate the antimicrobial resistance and virulence genes of Enterococcus faecalis isolated from subclinical bovine mastitis cases in China. Enterococcus faecalis isolates were identified by 16S rRNA amplification and sequencing. Antimicrobial susceptibility was determined by the disc diffusion method. Antimicrobial resistance and virulence genes were tested by PCR. Overall, E. faecalis was recovered from 81 of 1,787 (4.5%) mastitic milk samples. The isolates showed high resistance against tetracycline (87.7%) and erythromycin (79.0%). The most prevalent resistance genes found in the E. faecalis were tetK (96.3%), tetL (79.0%), and tetM (87.7%) for tetracycline and ermC (97.5%) for erythromycin. Moreover, gelE (70.4%), esp (85.2%), efaA (91.4%) were the most common virulence genes. This is the first report to characterize E. faecalis recovered from subclinical bovine mastitis cases in China. PMID- 30415851 TI - Infection dynamics across the dry period using Dairy Herd Improvement somatic cell count data and its effect on cow performance in the subsequent lactation. AB - In this study, we studied infection dynamics across the dry period using test-day somatic cell count (SCC) data from 739 Holstein cows from 33 randomly selected commercial dairy herds in Flanders, all of which applied blanket dry-cow therapy at dry-off. First, we determined infection dynamics, combining the last test-day SCC before dry-off and the first test-day SCC after calving. Next, we determined the effect of dry period infection dynamics, adjusting for the level of the second test-day SCC after calving, on the evolution of test-day SCC and milk yield (MY) and on clinical mastitis and culling hazard in the subsequent lactation. Using an SCC threshold of 200,000 cells/mL, 12.6% of the cows considered healthy before dry-off acquired a new intramammary infection (IMI) across the dry period, whereas 66.9% of the cows considered infected before dry off cured from IMI. Infection dynamics across the dry period significantly affect a cow's SCC, clinical mastitis risk, and culling hazard in the subsequent lactation. Cows with a new IMI, a cured IMI, or a chronic IMI across the dry period had higher test-day SCC than healthy cows, and their test-day SCC evolved differently over time. This was not the case for test-day milk yield, for which no association with infection dynamics was detected. Furthermore, cows with a second test-day SCC <200,000 cells/mL had a lower test-day SCC in the remainder of the lactation than cows with a second test-day SCC >=200,000 cells/mL, but this association was modified by infection dynamics across the dry period. The lowest test-day SCC in the remainder of the lactation was observed for cows that remained healthy across the dry period combined with a low (<200,000 cells/mL) second test-day SCC. Cows that cured from an IMI present at dry-off and cows with a chronic IMI across the dry period were more likely to develop clinical mastitis (hazard ratio = 2.22 and 2.89; 95% confidence interval = 1.45-3.43 and 1.60-5.20, respectively), and chronic IMI cows were more likely to be culled (hazard ratio = 3.68; 95% confidence interval = 1.64-8.20) in the subsequent lactation compared with healthy cows. This was not true for cows that became infected across the dry period. This study underlines the importance of good udder health management during lactation to prevent IMI at dry-off rather than curing infected cows during the dry period to ensure optimal udder health in the subsequent lactation. PMID- 30415852 TI - Symposium review: Macronutrient metabolism in the growing calf. AB - Recent interest in increasing rates of body weight gain in heifer calves before weaning is based on the promise of an increase in milk production during first lactation. This increase is usually realized by increasing milk or milk replacer intake, delaying the onset of rumen development. Simultaneously feeding liquids and solid feeds brings about new challenges. Macronutrient metabolism in growing calves is reviewed, combining literature from heifer and veal calves with the objective to provide insights useful for developing novel feeding strategies. Growing calves are not efficiently retaining digested N when compared with other growing species. Energy and protein appear to be simultaneously limiting growth. With the possible exception of very young calves, low responses to incremental intakes of AA indicate that the limiting AA rarely explains the low efficiency of N utilization. Nonetheless, there are indications that disproportionate oxidation of AA as a result of AA imbalance may occur, notably in splanchnic tissues. Long chain fatty acids, absorbed from the milk or calf milk replacer (CMR) are preferentially deposited as body fat, but this strongly depends on the need for ATP, fueled by the oxidation of carbohydrates. Hence, fatty acid oxidation typically decreases with an increased feeding level. Insulin sensitivity in calves is quite high at birth, but decreases independent of feeding strategy in early age to very low levels when compared with other species. Even though changes in insulin sensitivity may be provoked by early life nutrition, these effects are small and rather transient. In heavy calves, insulin sensitivity is invariably low. Large effects of dietary treatments on postprandial glucose and insulin responses, as often observed, are unlikely to be caused by differences in insulin sensitivity. Unlike in pigs, de novo fatty acid synthesis is not a significant route of disposal of glucose absorbed from the intestinal tract. Instead, high lactate fluxes in milk-fed calves suggest this may be an important route of disposal. When combining the feeding of milk or CMR with solid feeds, estimation of the contribution of the individual ration components is difficult, and interactions inside the gastrointestinal tract complicate the estimation of their feeding value. There are indications in veal calves that use of nutrients absorbed from a CMR is not dependent on the level of intake of solid feeds. PMID- 30415853 TI - Estimating the value of infectious or noninfectious foot disorder prevention strategies within dairy farms, as influenced by foot disorder incidence rates and prevention effectiveness. AB - A farm-level stochastic simulation model was adapted to estimate the value of implementing foot disorder prevention on a dairy farm by calculating the return on investment associated with implementation of foot disorder prevention. Two potential strategies for foot disorder prevention were tested: strategy 1 was prevention focused on reducing infectious foot disorders (i.e., digital dermatitis) in the model, and strategy 2 was prevention focused on reducing noninfectious foot disorders (i.e., sole ulcer and white line disease) in the model. For each strategy, we evaluated the effect of foot disorder incidence on the value of prevention by setting the incidence of foot disorders at 3 levels. For strategy 1, the level of digital dermatitis incidence without prevention in all parities was 20, 40, or 60%, and the incidence level of the noninfectious foot disorders in the model were held constant. For strategy 2, levels of sole ulcer and white line disease incidence without prevention in parity >=3 cows were 5, 15, or 25%, and the incidence level of the infectious foot disorders included in the model were held constant; the incidence levels of noninfectious foot disorders in younger cows were adjusted to be lower. Overall, 6 scenarios were run, 1 for each prevention strategy * foot disorder incidence rate combination. To evaluate how the effectiveness of each prevention strategy would influence the investment value, the effectiveness of prevention could vary from a prevention risk ratio (RR) of 0.0 (100% reduction in disorder incidence) to 1.0 (0% reduction in disorder incidence). When implementing strategy 1, the return on prevention investment per cow-year (mean +/- standard deviation) when prevention effectiveness was low (prevention RR = 0.91 to 1.0) and the digital dermatitis incidence rate was originally 20, 40, or 60% was $0.6 +/- 0.4, $1.2 +/- 0.9, and $1.8 +/- 1.3, respectively. In comparison, the return on prevention investment per cow-year when prevention effectiveness was high (prevention RR = 0.00 to 0.09) and the digital dermatitis incidence rate was originally 20, 40, or 60% was $12.2 +/- 3.0, $24.4 +/- 6.0, and $36.5 +/- 9.0, respectively. When implementing strategy 2, the return on prevention investment per cow-year when prevention effectiveness was low and noninfectious foot disorder incidence rates were originally 5, 15, or 25% in parity >=3 cows was $0.6 +/- 0.4, $1.9 +/- 1.1, and $3.2 +/- 1.9, respectively. In comparison, the return on prevention investment per cow-year when prevention effectiveness was high and noninfectious foot disorder incidence rates were originally 5, 15, or 25% in parity >=3 cows was $12.4 +/- 1.5, $37.3 +/- 4.6, and $62.2 +/- 7.6, respectively. The return on investment for foot disorder prevention would depend on the cost of the prevention strategy and the other benefits associated with the selected prevention strategy. This model could be used as a decision support tool to help identify the amount that could be paid to implement a selected prevention strategy. PMID- 30415854 TI - Association between teat skin colonization and intramammary infection with Staphylococcus aureus and Streptococcus agalactiae in herds with automatic milking systems. AB - The objective of this study was to investigate the association between teat skin colonization and intramammary infection (IMI) with Staphylococcus aureus or Streptococcus agalactiae at the quarter level in herds with automatic milking systems. Milk and teat skin samples from 1,142 quarters were collected from 300 cows with somatic cell count >200,000 cells/mL from 8 herds positive for Strep. agalactiae. All milk and teat skin samples were cultured on calf blood agar and selective media. A subset of samples from 287 quarters was further analyzed using a PCR assay (Mastit4 PCR; DNA Diagnostic A/S, Risskov, Denmark). Bacterial culture detected Staph. aureus in 93 (8.1%) of the milk samples and 75 (6.6%) of the teat skin samples. Of these, 15 (1.3%) quarters were positive in both the teat skin and milk samples. Streptococcus agalactiae was cultured in 84 (7.4%) of the milk samples and 4 (0.35%) of the teat skin samples. Of these, 3 (0.26%) quarters were positive in both the teat skin and milk samples. The PCR detected Staph. aureus in 29 (10%) of the milk samples and 45 (16%) of the teat skin samples. Of these, 2 (0.7%) quarters were positive in both the teat skin and milk samples. Streptococcus agalactiae was detected in 40 (14%) of the milk samples and 51 (18%) of the teat skin samples. Of these, 16 (5.6%) quarters were positive in both the teat skin and milk samples. Logistic regression was used to investigate the association between teat skin colonization and IMI at the quarter level. Based on bacterial culture results, teat skin colonization with Staph. aureus resulted in 7.8 (95% confidence interval: 2.9; 20.6) times higher odds of Staph. aureus IMI, whereas herd was observed as a major confounder. However, results from the PCR analyses did not support this association. Streptococcus agalactiae was isolated from the teat skin with both PCR and bacterial culture, but the number of positive teat skin samples detected by culture was too low to proceed with further analysis. Based on the PCR results, Strep. agalactiae on teat skin resulted in 3.8 (1.4; 10.1) times higher odds of Strep. agalactiae IMI. Our results suggest that Staph. aureus and Strep. agalactiae on teat skin may be a risk factor for IMI with the same pathogens. Focus on proper teat skin hygiene is therefore recommended also in AMS. PMID- 30415855 TI - Apoptosis and proliferation in Staphylococcus aureus-challenged, nonlactating mammary glands stimulated to grow rapidly and develop with estradiol and progesterone. AB - Bovine mastitis is a common and costly disease in the dairy industry and is known to negatively affect the amount of epithelium in nonlactating mammary glands. Despite this recognition, an understanding of the mechanisms contributing to reductions in epithelium is lacking. The objective of this study was to evaluate cellular apoptosis and proliferation in uninfected and Staphylococcus aureus infected mammary glands that were stimulated to rapidly grow and develop. Estradiol and progesterone injections were administered to 18 nonlactating dairy cows to induce mammary growth, and 2 quarters from each animal were infused with saline or Staph. aureus. Mammary tissues were collected at 5 (n = 9) and 10 d (n = 9) postinfusion and examined using quantitative bright field and florescent immunohistochemistry. Staphylococcus aureus mammary glands tended to have a greater number of mammary epithelial cells undergoing apoptosis than saline quarters. In the stromal compartment, challenged quarters contained a lower proportion of cells undergoing apoptosis than saline quarters overall; however, cell types undergoing apoptosis were differentially affected. Staphylococcus aureus quarters contained a lesser percentage of apoptotic fibroblasts while also containing more nonapoptotic immune cells than saline quarters in the intralobular stroma compartment. A similar number of proliferating epithelial cells were present in Staph. aureus and saline mammary tissues, but more proliferating cells were present in the intralobular stroma compartment of Staph. aureus-infused quarters than those infused with saline. When these cellular responses are considered together, it indicates that changes in cellular apoptosis and proliferation contribute to changes in the gland structure by potentiating the expansion of the intralobular stromal compartment, via cellular accumulation, and limiting the amount of epithelium due to increases in cellular apoptosis in affected glands. Reductions in mammary epithelium are expected to reduce future milk yields and productive herd life. PMID- 30415856 TI - Raman chemical feature extraction for quality control of dairy products. AB - As a fast information acquisition technique, Raman spectroscopy can be used to control the quality of dairy products. Feature extraction is a necessary processing step to improve the efficiency of Raman spectral data. Principal component analysis is a traditional method that can effectively extract the feature and reduce the dimension of spectral data. However, it is difficult to analyze the chemical information of the extracted feature, thus limiting its practical application. In this work, Raman spectral chemical feature extraction was carried out. The quality control of Dingxin dairy products (a famous dairy brand in China; purchased from Heilongjiang Zhaodong Tianlong Dairy Co. Ltd., Heilongjiang, China) was used as an example. Raman peak intensity, peak area, and peak ratio were extracted as chemical features and further investigated using Euclidean distance and the quality fluctuation control chart. The potential quality discrimination ability of the Raman feature extraction methods was demonstrated. The results showed that the Puzhen dairy products (purchased from Inner Mongolia Yinuo Halal Food Co. Ltd., Inner Mongolia, China) and Xueyuan dairy products (used as a control; purchased from Inner Mongolia Wulanchabu City Jining Xueyuan Dairy Co. Ltd., Inner Mongolia, China) could be distinguished from the Dingxin dairy products when the Raman chemical features special peak intensity, peak area, and peak ratio were used, and their discriminatory ability increased in sequence. Hence, it was shown that Raman chemical feature extraction can realize the quality control and discriminant analysis of dairy products and that the spectral information is clear. PMID- 30415858 TI - Influence of milk protein concentrates with modified calcium content on enteral dairy beverage formulations: Storage stability. AB - Control of calcium-mediated storage defects, such as age gelation and sedimentation, were evaluated in enteral high-protein dairy beverages during storage. To investigate the effects of reduced-calcium ingredients on storage stability, 2 batches each of milk protein concentrates (MPC) with 3 levels of calcium content were acquired [control, 20% calcium-reduced (MPC-20), and 30% calcium-reduced (MPC-30)]. Control and calcium-reduced MPC were used to formulate 8% (wt/wt) protein enteral dairy beverages. The formulation also consisted of other ingredients, such as gums, maltodextrin, potassium citrate, and sucrose. The pH-adjusted formulation was divided into 2 parts, one with 0.15% sodium hexametaphosphate (SHMP) and the other with 0% SHMP. The formulations were homogenized and retort sterilized at 121 degrees C for 15 min. The retort sterilized beverages were stored at room temperature for up to 90 d and particle size and apparent viscosity were measured on d 0, 7, 30, 60, and 90. Beverages formulated using control MPC with 0 and 0.15% SHMP exhibited sedimentation, causing a decrease in apparent viscosity by approximately 10 cP and clear phase separation by d 90. The MPC-20 beverages with 0% SHMP exhibited stable particle size and apparent viscosities during storage. In the presence of 0.15% SHMP, particle size increased rapidly by 40 nm on d 90, implying the start of progressive gelation. On the other hand, highest apparent viscosities leading to gelation were observed in MPC-30 beverages at both concentrations of SHMP studied. These results suggested that beverages formulated with MPC-20 and 0% SHMP would have better storage stability by maintaining lower apparent viscosities. Further reduction of calcium using MPC-30 resulted in rapid gelation of beverages during storage. PMID- 30415857 TI - Short communication: Purple corn (Zea mays L.) stover silage with abundant anthocyanins transferring anthocyanin composition to the milk and increasing antioxidant status of lactating dairy goats. AB - The present study used 16 multiparous lactating Saanen dairy goats (body weight, 41.80 +/- 2.92 kg; mean +/- standard deviation) with healthy and symmetrical udders. Goats were divided into 2 blocks of 8 goats based on milk yield averaged from 75 d in milk in a randomized completed block design. The 2 study groups were the control (CSSS), in which goats were fed sticky corn stover silage, and the treatment (TPSS), in which goats were fed anthocyanin-rich purple corn (Zea mays L.) stover silage (PSS). The results indicated that the TPSS group led to an elevation in the content of milk lactose relative to the CSSS. The inclusion of anthocyanin-rich PSS had no effect on the level of 5 particular anthocyanins [i.e., cyanidin-3-glucoside, delphinidin, cyanidin, pelargonidin (Pel), as well as total anthocyanins in milk]. The pelargonidin-3-glucoside and malvidin were unable to be detected in both groups. However, the TPSS resulted in higher levels of peonidin (Peo) and malvidin-3-O-glucoside (M3G) compared with the control. Moreover, goats receiving TPSS exhibited a higher level of superoxide dismutase (SOD) in plasma and milk relative to the CSSS. Interestingly, some positive correlations were detected between the certain milk components [i.e., fat and total solids as well as fat and solids-not-fat (SNF); protein and SNF; and total solids and SNF]. In addition, the positive correlations were observed between individual anthocyanins (cyanidin-3-glucoside, delphinidin, Peo, M3G, cyanidin, and Pel) and total anthocyanins. Specifically, stronger positive correlations were noted between several antioxidant enzymes and anthocyanin composition in milk (total antioxidant capacity and Pel; SOD and Peo as well as SOD and M3G). Taken together, PSS with abundant anthocyanins can transfer anthocyanins to the milk and enhance the amount of antioxidants in lactating dairy goats. PMID- 30415859 TI - Drinking water intake of newborn dairy calves and its effects on feed intake, growth performance, health status, and nutrient digestibility. AB - Although it is recommended to offer free drinking water (called drinking water hereafter) immediately after birth, producers wait, on average, 17 d to first offer drinking water to newborn dairy calves. The objective of this study was to examine water and feed intake, growth performance, health status, and nutrient digestibility of Holstein heifer calves offered drinking water from birth (W0) as compared with those offered it at 17 d of age (W17), when fed an ad libitum volume of milk. Thirty Holstein heifer calves, balanced for parity of the dam, birth weight, and birth week, were randomly assigned (n = 15) to W0 or W17. Calves had free access to drinking water and a starter ration, offered in 2 separate buckets, until they were 70 d of age. Calves were bottle-fed with pasteurized whole milk 3* per day (2.0 kg/feeding until d 14, and 3.2 kg/feeding thereafter). Calves were partially weaned (33% of the milk allowance 1 * per day) at 42 d of age and completely weaned at 49 d of age. Drinking water intake, starter intake, milk intake, ambient temperature, and the fecal consistency were recorded daily. Body weight, hip height, hip width, heart girth, and body length were measured weekly. Blood (drawn from a jugular vein) was analyzed for hematocrit and haptoglobin concentrations at 14 d of age. On d 69 and 70, total fecal output of individual calves was measured and analyzed for chemical composition to determine apparent total-tract digestibility of nutrients. When offered from birth, newborn calves consumed 0.75 +/- 0.05 kg/d water aside from the water they received from ad libitum milk allowance during the first 16 d. Once offered, W17 calves drank more water (59%) than W0 calves during the preweaning period. Starter intake of W0 and W17 calves was similar, but W0 calves consumed 0.285 kg/d more milk and tended to achieve greater body weight and heart girth compared with W17 calves during the preweaning period. Offering water from birth versus offering it later did not affect the number of days with diarrhea, intensity of diarrhea, or blood hematocrit and haptoglobin concentrations of preweaned calves. Despite a similar starter intake, W0 calves had greater hip height, body length, apparent total-tract digestibility of acid detergent fiber and neutral detergent fiber, and feed efficiency than W17 calves postweaning (50 to 70 d of age). When followed up to 5 mo of age, W0 calves had greater body weight than W17 calves. Provision of drinking water immediately after birth could improve growth and development of calves pre- and postweaning, potentially by stimulating rumen development, thus increasing nutrient availability. PMID- 30415861 TI - Perilipin 5 promotes hepatic steatosis in dairy cows through increasing lipid synthesis and decreasing very-low-density lipoprotein assembly. AB - Fatty liver is a common metabolic disorder in dairy cows during the transition period. Perilipin 5 (PLIN5), a lipid droplet coat protein, plays important roles in the development of hepatic steatosis in mice and humans. Whether PLIN5 plays a role in the development of fatty liver in dairy cows is unknown. An in vivo study consisting of 10 healthy and 10 cows with fatty liver was performed to harvest liver tissue and blood samples. In addition, hepatocytes isolated from calves were infected with PLIN5 overexpression adenovirus for 48 h; treated with 0, 0.6, 1.2, or 2.4 mM nonesterified fatty acids (NEFA) for 24 h; or infected with PLIN5 silencing adenovirus for 48 h and then treated with 1.2 mM NEFA for 24 h. Serum concentrations of NEFA and beta-hydroxybutyrate were greater in cows with fatty liver. Milk production and plasma glucose concentrations were lower in cows with fatty liver. The results revealed that PLIN5 is highly expressed in steatotic liver and localized to lipid droplets. The abundance of fatty acid and triacylglycerol (TAG) synthesis-related proteins including sterol regulatory element binding protein-1c, fatty acid synthase, acetyl-coA carboxylase 1, diacylglycerol acyltransferase 1, and diacylglycerol acyltransferase 2 was greater in the liver of cows with fatty liver. In contrast, the abundance of microsomal triglyceride transfer protein (MTP), apolipoprotein B100, and apolipoprotein E was lower in the liver of cows with fatty liver. Consequently, cows with fatty liver exhibited severe hepatic TAG accumulation and lower blood concentration of very-low-density lipoprotein apolipoprotein B (VLDL-ApoB). Overexpression of PLIN5 and exogenous NEFA in cultured hepatocytes increased the abundance of sterol regulatory element binding protein-1, fatty acid synthase, acetyl-coA carboxylase 1, diacylglycerol acyltransferase 1, and diacylglycerol acyltransferase 2 but decreased the abundance of microsomal triglyceride transfer protein, apolipoprotein B100, and apolipoprotein E, which promoted TAG synthesis and inhibited VLDL-ApoB assembly, inducing lipid accumulation. Importantly, knockdown of PLIN5 attenuated the upregulation of TAG synthesis and downregulation of VLDL-ApoB assembly induced by NEFA. Overall, these data suggest that NEFA activate PLIN5, leading to TAG accumulation and inhibition of VLDL assembly. As such, these mechanisms explain in part the development of hepatic steatosis in dairy cows. PMID- 30415860 TI - Technical note: Development of a noninvasive respiration rate sensor for cattle. AB - The measurement of the respiration rate (RR) in cattle is a valuable tool for monitoring health status. Thus, an RR sensor can be essential for stress detection, especially heat stress. Heat stress leads to a deviation of the normal RR and results in a decrease of milk production and fertility. Therefore, continuous monitoring of the RR can help early detection of heat stress and, thus, initiate timely counteractive actions to minimize physical stress. The most common method to measure the RR in cattle is to count the flank movement visually; however, this method is time-consuming and labor-intensive. In addition, the continuous measurement of the RR is difficult to implement and can be physically strenuous. Therefore, a device based on a differential pressure sensor that can record RR automatically has been developed to make continuous long-term studies possible. The aim of this study was to validate the data measured by the device with the help of a reference method. The reference method used was counting the flank movements of a total of 6 cows (Holstein-Friesian). The rear flank movements of each cow were recorded by a camera and counted independently of the device by an observer. Eight videos of 1 min each were recorded per cow. The data analysis was done with cows in 3 different body positions: dozing, lying, and standing. A total of 48 RR measurements of the device were compared with the counted RR frequencies of the video recording. The results were highly correlated during dozing [correlation coefficient (r) = 0.92, n = 13], lying (r = 0.98, n = 15), and standing (r = 0.99, n = 20). The evaluation showed that the device is suitable for automated RR counting. Further development of a marketable device is planned. PMID- 30415862 TI - Using serum and plasma samples to assess failure of transfer of passive immunity in dairy calves. AB - The objectives of this study were (1) to determine the differences in IgG and total protein (TP) content of serum and plasma samples collected from the same calves; (2) to evaluate the correlation between calf serum and plasma IgG levels, Brix scores, and TP concentrations; (3) to determine whether different cut-off values should be used for plasma and serum to assess failure of transfer of passive immunity (FTPI) in dairy calves; and (4) to evaluate the level of agreement between results obtained from using serum and plasma samples of the same calves to assess FTPI using optimal cut-off values. Blood samples (n = 217) were collected from Holstein calves at 3 to 10 d of age on 30 commercial dairy farms in Nova Scotia and Newfoundland, Canada. Paired serum and plasma samples were analyzed for IgG concentration by the reference radial immunodiffusion assay, transmission infrared (TIR) spectroscopy, digital and optical Brix refractometers, and optical TP refractometer. The IgG concentrations measured by RID and TIR spectroscopy in serum were similar to those in plasma. However, the Brix and TP refractometer readings were significantly higher in plasma than in serum. The prevalence of FTPI in serum and plasma samples based on a RID-IgG concentration <10 g/L was 43.3 and 46.5%, respectively. The RID-IgG concentration was correlated with TIR-IgG (r = 0.92 and 0.89), digital Brix (r = 0.80 and 0.80), optical Brix (r = 0.77 and 0.77), and optical TP (r = 0.75 and 0.77) refractometers in serum and plasma, respectively. The correlations between paired serum and plasma IgG content were 0.85 by TIR spectroscopy, 0.80 by digital Brix, 0.77 by optical Brix, and 0.79 by optical TP refractometer. The optimal cut-off values for TIR spectroscopy, digital Brix, optical Brix, and TP refractometers to assess FTPI using serum were 13.1 g/L, 8.7% Brix, 8.4% Brix and 5.1 g/dL, respectively; and the optimal cut-off values with plasma were 13.4 g/L, 9.4% Brix, 9.3% Brix and 5.8 g/dL, respectively. When using these optimal cut-off values, the level of agreement (88.1%) between results derived from testing serum and plasma by TIR spectroscopy was substantial, with a kappa (kappa) value of 0.76. The results derived from testing serum and plasma by digital Brix refractometer showed substantial agreement (83.4%), with a kappa value of 0.65, which is higher than the agreement and kappa value (74.7% and 0.51) reported for the optical Brix refractometer. Substantial agreement (81.6%) between serum and plasma TP was also obtained when using the optical TP refractometer, with a kappa value of 0.63. In conclusion, serum or plasma samples can be used interchangeably for measuring IgG concentrations and assessing FTPI in dairy calves. However, different cut-offs must be used to assess FTPI depending on the sample matrix. Furthermore, results obtained from serum samples showed higher agreement with the reference RID assay than those obtained from plasma samples. PMID- 30415863 TI - Academia-industry Cooperation in the Medical Field: Matching Opportunities in Japan. AB - In the field of medicine, cooperation between academia and industry has become increasingly important in order to create innovative pharmaceuticals and medical devices. This paper presents an overview of academia-industry cooperation within the medical field in Japan. The overview begins with a brief history of the origins of academia-industry cooperation in Japan, and how it has developed up to the present day. It continues with examples of current academia-industry cooperation in the medical field. This includes details about organizations such as the Academic Research Organization (ARO) established by Japanese universities and the government to promote academia-industry cooperation; details about various matching events such as BioJapan; information about networks such as ARDENT, established to return results of basic research to society, and information about a case study by Kyushu University's Hospital Center for Clinical and Translational Research. It concludes by suggesting what will need to be done in the future to improve academia-industry cooperation in Japan. PMID- 30415864 TI - Anti-depressive-like effect of 2-phenylethanol inhalation in mice. AB - Rose oil has traditionally been used to treat psychiatric disorders, but the scientific basis of this treatment remains poorly understood. The main odor component of rose oil is 2-phenylethanol (2-PE), but the neuropsychological effects of 2-PE have not been investigated in detail. Thus, we aimed to investigate the effects of 2-PE on mouse behavior. We first investigated whether 2-PE is attractive or repulsive to mice. After 2-PE inhalation, the mice underwent a series of behavioral experiments, such as the elevated plus maze, open field, Y-maze, tail-suspension, and Porsolt forced-swim tests. Mice did not have a strong interest in 2-PE but were not repelled by it nor were fearful. In the open field test, mice that had inhaled 2-PE spent less time in the center area, while in the tail suspension test, their immobility time decreased. There was no change in cognitive function, activity level, muscle strength, or aggression in these mice. Our results suggest that 2-PE elicits neuropsychological effects that alter the behavior of mice and may also elicit anti-depressive effects. Inhalation of rose oil containing 2-PE may be effective against depression and stress-related diseases. PMID- 30415865 TI - Are PROMs ideally suited for most common endocrine surgical patients and procedures? PMID- 30415866 TI - The association between the ultrasonography TIRADS classification system and surgical pathology among indeterminate thyroid nodules. AB - BACKGROUND: A high proportion of cytologically indeterminate, Afirma-suspicious thyroid nodules are benign. The Thyroid Imaging Reporting and Data System was proposed by the American College of Radiology in 2015 to determine appropriate management of thyroid nodules in a standardized fashion. Our aim was to determine the diagnostic value of the Thyroid Imaging Reporting and Data System in cytologically indeterminate and Afirma-suspicious nodules. METHODS: We retrospectively queried cytopathology archives for retrospectively for thyroid fine-needle aspiration specimens obtained between February 2012 and September 2016 that were associated with the following: (1) indeterminate diagnosis, (2) ultrasonographic imaging at our institution, (3) an Afirma Gene Expression Classifier-suspicious result, and (4) surgery at our institution. We then calculated the diagnostic value of the Thyroid Imaging Reporting and Data System in predicting surgical pathology. RESULTS: Our cohort consisted of 133 nodules among 131 patients who underwent thyroid surgery for cytologically indeterminate, Afirma-suspicious nodules. A total of 9 nodules (6.8%) were assigned TR2 "not suspicious," 25 (18.8%) TR3 "mildly suspicious," 81 (60.9%) TR4 "moderately suspicious," and 18 (13.5%) TR5 "highly suspicious." Among our cohort, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the Thyroid Imaging Reporting and Data System was 71.4%, 38.1%, 40.2%, 69.6%, and 50.4%, respectively. CONCLUSION: Among cytologically indeterminate and Afirma-suspicious nodules, the Thyroid Imaging and Reporting and Data System was a poor predictor of final surgical pathology. Additional prospective studies are needed to validate these findings. PMID- 30415867 TI - Parathyroidectomy versus Cinacalcet in the Management of Tertiary Hyperparathyroidism: Surgery Improves Renal Transplant Allograft Survival. AB - BACKGROUND: Renal transplant allograft function in patients with tertiary hyperparathyroidism who are treated with cinacalcet versus parathyroidectomy remains unclear. METHODS: This is a retrospective, single-center review of patients with tertiary hyperparathyroidism between 2000 and 2017. We compared clinical parameters and outcomes, including renal allograft failure in patients who had undergone parathyroidectomy versus treatment with cinacalcet therapy. RESULTS: A total of 133 patients were included (33 who received parathyroidectomy and 100 who received cinacalcet); median renal allograft survival was 5.9 years (interquartile range 4.0-9.0). There were no differences in age, sex, body mass index, comorbidities, duration of pretransplant dialysis, cadaveric donor utilization, or rates of delayed allograft function between cohorts. In the parathyroidectomy cohort, normalization of parathyroid hormone occurred more frequently (67% vs 15%, P < .001) and renal allograft failure rates were less (9% vs 33%, P = .007), with similar median posttransplant follow-up (7.0 years [interquartile range 4.5-10.0]). On multivariable analysis, parathyroidectomy was inversely associated with allograft failure (odds ratio 0.20, 95%-confidence interval 0.06-0.71, P = .013); there were no other associated factors. A greater median parathyroid hormone (pg/mL) 1 year posttransplant (348 [interquartile range 204-493] vs 195 [interquartile range 147-297], P = .025) was associated with allograft failure in the cinacalcet cohort. CONCLUSION: Parathyroidectomy for tertiary hyperparathyroidism is associated with lesser rates of renal allograft failure compared with cinacalcet management. Patients with inadequate parathyroid hormone control on cinacalcet at 1 year posttransplant should be considered for parathyroidectomy to prevent potential allograft failure. PMID- 30415868 TI - Unilateral benign multinodular versus solitary goiter: Long-term contralateral reoperation rates after lobectomy. AB - BACKGROUND: Few long-term studies define the appropriate extent of surgery and recurrence rates for unilateral multinodular goiter. We compared the rate and time to reoperation in patients with multinodular goiter who underwent lobectomy to that of patients with benign solitary nodule. METHODS: Retrospective study of a prospective database of all patients who underwent lobectomy for multinodular goiter or solitary nodule from 1991 to 2017. We analyzed reoperation rates and time to reoperation. Reoperation was defined as the need for completion thyroidectomy determined the following citeria: nodule greater than 3 cm, multiple nodules, nodule growth or suspicion for malignancy by ultrasound or fine needle aspiration biopsy, or compressive symptoms. RESULTS: Included in the study were 2,675 lobectomies; 852 (31.85%) for multinodular goiter. In total, 394 patients (14.7%) underwent reoperation: 261 (30.6%) with a previous multinodular goiter and 133 (7.29%) with solitary nodule (P < .0001). A total of 80% of the patients with multinodular goiter and 67.66% with solitary nodule recurred as multinodular goiter; 3.5% of all recurrences were carcinomas. The mean time to reoperation was 14.8 years, without difference between groups (P = .5765). Patients without reoperation were younger (47 +/- 15 vs 54 +/- 13 years of age, P < .0001) and more likely to be male (P < .0001). CONCLUSION: Lobectomy for unilateral multinodular goiter is the procedure of choice given the length of time to reoperation. Patients and surgeons should be aware of the need for long term surveillance. PMID- 30415869 TI - 68Gallium-DOTATATE positron emission tomography-computed tomography (PET CT) changes management in a majority of patients with neuroendocrine tumors. AB - BACKGROUND: 68Gallium-DOTATATE positron emission tomography-computed tomography (PET CT) has shown superior accuracy in detecting grade 1 and 2 neuroendocrine tumors over previous imaging modalities and was recently included in National Comprehensive Cancer Network guidelines. It remains unclear which patients benefit most from this imaging modality. We therefore reviewed our initial experience with 68Gallium-DOTATATE PET CT to evaluate its usefulness in diagnosing, staging, and surveilling neuroendocrine tumors. METHODS: Records of patients who underwent 68Gallium-DOTATATE PET CT from March to December 2017 were prospectively evaluated. The primary endpoint was whether 68Gallium-DOTATATE PET CT changes treatment in patients with neuroendocrine tumors. Descriptive statistics, Fisher exact tests, and nested logistic regressions were conducted. RESULTS: A total of 50 consecutive patients were included. Of these, 41 patients (82%) had a biopsy-proven neuroendocrine tumor at the time of imaging. The remaining 9 patients (18%) had symptoms or biochemistry suggestive of a neuroendocrine tumor with negative cross-sectional imaging. 68Gallium-DOTATATE PET CT changed management in 33 patients (66%). There were 24 patients with intermodality changes in management and 9 patients with intramodality changes in management. Patients with scans performed for staging had a higher likelihood of a change in management (P = .006). CONCLUSION: Performing 68Gallium-DOTATATE PET CT should be considered for staging and surveillance of neuroendocrine tumors because it is frequently associated with changes in management. PMID- 30415871 TI - The effect of total thyroidectomy on the recovery of bone mineral density in subjects with hyperthyroidism. AB - BACKGROUND: Although hyperthyroidism is associated with high turnover osteopenia and its recovery after treatment, the extent of recovery with different forms of therapy remains controversial. This prospective study evaluated the bone mineral density in thyrotoxic subjects undergoing total thyroidectomy and 131I radioactive iodine therapy. METHODS: Newly diagnosed subjects with hyperthyroidism undergoing total thyroidectomy (group 1; n = 127) and 131I radioactive iodine therapy (group 2; n = 30) were evaluated for bone mineral density by dual energy x-ray absorptiometry at the time of diagnosis (point A), on achieving euthyroidism with antithyroid drugs (point B), and 6 months after definitive treatment (point C). RESULTS: In group 1, bone mineral density (expressed as g/sq cm; mean +/- standard deviation) in the hip (0.842 +/- 0.157) and spine (0.97 +/- 0.155) at point A, improved at point B (hip, 0.853 +/- 0.157 and spine, 0.982 +/- 0.155), and further improved at point C (hip, 0.91 +/- 0.158 and spine, 1.053 +/- 0.161, each P < .001). In group 2, at point C, bone mineral density in the hip (0.761 +/- 0.168 versus point A, 0.741 +/- 0.146) and spine (0.831 +/- 0.159 versus point A, 0.823 +/- 0.158) were less than group 1 (each P < .01). CONCLUSION: Bone mineral density improved significantly after all forms of treatment of hyperthyroidism and was greatest in lumbar vertebrae (8.6%) as early as 6 months after total thyroidectomy. The delayed recovery of bone mineral density after 131I radioactive iodine therapy needs long-term evaluation. PMID- 30415870 TI - A prospective study of the pathophysiology of carcinoid crisis. AB - BACKGROUND: Sudden massive release of serotonin, histamine, kallikrein, and bradykinin is postulated to cause an intraoperative carcinoid crisis. The exact roles of each of these possible agents, however, remain unknown. Optimal treatment will require an improved understanding of the pathophysiology of the carcinoid crisis. METHODS: Carcinoid patients with liver metastases undergoing elective abdominal operations were studied prospectively, using intraoperative, transesophageal echocardiography, pulmonary artery catheterization, and intraoperative blood collection. Serotonin, histamine, kallikrein, and bradykinin levels were analyzed by enzyme-linked immunosorbent assay. RESULTS: Of 46 patients studied, 16 had intraoperative hypotensive crises. Preincision serotonin levels were greater in patients who had crises (1,064 vs 453 ng/mL, P = .0064). Preincision hormone profiles were otherwise diverse. Cardiac function on transesophageal echocardiography during the crisis was normal, but intracardiac hypovolemia was observed consistently. Pulmonary artery pressure decreased during crises (P = .025). Linear regression of preincision serotonin levels showed a positive relationship with mid-crisis cardiac index (r = 0.73, P = .017) and a negative relationship with systemic vascular resistance (r=-0.61, P = .015). There were no statistically significant increases of serotonin, histamine, kallikrein, or bradykinin levels during the crises. CONCLUSION: The pathophysiology of carcinoid crisis appears consistent with distributive shock. Hormonal secretion from carcinoid tumors varies widely, but increased preincision serotonin levels correlate with crises and with hemodynamic parameters during the crises. Statistically significant increases of serotonin, histamine, kallikrein, or bradykinin during the crises were not observed. PMID- 30415872 TI - Keeping primary aldosteronism in mind: Deficiencies in screening at-risk hypertensives. AB - BACKGROUND: Primary aldosteronism is a common but underdiagnosed cause of hypertension. Patients with this disorder have worse morbidity compared with those with essential hypertension, but with timely diagnosis and appropriate intervention these patients are potentially cured and may have reversal of target organ damage. The goal of this study was to determine if hypertensive patients considered high risk were checked for primary aldosteronism. METHODS: We reviewed electronic health records to identify patients age 18 years or older with coexisting hypertension and hypokalemia or hypertension and sleep apnea, then determined if they had been investigated with measurement of aldosterone or renin. We built regression models to identify explanatory variables for screening in these 2 high-risk groups. RESULTS: Of nearly 37,000 patients with hypertension and hypokalemia, only 2.7% were ever screened for primary aldosteronism. Most opportunities for case detection were during inpatient hospitalizations, yet in this setting, patients were less likely than clinic patients be screened. Similarly, 3.0% of hypertensive patients with sleep apnea were screened since the inclusion of this group in case detection recommendations. CONCLUSION: Uptake of practice guidelines by hospital physicians, fueled by support from their specialty societies, may help to identify many more patients with unrecognized primary aldosteronism. PMID- 30415873 TI - Stage migration with the new American Joint Committee on Cancer (AJCC) staging system (8th edition) for differentiated thyroid cancer. AB - BACKGROUND: Tumor, node, and metastasis staging in thyroid carcinoma is important for assessing prognosis. However, patients with stage III or IV disease have an overall survival rate of 90%. The change to 55 years of age as the cutoff will create stage migration and many patients will be downstaged. METHODS: We reviewed our database of 3,650 patients to analyze the impact of the new American Joint Committee on Cancer staging system. There were 994 men (27%) and 2,656 women (73%). The median age was 46 years. Patients were staged using both 7th and 8th editions, with a cutoff of 55 years of age and new definitions of T3 and T4, and nodal staging. RESULTS: Of 3,650 patients, 1,057 (29%) were downstaged. There were 104 (10%) who went from stage IV to I, 109 (10%) who went from stage IV to stage II, and 68 (6%) who went to stage III. There were 218 (21%) who went from stage III to I, 347 (33%) who went from stage III to stage II, and 211 (20%) who went from stage II to I. The overall disease-specific and relapse-free survival was analyzed and showed better stratification with the new staging system. CONCLUSION: The new staging system reflects more appropriately the biology of thyroid cancer and will have significant impact on the management of thyroid cancer. PMID- 30415874 TI - Characterization of somatostatin receptors (SSTRs) expression and antiproliferative effect of somatostatin analogues in aggressive thyroid cancers. AB - BACKGROUND: Certain human carcinomas have demonstrated a distinct expression of somatostatin receptors. Data on somatostatin receptor expression in follicular thyroid cancer and anaplastic thyroid cancer has been limited and conflicting. This study seeks to characterize somatostatin receptor expression in follicular thyroid cancer and anaplastic thyroid cancer and to assess the effects of somatostatin analogues. METHODS: Anaplastic thyroid cancer (Hth7 and 8505C) and follicular thyroid cancer (FTC-236) (Sigma-Aldrich, St. Louis, MO) cells were cultured. Capillary immunoblotting and reverse transcription polymerase chain reaction (RT-PCR) were used to determine the basal expression of protein and mRNA of SSTR1-SSTR5. Cells were treated with the somatostatin analogues octreotide, pasireotride (SOM230), and KE-108 for 48h. IC50 was determined via 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, and cell proliferation was measured by viable cell count. Presence of SSTR2 was assessed by immunohistochemistry. RESULTS: Immunoblotting analysis demonstrated that most cell lines expressed SSTR1-SSTR3 and SSTR5 in varying degrees. Reverse transcription polymerase chain reaction analysis showed that mRNA expression for SSTR2 and SSTR3 correlated with protein expression. MTT assays showed that KE-108 and SOM230 were able to inhibit cell proliferation. Tissue microarray (TMA) showed that SSTR2 was highly expressed in human tissues of aggressive thyroid carcinomas. CONCLUSION: Follicular thyroid cancer and anaplastic thyroid cancer express SSTR1-3 and SSTR5 in distinct fashions both at a message and protein level. Our results suggest that somatostatin receptors are still a relevant and promising drug target against non-medullary thyroid cancers. PMID- 30415875 TI - Complicated Mild Traumatic Brain Injury at a Level I Pediatric Trauma Center: Burden of Care and Imaging Findings. AB - OBJECTIVE: The aims of this study were: (1) to characterize mild traumatic brain injury (mTBI), mTBI with skull fracture, and complicated mTBI in school-aged children seen at a Level I pediatric trauma center and (2) to examine the nature of imaging findings seen in children with mTBI with skull fracture and those with complicated mTBI. METHODS: A total of 1777 pediatric patients (male: 1193 or 67.1%; age = 11.1 +/- 3.5 years) sustaining mTBI who presented to the Emergency Department or directly to the trauma service in the years 2010 to 2013 were identified and classified into mTBI (n = 1,319 or 74.2%), mTBI with skull fracture (n = 127 or 7.2%), and complicated mTBI (n = 331 or 18.6%). Patient characteristics and imaging findings were analyzed using descriptive statistics, Pearson's chi2 test, Fisher's exact test, and logistic regression analysis. RESULTS: In children with complicated mTBI, subdural hematoma (36.9%) was the most common finding. Of the 331 children with complicated mTBI, 241 (72.8%) had multiple findings compared with one (0.8%) of 127 children having mTBI with skull fracture (Fisher's exact P < 0.001), with logistic regression analysis revealing younger age as a potential risk factor (P < 0.01). Children sustaining a depressed or complex skull fracture were nearly twice as likely as those with simple, linear skull fracture to have intracranial abnormality. CONCLUSIONS: Multiple radiographic findings in children sustaining mTBI with skull fracture or complicated mTBI are prevalent (72.8%), with younger age as a potential risk factor. PMID- 30415876 TI - Diabetes mellitus and the risk of abdominal aortic aneurysm: A systematic review and meta-analysis of prospective studies. AB - BACKGROUND: Diabetes mellitus has been associated with reduced risk of abdominal aortic aneurysm in a number of epidemiological studies, however, until recently little data from prospective studies have been available. We therefore conducted a systematic review and meta-analysis of prospective studies to quantify the association. MATERIAL AND METHODS: Two investigators searched the PubMed and Embase databases for studies of diabetes and abdominal aortic aneurysm up to May 8th 2018. Prospective studies were included if they reported adjusted relative risk (RR) estimates and 95% confidence intervals (95% CIs) of abdominal aortic aneurysm associated with a diabetes diagnosis. Summary relative risks were estimated by use of a random effects model. RESULTS: We identified 16 prospective studies with 16,572 cases among 4,563,415 participants that could be included in the meta-analysis. The summary RR for individuals with diabetes compared to individuals without diabetes was 0.58 (95% CI: 0.51-0.66, I2 = 40.4%, pheterogeneity = 0.06). The results persisted when stratified by sex, duration of follow-up, and in most of the other subgroup analyses. There was no evidence of publication bias with Egger's test, p = 0.64 or by inspection of the funnel plots. CONCLUSIONS: These results suggest that individuals with diabetes mellitus are at a reduced risk of abdominal aortic aneurysm, however, whether pharmacological agents for diabetes mellitus explain this observation needs to be clarified in future studies. PMID- 30415877 TI - Contribution of HLA-DQ2/DQ8 haplotypes in type one diabetes patients with/without celiac disease. AB - BACKGROUND: Based on lack of data on the distribution of the related alleles in the T1D population in Iranian population, we assessed the frequency of HLA DQ2 and DQ8 haplotypes in patients with T1D with/without CD compared to healthy population. MATERIALS AND METHODS: 70 patients with T1D without celiac disease, 60 T1D cases with CD were compared to 150 healthy individuals during 2016. Ten mililiter Gheparinized blood samples were collected, genomic DNA was extracted and alleles were genotyped by Real-time PCR using SYBR Green as a low-resolution method. RESULTS: HLA-DQ2 and/or HLA-DQ8 genotypes was presented in 51% and 23% of T1D patients without CD respectively. Twenty one percent of those patients carried both alleles and 5% were negative for both alleles. T1D patients with CD had much higher DQ2 frequency (72%) and lower DQ8 (11.6%), than T1D patients without CD and controls, 14% carried both alleles and 3% were negative for both. The frequencies of DQ2 and DQ8 alleles in Iranian healthy population were 19 and 5% respectively. CONCLUSION: According to the same genetic background for CD and T1D we suggest that HLA-typing can be a very useful screening tool for CD in patients with type one diabetes. PMID- 30415878 TI - Comparison of Cancer Detection Rates Between TRUS-Guided Biopsy and MRI-Targeted Biopsy According to PSA Level in Biopsy-Naive Patients: A Propensity Score Matching Analysis. AB - BACKGROUND: The purpose of the study was to compare cancer detection rates between 12-core transrectal ultrasound-guided prostate biopsy (TRUS-Bx) and multiparametric magnetic resonance imaging (mpMRI)-guided target prostate biopsy (MRI-TBx) according to prostate-specific antigen (PSA) level in biopsy-naive patients. PATIENTS AND METHODS: A retrospective study was conducted in 2009 biopsy-naive patients with suspected prostate cancer (PSA <=20 ng/mL). Patients underwent TRUS-Bx (n = 1786) or MRI-guided target prostate biopsy (MRI-TBx; n = 223) from September 2013 to March 2017 and were stratified according to each of 4 PSA cutoffs. MRI-TBx was performed on lesions with Prostate Imaging Reporting and Data System (PI-RADS) scores of 3 to 5 on mpMRI. Clinically significant prostate cancer (csPCa) was defined as Gleason >=7. Propensity score matching was performed using the prebiopsy variables, which included age, PSA, prostate volume, and PSA density. RESULTS: Propensity score matching resulted in 222 patients in each group. There were significant differences between the TRUS-Bx and MRI-TBx groups in the overall detection rates of prostate cancer (41.4% vs. 55.4%; P = .003) and csPCa (30.1% vs. 42.8%; P = .005). However, across PSA cutoffs, MRI-TBx detected more prostate cancer than TRUS-Bx at PSA levels of 2.5 to <4 (29.5% vs. 56.6%; P < .001). The csPCa detection rates of TRUS-Bx and MRI TBx did not differ significantly within the PSA cutoffs. There was a significantly higher detection rate of prostate cancer and csPCa in lesions with PI-RADS scores 4 and 5 than in those with a score of 3. CONCLUSION: Prebiopsy mpMRI and subsequent targeted biopsy had a higher detection rate than TRUS-Bx in patients with prostate cancer and csPCa. PMID- 30415879 TI - Predicting human plasma concentrations of persistent organic pollutants from dietary intake and socio-demographic information in the Norwegian Women and Cancer study. AB - BACKGROUND: Concentrations of persistent organic pollutants (POPs) in humans are influenced by a large number of factors including birth year, reproductive history and diet. Accordingly, information on dietary habits and socio demographic variables may predict plasma concentrations of POPs, thus enabling studies on health effects in large epidemiological studies, without performing time consuming and expensive chemical analyses on entire cohorts. AIMS: To develop and evaluate statistical models for predicting concentrations of POPs in participants of the Norwegian Women and Cancer (NOWAC) study, using questionnaire information and measured plasma POP concentrations. MATERIALS AND METHODS: Information on estimated dietary intakes and socio-demographic variables from four different questionnaires (in 1991, 1994, 2004 and 2005) were obtained from participants in the NOWAC study. We measured POP concentrations in a total of 367 blood samples from 2005 and built multivariable linear regression models for p,p' DDE, PCB-118, -138, -153, -180 and summed PCB concentrations in one subsample (N = 259) and evaluated the models in another subsample (N = 108). Measured and predicted values were compared using correlation coefficients and inter-method agreement was evaluated using weighted Cohen's kappa for tertile categorization. RESULTS: Median POP concentrations in the population ranged from 13 ng/g lipid to 162 ng/g lipid (lowest for PCB-118 and highest for p,p'-DDE). Common predictors for all POPs were birth year, breastfeeding and the weight-related variables (BMI or weight change), whereas influential dietary variables differed and were of varying importance. The predicted plasma concentrations were significantly correlated with the measured values (rs = 0.24, 0.33, 0.41, 0.50, 0.56, and 0.54 for p,p'-DDE, PCB-118, -138, 153, -180 and summed PCBs, respectively). Tertiles of predicted plasma concentrations displayed significant, but varying agreement with measured concentrations (Weighted Cohen's kappa = 0.19, 0.22, 0.33, 0.42, 0.45, and 0.50 respectively). CONCLUSION: Predicted plasma concentrations of certain PCBs showed good precision (Kw > 0.4) when compared to measured concentrations. Thus, the models can be used to classify NOWAC participants into high, medium and low PCB exposure groups. PMID- 30415880 TI - Inter-observer Variability in the American College of Radiology Thyroid Imaging Reporting and Data System: In-Depth Analysis and Areas for Improvement. AB - The American College of Radiology (ACR) introduced a new standardized system for management of thyroid nodules, the Thyroid Imaging Reporting and Data System (TI RADS). The purpose of this retrospective study is to evaluate the inter-observer variability in applying TI-RADS in clinical practice without prior dedicated training. We evaluated a total of 180 nodules constituting all consecutive thyroid aspirations performed in the radiology department between January 1, 2014 and June 30, 2014, with exclusion of histologically inadequate samples. Four radiologists, blinded to each other's evaluation and to final pathology results, evaluated all of the nodules based on the TI-RADS lexicon. TI-RADS score and management recommendations were then deduced from the inputted features. Statistical analysis was performed to determine inter-observer agreement among all readers, as well as between each two readers, in all TI-RADS sonographic features and for recommended management per TI-RADS score with multi-user Cohen's kappa (Light's kappa) and percentage agreement using R. There was fair-to moderate inter-observer agreement in nodule composition (two-reader kappa range: 0.327-0.533) and presence of calcifications (kappa range: 0.229-0.527), but poor to-fair agreement in echogenicity (kappa range: 0.141-0.355), shape (kappa range: 0.0729-0.513) and margins (kappa range: 0.176-0.283). There was fair inter observer agreement regarding management recommendations (kappa range: 0.242 0.359). PMID- 30415881 TI - Phaseolus vulgaris is nodulated by the symbiovar viciae of several genospecies of Rhizobium laguerreae complex in a Spanish region where Lens culinaris is the traditionally cultivated legume. AB - Phaseolus vulgaris and Lens culinaris are two legumes with different distribution centers that were introduced in Spain at different times, but in some regions L. culinaris has been traditionally cultivated and P. vulgaris did not. Here we analysed the rhizobia isolated from nodules of these two legumes in one of these regions. MALDI-TOF MS analysis showed that all isolated strains matched with Rhizobium laguerreae and the phylogenetic analysis of rrs, atpD and recA genes confirmed these results. The phylogenetic analysis of these core genes allowed the differentiation of several groups within R. laguerreae and unexpectedly, strains with housekeeping genes identical to that of the type strain of R. laguerreae presented some differences in the rrs gene. In some strains this gene contains an intervening sequence (IVS) identical to that found in Rhizobium strains nodulating several legumes in different geographical locations. The atpD, recA and nodC genes of all isolated strains clustered with those of strains nodulating L. culinaris in its distribution centers, but not with those nodulating P. vulgaris in theirs. Therefore, all these strains belong to the symbiovar viciae, including those isolated from P. vulgaris, which in the studied region established effective symbiosis with the common endosymbiont of L. culinaris, instead to with its common endosymbiont, the symbiovar phaseoli. These results are particularly interesting for biogeography studies, because they showed that, due its high promiscuity degree, P. vulgaris is able to establish symbiosis with local symbiovars well established in the soil after centuries of cultivation with other legumes. PMID- 30415883 TI - Clinician's Guide to Reducing Inflammation to Reduce Atherothrombotic Risk: JACC Review Topic of the Week. AB - Life-threatening cardiovascular events occur despite control of conventional risk factors. Inflammation, as measured by high-sensitivity C-reactive protein (hsCRP) concentration, is associated with future vascular events in both primary and secondary prevention, independent of usual risk markers. Statins are powerful lipid-lowering agents with clinically relevant anti-inflammatory effects. Recent data support targeting the interleukin (IL)-1-to-IL-6-to-CRP signaling pathway as an adjunctive method for atheroprotection. The CANTOS (Canakinumab Anti inflammatory Thrombosis Outcomes Study) trial showed that reducing inflammation through IL-1beta inhibition significantly reduced vascular risk, beyond that achievable with lipid lowering. CANTOS further demonstrated a 31% reduction in cardiovascular mortality and all-cause mortality among patients treated with canakinumab who achieved the largest reductions in hsCRP, as well as efficacy in high-risk patients with chronic kidney disease and diabetes. This review outlines the clinical implications of CANTOS for patients with "residual inflammatory risk," the potential benefits and risks associated with anti-inflammatory therapy, and the importance of CANTOS for future drug development. PMID- 30415882 TI - [Trained eye vs. gold standard]. AB - OBJECTIVE: To determine the degree of correlation between the clinical diagnosis prior to the minor surgery process and its concordance with the results of histopathology report, as well as to determine the surgical data of little clinical importance compared to that which is really necessary and cost effective. MATERIAL AND METHOD: A descriptive, observational, retrospective and transversal study was conducted of the Minor Surgery Activities of a clinic in the Ciudad Real Health Centre I. RESULTS: A total of 124 surgical specimens were sent for clinical diagnostic comparison, of which, the main clinical diagnoses were: intradermal melanocytic nevi (34.67%), seborrheic keratosis (11.30%), and epidermoid or sebaceous cysts (10.48%). A correlation of 68% was obtained. The protocols of the work centre have been followed to carry out this study in relation to the confidentiality of the data. CONCLUSIONS: These results were analysed and compared with other similar works performed in the field of minor surgery in Primary Care, being able to affirm that there is a good correlation between the initial clinical diagnosis and the histopathology results. PMID- 30415884 TI - Executive summary: Consensus document of GEHEP of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), along with SOCIDROGALCOHOL, SEPD and SOMAPA on hepatitis C virus infection management in drug users. AB - The micro-elimination of HCV infection in drug users (DU) in our area is a priority in order to achieve the overall elimination of this disease. Coordinated action between specialists in addiction treatment, microbiologists and physicians who treat HCV infection is required to implement infection screening, to achieve universal access to treatment and to prevent new infections and reinfections. The objective of this document was to come to a consensus on the screening, hospital referral, treatment, follow-up and prevention of HCV infection in DU by an expert panel from GEHEP/SEIMC and three scientific societies of addiction treating physicians: SEPD, SOCIDROGALCOHOL and SOMAPA. PMID- 30415885 TI - Non-toxigenic Corynebacterium diphtheriae biotype belfanti in a diabetic patient with upper tract respiratory infection. PMID- 30415886 TI - Preface - Vol. 53. PMID- 30415887 TI - WHO tracking mechanism for IHR additional health measures. PMID- 30415888 TI - Etiology, clinical course and outcome of infant epilepsy: Experience of a tertiary center in Thailand. AB - PURPOSE: Explore etiology, clinical course and outcome of infant epilepsy in Bhumibol Adulyadej Hospital. METHOD: Retrospective and prospective descriptive analysis of infants 1 month to 1 year diagnosed with epilepsy between January 1, 2012, and April 30, 2018. RESULTS: Total 57 infants. Average age of seizure onset was 4.7 months. Follow-up period averaged 34.2 months. Prenatal risk factors were found in 28.1 percent (16/57). Of these, 50 percent (8/16) had seizure in neonatal period. An additional 6 infants without any prenatal risk factor had seizure in the neonatal period, bringing the total newborn with seizure to 24.6 percent (14/57). Family history of seizure was positive in only 15.8 percent (9/57). Neuroimaging was done 68.4 percent (39/57) and electroencephalogram 50.9 percent (29/57). The etiology was mostly structural 38.6 percent (22/57), followed by unknown 35.1 percent (20/57), genetics 14 percent (8/57), infection 10.5 percent (6/57) and metabolic 1.8 percent (1/57). Status epilepticus was found 21.1 percent of the times (12/57). Antiepileptic drugs were discontinued 19.3 percent (11/57). Intractable seizure was found 29.8 percent (17/57) and developmental delay 56.1 percent (32/57). By multivariate logistic regression analysis, status epilepticus and developmental delay predicted intractable seizure, whereas, abnormal neurological examination and abnormal neuroimaging predicted developmental delay. Mortality rate was 3.5 percent. CONCLUSION: The study shows that early onset of epilepsy in children under a year is similar to that found in children less than 2-3 years as found in prior studies. High percentages of intractable seizure and developmental delay were found. PMID- 30415889 TI - Neuregulin1 types mRNA level changes in autism spectrum disorder, and is associated with deficit in executive functions. AB - BACKGROUND: Autism spectrum disorder (ASD) is a pediatric heterogeneous psychiatric and neurodevelopmental disorder with social and communication deficits, language impairment and ritualistic or repetitive behaviors. ASD has significant genetic bases but candidate genes and molecular mechanisms of disorder are not clarified. Neuregulin1 (NRG1) gene, located in 8p12 is involved in development of central nervous system and was indicated as candidate gene in schizophrenia. METHODS: mRNA level of types I, II and III of NRG1 gene were studied in peripheral blood of 1540 ASD patients (IQ > 70) and 1490 control children by quantitative Real Time PCR. Also three domains of executive functions (working memory, response inhibition and vigilance) were examined in all subjects. FINDINGS: All three types were significantly down regulated in ASD patients. Significant deficiencies in executive functions (EF) were found in ASD patients. EF deficiencies mostly were associated with down expression of mRNA level of types I and III. Also correlations were found between NRG1 expression with gender and severity of ASD symptoms. INTERPRETATIONS: Findings primarily have been suggested involvement of NRG1 in etiology of ASD. Also correlation of NRG1 mRNA level with EF deficiencies could shed lights on EF mechanisms and may suggest targeted treatments to improve particular executive functions. FUND: Young researchers and elites club funded the project due to the annual grant of special talents of Club that gave to Arvin Haghighatfard. PMID- 30415890 TI - Dissociation between urate and blood pressure in mice and in people with early Parkinson's disease. AB - BACKGROUND: Epidemiological, laboratory and clinical studies have established an association between elevated urate and high blood pressure (BP). However, the inference of causality remains controversial. A naturally occurring antioxidant, urate may also be neuroprotective, and urate-elevating treatment with its precursor inosine is currently under clinical development as a potential disease modifying strategy for Parkinson's disease (PD). METHODS: Our study takes advantage of a recently completed phase II trial evaluating oral inosine in de novo non-disabling early PD with no major cardiovascular and nephrological conditions, and of three lines of genetically engineered mice: urate oxidase (UOx) global knockout (gKO), conditional KO (cKO), and transgenic (Tg) mice with markedly elevated, mildly elevated, and substantially reduced serum urate, respectively, to systematically investigate effects of urate-modifying manipulation on BP. FINDINGS: Among clinical trial participants, change in serum urate but not changes in systolic, diastolic and orthostatic BP differed by treatment group. There was no positive correlation between urate elevations and changes in systolic, diastolic and orthostatic BP ((p = .05 (in inverse direction), 0.30 and 0.63, respectively)). Between UOx gKO, cKO, or Tg mice and their respective wildtype littermates there were no significant differences in systolic or diastolic BP or in their responses to BP-regulating interventions. INTERPRETATION: Our complementary preclinical and human studies of urate modulation in animal models and in generally healthy early PD do not support a hypertensive effect of urate elevation or an association between urate and BP. FUND: U.S. Department of Defense, RJG Foundation, Michael J. Fox Foundation LEAPS program, National Institutes of Health, American Federation for Aging Research, Parkinson's Disease Foundation Advancing Parkinson's Therapies initiative. PMID- 30415891 TI - Metabolic adaptation in the human gut microbiota during pregnancy and the first year of life. AB - BACKGROUND: The relationship between the gut microbiome and the human host is dynamic and we may expect adjustments in microbiome function if host physiology changes. Metatranscriptomic approaches should be key in unraveling how such adjustments occur. METHODS: We employ metatranscriptomic sequencing analyses to study gene expression in the gut microbiota of infants through their first year of life, and of their mothers days before delivery and one year afterwards. FINDINGS: In infants, hallmarks of aerobic metabolism disappear from the microbial metatranscriptome as development proceeds, while the expression of functions related to carbohydrate transport and metabolism increases and diversifies, approaching that observed in non-pregnant women. Butyrate synthesis enzymes are overexpressed at three months of age, even though most butyrate producing organisms are still rare. In late pregnancy, the microbiota readjusts the expression of carbohydrate-related functions in a manner consistent with a high availability of glucose. INTERPRETATION: Our findings suggest that butyrate production may be ensured in the gut of young infants before the typical butyrate synthesizers of the adult gut become abundant. The late pregnancy gut microbiota may be able to access the high levels of blood glucose characteristic of this period. Moreover, late pregnancy gut bacteria may reach stationary phase, which may affect their likelihood of translocating across the intestinal epithelium. FUNDS: This work was supported by grants CSD2009-00006 (CONSOLIDER Program) and SAF2009-13032-C02-02 from MICINN (Ministry of Science and Innovation, Spain), and by grant SAF2012-31187 from MINECO (Ministry of Economics and Competitiveness, Spain). PMID- 30415892 TI - Understanding the Feasibility and Validity of Muscle Strength Measurements in Aging Adults. PMID- 30415893 TI - Reply to the Letter to Editor. PMID- 30415894 TI - Novel fluorescent triazinobenzimidazole derivatives as probes for labelling human A1 and A2B adenosine receptor subtypes. AB - The expression levels and the subcellular localization of adenosine receptors (ARs) are affected in several pathological conditions as a consequence of changes in adenosine release and metabolism. In this respect, labelled probes able to monitor the AR expression could be a useful tool to investigate different pathological conditions. Herein, novel ligands for ARs, bearing the fluorescent 7 nitrobenzofurazan (NBD) group linked to the N1 (1,2) or N10 (3,4) nitrogen of a triazinobenzimidazole scaffold, were synthesized. The compounds were biologically evaluated as fluorescent probes for labelling A1 and A2B AR subtypes in bone marrow-derived mesenchymal stem cells (BM-MSCs) that express both receptor subtypes. The binding affinity of the synthetized compounds towards the different AR subtypes was determined. The probe 3 revealed a higher affinity to A1 and A2B ARs, showing interesting spectroscopic properties, and it was selected as the most suitable candidate to label both AR subtypes in undifferentiated MSCs. Fluorescence confocal microscopy showed that compound 3 significantly labelled ARs on cell membranes and the fluorescence signal was decreased by the cell pre incubation with the A1 AR and A2B AR selective agonists, R-PIA and BAY 60-6583, respectively, thus confirming the specificity of the obtained signal. In conclusion, compound 3 could represent a useful tool to investigate the expression pattern of both A1 and A2B ARs in different pathological and physiological processes. Furthermore, these results provide an important basis for the design of new and more selective derivatives able to monitor the expression and localization of each different ARs in several tissues and living cells. PMID- 30415895 TI - Integrating Healthy Eating into Evidence-Based Home Visiting Models: An Analysis of Programs and Opportunities for Dietetic Practice. PMID- 30415896 TI - Novel Withdrawal Symptoms of a Neonate Prenatally Exposed to a Fentanyl Analog. AB - Neonatal abstinence syndrome (NAS) is a withdrawal syndrome observed in neonates exposed to drugs in utero, typically opioids, which is associated with symptoms affecting the central and autonomic nervous systems and the gastrointestinal system. West Virginia, particularly the southeastern region of the state, has remarkably higher rates of NAS than similar communities. Our facility is increasingly faced with complex cases of NAS caused by in utero exposure to multiple substances. We present a case report of a neonate born to a 25-year-old mother enrolled in a medication-assisted treatment program for substance use disorder who was noncompliant in prenatal care, using multiple substances throughout the pregnancy, including gabapentin and fentanyl. After birth, the neonate began to exhibit unusual withdrawal symptoms including arching, tongue thrusting, and irregular eye movements, which are typically associated with in utero gabapentin exposure. The parents denied consent to treat with gabapentin, the suggested management for these symptoms; thus, a treatment protocol for methadone and clonidine were followed. This case exemplifies the medical and social complexities involved in treating polysubstance exposure-associated NAS. PMID- 30415897 TI - The extent of drug-drug interaction between amlodipine and activated charcoal is attenuated by food intake in rats. AB - Activated charcoal decreases gastrointestinal absorption of concomitantly administered drugs. The absorption of amlodipine (AML) was reported as almost completely attenuated by 25 g of activated charcoal under a fasted condition, but not affected by 2 g of activated charcoal under a fed condition. However, it is not clear whether this difference resulted from the food intake or the dose of activated charcoal. The aim of this study was to quantitatively evaluate the effect of food intake on drug interactions caused by adsorption to activated charcoal in the gastrointestinal tract in rats. The rats were orally administered 0.08 mg/kg of AML, with or without 33 mg/kg of activated charcoal, under the fasted or fed condition and the plasma concentration profiles of AML were monitored. For the fed group, the standard breakfast used in clinical studies was smashed and administered at a dose of 11 g/kg. The AUC value of AML under the fasted condition was significantly decreased to 24.8% by coadministration of activated charcoal. On the other hand, activated charcoal moderately decreased the AUC value of AML to 74.8% under the fed condition. These results suggest that the extent of drug interactions caused by activated charcoal is attenuated by food intake. PMID- 30415899 TI - Discussion. PMID- 30415898 TI - The protective effect of prone lung position on ischemia-reperfusion injury and lung function in an ex vivo porcine lung model. AB - OBJECTIVE: Prone positioning has been shown to improve oxygenation in patients with lung injury. We hypothesized that prone positioning of lungs during ex vivo lung perfusion (EVLP) can not only improve oxygenation but also diminish ischemia reperfusion injury (IRI). The aim of our study was to evaluate the potential benefits of prone positioning of lungs during EVLP compared with the standard supine position. METHODS: Ten pigs were kept in the supine position at room temperature for 2 hours after circulatory death after which lungs were procured and subjected to 5 hours of cold storage. Lungs then underwent 2 hours of cellular EVLP with either supine positioning (Control group, n = 5) or prone positioning (Prone group, n = 5). Lung function was evaluated by assessment of physiological parameters and tissue histology and cytokines. RESULTS: IRI in the Prone group was significantly less than in the Control group. Lungs in the Prone group were significantly associated with greater partial pressure of oxygen/fraction of inspired oxygen ratio median (minimum-maximum) (301 mm Hg [272 414 mm Hg] vs 166 mm Hg [109-295] mm Hg, P = .03), better static compliance (38.9 mL/cmH2O [31.1-44.3 mL/cmH2O] vs 21.5 mL/cmH2O [12.2-33.3 mL/cmH2O], P = .03), lower lung weight ratio (1.26 [1.24-1.41] vs 1.48 [1.36-2.34], P = .02), and lower interleukin-1beta levels (1.6 ng/mL [0.9-5.3 ng/mL] vs 7.5 ng/mL [5.0-16.1 ng/mL], P = .04) compared with lungs in the Control group. CONCLUSIONS: These data suggest that prone positioning of lungs during EVLP may diminish IRI during EVLP and improve lung function. PMID- 30415900 TI - Structural valve deterioration of biosprosthetic aortic valves: An underestimated complication. AB - OBJECTIVES: Structural valve deterioration (SVD) remains a major bioprosthesis related complication, as recently described for the Mitroflow valve (models LX and 12A) (LivaNova, London, United Kingdom). The real incidence of the SVD risk remains unclear, often due to methodologic pitfalls by systematically using the Kaplan-Meier estimator and/or the Cox model. In this report, we propose for the first time a precise statistical modeling of this issue. METHODS: Five hundred sixty-one patients who underwent aortic valve replacement with the aortic Mitroflow valve between 2002 and 2007 were included. We used an illness-death model for interval-censored data. Median follow-up was 6.6 years; 103 cases of SVD were diagnosed. RESULTS: The 4-year and 7-year SVD cumulative incidences after the first anniversary of surgery were 15.2% (95% confidence interval, 11.9 19.1) and 31.0% (95% confidence interval, 25.8-37.2), respectively. Female gender, dyslipidemia, chronic obstructive pulmonary disease, and severe patient prosthesis mismatch were significant risk factors of SVD. The occurrence of SVD was associated with a 2-fold increase in the risk of death. CONCLUSIONS: Appropriate statistical models should be used to avoid underestimating the SVD complication associated with worse long-term survival. PMID- 30415901 TI - Prospective feasibility study of sealing pulmonary vessels with energy in lung surgery. AB - OBJECTIVE: Vascular sealing with an energy vessel sealing system during lung resection may allow surgeons to treat small vessels with minimal dissection, possibly decreasing likelihood of injury. Few large prospective trials have examined the proximal sides of vessels not ligated in addition to sealing during surgery. We therefore assessed feasibility of an energy device to seal pulmonary artery and vein branches without further ligation. METHODS: This prospective, preoperative registration study at 2 institutions evaluated safety of energy sealing with the LigaSure (Medtronic, Minneapolis, Minn), with no additional reinforcing material such as suture ligation, for pulmonary vessels as large as 7 mm during anatomic lung resection (cohort 1 study). A postoperative hemorrhage occurred in the 128th case, so a cohort 2 study proceeded after we changed inclusion criterion for pulmonary arteries from a maximum of 7 mm to a maximum of 5 mm. RESULTS: In cohort 1 (n = 128) and cohort 2 (n = 200), 216 and 250 pulmonary arteries and 189 and 213 pulmonary veins, respectively, were treated with energy sealing. Overall postoperative hemorrhage rate was 0.3% (1/328 patients); however, no serious postoperative complications were associated with energy sealing among the 200 patients in cohort 2. Subsequent inspection of the torn artery stump confirmed that the bleeding in the 128th case was in an area adjacent to the sealing zone. CONCLUSIONS: Energy sealing without reinforcement allows secure treatment during lung resection of pulmonary arteries as large as 5 mm in diameter and pulmonary veins as large as 7 mm. PMID- 30415903 TI - Managing the aorta in patients with a PRKG1 mutation. PMID- 30415902 TI - Outcomes after neoadjuvant or adjuvant chemotherapy for cT2-4N0-1 non-small cell lung cancer: A propensity-matched analysis. AB - OBJECTIVE: Comparative survival between neoadjuvant chemotherapy and adjuvant chemotherapy for patients with cT2-4N0-1M0 non-small cell lung cancer has not been extensively studied. METHODS: Patients with cT2-4N0-1M0 non-small cell lung cancer who received platinum-based chemotherapy were retrospectively identified. Exclusion criteria included stage IV disease, induction radiotherapy, and targeted therapy. The primary end point was disease-free survival. Secondary end points were overall survival, chemotherapy tolerance, and ability of Response Evaluation Criteria In Solid Tumors response to predict survival. Survival was estimated using the Kaplan-Meier method, compared using the log-rank test and Cox proportional hazards models, and stratified using matched pairs after propensity score matching. RESULTS: In total, 330 patients met the inclusion criteria (n = 92/group after propensity-score matching; median follow-up, 42 months). Five-year disease-free survival was 49% (95% confidence interval, 39-61) for neoadjuvant chemotherapy versus 48% (95% confidence interval, 38-61) for adjuvant chemotherapy (P = .70). On multivariable analysis, disease-free survival was not associated with neoadjuvant chemotherapy or adjuvant chemotherapy (hazard ratio, 1.1; 95% confidence interval, 0.64-1.90; P = .737), nor was overall survival (hazard ratio, 1.21; 95% confidence interval, 0.63-2.30; P = .572). The neoadjuvant chemotherapy group was more likely to receive full doses and cycles of chemotherapy (P = .014/0.005) and had fewer grade 3 or greater toxicities (P = .001). Response Evaluation Criteria In Solid Tumors response to neoadjuvant chemotherapy was associated with disease-free survival (P = .035); 15% of patients receiving neoadjuvant chemotherapy (14/92) had a major pathologic response. CONCLUSIONS: Timing of chemotherapy, before or after surgery, is not associated with an improvement in overall or disease-free survival among patients with cT2-4N0-1M0 non-small cell lung cancer who undergo complete surgical resection. PMID- 30415904 TI - HIF-1alpha, NOTCH1, ADAM12, and HB-EGF are overexpressed in mucoepidermoid carcinoma. AB - OBJECTIVE: Intratumoral hypoxia (IH) occurs during cellular proliferation of malignant tumors. This phenomenon is characterized by a decrease in oxygen levels in the neoplastic microenvironment. Throughout this condition, the proteins HIF 1alpha, NOTCH1, ADAM12, and HB-EGF can be activated, triggering signaling pathways associated with tumor invasiveness through invadopodia formation. This study aimed to evaluate the immunostaining of HIF-1alpha, NOTCH1, ADAM12, and HBEGF in 19 cases of mucoepidermoid carcinoma (MEC) and 10 samples of salivary glands (control group). STUDY DESIGN: The immunoperoxidase technique was employed to detect the proteins of interest. The Student t test was used to compare immunoexpression between MEC samples and the control group. RESULTS: Protein immunostaining was statistically significantly higher in MEC samples than in the control group (P < .01), and the proteins were especially overexpressed in epidermoid cells of MEC. CONCLUSIONS: We suggest that there is an association between the NOTCH1 signaling pathway activated by IH and the biologic behavior of MEC. PMID- 30415906 TI - A narrative review of interventions for improving sleep and reducing circadian disruption in medical inpatients. AB - Sleep and circadian disruptions are frequently observed in patients across hospital wards. This is alarming, since impaired nocturnal sleep and disruption of a normal circadian rhythm can compromise health and disturb processes involved in recovery from illness (eg, immune functions). With this in mind, the present narrative review discusses how patient characteristics (sleep disorders, anxiety, stress, chronotype, and disease), hospital routines (pain management, timing of medication, nocturnal vital sign monitoring, and physical inactivity), and hospital environment (light and noise) may all contribute to sleep disturbances and circadian misalignment in patients. We also propose hospital-based strategies that may help reduce sleep and circadian disruptions in patients admitted to the hospital. PMID- 30415905 TI - A comparison of panoramic radiography and cone beam computed tomography in the detection of osteosynthesis complications in sheep mandibular angle fractures. AB - OBJECTIVE: The aim of this study was to compare the diagnostic efficacy of panoramic radiography (PANO) and cone beam computed tomography (CBCT) in detecting simulated complications of plate osteosynthesis applied to mandibular angle fractures (MAFs). STUDY DESIGN: Unfavorable MAFs were created in 100 fresh sheep hemimandibles. Fractures were fixed with 4-hole titanium miniplates and screws. Bone necrosis around the screws, penetration of the screw into the inferior alveolar canal, screw loosening, and plate breakage were simulated. The diagnostic efficacy of the imaging techniques was compared by using intra- and interobserver agreement scores and area under the receiver operating characteristic curve (AUC) values. Examination time (ET), confidence scores (CS), and planar preference (PP) in CBCT evaluation were assessed. RESULTS: Intra- and interobserver agreement scores varied between 0.61 and 0.91. AUCs for screw penetration into the inferior alveolar canal and screw loosening were significantly higher in CBCT than in PANO (P < .05). CBCT presented significantly higher ET and CS values compared with PANO (P < .05). PP showed significant differences among types of complications (P < .05). CONCLUSIONS: PANO provided acceptable outcomes in the detection of bone necrosis and broken plates around the screw, but CBCT was more likely to enable detection of all simulated types of complications with higher confidence. PMID- 30415907 TI - Association between dietary inflammatory index and psychological profile in adults. AB - BACKGROUND & AIMS: Limited data are available on the association of inflammatory potential of the diet and odds of psychological disorders. We investigated the association between adherence to a pro-inflammatory diet, as measured by Dietary Inflammatory Index (DII), and odds of psychological disorders. METHODS: In this cross-sectional study, dietary intakes of 3363 Iranian adult participants were collected using a validated Dish-based 106-item Semi-quantitative Food Frequency Questionnaire (DS-FFQ). DII score was calculated based on participants' dietary intakes obtained from DS-FFQ. The Iranian validated version of Hospital Anxiety and Depression Scale (HADS) and General Health Questionnaire (GHQ) was used to assess psychological disorders. For depression and anxiety, scores of 8 or more on either subscale were considered as psychological disorders and scores of 0-7 were defined as "normal". In terms of psychological distress, the score of 4 or more was defined as psychological distress. RESULTS: Overall, 28% (n = 943) of study participants had depression, 13.3% (n = 448) were affected by anxiety and 22.6% (n = 760) by psychological distress. After controlling for potential confounders, individuals in the highest quintile of DII score had higher scores of depression (6.56 +/- 0.16 vs. 5.48 +/- 0.16; P < 0.001), anxiety (3.85 +/- 0.17 vs. 3.09 +/- 0.17; P = 0.006), and psychological distress (2.42 +/- 0.13 vs. 1.77 +/- 0.13; P = 0.001), compared with those in the lowest quintile. Participants in the top quintile of DII score had greater odds of depression (OR: 1.84, 95% CI: 1.30-2.60), anxiety (OR: 1.69, 95% CI: 1.07-2.67), and psychological distress (OR: 1.72, 95% CI: 1.20-2.46) than those in the bottom quintile. CONCLUSIONS: We found that adherence to a pro-inflammatory diet was positively associated with psychological disorders. PMID- 30415908 TI - Performance of CT-based low skeletal muscle index, low mean muscle attenuation, and bioelectric impedance derived low phase angle in the detection of an increased risk of nutrition related mortality. AB - BACKGROUND & AIMS: The aim of this study was to evaluate in a head to head comparison the performance of bioimpedance derived low phase angle (PA), CT-based low skeletal muscle index (SMI) and low mean muscle attenuation (MA), and Pandora Score (PS) to detect an increased nutrition related mortality in hospitalized patients. METHODS: A total of 7736 patients were hospitalized in Dessau community hospital (Nov 11, 2016-Feb 05, 2017). In 227/7736 patients an abdominal CT scan was obtained and low values (below threshold) of skeletal muscle index (SMI) and mean muscle attenuation (MA) were obtained at L3 level using Slice-O-Matic. In 180/227 patients, malnutrition screening (NRS-2002 >= 3), determination of low PA (<5th percentile) and calculation of 30-day mortality risk (PS >= 5%) were done within 6 days after the CT scan. RESULTS: PA was low in 116 (64%), SMI was low in 95 (53%), and MA was below threshold in 137 (77%) patients. Using hospital mortality (8.3%) as a gold standard, low SMI, low MA, or low PA showed high sensitivity (SMI 93.3%; MA 86.7%; PA 86.7%) and high negative predictive (NPV) values (SMI 98.9%; MA 95.3%; PA 96.9%) and improved specificity (NRS + SMI 65.5%; NRS + MA 50.3%; NRS + PA 50.3%) when combined with the criterion NRS >= 3. Using hospital mortality as a gold standard, a PS >= 36 (predicted mortality >= 5%) showed a sensitivity of 73.3%, a specificity of 62.2% and an NPV of 96.4%. PS predicted mortality was >=5% in 70 (39%) patients and was higher (median 5.2%; IQR: 2.8; 11.8 vs 1.7%; IQR: 1.0; 2.8; p < 0.001) in patients with a low PA and this was also observed for low vs normal SMI (median 5.7%; IQR: 2.6; 11.1 vs 2.7%; IQR:1.4;5.5; p < 0.001) but not for low vs normal MA (median 3.9%; IQR: 2.1; 8.8 vs 3.4%; IQR: 2.0; 8.1; ns). CONCLUSION: Determination of phase angle < 5th percentile is a convenient non-invasive and inexpensive bedside method with high sensitivity and a high negative predictive value to detect patients at risk of nutrition related mortality with a performance comparable to CT derived skeletal muscle index or mean muscle attenuation. PMID- 30415909 TI - Combination Therapy With Glucagon-Like Peptide-1 Receptor Agonists and Sodium Glucose Cotransporter 2 Inhibitors in Older Patients With Type 2 Diabetes: A Real World Evidence Study. AB - OBJECTIVES: Scientific literature about the combination of glucagon-like peptide 1 receptor agonists (GLP-1ra) and sodium-glucose cotransporter 2 (SGLT2) inhibitors in older patients is scarce. We sought to assess the real-world efficacy and safety of SGLT2 inhibitors and GLP-1ra combination therapy in older patients (>65 years of age). METHODS: This was an observational, prospective, multicenter study based on clinical practice. Patients were stratified according to tertiles of baseline glycated hemoglobin (A1C) levels and to treatment schedule. RESULTS: We included 113 patients (65.5% men, mean age 70.4+/-8.8 years). The body mass index was 36.5 (+/-6.6) kg/m2. The baseline A1C level was 8.0% (+/-1.2%). At the 6-month follow up, we found a significant reduction in A1C levels (-1.1%; p<0.0001), body mass index (-2.1 kg/m2; p<0.00003) and systolic blood pressure (-13 mmHg; p<0.000005). Patients who had the highest baseline A1C levels (>=8.4%) showed greater improvement in A1C levels (p<0.0001), weight (p<0.0001) and quality-of-life scores (p<0.0001). The greatest reduction in A1C levels and weight was seen in patients who started both drugs simultaneously (p<0.0001). The second greatest reduction was seen when GLP-1ra was added to previous treatment with an SGLT2i (p<0.0001). Also of note was a decrease in systolic blood pressure in patients for whom an SGLT2i was added to previous GLP 1ra treatment (p<0.0001). Of the patients, 34.3% achieved the combined endpoint of A1C levels <7% and weight loss >=5% without hypoglycemia. CONCLUSIONS: This study's findings provide evidence of clinically meaningful reductions in A1C level, body weight and systolic blood pressure in older patients with type 2 diabetes who are taking combined regimens. The dropout and hypoglycemia rates were minimal, and treatment was tolerated well. PMID- 30415911 TI - Caring: not just for patients and families. PMID- 30415910 TI - Process Evaluation of the Diabetes Canada Guidelines Dissemination Strategy Using the Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) Framework. AB - OBJECTIVES: Our purpose was to disseminate and implement the Diabetes Canada (formerly the Canadian Diabetes Association) 2013 Clinical Practice Guidelines and evaluate the impact of the dissemination and implementation strategy on process outcomes (reach, adoption, implementation and maintenance). METHODS: Our patient- and provider-directed strategy consisted of a guidelines website, electronic point-of-care decision-support tools, mobile applications, electronic medical record templates, laboratory prompts, continuing professional development modules, a communications campaign and printed education materials. We used the Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) framework to assess process-level outcomes. We report on the reach, adoption, implementation and organizational maintenance by using mixed methods and multiple data sources (communications reports, mailing lists, website-usage statistics, accreditation logs, session-evaluation forms, budgets). RESULTS: A total of 1,786,910 contacts were made with health-care professionals, the majority of whom were nurses. The greatest reach was through the website. A total of 35,573,154 contacts were made with the general population; the greatest reach occurred through media channels. We contacted 149 and collaborated with 18 governmental, professional and health advocacy organizations about activities such as distributing resources and implementing team-based care initiatives and screening policies. Most website users were young women, with use occurring during working hours. Interactive clinical decision-support tools were most commonly accessed. Website use increased with time. The institutionalization of guidelines occurred in a few areas such as the use of an adapted screening policy in the Northwest Territories. CONCLUSIONS: Our interactive tools were repeatedly accessed, signifying their relevance to problems in clinical care. Our synthesized analyses indicate that the guidelines website is resource intensive, with a wide reach and the potential to change outcomes. PMID- 30415912 TI - Response to the Letter to the Editor: Critically ill Haematological Cancer Patients: How far the Severity Index Score can determine the outcome and duration of Aggressive Support? PMID- 30415913 TI - Ventilation perfusion pulmonary scintigraphy in the evaluation of pre-and post lung transplant patients. AB - Lung transplantation is an established treatment for patients with a variety of advanced lung diseases. Imaging studies play a valuable role not only in evaluation of patients prior to lung transplantation, but also in the follow up of patients after transplantation for detection of complications. After lung transplantation, complications can occur as a result of surgical procedure, pulmonary embolism and ultimately chronic lung allograft dysfunction. Lung scintigraphy, which includes physiologic assessment of lung ventilation and perfusion by imaging, has become an important procedure in the evaluation of these patients, assuming a complementary role to high resolution anatomic imaging (computed tomography [CT]), as well as spirometry. The purpose of this atlas article is to demonstrate the uses of ventilation perfusion scintigraphy in the pre-transplantation setting for surgical planning and in the evaluation of complications post-lung transplantation based upon experience at our institution. PMID- 30415914 TI - Contributions of Glycosaminoglycans to Collagen Fiber Recruitment in Constitutive Modeling of Arterial Mechanics. AB - The contribution of glycosaminoglycans (GAGs) to the biological and mechanical functions of biological tissue has emerged as an important area of research. GAGs provide structural basis for the organization and assembly of extracellular matrix (ECM). The mechanics of tissue with low GAG content can be indirectly affected by the interaction of GAGs with collagen fibers, which have long been known to be one of the primary contributors to soft tissue mechanics. Our earlier study showed that enzymatic GAG depletion results in straighter collagen fibers that are recruited at lower levels of stretch, and a corresponding shift in earlier arterial stiffening (Mattson et al., 2016). In this study, the effect of GAGs on collagen fiber recruitment was studied through a structure-based constitutive model. The model incorporates structural information, such as fiber orientation distribution, content, and recruitment of medial elastin, medial collagen, and adventitial collagen fibers. The model was first used to study planar biaxial tensile stress-stretch behavior of porcine descending thoracic aorta. Changes in elastin and collagen fiber orientation distribution, and collagen fiber recruitment were then incorporated into the model in order to predict the stress-stretch behavior of GAG depleted tissue. Our study shows that incorporating early collagen fiber recruitment into the model predicts the stress stretch response of GAG depleted tissue reasonably well (rms = 0.141); considering further changes of fiber orientation distribution does not improve the predicting capability (rms = 0.149). Our study suggests an important role of GAGs in arterial mechanics that should be considered in developing constitutive models. PMID- 30415915 TI - Granulocyte macrophage-colony stimulating factor: A key modulator of renal mononuclear phagocyte plasticity. AB - Macrophage-colony stimulating factor (M-CSF) and granulocyte macrophage-colony stimulating factor (GM-CSF) play key roles in the differentiation of macrophages and dendritic cells (DCs). We examined the effect of treatment with M-CSF containing macrophage medium or GM-CSF-containing DC medium upon the phenotype of murine bone marrow-derived macrophages and DCs. Culture of macrophages for 5 days in DC medium reduced F4/80 expression and increased CD11c expression with cells effectively stimulating T cell proliferation in a mixed lymphocyte reaction. DC medium treatment of macrophages significantly reduced phagocytosis of both apoptotic cells and latex beads and strongly induced the expression of the chemokine receptor CCR7 known to be involved in DC trafficking to lymph nodes. Lysates of obstructed murine kidneys expressed both M-CSF and GM-CSF though M-CSF expression was dominant (M-CSF:GM-CSF ratio ~30:1). However, combination treatment with both M-CSF and GM-CSF (ratio 30:1) indicated that small amounts of GM-CSF skewed macrophages towards a DC-like phenotype. To determine whether macrophage phenotype might be modulated in vivo we tracked CD45.1+ bone marrow derived macrophages intravenously administered to CD45.2+ mice with unilateral ureteric obstruction. Flow cytometry of enzyme dissociated kidneys harvested 3 days later indicated CD11c and MHC Class II upregulation by adoptively transferred CD45.1+ cells with CD45.1+ cells evident in draining renal lymph nodes. Our data suggests that GM-CSF modulates mononuclear phagocyte plasticity, which likely promotes resolution of injury and healing in the injured kidney. PMID- 30415916 TI - Hospital Quality Metrics: "America's Best Hospitals" and Outcomes After Ischemic Stroke. AB - BACKGROUND: Developing quality metrics to assess hospital-level care and outcomes is increasingly popular in the United States. The U.S. News & World Report ranking of "America's Best Hospitals" is an existing, popular hospital-profiling system, but it is unknown whether top-ranked hospitals in their report have better outcomes according to other hospital quality metrics such as the Centers for Medicare and Medicaid Services (CMS) publicly reported 30-day stroke measures. METHODS: The analysis was based on the 2015-2016 U.S. News & World Report ranking of the 50 top-rated hospitals for neurology and neurosurgery and 2012-2014 CMS Hospital Compare Data. We used mixed models adjusted for hospital characteristics and weighted by hospital volume to compare 30-day risk standardized mortality and readmission between top-ranked and other hospitals. Among the 50 top-ranked hospitals, we determined whether ranking order was associated with the CMS outcomes. RESULTS: Compared with 2737 other hospitals, the 50 top-ranked hospitals had lower 30-day mortality (14.8% versus 15.3%) but higher readmission (14.5% versus 13.3%). These patterns persisted in adjusted analyses with top-ranked hospitals having .72% (95% confidence interval [CI] 1.09%, -.34%) lower mortality and .41% (95% CI .16%, .67%) higher readmission. Among top-ranked hospitals, rank order was not associated with mortality (.05% decrease in mortality with each rank, 95% CI -.10%, .01%) or readmission (.02% increase; 95% CI -.03%, .06%). CONCLUSION: Admission to a top-ranked hospital for neurology or neurosurgery was associated with lower 30-day risk-standardized mortality but higher readmission after ischemic stroke. There was heterogeneity in outcomes among the 50 top-ranked hospitals. PMID- 30415917 TI - The Role of Personalized Virtual Reality in Education for Patients Post Stroke-A Qualitative Case Series. AB - BACKGROUND: Education is essential to promote prevention of recurrent stroke and maximize rehabilitation; however, current techniques are limited and many patients remain dissatisfied. Virtual reality (VR) may provide an alternative way of conveying complex information through a more universal language. AIM: To develop and conduct preliminary assessments on the use of a guided and personalized 3D visualization education session via VR, for stroke survivors and primary caregivers. METHODS: Four poststroke patients and their 4 primary caregivers completed the 3D visualization education session as well as pre- and postintervention interviews. Each patient had a different stroke etiology (i.e., ischemic thrombotic stroke, ischemic embolic stroke, hemorrhagic stroke, and transient ischemic attack followed by ischemic stroke, respectively). This new approach uses preintervention interview responses, patient MRI and CT datasets, VR head mounted displays, 3D computer modeling, and game development software to develop the visualization. Pre- and postintervention interview responses were analyzed using a qualitative phenomenological methodology approach. RESULTS: All participants safely completed the study and were highly satisfied with the education session. In this subset of participants, prior formal stroke education provision was limited. All participants demonstrated varied improvements in knowledge areas including brain anatomy and physiology, brain damage and repair, and stroke-specific information such as individual stroke risk factors and acute treatment benefits. These improvements were accompanied by feelings of closure, acceptance, and a greater motivation to manage their stroke risk. CONCLUSIONS: Preliminary results suggest this approach provides a safe and promising educational tool to promote understanding of individualized stroke experiences. PMID- 30415918 TI - Impact of Elevated Hemoglobin A1c Levels on Functional Outcome in Patients with Acute Ischemic Stroke. AB - BACKGROUND: The association between hemoglobin A1c (HbA1c) and clinical outcomes of acute ischemic stroke is uncertain. We aimed to evaluate the association between initial hemoglobin A1c level and clinical outcome after acute ischemic stroke. METHODS: A total of 408 patients with first-ever acute ischemic stroke were included in this study. We divided the patients into three groups according to HbA1c level: low HbA1c level (HbA1c <5.7%), moderate HbA1c level (HbA1c 5.7 6.4%), and high HbA1c level (HbA1c >=6.5%). Poor neurological outcomes were defined as modified Rankin Scale (mRS) score of 2-6 at 3 months after stroke. The relation between HbA1c value and clinical outcomes were evaluated by using multivariate logistic regression analyses. RESULTS: Moderate HbA1c level was present in 126 (30.9%) patients and high HbA1c level in 129 (31.6%) patients. After adjustment for potential confounding variables, both patients in the high HbA1c level group (adjusted odds ratio [OR]: 2.387; 95% confidence interval [CI], 1.201-4.745; P = .013) and moderate HbA1c level group (adjusted OR: 1.797; 95% CI, 1.005-3.214; P = .048) had a significantly higher poor neurological outcomes than the group in the low HbA1c level. When separately analyzed according to with or without diabetes, the HbA1c level as continuous variable was also associated with poor functional outcome at 3 months in the diabetic patients (adjusted OR: 1.482, 95% CI, 1.013-2.167, P = .042), nor in nondiabetic group. CONCLUSIONS: Higher HbA1c on admission was an independent predictor of adverse functional outcome in ischemic stroke patients. Based on this point, tight glycemic control must be necessary for high-risk diabetic patients. PMID- 30415919 TI - The Influence of Weather on the Incidence of Primary Spontaneous Intracerebral Hemorrhage. AB - BACKGROUND: Intracerebral hemorrhage has been associated with changes in various weather conditions. The primary aim of this study was to examine the collective influence of temperature, barometric pressure, and dew point temperature on the incidence of primary spontaneous intracerebral hemorrhage (sICH). METHODS: Between January 2013 and December 2016, patients with sICH due to hypertension or amyloid angiopathy with a known time of onset were identified prospectively. Meteorological variables 6 hours prior to time of onset were obtained from the National Oceanic Atmospheric Administration via two weather stations. Using a Monte-Carlo simulation, random populations of meteorological conditions in a 6 hour time window during the same years were generated. The actual meteorological conditions 6-hours prior to sICH were compared to those from the randomly generated populations. The false discovery rate method was used to identify significant meteorological variables. RESULTS: Time of onset was identified in 455 of 603 (75.5%) patients. Distribution curves for change in temperature, mean barometric pressure, and change in barometric pressure 6-hours prior to hemorrhage ictus were found to be significantly different from the random populations. (FDR approach P < .05). For a given change in temperature associated with intracerebral hemorrhage, mean barometric pressure was higher (1018 millibar (mb) versus 1016 mb, P = .03). Barometric pressure data was not influenced by variations in temperature. CONCLUSIONS: We concluded that barometric pressure primarily influences the incidence of intracerebral hemorrhage. The association described in the literature between temperature and intracerebral hemorrhage is likely confounded by variations in barometric pressure. PMID- 30415920 TI - Risk Factors for Hemorrhagic and Cardioembolic Complications of Intracerebral Hemorrhage Associated with Anticoagulants. AB - BACKGROUND: Patients with intracerebral hemorrhage taking anticoagulants are increasingly common in Japan due to the aging population. The clinical benefit of restarting anticoagulants is established, but the optimal timing of resumption is controversial. Risk factors for hemorrhagic and cardioembolic events in the acute phase are also unknown. This study investigated hemorrhagic and cardioembolic events and risk factors in intracerebral hemorrhage patients taking anticoagulants. METHODS: The clinical data of 65 consecutive intracerebral hemorrhage patients taking anticoagulants were retrospectively reviewed. Hemorrhagic and cardioembolic complications and risk factors were analyzed. RESULTS: Lobar hemorrhage was the most frequent (21 of 65 cases, 32.3%). At discharge, 31 patients (47.7%) showed severe disability or had died. Eight (18.6%) of 43 patients who restarted anticoagulants after initial treatment developed hemorrhagic events, including recurrent intracerebral hemorrhage in 3. HAS-BLED score was 2-3 in these 3 patients. Six (15.8%) of 38 patients who took anticoagulants for cardiogenic factors suffered cardioembolism. Systemic inflammatory response syndrome was significantly more common in the cardioembolic group (66.7%) compared with the noncardioembolic group (21.9%, P < .05). CHA2DS2 VASc score was paradoxically high in the noncardioembolic group (3 versus 5, P < .05). CONCLUSION: HAS-BLED score and CHA2DS2-VASc score were not useful for risk assessment for hemorrhagic events, recurrent intracerebral hemorrhage, and cardioembolism in the acute phase. Inflammatory response might be important in the occurrence of cardioembolic events. PMID- 30415921 TI - Building on a Solid Foundation: Enhancing Bacillus Calmette-Guerin Therapy. AB - CONTEXT: More than 40 yr ago, bacillus Calmette-Guerin (BCG) was introduced as an adjuvant therapy following transurethral resection of papillary tumours and as a treatment for carcinoma in situ of the bladder. Some 30 yr after its introduction, BCG maintenance therapy was found to be superior to induction therapy alone, representing the most relevant clinical improvement to BCG therapy since its inception. OBJECTIVE: To review current efforts and future opportunities to improve BCG immunotherapy. EVIDENCE ACQUISITION: English online databases (eg, PubMed and clinicaltrials.gov) were searched for clinical trials and meta-analyses of BCG therapy for bladder cancer. The information retrieved was reviewed and sel ected by all the authors and, while representative of the field, is not necessarily exhaustive. EVIDENCE SYNTHESIS: Current knowledge supports the notion that careful patient management from diagnosis to therapy may contribute positively to outcome following BCG immunotherapy. In the future, patient evaluation using predictive immunological or molecular biomarkers will help in identifying those most likely to benefit from BCG therapy. Trials assessing immune modulators in combination with BCG or the use of recombinant BCG are ongoing and results will be forthcoming in the near future. CONCLUSIONS: Enhancing BCG to improve patient outcomes is the responsibility of treating physicians and researchers. Future efforts will continue to improve how non muscle-invasive urothelial carcinoma is evaluated, treated, and ultimately cured. PATIENT SUMMARY: Bacillus Calmette-Guerin (BCG) immunotherapy to prevent the recurrence and progression of urothelial carcinoma is invasive and demanding for patients. Meticulous diagnostics, correct application of BCG, and selection of patients likely to respond to therapy will ensure that the highest benefit can be attained from this therapy. Current research is focused on discovering biomarkers to identify patients most likely to benefit from BCG immunotherapy. Biomarker identification, new immune modulators, and genetically modified BCG strains are undergoing clinical trial testing to improve outcomes for bladder cancer patients. PMID- 30415922 TI - Robotic Inferior Vena Cava Thrombectomy: Are We Entering the House Through an Attic Window? AB - While feasible, it is unclear whether robotic inferior vena cava thrombectomy affords significant benefits. Outcomes are acceptable in carefully selected patients, but the approach is not applicable to all-comers. Higher costs are a challenge for health care systems and the value proposition for this approach is undefined. PMID- 30415923 TI - Genetic Analysis Reveals AMPK Is Required to Support Tumor Growth in Murine Kras Dependent Lung Cancer Models. AB - AMPK, a conserved sensor of low cellular energy, can either repress or promote tumor growth depending on the context. However, no studies have examined AMPK function in autochthonous genetic mouse models of epithelial cancer. Here, we examine the role of AMPK in murine KrasG12D-mediated non-small-cell lung cancer (NSCLC), a cancer type in humans that harbors frequent inactivating mutations in the LKB1 tumor suppressor-the predominant upstream activating kinase of AMPK and 12 related kinases. Unlike LKB1 deletion, AMPK deletion in KrasG12D lung tumors did not accelerate lung tumor growth. Moreover, deletion of AMPK in KrasG12D p53f/f tumors reduced lung tumor burden. We identified a critical role for AMPK in regulating lysosomal gene expression through the Tfe3 transcription factor, which was required to support NSCLC growth. Thus, AMPK supports the growth of KrasG12D-dependent lung cancer through the induction of lysosomes, highlighting an unrecognized liability of NSCLC. PMID- 30415924 TI - Interleukin-17 Drives Interstitial Entrapment of Tissue Lipoproteins in Experimental Psoriasis. AB - Lipoproteins trapped in arteries drive atherosclerosis. Extravascular low-density lipoprotein undergoes receptor uptake, whereas high-density lipoprotein (HDL) interacts with cells to acquire cholesterol and then recirculates to plasma. We developed photoactivatable apoA-I to understand how HDL passage through tissue is regulated. We focused on skin and arteries of healthy mice versus those with psoriasis, which carries cardiovascular risk in man. Our findings suggest that psoriasis-affected skin lesions program interleukin-17-producing T cells in draining lymph nodes to home to distal skin and later to arteries. There, these cells mediate thickening of the collagenous matrix, such that larger molecules including lipoproteins become entrapped. HDL transit was rescued by depleting CD4+ T cells, neutralizing interleukin-17, or inhibiting lysyl oxidase that crosslinks collagen. Experimental psoriasis also increased vascular stiffness and atherosclerosis via this common pathway. Thus, interleukin-17 can reduce lipoprotein trafficking and increase vascular stiffness by, at least in part, remodeling collagen. PMID- 30415925 TI - Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Production. AB - Diabetes is a bihormonal disorder resulting from combined insulin and glucagon secretion defects. Mice lacking fumarase (Fh1) in their beta cells (Fh1betaKO mice) develop progressive hyperglycemia and dysregulated glucagon secretion similar to that seen in diabetic patients (too much at high glucose and too little at low glucose). The glucagon secretion defects are corrected by low concentrations of tolbutamide and prevented by the sodium-glucose transport (SGLT) inhibitor phlorizin. These data link hyperglycemia, intracellular Na+ accumulation, and acidification to impaired mitochondrial metabolism, reduced ATP production, and dysregulated glucagon secretion. Protein succination, reflecting reduced activity of fumarase, is observed in alpha cells from hyperglycemic Fh1betaKO and beta-V59M gain-of-function KATP channel mice, diabetic Goto Kakizaki rats, and patients with type 2 diabetes. Succination is also observed in renal tubular cells and cardiomyocytes from hyperglycemic Fh1betaKO mice, suggesting that the model can be extended to other SGLT-expressing cells and may explain part of the spectrum of diabetic complications. PMID- 30415926 TI - Ketogenic diet as a successful early treatment modality for SCN2A mutation. AB - SCN2A mutations have been described in a very broad spectrum of clinical phenotypes including benign (familial) neonatal/infantile seizures and early infantile epileptic encephalopathies (EIEE) as Ohtahara syndrome (OS), Dravet syndrome (DS), epilepsy of infancy with migrating focal seizures and West syndrome (WS). Treatment modalities for epilepsy caused by SCN2A mutations mainly consist of sodium channel blockers but ketogenic diet (KD) is also considered as an option of treatment for intractible seizures caused by SCN2A mutations. Because of the wide nature of the heterogeneity of mutations related to SCN2A gene, the clinical phenotypes vary in severity and treatment response to KD has been reported to be controversial. We present a patient diagnosed with OS associated with a novel SCN2A mutation (c.408G > A, p.Met136lle; OMIM(r): 182390) who had a complete resolution of seizures and EEG abnormalities with KD commenced at 39 days of age. As far as we are aware our case is the youngest patient with SCN2A mutation treated with KD with complete resolution of epilepsy at an early age and has been seizure free of antiepileptic medications for a long duration. PMID- 30415928 TI - The influence of medical school on career choice: A longitudinal study of students' attitudes toward a career in general surgery. AB - BACKGROUND: Less than 80% of general surgery (GS) residency positions are filled by graduates from allopathic, U.S. medical schools. The aim of this study was to gauge students' interest in pursuing GS throughout their medical school matriculation and explore students' changing perceptions of the specialty. METHODS: Students at two medical schools were surveyed annually for 4 years. Survey responses regarding interest were compared to actual NRMP match results. RESULTS: Interest in a GS career was highest at the outset of medical school and declined steadily during the program, which was similar at both schools, including a positive effect on interest from the surgical clerkship. CONCLUSIONS: Our findings suggest that experiences during medical school impact students' perceptions of GS; specifically, lifestyle, work environment, and the length of training discouraged pursuit of GS. Perception of a GS's lifestyle and the educational environment are both highly modifiable factors that could increase interest in general surgery amongst graduates. PMID- 30415927 TI - Is initial optic nerve sheath diameter prognostic of specific head injury in emergency departments? AB - BACKGROUND: Emergency departments (EDs) are typically the first medical contact for patients with traumatic brain injury (TBI) and early diagnosis and treatment of intracranial pressure (ICP) in patients with neurotrauma primarily falls under the liability of emergency doctors. Monitoring ICP with optic nerve sheath diameter (ONSD) via tools has gained popularity among emergency service doctors. In this study, we aimed to evaluate the predictive value of ONSD for specific head injury on initial cranial tomography. METHODS: CT scans of 176 patients with a known intracranial pathology were retrospectively analyzed and compared with normal control CTs of 182 patients presented to ED at the same time interval. The attending radiologist analyzed all initial brain CT scans and randomly sampled control CTs were similarly assessed by the second senior radiologist whom were blind to the patients' medical histories and circumstances of TBI at the time of measurement. ONSD was measured at a distance of 3 mm behind the eyeball, immediately below the sclera. RESULTS: Right ONSD value was significantly higher in patients with herniation and SAH (p = 0,024 and 0,028, respectively). Left ONSD values was at the level of statistical significance and mean ONSD values was significantly higher in patients with SAH (p = 0.05 and 0.026, respectively). Right-left-mean ONSD values were statistically higher in study group with bilateral lesions on brain CT (p < 0,001). ONSD measurements and patient age were higher in patients who died (p < 0,001). CONCLUSIONS: ONSD measurement on initial brain CT is lesion dependent and indicates mortality. PMID- 30415929 TI - Cancel that PICC line order; cholecystostomy tube and short course of antibiotics. AB - BACKGROUND: Current guidelines do not specifically address optimal antibiotic duration following cholecystostomy. This study compares outcomes for short-course (<7 days) and long-course (>=7 days) antibiotics post-cholecystostomy. METHODS: This was a retrospective review of cholecystostomy patients (>=18 years) admitted (1/1/2007-12/31/2017) to one healthcare system. RESULTS: Overall, 214 patients were studied. Demographics were similar, except short-course patients had higher Charlson Comorbidity Index (p < 0.0001). There were no intergroup differences in tachycardia (22.5%[short-course] vs 23.3%[long-course]) or leukocytosis (67.1%[short-course] vs 64.4%[long-course]) at drain placement nor time to normalization for pulse, temperature or leukocytosis. There were no differences regarding Clostridium Difficile infection (5.0%[short-course] vs 1.6%[long course]) or cholecystitis recurrence (8.8%[short-course] vs 10.9%[long-course]). No differences were observed regarding gallbladder-related unplanned readmissions (30-day:18.8%[short-course] vs 17.2%[long-course]; 90-day: 20.0%[short-course] vs 25.8%[long-course]). There were no 30- or 90-day mortality differences (overall mortality: 18.3%). CONCLUSION: Post-cholecystostomy outcomes were comparable between short-course and long-course antibiotics, consistent with emerging literature supporting short-course antibiotics for intra-abdominal infection with source control. PMID- 30415930 TI - [Rare presentations of infantile hemangiomas: 4 cases]. AB - BACKGROUND: Infantile hemangioma (IH) is a common benign vascular tumor in children. In most cases, diagnosis is based entirely on clinical examination. When the diagnosis is uncertain, the first-line complementary examination is Doppler ultrasound. We report 4 cases of atypical infantile hemangiomas with delayed diagnosis and non-contributory imaging. PATIENTS AND METHODS: One child had congenital purple papules and nodules on the back of the foot, the second had inaugural ulceration of the buttocks, and the last two presented telangiectasia, either isolated or on an erythematous macula. In two cases, ultrasound showed no vascular lesions, and in the other two cases, the absence of hyperemia did not allow a diagnosis of IH to be made. For one patient, diagnosis was made on the basis of cutaneous biopsy, and for the other three, on the basis of clinical course. DISCUSSION: We report 4 rare forms of infantile hemangioma resulting in initial diagnostic error. The atypical nature of some IHs may direct the clinician and the radiologist toward other diagnoses that in some cases have no vascular contingent. It is important for the dermatologist to be aware of these rare forms of IH in order to reduce the time to diagnosis and allow early initiation of appropriate management. PMID- 30415931 TI - [Huriez syndrome finally explained: Haploinsufficiency of a gene involved in homologous recombination DNA repair]. PMID- 30415932 TI - [Recurrent pyogenic granuloma]. PMID- 30415933 TI - [Grover's-like drug eruption under anti-PD-1 therapy for metastatic melanoma]. PMID- 30415934 TI - Timing of anticoagulation after recent ischaemic stroke in patients with atrial fibrillation. AB - BACKGROUND: About 13-26% of all acute ischaemic strokes are related to non valvular atrial fibrillation, the most common cardiac arrhythmia globally. Deciding when to initiate oral anticoagulation in patients with non-valvular atrial fibrillation is a longstanding, common, and unresolved clinical challenge. Although the risk of early recurrent ischaemic stroke is high in this population, early oral anticoagulation is suspected to increase the risk of potentially harmful intracranial haemorrhage, including haemorrhagic transformation of the infarct. This assumption, and current treatment guidelines, are based on historical, mostly observational data from patients with ischaemic stroke and atrial fibrillation treated with heparins, heparinoids, or vitamin K antagonists (VKAs) to prevent recurrent ischaemic stroke. Randomised controlled trials have subsequently shown that direct oral anticoagulants (DOACs; ie, apixaban, dabigatran, edoxaban, and rivaroxaban) are at least as effective as VKAs in primary and secondary prevention of atrial fibrillation-related ischaemic stroke, with around half the risk of intracranial haemorrhage. However, none of these DOAC trials included patients who had experienced ischaemic stroke recently (within the first few weeks). Clinicians therefore remain uncertain regarding when to commence DOAC administration after acute ischaemic stroke in patients with atrial fibrillation. RECENT DEVELOPMENTS: Prospective observational studies and two small randomised trials have investigated the risks and benefits of early DOAC-administration initiation (most with a median delay of 3-5 days) in mild-to moderate atrial fibrillation-associated ischaemic stroke. These studies reported that early DOAC treatment was associated with a low frequency of clinically symptomatic intracranial haemorrhage or surrogate haemorrhagic lesions on MRI scans, whereas later DOAC-administration initiation (ie, >7 days or >14 days after index stroke) was associated with an increased frequency of recurrent ischaemic stroke. WHERE NEXT?: Adequately powered randomised controlled trials comparing early to later oral anticoagulation with DOACs in ischaemic stroke associated with atrial fibrillation are justified to confirm the acceptable safety and efficacy of this strategy. Four such randomised controlled trials (collectively planned to include around 9000 participants) are underway, either using single cutoff timepoints for early versus late DOAC-administration initiation, or selecting DOAC-administration timing according to the severity and imaging features of the ischaemic stroke. The results of these trials should help to establish the optimal timing to initiate DOAC administration after recent ischaemic stroke and whether the timing should differ according to stroke severity. Results of these trials are expected from 2021. PMID- 30415935 TI - The rise of neurology in Haiti. PMID- 30415937 TI - Mental health in Northern Ireland: an urgent situation. PMID- 30415936 TI - The economic case for deinstitutionalisation in post-communist Europe. PMID- 30415938 TI - Cost-effectiveness of care for people with psychosis in the community and psychiatric hospitals in the Czech Republic: an economic analysis. AB - BACKGROUND: The absence of economic evidence hinders current reforms of hospital based mental health systems in central and eastern Europe. We aimed to assess the cost-effectiveness of discharge to community care for people with chronic psychoses compared with care in psychiatric hospitals in the Czech Republic. METHODS: We did a prospective study of people aged 18-64 years with chronic psychotic disorders in the Czech Republic who had been discharged into community services or were receiving inpatient psychiatric care for at least 3 months at baseline. We measured health-related quality of life with the EuroQol five dimension five-level questionnaire. Adjusting for baseline differences between the two groups, we assessed differences in societal costs in 2016 and quality adjusted life-years (QALYs) during a 12-month follow-up, which we then used to estimate the incremental cost-effectiveness ratio (ICER). We did multiple sensitivity analyses to assess the robustness of our results. FINDINGS: In our baseline case scenario, we included 115 patients who were either community service users (n=35) or inpatients (n=80) at baseline. The two groups were similar in terms of baseline characteristics. The annual QALY was 0.77 in patients receiving community care at baseline compared with 0.80 in patients in hospital at baseline (difference 0.03, 95% CI -0.04 to 0.10), but the costs of discharge to the community were ?8503 compared with ?16 425 for no discharge (difference ?7922, 95% CI 4497-11 346), such that the ICER reached more than ?250 000 per QALY. This ICER is substantially higher than levels that are conventionally considered to be cost-effective and the estimated probability that discharge to the community was cost-effective was very high (>=97%). None of the sensitivity analyses changed these results qualitatively. INTERPRETATION: This study provides economic evidence for deinstitutionalisation by showing that discharge to community care is cost-effective compared with care in psychiatric hospitals in the Czech Republic. These findings add to the human rights and clinical-based arguments for mental health-care reforms in central and eastern Europe. FUNDING: Ministry of Education, Youth and Sports of the Czech Republic; EEA and Norway Grants. PMID- 30415939 TI - Regulation of Syntaxin 17 during Autophagosome Maturation. AB - During macroautophagy, cytosolic elements are confined in autophagosomes before fusion with endolysosomes for degradation or recycling. Recruitment of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) factor syntaxin 17 (STX17) is instrumental for this maturation step. Two recent studies indicate that the kinase ULK1 and the apoptosis modulator BRUCE both regulate STX17 engagement during autophagosome maturation in mammalian cells. PMID- 30415940 TI - Geriatric models revisited as age friendly health care. PMID- 30415942 TI - Update of screening and diagnostic modalities for connective tissue disease associated pulmonary arterial hypertension. AB - OBJECTIVE: Pulmonary arterial hypertension (PAH) has high morbidity and mortality in connective tissue diseases (CTDs), especially systemic sclerosis (SSc). In this systematic review, we provide an update on screening measures for early detection of PAH in CTD. METHODS: Manuscripts published between July 2012 and October 2017, which incorporated screening measures to identify patients with PAH by right heart catheterization, were identified. Risk of bias was assessed using the QUADAS-2 tool. RESULTS: The systematic review resulted in 1514 unique citations and 22 manuscripts were included for final review; the majority of manuscripts had a lower risk of bias based on the QUADAS-2 tool. There were 16 SSc cohort studies and 6 case-control studies (SSc 4, SLE 2). Four SSc cohort studies evaluated transthoracic echocardiography (TTE) only. Eight SSc cohort studies evaluated composite measures including ASIG, DETECT, and a combination of tricuspid regurgitation velocity (TRV) and PFT variables. DETECT and ASIG had greater sensitivity and negative predictive value (NPV) compared to the 2009 ESC/ERS guidelines in different cohorts. The addition of PFT variables, such as DLCO or FVC/ DLCO ratio, to TRV, resulted in greater sensitivity and NPV compared to TRV alone. CONCLUSION: Current screening for PAH in CTDs is centered on SSc. Data continues to support the use of TTE and provides additional evidence for use of composite measures. PMID- 30415941 TI - Progression of diabetic kidney disease and trajectory of kidney function decline in Chinese patients with Type 2 diabetes. AB - Diabetes is a major cause of end stage renal disease (ESRD), yet the natural history of diabetic kidney disease is not well understood. We aimed to identify patterns of estimated GFR (eGFR) trajectory and to determine the clinical and genetic factors and their associations of these different patterns with all-cause mortality in patients with type 2 diabetes. Among 6330 patients with baseline eGFR >60 ml/min per 1.73 m2 in the Hong Kong Diabetes Register, a total of 456 patients (7.2%) developed Stage 5 chronic kidney disease or ESRD over a median follow-up of 13 years (incidence rate 5.6 per 1000 person-years). Joint latent class modeling was used to identify different patterns of eGFR trajectory. Four distinct and non-linear trajectories of eGFR were identified: slow decline (84.3% of patients), curvilinear decline (6.5%), progressive decline (6.1%) and accelerated decline (3.1%). Microalbuminuria and retinopathy were associated with accelerated eGFR decline, which was itself associated with all-cause mortality (odds ratio [OR] 6.9; 95% confidence interval [CI]: 5.6-8.4 for comparison with slow eGFR decline). Of 68 candidate genetic loci evaluated, the inclusion of five loci (rs11803049, rs911119, rs1933182, rs11123170, and rs889472) improved the prediction of eGFR trajectories (net reclassification improvement 0.232; 95% CI: 0.057--0.406). Our study highlights substantial heterogeneity in the patterns of eGFR decline among patients with diabetic kidney disease, and identifies associated clinical and genetic factors that may help to identify those who are more likely to experience an accelerated decline in kidney function. PMID- 30415943 TI - How can we define low disease activity in systemic lupus erythematosus? AB - BACKGROUND: In recent years, low disease activity emerged as a state that is associated with improved long-term outcomes in systemic lupus erythematosus (SLE). Our aim was to review the current concepts for low disease activity in SLE in order to serve as the basis of a future consensus for standardization. METHODS: The PubMed database was searched for relevant articles from inception up to July 2018. Medical Subject Headings (MeSH terms) included "lupus" AND "low disease activity" OR "minimal disease activity". RESULTS: Three different definitions of low disease activity in lupus have been proposed. Minimal disease activity (MDA) is defined as a clinical SLE Disease Activity Index 2000 (SLEDAI 2K)<=1 on antimalarials, immunosuppressives in standard doses and prednisone <=5 mg/day. Low disease activity (LDA) allows for a clinical SLEDAI-2K<=2 maintained on antimalarials only. Lupus Low Disease Activity State (LLDAS) accepts a SLEDAI 2K<=4 with no activity from major organ systems, a Physician's Global Assessment of <=1 with no new activity, prednisone dose <=7.5 mg/day and standard doses of antimalarials, immunosuppressives and biologics. Active serology (anti-dsDNA and complement C3/C4) is not included in the MDA and LDA but counts towards disease activity in the LLDAS definition. All definitions were associated with less damage-accrual and mortality in the long-term that were comparable to those of clinical remission. CONCLUSIONS: There is solid evidence that low disease activity is associated with improved outcomes in SLE and could serve as a therapeutic target in daily practice and clinical trials. Future research should focus on advancing a consensus for the best possible definition. PMID- 30415944 TI - Advancing research paradigms and pathophysiological pathways in psoriatic arthritis and ankylosing spondylitis: Proceedings of the 2017 Platform for the Exchange of Expertise and Research (PEER) meeting. PMID- 30415945 TI - Poor long-term adherence to secondary penicillin prophylaxis in children with history of rheumatic fever. AB - OBJECTIVE: Recurrent episodes of acute rheumatic fever may contribute to the development or worsening of rheumatic heart disease. Secondary penicillin prophylaxis (SPP) has been found to significantly reduce the incidence of rheumatic heart disease. This study sought to evaluate adherence to oral and intramuscular SPP in pediatric patients with rheumatic fever using real-world data spanning 10 years. METHODS: The study population included patients <18 years old insured by a 2.1-million-member health maintenance organization in Israel who were diagnosed with acute rheumatic fever between 1/1996 and 5/2015 and had purchased at least one monthly dose of oral or intramuscular penicillin by prescription. The mean proportion of days covered by SPP was calculated. The endpoint of the retrospective follow-up for therapy discontinuation was leaving the health maintenance organization, death, age 18 years, or end of follow-up. RESULTS: The cohort included 842 children: 734 treated with oral penicillin and 108 with intramuscular penicillin. The respective mean (SD) ages of the two groups at diagnosis were 8.6 (3.7) years and 10.9 (3.2) years, and the median (interquartile range) proportions of days covered by SPP were 8% (2%-33%) and 10% (3%-28%). Overall, the number of days covered decreased exponentially from 103 days in the first year of therapy to 20 days in the tenth year of follow-up. CONCLUSION: Adherence to SPP for rheumatic fever is poor. This renders this mode of long term prophylaxis futile. Although the IM route has been previously shown to be more effective, the oral route was more extensively used. PMID- 30415946 TI - Spinal involvement with calcium pyrophosphate deposition disease in an academic rheumatology center: A series of 37 patients. AB - BACKGROUND: Calcium pyrophosphate dihydrate deposition disease (CPPD) has been reported to involve the spine, but few systematic studies have been published. OBJECTIVE: To further characterize the spinal involvement with CPPD by a review of CPPD patients hospitalized in a rheumatology department. METHODS: We retrospectively reviewed data for patients consecutively admitted with a diagnosis of CPPD in the rheumatology department of Lariboisiere hospital in Paris, France over 5 years by using a standardized protocol and electronic case report forms. Imaging studies were also reviewed. RESULTS: Spinal CPPD was diagnosed in 37/152 (24.3%) CPPD patients. Patient with spinal involvement had more widespread peripheral CC. The cervical (n = 21) and lumbar (n = 19) segments were most involved. CT-scan was more sensitive than plain radiographs for detecting spinal calcifications. Crown dens syndrome was a prominent feature of cervical involvement. Inflammatory sterile spondylo-discitis was observed in 6 patients. Lesions were frequently multiple and were classified into 4 types. Ruling out septic discitis required image-guided biopsies in 3 patients. Sacroiliac involvement included calcification in 5 patients and severe sterile destructive arthropathy and joint fusion in one patient each. Degenerative changes were common, and CPPD could not be implicated because of the patients 'age and lack of a control population. In 12 patients, severe clinical features requiring hospitalization were related to such degenerative changes. CONCLUSION: Symptomatic involvement of the spine was observed in 24% of this series of hospitalized CPPD patients. Specific entities were the cause of hospitalisation in 25 of the 37 patients with spinal calcification and included inflammatory pain related to crystal deposits and destructive arthropathy of the spine and sacroiliac joints. Discitis exhibited a wide range of MRI features and biopsies were needed to rule out infection in 3 of the 6 discitis. PMID- 30415947 TI - Glycosaminoglycans are differentially involved in bacterial binding to healthy and cystic fibrosis lung cells. AB - BACKGROUND: Glycosaminoglycans (GAGs) are essential in many infections, including recurrent bacterial respiratory infections, the main cause of mortality in cystic fibrosis (CF) patients. METHODS: Using a cellular model of healthy and CF lung epithelium, a comparative transcriptomic study of GAG encoding genes was performed using qRT-PCR, and their differential involvement in the adhesion of bacterial pathogens analyzed by enzymatic degradation and binding competition experiments. RESULTS: Various alterations in gene expression in CF cells were found which affect GAG structures and seem to influence bacterial adherence to lung epithelium cells. Heparan sulfate appears to be the most important GAG species involved in bacterial binding. CONCLUSIONS: Adherence to lung epithelial cells of some of the main pathogens involved in CF is dependent on GAGs, and the expression of these polysaccharides is altered in CF cells, suggesting it could play an essential role in the development of infectious pathology. PMID- 30415948 TI - A Nucleosome Bridging Mechanism for Activation of a Maintenance DNA Methyltransferase. AB - DNA methylation and H3K9me are hallmarks of heterochromatin in plants and mammals, and are successfully maintained across generations. The biochemical and structural basis for this maintenance is poorly understood. The maintenance DNA methyltransferase from Zea mays, ZMET2, recognizes dimethylation of H3K9 via a chromodomain (CD) and a bromo adjacent homology (BAH) domain, which flank the catalytic domain. Here, we show that dinucleosomes are the preferred ZMET2 substrate, with DNA methylation preferentially targeted to linker DNA. Electron microscopy shows one ZMET2 molecule bridging two nucleosomes within a dinucleosome. We find that the CD stabilizes binding, whereas the BAH domain enables allosteric activation by the H3K9me mark. ZMET2 further couples recognition of H3K9me to an increase in the specificity for hemimethylated versus unmethylated DNA. We propose a model in which synergistic coupling between recognition of nucleosome spacing, H3K9 methylation, and DNA modification allows ZMET2 to maintain DNA methylation in heterochromatin with high fidelity. PMID- 30415949 TI - An Insulin-Responsive Sensor in the SIRT1 Disordered Region Binds DBC1 and PACS-2 to Control Enzyme Activity. AB - Current models of SIRT1 enzymatic regulation primarily consider the effects of fluctuating levels of its co-substrate NAD+, which binds to the stably folded catalytic domain. By contrast, the roles of the sizeable disordered N- and C terminal regions of SIRT1 are largely unexplored. Here we identify an insulin responsive sensor in the SIRT1 N-terminal region (NTR), comprising an acidic cluster (AC) and a 3-helix bundle (3HB), controlling deacetylase activity. The allosteric assistor DBC1 removes a distal N-terminal shield from the 3-helix bundle, permitting PACS-2 to engage the acidic cluster and the transiently exposed helix 3 of the 3-helix bundle, disrupting its structure and inhibiting catalysis. The SIRT1 activator (STAC) SRT1720 binds and stabilizes the 3-helix bundle, protecting SIRT1 from inhibition by PACS-2. Identification of the SIRT1 insulin-responsive sensor and its engagement by the DBC1 and PACS-2 regulatory hub provides important insight into the roles of disordered regions in enzyme regulation and the mode by which STACs promote metabolic fitness. PMID- 30415950 TI - Spatial Organization of Single mRNPs at Different Stages of the Gene Expression Pathway. AB - mRNAs form ribonucleoprotein complexes (mRNPs) by association with proteins that are crucial for mRNA metabolism. While the mRNP proteome has been well characterized, little is known about mRNP organization. Using a single-molecule approach, we show that mRNA conformation changes depending on its cellular localization and translational state. Compared to nuclear mRNPs and lncRNPs, association with ribosomes decompacts individual mRNAs, while pharmacologically dissociating ribosomes or sequestering them into stress granules leads to increased compaction. Moreover, translating mRNAs rarely show co-localized 5' and 3' ends, indicating either that mRNAs are not translated in a closed-loop configuration, or that mRNA circularization is transient, suggesting that a stable closed-loop conformation is not a universal state for all translating mRNAs. PMID- 30415951 TI - The Deubiquitinase USP46 Is Essential for Proliferation and Tumor Growth of HPV Transformed Cancers. AB - High-risk human papilloma viruses (HPVs) cause cervical, anal, and oropharyngeal cancers, unlike the low-risk HPVs, which cause benign lesions. E6 oncoproteins from the high-risk strains are essential for cell proliferation and transformation in HPV-induced cancers. We report that a cellular deubiquitinase, USP46, is selectively recruited by the E6 of high-risk, but not low-risk, HPV to deubiqutinate and stabilize Cdt2/DTL. Stabilization of Cdt2, a component of the CRL4Cdt2 E3 ubiquitin ligase, limits the level of Set8, an epigenetic writer, and promotes cell proliferation. USP46 is essential for the proliferation of HPV transformed cells, but not of cells without HPV. Cdt2 is elevated in human cervical cancers and knockdown of USP46 inhibits HPV-transformed tumor growth in xenografts. Recruitment of a cellular deubiquitinase to stabilize key cellular proteins is an important activity of oncogenic E6, and the importance of E6-USP46 Cdt2-Set8 pathway in HPV-induced cancers makes USP46 a target for the therapy of such cancers. PMID- 30415952 TI - MYC Protein Interactome Profiling Reveals Functionally Distinct Regions that Cooperate to Drive Tumorigenesis. AB - Transforming members of the MYC family (MYC, MYCL1, and MYCN) encode transcription factors containing six highly conserved regions, termed MYC homology boxes (MBs). By conducting proteomic profiling of the MB interactomes, we demonstrate that half of the MYC interactors require one or more MBs for binding. Comprehensive phenotypic analyses reveal that two MBs, MB0 and MBII, are universally required for transformation. MBII mediates interactions with acetyltransferase-containing complexes, enabling histone acetylation, and is essential for MYC-dependent tumor initiation. By contrast, MB0 mediates interactions with transcription elongation factors via direct binding to the general transcription factor TFIIF. MB0 is dispensable for tumor initiation but is a major accelerator of tumor growth. Notably, the full transforming activity of MYC can be restored by co-expression of the non-transforming MB0 and MBII deletion proteins, indicating that these two regions confer separate molecular functions, both of which are required for oncogenic MYC activity. PMID- 30415954 TI - The peripheral portacath provides safe and convenient venous access in pediatric and adolescent patients. AB - INTRODUCTION: Adolescent patients with chronic conditions rely on permanent venous access for safe treatment and supportive care. Traditionally this is provided by a central venous access device (CVAD) e.g. Hickmann catheter or totally implanted subcutaneous port or also called Port-a-Cath (PaC). We reviewed the patient experience, safety and feasibility of insertion of peripheral inserted implanted subcutaneous port (peripheral PaC). METHODS: Medical records of patients who underwent insertion of peripheral PaC under ultrasound guidance at our institution since between 2012-2017 were reviewed to ascertain specific details including duration of insertion and complication rate. Short structured questionnaires were used to assess nursing and patient satisfaction. RESULTS: Twenty eight peripheral PaC were inserted at our institution. There were 17 female and 11 male patients aged between 12.3 and 18.7 years (median = 16.1). Six were inserted under local anesthetic (LA) in patients who were not fit for general owing to mediastinal mass or lung disease. At the time of analysis 2 PaCs remained in situ with a median duration of 8 months (range 3-48). Removal of 26 PaCs was under LA in 15 cases and under GA in 11. Complications were observed in 9 cases but only necessitated early removal or replacement in 3 cases (displacement and disconnection) and repositioning in 1 case. Thrombosis was seen in 2 patients who required systemic anticoagulation but had complete resolution. CONCLUSION: This study shows that the use of peripheral PaC is safe. The feedback from patients and nursing staff supports the use of the peripheral PaC. We are exploring additional patient groups that might benefit from this device. PMID- 30415956 TI - Meconium exposure in gastroschisis. PMID- 30415955 TI - Letter to the Editor. PMID- 30415953 TI - Higher-Order Organization Principles of Pre-translational mRNPs. AB - Compared to noncoding RNAs (ncRNAs), such as rRNAs and ribozymes, for which high resolution structures abound, little is known about the tertiary structures of mRNAs. In eukaryotic cells, newly made mRNAs are packaged with proteins in highly compacted mRNA particles (mRNPs), but the manner of this mRNA compaction is unknown. Here, we developed and implemented RIPPLiT (RNA immunoprecipitation and proximity ligation in tandem), a transcriptome-wide method for probing the 3D conformations of RNAs stably associated with defined proteins, in this case, exon junction complex (EJC) core factors. EJCs multimerize with other mRNP components to form megadalton-sized complexes that protect large swaths of newly synthesized mRNAs from endonuclease digestion. Unlike ncRNPs, wherein strong locus-specific structures predominate, mRNPs behave more like flexible polymers. Polymer analysis of proximity ligation data for hundreds of mRNA species demonstrates that nascent and pre-translational mammalian mRNAs are compacted by their associated proteins into linear rod-like structures. PMID- 30415957 TI - Incidence, severity and outcome of central line related complications in pediatric oncology patients; A single center study. AB - BACKGROUND: Central venous access device (CVAD)-related complications are associated with high morbidity rates. This study was performed to underline the importance of CVAD-complication prevention and treatment. METHODS: An audit of practice of CVAD-related complications in pediatric oncology patients receiving a CVAD between January 2015 and June 2017 was performed. CVADs included were totally implantable venous access ports (TIVAPs), Hickman-Broviac(r) (HB), nontunneled, and peripherally inserted CVADs. RESULTS: A total of 201 children, with 307 CVADs, were analyzed. The incidence rates per 1000 CVAD-days for the most common complications were 1.66 for malfunctions, and 1.51 for central line associated bloodstream infections (CLABSIs). Of all CVADs inserted, 37.1% were removed owing to complications, of which 45.6% were owing to CLABSIs. In 42% of the CLABSIs, the CLABSI could be successfully cured with systemic antibiotic treatment only. Of all included patients, 5.0% were admitted to the intensive care unit owing to CLABSI. The HB-CVAD compared to the TIVAP was a risk factor for CVAD-related complications, CLABSIs and dislocations in particular. CONCLUSIONS: The incidence of CVAD-related complications is high. Research on the prevention and treatment of CVAD-related complications in pediatric oncology patients should be a high priority for all health care professionals. TYPE OF STUDY: Prognosis study (retrospective). LEVEL OF EVIDENCE: Level II. PMID- 30415958 TI - Simple preoperative radiation safety interventions significantly lower radiation doses during central venous line placement in children. AB - PURPOSE: The purpose of this study was to reduce radiation exposure during pediatric central venous line (CVL) placement by implementing a radiation safety process including a radiation safety briefing and a job-instruction model with a preradiation time-out. METHODS: We reviewed records of all patients under 21 who underwent CVL placement in the operating room covering 22 months before the intervention through 10 months after 2013-2016. The intervention consisted of a radiation safety briefing by the surgeon to the intraoperative staff before each case and a radiation safety time-out. We measured and analyzed the dose area product (DAP), total radiation time pre- and postintervention, and the use of postprocedural chest radiograph. RESULTS: 100 patients with valid DAP measurements were identified for analysis (59 preintervention, 41 postintervention). Following implementation of the radiation safety process, there was a 79% decrease in median DAP (61.4 vs 13.1 rad*cm2, P < 0.001) and a 73% decrease in the median radiation time (28 vs 7.6 s, P < 0.001). Additionally, there was a significant reduction in use of confirmatory CXR (95% vs 15%, P < 0.01). CONCLUSION: A preoperative radiation safety briefing and a radiation safety time-out supported by a job-instruction model were effective in significantly lowering the absorbed doses of radiation in children undergoing CVL insertion. TYPE OF STUDY: Case-control study. LEVEL OF EVIDENCE: Level III. PMID- 30415959 TI - Therapeutic contact lens fitting in a large tertiary referral centre. PMID- 30415960 TI - Profile, knowledge, and attitude of contact lens users regarding contact lens wear in Ghana. AB - BACKGROUND: Contact lenses are gaining popularity in developing countries as an alternative to spectacles for the correction of refractive errors. It is needful, therefore, to generate information to guide the mode of practice, and assist the industry in developing products for the increasing contact-lenses-user population. The purpose of this study was to identify the demographic profile, as well as the knowledge, attitude to wear and care regimen of wearers of contact lenses in Ghana. METHODS: In a cross-sectional study, case folders of 87 users of contact lenses were selected from the database eye contact lenses practices. The folders were reviewed for the demographic profile, type, and purpose for which the contact lenses were prescribed. Forty-two (42) contact lenses users were then randomly surveyed, using a semi-structured questionnaire to collect information on their knowledge, lens wear regimen, and attitudes regarding lens hygiene. Chi square test was used to test associations between demographics and lens wear variables. RESULTS: Out of the 87 cases reviewed, 46 (52.9%) were females and 41 (47.1%) males. Their ages ranged from 15 to 68 years with a mean age of 28.62 +/- 9.38 years. The majority- 65 (75%) - were youthful (<= 40 years), with the highest proportion of them - 46 (53%) - being between 20-29 years. The majority - 60 (68.9%) - had a tertiary level of education. Soft contact lenses were commonly worn by 68 (78.2%) users while 19 (21.8%) wore rigid gas permeable lenses. The purpose for wearing contact lenses included for vision correction - 46 (52.9%), followed by for cosmesis - 23 (26.4%) - and therapeutic reasons -18 (20.7%). The commonest refractive error corrected was myopia - 38 (43.7%), followed by astigmatism -19 (21.8%) and hyperopia 6 (6.9%). Among the 42 users who responded to the questionnaire, by proportion, the majority -17 users (40.5%) - were introduced to contact lenses by optometrists. All respondents reported previous symptoms associated with the use of their contact lenses, but slightly more than half, 25 (57.1%) did yearly follow-up visits. CONCLUSION: The majority of contact lenses used in Ghana are soft lenses, for the purpose of vision correction. The use of contact lenses was common among individuals in their early adulthood and those with tertiary education. PMID- 30415961 TI - Type 2 persistent fifth aortic arch: An elusive entity diagnosed on computed tomography angiography. PMID- 30415962 TI - Retrospective comparison of the number of screws used for fixation of skeletal anchorage plates in orthodontics, and their failure rates. AB - The aim of this study was to compare the failure rate of fixation of skeletal orthodontic anchorage plates (SAP) with two screws with that of three screws, and to find out if there is a relation between the number of screws used to fix the plates and the failure rate. We reviewed clinical records of 65 patients from five hospitals with 176 SAP, and took into account other factors that may have affected the failure. The overall failure rate was 15/176 (8.5%), and for with two-screw fixation it was 9/86 compared with 6/90 for those with three-screw fixation. Age, sex, and coexisting medical conditions did not affect the failure rate. There was a higher failure rate for those placed in the mandible (11/105) than for those placed in the maxilla (4/71). SAP provide a stable source of skeletal anchorage for orthodontic treatment. Our results show that those fixed with two screws may be marginally more likely to fail than those fixed with three, but further studies are needed to investigate the association between failure and the number of screws used. PMID- 30415963 TI - Star flap: new reconstructive technique for defects of the scalp. PMID- 30415964 TI - Searching for an Optimal Systolic Blood Pressure Target: A Balance of Benefits and Risks. PMID- 30415965 TI - High-Throughput Plasma Lipidomics: Detailed Mapping of the Associations with Cardiometabolic Risk Factors. AB - High-throughput targeted lipid profiling with liquid chromatography-mass spectrometry (LC-MS) has been used extensively to identify associations between plasma lipid species and disease states. Such methods, used to characterize larger clinical cohorts, often suffer from an inability to differentiate isomeric forms of glycerophospholipids that are typically reported as the sum fatty acid carbons and double bonds. Here we report a chromatography gradient coupled with a detailed characterization of the human plasma lipidome to provide improved resolution and identification of 636 lipid species, including previously unreported species, in a 15-min analysis. We have utilized this method on a subset of the Australian Diabetes, Obesity, and Lifestyle Study and have detailed associations of plasma lipid species with anthropometric and blood glucose measures. These results highlight the importance and power of high-throughput lipidomics coupled with a detailed characterization of the lipidome to better understand lipid biology in a population setting. PMID- 30415966 TI - Melleolides from Honey Mushroom Inhibit 5-Lipoxygenase via Cys159. AB - 5-Lipoxygenase (5-LO) initiates the biosynthesis of pro-inflammatory leukotrienes from arachidonic acid, which requires the nuclear membrane-bound 5-LO-activating protein (FLAP) for substrate transfer. Here, we identified human 5-LO as a molecular target of melleolides from honey mushroom (Armillaria mellea). Melleolides inhibit 5-LO via an alpha,beta-unsaturated aldehyde serving as Michael acceptor for surface cysteines at the substrate entrance that are revealed as molecular determinants for 5-LO activity. Experiments with 5-LO mutants, where select cysteines had been replaced by serine, indicated that the investigated melleolides suppress 5-LO product formation via two distinct modes of action: (1) by direct interference with 5-LO activity involving two or more of the cysteines 159, 300, 416, and 418, and (2) by preventing 5-LO/FLAP assemblies involving selectively Cys159 in 5-LO. Interestingly, replacement of Cys159 by serine prevented 5-LO/FLAP assemblies as well, implying Cys159 as determinant for 5-LO/FLAP complex formation at the nuclear membrane required for leukotriene biosynthesis. PMID- 30415967 TI - Chemical Cross-Linking Enables Drafting ClpXP Proximity Maps and Taking Snapshots of In Situ Interaction Networks. AB - Detection of dynamic protein-protein interactions within complexes and networks remains a challenging task. Here, we show by the example of the proteolytic ClpXP complex the utility of combined chemical cross-linking and mass spectrometry (XL MS) to map interactions within ClpP and ClpX as well as across the enigmatic ClpX hexamer-ClpP heptamer interface. A few hot-spot lysines located in signature loops in ClpX were shown to be in proximity to several structural regions of ClpP providing an initial draft of the ClpX-ClpP interaction. Application of XL-MS further confirmed that Listeria monocytogenes ClpX interacts with the heterooligomeric ClpP1/2 complex solely via the ClpP2 apical site. Moreover, cellular interaction networks of human and bacterial proteases were elucidated via in situ chemical cross-linking followed by an antibody-based pull-down against ClpP. A subsequent mass spectrometric analysis demonstrated an up to 3 fold higher coverage compared with co-immunoprecipitation without cross-linker revealing unprecedented insight into intracellular ClpXP networks. PMID- 30415968 TI - Intracellular Cholesterol Transport by Sterol Transfer Proteins at Membrane Contact Sites. AB - Cholesterol is dynamically transported among membrane-bound organelles primarily by nonvesicular mechanisms. Sterol transfer proteins (STPs) bind cholesterol in their hydrophobic pockets and facilitate its transfer across the aqueous cytosol. However, STPs alone may not account for the specific and efficient movement of cholesterol between intracellular membranes. Accumulating evidence has shown that membrane contact sites (MCSs), regions where two distinct organelles are in close apposition to one another, can facilitate STP-mediated cholesterol trafficking in a cell. At some MCSs, cholesterol can move against its concentration by using phosphatidylinositol 4-phosphate (PI4P) metabolism as the driving force. Finally, the emergence of more MCSs and the discovery of a new STP family further highlight the crucial roles of MCSs and STPs in intracellular cholesterol transport. PMID- 30415969 TI - Resting coronary flow varies with normal cardiac catheter laboratory stimuli. AB - BACKGROUND: Growing evidence supports physiology-guided revascularization, with Fractional Flow Reserve (FFR) the most commonly used invasive measure of coronary blood flow impairment at the time of diagnostic angiography. Recently, there has been growing interest in stenosis severity indices measured at rest, such as Instantaneous Wave Free Ratio (iFR) and the ratio of distal coronary to aortic pressure at rest (resting Pd/Pa). Their reliability may, theoretically, be more susceptible to changes in microvascular tone and coronary flow. This study aimed to assess variability of resting coronary flow with normal catheter laboratory stimuli. METHODS: Simultaneous intracoronary pressure (Pd) and Doppler Average Peak Flow Velocity (APV) recordings were made at rest and following the verbal warning preceding an intravenous adenosine infusion. RESULTS: 72 patients undergoing elective angiography were recruited (mean age 62 years, 52.7% male) with a wide range of coronary artery disease severity (FFR 0.86 +/- 0.09). Average peak flow velocity varied significantly between measurements at rest and just prior to commencement of adenosine, with a mean variation of 10.2% (17.82 +/ 9.41 cm/s vs. 19.63 +/- 10.44 cm/s, p < 0.001) with an accompanying significant drop in microvascular resistance (6.27 +/- 2.73 mm Hg.cm-1.s-1 vs. 5.8 +/- 2.92 mm Hg.cm-1.s-1, p < 0.001). These changes occurred without significant change in systemic hemodynamic measures. Whilst there was a trend for an associated change in the resting indices, Pd/Pa and iFR, this was statistically and clinically not significant (0.92 +/- 0.08 vs. 0.92 +/- 0.08, p = 0.110; and 0.90 +/- 0.11 vs. 0.89 +/- 0.12, p = 0.073). CONCLUSION: Resting coronary flow and microvascular resistance vary significantly with normal catheter laboratory stimuli, such as simple warnings. The clinical impact of these observed changes on indices of stenosis severity, particularly those measured at rest, needs further assessment within larger cohorts. PMID- 30415970 TI - Approaching the post-femoral era for coronary angiography and intervention. PMID- 30415971 TI - Management of knee flexion contracture in haemophilia with the Ilizarov technique. AB - BACKGROUND: There are limited reports about management of Knee flexion contracture (KFC) in haemophiliacs with Ilizarov technique. The aim of this study was to retrospectively analyzed the results of Ilizarov technique to treat KFC. METHODS: Six patients with haemophilia A and one with haemophilia B were included in this study, with an average age of 17 years old. The mean preoperative KFC and flexion angle of the knee were 58 +/- 21 degrees (mean +/- standard deviation) and 127 +/- 12 degrees , respectively. Preoperative HSS score (hospital for special surgery knee score) was 51 +/- 4. The average time of follow-up was 39.3 +/- 23.3 months. RESULTS: All the patients achieved full correction of flexion contracture at the end of distraction and maintained at the last follow-up. The mean flexion angle at the end of distraction and at the last follow-up were 41 +/ 35 degrees and 38 +/- 19 degrees respectively, which were significantly lower than preoperative flexion angle. The mean HSS score at the end of distraction and at the last follow-up were 65 +/- 4 and 64 +/- 2 respectively, which were significantly higher than the preoperative HSS score. One patient suffered from transient numbness of left leg, and all the patients had loss of range of knee flexion at last follow-up. CONCLUSIONS: Ilizarov is an effective and safe procedure to treat KFC in haemophiliacs. However, loss of knee flexion was the most common complication. PMID- 30415972 TI - Histopathological changes in the infrapatellar fat pad in an experimental rabbit model of early patellofemoral osteoarthritis. AB - BACKGROUND: The purpose of this study was to characterise the histopathological changes in the infrapatellar fat pad (IPFP) in the early stage of patellofemoral osteoarthritis (PFOA). METHODS: Sixty-four New Zealand white rabbits were randomly divided into experimental (n = 24), sham (n = 16), and control groups (n = 24). In the experimental group, denoted as the patellar ligament uneven shortening group (US group), the patellar ligament (PL) was folded eight millimetres and sutured. After eight weeks, all animals were euthanised, and magnetic resonance imaging (MRI) evaluation, wet IPFP weight measurement, and histopathological and immunohistochemistry analysis were performed to analyse the histopathological changes in the IPFPs. RESULTS: The maximum cross-sectional area (CSA) of the IPFPs in the sagittal position of MRI in the control group, sham group, and US group were 45.50 +/- 7.19 mm2, 45.88 +/- 6.60 mm2 (vs. control group, P = 0.907), and 53.83 +/- 8.24 mm2 (vs. control group, P = 0.015; vs. sham group, P = 0.035), respectively. The MRI intensity of the IPFPs in the control group, sham group, and US group were 115.53 +/- 28.85, 108.53 +/- 26.73 (vs. control group, P = 0.589), and 154.52 +/- 18.48 (vs. control group, P = 0.002; vs. sham group, P = 0.002), respectively. The wet weight of the IPFPs in the control group, sham group, and US group were 0.32 +/- 0.05 g, 0.32 +/- 0.04 g (vs. control group, P = 0.895), and 0.38 +/- 0.06 g (vs. control group, P = 0.017; vs. sham group, P = 0.033), respectively. The Osteoarthritis Research Society International (OARSI) scores of the IPFPs in the US group were 6.00 +/- 1.91, which was higher than the scores of 2.50 +/- 2.02 (P < 0.001) in the control group and of 2.75 +/- 1.67 (P = 0.001) in the sham group. CONCLUSIONS: The histopathological changes of the IPFPs as determined via MRI and microscopic structure appeared to occur much earlier than cartilage damage in PFOA. Furthermore, detecting and treating the IPFP changes may offer aid in the diagnosis and treatment of PFOA. PMID- 30415973 TI - Is knee neuromuscular activity related to anterior cruciate ligament injury risk? A pilot study. AB - BACKGROUND: There is limited evidence on neuromuscular risk factors for anterior cruciate ligament (ACL) injuries, with most work mainly focusing on hamstrings and quadriceps muscle strength. This prospective pilot study explored if neuromuscular activation patterns of the quadriceps and hamstrings during a drop vertical jump influence ACL injury risk. METHODS: Forty-six female athletes performed a drop vertical jump at baseline. Injuries were monitored throughout a one-year follow-up. Neuromuscular activation patterns of the vastus medialis, vastus lateralis, hamstrings medialis and hamstrings lateralis, and selected landing kinematic and kinetic profiles (knee flexion, knee abduction and hip flexion angles, and knee abduction moments), were compared between athletes who sustained a non-contact ACL injury and those who remained injury free. Electromyogram vector fields were created to represent neuromuscular activation patterns of muscle pairs around the knee joint rather than only considering individual muscle activations, and compared using Statistical Parametric Mapping. RESULTS: Four athletes sustained an ACL injury. Significantly greater {hamstrings medials, hamstrings lateralis}, {vastus lateralis, hamstrings lateralis} and {hamstrings lateralis, vastus medialis} activations, mainly due to greater hamstrings lateralis activation, were found in the injured group around peak loading and just before take-off (P < 0.001). No group differences were found in knee flexion, knee abduction and hip flexion angles, or knee abduction moments. CONCLUSIONS: This pilot study revealed initial evidence that athletes already showed altered neuromuscular activation patterns prior to sustaining an ACL injury, namely increased lateral and posterior muscle activations. PMID- 30415974 TI - Hinged versus CCK revision arthroplasty for the stiff total knee. AB - BACKGROUND: Total knee arthroplasty (TKA) remains the gold standard for end-stage knee osteoarthritis. The prevalence of stiffness after this procedure described in literature varies from 1.3% to 5.3%. The causes of arthrofibrosis after total knee arthroplasty are multifactorial. Revision TKA is a successful procedure when performed for loosening, instability, mechanical implant failure, or infection. The results of revision TKA for idiopathic arthrofibrosis and stiffening are however less favorable. PURPOSE: It has been the authors' impression that the poor results in arthrofibrosis could be in part related to the use of traditional PS or CCK-type revision implants. Our hypothesis is that better results can be achieved in case a rotating hinge design (RHK) is used. The reason could be that RHK designs allow for much more aggressive capsuloligament debridement and therefore more adequate fibrosis removal, while securing optimal implant stability, tibiofemoral rotational freedom, and flexion-extension space stability. The purpose of our study was to investigate in our database whether this hypothesis is correct. METHODS: Retrospectively, 40 patients with the defined range of knee motion were identified. Patients with underlying mechanical malalignment, component malposition, soft-tissue imbalance or infections were excluded. Twenty-two patients received a hinged-type prosthetic device (18 Zimmer RHK, four Stryker RHK) and 18 patients received a less constrained condylar type prosthetic device (17 Legion CCK, one Vanguard CCK). RESULTS: Preoperative data were similar for RHK as CCK-type implants except for knee pain score, which was significantly worse for the RHK group (36 vs 44, p = 0.049). At two years of follow-up, compared to CCK, the RHK group demonstrated significantly better postoperative results for knee function scores (68.9 vs 54.2, p = 0.0015), knee function improvement (22.8 vs 4.8, p = 0.0015), knee pain improvement (26.4 vs 9.4, p = 0.0050), greater maximal flexion (99.9 degrees vs 81.4 degrees , p = 0.0005), better maximal extension (-1.9 degrees vs -6.2 degrees , p = 0.0447), greater flexion gain (35.8 degrees vs 14.2 degrees , p = 0.0002), and greater extension gain (8.6 degrees vs 2.0 degrees , p = 0.0083). CONCLUSION: Our data show that revision arthroplasty of the stiff knee using a rotating hinged device can provide excellent results in selected cases. To date, this is the first study to describe the difference in outcome between revision total knee arthroplasty for idiopathic arthrofibrosis using a hinged or a constrained condylar knee device. PMID- 30415975 TI - Letter to Editor "Histopathological study of the infrapatellar fat pad in the rat model of patellar tendinopathy: A basic study". PMID- 30415976 TI - Does the pre-operative status of the anterior cruciate ligament affect the outcomes following medial open-wedge high tibial osteotomy? AB - BACKGROUND: This study aimed to assess the morphological degeneration of the anterior cruciate ligament (ACL) through magnetic resonance imaging (MRI) and arthroscopy. It analyzed whether the pre-operative ACL status would affect the radiologic and clinical outcomes following medial open-wedge high tibial osteotomy (MOWHTO). METHODS: A total of 150 knees were enrolled that underwent MOWHTO concomitant arthroscopic debridement for the treatment of varus osteoarthritis. Mean age was 56.1 +/- 5.0 years and mean follow-up was 61.2 +/- 21.4 months. The ACLs were staged based on MRI and arthroscopy. To exclude the influence of demographic factors on outcomes, the between-group differences were assessed. Radiologic evaluation included hip-knee-ankle angle, femorotibial angle, medial proximal tibial angle, posterior tibial slope angle, and Kellgren Lawrence grade. Clinical evaluation included American Knee Society Score (AKSS) and knee joint range of motion (ROM). RESULTS: The ACLs were classified into intact (75 knees, 50.0%), mucoid degeneration (59, 39.3%), chronic partial tear (10, 6.7%), and complete tear (six, 4.0%) according to MRI. They were also classified into four stages: normal (95 knees, 63.3%), abnormal (36, 24.0%), partial tear (13, 8.7%), and complete tear (six, 4.0%) according to arthroscopic appearance. There were no significant between-group differences in each variable. Changes in Kellgren-Lawrence grade did not show significant between-group differences. No significant between-group differences were observed in AKSS and ROM. CONCLUSIONS: The pre-operative status of ACL did not influence the outcomes following MOWHTO at midterm follow-up. LEVEL OF EVIDENCE: Level IV, case series. PMID- 30415977 TI - Quantification of joint alignment and stability during a single leg stance task in a knee osteoarthritis cohort. AB - BACKGROUND: Knee osteoarthritis alters joint stability but its kinematics during functional weight-bearing tasks remain unclear. We propose and validate an assessment technique for the quantification of knee alignment and stability in patients during a short single leg stance task. METHODS: Three-dimensional knee kinematics were acquired non-invasively from 31 knee osteoarthritis patients (subdivided as moderate or severe) and 15 asymptomatic individuals during six short single-leg stance tasks. Data of participants achieving >=3 trials were retained. From flexion-extension signals, a data treatment method compared the average between-trial root-mean-square error (RMSE) across trial triplets, and the average within-trial range of movement (RoM) for two data windows. From secondary knee motions (ab/adduction and int/external rotations, anteroposterior and mediolateral translations), we extracted measures characterizing alignments (mean), largest deviations (maximum, minimum), and extent of micro-adjustments (RoM, length of knee excursion). Their sensitivity to disease and severity was determined using an ANOVA, and between-trial repeatability using ICC2,3. RESULTS: Ninety-four percent of patients achieved >=3 trials. The retained trial triplet and window reduced the RMSE (2.15 to 1.54) and RoM (4.9 degrees to 1.77 degrees ) for flexion-extension. Mean, minimum, and maximum measures were sensitive to disease for anteroposterior translations, and to severity for ab/adduction (P < 0.05). High repeatability was found for those measures (ICC >=0.84). RoM and length of knee excursion, although sensitive to disease for anteroposterior translations, had lower ICC. CONCLUSION: The proposed technique is feasible and exposed measures of knee alignment sensitive to knee osteoarthritis, for instance, an anterior femoral shift and an increased adduction malalignment with greater severity. PMID- 30415978 TI - Epilepsy after stroke: Definitions, problems and a practical approach for clinicians. AB - Stroke, whether ischemic or hemorrhagic, is the main etiology of epilepsy in the elderly. However, incidences and outcomes differ according to stroke subtype and delay of onset following the stroke. While the medical literature is extensive, it is not always consistent, and many questions still remain regarding risk factors and management of vascular epilepsy. Thus, the present report here is an overview of the clinical aspects of vascular epilepsy using a practical approach that integrates data from meta-analyses and the more recently published expert recommendations. PMID- 30415979 TI - Why is mother to child transmission (MTCT) of HIV a continual threat to new-borns in sub-Saharan Africa (SSA). AB - Sub-Saharan Africa (SSA) accounts for more than two thirds of the world's HIV infection. Despite scaled-up prevention of mother-to-child transmission of HIV (PMTCT) programmes, mother to child transmission of HIV (MTCT) continues to escalate. We describe the challenges faced by PMTCT in MTCT in SSA. The study reviewed articles and reports published online. The most common barriers and challenges were non-disclosure of HIV status, late initiation of ARVs treatment/adherence, STIs screening, long clinics waiting time, non-involvement of men in ANC/PMTCT, infant feeding methods and sensitization of community members on ANC/PMTCT programmes. The study highlights the need to expand PMTCT coverage and the implementation of the 90-90-90 programme toward MTCT elimination in SSA. That is " >=90% of pregnant and breast-feeding mothers must know their HIV status; >=90% of those that are positive are enrolled on ARVs treatment and care; >=90% of those on ARVs treatment and care are virally suppressed. PMID- 30415980 TI - Evaluation of abdominal aortic aneurysm in patients with nonvariceal upper gastrointestinal hemorrhage. PMID- 30415981 TI - History and physical exam predictors of intracranial injury in the elderly fall patient: A prospective multicenter study. AB - OBJECTIVES: A prior single-center study demonstrated historical and exam features predicting intracranial injury (ICI) in geriatric patients with low-risk falls. We sought to prospectively validate these findings in a multicenter population. METHODS: This is a prospective observational study of patients >=65 years presenting after a fall to three EDs. Patients were eligible if they were at baseline mental status and were not triaged to the trauma bay. Fall mechanism, head strike history, headache, loss of consciousness (LOC), anticoagulants/antiplatelet use, dementia, and signs of head trauma were recorded. Radiographic imaging was obtained at the discretion of treating physicians. Patients were called at 30 days to determine outcome in non-imaged patients. RESULTS: 723 patients (median age 83, interquartile range 74-88) were enrolled. Although all patients were at baseline mental status, 76 had GCS <15, and 154 had dementia. 406 patients were on anticoagulation/antiplatelet agents. Fifty-two (7.31%) patients had traumatic ICI. Two study variables were helpful in predicting ICI: LOC (odds ratio (OR) 2.02) and signs of head trauma (OR 2.6). The sensitivity of these items was 86.5% (CI 73.6-94) with a specificity of 38.8% (CI 35.1-42.7). The positive predictive value in this population was 10% (CI 7.5 13.3) with a negative predictive value of 97.3% (CI 94.4-98.8). Had these items been applied as a decision rule, 273 patients would not have undergone CT scanning, but 7 injuries would have been missed. CONCLUSION: In low-risk geriatric fall patients, the best predictors of ICI were physical findings of head trauma and history of LOC. PMID- 30415982 TI - Physiological effects of a spit sock. AB - OBJECTIVES: Healthcare providers and law enforcement utilize spit socks to prevent exposure to communicable diseases transmitted by bodily fluid projection from agitated individuals. There are cases in which death is reported due to breathing being limited by a spit sock. There are no formally published studies on their use and safety. The aim of this study was to evaluate whether wearing a spit sock causes a clinically significant impact on breathing. METHODS: Subjects sat with the spit mask over their heads for 15 min and their vital signs and ventilatory parameters were recorded after 5 min, 10 min and 15 min. Data were compared to baseline using Student's t-test with 95% confidence intervals using SPSS. RESULTS: The median age of the 15 subjects was 28 years and 53% were male. There was no significant difference between baseline and wearing the spit sock for 5, 10 or 15 min for heart rate (p = 0.250, p = 0.181, p = 0.546), oxygen saturation (p = 0.334, p = 1.00, p = 0.173), end-tidal pCO2 (p = 0.135, p = 0.384, p = 0.187), and diastolic blood pressure (p = 0.485, p = 0.508, p = 0.915). The respiratory rate was not significantly different after 5 and 10 min (p = 0.898, p = 0.583), but decreased at 15 min (p = 0.048). The systolic blood pressure was lower after 5 and 10 min (p = 0.028, p = 0.045), but not significantly different at 15 min (p = 0.146). No subject indicated distress nor did the study need to be terminated due to pre-determined concerning vital signs or ventilatory parameters. CONCLUSIONS: In healthy subjects there were no clinically significant changes in the physiologic parameters of breathing while wearing a spit sock. PMID- 30415983 TI - Brugada pattern exposed with administration of amiodarone during emergent treatment of ventricular tachycardia. AB - BACKGROUND: Brugada pattern is a well-known pathological finding on electrocardiogram (ECG) which increases the likelihood of cardiac arrest due to ventricular arrhythmia. These cases generally present in younger patients without evidence of an electrolyte abnormality, structural heart disease, or cardiac ischemia. In many instances, this pattern is either hidden on initial presentation or presents as an incidental finding on an EKG. Often times the Brugada syndrome leads to sudden cardiac death or more rarely can be unmasked with a class 1A or 1C anti-arrhythmic agent. Here, we present a distinctive case in which the pattern was exposed by amiodarone during the emergent treatment of Ventricular Tachycardia (VT). CASE REPORT: A 34-year-old female, without significant cardiac history, presented to the Emergency Department after multiple near syncopal episodes at home. Initial ECG showed VT vs. SVT. After a failed trial of adenosine, the patient was treated with 150 mg amiodarone and became hypotensive needing an electrical cardioversion. After becoming bradycardic, the amiodarone drip was discontinued and she was admitted to the MICU. An echocardiogram and left heart catheterization showed no evidence of coronary artery disease or decreased ejection fraction. The patient's ECG now showed a subtle Brugada Type 3 pattern and she received a dual chamber AICD upon discharge. CONCLUSION: This case emphasizes the awareness needed to seek out this pattern on subsequent ECG's. With the high lethality of Brugada, the emergency physician must recognize that multiple drugs can evoke this pattern after initial presentation. PMID- 30415984 TI - Effect of menstrual bleeding on the detection of anogenital injuries in sexual assault victims. PMID- 30415985 TI - Swollen and bloodshot eye following headache. AB - A ruptured cavernous carotid aneurysm (CCA) with carotid cavernous fistula can appear as a benign headache but progress to a swollen and bloodshot eye overnight. A 66-year-old woman visited emergency department with sudden onset of pain behind her left forehead and vomiting. She was treated for a migraine-like headache and discharged. She presented again on the next day with a persistent headache and a swollen left eye with blurred vision. An ophthalmologic examination revealed erythema of the left lid and chemosis at the temporal and lower bulbar conjunctiva. A cranial nonenhanced computed tomography (CT) scan had been performed at her previous visit. The scan exhibited a nodular mass lesion involving the left cavernous sinus. CT angiography was subsequently used to determine that the lesion was a giant aneurysm in the left cavernous internal carotid artery, causing enlargement of the left ophthalmic veins. The symptoms of her left eye rapidly progressed to severe chemosis, edematous change over periocular region, and limited movements after 8 h. The patient received emergent lateral canthotomy and inferior cantholysis to avoid acute orbital compartment syndrome and was subsequently treated with stent-assisted coil embolization. A ruptured CCA is an urgent condition that requires rapid assessment of both cranial vascular and ocular lesions. A history of sudden onset headache with a nonpainful acute unilateral red eye may serve as a clue to prompt additional diagnostic studies and ophthalmologist evaluation. Adequate radiological studies and early endovascular intervention can reduce the likelihood of permanent ocular injury and vision impairment. PMID- 30415986 TI - Insights into innovative breast imaging techniques. PMID- 30415987 TI - Long-Term Trends in Reproductive Behavior Among Young Women in Four Countries, 1995-2009. AB - PURPOSE: Identification of trends in the ability of young single women to protect themselves from unwelcome pregnancy is essential for evaluation and development of policies and programs. We document trends over a 15-year period in sexual activity, contraceptive use, and reproductive outcomes in four countries for single women aged 15-24 years. METHODS: Using retrospective month-by-month reproductive and contraceptive calendars, we constructed annual sexual, contraceptive, and reproductive profiles. The analysis was applied to all four countries (Colombia, Kenya, Peru, and Zimbabwe) that had collected complete reproductive calendars in three consecutive Demographic and Health Surveys. Women years were classified as sexually inexperienced (i.e., virgin), sexually experienced but using contraception, and sexually experienced without contraception. Conception rates were calculated and those ending in live births were classified as wanted or unwanted. RESULTS: While virginity decreased over time in the Latin American countries, it increased in the African settings. The contribution of condom to the sexually active time protected by contraception use increased in all countries. While the percentage of conceptions ending in spontaneous or induced abortion increased in Colombia and Peru to around 15% of the total pregnancy outcomes, it decreased in the African countries to less than 6%. CONCLUSIONS: Delayed sexual debut remains the major restraint on pregnancy in these four countries with the result that conception rates are very low. Condoms remain the most common method of contraception even in the two countries without severe HIV risks and efforts to displace condoms by nonbarrier methods should be pursued with caution. PMID- 30415988 TI - Rationale and Design of the IROCAS Study: Multicenter, International, Randomized Phase 3 Trial Comparing Adjuvant Modified (m) FOLFIRINOX to mFOLFOX6 in Patients With High-Risk Stage III (pT4 and/or N2) Colon Cancer-A UNICANCER GI-PRODIGE Trial. AB - BACKGROUND: According to the IDEA trial, 6-month adjuvant chemotherapy should remain the treatment standard in stage III T4 or N2 colon cancer. The relatively poor survival in this high-risk subgroup-a 3-year disease-free survival (DFS) rate of 65%-and the potential synergistic efficacy of 5-fluorouracil (5-FU), oxaliplatin, and irinotecan suggest that FOLFIRINOX may be a regimen of particular interest in this setting. PATIENTS AND METHODS: This multicenter international phase 3 trial (ClinicalTrials.gov NCT02967289) being conducted in 49 centers in France and Canada plans to randomize (1:1; minimization method) 640 patients aged 18 to 70 years with Eastern Cooperative Oncology Group performance status <= 1. Randomization occurs within 42 days (with treatment initiated within 56 days) after curative-intent R0 surgical resection of a pT4N1 or pT1-4N2 colon adenocarcinoma. Patients will be randomized to receive adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 180 mg/m2, and 5-FU 2.4 g/m2 over 46 hours) or modified FOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU bolus 400 mg/m2, then 2.4 g/m2 over 46 hours) every 2 weeks for 24 weeks (12 cycles). Patients will be followed for 5 years after the end of adjuvant chemotherapy. A gain of 9% in 3-year DFS (primary end point) is expected (74% in the experimental arm vs. 65% in the control arm; alpha, 5% [2 sided log-rank test]; 1-beta, 80%). Secondary end points of this study include 2 year DFS, overall survival, and toxicity. PMID- 30415989 TI - E-Cadherin in Colorectal Cancer: Relation to Chemosensitivity. AB - BACKGROUND: The conventional chemotherapy of colorectal cancer with irinotecan, 5 fluorouracil, and oxaliplatin remains one of the front-line treatments worldwide. However, its efficacy is quite low. Recently studies of the epithelial mesenchymal transition (EMT) have become the focus of investigations into the cause of chemoresistance in several types of cancer, including colorectal cancer. The data about the role of EMT in chemosensitivity are controversial. MATERIALS AND METHODS: Human colon adenocarcinoma cell lines HT29 and HCT116 and 14 primary short-term cultures established from patient tumors were used. The chemosensitivity to irinotecan, 5-fluorouracil, and oxaliplatin was assessed using the (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test. Immunocytochemistry, immunohistochemistry, and Western blot test were used to investigate the E-cadherin expression, the loss of which is a major hallmark of EMT. RESULTS: Elevated chemosensitivity of the cell line with EMT phenotype, HCT116, was demonstrated. Increased chemosensitivity was revealed in HT29 cell line upon EMT induction. E-cadherin-positive short-term cultures were more resistant to all the drugs tested, whereas each of E-cadherin-negative cultures showed sensitivity to at least one drug. The statistically significant dependency of cells viability on the E-cadherin expression (P < .04) was demonstrated on the short-term cultures using 2 concentrations of each drug. CONCLUSION: The data obtained may serve as a basis for the analysis of colon cancer chemosensitivity using short-term cultures and the assay of E-cadherin expression. PMID- 30415990 TI - Rising Incidence and Improved Survival of Anal Squamous Cell Carcinoma in Norway, 1987-2016. AB - BACKGROUND: Anal squamous cell carcinoma (ASCC) is a rare, human papilloma virus associated cancer. The purpose was to investigate the population-based incidence rates, age and gender distribution, and survival of ASCC. MATERIALS AND METHODS: All primary ASCC in 1987 to 2016 were identified in the Cancer Registry of Norway (N = 1548), with information on age, gender, stage, county of residence, radiotherapy, and survival. RESULTS: Median age was 66 years; 71% were females. World age-standardized incidence rates increased (1987-2016) from 0.79 (95% confidence interval [CI], 0.69-0.90) to 1.10 (95% CI, 1.00-1.22) per 100,000 person-years in females and, from 0.34 (95% CI, 0.28-0.42) to 0.47 (95% CI, 0.40 0.54) in males. Estimated annual percentage change was 1.7 (95% CI, 0.9-2.6) for females and 1.3 (95% CI, -0.1 to 2.7) for males. Incidence rates increased with age; the relative risk was higher in major cities. Five-year net survival increased from 63.4% to 72.7% (1987-2016), but for age >= 70 years remained ~57%. Net survival was dependant on stage, age, and gender. Five-year net survival (1997-2016) was 76.4% after curative radiotherapy, and 18.0% after palliative radiotherapy. CONCLUSION: ASCC incidence rates increased from 1987 to 2016, and survival improved for patients < 70 years. Five-year net survival was 76% after curative radiotherapy in Norway. PMID- 30415991 TI - Analysis of mutational signatures in primary and metastatic endometrial cancer reveals distinct patterns of DNA repair defects and shifts during tumor progression. AB - OBJECTIVE: Mutational signatures provide insights into the biological processes shaping tumor genomes and may inform patient therapy. We sought to define the mutational signatures of i) endometrioid and serous endometrial carcinomas (ECs), stratified into the four molecular subtypes, ii) uterine carcinosarcomas, and iii) matched primary and metastatic ECs. METHODS: Whole-exome sequencing MC3 data from primary endometrioid and serous carcinomas (n = 232) and uterine carcinosarcomas (n = 57) from The Cancer Genome Atlas (TCGA), and matched primary and metastatic ECs (n = 61, 26 patients) were reanalyzed, subjected to mutational signature analysis using deconstructSigs, and correlated with clinicopathologic and genomic data. RESULTS: POLE (ultramutated) and MSI (hypermutated) molecular subtypes displayed dominant mutational signatures associated with POLE mutations (15/17 cases) and microsatellite instability (55/65 cases), respectively. Most endometrioid and serous carcinomas of copy-number low (endometrioid) and copy number high (serous-like) molecular subtypes, and carcinosarcomas displayed a dominant aging-associated signature 1. Only 15% (9/60) of copy-number high (serous-like) ECs had a dominant signature 3 (homologous recombination DNA repair deficiency (HRD)-related), a prevalence significantly lower than that found in high-grade serous ovarian carcinomas (54%, p < 0.001) or basal-like breast cancers (46%, p < 0.001). Shifts from aging- or POLE- to MSI-related mutational processes were observed in the progression from primary to metastatic ECs in a subset of cases. CONCLUSIONS: The mutational processes underpinning ECs vary even among tumors of the same TCGA molecular subtype and in the progression from primary to metastatic ECs. Only a minority of copy-number high (serous-like) ECs display genomics features of HRD and would likely benefit from HRD-directed therapies. PMID- 30415992 TI - The prognostic value of p16 and p53 expression for survival after vulvar cancer: A systematic review and meta-analysis. AB - The tumor suppressor proteins p16 and p53 have been suggested to have prognostic value in some human papillomavirus (HPV)-associated cancers, however, this has been less well established for vulvar cancer. The aim of this review and meta analysis was to examine the prognostic value of p16 and p53 expression status on survival after vulvar squamous cell carcinoma (VSCC). We conducted a thorough systematic literature search of multiple databases to identify studies examining survival after histolocally verified VSCC that were tested for p16 and/or p53. A total of 18 eligible studies were included. Using a fixed-effects model we calculated study-specific and pooled hazard ratios (HRs) of 5-year overall survival (OS). In the analyses of OS, we included 475 VSCC cases tested for p16 expression of which 38% were p16 positive. The pooled HRp16 was 0.40 (95% CI: 0.29-0.55). In addition, the majority of results from studies with adjusted analyses on the prognostic value of p16 indicated that p16 expression status could be an independent prognostic marker for OS in women diagnosed with VSCC, and the same pattern was seen for disease specific survival (DSS). We also included 310 VSCC cases tested for p53 expression of which 54% were p53 positive. The pooled HRp53 was 1.81 (95% CI: 1.22-2.68) indicating that p53 positive VSCC have a significantly lower 5-year OS compared to p53 negative. The results in relation to p53 reported from adjusted analyses OS and on DSS and disease free survival were more equivocal. This meta-analysis and review suggests that p53 and especially p16 expression status are of prognostic importance in women diagnosed with VSCC. This may be clinically important in the future design of targeted therapy and when planning the optimal follow-up strategy. Future studies should include the combined use of biomarkers such as p16, p53 and HPV status. PMID- 30415993 TI - Primate Nigrostriatal Dopamine System Regulates Saccadic Response Inhibition. AB - Animals need to inhibit inappropriate actions that would lead to unwanted outcomes. Although this ability, called response inhibition, is impaired in neurological/psychiatric disorders with dopaminergic dysfunctions, how dopamine regulates response inhibition remains unclear. Here we investigated neuronal signals of the nigrostriatal dopamine system in monkeys performing a saccadic countermanding task. Subsets of dopamine neurons in the substantia nigra and striatal neurons receiving the dopaminergic input were activated when the monkey was required to cancel a planned saccadic eye movement. These activations were stronger when canceling the eye movements was successful compared with failed and were enhanced in demanding trials. The activated dopamine neurons were distributed mainly in the dorsolateral, but not in the ventromedial, part of the nigra. Furthermore, pharmacological blockade of dopaminergic neurotransmission in the striatum dampened the performance of canceling saccadic eye movements. The present findings indicate that disruption of nigrostriatal dopamine signaling causes impairments in response inhibition. PMID- 30415994 TI - Visual Control of Walking Speed in Drosophila. AB - An animal's self-motion generates optic flow across its retina, and it can use this visual signal to regulate its orientation and speed through the world. While orientation control has been studied extensively in Drosophila and other insects, much less is known about the visual cues and circuits that regulate translational speed. Here, we show that flies regulate walking speed with an algorithm that is tuned to the speed of visual motion, causing them to slow when visual objects are nearby. This regulation does not depend strongly on the spatial structure or the direction of visual stimuli, making it algorithmically distinct from the classic computation that controls orientation. Despite the different algorithms, the visual circuits that regulate walking speed overlap with those that regulate orientation. Taken together, our findings suggest that walking speed is controlled by a hierarchical computation that combines multiple motion detectors with distinct tunings. PMID- 30415995 TI - Merkel Cells Activate Sensory Neural Pathways through Adrenergic Synapses. AB - Epithelial-neuronal signaling is essential for sensory encoding in touch, itch, and nociception; however, little is known about the release mechanisms and neurotransmitter receptors through which skin cells govern neuronal excitability. Merkel cells are mechanosensory epidermal cells that have long been proposed to activate neuronal afferents through chemical synaptic transmission. We employed a set of classical criteria for chemical neurotransmission as a framework to test this hypothesis. RNA sequencing of adult mouse Merkel cells demonstrated that they express presynaptic molecules and biosynthetic machinery for adrenergic transmission. Moreover, live-cell imaging directly demonstrated that Merkel cells mediate activity- and VMAT-dependent release of fluorescent catecholamine neurotransmitter analogs. Touch-evoked firing in Merkel-cell afferents was inhibited either by pre-synaptic silencing of SNARE-mediated vesicle release from Merkel cells or by neuronal deletion of beta2-adrenergic receptors. Together, these results identify both pre- and postsynaptic mechanisms through which Merkel cells excite mechanosensory afferents to encode gentle touch. PMID- 30415996 TI - Segregated Subnetworks of Intracortical Projection Neurons in Primary Visual Cortex. AB - The rules by which neurons in neocortex choose their synaptic partners are not fully understood. In sensory cortex, intermingled neurons encode different attributes of sensory inputs and relay them to different long-range targets. While neurons with similar responses to sensory stimuli make connections preferentially, the relationship between synaptic connectivity within an area and long-range projection target remains unclear. We examined the local connectivity and visual responses of primary visual cortex neurons projecting to anterolateral (AL) and posteromedial (PM) higher visual areas in mice. Although the response properties of layer 2/3 neurons projecting to different targets were often similar, they avoided making connections with each other. Thus, projection target, in addition to response similarity, constrains local synaptic connectivity of AL and PM projection neurons. We propose that reduced crosstalk between different populations of projection neurons permits independent function of these output channels. PMID- 30415997 TI - A Brain Module for Scalable Control of Complex, Multi-motor Threat Displays. AB - Threat displays are a universal feature of agonistic interactions. Whether threats are part of a continuum of aggressive behaviors or separately controlled remains unclear. We analyze threats in Drosophila and show they are triggered by male cues and visual motion, and comprised of multiple motor elements that can be flexibly combined. We isolate a cluster of ~3 neurons whose activity is necessary for threat displays but not for other aggressive behaviors, and whose artificial activation suffices to evoke naturalistic threats in solitary flies, suggesting that the neural control of threats is modular with respect to other aggressive behaviors. Artificially evoked threats suffice to repel opponents from a resource in the absence of contact aggression. Depending on its level of artificial activation, this neural threat module can evoke different motor elements in a threshold-dependent manner. Such scalable modules may represent fundamental "building blocks" of neural circuits that mediate complex multi-motor behaviors. PMID- 30415998 TI - Complement C3aR Inactivation Attenuates Tau Pathology and Reverses an Immune Network Deregulated in Tauopathy Models and Alzheimer's Disease. AB - Strong evidence implicates the complement pathway as an important contributor to amyloid pathology in Alzheimer's disease (AD); however, the role of complement in tau modulation remains unclear. Here we show that the expression of C3 and C3a receptor (C3aR1) are positively correlated with cognitive decline and Braak staging in human AD brains. Deletion of C3ar1 in PS19 mice results in the rescue of tau pathology and attenuation of neuroinflammation, synaptic deficits, and neurodegeneration. Through RNA sequencing and cell-type-specific transcriptomic analysis, we identify a C3aR-dependent transcription factor network that regulates a reactive glial switch whose inactivation ameliorates disease associated microglia and neurotoxic astrocyte signatures. Strikingly, this C3aR network includes multiple genes linked to late-onset AD. Mechanistically, we identify STAT3 as a direct target of C3-C3aR signaling that functionally mediates tau pathogenesis. All together our findings demonstrate a crucial role for activation of the C3-C3aR network in mediating neuroinflammation and tau pathology. PMID- 30415999 TI - Calciphylaxis in patients with chronic kidney disease: A disease which is still bewildering and potentially fatal. AB - Calciphylaxis, also known as calcific uraemic arteriolopathy, is a rare syndrome that typically causes skin necrosis and usually affects dialysis patients. Its pathogenesis is multifactorial and is the consequence of many factors causing ectopic calcifications in patients with chronic kidney disease, such as calcium phosphate metabolism disorders, hyper- or hypo-parathyroidism, diabetes, obesity, systemic inflammation and the use of vitamin K antagonists, among others. From a clinical point of view, calciphylaxis may progress from painful purpura to extensive areas of skin necrosis that can potentially lead to superinfection and the death of the patient due to sepsis. Treatment is primarily based on managing the wounds, eliminating all the possible precipitating factors of ectopic calcification and administering agents which are capable of inhibiting the process of calcification. PMID- 30416000 TI - Corrigendum to "Isolating mitotic and meiotic germ cells from male mice by developmental synchronization, staging, and sorting" [Dev. Biol. 443 (2018) 19 34]. PMID- 30416001 TI - Auto-flocculation through cultivation of Chlorella vulgaris in seafood wastewater discharge: Influence of culture conditions on microalgae growth and nutrient removal. AB - Nowadays, the pretreatment of wastewater prior to discharge is very important in various industries as the wastewater without any treatment contains high organic pollution loads that would pollute the receiving waterbody and potentially cause eutrophication and oxygen depletion to aquatic life. The reuse of seafood wastewater discharge in microalgae cultivation offers beneficial purposes such as reduced processing cost for wastewater treatment, replenishing ground water basin as well as financial savings for microalgae cultivation. In this paper, the cultivation of Chlorella vulgaris with an initial concentration of 0.01 +/- 0.001 g?L-1 using seafood sewage discharge under sunlight and fluorescent illumination was investigated in laboratory-scale without adjusting mineral nutrients and pH. The ability of nutrient removal under different lighting conditions, the metabolism of C. vulgaris and new medium as well as the occurrence of auto flocculation of microalgae biomass were evaluated for 14 days. The results showed that different illumination sources did not influence the microalgae growth, chemical oxygen demand (COD) and biochemical oxygen demand (BOD) significantly. However, the total nitrogen (total-N) and total phosphorus (total-P) contents of microalgae were sensitive to the illumination mode. The amount of COD, BOD, total N and total-P were decreased by 88%, 81%, 95%, and 83% under sunlight mode and 81%, 74%, 79%, and 72% under fluorescent illumination, respectively. Furthermore, microalgae were auto-flocculated at the final days of cultivation with maximum biomass concentration of 0.49 +/- 0.01 g?L-1, and the pH value had increased to pH 9.8 +/- 0.1 under sunlight illumination. PMID- 30416002 TI - Quantitative Assessment of Tumor Cell Proliferation in Brain Gliomas with Dynamic Contrast-Enhanced MRI. AB - RATIONALE AND OBJECTIVES: This study aimed to investigate whether volume transfer constant (Ktrans) and volume of extravascular extracellular space per unit volume of tissue (Ve) derived from dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) could quantitatively assess the tumor proliferation index (Ki-67) of gliomas noninvasively. MATERIALS AND METHODS: The preoperative DCE MRI data of 69 patients with pathologically confirmed glioma (28, 8, and 33 cases in grades II, III, and IV) were retrospectively reviewed. The maximal Ktrans and Ve were measured in the tumor body. The immunohistochemistry was used to detect the expression of Ki-67 proteins in glioma specimens. The Mann-Whitney U test was applied to analyze the differences in Ktrans, Ve, and Ki-67 index across histologically defined glioma grades. Spearman correlation was performed between Ktrans, Ve, and Ki-67 index. The receiver operating characteristic curve analysis was used to determine the cutoff values of Ktrans and Ve in distinguishing different Ki-67 index expression levels. RESULTS: Ktrans, Ve, and Ki-67 index of grade II (0.027 min-1, 0.065, 4.04%) were significantly lower than those of grade III (0.093 min-1, 0.297, 25.13%) and IV (0.100 min-1, 0.299, 25.37%). Both Ktrans and Ve significantly correlated with the Ki-67 index in all tumors and high-grade gliomas (HGGs, grade III and IV). The receiver operating characteristic curve analysis revealed that the cutoff values for Ktrans (0.079 min-1) and Ve (0.249) provided the best combination of sensitivity and specificity to distinguish the gliomas with high Ki-67 index from those with low Ki-67 index. CONCLUSION: The DCE MRI-derived parameters were valuable in assessing the tumor cell proliferation in HGG noninvasively. PMID- 30416003 TI - Cost-Effectiveness Analysis: An Overview of Key Concepts, Recommendations, Controversies, and Pitfalls. AB - The field of radiology has witnessed a burst of technological advances that improve diagnostic quality, reduce harm to patients, support clinical needs, and better serve larger more diverse patient populations. One of the critical challenges with these advances is proving that value outweighs the cost. The use of cutting-edge technology is often expensive, and the reality is that our society cannot afford all the screening and diagnostic tests that are being developed. At the societal level, we need tools to help us decide which health programs should be funded. Therefore, decision makers are increasingly looking toward scientific methods to compare health technologies in order to improve allocation of resources. One of such methods is cost-effectiveness analysis. In this article, we review key features of cost-effectiveness analysis and its specific issues as they relate to radiology. PMID- 30416004 TI - Indicators of Readiness and Capacity for Implementation of Healthy Eating Strategies in Child Care Settings Serving Low-Income Children. AB - OBJECTIVE: Identify factors perceived to influence implementation of healthy eating policy, systems, and environmental strategies (PSEs) in child care settings serving low-income children. DESIGN: This mixed-methods study, conducted in 2015-2016, used semi-structured interviews (n = 18), focus groups (n = 23), and an expert panel. PARTICIPANTS: Public health (n = 11) and Supplemental Nutrition Assistance Program-Education practitioners (n = 9) and community residents (n = 174) from 9 counties in Ohio. Expert panelists (n = 10) had experience implementing PSEs in child care settings. PHENOMENON OF INTEREST: Implementation factors influencing healthy eating PSEs in child care settings. ANALYSIS: Qualitative thematic analysis of 41 transcripts using a grounded theory approach. Indicators for each theme were operationalized. Consensus feedback from an expert panel weighted themes and indicators based on perceived importance for implementation. RESULTS: Identified themes relevant to implementation of PSEs included (1) organizational and practitioner capacity, (2) child care capacity, (3) networks and relationships, and (4) community resources and motivations. Nineteen indicators related to the 4 themes were identified and weighted. CONCLUSIONS AND IMPLICATIONS: Findings highlighted key factors within domains of influence and informed the operationalization of the indicators and the development of an assessment tool. The assessment tool is designed to tailor PSE implementation to the realities of different child care settings. PMID- 30416005 TI - The vision and role of geriatric oncology in surgical treatment of the elderly patient. AB - The phenomenon of population aging is constantly on the rise, as are the medical needs of elderly subjects. Oncological treatment concerns an ever larger number of elderly patients, raising a number of not only practical and medical questions, but also the ethical interrogations associated with therapeutic decision-making, quality of life and therapeutic obstinacy (futile medical care). Surgeons are increasingly preoccupied by elderly patients on account of the cancer rate among them, and they are compelled to cope with challenges such as morbimortality and prolonged hospitalization. Geriatric oncology is a discipline of increasing importance of which the goal consists in comprehensive care of the elderly cancer patient, care taking into full account his physical and psychological aging, his somatic and cognitive comorbidities, and, last but least, his life expectancy. The opinions and recommendations of geriatric oncologists provide increasingly more orientation for the oncological therapeutic decision-making processes. The objective of this attempt at clarification is to discuss the contributions of this discipline to everyday surgical activity, to provide surgeons with some tools facilitating initial evaluation of their patients, and to remind the reader of situations in which oncological assistance is of paramount importance. PMID- 30416006 TI - SGLT1 in pancreatic alpha cells regulates glucagon secretion in mice, possibly explaining the distinct effects of SGLT2 inhibitors on plasma glucagon levels. AB - OBJECTIVES: It is controversial whether sodium glucose transporter (SGLT) 2 inhibitors increase glucagon secretion via direct inhibition of SGLT2 in pancreatic alpha cells. The role of SGLT1 in alpha cells is also unclear. We aimed to elucidate these points that are important not only for basic research but also for clinical insight. METHODS: Plasma glucagon levels were assessed in the high-fat, high-sucrose diet (HFHSD) fed C57BL/6J mice treated with dapagliflozin or canagliflozin. RT-PCR, RNA sequence, and immunohistochemistry were conducted to test the expression of SGLT1 and SGLT2 in alpha cells. We also used alphaTC1 cells and mouse islets to investigate the molecular mechanism by which SGLT1 modulates glucagon secretion. RESULTS: Dapagliflozin, but not canagliflozin, increased plasma glucagon levels in HFHSD fed mice. SGLT1 and glucose transporter 1 (GLUT1), but not SGLT2, were expressed in alphaTC1 cells, mouse islets and human islets. A glucose clamp study revealed that the plasma glucagon increase associated with dapagliflozin could be explained as a response to acute declines in blood glucose. Canagliflozin suppressed glucagon secretion by inhibiting SGLT1 in alpha cells; consequently, plasma glucagon did not increase with canagliflozin, even though blood glucose declined. SGLT1 effect on glucagon secretion depended on glucose transport, but not glucose metabolism. Islets from HFHSD and db/db mice displayed higher SGLT1 mRNA levels and lower GLUT1 mRNA levels than the islets from control mice. These expression levels were associated with higher glucagon secretion. Furthermore, SGLT1 inhibitor and siRNA against SGLT1 suppressed glucagon secretion in isolated islets. CONCLUSIONS: These data suggested that a novel mechanism regulated glucagon secretion through SGLT1 in alpha cells. This finding possibly explained the distinct effects of dapagliflozin and canagliflozin on plasma glucagon levels in mice. PMID- 30416007 TI - Hepatic schwannoma: CT and histologic features. PMID- 30416008 TI - Management of primary central nervous system lymphoma. AB - A rare tumor, primary central nervous system lymphoma can affect immunocompetent and immunocompromised patients. While sensitive to radiotherapy or chemotherapy crossing the blood-brain barrier, it often recurs. Modern treatment consists of high-dose methotrexate-based induction chemotherapy, often followed by consolidation with either radiotherapy or further chemotherapy. Neurotoxicity is however a concern with radiotherapy, especially for patients older than 60 years. The benefit of the addition of rituximab to chemotherapy is unclear. Targeted therapies and immunotherapy have been effective in some patients and are tested on a larger scale. Survival has improved in the last decade, but remains poor in older patients. PMID- 30416010 TI - Incorporating Patient- and Family-Centered Care Into Radiology Residency Training Through an Experiential Curriculum. PMID- 30416011 TI - SOHO State of the Art Update and Next Questions: IDH Therapeutic Targeting in AML. AB - Mutations in isocitrate dehydrogenase isoform (IDH) 1 and 2 occur in approximately 25% of patients with acute myeloid leukemia (AML). These mutations lead to a block in myeloid differentiation and ultimately, to the development of AML. Inhibitors of mutant IDH1 and 2 have recently been approved by the US Food and Drug Administration and their use has led to clinical responses with prolonged duration of response. IDH inhibitors in combination with standard-of care therapy and other small molecular inhibitors are now being used. PMID- 30416009 TI - ? AB - Bradykinin mediated angioedema (BK-AE) can be associated either with C1Inhibitor deficiency (hereditary and acquired forms), either with normal C1Inh (hereditary form and drug induced AE as angiotensin converting enzyme inhibitors...). In case of high clinical suspicion of BK-AE, C1Inh exploration must be done at first: C1Inh function and antigenemy as well as C4 concentration. C1Inh deficiency is significant if the tests are below 50 % of the normal values and controlled a second time. In case of C1Inh deficiency, you have to identify hereditary from acquired forms. C1q and anti-C1Inh antibody tests are useful for acquired BK-AE. SERPING1 gene screening must be done if a hereditary angioedema is suspected, even if there is no family context (de novo mutation 15 %). If a hereditary BK-AE with normal C1Inh is suspected, F12 and PLG gene screening is suitable. PMID- 30416012 TI - Spatiotemporal m(i)RNA Architecture and 3' UTR Regulation in the C. elegans Germline. AB - In animal germlines, regulation of cell proliferation and differentiation is particularly important but poorly understood. Here, using a cryo-cut approach, we mapped RNA expression along the Caenorhabditis elegans germline and, using mutants, dissected gene regulatory mechanisms that control spatiotemporal expression. We detected, at near single-cell resolution, >10,000 mRNAs, >300 miRNAs, and numerous unannotated miRNAs. Most RNAs were organized in distinct spatial patterns. Germline-specific miRNAs and their targets were co-localized. Moreover, we observed differential 3' UTR isoform usage for hundreds of mRNAs. In tumorous gld-2 gld-1 mutants, gene expression was strongly perturbed. In particular, differential 3' UTR usage was significantly impaired. We propose that PIE-1, a transcriptional repressor, functions to maintain spatial gene expression. Our data also suggest that cpsf-4 and fipp-1 control differential 3' UTR usage for hundreds of genes. Finally, we constructed a "virtual gonad" enabling "virtual in situ hybridizations" and access to all data (https://shiny.mdc-berlin.de/spacegerm/). PMID- 30416013 TI - Spatial Transcriptomics of C. elegans Males and Hermaphrodites Identifies Sex Specific Differences in Gene Expression Patterns. AB - To advance our understanding of the genetic programs that drive cell and tissue specialization, it is necessary to obtain a comprehensive overview of gene expression patterns. Here, we have used spatial transcriptomics to generate high resolution, anteroposterior gene expression maps of C. elegans males and hermaphrodites. To explore these maps, we have developed computational methods for discovering region- and tissue-specific genes. We have found extensive sex specific gene expression differences in the germline and sperm and discovered genes that are specifically expressed in the male reproductive tract. These include a group of uncharacterized genes that encode small secreted proteins that are required for male fertility. We conclude that spatial gene expression maps provide a powerful resource for identifying tissue-specific gene functions in C. elegans. Importantly, we found that expression maps from different animals can be precisely aligned, enabling transcriptome-wide comparisons of gene expression patterns. PMID- 30416014 TI - Effect of Prophylaxis for Early Adrenal Insufficiency Using Low-Dose Hydrocortisone in Very Preterm Infants: An Individual Patient Data Meta-Analysis. AB - OBJECTIVE: To assess the effect of prophylaxis for early adrenal insufficiency using low-dose hydrocortisone on survival without bronchopulmonary dysplasia (BPD) in very preterm infants using an individual patient data meta-analysis. STUDY DESIGN: All existing randomized controlled trials testing the efficacy of the prophylaxis of early adrenal insufficiency using low-dose hydrocortisone on survival without BPD were considered for inclusion when data were available. The primary outcome was the binary variable survival without BPD at 36 weeks of postmenstrual age. RESULTS: Among 5 eligible studies, 4 randomized controlled trials had individual patient data available (96% of participants identified; n = 982). Early low-dose hydrocortisone treatment for 10-15 days was associated with a significant increase in survival without BPD (OR, 1.45; 95% CI, 1.11-1.90; P = .007; I2 = 0%), as well as with decreases in medical treatment for patent ductus arteriosus (OR, 0.72; 95% CI, 0.56-0.93; P = .01; I2 = 0%) and death before discharge (OR, 0.70; 95% CI, 0.51-0.97; P = .03; I2 = 0%). The therapy was associated with an increased risk of spontaneous gastrointestinal perforation (OR, 2.50; 95% CI, 1.33-4.69; P = .004; I2 = 31.9%) when hydrocortisone was given in association with indomethacin exposure. The incidence of late-onset sepsis was increased in infants exposed to hydrocortisone (OR, 1.34; 95% CI, 1.02-1.75; P = .04; I2 = 0%), but no adverse effects were reported for either death or 2-year neurodevelopmental outcomes as assessed in an aggregate meta-analysis. CONCLUSIONS: This individual patient data meta-analysis showed that early low dose hydrocortisone therapy is beneficial for survival without BPD in very preterm infants. PMID- 30416015 TI - Pediatric Erythromelalgia and SCN9A Mutations: Systematic Review and Single Center Case Series. AB - OBJECTIVES: To evaluate the clinical features of erythromelalgia in childhood associated with gain-of-function SCN9A mutations that increase activity of the Nav1.7 voltage-gated sodium channel, we conducted a systematic review of pediatric presentations of erythromelalgia related to SCN9A mutations, and compared pediatric clinical presentations of symptomatic erythromelalgia, with or without SCN9A mutations. STUDY DESIGN: PubMed, Embase, and PsycINFO Databases were searched for reports of inherited erythromelalgia in childhood. Clinical features, management, and genotype were extracted. Case notes of pediatric patients with erythromelalgia from the Great Ormond Street Hospital Pain Service were reviewed for clinical features, patient-reported outcomes, and treatments. Children aged over 10 years were recruited for quantitative sensory testing. RESULTS: Twenty-eight publications described erythromelalgia associated with 15 different SCN9A gene variants in 25 children. Pain was severe and often refractory to multiple treatments, including nonspecific sodium channel blockers. Skin damage or other complications of cold immersion for symptomatic relief were common (60%). SCN9A mutations resulting in greater hyperpolarizing shifts in Nav1.7 sodium channels correlated with symptom onset at younger ages (P = .016). Variability in reporting, and potential publication bias toward severe cases, limit any estimations of overall prevalence. In our case series, symptoms were similar but comorbidities were more common in children with SCN9A mutations. Quantitative sensory testing revealed marked dynamic warm allodynia. CONCLUSIONS: Inherited erythromelalgia in children is associated with difficult-to-manage pain and significant morbidity. Standardized reporting of outcome and management in larger series will strengthen identification of genotype-phenotype relationships. More effective long-term therapies are a significant unmet clinical need. PMID- 30416016 TI - Variability of Tidal Breathing Parameters in Preterm Infants and Associations with Respiratory Morbidity during Infancy: A Cohort Study. AB - OBJECTIVE: To test whether low variability of tidal volume (VT) and capnographic indices are predictive of subsequent respiratory morbidity in preterm infants. STUDY DESIGN: In a birth cohort of 133 preterm infants, lung function was performed at 44 weeks postmenstrual age. Associations between the coefficient of variation (CV) of VT (CVVT) and of expired CO2 volume per breath (CVVE,CO2) with rehospitalization, wheeze, and inhalation therapy during infancy were assessed using logistic regression. Area under the curve (AUC) analysis was used to assess whether outcome prediction using bronchopulmonary dysplasia (BPD) classification was enhanced by CVVT or CVVE,CO2. RESULTS: For each IQR decrease in CVVT (range, 4%-35%) and CVVE,CO2 (range, 5%-40%), the OR for rehospitalization increased by 2.25 (95% CI, 1.21-4.20) and 2.31 (95% CI, 1.20-4.45), respectively. The predictive value of BPD for rehospitalization was improved when CVVT or CVVE,CO2 was added to the model, with the AUC increasing from 0.56 to 0.66 in both models. No association was found for the other outcomes. CONCLUSIONS: Compared with BPD classification alone, including near-term variability of tidal breathing parameters improves the prediction of rehospitalization in infancy. These findings may inform parent counseling and monitoring strategies in preterm infants. PMID- 30416017 TI - Coverage and timeliness of vaccination and the validity of routine estimates: Insights from a vaccine registry in Kenya. AB - BACKGROUND: The benefits of childhood vaccines are critically dependent on vaccination coverage. We used a vaccine registry (as gold standard) in Kenya to quantify errors in routine coverage methods (surveys and administrative reports), to estimate the magnitude of survivor bias, contrast coverage with timeliness and use both measures to estimate population immunity. METHODS: Vaccination records of children in the Kilifi Health and Demographic Surveillance System (KHDSS), Kenya were combined with births, deaths, migration and residence data from 2010 to 17. Using inverse survival curves, we estimated up-to-date and age-appropriate vaccination coverage, calculated mean vaccination coverage in infancy as the area under the inverse survival curves, and estimated the proportion of fully immunised children (FIC). Results were compared with published coverage estimates. Risk factors for vaccination were assessed using Cox regression models. RESULTS: We analysed data for 49,090 infants and 48,025 children aged 12 23 months in 6 birth cohorts and 6 cross-sectional surveys respectively, and found 2nd year of life surveys overestimated coverage by 2% compared to birth cohorts. Compared to mean coverage in infants, static coverage at 12 months was exaggerated by 7-8% for third doses of oral polio, pentavalent (Penta3) and pneumococcal conjugate vaccines, and by 24% for the measles vaccine. Surveys and administrative coverage also underestimated the proportion of the fully immunised child by 10-14%. For BCG, Penta3 and measles, timeliness was 23-44% higher in children born in a health facility but 20-37% lower in those who first attended during vaccine stock outs. CONCLUSIONS: Standard coverage surveys in 12-23 month old children overestimate protection by ignoring timeliness, and survivor and recall biases. Where delayed vaccination is common, up-to-date coverage will give biased estimates of population immunity. Surveys and administrative methods also underestimate FIC prevalence. Better measurement of coverage and more sophisticated analyses are required to control vaccine preventable diseases. PMID- 30416018 TI - Safety and immunogenicity of seasonal trivalent inactivated influenza vaccines in pregnant women. AB - BACKGROUND: In the United States, seasonal inactivated influenza vaccine (IIV) is recommended for pregnant women; however, in early 2009, immunization rates were low, partly due to limited prospective data and concerns about vaccine safety. OBJECTIVE: We conducted a randomized study of two licensed seasonal trivalent IIVs (IIV3) to assess their safety and immunogenicity in pregnant women. STUDY DESIGN: In this prospective, randomized clinical study, 100 pregnant women, 18-39 years of age and >=14 weeks gestation received a single intramuscular dose of 2008-2009 Fluzone(r) or Fluarix(r). Injection site and systemic reactions were recorded for 7 days after vaccination and serious adverse events (SAEs) and pregnancy outcomes were documented. Serum samples collected before and 28 days after vaccination were tested for hemagglutination inhibition (HAI) antibody levels. RESULTS: The majority of the injection site and systemic reactions were mild and self-limited after both vaccines. No fever >=100 degrees F was reported. There were no vaccine-associated SAEs. Immune responses to influenza vaccine antigens were similar for the two study vaccines, with robust HAI responses against influenza A strains, and relatively lower responses for influenza B strains. CONCLUSION: Seasonal inactivated influenza vaccines were well tolerated and immunogenic in pregnant women. SYNOPSIS: In this prospective clinical trial, we demonstrated that immunization with seasonal trivalent, inactivated influenza vaccine in the second and third trimester of pregnancy is immunogenic and safe. PMID- 30416019 TI - Spontaneous reports of vaccination errors in the European regulatory database EudraVigilance: A descriptive study. AB - BACKGROUND: Among all post-marketing medication error reports submitted to EudraVigilance, vaccines are the most frequently reported medicinal products. This study aims to describe the characteristics of vaccination errors submitted to Eudravigilance between 2001 and 2016. METHODS: EudraVigilance is a spontaneous reporting database for adverse events maintained by the European Medicines Agency. We extracted Individual Case Safety Reports (ICSRs) submitted to EudraVigilance between 1 January 2001 and 31 December 2016. Reports were included for analysis if a vaccine was reported as interacting or suspect drug and at least one medication error term was listed as an adverse reaction. ICSRs were stratified by age and gender, by year of reporting, region of origin, reporter profession, seriousness of outcome, ATC, and type of error. RESULTS: In total, 7097 ICSRs were included in the study. We observed a yearly increase in the reporting of vaccination errors, with the proportion to all vaccine ICSRs increasing from 0.4% to 4.0% between 2001 and 2016. The majority of reports was classified as serious (4248, 59.9%), but non-serious reports were increasingly reported since 2012. The mean age of patients was 24.1 years. The most frequently reported vaccines were influenza (13.5%), bacterial and viral combined (12.3%), and hepatitis vaccines (11.8%). A total of 8167 medication error terms were reported. The most frequently reported terms were "Inappropriate schedule of drug administration" (27.2%), "Incorrect route of drug administration" (12.5%) and "Drug administered to patient of inappropriate age" (10.0%). For infants and children, the error "Drug administered to patient of inappropriate age" was reported more often than for all other age categories. DISCUSSION: Vaccination errors are increasingly submitted to EudraVigilance. Errors related to the schedule are the most common errors reported with vaccines. However, consequences of vaccination errors appear to be relatively mild. PMID- 30416020 TI - Factors affecting Salmonella-based combination immunotherapy for prevention of type 1 diabetes in non-obese diabetic mice. AB - We previously reported the development of an oral vaccine for diabetes based on live attenuated Salmonella-expressing preproinsulin (PPI) as the autoantigen. When combined with host cell-expressed TGFbeta, the vaccine prevented the onset of diabetes in non-obese diabetic (NOD) mice. Herein, we investigated factors that could affect vaccine efficacy including vaccination number, optimization of the autoantigen codon sequence, Salmonella SPI2-TTSS promoter/effector combinations, concurrent short-course low-dose anti-CD3. We also evaluated autoantigen GAD65 and cytokine IL10 treatment upon vaccine efficacy. T-cells we employed to elucidate the mechanism of the vaccine action. Our results showed that GAD65+TGFbeta or PPI+TGFbeta+IL10 prevented the onset of diabetes in the NOD mice and maintained glucose tolerance. However, increasing the number of vaccine doses, codon-optimization of the autoantigen(s) or use of other Salmonella promoter/effector combinations had no in vivo effect. Interestingly, two doses of vaccine (PPI+TGFbeta+IL10) combined with a sub-therapeutic dose of anti-CD3 prevented diabetes and decreased hyperglycemia in mice. The combined therapy also increased splenic Tregs and local Tregs in pancreatic lymph nodes (PLN) and increased regulatory (IL10 and IL2) but reduced inflammatory (IFNgamma and TNFalpha) cytokines. Together, these results indicate that the combination of low vaccine dose number, less vaccine autoantigen expression and short-course low dose anti-CD3 can increase regulatory mechanisms and suppress autoimmunity. PMID- 30416021 TI - Sleep and emotional disturbance in patients with non-dialysis chronic kidney disease. AB - BACKGROUND/PURPOSE: Sleep disorder and depression are prevalent in patients on dialysis but less investigated in earlier-stage chronic kidney disease (CKD) patients. We aimed to evaluate the prevalence of depression, anxiety, health anxiety, and sleep disturbance and explore the association between CKD stage, psychological symptoms and sleep quality. METHODS: We recruited 326 patients with CKD (stage 1-5) not on dialysis from the nephrology clinic. All participants completed the Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory (BAI), Health Anxiety Questionnaire (HAQ), and Pittsburgh Sleep Quality Index (PSQI). Chi-square tests were used to assess the difference in psychological symptoms between CKD stages. Multiple linear regression was employed to assess relationships among selected variables and sleep/emotional disturbance. RESULTS: Clinically significant depression, anxiety, health anxiety, and sleep disturbance were found in 3.1%, 3.1%, 18%, and 36.2% of the patients, respectively. BDI-II, BAI, HAQ, and PSQI scores did not significantly differ across CKD stages. In a multiple linear regression model that included psychological variables, BDI-II score had a statistically significant association with PSQI score (beta = 0.418, p < 0.001). CONCLUSION: Depressive symptoms were associated with sleep quality of patients with earlier-stage CKD. However, there was no significant association between CKD stage and sleep disturbance or other psychological symptoms. PMID- 30416022 TI - [Current knowledge on contraceptive knowledge in France: CNGOF Contraception Guidelines]. AB - OBJECTIVE: To summarize current knowledge on contraceptive coverage in France and worldwide, describe the effectiveness of different types of contraceptives, describe the characteristics of women using contraception, contraceptive failure situations and describe the different medical risks associated with contraceptive methods. METHODS: Consultation of the Medline database and of national or international reports on contraception. RESULTS: Contraceptive coverage in France is high: 97% of women in 2013 use a contraceptive method (among fertile, sexually active women without a desire for pregnancy), with a majority using medical methods (72% using pills and other hormonal contraceptives, intrauterine devices and 25% using natural and traditional barrier methods). The 2013 pill scare called into question the use of estrogen-progestogenic contraception and the information provided by doctors, but the pill remains the first contraceptive method followed by the intrauterine device, condoms and the traditional and natural methods. Lifetime contraceptive coverage changes according to a defined standard in France: condoms for the teen-agers, pills before pregnancy and then intrauterine devices after childbirth. Sterilization is very rarely chosen and offered. Contraception in France remains a predominantly female domain. Women and couples should be informed about all contraceptive methods, allowing them to choose the method that best suits their health, living conditions and sexuality. PMID- 30416023 TI - [Contraception: CNGOF Guidelines for Clinical Practice (Short Version)]. AB - The French College of Obstetrics and Gynecology (CNGOF) releases its first global recommendations for clinical practice in contraception, to provide physicians with an updated synthesis of available data as a basis for their practice. The French Health Authority (HAS) methodology was used. Twelve practical issues were selected by the organizing committee and the task force members. The available literature was screened until December 2017, and allowed the release of evidence based, graded recommendations. This synthesis is issued from 12 developed texts, previously reviewed by experts and physicians from public and private practices, with an experience in the contraceptive field. Male and female sterilization, as well as the use of hormonal treatments without contraceptive label were excluded from the field of this analysis. Specific practical recommendations on the management of contraception prescription, patient information including efficacy, risks, and benefits of the different contraception methods, follow up, intrauterine contraception, emergency contraception, local and natural methods, contraception in teenagers and after 40, contraception in vascular high-risk situations, and in case of cancer risk are provided. The short/mid-term future of contraception mostly relies on improving the use of currently available methods. This includes reinforced information for users and increased access to contraception for women, whatever the social and clinical context. That is the goal of these recommendations. PMID- 30416025 TI - Geriatric Telepsychiatry: Systematic Review and Policy Considerations. AB - Telemental health (TMH) for older patients has the potential to increase access to geriatric specialists, reduce travel times for patients and providers, and reduce ever growing healthcare costs. This systematic review article examines the literature regarding psychiatric assessment and treatment via telemedicine for geriatric patients. English language literature was searched using Ovid Medline, PubMed, and PsycINFO with search terms including telemedicine, telemental health, aging, and dementia. Abstracts were reviewed for relevance based on inclusion criteria. Multiple study types were reviewed, including open label, qualitative and randomized controlled trial study designs. Data was compiled regarding participants, study intervention, and outcomes. 76 articles were included. TMH was shown to be feasible and well accepted in the areas of inpatient and nursing home consultation, cognitive testing, dementia diagnosis and treatment, depression in integrated and collaborative care models, and psychotherapy. There is limited data on cost-effectiveness of TMH in the elderly. This article will discuss the current barriers to broader implementation of telemedicine for geriatric patients including reimbursement from the Medicare program. Medicare reimbursement for telemedicine is limited to rural areas, which does not allow for the widespread development of telemedicine programs. All Medicare beneficiaries would benefit from increased access to telemedicine services, not only those living in rural areas. As many elderly and disabled individuals have mobility problems, home-based telemedicine services should also be made available. There are efforts in Congress to expand the coverage of these services under Medicare, but strong advocacy will be needed to ensure these efforts are successful. PMID- 30416024 TI - Nationwide survey of congenital cholesteatoma using staging and classification criteria for middle ear cholesteatoma proposed by the Japan Otological Society. AB - OBJECTIVE: This study was undertaken to determine the characteristics of congenital cholesteatoma (CC) in Japan, via a nationwide survey using staging and classification criteria for middle ear cholesteatoma, as proposed by the Japan Otological Society (JOS). METHODS: A nationwide survey regarding middle ear cholesteatoma treated in 2015 was performed. There were 1787 registrations from 74 facilities, among which, CC accounted for 12.9% (231 cases) of all middle ear cholesteatoma cases. The extent of the disease was classified according to the classification and staging of cholesteatoma proposed by JOS in 2015. RESULTS: The age of the patients ranged from 1 to 55 years (mean, 8.2 years; median, 6 years; 149 ears of males; 82 ears of females). Among these cases, 105 (45.5%) were classified as stage I, 121 (52.4%) as stage II, and 5 (2.1%) as stage III, with no cases in stage IV. In the sub classification of stage I, 35 (33%), 43 (41%) and 27 (26%) ears were classified as stages I-a, I-b and I-c, respectively. Stage I-b (cholesteatoma confined to the posterior half of the tympanic cavity) was more frequent than stage I-a (the anterior half of tympanic cavity). Pre operative hearing level of air-conduction was 20.5dB for stage I-a, 34.5dB for stage I-b, 30.5dB for stage I-c, 38.6dB for stage II, and 59.0dB for stage III. The rate of missing stapes superstructure increased as the disease progressed. In the same way, the mastoid development lowered as the stage of the disease progressed. There were significant differences in the age at operation, pre operative hearing level, status of stapes, and major ossiculoplasty, between stage l-a and l-b. CONCLUSIONS: The current condition of CC in Japan was been evaluated; in particular, it was observed that the cases limited to the posterior part of tympanic cavity were not rare. The JOS stage classification based on the progression of the disease seemed simple and efficient. PMID- 30416026 TI - Prophylactic Effect of Amiodarone Infusion on Reperfusion Ventricular Fibrillation After Release of Aortic Cross-Clamp in Patients with Left Ventricular Hypertrophy Undergoing Aortic Valve Replacement: A Randomized Controlled Trial. AB - OBJECTIVE: To investigate whether prophylactic amiodarone infusion prevents ventricular fibrillation after aortic cross-clamp release and attenuates cytokine production in patients with left ventricular hypertrophy undergoing cardiac surgery. DESIGN: Prospective, randomized controlled trial. SETTING: A public hospital. PARTICIPANTS: The study comprised 68 patients undergoing aortic valve replacement for severe aortic stenosis. INTERVENTIONS: Patients were randomly assigned to receive a 150 mg bolus then 30 mg/h continuous infusion of amiodarone (amiodarone group) or a 1 mg/kg bolus then 1 mg/kg/h continuous infusion of lidocaine (lidocaine group). The primary outcome was the ventricular fibrillation incidence rate after aortic cross-clamp release. Secondary outcomes included perioperative serum interleukin-6 and tumor necrosis factor-alpha levels. MEASUREMENTS AND MAIN RESULTS: The ventricular fibrillation incidence rate was significantly lower in the amiodarone than in the lidocaine group (20.6% v 50%, relative risk 0.41; 95% confidence interval [CI] 0.20-0.86; p = 0.021). Interleukin-6 levels 1 hour after aortic cross-clamp release and at intensive care unit admission were significantly lower in the amiodarone than in the lidocaine group (geometric mean [95% CI] 117.4 pg/mL [87.1-158.4] v 339.5 pg/mL [210.6-547.2]; p < 0.01 and 211.1 pg/mL [162.8-73.6] v 434.1 pg/mL [293.7-641.5]; p < 0.01, respectively). Tumor necrosis factor-alpha levels 1 hour after aortic cross-clamp release were significantly lower in the amiodarone than in the lidocaine group (geometric mean [95% CI] 1.624 pg/mL [1.359-1.940] v 2.283 pg/mL [1.910-2.731]; p = 0.02). CONCLUSIONS: Amiodarone prevented reperfusion ventricular fibrillation in patients with left ventricular hypertrophy undergoing aortic valve replacement to a greater extent than did lidocaine. Furthermore, amiodarone inhibited postoperative interleukin-6 and tumor necrosis factor-alpha production. PMID- 30416027 TI - Does Less Invasive Surgery Need Less Invasive Anesthesia? PMID- 30416029 TI - Dietary patterns, food groups, and incidence of aortic valve stenosis: A prospective cohort study. AB - BACKGROUND: The role of diet in the development of aortic valve stenosis (AVS) is unknown. We therefore examined the associations of two dietary patterns, including a modified Dietary Approaches to Stop Hypertension (mDASH) diet and a modified Mediterranean (mMED) diet, and the food items included in these dietary patterns with incidence of aortic valve stenosis (AVS) in a population-based cohort study. METHODS: The study cohort comprised 74,401 Swedish adults (54% men) who were free of cardiovascular disease at the time of completion of a baseline questionnaire about habitual diet and other risk factors for chronic diseases. Participants were followed-up through linkage with nationwide registers on hospitalization and causes of death. RESULTS: During 1,132,617 person-years (mean 15.2 years) of follow-up, 1338 incident AVS cases (801 in men and 537 in women) were ascertained. We found no significant associations of the mDASH and mMED dietary patterns or the food groups and beverages included in these diets (i.e., fruit, vegetables, legumes and nuts, whole grains, fish, low-fat dairy foods, full-fat dairy foods, red and processed meat, and sweetened beverages) with risk of AVS. The hazard ratios (95% confidence interval) of AVS per one standard deviation increase in the mDASH and mMED diet scores were respectively 1.02 (0.96 1.07) and 1.00 (0.95-1.06). CONCLUSION: This study found no evidence that diet plays a role in the development of AVS. PMID- 30416028 TI - High-sensitivity troponin T, NT-proBNP and glomerular filtration rate: A multimarker strategy for risk stratification in chronic heart failure. AB - BACKGROUND: In a recent individual patient data meta-analysis, high-sensitivity troponin T (hs-TnT) emerged as robust predictor of prognosis in stable chronic heart failure (HF). In the same population, we compared the relative predictive performances of hs-TnT, N-terminal fraction of pro-B-type natriuretic peptide (NT proBNP), hs-C-reactive protein (hs-CRP), and estimated glomerular filtration rate (eGFR) for prognosis. METHODS AND RESULTS: 9289 patients (66 +/- 12 years, 77% men, 85% LVEF <40%, 60% ischemic HF) were evaluated over a 2.4-year median follow up. Median eGFR was 58 mL/min/1.73 m2 (interquartile interval 46-70; n = 9220), hs-TnT 16 ng/L (8-20; n = 9289), NT-proBNP 1067 ng/L (433-2470; n = 8845), and hs CRP 3.3 mg/L (1.4-7.8; n = 7083). In a model including all 3 biomarkers, only hs TnT and NT-proBNP were independent predictors of all-cause and cardiovascular mortality and cardiovascular hospitalization. hs-TnT was a stronger predictor than NT-proBNP: for example, the risk for all-cause death increased by 54% per doubling of hs-TnT vs. 24% per doubling of NT-proBNP. eGFR showed independent prognostic value from both hs-TnT and NT-proBNP. The best hs-TnT and NT-proBNP cut-offs for the prediction of all-cause death increased progressively with declining renal function (eGFR >= 90: hs-TnT 13 ng/L and NT-proBNP 825 ng/L; eGFR < 30: hs-TnT 40 ng/L and NT-proBNP 4608 ng/L). Patient categorization according to these cut-offs effectively stratified patient prognosis across all eGFR classes. CONCLUSIONS: hs-TnT conveys independent prognostic information from NT proBNP, while hs-CRP does not. Concomitant assessment of eGFR may further refine risk stratification. Patient classification according to hs-TnT and NT-proBNP cut offs specific for the eGFR classes holds prognostic significance. PMID- 30416030 TI - Left bundle branch block in dilated cardiomyopathy with intermediate left ventricular dysfunction: Clinical phenotyping and outcome correlates. AB - BACKGROUND: Left bundle branch block (LBBB) negatively affects prognosis in heart failure patients with a reduced left ventricular ejection fraction (LVEF). Less is known about the prognostic role of LBBB in dilated cardiomyopathy (DCM) with intermediate LVEF (between 36% and 50%). We sought to assess the role of LBBB in optimally treated DCM patients with mildly to moderately reduced LVEF and to determine the possible variables associated with subsequent LVEF reduction. METHODS: We retrospectively analyzed DCM patients with LVEF >35% after 3-to-9 months of optimal medical treatment (OMT) consecutively evaluated from 1990 to 2010. All-cause mortality or heart transplantation (D/HTx) and sudden cardiac death (SCD) or major ventricular arrhythmias (MVA) were considered as outcome measures. LVEF deterioration during follow-up was also considered. RESULTS: Among 280 (49%) patients that met the study criteria, 76 had LBBB (27%). During a mean follow-up of 151 months, the rates of D/HTx and SCD/MVA were similar between LBBB and not LBBB patients (p value = 0.52 and p = 0.39, respectively). Twenty-six out of 76 (34%) patients with LBBB experienced LVEF deterioration below 36%. The persistence of moderate-severe mitral regurgitation (MR), left atrial end systolic area index and LV end-diastolic volume index emerged as independent predictors of LVEF deterioration and were associated with an increased risk of D/HTx during follow-up. CONCLUSIONS: LBBB does not affect mortality in DCM patients with intermediate LVEF after OMT. However, among these patients those with persistent significant MR, left atrial and LV remodeling carries a higher risk of LVEF deterioration during follow-up. PMID- 30416031 TI - The Role of Intimate Partner Violence in Homicides of Children Aged 2-14 Years. AB - INTRODUCTION: Child victims physically harmed in intimate partner violence incidents are understudied. The U.S. National Violent Death Reporting System abstractors can identify intimate partner violence-related child homicides in part through descriptive narratives from coroner/medical examiner and law enforcement reports. This study characterizes these homicides and assesses how well the coded and narrative data within the National Violent Death Reporting System align in identifying intimate partner violence-related child homicides. METHODS: This study examines homicides of children ages 2-14 years from 16 states for 2005-2014. An existing variable purportedly indicates intimate partner violence-related child homicides where the perpetrator also kills or attempts to kill the intimate partner (Type 1) or intimate partner conflict (e.g., divorce, separation, custody) precedes the homicide (Type 2). The authors read all narratives in 2018 to assess whether the death was intimate partner violence related and compared this classification to that coded by the National Violent Death Reporting System abstractor. RESULTS: Of 1,386 child homicide victims, 144 (10.4%) were coded in the National Violent Death Reporting System as intimate partner violence-related. However, from the narratives, an additional 138 were classified as intimate partner violence-related, identifying a total of 280 (20.2%) victims. Of the 280 victims, 54.3% were killed in Type 1 incidents. Compared with other perpetrators of child homicides, intimate partner violence related perpetrators were more likely to be white, use a firearm, and die by suicide. Type 2 incidents were more likely than Type 1 to be homicide-suicides. CONCLUSIONS: The National Violent Death Reporting System currently understates intimate partner violence-related child homicide cases. Many cases involve immediate intimate partner conflict, suggesting the need for services to help people cope before conflicts lead to deadly incidents. Primary prevention of intimate partner violence may have survival benefits for children. PMID- 30416032 TI - Novel mechanism for estrogen receptor alpha modulation of murine lupus. AB - Female sex is a risk factor for lupus. Sex hormones, sex chromosomes and hormone receptors are implicated in the pathogenic pathways in lupus. Estrogen receptor alpha (ERalpha) knockout (KO) mice are used for defining hormone receptor effects in lupus. Prior studies of ERalpha KO in lupus have conflicting results, likely due to sex hormone levels, different lupus strains and different ERalpha KO constructs. Our objective was to compare a complete KO of ERalpha vs. the original functional KO of ERalpha (expressing a short ERalpha) on disease expression and immune phenotype, while controlling sex hormone levels. We studied female lupus prone NZM2410 WT and ERalpha mutant mice. All mice (n = 44) were ovariectomized (OVX) for hormonal control. Groups of each genotype were estrogen (E2)-repleted after OVX. We found that OVXed NZM mice expressing the truncated ERalpha (ERalpha short) had significantly reduced nephritis and prolonged survival compared to both wildtype and the complete ERalphaKO (ERalpha null) mice, but surprisingly only if E2-repleted. ERalpha null mice were not protected regardless of E2 status. We observed significant differences in splenic B cells and dendritic cells and a decrease in cDC2 (CD11b+CD8-) dendritic cells, without a concomitant decrease in cDC1 (CD11b-CD8a+) cells comparing ERalpha short to ERalpha null or WT mice. Our data support a protective role for the ERalpha short protein. ERalpha short is similar to an endogenously expressed ERalpha variant (ERalpha46). Modulating its expression/activity represents a potential approach for treating female-predominant autoimmune diseases. PMID- 30416033 TI - Shared gut, but distinct oral microbiota composition in primary Sjogren's syndrome and systemic lupus erythematosus. AB - OBJECTIVE: Alterations in the microbiota composition of the gastro-intestinal tract are suspected to be involved in the etiopathogenesis of two closely related systemic inflammatory autoimmune diseases: primary Sjogren's syndrome (pSS) and systemic lupus erythematosus (SLE). Our objective was to assess whether alterations in gut and oral microbiota compositions are specific for pSS and SLE. METHODS: 16S ribosomal RNA gene sequencing was performed on fecal samples from 39 pSS patients, 30 SLE patients and 965 individuals from the general population, as well as on buccal swab and oral washing samples from the same pSS and SLE patients. Alpha-diversity, beta-diversity and relative abundance of individual bacteria were used as outcome measures. Multivariate analyses were performed to test associations between individual bacteria and disease phenotype, taking age, sex, body-mass index, proton-pump inhibitor use and sequencing-depth into account as possible confounding factors. RESULTS: Fecal microbiota composition from pSS and SLE patients differed significantly from population controls, but not between pSS and SLE. pSS and SLE patients were characterized by lower bacterial richness, lower Firmicutes/Bacteroidetes ratio and higher relative abundance of Bacteroides species in fecal samples compared with population controls. Oral microbiota composition differed significantly between pSS patients and SLE patients, which could partially be explained by oral dryness in pSS patients. CONCLUSIONS: pSS and SLE patients share similar alterations in gut microbiota composition, distinguishing patients from individuals in the general population, while oral microbiota composition shows disease-specific differences between pSS and SLE patients. PMID- 30416034 TI - Early versus late alveolar bone grafting in unilateral cleft lip and palate: Dental arch relationships in pre-adolescent patients. AB - OBJECTIVE: To evaluate the dental arch relationship in preadolescent children with complete unilateral cleft lip and palate after early secondary alveolar bone grafting (E-ABG) by comparing to late bone grafting (L-ABG). MATERIAL AND METHODS: Two raters blindly assessed the dental arch relationship with the modified Huddart-Bodenham (HB) Index for 2 groups: E-ABG group (36 children, mean age 9.6 years) and L-ABG group (56 children, mean age 11.1 years). The groups differed with respect to age at which alveolar bone grafting was performed: between 1.4 and 4.1 years (mean 2.2 years, E-ABG group) and after 8 years (L-ABG group). T-test was run to compare scores between 2 groups. Regression analysis was carried out to evaluate gender, age at cleft repair, age at ABG, and age at assessment with the HB index. RESULTS: The overall HB scores were -6.77 and -4.25 in the E-ABG and L-ABG groups, respectively (p = 0.025). Regression analysis showed that only the age at cleft repair influenced the HB scores. CONCLUSION: ABG carried out between 2 and 4 years of age does not seem to negatively affect the dental arch relationship at the age of 10 years in comparison to L-ABG. PMID- 30416035 TI - The role of C-reactive protein and white blood cell count in the prediction of length of stay in hospital and severity of odontogenic abscess. AB - INTRODUCTION: Odontogenic infections and subsequent developing abscess remain to be a potentially life-threatening event, due to septicemia, airway compression and spreading into sensitive anatomic tissues. C-reactive proten (CRP) and white blood cell (WBC) count are routinely blood-measured indicators for inflammation. Are CRP-levels and WBC-count predictive factors of the developement of odontogenic abscess? METHODS: A 4-year retrospective study evaluated hospital records of 218 patients, diagnosed and inpatiently treated for acute odontogenic abscess. They received surgical incision, drainage and intravenous antibiotics. CRP-levels and WBC-counts were measured preoperativly. RESULTS: 218 subjects were enrolled in this study. Patients hospitalized 10 days or more showed significantly higher CRP-levels (p = < 0.001) and WBC-counts (p = 0.006) on admission day than patients with lower LOS. CRP-levels of patients with LOS from 7-9 days were significantly lower (p = 0.47) than in people hospitalized 10 days or more. Abscess focus in the mandible shows significantly higher WBC-counts (p = 0.014). Multiple space infections present a significantly higher CRP (p = 0.003) and WBC (p < 0.001) on admission day. DISCUSSION: According to the presented data, CRP-levels and WBC-count can be regarded as predictive factors for LOS (length of stay in hospital) in patients with long term hospitalization (CRP:7-9 days and > 10 days; WBC: > 10 days). Further WBC and CRP are suitable to predict multiple space infections and localisation of the abscess (WBC) in certain limits. CONCLUSION: In predicting the developement of odontogenic abscess, CRP is more capable in providing exact statements regarding the LOS. However, WBC-counts are more suitable in predicting multiple space infections and localization of infection. PMID- 30416036 TI - Excitability of the supplementary motor area in Parkinson's disease depends on subcortical damage. AB - BACKGROUND: Cortical dysfunctioning significantly contributes to the pathogenesis of motor symptoms in Parkinson's disease (PD). OBJECTIVE: We aimed at testing whether an acute levodopa administration has measurable and specific cortical effects possibly related to striatal dopaminergic deficit. METHODS: In thirteen PD patients, we measured the electroencephalographic responses to transcranial magnetic stimulation (TMS/EEG) of the supplementary motor area and superior parietal lobule (n = 8) before and after an acute intake of levodopa. We also performed a single-photon emission computed tomography and [123I]N-omega fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl)nortropane to identify the more affected and the less affected brain side in each patient, according to the dopaminergic innervation loss of the putamen. Cortical excitability changes before and after an acute intake of levodopa were computed and compared between the more and the less affected brain side at the single-patient as well as at the group level. RESULTS: We found that levodopa intake induces a significant increase (P < 0.01) of cortical excitability nearby the supplementary motor area in the more affected brain side, greater (P < 0.025) than in the less affected brain side. Notably, cortical excitability changes nearby the superior parietal lobule were not statistically significant. CONCLUSIONS: These results strengthen the idea that dysfunction of specific cortico-subcortical circuits may contribute to pathophysiology of PD symptoms. Most important, they support the use of navigated TMS/EEG as a non-invasive tool to better understand the pathophysiology of PD. PMID- 30416037 TI - Species-Specific Functional Regions of the Green Alga Gamete Fusion Protein HAP2 Revealed by Structural Studies. AB - The cellular fusion protein HAP2, which is structurally homologous to viral class II fusion proteins, drives gamete fusion across several eukaryotic kingdoms. Gamete fusion is a highly controlled process in eukaryotes, and is allowed only between same species gametes. In spite of a conserved architecture, HAP2 displays several species-specific functional regions that were not resolved in the available X-ray structure of the green alga Chlamydomonas reinhardtii HAP2 ectodomain. Here we present an X-ray structure resolving these regions, showing a target membrane interaction surface made by three amphipathic helices in a horseshoe-shaped arrangement. HAP2 from green algae also features additional species-specific motifs inserted in regions that in viral class II proteins are critical for the fusogenic conformational change. Such insertions include a cystine ladder-like module evocative of EGF-like motifs responsible for extracellular protein-protein interactions in animals, and a mucin-like region. These features suggest potential HAP2 interaction sites involved in gamete fusion control. PMID- 30416038 TI - Sampling Native-like Structures of RNA-Protein Complexes through Rosetta Folding and Docking. AB - RNA-protein complexes underlie numerous cellular processes including translation, splicing, and posttranscriptional regulation of gene expression. The structures of these complexes are crucial to their functions but often elude high-resolution structure determination. Computational methods are needed that can integrate low resolution data for RNA-protein complexes while modeling de novo the large conformational changes of RNA components upon complex formation. To address this challenge, we describe RNP-denovo, a Rosetta method to simultaneously fold-and dock RNA to a protein surface. On a benchmark set of diverse RNA-protein complexes not solvable with prior strategies, RNP-denovo consistently sampled native-like structures with better than nucleotide resolution. We revisited three past blind modeling challenges involving the spliceosome, telomerase, and a methyltransferase-ribosomal RNA complex in which previous methods gave poor results. When coupled with the same sparse FRET, crosslinking, and functional data used previously, RNP-denovo gave models with significantly improved accuracy. These results open a route to modeling global folds of RNA-protein complexes from low-resolution data. PMID- 30416039 TI - Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1. AB - Nuclear receptor-related 1 protein (Nurr1/NR4A2) is an orphan nuclear receptor (NR) that is considered to function without a canonical ligand-binding pocket (LBP). A crystal structure of the Nurr1 ligand-binding domain (LBD) revealed no physical space in the conserved region where other NRs with solvent accessible apo-protein LBPs bind synthetic and natural ligands. Using solution nuclear magnetic resonance spectroscopy, hydrogen/deuterium exchange mass spectrometry, and molecular dynamics simulations, we show that the putative canonical Nurr1 LBP is dynamic with high solvent accessibility, exchanges between two or more conformations on the microsecond-to-millisecond timescale, and can expand from the collapsed crystallized conformation to allow binding of unsaturated fatty acids. These findings should stimulate future studies to probe the ligandability and druggability of Nurr1 for both endogenous and synthetic ligands, which could lead to new therapeutics for Nurr1-related diseases, including Parkinson's disease and schizophrenia. PMID- 30416040 TI - Just the fax, please: Updating electronic/hybrid methods for surveying pharmacists. PMID- 30416042 TI - Birth HIV testing and paediatric treatment programmes. PMID- 30416041 TI - Claudin 7 as a possible novel molecular target for the treatment of pancreatic cancer. AB - BACKGROUND/OBJECTIVES: Pancreatic cancer consists of various subpopulations of cells, some of which have aggressive proliferative properties. The molecules responsible for the aggressive proliferation of pancreatic cancer may become molecular targets for the therapies against pancreatic cancer. METHODS: From a human pancreatic cancer cell line, MIA PaCa-2, MIA PaCa-2-A cells with an epithelial morphology and MIA PaCa-2-R cells with a non-epithelial morphology were clonogenically isolated by the limiting dilution method. Gene expression of these subpopulations was analyzed by DNA microarray. Gene knockdown was performed using siRNA. RESULTS: Although the MIA PaCa-2-A and MIA PaCa-2-R cells displayed the same DNA short tandem repeat (STR) pattern identical to that of the parental MIA PaCa-2 cells, the MIA PaCa-2-A cells were more proliferative than the MIA PaCa-2-R cells both in culture and in tumor xenografts generated in immunodeficient mice. Furthermore, the MIA PaCa-2-A cells were more resistant to gemcitabine than the MIA PaCa-2-R cells. DNA microarray analysis revealed a high expression of claudin (CLDN) 7 in the MIA PaCa-2-A cells, as opposed to a low expression in the MIA PaCa-2-R cells. The knockdown of CLDN7 in the MIA PaCa-2-A cells induced a marked inhibition of proliferation. The MIA PaCa-2-A cells in which CLDN7 was knocked down exhibited a decreased expression of phosphorylated extracellular signal-regulated kinase (p-Erk)1/2 and G1 cell cycle arrest. CONCLUSIONS: CLDN7 may be expressed in the rapidly proliferating and dominant cell population in human pancreatic cancer tissues and may be a novel molecular target for the treatment of pancreatic cancer. PMID- 30416043 TI - 12-month outcomes of HIV-infected infants identified at birth at one maternity site in Johannesburg, South Africa: an observational cohort study. AB - BACKGROUND: Initiation of antiretroviral therapy (ART) following diagnosis of HIV infection at birth is an emerging area of paediatric HIV care. We present outcomes of HIV-infected infants identified at birth at Rahima Moosa Mother and Child Hospital in Johannesburg, South Africa. METHODS: From September, 2013 (era 1), only high-risk HIV-exposed infants were offered diagnostic HIV PCR tests at birth. From June, 2014 (era 2), all HIV-exposed infants were offered laboratory based diagnostic PCR tests. From October, 2014 (era 3), point of care (POC) diagnostic PCR tests were also done if staff availability allowed. We describe time to ART initiation, mortality, retention in care, and viral suppression among the HIV-infected infants identified across these eras. FINDINGS: We tested 5449 HIV-exposed infants who were born between Sept 1, 2013, and June 30, 2016. 88 neonates with confirmed HIV infection were identified and included in the study, of which 86 (98%) started ART. Median age at ART initiation decreased from 9 days (IQR 6-25) in eras 1 and 2 to 2 days (1-8) in era 3. In era 3, more neonates who were co-tested with POC testing started ART within 48 h of birth (29 [83%] of 35; median 1 day [IQR 1-2]) than infants who were not co-tested (one [4%] of 29; median 6 days [5-10]). The probability of mortality by 12 months across the eras was 14% (95% CI 8-24) and did not differ by era. Of the 72 infants who survived and initiated ART at the site, 56 (78%) were retained at 12 months. Of the 56 infants retained in care, 40 (71%) had a viral load less than 400 copies per mL at 12 months, with no differences between eras (p=0.23). INTERPRETATION: HIV infected infants can be identified at birth and ART can be initiated within hours to days. Although most infants in our cohort started ART, mortality remained unacceptably high with suboptimal retention and viral suppression. Reducing mortality and improving retention and viral suppression remain urgent priorities. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institute of Allergy and Infectious Disease, National Institutes of Health, USAID/PEPfAR, and the South African National HIV Programme. PMID- 30416044 TI - Vulnerabilities of radiomic signature development: The need for safeguards. AB - PURPOSE: Refinement of radiomic results and methodologies is required to ensure progression of the field. In this work, we establish a set of safeguards designed to improve and support current radiomic methodologies through detailed analysis of a radiomic signature. METHODS: A radiomic model (MW2018) was fitted and externally validated using features extracted from previously reported lung and head and neck (H&N) cancer datasets using gross-tumour-volume contours, as well as from images with randomly permuted voxel index values; i.e. images without meaningful texture. To determine MW2018's added benefit, the prognostic accuracy of tumour volume alone was calculated as a baseline. RESULTS: MW2018 had an external validation concordance index (c-index) of 0.64. However, a similar performance was achieved using features extracted from images with randomized signal intensities (c-index = 0.64 and 0.60 for H&N and lung, respectively). Tumour volume had a c-index = 0.64 and correlated strongly with three of the four model features. It was determined that the signature was a surrogate for tumour volume and that intensity and texture values were not pertinent for prognostication. CONCLUSION: Our experiments reveal vulnerabilities in radiomic signature development processes and suggest safeguards that can be used to refine methodologies, and ensure productive radiomic development using objective and independent features. PMID- 30416046 TI - Doses of radiation to the pericardium, instead of heart, are significant for survival in patients with non-small cell lung cancer. AB - BACKGROUND AND PURPOSE: Higher cardiac dose was associated with worse overall survival in the RTOG0617 study. Pericardial effusion (PCE) is a common cardiac complication of thoracic radiation therapy (RT). We investigated whether doses of radiation to the heart and pericardium are associated with PCE and overall survival in patients treated with thoracic radiation for non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: A total of 94 patients with medically inoperable/unresectable NSCLC treated with definitive RT in prospective studies were reviewed for this secondary analysis. Heart and pericardium were contoured consistently according to the RTOG1106 Atlas, with the great vessels and thymus of the upper mediastinal structures included in the upper part of pericardium, only heart chambers included in the heart structure. Clinical factors and dose volume parameters associated with PCE or survival were identified via Cox proportional hazards modeling. The risk of PCE and death were mapped using DVH atlases. RESULTS: Median follow-up for surviving patients was 58 months. The overall rate of PCE was 40.4%. On multivariable analysis, dosimetric factors of heart and pericardium were significantly associated with the risk of PCE. Pericardial V30 and V55 were significantly correlated with overall survival, but presence of PCE and heart dosimetric factors were not. CONCLUSION: PCE was associated with both heart and pericardial doses. The significance of pericardial dosimetric parameters, but not heart chamber parameters, on survival suggests the potential significance of radiation damage to the cranial region of pericardium. PMID- 30416045 TI - High-dose-rate brachytherapy monotherapy versus low-dose-rate brachytherapy with or without external beam radiotherapy for clinically localized prostate cancer. AB - BACKGROUND: To compare the outcome of high-dose-rate interstitial brachytherapy (HDR-BT) monotherapy and low-dose-rate brachytherapy (LDR-BT) with or without external beam radiotherapy (EBRT) for localized prostate cancer. METHODS AND MATERIALS: We compared 352 patients treated with HDR-BT as monotherapy (median follow-up time 84 months, NCCN risk classification; low: intermediate: high = 28:145:179) and 486 patients with LDR-BT with or without EBRT (90 months, 194:254:38). HDR-BT treated advanced disease with more hormonal therapy than LDR BT. LDR-BT excluded patients with T3b-T4 tumor and initial PSA >50 ng/ml. Inverse probability of treatment weighting (IPTW) involving propensity scores was used to reduce background selection bias. RESULTS: The actuarial 5-year biochemical failure-free survival rates (bNED) were 92.9% and 95.6% (p = 0.25) in the HDR-BT and LDR-BT groups, respectively, and it was 100% and 97.3% (p = 0.99) in the low risk, 95.6% and 94.3% (p = 0.19) in the intermediate, 89.6% and 94.9% (p = 0.26) in the high-risk groups, and 93.1% and 94.9% (p = 0.98) in selected high-risk group excluding T3b-4 and initial PSA >=50. IPTW correction also indicated no difference in bNED between LDR-BT and HDR-BT groups. LDR-BT showed a higher incidence of genitourinary (GU) toxicity grade >=2 than that of HDR-BT in the acute phase and grade 1 toxicity in late phase. Acute GU toxicity grade >=1 predicted late GU toxicity grade >=2. External beam radiotherapy plus LDR-BT elevated GI toxicity than LDR-BT only group. Accumulated incidence of late grade >=2 GU and GU toxicity was equivalent between HDR-BT and LDR-BT. No grade 4 or 5 toxicities were detected in either modality. CONCLUSION: HDR-BT monotherapy showed an equivalent outcome to that of LDR-BT with or without EBRT for low-, intermediate- and selected high-risk patients. LDR-BT showed equivalent incidence of grade >=2 late GI and GU toxicities and higher grade >=2 acute GU toxicity as that of HDR-BT as a monotherapy. PMID- 30416048 TI - The Ubiquitin-Proteasome System Is Indispensable for the Maintenance of Muscle Stem Cells. AB - Adult muscle stem cells (satellite cells) are required for adult skeletal muscle regeneration. A proper balance between quiescence, proliferation, and differentiation is essential for the maintenance of the satellite cell pool and their regenerative function. Although the ubiquitin-proteasome is required for most protein degradation in mammalian cells, how its dysfunction affects tissue stem cells remains unclear. Here, we investigated the function of the proteasome in satellite cells using mice lacking the crucial proteasomal component, Rpt3. Ablation of Rpt3 in satellite cells decreased proteasome activity. Proteasome dysfunction in Rpt3-deficient satellite cells impaired their ability to proliferate, survive and differentiate, resulting in defective muscle regeneration. We found that inactivation of proteasomal activity induced proliferation defects and apoptosis in satellite cells. Mechanistically, insufficient proteasomal activity upregulated the p53 pathway, which caused cell cycle arrest. Our findings delineate a critical function of the proteasome system in maintaining satellite cells in adult muscle. PMID- 30416047 TI - CIBERSAM: Ten years of collaborative translational research in mental disorders. PMID- 30416049 TI - Patient-Specific iPSC-Derived Endothelial Cells Provide Long-Term Phenotypic Correction of Hemophilia A. AB - We generated patient-specific disease-free induced pluripotent stem cells (iPSCs) from peripheral blood CD34+ cells and differentiated them into functional endothelial cells (ECs) secreting factor VIII (FVIII) for gene and cell therapy approaches to cure hemophilia A (HA), an X-linked bleeding disorder caused by F8 mutations. iPSCs were transduced with a lentiviral vector carrying FVIII transgene driven by an endothelial-specific promoter (VEC) and differentiated into bona fide ECs using an optimized protocol. FVIII-expressing ECs were intraportally transplanted in monocrotaline-conditioned non-obese diabetic (NOD) severe combined immune-deficient (scid)-IL2rgamma null HA mice generating a chimeric liver with functional human ECs. Transplanted cells engrafted and proliferated in the liver along sinusoids, in the long term showed stable therapeutic FVIII activity (6%). These results demonstrate that the hemophilic phenotype can be rescued by transplantation of ECs derived from HA FVIII corrected iPSCs, confirming the feasibility of cell-reprogramming strategy in patient-derived cells as an approach for HA gene and cell therapy. PMID- 30416050 TI - Excitable Adult-Generated GABAergic Neurons Acquire Functional Innervation in the Cortex after Stroke. AB - Ischemic stroke enhances the proliferation of adult-generated precursor cells that ectopically migrate toward the infarct. Studies have correlated precursor cell proliferation and subsequent adult neurogenesis with enhanced stroke recovery, yet it remains unclear whether stroke can generate new neurons capable of functional integration into the injured cortex. Here, using single and bitransgenic reporter mice, we identify spatial and temporal features of a multilineage cellular response to focal ischemia. We reveal that a small population of stroke-induced immature neurons accumulate within the peri-infarct region of the adult sensorimotor cortex, exhibit voltage-dependent conductances, fire action potentials, express GABAergic markers, and receive sparse GABAergic synaptic inputs. Collectively, these findings reveal that GABAergic neurons arising from the lateral ventricle have the capacity to integrate into the stroke injured cortex, although their limited number and exiguous synaptic integration may limit their ability to participate in stroke recovery. PMID- 30416052 TI - Characterization and expression profiles of muscle transcriptome in Schizothoracine fish, Schizothorax prenanti. AB - Schizothorax prenanti is a cold-water fish species with great economic importance in aquaculture in Western China, and the underlying mechanisms of muscle development and growth in S. prenanti remain to be elucidated. In this study, deep RNA sequencing was performed to provide an in-depth view of the transcriptome of skeletal muscle of S. prenanti with the specific objective to identify expressed genes in the skeletal muscle of S. prenanti at 30 days post hatching (S01), 1 year (S02), and 3 years (S03). De novo assembly of high-quality reads generated 132,784 transcripts with an average length of 1282 bp and 67,596 unigenes with an average length of 1559 bp. 2445 unigenes were differentially expressed with 1483 up-regulated and 962 down-regulated in the skeletal muscle of S. prenanti at S01 and S02 stages, and 1936 unigenes were significantly impacted at S02 and S03 stages with 1153 increased and 783 decreased. GO analysis showed that the differentially expressed genes are involved in various biological processes with dominance by cell & cell part, binding & catalytic activity, and cellular process & metabolic process. KEGG enrichment suggested that there are considerable differences in the physiological processes at different stages of muscle development and growth of S. prenanti. PPAR signaling pathway, cardiac muscle contraction, fatty acid metabolism, tight junction, and focal adhesion were the top pathways enriched in comparison between S01 and S02 stages. Whereas significant enrichment of the TCA cycle, fatty acid metabolism, fatty acid elongation in mitochondria, valine, leucine and isoleucine degradation, porphyrin and chlorophyll metabolism, and propanoate metabolism pathway was found in differentially expressed genes identified between S02 and S03 stages. This study provides not only an overall insight into the global gene expression landscape in the skeletal muscle of S. prenanti, but also candidate genes or markers that can be used for further investigations of the underlying mechanisms of skeletal muscle development and growth of S. prenanti. PMID- 30416051 TI - Atrial-like Engineered Heart Tissue: An In Vitro Model of the Human Atrium. AB - Cardiomyocytes (CMs) generated from human induced pluripotent stem cells (hiPSCs) are under investigation for their suitability as human models in preclinical drug development. Antiarrhythmic drug development focuses on atrial biology for the treatment of atrial fibrillation. Here we used recent retinoic acid-based protocols to generate atrial CMs from hiPSCs and establish right atrial engineered heart tissue (RA-EHT) as a 3D model of human atrium. EHT from standard protocol-derived hiPSC-CMs (Ctrl-EHT) and intact human muscle strips served as comparators. RA-EHT exhibited higher mRNA and protein concentrations of atrial selective markers, faster contraction kinetics, lower force generation, shorter action potential duration, and higher repolarization fraction than Ctrl-EHTs. In addition, RA-EHTs but not Ctrl-EHTs responded to pharmacological manipulation of atrial-selective potassium currents. RA- and Ctrl-EHTs' behavior reflected differences between human atrial and ventricular muscle preparations. Taken together, RA-EHT is a model of human atrium that may be useful in preclinical drug screening. PMID- 30416053 TI - Bayesian statistical methods in genetic association studies: Empirical examination of statistically non-significant Genome Wide Association Study (GWAS) meta-analyses in cancers: A systematic review. AB - A Bayesian statistical method was developed to assess the noteworthiness of a single nucleotide polymorphism (SNP)-phenotype association that shows statistical significance in various observational studies, but it has seldom been applied to GWAS meta-analyses in cancers. Data (i.e. allelic frequency, odds ratio, 95% confidence interval, etc.) on various SNP-cancer associations were extracted from meta-analysis of GWAS and the National Human Genome Research Institute (NHGRI) Catalog of Published GWAS and were used to compute the false positive report probability (FPRP) and Bayesian false discovery probability (BFDP) to evaluate the noteworthiness of SNP-cancer associations. Independent paired t-tests showed a direct relationship between SNP-cancer P-values and both FPRP and BFDP estimates. However, a discrepancy in the number of noteworthy associations between P-value comparison and either FPRP or BFDP was found using data extracted from meta-analyses of GWAS and the GWAS Catalog. Most P-values of associations with nonsignificant P-values but with noteworthy FPRP and BFDP estimates were within the range of 10-6 to 5 * 10-8. A poorly selected genome-wide significance threshold and inclusion of a nonsignificant SNP-phenotype association into the noteworthy test can, with either noteworthy FPRP or BFDP computation, give a false impression of noteworthiness for a nonsignificant association. PMID- 30416054 TI - Safety and pharmacokinetics of Alpha-1 MP (Prolastin(r)-C) in Japanese patients with alpha1-antitrypsin (AAT) deficiency. AB - BACKGROUND: Alpha1-Proteinase Inhibitor, Modified Process (Alpha-1 MP) is used for augmentation therapy in alpha1-antitrypsin deficiency (AATD), an extremely rare disease in Japan. Weekly doses of 60 mg/kg Alpha-1 MP have been shown to be safe and well tolerated in non-Japanese subjects, but the safety and pharmacokinetics (PK) have not been evaluated in Japanese subjects. The objectives of this study were to evaluate the safety and PK of 60 mg/kg Alpha-1 MP administered by weekly IV infusions over 8 weeks in Japanese subjects with AATD. METHODS: This was a multicenter, open-label trial in Japanese adults aged >=20 years with AATD. Samples for evaluation of serum alpha1-PI concentration and PK parameters were collected at 10 time points until the seventh day after the last dose at Week 8: immediately before dosing, immediately after dosing (time 0), and 0.25, 2, 4, 8, 24, 48, 120, and 168 hours after dosing. RESULTS: Four subjects were analyzed. The median tmax was 0.534 h. Mean +/- SD values for t1/2, Cmax, and AUC0-7days were 150.4 +/- 36.18 h, 174.2 +/- 30.51 mg/dL, and 14,913.2 +/- 1633.45 mg*h/dL, respectively. Mean trough concentration at week 8 was 55.4 +/- 7.23 mg/dL. Alpha-1 MP therapy was safe, with no serious adverse events or deaths reported. Two treatment-emergent adverse events of fatigue in one subject were considered to be possibly related. CONCLUSIONS: The PK and safety of Alpha-1 MP in Japanese subjects with AATD were consistent with the Alpha-1 MP profile in non-Japanese subjects (ClinicalTrials.gov: NCT02870309; JAPIC CTI: JapicCTI 163160). PMID- 30416056 TI - A Climate-Driven Functional Inversion of Connected Marine Ecosystems. AB - Sustainably managing natural resources under climate change requires understanding how species distribution shifts can impact ecosystem structure and functioning. While numerous studies have documented changes in species' distributions and abundances in response to warming [1, 2], the consequences for the functional structure of ecosystems (i.e., composition of species' functional traits) have received less attention. Here, using thirty years of fish monitoring, we show that two connected North Atlantic ecosystems (E. English Channel and S. North Sea) underwent a rapid shift in functional structure triggered by a climate oscillation to a prevailing warm-phase in the late-1990s. Using time-lag-based causality analyses, we found that rapid warming drove pelagic fishes with r-selected life history traits (e.g., low age and size at maturity, small offspring, low trophic level) to shift abruptly northward from one ecosystem to the other, causing an inversion in functional structure between the two connected ecosystems. While we observed only a one-year time-lag between the climate oscillation and the functional shift, indicating rapid responses to a changing environment, historical overfishing likely rendered these ecosystems susceptible to climatic stress [3], and declining fishing in the North Sea may have exacerbated the shift. This shift likely had major consequences for ecosystem functioning due to potential changes in biomass turnover, nutrient cycling, and benthic-pelagic coupling [4-6]. Under ongoing warming, climate oscillations and extreme warming events may increase in frequency and severity [7, 8], which could trigger functional shifts with profound consequences for ecosystem functioning and services. PMID- 30416057 TI - Sleep Counteracts Aging Phenotypes to Survive Starvation-Induced Developmental Arrest in C. elegans. AB - Sleep is ancient and fulfills higher brain functions as well as basic vital processes. Little is known about how sleep emerged in evolution and what essential functions it was selected for. Here, we investigated sleep in Caenorhabditis elegans across developmental stages and physiological conditions to find out when and how sleep in a simple animal becomes essential for survival. We found that sleep in worms occurs during most stages and physiological conditions and is typically induced by the sleep-active RIS neuron. Food quality and availability determine sleep amount. Extended starvation, which induces developmental arrest in larvae, presents a major sleep trigger. Conserved nutrient-sensing regulators of longevity and developmental arrest, AMP-activated kinase and FoxO, act in parallel to induce sleep during extended food deprivation. These metabolic factors can act in multiple tissues to signal starvation to RIS. Although sleep does not appear to be essential for a normal adult lifespan, it is crucial for survival of starvation-induced developmental arrest in larvae. Rather than merely saving energy for later use, sleep counteracts the progression of aging phenotypes, perhaps by allocating resources. Thus, sleep presents a protective anti-aging program that is induced by nutrient sensing longevity pathways to survive starvation-induced developmental arrest. All organisms are threatened with the possibility of experienced famine in their life, which suggests that the molecular coupling of starvation, development, aging, and sleep was selected for early in the evolution of nervous systems and may be conserved in other species, including humans. PMID- 30416055 TI - The Data Registry of the European Competence Network on Mastocytosis (ECNM): Set Up, Projects, and Perspectives. AB - Mastocytosis is a unique hematologic neoplasm with complex biology and pathology and a variable clinical course. The disease can essentially be divided into cutaneous mastocytosis (CM) and systemic mastocytosis (SM). In adults, SM is diagnosed in most cases and manifests as either indolent or advanced disease. Patients with advanced SM have an unfavorable prognosis with reduced survival. However, so far, little is known about the prevalence of various categories of SM and about prognostic factors. In an attempt to learn more about the behavior and evolution of various forms of CM and SM, the European Competence Network on Mastocytosis (ECNM) initiated a mastocytosis registry in 2012. In this article, the set up and start phase of this registry are described. Until 2018, more than 3000 patients from 12 countries and 25 centers have been enrolled. In a majority of all patients, robust follow-up data and relevant clinical end points are available. Using this data set, a series of registry projects have been launched, with the aim to validate previously identified diagnostic and prognostic variables and to identify new disease-related and patient-related parameters in various forms of mastocytosis. Moreover, the core data set of the registry will be useful to establish multiparametric scoring systems through which prognostication and individualized management of patients with mastocytosis should improve in the foreseeable future. PMID- 30416058 TI - Worldwide Occurrence and Activity of the Reef-Building Coral Symbiont Symbiodinium in the Open Ocean. AB - The dinoflagellate microalga Symbiodinium sustains coral reefs, one of the most diverse ecosystems of the biosphere, through mutualistic endosymbioses with a wide diversity of benthic hosts [1]. Despite its ecological and economic importance, the presence of Symbiodinium in open oceanic waters remains unknown, which represents a significant knowledge gap to fully understand the eco evolutionary trajectory and resilience of endangered Symbiodinium-based symbioses. Here, we document the existence of Symbiodinium (i.e., now the family Symbiodiniaceae [2]) in tropical- and temperate-surface oceans using DNA and RNA metabarcoding of size-fractionated plankton samples collected at 109 stations across the globe. Symbiodinium from clades A and C were, by far, the most prevalent and widely distributed lineages (representing 0.1% of phytoplankton reads), while other lineages (clades B, D, E, F, and G) were present but rare. Concurrent metatranscriptomics analyses using the Tara Oceans gene catalog [3] revealed that Symbiodinium clades A and C were transcriptionally active in the open ocean and expressed core metabolic pathways (e.g., photosynthesis, carbon fixation, glycolysis, and ammonium uptake). Metabarcodes and expressed genes of clades A and C were detected in small and large plankton size fractions, suggesting the existence of a free-living population and a symbiotic lifestyle within planktonic hosts, respectively. However, high-resolution genetic markers and microscopy are required to confirm the life history of oceanic Symbiodinium. Overall, the previously unknown, metabolically active presence of Symbiodinium in oceanic waters opens up new avenues for investigating the potential of this oceanic reservoir to repopulate coral reefs following stress-induced bleaching. PMID- 30416059 TI - Callose-Regulated Symplastic Communication Coordinates Symbiotic Root Nodule Development. AB - The formation of nitrogen-fixing nodules in legumes involves the initiation of synchronized programs in the root epidermis and cortex to allow rhizobial infection and nodule development. In this study, we provide evidence that symplastic communication, regulated by callose turnover at plasmodesmata (PD), is important for coordinating nodule development and infection in Medicago truncatula. Here, we show that rhizobia promote a reduction in callose levels in inner tissues where nodules initiate. This downregulation coincides with the localized expression of M. truncatula beta-1,3-glucanase 2 (MtBG2), encoding a novel PD-associated callose-degrading enzyme. Spatiotemporal analyses revealed that MtBG2 expression expands from dividing nodule initials to rhizobia-colonized cortical and epidermal tissues. As shown by the transport of fluorescent molecules in vivo, symplastic-connected domains are created in rhizobia-colonized tissues and enhanced in roots constitutively expressing MtBG2. MtBG2 overexpressing roots additionally displayed reduced levels of PD-associated callose. Together, these findings suggest an active role for MtBG2 in callose degradation and in the formation of symplastic domains during sequential nodule developmental stages. Interfering with symplastic connectivity led to drastic nodulation phenotypes. Roots ectopically expressing beta-1,3-glucanases (including MtBG2) exhibited increased nodule number, and those expressing MtBG2 RNAi constructs or a hyperactive callose synthase (under symbiotic promoters) showed defective nodulation phenotypes. Obstructing symplastic connectivity appears to block a signaling pathway required for the expression of NODULE INCEPTION (NIN) and its target NUCLEAR FACTOR-YA1 (NF-YA1) in the cortex. We conclude that symplastic intercellular communication is proactively enhanced by rhizobia, and this is necessary for appropriate coordination of bacterial infection and nodule development. PMID- 30416060 TI - An Evolutionarily Conserved Abscisic Acid Signaling Pathway Regulates Dormancy in the Liverwort Marchantia polymorpha. AB - Dormancy is a key process allowing land plants to adapt to changing conditions in the terrestrial habitat, allowing the cessation of growth in response to environmental or physiological cues, entrance into a temporary quiescent state, and subsequent reactivation of growth in more favorable environmental conditions [1-3]. Dormancy may be induced seasonally, sporadically (e.g., in response to drought), or developmentally (e.g., seeds and apical dominance). Asexual propagules, known as gemmae, derived via clonal reproduction in bryophytes, are often dormant until displaced from the parent plant. In the liverwort Marchantia polymorpha, gemmae are produced within specialized receptacles, gemma cups, located on the dorsal side of the vegetative thallus [4]. Mature gemmae are detached from the parent plant but may remain in the cup, with gemma growth suppressed as long as the gemmae remain in the gemma cup and the parental plant is alive [5]. Following dispersal of gemmae from gemma cups by rain, the gemmae germinate in the presence of light and moisture, producing clonal offspring [6]. In land plants, the plant hormone abscisic acid (ABA) regulates many aspects of dormancy and water balance [7]. Here, we demonstrate that ABA plays a central role in the control of gemma dormancy as transgenic M. polymorpha gemmae with reduced sensitivity to ABA fail to establish and/or maintain dormancy. Thus, the common ancestor of land plants used the ABA signaling module to regulate germination of progeny in response to environmental cues, with both gemmae and seeds being derived structures co-opting an ancestral response system. PMID- 30416061 TI - Electric-Color Sensing in Weakly Electric Fish Suggests Color Perception as a Sensory Concept beyond Vision. AB - Many sighted animals use color as a salient and reliable cue [1] to identify conspecifics [2-4], predators, or food [5-7]. Similarly, nocturnal, weakly electric fish Gnathonemus petersii might rely on "electric colors" [8] for unambiguous, critical object recognitions. These fish identify nearby targets by emitting electric signals and by sensing the object-evoked signal modulations in amplitude and waveform with two types of epidermal electroreceptors (active electrolocation) [9-12]. Electrical capacitive objects (animals, plants) modulate both parameters; resistive targets (e.g., rocks) modulate only the signal's amplitude [11, 12]. Ambiguities of electrosensory inputs arise when object size, distance, or position vary. While previous reports suggest electrosensory disambiguations when both modulations are combined as electric colors [8, 13, 14], this concept has never been demonstrated in a natural, behaviorally relevant context. Here, we assessed electric-color perception (1) by recording object evoked signal modulations and (2) by testing the fishes' behavioral responses to these objects during foraging. We found that modulations caused by aquatic animals or plants provided electric colors when combined as a ratio. Individual electric colors designated crucial targets (electric fish, prey insect larvae, or others) irrespective of their size, distance, or position. In behavioral tests, electrolocating fish reliably identified prey insect larvae of varying sizes from different distances and did not differentiate between artificial prey items generating similar electric colors. Our results indicate a color-like perceptual cue during active electrolocation, the computation [15], reliability, and use of which resemble those of color in vision. This suggests "color" perception as a sensory concept beyond vision and passive sensing. PMID- 30416062 TI - The Taurine Transporter Eaat2 Functions in Ensheathing Glia to Modulate Sleep and Metabolic Rate. AB - Sleep is critical for many aspects of brain function and is accompanied by brain wide changes in the physiology of neurons and synapses [1, 2]. Growing evidence suggests that glial cells contribute to diverse aspects of sleep regulation, including neuronal and metabolic homeostasis [3-5], although the molecular basis for this remains poorly understood. The fruit fly, Drosophila melanogaster, displays all the behavioral and physiological characteristics of sleep [1, 2], and genetic screening in flies has identified both conserved and novel regulators of sleep and wakefulness [2, 6, 7]. With this approach, we identified Excitatory amino acid transporter 2 (Eaat2) and found that its loss from glia, but not neurons, increases sleep. We show that Eaat2 is expressed in ensheathing glia, where Eaat2 functions during adulthood to regulate sleep. Increased sleep in Eaat2-deficient flies is accompanied by reduction of metabolic rate during sleep bouts, an indicator of deeper sleep intensity. Eaat2 is a member of the conserved EAAT family of membrane transport proteins [8], raising the possibility that it affects sleep by controlling the movement of ions and neuroactive chemical messengers to and from ensheathing glia. In vitro, Eaat2 is a transporter of taurine [9], which promotes sleep when fed to flies [10]. We find that the acute effect of taurine on sleep is abolished in Eaat2 mutant flies. Together, these findings reveal a wake-promoting role for Eaat2 in ensheathing glia through a taurine-dependent mechanism. PMID- 30416063 TI - Vocal Turn-Taking in Meerkat Group Calling Sessions. AB - Coordination is a fundamental aspect of social living, underlying processes ranging from the maintenance of group cohesion to the avoidance of competition. Coordination can manifest as synchronization, where individuals perform the same action at the same time but can also take the form of anti-synchronization or turn-taking. Turn-taking has mainly been studied in the context of the development of language [1] due to the fact that it is a universal feature in all languages and has been found to appear early in infancy [2, 3]. Recently, turn taking has received attention in animal communication research [4-7] as a potential foundation on which social communication was formed [1, 3]. In this study, we describe turn-taking in group-wide vocal interactions of meerkats (Suricata suricatta) during low-conflict sunning behavior, which is accompanied by the production of specific "sunning calls." We show that sunning-call production is socially stimulated and that at the group level, meerkats avoid overlap, thus fulfilling a key principle of turn-taking [8]. Through observational data and playback experiments, we show that these group-level patterns arise from two individual-level rules: call inhibition over short timescales, which prevents mutual interference, and call excitation over longer timescales, which stimulates further group calling. These simple rules suggest that hierarchy formation and turn allocation are not required for achieving group wide coordination of communication. We also suggest that the potential bonding function of turn-taking shown in humans might have similar effects in animal interactions. VIDEO ABSTRACT. PMID- 30416064 TI - Human Resting Energy Expenditure Varies with Circadian Phase. AB - There is emerging evidence that circadian misalignment may alter energy expenditure, leading to obesity risk among those with irregular schedules [1-5]. It has been reported that energy expenditure is affected by the timing of sleep, exercise, and meals [6]. However, it is unclear whether the circadian system also modulates energy expenditure, independent of behavioral state and food intake. Here, we used a forced desynchrony protocol to examine whether fasted resting energy expenditure (REE) varies with circadian phase in seven participants. This protocol allowed us to uncouple sleep-wake and activity-related effects from the endogenous circadian rhythm, demonstrating that REE varies by circadian phase. REE is lowest at circadian phase ~0 degrees , corresponding to the endogenous core body temperature (CBT) nadir in the late biological night, and highest at circadian phase ~180 degrees in the biological afternoon and evening. Furthermore, we found that respiratory quotient (RQ), reflecting macronutrient utilization, also varies by circadian phase. RQ is lowest at circadian phase ~240 degrees and highest at circadian phase ~60 degrees , which corresponds to biological morning. This is the first characterization of a circadian profile in fasted resting energy expenditure and fasted respiratory quotient (with rhythmic profiles in both carbohydrate and lipid oxidation), decoupled from effects of activity, sleep-wake cycle, and diet in humans. The rhythm in energy expenditure and macronutrient metabolism may contribute to greater weight gain in shift workers and others with irregular schedules. PMID- 30416065 TI - Five year experience of gallbladder polyp surveillance and cost effective analysis against new European consensus guidelines. AB - BACKGROUND: Gallbladder polyp (GBP) surveillance seeks to identify early neoplasms, but practice varies amongst surgical units. Recent European consensus guidelines have recommended an evidence-based GBP surveillance strategy. In a tertiary centre Hepato-Pancreato-Biliary unit we examine GBP surveillance, malignant yield, and assess cost-effectiveness of the new European consensus guidelines. METHODS: Respective data were collected from all patients with ultrasonography-detected GBPs between January 2008 and January 2013. RESULTS: 558 patients had GBPs detected on ultrasonography. Following initial ultrasonography, 304 (54.5%) had further ultrasonography surveillance of which 168 were in a formal GBP surveillance programme. Pre-malignant/malignant pathology yield was 1.97% with an annual detection rate of 12.0 cases per 1000 GBPs surveyed. Cost effectiveness analysis of European consensus guidelines calculated annual savings of L209 163 per 1000 GBPs surveyed. Compliance with these guidelines would result in an additional 12.5% of patients under surveillance requiring cholecystectomy. CONCLUSION: GBP surveillance uptake was suboptimal at 32.8%. The incidence of pre malignant/malignant lesions in GBPs emphasises the importance of surveillance for early detection and management with a view to avoiding the poor outcomes associated with more advanced gallbladder cancer. Adherence to the new European consensus guidelines would be clinically cost-effective with significant potential savings demonstrated in this study. PMID- 30416066 TI - Evaluation of a pharmacist-physician covisit model in a family medicine practice. AB - OBJECTIVES: To describe the financial implications, efficiency, and patient access to care with the use of a pharmacist-physician covisit model in a primary care practice. SETTING: A rural satellite practice of a large, teaching, multidisciplinary, family medicine organization. PRACTICE DESCRIPTION: Mountain Area Health Education Center (MAHEC) is a large, multisite, family medicine teaching practice. Our site is a rural practice of MAHEC that serves western North Carolina. PRACTICE INNOVATION: Pharmacist-physician covisit model. EVALUATION: Fourteen half-days of the covisit model from June 1, 2016, to January 31, 2017, were evaluated. Change in estimated clinic revenue was assessed for the physician only, separate pharmacist and physician visits, and the covisit model. Number and types of visits billed before and after implementation of the covisits were used to evaluate efficiency, and number of available appointments was used to evaluate patient access to care. RESULTS: Compared with physician billing alone, covisits generated an additional $4924.41 in 14 half-days or $158,291.04 over 1 year. Compared with separate visits, the covisit model increased estimated clinic revenue by $2757.89 over the 14 half-days and $88,646.47 over 1 year. During the pilot period of the covisit model, the pharmacist and physician combined billed a total of 189 visits, compared with 164 visits on matched days with separate visits. With covisits, more high-complexity codes and initial Medicare Annual Wellness Visits were billed. The physician was able to see an additional 1.3 patients per half-day in the covisit model compared with separate visits, and there was an average of 3.2 open physician appointments per half-day with covisits compared with 1.4 with separate visits. CONCLUSION: Compared with both the physician-only and the separate-visit models, the covisit model is projected to substantially increase clinic revenue. In this model, more patients can be seen, higher-complexity visits are billed, and there are more available appointments. PMID- 30416067 TI - Linking the patient-centered medical home to community pharmacy via an innovative pharmacist care model. AB - OBJECTIVES: To develop and pilot test a model that extends pharmacists' direct patient care from the patient-centered medical home (PCMH) to the community pharmacy. SETTING: Two Michigan Medicine PCMH clinics and 2 CVS Pharmacy sites in Ann Arbor, MI. PRACTICE DESCRIPTION: In the PCMH clinics, pharmacists have provided patient care using collaborative practice agreements for diabetes, hypertension, and hyperlipidemia for more than 5 years. PRACTICE INNOVATION: Legal agreements were developed for sharing data and for accessing the Michigan Medicine Electronic Medical Record (EMR) in the CVS pharmacies. An immersion training model was used to train 2 community pharmacists to provide direct patient care and change medications to improve disease control. Then these community pharmacists provided disease management and comprehensive medication reviews (CMRs) in either the PCMH clinic or in CVS pharmacies. MAIN OUTCOME MEASURES: Glycosylated hemoglobin (A1C <= 9% and < 7%) and blood pressure (BP < 140/90) were compared for patients seen by PCMH pharmacists, patients seen by community pharmacists, and a propensity score-generated control group. Surveys were used to assess patient satisfaction. RESULTS: Of 503 shared patients, 200 received disease management and 113 received a CMR from the community pharmacists. Lack of efficacy was the most common reason for medication changes in diabetes (n = 136) and hypertension (n = 188). For CMR, optimizing the dosage regimen was the most common intervention. For the community pharmacist group, the odds of patients having an A1C <= 9% increased by 8% in each time period, whereas the odds decreased by 16% for the control group (odds ratio 1.29; P = 0.0028). No statistically significant differences were seen in the outcomes for patients seen by PCMH versus community pharmacists. Most patients (90%) rated the care as excellent. CONCLUSION: Direct patient care provided by community pharmacists, either in PCMH clinics or CVS pharmacies, was consistent with care provided by PCMH pharmacists. Patients were highly satisfied with the services provided. PMID- 30416068 TI - Warnings for drug-drug interactions in consumer medication information provided by community pharmacies. AB - OBJECTIVES: In 2006, the U.S. Food and Drug Administration (FDA) issued a draft guidance for pharmacies to provide consumer medication information (CMI) to patients receiving prescription medications. The objective of this study was to evaluate CMI leaflets provided by community pharmacies for accuracy and completeness regarding drug-drug interactions (DDIs). METHODS: CMI leaflets were obtained for 3 commonly prescribed medications (azithromycin, ciprofloxacin, and simvastatin) from 14 community pharmacies that are part of 6 chain organizations that operate in southern Arizona. Three to 4 salient interacting medications for each leaflet medication were identified with the use of 2 well recognized drug compendia. The content of the DDI information in the leaflets was evaluated for completeness. The font size and reading level of each leaflet were assessed as well. RESULTS: The CMI provided by 14 pharmacies appeared to be produced by 2 information vendors, Wolters Kluwer and First Databank. This was evident based on the identical wording and attribution (e.g., copyright statements) on the leaflets. The CMI from First Databank mentioned 5 of the 11 previously identified interactions with the target medications, although 1 chain in this group chose not to print the DDI section at all and as a result scored 0. The CMI developed by Wolters Kluwer mentioned only 2 of the 11 identified DDIs. The average reading grade level for First Databank leaflets was 10.6 (SD 2.87), and the reading level for the CMI from Wolters Kluwer was 5.0 (SD 1.02). The font sizes varied from 8 to 12 points; FDA recommends that the information be printed in 12-point size or larger. CONCLUSION: Community pharmacies appear to be distributing CMI leaflets with limited warnings about serious and well known DDIs. The results of this study suggest that consumers are not being informed through the CMI about important known DDIs. PMID- 30416069 TI - Modeling specialty medicine access: Understanding key health system processes and players. AB - OBJECTIVES: To map the specialty medicine process from prescription writing to the patient obtaining medication, identify perceived barriers to access, and highlight potential opportunities for improved efficiency as understood from the perspective of 3 key stakeholder groups: specialty disease clinicians, staff members, and specialty pharmacists. DESIGN: Qualitative research study using semi structured individual interviews. SETTING AND PARTICIPANTS: Interviews were conducted at a single large tertiary care center targeting clinicians and staff in the hepatitis C, oncology, cystic fibrosis, multiple sclerosis, and rheumatoid arthritis clinics. The second set of participants was pharmacists and technicians at specialty community pharmacies within one large retail chain that was not directly affiliated with the health system. RESULTS: Four conceptual models of specialty medicine access were described by participants. These models varied by disease state, available human resources, and medication. Clinics and specialty pharmacies were not fully aware of the others' systems and contributions to the specialty medicine access process. Perceptions of inefficient communication resulted in frustration and higher perceived work burden. CONCLUSION: There is not a single streamlined pathway for clinics and patients to access specialty medicines in health systems that do not own their own specialty pharmacies. The current system architecture can lead to duplicative work, challenges in communication, and other inefficiencies. Future interventions should focus on streamlining communications between specialty pharmacies, clinics, manufacturers, and payors to create the most efficient access to specialty medicines. PMID- 30416070 TI - Cyclosporine H Overcomes Innate Immune Restrictions to Improve Lentiviral Transduction and Gene Editing In Human Hematopoietic Stem Cells. AB - Innate immune factors may restrict hematopoietic stem cell (HSC) genetic engineering and contribute to broad individual variability in gene therapy outcomes. Here, we show that HSCs harbor an early, constitutively active innate immune block to lentiviral transduction that can be efficiently overcome by cyclosporine H (CsH). CsH potently enhances gene transfer and editing in human long-term repopulating HSCs by inhibiting interferon-induced transmembrane protein 3 (IFITM3), which potently restricts VSV glycoprotein-mediated vector entry. Importantly, individual variability in endogenous IFITM3 levels correlated with permissiveness of HSCs to lentiviral transduction, suggesting that CsH treatment will be useful for improving ex vivo gene therapy and standardizing HSC transduction across patients. Overall, our work unravels the involvement of innate pathogen recognition molecules in immune blocks to gene correction in primary human HSCs and highlights how these roadblocks can be overcome to develop innovative cell and gene therapies. PMID- 30416071 TI - In Vitro Expansion of Primary Human Hepatocytes with Efficient Liver Repopulation Capacity. AB - Transplantation of human hepatocytes (HHs) holds significant potential for treating liver diseases. However, the supply of transplantable HHs is severely constrained by limited donor availability and compromised capacity for in vitro expansion. In response to chronic injury, some HHs are reprogrammed into proliferative cells that express both hepatocyte and progenitor markers, suggesting exploitable strategies for expanding HHs in vitro. Here, we report defined medium conditions that allow 10,000-fold expansion of HHs. These proliferating HHs are bi-phenotypic, partially retaining hepatic features while gaining expression of progenitor-associated genes. Importantly, these cells engraft into injured mouse liver at a level comparable to primary HHs, and they undergo maturation following transplantation in vivo or differentiation in vitro. Thus, this study provides a protocol that enables large-scale expansion of transplantable HHs, which could be further developed for modeling and treating human liver disease. PMID- 30416072 TI - Notch-Induced miR-708 Antagonizes Satellite Cell Migration and Maintains Quiescence. AB - Critical features of stem cells include anchoring within a niche and activation upon injury. Notch signaling maintains skeletal muscle satellite (stem) cell quiescence by inhibiting differentiation and inducing expression of extracellular components of the niche. However, the complete spectrum of how Notch safeguards quiescence is not well understood. Here, we perform Notch ChIP-sequencing and small RNA sequencing in satellite cells and identify the Notch-induced microRNA 708, which is a mirtron that is highly expressed in quiescent cells and sharply downregulated in activated cells. We employ in vivo and ex vivo functional studies, in addition to live imaging, to show that miR-708 regulates quiescence and self-renewal by antagonizing cell migration through targeting the transcripts of the focal-adhesion-associated protein Tensin3. Therefore, this study identifies a Notch-miR708-Tensin3 axis and suggests that Notch signaling can regulate satellite cell quiescence and transition to the activation state through dynamic regulation of the migratory machinery. PMID- 30416073 TI - Outcomes after minimally invasive surgery in cervical cancer. PMID- 30416074 TI - Biomarkers in renal-cell carcinoma: building on clinical paradigms. PMID- 30416075 TI - Long-term follow-up care needed for children surviving cancer: still a long way to go. PMID- 30416076 TI - Temporal patterns in the risk of chronic health conditions in survivors of childhood cancer diagnosed 1970-99: a report from the Childhood Cancer Survivor Study cohort. AB - BACKGROUND: Treatments for childhood cancer have evolved over the past 50 years, with the goal of maximising the proportion of patients who achieve long-term survival, while minimising the adverse effects of therapy. We aimed to assess incidence patterns of serious chronic health conditions in long-term survivors of childhood cancer across three decades of diagnosis and treatment. METHODS: We used data from the Childhood Cancer Survivor Study, a retrospective cohort with longitudinal follow-up of 5-year survivors of common childhood cancers (leukaemia, tumours of the CNS, Hodgkin lymphoma, non-Hodgkin lymphoma, Wilms tumour, neuroblastoma, soft tissue sarcoma, or bone tumours) who were diagnosed before the age of 21 years and from 1970 to 1999 in North America. We examined the cumulative incidence of severe to fatal chronic health conditions occurring up to 20 years post-diagnosis among survivors, compared by diagnosis decade. We used multivariable regression models to estimate hazard ratios per diagnosis decade, and we added treatment variables to assess whether treatment changes attenuated associations between diagnosis decade and chronic disease risk. FINDINGS: Among 23 601 survivors with a median follow-up of 21 years (IQR 15-25), the 20-year cumulative incidence of at least one grade 3-5 chronic condition decreased significantly from 33.2% (95% CI 32.0-34.3) in those diagnosed 1970-79 to 29.3% (28.4-30.2; p<0.0001) in 1980-89, and 27.5% (26.4-28.6; p=0.012 vs 1980 89) in 1990-99. By comparison, the 20-year cumulative incidence of at least one grade 3-5 condition in 5051 siblings was 4.6% (95% CI 3.9-5.2). The 15-year cumulative incidence of at least one grade 3-5 condition was lower for survivors diagnosed 1990-99 compared with those diagnosed 1970-79 for Hodgkin lymphoma (17.7% [95% CI 15.0-20.5] vs 26.4% [23.8-29.1]; p<0.0001), non-Hodgkin lymphoma (16.9% [14.0-19.7] vs 23.8% [19.9-27.7]; p=0.0053), astrocytoma (30.5% [27.8 33.2] vs 47.3% [42.9-51.7]; p<0.0001), Wilms tumour (11.9% [9.5-14.3] vs 17.6% [14.3-20.8]; p=0.034), soft tissue sarcoma (28.3% [23.5-33.1] vs 36.5% [31.5 41.4]; p=0.021), and osteosarcoma (65.6% [60.6-70.6] vs 87.5% [84.1-91.0]; p<0.0001). By contrast, the 15-year cumulative incidence of at least one grade 3 5 condition was higher (1990-99 vs 1970-79) for medulloblastoma or primitive neuroectodermal tumour (58.9% [54.4-63.3] vs 42.9% [34.9-50.9]; p=0.00060), and neuroblastoma (25.0% [21.8-28.2] vs 18.0% [14.5-21.6]; p=0.0045). Results were consistent with changes in treatment as a significant mediator of the association between diagnosis decade and risk of grade 3-5 chronic conditions for astrocytoma (HR per decade without treatment in the model = 0.77, 95% CI 0.64-0.92; HR with treatment in the model=0.89, 95% CI 0.72-1.11; pmediation=0.0085) and Hodgkin lymphoma (HR without treatment=0.75, 95% CI 0.65-0.85; HR with treatment=0.91, 95% CI 0.73-1.12; pmediation=0.024). Temporal decreases in 15-year cumulative incidence comparing survivors diagnosed 1970-79 to survivors diagnosed 1990-99 were noted for endocrinopathies (5.9% [5.3-6.4] vs 2.8% [2.5-3.2]; p<0.0001), subsequent malignant neoplasms (2.7% [2.3-3.1] vs 1.9% [1.6-2.2]; p=0.0033), musculoskeletal conditions (5.8% [5.2-6.4] vs 3.3% [2.9-3.6]; p<0.0001), and gastrointestinal conditions (2.3% [2.0-2.7] vs 1.5% [1.3-1.8]; p=0.00037), while hearing loss increased (3.0% [2.6-3.5] vs 5.7% [5.2-6.1]; p<0.0001). INTERPRETATION: Our results suggest that more recently treated survivors of childhood cancer had improvements in health outcomes, consistent with efforts over the same time period to modify childhood cancer treatment regimens to maximise overall survival, while reducing risk of long-term adverse events. Continuing advances in cancer therapy offer promise of further reducing the risk of long-term adverse events in childhood cancer survivors. However, achieving long-term survival for childhood cancer continues to come at a cost for many survivors, emphasising the importance of long-term follow-up care for this population. FUNDING: National Cancer Institute and the American Lebanese-Syrian Associated Charities. PMID- 30416078 TI - Surgical and medical management of small bowel gastrointestinal stromal tumors: A report of the Dutch GIST registry. AB - BACKGROUND: A cohort of 201 patients with small bowel gastrointestinal stromal tumors (GIST) treated between January 1st, 2009 and December 31st, 2016 in five GIST expertise centers in the Netherlands was analyzed. Goal of this study was to describe the clinical, surgical and pathological characteristics of this rare subpopulation of GIST patients, registered in the Dutch GIST registry. METHODS: Clinical outcomes and risk factors of patients with small bowel GIST who underwent surgery or treated with systemic therapy were analyzed. A classification was made based on disease status at diagnosis (localized vs. metastasized). RESULTS: 201 patients with small bowel GIST were registered of which 138 patients (69%) were diagnosed with localized disease and 63 patients (31%) with metastatic disease. Approximately 19% of the patients had emergency surgery, and in 22% GIST was an accidental finding. In patients with high risk localized disease, recurrence occurred less often in patients who received adjuvant treatment (4/32) compared to patients who did not (20/31, p < 0.01). Disease progression during palliative imatinib treatment occurred in 23 patients (28%) after a median of 20.7 (range 1.8-47.1) months. Ongoing response was established in 52/82 patients on first line palliative treatment with imatinib after a median treatment time of 30.6 (range 2.5-155.3) months. CONCLUSION: Patients with small-bowel GIST more frequently present with metastatic disease when compared to patients with gastric GIST in literature. We advocate for Prospective registration of these patients and investigate the use of surgery in patients with limited metastatic disease. PMID- 30416077 TI - Genomically annotated risk model for advanced renal-cell carcinoma: a retrospective cohort study. AB - BACKGROUND: The Memorial Sloan Kettering Cancer Center (MSKCC) risk model is an established prognostic tool for metastatic renal-cell carcinoma that integrates clinical and laboratory data, but is agnostic to tumour genomics. Several mutations, including BAP1 and PBRM1, have prognostic value in renal-cell carcinoma. Using two independent clinical trial datasets of patients with metastatic renal-cell carcinoma, we aimed to study whether the addition of the mutation status for several candidate prognostic genes to the MSKCC model could improve the model's prognostic performance. METHODS: In this retrospective cohort study, we used available formalin-fixed paraffin-embedded tumour tissue and clinical outcome data from patients with metastatic renal-cell carcinoma assigned to treatment with tyrosine kinase inhibitors in the COMPARZ trial (training cohort; n=357) and RECORD-3 trial (validation cohort; n=258). Eligible patients in both trials were treatment-naive; had histologically confirmed, advanced, or metastatic renal-cell carcinoma; and a Karnofsky performance status score of at least 70. For each cohort, data from patients in all treatment groups (sunitinib and pazopanib in the training cohort, and everolimus and sunitinib in the validation cohort) were pooled for this analysis. In the training cohort, tumour tissue was used to evaluate somatic mutations by next-generation sequencing, and the association between cancer-specific outcomes (overall survival, progression free survival, and overall response) and the mutation status of six genes of interest (BAP1, PBRM1, TP53, TERT, KDM5C, and SETD2) was tested. Only those genes with prognostic value in this setting were added to the MSKCC risk model to create a genomically annotated version. The validation cohort was used to independently test the prognostic value of the annotated model compared with the original MSKCC risk model. FINDINGS: 357 (32%) of 1110 patients assigned to protocol treatment in the COMPARZ study between August, 2008, and September, 2011, were evaluable for mutation status and clinical outcomes in the training cohort. The independent validation cohort included 258 (55%) of 471 evaluable patients, enrolled between October, 2009, and June, 2011, on the RECORD-3 study. In the training cohort, the presence of any mutation in BAP1 or TP53, or both, and absence of any mutation in PBRM1 were prognostic in terms of overall survival (TP53wt/BAP1mut, TP53mut/BAP1wt o TP53mut/BAP1mut vs TP53wt/BAP1wt hazard ratio [HR] 1.57, 95% CI 1.21-2.04; p=0.0008; PBRM1wt vs PBRMmut, HR 1.58, 1.16-2.14; p=0.0035). The mutation status for these three prognostic genes were added to the original MSKCC risk model to create a genomically annotated version. Distribution of participants in the training cohort into the three risk groups of the original MSKCC model changed from 87 (24%) of 357 patients deemed at favourable risk, 217 (61%) at intermediate risk, and 53 (15%) at poor risk, to distribution across four risk groups in the genomically annotated risk model, with 36 (10%) of 357 deemed at favourable risk, 77 (22%) at good risk, 108 (30%) at intermediate risk, and 136 (38%) at poor risk. Addition of genomic information improved model performance for predicting overall survival (C-index: original model, 0.595 [95% CI 0.557-0.634] vs new model, 0.637 [0.595-0.679]) and progression-free survival (0.567 [95% CI 0.529-0.604] vs 0.602 [0.560-0.643]) with adequate discrimination of the proportion of patients who achieved an objective response (Cochran Armitage one-sided p=0.0014). Analyses in the validation cohort confirmed the superiority of the genomically annotated risk model over the original version. INTERPRETATION: The mutation status of BAP1, PBRM1, and TP53 has independent prognostic value in patients with advanced or metastatic renal-cell carcinoma treated with first-line tyrosine kinase inhibitors. Improved stratification of patients across risk groups by use of a genomically annotated model including the mutational status of these three genes warrants further investigation in prospective trials and could be of use as a model to stratify patients with metastatic renal-cell carcinoma in clinical trials. FUNDING: Novartis Pharmaceuticals Corporation, MSKCC Support Grant/Core Grant, and the J Randall & Kathleen L MacDonald Research Fund. PMID- 30416079 TI - Arpin downregulation is associated with poor prognosis in pancreatic ductal adenocarcinoma. AB - INTRODUCTION: Arpin (Arp2/3 complex inhibitor), a novel protein found in 2013, plays a pivotal role in cell motility and migration. However, the prognostic value of Arpin in pancreatic ductal adenocarcinoma (PDAC) remains unknown. MATERIALS AND METHODS: We analyzed the gene expression of ARPIN using the GEO dataset (GSE71989) and validated the results by immunohistochemistry (IHC) and Western blot in our clinical database. Tissue microarray specimens from 214 patients who underwent curative pancreatectomy for PDAC were used. The tumors that expressed high and low levels of Arpin were compared with patient outcome using Kaplan-Meier curves and the multivariate Cox proportional hazard regression model. IHC was then used in 43 paired primary tumor tissues and metastasis tissues to detect the expression of Arpin. RESULTS: Arpin had low expression in the tumor tissue compared with the paracancerous tissue in PDAC. Patients with low intratumoral Arpin expression had worse overall survival (OS) and recurrence free survival (RFS) than patients with high expression in the training set (p < 0.001, p < 0.001) and validation set (p < 0.001, p < 0.001). The multivariate analysis revealed that the 8th edition TNM stage and Arpin expression were independent prognostic factors associated with OS and RFS in the training and validation sets, respectively. Arpin had lower expression in the metastasis tissues than in the primary tumors of patients with PDAC (p = 0.048). CONCLUSION: The Arpin level is an independent prognostic factor that can be a potential predictor to aid in the management of PDAC. PMID- 30416080 TI - Determinants of hypertension among adults in Bangladesh as per the Joint National Committee 7 and 2017 American College of Cardiology/American Hypertension Association hypertension guidelines. AB - We investigated determinants of hypertension in Bangladesh using both Joint National Committee 7 (JNC7) and 2017 American College of Cardiology/American Hypertension Association (2017 ACC/AHA) guidelines. After reporting background characteristics, odds ratios (ORs) were obtained by multilevel logistic regression. Among 7839 respondents aged >=35 years, 25.7% (n = 2016) and 48.0% (n = 3767) respondents had hypertension as per the JNC7 and 2017 ACC/AHA guidelines, respectively. The following factors were significant according to the 2017 ACC/AHA guideline: >=65 years (adjusted OR [AOR]: 2.4, 95% confidence interval [CI]: 2.2-3.0), 55-64 years (AOR: 1.6, 95% CI: 1.4-1.9), and 45-54 years (AOR: 1.4, 95% CI: 1.3-1.6) age groups, females (AOR: 2.0, 95% CI: 1.7-2.2), overweight/obesity (AOR: 2.4, 95% CI: 2.0-2.8), diabetes (AOR: 1.4, 95% CI: 1.2 1.6), secondary (AOR: 1.2, 95% CI: 1.1-1.4), or college education level (AOR: 1.8, 95% CI: 1.4-2.3), middle (AOR: 1.3, 95% CI: 1.1-1.6), richer (AOR: 1.5, 95% CI: 1.2-1.8) or richest (AOR: 2.0, 95% CI: 1.6-2.4) wealth quintiles, residence in Khulna (AOR: 1.5, 95% CI: 1.2-1.9), and Rangpur (AOR: 1.7, 95% CI: 1.3-2.2) divisions. All factors were significant as per the JNC7 guideline too. Both guidelines found similar determinants. Prevention and control programs should prioritize increasing awareness among people with higher likelihood of hypertension. PMID- 30416082 TI - The challenge of implementing AI models in the ICU. PMID- 30416081 TI - Mechanisms of HLA-DP Antigen Processing and Presentation Revisited. AB - Polymorphisms in HLA-DP can modulate interactions with the invariant chain chaperone, contributing independently to differences in the peptide repertoire presented on DP. The resulting presentation of intracellular antigens directly to CD4+ T cells may partly explain genetic and clinical studies describing previously unexplained links between polymorphism in DP and disease. PMID- 30416084 TI - 2-year safety and efficacy results for benralizumab. PMID- 30416085 TI - Cr (VI) induces crosstalk between apoptosis and autophagy through endoplasmic reticulum stress in A549 cells. AB - Hexavalent chromium [Cr (VI)], which is widely found in occupational environments, is a recognized human carcinogen. In this study, the role of endoplasmic reticulum (ER) stress in Cr (VI)-induced crosstalk of apoptosis and autophagy was investigated. Cr (VI) resulted in ER stress by upregulating the expression of GRP78 and p-PERK. 4-Phenylbutyric acid (4PBA), an inhibitor of ER stress, reduced both Cr (VI)-induced apoptosis and autophagy, suggesting that ER stress played an important role in Cr (VI)-induced apoptosis and autophagy in A549 cells. Furthermore, Cr (VI)-induced apoptosis preceded autophagy. Z-VAD-FMK, the suppressor of apoptosis, repressed Cr (VI)-induced autophagy. Pretreatment with 3-MA, the inhibitor of autophagy, increased Cr (VI)-induced apoptosis. Exposure to Cr (VI) significantly reduced mitochondrial membrane potential (MMP) during Cr (VI) treatment for 6-12 h. However, Cr (VI)-reduced MMP rescued significantly after treatment with Cr (VI) for 24 h compared with that of 6 h and 12 h groups, suggesting that Cr (VI)-induced autophagy at 24 h might rescue Cr (VI)-induced decrease of MMP through engulfing damaged mitochondria and then inhibit apoptosis in A549 cells. Above all, our results indicated that Cr (VI) induced ER stress plays an important role in the crosstalk between apoptosis and autophagy. The autophagy might be apoptosis-dependent and subsequently prevents apoptosis cell death to keep A549 cells resistant to Cr (VI)-induced further toxicity. This maybe underlies the mechanism of Cr (VI)-induced carcinogenesis. PMID- 30416086 TI - To reunite or not: A study of artificially fragmented Diacamma indicum ant colonies. AB - Social insects live together in groups and maintain cohesion to enhance their chances of survival and productivity. Colony cohesion is severely challenged during relocation. We examined the dynamics of colony reunification and the factors affecting nest choice of artificially fragmented colonies of the queenless ant Diacamma indicum. None of the twelve undisturbed colonies fragmented or relocated when a good nest was available in their neighbourhood. When colonies were artificially fragmented, they mostly (25/30) reunified into a single nest unlike in randomized time-ordered network models, indicating that reunification is not the result of random recruitment acts. When the reproductive individual was present in a good nest, the colonies reunified at this address. However, when she was present in a suboptimal nest, colonies relocated her to a better quality nest and reunified there, illustrating that quality of the new nest is more important. The work distribution and relocation dynamics of reunification were comparable to intact colonies relocating to a single new nest. This is made possible by enhanced exchange of information among tandem leaders in the form of increased number of tandem runs among them. We conclude that colony cohesion is very important and is maintained after incorporating the risks of relocation and preference for nest quality during decision making. PMID- 30416087 TI - Identification and characterization of carbapenem binding sites within the RND transporter AcrB. AB - Understanding the molecular determinants for recognition, binding and transport of antibiotics by multidrug efflux systems is important for basic research and useful for the design of more effective antimicrobial compounds. Imipenem and meropenem are two carbapenems whose antibacterial activity is known to be poorly and strongly affected by MexAB-OprM, the major efflux pump transporter in Pseudomonas aeruginosa. However, not much is known regarding recognition and transport of these compounds by AcrAB-TolC, which is the MexAB-OprM homologue in Escherichia coli and by definition the paradigm model for structural studies on efflux pumps. Prompted by this motivation, we unveiled the molecular details of the interaction of imipenem and meropenem with the transporter AcrB by combining computer simulations with biophysical experiments. Regarding the interaction with the two main substrate binding regions of AcrB, the so-called access and deep binding pockets, molecular dynamics simulations revealed imipenem to be more mobile than meropenem in the former, while comparable mobilities were observed in the latter. This result is in line with isothermal titration calorimetry, differential scanning experiments, and binding free energy calculations, indicating a higher affinity for meropenem than imipenem at the deep binding pocket, while both sharing similar affinities at the access pocket. Our findings rationalize how different physico-chemical properties of compounds reflect on their interactions with AcrB. As such, they constitute precious information to be exploited for the rational design of antibiotics able to evade efflux pumps. PMID- 30416088 TI - Comprehensive analysis of chromatin signature and transcriptome uncovers functional lncRNAs expressed in nephron progenitor cells. AB - Emerging evidence from recent studies has unraveled the roles of long noncoding RNAs (lncRNAs) in the function of various tissues. However, little is known about the roles of lncRNAs in kidney development. In our present study, we aimed to identify functional lncRNAs in one of the three lineages of kidney progenitor cells, i.e., metanephric mesenchymal (MM) cells. We conducted comprehensive analyses of the chromatin signature and transcriptome by RNA-seq and ChIP-seq. We found seventeen lncRNAs that were expressed specifically in MM cells with an active chromatin signature, while remaining silenced in a bivalent chromatin state in non-MM cells. Out of these MM specific lncRNAs, we identified a lncRNA, Gm29418, in a distal enhancer region of Six2, a key regulatory gene of MM cells. We further identified three transcript variants of Gm29418 by Rapid Amplification of cDNA Ends (RACE), and confirmed that the transcription-start-sites (TSSs) of these variants were consistent with the result of Cap Analysis Gene Expression (CAGE). In support of the enhancer-like function of Gm29418 on Six2 expression, we found that knock-down of Gm29418 by two independent anti-sense locked nucleic acid (LNA) phosphorothioate gapmers suppressed Six2 mRNA expression levels in MM cells. We also found that over-expression of Gm29418 led to an increase in Six2 mRNA expression levels in a mouse MM cell line. In conclusion, we identified a lncRNA, Gm29418, in nephron progenitor cells that has an enhancer-like function on a key regulatory gene, Six2. PMID- 30416089 TI - Attentional bias modification treatment for depression: Study protocol for a randomized controlled trial. AB - Theoretical models and empirical research point to negatively biased attention as a maintaining factor in depression. Although preliminary studies suggest experimentally modifying attentional biases (i.e., attentional bias modification; ABM) reduces depression symptoms and depression risk, relatively few rigorous studies with clinical samples have been completed. This clinical trial examines the impact of ABM on a sample of adults (N = 123) with elevated depression severity who also exhibit at least modest levels of negatively biased attention prior to treatment. Participants will be randomly assigned to either active ABM, placebo ABM, or an assessment-only control condition. Individuals assigned to ABM will complete 5 trainings per week (2 in-clinic, 3 brief trainings at-home) during a four-week period. Throughout this four-week period, participants will complete weekly assessments of symptom severity and putative treatment mediators measured across different levels of analysis (e.g., eye tracking, behavioral measures, and functional Magnetic Resonance Imaging). This article details the rationale and design of the clinical trial, including methodological issues that required more extensive consideration. Our findings may not only point to an easily-accessible, efficacious treatment for depression but may also provide a meaningful test of whether a theoretically important construct, negatively biased attention, maintains depression. PMID- 30416090 TI - Bleomycin-induced genotoxicity in vitro in human peripheral blood lymphocytes evidenced as complex chromosome- and chromatid-type aberrations. AB - Bleomycin is a chemotherapeutic and a radiomimetic drug which induces single and double-strand breaks in DNA by forming free radicals. We demonstrate in this study the capacity of bleomycin in inducing complex chromosome- and chromatid type aberrations. Human peripheral blood was exposed to different concentrations of bleomycin (0, 10, 20, 30 and 40 MUg/mL) and the aberrations induced were studied. The chromosomal-type aberrations studied were dicentrics, tricentrics, tetracentrics, centric rings and acentric fragments. The chromatid-type aberrations studied were double minutes, terminal lesions and terminal deletions. Though the overall trends that we obtained in the dose-dependent mitotic index and the chromosome- and chromatid-type aberrations conform to the reported literature, we could observe enhanced numbers and the types of such damages in this study. We could notice that chromosome-type aberrations were more than the chromatid-type aberrations. The enhanced numbers and the types of aberrations induced pave way for enhancing the sensitivity of genotoxic assays. Also, with more numbers and type of aberrations available, it would be useful to study the mechanisms of genotoxicity of drugs and in understanding phenomena such as "tolerance induction" to chronic exposure to such mutagens. PMID- 30416091 TI - Hepatotoxicity and hepatoprotection of Polygonum multiflorum Thund. as two sides of the same biological coin. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum multiflorum Thund., a well-known and commonly-used TCM (Traditional Chinese Medicine) for treating hypertension, hyperlipidemia, premature graying of hair, and etc., has aroused wide concern for its reported potential liver toxicity. Due to its various active ingredients, the mechanisms underlying the hepatotoxicity of raw Polygonum multiflorum Thund (RPM) remain largely unknown. AIM OF THE STUDY: 1H NMR metabolomics was used to study the mechanism of RPM induced hepatotoxicity and disclosed the existence of hepatotoxicity and hepatoprotection conversion during RPM administration in mice. MATERIALS AND METHODS: Three dosages of RPM were administered by gavage to mice for consecutive 28 days. The serum and liver samples were collected and then subjected for histopathology observation, biochemical measurement and 1H NMR metabolic profiling. RESULTS: RPM caused oxidative stress and mitochondria dysfunction in mice, resulting in significant disturbance in energy metabolism, amino acid metabolism and pyrimidine metabolism and also inducing inflammatory responses. RPM induced hepatotoxicity in an apparent non-linear manner: the most severe in low dosage group, and to a less extent in medium group according to metabolomics analysis. The attenuation of liver injury in mice livers might result from the therapeutic effects, such as anti-oxidative capacity of RPM components. CONCLUSION: RPM exerted a complicated non-linear manner in healthy recipients, switching between hepatoxicity and hepatoprotection dependent on the dosage and status of the body. PMID- 30416092 TI - Nordihydroguaiaretic acid prevents glycation induced structural alterations and aggregation of albumin. AB - This study demonstrates the antiglycation activity of Nordihydroguaiaretic acid, a lignin from the creosote bush (Larrea tridentate), which has also been proven to assist in the treatment of cancer, neurological disorders, and cardiovascular complications. We determined the antiglycation activity of NDG based on spectroscopic analysis, molecular interactions and circular dichroism studies with albumin. It was also seen that NDG inhibits the aggregation of albumin, after glycation, using Thioflavin T binding and confocal imaging. Results suggest that NDG is a potent inhibitor of advanced glycation end products formation. NDG was found to impart protective effects on albumin by preventing glycation modification of lysine residues (Lys20, Phe36, Lys41, Lys131, and Lys132) due to glycation. PMID- 30416093 TI - Investigation of potential genomic biomarkers for obesity and personalized medicine. AB - Obesity, as a global health issue, is a complex metabolic syndrome and its association with many chronic diseases. The pathology of obesity results from an interaction of psychological, environmental and variety of genetic factors. Etiologic determinants and molecular pathophysiology of obesity have not yet understood clearly. Previously shown that genetic markers have a significant role in the development of obesity, although results are divergent with populations. Turkish Cypriots have a unique mixture of allele distributions as being a small islander population. Therefore, the current study was aimed to evaluate the association between obesity and three putative obesity-related ADIPOQ, FTO and ACE gene markers, respectively. We investigated a possible association of ADIPOQ rs2241766 G>T, FTO rs9939609 A>T and ACE rs4340288 DIP variants among obese and non-obese Turkish Cypriot origin. Additionally, the correlation between these variants and biochemical and physical measurements were also evaluated to determine the possible biomarker for obesity in the population. Only FTO rs9939609 A>T polymorphism was associated with obesity and no association was observed with ADIPOQ rs2441666 G>T and ACE rs4340288 DIP. To conclude, FTO rs9939609 A allele found to have strong association with obesity in the population of Turkish Cypriots. PMID- 30416094 TI - Effect of amidated alginate on faecal lipids, serum and hepatic cholesterol in rats fed diets supplemented with fat and cholesterol. AB - The effect of octadecylamide of alginic acid on serum and hepatic cholesterol, and the faecal output of fat and sterols was examined in female rats fed diets containing cholesterol and palm fat at 10 and 50 g kg-1, respectively. Cholesterol supplementation significantly increased serum and hepatic cholesterol concentrations, and faecal output of cholesterol and coprostanol. Cholesterol and amidated alginate supplementations changed the profile of fatty acids in the faeces. Cholesterol increased molar percentages of saturated fatty acids and amidated alginate reversed this effect. Amidated alginate, supplied at 10, 20 and 40 g kg-1, significantly decreased serum cholesterol from 2.82 to 2.00, 1.95, and 1.63 MUmol mL-1, respectively, and significantly decreased hepatic cholesterol from 13.8 to 9.33, 7.81 and 6.3 MUmol g-1, respectively. Amidated alginate increased the faecal output of fat and neutral sterols in a dose-dependent manner. In contrast, the output of bile acids was significantly decreased. The faecal outputs of fat and serum cholesterol were negatively correlated. At the highest concentration tested, amidated alginate significantly reduced the serum concentration of triacylglycerols. It can be concluded that amidated alginate is an effective cholesterol-lowering agent and sorbent of dietary fat. PMID- 30416095 TI - Lignin for white natural sunscreens. AB - Long-time exposure to the sun's ultraviolet (UV) radiation is harmful and causes various skin problems. Natural sun blockers have been drawing considerable attention recently. Even though lignin, an abundant aromatic polymer from plants, is a natural UV screening agent, its unfavorable dark color hinders its high value-added applications in sunscreens and cosmetics. In this study, we separate lignin under mild conditions (at room temperature with neutral solvents) in order to prevent darkening occurring during delignification and apply the resultant lignin as a natural sunscreen ingredient for the first time. Lignins isolated from Miscanthus sacchariflorus (MWL-M) and from Pinus densiflora (MWL-P) are compared with organosolv lignin (OL), which showed the best sunscreen performance, in color and UV protection. MWLs separated under mild conditions were light in color unlike conventional lignins extracted under harsh conditions. UV absorption of light-colored MWL-M was revealed to be as high as dark-colored OL. MWLs also showed synergistic effects with a commercial sunscreen; exposure of the MWL-added sunscreen to UVA radiation greatly enhanced the sun protection factor (SPF) value of the sunscreen. PMID- 30416096 TI - Production of core-shell nanofibers from zein and tragacanth for encapsulation of saffron extract. AB - In this study, encapsulation of aqueous saffron extract (ASE) was studied using a core-shell nanofiber structure (zein-tragacanth) via coaxial electrospinning technique. Morphological features of nanofibers were investigated under different processing conditions (polymer concentration and applied voltage). The nanofibers produced under optimum criteria had diameter in a range of 95 to 271 nm. Concentration of zein and percentage of ASE were found to be critical factors affecting loading capacity (LC) and encapsulation efficiency (EE). The range of LC and EE were 3.57-9.52% and 60.89-91.55%, respectively. FTIR and differential scanning calorimetry (DSC) characterizations demonstrated that ASE was appropriately encapsulated in the nanofibers matrix with high thermal stability. TEM images showed a core-shell structure. Release values of 21.66, 27.75, 43.88 and 16.12% of saffron extract were observed in saliva, hot water, gastric and intestinal media, respectively. Mechanism of safranal release from fibers for saliva, water, gastric and intestinal were well demonstrated by Kopcha, Peppas Sahlin, Peppas-Sahlin and Ritger-Peppas models, respectively. Finally, the results of this research indicated that produced thermostable core-shell nanofibers can be used in various food industries such as chewing gum and tea bag development. PMID- 30416097 TI - Effect of magnetic field on the Eversa(r) Transform 2.0 enzyme: Enzymatic activity and structural conformation. AB - Alternatives to improve the stability and activity of enzymes have been rising in the last years due to the potential industrial application of these catalysts. However, the enzymes characteristics in terms of stability and catalytic efficiency can reduce, in some cases, due to the reaction conditions. Due to a lack in the literature concerning structural information related to the new commercial Eversa(r) Transform 2.0 enzyme (NS-40116) we investigated the conformational structure by spectroscopic and mass spectrometry techniques after exposure in permanent magnetic flux density (0.7 and 1.34 T) in recirculation mode (1, 2, and 4 h) at 0.06 L.min-1. The influence of pH on the enzymatic solution associated with the magnetic flux (pH 5, 7, and 9) was also evaluated. Under the best reaction condition (pH 7 after 4 h in a recirculation mode at 1.34 T), enzyme activity 77% higher than the control sample was obtained. Mass spectrometry techniques showed changes in the NS-40116 tertiary structure. Thus, the application of magnetic fields as an enzymatic pre-treatment showed to be a promising technique and a viable alternative to increase the enzymatic activity since it is a low cost, environmentally friendly, and ease operation process. PMID- 30416098 TI - Prevalence of children walking to school and related barriers-United States, 2017. AB - Children and adolescents can engage in an active lifestyle by walking to school; however, several barriers may limit this behavior. This study estimates the prevalence of walking to school and related barriers as reported by U.S. parents. Data from the 2017 SummerStyles, a Web-based survey conducted on a nationwide sample of U.S. adults, were analyzed in 2017. Parents of children aged 5-18 years (n = 1137) were asked whether their youngest child walked to or from school during a usual school week and what barriers make this difficult. Frequencies are presented overall and by parent characteristics. About 1 in 6 parents (16.5%) reported their youngest child walks to or from school at least once during a usual week. Prevalence differed by parental race/ethnicity, marital status, region, and distance from school. The most common barrier was living too far away (51.3%), followed by traffic-related danger (46.2%), weather (16.6%), "other" barrier (14.7%), crime (11.3%), and school policy (4.7%). The frequency at which parents reported certain barriers varied by their child's walking status, distance to school, age of youngest child, race/ethnicity, education level, household income, and metropolitan statistical area status. However, the relative ranking of barriers did not differ by these characteristics. Prevalence of walking to school is low in the U.S., and living too far away and traffic-related danger are common barriers reported by parents. Implementing Safe Routes to School programs and other initiatives that utilize strategies to overcome locally relevant barriers could help increase the prevalence of children walking to school. PMID- 30416083 TI - Long-term safety and efficacy of benralizumab in patients with severe, uncontrolled asthma: 1-year results from the BORA phase 3 extension trial. AB - BACKGROUND: Benralizumab is an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody that has been shown to safely reduce exacerbations and improve lung function for patients with asthma. We assessed the long-term safety and efficacy of benralizumab for patients with severe, uncontrolled eosinophilic asthma. METHODS: We conducted a randomised, double-blind, parallel-group, phase 3 extension study at 447 sites in 24 countries. Eligible patients had to have completed the SIROCCO or CALIMA trials and remained on subcutaneous benralizumab 30 mg every 4 weeks (Q4W) or every 8 weeks (Q8W). Patients who had received placebo in those trials were re-randomised in a 1:1 ratio, using an interactive web-based system, to benralizumab 30 mg either Q4W or Q8W (first three doses 4 weeks apart). Treatment lasted for 56 weeks for adult patients (age >=18 years) and 108 weeks for adolescent patients (age 12-17 years). The primary endpoint was the safety and tolerability of the two dosing regimens of benralizumab up to 68 weeks for adult patients (including the follow-up visit post-treatment) and up to 56 weeks for adolescent patients. This endpoint was assessed in the full analysis set, which included all patients from the SIROCCO and CALIMA predecessor studies who received at least one dose of study treatment in BORA and did not continue into another trial. This study is registered with ClinicalTrials.gov (NCT02258542). FINDINGS: Between Nov 19, 2014, and July 6, 2016, we enrolled 1926 patients, of whom 633 had received benralizumab Q4W and 639 had received benralizumab Q8W in SIROCCO or CALIMA. The remaining 654 patients had received placebo in those trials and were randomly re-assigned in this trial to receive benralizumab Q4W (n=320) or Q8W (n=334). 1576 patients, including 783 who received benralizumab Q4W (265 newly assigned) and 793 who received benralizumab Q8W (281 newly assigned), were included in the full analysis set. The most common adverse events in all groups were viral upper respiratory tract infection (14 16%) and worsening asthma (7-10%). The most common serious adverse events were worsening asthma (3-4%), pneumonia (<1% to 1%), and pneumonia caused by bacterial infection (0-1%). The percentages of patients who had any on-treatment adverse event, any serious adverse event, or any adverse event leading to treatment discontinuation during BORA were similar between patients originally assigned benralizumab and those originally assigned placebo and between benralizumab treatment regimens. The percentage of patients who had any adverse event was similar between SIROCCO or CALIMA (71-75%; benralizumab group only) and BORA (65 71%), as was the percentage of patients who had an adverse event that led to treatment discontinuation (2% in SIROCCO and CALIMA vs 2-3% in BORA). INTERPRETATION: The 2 years of safety results validate that observations observed in the first year of benralizumab continued through a second year of treatment. No new consequences of long-term eosinophil depletion occurred, and the incidence of other adverse events, including opportunistic infections, were similar during the second year. FUNDING: AstraZeneca and Kyowa Hakko Kirin. PMID- 30416099 TI - Evaluation of antibacterial and anticancer properties of poly(3-hydroxybutyrate) functionalized with different amino compounds. AB - The chemical modification of biodegradable poly(3-hydroxybutyrate) (PHB) is useful for biomedical applications. In this study, the transesterification reaction of PHB was carried out under reflux conditions in the presence of 1,4 butanediol to form telechelic PHB-diol. Further modification of PHB-diol into PHB diacrylate was carried out by the reaction of PHB-diol with acryloyl chloride. PHB-diacrylate was grafted with amino compounds such as 1,4-butanediamine, 1,3 propanediamine, 1,2-ethylenediamine, piperazine, cyclohexylamine, 2,2'-(ethane 1,2-diylbis(oxy)) diethanamine (jeffamine EDR 148) and morpholine via Michael type addition reaction. The functionalized amino-PHB polymers were characterized by using FTIR and 1H NMR techniques. XRD showed that amino-PHB polymers have different crystallinity compared with neat PHB. Some biological activities of amino-PHB polymers were determined such as antibacterial, antioxidant and anticancer activities. In this regard, the results showed that PHB ethylenediamine revealed a potent antibacterial activity against Staphlococcus aureus, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. All amino-PHB polymers under the study showed reasonable antioxidant activity. Among these polymers, PHB-piperazine showed a potent anticancer effect against in vivo Ehrlich ascetic carcinoma bearing mice. PMID- 30416100 TI - A radical containing injectable in-situ-oleogel and emulgel for prolonged in-vivo oxygen measurements with CW EPR. AB - Molecular oxygen, reactive oxygen species and free radicals derived from oxygen play important roles in a broad spectrum of physiological and pathological processes. The quantitative measurement of molecular oxygen in tissues by electron paramagnetic resonance (EPR) has great potential for understanding and diagnosing a number of diseases, and for developing and guiding therapies. This requires improvements in the free radical probe systems that sense and report molecular oxygen levels in vivo. We report on the encapsulation of existing free radical probes in lipophilic gel implants: an in-situ-oleogel and an emulgel, based only on well-known, safe excipients for the incorporation of lipophilic and hydrophilic radicals, respectively. The EPR signals of encapsulated radicals were not altered compared to dissolved radicals. The high solubility of oxygen in lipophilic solvents enhanced oxygen sensitivity. The gels extended the lifetime of the radicals in tissues from tens of minutes to many days, simplifying studies with extended series of measurements. The encapsulated radicals showed a good in vivo response to changes in oxygen supply and seem to circumvent concerns from toxicity of the radical probes. These gels simplify the development of new oxygen sensitive free radical probes for EPR oximetry by making their in vivo stability, persistence and toxicity a function of the encapsulating gel and not a set of additional requirements for the free radical probe. PMID- 30416102 TI - Effect of gender role orientation on attitudes toward menstruation in a sample of female University students. AB - OBJECTIVE: The aim of this study was to examine the effect of gender role orientation on attitudes toward menstruation in a sample of Iranian female students of medical sciences. MATERIALS AND METHODS: Three hundred female university students (94%; N = 282 response rate) via stratified random sampling were enrolled to the study. Data were collected using demographic questionnaire, Menstrual Attitude Questionnaire, and short version of the Bem Sex Role Inventory. Data were analyzed with SPSS v.18. Analyses were done using Kruskal Wallis test and Mann-Whitney U test. RESULTS: The mean scores of the MAQ subscales ranged from 3.7 +/- 1.35 to 5.6 +/- 1.3, indicating that most of the respondents had natural to moderate attitudes toward menstruation. When participants were classified into one of four gender-role categories of BSRI, results show that the undifferentiated group with 33.7% was higher than other gender role groups. The undifferentiated group was significantly less likely than the other groups to perceive "menstruation as a natural event". CONCLUSION: The study shows an association between gender role orientation and attitudes toward menstruation in female university students. However, further research is still necessary in this issue. PMID- 30416101 TI - Expression of Halo-hFGF18 and study of its effect on differentiation of ATDC5 cells. AB - Fibroblast growth factor 18 (FGF18) is a member of the fibroblast growth factor family and important in cartilage growth and development. However, the mechanism by which FGF18 mediates its biological functions is still unclear. In our study, we expressed the rhFGF18 protein fused to a HaloTag, (Halo-rhFGF18). MTT assay results indicated that both rhFGF18 and Halo-rhFGF18 have similar biological activities in NIH3T3 cells. However, basic FGF and acidic FGF were more potent than both rhFGF18 and Halo-rhFGF18. Confocal imaging data indicated that the red fluorescence labeled Halo-rhFGF18 strongly bound to ATDC5 cells and stimulated their proliferation and differentiation, which suggests that glycosaminoglycans may be involved in mediating the biological effects of rhFGF18 in ATDC5 cells. Moreover, western blot results demonstrated that, in ATDC5 cells, ERK1/2 signaling is activated upon stimulation with rhFGF18. Our results may open doors for the use of rhFGF18 as a drug to promote cartilage growth. PMID- 30416103 TI - Hydrophilic bile acids prevent liver damage caused by lack of biliary phospholipid in Mdr2 -/- mice. AB - Bile acid imbalance causes progressive familial intrahepatic cholestasis type 2 (PFIC2) or type 3 (PFIC3) - severe liver diseases associated with genetic defects in the biliary bile acid transporter BSEP (ABCB11), or phosphatidylcholine transporter MDR3 (ABCB4), respectively. Mdr2 -/- mice (a PFIC3 model) develop progressive cholangitis, ductular proliferation, periportal fibrosis, and hepatocellular carcinoma (HCC) because the non-micelle-bound bile acids in the bile of these mice are toxic. We asked whether the highly hydrophilic bile acids generated by Bsep -/- mice could protect Mdr2 -/- mice from progressive liver damage. We generated double knockout (DKO: Bsep -/- and Mdr2 -/-) mice. Their bile acid composition resembles that of Bsep-/- mice, with increased hydrophilic muricholic acids, tetrahydroxylated bile acids (THBA), and reduced hydrophobic cholic acid. These mice lack the liver pathology of their Mdr2 -/- littermates. The livers of DKO mice have gene expression profiles very similar to Bsep -/- mice, with 4410 out of 6134 gene expression changes associated with the Mdr2 -/- mutation being suppressed. Feeding with THBA partially alleviates liver damage in the Mdr2 -/- mice. Conclusion: Hydrophilic changes to biliary bile acid composition, including introduction of THBA, can prevent the progressive liver pathology associated with the Mdr2 -/- (PFIC3) mutation. PMID- 30416104 TI - Validation and modification of the Ottawa subarachnoid haemorrhage rule in risk stratification of Asian Chinese patients with acute headache. AB - OBJECTIVE: To validate the Ottawa subarachnoid haemorrhage (SAH) rule in an Asian Chinese cohort and to explore the roles of blood pressure and vomiting in prediction of SAH in patients with nontraumatic acute headache. METHODS: A retrospective cohort study was conducted in two regional hospitals. All patients aged >=16 years who presented with non-traumatic acute headache to the study centres from July 2013 to June 2016 were included. A logistic regression model was created for the variables of the Ottawa SAH rule and other potential predictors, including vomiting and systolic blood pressure (SBP) >160 mm Hg. Model discrimination was evaluated using the area under the receiver operating characteristic curve. Net reclassification improvement and integrated discrimination improvement indices were evaluated. The model's diagnostic characteristics, including sensitivities and specificities, were evaluated. RESULTS: A total of 500 eligible headache cases were included, in 50 of which SAH was confirmed (10%). In addition to the predictors of the Ottawa SAH rule, vomiting and SBP >160 mm Hg were found to be significant independent predictors of SAH. Net reclassification improvement and integrated discrimination improvement indices indicated that including vomiting and SBP >160 mm Hg would improve the model prediction. The Ottawa SAH rule had 94% sensitivity and 32.9% specificity. The modified Ottawa SAH rule that included both vomiting and SBP >160 mm Hg as criteria improved sensitivity to 100%, specificity to 13.1%, positive predictive value to 11.3%, and negative predictive value to 100%. CONCLUSIONS: The Ottawa SAH rule demonstrated high sensitivity. Addition of vomiting and SBP >160 mm Hg to the Ottawa SAH rule may increase its sensitivity. PMID- 30416105 TI - Group A Streptococcus disease in Hong Kong children: an overview. AB - Group A beta-haemolytic Streptococcus or Streptococcus pyogenes is a gram positive coccus that tends to grow in chains. Streptococcus pyogenes is the cause of many important human diseases, ranging from pharyngitis and mild superficial skin infections to life-threatening systemic diseases. Infections typically begin in the throat or skin. Mild Streptococcus pyogenes infections include pharyngitis (strep throat) and localised skin infections (impetigo). Erysipelas and cellulitis are characterised by multiplication and lateral spread of Streptococcus pyogenes in deep layers of the skin. Streptococcus pyogenes invasion and fascial involvement can lead to necrotising fasciitis, a life threatening condition. Scarlet fever is characterised by a sandpaper-like rash in children with fever and is caused by a streptococcal toxin. Severe infections that lead to septicaemia or toxic shock syndrome are associated with high mortality. Autoimmune reactions cause characteristic syndromes such as rheumatic fever and nephritis. Epidemiology, disease presentation, diagnosis, and treatment of paediatric patients in Hong Kong with group A beta-haemolytic Streptococcus are reviewed in this article. Streptococcus pyogenes disease is readily treatable, as the organism is invariably sensitive to penicillin. Delayed treatment of this common childhood pathogen is associated with significant mortality and morbidity. PMID- 30416107 TI - [Musical Hallucinosis]. AB - Musical hallucination is one of the most complex forms of auditory hallucinations, where subjects perceive complex sound in the form of music, in the absence of an acoustic stimulus. It has been reported in patients with diseases such as psychiatric disorders, organic brain diseases, and epilepsy. However, the most common of these are idiopathic musical hallucinations that occur alongside deafness in the elderly. In recent years, there have been many reports of musical hallucination occurring as a result of mild cognitive impairment and dementia. Musical hallucinations accompanying hearing loss may reflect deterioration of cerebral function. It has been suggested that auditory Charles Bonnet syndrome is a pathophysiological mechanism of musical hallucination. The decrease in auditory stimulation and activation of the auditory network may activate the cerebral network in relation to music. It is also thought that musical hallucination appears from disintegration of the complementary relationship between sensation and memory. Treatment is still the focus of extensive investigation. Some authors have reported that hearing aids, antiepileptic drugs, anticholinergics, and antipsychotics can relieve musical hallucination. It is possible that such treatment may lead to relief of musical hallucination in patients with various background diseases. Population aging in Japan has exceeded 20%, which is the highest in the world; therefore, there may be many undiagnosed patients throughout the country. PMID- 30416106 TI - [Delusions in Dementia]. AB - Delusion is a common neuropsychiatric symptom in dementia, especially in Alzheimer disease and dementia with Lewy bodies. Persecutory delusions are the most common, and include delusions of theft, jealousy, and abundant. Patients with persecutory delusions have impairment of the psychological processes mediating the formation and maintenance of normal social beliefs. Several disordered psychological processes such as attentional bias, attributional bias, jumping-to-conclusions reasoning bias, and theory of mild deficit may contribute to the delusion formation. Cognitive processes involving information about self, others, and social interaction are required in social cognition. Damage of the neural circuitry involved in social cognition ("social brain"), such as the medial prefrontal cortex, may be a neuroanatomical basis for persecutory delusions in dementia. PMID- 30416108 TI - [Impairment of Cross-modality: A New Cognitive Dysfunction in Parkinson's Disease]. AB - It is known that Parkinson's disease impairs various cognitive functions including olfaction. However, until recently it was unclear whether Parkinson's disease also affects cross-modal function of vision and olfaction. A recent study showed that odor evaluation in patients with Parkinson's disease is unaffected by visual information, while healthy controls overestimated smell, when sniffing odorless liquid while viewing pleasant or unpleasant visual cues. Dopamine transporter deficit in the striatum, in particular in the posterior putamen, correlated with the limited visual effect in patients with Parkinson's disease. The findings suggest that Parkinson's disease impairs cross-modal function of vision and olfaction due to posterior putamen deficit. This review discusses that the cross-modal dysfunction may serve as the basis of novel precursor assessment of Parkinson's disease. PMID- 30416109 TI - [Time Perception in an Individual with Split Brain]. AB - Time information is processed and perceived consciously and unconsciously in our daily life. Since time information is based on multiple inputs from multiple sensory modalities, its processing involves various brain regions. In this study, we investigated the role of the corpus callosum in time perception of task relevant visual stimuli, with inhibition of the task-irrelevant stimuli, in an individual with agenesis of the corpus callosum. PMID- 30416110 TI - [Pica]. AB - Pica is an extremely troublesome behaviors and causes a particularly high burdens for family caregivers. It can lead to dangerous medical consequences, such as malnutrition and intoxication, which sometimes require emergency medical treatment. Its neural basis and underlying mechanisms, however, have not been clarified. We addressed these issues by investigating patients with acquired brain injury who presented with pica. We found that semantic memory deficits were most often associated with pica rather than frontal release signs or changes in eating behaviors. Individuals with pica displayed lesion in the posterior part of the middle temporal gyrus, although spread across a wide area. Taken together, our findings suggest that semantic memory deficits, because of temporal lobe damage might be associated with pica. Moreover, Alzheimer's disease and semantic dementia are the two main degenerative disease etiologies that cause pica. Our findings may also be applied to degenerative disorders as temporal lobe involvement and semantic memory deficits are common. The most common items ingested in pica are daily necessities that are easy to swallow or drink; as such, these items should be avoided in patients with pica. PMID- 30416111 TI - [Delusional Misidentification Syndromes in Organic Brain Disorders]. AB - Delusional misidentification syndromes (DMSs) are a fascinating group of disorders involving a fixed, false belief about the identity of persons, places, and objects in one's environment. DMSs include Capgras syndrome, Fregoli syndrome, intermetamorphosis, the syndrome of subjective doubles, and reduplicative paramnesia. Although DMSs have been described in patients with focal neurological lesions, they are more commonly associated with neurodegenerative diseases, specifically dementia with Lewy bodies. Lesion network mapping was used to identify brain regions functionally connected to the lesion locations in patients with lesion-induced DMSs. The left retrosplenial cortex and the right ventral frontal cortex/anterior insula were functionally connected to almost all lesion locations. In a model of Capgras symptom as a mirror of prosopagnosia, there are two routes of visual recognition; one covert and one overt. Capgras symptom represents an interruption to the covert route with an intact overt route. This model, however, does not explain other DMSs. Therefore, propose a new model where the delusional belief content in DMSs results from dysfunctional linking between externally perceived objects and appropriately retrieved internal autobiographical memories associated with an object. PMID- 30416112 TI - [Brain Science on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome]. AB - Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. A variety of studies have been performed to establish objective biomarkers of the disease, including positron emission tomography (PET) molecular imaging and neuro functional imaging using magnetic resonance imaging (MRI) and magnetoencephalogram (MEG). In this chapter, we summarize the results from PET, MRI, and MEG imaging. Regional cerebral blood flow and glucose utilization rates are decreased in patients with ME/CFS as compared with age- and sex-matched healthy subjects. Acetyl-L-carnitine uptake into the releasable pool of glutamate and serotonin transporters densities are decreased in a few specific brain regions, mostly in the anterior cingulate in the patients. Although it is hypothesized that brain inflammation is involved in the pathophysiology of ME/CFS, there was no direct evidence of neuroinflammation in patients. Our recent PET study successfully demonstrated that neuroinflammation is present in widespread brain areas in ME/CFS patients, and is associated with the severity of neuropsychological symptoms. Evaluation of neuroinflammation in patients with ME/CFS may be essential for understanding the core pathophysiology, as well as for developing objective diagnostic criteria and effective medical treatments for ME/CFS. By using specific neurological features of these patients such as prefrontal cortical atrophies and the over-guarding phenomenon were found using MRI and functional MRI, respectively. We here describe related pathophysiological findings and topics in order to aid in the development of future therapies for ME/CFS patients. PMID- 30416113 TI - [Time and Self in Episodic Memory and Confabulation]. AB - Confabulation is defined as the production of narrative descriptions of events that never happened, and is often observed in amnesia with basal forebrain lesions. However, little is known about the possible mechanisms related to confabulation. In this review article, we summarized previous neuropsychological and neuroimaging studies associated with confabulation, and proposed a hypothetical mechanism of confabulation. Previous studies have demonstrated that amnesic patients with confabulation after basal forebrain damage are impaired in the processing of time-related information in episodic memory and that activation of this region is significant during the processing of time-related information in episodic memory. In addition, confabulating patients with basal forebrain lesions extending to the medial prefrontal cortex (mPFC), medial temporal, and thalamic regions are likely to show significant disturbances in age-awareness and significant false memories in personally experienced events. Given the importance of the mPFC in the self-referential process and of the hippocampus in the integration of episodic components, the basal forebrain region could play an important role in orienting the self in time by acting as an interface between the mPFC and the hippocampus. Confabulation in basal forebrain amnesia could be caused by a decline of the time-self interaction. PMID- 30416114 TI - [FMRI Neurofeedback and its Application to Psychiatric Disorders]. AB - Functional magnetic resonance imaging (fMRI) neurofeedback can train subjects to control their brain activity with real-time processing and high spatial resolution, as many advances in MRI data acquisition methods, computer hardware, and processing algorithms have improved the sensitivity and speed of fMRI neurofeedback. FMRI neurofeedback has been applied to psychiatric disorders, including schizophrenia, major depressive disorder, attention-deficit hyperactivity disorder, and obsessive-compulsive disorder. Some studies reported that fMRI neurofeedback improved the symptoms of patients with psychiatric disorders, although it remains unclear if the regulation of the targeted brain regions or the functional connectivities themselves improved the symptoms. It is necessary that researchers pay enough attention to their study's design, because many non-specific factors such as introduction, mental strategies, self-efficacy, attention, motivation, learning ability, and reward influence the results in fMRI neurofeedback studies. If the long-term effect of fMRI neurofeedback on the symptoms of psychiatric disorders are recognized, fMRI neurofeedback will be useful in treating heterogeneous patients with psychiatric disorders without side effects. PMID- 30416115 TI - [Mirror Movement]. AB - Mirror movement (MM) is involuntary symmetrical movement observed in the limb contralateral to the voluntary limb movement. This movement is temporally observed in the developmental period of the healthy child, but then disappears. Continuation of this movement is considered abnormal, and hereditary, congenital or acquired MM has been reported with or without neurological disorders. Supplementary motor area, corpus callosum, and cervical lesions have been linked to MM. The pathomechanism of MM is speculated to be abnormal descending corticospinal pathways or impaired cortical and subcortical motor control systems in the brain, and both mechanisms may be present. PMID- 30416116 TI - [What is the Core Symptom and Neural Mechanism of Asperger Syndrome? From Our Ten Years of Clinical Observation of Adults with Autism Spectrum Disorder]. AB - In 2008, we launched a new outpatient clinic and day care service designed exclusively for adults with autism spectrum disorder (ASD). Since then, more than 6000 people visited our facility. We have also launched the Medical Institute for Developmental Disabilities Research (MIDDR) at Showa University, where neuroimaging studies with a 3.0 Tesla MRI scanner and rehabilitation studies intended to support people with ASD for job seeking were conducted for the past five years. As our subjects were found to have normal or high intelligence, we present here our research studies on Asperger syndrome patients with the focus on their resting-state functional connectivity network. We also review hypotheses of brain functioning in Asperger syndrome. PMID- 30416117 TI - [Tourette Syndrome]. AB - Tourette syndrome (TS) is a neurodevelopmental disorder. TS was formerly considered to be a psychogenic disease; however, TS has recently been thought to be a heterogeneous disease with neurological bases and involving environmental and genetic factors. For example, it has been suggested that neurotransmitters including dopamine and cortico-striato-thalamo-cortical circuits are suggested to be associated with TS pathogenesis. According to these recent evidence, in addition to pharmacotherapy as the standard treatment, deep brain stimulation is being applied for patients with treatment-refractory TS in clinical settings. PMID- 30416118 TI - [Mental and Organic Features of Posttraumatic Stress Disorder]. AB - Posttraumatic stress disorder (PTSD) is a mental disorder that can develop following exposure to a traumatic event. Historically, it has been debated whether features of this disorder derive from mental or brain organic changes. Recent developments in neuroimaging and biological studies suggest a biological background of PTSD. In contrast, recent literature shows an impact of psychological context in the traumatic experiences, and concepts such as "moral injury" have been developed. Future studies are needed to better understand the mental and organic mechanisms underlying PTSD. PMID- 30416119 TI - [Development of a Therapeutic Drug for Narcolepsy]. AB - Narcolepsy-cataplexy is a debilitating disorder characterized by excessive daytime sleepiness and cataplexy, a bilateral loss of muscle tone triggered by positive emotions. The disease is caused by the loss of orexin-producing neurons in the hypothalamus. Currently, only symptom-oriented therapies are available for narcolepsy. We have recently discovered a potent, non-peptide orexin type-2 receptor (OX2R) agonist, YNT-185. We show that peripheral administration of YNT 185 significantly ameliorated the narcolepsy symptoms in a mouse model for narcolepsy. No desensitization was observed after repeated administration of YNT 185 with respect to the suppression of cataplexy-like episodes. These results provide a proof -of-concept for mechanistic therapy for narcolepsy-cataplexy using OX2R agonists. Additionally, YNT-185 promoted wakefulness in wild-type mice, suggesting that orexin receptor agonists may be useful for the treatment of excessive daytime sleepiness due to other conditions, such as sleepiness accompanying depression and sleepiness due to side effects of medicines or jet lag/shift work. PMID- 30416120 TI - [Biological Mechanisms of ADHD]. AB - Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inappropriate levels of inattention, hyperactivity and impulsivity. Recent developments in neuroimaging and functional brain studies have revealed volumetric reductions and decreased neural activities in the frontal lobe, basal ganglia, limbic system, and cerebellum. Based on these findings, impairment of executive function and the reward system, reffered to as the dual pathway model, and dysfunction of the default mode network have been proposed as biological changes underlying ADHD. Bio-pharmacological studies have shown dysfunctions in catecholamine- regulated neurotransmission, especially dysfunction of dopamine transporters, which the therapeutic drug of methylphenidate is thought to modulate. Agrowing body of genetic research suggests the high heritability of ADHD and several candidate genes relating to dopamine synthesis and transmission have been identified. Epigenetic modification is also garnering much attention in ADHD research and the mutual effects of environmental factors and genetic polymorphism have been reported. Despite such accumulative findings, how genes, the environment, and brain functioning interact and relate to create the symptoms of ADHD are still unknown and more research is needed to uncover the biological mechanisms of ADHD. PMID- 30416121 TI - [Kanashibari Phenomenon as a Sleep Disorder: Recurrent Idiopathic Sleep Paralysis]. AB - The phenomenon called kanashibari in Japan is otherwise known as sleep paralysis and, is an established symptom of narcolepsy. Its physiological correlate is an unusual occurrence of rapid eye movement (REM) sleep, i.e., sleep onset REM periods (SOREMPs). Various symptoms of the phenomenon are explained by the mechanisms of REM sleep. SOREMPs can be observed in various situations, which indicate a lower amplitude of circadian rhythms, such as during interupted sleep, acute reversal of sleep and wakefulness cycle, and disrupted sleep of depressive patients and in newborn babies. The lifetime prevalence of the phenomenon in the general population is as high about 40%. The phenomenon can be a mysterious and frightening experience far affected people and called as various names according to the folklore beliefs of local communities, e.g., nightmare in Europe, hexendrucken in Germany, cauchemar in France, and old hag in Newfoundland. Japanese college students are known for their very short sleep length and disturbed sleep wake rhythms. Many students claim to have experienced daytime sleepiness. Some of them meet the criterion concerning sleep latencies and frequency of SOREMPs for multiple sleep latency test (MSLT) as narcolepsy. SOREMPs are frequently seen in healthy college students with certain lifestyles. Practitioners should be cautious to diagnose narcolepsy if the student shows disturbed sleep wake schedules. PMID- 30416122 TI - [B-cell Depletion Therapy in Multiple Sclerosis]. AB - Since the initial observation of increased immunoglobulin concentrations in the cerebrospinal fluid of patients with multiple sclerosis (MS) in the 1940s, B cells have been considered to participate in the pathology of MS through the production of autoantibodies reactive against central nervous system antigens. However, it is now recognized that B cells contribute to MS relapses by antibody independent activities, including presenting antigens to T cells and releasing pro-inflammatory cytokines. In addition, the recent identification of B cell-rich follicle-like structures in the meninges of patients with MS suggests that pathogenic roles of B cells also exist at the progressive phase. Recently, large scale clinical trials have demonstrated the efficacy of B-cell depletion therapy using ocrelizumab, an anti-CD20-antibody, in relapsing-remitting as well as primary progressive MS; these findings have led to the approval of ocrelizumab by the Food and Drug Administration and the European Medical Agency for treating these conditions. B-cell depletion therapy is an important treatment option for MS based on its favorable benefit to risk balance in relapsing remitting MS, and as it is the only drug that has currently been demonstrated to be effective in treating primary progressive MS. PMID- 30416123 TI - [Nonstenotic Carotid Plaque in Patients with Anterior Circulation Embolic Stroke of Undetermined Source]. AB - Characteristics of nonstenotic (<50%) carotid plaque in embolic stroke of undetermined source (ESUS) are unclear. This study aimed to clarify the size and properties of carotid plaque in patients with ESUS. We retrospectively analyzed the results of carotid ultrasonography in 17 consecutive patients with anterior circulation ESUS and compared the size and morphology of carotid plaque on the ipsilateral and contralateral sides of the stroke lesion. The mean plaque thickness did not significantly differ between both sides (2.13 vs 1.86 mm, p = 0.54), but the mean noncalcified plaque thickness was greater on the ipsilateral side than on the contralateral side (1.15 vs 0.23mm, p = 0.025). Noncalcified plaque with thickness>=2.5mm was observed on the ipsilateral side in five of 17 patients, but not on the contralateral side, suggesting that noncalcified plaque with thickness>=2.5mm is a potential source of ESUS. (Received January 29, 2018; Accepted July 21, 2018; Published November 1, 2018). PMID- 30416124 TI - [Cryptococcal Meningitis in a Patient with Breast Cancer Receiving Everolimus: A Case of Successful Treatment with Continuous Cerebrospinal Fluid Drainage]. AB - Cryptococcosis is a fungal infection that mainly occurs in immunocompromised patients. We present the first case of cryptococcal meningitis in a patient who was being administered everolimus for breast cancer. Everolimus, a selective inhibitor of mammalian target of rapamycin, is a molecular targeting agent that is administered not only as an immunosuppressive agent, but also as an anticancer therapeutic. A 72-year-old woman with recurrent breast cancer had been receiving everolimus. She was admitted to our hospital with headache and vomiting. Lumbar puncture revealed high opening pressure, and cerebrospinal fluid (CSF) evaluation diagnosed cryptococcal meningitis. She was administered liposomal amphotericin-B, followed by fosfluconazole. Daily lumbar puncture was insufficient to reduce the high intracranial pressure; thus, continuous lumbar drainage was needed to improve her symptoms. The indwelling catheter was replaced regularly to prevent bacterial infection. She was treated successfully with extracorporeal CSF drainage for 86 days and fosfluconazole administration over 17 weeks. The patient recovered fully and was discharged on day 153 of hospitalization. As patients who receive everolimus are potentially immunocompromised hosts, we recommend that the medicine be administered with caution considering opportunistic infections when used in patients with cancer. (Received April 19, 2018; Accepted August 9, 2018; Published November 1, 2018). PMID- 30416125 TI - Retracing the "Art of Arts and Science of Sciences" from Gregory the Great to Philo of Alexandria. AB - This study considers the phrase "art of arts and science of sciences," and its variants, in antiquity. Often scholars who note the phrase in a particular ancient author's writing may make reference to another ancient author, but without considering the breadth or depth of its occurrences in antiquity. Beginning with the late sixth-century Gregory the Great's Book of Pastoral Rule, this article retraces the idea through history until reaching Philo of Alexandria. Philo's two uses of the phrase have been neglected in secondary scholarship, and yet his contributions foreshadow the semantic range that will subsequently be seen. PMID- 30416126 TI - The Ministerium Naturae: Natural Law in the Exegesis and Theological Discourse at Paris between 1160 and 1215. AB - During the 12th century and early 13th century, natural law was a central interest of canon lawyers and Roman lawyers, but theologians also debated it on the basis of the exegesis of some key passages of Scripture. Peter Lombard, with his understanding of the content of Paul's Epistle to the Romans 1:19 and 2:13-14 is at the origin of a relevant tradition within the Parisian theological framework. The article examines how natural law is analyzed by the Lombard and his major successors, namely Peter Comestor, Peter the Chanter, and Stephen Langton. PMID- 30416127 TI - Subjection without Servitude: The Imperial Protectorate in Renaissance Political Thought. AB - This article excavates some of the classical foundations of early modern European thinking about empire. It shows that Renaissance humanists drew from Roman sources a conceptual apparatus with which they described the Florentine Republic's subjection of neighboring peoples in terms that avoided the idea of slavery. Of particular importance to the humanists' ideological project was their exploitation of the Roman concept of patronage. The article concludes with an account of the radical reappraisal that this patronal vision of empire underwent in Machiavelli's theory of the imperial republic, a theory with the concept of slavery at its heart. PMID- 30416128 TI - Conway and Charleton on the Intimate Presence of Souls in Bodies. AB - Little is known about the shaping and development of Anne Conway's thought in relation to her early modern contemporaries. In one part of her only surviving treatise, The Principles, Conway criticises "those doctors" who uphold a dualist theory of soul and body, a mechanist conception of body (as dead and inert), and the view that the soul is "intimately present" in the body. In this paper, I argue that here she targets Walter Charleton, a well-known defender of Epicurean atomism in mid-seventeenth-century England. My intention is to highlight the sophistication of Conway's theory of soul-body relations vis-a-vis that of Charleton. PMID- 30416129 TI - Paul et Virginie, or the Enigma of Evil: The Double Theodicy of Bernardin de Saint-Pierre. AB - This article aims to show how Bernardin de Saint-Pierre-whose philosophical and theological thought is generally overlooked by scholars-provides an original solution to the problem of the existence of evil. A comparative reading of the systematic discussion of Providence that animates The Studies of Nature, his major theoretical work, and Paul and Virginia, a true Romanesque application of the philosophical treatise, brings out a double theodicy. In fact, Saint-Pierre establishes a fruitful synergy between Rousseau's anthropodicy, which provides a social and historical justification of evil, and Leibniz's eschatology, aimed at its metaphysical and otherworldly justification. PMID- 30416130 TI - Moral Comfort versus Tragic Downfall: Kant's Concept of the Dynamically Sublime and Schelling's Tragic Alternative. AB - The first few sections of this article concern the pleasure taken in the dynamically sublime. I argue that, according to Kant, intuited nature does not only serve to occasion that pleasure, but is actually a constitutive element of it. The latter sections concern the role of the dynamically sublime in Kant's philosophy. I argue that this notion is a significant link between morality and theology. This explains why some unique anti-Kantian arguments directed against the link have led Schelling to develop an alternative conception of the sublime, which must be understood in terms of tragedy. PMID- 30416131 TI - Japanese Right-Wing Discourse in International Context: Minoda Muneki's Interwar Writings on Class and Nation. AB - It is often taken for granted that ultranationalist ideologues of interwar Japan were anti-western, uncritical mouthpieces of state ideology. This article considers the case of Minoda Muneki (1894-1946) who led the purge of liberals and Marxists from imperial universities. In articulating his theory of nationalism and critique of Marxism, Minoda drew upon a global discourse of social theory. Furthermore, his rise to power was a product of a short-lived convergence of interests between his organization and government figures. I argue for a global historical approach to right-wing ideology that accounts for the relation between nationalist discourse and political power. PMID- 30416133 TI - Contents of Volume 79. PMID- 30416134 TI - The preoperative serum cystatin-C as an independent prognostic factor for survival in upper tract urothelial carcinoma. AB - Cystatin-C (Cys-C) has been reported as a valuable prognostic biomarker in various malignancies. However, its effect on upper tract urothelial carcinoma (UTUC) patients has not been investigated before. Thus, to explore the impact of Cys-C on survival outcomes in patients undergoing radical nephroureterectomy (RNU), a total of 538 patients with UTUC who underwent RNU between 2005 and 2014 in our center (West China Hospital, Chengdu, China) were included in this study. Kaplan-Meier method and Cox regression analyses were performed to assess the relationship between Cys-C and survival outcomes using SPSS version 22.0. The cutoff value of Cys-C was set as 1.4 mg l-1 using the receiver operating characteristic (ROC) curves and Youden index. The mean age of patients included was 66.1 +/- 11.1 years, and the median follow-up duration was 38 (interquartile range: 19-56) months. Overall, 162 (30.1%) patients had elevated Cys-C, and they were much older and had worse renal function than those with Cys-C <1.4 mg l-1 (both P < 0.001). Meanwhile, Kaplan-Meier analysis revealed that the group with elevated Cys-C had worse cancer-specific survival (CSS, P = 0.001), disease recurrence-free survival (RFS, P = 0.003), and overall survival (OS, P < 0.001). Multivariable Cox analysis suggested that the elevated Cys-C was identified as an independent prognostic predictor of CSS (hazard ratio [HR]: 1.997, 95% confidential interval [CI]: 1.331-2.996), RFS (HR: 1.429, 95% CI: 1.009-2.023), and OS (HR: 1.989, 95% CI: 1.366-2.896). In conclusion, our result revealed that the elevated preoperative serum Cys-C was significantly associated with worse outcomes in UTUC patients undergoing RNU. PMID- 30416135 TI - Validation of targeted microsurgical spermatic cord denervation: comparison of outcomes to traditional complete microsurgical spermatic cord denervation. AB - The aim of this study was to validate the effectiveness of targeted microsurgical spermatic cord denervation (MSCD) of the trifecta nerve complex in comparison to traditional full MSCD with complete skeletonization of the spermatic cord in men with chronic orchialgia. Retrospective chart review was performed by a single fellowship-trained microsurgeon between 2011 and 2016. Patients had follow-ups at 6 weeks, 6 months, and 1 year postoperatively. Thirty-nine men with chronic orchialgia underwent full MSCD between 2011 and 2013. In July 2013, after the publication of an anatomic study with identification of Wallerian degeneration of the trifecta nerve complex in men with chronic orchialgia, the technique was changed to targeted MSCD. From July 2013 to March 2016, 43 men underwent targeted MSCD. When comparing the full MSCD group to the targeted MSCD group, there was no significant difference in resolution of pain (66.7% vs 69.8%, P = 0.88), no difference in partial relief of pain (17.9% vs 23.3%, P = 0.55), and no difference in failure to respond rates (15.4% vs 7.0%, P = 0.22) between the two groups. There was no difference in mean change of visual analog pain scale scores between the two groups (P = 0.27). Targeted MSCD had a shorter operative time (53 min vs 21 min, P = 0.0001). Targeted MSCD offers patients comparable outcomes to traditional full MSCD, with a shorter operative time, a less technically challenging surgery, and potentially less risk to cord structures which should be preserved. PMID- 30416136 TI - Laparoscopic surgery for non-obstetric acute abdomen in pregnancy: A retrospective case series review. AB - Background: Laparoscopic techniques have been used during pregnancy by obstetricians since the 1970's, primarily to diagnose and treat ectopic and heterotopic pregnancies. Pregnancy was considered as an absolute contraindication to laparoscopy by surgeons as recently as 1991, and a few still doubt the safety of minimal access in gravid patients. When an emergent operation is indicated, the surgery should not be withheld on the sole basis of patient's gravid state. On the contrary, the alleviation of maternal disease is thought to take priority because the health of the foetus is dependant on the mother. Materials and Methods: This is a retrospective study of a case series of 18 obstetric patients who presented with non-obstetric causes of acute abdomen requiring surgical intervention. Ultrasonography and magnetic resonance imaging (MRI) along with other laboratory investigations were carried out to reach the diagnosis. Laparoscopic surgery was considered as the modality of treatment. All the patients were given the necessary care post-surgery and were followed up till parturition to look for any complications. Results: The data were analysed considering the presentation, diagnostic variations and the surgical modifications statistically. Conclusion: The decision of surgery should be prompt and should be weighed against complications of conserving the patient. Due to the diagnostic limitations of ultrasonography, MRI should be coupled to confirm the diagnosis. Laparoscopy offers less analgesic requirements and shorter hospital stay. The operative time is highly subjective to the experience and training of the surgeon and the laparoscopic set-up itself. PMID- 30416137 TI - Laparoscopic splenic pseudocyst management using indocyanine green dye: An adjunct tool for better surgical outcome. AB - Splenic cysts are not so common in incidence. Only 800-850 cases have been reported till now in the literature. Splenic cysts can be further classified into parasitic and non-parasitic cysts. Non-parasitic cyst is further subdivided into true and false or pseudocyst. Pseudocysts are those who are lacking any epithelial lining. Splenic pseudocysts are usually a result of trauma, infection or infarction. We present a case of splenic pseudocyst that was diagnosed incidentally on routine check-up, and we managed this case with minimally invasive approach with complete preservation of spleen and only removal of pseudocyst. We used indocyanine green dye that helped us in complete delineation of splenic parenchyma and vascular structure adjacent to it. In our view, as in this study also, adopting a new technique that can be helpful in better treatment of the patient and if it can change the surgical outcome of the disease in favour of the patient, it should be encouraged. PMID- 30416138 TI - Practicality and short-term outcomes of intracorporeal gastroduodenostomy in totally laparoscopic distal gastrectomy for gastric cancer: A single-centre retrospective study. AB - Objective: Totally laparoscopic distal gastrectomy (TLDG) with intracorporeal anastomosis is feasible because of improved approaches to laparoscopic surgery and the availability of a variety of surgical instruments. This study was designed to evaluate the practicality, safety and short-term operative outcomes of intracorporeal gastroduodenostomy in TLDG for gastric cancer. Materials and Methods: Medical records of patients with primary distal gastric cancer undergoing Billroth I (B-I) (n = 37) or B-II anastomosis (n = 41) in TLDG from February 2010 to November 2015 were retrospectively analysed. Perioperative data including the extent of lymph node dissection, number of stapler cartridges used, time required to create the anastomosis, operative time, estimated blood loss, proximal and distal margin length, and number of lymph nodes harvested were collected. Short-term post-operative outcomes evaluated during the initial 30 days after surgery included time to first flatus and earliest liquid consumption, length of post-operative hospital stay and incidence of post-operative complications. Results: B-I anastomosis was mainly applied to patients with carcinoma in the lower third of the gastric body (B-I, 81.08% vs. B-II, 31.71%; P < 0.001). Mean operating (B-I, 153.57 +/- 18.25 min vs. B-II, 120.17 +/- 11.74 min; P = 0.004) and anastomosis (B-I, 31.92 +/- 6.10 min vs. B-II, 25.29 +/- 3.84 min; P = 0.01) times were significantly longer for B-I anastomosis compared to B II anastomosis. There were no significant differences in the number of stapler cartridges used, estimated blood loss, time to first flatus and liquid consumption, length of hospital stay or incidence of complications between these groups. Conclusions: TLDG with B-I or B-II anastomosis is safe and feasible for gastric cancer. B-II anastomosis may require less time than B-I anastomosis. PMID- 30416139 TI - Predicting the degree of difficulty of laparoscopic cholecystectomy following endoscopic retrograde cholangiopancreatography- Subgroup analysis does not improve the prediction. PMID- 30416140 TI - High insertion of cystic duct at the gallbladder fundus: An undescribed anomaly! AB - The anatomy of the biliary tree is complex, and its variations of both intra- and extra-hepatic bile ducts can be found in approximately 30% of the general population. These variations are not picked up on routine pre-operative investigations of patients planned for a laparoscopic cholecystectomy (LC) and often present as an unusual 'surprise' and a challenge that can make dissection in the Calot's triangle difficult leading to iatrogenic injury. We present a case of a 53-year-old female with an undescribed anomaly encountered during an LC. There was a high insertion of the cystic duct into the fundus of the gallbladder. No such anomaly has been described in literature till date. PMID- 30416141 TI - Laparoscopic resection of large retrorectal developmental cysts in adults: Single centre experiences of 20 cases. AB - Context: Retrorectal tumours are rare with developmental cysts being the most common type. Conventionally, large retrorectal developmental cysts (RRDCs) require the combined transabdomino-sacrococcygeal approach. Aims: This study aims to investigate the surgical outcomes of the laparoscopic approach for large RRDCs. Settings and Design: A retrospective case series analysis. Subjects and Methods: Data of patients with RRDCs of 10 cm or larger in diameter who underwent the laparoscopic surgery between 2012 and 2017 at our tertiary centre were retrospectively analyzed. Statistical Analysis Used: Results are presented as median values or mean +/- standard deviation for continuous variables and numbers (percentages) for categorical variables. Results: Twenty consecutive cases were identified (19 females; median age, 36 years). Average tumour size was 10.9 +/- 1.1 cm. Cephalic ends of lesions ranged from S1/2 junction to S4 level. Caudally, 18 cysts extended to the sacrococcygeal hypodermis. Seventeen patients underwent the pure laparoscopy; three patients received a combined laparoscopic-posterior approach. The operating time was 167.1 +/- 57.3 min for the pure laparoscopic group and 212.0 +/- 24.5 min for the combined group. The intraoperative haemorrhage was 68.2 +/- 49.7 and 66.7 +/- 28.9 (mL), respectively. Post operative complications included one trocar site hernia, one wound infection and one delayed rectal wall perforation. The median post-operative hospital stay was 7 days. With a median follow-up period of 36 months, 1 lesions recurred. Conclusions: The laparoscopic approach can provide a feasible and effective alternative for large RRDCs, with advantages of the minimally invasive surgery. For lesions with ultra-low caudal ends, especially those closely clinging to the rectum, a combined posterior approach is still necessary. PMID- 30416142 TI - Safety, feasibility and clinical outcome of minimally invasive inguinal hernia repair in patients with previous radical prostatectomy: A systematic review of the literature. AB - Background: Radical prostatectomy (RP) represents an important acquired risk factor for the development of primary inguinal hernias (IH) with an estimated incidence rates of 15.9% within the first 2 years after surgery. The prostatectomy-related preperitoneal fibrotic reaction can make the laparoendoscopic repair of the IH technically difficult, even if safety and feasibility have not been extensively evaluated yet. We conducted a systematic review of the available literature. Methods: A comprehensive computer literature search of PubMed and MEDLINE databases was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Terms used to search were ('laparoscopic' OR 'laparoscopy') AND ('inguinal' OR 'groin' OR 'hernia') AND 'prostatectomy'. Results: The literature search from PubMed and MEDLINE databases revealed 156 articles. Five articles were considered eligible for the analysis, including 229 patients who underwent 277 hernia repairs. The pooled analysis indicates no statistically significant difference of post-operative complications (Risk Ratios [RR] 2.06; 95% confidence interval [CI] 0.85-4.97), conversion to open surgery (RR 3.91; 95% CI 0.85-18.04) and recurrence of hernia (RR 1.39; 95% CI 0.39-4.93) between the post-prostatectomy group and the control group. There was a statistically significant difference of minor intraoperative complications (RR 4.42; CI 1.05-18.64), due to an injury of the inferior epigastric vessels. Conclusions: Our systematic review suggests that, in experienced hands, safety, feasibility and clinical outcomes of minimally invasive repair of IH in patients previously treated with prostatectomy, are comparable to those patients without previous RP. PMID- 30416144 TI - Dulucq's technique for laparoscopic totally extraperitoneal hernioplasty. AB - Background: Inguinal hernia repair has been a controversial area in surgical practice. Its complexity is reflected by the fact that numerous different procedures including both open and laparoscopic techniques are in use today. Laparoscopic totally extraperitoneal (TEP) repair is preferred over transabdominal pre-peritoneal repair as the peritoneum is not breached and also due to fewer intra-abdominal complications. This is the most elegant technique but rather difficult to perform. Aim: The purpose of this study was to describe Dulucq's technique for inguinal hernia repair and the use of three-dimensional mesh without fixation in laparoscopic TEP inguinal hernioplasty. Methods: Surgical technique of laparoscopic TEP inguinal hernia repair is detailed in the text. Results: A total of 945 hernia repairs were included in the study. The hernias were repaired by Dulucq's technique. Mean operative time was 45 min in unilateral hernia and 65 min in bilateral hernia. There were no serious complications. Conclusion: The laparoscopic TEP hernioplasty by Dulucq's technique is feasible with fewer intra-abdominal complications. The dissection must always be done with the same stages with minimal monopolar diathermy and patient in a slight Trendelenburg position. PMID- 30416143 TI - Spondylodiscitis after minimally invasive recto- and colpo-sacropexy: Report of a case and systematic review of the literature. AB - Background: Rectopexy and colpopexy are established surgical techniques to treat pelvic organ prolapse. Spondylodiscitis (SD) after rectopexy and colpopexy represents a rare infectious complication with severe consequences. We presented a case of SD after rectopexy and performed a systematic review. Methods: A systematic literature search was performed to identify case reports or case series reporting on SD after rectopexy or colpopexy. The main outcomes measures were time from initial surgery to SD, presenting symptoms, occurrence of mesh erosion or fistula formation and type of treatment. Results: Forty-one females with a median age of 59 (54-66) years were diagnosed with SD after a median of 76 (30-165) days after initial surgery. Most common presenting symptoms were back pain (n = 35), fever (n = 20), pain radiation in the legs (n = 9) and vaginal discharge (n = 6). A mesh erosion (n = 8) or fistula formation (n = 7) was detected in a minority of cases. The treatment of SD consisted of conservative treatment with antibiotics alone in 29%, whereas 66% of the patients had to undergo additional surgical treatment. If a revision surgery was necessary, more than one intervention was performed in 40%. Mesh and tack excision was performed in most cases (n = 21), whereas a neurosurgical intervention was necessary in 10 patients. Conclusion: Although a rare complication, surgeons performing rectopexy and colpopexy must be aware of the potential risk of SD Careful suture or tack placement into the anterior longitudinal ligament at the level of the promontory while avoiding the disc space is of paramount importance. Prompt diagnosis and multidisciplinary management are the cornerstones of a successful treatment. PMID- 30416145 TI - Laparoscopic versus conventional open surgery in T4 rectal cancer: A case-control study. AB - Background: Laparoscopic surgery (LAS) for T4 rectal cancer (RC) is still controversial. This study aims to compare LAS with conventional open surgery in patients with T4 RC. Patients and Methods: Patients undergoing laparoscopic or open curative resection for T4 RC from January 2010 to September 2014 in our hospital were enrolled. Patients' clinicopathological characteristics and survival outcomes were collected and compared. All statistical analysis was performed using SPSS 22.0. Results: A total of 125 patients (39 open, 86 LAS) were included in this study finally. The baseline information between the two groups were comparable except that LAS group had a more anterior resection (P = 0.012) and less combined resection (P = 0.003). The results demonstrated that patients in LAS group had less blood loss (P < 0.001), smaller incision length (P < 0.001), faster time to first soft diet (P = 0.010) and less incidence of post operative complications, although it was not significantly different (P = 0.063). In addition, the operative time was also comparable (P = 0.140) and the conversion rate was low (2/86). The 3-year overall survival (OS) was 71.8%, 79.1% in open, LAS group respectively and the 3-year disease-free survival (DFS) was 66.7%, 68.6% in open, laparoscopic group, respectively. The Kaplan curves demonstrated that there was no significant difference between the two groups in OS (P = 0.981) or DFS (P = 0.900). Conclusions: LAS is safe and feasible in selected patients with T4 RC. It can achieve a better perioperative outcomes, and the long-time survival is not inferior to open surgery. Prospective studies should be conducted in the future to reduce the selection bias. PMID- 30416146 TI - Resection of giant hepatic cyst by hybrid minilaparoscopy. AB - A female patient, 59-year-old, was complaining of abdominal pain in the right hypochondrium and mesogastrium for 6 months. Ultrasonography and abdominal computed tomography were performed, both confirming a large hepatic cyst (10.6 cm * 7.6 cm * 7.3 cm) on the left lobe. A hybrid minilaparoscopic resection was proposed. We opted for unroofing the cyst, and the procedure was uneventfully performed, with a total surgical time of 60 min. In the post-operative the patient did well, with minimal abdominal pain, being discharged on the 5th post operative day, after drain removal due to the use of intravenous antibiotic therapy. PMID- 30416147 TI - Initial experience with minimally invasive extended pancreatectomies for locally advanced pancreatic malignancies: Report of six cases. AB - Background: Recently, there have been several reports on minimally-invasive surgery for extended pancreatectomy (MIEP) in the literature. However, to date, only a limited number of studies reporting on the outcomes of MIEP have been published. In the present study, we report our initial experience with MIEP defined according to the latest the International Study Group for Pancreatic Surgery (ISPGS) guidelines. Methods: Over a 14-month period, a total of 6 consecutive MIEP performed by a single surgeon at a tertiary institution were identified from a prospectively maintained surgical database. EP was defined as per the 2014 ISPGS consensus. Hybrid pancreatoduodenectomy (PD) was defined as when the entire resection was completed through minimally-invasive surgery, and the reconstruction was performed open through a mini-laparotomy incision. Results: Six cases were performed including 2 robotic extended subtotal pancreatosplenectomies with gastric resection, 1 laparoscopic-assisted (hybrid) extended PD with superior mesenteric vein wedge resection, 2 robotic-assisted (hybrid) PD with portal vein resection (1 interposition Polytetrafluoroethylene graft reconstruction and 1 wedge resection) and 1 totally robotic PD with wedge resection of portal vein. Median estimated blood loss was 400 (250-1500) ml and median operative time was 713 (400-930) min. Median post-operative stay was 9 (6 36) days. There was 1 major morbidity (Grade 3b) in a patient who developed early post-operative intestinal obstruction secondary to port site herniation necessitating repeat laparoscopic surgery. There were no open conversions and no in-hospital mortalities. Conclusion: Based on our initial experience, MIEP although technically challenging and associated with long operative times, is feasible and safe in highly selected cases. PMID- 30416148 TI - Laparoscopic approach to tailgut cyst (retrorectal cystic hamartoma). AB - Retrorectal cystic hamartomas, or tailgut cysts, are complex congenital cystic lesions which arise from embryologic tissues. Fewer than 200 cases have been reported worldwide, with women outnumbering men by 3:1. They are asymptomatic in 50% of the cases; the remainder present with back pain or mass effect as the most common symptoms. Malignant transformation rarely occurs. Guided biopsy is controversial, while surgery is the therapy of choice. We report the case of a 31 year-old woman complaining about perineal and vague lower abdominal pain, who was submitted to magnetic resonance imaging, which revealed a multilocular cystic, well-circumscribed retrorectal mass. Subsequently, laparoscopic excision was successfully accomplished. Operative time was 175 min. Intra- and post-operative course was uneventful. Hospital stay was 75 h. While any malignancy suspicion should lead to open surgery, given the risk of rupture, we support the benefits of laparoscopy may also be applied. PMID- 30416149 TI - Structural and sequence diversity of eukaryotic transposable elements. AB - The majority of eukaryotic genomes contain a large fraction of repetitive sequences that primarily originate from transpositional bursts of transposable elements (TEs). Repbase serves as a database for eukaryotic repetitive sequences and has now become the largest collection of eukaryotic TEs. During the development of Repbase, many new superfamilies/lineages of TEs, which include Helitron, Polinton, Ginger and SINEU, were reported. The unique composition of protein domains and DNA motifs in TEs sometimes indicates novel mechanisms of transposition, replication, anti-suppression or proliferation. In this review, our current understanding regarding the diversity of eukaryotic TEs in sequence, protein domain composition and structural hallmarks is introduced and summarized, based on the classification system implemented in Repbase. Autonomous eukaryotic TEs can be divided into two groups: Class I TEs, also called retrotransposons, and Class II TEs, or DNA transposons. Long terminal repeat (LTR) retrotransposons, including endogenous retroviruses, non-LTR retrotransposons, tyrosine recombinase retrotransposons and Penelope-like elements, are well accepted groups of autonomous retrotransposons. They share reverse transcriptase for replication but are distinct in the catalytic components responsible for integration into the host genome. Similarly, at least three transposition machineries have been reported in eukaryotic DNA transposons: DDD/E transposase, tyrosine recombinase and HUH endonuclease combined with helicase. Among these, TEs with DDD/E transposase are dominant and are classified into 21 superfamilies in Repbase. Non-autonomous TEs are either simple derivatives generated by internal deletion, or are composed of several units that originated independently. PMID- 30416150 TI - PTBP1 contributes to spermatogenesis through regulation of proliferation in spermatogonia. AB - Polypyrimidine tract-binding protein 1 (PTBP1) is a highly conserved RNA-binding protein that is a well-known regulator of alternative splicing. Testicular tissue is one of the richest tissues with respect to the number of alternative splicing mRNA isoforms, but the molecular role(s) of PTBP1 in the regulation of these isoforms during spermatogenesis is still unclear. Here, we developed a germ cell specific Ptbp1 conditional knockout (cKO) mouse model by using the Cre-loxP system to investigate the role of PTBP1 in spermatogenesis. Testis weight in Ptbp1 cKO mice was comparable to that in age-matched controls until 3 weeks of age; at >= 2 months old, testis weight was significantly lighter in cKO mice than in age-matched controls. Sperm count in Ptbp1 cKO mice at 2 months old was comparable to that in controls, whereas sperm count significantly decreased at 6 months old. Seminiferous tubules that exhibited degeneration in spermatogenic function were more evident in the 2-month-old Ptbp1 cKO mice than in controls. In addition, the early neonatal proliferation of spermatogonia, during postnatal days 1-5, was significantly retarded in Ptbp1 cKO mice compared with that in controls. An in vitro spermatogonia culture model (germline stem cells) revealed that hydroxytamoxifen-induced deletion of PTBP1 from germline stem cells caused severe proliferation arrest accompanied by an increase of apoptotic cell death. These data suggest that PTBP1 contributes to spermatogenesis through regulation of spermatogonia proliferation. PMID- 30416151 TI - Prostaglandin E2 Receptor EP4 Inhibition Contracts Rat Ductus Arteriosus. AB - BACKGROUND: Patent ductus arteriosus (PDA) is common in premature infants. Cyclooxygenase inhibitors such as indomethacin, which inhibit prostaglandin E2(PGE2) synthesis, are currently the sole treatments for patients with PDA. Their efficacy are, however, frequently limited, and adverse effects are problematic. Because the PGE2-specific receptor EP4 selectively expresses in rat ductus arteriosus (DA), it is hypothesized that EP4 inhibition would promote DA closure with fewer side-effects.Methods and Results:A new chemical compound EP4 antagonist, RQ-15986 (renamed from CJ-042794), was used. Whether RQ-15986 selectively contracted the DA was examined by measuring the isometric tension of rat DA ex vivo at embryonic day 19 (e19) and e21. RQ-15986 at a dose of 10-6mol/L increased the isometric tension of the DA up to 44.8+/-6.2% and 69.1+/-12.9% to the maximal KCl-induced tension at e19 and e21 respectively. The effect of RQ 15986 on rat DA in vivo was also tested by using a rapid whole-body freezing method. RQ-15986 inhibited PGE1-induced DA dilatation in neonatal rats. Furthermore, RQ-15986 contracted the DA in a dose-dependent manner, and the constriction was greater at e21 than at e19. Moreover, RQ-15986 did not contract the aorta or the marginal artery of the colon. CONCLUSIONS: EP4 inhibition contracts rat DA with fewer side-effects. EP4 inhibition is a promising alternative strategy to treat patients with PDA. PMID- 30416152 TI - [Recalcitrant pouchitis treated by budesonide foam:a case report]. AB - This report presents the case of a 54-year-old man who had undergone restorative proctocolectomy with ileal pouch-anal anastomosis 15 years previously because of acute severe ulcerative colitis. After the operation, he experienced recalcitrant pouchitis and recurrent ulcer bleeding. There was a marked improvement in his symptoms following the administration of twice-daily budesonide 2mg foam injection for two months. Budesonide foam is suggested as a new therapy for pouchitis. PMID- 30416153 TI - [Pancreatic arteriovenous malformation perforated into the common bile and pancreatic ducts:a case report]. AB - A 54-year-old man presented with melena and was conservatively monitored for duodenitis. He developed epigastric pain, and dynamic computed tomography revealed abnormal blood flow in the pancreatic head. The endoscopic retrograde cholangiography revealed that the common bile and pancreatic ducts were simultaneously enhanced, thereby indicating the perforation of an arteriovenous malformation into both ducts. Despite medical treatment, the epigastric pain rapidly worsened and therefore, pancreatoduodenectomy was performed. The present report suggests that if the patient's general condition permits, surgical resection should be actively considered for the treatment of symptomatic pancreatic arteriovenous malformation. PMID- 30416154 TI - [Novel perspectives in management of chronic constipation]. PMID- 30416155 TI - [Crucial role of microbiota in the pathogenesis of chronic constipation]. PMID- 30416156 TI - [Diagnosis and pathophysiology of constipation]. PMID- 30416157 TI - [Pharmacological treatment of chronic constipation]. PMID- 30416158 TI - [Surgery for chronic constipation]. PMID- 30416159 TI - [Inflammatory reactive polyposis caused by dasatinib:a case report]. AB - A 51-year-old man with chronic myeloid leukemia undergoing treatment with dasatinib received colonoscopy for a positive fecal occult blood test. Colonoscopy revealed more than 100 erythematous, multilobulated polyps with mucoid discharge. Endoscopic mucosal resection was performed for diagnosis, and the histological analysis of polyps showed hyperplastic glands and proliferative smooth muscle cells. Our findings suggested that the polyposis was caused by inflammation triggered due to the adverse effects associated with dasatinib. The patient discontinued dasatinib;the follow-up colonoscopy performed four months later revealed significantly improved polypoid lesions in the colon. The erythematous heads of the polyps and mucoid discharge disappeared. The cessation of dasatinib seemed to contribute to the improvement of inflammatory reactive polyposis;therefore, we inferred that the polyposis was caused by dasatinib in the present case. PMID- 30416160 TI - [Gastric tuberculosis in an elderly patient:a case report]. AB - A woman in her 70s presented to our hospital with epigastric pain, back pain, and weight loss. Esophagogastroduodenoscopy was performed, and numerous protuberances, which were suspected to be submucosal tumors, were found at the gastric corpus. The patient was diagnosed with gastric tuberculosis based on the biopsy results of these protuberances. Histopathological analysis demonstrated non-caseating epithelioid granuloma. A positive culture for Mycobacterium tuberculosis was also obtained on gastric juice analysis and confirmed using polymerase chain reaction assay. In the rapidly aging population in Japan, our findings emphasize on the importance of differentiating gastrointestinal tuberculosis, including gastric tuberculosis, from other diseases. This case may provide information about the development of gastric tuberculosis. PMID- 30416161 TI - [Pulmonary tuberculosis following anti-tumor necrosis factor-alpha therapy in Crohn's disease:a case report]. AB - Anti-tumor necrosis factor-alpha (TNF-alpha) is a principal treatment for Crohn's disease (CD). However, it increases the susceptibility to tuberculosis (TB) infection, and therefore, screening examination prior to treatment initiation is crucial. Here, we report the case of a patient with CD who developed pulmonary TB following anti-TNF-alpha therapy, despite negative screening. A 19-year-old female who had no history of TB or had traveled to TB-endemic regions was diagnosed with CD. After negative TB screening with chest X-ray and interferon gamma release assay, the patient was initiated on oral prednisolone and pH dependent mesalazine. The treatment was changed to infliximab (IFX) because of the inadequate response observed to prednisolone;however, she developed pulmonary TB only 10 weeks after the initiation of IFX. The standard short-course anti-TB regimen was initiated to treat pulmonary TB, whereas IFX was discontinued and replaced with budesonide. Our case suggests that the risk of developing TB should not be excluded, despite the initial negative TB screening, particularly when a patient develops respiratory symptoms during anti-TNF-alpha therapy. PMID- 30416162 TI - Severity of Nausea and Vomiting in Singleton and Twin Pregnancies in Relation to Fetal Sex: The Japan Environment and Children's Study (JECS). AB - BACKGROUND: Some studies have indicated that female birth and multiple births were risk factors for nausea and vomiting during pregnancy (NVP). The results, however, were conflicting. Our study was conducted to evaluate the association of maternal NVP with fetal sex in singleton and twin pregnancies. METHODS: We used the data set from a birth cohort study, the Japan Environment and Children's Study (JECS). In the self-administered questionnaire, participants were asked whether they experienced NVP prior to 12 gestational weeks. Main outcome measures were the presence of NVP and severity of NVP. We estimated the association of fetal sex and birth plurality with NVP using logistic regression analysis, followed by interaction analysis. RESULTS: Of 91,666 women, 75,828 (82.7%) experienced at least some symptoms of NVP and 10,159 (11.1%) experienced severe NVP. Women with female pregnancies and twin pregnancies had higher odds for the presence of NVP and severe NVP compared to women with male pregnancies and singleton pregnancies, respectively. Moreover, of mothers with twin pregnancies, higher odds for the presence of NVP and severe NVP were reported when one or both infants were female, compared to those in which both infants were male. There was no significant interaction between fetal sex and birth plurality. CONCLUSIONS: Female sex birth and multiple births are risk factors for the presence of NVP, and especially for severe NVP without interaction. These findings suggest that a factor abundant in the female fetus associates with the severity of NVP. PMID- 30416163 TI - Nationwide Survey of Pediatric Inpatients With Hand, Foot, and Mouth Disease, Herpangina, and Associated Complications During an Epidemic Period in Japan: Estimated Number of Hospitalized Patients and Factors Associated With Severe Cases. AB - BACKGROUND: Severe pediatric cases of hand, foot, and mouth disease (HFMD), herpangina (HA), and associated complications caused by enterovirus 71 (EV71) infection have brought substantial public health impact in Asia. This study aimed to elucidate the epidemiology of these pediatric cases in Japan. METHODS: A nationwide survey was conducted using stratified random sampling of hospital pediatric departments. We estimated the number of inpatients with HFMD, HA, and associated complications between April 1 and September 30, 2010, during which EV71 was circulating predominantly. Factors associated with severe cases with >=7 days of admission, sequelae, or outcome of death were analyzed using multivariate logistic regression. RESULTS: During the 6-month epidemic period, the number of pediatric inpatients aged <15 years was about 2,900 (estimated cumulative incidence of hospitalized cases: 17.0 per 100,000 population). Severe cases were significantly associated with younger age. Compared to patients >=5 years of age, the odds ratios (ORs) for <1 year of age and 1 to <3 years of age were 5.74 (95% confidence interval [CI], 2.14-15.4) and 2.94 (95% CI, 1.02-8.51), respectively. Elevated ORs for hyperglycemia (plasma glucose level of >=8.3 mmol/L) on admission (OR 3.60; 95% CI, 0.94-13.8) were also observed. CONCLUSIONS: Disease burden of pediatric inpatients with HFMD, HA, and associated complications in Japan was described for the first time. During an EV71 epidemic, younger age and, suggestively, hyperglycemia may have been critical factors requiring more careful treatment. PMID- 30416164 TI - Commentary: Test negative design reduces confounding by healthcare-seeking attitude in case-control studies. PMID- 30416165 TI - Host selectively contributes to shaping intestinal microbiota of carnivorous and omnivorous fish. AB - Fish production is increasingly important to global food security. A major factor in maintaining health, productivity and welfare of farmed fish is the establishment and promotion of a stable and beneficial intestinal microbiota. Understanding the effects of factors such as host and environment on gut microbial community structure is essential for developing strategies for stimulating the establishment of a health-promoting gut-microbiota. We compared intestinal microbiota of common carp and rainbow trout, two fish with different dietary habits, sourced from various farm locations. There were distinct differences in the gut microbiota of carp and trout intestine. The microbiota of carp was dominated by Fusobacteriia and Gammaproteobacteria, while the trout microbiota consisted predominantly of Mollicutes and Betaproteobacteria. The majority of bacterial sequences clustered into a relatively low number of operational taxonomic units (OTUs) revealing a comparatively simple microbiota, with Cetobacterium, Aeromonas and Mycoplasma being highly abundant. Within each species, fish from different facilities were found to have markedly similar predominant bacterial populations despite distinctly different rearing environments, demonstrating intra-species uniformity and significant influence of host selectivity. This study demonstrates that in fish the host species imparts substantial impact in shaping the community structure of the intestinal microbiota. PMID- 30416166 TI - L-type calcium channel-mediated Zinc wave is involved in the regulation of IL-6 by stimulating non-IgE with LPS and IL-33 in mast cells and dendritic cells. AB - The trace element zinc is essential for the immune system, and its dysregulation and deficiency results in impaired immune function. Recent studies have shown that zinc can behave as an intracellular signaling molecule in immune cells. We have previously demonstrated that L-type calcium channel (LTCC) is involved in the regulation of zinc signaling, Zinc wave and cytokine production by stimulating Fc epsilon receptor for IgE in mast cells. However, it is not known whether LTCC-mediated Zinc wave is required for cytokine production by stimulation of toll-like receptors and cytokine receptors in mast cells. Here we report that stimulation of toll-like receptors and cytokine receptors can induce Zinc wave in mast cells and regulate the expression of cytokine genes. The LTCC antagonist nicardipine inhibited LPS- and IL-33-mediated Zinc wave and the induction of cytokine genes such as IL-6. Consistent with these results, the zinc chelator TPEN also inhibited LPS- and IL-33-induced cytokine gene expression. Furthermore, LPS induced Zinc wave not only in mast cells but also in dendritic cells. Together, these observations show that Zinc wave is activated by various stimuli and is linked to cytokine gene induction in immune cells. PMID- 30416167 TI - Development of the Bioluminescent Immunoassay for the Detection of 5 Hydroxymethylcytosine in Dinoflagellate. PMID- 30416168 TI - Polyethylene Glycols for the Dispersion Development of Graphene in an Aqueous Surfactant Solution Studied by Affinity Capillary Electrophoresis. PMID- 30416169 TI - Mechanical properties of the coat protein layer and cortex in single Bacillus subtilis spores studied with the atomic force microscope and laser-induced surface deformation microscope. PMID- 30416170 TI - A benzothiazole-based ratiometric fluorescent probe for benzoyl peroxide and its applications for living cells imaging. PMID- 30416171 TI - Marked rebound thrombocytosis in response to glucocorticoids in a patient with acquired amegakaryocytic thrombocytopenia. AB - Acquired amegakaryocytic thrombocytopenia (AATP) is a rare disease characterized by thrombocytopenia and the disappearance of marrow megakaryocytes. A 43-year-old man was admitted because of thrombocytopenia of 1.0*109/L. Bone marrow aspirate demonstrated normal hematopoiesis lacking megakaryocytes, and AATP was diagnosed. The serum concentration of thrombopoietin (TPO) was high (7.72 fmol/mL). Prednisolone (PSL) at 60 mg/day was started and the platelet count recovered to 1,335*109/L; however, excessive megakaryocytopoiesis and subsequent decline in platelet count were noted 14 days later. At the peak platelet count, the TPO remained at 3.79 fmol/mL and returned to a normal level of 0.40 fmol/mL during the period of normal platelet count after PSL tapering. The marked thrombocytosis in response to prednisolone may have been caused by the high TPO after the resolution of suppressed megakaryopoiesis. Marked rebound thrombocytosis beyond 1,000*109/L after successful PSL treatment for AATP has not been previously reported. PMID- 30416172 TI - Hypercalcemia and osteolytic bone lesions as the major symptoms in a chronic lymphocytic leukemia/small lymphocytic lymphoma patient: a rare case. AB - We report a 40-year-old woman who presented with multiple osteolytic bone lesions and hypercalcemia, which are rarely caused by chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Although receiving intensive chemotherapy and allogeneic transplantation, the patient had a poor outcome with an overall survival of 2 years. To our knowledge, this presentation is extremely rare for B chronic lymphocytic leukemia, and new treatment strategies may be needed for long term control of the disease. PMID- 30416173 TI - Intraocular lymphoma as relapse after chemotherapy for primary breast diffuse large B-cell lymphoma. PMID- 30416175 TI - Studies on single-molecule bridging metal electrodes: development of new characterization technique and functionalities. AB - A single molecular junction is a nanoscale structure prepared by bridging a single molecule between macroscopic metal electrodes. It has attracted significant attention due to its unique structure and potential applications in ultra-small single molecular electronic devices. It has two metal-molecule interfaces, and thus the electronic structure of the molecule can be significantly modulated from its original one. The single molecular junction can be regarded as a new material that includes metal electrodes, a so-called "double interface material". Therefore, we can expect unconventional physical and chemical properties. To develop a better understanding of the properties and functionalities of single molecular junctions, their atomic and electronic structures should be characterized. In this review, we describe the development of these characterization techniques, such as inelastic electron tunneling spectroscopy, surface-enhanced Raman scattering, as well as shot noise and thermopower measurements. We have also described some unique properties and functionalities of single molecular junctions, such as switching and diode properties. PMID- 30416174 TI - Cytoskeletal control of nuclear migration in neurons and non-neuronal cells. AB - Cell migration is a complex molecular event that requires translocation of a large, stiff nucleus, oftentimes through interstitial pores of submicron size in tissues. Remarkable progress in the past decade has uncovered an ever-increasing array of diverse nuclear dynamics and underlying cytoskeletal control in various cell models. In many cases, the microtubule motors dynein and kinesin directly interact with the nucleus via the LINC complex and steer directional nuclear movement, while actomyosin contractility and its global flow exert forces to deform and move the nucleus. In this review, I focus on the synergistic interplay of the cytoskeletal motors and spatiotemporal sites of force transmission in various nuclear migration models, with a special focus on neuronal migration in the vertebrate brain. PMID- 30416176 TI - Evolutionary history of carabid ground beetles with special reference to morphological variations of the hind-wings. AB - Most beetles belonging to the subfamily Carabinae of the family Carabidae (so called carabid ground beetles) cannot fly, because their hind-wings are highly degenerated. However, about half of the species in the subtribe Calosomina within the same subfamily can fly. From extensive morphological examinations of the hind wings of Carabinae species in conjunction with DNA molecular phylogenetic trees, the process and possible causes of hind-wing degeneration in the Carabinae are discussed. PMID- 30416177 TI - Usefulness of MR Imaging in Idiopathic Oculomotor Nerve Palsy Cases: T2-weighted IDEAL. PMID- 30416178 TI - Diffusion Tensor Imaging of the Brachial Plexus: A Comparison between Readout segmented and Conventional Single-shot Echo-planar Imaging. AB - PURPOSE: Diffusion tensor imaging (DTI) adds functional information to morphological magnetic resonance neurography (MRN) in the assessment of the brachial nerve plexus. To determine the most appropriate pulse sequence in scan times suited for diagnostic imaging in clinical routine, we compared image quality between simultaneous multi-slice readout-segmented (rs-DTI) and conventional single-shot (ss-DTI) echo-planar imaging techniques. METHODS: Institutional Review Board (IRB) approved study including 10 healthy volunteers. The supraclavicular brachial plexus, covering the nerve roots and trunks from C5 to C7, was imaged on both sides with rs-DTI and ss-DTI. Both sequences were acquired in scan times <7 min with b-values of 900 s/mm2 and with isotropic spatial resolution. RESULTS: In rs-DTI image, the overall quality was significantly better and distortion artifacts were significantly lower (P = 0.001 0.002 and P = 0.001-0.002, respectively) for both readers. In ss-DTI, a trend toward lower degree of ghosting and motion artifacts was elicited (reader 1, P = 0.121; reader 2, P = 0.264). No significant differences between the two DTI techniques were found for signal-to-noise ratios (SNR), contrast-to-noise ratios (CNR) and fractional anisotropy (FA) (P >= 0.475, P >= 0.624, and P >= 0.169, respectively). Interreader agreement for all examined parameters and all sequences ranged from intraclass correlation coefficient (ICC) 0.064 to 0.905 and Kappa 0.40 to 0.851. CONCLUSION: Incomparable acquisition times rs-DTI showed higher image quality and less distortion artifacts than ss-DTI. The trend toward a higher degree of ghosting and motion artifacts in rs-DTI did not deteriorate image quality to a significant degree. Thus, rs-DTI should be considered for functional MRN of the brachial plexus. PMID- 30416179 TI - Impact of the Number of Iterations in Compressed Sensing Reconstruction on Ultrafast Dynamic Contrast-enhanced Breast MR Imaging. AB - PURPOSE: To assess the impact of the number of iterations of compressed sensing (CS) reconstruction on the kinetic parameters and image quality in dynamic contrast-enhanced (DCE)-MRI of the breast, with prospectively undersampled CS accelerated scans. MATERIALS AND METHODS: Breast examinations including ultrafast DCE-MRI using CS were conducted for 21 patients. Images were reconstructed with different numbers of iterations. The peak enhancement ratio of the aorta and wash in slope, initial area under the curve, and Ktrans of the breast lesions were measured. The root mean square error and structural similarity between the images using 50 iterations and images with a lower number of iterations were evaluated as criterion for quantitative image evaluation. RESULTS: Using an insufficient number of iterations, the contrast-enhanced effect was highly underestimated. In all semi-quantitative parameters, the number of iterations that stabilized the parameters in malignant lesions was higher than that in benign lesions. At least 15 iterations were needed for semi-quantitative parameters. For Ktrans, there were no significant differences between 10 and 50 iterations in both malignant and benign lesions. CONCLUSION: The kinetic parameters using ultrafast DCE-MRI with CS are affected by the number of iterations, especially in malignant lesions. However, if the images are reconstructed with an adequate number of iterations, ultrafast DCE-MRI with CS can be a powerful technique having high temporal and spatial resolution. PMID- 30416180 TI - A Fast GPU-optimized 3D MRI Simulator for Arbitrary k-space Sampling. AB - PURPOSE: To develop a fast 3D MRI simulator for arbitrary k-space sampling using a graphical processing unit (GPU) and demonstrate its performance by comparing simulation and experimental results in a real MRI system. MATERIALS AND METHODS: A fast 3D MRI simulator using a GeForce GTX 1080 GPU (NVIDIA Corporation, Santa Clara, CA, USA) was developed using C++ and the CUDA 8.0 platform (NVIDIA Corporation). The unique advantage of this simulator was that it could use the same pulse sequence as used in the experiment. The performance of the MRI simulator was measured using two GTX 1080 GPUs and 3D Cones sequences. The MRI simulation results for 3D non-Cartesian sampling trajectories like 3D Cones sequences using a numerical 3D phantom were compared with the experimental results obtained with a real MRI system and a real 3D phantom. RESULTS: The performance of the MRI simulator was about 3800-4900 gigaflops for 128- to 4-shot 3D Cones sequences with 2563 voxels, which was about 60% of the performance of the previous MRI simulator optimized for Cartesian sampling calculated for a Cartesian sampling gradient-echo sequence with 2563 voxels. The effects of the static magnetic field inhomogeneity, radio-frequency field inhomogeneity, gradient field nonlinearity, and fast repetition times on the MR images were reproduced in the simulated images as observed in the experimental images. CONCLUSION: The 3D MRI simulator developed for arbitrary k-space sampling optimized using GPUs is a powerful tool for the development and evaluation of advanced imaging sequences including both Cartesian and non-Cartesian k-space sampling. PMID- 30416181 TI - Signal Intensity of the Cerebrospinal Fluid after Intravenous Administration of Gadolinium-based Contrast Agents: Strong Contrast Enhancement around the Vein of Labbe. AB - PURPOSE: Since the first report on the deposition of gadolinium in the brain parenchyma after repeated intravenous administrations of gadolinium-based contrast agent GBCA (IV-GBCA), the mechanisms of penetration and retention are still remaining a hot topic of discussion and a target of investigation. We routinely obtain endolymphatic hydrops (EH) images at 4 h after IV administration of a single dose (SD) of GBCA (IV-SD-GBCA) using heavily T2-weighted three dimensional fluid-attenuated inversion recovery imaging (hT2W-3D-FLAIR). Occasionally, we have encountered cases, which indicate high-signal intensity (SI) in the cerebrospinal fluid (CSF) surrounding the vein of Labbe. The purpose of the present study was to investigate the degree of contrast enhancement of the CSF surrounding the vein of Labbe on hT2W-3D-FLAIR after IV-SD-GBCA in comparison with other CSF spaces. MATERIALS AND METHODS: In 25 patients with a suspicion of EH, a magnetic resonance cisternography (MRC) and an hT2W-3D-FLAIR were obtained at 4 h after IV-SD-GBCA. The perivascular space (PVS) in the basal ganglia, CSF spaces in the ambient cistern (CSF-Amb), the CSF surrounding the superficial middle cerebral vein (CSF-SMCV), and the CSF surrounding the vein of Labbe (CSF VL) were segmented on MRC. The PVS and CSF regions were co-registered onto the hT2W-3D-FLAIR and the SI of the PVS and CSF spaces were measured. The SI ratio (SIR) of the post-contrast hT2W-3D-FLAIR to the pre-contrast hT2W-3D-FLAIR was measured. Significant differences were evaluated using Steel-Dwass's test for multiple comparisons. RESULTS: The SIR of the CSF-VL was significantly higher than that of the PVS (P = 0.008), the CSF-Amb (P = 0.021), and the CSF-SMCV (P = 0.023). CONCLUSION: The strong contrast enhancement of CSF space around the vein of Labbe was confirmed on hT2W-3D-FLAIR at 4 h after IV-GBCA compared to the PVS and the other CSF spaces. PMID- 30416182 TI - Silver Nanoparticles. PMID- 30416183 TI - Application of Hierarchical CuO Bowl-like Array Film to Amperometric Detection of l-Ascorbic Acid. AB - A hierarchical CuO array film was fabricated by electrochemical deposition with the aid of a colloidal monolayer as a template, followed by oxidation at high temperature. The prepared CuO film with a granular structure was arranged with ordered, hexagonal close-packed, and bowl-like pores. Combined with a gold layer sputtered on a glass substrate, this CuO array film was used as an electrochemical electrode in the amperometric detection of l-ascorbic acid. The array film exhibited a high sensitivity of 3484 MUA mM-1 cm-2, a wide linear range from 1 MUM to 7 mM, and a detection limit of 0.2 MUM. Excellent stability was also achieved. The results demonstrate that the hierarchical CuO bowl-like array film is a promising new platform for the construction of non-enzymatic ascorbic acid sensors. PMID- 30416184 TI - A Microchip Electrophoresis Device Integrated with the Top-bottom Antiparallel Electrodes of Indium Tin Oxide to Detect Inorganic Ions by Contact Conductivity. AB - A microchip electrophoresis (ME) device with off-channel contact conductivity detection (C2D) was constructed using top-bottom antiparallel indium tin oxide (ITO) electrodes and a cross-type microchannel. The 500-m wide top-bottom antiparallel decouplers were found to effectively decrease the interference of the electrophoretic current. The cross-type microchannel was formed by bonding the patterned negative photoresist microstructures and the two top-bottom opposed ITO-deposited glass substrates. Five seconds of 150 V/cm injection field and the 100 V/cm separation field equipped with the C2D of AC 200 mV excitation voltage provided adequate ME operational parameters to obtain the K+ and Na+ peaks separation. The ME devices obtained good coefficients in a range of 11000 MUM for the K+ and Na+ detection. The calculated limit of detection was 1 MUM. This design for off-channel and top-bottom antiparallel electrodes shows that C2D ME devices have great potential for the measurement of inorganic ions. PMID- 30416185 TI - Amperometric Glucose Biosensor Utilizing Zinc Oxide-chitosan-glucose Oxidase Hybrid Composite Films on Electrodeposited Pt-Fe(III). AB - We developed an amperometric glucose biosensor based on glucose oxidase (GOx) embedded in zinc oxide (ZnO)-chitosan (CS) hybrid composite films on electrodeposited Pt-Fe(III). This sensor exhibited a fast amperometric response (less than 10 s) to glucose, linearity from 10 MUM to 11.0 mM of glucose with a detection limit of 1.0 MUM (S/N = 3) and sensitivity of 30.70 MUA mM-1 cm-2. An apparent Michaelis-Menten constant of 5.19 mM indicated high affinity between glucose and GOx immobilized in the ZnO-CS films. The effect of interferences such as uric acid, ascorbic acid, and acetaminophen on the performance of this sensor was negligible. In addition, this sensor retained 87% of its initial performance after two weeks of storage at 4 degrees C, indicating that the hybrid composite films allowed successful immobilization of GOx with its high enzymatic activity. PMID- 30416186 TI - A Novel Solution-auto-introduction Electrophoresis Microchip Based on Capillary Force. AB - A novel solution-auto-introduction electrophoresis microchip based on capillary force aimed at improving portability is proposed in this paper. Two kinds of materials with micropores, poly(vinyl alcohol) (PVA)-sponge and nano-sponge, were employed as suction pumps that realized the introduction of a running buffer into the reservoirs. The surfaces of the microchannels in the microchips were modified by PVA to improve the moving velocity of the running buffer and the detection performance of the microchip. The introduction velocity of a running buffer in the PVA-coated microchannels was increased by two times compared with that in the native microchannels. The electrophoresis detection performance of several microchips composed of different microchannels and suction materials were evaluated comparatively. The results indicated that the surface coating of PVA can significantly improve the repeatability of the detection results by 20 - 40%, and the noise of the detected signals in the PVA-coated microchips is much lower than that in the native microchips. The proposed solution-auto-introduction electrophoresis microchip is a successful attempt that completely avoids the external connectors to accomplish the auto-introduction of running buffer. The solution-auto-introduction method provides a new train of thought for portable detection instruments with electrophoresis microchips in the future. PMID- 30416189 TI - Effect of Statins on Mortality in Heart Failure With Preserved Ejection Fraction Without Coronary Artery Disease - Report From the JASPER Study. AB - BACKGROUND: Statins might be associated with improved survival in patients with heart failure with preserved ejection fraction (HFpEF). The effect of statins in HFpEF without coronary artery disease (CAD), however, remains unclear.Methods and Results:From the JASPER registry, a multicenter, observational, prospective cohort with Japanese patients aged >=20 years requiring hospitalization with acute HF and LVEF >=50%, 414 patients without CAD were selected for outcome analysis. Based on prescription of statins at admission, we divided patients into the statin group (n=81) or no statin group (n=333). We followed them for 25 months. The association between statin use and primary (all-cause mortality) and secondary (non-cardiac death, cardiac death, or rehospitalization for HF) endpoints was assessed in the entire cohort and in a propensity score-matched cohort. In the propensity score-matched cohort, 3-year mortality was lower in the statin group (HR, 0.21; 95% CI: 0.06-0.72; P=0.014). The statin group had a significantly lower incidence of non-cardiac death (P=0.028) and rehospitalization for HF (P<0.001), but not cardiac death (P=0.593). The beneficial effect of statins on mortality did not have any significant interaction with cholesterol level or HF severity. CONCLUSIONS: Statin use has a beneficial effect on mortality in HFpEF without CAD. The present findings should be tested in an adequately powered randomized clinical trial. PMID- 30416187 TI - Identification of Confusable Herbal Medicines by Mapping of Partial Degradation Products from Herbal Medicine Polysaccharides. AB - Partial degradation products (PDPs) of herbal medicine (HM) polysaccharides with precolumn derivatization using 1-phenyl-3-methy-5-pyrazolone (PMP) were mapped by high performance liquid chromatography (HPLC), and three groups of confusable HMs were differentiated using the PDP fingerprints assisted with cluster analysis (CA). Three variables of HPLC mobile phase, i.e. acetonitrile proportion, buffer concentration and pH value were optimized with PDP of beta-cyclodextrin. Radix Glehniae and Radix Adenophorae; Radix Sophorae Tokinensis and Rhizoma Menispermi; Radix Achyranthis Bidentatae and Radix Cyathulae were successfully distinguished by the method, respectively. The results involving mass spectrometry analysis showed that these PDPs primarily included oligosaccharides and a few monosaccharides. The method can be used as an effective approach for the identification and quality control of HMs, and can also facilitate the in-depth study of biological activity and further development of HM polysaccharides to some extent. PMID- 30416190 TI - First-in-Man Clinical Pilot Study Showing the Safety and Efficacy of Intramuscular Injection of Basic Fibroblast Growth Factor With Atelocollagen Solution for Critical Limb Ischemia. AB - BACKGROUND: Therapeutic angiogenesis with basic fibroblast growth factor (bFGF) with atelocollagen was confirmed in a study using a limb ischemia mouse model. Because the number of elderly patients with critical limb ischemia (CLI) is increasing, particularly that caused by arteriosclerosis obliterans (ASO), the development of less invasive angiogenesis therapies desired. Methods and Results: This first-in-man clinical study was designed to assess the safety and efficacy of i.m. injection of bFGF with atelocollagen. Human recombinant bFGF (200 MUg), combined with 4.8 mL 3% atelocollagen solution, was prepared and injected into the gastrocnemius muscle of the ischemic leg. The primary endpoint was safety, evaluated on all adverse events over 48 weeks after this treatment. The secondary endpoint was efficacy, evaluated by improvement of ischemic symptoms. No serious procedure-related adverse events were observed during the follow-up period. Visual analogue scale (VAS) score was significantly improved at 4, 24 and 48 weeks compared with baseline (P<0.05), and 7 patients became pain free during the follow-up period. Fontaine classification was improved in 4 of 10 patients at 48 weeks. Cyanotic lesions disappeared in 2 patients at 4 weeks. CONCLUSIONS: I.m. injection of bFGF with atelocollagen is safe and feasible in patients with CLI. Randomized controlled trials are therefore needed to confirm these results. PMID- 30416191 TI - Acute Coronary Syndrome With Unprotected Left Main Coronary Artery Culprit - An Observation From the AOI-LMCA Registry. AB - BACKGROUND: Data on the clinical outcomes of percutaneous coronary intervention (PCI) for unprotected left main coronary artery (LMCA) in patients with acute coronary syndrome (ACS) are limited. Therefore, this study aimed to assess the clinical outcome of patients with ACS who underwent PCI for LMCA culprit lesion.Methods and Results:Of 1,809 patients enrolled in the Assessing Optimal Percutaneous Coronary Intervention for the LMCA (AOI-LMCA) registry (a retrospective 6-center registry of consecutive patients undergoing LMCA stenting in Japan), the current study population consisited of 1,500 patients with unprotected LMCA stenting for LMCA ACS (ACS with shock: 115 patients, ACS without shock: 281 patients) and stable CAD (1,104 patients). The cumulative 180-day incidence of death was markedly higher in the ACS with shock group than in the other groups (49.5%, 8.6%, and 3.3%, respectively; P<0.0001), but mortality beyond 180-day was not significantly different among the 3 groups (30.2%, 20.4%, and 19.5%, respectively; P=0.65). In the ACS with shock group, the initial TIMI flow grade did not affect 5-year mortality (57.1% and 62.2%, P=0.99), but in the ACS without shock group, 5-year mortality was significantly higher in patients with initial TIMI flow grade <=1 than in patients with TIMI flow grade >=2 (44.4% and 23.7%, respectively; P=0.008). CONCLUSIONS: In patients with LMCA ACS, survival correlates with baseline hemodynamic and coronary flow status. PMID- 30416192 TI - Preventive measures for fire-related injuries and their risk factors in residential buildings: a systematic review. AB - BACKGROUND: Every year, a large number of people lose their lives or become injured seriously as a result of fires. Fires in buildings pose a great threat to resident safety. The aim of this systematic review is to identify preventive measures for fire-related injuries in residential buildings, taking into account associated risk factors. METHODS: In this study, a systematic review was performed of all studies conducted in the field of residential building fires, influencing factors and available safety procedures. From the earliest record up to 7 July 2017, databases of PubMed, Web of Science/Knowledge, and Scopus were searched and selected articles included in the study. RESULTS: A total of 5,613 published articles were examined, of which 30 were finally found to meet the inclusion criteria. The findings of the study were included in two main groups of preventive measures and risk factors for residential building fires and related injuries. Regarding preventive measures, the factors to reduce the risk of fire related injuries raised in the studies under review included rule amendments, changes and modification of the environment, behavior change such as emergency evacuation during fire occurrence, improvements to emergency medical services, and awareness-raising. Also, many of the studies showed that areas with a large number of young children, older people, people with physical and mental disabilities, alcohol and drug addicts, smokers, single-family households and low income families were particularly at risk of fire-related injuries and deaths. CONCLUSIONS: There are features in residential buildings and attributes among residents that can be related to fire hazard and fire-related injuries and deaths. The most important point of this study is to focus on preventive strategies including environmental modification, promotion of safety rules and changes in risk behavior among residents. Policy makers should pay more attention to these important issues in order to promote safety and injury prevention in relation to building fires. PMID- 30416193 TI - Chronic Hyponatremia Due to the Syndrome of Inappropriate Antidiuresis (SIAD) in an Adult Woman with Corpus Callosum Agenesis (CCA). AB - BACKGROUND Corpus callosum agenesis (CCA) is one of the most common congenital brain abnormalities, and is associated with neurodevelopmental and neuropsychiatric disorders. In CCA, defects in osmoregulation have been reported. This report presents a rare case of chronic hyponatremia associated with the syndrome of inappropriate antidiuresis (SIAD) in a woman with CCA. CASE REPORT A 41-year-old woman presented to the renal unit with symptomatic hyponatremia. In her past medical history, she had a four-year history of systemic arterial hypertension and Sjogren's syndrome, and a three-year history of systemic lupus erythematosus (SLE), which was treated with cyclophosphamide. She had CCA but with irregular neurological follow-up. During the previous eight years, her plasma sodium levels ranged from between 118-134 mEq/L. On this hospital admission, she had plasma hypo-osmolality, measured in milli-osmoles per kilogram of H2O (mOsm/kg H2O), of 251 mOsm/Kg H2O, and a urinary hyper-osmolality of 545 mOsm/Kg H2O, and increased level of plasma antidiuretic hormone (ADH) (1.8 pg/ml). Bone densitometry was consistent with osteoporosis. The patient remained asymptomatic during her hospital stay. Chronic hyponatremia associated with the SIAD was diagnosed. Water restriction and increased protein intake resulted in a partial improvement in the serum sodium level (128-134 mEq/L). The patient was discharged from the hospital with outpatient follow-up. CONCLUSIONS A rare case of chronic hyponatremia due to the SIAD associated with CCA is reported that demonstrates the importance of correct diagnosis, management, and clinical follow up of the SIAD, including bone densitometry. PMID- 30416194 TI - Long Noncoding RNA FEZF1-AS1 Promotes Proliferation and Inhibits Apoptosis in Ovarian Cancer by Activation of JAK-STAT3 Pathway. AB - BACKGROUND Long noncoding RNAs (lncRNAs) have been acknowledged as important regulators in human cancers, including ovarian cancer. Several reports identified lncRNA FEZF1-AS1 as an oncogene in gastric cancer, colorectal carcinoma, and non small cell lung cancer (NSCLC). However, the function of FEZF1-AS1 in ovarian cancer remains largely unknown. This study was aimed to investigate the role of FEZF1-AS1 in ovarian cancer. MATERIAL AND METHODS FEZF1-AS1 expression levels in pairs of ovarian cancer tissues and adjacent normal tissues were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Kaplan-Meier curve analysis was used to determine the correlation between FEZF1-AS1 expression and prognosis in ovarian cancer patients. The effects of FEZF1-AS1 knockdown on ovarian cancer cell proliferation, cell-cycle, and apoptosis were analyzed by Cell Counting Kit-8 (CCK8) and Fluorescence activated Cell Sorting (FACS) assays. Western blot was utilized to assess the effect of FEZF1-AS1 on the activation of JAK-STAT3 pathway. RESULTS FEZF1-AS1 was overexpressed in ovarian cancer tissues compared to adjacent normal tissues. Consistently, FEZF1-AS1 expression was also upregulated in ovarian cancer cell lines compared with normal cell line. Furthermore, higher expression of FEZF1-AS1 in ovarian cancer patients contributed to poorer prognosis. FEZF1-AS1 knockdown significantly suppressed the proliferation and promoted apoptosis in ovarian cancer cells. In mechanism, FEZF1 AS1 regulated activation of JAK-STAT3 signaling pathway by modulating STAT3 phosphorylation. Knockdown of FEZF1-AS1 significantly impaired the phosphorylation of STAT3. CONCLUSIONS Our study demonstrated that FEZF1-AS1 exerted an oncogenic role in ovarian cancer via modulating JAK-STAT3 pathway. PMID- 30416195 TI - Effect of Bariatric Surgery on Semen Parameters: A Systematic Review and Meta Analysis. AB - BACKGROUND The present systematic review and meta-analysis was performed to explore the possible effect of bariatric surgery on semen parameters. MATERIAL AND METHODS Studies on the effect of bariatric surgeries on semen parameters were collected by searching Cochrane Library, PUBMED, EMBASE, MEDLINE, and CNKI databases. We extracted information on essential data and outcome measures, including study design, bariatric surgery, and semen parameters at baseline and after the surgery from the included studies, and STATA 12.0 software was applied to conduct the meta-analysis. Predefined subgroup analyses were also conducted by study design and bariatric surgical procedures. The standard mean difference (SMD) was calculated to estimate the effect on semen parameters. RESULTS After the literature search, 6 articles that fulfilled the inclusion criteria were included in the present meta-analysis. The results revealed that patients who had undergone gastric bypass surgery had an increase in semen volume (SMD (95%CI)=0.583 (0.121-1.045), p=0.013). However, the seminal concentration (overall, SMD (95%CI)=-0.123 (-0.418-0.173), p=0.416) and the semen progressive motility (overall SMD (95%CI)=0.148 (-0.148-0.444), p=0.328) remained unchanged after the bariatric surgery. Nevertheless, semen normal morphology experienced an increase in the subgroup of prospective design and sleeve gastrectomy (prospective study, SMD (95%CI)= 0.385 (0.074-0.697), p=0.015, sleeve gastrectomy, SMD (95%CI)=0.880 (0.465-1.296), p=0.000; overall, SMD (95%CI)=0.372 (0.068-0.677), p=0.017). CONCLUSIONS In conclusion, based on the limitations of the present meta-analysis, definite conclusions cannot be reached regarding the possible effect of bariatric surgery on semen parameters. PMID- 30416196 TI - TWIK-1/TASK-3 heterodimeric channels contribute to the neurotensin-mediated excitation of hippocampal dentate gyrus granule cells. AB - Two-pore domain K+ (K2P) channels have been shown to modulate neuronal excitability. The physiological role of TWIK-1, the first identified K2P channel, in neuronal cells is largely unknown, and we reported previously that TWIK-1 contributes to the intrinsic excitability of dentate gyrus granule cells (DGGCs) in mice. In the present study, we investigated the coexpression of TWIK-1 and TASK-3, another K2P member, in DGGCs. Immunohistochemical staining data showed that TASK-3 proteins were highly localized in the proximal dendrites and soma of DGGCs, and this localization is similar to the expression pattern of TWIK-1. TWIK 1 was shown to associate with TASK-3 in DGGCs of mouse hippocampus and when both genes were overexpressed in COS-7 cells. shRNA-mediated gene silencing demonstrated that TWIK-1/TASK-3 heterodimeric channels displayed outwardly rectifying currents and contributed to the intrinsic excitability of DGGCs. Neurotensin-neurotensin receptor 1 (NT-NTSR1) signaling triggered the depolarization of DGGCs by inhibiting TWIK-1/TASK-3 heterodimeric channels, causing facilitated excitation of DGGCs. Taken together, our study clearly showed that TWIK-1/TASK-3 heterodimeric channels contribute to the intrinsic excitability of DGGCs and that their activities are regulated by NT-NTSR1 signaling. PMID- 30416198 TI - Education Outcomes of Immigrant Youth: The Role of Parental Engagement. AB - Using the 2009-2012 waves of the High School Longitudinal Survey, this article examines the role of parental engagement on academic achievement in the United States. Specifically, we examine the influence of parental engagement while also investigating the academic trajectories of racial/ethnic and immigrant groups, controlling for other standard factors. Results suggest that the progression of students' academic performance varies substantially by race/ethnicity and by immigrant generational status. After controlling for 9th grade test scores and family and other school-level characteristics, we find that first-generation immigrant youth generally have higher 11th grade test scores and lower probability of dropping out compared to native-born students who are second or third generation. Greater levels of parental engagement predict superior test scores and lower rates of dropout for youth of various racial and immigrant generation backgrounds, even in the presence of a variety of controls. PMID- 30416197 TI - Genotype Matters in Patients with Acute-on-chronic Liver Failure Due to Reactivation of Chronic Hepatitis B. AB - BACKGROUND: Acute-on-chronic liver failure (ACLF) can be caused by reactivation of chronic hepatitis B virus (HBV) infection (HBV-ACLF). It's unclear whether HBV genotypes affect the clinical and therapeutical outcomes of patients with HBV ACLF. This study was to investigate the short-term antiviral response and overall survival in HBV-ACLF patients treated by tenofovir or entecavir. METHODS: Seventy three consecutive patients with HBV-ACLF were stratified into genotype B group (n = 33) and C group (n = 40). They were prospectively followed-up. RESULTS: At 2 weeks, the genotype B group had significantly lower HBV-DNA load (P = 0.005), greater HBV-DNA decline (P = 0.026), higher proportion of patients with HBV-DNA < 500 IU/ml (P = 0.007), improved Child-Turcotte-Pugh (CTP; P = 0.032) and model for end-stage liver disease (MELD; P = 0.039) scores compared to the genotype C group. At three months, survivors in both groups had undetectable HBV-DNA loads, comparable CTP (P = 0.850) and MELD (P = 0.861) scores; the genotype C group had markedly lower overall survival rate than the B group (P = 0.013). The genotype (hazard ratio [HR]: 2.138; 95% confidence interval [CI]: 1.034-4.143; P = 0.041), MELD score (HR:1.664, 95%CI: 1.077-2.571; P = 0.022) and HBV-DNA decline (HR: 0.225, 95% CI: 0.067-0.758; P = 0.016) at 2 weeks were significantly associated with mortality at 3 months. No severe adverse event was noted. CONCLUSIONS: Genotype B was associated with better short-term antiviral response and clinical outcome compared to genotype C in patients with HBV-ACLF. PMID- 30416199 TI - Experimental explanation of the formation mechanism of surface mound-structures by femtosecond laser on polycrystalline Ni60Nb40. AB - Femtosecond laser surface processing (FLSP) is an emerging technique for creating functionalized surfaces with specialized properties, such as broadband optical absorption or superhydrophobicity/superhydrophilicity. It has been demonstrated in the past that FLSP can be used to form two distinct classes of mound-like, self-organized micro/nanostructures on the surfaces of various metals. Here, the formation mechanisms of below surface growth (BSG) and above surface growth (ASG) mounds on polycrystalline Ni60Nb40 are studied. Cross-sectional imaging of these mounds by focused ion beam milling and subsequent scanning electron microscopy revealed evidence of the unique formation processes for each class of microstructure. BSG-mound formation during FLSP did not alter the microstructure of the base material, indicating preferential valley ablation as the primary formation mechanism. For ASG-mounds, the microstructure at the peaks of the mounds was clearly different from the base material. Transmission electron microscopy revealed that hydrodynamic melting of the surface occurred during FLSP under ASG-mound forming conditions. Thus, there is a clear difference in the formation mechanisms of ASG- and BSG-mounds during FLSP. PMID- 30416200 TI - Understanding and Reducing False Alarms in Observational Fog Prediction. AB - The reduction in visibility that accompanies fog events presents a hazard to human safety and navigation. However, accurate fog prediction remains elusive, with numerical methods often unable to capture the conditions of fog formation, and observational methods having high false-alarm rates in order to obtain high hit rates of prediction. In this work, 5 years of observations from the Cabauw Experimental Site for Atmospheric Research are used to further investigate how false alarms may be reduced using the statistical method for diagnosing radiation fog events from observations developed by Menut et al. (Boundary-Layer Meteorol 150:277-297, 2014). The method is assessed for forecast lead times of 1-6 h and implementing four optimization schemes to tune the prediction for different needs, compromising between confidence and risk. Prediction scores improve significantly with decreased lead time, with the possibility of achieving a hit rate of over 90% and a false-alarm rate of just 13%. In total, a further 31 combinations of predictive variables beyond the original combination are explored (including mostly, e.g., variables related to moisture and static stability of the boundary layer). Little change to the prediction scores indicates any appropriate combination of variables that measure saturation, turbulence, and near-surface cooling can be used. The remaining false-alarm periods are manually assessed, identifying the lack of spatio-temporal information (such as the temporal evolution of the local conditions and the advective history of the airmass) as the ultimate limiting factor in the methodology's predictive capabilities. Future observational studies are recommended that investigate the near-surface evolution of fog and the role of non-local heterogeneity on fog formation. PMID- 30416201 TI - The accuracy of standard enthalpies and entropies for phases of petrological interest derived from density-functional calculations. AB - The internal energies and entropies of 21 well-known minerals were calculated using the density functional theory (DFT), viz. kyanite, sillimanite, andalusite, albite, microcline, forsterite, fayalite, diopside, jadeite, hedenbergite, pyrope, grossular, talc, pyrophyllite, phlogopite, annite, muscovite, brucite, portlandite, tremolite, and CaTiO3-perovskite. These thermodynamic quantities were then transformed into standard enthalpies of formation from the elements and standard entropies enabling a direct comparison with tabulated values. The deviations from reference enthalpy and entropy values are in the order of several kJ/mol and several J/mol/K, respectively, from which the former is more relevant. In the case of phase transitions, the DFT-computed thermodynamic data of involved phases turned out to be accurate and using them in phase diagram calculations yields reasonable results. This is shown for the Al2SiO5 polymorphs. The DFT based phase boundaries are comparable to those derived from internally consistent thermodynamic data sets. They even suggest an improvement, because they agree with petrological observations concerning the coexistence of kyanite + quartz + corundum in high-grade metamorphic rocks, which are not reproduced correctly using internally consistent data sets. The DFT-derived thermodynamic data are also accurate enough for computing the P-T positions of reactions that are characterized by relatively large reaction enthalpies (> 100 kJ/mol), i.e., dehydration reactions. For reactions with small reaction enthalpies (a few kJ/mol), the DFT errors are too large. They, however, are still far better than enthalpy and entropy values obtained from estimation methods. PMID- 30416202 TI - Radiation interception, extinction coefficient and use efficiency of wheat crop at various irrigation and nitrogen levels in a semi-arid location. AB - Field experiments were conducted to study the effect of irrigation and nitrogen levels on radiation use efficiency (RUE), radiation extinction coefficient (kappa) and temporal variation of leaf area index (LAI) and fraction intercepted photosynthetically active radiation (fIPAR). The LAI of wheat increased with increase in irrigation and nitrogen levels. The fIPAR also followed trend similar to LAI. The LAI and fIPAR showed logarithmic relationship with R2 value of 0.92 and 0.93 for the years 2013-2014 and 2014-2015, respectively. The kappa value varied between 0.41 and 0.78 and was significantly affected by nitrogen levels but was not influenced by irrigation levels. The grain and above ground biomass (AGB) yields of wheat were not affected significantly by irrigation levels. However, application of 160 kg N ha-1 (N160) registered higher grain (12-33%) and AGB (22-25%) yeilds as compared to that with application of 40 kg N ha-1 (N40). Similar to AGB, the total intercepted photosynthetically active radiation (TIPAR) was not affected by irrigation levels but N160 treatment registered 9-20% higher TIPAR compared to N40 treatment. The linear relationship between TIPAR and AGB revealed that 83-86% variation in AGB yield of wheat can be explained by TIfIPAR. The RUE of wheat under three irrigations (I3) was 6 and 18% higher (P < 0.05) than the five (I5) and two (I2) irrigation treatments, respectively for the year 2013-2014. However, there was no significant effect of irrigation on RUE of wheat in the year 2014-2015. N160 treatment registered 5-13% higher RUE than the N40 treatment. Thus wheat may be grown with three irrigations (CRI, flowering and grain filling) and 160 kg N ha-1 for higher RUE without significant reduction in AGB of wheat compared to five irrigation levels in semi-arid location of Delhi region. PMID- 30416203 TI - The evolution of caste-biasing symbionts in the social hymenoptera. AB - The separation of individuals into reproductive and worker castes is the defining feature of insect societies. However, caste determination is itself a complex phenomenon, dependent on interacting genetic and environmental factors. It has been suggested by some authors that widespread maternally transmitted symbionts such as Wolbachia may be selected to interfere with caste determination, whilst others have discounted this possibility on theoretical grounds. We argue that there are in fact three distinct evolutionary scenarios in which maternally transmitted symbionts might be selected to influence the process of caste determination in a social hymenopteran host. Each of these scenarios generate testable predictions which we outline here. Given the increasing recognition of the complexity and multi-faceted nature of caste determination in social insects, we argue that maternally transmitted symbionts should also be considered as possible factors influencing the development of social hymenopterans. PMID- 30416204 TI - Environmental barriers to sociality in an obligate eusocial sweat bee. AB - Understanding the ecological and environmental contexts in which eusociality can evolve is fundamental to elucidating its evolutionary origins. A sufficiently long active season is postulated to have been a key factor facilitating the transition to eusociality. Many primitively eusocial species exhibit an annual life cycle, which is thought to preclude the expression of eusociality where the active season is too short to produce successive worker and reproductive broods. However, few studies have attempted to test this idea experimentally. We investigated environmental constraints on the expression of eusociality in the obligate primitively eusocial sweat bee Lasioglossum malachurum, by transplanting nest foundresses from the south to the far north of the United Kingdom, far beyond the natural range of L. malachurum. We show that transplanted bees can exhibit eusociality, but that the short length of the season and harsher environmental conditions could preclude its successful expression. In one year, when foundresses were transplanted only after provisioning first brood (B1) offspring, workers emerged in the north and provisioned a second brood (B2) of reproductives. In another year, when foundresses were transplanted prior to B1 being provisioned, they were just as likely to initiate nesting and provisioned just as many B1 cells as foundresses in the south. However, the life cycle was delayed by approximately 7 weeks and nests suffered 100% B1 mortality. Our results suggest that short season length together with poor weather conditions represent an environmental barrier to the evolution and expression of eusociality in sweat bees. PMID- 30416206 TI - Multiple Pathways to Success: An Examination of Integrative Motivational Profiles Among Upper Elementary and College Students. AB - Two studies were conducted with distinct samples to investigate how motivational beliefs cohere and function together (i.e., motivational profiles) and predict academic adjustment. Integrating across motivational theories, participants (N Study 1 = 160 upper elementary students; N Study 2 = 325 college students) reported on multiple types of motivation (achievement goals, task value, perceived competence) for schooling more generally (Study 1) and in science (Study 2). Three profiles characterized by Moderate-High All, Intrinsic and Confident, and Average All motivation were identified in both studies. Profiles characterized by Very High All motivation (Study 1) and Moderate Intrinsic and Confident (Study 2) were also present. Across studies, the Moderate-High All and Intrinsic and Confident profiles were associated with the highest academic engagement and achievement. Findings highlight the benefit of integrating across motivational theories when creating motivational profiles, provide initial evidence regarding similarities and differences in integrative motivational profiles across distinct samples, and identify which motivational combinations are associated with beneficial academic outcomes in two educational contexts. PMID- 30416205 TI - Developmental changes in gene expression and enzyme activities of anabolic and catabolic enzymes for storage carbohydrates in the honeybee, Apis mellifera. AB - Glycogen and trehalose are important sources of energy in insects. The expression of genes encoding the key metabolic enzymes-glycogen synthase (GS), glycogen phosphorylase (GP), trehalose-6-phosphate synthase (TPS-1), soluble trehalase (Tre-1) and membrane-bound trehalase (Tre-2)-was analyzed in 12 developmental stages of Apis mellifera worker brood. The content of GS and GP proteins, TPS activity, total trehalase activity, and the activity of Tre-1 and Tre-2 were determined. Transcript quantity was not always correlated with the content of the encoded GS or GP protein. The correlation was higher for GS (r = 0.797) than GP (r = 0.651). The expression of the glycogen synthase gene (gs) and the glycogen phosphorylase gene (gp) was high in 4- and 7-day-old larvae and in pupae, excluding the last pupal stage. The expression of the tps-1 gene was highest in the mid-pupal stage and contributed to higher enzyme activity in that stage. The expression of the tre-1 gene was higher than the expression of the tre-2 gene throughout development. In newly hatched workers, the expression of genes encoding catabolic enzymes of both carbohydrates, gp and tre-1, was higher than the expression of genes encoding anabolic enzymes. The results of this study suggest that sugar metabolism genes have somewhat different control mechanisms during larval development and metamorphosis. PMID- 30416207 TI - Doing it All? Mothers' College Enrollment, Time Use, and Affective Well-being. AB - The rising share of women in college with dependent children and growing emphasis on two-generation policies for reducing socioeconomic inequality have galvanized research aimed at determining whether mothers' increased education can improve their and their children's well-being. Yet as part of this effort, scholars have overlooked signs that mothers' college enrollment may not be unequivocally good for families. This research brief aims to bring greater attention to this "side of the story." To do so, we analyze time diary (2003-2015) and well-being data (2010, 2011, 2013) from the American Time Use Survey. We find that mothers in college experience a time squeeze that limits their time in caregiving, self care, and work, on one hand, and school-related activities on the other. This time squeeze may explain why mothers enrolled in college (compared to mothers who were not in school) also reported less happiness and more fatigue during activities with their children. PMID- 30416208 TI - Stochastic Mirror Descent Dynamics and Their Convergence in Monotone Variational Inequalities. AB - We examine a class of stochastic mirror descent dynamics in the context of monotone variational inequalities (including Nash equilibrium and saddle-point problems). The dynamics under study are formulated as a stochastic differential equation, driven by a (single-valued) monotone operator and perturbed by a Brownian motion. The system's controllable parameters are two variable weight sequences, that, respectively, pre- and post-multiply the driver of the process. By carefully tuning these parameters, we obtain global convergence in the ergodic sense, and we estimate the average rate of convergence of the process. We also establish a large deviations principle, showing that individual trajectories exhibit exponential concentration around this average. PMID- 30416209 TI - Phase transitions in huddling emperor penguins. AB - Emperor penguins (Aptenodytes forsteri) are highly adapted to the harsh conditions of the Antarctic winter: they are able to fast for up to 134 days during breeding. To conserve energy, emperor penguins form tight groups (huddles), which is key for their reproductive success. The effect of different meteorological factors on the huddling behaviour, however, is not well understood. Using time-lapse image recordings of an emperor penguin colony, we show that huddling can be described as a phase transition from a fluid to a solid state. We use the colony density as order parameter, and an apparent temperature that is perceived by the penguins as the thermodynamic variable. We approximate the apparent temperature as a linear combination of four meteorological parameters: ambient temperature, wind speed, global radiation and relative humidity. We find a wind chill factor of -2.9 degrees C/(ms -1), a humidity chill factor of -0.5 degrees C/% rel. humidity, and a solar radiation heating factor of 0.3 degrees C//(Wm 2). In the absence of wind, humidity and solar radiation, the phase transition temperature (50% huddling probability) is -48.2 degrees C for the investigated time period (May 2014). We propose that higher phase transition temperatures indicate a shrinking thermal insulation and thus can serve as a proxy for lower energy reserves of the colony, integrating pre breeding foraging success at sea and energy expenditure at land due to environmental conditions. As current global change is predicted to have strong detrimental effects on emperor penguins within the next decades, our approach may thus contribute towards an urgently needed long-term monitoring system for assessing colony health. PMID- 30416210 TI - Hydration and Temperature Response of Water Mobility in Poly(diallyldimethylammonium)-Poly(sodium 4-styrenesulfonate) Complexes. AB - The combination of all-atom molecular dynamics simulations with differential scanning calorimetry (DSC) has been exploited to investigate the influence of temperature and hydration on the water distribution and mobility in poly(diallyldimethylammonium) (PDADMA) and poly(sodium 4-styrenesulfonate) (PSS) complexes. The findings show that the vast majority of the water molecules hydrating the polyelectrolyte complexes (PECs) with 18-30 wt % hydration are effectively immobilized due to the strong interactions between the PE charge groups and water. Temperature and hydration were found to decrease similarly the fraction of strongly bound water. Additionally, at low hydration or at low temperatures, water motions become dominantly local vibrations and rotations instead of translational motion; translation dominance is recovered in a similar fashion by increase of both temperature and hydration. DSC experiments corroborate the simulation findings by showing that nonfreezing, bound water dominates in hydrated PECs at comparable hydrations. Our results raise attention to water as an equal variable to temperature in the design and engineering of stimuli-responsive polyelectrolyte materials and provide mechanistic explanation for the similarity. PMID- 30416211 TI - Convergence analysis of domain decomposition based time integrators for degenerate parabolic equations. AB - Domain decomposition based time integrators allow the usage of parallel and distributed hardware, making them well-suited for the temporal discretization of parabolic systems. In this study, a rigours convergence analysis is given for such integrators without assuming any restrictive regularity on the solutions or the domains. The analysis is conducted by first deriving a new variational framework for the domain decomposition, which is applicable to the two standard degenerate examples. That is, the p-Laplace and the porous medium type vector fields. Secondly, the decomposed vector fields are restricted to the underlying pivot space and the time integration of the parabolic problem can then be interpreted as an operators splitting applied to a dissipative evolution equation. The convergence results then follow by employing elements of the approximation theory for nonlinear semigroups. PMID- 30416212 TI - A stratified random sampling design in space and time for regional to global scale burned area product validation. AB - The potential research, policy and management applications of global burned area products place a high priority on rigorous, quantitative assessment of their accuracy. Such an assessment can be achieved by implementing validation methods employing design-based inference in which the independent reference data are selected via a probability sampling design. The majority of global burned area validation exercises use Landsat data to derive the independent reference data. This paper presents a three-dimensional sampling grid that allows for probability sampling of Landsat data in both space and time. To sample the globe in the spatial domain with non-overlapping sampling units, the Thiessen Scene Area (TSA) tessellation of the Landsat path/row geometry is used. The TSA grid is combined in time with the 16-day Landsat acquisition calendar to provide three-dimensional elements (voxels).This allows for implementation of stratified random sampling designs, where not only the location but also the time interval of the independent reference data is explicitly drawn by probability sampling. To illustrate this, we use a stratification methodology based on the Olson global ecoregion map and on the MODIS global active fire product. Using the global MODIS burned area product to establish a hypothetical population of reference data, we show that a sampling scheme based on the proposed stratification with equal sample allocation among strata is effective in reducing the standard errors of accuracy and area estimators compared to simple random sampling. Globally, the standard errors were reduced by 63%, 54%, 22% and 53% for overall accuracy, omission error, commission error and total burned area estimates respectively. By incorporating probability sampling in both the spatial and temporal domains, the present study establishes the foundation for rigorous design-based validation of global burned area products and, more generally, of terrestrial thematic products that have high temporal variability. PMID- 30416213 TI - The conundrum of social class: Disparities in publishing among STEM students in undergraduate research programs at a Hispanic majority institution. AB - Research on the science, technology, engineering, and math (STEM) student development pipeline has largely ignored social class and instead examined inequalities based on gender and race. We investigate the role of social class in undergraduate student research publications. Data come from a sample of 213 undergraduate research participants majoring in STEM at a Hispanic-majority institution. Based on generalized estimating equations that adjust for student demographics, research confidence, mentoring experiences, duration/number of research experiences, and clustering by major, we find that higher income students and continuing-generation students (vs. first-generation students) were significantly more likely to publish. Continuing-generation students had an even greater likelihood of publishing than first-generation students as students accrued more research confidence, spent more hours/week with faculty mentors, and conducted research for more months. Results suggest that undergraduate research programs designed to enhance diversity may help close some gaps (e.g., gender) but inadvertently reproduce class inequalities. PMID- 30416214 TI - Syntheses of PDE3A inhibitor ORG9935 and determination of the absolute stereochemistries of its enantiomers by X-ray crystallography. AB - Two synthetic methods were developed for the synthesis of PDE3A inhibitor ORG9935. The first one proceeds in six steps and 34% overall yield and the second one in five steps and an overall yield of 69% starting from commercially available starting material 5,6-dimethoxybenzo[b]thiophene-2-carboxylic acid (6). The enantiomers of ORG9935 were separated by chiral column chromatography and the absolute stereochemistry of the (+)-enantiomer, ORG20865 was determined by X-ray crystallography to possess the (S)-configuration. The (-)-enantiomer, ORG20864, was therefore assigned the (R)-stereochemistry. The biologically less active (+) isomer ORG20865 was converted to racemic ORG9935 under basic conditions, which then can be separated again into the enantiomers. The crystal structure of ORG20865 is notable for having the highest Z' for any known pharmaceutical substance. PMID- 30416215 TI - Probing the Lipid Annular Belt by Gas-Phase Dissociation of Membrane Proteins in Nanodiscs. AB - Interactions between membrane proteins and lipids are often crucial for structure and function yet difficult to define because of their dynamic and heterogeneous nature. Here, we use mass spectrometry to demonstrate that membrane protein oligomers ejected from nanodiscs in the gas phase retain large numbers of lipid interactions. The complex mass spectra that result from gas-phase dissociation were assigned using a Bayesian deconvolution algorithm together with mass defect analysis, allowing us to count individual lipid molecules bound to membrane proteins. Comparison of the lipid distributions measured by mass spectrometry with molecular dynamics simulations reveals that the distributions correspond to distinct lipid shells that vary according to the type of protein-lipid interactions. Our results demonstrate that nanodiscs offer the potential for native mass spectrometry to probe interactions between membrane proteins and the wider lipid environment. PMID- 30416216 TI - Assessing the victim-offender overlap among Puerto Rican youth. AB - Purpose: Knowledge about offenders and knowledge about victims has traditionally been undertaken without formal consideration of the overlap among the two. A small but growing research agenda has examined the extent of this overlap. At the same time, there has been a minimal amount of research regarding offending and victimization among minority youth, and this is most apparent with respect to Hispanics, who have been increasing in population in the United States. Materials & Methods: This study explores the joint, longitudinal overlap between offending and victimization among a sample of Puerto Rican youth from the Bronx, New York. Results: Results indicate: (1) an overlap between offending and victimization that persists over time, (2) a considerable overlap in the number, type, direction, and magnitude of the effect of individual, familial, peer, and contextual factors on both offending and victimization, (3) some of the factors related to offending were only relevant at baseline and not for the growth in offending but that several factors were associated with the growth in victimization, and (4) various risk factors could not explain much of the overlap between offending and victimization. Conclusions: Theoretical, policy, and future research directions are addressed. PMID- 30416217 TI - Tracking the Transport of Silver Nanoparticles in Soil: a Saturated Column Experiment. AB - Silver nanoparticles (AgNPs) can enter the environment when released from products containing them. As AgNPs enter soil, they are often retained in the soil profile and/or leached to the groundwater. This research assessed the transport of AgNPs in their "particle form" through the soil profile using a series of columns. Three soil types were put into soil columns: LSH (loam with high organic matter (OM)), LSL (loam with low OM), and Sand (no OM). The results showed that AgNP transport and retention in soil as well as particle size changes are affected by soil organic matter (OM) and the cation exchange capacity (CEC) of soil. OM affected the transport and retention of AgNPs. This was evident in the LSH columns where the OM concentration was the highest and the AgNP content the lowest in the soil layers and in the effluent water. The highest transported AgNP content was detected in the Sand columns where OM was the lowest. CEC had an impact on the particle size of the AgNPs that were retained in the soil layers. This was clear in columns packed with high CEC-containing soils (LSL and LSH) where AgNP particle size decreased more substantially than in the columns packed with sand. However, the decrease in AgNP sizes in the effluent water was less than the decrease in particle size of AgNPs transported through but retained in the soil. This means that the AgNPs that reached the effluent were transported directly from the first layer through the soil macropores. This work highlights the ability to track AgNPs at low concentrations (50 MUg kg-1) and monitor the changes in particle size potential as the particles leach through soil all of which increases our knowledge about AgNP transport mechanisms in porous media. PMID- 30416218 TI - Atmospheric Factors Affecting a Decrease in the Night-Time Concentrations of Tropospheric Ozone in a Low-Polluted Urban Area. AB - Ozone (O3) decomposition in the troposphere is a very important process which prevents excessive O3 accumulation in the air. It is particularly significant on warm summer days which are marked by a high risk of photochemical smog. We used Spearman's rank correlation test to determine relationships between the drop in O3 concentrations over time (-DeltaO3), nitrogen oxide (NO), nitrogen dioxide (NO2), and total nitrogen oxide (NOx) concentrations and meteorological factors (1-h average) in low-polluted urban area in Olsztyn (north-eastern Poland). Nitrogen oxide concentrations were measured continuously by the chemiluminescence method, and O3 concentrations were determined by the UV photometric method. The obtained results suggest that the rate of decomposition of tropospheric O3 is affected mostly by the presence of NOx, high temperature, and air humidity (positive correlation) as well as by wind speed (negative correlation). Maximum correlation coefficient values were reported between -DeltaO3 and air temperature, -DeltaO3 and absolute air humidity when NOx concentrations were low (below 1.0 microgram per cubic meter), reaching 0.271 and 0.243, respectively. These results indicate that O3 also reacted with air components other than NO and NO2. Precipitation at average temperature of < 0 degrees C did not significantly contribute to a drop in O3 concentrations at night-time. In the warm season, precipitation slowed down the rate of O3 decomposition, mostly because NOx were scrubbed by rain. An analysis of seasonal and daily -DeltaO3 fluctuations revealed that -DeltaO3 values were highest in the summer and shortly after sunset in the diurnal cycle. PMID- 30416219 TI - Contribution of Poland to Atmospheric Nitrogen Deposition to the Baltic Sea. AB - Poland is the second most important emission source after Germany in contributing atmospheric nitrogen deposition to the Baltic Sea basin. The main sectors contributing to reactive nitrogen emissions from Polish sources, in the period 1995-2014, are combustion and transportation, responsible together for over 97% of nitrogen oxide emissions, and agriculture responsible for over 98% of ammonia emissions. The EMEP MSC-W model with 50-km resolution was used for estimating the contribution of nitrogen emission sources from Poland to nitrogen deposition into the Baltic Sea basin and its sub-basins, in the period 1995-2014. Polish contribution in this period is mainly visible in annual wet deposition of reduced nitrogen with the range 13-18% and in wet deposition of oxidized nitrogen: 9-15%. Concerning sub-basins, a major contribution for Polish sources to total nitrogen deposition can be noticed for Baltic Proper with the range 13-19%, followed by northern sub-basins (7-18%) and finally by three western sub-basins (5-7%). Polish contribution to the Baltic Sea Basin in the year 2013 was analyzed in more detail using two models, the EMEP MSC-W model with 50-km resolution and model developed at the Institute of Meteorology and Water Management in Warsaw with 14 km resolution (IMWM Model). Both models give similar results concerning the deposition of oxidized nitrogen from Polish sources, but results show that the deposition of reduced nitrogen calculated with IMWM model is lower. The most likely reasons for the differences are different parameterizations of the deposition processes and chemical reactions in both models. PMID- 30416220 TI - Kinetics of Biological Removal of the Selected Micropollutants and Their Effect on Activated Sludge Biomass. AB - 17alpha-Ethinylestradiol (EE2), diclofenac (DCF), and 4-nonylphenol (4NP) belong to the most common micropollutants (MPs) occurring in municipal wastewater treatment plants (WWTPs). The WWTPs are the primary barrier against the spread of micropollutants in the environment. The aim of this work was to study the kinetics of biological removal of the three aforementioned micropollutants from wastewater and to check whether the acclimation of biomass influenced on the kinetic parameters. In addition, the effect of MPs on the biochemical activity of microorganisms was tested. DCF inhibited the respiration activity of biomass to the highest extent, followed by 4NP and EE2, respectively. DCF occurred to be less susceptible to microbial decomposition than the other two MPs and was removed from wastewater at the lowest degree of 58%. The degrees of removal of EE2 and 4NP were higher than that of DCF and equal to 93 and 71%, respectively. The kinetic parameters determined in this work can be used in modelling and simulation of the removal of micropollutants from wastewater. They improve the predictive ability of the biokinetic models. The acclimation of the biomass to the relevant micropollutant does not influence on the kinetic parameters of biomass growth; however, it causes the increase of the yield coefficient for heterotrophic biomass. PMID- 30416221 TI - Detecting Seasonal Flow Pathways in Road Structures Using Tracer Tests and ERT. AB - Roads and traffic can be a source of water-bound pollutants, which can percolate through the unsaturated zone to groundwater. Deicing salt is widely used on roads in northern Europe during winter and is usually applied at a time when the temperature is below zero and the soil is partly frozen. Understanding the mechanism by which water-bound pollutants such as deicing salt are transferred from roads to groundwater is highly important for groundwater protection, environmental sustainability and road maintenance. Electrical resistivity tomography (ERT) can be used for tracing the infiltration of deicing salt in different seasons, including the frozen period, as a step towards identifying pollutant infiltration pathways. In this study, a tracer-ERT monitoring method and analytical process was developed and evaluated for use in investigating and demonstrating deicing salt infiltration pathways in road structures in different seasons and weather conditions. The method involves using dissolved sodium chloride as a tracer and monitoring its infiltration using a multi-electrode array system. The tracer tests were performed at the same location in different seasons over a 1-year period. The results indicated high seasonal variation in percolation pattern and flow velocity, with large decreases in December (winter), most likely due to preferential flow paths within the road shoulder. These findings can be applied to other water-soluble pollutants that move from the road surface to groundwater. PMID- 30416222 TI - Comparison of Photocatalytic and Photosensitized Oxidation of Paraben Aqueous Solutions Under Sunlight. AB - It is well-established that aquatic wildlife is exposed to natural and synthetic endocrine disrupting compounds which are able to interfere with the hormonal system. Although advanced oxidation processes (AOPs) have shown to be effective, their application is limited by a relatively high operational cost. In order to reduce the cost of energy consumed in the AOPs, widely available solar energy instead of UV light may be applied either as photocatalytic oxidation or as photosensitized oxidation. The main goal of the present study was to investigate the sunlight photodegradation of paraben mixture. Two processes, namely the photocatalytic oxidation with modified TiO2 nanoparticles and photosensitized oxidation with photosensitive chitosan beads, were applied. The oxidants were identified as singlet oxygen and hydroxyl radicals for photosensitized and photocatalytic oxidation, respectively. The toxicity, as well as ability to water disinfection of both processes under natural sunlight, has been investigated. Application of sunlight for the processes led to degradation of parabens. The efficiency of both processes was comparable. Despite the fact that singlet oxygen is weaker oxidant than hydroxyl radicals, the photosensitized oxidation seems to be more promising for wastewater purification, due to the possibility of chitosan bead reuse and more effective water disinfection. Graphical Abstract?. PMID- 30416224 TI - "Whatever I Have to Do That's Right:" Culture and the Precariousness of Personhood in a Poor Urban Neighborhood. AB - This article presents a person-centered case study of one woman's struggles to realize a meaningful sense of personhood in a low-income urban neighborhood in Milwaukee, Wisconsin. An analysis of longitudinal ethnographic data for this case reveals how everyday aspirations toward a morally resonant lived-sense of personhood were informed by a core assemblage of three cultural models: "providing" and "being there" as a parent and doing so within a framework of "defensive individualism". This assemblage of cultural models was particularly compelling because of a combination of the embodied residue of childhood experiences and moments of "moral breakdown" in adult life. The experiences of moral breakdown were particularly meaningful because recurrent episodes of material hardship that constantly threatened to upend past efforts to realize a meaningful sense of personhood in everyday life and, in turn, generated a constant effort to reclaim and repair the symbolic markers of an achieved personhood that had been lost. These observations point to a precariousness of personhood that seemed to further motivate an investment in a self-definition in terms of this combination of cultural models. PMID- 30416225 TI - Cohabitation in China: Trends and Determinants. PMID- 30416223 TI - Moving Beyond Housing: Service Implications for Veterans Entering Permanent Supportive Housing. AB - As a result of efforts to end homelessness among U.S. veterans, more former service members are entering permanent supportive housing (PSH). While PSH has been successfully used to house homeless veterans, more research is needed about services beyond housing placement and retention. This study uses the Gelberg Andersen behavioral model for vulnerable populations to determine associations between predisposing, enabling, and need characteristics and recent service use (i.e., services to satisfy basic needs, occupational development, financial, healthcare, mental health) among unaccompanied homeless veterans (N=126) entering PSH in Los Angeles. Among the significant findings, as indicated using univariable logistic regression models, were veterans who had incarceration histories were more likely to utilize basic needs services, compared to those without incarceration histories. Veterans who received an honorable discharge were more likely to utilize occupational development services, compared to veterans with other discharge statuses. Veterans who had a case manager were more likely to utilize mental health services than those without a case manager, while those who received social security were less likely to utilize mental health services compared to veterans who did not receive social security. Veterans who met criteria for a psychological disability and veterans who met criteria for probable PTSD were more likely to use basic needs services and mental health services than veterans who fell below these thresholds. Clinical implications for social workers including "equal access to services," "enhancing economic stability," "providing safe and affordable housing with trauma-informed services," and "training service social workers to deliver well-informed linkages and services" are discussed. PMID- 30416226 TI - Out-of-Pocket Medical Expenditures in the United States: Evidence from the Health and Retirement Study. PMID- 30416227 TI - Testing the Integral Model of treatment motivation in outpatients with severe mental illness. AB - The current study tested the Integral Model of treatment motivation (IM) in a sample of 294 outpatients with severe mental illness, using structural equation modelling. The obtained structural model was not consistent with original theory, nor was the model invariant across time and patient groups (psychotic disorders and personality disorders). The patient's perceived suitability of treatment, perceived costs of treatment and outcome expectancy were most strongly associated with motivation and treatment engagement. The model explained between 22 and 86% of variance in clinical outcomes, depending on the timing of the assessment. Currently, the IM does not constitute a robust framework for patterns through which patients become motivated to engage in treatment, but does explain substantial amounts of variance in clinical outcomes. The future potential of IM as a basis for interventions in the mental health care is discussed, including suggestions for subsequent research and potential alterations of the IM to improve its utility for application in clinical practice. PMID- 30416228 TI - The state of boredom: Frustrating or depressing? AB - Boredom is a prevalent emotion with potential negative consequences. Previous research has associated boredom with outcomes indicating both high and low levels of arousal and activation. In the present study we propose that the situational context is an important factor that may determine whether boredom relates to high versus low arousal/activation reactions. In a correlational (N = 443) and an experimental study (N = 120) we focused on the situational factor (perceived) task autonomy, and examined whether it explains when boredom is associated with high versus low arousal affective reactions (i.e., frustration versus depressed affect). Results of both studies indicate that when task autonomy is low, state boredom relates to more frustration than when task autonomy is high. In contrast, some support (i.e., Study 1 only) was found suggesting that when task autonomy is high, state boredom relates to more depressed affect than when task autonomy is low. These findings imply that careful attention is needed for tasks that are relatively boring. In order to reduce frustration caused by such tasks, substantial autonomy should be provided, while monitoring that this does not result in increased depressed affect. PMID- 30416230 TI - War-related excess mortality in The Netherlands, 1944-45: New estimates of famine and non-famine-related deaths from national death records. AB - Despite there being several estimates for famine-related deaths in the west of The Netherlands during the last stage of World War II, no such information exists for war-related excess mortality among the civilian population from other areas of the country. Previously unavailable data files from Statistics Netherlands allow researchers to estimate the number of war-related excess deaths during the last stage of the war in the whole country. This study uses a seasonal-adjusted mortality model combined with a difference-in-difference approach to estimate the number of excess deaths in the period between January 1944 and July 1945 at a total of close to 91,000 (75%) excess deaths. Almost half of all war-related excess mortality during the last year of the war occurred outside the west. PMID- 30416229 TI - Thought-Action Fusion in Individuals with a History of Recurrent Depression and Suicidal Depression: Findings from a Community Sample. AB - Although suicidal ideation is one of the most consistent symptoms across recurrent episodes of depression, the mechanisms underpinning its maintenance are poorly understood. In order to develop effective treatments for suicidally depressed patients, understanding what maintains suicidal distress is critical. We hypothesised that Thought-Action Fusion (TAF), i.e., to assume that having a thought has real world consequences, originally described in Obsessive-Compulsive Disorder, might be a bias in recurrently suicidally depressed people. To assess this, we revised the original TAF scale, and assessed TAF in three samples: healthy controls, recurrently depressed individuals with no history of suicidality (D-NS) and individuals with a history of recurrent suicidal depression (D-S). Exploratory and confirmatory factor analyses indicated a three factor solution of TAF: (1) TAF for uncontrollable events, (2) self-suicidal TAF for suicidal acts related to oneself, and (3) TAF for positive controllable events. Compared to healthy controls, the D-NS group reported significantly higher total TAF, TAF uncontrollable, and TAF self-suicidal subscales, whilst positive controllable TAF was lower compared to healthy controls. Both D-S and D NS samples reported higher TAF for suicidal thought compared to healthy controls, i.e., believing that having suicidal thoughts means they will act on them, however in the context of low mood this became more pronounced for the D-S group. These findings suggest that targeting TAF both in suicidal and non-suicidal depression has merit. PMID- 30416231 TI - Modeling motor learning using heteroskedastic functional principal components analysis. AB - We propose a novel method for estimating population-level and subject-specific effects of covariates on the variability of functional data. We extend the functional principal components analysis framework by modeling the variance of principal component scores as a function of covariates and subject-specific random effects. In a setting where principal components are largely invariant across subjects and covariate values, modeling the variance of these scores provides a flexible and interpretable way to explore factors that affect the variability of functional data. Our work is motivated by a novel dataset from an experiment assessing upper extremity motor control, and quantifies the reduction in motion variance associated with skill learning. PMID- 30416232 TI - Functional feature construction for individualized treatment regimes. AB - Evidence-based personalized medicine formalizes treatment selection as an individualized treatment regime that maps up-to-date patient information into the space of possible treatments. Available patient information may include static features such race, gender, family history, genetic and genomic information, as well as longitudinal information including the emergence of comorbidities, waxing and waning of symptoms, side-effect burden, and adherence. Dynamic information measured at multiple time points before treatment assignment should be included as input to the treatment regime. However, subject longitudinal measurements are typically sparse, irregularly spaced, noisy, and vary in number across subjects. Existing estimators for treatment regimes require equal information be measured on each subject and thus standard practice is to summarize longitudinal subject information into a scalar, ad hoc summary during data pre-processing. This reduction of the longitudinal information to a scalar feature precedes estimation of a treatment regime and is therefore not informed by subject outcomes, treatments, or covariates. Furthermore, we show that this reduction requires more stringent causal assumptions for consistent estimation than are necessary. We propose a data-driven method for constructing maximally prescriptive yet interpretable features that can be used with standard methods for estimating optimal treatment regimes. In our proposed framework, we treat the subject longitudinal information as a realization of a stochastic process observed with error at discrete time points. Functionals of this latent process are then combined with outcome models to estimate an optimal treatment regime. The proposed methodology requires weaker causal assumptions than Q-learning with an ad hoc scalar summary and is consistent for the optimal treatment regime. PMID- 30416233 TI - Quantile-Optimal Treatment Regimes. AB - Finding the optimal treatment regime (or a series of sequential treatment regimes) based on individual characteristics has important applications in areas such as precision medicine, government policies and active labor market interventions. In the current literature, the optimal treatment regime is usually defined as the one that maximizes the average benefit in the potential population. This paper studies a general framework for estimating the quantile optimal treatment regime, which is of importance in many real-world applications. Given a collection of treatment regimes, we consider robust estimation of the quantile-optimal treatment regime, which does not require the analyst to specify an outcome regression model. We propose an alternative formulation of the estimator as a solution of an optimization problem with an estimated nuisance parameter. This novel representation allows us to investigate the asymptotic theory of the estimated optimal treatment regime using empirical process techniques. We derive theory involving a nonstandard convergence rate and a non normal limiting distribution. The same nonstandard convergence rate would also occur if the mean optimality criterion is applied, but this has not been studied. Thus, our results fill an important theoretical gap for a general class of policy search methods in the literature. The paper investigates both static and dynamic treatment regimes. In addition, doubly robust estimation and alternative optimality criterion such as that based on Gini's mean difference or weighted quantiles are investigated. Numerical simulations demonstrate the performance of the proposed estimator. A data example from a trial in HIV+ patients is used to illustrate the application. PMID- 30416234 TI - A novel imputation methodology for time series based on pattern sequence forecasting. AB - The Pattern Sequence Forecasting (PSF) algorithm is a previously described algorithm that identifies patterns in time series data and forecasts values using periodic characteristics of the observations. A new method for univariate time series is introduced that modifies the PSF algorithm to simultaneously forecast and backcast missing values for imputation. The imputePSF method extends PSF by characterizing repeating patterns of existing observations to provide a more precise estimate of missing values compared to more conventional methods, such as replacement with means or last observation carried forward. The imputation accuracy of imputePSF was evaluated by simulating varying amounts of missing observations with three univariate datasets. Comparisons of imputePSF with well established methods using the same simulations demonstrated an overall reduction in error estimates. The imputePSF algorithm can produce more precise imputations on appropriate datasets, particularly those with periodic and repeating patterns. PMID- 30416235 TI - Comparison of different site preparation techniques: quality of planting spots, seedling growth and pine weevil damage. AB - In northern Europe, there are high risks of severe pine weevil (Hylobius abietis) damage to newly planted conifer seedlings. Site preparation is one of the most important measures for reducing these risks and as several studies have shown the damage is highly dependent on the amount of pure mineral soil around the seedlings. We investigated effects of three site preparation techniques: (1) disc trenching with a conventional Bracke T26, (2) MidiFlex unit and (3) soil inversion with a Karl Oskar unit on characteristics of the planting spots, growth and pine weevil damage and survival rates of untreated and insecticide treated planted Norway spruce (Picea abies) seedlings. All three site preparation techniques reduced pine weevil damage in comparison with no site preparation, and the proportion of spots with pure mineral soil they created was inversely related to the rate of mortality caused by pine weevil. The results indicate that the quality of the planting spots depends on the technique used. In areas where pine weevil is the major threat to seedling survival, the amount of mineral soil in the planting spots is the most important factor in order to protect the seedling from damage. Without site preparation most planting spots consisted of undisturbed humus. Generally, the Karl-Oskar created the most spots with pure mineral soil, but on very stony soils the Bracke T26 created more mineral soil spots than other methods. Site preparation is a valuable tool in order to improve survival in regeneration areas and it is of great importance to make the right choice of technique depending on the particular circumstances on the actual site. PMID- 30416236 TI - Survival, early growth and impact of damage by late-spring frost and winter desiccation on Douglas-fir seedlings in southern Sweden. AB - Introduction of non-native species, such as Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco), can be a means of mitigating the effects of climate change by meeting the growing demand for biomass and high quality wood. The aim of this study was to investigate early growth, survival and damage from late-spring frost and winter desiccation. A provenance trial with four coastal and three interior provenances of Douglas-fir originating from British Columbia, Canada, was established in Southwest Sweden (56 degrees 43'N, 13 degrees 08'E). Seedling height, length of the leading shoot, and occurrence of frost damage, were measured after one, three, and six growing seasons. Timing of bud break in spring was also observed. The interior Douglas-fir were more frequently damaged by late spring frost compared to the coastal Douglas-fir. The interior Douglas-fir still had a higher survival after six growing seasons compared to the coastal variety. All provenances were damaged by winter desiccation, but the provenances originating from the coastal area were more severely damaged. Choice of variety may reduce the risk for either late-spring frost or winter desiccation. PMID- 30416237 TI - Establishment strategies for poplars, including mulch and plant types, on agricultural land in Sweden. AB - Biomass from forestry is one of the largest components of Sweden's renewable resources. Poplars are currently the highest producing tree species available and are therefore natural choices for biomass-oriented production. Growing poplars has been of most interest on agricultural land, but the knowledge and experience about their cultivation is still limited. Factors that have a large impact on the regeneration results are plant material, competing vegetation, browsing and damage caused by voles or climatic factors. Due to large establishment costs, there is a need to find methods to secure the establishment both biologically and economically. In this study the effect of plastic mulch in combination with three different plant types (short cuttings, long cuttings and rooted plants) were tested at three different sites. Five years after planting, the overall effect of mulch was an improved plant survival and growth. In most cases, long cuttings outperformed short cuttings and rooted plants. Clonal differences were present, indicating the importance of using plant material adapted to site conditions. All sites were heavily affected by browsing and during the experimental period 100% of the plants were damaged at some point. Planting poplars without fencing is therefore doubtful. Results from this study conclude that poplars can be established with success on agricultural land if proper measures are used depending on the site to be planted. PMID- 30416238 TI - Transanal endoscopic microsurgical submucosa dissection in the treatment of rectal adenomas and T1 rectal cancer. AB - Background: The treatment of flat rectal adenomas is challenging. The technical difficulty and the potential of malignancy in suspected benign lesions are the factors in question. Surgical and interventional endoscopic techniques are implemented in Europe without a clear strategy. To minimize recurrent adenoma and unclear histopathological work up en bloc excision is desirable. Methods and results: We demonstrate in this article the transanal endoscopic microsurgical submucosa dissection (TEM-ESD) procedure as a feasible method for en bloc excision of rectal adenomas and early rectal cancer. The surgical technique is demonstrated in detail with the help of a video of the operation that is available online. The results of a consecutive series of 78 patients are presented. Conclusion: TEM-ESD is a safe procedure for resection of rectal adenomas and low risk carcinomas. It offers the possibility of organ preservation and minimizes functional disturbances. In case of a necessary salvage operation, the preserved integrity of the rectal muscle tube grants maximal oncological safety. PMID- 30416239 TI - Use of evidence-based interventions in child welfare: Do attitudes matter? AB - Implementation of evidence-based programs in progressed slowly, with the majority of services in child welfare settings lacking empirical evidence for effectiveness. In other settings, research has identified providers' attitudes about evidence-based practices (EBPs) as a potential barrier to adoption of EBPs. As little research has focused on the role of attitudes in influencing use after training in an EBP in child welfare, the potential for attitudes to impede implementation efforts in child welfare is unclear. This study addressed this question in a sample of 55 caseworkers and therapists randomly assigned to enhanced support to use an EBP following training or a training-only condition. Information on providers' use of the intervention after training and their attitudes about EBPs were measured for up to five time points. Results indicate that attitudes did not predict providers' use of the EBP, and attitudes did not change overall or in the enhanced condition that provided greater exposure to the intervention. Providers perceived of requirements to use a practice as more influential in their use than their openness to EBPs. However, those who were more open to EBPs were more likely to participate in implementation support after the training, suggesting that openness facilitates participation in activities that support use of a new intervention. PMID- 30416240 TI - Construction and Validation of the Touch Experiences and Attitudes Questionnaire (TEAQ): A Self-report Measure to Determine Attitudes Toward and Experiences of Positive Touch. AB - Despite growing interest in the beneficial effects of positive touch experiences throughout our lives, and individual differences in how these experiences are perceived, there is not yet available a contemporary self-report measure of touch experiences and attitudes, for which the factor structure has been validated. This article describes four studies carried out during the construction and validation of the Touch Experiences and Attitudes Questionnaire (TEAQ). The original TEAQ, containing 117 items relating to positive touch experiences was systematically constructed. Principal component analysis reduced this measure to 57 items and identified six components relating to touch experiences during childhood and adult experiences relating to current intimate touch and touch with friends and family. Three attitudinal components were identified relating to attitude to intimate touch, touch with unfamiliar people, and self-care. The structure of this questionnaire was confirmed through confirmatory factor analysis carried out on data obtained from a second sample. Good concurrent and predictive validity of the TEAQ compared to other physical touch measures currently available was identified. Known-group validity in terms of gender, marital status and age was determined, with expected group differences identified. This study demonstrates the TEAQ to have good face validity, internal consistency, construct validity in terms of discriminant validity, known-group validity and convergent validity, and criterion-related validity in terms of predictive validity and concurrent validity. We anticipate this questionnaire will be a valuable tool for the field of physical touch research. PMID- 30416242 TI - Crowd labeling latent Dirichlet allocation. AB - Large, unlabeled datasets are abundant nowadays, but getting labels for those datasets can be expensive and time-consuming. Crowd labeling is a crowdsourcing approach for gathering such labels from workers whose suggestions are not always accurate. While a variety of algorithms exist for this purpose, we present crowd labeling latent Dirichlet allocation (CL-LDA), a generalization of latent Dirichlet allocation that can solve a more general set of crowd labeling problems. We show that it performs as well as other methods and at times better on a variety of simulated and actual datasets while treating each label as compositional rather than indicating a discrete class. In addition, prior knowledge of workers' abilities can be incorporated into the model through a structured Bayesian framework. We then apply CL-LDA to the EEG independent component labeling dataset, using its generalizations to further explore the utility of the algorithm. We discuss prospects for creating classifiers from the generated labels. PMID- 30416243 TI - Influence of electron beam irradiation on water-saturated biodiesel. AB - The objective was to study changes in water-saturated biodiesel irradiated by electron beam and to analyse them considering the influence of absorbed dose. Based on obtained results it can be concluded that irradiation did not affect ester groups in FAME molecules, but strongly influenced on double bonds. Total ester content decreased linearly with the increase in absorbed dose, causing FAME not to meet the requirement of PN-EN 14214 concerning the ester content (96.5 wt%). Therefore, the use of ionizing radiation to improve biodiesel properties is unlikely, but it is worth to consider electron beam sterilisation of this biofuel. PMID- 30416241 TI - A Call for Theoretically Informed and Empirically Validated Military Family Interventions. AB - Although multiple evidence-based family interventions exist, less than a handful have been developed or rigorously tested specifically for military families. Indeed, few interventions available to military families are theory based or empirically validated; most have good face validity but little data on efficacy or effectiveness. This article argues for an emphasis on the rigorous evaluation, via pragmatic randomized controlled trials, of theory-based family interventions to strengthen and support military families. Data are provided from a theory based, empirically validated parenting program for families (After Deployment, Adaptive Parenting Tools, or ADAPT) to demonstrate the potential for randomized controlled trials to yield rich data about family functioning beyond program outcomes. Opportunities to generate theoretically informed, evidence-based family interventions for military families will contribute not only to testing theories about military families but also to advancing well-being for the next generation of service members and their families. PMID- 30416244 TI - Signal and noise characteristics of a CdTe-based photon counting detector: Cascaded systems analysis and experimental studies. AB - Recent advances in single photon counting detectors (PCDs) are opening up new opportunities in medical imaging. However, the performance of PCDs is not flawless. Problems such as charge sharing may deteriorate the performance of PCD. This work studied the dependence of the signal and noise properties of a cadmium telluride (CdTe)-based PCD on the charge sharing effect and the anti-charge sharing (ACS) capability offered by the PCD. Through both serial and parallel cascaded systems analysis, a theoretical model was developed to trace the origin of charge sharing in CdTe-based PCD, which is primarily related to remote k fluorescence re-absorption and spatial spreading of charge cloud. The ACS process was modeled as a sub-imaging state prior to the energy thresholding stage, and its impact on the noise power spectrum (NPS) of PCD can be qualitatively determined by the theoretical model. To validate the theoretical model, experimental studies with a CdTe-based PCD system (XC-FLITE X1, XCounter AB) was performed. Two x-ray radiation conditions, including an RQA-5 beam and a 40 kVp beam, were used for the NPS measurements. Both theoretical predictions and experimental results showed that ACS makes the NPS of the CdTe-based PCD flatter, which corresponds to reduced noise correlation length. The flatness of the NPS is further boosted by increasing the energy threshold or reducing the x-ray energy, both of which reduce the likelihood of registering multiple counts from the same incidenting x-ray photon. PMID- 30416245 TI - A Novel Filtering Approach for 3D Harmonic Phase Analysis of Tagged MRI. AB - Harmonic phase analysis has been used to perform noninvasive organ motion and strain estimation using tagged magnetic resonance imaging (MRI). The filtering process, which is used to produce harmonic phase images used for tissue tracking, influences the estimation accuracy. In this work, we evaluated different filtering approaches, and propose a novel high-pass filter for volumes tagged in individual directions. Testing was done using an open benchmarking dataset and synthetic images obtained using a mechanical model. We compared estimation results from our filtering approach with results from the traditional filtering approach. Our results indicate that 1) the proposed high-pass filter outperforms the traditional filtering approach reducing error by as much as 50% and 2) the accuracy improvements are especially marked in complex deformations. PMID- 30416247 TI - Testing Probabilistic Models of Choice using Column Generation. AB - In so-called random preference models of probabilistic choice, a decision maker chooses according to an unspecified probability distribution over preference states. The most prominent case arises when preference states are linear orders or weak orders of the choice alternatives. The literature has documented that actually evaluating whether decision makers' observed choices are consistent with such a probabilistic model of choice poses computational difficulties. This severely limits the possible scale of empirical work in behavioral economics and related disciplines. We propose a family of column generation based algorithms for performing such tests. We evaluate our algorithms on various sets of instances. We observe substantial improvements in computation time and conclude that we can efficiently test substantially larger data sets than previously possible. PMID- 30416246 TI - Novel block glycopolymers prepared as delivery nanocarriers for controlled release of bortezomib. AB - To explore block glycopolymers as novel polymeric delivery nanocarriers for anticancer drug bortezomib (BTZ), three types of block glycopolymers, poly(ethylene glycol)-block-poly(gluconamido ethyl methacrylate) (PEG113-b PGAMA20), poly(ethylene glycol)-block-poly(styrene)-block-poly(gluconamido ethyl methacrylate) (PEG113-b-PS50-b-PGAMA20), and poly(ethylene glycol)-block-poly(2 (diethyl amino) ethyl methacrylate)-block-poly(gluconamido ethyl methacrylate) (PEG113-b-PDEA50-b-PGAMA20), were synthesized via atom transfer radical polymerization (ATRP) using a PEG-based ATRP macroinitiator. Three glycopolymers possess the capacity to load BTZ via pH-induced dynamic covalent bonding and/or hydrophobic interaction with their specific self-assembly behaviors, and PEG113-b PS50-b-PGAMA20 carrier maintains the sustain release behavior of BTZ due to the stable micellar structure; PEG113-b-PDEA50-b-PGAMA20 carrier realizes the abrupt release at pH 5.5 by collapse of micellar structure, while PEG113-b-PGAMA20 carrier exhibits the fastest release at studied solution pHs. This study would provide a light to develop novel block glycopolymer carrier for the delivery of anticancer drug bearing boronic acid groups. Graphical abstract??. PMID- 30416248 TI - Do sedentary behavior and physical activity spatially cluster? Analysis of a population-based sample of Boston adolescents. AB - Sedentary behavior and lack of physical activity are key modifiable behavioral risk factors for chronic health problems, such as obesity and diabetes. Little is known about how sedentary behavior and physical activity among adolescents spatially cluster. The objective was to detect spatial clustering of sedentary behavior and physical activity among Boston adolescents. Data were used from the 2008 Boston Youth Survey Geospatial Dataset, a sample of public high school students who responded to a sedentary behavior and physical activity questionnaire. Four binary variables were created: 1) TV watching (>2 hours/day), 2) video games (>2 hours/day), 3) total screen time (>2 hours/day); and 4) 20 minutes/day of physical activity (>=5 days/week). A spatial scan statistic was utilized to detect clustering of sedentary behavior and physical activity. One statistically significant cluster of TV watching emerged among Boston adolescents in the unadjusted model. Students inside the cluster were more than twice as likely to report > 2 hours/day of TV watching compared to respondents outside the cluster. No significant clusters of sedentary behavior and physical activity emerged. Findings suggest that TV watching is spatially clustered among Boston adolescents. Such findings may serve to inform public health policymakers by identifying specific locations in Boston that could provide opportunities for policy intervention. Future research should examine what is linked to the clusters, such as neighborhood environments and network effects. PMID- 30416249 TI - Brachionus leydigii (Monogononta: Ploima) reported from the western basin of Lake Erie. AB - Several species of non-indigenous planktonic invertebrates have historically been introduced to the Laurentian Great Lakes. Previous introductions of non indigenous planktonic invertebrates to the Great Lakes have been crustacean zooplankton, specifically Cladocera and Copepoda. This report documents the first known occurrence of Brachionus leydigii var. tridentatus (Zernov, 1901) in Lake Erie and possibly the first detection of a non-indigenous rotifer species in the Laurentian Great Lakes. The specimen was collected from a U.S. EPA monitoring station in the western basin of Lake Erie on April 4, 2016. PMID- 30416250 TI - Trauma Without Borders: The Necessity for School-Based Interventions in Treating Unaccompanied Refugee Minors. AB - This article explores migration trauma among Mexican and Central American unaccompanied refugee minors (URM) with the purpose of developing an understanding of migration as a tripartite process consisting of: pre-migration exposure to traumatic stressors, in-journey stressors, and post-migration stressors. The migration experience of these youth may be subjectively different depending on a wide range of factors. The complexities of migration are explored as a traumatic, tripartite process. These three salient components of migration may act as precursors, often resulting in psychological sequelae such as: post traumatic stress disorder (PTSD), anxiety, and depression. Of all migrant groups, URM are more likely to develop psychiatric symptoms. Trauma-Focused Cognitive Behavioral Therapy (TF-CBT), Cognitive Behavioral Intervention for Trauma in Schools (CBITS), and Mental Health for Immigrants Program (MHIP) are among the most effective interventions in the treatment of PTSD, anxiety, and depression in refugee minors. Social workers in schools are in unique positions to provide mental health services to URM. A case example illustrating a cultural adaptation of TF-CBT in an urban public high school is included. Clinical implications of culturally responsive and trauma-informed treatment of URM in schools will be discussed. Additionally, this article will emphasize the importance of bridging the gap between research and culturally responsive, trauma-informed interventions for URM in schools. PMID- 30416251 TI - Changing Relationships through Interactions: Preliminary Accounts of Parent-Child Interactions after Undertaking Individual Parent Training. AB - Parent and child interaction training has been increasingly investigated over recent years. However, the mechanisms of change within individual training programmes are not well understood. To explore the factors that can facilitate or inhibit meaningful changes in interactions and ultimately relationships, the current study employed semi-structured interviews to obtain first person accounts from parents who had undertaken an individualised parent-training programme. Three participants provided accounts of the training programme and their perceived impact upon interactions with their children were analysed using inductive thematic analysis. The analysis resulted in three themes, which illustrate how participants adjusted their interactional style with their child to varying degrees through enhanced personal awareness, increased understanding of their child's emotional and interactional needs, and accepting the reciprocity of interactional accountability. Changes in interactional style enabled participants to alter their perceptions of their own behaviours, their child's behaviours, and how they influenced one another through interactions. Recommendations for future research and therapeutic practice are discussed in the context of the findings and the existing evidence base. PMID- 30416252 TI - Comparative Study of Life Quality Between Migrant Children and Local Students in Small and Medium-Sized Cities in China. AB - Every child deserves a fair chance in life. However, migrant children are at higher risk of developing mental health problems. The problem of migrant children who have left their hukou registration place for 6 months or longer with their parents from rural areas to cities in China has become a unique social issue in the social transformation of China. However, even up to this day, little is known about life satisfaction of migrant children in small and medium-sized cities. To investigate the current situation of migrant children's life satisfaction, several scales including Chinese Adolescent Students' Life Satisfaction Questionnaire, Social Economic Status Scale, Social Support Rating Scale and big five inventory were used to obtain data on 142 migrant children and 165 local primary school students. Results showed that migrant children's life satisfaction was significantly lower when compared to local non-migrant students. The study also highlighted that subjective and objective support, utilization of support, conscientiousness and parent's educational level were predictive factors of life satisfaction. Migrant children' life satisfaction was not optimistic and social support was significantly influencing factors of migrant children's life satisfaction, so they need a support system of government, school, community, family to help them through difficulties. PMID- 30416253 TI - Technology and interactive social media use among 8th and 10th graders in the U.S. and associations with homework and school grades. AB - This study examined differences by age, gender, and race/ethnicity in the use of technology and interactive social media from 2013-2016 using data from nationally representative samples of U.S. 8th and 10th graders (N=40,389). Results indicated that 8th graders watch TV and play video games more than 10th graders; boys play more video games and use interactive social media less than girls; and Black adolescents use most forms of media more often than those from other race/ethnicity groups, with the exception of using the computer for school reported most often by Asian adolescents. Mean differences showed that adolescents who spend more time on homework spend more time using the computer for school, and spend less time watching weekday TV, playing video games, and talking on the phone. Adolescents with higher grades spend more time using the computer for school and spend less time on all other types of technology and interactive social media, except for watching weekend TV. Multivariable logistic regression results indicate that watching TV on a weekday was consistently negatively associated with academic outcomes and using the computer for school was consistently positively associated with academic outcomes. PMID- 30416254 TI - Confirmatory factor structure and psychometric properties of the Multidimensional Peer Victimization Scale. AB - The Multidimensional Peer Victimization Scale (MPVS; Mynard & Joseph, 2000) is a 16-item self-report scale that captures peer victimization across four dimensions: physical victimization, verbal victimization, social manipulation, and attacks on property. Performance of the scale has not been evaluated among older adolescents. We examined the factor structure, internal consistency reliability, and performance of the scale in two separate epidemiological U.S. samples representing different age groups: 9-14 year olds (N=610) and 15-17 year olds (N=524). The four-factor structure of the scale was affirmed in both samples, however; there was not metric invariance by gender in the younger age group. The scale and its subscales were found to have good internal consistency. Expected relationships between the MPVS and measures of irritability, anxiety, and depression were affirmed. Results support continued use of the MPVS among child and adolescent samples. PMID- 30416255 TI - Numerical Simulation of Biomass Growth in OKTOP(r)9000 Reactor at Industrial Scale. AB - Computational fluid dynamics is a powerful method for scale-up of reactors although it is still challenging to fully embrace hydrodynamics and biological complexities. In this article, an aerobic fermentation of Pichia pastoris cells is modeled in a batch OKTOP(r)9000 reactor. The 800 m3 industrial scale reactor is equipped with a radial impeller, designed by Outotec Oy for gas dispersion in the draft tube reactor. Measured N p of the impeller is used in hydrodynamics validation. The resolved energy dissipation rate is compensated, and its influence on mass transfer is analyzed and discussed. Gas-liquid drag force is modified to simulate effects of liquid turbulence and bubble swarms. Resolved steady state multiphase hydrodynamics is used to simulate the fermentation process. Temporal evolution of species concentrations is compared to experimental data measured in a small copy of the reactor at lab scale (14 L). The effect of oxygenation on the P. pastoris cells cultivation is considered. PMID- 30416257 TI - Geographic Market Definition in the Merger Guidelines: A Retrospective Analysis. AB - Since the initial Merger Guidelines in 1968, the Department of Justice and Federal Trade Commission have revised their merger enforcement screen over the course of six versions. This article examines the evolution of the geographic market component of the Guidelines and the economic implications of changing standards of market delineation on merger enforcement. Using an illustration from the beer industry, we chronicle the development of geographic market definition and its varying effects on merger enforcement over the past 50 years. PMID- 30416256 TI - Refining the macromolecular model - achieving the best agreement with the data from X-ray diffraction experiment. AB - Refinement of macromolecular X-ray crystal structures involves using complex software with hundreds of different settings. The complexity of underlying concepts and the sheer amount sof instructions may make it difficult for less experienced crystallographers to achieve optimal results in their refinements. This tutorial review offers guidelines for choosing the best settings for the reciprocal-space refinement of macromolecular models and provides practical tips for manual model correction. To help aspiring crystallographers navigate the process, some of the most practically important concepts of protein structure refinement are described. Among the topics covered are the use and purpose of R free, geometrical restraints, restraints on atomic displacement parameters (ADPs), refinement weights, various parametrizations of ADPs (full anisotropic refinement and TLS), and omit maps. We also give practical tips for manual model correction in Coot, modelling of side-chains with poor or missing density, and ligand identification, fitting, and refinement. PMID- 30416259 TI - qPCR-based relative quantification of the brown algal endophyte Laminarionema elsbetiae in Saccharina latissima: variation and dynamics of host-endophyte interactions. AB - Morphological changes-such as dark spots, twisted stipes and deformed blades-have been observed in wild and cultivated Saccharina latissima. The putative cause for the disease symptoms is the filamentous endophytic brown alga Laminarionema elsbetiae, which is known to invade stipes and fronds of its hosts. Little is known about this interaction and its occurrence in the field, although former studies indicated high endophyte prevalence in kelp populations. Previous epidemiological studies on kelp endophytes were mainly based on the examination of microscopic sections, followed by time-consuming isolation and cultivation steps in order to identify the endophyte and a reliable method to quantify endophyte infections was missing. As a novel approach, we established and validated a qPCR assay for relative quantification of the endophyte L. elsbetiae within its host S. latissima, which allows to examine both, the prevalence of endophytic algae and the severity of infections. The assay was shown to be highly specific and suitable to reliably detect small amounts of endophyte DNA in the host. Using this method, we detected very high endophyte prevalence in the investigated kelp populations, up to 100% in young S. latissima sporophytes in Brittany during spring. Furthermore, our results suggest that Saccharina sporophytes are infected early in their life and that seasonality and environmental factors have a significant impact on infection rates. In the future, this approach could also be applied to study other host-endophyte pairs using specific primers. PMID- 30416258 TI - A Historical and Theoretical Review of Cognitive Behavioral Therapies: From Structural Self-Knowledge to Functional Processes. AB - This paper critically examines the historical conceptualization of cognitive behavioral psychotherapy approaches (CBT) as a direct clinical counterpart of the cognitive revolution. The main "second wave" cognitive psychotherapies, either standard cognitive therapy (CT) or constructivist, in spite of their differences, share a common conceptualization of psychopathological factors as superordinate structural cognitive content belonging to the self: self-beliefs, self-schemata, personality organizations and so on. On the other hand, rational emotive behavior therapy (REBT) is an exception given that in REBT self-knowledge is not the core psychopathological tenet, being rather a derivate mechanism. Moreover, in non clinical cognitive science cognition is conceived as a regulatory function that operates retroactively and not in a hierarchically super- ordered fashion centered on the self. A historical review suggests that in both CT and constructivist model the structuralistic model of self-centered cognition may have emerged for both cultural and scientific reasons: self-centered cognitive models may be more readily understandable to clinicians as they allow for a straightforward identification of operationalizable self-beliefs. The emergence of new "third wave" process-centered CBT approaches may represent a comeback to functionalism, where cognition is considered again a regulatory function and not a structure. In addition, REBT's interest in dysfunctional evaluations not focused on the self presaged this clinical and scientific turning point toward functionalism. PMID- 30416260 TI - Increased growth response of strawberry roots to a commercial extract from Durvillaea potatorum and Ascophyllum nodosum. AB - The withdrawal of soil fumigants like methyl bromide is forcing strawberry growers to consider supplementary and alternative ways of producing crops. In addition to controlling soil-borne pests, soil fumigation causes an increased growth response in strawberry roots, and the use of biostimulants may offer an alternative to replace this response. We tested the hypothesis that treatment with a commercial extract (Seasol(r)) from the seaweeds Duvillaea potatorum and Ascophyllum nodosum can increase root growth, and transplant (runner) and fruit yields of strawberry. From 2014 to 2016, we conducted three field trials on strawberry farms in the nursery sector at Toolangi and in the fruiting sector at Coldstream in Victoria, Australia. We applied the seaweed extract as a monthly drench (10 L ha-1) to two cultivars of strawberry ('Albion' and 'Fortuna'), compared with an untreated control. In the nursery sector, use of the extract significantly increased the density of secondary roots (feeder roots) on harvested runners by up to 22%. Treatment with the extract also significantly increased yields of marketable runners by 8-19%. In the fruit sector, use of the extract significantly increased the root length density (root length per volume of soil) of strawberry plants by 38% and marketable fruit yields by 8%. Root length density at final harvest and marketable fruit yield of strawberry were highly correlated (r = 0.94). This relationship provides an insight into the mode of action of seaweed extracts and is discussed. Overall, the results show the potential benefits of the integrated use of seaweed extracts in strawberry production across the nursery and fruit sectors, and their promise for supplementing or replacing the increased growth response provided by soil fumigants. PMID- 30416261 TI - Processing of expository and narrative texts by low- and high-comprehending children. AB - The present study investigated comprehension processes and strategy use of second grade low- and high-comprehending readers when reading expository and narrative texts for comprehension. Results from think-aloud protocols indicated that text genre affected the way the readers processed the texts. When reading narrative texts they made more text-based and knowledge-based inferences, and when reading expository texts they made more comments and asked more questions, but also made a higher number of invalid knowledge-based inferences. Furthermore, low- and high comprehending readers did not differ in the patterns of text-processing strategies used: all readers used a variety of comprehension strategies, ranging from literal repetitions to elaborate knowledge-based inferences. There was one exception: for expository texts, low-comprehending readers generated a higher number of inaccurate elaborative and predictive inferences. Finally, the results confirmed and extended prior research by showing that low-comprehending readers can be classified either as readers who construct a limited mental representation that mainly reflects the literal meaning of the text (struggling paraphrasers), or as readers who attempt to enrich their mental representation by generating elaborative and predictive inferences (struggling elaborators). A similar dichotomy was observed for high-comprehending readers. PMID- 30416262 TI - The role text structure inference skill plays for eighth graders' expository text comprehension. AB - The present study investigated whether text structure inference skill (i.e., the ability to infer overall text structure) has unique predictive value for expository text comprehension on top of the variance accounted for by sentence reading fluency, linguistic knowledge and metacognitive knowledge. Furthermore, it was examined whether the unique predictive value of text structure inference skill differs between monolingual and bilingual Dutch students or students who vary in reading proficiency, reading fluency or linguistic knowledge levels. One hundred fifty-one eighth graders took tests that tapped into their expository text comprehension, sentence reading fluency, linguistic knowledge, metacognitive knowledge, and text structure inference skill. Multilevel regression analyses revealed that text structure inference skill has no unique predictive value for eighth graders' expository text comprehension controlling for reading fluency, linguistic knowledge and metacognitive knowledge. However, text structure inference skill has unique predictive value for expository text comprehension in models that do not include both knowledge of connectives and metacognitive knowledge as control variables, stressing the importance of these two cognitions for text structure inference skill. Moreover, the predictive value of text structure inference skill does not depend on readers' language backgrounds or on their reading proficiency, reading fluency or vocabulary knowledge levels. We conclude our paper with the limitations of our study as well as the research and practical implications. PMID- 30416263 TI - Influence Function and Robust Variant of Kernel Canonical Correlation Analysis. AB - Many unsupervised kernel methods rely on the estimation of kernel covariance operator (kernel CO) or kernel cross-covariance operator (kernel CCO). Both are sensitive to contaminated data, even when bounded positive definite kernels are used. To the best of our knowledge, there are few well-founded robust kernel methods for statistical unsupervised learning. In addition, while the influence function (IF) of an estimator can characterize its robustness, asymptotic properties and standard error, the IF of a standard kernel canonical correlation analysis (standard kernel CCA) has not been derived yet. To fill this gap, we first propose a robust kernel covariance operator (robust kernel CO) and a robust kernel cross-covariance operator (robust kernel CCO) based on a generalized loss function instead of the quadratic loss function. Second, we derive the IF for robust kernel CCO and standard kernel CCA. Using the IF of the standard kernel CCA, we can detect influential observations from two sets of data. Finally, we propose a method based on the robust kernel CO and the robust kernel CCO, called robust kernel CCA, which is less sensitive to noise than the standard kernel CCA. The introduced principles can also be applied to many other kernel methods involving kernel CO or kernel CCO. Our experiments on both synthesized and imaging genetics data demonstrate that the proposed IF of standard kernel CCA can identify outliers. It is also seen that the proposed robust kernel CCA method performs better for ideal and contaminated data than the standard kernel CCA. PMID- 30416264 TI - Evolution and Disappearance of Solvent Drops on Miscible Polymer Subphases. AB - Traditionally, an interface is defined as a boundary between immiscible phases. However, previous work has shown that even when two fluids are completely miscible, they maintain a detectable "effective interface" for long times. Miscible interfaces have been studied in various systems of two fluids with a single boundary between them. However, this work has not extended to the three phase system of a fluid droplet placed on top of a miscible pool. We show that these three-phase systems obey the same wetting conditions as immiscible systems, and that their drop shapes obey the Augmented Young-Laplace Equation. Over time, the miscible interface diffuses and the shape of the drop evolves. We place 2 microliter drops of water atop miscible poly(acrylamide) solutions. The drop is completely wetted by the subphase, and then remains detectable beneath the surface for many minutes. An initial effective interfacial tension can be approximated to be on the order of 0.5 mN/m using the capillary number. Water and poly(acrylamide) are completely miscible in all concentrations, and yet, when viewed from the side, the drop maintains a capillary shape. Study of this behavior is important to the understanding of effective interfaces between miscible polymer phases, which are pervasive in nature. PMID- 30416265 TI - Applied Implications of Understanding the Natural Development of Effortful Control. AB - Effortful control (EC) is an important target for many interventions intended to facilitate positive psychosocial outcomes. The first wave of these efforts have emphasized adult-to-child instruction and individualized practice at target skills. Future tests of these ideas will be facilitated by efforts to critically evaluate and improve the construct validity of EC measures. New avenues for these applied approaches will also grow out of a more complete understanding of the processes that govern EC development. Specifically, I argue that the natural development of EC includes important roles for contextual and peer relationship factors that have yet to be capitalized on in efforts to increase EC in children. PMID- 30416266 TI - The Plague of Plagiarism: Prevention and Cure!!! AB - Plagiarism is a serious form of scientific misconduct. Literal meaning of the Latin word "to Plagiare" is "to steal or to kidnap". The act of taking the writings of another person and passing them off as one's own is plagiarism. It implies intellectual theft in the world of medical writing. The "copy and paste" culture is becoming rampant all over the world after the advent of electronic publications, and Indian medical literature is no exception. This editorial will enlighten aspiring authors and readers about various forms of plagiarism and reasons for engaging in plagiarism. More so, it will also elaborate on how to prevent and cure this plague. Possible consequences that authors may face on detection of the plagiarism are also discussed. I am concluding my editorial series on medical writing with this last editorial of the year. I sincerely hope that these editorials helped authors and readers and this journal continues to receive high-quality papers written with the greatest honesty and integrity. PMID- 30416267 TI - Cesarean Myomectomy: Necessity or Opportunity? AB - Fibroids in pregnancy are increasingly common, due to advanced maternal age, better diagnostic tools and use of assisted reproductive techniques. Cesarean section (CS) is the commonest mode of delivery in these patients. Cesarean myomectomy (CM) is the term used to describe the removal of fibroids at CS; it has always been a controversial topic, with two schools of thought. Some obstetricians advise against it due to the traditional fear of massive obstetric hemorrhage and its attendant complications. However, recent literature advocates elective or opportunistic myomectomy in well-selected cases during CS. This is especially valuable in low-resource settings where the patient may be spared a repeat surgery and problems of anesthesia and cost associated with it. This review examines the recent published data on CM, its indications, technique, safety and applicability in modern obstetrics. PMID- 30416268 TI - Prenatal Diagnosis of Single Umbilical Artery: Incidence, Counselling and Management in Indian Scenario. AB - Purpose: The objective of this study is to report the incidence of single umbilical artery (SUA) on prenatal diagnosis and formulate protocol for counselling and its management in Indian scenario. Method: A total of 1024 cases were screened for Single umbilical artery (SUA) between 12 and 20 weeks gestation during the 1 year period from May 2016 to April 2017. Targeted anomaly scan was performed for all cases at 18-20 weeks. Those with additional structural anomalies were subjected to invasive genetic testing. Serial growth monitoring starting from 28 weeks was done. Results: Out of ten cases diagnosed with SUA, five had isolated SUA. Two out of five cases of isolated SUA developed FGR in third trimester. Out of the remaining, three cases with additional structural anomalies had normal foetal karyotype, whereas other two cases showed chromosomal abnormalities (12pder and trisomy 18). Conclusion: Targeted anomaly scan is must in all cases of SUA. Invasive genetic testing must be offered in case of associated anomalies. Serial growth monitoring in third trimester is an important part of protocol. PMID- 30416269 TI - Pregnancy Check Point for Diagnosis of CKD in Developing Countries. AB - Objective: Evidences suggest that females with CKD are associated with high risk of maternal and fetal complications. Early referral in CKD with pregnancy for specialist care may prove useful for maternal and fetal outcome. Methods: Study looked for assessment of impact of CKD detection at the time of pregnancy and its impact on fetal and maternal outcome. Results: A total of 465 females were retrospectively evaluated for renal status during their pregnancies, 172 females were unaware about their renal illness at the time of pregnancy, while 208 females were under regular obstetrical and nephrological follow-up during their pregnancy. 44.1% of these females in both groups had GFR < 60 ml/min. Preeclampsia was observed in 17.6% of planned pregnancies, while it was observed in 47.5% of unplanned pregnancies. Worsening of renal failure during and following pregnancy was observed among all stages of CKD, and there was greater decline in GRF with progression to ESRD earlier during or after pregnancy among unplanned pregnancies. Planned pregnancy group had better fetal outcome. Low birth babies weighing < 2500 g in unplanned group were much higher than in planned pregnancies. Conclusions: Chronic kidney disease is often clinically silent until renal impairment is advanced. Pregnancy can be a check point for detection of renal disease and managed appropriately for better maternal and fetal outcome. PMID- 30416270 TI - A Review of Outcomes in Pregnant Women with Portal Hypertension. AB - Background: The course of pregnancy in a woman with portal hypertension is a difficult one as it is associated with complications like variceal bleeding, splenic artery rupture and coagulopathy. All these pose a threat to a woman's life. Although this condition is rare, every obstetrician should have a high index of suspicion when an antenatal mother presents with splenomegaly, thrombocytopenia or hematemesis. Hence, we aimed to review maternal and fetal outcomes in pregnant women with portal hypertension. Methods: In a retrospective observational study, 41 women and 47 pregnancies were evaluated, from January 2000-December 2015 at Fernandez Hospital, a tertiary referral perinatal center. Maternal outcomes studied were variceal bleed during pregnancy, surgical procedures, morbidity and mortality. Neonatal variables were gestational age at delivery, birth weight and morbidities. Results: Mean maternal age was 26.4 years. Average gestational age at delivery was 36.5 weeks. Mean birth weight was 2507.5 g. There were three maternal deaths out of 47 deliveries, the cause of death was massive variceal bleed in one, the second one was due to cardiac arrest on MRI table, and the third death was due to splenic hilar vessel bleed. There was one stillbirth, and no neonatal deaths. Conclusion: A multidisciplinary approach is essential to improve perinatal outcomes in pregnancy complicated by portal hypertension. Surgical measures to reduce portal venous pressure done before pregnancy or beta blockers during pregnancy might help reduce sudden variceal bleeds. PMID- 30416271 TI - Analysis of Proteinuria Estimation Methods in Hypertensive Disorders of Pregnancy. AB - Purpose of the Study: The gold-standard 24-h urine collection method for protein estimation is inconvenient and is associated with a delay in laboratory analysis. This study was undertaken to compare sulphosalicylic acid test, urine dipstick test, urine protein-to-creatinine ratio with 24-h urine protein estimation in pre eclampsia cases. Methods: This is a comparative study and consists of a single group of 764 subjects. This study was conducted in the Department of Obstetrics and Gynaecology in collaboration with the Department of Biochemistry, JIPMER, Pondicherry, India, from February 2011 to January 2014. The subjects included were 764 pre-eclampsia women. A first voided morning sample was obtained for sulphosalicylic acid test, dipstick test, urine protein and creatinine estimation and urine culture, and subsequent urine samples were collected for the 24-h urine protein estimation. Main Findings: For significant proteinuria, sulphosalicylic acid test with 1 + proteinuria has sensitivity, specificity, PPV and NPV of 59, 48, 39, 67, whereas with 2 + has sensitivity, specificity,PPV and NPV of 44, 88, 75 and 67%, respectively, dipstick test with 1 + proteinuria has sensitivity, specificity, PPV and NPV of 71, 52, 54 and 70%, whereas with 2 + has sensitivity, specificity,PPV and NPV of 49, 87, 75 and 69%, respectively. The spot urine protein-to-creatinine ratio and 24-h urine protein were significantly correlated (r = 0.98; p < 0.0001). The cut-off value for the protein-to-creatinine ratio as an indicator of protein excretion >= 300 mg/day was 0.285. The sensitivity, specificity PPV and NPV were 100, 99, 100 and 99%, respectively. Conclusion: The spot urine protein-to-creatinine ratio is a better method for estimation of proteinuria in pre-eclampsia. PMID- 30416272 TI - Prospective Comparative Study of Oral Versus Vaginal Misoprostol for Second Trimester Termination of Pregnancy. AB - Background: Various medical methods for second-trimester medical termination of pregnancy (MTP) exist. Misoprostol alone has been used with myriad variations in route and dosage. Comparison between oral and vaginal routes of misoprostol forms the basis of this study. Methods: This was a prospective comparative study of misoprostol for second-trimester (14-20 weeks) MTP, comparing oral versus vaginal routes. Sixty patients were randomly allotted to two groups; 30 received oral misoprostol 400 ug 4 h up to a maximum of five doses (2000 ug), and 30 received vaginal misoprostol in the same dose and duration. In both groups, oxytocin infusion was started if abortion did not occur. Efficacy of oral versus vaginal misoprostol, induction-abortion interval (AI) and need for surgical intervention were analyzed. Results: Both groups were well matched in terms of age, parity, previous LSCS, mean gestational age and indication for MTP. Overall mean induction-abortion interval was 19.59 h (21.66 vs. 18.57 h, oral vs. vaginal, respectively), with vaginal group taking lesser time (p 0.09). Sixty percentage in oral group required five doses, while 70% in vaginal group required 3-4 doses of misoprostol (p 0.010). 23.7 versus 6.7% in oral versus vaginal group required check curettage (p 0.038). There were no major complications, and there was only one failure in oral group. Conclusions: Though both oral and vaginal misoprostol are safe, vaginal route appears to be more efficacious for second-trimester MTP. PMID- 30416274 TI - Interstitial and Cornual Ectopic Pregnancy: Conservative Surgical and Medical Management. AB - Background: Interstitial and cornual ectopic pregnancy is rare, accounting for 2 4% of ectopic pregnancies and remains the most difficult type of ectopic pregnancy to diagnose due to low sensitivity and specificity of symptoms and imaging. The classic triad of ectopic pregnancy-abdominal pain, amenorrhea and vaginal bleeding-occurs in less than 40% of patients. The site of implantation in the intrauterine portion of fallopian tube and invasion through the uterine wall make this pregnancy difficult to differentiate from an intrauterine pregnancy on ultrasound. The high mortality in this type of pregnancy is partially due to delay in diagnosis as well as the speed of hemorrhage. Methods: Three cases of interstitial pregnancy were retrospectively analyzed. Result: Successful laparoscopic cornuostomy and removal of products of conception were performed in two cases, while one case was successfully managed by local injection with KCL and methotrexate followed by systemic methotrexate. Conclusion: Early diagnosis and timely management are key to the management of interstitial and cornual ectopic pregnancy. With expertise in ultrasound imaging and advances in laparoscopic skills progressively, conservative medical and surgical measures are being used to treat interstitial and cornual ectopic pregnancy successfully. PMID- 30416275 TI - Clinical Profile of Obstetric Patients Getting Admitted to ICU in a Tertiary Care Center Having HDU Facility: A Retrospective Analysis. AB - Background: The critically ill obstetric patient represents a challenge that usually requires a multidisciplinary approach. Lack of awareness and the absence of regular antenatal care make the critically ill patients to be referred late and sometimes in moribund conditions. The objective of the present study is to determine the incidence, predictors and outcome of obstetric ICU admissions. Methods: This retrospective study was conducted over a period of 2 year from July 2015 to June 2017 in Department of Obstetrics and Gynecology at Institute of Medical Sciences, BHU, Varanasi, India. Results: Out of a total of 4986 deliveries, 756 patients underwent HDU admission, while 92 obstetric patients were admitted to ICU during this study period. Maximum number of patients (73.91%) were in the age-group of 20-35 years, 64.13% of patients constitute lower socioeconomic status group, 68.47% of patients reside in rural area and there was inadequacy in receiving antenatal care in case of 60.86% of patients. Maximum number of patients were admitted for a period of 4-7 days. Blood transfusion (64.1%), the use of inotropic drugs (45.6%), central line placement (44.5%) and mechanical ventilation (26.08%) were the major interventions performed in ICU. Obstetric hemorrhage was found to be the most frequent clinical diagnosis leading to ICU admission (31.5%) followed by hypertensive disorders (25%). Conclusion: In addition to timely referral, health education and training of health professionals may improve clinical outcome and better obstetric practice, especially in countries like India. Obstetric ICU dedicated for the management of only obstetric patients should be constructed in order to compensate for heavy burden critically ill women. PMID- 30416273 TI - Single Nucleotide Polymorphism-Based Noninvasive Prenatal Testing: Experience in India. AB - Introduction: Noninvasive prenatal testing (NIPT) has revolutionized prenatal screening for chromosomal aneuploidies in some countries. Its implementation has been sporadic in developing countries. Given the genetic variation of the people in different countries, we evaluated the performance of the SNP-based NIPT in India . Materials and Methods: The PanoramaTM NIPT was performed in 516 pregnancies, which had tested intermediate-to-high risk on conventional first and second trimester screening. Results were confirmed either by invasive diagnostic testing or by clinical evaluation after birth. Results: Of 511 samples analyzed, results were obtained in 499 (97.7%). Of these, 480 (98.2%) were low risk and 19 were high risk. A sensitivity of 100% was obtained for detection of trisomies 21, 18, 13 and sex chromosomal abnormalities. The specificity ranged from 99.3 to 100% for abnormalities tested. Taken together, the positive predictive value for trisomies 21, 18, 13 and monosomy X was 85.7%. The average fetal fraction was 8.2%, which is lower than the average observed elsewhere. Conclusion: This is the first report of detailed experience with NIPT in India and demonstrates comparable performance in all aspects of testing to the results elsewhere. PMID- 30416276 TI - Labor Pattern Among Primigravida in Local Population. AB - Objectives: In this study, we tried to make the customized labor curve by studying the labor pattern among the primigravidas and we compared the cervicograph with Zhang's and Suzuki's curves. This study may be a motivator for future research to create own labor norms for our Indian population which may help in reducing the cesarean section rates, principally in primigravidas. Materials and Methods: It was a prospective observational study, which included 156 primigravidas with uncomplicated term singleton pregnancy with spontaneous onset and progression of labor, who had normal vaginal delivery with good maternal and neonatal outcome. Results: The shape of the labor curve of this study was similar to Zhang' and Suzuki-Horiuchi's curves which had slower progression. The active phase started from 5 to 6 cm of cervical dilatation onwards which was similar to Suzuki-Horiuchi's curve. In the present study, the mean rate of cervical dilatation in the active phase was 1.5 cm/hour in contrast to Friedman's study which had a mean rate of cervical dilatation of 3 cm/hour with lower limit of 1.2 cm/hour as 5th centile. Conclusion: In the present study the mean rate of cervical dilatation in active phase in Indian women was approximately equivalent to the lowest acceptable rate of cervical dilatation in Friedman's study. If we continued to follow Friedman's labor norms, it could result in increasing c-sections. Hence, it would be prudent to create a customized labor curve for the local population served based on their individual characteristics features. PMID- 30416278 TI - External Cephalic Version: A Dying Art Worth Reviving. AB - Purpose: Breech presentation is the most common abnormal presentation occurring in 3-4% of all deliveries. Incidence of caesarean section for breech presentation has increased markedly in the last few decades. Attempting external cephalic version (ECV) reduces the chance of non-cephalic presentation at term, thus reducing the rate of caesarean sections. Methods: Prospective study was conducted in secondary healthcare centre, in rural set-up from August 2013 to August 2015. A total of 52 patients were enrolled into the study. Results: ECV was successful in 32 out of 52 patients with overall success of 61.5%. Out of the 32 successful ECVs, 24 patients delivered vaginally (75%) (p value 0.00), 6 patients delivered by caesarean section, and 2 patients were lost to follow-up. Transverse lie had 100% success rate for ECV (p value 0.005). Gravidity, placental position, gestational age and use of tocolytics did not influence the success rate of ECV. Most common problem observed during the procedure was abdominal discomfort. Conclusion: ECV is a safe procedure with high percentage of patients delivering vaginally after successful version. Hence, acquiring skills in ECV should be considered mandatory in the postgraduate training of future obstetricians. PMID- 30416277 TI - Ectopic Pregnancy: Risk Factors, Clinical Presentation and Management. AB - Background: Ectopic pregnancy is increasing in incidence. Nevertheless, there is wide availability of tools for early diagnosis and advances in management. Though it is not a leading cause of maternal mortality, it significantly causes morbidity and jeopardizes reproductive outcome in women desirous of fertility. Aims: To determine incidence, risk factors, symptoms, signs, type of ectopic pregnancy and management. Settings and Design: This is a one-year prospective, descriptive study conducted in Department of Obstetrics and Gynaecology, Sri Ramachandra Medical College and Research Institute, Porur, Chennai. Results: There were 119 ectopic pregnancies during the study period. The incidence of ectopic pregnancy is 2.81/100 deliveries. Ectopic pregnancy was common in 26-30 years, the minimum age at diagnosis was 18 years and maximum age was 40 years. Fourteen women had previous one ectopic pregnancy. Four had previous two ectopic pregnancies. Previous cesarean and treatment for infertility were the commonest risk factors. The classic triad was present in only 27.7% of patients. Fourteen patients presented with shock. Five women were diagnosed even before they missed their periods. Success rate of medical treatment with methotrexate is 83.33%. Tubal pregnancy was the commonest type, and ampulla was the commonest site. Right side was affected more than left side. Thirty-three patients (27.7%) required blood transfusion. Seven developed morbidity. After 1-year follow-up of 68 women who were desirous of fertility, five women have become pregnant subsequently with intrauterine gestation. PMID- 30416279 TI - Ogilvie Syndrome with Caecal Perforation After Caesarean Section. PMID- 30416280 TI - Osseous Metaplasia of the Vaginal Vault: A Case Report. PMID- 30416281 TI - Heterotopic Quadruplet Pregnancy After ICSI Conception. AB - Background: Heterotopic pregnancy (HP) is a condition characterized by the coexistence of multiple fetuses at two or more implantation sites. It occurs in 1% of pregnancies after assisted reproductive techniques (ART). Presence of triplet intrauterine pregnancy with ectopic gestational sac is one of the rarest forms of HP. Ectopic pregnancy is implanted in the ampullary segment of the fallopian tube in 80% of cases. Most of the patients present with acute abdominal symptoms due to rupture of the tube. Case Presentation: This article reports a case of quadruplet heterotopic pregnancy after intracytoplasmic sperm injection (ICSI) with an ampullary ectopic pregnancy and intrauterine triplet pregnancies. The ruptured ampullary pregnancy was emergently managed by right salpingectomy. This was followed by embryo reduction at 12 + 6 weeks and successful outcome of intrauterine twin pregnancy. PMID- 30416282 TI - Uterine Balloon Tamponade: A Savior in Ruptured Uterine Arteriovenous Malformation. PMID- 30416283 TI - Comments on Manuscript: Intrauterine Inflated Foley's Catheter Balloon in the Management of Abnormally Invasive Placenta Previa: A Case-Control Study. PMID- 30416284 TI - Media and mental health. PMID- 30416285 TI - Clinical medicine to social medicine. PMID- 30416287 TI - Challenges and perspectives of child labor. AB - Child labor is one of the oldest problems in our society and still an ongoing issue. During the time, child labor evolved from working in agriculture or small handicraft workshops to being forced into work in factories in the urban setting as a result of the industrial revolution. Children were very profitable assets since their pay was very low, were less likely to strike, and were easy to be manipulated. Socioeconomic disparities and lack of access to education are among others contributing to the child labor. Religious and cultural beliefs can be misguiding and concealing in delineating the limits of child labor. Child labor prevents physical, intellectual, and emotional development of children. To date, there is no international agreement to fully enforced child labor. This public health issue demands a multidisciplinary approach from the education of children and their families to development of comprehensive child labor laws and regulations. PMID- 30416286 TI - Antecedents of depression in children and adolescents. AB - Depression in children and adolescents is a growing health problem in the 21st century. There is growing evidence that depression poses a significant risk in the developmental trajectory of children and adolescents. It is important to identify the antecedents of depression in this vulnerable group of individuals so as to develop specific and effective preventable techniques and strategies. In this brief review, we have tried to highlight the specific antecedents of childhood and adolescence depression on which evidence is available in a structured manner. Antecedents identified in childhood and adolescent depression were categorized into biological factors, temperament, cognitive vulnerability, family factors, sociodemographic factors, academic factors, changing social milieu, school factors, and peer group influence along with the emergence of the recentproblem of excessive social networking use. Biological and psychosocial factors are equally important in the development of depression in this age group. Antecedents of childhood and adolescence depression can be targeted both to prevent and intervene depression in this population. PMID- 30416288 TI - History of psychiatry: An Indian perspective. AB - A knowledge of history becomes important in learning the way concepts have evolved and how they are understood in different and conflicting traditions in psychiatry. Modern psychiatry and its history has always been observed through the prism of western science which has its own evolutionary line in which the eastern sciences can't fit and are always at a disadvantage. Especially the colonial bid to prove its legitimacy as a civilizing mission led to representation of European medicine as morally superior to the eastern practices resulting in a biased history. Though in reality, the history of psychiatry is heterogeneous and consists of many different scientific and cultural traditions which vary between populations. hence the Indian concept of "unmada" can't be compared or conformed to "schizophrenia" without addressing its cultural and historical contexts. Many suggest that in case of Indian patients, an understanding of illness through a Vedantic model of psych seems more appealing in comparison to the western constructs, as such an attitude has been transferred over generations. Therefore, a knowledge of history of psychiatry, especially from an Indian perspective becomes important. PMID- 30416289 TI - Knowledge, attitude, and practice among tobacco and alcohol addicts before and after psychological intervention in a de-addiction center at Madhya Pradesh, India. AB - Context: Tobacco and alcohol addiction has emerged as a major public health issue in most of the regions of the world. It has resulted in enormous disability, disease, and death and acquired the dimension of an epidemic. It is estimated that five million preventable deaths occur every year globally, attributable to tobacco use. The number is expected to double by 2020 if death due to tobacco continues to occur at the same rate. Alcohol, on the other hand, contributes to 25% of all deaths in the age group of 20-39 years. The interventions such as supportive pharmacotherapy, nicotine replacement therapy, counseling, behavioral intervention, psychotherapy, and detoxification therapy are being commonly employed in the management of patients with addiction to tobacco and alcohol. Aim: The aim of this study is to compare the knowledge, attitude, and practice (KAP) among tobacco and alcohol addicts before and after psychological intervention in a de-addiction center. Settings and Design: This study was a randomized control trial, focusing on psychological interventions practiced in a de-addiction center, Indore, Madhya Pradesh, India. Materials and Methods: The information on KAP related to tobacco and alcohol was collected at baseline from 83 participants. This was compared with the information collected in the postintervention follow-ups from each participant. Statistical Analysis Used: Statistical tests for parametric analysis were done using one-way ANOVA with Scheffe's post hoc test, RMANOVA with Mauchly's test for sphericity assumption, and Bonferroni test for comparing the main effects. Nonparametric tests included Pearson's Chi-square test, McNemar's Chi-square test, Spearman's rho, and Kruskal Wallis test. The statistical significance was fixed at 0.05. Results: The mean KAP score for the study population was highest at the first follow-up followed by the second follow-up for both tobacco and alcohol addiction. The least KAP score was observed at the baseline. Conclusions: Although a significant improvement in the mean KAP score was observed at the first follow-up, subsequent follow-up revealed a reduction in the overall KAP score in the present study. This could be attributed to the fact that following their discharge from the de-addiction center, most of the participants reverted back to their deleterious habits. PMID- 30416290 TI - Stress levels and its association with self-harm and risk-taking behavior in medical undergraduates. AB - Background: Medical studies are very challenging. As a result of the demands placed on them, students may be under stress, and this may affect their behavior and performance. Not many Indian studies have delved into this problem. Aim: The aim of the study is to assess the levels of stress and its associated adverse behavioral effects in undergraduate medical students in a tertiary care medical college. Materials and Methods: This cross-sectional, descriptive, and analytical study included medical students from 2nd to 4th year who had given informed consent to participate in the study. Students were assessed with a semi structured questionnaire, students stress scale (SSS), perceived stress questionnaire, and risk-taking and self-harm (RT and SH) inventory. Results: A total of 405 students (153 males and 252 females) participated in the study. There were no significant differences in the age, perceived family support, religious practices, physical activity, and SSS scores of the male and female students. A significantly higher score was obtained by boys as compared to the girls on the scores of the RT subscale and total score on RT and SH inventory. However, girls obtained significantly higher scores as compared to boys on the perceived stress scale. Among girls, 23.4% reported high stress, 63.5% had moderate stress, and 13.1% reported low stress. Among boys, 11.1% reported high stress, 68.6% had moderate stress, and 20.3% reported low stress. The difference was statistically significant. Conclusions: The majority of Medical undergraduates were under stress; however, the majority perceived themselves to be under moderate stress. Male students had higher scores on RT and SH inventory as compared to females. There is an urgent need to study the causes and devise effective management and preventive measures to avoid the harmful long-term effects of stress on their careers and well-being. PMID- 30416291 TI - Somatosensory amplification, health anxiety, and alexithymia in generalized anxiety disorder. AB - Aim: The aim of this study was to study somatosensory amplification, health anxiety (hypochondriasis), and alexithymia among patients with generalized anxiety disorder (GAD) and to evaluate the association of these variables with the severity of GAD. Materials and Methods: Cross-sectional design was employed, and patients were recruited from the outpatient clinic of the psychiatry department of a multispecialty tertiary care medical institute in North India. The patients who were clinically diagnosed to have GAD by the two independent qualified psychiatrists were screened with Mini International Neuropsychiatry Interview to confirm the diagnosis. Forty patients with GAD meeting the inclusion criteria were assessed with GAD-7 scale, somatosensory amplification scale (SSAS), the Whiteley Index (WI) and Toronto alexithymia scale - 20 Hindi version (TAS-H-20). Results: The mean scores of patients with GAD on SSAS, WI, TAS-H-20, and GAD-7 scale were 25.70 (SD-5.84), 7.75 (SD-3.30), 59.77 (SD- 8.63), and 13.37 (SD- 3.58), respectively. Half of the patients with GAD had significant health anxiety as defined by WI score of >7. Around 40% of GAD patients were alexithymic as defined with TAS-H-20 scores of >60. SSAS, WI, TAS-H-20 had a positive correlation with the severity of GAD as measured with GAD-7 scale. Conclusions: GAD patients have significant somatosensory amplification, health anxiety (hypochondriasis), and alexithymia. Accordingly, there is a need to develop effective psychological interventions focused on these factors in GAD. PMID- 30416292 TI - Efficacy of inhibitory learning theory-based exposure and response prevention and selective serotonin reuptake inhibitor in obsessive-compulsive disorder management: A treatment comparison. AB - Background: The majority of treatment research on obsessive-compulsive disorder (OCD) has focused on emotional processing theory (EPT)-based exposure-based interventions. Despite the outcomes of EPT-based exposure and response prevention (ERP), a sizeable percentage of patients do not respond whereas 50%-60% of those who respond experience at least partial relapse at follow-up assessments. Inhibitory learning theory (ILT) provides a novel foundation for understanding how exposure therapy can be maximized to overcome such deficits but has not been adequately studied and compared to other evidence-based management in OCD. Aim: The aim of this study was to compare ILT-based ERP plus selective serotonin reuptake inhibitor (SSRI) with only SSRI treatment in OCD patients. Materials and Methods: The present study is pretest/posttest control group design with single masking, where participants (n = 32) diagnosed with OCD were randomly assigned into two treatment groups, namely ILT-based ERP plus SSRI and SSRI alone. Yale Brown obsessive-compulsive scale was primary outcome measure. Intervention was done for 3 months. Thereafter, the participants were followed up for 6 months. Results: ILT-based ERP and SSRI are both effective treatments. There was no significant difference in treatment effects between combined treatments of SSRI plus ILT-based ERP and SSRI alone in immediate post assessment. However, combined treatment of SSRI plus ILT-based ERP had significantly better treatment effects on follow-ups than SSRI alone. Conclusions: SSRI combined with ILT-based strategies to maximize ERP is significantly better than SSRI alone in the treatment of OCD. PMID- 30416293 TI - A study on Internet addiction and its relation to psychopathology and self-esteem among college students. AB - Background: Internet use is one of the most important tools of our present-day society whose impact is felt on college students such as increased use of Internet. It brings change in mood, an inability to control the amount of time spent with the Internet, withdrawal symptoms when not engaged, a diminishing social life, and adverse work or academic consequences, and it also affects self esteem of the students. Objective: The main objective of this study is to explore the Internet use and its relation to psychopathology and self-esteem among college students. Methodology: A total of 200 college students were selected from different colleges of Kolkata through random sampling. After selection of the sample, Young's Internet Addiction Scale, Symptom Checklist-90-Revised, and Rosenberg Self-Esteem Scale were used to assess the Internet usage, psychopathology, and self-esteem of the college students. Results: Depression, anxiety, and interpersonal sensitivity were found to be correlated with Internet addiction. Along with that, low self-esteem has been found in students to be associated with possible users of Internet. Conclusion: Internet usage has been found to have a very strong impact on college students, especially in the areas of anxiety and depression, and at times it affected their social life and their relationship with their family. PMID- 30416294 TI - Proactive coping style and intentional self-harm: A cross-sectional study. AB - Background: Coping style adopted by a person has been identified as an important factor in precipitating or preventing an intentional self-harm attempt. While the influence of reactive coping has received lot of research attention, effects of proactive coping on suicidal behavior has not been studied, even though it is known that proactive coping is associated with better mental health. The authors in the current study sought to investigate the relationship of proactive coping style with attempted deliberate self-harm. Materials and Methods: A total of 44 individuals who presented with intentional self-harm were compared with age, sex, marital status, and education-matched healthy controls. Pierce Suicide Intent Scale was used to ascertain suicidal intent, and Proactive Coping Inventory was used to assess proactive coping. Results: There were no significant differences between subjects and controls for proactive coping, preventive coping, emotional support seeking, avoidance coping, and instrumental support seeking. However, participants scored higher in strategic planning (P = 0.027). Conclusions: Proactive coping has no significant relationship with intentional self-harm; however, more studies with better designs are needed to comment conclusively. PMID- 30416295 TI - To identify predictors of relapse in cases of alcohol dependence syndrome in relation to life events. AB - Background and Objectives: Relapse is a complex and dynamic phenomenon that appears to be determined by biological, psychological, and social factors and an interaction among these. This study examined the association between demographic variables, clinical parameters, and psychosocial factors that predict the vulnerability to relapse in cases of alcohol dependence syndrome. Materials and Methods: Structured assessments of clinical/demographic parameters, relapse precipitants, life events, and dysfunction were carried out among patients with alcohol dependence syndrome (n = 100) who had relapsed and compared with those (n = 100) who had managed to remain abstinent. Results: Patients who had relapsed were found to have significantly more positive family history of substance use, past history of alcohol-related comorbidity, experienced a higher number of undesirable life events, and higher negative mood states and social anxiety and dysfunction in social, vocational, personal, family, and cognitive spheres compared to patients who had remained abstinent. Conclusions: Relapse in alcohol dependents is an interaction of many factors, and multiple layers of assessment may be required to predict relapse. This study provided further evidence in support of the importance of certain clinical/psychosocial factors in relapse in substance dependence. It provides the basis for investigating the correlates of relapse in a wide range of behavioral and substance use problems. PMID- 30416296 TI - Study on risk factors in adolescents admitted with deliberate self-harm in Tata main hospital, Jamshedpur. AB - Background: Suicide ranks as the second cause of death worldwide among 15-19 years olds, with at least one lakh adolescents dying by suicide every year. Therefore, research on understanding the dynamics of suicide attempts in adolescents can be used as a means of suicide prevention. Objective: The objective of this study is to understand the psychological, social, and personality factors contributing to deliberate self-harm/suicide attempt in patients of adolescent age group admitted to Tata Main Hospital, Jamshedpur. Materials and Methods: This study was carried out at Tata Main Hospital Jamshedpur. Consecutive suicide attempters up to the age of 19 years referred from medical or surgical wards over a period of 1 year are taken up for study. Data were collected on socio-demographic sheet and specific pro forma to collect various risk factors contributing to this behavior specifically designed for this study. Data were analyzed using descriptive statistics and Chi-square test. Results: Majority of the suicide attempters were females of younger age, lower middle income status, urban background, and students. Two-third (68%) of the attempter had at least one psychiatric diagnosis. Nearly 75% of the suicide attempts were committed after a precipitating factor. The risk factors associated with suicide attempts in included increased family conflicts, peer-interpersonal problems, perceived humiliations and personality traits. Conclusion: The early identification and treatment of vulnerable populations with risk factors for suicide across the lifespan will help in planning and implementing strategies for prevention. PMID- 30416297 TI - 25 Hydroxyvitamin D levels, quality of life, and disability in long-standing patients of somatization. AB - Introduction: Somatization disorder is a debilitating condition, in which patients have multiple physical complaints with no explained cause and no relief even after consultations. Aim: The present study examined the association of 25 hydroxyvitamin D (25[OH]D) levels, quality of life, disability, and symptom profile in long standing with somatization disorder. Methods: One-hundred three patients of somatization disorder suffering for >=2 years, visiting psychiatry outpatient clinic during two consecutive summer season (April to June) of 2015 2016 were recruited. Symptom profile was studied using Patient-Health Questionnaire (PHQ-15) items (somatic symptoms), PHQ-9 items (depressive symptoms), Generalized Anxiety Disorder-7 (GAD-7) item (anxiety symptoms).quality of life was assessed using the World Health Organization Quality of Life BREF 26 item, and disability measure was World Health Organization Disability Assessment Schedule (WHODAS) 2.0. 25(OH) D levels were estimated using chemiluminescence binding assay. Results: The poor quality of life in somatization disorder was significantly associated with disability, symptom profile using PHQ-15, PHQ-9, and GAD-7. 25(OH)D levels were deficient in 56.31% of the study population. Conclusion: The high somatic symptom severity in majority of patients suffering from somatization disorder needs more attention from psychiatrists across cultures so that functional status and quality of life can be improved. Routine estimation of Vitamin D levels and correction of its deficiency may bring about symptomatic relief at an early stage, thereby reducing the morbidity associated with the disorder. PMID- 30416298 TI - A study of association of behavioral problems with scholastic backwardness in urban lower middle-class school children. AB - Introduction: Scholastic backwardness is a common phenomenon with multifactorial etiology. Behavioral problems are known to occur in children who are scholastically backward (SB). These may be a part of the broad phenomenon, or may exist in cause and effect relationship with scholastic backwardness. Aims: The aim of this study is to study the presence of behavioral problems associated with scholastic backwardness in school-going children in Pune cantonment. Materials and Methods: A total of 300school children aged 8-14 years studying in Class III IX from two government-aided semi-Marathi schools in Pune cantonment were screened for scholastic backwardness and evaluation of behavioral problems was carried out for positive cases and matched controls. Results: Out of the 28 SB children, behavioral problems were present in 17, giving a prevalence of 60.71%, in comparison with the scholastically normal (SN) group of 50, only 14 of which had behavioral problems, prevalence is 28%. A significant association was found between scholastic backwardness and behavioral problems, which were more prevalent in the SB group compared to matched controls. Conclusions: Behavioral problems are more prevalent among children who are SB when compared to their SN counterparts. Further research is required to assess in detail whether the behavioral problems are comorbid with scholastic backwardness, lead to scholastic backwardness or occur as a consequence of scholastic backwardness. PMID- 30416299 TI - Study of quality of life among health workers and psychosocial factors influencing it. AB - Background: To cope with the challenges in the health-care delivery system and to guarantee the quality of care rendered and client satisfaction on the care received, it is important to know how satisfied health-care workers are with their quality of life, job and what characteristics influence their quality of life. This study was undertaken in a tertiary care hospital to assess the same using validated questionnaires. Aim: This study aims to study the quality of life among the health workers (doctors and nurses) of a large multispecialty tertiary care hospital and the psychosocial factors influencing it. Materials and Methods: A total of 200 health-care workers with their background demographic data were assessed using quality of life questionnaire and occupational stress inventory. The data compiled were analyzed with appropriate statistical methods. Results: The overall quality of life among the study population was average, and the mean prevalence of occupational stress level was of mild level. There was a correlation between domains of occupational stress and domains of quality of life of health-care workers. Conclusion: Study findings revealed that overall perception of quality of life was average, overall stress level of health-care workers was moderately elevated and majority showed average coping resources. PMID- 30416300 TI - Role of personality in tobacco smoking behavior in corporate sector: A cross sectional study. AB - Background: India's corporate sector has grown steadily over the past decade, and it is providing a lot of work opportunities to Indian youth. Around 20% of employees in the corporate sector in India smoke cigarettes. In general, addictive behaviors including smoking are associated with certain personality dimensions. Hence, we conducted a study with the aims to assess the level of nicotine dependence in tobacco smokers (working in corporate sector), study their personality profile, and association of their personality traits with continuing smoking behavior. Materials and Methods: The study proposal along with its intended aims and objectives was cleared by the Institutional Ethical Review Board. It was a cross-sectional study. We used FTND for level of nicotine dependence and NEO FFI 3 for personality profile along with a structured proforma. Results: Most of the clients were of very low to low level of nicotine dependence. As high as 40% of the clients did not even attempt to quit smoking, most common reason for attempt at quitting was health concerns. Major causes of relapse were friends, people at workplace, and nature of work. Clients were high on neuroticism, average on extraversion and openness, and low on agreeableness and conscientiousness. Neuroticism was significantly associated with the level of nicotine dependence. Extraversion and openness were associated with health concerns, while agreeableness and conscientiousness were associated with social factors as a reason to quit. Extraversion and agreeableness were associated with occupational factors and social factors as reasons to relapse. Conclusion: Understanding one's personality would be helpful to identify health-enhancing (which help to attempt at quitting) and health-destructive (which were responsible for relapse) behaviors. This can further help in framing interventions that particularly target these personality traits and behaviors. PMID- 30416301 TI - Study of Internet addiction in children with attention-deficit hyperactivity disorder and normal control. AB - Background: In the current era, the use of electronic media in the form of Internet has increased exponentially, particularly among children, and has led to their excessive involvement in Internet. In this context, attention-deficit hyperactivity disorder (ADHD) children were found to have increased tendency for this addiction. Aims and Objectives: The aim is to study and compare Internet addiction between ADHD and normal children and the relation of demographic profile to Internet addiction. Materials and Methods: This was a cross-sectional study including 100 children (50 ADHD cases and 50 normal children without any psychiatric illness as controls) between the ages of 8 and 16 years. A semi structured pro forma for demographic profile and Internet usage using Young's Internet Addiction Test (YIAT) was used. Statistical analysis was done using SPSS 20. Results: Internet addiction among ADHD children was 56% (54% having "probable Internet addiction" and 2% having "definite Internet addiction"). This was statistically significant (P < 0.05) in comparison with normal children where only 12% had Internet addiction (all 12% had "probable Internet addiction"). ADHD children were 9.3 times more prone to the development of Internet addiction as compared to normal (odds ratio - 9.3). Significant increase in average duration of Internet usage in ADHD children with increasing score of YIAT (P < 0.05) was seen. The incidence of Internet addiction was more in male ADHD children as compared to normal (P < 0.05). Conclusions: ADHD children are more prone to Internet addiction as compared to normal children and thus require preventive strategies. PMID- 30416302 TI - A novel approach to suicide prevention - Educating when it matters. AB - Background: Looking at the burden of suicide, there is a dire need for medical schools to incorporate suicide prevention training. Effective communication helps in early detection and management of suicidal behavior. Medical students can act as a GATEKEEPER if they receive adequate training. Methodology: This was an educational intervention study done at tertiary care teaching hospital to assess the knowledge and attitude of medical students toward depression and suicide and to impart and assess communication skills for suicide prevention in one of the four batches of students in 4th semester. Pretest was conducted to assess knowledge and attitude toward depression and suicide, followed by training using interactive lectures, demonstration of interview, and hands-on training with patients and role-plays. The posttest and objective structured clinical examination (OSCE) were administered for skill assessment. Feedback was taken regarding this intervention. Results: The mean marks of the pre- and post-test were 8.96 (8.3-9.6) and 14.58 (13.8-15.3), respectively, out of 25. The difference was statistically significant (t = 13.24, P <= 0.0001) which suggests improvement in knowledge. We found mixed responses in attitude statements showing limited change. Mean obtained marks on OSCE examination out of 66 was 42.7. Among various components of OSCE, students scored high on rapport building. The most useful components of trainings were role-play, OSCE, and interaction with patients as per their feedback. Conclusion: The intervention was found effective in increasing knowledge, changing attitude, and enhancing communication skills of medical students toward suicide prevention. Training of communication skills for suicide prevention in depressed person should be given to every medical student as suggested by feedback. PMID- 30416303 TI - Attitude of undergraduate medical students toward psychiatry: A cross-sectional comparative study. AB - Context: Both psychiatry as a specialty and mental illnesses carry a lot of stigmatizing attitudes. Even medical professionals are not immune to prevailing stigma. Psychiatrists are perceived to have less scientific attitude, earn less money, to be less respected, and to have less prestige. Aims: The present study was designed to know the attitude of medical students with different years of exposure to medical education, toward psychiatry as a specialty. Settings and Design: The study was conducted at JLN medical College, Ajmer. The participants were divided into two groups, undergraduate and interns, respectively. It was a cross-sectional descriptive study. Materials and Methods: Self-administered sociodemographic and Attitude Toward Psychiatry-30 items questionnaires were given to the second-year and medical intern and the scores were analyzed using appropriate statistical tools. Statistical Analysis Used: Student's t-test and Chi-square test using SPSS version 21. Results: Nearly 84% of second-year medical students and 52% of interns had positive attitude toward psychiatry (P = 0.001). Only five second-year (5%) and two intern (1.8%) students affirmatively indicated to choose psychiatry as a career choice, while 73% denied choosing psychiatry as a specialty. Conclusions: Second-year medical students showed more positive attitude than the intern group. Increasing negative attitude in higher classes might be due to poor teaching of psychiatry in under graduate training, ridiculous stereotypic comments and remarks by medical teachers and practitioners belonging to other specialty branches. PMID- 30416304 TI - Prevalence of excessive internet use and its association with psychological distress among university students in South India. AB - Background: Excessive internet use, psychological distress, and its inter relationship among university students can impact their academic progress, scholastic competence, career goals, and extracurricular interests. Thus, a need exists to evaluate the addictive internet use among university students. Objectives: This study was set up to examine the internet use behaviors, internet addiction (IA), and its association with psychological distress primarily depression among a large group of university students from South India. Methods: Totally 2776 university students aged 18-21 years; pursuing undergraduate studies from a recognized university in South India participated in the study. The patterns of internet use and socioeducational data were collected through the internet use behaviors and demographic data sheet, IA test (IAT) was utilized to assess IA and psychological distress primarily depressive symptoms were evaluated with Self-Report Questionnaire-20. Results: Among the total n = 2776, 29.9% (n = 831) of university students met criterion on IAT for mild IA, 16.4% (n = 455) for moderate addictive use, and 0.5% (n = 13) for severe IA. IA was higher among university students who were male, staying in rented accommodations, accessed internet several times a day, spent more than 3 h per day on the Internet and had psychological distress. Male gender, duration of use, time spent per day, frequency of internet use, and psychological distress (depressive symptoms) predicted IA. Conclusions: IA was present among a substantial proportion of university students which can inhibit their academic progress and impact their psychological health. Early identification of risk factors of IA can facilitate the effective prevention and timely initiation of treatment strategies for IA and psychological distress among university students. PMID- 30416306 TI - Unusual cases of succubus: A cultural phenomenon manifesting as part of psychopathology. AB - Succubus is also known as demon female lover who approaches males in their dreams to have sex. This is the phenomenon which is rarely described in psychiatric literature. It is more identified as a cultural belief in different religions. We report the two cases diagnosed with schizophrenia, who reported this rare phenomenon of succubus as part of their psychopathology and discuss the phenomenon of succubus. PMID- 30416305 TI - A study of relationship between perceived stress, coping pattern, burnout, and general psychopathology among the postgraduate medical students. AB - Introduction: Medical postgraduate student experience considerable stress during their training, which may cause agony to the individual or affect care rendered to the patient. Significant burnout and psychopathology has not been uncommon. Materials and Methods: A study was done to assess the relation between perceived stress, coping pattern, burnout, and general psychopathology among the postgraduate medical students. Results: Perceived stress was associated with higher scores on general psychopathology and burnout. Postgraduate students who displayed positive coping strategies had lesser perceived stress. Females had higher scores on perceived stress and psychopathology. Conclusion: Stress is one of the major growing mental problems among highly educated health professional, and it should not be ignored as it can cause many other health issues. PMID- 30416307 TI - Identification and management of "delirious mania:" A rare clinical entity. AB - Little is known about the entity of delirious mania, apart from a few reports. Delirious mania, though a potentially lethal condition, has not found a place in the current classification system. We discuss the approach to the identification and management of delirious mania in a female patient presenting with catatonic and delirious features, with a past history of recurrent mood episodes. However, it must be emphasized that it is likely to be a rare clinical presentation of bipolar disorder and should not be the first diagnostic consideration. As a rule, any patient presenting with delirium or clouded consciousness first warrants a thorough medical workup and other specialty referrals. PMID- 30416308 TI - Flibanserin: A controversial drug for female hypoactive sexual desire disorder. AB - Sexual functioning is an integral part of human life. Female sexual dysfunction (FSD) adversely affects quality of life and general well-being. The Food and Drug Administration recently approved flibanserin, for treatment of female hypoactive sexual desire disorder (HSDD), regarded as the most common FSD, amid great controversy. A novel multifunctional serotonin agonist and antagonist, flibanserin, has been shown to be efficacious in treating HSDD but with a rather tenacious side effect profile. We review this interesting drug in its entirety. Data for the article were collected by reviewing articles on PubMed, the drug (Addyi) website, and related websites on the internet. PMID- 30416309 TI - Chronic hepatitis C, atherosclerosis and cardiovascular disease: What impact of direct-acting antiviral treatments? AB - Hepatitis C virus (HCV) infection is associated with extrahepatic manifestations, among these there is an increased risk of atherosclerosis and cardiovascular disease as well as an increased cardiovascular mortality. Several direct and indirect HCV pro-atherogenic mechanisms have been proposed. HCV lives and replicates within carotid plaques, promoting a local environment of pro atherogenic factors. In addition, it causes conditions such as insulin resistance, diabetes, hepatic steatosis, cryoglobulinemia and endotoxinemia that are associated with the development of atherosclerosis and cardiovascular disease. Therapeutic regimens based on direct-acting antiviral agents (DAA) are currently available with high efficacy in HCV clearance and improvement of liver disease, but does HCV eradication also improve atherosclerosis and the risk of cardiovascular disease? Recently, a multi-center study has shown that elimination of HCV improves carotid atherosclerosis. Two studies have shown that DAA treatments significantly reduce the risk of cardiovascular events. Several studies have assessed the impact of HCV clearance on pro-atherosclerosis metabolic conditions showing improvement in cardiovascular risk biomarkers, disappearance or improvement of insulin resistance, reduction of risk of developing diabetes and improvement of glycemic control. There are also evidences that HCV clearance promotes the recovery of cytokines and inflammatory markers associated with atherosclerosis and the disappearance of cryoglobulinemia. Available data show that clearance of HCV by DAAs is associated with an improvement in atherosclerosis and metabolic and immunological conditions that promote the development of cardiovascular disease. However, the data are not sufficient to allow definitive conclusions and further studies will be needed to definitively clarify the impact of HCV clearance on atherosclerosis and cardiovascular disease. PMID- 30416311 TI - Concept of histone deacetylases in cancer: Reflections on esophageal carcinogenesis and treatment. AB - Esophageal cancer (EC) presents a high mortality rate, mainly due to its aggressive nature. Squamous cell carcinoma is the most common histological type worldwide, though, a continuous increase in esophageal adenocarcinomas has been noted in the past decades. Common risk factors associated with EC include smoking, alcohol consumption, gastroesophageal reflux disease, Barrett's esophagus and obesity. In an effort to overcome chemotherapy resistance in oncology, it was discovered that histone acetylation/deacetylation equilibrium is altered in carcinogenesis, leading to changes in chromatin structure and altering expression of genes important in the cell cycle, differentiation and apoptosis. Based on this knowledge, histone acetylation was addressed as a potential novel chemotherapy drug target to repress cancer cell proliferation. There are four classes of histone deacetylases (HDACs) inhibitors with a variety of different mechanisms of actions that render them possible anti-cancer drugs. They arrest the cell cycle, inhibit differentiation and angiogenesis and induce apoptosis. They do not necessarily act on histone proteins, since they can also exert indirect anti-cancer effects, by modifying various cellular proteins. In addition, HDACs have also been associated with increased chemotherapy resistance. Based on the literature, HDACs have been associated with EC, with surveys revealing that increased expression of certain HDACs correlates with advanced TNM stages, tumor grade, metastatic potential and decreased 5-year overall and disease-free survival. The aim of this survey is to elucidate the molecular identity and mechanism of action of HDAC inhibitors as well as verify their potential utility as anti-cancer agents in esophageal cancer. PMID- 30416312 TI - Role of autophagy in tumorigenesis, metastasis, targeted therapy and drug resistance of hepatocellular carcinoma. AB - Autophagy is a "self-degradative" process and is involved in the maintenance of cellular homeostasis and the control of cellular components by facilitating the clearance or turnover of long-lived or misfolded proteins, protein aggregates, and damaged organelles. Autophagy plays a dual role in cancer, including in tumor progression and tumor promotion, suggesting that autophagy acts as a double-edged sword in cancer cells. Liver cancer is one of the greatest leading causes of cancer death worldwide due to its high recurrence rate and poor prognosis. Especially in China, liver cancer has become one of the most common cancers due to the high infection rate of hepatitis virus. In primary liver cancer, hepatocellular carcinoma (HCC) is the most common type. Considering the perniciousness and complexity of HCC, it is essential to elucidate the function of autophagy in HCC. In this review, we summarize the physiological function of autophagy in cancer, analyze the role of autophagy in tumorigenesis and metastasis, discuss the therapeutic strategies targeting autophagy and the mechanisms of drug-resistance in HCC, and provide potential methods to circumvent resistance and combined anticancer strategies for HCC patients. PMID- 30416310 TI - Damage-associated molecular patterns in inflammatory bowel disease: From biomarkers to therapeutic targets. AB - The chronic inflammatory process underlying inflammatory bowel disease (IBD), comprising Crohn's disease and ulcerative colitis, derives from the interplay of several components in a genetically susceptible host. These components include environmental elements and gut microbiota a dysbiosis. For decades, immune abnormalities have been investigated as critically important in IBD pathogenesis, and attempts to develop effective therapies have predominantly targeted the immune system. Nevertheless, immune events represent only one of the constituents contributing to IBD pathogenesis within the context of the complex cellular and molecular network underlying chronic intestinal inflammation. These factors need to be appreciated within the milieu of non-immune components. Damage-associated molecular patterns (DAMPs), which are essentially endogenous stress proteins expressed or released as a result of cell or tissue damage, have been shown to act as direct pro-inflammatory mediators. Excessive or persistent signalling mediated by such molecules can underlie several chronic inflammatory disorders, including IBD. The release of endogenous DAMPs amplifies the inflammatory response driven by immune and non-immune cells and promotes epigenetic reprogramming in IBD. The effects determine pathologic changes, which may sustain chronic intestinal inflammation and also underlie specific disease phenotypes. In addition to highlighting the potential use of DAMPs such as calprotectin as biomarkers, research on DAMPs may reveal novel mechanistic associations in IBD pathogenesis and is expected to uncover putative therapeutic targets. PMID- 30416313 TI - Mucosal adhesion and anti-inflammatory effects of Lactobacillus rhamnosus GG in the human colonic mucosa: A proof-of-concept study. AB - AIM: To investigate the adhesion and anti-inflammatory effects of Lactobacillus rhamnosus GG (LGG) in the colonic mucosa of healthy and ulcerative colitis (UC) patients, both in vivo and ex vivo in an organ culture model. METHODS: For the ex vivo experiment, a total of 98 patients (68 UC patients and 30 normal subjects) were included. Endoscopic biopsies were collected and incubated with and without LGG or LGG-conditioned media to evaluate the mucosal adhesion and anti inflammatory effects [reduction of tumor necrosis factor alpha (TNFalpha) and interleukin (IL)-17 expression] of the bacteria, and extraction of DNA and RNA for quantification by real-time (RT)-PCR occurred after the incubation. A dose response study was performed by incubating biopsies at "regular", double and 5 times higher doses of LGG. For the in vivo experiment, a total of 42 patients (20 UC patients and 22 normal controls) were included. Biopsies were taken from the colons of normal subjects who consumed a commercial formulation of LGG for 7 d prior to the colonoscopy, and the adhesion of the bacteria to the colonic mucosa was evaluated by RT-PCR and compared with that of control biopsies from patients who did not consume the formulation. LGG adhesion and TNFalpha and IL-17 expression were compared between UC patients who consumed a regular or double dose of LGG supplementation prior to colonoscopy. RESULTS: In the ex vivo experiment, LGG showed consistent adhesion to the distal and proximal colon in normal subjects and UC patients, with a trend towards higher concentrations in the distal colon, and in UC patients, adhesion was similar in biopsies with active and quiescent inflammation. In addition, bioptic samples from UC patients incubated with LGG conditioned media (CM) showed reduced expression of TNFalpha and IL-17 compared with the corresponding expression in controls (P < 0.05). Incubation with a double dose of LGG increased mucosal adhesion and the anti inflammatory effects (P < 0.05). In the in vivo experiment, LGG was detectable only in the colon of patients who consumed the LGG formulation, and bowel cleansing did not affect LGG adhesion. UC patients who consumed the double LGG dose had increased mucosal concentrations of the bacteria and reduced TNFalpha and IL-17 expression compared with patients who consumed the regular dose (48% and 40% reduction, respectively, P < 0.05). CONCLUSION: In an ex vivo organ culture model, LGG showed consistent adhesion and anti-inflammatory effects. Colonization by LGG after consumption for a week was demonstrated in vivo in the human colon. Increasing the administered dose increased the adhesion and effectiveness of the bacteria. For the first time, we demonstrated that LGG effectively adheres to the colonic mucosa and exerts anti-inflammatory effects, both ex vivo and in vivo. PMID- 30416314 TI - Typing of pancreatic cancer-associated fibroblasts identifies different subpopulations. AB - AIM: To determine whether it is possible to identify different immune phenotypic subpopulations of cancer-associated fibroblasts (CAFs) in pancreatic cancer (PC). METHODS: We defined four different stromal compartments in surgical specimens with PC: The juxtatumoural, peripheral, lobular and septal stroma. Tissue microarrays were produced containing all pre-defined PC compartments, and the expression of 37 fibroblast (FB) and 8 extracellular matrix (ECM) markers was evaluated by immunohistochemistry, immunofluorescence (IF), double-IF, and/or in situ hybridization. The compartment-specific mean labelling score was determined for each marker using a four-tiered scoring system. DOG1 gene expression was examined by quantitative reverse transcription PCR (qPCR). RESULTS: CD10, CD271, cytoglobin, DOG1, miR-21, nestin, and tenascin C exhibited significant differences in expression profiles between the juxtatumoural and peripheral compartments. The expression of CD10, cytoglobin, DOG1, nestin, and miR-21 was moderate/strong in juxtatumoural CAFs (j-CAFs) and barely perceptible/weak in peripheral CAFs (p-CAFs). The upregulation of DOG1 gene expression in PC compared to normal pancreas was verified by qPCR. Tenascin C expression was strong in the juxtatumoural ECM and barely perceptible/weak in the peripheral ECM. CD271 expression was barely perceptible in j-CAFs but moderate in the other compartments. Galectin-1 was stronger expressed in j-CAFs vs septal fibroblasts, PDGF-Rbeta, tissue transglutaminase 2, and hyaluronic acid were stronger expressed in lobular fibroblasts vs p-CAFs, and plectin-1 was stronger expressed in j-CAFs vs l-FBs. The expression of the remaining 33 markers did not differ significantly when related to the quantity of CAFs/FBs or the amount of ECM in the respective compartments. CONCLUSION: Different immune phenotypic CAF subpopulations can be identified in PC, using markers such as cytoglobin, CD271, and miR-21. Future studies should determine whether CAF subpopulations have different functional properties. PMID- 30416315 TI - Overexpression of G protein-coupled receptor 31 as a poor prognosticator in human colorectal cancer. AB - AIM: To investigate the expression of G protein-coupled receptor 31 (GPR31) and its clinical significance in human colorectal cancer (CRC). METHODS: To determine the association between the GPR31 expression and the prognosis of patients, we obtained paraffin-embedded pathological specimens from 466 CRC patients who underwent initial resection. A total of 321 patients from the First Affiliated Hospital of Sun Yat-sen University from January 1996 to December 2008 were included as a training cohort, whereas 145 patients from the Sixth Affiliated Hospital of Sun Yat-sen University from January 2007 to November 2008 were included as a validation cohort. We examined GPR31 expression levels in CRC tissues from two independent cohorts via immunohistochemical staining. All patients were categorized into either a GPR31 low expression group or a GPR31 high expression group. The clinicopathological factors and the prognosis of patients in the GPR31 low expression group and GPR31 high expression group were compared. RESULTS: We compared the clinicopathological factors and the prognosis of patients in the GPR31 low expression group and GPR31 high expression group. Significant differences were observed in the number of patients in pM classification between patients in the GPR31 low expression group and GPR31 high expression group (P = 0.007). The five-year survival and tumor-free survival rates of patients were 84.3% and 82.2% in the GPR31 low expression group, respectively, and both rates were 59.7% in the GPR31 high expression group (P < 0.05). Results of the Cox proportional hazard regression model revealed that GPR31 upregulation was associated with shorter overall survival and tumor-free survival of patients with CRC (P < 0.05). Multivariate analysis identified GPR31 expression in colorectal cancer as an independent predictive factor of CRC patient survival (P < 0.05). CONCLUSION: High GPR31 expression levels were found to be correlated with pM classification of CRC and to serve as an independent predictive factor of poor survival of CRC patients. PMID- 30416316 TI - End-stage renal disease is associated with increased post endoscopic retrograde cholangiopancreatography adverse events in hospitalized patients. AB - AIM: To determine if end-stage renal disease (ESRD) is a risk factor for post endoscopic retrograde cholangiopancreatography (ERCP) adverse events (AEs). METHODS: We performed a retrospective cohort study using the Nationwide Inpatient Sample (NIS) 2011-2013. We identified adult patients who underwent ERCP using the International Classification of Diseases 9th Revision (ICD-9-CM). Included patients were divided into three groups: ESRD, chronic kidney disease (CKD), and control. The primary outcome was post-ERCP AEs including pancreatitis, bleeding, and perforation determined based on specific ICD-9-CM codes. Secondary outcomes were length of hospital stay, in-hospital mortality, and admission cost. AEs and mortality were compared using multivariate logistic regression analysis. RESULTS: There were 492175 discharges that underwent ERCP during the 3 years. The ESRD and CKD groups contained 7347 and 39403 hospitalizations respectively, whereas the control group had 445424 hospitalizations. Post-ERCP pancreatitis (PEP) was significantly higher in the ESRD group (8.3%) compared to the control group (4.6%) with adjusted odd ratio (aOR) = 1.7 (95%CI: 1.4-2.1, a P < 0.001). ESRD was associated with significantly higher ERCP-related bleeding (5.1%) compared to the control group 1.5% (aOR = 1.86, 95%CI: 1.4-2.4, a P < 0.001). ESRD had increased hospital mortality 7.1% vs 1.15% in the control OR = 6.6 (95%CI: 5.3 8.2, a P < 0.001), longer hospital stay with adjusted mean difference (aMD) = 5.9 d (95%CI: 5.0-6.7 d, a P < 0.001) and higher hospitalization charges aMD = $+82064 (95%CI: $68221-$95906, a P < 0.001). CONCLUSION: ESRD is a risk factor for post-ERCP AEs and is associated with higher hospital mortality. Careful selection and close monitoring is warranted to improve outcomes. PMID- 30416317 TI - Risk of lymph node metastases in patients with T1b oesophageal adenocarcinoma: A retrospective single centre experience. AB - AIM: To assess clinical outcomes for submucosal (T1b) oesophageal adenocarcinoma (OAC) patients managed with either surgery or endoscopic eradication therapy. METHODS: Patients found to have T1b OAC following endoscopic resection between January 2008 to February 2016 at University College London Hospital were retrospectively analysed. Patients were split into low-risk and high-risk groups according to established histopathological criteria and were then further categorised according to whether they underwent surgical resection or conservative management. Study outcomes include the presence of lymph-node metastases, disease-specific mortality and overall survival. RESULTS: A total of 60 patients were included; 22 patients were surgically managed (1 low-risk and 21 high-risk patients) whilst 38 patients were treated conservatively (12 low-risk and 26 high-risk). Overall, lymph node metastases (LNM) were detected in 10 patients (17%); six of these patients had undergone conservative management and LNM were detected at a median of 4 mo after endoscopic mucosal resection (EMR). All LNM occurred in patients with high-risk lesions and this represented 21% of the total high-risk lesions. Importantly, there was no statistically significant difference in tumor-related deaths between those treated surgically or conservatively (P = 0.636) and disease-specific survival time was also comparable between the two treatment strategies (P = 0.376). CONCLUSION: T1b tumours without histopathological high-risk markers of LNM can be treated endoscopically with good out-comes. In selected patients, endoscopic therapy may be appropriate for high-risk lesions. PMID- 30416318 TI - Willingness to pay for colorectal cancer screening in Guangzhou. AB - AIM: To measure the willingness to pay for colorectal cancer screening in Guangzhou, and to identify those factors associated with it. METHODS: A face-to face questionnaire survey for pre-screening population from free and non-free colonoscopy districts was used to collect information on demographic characteristics, health behaviours, the intention of the cancer screenings and willingness to pay for colorectal cancer screening. A total of 1243 participants who took part in the pre-screening for colorectal cancer in Guangzhou were collected in the study. Categorical data were compared using the chi2 test to analyse significant differences. Non-conditional logistic regression and multi class logistic regression were also performed for multivariate analysis and to estimate the odds ratios. RESULTS: The percentage of participants willing to pay for colorectal cancer screening was 91.7%. "Unnecessary" was the dominant reason that participants gave for their unwillingness, accounting for 63.1%. Of those who were willing to pay, 29.2%, 20.7%, 14.8%, 13.0% and 22.4% of participants were willing to pay less than ?100, ?100-?199, ?200-299, ?300-?399 and more than ?400, respectively. Non-logistic regression analysis showed that respondents who were male, had a high level of education, were from the family with more children/older to raise, and accepted colorectal cancer screening were willing to pay for this screening. Multi-class logistic regression analysis showed that respondents with higher annual household income per capita, from government and private enterprises, government agency/institution and peasants, and less family medical expenditure were willing to pay more. CONCLUSION: Willingness to pay for colorectal cancer screening in Guangzhou is high, but the amount of willing to pay is not much. PMID- 30416319 TI - Ductopenia and cirrhosis in a 32-year-old woman with progressive familial intrahepatic cholestasis type 3: A case report and review of the literature. AB - Progressive familial intrahepatic cholestasis type 3 is caused by a mutation in the ATP-binding cassette, subfamily B, member 4 (ABCB4) gene encoding multidrug resistance protein 3. A 32-year-old woman with a history of acute hepatitis at age 9 years was found to have jaundice during pregnancy in 2008, and was diagnosed as having intrahepatic cholestasis of pregnancy. In 2009, she underwent cholecystectomy for gallstones and chronic cholecystitis. However, itching and jaundice did not resolve postoperatively. She was admitted to our hospital with fatigue, jaundice, and a recently elevated gamma-glutamyl transpeptidase level. Liver biopsy led to the diagnosis of biliary cirrhosis with ductopenia. Genetic testing revealed a pathogenic heterozygous mutation, ex13 c.1531G > A (p.A511T), in the ABCB4 gene. Her father did not carry the mutation, but her mother's brother carried the heterozygous mutation. We made a definitive diagnosis of familial intrahepatic cholestasis type 3. Her symptoms and liver function improved after 3 mo of treatment with ursodeoxycholic acid. PMID- 30416320 TI - ComClus: A Self-Grouping Framework for Multi-Network Clustering. AB - Joint clustering of multiple networks has been shown to be more accurate than performing clustering on individual networks separately. This is because multi network clustering algorithms typically assume there is a common clustering structure shared by all networks, and different networks can provide compatible and complementary information for uncovering this underlying clustering structure. However, this assumption is too strict to hold in many emerging applications, where multiple networks usually have diverse data distributions. More popularly, the networks in consideration belong to different underlying groups. Only networks in the same underlying group share similar clustering structures. Better clustering performance can be achieved by considering such groups differently. As a result, an ideal method should be able to automatically detect network groups so that networks in the same group share a common clustering structure. To address this problem, we propose a new method, ComClus, to simultaneously group and cluster multiple networks. ComClus is novel in combining the clustering approach of non-negative matrix factorization (NMF) and the feature subspace learning approach of metric learning. Specifically, it treats node clusters as features of networks and learns proper subspaces from such features to differentiate different network groups. During the learning process, the two procedures of network grouping and clustering are coupled and mutually enhanced. Moreover, ComClus can effectively leverage prior knowledge on how to group networks such that network grouping can be conducted in a semi supervised manner. This will enable users to guide the grouping process using domain knowledge so that network clustering accuracy can be further boosted. Extensive experimental evaluations on a variety of synthetic and real datasets demonstrate the effectiveness and scalability of the proposed method. PMID- 30416321 TI - The Psychometric Properties of the Swedish Version of the General Self-Efficacy Scale: A Rasch Analysis Based on Adolescent Data. AB - Self-efficacy describes people's belief in their own ability to perform the behaviors required to produce a desired outcome. The purpose of this study was to examine the psychometric properties of the Swedish version of the General Self Efficacy Scale (GSES) with an adolescent sample, using Rasch analysis. The scale was examined with a focus on invariant functioning along the latent trait as well as across sample groups. The data were collected 2009 and 2010 among 3764 students aged between 13 and 15 years, in the 7th to 9th grade, in compulsory schools in the municipality of Karlstad, Sweden. The item fit was acceptable, the categorization of the items worked well and the scale worked invariantly between years of investigations. Although the GSES worked well as a whole, there was some evidence of misfit indicating room for improvements. The targeting may be improved by adding more questions of medium difficulty. Also, further attention needs to be paid to the dimensionality of the GSES as well as to whether the psychometric properties of GSES are affected by using more recent data. PMID- 30416322 TI - Arousal and Subjective Significance Shapes Stimuli Interpretation across Warmth Vs. Competence Dimensions. AB - The current study sought to examine the impact of incidental activation defined as arousal and subjective significance, both represented in connotations of verbal materials, on social perception of unknown and thus ambiguous objects, in terms of two basic dimensions of social cognition: warmth and competence. Arousal was expected to promote interpretation of ambiguous stimuli in terms of warmth, while subjective significance in terms of competence. This means that both activation and social perception may be treated as examples dual-mind systems functioning. Sixty participants (30 women) were exposed to two subsequent tasks. The first involved memorizing 135 words (manipulation prepared in a factorial design contrasting 3 levels of arousal and 3 levels of subjective significance), and the second involved guessing the meaning of hexagram stimuli derived from Far East culture. An increasing level of arousal caused participants to interpret stimuli as increasingly related to warmth, while an increasing level of subjective significance led to interpretations more related to competence. This study shows that two distinct types of activation may trigger different interpretations of social stimuli, which means that there is a link between both types of processes. This finding is of great importance for the dual-mind approach, showing that a multitude of dualities indentified thus far may be related one another. Therefore, it is justified to treat them as emanations of more general mental systems. PMID- 30416323 TI - Emotion Dysregulation, Mentalization and Romantic Attachment in the Nonclinical Adolescent Female Sample. AB - The main goal of the current study is to verify the relationships between emotion dysregulation, mentalization, and romantic attachment in late adolescent girls (N = 120). Adolescence is a very dynamic and sensitive period, in which many changes occur in attachment and emotion regulation. The role of the primary attachment figures is gradually taken over by peers, and the beginnings of the development of romantic attachment are seen. In summary, this study was able to determine that the level of dysregulation of emotions in girls during late adolescence can be partially explained by mentalization and levels of anxiety (though not of avoidance) regarding a romantic partner, though attachment anxiety is more important for explaining emotion dysregulation than the level of mentalization. Only two aspects of emotion dysregulation show relationships with mentalization: nonacceptance of emotional responses and lack of emotional clarity. Adolescence is considered to be a critical period for interventions to protect against the onset of psychopathology. Confirmation of these relationships appears to be important for the design of therapeutic interventions. Our findings may suggest that attachment patterns, mentalization and emotion dysregulation may be good targets for therapeutic intervention in adolescence. PMID- 30416324 TI - Attitudes towards Ambiguity in Japanese Healthy Volunteers. AB - Multi-dimensional structure of the Attitudes Towards Ambiguity Scale (ATAS: original Japanese version) and its relationship with the Acceptance and Action Questionnaire (AAQ) were investigated. We administered the ATAS and the Japanese version of the AAQ to 1019 Japanese healthy volunteers (513 females and 506 males; age range 18-78 years). Trial of exploratory factor analysis extracted four distinct clusters (Enjoyment; alpha = .83, Anxiety; alpha = .75, Exclusion; alpha = .75, and Noninterference; alpha = .65) from the ATAS item pool, suggestive of diversity in cognitive/ emotional/ behavioral responses to ambiguity. Confirmative factor analysis showed similar goodness in fit indices between the new four-factor model in the present study and the original five factor model in our previous study (Nishimura 2007). Considering interpretability by using large number of representative samples with general population in the present study, we adopted the four-factor model. The ATAS Anxiety subscale was negatively correlated with the AAQ willingness subscale (r = -.39, p < .001), while the ATAS Enjoyment subscale was positively correlated with the AAQ Action subscale (r = .40, p < .001). It is thus suggested that one who enjoys ambiguous situations can adopt two distinct attitudes: Excluding ambiguity from active resolution, or not interfering with ambiguity due to good tolerance of this experience, which can lead to positive and flexible commitments in life. In contrast, one who tends to be anxious about ambiguity may be characterized by exclusion-based attitudes due to intolerance of ambiguity, leading to lowered acceptance of their feelings and of the reality of circumstances. Cognitive/emotional attitudes towards ambiguity may affect acceptance of inner experience and active commitment to reality. PMID- 30416325 TI - Models of brain injury vocational rehabilitation: The evidence for resource facilitation from efficacy to effectiveness. AB - BACKGROUND: Resource Facilitation (RF) is an intervention developed to improve return to work (RTW) following brain injury. RF is an individualized treatment specializing in connecting patients and caregivers with community-based resources and services to mitigate barriers to return to work. OBJECTIVES: Examine the effectiveness of the RHI RF program for a clinical prospective cohort of participants referred to this program from the State Vocational Rehabilitation agency. METHODS: Participants were 243 participants with data drawn from the two sources: 33 from previous randomized controlled trial (RCT) control groups who did not receive RF and 210 from clinical patients discharged from the RHI RF program. RESULTS: At discharge from RF, a greater proportion of the treatment group obtained employment than the control group [X2 (1) = 5.39, p = 0.018]. When controlling for baseline level of disability, treatment group significantly predicted employment outcome (Wald = 4.52, p = 0.033) and participants in the treatment group were 2.3 times more likely to return to work than controls. CONCLUSIONS: Previous RCTs have studied the RHI RF model and demonstrated significant efficacy. The findings from the present study are consistent with the employment rates found in the previous RCT's following RF, and also provide initial support for the clinical effectiveness of RF. PMID- 30416326 TI - FOOD IMAGE ANALYSIS: THE BIG DATA PROBLEM YOU CAN EAT! AB - Six of the ten leading causes of death in the United States can be directly linked to diet. Measuring accurate dietary intake, the process of determining what someone eats is considered to be an open research problem in the nutrition and health fields. We are developing image-based tools in order to automatically obtain accurate estimates of what foods a user consumes. We have developed a novel food record application using the embedded camera in a mobile device. This paper describes the current status of food image analysis and overviews problems that still need to be addressed. PMID- 30416327 TI - Interactive Visualization of Hierarchically Structured Data. AB - We introduce methods for visualization of data structured along trees, especially hierarchically structured collections of time series. To this end, we identify questions that often emerge when working with hierarchical data and provide an R package to simplify their investigation. Our key contribution is the adaptation of the visualization principles of focus-plus-context and linking to the study of tree-structured data. Our motivating application is to the analysis of bacterial time series, where an evolutionary tree relating bacteria is available a priori. However, we have identified common problem types where, if a tree is not directly available, it can be constructed from data and then studied using our techniques. We perform detailed case studies to describe the alternative use cases, interpretations, and utility of the proposed visualization methods. PMID- 30416328 TI - Advancing Ego Development in Adulthood Through Study of the Enneagram System of Personality. AB - A rapidly growing number of working professionals, academic communities, and businesses have applied the Enneagram personality system of nine types to enhance psychological growth in their personal and professional lives. However, there are no existing studies that measure the effects of the application of Enneagram training programs to promote ego development. This study examined if ego development took place among individuals enrolled in Enneagram training programs in the Narrative Tradition. Two groups of participants (N = 122) were assessed using the Washington University Sentence Completion Test (WUSCT) at baseline (pretest) before the training began and then again 18 months later (posttest); one of the groups participated in Enneagram Intensive training programs (n = 73) and the other group participated in introductory Enneagram trainings (n = 49). Data revealed an advancement in ego development among some of the participants who received at least 40-50 h of training. The findings suggest that Enneagram Intensive trainings may be beneficial for promoting psychological growth and ego development. Clinical applications and future research directions are discussed. PMID- 30416329 TI - Emotional Intelligence Profiles in College Students and Their Fathers' and Mothers' Parenting Practices. AB - The present study has two objectives: first, to analyze whether the dimensions that make up emotional intelligence (attention, clarity, and repair) give rise to different profiles of university students, and secondly, to determine whether these different profiles are differentially associated with the parenting practices that students report with regard to their fathers and mothers. Results obtained indicate the existence of different profiles of college students. The profile that corresponds to adequate emotional skills presents a lower score in attention, but higher scores in clarity, and especially in mood repair. The other two profiles are inadequate, in the first case because a higher score in emotional attention is accompanied by low scores in mood repair, and in the second case because low scores are presented in all three dimensions. Likewise, we verified the existence of significant differences in the educational practices of parents, the adequate profile is characterized by greater use of parenting dimensions considered to be positive, and at the same time, lower scores on dimensions considered to be negative. One of the dysfunctional profiles is associated with higher scores in positive practices, and is also associated with higher scores in practices considered to produce a negative effect. The second dysfunctional profile is associated with higher scores on the dimensions considered to be negative and lower scores on positive dimensions. PMID- 30416330 TI - Adaptive Equilibrium Regulation: Modeling Individual Dynamics on Multiple Timescales. AB - Damped Linear Oscillators estimated by 2nd-order Latent Differential Equation have assumed a constant equilibrium and one oscillatory component. Lower frequency oscillations may come from seasonal background processes, which non randomly contribute to deviation from equilibrium at each occasion and confound estimation of dynamics over shorter timescales. Boker (2015) proposed a model of individual change on multiple timescales, but implementation, simulation, and applications to data have not been demonstrated. This study implemented a generalization of the proposed model; examined robustness to varied timescale ratios, measurement error, and occasions-per-person in simulated data; and tested for dynamics at multiple timescales in experience sampling affect data. Results show small standard errors and low bias to dynamic estimates at timescale ratios greater than 3:1. Below 3:1, estimate error was sensitive to noise and total occasions; rates of non-convergence increased. For affect data, model comparisons showed statistically significant dynamics at both timescales for both participants. PMID- 30416331 TI - Flexible quantum dot light-emitting devices for targeted photomedical applications. AB - Quantum dot light-emitting devices (QLEDs), originally developed for displays, were recently demonstrated to be promising light sources for various photomedical applications, including photodynamic therapy cancer cell treatment and photobimodulation cell metabolism enhancement. With exceptional emission wavelength tunability and potential flexibility, QLEDs could enable wearable, targeted photomedicine with maximized absorption of different medical photosensitizers. In this paper, we report, for the first time, the in vitro study to demonstrate that QLEDs-based photodynamic therapy can effectively kill Methicillin-resistant Staphylococcus aureus, an antibiotic-resistant bacterium. We then present successful synthesis of highly efficient quantum dots with narrow spectra and specific peak wavelengths to match the absorption peaks of different photosensitizers for targeted photomedicine. Flexible QLEDs with a peak external quantum efficiency of 8.2% and a luminance of over 20,000 cd/m2 at a low driving voltage of 6 V were achieved. The tunable, flexible QLEDs could be employed for oral cancer treatment or diabetic wound repairs in the near future. These results represent one fresh stride toward realizing QLEDs' long-term goal to enable the wide clinical adoption of photomedicine. PMID- 30416332 TI - Indium Phosphide Photonic Integrated Circuits for Free Space Optical Links. AB - An indium phosphide (InP)-based photonic integrated circuit (PIC) transmitter for free space optical communications was demonstrated. The transmitter consists of a sampled grating distributed Bragg reflector (SGDBR) laser, a high-speed semiconductor optical amplifier (SOA), a Mach-Zehnder modulator, and a high-power output booster SOA. The SGDBR laser tunes from 1521 nm to 1565 nm with >45 dB side mode suppression ratio. The InP PIC was also incorporated into a free space optical link to demonstrate the potential for low cost, size, weight and power. Error-free operation was achieved at 3 Gbps for an equivalent link length of 180 m (up to 300 m with forward error correction). PMID- 30416333 TI - Non-homologous recombination between Alu and LINE-1 repeats results in a 91 kb deletion in MERTK causing severe retinitis pigmentosa. AB - Purpose: Retinitis pigmentosa (RP) represents a large group of inherited retinal diseases characterized by clinical and genetic heterogeneity. Among patients with RP in northern Sweden, we identified two severely affected siblings and aimed to reveal a genetic cause underlying their disease. Methods: Whole exome sequencing (WES) was performed on both affected individuals. Sequence variants were filtered using a custom pipeline to find a rare or novel variant predicted to affect protein function. Genome-wide genotyping was used to identify copy number variants (CNVs) and homozygous regions with potential disease causative genes. Results: WES uncovered a novel heterozygous variant in the MER proto-oncogene, tyrosine kinase (MERTK) gene, c.2309A>G, p.Glu770Gly located in the tyrosine kinase domain and predicted to be likely pathogenic. The second variant, a large heterozygous deletion encompassing exons 1 to 7 of the MERTK gene, was revealed with genome-wide genotyping. The CNV analysis suggested breakpoints of the deletion, in the 5'-untranslated region and in intron 7. We identified genomic sequences at the site of the deletion as part of L1ME4b (LINE/L1) and AluSx3 that indicated a non-homologous recombination as a mechanism of the deletion evolvement. Conclusions: Patients with RP in this study were carriers of two novel allelic mutations in the MERTK gene, a missense variant in exon 17 and an approximate 91 kb genomic deletion. Mapping of the deletion breakpoints allowed molecular testing of a cohort of patients with RP with allele-specific PCR. These findings provide additional information about mutations in MERTK for molecular testing of unsolved recessive RP cases and highlight the necessity for analysis of large genomic deletions. PMID- 30416334 TI - Advanced molecular approaches pave the road to a clear-cut diagnosis of hereditary retinal dystrophies. AB - Purpose: The aim of this study was to identify the molecular genetic basis of hereditary retinal dystrophies (HRDs) in five unrelated Iranian families. Methods: Whole exome sequencing and Sanger sequencing were performed in all families. Variants were analyzed using various bioinformatics databases and software. Results: Based on the selected strategies, we identified potentially causative variants in five families with HRDs: the novel homozygous deletion mutation c.586_589delTTTG (p.F196Sfs*56) in the TTC8 gene of family A, the novel homozygous missense mutation c.2389T>C (p.S797P) in the CRB1 gene in family B, the novel homozygous frameshift mutation c.2707dupA (p.S903Kfs*66) in the LRP5 gene in family C, the novel homozygous splice mutation c.584-1G>T in the MERTK gene in family D, and the novel homozygous missense mutation c.1819G>C (p.G607R) rs61749412 in the ABCA4 gene of family E. Conclusions: This study highlights the presence of five novel variants associated with retinal dystrophies in selected Iranian families with hereditary blindness. PMID- 30416336 TI - The first record of the anopsobiid genus Shikokuobius Shinohara, 1982 in continental Asia, with the description of a new species from the Altais, southwestern Siberia, Russia (Chilopoda, Lithobiomorpha, Anopsobiidae). AB - A new lithobiomorph species, Shikokuobiusaltaicus sp. n., is described from the Altai Mountains in southwestern Siberia, Russia. This is the first record of the genus Shikokuobius Shinohara, 1982 in continental Asia, all previous reports being from Japan. The distribution of Shikokuobius is mapped. PMID- 30416335 TI - Evaluation of dysphagia in different phenotypes of early and idiopathic Parkinsonism. AB - Background: Parkinsonism (PD) is a common neurodegenerative disorders into which dysphagia occurs mainly in the late stage and to a lesser extent in an early stage. Diagnosis of dysphagia particularly in early idiopathic Parkinson's disease (IPD) is important as dysphagia affects the quality of life of patients and most of the patients are unaware of this important symptom. Method: Fifty four patients were enrolled in this study presented with early IPD attending to the outpatient clinic of Sohag University Hospital. All PD patients were assessed by using Unified Parkinson's Disease Rating Scale (UPDRS) and modified Hoehn and Yahr scale. IPD patients were classified into tremor dominant (TD) and postural instability/gait disorder (PIGD) phenotypes. Swallowing disturbance questionnaire (SDQ) and fiberoptic endoscopic evaluation of swallowing (FEES) were used to evaluate dysphagia. Results: Thirty-five percent of patients experienced dysphagia when the patients were questioned, and this percent rises to 40% on using FEES. The results of SDQ were significantly correlated to the results of more accurate FEES. The percentage of dysphagia was higher in patients with PIGD than TD phenotype. Dysphagia was significantly associated with the mean of the Mini-Mental State Examination (MMSE), UPDRS, and modified Hoehn and Yahr scale. Conclusions: Dysphagia is a prevalent symptom in early IPD and significantly correlated with Parkinsonism phenotype, UPDRS, and modified Hoehn and Yahr scale. PMID- 30416337 TI - Description of three new species of Scolanthus (Cnidaria, Anthozoa, Actiniaria, Edwardsiidae): first records of the genus from Japan. AB - Scolanthus is one genus of Edwardsiidae, a speciose family of burrowing worm-like sea anemones characterized by lacking a physa-like aboral end and by possessing nemathybomes on the whole body except at the distal end. This genus has been recorded worldwide, but there have been no specimens collected from Japan. In this study, we discovered four Scolanthus species in Japan for the first time: Scolanthusarmatus (Carlgren, 1931) and Scolanthuskopepe sp. n. from the Ogasawara Islands, Scolanthusena sp. n. from Ena Bay, Kanagawa, and Scolanthusisei sp. n. from Sugashima Island, Mie. PMID- 30416338 TI - An example of a possible leech-bryozoan association in freshwater. AB - Associations of various invertebrate species with bryozoans and sponges are a well-known marine phenomenon but such epizooic communities are far less diverse in freshwater environments. Here an occurrence of numerous leeches Alboglossiphoniacf.papillosa (Braun, 1805), in interstitial spaces between zooids of a colony of the freshwater bryozoan species Plumatellaaff.fungosa (Pallas, 1768) in Eastern Siberia is described. To the best of our knowledge, this record appears to be the first known example of a leech-bryozoan association, although such relationships deserve further research. PMID- 30416339 TI - A new genus of oonopid spiders from Myanmar (Araneae, Oonopidae). AB - A new genus, Kachinia Tong & Li, gen. n., including two new species, K.putao Tong & Li, sp. n., and K.mahmolae Tong & Li, sp. n., is described from Myanmar. The new genus belonging to the subfamily Oonopinae Simon, 1890, currently is the only member of the Brignolia-Opopaea clade with leg spines. PMID- 30416340 TI - Taxonomy of Baetis Leach in Israel (Ephemeroptera, Baetidae). AB - The taxonomy and systematics of the genus Baetis Leach (Ephemeroptera: Baetidae) in Israel is clarified for the first time as part of an ongoing comprehensive survey of the Israeli mayfly fauna. Six clearly defined species are currently recognized in Israel, four of which are described here as new to science. The validity of all species is supported by a molecular analysis of the mitochondrial COI gene. A key for the identification of the Israeli species based on the nymphal stage is provided, as well as data on their distribution patterns and ecology. The local fauna represents four Palearctic species groups, three of which reach their limit of distribution range in Israel. Baetis species typically inhabit lotic, pristine habitats in northern Israel, with few exceptions for some species that can be found in the Dead Sea area or in ephemeral ponds. PMID- 30416341 TI - One new genus and three new species in the leafhopper tribe Coelidiini from the Neotropical Region (Hemiptera, Cicadellidae, Coelidiinae). AB - One new leafhopper genus Paracodilia gen. n. with one new species P.geniculata sp. n., and two other new species in different genera, Bolivielaexpanda and Armaturolidiasymmetrica spp. n., are described in the tribe Coelidiini (Cicadellidae: Coelidiinae) from the Neotropical region. Photographs and illustrations are provided. PMID- 30416342 TI - Review of Brazilian jawfishes of the genus Opistognathus with descriptions of two new species (Teleostei, Opistognathidae). AB - A new species of jawfish, Opistognathusthionyi sp. n., is described from the Vitoria-Trindade Chain and Fernando de Noronha Archipelago off Brazil, a disjunct distribution of ca. 1,800 km. Opistognathusthionyi and its allopatric Caribbean sister-species, Opistognathusmaxillosus, both have a wide, fan-like upper margin of the subopercular flap and mostly over-lapping meristic data. The new species differs from O.maxillosus in having the darkest spot on the spinous dorsal fin, when present, between spines 2-5, versus always present between spines 6-9, the buccal area surrounding the esophageal opening pale versus very dark and fewer oblique scale rows in longitudinal series (45-52 vs. 69-85). A second new species, Opistognathusvicinus sp. n., known from Brazil's mainland, has completely over-lapping meristic values with its allopatric Caribbean sister species O.whitehursti, but differs in lacking vomerine teeth and a supramaxilla and retaining the juvenile color pattern of the latter species in adults. Diagnoses, photographs, an identification key, and distributional maps are given for all Brazilian species of Opistognathus. Molecular phylogenetic analysis of partial cytochrome c oxidase subunit-I sequences indicates that specimens of the two allopatric pairs, O.thionyi - O.maxillosus and O.vicinus - O.whitehursti, form reciprocally monophyletic groups that differ from each other on average by 9 to 11%, with less than 1% average pair-wise genetic distance within-species. Similar patterns of phylogenetic structure were observed between reciprocally monophyletic (predominately allopatric) groups within nominal species of Opistognathusaurifrons, suggesting the possibility of at least two additional undescribed species from the Brazilian Province. PMID- 30416343 TI - A new cryptic species of Anolis lizard from northwestern South America (Iguanidae, Dactyloinae). AB - A new species of Anolis lizard from the Andean slopes of southwestern Colombia and northwestern Ecuador, from between 1187 and 2353 m in elevation, is described. The new species can be distinguished from other Anolis in squamation, cranial osteology, hemipenial morphology, and nuclear and mitochondrial DNA. The new species is sister to Anolisaequatorialis, and it is suggested that previous records of A.aequatorialis in Colombia correspond to the new species described herein. PMID- 30416344 TI - Begoniayenyeniae (Begoniaceae), a new species from Endau Rompin National Park, Johor, Malaysia. AB - Begoniayenyeniae is a new species of horticultural value known only from the Endau Rompin National Park, Peninsular Malaysia. It is similar to Begoniarajah with which it had previously been confused in the number of tepals and leaf characters. The new species is compared with three similar species, B.foxworthyi, B.rajah and B.reginula and photographs of all four species and descriptions of B.yenyeniae and B.rajah are provided. Molecular analysis using the ndhF-rpl132 chloroplast marker confirms the four species as distinct. Amongst native species, the three variegated species, B.yenyeniae, B.rajah and B.reginula, are some of the most popular Malaysian begonias in cultivation. Based on its restricted distribution, Begoniayenyeniae, under the IUCN Red List Categories and Criteria, is assessed as Critically Endangered. PMID- 30416345 TI - Ocular administration of acetazolamide microsponges in situ gel formulations. AB - In the present work, the antiglaucoma drug, acetazolamide, was formulated as microsponges in situ gel for ocular drug delivery aiming an improved therapeutic efficacy and reduction in the systemic side effects of oral acetazolamide. The microsponges were prepared by the quasi emulsion solvent diffusion method and were incorporated into 25% pluronic F-127 in situ gel. Ethyl cellulose polymer in different proportions with drug was used to prepare the microsponges. Different parameters were evaluated to select the best formulation. The formula S2 with drug to polymer ratio (2:1) showed high entrapment efficiency of about 82% and mean particle size of about 10 um with polydispersity index (PDI) of 0.22, which are suitable characters for ocular delivery. The in situ gels were evaluated for physicochemical properties (pH, gelling capacity, gelation time and rheological properties) and in vivo studies. S2 formulation showed higher therapeutic efficacy compared to free drug in gel. It was non irritant to the rabbit's eye. These results indicated that acetazolamide microsponges in situ gel have potential ability for ophthalmic delivery. PMID- 30416346 TI - Development of differentiated pharmaceutical packaging for greater autonomy and quality of life for physically and visually impaired patients. AB - 20-45% of the world population present special needs, permanent or provisional. This index is higher than that presented by the WHO, which determines that 10% of a country's population has some kind of disabled, in times of peace. This work proposes, focused on Assistive Technology, to seek solutions to daily problems encountered during the distribution of toothpaste for the toothbrushing of persons with visual impairment or with reduced mobility, through the development of a device that assists in the autonomy and independence of the individual, allowing their well-being and social inclusion. For this, an innovative packaging for toothpaste with important characteristics for the support was proposed, such as the presence of a pump valve and an adapter that guides the user to locate the exit of a predefined quantity of the toothpaste, without the need to handle the bristles of the brush, avoiding contaminations. The developed packaging material allows the user independence in day-to-day activities, which strengthens their self-esteem and quality of life, leading, consequently, to family well-being. PMID- 30416347 TI - Knowledge, attitudes & practices of healthcare professionals in hospitals towards the reporting of adverse drug reactions in Saudi Arabia: A multi-centre cross sectional study. AB - Introduction: Adverse drug reactions (ADRs) are a major global clinical problem, causing substantial mortality and morbidity especially in hospitals. Healthcare professionals (HCPs) knowledges', attitude and practices are crucial points to evaluate the hospital safety environment. Objective of the study was to investigate the knowledge, attitudes, and practices of HCPs regarding the ADRs reporting system. Methods: A cross-sectional survey was conducted between January and February of 2013 in nine tertiary care hospitals (governmental and private) that provide highly specialized medical services in Riyadh, Qassim, and the Eastern region of the Kingdom of Saudi Arabia. A validated questionnaire was used to assess the knowledge, attitudes, and practices of HCPs regarding the ADR reporting system. All statistical analyses were performed using SAS version 9.2. Results: In total, 480 questionnaires were distributed, and the response rate was 70% (n = 336). Only 33% of the participants were aware of the National Pharmacovigilance Centre (NPC). Of those HCPs who were familiar with the NPC and their responsibility to report ADRs, most (50%) were pharmacists, followed by physicians (24%) and nurses (16%), and these differences were statistically significant (p < 0.01). Twenty-seven percent of the participants were involved in reporting ADRs; among these HCPs, 62% were pharmacists, 26% were nurses, and 6% were physicians. Most participants (95%) favoured reporting ADRs caused by antibiotics and new/old drugs. The prominent factors discouraging ADR reporting included fear that the report might be incorrect (46%) and lack of time (44%). Conclusions: A significant lack of knowledge, positive attitudes, and practices regarding ADRs and reporting was observed in hospital HCPs. This finding represents an international concern, and urgent action is needed to promote drug safety and pharmacovigilance in this region. PMID- 30416348 TI - Physical and chemical screening of honey samples available in the Saudi market: An important aspect in the authentication process and quality assessment. AB - Honey is becoming accepted as a reputable and effective therapeutic agent by practitioners of conventional medicine and by the general public. It has many biological activities and has been effectively used in the treatment of many diseases, e.g. gastrointestinal diseases, skin diseases, cancer, heart diseases, and neurological degeneration. Honey is an excellent source of energy containing mainly carbohydrates and water, as well as, small amounts of organic acids, vitamins, minerals, flavonoids, and enzymes. As a natural product with a relatively high price, honey has been for a long time a target for adulteration. The authenticity of honey is of great importance from commercial and health aspects. The study of the physical and chemical properties of honey has been increasingly applied as a certification process for the purpose of qualification of honey samples. The current work focusses on studying the authenticity of various types of honey sold in Riyadh market (24 samples). For this purpose, physical properties (pH, hydroxylmethylfurfural HMF, and pollen test) were measured. Besides, sugar composition was evaluated using Fehling test and an HPLC method. Elemental analysis was carried out using inductively coupled plasma (ICP). In addition, the presence of drug additives was assessed by means of GC MS. The obtained results were compared with the Saudi Arabian standards, Codex Alimentarius Commission (2001), and harmonized methods of the international honey commission. PMID- 30416349 TI - The relationship between blood eosinophil count and disease activity in ankylosing spondylitis patients treated with TNF-alpha inhibitors. AB - Aim: Anti-tumor necrosis factor-alpha (Anti-TNF-alpha) therapy has achieved an important position, are widely used for ankylosing spondylitis (AS) patients. TNF alpha inhibition improves clinical outcomes and has differential effects on haematopoiesis. Information about effects on eosinophils is limited. The aim of our study is to determine the relationship between blood eosinophil counts in AS patients treated with TNF-alpha inhibitors. Methods: Seventy-five patients diagnosed with AS according to modified New York criteria were enrolled in this study. Disease activity was assessed by BASDAI, and erythrocyte sedimentation rate, C-reactive protein of patients were evaluated. All data were analyzed with Spearman's correlation and Friedman's Two-Way by using SPSS version 19.0 statistical software, and p < 0.05 was considered as statistically significant. Results: Seventy-five AS (F/M: 27/48, the mean age of 41 +/- 10 years) patients were evaluated. On the 3rd month of treatment, there was a correlation between BASDAI and CRP (r = 0.32, p = 0.005), but no correlation between BASDAI and ESR (r = 0.21, p = 0.06). Blood eosinophil count was not correlated with BASDAI, ESR and CRP on pre-, post-therapy (p > 0.05). It counts lower before anti-TNF-alpha therapy compare with post-treatment (130/mm3, 140/mm3 and 190/mm3, respectively). There was no statistically significant difference between pre- and 3rd month (p > 0.05), while correlation was found between pre- and 6th month, and also 3rd month and 6th month (p < 0.001, p = 0.002, respectively) for blood eosinophil count. Conclusion: To the best of our knowledge, our study is the first to evaluate blood eosinophil counts and disease activity with anti-TNF-alpha therapy. Blood eosinophil count may be affected by TNF-alpha inhibition in patients with AS. PMID- 30416350 TI - Drug shortages in Saudi Arabia: Root causes and recommendations. AB - Drug shortages are a multifaceted problem that has been recurring in Saudi Arabia over the past decade with its significant negative impact on patient care. However, there is a dearth of evidence about possible domestic reasons, if any, behind this recurring problem. Recently, the Pharmacy Education Unit at King Saud University College of Pharmacy has called for a meeting with multiple stakeholders from academia, pharmaceutical care, pharmaceutical industry, purchasing and planning, and regulatory bodies to unveil the root domestic causes of the drug shortages in the Kingdom. Four major topics were used to guide the discussion in this meeting, including: current situation of drug shortages in Saudi Arabia, major factors contributing to drug shortages, challenges and obstacles to improve drug supply, and stakeholders' recommendations to manage drug shortages. The meeting was audio-recorded and transcribed into verbatim by five authors. The text was then reviewed and analyzed to identify different themes by the first and third authors. Multiple causes were identified and several recommendations were proposed. The main domestic causes of drug shortages that were explored in this study included poor medication supply chain management, lack of government regulation that mandates early notification of drug shortages, a government procurement policy that does not keep pace with the changes in the pharmaceutical market, low profit margins of some essential drugs, weak and ineffective law-violation penalties against pharmaceutical companies and licensed drug importers and distributors, and overdependence on drug imports. The participants have also proposed multiple recommendations to address drug shortages. Policy makers should consider these factors that contribute to drug shortages in Saudi Arabia as well as the recommendations when designing future initiatives and interventions to prevent drug shortages. PMID- 30416351 TI - Anticancer effect of Cenchrus ciliaris L. AB - Cenchrus ciliaris L total alcohol and successive extracts of both aerial and root parts were tested for their anticancer activities against lung (A-549), intestinal (CACO), colon (HCT-116), cervical (Hela), hepatocellular (HepG-2), and breast (MCF-7) (PC3) cell lines and compared with the standard drug vinblastine sulphate. The obtained results exhibited direct cytotoxic effect with variable inhibiting effect on the growth of the listed cell lines comparing to vinblastine sulphate as reference standard drug, these effects showed different IC50 ranged from 11.1 +/- 0.3 to 267 +/- ug/ml. All root extracts showed the best activities against most of the tested cell lines specially HepG-2 (Hepatocellular carcinoma) (9 +/- 2.1 ug/ml) which was somewhat closely related to the effect of vinblastine sulphate (2.93 +/- 0.3 ug/ml). The highest anticancer effect of Cenchrus ciliaris L aerial parts and root extracts were recorded on HepG-2 (Hepatocellular carcinoma) their IC50 were 12 +/- 0.8 & 9 +/- 2.1 respectively, CACO (colorectal carcinoma) their IC50 were 27.2 +/- 1.6 & 20.5 +/- 0.6 respectively, A-549 (Lung carcinoma) their IC50 were 14.5 +/- 0.7& 11.1 +/- 0.3 respectively which were better than the standard drug especially in case the anticancer effect on CACO (colorectal carcinoma) and A-549 (Lung carcinoma). Chloroform extracts of both aerial and roots achieved the best anticancer activities on all of the cell lines especially with colorectal (CACO) and Lung carcinoma (A-549). Cenchrus ciliaris could be a promising source of new chemical moieties used to target cancer cells. PMID- 30416352 TI - Evaluation of anti-ulcer and ulcerative colitis of Sonchus oleraceus L. AB - Sonchus oleraceus L. was evaluated for its gastro antiulcerogenic and anti ulcerative colitis activities Different extracts and fractions from Sonchus oleraceus aerial parts and roots were evaluated at different dose; total alcohol extracts of aerial parts SA and roots SR were evaluated doses 250 & 500 mg/kg, While Successive extracts (SAL, SRL, CSA, CSR, BSA & BSR) were evaluated at dose of 150 mg/kg. Absolute ethanol-induced ulcer model was used for evaluation of the anti-ulcerogenic activity. The root extract showed promising antiulcerogenic activity as the total alcohol extract of the root SR (500 mg/kg) produced 88.5% protection from control ulcer which is significantly more effective than the standard drug omeprazole (20 mg/kg), in addition, the butanol fraction of the root extract BSR also produced 76.66% protection from control ulcer. On the other hand, the aerial parts total extract SA showed low antiulcerogenic activity in both tested doses (250 & 500 mg/kg) as it produced 25% & 28.33% protection from control ulcer respectively. Only the butanol fraction of the aerial parts extract BSA showed promising activity 54.16%. In the acetic acid-induced ulcerative colitis model, among the investigated extracts of Sonchus oleraceus; only the total extract of the aerial parts (SA) at dose 500 mg/kg showed strong anti ulcerative colitis activity and this activity is followed by the activity of the butanol and chloroform fractions of the aerial parts, they produced 77.28%, 57.4% & 47.68% protection from control colitis respectively. The standard drug dexamethasone produced 63.36% protection from control colitis. The total alcohol extracts SR & SA showed no alteration on liver and kidney functions and these extracts are safe up to 5000 mg/kg. Phytochemical screening of the investigated extracts revealed the presence of carbohydrates, flavonoids, tannins, unsaturated sterols, proteins and lactones which could be responsible for the activities. PMID- 30416353 TI - The roles of valerenic acid on BDNF expression in the SH-SY5Y cell. AB - The roots of Valeriana officinalis L. (Valerianaceae) are used for treating sleep disorders and/or mild nerve tension. The effect of valerenic acid on brain derived neurotrophic factor (BDNF) has not yet been studied, although it is known that gamma-amino butyric acid A (GABAA) receptor is regulated by BDNF, which modulates the depressive-like behavior and neurogenesis. The purpose of this study is to determine the effect of V. officinalis root extract (VO), its main constituents valerenic acid (VA) and acetoxy valerenic acid (AVA) as well as valerenic acid-free (VAF), acetoxy valerenic acid-free (AVAF) extracts and increasing amounts of valerenic acid containing extracts on the BDNF expression in SH-SY5Y cell lines. The effect of methanolic extracts of VO, VA, AVA, VAF, AVAF, and the extracts whose amount of VA were increased gradually, were tested using a Human BDNF ELISA kit with 17beta-estradiol as a positive control. The VO and VA extracts caused a significant (p < 0.001) increase in the BDNF expression in SH-SY5Y cells compared to control. This effect completely disappeared when cells were treated with VAF extract. AVA alone did not show any significant change in the BDNF levels. The extracts with increasing amount of VA led to a concentration- dependent effect on the cells. In conclusion, our findings suggest that the antidepressant-like effect of the VO extract is also related to BDNF expression, and that this is mainly due to the presence of VA in the extract. Removing VA from VO extract leads to a loss of activity. Moreover, the concentration of VA plays a role for BDNF expressions in SH-SY5Y cells, which demonstrates the importance of quality control on the commercially available products. PMID- 30416354 TI - Higher rate of hyperglycemia than hypoglycemia during Ramadan fasting in patients with uncontrolled type 1 diabetes: Insight from continuous glucose monitoring system. AB - Background: Patients with uncontrolled type 1 diabetes mellitus (T1DM) are at a high risk for Ramadan fasting and are exempt from fasting; however, most still insist on fasting. The aim of this study was to examine glucose level fluctuations in those patients during Ramadan fasting using a real-time continuous glucose monitoring system (RT-CGMS). Methods: This pilot study involved adult patients with uncontrolled T1DM (HbA1c > 7%) who insisted on fasting during Ramadan in 2014 from Maternity and Children's Hospital, Medina, Saudi Arabia. A Medtronic RT-CGMS was used to monitor the participants' glucose levels for 3 consecutive days during fasting. Results: The study included 22 patients (mean age 22 +/- 6 years, duration of diabetes 10.9 +/- 7.2 years, HbA1c level 9.3 +/- 1.2). All participants were using the basal-bolus insulin regimen, except for one patient who was on an insulin pump. Sensor glucose (SG) profiles typically followed a pattern that was characterized by an exaggerated increase after iftar, which was sustained overnight, and a second rapid rise after suhoor, with a prolonged glucose decay over the daylight hours. The average SG was 199 +/ 104.1 mg/dl, which was lower during fasting 188.4 +/- 103.41 mg/dl than during the eating hours 212.5 +/- 103.51 mg/dl (P = 0.00). There was a higher rate of hyperglycemia (48%) than hypoglycemia (10%). Conclusions: Patients with uncontrolled T1DM who fasted during Ramadan experienced a wide fluctuation of glucose levels between fasting and eating hours, exhibiting a greater tendency toward hyperglycemia. The long-term effects for this finding are not known and warrant further investigation. PMID- 30416355 TI - Development and validation of UPLC-PDA method for concurrent analysis of bergenin and menisdaurin in aerial parts of Flueggea virosa (Roxb. ex Willd.). AB - Bergenin and menisdaurin are biologically active components which are found in plant Flueggea virosa (Phyllanthaceae). Bergenin has pharmacological actions such as chemopreventive and antihepatotoxic while menisdaurin has an anti-viral activity which needs its evaluation by an analytical method (UPLC-PDA method) that can be applied to the quality control of pharmaceutical preparations. The developed UPLC-PDA method was applied for identification and quantification of standards bergenin and menisdaurin in the methanol extract of F. virosa (FVME). The analysis was carried out using Eclipse C18 (4.6 * 100 mm, 3.5 um) UPLC column. The optimized chromatographic condition was achieved at 0.16 mL/min flow rate using gradient system with acetonitrile and water as mobile phase. Both biomarkers were measured at lambdamax 235 nm in PDA detector at ambient temperature. The developed method furnished sharp and intense peaks of menisdaurin and bergenin at Rt = 2.723 and 3.068 min, respectively along with r2 > 0.99 for both. The recoveries of bergenin and menisdaurin were found in the range of 99.37-101.49% and 98.20-100.08%, respectively. With other validation data, including precision, specificity, accuracy, and robustness, this method demonstrated excellent reliability and sensitivity. The separation parameters i.e. retention, separation, and resolution factors for resolved standards (bergenin and menisdaurin) were >1, which showed good separation. The quantity of bergenin and menisdaurin in the FVME sample was found as 15.16 and 3.28% w/w, respectively. The developed UPLC-PDA method could be conveniently adopted for the routine quality control analysis. PMID- 30416356 TI - Systematic review of the safety of medication use in inpatient, outpatient and primary care settings in the Gulf Cooperation Council countries. AB - Background: Errors in medication use are a patient safety concern globally, with different regions reporting differing error rates, causes of errors and proposed solutions. The objectives of this review were to identify, summarise, review and evaluate published studies on medication errors, drug related problems and adverse drug events in the Gulf Cooperation Council (GCC) countries. Methods: A systematic review was carried out using six databases, searching for literature published between January 1990 and August 2016. Research articles focussing on medication errors, drug related problems or adverse drug events within different healthcare settings in the GCC were included. Results: Of 2094 records screened, 54 studies met our inclusion criteria. Kuwait was the only GCC country with no studies included. Prescribing errors were reported to be as high as 91% of a sample of primary care prescriptions analysed in one study. Of drug-related admissions evaluated in the emergency department the most common reason was patient non-compliance. In the inpatient care setting, a study of review of patient charts and medication orders identified prescribing errors in 7% of medication orders, another reported prescribing errors present in 56% of medication orders. The majority of drug related problems identified in inpatient paediatric wards were judged to be preventable. Adverse drug events were reported to occur in 8.5-16.9 per 100 admissions with up to 30% judged preventable, with occurrence being highest in the intensive care unit. Dosing errors were common in inpatient, outpatient and primary care settings. Omission of the administered dose as well as omission of prescribed medication at medication reconciliation were common. Studies of pharmacists' interventions in clinical practice reported a varying level of acceptance, ranging from 53% to 98% of pharmacists' recommendations. Conclusions: Studies of medication errors, drug related problems and adverse drug events are increasing in the GCC. However, variation in methods, definitions and denominators preclude calculation of an overall error rate. Research with more robust methodologies and longer follow up periods is now required. PMID- 30416358 TI - The effect of polymer length on the in vitro characteristics of a drug loaded and targeted silica nanoparticles. AB - The objective of this research was to investigate the effect of polymer length on the in vitro characteristics of thymoquinone-melatonin (TQ-MLT) when loaded into our previously prepared targeted drug delivery system (TDDS). Our system constructed from silica nanoparticles (NPs) and modified with diamine polymer (D4000), carboxymethyl-beta-cyclodextrin (CM-beta-CD) and folic acid (FA), respectively. In this study, three other different lengths of polymers (D230, D400 and D2000) were used and compared to D4000. The surface modification was characterized using fourier transform infrared spectroscopy (FTIR) and the mean particle size as well as polydispersity (PD) was measured using dynamic light scattering (DLS). The results, in general, showed that the release rate increases as the polymer length decreases. Also, shorter polymers showed an obvious burst release of most of the drug within the first hour. On the other hand, longer polymers exhibited a more sustained release in a pulsatile manner, with two moderate drug burst patterns occurred within the first and the last few hours. The in vitro cell viability assay showed that the percentage of cell toxicity toward HeLa cells increases with increasing the polymer length. PMID- 30416357 TI - The use of proton pump inhibitors among older adults with intellectual disability: A cross sectional observational study. AB - Background: Older people with Intellectual Disability (ID) have a high prevalence of gastrointestinal conditions such as Gastro-Oesophageal Reflux Disease (GORD). However, despite this, information about treatment, in particular the use of Proton Pump Inhibitors (PPIs), in this population is sparse and limited. Objective: To investigate the prevalence and pattern of PPI use among older people with ID. Method: Data on PPI use and key demographics was analysed from Wave 2 (2013/2014) of IDS-TILDA, a nationally representative longitudinal study of 677 participants aged 40 years and above in Ireland. Descriptive statistics, bivariate analyses and binary logistic regression were carried out. Results: Just over a quarter, 27.9% (n = 189), of participants reported use of PPIs, and 53.4% (n = 101) were female. The largest proportion of PPI users (53.4%) were aged between 50 and 64 yrs. Most of the PPIs were used in maximum doses (66.7%). However only 43.9% of PPI users had an indication for PPI use (GORD, stomach ulcer or/and an NSAID use), and further 13.2% were also taking an antiplatelet agent. Use among those in residential care homes (54.3%) was much higher than for those living independently or with family (7%). PPI use among those who have severe/profound ID was 25% higher than those with mild ID. Information about the length of PPI use was missing for 31.2%, but of those with data, just over half recorded using the PPIs for more than a year. Apart from an indication, the factors associated with PPI use were older ages (>=50 years), severe/profound level of ID. Conclusion: PPI use among older people with intellectual disability is prevalent and frequently long term, often without a clear indication. PPI use especially among those with severe/profound ID and those who live in residential care homes, could predispose these individuals to additional comorbidities and in order to avoid inappropriate long term of use regular review is required. PMID- 30416359 TI - Quantitative determination of doxorubicin in the exosomes of A549/MCF-7 cancer cells and human plasma using ultra performance liquid chromatography-tandem mass spectrometry. AB - In cancer therapy, exosomes efflux enhances resistance of cancer cells toward anticancer agents through mediating the transport of anticancer drugs outside the cells. In this study, a rapid, simple and highly sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the determination of Doxorubicin (DOX) in exosomes of cancer cells and human plasma using Ketotifen as an internal standard (IS). Plasma samples spiked with DOX and two cancer cell lines (A549 & MCF-7) were incubated with different concentrations of DOX and IS. The analytes were then extracted with methanol after protein precipitation and the chromatographic separation was carried out using a C18 column, with a mixture of acetonitrile-water- formic acid (85:15:0.1%, v/v/v) as mobile phase. Multiple reaction monitoring (MRM) was utilized to monitor the protonated precursor to product ion transitions of m/z 544.25 > 397.16 and m/z 310.08 > 96.97 for the quantification of DOX and IS, respectively. The method was linear over ranges of 1-1000 ng/mL for DOX in plasma and 2-1000 ng/mL for DOX in exosome samples. The lower limit of quantification of this method was 1 ng/mL, 2 ng/mL and 2 ng/mL in human plasma, A549 & MCF-7 cells respectively. Intra- and inter day precision of all quality control concentrations were less than 10.33% and the accuracy values ranged from -4.82 to 12.60%. The optimized UPLC-MS/MS method proved to be fast, specific, simple and highly sensitive and was successfully applied for the estimation of DOX in the exosomes of cancer cells and plasma. PMID- 30416360 TI - Gold-containing compound BDG-I inhibits the growth of A549 lung cancer cells through the deregulation of miRNA expression. AB - Gold complex bis(diethyldithiocarbamato-gold(I)) bis(diphenylphosphino) methane (BDG-I) is cytotoxic toward different cancer cell lines. We compared the cytotoxic effect of BDG-I with that of cisplatin in the A549 lung cancer cell line. Additionally, we investigated the molecular mechanism underlying the toxic effect of BDG-I toward the A549 cell line and the identification of cancer related miRNAs likely to be involved in killing the lung cancer cells. Further, X ray crystallographic data of the compound were acquired. Using microarray, global miRNA expression profiling in BDG-I-treated A549 cells revealed 64 upregulated and 86 downregulated miRNAs, which targeted 4689 and 2498 genes, respectively. Biological network connectivity of the miRNAs was significantly higher for the upregulated miRNAs than for the downregulated miRNAs. Two of the 10 most upregulated miRNAs (hsa-mir-20a-5p and hsa-mir-15b-5p) were associated with lung cancer. AmiGo2 server and Panther pathway analyses indicated significant enrichment in transcription regulation of miRNA target genes that promote intrinsic kinase-mediated signaling, TGF-beta, and GnRH signaling pathways, as well as oxidative stress responses. BDG-I crystal structure X-ray diffraction studies revealed gold-gold intramolecular interaction [Au...Au = 3.1198 (3) A] for a single independent molecule, reported to be responsible for its activity against cancer. Our present study sheds light on the development of novel gold complex with favorable anti-cancer therapeutic functionality. PMID- 30416361 TI - Effects of melatonin on oxidative stress parameters and pathohistological changes in rat skeletal muscle tissue following carbon tetrachloride application. AB - Animal models demonstrating skeletal muscle (SM) disorders are rarely investigated, although these disorders accompany liver disorders and can occur during prolonged exercise/training. In cases of SM disorders exogenous antioxidants, such as melatonin, could help by generally improving tissues antioxidant capacities. We aimed to analyze the potential of melatonin in preventing biochemical and structural changes in rat biceps muscle (BM) occurring after an acute exposure to carbon tetrachloride (CCl4). Biceps muscles obtained from male Wistar rats belonging to different experimental groups were biochemically (determination of tissue MDA, total antioxidant capacity, GSH, CAT, SOD and GPx activities) and pathologically analyzed. Also, serum levels of potassium, LHD and CK were analyzed in all experimental animals. The obtained results were statically compared with those from vehicle-treated control group. The applied melatonin prevented potassium and intracellular enzyme leakage (CK and LDH) that was induced by CCl4, as well as an increase in tissue MDA. From a panel of determined oxidative stress parameters melatonin was able to statistically significantly prevent changes in total antioxidative capacity and in CAT, SOD and GPx activities induced by CCl4. Microscopic analysis of BM from the animals exposed to CCl4 revealed significant muscle fiber disorganization and massive inflammatory cell infiltration. All these changes were significantly ameliorated in the group that received melatonin prior to CCl4. Changes in serum and tissue biochemical parameters accompanied the observed pathological changes, which demonstrated a significant influence of melatonin in preventing skeletal muscle damage induced by CCl4. PMID- 30416364 TI - A small, lightweight multipollutant sensor system for ground-mobile and aerial emission sampling from open area sources. AB - Characterizing highly dynamic, transient, and vertically lofted emissions from open area sources poses unique measurement challenges. This study developed and applied a multipollutant sensor and time-integrated sampler system for use on mobile applications such as vehicles, tethered balloons (aerostats) and unmanned aerial vehicles (UAVs) to determine emission factors. The system is particularly applicable to open area sources, such as forest fires, due to its light weight (3.5 kg), compact size (6.75 L), and internal power supply. The sensor system, termed "Kolibri", consists of sensors measuring CO2 and CO, and samplers for particulate matter (PM) and volatile organic compounds (VOCs). The Kolibri is controlled by a microcontroller which can record and transfer data in real time through a radio module. Selection of the sensors was based on laboratory testing for accuracy, response delay and recovery, cross-sensitivity, and precision. The Kolibri was compared against rack-mounted continuous emissions monitoring system (CEMs) and another mobile sampling instrument (the "Flyer") that has been used in over ten open area pollutant sampling events. Our results showed that the time series of CO, CO2, and PM2.5 concentrations measured by the Kolibri agreed well with those from the CEMs and the Flyer, with a laboratory- tested percentage error of 4.9%, 3%, and 5.8%, respectively. The VOC emission factors obtained using the Kolibri were consistent with existing literature values that relate concentration to combustion efficiency. The potential effect of rotor downwash on particle sampling was investigated in an indoor laboratory and the preliminary results suggested that its influence is minimal. Field application of the Kolibri sampling open detonation plumes indicated that the CO and CO2 sensors responded dynamically and their concentrations co-varied with emission transients. The Kolibri system can be applied to various challenging open area scenarios such as fires, lagoons, flares, and landfills. PMID- 30416362 TI - Somatostatin receptors as a new active targeting sites for nanoparticles. AB - The delivery of nanoparticles through receptor-mediated cell interactions has nowadays a major attention in the area of drug targeting applications. This specific kind of targeting is mediated by localized receptors impeded into the target site with subsequent drugs internalization. Hence, this type of interaction would diminish side effects and enhance drug delivery efficacy to the target site. Somatostatin receptors (SSTRs) are one type of G protein-coupled receptors, which could be active targeted for various purposes. There are five SSTRs types (SSTR1-5) which are localized at various organs in the body and spread into different tissues. SSTRs could be considered as a promising target to various nanoparticles which is facilitated when nanoparticles are modified through specific ligand or coating to allow better binding. This review discusses the exploration of SSTRs for active targeting of nanoparticles with certain emphasize on their interaction at the cellular level. PMID- 30416365 TI - Field Determination of Multipollutant, Open Area Combustion Source Emission Factors with a Hexacopter Unmanned Aerial Vehicle. AB - An emission sensor/sampler system was coupled to a National Aeronautics and Space Administration (NASA) hexacopter unmanned aerial vehicle (UAV) to characterize gases and particles in the plumes emitted from open burning of military ordnance. The UAV/sampler was tested at two field sites with test and sampling flights spanning over 16 hours of flight time. The battery-operated UAV was remotely maneuvered into the plumes at distances from the pilot of over 600 m and at altitudes of up to 122 m above ground level. While the flight duration could be affected by sampler payload (3.2 to 4.6 kg) and meteorological conditions, the 57 sampling flights, ranging from 4 to 12 min, were typically terminated when the plume concentrations of CO2 were diluted to near ambient levels. Two sensor/sampler systems, termed "Kolibri," were variously configured to measure particulate matter, metals, chloride, perchlorate, volatile organic compounds, chlorinated dioxins/furans, and nitrogen-based organics for determination of emission factors. Gas sensors were selected based on their applicable concentration range, light weight, freedom from interferents, and response/recovery times. Samplers were designed, constructed, and operated based on U.S. Environmental Protection Agency (EPA) methods and quality control criteria. Results show agreement with published emission factors and good reproducibility (e.g., 26% relative standard deviation for PM2.5). The UAV/Kolibri represents a significant advance in multipollutant emission characterization capabilities for open area sources, safely and effectively making measurements heretofore deemed too hazardous for personnel or beyond the reach of land-based samplers. PMID- 30416366 TI - A stereoselective synthesis of (-)-tetrahydrolipstatin. PMID- 30416363 TI - Anticancer activity and concurrent analysis of ursolic acid, beta-sitosterol and lupeol in three different Hibiscus species (aerial parts) by validated HPTLC method. AB - The genus Hibiscus contains about 275 species of flowering plants widely grown in the tropics and sub-tropics. The available literature revealed that several Hibiscus species exhibited excellent anticancer activity against several cancer cells like lung, breast, and liver. This motivated the authors to explore the anticancer property of other Hibiscus species (Hibiscus calyphyllus, H. deflersii and H. micranthus) along with development of a validated HPTLC method for the concurrent analysis of three anticancer biomarkers (ursolic acid, beta-sitosterol and lupeol) in different Hibiscus species. The anticancer activity of various fractions (petroleum ether, toluene, dichloromethane, ethyl acetate and n butanol) of all the Hibiscus species (aerial parts) were evaluated in vitro against HepG2 and MCF-7 cell lines using MTT assay. The HPTLC analysis was carried out using chloroform and methanol as mobile phase (97:3; v/v) on 20 * 10 cm glass-backed silica gel 60F254 plates and analyzed different phytoconstituents present in all fractions at lambda = 575 nm wavelength. Of the tested fractions of H. calyphyllus, H. deflersii and H. micranthus, HdP (H. deflersii petroleum ether fraction) exhibited the most potent cytotoxic effect on HepG2 and MCF-7 (IC50: 14.4 and 11.1 MUg/mL, respectively) cell lines. Using the developed HPTLC method a compact and intense peak of ursolic acid, beta-sitosterol and lupeol were obtained at Rf = 0.22, 0.39 and 0.51, respectively. The LOD/LOQ (ng) for ursolic acid, beta-sitosterol and lupeol were found as 42.30/128.20, 13.20/40.01 and 31.57/95.68, respectively in the linearity range 100-1200 ng/spot. The obtained result showed maximum presence of ursolic acid, beta-sitosterol and lupeol (5.50, 11.85 and 7.47 MUg/mg, respectively) in HdP which also supported its strong anticancer effect. Our data suggest that H. deflersii petroleum ether fraction (HdP) can be further subjected to the isolation of active cytotoxic phytoconstituents and establishment of their mechanism of action. The maiden developed HPTLC method for concurrent analysis of anticancer biomarkers may be further employed in the in process quality control of herbal formulation containing the said biomarkers. PMID- 30416367 TI - Toward Performance Specifications for Flashing Warning Beacons. AB - Yellow flashing warning beacons help protect front line service workers, including those in transportation, utility and construction sectors. To safeguard these workers, beacons should be readily detected and should provide veridical information about their relative movement. Two psychophysical laboratory experiments were conducted to provide empirical foundations for two aspects of warning beacon performance, detection and judgments of relative movement. In the first experiment reaction times were measured to the onset of flashing warning beacons varying in peak intensity while observers viewed different scene conditions. Observers also judged the visibility of nearby low-contrast targets in the presence of the flashing warning beacons. Asymptotic response times to the onset of beacons occurred when their peak intensity was at least 750 cd during daytime. Visibility of low contrast targets during nighttime, when glare is most critical, did not decrease substantially when the peak intensity was below 2000 cd. In the second experiment response times were measured to warning beacons of different flash-sequence patterns as they approached the observer. Judgments of gap closure were improved, relative to fully-on/fully-off flashing, with flash sequences where the minimum beacon intensity was at least 10% of the peak intensity and with two synchronized flashing beacons rather than one. With regard to performance specifications, the minimum value for the peak intensity of warning beacons should be 750 cd, with a maximum value of 2000 cd for detection. Fully-on/fully-off flash sequences should be changed to fully-on/partial-off to enhance judgments of gap closure on moving vehicles. Moreover, two flashing warning beacons, rather than one, should be mounted on service vehicles to improve gap closure judgments. PMID- 30416368 TI - Development of species diagnostic SNP markers for quality control genotyping in four rice (Oryza L.) species. AB - Species misclassification (misidentification) and handling errors have been frequently reported in various plant species conserved at diverse gene banks, which could restrict use of germplasm for correct purpose. The objectives of the present study were to (i) determine the extent of genotyping error (reproducibility) on DArTseq-based single-nucleotide polymorphisms (SNPs); (ii) determine the proportion of misclassified accessions across 3134 samples representing three African rice species complex (Oryza glaberrima, O. barthii, and O. longistaminata) and an Asian rice (O. sativa), which are conserved at the AfricaRice gene bank; and (iii) develop species- and sub-species (ecotype) specific diagnostic SNP markers for rapid and low-cost quality control (QC) analysis. Genotyping error estimated from 15 accessions, each replicated from 2 to 16 times, varied from 0.2 to 3.1%, with an overall average of 0.8%. Using a total of 3134 accessions genotyped with 31,739 SNPs, the proportion of misclassified samples was 3.1% (97 of the 3134 accessions). Excluding the 97 misclassified accessions, we identified a total of 332 diagnostic SNPs that clearly discriminated the three indigenous African species complex from Asian rice (156 SNPs), O. longistaminata accessions from both O. barthii and O. glaberrima (131 SNPs), and O. sativa spp. indica from O. sativa spp. japonica (45 SNPs). Using chromosomal position, minor allele frequency, and polymorphic information content as selection criteria, we recommended a subset of 24 to 36 of the 332 diagnostic SNPs for routine QC genotyping, which would be highly useful in determining the genetic identity of each species and correct human errors during routine gene bank operations. PMID- 30416369 TI - A systematic approach to normalization in probabilistic models. AB - Every information retrieval (IR) model embeds in its scoring function a form of term frequency (TF) quantification. The contribution of the term frequency is determined by the properties of the function of the chosen TF quantification, and by its TF normalization. The first defines how independent the occurrences of multiple terms are, while the second acts on mitigating the a priori probability of having a high term frequency in a document (estimation usually based on the document length). New test collections, coming from different domains (e.g. medical, legal), give evidence that not only document length, but in addition, verboseness of documents should be explicitly considered. Therefore we propose and investigate a systematic combination of document verboseness and length. To theoretically justify the combination, we show the duality between document verboseness and length. In addition, we investigate the duality between verboseness and other components of IR models. We test these new TF normalizations on four suitable test collections. We do this on a well defined spectrum of TF quantifications. Finally, based on the theoretical and experimental observations, we show how the two components of this new normalization, document verboseness and length, interact with each other. Our experiments demonstrate that the new models never underperform existing models, while sometimes introducing statistically significantly better results, at no additional computational cost. PMID- 30416370 TI - Improved regional groundwater flow modeling using drainage features: a case study of the central northern karst aquifer system of Puerto Rico (USA). AB - In northern Puerto Rico (USA), subsurface conduit networks with unknown characteristics, and surface features such as springs, rivers, lagoons and wetlands, drain the coastal karst aquifers. In this study, drain lines connecting sinkholes and springs are used to improve the developed regional model by simulating the drainage effects of conduit networks. Implemented in an equivalent porous media (EPM) approach, the model with drains is able to roughly reproduce the spring discharge hydrographs in response to rainfall. Hydraulic conductivities are found to be scale dependent and significantly increase with higher test radius, indicating scale dependency of the EPM approach. Similar to other karst regions in the world, hydraulic gradients are steeper where the transmissivity is lower approaching the coastline. This study enhances current understanding of the complex flow patterns in karst aquifers and suggests that using a drainage feature improves modeling results where available data on conduit characteristics are minimal. PMID- 30416371 TI - Watershed Land Use and Seasonal Variation Constrain the Influence of Riparian Canopy Cover on Stream Ecosystem Metabolism. AB - Ecosystem metabolism is an important determinant of trophic structure, nutrient cycling, and other critical ecosystem processes in streams. Whereas watershed- and local-scale controls on stream metabolism have been independently investigated, little is known about how controls exerted at different scales interact to determine stream metabolic rates, particularly in urban streams and across seasons. To address this knowledge gap, we measured ecosystem metabolism in four urban and four reference streams in northern Kentucky, USA, with paired closed and open riparian canopies, during each of the four seasons. Gross primary production (GPP), ecosystem respiration, and net ecosystem production (NEP) were all best predicted by models with season as a main effect, but interactions between season, canopy, and watershed varied for each response. Urban streams exhibited higher GPP during most seasons, likely due to elevated nutrient loads. Open canopy reaches in both urban and forested streams, supported higher rates of GPP than the closed canopy which reaches during the summer and fall, when the overhead vegetation shaded the closed reaches. The effect of canopy cover on GPP was similar among urban and forested streams. The combination of watershed and local-scale controls resulted in urban streams that alternated between net heterotrophy (NEP <0) and net autotrophy (NEP >0) at the reach-scale during seasons with dense canopy cover. This finding has management relevance because net production can lead to accumulation of algal biomass and associated issues like nighttime hypoxia. Our study suggests that although watershed urbanization fundamentally alters ecosystem function, the preservation and restoration of canopied riparian zones can provide an important management tool at the local scale, with the strongest impacts on stream metabolism during summer. PMID- 30416373 TI - A bbb-b- di-bottomonium at the LHC? AB - We study the case of a di-bottomonium bbb-b- particle at the LHC. Its mass and decay width are obtained within a new model of diquark-antidiquark interactions in tetraquarks. The same model solves several open problems on the phenomenology of the experimentally better known X, Z states. We show that the bbb-b- tetraquark is expected approximately 100 MeV below threshold, and compare to a recent analysis by LHCb seeking it in the UpsilonMUMU final state. PMID- 30416372 TI - Thermally Induced Oxidation of [FeII(tacn)2](OTf)2 (tacn = 1,4,7 triazacyclononane). AB - We previously reported the spin-crossover (SC) properties of [FeII(tacn)2](OTf)2 (1) (tacn = 1,4,7-triazacyclononane) [Eur. J. Inorg. Chem. 2013, 2115]. Upon heating under dynamic vacuum, 1 undergoes oxidation to generate a low spin iron(III) complex. The oxidation of the iron center was found to be facilitated by initial oxidation of the ligand via loss of an H atom. The resulting complex was hypothesized to have the formulation [FeIII(tacn)(tacn-H)](OTf)2 (2) where tacn-H is N-deprotonated tacn. The formulation was confirmed by ESI-MS. The powder EPR spectrum of the oxidized product at 77 K reveals the formation of a low-spin iron(III) species with rhombic spectrum (g = 1.98, 2.10, 2.19). We have indirectly detected H2 formation during the heating of 1 by reacting the headspace with HgO. Formation of water (1HNMR in anhydrous d6-DMSO) and elemental mercury were observed. To further support this claim, we independently synthesized [FeIII(tacn)2](OTf)3 (3) and treated it with one equiv base yielding 2. The structures of 3 was characterized by X-ray crystallography. Compound 2 also exhibits a low spin iron(III) rhombic signal (g = 1.97, 2.11, 2.23) in DMF at 77 K. Variable temperature magnetic susceptibility measurements indicate that 3 undergoes gradual spin increase from 2 to 400 K. DFT studies indicate that the deprotonated nitrogen in 2 forms a bond to iron(III) exhibiting double bond character (Fe-N, 1.807 A). PMID- 30416374 TI - Sociocultural variability in the Latino population: Age patterns and differences in morbidity among older US adults. AB - BACKGROUND: The US Latino population is rapidly aging and becoming increasingly diverse with respect to nativity and national origin. Increased longevity along with medical advancements in treatment have resulted in a higher number of older Latinos living with morbidity. Therefore, there is a need to understand variability in Latino health among older adults. OBJECTIVES: This paper documents mid- and late-life health differences in morbidity by race/ethnicity, nativity, and country of origin among adults aged 50 and older. METHODS: We use data from the 2000-2015 National Health Interview Survey to calculate age-and gender specific proportions based on reports of five morbidity measures: hypertension, heart disease, stroke, cancer, and diabetes among non-Latino Whites and seven Latino subgroups. RESULTS: The foreign-born from Mexico, Cuba, and Central/South America, regardless of gender, exhibit an immigrant advantage for heart disease and cancer in comparison to non-Latino Whites across all age categories. Conversely, island-born Puerto Ricans are generally characterized with higher levels of morbidity. Similarly, US-born Puerto Ricans and Mexicans exhibit morbidity patterns indicative of their minority status. Latinos, regardless of gender, were more likely to report diabetes than non-Latino Whites. Hypertension and stroke have significant variability in age patterns among US-and foreign-born Latinos. CONCLUSION: Recognizing the importance of within-Latino heterogeneity in health is imperative if researchers are to implement social services and health policies aimed at ameliorating the risk of disease. CONTRIBUTION: Considering intersectional ethnic, nativity, and country-of-origin characteristics among older Latinos is important to better understand the underlying causes of racial/ethnic disparities in morbidity across the life course. PMID- 30416376 TI - Polyclonal Rabbit Anti-Cancer-Associated Fibroblasts Globulins Induce Cancer Cells Apoptosis and Inhibit Tumor Growth. AB - Cancer-associated fibroblasts (CAFs) constitute a major component of the tumor microenvironment. CAFs regulated the growth and development, invasion and metastasis of primary tumors, as well as response to treatment. Recent studies indicated that monoclonal antibody therapies had limited success, thus more effective polyclonal antibodies (Poly Abs) is urgently needed. Poly Abs is a possible alternative because they target multiple antigens simultaneously. In this report, we prepared Poly Abs by immunizing rabbits with the bFGF-activated fibroblasts. The Poly Abs inhibited the cancer cells proliferation as revealed by MTT analysis. The Poly Abs induced apoptosis as indicated by flow cytometric analysis, and microscopic observation of apoptotic changes in morphology. Compared with the control IgG, Poly Abs significantly inhibited tumor cells migration as indicated by wound healing and transwell analysis in vitro, and lung metastasis analysis in vivo. Serial intravenous injections of Poly Abs inhibited tumor growth in mice bearing murine CT26 colon carcinoma. Ki67 analysis indicated that Poly Abs significantly inhibited tumor cells proliferation, as compared to control Ig G treatments. Our findings suggested that Poly Abs was an effective agent for apoptosis induction, migration and metastasis inhibition. The Poly Abs may be useful as a safe anticancer agent for cancer immunotherapy in the future. PMID- 30416375 TI - Extracellular Vesicles: Potential Participants in Circadian Rhythm Synchronization. AB - The circadian rhythm (CR) is a set of autonomous endogenous oscillators. Exposure to the 24-hour day-night cycle synchronizes our CR system, maintaining homeostasis and human health. Several mechanisms for the CR system have been proposed, including those underlying the function (transcriptional-translational negative-feedback loops, or TTFLs), mechanisms regulating the TTFLs, and the mechanism by which the "server clock" is synchronized to environmental time. Several pathways downstream of the "server clock" perform well-characterized biological functions. However, the synchronization between the "server clock" (the endogenous master clock seated in the suprachiasmatic nucleus within the hypothalamus) and the "client clock" (imbedded in nearly every cell in the form of interlocking TTFLs) is difficult to explain with current theories. Extracellular vesicles (EVs), which are involved in intercellular communication and have recently been found to participate in regulation of the "client clock", might be the answer to this question. In this review, we summarize the current knowledge of CRs, TTFLs, and EVs, examine research findings about the functions of EVs in the CR system, and discuss the issues requiring attention in future research. PMID- 30416377 TI - The Biological Roles of Translation Initiation Factor 3b. AB - Translation has important roles in almost all physiological and pathological processes, and translation initiation factors are particularly relevant to the translation initiation step, which is the most important step in translation regulation. Translation initiation factor 3b (eIF3b), a key subunit of the largest translation initiation factor 3 (eIF3), is widely considered a scaffold protein that acts to ensure the accuracy of translation initiation. A series of recent finds has revealed that eIF3 is closely related to oncogenesis. However, the concrete mechanism by which eIF3b is involve in carcinogenesis remains elusive. Here, we summarize a series of research findings regarding the relationship between eIF3b, translation and cancer. PMID- 30416378 TI - Role of canonical Hedgehog signaling pathway in liver. AB - Hedgehog (Hh) signaling pathway plays an important role in embryonic development. It becomes reactivated in many types of acute and chronic liver injuries. Hh signaling is required for liver regeneration, regulates capillarisation, controls the fates of hepatic stellate cells, promotes liver fibrosis and liver cancers. In this review, we summarize the current knowledge of the role of canonical Hh signaling pathway in adult liver. This help to understand the pathogenesis of liver diseases and find out the new effective targeted therapeutic strategies for liver diseases treatments. PMID- 30416380 TI - Epigenetic alterations of a novel antioxidant gene SLC22A3 predispose susceptible individuals to increased risk of esophageal cancer. AB - Esophageal squamous cell carcinoma (ESCC) occurs with the highest frequency in China, especially in the high-risk Northern Chinese. Recent studies have reported that SLC22A3 is significantly downregulated in non-tumor (NT) esophageal tissues from familial ESCC patients compared with those from sporadic ESCC. However, the mechanism of how SLC22A3 regulates familial ESCC remains unknown. In this study, post hoc genome-wide association studies (GWAS) in 496 cases with a family history of upper gastrointestinal tract cancers and 1056 controls were performed and the results revealed that SLC22A3 is a novel susceptibility gene for familial ESCC. Reduced expression of SLC22A3 in NT esophageal tissues from familial ESCC patients significantly correlates with its promoter hypermethylation. Moreover, case-control study of Chinese descendants from different risk areas of China revealed that the methylation of the SLC22A3 gene in peripheral blood leukocyte (PBL) DNA samples could be a risk factor for developing ESCC in this high-risk population. Functional studies showed that SLC22A3 is a novel antioxidant gene, and deregulation of SLC22A3 facilitates heat stress-induced oxidative DNA damage and formation of gamma-H2AX foci in normal esophageal epithelial cells. Collectively, we show that epigenetic alterations of SLC22A3 predispose susceptible individuals to increased risk of esophageal cancer. PMID- 30416381 TI - BERMP: a cross-species classifier for predicting m6A sites by integrating a deep learning algorithm and a random forest approach. AB - N6-methyladenosine (m6A) is a prevalent RNA methylation modification involved in several biological processes. Hundreds or thousands of m6A sites identified from different species using high-throughput experiments provides a rich resource to construct in-silico approaches for identifying m6A sites. The existing m6A predictors are developed using conventional machine-learning (ML) algorithms and most are species-centric. In this paper, we develop a novel cross-species deep learning classifier based on bidirectional Gated Recurrent Unit (BGRU) for the prediction of m6A sites. In comparison with conventional ML approaches, BGRU achieves outstanding performance for the Mammalia dataset that contains over fifty thousand m6A sites but inferior for the Saccharomyces cerevisiae dataset that covers around a thousand positives. The accuracy of BGRU is sensitive to the data size and the sensitivity is compensated by the integration of a random forest classifier with a novel encoding of enhanced nucleic acid content. The integrated approach dubbed as BGRU-based Ensemble RNA Methylation site Predictor (BERMP) has competitive performance in both cross-validation test and independent test. BERMP also outperforms existing m6A predictors for different species. Therefore, BERMP is a novel multi-species tool for identifying m6A sites with high confidence. This classifier is freely available at http://www.bioinfogo.org/bermp. PMID- 30416379 TI - Cardiac fibrosis: new insights into the pathogenesis. AB - Cardiac fibrosis is defined as the imbalance of extracellular matrix (ECM) production and degradation, thus contributing to cardiac dysfunction in many cardiac pathophysiologic conditions. This review discusses specific markers and origin of cardiac fibroblasts (CFs), and the underlying mechanism involved in the development of cardiac fibrosis. Currently, there are no CFs-specific molecular markers. Most studies use co-labelling with panels of antibodies that can recognize CFs. Origin of fibroblasts is heterogeneous. After fibrotic stimuli, the levels of myocardial pro-fibrotic growth factors and cytokines are increased. These pro-fibrotic growth factors and cytokines bind to its receptors and then trigger the activation of signaling pathway and transcriptional factors via Smad dependent or Smad independent-manners. These fibrosis-related transcriptional factors regulate gene expression that are involved in the fibrosis to amplify the fibrotic response. Understanding the mechanisms responsible for initiation, progression, and amplification of cardiac fibrosis are of great clinical significance to find drugs that can prevent the progression of cardiac fibrosis. PMID- 30416382 TI - The Pathogenesis of Atherosclerosis Based on Human Signaling Networks and Stem Cell Expression Data. AB - Atherosclerosis is a common and complex disease, whose morbidity increased significantly. Here, an integrated approach was proposed to elucidate systematically the pathogenesis of atherosclerosis from a systems biology point of view. Two weighted human signaling networks were constructed based on atherosclerosis related gene expression data of stem cells. Then, 37 candidate Atherosclerosis-risk Modules were detected using four kinds of permutation tests. Five Atherosclerosis-risk Modules (three Absent Modules and two Emerging Modules) enriched in functions significantly associated with disease genes were identified and verified to be associated with the maintenance of normal biological process and the pathogenesis and development of atherosclerosis. Especially for Atherosclerosis-risk Emerging Module P96, it could distinguish between normal and disease samples by Supporting Vector Machine with the average expression value of the module as classification feature. These identified modules and their genes may act as potential atherosclerosis biomarkers. Our study would shed light on the signal transduction of atherosclerosis, and provide new insights to its pathogenesis from the perspective of stem cells. PMID- 30416383 TI - Paired box 5 is a novel marker of breast cancers that is frequently downregulated by methylation. AB - Identifying markers for breast cancer is important for both diagnosis and the design of treatment strategies. Recent studies have implicated Paired box 5 (PAX5) as a suppressor in various cancer types, where it is silenced by hypermethylation. However, determining the role of PAX5 in breast cancer requires further study, and the relationship between PAX5 methylation and breast cancer remains unclear. In this study, we found that PAX5 expression was frequently silenced or reduced by methylation in breast cancer cell lines as well as in breast cancer tissues. Restoring expression of PAX5 in breast cancer cells led to tumor suppression through inhibited proliferation and invasion, which resulted from modulation of the cell cycle and altered vascular endothelial growth factor (VEGF) expression. Most importantly, we found that PAX5 methylation status in breast cancer tissues was significantly correlated with patients' age, estrogen receptor (ER) status, progesterone receptor (PR) status, indicating that PAX5 could serve as a marker for breast cancer diagnosis and treatment strategy design. PMID- 30416384 TI - GLP-1 treatment protects endothelial cells from oxidative stress-induced autophagy and endothelial dysfunction. AB - Endothelial dysfunction and excessively stimulated autophagy, often caused by oxidant injury or inflammation, will lead to atherosclerosis development and progression in diabetes. The aim of this study is to investigate the protective effect of glucagon-like peptide-1 (GLP-1) treatment on preventing oxidative stress-induced endothelial dysfunction and excessively stimulated autophagy. Treatment of endothelial cells with GLP-1 significantly attenuated oxidative stress-induced endothelial dysfunction and autophagy, which was associated with the reduction of intracellular reactive oxygen species (ROS) levels. These protective effects of GLP-1 were likely mediated by reducing phosphorylation of ERK1/2. We further demonstrated that GLP-1 treatment could reverse downregulation of epigenetic factor histone deacetylase 6 (HDAC6), a downstream molecular of the EKR1/2, induced by oxidant injury. In conclusion, our results suggest that GLP-1 produces a protective effect on endothelial cells from oxidant injury by preventing endothelial dysfunction and autophagy, which may be dependent on restoring HDAC6 through a GLP-1R-ERK1/2-dependent manner. PMID- 30416385 TI - Alternative polyadenylation analysis in animals and plants: newly developed strategies for profiling, processing and validation. AB - Alternative polyadenylation is an essential RNA processing event that contributes significantly to regulation of transcriptome diversity and functional dynamics in both animals and plants. Here we review newly developed next generation sequencing methods for genome-wide profiling of alternative polyadenylation (APA) sites, bioinformatics pipelines for data processing and both wet and dry laboratory approaches for APA validation. The library construction methods LITE Seq (Low-Input 3'-Terminal sequencing) and PAC-seq (PolyA Click sequencing) tag polyA+ cDNA, while BAT-seq (BArcoded, three-prime specific sequencing) and PAPERCLIP (Poly(A) binding Protein-mediated mRNA 3'End Retrieval by CrossLinking ImmunoPrecipitation) enrich polyA+ RNA. Interestingly, only WTTS-seq (Whole Transcriptome Termini Site sequencing) targets both polyA+ RNA and polyA+ cDNA. Varieties of bioinformatics pipelines are well established to pursue read quality control, mapping, clustering, characterization and pathway analysis. The RHAPA (RNase H alternative polyadenylation assay) and 3'RACE-seq (3' rapid amplification of cDNA end sequencing) methods directly validate APA sites, while WTSS-seq (whole transcriptome start site sequencing), RNA-seq (RNA sequencing) and public APA databases can serve as indirect validation methods. We hope that these tools, pipelines and resources trigger huge waves of interest in the research community to investigate APA events underlying physiological, pathological and psychological changes and thus understand the information transfer events from genome to phenome relevant to economically important traits in both animals and plants. PMID- 30416386 TI - TGF-beta/SMAD4-Regulated LncRNA-LINP1 Inhibits Epithelial-Mesenchymal Transition in Lung Cancer. AB - Lung cancer is the leading cause of cancer related deaths worldwide. TGF-beta induced epithelial-mesenchymal transition (EMT) is a key cell-intrinsic identity for tumor cell migration, invasion, and stemness acquisition in cancer metastasis. Long noncoding RNAs (lncRNAs) have not been fully investigated for their involvement in regulating TGF-beta-induced EMT and metastasis in lung cancer. Here, we demonstrated that the transcription of lncRNA in nonhomologous end joining (NHEJ) pathway 1 (LINP1) was inhibited by TGF-beta1 in a SMAD4 dependent manner. LINP1 suppressed EMT of lung cancer cells, thereby controlling cancer cell migration, invasion, and stemless. Moreover, LINP1 inhibited TGF-beta induced EMT and cell invasion in lung cancer cells. Our study reveals the role of LINP1 in the regulation of TGF-beta-induced EMT in human lung cancer. PMID- 30416387 TI - TFmapper: A Tool for Searching Putative Factors Regulating Gene Expression Using ChIP-seq Data. AB - Background: Next-generation sequencing coupled to chromatin immunoprecipitation (ChIP-seq), DNase I hypersensitivity (DNase-seq) and the transposase-accessible chromatin assay (ATAC-seq) has generated enormous amounts of data, markedly improved our understanding of the transcriptional and epigenetic control of gene expression. To take advantage of the availability of such datasets and provide clues on what factors, including transcription factors, epigenetic regulators and histone modifications, potentially regulates the expression of a gene of interest, a tool for simultaneous queries of multiple datasets using symbols or genomic coordinates as search terms is needed. Results: In this study, we annotated the peaks of thousands of ChIP-seq datasets generated by ENCODE project, or ChIP-seq/DNase-seq/ATAC-seq datasets deposited in Gene Expression Omnibus (GEO) and curated by Cistrome project; We built a MySQL database called TFmapper containing the annotations and associated metadata, allowing users without bioinformatics expertise to search across thousands of datasets to identify factors targeting a genomic region/gene of interest in a specified sample through a web interface. Users can also visualize multiple peaks in genome browsers and download the corresponding sequences. Conclusion: TFmapper will help users explore the vast amount of publicly available ChIP-seq/DNase-seq/ATAC-seq data and perform integrative analyses to understand the regulation of a gene of interest. The web server is freely accessible at http://www.tfmapper.org/. PMID- 30416388 TI - The small molecule NSM00191 specifically represses the TNF-alpha/NF-kB axis in foot and ankle rheumatoid arthritis. AB - The activation of TNF-alpha/NF-kB signaling is involved in the regulation of a wide range of biological processes, such as cell proliferation, differentiation and apoptosis, eventually causing a number of diseases, such as cancer and inflammation. Here, we found that TNF-alpha/NF-kB signaling was activated in a large number of blood samples taken from foot and ankle rheumatoid arthritis (RA) patients. By applying a microarray assay to the human synovial sarcoma cell line SW982 and the human fibroblast-like synoviocyte cell line HFLS-RA, as well as in their corresponding p65 knockdown and -overexpressing cells, we identified and verified the activation of many p65 targets, including cytokines (e.g., TNF-alpha and IL-6), chemokines (e.g., MCP-1 and PANTES), protein receptors (e.g., CD-40 and MHC-1), and inducible enzymes (e.g., COX2). In addition, we subjected microRNAs from foot and ankle RA patients to a microRNA-specific microarray and found that miR-7-5p targeted the 3'-UTR of p65, negatively regulating its expression. By applying an in vitro screen to identify small molecules that specifically inhibited the interaction between TRADD and TNFR2, we found that NSM00191 strongly inhibited the activation of TNF-alpha/NF-kB signaling in vitro and in vivo, causing the downregulation of NF-kB targets and the decrease of arthritis scores. Collectively, our findings shed new light on the regulation of the TNF-alpha/NF-kB axis and might provide a new avenue for RA treatment. PMID- 30416390 TI - Inhibition of Estrogen Signaling Reduces the Incidence of BRCA1-associated Mammary Tumor Formation. AB - BRCA1-deficient breast cancer is a very well-known hereditary cancer. However, except for resection of normal mammary glands and ovaries, there is no acceptable measure for proactively preventing tumor development. Importantly, inherited BRCA1 mutations are closely associated with tumors in hormone-responsive tissues. Here, we examined the effects of estrogen on the accumulation of genetic instabilities upon loss of BRCA1, and assessed the contribution of estrogen signaling to the incidence and progression of Brca1-mutated mammary tumors. Our in vitro studies showed that treatment of BRCA1-depleted breast cancer cells with estrogen induced proliferation. Additionally, estrogen reduced the ability of these BRCA1-knockdown cells to sense radiation-induced DNA damage and also facilitated G1/S progression. Moreover, long-term treatment of Brca1-mutant (Brca1co/coMMTV-Cre) mice with the selective estrogen receptor (ER)-alpha degrader, fulvestrant, decreased the tumor formation rate from 64% to 36%, and also significantly reduced mammary gland density in non-tumor-bearing mice. However, in vivo experiments showed that fulvestrant treatment did not alter the progression of ER-positive Brca1-mutant tumors, which were frequently identified in the aged population and showed less aggressive tendencies. These findings enhance our understanding of how ER-alpha signaling contributes to BRCA1 deficient mammary tumors and provide evidence suggesting that targeted inhibition of ER-alpha signaling may be useful for the prevention of BRCA1-mutated breast cancer. PMID- 30416391 TI - Manic temporality. AB - Time-consciousness has long been a focus of research in phenomenology and phenomenological psychology. We advance and extend this tradition of research by focusing on the character of temporal experience under conditions of mania. Symptom scales and diagnostic criteria for mania are peppered with temporally inflected language: increased rate of speech, racing thoughts, flight-of-ideas, hyperactivity. But what is the underlying structure of temporal experience in manic episodes? We tackle this question using a strategically hybrid approach. We recover and reconstruct three hypotheses regarding manic temporality that were advanced and modeled by two pioneers of clinical phenomenology: Eugene Minkowski (1885-1972) and Ludwig Binswanger (1881-1966). We then test, critique, and refine these hypotheses using heterophenomenological methods in an interview-based study of persons with a history of bipolar and a current diagnosis of acute mania. Our conclusions support a central hypothesis due to Minkowski and Binswanger, namely, that disturbance in the formal structure of temporal experience is a core feature of mania. We argue that a suitably refined variant of Binswanger's model of disturbance in manic protention helps to explain a striking pattern of impaired insight and impaired reasoning in manic episodes. PMID- 30416389 TI - Targeting phosphodiesterase 4 as a potential therapeutic strategy for enhancing neuroplasticity following ischemic stroke. AB - Sensorimotor recovery following ischemic stroke is highly related with structural modification and functional reorganization of residual brain tissues. Manipulations, such as treatment with small molecules, have been shown to enhance the synaptic plasticity and contribute to the recovery. Activation of the cAMP/CREB pathway is one of the pivotal approaches stimulating neuroplasticity. Phosphodiesterase 4 (PDE4) is a major enzyme controlling the hydrolysis of cAMP in the brain. Accumulating evidences have shown that inhibition of PDE4 is beneficial for the functional recovery after cerebral ischemia; i. subtype D of PDE4 (PDE4D) is viewed as a risk factor for ischemic stroke; ii. inhibition of PDE4 enhances neurological behaviors, such as learning and memory, after stroke in rodents; iii.PDE4 inhibition increases dendritic density, synaptic plasticity and neurogenesis; iv. activation of cAMP/CREB signaling by PDE4 inhibition causes an endogenous increase of BDNF, which is a potent modulator of neuroplasticity; v. PDE4 inhibition is believed to restrict neuroinflammation during ischemic stroke. Cumulatively, these findings provide a link between PDE4 inhibition and neuroplasticity after cerebral ischemia. Here, we summarized the possible roles of PDE4 inhibition in the recovery of cerebral stroke with an emphasis on neuroplasticity. We also made some recommendations for future research. PMID- 30416393 TI - A COMPARISON OF FOOD PORTION SIZE ESTIMATION USING GEOMETRIC MODELS AND DEPTH IMAGES. AB - Six of the ten leading causes of death in the United States, including cancer, diabetes, and heart disease, can be directly linked to diet. Dietary intake, the process of determining what someone eats during the course of a day, provides valuable insights for mounting intervention programs for prevention of many of the above chronic diseases. Measuring accurate dietary intake is considered to be an open research problem in the nutrition and health fields. In this paper we compare two techniques to estimating food portion size from images of food. The techniques are based on 3D geometric models and depth images. An expectation maximization based technique is developed to detect the reference plane in depth images, which is essential for portion size estimation using depth images. Our experimental results indicate that volume estimation based on geometric model is more accurate for objects with well-defined 3D shapes compared to estimation using depth images. PMID- 30416392 TI - Non-visual effects of light: how to use light to promote circadian entrainment and elicit alertness. AB - In addition to stimulating the visual system, light incident on the retina stimulates other biological functions, also referred to as non-visual responses. Among the most notable biological functions are human circadian rhythms, which are bodily rhythms that, in constant darkness, oscillate with a period close to, but typically slightly longer than 24 hours. Twenty-four-hour light-dark patterns incident on the retina are the major synchronizer of circadian rhythms to the local time on Earth. Entrainment of circadian rhythms has been implicated in health and well-being. Light can also elicit an acute alerting effect on people, similar to a "cup of coffee." This review summarizes the literature on how light affects entrainment and alertness and how it can be used to achieve these aims. PMID- 30416394 TI - EFFICIENT SUPERPIXEL BASED SEGMENTATION FOR FOOD IMAGE ANALYSIS. AB - In this paper, we propose a segmentation method based on normalized cut and superpixels. The method relies on color and texture cues for fast computation and efficient use of memory. The method is used for food image segmentation as part of a mobile food record system we have developed for dietary assessment and management. The accurate estimate of nutrients relies on correctly labelled food items and sufficiently well-segmented regions. Our method achieves competitive results using the Berkeley Segmentation Dataset and outperforms some of the most popular techniques in a food image dataset. PMID- 30416395 TI - WEAKLY SUPERVISED FOOD IMAGE SEGMENTATION USING CLASS ACTIVATION MAPS. AB - Food image segmentation plays a crucial role in image-based dietary assessment and management. Successful methods for object segmentation generally rely on a large amount of labeled data on the pixel level. However, such training data are not yet available for food images and expensive to obtain. In this paper, we describe a weakly supervised convolutional neural network (CNN) which only requires image level annotation. We propose a graph based segmentation method which uses the class activation maps trained on food datasets as a top-down saliency model. We evaluate the proposed method for both classification and segmentation tasks. We achieve competitive classification accuracy compared to the previously reported results. PMID- 30416396 TI - Sparse concordance-assisted learning for optimal treatment decision. AB - To find optimal decision rule, Fan et al. (2016) proposed an innovative concordance-assisted learning algorithm which is based on maximum rank correlation estimator. It makes better use of the available information through pairwise comparison. However the objective function is discontinuous and computationally hard to optimize. In this paper, we consider a convex surrogate loss function to solve this problem. In addition, our algorithm ensures sparsity of decision rule and renders easy interpretation. We derive the L 2 error bound of the estimated coefficients under ultra-high dimension. Simulation results of various settings and application to STAR*D both illustrate that the proposed method can still estimate optimal treatment regime successfully when the number of covariates is large. PMID- 30416397 TI - The Challenge Posed by Geomagnetic Activity to Electric Power Reliability: Evidence From England and Wales. AB - This paper addresses whether geomagnetic activity challenged the reliability of the electric power system during part of the declining phase of solar cycle 23. Operations by National Grid in England and Wales are examined over the period of 11 March 2003 through 31 March 2005. This paper examines the relationship between measures of geomagnetic activity and a metric of challenged electric power reliability known as the net imbalance volume (NIV). Measured in megawatt hours, NIV represents the sum of all energy deployments initiated by the system operator to balance the electric power system. The relationship between geomagnetic activity and NIV is assessed using a multivariate econometric model. The model was estimated using half-hour settlement data over the period of 11 March 2003 through 31 December 2004. The results indicate that geomagnetic activity had a demonstrable effect on NIV over the sample period. Based on the parameter estimates, out-of-sample predictions of NIV were generated for each half hour over the period of 1 January to 31 March 2005. Consistent with the existence of a causal relationship between geomagnetic activity and the electricity market imbalance, the root-mean-square error of the out-of-sample predictions of NIV is smaller; that is, the predictions are more accurate, when the statistically significant estimated effects of geomagnetic activity are included as drivers in the predictions. PMID- 30416398 TI - When veps cry: Two-year-olds efficiently learn novel words from linguistic contexts alone. AB - We assessed 24-month-old infants' lexical processing efficiency for both novel and familiar words. Prior work documented that 19-month-olds successfully identify referents of familiar words (e.g., The dog is so little) as well as novel words whose meanings were informed only by the surrounding sentence (e.g., The vep is crying), but that the speed with which they identify the referents of novel words lagged far behind that for familiar words. Here we take a developmental approach, extending this work to 24-month-olds. By comparing the performance of 19- and 24-month-olds directly, we document that during this period of rapid vocabulary growth, infants make significant processing gains for both familiar and novel words. We also offer the first evidence to date that, at both 19- and 24-months, the number of verbs infants know predicts their ability to use known verbs to learn novel nouns. These results reveal that 24-month-olds can efficiently learn novel words just by listening to the conversations around them. PMID- 30416399 TI - Through the Looking Glass: Parental Group Experiences Observing Sensory Motor Therapy. AB - Objective: The benefits of group therapy in pediatric rehabilitation have been identified. However, a unique small group occupational therapy model with a large emphasis on parental group education and observation of their children has not been extensively studied. In this model, parents observe their child's sensory motor group therapy through a one-way mirror and work with the occupational therapist together after each session, to receive education and develop strategies. In other models, parents sit in the waiting room or observe without working with an occupational therapist as a group afterwards. Method: A descriptive qualitative study was conducted to explore the parental experiences of observing and receiving information as a group regarding their child's participation in sensory motor group therapy. Individual in-depth interviews were conducted with ten parents who observed their children together through a one-way mirror during their children's therapy. Conventional thematic content analysis was used to analyze the interview transcripts to determine themes. Ten parents were interviewed. Results: There were three major themes that surfaced: parent support, the value of observation, and knowledge. Parents enjoyed and perceived benefits for themselves and their children from the opportunity to observe sessions and receive information as a group during therapy. Conclusion: The experiences of parents in this group model suggest that knowledge translation and provision of support to parents and their children regarding their sensory motor needs are beneficial. Administrators may appreciate additional gains of reducing costs and improving access to service. PMID- 30416400 TI - "They Can't Search Her": How Gender Imbalances in the Police Force Contribute to Perceptions of Procedural Unfairness. AB - Research suggests that gender imbalances in police forces can significantly affect individuals' experiences when interacting with police. Of importance, yet rarely examined, is the extent to which predominantly male police forces, in conjunction with adherence to gendered departmental policies, can simultaneously send signals of procedural justice and procedural injustice. Drawing on data from 253 in-depth interviews of San Francisco-based male and female drug-dealing gang members, we investigated how interactions with a male-dominated police force, who were required to search only suspects of the same gender, affected perceptions of fair policing. Our findings revealed that the study participants raised concerns that the police unfairly enforced the law to the detriment of the men in the study. The gang members were aware that male officers could only search same-sex suspects, and this exacerbated the gendered experiences of the gang members. Specifically, it contributed to the perception that male officers targeted male gang members to the omission of women and, if women were stopped, they were frequently released. These findings suggest that the gender composition of the police force is important in shaping attitudes toward equitable enforcement of the law and procedural fairness. Of theoretical importance, these findings highlight a contradiction that compliance with rules can contribute, counter intuitively, to perceptions of procedural injustice. Procedurally unfair police behavior may be a systemic problem where the gender composition of the police force itself creates an inherently unfair system. PMID- 30416401 TI - Alcohol Text Messages: A Developmental Study. AB - Risky paternal alcohol use is associated with maternal alcohol use during pregnancy, poor fetal and infant outcomes, domestic violence and depression. This study developed 30 SMS text messages about alcohol for fathers who drink at risky levels. The text messages were developed using two motivational styles: messages presented in a second person voice and the same messages presented in a child's voice. Fifty-one fathers were recruited through social media to complete an online survey rating the SMS text messages for message importance and likelihood of seeking further information and measuring risky alcohol use and psychosocial distress. Seventeen participants then participated in a semi-structured qualitative interview. Fathers rated the text messages presented in the child's voice as more important than messages presented in the second person. Qualitative data supported survey results that motivational SMS text messages could provide an acceptable way to raise awareness of risky alcohol consumption for future fathers. PMID- 30416402 TI - A Comparison of Online Versus Offline Gambling Harm in Portuguese Pathological Gamblers: An Empirical Study. AB - Over the past decade, gambling has become a very popular activity across Europe including the growth of Internet gambling. Portugal is one of the few European countries where little research has been carried out. Given the lack of studies, a Portuguese sample (N = 1,599) was surveyed concerning their online and offline gambling habits. More specifically, the aim of this study was to identify and compare from the total sample, online pathological gamblers (PGON) (n = 171) and offline pathological gamblers' (PGOF) (n = 171) characteristics, and eventual risk factors for the development of problem gambling. Results demonstrated that PGON had different profiles compared to PGOF, although there were also similarities. Situational characteristics were much more significant for PGON than PGOF (e.g., availability, accessibility, affordability), but PGOF had higher scores than PGON on factors concerning individual characteristics (e.g., intensity of feelings while gambling, depression, suicidal ideation, etc.). Findings also showed differences concerning attitudes toward responsible gambling measures. The fact that situational characteristics are more attractive to online gamblers confirms differences between PGON and PGOF and suggests that this preferred attractiveness may enhance problem gambling potential. Further research is needed to better understand the interaction between Internet situational characteristics and the individual characteristics of gamblers, as well as the profile of the growing population of gamblers that uses both online and offline modes to gamble. PMID- 30416403 TI - Quantifying contributions to light attenuation in estuaries and coastal embayments: Application to Narragansett Bay, Rhode Island. AB - In Narragansett Bay, light attenuation by total suspended sediments (TSS), colored dissolved organic matter (CDOM), and phytoplankton chlorophyll-a (chl-a) pigment is 129%, 97%, and 70%, respectively, of that by pure seawater. Spatial distribution of light attenuation indicates higher values in the upper Bay, where rivers with sediment and nutrient-rich waters enter and elevate TSS, CDOM, and chl-a concentrations. The temporal trends of light attenuation during the summer months (July-August) differed at various locations in the Bay, having the highest values in July. For the same period, spectral methods overestimated attenuation throughout the Bay. These findings quantify the behavior of light attenuation in space and time, providing information that can guide decisions related to improving water clarity and help understanding the effects of various environmental and management scenarios on it. PMID- 30416404 TI - A Tetra-Orthogonal Strategy for the Efficient Synthesis of Scaffolds Based on Cyclic Peptides. AB - We have developed a straightforward and robust strategy for synthesizing a family of cyclic peptide scaffolds for the presentation of defined moieties in a wide range of orientations. Specifically we are exploring quinoxaline as the moiety, as a potential nucleic acid binding motif. The method requires the use of four degrees of orthogonality, which in turn allow the extension of the main chain, incorporation of the target side chains, on-resin cyclization, and the revelation of an amino group upon cleavage to increase solubility. We show that related approaches fail for a range of reasons, including the failure of cyclization. Following the optimization of the approach with a single cyclic peptide, we synthesized a family of all possible bis and tris quinoxaline adducts showing by ESI-MS that the desired full length cyclic product is produced in a majority of cases. PMID- 30416405 TI - Apoptotic Effect of Melittin Purified from Iranian Honey Bee Venom on Human Cervical Cancer HeLa Cell Line. AB - Melittin, an amphipathic 26-residue peptide, is the main component of honey bee venom. Studies have been demonstrated that melittin has an inhibitory effect on proliferation of cancer cells. However, the precise mechanism of action is not completely understood. In the present study we have shown that purified melittin from Iranian honey bee venom shows anti-cancer effects on human cervical cancer cell line through induction of apoptosis. The venom was collected from Iranian honey bee (Apis mellifera meda) and melittin isolated using reversed phase HPLC. Biological activity of melittin was analyzed by hemolytic test on human red blood cells. In order to investigate whether melittin inhibits proliferation of cervical cancer cells, the viability of the melittin treated HeLa cell line was measured via MTT assay. Finally, cell death analysis was performed using Propidum iodide and Annexin V-FITC dual staining. The results showed that the half hemolytic concentration (HD50) induced by mellitin was 0.5 ug/ml in free FBS solution. IC50 obtained after 12 h at 1.8 ug/ml by MTT assay. According to flow cytometric analysis, melittin induced apoptosis at concentrations more than 1 ug/ml. These results suggest that melittin induces apoptotic cell death in cervical cancerous cells as observed by flow cytometric assay. It is concluded that melittin could be regarded as a potential candidate in future studies to discovery of new anticancer agents. PMID- 30416406 TI - The Effect of Anti-aging Peptides on Mechanical and Biological Properties of HaCaT Keratinocytes. AB - Atomic force microscopy (AFM) and fluorescence microscopy was applied to determine the influence of the anti-aging peptides on the morphology and the mechanical properties of keratinocytes. Immortalized human keratinocytes (HaCaT) were treated with two anti-aging bioactive peptides: Acetyl Tetrapeptide-2 and Acetyl Hexapeptide-50 (Lipotec). The AFM measurement of the keratinocyte stiffness were carried after 48 h exposure at an indentation depth of 200 nm. AFM analysis showed increase of the cell stiffness for cells treated with Acetyl Tetrapeptide-2 (P1) in concentration range. Acetyl Hexapeptide-50 (P2) at concentration of 0.05 ug/ml also increased the stiffness of HaCaT cells but at higher concentrations 0.5 and 5 ug/ml cell stiffness was lower as compared to untreated control. Fluorescence microscopy revealed remodeling of actin filaments dependent on the concentration of P2 peptide. The mechanical response of HaCaT cells treated with P2 peptide corresponds to change of transcription level of ACTN1 and SOD2 which activity was expected to be modulated by P2 treatment. PMID- 30416407 TI - Integrity of Authorship and Peer Review Practices: Challenges and Opportunities for Improvement. AB - Integrity of authorship and peer review practices are important considerations for ethical publishing. Criteria for authorship, as delineated in the guidelines by the International Committee of Medical Journal Editors (ICMJE), have undergone evolution over the decades, and now require fulfillment of four criteria, including the need to be able to take responsibility for all aspects of the manuscript in question. Although such updated authorship criteria were published nearly five years ago, still, many major medical and specialist journals have yet to revise their author instructions to conform to this. Inappropriate authorship practices may include gift, guest or ghost authorship. Existing literature suggests that such practices are still widely prevalent, especially in non English speaking countries. Another emerging problem is that of peer review fraud, mostly by authors, but also rarely by handling editors. There is literature to suggest that a proportion of such fake peer review may be driven by the support of some unscrupulous external editing agencies. Such inappropriate practices with authorship malpractices or disagreement, or peer review fraud, have resulted in more than 600 retractions each, as identified on the retractions database of Retractionwatch.com. There is a need to generate greater awareness, especially in authors from non-English speaking regions of the world, about inappropriate authorship and unethical practices in peer review. Also, support of any external editing agency should be clearly disclosed by authors at the time of submission of a manuscript. PMID- 30416408 TI - Burden of Disease Attributable to Inadequate Drinking Water, Sanitation, and Hygiene in Korea. AB - Background: Diarrheal and intestinal infectious disease caused by inadequate drinking water, sanitation, and hygiene (WASH) is not only a great concern in developing countries but also a problem in low-income populations and rural areas in developed countries. In this study, we assessed the exposure to inadequate WASH in Korea and estimated the burden of disease attributable to inadequate WASH. Methods: We used observational data on water supply, drinking water, sewage treatment rate, and hand washing to assess inadequate WASH conditions in Korea, and estimated the level of exposure in the entire population. The disease burden was estimated by applying the cause of death data from death registry and the morbidity data from the national health insurance to the population attributable fraction (PAF) for the disease caused by inappropriate WASH. Results: In 2013, 1.4% of the population were exposed to inadequate drinking water, and 1.0% were living in areas where sewerage was not connected. The frequency of handwashing with soap after contact with excreta was 23.5%. The PAF due to inadequate WASH as a cluster of risk factors was 0.353 (95% confidence interval [CI], 0.275-0.417), among which over 90% were attributable to hand hygiene factors that were significantly worse than those in American and European high-income countries. Conclusion: The level of hand hygiene in Korea has yet to be improved to the extent that it shows a significant difference compared to other high-income countries. Therefore, improving the current situation in Korea requires a continuous hand washing campaign and a program aimed at all people. In addition, continuous policy intervention for improvement of sewage treatment facilities in rural areas is required, and water quality control monitoring should be continuously carried out. PMID- 30416409 TI - The Prevalence of Cerebral Microbleeds in Non-Demented Parkinson's Disease Patients. AB - Background: Cerebral microbleeds (CMBs) are associated with cerebrovascular risk factors and cognitive dysfunction among patients with Parkinson's disease (PD). However, whether CMBs themselves are associated with PD is to be elucidated. Methods: We analyzed the presence of CMBs using 3-Tesla brain magnetic resonance imaging in non-demented patients with PD and in age-, sex-, and hypertension matched control subjects. PD patients were classified according to their motor subtypes: tremor-dominant, intermediate, and postural instability-gait disturbance (PIGD). Other cerebrovascular risk factors and small vessel disease (SVD) burdens were also evaluated. Results: Two-hundred and five patients with PD and 205 control subjects were included. The prevalence of CMBs was higher in PD patients than in controls (16.1% vs. 8.8%; odds ratio [OR], 2.126; P = 0.019); CMBs in the lobar area showed a significant difference between PD patients and controls (11.7% vs. 5.9%; OR, 2.234; P = 0.032). According to the motor subtype, CMBs in those with PIGD type showed significant difference from controls with respect to the overall brain area (21.1% vs. 8.9%; OR, 2.759; P = 0.010) and lobar area (14.6% vs. 4.9%; OR, 3.336; P = 0.016). Among PD patients, those with CMBs had higher age and more evidence of SVDs than those without CMBs. Conclusion: We found that CMBs are more frequent in PD patients than in controls, especially in those with the PIGD subtype and CMBs on the lobar area. Further study investigating the pathogenetic significance of CMBs is required. PMID- 30416410 TI - Antidepressant Prescription Patterns in Bipolar Disorder: a Nationwide, Register based Study in Korea. AB - Background: The role of antidepressants (ADs) in bipolar disorder is long standing controversial issue in psychiatry. Many clinicians have used ADs as a treatment for bipolar depression, and the selection of therapeutic agents is very diverse and inconsistent. This study aimed to examine recent AD prescription patterns for patients with bipolar disorder in Korea, using the nationwide, population-based data. Methods: This study utilized the Korean nationwide, whole population-based registry data of the year 2010, 2011, and 2013. All prescription data of the ADs, antipsychotics, and mood stabilizers of the sampled patients diagnosed with bipolar disorder (n = 2,022 [in 2010]; 2,038 [in 2011]; 2,626 [in 2013]) were analyzed for each year. Results: Annual prescription rate of ADs was 27.3%-33.6% in bipolar disorder, which was gradually increasing over the 3-year period. The combination pattern of ADs and antipsychotic drugs tended to increase over 3 years. The proportion of females and the prevalence of comorbid anxiety disorder were significantly higher in AD user group in all three years. Among individual ADs, escitalopram was prescribed most frequently, and fluoxetine and bupropion were prescribed to the next many patients. The mean duration of bipolar depressive episodes was 135.90-152.53 days, of which ADs were prescribed for 115.60-121.98 days. Conclusion: Our results show prescription rate of ADs in bipolar disorder was maintained at substantial level and increased in recent 3 years. More empirical data and evidence are needed to establish practical treatment consensuses. PMID- 30416411 TI - Cerebral Microbleeds and the Heterogeneity of Parkinson's Disease. PMID- 30416412 TI - Cost-Effectiveness of Voluntary HIV Testing Strategies in a Very Low-Prevalence Country, the Republic of Korea. AB - Background: The Republic of Korea has a very low prevalence of human immunodeficiency virus (HIV) infection, but the number of new HIV diagnoses has steadily risen, strongly indicating a large number of undetected HIV infections. Thus, it is important for Korean public health authorities to adopt and encourage cost-effective HIV detection tools, such as rapid HIV screening tests. In this study, we aimed to evaluate the cost-effectiveness of enzyme-linked immunosorbent assays (ELISA) and rapid tests in a public health center (PHC) setting. Methods: We developed a decision analytic model to assess the per-examinee cost and the cost-effectiveness of identifying HIV patients in a PHC setting using two HIV testing strategies: conventional HIV screening by ELISA versus rapid HIV testing. Analysis was performed in two scenarios: HIV testing in an average-risk population and in a high-risk population. Results: Compared to the ELISA, the rapid test was cost-saving and cost-effective. The per-examinee cost was USD 1.61 with rapid testing versus USD 3.38 with ELISA in an average-risk population, and USD 4.77 with rapid testing versus USD 7.62 with ELISA in a high-risk population. The cost of identifying a previously undiagnosed HIV case was USD 26,974 with rapid testing versus USD 42,237 with ELISA in an average-risk population, and USD 153 with rapid testing versus USD 183 with ELISA in a high-risk population. Conclusion: Rapid testing would be more cost-effective than using conventional ELISA testing for identifying previously undiagnosed HIV-infected cases in Korea, a country with extremely low HIV prevalence. PMID- 30416413 TI - Effects of Collagen Crosslink Augmentation on Mechanism of Compressive Load Sharing in Intervertebral Discs. AB - Exogenous crosslinking has been shown to have potential for treating disc degeneration and back pain due to its ability to increase the strength and toughness of the annulus fibrosus, increase intervertebral joint stability, decrease intradiscal pressure, and increase fluid flow through the disc. Some results imply that crosslink augmentation may also lead to changes in the compressive load sharing properties of the disc. The objective of the present study was to evaluate directional stress distribution changes of the disc following genipin crosslinking treatment. Bovine lumbar motion segments were randomly divided into control and crosslinked groups. Annular strains were determined from simultaneous deformation measurements at various time points during compressive creep testing. Four stress components of the annulus were then calculated according to the previously measured modulus data. Immediately after the application of a 750-N compressive load, mean axial and radial compressive stresses in the crosslinked group were twofold higher than control means. Conversely, mean lamellae-aligned and circumferential tensile stresses of the crosslinked discs were 8- and threefold lower, respectively, compared to control means. After 1-h creep loading, the two compressive mean stresses in both the control and genipin-crosslinked specimens increased approximately threefold from their initial 750-N-loaded values. The two tensile mean stresses in the crosslinked group remained lower than the respective levels of the control means after creep loading. A greater proportion of annular compressive load support under compressive creep loading, with a commensurate decrease in both tensile stresses and strains, was seen in the discs following exogenous crosslink augmentation. PMID- 30416414 TI - An Acoustic Tracking Approach for Medical Ultrasound Image Simulator. AB - Ultrasound examinations are a standard procedure in the clinical diagnosis of many diseases. However, the efficacy of an ultrasound examination is highly dependent on the skill and experience of the operator, which has prompted proposals for ultrasound simulation systems to facilitate training and education in hospitals and medical schools. The key technology of the medical ultrasound simulation system is the probe tracking method that is used to determine the position and inclination angle of the sham probe, since this information is used to display the ultrasound images in real time. This study investigated a novel acoustic tracking approach for an ultrasound simulation system that exhibits high sensitivity and is cost-effective. Five air-coupled ultrasound elements are arranged as a 1D array in front of a sham probe for transmitting the acoustic signals, and a 5 * 5 2D array of receiving elements is used to receive the acoustic signals from the moving transmitting elements. Since the patterns of the received signals can differ for different positions and angles of the moving probe, the probe can be tracked precisely by the acoustic tracking approach. After the probe position has been determined by the system, the corresponding ultrasound image is immediately displayed on the screen. The system performance was verified by scanning three different subjects as image databases: a simple commercial phantom, a complicated self-made phantom, and a porcine heart. The experimental results indicated that the tracking and angle accuracies of the presented acoustic tracking approach were 0.7 mm and 0.5 degrees , respectively. The performance of the acoustic tracking approach is compared with those of other tracking technologies. PMID- 30416416 TI - Words from the Editor. PMID- 30416417 TI - Development of Reference Methods and Reference Materials by the IFCC: An Overview. PMID- 30416415 TI - Hybrid Paper-Plastic Microchip for Flexible and High-Performance Point-of-Care Diagnostics. AB - A low-cost and easy-to-fabricate microchip remains a key challenge for the development of true point-of-care (POC) diagnostics. Cellulose paper and plastic are thin, light, flexible, and abundant raw materials, which make them excellent substrates for mass production of POC devices. Herein, a hybrid paper-plastic microchip (PPMC) is developed, which can be used for both single and multiplexed detection of different targets, providing flexibility in the design and fabrication of the microchip. The developed PPMC with printed electronics is evaluated for sensitive and reliable detection of a broad range of targets, such as liver and colon cancer protein biomarkers, intact Zika virus, and human papillomavirus nucleic acid amplicons. The presented approach allows a highly specific detection of the tested targets with detection limits as low as 102 ng mL-1 for protein biomarkers, 103 particle per milliliter for virus particles, and 102 copies per microliter for a target nucleic acid. This approach can potentially be considered for the development of inexpensive and stable POC microchip diagnostics and is suitable for the detection of a wide range of microbial infections and cancer biomarkers. PMID- 30416419 TI - The IVD Directive and Availability of Reference Systems for IVD Medical Devices: A View from Industry. PMID- 30416418 TI - Reference Materials for the Standardization of the Apolipoproteins A-I and B, and Lipoprotein(a). AB - Measurement of the apolipoproteins A-I and B, and lipoprotein(a) enable identification of individuals at increased risk of cardiovascular disease. However, the lack of standardized methods to measure these risk markers has resulted for many years in the non-comparability of values and often a conflicting interpretation of clinical studies. Due to the collaborative efforts of the International Federation of Clinical Chemistry and Laboratory Medicine, research organizations, clinical chemistry laboratories and diagnostic companies, secondary reference materials for the apolipoproteins A-I and B, and lipoprotein(a) have been prepared and tested for their ability to harmonize test values. SP1-01 and SP3-07 WHO-IFCC reagents are now available to manufacturers for use in the value transfer of apolipoprotein A-I and B values to master calibrators, and PRM is proposed to be the secondary reference material for Lp(a). By the worldwide use of such reference materials a better traceability and standardization of measurement is being achieved in the clinical laboratories. PMID- 30416420 TI - Reference Systems in Clinical Enzymology. PMID- 30416421 TI - IFCC Professional Scientific Exchange Programme Report: Effects of Cytokines on the Expression of Adhesion Molecules on Human Umbilical Vein Endothelial Cells (HUVECs). PMID- 30416423 TI - How Is the Neural Response to the Design of Experience Goods Related to Personalized Preference? An Implicit View. AB - Understanding the process by which consumers evaluate the designs of experience goods is critical for firms designing and delivering experience products. As the implicit process involved in this evaluation, and given the possible social desirability bias inherent to traditional methods of product design evaluation in certain conditions, neuroscientific methods are preferred to gain insight into the neural basis of consumers' evaluation of experience good designs. We here used event-related potentials (ERPs) and a revised go/no-go paradigm to investigate consumers' neural responses to experience good designs. Personalized product designs and neutral landscape pictures were randomly presented to 20 student participants; they were asked to view these product designs without making any decisions. The paired t-test and repeated-measures analysis of correlation showed that the P200 and late positive potential (LPP) elicited by the most-preferred experience good designs were significantly higher than that elicited by least-preferred designs, and the two ERP components were positively correlated with the personalized rating scores. Thus, P200 and LPP might be the early and late indices of consumers' evaluation of experience good designs, respectively, and may facilitate an understanding of the temporal course of this evaluation. Furthermore, these two ERP components can be used to identify consumers' preferences toward experience good designs. In addition, given the use of personalized experimental stimuli, these findings may help to explain why customized products are preferred by consumers. PMID- 30416424 TI - Tapered Fibers Combined With a Multi-Electrode Array for Optogenetics in Mouse Medial Prefrontal Cortex. AB - Optogenetics offers many advantages in terms of cell-type specificity, allowing to investigate functional connectivity between different brain areas at high spatial and neural population selectivity. In order to obtain simultaneous optical control and electrical readout of neural activity, devices called "optrodes" are employed. They are typically composed of a linear array of microelectrodes integrated on a slender probe shafts combined with flat-cleaved optical fibers (FF) placed above the recording sites. However, due to tissue absorption and scattering, light delivered by the FF unevenly illuminates the region of interest. This issue is of particular relevance when cellular populations are disposed along the dorso-ventral axis, such as in medial prefrontal cortex (mPFC) where cortical layers are aligned vertically. The study presented here aims at using tapered optical fibers (TFs) in combination with a 16-electrode neural probe to better access neural populations distributed along the dorso-ventral axis in the mPFC of newborn mice, restricting light delivery over a specific portion of the cortical layer of interest. Half of the TF surface is coated with a reflecting metal blocking the light to enable light delivery from one side of the probe's shaft only, with the probe base being designed to host the fiber without interfering with the wire-bonds that connect the recording sites to a printed circuit board. Monte-Carlo simulations have been implemented to define the relative TF-probe position and to identify the light intensity distribution above the recording sites. In vivo recordings indicate that simultaneous optical stimulation and electrical readout of neural activity in the mPFC benefit from the use of the engineered TF-based optrode in terms of a more uniform light distribution along the dorso-ventral axis and the possibility of restricting light delivery to a subset of electrical recording sites of interest. PMID- 30416422 TI - The Endocannabinoid System and Oligodendrocytes in Health and Disease. AB - Cannabinoid-based interventions are being explored for central nervous system (CNS) pathologies such as neurodegeneration, demyelination, epilepsy, stroke, and trauma. As these disease states involve dysregulation of myelin integrity and/or remyelination, it is important to consider effects of the endocannabinoid system on oligodendrocytes and their precursors. In this review, we examine research reports on the effects of the endocannabinoid system (ECS) components on oligodendrocytes and their precursors, with a focus on therapeutic implications. Cannabinoid ligands and modulators of the endocannabinoid system promote cell signaling in oligodendrocyte precursor survival, proliferation, migration and differentiation, and mature oligodendrocyte survival and myelination. Agonist stimulation of oligodendrocyte precursor cells (OPCs) at both CB1 and CB2 receptors counter apoptotic processes via Akt/PI3K, and promote proliferation via Akt/mTOR and ERK pathways. CB1 receptors in radial glia promote proliferation and conversion to progenitors fated to become oligodendroglia, whereas CB2 receptors promote OPC migration in neonatal development. OPCs produce 2 arachidonoylglycerol (2-AG), stimulating cannabinoid receptor-mediated ERK pathways responsible for differentiation to arborized, myelin basic protein (MBP) producing oligodendrocytes. In cell culture models of excitotoxicity, increased reactive oxygen species, and depolarization-dependent calcium influx, CB1 agonists improved viability of oligodendrocytes. In transient and permanent middle cerebral artery occlusion models of anoxic stroke, WIN55212-2 increased OPC proliferation and maturation to oligodendroglia, thereby reducing cerebral tissue damage. In several models of rodent encephalomyelitis, chronic treatment with cannabinoid agonists ameliorated the damage by promoting OPC survival and oligodendrocyte function. Pharmacotherapeutic strategies based upon ECS and oligodendrocyte production and survival should be considered. PMID- 30416426 TI - Things Become Appealing When I Win: Neural Evidence of the Influence of Competition Outcomes on Brand Preference. AB - Against the background of an increasingly competitive market environment, the current study aimed to investigate whether and how victory and defeat, as two critical factors in competition outcomes, would affect consumers' preference of unfamiliar brands. In the experiment, participants' status of victory or defeat was induced by a pseudo-online game, followed by a main task of brand preference rating. Using the precise and intuitive attributes of neuroscientific techniques, we adopted event-related potentials to analyze brain activity precisely during brand information processing when individuals experienced victory or defeat. Behavioral data showed that individuals had a stronger preference for unfamiliar brands in victory trials than in defeat trials, even if the brand was completely unrelated to the competition; this indicated a transfer of valence. Three emotion related event-related potential components, N1, P2 and later positive potentials, were elicited more negatively in victory trials than in defeat trials, indicating the existence of incidental emotions induced by victory or defeat. No significant correlation was found between any pair of ERP components and preference scores. These results suggest that the experience of victory and defeat can evoke corresponding incidental emotions without awareness, and further affect the individual's preference for unfamiliar brands. Therefore, playing a game before presenting brand information might help promote the brand by inducing a good impression of the brand in consumers. PMID- 30416425 TI - Sirtuins in Neuroendocrine Regulation and Neurological Diseases. AB - Silent information regulator 1 (SIRT1) is a mammalian homolog of the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin family. Sirtuin was originally studied as the lifespan-extending gene, silent information regulator 2 (SIRT2) in budding yeast. There are seven mammalian homologs of sirtuin (SIRT1 7), and SIRT1 is the closest homolog to SIRT2. SIRT1 modulates various key targets via deacetylation. In addition to histones, these targets include transcription factors, such as forkhead box O (FOXO), Ku70, p53, NF-kappaB, PPAR gamma co-activator 1-alpha (PGC-1alpha), and peroxisome proliferator-activated receptor gamma (PPARgamma). SIRT1 has many biological functions, including aging, cell survival, differentiation, and metabolism. Genetic and physiological analyses in animal models have shown beneficial roles for SIRT1 in the brain during both development and adulthood. Evidence from in vivo and in vitro studies have revealed that SIRT1 regulates the cellular fate of neural progenitors, axon elongation, dendritic branching, synaptic plasticity, and endocrine function. In addition to its importance in physiological processes, SIRT1 has also been implicated in protection of neurons from degeneration in models of neurological diseases, such as traumatic brain injury and Alzheimer's disease. In this review, we focus on the role of SIRT1 in the neuroendocrine system and neurodegenerative diseases. We also discuss the potential therapeutic implications of targeting the sirtuin pathway. PMID- 30416429 TI - Short-Term Plasticity at Olfactory Cortex to Granule Cell Synapses Requires CaV2.1 Activation. AB - Output projections of the olfactory bulb (OB) to the olfactory cortex (OCX) and reciprocal feedback projections from OCX provide rapid regulation of OB circuit dynamics and odor processing. Short-term synaptic plasticity (STP), a feature of many synaptic connections in the brain, can modulate the strength of feedback based on preceding network activity. We used light-gated cation channel channelrhodopsin-2 (ChR2) to investigate plasticity of excitatory synaptic currents (EPSCs) evoked at the OCX to granule cell (GC) synapse in the OB. Selective activation of OCX glutamatergic axons/terminals in OB generates strong, frequency-dependent STP in GCs. This plasticity was critically dependent on activation of CaV2.1 channels. As acetylcholine (ACh) modulates CaV2.1 channels in other brain regions and as cholinergic projections from the basal forebrain heavily target the GC layer (GCL) in OB, we investigated whether ACh modulates STP at the OCX->GC synapse. ACh decreases OCX->GC evoked EPSCs, it had no effect on STP. Thus, ACh impact on cortical feedback is independent of CaV2.1-mediated STP. Modulation of OCX feedback to the bulb by modulatory transmitters, such as ACh, or by frequency-dependent STP could regulate the precise balance of excitation and inhibition of GCs. As GCs are a major inhibitory source for OB output neurons, plasticity at the cortical feedback synapse can differentially impact OB output to higher-order networks in situations where ACh inputs are activated or by active sniff sampling of odors. PMID- 30416427 TI - The Neuroprotective Effects of 17beta-Estradiol Pretreatment in a Model of Neonatal Hippocampal Injury Induced by Trimethyltin. AB - Hippocampal dysfunction plays a central role in neurodevelopmental disorders, resulting in severe impairment of cognitive abilities, including memory and learning. On this basis, developmental studies represent an important tool both to understanding the cellular and molecular phenomena underlying early hippocampal damage and to study possible therapeutic interventions, that may modify the progression of neuronal death. Given the modulatory role played by 17beta-estradiol (E2) on hippocampal functions and its neuroprotective properties, the present study investigates the effects of pretreatment with E2 in a model of neonatal hippocampal injury obtained by trimethyltin (TMT) administration, characterized by neuronal loss in CA1 and CA3 subfields and astroglial and microglial activation. At post-natal days (P)5 and P6 animals received E2 administration (0.2 mg/kg/die i.p.) or vehicle. At P7 they received a single dose of TMT (6.5 mg/kg i.p.) and were sacrificed 72 h (P10) or 7 days after TMT treatment (P14). Our findings indicate that pretreatment with E2 exerts a protective effect against hippocampal damage induced by TMT administration early in development, reducing the extent of neuronal death in the CA1 subfield, inducing the activation of genes involved in neuroprotection, lowering the neuroinflammatory response and restoring neuropeptide Y- and parvalbumin- expression, which is impaired in the early phases of TMT-induced damage. Our data support the efficacy of estrogen-based neuroprotective approaches to counteract early occurring hippocampal damage in the developing hippocampus. PMID- 30416430 TI - Development of an Acute Method to Deliver Transgenes Into the Brains of Adult Xenopus laevis. AB - The central vocal pathway of the African clawed frog, Xenopus laevis, is a powerful vertebrate model to understand mechanisms underlying central pattern generation. However, fast and efficient methods of introducing exogenous genes into the neurons of adult X. laevis are currently not available. Here, we systematically tested methods of transgene delivery into adult X. laevis neurons. Although successfully used for tadpole neurons for over a decade, electroporation was not efficient in transfecting adult neurons. Similarly, adeno-associated virus (AAV) was not reliable, and lentivirus (LV) failed to function as viral vector in adult Xenopus neurons. In contrast, vesicular stomatitis virus (VSV) was a fast and robust vector for adult X. laevis neurons. Although toxic to the host cells, VSV appears to be less virulent to frog neurons than they are to mice neurons. At a single cell level, infected neurons showed normal physiological properties up to 7 days post infection and vocal circuits that included infected neurons generated normal fictive vocalizations up to 9 days post infection. The relatively long time window during which the physiology of VSV-infected neurons can be studied presents an ideal condition for the use of optogenetic tools. We showed that VSV does not gain entry into myelinated axons, but is taken up by both the soma and axon terminal; this is an attractive feature that drives transgene expression in projection neurons. Previous studies showed that VSVs can spread across synapses in anterograde or retrograde directions depending on the types of glycoprotein that are encoded. However, rVSV did not spread across synapses in the Xenopus central nervous system. The successful use of VSV as a transgene vector in amphibian brains not only allows us to exploit the full potential of the genetic tools to answer questions central to understanding central pattern generation, but also opens the door to other research programs that focus on non-genetic model organisms to address unique questions. PMID- 30416428 TI - Neurologic Alterations Due to Respiratory Virus Infections. AB - Central Nervous System (CNS) infections are one of the most critical problems in public health, as frequently patients exhibit neurologic sequelae. Usually, CNS pathologies are caused by known neurotropic viruses such as measles virus (MV), herpes virus and human immunodeficiency virus (HIV), among others. However, nowadays respiratory viruses have placed themselves as relevant agents responsible for CNS pathologies. Among these neuropathological viruses are the human respiratory syncytial virus (hRSV), the influenza virus (IV), the coronavirus (CoV) and the human metapneumovirus (hMPV). These viral agents are leading causes of acute respiratory infections every year affecting mainly children under 5 years old and also the elderly. Up to date, several reports have described the association between respiratory viral infections with neurological symptoms. The most frequent clinical manifestations described in these patients are febrile or afebrile seizures, status epilepticus, encephalopathies and encephalitis. All these viruses have been found in cerebrospinal fluid (CSF), which suggests that all these pathogens, once in the lungs, can spread throughout the body and eventually reach the CNS. The current knowledge about the mechanisms and routes used by these neuro-invasive viruses remains scarce. In this review article, we describe the most recent findings associated to neurologic complications, along with data about the possible invasion routes of these viruses in humans and their various effects on the CNS, as studied in animal models. PMID- 30416431 TI - Auditory and Visual Motion Processing and Integration in the Primate Cerebral Cortex. AB - The ability of animals to detect motion is critical for survival, and errors or even delays in motion perception may prove costly. In the natural world, moving objects in the visual field often produce concurrent sounds. Thus, it can highly advantageous to detect motion elicited from sensory signals of either modality, and to integrate them to produce more reliable motion perception. A great deal of progress has been made in understanding how visual motion perception is governed by the activity of single neurons in the primate cerebral cortex, but far less progress has been made in understanding both auditory motion and audiovisual motion integration. Here we, review the key cortical regions for motion processing, focussing on translational motion. We compare the representations of space and motion in the visual and auditory systems, and examine how single neurons in these two sensory systems encode the direction of motion. We also discuss the way in which humans integrate of audio and visual motion cues, and the regions of the cortex that may mediate this process. PMID- 30416433 TI - Early Visual Processing of Feature Saliency Tasks: A Review of Psychophysical Experiments. AB - The visual system is constantly bombarded with information originating from the outside world, but it is unable to process all the received information at any given time. In fact, the most salient parts of the visual scene are chosen to be processed involuntarily and immediately after the first glance along with endogenous signals in the brain. Vision scientists have shown that the early visual system, from retina to lateral geniculate nucleus (LGN) and then primary visual cortex, selectively processes the low-level features of the visual scene. Everything we perceive from the visual scene is based on these feature properties and their subsequent combination in higher visual areas. Different experiments have been designed to investigate the impact of these features on saliency and understand the relative visual mechanisms. In this paper, we review the psychophysical experiments which have been published in the last decades to indicate how the low-level salient features are processed in the early visual cortex and extract the most important and basic information of the visual scene. Important and open questions are discussed in this review as well and one might pursue these questions to investigate the impact of higher level features on saliency in complex scenes or natural images. PMID- 30416434 TI - Reusable Multielectrode Array Technique for Electroencephalography in Awake Freely Moving Mice. AB - Translational comparison of rodent models of neurological and neuropsychiatric diseases to human electroencephalography (EEG) biomarkers in these conditions will require multisite rodent EEG on the skull surface, rather than local area electrocorticography (ECoG) or multisite local field potential (LFP) recording. We have developed a technique for planar multielectrode array (MEA) implantation on the mouse skull surface, which enables multisite EEG in awake and freely moving mice and reusability of the MEA probes. With this method, we reliably obtain 30-channel low-noise EEG from awake mice. Baseline and stimulus-evoked EEG recordings can be readily obtained and analyzed. For example, we have demonstrated EEG responses to auditory stimuli. Broadband noise elicits reliable 30-channel auditory event-related potentials (ERPs), and chirp stimuli induce phase-locked EEG responses just as in human sound presentation paradigms. This method is unique in achieving chronic implantation of novel MEA technology onto the mouse skull surface for chronic multisite EEG recordings. Furthermore, we demonstrate a reliable method for reusing MEA probes for multiple serial implantations without loss of EEG quality. This skull surface MEA methodology can be used to obtain simultaneous multisite EEG recordings and to test EEG biomarkers in diverse mouse models of human neurological and neuropsychiatric diseases. Reusability of the MEA probes makes it more cost-effective to deploy this system for various studies. PMID- 30416432 TI - The Synaptic Theory of Memory: A Historical Survey and Reconciliation of Recent Opposition. AB - Trettenbrein (2016) has argued that the concept of the synapse as the locus of memory is outdated and has made six critiques of this concept. In this article, we examine these six critiques and suggest that the current theories of the neurobiology of memory and the empirical data indicate that synaptic activation is the first step in a chain of cellular and biochemical events that lead to memories formed in cell assemblies and neural networks that rely on synaptic modification for their formation. These neural networks and their modified synaptic connections can account for the cognitive basis of learning and memory and for memory deterioration in neurological disorders. We first discuss Hebb's (1949) theory that synaptic change and the formation of cell assemblies and phase sequences can link neurophysiology to cognitive processes. We then examine each of Trettenbrein's (2016) critiques of the synaptic theory in light of Hebb's theories and recent empirical data. We examine the biochemical basis of memory formation and the necessity of synaptic modification to form the neural networks underlying learning and memory. We then examine the use of Hebb's theories of synaptic change and cell assemblies for integrating neurophysiological and cognitive conceptions of learning and memory. We conclude with an examination of the applications of the Hebb synapse and cell assembly theories to the study of the neuroscience of learning and memory, the development of computational models of memory and the construction of "intelligent" robots. We conclude that the synaptic theory of memory has not met its demise, but is essential to our understanding of the neural basis of memory, which has two components: synaptic plasticity and intrinsic plasticity. PMID- 30416435 TI - Effects of Cage Enrichment on Behavior, Welfare and Outcome Variability in Female Mice. AB - The manner in which laboratory rodents are housed is driven by economics (minimal use of space and resources), ergonomics (ease of handling and visibility of animals), hygiene, and standardization (reduction of variation). This has resulted in housing conditions that lack sensory and motor stimulation and restrict the expression of species-typical behavior. In mice, such housing conditions have been associated with indicators of impaired welfare, including abnormal repetitive behavior (stereotypies, compulsive behavior), enhanced anxiety and stress reactivity, and thermal stress. However, due to concerns that more complex environmental conditions might increase variation in experimental results, there has been considerable resistance to the implementation of environmental enrichment beyond the provision of nesting material. Here, using 96 C57BL/6 and SWISS female mice, respectively, we systematically varied environmental enrichment across four levels spanning the range of common enrichment strategies: (1) bedding alone; (2) bedding + nesting material; (3) deeper bedding + nesting material + shelter + increased vertical space; and (4) semi-naturalistic conditions, including weekly changes of enrichment items. We studied how these different forms of environmental enrichment affected measures of animal welfare, including home-cage behavior (time-budget and stereotypic behavior), anxiety (open field behavior, elevated plus-maze behavior), growth (food and water intake, body mass), stress physiology (glucocorticoid metabolites in fecal boluses and adrenal mass), brain function (recurrent perseveration in a two-choice guessing task) and emotional valence (judgment bias). Our results highlight the difficulty in making general recommendations across common strains of mice and for selecting enrichment strategies within specific strains. Overall, the greatest benefit was observed in animals housed with the greatest degree of enrichment. Thus, in the super-enriched housing condition, stereotypic behavior, behavioral measures of anxiety, growth and stress physiology varied in a manner consistent with improved animal welfare compared to the other housing conditions with less enrichment. Similar to other studies, we found no evidence, in the measures assessed here, that environmental enrichment increased variation in experimental results. PMID- 30416438 TI - A Novel Method for Classifying Driver Mental Workload Under Naturalistic Conditions With Information From Near-Infrared Spectroscopy. AB - Driver cognitive distraction is a critical factor in road safety, and its evaluation, especially under real conditions, presents challenges to researchers and engineers. In this study, we considered mental workload from a secondary task as a potential source of cognitive distraction and aimed to estimate the increased cognitive load on the driver with a four-channel near-infrared spectroscopy (NIRS) device by introducing a machine-learning method for hemodynamic data. To produce added cognitive workload in a driver beyond just driving, two levels of an auditory presentation n-back task were used. A total of 60 experimental data sets from the NIRS device during two driving tasks were obtained and analyzed by machine-learning algorithms. We used two techniques to prevent overfitting of the classification models: (1) k-fold cross-validation and principal-component analysis, and (2) retaining 25% of the data (testing data) for testing of the model after classification. Six types of classifier were trained and tested: decision tree, discriminant analysis, logistic regression, the support vector machine, the nearest neighbor classifier, and the ensemble classifier. Cognitive workload levels were well classified from the NIRS data in the cases of subject-dependent classification (the accuracy of classification increased from 81.30 to 95.40%, and the accuracy of prediction of the testing data was 82.18 to 96.08%), subject 26 independent classification (the accuracy of classification increased from 84.90 to 89.50%, and the accuracy of prediction of the testing data increased from 84.08 to 89.91%), and channel-independent classification (classification 82.90%, prediction 82.74%). NIRS data in conjunction with an artificial intelligence method can therefore be used to classify mental workload as a source of potential cognitive distraction in real time under naturalistic conditions; this information may be utilized in driver assistance systems to prevent road accidents. PMID- 30416439 TI - Grading of Frequency Spectral Centroid Across Resting-State Networks. AB - Ongoing, slowly fluctuating brain activity is organized in resting-state networks (RSNs) of spatially coherent fluctuations. Beyond spatial coherence, RSN activity is governed in a frequency-specific manner. The more detailed architecture of frequency spectra across RSNs is, however, poorly understood. Here we propose a novel measure-the Spectral Centroid (SC)-which represents the center of gravity of the full power spectrum of RSN signal fluctuations. We examine whether spectral underpinnings of network fluctuations are distinct across RSNs. We hypothesize that spectral content differs across networks in a consistent way, thus, the aggregate representation-SC-systematically differs across RSNs. We therefore test for a significant grading (i.e., ordering) of SC across RSNs in healthy subjects. Moreover, we hypothesize that such grading is biologically significant by demonstrating its RSN-specific change through brain disease, namely major depressive disorder. Our results yield a highly organized grading of SC across RSNs in 820 healthy subjects. This ordering was largely replicated in an independent dataset of 25 healthy subjects, pointing toward the validity and consistency of found SC grading across RSNs. Furthermore, we demonstrated the biological relevance of SC grading, as the SC of the salience network-a RSN well known to be implicated in depression-was specifically increased in patients compared to healthy controls. In summary, results provide evidence for a distinct grading of spectra across RSNs, which is sensitive to major depression. PMID- 30416437 TI - The Modulating Role of Sex and Anabolic-Androgenic Steroid Hormones in Cannabinoid Sensitivity. AB - Cannabis is the most commonly used illicit drug worldwide. Although its use is associated with multiple adverse health effects, including the risk of developing addiction, recreational and medical cannabis use is being increasing legalized. In addition, use of synthetic cannabinoid drugs is gaining considerable popularity and is associated with mass poisonings and occasional deaths. Delineating factors involved in cannabis use and addiction therefore becomes increasingly important. Similarly to other drugs of abuse, the prevalence of cannabis use and addiction differs remarkably between males and females, suggesting that sex plays a role in regulating cannabinoid sensitivity. Although it remains unclear how sex may affect the initiation and maintenance of cannabis use in humans, animal studies strongly suggest that endogenous sex hormones modulate cannabinoid sensitivity. In addition, synthetic anabolic-androgenic steroids alter substance use and further support the importance of sex steroids in controlling drug sensitivity. The recent discovery that pregnenolone, the precursor of all steroid hormones, controls cannabinoid receptor activation corroborates the link between steroid hormones and the endocannabinoid system. This article reviews the literature regarding the influence of endogenous and synthetic steroid hormones on the endocannabinoid system and cannabinoid action. PMID- 30416436 TI - Putative Inflammatory Sensitive Mechanisms Underlying Risk or Resilience to Social Stress. AB - It has been well recognized that exposure to stress can lead to the onset of psychosocial disorders such as depression. While there are a number of antidepressant therapies currently available and despite producing immediate neurochemical alterations, they require weeks of continuous use in order to exhibit antidepressant efficacy. Moreover, up to 30% of patients do not respond to typical antidepressants, suggesting that our understanding of the pathophysiology underlying stress-induced depression is still limited. In recent years inflammation has become a major focus in the study of depression as several clinical and preclinical studies have demonstrated that peripheral and central inflammatory mediators, including interleukin (IL)-1beta, are elevated in depressed patients. Moreover, it has been suggested that inflammation and particularly neuroinflammation may be a direct and immediate link in the emergence of stress-induced depression due to the broad neural and glial effects that are elicited by proinflammatory cytokines. Importantly, individual differences in inflammatory reactivity may further explain why certain individuals exhibit differing susceptibility to the consequences of stress. In this review article, we discuss sources of individual differences such as age, sex and coping mechanisms that are likely sources of distinct changes in stress induced neuroimmune factors and highlight putative sources of exaggerated neuroinflammation in susceptible individuals. Furthermore, we review the current literature of specific neural and glial mechanisms that are regulated by stress and inflammation including mitochondrial function, oxidative stress and mechanisms of glutamate excitotoxicity. Taken together, the impetus for this review is to move towards a better understanding of mechanisms regulated by inflammatory cytokines and chemokines that are capable of contributing to the emergence of depressive-like behaviors in susceptible individuals. PMID- 30416442 TI - Baicalein Enhances the Oral Bioavailability and Hepatoprotective Effects of Silybin Through the Inhibition of Efflux Transporters BCRP and MRP2. AB - Although hepatoprotective properties of silybin are well documented, the clinical therapeutic efficacy is limited by its low bioavailability due to absorption rates, extensive phase II metabolism, and biliary excretion. As our previous study indicated that metabolic enzymes may have limited effects on the pharmacokinetic (PK) behavior of silymarin, here, we intended to increase the oral bioavailability and bio-efficacy of silybin through the inhibition of active efflux. In Caco-2 and transfected MDCKII cell models, flavone baicalein significantly inhibited the efflux of silybin as a BCRP and MRP2 inhibitor. In addition, baicalein reduced the biliary excretion index (BEI) and biliary clearance of silybin conjugates in the sandwich-cultured rat hepatocyte (SCH) model, indicating the inhibition of baicalein in biliary excretion of conjugated silybin metabolites. PK study demonstrated that baicalein significantly increased the area under the curve (AUC) and Cmax of silybin and its conjugates, suggesting enhanced absorption in vivo. Moreover, coadministration of silybin with baicalein boosted the liver protective, antioxidant, and anti-inflammatory effects of silybin in the carbon tetrachloride (CCl4)-induced liver injury model in comparison with silybin given alone. In summary, efflux transporters play a critical role in the low bioavailability of silybin, while inhibition of breast cancer resistance protein (BCRP) and multi-drug resistance protein 2 (MRP2) by baicalein can significantly increase the absorption and bio-efficacy of silybin, which provides a new combination therapeutic approach for the treatment of chronic liver diseases. PMID- 30416440 TI - Existence of Initial Dip for BCI: An Illusion or Reality. AB - A tight coupling between the neuronal activity and the cerebral blood flow (CBF) is the motivation of many hemodynamic response (HR)-based neuroimaging modalities. The increase in neuronal activity causes the increase in CBF that is indirectly measured by HR modalities. Upon functional stimulation, the HR is mainly categorized in three durations: (i) initial dip, (ii) conventional HR (i.e., positive increase in HR caused by an increase in the CBF), and (iii) undershoot. The initial dip is a change in oxygenation prior to any subsequent increase in CBF and spatially more specific to the site of neuronal activity. Despite additional evidence from various HR modalities on the presence of initial dip in human and animal species (i.e., cat, rat, and monkey); the existence/occurrence of an initial dip in HR is still under debate. This article reviews the existence and elusive nature of the initial dip duration of HR in intrinsic signal optical imaging (ISOI), functional magnetic resonance imaging (fMRI), and functional near-infrared spectroscopy (fNIRS). The advent of initial dip and its elusiveness factors in ISOI and fMRI studies are briefly discussed. Furthermore, the detection of initial dip and its role in brain-computer interface using fNIRS is examined in detail. The best possible application for the initial dip utilization and its future implications using fNIRS are provided. PMID- 30416443 TI - In vitro Methods for the Development and Analysis of Human Primary Airway Epithelia. AB - Cystic fibrosis (CF) is a chronic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which encodes for a channel expressed at the apical surface of epithelial tissues. Defective chloride and bicarbonate secretion, arising from CFTR mutations, cause a multi-organ disease. In the airways, impaired ion transport results in a thick mucus, dehydration of the periciliar region and bacterial infections. Over the last years, basic research has sustained a great effort to identify therapies that are able to correct defective CFTR. For this purpose, in vitro cell models have played a key role in the study of mechanisms of the disease and to assess CFTR modulator therapies. Cultures of human primary bronchial epithelia are considered a physiologically relevant disease model due to their ability to maintain most of the morphological and functional characteristics of the airway epithelium in vivo. Despite their value, these cells are limited by the availability of human lung tissue and by the complexity of the culture procedure. However, primary human nasal cells can be considered as an alternative model for the study of CF pathophysiology since they are easier to obtain and recapitulate the properties of bronchial cultures. Over the years, several groups have optimized a protocol with key steps to culture and fully amplify differentiated primary airway epithelia. Our approach provides epithelia monolayers grown on porous filters, characterized by high transepithelial electrical resistance and an electrical potential difference. These parameters are required to perform electrophysiological experiments devoted to the study of ion transport mechanisms in airway epithelia. The aim of this study was to describe different methods to expand and differentiate isolated cells into fully polarized monolayers of airway epithelium, in order to provide an optimized protocol to support physiopathology analysis and to evaluate therapeutic strategies. PMID- 30416444 TI - The Effect of Acupuncture on the Quality of Life in Patients With Migraine: A Systematic Review and Meta-Analysis. AB - Background: Acupuncture is frequently used as an efficient method to prevent and treat migraines. However, its effect on the quality of life remains controversial. Methods: Seven databases, such as PubMed and Cochrane Library were searched to retrieve reference lists of eligible trials and related reviews. Randomized controlled trials that were published in Chinese and English were included. Results: Acupuncture resulted in lower Visual Analog Scale scores than the medication group at 1 month after treatment (MD -1.22, 95%CI -1.57 to -0.87; low quality) and 1-3 months after treatment (MD -1.81, 95%CI -3.42 to -0.20; low quality). Compared with sham acupuncture, acupuncture resulted in lower Visual Analog Scale scores at 1 month after treatment (MD -1.56, 95%CI -2.21 to -0.92; low quality). Conclusion: Acupuncture exhibits certain efficacy both in the treatment and prevention of migraines, which is superior to no treatment, sham acupuncture and medication. Further, acupuncture enhanced the quality of life more than did medication. PMID- 30416445 TI - Postmortem Toxicology of New Synthetic Opioids. AB - One hundred fifteen Americans die every day from opioid overdose. These overdose fatalities have been augmented by the increased availability of potent synthetic opioids, such as fentanyl and its derivatives. The death rate of synthetic opioids, other than methadone, increased by 72.2% from 2014 to 2015, and doubled from 2015 to 2016, situating the USA in the midst of an opioid overdose epidemic. The analytical identification of these opioids in postmortem samples and the correct toxicological data interpretation is critical to identify and implement preventive strategies. This article reviews the current knowledge of postmortem toxicology of synthetic opioids and the chemical and pharmacological factors that may affect drug concentrations in the different postmortem matrices and therefore, their interpretation. These factors include key chemical properties, essential pharmacokinetics parameters (metabolism), postmortem redistribution and stability data in postmortem samples. Range and ratios of concentrations reported in traditional and non-traditional postmortem specimens, blood, urine, vitreous humor, liver and brain, are summarized in tables. The review is focused on fentanyl and derivatives (e.g., acetyl fentanyl, butyryl fentanyl, carfentanil, furanyl fentanyl, 4-methoxybutyrylfentanyl, 4-fluorobutyrylfentanyl, ocfentanil) and non-traditional opioid agonists (e.g., AH-7921, MT-45, U-47700). All of these data are critically compared to postmortem data, and chemical and pharmacological properties of natural opioids (morphine), semi-synthetic (oxycodone, hydrocodone, hydromorphone, and oxymorphone), and synthetic opioids (methadone and buprenorphine). The interpretation of drug intoxication in death investigation is based on the available published literature. This review serves to facilitate the evaluation of cases where synthetic opioids may be implicated in a fatality through the critical review of peer reviewed published case reports and research articles. PMID- 30416441 TI - Astrocytes and Aging. AB - By 2050, the aging population is predicted to expand by over 100%. Considering this rapid growth, and the additional strain it will place on healthcare resources because of age-related impairments, it is vital that researchers gain a deeper understanding of the cellular interactions that occur with normal aging. A variety of mammalian cell types have been shown to become compromised with age, each with a unique potential to contribute to disease formation in the aging body. Astrocytes represent the largest group of glial cells and are responsible for a variety of essential functions in the healthy central nervous system (CNS). Like other cell types, aging can cause a loss of normal function in astrocytes which reduces their ability to properly maintain a healthy CNS environment, negatively alters their interactions with neighboring cells, and contribute to the heightened inflammatory state characteristic of aging. The goal of this review article is to consolidate the knowledge and research to date regarding the role of astrocytes in aging. In specific, this review article will focus on the morphology and molecular profile of aged astrocytes, the consequence of astrocyte dysfunction on homeostatic functions during aging, and the role of astrocytes in age-related neurodegenerative diseases. PMID- 30416447 TI - Identification and Characterization of Novel CFTR Potentiators. AB - There is still a high unmet need for the treatment of most patients with cystic fibrosis (CF). The identification and development of new Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators is necessary to achieve higher clinical benefit in patients. In this report we describe the characterization of novel potentiators. From a small screening campaign on F508del CFTR, hits were developed leading to the identification of pre-clinical candidates GLPG1837 and GLPG2451, each derived from a distinct chemical series. Both drug candidates enhance WT CFTR activity as well as low temperature or corrector rescued F508del CFTR, and are able to improve channel activity on a series of Class III, IV CFTR mutants. The observed activities in YFP halide assays translated well to primary cells derived from CF lungs when measured using Trans-epithelial clamp circuit (TECC). Both potentiators improve F508del CFTR channel opening in a similar manner, increasing the open time and reducing the closed time of the channel. When evaluating the potentiators in a chronic setting on corrected F508del CFTR, no reduction of channel activity in presence of potentiator was observed. The current work identifies and characterizes novel CFTR potentiators GLPG1837 and GLPG2451, which may offer new therapeutic options for CF patients. PMID- 30416446 TI - Ninjinyoeito Improves Behavioral Abnormalities and Hippocampal Neurogenesis in the Corticosterone Model of Depression. AB - Ninjinyoeito (NYT), a traditional Chinese medicine consisting of 12 herbs, is designed to improve fatigue, cold limbs, anorexia, night sweats, and anemia. Recently, NYT was reported to improve cognitive outcome and depression in patients with Alzheimer's disease. However, little is known about how NYT alleviates depression and cognitive dysfunction. In this study, we investigated the effects and mechanisms of NYT in a corticosterone (CORT)-induced model of depression. Chronic NYT treatment ameliorated the depressive-like behaviors induced by CORT treatment in three types of behavioral tests. In addition, chronic NYT treatment also improved memory disruptions induced by CORT in both the Y-maze and novel object recognition tests, without affecting locomotor activity. Furthermore, we also showed that NYT treatment attenuated the CORT induced reduction in cell proliferation and immature neuronal cell numbers in mouse hippocampal dentate gyrus. These results suggest that NYT has therapeutic effects on CORT-induced behavioral abnormalities and inhibition of hippocampal neurogenesis. PMID- 30416448 TI - Resistin-Induced Endoplasmic Reticulum Stress Contributes to the Impairment of Insulin Signaling in Endothelium. AB - Background: Endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of obesity, insulin resistance and cardiovascular diseases (CVDs). Impairment of insulin vascular action may represent a mechanism linking insulin resistance and CVDs. The present study tested the hypothesis that adipocyte derived resistin inhibits insulin-stimulated endothelial NO production through the induction of ER stress. Methods and Results: Human umbilical vein endothelial cells (HUVC) were incubated with tunicamycin (an inducer of ER stress, 1-20 MUg/mL) or resistin (10-100 ng/mL) for 1 h. Either tunicamycin or resistin increased GRP78 (an ER stress marker) expression associated with the impairment of insulin-stimulated Akt/eNOS phosphorylation, which were prevented by TUDCA (an ER stress suppressor). Resistin increased reactive oxygen species (ROS) production, antioxidant treatment inhibited resistin-induced GRP78 expression and impairment of insulin Akt/eNOS signaling, suggesting that ROS may involve resistin-induced ER stress. Resistin also increased JNK phosphorylation, which was prevented by TUDCA. JNK inhibitor SP600125 relieved the resistin inhibitory effects on endothelial insulin Akt/eNOS signaling. In ex vivo experiments, the incubation of aortic rings with resistin impaired insulin- but not acetylcholine induced vasodilation, which was restored by TUDCA. LNAME (a NOS inhibitor) abolished insulin-induced vasorelaxation in the control or the resistin-treated aortic rings. In addition, resistin increased the mRNA expressions of proinflammatory cytokines tumor nuclear factor (TNF)alpha and interleukin (IL) 1beta, which were also prevented by TUDCA. Conclusion: Our results support the ideal that ER stress may play an important role for resistin impairment of vascular insulin signaling and insulin action. The mitigation of ER stress may represent a new strategy for prevention and treatment of CVDs in obesity and insulin resistant-related diseases. PMID- 30416449 TI - Enrichment of Autophagy and Proteosome Pathways in Breast Muscle of Feed Efficient Pedigree Male Broilers. AB - Background: Feed efficiency (FE) is an important genetic trait in poultry and livestock. Autophagy (self-eating) and proteosomes are cellular processes that remove damaged cell components (e.g., proteins, organelles). As evidence of extensive protein oxidation was observed in Pedigree Male (PedM) broilers exhibiting a low FE (LFE) phenotype compared to a high FE (HFE) phenotype, the main goal of this study was to assess gene and protein expression of the autophagy and proteosome pathways in breast muscle obtained in PedM broilers exhibiting HFE and LFE phenotypes. Methods: Feed efficiency was calculated as weight gain divided by feed intake gain in individual PedM broilers that were measured between 6 and 7 weeks of age. Targeted gene expression was conducted on breast muscle using quantitative real-time polymerase chain reaction (qPCR) to determine mRNA expression of genes associated with the autophagy pathway; AMP activated protein kinase alpha 1 (AMPKalpha1), mammalian target of rapamycin (mTOR), Beclin 1, and autophagy genes (Atg) 3, Atg7, and Atg16L1. Binomial distribution analysis was conducted on transcriptomic and data obtained by RNAseq and shotgun proteomics, respectively on the same set of tissues for genes associated with autophagy, vacuole formation, and proteosome expression. Results: Greater efficiency was attained in the HFE PedM broilers by greater weight gain on the same amount of feed consumed resulting in FEs of 0.65 +/- 0.01 and 0.46 +/ 0.01 in the HFE and LFE phenotypes, respectively. Targeted mRNA expression analysis revealed significant (P < 0.05) elevations in AMPKa1, mTOR, Atg16L1, and Atg7 and a marginal (P = 0.07) elevation in Beclin1. Binomial distribution analysis transcriptomic and proteomic data revealed significant skews favoring autophagy-, vacuole-, and proteosome-related genes in the HFE phenotype. These results indicate that the autophagy and proteosome expression is enhanced in the HFE compared to the LFE pedigree male broiler phenotype suggesting that protein and organelle quality control may be enhanced in high feed efficiency. PMID- 30416450 TI - The Effect of Chinese Herbal Medicine on Quality of Life and Exercise Tolerance in Heart Failure With Preserved Ejection Fraction: A Systematic Review and Meta Analysis of Randomized Controlled Trials. AB - Background: Chinese herbal medicine (CHM) has a good effect of alleviating symptoms and improving quality of life and exercise tolerance in patients with heart failure with preserved ejection fraction (HFpEF), but it wasn't sufficiently valued and promoted because of the lack of evidence-based medical evidence. Aim: To systematically review the effect of CHM on quality of life and exercise tolerance in patients with HFpEF. Methods: We conducted a systematic literature search for Chinese and English studies in PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Chinese Biomedical Literature Database, China Knowledge Resource Integrated Database, Wanfang Data, and China Science and Technology Journal Database. Databases were searched using terms relating to or describing CHM, HFpEF and randomized controlled trials, without any exclusion criteria for other types of diseases or disorders. Literature retrieval, data extraction, and risk of bias assessments were performed independently by two investigators. Differences were resolved by consensus. RevMan 5.3.0 was used for data analysis. Quantitative synthesis was used when the included studies were sufficiently homogeneous and subgroup analyses were performed for studies with different sample sizes and blind methods. GRADEpro was used to grade the available evidence to minimize bias in our findings. Results: Seventeen studies with 2,724 patients were enrolled in this review. ROB assessments showed a relatively high selection and performance bias. Meta-analyses showed that compared with conventional western medicine, combined CHM and conventional western medicine could significantly improve 6-min walk distance (MD = 52.13, 95% CI [46.91, 57.34], P < 0.00001), and it seemed to be more effective as compared with combined placebo and conventional western medicine. Similar results were observed for quality of life and the results were better in a larger sample. The GRADEpro showed a very low to moderate level of the available evidence. Conclusion: Combined CHM and conventional western medicine might be effective to improve exercise tolerance and quality of life in HFpEF patients, but new well designed studies with larger sample size, strict randomization, and clear description about detection and reporting processes are needed to further strengthen this evidence. PMID- 30416451 TI - Effect of Ischemic Preconditioning on the Recovery of Cardiac Autonomic Control From Repeated Sprint Exercise. AB - Repeated sprint exercise (RSE) acutely impairs post-exercise heart rate (HR) recovery (HRR) and time-domain heart rate variability (i. e., RMSSD), likely in part, due to lactic acidosis-induced reduction of cardiac vagal reactivation. In contrast, ischemic preconditioning (IPC) mediates cardiac vagal activation and augments energy metabolism efficiency during prolonged ischemia followed by reperfusion. Therefore, we investigated whether IPC could improve recovery of cardiac autonomic control from RSE partially via improved energy metabolism responses to RSE. Fifteen men team-sport practitioners (mean +/- SD: 25 +/- 5 years) were randomly exposed to IPC in the legs (3 * 5 min at 220 mmHg) or control (CT; 3 * 5 min at 20 mmHg) 48 h, 24 h, and 35 min before performing 3 sets of 6 shuttle running sprints (15 + 15 m with 180 degrees change of direction and 20 s of active recovery). Sets 1 and 2 were followed by 180 s and set 3 by 360 s of inactive recovery. Short-term HRR was analyzed after all sets via linear regression of HR decay within the first 30 s of recovery (T30) and delta from peak HR to 60 s of recovery (HRR60s). Long-term HRR was analyzed throughout recovery from set 3 via first-order exponential regression of HR decay. Moreover, RMSSD was calculated using 30-s data segments throughout recovery from set 3. Energy metabolism responses were inferred via peak pulmonary oxygen uptake ( VO2 peak), peak carbon dioxide output ( VO2 peak), peak respiratory exchange ratio (RERpeak), first-order exponential regression of VO2 decay within 360 s of recovery and blood lactate concentration ([Lac-]). IPC did not change T30, but increased HRR60s after all sets (condition main effect: P = 0.03; partial eta square (eta2 p ) = 0.27, i.e., large effect size). IPC did not change long-term HRR and RMSSD throughout recovery, nor did IPC change any energy metabolism parameter. In conclusion, IPC accelerated to some extent the short term recovery, but did not change the long-term recovery of cardiac autonomic control from RSE, and such accelerator effect was not accompanied by any IPC effect on surrogates of energy metabolism responses to RSE. PMID- 30416452 TI - The Melanocortin MC5R as a New Target for Treatment of High Glucose-Induced Hypertrophy of the Cardiac H9c2 Cells. AB - The study explored the anti-hypertrophic effect of the melanocortin MC5R stimulation in H9c2 cardiac myocytes exposed to high glucose. This has been done by using alpha-MSH and selective MC5R agonists and assessing the expression of GLUT4 and GLUT1 transporters, miR-133 and urotensin receptor levels as a marker of cardiac hypertrophy. The study shows for the first time an up-regulation of MC5R expression levels in H9c2 cardiomyocytes exposed to high glucose medium (33 mM D-glucose) for 48 h, compared to cells grown in normal glucose medium (5.5 mM D-glucose). Moreover, H9c2 cells exposed to high glucose showed a significant reduction in cell viability (-40%), a significant increase in total protein per cell number (+109%), and an increase of the urotensin receptor expression levels as an evidence of cells hypertrophy. The pharmacological stimulation of MC5R with alpha-MSH (90 pM)of the high glucose exposed H9c2 cells increased the cell survival (+50,8%) and reduced the total protein per cell number (-28,2%) with respect to high glucose alone, confirming a reduction of the hypertrophic state as per cell area measurement. Similarly, PG-901 (selective agonist, 10-10 M) significantly increased cell viability (+61,0 %) and reduced total protein per cell number (-40,2%), compared to cells exposed to high glucose alone. Interestingly, the MC5R agonist reduced the GLUT1/GLUT4 glucose transporters ratio on the cell membranes exhibited by the hypertrophic H9c2 cells and increased the intracellular PI3K activity, mediated by a decrease of the levels of the miRNA miR-133a. The beneficial effects of MC5R agonism on the cardiac hypertrophy caused by high glucose was also observed also by echocardiographic evaluations of rats made diabetics with streptozotocin (65 mg/kg i.p.). Therefore, the melanocortin MC5R could be a new target for the treatment of high glucose-induced hypertrophy of the cardiac H9c2 cells. PMID- 30416453 TI - Analysis of in situ Transcriptomes Reveals Divergent Adaptive Response to Hyper- and Hypo-Salinity in the Hong Kong Oyster, Crassostrea hongkongensis. AB - Crassostrea hongkongensis, a commercially valuable aquaculture species dwelling in estuaries along the coast of the South China Sea, is remarkable for its eurysalinity traits that enable its successful colonization of diverse osmotic niches ranging from near freshwater to seawater. In order to elucidate how this oyster copes with coastal waters with immense salinity differences, we performed in situ transcriptomic analysis (RNA-seq) to characterize the global expression patterns of oysters distributed across naturally formed salinity gradients in Zhenhai Bay along the northern coast of the South China Sea. Principal component analysis reveals distinct expression profiles of oysters living in the extreme conditions of hypo-salinity and hyper-salinity. Compared with the situation of optimal salinity for oyster growth, hypo-salinity mainly regulated expression of genes involved in FoxO and oxytocin signaling, tight junction and several immune pathways, while hyper-salinity altered gene expression implicated in amino acid metabolism, AMPK and PI3K-AKt signaling pathways, demonstrating the complexity and plasticity of transcriptomic expression underpinning oyster eurysalinity. Furthermore, the expression patterns of several genes correlated with salinity gradients reveals the fine-tuned coordination of molecular networks necessary for adaptive homeostasis in C. hongkongensis. In conclusion, a striking capacity and distinct patterns of transcriptomic expression contribute to eurysalinity adaptation in C. hongkongensis, which provides new mechanistic insights into the adaptive plasticity and resilience of marine mollusks. PMID- 30416454 TI - Diurnal Variation of Short-Term Repetitive Maximal Performance and Psychological Variables in Elite Judo Athletes. AB - Objectives: The aim of this study was to examine the effect of time of day on short-term repetitive maximal performance and psychological variables in elite judo athletes. Methods: Fourteen Tunisian elite male judokas (age: 21 +/- 1 years, height:172 +/- 7 cm, body-mass: 70.0 +/- 8.1 kg) performed a repeated shuttle sprint and jump ability (RSSJA) test (6 m * 2 m * 12.5 m every 25-s incorporating one countermovement jump (CMJ) between sprints) in the morning (7:00 a.m.) and afternoon (5:00 p.m.). Psychological variables (Profile of mood states (POMS-f) and Hooper questionnaires) were assessed before and ratings of perceived exertion (RPE) immediately after the RSSJA. Results: Sprint times (p > 0.05) of the six repetition, fatigue index of sprints (p > 0.05) as well as mean (p > 0.05) jump height and fatigue index (p > 0.05) of CMJ did not differ between morning and afternoon. No differences were observed between the two times-of-day for anxiety, anger, confusion, depression, fatigue, interpersonal relationship, sleep, and muscle soreness (p > 0.05). Jump height in CMJ 3 and 4 (p < 0.05) and RPE (p < 0.05) and vigor (p < 0.01) scores were higher in the afternoon compared to the morning. Stress was higher in the morning compared to the afternoon (p < 0.01). Conclusion: In contrast to previous research, repeated sprint running performance and mood states of the tested elite athletes showed no-strong dependency of time-of-day of testing. A possible explanation can be the habituation of the judo athletes to work out early in the morning. PMID- 30416456 TI - Corrigendum: Frequency-Specific Fractal Analysis of Postural Control Accounts for Control Strategies. AB - [This corrects the article DOI: 10.3389/fphys.2018.00293.]. PMID- 30416455 TI - The Mitochondrial Translocator Protein and the Emerging Link Between Oxidative Stress and Arrhythmias in the Diabetic Heart. AB - The mitochondrial translocator protein (TSPO) is a key outer mitochondrial membrane protein that regulates the activity of energy-dissipating mitochondrial channels in response to oxidative stress. In this article, we provide an overview of the role of TSPO in the systematic amplification of reactive oxygen species (ROS) through an autocatalytic process known as ROS-induced ROS-release (RIRR). We describe how this TSPO-driven process destabilizes the mitochondrial membrane potential leading to electrical instability at the cellular and whole heart levels. Finally, we provide our perspective on the role of TSPO in the pathophysiology of diabetes, in general and diabetes-related arrhythmias, in particular. PMID- 30416457 TI - The Factorial Structure of Trait Anxiety and Its Mediating Effect Between Mindfulness and Depression. AB - Background: Increasing studies have found that high trait anxiety is a key susceptibility phenotype that causes depression. Mindfulness-based interventions can target on dealing with depressogenic vulnerability effectively. Evidence indicates that trait anxiety could affect the trajectory of anti-depressive psychotherapy, and play an important role in the relationship between mindfulness and depression. Furthermore, related studies have found that trait anxiety could involve factors beyond anxiety and be a two-factor construct instead of one dimensional concept. This viewpoint provides a new prospective for exploring the pathways of the two factors of trait anxiety in the complex relationship and further understand the potential mechanism of vulnerable personality mediated the link of mindfulness and depression. Methods: A cross-sectional survey and a preliminary intervention study were conducted. Thousand two hundred and sixty-two subjects completed a set of self-reported questionnaires that evaluated trait anxiety, mindfulness, and depressive symptoms. Twenty-Three eligible participants with depression were recruited to attend mindfulness-based cognitive training for eight weeks. The same questionnaires were completed 1 week before the training and 6 months after the training. Factor analysis was performed on the 1262 subject sample to explore and confirm the factorial structure of trait anxiety. In addition, mediating effect analysis was conducted in the two studies to test whether two factors of trait anxiety were mediators of the relationship between mindfulness and depression. Results: The exploratory factor analysis extracted two dimensions of trait anxiety, namely, trait anxiety-present factor (TA-P) and trait anxiety-absent factor (TA-A). And confirmatory factor analysis showed that the fit of the two-factor model was acceptable. Both TA-P and TA-A were significantly negatively correlated with mindfulness and positively correlated with depression, and they played a mediating role between mindfulness and depression. The two factors of trait anxiety had multiple mediating effects on the relationship between mindfulness and depression, and the mediating effect of the TA-P factor was stronger than that of the TA-A factor. Conclusion: Our results demonstrated a two-factor model of trait anxiety in the Chinese population. TA-P and TA-A played a multiple mediating role in the relationship between mindfulness and depression. The findings provide new perspectives for psychological interventions to treat depression for people with susceptible personalities. Aiming to reduce negative emotional tendencies (TA-P factor) and enhance positive cognition (TA-A factor) may achieve the early prevention and efficient treatment of depression. PMID- 30416458 TI - The Moral Obligation to Prioritize Research Into Deep Brain Stimulation Over Brain Lesioning Procedures for Severe Enduring Anorexia Nervosa. AB - Deep Brain Stimulation is currently being investigated as an experimental treatment for patients suffering from treatment-refractory AN, with an increasing number of case reports and small-scale trials published. Although still at an exploratory and experimental stage, initial results have been promising. Despite the risks associated with an invasive neurosurgical procedure and the long-term implantation of a foreign body, DBS has a number of advantageous features for patients with SE-AN. Stimulation can be fine-tuned to the specific needs of the particular patient, is relatively reversible, and the technique also allows for the crucial issue of investigating and comparing the effects of different neural targets. However, at a time when DBS is emerging as a promising investigational treatment modality for AN, lesioning procedures in psychiatry are having a renaissance. Of concern it has been argued that the two kinds of interventions should instead be understood as rivaling, yet "mutually enriching paradigms" despite the fact that lesioning the brain is irreversible and there is no evidence base for an effective target in AN. We argue that lesioning procedures in AN are unethical at this stage of knowledge and seriously problematic for this patient group, for whom self-control is particularly central to wellbeing. They pose a greater risk of major harms that cannot justify ethical equipoise, despite the apparent superiority in reduced short term surgical harms and lower cost. PMID- 30416459 TI - Comparing Attitudes to Containment Measures of Patients, Health Care Professionals and Next of Kin. AB - Background: In clinical psychiatric practice, health care professionals (HCP) must decide in exceptional circumstances after the weighing of interests, which, if any, containment measures including coercion are to be used. Here, the risk for patients, staff, and third parties, in addition to therapeutic considerations, factor into the decision. Patients' preference and the inclusion of relatives in these decisions are important; therefore, an understanding of how patients and next of kin (NOK) experience different coercive measures is crucial for clinical decision making. The aim of this study is to compare how patients, HCP, and NOK assess commonly used coercive measures. Methods: A sample of 435 patients, 372 HCP, and 230 NOK completed the Attitudes to Containment Measures Questionnaire (ACMQ). This standardized self-rating questionnaire assessed the degree of acceptance or rejection of 11 coercive measures. Results: In general, HCPs rated the coercive measures as more acceptable than did NOK and patients. The largest discrepancy in the ratings was found in regard to the application of coercive intramuscular injection of medication (effect size: 1.0 HCP vs. patients). However, the ratings by NOK were significantly closer to the patients' ratings compared to patients and HCP. The only exception was the acceptance of treatment in a closed acute psychiatric ward, which was deemed significantly more acceptable by NOK than by patients. Also, patients who had experienced coercive measures themselves more strongly refused other measures. Conclusion: Patients most firmly rejected intramuscular injections, and the authors agree that these should only be used with reservation considering a high threshold. This knowledge about the discrepancy of the ratings should therefore be incorporated into professional training of HCP. PMID- 30416460 TI - Lower Income Levels in Australia Are Strongly Associated With Elevated Psychological Distress: Implications for Healthcare and Other Policy Areas. AB - Background: Australia is a high-income country with increasing income inequality. It is unclear whether Australia's well-developed mental healthcare system is making a difference to population mental health and the Federal Government has targeted outcomes accountability in service funding strategies. In high-income countries, evidence generally suggests that income inequalities increase mental disorders among the poor. This study examined psychological-distress rates-a marker of mental ill- health-as varying by income among Australians living within and outside of capital cities. Methods: Secondary data analysis was undertaken using the population-level mental health indicator of the Kessler Psychological Distress Scale (K10) as reported for 12,332 adults in the 2011/2012 National Health Survey (NHS) of Australia. K10 scores of 22 and higher indicated high/very high distress, and 30 and higher denoted very-high distress. Very-high distress levels are strongly predictive of serious mental illness. Results: Among the poorest one-fifth of Australians, 1 in 4 people have psychological distress at a high/very-high level; this compares to about 1 in 20 people in the richest one fifth of Australians. About 1-in-10 people making up the poorest one-fifth of Australians have current very-high distress, and this reduces to <1-in-50 people in the richest one-fifth. These disparities are consistent both within and outside of capital cities. The national prevalence of elevated distress within income quintiles varies greatly, with Poor/Rich Quintile Ratios of typically 4-5 for high/very-high levels and 7-8 for very-high levels. These effects operate more powerfully in areas marked by higher scores on the Index of Relative Socioeconomic Disadvantage. Conclusions: Altering the strong association of lower income levels in Australia with elevated psychological distress would require a multi-dimensional social policy and healthcare approach. To assess the effectiveness of adopted strategies, population level indicators need to be developed with regular data-collection. The Poor/Rich quintile ratio (P/R QR) for high/very high K10 scores is a potential candidate for a mental health inequality outcome indicator since it is easily calculated from data obtained from a regularly conducted national survey, is easily understood and resonates with a wider audience. Further research on the development of such indicators is also needed. PMID- 30416461 TI - Yield and Efficiency of Mental Disorder Screening at Intake to Prison: A Comparison of DIA-X Short- and Long-Screening-Protocols in Compensation Prisoners. AB - Background: Inmates are several times more likely to suffer from mental disorders than the general population.In order to take appropriate curative or preventive measures, a precise psychiatric diagnosis at detention start would therefore be imperative, but is frequently not carried out for reasons of time. The computer aided expert system DIA-X enables a rapid and reliable diagnosis of psychiatric disorders. DIA-X is available as a short screening questionnaire with a processing time of a few minutes and as a standardized interview, which takes ~1 h to complete. Objective: The aim of this study was to assess the efficiency and accuracy of the DIA-X short screening questionnaire. Methods: One hundred detainees were recruited randomly from compensation prisoners, who were imprisoned because they were unwilling or unable to pay a fine for committing a criminal offence, from the penal institution Berlin-Plotzensee in 2017. Both the short screening questionnaire and the standardized interview from the DIA-X expert system were used for diagnosing mental disorders. Based on the results of the standardized interview from four study populations of compensation prisoners from 1999, 2004, 2010, and 2017, the sensitivity, specificity and the predictive values of the screening form were inferred. Results: More than half of the compensation prisoners suffered from mental and behavioral disorders caused by the abuse of alcohol or psychoactive substances. Phobic anxiety disorders were detected in one out of ten compensation prisoners and two out of ten compensation prisoners suffered from major depressive disorders. The DIA-X screening questionnaire was able to detect all mental illnesses with a sensitivity of 100%. However, specificities were low for nicotine dependency, drug and alcohol abuse. High specificities and high predictive values were obtained for psychoses and anxiety disorders. Conclusions: As the main test quality criteria of the DIA-X screening forms were so low, we cannot recommend the application of the DIA-X screening form for obtaining a valid diagnosis. Therefore, we explicitly recommend using the long form DIA-X for the detection of the most serious cases of mental illness. Then, these prisoners could receive either therapy or special social training. PMID- 30416462 TI - The Effect of Moral Congruence of Calls to Action and Salient Social Norms on Online Charitable Donations: A Protocol Study. AB - Online advertising is an important tool that can be utilized by charities to elicit attention and funding. A critical examination of advertisement strategies is thus necessary to increase the efficacy of fundraising efforts. Previous studies have shown that individuals' moral views and perceptions of social norms can play important roles in charitable behavior. Thus, the current protocol describes a study to examine whether framing charitable advertisements in line with participants' morality and increasing the salience of descriptive social norms increases subsequent charitable behavior. We describe experimental, online methods, whereby participants are provided with a framed call-to-action and normative information within a custom-developed application or existing survey platform. Furthermore, in the exploratory fashion, we discuss the possibility of collecting participants' Facebook data and predicting moral profiles from this data. If there is an increased rate of donations as a result of moral compatibility and/or increased norm salience, charities can leverage this knowledge to increase the donations by tailoring their campaigns in a more appealing way for their prospective donors. Moreover, if it turns out to be possible to predict one's moral profile from Facebook footprints, charities can use this knowledge to find and target people that are more likely to support their cause. However, this introduces important ethical questions that are discussed within this protocol. PMID- 30416463 TI - Content Matters, a Qualitative Analysis of Verbal Hallucinations. AB - Auditory verbal hallucinations have traditionally especially been researched from a form-based approach, with content getting much less attention. In this article, we argue for the importance of looking at content to get a fuller understanding of the hallucinatory experience. Guided by Lacanian psychoanalysis, we conducted a thematic and a narrative analysis on interviews with 10 schizophrenic patients about their hallucinations. We discerned five themes in the data, which were based on Lacanian theory and had to do with existential questions: parenthood and authority, sexuality and relationships, gender identity, life in the light of death, and what does the other want? Furthermore, we added a theme for unclassified content. Narratively, we found that participants constructed a story of four steps about their hallucinatory experiences. These steps were disturbing events in the past posing an existential question, triggering event, period of confusion, and hearing voices that allude to existential themes. Participants succeed in different degrees in integrating their hallucinatory experiences in their own life history. These stories can be situated on a continuum by making use of three prototypical narrating styles: the meta-delusional, delusional, and chaotic narrative type. Overall, our analysis shows that hallucinations can both be thematically and narratively organized, by making use of a theoretical framework like Lacanian psychoanalysis. Our research demonstrates that hallucinatory contents are not random but are about existential issues imbedded in a life narrative. Future research would benefit of integrating content and form-based approaches. PMID- 30416464 TI - More Than Eggs - Relationship Between Productivity and Learning in Laying Hens. AB - The intense selection of chickens for production traits, such as egg laying, is thought to cause undesirable side effects and changes in behavior. Trade-offs resulting from energy expenditure in productivity may influence other traits: in order to sustain energetic costs for high egg production, energy expenditure may be redirected away from specific behavioral traits. For example, such energetic trade-offs may change the hens' cognitive abilities. Therefore, we hypothesized highly productive laying hens to show reduced learning performance in comparison to moderate productive lines. We examined the learning ability of four chicken lines that differed in laying performance (200 versus 300 eggs/year) and phylogenetic origin (brown/white layer; respectively, within performance). In total 61 hens were tested in semi-automated Skinner boxes in a three-phase learning paradigm (initial learning, reversal learning, extinction). To measure the hens' learning performance within each phase, we compared the number of active decisions needed to fulfill a learning criteria (80% correct choices for learning, 70% no responses at extinction) using linear models. Differences between the proportions of hens per line that reached criterion on each phase of the learning tasks were analyzed by using a Kaplan-Meier (KM) survival analysis. A greater proportion of high productive hens achieved the learning criteria on each phase compared to less productive hens (Chi2 3 = 8.25, p = 0.041). Furthermore, high productive hens accomplished the learning criteria after fewer active decisions in the initial phase (p = 0.012) and in extinction (p = 0.004) compared to the less selected lines. Phylogenetic origin was associated with differences in learning in extinction. Our results contradict our hypothesis and indicate that the selection for productivity traits has led to changes in learning behavior and the high productive laying hens possessed a better learning strategy compared to moderate productive hens in a feeding-rewarding context. This better performance may be a response to constraints resulting from high selection as it may enable these hens to efficiently acquire additional energy resources. Underlying mechanisms for this may be directly related to differences in neuronal structure or indirectly to foraging strategies and changes in personality traits such as fearfulness and sociality. PMID- 30416465 TI - Is Mindful Parenting Associated With Adolescents' Emotional Eating? The Mediating Role of Adolescents' Self-Compassion and Body Shame. AB - This study aimed to explore whether parents' mindful parenting skills were associated with adolescents' emotional eating through adolescents' levels of self compassion and body shame. The sample included 572 dyads composed of a mother or a father and his/her child (12-18 years old), with normal weight (BMI = 5-85th percentile) or with overweight/obesity with or without nutritional treatment (BMI >= 85th percentile) according to the WHO Child Growth Standards. Parents completed self-report measures of mindful parenting (Interpersonal Mindfulness in Parenting Scale), and adolescents completed measures of self-compassion (Self Compassion Scale-Short Form), body shame (Experience of Shame Scale), and emotional eating (Dutch Eating Behavior Questionnaire). Two path models, one with the total score for mindful parenting and the other with its dimensions, were tested in AMOS. Mindful parenting, specifically the dimension of compassion for the child, was indirectly associated with emotional eating through adolescents' self-compassion (point estimate = -0.27, p = 0.03, CI 95% [-0.61, -0.06]) and through self-compassion and body shame sequentially (point estimate = -0.19, p = 0.03, CI 95% [-0.37, -0.05]). The path model was invariant across weight groups but not across adolescents' sex (the indirect effects were significant among girls only). This study provides a novel comprehensive model of how mindful parenting, especially the dimension of compassion for the child, can be associated with adolescents' emotional eating behaviors by suggesting a potential sequence of mechanisms that may explain this association. This study suggests the beneficial effect of both mindful parenting and adolescents' self-compassion skills for adolescent girls struggling with feelings of body shame and emotional eating behaviors. PMID- 30416466 TI - Longitudinal Effects of Activity-Based Flexible Office Design on Teamwork. AB - This three-wave longitudinal interview study (time lag: 12 and 18 months) investigates the impact of working in an activity-based flexible office (A-FO) on processes within and across teams (i.e., communication, trust, cohesion, and collaboration) and team management. Based on a new theoretical framework on benefits and risks of A-FOs (A-FO-M; Wohlers and Hertel, 2017), we conducted interviews with 25 employees of an in-house training institute who recently switched from single cell or shared offices to an A-FO. The A-FO consisted of a main open-layout environment without assigned workstations and provided additional working zones appropriate for specific work activities. According to the A-FO-M, A-FO features are expected to alter visibility and proximity of employees compared to office environments with assigned workstations. Altered visibility and proximity, in turn, should be related to team processes, such as communication. The interview material was analyzed using qualitative content analysis. This textual analysis procedure revealed that the interviewees reported that inter-team collaboration improved while working in the A-FO. Reasons that were mentioned for this positive effect were more contact, communication, collaboration possibilities (joint project work), and trusting relationships. However, interviewees also reported negative effects, such as that teamwork suffered due to less communication and cooperation. Along with that, especially ensuring team cohesion and communication among team partners were the most often mentioned challenges for management since team members were spatially dispersed within the office building. Theoretical and practical implications, such as assigning additional team areas to support teamwork, as well as recommendations for future research are discussed. PMID- 30416468 TI - Detecting Temporal Cognition in Text: Comparison of Judgements by Self, Expert and Machine. AB - Background: There is a growing research focus on temporal cognition, due to its importance in memory and planning, and links with psychological wellbeing. Researchers are increasingly using diary studies, experience sampling and social media data to study temporal thought. However, it remains unclear whether such reports can be accurately interpreted for temporal orientation. In this study, temporal orientation judgements about text reports of thoughts were compared across human coding, automatic text mining, and participant self-report. Methods: 214 participants responded to randomly timed text message prompts, categorically reporting the temporal direction of their thoughts and describing the content of their thoughts, producing a corpus of 2505 brief (1-358, M = 43 characters) descriptions. Two researchers independently, blindly coded temporal orientation of the descriptions. Four approaches to automated coding used tense to establish temporal category for each description. Concordance between temporal orientation assessments by self-report, human coding, and automatic text mining was evaluated. Results: Human coding more closely matched self-reported coding than automated methods. Accuracy for human (79.93% correct) and automated (57.44% correct) coding was diminished when multiple guesses at ambiguous temporal categories (ties) were allowed in coding (reduction to 74.95% correct for human, 49.05% automated). Conclusion: Ambiguous tense poses a challenge for both human and automated coding protocols that attempt to infer temporal orientation from text describing momentary thought. While methods can be applied to minimize bias, this study demonstrates that researchers need to be wary about attributing temporal orientation to text-reported thought processes, and emphasize the importance of eliciting self-reported judgements. PMID- 30416469 TI - Enacting Phenomenological Gestalts in Ultra-Trail Running: An Inductive Analysis of Trail Runners' Courses of Experience. AB - Using an enactive approach to trail runners' activity, this study sought to identify and characterize runners' phenomenological gestalts, which are forms of experience that synthesize the heterogeneous sensorimotor, cognitive and emotional information that emerges in race situations. By an in-depth examination of their meaningful experiences, we were able to highlight the different typologies of interactions between bodily processes (e.g., sensations and pains), behaviors (e.g., actions and strategies), and environment (e.g., meteorological conditions and route profile). Ten non-professional runners who ran an ultra trail running race (330 km, 24,000 m of elevation gain) volunteered to participate in the study. Data were collected in two steps: (1) collection of past activity traces (i.e., race maps, field notes, and self-assessment scales) and (2) enactive interviews using the past activity traces in which the runners were invited to relive their experience and describe their activity. The enactive interviews were coded using the course-of-experience methodology to identify the phenomenological gestalts that emerged from activity and scaffolded the runners' courses of experience. The results revealed that runners typically enact three phenomenological gestalts: controlling global ease, enduring general fatigue and experiencing difficult situations, and feeling freedom in the running pace. These phenomenological gestalts were made up of specific behaviors, involvements, and meaningful situated elements that portrayed various ways of achieving an ultra endurance performance in the race situation. They also highlighted how runners enact a meaningful world by acting in relation to the fluctuations in physical sensations and environmental conditions during an ultra-trail race. Practical applications for preparation, race management and sports psychology interventions are proposed to enrich the existing recommendations. In conclusion, this approach provides new research perspectives by offering a more holistic grasp of activity in trail running through an in-depth analysis of athletes' experience. In doing so, we may expect that runners can connect these typical gestalts to their own personal experiences and stories as trail runners in order to sustain a viable approach to their sport. PMID- 30416467 TI - Gene * Environment Interaction in Developmental Disorders: Where Do We Stand and What's Next? AB - Although the field of psychiatry has witnessed the proliferation of studies on Gene * Environment (G*E) interactions, still limited is the knowledge we possess of G*E interactions regarding developmental disorders. In this perspective paper, we discuss why G*E interaction studies are needed to broaden our knowledge of developmental disorders. We also discuss the different roles of hazardous versus self-generated environmental factors and how these types of factors may differentially engage with an individual's genetic background in predicting a resulting phenotype. Then, we present examplar studies that highlight the role of G*E in predicting atypical developmental trajectories as well as provide insight regarding treatment outcomes. Supported by these examples, we explore the need to move beyond merely examining statistical interactions between genes and the environment, and the motivation to investigate specific genetic susceptibility and environmental contexts that drive developmental disorders. We propose that further parsing of genetic and environmental components is required to fully understand the unique contribution of each factor to the etiology of developmental disorders. Finally, with a greater appreciation of the complexities of G*E interaction, this discussion will converge upon the potential implications for clinical and translational research. PMID- 30416471 TI - Development of Emotional Skills in Adolescents to Prevent Cyberbullying and Improve Subjective Well-Being. AB - Bullying behavior alters the way in which students coexist together in the classroom and negatively affects adolescents' well-being. Research highlights the importance of emotional skills in promoting positive youth development and optimal social functioning. Therefore, education in these skills is a potential target for interventions aimed at reducing cyberbullying and promoting satisfaction with life during adolescence. This study analyzes the impact of an emotion education program in adolescents to promote classroom coexistence and well-being. The sample comprised 148 students from 7th and 8th grade of secondary school aged between 12 and 15 years (M age = 12.63, SD age = 0.74; 57% girls). A quasi-experimental design with longitudinal data collection was used in this study with randomized classroom assignment to the experimental group and the control group. The intervention program was based on the emotional intelligence model of Mayer and Salovey (1997). Its objective was to develop adolescents' emotional skills to improve the quality of interpersonal relationships and reduce conflicts between peers, positively influencing coexistence and well-being. The intervention took place in eleven sessions during school hours over a period of 3 months. Participants completed the emotional competence questionnaire, the cyberbullying scale and the life satisfaction scale before (T1), immediately after (T2), and 6 months after the intervention (T3). The results showed that the intervention program reduced victimization and assault via mobile phones and the Internet in T2 and T3. In the follow-up (T3), the intervention group had enhanced emotional perception and regulation skills and reported an increase in life satisfaction in comparison to the control group. Our findings suggest that implementing classroom intervention programs to develop students' emotional competencies could be beneficial for their subjective well-being and peer coexistence. PMID- 30416472 TI - Imprecise Uncertain Reasoning: A Distributional Approach. AB - The contribution proposes to model imprecise and uncertain reasoning by a mental probability logic that is based on probability distributions. It shows how distributions are combined with logical operators and how distributions propagate in inference rules. It discusses a series of examples like the Linda task, the suppression task, Doherty's pseudodiagnosticity task, and some of the deductive reasoning tasks of Rips. It demonstrates how to update distributions by soft evidence and how to represent correlated risks. The probabilities inferred from different logical inference forms may be so similar that it will be impossible to distinguish them empirically in a psychological study. Second-order distributions allow to obtain the probability distribution of being coherent. The maximum probability of being coherent is a second-order criterion of rationality. Technically the contribution relies on beta distributions, copulas, vines, and stochastic simulation. PMID- 30416470 TI - Low-Resolution Place and Response Learning Capacities in Down Syndrome. AB - Down syndrome (DS), the most common genetic cause of intellectual disability, results from the partial or complete triplication of chromosome 21. Individuals with DS are impaired at using a high-resolution, allocentric spatial representation to learn and remember discrete locations in a controlled environment. Here, we assessed the capacity of individuals with DS to perform low resolution spatial learning, depending on two competing memory systems: (1) the place learning system, which depends on the hippocampus and creates flexible relational representations of the environment; and (2) the response learning system, which depends on the striatum and creates fixed stimulus-response representations of behavioral actions. Individuals with DS exhibited a preservation of the low-resolution spatial learning capacities subserved by these two systems. In place learning, although the average performance of individuals with DS was lower than that of typically developing (TD) mental age (MA)-matched children and TD young adults, the number of individuals with DS performing above chance level did not differ from TD children. In response learning, the average performance of individuals with DS was lower than that of TD adults, but it did not differ from that of TD children. Moreover, the number of individuals with DS performing above chance level did not differ from TD adults, and was higher than that of TD children. In sum, whereas low-resolution place learning appears relatively preserved in individuals with DS, response learning appears facilitated. Our findings are consistent with the hypothesis that the neural pathways supporting low-resolution place learning and response learning are relatively preserved in DS. PMID- 30416473 TI - Human Observers and Automated Assessment of Dynamic Emotional Facial Expressions: KDEF-dyn Database Validation. AB - Most experimental studies of facial expression processing have used static stimuli (photographs), yet facial expressions in daily life are generally dynamic. In its original photographic format, the Karolinska Directed Emotional Faces (KDEF) has been frequently utilized. In the current study, we validate a dynamic version of this database, the KDEF-dyn. To this end, we applied animation between neutral and emotional expressions (happy, sad, angry, fearful, disgusted, and surprised; 1,033-ms unfolding) to 40 KDEF models, with morphing software. Ninety-six human observers categorized the expressions of the resulting 240 video clip stimuli, and automated face analysis assessed the evidence for 6 expressions and 20 facial action units (AUs) at 31 intensities. Low-level image properties (luminance, signal-to-noise ratio, etc.) and other purely perceptual factors (e.g., size, unfolding speed) were controlled. Human recognition performance (accuracy, efficiency, and confusions) patterns were consistent with prior research using static and other dynamic expressions. Automated assessment of expressions and AUs was sensitive to intensity manipulations. Significant correlations emerged between human observers' categorization and automated classification. The KDEF-dyn database aims to provide a balance between experimental control and ecological validity for research on emotional facial expression processing. The stimuli and the validation data are available to the scientific community. PMID- 30416474 TI - Context-Dependent Risk Aversion: A Model-Based Approach. AB - Most research on risk aversion in behavioral science with human subjects has focused on a component of risk aversion that does not adapt itself to context. More recently, studies have explored risk aversion adaptation to changing circumstances in sequential decision-making tasks. It is an open question whether one can identify evidence, at the single subject level, for such risk aversion adaptation. We conducted a behavioral experiment on human subjects, using a sequential decision making task. We developed a model-based approach for estimating the adaptation of risk-taking behavior with single-trial resolution by modeling a subject's goals and internal representation of task contingencies. Using this model-based approach, we estimated the subject-specific adaptation of risk aversion depending on the current task context. We found striking inter subject variations in the adaptation of risk-taking behavior. We show that these differences can be explained by differences in subjects' internal representations of task contingencies and goals. We discuss that the proposed approach can be adapted to a wide range of experimental paradigms and be used to analyze behavioral measures other than risk aversion. PMID- 30416475 TI - Learning From Elite Athletes' Experience of Depression. AB - Sport has become increasingly aware of the challenges associated with Mental Disorders and, to a greater extent, mental health issues (MHIs). This study sought to explore in depth the subjective experiences of elite athletes who suffered from a specific clinical MHI, namely depression. In addition, we explored their perceptions of the prevalence and stigma surrounding MHIs in elite sport environments. Data were collected from four elite athletes (1 female and 3 males; 2 team and 2 individual sports) using semi-structured interviews and analysed using Interpretative Phenomenological Analysis. Participants described both sport and non-sport related triggers in regard to their depression (e.g., institutional mistreatment and bullying, injuries, previous MHI, and miscarriage), as well as a range of behaviour, performance (e.g., decline), and personality changes compared to their normal functioning. Although the participants stressed the widespread prevalence of MHIs in elite sport, they also acknowledged the stigma associated with MHIs in high-level sport environments and its detrimental role for athletes. This study has important practical and diagnostic implications, and highlights the need for further research to assess the extent and scope of clinical MHIs in sport as well as to inform the care for this unique population. PMID- 30416476 TI - Multiple Dissociations in Patients With Disorders of Body Awareness: Implications for the Study of Consciousness. PMID- 30416477 TI - Groups and Emotional Arousal Mediate Neural Synchrony and Perceived Ritual Efficacy. AB - We present the first neurophysiological signatures showing distinctive effects of group social context and emotional arousal on cultural perceptions, such as the efficacy of religious rituals. Using a novel protocol, EEG data were simultaneously recorded from ethnic Chinese religious believers in group and individual settings as they rated the perceived efficacy of low, medium, and high arousal spirit-medium rituals presented as video clips. Neural oscillatory patterns were then analyzed for these perceptual judgements, categorized as low, medium, and high efficacy. The results revealed distinct neural signatures and behavioral patterns between the experimental conditions. Arousal levels predicted ratings of ritual efficacy. Increased efficacy was marked by suppressed alpha and beta power, regardless of group or individual setting. In groups, efficacy ratings converged. Individual setting showed increased within-participant phase synchronization in alpha and beta bands, while group setting enhanced between participant theta phase synchronization. This reflected group participants' orientation toward a common perspective and social coordination. These findings suggest that co-presence in groups leads to a social-tuning effect supported by between-participant theta phase synchrony. Together these neural synchrony patterns reveal how collective rituals have both individual and communal dimensions. The emotionality of spirit-medium rituals drives individual perceptions of efficacy, while co-presence in groups signals the significance of an event and socially tunes enhanced agreement in perceptual ratings. In other words, mass gatherings may foster social cohesion without necessarily requiring group-size scaling limitations of direct face-to-face interaction. This could have implications for the scaling computability of synchrony in large groups as well as for humanistic studies in areas such as symbolic interactionism. PMID- 30416479 TI - Editorial: Neuroimaging of Affective Empathy and Emotional Communication. PMID- 30416478 TI - Position as Well as Velocity Dependence of Spasticity-Four-Dimensional Characterizations of Catch Angle. AB - We investigated the muscle alterations related to spasticity in stroke quantitatively using a portable manual spasticity evaluator. Methods: Quantitative neuro-mechanical evaluations under controlled passive elbow stretches in stroke survivors and healthy controls were performed in a research laboratory of a rehabilitation hospital. Twelve stroke survivors and nine healthy controls participated in the study. Spasticity and catch angle were evaluated at 90 degrees /s and 270 degrees /s with the velocities controlled through real-time audiovisual feedback. The elbow range of motion (ROM), stiffness, and energy loss were determined at a slow velocity of 30 degrees /s. Four-dimensional measures including joint position, torque, velocity and torque change rate were analyzed jointly to determine the catch angle. Results: The catch angle was dependent on the stretch velocity and occurred significantly later with increasing velocity (p < 0.001), indicating position dependence of spasticity. The higher resistance felt by the examiner at the higher velocity was also due to more extreme joint position (joint angle) since the spastic joint was moved significantly further to a stiffer elbow position with the higher velocity. Stroke survivors showed smaller ROM (p < 0.001), higher stiffness (p < 0.001), and larger energy loss (p = 0.005). Compared to the controls, stroke survivors showed increased reflex excitability with higher reflex-mediated torque (p < 0.001) and at higher velocities (p = 0.02). Conclusion: Velocity dependence of spasticity is partially due to joint angle position dependence with the joint moved further (to a stiffer position where higher resistance was felt) at a higher velocity. The "4 dimensional characterization" including the joint angle, velocity, torque, and torque change rate provides a systematic tool to characterize catch angle and spasticity quantitatively. PMID- 30416480 TI - Measuring Habitual Arm Use Post-stroke With a Bilateral Time-Constrained Reaching Task. AB - Background: Spontaneous use of the more-affected arm is a meaningful indicator of stroke recovery. The Bilateral Arm Reaching Test (BART) was previously developed to quantify arm use by measuring arm choice to targets projected over a horizontal hemi-workspace. In order to improve clinical validity, we constrained the available movement time, thereby promoting more spontaneous decision making when selecting between the more-affected and less affected arm during the BART. Methods: Twenty-two individuals with mild to moderate hemiparesis were tested with the time-based BART in three time-constraint conditions: no-time constraint, medium, and fast conditions. Arm use was measured across three sessions with a 2 week interval in a spontaneous choice block, in which participants were instructed to use either the more-affected or the less-affected arm to reach targets. We tested the effect of time-constraint condition on the more-affected arm use, external validity of the BART with the Actual Amount of Use Test (AAUT), and test-retest reliability across the three test sessions. Results: The fast condition in the time-based BART showed reduced use of the more-affected arm compared to the no-time constraint condition P < 0.0001) and the medium condition P = 0.0006; Tukey post hoc analysis after mixed-effect linear regression). In addition, the fast condition showed strong correlation with the AAUT r = 0.829, P < 0.001), and excellent test-retest reliability (ICC = 0.960, P < 0.0001). Conclusion: The revised BART with a time-restricted fast condition provides an objective, accurate, and repeatable measure of spontaneous arm use in individuals with chronic stroke hemiparesis. PMID- 30416482 TI - Clinical Features of Probable Cluster Headache: A Prospective, Cross-Sectional Multicenter Study. AB - Background: Epidemiological data of probable cluster headaches (CH) are scarce in the relevant literature. Here, we sought to assess the prevalence and clinical characteristics of probable CH in comparison with definite CH. Methods: Data used in this study were obtained from the Korean Cluster Headache Registry (KCHR), a prospective, cross-sectional, multicenter headache registry that collected data from consecutive patients diagnosed with CH. Results: In total, 159 patients were enrolled in this study; 20 (12.6%) were diagnosed with probable CH. The most common unfulfilled criterion in patients with probable CH was the duration of attack, which was found in 40% of patients with probable CH. Among clinical characteristics, the number of autonomic symptoms tended to be lower in probable CH than in definite CH (1.7 +/- 1.2 vs. 2.4 +/- 1.5, p = 0.051) and conjunctival injection and lacrimation showed an increased odds ratio (OR) [OR = 3.03; 95% confidence interval (CI): 1.03-8.33] in definite CH. The groups did not differ with regard to baseline demographic characteristics, disability, impact on life, or treatment response. Conclusions: Probable CH is relatively common among CH disorders, with a clinical impact similar to that of definite CH. PMID- 30416483 TI - ED Referral Dramatically Reduces Delays of Initial Evaluation in a French TIA Clinic. AB - Background: The risk of recurrent brain infarction (BI) is high within the first hours after a transient ischemic attack (TIA). Emergent, specialized, and tailored patient management in a TIA program reduces the risk of recurrent BI after TIA by 80%. New antithrombotic strategies have been successfully tested within 12 h after TIA onset. We aim to investigate the factors associated with a delay of more than 12 h from TIA onset to evaluation in our TIA clinic. Methods: In consecutive patients evaluated in our TIA clinic from 01/2012 to 11/2013, we prospectively collected delays from onset to arrival, baseline characteristics, discharge diagnosis and recurrent BI at 1 week. Referring pathways were dichotomized between office-based physicians (OBP) and emergency departments (ED). Univariate and multivariate logistic regression were performed. Results: 354 patients were evaluated. Mean (+/- SD) age was 61 years (+/-18). Median (IQR) ABCD2 score was 3 (2-4). Median (IQR) delay from onset to evaluation was 8 h (4 48). Overall, 185 (52%) were referred by OBP vs. 169 (48%) by ED. Evaluation was initiated within 12 h among 201 (57%) patients. After logistic regression, OBP referral was by comparison with ED the only independent factor associated with an evaluation delay >12 h (OR 5.7, 95% CI: 3.5-9.3, p < 0.0001). Conclusion: Our results suggest that preliminary assessment by OBP may increase the delay to initiate the emergent evaluation of TIA patients. Promoting direct admission to TIA clinics through ED may be an efficient alternative for high risk TIAs. PMID- 30416484 TI - Somatic SMARCB1 Mutation in Sporadic Multiple Meningiomas: Case Report. AB - Background: Multiple intracranial meningiomas account for <10% of all meningiomas. Familial multiple meningiomas have been linked to germline mutations in two genes: neurofibromatosis type 2 (NF2) and SWIch/Sucrose Non-Fermentable (SWI/SNF)-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1). Sporadic multiple meningiomas have been associated with somatic NF2 mutations and, to date, there has been no case related to somatic SMARCB1 mutations. Here, we describe the first case. Case Report: A 45-year-old female suffered a head trauma while snowboarding. Subsequent to her injury, she experienced persistent headache, nausea, vomiting, dizziness, and flashing lights in the right eye. Magnetic resonance imaging (MRI) of her brain revealed multiple intracranial meningiomas. She underwent a two staged craniotomy to remove frontal/parietal/temporal and occipital extra-axial tumors. Pathology confirmed the masses as meningiomas, WHO Grade I. Tumor genetic testing was positive for SMARCB1 mutation but blood genetic testing was negative for SMARCB1 mutation. Conclusion: In sporadic multiple meningiomas, somatic NF2 mutations are usually the suspected genetic alternations. Our case illustrates that somatic SMARCB1 mutation is another genetic risk factor for sporadic multiple meningiomas, albeit rare. PMID- 30416481 TI - Sensorimotor Manipulations of the Balance Control Loop-Beyond Imposed External Perturbations. AB - Standing balance relies on the integration of multiple sensory inputs to generate the motor commands required to stand. Mechanical and sensory perturbations elicit compensatory postural responses that are interpreted as a window into the sensorimotor processing involved in balance control. Popular methods involve imposed external perturbations that disrupt the control of quiet stance. Although these approaches provide critical information on how the balance system responds to external disturbances, the control mechanisms involved in correcting for these errors may differ from those responsible for the regulation of quiet standing. Alternative approaches use manipulations of the balance control loop to alter the relationship between sensory and motor cues. Coupled with imposed perturbations, these manipulations of the balance control loop provide unique opportunities to reveal how sensory and motor signals are integrated to control the upright body. In this review, we first explore imposed perturbation approaches that have been used to investigate the neural control of standing balance. We emphasize imposed perturbations that only elicit balance responses when the disturbing stimuli are relevant to the balance task. Next, we highlight manipulations of the balance control loop that, when carefully implemented, replicate and/or alter the sensorimotor dynamics of quiet standing. We further describe how manipulations of the balance control loop can be used in combination with imposed perturbations to characterize mechanistic principles underlying the control of standing balance. We propose that recent developments in the use of robotics and sensory manipulations will continue to enable new possibilities for simulating and/or altering the sensorimotor control of standing beyond compensatory responses to imposed external perturbations. PMID- 30416485 TI - Real-Time MRI Guidance for Reproducible Hyperosmolar Opening of the Blood-Brain Barrier in Mice. AB - The blood-brain barrier (BBB) prevents effective delivery of most therapeutic agents to the brain. Intra-arterial (IA) infusion of hyperosmotic mannitol has been widely used to open the BBB and improve parenchymal targeting, but the extent of BBB disruption has varied widely with therapeutic outcomes often being unpredictable. In this work, we show that real-time MRI can enable fine-tuning of the infusion rate to adjust and predict effective and local brain perfusion in mice, and thereby can be allowed for achieving the targeted and localized BBB opening (BBBO). Both the reproducibility and safety are validated by MRI and histology. The reliable and reproducible BBBO we developed in mice will allow cost-effective studies on the biology of the BBB and drug delivery to the brain. In addition, the IA route for BBBO also permits subsequent IA delivery of a specific drug during the same procedure and obtains high targeting efficiency of the therapeutic agent in the targeted tissue, which has great potential for future clinical translation in neuro-oncology, regenerative medicine and other neurological applications. PMID- 30416487 TI - Aglycemic HepG2 Cells Switch From Aminotransferase Glutaminolytic Pathway of Pyruvate Utilization to Complete Krebs Cycle at Hypoxia. AB - Human hepatocellular carcinoma HepG2 cells are forced to oxidative phosphorylation (OXPHOS), when cultured in aglycemic conditions at galactose and glutamine. These Oxphos cells represent a prototype of cancer cell bioenergetics with mixed aerobic glycolysis and OXPHOS. We aimed to determine fractions of (i) glutaminolytic pathway involving aminotransferase reaction supplying 2 oxoglutarate (2OG) to the Krebs cycle vs. (ii) active segment of the Krebs cycle with aconitase and isocitrate dehydrogenase-3 (ACO-IDH3), which is typically inactive in cancer cells due to the citrate export from mitochondria. At normoxia, Oxphos cell respiration was decreased down to ~15 and ~10% by the aminotransferase inhibitor aminooxyacetate (AOA) or with AOA plus the glutamate dehydrogenase inhibitor bithionol, respectively. Phosphorylating to non phosphorylating respiration ratios dropped from >6.5 to 1.9 with AOA and to zero with AOA plus bithionol. Thus, normoxic Oxphos HepG2 cells rely predominantly on glutaminolysis. Addition of membrane-permeant dimethyl-2-oxoglutarate (dm2OG) to inhibited cells instantly partially restored respiration, evidencing the lack of 2OG-dehydrogenase substrate upon aminotransferase inhibition. Surprisingly, after 72 hr of 5% O2 hypoxia, the AOA (bithionol) inhibition ceased and respiration was completely restored. Thus in aglycemic HepG2 cells, the hypoxia-induced factor (HIF) upregulation of glycolytic enzymes enabled acceleration of glycolysis pathway, preceded by galactolysis (Leloir pathway), redirecting pyruvate via still incompletely blocked pyruvate dehydrogenase toward the ACO-IDH3. Glycolytic flux upregulation at hypoxia was evidently matched by a higher activity of the Leloir pathway in Oxphos cells. Hypoxic Oxphos cells increased 2-fold the NADPH oxidase activity, whereas hypoxic glycolytic cells decreased it. Oxphos cells and glycolytic cells at 5 mM glucose decreased their reduced glutathione fraction. In contrast to aglycemic cells, glycolytic HepG2 cells decreased their respiration at hypoxia despite the dm2OG presence, i.e., even at unlimited respiratory substrate availability for 72 hr at 5% O2, exhibiting the canonical HIF-mediated adaptation. Nevertheless, their ATP content was much higher with dm2OG as compared to its absence during hypoxic adaptation. Thus, the metabolic plasticity of cancer cells is illustrated under conditions frequently established for solid tumors in vivo, such as aglycemia plus hypoxia. Consequently, a wide acceptance of the irreversible and exclusive Warburg phenotype in cancer cells is incorrect. PMID- 30416488 TI - The Conserved Cys-2232 in Clostridioides difficile Toxin B Modulates Receptor Binding. AB - Clostridioides difficile toxins TcdA and TcdB are large clostridial glucosyltransferases which are the main pathogenicity factors in C. difficile associated diseases. Four highly conserved cysteines are present in all large clostridial glucosyltransferases. In this study we focused on the conserved cysteine 2232 within the combined repetitive oligopeptide domain of TcdB from reference strain VPI10463 (clade I). Cysteine 2232 is not present in TcdB from hypervirulent strain R20291 (clade II), where a tyrosine is found instead. Replacement of cysteine 2232 by tyrosine in TcdBV PI10463 reduced binding to the soluble fragments of the two known TcdB receptors, frizzled-2 (FZD2) and poliovirus receptor-like protein-3/nectin-3 (PVRL3). In line with this, TcdBR20291 showed weak binding to PVRL3 in pull-down assays which was increased when tyrosine 2232 was exchanged for cysteine. Surprisingly, we did not observe binding of TcdBR20291 to FZD2, indicating that this receptor is less important for this toxinotype. Competition assay with the receptor binding fragments (aa 1101-1836) of TcdBV PI10463 and TcdBR20291, as well as antibodies newly developed by antibody phage display, revealed different characteristics of the yet poorly described delivery domain of TcdB harboring the second receptor binding region. In summary, we found that conserved Cys-2232 in TcdB indirectly contributes to toxin-receptor interaction. PMID- 30416486 TI - The Divergent Function of Androgen Receptor in Breast Cancer; Analysis of Steroid Mediators and Tumor Intracrinology. AB - Androgen receptor (AR) is the most widely expressed steroid receptor protein in normal breast tissue and is detectable in approximately 90% of primary breast cancers and 75% of metastatic lesions. However, the role of AR in breast cancer development and progression is mired in controversy with evidence suggesting it can either inhibit or promote breast tumorigenesis. Studies have shown it to antagonize estrogen receptor alpha (ERalpha) DNA binding, thereby preventing pro proliferative gene transcription; whilst others have demonstrated AR to take on the mantle of a pseudo ERalpha particularly in the setting of triple negative breast cancer. Evidence for a potentiating role of AR in the development of endocrine resistant breast cancer has also been mounting with reports associating high AR expression with poor response to endocrine treatment. The resurgence of interest into the function of AR in breast cancer has resulted in various emergent clinical trials evaluating anti-AR therapy and selective androgen receptor modulators in the treatment of advanced breast cancer. Trials have reported varied response rates dependent upon subtype with overall clinical benefit rates of ~19-29% for anti-androgen monotherapy, suggesting that with enhanced patient stratification AR could prove efficacious as a breast cancer therapy. Androgens and AR have been reported to facilitate tumor stemness in some cancers; a process which may be mediated through genomic or non-genomic actions of the AR, with the latter mechanism being relatively unexplored in breast cancer. Steroidogenic ligands of the AR are produced in females by the gonads and as sex-steroid precursors secreted from the adrenal glands. These androgens provide an abundant reservoir from which all estrogens are subsequently synthesized and their levels are undiminished in the event of standard hormonal therapeutic intervention in breast cancer. Steroid levels are known to be altered by lifestyle factors such as diet and exercise; understanding their potential role in dictating the function of AR in breast cancer development could therefore have wide-ranging effects in prevention and treatment of this disease. This review will outline the endogenous biochemical drivers of both genomic and non genomic AR activation and how these may be modulated by current hormonal therapies. PMID- 30416489 TI - Characterization of the Microbiome at the World's Largest Potable Water Reuse Facility. AB - Conventional water resources are not sufficient in many regions to meet the needs of growing populations. Due to cyclical weather cycles, drought, and climate change, water stress has increased worldwide including in Southern California, which serves as a model for regions that integrate reuse of wastewater for both potable and non-potable use. The Orange County Water District (OCWD) Advanced Water Purification Facility (AWPF) is a highly engineered system designed to treat and produce up to 100 million gallons per day (MGD) of purified water from a municipal wastewater source for potable reuse. Routine facility microbial water quality analysis is limited to standard indicators at this and similar facilities. Given recent advances in high throughput DNA sequencing techniques, complete microbial profiling of communities in water samples is now possible. By using 16S/18S rRNA gene sequencing, metagenomic and metatranscriptomic sequencing coupled to a highly accurate identification method along with 16S rRNA gene qPCR, we describe a detailed view of the total microbial community throughout the facility. The total bacterial load of the water at stages of the treatment train ranged from 3.02 * 106 copies in source, unchlorinated wastewater feed to 5.49 * 101 copies of 16S rRNA gene/mL after treatment (consisting of microfiltration, reverse osmosis, and ultraviolet/advanced oxidation). Microbial diversity and load decreased by several orders of magnitude after microfiltration and reverse osmosis treatment, falling to almost non-detectable levels that more closely resembled controls of molecular grade laboratory water than the biomass detected in the source water. The presence of antibiotic resistance genes and viruses was also greatly reduced. Overall, system design performance was achieved, and comprehensive microbial community analysis was found to enable a more complete characterization of the water/wastewater microbial signature. PMID- 30416491 TI - Identification of Enolase as the Target of 2-Aminothiazoles in Mycobacterium tuberculosis. AB - Tuberculosis is a massive global burden and Mycobacterium tuberculosis is increasingly resistant to first- and second-line drugs. There is an acute need for new anti-mycobacterial drugs with novel targets. We previously evaluated a series of 2-aminothiazoles with activity against Mycobacterium tuberculosis. In this study, we identify the glycolytic enzyme enolase as the target of these molecules using pull down studies. We demonstrate that modulation of the level of enolase expression affects sensitivity to 2-aminothiazoles; increased expression leads to resistance while decreased protein levels increase sensitivity. Exposure to 2-aminothiazoles results in increased levels of metabolites preceding the action of enolase in the glycolytic pathway and decreased ATP levels. We demonstrate that 2-aminothiazoles inhibit the activity of the human alpha enolase, which could also account for the cytotoxicity of some of those molecules. If selectivity for the bacterial enzyme over the human enzyme could be achieved, enolase would represent an attractive target for M. tuberculosis drug discovery and development efforts. PMID- 30416490 TI - Recombinant Protein Expression System in Corynebacterium glutamicum and Its Application. AB - Corynebacterium glutamicum, a soil-derived gram-positive actinobacterium, has been widely used for the production of biochemical molecules such as amino acids (i.e., L-glutamate and L-lysine), nucleic acids, alcohols, and organic acids. The metabolism of the bacterium has been engineered to increase the production of the target biochemical molecule, which requires a cytosolic enzyme expression. As recent demand for new proteinaceous biologics (such as antibodies, growth factors, and hormones) increase, C. glutamicum is attracting industrial interest as a recombinant protein expression host for therapeutic protein production due to the advantages such as low protease activity without endotoxin activity. In this review, we have summarized the recent studies on the heterologous expression of the recombinant protein in C. glutamicum for metabolic engineering, expansion of substrate availability, and recombinant protein secretion. We have also outlined the advances in genetic components such as promoters, surface anchoring systems, and secretory signal sequences in C. glutamicum for effective recombinant protein expression. PMID- 30416492 TI - Structural and Functional Interrogation of Selected Biological Nitrogen Removal Systems in the United States, Denmark, and Singapore Using Shotgun Metagenomics. AB - Conventional biological nitrogen removal (BNR), comprised of nitrification and denitrification, is traditionally employed in wastewater treatment plants (WWTPs) to prevent eutrophication in receiving water bodies. More recently, the combination of selective ammonia to nitrite oxidation (nitritation) and autotrophic anaerobic ammonia oxidation (anammox), collectively termed deammonification, has also emerged as a possible energy- and cost-effective BNR alternative. Herein, we analyzed microbial diversity and functional potential within 13 BNR processes in the United States, Denmark, and Singapore operated with varying reactor configuration, design, and operational parameters. Using next-generation sequencing and metagenomics, gene-coding regions were aligned against a custom protein database expanded to include all published aerobic ammonia oxidizing bacteria (AOB), nitrite oxidizing bacteria (NOB), anaerobic ammonia oxidizing bacteria (AMX), and complete ammonia oxidizing bacteria (CMX). Overall contributions of these N-cycle bacteria to the total functional potential of each reactor was determined, as well as that of several organisms associated with denitrification and/or structural integrity of microbial aggregates (biofilm or granules). The potential for these engineered processes to foster a broad spectrum of microbial catabolic, anabolic, and carbon assimilation transformations was elucidated. Seeded sidestream DEMON(r) deammonification systems and single-stage nitritation-anammox moving bed biofilm reactors (MBBRs) and a mainstream Cleargreen reactor designed to enrich in AOB and AMX showed lower enrichment in AMX functionality than an enriched two-stage nitritation anammox MBBR system treating mainstream wastewater. Conventional BNR systems in Singapore and the United States had distinct metagenomes, especially relating to AOB. A hydrocyclone process designed to recycle biomass granules for mainstream BNR contained almost identical structural and functional characteristics in the overflow, underflow, and inflow of mixed liquor (ALT) rather than the expected selective enrichment of specific nitrifying or AMX organisms. Inoculum used to seed a sidestream deammonification process unexpectedly contained <10% of total coding regions assigned to AMX. These results suggest the operating conditions of engineered bioprocesses shape the resident microbial structure and function far more than the bioprocess configuration itself. We also highlight the advantage of a systems- and metagenomics-based interrogation of both the microbial structure and potential function therein over targeting of individual populations or specific genes. PMID- 30416493 TI - An Investigation of an Acute Gastroenteritis Outbreak: Cronobacter sakazakii, a Potential Cause of Food-Borne Illness. AB - Whole genome sequencing (WGS) has been widely used in traceability of food-borne outbreaks nowadays. Here, an interesting connection between Cronobacter sakazakii and food-borne acute gastroenteritis (AGE) was noticed. In October 2016, an AGE outbreak affecting 156 cases occurred in a local senior high school. Case-control study including 70 case-patients and 295 controls indicated a strong association between eating supper at school canteen of the outbreak onset and AGE, as revealed by the Odds Ratio (OR: 95.32). Six recovered Cronobacter strains were evaluated and compared using pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST) and WGS. A phylogenetic tree of whole genomic single nucleotide polymorphisms (wgSNPs) were generated to traceback the potential contamination source in this outbreak. C. sakazakii isolates S2 from a patient's rectal swab and S4 from leftover food sample shared identical PFGE pattern and sequence type (ST73), and clustered tightly together in the SNP phylogenetic tree. C. sakazakii isolates S5 and S6 from food delivery containers were both ST4 but with different PFGE patterns. Cronobacter isolates S1 and S3 from two patients' rectal swab were sequenced to be C. malonaticus and shared another PFGE pattern (ST567). The interesting feature of this study was the implication of C. sakazakii as a causative agent in food-borne AGE occurring in healthy adults, although C. sakazakii is considered as an opportunistic pathogen and generally affects neonates, infants and immunocompromised adults. PMID- 30416494 TI - Prediction of Antimicrobial Potential of a Chemically Modified Peptide From Its Tertiary Structure. AB - Designing novel antimicrobial peptides is a hot area of research in the field of therapeutics especially after the emergence of resistant strains against the conventional antibiotics. In the past number of in silico methods have been developed for predicting the antimicrobial property of the peptide containing natural residues. This study describes models developed for predicting the antimicrobial property of a chemically modified peptide. Our models have been trained, tested and evaluated on a dataset that contains 948 antimicrobial and 931 non-antimicrobial peptides, containing chemically modified and natural residues. Firstly, the tertiary structure of all peptides has been predicted using software PEPstrMOD. Structure analysis indicates that certain type of modifications enhance the antimicrobial property of peptides. Secondly, a wide range of features was computed from the structure of these peptides using software PaDEL. Finally, models were developed for predicting the antimicrobial potential of chemically modified peptides using a wide range of structural features of these peptides. Our best model based on support vector machine achieve maximum MCC of 0.84 with an accuracy of 91.62% on training dataset and MCC of 0.80 with an accuracy of 89.89% on validation dataset. To assist the scientific community, we have developed a web server called "AntiMPmod" which predicts the antimicrobial property of the chemically modified peptide. The web server is present at the following link (http://webs.iiitd.edu.in/raghava/antimpmod/). PMID- 30416495 TI - The MAP Kinase SsKpp2 Is Required for Mating/Filamentation in Sporisorium scitamineum. AB - In the phytopathogenic fungus Sporisorium scitamineum, sexual mating between two compatible haploid cells and the subsequent formation of dikaryotic hyphae is essential for infection. This process was shown to be commonly regulated by a mitogen-activated protein kinase (MAPK) and a cAMP/PKA signaling pathway in the corn smut fungus Ustilago maydis but remains largely unknown in S. scitamineum. In this study, we identified a conserved putative MAP kinase Kpp2 in S. scitamineum and named it as SsKpp2. The sskpp2Delta mutant displayed significant reduction in mating/filamentation, which could be partially restored by addition of cAMP or tryptophol, a quorum-sensing molecule identified in budding yeast. Transcriptional profiling showed that genes governing S. scitamineum mating or tryptophol biosynthesis were significantly differentially regulated in the sskpp2Delta mutant compared to the WT, under mating condition. Our results demonstrate that the MAP kinase SsKpp2 is required for S. scitamineum mating/filamentation likely through regulating the conserved pheromone signal transduction pathway and tryptophol production. PMID- 30416496 TI - Complex Effects of Cytochrome P450 Monooxygenase on Purple Membrane and Bacterioruberin Production in an Extremely Halophilic Archaeon: Genetic, Phenotypic, and Transcriptomic Analyses. AB - Halophilic archaea are known to produce a diverse array of pigments for phototrophy and photoprotection. The aim of this paper was to determine the role of a Halobacterium gene encoding the predicted cytochrome P450 monooxygenase (CYP174A1) in pigment synthesis through a combined genetic, phenotypic, and transcriptomic approach. We report on the observed phenotype changes [increased bacterioruberin levels and the loss of purple membrane (PM)] between the Halobacterium salinarum R1 and its CYP174A1-deletion mutant. In addition, we report on the whole-genome DNA microarray analysis, which supports the phenotype of PM loss. This work expands our understanding of the bop-gene regulon, and its relation to carotenoid biosynthesis, and sheds light on our broader understanding of the role (s) of CYP174A1 in archaeal pigment synthesis. To date, this is the first study in which the physiological role of any cytochrome P450 monooxygenase (CYP450) in extremely halophilic archaea has been reported. PMID- 30416497 TI - Organic Particles: Heterogeneous Hubs for Microbial Interactions in Aquatic Ecosystems. AB - The dynamics and activities of microbes colonizing organic particles (hereafter particles) greatly determine the efficiency of the aquatic carbon pump. Current understanding is that particle composition, structure and surface properties, determined mostly by the forming organisms and organic matter, dictate initial microbial colonization and the subsequent rapid succession events taking place as organic matter lability and nutrient content change with microbial degradation. We applied a transcriptomic approach to assess the role of stochastic events on initial microbial colonization of particles. Furthermore, we asked whether gene expression corroborates rapid changes in carbon-quality. Commonly used size fractionated filtration averages thousands of particles of different sizes, sources, and ages. To overcome this drawback, we used replicate samples consisting each of 3-4 particles of identical source and age and further evaluated the consequences of averaging 10-1000s of particles. Using flow-through rolling tanks we conducted long-term experiments at near in situ conditions minimizing the biasing effects of closed incubation approaches often referred to as "the bottle-effect." In our open flow-through rolling tank system, however, active microbial communities were highly heterogeneous despite an identical particle source, suggesting random initial colonization. Contrasting previous reports using closed incubation systems, expression of carbon utilization genes didn't change after 1 week of incubation. Consequently, we suggest that in nature, changes in particle-associated community related to carbon availability are much slower (days to weeks) due to constant supply of labile, easily degradable organic matter. Initial, random particle colonization seems to be subsequently altered by multiple organismic interactions shaping microbial community interactions and functional dynamics. Comparative analysis of thousands particles pooled togethers as well as pooled samples suggests that mechanistic studies of microbial dynamics should be done on single particles. The observed microbial heterogeneity and inter-organismic interactions may have important implications for evolution and biogeochemistry in aquatic systems. PMID- 30416498 TI - PredT4SE-Stack: Prediction of Bacterial Type IV Secreted Effectors From Protein Sequences Using a Stacked Ensemble Method. AB - Gram-negative bacteria use various secretion systems to deliver their secreted effectors. Among them, type IV secretion system exists widely in a variety of bacterial species, and secretes type IV secreted effectors (T4SEs), which play vital roles in host-pathogen interactions. However, experimental approaches to identify T4SEs are time- and resource-consuming. In the present study, we aim to develop an in silico stacked ensemble method to predict whether a protein is an effector of type IV secretion system or not based on its sequence information. The protein sequences were encoded by the feature of position specific scoring matrix (PSSM)-composition by summing rows that correspond to the same amino acid residues in PSSM profiles. Based on the PSSM-composition features, we develop a stacked ensemble model PredT4SE-Stack to predict T4SEs, which utilized an ensemble of base-classifiers implemented by various machine learning algorithms, such as support vector machine, gradient boosting machine, and extremely randomized trees, to generate outputs for the meta-classifier in the classification system. Our results demonstrated that the framework of PredT4SE Stack was a feasible and effective way to accurately identify T4SEs based on protein sequence information. The datasets and source code of PredT4SE-Stack are freely available at http://xbioinfo.sjtu.edu.cn/PredT4SE_Stack/index.php. PMID- 30416499 TI - Manifold Routes to a Nucleus. AB - It is widely assumed that there is a clear distinction between eukaryotes, with cell nuclei, and prokaryotes, which lack nuclei. This suggests the evolution of nuclear compartmentation is a singular event. However, emerging knowledge of the diversity of bacterial internal cell structures suggests the picture may not be as black-and-white as previously thought. For instance, some members of the bacterial PVC superphylum appear to have nucleus-like compartmentation, where transcription and translation are physically separated, and some jumbophages have recently been shown to create nucleus-like structures within their Pseudomonad hosts. Moreover, there is also tantalizing metagenomic identification of new Archaea that carry homologs of genes associated with internal cell membrane structure in eukaryotes. All these cases invite comparison with eukaryote cell biology. While the bacterial cases of genetic compartmentation are likely convergent, and thus viewed by many as not germane to the question of eukaryote origins, we argue here that, in addressing the broader question of the evolution of compartmentation, other instances are at least as important: they provide us with a point of comparison which is critical for a more general understanding of both the conditions favoring the emergence of intracellular compartmentation of DNA and the evolutionary consequences of such cellular architecture. Finally, we consider three classes of explanation for the emergence of compartmentation: physical protection, crosstalk avoidance and nonadaptive origins. PMID- 30416500 TI - Immunoproteasome Inhibition Impairs T and B Cell Activation by Restraining ERK Signaling and Proteostasis. AB - Immunoproteasome (IP) inhibition holds potential as a novel treatment option for various immune-mediated pathologies. The IP inhibitor ONX 0914 reduced T cell cytokine secretion and Th17 polarization and showed pre-clinical efficacy in a range of autoimmune disorders, transplant-allograft rejection, virus-mediated tissue damage, and colon cancer progression. However, the molecular basis of these effects has remained largely elusive. Here, we have analyzed the effects of ONX 0914 in primary human and mouse lymphocytes. ONX 0914-treatment impaired primary T cell activation in vitro and in vivo. IP inhibition reduced ERK phosphorylation sustainment, while leaving NF-kappaB and other signaling pathways unaffected. Naive T and B cells expressed nearly exclusively immuno- or mixed proteasomes but no standard proteasomes and IP inhibition but not IP-deficiency induced mild proteostasis stress, reduced DUSP5 expression and enhanced DUSP6 protein levels due to impaired degradation. However, accumulation of DUSP6 did not cause the reduced ERK-phosphorylation in a non-redundant manner. We show that broad-spectrum proteasome inhibition and immunoproteasome inhibition have distinct effects on T cell activation at the molecular level. Notably, ONX 0914 treated T cells recovered from proteostasis stress without apoptosis induction, apparently via Nrf1-mediated up-regulation of standard proteasomes. In contrast, B cells were more susceptible to apoptosis after ONX 0914-treatment. Our data thus provide mechanistic insights how IP inhibition functionally impedes T and B cells likely accounting for its therapeutic benefits. PMID- 30416501 TI - Protein Inhibitor of Activated STAT (PIAS) Negatively Regulates the JAK/STAT Pathway by Inhibiting STAT Phosphorylation and Translocation. AB - Protein inhibitor of activated STAT (PIAS) proteins are activation-suppressing proteins for signal transducer and activator of transcription (STAT), which involves gene transcriptional regulation. The inhibitory mechanism of PIAS proteins in the Janus kinase (JAK)/STAT signaling pathway has been well studied in mammals and Drosophila. However, the roles of PIAS in crustaceans are unclear. In the present study, we identified PIAS in kuruma shrimp Marsupenaeus japonicus and found that its relative expression could be induced by Vibrio anguillarum stimulation. To explore the function of PIAS in shrimp infected with V. anguillarum, we performed an RNA interference assay. After knockdown of PIAS expression in shrimp subjected to V. anguillarum infection, bacterial clearance was enhanced and the survival rate increased compared with those in the control shrimp (dsGFP injection). Simultaneously, the expression levels of antimicrobial peptides (AMPs), including anti-lipopolysaccharide factor (ALF) A1, C1, C2, and CruI-1, increased. Further study revealed that knockdown of PIAS also enhanced STAT phosphorylation and translocation. Pulldown assay indicated that PIAS interacts with activated STAT in shrimp. In conclusion, PIAS negatively regulates JAK/STAT signaling by inhibiting the phosphorylation and translocation of STAT through the interaction between PIAS and STAT, which leads to the reduction of AMP expression in shrimp. Our results revealed a new mechanism of PIAS-mediated gene regulation of the STAT signal pathway. PMID- 30416503 TI - Modulation of Antibody Responses to the V1V2 and V3 Regions of HIV-1 Envelope by Immune Complex Vaccines. AB - Prophylactic HIV vaccines must elicit antibodies (Abs) against the virus envelope glycoproteins (Env) to effectively prevent HIV infection. We investigated a vaccine platform that utilizes immune complexes made of Env proteins gp120 and monoclonal Abs (mAbs) against different gp120 epitopes. We previously observed alterations in V3 antigenicity upon formation of certain gp120/mAb complexes and demonstrated the ability of these complexes to modulate the elicitation of V3 Ab responses. However, the effects on the V1V2 domain, an important target for Abs that correlate with vaccine-induced protection against HIV, have not been studied, nor have immune complex vaccines made with non-B subtype Env. This study compared subtypes B (JRFL) and CRF_01.AE (A244) Env gp120 proteins in complex with selected gp120-specific mAbs. Allosteric and antigenic changes were detected on these immune complexes, indicating that gp120/mAb interaction induces alterations on the Env surface that may modify the Env immunogenic properties. To evaluate this idea, mice were immunized with gp120/mAb complexes or their uncomplexed gp120 counterparts. The overall serum IgG titers elicited against gp120 were comparable, but a marked skewing toward V1V2 or V3 was evident and dependent on the gp120 strain and the specificity of the mAb used to form the complexes. Compared with uncomplexed gp120JRFL, gp120JRFL complexed with CD4bs or V1V2 mAbs, but not with C2 or V3 mAbs, elicited V3 Abs of greater titers and breadth, and Abs more capable of neutralizing tier 1 virus. Epitope mapping revealed a shift to a more conserved site in the V3 crown. However, the complexes did not enhance V1V2 Ab response, and the elicited V1V2 Abs were not cross reactive. This profile contrasts with Ab responses to gp120A244/mAb complexes. Notably, gp120A244/mAb complexes induced higher levels of V1V2 Abs with some cross-reactivity, while also stimulating weak or strain-specific V3 Abs. Sera from gp120A244/mAb complex-immunized animals displayed no measurable virus neutralization but did mediate Ab-dependent cellular phagocytosis, albeit at levels similar to that induced by gp120A244 alone. These data indicate the potential utility of immune complexes as vaccines to shape Ab responses toward or away from Env sites of interest. PMID- 30416502 TI - Innate Lymphoid Cells in the Maternal and Fetal Compartments. AB - Pregnancy success is orchestrated by the complex balance between the maternal and fetal immune systems. Herein, we summarize the potential role of innate lymphoid cells (ILCs) in the maternal and fetal compartments. We reviewed published literature describing different ILC subsets [ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer (LTi) cells] in the uterus, decidua, fetal tissues [liver, secondary lymphoid organs (SLO), intestine, and lung] and amniotic cavity. ILC1s, ILC2s, and ILC3s are present in the murine uterus prior to and during pregnancy but have only been detected in the non-pregnant endometrium in humans. Specifically, ILC2s reside in the murine uterus from mid-pregnancy to term, ILC1s increase throughout gestation, and ILC3s remain constant. Yet, LTi cells have only been detected in the non-pregnant murine uterus. In the human decidua, ILC1s, ILC3s, and LTi-like cells are more abundant during early gestation, whereas ILC2s increase at the end of pregnancy. Decidual ILC1s were also detected during mid-gestation in mice. Interestingly, functional decidual ILC2s and ILC3s increased in women who underwent spontaneous preterm labor, indicating the involvement of such cells in this pregnancy complication. Fetal ILCs exist in the liver, SLO, intestine, lung, and amniotic cavity. The fetal liver is thought to be the source of ILC progenitors since the differentiation of these cells from hematopoietic stem cells occurs at this site, and mature ILC subsets can be found in this compartment as well. The interaction between LTi cells and specialized stromal cells is important during the formation of SLO. Mature ILCs are found at the mucosal surfaces of the lung and intestine, from where they can extravasate into the amniotic cavity. Amniotic fluid ILCs express high levels of RORgammat, CD161, and CD103, hallmarks of ILC3s. Such cells are more abundant in the second trimester than later in gestation. Although amniotic fluid ILC3s produce IL-17A and TNFalpha, indicating their functionality, their numbers in patients with intra-amniotic infection/inflammation remain unchanged compared to those without this pregnancy complication. Collectively, these findings suggest that maternal (uterine and decidual) ILCs play central roles in both the initiation and maintenance of pregnancy, and fetal ILCs participate in the development of immunity. PMID- 30416504 TI - CD169+ Macrophages Capture and Dendritic Cells Instruct: The Interplay of the Gatekeeper and the General of the Immune System. AB - Since the seminal discovery of dendritic cells (DCs) by Steinman and Cohn in 1973, there has been an ongoing debate to what extent macrophages and DCs are related and perform different functions. The current view is that macrophages and DCs originate from different lineages and that only DCs have the capacity to initiate adaptive immunity. Nevertheless, as we will discuss in this review, lymphoid tissue resident CD169+ macrophages have been shown to act in concert with DCs to promote or suppress adaptive immune responses for pathogens and self antigens, respectively. Accordingly, we propose a functional alliance between CD169+ macrophages and DCs in which a division of tasks is established. CD169+ macrophages are responsible for the capture of pathogens and are frequently the first cell type infected and thereby provide a confined source of antigen. Subsequently, cross-presenting DCs interact with these antigen-containing CD169+ macrophages, pick up antigens and activate T cells. The cross-priming of T cells by DCs is enhanced by the localized production of type I interferons (IFN-I) derived from CD169+ macrophages and plasmacytoid DCs (pDCs) that induces DC maturation. The interaction between CD169+ macrophages and DCs appears not only to be essential for immune responses against pathogens, but also plays a role in the induction of self-tolerance and immune responses against cancer. In this review we will discuss the studies that demonstrate the collaboration between CD169+ macrophages and DCs in adaptive immunity. PMID- 30416506 TI - Expanding the Therapeutic Window for CAR T Cell Therapy in Solid Tumors: The Knowns and Unknowns of CAR T Cell Biology. AB - A major obstacle for chimeric antigen receptor (CAR) T cell therapy in solid tumors is the lack of truly tumor-specific target antigens, which translates to the targeting of tumor-associated antigens (TAAs) overexpressed on tumors but shared with normal organs, raising safety concerns. In addition, expression of TAAs in solid tumors is particularly heterogeneous. In this regard, it is critical to deeply understand the sensitivity of CAR T cells, especially against low-density targets and the possible therapeutic window of antigen density targeted by CAR T cells. In this review, we discuss the recent findings of mechanisms of antigen recognition through CAR, including immunological synapse formation, and the impact of target antigen density for induction of distinct T cell functions. We also discuss rational strategies to adjust and expand the therapeutic window for effective and safe targeting of solid tumors by CAR T cell platforms. PMID- 30416509 TI - Association between the level of CD4+ T lymphocyte microRNA-155 and coronary artery disease in patients with unstable angina pectoris. AB - Objective: To study the association between the expression of microRNA-155 (miRNA 155) in peripheral blood CD4+ T lymphocytes and the level of serum interferon gamma (IFN-gamma) concentration and the severity of coronary artery disease (CAD). Methods: After coronary angiography, 252 patients with suspected unstable angina pectoris (UAP) were divided into the UAP group (128 patients with CAD confirmed by angiography) and the control group (124 patients without CAD confirmed by angiography). Fresh peripheral blood was extracted 16-24 h before coronary angiography, CD4+ T lymphocytes was tested using immunomagnetic beads, the expression of miRNA-155 was tested using quantitative PCR and the expression of IFN-gamma was tested using enzyme-linked immunosorbent assay (ELISA). According to the results of angiography, Gensini score of coronary artery lesions was analyzed. Furthermore, we also analysis the association between the level of miRNA-155 in peripheral blood CD4+ T lymphocytes, the level of serum IFN-gamma and Gensini score of coronary lesion. Results: The levels of miRNA-155 (0.49 +/- 0.08 vs. 0.23 +/- 0.09) and IFN-gamma (227.58 +/- 26.01 vs. 141.23 +/- 17.89) in the UAP group were significantly higher than that of the control group, the difference was statistically significant. The level of miRNA-155 and IFN-gamma were positively correlated with Gensini score of CAD (r = 0.534, r = 0.713, respectively, all P < 0.05). The level of miRNA-155 was positively correlated with the level of IFN-gamma (r = 0.686, P < 0.05). Conclusions: The level of miRNA-155 in peripheral blood CD4+ T lymphocytes and the level of IFN-gamma are closely correlated with the severity of CAD. PMID- 30416505 TI - Induction of Tolerogenic Dendritic Cells by Endogenous Biomolecules: An Update. AB - The importance of microenvironment on dendritic cell (DC) function and development has been strongly established during the last two decades. Although DCs with general tolerogenic characteristics have been isolated and defined as a particular sub-population, it is predominantly their unequivocal biological plasticity, which allows for unparalleled responsiveness to environmental ques and shaping of their tolerogenic characteristics when interacting with tolerance inducing biomolecules. Dendritic cells carry receptors for a great number of endogenous factors, which, after ligation, can importantly influence the development of their activation state. For this there is ample evidence merely by observation of DC characteristics isolated from various anatomical niches, e.g., the greater immunosuppressive potential of DCs isolated from intestine compared to conventional blood DCs. Endogenous biomolecules present in these environments most likely play a major role as a determinant of their phenotype and function. In this review, we will concisely summarize in what way various, tolerance inducing endogenous factors influence DC biology, the development of their particular tolerogenic state and their subsequent actions in context of immune response inhibition and induction of regulatory T cells. PMID- 30416508 TI - Novel Traits, Flower Symmetry, and Transcriptional Autoregulation: New Hypotheses From Bioinformatic and Experimental Data. AB - A common feature in developmental networks is the autoregulation of transcription factors which, in turn, positively or negatively regulate additional genes critical for developmental patterning. When a transcription factor regulates its own expression by binding to cis-regulatory sites in its gene, the regulation is direct transcriptional autoregulation (DTA). Indirect transcriptional autoregulation (ITA) involves regulation by proteins expressed downstream of the target transcription factor. We review evidence for a hypothesized role of DTA in the evolution and development of novel flowering plant phenotypes. We additionally provide new bioinformatic and experimental analyses that support a role for transcriptional autoregulation in the evolution of flower symmetry. We find that 5' upstream non-coding regions are significantly enriched for predicted autoregulatory sites in Lamiales CYCLOIDEA genes-an upstream regulator of flower monosymmetry. This suggests a possible correlation between autoregulation of CYCLOIDEA and the origin of monosymmetric flowers near the base of Lamiales, a pattern that may be correlated with independently derived monosymmetry across eudicot lineages. We find additional evidence for transcriptional autoregulation in the flower symmetry program, and report that Antirrhinum DRIF2 may undergo ITA. In light of existing data and new data presented here, we hypothesize how cis-acting autoregulatory sites originate, and find evidence that such sites (and DTA) can arise subsequent to the evolution of a novel phenotype. PMID- 30416510 TI - Repeated measurement of growth-differentiation factor-15 in Chinese Han patients with post-myocardial infarction chronic heart failure. AB - Background: Growth-differentiation factor-15 (GDF-15) is a promising prognostic biomarker in patients with chronic heart failure (CHF). Comparatively little is known about the value of repeated measurement of GDF-15 with CHF in Chinese Han population. This study sought to identify the clinical value of repeated measurement of GDF-15 in Chinese Han patients with post-myocardial infarction CHF. Methods: In total, 232 consecutive Chinese Han patients with post-myocardial infarction CHF were enrolled prospectively from January 2014 to June 2016.The plasma concentration of GDF-15 was determined on admission and over 12 months. Patients were followed up for all-cause death and a composite outcome of major adverse cardiac events (MACE) included all-cause death, myocardial infarction and first heart failure (HF) re-hospitalization. Association with other clinical variables and adverse outcomes of repeated measurement of GDF-15 was explored. Results: The median baseline GDF-15 level was 2025 ng/L. Baseline GDF-15 was moderately associated with baseline N-terminal pro-B type natriuretic peptide (NT proBNP) (coefficient 0.561, P < 0.001). During a median follow-up of 20 months, there were 53 deaths and 100MACE. GDF-15 remained an independent predictor of all cause death (adjusted hazard ratio 1.826 per 1 Ln U, 95% CI: 1.037-8.360; P = 0.037) and MACE (adjusted hazard ratio 2.243 per 1 Ln U, 95% CI: 1.181-1.775; P < 0.001) adjusted for established risk factors. Repeated measurement of GDF-15 was performed in 173 survivals over 12months. Increase of GDF-15 over 12 months was associated with dilatation of left ventricle and acted as an independent predictor of subsequent all-cause death (adjusted HR = 3.164, 95% CI: 1.245 0.041; P = 0.015). In the joint model, GDF-15 was also shown to be a risk factor for all-cause death (HR = 2.749, 95% CI: 1.667-3.831; P < 0.001) and MACE (HR = 2.434, 95% CI: 1.425-3.443; P < 0.001). Conclusions: Repeated measurements of GDF 15 have promising prognostic value of the risk of all-cause death in Chinese Han patients with CHF post-myocardial infarction. GDF-15 may influence the post myocardial infarction CHF through the path physiological pathway of myocardial remodeling. PMID- 30416511 TI - Analyses of risk factors and prognosis for new-onset atrial fibrillation in elderly patients after dual-chamber pacemaker implantation. AB - Objective: To retrospectively identify risk factors and the prognosis for new onset atrial fibrillation (AF) after implantation of dual-chamber pacemakers in elderly patients. Methods: Consecutive patients aged >= 65 years who underwent their first implantation of a dual-chamber permanent pacemaker in Beijing Anzhen Hospital from October 2013 to May 2016 were enrolled. Their complete programming and follow-up data were recorded. Follow-up end points included new-onset AF and major adverse cardiovascular and cerebrovascular events. Results: Altogether, 322 patients were enrolled, with new-onset AF observed in 79 (24.5%) during their follow-up. Multivariable analysis identified four independent predictors of new onset AF in elderly patients after pacemaker implantation: hypertension (HR = 3.040, 95% CI: 1.09-3.05, P = 0.00); age (HR = 1.966, 95% CI: 1.57-3.68, P = 0.01); left atrial enlargement (HR = 1.645, 95% CI: 1.05-1.25, P = 0.03); high ventricular pacing rate (HR = 1.137, 95% CI: 1.01-1.06, P = 0.01). Univariable analysis indicated that the CHA2DS2-VASc score was also a risk factor for AF (HR = 1.368, 95% CI: 1.178-1.589, P = 0.002), whereas multivariable regression analysis did not. Kaplan-Meier survival analysis showed that the risk for ischemic stroke was significantly higher in the new-onset AF group than in the non-AF group (P < 0.05). Conclusion: Hypertension, age, left atrial enlargement, and high ventricular pacing rate were independent predictors of new-onset AF in elderly patients after implantation of a permanent pacemaker. New-onset AF increased the risk for ischemic stroke. PMID- 30416507 TI - The Pro-tumorigenic IL-33 Involved in Antitumor Immunity: A Yin and Yang Cytokine. AB - Interleukin-33 (IL-33), considered as an alarmin released upon tissue stress or damage, is a member of the IL-1 family and binds the ST2 receptor. First described as a potent initiator of type 2 immune responses through the activation of T helper 2 (TH2) cells and mast cells, IL-33 is now also known as an effective stimulator of TH1 immune cells, natural killer (NK) cells, iNKT cells, and CD8 T lymphocytes. Moreover, IL-33 was shown to play an important role in several cancers due to its pro and anti-tumorigenic functions. Currently, IL-33 is a possible inducer and prognostic marker of cancer development with a direct effect on tumor cells promoting tumorigenesis, proliferation, survival, and metastasis. IL-33 also promotes tumor growth and metastasis by remodeling the tumor microenvironment (TME) and inducing angiogenesis. IL-33 favors tumor progression through the immune system by inducing M2 macrophage polarization and tumor infiltration, and upon activation of immunosuppressive cells such as myeloid derived suppressor cells (MDSC) or regulatory T cells. The anti-tumor functions of IL-33 also depend on infiltrated immune cells displaying TH1 responses. This review therefore summarizes the dual role of this cytokine in cancer and suggests that new proposals for IL-33-based cancer immunotherapies should be considered with caution. PMID- 30416512 TI - Transradial supra-aortic arteries interventions: a good option for elderly patients. PMID- 30416513 TI - Double-vessel very late stent thrombosis following Resolute Onyx zotarolimus eluting stents implantation in an octogenarian. PMID- 30416514 TI - Orthostatic hypotension, an often-neglected problem in community-dwelling older people: discrepancies between studies and real life. PMID- 30416515 TI - Successful capture of red thrombus in acute inferior ST-elevation myocardial infarction. PMID- 30416516 TI - Superior sinus venosus atrial septal defect. PMID- 30416517 TI - Successful occluding by absorbable sutures for epicardial collateral branch perforation. PMID- 30416518 TI - Structural Properties and Reactive Site Selectivity of Some Transition Metal Complexes of 2,2'(1E,1'E)-(ethane-1,2-diylbis(azan-1-yl-1 ylidene))bis(phenylmethan-1-yl-1-ylidene)dibenzoic Acid: DFT, Conceptual DFT, QTAIM, and MEP Studies. AB - Herein is presented a density functional theory (DFT) study of reactivity and structural properties of transition metal complexes of the Schiff base ligand 2,2'(1E,1'E)-(ethane-1,2-diylbis(azan-1-yl-1-ylidene))bis(phenylmethan-1-yl-1 ylidene)dibenzoic acid (hereafter denoted EDA2BB) with Cu(II), Mn(II), Ni(II), and Co(II). The quantum theory of atoms-in-molecules (QTAIM), conceptual DFT, natural population analysis (NPA), and molecular electrostatic potential (MEP) methods have been used. Results have revealed a distorted octahedral geometry around the central metal ion in each gas phase complex. In the DMSO solvent, a general axial elongation of metal-oxygen bonds involving ancillary water ligands has been observed, suggestive of loosely bound water molecules to the central metal ion that may be acting as solvent molecules. Weak, medium, and strong intramolecular hydrogen bonds along with hydrogen-hydrogen and van der Waals interactions have been elucidated in the complexes investigated via geometric and QTAIM analyses. From the chemical hardness values, the complex [Co(EDA2BB)(OH2)2] is the hardest, while [Cu(EDA2BB)(OH2)2] is the softest. Based on the global electrophilicity index, the complexes [Ni(EDA2BB)(OH2)2] and [Cu(EDA2BB)(OH2)2] are the strongest and weakest electrophiles, respectively, among the complexes studied. In conclusion, the reactivity of the complexes is improved vis-a-vis the ligand, and stable geometries of the complexes are identified, alongside their prominent electrophilic and nucleophilic sites. PMID- 30416519 TI - Information-Based Boundary Equilibrium Generative Adversarial Networks with Interpretable Representation Learning. AB - This paper describes a new image generation algorithm based on generative adversarial network. With an information-theoretic extension to the autoencoder based discriminator, this new algorithm is able to learn interpretable representations from the input images. Our model not only adversarially minimizes the Wasserstein distance-based losses of the discriminator and generator but also maximizes the mutual information between small subset of the latent variables and the observation. We also train our model with proportional control theory to keep the equilibrium between the discriminator and the generator balanced, and as a result, our generative adversarial network can mitigate the convergence problem. Through the experiments on real images, we validate our proposed method, which can manipulate the generated images as desired by controlling the latent codes of input variables. In addition, the visual qualities of produced images are effectively maintained, and the model can stably converge to the equilibrium. However, our model has a difficulty in learning disentangling factors because our model does not regularize the independence between the interpretable factors. Therefore, in the future, we will develop a generative model that can learn disentangling factors. PMID- 30416520 TI - Pilot Study on Gait Classification Using fNIRS Signals. AB - Rehabilitation training is essential for motor dysfunction patients, and the training through their subjective motion intention, comparing to passive training, is more conducive to rehabilitation. This study proposes a method to identify motion intention of different walking states under the normal environment, by using the functional near-infrared spectroscopy (fNIRS) technology. Twenty-two healthy subjects were recruited to walk with three different gaits (including small-step with low-speed, small-step with midspeed, midstep with low-speed). The wavelet packet decomposition was used to find out the main characteristic channels in different motion states, and these channels with links in frequency and space were combined to define as feature vectors. According to different permutations and combinations of all feature vectors, a library for support vector machines (libSVM) was used to achieve the best recognition model. Finally, the accuracy rate of these three walking states was 78.79%. This study implemented the classification of different states' motion intention by using the fNIRS technology. It laid a foundation to apply the classified motion intention of different states timely, to help severe motor dysfunction patients control a walking-assistive device for rehabilitation training, so as to help them restore independent walking abilities and reduce the economic burdens on society. PMID- 30416521 TI - Corrigendum to "Pregabalin Effect on Acute and Chronic Pain after Cardiac Surgery". AB - [This corrects the article DOI: 10.1155/2017/2753962.]. PMID- 30416522 TI - Palmitic Acid Downregulates Thyroglobulin (Tg), Sodium Iodide Symporter (NIS), and Thyroperoxidase (TPO) in Human Primary Thyrocytes: A Potential Mechanism by Which Lipotoxicity Affects Thyroid? AB - Our previous studies suggested that the thyroid might be a target organ affected by lipotoxicity, which might be partially related to the increasing prevalence of subclinical hypothyroidism. However, the underlying molecular mechanism is not yet clearly established. This study aimed to assess the effect of palmitic acid stimulation on thyrocyte function. Upon palmitic acid stimulation, intracellular contents of lipids, as well as the expression and activity of three key molecules in thyroid hormone synthesis (i.e., thyroglobulin, sodium iodide symporter, and thyroperoxidase), were determined in human primary thyrocytes. The contents of BODIPY(r) FL C16 (the fluorescently labeled palmitic acid analogue) entering into the thyrocytes were gradually increased with time extending. Accordingly, the intracellular accumulation of both triglyceride and free fatty acids increased in dose- and time-dependent manners. The effect of palmitic acid stimulation on thyroid hormone synthesis was then determined. Both the mRNA and protein levels of thyroglobulin, sodium iodide symporter, and thyroperoxidase were decreased following palmitic acid stimulation. Consistently, upon palmitic acid stimulation, the secreted thyroglobulin levels in supernatants, 131I uptake, and extracellular thyroperoxidase activity were all decreased in a dose-dependent manner. Our results demonstrated that upon palmitic acid stimulation, the expressions of the key molecules (thyroglobulin, sodium iodide symporter, and thyroperoxidase) were reduced and their activities were suppressed, which might lead to impaired thyroid hormone synthesis. PMID- 30416523 TI - The Epidemiology and Trend of Cancer in Jordan, 2000-2013. AB - Objectives: This study aimed to determine the overall incidence, trend, and epidemiology of cancer among Jordanians from 2000 to 2013 using data extracted from Jordan's Cancer Registry (JCR). Methods: All cancer cases among Jordanians registered between 2000 and 2013 were analyzed using CanReg software and SPSS. The overall crude incidence rates (CIRs) and the age standardized rates (ASRs) of cancer per 100,000 were calculated. Results: A total of 58788 cancer cases were registered during the period 2000-2013. Of those, 28545 (48.6%) were males and 30243 (51.4%) were females. About three-quarters (77.3%) of the registered patients were >= 40 years in age. Overall, the average crude cancer incidence rate was 82.8/100,000 population during the 14-year study period. On the other hand, the ASR was 126/100,000 during the same period (124.2 /100,000 for males and 128.4 /100,000 for females). The cumulative top cancers among males were colorectal, lung, lymphoma, urinary bladder, and prostate, respectively, while those among females were breast, colorectal, lymphoma, thyroid, and uterine. The number of cancer cases has increased from 3370 in 2000 to 5409 in 2013 (60.5% increase over the 14 years). The percentage of increase was 68.4% in females and 52.5% in males. The ASR has also increased from 113.6 per 100,000 in 2000 to 142.1 per 100.000 in 2013 with a 25.1% of increase during the 14 years. Conclusion: Over the 14-year study period, incidence of cancer in Jordan has increased. However, it remains lower than that in other Eastern Mediterranean and Western countries. We recommend initiating screening programs for the most common types of cancer in Jordan that have valid screening tests to detect cancer during its early stages and reduce overall morbidity and mortality. PMID- 30416525 TI - Altered Expression of Hematopoiesis Regulatory Molecules in Lipopolysaccharide Induced Bone Marrow Mesenchymal Stem Cells of Patients with Aplastic Anemia. AB - We have investigated the expression of RNA transcripts of hematopoiesis regulatory molecules, viz., macrophage inflammatory protein (MIP)-1alpha, tumor necrosis factor (TNF)-alpha, granulocyte colony-stimulating factor (G-CSF), stromal cell-derived factor (SDF)-1alpha, stem cell factor (SCF), and transforming growth factor (TGF)-beta in lipopolysaccharide-induced bone marrow mesenchymal stem cells (BM-MSCs) and levels of their soluble forms in the culture supernatants of BM-MSCs and BM plasma of patients with acquired aplastic anemia (AA) (n = 29) and controls (n = 29). The BM-MSCs of AA patients as compared to controls had markedly lower expression of MIP-1alpha transcripts (p < 0.001), higher expression of TNF-alpha (p < 0.001), G-CSF (p < 0.001), and SDF-1alpha (p < 0.01) transcripts, and no difference in the expression of SCF and TGF-beta transcripts. The culture supernatants of BM-MSCs and BM plasma of AA patients in comparison to controls also had lower levels of MIP-1alpha (p < 0.01 and p < 0.001, respectively) and higher levels of TNF-alpha (p < 0.05 for both) and G-CSF (p < 0.05 and p < 0.001, respectively) but with no difference in the levels of SDF-1alpha and SCF. The levels of TGF-beta were although similar in culture supernatants of BM-MSCs of both the groups, but they were significantly lower in BM plasma of the patients than controls (p < 0.001). Our data shows that BM-MSCs of AA patients have altered expression of hematopoiesis regulatory molecules suggesting that they may have a role in the pathogenesis of the disease. PMID- 30416524 TI - Effect of Surgical Installation of Dental Implants on Surface Topography and Its Influence on Osteoblast Proliferation. AB - Surface treatment alone does not determine the final microtopography of a dental implant, which can be influenced by implant design and the surgical procedure. This study investigated the effect of surgical placement of dental implants with same surface treatments on surface roughness. Three implants (SIN) of each group with different macrogeometries (Strong, Stylus, and Tryon) were analyzed using laser interferometry and scanning electron microscopy to evaluate surface topography. All threaded regions of the implants, namely, top, flank, and valley, were analyzed individually. Relevant surface parameters (S a, S sk, S ku, S tr, and S dq) were calculated for the different regions on each implant before (B) (n = 9) and after (A) (n = 9) placement into porcine rib bones. The behavior and proliferation of a preosteoblastic cell line MC3T3-E1 on titanium surface, cell viability, and osteopontin secretion were evaluated after 24 h, 48 h, and 96 h, also before (n = 18) and after (n = 18) implant placement into porcine ribs bone. As results, the valleys of all implants had an increase in S a values after implant placement. By contrast, the tops of the Stylus A implant and the flanks of the Tryon A implant showed a significant decrease in mean height of the irregularities (S a), 0.16 um and 1.25 um, respectively. The Stylus implant presented significantly (p < 0.05) higher asymmetry values on the distribution curve for irregularity heights (S ku) in all regions after insertion into bone (6.99 for tops, 9.54 for flanks, and 17.64 for valleys), indicating a greater preponderance of peaks over valleys. An increase in roughness gradients (S dq) was observed for all macrogeometries after insertion into bone. The cell culture results showed no significant difference (p > 0.05) for all macrogeometries after bone placement. In conclusion, a subtle change in implant surface roughness was detected after insertion into bone for all the macrogeometries, without significantly affecting the cellular parameters studied. PMID- 30416526 TI - Relationship between Flooding and Out Break of Infectious Diseasesin Kenya: A Review of the Literature. AB - Flooding can potentially increase the spread of infectious diseases. To enhance good understanding of the health consequences of flooding and facilitate planning for mitigation strategies, deeper consideration of the relationship between flooding and out-break of infectious diseases is required. This paper examines the relationship between occurrence of floods in Kenya and outbreak of infectious diseases and possible interventions. This review intended to build up the quality and comprehensiveness of evidence on infectious diseases arising after flooding incidence in Kenya. An extensive literature review was conducted in 2017, and published literature from 2000 to 2017 was retrieved. This review suggests that infectious disease outbreaks such as waterborne, rodent-borne, and vector-borne diseases have been associated with flooding in Kenya. But there is need for more good quality epidemiological data to cement the evidence. Comprehensive surveillance and risk assessment, early warning systems, emergency planning, and well-coordinated collaborations are essential in reducing future vulnerability to infectious diseases following flooding. PMID- 30416527 TI - Rivers and streams in the media: a content analysis of ecosystem services. AB - Although ecosystem services research has become common, few efforts are directed toward in-depth understanding of the specific ecological quantities people value. The theoretical framework of final ecosystem services focuses attention on such measurable attributes, as a common currency for social-ecological systems research. Environmental communications as well as ecological monitoring and analysis efforts could be enhanced through increased documentation of final ecosystem services. For example, small changes in the way ecosystems are described could strongly influence relevance to the public and improve the foundation for environmental decision making. Focusing on rivers and streams, we conducted a content analysis of existing publications to document the breadth and frequency with which various measurable attributes, such as flooding, water quality characteristics, and wildlife appeared in different news sources over a multiyear timeline. In addition to attributes, motivations for human interest in river-related resources were also coded, such as recreation or preservation for future generations. To allow testing of differences between materials written for different audiences, three sources were sampled: a blog hosted by National Geographic, New York Times articles, and Wall Street Journal articles. The coding approach was rigorously tested in a pilot phase, with measures developed to ensure high data quality, including use of two independent coders. Results show numerous similarities across sources with some notable differences in emphasis. Significant relationships between groups of attribute and motivation codes were also found, one outcome of which is further support for the importance of nonuse values for fish and wildlife. Besides offering insight on ecosystem services, the project demonstrates an in-depth quantitative approach to analyzing preexisting qualitative data. PMID- 30416529 TI - A paradigm shift for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer: a review of CDK inhibitors. AB - In the last 3 years, a novel class of targeted therapy has been approved for patients with hormone receptor-positive, human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer. There are currently three approved agents, which are oral cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. All of the approved drugs exhibit progression-free survival benefit when compared to standard of care and generally have less adverse events compared to traditional chemotherapeutic options. The treatment of HR+/HER2- advanced breast cancer is a continuously evolving landscape, and the addition of CDK4/6 inhibitors is the newest mechanism for treatment. In this review, we summarize all available data, highlight the unanswered questions, and discuss pharmacological differences between each CDK4/6 inhibitor. PMID- 30416528 TI - Sublingual allergen immunotherapy for respiratory allergy: a systematic review. AB - The objective of the systematic review is to provide complete and updated information on efficacy and safety of sublingual immunotherapy (SLIT) formulations for the treatment of allergic respiratory diseases (ARDs). The literature search was conducted on PubMed database, involving double-blind, randomized clinical trials published between January 1992 and 2018, written in English, and performed in humans. The number of articles finally selected for review was 112. Data from the majority of properly controlled clinical trials demonstrate that SLIT is effective not only with short-term use (first year) but also with long-term use (up to the third year of active therapy), for treating ARDs in children and adults. Both continuous and discontinuous schemes of administration showed significant reductions in symptom and medication scores. Moreover, a SLIT-induced disease-modifying effect has been documented mainly with grass pollen extracts, since improvement is maintained during at least 2 years of follow-up after a 3-year treatment period. Additionally, allergen immunotherapy should also be considered a preventive strategy, especially for decreasing bronchial asthma incidence in children and adolescents with allergic rhinitis treated with SLIT. This therapy is also safe, producing only a few mainly local and mild-to-moderate adverse events, and usually self-limited in time. The registration and authorization of allergen SLIT preparations (grasses and house dust mite tablets) as drugs by regulatory agencies, such as the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA), has represented a landmark in allergy immunotherapy research. Further long-term studies, specially designed with allergens other than grass pollen or house-dust mites, not only in allergic rhinoconjunctivitis but also on asthmatic subjects, as well as studies comparing different administration schedules and/or routes, are required in order to continue the progress in the modern development of this particularly promising therapy. PMID- 30416530 TI - In Vitro Effect of Cinnamomum zeylanicum Blume Essential Oil on Candida spp. Involved in Oral Infections. AB - The present study demonstrates the antifungal potential of chemically characterized essential oil (EO) of Cinnamomum zeylanicum Blume on Candida spp. biofilm and establishes its mode of action, effect on fungal growth kinetics, and cytotoxicity to human cells. The minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) values varied from 62.5 to 1,000 MUg/mL, and the effect seems to be due to interference with cell wall biosynthesis. The kinetics assay showed that EO at MICx2 (500 MUg/mL) induced a significant (p < 0.05) reduction of the fungal growth after exposure for 8 h. At this concentration, the EO was also able to hinder biofilm formation and reduce Candida spp. monospecies and multispecies in mature biofilm at 24 h and 48 h (p < 0.05). A protective effect on human red blood cells was detected with the EO at concentrations up to 750 MUg/mL, as well as an absence of a significant reduction (p > 0.05) in the viability of human red blood cells at concentrations up to 1,000 MUg/mL. Phytochemical analysis identified eugenol as the main component (68.96%) of the EO. C. zeylanicum Blume EO shows antifungal activity, action on the yeast cell wall, and a deleterious effect on Candida spp. biofilms. This natural product did not show evidence of cytotoxicity toward human cells. PMID- 30416531 TI - Hepatoprotective Activity of the Ethanolic Extract of Polygonum multiflorum Thunb. against Oxidative Stress-Induced Liver Injury. AB - Oxidative stress is an important pathological mechanism in various liver diseases. Polygonum multiflorum Thunb. (PM) can be used for the treatment of diseases associated with aging, hyperlipidemia, and oxidative stress in traditional Chinese medicine. In this study, we examined the hepatoprotective effects of the ethanolic extract of PM (PME) in in vitro and in vivo models. The PME induced expression of antioxidant-response-element- (ARE-) related genes in HepG2 cells showed a dose-dependent manner. Pretreatment of HepG2 cell with PME suppressed H2O2- and acetaminophen- (APAP-) induced cellular reactive oxygen species (ROS) generation and cytotoxicity. In APAP-induced mouse liver injury, pretreatment with PME also showed ability to increase the survival rate and reduce the severity of liver injury. Treatment with PME attenuated bile duct ligation-induced extrahepatic cholestatic liver injury and further increased multidrug resistance protein 4 (MRP4) and reduced organic anion-transporting polypeptide (OATP) expression. Furthermore, increased nuclear translocation of the nuclear factor erythroid 2-related factor 2 (Nrf2) was observed after treatment with PME in both in vivo models. In conclusion, the current study showed the hepatoprotective activity of PME by regulating the redox state in liver injury through Nrf2 activation and controlling hepatic bile acid homeostasis in obstructive cholestasis, through bile acid transporter expression modulation. PMID- 30416532 TI - N-Acetylcysteine (NAC) Ameliorates Lipid-Related Metabolic Dysfunction in Bone Marrow Stromal Cells-Derived Adipocytes. AB - Recent experimental data suggest that fatty acids and lipotoxicity could play a role in the initiation and evolution of metabolic bone diseases such as osteoporosis. A functional bone marrow adipose tissue (BMAT) may provide support to surrounding cells and tissues or may serve as a lipid reservoir that protects skeletal osteoblasts from lipotoxicity. The present study examined the effect of N-acetylcysteine (NAC), a powerful antioxidant and precursor of glutathione, commonly used to treat chronic obstructive pulmonary disease, on triglycerides accumulation in bone marrow stromal cells-derived adipocytes. Quantification of Oil Red O stained cells showed that lipid droplets decreased following NAC treatment. Additionally, exposure of bone marrow stromal cells (HS-5) to NAC increased adiponectin, PPARgamma, HO-1, and SIRT-1 and increased beta-oxidation markers such as PPARalpha and PPARdelta mRNA levels. As there is now substantial interest in alternative medicine, the observed therapeutic value of NAC should be taken into consideration in diabetic patients. PMID- 30416534 TI - Giant anomalous Hall effect in a ferromagnetic Kagome-lattice semimetal. AB - Magnetic Weyl semimetals with broken time-reversal symmetry are expected to generate strong intrinsic anomalous Hall effects, due to their large Berry curvature. Here, we report a magnetic Weyl semimetal candidate, Co3Sn2S2, with a quasi-two-dimensional crystal structure consisting of stacked Kagome lattices. This lattice provides an excellent platform for hosting exotic topological quantum states. We observe a negative magnetoresistance that is consistent with the chiral anomaly expected from the presence of Weyl nodes close to the Fermi level. The anomalous Hall conductivity is robust against both increased temperature and charge conductivity, which corroborates the intrinsic Berry curvature mechanism in momentum space. Owing to the low carrier density in this material and the significantly enhanced Berry curvature from its band structure, the anomalous Hall conductivity and the anomalous Hall angle simultaneously reach 1130 Omega-1 cm-1 and 20%, respectively, an order of magnitude larger than typical magnetic systems. Combining the Kagome-lattice structure and the out-of plane ferromagnetic order of Co3Sn2S2, we expect that this material is an excellent candidate for observation of the quantum anomalous Hall state in the two-dimensional limit. PMID- 30416536 TI - Keratoconus: Challenges and Emerging Trends. PMID- 30416537 TI - Cosine Similarity Measure between Hybrid Intuitionistic Fuzzy Sets and Its Application in Medical Diagnosis. AB - In this paper, a cosine similarity measure between hybrid intuitionistic fuzzy sets is proposed. The aim of the paper is to investigate the cosine similarity measure with hybrid intuitionistic fuzzy information and apply it to medical diagnosis. Firstly, we construct the cosine similarity measure between hybrid intuitionistic fuzzy sets, and the relevant properties are also discussed. In order to obtain a reasonable evaluation in group decision, the weight of experts under different attributes is determined by the projection of individual decision information on the ideal decision information, where the ideal decision information is the average values of each expert's evaluation. Furthermore, we propose a decision method for medical diagnosis based on the cosine similarity measure between hybrid intuitionistic fuzzy sets, and the patient can be diagnosed with the disease according to the values of proposed cosine similarity measure. Finally, an example is given to illustrate feasibility and effectiveness of the proposed cosine similarity measure, which is also compared with the existing similarity measures. PMID- 30416533 TI - Acupuncture on the Stress-Related Drug Relapse to Seeking. AB - Drug addiction is a chronic relapsing disease, which causes serious social and economic problems. The most important trial for the successful treatment of drug addiction is to prevent the high rate of relapse to drug-seeking behaviors. Opponent process as a motivational theory with excessive drug seeking in the negative reinforcement of drug dependence reflects both loss of brain reward system and recruitment of brain stress system. The negative emotional state produced by brain stress system during drug withdrawal might contribute to the intense drug craving and drive drug-seeking behaviors via negative reinforcement mechanisms. Decrease in dopamine neurotransmission in the nucleus accumbens and recruitment of corticotropin-releasing factor in the extended amygdala are hypothesized to be implicated in mediating this motivated behavior. Also, a brain stress response system is hypothesized to increase drug craving and contribute to relapse to drug-seeking behavior during the preoccupation and anticipation stage of dependence caused by the exposure to stress characterized as the nonspecific responses to any demands on the body. Acupuncture has proven to be effective for reducing drug addiction and stress-related psychiatric disorders, such as anxiety and depression. Furthermore, acupuncture has been shown to correct reversible brain malfunctions by regulating drug addiction and stress-related neurotransmitters. Accordingly, it seems reasonable to propose that acupuncture attenuates relapse to drug-seeking behavior through inhibition of stress response. In this review, a brief description of stress in relapse to drug seeking behavior and the effects of acupuncture were presented. PMID- 30416538 TI - Short-term trends in China's income inequality and poverty: evidence from a longitudinal household survey. AB - In the past three decades, income inequality in China has increased rapidly relative to both China's own past and other countries at similar levels of economic development. Using recent longitudinal data from the China Family Panel Studies (CFPS), this article examines changes in income inequality and poverty prevalence between 2010 and 2012. Surprisingly, we find a modest decline in income inequality as measured by the Gini coefficients in the CFPS data. The urban-rural gap narrowed, with rural families enjoying faster income growth than urban families enjoyed. Income growth was greater for middle-income families than for families with either high or low incomes in 2010. By all measures, poverty was greatly reduced between 2010 and 2012. Two-thirds of families that had been poor in 2010 escaped poverty by 2012. PMID- 30416535 TI - Please stand by: how oncolytic viruses impact bystander cells. AB - Oncolytic viruses (OVs) do more than simply infect and kill host cells. The accepted mechanism of action for OVs consists of a primary lytic phase and a subsequent antitumor and antiviral immune response. However, not all cells are subject to the direct effects of OV therapy, and it is becoming clear that OVs can also impact uninfected cells in the periphery. This review discusses the effects of OVs on uninfected neighboring cells, so-called bystander effects, and implications for OV therapies alone or in combination with other standard of care chemotherapy. PMID- 30416541 TI - Foreword. PMID- 30416539 TI - Strategies to promote abundance of Akkermansia muciniphila, an emerging probiotics in the gut, evidence from dietary intervention studies. AB - Akkermansia muciniphila is a mucin-degrading bacterium commonly found in human gut. A. muciniphila has been inversely associated with obesity, diabetes, inflammation, and metabolic disorders. Due to its highly promising probiotic activities against obesity and diabetes, A. muciniphila has drawn intensive interest for research and development in recent years. A number of human and animal studies have shown that the abundance of A. muciniphila in the gut can be enhanced through dietary interventions. The present review focuses on evidence based dietary strategies of improving A. muciniphila abundance in the gut by critically appraising up-to-date available human and animal intervention studies on A. muciniphila growth and their impact on risk factors of obesity and diabetes. Their potential mechanisms in promoting A. muciniphila are also discussed along with the discussions of mechanism of action for A. muciniphila to exert probiotic functions. PMID- 30416542 TI - Ischemic Heart Disease in Women: Not About Religion. PMID- 30416540 TI - Physicochemical differences between malanga (Xanthosoma sagittifolium) and potato (Solanum tuberosum) tubers are associated with differential effects on the gut microbiome. AB - Malanga (Xanthosoma sagittifolium) is used as a medicinal food for infant development and gastritis. We compared the physicochemical properties and gut microbial effects of malanga versus potato (Solanum tuberosum) using nutritional analysis, rheometry, in vitro TNO Intestinal Model, and C57Bl/6J mouse models. Malanga was characterized by higher starch (70.7% v. 66.3%), lower amylose:amylopectin (0.33 v. 0.59), higher free sugar (5.44% v. 3.23%), lower viscosity (271.0 v. 863.0 mPa.s), and higher bioaccessible and bioavailable sugar (0.89 v. 0.11 g bioaccessible sucrose per 20 g load in vitro; blood glucose levels of 129.1 v. 95.2 and 133.8 v. 104.3 mg/dL after 20 and 60 min in vivo). Gut microbiota of mice fed a high fat diet containing 20% malanga for 14 d exhibited significantly higher alpha diversity than those fed 20% potato, indicating that minor physicochemical differences between similar tuber crops are associated with significantly different effects on the gut microbiome. PMID- 30416543 TI - Cardiovascular Disease in Women: Understanding Symptoms and Risk Factors. AB - Cardiovascular disease (CVD) in women remains under-diagnosed and undertreated due to the diagnostic challenge it presents, as well as the persisting attitude that CVD predominantly affects men. Gender-related risk factors have now been identified but there is a lack of clinical application, leading to the misdiagnosis and poor management of women with CVD. It is necessary to address gender-specific symptomatology and risk factors in order to optimise management and positively influence morbidity and mortality in this cohort of patients. PMID- 30416546 TI - Noise Pollution and Arterial Hypertension: Can we Remain Mute Anymore? PMID- 30416544 TI - Women with Stable Angina Pectoris and No Obstructive Coronary Artery Disease: Closer to a Diagnosis. AB - A large proportion of women with chest pain have no obstructive coronary artery disease. Recent studies have demonstrated that these women continue to have symptoms and are at increased risk of cardiovascular morbidity and mortality. Coronary microvascular dysfunction (CMD) leads to an impairment of blood flow regulation to the myocardium and possible transient ischaemia. CMD is a disease entity with several pathophysiologic aspects and diagnostic modalities continue to be developed. However, due to the complexity of the disease, it remains elusive whether CMD is the explanation for the symptoms and the poor prognosis in women with angina and no obstructive coronary artery disease. PMID- 30416545 TI - Cardiac Disease after Pregnancy: A Growing Problem. AB - Pregnancy complications, such as hypertensive disorders or preterm delivery, identify families predisposed to cardiovascular problems at other times in life. Whether the pregnancy complication induces cardiac disease or whether the pregnancy stress unmasks an underlying predisposition remains unclear. However, improved survival following severe pregnancy complications for both the mother and, in particular, the offspring - who is often born preterm - has resulted in a growing cohort of individuals who carry this increased cardiovascular risk. Research to understand the underlying pathological mechanisms that link these conditions might ultimately lead to novel therapeutic or prevention strategies for both cardiovascular and pregnancy disease. PMID- 30416547 TI - Noise Pollution and Arterial Hypertension. AB - Noise exposure modifies the function of multiple organs and systems. Acute noise exposure - both in laboratory settings where traffic noise is simulated and in real-life working environments - can cause increases in blood pressure, heart rate and cardiac output. This review examines the effects of noise pollution on the cardiovascular system, with a particular focus on non-auditory effects such as noise-induced arterial hypertension. PMID- 30416548 TI - Key Recent Advances in Atherosclerosis Treatment with Modern Lipid-lowering Drugs: The New Frontier with PCSK9 Inhibitors. PMID- 30416550 TI - Contemporary Management of Stroke Prevention in Atrial Fibrillation Following the European Society of Cardiology Guidelines. AB - The recent publication of the European Society of Cardiology (ESC) guidelines for the management of atrial fibrillation provides a timely update at a time when the rapid uptake of non-vitamin K antagonist oral anticoagulants has changed the landscape of clinical practice. Several key changes have been highlighted, including better identification of those deemed to be low risk for thromboembolic complications and a more standardised approach to patients with atrial fibrillation who require concomitant antiplatelet therapy following either percutaneous coronary intervention or an acute coronary syndrome. This article distils the key messages from the ESC guidelines and draws the reader's attention to both gaps and advances in our knowledge. PMID- 30416549 TI - Antiplatelet Therapy in Acute Coronary Syndrome. AB - Antiplatelet agents have for decades been used to improve outcomes in patients with acute coronary syndromes and have become increasingly valued, not only for their antithrombotic properties but also for their anti-inflammatory effects. The drug class continues to evolve as novel agents with increasingly efficacious antiplatelet actions are identified. This review will discuss antiplatelet agents, including aspirin, the P2Y12 receptor antagonists and the glycoprotein IIb/IIIa inhibitors, that are currently used to treat patients with unstable angina and myocardial infarction, focusing on their pharmacological properties and the clinical evidence supporting their use. PMID- 30416551 TI - Direct Oral Anticoagulants: A Quick Guide. AB - Vitamin K antagonists, such as warfarin, have been the anticoagulants of choice for many years for patients with AF and other thrombotic conditions. The introduction of direct oral anticoagulants (DOACs) as alternatives represents a major advance in anticoagulation. DOACs have been found to be at least as safe and effective as vitamin K antagonists in randomised, controlled trials for stroke prevention in AF and the management of venous thromboembolism, with real world data showing similar outcomes. With the availability of several agents, selecting the most appropriate DOAC can be challenging. The aim of the present article is to provide useful guidance on the implementation of DOAC treatment in clinical practice. PMID- 30416552 TI - Hybrid Approach to Percutaneous Coronary Intervention to Treat Chronic Total Occlusions. AB - The hybrid approach is a systematic algorithm-led percutaneous coronary intervention strategy based on the identification of key anatomical features on coronary angiography to treat chronic total occlusions. The aims of this approach are to provide a standardised tool for physician training and programme development, avoiding futile strategies to improve safety, procedural success and reduce the contrast and radiation required to complete the case. PMID- 30416554 TI - Featuring: Prof Carlo Patrono. PMID- 30416555 TI - Foreword. PMID- 30416553 TI - Cardiac Magnetic Resonance in Takotsubo Syndrome. AB - Takotsubo syndrome is an acute, profound but reversible heart failure syndrome of unknown aetiology, usually but not always triggered by physical or emotional stress. Cardiac magnetic resonance has become an important tool for the non invasive assessment of the syndrome, allowing for a comprehensive, safe and reproducible assessment of functional and anatomical myocardial properties, including perfusion, oedema and necrosis. This review focuses on the emerging role of cardiac magnetic resonance for the characterisation, differential diagnosis as well as risk stratification of patients with Takotsubo syndrome. PMID- 30416556 TI - Highlights of the 2016 European Society of Cardiology Guidelines on Heart Failure. AB - The European Society of Cardiology guidelines for the diagnosis and treatment of heart failure (HF) was updated in 2016. In this article, highlights of the updates made based on new findings and practical recommendations are presented. The 2016 guidelines include definitions and criteria for diagnosing the different types of HF. In addition, a newly developed algorithm is proposed for treating particularly symptomatic HF with reduced ejection fraction, including the use of the angiotensin-converting enzyme inhibitors, beta-blockers, mineralocorticoid receptor antagonists and the angiotensin receptor neprilysin inhibitor sacubitril/valsartan. Further evidence is required for some aspects of the diagnosis and treatment of HF, but these guidelines will prove useful for decision making in this setting. PMID- 30416557 TI - Impact on Patient Care: The 2016 European Heart Failure Guidelines. PMID- 30416558 TI - Hypertrophic Cardiomyopathy in Athletes. AB - Sudden cardiac death (SCD) in a young person is a rare but tragic occurrence. The impact is widespread, particularly in the modern era of media coverage and visibility of social media. Hypertrophic cardiomyopathy (HCM) is reported historically as the most common cause of SCD in athletes younger than 35 years of age. A diagnosis of HCM may be challenging in athletes as pathological hypertrophy of the left ventricle may also mimic physiological left ventricular hypertrophy (LVH) in response to exercise. Differentiation of physiological LVH from HCM requires an array of clinical tools that rely on detecting subtle features of disease in a supposedly healthy person who represents the segment of society with the highest functional capacity. Most studies are based on comparisons of clinical tests between healthy unaffected athletes and sedentary individuals with HCM. However, data are emerging that report the clinical features of athletes with HCM. This article focuses on studies that help shed further light to aid the clinical differentiation of physiological LVH from HCM. This distinction is particularly important in a young person: a diagnosis of HCM has significant ramifications on participation in competitive sport, yet an erroneous diagnosis of physiological adaptation in a young athlete with HCM may subject them to an increased risk of SCD. PMID- 30416560 TI - Cardiovascular Risk Management Targeting Inflammation in Addition to Lipid lowering Therapy. PMID- 30416559 TI - Role of Testosterone in the Treatment of Cardiovascular Disease. AB - Cardiovascular disease (CVD) is the most prevalent non-communicable cause of death worldwide. Testosterone is a sex hormone that is predominant in males but also occurs in lower concentrations in females. It has effects directly on the blood vessels of the cardiovascular system and on the heart, as well as effects on risk factors for CVD. Serum testosterone concentrations are known to decrease with age and reduced testosterone levels are linked to premature coronary artery disease, unfavourable effects on CVD risk factors and increased risk of cardiovascular mortality independent of age. A significant number of men with heart failure demonstrate reduced serum testosterone concentrations and there is early evidence suggesting that low testosterone levels affect cardiac repolarisation. Any association between endogenous testosterone concentrations and CVD in women has yet to be established. Testosterone replacement is used to treat men with hypogonadism but also has cardiovascular effects. This review will present the current evidence, expert opinion and controversies around the role of testosterone in the pathophysiology of CVD and surrounding the use of testosterone treatment and its effects on the cardiovascular system and CVD. PMID- 30416561 TI - Inflammation Revisited: Atherosclerosis in The Post-CANTOS Era. AB - It is fairly well accepted in the scientific community that atherosclerosis carries features of a local and low-grade systemic inflammation. However, it was unclear thus far whether this is simply an epiphenomenon or if it plays a causal role in atherosclerosis and its clinical complications. After several failed attempts, the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) has provided convincing evidence of interleukin-1 beta as a target whose neutralisation by a selective antibody reduces major cardiovascular events without affecting LDL-cholesterol. This provides strong evidence in support of the inflammation hypothesis and will certainly stimulate research in this area and open the way for novel therapy in high-risk patients following MI. PMID- 30416562 TI - The Best Posters from XXII Annual Scientific Meeting of the International Society of Cardiovascular Pharmacotherapy (ISCP). PMID- 30416563 TI - Cardiac Resynchronization is Associated with Reduction in the Rate of ICD Therapies, While Improves Ventricular Function. PMID- 30416564 TI - Prevalence of Appropriate Non-Antiarrhythmic Pharmacotherapy in Atrial Fibrillation Patients with Rhythm Control Strategy. PMID- 30416565 TI - Oral Anticoagulation and Prognosis of Patients with Atrial Fibrillation After Ischemic Stroke: A Real-world Data Analysis. PMID- 30416566 TI - Effects of Pharmacotherapy for Smoking Cessation on LOX Index, a Cardiovascular Risk Marker. PMID- 30416567 TI - Impact of an Integral Assistance on the Management of Patients with Chronic Heart Diseases. PMID- 30416568 TI - 5-Year Outcomes After Implementation of Optimal Medical Therapy in General Practice Using Liaison Critical Pathway for Secondary Prevention of Coronary Artery Disease: An Observational Study. PMID- 30416569 TI - A Risk Score to Predict the Absence of Left Ventricular Reverse Remodelling: Implications for the Timing of ICD Implantation in Primary Prevention. PMID- 30416570 TI - Does Angiotensin Receptor Neprilysin Inhibitor (ARNI) Improve Functional Capacity Assessed by 6 Minutes Walking Test? PMID- 30416571 TI - External 30 Days Holter Usefulness in Unexplained Syncope, Palpitations and Cardioembolic Suspected Cryptogenic Stroke Study. PMID- 30416572 TI - Differences in Clinical Characteristics, Results and Management of Patients Referred for Pharmacologic Cardiac Stress SPECT Depending on the Protocol Used. PMID- 30416573 TI - Secondary Prevention in Patients with Non Valvular Atrial Fibrillation and Previous Stroke. Is It Possible to Have an Appropriate INR Control? PMID- 30416574 TI - Consensus is Possible: Initiation and Exchange of Oral Anticoagulants in Non valvular Atrial Fibrillation, According to a Territorial Protocol in a Period of Time. PMID- 30416575 TI - A Novel Target Molecule of Nobiletin Derived from Citrus Peels has a Therapeutic Potency Against the Development of Heart Failure. PMID- 30416576 TI - Curcumin Analogue GO-Y030 Significantly Improves Pressure Overload-induced Heart Failure in Vivo. PMID- 30416577 TI - The Inhibitory Effects of Crucumin Glucuronide on p300-HAT Activity and Hypertrophic Phenylephrine-Induced Responses in Cardiomyocytes. PMID- 30416578 TI - Prospective and Centralized Follow-Up of a Territorial Protocol of Use of Direct Oral Anticoagulants in Non Valvular Atrial Fibrillation. PMID- 30416579 TI - Choice of Anticoagulation Therapy in Atrial Patients with Rate Control and Rhythm Control Strategy - Data from a Multicenter Real-life Registry. PMID- 30416580 TI - A Transcriptional Co-activator, p300 is Involved in the Epigenetic Gene Activation on Hypertrophic Response Gene Promoters in Heart Failure. PMID- 30416581 TI - Analysis of Factors Associated with Smoking Relapse. PMID- 30416584 TI - Featuring: Dr Peter Libby. PMID- 30416583 TI - Viewpoint: Recent Advances in Intracoronary Imaging for Vasa Vasorum Visualisation. AB - The coronary adventitia harbours the vasa vasorum (VV), which has a diameter of 50-300 um and plays an important role as a network of nutrient blood vessels to the arterial wall. The VV is thought to be involved in the development of coronary atherosclerosis. Recent advances in the field of intracoronary imaging, including optical coherence tomography, have enabled us to visualise coronary VV in humans in vivo and increased the clinical relevance of the VV in patients with coronary artery disease. PMID- 30416582 TI - QT Prolongation and Malignant Arrhythmia: How Serious a Problem? AB - QT prolongation constitutes one of the most frequently encountered electrical disorders of the myocardium. This is due not only to the presence of several associated congenital syndrome but also, and mainly, due to the QT-prolonging effects of several acquired conditions, such as ischaemia and heart failure, as well as multiple medications from widely different categories. Propensity of repolarization disturbances to arrhythmia appears to be inherent in the function of and electrophysiology of the myocardium. In the present review the issue of QT prolongation will be addressed in terms of pathophysiology, arrhythmogenesis, treatment and risk stratification approaches. Although already discussed in literature, it is hoped that the mechanistic approach of the present review will assist in improved understanding of the underlying changes in electrophysiology, as well as the rationale for current diagnostic and therapeutic approaches. PMID- 30416585 TI - Rapid coastal deoxygenation due to ocean circulation shift in the NW Atlantic. AB - Global observations show that the ocean lost approximately 2% of its oxygen inventory over the last five decades 1-3, with important implications for marine ecosystems 4, 5. The rate of change varies with northwest Atlantic coastal waters showing a long-term drop 6, 7 that vastly outpaces the global and North Atlantic basin mean deoxygenation rates 5, 8. However, past work has been unable to resolve mechanisms of large-scale climate forcing from local processes. Here, we use hydrographic evidence to show a Labrador Current retreat is playing a key role in the deoxygenation on the northwest Atlantic shelf. A high-resolution global coupled climate-biogeochemistry model 9 reproduces the observed decline of saturation oxygen concentrations in the region, driven by a retreat of the equatorward-flowing Labrador Current and an associated shift toward more oxygen poor subtropical waters on the shelf. The dynamical changes underlying the shift in shelf water properties are correlated with a slowdown in the simulated Atlantic Meridional Overturning Circulation 10. Our results provide strong evidence that a major, centennial-scale change of the Labrador Current is underway, and highlight the potential for ocean dynamics to impact coastal deoxygenation over the coming century. PMID- 30416586 TI - Long-distance migratory birds threatened by multiple independent risks from global change. AB - Many species migrate long distances annually between their breeding and wintering areas1. While global change affects both ranges, impact assessments have generally focused on breeding ranges and ignore how environmental changes influence migrants across geographic regions and the annual cycle2,3. Using range maps and species distribution models, we quantified the risk of summer and winter range loss and migration distance increase from future climate and land cover changes on long-distance migratory birds of the Holarctic (n=715). Risk estimates are largely independent of each other and magnitudes vary geographically. If seasonal range losses and increased migration distances are not considered, we strongly underestimate the number of threatened species by 18-49% and the overall magnitude of risk for 17-50% species. Many of the analysed species facing multiple global change risks are not listed by IUCN as threatened or near threatened. Neglecting seasonal migration in impact assessments could thus seriously misguide species' conservation. PMID- 30416588 TI - Teleconsent - A New Modality for Informed Consenting. PMID- 30416587 TI - Nonlinear optical properties in open-shell molecular systems. AB - For more than 30 years, nonlinear optical (NLO) properties of molecular systems have been actively studied both theoretically and experimentally due to their potential applications in photonics and optoelectronics. Most of the NLO molecular systems are closed-shell species, while recently open-shell molecular species have been theoretically proposed as a new class of NLO systems, which exhibit larger NLO properties than the traditional closed-shell NLO systems. In particular, the third-order NLO property, the second hyperpolarizability gamma, was found to be strongly correlated to the diradical character y, which is a quantum-chemically defined index of effective bond weakness or of electron correlation: the gamma values are enhanced in the intermediate y region as compared to the closed-shell (y = 0) and pure open-shell (y = 1) domains. This principle has been exemplified by accurate quantum-chemical calculations for polycyclic hydrocarbons including graphene nanoflakes, multinuclear transition metal complexes, main group compounds, and so on. Subsequently, some of these predictions have been substantiated by experiments, including two-photon absorption. The fundamental mechanism of the y-gamma correlation has been explained by using a simple two-site model and the valence configuration interaction method. On the basis of this y-gamma principle, several molecular design guidelines for controlling gamma have been proposed. They consist in tuning the diradical characters through chemical modifications of realistic open shell singlet molecules. These results open a new path toward understanding the structure-NLO property relationships and toward realizing a new class of highly efficient NLO materials. WIREs Comput Mol Sci 2016, 6:198-210. doi: 10.1002/wcms.1242. PMID- 30416589 TI - Saudi lung cancer prevention and screening guidelines. PMID- 30416590 TI - Saudi lung cancer prevention and screening guidelines. AB - BACKGROUND: While lung cancer is the leading cancer cause of death, it is largely preventable. Furthermore, early diagnosis enhances the chance of cure. Therefore, we developed guidelines for lung cancer prevention and early detection. METHODS: A multidisciplinary team of experts in lung cancer representing different health care sectors was assembled based on the National Cancer Center request and in coordination with the Saudi Lung Cancer Association of Saudi Thoracic Society. The team reviewed various reliable international guidelines and the data and experience in the Kingdom and formulated guidelines that address the primary and secondary prevention approaches in lung cancer, including tobacco control, early diagnosis, and lung cancer screening. RESULTS: The team developed guidelines to assist healthcare professionals in the Kingdom manage the different aspects of lung cancer prevention. Primary prevention through tobacco control: the recommendations encourage all healthcare professionals in all practice settings to screen their patients for smoking and to provide counseling and if needed referral to smoking cessation programs for current smokers. For early diagnosis of patients with symptoms suspicions of lung cancer, it is expected standard of care to investigate, work up, and refer the patients appropriately. Mass screening of patients at high risk for developing lung cancer: the recommendations listed the program requirements, eligible patients, and algorithm to manage findings. However, the team does not recommend that national screening program be mandated or implemented for lung cancer at this stage until more data and studies provide stronger evidence to justify adopting a national program. CONCLUSIONS: Physicians can play an important role in preventing lung cancer by tobacco control and also detect lung cancer at earlier presentation. However, national mass screening programs require further study. PMID- 30416591 TI - Bronchial thermoplasty-an update. AB - Bronchial Thermoplasty is a procedure that involves the delivery of radiofrequency energy during bronchoscopy to airways in order to selectively ablate airway smooth muscles. Bronchial Thermoplasty was approved by the FDA in 2010 and remains the only device based non-pharmacological treatment approach for severe asthma. We appraise the trials leading to the approval of Bronchial Thermoplasty in light of the FDA approval process. Current international guidelines regarding use of Bronchial Thermoplasty and emering pharmacological options for severe asthma are reviewed. PMID- 30416592 TI - Assessment of proximal and peripheral airway dysfunction by computed tomography and respiratory impedance in asthma and COPD patients with fixed airflow obstruction. AB - OBJECTIVE: To ascertain: (i) if elderly patients with fixed airflow obstruction (FAO) due to asthma and chronic obstructive pulmonary disease (COPD) have distinct airway morphologic and physiologic changes; (ii) the correlation between the morphology of proximal/peripheral airways and respiratory impedance. METHODS: Twenty-five asthma cases with FAO and 22 COPD patients were enrolled. High resolution computed tomography was used to measure the wall area (WA) and lumen area (LA) of the proximal airway at the apical segmental bronchus of the right upper lobe (RB1) adjusted by body surface area (BSA) and bronchial wall thickening (BWT r ) of the peripheral airways and extent of expiratory air trapping (AT exp ). Respiratory impedance included resistance at 5 Hz (R5) and 20 Hz (R20) and resonant frequency (Fres). Total lung capacity (TLC) and residual volume (RV) were measured. RESULTS: Asthma patients had smaller RB1-LA/BSA than COPD patients (10.5 +/- 3.4 vs. 13.3 +/- 5.0 mm2/m2, P = 0.037). R5(5.5 +/- 2.0 vs. 3.4 +/- 1.0 cmH2O/L/s, P = 0.02) and R20(4.2 +/- 1.7 vs. 2.6 +/- 0.7 cmH2O/L/s, P = 0.001) were higher in asthma cases. AT exp and BWT r were similar in both groups. Regression analysis in asthma showed that forced expiratory volume in one second (FEV1) and Fres were associated with RB1-WA/BSA (R2= 0.34, P = 0.005) and BWT r (0.5, 0.012), whereas RV/TLC was associated with AT exp (0.38, 0.001). CONCLUSIONS: Asthma patients with FAO had a smaller LA and higher resistance of the proximal airways than COPD patients. FEV1 and respiratory impedance correlated with airway morphology. PMID- 30416593 TI - Poor sleep in concurrent users of alcohol, khat, and tobacco smoking in community dwelling Ethiopian adults. AB - BACKGROUND: Polysubstance dependence, stress, and sleep disturbances are inter related by shared physiological pathways. No study has investigated the relationship between sleep and concurrent use of alcohol and khat. OBJECTIVES: The aim of the study was to assess the effect of the concurrent use of alcohol and khat as well as concurrent alcohol, khat, and tobacco smoking on sleep patterns. METHODS: A sample of community-dwelling adults (n = 339, age = 25.5 +/- 5.7 years, body mass index = 22.0 +/- 2.2 kg/m2) from Mizan-Aman, Ethiopia, participated in a cross-sectional study. Semi-structured tool for sociodemographics, substance use habit, and the Pittsburgh Sleep Quality Index (PSQI) were used. The difference in sleep patterns among substance use groups, i.e., nonusers, alcohol use only, concurrent alcohol and khat use, and concurrent alcohol, khat and tobacco smoking was assessed. RESULTS: The poorest sleep quality was found among concurrent users of alcohol, khat, and tobacco smoking (PSQI global score = 8.2 +/- 2.4), followed by concurrent users of alcohol and khat (PSQI global score = 7.3 +/- 2.9) (F (3.335) = 23.64, P < 0.001). There were significant differences in the PSQI component score of sleep quality chi 2(3) =159.09, P < 0.001, the PSQI component score of sleep latency chi 2(3) = 128.09, P < 0.001, and the PSQI component score of sleep disturbances chi 2(3) = 37.69, P < 0.001 between substance use groups. CONCLUSION: Concurrent use of alcohol, khat as well as alcohol, khat, and tobacco smoking was associated with poor sleep. Sleep disturbances in this group need management to avoid the prospective development of psychosocial disturbances in polysubstance users. PMID- 30416594 TI - Porous alumina ceramic sternum: A reliable option for sternal replacement. AB - CONTEXT: To date, there is no gold standard technique for sternum replacement. Current techniques rely on metallic prosthesis, meshes and bars, or bone grafts. However, they have several pitfalls. AIMS: The aim of this article is to report the results of sternal replacement with a porous alumina ceramic sternum. SETTINGS AND DESIGN: Surgeries were performed in two teaching hospitals in France. METHODS: We designed a porous alumina ceramic prosthesis which possesses interesting characteristics for this surgery such as great biocompatibility, a certain level of bacterial resistance, radiolucency, and compatibility with radiotherapy. The implant is stitched to the ribs with suture thread and does not require osteosynthesis material. RESULTS: Six patients with a mean age of 60.6 years received this prosthesis. Indication was tumor in five cases and mediastinitis in one case. The mean follow-up is 20 months (3-37 months). No major complication occurred and healing was fine for all patients. Patients did not complain of breathing discomfort or pain related to the prosthesis. CONCLUSIONS: This new technique is promising even if there are only six patients in this study. PMID- 30416595 TI - Clinical characteristics and outcomes of human rhinovirus positivity in hospitalized children. AB - BACKGROUND: The clinical relevance of positive human rhinovirus (HRV) in hospitalized patients is unclear. Our objective was to describe the clinical characteristics and outcomes of HRV positivity in a heterogeneous population of hospitalized children, compared to those positive for another respiratory virus and those where no respiratory virus was detected. METHODS: A retrospective case control study of children hospitalized between January 2014 to April 2015 who had a respiratory viral specimen collected. Clinical and laboratory data were collected, and baseline characteristics and clinical variables were compared. RESULTS: During the study period, there were 671 specimens obtained from 577 patients that were processed for the respiratory viral polymerase chain reaction assay, of which 198 were positive for HRV, 167 positive for another respiratory virus, and 306 where no respiratory virus was detected. A history of asthma was significantly associated with HRV-positive patients (odds ratio [OR] 3.71; P < 0.001). On multivariate analysis, HRV-positive patients had a higher requirement for mechanical ventilation (OR 1.44), lower rates of readmission (OR 0.53), and lower mortality (OR 0.35) compared to patients with no respiratory virus isolated; however, none were statistically significant. HRV-positive patients did have a significantly shorter length of stay (LOS) compared with patients with no respiratory virus isolated (difference-0.35; P = 0.001). Similar outcomes were seen in patients positive for other respiratory viruses. CONCLUSIONS: HRV positive hospitalized pediatric patients with a heterogeneous set of clinical diagnoses had higher association with asthma compared to patients who had another, or no, respiratory virus isolated. HRV-positive patients had shorter LOS compared to patients who had no respiratory viruses isolated. These findings suggest that HRV positivity in hospitalized pediatric patients may not lead to adverse clinical outcomes, although asthma is a risk factor regardless of clinical comorbidities and diagnoses. Further research is warranted to understand the predisposition of asthma to HRV positivity. PMID- 30416596 TI - Noninvasive ventilation utilization in the Kingdom of Saudi Arabia: Results of a national survey. AB - INTRODUCTION: Noninvasive ventilation (NIV) has been extensively used globally and is often administered as the first-line treatment. Currently, data regarding the utilization of NIV in the Kingdom of Saudi Arabia (KSA) is scarce. The present study aimed to assess and quantify the utilization of NIV in clinical practice across the KSA and investigate obstacles that may cause NIV underutilization. METHODS: A web-based survey composed of a 31-item, self administered questionnaire was developed and validated. The questionnaire was designed to obtain general information about each hospital, availability of NIV practice, use of NIV, and obstacles that can hinder NIV use in clinical settings; the survey was sent to senior respiratory therapists (RTs) of 76 hospitals. Descriptive statistics were used to analyze the data. RESULTS: Sixty-one hospitals (80.3%) responded to the survey (47 governmental and 14 private). NIV was available in all hospitals and all the Intensive Care Units. The majority of RTs (85%) reported having a good experience with NIV, with a confidence rate of 60%; however, only 22% of the RTs had received formal training. Although NIV setup was the sole responsibility of RTs, only 69% participated in NIV management. Moreover, 72% of hospitals had an NIV setup protocol in place. However, 50% of them lacked a protocol for NIV failure. NIV protocols for specific indications were present in 64% of the hospitals: 47.2% for monitoring and 42% for weaning. The perceived efficiency of NIV practice was low in the medical wards, with a <49% success rate in 39% of the hospitals. Shortage of staff and lack of formal training were the most common reasons for NIV underutilization. CONCLUSION: The efficiency of NIV in the KSA was low. The RTs expressed moderate confidence in administering NIV. Lack of appropriate exposure and formal training could have negative impacts on NIV practice. PMID- 30416598 TI - Pleomorphic carcinoma of the lung mimicking synchronous pulmonary adenocarcinoma and small bowel sarcoma. AB - Pulmonary pleomorphic carcinoma is defined as a nonsmall cell lung carcinoma (NSCLC) that contains at least 10% sarcomatoid components. We report a case of pulmonary pleomorphic carcinoma of which only the sarcomatoid component metastasized to the small bowel and adenocarcinoma was identified on percutaneous transthoracic needle biopsy (PTNB). We suggest that if an NSCLC is diagnosed by PTNB and a sarcoma is found at another site, or vice versa, pulmonary pleomorphic carcinoma with a single metastasis should be considered as a differential diagnosis to establish the best effective treatment plan. PMID- 30416597 TI - Efficacy and safety of thermal ablation of lung malignancies: A Network meta analysis. AB - OBJECTIVE: The objective of this study was to compare the efficacy and safety of radiofrequency ablation (RFA), cryoablation, and microwave ablation (MWA) for patients with lung malignancies. METHODS: We performed a network meta-analysis to identify both direct and indirect evidence from relevant trials by searching PubMed, Embase, and the Cochrane Library to December 31, 2017, for the treatment of malignant lung tumors with the use of RFA, MWA, or cryoablation. We extracted the relevant information from the published studies with a predefined data sheet and assessed the risk of bias with the Cochrane risk of bias tool. The primary outcomes were efficacy (local progression rate and overall survival rate) and safety (major complications rate). We did a random-effects network meta-analysis within a Bayesian framework as well as assessed the quality of evidence contributing to each network estimate using GRADE framework. RESULTS: We collected 34 studies eligible which included 1840 participants and 2520 lung malignancies (1318 primary lung cancer and 1202 pulmonary metastatic tumors). The quality of evidence was rated as very low in most comparisons. From the point of local progression rate, RFA and MWA were significantly more effective than cryoablation with odds ratio (OR) of 0.04 (95% confidence interval [CI]: 0.004, 0.38; P = 0.005) and 0.02 (95% CI: 0.002, 0.24; P = 0.001), respectively. No significant difference was found between MWA and RFA with an OR of 0.63 (95% CI: 0.04, 10.39; P = 0.745). Regarding the major complications, RFA, MWA, and cryoablation showed the comparable safety (P > 0.05). CONCLUSION: RFA and MWA offer an advantage over cryoablation for patients with malignant lung tumors. PMID- 30416600 TI - Pattern of bone metastasis in patients with nonsmall cell lung cancer. PMID- 30416599 TI - Near-fatal presentation of bilateral pneumothorax in cutis laxa patient: Case report, and review of the literature. AB - Cutis laxa (CL) is a rare connective tissue disease characterized by a loose, wrinkled, and inelastic skin. Here, we report an unusual presentation in a 15 year-old male patient who is a known patient of CL who presented with bilateral pneumothorax. He was successfully managed initially by chest tube insertion and then he was treated surgically with bilateral staged thoracoscopy, apical bullectomy, and pleurodesis with full uneventful recovery. PMID- 30416601 TI - Author's Reply. PMID- 30416602 TI - An illustrated catalogue of Rudolf Sturany's type specimens in the Naturhistorisches Museum Wien, Austria (NHMW): deep-sea Eastern Mediterranean molluscs. AB - The "Pola" expeditions were the first to explore the deep Eastern Mediterranean Sea in the 1890s. They remained the most intense surveys in that area for a century and constitute today a fundamental baseline to assess change in the basin, whose fauna is still inadequately described. Solid taxonomic foundations for the study of deep-sea organisms are needed and we here contribute by revising the name-bearing types of mollusc species introduced by Rudolf Sturany on the basis of the "Pola" material from the Eastern Mediterranean Sea stored in the Natural History Museum in Vienna. Sturany introduced 15 names (Marginella occulta var. minor Sturany, 1896 shall not be considered as the introduction of a new name). He described and established two manuscript names by Monterosato: Jujubinus igneus and Pseudomurex ruderatus. The genus Isorropodon was also introduced together with its type species I. perplexum. For each name, we list the available type material, provide the original description and a translation into English and illustrate the specimens in colour and with SEM imaging. PMID- 30416603 TI - Restoring vasculogenic potential of endothelial cells from diabetic patients through spheroid formation. AB - Introduction: Diabetes is an emerging epidemic in the developing world and represents a major risk factor for cardiovascular disease. Among other issues, patients with diabetes suffer from diminished endothelial cell (EC) function, which contributes to impaired vasculogenesis and recovery from ischemic insult. The formation of cells into three-dimensional spheroids promotes cell survival and activates key signaling pathways through the upregulation of cell-cell contacts, providing an opportunity to overcome shortcomings associated with individual autologous cells. Methods: We hypothesized that forming human microvascular endothelial cells (HMVECs) from diabetic patients into spheroids would restore their vasculogenic potential following upregulation of these cell cell interactions. HMVEC spheroids were formed and suspended in fibrin gels to quantify vasculogenic potential. Results: Individual HMVECs from diabetic patients exhibited similar proliferative and chemotactic potential to cells from healthy donors but reduced tubulogenesis. HMVEC spheroids formed from diabetic donors formed more sprouts than spheroids from healthy donors, and more sprouts than individual cells from either population. Conclusions: Compared to cells from healthy donors, sprout formation was more efficiently abrogated in HMVECs from diabetic patients by blocking matrix metalloproteinase activity. This study demonstrates a promising approach for restoring the diminished vasculogenic potential of endothelial cells in diabetic patients. PMID- 30416606 TI - Natural Sensations Evoked in Distal Extremities Using Surface Electrical Stimulation. PMID- 30416605 TI - Systematic Development of a Dutch School-Based Sexual Prejudice Reduction Program: an Intervention Mapping Approach. AB - Experiences of sexual prejudice threaten the quality of life and psychological well-being of sexual minority youth. The aim of this paper is to provide a comprehensive overview of how we developed a theory- and evidence-based sexual prejudice reduction program suitable for the Dutch high school context, guided by the intervention mapping approach (IM). In line with IM, six steps were followed: an initial needs assessment in which empirical, theoretical, and new data were gathered to acquire a thorough understanding of the problem (step 1); the formulation of program objectives for both students and teachers (step 2); the selection of theory-based methods and applications (step 3); program development (step 4); the provision of an adoption and implementation plan (step 5); and the development of an evaluation plan (step 6). In conclusion, developing a sexual prejudice reduction program for schools is a challenging but feasible process. IM is an effective tool for the systematic (theory- and evidence-driven) development of such a program. PMID- 30416604 TI - C60 fullerene and its nanocomplexes with anticancer drugs modulate circulating phagocyte functions and dramatically increase ROS generation in transformed monocytes. AB - Background: C60 fullerene-based nanoformulations are proposed to have a direct toxic effect on tumor cells. Previous investigations demonstrated that C60 fullerene used alone or being conjugated with chemotherapeutic agents possesses a potent anticancer activity. The main aim of this study was to investigate the effect of C60 fullerene and its nanocomplexes with anticancer drugs on human phagocyte metabolic profile in vitro. Methods: Analysis of the metabolic profile of phagocytes exposed to C60 fullerene in vitro revealed augmented phagocytic activity and down-regulated reactive nitrogen species generation in these cells. Additionally, cytofluorimetric analysis showed that C60 fullerene can exert direct cytotoxic effect on normal and transformed phagocytes through the vigorous induction of intracellular reactive oxygen species generation. Results: Cytotoxic action as well as the pro-oxidant effect of C60 fullerene was more pronounced toward malignant phagocytes. At the same time, C60 fullerenes have the ability to down-regulate the pro-oxidant effect of cisplatin on normal cells. These results indicate that C60 fullerenes may influence phagocyte metabolism and have both pro oxidant and antioxidant properties. Conclusions: The antineoplastic effect of C60 fullerene has been observed by direct toxic effect on tumor cells, as well as through the modulation of the functions of effector cells of antitumor immunity. PMID- 30416607 TI - Investigating the Conformation of S100beta Protein Under Physiological Parameters Using Computational Modeling: A Clue for Rational Drug Design. PMID- 30416608 TI - Reliability, Learnability and Efficiency of Two Tools for Cement Crowns Retrieval in Dentistry. PMID- 30416609 TI - Minimal Increase in Total Hip Arthroplasty Surgical Procedural Time with the Use of a Novel Surgical Navigation Tool. AB - Background: Computer-assisted navigation has proven effective at improving the accuracy of component placement during Total Hip Arthroplasty (THA); however, the material costs, line-of-site issues and potential for significant time increases have limited their widespread use. Objective: The purpose of this study was to investigate the impact of an imageless navigation device on surgical time, when compared with standard mechanical guides. Methods: We retrospectively reviewed prospectively collected data from 61 consecutive primary unilateral THA cases (posterior approach) performed by a single surgeon. Procedural time (incision to closure) for THA performed with (intervention) or without (control) a computer assisted navigation system was compared. In the intervention group, the additional time associated with the use of the device was recorded. Mean times were compared using independent samples t-tests with statistical significance set a priori at p<0.05. Results: There was no statistically significant difference between procedural time in the intervention and control groups (102.3+/-28.3 mins vs. 99.1+/-14.7 mins, p=0.60). The installation and use of the navigation device accounted for an average of 2.9 mins (SD: 1.6) per procedure, of which device related setup performed prior to skin incision accounted for 1.1 mins (SD: 1.1) and intra-operative tasks accounted for 1.6 mins (SD: 1.2). Conclusion: In this series of 61 consecutive THAs performed by a single surgeon, the set-up and hands on utilization of a novel surgical navigation tool required an additional 2.9 minutes per case. We suggest that the intraoperative benefits of this novel computer-assisted navigation platform outweigh the minimal operative time spent using this technology. PMID- 30416610 TI - Exosome Biogenesis and Biological Function in Response to Viral Infections. AB - Introduction: Exosomes are extracellular vesicles that originate as intraluminal vesicles during the process of multivescular body formation. Exosomes mediate intercellular transfer of functional proteins, lipids, and RNAs. The investigation into the formation and role of exosomes in viral infections is still being elucidated. Exosomes and several viruses share similar structural and molecular characteristics. Explanation: It has been documented that viral hijacking exploits the exosomal pathway and mimics cellular protein trafficking. Exosomes released from virus-infected cells contain a variety of viral and host cellular factors that are able to modify recipient host cell responses. Recent studies have demonstrated that exosomes are crucial components in the pathogenesis of virus infection. Exosomes also allow the host to produce effective immunity against pathogens by activating antiviral mechanisms and transporting antiviral factors between adjacent cells. Conclusion: Given the ever growing roles and importance of exosomes in both host and pathogen response, this review will address the impact role of exosome biogenesis and composition after DNA, RNA virus, on Retrovirus infections. This review also will also address how exosomes can be used as therapeutic agents as well as a vaccine vehicles. PMID- 30416612 TI - Comparative Clinical Analysis of Gastroenteropancreatic Neuroendocrine Carcinomas with Liver Metastasis and Primary Hepatic Neuroendocrine Carcinomas. AB - Purpose: The objective of this study was to analyze the clinical features and prognosis of gastroenteropancreatic (GEP) neuroendocrine carcinomas (NECs) with liver metastasis and primary hepatic neuroendocrine carcinomas (PHNECs), as these rare hepatic neuroendocrine carcinomas have not been exhaustively studied. Methods: The clinical data of 47 patients with hepatic NECs were retrospectively reviewed and categorized to analyze features and prognosis. Results: The 47 studied cases comprised 13 cases of primary hepatic NECs (primary group) and 34 cases of metastatic hepatic NECs (metastatic group). Male patients were slightly dominant in both groups, while no age predilection was present. PHNECs were mostly single nodules located in the right lobe of the liver. Metastatic hepatic NECs originated mostly from the pancreas and stomach without distinction of the lobes of the liver. Univariate analysis showed that the treatment protocol (radical operation or others) was correlated with the overall survival (OS; p < 0.05) in the primary group, while treatment protocol and cytokeratin 7 (CK7) were associated with OS (p < 0.05) in the metastatic group. Cox proportional hazard regression showed that radical operation was an independent prognostic factor (p < 0.05) for OS in the metastatic group. Conclusions: No significant differences in the clinicopathological features between PHNECs and metastatic hepatic GEP NECs were found, but radical operation was significantly correlated with OS for both carcinomas. Radical operation is the first choice for patients who are eligible for operation. PMID- 30416611 TI - The role of emotion regulation in moral judgment. AB - Moral judgment has typically been characterized as a conflict between emotion and reason. In recent years, a central concern has been determining which process is the chief contributor to moral behavior. While classic moral theorists claimed that moral evaluations stem from consciously controlled cognitive processes, recent research indicates that affective processes may be driving moral behavior. Here, we propose a new way of thinking about emotion within the context of moral judgment, one in which affect is generated and transformed by both automatic and controlled processes, and moral evaluations are shifted accordingly. We begin with a review of how existing theories in psychology and neuroscience address the interaction between emotion and cognition, and how these theories may inform the study of moral judgment. We then describe how brain regions involved in both affective processing and moral judgment overlap and may make distinct contributions to the moral evaluation process. Finally, we discuss how this way of thinking about emotion can be reconciled with current theories in moral psychology before mapping out future directions in the study of moral behavior. PMID- 30416613 TI - Percutaneous coronary intervention in a rare case of Type V dual LAD. AB - Congenital coronary anomalies are rare and reported to occur in 0.64-1.3% of patients undergoing coronary angiography. The dual left anterior descending coronary artery (LAD) is a rare coronary anomaly defined as the presence of two LADs in the anterior interventricular sulcus (AIVS). It consists of a short LAD that ends high in the AIVS and a longer LAD that enters the distal AIVS and feeds apex. Percutaneous interventions are even more uncommon in dual LAD especially Type V LAD. Thus we describe an interesting case of percutaneous transluminal coronary angioplasty (PTCA) with stenting to Type V dual LAD in a patient with chronic stable angina who was refractory to maximal anti-anginal medications. Our case was unique for these aspects - 1)Type V dual LAD is rare.2)Ramus artery is present in fewer cases of dual LAD.3)Long LAD had a myocardial bridge.4)Few cases have been reported of PTCA with stenting to short LAD. . PMID- 30416614 TI - A case of spontaneous coronary artery dissection complicated with pseudoaneurysm healed by medical treatment: Follow-up by multidetector computed tomography. AB - Spontaneous coronary artery dissection (SCAD) is a rare cause of acute myocardial ischemia. Identification of intimal flap, true and false lumens in coronary angiogram (CAG) is the standard method to diagnose SCAD. In cases of obscure intimal flap, intravascular ultrasound (IVUS) is a useful method to diagnose, although crossing the wire and IVUS in the dissected lesion is invasive. Multidetector computed tomography (MDCT) provides valuable information in any clinical setting less invasively. We report here a rare case of spontaneous dissecting coronary artery pseudoaneurysm diagnosed by CAG and MDCT, healed by medical treatment, and followed up by MDCT over a 2-year period. . PMID- 30416615 TI - Multiple coronary and cerebral aneurysms in a patient with chronic thromboangiitis. AB - A 73-year-old man had multiple coronary aneurysms that resulted in acute myocardial infarction on the day before surgery for cerebral aneurysms. Emergent coronary angiography revealed that the lesion that caused the myocardial infarction was a distal left circumflex artery, and two huge coronary aneurysms were also found in the left circumflex artery. A two-stage treatment strategy was planned, including coronary aneurysm surgery, followed by cerebral aneurysm surgery. He underwent coronary artery aneurysmorrhaphy with closure of the ostia of the afferent and efferent arteries, and coronary artery bypass grafting with a saphenous vein graft applied to the left circumflex artery. The pathological findings suggested chronic thromboangiitis, as the inflammatory cells were observed to have infiltrated the coronary artery wall. The tissue remodeling of the aneurysmal wall indicated a positive response to tenascin C. We report a case of multiple coronary aneurysms, focusing on the pathological findings. . PMID- 30416616 TI - Detecting intimal tear and subintimal blood flow of thrombosed acute aortic dissection with ulcer-like projections using non-obstructive angioscopy. AB - A 73-year-old man reporting severe chest and back pain for 20 min was admitted to our hospital. The pain occurred 3 days before admission. Computed tomography angiography showed a hazy-surfaced low-density area in the aortic arch with aneurysmal formation of unknown etiology. It was inconclusive whether the aortic change was acute or chronic because no previous information was available. To investigate the etiology, non-obstructive angioscopy (NOA) was performed. A fissure with blood flow was detected at the surface of the low-density area and active subintimal blood flow was demonstrated on NOA. An entry tear and active blood flow below the intima at the seemingly thrombosed area suggested that the patient had a thrombosing type B aortic dissection. . PMID- 30416617 TI - Inferior vena cava thrombus due to hyperhomocysteinemia. AB - We report a case of a 39-year-old man with inferior vena cava (IVC) thrombus after withdrawal of IVC filter. He complained of 1-week history of swelling in his right leg, and computed tomography (CT) demonstrated occlusive thrombus in right femoral and popliteal veins. Venous thrombectomy was attempted after IVC filter placement. The filter was withdrawn without IVC filter-associated thrombus and the patient was discharged on warfarin. On day 21 after discharge, he complained of progressive swelling and CT revealed a significant amount of thrombus in IVC where the filter had been placed. Despite adequate anticoagulant therapy, CT showed increased thrombus extending from infra-renal IVC to common iliac vein. Systemic work-up for the risk factors of venous thromboembolism revealed the presence of hyperhomocysteinemia (total homocysteine 83.1 MUmol/L; normal range 5-15 MUmol/L) due to unbalanced diet with deficiency of folic acid and vitamin B12. Four weeks after administration of folic acid, vitamin B6/B12 as the treatment of hyperhomocysteinemia in addition to warfarin, swelling of his leg improved with significant resolution of thrombus by CT. CT also demonstrated a severe stenosis of the IVC just below the renal veins. At 6 months, he complained of mild post-thrombotic sequelae with no evidence of recurrent IVC thrombus. . PMID- 30416618 TI - Critical exacerbation of idiopathic pulmonary fibrosis after transcatheter aortic valve implantation: Need for multidisciplinary care beyond "heart team". AB - An 82-year-old man with severe aortic stenosis and idiopathic pulmonary fibrosis (IPF) underwent transcatheter aortic valve implantation (TAVI) under general anesthesia. However, following a successful TAVI procedure, he developed progressive respiratory failure because of the exacerbation of IPF. Despite the use of immunosuppressants, the patient could not be saved and he died of respiratory failure. Although TAVI is a less invasive procedure compared to conventional surgical aortic valve replacement, it is currently selected for management of severely ill, frail, and elderly patients. This case highlights the potential risk of IPF exacerbation following a TAVI procedure performed under general anesthesia. . PMID- 30416619 TI - A case of medical management of tricuspid regurgitation related to atrial fibrillation with constrictive pericarditis-like hemodynamics. AB - Severe tricuspid regurgitation (TR) is reported to represent a hemodynamic pattern similar to that of constrictive pericarditis (CP), which should be clearly differentiated for appropriate management. We report the case of a patient with severe TR due to atrial fibrillation (AF) in whom hemodynamic monitoring played a role in the selection of the management strategy. An 81-year old Japanese man with chronic AF was admitted due to worsening heart failure. Echocardiography showed the dilation of bilateral atria and a right ventricle with severe TR. The right heart catheterization demonstrated the elevation and equalization of diastolic pressures of four cardiac chambers with impaired diastolic filling pattern, which are hallmarks of pericardial constriction due to CP. Of note, the CP-like hemodynamics were completely normalized by 10 days of medical therapies including diuretics and carperitide. After his discharge and over a 1-year follow-up, he has never experienced worsening heart failure and remained NYHA class II with moderate TR. Medical management targeted at volume reduction and vasodilation can be a therapeutic option for CP-like hemodynamics in isolated severe TR related to AF. Repeated hemodynamic assessment is an appropriate tool to help our understanding of the CP-like physiology caused by severe TR based on chronic AF. . PMID- 30416620 TI - Source of medicines and medicine information by self-reported persons living with hypertension and diabetes in rural and urban Ghana. AB - Objectives: This study was conducted to determine the source of medicines and medicine information of persons living with hypertension and diabetes in rural and urban Ghana and assessing if they are influenced by predisposing and enabling factors as defined by Andersen's behavioural model. Methods: A population based cross sectional study was conducted in four (4) rural and four (4) urban districts in the Ashanti Region of Ghana. A multistage and proportional sampling method was used in enrolling participants aged 18 years and above. A pre-tested structured questionnaire was used to collect primary data from respondents. Data collected was exported to STATA for analysis. Descriptive analysis was performed. Chi-square tests/Fisher's exact test and multinomial logistic regression models were used to establish association between variables. Results: A total of 336 self -reported persons with hypertension and diabetes were enrolled in the study with 199(59.23%) living in urban communities. The majority of participants with hypertension and diabetes living in the rural communities 77 (56.20%) were females contrasting with the male majority in urban communities 106 (53. 27%). In the rural communities, 49 (35.77%) of participants sourced medicines from the health centre while 45 (32.85%) and 35(25.55%) sourced medicines from the hospital and over the counter medicine shop (OTCMS) respectively. In the urban communities, 153 (76.88%) sourced medicines from the hospital while 33 (16.58%) sourced medicines from the pharmacy. The predisposing factor age (OR: 1.1, 95%CI 1.040-1.210) under OTCMS, age (OR 1.0, 95% CI: 1.002-1.066) under hospital and enabling factor socioeconomic status (OR: 0.3, 95%CI 0.085-0.855) under Hospital influenced participant's source of medicine in the urban communities. The results also revealed that majority of participants in both rural 99 (72.26%), and urban 164 (82.41%) communities sourced medicine information mainly from public healthcare facilities, pre-disposing factors; age (OR 1.1 95%CI 1.032-1.270) under family member, age (OR 1.1, 95%CI 1.022-1.167) under friend health professional, age (OR 1.1, 95%CI 1.050-1.147) under nearest health institution, marital status (OR: 0.004, 95%CI 0.003-0.441) under friend health Professional were found to influence participants' source of medicine information in the urban communities while in the rural communities the predisposing factor marital status (OR 10.6, 95%CI 1.044 -106.835), education (OR: 26.1, 95%CI 1.271-537.279) under friend health professional, age (OR 1.1, 95%CI 1.002-1.187), educational level (OR 30.6, 95%CI 1.718-546.668) under nearest health institution and enabling factor socio-economic status (OR 6.6, 95%CI 1.016 -43.510) under nearest health institution influenced one's source of medicine information. Conclusions: Majority of inhabitants with hypertension and diabetes in both rural and urban communities, sourced medicines and medicine information from public health institutions though a larger proportion was recorded in the urban communities. More participants in the rural communities than in the urban communities sourced medicines and medicine information from community pharmacies. Participants' source of medicine and medicine information was influenced by both predisposing and enabling factors. PMID- 30416621 TI - Knowledge of pharmacists and parents towards antibiotic use in pediatrics: a cross-sectional study in Lebanon. AB - Objectives: to assess the knowledge of both parents and community pharmacists regarding antibiotics use and resistance in pediatrics in Lebanon. Methods: A cross-sectional study was conducted between June and August 2017 in community pharmacies. A pre-established questionnaire targeting knowledge of parents and pharmacists regarding antibiotics use/misuse was carried out. An index of knowledge was computed to assess factors associated with good knowledge on antibiotics use/misuse. Results: The study showed that 28.7% of pharmacists did not know which factors may contribute to antimicrobial resistance. Concerning the misuse of antibiotics, pharmacists blamed at first parents (90.1%), at second level physicians (72.8%), and third themselves (59.4%). Furthermore, pharmacists believed that the socioeconomic problems of the country (86.1%), the level of resistance to the molecule of choice (80.8%), the lack of consultation time (71.2%) and the lack of national guidelines/recommendations (66.3%) might be additional factors contributing to antimicrobial resistance. In case of acute otitis media, the majority of pharmacists chose the correct treatment, dose and duration according to international guidelines; this was in contrast to the results obtained in case of pharyngitis. Female pharmacists had a significantly higher knowledge score compared to their male counterparts (ORa=2.51). Half of parents (42.6%) declared that antibiotics act against both viruses and bacteria, 55.9% still believe that the presence of fever requires the administration of antibiotics, 50% didn't know the consequences of antibiotics misuse, 58.4% said that it is okay to give their child antibiotics without a physician's advice or based on a pharmacist's recommendation, and 66.7% trusted the pharmacist in the antibiotic prescription. Parents with a university level of education or a master's degree had significantly better knowledge compared to illiterate ones (ORa=9.04 and ORa=16.46, respectively). Conclusions: Based on the results obtained, it would be necessary to implement educational campaigns in order to increase awareness on antibiotics misuse and resistance in pediatrics. PMID- 30416622 TI - Evaluation of a vancomycin dosing nomogram in obese patients weighing at least 100 kilograms. AB - Background: There remains variability in both practice and evidence related to optimal initial empiric dosing strategies for vancomycin. Objective: Our primary objective was to describe the percentage of obese patients receiving vancomycin doses consistent with nomogram recommendations achieving targeted initial steady state serum vancomycin concentrations. Secondary objectives were to describe the primary endpoint in subgroups based on patient weight and estimated creatinine clearance, to describe the rate of supratherapeutic vancomycin accumulation following an initial therapeutic trough concentration, and to describe the rate of vancomycin-related adverse events. Methods: This single-center, IRB-approved, retrospective cohort included adult patients >= 100 kilograms total body weight with a body mass index (BMI) >30 kilograms/m2 who received a stable nomogram based vancomycin regimen and had at least one steady-state vancomycin trough concentration. Data collected included vancomycin regimens and concentrations, vancomycin indication, serum creatinine, and vancomycin-related adverse events. Patients were divided into two cohorts by goal trough concentration: 10-15 mcg/mL and 15-20 mcg/mL. Results: Of 325 patients screened, 85 were included. Goal steady-state concentrations were reached in 42/85 (49.4%) of total patients. Conclusions: Achievement of initial steady-state vancomycin serum concentrations in the present study (approximately 50%) was consistent with the use of published vancomycin dosing nomograms. PMID- 30416623 TI - Falls in the elderly: assessment of prevalence and risk factors. AB - Background: Falls in elderly people can lead to serious health problems. There is limited knowledge about the prevalence of falls, risk factors and causes of falls in the United Arab Emirates. Objective: To assess the prevalence of falls among older adults aged 60 years and above and to determine the risk factors associated with falls. Methods: This cross-sectional study was conducted using an anonymous, 20-item questionnaire which was developed in English and Arabic to be delivered as a semi-structured interview. The pre-piloted questionnaire was distributed to 510 families with at least one elderly person. The study was conducted in Sharjah and Dubai, United Arab Emirates, from September to November 2017. Results: Participants were Arabs (368; 99.5%), living with family (339; 91.6%), females (256; 69.2%), married (240; 64.9%), holders of a university Bachelor's degree (110; 29.7%), and unemployed (154; 41.6%). Almost half of the participants (188; 50.8%) had a fall in the past two years, and three quarters (141; 75%) of those claimed that their illness was the reason for their fall. The results indicate that female and 70 years and above old participants are more likely to experience falls than males and younger counterparts respectively. A larger proportion of elderly participants not taking medications did not experience falls, while those on 1-4 medications fallers were less than non-fallers. However as the number of medications increased to 5-8 and more than 8 the number of those experiencing falls was significantly higher than non-fallers. Conclusions: Falls are prevalent among the elderly population studied and efforts should be made to decrease the incidence of falls, identify those at risk and increase awareness about falls and their health consequences among the elderly and the general public. PMID- 30416624 TI - Measuring the health literacy level of Arabic speaking population in Saudi Arabia using translated health literacy instruments. AB - Background: Health literacy is an essential predictor of health status, disease control and adherence to medications. Objectives: The study goals were to assess the health literacy level of the general population in Saudi Arabia using translated Gulf Arabic version of the short-version of the Test of Functional Health Literacy in Adults (S-TOFHLA) and Single Item Literacy Screener (SILS) tests and to measure the relationship between health literacy and education level. Methods: The study was a cross-sectional with a convenience sample of 123 participants from the general population in Riyadh. Data were collected using the modified (Gulf) Arabic versions of both S-TOFHLA and SILS. Fisher's Exact test was used to measure the difference of the health literacy scores according to the education degrees and Cronbach's alpha was used to measure the internal consistency of the S-TOFHLA items. Results: More than half (55.4%) of the participants were male, 50.4% had a middle school or less education level, and we found that 84.4% had adequate health literacy as measured by the S-TOFHLA, compared to 49.6% as measured by SILS. The Fisher's Exact test showed a significant difference (P<.05) in the S-TOFHLA and SILS scores according to education categories. Conclusions: The level of education has a significant positive association with S-TOFHLA and SILS results. The Gulf Arabic version of S TOFHLA is a reliable test with a good internal consistency and a significant positive correlation between the two parts of S-TOFHLA. We recommend the use of S TOFHLA or SILS at the first patient visit. PMID- 30416625 TI - Assessing pet owner and veterinarian perceptions of need for veterinary compounding services in a community pharmacy setting. AB - Background: Pets, pet owners (referred to as clients in veterinary medicine and throughout this article), veterinarians, and community pharmacies may all benefit from veterinary compounding services provided in community pharmacies, but the benefits of this service are not well-documented in the literature. Objectives: This study identified perceived benefits and barriers and evaluated the need for veterinary compounding services in community pharmacies; it also evaluated current business practices related to veterinary compounding services. Methods: A cross-sectional survey was administered to three groups: 1) clients who filled a pet prescription at a study pharmacy, 2) clients who had not filled pet prescriptions, and 3) local veterinarians. Eligible participants were 18 or older; clients must have owned a pet in the past five years. The surveys collected demographic information and assessed benefits, barriers, need, and business practices regarding veterinary compounding services. Demographics were evaluated through descriptive statistics. Responses to Likert-scale items were compared between groups using the Mann-Whitney U test. Qualitative responses were assessed for emerging themes. Results: One hundred eighteen clients and 15 veterinarians participated in the study. Seventy-two of 116 clients (62%) and eight of 10 veterinarians (80%) agreed that clients would benefit from veterinary compounds provided in community pharmacies. Only 40% of veterinarians agreed that community pharmacists have the knowledge to compound pet medications, compared to 67% of clients (P=0.010). Similarly, 47% of veterinarians agreed that community pharmacists have the skills to compound pet medications, compared to 72% of clients (P=0.016). Forty-eight of 118 clients (41%) would travel 10 miles or more out of their way for veterinary compounding services at community pharmacies. Conclusions: This study assessed client and veterinarian perceptions of veterinary compounding service benefits, barriers, and need in community pharmacies. Clients identified more opportunities for veterinary compounding services in community pharmacies when compared to veterinarians. Both groups identified a need for veterinary compounding services and agreed community pharmacies providing these services would benefit pets and clients. PMID- 30416626 TI - Potentially inappropriate medication use among older patients attending a geriatric centre in south-west Nigeria. AB - Objectives: To determine the prevalence and describe factors associated with the use of potentially inappropriate medication (PIM) among older patients. Methods: Cross sectional study of 400 older patients selected systematically at the geriatric centre, University College Hospital, Ibadan between July and September 2016. With the aid of semi-structured questionnaires, information on the socio demographic characteristics, lifestyle habits, healthcare utilisation and morbidities was obtained. The Beer's criteria 2015 update was used to identify the PIMs. Predictors of PIMs were determined using multivariate analyses at alpha 0.05. Results: Age was 70.2 (SD=5.9) years and 240 (60%) were females. General prescription pattern showed antihypertensives (34.7%) as the commonest medications used. The point prevalence of PIMs use was 31%. In all, 10 PIMs were used by the respondents. The majority (81.5%) were using one PIM, while (17.7%) used two PIMs and (0.8%) 3 PIMs. NSAIDs (72.6%) were the commonest PIMs identified, followed by the benzodiazepines (24.2%). Respondents had an average of 1.9 morbidities, and mulitmorbidity found in 60.5%. Logistic regression analysis showed self-rated health assessed as better compared with age-mates [OR =1.718 (1.080-2.725)] and being physically active [OR =1.879 (1.026-3.436)] as the most significantly associated with PIMs use. Conclusions: The use of PIMs among older patients in our setting was high with NSAIDs being the most frequently used medications. An interdisciplinary approach, of medication review by pharmacists', working with physicians may improve prescribing practices among older persons. Therefore, it is necessary to create public health awareness on the use of PIMs among older persons. PMID- 30416627 TI - Evaluation of a prompt card for community pharmacists performing consultations with patients on anticoagulation - lessons learned. AB - Objectives: To evaluate a prompt card (i.e., a post-card sized tool that lists counselling prompt information) with 5 key elements and 3 open key questions to ask patients in community pharmacies. Methods: Community pharmacists practicing in England and accredited to perform consultations used the prompt card during a formal consultation with emphasis on patients receiving oral anticoagulation. Main outcome measure was the number of performed consultations with pharmacists' thoughts and feedbacks in writing. Results: During 8 weeks, 19 pharmacists (mean age: 36.6 (SD=9) years; 7 women; accredited an average of 12.9 (SD=9.8) years) performed 1,034 consultations and used the prompt card 104 times during anticoagulation consultations. Overall the prompt card was judged practical and relevant by the 16 pharmacists who used it (100%), especially because it outlines what a good consultation should comprise. The key elements offered a logical framework to guide the overall approach when undertaking a consultation. The two questions, "Why do you want to use this medicine?" and "Why would you not want to use this medicine?" generated negative responses from the patient and pharmacists, respectively. Conclusions: Our prompt card with key questions summarizing all the points that should be addressed in a consultation supported effective communication during patient-pharmacist interaction. Two questions need rephrasing and a further question is needed to determine how patients are using their medicines. PMID- 30416628 TI - Benzodiazepine and z-hypnotic prescribing from acute psychiatric inpatient discharge to long-term care in the community. AB - Background: Benzodiazepine and z-hypnotic prescribing has slowly decreased over the past 20 years, however long-term chronic prescribing still occurs and is at odds with prescribing guidance. Objectives: To identify the pattern of benzodiazepine and z-hypnotic prescribing in psychiatric inpatients at discharge and 12 months post-discharge. Methods: Retrospective observational longitudinal cohort study of patients admitted to two adult psychiatric wards between June and November 2012 (inclusive) who were discharged with a prescription for a benzodiazepine or z-hypnotic drug. Routinely collected prescription data available from NHS Scotland Prescribing Information System was used to identify and follow community prescribing of benzodiazepine and z-hypnotics for a 12 month period post-discharge. Data were entered in Excel(r) and further analysed using SPSS 23. Ethical approval was not required for this service evaluation however Caldicott Guardian approval was sought and granted. Results: Eighty patients were admitted during the study period however only those patients with a single admission were included for analysis (n=74). Thirty per cent (22/74) of patients were prescribed a benzodiazepine or z-hypnotics at discharge; 14 of whom received 'long-term' benzodiazepine and z-hypnotics i.e. continued use over the 12 month period. Seven patients received a combination of anxiolytics and hypnotics (e.g., diazepam plus temazepam or zopiclone). Long-term use was associated with a non significant increase in median benzodiazepine or z-hypnotic dose, expressed as diazepam equivalents. Conclusions: One in three patients were prescribed a benzodiazepine or z-hypnotics at discharge with 1 in 5 receiving continuous long term treatment (prescriptions) for 12 months post-discharge. As chronic long-term B-Z prescribing and use still remains an issue, future strategies using routine patient-level prescribing data may support prescribers to review and minimise inappropriate long-term prescribing. PMID- 30416629 TI - Pain management in hospitals: patients' satisfaction and related barriers. AB - Background: Suboptimal pain control has been frequently reported in healthcare settings and documented to negatively impact patients' health. Patients' perception regarding pain management may influence their satisfaction regarding treatment. Objectives: This study focuses on the assessment of patients' satisfaction regarding pain therapy and defining patient-related barriers for its implication. Methods: A cross-sectional study was conducted in two tertiary care hospitals from April till July 2017. A face-to face interview questionnaire was filled regarding pain scores and patients' attitudes regarding pain management. Both medical and post-surgical adult patients with all types of pain were eligible to participate. A descriptive analysis of patient satisfaction and perceptions regarding pain management was done. Results: Results from 183 participants with a mean age of 49 (SD=17.33) revealed that pain was their main reason for hospitalization (71.6% of the cases). Numeric pain scores were recorded only in 14.2% of the patient medical files. Pain intensity documentation by healthcare professionals was found in 41.5% of the cases, and 7.7% of the patients had to wait for more than 30 minutes before getting the pain medication. Around 85% of the patients were satisfied with their pain management. Patients' barriers to effective pain therapy were mainly fear of adverse effects, addiction, and additional costs (p<0.05). Conclusions: Pain remains a prevalent problem that requires more efforts for improvement. Our study can effectively serve as a start for larger studies where barriers to pain management can be assessed as an independent variable affecting pain management practice. PMID- 30416630 TI - Knowledge, practice and attitudes regarding antibiotics use among Lebanese dentists. AB - Objectives: Explore antibiotic use, assess conformity with evidence-practice guidelines, and describe knowledge and attitudinal factors among Lebanese dentists. Methods: National cross-sectional telephonic survey, using a standardized questionnaire addressing demographic, educational and professional data, usual antibiotics prophylactic and curative prescription pattern and influential factors, knowledge concerning antibiotics use in selected patient populations, and attitude regarding antimicrobial resistance. Analyses used descriptive statistics, and bivariate analysis to observe predictors of higher knowledge. Results: the overall response rate for the study was around 21%. 322 dentists participated. On average, 17.51% of consultations resulted in antibiotic use; previous antibiotic experience mostly influenced prescriptions (81.3%). Referral of pregnant and lactating women and cardiac patients, when antibiotics are needed, was high (26.9%, 28.5% and 79.4%, respectively). Macrolides were the dominant first-line antibiotics in penicillin allergy (47.4%). Penicillins were most common for pregnant and lactating women. Penicillins (95.0%), 2g (63.9%), and 1 hour pre-procedure (34%) were the main components of prophylaxis for cardiac patients. Prophylactic and curative use varied widely; few dentists exhibited guideline-conform prescriptions. Mean knowledge scores of prophylaxis for cardiac and non-cardiac patients, and antibiotics' side effects were predominantly poor (46.75+/-14.82, 39.21+/-33.09 and 20.27+/-18.77, respectively over 100). Practicing outside Beirut, undergraduate qualification in Lebanon, and post-graduate qualification predicted higher knowledge. 75.9% acknowledged the contribution of dentistry-based prescribing to antibiotic resistance and 94.7% knew at least one cause of resistance. Conclusions: Dentists show positive attitude towards antimicrobial resistance. Yet, they lack uniformity in antibiotic stewardship. Poor knowledge and guideline-incongruent prophylactic and therapeutic prescribing are observed. Development of targeted interventions is needed to promote judicious antibiotic use within Lebanese dentistry. PMID- 30416631 TI - Erratum to: What drives using antibiotic without prescriptions? A qualitative interview study of university students in United Arab Emirates. AB - [This corrects the article on p. 1172 in vol. 16, PMID: 30023027.]. PMID- 30416632 TI - Management of allergic rhinitis in the community pharmacy: identifying the reasons behind medication self-selection. AB - Background: Community pharmacists have a key role to play in the management of allergic rhinitis (AR). Their role is especially important because the majority of medications used to treat AR are available for purchase over-the-counter (OTC), allowing patients to self-select their own medications and bypass the pharmacists. Patients' self-selection often results in suboptimal treatment selection, undertreated AR and poor clinical outcomes. In order for pharmacists to optimise the care for AR patients in the pharmacy, pharmacists need to be able to identify patient cohorts who self-select and are at high risk of mismanagement. Objectives: This study aimed to compare the demographics, clinical characteristics and medication selected, between pharmacy customers who choose to self-select and those who speak with a pharmacist when purchasing medication for their AR in a community pharmacy and identify factors associated with AR patients' medication(s) self-selection behaviour. Methods: A cross-sectional observational study was conducted in a convenience sample of community pharmacies from the Sydney metropolitan area. Demographics, pattern of AR symptoms, their impact on quality of life (QOL) and medication(s) selected, were collected. Logistic regressions were used to identify factors associated with participants' medication self-selection behaviour. Results: Of the 296 recruited participants, 202 were identified with AR; 67.8% were female, 54.5% were >40 years of age, 64.9% had a doctor's diagnosis of AR, and 69.3% self-selected medication(s). Participants with AR who self-select were 4 times more likely to experience moderate-severe wheeze (OR 4.047, 95% CI 1.155-14.188) and almost 0.4 times less likely to experience an impact of AR symptoms on their QOL (OR 0.369, 95% CI 0.188-0.727). Conclusions: The factors associated with AR patients' self selecting medication(s) are the presence of wheeze and the absence of impact on their QOL due to AR symptoms. By identifying this cohort of patients, our study highlights an opportunity for pharmacists to engage these patients and encourage discussion about their AR and asthma management. PMID- 30416633 TI - Resource-based theory of competitive advantage - a framework for pharmacy practice innovation research. AB - A growing body of research demonstrates the effectiveness of evidence-based pharmacy practice, but too many practice innovations fail to survive past the initial implementation and study phase. This paper presents the resource-based theory of competitive advantage as a framework for describing, understanding, and predicting the adoption and dissemination pharmacy service innovations into routine practice. The theory argues that the sustainability of any business innovation (e.g., pharmacy service) is based upon (1) the internal resources of the firm offering it, (2) the firm's capabilities in using those resources, (3) the competitive advantage to the firm of its resources and capabilities, (4) the attractiveness of the market in which it competes, and (5) the innovation's contribution to financial performance of the firm. This paper argues that the resource-based theory of competitive advantage provides a foundation for comparing findings from different research frameworks and studies relating to innovations in services, service processes, and service business models. The paper also poses a number of research questions related to the theory that can be used to further the literature about pharmacy practice innovations. Finally, it makes a case that competition is a fundamental aspect of pharmacy practice and the resource-based theory of competitive advantage can serve as a general theory for studying innovations in pharmacy practice and in the social and administrative sciences. PMID- 30416634 TI - Psychiatric Disorders in Complex Regional Pain Syndrome (CRPS): The Role of the Consultation-Liaison Psychiatrist. AB - Background: Complex regional pain syndrome (CRPS) is a multifactorial disorder with complex aetiology and pathogenesis. At the outpatient pain clinic of Magdeburg University Hospital, all patients, without exception, are subject to permanent psychiatric care delivered by a consultation-liaison psychiatrist. In CRPS, psychological stabilization and treatment of the neuropathic aspects are equally important. The aim of this single-center retrospective study was to determine mental/psychiatric defects impairing pain processing at the time of investigation and show the effects of treating mental disorders and neuropathic pain with the same psychotropic drugs. Method: On admission, the consultation liaison psychiatrist examined the mental state of every patient in a semistructured interview according to AMDP (working group for methods and documentation in psychiatry). Due to the model of the Department of Anaesthesiology, we are able to compare the group of CRPS patients with all other outpatients treated for pain. Results: The medical treatment of psychiatric dysfunction leads to an analgesic effect. Only every second CRPS patient had an additional psychiatric diagnosis, and 15.6% were diagnosed with depressive mood disorders and show a higher prevalence of depressive symptoms than the general population and exceed the mean for all patients treated in our pain clinic. Conclusions: In neuropathies, treatment of the neuropathic pain has a modulating effect on mental disorders. As CRPS patients are frequently affected by depressions, and owing to the connection between depression and suicidal tendencies, patients should be seen by a consultation-liaison psychiatrist, and nonpsychiatrists should pay special attention to this patient group. PMID- 30416635 TI - The Analgesic Efficacy of Transverse Abdominis Plane Block versus Epidural Block after Caesarean Delivery: Which One Is Effective? TAP Block? Epidural Block? AB - Introduction and Objective: TAP block has gained popularity to provide postoperative analgesia after abdominal surgery but its advantage over epidural analgesia is disputed. For lower abdominal surgeries, epidural analgesia has been the gold standard and time-tested technique for providing postoperative analgesia, but contraindications for the same would warrant need for other equally good analgesic techniques. The objective of this study is to compare the analgesic efficacy of both the techniques. Materials and Methods: Eighty patients in the ASA I-II risk group, undergone an elective C-section, were randomly assigned to the study. In the TAP group, before the C-section, a single-dose spinal anaesthesia was performed by administering 3 ml of 0.5% hyperbaric bupivacaine to the patients when they were in the sitting position. After the C section, an ultrasound-guided bilateral TAP block was performed in these patients in the recovery room for postoperative analgesia. In the single-dose EPI group, the patients received 16 cc of isobaric bupivacaine, 3 mg of morphine, and 50 mcg of fentanyl, making a total volume of 20 cc and being administered to the epidural space. Results: A higher level of patient satisfaction was observed in the EPI group (p=0.003). The amount (mg) of total analgesics received by the patients in the first 24 hours of the postoperative period was statistically significantly higher (p=0.021) in the TAP group compared to the EPI group. The visual analogue scale (VAS) scores of the EPI group were significantly lower compared to that of the TAP group (p < 0.001). Conclusion: The epidural anaesthesia is still the golden standard to achieve a postcaesarean analgesia. Epidural anaesthesia is a considerably effective method in controlling the postoperative pain. We are of the opinion that epidural anaesthesia should be preferred in the first place to achieve a successful postcaesarean analgesia as it provides more effective pain control. PMID- 30416636 TI - Early recognition and diagnosis of Ewing sarcoma of the cervical spine. AB - Ewing sarcoma of the cervical spine is a rare diagnosis. Early recognition and treatment of this condition improves survival. Reported is a case of a 20-year old male patient who presented with increasing neck pain. Computed tomography and magnetic resonance imaging showed a mass with a primary differential diagnosis of Ewing sarcoma. As a result of mass effect and spinal cord compression, immediate medical intervention was deemed necessary to prevent neurologic deficits. PMID- 30416637 TI - Computed tomography imaging characteristics of shone syndrome. AB - Shone syndrome was first described in 1963 by Dr JD Shone. It is a constellation of congenital abnormalities compromising approximately 0.6% of all cases of congenital cardiac abnormalities. Shone syndrome is also known as Shone complex, involving several characteristic cardiac abnormalities: coarctation of the aorta, subaortic stenosis, supravalvular mitral ring, and a parachute mitral valve. Given the uncommon nature of the disease, we present this case to illustrate potential postsurgical appearances of Shone syndrome, specifically on computed tomography imaging. PMID- 30416638 TI - A very rare case: Hydatid cyst surrounding uterus and magnetic resonance imaging findings in the pregnant patient. AB - Hydatid cyst disease is very rare in pregnancy having an incidence of 1 in 20,000 pregnancies and there is no recommended standard treatment. Both surgical and medical modalities have been tried. Modalities that do not use ionizing radiation such as ultrasound and magnetic resonance imaging should be preferred for diagnosis and evaluating acute conditions in a pregnant patient. In this article, a rare pelvic cyst hydatid case surrounding the uterus and MRI findings in a young pregnant patient who was coincidentally determined is represented. PMID- 30416639 TI - Congenital intestinal hypoganglionosis: A radiologic mimic of Hirschsprung's disease. AB - Intestinal hypoganglionosis or isolated hypoganglionosis is a rare entity with a clinical and radiologic presentation that can mimic Hirschsprung's disease in the neonatal period. The diagnosis of this entity can be challenging with suction rectal biopsies that are standard for diagnosing Hirschsprung's disease. We present this case of congenital intestinal hypoganglionosis detailing the neonatal course, due to its rarity and the conundrums faced before an eventual diagnosis could be rendered. This case also illustrates the role of full thickness rectal biopsy in selected cases such as ours where the radiologic features are typical of Hirschsprung's, despite negative suction biopsies. PMID- 30416640 TI - TPRM: TENSOR PARTITION REGRESSION MODELS WITH APPLICATIONS IN IMAGING BIOMARKER DETECTION. AB - Medical imaging studies have collected high dimensional imaging data to identify imaging biomarkers for diagnosis, screening, and prognosis, among many others. These imaging data are often represented in the form of a multi-dimensional array, called a tensor. The aim of this paper is to develop a tensor partition regression modeling (TPRM) framework to establish a relationship between low dimensional clinical outcomes (e.g., diagnosis) and high dimensional tensor covariates. Our TPRM is a hierarchical model and efficiently integrates four components: (i) a partition model, (ii) a canonical polyadic decomposition model, (iii) a principal components model, and (iv) a generalized linear model with a sparse inducing normal mixture prior. This framework not only reduces ultra-high dimensionality to a manageable level, resulting in efficient estimation, but also optimizes prediction accuracy in the search for informative subtensors. Posterior computation proceeds via an efficient Markov chain Monte Carlo algorithm. Simulation shows that TPRM outperforms several other competing methods. We apply TPRM to predict disease status (Alzheimer versus control) by using structural magnetic resonance imaging data obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. PMID- 30416641 TI - Crystal Structure Prediction of Magnetic Transition-Metal Oxides by Using Evolutionary Algorithm and Hybrid DFT Methods. AB - Although numerous crystal structures have been successfully predicted by using currently available computational techniques, prediction of strongly correlated systems such as transition-metal oxides remains a challenge. To overcome this problem, we have interfaced evolutionary algorithm-based USPEX method with the CRYSTAL code, enabling the use of Gaussian-type localized atomic basis sets and hybrid density functional (DFT) methods for the prediction of crystal structures. We report successful crystal structure predictions of several transition-metal oxides (NiO, CoO, alpha-Fe2O3, V2O3, and CuO) with correct atomic magnetic moments, spin configurations, and structures by using the USPEX method in combination with the CRYSTAL code and Perdew-Burke-Ernzerhof (PBE0) hybrid functional. Our benchmarking results demonstrate that USPEX + hybrid DFT is a suitable combination to reliably predict the magnetic structures of strongly correlated materials. PMID- 30416643 TI - High-Dimensional Inference for Personalized Treatment Decision. AB - Recent development in statistical methodology for personalized treatment decision has utilized high-dimensional regression to take into account a large number of patients' covariates and described personalized treatment decision through interactions between treatment and covariates. While a subset of interaction terms can be obtained by existing variable selection methods to indicate relevant covariates for making treatment decision, there often lacks statistical interpretation of the results. This paper proposes an asymptotically unbiased estimator based on Lasso solution for the interaction coefficients. We derive the limiting distribution of the estimator when baseline function of the regression model is unknown and possibly misspecified. Confidence intervals and p-values are derived to infer the effects of the patients' covariates in making treatment decision. We confirm the accuracy of the proposed method and its robustness against misspecified function in simulation and apply the method to STAR*D study for major depression disorder. PMID- 30416642 TI - GENETIC AND EPIGENETIC CAUSES OF OBESITY. AB - Obesity is a complex, heritable trait influenced by the interplay of genetics, epigenetics, metagenomics and the environment. With the increasing access to high precision diagnostic tools for genetic investigations, numerous genes influencing the phenotype have been identified, especially in early onset severe obesity. This review summarizes the current knowledge on the known genetic causes of obesity and the available therapeutic options. Furthermore, we discuss the role and potential mechanism of epigenetic changes that may be involved as mediators of the environmental influences and that may provide future opportunities for intervention. PMID- 30416644 TI - Fremyella diplosiphon as a biodiesel agent: Identification of fatty acid methyl esters via microwave-assisted direct in situ transesterification. AB - Increasing concerns on environmental and economic issues linked to fossil fuel use has driven great interest in cyanobacteria as third generation biofuel agents. In this study, the biodiesel potential of a model photosynthetic cyanobacterium, Fremyella diplosiphon, was identified by fatty acid methyl esters (FAME) via direct transesterification. Total lipids in wild type (Fd33) and halotolerant (HSF33-1 and HSF33-2) strains determined by gravimetric analysis yielded 19% cellular dry weight (CDW) for HSF33-1 and 20% CDW for HSF33-2, which were comparable to Fd33 (18% CDW). Gas chromatography-mass spectrometry detected a high ratio of saturated to unsaturated FAMEs (2.48-2.61) in transesterified lipids, with methyl palmitate being the most abundant (C16:0). While theoretical biodiesel properties revealed high cetane number and oxidative stability, high cloud and pour point values indicated that fuel blending could be a viable approach. Significantly high FAME abundance in total transesterified lipids of HSF33-1 (40.2%) and HSF33-2 (69.9%) relative to Fd33 (25.4%) was identified using comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry, indicating that robust salt stress response corresponds to higher levels of extractable FAME. Alkanes, a key component in conventional fuels, were present in F. diplosiphon transesterified lipids across all strains confirming that natural synthesis of these hydrocarbons is not inhibited during biodiesel production. While analysis of photosynthetic pigments and phycobiliproteins did not reveal significant differences, FAME abundance varied significantly in wild type and halotolerant strains indicating that photosynthetic pathways are not the sole factors that determine fatty acid production. We characterize the potential of F. diplosiphon for biofuel production with FAME yields in halotolerant strains higher than the wild type with no loss in photosynthetic pigmentation. PMID- 30416645 TI - Extracorporeal Shock Wave-Supported Adipose-Derived Fresh Stromal Vascular Fraction Preserved Left Ventricular (LV) Function and Inhibited LV Remodeling in Acute Myocardial Infarction in Rat. AB - This study tested the hypothesis that extracorporeal shock wave- (ECSW-) assisted adipose-derived stromal vascular fraction (SVF) therapy could preserve left ventricular ejection fraction (LVEF) and inhibit LV remodeling in a rat after acute myocardial infarction (AMI). Adult male SD rats were categorized into group 1 (sham control), group 2 (AMI induced by left coronary artery ligation), group 3 [AMI + ECSW (280 impulses at 0.1 mJ/mm2, applied to the chest wall at 3 h, days 3 and 7 after AMI), group 4 [AMI + SVF (1.2 * 106) implanted into the infarct area at 3 h after AMI], and group 5 (AMI + ECSW-SVF). In vitro, SVF protected H9C2 cells against menadione-induced mitochondrial damage and increased fluorescent intensity of mitochondria in nuclei (p < 0.01). By day 42 after AMI, LVEF was highest in group 1, lowest in group 2, significantly higher in group 5 than in groups 3 and 4, and similar between the latter two groups (all p < 0.0001). LV remodeling and infarcted, fibrotic, and collagen deposition areas as well as apoptotic nuclei exhibited an opposite pattern to LVEF among the groups (all p < 0.0001). Protein expressions of CD31/vWF/eNOS/PGC-1alpha/alpha-MHC/mitochondrial cytochrome C exhibited an identical pattern, whilst protein expressions of MMP 9/TNF-alpha/IL-1beta/NF-kappaB/caspase-3/PARP/Samd3/TGF-beta/NOX-1/NOX-2/oxidized protein/beta-MHC/BNP exhibited an opposite pattern to LVEF among five groups (all p < 0.0001). Cellular expressions of CXCR4/SDF-1alpha/Sca-1/c-Kit significantly and progressively increased from groups 1 to 5 (all p < 0.0001). Cellular expression of gamma-H2AX/CD68 displayed an opposite pattern to LVEF among the five groups (all p < 0.0001). In conclusion, ECSW-SVF therapy effectively preserved LVEF and inhibited LV remodeling in rat AMI. PMID- 30416646 TI - Scaffold-free cartilage cell sheet combined with bone-phase BMSCs-scaffold regenerate osteochondral construct in mini-pig model. AB - Tissue-engineered condyles provide a promising approach for end-stage osteoarthritis to reconstruct normal physiological structure and function of the temporomandibular joint (TMJ). However, lack of successful biological condyles in large animals restricts clinical translation. Scaffold-free cartilage cell sheets do not contain any polymeric material which potentially risks local nonspecific inflammatory reactions. In this study, we used cartilage cell sheets covering bone marrow mesenchymal stem cells-Polycaprolactone/Hydroxyapatite (BMSCs-PCL/HA) scaffolds (cell sheet group) transplanted subcutaneously and intramuscularly in mini-pigs. In contrast, autogenous chondrocytes were seeded on polyglycolic acid/ polylactic acid (PGA/PLA) scaffolds for 4 and 12 weeks in-vitro pre-cultivation. Then, they were used as a cartilage-phase composition covering BMSCs-PCL/HA scaffolds, then the entirety (biphase scaffold group) was transplanted subcutaneously into mini-pigs. After 12 weeks, the harvested samples were examined histologically. The cartilage layer was evaluated for thickness, glycosaminoglycan (GAG) quantitation, total collagen quantitation and Young's modulus. The biphase scaffold group failed in regeneration, while the cell sheet group regenerated biological condyle with healthy osteochondral construct. The GAG quantitation, total collagen quantitation and Young's modulus of regenerated cartilage was close to those of the natural condyle. Collectively, cartilage cell sheets combined with bone-phase composition had the potential to regenerate biological condylar. PMID- 30416647 TI - Positive effect of RORgammat on the prognosis of thyroid papillary carcinoma patients combined with Hashimoto's thyroiditis. AB - OBJECTIVES: To investigate the positive effect of Th17 cells on the prognosis of patients with PTC and HT. METHODS: The expression of nuclear specific marker RORgammat of Th17 cells in fresh and paraffin thyroid tissues and serum specimens were analyzed. Flow cytometry was used to detect the formation rates of Th17 cells (CD3+CD8-IL-17A+/CD3+CD8-%) at different time points after co-culture of thyroid papillary carcinoma cell line (TPC-1 and K1) and umbilical cord blood initial T lymphocytes. The protein expression of RORgammat in T lymphocytes after co-culture was detected. Preoperative serum levels of Th17 (IL-17) cytokines were measured. RESULTS: The positive expression of RORgammat in the tumor microenvironment of PTC patients with or without HT could inhibit the lymph node metastasis of the tumor. PTC cancer cells could induce initial T lymphocyte to differentiate into Th17 cells, and the K1 cell line with lymph node metastasis induced a higher proportion of RORgammat protein than that in TPC-1 cell line without lymph node metastasis. In PTC patients with HT, serum IL-17 concentration was negatively correlated with lymph node metastasis in the central group. CONCLUSIONS: RORgammat may play an anti-tumor role in reducing thyroid cell damage by reducing the thyroid autoimmune antibodies TPOAb and TGAb in the PTC population in Yunnan plateau region. PMID- 30416648 TI - Improved speckle contrast optical coherence tomography angiography. AB - Optical coherence tomography (OCT) is becoming a clinically useful and important imaging technique due to its ability to provide high-resolution structural imaging in vivo. Optical coherence tomography angiography (OCTA) can visualize vasculature imaging of biological tissues. With the advent of Fourier-domain OCT, numerous OCTA techniques have been developed to detect the microvasculature in vivo. The macular region of the fundus is separated into retinal and choroid regions by segmentation algorithm in the data processing, a false blood flow signal is generated due to bulk motion when vasculature imaging was segmented in the retinal regions. However, the most recent OCT angiographic approaches are sensitive to bulk motion noise. To overcome this limitation, we proposed an improved speckle contrast optical coherence tomography angiography (ISC-OCTA) algorithm to image vasculature network in vivo. The improved speckle contrast image was acquired by the improved speckle contrast algorithm for N consecutive frames of the same location, and the vasculature of the tissue was generated by masking the averaged image with the improved speckle contrast image. ISC-OCTA was tested on in vivo images of a phantom mouse ear and a human macula. Compared to the recently reported algorithms, we found that ISC-OCTA can distinguish the dynamic information of blood flow from static tissue and visualize capillary vessels. Especially when the segmentation data generates false information, the ISC-OCTA algorithm has a significant effect on the suppression of the line noise. ISC-OCTA can provide clear visualization of vessels as other algorithms and may be useful in the diagnosis of ophthalmic diseases. PMID- 30416649 TI - HMGA2 gene silencing reduces epithelial-mesenchymal transition and lymph node metastasis in cervical cancer through inhibiting the ATR/Chk1 signaling pathway. AB - Many cervical cancer (CC) patients suffer from cancer invasion and lymph node metastasis, resulting in poor therapeutic outcome. Evidence has indicated the involvement of misexpressed high-mobility group AT-hook 2 (HMGA2) in poor survival of cancer patients. This study hereby aims to investigate the role of HMGA2 in CC cell biological functions via the ATR/Chk1 signaling pathway. The cell line with the highest HMGA2 expression was selected to establish cell lines with wild-type and stable HMGA2 silencing. The underlying regulatory mechanisms of HMGA2 in CC cells were analyzed with the treatment of the ATR/Chk1 signaling pathway activator, inhibitor, shRNA against HMGA2 or pcDNA-HMGA2 plasmids, followed by quantification of expression levels of ATR, Chk1, Bcl-2, Bax, MMP-2, MMP-9, E-cadherin and N-cadherin. CC cell apoptosis, proliferation, migration, invasion and lymph node metastasis in nude mice were evaluated. The HeLa cell line with the highest HMGA2 expression was selected. HMGA2 inhibited the activation of the ATR/Chk1 signaling pathway. Notably, HMGA2 silencing or inhibition of the ATR/Chk1 signaling pathway inhibited epithelial mesenchymal transition (EMT), CC cell proliferation, invasion, migration, tumorigenicity and lymph node metastasis while promoting apoptosis, indicated by reduced expression of Bcl-2, MMP-2, MMP-9 and N-cadherin, with increased expression of E-cadherin and Bax. Collectively, our study provides evidence that HMGA2 gene silencing inhibits the activation of the ATR/Chk1 signaling pathway, whereby repressing EMT, proliferation, migration and invasion of CC cells and lymph node metastasis, and promoting CC cell apoptosis. PMID- 30416650 TI - Inducible pluripotent stem cell-derived mesenchymal stem cell therapy effectively protected kidney from acute ischemia-reperfusion injury. AB - This study tested whether inducible pluripotent stem cell (iPSC)-derived mesenchymal stem cell (MSC) therapy could effectively protect kidney from acute ischemia (1 h) - reperfusion (5 day) injury (IRI). Male-adult SD-rats (n = 24) were equally categorized into groups 1 (sham-control), 2 [sham-control + iPSC-MSC (1.2 * 106 cells/rat)], 3 (IR only) and 4 (IR + iPSC-MSC). Blood urine nitrogen/creatinine levels and ratio of urine protein to creatinine, kidney weight and expressions of inflammation (TNF-alpha/NF-kappaB), oxidative-stress (NOX-1/NOX-2/oxidized protein) and apoptosis (mitochondrial-Bax/cleaved caspase 3/PARP) were significantly higher in group 3 than in groups 1, 2 and 4 and significantly higher in group 4 than in groups 1 and 2 (all P<0.0001), but showed no differences between groups 1 and 2, whereas the protein expressions of anti inflammation (IL-4/IL-10) and endothelial (CD31/vWF) markers exhibited an opposite pattern to inflammation among the four groups (all P<0.0001). Protein expressions of angiogenesis (VEGF/CXCR4/SDF-1alpha) markers progressively increased from groups 1 to 4 (all P<0.0001). Cellular expressions of kidney injury score/DNA-damage (gamma-H2AX)/apoptotic nuclei and glomerulus-tubular damage (KIM/FSP-1) displayed an identical pattern to inflammation, whereas the cellular expressions of glomerulus-tubular-integrity (dystroglycan/podocin/p cadherin/synaptopodin/ZO-1/fibronectin) revealed an opposite pattern to inflammation among the four groups (all P<0.0001). In conclusion, iPSC-derived MSC therapy effectively protected kidney against IRI. PMID- 30416651 TI - The MEK-ERK1/2 signaling pathway regulates hyaline cartilage formation and the redifferentiation of dedifferentiated chondrocytes in vitro. AB - The aim of this study was to investigate the role of the mitogen-activated protein kinase kinase-extracellular signal-regulated kinases 1/2 (MEK-ERK1/2) signaling pathway in chondrocyte differentiation and cartilage tissue construction in vitro. Chondrocytes were stimulated with rat serum (RS) and fetal bovine serum (FBS), and chondrocyte phenotypes were investigated microscopically. Chondrocyte proliferation was analyzed using fluorescence activated cell sorting (FACS) and the CCK8 method. Protein and mRNA expressions were assessed by western blot and RT-qPCR. Constructed cartilage tissues were examined by Safranin O-Fast Green FCF staining and immunofluorescence. In contrast to FBS, RS induced rapid dedifferentiation of chondrocytes and decreased type II collagen expression and proteoglycan synthesis. ERK1/2 and type I collagen expression increased during dedifferentiation and decreased during redifferentiation. Increased MEK-ERK1/2 pathway activity resulted in chondrocyte dedifferentiation, and inhibition of ERK1/2 by the inhibitor PD0325901 reversed dedifferentiation and led to redifferentiation. These data suggest strongly that inhibition of MEK-ERK1/2 activation prevents chondrocyte dedifferentiation and fibrocartilage formation. PMID- 30416652 TI - Metformin inhibits ovarian cancer growth and migration in vitro and in vivo by enhancing cisplatin cytotoxicity. AB - The purpose of the current study was to investigate whether metformin can enhance the anti-cancer effect of cisplatin on epithelial ovarian cancer in vitro and in vivo. CCK-8 assays were performed to detect cell viability, and flow cytometry was performed to measure cell apoptosis rates. Transwell assays were used to detect the migration and invasion ability of ovarian cancer cells. Western blotting and qRT-PCR were performed to detect protein expression. Xenograft mouse models were constructed to clarify the treatment response in vivo. Metformin alone or cisplatin alone dose-dependently inhibited SKOV3 and Hey cell proliferation. The combination of these two drugs exerted a stronger inhibitory effect with a higher apoptosis rate than administration of either drug alone. Transwell assay results revealed that metformin promoted the inhibitory effect of cisplatin on ovarian cancer cell metastasis. Metformin and cisplatin co-treatment significantly inhibited N-cadherin and MMP-9 expression. The Western blotting results revealed that metformin and cisplatin co-treatment inhibited TGFbeta1 expression and Smad2 and Smad3 phosphorylation. The in vivo study results were consistent with results from the in vitro study. Data from our study suggest that metformin enhanced the anti-tumour effect of cisplatin on epithelial ovarian cancer in vitro and in vivo, which provides more evidence supporting the use of metformin to treat epithelial ovarian cancer. PMID- 30416653 TI - Therapeutic ultrasound potentiates the anti-nociceptive and anti-inflammatory effects of curcumin to postoperative pain via Sirt1/NF-kappaB signaling pathway. AB - Background: Postoperative pain has well defined and is perceived by patients as one of the most obnoxious aspects of surgical pain. The aim of this study was to determine whether the combination of Therapeutic ultrasound (TUS) and Curcumin (CUR) resulted in an enhancement of their pain relieving activities in a rat model of postoperative pain. Methods: We explored the effect of these treatment and their interaction with signal transduction pathways involved in inflammatory. In this study, TUS and CUR alone or in combination were administered prior to or simultaneously with or after the incisional surgery. Results: At the start time of administration, we observed that the TUS plus CUR treatment reduced the mean paw withdrawal threshold more efficiently than CUR alone. Then we demonstrated that TUS potentiates the antinociceptive effect of CUR in a rat model of chronic postoperative pain and that the combination could facilitate the recovery of surgical pain. However, preventive value was not statistically significant when the treatments were given prior to the incisional surgery. We provide evidence that TUS plus CUR administrations were safe and significantly reduced the ED50 compared to treatment with the single CUR treatment in rats. TUS plus CUR administrations decreases incisional surgery induced activation of inflammatory cells and down-regulation of chemokines and proinflammatory cytokines, MCP-1, MIP 1alpha, IL-1beta, and TNF-alpha through regulating Sirt1/NF-kappaB signaling pathway. Conclusions: Taken together, our results indicate that the combinations of TUS and CUR can be more effective in the anti-nociceptive effects than the treatment with CUR alone. PMID- 30416654 TI - Olfactory ensheathing cells transplantation attenuates chronic cerebral hypoperfusion induced cognitive dysfunction and brain damages by activating Nrf2/HO-1 signaling pathway. AB - Chronic cerebral hypoperfusion (CCH) has become a crucial factor contributing to neurological disorders and cognitive deficits. Olfactory ensheathing cells (OECs) transplantation has been widely used to repair central nerve systems (CNS) injury, however, whether this intervention has therapeutic effects on CCH-induced cognitive dysfunction and brain damages is still unknown. In this study, we sought to determine the potential therapeutic effects of OECs transplantation on CCH. Two days after the establishment of 2VO rat model, OECs or its medium transplantation were performed via intrastriatal injection. In our study, OECs treatment significantly improved learning and memory in 2VO rats. Transplantation of OECs also significantly reduced brain cell death, neuroinflammation and oxidative stress. Mechanistically, transplantation of OECs increased the expression of nuclear factor-like 2 (Nrf2) and hemeoxygenase 1 (HO-1). Finally, treatment with Brusatol, a Nrf2 inhibitor, markedly abolished the neuroprotective effects of OECs on cognitive decline, oxidative stress, Nrf2 and HO-1 expression. These results demonstrated that OECs transplantation protected CCH-induced cognitive impairment and brain injury by suppressing neuroinflammation and oxidative stress. The activation of Nrf2/HO-1 signaling pathway may contribute to the neuroprotection of OECs transplantation in CCH. PMID- 30416655 TI - Downregulation of MiR-196b-5p impedes cell proliferation and metastasis in breast cancer through regulating COL1A1. AB - Breast cancer is considered to be the most frequently diagnosed malignancy in women worldwide. MicroRNAs (miRNAs) play key roles in the regulation of tumor properties based on their capacity to regulate the expression of tumor-related genes. However, the involvement of miR-196b-5p in breast cancer development is largely unknown. Here, we showed that the expression levels of miR-196b-5p were significantly down-regulated in breast cancer samples and cell lines compared to the matched normal tissues and breast epithelial cell line, respectively. Notably, the expression of miR-196b-5p was negatively associated with lymph node metastasis and the progression of clinical stage in patients with breast cancer. MiR-196b-5p over-expression significantly inhibited the proliferation and migration of MDA-MB-231 and MDA-MB-468 cells in breast cancer. Furthermore, combining bioinformatics prediction and biochemical analyses, we showed that COL1A1 (collagen type I alpha 1 chain) was a direct downstream target gene of miR 196b-5p. Furthermore, overexpression of COL1A1 partly abrogated miR-196b-5p mediated inhibition of proliferation and migration in MDA-MB-231 and MDA-MB-468 cells. Our data collectively indicate that miR-196b-5p inhibits cell growth and metastasis in breast cancer through down-regulating COL1A1, supporting the targeting of the new miR-196b-5p/COL1A1 axis as a promising effective therapeutic approach for breast cancer. PMID- 30416656 TI - Eotaxin-2 induces monocytic apoptosis in patients who have undergone coronary artery bypass surgery and in THP-1 cells in vitro regulated by thrombomodulin. AB - Cardiopulmonary bypass (CPB) induces cytokine production and causes postoperative monocytic inflammatory responses, which are associated with patient outcomes. In fact, monocytes regulate immunity through dynamic networks of survival and cellular apoptosis as well as thrombomodulin (TM)-associated differenciiation. Whether CPB affects the plasma level of eotaxin-2, a potent chemoattractant, or stimulates monocyte apoptosis among patients undergoing elective coronary artery bypass graft (CABG) surgery is also unknown. Thus, we aimed to investigate this subject and explored the feasible roles of TM in the phenomena. Firstly, clinical data showed that after CABG surgery, patients with lower plasma eotaxin-2 levels and higher TM expression levels exhibited reduced monocytic apoptosis, compared with that in patients with lower TM expression levels. Subsequently, to explore the hypothesis that eotaxin-2 induces monocytic apoptosis mediation by TM expression, we used in vitro monocytic THP-1 cells. The results indicated that treatment of THP-1 cells with eotaxin-2 markedly increased apoptosis. Knockdown of TM significantly increased, and overexpression of TM significantly reversed eotaxin-2-induced monocyte apoptosis, which was compared with that of only eotaxin-2-treated THP-1 cells. TM may regulate mitochondria-mediated apoptosis by its PI3K/Akt axis signaling pathway, which acts as an extinguisher for p53 and BAX activation, as well as limit further downstream release of cytochrome c and cleavage of caspases 8 and 3; we suggest that TM interacts with the cofilin cytoskeleton, which further supports a role for TM in eotaxin-induced THP-1 cell apoptosis. Based on clinical observation and in vitro study, we conclude that TM expression on monocytes is associated with their apoptosis. The above mechanisms may be relevant to clinical phenomena in which patients exhibiting more monocytic apoptosis are complicated by higher plasma levels of eotaxin-2 and lower TM expression on monocytes after CABG surgery. PMID- 30416657 TI - BMAL1 suppresses ROS-induced endothelial-to-mesenchymal transition and atherosclerosis plaque progression via BMP signaling. AB - Circadian rhythm disruption is intimately linked to atherosclerosis, and endothelial-to-mesenchymal transition (EndMT) is a major feature of atherosclerosis progression and unstable plaques. However, the mechanisms underlying the roles of Brain and Muscle ARNT-Like Protein-1 (BMAL1), an essential clock transcription activator, in EndMT and plaque instability have not been characterized. In the present study, we found a positive relationship among BMAL1 expression loss, EndMT, and plaque vulnerability in human carotid plaques. Furthermore, loss- and gain-of-function studies in human aortic endothelial cells (HAECs) revealed that BMAL1 inhibited oxidized low-density lipoprotein (oxLDL) induced intracellular reactive oxygen species (ROS) accumulation and subsequent EndMT. Mechanistically, BMAL1 deficiency aggravated EndMT through BMP-mediated signaling. Collectively, our study demonstrates the underlying mechanism for the central role of BMAL1 loss in atherosclerosis progression and plaque stability transition promoted by oxidative stress, which can be targeted therapeutically to prevent the occurrence and progression of atherosclerosis. PMID- 30416658 TI - 880 kHz ultrasound treatment for drug delivery to the vitreous humor. AB - Clinical management of many chronic ophthalmological disorders requires direct delivery of drugs into the vitreous. There is an important need to investigate novel needle-less alternatives to deliver drugs to the vitreous. The purpose of this study is to assess the effects of a needle-less system using ultrasound to enhance vitreal delivery of small molecules through the sclera in an ex vivo model and to evaluate whether changes in permeability are mainly due to the heat generated by sonication. An eye cup containing 1 mL of sodium fluorescein 0.1% was placed on top of the sclera of cadaveric rabbit eyes. Treated eyes were sonicated for 10 minutes, and left in contact with the fluorescein solution for an additional 50 minutes. Control eyes received the same exposure to fluorescein solution (60 minutes) in the eye cup without ultrasound treatment. Vitreous humor was collected and analyzed using a fluorescence spectrophotometer to calculate the concentration of fluorescein that diffused into the vitreous humor. An additional set of eyes was treated using a heating probe to evaluate whether changes in permeability were mainly due to heat. Vitreous samples from ultrasound treated eyes showed a 44.6% higher concentration of fluorescein compared to control eyes. The concentration of fluorescein in the vitreous of heat-treated eyes did not show a significant difference when compared to control eyes. Thus, phonophoresis is a promising needle-less method for vitreal drug delivery, and local heating conducted to the surface of the sclera should be mitigated because it does not enhance the efficacy of the method. PMID- 30416659 TI - Alterations of fecal bacterial communities in patients with lung cancer. AB - Emerging evidence suggests the microbiome may affect a number of diseases, including lung cancer. However, the direct relationship between gut bacteria and lung cancer remains uncharacterized. In this study, we directly sequenced the hypervariable V1-V2 regions of the 16S rRNA gene in fecal samples from patients with lung cancer and healthy volunteers. Unweighted principal coordinate analysis (PCoA) revealed a clear difference in the bacterial community membership between the lung cancer group and the healthy control group. The lung cancer group had remarkably higher levels of Bacteroidetes, Fusobacteria, Cyanobacteria, Spirochaetes, and Lentisphaerae but dramatically lower levels of Firmicutes and Verrucomicrobia than the healthy control group (P < 0.05). Despite significant interindividual variation, eight predominant genera were significantly different between the two groups. The lung cancer group had higher levels of Bacteroides, Veillonella, and Fusobacterium but lower levels of Escherichia-Shigella, Kluyvera, Fecalibacterium, Enterobacter, and Dialister than the healthy control group (P < 0.05). Most notably, correlations between certain specific bacteria and serum inflammatory biomarkers were identified. Our findings demonstrated an altered bacterial community in patients with lung cancer, providing a significant step in understanding the relationship between gut bacteria and lung cancer. To our knowledge, this is the first study to evaluate the correlations between certain specific bacteria and inflammatory indicators. To better understand this relationship, further studies should investigate the underlying mechanisms of gut bacteria in lung cancer animal models. PMID- 30416660 TI - LncRNA MALAT1 promotes relapse of breast cancer patients with postoperative fever. AB - Postoperative fever is prevalent in many breast cancer patients. Some retrospective studies proposed that postoperative fever might also be considered as a rapid rough indicator for the poor prognosis of breast cancer patients. This study aims to explore the possible molecular mechanisms underlying the relapse of breast cancer patients with early postoperative fever. Our results indicated plasma levels of lncRNA MALAT1 were elevated in breast cancer patients with early postoperative fever and were associated with RFS. Lipopolysaccharide (LPS) was able to induce fever and systemic inflammatory responses in 4T1 xenograft mice, and promote lung metastasis. But after knocking down lncRNA MALAT1, the inflammatory responses and metastasis of lung were significantly reduced. Moreover, after knocking down lncRNA MALAT1 in the 4T1 cells, TNF-alpha level in the supernatants was sharply decreased, and the invasion and migration induced by LPS was also weakened. Cumulatively, our data indicates that MALAT1 is closely related to recurrence and metastasis of breast cancer patients with early postoperative fever. PMID- 30416661 TI - Xin Fu Kang oral liquid inhibits excessive myocardial mitophagy in a rat model of advanced heart failure. AB - Heart failure caused by myocardial infarction is a common cardiovascular disease with high mortality rate. Myocardial mitophagy is involved in the process of occurrence and development of heart failure. In this study, we aimed to investigate the effects of Xin Fu Kang (XFK) oral liquid on myocardial mitophagy in a rat model of advanced heart failure. The rat model of advanced heart failure was established by ligating the left anterior descending (LAD) artery for eight weeks. Captopril and XFK were given by gavage separately. Cardiac function and myocardial mitochondrial ultrastructure were observed. Co-localization of mitophagy-related proteins was observed by fluorescence microscopy. Quantitative polymerase chain reaction (qPCR) and western blotting were performed for mRNA and protein level detection, respectively. Compared with the sham group, advanced heart failure group showed a significant reduction in cardiac function with destruction of myocardial mitochondrial structure. Co-localization between mitophagy-related proteins (parkin, p62, and LC3) and mitochondria increased significantly. The mRNA and protein levels of pink1, parkin, p62, and LC3 indicated that excessive mitophagy was observed in the rat model of advanced heart failure. XFK intervention could regulate pink/parkin pathway and inhibit excessive mitophagy. PMID- 30416662 TI - The FENDRR/miR-214-3P/TET2 axis affects cell malignant activity via RASSF1A methylation in gastric cancer. AB - To explore the effect of fetal-lethal non-coding developmental regulatory RNA (FENDRR) in the initiation and progression of gastric cancer (GC). We detected the levels of FENDRR, microRNA-214-3p (miR-214-3p), and ten-eleven-translocation (TET2) in GC tissues and GC cell lines. In addition, we evaluated the location of FENDRR in GC cell lines by fluorescence in situ hybridization (FISH). Cell proliferation and apoptosis were measured by CCK-8 and Hoechst staining assays. Methylation-specific PCR assay (MSP) was used to evaluate the methylation status of ras-association domain family 1A (RASSF1A). We also observed the direct binding of miR-214-3p on FENDRR by dual-luciferase activity assay in GC cells. FENDRR and TET2 expressions were significantly down-regulated and miR-214-3p was up-regulated in gastric cancer tissues compared to adjacent unaffected tissues. In addition, RASSF1A was hypermethylated in gastric cancer tissues compared to adjacent tissues. The expressions of all the three indicators were influenced by differentiation of tumor, TNM stage of tumors, and lymph node metastasis in patients with GC. A gastric cancer cell line with low FENDRR expression compared to a high FENDRR expressing cell line showed again increased miR-214-3p expression, decreased TET2 and RASSF1A expressions, and RASSF1A hypermethylation, resulting in decreased apoptosis and increased proliferation. Furthermore, we observed a negative correlation between FENDRR and miR-214-3p in GC. The FENDRR/miR-214-3P/TET2 axis plays a critical role in GC progress via methylation of RASSF1A. PMID- 30416663 TI - The role and mechanism of miR-374 regulating the malignant transformation of mesenchymal stem cells. AB - MicroRNAs (miRNAs) play important roles in cell transformation and carcinogenesis. We have previously established a tumor cell line K3 transformed from rat bone marrow-derived mesenchymal stem cells (rBM-MSCs). However, the underlying mechanism involved in MSC transformation remains unclear. Herein, we identified the key miRNAs that regulate the transformation of rBM-MSCs, and clarified their biological roles. Microarray and qRT-PCR results showed an increased expression of miR-374 but decreased expressions of miR-199a, miR-145, miR-34a, and miR-214 in K3 cells compared to rBM-MSCs. MiR-374 overexpression in rBM-MSCs increased the colony number and the proportion of the cells in S-phase. In addition, miR-374 overexpression reduced E-cadherin expression and increased N cadherin expression in rBM-MSCs, promoting the migration ability of these cells. On the contrary, miR-374 knockdown in K3 cells led to impaired proliferation and migration capacities. Furthermore, wnt5a was identified as a target gene of miR 374. MiR-374 overexpression upregulated beta-catenin expression in rBM-MSCs while miR-374 knockdown downregulated that in K3 cells. In conclusion, miR-374 promotes the proliferation and migration of transformed MSCs by regulating Wnt5a/beta catenin signaling pathway, which provides evidence for the contribution of miRNA to MSC transformation and suggests a new role of miR-374 in cancer development and progression. PMID- 30416664 TI - The long-term clinical outcomes of robotic gastrectomy for gastric cancer: a large-scale single institutional retrospective study. AB - BACKGROUNDS AND PURPOSE: Robotic surgery has been applied in gastric carcinoma over a decade. Although a series of studies were performed to investigate the short-term outcomes of robot-assisted gastrectomy, few papers were in view of long-term outcomes. The current study was aimed to explore the oncological outcomes of robotic gastrectomy for gastric cancer patients. METHODS: A total of 606 gastric cancer patients who underwent robot-assisted gastrectomy during March 2010 through March 2017, were enrolled in this research. The clinicopathologic characteristics, surgical procedures along with follow-up information and prognostic factors were recorded in detail. The disease-free survival and overall survival rates were tested by Kaplan-Meier analysis. RESULTS: All the patients underwent the robotic surgery including 15 proximal gastrectomies, 403 distal gastrectomies, 169 total gastrectomies and 19 remnant gastrectomies. Fifiy-six (9.24%) patients were lost in the follow-up process (3-87 months, a media of 42 months). There were 119 recurrences observed, including 55 local recurrences, 51 peritoneal metastasis and 13 distant metastasis. The 3-year disease-free survival and overall survival were 73.60% and 74.24%, while the 5-year disease-free survivorship and overall survival rates were 68.73% and 69.33%. The 5-year overall survival rates grouped based on TNM stage were 96.58% for IA, 88.16% for IB, 87.03% for IIA, 80.62% fo IIB, 58.50% for IIIA, 48.62% for IIIB, 45.32% for IIIC and 17.03% for IV. CONCLUSION: Robot-assisted gastrectomy is a valuable procedure for gastric cancer patients. Beside its feasibility and safety, it reveals an acceptable long-term clinical outcome. PMID- 30416666 TI - Verification of exercise-induced transient postural tachycardia phenotype in Gulf War Illness. AB - One third of Gulf War Illness (GWI) subjects in a recent study were found to develop transient postural tachycardia after submaximal exercise stress tests. Post-exercise postural tachycardia is a previously undescribed physiological finding. A new GWI cohort was studied to verify this novel finding and characterize this cardiovascular phenomenon. Subjects followed the same protocol as before. The change in heart rate between recumbent and standing postures (DeltaHR) was measured before exercise, and after submaximal bicycle exercise. About one-fourth of the verification cohort (14/57) developed transient postural tachycardia after submaximal exercise. These subjects were the Stress Test Activated Reversible Tachycardia (START) phenotype. The largest change was observed between pre-exercise and time points 2 +/- 1 (mean +/- SD) hours post exercise (1st Peak Effect). Eleven subjects had Postural Tachycardia Syndrome (POTS) before and after exercise. The remaining subjects had normal DeltaHR (12 +/- 5 bpm) and no 1st Peak Effect, and were the Stress Test Originated Phantom Perception phenotype (STOPP). These findings indicate that about one-fourth of all Gulf War Illness study participants (24/90) developed transient postural tachycardia after the submaximal exercise stress test. The START phenotype was defined as being distinctly different from POTS. Additional studies are required to examine this phenomenon in other illnesses and to determine pathological mechanisms. PMID- 30416665 TI - Prognostic significance of PD-L1 expression and tumor infiltrating lymphocytes in large cell neuroendocrine carcinoma of lung. AB - OBJECTIVES: Since large cell neuroendocrine carcinoma (LCNEC) is a relatively rare histologic type of primary lung cancer, little is known about the immunological status of patients with LCNEC. We aimed to clarify the expression and prognostic impact of programmed cell death ligand 1 (PD-L1), CD8, CD4, and Forkhead box protein P3 (Foxp3) in LCNEC. METHODS: We retrospectively analyzed PD L1, CD8, CD4, and Foxp3 expressions in 95 surgically resected LCNEC. PD-L1 positive staining was determined in tumors with more than 1% of tumor cells stained to any intensity, and CD8, CD4, and Foxp3 positivity was determined in tumors with more than 5% of lymphocytes stained. RESULTS: Positive expression of PD-L1, CD8, CD4, and Foxp3 was observed in 70 (74%), 52 (55%), 76 (80%), and 43 (45%) tumors, respectively. The expression of PD-L1 was significantly correlated with positive lymphatic permeation. Positive correlations were mutually observed among tumor infiltrating immune cells. Univariate and multivariate analyses showed that positive pleural invasion and Foxp3 negative expression were independent unfavorable prognostic factors for overall survival (OS). Advanced pathological stage, positive pleural invasion, CD4 negative expression in cancer stroma, and Foxp3 negative expression were identified as independent unfavorable prognostic factors for recurrence free survival (RFS). CONCLUSIONS: Foxp3 positive tumor infiltrating lymphocytes (TILs) were an independent favorable prognostic factor for both OS and RFS, whereas CD4 positive TILs were an independent significant unfavorable prognostic factor for RFS. The high frequency of PD-L1 expression could support the use of anti-programmed cell death 1 antibody in the treatment of LCNEC. PMID- 30416667 TI - Relevance of inflammation and matrix remodeling in abdominal aortic aneurysm (AAA) and popliteal artery aneurysm (PAA) progression. AB - Aneurysm is a multifactorial degenerative disease characterized by focal dilatation of blood vessels. Although abdominal aortic (AAA) and popliteal aneurysms (PAA) are the most common dilatative vascular diseases and share some features, a comparison between the different anatomical sites and the relative pathophysiological differences has not been established. In order to gain deeper insights to AAA and PAA, we have characterized the role of matrix remodelling, vascular cells phenotype depletion and the inflammatory process in both diseases. Results show a more extensive presence of T-cell, B-cell and monocyte-macrophage infiltration in AAA with respect to PAA. Concurring with this aspect, IL-6, IL-8 and MCP-1 are 10-fold increased in AAA. Moreover, MMP-9, and metalloproteinase inhibitor 3 (TIMP3) resulted up-regulated in AAA tissues. Regarding the catalytic activity, which is tightly related to the oxidative stress, we found an up regulation of superoxide dismutase [Mn] mitochondrial (SODM), glutathione peroxidase 3 (GPX3) and peroxiredoxin-1 (PRDX1). Histological analyses clearly showed a massive elastin fragmentation in AAA. This may enhance the inflammatory response, which has a prevalent role in AAA, while PAA is mainly guided by a loss of the contractile phenotype. These findings suggest insight in these potentially devastating diseases in term of their progression, aiming to identify potential specific markers respectively for AAA and PAA treatment. PMID- 30416668 TI - Green tea polyphenols protect against preglomerular arteriopathy via the jagged1/notch1 pathway. AB - Preglomerular arteriopathy (PA) induced by hyperuricemia contributes to the progression of chronic kidney disease (CKD). Green tea polyphenols (GTPs) are antioxidant ingredients thought to assist in preventing hyperuricemia. However, the underlying mechanism by which GTPs affect renal function remains unclear. Both normal and remnant kidney (RK) rats were administrated oxonic acid (OX) to induce hyperuricemia. The hyperuricemia RK rats were concomitantly treated with GTPs. Hematoxlyin-eosin (H&E) and periodic acid-Schiff (PAS) staining methods were used to examine renal function and arterial morphology. The expression of proteins in the Jagged1/Notch1 pathway was assessed via immunohistochemistry, in situ hybridization, the quantitative polymerase chain reaction (qPCR), and western blotting techniques. Our results showed that an RK rat model with preglomerular vascular disease had been successfully established. Treatment of the RK rats with GTPs effectively alleviated the damage due to preglomerular arteriopathy, significantly alleviated pathological symptoms, and reduced the levels of proteinuria, serum UA, BUN, and creatinine. Our results also suggested involvement of the Jagged1/Notch1 pathway in the preglomerular vascular lesions. The levels of Jagged1, Notch1-ICD, Hes5, and p-STAT3 were significantly decreased in RK + OA-treated rats when compared with those in RK rats. Treatment with GTPs upregulated the levels of Jagged1, Notch1, Hes5, p-STAT3, and MnSOD2, and downregulated xanthine oxidase (XO) expression in rats with preglomerular arteriopathy. However, the beneficial effects of GTPs were lost when the Jagged1/Notch1-STAT3 pathway was inactivated by siRNA. In conclusion, GTPs exert a therapeutic effect on perglomerular arteriopathy. Our results also revealed a novel mechanism that mediates preglomerular arteriopathy, and suggest GTPs as effective novel renal protective agents. PMID- 30416669 TI - COMPUTER-AIDED DETECTION OF PATTERN CHANGES IN LONGITUDINAL ADAPTIVE OPTICS IMAGES OF THE RETINAL PIGMENT EPITHELIUM. AB - Retinal pigment epithelium (RPE) defects are indicated in many blinding diseases, but have been difficult to image. Recently, adaptive optics enhanced indocyanine green (AO-ICG) imaging has enabled direct visualization of the RPE mosaic in the living human eye. However, tracking the RPE across longitudinal images on the time scale of months presents with unique challenges, such as visit-to-visit distortion and changes in image quality. We introduce a coarse-to-fine search strategy that identifies paired patterns and measures their changes. First, longitudinal AO-ICG image displacements are estimated through graph matching of affine invariant maximal stable extremal regions in affine Gaussian scale-space. This initial step provides an automatic means to designate the search ranges for finding corresponding patterns. Next, AO-ICG images are decomposed into superpixels, simplified to a pictorial structure, and then matched across visits using tree-based belief propagation. Results from human subjects in comparison with a validation dataset revealed acceptable accuracy levels for the level of changes that are expected in clinical data. Application of the proposed framework to images from a diseased eye demonstrates the potential clinical utility of this method for longitudinal tracking of the heterogeneous RPE pattern. PMID- 30416670 TI - FETAL CORTICAL PARCELLATION BASED ON GROWTH PATTERNS. AB - Dividing the human cerebral cortex into structurally and functionally distinct regions is important in many neuroimaging studies. Although many parcellations have been created for adults, they are not applicable for fetal studies, due to dramatic differences in brain size, shape and folding between adults and fetuses, as well as dynamic growth of fetal brains. To address this issue, we propose a novel method to divide a population of fetal cortical surfaces into distinct regions based on the dynamic growth patterns of cortical properties, which indicate the underlying changes of microstructures. As microstructures determine the molecular organization and functional principles of the cortex, growth patterns enable an accurate definition of distinct regions in development, microstructure, and function. To comprehensively capture the similarities of cortical growth patterns among vertices, we construct two complementary similarity matrices. One is directly based on the growth trajectories of vertices and the other is based on the correlation profiles of vertices' growth trajectories in relation to those of reference points. Then, we nonlinearly fuse these two similarity matrices into a single one, which can better captures both their common and complementary information than by simply averaging them. Finally, based on this fused matrix, we perform spectral clustering to divide fetal cortical surfaces into distinct regions. We have applied our method on 25 normal fetuses from 26 to 29 gestational weeks and generated biologically meaningful parcellations. PMID- 30416671 TI - CONSTRUCTION OF SPATIOTEMPORAL INFANT CORTICAL SURFACE ATLAS OF RHESUS MACAQUE. AB - As a widely used animal model in MR imaging studies, rhesus macaque helps to better understand both normal and abnormal neural development in the human brain. However, the available adult macaque brain atlases are not well suitable for study of brain development at the early postnatal stage, since this stage undergoes dramatic changes in brain appearances and structures. Building age matched atlases for this critical period is thus highly desirable yet still lacking. In this paper, we construct the first spatiotemporal (4D) cortical surface atlases for rhesus macaques from 2 weeks to 24 months, using 138 longitudinal MRI scans from 32 healthy rhesus monkeys. Specifically, we first perform intra-subject cortical surface registration to obtain within-subject mean cortical surfaces. Then, we perform inter-subject registration of within-subject mean surfaces to obtain unbiased and longitudinally-consistent 4D cortical surface atlases. Based on our 4D rhesus monkey atlases, we further chart the first developmental-trajectories-based parcellation maps using the local surface area and spectral clustering algorithm. Our 4D macaque surface atlases and parcellation maps will greatly facilitate early brain development studies of macaques. PMID- 30416672 TI - CONSTRUCTION OF SPATIOTEMPORAL NEONATAL CORTICAL SURFACE ATLASES USING A LARGE SCALE DATASET. AB - The cortical surface atlases constructed from a large representative population of neonates are highly needed in the neonatal neuroimaging studies. However, existing neonatal cortical surface atlases are typically constructed from small datasets, e.g., tens of subjects, which are inherently biased and thus are not representative to the neonatal population. In this paper, we construct neonatal cortical surface atlases based on a large-scale dataset with 764 subjects. To better characterize the dynamic cortical development during the first postnatal weeks, instead of constructing just a single atlas, we construct a set of spatiotemporal atlases at each week from 39 to 44 gestational weeks. The central idea is that, for all cortical surfaces, we first group-wisely register them into the common space to ensure the unbiasedness. Then, rather than simply averaging over the co-registered cortical surfaces, which generally leads to over-smoothed cortical folding patterns, we adopt a spherical patch-based sparse representation using an augmented dictionary to overcome the noises and potential registration errors. Through the group-wise sparsity constraint, we obtain consistent geometric cortical folding attributes on the atlases. Our atlases preserve the sharp cortical folding patterns, thus leading to better registration accuracy when aligning new subjects onto the atlases. PMID- 30416673 TI - Analysis of Evaporative and Exhaust-Related On-Board Diagnostic (OBD) Readiness Monitors and DTCs Using I/M and Roadside Data. AB - Under contract to the EPA, Eastern Research Group analyzed light-duty vehicle OBD monitor readiness and diagnostic trouble codes (DTCs) using inspection and maintenance (I/M) data from four states. Results from roadside pullover emissions and OBD tests were also compared with same-vehicle I/M OBD results from one of the states. Analysis focused on the evaporative emissions control (evap) system, the catalytic converter (catalyst), the exhaust gas recirculation (EGR) system and the oxygen sensor and oxygen sensor heater (O2 system). Evap and catalyst monitors had similar overall readiness rates (90% to 95%), while the EGR and O2 systems had higher readiness rates (95% to 98%). Approximately 0.7% to 2.5% of inspection cycles with a "ready" evap monitor had at least one stored evap DTC, but DTC rates were under 1% for the catalyst and EGR systems, and under 1.1% for the O2 system, in the states with enforced OBD programs. Monitor readiness decreased, and DTC rates increased, as vehicles aged. DTCs were typically limited to a small subset of all possible DTCs for any particular system. For the on-road versus I/M analysis, lower overall readiness rates and higher overall DTC rates occurred during the roadside test than during the I/M test, and the prevalence of roadside DTCs was shown to decrease around the time of the vehicle's I/M test, possibly indicating some positive I/M influence of reducing on-road DTCs. Roadside Acceleration Simulation Mode (ASM) fail rates also decreased around the time of the I/M test, suggesting a positive influence of I/M programs on reducing vehicle emissions. PMID- 30416674 TI - Comment. AB - We congratulate the authors on their comments on innovative approaches to drug development that fall out of the traditional mold and may result in more quickly bringing safe and effective treatments to patients. Changes in the overall clinical develop approach are most relevant to "breakthrough" therapies, which have generally yielded exceptional efficacy data in early clinical studies, motivating exploration of accelerated development and regulatory approaches, as well as a potential ethical need for crossover upon progression in randomized controlled studies (Horning et al., 2015). As is clear from the manuscript, it will be important to develop an understanding of what works well and where the pitfalls in new approaches are. We comment briefly on the four topics mentioned by the authors, combining comments on items 2 and 3: 1) non-proportional hazards, 2) interpretability of extended Phase I trials, 3) single-arm trials as a basis for approval, and 4) recent innovations in trial design. PMID- 30416675 TI - Effects of Femtosecond Laser Surface Processed Nanoparticle Layers on Pool Boiling Heat Transfer Performance. AB - An experimental investigation of the effects of layers of nanoparticles formed during femtosecond laser surface processing (FLSP) on pool boiling heat transfer performance has been conducted. Five different stainless steel 304 samples with slightly different surface features were fabricated through FLSP, and pool boiling heat transfer experiments were carried out to study the heat transfer characteristics of each surface. The experiments showed that the layer(s) of nanoparticles developed during the FLSP processes, which overlay FLSP self organized microstructures, can either improve or degrade boiling heat transfer coefficients (HTC) depending on the overall thickness of the layer(s). This nanoparticle layer thickness is an indirect result of the type of microstructure created. The HTCs were found to decrease with increasing nanoparticle layer thickness. This trend has been attributed to added thermal resistance. Using a focused ion beam milling process and transmission electron microscopy (TEM), the physical and chemical properties of the nanoparticle layers were characterized and used to explain the observed heat transfer results. Results suggest that there is an optimal nanoparticle layer thickness and material composition such that both the HTCs and critical heat flux (CHF) are enhanced. PMID- 30416676 TI - Stereotactic radiosurgery practice patterns for brain metastases in the United States: a national survey. AB - Background: Stereotactic radiosurgery (SRS) has emerged as an important modality for the treatment of intracranial metastases. There are currently few established guidelines delineating indications for SRS use and fewer still regarding plan evaluation in the treatment of multiple brain metastases. Methods: An 18 question electronic survey was distributed to radiation oncologists at National Cancer Institute (NCI) designated cancer centers in the USA (60). Centers without radiation oncologists were excluded. Physicians who indicated that they do not prescribe SRS were excluded from the remaining survey questions. Sign test and Chi-square test were used to determine if responses differed significantly from random distribution. Results: One hundred sixteen of the 697 radiation oncologists surveyed completed the questionnaire, representing 51 institutions. Sixty-two percent reported treating patients with brain metastases using SRS. Radiation oncologists prescribing SRS most commonly treat CNS (66.2%) and lung (49.3%) malignancies. SRS was used more frequently for < 10 brain metastases (73.7%; p < 0.0001) and whole brain radiation therapy (WBRT) for > 10 brain metastases (82.5%; p < 0.0001). The maximum number of lesions physicians were willing to treat with SRS without WBRT was 1-4 (40.4%) and 5-10 (42.4%) (p < 0.0001 compared to 11-15, 16-20 and no limit). The most important criteria for choosing SRS or WBRT were number of lesions (p < 0.0001) and performance status (p = 0.016). The most common margin for SRS was 0 mm (49.1%; p = 0.0021). The most common dose constraints other than critical structure was conformity index (84.2%) and brain V12 (61.4%). The LINAC was the most common treatment modality (54.4%) and mono-isocenter technique for multiple brain metastases was commonly used (43.9%; p = 0.23). Most departments do not have a policy for brain metastases treatment (64.9%; p = 0.024). Conclusions: This is one of the first national surveys assessing the use of SRS for brain metastases in clinical practice. These data highlight some clinical considerations for physicians treating brain metastases with SRS. PMID- 30416677 TI - Chronic heart failure is characterized by altered mitochondrial function and structure in circulating leucocytes. AB - Oxidative stress is currently viewed as a key factor in the genesis and progression of Heart Failure (HF). The aim of this study was to characterize the mitochondrial changes linked to oxidative stress generation in circulating peripheral blood mononuclear cells isolated from chronic HF patients (HF_PBMCs) in order to highlight the involvement of mitochondrial dysfunction in the pathophysiology of HF. To assess the production of reactive oxygen species (ROS), mitochondrial function and ultrastructure and the mitophagic flux in circulating PBMCs we enrolled 15 patients with HF and a control group of ten healthy subjects. The HF_PBMCs showed a mitochondrial population consisting of damaged and less functional organelles responsible of higher superoxide anion production both at baseline and under in vitro stress conditions, with evidence of cellular apoptosis. Although the mitophagic flux at baseline was enhanced in HF_PBMCs at level similar to those that could be achieved in control PBMCs only under inflammatory stress conditions, the activation of mitophagy was unable to preserve a proper mitochondrial dynamics upon stress stimuli in HF. In summary, circulating HF_PBMCs show structural and functional derangements of mitochondria with overproduction of reactive oxidant species. This mitochondrial failure sustains a leucocyte dysfunctional status in the blood that may contribute to development and persistence of stress conditions within the cardiovascular system in HF. PMID- 30416678 TI - Molecular analysis of the dual targeting of the epidermal growth factor receptor and the O6-methylguanine-DNA methyltransferase with a double arm hybrid molecule. AB - Disordered expression of the epidermal growth factor receptor (EGFR) has been associated with induction of DNA repair genes (e.g. XRCC1, ERCC1) and resistance to radiation and genotoxic drugs. However, our previous work showed that EGFR inhibition did not affect O6-methylguanine-DNA methyltransferase (MGMT)-mediated resistance. In order to block uncoupled events associated with EGFR and MGMT, we designed MR30, a single molecule termed "combi-molecule" that contains a quinazoline arm targeted to EGFR and an O6-benzylguanine (O6-BG) moiety to block MGMT. Molecular analysis of the mechanism of action of its two arms showed that: (a) it could block EGFR phosphorylation, (b) down-regulate the RAF-MAPK and the PI3K-AKT pathways, and (c) covalently modify MGMT through S-benzylation, as confirmed by MALDI analysis of a direct binding assay with isolated MGMT, (d) it induced a dose-dependent down-regulation of MGMT in lung and melanoma cells. The pleiotropic mechanism of action of MR30 culminated into strong growth inhibition (IC50: 0.018-6.02 MUM), with superior activity when compared with an equimolar combination of gefitinib (a clinical EGFR inhibitor) and O6-BG (a known MGMT inhibitor). Pulse exposure experiments were required to attenuate the contribution of EGFR inhibition to the strong potency of MR30, thereby allowing to achieve the dose level required to sensitize cells to temozolomide (TMZ). Indeed, MR30 significantly sensitized EGFR-MGMT co-expressing cells to TMZ (p<0.05-0.0001). The results in toto suggest that MR30 is the first prototype of agents that may be used against tumours addicted to EGFR and to sensitize resistant tumours co-expressing EGFR and MGMT to TMZ. PMID- 30416679 TI - Predictive values of two frailty screening tools in older patients with solid cancer: a comparison of SAOP2 and G8. AB - Objectives: Comprehensive Geriatric Assessment (CGA), the gold standard for detecting frailty in elderly cancer patients, is time-consuming and hard to apply in routine clinical practice. Here we compared the performance of two screening tools for frailty, G8 and SAOP2 for their accuracy in identifying vulnerable patients. Material and Methods: We tested G8 and SAOP2 in 282 patients aged 65 or older with a diagnosis of solid cancer and candidate to undergo surgical, medical and/or radiotherapy treatment. CGA, including functional and cognitive status, depression, nutrition, comorbidity, social status and quality of life was used as reference. ROC curves were used to compare two screening tools. Results: Mean patient age was 79 years and 54% were female. Colorectal and breast cancer were the most common types cancer (49% and 24%). Impaired CGA, G8, and SAOP2 were found in 62%, 89%, and 94% of the patients, respectively. SAOP2 had a better sensitivity (AUC 0.85, p<0.032) than G8 (AUC 0.79), with higher performance in breast cancer patients (AUC 0.93) and in patients aged 70-80 years (AUC 0.87). Conclusions: G8 and SAOP2 both showed good screening capacity for frailty in the cancer patient population we examined with SAOP2 showing a slightly better performance than G8. PMID- 30416680 TI - The Cockayne syndrome protein B is involved in the repair of 5-AZA-2' deoxycytidine-induced DNA lesions. AB - The Cockayne Syndrome Protein B (CSB) plays an essential role in Transcription Coupled Nucleotide Excision Repair (TC-NER) by recruiting repair proteins once transcription is blocked with a DNA lesion. In fact, CSB-deficient cells are unable to recover from transcription-blocking DNA lesions. 5-Aza-2'-deoxycytidine (5-azadC) is a nucleoside analogue that covalently traps DNA methyltransferases (DNMTs) onto DNA. This anticancer drug has a double mechanism of action: it reverts aberrant hypermethylation in tumour-suppressor genes, and it induces DNA damage. We have recently reported that Homologous Recombination and XRCC1/PARP play an important role in the repair of 5-azadC-induced DNA damage. However, the mechanisms involved in the repair of the DNMT adducts induced by azadC remain poorly understood. In this paper, we show for the first time the importance of CSB in the repair of azadC-induced DNA lesions. We propose a model in which CSB initiates a signalling pathway to repair transcription blocks induced by incorporated 5-azadC. Indeed, CSB-deficient cells treated with 5-azadC show a delay in the repair of trapped DNMT1, increased levels of DNA damage and reduced survival. PMID- 30416681 TI - LncRNAs as novel players in hepatocellular carcinoma recurrence. AB - Long non-coding RNAs (lncRNAs) are ncRNAs more than 200 nucleotides long that participate to a wide range of biological functions. However, their role in cancer is poorly known. By using an NGS-based approach we analyzed the intragenic and poliA-lncRNAs in hepatocellular carcinoma (HCC) and we assayed the relationships between their deregulated expression and clinical-pathological characteristics. The expression profile of lncRNAs was studied in a discovery series of 28 HCC and matched cirrhosis and was validated in an independent cohort of 32 HCC patients both in tissue and serum. The correlation between lncRNA expression and clinical-pathological variables, EMT markers and putative sponged microRNAs level were investigated. Functional experiments were performed in HCC derived cell lines to clarify the role of selected lncRNAs in HCC. A panel of deregulated lncRNAs differentiated HCC from cirrhotic tissue. CASC9 and LUCAT1 were up-regulated in a subset of HCC-derived cell lines and in half of HCCs which displayed a lower recurrence after surgery. LUCAT1 and CASC9 silencing increased cell motility and invasion capability in HCC cells and influenced the EMT phenotype. LUCAT1 was demonstrated to directly sponge the onco-miR-181d-5p. Both LUCAT1 and CASC9 were secreted in exosomes, and higher circulating CASC9 levels were associated with tumor size and HCC recurrence after surgery, suggesting its potential usage as putative non-invasive prognostic biomarker of recurrence. PMID- 30416683 TI - MicroRNA expression profile during different conditions of hypoxia. AB - Introduction: MicroRNAs (miRNAs) are small non coding RNAs which play a role in several cellular processes. MiRNA expression is influenced by oxidative stress, inflammatory cascade and hypoxia. Effects of different types of hypoxia (intermittent and chronic) have been poorly investigated. The aim of this study was to evaluate how intermittent and chronic hypoxia influence the expression of a pool of miRNAs. Results: Subjects with HI presented higher levels of miR-21, miR-23b, miR-145 and miR-210 compared to the other groups, while higher levels of miR-26 was observed in the HC group. Subjects with HCHI had lower levels of all selected miRNAs. A strong correlation was found between miR-23b and miR-210 and both correlated with PaO2, age and FEV1. MiR-145 is correlated with miR-21 but no correlations were found with other parameters. The level of miR-26a seems to be correlated only with BMI. Materials and Methods: We used RT-PCR to detect the miRNAs expression in three different models of hypoxemia: intermittent (HI), chronic (HC) and both of them (HCHI). Expression of miRNAs was analyzed using ANOVA and post hoc analysis, moreover, Spearman correlation and Cluster analysis were applied to study the relationship between miRNAs and main clinical parameters. Conclusions: Intermittent hypoxia induces the expression of some miRNAs more than chronic hypoxia. These miRNAs may play an important role in the development of different diseases usually associated with OSA such as cardiovascular disease. In addition, mechanisms involved in cancer progression may be induced in the presence of chronic and more often intermittent hypoxia. PMID- 30416682 TI - IDH1R132H is intrinsically tumor-suppressive but functionally attenuated by the glutamate-rich cerebral environment. AB - Recurrent heterozygous mutation of isocitrate dehydrogenase 1 gene (IDH1), predominantly resulting in histidine substitution at arginine 132, was first identified in glioma. The biological significance of IDH1R132H, however, has been controversial, and its prevalent association with glioma remains enigmatic. Although recent studies indicate that IDH1R132H is nonessential to tumor growth or even anti-tumor growth, whether IDH1R132H initiates gliomagenesis remains obscure. In this study, we report that IDH1R132H is intrinsically tumor suppressive but the activity can be attenuated by glutamate-the cerebral neurotransmitter. We observed that IDH1R132H was highly suppressive of subcutaneous tumor growth driven by platelet-derived growth factor B (PDGFB), but IDH1R132H tumor growth and glioma penetrance were virtually indistinguishable from those of IDH1-wildtype tumors in orthotopic models. In vitro, addition of glutamate compromised IDH1R132H inhibition of neurosphere genesis, indicating glutamate promotion of oncogenic dominance. Furthermore, we observed that IDH1R132H expression was markedly decreased in tumors but became more permissible upon the deletion of tumor-suppressor gene Cdkn2a. To provide direct evidence for the opposing effect of IDH1R132H on PDGFB-driven glioma development, we explored tandem expression of the two molecules from a single transcript to preclude selection against IDH1R132H expression. Our results demonstrate that when juxtaposed with oncogenic PDGFB, IDH1R132H overrides the oncogenic activity and obliterates neurosphere genesis and gliomagenesis even in the glutamate-rich microenvironment. We propose therefore that IDH1R132H is intrinsically suppressive of glioma initiation and growth but such tumor-suppressive activity is compromised by the glutamate-rich cerebral cortex, thereby offering a unifying hypothesis for the perplexing role of IDH1R132H in glioma initiation and growth. PMID- 30416684 TI - CXCR4- and BCR-triggered integrin activation in B-cell chronic lymphocytic leukemia cells depends on JAK2-activated Bruton's tyrosine kinase. AB - Bruton's tyrosine kinase (BTK) regulates the B-cell receptor (BCR) signaling pathway, which, in turn, plays a critical role in B-cell chronic lymphocytic leukemia (B-CLL) pathogenesis. The BTK-specific inhibitor Ibrutinib blocks BCR signaling and is now approved as effective B-CLL therapy. Chemokines, such as the homeostatic chemokine CXCL12, play a central role in B-CLL pathogenesis and progression, by regulating CLL cell interaction with the stromal microenvironment, leading to cells survival and proliferation. In this study, we investigated, in normal versus CLL B-lymphocytes, the role of BTK in signal transduction activated by the CXCL12-CXCR4 signaling axis and its involvement in rapid integrin activation. We show that BTK is rapidly activated by CXCL12 in healthy as well as CLL B-lymphocytes, with a kinetic of tyr-phosphorylation coherent with rapid adhesion triggering. BTK inhibition prevents CXCL12-induced triggering of lymphocyte function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4) integrins. Furthermore, BTK inhibition blocks the activation of the small GTP-binding protein RhoA, controlling integrin affinity. Very importantly, we show that BTK tyr-phosphorylation and activation by CXCL12 depends on upstream activation of JAK2 tyrosine kinase. A comparative analysis of 36 B-CLL patients demonstrates that JAK2-dependent BTK regulatory role on integrin activation by CXCL12 is fully conserved in CLL cells. Finally, we show that the JAK2-BTK axis also regulates signaling to integrin activation by BCR. Thus, BTK and JAK protein tyrosine kinases (PTKs) manifest a hierarchical activity both in chemokine- as well as BCR-mediated integrin activation and dependent adhesion, potentially suggesting the possibility of combined therapeutic approaches to B-CLL treatment. PMID- 30416685 TI - Antitumor profile of the PI3K inhibitor ZSTK474 in human sarcoma cell lines. AB - Treatment of patients with advanced sarcoma remains challenging due to lack of effective medicine, with the development of novel drugs being of keen interest. A pan-PI3K inhibitor, ZSTK474, has been evaluated in clinical trials against a range of advanced solid tumors, with clinical benefit shown in sarcoma patients. In the present study, we developed a panel of 14 human sarcoma cell lines and investigated the antitumor effect of 24 anticancer agents including ZSTK474, other PI3K inhibitors, and those clinically used for sarcoma treatment. ZSTK474 exhibited a similar antiproliferative profile to other PI3K inhibitors but was clearly different from the other drugs examined. Indeed, ZSTK474 inhibited PI3K downstream pathways, in parallel to growth inhibition, in all cell lines examined, showing proof-of-concept of PI3K inhibition. In addition, ZSTK474 induced apoptosis selectively in Ewing's sarcoma (RD-ES and A673), alveolar rhabdomyosarcoma (SJCRH30) and synovial sarcoma (SYO-1, Aska-SS and Yamato-SS) cell lines, all of which harbor chromosomal translocation and resulting oncogenic fusion genes, EWSR1-FLI1, PAX3-FOXO1 and SS18-SSX, respectively. Finally, animal experiments confirmed the antitumor activity of ZSTK474 in vivo, with superior efficacy observed in translocation-positive cells. These results suggest that ZSTK474 could be a promising drug candidate for treating sarcomas, especially those harboring chromosomal translocation. PMID- 30416686 TI - Transcriptomic and genomic profiling of early-stage ovarian carcinomas associated with histotype and overall survival. AB - Ovarian cancer is the most lethal gynecological malignancy in the western world. Despite recent efforts to characterize ovarian cancer using molecular profiling, few targeted treatment options are currently available. Here, we examined genetic variants, fusion transcripts, SNP genotyping, and gene expression patterns for early-stage (I and II) ovarian carcinomas (n=96) in relation to clinicopathological characteristics and clinical outcome, thereby identifying novel genetic features of ovarian carcinomas. Furthermore, mutation frequencies of specific genetic variants and/or their gene expression patterns were associated with histotype and overall survival, e.g. SLC28A2 (mucinous ovarian carcinoma histotype), ARCN1 (low expression in 0-2 year survival group), and tumor suppressor MTUS1 (mutation status and overall survival). The long non coding RNA MALAT1 was identified as a highly promiscuous fusion transcript in ovarian carcinoma. Moreover, gene expression deregulation for 23 genes was associated with tumor aggressiveness. Taken together, the novel biomarkers identified here may improve ovarian carcinoma subclassification and patient stratification according to histotype and overall survival. PMID- 30416688 TI - Correction: The nuclear-cytoplasmic trafficking of a chromatin-modifying and remodelling protein (KMT2C), in osteosarcoma. AB - [This corrects the article DOI: 10.18632/oncotarget.25755.]. PMID- 30416687 TI - Brain metastases in ALK-positive NSCLC - time to adjust current treatment algorithms. AB - The progress in molecular biology has revolutionized systemic treatment of advanced non-small-cell lung cancer (NSCLC) from conventional chemotherapy to a treatment stratified by histology and genetic aberrations. Tumors harboring a translocation of the anaplastic-lymphoma-kinase (ALK) gene constitute a distinct genetic and clinico-pathologic NSCLC subtype with patients with ALK-positive disease being at a higher risk for developing brain metastases. Due to the introduction of effective targeted therapy with ALK-inhibitors, today, patients with advanced ALK-positive NSCLC achieve high overall response rates and remain progression-free for long time intervals. Moreover, ALK-inhibitors seem to exhibit efficacy in the treatment of brain metastases. In the light of this, it needs to be discussed how treatment algorithms for managing patients with brain metastases should be modified. By integrating systemic ALK-inhibitor therapy, radiotherapy, in particular whole brain radiotherapy might be postponed deferring potential long-term impairment by neurocognitive deficits to a later time point in the course of the disease. An early treatment of asymptomatic brain metastases might offer patients a longer time without impairment of cerebral symptoms or radiotherapeutic interventions. Based on an updated extensive review of the literature this article provides an overview on the epidemiology and the treatment of patients' brain metastases. It describes the specifics of ALK positive disease and proposes an algorithm for the treatment of patients with advanced ALK-positive NSCLC and brain metastases. PMID- 30416689 TI - Erratum: Disruption of Myc-Max Heterodimerization with Improved Cell-Penetrating Analogs of the Small Molecule 10074-G5. AB - [This corrects the article DOI: 10.18632/oncotarget.1108.]. PMID- 30416690 TI - The JAK2V617F Point Mutation Increases the Osteoclast Forming Ability of Monocytes in Patients with Chronic Myeloproliferative Neoplasms and Makes their Osteoclasts more Susceptible to JAK2 Inhibition. AB - JAK2V617F is a gain of function point mutation that occurs in Myeloproliferative Neoplasm (MPN) patients and deranges their hemopoiesis at cellular level. We speculate that hyperfunctioning JAK2 can modify osteoclast (OCL) homeostasis in MPN patients. We studied 18 newly diagnosed MPN patients and four age-matched normal donors (ND). Osteoclast forming assays started from selected monocytes also and under titrated concentrations of the JAK2 Inhibitor AG-490 (Tyrphostin). Genomic DNA was extracted from the formed osteoclasts, and the JAK2V617F/JAK2WT genomic DNA ratio was calculated. OCLs formed from monocytes derived from heterozygous (Het) for the JAK2V617F mutation MPN patients, were three times more compared to those from JAK2 wild type (WT) MPN patients (p=0,05) and from ND as well (p=0,03). The ratio of JAK2V617F/JAK2WT genomic DNA was increased in OCLs compared to the input monocyte cells showing a survival advantage of the mutated clone. In comparison to ND and JAK2 WT MPN patients, OCLs from patients JAK2V617F (Het) were more susceptible to JAK2 inhibition. These alterations in osteoclast homeostasis, attributed to mutated JAK2, can deregulate the hemopoietic stem cell niche in MPN patients. PMID- 30416691 TI - Molecular Expression of Bone Marrow Angiogenic Factors, Cell-Cell Adhesion Molecules and Matrix-Metallo-Proteinases in Plasmacellular Disorders: a Molecular Panel to Investigate Disease Progression. PMID- 30416692 TI - Insights into the Interplay between KIR Gene Frequencies and Chronic HBV Infection in Burkina Faso. AB - Background/Objective: Hepatitis B virus (HBV) infection is the leading risk factor for cirrhosis and hepatocellular carcinoma (HCC). The objective of this investigation was to assess the association between "Killer Cell Immunoglobulin Like Receptor" (KIR) gene frequencies and chronic HBV infection. Methods: Chronic HBV carriers and healthy patients were selected for this study. The viral load for HBV were performed, and SSP-PCR was used to characterize the frequencies of KIR genes. Results: The study suggested that inhibitory genes KIR2DL2 (crude OR = 2.82; p < 0.001), KIR2DL3 (crude OR = 2.49; p < 0.001) and activator gene KIR2DS2 (crude OR = 3.95; p< 0.001) might be associated with chronic stages of HBV infection. Conversely the inhibitory genes KIR3DL1 (crude OR = 0.49; p = 0.0018) and KIR3DL2 (crude OR = 0.41; p = 0.005), the activator gene KIR2DS1 (crude OR = 0.48; p = 0.014) and the pseudo gene KIR2DP1 (crude OR = 0.49; p = 0.008) could be associated with immunity against HBV infection. Chronic HBV patients who are carriers for the KIR3DL3 gene (crude OR = 8; p = 0.048) were positive for HBeAg and patients who carried the KIR3DL2 gene (crude OR = 3.21; p = 0.012) had a high HBV viral load compared to the rest of the study population. Conclusion: Our data showed evidence of a correlation between the risk of developing chronic HBV infection and certain KIR gene frequencies and also show that KIR3DL1, KIR3DL2, KIR2DS1 might confer a protective status against chronic HBV infection. PMID- 30416694 TI - Severe Liver Iron Concentrations (LIC) in 24 Patients with beta-Thalassemia Major: Correlations with Serum Ferritin, Liver Enzymes and Endocrine Complications. AB - Introduction: Chronic blood transfusion is the mainstay of care for individuals with beta-thalassemia major (BTM). However, it causes iron-overload that requires monitoring and management by long-term iron chelation therapy to prevent endocrinopathies and cardiomyopathies, which can be fatal. Hepatic R2 MRI method (FerriScan(r)) has been validated as the gold standard for evaluation and monitoring liver iron concentration (LIC) that reflects the total body iron overload. Although adequate oral iron chelation therapy (OIC) is promising for the treatment of transfusional iron-overload, some patients are less compliant with it, and others suffer from long-term effects of iron overload. Objective: The aim of our study was to evaluate the prevalence of endocrinopathies and liver dysfunction, in relation to LIC and serum ferritin level, in a selected group of adolescents and young adult BTM patients with severe hepatic iron overload (LIC from 15 to 43 mg Fe/g dry weight). Patients and Methods: Twenty-four selected BTM patients with severe LIC, due to transfusion-related iron-overload, followed at the Haematology Section, National Centre for Cancer Care and Research, Hamad Medical Corporation of Doha (Qatar), from April 2015 to July 2017, were retrospectively evaluated. The prevalence of short stature, hypogonadism, hypothyroidism, hypoparathyroidism, impaired fasting glucose (IFG), diabetes, and adrenal insufficiency was defined and assessed according to the International Network of Clinicians for Endocrinopathies in Thalassemia (ICET) and American Diabetes Association criteria. Results: Patients' most common transfusion frequency was every three weeks (70.8%). At the time of LIC measurements, their median age was 21.5 years with a mean age of 21.7 +/- 8.0 years. Mean LIC was 32.05 +/- 10.53 mg Fe/g dry weight (range: 15 to 43 mg Fe/g dry weight), and mean serum ferritin level was 4,488.6 +/- 2,779 MUg/L. LIC was correlated significantly with serum ferritin levels (r = 0.512; p = 0.011). The overall prevalence of short stature was 26.1% (6/23), IFG was 16.7% (4/24), sub-clinical hypothyroidism was 14.3% (3/21), hypogonadotropic hypogonadism was 14.3% (2/14), diabetes mellitus was 12.5% (3/24), and biochemical adrenal insufficiency was 6.7% (1/15). The prevalence of hepatitis C positivity was 20.8% (5/24). No case of clinical hypothyroidism, adrenal insufficiency or hypoparathyroidism was detected in this cohort of patients. The prevalence of IFG impaired fasting glucose was significantly higher in BTM patients with very high LIC (>30 mg Fe/g dry liver) versus those with lower LIC (p = 0.044). The prevalence of endocrinopathies was not significantly different between the two groups of patients with LIC above and below 15 mg Fe/g dry weight. Conclusions: A significant number of BTM patients, with high LIC and endocrine disorders, still exist despite the recent developments of new oral iron chelating agents. Therefore, physicians' strategies shall optimize early identification of those patients to optimise their chelation therapy and to avoid iron-induced organ damage. We believe that further studies are needed to evaluate if serial measurements of quantitative LIC may predict the risk for endocrine complications. Until these data are available, we recommend a close monitoring of endocrine and other complications, according to the international guidelines. PMID- 30416693 TI - Human Herpesvirus 8 and Lymphoproliferative Disorders. AB - The spectrum of lymphoproliferative disorders linked to human herpesvirus 8 (HHV 8) infection has constantly been increasing since the discovery of its first etiologic association with primary effusion lymphoma (PEL). PEL is a rapidly progressing non-Hodgkin's B-cell lymphoma that develops in body cavities in an effusional form. With the increase in the overall survival of PEL patients, as well as the introduction of HHV-8 surveillance in immunocompromised patients, the extracavitary, solid counterpart of PEL was later identified. Moreover, virtually all plasmablastic variants of multicentric Castleman's disease (MCD) developing in HIV-1-infected individuals harbor HHV-8, providing a strong etiologic link between MCD and this oncogenic herpesvirus. Two other pathologic conditions develop in HIV-1-infected persons concomitantly with MCD: MCD with plasmablastic clusters and HHV-8-positive diffuse large B-cell lymphoma not otherwise specified (HHV-8+ DLBCL NOS), the first likely representing an intermediate stage preceding the full neoplastic form. MCD in leukemic phase has also been described, albeit much less commonly. The germinotropic lymphoproliferative disorder (GLPD) may resemble extracavitary PEL, but develops in immune competent HHV8-infected individuals, and, unlike the other disorders, it responds well to conventional therapies. Almost all HHV-8-mediated lymphoproliferative disorders are the result of an interaction between HHV-8 infection and a dysregulated immunological system, leading to the formation of inflammatory niches in which B cells, at different developmental stages, are infected, proliferate and may eventually shift from a polyclonal state to a monoclonal/neoplastic disorder. Herein, we describe the association between HHV-8 and lymphoproliferative disorders and highlight the predominant distinctive features of each disease. PMID- 30416695 TI - Invasive Fungal Infections in Patients with Chronic Lymphoproliferative Disorders in the Era of Target Drugs. AB - This review summarizes the more recent evidence about epidemiology and risk factors for invasive fungal infections (IFI) in patients affected by Chronic Lymphocytic Leukemia (CLL), indolent Non Hodgkin Lymphoma (iNHL) and Multiple Myeloma (MM). Despite advances in the prognosis and treatment of hematological malignancies in recent years, susceptibility to infection remains a significant challenge to patient care. A large amount of data regarding patients with acute leukemia has been published while little information is available on the incidence of IFI in chronic lymphoproliferative disorders (CLD). New drugs are now available for treatment of lymphoproliferative disorders which may cause suppression of humoral immunity, cellular immunity, and deficiency of white blood cells, increasing the risk for infections which remain the leading cause of mortality in these patients. PMID- 30416696 TI - Jadenu(r) Substituting Exjade(r) in Iron Overloaded beta-Thalassemia Major (BTM) Patients: A Preliminary Report of the Effects on the Tolerability, Serum Ferritin Level, Liver Iron Concentration and Biochemical Profiles. AB - Introduction: Due to the chronic nature of chelation therapy and the adverse consequences of iron overload, patient adherence to therapy is an important issue. Jadenu (r) is a new oral formulation of deferasirox (Exjade (r)) tablets for oral suspension. While Exjade(r) is a dispersible tablet that must be mixed in liquid and taken on an empty stomach, Jadenu (r) can be taken in a single step, with or without a light meal, simplifying administration for the treatment of patients with chronic iron overload. This may significantly improve the compliance to treatment of patients with beta-thalassemia major (BMT). The aim of this study was to evaluate the drug tolerability and the effects of chelation therapy on serum ferritin concentration, liver iron concentration (LIC) and biochemical profiles in patients with BMT and iron overload. Patients and Methods: Twelve selected adult patients BMT (mean age: 29 years; range:15-34 years) were enrolled in the study. All patients were on monthly regular red cell transfusion therapy to keep their pre-transfusional hemoglobin (Hb) level not less than 9 g/dL. They were on Exjade(r) therapy (30 mg/kg per day) for two years or more before starting Jadenu(r) therapy (14-28 mg/kg/day). The reason for shifting from Deferasirox(r) to Jadenu(r) therapy was lack of tolerability, as described by patients, such as nausea, vomiting, diarrhea, stomach pain. Most of them also reported that Deferasirox(r) was not palatable. Lab investigations included monthly urine analysis and measurement of their serum concentrations of creatinine, fasting blood glucose (FBG), serum ferritin, alkaline phosphatase (ALP), alanine transferase (ALT), aspartate transferase (AST) and albumin concentrations. LIC was measured using FerriScan (r). Thyroid function, vitamin D and serum parathormone, before and one year after starting Jadenu (r) therapy, were also assessed. Results: Apart from some minor gastrointestinal complaints reported in 3 BMT patients that did not require discontinuation of therapy, other side effects were not registered during the treatment. Subjectively, patients reported an improvement in the palatability of Jadenu(r) compared to Exjade(r) therapy in 8 out of 12 BMT patients. A non-significant decrease in LIC measured by FerriScan(r) and serum ferritin levels was observed after one year of treatment with Jadenu(r). A significant positive correlation was found between serum ferritin level and LIC measured by the FerriScan(r) method. LIC and serum ferritin level correlated significantly with ALT level (r = 0.31 and 0.45 respectively, p < 0.05). No significant correlation was detected between LIC and other biochemical or hormonal parameters. Conclusions: Our study shows that short term treatment with Jadenu (r) is safe but is associated with a non-significant decrease in LIC and serum ferritin levels. Therefore, there is an urgent need for adequately-powered and high-quality trials to assess the clinical efficacy and the longterm outcomes of new deferasirox formulation. PMID- 30416697 TI - Cutaneous Manifestations of Primary Immunodeficiency Diseases in Tunisian Children. AB - Skin manifestations are frequent among patients with primary immunodeficiency diseases (PIDs). Their prevalence varies according to the type of immunodeficiency. This review provides the reader with an up-to-date summary of the common dermatologic manifestations of PIDs among Tunisian children. We conducted a prospective study on two hundred and ninety children with immune deficiency. Demographic details (including age, sex, and consanguinity) with personal and family history were recorded. Special attention was paid to cutaneous manifestations. Dermatological involvements were grouped according to the etiology of their most prominent sign. Cutaneous manifestations were found in 164 patients (56.5%). They revealed the diagnosis of PIDs in 71 patients (24.5 %). The mean age at presentation was 21 months. Overall the most prominent cutaneous alterations were infectious. They accounted for 106 cases (36.55%). The most prevalent causes of cutaneous infections were bacterial: 93 cases (32.06%). Immuno-allergic skin diseases were among the common findings in our study. These include eczematous dermatitis found in 62 cases (21.38%). Malignancy related PIDs was seen in a boy with Wiskott Aldrich syndrome. He developed Kaposi's sarcoma at the age of 14 months. Cutaneous changes are common among children with PIDs. In pediatric patients with failure to thrive, chronic refractory systemic manifestations often present in other family members, recurrent cutaneous infections unresponsive to adequate therapy, atypical forms of eczematous dermatitis or unusual features should arouse the suspicion of PIDs and prompt specialized immunologic consultation should be made. PMID- 30416698 TI - Deferasirox: Over a Decade of Experience in Thalassemia. AB - Thalassemia incorporates a broad clinical spectrum characterized by decreased or absent production of normal hemoglobin leading to decreased red blood cell survival and ineffective erythropoiesis. Chronic iron overload remains an inevitable complication resulting from regular blood transfusions (transfusion dependent) and/or increased iron absorption (mainly non-transfusion-dependent thalassemia), requiring adequate treatment to prevent the significant associated morbidity and mortality. Iron chelation therapy has become a cornerstone in the management of thalassemia patients, leading to improvements in their outcome and quality of life. Deferasirox (DFX), an oral iron chelating agent, is approved for use in transfusion dependent and non-transfusion-dependent thalassemia and has shown excellent efficacy in this setting. We herein present an updated review of the role of deferasirox in thalassemia, exploring over a decade of experience, which has documented its effectiveness and convenience; in addition to its manageable safety profile. PMID- 30416701 TI - Cardiac Toxicity Associated with HCV Direct Antiviral Agents. PMID- 30416699 TI - The Broad-Ranging Panorama of Systemic Autoinflammatory Disorders with Specific Focus on Acute Painful Symptoms and Hematologic Manifestations in Children. AB - Systemic autoinflammatory disorders (SAIDs) are inherited defects of innate immunity characterized by recurrent sterile inflammatory attacks involving skin, joints, serosal membranes, gastrointestinal tube, and other tissues, which recur with variable rhythmicity and display reactive amyloidosis as a potential long term complication. Dysregulated inflammasome activity leading to overproduction of many proinflammatory cytokines, such as interleukin-1 (IL-1), and delayed shutdown of inflammation are considered crucial pathogenic keys in the vast majority of SAIDs. Progress of cellular biology has partially clarified the mechanisms behind monogenic SAIDs, such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndrome, mevalonate kinase deficiency, hereditary pyogenic diseases, idiopathic granulomatous diseases and defects of the ubiquitin-proteasome pathway. Whereas, little is clarified for the polygenic SAIDs, such as periodic fever, aphthous stomatitis, pharyngitis, and cervical adenopathy (PFAPA) syndrome. The puzzle of symptomatic febrile attacks recurring over time in children requires evaluating the mixture of clinical data, inflammatory parameters in different disease phases, the therapeutic efficacy of specific drugs such as colchicine, corticosteroids or IL-1 antagonists, and genotype analysis in selected cases. The long-term history of periodic fevers should also need to rule out chronic infections and malignancies. This review is conceived as a practical template for proper classification of children with recurring fevers and includes tips useful for the diagnostic approach to SAIDs, focusing on the specific acute painful symptoms and hematologic manifestations encountered in childhood. PMID- 30416702 TI - Phenotyping of Rh, Kell, Duffy and Kidd Blood Group Antigens among Non-Tribal and Tribal Population of South Gujarat and its Implication in Preventing Alloimmunization in Multitransfused Patients. PMID- 30416703 TI - Indication of Mental Health from Fingertip Pulse Waves and Its Application. AB - This article is a comprehensive review of recent studies of the authors on the indication of mental health from biological information contained in pulse waves. A series of studies discovered that the largest Lyapunov exponent (LLE) of the attractor, which is constructed for the time series data from pulse waves, can provide as an effective indicator of mental health. A low level of LLE indicates insufficiency of external adaptability, which is characteristic of dementia and depression sufferers. On the contrary, a continuous high level of LLE indicates excessive external adaptability, and people in this condition tend to resort to violence. With this discovery, real-time display of the LLE, combined with other physiological indexes such as the autonomic nerve balance (ANB), sample entropy, and vascular age, as a reference, can enable people to conduct self-check of mental status. To this end, software development was performed in order to enable users to conduct pulse wave measurement anywhere at any time and display the analytical results in real time during the measurement. PMID- 30416700 TI - Megakaryocyte Contribution to Bone Marrow Fibrosis: many Arrows in the Quiver. AB - In Primary Myelofibrosis (PMF), megakaryocyte dysplasia/hyperplasia determines the release of inflammatory cytokines that, in turn, stimulate stromal cells and induce bone marrow fibrosis. The pathogenic mechanism and the cells responsible for progression to bone marrow fibrosis in PMF are not completely understood. This review article aims to provide an overview of the crucial role of megakaryocytes in myelofibrosis by discussing the role and the altered secretion of megakaryocyte-derived soluble factors, enzymes and extracellular matrices that are known to induce bone marrow fibrosis. PMID- 29118975 TI - Interfacial microscopic examination and chemical analysis of resin-dentin interface of self-adhering flowable resin composite. AB - Background: The newly introduced self-adhering flowable resin-composites decrease the required time for application by incorporation of an acidic adhesive monomer, thus reducing the number of steps, but its bonding is still uncertain. The aim of this study was to evaluate the interfacial microscopic examination and chemical analysis at the resin-dentin interface of a self-adhering flowable resin composite (VertiseTMFlow Self-Adhering Flowable Composite, Kerr Dental, USA) versus a total-etch (Te-Econom Plus) resin composite, using an etching agent (Eco Etch gel) and bonding agent (Single Bond Universal). Methods: Sixteen freshly extracted sound human posterior teeth were used. The teeth were randomly divided into two groups: 8 specimens per type of composite. Standard-shaped class V cavities were prepared on the buccal surface. One group was restored by Te-Econom Plus resin composite by total-etch technique using Eco-Etch gel, which was applied to dentine for 15 seconds, followed by rinsing, drying and bonding agent application (Single Bond Universal). The other group restored directly with self adhering resin composite (Vertise-Flow) without application of etch or bond. Curing was done for 20 seconds using a light emitting diode light curing unit. Evaluation of the resin-dentin interface was done microscopically by examination of marginal gap distance in MUm using scanning electron microscope (SEM), and chemical analysis of silver particles was observed using SEM with energy dispersive X-ray spectrometry after 24 hours of specimen storage in ammoniacal silver nitrate. Results: Regarding marginal gap distance (um) and silver atomic % mean values, teeth restored with self-adhering resin composite (Vertise-Flow) showed significantly higher mean values than the multi-step etch and rinse resin composite group (5.2 vs 0; 12.2 vs 8.2, respectively). Conclusions: Resin-dentin bonding using total-etch resin composite technique was more effective than self adhering flowable resin composite (Vertise-Flow) regarding marginal gap formation and penetration of silver particles. Further studies for bond strength could be performed. PMID- 30416704 TI - Association between Objectively Measured Physical Activity and Gait Patterns in People with Parkinson's Disease: Results from a 3-Month Monitoring. AB - Background: Although physical activity (PA) is known to be beneficial in improving motor symptoms of people with Parkinson's disease (pwPD), little is known about the relationship between gait patterns and features of PA performed during daily life. Objective: To verify the existence of possible relationships between spatiotemporal and kinematic parameters of gait and amount/intensity of PA, both instrumentally assessed. Methods: Eighteen individuals affected by PD (10F and 8M, age 68.0 +/- 10.8 years, 1.5 <= Hoehn and Yahr (H&Y) < 3) were required to wear a triaxial accelerometer 24 h/day for 3 consecutive months. They also underwent a 3D computerized gait analysis at the beginning and end of the PA assessment period. The number of daily steps and PA intensity were calculated on the whole day, and the period from 6:00 to 24:00 was grouped into 3 time slots, using 3 different cut-point sets previously validated in the case of both pwPD and healthy older adults. 3D gait analysis provided spatiotemporal and kinematic parameters of gait, including summary indexes of quality (Gait Profile Score (GPS) and Gait Variable Score (GVS)). Results: The analysis of hourly trends of PA revealed the existence of two peaks located in the morning (approximately at 10) and in the early evening (between 18 and 19). However, during the morning time slot (06:00-12:00), pwPD performed significantly higher amounts of steps (4313 vs. 3437 in the 12:00-18:00 time slot, p < 0.001, and vs. 2889 in the 18:00 24:00 time slot, p=0.021) and of moderate-to-vigorous PA (43.2% vs. 36.3% in the 12:00-18:00 time slot, p=0.002, and vs. 31.4% in the 18:00-24:00 time slot, p=0.049). The correlation analysis shows that several PA intensity parameters are significantly associated with swing-phase duration (rho = -0.675 for sedentary intensity, rho = 0.717 for moderate-to-vigorous intensity, p < 0.001), cadence (rho = 0.509 for sedentary intensity, rho = -0.575 for moderate-to-vigorous intensity, p < 0.05), and overall gait pattern quality as expressed by GPS (rho = -0.498 to -0.606 for moderate intensity, p < 0.05) and GVS of knee flexion extension (rho = -0.536 for moderate intensity, p < 0.05). Conclusions: Long-term monitoring of PA integrated by the quantitative assessment of spatiotemporal and kinematic parameters of gait may represent a useful tool in supporting a better targeted prescription of PA and rehabilitative treatments in pwPD. PMID- 30416707 TI - Mask ventilation. AB - Effective mask ventilation is an essential skill for any practitioner engaged in airway management. Recent methods to objectively describe mask ventilation using waveform capnography help practitioners to monitor and communicate the effectiveness of mask ventilation. Gentle mask ventilation is now considered acceptable during rapid sequence induction/intubation after loss of consciousness, hence reducing the incidence of hypoxia prior to tracheal intubation. Mask ventilation can be enhanced with muscle relaxation, a double C-E grip, and jaw thrust. This is particularly relevant for patients with reduced apnoea time. An awareness of the complications associated with mask ventilation may help reduce the morbidity associated with this technique. Effective ventilation technique and optimum device selection are important aspects for resuscitation of the newborn. Teaching correct establishment and maintenance of mask ventilation is essential for safe patient care. This review will examine some of the latest developments concerning mask ventilation for adult and paediatric patients. PMID- 30416706 TI - Recent advances in lung transplantation. AB - Lung transplantation can improve quality of life and prolong survival for individuals with end-stage lung disease, and many advances in the realms of both basic science and clinical research aspects of lung transplantation have emerged over the past few decades. However, many challenges must yet be overcome to increase post-transplant survival. These include successfully bridging patients to transplant, expanding the lung donor pool, inducing tolerance, and preventing a myriad of post-transplant complications that include primary graft dysfunction, forms of cellular and antibody-mediated rejection, chronic lung allograft dysfunction, and infections. The goal of this manuscript is to review salient recent and evolving advances in the field of lung transplantation. PMID- 30416708 TI - Epigenomic regulation of heart failure: integrating histone marks, long noncoding RNAs, and chromatin architecture. AB - Epigenetic processes are known to have powerful roles in organ development across biology. It has recently been found that some of the chromatin modulatory machinery essential for proper development plays a previously unappreciated role in the pathogenesis of cardiac disease in adults. Investigations using genetic and pharmacologic gain- and loss-of-function approaches have interrogated the function of distinct epigenetic regulators, while the increased deployment of the suite of next-generation sequencing technologies have fundamentally altered our understanding of the genomic targets of these chromatin modifiers. Here, we review recent developments in basic and translational research that have provided tantalizing clues that may be used to unlock the therapeutic potential of the epigenome in heart failure. Additionally, we provide a hypothesis to explain how signal-induced crosstalk between histone tail modifications and long non-coding RNAs triggers chromatin architectural remodeling and culminates in cardiac hypertrophy and fibrosis. PMID- 30416709 TI - Helminth parasites and immune regulation. AB - Helminth parasites are complex metazoans that belong to different taxonomic families but that collectively share the capacity to downregulate the host immune response directed toward themselves (parasite-specific immunoregulation). During long-standing chronic infection, these helminths appear able to suppress immune responses to bystander pathogens/antigens and atopic, autoimmune, and metabolic disorders. Helminth-induced immunoregulation occurs through the induction of regulatory T cells or Th2-type cells (or both). However, secreted or excreted parasite metabolites, proteins, or extracellular vesicles (or a combination of these) may also directly induce signaling pathways in host cells. Therefore, the focus of this review will be to highlight recent advances in understanding the immune responses to helminth infection, emphasizing the strategies/molecules and some of the mechanisms used by helminth parasites to modulate the immune response of their hosts. PMID- 30416711 TI - Recent advances in understanding the relationship between long- and short-term weight change and fertility. AB - The impact of excess body weight on fertility is well recognized among both women attempting to conceive spontaneously and those attempting to conceive with medical assistance. Although many leading societies of reproductive medicine have proposed weight loss as a means to counteract the negative consequences of obesity on fertility, there is limited research on this topic. In this review, we provide a brief overview of the recent advances in the literature focused on how long- and short-term weight change affects fertility among women. Overall, despite initial hope that weight loss may be beneficial for fertility, two large well-conducted randomized controlled trials have consistently shown that short term weight loss among overweight and obese women undergoing infertility treatment does not improve a woman's probability of live birth. The observational evidence among women attempting to conceive without medical assistance also suggests limited benefits of weight loss on fecundity or pregnancy loss. In contrast, substantial weight gain between consecutive pregnancies, in the year prior to pregnancy attempt, and throughout adulthood appears to be harmful for not only time to pregnancy but also pregnancy maintenance. Future research focused on efforts to prevent weight gain during adulthood is needed to better understand whether these types of interventions may have beneficial effects on fertility. PMID- 30416712 TI - Managing invasive species. AB - Invasive species pose considerable harm to native ecosystems and biodiversity and frustrate and at times fascinate the invasive species management and scientific communities. Of the numerous non-native species established around the world, only a minority of them are invasive and noxious, whereas the majority are either benign or in fact beneficial. Agriculture in North America, for example, would look dramatically different if only native plants were grown as food crops and without the services of the European honey bee as a pollinator. Yet the minority of species that are invasive negatively alter ecosystems and reduce the services they provide, costing governments, industries, and private citizens billions of dollars annually. In this review, I briefly review the consequences of invasive species and the importance of remaining vigilant in the battle against them. I then focus on their management in an increasingly connected global community. PMID- 30416710 TI - Recent advances in understanding Crimean-Congo hemorrhagic fever virus. AB - Crimean-Congo hemorrhagic fever virus (CCHFV) is a widely distributed hemorrhagic fever virus and the cause of hemorrhagic disease in Africa, Southern and Eastern Europe, the Middle East, India and Asia. Recent emergence of CCHFV into Spain indicates that the geographic range of this virus is expanding and the presence of its tick vector in several countries without reported disease suggest that CCHFV will continue to spread. Research into CCHFV was historically limited by a lack of suitable animal models and tools to study viral pathogenesis. However, in the past few years the toolset for studying CCHFV has expanded with small animal and non-human primate models for CCHFV being developed along with a reverse genetics system that allows for investigation of viral determinants of disease. These tools have been utilized to understand how CCHFV antagonizes host restriction factors and to develop novel vaccine candidates that may help limit the substantial morbidity and mortality in humans caused by CCHFV. PMID- 30416713 TI - Explicit interaction information from WikiPathways in RDF facilitates drug discovery in the Open PHACTS Discovery Platform. AB - Open PHACTS is a pre-competitive project to answer scientific questions developed recently by the pharmaceutical industry. Having high quality biological interaction information in the Open PHACTS Discovery Platform is needed to answer multiple pathway related questions. To address this, updated WikiPathways data has been added to the platform. This data includes information about biological interactions, such as stimulation and inhibition. The platform's Application Programming Interface (API) was extended with appropriate calls to reference these interactions. These new methods of the Open PHACTS API are available now. PMID- 30416715 TI - Central sensitization and pain hypersensitivity: Some critical considerations. AB - Since its discovery, central sensitization has gained enormous popularity. It is widely used to explain pain hypersensitivity in a wide range of clinical pain conditions. However, at present there is no general consensus on the definition of central sensitization. Moreover, the use of the term central sensitization in the clinical domain has been criticized. The aim of this paper is to foster the discussion on the definition of central sensitization and its use. PMID- 30410728 TI - Fuchs heterochromic iridocyclitis-associated glaucoma: a retrospective comparison of primary Ahmed glaucoma valve implantation and trabeculectomy with mitomycin C. AB - Background: The aim of this study was to compare the safety and efficacy of primary trabeculectomy with mitomycin C and Ahmed glaucoma valve (AGV) implantation in patients with Fuchs heterochromic iridocyclitis (FHIC)-related glaucoma, a rare complication of an uncommon form of uveitis. Methods : In this retrospective comparative case series, 26 FHIC-associated glaucoma patients received trabeculectomy (n=12) or an AGV (n=14). Primary outcome measures were surgical success, defined as intraocular pressure (IOP) <=21 mmHg, decreasing >=20% from baseline, and no secondary glaucoma surgery. Secondary outcome measures were the number of glaucoma medications, complications, best corrected visual acuity (BCVA), and IOP. Results: The follow-up was 34.0+/-17.7 months in patients that received trabeculectomy and 33.4+/-18.6 months in AGV (P= 0.837). The cumulative probability of success rate was 41.7% for trabeculectomy and 85.7% for AGV, with no significant difference in complications (P>0.05). The IOP in patients that received trabeculectomy dropped from 23.4+/-3.3 mmHg to 21.6+/-5.2 mmHg at the final visit (P= 0.041). In patients that received AGV, the IOP decreased from 24+/-7.8 to 17.1+/-2.6 mmHg (P= 0.003). The number of glaucoma medications at baseline were 3.3+/-0.5 in those that received trabeculectomy and 3+/-0.6 in those that received AGV (P=0.233), and decreased to 2.4+/-1.0 (P=0.008) and 1.7+/-0.6 (P=0.002), respectively. BCVA was equal in both groups and did not change (P>0.05). Conclusion: Primary AGV had a higher success rate than trabeculectomy, with patients also needing fewer medications for the management of FHIC-associated glaucoma. PMID- 30416716 TI - Antimicrobial activity of Terminalia catappa brown leaf extracts against Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 27853. AB - The aim of this study was to determine the effects of various concentration of Terminalia catappa brown leaves extract which can inhibit the growth of Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 27853. The crushed-brown leaves of Terminalia catappa was extracted using 95% ethanol, filtered, and evaporated. The dried T. catappa extract was used to identify phytochemical content qualitatively. Total phenolic and flavonoid contents were also measured quantitatively from dried extract. The dried extracts were also dissolved in sterile aquadest and serial dilutions were prepared to final concentration of 30, 60 and 90%. A disc diffusion method was used to evaluate the antibacterial activity of various concentrations of ethanol extract of brown leaves of T. catappa. Inhibition zone diameter was measured to determine antibacterial activity. Gentamycin sulfate and distilled water were used as positive and negative controls, respectively. Dried ethanolic extract of brown T. catappa leaves contained flavonoid, quinon, phenolic, triterpenoid, and tannin. A total of 208.722 mg gallic acid equivalent/g extract of total phenolic and 35.7671 mg quercetin equivalent/g extract of total flavonoid were also found in the dried extract. The inhibition zone diameters of ethanolic extracts ranged from 1.73 to 9.06 mm ( S. aureus) and from 1.83 to 6.5 mm ( P. aeruginosa). The higher concentration of extract, the wider the inhibition zone diameters for both bacteria. P. aeruginosa was more resistant to high concentrations of extract (90%) than S. aureus. Ethanolic extracts of the brown leaves of T. catappa had different antibacterial effects against S. aureus and P. aeruginosa. The higher the concentration of extract, the wider the inhibition zone diameter for both bacteria. P. aeruginosa was more resistant to high concentrations of ethanolic extracts of the brown leaves of T. catappa. PMID- 30416717 TI - ITSxpress: Software to rapidly trim internally transcribed spacer sequences with quality scores for marker gene analysis. AB - The internally transcribed spacer (ITS) region between the small subunit ribosomal RNA gene and large subunit ribosomal RNA gene is a widely used phylogenetic marker for fungi and other taxa. The eukaryotic ITS contains the conserved 5.8S rRNA and is divided into the ITS1 and ITS2 hypervariable regions. These regions are variable in length and are amplified using primers complementary to the conserved regions of their flanking genes. Previous work has shown that removing the conserved regions results in more accurate taxonomic classification. An existing software program, ITSx, is capable of trimming FASTA sequences by matching hidden Markov model profiles to the ends of the conserved genes using the software suite HMMER. ITSxpress was developed to extend this technique from marker gene studies using Operational Taxonomic Units (OTU's) to studies using exact sequence variants; a method used by the software packages Dada2, Deblur, QIIME 2, and Unoise. The sequence variant approach uses the quality scores of each read to identify sequences that are statistically likely to represent real sequences. ITSxpress enables this by processing FASTQ rather than FASTA files. The software also speeds up the trimming of reads by a factor of 14-23 times on a 4-core computer by temporarily clustering highly similar sequences that are common in amplicon data and utilizing optimized parameters for Hmmsearch. ITSxpress is available as a QIIME 2 plugin and a stand-alone application installable from the Python package index, Bioconda, and Github. PMID- 30416718 TI - Prophylactic potential of a Panchgavya formulation against certain pathogenic bacteria. AB - A Panchgavya preparation was evaluated for its prophylactic efficacy against bacterial infection, employing the nematode worm Caenorhabditis elegans as a model host. Worms fed with the Panchgavya preparation prior to being challenged with pathogenic bacteria had a better survival rate against four out of five test bacterial pathogens, as compared to the control worms. Panchgavya feeding prior to bacterial challenge was found to be most effective against Staphylococcus aureus, resulting in 27% (p=0.0001) better worm survival. To the best of our awareness, this is the first report demonstrating in vivo prophylactic efficacy of Panchgavya mixture against pathogenic bacteria. PMID- 30416719 TI - Publishing peer review materials. AB - Publishing peer review materials alongside research articles promises to make the peer review process more transparent as well as making it easier to recognise these contributions and give credit to peer reviewers. Traditionally, the peer review reports, editors letters and author responses are only shared between the small number of people in those roles prior to publication, but there is a growing interest in making some or all of these materials available. A small number of journals have been publishing peer review materials for some time, others have begun this practice more recently, and significantly more are now considering how they might begin. This article outlines the outcomes from a recent workshop among journals with experience in publishing peer review materials, in which the specific operation of these workflows, and the challenges, were discussed. Here, we provide a draft as to how to represent these materials in the JATS and Crossref data models to facilitate the coordination and discoverability of peer review materials, and seek feedback on these initial recommendations. PMID- 30416720 TI - At diagnosis of hepatocellular carcinoma, African Americans with hepatitis C have better liver function than other patients. PMID- 30416721 TI - Broadband achromatic dielectric metalenses. AB - Metasurfaces offer a unique platform to precisely control optical wavefronts and enable the realization of flat lenses, or metalenses, which have the potential to substantially reduce the size and complexity of imaging systems and to realize new imaging modalities. However, it is a major challenge to create achromatic metalenses that produce a single focal length over a broad wavelength range because of the difficulty in simultaneously engineering phase profiles at distinct wavelengths on a single metasurface. For practical applications, there is a further challenge to create broadband achromatic metalenses that work in the transmission mode for incident light waves with any arbitrary polarization state. We developed a design methodology and created libraries of meta-units-building blocks of metasurfaces-with complex cross-sectional geometries to provide diverse phase dispersions (phase as a function of wavelength), which is crucial for creating broadband achromatic metalenses. We elucidated the fundamental limitations of achromatic metalens performance by deriving mathematical equations that govern the tradeoffs between phase dispersion and achievable lens parameters, including the lens diameter, numerical aperture (NA), and bandwidth of achromatic operation. We experimentally demonstrated several dielectric achromatic metalenses reaching the fundamental limitations. These metalenses work in the transmission mode with polarization-independent focusing efficiencies up to 50% and continuously provide a near-constant focal length over lambda = 1200 1650 nm. These unprecedented properties represent a major advance compared to the state of the art and a major step toward practical implementations of metalenses. PMID- 30416722 TI - More than two decades trapped. AB - Optical tweezers, crowned by Nobel Prize the first time in 1990s, have widely impacted the research landscape of atom cooling, particle manipulation/sorting, and biology. After more than two decades of steady development, it received the deserving recognition once again in 2018. Unprecedented advancements across various disciplines are believed to be spurred furthermore by this important tool of optical manipulation. PMID- 30416723 TI - Association between Entamoeba histolytica infection and human leukocyte antigen HLA- DRB1. AB - Background: Entamoeba histolytica is the parasitic amoeba which caused amebiasis in human and responsible of 100,000 deaths every year. There is currently no vaccine against this parasite. The innate and adaptive immunity are important in protection against infection. Aim of the study: To investigate the association between HLA-DRB1 and Entamoeba histolytica infection. Patients and methods: The study is a case-controlled consisted from thirty Iraqi Arab Muslims patients with Entamoeba histolytica infection. The patients were consulted medical city and AL Karama hospital for the period between May 2016 till February 2017. The control groups were sex and age matched with patient study group, they were consisted of thirty Iraqi Arab Muslims healthy individuals. HLA-DRB1 was done by SSOP method. Results: A total of 30 patients with Entamoeba histolytica infection were participated in this study. Their ages were range from 21 to 55 years. Males were 83.3% and the rest were females. The other is 30 control group was sex and age matched with patient study group. There was an increased frequency of HLADRB1*03:0101 and *11:0101 in patients group compared to control group (P = 0.002, Odds ratio = 7.42, 95% CI:2.07 to 26.55) and (P = 0.01, Odd ratio = 4.29, 95% CI: 1.41 to 13.06) respectively. Conclusions: HLA-DRB1*03:0101 and HLA DRB1*110,101 may have a role in susceptibility to amebiasis. PMID- 30416724 TI - Plasma d-dimer level correlated with advanced breast carcinoma in female patients. AB - Background: Advanced breast cancer is a common disease among female in the world. There is a correlation between cancer and hyper coagulation. In a cancer state, there is an increase in the level of cross-linked fibrin degradation product (d dimer)which indicates systemic activation of fibrinolysis and hemostasis. So, there is a relation between increase d-dimer value and advanced breast disease. Objective: To confirm the relation between increase d-dimer levels and advanced breast carcinoma in female patients. Patients and methods: A prospective study (cohort study) done in Baghdad teaching hospital (department of surgery) from Jan 2014 to Jan 2016. Seventy patients were categorized intotwo equal groups, group 1 with breast carcinoma, group 2 with benign breast tumor. Plasma d-dimer levels compared for each group, and in relation to (tumor size, stage, grade, lympho vascular invasion, and lymph nodes involvement). Results: D-dimer level was normal in group two (<0.25) mg/l and high in group one in other words, d-dimer level was increasing in advanced breast carcinoma group with enlarge tumor size, high stage, grade, lympho-vascular invasion and lymph nodes involvement. Conclusions: Plasma d-dimer levels was good prognostic factor in breast carcinoma specially in advanced breast carcinoma and its considered factor clinical stage progression lympho-vascular invasion and metastasis. PMID- 30416725 TI - Preprints and STM publishing: A New Challenge to the Editors of Scientific and Medical Journals. PMID- 30416726 TI - Progress Continues in Our Quest to Cure All Types of Cardiac Arrhythmias with Catheter Ablation. PMID- 30416727 TI - Do We Need an Implantable Cardioverter-defibrillator for Primary Prevention in Cardiac Resynchronisation Therapy Patients? PMID- 30416728 TI - Practical Guide to Ablation for Epicardial Ventricular Tachycardia: When to Get Access, How to Deal with Anticoagulation and How to Prevent Complications. AB - Epicardial ablation is needed to eliminate ventricular tachycardia (VT) in some patients with nonischaemic cardiomyopathy. The 12-lead electrocardiogram of VT, pre-procedural imaging and endocardial unipolar voltage maps can predict a high likelihood of epicardial substrate and VT. A septal VT substrate may preclude the need for epicardial access and mapping and can be identified with imaging, pacing and voltage mapping. Pericardial access is usually obtained prior to systemic anticoagulation or after reversal of systemic anticoagulation. A unique set of complications can be encountered with epicardial access, mapping and ablation, which include haemopericardium, phrenic nerve injury, damage to major coronary arteries and pericarditis. Anticipating, preventing and, if necessary, managing these complications are paramount for patient safety. Best practices are reviewed. PMID- 30416729 TI - Source Determination in Atrial Fibrillation. AB - Techniques to ablate persistent atrial fibrillation (AF) continue to evolve. Recent technological and strategic innovations have included a focus on mapping and ablating AF sources. These attempts have not yet yielded a consistent improvement in clinical outcomes following AF ablation. Advancements in these techniques in the next few years, however, may enhance our ability to map and ablate AF as well as further our understanding of the mechanisms behind AF initiation, perpetuation, and recurrence. PMID- 30416731 TI - Arrhythmogenic Inflammatory Cardiomyopathy: A Review. AB - Arrhythmogenic inflammatory cardiomyopathy is a recent clinical description of a subgroup of patients with non-ischaemic cardiomyopathy who are referred to electrophysiologists for evaluation and management of ventricular arrhythmias and are found to have evidence of active cardiac inflammation. The identification of these patients is key, since the aetiology of their arrhythmic burden is likely both related to scar-mediated and direct inflammatory mechanisms, which may have different treatment approaches. Evaluation of these patients starts with a full clinical history and physical examination along with echocardiography, as with most patients with cardiomyopathy, however, additional imaging with fluorodeoxyglucose PET-CT and cardiac MRI is crucial. Medical treatment is aimed at targeting traditional neurohumeral mediators to achieve recovery of ejection fraction, in addition to immunosuppressant medication to directly treat inflammation. While medical treatment alone is successful in many patients, some will require further invasive management with electrophysiologic study and radiofrequency catheter ablation. PMID- 30416732 TI - Long-QT Syndrome and Competitive Sports. AB - Long QT syndrome (LQTS) is an inherited channelopathy which exposes athletes to a risk of sudden cardiac death. Diagnosis is more difficult in this population because: the QT interval is prolonged by training; and the extreme bradycardia frequently observed in athletes makes the QT correction formula less accurate. Based on limited clinical data which tend to demonstrate that exercise, especially swimming, is a trigger for cardiac events, participation in any competitive sports practice is not supported by 2005 European guidelines. However, based on recent retrospective studies and adopting a different medical approach, involving the patient-athlete in shared decision making, the 2015 US guidelines are less restrictive, especially in asymptomatic genotype positive/phenotype-negative athletes. These guidelines also consider giving medical clearance to competitive sport participation in asymptomatic athletes with appropriate medical therapy. PMID- 30416733 TI - Heart Rate Variability: An Old Metric with New Meaning in the Era of using mHealth Technologies for Health and Exercise Training Guidance. Part One: Physiology and Methods. AB - The autonomic nervous system plays a major role in optimising function of the cardiovascular (CV) system, which in turn has important implications for CV health. Heart rate variability (HRV) is a measurable reflection of this balance between sympathetic and parasympathetic tone and has been used as a marker for cardiac status and predicting CV outcomes. Recently, the availability of commercially available heart rate (HR) monitoring systems has had important CV health implications and permits ambulatory CV monitoring on a scale not achievable with traditional cardiac diagnostics. The focus of the first part of this two-part review is to summarise the physiology of HRV and to describe available technologies for HRV monitoring. Part two will present HRV measures for assessing CV prognosis and athletic training. PMID- 30416730 TI - The Impact of Advances in Atrial Fibrillation Ablation Devices on the Incidence and Prevention of Complications. AB - The number of patients with atrial fibrillation currently referred for catheter ablation is increasing. However, the number of trained operators and the capacity of many electrophysiology labs are limited. Accordingly, a steeper learning curve and technical advances for efficient and safe ablation are desirable. During the last decades several catheter-based ablation devices have been developed and adapted to improve not only lesion durability, but also safety profiles, to shorten procedure time and to reduce radiation exposure. The goal of this review is to summarise the reported incidence of complications, considering device related specific aspects for point-by-point, multi-electrode and balloon-based devices for pulmonary vein isolation. Recent technical and procedural developments aimed at reducing procedural risks and complications rates will be reviewed. In addition, the impact of technical advances on procedural outcome, procedural length and radiation exposure will be discussed. PMID- 30416736 TI - Letter to the Editor: His Bundle Pacing: A New Frontier in the Treatment of Heart Failure. PMID- 30416737 TI - Bilingual children's use of lexical strategies under narrative monologue and dialogue conditions. AB - Purpose: This study examined lexical strategies produced by Spanish-English bilingual kindergartners across two different narrative elicitation tasks. Method: Fifty participants (M = 67.24 months) produced narratives in English under monologue and dialogue conditions. Participants were placed in high and low language performance groups determined by results from a bilingual language screener. Per parent report, children were matched by age, current language use, and age of first exposure to English. Analyses examined strategy types across participants' performance levels and task condition. Further evaluation compared strategy usage with general language productivity measures. Results: Child learners access similar lexical strategies as reported for adult second language learners. Performance level did not differentiate strategy type and frequency of use. Overall, participants relied more on all-purpose words and code-switching in the monologue condition, while employment of word approximation and literal translation increased during the mediated dialogue sessions. Application of all purpose words, word approximations, and literal translation influenced utterance length and lexical diversity. Conclusions: Participants adjusted lexical strategy use according to narrative condition. The application of mediated learning serves as an instructional model that reveals information specific to young second language learners. Application of all-purpose words, word approximations, and literal translation influenced utterance length and lexical diversity. Implications: Insight to the characteristics of bilingual children's language processing skills guides evidenced-based instructional decisions. PMID- 30416734 TI - Mechanisms Underlying the Actions of Antidepressant and Antipsychotic Drugs That Cause Sudden Cardiac Arrest. AB - A number of antipsychotic and antidepressant drugs are known to increase the risk of ventricular arrhythmias and sudden cardiac death. Based largely on a concern over the development of life-threatening arrhythmias, a number of antipsychotic drugs have been temporarily or permanently withdrawn from the market or their use restricted. While many antidepressants and antipsychotics have been linked to QT prolongation and the development of torsade de pointes arrhythmias, some have been associated with a Brugada syndrome phenotype and the development of polymorphic ventricular arrhythmias. This article examines the arrhythmic liability of antipsychotic and antidepressant drugs capable of inducing long QT and/or Brugada syndrome phenotypes. The goal of this article is to provide an update on the ionic and cellular mechanisms thought to be involved in, and the genetic and environmental factors that predispose to, the development of cardiac arrhythmias and sudden cardiac death among patients taking antidepressant and antipsychotic drugs that are in clinical use. PMID- 30416735 TI - Transvenous Lead Extractions: Current Approaches and Future Trends. AB - The use of cardiac implantable electronic devices (CIEDs) has continued to rise along with indications for their removal. When confronted with challenging clinical scenarios such as device infection, malfunction or vessel occlusion, patients often require the prompt removal of CIED hardware, including associated leads. Recent advancements in percutaneous methods have enabled physicians to face a myriad of complex lead extractions with efficiency and safety. Looking ahead, emerging technologies hold great promise in making extractions safer and more accessible for patients worldwide. This review will provide the most up-to date indications and procedural approaches for lead extractions and insight on the future trends in this novel field. PMID- 30416738 TI - First Acid Ionization Constant of the Drinking Water Relevant Chemical Cyanuric Acid from 5 to 35 degrees C. AB - Cyanuric acid is present in drinking water when chemicals commonly referred to as dichlor (anhydrous sodium dichloroisocyanurate or sodium dichloroisocyanurate dihydrate) or trichlor (trichloroisocyanuric acid) are used as alternative free chlorine sources. Cyanuric acid and its ionization products combine with hypochlorous acid, forming various chlorinated cyanurates through a series of equilibrium reactions. Methods to measure the free chlorine (hypochlorous acid plus hypochlorite ion) concentration in systems adding cyanuric acid exhibit measurement bias. To overcome this limitation, one option is use of the established water chemistry of the free chlorine and cyanuric acid system to estimate free chlorine concentrations. Unfortunately, the equilibrium water chemistry has only been determined for 25 degrees C, limiting the usefulness of the water chemistry estimate in actual drinking water systems where temperatures may vary over a wide range (e.g., 5 to 35 degrees C). As a first step in extending the water chemistry model to relevant drinking water temperatures, the first acid ionization constant (K6) for cyanuric acid (H3Cy) and its first ionization product (H2Cy-) was determined using spectrophotometric techniques from 5 to 35 degrees C where ln?K6=-4,013TK-2.58 or pK6=1,743TK+1.12 and DeltaH degrees = 33.4 +/- 1.7 kJ mol-1. As an example of temperature's impact (pH 7), the H2Cy- fraction of total cyanurate (sum of H3Cy and H2Cy-) effectively doubles from 5 to 35 degrees C. With K6's temperature dependence established, studies can be conducted to update the existing water chemistry model with temperature dependence, allowing free chlorine concentration simulation in drinking water systems with cyanuric acid present. PMID- 30416739 TI - Erratum: Author Correction: GePMI: a statistical model for personal intestinal microbiome identification. AB - [This corrects the article DOI: 10.1038/s41522-018-0065-2.]. PMID- 30416741 TI - Functional foods and cancer on Pinterest and PubMed: myths and science. AB - Aim: This article examines whether social media postings dealing with cancer and so-called 'functional foods' simply reflect a fashionable subject or are based on scientific evidence. Methods: The first step consisted of an analysis of a sample of Pins published on Pinterest. The second consisted of an analysis to determine whether the content of the Pins was based on scientific research. Results: From a set of 507 Pins on cancer, we found 204 that also dealt with food. We selected 75 Pins representing different foods and we identified about 80,000 scientific articles on cancer and food indexed in PubMed. Conclusion: We concluded that material published on Pinterest has some correlation with the scientific literature. PMID- 30416740 TI - CA1 Nampt knockdown recapitulates hippocampal cognitive phenotypes in old mice which nicotinamide mononucleotide improves. AB - Cognitive dysfunction is one of the most concerning outcomes in global population aging. However, the mechanisms by which cognitive functions are impaired during aging remain elusive. It has been established that NAD+ levels are reduced in multiple tissues and organs, including the brain. We found that NAD+ levels declined in the hippocampus of mice during the course of aging, and whereas we observed minimal age-related effects on spatial learning/memory capabilities in old mice, we discovered that they developed cognitive hypersensitivity in response to aversive stimulation during contextual fear conditioning tests. This cognitive hypersensitivity appears to be associated with alterations in emotionality (fear/anxiety) and sensory processing (shock sensitivity), rather than reflect genuine conditioning/retention effects, during aging. Supplementation of nicotinamide mononucleotide (NMN) improved the sensory processing aspect of the hypersensitivity and possibly other related behaviors. Specific knockdown of nicotinamide phosphoribosyltransferase (Nampt) in the CA1 region, but not in the dentate gyrus, recapitulates this cognitive hypersensitivity observed in old mice. We identified calcium/calmodulin-dependent serine protein kinase (Cask) as a potential downstream effector in response to age-associated NAD+ reduction in the hippocampus. Cask expression is responsive to NAD+ changes and also reduced in the hippocampus during aging. Short-term NMN supplementation can enhance Cask expression in the hippocampus of old mice. Its promoter activity is regulated in a Sirt1-dependent manner. Taken together, NAD+ reduction in the CA1 region contributes to development of age-associated cognitive dysfunction, aspects of which may be prevented or treated by enhancing NAD+ availability through supplementation of NAD+ intermediates, such as NMN. PMID- 30416742 TI - Genetic polymorphisms of matrix metalloproteinases 1-3 and their inhibitor are not associated with premature labor. AB - Aim: Extracellular matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of metalloproteinases [TIMPs]) are involved in the breakdown of fetal membranes before delivery. Our aim was to investigate the occurrence of any polymorphism on genes coding for MMPs 1-3 and TIMP 2 in preterm laboring patients as a potential source of this phenomenon. This question has not been studied before. Methodology & results: A prospective population study was performed in a Greek university hospital. Group A (control) included 66 women with no symptoms of premature labor. Group B (research) comprised 66 women, exhibiting signs of threatened preterm labor. No statistically significant difference in polymorphism, both in the distribution of genotype as well as allele frequencies, was detected between the two groups. This also applied to gestational age less or greater than 32 weeks. Conclusion: Gene polymorphisms of MMP 1-3 and TIMP 2 are not associated with premature rupture of membranes/contractions, as well as gestational age at preterm labor. PMID- 30416743 TI - Analysis of nutrition clinical studies involving children in the Middle East and globally. AB - Aim: To assess pediatric clinical nutrition research by analyzing clinical studies in the Middle East (ME) and globally. Methods: Using ClinicalTrials.gov, the numbers of clinical studies in the ME and globally were analyzed. Results: The majority of clinical nutrition trials are in North America and Europe. The ME accounts for 4% of all nutrition trials. The majority of pediatric nutrition studies in the ME are in the later phases or are observational and/or epidemiological studies with a focus on poor nutrition or nutrition disorders. Industry funding in the ME is mostly by regional or local companies; few major global companies are involved. Conclusion: The ME is not well represented in clinical nutrition studies involving children. Effort should be expended to rectify this. PMID- 30416744 TI - Survival and glycemic control in patients with colorectal cancer and diabetes mellitus. AB - Aim: The impact of diabetes mellitus (DM) on survival in patients with colorectal cancer and the impact of colorectal cancer on glycemic control were examined. Materials & methods: Patients with colorectal cancer with and without DM were matched 1:1 (2007-2015). Characteristics were compared between the two groups and survival assessed with the Kaplan-Meier method. Mixed models compared hemoglobin A1c and glucose levels over time. Results: In both groups, glucose values decreased during the year following cancer diagnosis (p < 0.001). 5-year overall survival was 56% (95% CI: 42-68%) for DM patients versus 57% (95% CI: 43-69%) for non-DM patients (p = 0.62). Conclusion: DM did not adversely impact survival of patients with colorectal cancer. Colorectal cancer did not affect glycemic control. PMID- 30416745 TI - Recovery of whole mitochondrial genome from compromised samples via multiplex PCR and massively parallel sequencing. AB - In forensic casework, compromised samples often possess limited or degraded nuclear DNA, rendering mitochondrial DNA a more feasible option for forensic DNA analyses. The emergence of massively parallel sequencing (MPS) has enabled the recovery of extensive sequence information from very low quantities of DNA. We have developed a multiplex PCR method that amplifies the complete mitochondrial genome in a range of forensically relevant samples including single cells, cremated remains, bone, maggot and hairs isolated from dust bunnies. Following library preparation, MPS yields complete or nearly complete mitochondrial genome coverage for all samples. To confirm concordance between sample types and between sequencing platforms, we compared sequencing results from hair and buccal swabs from two references. Low initial DNA input into the multiplex PCR allows for conservation of precious DNA while MPS maximizes recovery of genetic information. PMID- 30416747 TI - Gram-negative infections: evolving treatments with expanding options. AB - Antibiotic resistance was a major topic of interest for the nearly 13,000 physicians, microbiologists and scientists who attended European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) 2018. Much discussion centered round the potential benefits of novel antibiotics that are either already approved or under investigation in the treatment of infections caused by resistant Gram-negative pathogens. There was also general acceptance of the importance of ensuring that antibiotic stewardship is implemented in every ward throughout every hospital to ensure that these novel drugs are used appropriately and to combat the development of resistance. PMID- 30416746 TI - Recent advances in the discovery of small-molecule inhibitors of HIV-1 integrase. AB - AIDS caused by the infection of HIV is a prevalent problem today. Rapid development of drug resistance to existing drug classes has called for the discovery of new targets. Within the three major enzymes (i.e., HIV-1 protease, HIV-1 reverse transcriptase and HIV-1 integrase [IN]) of the viral replication cycle, HIV-1 IN has been of particular interest due to the absence of human cellular homolog. HIV-1 IN catalyzes the integration of viral genetic material with the host genome, a key step in the viral replication process. Several novel classes of HIV IN inhibitors have been explored by targeting different sites on the enzyme. This review strives to provide readers with updates on the recent developments of HIV-1 IN inhibitors. PMID- 30416748 TI - Profiling and bioinformatics analyses of differential circular RNA expression in prostate cancer cells. AB - Aim: There is little knowledge about the expression profile and function of circular RNAs (circRNAs) in prostate cancer (PCa). Methods: The expression profiles of circRNAs in RWPE-1, 22RV1 and PC3 cells were explored via high throughput circRNAs sequencing and validated by real-time qPCR. The roles of differentially expressed circRNAs were evaluated by bioinformatics analyses. Results: Altogether 9545 circRNAs were identified and hundreds of differentially expressed circRNAs were recognized. CircRNA-miRNA networks analysis showed that many circRNAs, including circSLC7A6, circGUCY1A2 and circZFP57 could cross-talk with tumor-related miRNAs such as miR-21, miR-143 and miR-200 family. Conclusion: The results of our bioinformatics analyses suggested that circRNAs should play critical roles in the development and progression of PCa. PMID- 30416749 TI - Response dynamics of midbrain dopamine neurons and serotonin neurons to heroin, nicotine, cocaine, and MDMA. AB - Heroin, nicotine, cocaine, and MDMA are abused by billions of people. They are believed to target midbrain dopamine neurons and/or serotonin neurons, but their effects on the dynamic neuronal activity remain unclear in behaving states. By combining cell-type-specific fiber photometry of Ca2+ signals and intravenous drug infusion, here we show that these four drugs of abuse profoundly modulate the activity of mouse midbrain dopamine neurons and serotonin neurons with distinct potency and kinetics. Heroin strongly activates dopamine neurons, and only excites serotonin neurons at higher doses. Nicotine activates dopamine neurons in merely a few seconds, but produces minimal effects on serotonin neurons. Cocaine and MDMA cause long-lasting suppression of both dopamine neurons and serotonin neurons, although MDMA inhibits serotonin neurons more profoundly. Moreover, these inhibitory effects are mediated through the activity of dopamine and serotonin autoreceptors. These results suggest that the activity of dopamine neurons and that of serotonin neurons are more closely associated with the drug's reinforcing property and the drug's euphorigenic property, respectively. This study also shows that our methodology may facilitate further in-vivo interrogation of neural dynamics using animal models of drug addiction. PMID- 30416750 TI - Systemic network analysis identifies XIAP and IkappaBalpha as potential drug targets in TRAIL resistant BRAF mutated melanoma. AB - Metastatic melanoma remains a life-threatening disease because most tumors develop resistance to targeted kinase inhibitors thereby regaining tumorigenic capacity. We show the 2nd generation hexavalent TRAIL receptor-targeted agonist IZI1551 to induce pronounced apoptotic cell death in mutBRAF melanoma cells. Aiming to identify molecular changes that may confer IZI1551 resistance we combined Dynamic Bayesian Network modelling with a sophisticated regularization strategy resulting in sparse and context-sensitive networks and show the performance of this strategy in the detection of cell line-specific deregulations of a signalling network. Comparing IZI1551-sensitive to IZI1551-resistant melanoma cells the model accurately and correctly predicted activation of NFkappaB in concert with upregulation of the anti-apoptotic protein XIAP as the key mediator of IZI1551 resistance. Thus, the incorporation of multiple regularization functions in logical network optimization may provide a promising avenue to assess the effects of drug combinations and to identify responders to selected combination therapies. PMID- 30416752 TI - Diversifying audiences and producers of public involvement in scientific research: the AudioLab. AB - Plain English summary: A partnership between a public engagement specialist, and a director of a digital radio station working towards social change, The AudioLab is a creative and innovative way to support diverse young people to connect with and get actively involved in health research. We worked with 25 creative young adults at relative socioeconomic, educational and/or health disadvantage in 2016 and 2017. Facilitated by the project leads, the emerging young talents connected with science in a series of culturally- and personally-relevant and creative sessions, culminating in their production of digital content and a one-hour live radio show, which reached at least 2324 people online. As a result of taking part in The AudioLab, the young adults felt more confident about themselves and about science; they could see a role for their creative talents in science communication, and felt able to become actively involved in health research. After the project, the ongoing partnership between the project leads and the young adults helped 12 of the participants to progress to employment, training and voluntary roles within health, research, creative and communications environments. We believe that the AudioLab presents a way of working that takes a step towards greater diversity and inclusion among both the audiences and producers of public involvement in health research. It has the potential to be reproduced as a method in other locations. Abstract: Background The AudioLab is an innovative way to support greater inclusion in public engagement and involvement in health research. A partnership between a public engagement with research specialist, and a director of a digital radio station working towards social change, The AudioLab piloted an approach working with young people at relative socioeconomic, educational and/or health disadvantage to engage and involve them meaningfully, and sustainably, with health science and research. Methods Twenty-five young adults from diverse backgrounds took part in AudioLab pilots in 2016 and 2017. Facilitated by the project leads, they engaged with science in a series of culturally-relevant and creative sessions, culminating in their production of digital content and a one-hour live radio show, the latter reaching at least 2324 people online. Results Young adults' agency within health research and science engagement was increased, with 12 of the participants progressing to roles within health, research, creative and communications environments. Conclusions Through partnership working between the project leads, co-production of creative outputs by the young people with scientists and science communicators, and a 'reimagining' of the positive assets that diverse young adults bring to engagement with health research, the AudioLab presents a way of working that takes a step towards greater diversity and inclusion among both the audiences and producers of public involvement in health research. Further, the AudioLab has the potential to be reproduced as a method in other locations. PMID- 30416751 TI - Role of noise and parametric variation in the dynamics of gene regulatory circuits. AB - Stochasticity in gene expression impacts the dynamics and functions of gene regulatory circuits. Intrinsic noises, including those that are caused by low copy number of molecules and transcriptional bursting, are usually studied by stochastic simulations. However, the role of extrinsic factors, such as cell-to cell variability and heterogeneity in the microenvironment, is still elusive. To evaluate the effects of both the intrinsic and extrinsic noises, we develop a method, named sRACIPE, by integrating stochastic analysis with random circuit perturbation (RACIPE) method. RACIPE uniquely generates and analyzes an ensemble of models with random kinetic parameters. Previously, we have shown that the gene expression from random models form robust and functionally related clusters. In sRACIPE we further develop two stochastic simulation schemes, aiming to reduce the computational cost without sacrificing the convergence of statistics. One scheme uses constant noise to capture the basins of attraction, and the other one uses simulated annealing to detect the stability of states. By testing the methods on several synthetic gene regulatory circuits and an epithelial mesenchymal transition network in squamous cell carcinoma, we demonstrate that sRACIPE can interpret the experimental observations from single-cell gene expression data. We observe that parametric variation (the spread of parameters around a median value) increases the spread of the gene expression clusters, whereas high noise merges the states. Our approach quantifies the robustness of a gene circuit in the presence of noise and sheds light on a new mechanism of noise induced hybrid states. We have implemented sRACIPE as an R package. PMID- 30416754 TI - Citizen Science for Mining the Biomedical Literature. AB - Biomedical literature represents one of the largest and fastest growing collections of unstructured biomedical knowledge. Finding critical information buried in the literature can be challenging. To extract information from free flowing text, researchers need to: 1. identify the entities in the text (named entity recognition), 2. apply a standardized vocabulary to these entities (normalization), and 3. identify how entities in the text are related to one another (relationship extraction). Researchers have primarily approached these information extraction tasks through manual expert curation and computational methods. We have previously demonstrated that named entity recognition (NER) tasks can be crowdsourced to a group of non-experts via the paid microtask platform, Amazon Mechanical Turk (AMT), and can dramatically reduce the cost and increase the throughput of biocuration efforts. However, given the size of the biomedical literature, even information extraction via paid microtask platforms is not scalable. With our web-based application Mark2Cure (http://mark2cure.org), we demonstrate that NER tasks also can be performed by volunteer citizen scientists with high accuracy. We apply metrics from the Zooniverse Matrices of Citizen Science Success and provide the results here to serve as a basis of comparison for other citizen science projects. Further, we discuss design considerations, issues, and the application of analytics for successfully moving a crowdsourcing workflow from a paid microtask platform to a citizen science platform. To our knowledge, this study is the first application of citizen science to a natural language processing task. PMID- 30416755 TI - Intramedullary schwannoma of conus medullaris: rare site for a common tumor with review of literature. AB - Introduction: Schwannomas at an intramedullary location constitute only 0.3% of primary spinal tumors. Those in the conus are extremely rare, especially in the absence of neurofibromatosis, with only 12 cases reported in the literature so far, excluding the present case. Case presentation: We report the case of a 27 year-old female who presented with complaints of backache since 1 year, weakness in both lower limbs with tingling and numbness since 6 months, and urinary incontinence since 1 month. There was no history of trauma or any skin lesions. Magnetic resonance imaging (MRI) of the spine provided a provisional diagnosis of ependymoma. The patient was operated upon, histopathology revealed it to be a schwannoma. Discussion: Intramedullary schwannomas without neurofibromatosis are extremely rare at the conus and can be completely resected unless there is infiltration. Gliomas and ependymomas are commoner entities at this site, which are usually subtotally resected. This case highlights that although extremely rare, the possibility of a schwannoma may be considered in the differentials of an intramedullary spinal lesion. PMID- 30416753 TI - Parallels between vertebrate cardiac and cutaneous wound healing and regeneration. AB - The cellular events that contribute to tissue healing of non-sterile wounds to the skin and ischaemic injury to internal organs such as the heart share remarkable similarities despite the differences between these injury types and organs. In adult vertebrates, both injuries are characterised by a complex series of overlapping events involving multiple different cell types and cellular interactions. In adult mammals both tissue-healing processes ultimately lead to the permanent formation of a fibrotic, collagenous scar, which can have varying effects on tissue function depending on the site and magnitude of damage. Extensive scarring in the heart as a result of a severe myocardial infarction contributes to ventricular dysfunction and the progression of heart failure. Some vertebrates such as adult zebrafish, however, retain a more embryonic capacity for scar-free tissue regeneration in many tissues including the skin and heart. In this review, the similarities and differences between these different types of wound healing are discussed, with special attention on recent advances in regenerative, non-scarring vertebrate models such as the zebrafish. PMID- 30416756 TI - Post-transplant lymphoproliferative disorder of the cauda equina in a kidney transplant recipient. AB - Introduction: Post-transplant lymphoproliferative disorder (PTLD) is a condition associated with post-transplant immunosuppression that can develop in various organs, including the grafted one. However, it has rarely been reported in nerve tissue. We encountered an unexpected case of PTLD in the cauda equina of a kidney transplant recipient who was being treated with chronic immunosuppressive therapies. Case presentation: The patient was a 39-year-old woman in whom lower limb muscle weakness appeared and progressed rapidly 10 years after kidney transplantation for glomerulonephritis. Magnetic resonance imaging (MRI) findings were suggestive of an intradural extramedullary tumor. Diagnosis of PTLD was established on open biopsy. Culprit immunosuppressants (tacrolimus, mycophenolate mofetil, and prednisolone) were discontinued, and rituximab and radiation therapy were started. The paraplegia gradually improved after drug discontinuation, and the lesion diminished in size 3 months after this series of treatment, and finally disappeared on MRI as of 1 year after treatment. Discussion: PTLD in the cauda equina is extremely rare, and only one case involving the cauda equina has been reported previously. Biopsy should be performed initially for definitive diagnosis, after which the suspected culprit immunosuppressants should be immediately discontinued. PMID- 30416757 TI - Autophagy modulates temozolomide-induced cell death in alveolar Rhabdomyosarcoma cells. AB - Rhabdomyosarcoma (RMS) is a muscle-derived tumor. In both pre-clinical and clinical studies Temozolomide (TMZ) has been recently tested against RMS; however, the precise mechanism of action of TMZ in RMS remains unclear. Here we demonstrate that TMZ decreases the cell viability of the RH30 RMS and C2C12 cell line, where cells display evidence of mitochondrial outer membrane permeability. Interestingly, the C2C12 mouse myoblast line was relatively more resistant to TMZ induced apoptosis. Moreover, we observed that TMZ activated biochemical and morphological markers of autophagy in both cell lines. Autophagy inhibition in both RH30 and C2C12 cells significantly increased TMZ-induced cell death. In RH30 cells, TMZ increased Mcl-1 and Bax protein expression compared to corresponding time match controls while in C2C12 Mcl-1, Bcl-2, Bcl-XL, and Bax protein expression were not changed. Baf-A1 co-treatment with TMZ significantly decrease Mcl-1 expression compared to TMZ while increase Bax expression in C2C12 cells (Bcl2 and Bcl-XL do not significantly change in Baf-A1/TMZ co-treatment). Using a three-dimensional (3D) C2C12 and RH30 culture model we demonstrated that TMZ is significantly more toxic in RH30 cells (live/dead assay). Additionally, we have observed in our 3D culture model that TMZ induced both apoptosis (cleavage of PARP) and autophagy (LC3-puncta and localization of LC3/p62). Therefore, our data demonstrate that TMZ induces simultaneous autophagy and apoptosis in both RH30 and C2C12 cells in 2D and 3D culture model, where RH30 cells are more sensitive to TMZ-induced death. Furthermore, autophagy serves to protect RH30 cells from TMZ-induced death. PMID- 30416758 TI - Extracellular and ER-stored Ca2+ contribute to BIRD-2-induced cell death in diffuse large B-cell lymphoma cells. AB - The anti-apoptotic protein Bcl-2 is upregulated in several cancers, including diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). In a subset of these cancer cells, Bcl-2 blocks Ca2+-mediated apoptosis by suppressing the function of inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) located at the endoplasmic reticulum (ER). A peptide tool, called Bcl-2/IP3 receptor disruptor-2 (BIRD-2), was developed to disrupt Bcl-2/IP3R complexes, triggering pro-apoptotic Ca2+ signals and killing Bcl-2-dependent cancer cells. In DLBCL cells, BIRD-2 sensitivity depended on the expression level of IP3R2 channels and constitutive IP3 signaling downstream of the B-cell receptor. However, other cellular pathways probably also contribute to BIRD-2-provoked cell death. Here, we examined whether BIRD-2-induced apoptosis depended on extracellular Ca2+ and more particularly on store-operated Ca2+ entry (SOCE), a Ca2+-influx pathway activated upon ER-store depletion. Excitingly, DPB162-AE, a SOCE inhibitor, suppressed BIRD-2-induced cell death in DLBCL cells. However, DPB162-AE not only inhibits SOCE but also depletes the ER Ca2+ store. Treatment of the cells with YM-58483 and GSK-7975A, two selective SOCE inhibitors, did not protect against BIRD-2-induced apoptosis. Similar data were obtained by knocking down STIM1 using small interfering RNA. Yet, extracellular Ca2+ contributed to BIRD-2 sensitivity in DLBCL, since the extracellular Ca2+ buffer ethylene glycol tetraacetic acid (EGTA) blunted BIRD-2-triggered apoptosis. The protective effects observed with DPB162-AE are likely due to ER Ca2+-store depletion, since a similar protective effect could be obtained using the sarco/endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin. Thus, both the ER Ca2+-store content and extracellular Ca2+, but not SOCE, are critical factors underlying BIRD-2-provoked cell death. PMID- 30416761 TI - Design, Manufacture, and In vivo Testing of a Tissue Scaffold for Permanent Female Sterilization by Tubal Occlusion. AB - Current FDA-approved permanent female sterilization procedures are invasive and/or require the implantation of non-biodegradable materials. These techniques pose risks and complications, such as device migration, fracture, and tubal perforation. We propose a safe, non-invasive biodegradable tissue scaffold to effectively occlude the Fallopian tubes within 30 days of implantation. Specifically, the Fallopian tubes are mechanically de-epithelialized, and a tissue scaffold is placed into each tube. It is anticipated that this procedure can be performed in less than 30 minutes by an experienced obstetrics and gynaecology practitioner. Advantages of this method include the use of a fully bio-resorbable polymer, low costs, lower risks, and the lack of general anaesthesia. The scaffold devices are freeze-cast allowing for the custom-design of structural, mechanical, and chemical cues through material composition, processing parameters, and functionalization. The performance of the biomaterial and de-epithelialization procedure was tested in an in vivo rat uterine horn model. The scaffold response and tissue-biomaterial interactions were characterized microscopically post-implantation. Overall, the study resulted in the successful fabrication of resilient, easy-to-handle devices with an anisotropic scaffold architecture that encouraged rapid bio-integration through notable angiogenesis, cell infiltration, and native collagen deposition. Successful tubal occlusion was demonstrated at 30 days, revealing the great promise of a sterilization biomaterial. PMID- 30416760 TI - Metabolite sensing and signaling in cell metabolism. AB - Metabolite sensing is one of the most fundamental biological processes. During evolution, multilayered mechanisms developed to sense fluctuations in a wide spectrum of metabolites, including nutrients, to coordinate cellular metabolism and biological networks. To date, AMPK and mTOR signaling are among the best understood metabolite-sensing and signaling pathways. Here, we propose a sensor transducer-effector model to describe known mechanisms of metabolite sensing and signaling. We define a metabolite sensor by its specificity, dynamicity, and functionality. We group the actions of metabolite sensing into three different modes: metabolite sensor-mediated signaling, metabolite-sensing module, and sensing by conjugating. With these modes of action, we provide a systematic view of how cells sense sugars, lipids, amino acids, and metabolic intermediates. In the future perspective, we suggest a systematic screen of metabolite-sensing macromolecules, high-throughput discovery of biomacromolecule-metabolite interactomes, and functional metabolomics to advance our knowledge of metabolite sensing and signaling. Most importantly, targeting metabolite sensing holds great promise in therapeutic intervention of metabolic diseases and in improving healthy aging. PMID- 30416762 TI - Combination immuno-oncology therapy with pembrolizumab, an anti-PD-1 monoclonal antibody targeting immune evasion, and standard chemotherapy for patients with the squamous and non-squamous subtypes of non-small cell lung cancer. PMID- 30416763 TI - Non-small cell lung cancer: land of conquest for immunotherapy. PMID- 30416759 TI - Biomaterials to model and measure epithelial cancers. AB - The use of biomaterials has substantially contributed to both our understanding of tumorigenesis and our ability to identify and capture tumour cells in vitro and in vivo. Natural and synthetic biomaterials can be applied as models to recapitulate key features of the tumour microenvironment in vitro, including architectural, mechanical and biological functions. Engineered biomaterials can further mimic the spatial and temporal properties of the surrounding tumour niche to investigate the specific effects of the environment on disease progression, offering an alternative to animal models for the testing of cancer cell behaviour. Biomaterials can also be used to capture and detect cancer cells in vitro and in vivo to monitor tumour progression. In this Review, we discuss the natural and synthetic biomaterials that can be used to recreate specific features of tumour microenvironments. We examine how biomaterials can be applied to capture circulating tumour cells in blood samples for the early detection of metastasis. We highlight biomaterial-based strategies to investigate local regions adjacent to the tumour and survey potential applications of biomaterial based devices for diagnosis and prognosis, such as the detection of cellular deformability and the non-invasive surveillance of tumour-adjacent stroma. PMID- 30416764 TI - Moving away (finally) from doublet therapy in lung cancer: immunotherapy and KEYNOTE-189. PMID- 30416765 TI - Broader indications for checkpoint inhibitors in NSCLC. PMID- 30416766 TI - Is the new distribution of early esophageal adenocarcinoma stages improving the prognostic prediction of the 8th edition of the TNM staging system for esophageal cancer? AB - Background: The 8th edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system released in 2017 reclassified the pTNM stage of early esophageal adenocarcinoma from stage IA in the 7th edition to stage IA and IB and from stage IB in the 7th edition to stage IC. In this study, we analyzed the reliability of the new staging system through clinical data analysis. Methods: We selected patient data from the Surveillance, Epidemiology, and End Results (SEER) database. From 2004 to 2014, data for a total of 714 patients were included in the study and were divided into groups representing stage IA (n=84), IB (n=386) and IC (n=244) according to the 8th edition. Results: In the 8th edition, there was no significant difference between groups IA and IB in overall survival (OS) (P=0.331) or esophageal cancer specific survival (ECSS) (P=0.341). However, the long-term survival rates of groups IA and IB were significantly higher than those of group IC. Cox regression analysis indicated that the use of new staging system does not affect prognosis. We also attempted to stratify the tumors by T stage and histological grade but found no significant difference. Conclusions: We used the SEER database to compare the staging of early esophageal adenocarcinomas between the 8th and 7th editions of the AJCC/UICC TNM staging system. Based on our data, the 8th edition is not superior to the 7th edition. PMID- 30416767 TI - Application of the "continuous suture dividing and equal suture tightening" method in video-assisted thoracoscopic surgery sleeve lobectomy. AB - Background: The primary focus of video-assisted thoracoscopic surgery (VATS) sleeve lobectomy is bronchial anastomosis. Both interrupted suture and continuous suture cannot overcome entanglement of the suture threads. The present study used the "continuous suture dividing and equal suture tightening" method in VATS sleeve lobectomy for bronchial anastomosis and discussed the feasibility of this approach. Methods: A total of 17 patients underwent VATS sleeve lobectomy with bronchial anastomosis using the "continuous suture dividing and equal suture tightening" method. Four incisions were utilized in the operation as follows: (I) the pulmonary arteries and veins were cut-off using an endoscopic linear stapler. Systematic hilar and mediastinal lymph node dissection was performed; (II) the surgeon used a surgical knife for incision into the thoracic cavity and to cut the lung lobe and main bronchi. Intraoperative pathological analysis revealed negative bronchial margins; (III) the "continuous suture dividing and equal suture tightening" method was performed for anastomosis; (IV) the integrity of the anastomosis was assessed by intraoperative bronchoscopy. Computed tomography (CT), three-dimensional (3D) reconstruction and bronchoscopy assessed the anastomosis 1-week postoperatively. A follow-up was conducted using a 3-month bronchoscopy, and CT scans monitored the recurrence and stenosis of the anastomosis. Results: The method was successfully completed for VATS sleeve lobectomy with bronchial anastomosis in 17 cases. Although various histological profiles were observed, the 1-week postoperative CT and bronchoscopy showed adequate healing of the anastomotic stoma as well as the absence of postoperative mortality and bronchial pleural fistula. All patients were alive and followed up for 31-49 months postoperatively; local recurrence and anastomotic stenosis were not detected. Conclusions: The continuous suture dividing and equal suture tightening method is convenient, feasible, and safe for bronchial anastomosis in VATS sleeve lobectomy. It can effectively avoid the entanglement of the suture threads, thereby enabling the widespread adoption of VATS sleeve lobectomy. PMID- 30416768 TI - Deep sternal infections after in situ bilateral internal thoracic artery grafting for left ventricular myocardial revascularization: predictors and influence on 20 year outcomes. AB - Background: The incidence and potential factors influencing deep sternal wound infection (DSWI) in a cohort of patients undergoing coronary artery bypass grafting (CABG) using skeletonized bilateral internal thoracic artery (BITA) was explored. Furthermore, we studied influence of DSWI on long-term survival, major adverse cardiac events (MACEs) and repeat coronary revascularization (RCR). Methods: The study cohort consisted of 1,325 consecutive patients who were divided in two groups: patients experiencing DSWI (n=33, group 1) and those who did not have sternal infection (n=1,292, group 2). A logistic regression model was employed to find predictors of DSWI whereas Cox regression and a competing risk models were carried out to test predictors of late death, MACE and RCR, respectively. Follow up was 100% complete and ranged from 1 to 245 months. Median follow-up was 103 months (IQR, 61 to 189 months). Cumulative follow-up was 16,430 patient years. Results: The incidence of DSWI was 2.4%. Multivariable logistic regression analysis found any single independent predictor of DSWI. However, the association of peripheral vascular disease (PVD) and diabetes increased the risk by 1.4 and 1.6 times. When DM was associated with obesity the risk increased by 2.1 and 2.6 times compared to the single factors, respectively. Obese female patients were at a 1.6-fold higher risk when compared to the association of DM with obesity. DSWI was not an independent predictor of long-term survival (HR, 2.31; 95% CI: 0.59-9.12), RCR (SHR, 2.89; 95% CI: 0.65-10.12), or MACE (SHR, 1.98; 95% CI: 0.44-8.56). Conclusions: With an accurate patient selection (i.e., exclusion of obese diabetic females) and strict DM control BITA represents a first choice for most of CABG patients, even at high risk for DSWI. The occurrence of DSWI does not influence long-term survival and late outcomes. Our findings should be confirmed by further larger research. PMID- 30416769 TI - Transcatheter perimembranous ventricular septal defect closure under transthoracic echocardiographic guidance without fluoroscopy. AB - Background: Transcatheter device closure has become an alternative therapy for ventricular septal defect (VSD). This study aimed to investigate the feasibility and safety of transcatheter perimembranous VSD (pm-VSD) closure under transthoracic echocardiography (TTE) guidance alone. Methods: Between October 2012 and July 2016, 118 patients with pm-VSD underwent an attempt of transcatheter device closure for pm-VSD through the femoral artery under TTE guidance alone. Patients were followed-up at 1, 3, 6, and 12 months after the procedure and yearly after discharge. Results: The mean age was 11.7+/-12.5 years (range, 1.0-53.0 years) and the mean body weight was 32.2+/-21.6 kg (range, 11.5 102.0 kg). The mean diameter of the VSD was 4.0+/-1.1 mm (range, 3.0-8.0 mm). Transcatheter device closure under TTE guidance alone was successful in 111 patients. The average procedural time was 44.9+/-7.3 minutes (range, 29.0-65.0 minutes). All 111 patients were followed-up for 3.4+/-2.3 years. At the last follow-up, two patients had a residual shunt smaller than 2 mm, seven patients had right bundle branch block (RBBB) including one patient with complete RBBB, six patients had mild or less tricuspid regurgitation, and two patients still had trivial aortic regurgitation including one patient that had it before the procedure. Occluder malposition, complete atrioventricular block, or other complications were not observed. Conclusions: Transcatheter pm-VSD closure can be successfully performed under TTE guidance alone with outcomes similar to those achieved with fluoroscopic guidance in selected patients with weight more than 10 kg and VSD smaller than 8 mm. However, long-term follow-up in a large number of patients would be necessary. PMID- 30416770 TI - Neutrophil/lymphocyte ratio is helpful for predicting weaning failure: a prospective, observational cohort study. AB - Background: To assess the usefulness of the neutrophil/lymphocyte ratio (NLR), a marker of inflammation and/or stress, for predicting weaning failure in patients receiving invasive mechanical ventilation (IMV), compared to levels of leukocytes and C-reactive protein (CRP). Methods: This observational prospective cohort study was conducted from July 2013 to December 2016 in an intensive care unit in China, enrolling 269 consecutive patients receiving IMV. Patients underwent a spontaneous breathing trial (SBT) if they were ready to wean, and underwent extubation if they passed the SBT. The evaluated markers were measured immediately prior to SBT, and compared between weaning-failure and weaning success patients. Receiver-operating characteristic (ROC) curve and logistic regression analyses were used to evaluate the ability of these markers to predict weaning failure. Results: In all, 94 (34.9%) patients failed the weaning process (66 failed SBT and 28 presented with post-extubation respiratory distress). NLR was a better predictor of failure (area under the ROC curve, 0.69; 95% CI, 0.62 0.76) than leukocyte levels (0.60, 0.53-0.67) and CRP values (0.58, 0.51-0.65). NLR >11, leukocyte counts >10.5*109/L, and CRP >58 mg/L prior to weaning had the best combination of sensitivity (73%, 64%, and 63%, respectively), specificity (59%, 55%, and 63%), positive predictive value (49%, 43%, and 48%), negative predictive value (81%, 74%, and 76%), and diagnostic accuracy (64%, 58%, and 63%) for predicting weaning failure. However, only NLR >11 (odds ratio, 5.91; 95% CI, 3.08-11.33; P<0.001) was an independent predictor of weaning failure in the adjusted logistic regression model. Conclusions: NLR may be a useful marker for predicting weaning failure, and weaning at NLR >11 might be considered with caution. Further study with a larger sample size and with weaning outcome as a variable of concern is warranted. Trial registration: ClinicalTrials.gov identifier: NCT02981589. PMID- 30416771 TI - Elevated interleukin-6 and bronchiectasis as risk factors for acute exacerbation in patients with tuberculosis-destroyed lung with airflow limitation. AB - Background: Patients with tuberculosis-destroyed lungs (TDLs), with airflow limitation, have clinical characteristics similar to those of patients with chronic obstructive pulmonary disease (COPD). Acute exacerbation is an important factor in the management of TDL. Therefore, the aim of this study was to investigate the factors associated with acute exacerbations in patients with stable TDL with airflow limitation. Methods: We evaluated the clinical characteristics, such as lung function, image findings, and serum laboratory findings, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and interleukin (IL)-6, in patients with TDL with chronic airflow limitation (n=94). We evaluated the correlation of these parameters with acute exacerbation. Results: We found that patients with exacerbation were more likely to have bronchiectasis than those without exacerbation (patients with exacerbation, 66.7%; patients without exacerbation, 30.5%; P=0.001). CRP and IL-6 levels were significantly higher in patients with exacerbation than in those without exacerbation (P=0.001 and P<0.001, respectively). Bronchiectasis [OR, 3.248; 95% confidence interval (CI), 1.063-9.928; P=0.039] and elevated IL-6 levels (OR, 1.128; 95% CI, 1.013-1.257; P=0.028) were the most important parameters associated with acute exacerbation in patients with TDL with airflow limitation. Conclusions: Patients with bronchiectasis and high IL-6 levels may require more intensive treatment to prevent acute exacerbation. PMID- 30416772 TI - Clinical predictors of pathologically response after neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma: long term outcomes of a phase II study. AB - Background: A pathologically complete response (pCR) or near pCR to neoadjuvant chemoradiotherapy (NCRT) might imply a better prognosis in patients with esophageal cancer. The aim of the study is to identify clinical factors associated with a pCR or near pCR. Methods: We retrospectively analyzed 40 patients with radical esophagectomy after NCRT for esophageal squamous cell carcinoma (ESCC) from January 2001 to December 2006 in Sun Yat-sen University Cancer Center. Clinical factors included age, gender, weight loss, dysphagia, drinking status, smoking status, tumor location, tumor length, tumor grade, cT status, cN status, the regimen of chemotherapy and the interval between NCRT and surgery as potential predictors for a pCR or near pCR. Logistic regression was used to estimate the independent factors for a pCR or near pCR. Results: After surgical resection, 22.5% of the patients obtained the pCR. Patients with pCR had a better prognosis than those with non-pCR. However, there was no statistically significantly difference between the two groups (P=0.124). We separated the patients into pCR or near pCR (good responders, GRs) and poor responders (PR) based on the histology. GR showed better overall survival (OS) than PR (P=0.014). Univariate analysis indicated that short tumor length, good tumor grade and never drinking were associated with GR to NCRT. Using logistic regression analysis, good tumor grade was the only independent factor for the GR to NCRT (P=0.021). Cox regression revealed that weight loss, drinking status and GR were independent factors in ESCC patients with radical esophagectomy after NCRT. Conclusions: Our study indicated that good tumor grade were an independent significant factor for the GR to NCRT. Weight loss, drinking status and GR were independent factors in patients with radical esophagectomy after NCRT. GR may improve OS of ESCC patients receiving NCRT. PMID- 30416773 TI - Fibrinogen as a potential biomarker for clinical phenotype in patients with chronic obstructive pulmonary disease. AB - Background: Under the Food and Drug Administration's drug development tool qualification program, fibrinogen is the first biomarker drug development tool used in chronic obstructive pulmonary disease (COPD). However, the correlation between fibrinogen and exacerbations among Korean patients with COPD remains unclear. Methods: In this retrospective cross-sectional study, we included patients with COPD for whom plasma fibrinogen assessment results, without exacerbation, were available. Then, we compared subgroups according to fibrinogen level (threshold: 350 mg/dL). We used multivariate linear regression analysis to investigate the clinical phenotype of COPD with high fibrinogen level, analyzed the correlation between the COPD severity indexes and fibrinogen level. Results: Of 140 patients, we confirmed 48 (34.3%) patients in the high-level fibrinogen group. The high-level group demonstrated a medical history of more exacerbations than the low-level group. Lung functions [forced expiratory volume in 1 s (FEV1), forced vital capacity, and 6-minute walk distance] were more deteriorated in the high-level group. Multivariate regression analysis revealed that fibrinogen level was associated with high COPD assessment test score, and experience of exacerbation. Fibrinogen level exhibited a statistically significant positive correlation with COPD severity indexes. Conclusions: High fibrinogen level seems to reflect frequent exacerbation and severe symptomatic phenotypes in Korean patients with COPD. PMID- 30416774 TI - Thoracic ultrasound versus artificial pneumothorax in complications of medical thoracoscopy-a propensity score matching analysis. AB - Background: Evaluation and location of the approaches is the key step of medical thoracoscopy. The previous standard for the step in many countries is artificial pneumothorax (AP). Recently, thoracic ultrasound (TU) has been considered as one of the choices for the development of technology. While there was a lack of data in investigating the complications of medical thoracoscopy locating approach with AP comparing TU. Methods: A total of 108 patients who underwent medical thoracoscopy were retrospectively observed in Peking University First Hospital from January 2011 to April 2017, including 92 patients of the AP group and 16 patients of the TU group. Propensity score matching (PSM) was used to balance the covariance between the two groups. And the complications of the procedures between the groups were compared. Results: Before PSM, there was one unbalanced covariates in the two groups. The overall complication rate was 7.6% (7/92) in the AP group, comparing 6.2% (1/16) in the TU group. There was no significant difference between the two groups (P=0.848). After balancing the covariate with 2:1 matched, the overall complication rate was 9.4% (3/32) in the AP group, comparing 6.2% (1/16) in the TU group. There was still no significant difference between the two groups (P=0.712). Conclusions: TU is a locating approach method which does not increase the complication rate comparing with AP. And it could be a good choice in medical thoracoscopy. PMID- 30416775 TI - Effect of cyclosporine A on mortality after acute exacerbation of idiopathic pulmonary fibrosis. AB - Background: There is currently no recognized treatment for acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF), and the effect of cyclosporine A in patients with AE-IPF remains unknown. Methods: We identified patients with AE-IPF who received high-dose methylprednisolone plus cyclosporine A or high-dose methylprednisolone alone from July 1, 2010, to March 31, 2014, using the Diagnosis Procedure Combination database in Japan. We compared in-hospital mortality between patients with and without cyclosporine A by multivariable logistic regression analysis, with adjustment for patient and hospital covariates. Unmeasured confounders were accounted for by instrumental variable analysis based on differential distance. Results: Eligible patients (n=7,989) were divided into a high-dose methylprednisolone plus cyclosporine A group (n=384) and a high-dose methylprednisolone alone group (n=7,605). There was no significant difference in terms of in-hospital mortality between the groups according to multivariable logistic regression [odds ratio, 1.27; 95% confidence interval (CI), 0.99-1.64; P=0.06] or instrumental variable analysis (odds ratio, 0.94; 95% CI, 0.12-7.67; P=0.96). Conclusions: Cyclosporine A did not reduce in hospital mortality in patients with AE-IPF. Randomised controlled studies are required to confirm this apparent lack of effect of cyclosporine A in AE-IPF. PMID- 30416776 TI - Over-expression of calpastatin attenuates myocardial injury following myocardial infarction by inhibiting endoplasmic reticulum stress. AB - Background: Ischemic heart injury activates calpains and endoplasmic reticulum (ER) stress in cardiomyocytes. This study investigated whether over-expression of calpastatin, an endogenous calpain inhibitor, protects the heart against myocardial infarction (MI) by inhibiting ER stress. Methods: Mice over-expressing calpastatin (Tg-CAST) and littermate wild type (WT) mice were divided into four groups: WT-sham, Tg-CAST-sham, WT-MI, and Tg-CAST-MI, respectively. WT-sham and Tg-CAST-sham mice showed similar cardiac function at baseline. MI for 7 days impaired cardiac function in WT-MI mice, which was ameliorated in Tg-CAST-MI mice. Results: Tg-CAST-MI mice exhibited significantly decreased diameter of the left ventricular cavity, scar area, and cardiac cell death compared to WT-MI mice. WT-MI mice had higher cardiac expression of C/EBP homologous protein (CHOP) and BIP, indicators of ER stress, compared to WT-sham mice, indicative of MI induced ER stress. This increase was abolished in Tg-CAST-MI hearts. Furthermore, administration of tauroursodeoxycholic acid, an inhibitor of ER stress, reduced MI-induced expression of CHOP and BIP, scar area, and myocardial dysfunction. In an in vitro model of oxidative stress, H2O2 stimulation of H9c2 cardiomyoblasts induced calpain activation, CHOP expression, and cell death, all of which were prevented by the calpain inhibitor PD150606, as well as CHOP silencing. Conclusions: Over-expression of calpastatin ameliorates MI-induced myocardial injury in mice. These protective effects of calpastatin are partially achieved through suppression of the ER stress/CHOP pathway. PMID- 30416777 TI - Prognostic value of prognostic nutritional index in lung cancer: a meta-analysis. AB - Background: Previous studies reported pretreatment prognostic nutritional index (PNI) was associated with clinical outcome of lung cancer. However, the result was not conclusive. We conducted a comprehensive meta-analysis to clarify the impact of PNI in lung cancer prognosis. Methods: We identified eligible studies by searching PubMed, EMBASE, and Web of Science, up to August 15, 2017. Overall survival (OS) and clinicopathological characteristics were collected from included studies. Pooled hazard ratios (HR) and corresponding 95% confidence intervals (CIs) were used to estimate clinical and prognostic value of PNI in lung cancer. Results: Ten studies including 5,085 patients were enrolled in the meta-analysis. The result demonstrated that low PNI was correlated with unfavorable OS in lung cancer (HR =1.72; 95% CI, 1.43-2.06; P=0.000), especially among non-small cell lung cancer patients (HR =1.93; 95% CI, 1.56-2.37; P=0.000). As for clinical characteristics, low PNI status was found related to gender (female versus male, HR =0.68; 95% CI, 0.554-0.857; P=0.001) and histology (adenocarcinoma versus non-adenocarcinoma, HR =0.59; 95% CI, 0.47-0.74, P=0.000), but not smoking status (smoker versus never smoker, HR =1.49; 95% CI, 0.99-2.25, P=0.056). No significant publication bias was found (P=0.210). Conclusions: PNI was an independent prognostic indicator for lung cancer, and can serve as a novel biomarker to help guide clinical practice and promote clinical outcomes of lung cancer patients. PMID- 30416778 TI - Spread through air spaces predicts a worse survival in patients with stage I adenocarcinomas >2 cm after radical lobectomy. AB - Background: The aim of this study was to evaluate the significance of spread through air spaces (STAS) in early lung adenocarcinomas after radical lobectomy and lymphadenectomy. Methods: A total of 242 patients with lung adenocarcinomas less than 4 cm (8th pStage I) were selected from the lung cancer patients surgically treated from January, 2009 to September, 2011. Pathological review focused on STAS as well as histological subtypes, blood vessel & neural invasion, pathological tumor size etc. Recurrence or disease-free survival (DFS) and overall survival (OS) were compared between patients as stratified by STAS and tumor size. Results: STAS was observed in 33.47% (81/242) patients, which was significantly correlated with histological predominant subtype (chi2=25.903, P=0.093*10-3) and differentiation grade (chi2=23.986, P=0.025*10-3). Patients with STAS (+) showed a comparable PFS (P=0.268) and OS rates (P=0.100) in all stage I cases, but a significant lower PFS (P=0.029) and OS (P=0.013) in tumors within 2< tumors <=4 cm. Multivariate analysis revealed STAS to be an independent worse prognostic factor in lung adenocarcinomas within 2< tumors <=4 cm, both for PFS (P=0.004) and OS (P=0.002), while no significant difference was found in patients with tumors <=2 cm (PFS, P=0.537; OS, P=0.448), after adjusting by other clinicopathological parameters as age, gender, smoking etc. Conclusions: Presence of STAS was a significant worse predictor for pStage I patients with lung adenocarcinoma >2 cm who underwent radical lobectomy, while it is not significant in patients with tumor <=2 cm. These findings may be helpful in assessing postoperative therapy stratified by tumor size and STAS status. PMID- 30416779 TI - Pulmonary and mediastinal paragangliomas: rare endothoracic malignancies with challenging diagnosis and treatment. AB - Background: Pulmonary and mediastinal paragangliomas are rare tumors that may have neuroendocrine activity or be non-functional, incidental, in asymptomatic patients, or causing mass effect symptoms. Although being low-grade tumors, they can display an aggressive behaviour, developing local infiltration and distant metastases. We report our experience with three endothoracic paragangliomas and a Literature review, to point out diagnostic difficulties and problems related to surgical treatment. Methods: From 2009 to 2017, we treated 3 patients with histological diagnosis of paraganglioma: 2 pulmonary, 1 mediastinal. No one presented catecholamine-secreting syndromes; pulmonary cases were asymptomatic, while the mediastinal one had aspecific cough and dyspnea. Imaging diagnosis was based on chest computerized tomography (CT) and magnetic resonance imaging (MRI) scan. No patient had preoperative histological diagnosis. Intraoperative pathological examination was suggestive for malignancy: in pulmonary cases, wedge resection and lobectomy were performed; the middle mediastinal mass was completely removed after challenging dissection, isolation and section of numerous vascular pedicles. Results: Postoperative course was uneventful in all cases. No patient received adjuvant treatments. At a median follow-up of 47 months (range, 6-102 months), two patients are alive, without local or distant recurrence; one patient died 6 months after surgery, due to disease progression. Conclusions: Endothoracic paragangliomas, rare and often asymptomatic tumors, are of difficult diagnosis and should be considered malignant tumors, due to the potential aggressive behaviour of cases with high mitotic index and the frequent possibility of recurrence and metastases. Surgical resection is the treatment of choice and careful intraoperative manipulation is recommended, due to the high vascularity of these tumors, to prevent complications. After complete excision, long-term prognosis is generally good. However, even after surgical removal, a close, periodical and life-long follow-up is mandatory. PMID- 30416780 TI - A subset of esophageal squamous cell carcinoma patient-derived xenografts respond to cetuximab, which is predicted by high EGFR expression and amplification. AB - Background: Epidermal growth factor receptor (EGFR) is reportedly overexpressed in most esophageal tumors, but most targeted therapies showed no efficacy in non selected patients. This study aims at investigating the adaptive cetuximab subset in a cohort of esophageal squamous cell carcinoma (ESCC) patient-derived xenografts (PDXs). Methods: A large panel of ESCC PDXs has been established. The copy number, mRNA expression and immunohistochemistry (IHC) of key EGFR pathways have been examined along with cetuximab response. A preclinical trial on a randomly selected cohort of 16 ESCC PDXs was conducted, and the genomic annotations of these models were compared against the efficacy readout of the mouse trial. Results: The trial identified that 7 of 16 (43.8%) responded to cetuximab (DeltaT/DeltaC <0 as responders). The gene amplification and expression analysis indicated that EGFR copy number >=5 (P=0.035), high EGFR mRNA expression (P=0.001) and IHC score of 2-3 (P=0.034) are associated with tumor growth inhibition by cetuximab, suggesting EGFR may function as a single predictive biomarker for cetuximab response in ESCC. Conclusions: Overall, our results suggest that an ESCC subtype with EGFR amplification and overexpression benefits from cetuximab treatment, which warrants further clinical confirmation. PMID- 30416781 TI - Suturing of the laser resection area is recommended over a depth of 2 cm in an experimental porcine lung model. AB - Background: Lung metastases can be removed by an Nd:YAG laser to save lung parenchyma. At these sites, a coagulated lung surface remains. Airtightness was investigated in relation to the depth of resection on an ex vivo porcine lung model. Methods: Freshly slaughtered porcine double lung preparations were connected to a ventilator via a tube. Non-anatomical laser resections were performed with an 800 um laser fiber and the Nd:YAG laser LIMAX(r) 120 (power: 40 and 60 watts). The following resection depths (each n=12) from the lung surface were examined: 0.5, 1, 1.5 and 2.0 cm. After resection the lungs were submerged under water and ventilated (frequency 10/min, Pinsp =25 mbar, PEEP =5 mbar). Airtightness of resection surfaces was determined by a leakage score, as well as the measurement of the leakage volume (in mL) per respiration (Group 1). Afterwards, the resection areas were coagulated for 5 seconds with a laser power of 60 watts at a distance of approximately 1 cm from the surface. This was followed by a re-evaluation for airtightness (Group 2). Finally, the resection surface was closed by a suture (PDS USP 4-0) and re-tested for airtightness (Group 3). The individual groups were compared for their significance (P<0.05) using a nonparametric test. Results: Up to a resection depth of 1.5 cm, the ventilated resection surfaces were completely airtight regardless of the laser power. From a depth of resection of 1.5 cm, a mean air volume loss of 28.9+/-5.3 mL/respiratory cycle at 40 watts and of 26.4+/-5.8 mL at 60 watts was found. Additional surface coagulation did not significantly reduce the leakage rate. In contrast, suturing significantly reduced (P<0.0001) to 7.2+/-3.7 mL/ventilation (40 watts) and 6.0+/-3.4 mL/ventilation. At a resection depth of 2 cm, the leakage volume was 42.9+/-3.3 mL/respiratory cycle (40 watt) and 46.3+/-6.4 mL/respiratory cycle (60 watt). Additional surface coagulation failed to significantly reduce leakage volume, but suture closure provided airtightness. Conclusions: In non-ventilated porcine lungs, Nd:YAG laser resection surfaces up to a resection depth of 1.5 cm are airtight after ventilation onset. From a depth of 1.5 cm, closure of resection surfaces by an additional suture is needed. Airtightness of resection surfaces was not increased by additional coagulation. PMID- 30416783 TI - Fluorescent image-based evaluation of gastric conduit perfusion in a preclinical ischemia model. AB - Background: This study evaluated near-infrared (NIR) fluorescent images to assess gastric conduit perfusion after an esophagectomy in a porcine model of gastric conduit ischemia. The time necessary to acquire a sufficient fluorescent signal to confirm ischemia in the gastric conduit after peripheral or central venous injection of indocyanine green (ICG) was also investigated. Methods: A reversible gastric conduit ischemic pig model was established through ligation and release of the right gastroepiploic artery (RGEA, n=10). The esophageal reconstruction was performed to create an esophagogastric anastomosis. After ligation of the RGEA, ICG was injected into an ear vein (n=6) or the inferior vena cava (n=4). Under fluorescent imaging system guidance, the fluorescent signal-to-background ratio (SBR) in the gastric conduit or esophagus was measured during the entire procedure. We estimated the time necessary to acquire fluorescent signals in the gastric conduit using two different injection routes. Results: When the RGEA was ligated, the SBR in the esophagus was significantly higher than that in the gastric conduit (P=0.02), and the SBR in the gastric conduit recovered within 180 s after release of the ligation. The time to acquire a fluorescent signal was faster with a central route than with a peripheral route (P=0.04). Conclusions: We successfully created an ischemic animal model of the gastric conduit. Using this animal model, we evaluated the sensitivity and applicability of the fluorescent imaging system for observation and identification of ischemic areas during an esophagectomy. PMID- 30416782 TI - Serum decorin is a potential prognostic biomarker in patients with acute exacerbation of idiopathic pulmonary fibrosis. AB - Background: Decorin is a small leucine-rich repeat proteoglycan that plays a critical role in collagen fibrillogenesis, and regulates inflammation, wound healing and angiogenesis. In idiopathic pulmonary fibrosis (IPF), decorin is expressed in fibrotic lesions; furthermore, intratracheal gene transfer of decorin has been demonstrated to inhibit bleomycin-induced pulmonary fibrosis. Although these results suggest the critical role of decorin in pulmonary fibrosis, the role of decorin in the acute exacerbation of idiopathic interstitial pneumonia (AE-IIP) has not been clarified in detail. Thus, the goal of this study was to determine the role of decorin in AE-IIP. Methods: We retrospectively analyzed AE-IIP patients who had been admitted to our hospital. First, serum decorin levels were compared among patients with AE-IIP, patients with stable idiopathic interstitial pneumonia (SD-IIP), and healthy subjects. Next, the relationship between serum decorin levels and clinical parameters was analyzed in AE-IIP patients. Finally, the association between serum decorin levels and prognosis was evaluated in AE-IIP patients. IIP was divided into IPF and non-IPF, according to the published guidelines. Results: The serum decorin levels of AE-IIP patients were significantly lower than those of both healthy subjects and SD-IIP patients. Serum decorin levels were not related with the clinical parameters and prognosis, when all IIP patients were analyzed. In IPF patients, serum decorin levels had a significant correlation with oxygenation, and IPF patients with low serum decorin levels had a significantly higher survival rate than those with high serum decorin levels. Conclusions: Serum decorin levels are a potential prognostic biomarker in AE-IPF. PMID- 30416784 TI - Risk factors of cough in non-small cell lung cancer patients after video-assisted thoracoscopic surgery. AB - Background: Cough is a common respiratory complication in non-small cell lung cancer (NSCLC) patients after surgery. Previous studies have proposed a number of risk factors for postoperative cough; however, these studies are mainly based on traditional thoracotomies and tend to lack adequate objective assessment methods. The purpose of this study was to identify the risk factors of cough in NSCLC patients after video-assisted thoracoscopic surgery (VATS) using the Leicester Cough Questionnaire in Mandarin Chinese (LCQ-MC) to evaluate postoperative cough. Methods: A total of 198 NSCLC patients were enrolled. Overall, 91 patients (46.0%) developed cough after VATS, and 73 patients remained cough after 1 month. Univariate and multivariate logistic regression analyses were performed to identify the independent risk factors of postoperative cough. Results: The independent factors of postoperative cough included female sex [odds ratio (OR) 2.399, 95% confidence interval (CI): 1.260-4.565, P=0.008], duration of anesthesia (over 164 minutes; OR 2.810, 95% CI: 1.368-5.771, P=0.005), resection of the lower paratracheal nodes (OR 3.697, 95% CI: 1.439-9.499, P=0.007), and resection of the subcarinal nodes (OR 4.175, 95% CI: 1.203-14.495, P=0.024). The follow-up LCQ-MC total score after 1 month (18.00+/-1.80) was significantly higher than the postoperative total score (16.35+/-2.26; P=0.004). Conclusions: Female sex, duration of anesthesia over 164 minutes, lower paratracheal node resection and subcarinal node resection were independent risk factors related to cough in NSCLC patients after VATS. In addition, the LCQ-MC performed satisfactorily in describing the longitudinal changes in cough symptoms. PMID- 30416785 TI - Frozen elephant trunk with modified en bloc arch reconstruction and left subclavian transposition for chronic type A dissection. AB - Background: Several methods of arch vessel reconstruction, such as en bloc (island) and branched graft techniques, have been proposed to treat aortic arch pathologies during total arch replacement (TAR). We seek to review our experience with modified en bloc technique and left subclavian (LSCA)-left carotid artery (LCCA) transposition in TAR and frozen elephant trunk (FET) procedure for chronic type A aortic dissection (CTAAD). Methods: From September 2010 to September 2016, 35 consecutive patients with CTAAD underwent modified en bloc arch reconstruction with LSCA-LCCA transposition during TAR and FET procedure. Computed tomographic angiography (CTA) was performed during follow-up. Results: In-hospital mortality was 5.7% (2/35). No neurological deficit or spinal cord injury occurred. Re exploration for bleeding and continuous renal replacement therapy were required in 2 patients each (5.7%). Follow-up was complete in 100% for a mean duration of 4.1+/-1.8 years (range, 0.5-6.7 years). One patient experienced a transient stroke and thoracoabdominal aortic replacement was performed in 1. There were 2 late non-cardiac deaths. Survival was 87.9% (95% CI, 70.7-95.3%) at 6 years. At 6 years, the incidence was 3% for reoperation, 12% for late death, and 85% of patients were alive without reoperation. The anastomosis between the LSCA and LCCA was patent in 100%. Conclusions: Acceptable early and mid-term outcomes were achieved for patients with chronic type A dissection using en bloc technique with LSCA-LCCA transposition during TAR and FET procedure. This technique may be an alternative approach to chronic type A dissection in selected patients. PMID- 30416786 TI - Micropapillary or solid pattern predicts recurrence free survival benefit from adjuvant chemotherapy in patients with stage IB lung adenocarcinoma. AB - Background: Our study aimed to evaluate the prognostic significance and adjuvant chemotherapy (ACT) benefits of a micropapillary/solid (MS) pattern in patients with stage IB lung adenocarcinoma. Methods: Patients with pathologically confirmed stage IB adenocarcinoma who underwent surgical resection between January 2009 and December 2011 were included. The tumors were reclassified into three categories: MS patterns absent (MS-); non-predominant MS patterns (MS+); predominant MS (MS++). The correlations of prognosis and ACT with recurrence-free survival (RFS) were evaluated. Results: Overall, 497 (MS-, n=269; MS+, n=177; MS++, n=51) patients were enrolled in the study. In univariate analysis, the MS+ [hazard ratio (HR), 1.437; 95% confidence interval (CI), 1.030-2.006; P=0.033] and MS++ (HR, 2.818; 95% CI, 1.792-4.432; P<0.001) groups had significantly poor prognosis compared with MS- group. Multivariate analysis revealed that age >=65 (HR, 1.504; 95% CI, 1.077-2.099; P=0.017), serum level of carcinoembryonic antigen (CEA) >=10 ng/mL (HR, 1.658; 95% CI, 1.048-2.623; P=0.031) and MS++ (HR, 2.529; 95% CI, 1.550-4.126; P<0.001) were significant prognostic factors. Furthermore, subgroup analysis showed that MS++ patients but not MS- and MS+ derived RFS (recurrence-free survival) benefit from ACT (HR, 0.357; 95% CI, 0.152 0.836; P=0.018). Conclusions: MS pattern successfully differentiated the prognosis difference among stage IB lung adenocarcinomas and identified patients who benefitted from ACT. PMID- 30416787 TI - Practice of diagnosis and management of acute respiratory distress syndrome in mainland China: a cross-sectional study. AB - Background: Although acute respiratory distress syndrome (ARDS) has been recognized for more than 50 years, limited information exists about the incidence and management of ARDS in mainland China. To evaluate the potential for improvement in management of patients with ARDS, this study was designed to describe the incidence and management of ARDS in mainland China. Methods: National prospective multicenter observational study over one month (August 31st to September 30th, 2012) of all patients who fulfilled the Berlin or American European Consensus Conference (AECC) definition of ARDS in 20 intensive care units, with data collection related to the management of ARDS, patient characteristics and outcomes. Results: Of the 1,814 patients admitted during the enrollment period, 149 (8.2%) and 147 (8.1%) patients were diagnosed by AECC and Berlin definition, respectively. Lung protective strategy with low tidal volume (Vt) (<=8 mL/kg) and limitation of the plateau pressure (Pplat) (<=30 cmH2O) was performed in 75.2% patients. And, 36%, 21.1% and 4.1% patients with severe, moderate and mild ARDS had the driving pressure more than 14 cmH2O (P<0.05). Pplat and driving pressure increased significantly in patients with a higher degree of ARDS severity (P=0.002 and P<0.001, respectively), but Vt were comparable in the three groups (P>0.05). In severe ARDS, patient median positive end expiratory pressure (PEEP) was 10.0 (8.0-11.3) cmH2O and median FiO2 was 90%. A recruitment maneuver was performed in 35.5% of the patients, and 8.7% of patients with severe ARDS received prone position. Overall hospital mortality was 34.0%. Hospital mortality was 21.8% for mild, 31.1% for moderate, and 60.0% for patients with severe ARDS (P=0.004). Conclusions: Despite general acceptance of low Vt and limited Pplat, high driving pressure, low PEEP and low use of adjunctive measures may still be a concern in mainland China, especially in patients with severe ARDS. Trial Registration: ClinicalTrials.gov NCT01666834; date of registration release: August 14th 2012. PMID- 30416788 TI - Nationwide use of inhaled corticosteroids by South Korean asthma patients: an examination of the Health Insurance Review and Service database. AB - Background: Previous studies have found that the prescription rates of inhaled corticosteroid (ICS) were considerably low although it is recommended as the optimal asthma treatment. The aim of this study was to analyze the current status of ICS prescription for asthma patients in the South Korea. Methods: We evaluated quality assessment data based on nationwide Health Insurance Review and Service (HIRA) database from July 2013 to June 2014. ICS prescription rates in asthma patients were analyzed by types and specialty of medical institutions. Also, we graded medical institutions by their ICS prescription rate. In addition, ICS prescription rates were calculated by patient gender, age, and insurance type. Results: This study included 831,613 patients and 16,804 institutions in the analysis. The overall mean ICS prescription rate was 22.58%. Tertiary hospitals had the highest mean prescription rate (84.16%) whereas primary healthcare clinics had the lowest (20.71%). By specialty, internal medicine physicians prescribed ICS more frequently compared to other specialists. Of all, 47.17% of medical institutions prescribed ICS to <10% of asthma patients, while less than 6% of institutions prescribed ICS to >80% of asthma patients. Also, we found that female and patients with age >90 or <20 years exhibited lower ICS prescription rate. Conclusions: The ICS prescription rate was found to be inadequate, given the importance of ICS as an asthma treatment. The prescription rates were especially low in primary healthcare clinics, and by specialists in fields other than internal medicine. PMID- 30416789 TI - Characteristics and survival difference of clinical tumor size 0 extensive-stage small cell lung cancer with different metastasis pattern. AB - Background: Few studies were focused on the characteristics and survival prognosis of clinical tumor size 0 (cT0) extensive-stage small cell lung cancer (ES-SCLC) patients with distant metastasis. Methods: The proper patients were screened based on the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2013. Chi-square test was used to analyze the characteristics of cT0 stage. The risk factors on cT0 stage were analyzed by Logistic regression model. The survival difference was compared by the Log rank test. The prognostic factors on survival were analyzed by univariate and multivariate Cox regression model. Results: Only 1.2% of patients were diagnosed at cT0 stage. Clinical nodal status 0 (cN0) stage, no bone metastasis and no lung metastasis were all risk factors on cT0 stage. The patients at cT0 stage had better cancer specific survival (CSS) benefit (P=0.011). The cT0 stage was also an independent prognostic factor on CSS (P=0.018). Conclusions: The patients at cT0 stage was a different subgroup compared with the patients at cT1-4 stage for ES-SCLC patients with distant metastasis. PMID- 30416790 TI - Contemporary outcomes of surgical management of complex thoracic infections. AB - Background: Surgery plays an important role in the management of complex thoracic infections (CTIs). We aimed to describe the contemporary surgical outcomes of CTIs. Methods: The 2014-2017 National Surgical Quality Improvement Program (NSQIP) database was queried for patients with the following procedures: bilobectomy, decortication, lung release, lobectomy, thoracoscopic lobectomy, thoracoscopic pleurodesis, thoracoscopic wedge resection, thoracoscopic biopsy, thoracoscopy, thoracotomy, thoracotomy with wedge resection, thoracotomy with decortication, and thoracotomy with lobectomy. Patients were classified into: drainage procedures (DP) and lung resection (LR). Descriptive statistics and univariate/multivariate analysis were executed. A P value <0.05 was considered significant. Results: A total of 1,275 patients (30.3%) underwent surgical management for a CTI. Nine hundred and seven patients (71.1%) underwent a DP, and 368 patients (28.9%) underwent a LR. A thoracic surgeon performed 64% and 79% of cases in the DP and LR groups, respectively. On univariate analysis, the patients in the LR group were less likely to be male, diabetic, active smokers, dyspneic on exertion, hypertensive, malnourished, or American Society of Anesthesiologist (ASA) >3. There was no difference in overall postoperative complications, re intubation, or reoperation between groups. The patients in the LR group were less likely to develop sepsis or respiratory failure. There was no difference in 30 day mortality between groups (5.3% vs. 3.8%, P=0.26). The total length of stay was 13.82+/-10.17 and 8.7+/-15.05 days, in the DP and LR groups, respectively (P=0.001). Multivariate analysis revealed increased risk of 30-day mortality was associated with age, preoperative steroid use, renal failure, leukocytosis, pulmonary embolism, and sepsis. Conclusions: CTI's are a common indication for thoracic surgical management. This contemporary, national sampling demonstrates that approximately one third of identified cases were associated with a LR. These cases demonstrated a comparable morbidity and mortality with surgical DP, but shorter hospital stays. To aid in the management of these complex disease processes, early consultation of a multidisciplinary management service for these patients should be considered. Furthermore, the appropriate use of LR for infectious etiologies may lead to safer postoperative outcomes than previously thought. PMID- 30416791 TI - The impact of histology and ground-glass opacity component on volume doubling time in primary lung cancer. AB - Background: Correlations between volume doubling time (VDT) of primary lung cancer (PLC), histology, and ground glass opacity (GGO) components remain unclear. The purpose of this study was to evaluate and compare VDT of PLC in terms of histology and presence or absence of GGO components. Methods: A total of 371 surgically resected PLCs from 2003 to 2015 in our institute were retrospectively reviewed. The VDT was calculated both from the diameters of the entire tumor and of consolidation by using the approximation formula of Schwartz. Results: The median VDTs of adenocarcinoma, squamous cell carcinoma, and others (large cell neuroendocrine carcinomas, small cell lung carcinomas, pulmonary pleomorphic carcinomas, and large cell carcinomas combined) were 261, 70, and 70 days, respectively; these differ significantly (P<0.001). All PLCs with GGO were adenocarcinomas. The VDT of adenocarcinomas with GGO was significantly longer than that of those without GGO (median VDT: 725 and 177 days, respectively), squamous cell carcinomas, and others. When the VDT calculated from the maximum diameter of consolidation component was compared, adenocarcinomas with GGO also showed significantly slower growth than those without GGO (median VDT: 248 versus 177 days, respectively, P=0.040). Conclusions: The VDT of PLCs is longest for adenocarcinomas. VDT was significantly longer in adenocarcinomas with GGO components than in those without such components, irrespective of VDT calculated on the basis of either the entire tumor diameter or consolidation diameter. PMID- 30416792 TI - Lung function changes after chemoradiation therapy in patients with lung cancer treated by three usual platinum combinations. AB - Background: Reports point out lung toxicity of chemotherapeutic agents and radiation therapy in cancer patients. The aim of our study was to assess lung function after sequential chemoradiation therapy in patients with lung cancer. Methods: Fifteen lung cancer patients participated the study and underwent lung function assessment before and after sequential treatment of chemotherapy with the 3 most applied platinum-based combinations: of vinorelbine (VN) 6 patients, gemcitabine (GEM) 4 patients and etoposide (EP) 5 patients and radiation therapy. Lung function tests were forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), total lung capacity (TLC), diffusing capacity for carbon monoxide (DLCO) and carbon monoxide transfer coefficient (Kco). Results: Mean patients' age was 58+/-9.4 years (42-75 years). Male patients were 14 (93.3%), all smokers. Overall, after chemoradiation treatment significant changes were noted in FEV1 (P=0.012), FVC (P=0.046), TLC (P=0.04) from baseline. The drop from baseline was more significant after chemoradiation therapy in DLCO (P=0.002) and KCO (P=0.008). Conclusions: According to our results, sequential chemoradiation causes significant changes in lung function parameters in patients with lung cancer. PMID- 30416793 TI - Comparison of additional minocycline versus iodopovidone pleurodesis during video assisted thoracoscopic bleb resection for primary spontaneous pneumothorax: a propensity score-matched analysis. AB - Background: The optimal chemical agent for additional pleurodesis during video assisted thoracoscopic surgery (VATS) bleb resection in primary spontaneous pneumothorax (PSP) remains controversial. We compared the efficacy and safety of iodopovidone with those of minocycline for additional chemical pleurodesis during VATS bleb resection. Methods: Of 332 patients who underwent VATS bleb resection, 299 patients diagnosed with PSP were enrolled in this study. The patients were divided into two groups according to the chemical agents used for additional pleurodesis (iodopovidone versus minocycline). Propensity score matching was performed on the basis of the preoperative clinical parameters. Postoperative complications, chest tube indwelling time, postoperative hospital stay, and recurrence rate were compared between the two groups. Results: The median duration of follow-up was 14 months (range, 1-94 months). After propensity score matching, 94 patients from the iodopovidone group and 94 patients from the minocycline group were matched. The perioperative outcomes, including fever, prolonged air-leak, prolonged-effusion, postoperative bed-side pleurodesis, and rehospitalization because of complications, were not significantly different between the two groups. However, the amount of drainage during the first two postoperative days, duration of chest tube indwelling, and duration of hospitalization were significantly shorter in the minocycline group (P<0.001). Conclusions: This study confirmed the safety of both minocycline and iodopovidone for additional pleurodesis. However, we carefully recommend minocycline over iodopovidone for pleurodesis because of faster postoperative recovery. PMID- 30416794 TI - Association of eosinophil-to-monocyte ratio with 1-month and long-term all-cause mortality in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. AB - Background: To determine the relationship between eosinophil-to-monocyte ratio (EMR) on admission and one-month and long-term all-cause mortality in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (P-PCI). Methods: A total of 426 consecutive STEMI patients treated with P-PCI were enrolled and categorized in terms of tertiles of EMR on admission between September 2015 and October 2017. Final follow-up for long-term outcomes was January 2017. Results: As EMR decreased, all-cause mortality at 1 month (mean, 29.5+/-3.5 days) and at mean 14.1+/-7.8 months follow-up increased (P=0.012, P=0.003, respectively). Kaplan-Meier survival curve analysis showed EMR was associated with 1-month and long-term all-cause mortality (P=0.048, P=0.015, respectively). In multivariate Cox proportional hazards analysis, EMR was independently associated with one-month and long-term mortality (hazard ratio =0.097; 95% CI, 0.010-0.899; P=0.04; hazard ration =0.176; 95% CI, 0.045-0.694; P=0.013). The area under the curve of EMR for the prediction of 1-month and long term total mortality in receiver operating characteristic analysis was 0.789 (95% CI, 0.658-0.921; P=0.003) and 0.752 (95% CI, 0.619-0.884; P=0.001), respectively. Conclusions: EMR on admission was independently correlated with 1-month and long term all-cause mortality in STEMI patients undergoing P-PCI, suggesting EMR as a potential simple, useful, and inexpensive index for risk stratification of STEMI patients. PMID- 30416795 TI - Expression and pathological significance of CC chemokine receptor 7 and its ligands in the airway of asthmatic rats exposed to cigarette smoke. AB - Background: Cigarette smoking aggravates the symptoms of asthma, leading to the rapid decline of lung function. Dendritic cells (DCs) and lymphocytes are considered initiating and promoting factors for the airway inflammation reactions of asthma. In addition, activation of CC chemokine receptor 7 (CCR7) by chemokine (C-C motif) ligand (CCL) 19 and 21 promotes DCs and T cells migration to lymphoid tissues during inflammation. We aimed to examine how cigarette smoke affects the expression of CCR7 in the lungs of asthmatic rats and explore the signaling mechanism linking CCR7 expression to exacerbation of symptoms. Methods: Forty Wistar rats were randomized to four groups: control, asthma, smoke exposure, and asthma with smoke exposure groups. A rat asthma model was established by intraperitoneal ovalbumin injection. CCR7 expression was examined with immunohistochemistry and western blotting. The number of airway DCs was determined by OX62 immunohistochemistry. Interferon (INF)-gamma, interleukin (IL) 4, CCL19, and CCL21 expression levels in blood and bronchioalveolar lavage fluid (BALF) were determined by enzyme-linked immunosorbent assays (ELISAs). Results: Tissue CCR7 expression, peripheral blood and BALF CCL19 and CCL21 concentrations, and the number of airway DCs were significantly higher in the asthma with smoke exposure group than the asthma group (P<0.01). In addition, INF-gamma expression was decreased and IL-4 increased in the asthma and asthma with smoke exposure groups compared with the control group (P<0.01), and in the asthma with smoke exposure group compared with the asthma group (P<0.01). Expression of CCR7 correlated negatively with INF-gamma expression in peripheral blood and BALF (P<0.01), and positively with the airway DCs and IL-4 expression in the peripheral blood and BALF (P<0.01). Conclusions: Cigarette smoking may aggravate asthma symptoms by attenuating immunity, possibly through CCR7-mediated DCs aggregation in lung tissue. PMID- 30416796 TI - Changes in non-small cell lung cancer diagnosis, molecular testing and prognosis 2011-2016. AB - Background: Non-small cell lung cancer (NSCLC) is a leading cause of death all over the world. Diagnostic and therapeutic arsenals have improved in recent years, but we are unsure as to whether these advances have been transferred to clinical practice. The aim of this study was to evaluate differences in NSCLC diagnostic processes and short-term survival rates between two recent cohorts. Methods: A prospective, observational study was conducted with patients diagnosed with NSCLC in the period of 2011-2016. Patients were divided into two cohorts (2011-2013 and 2014-2016), and monitored for up to 1 year after diagnosis. Results: A total of 713 patients with lung cancer were selected, 500 of whom had NSCLC (222 patients in the 2011-2013 cohort, and 278 in the 2014-2016 cohort). We observed a chronological increase in the use of endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) and ultrasound-guided transthoracic puncture (US-TTP) between the cohorts. Overall short-term survival was similar between the two groups, both for locally and for advanced disease. Treatment with tyrosine kinase inhibitors (TKI) was the only therapeutic factor associated with an improved likelihood of survival. Conclusions: Changes in diagnostic process in NSCLC have been observed towards a more precise stratification. Although short term survival has not changed for advanced NSCLC, some of the newer therapeutic options are associated with increased survival in real-world scenarios. PMID- 30416798 TI - MicroRNA-374b inhibits the tumor growth and promotes apoptosis in non-small cell lung cancer tissue through the p38/ERK signaling pathway by targeting JAM-2. AB - Background: MicroRNAs (miRNAs) are reportedly involved in various cancers. The present study aimed to investigate the role of miRNA-374b in cell viability, proliferation, apoptosis, and tumor formation in non-small cell lung cancer (NSCLC) in humans. Methods: The expression level of miRNA-374b in blood and tumor tissues from NSCLC patients was analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). A 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay was performed to assess the viability of NSCLC cells after transfection with miRNA-374b. Colony formation assay was performed to assess the proliferation of cells pretreated with miRNA-374b. The terminal deoxynucleotidyl transferase-dUTP nick-end labeling (TUNEL) assay was performed to determine the role of miRNA-374b in apoptosis in NSCLC cells. A tumor formation assay was performed to assess the effects of miRNA-374b on tumorigenesis in NSCLC. Results: miRNA-374b was markedly downregulated in the blood and tumor tissues from NSCLC patients. Furthermore, overexpression of miRNA 374b markedly reduced the viability of NSCLC cells, but miRNA-374b inhibitor increased the viability of NSCLC cells compared with that in negative controls. Moreover, miRNA-374b decreased the number of colonies; however, its corresponding anti-miRNA oligonucleotide (AMO) markedly increased colony formation by NSCLC cells. Also, miRNA-374b promoted the apoptosis and inhibited tumor formation in NSCLC; however, this inhibition was reversed upon treatment with the AMO. Western blot analysis revealed that miRNA-374b regulates tumor progression through the p38/ERK signaling pathway by inhibiting JAM-2 in NSCLC. Conclusions: The present results indicate that miRNA-374b inhibits tumor growth and promotes apoptosis in NSCLC through the p38/ERK signaling pathway by targeting JAM-2. PMID- 30416797 TI - Sonic hedgehog promotes endothelial differentiation of bone marrow mesenchymal stem cells via VEGF-D. AB - Background: Bone marrow-derived mesenchymal stem cells (BMSCs) have been proved to be capable of differentiating into endothelial cells (ECs), however, the differentiation efficiency is rather low. Sonic hedgehog (Shh), an important factor in vascular development and postnatal angiogenesis, exerted promotional effect on new vessel formation in the ischemic animal models. Therefore, the current study aims to investigate whether Shh could induce the endothelial differentiation of BMSCs both in vitro and in vivo, as well as the mechanism of differentiation induction. Methods: The current study over-expressed Shh in BMSCs by lentivirus transduction. Reverse-transcription quantitative polymerase chain reaction (RT-qPCR) analysis was performed to determine the angiogenic factors in both control BMSCs and Shh over-expressed BMSCs. Immunocytochemistry was also conducted to examine the EC markers. Angiogenesis was determined by in vitro tube forming assay on Matrigel and in vivo Matrigel plug in severe combined immunodeficient (SCID) mice. Last, mRNA sequencing analysis was used to elaborate the underlying mechanisms. Loss of function study was performed by vascular endothelial growth factor D (VEGF-D) siRNA. Results: Shh expression was increased by about 3,000-fold and 5,000-fold at 3 days-transfection and 7 days transfection, respectively. Patched 1 (Ptch1), the receptor for Shh, had a two fold increase after transduction. The angiogenic factors such as hepatocyte growth factor (HGF), angiopoietin-1 (Ang-1), insulin-like growth factor 1 (IGF1) and vascular endothelial growth factor A (VEGF-A) had at least a 1.5-fold increase after transduction. Expression of EC-lineage markers, CD31 and VE cadherin, on Shh-overexpressed BMSCs were increasingly detected by immunocytostaining. Angiogenesis of BMSCs could be efficiently induced by Shh overexpression in the in vitro tube-formation assay and in vivo Matrigel plug. Additionally, mRNA sequencing analysis revealed that Shh activation upregulated the expression of several pro-angiogenic factors, like Angptl4, Egfl6, VEGF-D. Loss of function study by VEGF-D siRNA confirmed that Shh enhanced the angiogenic ability of BMSCs via VEGF-D. Conclusions: This study demonstrated that Shh could promote endothelial differentiation of BMSCs via VEGF-D. PMID- 30416799 TI - Strong expression of Id-1 in metastatic lymph nodes from esophageal squamous cell carcinoma is associated with better clinical outcome. AB - Background: Over-expression of inhibitor of differentiation or DNA binding 1 (Id 1) is associated with poor prognosis in esophageal squamous cell carcinoma (ESCC). However, some biomarkers discordant expression in metastasis has been reported previously. We aimed to confirm possible differential expression and prognostic value of Id-1 in paired metastatic lymph node (PMLN). Methods: Expression of Id-1 in primary tumors (PT) and paired regional metastatic lymph nodes of ESCC were evaluated with immunohistochemical (IHC) analysis. Statistical analysis of Kaplan-Meier method was performed to test the prognostic significance of Id-1 expression. Results: The expression of Id-1 was down-regulated in metastatic lymph nodes compared with primary esophageal tumors (P<0.001). Patients with 1 to 2 lymph nodes involved had significantly higher Id-1 expression in metastatic lymph nodes (P=0.028). The similar association was observed between a ratio of involved to examined lymph nodes <=0.2 and high level Id-1 expression in lymphatic metastases (P=0.011). Better overall survival with statistical significance was observed in patients with higher level Id-1 expression in metastatic lymph nodes (P=0.015). The results of Id-1 expression in metastatic lymph node and paired PT was to predict prognosis effective in out cohort (P=0.035). Conclusions: The level of Id-1 protein expression was down regulated from PT to metastatic lymph node. It was contrary to previous studies that strong expression of Id-1 in metastatic lymph nodes was associated with better clinical outcomes in patients with stage T3N1-3M0 ESCC. PMID- 30416800 TI - Sputum purulence-associated microbial community compositions in adults with bronchiectasis. PMID- 30416801 TI - IQQA-3D imaging interpretation and analysis system-guided single-port video assisted thoracic surgery for anatomical sub-segmentectomy (LS1+2a+b). PMID- 30416802 TI - Role of p16 deletion and BAP1 loss in the diagnosis of malignant mesothelioma. PMID- 30416803 TI - A phase I/II study of bexarotene with carboplatin and weekly paclitaxel for the treatment of patients with advanced non-small cell lung cancer. AB - Background: Rexinoids demonstrate anti-proliferative differentiation-inducing activity in multiple cancer types, including NSCLC. Prior studies have shown promising results when combining rexinoids with chemotherapy. This phase I/II study evaluates the tolerability and activity of a rexinoid, bexarotene, combined with weekly paclitaxel and monthly carboplatin. Methods: Patients with confirmed advanced stage IIIB or IV NSCLC and adequate organ function were enrolled. They were scheduled to receive carboplatin (AUC =6) and 3 doses of weekly paclitaxel (100 mg/m2) every 4 weeks. Oral bexarotene was administered daily at two doses: 300 and 400 mg/m2/day. Results: Thirty-three patients were enrolled. Fourteen received 300 mg/m2/day and 19 received 400 mg/m2/day of bexarotene. Hematologic toxicity included grade 3 neutropenia in 7 patients. Hyperlipidemia was a major non-hematologic toxicity which was medically managed. The recommended phase II dose of bexarotene was 400 mg/m2/day. Response rate was 35%. Median overall survival (OS) for all patients was 8.3 months with 1-year survival of 43%. Median OS for the 300 mg/m2 dose of bexarotene was 6.6 versus 9.8 months for the 400 mg/m2 dose (HR, 0.73; Log rank P=0.37). Patients who experienced hypertriglyceridemia had a median OS of 9.8 months compared to 4.9 months for those who did not (HR, 0.69; Log rank P=0.33). Conclusions: The 43% 1-year survival for patients receiving bexarotene with weekly paclitaxel and monthly carboplatin is encouraging. With the availability of new classes of agents for lung cancer, further evaluation of this regimen in unselected patients is not warranted. Our study confirms prior subgroup analyses showing a significant correlation between bexarotene-induced hypertriglyceridemia and survival. Further research is needed to identify molecular biomarkers to identify this subset of patients and to explore rexinoids in other combinations, especially with immunotherapy. PMID- 30416806 TI - The utilization of resuscitative endovascular balloon occlusion of the aorta: preparation, technique, and the implementation of a novel approach to stabilizing hemorrhage. AB - Noncompressible torso hemorrhage (NCTH), if not controlled promptly, leads to death. In the acute setting, aortic occlusion can be performed as damage control surgery (DCS) for hemorrhage originating from the abdomen and pelvis. With the development of endovascular technology, an intra-aortic balloon can be used to achieve aortic occlusion and decrease hemorrhage. Recently, resuscitative endovascular balloon occlusion of the aorta (REBOA) has been accepted as a salvage technique for the temporary stabilization of patients with NCTH. However, balloon occlusion is not easily performed in trauma patients. In this article, we described preparation, technical description, and conceptual understanding of REBOA. PMID- 30416804 TI - The Society for Translational Medicine: indications and methods of percutaneous transthoracic needle biopsy for diagnosis of lung cancer. PMID- 30416805 TI - Society for Translational Medicine Expert Consensus on the preoperative assessment of circulatory and cardiac functions and criteria for the assessment of risk factors in patients with lung cancer. PMID- 30416807 TI - Pulmonary vasculitis. AB - Systemic vasculitides frequently affect the pulmonary vasculature. As the signs and symptoms of pulmonary vasculitis are variable and nonspecific, diagnosis and treatment represent a real challenge. Vasculitides should be given consideration, as these diseases present severe manifestations of rapidly progressing pulmonary disease. Examining other organs usually affected by vasculitides (e.g., the skin and kidneys) and determining autoantibody levels are essential to a better management of the disease. A radiological study would also contribute to establishing a diagnosis. The lungs are commonly involved in small-vessel vasculitis, anti-glomerular basement membrane disease, and vasculitides associated with antineutrophil cytoplasmic antibodies. Associated life threatening diffuse alveolar haemorrhages and irreversible damage to other organs usually the kidneys-are severe complications that require early diagnosis. Vasculitides are rare diseases that affect multiple organs. An increasing number of treatments-including biological agent-based therapies-requiring cooperation between specialists and centers have become available in the recent years. In the same way, clinicians should be familiar with the complications associated with immunosuppressive therapies. PMID- 30416808 TI - Surgical treatment of bronchial rupture in blunt chest trauma: a review of literature. AB - Bronchial rupture by blunt chest trauma is rare. We present a case of bronchial injury after blunt chest trauma that was repaired surgically by primary reconstruction. We performed a review of literature to verify if primary reconstruction is suitable for the treatment of adult patients with blunt bronchial injury. A systematic search was conducted to identify cohort studies of bronchial rupture after blunt chest trauma in adult patients between 1985 and 2016 (n=215 articles). Studies were included concerning four or more patients and in case patient data could be extracted. This resulted in 19 articles for final review, consisting of 155 patients. Mean age of 155 patients was 28 (range, 18 60) years. The main bronchus was mostly injured (81%), in 5% including an injury of the trachea and in 14% lobar bronchi injury. Surgical repair was performed in 95% of patients: primary anastomosis in 72%, pneumonectomy in 15%, lobectomy or sleeve resection in 12% and other in 1%. Perioperative mortality rate was 10%. Other complications occurred in 17% (empyema, rebleeding, stenosis and fistula, among others). Data concerning the occurrence of long-term complications or long term follow-up was not found. Statistical evaluation could not be performed due to lack of consistent patient data. No strong recommendations regarding type and timing of surgery can be made based on the available literature. Based on our multidisciplinary opinion we would advocate primary anastomosis in case of stable vital signs with the goal to preserve healthy lung parenchyma. Moreover, it may be considered transferring these rare cases to an experienced thoracic and trauma surgery center. PMID- 30416810 TI - The nationwide program of allergic disease prevention as an implementation of GARD guidelines in Poland. AB - Background: In 2006, the Global Alliance against Chronic Respiratory Diseases (GARD) was established. The GARD strategy is based mainly on activities aimed at implementing preventive tasks at a local and global level. In Poland, the National Health Program (NHP) is the strategic document describing the tasks of governmental and local administration in the field of public health. One of the activities under the NHP is a project to carry out mass allergy screening (of children and adolescents at school age) and to organize an information and education campaign. Methods: In 2017-2018, the screening will cover a group of at least 10,000 children and adolescents at school age (6-18 years of age) in 10 of 16 voivodships in Poland. In the study, the e-health tool for early pre-medical risk assessment of allergic diseases was used. The algorithm determines the risk of bronchial asthma (BA) and allergic rhinitis (AR) based on a series of 38 questions on the symptoms of allergic diseases. In order to assess the effectiveness of the screening test (algorithm) a validation study was carried out before screening. Moreover, the algorithm was calibrated on the basis of the obtained results. The screening is accompanied by a nationwide information and education campaign carried out by means of new media. Results: A total of 1,008 children and adolescents participated in the validation study. In outpatient examination AR was diagnosed in 46.4% and BA in 11.2%. In the case of AR, the sensitivity of the calibrated version of the algorithm was 0.852 and the specificity was 0.840. In the case of BA, it was 0.841 and 0.912, respectively. In 2017, 1,512 people used the screening tool, of which 1,472 respondents went through all stages of the assessment. BA positive AR result (probably sick) was found in 19.5% of respondents and BA in 8.4%. Conclusions: The use of e-health tools in mass screening and new media to conduct information and education campaigns allows for the reduction of costs and for efficient implementation of activities. It is important to popularize the use of this type of solutions both at national and local level. PMID- 30416809 TI - Patient screening for early detection of aortic stenosis (AS)-review of current practice and future perspectives. AB - In Europe, approximately one million people over 75 years suffer from severe aortic stenosis (AS), one of the most serious and most common valve diseases, and this disease burden is increasing with the aging population. A diagnosis of severe symptomatic AS is associated with an average life expectancy of 2-3 years and necessitates a timely valve intervention. Guidelines for valve replacement therapy have been established but only a proportion of patients with symptomatic AS actually receive this life-saving treatment. The decision for valve intervention in asymptomatic patients with severe AS is often more challenging and likely results in fewer patients receiving treatment in comparison to their symptomatic counterparts. This article reviews the epidemiology and clinical manifestations of AS, the associated economic burden of AS to the healthcare system, the diagnosis of AS and the possible mechanisms for the introduction of routine screening in elderly patients. Elderly patients typically visit healthcare providers more frequently than younger patients, thereby providing increased opportunities for ad hoc AS screening and this, along with raising patient awareness of the symptoms of AS, has the potential to result in the earlier diagnosis and treatment of AS and increased patient survival. PMID- 30416811 TI - Introduction to Journal of Thoracic Disease new column: Critical Care Frontier and Horizon. PMID- 30416813 TI - Impact of simulation training on performance and outcomes of endobronchial ultrasound-guided transbronchial needle aspiration performed by trainees in a tertiary academic hospital. AB - Background: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has a high diagnostic yield and low complication rate. Whilst it has been included in international guidelines for the diagnosis and staging of lung cancer, current results are mostly based on EBUS experts performing EBUS-TBNA in centres of excellence. The impact of simulation training on diagnostic yield, complications, scope damage and repair cost in a real-world teaching hospital is unclear. Methods: A review of our hospital EBUS-TBNA registry from August 2008 to December 2016 was performed. A positive diagnosis was defined as a confirmed histological or microbiological diagnosis based on EBUS sampling. Complications were classified as major or minor according to the British Thoracic Society guidelines. In addition, we assessed the cost of repairs for scope damage before and after simulation training was implemented. Using CUSUM analysis, the learning curves of individual trainees and the institution were plotted. Results: There were 608 EBUS-TBNA procedures included in the study. The number of procedures performed by trainees who underwent conventional training was 331 and those who underwent simulation training performed 277 procedures. Diagnostic yield for trainees without simulation training was 88.2% vs. 84.5% for trainees with simulation training (P=0.179). There was no statistical difference in the diagnostic yield between the groups of trainees (OR: 0.781, 95% CI: 0.418-1.460, P=0.438) after adjusting for risk factors. There was an increase in overall complications from 13.6% to 16.6% (OR: 2.247, 95% CI: 1.297-3.891, P=0.004) after introduction of the simulation training, but a trend to decrease in major complications 3.6% to 0.7% (P=0.112). The cost for scope repairs for the trainees without simulation training was SGD 413.88 per procedure vs. SGD 182.79 per procedure for the trainees with simulation training, with the mean difference being SGD 231.09 per procedure (95% CI: 178.40-640.60, P=0.268). CUSUM analysis showed an increasing learning curve for the trainees with simulation training after an initial competency period. Conclusions: There was no statistical difference in diagnostic yield from EBUS-TBNA and cost of scope damage after simulation training was introduced into our training program. Interestingly, there was an increase in minor complications. CUSUM analysis can provide additional information on institutional learning curves. The value of simulation training in EBUS-TBNA remains uncertain. PMID- 30416812 TI - Cell therapy in acute respiratory distress syndrome. AB - Acute respiratory distress syndrome (ARDS) is driven by a severe pro-inflammatory response resulting in lung damage, impaired gas exchange and severe respiratory failure. There is no specific treatment that effectively improves outcome in ARDS. However, in recent years, cell therapy has shown great promise in preclinical ARDS studies. A wide range of cells have been identified as potential candidates for use, among these are mesenchymal stromal cells (MSCs), which are adult multi-lineage cells that can modulate the immune response and enhance repair of damaged tissue. The therapeutic potential of MSC therapy for sepsis and ARDS has been demonstrated in multiple in vivo models. The therapeutic effect of these cells seems to be due to two different mechanisms; direct cellular interaction, and paracrine release of different soluble products such as extracellular vesicles (EVs)/exosomes. Different approaches have also been studied to enhance the therapeutic effect of these cells, such as the over expression of anti-inflammatory or pro-reparative molecules. Several clinical trials (phase I and II) have already shown safety of MSCs in ARDS and other diseases. However, several translational issues still need to be addressed, such as the large-scale production of cells, and their potentiality and variability, before the therapeutic potential of stem cells therapies can be realized. PMID- 30416814 TI - Bronchoscopic advances in the management of aerodigestive fistulas. AB - Malignant aerodigestive fistula (ADF) is an uncommon condition complicating thoracic malignancies. It results in increased morbidity and mortality and warrants therapeutic intervention. The management approach depends on symptoms, configuration, location, and extent of the fistula. This article will discuss the therapeutic considerations in the management of ADF. PMID- 30416815 TI - A suspected case of inflammatory bronchial polyp induced by bronchial thermoplasty but resolved spontaneously. PMID- 30416816 TI - Detection of reverse triggering in a 55-year-old man under deep sedation and controlled mechanical ventilation. PMID- 30416817 TI - Hemorrhage of a pancreatic metastasis from lung adenocarcinoma after osimertinib therapy. PMID- 30416818 TI - Case of spontaneous whole-lung torsion with literature review. PMID- 30416819 TI - Atypical pulmonary alveolar proteinosis presenting as a mixed nodular ground glass opacity with focal mucinosis mimicking lung cancer. PMID- 30416820 TI - A case of coronary arterio-venous fistula: the role of cardiac computed tomography. PMID- 30416821 TI - Cardiac hemangioma with epicardial infiltration. PMID- 30416822 TI - Double-barreled bronchoplasty for a carcinoid tumor with a rare variation of displaced bronchus. PMID- 30416823 TI - Bilateral pulmonary sequestrations mimicking advanced lung malignancy. PMID- 30416824 TI - Prof. Bo Lu: patients come first-the direction of lung cancer treatment. PMID- 30416825 TI - Role of 25 MHz Ultrasound Biomicroscopy in the Detection of Subluxated Lenses. AB - Background: The purpose of this observational case series study was to investigate the role of 25 MHz ultrasound biomicroscopy (UBM) in detecting subluxated lenses and compare it with 50 MHz UBM. Methods: 45 patients (49 eyes) with suspected subluxation of the lens and 20 normal volunteers (40 eyes) were included. Different cross-sectional images of the lens position were captured in axial and longitudinal scanning modes using 25 and 50 MHz UBM. The main outcome measurements included the linear distance between the lens equator and ciliary process, the difference value (D-value) between the same cross section of the above bilateral linear distance in the normal and the subluxated subjects, the diagnostic accuracy, and the testing times obtained with 25 and 50 MHz UBM. Results: The position of the lens on axial sections could be clearly shown by using 25 MHz UBM. The D-value of the subluxated eyes was 1-2 mm longer than that of the normal ones. There was a statistically significant difference between 25 and 50 MHz UBM in showing subluxation of the lens, the testing time was significantly faster (2.0 min versus 7.5 min), and the diagnostic accuracy was much higher (98.0% versus 71.4%) with 25 versus 50 MHz UBM. Fifteen eyes with slightly subluxated lens were detected by 25 MHz UBM, and only one eye with slight lens subluxation was detected by 50 MHz UBM. Conclusions: The results indicated that 25 MHz UBM has a greater diagnostic value than 50 MHz UBM in verifying the status of the lens subluxation and can provide reliable and quantitative imaging evidence for clinical use. This trial is registered with ChiCTR-DOD -15007603. PMID- 30416826 TI - Preliminary Investigation of the Mechanical Anisotropy of the Normal Human Corneal Stroma. AB - Purpose: To investigate the anisotropic characteristics of the normal human corneal stroma using fresh corneal tissue. Methods: Sixty-four corneal specimens extracted from stromal lenticules were included in this study. The specimens were cut in the temporal-nasal (horizontal) or superior-inferior (vertical) direction. Strip specimens were subjected to uniaxial tensile testing. The tensile properties of the specimens were measured and compared in the two directions. Results: The low-strain tangent modulus was statistically significantly greater in the vertical direction than in the horizontal direction (1.32 +/- 0.50 MPa vs 1.17 +/- 0.43 MPa; P=0.035), as was the high-strain tangent modulus (51.26 +/- 8.23 MPa vs 43.59 +/- 7.96 MPa; P <= 0.001). The elastic modulus in the vertical direction was also higher than that in horizontal direction at stresses of 0.01, 0.02, and 0.03 MPa, but not statistically significant; so, P=0.338, 0.373, and 0.417, respectively. Conclusions: The biomechanical behavior in normal human corneal stroma tissue is slightly stiffer in the vertical direction than in the horizontal direction. This information may aid our understanding of the biomechanical properties of the cornea and related diseases. PMID- 30416828 TI - Ghanaians Might Be at Risk of Excess Dietary Intake of Potassium Based on Food Supply Data. AB - The World Health Organization (WHO) has highlighted the beneficial role of adequate intake of potassium (K) in combating the global burden of noncommunicable diseases (NCDs), mainly hypertension and cardiovascular diseases. Diets are the main source of K supply to humans and can contribute to both K deficiency (hypokalemia) and excess (hyperkalemia). While global attention is currently devoted to K deficiency, K excess can be even more dangerous and deserves equal attention. The objectives of this paper were to (i) estimate the K intake of Ghanaian population using food supply and food composition data and (ii) compare this estimate with the WHO-recommended requirement for K in order to assess if there is a risk of inadequate or excess K intake. Food supply data (1961-2011) were obtained from the Food Balance Sheet (FBS) of the Food and Agriculture Organization of the United Nations to derive trends in food and K supply. The average food supply in the FBS for 2010 and 2011 was used in assessing the risk of inadequate or excess dietary intake of K. The K content of the food items was obtained from food composition databases. Based on 2010-2011 average data, the K supply per capita per day was approximately 9,086 mg, about 2.6-fold larger than the WHO-recommended level (3,510 mg). The assessment suggests a potentially large risk of excess dietary K supply at both individual and population levels. The results suggest the need for assessing options for managing K excess as part of food security and public health strategies. The results further underscore a need for assessment of the K status of staple food crops and mixed diets, as well as K management in food crop production systems in Ghana. PMID- 30416827 TI - Ocular Biometric Characteristics of Chinese with History of Acute Angle Closure. AB - Purpose: To investigate the biometric characteristics of Chinese patients with a history of acute angle closure (AAC). Methods: In this clinic-based, retrospective, observational, cross-sectional study, biometric parameters of eyes were acquired from a general population of Chinese adults. The crowding value (defined as lens thickness (LT); central corneal thickness (CCT); anterior chamber depth (ACD)/axial length (AL)) was calculated for each patient. Logistic regression analysis was performed to identify risk factors for AAC. Receiver operating characteristic (ROC) curves were plotted, and biometric variables were compared to compile a risk assessment for AAC. Result: This study included 1500 healthy subjects (2624 eyes, mean age of 66.54 +/- 15.82 years) and 107 subjects with AAC (202 eyes, mean age of 70.01 +/- 11.05 years). Eyes with AAC had thicker lens (P <= 0.001), shallower anterior chamber depth (P <= 0.001), and shorter axial length (P <= 0.001) than healthy eyes. Logistic regression analysis and ROC curve analysis indicated that a crowding value above 0.13 was a significant (P < 0.05) risk factor for the development of AAC. Conclusions: Biometric parameters were significantly different between the eyes from the AAC group to the normal group. Ocular crowding value might be a new noncontact screening method to assess the risk of AAC in adults. PMID- 30416829 TI - A Higher Fructose Intake Is Associated with Greater Albuminuria in Subjects with Type 2 Diabetes Mellitus. AB - The aim of this single center cross-sectional study was to investigate the association between fructose intake and albuminuria in subjects with type 2 diabetes mellitus (T2DM). This is a single center cross-sectional study. One hundred and forty-three subjects with T2DM were recruited from the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran. The median daily fructose intake was estimated with a prospective food registry during 3 days (2 week-days and one weekend day) and they were divided into low fructose intake (<25 g/day) and high fructose intake (>= 25 g/day). Complete clinical and biochemical evaluations were performed, including anthropometric variables and a 24-hour urine collection for albuminuria determination. One hundred and thirty six subjects were analyzed in this study. We found a positive significant association between daily fructose intake and albuminuria (rho= 0.178, p=0.038) in subjects with type 2 diabetes mellitus. Other variables significantly associated with albuminuria were body mass index (BMI) (rho= 0.170, p=0.048), mean arterial pressure (MAP) (rho= 0.280, p=0.001), glycated hemoglobin (A1c) (rho= 0.197, p=0.022), and triglycerides (rho= 0.219, p=0.010). After adjustment for confounding variables we found a significant and independent association between fructose intake and albuminuria (beta= 13.96, p=0.006). We found a statistically significant higher albuminuria (60.8 [12.8-228.5] versus 232.2 [27.2-1273.0] mg/day, p 0.002), glycated hemoglobin (8.6+/-1.61 versus 9.6+/-2.1 %), p= 0.003, and uric acid (6.27+/-1.8 versus 7.2+/-1.5 mg/dL), p=0.012, in the group of high fructose intake versus the group with low fructose intake, and a statistically significant lower creatinine clearance (76.5+/-30.98 mL/min versus 94.9+/-36.8, p=0.014) in the group with high fructose intake versus the group with low fructose intake. In summary we found that a higher fructose intake is associated with greater albuminuria in subjects with T2DM. PMID- 30416830 TI - Pharmacological Management of Severe Neuropathic Pain in a Case of Eosinophilic Meningitis Related to Angiostrongylus cantonensis. AB - Angiostrongylus cantonensis, the rat lungworm, is the most common infectious cause of eosinophilic meningitis and can be fatal. The parasite can be found throughout Southeast Asia and Pacific Islands and the global distribution is expanding. We present the case of a fourteen-year-old female who had previously traveled to Hawaii and developed severe neuropathic pain related to A. cantonensis infection refractory to gabapentin and pregabalin monotherapy, who was eventually managed with an ultralow dose ketamine infusion, methadone, and serotonin-norepinephrine reuptake inhibitor. PMID- 30416832 TI - Suspected Pericardial Tuberculosis Revealed as an Amyloid Pericardial Mass. AB - Primary systemic amyloidosis is not easily diagnosed. The immunoglobulin deposits are usually localized in the kidney, heart, and liver. We describe an unusual case of a patient suffering from a pericardial amyloidoma with internal calcifications and air bubbles that compressed the right ventricle and shifted the heart to the left. Since the patient was in shock, urgent pericardiotomy was performed. This site showed PET uptake. A monoclonal component was present. On these findings, differential diagnoses included multiple myeloma and atypical pericardial tuberculosis, whereas a periumbilical fat tissue biopsy demonstrated amyloidosis. A previous Salmonella species infection had most likely stimulated the production of amyloid. The patient received bortezomib/dexamethasone treatment and achieved a good response. PMID- 30416831 TI - A Rare Case of Heterozygous Gain of Function Thyrotropin Receptor Mutation Associated with Development of Thyroid Follicular Carcinoma. AB - Activating mutations in thyrotropin receptor (TSHR) have been previously described in the context of nonautoimmune hyperthyroidism and thyroid adenomas. We describe, for the first time, a mutation in TSHR contributing to follicular thyroid carcinoma (FTC) in an adolescent. A 12-year-old girl presented with a right-sided neck swelling, increasing in size over the previous four weeks. Clinical examination revealed a firm, nontender thyroid nodule. Ultrasound scan of the thyroid showed a heterogeneous highly vascular mass. Thyroid function tests showed suppressed TSH [<0.03mU/L], normal FT4 [10.1pmol/L, 9-19], and raised FT3 [9.1pmol/L, 3.6-6.4]. Thyroid [TPO and TRAB] antibodies were negative. A right hemithyroidectomy was performed and the histology of the sample revealed follicular carcinoma with mild to moderate nuclear pleomorphism and evidence of capsular and vascular invasion (pT1b). Sanger sequencing of DNA extracted from the tumour tissue revealed a missense somatic mutation (c.1703T>C, p.Ile568Thr) in TSHR. Papillary thyroid carcinomas constitute the most common thyroid malignancy in childhood, while FTC is rare. FTC due to TSHR mutation suggests an underlying, yet to be explored, molecular pathway leading to the development of malignancy. The case is also unique in that the clinical presentation of FTC as a toxic thyroid nodule has not been previously reported in children. PMID- 30416833 TI - A Rare Case of Pembrolizumab-Induced Reactivation of Hepatitis B. AB - Hepatitis B virus (HBV) infection is common across the world, especially in Asia, Africa, Southern Europe, and Latin America. The association of HBV infection in patients suffering from different oncological conditions is well established. Many cases of HBV reactivation have been reported in patients on immunosuppressive chemotherapy and in patients undergoing hematopoietic bone marrow transplantations. Only one case has been reported so far of HBV reactivation in a patient treated with programmed cell death receptor 1 (PD-1) checkpoint inhibitors in the setting of HIV status. We report a case of a 51-year old male, former smoker, diagnosed with stage IV poorly differentiated adenocarcinoma of the lung, and started on pembrolizumab, who developed reactivation of chronic hepatitis requiring antiviral therapy. PMID- 30416834 TI - Non-Hodgkin's Lymphoma of the Middle Ear Presenting as Mastoiditis. AB - Lymphoma originating from the middle ear is rare. The diagnosis of lymphoma as with other cancers of the temporal bone is often made late, and this has a negative implication on the treatment and prognosis of the condition. The delay of diagnosis is mainly due to the similar presentation shared with other benign conditions of the middle ear. We present a case of a 62-year-old man who was treated as a case of chronic otitis media for a period of time before presenting with advanced symptoms; a final diagnosis of lymphoma of the middle ear was given. Other similar cases in the literature are discussed and reviewed. Severe and persistent symptoms of the middle ear should raise red flags and warrant detailed investigations. PMID- 30416835 TI - In Utero Diagnoses of Strikingly Similar Presentations of Complete Atrioventricular Septal Defects in a Pair of Dizygotic Twins Concordant for Trisomy 21. AB - Trisomy 21, or Down syndrome (DS), is a genetic disorder affecting approximately 1 in 500-750 live births. The prevalence of DS has increased over the past two decades, correlating with a rise in the proportion of pregnancies complicated by advanced maternal age. There is also a correlation between advanced maternal age and dizygotic twinning rates. There is an increased risk of at least one twin being affected in dizygotic pregnancies compared to singletons. However, despite this greater relative risk, reports of concordance of DS in both dizygotic twins are very rare. Congenital heart disease (CHD) occurs in roughly 40% of individuals with DS, but there can be considerable phenotypic variation. The most common, atrioventricular septal defect accounts for only 40% of CHD seen in DS. There is also a higher incidence of CHD in twins, but also with a low incidence of concordance. There have been only five reported cases of concordant DS in dizygotic twins with confirmed chromosomal analyses; none of which describe concordant congenital heart disease. Here, we describe an unusual case of dizygotic twins of differing genders concordant for both Down syndrome and congenital heart disease of a strikingly similar presentation. PMID- 30416837 TI - A Case Report of Compassion Focused Therapy (CFT) for a Japanese Patient with Recurrent Depressive Disorder: The Importance of Layered Processes in CFT. AB - Major depressive disorder is a common mental health problem around the world. To treat depression, cognitive behavioural therapy is highly recommended by some guidelines. However, there are reports pointing out the existence of patients who do not respond to cognitive behavioural therapy because of dissociation between thoughts and experiences. To treat such patients, compassion focused therapy was developed, but there are no reports of compassion focused therapy for Japanese patients. This report presents a case of compassion focused therapy for a Japanese female with major depressive disorder and suicidal feelings. After receiving compassion focused therapy, the patient recovered and began to have social interaction with others again. This case suggested the importance of psychoeducation, exercises involving compassionate images and breathing, and a compassionate relationship in conducting compassion focused therapy. PMID- 30416836 TI - Modafinil Induced Psychosis in a Patient with Bipolar 1 Depression. AB - Modafinil has been used as an adjunctive medication in the treatment of bipolar 1 depression with reported success. Case reports have been published demonstrating modafinil induced mania in bipolar patients and modafinil induced psychosis in schizophrenic patients. To our knowledge, we report the only case of modafinil induced psychosis in a patient with bipolar depression treated with both mood stabilizers and antipsychotics. In addition, it is the quickest onset to psychosis (2 days) at the lowest dosage of modafinil (100 mg/day) reported in the literature. Although favorable outcomes using modafinil for treatment of bipolar depression have been reported in literature, clinicians should remain cautious of the potential to rapidly induce psychosis with modafinil at low dosages in patients with bipolar depression despite being treated with mood stabilizers and antipsychotics. PMID- 30416838 TI - Intestinal Obstruction following Ingestion of Metallic Instruments in a Psychiatric Patient. AB - Pica among psychiatric patients has been well documented. We report a 25-year-old female patient who presented with abdominal distension for one week. She is a known psychiatric patient for 5 years. Through history taking, physical examination, and investigations, the patient was found to have psychotic features and features of intestinal obstruction. Surgery was done by opening the abdomen and then the stomach. The stomach, together with the proximal intestine, was found to be filled with metallic instruments weighing 780 mg. The diagnosis of a metalophagia type of pica was reached. All instruments were removed and the patient did well postoperatively. PMID- 30416840 TI - MOESHA: A Genetic Algorithm for Automatic Calibration and Estimation of Parameter Uncertainty and Sensitivity of Hydrologic Models. AB - Characterization of the uncertainty and sensitivity of model parameters is an essential facet of hydrologic modeling. This article introduces the multi objective evolutionary sensitivity handling algorithm (MOESHA) that combines input parameter uncertainty and sensitivity analyses with a genetic algorithm calibration routine to dynamically sample the parameter space. This novel algorithm serves as an alternative to traditional static space-sampling methods, such as stratified sampling or Latin hypercube sampling. In addition to calibrating model parameters to a hydrologic model, MOESHA determines the optimal distribution of model parameters that maximizes model robustness and minimizes error, and the results provide an estimate for model uncertainty due to the uncertainty in model parameters. Subsequently, we compare the model parameter distributions to the distribution of a dummy variable (i.e., a variable that does not affect model output) to differentiate between impactful (i.e., sensitive) and non-impactful parameters. In this way, an optimally calibrated model is produced, and estimations of model uncertainty as well as the relative impact of model parameters on model output (i.e., sensitivity) are determined. A case study using a single-cell hydrologic model (EXP-HYDRO) is used to test the method using river discharge data from the Dee River catchment in Wales. We compare the results of MOESHA with Sobol's global sensitivity analysis method and demonstrate that the algorithm is able to pinpoint non-impactful parameters, demonstrate the uncertainty of model results with respect to uncertainties in model parameters, and achieve excellent calibration results. A major drawback of the algorithm is that it is computationally expensive; therefore, parallelized methods should be used to reduce the computational burden. PMID- 30416839 TI - Gut microbiota, fatty liver disease, and hepatocellular carcinoma. AB - Intestinal bacteria contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Recently developed microbial profiling techniques are beginning to shed light on the nature of the changes in the gut microbiota that accompany NAFLD and non-alcoholic steatohepatitis (NASH). In this review, we summarize the role of gut microbiota in the development of NAFLD, NASH, and hepatocellular carcinoma (HCC). We highlight the mechanisms by which gut microbiota contribute to NAFLD/NASH, including through alterations in gut epithelial permeability, choline metabolism, endogenous alcohol production, release of inflammatory cytokines, regulation of hepatic Toll-like receptor (TLR), and bile acid metabolism. In addition, we analyze possible mechanisms for enhanced hepatic carcinogenesis, including alterations in bile acid metabolism, release of inflammatory cytokines, and expression of TLR-4. Finally, we describe therapeutic approaches for NAFLD/NASH and preventive strategies for HCC involving modulation of the intestinal microbiota or affected host pathways. Although recent studies have provided useful information, large-scale prospective studies are required to better characterize the intestinal microbiota and metabolome, in order to demonstrate a causative role for changes in the gut microbiota in the etiology of NAFLD/NASH, to identify new therapeutic strategies for NAFLD/NASH, and to develop more effective methods of preventing HCC. PMID- 30416841 TI - Preparation of Cobalt Nanocrystals Supported on Metal Oxides To Study Particle Growth in Fischer-Tropsch Catalysts. AB - Colloidal synthesis of nanocrystals (NC) followed by their attachment to a support and activation is a promising route to prepare model catalysts for research on structure-performance relationships. Here, we investigated the suitability of this method to prepare well-defined Co/TiO2 and Co/SiO2 catalysts for the Fischer-Tropsch (FT) synthesis with high control over the cobalt particle size. To this end, Co-NC of 3, 6, 9, and 12 nm with narrow size distributions were synthesized and attached uniformly on either TiO2 or SiO2 supports with comparable morphology and Co loadings of 2-10 wt %. After activation in H2, the FT activity of the TiO2-supported 6 and 12 nm Co-NC was similar to that of a Co/TiO2 catalyst prepared by impregnation, showing that full activation was achieved and relevant catalysts had been obtained; however, 3 nm Co-NC on TiO2 were less active than anticipated. Analysis after FT revealed that all Co-NC on TiO2 as well as 3 nm Co-NC on SiO2 had grown to ~13 nm, while the sizes of the 6 and 9 nm Co-NC on SiO2 had remained stable. It was found that the 3 nm Co-NC on TiO2 already grew to 10 nm during activation in H2. Furthermore, substantial amounts of Co (up to 60%) migrated from the Co-NC to the support during activation on TiO2 against only 15% on SiO2. We showed that the stronger interaction between cobalt and TiO2 leads to enhanced catalyst restructuring as compared to SiO2. These findings demonstrate the potential of the NC-based method to produce relevant model catalysts to investigate phenomena that could not be studied using conventionally synthesized catalysts. PMID- 30416842 TI - Predictors of Mortality in a Clinic Cohort of HIV-1 Infected Children Initiated on Antiretroviral Therapy in Jos, Nigeria. AB - Background: Mortality among human immunodeficiency virus-1 (HIV-1) infected children initiated on antiretroviral therapy (ART) though on a decline still remains high in resource-limited countries (RLC). Identifying baseline factors that predict mortality could allow their possible modification in order to improve pediatric HIV care and reduce mortality. Methods: We conducted a retrospective cohort study analyzing data on 691 children, aged 2 months-15 years, diagnosed with HIV-1 infection and initiated on ART between July 2005 and March 2013 at the pediatric HIV clinic of Jos University Teaching Hospital. Lost to follow-up children were excluded from the analyses. A multivariate Cox proportional hazards model was fitted to identify predictors of mortality. Results: Median follow-up time for the 691 children initiated on ART was 4.4 years (interquartile range (IQR), 1.8-5.9) and at the end of 2752 person-years of follow-up, 32 (4.6%) had died and 659 (95.4%) survived. The mortality rate was 1.0 per 100 child-years of follow-up period. The median age of those who died was about two times lower than that of survivors [1.7 years (IQR, 0.6-3.6) versus 3.9 years (IQR, 3.9-10.3), p<0.001]. On unadjusted Cox regression, the risk of dying was about three and half times more in children <5 years of age compared to those >5 years (p=0.02) Multivariate modeling identified age as the main predictor of death with mortality decreasing by 24% for every 1 year increase in age (Adjusted Hazard Ratio (AHR)=0.76 [0.62-0.94], p=0.013. Conclusion: The lower mortality rate for our study suggests that even in RLC, mortality rates could be reduced given a good standard of care. Early initiation of ART in younger children with close monitoring during follow-up could further reduce mortality. PMID- 30416843 TI - Human Absorbable MicroRNA Prediction based on an Ensemble Manifold Ranking Model. AB - MicroRNAs, a class of short non-coding RNAs, are able to regulate more than half of human genes and affect many fundamental biological processes. It has been long considered synthesized endogenously until very recent discoveries showing that human can absorb exogenous microRNAs from dietary resources. This finding has raised a challenge scientific question: which exogenous microRNAs can be integrated into human circulation and possibly exert functions in human? Here we present a well-designed ensemble manifold ranking model for identifying human absorbable exogenous miRNAs from 14 common dietary species. Specifically, we have analyzed 4,910 dietary microRNAs with 1,120 features derived based on the microRNA sequence and structure. In total, 70 discriminative features were selected to characterize the circulating microRNAs in human and have been used to infer the possibility of a certain exogenous microRNA getting integrated into human circulation. Finally, 461 dietary microRNAs have been identified as transportable exogenous microRNAs. To assess the performance of our ensemble model, we have validated the top predictions through a milk-feeding study. In addition, 26 microRNAs from two virus species were predicted as transportable and have been validated in two external experiments. The results demonstrate the data driven computational model is highly promising to study transportable microRNAs while bypassing the complex mechanistic details. PMID- 30416844 TI - Optogenetics: the new molecular approach to control functions of neural cells in epilepsy, depression and tumors of the central nervous system. AB - The optogenetic tools have been described as valuable techniques to study neural activity through light stimulation, as well as potential neuromodulator approaches in the management of several central nervous system (CNS) diseases. Since the first bacteriorhodopsin protein described as a single-component light activated regulator of transmembrane ion flow description, in 1980's, the focus has been on channel proteins for neurobiology; however, the advances in engineering techniques showed involvement changes in cellular biological behavior in several types of proteins involved in cell cytoskeleton regulation, motility and gene expression. Although the use of this technology has been published in many papers, a question still remains regarding real results and potential clinical applicability in CNS diseases, as well as the publications scarcity that systematically analyses the published results. Lastly, the aim of this review is to discuss the experimental results, molecular mechanisms and potential clinical applications of optogenetic tools in epilepsy and depression treatment, as well as its applicability in the treatment of CNS tumors. PMID- 30416845 TI - The emerging role of circular RNAs in gastric cancer. AB - Gastric cancer (GC) ranks as the fourth most common cancer and the third leading cause of cancer-related death worldwide. Circular RNAs (circRNAs) are a new class of long noncoding RNAs characterized by a single-stranded covalently closed loop structure. Emerging evidence reveals the essential function of circRNAs in the occurrence and development of human diseases. Among these, circRNAs are aberrantly expressed in GC and are involved in the progression of GC. In this review, we briefly summarize the current knowledge of the classification, biogenesis and biological functions of circRNAs, with an emphasis on their relationship with GC. As our understanding of the relation between circRNAs and GC advances, more diagnostic and therapeutic protocols will be developed for the prevention and treatment of GC. PMID- 30416846 TI - Iron and magnetic: new research direction of the ferroptosis-based cancer therapy. AB - Ferroptosis is an iron depend cell death which caused by lipid peroxidation. Abnormal iron metabolism and high intracellular iron content are the characteristics of most cancer cells. Iron is a promoter of cell growth and proliferation. However, iron also could take part in Fenton reaction to produce reactive oxygen species (ROS). The intercellular ROS could induce lipid peroxidation, which is necessary for ferroptosis. Iron metabolism mainly includes three parts: iron uptake, storage and efflux. Therefore, iron metabolism-related genes could regulate intercellular iron content and status, which can be involved ferroptosis. In recent years, the application of nanoparticles in cancer therapy research has become more and more extensive. The iron-based nanoparticles (iron based NPs) can release ferrous (Fe2+) or ferric (Fe3+) in acidic lysosomes and inducing ferroptosis. Magnetic field is widely used in the targeted concentration of iron-based NPs related disease therapy. Furthermore, multiple studies showed that magnetic fields can inhibit cancer cell proliferation by promoting intracellular ROS production. Herein, we focus on the relationship of between ferroptosis and iron metabolism in cancer cells, the application of nanoparticles and magnetic field in inducing ferroptosis of cancer cells, and trying to provide new ideas for cancer treatment research. PMID- 30416847 TI - Promising clinical application of ctDNA in evaluating immunotherapy efficacy. AB - An increasing number of promising immunotherapies and related clinical trials have led to several major breakthroughs in multiple cancers, but a reliable and precise biomarker for evaluating efficacy and prognosis has not yet been established. As a typical representation of a liquid biopsy, circulating cell free DNA (ctDNA) possesses the functions and advantages of tissue biopsy but its distinct advantages of convenience, real-time nature, non-invasiveness and homogeneity make it superior to tissue biopsy. Indeed, compared with routine imaging and tumor markers, ctDNA offers an earlier indication and provides more precise information. ctDNA is reportedly able to identify immunotherapy responders, evaluate efficacy and survival time, screen immune checkpoint inhibitor resistance and pseudo-progress and predict tumor recurrence and metastasis. Thus, ctDNA can act as an "Eagle Eye" by comprehensively monitoring both macro- and micro-changes in the immunotherapy process. Although ctDNA has become a research topic of interest, its limitations cannot be ignored, and improvements in its sensitivity and standardization are urgently needed. This review reveals the advantages and limitations of ctDNA as a precise biomarker and supports the feasibility of using ctDNA detection for common monitoring during immunotherapy. PMID- 30416848 TI - N6-methyladenine RNA modification and cancers. AB - Similar to DNA methylation modifications, N6-methyladenine (m6A) has been identified as a dynamic and reversible modification in messenger RNA (mRNA), regulated by m6A methyltransferases and demethylases. m6A modifications regulate gene expressions and play vital roles in many life processes. Some proteins serve as m6A-binding proteins to perform the m6A-modified biological functions. Recently, m6A modifications have been reported to play critical roles in human cancers, including lung cancer, brain tumor, leukemia, and many others. In this comprehensive review, we have described the roles played by m6A modifications of mRNA in the development of cancers. These modifications appear to have an oncogenic role in some cancers while a tumor-suppressor role in others. Therefore, it would be of great significance to study the biological functions of genes regulated by m6A in different cancers and identify the key m6A target genes to understand the potential mechanism underlying the pathogenesis of cancer. PMID- 30416849 TI - An overview of MCT1 and MCT4 in GBM: small molecule transporters with large implications. AB - Monocarboxylate transporters (MCTs) represent a diverse group of transmembrane proteins encoded by the SLC16 gene family found ubiquitously across mammalian species. Two members of this family, MCT1 and MCT4, have been linked to key roles in the metabolic activity of tissues through the proton-coupled transport of monocarboxylates, most notably L-lactate, ketone bodies, and pyruvate. This review aims to provide an overview of MCT1 and MCT4, followed by the implications of their expression in a multitude of cancers and in glioblastoma (GBM) specifically. Further, the possible mechanisms underlying these effects will be discussed. Given the relationships between MCT1 and MCT4 and cancer, they offer a unique opportunity for novel treatment strategies. We aim to explore current therapies focused on MCT1 and MCT4 and propose future studies to better understand their role in GBM to optimize future treatment regimens. PMID- 30416850 TI - Mismatch repair-based stratification for immune checkpoint blockade therapy. AB - Mismatch repair (MMR) plays a key role in maintaining genomic stability. Mismatch repair deficiency (MMR-D) causes a molecular feature of microsatellite instability (MSI) and contributes to the development of human cancers and genetic diseases with cancer predisposition such as Lynch syndrome. Recent studies have shown that immune checkpoint blockade therapy has a promising response in MMR-D cancers regardless of the tissue of origin. Being able to identify patients with MMR-D cancers is an important challenge in clinical practice. Although immunohistochemistry (IHC) and polymerase chain reaction (PCR)-based MSI analysis combined with a subsequent MMR gene test are used as the standard of care in the clinical setting to identify patients with MMR-D cancers, these methods have limitations as a pan-cancer testing strategy. Next-generation sequencing (NGS) has developed and matured as a clinical option and NGS has advantages for use as a novel testing strategy for MMR-D detection. In this review, we describe the genetic basis of MMR-D, current diagnostic algorithms in the clinical management of MMR-D, the novel NGS approach, and potential detection strategy of anti-cancer immunity biomarkers of MMR-D. PMID- 30416851 TI - FOXA1 transcriptionally up-regulates cyclin B1 expression to enhance chondrosarcoma progression. AB - Chondrosarcoma is a malignant and common bone tumor that is highly resistant to radiation and chemotherapy. At this moment, amputation surgery is the only option which unfortunately has serious impact to daily lives of the patients. Thus, there is an urgent need to understand causative molecular mechanisms underlying the disease for more accurate prognosis and more effective targeted treatment. In the current study, we identify the transcription factor FOXA1 through cDNA microarray screening comparing normal versus chondrosarcoma cells and investigate the mechanisms underlying its function in chondrosarcoma development. We show that FOXA1 enhances expression of the cyclin B1 gene, which in turn drives cell cycle progression through G2-M transition thus promotes cell cycle progression of chondrosarcoma cells. PMID- 30416853 TI - Long non-coding RNA LINC01296 promotes esophageal squamous cell carcinoma cell proliferation and invasion by epigenetic suppression of KLF2. AB - Dysregulated long non-coding RNAs (lncRNAs) are found in many types of tumors, including esophageal squamous cell carcinoma (ESCC); however, the pattern of expression and function of LINC01296 in esophageal squamous cell carcinoma are unknown. In the current study we showed that LINC01296 expression is significantly higher in ESCC tissues when compared with corresponding adjacent normal tissues. Higher LINC01296 expression was associated with lymph node metastasis, TNM stage, and worse overall survival rate in ESCC patients. Furthermore, functional assays in vitro demonstrated that knockdown of LINC01296 inhibited ESCC cell proliferation, colony formation, migration, and invasiveness. Moreover, RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) assays demonstrated that LINC01296 promotes cell proliferation and invasion by epigenetic suppression of KLF2 expression via an interaction with EZH2 in ESCC cells. We also demonstrated that knockdown of LINC01296 inhibited cell growth and up-regulated KLF2 expression in vivo. These results indicate that LINC01296 acts as an oncogene and may serve as a potential target in ESCC treatment. PMID- 30416852 TI - Novel nano-drug combination therapeutic regimen demonstrates significant efficacy in the transgenic mouse model of pancreatic ductal adenocarcinoma. AB - The current work studied the chemopreventive efficacy of orally administered chitosan coated solid-lipid nanoparticle (c-SLN) encapsulated aspirin (ASP), curcumin (CUR) and free sulforaphane (SFN), ACS-cSLN, in the LSL-Kras G12D/+; Pdx 1 Cre/+ transgenic mouse model of pancreatic ductal adenocarcinoma (PDAC). In vitro uptake study and intracellular localization of ODA-FITC labeled ASP and CUR c-SLNs were performed in Panc-1 and MIA PaCa-2 cells by fluorescence microscopy. LSL-Kras G12D/+; Pdx-1 Cre/+ transgenic mice (n = 30) were randomly divided into 5 groups. Treatment groups were orally gavaged with ACS c-SLNs in three doses: low (2 + 4.5 + 0.16 mg/kg), medium (20 + 45 + 1.6 mg/kg) and high (60 + 135 + 4.8 mg/kg), respectively. After 20 weeks of treatment, mice pancreas were harvested, stained with dye and scored according to various pancreatic intraepithelial neoplasms (PanIN) categories by an independent observer. In vitro, cellular uptake evaluated on Panc-1 and MIA PaCa-2 cells resulted in higher fluorescence intensities, indicating increased cellular uptake of ASP and CUR c-SLNs. For further evidence, the addition of lysoID (red fluorescence) demonstrated location and uptake of ASP and CUR c-SLNs into the lysosome. In vivo, treatment with ACS c SLN for 20-weeks did not cause obvious adverse effects on growth and no statistically significant differences in body weight were observed between groups. However, the weight (mean +/- SEM) of pancreas at the end of the study was higher in blank c-SLN group (223.6 +/- 42.2 mg) compared to low (138.0 +/- 26.0 mg; not significant [NS]), medium (145.0 +/- 9.0 mg; NS), and high (133.8 +/ 20.3 mg; NS) ACS c-SLN treated groups, demonstrating the efficacy of ACS c-SLN nanoformulations. The low, medium and high dose of ACS c-SLN combinations exhibited a reduction in tumor incidence (PanIN count) by 16.6% (P < 0.01), 66.8% (P < 0.01), and 83.4% (P < 0.01), respectively. These studies provide further proof for the use of an oral, low dose nanotechnology-based combinatorial regimen for the chemoprevention of PDAC. PMID- 30416854 TI - BRMS1 coordinates with LSD1 and suppresses breast cancer cell metastasis. AB - Breast carcinoma metastasis suppressor gene 1 (BRMS1) encodes an inhibitor of metastasis and is reported in many types of tumor metastasis. However, the mechanism of BRMS1-mediated inhibition of breast cancer metastasis at the transcriptional level remains elusive. Here, we identified using affinity purification and mass spectrometry (MS) that BRMS1 is an integral component of the LSD1/CoREST corepressor complex. Analysis of the BRMS1/LSD1 complex using high-throughput RNA deep sequencing (RNA-seq) identified a cohort of target genes such as VIM, INSIG2, KLK11, MRPL33, COL5A2, OLFML3 and SLC1A1, some of which are metastasis-related. Our results have showed that BRMS1 together with LSD1 are required for inhibition of breast cancer cell migration and invasion. Collectively, these findings demonstrate that BRMS1 executes transcriptional suppression of breast cancer metastasis by associating with the LSD1 and thus can be targeted for breast cancer therapy. PMID- 30416856 TI - Monepantel considerably enhances the therapeutic potentials of PEGylated liposomal doxorubicin and gemcitabine in ovarian cancer: in vitro and in vivo studies. AB - Ovarian cancer is a lethal disease since treated patients often die from relapse. Resistance to current treatment regime involving doxorubicin and gemcitabine is well known. Hence, we set forth to develop a more effective therapy by combining current treatment drugs with monepantel, an antihelminth drug with proven anticancer effect. In vitro cytotoxicity were first investigated with pegylated liposomal doxorubicin (PLD), gemcitabine, monepantel as single agents and then in combination with monepantel on ovarian tumor cells. Drug effect on oncogenic proteins was determined by western blot analysis and resistance to drugs by colony formation assays. Using in vivo model (nude mice), a similar study, as above, was carried out to determine correlation to in vitro findings. Close correlation existed between in vitro and in vivo studies with the latter indicating that combination of monepantel with either low or high dose PLD was more effective compared to single drug therapy. A similar finding existed for gemcitabine, with gemcitabine showing a more superior efficacy (100% ablation) in combination with MPL. Western blot analysis indicated p-mTOR, p70s6K and 4E-BP1 were severely inhibited by combination of MPL with either PLD or gemcitabine. Colony formation assay indicated a dramatic reduction of colonies with combination treatment suggesting a considerable reduction of resistance. After 28 days, treatment using a combination of MPL with either PLD or gemcitabine showed tumor regression. Hence, the combination of gemcitabine or doxorubicin with monepantel may serve as a more effective therapy for ovarian cancer. PMID- 30416855 TI - VEGF-C/Flt-4 axis in tumor cells contributes to the progression of oral squamous cell carcinoma via upregulating VEGF-C itself and contactin-1 in an autocrine manner. AB - Tumor cell-derived vascular endothelial growth factor (VEGF)-C has been primarily implicated in promoting lymphangiogenesis by activating Flt-4 (VEGFR-3) expressed on lymphatic endothelial cells via a paracrine mechanism. Flt4 has also been shown to be expressed selectively in subsets of cancer cells. However, little is known about the functional role of VEGF-C/Flt4 signaling via an autocrine mechanism, as well as the clinicopathological implication of the VEGF-C/Flt4 axis and its downstream effector molecules, in head and neck squamous cell carcinoma (HNSCC), including oral squamous cell carcinoma (OSCC). In the present study, we detected Flt-4 expression selectively in several HNSCC cell lines by quantitative PCR, and its internalization reflecting receptor activation was confirmed by immunocytochemistry in SAS and HO1U1 cells. Flt-4 stimulation upregulated the expression of contactin-1 (CNTN-1, a neural cell adhesion molecule) and VEGF-C itself in SAS cells, while Flt-4 inhibition downregulated the expression of CNTN 1 in both SAS and HO1U1 cells and that of VEGF-C itself in SAS cells. In vitro cell proliferation and migration assays using SAS cells demonstrated that both cell proliferation and migration were promoted by Flt-4 stimulation, while those were suppressed by Flt-4 inhibition. Clinicopathological factors and immunohistochemical expression of Flt-4, VEGF-C, and CNTN-1 in tumor cells were evaluated using surgical specimens from patients with tongue squamous cell carcinoma. We found a significant correlation of CNTN-1 expression with both VEGF C and Flt-4 expression, but not between VEGF-C and Flt-4. Multivariate logistic regression analysis revealed that T classification (P = 0.003), lymphatic invasion (P = 0.024), and Flt-4 expression in tumor cells (P = 0.046) were independently predictive of neck lymph node metastasis. These results suggest that the VEGF-C/Flt-4 axis in tumor cells enhances tumor cell proliferation and migration via upregulating the expression of VEGF-C itself and CNTN-1 in an autocrine manner, thereby contributing to cancer progression of OSCC, including neck metastasis. Hence, targeting the VEGF-C/Flt-4 axis in tumor cells can be an attractive therapeutic strategy for the treatment of cancer. PMID- 30416857 TI - Abnormal expression of YEATS4 associates with poor prognosis and promotes cell proliferation of hepatic carcinoma cell by regulation the TCEA1/DDX3 axis. AB - YEATS domain containing 4 (YEATS4) is usually amplified and functions as an oncogene in several malignancies, such as colorectum, ovarian, breast and lung. However, the biological role of YEATS4 in hepatocellular carcinoma (HCC) has not yet been discussed. Herein, we found that YEATS4 was significantly upregulated in HCC compared to para-cancerous tissues, and was associated with poor prognosis, large tumor size, poor differentiation and distant metastasis. In addition, YEATS4 promoted HCC cell proliferation and colony formation by binding to and increasing the transcriptional activity of the TCEA1 promoter. Concurrently, upregulation of TCEA1 increased the stability of the DDX3 protein, a member of the DEAD box RNA helicase family, and augmented the proliferative and colony forming ability of HCC cells. Furthermore, YEATS4 accelerated tumor growth in vivo in a xenograft HCC model. Taken together, our study provides evidence for the first time on the potential role of the YEATS4/TCEA1/DDX3 axis in regulating HCC progression, and presents YEATS4 as a promising therapeutic target and prognosis maker for HCC. PMID- 30416858 TI - The extrema of circulating miR-17 are identified as biomarkers for aggressive prostate cancer. AB - MicroRNAs (miRNAs) constitute short non-coding RNAs that can post transcriptionally modulate the expression of many oncogenes and tumor suppressor genes engaged in key cellular processes. Deregulated serum miRNA signatures have been detected in various solid cancers including prostate cancer, suggesting that circulating miRNAs could function as non-invasive biomarkers of tumor emergence and progression. To determine whether serum miRNA expression levels are different between patients with aggressive and non-aggressive prostate cancer, we analyzed a panel of miRNAs from the blood of African American (AA) prostate cancer patients using a new recursive partitioning method that allows hypothesis testing of each split. We observed that both extrema of circulating miR-17, i.e. upregulation and downregulation, are associated with aggressive prostate cancer. A similar effect was observed in tumor samples from a separate dataset representing a different population of prostate cancer patients and in AA prostate cancer samples from the TCGA. The dual effect is consistent with the contradictory findings on the role of miR-17 in prostate cancer progression, whereby it controls important oncogenic and tumor-suppressive genes. PMID- 30416859 TI - Predictive value of ERCC1, ERCC2, ERCC4, and glutathione S-Transferase Pi expression for the efficacy and safety of FOLFIRINOX in patients with unresectable pancreatic cancer. AB - The platinum-based chemotherapy regimen FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) is currently used as a standard treatment for patients with unresectable pancreatic cancer. FOLFIRINOX is associated with severe toxicities, including neutropenia, febrile neutropenia, and anorexia; however, there are currently no reliable biomarkers to predict its efficacy and safety. Several studies of patients with various cancers have shown that tumor expression of excision repair cross-complementing (ERCC) proteins and glutathione S-transferase Pi (GSTPi) correlates with the response to platinum-based chemotherapies. Therefore, in this study, we examined the associations between expression of ERCC proteins and GSTPi and the safety and efficacy of FOLFIRINOX in 34 patients with unresectable pancreatic cancer. ERCC1, ERCC2, ERCC4, and GSTPi expression were examined by immunohistochemical staining of tumor specimens and the results were correlated with overall survival, progression-free survival, response rate, disease control rate, and the frequency of grade 3-4 neutropenia and non-hematologic toxicities. We found that ERCC1, ERCC2, ERCC4, and GSTPi were expressed in tumor samples from 64%, 24%, 18%, and 64% of patients, respectively. Notably, there were no statistically significant associations between the expression pattern of any of the proteins and either the clinical outcomes or the frequency of grade 3-4 neutropenia or grade 3-4 anorexia. Collectively, these data indicate that tumor expression of ERCC1, ERCC2, ERCC4, and GSTPi does not predict the safety or efficacy of FOLFIRINOX in patients with pancreatic cancer. PMID- 30416860 TI - Immunotherapy strategy of EGFR mutant lung cancer. AB - EGFR-mutant lung cancer is an important molecular subtype in Asia considering that almost 40%-50% of patients with lung adenocarcinoma in Asian carry the active EGFR mutaiton. People have greatly anticipated the efficacy of PD-1/PD-L1 monoclonal antibody in lung cancer treatment but anti-PD-1/PD-L1 treatment failed to positively affect these patients. The NCCN guidelines do not recommend immunotherapy to patients with NSCLC carrying EGFR mutation at present. However, the reason why EGFR-mutant lung cancer patients show poor response to anti-PD 1/PD-L1 treatment is still unknown. Immune suppression and tolerance are the main characteristics of tumor. The PD-1/PD-L1 co-inhibitory molecule is probably not the main escape route of this tumor type. The main characteristic of EGFR-mutant lung cancer is the activation of the EGFR signaling pathway. EGFR activation is likely responsible for the uninflamed tumor microenvironment of this type tumor and particiaptes in immunosuppression and immune escape. Accumulating evidence proved that activation of EGFR signaling pathway is essential to the generation of Treg and tolerogenic DCs. In this review, we summarize the efficacy of PD-1/PD L1 monoclonal antibiodies in patients with EGFR-mutant lung cancer patients; provide evidence to analyze the potential reason why these patients cannot benefit from anti-PD-1/PD-L1 treatment, and explore the strategy that shoud be adopted in the future. PMID- 30416861 TI - Downregulated miR-621 promotes cell proliferation via targeting CAPRIN1 in hepatocellular carcinoma. AB - MicroRNAs (miRNAs) have been reported to play an essential role in tumor development and progression. However, the function of miR-621 in hepatocellular carcinoma (HCC) remains largely unexplored. In this study, we found that miR-621 was downregulated in the HCC specimens and cell lines, and lower expression of miR-621 indicated poor survival. Overexpression of miR-621 was shown to induce G0/G1 cell cycle arrest and inhibit cell proliferation in vitro and in vivo. Luciferase assays revealed that cell cycle-associated protein 1 (CAPRIN1) is a novel functional downstream target of miR-621. miR-621 could regulate c-MYC and cyclin D2 expression by directly targeting CAPRIN1. Further study revealed that CAPRIN1 was upregulated in the HCC specimens and cell lines. Restoration of CAPRIN1 neutralized the miR-621-induced cell cycle arrest and cell proliferation inhibition. Taken together, our findings suggest that miR-621 acts as a tumor suppressor gene in HCC progression by downregulating CAPRIN1 expression and could be a novel potential diagnostic and prognostic biomarker for HCC. PMID- 30416862 TI - The oncogenic role of MST3 in human gastric cancer. AB - MST3 (mammalian STE20-like kinase) is one of the protein kinase of the GCK III subfamily STE 20, and is known to play a role in cell growth and apoptosis. Our laboratory has demonstrated that MST3 promotes tumorigenicity through the VAV2/Rac1 signal axis in breast cancer. In this report, we further investigated the potential oncogenic role of MST3 in gastric cancer. Examination of tissue samples from 101 gastric cancer patients revealed that higher expression of MST3 was observed in tumor part with immunohistochemistry. Furthermore, high expression of MST3 predicts poor prognosis in gastric cancer patients. To investigate the function of MST3 in vitro, MKN45 and NCI-N87 cell lines were transfected with the MST3 shRNA and stable clones were established. Downregulation of MST3 inhibited cell proliferation. The p21 expression was enhanced by MST3 shRNA in MKN45 gastric cancer cell line. Finally, downregulation of MST3 attenuated the anchorage-independent growth in soft agar and tumor growth in NOD/SCID mice. Altogether, our results indicate that MST3 potentially plays an oncogenic role in gastric cancer. PMID- 30416864 TI - Routine to Rare Risk - A Case Study of Firecracker Explosion Disaster in India. AB - Introduction: In India quite a few religious festivals and cultural fairs are accompanied by public display of fireworks. The grandeur of the festivals is often evaluated by the common man with respect to its colorful firework displays. Firecracker accidents during mass fireworks at public display venues may be disastrous in its consequences and damages. A fire cracker disaster which occurred during a religious public firework display event at Puttingal in Kerala, India was documented and analyzed to figure out the safety concerns and good practices, towards making a reference for effective emergency management. Methods: The fire cracker incident was studied on the broader perspective of disaster management. Inputs from agencies involved in emergency response, casualty management, damage assessment and general administration as well as the perspective of victims and the public who witnessed the event was incorporated in to the study through participatory observation, field visits and face to face discussions. Result: The response followed by the firecracker explosion was analyzed in three phases based on the time frame of response. Influence of traditions and culture in firework organization, the mandatory legal requirements for firework displays and the current safety practices followed were evaluated in the background of this rare firecracker risk which turned out to be a major disaster in the state of Kerala in India. Conclusion: Public display of fireworks in Puttingal temple was organised despite of the legal permission from competitive authority. Negligence of law, non-sensitivity of public towards fire work safety, competitive nature of event organizers and social pressure from religious groups traversed the basic fire work safety requirements, ultimately triggered the largest fire cracker disaster in Kerala. PMID- 30416863 TI - URI knockdown induces autophagic flux in gastric cancer cells. AB - URI, a member of the prefoldin family of molecular chaperones, functions in the regulation of nutrient-sensitive, mTOR-dependent transcription signaling pathways. Previous studies of several tumor types demonstrated that URI exhibits characteristics similar to those of an oncoprotein. URI has been shown as a mitochondrial substrate of S6 kinase 1 (S6K1), which acts to integrate nutrient and growth factor signals to promote cell growth and survival. Notably, the Akt/mTOR/p70S6K signaling pathway constitutes major negative regulatory mechanism of autophagy. However, the role of URI in autophagy has not been explored. Here, we investigated the involvement of URI in autophagy by manipulating its expression in MGC-803 and HGC-27 cells using siRNA and transfection approaches. GFP-LC3 punctum aggregation was assessed by confocal microscopy, whereas formation of autophagic vesicles was assessed using transmission electron microscopy. NH4Cl was used to inhibit autophagosome-lysosome fusion and to monitor autophagic flux. Expression of LC3-I, LC3-II, beclin1, total and phosphorylated mTOR, and p70S6k was assessed by Western blotting. The results showed that knockdown of URI induced significant autophagic flux in gastric cancer cells. URI regulates the expression of beclin1, which is essential for initiation of conventional autophagy. Levels of p-mTOR (Ser2448) and p-p70S6K (Thr389) increased in URI-overexpressing cells treated with the mTOR inhibitor rapamycin but decreased in URI-silenced cells. The inhibitory effect of URI silencing on mTOR and p70S6K phosphorylation was antagonized by the autophagy inhibitor 3-methyladenine. These results suggest that URI knockdown-induced autophagy is associated with the mTOR/p70S6K signaling pathway, indicating the potential existence of a novel autophagy regulatory mechanism mediated by URI. PMID- 30416865 TI - A Mobile-Based Diet Monitoring System for Obesity Management. AB - Personal diet management is key to fighting the obesity epidemic. Recent advances in smartphones and wearable sensor technologies have empowered automated food monitoring through food image processing and eating episode detection, with the goal to conquer drawbacks of traditional food journaling that is labour intensive, inaccurate, and low adherent. In this paper, we present a new interactive mobile system that enables automated food recognition and assessment based on user food images and provides dietary intervention while tracking users' dietary and physical activities. In addition to using techniques in computer vision and machine learning, one unique feature of this system is the realization of real-time energy balance monitoring through metabolic network simulation. As a proof of concept, we have demonstrated the use of this system through an Android application. PMID- 30416866 TI - Microscopy with ultraviolet surface excitation for rapid slide-free histology. AB - Histologic examination of tissues is central to the diagnosis and management of neoplasms and many other diseases, and is a foundational technique for preclinical and basic research. However, commonly used bright-field microscopy requires prior preparation of micrometre-thick tissue sections mounted on glass slides, a process that can require hours or days, that contributes to cost, and that delays access to critical information. Here, we introduce a simple, non destructive slide-free technique that within minutes provides high-resolution diagnostic histological images resembling those obtained from conventional haematoxylin-and-eosin-histology. The approach, which we named microscopy with ultraviolet surface excitation (MUSE), can also generate shape and colour contrast information. MUSE relies on ~280-nm ultraviolet light to restrict the excitation of conventional fluorescent stains to tissue surfaces, and it has no significant effects on downstream molecular assays (including fluorescence in situ hybridization and RNA-seq). MUSE promises to improve the speed and efficiency of patient care in both state-of-the-art and low-resource settings, and to provide opportunities for rapid histology in research. PMID- 30416867 TI - Investigation of femtosecond laser induced ripple formation on copper for varying incident angle. AB - The hydrodynamic mechanisms associated with the formation of femtosecond laser induced ripples on copper for two angles of incidence are reported. Laser pulse length used for this work is 35 fs. A revised two-temperature model is presented that comprises transient changes of optical characteristics during the irradiation with femtosecond pulses to model relaxation processes and thermal response in bulk copper. The theoretical model takes into account the fluid flow dynamics that result in ripple periods shorter than the wavelength of the surface plasmon polaritons. Theoretical and experimental results are reported for incident angles of 0 degrees and 45 degrees relative to the surface normal. There is agreement between the experimentally measured and the theoretically predicted ripple periodicity for 50 pulses at 0 degrees incidence. By contrast, for 100 pulses at 0 degrees incidence, and 50 and 100 pulses at 45 degrees incidence, the experimentally measured ripples have a larger period than the one predicted by the model while the trends in period with increased incident angle, and increased fluence are in agreement between the experimental and the theoretical results. PMID- 30416868 TI - Multi-Layer Multi-View Classification for Alzheimer's Disease Diagnosis. AB - In this paper, we propose a novel multi-view learning method for Alzheimer's Disease (AD) diagnosis, using neuroimaging and genetics data. Generally, there are several major challenges associated with traditional classification methods on multi-source imaging and genetics data. First, the correlation between the extracted imaging features and class labels is generally complex, which often makes the traditional linear models ineffective. Second, medical data may be collected from different sources (i.e., multiple modalities of neuroimaging data, clinical scores or genetics measurements), therefore, how to effectively exploit the complementarity among multiple views is of great importance. In this paper, we propose a Multi-Layer Multi-View Classification (ML-MVC) approach, which regards the multi-view input as the first layer, and constructs a latent representation to explore the complex correlation between the features and class labels. This captures the high-order complementarity among different views, as we exploit the underlying information with a low-rank tensor regularization. Intrinsically, our formulation elegantly explores the nonlinear correlation together with complementarity among different views, and thus improves the accuracy of classification. Finally, the minimization problem is solved by the Alternating Direction Method of Multipliers (ADMM). Experimental results on Alzheimers Disease Neuroimaging Initiative (ADNI) data sets validate the effectiveness of our proposed method. PMID- 30416869 TI - Family Background, Private Tutoring, and Children's Educational Performance in Contemporary China. AB - The prevalence of private tutoring is often noted in the literature on education in East Asia. Empirical evidence concerning the causes and consequences of private tutoring, however, is sparse, especially for China. In this article, we draw upon data from the 2010 China Family Panel Studies to explore whether children's tutoring experiences are influenced by family background and whether private tutoring benefits children's educational performance. Our empirical analyses show that higher parental education, higher family income, and fewer siblings are all associated with a higher likelihood of private tutoring and higher levels of spending on it. Furthermore, private tutoring and spending on tutoring are predictive of higher verbal and math performances, although the difference in math performance between children who received private tutoring and those who did not is statistically insignificant after controlling for family background. PMID- 30416870 TI - Knowledge and Attitudes Towards Fluoride Supplementation: A Survey of Pediatric Medical and Dental Providers in the State of Hawai'i. AB - Hawai'i has the lowest rate of community water fluoridation in the nation, which has contributed to poor oral health for children statewide. When properly prescribed, the benefits of fluoride supplementation for oral health outweigh any potential side effects to the body. Official recommendations give pediatric healthcare providers the authority to prescribe fluoride supplements and guide parents in daily usage. However, knowledge of actual practice and adherence for both providers and patients have never been examined in Hawai'i. This study aims to evaluate pediatric healthcare providers' attitudes, knowledge, and practices, regarding fluoride supplementation. A 37-item survey was developed investigating these domains, and was distributed to pediatric dentists, family practitioners, and pediatricians in the state. One hundred and three responses were collected during the time period of May 2014 through May 2015. Descriptive and bivariate associations with several outcomes were assessed. The majority (87%) reported at least some knowledge of the official guidelines. There was uncertainty in knowledge of fluorosis and the seriousness of the health risk. A recent educational session on fluoride was associated with more knowledge of the guidelines and the signs and symptoms of fluorosis. The majority of providers started fluoride at the recommended age whereas there was more variablility on stopping fluoride. On the patient side, providers reported that 67% of the parents forget to administer and 53% reported that their child does not like the taste. This study provides some information regarding the clinical use of fluoride supplementation in children. More efforts are needed to raise awareness in a consistent manner by both the dental and medical communities on the importance of fluoride supplementation to promote oral health in children while addressing concerns of professionals and the community. PMID- 30416871 TI - High Prevalence of Non-Communicable Disease Risk Factors among Adolescents in Pohnpei, Micronesia. AB - Non-communicable disease (NCD) related behaviors among adolescents are on the rise globally and in the Pacific region. To better understand and elucidate the prevalence of NCD risk factors among adolescents in Pohnpei state, Federated States of Micronesia, a cross-sectional study was conducted among secondary school students. Of 2965 students enrolled in the 2015-2016 academic year, 2555 (86.2%) completed the survey, and 2386 (80.5%) were included in the final analysis. Of the survey respondents, 21.7% of students self-reported smoking tobacco in the past 30 days, 30.3% self-reported drinking alcohol in the past 30 days, 40.9% self-reported chewing betel nut in the past 30 days, and 21.2% self reported chewing tobacco with or without betel nut in the last 30 days. Male students, older students, and public school students had higher prevalence of substance use. Additionally, about 17.3% of students were overweight and 10.1% were obese according to physical measures of height and weight. Female students and private school students had higher prevalence of overweight and obesity than male students, and prevalence of overweight was higher in older age groups. These findings indicate a cohort of adolescents at substantial risk for the development of NCDs and signal an urgent need for public health interventions to address NCD risk factors. PMID- 30416872 TI - Are There Gender Differences in the Psychological Effects of Ethnic Identity and Discrimination in Hawai'i? AB - The purpose of this study is to investigate whether there are gender differences in the psychological effects of ethnic identity and discrimination in Hawai'i. Using data from an anonymous survey of undergraduate students (N = 1,033) at a university in Hawai'i, regression results revealed that higher levels of ethnic identification were associated with significantly lower levels of depressive symptoms. This association was statistically significant (P < .001), adjusting for gender, age, socioeconomic status, racial/ethnic group, mixed racial/ethnic status, years living in Hawai'i, immigrant status, and discrimination. Interaction effects (b = 2.55; P < .05) further indicated that the inverse relationship between ethnic identity and symptoms of depression was stronger for men than women. Also, everyday discrimination was significantly more psychologically distressing for women (b = 0.19; P < .05) than men. Overall, these findings suggest that a strong ethnic identity, which encompasses ethnic pride and knowledge, involvement in ethnic practices, and a cultural commitment or feeling of belonging to one's ethnic group, significantly benefits mental health, and to a greater extent among men. Although the chronic stress of discrimination (not necessarily due to race/ethnicity) was linked with increased levels of distress among both men and women, it was significantly more intense among women. Future research is needed to uncover why the mental health consequences of everyday discrimination and a salient ethnic identity would be different for young men and women in this cultural context and whether this holds true in other locations in the United States. PMID- 30416873 TI - Medical School Hotline: Student Reactions to Receiving Their Acceptance Letter to the John A. Burns School of Medicine. PMID- 30416874 TI - Insights in Public Health: Data Highlights from the Hawai'i Youth Risk Behavior Survey: Links Between Academic Achievement and Health Behaviors. AB - The Youth Risk Behavior Survey is administered biennially in odd years to public middle and high school students in Hawai'i. Data highlights are presented from Hawaii's 2017 high school survey results to enhance understanding of the relationship between health and academic achievement. This article reviews a select set of health-risk behaviors and their association with academic grades for Hawai'i public school students. The findings demonstrate that students who self-reported engaging in health protective behaviors also reported higher academic grades in school, while those who engaged in health-risk behaviors were more likely to report lower grades in school. This discussion can provide useful background information and benchmarks for research, policy, and local initiatives. It also supports the need for continued collaboration and a synergistic approach between education and health partners in Hawai'i in order to improve the health and academic achievement of our youth. PMID- 30416875 TI - Hawai'i Journal Watch: Highlights of recent research from the University of Hawai'i and the Hawai'i State Department of Health. PMID- 30416877 TI - The General Factor of Psychopathology and Personality. PMID- 30416878 TI - Genetic population structure of the pelagic mollusk Limacina helicina in the Kara Sea. AB - Background: Pelagic pteropods Limacina helicina are widespread and can play an important role in the food webs and in biosedimentation in Arctic and Subarctic ecosystems. Previous publications have shown differences in the genetic structure of populations of L. helicina from populations found in the Pacific Ocean and Svalbard area. Currently, there are no data on the genetic structure of L. helicina populations in the seas of the Siberian Arctic. We assessed the genetic structure of L. helicina from the Kara Sea populations and compared them with samples from around Svalbard and the North Pacific. Methods: We examined genetic differences in L. helicina from three different locations in the Kara Sea via analysis of a fragment of the mitochondrial gene COI. We also compared a subset of samples with L. helicina from previous studies to find connections between populations from the Atlantic and Pacific Oceans. Results: 65 individual L. helinica from the Kara Sea were sequenced to produce 19 different haplotypes. This is comparable with numbers of haplotypes found in Svalbard and Pacific samples (24 and 25, respectively). Haplotypes from different locations sampled around the Arctic and Subarctic were combined into two different groups: H1 and H2. The H2 includes sequences from the Kara Sea and Svalbard, was present only in the Atlantic sector of the Arctic. The other genetic group, H1, is widespread and found throughout all L. helicina populations. phi ST analyses also indicated significant genetic difference between the Atlantic and Pacific regions, but no differences between Svalbard and the Kara Sea. Discussion: The obtained results support our hypothesis about genetic similarity of L. helicina populations from the Kara Sea and Svalbard: the majority of haplotypes belongs to the haplotype group H2, with the H1 group representing a minority of the haplotypes present. In contrast, in the Canadian Arctic and the Pacific Ocean only haplogroup H1 is found. The negative values of Fu's Fs indicate directed selection or expansion of the population. The reason for this pattern could be an isolation of the Limacina helicina population during the Pleistocene glaciation and a subsequent rapid expansion of this species after the last glacial maximum. PMID- 30416879 TI - Optimization of the cytogenetic protocol for Pangasianodon hypophthalmus (Sauvage, 1878) and Clarias gariepinus (Burchell, 1822). AB - To obtain well spread chromosomes, the cytogenetic protocol for Pangasianodon hypophthalmus and Clarias gariepinus were optimized. This includes, the colchicine concentration (0.01%, 0.025%, 0.05%)/exposure duration (1, 3, and 5 h), hypotonic solution (distilled water or 0.075M KCl solution)/exposure duration (30 min, 1, and 2 h), the time of cell suspension preparation (at hypotonic treatment or before slide preparation) and chromosome aging period (0, 3, and 7 days in Carnoy's fixative). In addition, the type (i.e., fin, gill or kidney) and the amount of tissue (10, 50, 100 or 150 mg) were also investigated. Regardless of the species, the result obtained showed that well-spread chromosomes could be obtained using the following optimized protocol: Juveniles are injected with 0.05% colchicine (at one ml kg-1) and allowed to swim for 3 h. Then, 50 mg of gill tissue is made into cell suspension in 0.075M KCl for 1 h. The cell suspension is treated in Carnoy's fixative (changed three times at 20 min interval) and then aged for 3 days. Finally, chromosome slides are made and stained with 10% Giemsa for 1 h. PMID- 30416880 TI - Sexual dimorphism in the Arachnid orders. AB - Sexual differences in size and shape are common across the animal kingdom. The study of sexual dimorphism (SD) can provide insight into the sexual- and natural selection pressures experienced by males and females in different species. Arachnids are diverse, comprising over 100,000 species, and exhibit some of the more extreme forms of SD in the animal kingdom, with the males and females of some species differing dramatically in body shape and/or size. Despite this, research on arachnid SD has primarily focused on specific clades as opposed to observing traits across arachnid orders, the smallest of which have received comparatively little attention. This review provides an overview of the research to date on the trends and potential evolutionary drivers for SD and sexual size dimorphism (SSD) in individual arachnid orders, and across arachnids as a whole. The most common trends across Arachnida are female-biased SSD in total body size, male-biased SSD in relative leg length and SD in pedipalp length and shape. However, the evolution of sexually dimorphic traits within the group is difficult to elucidate due to uncertainty in arachnid phylogenetic relationships. Based on the dataset we have gathered here, we highlight gaps in our current understanding and suggest areas for future research. PMID- 30416881 TI - Unimodal head-width distribution of the European eel (Anguilla anguilla L.) from the Zeeschelde does not support disruptive selection. AB - Since the early 20th century, European eels (Anguilla anguilla L.) have been dichotomously classified into 'narrow' and 'broad' heads. These morphs are mainly considered the result of a differential food choice, with narrow heads feeding primarily on small/soft prey and broad heads on large/hard prey. Yet, such a classification implies that head-width variation follows a bimodal distribution, leading to the assumption of disruptive selection. We investigated the head morphology of 272 eels, caught over three consecutive years (2015-2017) at a single location in the Zeeschelde (Belgium). Based on our results, BIC favored a unimodal distribution, while AIC provided equal support for a unimodal and a bimodal distribution. Notably, visualization of the distributions revealed a strong overlap between the two normal distributions under the bimodal model, likely explaining the ambiguity under AIC. Consequently, it is more likely that head-width variation followed a unimodal distribution, indicating there are no disruptive selection pressures for bimodality in the Zeeschelde. As such, eels could not be divided in two distinct head-width groups. Instead, their head widths showed a continuum of narrow to broad with a normal distribution. This pattern was consistent across all maturation stages studied here. PMID- 30416882 TI - Host anemone size as a determinant of social group size and structure in the orange clownfish (Amphiprion percula). AB - The size and structure of social groups of animals can be governed by a range of ecological factors and behavioral interactions. In small, highly site-attached coral reef fishes, group size is often constrained by the size of the habitat patch they are restricted to. However, group size may also be influenced by changes in abundance along important environmental gradients, such as depth or distance offshore. In addition, the body size and sex structure within social groups can be determined by the size of the habitat patch and the dominance relationships among group members. Here we examined the roles of ecological factors and behavioral interactions in governing group size and structure in the orange clownfish, Amphiprion percula, on inshore reefs in Kimbe Bay, Papua New Guinea. We quantified relationships between ecological variables (anemone size, depth, and distance from shore) and social group variables (group size, and total body length of the three largest individuals (ranks 1, 2, and 3)). Anemone size explained the greatest amount of variation in group variables, with strong, positive relationships between anemone surface area and group size, and total length of individuals ranked 1, 2, and 3. Group structure was also weakly correlated with increasing depth and distance from shore, most likely through the indirect effects of these environmental gradients on anemone size. Variation in group size and the lengths of ranks 2 and 3 were all closely related to the length of rank 1. Path analysis indicated that anemone size has a strong direct effect on the length of rank 1. In turn, the length of rank 1 directly affects the size of the subordinate individuals and indirectly affects the group size through its influence on subordinates. Hence, anemone size directly and indirectly controls social group size and structure in this space-limited fish species. It is also likely that anemonefish have feedback effects on anemone size, although this could not be differentiated in the path analysis. PMID- 30416883 TI - Effects of mixed reality head-mounted glasses during 90 minutes of mental and manual tasks on cognitive and physiological functions. AB - Background: We evaluated the effects of a mixed reality (MR) head-mounted deviceon some cognitiveand physiological functions during 90 min tasks in an attempt to determine their safety for workers. Methods: A total of 12 volunteers performed 90-min intellectual and manual tasks with and without MR glasses. Balance, Stroop, and memory tests were conducted before, during and after these tasks. Heart rate and electromyographic activity of some muscles were recorded. A survey was used to determine subjective fatigue, pain, or discomfort. Results: Balance, heart rate, rate of perceived exertion, memory, and attention were unaffected by wearing MR glasses. Electromyographic activity increased with MR glasses for deltoid, biceps brachii, and soleus muscles. Few subjects reported discomfort, pain, or visual fatigue with MR glasses. Some participants reported they lost the notion of time and reality. Discussion: Accordingly, we concluded that the MR glasses under investigation (Hololens) can be used safely. An appropriate setup and familiarization are needed to optimize use. PMID- 30416885 TI - All you can eat: the functional response of the cold-water coral Desmophyllum dianthus feeding on krill and copepods. AB - The feeding behavior of the cosmopolitan cold-water coral (CWC) Desmophyllum dianthus (Cnidaria: Scleractinia) is still poorly known. Its usual deep distribution restricts direct observations, and manipulative experiments are so far limited to prey that do not occur in CWC natural habitat. During a series of replicated incubations, we assessed the functional response of this coral feeding on a medium-sized copepod (Calanoides patagoniensis) and a large euphausiid (Euphausia vallentini). Corals showed a Type I functional response, where feeding rate increased linearly with prey abundance, as predicted for a tentaculate passive suspension feeder. No significant differences in feeding were found between prey items, and corals were able to attain a maximum feeding rate of 10.99 mg C h-1, which represents an ingestion of the 11.4% of the coral carbon biomass per hour. These findings suggest that D. dianthus is a generalist zooplankton predator capable of exploiting dense aggregations of zooplankton over a wide prey size-range. PMID- 30416884 TI - Structural and functional analysis of the roles of the HCV 5' NCR miR122 dependent long-range association and SLVI in genome translation and replication. AB - The hepatitis C virus RNA genome possesses a variety of conserved structural elements, in both coding and non-coding regions, that are important for viral replication. These elements are known or predicted to modulate key life cycle events, such as translation and genome replication, some involving conformational changes induced by long-range RNA-RNA interactions. One such element is SLVI, a stem-loop (SL) structure located towards the 5' end of the core protein-coding region. This element forms an alternative RNA-RNA interaction with complementary sequences in the 5' untranslated regions that are independently involved in the binding of the cellular microRNA 122 (miR122). The switch between 'open' and 'closed' structures involving SLVI has previously been proposed to modulate translation, with lower translation efficiency associated with the 'closed' conformation. In the current study, we have used selective 2'-hydroxyl acylation analysed by primer extension to validate this RNA-RNA interaction in the absence and presence of miR122. We show that the long-range association (LRA) only forms in the absence of miR122, or otherwise requires the blocking of miR122 binding combined with substantial disruption of SLVI. Using site-directed mutations introduced to promote open or closed conformations of the LRA we demonstrate no correlation between the conformation and the translation phenotype. In addition, we observed no influence on virus replication compared to unmodified genomes. The presence of SLVI is well-documented to suppress translation, but these studies demonstrate that this is not due to its contribution to the LRA. We conclude that, although there are roles for SLVI in translation, the LRA is not a riboswitch regulating the translation and replication phenotypes of the virus. PMID- 30416886 TI - Canadian packaged gluten-free foods are less nutritious than their regular gluten containing counterparts. AB - Background: A strict gluten-free (GF) diet is required for the management of celiac disease (CD). The nutritional adequacy of this diet has been questioned due to the elimination of wheat, an important vehicle for micronutrient fortification and source of fibre. While novel and/or reformulated packaged GF products have rapidly entered the marketplace, providing alternatives to wheat based staples, it is unknown whether these new products are nutritionally comparable. Methods: From a database of 3,851 foods collected across 21 grocery stores in Eastern Canada, we compared the nutrient content of 398 unique GF items with 445 gluten-containing (GC) equivalents. Wilcoxon rank tests were conducted on listed nutrient content (g, mg, ug) per 100 g of product and the nutrient contribution of iron, folate and fibre were evaluated using Health Canada's nutrient claim regulations. Results: GF staples (cereals, breads, flours, pastas) contained 1.3 times more fat and less iron (by 55%), folate (by 44%) and protein (by 36%), than GC counterparts (P < 0.0001). On average, GF pastas had only 37% of the fibre in GC pastas (P < 0.0001). Notably, GF and GC flours were equivalent in nutrient content. Despite GF and GC flours having similar nutritional content, the vast majority of the processed GF foods fell short in key nutrients. Discussion: Packaged GF foods in Canada are generally less nutritious than their GC counterparts, suggesting that GF diets should not be promoted to those who do not require it. The use of nutrient-dense GF flours in homemade foods may improve nutrient intakes on the GF diet. PMID- 30416887 TI - Sociality genes are associated with human-directed social behaviour in golden and Labrador retriever dogs. AB - Background: Dogs have human-directed social skills that allow them to communicate and cooperate with humans. We have previously identified two loci on chromosome 26 associated with human contact-seeking behaviors during an unsolvable problem task in laboratory beagles (Persson et al., 2016). The aim of the present study was to verify the single nucleotide polymorphisms (SNPs) in additional dog breeds. We also studied how the allele frequencies have changed during domestication and recent selection. Methods: Dogs of two breeds, 61 golden retrievers and 100 Labrador retrievers, were phenotyped and genotyped, and 19 wolves were genotyped. The Labrador retrievers were divided into common and field type by pedigree data to make it possible to study the effects of recent selection. All dogs were tested in an unsolvable problem task where human directed social behaviors were scored. DNA from dogs (buccal swabs) and wolves (blood or brain tissue) was analyzed for genotype on two of the previously identified SNP markers, BICF2G630798942 (SNP1) and BICF2S23712114 (SNP2), by pyrosequencing. Results: There was genetic variation for SNP1 in both dog breeds whereas the wolves were fixed for this polymorphism, and for SNP2 there was variation in both dogs and wolves. For both SNPs, Labrador retriever types differed significantly in allele frequencies. We found associations between SNPs and human-directed social behavior in both dog breeds. In golden retrievers, SNP1 was associated with physical contact variables, for example, with the duration of physical contact with the owner (F 2,56 = 4.389, p = 0.017). SNP2 was associated with several behavioral variables in both breeds, among others owner gazing frequency in both golden retrievers (F 2,55 = 6.330, p = 0.003) and Labradors (F 1,93 = 5.209, p = 0.025). Discussion: Our results verify the association between the previously identified SNPs and human-directed social behavior scored in an unsolvable problem task. Differences in allele frequencies suggest that these loci have been affected by selection. The results indicate that these genomic regions are involved in human-directed social behavior in not only beagles but in other dog breeds as well. We hypothesize that they may have been important during dog domestication. PMID- 30416888 TI - Experimental food supplementation increases reproductive effort in the Variable Antshrike in subtropical Brazil. AB - Food limitation may interact with nest predation and influence nesting patterns, such as breeding season length and renesting intervals. If so, reproductive effort should change with food availability. Thus, when food is limited, birds should have fewer attempts and shorter seasons than when food is not limiting. Here we experimentally test that increased food availability results in increased reproductive effort in a fragmented landscape in the Variable Antshrike (Thamnophilus caerulescens) in southern Brazil. We followed nesting pairs in a naturally fragmented habitat and experimentally supplemented food for half of those pairs. Birds were seen, but evidence of nesting was never found in two small fragments, even though these fragments were larger than individual territories. Pairs with supplemented food were more likely to increase clutch size from two to three eggs and tended to renest sooner (20 d on average) than control pairs. Also, fragment size was associated with breeding patterns, although fragment replicates were unavailable. Nest duration, nest success and breeding season length were all greater, while renesting intervals were shorter, in the largest fragments. Simulations showed that only the largest fragments were able to have a net production of young. Food availability clearly influenced reproductive effort and as a consequence, because of the interaction with predation risk, forest fragments of varying sizes will have complex reproductive dynamics. PMID- 30416889 TI - Trait-based predation suitability offers insight into effects of changing prey communities. AB - Increasing environmental pressures and human impacts are reshaping community structures and species interactions throughout all trophic levels. The morphological and behavioural characteristics of species communities contain key ecological information on why prey species appear attractive to predators but are rarely applied when exploring predator-prey (PP) relationships. Expanding our knowledge on how changing prey communities can alter the food resource suitability (RS) for predators is vital for understanding PP dynamics in changing ecosystems. Detailed predator diet data are commonly restricted to commercially important species and often not available over long temporal scales. To find out whether structural changes of prey communities impact the food RS for predator communities over space and time, we apply a novel framework to describe and interpret changes in predator diet-suitability based on predation-relevant traits of prey. We use information on described feeding links from the literature to compile the prey spectrum for each predator and subsequently translate the prey species into a prey-trait spectrum. For each predator, we then calculate a frequency-based prey-trait affinity score and relate it to the available food resource pool, the community weighted means of prey traits, resulting in a prey suitability measure. We aim to reveal whether a described multi-decadal change in the community structure of zoobenthos had an impact on the food suitability for the benthic-feeding fish in a coastal system of the Baltic Sea. We assess the direction of change in resource quality from the perspective of benthic-feeding fish and describe predator-specific responses to examine which species are likely to profit or be disadvantaged by changes in their prey spectrum. Furthermore, we test the relationship between functional diversity of prey communities and food suitability for predators, and whether predation linkage-structures are affected through prey community-changes. Our results show that changes in zoobenthic communities had a positive effect on the food suitability for most benthic feeding fish, implying more suitable food resources. Species-specific responses of predators suggest varying plasticity to cope with prey assemblages of different trait compositions. Additionally, the functional diversity of zoobenthos had a positive effect on the food suitability for predator fish. The changing trait compositions of prey influenced the PP linkage-structure, indicating varying specialisation of benthic feeding fish towards available food resources. Our findings suggest that changing morphological characteristics of prey can impact food RS features for its predators. This approach enables long term evaluation of prey quality characteristics where no detailed diet data is available and allows for cross-system comparison as it is not relying on taxonomic identities per se. PMID- 30416890 TI - Mapping the distribution of scale-rayed wrasse Acantholabrus palloni in Swedish Skagerrak using angling records. AB - In this paper, we map the distribution of scale-rayed wrasse Acantholabrus palloni in eastern Skagerrak based on a combination of verified and personally communicated angling records. Long thought to be occasional vagrants outside its known range in the eastern Atlantic Ocean and Mediterranean Sea, we ask if this rare and understudied labrid has expanded its range and become established in Swedish waters. A recent surge in verified angling records in the Swedish Anglers Association's specimen database Storfiskregistret provides information to suggest that this species should no longer be considered an occasional guest, but rather a species established in the Swedish parts of Skagerrak. These records are supported by additional personal communications with anglers. The species is currently well spread geographically along the Swedish Skagerrak coast, with many locations providing repeated captures of adult fish over multiple years. The typical Swedish catch sites are rocky reefs located between the general 40- and 80-m depth curves, likely influenced by currents bringing higher-salinity water from the North Sea. The present study show that angling records can provide an important, but underutilized, resource for mapping the distribution of data deficient fish species. PMID- 30416891 TI - Facile and Low Environmental Impact Approach to Prepare Thermally Conductive Nanocomposites Based on Polylactide and Graphite Nanoplatelets. AB - In this work, the preparation of nanocomposites based on poly(l-lactide) PLLA and graphite nanoplatelets (GNP) was assessed by applying, for the first time, the reactive extrusion (REX) polymerization approach, which is considered a low environmental impact method to prepare polymer systems and which allows an easy scalability. In particular, ad hoc synthesized molecules, constituted by a pyrene end group and a poly(d-lactide) (PDLA) chain (Pyr-d), capable of interacting with the surface of GNP layers as well as forming stereoblocks during the ring-opening polymerization (ROP) of l-lactide, were used. The nanocomposites were synthesized by adding to l-lactide the GNP/initiator system, prepared by dispersing the graphite in the acetone/Pyr-d solution, which was dried after the sonication process. DSC and X-ray diffraction measurements evidenced the stereocomplexation of the systems synthesized by using the pyrene-based initiators, whose extent turned out to depend on the PDLA chain length. All the prepared nanocomposites, including those synthesized starting from a classical initiator, that is, 1 dodecanol, retained similar electrical conductivity, whereas the thermal conductivity was found to increase in the stereocomplexed samples. Preferential localization of stereocomplexed PLA close to the interface with GNP was demonstrated by scanning probe microscopy (SPM) techniques, supporting an important role of local crystallinity in the thermal conductivity of the nanocomposites. PMID- 30416892 TI - Platinum Recovery from Industrial Process Solutions by Electrodeposition-Redox Replacement. AB - In the current study, platinum-present as a negligible component (below 1 ppb, the detection limit of the HR-ICP-MS at the dilutions used) in real industrial hydrometallurgical process solutions-was recovered by an electrodeposition-redox replacement (EDRR) method on pyrolyzed carbon (PyC) electrode, a method not earlier applied to metal recovery. The recovery parameters of the EDRR process were initially investigated using a synthetic nickel electrolyte solution ([Ni] = 60 g/L, [Ag] = 10 ppm, [Pt] = 20 ppm, [H2SO4] = 10 g/L), and the results demonstrated an extraordinary increase of 3 * 105 in the [Pt]/[Ni] on the electrode surface cf. synthetic solution. EDRR recovery of platinum on PyC was also tested with two real industrial process solutions that contained a complex multimetal solution matrix: Ni as the major component (>140 g/L) and very low contents of Pt, Pd, and Ag (i.e., <1 ppb, 117 and 4 ppb, respectively). The selectivity of Pt recovery by EDRR on the PyC electrode was found to be significant-nanoparticles deposited on the electrode surface comprised on average of 90 wt % platinum and a [Pt]/[Ni] enrichment ratio of 1011 compared to the industrial hydrometallurgical solution. Furthermore, other precious metallic elements like Pd and Ag could also be enriched on the PyC electrode surface using the same methodology. This paper demonstrates a remarkable advancement in the recovery of trace amounts of platinum from real industrial solutions that are not currently considered as a source of Pt metal. PMID- 30416893 TI - Passive Self Resonant Skin Patch Sensor to Monitor Cardiac Intraventricular Stroke Volume Using Electromagnetic Properties of Blood. AB - This paper focuses on the development of a passive, lightweight skin patch sensor that can measure fluid volume changes in the heart in a non-invasive, point-of care setting. The wearable sensor is an electromagnetic, self-resonant sensor configured into a specific pattern to formulate its three passive elements (resistance, capacitance, and inductance). In an animal model, a bladder was inserted into the left ventricle (LV) of a bovine heart, and fluid was injected using a syringe to simulate stoke volume (SV). In a human study, to assess the dynamic fluid volume changes of the heart in real time, the sensor frequency response was obtained from a participant in a 30 degrees head-up tilt (HUT), 10 degrees HUT, supine, and 10 degrees head-down tilt positions over time. In the animal model, an 80-mL fluid volume change in the LV resulted in a downward frequency shift of 80.16 kHz. In the human study, there was a patterned frequency shift over time which correlated with ventricular volume changes in the heart during the cardiac cycle. Statistical analysis showed a linear correlation [Formula: see text] and 0.87 between the frequency shifts and fluid volume changes in the LV of the bovine heart and human participant, respectively. In addition, the patch sensor detected heart rate in a continuous manner with a 0.179% relative error compared to electrocardiography. These results provide promising data regarding the ability of the patch sensor to be a potential technology for SV monitoring in a non-invasive, continuous, and non-clinical setting. PMID- 30416894 TI - Isolated Laryngeal Amyloidosis Mimicking Laryngeal Cancer. AB - Amyloidosis is the deposition of an extracellular fibrillar protein in the tissues leading to organ dysfunction. Laryngeal amyloidosis is a rare phenomenon. We report a case of isolated laryngeal amyloidosis which was initially suspicious for laryngeal cancer on magnetic resonance imaging (MRI) but histopathology showed the presence of amyloid. Systemic workup was negative. The patient is being managed conservatively. PMID- 30416895 TI - The Killer Virus Called Nipah: A Review. AB - Nipah virus (NiV) is a deadly virus with a high mortality rate that has affected many developing countries in the past. According to the Centers for Disease Control and Prevention (CDC), many economically deprived countries such as Madagascar, Cambodia, and Thailand are also at high risk for future outbreaks. The first case of NiV was reported in 1998 and almost two decades later, little scientific progress has been made in finding a proper treatment and prevention vaccine. As many developing countries are not properly equipped to fight the infection, it is vital to properly educate the health systems. The aim of this review is to provide an epidemiological background as well as to understand the transmission routes, presentation, and the diagnosis and prevention of this deadly virus. PMID- 30416897 TI - A Rare Variant of Penile Squamous Cell Carcinoma in a Man with Paraplegia. AB - Verrucous carcinoma (VC) is a rare variant of squamous cell carcinoma (SCC). It is described as a low grade, slow growing, locally infiltrative neoplasm that accounts for 3%-8% of penile SCCs. Here we report a case of destructive VC of the glans penis in a paraplegic man resulting in a hypospadias from the tip of the glans to the corona. Histology demonstrated exophytic squamous epithelial proliferation with characteristic round, pushing borders. In situ hybridization was positive for both low-risk and high-risk strains of human papillomavirus. PMID- 30416896 TI - A Review of Three New Anti-interleukin-5 Monoclonal Antibody Therapies for Severe Asthma. AB - Asthma is a chronic respiratory condition that is characterized by reversible airflow obstruction. Interleukin-5 (IL-5) is involved in the pathophysiology of the disease and drugs targeting IL-5 have been studied for years as a possible treatment option for severe asthma. In this review, the authors searched PubMed for major drug therapies and clinical trials against IL-5. A total of 29 articles met the criteria for selection and were shortlisted; of these, 10 papers were on benralizumab, 14 on mepolizumab, and five on reslizumab. The three drugs proved to be safe and efficacious for patients with severe asthma, leading to decreased rates of asthma exacerbations, lowered levels of eosinophils, and improved pulmonary functions in various studies. Patients also reported an improvement in the quality of life. The side effects of these three drugs were mild and no deaths directly linked to the drug were reported. However, longer duration studies are required to draw firm and strong conclusions on the safety of these therapeutic agents. PMID- 30416898 TI - Emergency Departments as the Health Safety Nets of Society: A Descriptive and Multicenter Analysis of Social Worker Support in the Emergency Room. AB - Introduction Social Work (SW) referrals made in the emergency department (ED) highlight the weaknesses in the existing support system for vulnerable and disadvantaged patients. SW personnel play a pivotal role in some EDs but are not integrated into the team in several jurisdictions. Our objective was to provide a detailed description of the need for SW support in the ED setting by describing SW consultation patterns in an urban ED location. Methods A three-year analysis of ED SW referrals made through a network of four acute care hospitals serving a city population of 1.2 million inhabitants where social workers operate from 8 a.m. to 10 p.m. The study design was descriptive reporting proportions. The descriptors of interest were the types of ED patients receiving SW consultations and the reasons for patient referral to the SW Department. Results During the study period, there were 46,970 SW consultations, representing 8.02% of the 572,804 patients who visited the ED across Calgary, yielding 42.9 referrals per day to social workers through the ED. Consultations for domestic violence were three times more prevalent for women (6% of referrals). However, domestic violence consultations were still an active issue for men (1.9%). Comparisons by age group yielded illness adjustments (15.3%), discharge planning (31.2%), and legal decision making (23.9%) as the most common reasons for referral of patients over 75 years old; 92.8% of patients over 75 years were admitted following the SW consultation. Reasons for deferral of patients under 30 years of age were illness adjustments (12.2%), discharge planning (16.4 %), and legal decision making (1.4%); 57.3% of patients under 30 years were admitted following the consultation. Addiction/drug use and homelessness were more common in those under the age of 30, comprising 24.1% and 15.4% of the SW referrals, respectively, compared to 1.6% and 0.4% of referrals for those over age 75, respectively. Conclusions The demand for SW support is significant and complex in these large urban EDs. However, the impact on patient care and resource use is substantial, and the data indicates that SW integration may be of universal benefit to EDs. Further studies are warranted to accurately characterize the amount and type of SW necessary for optimal patient outcomes and hospital resource use. PMID- 30416899 TI - Variations of the Transverse Sinus: Review with an Unusual Case Report. AB - The dural venous sinuses are venous channels in the cranium that drain blood and cerebrospinal fluid circulating from the brain into the vascular system via the internal jugular veins. The transverse sinus is a dural venous sinus present in the posterior aspect of the cranium. We report an unusual variant of this sinus with the presence of a fenestration at its proximal segment. We will review and discuss the background and the potential clinical relevance of this anatomical variation. PMID- 30416900 TI - Atypical Presentation of Gastric Cancer Approached Via Retrograde Single Balloon Enteroscopy. AB - The paradigm for the diagnosis and management of gastric cancer is changing with advanced diagnostic and therapeutic interventions. Prior gastric surgery (20 years or more) is one of the risk factors for gastric cancer. Increased intragastric carcinogen formation is thought to contribute toward gastric cancer development in the remaining portion of the stomach. This case illustrates the importance of a thorough clinical and pathologic workup and highlights the advanced technique of single-balloon enteroscopy (SBE) and its role in managing patient's health. PMID- 30416901 TI - Cognitive Behavioral Therapy versus Eye Movement Desensitization and Reprocessing in Patients with Post-traumatic Stress Disorder: Systematic Review and Meta analysis of Randomized Clinical Trials. AB - Background Post-traumatic stress disorder (PTSD) is prevalent in children, adolescents and adults. It can occur alone or in comorbidity with other disorders. A broad range of psychotherapies such as cognitive behavioral therapy (CBT) and eye movement desensitization and reprocessing (EMDR) have been developed for the treatment of PTSD. Aim Through quantitative meta-analysis, we aimed to compare the efficacy of CBT and EMDR: (i) relieving the post-traumatic symptoms, and (ii) alleviating anxiety and depression, in patients with PTSD. Methods We systematically searched EMBASE, Medline and Cochrane central register of controlled trials (CENTRAL) for articles published between 1999 and December 2017. Randomized clinical trials (RCTs) that compare CBT and EMDR in PTSD patients were included for quantitative meta-analysis using RevMan Version 5. Results Fourteen studies out of 714 were finally eligible. Meta-analysis of 11 studies (n = 547) showed that EMDR is better than CBT in reducing post-traumatic symptoms [SDM (95% CI) = -0.43 (-0.73 - -0.12), p = 0.006]. However, meta analysis of four studies (n = 186) at three-month follow-up revealed no statistically significant difference [SDM (95% CI) = -0.21 (-0.50 - 0.08), p = 0.15]. The EMDR was also better than CBT in reducing anxiety [SDM (95% CI) = 0.71 (-1.21 - -0.21), p = 0.005]. Unfortunately, there was no difference between CBT and EMDR in reducing depression [SDM (95% CI) = -0.21 (-0.44 - 0.02), p = 0.08]. Conclusion The results of this meta-analysis suggested that EMDR is better than CBT in reducing post-traumatic symptoms and anxiety. However, there was no difference reported in reducing depression. Large population randomized trials with longer follow-up are recommended to build conclusive evidence. PMID- 30416902 TI - Embolization-induced Renal Tumor Shrinkage Followed by Definitive Cryoablation. AB - Significant incidental findings reported on computed tomography (CT) scans are common. This article describes a 72-year-old man evaluated for possible bowel obstruction in whom was found a 3.1-cm x 2.6-cm centrally located enhancing mass in the left kidney highly suspicious for renal cell carcinoma. Due to substantial medical comorbidities, the patient was deemed a poor surgical candidate for either partial or complete nephrectomy. Interventional radiology was consulted for a minimally invasive ablation procedure. The large size and central location of the tumor involving the renal collecting system initially precluded definitive percutaneous cryoablation. Intra-arterial embolization was used as neoadjuvant therapy to decrease tumor burden. Fluoroscopy-guided bland embolization was performed targeting the arterial supply of the mass until stagnation of flow was achieved. A subsequent two-month post-embolization follow-up CT scan showed a 30% reduction in tumor size. Shrinkage of the mass from a central to a more peripheral location allowed for a cryoablation approach that would avoid damage to the vulnerable collecting system. Cryoablation was performed, and intraoperative CT demonstrated complete coverage of the tumor by the ice ball with no damage to the renal collecting system. A follow-up CT scan four years later showed no residual malignancy at the ablation site. PMID- 30416903 TI - Normal Correction of Sodium Leading to Central Pontine Demyelinosis: A Rare Occurrence. AB - Central pontine myelinolysis is a rare condition arising from the myelinolysis of white matter tracts in the pons, most commonly in response to iatrogenic hypertonic stress caused by the rapid correction of hyponatremia. Here, we present an interesting case of central pontine myelinolysis subsequent to normal saline infusion despite strict adherence to the guideline protocol. PMID- 30416904 TI - Immunotherapy in Advanced Non-small Cell Lung Cancer Patients: Ushering Chemotherapy Through the Checkpoint Inhibitors? AB - New ways of exploiting the immune system for cancer treatment have been tested for decades with moderate outcomes. Based on previous immunotherapy knowledge, agents targeting immune checkpoints seem to be remarkably effective in a wide range of tumors. Immune checkpoint inhibitors in metastatic non-small cell lung cancer (NSCLC) provide longlasting responses in specific patients. Nevertheless, with overall response rates <= 20%, combinational protocols for various patient subgroups are needed. A good partner treatment to immunotherapy could be chemotherapy, as it successfully modulates the immune response either by controlling or enhancing the antitumor immune activity. Primary research provides promising results in metastatic NSCLC patients using this approach, but further large-scale trials are needed. The implementation of immunotherapy in nonmetastatic cases is also appealing. We review the potential clinical benefits of immunotherapy alone or in concert with chemotherapy in NSCLC. PMID- 30416905 TI - Paving a Shorter Path Towards Diagnosis: A Case on Adult Onset Still's Disease from Pakistan. AB - Adult onset Still's disease (AOSD) is a rare clinical entity with unknown etiology, characterized by arthritis, fever, erythematous rash, and other systemic presentations. We report a case of a 21-year-old male who presented with high spiking fever, dry cough, generalized body ache, arthralgia, and an erythematous rash. He was eventually diagnosed to have AOSD based on the Yamaguchi criteria, after a month of visiting three different healthcare facilities and receiving two misdiagnoses and treatment regimes not specific to his diagnosis. The patient immediately responded to prednisoloneand was healthy upon discharge. PMID- 30416906 TI - Ultrasound-guided Microbubble in the Treatment of Cancer: A Mini Narrative Review. AB - Microbubble is an emerging modality in the field of Medicine for treatment and imaging. Ultrasound-guided microbubble is an effective diagnosing and treatment technique as it can reduce the systemic toxicity of chemotherapeutic drugs. It is also used in targeted gene delivery in gene therapy. The objective of the review article is to formulate a narrative review on the emerging importance of microbubbles in the diagnosis and treatment of cancer and its future in cancer management. The article focuses on the effectiveness of ultrasound-targeted microbubble in the treatment of malignancy. PMID- 30416907 TI - Acute Liver Injury Induced by Synthetic Cannabinoid Abuse. AB - Synthetic cannabinoid abuse can manifest with an array of unpredictable reactions ranging from sedation to hallucinations, psychosis, and seizures. Acute liver injury associated with the synthetic cannabinoid use is a rare complication. We present a case of a 22-year-old homeless male presented with abdominal pain and vomiting. He admitted regular synthetic cannabinoid use, and binge alcohol use once a week. Physical examination was remarkable only for mild icterus. The laboratory result shows abnormal liver functions tests. Viral, autoimmune, metabolic and other toxic etiologies of liver injury were ruled out. The acute liver injury was deemed to be secondary to synthetic cannabinoids toxicity. Spice induced liver injury remains a diagnosis of exclusion after all other identifiable causes ruled out. Clinicians should have a high index of suspicion for synthetic cannabinoid abuse in a patient with acute hepatotoxicity who had a history of polysubstance abuse. PMID- 30416908 TI - Parental Perceptions of Emotional and Behavioral Difficulties Among Prepubertal Gender-Nonconforming Children. AB - The purpose of this study was to better understand parents' perceptions of how, if at all, their transgender and gender-nonconforming (TGNC) children exhibited common childhood emotional and behavioral concerns in relation to gender nonconformity/gender dysphoria (GD), and to identify ways in which evidence-based interventions (EBI) targeting emotional and behavioral concerns could be adapted to best serve TGNC children. Qualitative data were gathered from a targeted focus group activity with 40 parents (25 mothers, 15 fathers) of 24 TGNC children ages 4-11 years old. Parents of TGNC children described how 4 prespecified domains of emotional and behavioral problems (i.e., oppositional behavior, anger, sadness, and fears/worries) are characterized in the context of gender-nonconformity/GD. Parents also identified precipitants of these problems. Overall study findings indicate there is a role for EBI adaptation as parents identified many different examples of emotional and behavioral challenges emerging in unique and nuanced ways in TGNC children. PMID- 30416909 TI - A Behavioral Family Intervention for Children with Overweight and Asthma. AB - Objective: The Childhood Health and Asthma Management Program (CHAMP) is a behavioral family lifestyle intervention for youth with overweight or obesity (OV/OB) and asthma. This pilot randomized controlled trial examined the feasibility, acceptability, and preliminary efficacy of CHAMP. Methods: A sample of 24 children (Mage = 8.67) with asthma and a BMI >= 85th percentile and their caregivers participated in a pilot randomized controlled trial. Families were recruited from local pediatrician offices and pediatric pulmonary and allergy clinics and randomized to CHAMP or a health education attention control condition. Children's height, weight, lung function, asthma control, and asthma related quality of life (QOL) were collected at baseline, post-intervention, and 6-months post-treatment. Analysis of covariance and standardized mean differences were used to assess changes in outcome variables among participants attending > 50% of sessions (n = 12). Results: Families participating in CHAMP reported high satisfaction; however, there were a number of barriers to recruitment and regular session attendance. There were no statistically significant between group differences at post-intervention or long-term follow-up. From baseline to post intervention, there were small to large effect sizes favoring CHAMP for BMI z scores, asthma control, and measures of lung function. There were small to medium effect sizes favoring CHAMP at long-term follow-up for BMI z-scores, asthma control, and asthma-related QOL. Conclusions: CHAMP had adequate acceptability in this trial. We did not find significant results favoring CHAMP in comparison to the control group, however, lessons learned provide important directions for modifications in anticipation of a larger trial. PMID- 30416910 TI - Microphysical and kinematic processes associated with anomalous charge structures in isolated convection. AB - Microphysical and kinematic characteristics of two storm populations, based on their macroscale charge structures, are investigated in an effort to increase our understanding of the processes that lead to anomalous (or inverted charge) structures. Nine normal polarity cases (mid-level negative charge) with dual Doppler and polarimetric coverage that occurred in northern Alabama, and six anomalous polarity cases (mid-level positive charge) that occurred in northeastern Colorado are included in this study. The results show that even though anomalous polarity storms formed in environments with similar instability, they had significantly larger and stronger updrafts. Moreover, the anomalous polarity storms evidently have more robust mixed-phase microphysics, based on a variety of metrics. Anomalous polarity storms in Colorado have much higher cloud base heights and shallower warm cloud depths in this study, leading us to hypothesize that anomalous polarity storms have lower amounts of dilution and entrainment. We infer positively charged graupel, and therefore high supercooled water contents, in the mid-levels of the anomalous storms based on the relationship between colocations of graupel and inferred positive charge from Lightning Mapping Array data. Using representative updraft speeds and warm cloud depths, the time required for a parcel to traverse from cloud base to the freezing level was estimated for each storm observation. We suggest this metric is the key discriminator between the two storm populations and leads us to hypothesize that it strongly influences the amount of supercooled water and the probability of positive charge in the midlevels, leading to an anomalous charge structure. PMID- 30416911 TI - Enhancement of X-ray emission from nanocolloidal gold suspensions under double pulse excitation. AB - Enhancement of X-ray emission was observed from a micro-jet of a nano-colloidal gold suspension in air under double-pulse excitation of ultrashort (40 fs) near IR laser pulses. Temporal and spatial overlaps between the pre-pulse and the main pulse were optimized for the highest X-ray emission. The maximum X-ray intensity was obtained at a 1-7 ns delay of the main pulse irradiation after the pre-pulse irradiation with the micro-jet position shifted along the laser beam propagation. It was revealed that the volume around gold nanoparticles where the permittivity is near zero, epsilon ~ 0, accounts for the strongest absorption, which leads to the effective enhancements of X-ray emission. PMID- 30416912 TI - Characterization of the microscopic tribological properties of sandfish (Scincus scincus) scales by atomic force microscopy. AB - Lizards of the genus Scincus are widely known under the common name sandfish due to their ability to swim in loose, aeolian sand. Some studies report that this fascinating property of sandfish is accompanied by unique tribological properties of their skin such as ultra-low adhesion, friction and wear. The majority of these reports, however, is based on experiments conducted with a non-standard granular tribometer. Here, we characterise microscopic adhesion, friction and wear of single sandfish scales by atomic force microscopy. The analysis of frictional properties with different types of probes (sharp silicon tips, spherical glass tips and sand debris) demonstrates that the tribological properties of sandfish scales on the microscale are not exceptional if compared to snake scales or technical surfaces such as aluminium, Teflon, or highly oriented pyrolytic graphite. PMID- 30416914 TI - Nanostructured liquid crystal systems and applications. PMID- 30416913 TI - Impact of the anodization time on the photocatalytic activity of TiO2 nanotubes. AB - Titanium oxide nanotubes (TNTs) were anodically grown in ethylene glycol electrolyte. The influence of the anodization time on their physicochemical and photoelectrochemical properties was evaluated. Concomitant with the anodization time, the NT length, fluorine content, and capacitance of the space charge region increased, affecting the opto-electronic properties (bandgap, bathochromic shift, band-edge position) and surface hydrophilicity of TiO2 NTs. These properties are at the origin of the photocatalytic activity (PCA), as proved with the photooxidation of methylene blue. PMID- 30416916 TI - Polarization-dependent strong coupling between silver nanorods and photochromic molecules. AB - Active plasmonics is a key focus for the development of advanced plasmonic applications. By selectively exciting the localized surface plasmon resonance sustained by the short or the long axis of silver nanorods, we demonstrate a polarization-dependent strong coupling between the plasmonic resonance and the excited state of photochromic molecules. By varying the width and the length of the nanorods independently, a clear Rabi splitting appears in the dispersion curves of both resonators. PMID- 30416917 TI - Silicene, germanene and other group IV 2D materials. PMID- 30416915 TI - Nanoantenna structures for the detection of phonons in nanocrystals. AB - We report a study of the infrared response by localized surface plasmon resonance (LSPR) modes in gold micro- and nanoantenna arrays with various morphologies and surface-enhanced infrared absorption (SEIRA) by optical phonons of semiconductor nanocrystals (NCs) deposited on the arrays. The arrays of nano- and microantennas fabricated with nano- and photolithography reveal infrared-active LSPR modes of energy ranging from the mid to far-infrared that allow the IR response from very low concentrations of organic and inorganic materials deposited onto the arrays to be analyzed. The Langmuir-Blodgett technology was used for homogeneous deposition of CdSe, CdS, and PbS NC monolayers on the antenna arrays. The structural parameters of the arrays were confirmed by scanning electron microscopy. 3D full-wave electromagnetic simulations of the electromagnetic field distribution around the micro- and nanoantennas were employed to realize the maximal SEIRA enhancement for structural parameters of the arrays whereby the LSPR and the NC optical phonon energies coincide. The SEIRA experiments quantitatively confirmed the computational results. The maximum SEIRA enhancement was observed for linear nanoantennas with optimized structural parameters determined from the electromagnetic simulations. The frequency position of the feature's absorption seen in the SEIRA response evidences that the NC surface and transverse optical phonons are activated in the infrared spectra. PMID- 30416918 TI - Two-dimensional semiconductors pave the way towards dopant-based quantum computing. AB - Since the proposal in 1998 to build a quantum computer using dopants in silicon as qubits, much progress has been made in the nanofabrication of semiconductors and the control of charge and spins in single dopants. However, an important problem remains unsolved, namely the control over exchange interactions and tunneling between two donors, which presents a peculiar oscillatory behavior as the dopants relative positions vary at the scale of the lattice parameter. Such behavior is due to the valley degeneracy in the conduction band of silicon, and does not occur when the conduction-band edge is at k = 0. We investigate the possibility of circumventing this problem by using two-dimensional (2D) materials as hosts. Dopants in 2D systems are more tightly bound and potentially easier to position and manipulate. Moreover, many of them present the conduction band minimum at k = 0, thus no exchange or tunnel coupling oscillations. Considering the properties of currently available 2D semiconductor materials, we access the feasibility of such a proposal in terms of quantum manipulability of isolated dopants (for single qubit operations) and dopant pairs (for two-qubit operations). Our results indicate that a wide variety of 2D materials may perform at least as well as, and possibly better, than the currently studied bulk host materials for donor qubits. PMID- 30416919 TI - Silencing the second harmonic generation from plasmonic nanodimers: A comprehensive discussion. AB - The silencing of the second harmonic generation process from plasmonic nanostructures corresponds to the limited far-field second harmonic radiation despite the huge fundamental electric field enhancement in the interstice between two plasmonic nanoparticles forming a nanodimer. In this article, we report a comprehensive investigation of this effect using a surface integral equation method. Various geometries are considered, including nanoantennas with cylindrical and rectangular arms as well as nanodimers with surface defects. The existence of the silencing of the second harmonic generation from plasmonic nanogaps is first confirmed, and the problem of the origin of the second harmonic light from these plasmonic nanostructures is addressed in detail. Our results show that the distribution of the second harmonic sources, especially on the arm sides, plays a non-negligible role in the overall second harmonic emission. This contribution is induced by retardation effects at the pump wavelength and results in a dipolar second harmonic emission. PMID- 30416921 TI - Optimization of Mo/Cr bilayer back contacts for thin-film solar cells. AB - Molybdenum (Mo) is the most commonly used material as back contact in thin-film solar cells. Adhesion of Mo film to soda-lime glass (SLG) substrate is crucial to the performance of solar cells. In this study, an optimized bilayer structure made of a thin layer of Mo on an ultra-thin chromium (Cr) adhesion layer is used as the back contact for a copper zinc tin sulfide (CZTS) thin-film solar cell on a SLG substrate. DC magnetron sputtering is used for deposition of Mo and Cr films. The conductivity of Mo/Cr bilayer films, their microstructure and surface morphology are studied at different deposition powers and working pressures. Good adhesion to the SLG substrate has been achieved by means of an ultra-thin Cr layer under the Mo layer. By optimizing the deposition conditions we achieved low surface roughness, high optical reflectance and low sheet resistivity while we could decrease the back contact thickness to 600 nm. That is two thirds to half of the thickness that is currently being used for bilayer and single layer back contact for thin-film solar cells. We demonstrate the excellent properties of Mo/Cr bilayer as back contact of a CZTS solar cell. PMID- 30416922 TI - Disorder in H+-irradiated HOPG: effect of impinging energy and dose on Raman D band splitting and surface topography. AB - Disorder was induced in pristine highly oriented pyrolytic graphite (HOPG) by irradiation with H+ ions with energies of 0.4 MeV and 1 MeV, and doses of 1014 ions/cm2 and 1016 ions/cm2. Raman spectroscopy was used as the main technique to characterize different samples and gain new insights on the splitting of the D band into two components (D1 and D2), trying to correlate this feature of the vibrational spectrum with the impinging energy and dose. An increased I D2/I G ratio in comparison with I D1/I G was observed in the irradiated samples. This behavior indicates that the impinging energy mainly affects the D1 component, while the D2 component is strongly dominated by the dose. We expect a larger contribution of defects (originating from the rupture of C-C sp2 symmetry through the formation of C-H sp3 bonds) to the D2 component than to the D1 component. SQUID measurements of the irradiated samples showed an enhancement in the normalized remanence, as well as an increment in coercivity compared to pristine HOPG, consistent with H+-induced point-like defects as well as C-H bonds. AFM scanning after Raman and SQUID characterization showed a distribution of surface defects, which were ascribed to the burst of hydrogen blisters formed as a consequence of the irradiation process. The results presented in this work contribute to the current trend in nanotechnology in areas devoted to the control of properties by defect engineering in carbon-based materials. PMID- 30416920 TI - Size-selected Fe3O4-Au hybrid nanoparticles for improved magnetism-based theranostics. AB - Size-selected Fe3O4-Au hybrid nanoparticles with diameters of 6-44 nm (Fe3O4) and 3-11 nm (Au) were prepared by high temperature, wet chemical synthesis. High quality Fe3O4 nanocrystals with bulk-like magnetic behavior were obtained as confirmed by the presence of the Verwey transition. The 25 nm diameter Fe3O4-Au hybrid nanomaterial sample (in aqueous and agarose phantom systems) showed the best characteristics for application as contrast agents in magnetic resonance imaging and for local heating using magnetic particle hyperthermia. Due to the octahedral shape and the large saturation magnetization of the magnetite particles, we obtained an extraordinarily high r 2-relaxivity of 495 mM-1.s-1 along with a specific loss power of 617 W.gFe -1 and 327 W.gFe -1 for hyperthermia in aqueous and agarose systems, respectively. The functional in vitro hyperthermia test for the 4T1 mouse breast cancer cell line demonstrated 80% and 100% cell death for immediate exposure and after precultivation of the cells for 6 h with 25 nm Fe3O4-Au hybrid nanomaterials, respectively. This confirms that the improved magnetic properties of the bifunctional particles present a next step in magnetic-particle-based theranostics. PMID- 30416923 TI - Low cost tips for tip-enhanced Raman spectroscopy fabricated by two-step electrochemical etching of 125 um diameter gold wires. AB - Tip-enhanced Raman spectroscopy (TERS) has become a well-applied technique for nanospectroscopy, allowing for single molecule sensitivity with sub-nanometer spatial resolution. The demand for efficient, reproducible and cost-effective probes for TERS is increasing. Here we report on a new electrochemical etching protocol to fabricate TERS tips starting from 125 um diameter gold wires in a reproducible way. The process is reliable (50% of the tips have radius of curvature <35 nm, 66% <80 nm), fast (less than 2 min) and 2.5 times cheaper than the etching of standard 250 um diameter wires. The TERS performance of the tips is tested on dyes, pigments and biomolecules and enhancement factors higher than 105 are observed. TERS mapping with a spatial resolution of 5 nm is demonstrated. PMID- 30416924 TI - Oriented zinc oxide nanorods: A novel saturable absorber for lasers in the near infrared. AB - Zinc oxide (ZnO) nanorods (NRs) oriented along the crystallographic [001] axis are grown by the hydrothermal method on glass substrates. The ZnO NRs exhibit a broadband (1-2 um) near-IR absorption ascribed to the singly charged zinc vacancy VZn -1. The saturable absorption of the ZnO NRs is studied at ~1 um under picosecond excitation, revealing a low saturation intensity, ~10 kW/cm2, and high fraction of the saturable losses. The ZnO NRs are applied as saturable absorbers in diode-pumped Yb (~1.03 um) and Tm (~1.94 um) lasers generating nanosecond pulses. The ZnO NRs grown on various optical surfaces are promising broadband saturable absorbers for nanosecond near-IR lasers in bulk and waveguide geometries. PMID- 30416925 TI - Contactless photomagnetoelectric investigations of 2D semiconductors. AB - Background: Applications of two-dimensional (2D) materials in electronic devices require the development of appropriate measuring methods for determining their typical semiconductor parameters, i.e., mobility and carrier lifetime. Among these methods, contactless techniques and mobility extraction methods based on field-effect measurements are of great importance. Results: Here we show a contactless method for determining these parameters in 2D semiconductors that is based on the photomagnetoelectric (PME) effect (also known as the photoelectromagnetic effect). We present calculated dependences of the PME magnetic moment, evoked in 2D Corbino configuration, on the magnetic field as well as on the intensity and spatial distribution of illumination. The theoretical predictions agree with the results of the contactless investigations performed on non-suspended single-layer graphene. We use the contactless PME method for determining the dependence of carrier mobility on the concentration of electrons and holes induced by a back-gate voltage. Conclusion: The presented contactless PME method, used in Corbino geometry, is complementary to the mobility extraction methods based on field-effect measurements. It can be used for determining the mobility and diffusion length of carriers in different 2D materials. PMID- 30416926 TI - Accurate control of the covalent functionalization of single-walled carbon nanotubes for the electro-enzymatically controlled oxidation of biomolecules. AB - Single-walled carbon nanotubes (SWCNTs) were functionalized by ferrocene through ethyleneglycol chains of different lengths (FcETGn) and the functionalized SWCNTs (f-SWCNTs) were characterized by different complementary analytical techniques. In particular, high-resolution scanning electron transmission microscopy (HRSTEM) and electron energy loss spectroscopy (EELS) analyses support that the outer tubes of the carbon-nanotube bundles were covalently grafted with FcETGn groups. This result confirms that the electrocatalytic effect observed during the oxidation of the reduced form of nicotinamide adenine dinucleotide (NADH) co factor by the f-SWCNTs is due to the presence of grafted ferrocene derivatives playing the role of a mediator. This work clearly proves that residual impurities present in our SWCNT sample (below 5 wt. %) play no role in the electrocatalytic oxidation of NADH. Moreover, molecular dynamic simulations confirm the essential role of the PEG linker in the efficiency of the bioelectrochemical device in water, due to the favorable interaction between the ETG units and water molecules that prevents pi-stacking of the ferrocene unit on the surface of the CNTs. This system can be applied to biosensing, as exemplified for glucose detection. The well-controlled and well-characterized functionalization of essentially clean SWCNTs enabled us to establish the maximum level of impurity content, below which the f-SWCNT intrinsic electrochemical activity is not jeopardized. PMID- 30416928 TI - A decade of fluvial morphodynamics: relocation and restoration of the Inde River (North-Rhine Westphalia, Germany). AB - Background: Relocations and restorations do not only change the ecological passability and sediment continuity of a river but also its flow behavior and fluvial morphodynamics. Sediment transport processes and morphological development can be assessed with field measurements, also taking the transport of sediment-bounded contaminants as a tracer material for fluvial morphodynamics into account. The objective of this study was to determine the morphological development of the Inde River (a tributary of the Rur River in North-Rhine Westphalia, Germany) towards its pre-defined guiding principle after a relocation and restoration in 2005 AD. Methods: The fluvial morphodynamics of the Inde River were analyzed over a period of almost 15 years taking sediment samples, analyzing echo soundings of the river's bathymetry and determining the heavy metal content of the sediment as a tracer material for the morphological development. Results: The results show that the relocation and restoration of the Inde River initiates new hydrodynamic processes, which cause morphological changes of the river widths, meander belts and channel patterns. The riverbed of the new Inde River has incised into the ground due to massive erosion, which has led to increased fine sediment transport in the downstream direction. The reasons for and consequences of this fine sediment transport are discussed and correlated to the sediment continuity of a river. Conclusions: Overall, the new Inde River has reached its goal of being a natural river as a consequence of the relocation and restoration and has adapted its new conditions towards a dynamic morphological equilibrium. PMID- 30416927 TI - Limits of Concern: suggestions for the operationalisation of a concept to determine the relevance of adverse effects in the ERA of GMOs. AB - Background: The European Food Safety Authority proposed a concept for the environmental risk assessment of genetically modified plants in the EU that is based on the definition of thresholds for the acceptability of potential adverse effects on the environment. This concept, called Limits of Concern (LoC), needs to be further refined to be implemented in the environmental risk assessment of genetically modified organisms. Methods: We analyse and discuss how LoC can be defined for the environmental risk assessment for three different types of genetically modified plants. We outline protection goals relevant to the genetically modified plants in question and discuss existing concepts and suggestions for acceptability thresholds from the environmental risk assessment of different regulatory areas. We make specific recommendations for the setting and use of LoC for each type of genetically modified plant. Results: The LoC concept can be suitably applied for the environmental risk assessment of genetically modified organisms, if the different protection goals in agro environments are specifically considered. Not only biodiversity protection goals but also agricultural protection goals need to be addressed. The different ecosystem services provided by weeds inside and outside agricultural fields have to be considered for genetically modified herbicide-tolerant crops. Exposure based LoCs are suggested based on knowledge about dose-effect relationships between maize pollen and non-target Lepidoptera for insect-resistant maize. Due to the long-term nature of biological processes such as spread and establishment, LoCs for genetically modified oilseed rape should be defined for the presence of the genetically modified plant or its genetically modified traits in relevant protection goals. Conclusions: When setting LoCs, the focus should be on protection goals which are possibly affected. Potential overlaps of the LoC concept with the ecosystem service concept have to be clarified to harmonise protection levels in the agro-environment for different stressors. If additional impacts on agro-biodiversity resulting from the cultivation of genetically modified plants are to be avoided, then high protection levels and low thresholds for acceptable effects (i.e. LoC) should be set. PMID- 30416929 TI - SETAC GLB and SETAC Europe SAC: a liaison promoting the next generation of ecotoxicologists and environmental chemists. AB - This commentary is an introduction for students to the Society of Environmental Toxicology and Chemistry (SETAC) and its Student Advisory Council (SAC). As young academics face challenges while trying to develop their careers, SETAC and the SAC help facilitate student involvement in the various communities within the society that can help to develop the students' careers within the environmental sciences [e.g. the German Language Branch (GLB)]. This piece would also like to emphasize and pay homage to the continual cooperation between the SAC and the ESEU, which provides a scientific platform to communicate internationally and beyond the borders of SETAC, as well as offer heartfelt congratulations from the SAC to the GLB for their "20 Years SETAC GLB" and deep gratitude for their strong advocacy and support of the SAC. PMID- 30416930 TI - Digital technologies for social inclusion of individuals with disabilities. AB - Information technology can be an important facilitator of social inclusion for people with disabilities into society. However, the goals specified in this area by organizations such as the European Commission have not yet been achieved in their totality. The aim of this paper is to explore which types of information communication technology-based applications and/or digital services have been suggested to facilitate the social integration of people who suffer from different types of disabilities. We performed a literature review that included studies published during a period of 6 years (2010-2016). The results show that, in the data we have had access to, no concrete patterns can be identified regarding the type of technology or technological trends that can be used to support the social integration of individuals with disabilities. This literature review is of relevance to the identification of further research areas and to the identification of issues which have to be considered in the context of the development and implementation of technological innovations that are aimed at promoting or facilitating social inclusion of individuals with disabilities. PMID- 30416931 TI - MECHANISMS OF BEHAVIOR CHANGE IN 12-STEP APPROACHES TO RECOVERY IN YOUNG ADULTS. AB - Purpose of review: Empirical evidence indicates that, in general, treatments which systematically engage adults with freely available twelve-step mutual-help organizations (TSMHOs), such as Alcoholics Anonymous (AA) and Narcotics Anonymous (NA) often enhance treatment outcomes while reducing health care costs. Also evident is that TSMHOs facilitate recovery through mechanisms similar to those mobilized by professional interventions, such as increased abstinence self efficacy and motivation, as well changing social networks. Much less is known, however, regarding the utility of these resources specifically for young adults and whether the TSMHO mechanisms are similar or different for young adults. This article provides a narrative review of the clinical and public health utility of TSMHOs for young adults, and summarizes theory and empirical research regarding how young adults benefit from TSMHOs. Recent findings: Results indicate that, compared to older adults, young adults are less likely to attend TSMHOs and attend less frequently, but derive similar benefit. The mechanisms, however, by which TSMHOs help, differ in nature and magnitude. Also, young adults appear to derive greater benefit initially from meetings attended by similar aged peers, but this benefit diminishes over time. Summary: Findings offer developmentally specific insights into TSMHO dynamics for young adults and inform knowledge of broader recovery needs and challenges. PMID- 30416932 TI - Longer-Term Outdoor Temperatures and Health Effects: A Review. AB - Purpose of review: Our goal was to assess current literature and knowledge on associations between characteristics (mean, variability, extremes) of ambient temperatures and human health. We were motivated by concerns that climate change, which operates on a time frame of decades or longer, may influence not only shorter-term associations between weather and health (daily/weekly) but also have enduring implications for population health. We reviewed papers published between 2010 and 2017 on the health effects of longer-term (3 weeks to years) exposures to ambient temperature. We sought to answer: 'What health outcomes have been associated with longer-term exposures?' We included studies on a diverse range of health outcomes, with the exception of vector borne diseases such as malaria. Longer-term exposures were considered to be exposures to annual and seasonal temperatures and temperature variability. Recent findings: We found 26 papers meeting inclusion criteria, which addressed mortality, morbidity, respiratory disease, obesity, suicide, infectious diseases and allergies among various age groups. In general, most studies found associations between longer-term temperature metrics and health outcomes. Effects varied by population subgroup. For example, associations with suicide differed by sex and underlying chronic illness modified effects of heat on mortality among the elderly. Summary: We found that regional and local temperatures, and changing conditions in weather due to climate change, were associated with a diversity of health outcomes through multiple mechanisms. Future research should focus on evidence for particular mechanistic pathways in order to inform adaptation responses to climate change. PMID- 30416934 TI - Long-acting muscarinic antagonists for the treatment of asthma in children-a new kid in town. AB - Background: Asthma is the most prevalent chronic airway disease observed in children and adolescents, yet the variety of treatment options available for this age group is limited. With many factors influencing therapeutic efficacy including patient knowledge, adherence, and therapy choice as well as delivery device, it is important to have more options to tailor to individual patient needs. Methods: This article is an overview of recent scientific articles using a systematic literature search in PubMed and specialist databases. Results: Tiotropium is the first long-acting muscarinic antagonist to be licensed for treatment of asthma and has been demonstrated to be an effective add-on therapy across all age groups. Its therapeutic success in clinical trials resulted in Food and Drug Administration and the European Medicines Agency approval for asthma treatment in people over the age of 6 years in the US and EU. Conclusion: Further studies into the use of tiotropium, especially in younger children, could be of interest for future treatment decisions. PMID- 30416933 TI - Posttransplant Medical Adherence: What Have We Learned and Can We Do Better? AB - Purpose of review: Non-adherence to the medical regimen after kidney transplantation can contribute to poor clinical outcomes, and strategies to maximize adherence are sought by care providers and patients alike. We assessed recent evidence on prevalence, risk factors, and clinical outcomes associated with non-adherence to the medical regimen after kidney transplantation. We summarized recent clinical trials testing interventions to improve adherence and generated recommendations for future research and clinical practice. Recent findings: A large evidence base documents rates of non-adherence to each of the multiple components of the regimen, including medication-taking, lifestyle activities, clinical care requirements, and substance use restrictions. Some risk factors for non-adherence are well known but the full range of risk factors remains unclear. Non-adherence to immunosuppressants and to other components of the regimen increases morbidity and mortality risks. Recent interventions, including education and counseling; electronic health strategies; and medication dose modifications, show promise for reducing immunosuppressant non-adherence. However, most of these interventions would be difficult to deploy in everyday clinical practice. Systematic dissemination of efficacious interventions into clinical practice has not been undertaken. Summary: Rates and risk factors for non-adherence to the medical regimen have been examined and there is evidence that non-adherence may be ameliorated by a range of interventions. Although gaps in the evidence base remain, it would be timely to devote greater efforts to dissemination of findings. Thus, efforts are needed to assist transplant programs in using existing evidence to better identify patients who are non-adherent and to design and implement strategies to reduce or prevent non-adherence. PMID- 30416935 TI - Systematic engineering design helps creating new soft machines. AB - Soft robotics is an emerging field in the robotics community which deals with completely new types of robots. However, often new soft robotic designs depend on the ingenuity of the engineer rather being systematically derived. For this reason, in order to support the engineer in the design process, we present a design methodology for general technical systems in this paper and explain it in depth in the context of soft robotics. The design methodology consists of a combination of state-of-the-art engineering concepts that are arranged in such a way that the engineer is guided through the design process. The effectiveness of a systematic approach in soft robotics is illustrated on the design of a new gecko-inspired, climbing soft robot. PMID- 30416936 TI - Tracking online topics over time: understanding dynamic hashtag communities. AB - Background: Hashtags are widely used for communication in online media. As a condensed version of information, they characterize topics and discussions. For their analysis, we apply methods from network science and propose novel tools for tracing their dynamics in time-dependent data. The observations are characterized by bursty behaviors in the increases and decreases of hashtag usage. These features can be reproduced with a novel model of dynamic rankings. Hashtag communities in time: We build temporal and weighted co-occurrence networks from hashtags. On static snapshots, we infer the community structure using customized methods. On temporal networks, we solve the bipartite matching problem of detected communities at subsequent timesteps by taking into account higher-order memory. This results in a matching protocol that is robust toward temporal fluctuations and instabilities of the static community detection. The proposed methodology is broadly applicable and its outcomes reveal the temporal behavior of online topics. Modeling topic-dynamics: We consider the size of the communities in time as a proxy for online popularity dynamics. We find that the distributions of gains and losses, as well as the interevent times are fat-tailed indicating occasional, but large and sudden changes in the usage of hashtags. Inspired by typical website designs, we propose a stochastic model that incorporates a ranking with respect to a time-dependent prestige score. This causes occasional cascades of rank shift events and reproduces the observations with good agreement. This offers an explanation for the observed dynamics, based on characteristic elements of online media. PMID- 30416937 TI - Social learning for resilient data fusion against data falsification attacks. AB - Background: Internet of Things (IoT) suffers from vulnerable sensor nodes, which are likely to endure data falsification attacks following physical or cyber capture. Moreover, centralized decision-making and data fusion turn decision points into single points of failure, which are likely to be exploited by smart attackers. Methods: To tackle this serious security threat, we propose a novel scheme for enabling distributed decision-making and data aggregation through the whole network. Sensor nodes in our scheme act following social learning principles, resembling agents within a social network. Results: We analytically examine under which conditions local actions of individual agents can propagate through the network, clarifying the effect of Byzantine nodes that inject false information. Moreover, we show how our proposed algorithm can guarantee high network performance, even for cases when a significant portion of the nodes have been compromised by an adversary. Conclusions: Our results suggest that social learning principles are well suited for designing robust IoT sensor networks and enabling resilience against data falsification attacks. PMID- 30416938 TI - Network partitioning algorithms as cooperative games. AB - The paper is devoted to game-theoretic methods for community detection in networks. The traditional methods for detecting community structure are based on selecting dense subgraphs inside the network. Here we propose to use the methods of cooperative game theory that highlight not only the link density but also the mechanisms of cluster formation. Specifically, we suggest two approaches from cooperative game theory: the first approach is based on the Myerson value, whereas the second approach is based on hedonic games. Both approaches allow to detect clusters with various resolutions. However, the tuning of the resolution parameter in the hedonic games approach is particularly intuitive. Furthermore, the modularity-based approach and its generalizations as well as ratio cut and normalized cut methods can be viewed as particular cases of the hedonic games. Finally, for approaches based on potential hedonic games we suggest a very efficient computational scheme using Gibbs sampling. PMID- 30416939 TI - Multiscale higher-order TV operators for L1 regularization. AB - In the realm of signal and image denoising and reconstruction, l1 regularization techniques have generated a great deal of attention with a multitude of variants. In this work, we demonstrate that the l1 formulation can sometimes result in undesirable artifacts that are inconsistent with desired sparsity promoting l0 properties that the l1 formulation is intended to approximate. With this as our motivation, we develop a multiscale higher-order total variation (MHOTV) approach, which we show is related to the use of multiscale Daubechies wavelets. The relationship of higher-order regularization methods with wavelets, which we believe has generally gone unrecognized, is shown to hold in several numerical results, although notable improvements are seen with our approach over both wavelets and classical HOTV. These results are presented for 1D signals and 2D images, and we include several examples that highlight the potential of our approach for improving two- and three-dimensional electron microscopy imaging. In the development approach, we construct the tools necessary for MHOTV computations to be performed efficiently, via operator decomposition and alternatively converting the problem into Fourier space. PMID- 30416941 TI - Prolonged Cefoxitin Infusion Using Mobile Elastomeric Infusors In Outpatients With Bone And Joint Infection. AB - We reviewed all outpatients with bone and joint infection treated with cefoxitin in continuous intravenous infusion using mobile elastomeric infusors in our regional reference center between 2014 and 2017. The stability of cefoxitin provides an interesting and well-tolerated alternative for continuous infusion in outpatients with polymicrobial bone and joint infection. PMID- 30416940 TI - Redox Modulation at Work: Natural Phytoprotective Polysulfanes From Alliums Based on Redox-Active Sulfur. AB - Purpose of review: This article provides a brief overview of natural phytoprotective products of allium with a special focus on the therapeutic potential of diallyl polysulfanes from garlic, their molecular targets and their fate in the living organisms. A comprehensive overview of antimicrobial and anticancer properties of published literature is presented for the reader to understand the effective concentrations of polysulfanes and their sensitivity towards different human pathogenic microbes, fungi, and cancer cell lines. Recent findings: The article finds polysulfanes potentials as new generation novel antibiotics and chemo preventive agent. The effective dose rates of polysulfanes for antimicrobial properties are in the range of 0.5-40 mg/L and for anticancer 20-100 MUM. The molecular targets for these redox modulators are mainly cellular thiols as well as inhibition and/or activation of certain cellular proteins in cancer cell lines. Summary: Antimicrobial and anticancer activities of polysulfanes published in the literature indicate that with further development, they could be promising candidates for cancer prevention due to their selectivity towards abnormal cells. PMID- 30416942 TI - Antibiotic Elution and Mechanical Strength of PMMA Bone Cement Loaded With Borate Bioactive Glass. AB - Introduction: Local delivery of antibiotics using bone cement as the delivery vehicle is an established method of managing implant-associated orthopedic infections. Various fillers have been added to cement to increase antibiotic elution, but they often do so at the expense of strength. This study evaluated the effect of adding a borate bioactive glass, previously shown to promote bone formation, on vancomycin elution from PMMA bone cement. Methods: Five cement composites were made: three loaded with borate bioactive glass along with 0, 1, and 5 grams of vancomycin and two without any glass but with 1 and 5 grams vancomycin to serve as controls. The specimens were soaked in PBS. Eluate of vancomycin was collected every 24 hours and analyzed by HPLC. Orthopedic-relevant mechanical properties of each composite were tested over time. Results: The addition of borate bioactive glass provided an increase in vancomycin release at Day 1 and an increase in sustained vancomycin release throughout the treatment period. An 87.6% and 21.1% increase in cumulative vancomycin release was seen for both 1g and 5g loading groups, respectively. Compressive strength of all composites remained above the weight-bearing threshold of 70 MPa throughout the duration of the study with the glass-containing composites showing comparable strength to their respective controls. Conclusion: The incorporation of borate bioactive glass into commercial PMMA bone cement can significantly increase the elution of vancomycin. The mechanical strength of the cement-glass composites remained above 70 MPa even after soaking for 8 weeks, suggesting their suitability for orthopedic weight-bearing applications. PMID- 30416943 TI - Economic Impact of Prosthetic Joint Infection - an Evaluation Within the Portuguese National Health System. AB - Introduction: Prosthetic infection is a devastating complication of arthroplasty and carries significant economic burden. The objective of this study was to analyze the economic impact of prosthetic hip and knee infection in Portuguese National Health System. Material and Methods: Case-control study carried out from January 2014 to December 2015. The mean costs of primary arthroplasties and prosthetic revision surgeries for non-infectious reasons were compared with the costs of prosthetic infections treated with debridement and preservation of the prosthesis or with two-stage exchange arthroplasty.The reimbursement for these cases was also evaluated and compared with its real costs. Results: A total of 715 primary arthroplasties, 35 aseptic revisions, 16 surgical debridements and 15 revisions for infectious reasons were evaluated. The cost of primary arthroplasties was 3,230? in the hips and 3,618? in the knees. The cost of aseptic revision was 6,089? in the hips and 7,985? in the knees. In the cases treated with debridement and implant retention the cost was 5,528? in the hips and 4,009? in the knees. In cases of infections treated with a two-stage revision the cost was 11,415? and 13,793? for hips and knees, respectively. Conclusion: As far as we know this is the first study that analyzes the economic impact of prosthetic infection in the Portuguese context. Although direct compensation for treating infected cases is much lower than calculated costs, infected cases push the overall hospital case-mix-index upwards thus increasing financial compensation for the entire cohort of treated patients. This knowledge will allow for more informed decisions about health policies in the future. PMID- 30416944 TI - Successful Debridement of a Knee Joint Prosthesis Infected with Listeria Monocytogenes. Case Report and Review of Current Literature. AB - According to the relevant literature, prosthetic joint infections caused by Listeria monocytogenes require two stage revision surgery or prosthesis removal for a successful outcome. We present the case of a patient who suffered such an infection after Total Knee Replacement surgery and was successfully treated with antibiotics, joint lavage, debridement and retention of the prosthesis. PMID- 30416945 TI - Daptomycin Plus Fosfomycin as Salvage Therapy in a Difficult-to-Treat Total Femoral Replacement Infection. AB - The highly active anti-biofilm combination of daptomycin plus fosfomycin was successfully used in a difficult-to-treat infection of a total femoral replacement caused by multi-drug resistant Staphylococcus epidermidis in a 79 year-old woman. There was no need to remove the orthopedic hardware, and the patient is currently pain free and able to walk. PMID- 30416947 TI - Erysipelas or cellulitis with a prosthetic joint in situ. AB - We describe a case of a 60-year old male who developed an acute prosthetic joint infection (PJI) of the knee, secondary to erysipelas of the lower leg due to beta hemolytic Group G streptococci. As it is unknown how often this phenomenon occurs in patients with prosthetic implants and which patients are most prone to develop this complication, we analyzed: i) the incidence of the development of a PJI in these patients and ii) the clinical characteristics of streptococcal PJI during an episode of erysipelas/cellulitis. Based on a retrospective analysis of patients with a prosthetic implant in situ presenting at the emergency department with erysipelas/cellulitis, 1 out of 10 patients developed a PJI. An additional analysis within a multicenter cohort on streptococcal PJI demonstrated in 22 patients that a secondary PJI due to erysipelas/cellulitis mostly develops in young implants (<5 years old). In 20 cases (91%), the skin infection was in the same limb as the joint prosthesis suggesting contiguous spread of bacteria. These data emphasizes the importance of preventive measures to reduce the occurrence of skin infections in patients with prosthetic implants, and if an erysipelas or cellulitis does occur, to monitor patients carefully. PMID- 30416948 TI - Intestinal Perforation by a Toothpick as Reason for Necrotizing Fasciitis. AB - Necrotizing fasciitis is an uncommon but often fatal disease. Given the various causes of necrotizing fasciitis, we report a case of sigmoid colon perforation caused by a toothpick subsequently resulting in fulminant necrotizing fasciitis of the retroperitoneum and right thigh successfully treated by hemipelvectomy and Hartmann's procedure. PMID- 30416946 TI - In vitro study of new combinations for local antibiotic therapy with calcium sulphate - Near constant release of ceftriaxone offers new treatment options. AB - INTRODUCTION: Local application of antibiotics provides high concentrations at the site of interest, with minimal systemic toxicity. Carrier materials might help manage dead space. Calcium sulphate (CaSO4) has a dissolution time that only slightly exceeds the usually recommended duration of systemic antibiotic treatments. This in vitro study evaluates compatibility, release kinetics and antibacterial activity of new combinations of antibiotics with CaSO4 as carrier material. METHODS: CaSO4 pellets added with 8% w/w antibiotic powder were exposed once in phosphate-buffered saline (PBS) solution and once in bovine plasma, in an elution experiment run over 6 weeks at 37 degrees C. Antibiotic elution was examined at various time points. Concentration was measured by liquid chromatography with tandem mass spectrometry. Antimicrobial activity was checked with an agar diffusion test. RESULTS: Piperacillin-tazobactam, ceftazidime, cefepime, and meropenem showed fast reduction of concentration and activity. Flucloxacillin and cefuroxime remained present in relevant concentrations for 4 weeks. Ciprofloxacin, levofloxacin and clindamycin lasted for 6 weeks, but also at cell toxic concentrations. Ceftriaxone showed a near-constant release with only a small reduction of concentration from 130 to 75 mg/l. Elution profiles from PBS and plasma were comparable. CONCLUSION: CaSO4 provides new possibilities in the local treatment of bone and joint infections. Ceftriaxone appears to be of particular interest in combination with CaSO4. Release persists at clinically promising concentrations, and appears to have a depot-like slow release from CaSO4, with only a small reduction in activity and concentration over 6 weeks. To the best of our knowledge, such a particular persistent release never was described before, for any antibiotic in combination with a carrier material for local application. PMID- 30416949 TI - A Case Of Recurrent Helicobacter cinaedi Prosthetic Joint Infection In An HIV Infected Man. AB - We describe the case of an HIV-infected man who developed twice a Helicobacter cinaedi prosthetic joint infection. In our knowledge, it is the first case to date. Furthermore, it illustrates the fact that this bacterium is difficult to isolate and that recurrences can occur even after apparently successful treatment. PMID- 30416950 TI - Antibiotic Elution Characteristics and Pharmacokinetics of Gentamicin and Vancomycin from a Mineral Antibiotic Carrier: An in vivo Evaluation of 32 Clinical Cases. AB - Introduction: Locally implanted antibiotic-eluting carriers may be a valuable adjuvant to the management of prosthetic joint infections. Aim: to assess local and plasma antibiotic concentrations as well as cumulative antibiotic urine excretion associated with clinical use of a gentamicin - or vancomycin-loaded mineral composite antibiotic carrier. Methods: 32 patients (male/female=19/13, mean age=56; 21-82 years) were prospectively followed after implantation of gentamicin (n=11), vancomycin (n=15), or a combination (n=7), using an antibiotic carrier (CERAMENTTM|G or CERAMENTTM|V, mean amount 11 (3-20) mL) during resection arthroplasty of the hip/knee. We measured antibiotic concentrations in plasma (1h, 3h, 24h, 48h and 72h post-implantation), urine (24h, 48h and 72h post implantation) and in drain (n=15). Results: We observed low antibiotic concentrations in plasma (Gentamicin: 0.33 mg/L (95%-CI: 0.25-0.44) and vancomycin: 1.33 mg/L (95%-CI: 1.02-1.66)) and high concentrations in drain (Gentamicin: mean 57.8 mg/L (95%-CI: 45.8-69.7) and vancomycin: mean 234.4 mg/L (95%-CI: 198.9-269.7)). Use of a drain was associated with a statistically significant reduction in vancomycin urine excretion (55.6% (95% CI: 36.45-74.92) to 28.71% (95% CI: 13.07-44.35), p=0.042). A similar trend was observed for gentamicin (34.17% (95% CI: 24.62-43.72) to 16.22% (95% CI: 0-33.86), p=0.078). Conclusions: CERAMENTTMG/V was associated with safe plasma concentrations and high local concentrations above minimum inhibitory concentration. Installation of a surgical drain results in removal of a substantial amount of antibiotics and reduces antibiotic urine excretion. PMID- 30416951 TI - Response to reduced nicotine content cigarettes among smokers with chronic health conditions. AB - Individuals with chronic health conditions persist in smoking despite the presence of smoking-related illness. The aim of this study was to examine whether chronic health conditions moderate response to reduced nicotine content cigarettes (0.4, 2.4, 5.2, 15.8 mg/g of tobacco). This is a secondary analysis of a controlled clinical laboratory study that examined the acute effects of cigarettes varying in nicotine content among individuals especially vulnerable to smoking and tobacco dependence. Participants in the present study were categorized as having 0, 1-2, or >=3 smoking-related chronic health conditions (i.e., chronic condition severity, CCS). Repeated-measures analysis of variance was used to examine whether CCS moderated response to cigarettes across measures of addiction potential (i.e., concurrent choice testing between nicotine dose pairs, Cigarette Purchase Task (CPT) performance, positive subjective effects), tobacco withdrawal, cigarette craving, and smoking topography. No main effects of CCS or interactions of CCS and nicotine dose were observed for concurrent choice testing, positive subjective effects, tobacco withdrawal, or smoking topography. Main effects of CCS were noted on the CPT with greater CCS being associated with less persistent demand. There was an interaction of CCS and nicotine dose on Factor 1 of the Questionnaire on Smoking Urges with the effects of dose significant only among those with 1-2 chronic conditions. Overall, we see minimal evidence that chronic condition severity affects response to reduced nicotine content cigarettes. A policy that reduces the nicotine content of cigarettes to minimally addictive levels may benefit smokers already experiencing smoking related chronic conditions. PMID- 30416952 TI - Failure to meet aerobic fitness standards among urban elementary students. AB - The aim of this study was to explore the relationship of aerobic fitness with the elementary school environment and student characteristics among 4th and 5th grade children attending urban public schools in St. Louis, MO, USA. This cross sectional study was conducted during 2012-2015 and included 2381 children (mean age 10.5 y) who completed the FITNESSGRAM(r) 20-m Progressive Aerobic Cardiovascular Endurance Run. Healthy Fitness Zone (HFZ) was defined according to FITNESSGRAM(r) aerobic capacity criteria. Other student-level variables included age, race, National School Lunch Program eligibility, BMI z-score, weight status, and daily pedometer steps. School environment variables included playground features and playground safety, physical education and recess practices, and school census tract data on vacant houses and median household income. Bivariate analyses with sex stratification were used to identify student-level and school level predictors of failure to achieve the aerobic HFZ; predictors were then included in a multivariable logistic regression model. Failure to meet the aerobic HFZ was observed among 33% of boys and 57% of girls. School environment was not predictive, but higher age and fewer daily steps were: each additional year of age was associated with 41% higher odds of failing to meet the aerobic HFZ among boys and 100% higher odds among girls. Conversely, each additional 1000 daily steps was associated with 15% (boys) and 13% (girls) lower odds of failure. Obesity posed a 60% higher risk of failure to meet HFZ among girls. These results highlight the importance of childhood physical activity opportunities, especially for girls residing in low-resource areas. PMID- 30416953 TI - Mosquito-borne infectious disease, risk-perceptions, and personal protective behavior among U.S. international travelers. AB - Vector-borne diseases account for a significant amount of the global infectious disease burden, including morbidity and mortality. In particular, mosquito-borne infectious diseases (MBIDs) have the greatest burden in number of cases, mortality, and disability-adjusted life years and their prevention and control is critical. However, prevention efforts are hindered by the absence of vaccines and failure of long-term mosquito vector control for these MBIDs. Thus, personal protective behaviors (PPBs) may offer the most promising and effective mode of prevention. This study examines the impact of awareness, perceived susceptibility, and perceived severity for five MBIDs (e.g., Malaria, Dengue, Zika, Chikungunya and West Nile) on the adoption of PPBs. Study participants (n = 1043) were recruited from a probability-based internet panel of adult United States residents with a history of traveling outside of the country in the past year. Data were collected in the U.S. between June 7, 2017 and June 12, 2017. Our findings show that awareness of Zika disease among respondents was consistently associated with adoption of all three PPBs. Respondents that reported high perceived severity for all five MBIDs were also more likely to report adopting the PPBs of wearing covering clothing and use of mosquito repellent spray. Our findings indicate that U.S. travelers are largely more concerned about Zika, Chikungunya, and Dengue than Malaria and West Nile and that these concerns drive their adoption of the three recommended PPBs. This information should inform the development and design of future public health campaigns for behavior modification to prevent MBIDs. PMID- 30416954 TI - Aspergillus endocarditis diagnosed by fungemia plus serum antigen testing. AB - Fungal endocarditis remains an uncommon clinical diagnosis, though is likely to become more frequent due to the global increase in transplantations and cardiac valvular surgery. A case of prosthetic valve endocarditis due to Aspergillus fumigatus is described that was diagnosed with serologic fungal markers and confirmed with positive blood cultures, an uncommon finding. PMID- 30416955 TI - Lung function improvements in emphysema following pneumonia. AB - We describe two cases of patients with emphysema who, in the lead up to hyperinflation intervention, developed pneumonia with significant physiological, anatomical, functional and quality of life improvement observed following. This directly goes against the natural history of both disease processes, demonstrating the benefit resulting from infective autobullectomy. PMID- 30416956 TI - Breathlessness worsened by haemodialysis. AB - A 54 year old lady with underlying chronic lung disease on long term oxygen therapy and end stage renal disease of unknown aetiology on regular haemodialysis for two years started developing progressive shortness of breath during her routine haemodialysis. She was unable to tolerate her haemodialysis sessions which had to be terminated prematurely in view of her symptoms despite adjustment of her dry weight and treatment of anaemia. She was not in chronic fluid overload and her symptoms always worsened after initiation of haemodialysis and improved after termination of haemodialysis. She was admitted to hospital for further investigations and initially treated for a lung infection but her symptoms did not improve. A computed tomography pulmonary angiography did not reveal any evidence of pulmonary embolism, and was consistent with chronic fibrotic changes. Her hypoxemia was concluded to be due to her underlying chronic lung disease, worsened by alveolar hypoventilation during haemodialysis. Her symptoms improved slightly with supplemental oxygen during her routine haemodialysis but we had to shorten her haemodialysis duration to 3 hours. PMID- 30416957 TI - High-dose methotrexate vs. Capizzi methotrexate for the treatment of childhood T cell acute lymphoblastic leukemia. AB - Sixty-three children (1-14 years of age) newly diagnosed with T-cell acute lymphoblastic leukemia were treated from January 2001 to December 2014. Patient outcomes were evaluated based on the regimen received; Capizzi methotrexate (C MTX) vs. high-dose methotrexate (HDMTX). Complete remission (CR) was achieved in 54 of 60 (90.0%) patients and 3 patients died during induction. The 5-year overall survival (OS) and disease-free survival (DFS) were 88.3 +/- 6.5% and 85 +/- 7.5%, respectively. Post-induction, 35 patients were treated with HDMTX and 25 with C-MTX. There was no difference in OS or DFS for patients treated with HDMTX vs. C-MTX (P > 0.05 for both). Central nervous system involvement (CNS3) was associated with inferior survival outcomes compared to Non-CNS3 patients (OS, CNS3 73.3 +/- 9.1% vs.non-CNS3 93.2 +/- 2.6%, (P = 0.045) and DFS, CNS3 66.7 +/- 10.4% vs. non-CNS3 90.9 +/- 3.1% (P = 0.0163)). Delayed radiation in CNS3 was associated with relapse (P = 0.0037) regardless of regimen. Thus optimization of CNS-directed therapy for patients with CNS3 is needed. PMID- 30416958 TI - Qualitative and quantitative methods for estimating Spirorchiidiasis burden in sea turtles. AB - Infection by blood flukes Hapalotrema mistroides and Neospirorchis sp. (Digenea: Spirorchiidae) has been recently reported in Caretta caretta (Linnaeus, 1758) in the Mediterranean Sea. Observations of post mortem lesions are generally used to assess disease severity, and few attempts have been made to standardize the evaluation of the parasitic burden from tissue egg counts. Faeces and spleen homogenates of 105 loggerheads from the northwestern Adriatic Sea were submitted to a sedimentation-flotation technique for the research of spirorchiid eggs; molecular techniques were used for unequivocal identification. Egg quantification for positive faeces and spleen samples was achieved using a modified McMaster method. Spleen samples were also submitted to quantification through the only method cited in the literature for similar purposes, which involves preventive chemical digestion. Correlations between splenic counts obtained from the two different methods and between faecal and splenic egg burdens were calculated using Spearman's rho test. Concordance between studies on eggs in faeces and spleen tissue was also calculated. Eggs of H. mistroides and Neogen-11 were found in spleen and faecal samples. Strong correlations were found between splenic egg burdens calculated from the two methods for H. mistroides, demonstrating that the modified McMaster method can be used for quantification. A multiplying factor must be used before drawing comparisons, as egg burdens are higher in value when measured after chemical digestion. High concordance was obtained from a qualitative examination of faeces and spleen tissue of H. mistroides, showing that copromicroscopic examination can be used for in vivo diagnosis. As weak correlations were found between faecal and splenic egg counts, faecal burden cannot be regarded as indicative of disease severity. For Neogen-11, low concordance was found between faeces and spleen tissue, likely reflecting lower levels of egg embolization in organs. PMID- 30416959 TI - First molecular identification of Vorticella sp. from freshwater shrimps in Tainan, Taiwan. AB - Freshwater shrimps are the most common crustaceans kept in an aquarium. This study was a survey seeking parasites infecting cultured freshwater atyid shrimps at aquarium stores in Tainan, Taiwan. We observed that atyid shrimps were infested with Vorticella and Scutariella. Scutariella is a common shrimp parasite; thus, we focused on Vorticella infection in the atyid shrimps. Vorticella aequilata-like pop TW, a freshwater peritrich ciliate, was isolated from the atyid shrimps. The morphological characteristics were investigated using live observations. Specimens from the population showed identical arrangement of the infraciliature and identical ITS1-5.8SITS2 region sequences. The zooids are bell-shaped, 40-58 MUm wide and 47-70 MUm in long in vivo. The food vacuole is variable in shape and is located in the middle of the cell. ITS1-5.8S-ITS2 sequences of Vorticella aequilata-like pop TW did not match any available sequences in GenBank. Phylogenetically, Vorticella aequilata-like pop TW clusters with the other Vorticella within the family Vorticellidae and nests with Vorticella aequilata in the subclade. Above all, the morphological characteristics and molecular analyses show that the investigated Vorticella is a Vorticella aequilata-like species. The phylogenetic analyses of ciliates based on the ITS1-5.8S-ITS2 sequences reveal that the Vorticella genus consists of Vorticella morphospecies and that taxonomic revision of the genus is needed. Morphometric criteria and molecular analysis were used to describe and identify the Vorticella specie and this study presents the first molecular identification analysis of the Vorticella species in the cultured atyid shrimps in Tainan, Taiwan. PMID- 30416960 TI - Routine replacement of a vagal nerve stimulator generator leading to asystole. AB - A 52-year-old female with a longstanding history of drug-resistant epilepsy that included focal impaired awareness seizure presented at end of service of her vagus nerve stimulator (VNS) generator. She had undergone a generator replacement in 2010 without complication. However, her latest replacement was accompanied by multiple bouts of asystole. We discuss the case, possible causes of the asystole, and its relevance to the future of VNS generator replacement and epilepsy treatment. PMID- 30416961 TI - Post-operative nonketotic hyperglycemic induced focal motor status epilepticus related to treatment with corticosteroids following standard anterior temporal lobectomy. AB - *Complications from standard ATL are uncommon and the use of post-operative corticosteroids may reduce complications.*Following standard ATL, FMSE was present after treatment with corticosteroids that resolved after blood sugar control.*After epilepsy surgery, corticosteroids should be used cautiously in people with comorbid diabetes mellitus. PMID- 30416962 TI - Recurrent focal seizures as a feature of status epilepticus presenting as a peri ictal water drinking. AB - We report a case of focal status epilepticus (SE) associated with peri-ictal water drinking (PIWD) behavior in a nine-year-old left-handed boy with epilepsy. We reviewed prior cases of epileptic peri-ictal water drinking. Only one adult patient with status epilepticus and PIWD has been reported previously. This is the first reported case of PIWD SE in a pediatric patient with frontal lobe epilepsy. We found PIWD to have no lateralizing value. PMID- 30416963 TI - Vanadate inhibits transcription of the rat insulin receptor gene via a proximal sequence of the 5'flanking region. AB - Vanadate, a protein tyrosine phosphatase inhibitor which elicits insulin-like effects, has previously been shown to inhibit expression of the insulin receptor gene at the transcriptional level in rat hepatoma cells. In an attempt to identify the DNA sequence and transcription factors potentially involved in this effect, a fragment of the proximal 5'flanking region of the IR gene (-1143/-252 upstream the ATG codon) has been cloned and functionally characterized. RNase protection allowed the identification of several transcription start sites in the conserved region of the gene, among which two major sites at -455 and -396. Upon fusion to the luciferase gene and transient transfection into hepatoma cells, the -1143/-252 fragment showed promoter activity. This was unaffected by deletion of the -1143/-761 sequence, but markedly decreased (90%) by additional deletion of the -760/-465 sequence. Treatment of hepatoma cells with vanadate led to a dose dependent decrease in promoter activity of the 1143/-252, -760/-252 and -464/-252 constructs (change relative to untreated cells, 40, 55 and 23% at 125 MUM, and 70, 85 and 62% at 250 MUM, respectively). These data suggest that although the entire DNA sequence upstream the transcription start sites is probably involved in vanadate-induced inhibition, the short sequence downstream of position -464 and is sufficient for inhibition. Potential targets of vanadate are the transcription factors FoxO1 and HMGA1, two downstream targets of the insulin signaling pathway which have been shown to mediate the inhibitory effect of insulin on IR gene expression. PMID- 30416964 TI - Magnetic resonance imaging features for the differential diagnosis of local recurrence of bone sarcoma after prosthesis replacement. AB - Objective: To explore the imaging features of local recurrences (LRs) based on magnetic resonance imaging (MRI) after oncological orthopaedic surgery with prosthesis reconstruction. Methods: A total of 78 cases totalling 157 scans were retrospectively reviewed. Patients with nodule/mass-like signals were retrospectively classified into LR, infectious pseudotumour, and asymptomatic pseudotumour according to clinicopathological data. LRs were histologically confirmed, and the patients without recurrences were followed up for at least 2 years. Mass size distribution and radiological characteristics were analysed for differential diagnosis of the LR versus pseudotumour. Results: Thirty-three of 78 cases were positive with nodule/mass-like signal findings on the post-operative MRI images. By analysing the size distribution, we found that masses >2.1 cm (14) were almost attributable (98% specificity) to LRs and mostly (84.6%) timely treated. Contrarily, masses <=2.1 cm (19) are challenging for differential diagnosis of LRs versus pseudotumour and were undertreated in five of the nine LR cases. MRI characteristics of masses <=2.1 cm were found to be highly heterogeneous, with solid appearance, adjacent infiltration, and less peritumour oedema being significant indicators for LRs (P<0.05). Receiver operating characteristic curve showed area under curve of 0.93 for this predictive model. Conclusions: For the post-operative MRI surveillance of oncological orthopaedic surgery with prosthesis reconstruction, a mass larger than 2.1 cm was highly specific for recurrence. When a mass was smaller than 2.1 cm, more solid property, more adjacent tissue infiltration, and less muscular oedema indicated recurrence rather than a benign mass. The translational potential of this article: There has been very little data associated with the post-operative magnetic resonance imaging features indicating recurrence in patients with malignant bone sarcoma after prosthesis replacement. This study could help develop diagnostic features of magnetic resonance imaging for differentiating recurrence from benign changes in these patients after prosthesis replacement. PMID- 30416965 TI - Listeria peritonitis and bacteremia in a patient with cholangiocarcinoma. AB - We are presenting a case of Listeria monocytogenes spontaneous bacterial peritonitis (SBP) monomicrobial non-neutrocytic bacterascites (MNS) in a patient with malignant ascites secondary to cholangiocarcinoma who underwent peritoneal catheter placement. Listeria peritonitis is uncommon, with cancer patients at a higher risk. Listeria infection should be suspected in susceptible patients once there is no response to empiric antibacterial or if the initial culture report shows gram positive bacilli, the antibacterial of choice is ampicillin. PMID- 30416966 TI - Cavo-atrial endocarditis: A case of non-valvular endocarditis in a hemodialysis patient. PMID- 30416968 TI - Distal corporoplasty using an autologous tunica in the management of penile prosthesis pseudo aneurysm. PMID- 30416967 TI - Reproductive experience of women living with phenylketonuria. AB - Introduction: Many women with PKU are well-informed about the risks of maternal PKU but there are several barriers to achieving satisfactory metabolic control before and during pregnancy. Many studies have documented the outcome of maternal PKU infants, but very little has been reported about the experiences of women of reproductive age with PKU, particularly about their psychosexual development, pre conception, pregnancy and postnatal experience. Methods: In the UK, in a subsection of an online questionnaire conducted by the National Society for PKU (NSPKU) about living with PKU, women aged 18 years and over completed 9 closed questions about their pre-conception, pregnancy and post-natal experiences and an open-ended question on their reproductive health. Results: 300 women aged 18 years and over with PKU completed this questionnaire with 37% (n = 111/300) of women already having children. 56% (n = 71/128) of pregnancies were planned and a further 18% (n = 23/128) of women had both planned and unplanned pregnancies. Most women (73%, n = 200/273) expressed concerns, fears and distress about pregnancy and two thirds of women who had at least one pregnancy stated that having PKU made pregnancy more stressful and difficult. 60% (n = 164/273) were concerned that they may cause harm to a baby, 58% (n = 159/273) worried about their ability to manage a strict diet during pregnancy, 54% (n = 147/273) had anxiety about their ability to maintain blood Phe within target range, and 48% (n = 132/273) feared having an unplanned pregnancy.Postnatally, 48% (n = 45/93) had low mood or sadness, 41% (n = 38/93) were depressed, 34% (n = 32/93) felt unable to cope, 33% (n = 31/93) said they could not manage their PKU and care for their baby, 14% (n = 13/93) struggled with child care needs and 4% (n = 4/94) worried they might hurt themselves or their baby through being unable to manage their diet. Conclusions: Many women with PKU have unmet sexual and reproductive health needs. Pregnancy fears are prominent from adolescence onwards and for some women overarching concerns about their ability to cope with pregnancy led to a decision not to have children. Interventions are needed to reduce the psychological impact of the risk of maternal PKU syndrome and assist with safe pregnancies. Post-natal experiences of women with PKU give rise to concern. PMID- 30416969 TI - Why here? Factors influencing Palestinian refugees from Syria in choosing Germany or Sweden as asylum destinations. AB - This paper presents the findings of 33 interviews, carried out in 2017, examining the factors influencing Palestinian refugees from Syria (PRS) in choosing Germany or Sweden as asylum destinations. The findings showed that there was a very high degree of destination specificity towards Sweden for nearly all of the participants. This was based on their desire to reach Sweden due to its accessible citizenship as compared to other European or Arab states. This paper details how most of the refugees had conducted research, drawing on information from social networks and other sources, in order to establish in which European country they could most easily and quickly acquire citizenship. As a consequence of the prioritisation of resolving their and their families' statelessness as quickly as possible, the interviewees often devalued social and human capital. Considerations related to economic or educational opportunities played only a marginal role in the decision making. This research finds that in order to better understand the migration of stateless refugees, their desire to resolve their statelessness should be considered as a potentially significant aspect of their choice of asylum destination. PMID- 30416970 TI - Inter-generational transnationalism: the impact of refugee backgrounds on second generation. AB - This paper explores transnational activities among the UK born second generation from three refugee backgrounds: Tamils from Sri Lanka, Kurds from Turkey and Vietnamese. Drawing on qualitative interview data from 45 interviews, the paper explores the views and experiences of the second generation but also their reflections and interpretations of their parent's histories and transnational activities. The paper takes a comparative and inter-generational approach. It compares transnationalism among second generation with that of the refugee generation and highlights generational differences. The intersections of refugee histories with transnationalism are brought to the forefront of the analysis and in so doing demonstrates the significance of refugee backgrounds on transnational practices. PMID- 30416971 TI - Sampling migrants in six European countries: how to develop a comparative design? AB - This article discusses the possibilities and constraints of designing an identical or at least comparable sampling strategy across different European countries. It is based on expert reviews from six European Union member states that discuss the possibilities of sampling migrants in their respective countries. The country sample includes two countries from Northern Europe (Sweden, Denmark), two from Continental Europe (Germany, The Netherlands), and two from Southern Europe (Spain, Italy). After a discussion of various definitions of the target population and an overview of existing strategies to sample them, it is investigated which of them can be used in the six countries analyzed in the expert reviews. The focus is on probability samples and the use of population registers, while other sampling strategies are only briefly touched upon. The analysis shows that even with only six European countries an identical register-based sampling design is difficult. The authors propose that, by focusing on sampling immigrants in cities, researchers can better implement sampling strategies which result in comparable samples. PMID- 30416973 TI - A higher blood glucose level pre-breakfast in comparison to bedtime is a contraindication for intensification of prandial insulin therapy in patients with type 2 diabetes - The impact of a negative BeAM value. AB - Aims: The BeAM value refers to the difference between a patient's blood glucose level at bedtime (Be) and the following morning before breakfast (AM). The clinical impact of a negative BeAM value (AM blood glucose reading compared to that taken at bedtime) is unknown. Methods: T2DM patients of the OPAL and POC trials were pooled and their BeAM values calculated. Results: From a total of 358 patients, 31 were calculated as having a negative BeAM value at baseline, while 182 had a high value. Patients in the negative BeAM group were younger, had shorter diabetes duration, and lower HbA1c levels. Fasting blood glucose levels were higher in the negative BeAM group, and these increased to a greater extent during the trial periods. No significant differences in hypoglycaemia occurrence were observed. Multivariate adjusted analysis indicated no association between a negative BeAM value and achievement of HbA1c < 7%, or composite endpoints that additionally included no hypoglycaemia and no weight gain. Conclusions: Supplementation of BOT with prandial insulin is not beneficial for patients who have a higher blood glucose reading before breakfast in comparison to before bedtime. Further investigation into the cause of the high morning reading in these patients is indicated. PMID- 30416972 TI - Less known aspects of central hypothyroidism: Part 1 - Acquired etiologies. AB - Central hypothyroidism (CH) is a rare cause of hypothyroidism. CH is frequently overlooked, as its clinical picture is subtle and includes non-specific symptoms; furthermore, if measurement of TSH alone is used to screen for thyroid function, TSH concentrations can be normal or even above the upper normal reference limit. Indeed, certain patients are at risk of developing CH, such as those with a pituitary adenoma or hypophysitis, those who have been treated for a childhood malignancy, have suffered a head trauma, sub-arachnoid hemorrhage or meningitis, and those who are on drugs capable to reduce TSH secretion. PMID- 30416974 TI - Gender-specific correlation of intranodular chronic lymphocytic thyroiditis with thyroid nodule size, echogenicity, and histologically-verified cytological class of malignancy risk. AB - No data are available on the cytologically and histologically demonstrated presence of intranodular chronic lymphocytic thyroiditis (ICLT) and on the ICLT relationship with thyroid nodule characteristics such as size, echotexture and nature (benign or malignant). We wished to fill this gap by analyzing data in a gender-specific fashion. We studied 408 thyroid nodules from 408 consecutive persons (325 females and 83 males). Nodules were isoechoic (n = 268) or hypoechoic (n = 140), ICLT +ve (n = 113 [27.7%]) or ICLT -ve (n = 295), cytologically low-risk (n = 197) or high-risk (n = 211), histologically benign (n = 263) or malignant (n = 145). ICLT prevailed in females (97/113) and in hypoechoic nodules (58/140 [41.4%] vs 55/268 [20.5%], P < 0.0001). Compared to males, females had (i) smaller nodules (18.5 +/- 9.4 vs 23.3 +/- 13.4 mm, P = 0.0002), a difference due to the isoechoic nodules (21.1 +/- 9.8 vs 26.6 +/- 14.1 mm, P = 0.0006), (ii) lower rates of high-risk nodules (161/325 [49.5%] vs 50/83 [60.2%], P = 0.082) and malignant nodules (110/325 [33.8%] vs 35/83 [42.2%] P = 0.16). ICLT +ve nodules were smaller than the ICLT -ve ones (15.4 +/- 6.9 vs 20.9 +/- 11.2 mm, P < 0.0001), a difference due to the isoechoic nodules (17.5 +/- 6.5 vs 23.6 +/- 11.7 mm, P = 0.0003). The smallest nodules were hypoechoic, cancerous and ICLT +ve nodules in males (9.5 +/- 4.0 mm); the largest were isoechoic, cytologically risky and ICLT -ve in males (29.1 +/- 13.2 mm). Compared to ICLT ve nodules, malignancy prevailed in ICLT +ve nodules (55/113 [48.7%] vs 90/295 [30.5%], P = 0.0006), both in hypoechoic (37/58 [63.8%] vs 41/82 [50.0%]) and isoechoic nodules (18/55 [32.7%] vs 49/213 [23.0%]). ICLT +ve hypoechoic nodules of females and ICLT -ve hypoechoic nodules of males had the greatest rate of malignancy (67% both), while ICLT -ve isoechoic nodules of females had the lowest (19%). In conclusion, presence/absence of ICLT is associated with some sexually dimorphic characteristics of thyroid nodules. Adding the specification of ICLT positivity/negativity in cytological reports may help improving the risk of malignancy at least in some groups of thyroid nodules. PMID- 30416975 TI - Factors related to stress fracture after unicompartmental knee arthroplasty. AB - Background/objective: Unicompartmental knee arthroplasty (UKA) is a low-invasive knee surgery that enables early recovery. Stress fracture of the medial tibial plateau (MTP) is a complication of UKA that prolongs treatment once it has occurred. We investigated factors affecting its occurrence. Methods: The study subjects were 167 patients who underwent fixed-bearing UKA between 2009 and 2016 (45 men and 122 women of mean age 77 years, including 134 with osteoarthritis of the knee and 33 with spontaneous osteonecrosis). We measured bone mineral density, installation angle of the tibial component, and leg alignment in those patients who developed stress fracture within 3 months after UKA. Results: Stress fracture did not occur in 155 patients (N group, 45 men and 110 women) and did occur in 12 (SF group, 12 women). The bone mineral density (BMD) of the proximal femur was significantly lower in the SF group, indicating that bone fragility may have contributed to stress fractures at this site. There was no significant difference in the preoperative tibio-femoral angle (TFA), however, postoperative TFA was larger and the magnitude of the change in the valgus direction (DeltaTFA) was smaller in the SF group. Discussion: In usual UKA for medial compartment, the leg is more extroverted postoperatively than preoperatively, and leaving the knee in the genu varus position, which places a greater load on the tibial component, may raise the risk of stress fracture. Although there was no difference between the two groups in the varus angle of the tibial component, in a scatter plot of postoperative TFA and the installation angle of the tibial component members of the SF group were concentrated in the region of high TFA and low varus angle. Varus of the leg and a low varus angle of the tibial component may thus be factors in the occurrence of stress fracture. Conclusion: Our results suggested that low BMD in the affected femur, large postoperative TFA, and a combination of large postoperative TFA and small varus angle of the tibial component may contribute to stress fracture of the MTP following UKA. PMID- 30416976 TI - Toxicological evaluation of a saponin-rich standardized extract of fenugreek seeds (FenuSMART(r)): Acute, sub-chronic and genotoxicity studies. AB - The present study investigated the safety of a saponin-rich standardized extract of fenugreek seeds (FenuSMART(r); FHE), that has been clinically shown to be effective in ameliorating the postmenopausal discomforts and establishing hormonal balance. The safety was assessed by oral acute (2500 mg/kg b. wt. for 14 days) and subchronic (250, 500 and 1000 mg/kg b. wt. for 90 days) toxicity studies on Wistar rats and mutagenicity studies employing Salmonella typhimurium strains. Administration of FHE did not produce any toxicologically significant changes in clinical/behavioral observations, ophthalmic examinations, body weight, organ weight, feed consumption, urinalysis, hematology and clinical biochemistry parameters when compared to the untreated control group of animals. Highest dose recovery group (1000 mg/kg b. wt.) of animals also showed no mortality or adverse events; with hematological and biochemical parameters at par with those of controls. Terminal autopsy revealed no alterations in relative organ weight or any treatment-related histopathology changes. FHE also showed no mutagenicity upon Ames test employing TA-98, TA-100 and TA-102 Salmonella typhimurium strains with or without metabolic activation. Based on the results of the study, the no observed-adverse-effect level (NOAEL) of FHE was determined as 1000 mg/kg b. wt./day, the highest dose tested. PMID- 30416977 TI - Twin pregnancy complicated by total placenta previa in a Fontan-palliated patient: A case report. AB - We present a case of a twin pregnancy in a Fontan-palliated woman that was complicated by total placenta previa. The patient was diagnosed with tricuspid atresia type II, and underwent the Fontan operation at 11 years of age. At 32 years of age, she was shown to have a dichorionic diamniotic twin pregnancy. A placenta previa was also noted. At 26 weeks' gestation, she had difficulty breathing, cardiomegaly, and worsening mitral regurgitation. At 29 weeks' gestation, an emergency cesarean section was performed, as the patient had massive genital bleeding. A postoperative cardiac catheterization demonstrated a leak from the lateral tunnel to the atrium, which was considered a cause of hypoxemia during the peripartum period. The cardiac workload in a twin pregnancy is greater, which places a Fontan-palliated patient at increased risk. Careful follow-up monitoring with multidisciplinary expertise is recommended. PMID- 30416978 TI - Development of underwater radiography scanner for reactor-pool experiment at the TRIGA PUSPATI reactor. AB - This paper describes the development of a custom-designed underwater scanner to support the experimental works for characterizing irradiated fuel stored in the TRIGA PUSPATI pool by means of radiography technique. Materials used to build the scanner are aluminum 6061, lead and teflon. Three main units that make up the scanner are rig structure, arm block and collimator. Collimator is designed to control radiation exposure by opening and closing the shutter. The experimental works were conducted underwater at 5-m depth hence water tightness is one of the main design criteria. Radiation in terms of gamma energy is captured by radiography film which after development and processing revealed the image of the radiation impact in terms of pixel and gray value. The film size used is 4in x 8in which was slot in the collimator. To validate the scanner, fuel element containing 8.5 wt% and 12 wt% enriched Uranium 235 were used. It was found that the experimental output is consistent with the fuel type and confirmed that the scanner is viable for fuel characterization study. PMID- 30416979 TI - Health improvement of human hair and their reshaping using recombinant keratin K31. AB - Hair, being one of the most important components of the beauty care processes, attracts the use of a variety of hair treating cosmetics. Conventional hair treating cosmetics are not satisfactory for one reason or the other. Commercially used keratins are isolated from wool or chicken feathers. As these lack complete sequence identity with human hair keratin, are likely to be less efficient than the human hair keratin. K31, a type I acidic keratin, is a major protein of human hair keratin complex and it is essential for maintaining the hair tensile strength. In this study keratin K31 (46 kDa) gene was expressed in Escherichia coli at a level of approximately 35% of the total cell proteins. The protein, however, was expressed as insoluble inclusion bodies. The expressed protein was refolded and purified by FPLC using an anion-exchange column. The CD analysis results showed that the K31 was properly refolded. MALDI-TOF mass spectroscopy showed the characteristics expected for human K31 keratin. The refolded and partially purified K31 protein, when applied on chemically damaged hairs, increased the diameter of the hair up to 49%. The mechanical strength of the bleached hair increased by almost 2 fold after a single treatment of K31. The protein also straightened curly hair efficiently on a single treatment for one hour. Application of K31 resulted in marked improvements in smoothness, diameter and mechanical strength of the damaged hair. PMID- 30416980 TI - Evaluation of gradual adaptation of mixed microalgae consortia cultivation using textile wastewater via fed batch operation. AB - This study investigated mixed microalgae consortia cultivation in a fed batch reactor using textile wastewater. The results showed 95% of total phosphorus (TP) and 70% of total nitrogen (TN) depletion during the operational period. Algal biomass growth, pollutant removal, and biomass constituents were examined for five cycles of the fed batch operation. The length of the cycles decreased from 30 days to 10 days as the cycle repeated, which implied gradual adaptation of microalgae to textile wastewater. Color of textile wastewater was removed in the range of 68-72% in all the cycles experimented. Microbial algal cultivation with textile wastewater would be a feasible approach for remediation and resource recovery purpose. PMID- 30416981 TI - HPV-Related Cancer Prevention and Control Programs at Community-Based HIV/AIDS Service Organizations: Implications for Future Engagement. AB - Background: People living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and, men who have sex with men (MSM) are disproportionately affected by genital warts and cancers caused by human papillomavirus (HPV). We assessed community-based HIV/AIDS service organizations' (ASOs) staff awareness, knowledge, attitudes, and beliefs about HPV and effective cancer prevention tools, namely HPV vaccination, Pap, and HPV tests. The potential engagement of ASO staff in future efforts to reduce the disproportionate burden of genital warts and HPV-related cancers among HIV positive women and MSM was explored. Methods: In May-June 2016, staff were recruited from three ASOs located in the South United States Census region-a geographical area disproportionately affected by HIV/AIDS. Participants completed a 30-min self-administered, 118-item paper and pencil survey about HPV and cancer. Data analysis was conducted using Stata/SE 14.2. Results: ASO staff (n = 30) were 83% non-Hispanic Black, 40% lesbian/gay, and worked with people living with HIV for an average of 11.4 +/- 7.7 years. All reported hearing of HPV and 77% had heard of the HPV vaccine (n = 23). While all knew HPV can cause cervical cancer, only 67% knew HPV can cause anal cancer. Most (61%) thought the HPV vaccine could prevent cervical cancer. Fewer (39-48%) thought the HPV vaccine could prevent anal, oral, penile, vaginal, and vulvar cancers. All were willing to encourage MSM and female clients to talk to a healthcare provider about HPV vaccination. Almost all were willing to promote HPV vaccination to clients (91 95%) and navigate clients to adult safety net HPV vaccine providers (86-95%). More than half (59-67%) thought they could positively influence their MSM and female clients' HPV vaccine decision-making. Conclusion: HPV vaccination and the Pap and HPV tests are effective cancer prevention tools that can reduce the disproportionate burden of genital warts and HPV-related cancers among HIV positive women and MSM. Engaging ASO staff in cancer prevention efforts may increase HPV vaccination rates and early detection of HPV-related cancers among HIV-positive women and MSM. Exploring ASOs as community-based settings for promoting effective cancer prevention tools may foster opportunities to reduce the disproportionate burden of genital warts and HPV-related cancers among HIV positive women and MSM. PMID- 30416984 TI - Editorial: Precision Medicine in Oncology. PMID- 30416983 TI - Management and Prognostic Factors for Thyroid Carcinoma Showing Thymus-Like Elements (CASTLE): A Case Series Study. AB - Introduction: This study aims to identify the prognostic factors that influence therapeutic modalities for thyroid carcinoma showing thymus-like elements (CASTLE). Materials and Methods: Reported studies with CASTLE patients published between 2004 and 2018 were retrieved from a cross-database literature search. Three patients treated in our institute were also included as one case series. Standardized data collection was performed; data pertaining to clinical stages, treatment regimens, and survival time were collected and statistically analyzed. Results: Up to 26 case series of CASTLE were selected, including 51 males and 38 females with a median age of 48 years. Follow-up time ranged from 2 to 362 months and the median survival time was 158.03 months. Lymph node metastasis and tumor invasion of adjacent tissue both showed a significant negative effect on survival (p = 0.001 and 0.013, respectively). Radiotherapy significantly improved survival (p = 0.034), while neck dissection significantly prolonged survival only in patients with extrathyroidal extension (p = 0.043). Conclusions: Extrathyroidal infiltration and nodal metastasis are important factors in cancer outcomes. Radiation therapy appears to be important for better outcomes in CASTLE patients, and neck dissection is recommended for patients with extrathyroidal extension. PMID- 30416985 TI - Vaccination With a FAT1-Derived B Cell Epitope Combined With Tumor-Specific B and T Cell Epitopes Elicits Additive Protection in Cancer Mouse Models. AB - Human FAT1 is overexpressed on the surface of most colorectal cancers (CRCs) and in particular a 25 amino acid sequence (D8) present in one of the 34 cadherin extracellular repeats carries the epitope recognized by mAb198.3, a monoclonal antibody which partially protects mice from the challenge with human CRC cell lines in xenograft mouse models. Here we present data in immune competent mice demonstrating the potential of the D8-FAT1 epitope as CRC cancer vaccine. We first demonstrated that the mouse homolog of D8-FAT1 (mD8-FAT1) is also expressed on the surface of CT26 and B16F10 murine cell lines. We then engineered bacterial outer membranes vesicles (OMVs) with mD8-FAT1 and we showed that immunization of BALB/c and C57bl6 mice with engineered OMVs elicited anti-mD8-FAT1 antibodies and partially protected mice from the challenge against CT26 and EGFRvIII-B16F10 cell lines, respectively. We also show that when combined with OMVs decorated with the EGFRvIII B cell epitope or with OMVs carrying five tumor-specific CD4+ T cells neoepitopes, mD8-FAT1 OMVs conferred robust protection against tumor challenge in C57bl6 and BALB/c mice, respectively. Considering that FAT1 is overexpressed in both KRAS+ and KRAS- CRCs, these data support the development of anti-CRC cancer vaccines in which the D8-FAT1 epitope is used in combination with other CRC specific antigens, including mutation-derived neoepitopes. PMID- 30416986 TI - FoxM1 Promotes Cell Proliferation, Invasion, and Stem Cell Properties in Nasopharyngeal Carcinoma. AB - Background: The self-renewal and tumourigenicity of FoxM1 in nasopharyngeal carcinoma (NPC) remain largely unknown. In this study, we attempt to investigate the self-renewal and tumourigenicity of FoxM1 and its clinical significance in nasopharyngeal carcinoma (NPC). Methods: Several assays including cell counting Kit-8 (CCK-8) assays, colony formation, flow cytometry, immunofluorescence, tumor spheres, and mice model were used to detect the biological function of FoxM1 in NPC. The association between FoxM1 and clinical pathological features, and stem cell markers was analyzed using immunohistochemistry. Results: High expression of FoxM1 was prominently present in the T4 stages, cancer cells migrating into the stroma and vasculature. Overexpression of FoxM1 enhanced tumor proliferation, cell cycle progression, migration and stress fibers formation in vitro. In NPC tissues, FoxM1 correlated significantly with stem cells-related clinical pathological features including late clinical stage, tumor recurrence and distant metastasis. Meanwhile, FoxM1 linked closely with the expression levels of stem cell markers including Nanog, Sox2, and OCT4 in tumor samples, and also promoted the expression of these stemness-related genes in vitro. Moreover, FoxM1 conferred the self-renewal properties of cancer cells by increasing side populations (SP) cells and formed larger and more tumor spheres. Importantly, FoxM1 enhanced the ability of tumourigenicity of NPC cell lines in mice xenograft. Conclusions: We demonstrate that FoxM1 greatly induces cancer progression and cancer stem cell (CSC) features in NPC. PMID- 30416982 TI - Soft Tissue Sarcoma Cancer Stem Cells: An Overview. AB - Soft tissue sarcomas (STSs) are an uncommon group of solid tumors that can arise throughout the human lifespan. Despite their commonality as non-bony cancers that develop from mesenchymal cell precursors, they are heterogeneous in their genetic profiles, histology, and clinical features. This has made it difficult to identify a single target or therapy specific to STSs. And while there is no one cell of origin ascribed to all STSs, the cancer stem cell (CSC) principle-that a subpopulation of tumor cells possesses stem cell-like properties underlying tumor initiation, therapeutic resistance, disease recurrence, and metastasis-predicts that ultimately it should be possible to identify a feature common to all STSs that could function as a therapeutic Achilles' heel. Here we review the published evidence for CSCs in each of the most common STSs, then focus on the methods used to study CSCs, the developmental signaling pathways usurped by CSCs, and the epigenetic alterations critical for CSC identity that may be useful for further study of STS biology. We conclude with discussion of some challenges to the field and future directions. PMID- 30416987 TI - Mutation Status and Immunohistochemical Correlation of KRAS, NRAS, and BRAF in 260 Chinese Colorectal and Gastric Cancers. AB - KRAS, NRAS and BRAF are kinases involved in the RAS-RAF-MAPK signaling pathway and also potential tumor-driven genes. Patients with KRAS/NRAS/BRAF mutations are resistant to anti-EGFR monoclonal antibody therapy. The main purpose of this study is to investigate the mutation status and distribution of KRAS/NRAS/BRAF in Chinese colorectal and gastric cancers, and to explore the histopathological changes and related immunohistochemical marker changes caused by these mutations. The mutation status of KRAS (exons 2, codon 12/13), NRAS (exons 2/3/4, codon 12/13/59/61/117/146) and BRAF (exons 15, codon 600) were detected by amplification refractory mutation system polymerase chain reaction (ARMS-PCR) in 86 colon cancer, 140 rectal cancer and 34 gastric cancer tissues. Then, the frequencies and distribution of KRAS/NRAS/BRAF mutations were described in detail. Furthermore, the relationship between KRAS/NRAS/BRAF mutations and the features of histopathological and related immunohistochemical markers were analyzed. The results showed that KRAS/NRAS/BRAF mutation rates in colon cancer were 44.2, 1.2, and 3.5%; in rectal cancer were 37.1, 4.3, and 0.7%; in gastric cancer were none, none and 2.9%. The mutation rate of KRAS in female (48.8%) is significantly higher than that of male (27.8%), and the mutation rate increased with the higher degree of differentiation. Additionally, the mutation rate of BRAF detected by ARMS-PCR (1.77%) was significantly lower than that by immunohistochemistry (4.11%). It also showed that the KRAS/NRAS/BRAF mutation status had a certain relationship with the expression of some immunohistochemical markers. This study provides more data support for clinical research on KRAS/NRAS/BRAF mutation in CRCs or gastric cancers. PMID- 30416989 TI - Radiomics: is it time to compose the puzzle? PMID- 30416988 TI - Increased Virulence of Bloodstream Over Peripheral Isolates of P. aeruginosa Identified Through Post-transcriptional Regulation of Virulence Factors. AB - The factors influencing the virulence of P. aeruginosa in the development of invasive infection remain poorly understood. Here, we investigated the role of the host microenvironment in shaping pathogen virulence and investigated the mechanisms involved. Comparing seven paired genetically indistinguishable clinical bloodstream and peripheral isolates of P. aeruginosa, we demonstrate that isolates derived from bloodstream infections are more virulent than their peripheral counterparts (p = 0.025). Bloodstream and peripheral isolates elicited similar NF-kB responses in a THP-1 monocyte NF-kappaB reporter cell line implicating similar immunogenicity. Proteomic analysis by mass spectrometry identified multiple virulence and virulence-related factors including LecA and RpoN in significantly greater abundance in the bacterial supernatant from the bloodstream isolate in comparison to that from the corresponding peripheral isolate. Investigation by qPCR revealed that control of expression of these virulence factors was not due to altered levels of transcription. Based on these data, we hypothesize a post-transcriptional mechanism of virulence regulation in P. aeruginosa bloodstream infections influenced by surrounding microenvironmental conditions. PMID- 30416990 TI - Low Bacterial Co-infection Invalidates the Early Use of Non-anti-Mycoplasma pneumoniae Antibiotics in Pediatric Refractory Mycoplasma pneumoniae Pneumonia Patients. AB - Background: Childhood refractory mycoplasma pneumoniae (MP) pneumonia (RMPP) is a lung disease with elevated level of C-reactive protein and severe clinical and radiological deterioration. Whether bacterial co-infection contributes to disease of RMPP and whether inclusion of non-anti-MP antibiotics in treatment regimen would benefit RMPP patients remains elusive. Methods: We retrospectively reviewed the medical records of 675 RMPP children. Traditional bacterial culture and next generation sequencing (NGS) were used to detect bacteria in bronchoalveolar lavage fluid in all the 675 patients and 18 patients respectively. Antibiotics used and clinical outcomes were analyzed along with other clinical measurements. Results: Positive bacterial cultures were only found in 18 out of 675 cases (2.67%) and NGS analyses of another 18 cases did not revealed positive bacterial infection, which were consistent with the results of bacterial cultures. Non-anti MP antibiotics were utilized in 630 cases (93.33%), even last-line antibiotics, such as glycopeptides or carbapenems, were frequently used. Conclusion: Bacterial co-infection in RMPP was rare and non-anti-MP antibiotics didn't show any efficacy for early treatment of RMPP patients, which may provide a rationale for restricting the use of non-anti-MP antibiotics in RMPP patients and preventing antibiotic resistance globally. PMID- 30416992 TI - Development of an Implementation Intervention Using Intervention Mapping to Increase Mammography Among Low Income Women. AB - Background: Although much work has begun to elucidate contextual factors influencing implementation, the specific processes that facilitate and hinder adoption, implementation, and maintenance of evidence-based interventions (EBIs) in clinical settings remains poorly understood. Intervention Mapping (IM) is a systematic process that facilitates planning and design for dissemination, implementation and maintenance of EBIs in practice. IM has been used to guide the design of many health interventions, focusing on program implementation. Less studied is its use to adapt and scale screening interventions within the healthcare clinic setting. This paper describes the development of an implementation intervention using IM to facilitate the adoption, implementation, and maintenance of an EBI designed to increase mammography adherence in healthcare clinics, the adapted Peace of Mind Program (PMP). Methods: IM framework, Step 5, was used to guide the implementation intervention planning. IM guided identification of specific adoption, implementation, and maintenance performance objectives. We formed an implementation intervention planning group consisting of members of the academic team, our community partner and community health workers (CHWs) with substantial experience working on mammography screening programs in federally qualified health centers (FQHCs) and charity clinics. Results: Results are presented by Intervention Mapping task for Step 5 (Program Implementation Plan). We describe how the consolidated framework for implementation research (CFIR) informed the selection of performance objectives, determinants, methods, and practical applications in the final implementation intervention. Conclusions: This paper provides an example of the use of Intervention Mapping Step 5 and CFIR to create an implementation intervention to support EBI scale up of an evidence-based mammography intervention within a specific setting. Clinical trials registration number: NCT02296177. PMID- 30416993 TI - Tobacco Smoking, Lung Cancer, and Therapy in Iraq: Current Perspective. AB - Tobacco smoking is a research topic of high interest to the public health in Iraq. Although Iraq is a country with a high percentage of smokers, we noticed the dearth of adequate studies and programs to deal with this problem. The percentage of smokers exceed 30% of the population and smoking problem becomes a permanent habit in adults and young people. The problems associated with tobacco smoking behavior related to individuals' post-traumatic stress disorder following post-war conflicts, and the social and cultural environment. The health consequences of tobacco smoking can harm almost every organ in the body, and there are reports confirmed the tobacco smoking is a high-risk factor for lung cancer and other diseases. The relative risk of lung cancer increases with increasing duration and intensity of smoking. Also, smoking associated with bladder, prostate, and head and neck cancers, in addition to respiratory diseases. Intervention efforts should focus on reducing the prevalence of cigarette smoking, introduce effective treatments for cancer and quit smoking. In this perspective article, we present our viewpoint and three scenarios to deal with the problem of tobacco smoking in Iraq. We recommend introducing educational, health and legislative policies for quitting smoking and using effective treatments for cancer. PMID- 30416994 TI - Big Data and the Study of Social Inequalities in Health: Expectations and Issues. AB - Understanding the construction of the social gradient in health is a major challenge in the field of social epidemiology, a branch of epidemiology that seeks to understand how society and its different forms of organization influence health at a population level. Attempting to answer these questions involves large datasets of varied heterogeneous data suggesting that Big Data approaches could be then particularly relevant to the study of social inequalities in health. Nevertheless, real challenges have to be addressed in order to make the best use of the development of Big Data in health for the benefit of all. The main purpose of this perspective is to discuss some of these challenges, in particular: (i) the perimeter and the particularity of Big Data in health, which must be broader than a vision centerd solely on care, the individual and his or her biological characteristics; (ii) the need for clarification regarding the notion of data, the validity of data and the question of causal inference for various actors involved in health, such data as researchers, health professionals and the civilian population; (iii) the need for regulation and control of data and their uses by public authorities for the common good and the fight against social inequalities in health. To face these issues, it seems essential to integrate different approaches into a close dialog, integrating methodological, societal, and ethical issues. This question cannot escape an interdisciplinary approach, including users or patients. PMID- 30416991 TI - The Role of Echocardiography in Neonates and Pediatric Patients on Extracorporeal Membrane Oxygenation. AB - Indications for extracorporeal membrane oxygenation (ECMO) and extracorporeal cardiopulmonary resuscitation (ECPR) are expanding, and echocardiography is a tool of utmost importance to assess safety, effectiveness and readiness for circuit initiation and separation. Echocardiography is key to anticipating complications and improving outcomes. Understanding the patient's as well as the ECMO circuit's anatomy and physiology is crucial prior to any ECMO echocardiographic evaluation. It is also vital to acknowledge that the utility of echocardiography in ECMO patients is not limited to the evaluation of cardiac function, and that clinical decisions should not be made exclusively upon echocardiographic findings. Though echocardiography has specific indications and applications, it also has limitations, characterized as: prior to and during cannulation, throughout the ECMO run, upon separation and after separation from the circuit. The use of specific and consistent echocardiographic protocols for patients on ECMO is recommended. PMID- 30416995 TI - Wavelet Transform-Based UV Spectroscopy for Pharmaceutical Analysis. AB - In research and development laboratories, chemical or pharmaceutical analysis has been carried out by evaluating sample signals obtained from instruments. However, the qualitative and quantitative determination based on raw signals may not be always possible due to sample complexity. In such cases, there is a need for powerful signal processing methodologies that can effectively process raw signals to get correct results. Wavelet transform is one of the most indispensable and popular signal processing methods currently used for noise removal, background correction, differentiation, data smoothing and filtering, data compression and separation of overlapping signals etc. This review article describes the theoretical aspects of wavelet transform (i.e., discrete, continuous and fractional) and its characteristic applications in UV spectroscopic analysis of pharmaceuticals. PMID- 30416996 TI - Synthesis of Flower-Like AgI/BiOCOOH p-n Heterojunctions With Enhanced Visible Light Photocatalytic Performance for the Removal of Toxic Pollutants. AB - In this study, flower-like AgI/BiOCOOH heterojunctions were constructed through a two-step procedure involving the solvothermal synthesis of BiOCOOH microflowers followed by AgI modification using a precipitation method. These novel photocatalysts were systematically examined by XRD, UV-vis DRS, SEM, TEM, EDS, and PL spectroscopy techniques. The AgI/BiOCOOH heterojunction were studied as a decent photocatalyst for the removal of the industrial dye (rhodamine B, and methyl blue) and antibiotic (tetracycline) under visible light. The AgI/BiOCOOH heterojunctions are much more active than bare BiOCOOH, and AgI, which could be ascribed to the improved separation of charge carriers, resulting from the formation of p-n heterojunction between two constituents. The holes (h+) and superoxide radical (*O 2- ) were detected as the main active species responsible for the pollutant degradation. The results showed that a highly efficient visible light-driven photocatalytic system was developed for the decomposition of toxic pollutants. PMID- 30416997 TI - The Structure and Biological Function of CREG. AB - The cellular repressor of E1A-stimulated genes (CREG) is a 220 amino acid glycoprotein structurally similar to oxidoreductases. However, CREG does not have enzymatic activities because it cannot bind to the cofactor flavin mononucleotide. Although CREG can be secreted, it is mainly an intracellular protein localized in the endocytic-lysosomal compartment. It undergoes proteolytic maturation mediated by lysosomal cysteine proteases. Biochemical studies have demonstrated that CREG interacts with mannose-6-phosphate/insulin like growth factor-2 receptor (M6P/IGF2R) and exocyst Sec8. CREG inhibits proliferation and induces differentiation and senescence when overexpressed in cultured cells. In Drosophila, RNAi-mediated knockdown of CREG causes developmental lethality at the pupal stage. In mice, global deletion of the CREG1 gene leads to early embryonic death. These findings establish an essential role for CREG in development. CREG1 haploinsufficient and liver-specific knockout mice are susceptible to high fat diet-induced obesity, hepatic steatosis and insulin resistance. The purpose of this review is to provide an overview of what we know about the biochemistry and biology of CREG and to discuss the important questions that remain to be addressed in the future. PMID- 30416999 TI - Reduction of the Bitter Taste in Packaged Natural Black Manzanilla Olives by Zinc Chloride. AB - The work assays the use of various concentrations of ZnCl2 (0.0-0.1%, w/v) in packaged natural black Manzanilla table olives. The transformations were followed for 4 months. The presence of Zn modified the leaching of total sugars (sucrose, glucose, fructose, and mannitol) into the brine, which decreased as the ZnCl2 content increased. Over the study, sucrose and glucose were exhausted while fructose, although consumed, left some final residues and the use of mannitol was limited. Titratable acidity was always gradually formed causing the subsequent pH decrease, which stabilized at ~3.5. Acetic and mainly lactic acid were also formed during the assay, reaching the highest level of lactic acid in the 0.050% ZnCl2 treatment, followed by the Control. The acids were formed by lactic acid bacteria (LAB) (Lactobacillus pentosus, 39%, and Lactobacillus plantarum, 61%). However, the most outstanding Zn effect was found on the olive sensory characteristics: its presence markedly reduced the bitter notes, increased the overall appreciation, and the treatment containing 0.075% ZnCl2 had the highest scores in hardness, crunchiness, and overall appreciation. Therefore, the addition of ZnCl2 into packaged natural table olives may lead to healthy products with desirable sensory characteristics which, in turn, could promote consumption. PMID- 30416998 TI - Glucagon-Like Peptide-2 and the Enteric Nervous System Are Components of Cell Cell Communication Pathway Regulating Intestinal Na+/Glucose Co-transport. AB - The Na+/glucose cotransporter 1, SGLT1 is the major route for transport of dietary glucose from the lumen of the intestine into absorptive enterocytes. Sensing of dietary sugars and artificial sweeteners by the sweet taste receptor, T1R2-T1R3, expressed in the enteroendocrine L-cell regulates SGLT1 expression in neighboring absorptive enterocytes. However, the mechanism by which sugar sensing by the enteroendocrine cell is communicated to the absorptive enterocytes is not known. Here, we show that glucagon-like peptide-2 (GLP-2) secreted from the enteroendocrine cell in response to luminal sugars regulates SGLT1 mRNA and protein expression in absorptive enterocytes, via the enteric neurons. Glucose and artificial sweeteners induced secretion of GLP-2 from mouse small intestine, which was inhibited by the sweet-taste receptor inhibitor, gurmarin. In wild type mice there was an increase in sugar-induced SGLT1 mRNA and protein abundance that was not observed in GLP-2 receptor knockout mice. GLP-2 receptor is expressed in enteric neurons, and not in absorptive enterocytes ruling out a paracrine effect of GLP-2. Electric field stimulation of the intestine resulted in upregulation of SGLT1 expression that was abolished by the nerve blocking agent tetrodotoxin. We conclude that GLP-2 and the enteric nervous system are components of the enteroendocrine-absorptive enterocyte communication pathway regulating intestinal glucose transport. PMID- 30417000 TI - Expression of Embryonic Stem Cell Markers on the Microvessels of WHO Grade I Meningioma. AB - Aim: The presence of cells within meningioma (MG) that express embryonic stem cell (ESC) markers has been previously reported. However, the precise location of these cells has yet to be determined. Methods: 3,3-Diaminobenzidine (DAB) immunohistochemical (IHC) staining was performed on 11 WHO grade I MG tissue samples for the expression of the ESC markers OCT4, NANOG, SOX2, KLF4 and c-MYC. Immunofluorescence (IF) IHC staining was performed to investigate the localization of each of these ESC markers. NanoString and colorimetric in situ hybridization (CISH) mRNA expression analyses were performed on six snap-frozen MG tissue samples to confirm transcriptional activation of these proteins, respectively. Results: DAB IHC staining demonstrated expression of OCT4, NANOG, SOX2, KLF4, and c-MYC within all 11 MG tissue samples. IF IHC staining demonstrated the expression of the ESC markers OCT4, NANOG, SOX2, KLF4, and c-MYC on both the endothelial and pericyte layers of the microvessels. NanoString and CISH mRNA analyses confirmed transcription activation of these ESC markers. Conclusion: This novel finding of the expression of all aforementioned ESC markers in WHO grade I MG infers the presence of a putative stem cells population which may give rise to MG. PMID- 30417001 TI - Algal Polysaccharides as Therapeutic Agents for Atherosclerosis. AB - Seaweed-derived polysaccharides including agar and alginate, have found widespread applications in biomedical research and medical therapeutic applications including wound healing, drug delivery, and tissue engineering. Given the recent increases in the incidence of diabetes, obesity and hyperlipidemia, there is a pressing need for low cost therapeutics that can economically and effectively slow the progression of atherosclerosis. Marine polysaccharides have been consumed by humans for millennia and are available in large quantities at low cost. Polysaccharides such as fucoidan, laminarin sulfate and ulvan have shown promise in reducing atherosclerosis and its accompanying risk factors in animal models. However, others have been tested in very limited context in scientific studies. In this review, we explore the current state of knowledge for these promising therapeutics and discuss the potential and challenges of using seaweed derived polysaccharides as therapies for atherosclerosis. PMID- 30417003 TI - A Retrospective Study on Bovine Tuberculosis in Cattle on Fiji: Study Findings and Stakeholder Responses. AB - Bovine tuberculosis (bTB) is globally significant due to its impacts on cattle production. A Brucellosis and Tuberculosis Eradication and Control (BTEC) program commenced in Fiji during the 1980's and has since been sustained by government funding and industry cooperation. A retrospective study of bTB data obtained during the Fiji BTEC program from 1999 to 2014 was undertaken at the University of Sydney with support from the Government of Fiji. It confirmed that bTB is well established in dairy cattle farms in Naitasiri and Tailevu provinces of Central Division on the main island of Viti Levu, and suggested that the disease is present among cattle on farms in all or most provinces across three (Central, Northern, Western) of the four divisions in the country. It was evident that despite sustained efforts, disease reduction and containment was not being achieved. Reasons contributing to this situation included the appropriateness of the protocol for conduct of the single intradermal test (SID) in cattle, absence of regular quality assurance training of BTEC field staff, lack of standard procedures for bTB data collation and evaluation, unregulated cattle movements and the presence of stray cattle. The Fiji Ministry of Agriculture responded proactively to these findings by implementing revision to the use of the SID in cattle and refresher training for staff along with the Biosecurity Authority of Fiji who implemented cattle movement restriction. A subsequent apparent outbreak of bTB in some farms due to increased detection by the new test protocol raised concerns for the local dairy industry. To clarify the status and extent of bTB infection and the challenges faced by the industry, a stakeholder forum was held in May 2017, and a new BTEC strategy was formulated and endorsed by stakeholders. bTB remains a focus for cattle disease control by the government of Fiji. This case study highlights the challenges for bTB control in Fiji and underlines the importance of technical and social considerations to achieve success in disease control. PMID- 30417002 TI - Efficacy and Safety of BCG Vaccine for Control of Tuberculosis in Domestic Livestock and Wildlife. AB - Bovine tuberculosis (TB) continues to be an intractable problem in many countries, particularly where "test and slaughter" policies cannot be implemented or where wildlife reservoirs of Mycobacterium bovis infection serve as a recurrent source of infection for domestic livestock. Alternative control measures are urgently required and vaccination is a promising option. Although the M. bovis bacille Calmette-Guerin (BCG) vaccine has been used in humans for nearly a century, its use in animals has been limited, principally as protection against TB has been incomplete and vaccination may result in animals reacting in the tuberculin skin test. Valuable insights have been gained over the past 25 years to optimise protection induced by BCG vaccine in animals and in the development of tests to differentiate infected from vaccinated animals (DIVA). This review examines factors affecting the efficacy of BCG vaccine in cattle, recent field trials, use of DIVA tests and the effectiveness of BCG vaccine in other domestic livestock as well as in wildlife. Oral delivery of BCG vaccine to wildlife reservoirs of infection such as European badgers, brushtail possums, wild boar, and deer has been shown to induce protection against TB and could prove to be a practical means to vaccinate these species at scale. Testing of BCG vaccine in a wide range of animal species has indicated that it is safe and vaccination has the potential to be a valuable tool to assist in the control of TB in both domestic livestock and wildlife. PMID- 30417005 TI - Tunable 3D Nanofiber Architecture of Polycaprolactone by Divergence Electrospinning for Potential Tissue Engineering Applications. AB - The creation of biomimetic cell environments with micro and nanoscale topographical features resembling native tissues is critical for tissue engineering. To address this challenge, this study focuses on an innovative electrospinning strategy that adopts a symmetrically divergent electric field to induce rapid self-assembly of aligned polycaprolactone (PCL) nanofibers into a centimeter-scale architecture between separately grounded bevels. The 3D microstructures of the nanofiber scaffolds were characterized through a series of sectioning in both vertical and horizontal directions. PCL/collagen (type I) nanofiber scaffolds with different density gradients were incorporated in sodium alginate hydrogels and subjected to elemental analysis. Human fibroblasts were seeded onto the scaffolds and cultured for 7 days. Our studies showed that the inclination angle of the collector had significant effects on nanofiber attributes, including the mean diameter, density gradient, and alignment gradient. The fiber density and alignment at the peripheral area of the 45 degrees -collector decreased by 21% and 55%, respectively, along the z-axis, while those of the 60 degrees -collector decreased by 71% and 60%, respectively. By altering the geometry of the conductive areas on the collecting bevels, polyhedral and cylindrical scaffolds composed of aligned fibers were directly fabricated. By using a four-bevel collector, the nanofibers formed a matrix of microgrids with a density of 11%. The gradient of nitrogen-to-carbon ratio in the scaffold-incorporated hydrogel was consistent with the nanofiber density gradient. The scaffolds provided biophysical stimuli to facilitate cell adhesion, proliferation, and morphogenesis in 3D. PMID- 30417004 TI - Biogreen Synthesis of Carbon Dots for Biotechnology and Nanomedicine Applications. AB - Over the past decade, carbon dots have ignited a burst of interest in many different fields, including nanomedicine, solar energy, optoelectronics, energy storage, and sensing applications, owing to their excellent photoluminescence properties and the easiness to modify their optical properties through doping and functionalization. In this review, the synthesis, structural and optical properties, as well as photoluminescence mechanisms of carbon dots are first reviewed and summarized. Then, we describe a series of designs for carbon dot based sensors and the different sensing mechanisms associated with them. Thereafter, we elaborate on recent research advances on carbon dot-based sensors for the selective and sensitive detection of a wide range of analytes, including heavy metals, cations, anions, biomolecules, biomarkers, nitroaromatic explosives, pollutants, vitamins, and drugs. Lastly, we provide a concluding perspective on the overall status, challenges, and future directions for the use of carbon dots in real-life sensing. PMID- 30417006 TI - Indocyanine Green-Conjugated Magnetic Prussian Blue Nanoparticles for Synchronous Photothermal/Photodynamic Tumor Therapy. AB - Indocyanine green (ICG) is capable of inducing a photothermal effect and the production of cytotoxic reactive oxygen species for cancer therapy. However, the major challenge in applying ICG molecules for antitumor therapy is associated with their instability in aqueous conditions and rapid clearance from blood circulation, which causes insufficient bioavailability at the tumor site. Herein, we conjugated ICG molecules with Prussian blue nanoparticles enclosing a Fe3O4 nanocore, which was facilitated by cationic polyethyleneimine via electrostatic adsorption. The nanocarrier-loaded ICG formed stable aggregates that enhanced cellular uptake and prevented fluorescence quenching. Moreover, the strong superparamagnetism of the Fe3O4 core in the obtained nanocomposites further improved cellular internalization of the drugs guided by a localized magnetic field. The therapeutic efficacy of this nanoplatform was evaluated using tumor models established in nude mice, which demonstrated remarkable tumor ablation in vivo due to strong photothermal/photodynamic effects. This study provides promising evidence that this multifunctional nanoagent might function as an efficient mediator for combining photothermal and photodynamic cancer therapy. PMID- 30417007 TI - SCAR Marker for Gender Identification in Date Palm (Phoenix dactylifera L.) at the Seedling Stage. AB - Date palm (Phoenix dactylifera L.) is cultivated in arid and semiarid regions worldwide. Given the dioecious nature of this plant, gender identification is very important at the seedling stage. Molecular markers are very effective tools that help in gender identification at this stage. A sequence characterized amplified region (SCAR) marker linked to sex-specific regions in the genome of date palm was developed. Of the 300 tested randomly amplified polymorphic DNA (RAPD) primers, only one primer (OPC-06) produced reproducible band (294 bp) in male plants. The PCR product of this primer was cloned and sequenced. The specific primers were synthesized for amplification of a 186 bp fragment in male date palm plants. These primers were validated in male and female date palm plants, wherein the designed SCAR marker was reported only in male plants and no amplification was observed in female plants. The developed SCAR marker was used with seedlings of date palm and proved very effective in identification of gender. PMID- 30417010 TI - Reconstruction of Ovine Trachea with a Biomimetic Composite Biomaterial. AB - The aim of this study was to evaluate a novel composite material for tracheal reconstruction in an ovine model. A polymer containing various forms of carbon fibers (roving, woven, and nonwoven fabric) impregnated with polysulfone (PSU) was used to create cylindrical tracheal implants, 3 cm in length and 2.5 cm in diameter. Each implant, reinforced with five rings made of PSU-impregnated carbon fiber roving, had three external layers made of carbon-fiber woven fabric and the inner layer formed of carbon-fiber nonwoven fabric. The inner surface of five implants was additionally coated with polyurethane (PU), to promote migration of respiratory epithelium. The implants were used to repair tracheal defects (involving four tracheal rings) in 10 sheep (9-12 months of age; 40-50 kg body weight). Macroscopic and microscopic characteristics of the implants and tracheal anastomoses were examined 4 and 24 weeks after implantation. At the end of the follow-up period, outer surfaces of the implants were covered with the tissue which to various degree resembled histological structure of normal tracheal wall. In turn, inner surfaces of the prostheses were covered only with vascularized connective tissue. Inner polyurethane coating did not improve the outcomes of tracheal reconstruction and promoted excessive granulation, which contributed to moderate to severe stenosis at the tracheal anastomoses. The hereby presented preliminary findings constitute a valuable source of data for future research on a tracheal implant being optimally adjusted for medical needs. PMID- 30417009 TI - GPRC5A: An Emerging Biomarker in Human Cancer. AB - Aberrant expression of G protein-coupled receptors (GPCRs) is frequently associated with tumorigenesis. G Protein-coupled receptor class C group 5 member A (GPRC5A) is a member of the GPCR superfamily, is expressed preferentially in lung tissues, and is regulated by various entities at multiple levels. GPRC5A exerts a tumor suppressive role in lung cancer and GPRC5A deletion promotes lung tumor initiation and progression. Recent advances have highlighted that GPRC5A dysregulation is found in various human cancers and is related to many tumor associated signaling pathways, including the cyclic adenosine monophosphate (cAMP), nuclear factor (NF)-kappaB, signal transducer and activator of transcription (STAT) 3, and focal adhesion kinase (FAK)/Src signaling. This review aimed to summarize our updated view on the biology and regulation of GPRC5A, its expression in human cancers, and the linked signaling pathways. A better comprehension of the underlying cellular and molecular mechanisms of GPRC5A will provide novel insights into its potential diagnostic and therapeutic value. PMID- 30417008 TI - The Role of Glucocorticoid Receptors in Podocytes and Nephrotic Syndrome. AB - Glucocorticoid receptor (GC), a founding member of the nuclear hormone receptor superfamily, is a glucocorticoid-activated transcription factor that regulates gene expression and controls the development and homeostasis of human podocytes. Synthetic glucocorticoids are the standard treatment regimens for proteinuria (protein in the urine) and nephrotic syndrome (NS) caused by kidney diseases. These include minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN) and immunoglobulin A nephropathy (IgAN) or subsequent complications due to diabetes mellitus or HIV infection. However, unwanted side effects and steroid-resistance remain major issues for their long term use. Furthermore, the mechanism by which glucocorticoids elicit their renoprotective activity in podocyte and glomeruli is poorly understood. Podocytes are highly differentiated epithelial cells that contribute to the integrity of kidney glomerular filtration barrier. Injury or loss of podocytes leads to proteinuria and nephrotic syndrome. Recent studies in multiple experimental models have begun to explore the mechanism of GC action in podocytes. This review will discuss progress in our understanding of the role of glucocorticoid receptor and glucocorticoids in podocyte physiology and their renoprotective activity in nephrotic syndrome. PMID- 30417011 TI - Manifestations and Outcomes of Patients with Parkinson's Disease and Serious Infection in the Emergency Department. AB - Background: Several comorbidities contribute to an increased risk of infections in Parkinson's disease (PD) as the disease progresses. However, few studies have examined the correlation between sepsis and PD. Aim: The aim of this study is to disclose the presentation and outcome of serious infection in patients with PD in the emergency department. Methods: This retrospective cohort study enrolled patients with PD who had serious infection and were admitted to the emergency department between January 2007 and December 2013. For clinical comparison, we compared the clinical features, laboratory data, and outcomes with those of age- and sex-matched patients who had serious infection but not PD. Results: There were a total of 1,200 episodes of infected PD patients and 2,400 age- and sex matched infected patients without PD as disease controls. PD patients had fewer comorbidities and lower severity of infectious disease but longer hospital stays than control group patients. The incidences of respiratory tract and urinary tract infections were higher in PD patients. The levels of inflammatory and organ dysfunction biomarkers in PD were lower and compatible with the severity of infectious disease. A total of 86 (7.2%) infected PD patients died during the 28 day admission compared to 339 (14.1%) in non-PD patients. Serum C-reactive protein, bandemia, and lactate could be used to predict mortality in infected PD patients. Conclusions: In infected patients with PD, respiratory and urinary tract infections were the two most common infectious sources. Empiric therapy based on experience could treat both respiratory and urinary tract infections. Early diagnosis and treatment are essential for survival. PMID- 30417013 TI - Low Hematocrit Is a Strong Predictor of Poor Prognosis in Lung Cancer Patients. AB - Morbidity and mortality of lung cancer rank first in China and worldwide. Thus, noninvasive prognostic biomarkers are critical for clinicians to perform risk assessment in lung cancer patients prior to or during the course of treatment. In this study, we evaluated the prognostic value of preoperative hematocrit (HCT) count reduction on the long-term survival of lung cancer patients undergoing pneumonectomy and analyzed the correlation between reduced HCT counts and patients' clinicopathological features. A total of 1022 patients who underwent surgical treatment in Harbin Medical University Cancer Hospital, China, from February 2006 to December 2013, were enrolled in this study. The association between the clinicopathologic variables and HCT were evaluated by Mann-Whitney U test and chi-square test, respectively. Survival curves were generated using Kaplan-Meier estimates, and differences between the curves were analyzed by a log rank test. Multivariable analysis showed that high HCT (P < 0.001, HR: 0.595, 95% CI: 0.458-0.774) was favorable for patients' survival. Low HCT patients presented shorter mean months of OS than that of high HCT patients (P < 0.001). Male adenocarcinoma carcinoma patients with lower body mass index (BMI) and advanced tumor stage were more likely to observe low HCT. We identified for the first time reduced preoperative HCT count as an independent risk factor leading to poor prognosis in lung cancer patients who underwent surgical treatment. PMID- 30417012 TI - Prognostic Value of Excision Repair Cross-Complementing mRNA Expression in Gastric Cancer. AB - Except for excision repair cross-complementing 1 (ERCC1), mRNA expression of the remaining ERCC genes has not been investigated in the prognosis of gastric cancer (GC). The present study aimed to explore the mRNA expression and prognostic values of each member of the ERCC family in GC patients by using the Kaplan-Meier (KM) plotter tool. The details of each ERCC family member were entered into a database and GC patients were separated into high and low expression to draw survival plots using the KM plotter. In the present study, we observed that high expression of ERCC1 mRNA was significantly associated with longer overall survival (OS) for all GC patients (hazard ratio [HR]=0.77, 95% confidence intervals [CI]=0.63-0.95, P=0.016) compared with low expression. High expression of ERCC4 and ERCC6 mRNA indicated a worse OS for all GC patients (HR=1.28, 95% CI=1.02-1.6, P=0.035 and HR=1.25, 95% CI=1.02-1.54, P=0.029, respectively) and especially for patients with intestinal-type GC (HR=1.87, 95% CI=1.26-2.79, P=0.0018 and HR=1.62, 95% CI=1.04-2.54, P=0.033, respectively). High ERCC8 mRNA expression indicated a worse OS for all GC patients (HR=1.34, 95% CI=1.02-1.76, P=0.034) and especially for patients with diffuse-type GC (HR=2.25, 95% CI=1.36 3.75, P=0.0013). In conclusion, our findings indicate that ERCC4, ERCC6, and ERCC8 may be potential biomarkers for GC prognosis and may serve as potential therapeutic targets for GC. However, these findings still need further verification. PMID- 30417014 TI - Parallel MapReduce: Maximizing Cloud Resource Utilization and Performance Improvement Using Parallel Execution Strategies. AB - MapReduce is the preferred cloud computing framework used in large data analysis and application processing. MapReduce frameworks currently in place suffer performance degradation due to the adoption of sequential processing approaches with little modification and thus exhibit underutilization of cloud resources. To overcome this drawback and reduce costs, we introduce a Parallel MapReduce (PMR) framework in this paper. We design a novel parallel execution strategy of Map and Reduce worker nodes. Our strategy enables further performance improvement and efficient utilization of cloud resources execution of Map and Reduce functions to utilize multicore environments available with computing nodes. We explain in detail makespan modeling and working principle of the PMR framework in the paper. Performance of PMR is compared with Hadoop through experiments considering three biomedical applications. Experiments conducted for BLAST, CAP3, and DeepBind biomedical applications report makespan time reduction of 38.92%, 18.00%, and 34.62% considering the PMR framework against Hadoop framework. Experiments' results prove that the PMR cloud computing platform proposed is robust, cost effective, and scalable, which sufficiently supports diverse applications on public and private cloud platforms. Consequently, overall presentation and results indicate that there is good matching between theoretical makespan modeling presented and experimental values investigated. PMID- 30417015 TI - Low Performance of a Clinical-Genetic Model in the Estimation of Time in Therapeutic Range in Acenocoumarol-Adherent Patients with Nonvalvular Atrial Fibrillation: The Quality of Anticoagulation Challenge. AB - Background: Anticoagulation with vitamin K antagonists continues to be a challenging task given the difficulty of achieving a correct time in therapeutic range (TTR). The SAMeTT2R2 score has been proposed to identify patients that will be good responders. In this study we aimed to analyse clinical and genetic factors involved in a correct level of anticoagulation in patients with atrial fibrillation and thereby potentially improve the diagnostic performance of SAMeTT2R2 score. Methods: We prospectively included 212 consecutive patients with nonvalvular atrial fibrillation under treatment with acenocoumarol for at least 6 months that were attended in a cardiology outpatient clinic and were categorized as adherent to medication. We carried out a multivariate regression analysis to detect the independent predictive factors of good control. In all patients VKORC1, CYP2C9*2, CYP2C9*3, and MIR133A2 genotyping was performed. Results: A total of 128 (60.4%) patients presented TTR <70% (average TTR = 63.2). We identified body mass index (OR 0.94, 95%CI 0.89-0.99, p=0.032) and regular vitamin K intake (OR 0.53, 95%CI 0.28-0.99, p= 0.046) as independent predictors of poor anticoagulation control. The discriminatory power of a clinical-genetic model derived from our cohort was significantly better compared to the SAMeTT2R2 score (C-statistic 0.658 versus 0.524, p<0.001). Conclusions: In our study the SAMeTT2R2 score revealed a poor ability in the prediction of TTR. Besides SAMeTT2R2, body mass index and possibly vitamin K intake should be taken into account when deciding the optimal anticoagulation strategy. The information provided by the identified genotypes was marginal. PMID- 30417016 TI - Understanding Deep Brain Stimulation: In Vivo Metabolic Consequences of the Electrode Insertional Effect. AB - Deep brain stimulation (DBS) is a neurosurgery technique widely used in movement disorders, although its mechanism of action remains unclear. In fact, apart from the stimulation itself, the mechanical insertion of the electrode may play a crucial role. Here we aimed to distinguish between the insertional and the DBS effects on brain glucose metabolism. To this end, electrodes were implanted targeting the medial prefrontal cortex in five adult male Wistar rats. Positron Emission Tomography (PET) studies were performed before surgery (D0) and seven (D7) and nine days (D9) after that. DBS was applied during the 18FDG uptake of the D9 study. PET data were analysed with statistical parametric mapping. We found an electrode insertional effect in cortical areas, while DBS resulted in a more widespread metabolic pattern. The consequences of simultaneous electrode and DBS factors revealed a combination of both effects. Therefore, the insertion metabolic effects differed from the stimulation ones, which should be considered when assessing DBS protocols. PMID- 30417017 TI - Tumor Segmentation in Contrast-Enhanced Magnetic Resonance Imaging for Nasopharyngeal Carcinoma: Deep Learning with Convolutional Neural Network. AB - Objectives: To evaluate the application of a deep learning architecture, based on the convolutional neural network (CNN) technique, to perform automatic tumor segmentation of magnetic resonance imaging (MRI) for nasopharyngeal carcinoma (NPC). Materials and Methods: In this prospective study, 87 MRI containing tumor regions were acquired from newly diagnosed NPC patients. These 87 MRI were augmented to >60,000 images. The proposed CNN network is composed of two phases: feature representation and scores map reconstruction. We designed a stepwise scheme to train our CNN network. To evaluate the performance of our method, we used case-by-case leave-one-out cross-validation (LOOCV). The ground truth of tumor contouring was acquired by the consensus of two experienced radiologists. Results: The mean values of dice similarity coefficient, percent match, and their corresponding ratio with our method were 0.89+/-0.05, 0.90+/-0.04, and 0.84+/ 0.06, respectively, all of which were better than reported values in the similar studies. Conclusions: We successfully established a segmentation method for NPC based on deep learning in contrast-enhanced magnetic resonance imaging. Further clinical trials with dedicated algorithms are warranted. PMID- 30417018 TI - Anti-ICOSL New Antigen Receptor Domains Inhibit T Cell Proliferation and Reduce the Development of Inflammation in the Collagen-Induced Mouse Model of Rheumatoid Arthritis. AB - Lymphocyte costimulation plays a central role in immunology, inflammation, and immunotherapy. The inducible T cell costimulator (ICOS) is expressed on T cells following peptide: MHC engagement with CD28 costimulation. The interaction of ICOS with its sole ligand, the inducible T cell costimulatory ligand (ICOSL; also known as B7-related protein-1), triggers a number of key activities of T cells including differentiation and cytokine production. Suppression of T cell activation can be achieved by blocking this interaction and has been shown to be an effective means of ameliorating disease in models of autoimmunity. In this study, we isolated specific anti-ICOSL new antigen receptor domains from a synthetic phage display library and demonstrated their ability to block the ICOS/ICOSL interaction and inhibit T cell proliferation. Anti-mouse ICOSL domains, considered here as surrogates for the use of anti-human ICOSL domains in patient therapy, were tested for efficacy in a collagen-induced mouse model of rheumatoid arthritis where they significantly decreased the inflammation of joints and delayed and reduced overall disease progression and severity. PMID- 30417019 TI - Essential Role of Zinc and Zinc Transporters in Myeloid Cell Function and Host Defense against Infection. AB - Zinc is an essential micronutrient known to play a vital role in host defense against pathogens. Diets that are deficient in zinc lead to impaired immunity and delayed recovery from and worse outcomes following infection. Sustained insufficient zinc intake leads to dysregulation of the innate immune response and increases susceptibility to infection whereas zinc supplementation in at-risk populations has been shown to restore host defense and reduce pathogen-related morbidity and mortality. Upon infection, zinc deficiency leads to increased pathology due to imbalance in key signaling networks that result in excessive inflammation and collateral tissue damage. In particular, zinc impacts macrophage function, a critical front-line cell in host defense, in addition to other immune cells. Deficits in zinc adversely impact macrophage function resulting in dysregulation of phagocytosis, intracellular killing, and cytokine production. An additional work in this field has revealed a vital role for several zinc transporter proteins that are required for proper bioredistribution of zinc within mononuclear cells to achieve an optimal immune response against invading microorganisms. In this review, we will discuss the most recent developments regarding zinc's role in innate immunity and protection against pathogen invasion. PMID- 30417020 TI - The Central Role of Inflammation Associated with Checkpoint Inhibitor Treatments. AB - An important function of the immune system is its ability to differentiate between healthy cells in the organism and "foreign" cells, allowing the latest to be attacked and the first ones to be conserved. The most important molecules in this process are considered to be checkpoint inhibitors. This review is focused on the association between cancer and inflammation, underlying the mechanisms of action of monoclonal antibodies that are targeting checkpoint inhibitors: ipilimumab against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and pembrolizumab and nivolumab against programmed cell death protein 1 (PD-1), their indications for treatment, and side effects. Presence of antibodies against checkpoint inhibitors shows promising results in the clinical trials in patients with types of cancer difficult to treat until now such as melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma, offering an increase in the overall survival rate, response rate, and progression-free rate. Resistance is now observed to emerge in patients treated with this therapy, showing the need for more studies in order to design a biomarker that will predict the type of response to immunotherapy. PMID- 30417021 TI - Differential Intestinal Mucosa Transcriptomic Biomarkers for Crohn's Disease and Ulcerative Colitis. AB - Genetic research has shaped the inflammatory bowel disease (IBD) landscape identifying nearly two hundred risk loci. Nonetheless, the identified variants rendered only a partial success in providing criteria for the differential diagnosis between ulcerative colitis (UC) and Crohn's disease (CD). Transcript levels from affected intestinal mucosa may serve as tentative biomarkers for improving classification and diagnosis of IBD. The aim of our study was to identify gene expression profiles specific for UC and CD, in endoscopically affected and normal intestinal colonic mucosa from IBD patients. We evaluated a panel of 84 genes related to the IBD-inflammatory pathway on 21 UC and 22 CD paired inflamed and not inflamed mucosa and on age-matched normal mucosa from 21 non-IBD controls. Two genes in UC (CCL11 and MMP10) and two in CD (C4BPB and IL1RN) showed an upregulation trend in both noninflamed and inflamed mucosa compared to controls. Our results suggest that the transcript levels of CCL11, MMP10, C4BPB, and IL1RN are candidate biomarkers that could help in clinical practice for the differential diagnosis between UC and CD and could guide new research on future therapeutic targets. PMID- 30417023 TI - P-FN12, an H4R-Based Epitope Vaccine Screened by Phage Display, Regulates the Th1/Th2 Balance in Rat Allergic Rhinitis. AB - Allergic rhinitis (AR) involves antigen-specific immune-inflammation of the nasal mucosa. Classical therapy for AR targets the histamine pathway, e.g., histamine receptor blockers. Histamine H4 receptor (H4R) was suggested as a novel therapeutic target due to its wide expression on almost all immune-related cells. A 12-mer random peptide library was used to select the specific epitope of the H4R. The phage clone showing the highest degree of activation was verified and translated to the corresponding peptide. The peptide FNKWMDCLSVTH, designated as P-FN12, was bound by H4R monoclonal antibody (mcAb) with high affinity. Moreover, the P-FN12 + CTB@Lipo-formulated vaccine, used as nasal drops, decreased allergic symptoms such as sneezing and nasal rubbing in a rat model. The level of ovalbumin (OVA)-specific immunoglobulin E (IgE) decreased significantly after vaccine administration. It also elicited increased levels of interferon (IFN) gamma and interleukin-2 (IL-2) but a decreased level of IL-4, and it elevated the T helper type 1 (Th1):T helper type 2 (Th2) cell ratio in peripheral blood mononuclear cell cultures. Our results indicated that the reduction of allergic inflammation by P-FN12-based vaccine was related to a decrease in production of OVA-specific IgE, Th2 immunity, and tissue eosinophilia. P-FN12 + CTB@Lipo is a promising vaccine that could suppress Th2 response and enhance the induction of Th1 cells in an AR model. PMID- 30417022 TI - The Prevalence of Abdominal Obesity and Its Correlates among the Adults in Dodoma Region, Tanzania: A Community-Based Cross-Sectional Study. AB - Introduction: Overweight and obesity are a threat to the public health following their association with noncommunicable diseases, such as type 2 diabetes mellitus, cardiovascular disease, and some cancers. Despite this fact, the information on overweight and obesity, particularly in most developing countries, is still scarce to address the problem. This article partly addresses the gap through the findings of a cross-sectional survey that was conducted in Dodoma Region, Central Tanzania, to determine the prevalence and correlates of abdominal obesity among adults. Methods: Using a community-based cross-sectional survey, data were generated from the participants who aged 18 years and above. Simple random sampling and Kish selection table techniques were used to get the sample who responded through a face-to-face-administered questionnaire. Waist circumference was measured using the guideline of the WHO protocol of measuring waist and hip circumference. Abdominal obesity is defined as a condition with waist circumference >102 cm for men and >88 cm for women. Prevalence was computed with a 95% confidence interval. Simple and multiple logistic regression models were fitted to identify the risk factors associated with abdominal obesity. Results: A total of 840 respondents took part in the study. The overall prevalence of abdominal obesity was found to be 24.88% (209/840). The prevalence of abdominal obesity was significantly higher among women than men (35.14% vs. 6.89%, p < 0.0001) and higher among urban dwellers (33.56%) than their rural counterparts (15.56%). Correlates of abdominal obesity was found to be gender, marital status, place of residence, age, education level, and the time used in watching television. Conclusion: This study revealed a high prevalence of abdominal obesity among the people living in the Dodoma Region. Increased age, urban residence, more time spent on television, less walking per day, and being ever married were all associated with having abdominal obesity in this population. PMID- 30417024 TI - Micro-utrophin Improves Cardiac and Skeletal Muscle Function of Severely Affected D2/mdx Mice. AB - Duchenne muscular dystrophy (DMD) is an X-linked muscle-wasting disease caused by mutations in the dystrophin gene. DMD boys are wheelchair-bound around 12 years and generally survive into their twenties. There is currently no effective treatment except palliative care, although personalized treatments such as exon skipping, stop codon read-through, and viral-based gene therapies are making progress. Patients present with skeletal muscle pathology, but most also show cardiomyopathy by the age of 10. A systemic therapeutic approach is needed that treats the heart and skeletal muscle defects in all patients. The dystrophin related protein utrophin has been shown to compensate for the lack of dystrophin in the mildly affected BL10/mdx mouse. The purpose of this investigation was to demonstrate that AAV9-mediated micro-utrophin transgene delivery can not only functionally replace dystrophin in the heart, but also attenuate the skeletal muscle phenotype in severely affected D2/mdx mice. The data presented here show that utrophin can indeed alleviate the pathology in skeletal and cardiac muscle in D2/mdx mice. These results endorse the view that utrophin modulation has the potential to increase the quality life of all DMD patients whatever their mutation. PMID- 30417025 TI - Dose-Dependent Effects of FKRP Gene-Replacement Therapy on Functional Rescue and Longevity in Dystrophic Mice. AB - Muscular dystrophy-dystroglycanopathies (MDDGs) resulting from fukutin-related protein (FKRP) gene mutations are rare disorders that result in a wide spectrum of clinical severity based on the age of onset, the degree of myogenic atrophy, and/or neurologic involvement. There is no cure for any of the FKRP-related disorders, and few options are available for symptom management. Herein, we examine the longitudinal effects of a dose-escalation study to evaluate the safety and therapeutic potential of FKRP gene-replacement therapy in a p.P448L (FKRPP448L) mouse model of MDDG. A recombinant adeno-associated virus (AAV) serotype 9 vector expressing human FKRP (AAV9-FKRP) was systemically administered to FKRPP448L mice at 5 weeks of age, when early onset of the disease is evidenced. A comprehensive analysis of protein and gene expression, histopathology, skeletal muscle function, and cardiorespiratory function was performed over short (9-week) and/or long-term (52-week) study periods. Additional studies assessed the impact of FKRP gene-replacement therapy on lifespan at an advanced stage of disease progression. Results indicate that treatment intervention can restore the biochemical defects in a dose-dependent manner, with potential for improvement in the trajectory of disease progression and extension of the expected lifespan. This study supports the initiation of early-stage clinical trials for FKRP-related disorders. PMID- 30417027 TI - Ultrafast time-resolved extreme ultraviolet (XUV) photoelectron spectroscopy of hole transfer in a Zn/n-GaP Schottky junction. AB - The addition of a metal overlayer to a semiconductor photocatalyst is a frequently used synthetic route to passivate the surface and, via the formation of a Schottky barrier, to enhance catalytic activity of the photocatalyst material. While it is known that Schottky junctions decrease recombination by charge separation, measurements of the depletion region dynamics have remained elusive. Here, we use ultrafast pump-probe transient photoelectron spectroscopy to measure material-specific dynamics of the Zn/n-GaP(100) system. Through photoemission measurements the Schottky barrier height is determined to be 2.1 +/ 0.1 eV at 10 monolayers of total Zn deposition. Transient photoemission measurements utilizing a 400 nm pump pulse show that, after excitation, holes are transferred from n-GaP(100) to the Zn overlayer within a few ps, as evidenced by shifts of the Zn 3d and Ga 3d core levels to higher binding energies. Within the timescale of the experiment (130 ps) no carrier recombination is observed in the junction. Furthermore, a long-lived surface photovoltage signal is observed at times >1 ms after photoexcitation. This work further exemplifies the potential of transient extreme ultraviolet photoelectron spectroscopy as a material-specific technique for the study of heterojunctions. PMID- 30417028 TI - Inhibition of N-Glycosylation towards Novel Anti-Cancer Chemotherapeutics. PMID- 30417026 TI - Surface-Engineered Lentiviral Vectors for Selective Gene Transfer into Subtypes of Lymphocytes. AB - Lymphocytes have always been among the prime targets in gene therapy, even more so since chimeric antigen receptor (CAR) T cells have reached the clinic. However, other gene therapeutic approaches hold great promise as well. The first part of this review provides an overview of current strategies in lymphocyte gene therapy. The second part highlights the importance of precise gene delivery into B and T cells as well as distinct subtypes of lymphocytes. This can be achieved with lentiviral vectors (LVs) pseudotyped with engineered glycoproteins recognizing lymphocyte surface markers as entry receptors. Different strategies for envelope glycoprotein engineering and selection of the targeting ligand are discussed. With a CD8-targeted LV that was recently used to achieve proof of principle for the in vivo reprogramming of CAR T cells, these vectors are becoming a key tool to genetically engineer lymphocytes directly in vivo. PMID- 30417029 TI - Finite-Size Effects in Metasurface Lasers Based on Resonant Dark States. AB - The quest for subwavelength coherent light sources has recently led to the exploration of dark-mode based surface lasers, which allow for independent adjustment of the lasing state and its coherent radiation output. To understand how this unique design performs in real experiments, we need to consider systems of finite size and quantify finite-size effects not present in the infinite dark mode surface laser model. Here we find that, depending on the size of the system, distinct and even counterintuitive behavior of the lasing state is possible, determined by a balanced competition between multiple loss channels, including dissipation, intentional out-coupling of coherent radiation, and leakage from the edges of the finite system. The conclusions are crucial for the design of future experiments that will enable the realization of ultrathin coherent light sources. PMID- 30417030 TI - Simultaneous Characterization of Nanoparticle Size and Particle-Surface Interactions with Three-Dimensional Nanophotonic Force Microscopy. AB - The behavior of a nanoparticle in solution depends strongly on the particle's physical and chemical characteristics, most notably the particle size and the surface properties. Accurately characterizing these properties is critical for quality control in a wide variety of industries. To understand a complex and polydisperse nanoparticle suspension, however, ensemble averaging is not sufficient, and there is a great need for direct measurements of size and surface properties at the individual nanoparticle level. In this work, we present an analysis technique for simultaneous characterization of particle-surface interactions and size using near-field light scattering and verify it using Brownian-dynamics simulations. Using a nanophotonic waveguide, single particles can be stably held near the waveguide's surface by strongly localized optical forces. By tracking the dynamic 3D motion of the particle under the influence of these forces using an optical microscope, it is possible to extract the particle surface interaction forces, as well as to estimate the size and refractive index of the nanoparticle. Because of the strong light-scattering signal, this method is viable for high-throughput characterization of particles as small as 100 nm in only a few seconds each. PMID- 30417031 TI - Artificial Inhalation Protocol in Adult Mice. AB - Research in the area of in vivo olfactory physiology benefits from having direct access to the nasal airways through which odorants can be presented. Ordinarily, the passage of odorants through the airways is controlled by respiratory rhythm. This fact makes it difficult to control the timing and strength of an olfactory stimulus, since animals must breathe regularly, and the act of breathing itself also controls odorant presentation. However, using an artificial inhalation preparation allows us to decouple breathing from olfaction. With this technique we present oxygen and anesthetic (if desired) to the lungs directly and independently control odorant access to the nasal passages. This technique allows for direct control of odorant presentation in vivo, enabling more precise control of parameters of stimulation when investigating olfactory processing. This technique may have additional applications, for example in aerosolized drug delivery. PMID- 30417032 TI - Fluorescence Titrations to Determine the Binding Affinity of Cyclic Nucleotides to SthK Ion Channels. AB - The cyclic-nucleotide modulated ion channel family includes cyclic nucleotide gated (CNG) and hyperpolarization-activated and cyclic nucleotide-modulated (HCN) channels, which play essential roles in visual and olfactory signaling and the heart pacemaking activity. Functionally, these channels have been extensively characterized by electrophysiological techniques from protein heterologously expressed in Xenopus oocytes and mammalian cells. On the other hand, expression and purification of these proteins for biophysical and structural analyses in vitro is problematic and expensive and, accordingly, only limited information on the purified channels is available in the literature. Here we describe a protocol for binding studies of fluorescently labeled cyclic nucleotides to a homologue of eukaryotic CNG channels. Furthermore, we describe how to directly probe binding of unlabeled cyclic nucleotides in a competition assay. The use of fluorescence as a sensitive probe for ligand binding reduces the amount of protein needed and enables fast and easy measurements using standard laboratory equipment. PMID- 30417033 TI - Assessment and Treatment Strategies for a Multiple Sclerosis Relapse. AB - Relapses are the hallmark features of relapsing-remitting multiple sclerosis (RRMS). True relapses may be challenging to accurately diagnose. A clinician must rely on a combination of history, exam findings, laboratory studies, and neuroimaging to decide whether or not to treat for a presumed relapse. Although many consider MRI as the gold standard diagnostic test, it may not be rapidly accessible and still could miss lesions. In light of this diagnostic complexity, future directions including development and validation of a scale to assess MS relapse probability and severity would be useful to multiple sclerosis specialists and practicing neurologists. Given the complex pathophysiology of MS, more research is needed to ascertain the validity of promising biomarkers for predicting relapse. PMID- 30417034 TI - Reduced Nicotine Content Cigarettes and Cannabis Use in Vulnerable Populations. AB - Objective: We estimated whether recent cannabis use moderates response to cigarettes varying in nicotine content (0.4, 2.4, 5.2, 15.8 mg/g) among smokers with concurrent affective disorders, opioid dependence, or socioeconomic disadvantage. Methods: We conducted a secondary analysis of a multi-site, double blind, laboratory study examining acute response to reduced nicotine content cigarettes (RNCC) in 169 adult smokers with co-morbid conditions. Participants positive for recent cannabis use or self-reported past 30-day cannabis use at baseline were categorized as current cannabis users (N = 63). Repeated measures analysis of variance tests assessed whether baseline cannabis use moderated cigarette reinforcement, tobacco withdrawal, craving, smoking topography, or carbon monoxide boost. Results: Cannabis users were younger, less educated, and had more depression and anxiety than non-users (p < .05). Cannabis use status did not moderate the effects of nicotine dose on concurrent choice testing, subjective effects of RNCCs, or smoking topography. After adjusting for sociodemographic characteristics, cannabis users had higher ratings on Smoking Satisfaction, Enjoyment of Respiratory Tract Sensations, and Craving Reduction across all nicotine doses. Cannabis users reported longer withdrawal symptom duration and more rapid decline of carbon monoxide boost than non-users. Conclusions: Findings suggest RNCCs decrease the addiction potential of cigarettes in vulnerable populations independent of cannabis use status. PMID- 30417035 TI - Highly parallel, interferometric diffusing wave spectroscopy for monitoring cerebral blood flow dynamics. AB - Light-scattering methods are widely used in soft matter physics and biomedical optics to probe dynamics in turbid media, such as diffusion in colloids or blood flow in biological tissue. These methods typically rely on fluctuations of coherent light intensity, and therefore cannot accommodate more than a few modes per detector. This limitation has hindered efforts to measure deep tissue blood flow with high speed, since weak diffuse light fluxes, together with low single mode fiber throughput, result in low photon count rates. To solve this, we introduce multimode fiber (MMF) interferometry to the field of diffuse optics. In doing so, we transform a standard complementary metal-oxide-semiconductor (CMOS) camera into a sensitive detector array for weak light fluxes that probe deep in biological tissue. Specifically, we build a novel CMOS-based, multimode interferometric diffusing wave spectroscopy (iDWS) system and show that it can measure ~20 speckles simultaneously near the shot noise limit, acting essentially as ~20 independent photon-counting channels. We develop a matrix formalism, based on MMF mode field solutions and detector geometry, to predict both coherence and speckle number in iDWS. After validation in liquid phantoms, we demonstrate iDWS pulsatile blood flow measurements at 2.5 cm source-detector separation in the adult human brain in vivo. By achieving highly sensitive and parallel measurements of coherent light fluctuations with a CMOS camera, this work promises to enhance performance and reduce cost of diffuse optical instruments. PMID- 30417036 TI - High-precision method for cyclic loading of small-animal vertebrae to assess bone quality. AB - One potentially important bone quality characteristic is the response of bone to cyclic (repetitive) mechanical loading. In small animals, such as in rats and mice, cyclic loading experiments are particularly challenging to perform in a precise manner due to the small size of the bones and difficult-to-eliminate machine compliance. Addressing this issue, we developed a precise method for ex vivo cyclic compressive loading of isolated mouse vertebral bodies. The method has three key characteristics: 3D-printed support jigs for machining plano parallel surfaces of the tiny vertebrae; pivotable loading platens to ensure uniform contact and loading of specimen surfaces; and specimen-specific micro-CT based finite element analysis to measure stiffness to prescribe force levels that produce the same specified level of strain for all test specimens. To demonstrate utility, we measured fatigue life for three groups (n = 5-6 per group) of L5 vertebrae of C57BL/6J male mice, comparing our new method against two methods commonly used in the literature. We found reduced scatter of the mechanical behavior for this new method compared to the literature methods. In particular, for a controlled level of strain, the standard deviation of the measured fatigue life was up to 5-fold lower for the new method (F-ratio = 4.9; p < 0.01). The improved precision for this new method for biomechanical testing of small-animal vertebrae may help elucidate aspects of bone quality. PMID- 30417037 TI - The data of Escherichia coli strains genes in different types of wastewater. AB - From April 2016 to March 2017, a number of 99 isolates of Escherichia coli were collected from three types of wastewater including urban wastewater (33 isolates), livestock slaughterhouse wastewater (33 isolates) and poultry slaughterhouse wastewater (33 isolate). The specimens were cultured on microbiological media. The bacterial identification was performed by morphological and biochemical tests. Polymerase chain reaction (PCR) method was carried out to detect 2 virulence genes (traT, and fimH) and 4 antibiotic resistance genes (bla TEM, CTX, SHV , and tetA). The data showed that the prevalence rate of traT, fimH,blaCTX, blaTEM,blaSHV, tetA genes were 89.9%, 91.9%, 79.8%, 40.4%, 6.1%, and 91.9%, respectively. PMID- 30417038 TI - The experimental data of investigating the efficiency of zinc oxide nanoparticles technology under ultraviolet radiation (UV/ZnO) to remove Acid - 32 - Cyanine 5R from aqueous solutions. AB - The aim of this data was to evaluate the efficiency of zinc oxide nanoparticles plus ultraviolet radiation (UV/ZnO) technology to remove Acid - 32 - Cyanine 5R. The effect of optimal parameters including initial pH (5,10), contact time (2-20 min), initial dye concentration (0.5-2 mg/L), and zinc oxide dosage (0.1 and 0.2 g/L) was investigated. The data showed that under alkaline conditions (pH = 10) and 0.2 g/L of ZnO nanoparticles, the maximum dye removal efficiency was observed under UV/ZnO process conditions. Furthermore, with the increase in Acid - 32 - Cyanine 5R dye concentration, the removal efficiency of the dye diminished, while with prolongation of the radiation time, the removal efficiency increased. In the presence of ultraviolet radiation, there is a need to longer time and higher radiation intensity for complete removal of the dye. However, in the presence of ZnO nanoparticles alone, around 5-10% of the dye is removed. The highest removal efficiency of Acid - 32 dye was through radiation by ultraviolet lamp 150 W at an initial dye concentration of 1 mg/L, in pH 5 and 10, respectively, at 98.5% and 99% respectively. On the other hand, through hybrid use of UV/ZnO, within a shorter time, complete removal (100%) is achieved. Generally, use of UV/ZnO process can be utilized as a suitable method for dye wastewaters treatment. PMID- 30417039 TI - Data on transcriptome profiling of circulating microRNAs in dairy cattle. AB - MicroRNA (miRNA) are found in numerous biofluids including blood and are considered a new class of biomarkers. The data presented here are related to the research article entitled "Profiling and identification of pregnancy-associated circulating microRNAs in dairy cattle" (Markkandan et al. 2018). In the cited article, we sequenced the circulating microRNAs of the three healthy dairy cows of normal and 30 days of pregnancy (DOP) using Illumina RNA-Seq. Differentially expressed genes (DEG) analysis between normal and pregnant samples showed perturbations in miRNA expression. Herein, we made a comparison of DEGs at normal and 60 DOP libraries. The analysis results showed that 147 known miRNAs were differently expressed at 60 DOP groups when compared to the normal group. In addition, stage specific miRNAs were also predicted. PMID- 30417040 TI - Functional connectivity analysis of fMRI data collected from human subjects with chronic tinnitus and varying levels of tinnitus-related distress. AB - The data presented here are functional connectivity analyses based on fMRI scans from a clinical sample of the chronic tinnitus population (n = 75). All data were obtained during an experiment in which subjects listened to auditory stimuli via headphones while undergoing fMRI scanning. The stimuli consisted of tones and bandpass noise presented at different frequencies. Stimulus frequency was the experimental factor, which was set (1) at each subject's tinnitus percept frequency (TF) and (2) at an unrelated control frequency (CF) at least one octave away from the TF stimuli. All subjects were presented with stimuli at these two frequencies. We refer the reader to our original research article "Functional brain changes in auditory phantom perception evoked by different stimulus frequencies" (Hullfish et al., 2018) for further discussion. Here, we present data specifically from group-level analyses where the subjects were divided according to their level of tinnitus-related distress. The high-distress (HD) group comprised 43 subjects with Tinnitus Questionnaire (TQ) scores greater than or equal to 47, out of a possible 82 points. The low-distress (LD) group comprised the remaining 32 subjects with TQ score less than 47. The data presented include contrasts of functional connectivity elicited by TF and CF stimuli in each group as well as contrasts between the two groups. PMID- 30417041 TI - Data on excessive risk of cancer from gamma radiation in residents of Bojnurd city. AB - The aim of the data was to measure the absorbed dose of gamma radiation in order to estimate the excessive risk of cancer-induced gamma radiation during the lifetime of Bojnurd residents. In this descriptive cross-sectional study, gamma radiations in 30 places was measured in Bojnurd City during four seasons in 2015. A dosimeter was stacked on a tripod at 1 m from the ground for 50 minutes, and then, the absorbed dose of gamma radiation was recorded in the checklist. Ultimately, the effective dose and the excessive lifetime risk of cancer were determined. The mean +/- SE of absorbed dose of gamma radiation in spring, summer, autumn, winter was 134.25 +/- 1.45; 139.89 +/- 1.64; 134.40 +/- 1.25; 143.80 +/- 1.73 nGy, respectively. The average annual effective dose by residents in open space was estimated at an average of 0.167 mSv. Also, the excessive risk of cancer-induced gamma radiation was equal to 0.67 * 10-3. The annual effective dose and the excessive risk of cancer-induced gamma radiation during the lifetime of Bojnurd residents are higher than the global average. PMID- 30417042 TI - Maps of electrical activity in diabetic patients and normal individuals. AB - Here, data related to the electrical activity of the human skin are presented in detail. The 3D electrical activity maps in normal and diabetic individuals are shown and described using raw data obtained with Photon-Pixel coupling. Average electrical activity matrices are shown by subject, gender and group. Distributions of the electrical activity data are shown in connection with the ventral and dorsal side of the human torso. For a better understanding of the electrical activity data, critical parameters of the individuals that participated in the study are also presented. PMID- 30417043 TI - Assessing the performance of Granger-Geweke causality: Benchmark dataset and simulation framework. AB - Nonparametric methods based on spectral factorization offer well validated tools for estimating spectral measures of causality, called Granger-Geweke Causality (GGC). In Pagnotta et al. (2018) [1] we benchmarked nonparametric GGC methods using EEG data recorded during unilateral whisker stimulations in ten rats; here, we include detailed information about the benchmark dataset. In addition, we provide codes for estimating nonparametric GGC and a simulation framework to evaluate the effects on GGC analyses of potential problems, such as the common reference problem, signal-to-noise ratio (SNR) differences between channels, and the presence of additive noise. We focus on nonparametric methods here, but these issues also affect parametric methods, which can be tested in our framework as well. Our examples allow showing that time reversal testing for GGC (tr-GGC) mitigates the detrimental effects due to SNR imbalance and presence of mixed additive noise, and illustrate that, when using a common reference, tr-GGC unambiguously detects the causal influence's dominant spectral component, irrespective of the characteristics of the common reference signal. Finally, one of our simulations provides an example that nonparametric methods can overcome a pitfall associated with the implementation of conditional GGC in traditional parametric methods. PMID- 30417044 TI - Microarray dataset of after-ripening induced mRNA oxidation in wheat seeds. AB - The dataset presented here profiles oxidative modification of mRNAs in wheat seeds in response to after-ripening, a treatment that releases seeds from the state of dormancy. The level of dormancy in wheat seeds is closely associated with preharvest sprouting, defined as the germination of seeds while they are on the mother plant, which negatively affects wheat yield and quality. Understanding the molecular mechanisms involved in the control of seed dormancy is critical for improving the tolerance of wheat seeds to preharvest sprouting. The dataset were generated using oxidized mRNA samples derived from three independent biological replicates of dormant and after-ripened (non-dormant) wheat seeds and a microarray based experimental procedures that involved the use of Affymetrix GeneChip Wheat Genome Array. The raw and normalized data are available in NCBI's Gene Expression Ominbus (GEO) database with accession number GSE41949, and a related research article has been published in Plant Biotechnology Journal (Gao et al., 2013). PMID- 30417045 TI - Correlated lip motion and voice audio data. AB - This data set is comprised of correlated audio and lip movement data in multiple videos of multiple subjects reading the same text. It was collected to facilitate the development and validation of algorithms used to train and test a compound biometric system that consists of lip-motion and voice recognition. The data set is a collection of videos of volunteers reciting a fixed script that is intended to be used to train software to recognize voice and lip-motion patterns. A second video is included of the individual reciting a shorter phrase, which is designed to be used to test the recognition functionality of the system. The recordings were collected in a controlled, indoor setting with a 4K professional-grade camcorder and adjustable, LED lights. PMID- 30417046 TI - Urinary Biomarkers in the Evaluation of Primary Hematuria: A Systematic Review and Meta-Analysis. AB - Introduction: Urinary biomarkers are entering the clinical landscape as a non invasive method to evaluate patients for bladder cancer, however it is currently predominantly used in the surveillance setting. The use of biomarkers in the setting of primary hematuria is not widespread despite initial promising results. This study comprehensively reviews the literature on the diagnostic performance of FDA-approved biomarkers in the evaluation of primary hematuria. Methods: According to the Preferred Reporting Items for Systematic Review and Meta analysis (PRISMA) statement, MEDLINE, EMBASE, ScienceDirect, Cochrane Libraries, HTA database, Google Scholar and Web of Science were searched up to June 2017 for studies assessing the diagnostic accuracy of FDA-approved urinary biomarkers amongst patients presenting with primary hematuria. The quality of included studies was assessed using the QUADAS-2 tool. Results: Fourteen studies met the pre-specified eligibility criteria and were included for analysis. The biomarkers assessed in these studies were AssureMDx, Bladder tumor antigen, CxBladder, NMP22, UroVysion and uCyt+. Across these four biomarkers, the sensitivity ranged from 0.67 to 0.95, and specificity from 0.68 to 0.93, respectively. There was significant heterogeneity between the included studies. Limited head-to-head comparison with urine cytology demonstrated that in general, the biomarkers have superior sensitivity but inferior specificity. Overall, the quality of evidence was graded as moderate primarily because of inadequate blinding. Conclusion: The current diagnostic performance of biomarkers are inadequate to replace cystoscopy in the primary hematuria setting. However, AssureMDx in particular may have a role as a triage test for cystoscopy but further prospective data is required to validate these findings. Given the current evidence, the use of these markers as an adjunct to cystoscopy for the evaluation of hematuria should be considered investigational. PMID- 30417047 TI - Intravesical Radiofrequency-Induced Chemohyperthermia for Carcinoma in Situ of the Urinary Bladder: A Retrospective Multicentre Study. AB - Objective: To examine the effect of intravesical radiofrequency-induced chemohyperthermia (RF-CHT) in carcinoma in-situ (CIS) patients overall and split according to previously received therapy. Methods: CIS patients that underwent an induction and maintenance phase of>=6 RF-CHT instillations, and had either pathology or cystoscopy plus cytology available at 6 months of follow-up were retrospectively included. Complete response (CR), recurrences, cystectomy-free rate, overall survival (OS), and adverse events were evaluated. Analysis was performed for overall, bacillus Calmette-Guerin (BCG)-unresponsive, other BCG treated, and treatment naive patients. Results: Patients (n = 150) had a mean of 17.5, 9.2, or 0 previous BCG instillations in the BCG-unresponsive (n = 50), other BCG-treated (n = 46, missing n = 4), and treatment naive groups (n = 47, missing n = 3), respectively. After 6 months, a CR of 46.0%, 71.7%, and 83.0% was found (p < 0.001). Subsequent 2-year recurrence rates were 17.4%, 27.3%, and 12.8%, respectively. The overall cystectomy-free rate and OS at mean follow-up (35.8 months) were 78.5% and 78.0%, respectively. These were 71.4% vs. 84.1% vs. 86.7% (cystectomy-free rate, p = 0.006) and 76.0% vs. 69.6% vs. 87.2% (OS, p = 0.06) for BCG-unresponsive vs. other BCG-treated vs. treatment naive patients. Progression to muscle-invasive disease was seen in 13.3% of patients. Patients stopped induction or maintenance RF-CHT instillations due to adverse events in respectively 13.4% and 17.8%. Conclusions: Intravesical RF-CHT showed good results in both treatment naive and BCG-treated CIS patients, avoiding the need for cystectomy in 78.5% of cases for at least 3 years with a modest risk of progression. Thus, RF-CHT proves an alternative to cystectomy in selected high risk patients. PMID- 30417049 TI - Evaluation of Intraoperative Versus Postoperative Adjuvant Mitomycin C with Nephroureterectomy for Urothelial Carcinoma of the Upper Urinary Tract. AB - Background: Results of randomized trials support a single dose of intravesical chemotherapy following radical nephroureterectomy (RNU) for urothelial carcinoma. Objective: To evaluate the impact of the timing of intravesical mitomycin C (MMC) administration on the rate of bladder tumor recurrence (BTR) following RNU. Methods: We performed a retrospective review of patients who underwent RNU for upper tract urothelial carcinoma (UTUC) and received intravesical MMC between 2008 and 2016. Patients were categorized into two separate groups based on the timing of MMC administration: patients who received MMC intraoperatively (IO) and patients who received MMC on post-operative day 1 or later (PO). Our primary endpoint was BTR rate within the first year after surgery. Results: Fifty-one patients met our inclusion criteria: (IO: n = 30; PO: n = 21). There were no statistically significant differences in baseline characteristics of age, gender, race, surgical approach, tumor grade, tumor stage, surgical margins, nodal status, concomitant CIS, or history of bladder cancer. The median length of follow-up for each group was 22 months for IO and 12 months for PO (P = 0.10). The estimated probability of 1-year BTR rates for the IO and PO groups were 16% and 33%, respectively (p = 0.09). Cox analysis noted that the IO patients had a significantly lower rate of BTR in the first year postoperatively (HR = 0.113, 95% CI = 0.28-0.63, p = 0.01). Conclusions: The use of intraoperative MMC at the time of RNU was associated with a decrease in the risk of 1-year recurrence within the bladder. PMID- 30417048 TI - Early Complications and Mortality following Radical Cystectomy: Associations with Malnutrition and Obesity. AB - Background: There are conflicting data regarding the impact of obesity on postoperative outcomes following radical cystectomy (RC) and how obesity and malnutrition interact in patients undergoing RC. Objective: To evaluate associations of body mass index (BMI), significant preoperative weight loss, and hypoalbuminemia with 30-day complications and mortality after RC. Methods: Review of the American College of Surgeons National Surgical Quality Improvement Program database identified 2,055 patients who underwent RC (2006-12). Univariate and multivariable logistic regression models were developed to assess associations between hypoalbuminemia (<3.5 g/dL), >10% preoperative weight loss, obesity as characterized by BMI (class I: 30-34.9, II: 35-39.9, III: >=40 kg/m2), and 30-day complications and mortality. Results: The median BMI of the study cohort was 27.82 kg/m2 with 22.4% classified as having class I, 7.5% class II, and 4.2% class III obesity, respectively. Hypoalbuminemia and >10% weight loss were present in 16.7% and 3.5%, respectively. Among obese patients, 13.4% had hypoalbuminemia. On multivariable analysis, class I (OR 1.43, p = 0.01), class II (OR 1.92, p < 0.001), and class III (OR 2.32, p < 0.001) obesity and hypoalbuminemia (OR 1.47, p = 0.02) were independently associated with 30-day complications, and class III obesity (OR 2.96, p = 0.02) and hypoalbuminemia (OR 2.33, p = 0.03) were independently associated with 30-day mortality. Conclusion: Increasing class of obesity and hypoalbuminemia were independently associated with increased complications following RC. Hypoalbuminemia and class III obesity were associated with early mortality. This study highlights the fact that malnutrition may coexist in obese patients and underscores the need to identify patients with malnutrition who may be candidates for preoperative nutritional optimization. PMID- 30417050 TI - Hyperthermic Intravesical Chemotherapy for BCG Unresponsive Non-Muscle Invasive Bladder Cancer Patients. AB - Background: Adjuvant intravesical instillations with bacillus Calmette-Guerin (BCG) is the recommended treatment option for patients with intermediate-and high risk non-muscle invasive bladder cancer (NMIBC). Despite adequate BCG treatment, a large proportion of patients experience a recurrence. Although radical cystectomy is the gold standard for BCG unresponsive NMIBC, some patients are unfit or unwilling to consider this option. Objective: To assess the effectiveness of Hyperthermic IntraVEsical Chemotherapy (HIVEC(r)) in BCG unresponsive NMIBC patients. Methods: A post-hoc analysis was conducted of prospectively included intermediate-and high-risk NMIBC patients who were planned to receive HIVEC(r) treatment between October 2014 and November 2017. For the present analysis, only patients who met the BCG unresponsive definition were included. Patients were followed by cystoscopy and cytology every 3 months and a CT-urography scan yearly. The primary outcome was the disease-free survival (DFS). The Common Terminology Criteria for Adverse Events (CTCAE) was used to assess side-effects. Results: The study population consisted of 55 BCG unresponsive NMIBC patients of whom 52 underwent>=5 HIVEC(r) treatments. The median age and follow-up were 73 years and 14.0 months (IQR 7.6 - 24.6). The median DFS was 17.7 months (SE 6.72) and progression occurred in four patients. The 1-year cumulative incidence rate of disease recurrence/progression was 53%. Two patients experienced severe side-effects (CTCAE>=3). Conclusions: HIVEC(r) seems a valid treatment option for BCG unresponsive NMIBC patients. We report a median DFS of 17.7 months (SE 6.72), potentially avoiding or postponing the need for radical surgery in a proportion of these patients. PMID- 30417051 TI - Increased Surgical Complications in Smokers Undergoing Radical Cystectomy. AB - Background: Not only is smoking a risk factor for the development of bladder cancer, it has also been implicated in increasing surgical morbidity and mortality. In general, the demographic and clinical characteristics of smokers are different to non-smokers which can bias the results of the impact of smoking. Objective: To evaluate the impact of smoking on radical cystectomy outcomes. Methods: Radical cystectomy cases were identified in the National Surgical Quality Improvement Program database from 2007-2015. Smokers were matched with non-smokers using propensity scores in a 1:1 ratio. Multivariate logistic regression was performed to evaluate the overall incidence of Clavien III-V complications. Secondary analysis was performed for the incidence of each complication recorded in NSQIP. Results: A total of 850 smokers undergoing radical cystectomy were matched to 850 non-smokers. The matching process improved the balance of covariates between smokers and non-smokers. The overall incidence of Clavien III-V complications was higher in smokers (13.1% vs 7.4%, p < 0.001). This corresponded to an adjusted odds ratio of 1.9 [95% CI 1.4-2.6, p = 0.028]. Other comorbid conditions worsened post-operative complications amongst smokers. When evaluating each complication recorded in the database, smokers had a higher incidence of wound dehiscence, pneumonia and myocardial infarction. Conclusion: Current smokers have a greater risk of morbidity following radical cystectomy. This should be considered when evaluating safety of surgery and patients should be counselled accordingly. Furthermore, even a short period of pre-operative smoking cessation can improve surgical outcomes. PMID- 30417052 TI - Changes in Lean Muscle Mass Associated with Neoadjuvant Platinum-Based Chemotherapy in Patients with Muscle Invasive Bladder Cancer. AB - Background: Baseline sarcopenia or severe lean muscle deficiency is independently associated with increased mortality after cystectomy for muscle-invasive urothelial carcinoma of the bladder (MIUC). The impact of chemotherapy on muscle mass in MIUC patients remains undefined. Objectives: To describe preoperative changes in body composition in MIUC patients receiving platinum-based neoadjuvant chemotherapy (NC). Methods: Patients with cT2-4 N0-1 M0 UC of the bladder who received NC were identified. Lumbar skeletal muscle index (SMI, cm2/m2), visceral adipose index (VAI, cm2/m2), and the subcutaneous and intramuscular adipose index (SAI, cm2/m2) were calculated using validated methodology (cross sectional area of skeletal muscle/height2 at L3) from measurement of soft tissue areas on pre- (pre-NC) and post-NC (post-NC) computed tomography. Patients were classified as sarcopenic according to consensus definitions: Male: SMI <55 cm2/m2, Female: SMI <38.5 cm2/m2. Pre-NC and post-NC median body mass index (BMI kg/m2), SMI, and adipose indices were compared. Results: The study cohort consisted of 26 patients, with a median age 70 years, including 7 females (27%). Chemotherapy regimens included dose-dense methotrexate, vinblastine, doxorubicin and cisplatin (31%), gemcitabine/cisplatin (62%) and gemcitabine/carboplatin (3.8%) with a median of 3.5 (range 2-6) cycles. Median pre- and post-NC BMI were 27.1 kg/m2 and 27.2 kg/m2 (p = 0.36). Median pre- and post-NC SMI were 49.1 cm2/m2 and 44.5 (p < 0.001) respectively. Median percent change in SMI was -6.4% (range -30% to 10%). Pre-NC, 18 (69%) patients were sarcopenic vs. 21 (81%, p = 0.002) post-NC. Median time between initiation of chemotherapy and cystectomy was 110 days. Conclusions: We observed a significant decrease in lean muscle mass among MIUC patients treated with platinum-based NC prior to cystectomy, with an associated increase in the prevalence of sarcopenia. Patients undergoing NC may benefit from pre habilitative interventions to mitigate lean muscle loss prior to cystectomy. PMID- 30417055 TI - Challenging Cases in Urothelial Cancer. PMID- 30417053 TI - Venous Thromboembolism and Peri-Operative Chemotherapy for Muscle-Invasive Bladder Cancer: A Population-based Study. AB - Background: Chemotherapy and major pelvic surgery are established risk factors for venous thromboembolism (VTE). We evaluate the incidence rate, timing, and factors associated with VTE in patients with bladder cancer who underwent radical cystectomy and peri-operative chemotherapy in routine clinical practice. Methods: Electronic records of treatment were linked to the population-based Ontario Cancer Registry to identify all patients who underwent cystectomy for bladder cancer in Ontario 1994-2013. VTE events within 6 months of before or after cystectomy were identified using diagnostic codes recorded on hospital admissions and emergency department visits. Multivariable logistic regression was used to analyze factors associated with VTE prior to surgery, within 90-days of cystectomy, and 120-days after the start of adjuvant chemotherapy. Results: 4205 patients had cystectomy and 26% (1084/4205) received peri-operative chemotherapy. The overall incidence rate of VTE within 6 months of cystectomy was 9% (363/4205). VTE rate was highest among those patients treated with neoadjuvant chemotherapy (NACT) compared to patients treated with no chemotherapy or only adjuvant chemotherapy (ACT) (12% vs 8% vs 9%, p = 0.002). Among all VTE events, 10%, 28%, and 61% occurred before, during, and after hospitalization for cystectomy. Pre-operative VTE rate was highest among cases treated with NACT (4%) compared to patients with no chemotherapy (<1%) or ACT (<1%) (p < 0.001). VTE within 90 days of surgery was associated with greater length of hospital admission (p < 0.001) across all treatment groups. Conclusions: A substantial proportion of patients treated with peri-operative chemotherapy will develop VTE. The majority of these occur after discharge from hospital following cystectomy. Extended thromboprophylaxis treatment in high-risk patients including those who receive peri-operative chemotherapy should be considered. PMID- 30417056 TI - Perioperative Blood Transfusions and Bladder Cancer Outcomes. PMID- 30417057 TI - Clinical Trials Corner. PMID- 30417054 TI - Immunology, Immunotherapy, and Translating Basic Science into the Clinic for Bladder Cancer. AB - The Fourth Annual Albert Institute Bladder Cancer Care and Research Symposium was held from September 14th-16th in Houston, Texas. The symposium covered a range of topics relevant to bladder cancer, including basic science aspects of immunology and immunotherapy that inform clinical management; intravesical therapy for non muscle invasive disease; understanding the nuances of carcinoma in situ; and optimizing patient care and outcomes following therapy. The moving landscape of bladder cancer from an industry perspective was also discussed. In the following sections we discuss intrinsic and extrinsic factors, including the immune microenvironment and sex bias, in the context of bladder cancer; how these influence tumor development, progression, and treatment strategies; and how the interpretation of immune features in relation to molecular subtypes informs both treatment decisions and response. We conclude with a summary of key points that will need to be addressed to ensure best use of new knowledge in this area for improved clinical management of patients with bladder cancer. PMID- 30417058 TI - In vivo multiphoton microscopy of scabies. PMID- 30417059 TI - Topical tofacitinib solution for the treatment of alopecia areata affecting eyelashes. PMID- 30417060 TI - Cutaneous and laryngopharyngeal papules of xanthoma disseminatum successfully treated with 2-chlorodeoxyadenosine. PMID- 30417061 TI - Familiar palmoplantar keratoderma, flaccid blisters, and widespread scaling. PMID- 30417062 TI - A case of combined Merkel cell carcinoma and squamous cell carcinoma: Molecular insights and diagnostic pitfalls. PMID- 30417063 TI - Reflectance confocal microscopy features of labial melanotic macule: Report of three cases. PMID- 30417064 TI - A report of Bell's Palsy triggered by leptomeningeal metastases from recurrent high grade serous ovarian cancer. AB - *CNS metastases involving leptomeninges (LM) are extremely rare in patients with ovarian cancer.*Prognosis for ovarian cancer patients with LM metastases is very poor and treatment is palliative in nature.*Chemotherapy is administered intrathecally via an Ommaya reservoir or intra-CSF via repeated lumbar punctures.*Early recognition of LM metastases can help maintain the patients' quality of life by minimizing neurological deficits. PMID- 30417065 TI - Economic insecurity: A socioeconomic determinant of mental health. AB - Economic insecurity is an emerging topic that is increasingly relevant to the labour markets of developed economies. This paper uses data from the British Household Panel Survey to assess the causal effect of various aspects of economic insecurity on mental health in the UK. The results support the idea that economic insecurity is an emerging socioeconomic determinant of mental health, although the size of the effect varies across measures of insecurity. In particular, perceived future risks are more damaging to mental health than realised volatility, insecurity is more damaging for men, and the negative effect of insecurity is constant throughout the income distribution. Importantly, these changes in mental health are experienced without future unemployment necessarily occurring. PMID- 30417067 TI - Credibility of subgroup analyses by socioeconomic status in public health intervention evaluations: An underappreciated problem? AB - There is increasing interest amongst researchers and policy makers in identifying the effect of public health interventions on health inequalities by socioeconomic status (SES). This issue is typically addressed in evaluation studies through subgroup analyses, where researchers test whether the effect of an intervention differs according to the socioeconomic status of participants. The credibility of such analyses is therefore crucial when making judgements about how an intervention is likely to affect health inequalities, although this issue appears to be rarely considered within public health. The aim of this study was therefore to assess the credibility of subgroup analyses in published evaluations of public health interventions. An established set of 10 credibility criteria for subgroup analyses was applied to a purposively sampled set of 21 evaluation studies, the majority of which focussed on healthy eating interventions, which reported differential intervention effects by SES. While the majority of these studies were found to be otherwise of relatively high quality methodologically, only 8 of the 21 studies met at least 6 of the 10 credibility criteria for subgroup analysis. These findings suggest that the credibility of subgroup analyses conducted within evaluations of public health interventions' impact on health inequalities may be an underappreciated problem. PMID- 30417068 TI - Noncommunicable disease-attributable medical expenditures, household financial stress and impoverishment in Bangladesh. AB - Background: Treatment of noncommunicable diseases (NCDs) in low-income countries can entail large out-of-pocket (OOP) medical expenditures, which can increase the likelihood of household impoverishment and perpetuate the poverty cycle. This paper studies the implications of NCDs on household medical expenditure, household financial stress (e.g. selling assets or borrowing for treatment financing), catastrophic OOP expenditure, and impoverishment in Bangladesh. Methods: We used self-reported health status and household expenditure survey data from 12,240 households in Bangladesh. NCD-afflicted households were defined by presence of at least one of the following conditions within the household - heart disease, hypertension, asthma, diabetes, cancer, or kidney disease. Using linear regression models, we examined whether NCD households incur more medical expenditures, allocate a larger budget share on medical expenditures, and have greater probability of experiencing catastrophic medical expenditure or financial stress from OOP spending than non-NCD households. Finally, using survey weights, we extrapolated how NCD-attributable medical expenditure can result in impoverishment and downward movement in net consumption status at the population level. Results: NCD-afflicted households allocate a greater share of household expenditures for medical care than households without NCDs, and their probability of incurring catastrophic medical expenditure is higher by 6.7 percentage points compared to the households with no reported conditions. NCD households are 85% more likely to sell assets or borrow from informal sources to finance treatment cost. Household spending on NCD care is estimated to account for the impoverishment of 0.66 million persons in Bangladesh in 2010, and for reducing the net consumption status of 7.63 million persons on both sides of the poverty line after accounting for NCD-related OOP expenditures. Conclusion: NCD-related household medical expenditure is associated with experiencing financial distress and aggravating poverty in Bangladesh. PMID- 30417066 TI - Blue-collar work and women's health: A systematic review of the evidence from 1990 to 2015. AB - Despite the implications of gender and sex differences for health risks associated with blue-collar work, adverse health outcomes among blue-collar workers has been most frequently studied among men. The present study provides a "state-of-the-field" systematic review of the empiric evidence published on blue collar women's health. We systematically reviewed literature related to the health of blue-collar women published between January 1, 1990 and December 31, 2015. We limited our review to peer-reviewed studies published in the English language on the health or health behaviors of women who were presently working or had previously worked in a blue-collar job. Studies were eligible for inclusion regardless of the number, age, or geographic region of blue-collar women in the study sample. We retained 177 studies that considered a wide range of health outcomes in study populations from 40 different countries. Overall, these studies suggested inferior health among female blue-collar workers as compared with either blue-collar males or other women. However, we noted several methodological limitations in addition to heterogeneity in study context and design, which inhibited comparison of results across publications. Methodological limitations of the extant literature, alongside the rapidly changing nature of women in the workplace, motivate further study on the health of blue-collar women. Efforts to identify specific mechanisms by which blue-collar work predisposes women to adverse health may be particularly valuable in informing future workplace-based and policy-level interventions. PMID- 30417070 TI - Temporospatial components of brain ERPs as biomarkers for Alzheimer's disease. AB - Introduction: Developing biomarkers that distinguish individuals with Alzheimer's disease (AD) from those with normal cognition remains a crucial goal for improving the health of older adults. We investigated adding brain spatial information to temporal event-related potentials (ERPs) to increase AD identification accuracy over temporal ERPs alone. Methods: With two-step principal components analysis, we applied multivariate analyses that incorporated temporal and spatial ERP information from a cognitive task. Discriminant analysis used temporospatial ERP scores to classify participants as belonging to either the AD or healthy control group. Results: Temporospatial ERPs produced a cross validated area under the curve of 0.84. Adding spatial information through a formal procedure significantly improves classification accuracy. Discussion: A weighted combination of temporospatial ERP markers performs well in detecting AD. Because ERPs are noninvasive and inexpensive, they may be promising biomarkers for AD that can add functional information to other biomarker systems while providing the individual's probability of correct classification. PMID- 30417069 TI - A multivariate metabolic imaging marker for behavioral variant frontotemporal dementia. AB - Introduction: The heterogeneity of behavioral variant frontotemporal dementia (bvFTD) calls for multivariate imaging biomarkers. Methods: We studied a total of 148 dementia patients from the Feinstein Institute (Center-A: 25 bvFTD and 10 Alzheimer's disease), Technical University of Munich (Center-B: 44 bvFTD and 29 FTD language variants), and Alzheimer's Disease Neuroimaging Initiative (40 Alzheimer's disease subjects). To identify the covariance pattern of bvFTD (behavioral variant frontotemporal dementia-related pattern [bFDRP]), we applied principal component analysis to combined 18F-fluorodeoxyglucose-positron emission tomography scans from bvFTD and healthy subjects. The phenotypic specificity and clinical correlates of bFDRP expression were assessed in independent testing sets. Results: The bFDRP was identified in Center-A data (24.1% of subject * voxel variance; P < .001), reproduced in Center-B data (P < .001), and independently validated using combined testing data (receiver operating characteristics-area under the curve = 0.97; P < .0001). The expression of bFDRP was specifically elevated in bvFTD patients (P < .001) and was significantly higher at more advanced disease stages (P = .035:duration; P < .01:severity). Discussion: The bFDRP can be used as a quantitative imaging marker to gauge the underlying disease process and aid in the differential diagnosis of bvFTD. PMID- 30417071 TI - Multimodal neuroimaging study of cerebrovascular disease, amyloid deposition, and neurodegeneration in Alzheimer's disease progression. AB - Introduction: Cerebrovascular disease (CVD) is not currently considered a core pathological feature of Alzheimer's disease (AD), but mounting evidence suggests that concurrent CVD may exacerbate AD progression. The purpose of this study was first to examine the relationship among amyloid, CVD, and neurodegeneration and second to examine the extent to which amyloid and CVD pathology drive subsequent neurodegeneration over time. Methods: Six hundred eight (224 normal controls, 291 mild cognitive impairment, 93 AD) subjects from the Alzheimer's Disease Neuroimaging Initiative with longitudinal AV45 positron emission tomography imaging and MR imaging were investigated. Results: Amyloid and white matter hyperintensity (WMH) burden increased across clinical diagnosis groups (normal control < mild cognitive impairment < AD). Amyloid pathology and WMH volume were related to lower cortical thickness, while WMH burden was associated with neurodegenerative/atrophic changes over time in key AD-related brain regions. Discussion: CVD and AD may be etiologically independent, but our findings suggest that CVD should be considered explicitly for its effect on AD progression. PMID- 30417073 TI - Single-center experience of hemodialysis in patients after Fontan palliation. PMID- 30417072 TI - Utility of perfusion PET measures to assess neuronal injury in Alzheimer's disease. AB - Introduction: 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is commonly used to estimate neuronal injury in Alzheimer's disease (AD). Here, we evaluate the utility of dynamic PET measures of perfusion using 11C-Pittsburgh compound B (PiB) to estimate neuronal injury in comparison to FDG PET. Methods: FDG, early frames of PiB images, and relative PiB delivery rate constants (PiB R1) were obtained from 110 participants from the Dominantly Inherited Alzheimer Network. Voxelwise, regional cross-sectional, and longitudinal analyses were done to evaluate the correlation between images and estimate the relationship of the imaging biomarkers with estimated time to disease progression based on family history. Results: Metabolism and perfusion images were spatially correlated. Regional PiB-R1 values and FDG, but not early frames of PiB images, significantly decreased in the mutation carriers with estimated year to onset and with increasing dementia severity. Discussion: Hypometabolism estimated by PiB-R1 may provide a measure of brain perfusion without increasing radiation exposure. PMID- 30417075 TI - Does affirmative action in Chinese college admissions lead to mismatch? Educational quality and the relative returns to a baccalaureate degree for minorities in China. AB - This paper provides a unique illustration of the benefits of affirmative action in higher educaiton. It focuses on China in the early 21st Century to gauge the impacts of advantges afforded to ethnic minority group members in admissions to colleges and univerities. It specifically addresses a variant of the mismatch hypothesis that alleges that minority students sorted into higher ranked universities are worse off than equallty qualified minorities attending lower ranked universities. In particular, we examine the expected earnings of minorities vs non-minorities attending elite vs less selective colleges and universities in China. The paper utilizes data from the 2002 Chinese Household Income Project to estimate the labor market return to graduating from college relative to high school to assess the impact of post-reform affirmative action in college/univerity admissions in China. Parameter estimates of heterogeneous treatment effects reveal that for minorities, the average treatment effect of earning a baccalaureate degree from colleges/universities ranked good and very good is high relative to the Han majority, and for those actually receiving the treatment from colleges/universities ranked good, and would be positive for those who could have earned a baccalaureate degree from colleges/universities ranked good and very good, but did not. Our results suggest that post-reform affirmative action education policies in China have been effective at improving the education and labor market outcomes of minorities, and that existing minority-Han disparities can be eliminated, and Chinese economic growth can be enhanced, by further expanding the pipeline of minorities that complete high school and enter into colleges/universities that grant baccalaureate degrees. Our findings suggest that the mismatch hypothesis cannot be viewed as a universal phenomenon that renders affirmative action in college/university admissions an ineffective policy tool to redress/remedy historic discrimination against minority groups. PMID- 30417074 TI - Cooperative Effects of Vascular Angiogenesis and Lymphangiogenesis. AB - In this study, we modeled lymphangiogenesis and vascular angiogenesis in a microdevice using a tissue engineering approach. Lymphatic vessels (LV) and blood vessels (BV) were fabricated by sacrificial molding with seeding human lymphatic endothelial cells and human umbilical vein endothelial cells into molded microchannels (600 MUm diameter). During subsequent perfusion culture, lymphangiogenesis and vascular angiogenesis were induced by addition of phorbol 12-myristate 13-acetate (PMA) and VEGF-C or VEGF-A characterized by podoplanin and Prox-1 expression. The lymphatic capillaries formed button-like junctions treated with dexamethasone. To test the potential for screening anti-angiogenic (vascular and lymphatic) factors, antagonists of VEGF were introduced. We found that an inhibitor of VEGF-R3 did not completely suppress lymphatic angiogenesis with BVs present, although lymphatic angiogenesis was selectively prevented by addition of a VEGF-R3 inhibitor without BVs. To probe the mechanism of action, we focus on matrix metalloproteinase (MMP) secretion by vascular endothelial cells and lymphatic endothelial cells under monoculture or co-culture conditions. We found that vascular angiogenesis facilitated lymphangiogenesis via remodeling of the local microenvironment by the increased secretion of MMP, mainly by endothelial cells. Applications of this model include a drug screening assay for corneal disease and models for tumorigenesis including lymphatic angiogenesis and vascular angiogenesis. PMID- 30417076 TI - Changes in GABAergic Transmission to and Intrinsic Excitability of Gonadotropin Releasing Hormone (GnRH) Neurons during the Estrous Cycle in Mice. AB - Gonadotropin-releasing hormone (GnRH) neurons form the final common central output pathway controlling fertility and are regulated by steroid feedback. In females, estradiol feedback action varies between negative and positive; negative feedback typically regulates episodic GnRH release whereas positive feedback initiates a surge of GnRH, and subsequently luteinizing hormone (LH) release ultimately triggering ovulation. During the estrous cycle, changes between estradiol negative and positive feedback occur with cycle stage and time of day, with positive feedback in the late afternoon of proestrus in nocturnal species. To test the hypotheses that synaptic and intrinsic properties of GnRH neurons are regulated by cycle stage and time of day, we performed whole-cell patch-clamp studies of GnRH neurons in brain slices from mice at two times considered negative feedback (diestrous PM and proestrous AM) and during positive feedback (proestrous PM). GABAergic transmission can excite GnRH neurons and was higher in cells from proestrous PM mice than cells from proestrous AM mice and approached traditional significance levels relative to cells from diestrous PM mice. Action potential response to current injection was also greater in cells from proestrous PM mice than the other two groups. Interestingly, the hormonal milieu of proestrous AM provided stronger negative feedback on both GnRH neuron excitability and GABAergic postsynaptic current (PSC) amplitude than diestrous PM. These observations demonstrate elements of both synaptic and intrinsic properties of GnRH neurons are regulated in a cycle-dependent manner and provide insight into the neurobiological mechanisms underlying cyclic changes in neuroendocrine function among states of estradiol negative and positive feedback. PMID- 30417078 TI - Blocking H2A.Z Incorporation via Tip60 Inhibition Promotes Systems Consolidation of Fear Memory in Mice. AB - Memory formation is a protracted process that initially involves the hippocampus and becomes increasingly dependent on the cortex over time, but the mechanisms of this transfer are unclear. We recently showed that hippocampal depletion of the histone variant H2A.Z enhances both recent and remote memories, but the use of virally mediated depletion reduced H2A.Z levels throughout testing, making its temporally specific function unclear. Given the lack of drugs that target histone variants, we tested existing drugs for efficacy against H2A.Z based on their targeting of known H2A.Z regulators. The Tip60 (part of H2A.Z deposition complex) inhibitor Nu9056 reduced H2A.Z binding, whereas the histone deacetylase (HDAC) inhibitor Trichostatin-A increased H2A.Z acetylation without influencing total H2A.Z in cultured hippocampal neurons. Tip60 (but not HDAC) inhibition 23 h after learning enhanced remote (tested at 7 d) and not recent (tested at 24 h) contextual fear memory in mice. In contrast, Tip60 inhibition 30 d after learning impaired recall of remote memory after 1 h, but protected the memory from further decline 24 h later. These data provide the first evidence of a delayed postlearning role for histone variants in supporting memory transfer during systems consolidation. PMID- 30417077 TI - Contribution of CD137L to Sensory Hypersensitivity in a Murine Model of Neuropathic Pain. AB - CD137L (4-1BBL) is a costimulatory molecule whose signaling can promote monocyte/macrophage functions; however, CD137L-mediated microglial response and its role in neuropathic pain remain unknown. We investigated CD137L following peripheral nerve injury-induced neuropathic pain using a spinal nerve L5 transection (L5Tx) murine model in both sexes. First, C57BL/6_CD137L knock-out (KO) mice displayed decreased mechanical and diminished heat hypersensitivity compared to wild-type (WT) controls, beginning on day 3 to up to day 35 post L5Tx. Purified anti-mouse CD137L neutralizing monoclonal antibody (0.1 or 0.5 ug) was also used to identify CD137L's window of action in BALB/c mice. Anti-CD137L antibody was intrathecally administered either from day 0 (before surgery) to day 7 (early treatment), or from day 6 to 13 post-L5Tx (late treatment), and nociceptive thresholds were assessed before surgery to up to day 35 post-surgery. Early treatment with anti-CD137L reduced L5Tx-induced mechanical but not heat hypersensitivity, while later treatment did not alter either sensitivity. Pro- versus anti-inflammatory responses within the lumbar spinal cord following L5Tx were further evaluated via quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) in time-course studies. Following L5Tx, female CD137L KO mice did not show increased iNOS mRNA and had reduced numbers of IL-1beta+ cells compared to WT. At 21 d post-surgery, CD137L KO mice had higher total numbers of arginase (Arg)-1+ cells and Arg-1+ microglia. Altogether, results indicate that spinal cord CD137L contributes to the development of peripheral nerve injury-induced neuropathic pain, which may be in part mediated through CD137L's modulation of the pro- and anti-inflammatory balance within the spinal cord. PMID- 30417080 TI - Orexinergic Modulation of Spinal Motor Activity in the Neonatal Mouse Spinal Cord. AB - The role of orexin during development, and especially in terms of spinal cord function, is not well understood. It is for this reason that we focused on the network actions of orexin during the first week of development. We found that orexinergic fibers were present in the lumbar spinal cord of postnatal day 0 (P0) to P3 mice. The fibers were expressed mainly in the dorsal horn, but occasional fibers were observed in the ventral horn. Both orexin (OX) A and OXB increased the motoneurons (MNs) tonic neurogram discharge. However, only OXA was found to significantly increase spontaneous bursting activity and the frequency of fictive locomotor bursts. We show that OXA is able to act directly on MNs. To test the contribution of the recurrent MN collaterals, we blocked the nicotinic cholinergic drive and observed that OXA retained its ability to increase fictive locomotor activity. Additionally, we recorded neurograms from ventral lateral funiculi, where OXA had no effect on population discharge. These effects were also confirmed by recording from descending commissural interneurons via patch recordings. The loci of the effects of OXA were further investigated in a dorsal horn-removed preparation where OXA also shows an increase in the discharge from ventral root neurograms but no increase in the frequency of spontaneous or fictive locomotion burst activity. In summary, multiple lines of evidence from our work demonstrate the robust effects of orexins on spinal cord networks and MNs at the time of birth. PMID- 30417079 TI - p11 in Cholinergic Interneurons of the Nucleus Accumbens Is Essential for Dopamine Responses to Rewarding Stimuli. AB - A recent study showed that p11 expressed in cholinergic interneurons (CINs) of the nucleus accumbens (NAc) is a key regulator of depression-like behaviors. Dopaminergic neurons projecting to the NAc are responsible for reward-related behaviors, and their function is impaired in depression. The present study investigated the role of p11 in NAc CINs in dopamine responses to rewarding stimuli. The extracellular dopamine and acetylcholine (ACh) levels in the NAc were determined in freely moving male mice using in vivo microdialysis. Rewarding stimuli (cocaine, palatable food, and female mouse encounter) induced an increase in dopamine efflux in the NAc of wild-type (WT) mice. The dopamine responses were attenuated (cocaine) or abolished (food and female mouse encounter) in constitutive p11 knock-out (KO) mice. The dopamine response to cocaine was accompanied by an increase in ACh NAc efflux, whereas the attenuated dopamine response to cocaine in p11 KO mice was restored by activation of nicotinic or muscarinic ACh receptors in the NAc. Dopamine responses to rewarding stimuli and ACh release in the NAc were attenuated in mice with deletion of p11 from cholinergic neurons (ChAT-p11 cKO mice), whereas gene delivery of p11 to CINs restored the dopamine responses. Furthermore, chemogenetic studies revealed that p11 is required for activation of CINs in response to rewarding stimuli. Thus, p11 in NAc CINs plays a critical role in activating these neurons to mediate dopamine responses to rewarding stimuli. The dysregulation of mesolimbic dopamine system by dysfunction of p11 in NAc CINs may be involved in pathogenesis of depressive states. PMID- 30417082 TI - In Vivo Volume Dynamics of Dendritic Spines in the Neocortex of Wild-Type and Fmr1 KO Mice. AB - Excitatory synapses are often formed at small protrusions of dendrite, called dendritic spines, in most projection neurons, and the spine-head volumes show strong correlations with synaptic connectivity. We examined the dynamics of spine volume in the adult mouse visual cortex using time-lapse in vivo two-photon imaging with a resonant Galvano scanner. Contrary to expectations, we found that the spines in the adult neocortex showed fluctuations to a similar degree as that observed in young hippocampal preparations, but there were systematic differences in how the dynamics were dependent on spine volumes, thus allowing for fewer fluctuations in small spines, which could account for the relatively low turnover rates of neocortical spines in vivo. We found that spine volumes fluctuated to a greater extent in a mouse model (Fmr1 knockout) of fragile X mental retardation than in wild-type mice, and the spine turnover rates were also higher in Fmr1 knock-out mice. Such features of spine dynamics in Fmr1 knock-out mice could be represented by a single slope factor in our model. Our data and model indicate a small but significant change in the average spine volume and more eminent differences in the statistical distribution in Fmr1 knock-out mice even in adulthood, which reflects the abnormal in vivo dynamics of spine volumes. PMID- 30417081 TI - Liquefaction of the Brain following Stroke Shares a Similar Molecular and Morphological Profile with Atherosclerosis and Mediates Secondary Neurodegeneration in an Osteopontin-Dependent Mechanism. AB - Here we used mouse models of heart and brain ischemia to compare the inflammatory response to ischemia in the heart, a protein rich organ, to the inflammatory response to ischemia in the brain, a lipid rich organ. We report that ischemia induced inflammation resolves between one and four weeks in the heart compared to between eight and 24 weeks in the brain. Importantly, we discovered that a second burst of inflammation occurs in the brain between four and eight weeks following ischemia, which coincided with the appearance of cholesterol crystals within the infarct. This second wave shares a similar cellular and molecular profile with atherosclerosis and is characterized by high levels of osteopontin (OPN) and matrix metalloproteinases (MMPs). In order to test the role of OPN in areas of liquefactive necrosis, OPN-/- mice were subjected to brain ischemia. We found that at seven weeks following stroke, the expression of pro-inflammatory proteins and MMPs was profoundly reduced in the infarct of the OPN-/- mice, although the number of cholesterol crystals was increased. OPN-/- mice exhibited faster recovery of motor function and a higher number of neuronal nuclei (NeuN) positive cells in the peri-infarct area at seven weeks following stroke. Based on these findings we propose that the brain liquefies after stroke because phagocytic cells in the infarct are unable to efficiently clear cholesterol rich myelin debris, and that this leads to the perpetuation of an OPN-dependent inflammatory response characterized by high levels of degradative enzymes. PMID- 30417084 TI - Differential contributions of subthalamic beta rhythms and 1/f broadband activity to motor symptoms in Parkinson's disease. AB - Excessive beta oscillatory activity in the subthalamic nucleus (STN) is linked to Parkinson's Disease (PD) motor symptoms. However, previous works have been inconsistent regarding the functional role of beta activity in untreated Parkinsonian states, questioning such role. We hypothesized that this inconsistency is due to the influence of electrophysiological broadband activity a neurophysiological indicator of synaptic excitation/inhibition ratio- that could confound measurements of beta activity in STN recordings. Here we propose a data-driven, automatic and individualized mathematical model that disentangles beta activity and 1/f broadband activity in the STN power spectrum, and investigate the link between these individual components and motor symptoms in thirteen Parkinsonian patients. We show, using both modeled and actual data, how beta oscillatory activity significantly correlates with motor symptoms (bradykinesia and rigidity) only when broadband activity is not considered in the biomarker estimations, providing solid evidence that oscillatory beta activity does correlate with motor symptoms in untreated PD states as well as the significant impact of broadband activity. These findings emphasize the importance of data-driven models and the identification of better biomarkers for characterizing symptom severity and closed-loop applications. PMID- 30417083 TI - Successful Encoding during Natural Reading Is Associated with Fixation-Related Potentials and Large-Scale Network Deactivation. AB - Reading literature (e.g., an entire book) is an enriching experience that qualitatively differs from reading a single sentence; however, the brain dynamics of such context-dependent memory remains unclear. This study aimed to elucidate mnemonic neural dynamics during natural reading of literature by performing electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI). Brain activities of human participants recruited on campus were correlated with their subsequent memory, which was quantified by semantic correlation between the read text and reports subsequently written by them based on state of the art natural language processing procedures. The results of the EEG data analysis showed a significant positive relationship between subsequent memory and fixation related EEG. Sentence-length and paragraph-length mnemonic processes were associated with N1-P2 and P3 fixation-related potential (FRP) components and fixation-related theta-band (4-8 Hz) EEG power, respectively. In contrast, the results of fMRI analysis showed a significant negative relationship between subsequent memory and blood oxygenation level-dependent (BOLD) activation. Sentence-length and paragraph-length mnemonic processes were associated with networks of regions forming part of the salience network and the default mode network (DMN), respectively. Taken together with the EEG results, these memory related deactivations in the salience network and the DMN were thought to reflect the reading of sentences characterized by low mnemonic load and the suppression of task-irreverent thoughts, respectively. It was suggested that the context dependent mnemonic process during literature reading requires large-scale network deactivation, which might reflect coordination of a range of voluntary processes during reading. PMID- 30417085 TI - Single-bubble water boiling on small heater under Earth's and low gravity. AB - Today's trends for enhancing boiling heat transfer in terrestrial and space applications focus on removal of bubbles to prevent formation of a vapor layer over the surface at high overheat. In contrast, this paper presents a new boiling regime that employs a vapor-air bubble residing on a small heater for minutes and driving cold water over the surface to provide high heat flux. Single-bubble boiling of water was investigated under normal gravity and low gravity in parabolic flights. Experiments demonstrated a negligible effect of gravity level on the rate of heat transfer from the heater. Due to self-adjustment of the bubble size, the heat flux provided by boiling rose linearly up with increasing heater temperature and was not affected by a gradually rising water temperature. The fast response and stable operation of single-bubble boiling over a broad range of temperatures pave the way for development of new devices to control heat transfer by forming surface domains with distinct thermal properties and wettability. The bubble lifetime can be adjusted by changing the water temperature. The ability of heating water on millimeter scales far above 100 degrees C without an autoclave or a powerful laser provides a new approach for processing of biomaterials and chemical reactions. PMID- 30417086 TI - Exploring the Concept of Radiation "Booster Shot" in Combination with an Anti-PD L1 mAb to Enhance Anti-Tumor Immune Effects in Mouse Pancreas Tumors. AB - Radiotherapy (RT) has long been known to be immunogenic. Mounting preclinical data demonstrate a synergistic anti-tumor effect when RT is used in combination with immune check point inhibitors (ICI). However, it is unclear how to best integrate RT with an ICI (i.e. dose fractionation, sequence, etc.). Here we explored the concept that RT delivered as an in situ tumor vaccine sequentially to separate tumors over time might stimulate more potent and rapid antitumor immune response than RT delivered to only one tumor. In essence, radiation to a second tumor could be likened to giving a vaccine "booster shot". Mice bearing pancreatic tumors in three different sites were injected with anti-PD-L1 antibody and exposed to three daily consecutive fractions of 4 Gy each at one or two sites with a one week interval. Our data indicate that delivering an RT to one tumor followed by an RT "booster shot" to a second tumor, compared to treating only one tumor with RT, significantly reduced tumor growth at a third non-irradiated site. This abscopal effect to the non-irradiated site was observed earlier (day 9) in mice that received RT to two tumors versusa single tumor (day 17). Decreased growth of the non-irradiated tumor correlated with a transient increase of the CD4/CD8 ratio in the tumor, increase myeloid-derived suppressor cells and tumor associated macrophages in the draining lymph nodes. These data warrant further exploration of sequentially treating multiple lesions with RT and ICI with the intent of generating a robust anti-tumor immune response. PMID- 30417087 TI - Surface-Modified Shortwave-Infrared-Emitting Nanophotonic Reporters for Gene Therapy Applications. AB - Gene therapy is emerging as the next generation of therapeutic modality with United States Food and Drug Administration approved gene-engineered therapy for cancer and a rare eye-related disorder, but the challenge of real-time monitoring of on-target therapy response remains. In this study, we have designed a theranostic nanoparticle composed of shortwave-infrared-emitting rare-earth-doped nanoparticles (RENPs) capable of delivering genetic cargo and of real-time response monitoring. We showed that the cationic coating of RENPs with branched polyethylenimine (PEI) does not have a significant impact on cellular toxicity, which can be further reduced by selectively modifying the surface characteristics of the PEI coating using counter-ions and expanding their potential applications in photothermal therapy. We showed the tolerability and clearance of a bolus dose of RENPs@PEI in mice up to 7 days after particle injection in addition to the RENPs@PEI ability to distinctively discern lung tumor lesions in a breast cancer mouse model with an excellent signal-to-noise ratio. We also showed the availability of amine functional groups in the collapsed PEI chain conformation on RENPs, which facilitates the loading of genetic cargo that hybridizes with target gene in an in vitro cancer model. The real-time monitoring and delivery of gene therapy at on-target sites will enable the success of an increased number of gene- and cell-therapy products in clinical trials. PMID- 30417088 TI - Ancient genomes suggest the eastern Pontic-Caspian steppe as the source of western Iron Age nomads. AB - For millennia, the Pontic-Caspian steppe was a connector between the Eurasian steppe and Europe. In this scene, multidirectional and sequential movements of different populations may have occurred, including those of the Eurasian steppe nomads. We sequenced 35 genomes (low to medium coverage) of Bronze Age individuals (Srubnaya-Alakulskaya) and Iron Age nomads (Cimmerians, Scythians, and Sarmatians) that represent four distinct cultural entities corresponding to the chronological sequence of cultural complexes in the region. Our results suggest that, despite genetic links among these peoples, no group can be considered a direct ancestor of the subsequent group. The nomadic populations were heterogeneous and carried genetic affinities with populations from several other regions including the Far East and the southern Urals. We found evidence of a stable shared genetic signature, making the eastern Pontic-Caspian steppe a likely source of western nomadic groups. PMID- 30417089 TI - Memory enhancement by ferulic acid ester across species. AB - Cognitive impairments can be devastating for quality of life, and thus, preventing or counteracting them is of great value. To this end, the present study exploits the potential of the plant Rhodiola rosea and identifies the constituent ferulic acid eicosyl ester [icosyl-(2E)-3-(4-hydroxy-3-methoxyphenyl) prop-2-enoate (FAE-20)] as a memory enhancer. We show that food supplementation with dried root material from R. rosea dose-dependently improves odor-taste reward associative memory scores in larval Drosophila and prevents the age related decline of this appetitive memory in adult flies. Task-relevant sensorimotor faculties remain unaltered. From a parallel approach, a list of candidate compounds has been derived, including R. rosea-derived FAE-20. Here, we show that both R. rosea-derived FAE-20 and synthetic FAE-20 are effective as memory enhancers in larval Drosophila. Synthetic FAE-20 also partially compensates for age-related memory decline in adult flies, as well as genetically induced early-onset loss of memory function in young flies. Furthermore, it increases excitability in mouse hippocampal CA1 neurons, leads to more stable context-shock aversive associative memory in young adult (3-month-old) mice, and increases memory scores in old (>2-year-old) mice. Given these effects, and given the utility of R. rosea-the plant from which we discovered FAE-20-as a memory enhancer, these results may hold potential for clinical applications. PMID- 30417090 TI - Fear extinction requires ASIC1a-dependent regulation of hippocampal-prefrontal correlates. AB - Extinction of conditioned fear necessitates the dynamic involvement of hippocampus, medial prefrontal cortex (mPFC), and basolateral amygdala (BLA), but key molecular players that regulate these circuits to achieve fear extinction remain largely unknown. Here, we report that acid-sensing ion channel 1a (ASIC1a) is a crucial molecular regulator of fear extinction, and that this function requires ASIC1a in ventral hippocampus (vHPC), but not dorsal hippocampus, mPFC, or BLA. While genetic disruption or pharmacological inhibition of ASIC1a in vHPC attenuated the extinction of conditioned fear, overexpression of the channel in this area promoted fear extinction. Channelrhodopsin-2-assisted circuit mapping revealed that fear extinction involved an ASIC1a-dependent modification of the long-range hippocampal-prefrontal correlates in a projection-specific manner. Gene expression profiling analysis and validating experiments identified several neuronal activity-regulated and memory-related genes, including Fos, Npas4, and Bdnf, as the potential mediators of ASIC1a regulation of fear extinction. Mechanistically, genetic overexpression of brain-derived neurotrophic factor (BDNF) in vHPC or supplement of BDNF protein in mPFC both rescued the deficiency in fear extinction and the deficits on extinction-driven adaptations of hippocampal-prefrontal correlates caused by the Asic1a gene inactivation in vHPC. Together, these results establish ASIC1a as a critical constituent in fear extinction circuits and thus a promising target for managing adaptive behaviors. PMID- 30417092 TI - Congo Basin forest loss dominated by increasing smallholder clearing. AB - A regional assessment of forest disturbance dynamics from 2000 to 2014 was performed for the Congo Basin countries using time-series satellite data. Area of forest loss was estimated and disaggregated by predisturbance forest type and direct disturbance driver. An estimated 84% of forest disturbance area in the region is due to small-scale, nonmechanized forest clearing for agriculture. Annual rates of small-scale clearing for agriculture in primary forests and woodlands doubled between 2000 and 2014, mirroring increasing population growth. Smallholder clearing in the Democratic Republic of the Congo alone accounted for nearly two-thirds of total forest loss in the basin. Selective logging is the second most significant disturbance driver, contributing roughly 10% of regional gross forest disturbance area and more than 60% of disturbance area in Gabon. Forest loss due to agro-industrial clearing along the Gulf of Guinea coast more than doubled in the last half of the study period. Maintaining natural forest cover in the Congo Basin into the future will be challenged by an expected fivefold population growth by 2100 and allocation of industrial timber harvesting and large-scale agricultural development inside remaining old-growth forests. PMID- 30417091 TI - A tyrosine sulfation-dependent HLA-I modification identifies memory B cells and plasma cells. AB - Memory B cells and plasma cells are antigen-experienced cells tasked with the maintenance of humoral protection. Despite these prominent functions, definitive cell surface markers have not been identified for these cells. We report here the isolation and characterization of the monoclonal variable lymphocyte receptor B (VLRB) N8 antibody from the evolutionarily distant sea lamprey that specifically recognizes memory B cells and plasma cells in humans. Unexpectedly, we determined that VLRB N8 recognizes the human leukocyte antigen-I (HLA-I) antigen in a tyrosine sulfation-dependent manner. Furthermore, we observed increased binding of VLRB N8 to memory B cells in individuals with autoimmune disorders multiple sclerosis and systemic lupus erythematosus. Our study indicates that lamprey VLR antibodies uniquely recognize a memory B cell- and plasma cell-specific posttranslational modification of HLA-I, the expression of which is up-regulated during B cell activation. PMID- 30417093 TI - Ponatinib (AP24534) inhibits MEKK3-KLF signaling and prevents formation and progression of cerebral cavernous malformations. AB - Cerebral cavernous malformation (CCM) is a common cerebrovascular disease that can occur sporadically or be inherited. They are major causes of stroke, cerebral hemorrhage, and neurological deficits in the younger population. Loss-of-function mutations in three genes, CCM1, CCM2, and CCM3, have been identified as the cause of human CCMs. Currently, no drug is available to treat CCM disease. Hyperactive mitogen-activated protein kinase kinase Kinase 3 (MEKK3) kinase signaling as a consequence of loss of CCM genes is an underlying cause of CCM lesion development. Using a U.S. Food and Drug Administration-approved kinase inhibitor library combined with virtual modeling and biochemical and cellular assays, we have identified a clinically approved small compound, ponatinib, that is capable of inhibiting MEKK3 activity and normalizing expression of downstream kruppel like factor (KLF) target genes. Treatment with this compound in neonatal mouse models of CCM can prevent the formation of new CCM lesions and reduce the growth of already formed lesions. At the ultracellular level, ponatinib can normalize the flattening and disorganization of the endothelium caused by CCM deficiency. Collectively, our study demonstrates ponatinib as a novel compound that may prevent CCM initiation and progression in mouse models through inhibition of MEKK3-KLF signaling. PMID- 30417094 TI - Deciphering and engineering chromodomain-methyllysine peptide recognition. AB - Posttranslational modifications (PTMs) play critical roles in regulating protein functions and mediating protein-protein interactions. An important PTM is lysine methylation that orchestrates chromatin modifications and regulates functions of non-histone proteins. Methyllysine peptides are bound by modular domains, of which chromodomains are representative. Here, we conducted the first large-scale study of chromodomains in the human proteome interacting with both histone and non-histone methyllysine peptides. We observed significant degenerate binding between chromodomains and histone peptides, i.e., different histone sites can be recognized by the same set of chromodomains, and different chromodomains can share similar binding profiles to individual histone sites. Such degenerate binding is not dictated by amino acid sequence or PTM motif but rather rooted in the physiochemical properties defined by the PTMs on the histone peptides. This molecular mechanism is confirmed by the accurate prediction of the binding specificity using a computational model that captures the structural and energetic patterns of the domain-peptide interaction. To further illustrate the power and accuracy of our model, we used it to effectively engineer an exceptionally strong H3K9me3-binding chromodomain and to label H3K9me3 in live cells. This study presents a systematic approach to deciphering domain-peptide recognition and reveals a general principle by which histone modifications are interpreted by reader proteins, leading to dynamic regulation of gene expression and other biological processes. PMID- 30417095 TI - Concurrent processes set E. coli cell division. AB - A cell can divide only upon completion of chromosome segregation; otherwise, its daughters would lose genetic material. However, we do not know whether the partitioning of chromosomes is the key event for the decision to divide. We show how key trends in single-cell data reject the classic idea of replication segregation as the rate-limiting process for cell division. Instead, the data agree with a model where two concurrent processes (setting replication initiation and interdivision time) set cell division on competing time scales. During each cell cycle, division is set by the slowest process (an "AND" gate). The concept of transitions between cell cycle stages as decisional processes integrating multiple inputs instead of cascading from orchestrated steps can affect the way we think of the cell cycle in general. PMID- 30417096 TI - The genetic prehistory of the Andean highlands 7000 years BP though European contact. AB - The peopling of the Andean highlands above 2500 m in elevation was a complex process that included cultural, biological, and genetic adaptations. Here, we present a time series of ancient whole genomes from the Andes of Peru, dating back to 7000 calendar years before the present (BP), and compare them to 42 new genome-wide genetic variation datasets from both highland and lowland populations. We infer three significant features: a split between low- and high elevation populations that occurred between 9200 and 8200 BP; a population collapse after European contact that is significantly more severe in South American lowlanders than in highland populations; and evidence for positive selection at genetic loci related to starch digestion and plausibly pathogen resistance after European contact. We do not find selective sweep signals related to known components of the human hypoxia response, which may suggest more complex modes of genetic adaptation to high altitude. PMID- 30417097 TI - An ancient Turing-like patterning mechanism regulates skin denticle development in sharks. AB - Vertebrates have a vast array of epithelial appendages, including scales, feathers, and hair. The developmental patterning of these diverse structures can be theoretically explained by Alan Turing's reaction-diffusion system. However, the role of this system in epithelial appendage patterning of early diverging lineages (compared to tetrapods), such as the cartilaginous fishes, is poorly understood. We investigate patterning of the unique tooth-like skin denticles of sharks, which closely relates to their hydrodynamic and protective functions. We demonstrate through simulation models that a Turing-like mechanism can explain shark denticle patterning and verify this system using gene expression analysis and gene pathway inhibition experiments. This mechanism bears remarkable similarity to avian feather patterning, suggesting deep homology of the system. We propose that a diverse range of vertebrate appendages, from shark denticles to avian feathers and mammalian hair, use this ancient and conserved system, with slight genetic modulation accounting for broad variations in patterning. PMID- 30417098 TI - The optimal mating distance resulting from heterosis and genetic incompatibility. AB - Theory predicts that the fitness of an individual is maximized when the genetic distance between its parents (i.e., mating distance) is neither too small nor too large. However, decades of research have generally failed to validate this prediction or identify the optimal mating distance (OMD). Respectively analyzing large numbers of crosses of fungal, plant, and animal model organisms, we indeed find the hybrid phenotypic value a humped quadratic polynomial function of the mating distance for the vast majority of fitness-related traits examined, with different traits of the same species exhibiting similar OMDs. OMDs are generally slightly greater than the nucleotide diversities of the species concerned but smaller than the observed maximal intraspecific genetic distances. Hence, the benefit of heterosis is at least partially offset by the harm of genetic incompatibility even within species. These results have multiple theoretical and practical implications for speciation, conservation, and agriculture. PMID- 30417099 TI - Engineering human megakaryocytic microparticles for targeted delivery of nucleic acids to hematopoietic stem and progenitor cells. AB - Hematopoietic stem and progenitor cells (HSPCs) are important target cells for gene therapy applications. Current genetic modifications of HSPCs rely on viral vectors in vivo or electroporation ex vivo. Here, we developed a nonviral system based on megakaryocytic microparticles (MPs) for targeted delivery of plasmid DNA (pDNA) and small RNAs to HSPCs. We have previously shown that megakaryocytic MPs, the most abundant MPs in blood circulation, target specifically and deliver cargo to HSPCs both in vitro and in vivo. With an optimized electroporation protocol, an average of 4200 plasmid copies per MP were loaded into MP, thus enabling effective delivery of green fluorescent protein (GFP)-encoding pDNA to HSPCs and HSPC nuclei, with up to 81% nuclei containing pDNA. Effective functional small interfering RNA (siRNA) and microRNA (miRNA) delivery were also demonstrated. As patient-specific or generic megakaryocytic MPs can be readily generated and stored frozen, our data suggest that this system has great potential for therapeutic applications targeting HSPCs. PMID- 30417100 TI - TET2 coactivates gene expression through demethylation of enhancers. AB - The tet methylcytosine dioxygenase 2 (TET2) enzyme catalyzes the conversion of the modified DNA base 5-methylcytosine to 5-hydroxymethylcytosine. TET2 is frequently mutated or dysregulated in multiple human cancers, and loss of TET2 is associated with changes in DNA methylation patterns. Here, using newly developed TET2-specific antibodies and the estrogen response as a model system for studying the regulation of gene expression, we demonstrate that endogenous TET2 occupies active enhancers and facilitates the proper recruitment of estrogen receptor alpha (ERalpha). Knockout of TET2 by CRISPR-CAS9 leads to a global increase of DNA methylation at enhancers, resulting in attenuation of the estrogen response. We further identified a positive feedback loop between TET2 and ERalpha, which further requires MLL3 COMPASS at these enhancers. Together, this study reveals an epigenetic axis coordinating a transcriptional program through enhancer activation via DNA demethylation. PMID- 30417101 TI - Mechanism of FACT removal from transcribed genes by anticancer drugs curaxins. AB - Human FACT (facilitates chromatin transcription) is a multifunctional protein complex that has histone chaperone activity and facilitates nucleosome survival and transcription through chromatin. Anticancer drugs curaxins induce FACT trapping on chromatin of cancer cells (c-trapping), but the mechanism of c trapping is not fully understood. Here, we show that in cancer cells, FACT is highly enriched within the bodies of actively transcribed genes. Curaxin dependent c-trapping results in redistribution of FACT from the transcribed chromatin regions to other genomic loci. Using a combination of biochemical and biophysical approaches, we have demonstrated that FACT is bound to and unfolds nucleosomes in the presence of curaxins. This tight binding to the nucleosome results in inhibition of FACT-dependent transcription in vitro in the presence of both curaxins and competitor chromatin, suggesting a mechanism of FACT trapping on bulk nucleosomes (n-trapping). PMID- 30417102 TI - THE USE OF CO-OCCURRENCE PATTERNS IN SINGLE IMAGE BASED FOOD PORTION ESTIMATION. AB - Measuring accurate dietary intake is considered to be an open research problem in the nutrition and health fields. Food portions estimation is a challenging problem as food preparation and consumption process pose large variations on food shapes and appearances. We use geometric model based technique to estimate food portions and further improve estimation accuracy using co-occurrence patterns. We estimate the food portion co-occurrence patterns from food images we collected from dietary studies using the mobile Food Record (mFR) system we developed. Co occurrence patterns is used as prior knowledge to refine portion estimation results. We show that the portion estimation accuracy has been improved when incorporating the co-occurrence patterns as contextual information. PMID- 30417103 TI - Expression characterization and functional implication of the collagen-modifying Leprecan proteins in mouse gonadal tissue and mature sperm. AB - The Leprecan protein family which includes the prolyl 3-hydroxylase enzymes (P3H1, P3H2, and P3H3), the closely related cartilage-associated protein (CRTAP), and SC65 (Synaptonemal complex 65, aka P3H4, LEPREL4), is involved in the post translational modification of fibrillar collagens. Mutations in CRTAP, P3H1 and P3H2 cause human genetic diseases. We recently showed that SC65 forms a stable complex in the endoplasmic reticulum with P3H3 and lysyl hydroxylase 1 and that loss of this complex leads to defective collagen lysyl hydroxylation and causes low bone mass and skin fragility. Interestingly, SC65 was initially described as a synaptonemal complex-associated protein, suggesting a potential additional role in germline cells. In the present study, we describe the expression of SC65, CRTAP and other Leprecan proteins in postnatal mouse reproductive organs. We detect SC65 expression in peritubular cells of testis up to 4 weeks of age but not in cells within seminiferous tubules, while its expression is maintained in ovarian follicles until adulthood. Similar to bone and skin, SC65 and P3H3 are also tightly co-expressed in testis and ovary. Moreover, we show that CRTAP, a protein normally involved in collagen prolyl 3-hydroxylation, is highly expressed in follicles and stroma of the ovary and in testes interstitial cells at 4 weeks of age, germline cells and mature sperm. Importantly, CrtapKO mice have a mild but significant increase in morphologically abnormal mature sperm (17% increase compared to WT). These data suggest a role for the Leprecans in the post translational modification of collagens expressed in the stroma of the reproductive organs. While we could not confirm that SC65 is part of the synaptonemal complex, the expression of CRTAP in the seminiferous tubules and in mature sperm suggest a role in the testis germ cell lineage and sperm morphogenesis. PMID- 30417104 TI - Luminescent Probe Based Techniques for Hypoxia Imaging. AB - Hypoxia is a condition of tissue environments wherein a lower than normal level of oxygen is available, and it serves as the root cause and indicator of various diseases. Detection of hypoxia in tumors is imperative for furthering our understanding of the pathological effects and the development of proper treatments, as it is well established that hypoxic tumors are able to impede the cancer treatment process by being resistant to many therapies. It is important therefore to be able to detect hypoxia in tissues and tumors through in vivo imaging methods. A growing area for detection of hypoxia in vivo is the use of fluorescent/luminescent probes which has accelerated in recent years. The continued quest for improvements in selectivity and sensitivity has inspired researchers to pursue new strategies for fluorescence/luminescent probe design. This review will discuss various luminescent probes based on small molecules, dyes, macromolecules, and nanoparticles for sensitive and specific detection of oxygen levels directly or by indirect mechanisms such as the presence of enzymes or related factors that arise in a hypoxic environment. Following the particular mechanism of detection, each probe has specific structural and photophysical properties which permit its selectivity and sensitivity. These probes show promise in terms of low toxicity and high specificity among other merits discussed, and in providing new dimensions for hypoxia detection, these works contribute to future potential methods for clinical diagnosis of hypoxic tissues and tumors. PMID- 30417105 TI - Using Healthy Defaults in Walt Disney World Restaurants to Improve Nutritional Choices. AB - A retrospective study of kids' meals purchased at Walt Disney World was conducted to determine acceptance rates for healthy sides and beverages. Purchase data from all 145 Walt Disney World restaurants were analyzed using a log-linear model and a Poisson regression. Across all restaurants, 47.9% and 66.3% of guests accepted healthy default sides and beverages, respectively. Acceptance rates of sides and beverages were higher at quick-service restaurants (49.4% and 67.8%, respectively) compared to table-service restaurants (40.3% and 45.6%, respectively). The healthy defaults reduced calories (21.4%), fat (43.9%), and sodium (43.4%) for kids' meal sides and beverages. This study contributes by examining the use of kids' meal healthy defaults in quick-service and table service restaurant formats at the world's largest theme park, a previously unstudied setting, and by providing the largest ever healthy default data set. The results suggest that healthy defaults can shift food and beverage selection patterns toward healthier options. PMID- 30417106 TI - Machine Learning Reveals Missing Edges and Putative Interaction Mechanisms in Microbial Ecosystem Networks. AB - Microbes affect each other's growth in multiple, often elusive, ways. The ensuing interdependencies form complex networks, believed to reflect taxonomic composition as well as community-level functional properties and dynamics. The elucidation of these networks is often pursued by measuring pairwise interactions in coculture experiments. However, the combinatorial complexity precludes an exhaustive experimental analysis of pairwise interactions, even for moderately sized microbial communities. Here, we used a machine learning random forest approach to address this challenge. In particular, we show how partial knowledge of a microbial interaction network, combined with trait-level representations of individual microbial species, can provide accurate inference of missing edges in the network and putative mechanisms underlying the interactions. We applied our algorithm to three case studies: an experimentally mapped network of interactions between auxotrophic Escherichia coli strains, a community of soil microbes, and a large in silico network of metabolic interdependencies between 100 human gut associated bacteria. For this last case, 5% of the network was sufficient to predict the remaining 95% with 80% accuracy, and the mechanistic hypotheses produced by the algorithm accurately reflected known metabolic exchanges. Our approach, broadly applicable to any microbial or other ecological network, may drive the discovery of new interactions and new molecular mechanisms, both for therapeutic interventions involving natural communities and for the rational design of synthetic consortia. IMPORTANCE Different organisms in a microbial community may drastically affect each other's growth phenotypes, significantly affecting the community dynamics, with important implications for human and environmental health. Novel culturing methods and the decreasing costs of sequencing will gradually enable high-throughput measurements of pairwise interactions in systematic coculturing studies. However, a thorough characterization of all interactions that occur within a microbial community is greatly limited both by the combinatorial complexity of possible assortments and by the limited biological insight that interaction measurements typically provide without laborious specific follow-ups. Here, we show how a simple and flexible formal representation of microbial pairs can be used for the classification of interactions via machine learning. The approach we propose predicts with high accuracy the outcome of yet-to-be performed experiments and generates testable hypotheses about the mechanisms of specific interactions. PMID- 30417107 TI - Loss of Bacitracin Resistance Due to a Large Genomic Deletion among Bacillus anthracis Strains. AB - Bacillus anthracis is a Gram-positive endospore-forming bacterial species that causes anthrax in both humans and animals. In Zambia, anthrax cases are frequently reported in both livestock and wildlife, with occasional transmission to humans, causing serious public health problems in the country. To understand the genetic diversity of B. anthracis strains in Zambia, we sequenced and compared the genomic DNA of B. anthracis strains isolated across the country. Single nucleotide polymorphisms clustered these strains into three groups. Genome sequence comparisons revealed a large deletion in strains belonging to one of the groups, possibly due to unequal crossing over between a pair of rRNA operons. The deleted genomic region included genes conferring resistance to bacitracin, and the strains with the deletion were confirmed with loss of bacitracin resistance. Similar deletions between rRNA operons were also observed in a few B. anthracis strains phylogenetically distant from Zambian strains. The structure of bacitracin resistance genes flanked by rRNA operons was conserved only in members of the Bacillus cereus group. The diversity and genomic characteristics of B. anthracis strains determined in this study would help in the development of genetic markers and treatment of anthrax in Zambia. IMPORTANCE Anthrax is caused by Bacillus anthracis, an endospore-forming soil bacterium. The genetic diversity of B. anthracis is known to be low compared with that of Bacillus species. In this study, we performed whole-genome sequencing of Zambian isolates of B. anthracis to understand the genetic diversity between closely related strains. Comparison of genomic sequences revealed that closely related strains were separated into three groups based on single nucleotide polymorphisms distributed throughout the genome. A large genomic deletion was detected in the region containing a bacitracin resistance gene cluster flanked by rRNA operons, resulting in the loss of bacitracin resistance. The structure of the deleted region, which was also conserved among species of the Bacillus cereus group, has the potential for both deletion and amplification and thus might be enabling the species to flexibly control the level of bacitracin resistance for adaptive evolution. PMID- 30417108 TI - Transcriptionally Active Lung Microbiome and Its Association with Bacterial Biomass and Host Inflammatory Status. AB - Alteration of the lung microbiome has been observed in several respiratory tract diseases. However, most previous studies were based on 16S ribosomal RNA and shotgun metagenome sequencing; the viability and functional activity of the microbiome, as well as its interaction with host immune systems, have not been well studied. To characterize the active lung microbiome and its associations with host immune response and clinical features, we applied metatranscriptome sequencing to bronchoalveolar lavage fluid (BALF) samples from 25 patients with chronic obstructive pulmonary disease (COPD) and from nine control cases without known pulmonary disease. Community structure analyses revealed three distinct microbial compositions, which were significantly correlated with bacterial biomass, human Th17 immune response, and COPD exacerbation frequency. Specifically, samples with transcriptionally active Streptococcus, Rothia, or Pseudomonas had bacterial loads 16 times higher than samples enriched for Escherichia and Ralstonia. These high-bacterial-load samples also tended to undergo a stronger Th17 immune response. Furthermore, an increased proportion of lymphocytes was found in samples with active Pseudomonas. In addition, COPD patients with active Streptococcus or Rothia infections tended to have lower rates of exacerbations than patients with active Pseudomonas and patients with lower bacterial biomass. Our results support the idea of a stratified structure of the active lung microbiome and a significant host-microbe interaction. We speculate that diverse lung microbiomes exist in the population and that their presence and activities could either influence or reflect different aspects of lung health. IMPORTANCE Recent studies of the microbiome proposed that resident microbes play a beneficial role in maintaining human health. Although lower respiratory tract disease is a leading cause of sickness and mortality, how the lung microbiome interacts with human health remains largely unknown. Here we assessed the association between the lung microbiome and host gene expression, cytokine concentration, and over 20 clinical features. Intriguingly, we found a stratified structure of the active lung microbiome which was significantly associated with bacterial biomass, lymphocyte proportion, human Th17 immune response, and COPD exacerbation frequency. These observations suggest that the microbiome plays a significant role in lung homeostasis. Not only microbial composition but also active functional elements and host immunity characteristics differed among different individuals. Such diversity may partially account for the variation in susceptibility to particular diseases. PMID- 30417109 TI - Is Host Filtering the Main Driver of Phylosymbiosis across the Tree of Life? AB - Host-associated microbiota composition can be conserved over evolutionary time scales. Indeed, closely related species often host similar microbiota; i.e., the composition of their microbiota harbors a phylogenetic signal, a pattern sometimes referred to as "phylosymbiosis." Elucidating the origins of this pattern is important to better understand microbiota ecology and evolution. However, this is hampered by our lack of theoretical expectations and a comprehensive overview of phylosymbiosis prevalence in nature. Here, we use simulations to provide a simple expectation for when we should expect this pattern to occur and then review the literature to document the prevalence and strength of phylosymbiosis across the host tree of life. We demonstrate that phylosymbiosis can readily emerge from a simple ecological filtering process, whereby a given host trait (e.g., gut pH) that varies with host phylogeny (i.e., harbors a phylogenetic signal) filters preadapted microbes. We found marked differences between methods used to detect phylosymbiosis, so we proposed a series of practical recommendations based on using multiple best-performing approaches. Importantly, we found that, while the prevalence of phylosymbiosis is mixed in nature, it appears to be stronger for microbiotas living in internal host compartments (e.g., the gut) than those living in external compartments (e.g., the rhizosphere). We show that phylosymbiosis can theoretically emerge without any intimate, long-term coevolutionary mechanisms and that most phylosymbiosis patterns observed in nature are compatible with a simple ecological process. Deviations from baseline ecological expectations might be used to further explore more complex hypotheses, such as codiversification. IMPORTANCE Phylosymbiosis is a pattern defined as the tendency of closely related species to host microbiota whose compositions resemble each other more than host species drawn at random from the same tree. Understanding the mechanisms behind phylosymbiosis is important because it can shed light on rules governing the assembly of host-associated microbiotas and, potentially, their coevolutionary dynamics with hosts. For example, is phylosymbiosis a result of coevolution, or can it be generated by simple ecological filtering processes? Beyond qualitative theoretical models, quantitative theoretical expectations can provide new insights. For example, deviations from a simple baseline of ecological filtering may be used to test more-complex hypotheses (e.g., coevolution). Here, we use simulations to provide evidence that simple host-related ecological filtering can readily generate phylosymbiosis, and we contrast these predictions with real world data. We find that while phylosymbiosis is widespread in nature, phylosymbiosis patterns are compatible with a simple ecological model in the majority of taxa. Internal compartments of hosts, such as the animal gut, often display stronger phylosymbiosis than expected from a purely ecological filtering process, suggesting that other mechanisms are also involved. PMID- 30417111 TI - High-Throughput Miniaturized 16S rRNA Amplicon Library Preparation Reduces Costs while Preserving Microbiome Integrity. AB - Next-generation sequencing technologies have enabled many advances across biology, with microbial ecology benefiting primarily through expanded sample sizes. Although the cost of running sequencing instruments has decreased substantially over time, the price of library preparation methods has largely remained unchanged. In this study, we developed a low-cost miniaturized (5-ul volume) high-throughput (384-sample) amplicon library preparation method with the Echo 550 acoustic liquid handler. Our method reduces costs of library preparation to $1.42 per sample, a 58% reduction compared to existing automated methods and a 21-fold reduction from commercial kits, without compromising sequencing success or distorting the microbial community composition analysis. We further validated the optimized method by sampling five body sites from 46 Pacific chub mackerel fish caught across 16 sampling events over seven months from the Scripps Institution of Oceanography pier in La Jolla, CA. Fish microbiome samples were processed with the miniaturized 5-ul reaction volume with 0.2 ul of genomic DNA (gDNA) and the standard 25-ul reaction volume with 1 ul of gDNA. Between the two methods, alpha diversity was highly correlated (R 2 > 0.95), while distances of technical replicates were much lower than within-body-site variation (P < 0.0001), further validating the method. The cost savings of implementing the miniaturized library preparation (going from triplicate 25-ul reactions to triplicate 5-ul reactions) are large enough to cover a MiSeq sequencing run for 768 samples while preserving accurate microbiome measurements. IMPORTANCE Reduced costs of sequencing have tremendously impacted the field of microbial ecology, allowing scientists to design more studies with larger sample sizes that often exceed 10,000 samples. Library preparation costs have not kept pace with sequencing prices, although automated liquid handling robots provide a unique opportunity to bridge this gap while also decreasing human error. Here, we take advantage of an acoustic liquid handling robot to develop a high-throughput miniaturized library preparation method of a highly cited and broadly used 16S rRNA gene amplicon reaction. We evaluate the potential negative effects of reducing the PCR volume along with varying the amount of gDNA going into the reaction. Our optimized method reduces sample-processing costs while continuing to generate a high-quality microbiome readout that is indistinguishable from the original method. PMID- 30417110 TI - Microbial Functional Responses to Cholesterol Catabolism in Denitrifying Sludge. AB - The 2,3-seco pathway, the pathway for anaerobic cholesterol degradation, has been established in the denitrifying betaproteobacterium Sterolibacterium denitrificans. However, knowledge of how microorganisms respond to cholesterol at the community level is elusive. Here, we applied mesocosm incubation and 16S rRNA sequencing to reveal that, in denitrifying sludge communities, three betaproteobacterial operational taxonomic units (OTUs) with low (94% to 95%) 16S rRNA sequence similarity to Stl. denitrificans are cholesterol degraders and members of the rare biosphere. Metatranscriptomic and metabolite analyses show that these degraders adopt the 2,3-seco pathway to sequentially catalyze the side chain and sterane of cholesterol and that two molybdoenzymes-steroid C25 dehydrogenase and 1-testosterone dehydrogenase/hydratase-are crucial for these bioprocesses, respectively. The metatranscriptome further suggests that these betaproteobacterial degraders display chemotaxis and motility toward cholesterol and that FadL-like transporters may be the key components for substrate uptake. Also, these betaproteobacteria are capable of transporting micronutrients and synthesizing cofactors essential for cellular metabolism and cholesterol degradation; however, the required cobalamin is possibly provided by cobalamin-de novo-synthesizing gamma-, delta-, and betaproteobacteria via the salvage pathway. Overall, our results indicate that the ability to degrade cholesterol in sludge communities is reserved for certain rare biosphere members and that C25 dehydrogenase can serve as a biomarker for sterol degradation in anoxic environments. IMPORTANCE Steroids are ubiquitous and abundant natural compounds that display recalcitrance. Biodegradation via sludge communities in wastewater treatment plants is the primary removal process for steroids. To date, compared to studies for aerobic steroid degradation, the knowledge of anaerobic degradation of steroids has been based on only a few model organisms. Due to the increase of anthropogenic impacts, steroid inputs may affect microbial diversity and functioning in ecosystems. Here, we first investigated microbial functional responses to cholesterol, the most abundant steroid in sludge, at the community level. Our metagenomic and metatranscriptomic analyses revealed that the capacities for cholesterol approach, uptake, and degradation are unique traits of certain low-abundance betaproteobacteria, indicating the importance of the rare biosphere in bioremediation. Apparent expression of genes involved in cofactor de novo synthesis and salvage pathways suggests that these micronutrients play important roles for cholesterol degradation in sludge communities. PMID- 30417112 TI - Butyrate Producers as Potential Next-Generation Probiotics: Safety Assessment of the Administration of Butyricicoccus pullicaecorum to Healthy Volunteers. AB - Advances in gut microbiota research have triggered interest in developing colon butyrate producers as niche-specific next-generation probiotics, targeted at increasing colon butyrate production and countering disease-associated microbiota alterations. Crucial steps in the development of next-generation probiotics are the design of formulations with a reasonable shelf life as well as the safety demonstration of an intervention in healthy volunteers. One such potential next generation butyrate-producing probiotic is Butyricicoccus pullicaecorum 25-3T, with demonstrated safety in in vitro as well as animal models. Here, we examined the strain's safety, tolerability, and impact on microbiota composition and metabolic activity in healthy volunteers in a randomized, double-blind, placebo controlled crossover study in 30 healthy volunteers. The study design consisted of two 4-week intervention periods (108 CFU B. pullicaecorum [treatment] or maltodextrin [placebo] per day) with a 3-week washout in between. We assessed adverse events, blood parameters (primary endpoints), and fecal microbiota composition and metabolite profiles (secondary endpoints). The number of reported adverse events during the B. pullicaecorum treatment was similar to that of placebo intervention, as were observed changes in blood chemistry parameters, bowel habits, and fecal calprotectin concentrations. Administration of the strain did not induce any disruptive effect in microbiota composition or metabolic activity. In this first human intervention trial with a butyrate-producing Clostridium cluster IV isolate, we demonstrated B. pullicaecorum 25-3T administration to be both safe and well tolerated by healthy participants. This safety study paves the way for the further development of the strain as a next generation probiotic. IMPORTANCE This study is the first to determine the safety and tolerance in humans of a butyrate-producing Clostridium cluster IV next generation probiotic. Advances in gut microbiota research have triggered interest in developing colon butyrate producers as next-generation probiotics. Butyricicoccus pullicaecorum 25-3T is one such potential probiotic, with demonstrated safety in vitro as well as in animal models. Here, we produced an encapsulated B. pullicaecorum formulation that largely preserved its viability over an 8-month storage period at 4 degrees C. Administration of this formulation to healthy volunteers allowed us to establish the intervention as safe and well tolerated. The probiotic intervention did not cause disruptive alterations in the composition or metabolic activity of health-associated microbiota. The results presented pave the way for the exploration of the impact of the strain on microbiota alterations in a clinical setting. PMID- 30417113 TI - Multiple Sclerosis-Associated Changes in the Composition and Immune Functions of Spore-Forming Bacteria. AB - Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by adaptive and innate immune system dysregulation. Recent work has revealed moderate alteration of gut microbial communities in subjects with MS and in experimental, induced models. However, a mechanistic understanding linking the observed changes in the microbiota and the presence of the disease is still missing. Chloroform-resistant, spore-forming bacteria, which primarily belong to the classes Bacilli and Clostridia in the phylum Firmicutes, have been shown to exhibit immunomodulatory properties in vitro and in vivo, but they have not yet been characterized in the context of human disease. This study addresses the community composition and immune function of this bacterial fraction in MS. We identify MS-associated spore-forming taxa (primarily in the class Clostridia) and show that their presence correlates with impaired differentiation of IL-10 secreting, regulatory T lymphocytes in vitro. Colonization of antibiotic-treated mice with spore-forming bacteria allowed us to identify some bacterial taxa favoring IL-10+ lymphocyte differentiation and others inducing differentiation of proinflammatory, IFN-gamma+ T lymphocytes. However, when fed into antibiotic treated mice, both MS and control-derived spore-forming bacteria were able to induce similar IL-10-expressing Treg immunoregulatory responses, thus ameliorating symptoms of experimental allergic encephalomyelitis (EAE). Our analysis also identified Akkermansia muciniphila as a key organism that may interact either directly or indirectly with spore-forming bacteria to exacerbate the inflammatory effects of MS-associated gut microbiota. Thus, changes in the spore-forming fraction may influence T lymphocyte-mediated inflammation in MS. This experimental approach of isolating a subset of microbiota based on its functional characteristics may be useful to investigate other microbial fractions at greater depth. IMPORTANCE To address the impact of microbiome on disease development, it is essential to go beyond a descriptive study and evaluate the physiological importance of microbiome changes. Our study integrates computational analysis with in vitro and in vivo exploration of inflammatory properties of spore-forming microbial communities, revealing novel functional correlations. We specifically show that while small differences exist between the microbiomes of MS patients and healthy subjects, these differences are exacerbated in the chloroform-resistant fraction. We further demonstrate that, when purified from MS patients, this fraction is correlated with impaired immunomodulatory responses in vitro. PMID- 30417114 TI - Influence of Feeding Type and Nosema ceranae Infection on the Gut Microbiota of Apis cerana Workers. AB - The gut microbiota plays an essential role in the health of bees. To elucidate the effect of feed and Nosema ceranae infection on the gut microbiota of honey bee (Apis cerana), we used 16S rRNA sequencing to survey the gut microbiota of honey bee workers fed with sugar water or beebread and inoculated with or without N. ceranae. The gut microbiota of A. cerana is dominated by Serratia, Snodgrassella, and Lactobacillus genera. The overall gut microbiota diversity was show to be significantly differential by feeding type. N. ceranae infection significantly affects the gut microbiota only in bees fed with sugar water. Higher abundances of Lactobacillus, Gluconacetobacter, and Snodgrassella and lower abundances of Serratia were found in bees fed with beebread than in those fed with sugar water. N. ceranae infection led to a higher abundance of Snodgrassella and a lower abundance of Serratia in sugar-fed bees. Imputed bacterial Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways showed the significant metagenomics functional differences by feeding and N. ceranae infections. Furthermore, A. cerana workers fed with sugar water showed lower N. ceranae spore loads but higher mortality than those fed with beebread. The cumulative mortality was strongly positive correlated (rho = 0.61) with the changes of overall microbiota dissimilarities by N. ceranae infection. Both feeding types and N. ceranae infection significantly affect the gut microbiota in A. cerana workers. Beebread not only provides better nutrition but also helps establish a more stable gut microbiota and therefore protects bees in response to N. ceranae infection. IMPORTANCE The gut microbiota plays an essential role in the health of bees. Scientific evidence suggests that diet and infection can affect the gut microbiota and modulate the health of the gut; however, the interplay between those two factors and the bee gut microbiota is not well known. In this study, we used a high-throughput sequencing method to monitor the changes of gut microbiota associated with both feeding types and Nosema ceranae infection. Our results showed that the gut microbiota composition and diversity of Asian honey bee were significantly associated with both feeding types and the N. ceranae infection. More interestingly, bees fed with beebread showed higher microbiota stability and lower mortality rates than those fed with sugar water when infected by N. ceranae. Those data suggest that beebread has the potential not only to provide better nutrition but also help to establish a more stable gut microbiota to protect bees against N. ceranae infection. PMID- 30417115 TI - Multiplatform Physiologic and Metabolic Phenotyping Reveals Microbial Toxicity. AB - The gut microbiota is susceptible to modulation by environmental stimuli and therefore can serve as a biological sensor. Recent evidence suggests that xenobiotics can disrupt the interaction between the microbiota and host. Here, we describe an approach that combines in vitro microbial incubation (isolated cecal contents from mice), flow cytometry, and mass spectrometry- and 1H nuclear magnetic resonance (NMR)-based metabolomics to evaluate xenobiotic-induced microbial toxicity. Tempol, a stabilized free radical scavenger known to remodel the microbial community structure and function in vivo, was studied to assess its direct effect on the gut microbiota. The microbiota was isolated from mouse cecum and was exposed to tempol for 4 h under strict anaerobic conditions. The flow cytometry data suggested that short-term tempol exposure to the microbiota is associated with disrupted membrane physiology as well as compromised metabolic activity. Mass spectrometry and NMR metabolomics revealed that tempol exposure significantly disrupted microbial metabolic activity, specifically indicated by changes in short-chain fatty acids, branched-chain amino acids, amino acids, nucleotides, glucose, and oligosaccharides. In addition, a mouse study with tempol (5 days gavage) showed similar microbial physiologic and metabolic changes, indicating that the in vitro approach reflected in vivo conditions. Our results, through evaluation of microbial viability, physiology, and metabolism and a comparison of in vitro and in vivo exposures with tempol, suggest that physiologic and metabolic phenotyping can provide unique insight into gut microbiota toxicity. IMPORTANCE The gut microbiota is modulated physiologically, compositionally, and metabolically by xenobiotics, potentially causing metabolic consequences to the host. We recently reported that tempol, a stabilized free radical nitroxide, can exert beneficial effects on the host through modulation of the microbiome community structure and function. Here, we investigated a multiplatform phenotyping approach that combines high-throughput global metabolomics with flow cytometry to evaluate the direct effect of tempol on the microbiota. This approach may be useful in deciphering how other xenobiotics directly influence the microbiota. PMID- 30417116 TI - Distance delivery of a parent-implemented language intervention for young boys with fragile X syndrome. AB - Background: In addition to significant cognitive delays, boys with fragile X syndrome display phenotypic characteristics that include delays in language, inattention, social anxiety, and escape-maintained challenging behaviors. Despite these challenges, families affected by fragile X syndrome often have limited access to center-based intervention programs. Methods: The present study utilized a multiple baseline design across participants to examine the preliminary effectiveness of a 12-week, parent-implemented spoken language intervention for three 5- to 7-year-old boys with fragile X syndrome. The goal of the intervention was to teach the biological mothers of each boy to use a set of verbally responsive language support strategies while participating in shared book reading activities with her child. All aspects of the intervention, including pre- and post-treatment measures, were delivered into the family's home via distance video teleconferencing. Results: Results from this study provide preliminary support for the efficacy of this parent-implemented language intervention approach by demonstrating generalized improvements in both targeted maternal strategy use and measures of child spoken language. Conclusions: The present study expands upon prior language intervention research utilizing distance delivery of services for families affected by fragile X syndrome. Additionally, the study provides early support for the feasibility of collecting pre- and post-treatment assessments at a distance. PMID- 30417117 TI - Multi-faceted computational assessment of risk and progression in oligodendroglioma implicates NOTCH and PI3K pathways. AB - Oligodendrogliomas are diffusely infiltrative gliomas defined by IDH-mutation and co-deletion of 1p/19q. They have highly variable clinical courses, with survivals ranging from 6 months to over 20 years, but little is known regarding the pathways involved with their progression or optimal markers for stratifying risk. We utilized machine-learning approaches with genomic data from The Cancer Genome Atlas to objectively identify molecular factors associated with clinical outcomes of oligodendroglioma and extended these findings to study signaling pathways implicated in oncogenesis and clinical endpoints associated with glioma progression. Our multi-faceted computational approach uncovered key genetic alterations associated with disease progression and shorter survival in oligodendroglioma and specifically identified Notch pathway inactivation and PI3K pathway activation as the most strongly associated with MRI and pathology findings of advanced disease and poor clinical outcome. Our findings that Notch pathway inactivation and PI3K pathway activation are associated with advanced disease and survival risk will pave the way for clinically relevant markers of disease progression and therapeutic targets to improve clinical outcomes. Furthermore, our approach demonstrates the strength of machine learning and computational methods for identifying genetic events critical to disease progression in the era of big data and precision medicine. PMID- 30417118 TI - Repeat bleaching of a central Pacific coral reef over the past six decades (1960 2016). AB - The oceans are warming and coral reefs are bleaching with increased frequency and severity, fueling concerns for their survival through this century. Yet in the central equatorial Pacific, some of the world's most productive reefs regularly experience extreme heat associated with El Nino. Here we use skeletal signatures preserved in long-lived corals on Jarvis Island to evaluate the coral community response to multiple successive heatwaves since 1960. By tracking skeletal stress band formation through the 2015-16 El Nino, which killed 95% of Jarvis corals, we validate their utility as proxies of bleaching severity and show that 2015-16 was not the first catastrophic bleaching event on Jarvis. Since 1960, eight severe (>30% bleaching) and two moderate (<30% bleaching) events occurred, each coinciding with El Nino. While the frequency and severity of bleaching on Jarvis did not increase over this time period, 2015-16 was unprecedented in magnitude. The trajectory of recovery of this historically resilient ecosystem will provide critical insights into the potential for coral reef resilience in a warming world. PMID- 30417119 TI - Elevated atmospheric CO2 promoted speciation in mosquitoes (Diptera, Culicidae). AB - Mosquitoes are of great medical significance as vectors of deadly diseases. Despite this, little is known about their evolutionary history or how their present day diversity has been shaped. Within a phylogenetic framework, here we show a strong correlation between climate change and mosquito speciation rates: the first time to our knowledge such an effect has been demonstrated for insects. Information theory reveals that although climate change is correlated with mosquito evolution there are other important factors at play. We identify one such driver to be the rise of mammals, which are predominant hosts of Culicidae. Regardless of the precise mechanism, we demonstrate a strong historical association. This finding, taken in combination with projected rises in atmospheric CO2 from anthropogenic activity, has important implications for culicid vector distributions and abundance, and consequently for human health. PMID- 30417120 TI - An asparagine/glycine switch governs product specificity of human N-terminal methyltransferase NTMT2. AB - alpha-N-terminal methylation of proteins is an important post-translational modification that is catalyzed by two different N-terminal methyltransferases, namely NTMT1 and NTMT2. Previous studies have suggested that NTMT1 is a tri methyltransferase, whereas NTMT2 is a mono-methyltransferase. Here, we report the first crystal structures, to our knowledge, of NTMT2 in binary complex with S adenosyl-L-methionine as well as in ternary complex with S-adenosyl-L homocysteine and a substrate peptide. Our structural observations combined with biochemical studies reveal that NTMT2 is also able to di-/tri-methylate the GPKRIA peptide and di-methylate the PPKRIA peptide, otherwise it is predominantly a mono-methyltransferase. The residue N89 of NTMT2 serves as a gatekeeper residue that regulates the binding of unmethylated versus monomethylated substrate peptide. Structural comparison of NTMT1 and NTMT2 prompts us to design a N89G mutant of NTMT2 that can profoundly alter its catalytic activities and product specificities. PMID- 30417121 TI - Coral metabolite gradients affect microbial community structures and act as a disease cue. AB - Corals are threatened worldwide due to prevalence of disease and bleaching. Recent studies suggest the ability of corals to resist disease is dependent on maintaining healthy microbiomes that span coral tissues and surfaces, the holobiont. Although our understanding of the role endosymbiotic microbes play in coral health has advanced, the role surface-associated microbes and their chemical signatures play in coral health is limited. Using minimally invasive water sampling, we show that the corals Acropora and Platygyra harbor unique bacteria and metabolites at their surface, distinctly different from surrounding seawater. The surface metabolites released by the holobiont create concentration gradients at 0-5 cm away from the coral surface. These molecules are identified as chemo-attractants, antibacterials, and infochemicals, suggesting they may structure coral surface-associated microbes. Further, we detect surface associated metabolites characteristic of healthy or white syndrome disease infected corals, a finding which may aid in describing effects of diseases. PMID- 30417122 TI - Persistence of environmental DNA in marine systems. AB - As environmental DNA (eDNA) becomes an increasingly valuable resource for marine ecosystem monitoring, understanding variation in its persistence across contrasting environments is critical. Here, we quantify the breakdown of macrobial eDNA over a spatio-temporal axis of locally extreme conditions, varying from ocean-influenced offshore to urban-inshore, and between winter and summer. We report that eDNA degrades 1.6 times faster in the inshore environment than the offshore environment, but contrary to expectation we find no difference over season. Analysis of environmental covariables show a spatial gradient of salinity and a temporal gradient of pH, with salinity-or the biotic correlates thereof most important. Based on our estimated inshore eDNA half-life and naturally occurring eDNA concentrations, we estimate that eDNA may be detected for around 48 h, offering potential to collect ecological community data of high local fidelity. We conclude by placing these results in the context of previously published eDNA decay rates. PMID- 30417123 TI - Substrate specificity of plant nitrilase complexes is affected by their helical twist. AB - Nitrilases are oligomeric, helix-forming enzymes from plants, fungi and bacteria that are involved in the metabolism of various natural and artificial nitriles. These biotechnologically important enzymes are often specific for certain substrates, but directed attempts at modifying their substrate specificities by exchanging binding pocket residues have been largely unsuccessful. Thus, the basis for their selectivity is still unknown. Here we show, based on work with two highly similar nitrilases from the plant Capsella rubella, that modifying nitrilase helical twist, either by exchanging an interface residue or by imposing a different twist, without altering any binding pocket residues, changes substrate preference. We reveal that helical twist and substrate size correlate and when binding pocket residues are exchanged between two nitrilases that show the same twist but different specificities, their specificities change. Based on these findings we propose that helical twist influences the overall size of the binding pocket. PMID- 30417126 TI - Conditioned media from human umbilical cord blood-derived mesenchymal stem cells stimulate rejuvenation function in human skin. AB - Developing treatments that inhibit skin aging is an important research project. Rejuvenation, which focuses on prevention of skin aging, is one of the major issues. Recent studies suggested that mesenchymal stem cells (MSCs) secrete many cytokines, which are important in wound healing. In this study, we investigated the effect of human umbilical cord blood-derived mesenchymal stem cells conditioned media (USC-CM) in cutaneous wound healing and collagen synthesis. We found that USC-CM has many useful growth factors associated with skin rejuvenation, such as Epithelial Growth Factor (EGF), basic Fibroblast Growth Factor (bFGF), Platelet Derived Growth Factor (PDGF), Hepatocyte Growth Factor (HGF), Collagen type 1, and especially, one of the rejuvenation factors, the growth differentiation factor-11 (GDF-11). Our in vitro results showed that USC CM stimulate growth and extracellular matrix (ECM) production of Human Dermal Fibroblasts (HDFs) compared to those of other MSCs conditioned media (CM) from different origins. Moreover, we evaluated the roles of GDF-11. The results showed that GDF-11 accelerates growth, migration and ECM production of HDFs. Our In vivo results showed that topical treatment of USC-CM showed anti-wrinkle effect and significantly increased dermal density in women. In conclusion, USC-CM has various useful growth factors including GDF-11 that can stimulate skin rejuvenation by increasing growth and ECM production of HDFs. PMID- 30417124 TI - Conserved Pbp1/Ataxin-2 regulates retrotransposon activity and connects polyglutamine expansion-driven protein aggregation to lifespan-controlling rDNA repeats. AB - Ribosomal DNA (rDNA) repeat instability and protein aggregation are thought to be two major and independent drivers of cellular aging. Pbp1, the yeast ortholog of human ATXN2, maintains rDNA repeat stability and lifespan via suppression of RNA DNA hybrids. ATXN2 polyglutamine expansion drives neurodegeneration causing spinocerebellar ataxia type 2 and promoting amyotrophic lateral sclerosis. Here, molecular characterization of Pbp1 revealed that its knockout or subjection to disease-modeling polyQ expansion represses Ty1 (Transposons of Yeast) retrotransposons by respectively promoting Trf4-depedendent RNA turnover and Ty1 Gag protein aggregation. This aggregation, but not its impact on retrotransposition, compromises rDNA repeat stability and shortens lifespan by hyper-activating Trf4-dependent turnover of intergenic ncRNA within the repeats. We uncover a function for the conserved Pbp1/ATXN2 proteins in the promotion of retrotransposition, create and describe powerful yeast genetic models of ATXN2 linked neurodegenerative diseases, and connect the major aging mechanisms of rDNA instability and protein aggregation. PMID- 30417125 TI - APOL1 risk allele RNA contributes to renal toxicity by activating protein kinase R. AB - APOL1 risk alleles associate with chronic kidney disease in African Americans, but the mechanisms remain to be fully understood. We show that APOL1 risk alleles activate protein kinase R (PKR) in cultured cells and transgenic mice. This effect is preserved when a premature stop codon is introduced to APOL1 risk alleles, suggesting that APOL1 RNA but not protein is required for the effect. Podocyte expression of APOL1 risk allele RNA, but not protein, in transgenic mice induces glomerular injury and proteinuria. Structural analysis of the APOL1 RNA shows that the risk variants possess secondary structure serving as a scaffold for tandem PKR binding and activation. These findings provide a mechanism by which APOL1 variants damage podocytes and suggest novel therapeutic strategies. PMID- 30417127 TI - Estradiol promotes rapid degradation of HER3 in ER-positive breast cancer cell line MCF-7. AB - HER3, a member of the receptor tyrosine kinase super family, is overexpressed in a number of cancers, and is associated with malignant phenotypes. Control of the protein stability of the membrane, as well as nuclear receptors, has been known to be an important process affecting tumor cells; however, their relationships have yet to be elucidated. In this study, we demonstrate that estradiol promotes rapid degradation of HER3 via the proteasome pathway in ER-positive breast cancer, MCF-7. ER prevented HER3 degradation, and knockdown of ER expression by si-RNA promoted rapid degradation of HER3. Breakdown of HER3 and ER were regulated by a ubiquitin ligase Nedd4-1 in the presence of estradiol stimulation. We speculate that estradiol quickly degrades ER, making HER3 accessible by Nedd4 1, and leads to the rapid degradation of HER3. In addition, knockdown of ubiquitin ligase Nedd4-1 enhances estradiol induced cell proliferation. These results indicate that HER3 and Nedd4-1 in ER-positive breast cancers might be an important therapeutic target. PMID- 30417128 TI - Bone marrow neutrophil aging in sickle cell disease mice is associated with impaired osteoblast functions. AB - Bone loss is a common complication in individuals with sickle cell disease (SCD). The mechanism(s) of bone loss in SCD subjects has not been fully investigated, and there are no targeted therapies to prevent or treat compromised bone health in this population. Recent studies showed that depletion of gut microbiota with antibiotics significantly reduced the number of aged neutrophils, thereby dramatically improved the inflammation-related organ damages in SCD mice. Since neutrophils, abundantly present in bone marrow (BM), regulate bone cells, and BM neutrophils, induced by inflammatory cytokines, are associated with a low number of osteoblasts (OBs), we hypothesize that neutrophil aging in the BM of SCD mice impairs OB function. Flow cytometry analysis showed BM neutrophil aging was significantly increased in SCD mice that was reduced with antibiotic treatment. In vitro co-culture of calvarial OBs from control (Ctrl) mice with BM neutrophils from Ctrl or SCD mice showed that BM neutrophils from SCD mice inhibit OB function but was rescued when neutrophils were from antibiotic-treated SCD mice. In summary, there is an accumulation of aged neutrophils in BM from SCD mice that may contribute to impaired OB function, and antibiotic treatment is able to partially rescue impaired OB function by decreasing neutrophil aging in the BM of SCD mice. PMID- 30417129 TI - Onset of deaminase APOBEC3B induction in response to DNA double-strand breaks. AB - Deamination of 5-methyl cytosine is a major cause of cancer-driver mutations in inflammation-associated cancers. The deaminase APOBEC3B is expressed in these cancers and causes mutations under replication stress; however, the mechanisms by which APOBEC3B mediates deamination and its association with genomic disorders are still unclear. Here, we show that APOBEC3B is stabilized to induce deamination reaction in response to DNA double-strand breaks (DSBs), resulting in the formation of long-lasting DSBs. Uracil, the major deamination product, is subsequently targeted by base excision repair (BER) through uracil-DNA glycosylase 2 (UNG2); hence late-onset DSBs arise as by-products of BER. The frequency of these delayed DSBs was increased by treatment of cells with a PARP inhibitor, and was suppressed following knock-down of UNG2. The late-onset DSBs were induced in an ATR-dependent manner. Those secondary DSBs were persistent, unlike DSBs directly caused by gamma-ray irradiation. Overall, these results suggest that the deaminase APOBEC3B is induced in response to DSBs, leading to long-lasting DSB formation in addition to mutagenic 5me-C>T transition induction. PMID- 30417130 TI - Comparison of in vitro and in vivo oligomeric states of a wild type and mutant trimeric inner membrane multidrug transporter. AB - Many membrane proteins exist and function as oligomers or protein complexes. Routine analytical methods involve extraction and solubilization of the proteins with detergents, which could disturb their actual oligomeric state. AcrB is a trimeric inner membrane multidrug transporter in E. coli. In previous studies, we created a mutant AcrBP223G, which behaves like a monomer when extracted from the cell membrane. However, the actual oligomeric state of AcrBP223G in cell membranes remained unclear, which complicated the interpretation of the mechanism by which the mutation affects function. Here we used several complementary methods to determine the oligomeric state of AcrBP223G in E. coli cell membranes. Two sets of quantitative fluorescent techniques were exploited. For these, we created fluorescent tagged AcrB, AcrB-CFP and AcrB-YPet. Fluorescence resonance energy transfer (FRET) and fluorescence recovery after photobleaching (FRAP) were employed to characterize independently the efficiency of energy transfer between co-expressed AcrB-CFP and AcrB-YPet, and the diffusion coefficient of AcrB-YPet and AcrBP223G-YPet in live E. coli cells. Second, we introduced Cys pairs at the inter-subunit interface and used controlled oxidation to probe inter-subunit distances. The results from all studies converge on the conclusion that AcrBP223G exists as a trimer in cell membranes, which dissociates during the purification steps. The small change in trimer affinity and structure leads to a significant loss of AcrB activity. In addition, throughout this study we developed protocols and established benchmark values, useful for further studies on membrane protein associations in cell membranes. PMID- 30417131 TI - Doublecortin-like kinase 1 compromises DNA repair and induces chromosomal instability. AB - Doublecortin-like kinase 1 (DCLK1) is a serine/threonine-kinase with two doublecortin (DCX) domains. DCLK1 is associated with microtubules via DCX domains and regulates microtubule polymerization. DCLK1 is known to be expressed in cancer stem cells and provides cancer cells with tumor-initiating capacity. Accumulating clinical evidence supports that DCLK1 is associated with tumor aggressiveness and is an important prognostic marker in various human cancers. However, the mechanism, by which DCLK1 causes oncogenesis, is not yet elucidated. In this study, we showed that DCLK1 empowers human mammary epithelial MCF10A cells to form spheres under floating condition in serum-free medium, which are reminiscent of mammospheres formed by mammary epithelial stem cells. We demonstrated that DCLK1 causes chromatin instability in MCF10A cells. DCLK1 impairs DNA repairs in human colon cancer HCT116 and lung cancer H1299 cells. The kinase-negative DCLK1 mutant and the mutant that is not associated with microtubules compromise DNA repair. In conclusion, DCLK1 interferes with DNA repair and induces tumorigenesis through genomic instability and this function is independent of the kinase activity and the regulation of microtubules. PMID- 30417132 TI - Domain unfolding of monoclonal antibody fragments revealed by non-reducing SDS PAGE. AB - Monoclonal antibodies and derived fragments are used extensively both experimentally and therapeutically. Thorough characterization of such antibodies is necessary and includes assessment of their thermal and storage stabilities. Thus, assessment of the underlying conformational stabilities of the antibodies is also important. We recently documented that non-reducing SDS-PAGE can be used to assess both monoclonal and polyclonal IgG domain thermal unfolding in SDS. Utilizing this same h2E2 anti-cocaine mAb, in this study we generated and analyzed various mAb antibody fragments to delineate the structural domains of the antibody responsible for the observed discrete bands following various heating protocols and analysis by non-reducing SDS-PAGE. Previously, these domain unfolding transitions and gel bands were hypothesized to stem from known mAb structural domains based on the relative thermal stability of those CH2, CH3, and Fab domains in the absence of SDS, as measured by differential scanning calorimetry. In this study, we generated and analyzed F(ab')2, Fab, and Fc fragments, as well as a mAb consisting of only heavy chains, and examined the thermally induced domain unfolding in each of these fragments by non-reducing SDS PAGE. The results were interpreted and integrated to generate an improved model of thermal unfolding for the mAb IgG in SDS. These results and the model presented should be generally applicable to many monoclonal and polyclonal antibodies and allow novel comparisons of conformational stabilities between chemically or genetically modified versions of a given antibody. Such modified antibodies and antibody drug conjugates are commonly utilized and important for experimental and therapeutic applications. PMID- 30417134 TI - Coil Embolisation for Endovascular Treatment of Proper Hepatic Artery Aneurysm Using the Balloon Occlusion Technique. AB - Introduction: Endovascular repair (ER) as a minimally invasive approach can be effective for treating hepatic artery aneurysm (HAA) with gratifying results. Microcoil embolisation is the main technique used in ER. However, the coil embolisation of a large proper HAA (PHAA) with a very wide neck tends to be extremely troublesome owing to the limited length of the inflow and outflow artery. Moreover, it is difficult because of rapid blood flow in the proper hepatic artery (PHA) and the difficulty in preserving its branch flow. Microcoil embolisation of the inflow and outflow of a PHAA with the balloon occlusion technique through an originally developed single guiding sheath system was performed successfully. Report: A 73 year old woman was diagnosed with large PHAA (65 mm) by computed tomography examination. The PHAA was successfully treated by endovascular embolisation with microcoils using the balloon occlusion technique through a single guiding sheath system. Discussion: This method is safe and effective for the treatment of a large PHAA. PMID- 30417133 TI - The calcium sensitizer drug MCI-154 binds the structural C-terminal domain of cardiac troponin C. AB - The compound MCI-154 was previously shown to increase the calcium sensitivity of cardiac muscle contraction. Using solution NMR spectroscopy, we demonstrate that MCI-154 interacts with the calcium-sensing subunit of the cardiac troponin complex, cardiac troponin C (cTnC). Surprisingly, however, it binds only to the structural C-terminal domain of cTnC (cCTnC), and not to the regulatory N terminal domain (cNTnC) that determines the calcium sensitivity of cardiac muscle. Physiologically, cTnC is always bound to cardiac troponin I (cTnI), so we examined its interaction with MCI-154 in the presence of two soluble constructs, cTnI1-77 and cTnI135-209, which contain all of the segments of cTnI known to interact with cTnC. Neither the cTnC-cTnI1-77 complex nor the cTnC-cTnI135-209 complex binds to MCI-154. Since residues 39-60 of cTnI are known to bind tightly to the cCTnC domain to form a structured core that is invariant throughout the cardiac cycle, we conclude that MCI-154 does not bind to cTnC when it is part of the intact cardiac troponin complex. Thus, MCI-154 likely exerts its calcium sensitizing effect by interacting with a target other than cardiac troponin. PMID- 30417135 TI - Cross-border preimplantation genetic diagnosis. PMID- 30417138 TI - New KAT6 inhibitors induce senescence and arrest cancer growth. AB - Lysine acetyltransferases (KATs) catalyze lysine acetylation, a reversible protein modification implicated in a wide variety of disease states. Histone acetyltransferases (HATs) comprise a KAT sub-class that acetylate specific lysines in histones, hence playing an important role in the regulation of chromatin organization and function. HATs are critical regulators of signaling in many diseases, including cancer. KAT6A (also known as monocytic leukemia zinc finger protein, MOZ) and KAT6B (also known as MORF and QKF) belong to the MYST family of HATs, that comprise KAT5-KAT8. They are the targets of chromosomal translocations identified in acute myeloid leukaemia and various cancers. It seems logical therefore that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer. Baell et al. discovered a new class of anti-cancer drug that can put cancer cells into a permanent sleep or senescence, using high throughput screening followed by medicinal chemistry optimization, in-cell assays, biochemical assessment of target engagement, and tumour models in mice and fish. This research showed promise in arresting tumour growth in pre-clinical models of blood and liver cancers as well as delaying or stopping relapse without damaging the cells' DNA or some harmful side-effects caused by chemotherapy and radiotherapy. PMID- 30417137 TI - Enhancement of precursor amino acid supplies for improving bacitracin production by activation of branched chain amino acid transporter BrnQ and deletion of its regulator gene lrp in Bacillus licheniformis. AB - Bacitracin, a new type of cyclic peptide antibiotic, is widely used as the feed additive in feed industry. Branched chain amino acids (BCAAs) are the key precursors for bacitracin synthesis. In this research, soybean meal was served as the raw material to supply precursor amino acids for bacitracin synthesis, and enhanced production of bacitracin was attempted by engineering BCAA transporter BrnQ and its regulator Lrp in the bacitracin industrial production strain Bacillus licheniformis DW2. Firstly, our results confirmed that Lrp negatively affected bacitracin synthesis in DW2, and deletion of lrp improved intracellular BCAA accumulations, as well as the expression level of BCAA transporter BrnQ, which further led to a 14.71% increase of bacitracin yield, compared with that of DW2. On the contrary, overexpression of Lrp decreased bacitracin yield by 12.28%. Secondly, it was suggested that BrnQ acted as a BCAA importer in DW2, and overexpression of BrnQ enhanced the intracellular BCAA accumulations and 10.43% of bacitracin yield. While, the bacitracin yield decreased by 18.27% in the brnQ deletion strain DW2?brnQ. Finally, BrnQ was further overexpressed in lrp deletion strain DW2?lrp, and bacitracin yield produced by the final strain DW2?lrp::BrnQ was 965.34 U/mL, increased by 22.42% compared with that of DW2 (788.48 U/mL). Collectively, this research confirmed that Lrp affected bacitracin synthesis via regulating the expression of BCAA transporter BrnQ and BCAA distributions, and provided a promising strain for industrial production of bacitracin. PMID- 30417136 TI - Regulation of antibiotic biosynthesis in actinomycetes: Perspectives and challenges. AB - Actinomycetes are the main sources of antibiotics. The onset and level of production of each antibiotic is subject to complex control by multi-level regulators. These regulators exert their functions at hierarchical levels. At the lower level, cluster-situated regulators (CSRs) directly control the transcription of neighboring genes within the gene cluster. Higher-level pleiotropic and global regulators exert their functions mainly through modulating the transcription of CSRs. Advances in understanding of the regulation of antibiotic biosynthesis in actinomycetes have inspired us to engineer these regulators for strain improvement and antibiotic discovery. PMID- 30417140 TI - Creating an oil yeast from brewing yeast. PMID- 30417139 TI - Nocardiopsistins A-C: New angucyclines with anti-MRSA activity isolated from a marine sponge-derived Nocardiopsis sp. HB-J378. AB - Marine natural products have become an increasingly important source of new drug leads during recent years. In an attempt to identify novel anti-microbial natural products by bioprospecting deep-sea Actinobacteria, three new angucyclines, nocardiopsistins A-C, were isolated from Nocardiopsis sp. strain HB-J378. Notably, the supplementation of the rare earth salt Lanthanum chloride (LaCl3) during fermentation of HB-J378 significantly increased the yield of these angucyclines. The structures of nocardiopsistins A-C were identified by 1D and 2D NMR and HR-MS data. Nocardiopsistins A-C have activity against MRSA (methicillin resistant Staphylococcus aureus) with MICs of 3.12-12.5 MUg/mL; the potency of nocardiopsistin B is similar to that of the positive control, chloramphenicol. Bioinformatic analysis of the draft genome of HB-J378 identified a set of three core genes in a biosynthetic gene cluster that encode a typical aromatic or type II polyketide synthase (PKS) system, including ketoacyl:ACP synthase alpha subunit (KSalpha), beta-subunit (KSbeta) and acyl carrier protein (ACP). The production of nocardiopsistins A-C was abolished when the three genes were knocked out, indicating their indispensable role in the production of nocardiopsistins. PMID- 30417141 TI - Activation of three natural product biosynthetic gene clusters from Streptomyces lavendulae CGMCC 4.1386 by a reporter-guided strategy. AB - Along with the fast developing of DNA sequencing technology, a great number of natural product biosynthetic gene clusters have been discovered by bioinformatic analysis, which demands novel high-throughput genome mining methods to obtain the diverse compounds dictated by those gene clusters. In this work, a method based on the reporter gene xylE was established to screen for the activation conditions of thirteen different gene clusters from Streptomyces lavendulae CGMCC 4.1386. In this reporter-guided method, the key structure gene was replaced by a xylE-kana R cassette with the xylE gene being controlled by the transcription and translation machinery of the key structure gene. It not only facilitated the screening of activation conditions, but also provided the null mutants of specific natural product gene clusters as controls to link those clusters with their products conveniently. The potential activation conditions of eleven gene clusters from S. lavendulae CGMCC 4.1386 were obtained. In addition, activation of three of the eleven gene clusters was confirmed and their products were identified. PMID- 30417142 TI - SCO3129, a TetR family regulator, is responsible for osmotic stress in Streptomyces coelicolor. AB - Streptomyces are the soil-dwelling bacteria with a complex lifecycle and a considerable ability to produce a variety of secondary metabolites. Osmoregulation is important for their lifecycle in nature. In the genome of Streptomyces coelicolor M145, SCO3128 (encodes a putative fatty acid desaturase), SCO3129 (encodes a putative TetR family regulator) and SCO3130 (encodes a putative l-carnitine dehydratase) constitute a transcriptional unit, and its transcript was found to be in response to osmotic stress. Disruption of SCO3130 led to a bald phenotype on MMG medium and the mycelia lysis on the edge of the colony when KCl/NaCl was added to the medium. These results indicated that SCO3130 is important for the osmotic stress resistance in S. coelicolor. Transcriptional analysis and electrophoretic mobility shift assays (EMSA) demonstrated that SCO3129 repressed the transcription of SCO3128-3130 operon through directly binding to the promoter region of SCO3128, indicating that SCO3129 regulates the transcription of SCO3128-3130 in response to osmotic stress. PMID- 30417143 TI - Genomics-guided discovery of a new and significantly better source of anticancer natural drug FK228. AB - FK228 is an FDA-approved anticancer drug naturally produced by Chromobacterium violaceum No. 968 up to 19 mg/L in a pilot industry-scale batch fermentation. Here we report a genomics-guided discovery of Burkholderia thailandensis MSMB43 as a new and significantly better source of FK228. The genome of B. thailandensis MSMB43 was found to contain a functional biosynthetic gene cluster highly homologous to that of FK228 in C. violaceum No. 968, and the bacterium indeed produces authentic FK228. By simple fermentation in shaking flasks in a preferred M8 medium, B. thailandensis MSMB43 produced FK228 up to 67.7 mg/L; by fed-batch fermentation in a 20-L fermentor in M8 medium, B. thailandensis MSMB43 produced FK228 up to 115.9 mg/L, which is 95 fold higher than that of C. violaceum No. 968 under the same laboratory fermentation conditions. RT-PCR analysis indicated that the high FK228 yield of B. thailandensis MSMB43 was due to high expression of biosynthetic genes, represented by Bth_depA, during the fermentation process. Further genetic manipulation resulted in a recombinant strain, B. thailandensis MSMB43/pBMTL3-tdpR, which harbors a broad host-range vector expressing the thailandepsin biosynthetic pathway regulatory gene tdpR. This engineered strain produced up to 168.5 mg/L of FK228 in fed-batch fermentation in a 20-L fermentor in M8 medium. Therefore, the wild-type B. thailandensis MSMB43 or its engineered derivative could potentially be a good starting point for an industrial process to improve FK228 production for its expanding use in therapy. PMID- 30417144 TI - Gene's hubs in retinal diseases: A retinal disease network. AB - Background: Retinal diseases associated with the dysfunction or death of photoreceptors are a major cause of blindness around the world, improvements in genetics tools, like next generation sequencing (NGS) allows the discovery of genes and genetic changes that lead to many of those retinal diseases. Though, there very few databases that explores a wide spectrum of retinal diseases, phenotypes, genes, and proteins, thus creating the need for a more comprehensive database, that groups all these parameters. Methods: Multiple open access databases were compiled into a new comprehensive database. A biological network was then crated, and organized using Cytoscape. The network was scrutinized for presence of hubs, measuring the concentration of grouped nodes. Finally, a trace back analysis was performed in areas were the power law reports a high r-squared value near one, that indicates high nodes density. Results: This work leads to creation of a retinal database that includes 324 diseases, 803 genes, 463 phenotypes, and 2461 proteins. Four biological networks (1) a disease and gene network connected by common phenotypes, (2) a disease and phenotype network connected by common genes, (3) a disease and gene network with shared disease or gene as the cause of an edge, and (4) a protein and disease network. The resulting networks will allow users to have easier searching for retinal diseases, phenotypes, genes, and proteins and their interrelationships. Conclusions: These networks have a broader range of information than previously available ones, helping clinicians in the comprehension of this complex group of diseases. PMID- 30417147 TI - Effect of pennyroyal, savory and thyme essential oils on Japanese quail physiology. AB - An experiment was conducted to show the effects of different levels of pennyroyal, thyme and savory essential oils dietary supplementation on performance, organs weight, intestinal morphology, and serum lipids in quails. A total of 550 day-old Japanese quail chicks were allocated into 11 dietary treatments of 5 replications (10 birds in each cage) under a randomized experimental design. The treatments were a basal diet (Control), or 3 levels (200, 300, and 400 ppm) of thyme essential oil (TO), or 3 levels (200, 300, and 400 ppm) of savory essential oil (SO), or 3 levels (200, 300, and 400 ppm) of pennyroyal essential oil (PO) added separately to the basal diet, or also the basal diet supplemented with 100 ppm of flavophospholipol. Body weight gain (BWG), feed intake (FI) and feed conversion ratio (FCR) were measured weekly and calculated totally for 35 d. The organs weight and morphology of intestine parts of one bird from each cage were measured on 35 d. At the same day, blood samples were collected and cholesterol and triglyceride values were separately determined for male and female quails. Although the addition of different levels of essential oils in quail's diet did not affect BWG, a significant decline in FI was observed in the group supplemented with 400 ppm of TO. At the same time, FCR significantly improved (P < 0.05) in the same group as well as in the group supplemented with the antibiotic. However, the organs weight was not significantly affected by the experimental treatments. Nevertheless, villi height of duodenum, jejunum and ileum was significantly increased and crypt depth was significantly decreased in the quails fed diets supplemented with different levels of TO and SO. The values of serum triglycerides decreased in both sexes in the groups that received diets supplemented with different levels of essential oils whereas the values of cholesterol decreased only in males of the essential oils supplemented groups. From the present observations it can be concluded that thyme and savory essential oils can improve FCR by decreasing FI through boosting the absorption of nutrients in intestine. These plant essential oils can replace antibiotic growth parameters without having any adverse effect on quail's health with thyme essential oil exerting the most effective activity. PMID- 30417148 TI - Self-compassion, the 'quiet ego' and materialism. AB - The research is an investigation of self-compassion and materialism. Self compassion is when an individual has a caring, non-judgmental view of the self. This quality has been related to lower depression, less negative emotion and higher psychological health (Neff, 2003). Materialism has been consistently associated with low subjective well-being and unhappiness. A related concept is that of the 'quiet ego', which is a less competitive, less self-centered individual with more concern with connecting with others and with personal growth (Wayment et al., 2015). Therefore, it is hypothesized that highly materialistic individuals will be lower in self-compassion and have a fear of compassion from others and towards others and that self-compassion and fears of compassion will mediate the relationship between materialism and low subjective well-being. As materialistic individuals are more likely to be competitive and individualistic, it is hypothesized that the 'quiet ego' will be negatively related to materialism. These hypotheses were investigated using a set of questionnaires with 423 undergraduate participants. The results indicated a relationship between materialism and fear of compassion for others and of responding to the compassion of others. Materialism was also negatively related to the 'quiet ego' and related constructs such as: mindfulness, satisfaction with life and generativity. Self compassion, fears of compassion and the quiet-ego were also found to mediate the relationship between materialism and measures of well-being. The results are consistent with several theoretical explanations for the development of materialism. It is possible that increasing self-compassion, reducing fears of compassion and 'ego-quieting' procedures could be developed as methods of reducing materialistic tendencies. PMID- 30417146 TI - Immune and genomic signatures in oral (head and neck) cancer. AB - Head and neck squamous cell carcinoma (HNSCC) is responsible for a large number of deaths each year. Oral cancer is the most frequent subtype of HNSCC. Historically, oral cancer has been associated with an increase in the consumption of tobacco and alcohol products, seen especially in the Asian subcontinent. It has also been associated with infection by the human papilloma virus (HPV), particularly strain HPV16. Treatment usually involves a multidisciplinary approach of surgery combined with chemotherapy and radiation. The advent of immunotherapy has broadened the scope for treatment. A better immune response to the tumour can also elicit the action of other therapeutic approaches. A heightened immune response, on the other hand, can lead to resistant tumour formation through the process of immunoediting. Molecular profiling of the tumour microenvironment (TME) can provide us with better insight into the mechanism and progression of the disease, ultimately opening up new therapeutic options. High throughput molecular profiling techniques over the past decade have enabled us to appreciate the heterogeneity of the TME. In this review, we will be describing the clinicopathological role of the immune and genomic landscape in oral cancer. This study will update readers on the several immunological and genetic factors that can play an important function as predictive and prognostic biomarkers in various forms of head and neck cancer, with a special emphasis on oral carcinoma. PMID- 30417145 TI - Oral hygiene might prevent cancer. AB - Many evidences support that species from the Human Oral Microbiome Database such as Fusobacterium nucleatum or Bacteroides, linked previously to periodontitis and appendicitis, play a role in colorectal cancer (CRC), including metastasis. These typically oral species are invasive anaerobes that form biofilms in their virulent state. Aspirin (a NSAID) has been recently included into routine CRC prevention rationale. NSAIDs can prevent the growth of neoplastic lesions by inhibiting COX enzymes and another set of recently identified COX-independent targets, which include the WNT, AMPK and MTOR signaling pathways, the crosstalk between nucleoli and NF-kappaB transcriptional activity in apoptosis, and the biochemistry of platelets. These are signaling pathways related to tumor promoting inflammation. In this process, pathogens or simple deregulation of the microbiota play an important role in CRC. Aspirin and other NSAIDs are efficient inhibitors of biofilm formation and able to control periodontitis development preventing inflammation related to the microbiota of the gingival tissue, so its seems plausible to include this pathway in the mechanisms that aspirin uses to prevent CRC. We propose arguments suggesting that current oral hygiene methods and other future developments against periodontitis might prevent CRC and probably other cancers, alone or in combination with other options; and that the multidisciplinary studies needed to prove this hypothesis might be relevant for cancer prevention. PMID- 30417149 TI - The use of hydroxyapatite bone substitute grafting for alveolar ridge preservation, sinus augmentation, and periodontal bone defect: A systematic review. AB - Objectives: We determined and structurally analyzed the reported effect of hydroxyapatite (HA) bone substitute on alveolar bone regeneration. To the best of our knowledge, no systematic reviews have previously reported the bone regenerative effect of the HA bone substitute. Materials and methods: A literature search was performed for articles published up to August 2015 using MEDLINE with the search terms "hydroxyapatite," "bone regeneration," and "alveolar bone" as well as their known synonyms. The inclusion criteria were set up for human trials with at least five patients. The literature search, eligible article selection, and data extraction were independently performed by two readers, and their agreement was reported by kappa value. Results: Of the 504 studies found using the MEDLINE literature search, 241 were included for further steps (inter-reader agreement, kappa = 0.968). Abstract screening yielded 74 studies (kappa = 0.910), with 42 completely fulfilling the inclusion criteria (kappa = 0.864). In a final step, 42 studies were further analyzed, with 17 and 25 studies with and without statistical analysis, respectively. The 17 studies reporting similar outcome measures were compared using the calculated 95% confidence intervals. The effect of HA on ridge preservation could not be evaluated. Conclusions: The use of the HA bone substitute interfered with the normal healing process, with significant differences found for sinus augmentation but not for periodontal bone defects. Thus, a bone substitute with optimal bone regenerative properties for alveolar ridge or socket preservation, sinus augmentation, and periodontal bony defect should be developed. PMID- 30417150 TI - Comparison of ethanol yield from pretreated lignocellulo-starch biomass under fed batch SHF or SSF modes. AB - The ethanol yields from lignocellulo-starch biomass (peels of sweet potato, elephant foot yam, tannia, greater yam and beet root) by fed-batch separate hydrolysis and fermentation (F-SHF) and simultaneous saccharification and fermentation (F-SSF) using Saccharomyces cerevisiae were compared. Fed-batch saccharification of steam or dilute sulphuric acid pretreated biomass enhanced the reducing sugar yield which resulted in high RS consumption, volumetric ethanol productivity and ethanol yield during the first 24 h fermentation under F SHF mode, while continuous production and utilization of reducing sugars occurred up to 72 h in F-SSF. Dilute sulphuric acid pretreated residues under F-SHF gave higher ethanol yield (34-43 g/L) and productivity (274-346 ml/kg dry biomass) than steam pretreatment (27-36 g/L and 223-295 ml/kg respectively), while F-SSF was superior for steam pretreated peels of sweet potato, elephant foot yam and tannia giving ethanol yields from 281 to 302 ml/kg. Glucose and xylose were present in all the hydrolysates with a preponderance of glucose and fermentation resulted in significant reduction in glucose levels in both F-SHF and F-SSF. Higher levels of total soluble phenolics and hydroxymethyl furfural were observed in the hydrolysates from dilute sulphuric acid pretreatment and yeast assimilated/detoxified part of the inhibitors, while only trivial amounts of furfural were present due to the low xylose content in the hydrolysates. Continuous formation led to higher accumulation of inhibitors in F-SSF despite supplementation with the detoxification mix comprising Tween 20, polyethylene glycol and sodium borohydride. F-SHF of dilute sulphuric acid pretreated biomass could be considered as a comparatively advantageous process where only one time feeding of enzyme cocktail and yeast was adopted compared to multiple feeds of enzymes and yeast along with other additives such as detoxification mix or nutrient solution in F-SSF. PMID- 30417151 TI - Hypoglycaemic unawareness: A systematic review of qualitative studies of significant others' (SO) supportive interventions for patients with diabetes mellitus. AB - Background: Hypoglycemia unawareness (HU) has been attributed to both a downward shift in central nervous system (CNS)-triggered sympatho-adrenal responses to low glycaemic thresholds and a subsequent loss of adrenergic symptoms, which, in addition, to cerebral cortex adaptations permit normal function under hypoglycaemic conditions. Both of these mechanisms are brought about by recurring hypoglycemic events (hypoglycemia-associate autonomic failure, HAAF). This can contribute to repetitive cycles of increasingly severe hypoglycaemia, the consequences of which have considerable impact on relatives and significant others (SO) when providing care to patients with diabetes. Methods: A Systematic Review (SR) of 639 qualitative studies was carried out in accordance with the Preferred Reporting Items for Systematic Review (PRISMA) principles. The search strategy was developed using MeSH terms for a range of electronic databases: CINAHL, Pubmed, EMBASE, Medline, AMED and ASSIA were systematically searched in order to identify a variety of literature relevant to the review topic. Four duplicate studies were removed and a further 630 studies were excluded due to being irrelevant. Five qualitative studies were retained and analysed. Results: The three resultant findings from the literature appraised were i) Experiences and views of Significant Others' (SO) with adult relatives that have HU ii) Support needs of SO and iii) Health professionals interventions to address SO support needs and improve overall HU care. A clear finding was that SO experience difficulties managing HU and this can impact on the relationships that SO and HU patients have. Support needs of SO highlighted were both educational and psychological in nature, with there being a requirement for additional raised awareness within the wider community. Conclusion: It is essential that healthcare professionals offer support, such as teaching and support groups. In addition, providing interventions into improving family knowledge of diabetes and support with regard to psychosocial, behavioural and practical support for the person with diabetes. Moreover, improving resources for families to improve diabetes care. However, as the literature was of a qualitative nature, future recommendations would be quantitative research into these suggested nursing implementations to quantitatively assess their usefulness in practice. PMID- 30417152 TI - Adaptive co-management of conservation conflicts - An interactional experiment in the context of German national parks. AB - Social-ecological systems are characterized by complexity, uncertainty, and change. Adaptive co-management may help to improve adaptability and resilience and to develop 'no-regret strategies' for a sustainable management. It is a dynamic, inductive, and self-organized process based on social learning and collaboration. In this regard, conservation conflicts, conflicts between humans about wildlife, are a contemporary environmental management issue. Their management may be facilitated through adaptive co-management. However, adaptive co-management typically emerges because of a crisis or changing context and is difficult to be applied intentionally. We hypothesize that it may be possible to lay the ground for an adaptive co-management process by activating stakeholders to interact experimentally without a prescriptive application of adaptive co management criteria. We examined conservation conflicts in the context of three German national parks, where we triggered interaction between 68 stakeholders in nine moderated focus groups. These were recorded and analyzed. Stakeholders discussed similar conflict issues and conflict management suggestions. Subsequently, we conducted a literature synthesis, resulting in 13 adaptive co management characteristics, and analyzed concurrencies between these and stakeholders' management suggestions. Management suggestions reflected collaborative, interactional, structural, and practice-oriented adaptive co management characteristics, while political context, rules, adaptability, learning, and monitoring were underrepresented. These underrepresented adaptive co-management characteristics may be harder to be recognized by stakeholders. An implementation of stakeholder-based management suggestions may prepare the systems for change. However, policy windows and resilience have to be observed, underrepresented characteristics have to be examined, and political context, long term support, monitoring, and facilitation have to be considered. The approach fosters conservation conflict solution. The results could help protected area managers to further develop a local process. The experiment empowered stakeholders and resulted in case-specific suggestions, backed up by adaptive co management literature. Research should focus on bridging knowledge between case studies as well as between politics, management, stakeholders, and scientists and on further examining stakeholders' capabilities to develop adaptive co-management approaches. PMID- 30417154 TI - Estimation of measles risk using the World Health Organization Measles Programmatic Risk Assessment Tool, Iran. AB - Introduction: Based on the World Health Organization (WHO) reports the EMRO countries did not reached to eradication of measles at 2010. This study aimed to estimate the risk of measles outbreak in different districts of Iran to identify high-risk areas based on WHO measles programmatic risk assessment tool. Materials and methods: The WHO measles programmatic risk assessment tool was used to estimate the overall risk of measles in 31 providences and 322 districts of Iran at 2017. The measles risk was calculated by a function of four indicator scores including population immunity, surveillance quality, program performance, and threat assessment and the overall risk of measles for each districts calculated. Then, the tool assigned each district a risk category of low, medium, high, or very high according to the overall risk score. Results: Of the 322 districts in Iran, all districts were categorized as low risk and there was no very high risk, high risk and medium risk district in Iran. Twenty-six districts (7.4%) received to risk point higher than 20. Based on population immunity and program delivery performance indicators, all districts in Iarn were categorized as low risk and 92.86% of districts were in low risk category by surveillance quality indicator. Conclusion: The overall risk of measles profile was categorized as low risk and Iranian practices for measles elimination is very good in comparing other studies in this area. However, more attempts should be conducted to sustaining the surveillance quality indicators in all districts. PMID- 30417153 TI - Biological consequences of structural and functional proteasome diversity. AB - Cell homeostasis and regulation of metabolic pathways are ensured by synthesis, proper folding and efficient degradation of a vast amount of proteins. Ubiquitin proteasome system (UPS) degrades most intracellular proteins and thus, participates in regulation of cellular metabolism. Within the UPS, proteasomes are the elements that perform substrate cleavage. However, the proteasomes in the organism are diverse. Structurally different proteasomes are present not only in different types of cells, but also in a single cell. The reason for proteasome heterogeneity is not fully understood. This review briefly encompasses mammalian proteasome structure and function, and discusses biological relevance of proteasome diversity for a range of important cellular functions including internal and external signaling. PMID- 30417155 TI - The effects of packaging and storage temperature on the shelf-life of extra virgin olive oil. AB - This research aimed to study the effects of packaging and storage temperature on the shelf-life of an extra virgin olive oil (EVOO) as it can occur in most points of sale. The evolution of the chemical and sensory characteristics of an EVOO, initially stored in stainless steel silos under nitrogen at 12-18 degrees C, was evaluated after packaging. Tinplate tin (TT) and greenish glass (GG), the most used packaging containers, and temperatures of 6 and 26 degrees C were taken into consideration. After 125 days from packaging all the samples maintained clearness, green and yellow reflections and the positive sensory notes of bitterness and pungency of the starting EVOO. Shelf-life of EVOO was significantly affected by different storage conditions: oil samples stored in GG at 6 degrees C preserved for the most part the positive attributes, whereas those stored in TT at 26 degrees C showed a significant presence of the rancid flavor due to oxidative processes. Moreover, samples stored in GG at 6 degrees C maintained the highest bitterness intensity and did not show defects at the end of the storage period. The results suggest that storage in GG at a low temperature could represent a promising storage condition to slow-down the oil degradation during market storage. PMID- 30417156 TI - On variability & human consciousness. AB - The topic of consciousness remains central across numerous academic fields ranging from philosophy to cognitive neuroscience. Scholars in all of these fields continue to debate the origins of conscious experiences. More recently, scientists have applied advanced imaging techniques to illuminate brain regions that are at least associated with our subjective feelings of conscious experience. Though much disagreement remains, one point that is generally accepted across fields is that consciousness is not the product of an immaterial substance, but rather is produced by functioning across physical substrates in the brain. This point of agreement is enough to suggest that genetically and environmentally underpinned individual variation in brain structure may contribute to individual variation in consciousness. To the extent that this is correct, it may provide insight on a host of important questions across various academic fields. Equally important, understanding sources of variability in consciousness may be a key piece of the puzzle for understanding not only how consciousness evolved but also how selection pressures might continue to act on the human experience of consciousness across subsequent generations. PMID- 30417157 TI - Community clinic-based lifestyle change for prevention of metabolic syndrome: Rationale, design and methods of the 'Vida Sana/healthy life' program. AB - Purpose: and Objectives: The risk of diseases associated with Metabolic Syndrome (MetS) is higher for Hispanics living in the northeastern United States than for other racial and ethnic groups. Higher risk of diabetes, high blood lipids, obesity and limited access to continuity of care are all factors that also contribute to disproportionately poorer chronic disease outcomes for Hispanics. Intervention approach: This article describes the planning and implementation of, and evaluation plans for the Vida Sana Program (VSP), a community-based group intervention created to address the identified MetS risks by encouraging healthier diet and physical activity behaviors among a low-income, largely Spanish speaking, and literacy limited uninsured population. Developed in response to recent calls for culturally-tailored interventions, VSP is conducted by trained bicultural/bilingual Navegantes, who deliver a culturally sensitive, fun and engaging eight-week, in-person educational series through group meetings. The intervention also includes a 40-page colorful, picture and graphic enhanced booklet to be used in the group setting and at home. The intervention focused on screening for MetS-associated disease risk factors, understanding chronic disease management, encouraging medication adherence, increasing physical activity, and healthful dietary changes such as limiting alcohol, sodium, unhealthy fats and excess carbohydrate intake, while emphasizing portion control, whole grains and healthy fats. Conclusions: This creative, community-based approach fills an important gap in the community and in the public health literature, is well liked by health literacy limited patients, and will provide an important model of successfully engaging the Hispanic community on these important health issues. PMID- 30417158 TI - Remembering the past: Mitotic bookmarking in a developing embryo. AB - During development, transcriptional properties of progenitor cells are stably propagated across multiple cellular divisions. Yet, at each division, chromatin faces structural constraints imposed by the important nuclear re-organization operating during mitosis. It is now clear that not all transcriptional regulators are ejected during mitosis, but rather that a subset of transcription factors, chromatin regulators and epigenetic histone marks are able to 'bookmark' specific loci, thereby providing a mitotic memory. Here we review mechanisms of mitotic bookmarking and discuss their impact on transcriptional dynamics in the context of multicellular developing embryos. We document recent discoveries and technological advances, and present current mathematical models of short-term transcriptional memory. PMID- 30417159 TI - A novel and remote biochemical verification method of smoking abstinence: Predictors of participant compliance. AB - INTRODUCTION: Biochemical verification of smoking abstinence remains an important validity check of cessation trial outcomes. Digital health trials rarely establish in-person contacts between participants and intervention providers, requiring novel strategies to biochemically verify outcomes. We describe remote verification of smoking abstinence via saliva cotinine and individual predictors of compliance in a digital intervention. METHODS: Data came from a feasibility trial and randomized controlled trial of a Facebook smoking cessation intervention for young adults. In both trials, participants completed baseline and follow-up surveys at 3, 6 and 12 months. Participants indicating past 7-day point prevalence smoking abstinence were mailed a saliva cotinine kit. Participants were instructed to electronically send two photos - one of them giving a saliva sample and the other with the test results. We investigated predictors of compliance with these procedures, independent of verification results, among participants that were mailed a kit at any follow-up point (N=130; mean age = 21.3; 59.2% female) using logistic and multinomial regression. RESULTS: A total of 189 kits were sent out, of which 97 were completed (51.3% compliance). We did not identify significant predictors of completing any vs no kits using logistic regression. We also found no significant predictors of extent of kit completion (none vs some; none vs all) using multinomial regression and controlling for number of kits sent. CONCLUSIONS: Findings demonstrate the feasibility of this biochemical verification method and suggest low risk for bias of results. Future studies should replicate findings in larger samples and improve compliance with verification procedures. PMID- 30417160 TI - mTOR/AMPK signaling in the brain: Cell metabolism, proteostasis and survival. AB - The mechanistic (or mammalian) target of rapamycin (mTOR) and the adenosine monophosphate-activated protein kinase (AMPK) regulate cell survival and metabolism in response to diverse stimuli such as variations in amino acid content, changes in cellular bioenergetics, oxygen levels, neurotrophic factors and xenobiotics. This Opinion paper aims to discuss the current state of knowledge regarding how mTOR and AMPK regulate the metabolism and survival of brain cells and the close interrelationship between both signaling cascades. It is now clear that both mTOR and AMPK pathways regulate cellular homeostasis at multiple levels. Studies so far demonstrate that dysregulation in these two pathways is associated with neuronal injury, degeneration and neurotoxicity, but the mechanisms involved remain unclear. Most of the work so far has been focused on their antagonistic regulation of autophagy, but recent findings highlight that changes in protein synthesis, metabolism and mitochondrial function are likely to play a role in the regulatory effects of both mTOR and AMPK on neuronal health. Understanding the role and relationship between these two master regulators of cell metabolism is crucial for future therapeutic approaches to counteract alterations in cell metabolism and survival in brain injury and disease. PMID- 30417161 TI - Urokinase-type Plasminogen Activator Induces Neurorepair in the Ischemic Brain. AB - Urokinase-type plasminogen activator (uPA) is a serine proteinase that upon binding to its receptor (uPAR) catalyzes the conversion of plasminogen into plasmin on the cell surface. Recent studies indicate that neurons but not astrocytes release uPA during the recovery phase from an ischemic injury, and that binding of uPA to uPAR promotes neurorepair in the ischemic brain by a mechanism that does not require plasmin generation. A combined approach of in vitro and in vivo studies has shown that uPA binding to uPAR induces the reorganization of the actin cytoskeleton in dendritic spines and axons that have suffered an ischemic injury. Furthermore, recent data indicate that uPA-uPAR binding induces astrocytic activation and a crosstalk between activated astrocytes and the injured neuron that triggers a sequence of biochemical events that promote the repair of synapses injured by the ischemic insult. The translational relevance of these observations is noteworthy because following its intravenous administrations recombinant uPA (ruPA) reaches the ischemic tissue, thus raising the question of whether treatment with ruPA is an effective therapeutic strategy to promote neurorepair functional recovery among ischemic stroke survivors. PMID- 30417162 TI - Optimization of Energy Combination for Gold-based Contrast Agents below K-edges in Dual-energy Micro-CT. AB - Dual-energy micro-Computed Tomography provides high resolution non-invasive images at low cost. It can determine the concentrations of component materials in a mixture. Taking the advantages of K-edge, the gold-based agents contribute to improve the contrast of some physiological tissues with low natural contrast. Because the K-edge of gold (80.7 kVp) is excessively high, the anatomical structures could not be identified clearly in in vivo small animal experiments. In this study, the energy combination below K-edge is optimized to differentiate bone, soft tissue and gold. Furthermore, we evaluate the effects of concentration of contrast agents, the extrinsic filtration setting and dose level. Based on the quantitative analysis results of material decomposition, the optimized energy pair gathered in a certain range where the low-energy is 30kVp-40kVp. Our results can provide a practical guidance for the design of in vivo small animal experiments using gold-based contrast agents. PMID- 30417163 TI - Transmural remodeling of right ventricular myocardium in response to pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) imposes substantial pressure overload on the right ventricular free wall (RVFW), leading to myofiber hypertrophy and remodeling of its collagen fiber architecture. The transmural nature of these adaptations and their effects on the macroscopic mechanical behavior of the RVFW remain largely unexplored. In the present work, we extended our constitutive model for RVFW myocardium to investigate the transmural mechanical and structural remodeling post-PAH. Recent murine experimental studies provided us with comprehensive histomorphological and biaxial mechanical data for viable, passive myocardium for normal and post hypertensive cases. Multiple fiber-level remodeling events were found to be localized in the midwall region (40% < depth < 60%): (i) reorientation and alignment of both myo- and collagen fibers towards longitudinal (apex-to-outflow tract) direction, (ii) substantial increase in the rate of the recruitment of collagen fibers with strain, and (iii) a corresponding increase in the mechanical interactions between the collagen and myofibers. These adaptations suggest a denser and more fibrous connective tissue in the midwall region, and led to a substantially stiffer mechanical response along the longitudinal direction in post-PAH tissues. Moreover, using a Laplace-type mechanical equilibrium analysis of the right ventricle to approximate the wall stress state, we estimated that the longitudinal component of stress remained higher in the hypertensive state while the circumferential component approximately maintained homeostasis values. This result was consistent with our observation from the fiber- and tissue-level remodeling that longitudinally oriented collagen fibers, localized in the midwall region, dominated the remodeling process. The findings of this study highlight the need for more integrated cellular-tissue-organ analysis to better understand the remodeling events during PAH and design interventions. PMID- 30417164 TI - Progress Estimation and Phase Detection for Sequential Processes. AB - Process modeling and understanding are fundamental for advanced human-computer interfaces and automation systems. Most recent research has focused on activity recognition, but little has been done on sensor-based detection of process progress. We introduce a real-time, sensor-based system for modeling, recognizing and estimating the progress of a work process. We implemented a multimodal deep learning structure to extract the relevant spatio-temporal features from multiple sensory inputs and used a novel deep regression structure for overall completeness estimation. Using process completeness estimation with a Gaussian mixture model, our system can predict the phase for sequential processes. The performance speed, calculated using completeness estimation, allows online estimation of the remaining time. To train our system, we introduced a novel rectified hyperbolic tangent (rtanh) activation function and conditional loss. Our system was tested on data obtained from the medical process (trauma resuscitation) and sports events (Olympic swimming competition). Our system outperformed the existing trauma-resuscitation phase detectors with a phase detection accuracy of over 86%, an F1-score of 0.67, a completeness estimation error of under 12.6%, and a remaining-time estimation error of less than 7.5 minutes. For the Olympic swimming dataset, our system achieved an accuracy of 88%, an F1-score of 0.58, a completeness estimation error of 6.3% and a remaining time estimation error of 2.9 minutes. PMID- 30417165 TI - rConverse: Moment by Moment Conversation Detection Using a Mobile Respiration Sensor. AB - Monitoring of in-person conversations has largely been done using acoustic sensors. In this paper, we propose a new method to detect moment-by-moment conversation episodes by analyzing breathing patterns captured by a mobile respiration sensor. Since breathing is affected by physical and cognitive activities, we develop a comprehensive method for cleaning, screening, and analyzing noisy respiration data captured in the field environment at individual breath cycle level. Using training data collected from a speech dynamics lab study with 12 participants, we show that our algorithm can identify each respiration cycle with 96.34% accuracy even in presence of walking. We present a Conditional Random Field, Context-Free Grammar (CRF-CFG) based conversation model, called rConverse, to classify respiration cycles into speech or non speech, and subsequently infer conversation episodes. Our model achieves 82.7% accuracy for speech/non-speech classification and it identifies conversation episodes with 95.9% accuracy on lab data using a leave-one-subject-out cross validation. Finally, the system is validated against audio ground-truth in a field study with 32 participants. rConverse identifies conversation episodes with 71.7% accuracy on 254 hours of field data. For comparison, the accuracy from a high-quality audio-recorder on the same data is 71.9%. PMID- 30417167 TI - Of carrots and sticks: the effect of workfare announcements on the job search behaviour and reservation wage of welfare recipients. AB - The German workfare scheme 'One-Euro-Jobs', which provides additional jobs of public interest for welfare recipients, has a number of different goals. On the one hand, One-Euro-Jobs are intended to increase the participants' employment prospects in the medium term. On the other hand, they can be used to test welfare recipients' willingness to work. We use survey data from the Panel Study 'Labour Market and Social Security' and propensity score matching methods to study the intention-to-treat effect of receiving a One-Euro-Job announcement on job search behaviour, reservation wage and labour market performance of welfare recipients. We find that receiving a One-Euro-Job announcement increases job search activities significantly and decreases the reservation wage for women and individuals who have been employed within the last 4 years, but does not affect the short-term employment probability. PMID- 30417166 TI - A family of small, cyclic peptides buried in preproalbumin since the Eocene epoch. AB - Orbitides are cyclic ribosomally-synthesized and post-translationally modified peptides (RiPPs) from plants; they consist of standard amino acids arranged in an unbroken chain of peptide bonds. These cyclic peptides are stable and range in size and topologies making them potential scaffolds for peptide drugs; some display valuable biological activities. Recently two orbitides whose sequences were buried in those of seed storage albumin precursors were said to represent the first observable step in the evolution of larger and hydrophilic bicyclic peptides. Here, guided by transcriptome data, we investigated peptide extracts of 40 species specifically for the more hydrophobic orbitides and confirmed 44 peptides by tandem mass spectrometry, as well as obtaining solution structures for four of them by NMR. Acquiring transcriptomes from the phylogenetically important Corymboideae family confirmed the precursor genes for the peptides (called PawS1-Like or PawL1) are confined to the Asteroideae, a subfamily of the huge plant family Asteraceae. To be confined to the Asteroideae indicates these peptides arose during the Eocene epoch around 45 Mya. Unlike other orbitides, all PawL-derived Peptides contain an Asp residue, needed for processing by asparaginyl endopeptidase. This study has revealed what is likely to be a very large new family of orbitides, uniquely buried alongside albumin and processed by asparaginyl endopeptidase. PMID- 30417168 TI - The Virtual Personalities Neural Network Model: Neurobiological Underpinnings. AB - The Virtual Personalities Model is a motive-based neural network model that provides both a psychological model and a computational implementation that explicates the dynamics and often large within-person variability in behavior that arises over time. At the same time the same model can produce -- across many virtual personalities - between subject variability in behavior that when factor analyzed yields familiar personality structure (e.g., the Big-5). First, we describe our personality model and its implementation as a neural network model. Second, we focus on detailing the neurobiological underpinnings of this model. Third, we examine the learning mechanisms, and their biological substrates, as ways that the model gets "wired up", discussing Pavlovian and instrumental conditioning, Pavlovian to instrumental transfer (PIT), and habits. Finally, we describe the dynamics of how initial differences in propensities (e.g., dopamine functioning), wiring differences due to experience, and other factors could operate together to develop and change personality over time, and how this might be empirically examined. Thus, our goal is to contribute to the rising chorus of voices seeking a more precise neurobiologically-based science of the complex dynamics underlying personality. PMID- 30417170 TI - Therapeutic administration of IL-10 and amphiregulin alleviates chronic skeletal muscle inflammation and damage induced by infection. AB - Maintenance of tissue integrity in skeletal muscle requires the immunomodulatory and regenerative functions of muscle-resident regulatory T cells (Tregs). Chronic skeletal muscle infections, such as with Toxoplasma gondii disrupt normal immuno regulatory networks and lead to pathogenic changes in Treg function. Specifically, Tregs during chronic T. gondii infection reinforce an inflammatory macrophage bias that exacerbates injury in skeletal muscle. In this study, we investigated whether the aberrations in skeletal muscle Treg function during chronic infection could be overcome by treatment with Treg-related factors associated with enhanced muscle regeneration during sterile injury. We show treatment of chronically infected mice with the Treg promoting therapies, interleukin-2 complexed with anti-IL-2 antibody or interleukin-33 (IL-33), did not restore macrophage dynamics or muscle function, respectively, in vivo. However supplementation of known Treg-derived factors, interleukin-10 (IL-10) and amphiregulin (Areg) improved muscle function and skewed macrophages toward a restorative phenotype in the presence of chronic infection. These shifts in macrophage phenotype are coupled with enhanced physiologic parameters of regeneration. Together, these data suggest that while Treg-mediated immuno regulation is compromised during chronic skeletal muscle infection, supplementation of canonical Treg-derived factors such as IL-10 and Areg can restore immunologic balance and enhance muscle repair. PMID- 30417169 TI - Astrocytes, emerging stars of energy homeostasis. AB - Astrocytes have historically been considered structural supporting cells for neurons. Thanks to new molecular tools, allowing specific cell ablation or over expression of genes, new unexpected astrocytic functions have recently been unveiled. This review focus on emerging groundbreaking findings showing that hypothalamic astrocytes are pivotal for the regulation of whole body energy homeostasis. Hypothalamic astrocytes sense glucose and fatty acids, and express receptors for several peripheral hormones such as leptin and insulin. Furthermore, they display striking sexual dimorphism which may account, at least partially, for gender specific differences in energy homeostasis. Metabolic alterations have been shown to influence the initiation and progression of many neurodegenerative disorders. A better understanding of the roles and interplay between the different brain cells in regulating energy homeostasis could help develop new therapeutic strategies to prevent or cure neurodegenerative disorders. PMID- 30417172 TI - Central Nervous System and Head and Neck Histiocytoses: A Comprehensive Review on the Spectrum of Imaging Findings. AB - : The histiocytoses are a rare group of varied but related disorders characterized by abnormal tissue proliferation of macrophages and dendritic cells within tissues. The purpose of this article was to review the imaging findings in patients presenting with CNS and with head and neck manifestations of these disorders. Histiocytoses include but are not limited to Rosai-Dorfman disease, Erdheim Chester disease, Langerhans cell histiocytosis, histiocytic sarcoma, and juvenile xanthogranuloma. A review of the literature was performed to determine the sites of disease involvement. This article includes the demographics, histopathologic criteria for diagnosis, and imaging features of these histiocytoses, and describes the manifestations in locations known to harbor disease: intraaxial and extra-axial intracranial regions, the calvaria, skull base, hypothalamopituitary axis, orbits, paranasal sinuses, spine, and the head and neck region. Histiocytoses have variable imaging appearances in the CNS and in the head and neck region, and radiologists should be aware of the spectrum of findings to avoid mistaking them for other disease processes. Learning Objective: To understand the general pathophysiology, clinical presentation, and typical imaging characteristics of the most common histiocytoses; comprehend the morphologic and immunohistochemical characteristics of these histiocytoses and the hallmark findings on pathology; and be able to differentiate between these disorders based on their most common presentations. PMID- 30417171 TI - Targeting of Liver Mannan-Binding Lectin-Associated Serine Protease-3 with RNA Interference Ameliorates Disease in a Mouse Model of Rheumatoid Arthritis. AB - Mannan-binding lectin-associated serine protease 3 (MASP-3) regulates the alternative pathway of complement and is predominantly synthesized in the liver. The role of liver-derived MASP-3 in the pathogenesis of rheumatoid arthritis (RA) is unknown. We hypothesized that liver-derived MASP-3 is essential for the development of joint damage and that targeted inhibition of MASP-3 in the liver can attenuate arthritis. We used MASP-3-specific small interfering RNAs (siRNAs) conjugated to N-acetylgalactosamine (GalNAc) to specifically target the liver via asialoglycoprotein receptors. Active GalNAc-MASP3-siRNA conjugates were identified, and in vivo silencing of liver MASP-3 mRNA was demonstrated in healthy mice. The s.c. treatment with GalNAc-MASP-3-siRNAs specifically decreased the expression of MASP-3 in the liver and the level of MASP-3 protein in circulation of mice without affecting the levels of the other spliced products. In mice with collagen Ab-induced arthritis, s.c. administration of GalNAc-MASP-3 siRNA decreased the clinical disease activity score to 50% of controls, with decrease in histopathology scores and MASP-3 deposition. To confirm the ability to perform MASP-3 gene silencing in human cells, we generated a lentivirus expressing a short hairpin RNA specific for human MASP-3 mRNA. This procedure not only eliminated the short-term (at day 15) expression of MASP-3 in HepG2 and T98G cell lines but also diminished the long-term (at day 60) synthesis of MASP-3 protein in T98G cells. Our study demonstrates that isoform-specific silencing of MASP-3 in vivo modifies disease activity in a mouse model of RA and suggests that liver-directed MASP3 silencing may be a therapeutic approach in human RA. PMID- 30417174 TI - Semi-synthetic Trauma Resuscitation Process Data Generator. PMID- 30417175 TI - Improving STI and HIV Passive Partner Notification using the Model for Improvement: A Quality Improvement Study in Lilongwe Malawi. AB - Background: In Malawi, passive partner notification is the mainstay method of partner notification (PN). Despite its wide use, the proportion of sexual partners referred for care through this method is very low. We aimed to increase the proportion of sexual partner referral through passive PN. Methods: We implemented a quality improvement (QI) project at Bwaila STI unit in Lilongwe, Malawi between January and June 2017 using a pre- and post- intervention quasi experimental study design. Pre-intervention, we conducted key-informant interviews and clinic observations and used the findings to design a QI project using expert opinion. The intervention included three change ideas: early start time of the clinic, shortening of the group health talk and expedited clinic flow for sexual partners. Each change idea was tested twice through 1-week long Plan Do-Study-Act cycles using the model for improvement (MFI) and then combined and tested twice. Process data were collected and monitored using run charts. Post intervention, we evaluated the proportion of sexual partners who presented to the clinic, to detect a 10% increase at 95% power and alpha=0.05, between pre- and post-intervention periods. Results: The average duration of the group health talk dropped from 56 minutes to 38 minutes and the duration of clinic stay for sexual partners reduced by 45 minutes (from 1hour 36 minutes to 51 minutes). The average clinic start time improved from 09:02 hours to 08:17 hours. The proportion of sexual partner referral increased by 37% (P=0.04) - from 15.6% to 21.4%. We observed an upward trend in the proportion of sexual partners referred in the post-intervention period. Conclusion: The yield of sexual partners through passive PN was improved using a simple QI intervention implemented using the MFI. However, the proportion of sexual partner referral remains suboptimal. More effort is required to increase the proportion of sexual partner referral in Malawi. PMID- 30417173 TI - Analysis of Evidence for the Combination of Pro-dopamine Regulator (KB220PAM) and Naltrexone to Prevent Opioid Use Disorder Relapse. AB - Blum's laboratory first showed the benefits of naloxone or narcotic antagonists in the treatment of alcohol dependence. This seminal work published in Nature in the early 70's, in conjunction with many other studies, later served as the basis for the development of the narcotic antagonist (NTX) now used to treat both alcohol and opioid dependence. In 2006 an extended-release injectable of Naltrexone (XR-NTX) was approved by the FDA. Naltrexone is a relatively weak antagonist of kappa- and delta-receptors and is also a potent MU-receptor antagonist. Dosages of naltrexone that effectively reduce opioid and alcohol consumption also actively block MU-receptors, but chronically down-regulate mesolimbic dopamine release. While studies show benefit especially in the short term, there is ongoing evidence that the retention and compliance with NTX are not sufficient to characterize adherence as high. However, extended-release NTX opioid treatment is associated with superior outcomes including less likely relapse (defined as daily use), and much longer time to relapse despite higher rates of concurrent non-opioid substance use like cocaine. Regarding long-term extended-release injectable (XR-NTX) for opioid dependence; there was higher compliance with Opioid Use Disorder (OUD) than for Alcohol Use Disorder (AUD.). Consideration of modalities in combination with XR-NTX is imperative. Research by Blum., et al. showed that a combination of Naltrexone and a pro-dopamine regulator neuro-nutrient (KB220) significantly prevented opioid relapse. Thus, early identification of addiction vulnerability with the Genetic Addiction Risk Score (GARSTM) a panel of polymorphic risk alleles from ten reward circuitry genes will provide valuable information especially as it relates to genetically guided therapy with the KB220 neuro nutrient termed 'Precision Addiction Management". PMID- 30417177 TI - MetaMap is a superior baseline to a standard document retrieval engine for the task of finding patient cohorts in clinical free text. AB - The goal of this work was to establish a reasonable baseline for research in patient cohort retrieval from clinical free text. Much recent work has used Lucene for this purpose. Our approach was to use MetaMap alone. We found that although many TREC 2011 Electronic Medical Records track participants found it difficult to beat a Lucene baseline, our MetaMap-based baseline did outperform a number of Lucene runs. We propose that MetaMap is a more valid baseline than Lucene, providing essential concept extraction, and that failure to make use of this industry-standard tool results in an unfairly low baseline for evaluation of system outputs. PMID- 30417176 TI - Predicting MeSH Beyond MEDLINE. AB - Medical subject headings (MeSH) are a flexible and useful tool for describing biomedical concepts. Here, we present MeSHier, a tool for assigning MeSH terms to biomedical documents based on abstract similarity and references to MEDLINE records. When applied to PubMedCentral papers, NIH grants, and USPTO patents we find that these two sources of information produce largely disjoint sets of related MEDLINE records, albeit with some overlap in MeSH. When combined they provide an enriched topical annotation that would not have been possible with either alone. MeSHier is available as a demo tool that can take as input IDs of PubMed papers, USPTO patents, and NIH grants: http://abel.lis.illinois.edu/cgi bin/meshier/search.py. PMID- 30417178 TI - Geographical Distribution of Biomedical Research in the USA and China. AB - We analyze nearly 20 million geocoded PubMed articles with author affiliations. Using K-means clustering for the lower 48 US states and mainland China, we find that the average published paper is within a relatively short distance of a few centroids. These centroids have shifted very little over the past 30 years, and the distribution of distances to these centroids has not changed much either. The overall country centroids have gradually shifted south (about 0.2 degrees for the USA and 1.7 degrees for China), while the longitude has not moved significantly. These findings indicate that there are few large scientific hubs in the USA and China and the typical investigator is within geographical reach of one such hub. This sets the stage to study centralization of biomedical research at national and regional levels across the globe, and over time. PMID- 30417179 TI - Ba3B10O17Br2: a new barium borate halide with B-O layered structure. AB - A new barium borate halide, Ba3B10O17Br2, has been obtained. A detailed structural comparison with other barium borate halides suggested that Ba3B10O17Br2 is the first barium borate halide with a B-O layered structure. First-principles theoretical studies were conducted to aid understanding of the electronic structure and optical properties. PMID- 30417180 TI - Metal-organic frameworks-derived core-shell Fe3O4/Fe3N@graphite carbon nanocomposites as excellent non-precious metal electrocatalyst for oxygen reduction. AB - Metal-organic frameworks (MOFs), as precursors for synthesizing new carbon materials, hold promise for applications in the oxygen reduction reaction (ORR) as efficient non-precious metal catalysts. Here, a facile template-assisted strategy was adopted to fabricate a core-shell structure derived from MIL-101(Fe) and polyaniline. MIL-101(Fe) nanoparticles obtained by microwave-assisted synthesis were combined with PAni in different ratios and carbonized at 900 degrees C under flowing N2. An optimized core-shell Fe3O4/Fe3N@graphite carbon structure was successfully prepared and exhibited attractive ORR activity, with a half-wave potential of 0.916 V vs. RHE and an electron transfer number of 4.0 at 0.4 V vs. RHE. Furthermore, the catalyst displayed excellent stability in an alkaline solution. The superior ORR performance of the catalyst is mainly attributed to its stable core-shell structure, large specific surface area and high content of electrocatalytically active N species. PMID- 30417181 TI - Single-ion magnetic anisotropy in a vacant octahedral Co(ii) complex. AB - The first example of a pentacoordinate CoII single-ion magnet based on a P-donor ligand with vacant octahedral coordination geometry is reported here. Thorough magnetic measurements reveal the presence of field induced slow relaxation behavior with an easy-plane magnetic anisotropy. The combined theoretical and experimental studies disclose that direct and quantum tunneling processes become dominant at low temperature to relax the magnetization; however, from the thermal dependence of relaxation time it can be observed that the optical or acoustic Raman processes become important to the overall relaxation process. PMID- 30417182 TI - An organometallic half-sandwich supramolecular complex {K(18-Crown-6)(etan C6H5B(C6H5)3)} (n = 1-6) exhibiting a reversible breaking-symmetry phase transition and switchable dielectric behaviour. AB - A supramolecular crystal, built from a 1 : 1 molar ratio of potassium tetraphenylboron (KBPh4) with 1,4,7,10,13,16-hexaoxacyclooctadecane (18-Crown-6), contains an organometallic half-sandwich superstructure unit {K(18-Crown-6)(etan C6H5B(C6H5)3)} (1 with n = 1-6), and shows a reversible phase transition at ~211 K. The analysis of crystal structures at 173 K in the low-temperature phase, and 293 and 423 K in the high-temperature phase revealed that the breaking-symmetry phase transition is associated with the order-disorder transformation of [K(18 Crown-6)]+ and the change of the coordination mode of the phenyl ring to K+. A dielectric anomaly appears at ca. 212 K and dielectric relaxation occurs above 375 K in 1. The dielectric and thermal anomaly temperatures are close to each other, and the dielectric relaxation is relevant to the relative displacement of [K(18-Crown-6)]+ and the tetraphenylboron anion. PMID- 30417183 TI - All-solution-processed perovskite light-emitting diodes with all metal oxide transport layers. AB - All-solution-processed perovskite light-emitting diodes (PeLEDs) with all metal oxide transport layers were successfully realized based on an ITO/NiOx/CsPbBr3/ZnMgO/Al conventional device structure. A unique perovskite polymer composite method enables the deposition of solution-processed ZnMgO nanoparticles on the perovskite film. As a result, we achieved highly efficient PeLEDs with a maximum luminance of 17 017 cd m-2, and the efficiency showed little roll-off with increasing current density. PMID- 30417184 TI - RuOx-decorated multimetallic hetero-nanocages as highly efficient electrocatalysts toward the methanol oxidation reaction. AB - Direct methanol fuel cell technology awaits the development of highly efficient and robust nanocatalysts driving the methanol oxidation reaction (MOR) in a CO poisoning-free fashion. Thus far, various Pt-based alloy nanoparticles have been studied as electrocatalysts toward the MOR, and it has been found that the introduction of dopants such as Ru and Cu to Pt has been particularly successful in mitigating the CO poisoning problem. Herein, we report a facile synthesis of Ru-branched RuPtCu nanocages that involves in situ formation of Ru-doped PtCu nanoparticles and subsequent outgrowth of Ru branches by insertion of additional Ru precursors. We show that the electrocatalytic activity and stability of Ru branched RuPtCu ternary nanocages toward the MOR are greatly improved compared to those of PtCu/C and RuPtCu/C counterparts and state-of-the-art PtRu/C and Pt/C catalysts, mainly due to the synergy between the CO-tolerant RuOx phase and the highly open and robust RuPtCu nanoframe. PMID- 30417185 TI - Impact of radiation induced crystallization on programmable metallization cell electrical characteristics and reliability. AB - Chalcogenide-based, programmable metallization cells (PMC) cells have been characterized after exposure to increasing levels of absorbed dose (i.e., ionizing radiation exposure). We found, and show here for the first time, that total absorbed dose effects induce a slight modification of the switching phenomena with a moderate increase of the programmable low resistance state (LRS) of the PMCs after repeated switching depending on the processing conditions, while it does not impact the state programmed before exposure. We also show that an increase of the programmable high resistance state (HRS) occurs with irradiation. Such observations are discussed through correlation with crystallization observed in the concurrent X-ray diffraction (XRD) characterization of representative thin-film stacks of the PMCs. These new results are compared to previous results obtained on chalcogenide-based PMCs that did not identify/observe such effects. PMID- 30417186 TI - In-memory direct processing based on nanoscale perpendicular magnetic tunnel junctions. AB - Perpendicular magnetic tunnel junctions (p-MTJs) provide advantages such as infinite endurance, high thermal stability, and fast and low-power switching. They are considered as a promising non-volatile memory device to build non-von Neumann computing paradigms and definitively overcome the power bottleneck. Numerous design proposals have been made for p-MTJ logic, but a few physical realizations have been reported. In this paper, we present the experimental implementation of universal stateful logic gates such as "OR", "AND", and material implication ("IMP") by connecting two nanoscale p-MTJs in parallel. Owing to the voltage dependence of switching probability for the spin transfer torque mechanism, the same structure can be reconfigured to different logic gates with only electrical signals. One single-cycle operation is thus required for all the basic Boolean functions. Such in-memory direct processing has great potential to meet some key requirements such as a high energy/areal efficiency and high speed for future computing hardware. PMID- 30417187 TI - Colloidal lead iodide nanorings. AB - Colloidal chemistry of nanomaterials experienced a tremendous development in the last decades. In the course of the journey 0D nanoparticles, 1D nanowires, and 2D nanosheets have been synthesized. They have in common to possess a simple topology. We present a colloidal synthesis strategy for lead iodide nanorings, with a non-trivial topology. First, two-dimensional structures were synthesized in nonanoic acid as the sole solvent. Subsequently, they underwent an etching process in the presence of trioctylphosphine, which determines the size of the hole in the ring structure. We propose a mechanism for the formation of lead iodide nanosheets which also explains the etching of the two-dimensional structures starting from the inside, leading to nanorings. In addition, we demonstrate a possible application of the as-prepared nanorings in photodetectors. These devices are characterized by a fast response, high gain values, and a linear relation between photocurrent and incident light power intensity over a large range. The synthesis approach allows for inexpensive large scale production of nanorings with tunable properties. PMID- 30417188 TI - Photoactive metal-organic framework as a bifunctional material for 4-hydroxy-4' nitrobiphenyl detection and photodegradation of methylene blue. AB - Environmental pollution resulting from organic pollutants is becoming an overwhelming problem throughout the world, and how to efficiently detect or eliminate these organic pollutants remains an important issue for environmental protection. Herein, a cadmium(ii)-based MOF, Cd-TCAA, was successfully prepared by the hydrothermal reaction of 4,4',4''-tricarboxyltriphenylamine (H3tca), (E) 1,2-di(pyridin-4-yl)diazene (abp) and cadmium nitrate. Because the H3tca moiety is a typically versatile functional material that exhibits good hole-transporting capabilities, efficient light harvesting, and excellent electron-donating properties, this novel photoactive metal-organic framework operates as a bifunctional material for the detection and degradation of organic pollutants. It exhibits excellent selectivity and sensitivity towards 4-hydroxy-4'-nitrobiphenyl (HNBP) with a detection limit of 50 nM in solution, and represents the first example of a MOF-based sensor for the detection of HNBP. The photocatalytic activity of Cd-TCAA was also determined by investigating the photo-induced degradation of methylene blue (MB). Cd-TCAA has the advantages of excellent catalytic activity, stability, and recyclability. PMID- 30417189 TI - Evaluating rotation diffusion properties of molecules from short trajectories. AB - We show that under proper assumptions it is possible to estimate with good precision the principal values of the rotational diffusion tensor of proteins from the analysis of short (up to 2-3 ns) molecular dynamics trajectories. We apply this analysis to a few model cases: three polyalanine peptides (2, 5, and 10 aminoacids), the fragment B3 of protein G (GB3), the bovine pancreatic trypsin inhibitor (BPTI), the hen egg-white lysozyme (LYS), the B1 domain of plexin (PB1), and thrombin. The protocol is based on the analysis of the global angular momentum autocorrelation functions, complementing the standard approach based on rotational autocorrelation functions, which requires much longer trajectories. A comparison with values predicted by hydrodynamic modeling and available experimental data is presented. PMID- 30417190 TI - An innovative peptide with high affinity to GPC3 for hepatocellular carcinoma diagnosis. AB - Glypican-3 (GPC3) is a key biomarker for early diagnosis of human hepatocellular carcinoma (HCC) due to its overexpression in most HCC tumor tissues. Recently, peptides with high affinity to GPC3 have attracted more attention because of their high biocompatibility, non-immunogenicity, fast clearing and easy modification. Herein, we have designed an innovative GPC3 targeting peptide (sequence: DYEMHLWWGTEL, denoted as IPA) by using structure-based virtual simulation. The higher binding abilities of IPA over the reported peptide (YP) were displayed on different cell lines, showing a positive correlation with GPC3 expressions, which were further verified by the GPC3 protein binding assay. The GPC3 targeting specificity of IPA was proved by peptide blocking and siRNA experiment. The localized anchor of peptide IPA on the cell membranes of HepG2 and Huh-7 with GPC3 overexpression confirmed the GPC3 binding capacity. By connecting a near-infrared dye MPA, the in vivo identification ability of IPA to GPC3 was also demonstrated on GPC3-positive (HepG2) and GPC3-negative (U87) xenograft-bearing mice. These results indicated that the designed IPA presented desirable GPC3 targeting ability, showing promising prospects in detecting the expression of GPC3 for HCC targeting imaging. PMID- 30417191 TI - Edge morphology induced rectifier diode effect in C3N nanoribbon. AB - The two-dimensional material C3N has a honeycomb structure similar to graphene, but its heterogeneity of carbon and nitrogen elements makes it multifunctional. By performing a first-principles study, we find that edge morphology induces interesting electronic transport properties in step-like heterojunction devices composed of width-variable zigzag C3N nanoribbons. As long as the right part has an edge of all-carbon morphology, negative differential resistance and rectification effects will occur. If both edges are not of all-carbon morphology due to the presence of N atoms, a forward-conducting and reverse-blocking rectifier diode behavior will appear. These phenomena originate from the peculiar electronic structure of the zigzag C3N nanoribbons. The number of energy bands crossing the Fermi level gradually decreases from 2 to 0 as the number of all carbon edges decreases, realizing a transition from metal to semiconductor. The band gap determines the cut-off region at low bias and the presence of an interface barrier causes the cut-off state to continue under high reverse bias. Diverse edge morphologies, simple cutting methods and rich electronic transport properties make C3N materials competitive in nanodevice applications. PMID- 30417192 TI - Asymmetric nitrogen-rich energetic materials resulting from the combination of tetrazolyl, dinitromethyl and (1,2,4-oxadiazol-5-yl)nitroamino groups with furoxan. AB - Three classes of nitrogen-rich energetic compounds 7-9 (combination of tetrazolyl, dinitromethyl and furoxan), 12-17 (combination of tetrazolyl, (1,2,4 oxadiazol-5-yl)nitroamino and furoxan) and 20-22 (combination of dinitromethyl, (1,2,4-oxadiazol-5-yl)nitroamino and furoxan) were obtained by selected reactions with 3,4-dicyano-furoxan. All the new compounds were thoroughly characterized by IR, NMR [1H, 13C{1H}], elemental analysis, and differential scanning calorimetry (DSC). Compounds 7, 13, 20 and 22 were also further characterized with single crystal X-ray diffraction studies. Heats of formation and detonation performances for nine compounds were determined using Gaussian 03 and EXPLO5 v6.01 programs, showing that 15 as a secondary explosive is superior to 1,3,5 trinitrotriazacyclohexane (RDX) and 20 is a promising green primary explosive. PMID- 30417193 TI - Percolation limited emission intensity from upconverting NaYF4:Yb3+,Er3+ nanocrystals - a single nanocrystal optical study. AB - Upconverting nanocrystals (UCNC) have recently been subjected to intensive investigation due to their interesting optical properties and high potential for practical applications. Despite the level of attention paid to these materials, very low quantum yield is still an important issue. In order to break through this limitation, understanding of the emission intensity limitation is crucial. In this paper, we investigate the influence of percolation phenomena on the limitation of the emission intensity from NaYF4:Yb3+,Er3+ nanocrystals. We propose a numerical model and support this experimentally at the single nanocrystal level, explaining the influence of Yb3+ concentration on the optical properties of UCNC. Moreover, based on the experimental and numerical results, we explain the existence of the optimal Yb3+ concentration in the core architecture often reported in the literature. All the measurements have been performed using a custom-built wide-field fluorescence microscope to analyze the emission from hundreds of single nanocrystals and thus make analysis independent of UCNC concentration. PMID- 30417194 TI - Reversal of tumor malignization and modulation of cell behaviors through genome editing mediated by a multi-functional nanovector. AB - To effectively reverse tumor malignization by genome editing, a multi-functional self-assembled nanovector for the delivery of a genome editing plasmid specifically to tumor cells was developed. The nanovector core consisting of protamine and calcium carbonate entrapping the CRISPR-Cas9 plasmid is decorated by aptamer incorporated heparin. Owing to a high affinity between a MUC1 specific aptamer and mucin 1 (MUC1) overexpressed in tumor cells as well as the interaction between AS1411 and nucleolin on the tumor cell surface and cell nuclei, the nanovector can target the nuclei of tumorous cells for the knockout of focal adhesion kinase (FAK). Notably, the genome editing mediated by our delivery systems can effectively modulate cell behaviors and thus reverse tumor malignization. Up-regulated p53, p16, p21, E-cadherin, CD80, MICA, MICB and Fas, together with down-regulated MMP-9, vimentin, VEGF, TGF-beta, CD47 and CD133 in genome edited cells indicate that the genome editing system can inhibit cancerous cell growth, prevent tumor invasion and metastasis, reverse tumor-induced immune suppression, and inhibit cancer stemness. More importantly, the edited cells can maintain the modulated cellular function after succeeding subcultures. PMID- 30417195 TI - Thiol-ene click reaction-induced fluorescence enhancement by altering the radiative rate for assaying butyrylcholinesterase activity. AB - Butyrylcholinesterase (BChE) generally acts as an important plasma biomarker for clinical diagnosis due to its major contribution to human plasma cholinesterase levels, but its current fluorometric assay relying on fluorogenic substrates frequently suffers from the lack of sufficiently fast response time and specific recognition of substrates relative to the traditional Ellman's method. In this work, we report a fluorescent molecular probe for assaying BChE activity based on thiol-triggered fluorescence enhancement via thiol-ene click reactions. A low temperature experiment and theoretical analysis exclude the possibility of weak fluorescence of the probe caused by an intramolecular photoinduced electron transfer process and support the main cause of an ultraslow radiative rate due to the introduction of two acrylyl groups. This probe has sensitive fluorescence responses to thiols via thiol-ene click chemistry, and it can distinguish between glutathione and cysteine or homocysteine in different emission colors. The rapid reaction kinetics of this probe enables it to monitor hydrolysis reactions catalyzed by butyrylcholinesterase (BChE) in a real-time manner. This probe is used to develop the first fluorometric assay of BChE activity based on fluorescence enhancement triggered by thiol-ene click chemistry using butyrylthiocholine as the substrate. The established BChE assay shows excellent sensitivity, and is capable of avoiding the interference from glutathione and acetylcholinesterase (AChE) in a complex matrix. The inhibition test of tacrine on BChE with this assay substantiates its feasibility in screening potential inhibitors of BChE. This work demonstrates a design strategy of fluorescent probes lighted up by thiol-ene click reactions, reveals the main cause of thiol triggered fluorescence enhancement by altering the radiative rate, and provides the first fluorometric assay of BChE based on rapid thiol-ene click reactions. PMID- 30417196 TI - Conjugation of carboxymethyl cellulose and dopamine for cell sheet harvesting. AB - In this study, we investigated the feasibility of enzymatic digestion of polysaccharides for cell sheet harvesting. Cellulose was digested using cellulase; in brief, cellulose was pre-coated under a confluent cell layer, and then enzymatic digestion of cellulose under the confluent cell layer enabled cell detachment with minimal cell damage, yielding cell sheets. For the surface adhesion of the cellulose, carboxymethyl cellulose (CMC) molecules were conjugated with dopamine (DA), and the synthesized CMC-DA was pre-treated onto the surface of the culture plates. Then, human mesenchymal stem cells (hMSCs) or corneal limbal epithelial cells (hCLEs) were cultured on the pre-coated CMC-DA and harvested using cellulase containing cell culture medium. Single hMSCs treated with cellulase showed higher proliferative activity, showing an aggregated morphology compared with trypsin-treated hMSCs. Additionally, hMSC sheets were detached from the pre-coated CMC-DA surface 10 min after cellulase treatment. Also, hCLE sheets were generated with a well-preserved morphology and transparency after cellulase-assisted cell sheet generation. These results demonstrate that the strategy of CMC-DA coating combined with cellulase enzymatic harvesting is an effective option for harvesting cell sheets. PMID- 30417197 TI - Broadband polarization-insensitive saturable absorption of Fe2O3 nanoparticles. AB - The synthesis and functionalization of transition-metal oxides are one of the most active research areas in advanced materials. As a typical transition-metal oxide, iron oxide has been widely used in lithium-ion batteries, gas sensors, and for water treatment. Herein, we synthesized Fe2O3 nanoparticles by a co precipitation method that is inexpensive and non-toxic. The Fe2O3 nanoparticles exhibited broadband saturable absorption. Furthermore, thin Fe2O3 polyvinyl alcohol films were prepared to realize Q-switched operations in a ytterbium-doped fibre laser, an erbium-doped fibre laser, and a thulium-doped fibre laser. Attributed to the polarization-insensitive feature of the saturable absorber, Q switched cylindrical vector beams were also generated based on mode coupling and selection in two-mode fibre lasers. Such Fe2O3 nanoparticles show great promise for use in Q-switching applications of infrared fibre lasers and cylindrical vector lasers. PMID- 30417198 TI - Ferret badger rabies in Zhejiang, Jiangxi and Taiwan, China. AB - Ferret badger (FB, Melogale moschata) rabies is an increasing public health threat to humans, with FBs being a major reservoir and vector of rabies in China. Based on 152 published nucleotide sequences of the FB rabies virus (RABV) nucleoprotein, phylogenetic analysis revealed them to be clustered into six FB related lineages, FB-I to FB-VI. The genetic features of members of lineage FB-VI suggest that cross-species transmission occurs between FBs and dogs. Here, we describe the phylogenetic relationships between FB-RABVs, their geographic segregation, and their evolutionary dynamics in epizootic regions. PMID- 30417199 TI - Bovine papillomavirus 24: a novel member of the genus Xipapillomavirus detected in the Amazon region. AB - Bovine papillomaviruses (BPVs) have been described as etiologic agents of cutaneous and mucosal papillomas in cattle. In the present study, we describe a new BPV that was detected in a cutaneous papilloma from a cow. Phylogenetic analysis suggests that this virus belong to the genus Xipapillomavirus, and we refer to it here as BPV type 24 (BPV24). Coinfection with members of the genera Epsilonpapillomavirus and Deltapapillomavirus in a cutaneous papilloma from a different animal was also detected, and the full genomes of these viruses were sequenced. Both papillomas were from cattle within Acre State in the Amazon region of Brazil. The data presented here demonstrate the utility of using high throughput methods to indentify coinfections and allow the characterization of new genomes. PMID- 30417200 TI - Analysis of fitness differences of hepatitis B virus genotypes D and F using a cotransfection assay. AB - Hepatitis B virus (HBV) circulates as a collection of genetically related variants that evolve throughout the chronic infection. Those viral variants that have the greatest fitness are fixed. We recently showed different fitness for HBV variants involved in two epidemiological situations. To understand these fitness differences better, we determined the levels of extracellular HBV DNA, the synthesis of HBV DNA intermediates, and the expression of HBeAg and HBsAg in transfection and cotransfection assays. Our results show that for the subgenotype (sgt) D1, which has an 8-nucleotide deletion (sgtD1del) and exhibits lower fitness, the levels of extracellular DNA and intracellular replicative intermediates were much lower than with sgtD1wt or sgtD1mut (G1896A), which had higher fitness. In addition, in the cotransfection assay, sgtD1del inhibited sgtD1mut but not sgtD1wt replication. We also found that sgtF1b, which exhibits higher fitness, produces significantly higher levels of both extracellular DNA and intracellular replicative intermediates than does the lower-fitness sgtF4. These results demonstrate a relationship between fitness and the replicative ability of the HBV genome in the transfection assay. In addition, the data obtained by cotransfecting cells with sgtD1del and sgtD1mut provide new information about the impact of simultaneous replication of two viral variants in the same cell system on HBV replication. PMID- 30417201 TI - To what extent does the air flow initialisation of the ENVI-met model affect human heat stress simulated in a common street canyon? AB - This study concerns the effects of the air flow initialisation of the ENVI-met model on simulated human heat stress in a fictive E-W street canyon with different aspect ratios that is typical of Central European cities. Human heat stress is described by near-surface air temperature (Ta), mean radiant temperature (Tmrt) and physiologically equivalent temperature (PET). The numerical simulations, which are performed for a Central European heat wave day in order to consider the increase of severe heat due to regional climate change, are based on the version 4.0 BETA of ENVI-met. The simulation results in terms of grid-related Ta, Tmrt and PET values as well as mean values for both sidewalks of the street canyon are averaged over the period 10-16 CET, because they should be representative of outdoor human heat stress in Central European cities. The simulation results point to the significance of the type of inflow direction in relation to the orientation of the street canyon, i.e. whether it is flowed parallel or across. The type of inflow direction determines the modification of the inflow speed within the street canyon. Due to its physical basis, mean Tmrt does not show a noticeable impact by the inflow conditions. They also influence mean Ta relatively low. However, PET is much more affected by the inflow conditions as it depends on the local wind speed. This impact can reach the magnitude of thermal grassland effects within urban quarters, i.e. it cannot be ignored under a human-biometeorological perspective. PMID- 30417202 TI - Minimally invasive anterior cervical discectomy and fusion: a valid alternative to open techniques. AB - BACKGROUND: Anterior cervical discectomy and fusion (ACDF) is a well-standardized treatment for cervical myelopathy/radiculopathy. The aim of this study is to assess the feasibility of minimally invasive ACDF. METHOD: Retrospective review of six patients who underwent minimally invasive ACDF using microscope and tubular retractors. Clinical and radiological outcomes and surgical complications were reviewed. CONCLUSION: Minimally invasive microscopic ACDF through tubular retractors is a feasible option and therefore an alternative to conventional open procedures. However, it does require advanced technical skills and good understanding of the MIS principles and limitations of the technique. PMID- 30417203 TI - How I do it: percutaneous transforaminal endoscopic discectomy for lumbar disk herniation. AB - BACKGROUND: Percutaneous transforaminal endoscopic discectomy (PTED) has emerged as a less invasive technique to treat symptomatic lumbar disk herniation (LDH). PTED is performed under local anesthesia with the advantage of immediate intraoperative feedback of the patient. In this paper, the technique is described as conducted in our hospital. METHODS: PTED is performed under local anesthesia in prone position on thoracopelvic supports. The procedure is explained stepwise: e.g. marking, incision, introduction of the 18-gauge needle and guidewire to the superior articular process, introduction of the TomShidi needle and foraminotomy up to 9 mm, with subsequently removal of disk material through the endoscope. Scar size is around 8 mm. CONCLUSION: PTED seems a promising alternative to conventional discectomy in patients with LDH and can be performed safely. PMID- 30417204 TI - Insectivorous Birds Are Attracted by Plant Traits Induced by Insect Egg Deposition. AB - Insectivorous birds feed upon all developmental stages of herbivorous insects, including insect eggs if larvae and adults are unavailable. Insect egg deposition on plants can induce plant traits that are subsequently exploited by egg parasitoids searching for hosts. However, it is unknown whether avian predators can also use egg-induced plant changes for prey localization. Here, we studied whether great tits (Parus major) and blue tits (Cyanistes caeruleus) are attracted by traits of the Scots pine (Pinus sylvestris) induced by pine sawfly (Diprion pini) egg deposition. We chose this plant - insect system because sawfly egg deposition on pine needles is known to locally and systemically induce a change in pine volatile organic compounds (VOCs), and tits are known to prey upon sawfly eggs. In dual choice laboratory experiments, we simultaneously offered the birds an egg-free control branch and a systemically egg-induced branch. Significantly more birds visited the egg-induced branch first. We confirmed by GC MS analyses that systemically egg-induced branches released more (E)-beta farnesene compared to control branches. Spectrophotometric analyses showed that control branches reflected more light than egg-induced branches throughout the avian visual range. Although a discrimination threshold model for blue tits suggests that the birds are poor at discriminating this visual difference, the role of visual stimuli in attracting the birds to egg-induced pines cannot be discounted. Our study shows, for the first time, that egg-induced odorous and/or visual plant traits can help birds to locate insect eggs without smelling or seeing those eggs. PMID- 30417205 TI - Communication changes with laryngectomy and impact on quality of life: a review. AB - PURPOSE: Patients with throat cancer at later stages often undergo total laryngectomy, a procedure that removes the larynx (voice box) and directly impacts the patient's ability to produce natural voice and communication. This narrative review aimed to explore how changes to communication following laryngectomy may impact quality of life (QoL) for patients. METHODS: Literature searches were conducted using CINAHL, MEDLINE and PsychInfo databases for studies published between 2007 and 2018. The search terms (and derivatives) of laryngectomy AND communication AND quality of life were used. A synthesis and appraisal of the studies was conducted. RESULTS: Twelve studies met the inclusion criteria and were included in this review. The two main themes identified relating to changes in communication and impact on QoL were changes in communication competency (immediate changes and communication option used) and adaptation to change (e.g. self-related factors and relationships with others). Regardless of the type of communication option used, participants in all studies reported negative changes in their communication competency and QoL post laryngectomy. Voice-related factors and aesthetics of the communication option used were noted to influence self-ratings of QoL for the participants, rather than how well others understood them. Participants using tracheoesophageal speech (TES) consistently showed the highest self-reported QoL across the majority of studies. A model incorporating the findings from this review has been proposed which outlines how changes in communication post-laryngectomy may lead to an impact on QoL. Here, the factors of changes in communication competency, self perception and social engagement impact each other and are also influenced by adaptation to change. CONCLUSION: This review has highlighted the complex nature of changes faced by patients following laryngectomy in relation to communication and QoL. The model linking communication changes to QoL may become a useful tool for researchers and clinicians in supporting the management of patients post laryngectomy. PMID- 30417206 TI - Does the ICECAP-O cover the physical, mental and social functioning of older people in the UK? AB - PURPOSE: The ICEpop CAPability measure for Older people (ICECAP-O) is intended for use in economic evaluations of care services for older people. Although studies support the validity of the ICECAP-O, it does not directly ask older people about their health. This raises questions about its ability to capture health indirectly. Previous studies found mixed results in this aspect, especially for physical health. This study further investigates whether the ICECAP-O indirectly includes health. METHODS: Using a cross-sectional design, a sampling agency retrieved data from 516 people aged 70 and older from the UK through an online questionnaire. The overlap in underlying constructs of the ICECAP-O and EQ-5D-5L was assessed using exploratory factor analysis. Spearman correlations and variance analysis were conducted by relating the ICECAP-O to measures of physical, mental and social functioning. RESULTS: The ICECAP-O and EQ 5D-5L items loaded on two factors. Their overlap was limited, as four out of five EQ-5D-5L items loaded on the first factor, while four out of five ICECAP-O items loaded on the second. The ICECAP-O correlated highly with (mental and social functioning) health measures, and was able to differentiate between individuals with different scores on these measures. However, the correlation with the Barthel Index, a measure of physical functioning, was moderate. CONCLUSIONS: The ICECAP-O may not fully cover all aspects of health. Therefore, a complementary health measure should be used in addition to the ICECAP-O to capture the full benefits of care interventions for older people in economic evaluations. PMID- 30417207 TI - Leptin is a direct transcriptional target of EGR1 in human breast cancer cells. AB - Leptin is a cytokine that regulates energy metabolism. Leptin can promote breast cancer progression in obese women. However, the mechanism of regulation of leptin expression in breast cancer cells is unclear. Tumor necrosis factor-alpha (TNF alpha) stimulated the transcription of the leptin gene. Using mutant promoter constructs, we demonstrated that the EGR1-binding motif in the proximal region of the leptin gene is required for leptin transcription by TNF-alpha. Forced expression of EGR1 stimulated leptin promoter activity, whereas silencing of EGR1 by RNA interference reduced TNF-alpha-induced leptin protein accumulation. The ERK1/2 pathway contributed to the expression of EGR1 and leptin by TNF-alpha. Our results suggest that EGR1 targets the leptin gene in response to TNF-alpha stimulation in breast cancer cells. PMID- 30417208 TI - Risk factors of postoperative valgus malalignment in mobile-bearing medial unicompartmental knee arthroplasty. AB - OBJECTIVE: The aim of this observational study was to investigate the risk factors of postoperative valgus malalignment after mobile-bearing medial unicompartmental knee arthroplasty (UKA). METHODS: We retrospectively evaluated radiographic and surgical characteristics in 122 consecutive Oxford phase 3 UKAs. According to postoperative hip-knee-ankle angle (HKAA), 24 knees were sorted into group valgus with HKAA > 180 degrees and 98 knees were sorted into group non valgus with HKAA <= 180 degrees . Logistic regression was performed to analyze risk factors including age, gender, BMI, side, preoperative limb alignment HKAA, preoperative LDFA, MPTA, FTFA, thickness of polyethylene bearing insert, tibial prothesis size, femoral prothesis size, medial tibial cut thickness, thickness of distal femoral mill, prothesis angle of coronal, and sagittal plane. RESULTS: The mean mechanical preoperative HKAA of 174.39 degrees +/-4.23 degrees was corrected to 178.18 degrees +/-3.49 degrees postoperatively (t = - 13.45, p = 0.000). The mean of postoperative HKAA in valgus group and non-valgus group was 183.45 +/- 2.21 degrees and 176.88 +/- 2.35 degrees , respectively (t = 12.44, p = 0.000). After statistical analysis with univariate analysis, eight risk factor variables among 16 independent variables were identified as potential predictors with p value <= 0.1. Multivariate logistic regression analysis for these eight potential predictors revealed that tibial cut (p = 0.046), LDFA (p = 0.003), MPTA (p = 0.011), and FTFA (p = 0.008) were significant risk factors predicting postoperative valgus malalignment after mobile-bearing UKA. CONCLUSIONS: Preoperative smaller LDFA, FTFA, larger MPTA and less medial tibial cut thickness were significantly associated with postoperative valgus malalignment in mobile bearing UKA. PMID- 30417209 TI - Attrition of rotator cuff without progression to tears during 2-5 years of conservative treatment for impingement syndrome. AB - PURPOSE: The purpose of this study was to investigate the natural history of intact rotator cuff in impingement syndrome patients with concomitant spur protruding from the undersurface of acromion. METHODS: This retrospective study included 119 patients with an intact rotator cuff who underwent conservative treatment for a spur protruding from the undersurface of the acromion. The protruded spur was defined as a trapezoid- or tetragon-shaped bony protrusion with a downward peak extending more than 3 mm in length from the baseline drawn along the acromial undersurface on the coronal view of magnetic resonance imaging (MRI) or computed tomography arthrography (CTA). Functional outcomes were evaluated by the visual analogue scale for pain, subjective shoulder value, American Shoulder and Elbow Surgeons score, University of California Los Angeles shoulder score, and active range of motion (ROM). To evaluate cuff integrity, follow-up MRI, CTA, or ultrasound were performed at least 2 years after the initial presentation. RESULTS: No new rotator cuff tears were noted in any patient during the follow-up imaging studies. However, 18 patients (15%) underwent arthroscopic acromioplasty during the study period. During the arthroscopic examinations, moderate to severe attrition of the cuff was identified, although no tears were seen. At the final follow-up, pain level and shoulder function, including ROM, showed satisfactory outcomes. CONCLUSION: Spurs protruding from the acromial undersurface did not lead to rotator cuff tears during 2-5 years of conservative treatment. However, attrition of the rotator cuff was found during arthroscopic acromioplasty, suggesting that the protruding spurs caused extrinsic impingement of the cuff. LEVEL OF EVIDENCE: Therapeutic case series Level IV. PMID- 30417210 TI - Early intraventricular baclofen therapy (IVB) for children with dystonic and dysautonomic storm. AB - INTRODUCTION: Intrathecal baclofen (ITB) is an effective treatment for managing primary and secondary dystonia. Intraventricular baclofen (IVB) was first developed to allow treating patients in which the use of ITB was difficult due to anatomic anomalies. After that, several studies indicate that intraventricular administration of baclofen, is more effective than ITB in refractory dystonia. CLINICAL MATERIAL: We report three cases of children with acute dystonic and dysautonomic storm, treated with IVB. The clinical outcome was satisfactory. The response to the treatment continued after the pump disconnection, suggesting that in this kind of cerebral dysregulations, short-term IVB is an effective treatment. CONCLUSION: Early treatment with IVB may be an effective option in patients with post-anoxic dysautonomic and dystonic storm. PMID- 30417211 TI - Nimotuzumab-containing regimen for pediatric diffuse intrinsic pontine gliomas: a retrospective multicenter study and review of the literature. AB - PURPOSE: Nimotuzumab is an IgG1 antibody that targets epidermal growth factor receptor (EGFR). Overexpression of EGFR is detected in some pediatric brain tumors including diffuse intrinsic pontine gliomas (DIPG)s. METHODS: Since May 2010, nimotuzumab, combined with carboplatin or vinorelbine or Temozolomide (TMZ), was administered during progressive disease (PD) after the use of the institutional protocol consisting of radiotherapy (RT) + TMZ and adjuvant TMZ. After May 2012, children with newly diagnosed disease received TMZ during RT, and nimotuzumab and TMZ after RT. Nimotuzumab was given as 150 mg/m2/dose once a week for 12 weeks, and then every other week with TMZ until PD. PD patients were switched to nimotuzumab + vinorelbine combination until death. RESULTS: Nimotuzumab was used in 24 children with DIPG (seven in the PD group, 17 in the newly diagnosed patient group). In the PD group, median survival time was 12 months (7-42 months); 1-year and 2-year overall survival (OS) rates were 42.9 +/- 18% and 14.3 +/- 13%, respectively. The median survival in this group, after the initiation of nimotuzumab was 6 months (3-8 months). In the newly diagnosed patient group, median survival time was 11 months (3-35 months) and median progression free survival was 4 months (1-21 months). The 1-year OS in this group was 35.3 +/- 11% and 2 year OS was 11.8 +/- 7%. Nimotuzumab +/- chemotherapy was well tolerated with no major adverse effect. CONCLUSION: Nimotuzumab-containing regimens are feasible and tolerable; it might be that some patients either with newly diagnosed DIPG or with progressive disease may benefit modestly from nimotuzumab-containing combinations. PMID- 30417213 TI - Quantitative evaluation of diffusion tensor imaging for clinical management of glioma. AB - Diffusion tensor imaging (DTI), assessing physiological motion of water in vivo, provides macroscopic view of microstructures of white matter in the central nervous system, and such imaging technique had been extensively used for the clinical treatment and research of glioma. This review mainly focuses on illuminating the merits of quantitative evaluation of DTI for glioma management. The content of the article includes DTI's application on tissue characterization, white matter tracts mapping, radiotherapy delineation, post-therapy outcome assessment, and multimodal imaging. At last, we elucidate a synoptic presentation of DTI limitation, which is critical for physicians making DTI-based clinical decisions in glioma management. PMID- 30417212 TI - A new colorimetric method for rapid detection of ethambutol and streptomycin resistance in Mycobacterium tuberculosis: crystal violet decolorization assay (CVDA). AB - Streptomycin (STR) and ethambutol (EMB) are important drugs used for the treatment of tuberculosis. There is a need for fast, reliable and inexpensive methods for detecting resistance to these drugs. The aim of this study was to evaluate the performance of the crystal violet decolorization assay (CVDA) for the detection of STR and EMB resistance that is important drugs in tuberculosis treatment. In this study, drug susceptibility testing was performed on 140 Mycobacterium tuberculosis isolates provided from nine centers. Three tubes were used for each isolate. One of the tubes had a concentration of 2 mg/L STR and the other 5 mg/L EMB. The third was drug-free control tube. Sensitivity, specificity, positive predictive value (PPD), negative predictive value (NPD) and agreement for STR were found to be 81.8%, 94.6%, 87.8%, 91.5% and 90.57%, respectively. For EMB, sensitivity, specificity, PPD, NPD, and agreement were found to be 76%, 98.23%, 90.47%, 94.87% and 94.2%, respectively. The results were obtained in 11.3 +/- 2.7 days (8-21 days). CVDA is rapid, reliable, inexpensive, and easy to perform for rapid detection of STR and EMB resistance, and it could be adapted for drug susceptibility testing. PMID- 30417214 TI - Treatment of a broncho-esophageal fistula complicated by severe ARDS. AB - INTRODUCTION: Broncho-esophageal fistula formation is a rare complication of tuberculosis, most often seen in immunocompromised patients. METHODS AND RESULTS: In this paper, we report the case of a young non-immunocompromised refugee from Somalia diagnosed with open pulmonary tuberculosis complicated by extensive osseous involvement and a broncho-esophageal fistula with consecutive aspiration of gastric contents. The patient rapidly developed a severe acute respiratory distress syndrome (ARDS) requiring venovenous extracorporeal membrane oxygenation (ECMO) therapy for nearly 2 months. The fistula was initially treated by standard antituberculous combination therapy and implantation of an esophageal and a bronchial stent. Long-term antibiotic treatment was instituted for pneumonia and mediastinitis. 7 months later, discontinuity resection of the esophagus was performed and the bronchial fistula covered by an intercostal muscle flap. DISCUSSION: This case illustrates that tuberculosis should always be suspected in patients from high-incidence countries in case of lung involvement and that an interdisciplinary approach including long-term intensive care management can enable successful treatment of tuberculosis with severe, near-fatal complications. PMID- 30417215 TI - Real-Time Antimicrobial Susceptibility Assay of Planktonic and Biofilm Bacteria by Isothermal Microcalorimetry. AB - Most antimicrobials currently used in the clinical practice are tested as growth inhibitors against free-floating microorganisms in a liquid suspension, rather than against sessile cells constituting biofilms. Hence, reliable, fast, and reproducible methods for assessing biofilm susceptibility to antimicrobials are strongly needed. Isothermal microcalorimetry (IMC) is a nondestructive sensitive technique that allows for the real-time monitoring of microbial viability in the presence or absence of antimicrobial compounds. Therefore, the efficacy of specific antimicrobials, alone or in combination, may be promptly validated supporting the development of new drugs and avoiding the administration of ineffective therapies. Furthermore, the susceptibility of both planktonic and biofilm cells to antimicrobials can be conveniently assessed without the need for elaborated staining procedures and under nontoxic working conditions. Quantitative data regarding the antimicrobial effect against different strains might be collected by monitoring the microbial cell replication, and, more importantly, a dose-dependent activity can be efficiently detected by measuring the delay and decrease in the heat flow peak of the treated samples. A limitation of IMC for anti-biofilm susceptibility test is the inability to directly quantify the non-replicating cells in the biofilm or the total biomass. However, as IMC is a nondestructive method, the samples can be also analyzed by using different techniques, acquiring more information complementary to calorimetric data. IMC finds application also for the investigation of antibiotic eluting kinetics from different biomaterials, as well as for studying bacteriophages activity against planktonic and biofilm bacteria. Thus, the wide applicability of this ultra sensitive and automated technique provides a further advance in the field of clinical microbiology and biomedical sciences. PMID- 30417216 TI - Characterization of purinergic receptor expression in ARPKD cystic epithelia. AB - Polycystic kidney diseases (PKDs) are a group of inherited nephropathies marked by formation of fluid-filled cysts along the nephron. Growing evidence suggests that in the kidney formation of cysts and alteration of cystic electrolyte transport are associated with purinergic signaling. PCK/CrljCrl-Pkhd1pck/CRL (PCK) rat, an established model of autosomal recessive polycystic kidney disease (ARPKD), was used here to test this hypothesis. Cystic fluid of PCK rats and their cortical tissues exhibited significantly higher levels of ATP compared to Sprague Dawley rat kidney cortical interstitium as assessed by highly sensitive ATP enzymatic biosensors. Confocal calcium imaging of the freshly isolated cystic monolayers revealed a stronger response to ATP in a higher range of concentrations (above 100 MUM). The removal of extracellular calcium results in the profound reduction of the ATP evoked transient, which suggests calcium entry into the cyst-lining cells is occurring via the extracellular (ionotropic) P2X channels. Further use of pharmacological agents (alpha,beta-methylene-ATP, 5 BDBD, NF449, isoPPADS, AZ10606120) and immunofluorescent labeling of isolated cystic epithelia allowed us to narrow down potential candidate receptors. In conclusion, our ex vivo study provides direct evidence that the profile of P2 receptors is shifted in ARPKD cystic epithelia in an age-related manner towards prevalence of P2X4 and/or P2X7 receptors, which opens new avenues for the treatment of this disease. PMID- 30417217 TI - Multidimensional communication of microRNAs and long non-coding RNAs in lung cancer. AB - PURPOSE: Non-coding RNAs (ncRNAs) have been a hot topic for many years in the field of cancer research, especially miRNAs and lncRNAs. Because they play critical roles in regulating various cellular processes and are more often involved in tumorigenesis than protein-coding genes. But the cross talk between miRNAs and lncRNAs in cancer has been scarcely studied. This article aims to provide a retrospective review of the latest research on the link between miRNAs and lncRNAs in lung cancer and discusses their potential role as diagnostic biomarkers and therapeutic targets for lung cancer in clinical practice. METHODS: We reviewed literatures about ncRNAs and lung cancer from PUBMED databases in this article. RESULTS: As shown in our review, miRNAs and lncRNAs could represent underlying targets for diagnosis, therapy, prognosis, and drug resistence of lung cancer. By acting as ceRNAs, lncRNAs can competitively inhibit the expression levels of miRNAs, and the lncRNA/miRNA axis can contribute to tumorigenesis, metastasis, and mutidrug resistance in lung cancer via various classic signaling pathways or related proteins. CONCLUSION: Based on present knowledge, ncRNAs may provide a novel perspective to understand the pathogenesis of lung cancer and could be candidates in screening of therapeutic targets for lung cancer. PMID- 30417218 TI - Safety of pioglitazone during and after radiation therapy in patients with brain tumors: a phase I clinical trial. AB - INTRODUCTION: Radiation-induced cognitive decline (RICD) is a late effect of radiotherapy (RT) occurring in 30-50% of irradiated brain tumor survivors. In preclinical models, pioglitazone prevents RICD but there are little safety data on its use in non-diabetic patients. We conducted a dose-escalation trial to determine the safety of pioglitazone taken during and after brain irradiation. METHODS: We enrolled patients > 18 years old with primary or metastatic brain tumors slated to receive at least 10 treatments of RT (<= 3 Gy per fraction). We evaluated the safety of pioglitazone at 22.5 mg and 45 mg with a dose-escalation phase and dose-expansion phase. Pioglitazone was taken daily during RT and for 6 months after. RESULTS: 18 patients with a mean age of 54 were enrolled between 2010 and 2014. 14 patients had metastatic brain tumors and were treated with whole brain RT. Four patients had primary brain tumors and received partial brain RT and concurrent chemotherapy. No DLTs were identified. In the dose-escalation phase, there were only three instances of grade >= 3 toxicity: one instance of neuropathy in a patient receiving 22.5 mg, one instance of fatigue in a patient receiving 22.5 mg and one instance of dizziness in a patient receiving 45 mg. The attribution in each of these cases was considered "possible." In the dose expansion phase, nine patients received 45 mg and there was only one grade 3 toxicity (fatigue) possibly attributable to pioglitazone. CONCLUSION: Pioglitazone was well tolerated by brain tumor patients undergoing RT. 45 mg is a safe dose to use in future efficacy trials. PMID- 30417220 TI - Association between physical activity and sub-types of cardiovascular disease death causes in a general population cohort. AB - Physical activity is thought to be cardioprotective, but associations with different subtypes of cardiovascular disease (CVD) are poorly understood. We examined associations between physical activity and seven major CVD death causes. The sample comprised 65,093 adults (aged 58 +/- 12 years, 45.4% men) followed up over mean [SD] 9.4 +/- 4.5 years, recruited from The Health Survey for England and the Scottish Health Surveys. A CVD diagnosis was reported in 9.2% of the sample at baseline. Physical activity was self-reported. Outcomes were subtypes of CVD death; acute myocardial infarction; chronic ischaemic heart disease; pulmonary heart disease; a composite of cardiac arrest, arrhythmias, and sudden cardiac death; heart failure; cerebrovascular; composite of aortic aneurysm and other peripheral vascular diseases. There were 3050 CVD deaths (30.8% of all deaths). In Cox proportional hazards models adjusted for confounders, physical activity was associated with reduced relative risk of all CVD outcomes; compared with the lowest, the highest physical activity quintile was associated with reduced risk of acute myocardial infarction (Hazard ratio 0.66: 95% CI 0.50, 0.89), chronic ischaemic heart disease (0.49: 0.38, 0.64), pulmonary heart disease (0.48: 0.22, 1.07), arrhythmias (0.18: 0.04, 0.76); heart failure (0.35: 0.20, 0.63), cerebrovascular events (0.53: 0.38, 0.75); aneurysm and peripheral vascular diseases (0.54: 0.34, 0.93). Results were largely consistent across participants with and without existing CVD at baseline. Physical activity was associated with reduced risk of seven major CVD death causes. Protective benefits were apparent even at levels of activity below the current recommendations. PMID- 30417219 TI - Combined immunomagnetic capture coupled with ultrasensitive plasmonic detection of circulating tumor cells in blood. AB - We demonstrate enhanced on-chip circulating tumor cell (CTC) detection through the incorporation of plasmonic-enhanced near-infrared (NIR) fluorescence screening. Specifically, the performance of plasmonic gold coated chips was evaluated on our previously reported immunomagnetic CTC capture system and compared to the performance of a regular chip. Three main performance metrics were evaluated: capture efficiency, capture reproducibility, and clinical efficacy. Use of the plasmonic chip to capture SK-BR-3 cells in PBS, resulted in a capture efficiency of 82%, compared to 76% with a regular chip. Both chips showed excellent capture reproducibility for all three cells lines evaluated (MCF 7, SK-BR-3, Colo 205) in both PBS and peripheral blood, with R2 values ranging from 0.983 to 0.996. Finally, performance of the plasmonic chip was evaluated on thirteen peripheral blood samples in patients with both breast and prostate cancer. The regular chip detected 2-8 cells per 5 mL of blood, while the plasmonic chip detected 8-85 cells per 5 mL of blood in parallel samples. In summary, we successfully demonstrate improved CTC capture and detection capabilities through use of plasmonic-enhanced near-infrared (NIR) fluorescence screening in both in vitro and ex vivo experiments. This work not only has the potential to improve clinical outcomes though improved CTC analysis, but also demonstrates successful interface design between plasmonic materials and cell capture for bioanalytical applications. PMID- 30417221 TI - Ligating the pulmonary vein at the pericardial reflection is useful for preventing thrombus formation in the pulmonary vein stump after left upper lobectomy. AB - OBJECTIVES: Thrombus formation in the pulmonary vein stump after left upper lobectomy is supposedly a risk factor for systemic thrombosis, resulting in a critical course for the patient. The purpose of this study was to assess the efficacy of the proximal ligation method preventing thrombus formation and thrombosis comparing the two groups of patients (those who did and those who did not undergo pulmonary vein ligation). METHODS: We performed a surgical procedure to shorten the pulmonary vein stump in the left upper lobectomy. In this procedure, we first dissected the pericardium from the left upper pulmonary vein, and then we ligated the pulmonary vein at the pericardial reflection before stapling transection. RESULTS: In the group that was not treated with the proximal ligation method, thrombus formation in the pulmonary vein stump was detected in all four cases. In contrast, thrombus formation in the pulmonary vein stump was detected in one only case of the eight cases treated with the proximal ligation method, which was significantly fewer than among those not treated with the ligation method (p = 0.010). The logistic regression analysis revealed in both the univariate (p = 0.0014) and multivariate analyses (p = 0.0071) that the proximal ligation method was significantly associated with reduced thrombus formation in the pulmonary vein stump. CONCLUSIONS: Thrombus formation in the pulmonary vein stump was significantly reduced by ligating the pulmonary vein at the pericardial reflection. PMID- 30417222 TI - Experimental Testing of Dispersal Limitation in Soil Bacterial Communities with a Propagule Addition Approach. AB - The role of dispersal in the assembly of microbial communities remains contentious. This study tested the importance of dispersal limitation for the structuring of local soil bacterial communities using an experimental approach of propagule addition. Microbes extracted from soil pooled from samples collected at 20 localities across ~ 400 km in a temperate steppe were added to microcosms of local soils at three sites; the microcosms were then incubated in situ for 3 months. We then assessed the composition and diversity of bacterial taxa in the soils using 16S rRNA gene amplicon sequencing. The addition of the regional microbial pool did not cause significant changes in the overall composition or diversity of the total bacterial community, although a very small number of individual taxa may have been affected by the addition treatment. Our results suggest a negligible role of dispersal limitation in structuring soil bacterial communities in our study area. PMID- 30417223 TI - Validation of a new symptom outcome for knee osteoarthritis: the Ambulation Adjusted Score for Knee pain. AB - OBJECTIVE: Validation of a symptom measure for early knee OA may help identify new treatments and modifiable risk factors. Symptom measures that consider pain in the context of activity level may provide better discrimination than pain alone. Therefore, we aimed to compare sensitivity to change for radiographic progression between Ambulation Adjusted Score for Knee pain (AASK), which accounts for self-reported ambulation, and Western Ontario McMaster Osteoarthritis (WOMAC) knee pain score. DESIGN: Participants were assessed annually up to 48 months using WOMAC, Physical Activity Scale for the Elderly (PASE) ambulation, and knee radiographs. AASK was defined as ((WOMAC pain) + 1)/((average daily hours of walking) + 1). Radiographs were scored for Kellgren Lawrence (KL) grade. Linear regression, stratified by OA status, evaluated relationships between changes in AASK and WOMAC pain and KL grade over time. RESULTS: For 4191 people (8030 knees), the mean age was 61.2 (+ 9.2) years old and BMI was 28.6 (+ 4.8) kg/m2; 58% female. Over 40% of knees had WOMAC pain scores of 0; by design, no knees had AASK scores of 0. Annual changes in AASK were more sensitive to changes in KL than changes in WOMAC in those without baseline OA (0.20 and 0.16 change per unit KL change, p = 0.005 and 0.070 respectively), but performed similarly in knees with OA. CONCLUSION: AASK is simple to assess using existing validated questionnaires. AASK performs well in individuals with and without OA and should be considered in clinical trials and observational studies of early knee OA. PMID- 30417224 TI - Correction to: Gene activation in human cells using CRISPR/Cpf1-p300 and CRISPR/Cpf1-SunTag systems. AB - In the original publication the Supplementary Material and Fig. 2 are incorrect. The correct version is provided in this correction article. The text HBG2 appearing in the article should be read as HBG1. PMID- 30417225 TI - Influence of treatment duration on the efficacy of at-home bleaching with daytime application: a randomized clinical trial. AB - OBJECTIVE: The aim of this study is to determine whether prolonging the daytime at-home bleaching treatment by 1 week increases the bleaching effect without causing more side effects. MATERIALS AND METHODS: Fifty participants were randomly divided into two groups, (A) with a 14-day treatment and (B) with a 21 day treatment. A gel with 10% carbamide peroxide was applied for 2 h a day in custom trays. Color measurement was performed using a dental spectrophotometer on the right maxillary central incisor and the canine at baseline, at the end of treatment, and 1 and 6 months afterwards. Daily, participants recorded their tooth sensitivity and gingival irritation. RESULTS: At the end of the treatment, the DeltaE00 of group B (5.77 +/- 2.15) was significantly higher than the DeltaE00 of group A (4.74 +/- 1.94) (p = 0.005 (95% CI: - 2.13 to - 0.39)). After 6 months, tooth color was more stable in group B. The DeltaSGU values between the different appointment times were higher in the 3-week group. Participants from group B reported more side effects, but statistically, there were no differences compared with group A (p = 0.225 for tooth sensitivity and p = 0.758 for gingival irritation). CONCLUSIONS: Daytime application of at-home bleaching for 3 weeks achieves greater bleaching results than for 2 weeks, immediately after treatment and 1 and 6 months afterwards. However, slightly more side effects could occur. CLINICAL RELEVANCE: When daytime application of at-home bleaching is required, the treatment duration should be prolonged from 2 to 3 weeks to achieve greater and more stable results. PMID- 30417226 TI - Micro-CT comparison of XP-endo Finisher and passive ultrasonic irrigation as final irrigation protocols on the removal of accumulated hard-tissue debris from oval shaped-canals. AB - OBJECTIVE: To compare the effectiveness of the XP-endo Finisher instrument and passive ultrasonic irrigation (PUI) as final irrigation protocols on the removal of accumulated hard-tissue debris (AHTD) from oval-shaped canals using micro computed tomographic (micro-CT) analysis. METHODS: Twenty mandibular incisors were anatomically pair-matched based on similar morphological dimensions (length, volume, aspect ratio, and configuration) through micro-CT analysis, prepared with Reciproc R25 instrument, scanned again, and assigned to one of the two experimental groups (n = 10), according to the final irrigation protocol: XP-endo Finisher and PUI. After the final irrigation protocols, the specimens were rescanned and the registered datasets were examined to quantify the amount of AHTD. Data were statistically analyzed using Student's t test with a significance level of 5%. RESULTS: The final irrigation protocols were highly similar in terms of volumetric percentage reduction of AHTD (P = 1.000). CONCLUSIONS: XP-endo Finisher and PUI showed the same effectiveness on the removal of AHTD. None of the tested final irrigation protocols completely removed the AHTD from oval shaped root canals. CLINICAL RELEVANCE: AHTD may be considered clinically relevant because it could harbor bacterial contents away from the disinfection procedures. Both final irrigation protocols were effective on the removal of AHTD. PMID- 30417227 TI - Comparative study of articaine and lidocaine without palatal injection for maxillary teeth extraction. AB - OBJECTIVES: There is significant evidence that articaine and lidocaine buccal injections alone are sufficient for painless extraction of maxillary teeth. The aim of this study was to evaluate the extraction of permanent maxillary teeth and to compare pain control between articaine and lidocaine without palatal injection. MATERIALS AND METHODS: Group A received buccal and palatal injections of 2% lidocaine with 0.015 mg/ml epinephrine. Group B received only buccal local anesthetic injection of 2% lidocaine with 0.015 mg/ml epinephrine. Group C received only buccal injection of 4% articaine with 0.012 mg/ml epinephrine. The patients' perception of pain was assessed using visual analogue scale and verbal response scale after the injection and the extraction. RESULTS: Statistical analysis showed that the difference in pain perception of local anesthetic injection was statistically significant between groups A and B and between groups A and C (p < 0.05). CONCLUSION: The extraction of permanent maxillary teeth is possible without palatal injections and there is no difference between articaine and lidocaine. CLINICAL RELEVANCE: Local anesthetic agents are the most frequently administered drugs in dentistry and represent the primary method of pain control for patients undergoing intraoral procedures. PMID- 30417228 TI - Health-related quality of life, educational and family outcomes in survivors of congenital diaphragmatic hernia. AB - PURPOSE: Congenital diaphragmatic hernia (CDH) survivors experience increased risk of medical and neurodevelopmental challenges. This study describes the health-related quality of life (HRQOL), special education utilization and the family impact among neonatal CDH survivors. METHODS: A single-center prospective cohort of CDH survivors born between 1995 and 2006 was followed. Parents completed the PedsQL HRQOL index and a Family Impact survey to assess the need for medical equipment, home health services, and special education and quantify the burden placed on the family by their child's medical needs. RESULTS: Parents of 32 survivors participated at a mean survivor age of 8 +/- 4 years. Many survivors utilized medical equipment (62%), home health services (18%) and special education (28%). CDH survivor HRQOL (79 +/- 17) did not differ significantly from that of healthy children (83 +/- 15, p = 0.12). HRQOL was diminished among survivors who required special education (67 +/- 8 vs 82 +/- 3; p = 0.04) and those reporting increased Family Impact score (p = 0.001). CONCLUSION: Many CDH survivors continue to require home medical equipment and home health services at school age. Most survivors have normal parent-reported HRQOL; however, the need for special education and higher family impact of neonatal CDH correlates with decreased HRQOL. PMID- 30417229 TI - Transanastomotic tubes reduce the cost of nutritional support in neonates with congenital duodenal obstruction. AB - PURPOSE: To determine the impact of intra-operative Trans-anastomotic Tube (TAT) placement on the cost of post-operative nutrition in infants with congenital duodenal obstruction (CDO). METHODS: A retrospective analysis of patients undergoing corrective surgery for CDO, with birth-weight over 1.5 kg over a 10 year period. Data are presented as median (inter-quartile range) and analysed with Mann-Whitney U test and Fisher's exact test as appropriate. RESULTS: 59 patients were included. There was no difference between TAT and non-TAT groups for baseline characteristics, age at operation and abnormality. In the TAT group there was a significant reduction in the duration of post-operative parenteral nutrition (PN) [6 (0-11) vs 12 (8-19) days, p = 0.006], the cost of PN [L750 (0 1375) vs L1500 (1000-2375), p = 0.006] and the total cost of nutrition [L765.26 (38.36-1404) vs L1387.52 (1008.23-2363.08), p = 0.015], thereby demonstrating a median cost saving of L622.26 per patient. 14% experienced TAT displacement but no other TAT complications were encountered. CONCLUSION: The use of a TAT is a safe and effective way to reduce the duration of PN required in patients with CDO. This infers a significant cost saving per patient, a factor that cannot be overlooked in this period of austerity. PMID- 30417230 TI - Flow plate separation of cells based on elastic properties: a computational study. AB - Medical studies have consistently shown that the best defense against cancer is early detection. Due to this, many efforts have been made to develop methods of screening patient blood quickly and cheaply. These methods range from separation via differences in size, electrostatic potential, chemical potential, antibody binding affinity, among others. We propose a method of separating cells which have similar size and outer coatings, but which differ in their elastic properties. Such a method would be useful in detecting cancerous cells, which may have similar properties to leukocytes or erythrocytes but differ in their stiffness and deformation response. Here, we use coarse-grained model of a cell with membrane, cytoskeleton, and inner fluid to determine how small changes in the cell stiffness may be used to quickly and efficiently separate out irregular cells such as circulating tumor cells from a sample of blood. We focus specifically on the effects of volumetric flux and plate geometry on the ability of a separation plate to differentiate cells of similar but disparate stiffnesses. We show that volumetric flux is crucial in determining the stiffness cutoff for separating out cells of similar sizes, while the angle of the separation plate plays a less important role. With this work, we provide a comprehensive approach to the design factors of cell separation via elastic properties and hope to offer a guideline for the development of novel cytometry devices for the detection of irregular cells such as circulating tumor cells. PMID- 30417231 TI - Long-Term Effects of Bosentan on Cardiovascular Events in Hispanic Patients with Intermittent Claudication: Four-Year Follow-up of the CLAU Trial : The CLAU Randomized Trial Long-Term Outcome. AB - INTRODUCTION: The Clinical and Endothelial Function Assessment after Endothelin Receptor Antagonist (CLAU) trial demonstrated the effect of bosentan on the endothelial function, inflammatory status and claudication distance in Hispanic patients with incipient peripheral arterial disease (PAD). Our aim was to assess the protective effect on cardiovascular events of bosentan versus conventional anti-atherosclerosis therapy. METHODS: CLAU included 56 patients with intermittent claudication, randomized 1:1 to receive bosentan for 12 weeks (n = 27) or placebo (n = 29), associating the best medical treatment. Log-rank and hazard ratio (HR) analyses were performed to estimate the relative efficacy of bosentan in preventing incidence of major adverse events (MAE) including target limb revascularization (TLR), amputation, myocardial infarction (MI), and all cause death; major cardiovascular adverse events (MACE) including TLR, amputation, MI, stroke, and cardiovascular-cause death; and major adverse limb events (MALE), which combines TLR and amputation. RESULTS: During the follow-up period (34 +/- 5 months), five MAE occurred in the control group only (17.2%), including two TLR, one amputation, one stroke, and an MI. The ratio of event-free survival for MAE to 3 years follow-up was higher in the group treated with bosentan (100% vs 66%, p = 0.01, HR = 76; 95% confidence interval 0.05-104,677, p = 0.24). A similar trend was observed in incidence of MACE (100% vs 66%, p = 0.01) and MALE (100% vs 80%, p = 0.15). CONCLUSION: Treatment with bosentan in the early low-to-mild stages of PAD may prevent cardiovascular events and the need for lower limb revascularization in the Hispanic population. Trial Registration ClinicalTrials.gov identifier NCT25102012. PMID- 30417232 TI - Effects of caffeine on intraocular pressure are subject to tolerance: a comparative study between low and high caffeine consumers. AB - BACKGROUND: Caffeine has a well-established effect on intraocular pressure (IOP) and ocular perfusion pressure (OPP); however, the possible differences between low- and high-caffeine consumers remain unknown. METHODS: In this placebo controlled, double-blind, and balanced crossover study, 40 healthy individuals were divided in low- (n = 21) and high (n = 19)-caffeine consumers, according to their daily caffeine consumption. All participants ingested either caffeine (4 mg/kg) or placebo, and IOP and OPP were measured after 30, 60, and 90 min of ingesting caffeine or placebo. Subjective feelings of arousal were also obtained. RESULTS: Caffeine induced an acute IOP rise (p < 0.001, np2 = 0.408), whereas habitual caffeine demonstrated a mediating effect on the IOP changes induced by caffeine intake, with high-caffeine consumers showing a less accentuated IOP rise in comparison to low-caffeine consumers. The greatest IOP change induced by caffeine intake was reached after 90 min from capsule ingestion, being more accentuated for the low-caffeine consumers (+ 3.4 mmHg) than for the high caffeine consumers (+ 1.2 mmHg). Consequently, the participants reported higher levels of perceived arousal after ingesting caffeine in comparison to placebo (p = 0.002, np2 = 0.222); however, similar responses were given by high- and low caffeine consumers (p = 0.256). Our data did not reveal any effect of caffeine consumption on OPP (p = 0.304). CONCLUSIONS: These results suggest that IOP responsiveness to caffeine ingestion is subject to tolerance, which could have important implication in the management of glaucoma. This finding may be due to alterations in the adenosine receptor system caused by chronic caffeine consumption. Future studies are needed to assess if these findings are also applicable to patients with glaucoma. PMID- 30417233 TI - Hippocampal network oscillations at the interplay between innate anxiety and learned fear. AB - The hippocampus plays a central role as a hub for episodic memory and as an integrator of multimodal sensory information in time and space. Thereby, it critically determines contextual setting and specificity of episodic memories. It is also a key site for the control of innate anxiety states and involved in psychiatric diseases with heightened anxiety and generalized fear memory such as post-traumatic stress disorder (PTSD). Expression of both innate "unlearned" anxiety and "learned" fear requires contextual processing and engagement of a brain-wide network including the hippocampus together with the amygdala and medial prefrontal cortex. Strikingly, the hippocampus is also the site of emergence of oscillatory rhythms that coordinate information processing and filtering in this network. Here, we review data on how the hippocampal network oscillations and their coordination with amygdalar and prefrontal oscillations are engaged in innate threat evaluation. We further explore how such innate oscillatory communication might have an impact on contextualization and specificity of "learned" fear. We illustrate the partial overlap of fear and anxiety networks that are built by the hippocampus in conjunction with amygdala and prefrontal cortex. We further propose that (mal)-adaptive interplay via (dis) balanced oscillatory communication between the anxiety network and the fear network may determine the strength of fear memories and their resistance to extinction. PMID- 30417235 TI - Pressure and impact of anthropogenic litter on marine and estuarine reptiles: an updated "blacklist" highlighting gaps of evidence. AB - We report an arrangement on the effect of anthropogenic litter on marine and estuarine reptiles, checking for evidence about different types of impact (ingestion vs. entanglement) and pressure (three size-based categories). From 1976 to 2018, we obtained a "blacklist" of 11 species impacted by marine litter (about 13% of 85 species of marine and estuarine reptiles), belonging to three orders (Testudines, Squamata, and Crocodilia). We obtained only occasional evidence of an impact for Squamata (Hidrophis elegans, Disteira major) and Crocodilia (Crocodylus porosus). Regarding the different types of pressure, the highest number of evidence has been obtained for macro-litter (10 species) and the lowest for micro-litter (4 species, all Chelonidae). Among Testudines, Lepidochelys kempii and Natator depressus evidenced a lack of data for micro plastic. In Squamata, information is lacking for micro-plastic with only occasional references for meso-plastic (in Hydrophis elegans) and macro-plastic (Disteira major and Crocodylus porosus). We obtained a direct correlation between the research effort and the number of citations regarding different types of pressure and impact of marine litter: therefore, our blacklist of impacted species could be increased, carrying out further research focused on other poorly studied marine and estuarine reptiles. We suggest the use of a standardized nomenclature to reduce the amount of lost information. PMID- 30417234 TI - New application of dynamic magnetic resonance imaging for the assessment of deglutitive tongue movement. AB - BACKGROUND: Deglutitive motion of the tongue may function to maintain tooth position. However, the causation between abnormal patterns of orofacial muscle function and dental malocclusion remains unclear. To clarify the pathogenic mechanism of malocclusion, it is important to determine the relative positional relationship between the tongue tip and incisor edge or the dorsal tongue and palate during deglutition. Here, we assessed the utility of 3-T segmented cine magnetic resonance (MR) imaging, combined with static MR images for hard tissue visualization, in assessing the relationship between the tongue and the surrounding tissues during deglutitive tongue movement. METHODS: Cine-MR images were acquired from three healthy female volunteers during deglutition who had no history of swallowing disorder or other chronic illness, normal alignment and occlusion, and a skeletal class I relationship. Three cine-MR images were taken during deglutition in accordance with an auditory cue for each volunteer. During static imaging, custom-made, contrast-medium-filled clear retainers were positioned in the mouth to allow visualization of the upper and lower incisors and hard palate boundaries. Static images were superimposed onto images of the three stages in deglutitive tongue movement, which were selected from a series of cine-MR images. These superimpositions were assessed five times by tracing cephalometric parameters to examine the reproducibility of the method. RESULTS: Traces varied little across repeated measurements, and all subjects had a similar pattern of dorsal tongue movement. Tongue-to-palate contact increased slightly during the first to second stage of swallowing and abruptly increased during the second to third stage, while the tongue tip position remained constant. CONCLUSIONS: Segmented cine-MR imaging combined with static MR images is useful for assessing soft tissue motion during deglutition. This method is particularly useful in dentistry to evaluate the relationship between tongue function and maxillofacial morphology in terms of orthodontic treatment and orofacial myofunctional therapy, and for improving tongue movement during speech therapy. PMID- 30417236 TI - The influence of traffic density on heavy metals distribution in urban road runoff in Beijing, China. AB - The concentrations, potential risk, and distributions of heavy metals in urban road runoff from different traffic density were determined and compared in Beijing, China. It showed that the concentrations of heavy metals in road runoff were strongly influenced by traffic density, resulting in total concentrations of Cu, Zn, Fe, Mn, and Pb in the runoff from highway higher than those from the road nearby campus. The potential ecological risk of heavy metals in the runoff from highway was higher than those from the road nearby campus. The distributions of heavy metals were not influenced by the traffic density. Cu, Zn, Cr, Cd, Pb, and Mn in road runoff transported predominantly in particulate-bound form and the dissolved form mainly distributed in colloidal fraction (1 kDa to 0.45 MUm). Traffic density did not change the speciation of heavy metals in the road runoff, in which Cr and Zn mainly expressed in organic colloidal fraction while Fe, Mn, Cd, Pb, and Cu expressed in inorganic colloidal fraction. The traffic activities would contribute to the strong correlations between Fe, Zn, Mn, Cr, and Pb because of the similar sources. PMID- 30417237 TI - Is the World Health Organization predicted exposure assessment model for space spraying of insecticides applicable to agricultural farmers? AB - Agricultural farmers in developing countries are at high risk of pesticide exposure and adverse effects because of unsafe practices and inappropriate legislation. Biological monitoring is considered a useful tool for pesticide exposure assessment; however, its use is limited in developing countries due to a lack of techniques and resources such as laboratory analysis, trained staff and budgets. This study examines whether the World Health Organization predicted exposure assessment model (WHO-PEAM) is a suitable alternative tool for assessing insecticide exposure among agricultural farmers. WHO-PEAM was used to predict daily doses (PDD) of chlorpyrifos for a group of Vietnamese rice farmers using a set of exposure parameters obtained from a questionnaire survey of participant famers during a field study. These results were compared to absorbed daily doses (ADD) of chlorpyrifos for the farmers measured using a biological monitoring program, in which 24-h urine samples were collected and analysed for the chlorpyrifos metabolite, 3,5,6-trichloro-2-pyridinol (TCP) using LC/MS. Validation of the model results was tested using the Wilcoxon signed-rank test (WSR) and two-way mixed-model intraclass correlation coefficient (ICC). The mean of total ADD was 20 MUg/kg/day while that of total PDD was 22 MUg/kg/day. The WSR test revealed no statistically significant difference in the average values of ADDT and PDDT. ICC indicated substantial agreement for both single and average measures between ADDT and PDDT (ICC, 0.62 and 0.77, respectively). The results demonstrate that a refined WHO-PEAM model can be readily used as a field method, without biological monitoring, to evaluate chlorpyrifos exposure among agricultural farmers in Vietnam and similar developing countries. PMID- 30417238 TI - Response of secondary metabolites to Cu in the Cu-hyperaccumulator lichen Stereocaulon japonicum. AB - Lichen secondary metabolites are known to be associated with heavy metal uptake and tolerance in lichens. Understanding the relationship between their secondary metabolites and heavy metals in them is important for clarifying the mechanisms of their heavy metal accumulation and tolerance. To determine the relationships between the concentrations of secondary metabolites and Cu in the Cu hyperaccumulator lichen Stereocaulon japonicum and to clarify its response to Cu, we collected Cu-contaminated and uncontaminated samples of the lichen and determined relative concentrations of secondary metabolites and concentrations of Cu, K, glucose, and sugar alcohols in them. We found significant negative correlations between the relative concentrations of secondary metabolites atranorin and stictic acid-and the concentration of Cu. These negative correlations can be interpreted in one of two ways: (a) S. japonicum itself reduced the relative concentrations of secondary metabolites in response to the increase of Cu concentration or (b) its carbon and energy metabolism was damaged by Cu stress, resulting in the reduction of the relative concentrations of secondary metabolites. The analysis of K, glucose, and sugar alcohols showed no effect of Cu on these concentrations, which means that the carbon and energy metabolism was not damaged by Cu stress. Therefore, the negative correlations can be interpreted that S. japonicum itself reduced the relative concentrations of secondary metabolites with the increase of Cu concentration. These findings provide a deeper understanding of the response of secondary metabolites to Cu in the lichen. PMID- 30417239 TI - How Kentucky bluegrass tolerate stress caused by sodium chloride used for road de icing? AB - Salts used in road de-icing during winter season inhibit the growth and development of lawn grass species. The mechanism of plant tolerance/sensitivity to such treatments is still not clear. Moreover, there is a lack of fast and non invasive tool to detect the effect of these salts on plants growth. This study was designed to understand the tolerance mechanism of Kentucky bluegrass plants on salinity, based on some biometric and physiological parameters. In this experiment, we simulated the urban conditions where salts are used intensively for roads de-icing. Germination capacity was evaluated at five salt solutions of NaCl (0, 50, 100, 150 and 200 mM), and physiological parameters were measured during the tillering phase at salinity levels of 0, 150 and 300 mM of NaCl. Seeds of Kentucky bluegrass did not germinate under salinity. During tillering phase, salinity affected length, area and dry mass of roots as well as the relative water content of plants, negatively. Moreover, it influenced the maximum chlorophyll fluorescence yield, quantum yield of photosystem II and electron transport rate at early period of stress. This allows us to recommend these parameters for early detection of soil salinity effects on Kentucky bluegrass plants. It seems to be that the tolerance of this plant towards salinity is based on retaining water content in leaves that allow more efficient functioning of photosynthetic apparatus. PMID- 30417240 TI - Adsorption of gallic acid on nanoclay modified with poly(diallyldimethylammonium chloride). AB - In this work, particles of nanoclay modified with poly(diallyldimethylammonium), PDDA, namely PDDA/PGV, were obtained and characterized by infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), X-ray diffraction (XRD), surface area measurement (BET surface area), measurement of zero charge point (pHPCZ), and scanning electron microscopy with energy-dispersive spectroscopy (SEM/EDS). The PDDA/PGV particles were applied as adsorbent for the removal of gallic acid (GA) from aqueous solution. The effect of various parameters, such as solution pH, contact time, adsorbent mass, and temperature, was studied. The maximum adsorption capacity of PDDA/PGV (238.45 mg g-1) was observed at pH 4 and 15 degrees C. The study of adsorption kinetics and isotherms revealed that the adsorption process was better fitted by pseudo-first order and Freundlich model, respectively. The obtained thermodynamic parameters indicate that the adsorption of GA is spontaneous and enthalpy-driven. PMID- 30417241 TI - The 2007 crisis and Greek wildfires: a multivariate analysis of suppression times. AB - Shifts in government priorities in response to the 2007 global recession have affected wildfire management and natural disaster funding arrangements, leading to a reduced effectiveness of fire suppression actions and increasing fire vulnerability. Our study investigates the role of local socioeconomic contexts on fire suppression effectiveness under economic expansion and recession in a Mediterranean region (Attica, Greece) strongly affected by 2007 crisis and displaying a persistently high density of peri-urban wildfires. Basic characteristics of wildfires (spatial distribution, intensity, and land use preferences) were investigated in the study area over two consecutive 8-year time intervals characterized by economic expansion (2000-2007) and recession (2008 2015). An integrated approach based on multivariate statistics and artificial neural networks was implemented to evaluate latent relationships between fire suppression time, wildfire characteristics, and socioeconomic dynamics. Controlling for wildfires' characteristics over the two time intervals, fire time length increased under crisis-mainly for small and medium-sized fires-possibly as an indirect response to reduced effectiveness of forest land management. Local contexts and political decisions influenced by economic downturns are relevant factors shaping wildfires' severity in the Mediterranean region. With recession, local contexts vulnerable to wildfires require more effective fire prevention measures, sustainable forest management, and regional planning. PMID- 30417242 TI - An Insight into DNA-free Reprogramming Approaches to Generate Integration-free Induced Pluripotent Stem Cells for Prospective Biomedical Applications. AB - More than a decade ago, a pioneering study reported generation of induced Pluripotent Stem Cells (iPSCs) by ectopic expression of a cocktail of reprogramming factors in fibroblasts. This study has revolutionized stem cell research and has garnered immense interest from the scientific community globally. iPSCs hold tremendous potential for understanding human developmental biology, disease modeling, drug screening and discovery, and personalized cell based therapeutic applications. The seminal study identified Oct4, Sox2, Klf4 and c-Myc as a potent combination of genes to induce reprogramming. Subsequently, various reprogramming factors were identified by numerous groups. Most of these studies have used integrating viral vectors to overexpress reprogramming factors in somatic cells to derive iPSCs. However, these techniques restrict the clinical applicability of these cells as they may alter the genome due to random viral integration resulting in insertional mutagenesis and tumorigenicity. To circumvent this issue, alternative integration-free reprogramming approaches are continuously developed that eliminate the risk of genomic modifications and improve the prospects of iPSCs from lab to clinic. These methods establish that integration of transgenes into the genome is not essential to induce pluripotency in somatic cells. This review provides a comprehensive overview of the most promising DNA-free reprogramming techniques that have the potential to derive integration-free iPSCs without genomic manipulation, such as sendai virus, recombinant proteins, microRNAs, synthetic messenger RNA and small molecules. The understanding of these approaches shall pave a way for the generation of clinical grade iPSCs. Subsequently, these iPSCs can be differentiated into desired cell type(s) for various biomedical applications. PMID- 30417243 TI - A growing problem: cycling referrals to the National Centre for Pelvic and Acetabular Fracture Management in Ireland. AB - BACKGROUND: Popularity in cycling continues to grow. In Ireland, in the last 5 years, 42% more people now use it to travel to work. This has been mirrored by a rise in cycling-related trauma and deaths. The popularity amongst men has led to the term middle-aged men in Lycra (MAMIL) being coined. AIMS: The purpose of our study was to quantify cycling-related pelvic and acetabular fracture referrals in Ireland and determine injury patterns, cost and functional outcomes following these injuries. METHODS: A retrospective cohort study was conducted of all referrals to our institution, the National Centre for Pelvis and Acetabular Fracture Management, in 2016 and 2017. Demographic, mechanism of injury, concomitant trauma and treatment data were analysed. Patients were contacted to assess return to work, sport and quality of life (EQ-5D-3L). RESULTS: Cycling injury referrals increased by 90% between 2016 and 2017 with a greater number of cycling than motorbike injury referrals. Twenty-nine patients sustained a pelvic and acetabular (PA) injury while cycling. The mean patient age was 51.7 years of which 86.2% were male with 41% suffering a concomitant injury. Fourteen patients (48.3%) required surgery of which 60% have returned to cycling. Mean cost of treatment was ?11,757. The median EQVAS was 80. CONCLUSIONS: The rise in popularity of cycling has been mirrored by an increase in PA injuries and deaths. These injuries are associated with significant costs to the patient, hospital and society. Greater investment in safety and awareness is needed to protect this vulnerable group. PMID- 30417244 TI - Practical guide for the management of systemic toxicity caused by local anesthetics. AB - Systemic toxicity from local anesthetics can occur in any of the wide range of situations in which these agents are used. This practical guide is created to generate a shared awareness of the prevention, diagnosis, and treatment of local anesthetic systemic toxicity among all medical professionals who perform nerve blocks. Systemic toxicity of local anesthetic is induced by an increase of its protein-unbound plasma concentration. Initial symptoms are characterized by central nervous system signs such as excitation, convulsions, followed by loss of consciousness and respiratory arrest. These symptoms are often accompanied with cardiovascular signs such as hypertension, tachycardia and premature ventricular contractions. Further increase of plasma concentration of local anesthetic induces bradycardia, conduction disturbances, circulatory collapse and asystole. The incidence of local anesthetic systemic toxicity is 1-11 cases per 10,000. Infants, patients with decreased liver function and low cardiac output are vulnerable to systemic toxicity. When performing regional anesthesia, the guideline-directed monitoring, securing a venous line, preparation of medication to treat convulsions and lipid emulsions are required. For prevention of local anesthetic systemic toxicity, small-dose, divided administration, using agents with low toxicity such as ropivacaine and levobupivacaine, performing an aspiration test are recommended. If systemic toxicity is suspected, halt administration of local anesthetic, request assistance, secure venous line, airway, administration of 100% oxygen and if necessary tracheal intubation and artificial respiration should be immediately performed. Benzodiazepines are recommended to treat convulsions. Administration of 20% lipid emulsion according to the protocol is recommended to treat severe hypotension and arrhythmia. PMID- 30417245 TI - Metabolic characteristics and nutrient utilization in high-feed-efficiency pigs selected using different feed conversion ratio models. AB - An understanding of the nutrient utilization characteristics of pigs with different feed efficiencies (FEs) will help us to develop new strategies to reduce the costs of pig production. In this study, we selected pigs with a range of FEs according to two feed conversion ratio models: the feed intake (FI) model, where pigs had the same average daily gains (ADGs) but different FIs, and the ADG model, where pigs had the same FIs but different ADGs. High-FE pigs had a higher abundance of short chain fatty acid (SCFA)-producing bacteria (Lachnospiraceae, Clostridiaceae_1, and Coriobacteriaceae) in their caecum in the FI model, and low FE pigs had a higher abundance of two families (Bacteroidales_S24_7_group and Peptococcaceae) and two genera (Anaerotruncus and Candidatus_Soleaferrea) in both models. By contrast, high-FE pigs had more goblet cells and higher mRNA expression of insulin-like growth factor 1 (IGF-1) in the FI model, and higher mRNA expression of occludin but lower expressions of adenosine monophosphate activated protein kinase (AMPK)-alpha2 and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1alpha) in the ADG model. These findings suggest that the presence of SCFA-producing bacteria in the caecum and increased muscular growth may contribute to the high FE of low-FI pigs, while improved intestinal functions and decreased mitochondrial activity in the skeletal muscle are related to the high FE of high-ADG pigs. PMID- 30417246 TI - Altered small-world, functional brain networks in patients with lower back pain. AB - In this study, we aimed to investigate the functional network changes that occur in patients with lower back pain (LBP). We also investigated the link between LBP and the small-world properties of functional networks within the brain. Functional MRI (fMRI) was performed on 20 individuals with LBP and 17 age and gender-matched normal controls during the resting state. The severity of the pain in the individuals with LBP ranged from 5 to 8 on a 0-10 scale, with 0 indicating no pain. Network-based statistics were performed to investigate the differences between the brain networks of individuals with LBP and those of normal controls. Several small-world parameters of brain networks were calculated, including the clustering coefficient, characteristic path length, local efficiency, and global efficiency. These criteria reflect the overall network efficiency. The brain networks in the individuals with LBP due to herniation of a lumbar disc demonstrated a significantly longer characteristic path length as well as a lower clustering coefficient, global efficiency, and local efficiency compared to those in control subjects. We found that LBP patients tended to have unstable and inefficient brain networks when compared with healthy controls. In addition, LBP individuals showed significantly decreased functional connectivity in the anterior cingulate cortex, middle cingulate cortex, post cingulate cortex, inferior frontal gyrus, middle temporal gyrus, occipital gyrus, postcentral gyrus, precentral gyrus, supplementary motor area, thalamus, fusiform, caudate, and cerebellum. We believe that these regions may be involved in the pathophysiology of lower back pain. PMID- 30417247 TI - Improved detection of DNA Schistosoma haematobium from eggs extracted by bead beating in urine. AB - Diagnosis of Schistosoma haematobium relies primarily on microscopical analysis of urine. The method is time consuming and requires some expertise. Genus specific real-time PCRs have been developed, but we still observed low sensitivity. In the present study, in order to achieve a more sensitive DNA detection of eggs of S. haematobium in urine samples, we wanted to develop a novel protocol of DNA extraction using mechanic disruption of eggs by bead beating as supplementary step. We tested Schistosoma spp. internal transcribed spacer 2 real-time PCR after both methods with and without bead beating. First, we preliminary assessed the DNA detection after bead beating using dilution of 2, 10, 50, and 90 eggs/10 mL, and the Ct value analysis showed significant improved DNA detection per each point of egg concentration using the novel supplementary step. Twenty microscopy positive and five microscopy negative urine samples were used to validate the procedure. All urines came from imported cases and admitted at center for tropical medicine, and were examined by microscopy. PCR results after novel method with bead beating showed 100% to be positive for S. haematobium, compared with 85% positive by our standard extraction procedure. Results confirmed mechanic disruption of eggs by bead beating before DNA extraction to be highly effective method for the detection of S. haematobium DNA in urine. PMID- 30417248 TI - Unusual 18S rDNA of Acanthamoeba containing intron turned out to be a T5/T4 chimera. AB - The free-living amoebae of the genus Acanthamoeba are widely investigated for their diversity and evolution. Studies usually employ biomolecular methods targeting the 18S rRNA gene, assigning strains according to a well-established genotyping system. Strains from at least four genotypes contain introns in their rDNA. By retracing the evolutionary history of these introns within the amoebae, we found that the 18S rDNA of TUMSJ-341 strain (ATCC PRA-11), assigned to the genotype T5 (A. lenticulata), proved very unusual in our analyses, not corresponding to the characteristics of the group. The sequence contains a group I intron recovered only in A. lenticulata. At BLAST, however, the intron-less 18S rDNA of TUMSJ-341 does not match with T5 strains but shows some affinity with strains from genotype T4, suggesting a new genotype. Our accurate analysis of this sequence finally revealed a mixture of variable regions, showing that such discordant results are due to the insertion into the gene of a strain T5 of a DNA fragment containing hypervariable regions specific for a T4 strain. Data presented herein indicate that this sequence is probably a chimera. PMID- 30417249 TI - Development of a Highly Selective Two-Photon Probe for Methylglyoxal and its Applications in Living Cells, Tissues, and Zebrafish. AB - Methylglyoxal (MGO) is one of the most important active carbonyl compounds in living organisms. It is a metabolic by product of glycolysis. MGO participates in glycosylation of proteins and nucleic acids to trigger carbonyl stress, inducing pathological status and even exacerbateing the development of chronic degenerative diseases. In order to study the diseases caused by MGO, it is meaningful for us to develop methods that could efficiently detect MGO. In our work, a new two-photon fluorescent turn-on probe which named NP has been designed which was made up of naphthalimides dye as the two-photon fluorescent platform and the o-phenylenediamine as recognition site. When reacted with MGO, NP showed excellent sensitivity and selectivity. Based on the two-photon fluorescence imaging technology, NP has firstly successful application in living cells, tissues and zebrafish to detecting MGO. PMID- 30417250 TI - SLC41A1 is essential for magnesium homeostasis in vivo. AB - Solute carrier family 41 member A1 (SLC41A1) has been suggested to mediate magnesium (Mg2+) transport by several in vitro studies. However, the physiological function of SLC41A1 remains to be elucidated. In this study, cellular Mg2+ transport assays combined with zebrafish slc41a1 knockdown experiments were performed to disclose SLC41A1 function and its physiological relevance. The gene slc41a1 is ubiquitously expressed in zebrafish tissues and is regulated by water and dietary Mg2+ availability. Knockdown of slc41a1 in zebrafish larvae grown in a Mg2+-free medium resulted in a unique phenotype characterized by a decrease in zebrafish Mg content. This decrease shows that SLC41A1 is required to maintain Mg2+ balance and its dysfunction results in renal Mg2+ wasting in zebrafish larvae. Importantly, the Mg content of the larvae is rescued when mouse SLC41A1 is expressed in slc41a1-knockdown zebrafish. Conversely, expression of mammalian SLC41A1-p.Asp262Ala, harboring a mutation in the ion-conducting SLC41A1 pore, did not reverse the renal Mg2+ wasting. 25Mg2+ transport assays in human embryonic kidney 293 (HEK293) cells overexpressing SLC41A1 demonstrated that SLC41A1 mediates cellular Mg2+ extrusion independently of sodium (Na+). In contrast, SLC41A1-p.Asp262Ala expressing HEK293 cells displayed similar Mg2+ extrusion activities than control (mock) cells. In polarized Madin-Darby canine kidney cells, SLC41A1 localized to the basolateral cell membrane. Our results demonstrate that SLC41A1 facilitates renal Mg2+ reabsorption in the zebrafish model. Furthermore, our data suggest that SLC41A1 mediates both Mg2+ uptake and extrusion. PMID- 30417251 TI - The Longitudinal Relation between Observed Maternal Parenting in the Preschool Period and the Occurrence of Child ADHD Symptoms in Middle Childhood. AB - In this longitudinal population-based cohort (N = 547) we examined the relation between maternal discipline and sensitivity in the preschool period and the occurrence of attention-deficit hyperactivity disorder (ADHD) symptoms in middle childhood, taking into account pre-existing child attention and executive function (EF) problems, and oppositional defiant disorder (ODD) symptom comorbidity. Maternal parenting was observed during a 'do not touch task' (positive and negative discipline) and a teaching task (sensitivity) at age 3. Parents reported on the occurrence of ADHD and ODD symptoms at age 8 using the Conners' Parent Rating Scale. Attention and executive function problems were assessed using parent questionnaires at age 4. Important covariates such as harsh discipline and maternal depression were also taken into account. Maternal sensitivity significantly predicted later ADHD symptoms beyond pre-existing child attention and EF problems, and comorbid ODD symptoms. However, maternal negative and positive discipline did not significantly predict later ADHD symptoms over and above these covariates. This study demonstrates the importance of maternal sensitivity in the etiology of core ADHD symptoms above and beyond pre-existing child attention and EF problems, and comorbid ODD symptoms. PMID- 30417252 TI - Dyadic Peer Interactions: the Impact of Aggression on Impression Formation with New Peers. AB - Little is known about youth's initial interactions with previously unfamiliar peers and how aggression can affect behavior in these interactions. We observed previously unfamiliar youth engaging in a dyadic activity to determine how tendencies toward aggression related to behavior within the activity (i.e., collaboration) and how collaboration affected initial impression formation. From a dyadic perspective, we assessed how similarities versus differences in tendencies toward aggression affected the nature of the interaction. Participants were 108 5th grade dyads (M = 11.13 years; 50% female; 67% White), observed in a laboratory session. Teachers rated individuals' aggression; ratings were used to calculate dyadic-level aggression (the discrepancy between partners). Observers rated dyads' collaboration during the interaction and participants reported perceptions about their partner after the interaction. Results indicated that collaboration mediated the link between discrepancy in aggression and peers' perceptions of one another. Specifically, dyads more discrepant in their aggression collaborated less and had less positive perceptions of one another. Results highlight the importance of considering a dyadic perspective and indicate a potential intervention point to improve youth's peer relationships. PMID- 30417255 TI - A Bibliometric Study of Authorship and Collaboration Trends Over the Past 30 Years in Four Major Musculoskeletal Science Journals. AB - This study explored changes in bibliometric variables over the last 30 years for four major musculoskeletal science journals (BONE(r)), Calcified Tissue International(r) (CTI(r)), Journal of Bone and Mineral Research(r) (JBMR(r)), and Journal of Orthopaedic Research(r) (JOR(r)), with a specific focus on author gender. Bibliometric data were collected for all manuscripts in 1985 (BONE(r), CTI(r), JOR(r)), 1986 (JBMR(r)), 1995, 2005, and 2015; 2776 manuscripts met inclusion criteria. Manuscripts from Europe were more often published in BONE(r) or CTI(r), while those from North America in JBMR(r) or JOR(r). All journals demonstrated an increase over time in the number of authors (3.67-7.3), number of countries (1.1-1.4), number of institutions (1.4-3.1), and number of references (25.1-45.4). The number of manuscript pages increased (6.6-8.9) except for JOR(r) which showed a decline. CTI(r) had the lowest number of authors (4.9 vs. 5.6 6.8). There was a change in the corresponding author position from first to last for all journals; this change was highest for CTI(r) (35%) and lowest for BONE(r) (14.0%). All journals demonstrated an increase over time in female authors; however, CTI(r) was the highest amongst these four journals. The percentage of female first authors rose from 24.6 to 44.3% (CTI(r) 29.1-52.3%). The percentage of corresponding female authors rose from 17.5 to 33.6% (CTI(r) 22.9-40.0%). The proportion of female authors is increasing, likely reflecting the increasing number of women obtaining doctorates in science, medicine, and engineering. PMID- 30417256 TI - Distribution pattern and health risk assessment of polycyclic aromatic hydrocarbons in the water and sediment of Algoa Bay, South Africa. AB - Polycyclic aromatic hydrocarbons are amongst the pollutants of major concern in the terrestrial and aquatic habitats. They are mostly characterised by carcinogenic and non-carcinogenic effects. Distribution and potential health risks of sixteen priority PAHs in the water and sediment samples collected between December 2015 and June 2016 from Algoa Bay, South Africa, were evaluated. Water and sediment samples collected were extracted with liquid-liquid and soxhlet extraction methods, respectively, and then cleaned up using glass column loaded with silica gel. Final concentrations of the target PAHs were determined by gas chromatography interfaced with flame ionization detector. Results indicated that individual PAH concentrations in surface water, bottom water and sediment samples ranged from not detected (ND) to 24.66 ug/L, ND to 22.81 ug/L and ND to 5.23 mg/kg correspondingly. Total PAHs concentrations varied as 12.78 78.94 ug/L, 1.20-90.51 ug/L and 1.17-10.47 mg/kg in the three environmental matrices in that order. The non-carcinogenic risk was generally below 1, whereas risk indices (dermal contact) were above the acceptable limit of 1 * 10-4 in the water column, suggesting possible carcinogenic effects to humans, with adults being the most vulnerable. Similarly, highest contributions to TEQs and MEQs in the sediments were made by benzo(a)pyrene and dibenzo(a,h)anthracene, the two most toxic congeners, signifying the possibility of carcinogenicity and mutagenicity in humans. Diagnostic ratios of PAHs reflect a prevailing pyrogenic input all through. The pollution was albeit moderate, yet regular check is recommended to ensure safe and healthy environment for human and aquatic lives. PMID- 30417253 TI - A systematic review of factors affecting medication adherence among patients with osteoporosis. AB - : The aim of this review was to identify factors that influence patients' adherence to anti-osteoporotic therapy. Factors identified that were associated with poorer medication adherence included polypharmacy, older age, and misconceptions about osteoporosis. Physicians need to be aware of these factors so as to optimize therapeutic outcomes for patients. INTRODUCTION: To identify factors that influence patients' adherence to anti-osteoporotic therapy. METHODS: A systematic review of literature was performed for articles published up till January 2018 using PubMed(r), PsychINFO(r), Embase(r), and CINAHL(r). Peer reviewed articles which examined factors associated with anti-osteoporotic medication adherence were included. Classes of anti-osteoporotic therapy included bisphosphonates, parathyroid hormone-related analogue, denosumab, selective estrogen receptor modulators, estrogen/progestin therapy, calcitonin, and strontium ranelate. Meta-analyses, case reports/series, and other systematic reviews were excluded. Identified factors were classified using the World Health Organization's five dimensions of medication adherence (condition, patient, therapy, health-system, and socio-economic domains). RESULTS: Of 2404 articles reviewed, 124 relevant articles were identified. The prevalence of medication adherence ranged from 12.9 to 95.4%. Twenty-four factors with 139 sub-factors were identified. Bisphosphonates were the most well-studied class of medication (n = 59, 48%). Condition-related factors that were associated with poorer medication adherence included polypharmacy, and history of falls was associated with higher medication adherence. Patient-related factors which were associated with poorer medication adherence included older age and misconceptions about osteoporosis while therapy-related factors included higher dosing frequency and medication side effects. Health system-based factors associated with poorer medication adherence included care under different medical specialties and lack of patient education. Socio-economic-related factors associated with poorer medication adherence included current smoker and lack of medical insurance coverage. CONCLUSION: This review identified factors associated with poor medication adherence among osteoporotic patients. To optimize therapeutic outcomes for patients, clinicians need to be aware of the complexity of factors affecting medication adherence. PMID- 30417254 TI - RNA sequencing-based transcriptomic profiles of embryonic lens development for cataract gene discovery. AB - Isolated or syndromic congenital cataracts are heterogeneous developmental defects, making the identification of the associated genes challenging. In the past, mouse lens expression microarrays have been successfully applied in bioinformatics tools (e.g., iSyTE) to facilitate human cataract-associated gene discovery. To develop a new resource for geneticists, we report high-throughput RNA sequencing (RNA-seq) profiles of mouse lens at key embryonic stages (E)10.5 (lens pit), E12.5 (primary fiber cell differentiation), E14.5 and E16.5 (secondary fiber cell differentiation). These stages capture important events as the lens develops from an invaginating placode into a transparent tissue. Previously, in silico whole-embryo body (WB)-subtraction-based "lens-enriched" expression has been effective in prioritizing cataract-linked genes. To apply an analogous approach, we generated new mouse WB RNA-seq datasets and show that in silico WB subtraction of lens RNA-seq datasets successfully identifies key genes based on lens-enriched expression. At >=2 counts-per-million expression, >=1.5 log2 fold-enrichment (p < 0.05) cutoff, E10.5 lens exhibits 1401 enriched genes (17% lens-expressed genes), E12.5 lens exhibits 1937 enriched genes (22% lens expressed genes), E14.5 lens exhibits 2514 enriched genes (31% lens-expressed genes), and E16.5 lens exhibits 2745 enriched genes (34% lens-expressed genes). Biological pathway analysis identified genes associated with lens development, transcription regulation and signaling pathways, among other functional groups. Furthermore, these new RNA-seq data confirmed high expression of established cataract-linked genes and identified new potential regulators in the lens. Finally, we developed new lens stage-specific UCSC Genome Brower annotation tracks and made these publicly accessible through iSyTE ( https://research.bioinformatics.udel.edu/iSyTE/ ) for user-friendly visualization of lens gene expression/enrichment to prioritize genes from high-throughput data from cataract cases. PMID- 30417257 TI - Language delay and poorer school performance in children of mothers with inadequate iodine intake in pregnancy: results from follow-up at 8 years in the Norwegian Mother and Child Cohort Study. AB - PURPOSE: Some studies indicate that mild-to-moderate iodine deficiency in pregnant women might negatively affect offspring neurocognitive development, including previous results from the Norwegian Mother and Child Cohort study (MoBa) exploring maternally reported child development at age 3 years. The aim of this follow-up study was to investigate whether maternal iodine intake in pregnancy is associated with language and learning at 8 years of age. METHODS: The study sample includes 39,471 mother-child pairs participating in MoBa with available information from a validated food frequency questionnaire covering the first half of pregnancy and a questionnaire on child neurocognitive development at 8 years. Multivariable regression was used to explore associations of iodine intake from food and supplements with maternally reported child outcomes. RESULTS: Maternal iodine intake from food less than ~ 150 ug/day was associated with poorer child language skills (p-overall = 0.013), reading skills (p-overall = 0.019), and writing skills (p-overall = 0.004) as well as poorer school test result in reading (p < 0.001), and increased likelihood of the child receiving special educational services (p-overall = 0.042) (in non-iodine supplement users). Although significant, differences were generally small. Maternal use of iodine supplements in pregnancy was not significantly associated with any of the outcomes. CONCLUSIONS: Low habitual iodine intake in pregnant women, i.e., lower than the recommended intake for non-pregnant women, was associated with mothers reporting poorer child language, school performance, and increased likelihood of special educational services. We found no indications of benefits or harm of using iodine-containing supplements in pregnancy. Initiating use in pregnancy might be too late. PMID- 30417258 TI - Applying machine learning to continuously monitored physiological data. AB - The use of machine learning (ML) in healthcare has enormous potential for improving disease detection, clinical decision support, and workflow efficiencies. In this commentary, we review published and potential applications for the use of ML for monitoring within the hospital environment. We present use cases as well as several questions regarding the application of ML to the analysis of the vast amount of complex data that clinicians must interpret in the realm of continuous physiological monitoring. ML, especially employed in bidirectional conjunction with electronic health record data, has the potential to extract much more useful information out of this currently under-analyzed data source from a population level. As a data driven entity, ML is dependent on copious, high quality input data so that error can be introduced by low quality data sources. At present, while ML is being studied in hybrid formulations along with static expert systems for monitoring applications, it is not yet actively incorporated in the formal artificial learning sense of an algorithm constantly learning and updating its rules without external intervention. Finally, innovations in monitoring, including those supported by ML, will pose regulatory and medico-legal challenges, as well as questions regarding precisely how to incorporate these features into clinical care and medical education. Rigorous evaluation of ML techniques compared to traditional methods or other AI methods will be required to validate the algorithms developed with consideration of database limitations and potential learning errors. Demonstration of value on processes and outcomes will be necessary to support the use of ML as a feature in monitoring system development: Future research is needed to evaluate all AI based programs before clinical implementation in non-research settings. PMID- 30417259 TI - Incidence of emergency department presentations for traumatic brain injury in Indigenous and non-Indigenous residents aged 15-64 over the 9-year period 2007 2015 in North Queensland, Australia. AB - BACKGROUND: Traumatic brain injury (TBI) is a leading cause of disability worldwide. Previous studies have shown that males have a higher incidence than females, and Indigenous populations have a higher rate than non-Indigenous. To date, no study has compared the incidence rate of TBI between Indigenous and non Indigenous Australians for any cause. Here we add to this rather sparse literature. METHODS: Retrospective analysis of data from North Queensland Emergency Departments between 2007 and 2015 using Australian Bureau of Statistics population estimates for North Queensland residents aged 15-64 years as denominator data. Outcome measures include incidence rate ratios (IRR) for TBI presentations by Indigenous status, age, sex, year of presentation, remoteness, and socio-economic indicator. RESULTS: Overall incidence of TBI presentations per 100,000 population was 97.8. Indigenous people had an incidence of 166.4 compared to an incidence in the non-Indigenous population of 86.3, providing an IRR of 1.93 (95% CI 1.77-2.10; p < 0.001). Males were 2.29 (95% CI 2.12-2.48; p < 0.001) times more likely to present than females. Incidence increased with year of presentation only in the Indigenous male population. CONCLUSIONS: The greater burden of ED presentations for TBI in the Indigenous compared with the non Indigenous population is of concern. Importantly, the need to provide quality services and support to people living with TBI in remote and very remote areas, and the major role of the new National Disability Insurance Scheme is discussed. PMID- 30417260 TI - Transient systolic anterior motion with junctional rhythm after mitral valve repair in the intensive care unit. AB - Systolic anterior motion (SAM) after mitral valve repair (MVR) can adversely affect hemodynamics due to exacerbation of left ventricular outflow tract obstruction and mitral regurgitation. Intraoperative transient SAM after MVR can usually be managed with hemodynamic maneuvers under continuous monitoring by transesophageal echocardiography (TEE). However, during postoperative intensive care management, transient SAM is seldom diagnosed and the start of treatment may be delayed. We present a case of transient SAM after MVR with abrupt deterioration due to junctional rhythm in the intensive care unit (ICU). TEE revealed that conversion from normal sinus rhythm into junctional rhythm induced the exacerbation of SAM. TEE was useful for identifying the etiology of unstable hemodynamics after cardiac surgery in the ICU, similar to its use in the operating room. PMID- 30417261 TI - The Mitochondrion: A Potential Therapeutic Target for Alzheimer's Disease. PMID- 30417262 TI - Prognosis associated with synchronous or metachronous multiple primary malignancies in patients with completely resected non-small cell lung cancer. AB - PURPOSE: To investigate the influence of multiple primary malignancies (MPMs) on the prognosis of patients with completely resected non-small cell lung cancer (NSCLC). METHODS: The subjects of this retrospective study were 521 patients who underwent complete curative pulmonary resection for NSCLC. Patients were divided into two groups: those with and those without MPMs. RESULTS: The 521 NSCLC patients included 184 patients (35.3%) with MPMs and 337 patients without MPMs. The overall 5-year survival rates for patients with vs those without MPMs were 66.1 and 75.6%, respectively (p = 0.0061). According to multivariate analysis, MPMs, age, gender, pathological stage, and interstitial pneumonia were independent predictors of prognosis. The 47 patients with synchronous MPMs and the 82 patients with metachronous MPMs found within the last 5 years had significantly poorer prognoses than patients without MPMs (p = 0.0048 and p = 0.0051, respectively). However, the prognoses of the 55 patients with metachronous MPMs that had been present for over 5 years did not differ from those of the patients without MPMs. CONCLUSIONS: NSCLC patients with synchronous MPMs or metachronous MPMs diagnosed within the last 5 years had poor prognoses. Decisions about the best therapeutic strategies require comprehensive consideration of the organ location, malignant potential, recurrence, and prognosis of the MPMs. In contrast, decisions about the best therapeutic strategies for NSCLC patients with metachronous MPMs present for over 5 years should be based solely on the NSCLC. PMID- 30417263 TI - Beneficial Effects of N-Acetyl-L-cysteine or Taurine Pre- or Post-treatments in the Heart, Spleen, Lung, and Testis of Hexavalent Chromium-Exposed Mice. AB - Hexavalent chromium[Cr(VI)] compounds may induce toxic effects, possibly via reactive intermediates and radicals formed during Cr(VI) reduction. In this study, we probed the possible effects of N-acetyl-L-cysteine (NAC) and taurine pre- or post-treatments on Cr(VI)-induced changes in lipid peroxidation and nonprotein thiols (NPSH) in mice heart, lung, spleen, and testis tissues. The mice were randomly assigned to six groups, consisting of control, Cr(VI)-exposed (20 mg Cr/kg, intraperitoneal ,ip), NAC (200 mg/kg, ip) as pre-treatment and post treatment, and taurine (1 g/kg, ip) pre-treatment and post-treatment groups. Lipid peroxidation and NPSH levels were determined and the results were compared with regard to tissue- and antioxidant-specific basis. Exposure to Cr(VI) significantly increased lipid peroxidation in all tissues as compared to the control (p < 0.05); and consistent with this data, NPSH levels were significantly decreased (p < 0.05). Notably, administration of NAC and taurine, either before or after Cr(VI) exposure, was able to ameliorate the lipid peroxidation (p < 0.05) in all tissues. In the case of NPSH content, while the decline could be alleviated by both NAC and taurine pre- and post-treatments in the spleen, diverging results were obtained in other tissues. The effects of Cr(VI) on the lung thiols were abolished by pre-treatment with NAC and taurine; however, post treatments could not exert significant effect. While thiol depletion in the heart was totally replenished by NAC and taurine administrations, NAC pre-treatment was partially more effective than post-treatment. In contrast with lipid peroxidation data, NAC treatment could not provide a statistically significant beneficial effect on NPSH content of the testis, whereas the effect in this tissue by taurine was profound. Thus, these data highlight the importance of tissue specific factors and the critical role of administration time. Overall, our data suggest that NAC and taurine may have potential in prevention of Cr(VI)-induced toxicity in the heart, lung, spleen, and testis tissues. PMID- 30417264 TI - Improving the reliability of the iron concentration quantification for iron oxide nanoparticle suspensions: a two-institutions study. AB - Most iron oxide nanoparticles applications, and in special biomedical applications, require the accurate determination of iron content as the determination of particle properties from measurements in dispersions is strongly dependent on it. Inductively coupled plasma (ICP) and spectrophotometry are two typical worldwide used analytical methods for iron concentration determination. In both techniques, precise determination of iron is not straightforward and nanoparticle digestion and dilution procedures are needed prior to analysis. The sample preparation protocol has been shown to be as important as the analytical method when accuracy is aimed as many puzzling reported results in magnetic, colloidal, and structural properties are simply attributable to inadequate dissolution procedures. Therefore, a standard sample preparation protocol is needed to ensure the adequate and complete iron oxide nanoparticle dissolution and to harmonize this procedure. In this work, an interlaboratory evaluation of an optimized iron oxide nanoparticle digestion/dilution protocol was carried out. The presented protocol is simple, inexpensive, and does not involve any special device (as microwave, ultrasound, or other high-priced digestion devices). Then, iron concentration was measured by ICP-OES (performed in ICMM/CSIC-Spain) and spectrophotometry (NanoPET-Germany) and the obtained concentration values were analyzed to determine the most probable error causes. Uncertainty values as low as 1.5% were achieved after the optimized method was applied. Moreover, this article provides a list of recommendations to significantly reduce uncertainty in both sample preparation and analysis procedures. Graphical abstract ?. PMID- 30417265 TI - Spatial and molecular changes of mouse brain metabolism in response to immunomodulatory treatment with teriflunomide as visualized by MALDI-MSI. AB - Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease of the central nervous system (CNS). One of the most promising recent medications for MS is teriflunomide. Its primary mechanism of action is linked to effects on the peripheral immune system by inhibiting dihydroorotate dehydrogenase (DHODH) catalyzed de novo pyrimidine synthesis and reducing the expansion of lymphocytes in the peripheral immune system. Some in vitro studies suggested, however, that it can also have a direct effect on the CNS compartment. This potential alternative mode of action depends on the drug's capacity to traverse the blood brain barrier (BBB) and to exert an effect on the complex network of brain biochemical pathways. In this paper, we demonstrate the application of high resolution/high-accuracy matrix-assisted laser desorption/ionization Fourier transform ion cyclotron resonance mass spectrometry for molecular imaging of the mouse brain coronal sections from animals treated with teriflunomide. Specifically, in order to assess the effect of teriflunomide on the mouse CNS compartment, we investigated the feasibility of teriflunomide to traverse the BBB. Secondly, we systematically evaluated the spatial and semi-quantitative brain metabolic profiles of 24 different endogenous compounds after 4-day teriflunomide administration. Even though the drug was not detected in the examined cerebral sections (despite the high detection sensitivity of the developed method), in-depth study of the endogenous metabolic compartment revealed noticeable alterations as a result of teriflunomide administration compared to the control animals. The observed differences, particularly for purine and pyrimidine nucleotides as well as for glutathione and carbohydrate metabolism intermediates, shed some light on the potential impact of teriflunomide on the mouse brain metabolic networks. Graphical Abstract. PMID- 30417266 TI - Simplifying the complex: metabolomics approaches in chemical ecology. AB - Chemical signals are important mediators of organismal interactions. These interactions significantly influence ecosystem structure and thus are crucial to understand. Ecologists and analytical chemists work closely together to identify the specific molecules regulating ecological interactions. However, limitations in the analytical techniques on the one hand and time-demanding bioassays on the other have been restraining chemical ecology research. Application of metabolomics techniques has recently led to significant advancement of the field. Here, we discuss modifications to the traditional bioassay-guided fractionation approach with metabolomics techniques. We focus on two challenging topics within chemical ecology, waterborne cues and single-cell investigations, to highlight how metabolomics techniques can succeed where traditional approaches have failed. Graphical abstract ?. PMID- 30417268 TI - Are Developmental Assets Protective Against Suicidal Behavior? Differential Associations by Sexual Orientation. AB - Sexual orientation disparities in suicide behavior are well-documented. Yet, few studies have examined how developmental assets - key values, self-perceptions, skills, relationships, and opportunities that have been identified as the building blocks of positive youth development - are associated with suicide behaviors, particularly among sexual minority youth. This study examined concurrent associations between young people's developmental assets and suicidal behavior by sexual orientation using a large sample of 116,925 in-school U.S. adolescents (ages 11 to 19, M = 14.74, SD = 1.78). Most of the sample identified as only heterosexual (90.2%); 5% identified as mostly heterosexual, 3.5% as bisexual, 0.6% as mostly lesbian/gay, and 0.7% as only lesbian/gay. Most participants identified as White, non-Latina/o (62.6%) and as cisgender female (50.3%) or cisgender male (47.8%). Compared to only heterosexual adolescents, youth with all other sexual orientations reported lower levels of internal and external developmental assets except for non-sports extracurricular activity participation and social justice values. Identifying as a racial/ethnic minority, particularly for only heterosexual adolescents, and specifically as Latina/o for sexual minority adolescents was associated with greater risk for suicidal behavior. Further, identifying as a gender minority exacerbated risk for suicidal behavior. Relatedly, when youth reported feeling unsafe with their family, or in their school or neighborhood, they were at greater risk for suicidal behavior, regardless of sexual orientation. Feeling hopeful was associated with lower risk for suicidal behavior for all youth. Regardless of sexual orientation, planning and decision-making skills were associated with lower risk and social-emotional skills were associated with heightened risk for suicidal behavior. School boundaries and social justice values were associated with lower risk for suicidal behavior among bisexual adolescents; there were no additional protective assets for mostly/only lesbian/gay adolescents. In conclusion, sexual orientation disparities exist in the lives of adolescents for several internal and external developmental assets. Disparities in suicidal behavior by sexual orientation, however, were largely unexplained by differential associations between developmental assets and suicidal behavior. PMID- 30417267 TI - Yeast two-hybrid screening identifies MPZ-1 and PTP-1 as candidate scaffolding proteins of metabotropic glutamate receptors in Caenorhabditis elegans. AB - The metabotropic glutamate receptors (mGluRs) are a class of G-protein-coupled receptor that undergo extensive interactions with scaffolding proteins, and this is intrinsic to their function as an important group of neuromodulators at glutamatergic synapses. The Caenorhabditis elegans nervous system expresses three metabotropic glutamate receptors, MGL-1, MGL-2 and MGL-3. Relatively little is known about how the function and signalling of these receptors is organised in C. elegans. To identify proteins that scaffold the MGL-1 receptor, we have conducted a yeast two-hybrid screen. Three of the interacting proteins, MPZ-1, NRFL-1 and PTP-1, displayed motifs characteristic of mammalian mGluR scaffolding proteins. Using cellular co-expression criterion, we show mpz-1 and ptp-1 exhibited overlapping expression patterns with subsets of mgl-1 neurons. This included neurones in the pharyngeal nervous system that control the feeding organ of the worm. The mGluR agonist L-CCG-I inhibits the activity of this network in wild type worms, in an MGL-1 and dose-dependent manner. We utilised L-CCG-I to identify if MGL-1 function was disrupted in mutants with deletions in the mpz-1 gene. The mpz-1 mutants displayed a largely wild-type response to L-CCG-I, suggesting MGL-1 signalling is not overtly disrupted consistent with a non obligatory modulatory function in receptor scaffolding. The selectivity of the protein interactions and overlapping expression identified here warrant further investigation of the functional significance of scaffolding of metabotropic glutamate receptor function. PMID- 30417271 TI - "Mesentery-based surgery" to prevent surgical recurrence in Crohn's disease: from basics to surgical practice. PMID- 30417269 TI - Factors associated with the likelihood of fall-related injury among people with lower limb loss. AB - BACKGROUND: People with lower limb loss that live in the community fall at a rate that exceeds that of other vulnerable populations such as hospitalized elderly people. Past research in a small single state study has identified factors associated with fall-related injury. The purpose of this study was to use a larger multistate sample of people with lower limb loss living in community settings to evaluate factors associated with fall-related injury in a multivariable model. METHOD: This retrospective cohort study included community dwelling people with lower limb loss participating in wellness-walking programs in 6 states within the United States. Fall-related injury was considered injury sustained during a fall to the ground that required medical care. Pearson's Chi squared test and student's t-test were used for descriptive statistics. Odds ratios and 95% confidence intervals from multivariable logistic regression modelling were used to estimate the likelihood of fall-related injuries. RESULTS: Of the 303 subjects recruited, 257 (84.8%) were included in the analyses. Overall, 45 subjects (17.5%) reported at least a single fall-related injury. Most subjects reported two or more falls within the previous 12 months (N = 161, 63.1%), were male (N = 177, 68.9%), and were White (N = 212, 83.8%). Most falls were associated with gait (44.5%), activities of daily living (ADL, 15.7%), or ramps and/or stairs (12%). The likelihood of fall-related injury was elevated among females versus males (OR = 2.90, 95% CI 1.35, 6.24), people of non-White versus White race (OR = 4.79, 95% CI 1.06, 21.76), people with vascular amputations due to peripheral artery disease or diabetes versus non-vascular amputations (OR = 2.22, 95% CI 1.04, 4.73) and people with transtibial versus transfemoral amputations (OR = 2.32, 95% CI 1.01, 4.89). DISCUSSION: Results of this study show that the likelihood of fall-related injury was significantly higher among women, non-White race, people with vascular and transtibial amputations. The results from this study were largely consistent with results from the prior multivariable fall-related injury model. CONCLUSION: The results highlight the association of female sex, non-White race, vascular and transtibial amputations with the likelihood of fall-related injury. Future studies may use the study findings to develop educational fall prevention programs for women, minorities, and people with vascular etiology and transtibial amputations. PMID- 30417272 TI - Letter to the Editor: Circulating Adult Stem and Progenitor Cells After Roux-en-Y Gastric Bypass Surgery in Myotonic Dystrophy. PMID- 30417270 TI - Anxiety and Mood Disorders in Systemic Lupus Erythematosus: Current Insights and Future Directions. AB - PURPOSE OF REVIEW: Optimal management of anxiety and mood disorders in patients with systemic lupus erythematosus (SLE) is limited by an incomplete understanding of their pathophysiology and a lack of treatment guidelines. This review aims to critically synthesize recent literature on these conditions in adults with SLE, focusing on their etiology, assessment, and management. RECENT FINDINGS: Along with psychosocial factors, there is growing evidence for a bidirectional interaction between inflammatory pathways and SLE-associated anxiety and mood disorders. Direct immune-mediated mechanisms via autoantibodies may also play a role in some cases. With a growing number of tools used in SLE for the assessment of these conditions, the search continues for the ideal instrument to use in all future investigations to allow comparisons across studies. There is data supporting psychological interventions, but a dearth of literature on pharmacotherapy for the treatment of anxiety and mood disorders in SLE. There is a clear need for further research in anxiety and mood disorders in SLE, particularly with respect to diagnostic tools and medications, which could inform much-needed updates to current guidelines. PMID- 30417273 TI - Bariatric Surgery Did Not Increase the Risk of Gallstone Disease in Obese Patients: a Comprehensive Cohort Study. AB - PURPOSE: The aim of this study was to evaluate the influence of bariatric surgery on gallstone disease in obese patients. MATERIALS AND METHODS: This large cohort retrospective study was conducted based on the Taiwan National Health Insurance Research Database. All patients 18-55 years of age with a diagnosis code for obesity (ICD-9-CM codes 278.00-278.02 or 278.1) between 2003 and 2010 were included. Patients with a history of gallstone disease and hepatic malignancies were excluded. The patients were divided into non-surgical and bariatric surgery groups. Obesity surgery was defined by ICD-9-OP codes. We also enrolled healthy civilians as the general population. The primary end point was defined as re hospitalization with a diagnosis of gallstone disease after the index hospitalization. All patients were followed until the end of 2013, a biliary complication occurred, or death. RESULTS: Two thousand three hundred seventeen patients in the bariatric surgery group, 2331 patients in the non-surgical group, and 8162 patients in the general population were included. Compared to the non surgery group (2.79%), bariatric surgery (2.89%) did not elevate the risk of subsequent biliary events (HR = 1.075, p = 0.679). Compared to the general population (1.15%), bariatric surgery group had a significantly higher risk (HR = 4.996, p < 0.001). In the bariatric surgery group, female gender (HR = 1.774, p = 0.032) and a restrictive procedure (HR = 1.624, p = 0.048) were risk factors for gallstone disease. CONCLUSION: The risk for gallstone disease did not increase after bariatric surgery, although the risk was still higher than the general population. The benefit of concomitant cholecystectomy during bariatric surgery should be carefully evaluated. PMID- 30417274 TI - Transforming growth factor-beta1 mediated CHST11 and CHSY1 mRNA expression is ROS dependent in vascular smooth muscle cells. AB - Transforming growth factor (TGF)-beta1 mediates glycosaminoglycan (GAG) chain hyperelongation on secreted proteoglycans and these modifications are associated with increased lipid binding in the vessel wall and the development of atherosclerosis. In vascular smooth muscle cells (VSMCs), TGF-beta1 regulated GAG elongation via extracellular signal-regulated kinase (ERK) and p38 as well as Smad2 linker region phosphorylation. In this study, our aim was to identify the TGF-beta1 mediated signalling pathway involving reactive oxygen species (ROS) and Smad2 linker region phosphorylation that regulate the mRNA expression of GAG synthesizing enzymes, chondroitin 4-O-sulfotransferase 1 (CHST11) and chondroitin sulfate synthase 1 (CHSY1) which are the rate limiting enzymes involved in GAG chain elongation. Signalling molecules were assessed by western blotting, quantitative real-time PCR was used for analysis of gene expression and intracellular ROS level was measured by a fluorescence based assay. TGF-beta1 induced ROS production in VSMCs. Nicotinamide adenine dinucleotide phosphate oxidase (Nox) inhibitors, diphenyleneiodonium (DPI) and apocynin blocked TGF beta1 mediated Smad2 linker region phosphorylation. TGF-beta1 treatment increased the mRNA levels of CHST11 and CHSY1. Pharmacological inhibition of Nox blocked TGF-beta1 mediated mitogen activated protein kinases (MAPKs) phosphorylation and TGF-beta1 stimulated CHST11 and CHSY1 mRNA expression. These findings demonstrated that TGF-beta1 mediated expression of CHST11 and CHSY1 can occur via Nox-dependent pathways and Smad2 linker region phosphorylation. PMID- 30417276 TI - The basic helix-loop-helix transcription factor, bHLH11 functions in the iron uptake system in Arabidopsis thaliana. AB - Iron (Fe) is a micronutrient that is essential for plant development and growth. Basic helix-loop-helix (bHLH) transcription factors are a superfamily of transcription factors that are important regulatory components in transcriptional networks in plants. bHLH transcription factors have been divided into subclasses based on their amino acid sequences and domain structures. Among the members of clade IVb (PYE, bHLH121, and bHLH11), the functions of bHLH11 remain unclear. In the present study, we characterized bHLH11 as a negative regulator of Fe homeostasis. bHLH11 expression levels were high in the roots and up-regulated after plants were transferred to Fe sufficient conditions. Although T-DNA knockout mutants of bHLH11 were lethal, dominant negative (DN-) and overexpression (OX-) of bHLH11 plants exhibited sensitivity to Fe deficiency. Furthermore, the expression of FIT, a master regulator of Fe deficiency responses, was suppressed in the transgenic plants. These results suggest that the transcriptional repressor bHLH11 functions as a negative regulator of FIT dependent Fe uptake and modulates Fe levels in Arabidopsis plants. Salicylic acid (SA) modulates the expression of genes involved in Fe-deficient responses. We found that SA levels were elevated in DN- and OX-bHLH11 plants. The T-DNA insertion mutant sid2-1, which was defective for the production of SA, did not exhibit sensitivity to Fe deficiency; however, the crossed plants of OX-bHLH11 and sid2-1 relieved sensitivity to the Fe deficiency observed in OX-bHLH11 plants. These results suggest that the accumulation of SA is closely related to iron homeostasis. PMID- 30417277 TI - Improvement in Patient-Reported Outcomes (Dermatology Life Quality Index and the Psoriasis Symptoms and Signs Diary) with Guselkumab in Moderate-to-Severe Plaque Psoriasis: Results from the Phase III VOYAGE 1 and VOYAGE 2 Studies. AB - BACKGROUND: Health-related quality of life (HRQoL) may be markedly impaired in patients with moderate-to-severe psoriasis. OBJECTIVES: Our objectives were to compare improvements in Dermatology Life Quality Index (DLQI) and Psoriasis Symptoms and Signs Diary (PSSD) scores between patients receiving guselkumab compared with placebo or adalimumab and to correlate these improvements with skin clearance. METHODS: Pooled phase III VOYAGE 1 and VOYAGE 2 data were evaluated through week 24. At baseline, patients were randomized to guselkumab 100 mg, placebo, or adalimumab 40 mg. At week 16, patients receiving placebo switched to guselkumab. Assessment measures included DLQI percent change from baseline, DLQI 0/1, DLQI minimal clinically important difference (MCID), individual domain scores, PSSD symptoms and signs score = 0, DLQI association with PSSD, Investigator's Global Assessment (IGA), and Psoriasis Area and Severity Index (PASI). RESULTS: Significantly greater improvements from baseline DLQI were observed with guselkumab versus placebo (weeks 8 and 16) and versus adalimumab (week 24; p < 0.001). The proportion of patients achieving DLQI 0/1 ("no impact") at week 24 was higher with guselkumab than with adalimumab (58.9 vs. 40.2%; p < 0.001), and more patients attained a >= 4-point reduction in DLQI (MCID) at this timepoint (p < 0.001). Changes in individual DLQI domains were significantly greater for patients receiving guselkumab than for those receiving adalimumab, and among patients with individual baseline domain scores = 3 or 6 (severest impact), more guselkumab recipients than those receiving adalimumab achieved a score = 0 across all domains at week 24. DLQI 0/1 scores were associated with a PSSD symptom or sign score = 0 (no impact) and greater improvement of PASI and IGA (week 24). CONCLUSIONS: Pooled VOYAGE 1/VOYAGE 2 data demonstrated that guselkumab was superior to adalimumab in improving HRQoL, which was associated with greater skin clearance. CLINICAL TRIAL REGISTRATION: NCT02207231 and NCT02207244. PMID- 30417278 TI - Sleep duration mediates abdominal and lower-extremity pain after night work in nurses. AB - OBJECTIVES: The aim of this study was to investigate the association between different working shifts (i.e. morning, evening, night shifts) and headache, musculoskeletal and abdominal pain, and the extent to which reduced sleep duration could account for these associations. METHODS: Nurses (N = 679, 649 female, aged 22-53 years) were followed up for a period of 28 consecutive days, responding to a diary about sleep, shift type and pain complaints (measured on a Likert-type scale ranging from 0 to 3). Generalised structural equation modelling mediation analysis (GSEM) was performed to test whether shift type was associated with higher incidence or higher intensity of pain (headache, pain in neck/shoulders/upper back, upper extremity, low back, lower extremity and abdominal pain), and if this effect was mediated by sleep duration (continuous variable), after controlling for age, work and lifestyle factors. RESULTS: Pain scores in lower extremities were decreased following night shifts in general. However, when night shifts were followed by short sleep duration, the risk of pain in the lower extremities and abdominal pain were increased. Headache and pain in the upper extremity were increased after night shifts, but were not associated with sleep duration. Pain in the neck/shoulder/upper back and lower back was not related to shift work. CONCLUSIONS: Among nurses in a three-shift rotating schedule, night shifts increased the risk of pain in several regions, but only pain in the lower extremities and abdomen was related to reduced sleep duration. PMID- 30417279 TI - A randomized placebo-controlled single-center pilot study of the safety and efficacy of apremilast in subjects with moderate-to-severe alopecia areata. AB - Alopecia areata (AA) is a common autoimmune disease that results in non-scarring hair loss. AA pathogenesis is thought to involve multiple inflammatory cytokines. Apremilast is a phosphodiesterase 4 (PDE4) inhibitor that reduces pro inflammatory cytokine production. Recent studies demonstrate upregulation of PDE4 in human scalp lesions of AA patients and hair regrowth in a humanized AA mouse model upon apremilast treatment, suggesting a possible potential of apremilast in AA. To assess the efficacy and safety of apremilast in AA, we conducted a double blind, placebo-controlled single-center pilot study in 30 moderate-to-severe AA patients (>= 50% scalp involvement) that were randomized 2:1 to receive apremilast (n = 20) or placebo (n = 10) orally for 24 weeks. The primary endpoint was the percentage of patients achieving 50% reduction in severity of alopecia tool (SALT) score (SALT50) at 24 weeks compared to baseline, and the secondary endpoints included the percent change in SALT score at weeks 24 and 48. Eight patients in the apremilast arm withdrew prior to week 24 along with two patients in the placebo group, mostly due to lack of efficacy and adverse events. At 24 weeks, only 1 of 12 apremilast-treated subjects achieved SALT50, and similarly 1 of 8 placebo-treated subjects achieved SALT50. The difference between the mean percent improvement in SALT score at week 24 compared to baseline of the two study arms was not statistically significant (p = 0.38). The lack of treatment response in most of our patients argues against a pathogenic role for PDE4 specifically in moderate-to-severe AA, but targeting this pathway may still be of value in patients with mild AA as there is less of an inflammatory burden in this population. However, future larger studies may be needed to conclude apremilast's lack of efficacy in moderate-to-severe AA. PMID- 30417280 TI - A modified preplate technique for efficient isolation and proliferation of mice muscle-derived stem cells. AB - We modified an existing protocol to develop a more efficient method to acquire and culture muscle-derived stem cells (MDSCs) and compared the characteristics of cells obtained from the two methods. This method is based on currently used multistep enzymatic digestion and preplate technique. During the replating process, we replaced the traditional medium with isolation medium to promote fibroblast-like cell adherence at initial replating step, which shortened the purifying duration by up to 4 days. Moreover, we modified the culture container to provide a stable microenvironment that promotes MDSC adherence. We compared the cell morphology, growth curve and the expression of specific markers (Sca-1, CD34, PAX7 and Desmin) between the two cell groups separately obtained from the two methods. Afterwards, we compared the neural differentiation capacity of MDSCs with other muscle-derived cell lineages. The protocol developed here is a fast and effective method to harvest and purify MDSCs from mice limb skeletal muscle. PMID- 30417282 TI - Antioxidant Properties of a Pharmaceutical Substance Hypocard, a Potential Drug for Ischemic Disease. AB - Antioxidant activity of a pharmaceutical substance hypocard was compared with activity of nitromalic acid and well-known agents nicorandil and Mexidol. The ability of these substances to inhibit spontaneous and oxidant-induced LPO process in rat brain homogenate was analyzed. The mechanisms of these effects were studied. The antioxidant properties of hypocard manifested in the inhibition of Fe(II)-induced LPO were significantly more pronounced in comparison with Mexidol and nicorandil. PMID- 30417281 TI - Extended laparoscopic distal pancreatectomy for adenocarcinoma in the body and tail of the pancreas: a single-center experience. AB - PURPOSE: Extended resection is required for pancreatic adenocarcinoma infiltrating adjacent organs and structures. The role of laparoscopy in this setting is unclear. In this study, the outcomes of extended laparoscopic distal pancreatectomy (ELDP) for pancreatic body/tail adenocarcinoma were examined. METHODS: Perioperative and oncologic data were analyzed in patients undergoing laparoscopic distal pancreatectomy (LDP) for adenocarcinoma at Oslo University Hospital. ELDP was defined as suggested by the International Study Group for Pancreatic Surgery. The outcomes of ELDP were compared to those following standard LDP (SLDP). RESULTS: From August 2001 to June 2016, 460 consecutive patients underwent LDP for pancreatic neoplasms including 116 (25%) adenocarcinoma. SLDP and ELDP were applied in 78 and 31 patients, respectively. The adrenal gland (33%) and colon (21%) were the most frequently resected organs during ELDP. The latter was associated with larger tumor size (5.5 vs 4 cm, p = 0.03), longer operative time (236 vs 158 min, p = 0.001) and higher conversion rate (16 vs 3%, p = 0.019) compared with SLDP. Morbidity and 90-day mortality were similar. Median follow-up was 18 months. In patients with ductal adenocarcinoma, ELDP (n = 22) was associated with significantly shorter recurrence-free and overall survival than SLDP (n = 59) (6.2 vs 9.6 months, p = 0.047 and 12.9 vs 27 months, p < 0.01, respectively). CONCLUSION: Although technically challenging, ELDP is feasible in patients with adenocarcinoma providing acceptable surgical outcomes. ELDP for ductal adenocarcinoma is associated with worse prognosis than SLDP, while its potential benefits over palliative care deserve further scrutiny. PMID- 30417283 TI - Surface Molecular Markers of Cancer Stem Cells: Computation Analysis of Full-Text Scientific Articles. AB - The data on cancer stem cell surface molecular markers of 27 most common cancer diseases were analyzed using natural language processing and data mining techniques. As a source, 8933 full-text open-access English-language scientific articles available on the Internet were used. Text mining was based on searching for three entities within one sentence, namely a tumor name, a phrase "cancer stem cells" or its synonym, and a name of differentiation cluster molecule. As a result, a list of surface molecular markers was formed that included markers most frequently mentioned in the context of certain tumor diseases and used in studies of human and animal tumor cells. Based on similarity of the associated markers, the tumors were divided into five groups. PMID- 30417284 TI - The Dependence of the Mutagenic Effect on the Dose of X-Ray Irradiation in an In Vivo Experiment on Female (CBA*C57Bl/6)F1 Mice. AB - We studied the mutagenic effect of X-ray irradiation in doses of 0.5, 1, and 1.5 Gy on female (CBA*C57Bl/6)F1 mice. The mutagenic effect (assessed by the parameter "frequency of bone marrow polychromatophilic erythrocytes with micronuclei") linearly depended on the dose of X-ray irradiation in the range of up to 1 Gy and reached the plateau at 1.5 Gy. The fraction of polychromatophilic erythrocytes was 45, 45, and 46% under control conditions (without exposure) and exposure to the irradiation in the doses of 0.5 and 1 Gy, respectively. Irradiation in a dose of 1.5 Gy induced a slight inhibition of erythropoiesis. These data confirm the hypothesis on possible death of highly aberrant erythrocyte precursors after irradiation in high doses. PMID- 30417285 TI - Comparative Analysis of the Formation of gammaH2AX Foci in Human Mesenchymal Stem Cells Exposed to 3H-Thymidine, Tritium Oxide, and X-Rays Irradiation. AB - We performed a comparative study of the formation of gammaN2AX foci (a marker of DNA doublestrand breaks) in human bone marrow mesenchymal stem cells after 24-h incubation with 3N-thimidin and tritium oxide with low specific activities (50 800 MBq/liter). The dependence of the number of gammaH2AX foci on specific activity of 3H-thymidine was described by a linear equation y=2.21+43.45x (R2=0.96), where y is the number of gammaH2AX foci per nucleus and x is specific activity in 1000 MBq/liter. For tritium oxide, the relationship was described by a linear equation y=2.52+6.70x (R2=0.97). Thus, the yield of DNA double-strand breaks after exposure to 3H-thymidine was 6.5-fold higher than after exposure to tritium oxide. Comparison of the effects of tritium oxide and X-ray radiation on the yield of DNA double-strand breaks showed that the relative biological efficiency of tritium oxide in a dose range of 3.78-60.26 mGy was 1.6-fold higher than that of X-ray radiation. Improvement of the methods of analysis of DNA double-strand breaks repair foci is highly promising in the context of creation of highly sensitive biodosimetry technologies for tritium compounds in humans. PMID- 30417286 TI - A Cell Model of Human Small Intestinal Wall Based on Genetically Modified Caco-2 Cells. AB - We propose a cell model of the human small intestinal wall based on genetically modified Caco-2 cells that allows visualization and quantitative assessment of activation of NF-kappaB factor and related intracellular pathway by using fluorescence microscopy. A dose-dependent increase in fluorescence intensity of the obtained cells in response to TNFalpha exposure in concentrations of 1-100 ng/ml was demonstrated. It was found that this parameter correlates with a decrease in the transepithelial resistance of the cell monolayer in response to TNFalpha and can be used to assess the toxic effects of substances on epithelial cells of the human small intestine. PMID- 30417287 TI - Non-Invasive Evaluation of Extracellular Matrix Formation in the Intestinal Epithelium. AB - Differentiation of colorectal cancer Caco-2 cells was assessed using Affymetrix Human Gene 1.0 ST arrays and by the main electrical parameters measured by bioimpedance spectroscopy. Transepithelial electrical resistance (TEER) was maximum on day 7, then decreased by day 11, and remained stable. The baseline resistance was maximum on day 4, minimum on day 7, but then gradually increased over 2 weeks, which can be explained by the formation of the basement membrane components or the apical mucous layer. Caco-2 cells express components of laminin 111 and laminin-511. A synchronous increase in the expression of mucin 3 mRNA (MUC3A/MUC3B) and mucin 17 mRNA (MUC17) and reduced expression of miR-21 and miR 622 microRNA genes were observed. Possible use of the described approach for studying the formation of extracellular matrix is discussed. PMID- 30417288 TI - Assessment of Lactate Production and Proteoglycans Synthesis by the Intact and Degenerated Intervertebral Disc Cells under the Influence of Activated Macrophages: an In Vitro Study. AB - The effects of proinflammatory cytokines on the secretion of glycosaminoglycans and lactate production by normal and degenerated intervertebral disk cells were studied on the model of their co-culturing with activated macrophage-like cells. It was found that proinflammatory cytokines produced a direct effect on intervertebral disk cells in a 3D culture reducing the rate of glycolysis and synthetic activity of both normal and degenerated cells of annulus fibrosus and nucleus pulposus, which is an important factor in progression of intervertebral disk degeneration. PMID- 30417289 TI - Induction of Vasculo- and Osteogenesis in Spheroids Formed by Adipose-Derived Stromal Cells. AB - Vascularization of bioengineered bone tissue constructs remains a challenging problem of regenerative medicine. Spheroids generated in 3D culture of adipose derived stromal cells supplemented with inducing factors demonstrate stable characteristics and express of mesenchymal, endothelial, and osteoblasts markers, and represent a prototype of vascularized microtissue. Adipose-derived stromal cells spheroids induced to both angio- and osteogenic differentiation can be used in development of new innovative technologies for in vitro fabrication of vascularized bioequivalents for repair of large bone defects. PMID- 30417290 TI - DMSO-Free Cryopreservation of Human Umbilical Cord Tissue. AB - Human umbilical cord represents a source of multipotent stromal cells of a supreme therapeutic potential. The cells can be isolated from either fresh or cryopreserved umbilical cord tissues. DMSO is a cryoprotectant most commonly used for preservation of umbilical cord tissues; however, cyto- and genotoxicity of this compound is evident and well documented. In the present study we performed successful cryopreservation of the umbilical cord tissue using other cryoprotectants: propylene glycol, ethylene glycol, and glycerol. Of these, 1.5 M ethylene glycol and 20% glycerol turned out to be the best in terms of the preservation of living cells within the frozen tissue, early onset of migration of these cells out of the thawed explants, and overall efficacy of multipotent stromal cell isolation. Cryobanking of tissues can improve availability of multiple cell products for medical purposes and promote the development of personalized medicine. PMID- 30417291 TI - Development of an In Vitro Model of Inflammatory Cytokine Influences on Intervertebral Disk Cells in 3D Cell Culture Using Activated Macrophage-Like THP 1 Cells. AB - We developed a new model for evaluation of the influence of proinflammatory cytokines on intervertebral disc cells in a 3D culture based on co-culturing of these cells with activated macrophage-like THP-1 cells. The levels of TNFalpha, IL-1beta, IL-6, IL-8, IL-10, and IL-12p70 production were assessed by flow cytofluorometry using microspheres. Considerable differences in the level of spontaneous cytokine secretion by normal and degenerated intervertebral disc cells were revealed. A significant increase in the level of IL-1beta and IL-8 was observed during co-culturing, which confirms consistency of the developed model. PMID- 30417292 TI - Effect of 30-Day Hindlimb Unloading and Hypergravity on Bone Marrow Stromal Progenitors in C57Bl/6N Mice. AB - We studied the effect of 30-day hindlimb unloading and subsequent simulated hypergravity on the cellularity and proliferative, clonogenic, and differentiation potential of bone marrow stromal progenitors in mice. Clonogenic and differentiation activity of stromal cells decreased after unloading; proliferative and differentiation activity of bone marrow stromal progenitors increased after hypergravity simulation. Our findings demonstrated negative effect of unloading on functional activity of mouse bone marrow stromal progenitors. Short-term hypergravity after unloading produced a stimulating effect on the bone marrow stromal progenitors. PMID- 30417293 TI - Human Umbilical Cord Mesenchymal Stromal Cell-Derived Microvesicles Express Surface Markers Identical to the Phenotype of Parental Cells. AB - Production of microvesicles in culture of human umbilical cord multipotent mesenchymal stromal cells was studied and comparative analysis of the expression of some surface molecules (clusters of differentiation, CD) was performed. It was found that the mesenchymal stromal cells produce microvesicles in the amount sufficient for their detection by flow cytometry. Parallel analysis of the phenotypes of maternal mesenchymal stromal cells and secreted microvesicles revealed identical expression of surface molecules CD13, CD29, CD44, CD54, CD71, CD73, CD90, CD105, CD106, and HLA-I. The concentration of microvesicles in the conditioned medium was 17.9+/-4.6*106/ml; i.e. one cell produced ~40-50 (44.7+/ 11.5) microvesicles over 2 days in culture. PMID- 30417295 TI - Individual Peculiarities of the Development and Differentiation of Embryonic Neocortex Transplants in Intact Adult Mouse Brain. AB - We studied individual peculiarities of the development and differentiation of allogeneic transplants of neocortical cells isolated from embryos at different stages of development in intact brain of adult mice. Despite standard transplantation technique, intraparenchymal grafts considerably varied in size, morphology, and structural organization. The cells in the transplants developing inside the brain ventricles of the recipient formed histotypical structures resembling organoids. Transplants of each age group (12.5, 14.5, and 19.5 days) demonstrated individual peculiarities of cell migration, differentiation, and fiber growth. Only from cells of 12.5-day transplants formed spiny pyramidal neurons typical of V layer of the cerebral cortex. Differentiation of catecholaminergic neurons untypical of brain cortex was observed only in 14.5-day transplants. In few transplants of each age group, extensive cell migration from the transplant was observed. In some transplants, dense astrocyte accumulation was seen. In all cases (n=52), the response of the recipient's glia to the transplant was observed, but formation of an extensive glial barrier was noted only in one case. Our findings suggest that the entire range of the results determined by individual peculiarities of the transplant growth and recipient's response should be thoroughly realized when introducing the methods of neurotransplantation into regenerative medicine. PMID- 30417294 TI - Survival and Migration of Rat Olfactory Ensheathing Cells after Transplantation into Posttraumatic Cysts in the Spinal Cord. AB - We studied survival of rat ensheathing cells after transplantation into experimental posttraumatic cysts. These cells were prepared according to our original protocol, labeled with intravital membrane dye PKH26, and transplanted into posttraumatic cysts of the spinal cord. The presence of cysts was verified by magnetic resonance imaging. Olfactory ensheathing cells were detected in the spinal cord by the immunofluorescence method. It was shown that rat olfactory ensheathing cells survived in the spinal cord over 4 weeks and their migration was observed. High survival rate and the possibility of obtaining olfactory ensheathing cells from the olfactory mucosa of patients for creation of an autologous preparation allow considering them as very promising material for the treatment of patients with posttraumatic cysts of the spinal cord. PMID- 30417296 TI - Blood Pressure Changes After Exposures Increasing Angiotensin-Converting Enzyme Activity and After Its Normalization with Dihydroquercetin in Male Wistar Rats. AB - Changes in BP and HR were assessed after exposures increasing activity of angiotensin-converting enzyme: ionizing radiation, NO synthase inhibitor (L NAME), and dexamethasone. Effects of dihydroquercetin and angiotensin-converting enzyme inhibitor enalapril on activity of this enzyme, BP, and HR were also evaluated under these exposures. Wistar male rats were subjected to X-ray irradiation in a dose of 2.5 Gy. Angiotensin-converting enzyme activity in the aorta sections was determined by Hip-His-Leu hydrolysis. BP and HR were recorded using a non-invasive tail-cuff method and PowerLab 8/35 software. BP and HR were not altered with the increase in activity of angiotensin-converting enzyme after irradiation. In case of prolonged (7 days) treatment with NO synthase inhibitor and dexamethasone, the increase in enzyme activity was accompanied by elevation of BP and, in the case of NO synthase inhibitor, HR reduction. Dihydroquercetin normalized the enzyme activity and lowered BP, but not to the normal level. Enalapril normalized BP, increased by NO synthase inhibitor solution intake; at the same time, the angiotensinconverting enzyme activity decreased more than 2 fold in comparison with the normal. PMID- 30417297 TI - Biochemical and Morphological Parameters of Inbred/Outbred Lines and DBCB Tetrahybrid Mouse in High-Sugar In Vivo Model of Metabolic Syndrome. AB - Integral, biochemical, and morphological parameters and concentrations of vitamins, particularly lipid soluble vitamins, were analyzed in female mice of inbred DBA/2J line, outbred ICR-1 (CD-1) line, and DBCB tetrahybrid mice on the in vivo model of metabolic syndrome induced by consumption of 30% sucrose for 2 days. In contrast to inbred and outbred lines, DBCB tetrahybrid mice developed abdominal obesity, hypercholesterolemia, and pronounced morphological picture of fatty liver disease. The lipid-coupled transport of vitamin E to the liver is also enhanced in these animals, which compensated decreased supply of vitamin E to the liver under conditions of high-sugar ration. The observed interstrain differences can be related to genetic features of the used mouse lines and DBCB tetrahybrid mice and require further genomic, transcriptomic, proteomic, and morphological studies. The results of the study based on the in vivo model of metabolic syndrome allow identifying the key biomarkers for complex diagnostics and prognosis of metabolic syndrome complications, such as nonalcoholic steatosis of the liver. PMID- 30417298 TI - Aminoethane Sulfonic Acid Magnesium Salt Inhibits Ca2+ Entry Through NMDA Receptor Ion Channel In Vitro. AB - The effect of a cerebroprotective agent magnesium bis-aminoethanesulfonate (laboratory code FS-LKhT-317) on intracellular calcium concentration was studied by the fluorescent imaging technique on neuroglial cell culture from Spraque Dawley rat hippocampus. The substance produced a pronounced inhibitory effect and suppressed NMDA receptor activity in concentrations of >=50 MUM. The observed effects were reversible or partially reversible and were detected by a decrease in Ca2+ signal amplitude in neurons in response to NMDA applications in a Mg2+ free medium and by inhibition of Ca2+ pulses in magnesium-free medium (elimination of magnesium block). PMID- 30417299 TI - Immunohistochemical Features of Different Types of Unstable Atherosclerotic Plaques of Coronary Arteries. AB - We performed a complex morphological study of samples of different types of unstable atherosclerotic plaques obtained from 33 men with occlusive coronary atherosclerosis, who underwent coronary artery endarterectomy during coronary artery bypass surgery. In the samples, expression of MMP-2 and MMP-9, collagen IV, CD31, CD34, factor VIII, and actin of smooth muscle cells was evaluated by morphometric and immunohistochemical methods. The maximum expression of MMP-9 was found in unstable plaques of the lipid type, where it 1.4- and 1.24-fold surpassed the corresponding levels in plaques of the inflammatory-erosive and degenerative-necrotic types. Unstable plaques of the degenerative-necrotic type are characterized by the most intensive expression of collagen IV in comparison with plaques of the inflammatory-erosive and lipid types (by 2.8 and 2.2 times, respectively). The maximum neovascularization was detected in inflammatory erosive plaques, which was confirmed by enhanced expression of CD31 and CD34 markers in comparison with plaques of the lipid (by 7.6 and 18.95 times, respectively) and degenerative-necrotic (by 31.1 and 39.8 times) types. PMID- 30417300 TI - Extracellular DNA in the Dynamics of Uncomplicated Pregnancy. AB - We analyzed the concentration of extracellular DNA and its fractions in the dynamics of uncomplicated pregnancy Thirty women with singleton pregnancy were examined. The concentration of total, maternal, and fetal cell-free DNA in maternal blood was measured at gestation weeks 11-14, 24-26, and 30-32. The level of total cell-free DNA was evaluated by measuring the concentration of RASSF1A gene using quantitative PCR analysis, the level of cell-free fetal DNA was assessed by determining the hypermethylated part of RASSF1A gene. The concentration of total cell-free DNA and cell-free maternal DNA did not change during the first half of pregnancy, but increased after 24-26 weeks. The level of cell-free fetal DNA increased from the first to the second and third trimester: 14.15 (2.32-36.25), 24.87 (6.29-129.32), and 32.62 (8.97-133.52) GE/ml (p<0.05), respectively. Our results characterize the dynamics of the content of cell-free DNA and its fractions during pregnancy, which should be taken into account when using cell-free DNA for prediction of placenta-associated complications. PMID- 30417301 TI - Changes in the Expression of Calbindin and Calretinin in Interneurons of the Spinal Dorsal Horns Under Conditions of Antiorthostatic Suspension in Mice. AB - In female C57Bl/6 mice subjected to antiorthostatic suspension of the hind limbs for 30 days, calbindin- and calretinin-containing interneurons of the dorsal horns of the upper thoracic segments of the spinal cord were studied using immunohistochemical methods. In mice of the experimental group, cross-sectional area of calbindin- and calretinin-containing interneurons decreased in laminae I, II, and III and increased in laminae IV and V and in the region of the medial edge of the dorsal horn. After antiorthostatic suspension, expression of calretinin decreased in interneurons of laminae I and II and calbindin expression increased in the interneurons of laminae III, IV, and V. The total number of interneurons in laminae of the spinal cord detected by Nissl staining in the control and experimental groups remained unchanged. After antiorthostatic suspension and in control group, number of interneurons immunoreactive for calbindin and calretinin was maximum in lamina II and minimum in laminae IV and V and in the region of the medial edge of the spinal dorsal horn. PMID- 30417302 TI - Neuroprotective Effects of Dibornol in Focal Cerebral Ischemia/Reperfusion in Rats. AB - Neuroprotective activity of 2,6-diisobornyl-4-methylphenol (Dibornol) was studied under conditions of experimental focal cerebral ischemia/reperfusion modeled by intraluminal occlusion of the left middle cerebral artery for 1 h followed by recirculation. Dibornol administered in a dose of 10 mg/kg intragastrically 24 h and 30 min before and 24 h after focal ischemia/reperfusion modeling reduced the size of the brain infarction zone by 52% (48 h after recirculation) and neurological deficit by 1.7-2.4 times in comparison with that in control animals. PMID- 30417303 TI - Combined Effect of TLR2 Ligands on ROS Production by Mouse Peritoneal Macrophages. AB - TLR2-mediated ROS production by mouse peritoneal macrophages was studied by luminoldependent chemiluminescence under conditions of cell stimulation with zymosan (TLR2/6 ligand) and peptidoglycan (TLR2/1 ligand). ROS production by macrophages stimulated with zymosan and peptidoglycan simultaneously depended on the ratio of ligand concentrations. Three effects were revealed: additivity of the stimulating effects of the ligands used, competitive ligand binding, and effect of macrophage priming with peptidoglycan during cell stimulation with zymosan. The mechanisms of these effects are discussed. PMID- 30417304 TI - Polyunsaturated Fatty Acids and Their Correlations with Parameters of Oxidative/Antioxidant Potential of the Blood and Lipoprotein-Associated Phospholipase A2 in Coronary Atherosclerosis. AB - We studied serum content of some polyunsaturated fatty acids and their correlations with parameters of oxidative stress (FORT), antioxidant protection (FORD), lipoprotein-associated phospholipase A2 (LP-PLA2), and serum level of LPO products in male patients with coronary atherosclerosis. The mass fraction of polyunsaturated fatty acids and FORD were lower, while LP-PLA2, FORT, and concentration of LPO products were higher than in the control group (conventionally healthy men). Negative correlations of medium strength of polyunsaturated fatty acids with inflammation markers and oxidative stress were revealed, which can indicate that the decrease in polyunsaturated fatty acids content is associated with enhanced generation of free radicals, and consequently with increased risk of early atherosclerosis development. PMID- 30417305 TI - Peculiarities of Participation of DNA Methyltransferases in the Mechanisms of Storage, Impairment, and Recovery of Conditioned Food Aversion Memory. AB - We studied the participation of DNA-methylation processes in the mechanisms of memory storage and reconsolidation, amnesia induction, and in recovery of the conditioned food aversion memory in edible snails. It was found that daily injections of DNA methyltransferases inhibitor over 3 days combined with a reminder of a conditioned food stimulus did not affect memory storage. The administration of DNA methyltransferase inhibitors did not suppress induction of amnesia caused the NMDA receptor antagonist/reminder. Injections of DNA methyltransferase inhibitors combined with the reminder led to memory recovery in 3 days after amnesia induction. Thus, DNA methyltransferase inhibitors in the same doses did not affect storage and reconsolidation of memory, as well as the mechanisms of amnesia induction. At the same time, injections of inhibitors led to memory recovery, apparently, due to disruption of reactivation and amnesia development. PMID- 30417307 TI - Biosynthesis of omega-hydroxy fatty acids and related chemicals from natural fatty acids by recombinant Escherichia coli. AB - omega-Hydroxy fatty acids (omega-HFAs) are of great interest because they provide the long carbon chain monomers in the synthesis of polymer materials due to the location of the hydroxyl group close to the end of the first methyl carbon. omega HFAs are widely used as building blocks and intermediates in the chemical, pharmaceutical, and food industries. Recent achievements in metabolic engineering and synthetic biology enabled Escherichia coli to produce these fatty acids with high yield and productivity. These include (i) design and engineering of the omega-HFA biosynthetic pathways, (ii) enzyme engineering to enhance stability and activity, and (iii) increase of tolerance of E. coli to toxic effects of fatty acids. Strategies for improving product yield and productivity of omega-HFAs and their related chemicals (e.g., alpha,omega-dicarboxylic acids and omega-amino carboxylic acids) are systematically demonstrated in this review. PMID- 30417306 TI - Multiplex PCR coupled with direct amplicon sequencing for simultaneous detection of numerous waterborne pathogens. AB - The current water quality monitoring and regulation approaches use fecal indicator bacteria (FIB) to indirectly assess health risks from fecal pathogens. Direct detection of waterborne pathogens is expected to provide more accurate and comprehensive risk assessment, which however has been hindered by the lack of methods for simultaneous detection of the numerous waterborne pathogens. This study aimed to develop a mPCR-NGS approach that uses the high sequencing depth of NGS and sequence-based detection to significantly increase the multiplex level of mPCR for direct pathogen detection in water. Individual PCR primers were designed for 16 target marker genes of nine different bacterial pathogens, and an optimal combination of primers with least primer complementarities was identified for the multiplex setting. Using an artificial tester sample, the mPCR system was optimized for annealing temperature and primer concentration, and bioinformatic procedures were developed to directly detect the target marker gene amplicons in NGS sequence reads, which showed simultaneous detection of 14 different target genes in one reaction. The effectiveness of the developed mPCR-NGS approach was subsequently demonstrated on DNA extracts from stream water samples and their counterparts that were spiked with various target pathogen DNA, and all target genes spiked into the environmental water samples were successfully detected. Several key issues for further improving the mPCR-NGS approach were also identified and discussed. PMID- 30417308 TI - Characterization and functional analysis of calcium/calmodulin-dependent protein kinases (CaMKs) in the nematode-trapping fungus Arthrobotrys oligospora. AB - Ca2+/calmodulin-dependent protein kinases (CaMKs) are unique second-messenger molecules that impact almost all cellular processes in eukaryotes. In this study, five genes encoding different CaMKs were characterized in the nematode-trapping fungus Arthrobotrys oligospora. These CaMKs, which were retrieved from the A. oligospora genome according to their orthologs in fungi such as Aspergillus nidulans and Neurospora crassa, were expressed at a low level in vitro during mycelial growth stages. Five deletion mutants corresponding to these CaMKs led to growth defects in different media and increased sensitivity to several environmental stresses, including H2O2, menadione, SDS, and Congo red; they also reduced the ability to produce conidia and traps, thus causing a deficiency in nematicidal ability as well. In addition, the transcriptional levels of several typical sporulation-related genes, such as MedA, VelB, and VeA, were down regulated in all DeltaCaMK mutants compared with the wild-type (WT) strain. Moreover, these mutants exhibited hypersensitivity to heat shock and ultraviolet radiation stresses compared with the WT strain. These results suggest that the five CaMKs in A. oligospora are involved in regulating multiple cellular processes, such as growth, environmental stress tolerance, conidiation, trap formation, and virulence. PMID- 30417309 TI - Synthesis of CdS1-XSeX quantum dots in a protozoa Tetrahymena pyriformis. AB - Quantum dots (QDs) are recognized as the excellent fluorescence and photochemical materials to be applied in bioimaging, biomedical, and solar cell fields. Biosynthesized QDs (bio-QDs) have attracted attention due to their simple, eco friendly, and excellent biocompatible traits. Moreover, bio-QDs could not be replaced by chemically fabricated QDs in many fields. Bio-QDs synthesized by different microorganisms have diverse characteristics. In this work, the biosynthesis of QDs by Tetrahymena pyriformis, a typical protozoa in aquatic environments, was achieved for the first time. The synthesized materials by T. pyriformis emitted yellow fluorescence and had an average diameter of 8.27 +/- 0.77 nm. Spectral characterization results demonstrated that the synthesized QDs were CdS1-XSeX. Meanwhile, the fluorescence intensities of the synthesized bio QDs showed a linear relationship with Cd2+ dosage ranging from 20 to 80 MUM. The fluorescence enhancement of the synthesized QDs was highly selective to Cd2+ compared to other metal ions. The bio-QDs were demonstrated to have a great potential to be applied for Cd2+ detection. This work provides valuable information about the transformation of heavy metal ions in protozoan and is useful to accelerate the applications of the synthesized QDs. PMID- 30417310 TI - Improving extracellular protein production in Escherichia coli by overexpressing D,D-carboxypeptidase to perturb peptidoglycan network synthesis and structure. AB - Most recombinant proteins in Escherichia coli are not efficiently secreted to the extracellular space. Structural stabilisation of the cell wall is essential for extracellular protein production in E. coli, for which D,D-carboxypeptidases are essential. Herein, we perturbed the peptidoglycan structure of the E. coli cell wall by overexpressing D,D-carboxypeptidase genes dacA or dacB, and investigated the effect on extracellular protein production. Overexpression of dacA or dacB promoted the accumulation of intracellular soluble peptidoglycan, altered cell morphology (shape and size) and led to the formation of transparent globular structures in E. coli cells. Compared with controls (CK), extracellular production of recombinant green fluorescent protein (GFP) was increased by 1.7- and 2.3-fold upon overexpression of dacA and dacB, respectively. Similarly, extracellular production of recombinant amylase and alpha-galactosidase was increased by 4.5- and 2.8-fold, respectively, upon overexpression of dacA, and by 11.9- and 2.5-fold, respectively, upon overexpression of dacB. Overexpression of dacA or dacB enhanced both the outer and inner membrane permeability of E. coli. This cell wall engineering strategy opens up a new direction for enhancing extracellular protein and chemical production in E. coli. PMID- 30417311 TI - Modified ERG-JetTM contact lens electrodes for use in infants and toddlers update. AB - PURPOSE: To describe recent changes in the dimensions of the ERG-jet contact lens electrode, and to suggest corresponding changes in the dimensions of cylindrical stents to facilitate the use of ERG-jet contact lens electrodes in infants and small children. METHODS: Upon the observation that existing cylindrical stents no longer fit newly purchased ERG-jet contact lenses, the spacings between the "bumps" on the front surface of old and new electrodes were measured with calipers, and prototype stents were newly machined from acrylic plastic. RESULTS: Cylindrical stents with an outside diameter of 0.277 inches (about 7.04 mm) were found to fit snugly between the front surface "bumps" of new ERG-jet contact lens electrodes. CONCLUSIONS: Recent modifications in the injection molds for ERG-jet contact lens electrodes have resulted in an increase in the space between the "bumps" on the front surface of the electrodes, necessitating a corresponding increase in the outside diameter of cylindrical stents intended to fit snugly between the "bumps" for ease of insertion and prevention of lid closure. PMID- 30417312 TI - Differences in Cardiovascular Manifestation of Marfan Syndrome Between Children and Adults. AB - Marfan syndrome (MFS) is a connective tissue disorder characterized by a broad range of clinical manifestations. Cardiovascular involvement is the most life threatening aspect of the syndrome. Although abnormalities within the cardiovascular system in adults are well documented, there is still a paucity of data regarding manifestation of MFS in childhood. The aim of the study was to compare cardiovascular manifestation of MFS between children and adults. The study population consisted of 236 patients (144 children and 92 adults), who were referred to our department with suspicion of MFS. All patients underwent complete clinical evaluation in order to confirm the diagnosis of MFS according to the modified Ghent criteria. MFS was diagnosed in 101 (44 children and 57 adults) out of the 236 patients. The other patients were diagnosed with Ehlers-Danlos syndrome, Loeys-Dietz syndrome, MASS phenotype, ectopia lentis syndrome, marfanoid habitus and other rare syndromes. The most common cardiovascular abnormality was aortic root dilatation (81.19% of patients). It was found that both adults and children had similar high rates of aortic root dilatation. Similarly, there was no significant difference with regard to the prevalence of aortic valve regurgitation and mitral valve prolapse among children and adults. These findings equivocally indicate that the aforementioned abnormalities develop in early childhood, therefore, they may be used in the early identification of patients with MFS. Other assessed abnormalities, which included mitral valve regurgitation, pulmonary artery dilation, aneurysms of aortic arch, descending thoracic aorta and abdominal aorta were found mostly in adults, and thus, are of less use in the early detection of MFS. PMID- 30417313 TI - Prognostic significance of serum alkaline phosphatase and lactate dehydrogenase levels in patients with unresectable advanced gastric cancer. AB - BACKGROUND: This study evaluated the prognostic value of alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) together with host-related factors in patients with unresectable advanced gastric cancer. METHODS: The study enrolled 262 patients who received chemotherapy for unresectable advanced gastric cancer at Kochi Medical School from 2007 to 2015. Clinicopathological information and systemic inflammatory response data were analyzed for associations between baseline cancer-related prognostic variables and survival outcomes. RESULTS: The median survival time was significantly lower for patients with high ALP, high LDH, high total bilirubin, high aspartate aminotransferase, high alanine transaminase, high gamma-glutamyltransferase, high creatinine, a Glasgow prognostic score (GPS) of 1 or 2 score compared to GPS 0, higher compared to lower neutrophil to lymphocyte ratio (NLR) 3.9, lower compared to higher prognostic nutrition index 36.1, T3-4 compared to T1-2 tumor and diffuse-type compared to intestinal-type histology. Multivariate survival analysis identified high ALP 322 (HR 1.808; 95% CI 1.015-3.220; P = 0.044), T2-3 (HR 2.622; 95% CI 1.224-5.618; P = 0.013), and diffuse-type gastric cancer (HR 2.325; 95% CI 1.341 4.032; P = 0.003) as significant independent predictors of worse prognosis in the studied group of cancer patients. CONCLUSIONS: High level of ALP is an independent, worse prognosis factor for patients receiving chemotherapy for unresectable and recurrent gastric cancer. PMID- 30417315 TI - The ftsA gene as a molecular marker for phylogenetic studies in Bradyrhizobium and identification of Bradyrhizobium japonicum. AB - The use of ftsA gene sequences for taxonomic studies of the genus Bradyrhizobium bacteria was assessed. The ftsA gene codes for an actin-like protein involved in prokaryotic cell division. Up to now, this gene has not been used as a phylogenetic marker for analysis of bacteria establishing root nodule symbiosis with Fabaceae plants. In this study, the ftsA gene sequences obtained for bradyrhizobia forming N2 fixing symbiosis with four Genisteae tribe plants growing in Poland and most of the type strains of the genus Bradyrhizobium species were analyzed and evaluated as molecular markers for phylogenetic studies of these bacteria for the first time. The ftsA gene sequences of all bradyrhizobial strains with completely or partially sequenced genomes, available in the GenBank database, were also included into the analysis. The phylogeny of the ftsA gene was compared to the phylogenies of other chromosomal genes commonly used in the studies of Bradyrhizobium bacteria. The results showed that the phylogenies of ftsA and the core genes recA and glnII were congruent, making the ftsA gene useful as a phylogenetic marker. Analysis of the ftsA gene sequences revealed a single-nucleotide polymorphism unique to Bradyrhizobium japonicum strains, and the potential use of this SNP for identification of this species was discussed. PMID- 30417314 TI - State of the Art Management of Mechanical Heart Valves During Pregnancy. AB - PURPOSE OF THE REVIEW: To review the management of women with mechanical heart valves during pregnancy, from preconception counseling through delivery with a summary of the latest guidelines. RECENT FINDINGS: The hypercoagulability of pregnancy combined with the imperfect choices of anticoagulant agents contribute to a high risk of complications in pregnant women with mechanical heart valves. Valve thrombosis remains a major concern, much of which occurs during the first trimester transition to heparin-based products. The safest method of anticoagulation, with the best balance of maternal and fetal risk, is use of low dose vitamin K antagonists, but only if therapeutic anticoagulation can be achieved with warfarin doses of <= 5 mg/day. Management of mechanical heart valves in pregnancy remains fraught with difficult decisions involving balancing of maternal and fetal risks as well as a high risk of maternal and fetal complications. Preconception counseling and planning is imperative. A risk benefit discussion with the patient will help guide the choice of anticoagulation and outline the plan for safe delivery options. A multidisciplinary approach to management is advisable with close follow-up and care in a tertiary center. PMID- 30417316 TI - A deep learning approach for 18F-FDG PET attenuation correction. AB - BACKGROUND: To develop and evaluate the feasibility of a data-driven deep learning approach (deepAC) for positron-emission tomography (PET) image attenuation correction without anatomical imaging. A PET attenuation correction pipeline was developed utilizing deep learning to generate continuously valued pseudo-computed tomography (CT) images from uncorrected 18F-fluorodeoxyglucose (18F-FDG) PET images. A deep convolutional encoder-decoder network was trained to identify tissue contrast in volumetric uncorrected PET images co-registered to CT data. A set of 100 retrospective 3D FDG PET head images was used to train the model. The model was evaluated in another 28 patients by comparing the generated pseudo-CT to the acquired CT using Dice coefficient and mean absolute error (MAE) and finally by comparing reconstructed PET images using the pseudo-CT and acquired CT for attenuation correction. Paired-sample t tests were used for statistical analysis to compare PET reconstruction error using deepAC with CT based attenuation correction. RESULTS: deepAC produced pseudo-CTs with Dice coefficients of 0.80 +/- 0.02 for air, 0.94 +/- 0.01 for soft tissue, and 0.75 +/ 0.03 for bone and MAE of 111 +/- 16 HU relative to the PET/CT dataset. deepAC provides quantitatively accurate 18F-FDG PET results with average errors of less than 1% in most brain regions. CONCLUSIONS: We have developed an automated approach (deepAC) that allows generation of a continuously valued pseudo-CT from a single 18F-FDG non-attenuation-corrected (NAC) PET image and evaluated it in PET/CT brain imaging. PMID- 30417317 TI - Guanosine Protects Striatal Slices Against 6-OHDA-Induced Oxidative Damage, Mitochondrial Dysfunction, and ATP Depletion. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons in substantia nigra pars compacta which induces severe motor symptoms. 6-OHDA is a neurotoxin widely used in PD animal models due to its high affinity by dopamine transporter, its rapid non enzymatic auto-oxidation which generates reactive oxygen species (ROS), oxidative stress, and for induced mitochondrial dysfunction. We previously reported an in vitro protocol of 6-OHDA-induced toxicity in brain regions slices, as a simple and sensitive assay to screen for protective compounds related to PD. Guanosine (GUO), a guanine-based purine nucleoside, is a neuroprotective molecule that is showing promising effects as an antiparkinsonian agent. To investigate the mechanisms involved on GUO-induced neuroprotection, slices of cortex, striatum, and hippocampus were incubated with GUO in the presence of 6-OHDA (100 MUM). 6 OHDA promoted a decrease in cellular viability and increased ROS generation in all brain regions. Disruption of mitochondrial potential, depletion in intracellular ATP levels, and increase in cell membrane permeabilization were evidenced in striatal slices. GUO prevented the increase in ROS generation, disruption in mitochondrial potential, and depletion of intracellular ATP induced by 6-OHDA in striatal slices. In conclusion, GUO was effective to prevent oxidative events before cell damage, such as mitochondrial disruption, intracellular ATP levels depletion, and ROS generation in striatal slices subjected to in vitro 6-OHDA-induced toxicity. PMID- 30417318 TI - Serum Zinc Measurement, Total Antioxidant Capacity, and Lipid Peroxide Among Acute Coronary Syndrome Patients With and Without ST Elevation. AB - Despite advances in the management of cardiovascular diseases, acute coronary syndrome (ACS) remains the leading cause of death worldwide. ACS is associated with an imbalance between coronary blood supply and metabolic requirements. Lipid peroxidation and production of reactive oxygen species (ROS) damage the cardiac cell membrane. A total of 130 subjects, 65 ACS patients (45 with ST segment elevation (STE-ACS), 20 non-STE-ACS), and 65 healthy controls were recruited. Measurement of serum zinc, total antioxidant capacity (TAC) and malondialdehyde (MDA) by spectrophotometric methods 24 h after onset of ACS, and relations between the studied biochemical parameters and risk factors were performed. MDA levels were significantly increased; TAC and zinc levels were significantly decreased in ACS patients compared to the controls (P < 0.001 for each). No significant difference was detected between the different types of ACS and each of the oxidative stress parameters, cardiac biomarkers, lipogram, and risk factors. Only serum zinc in STE-ACS patients was significantly lower compared with NSTE-ACS patients (P < 0.001). Serum zinc showed the greatest AUC (area under the ROC curve) of 0.926 with 76.92% sensitivity and 95.38% specificity. Negative and positive correlations between MDA and zinc and between TAC and zinc levels respectively (P < 0.01) were found in ACS. Week negative correlation was observed between serum zinc and SYNTAX score (r = - 0.434, P = 0.049). Our results indicate that deficient serum zinc concentration strongly associated with the etiopathogenesis of ACS. PMID- 30417319 TI - Enzymatic Activity of Urokinase Immobilized onto Cu2+-Chelated Cibacron Blue F3GA Derived Poly (HEMA) Magnetic Nanoparticles. AB - In this presented work, magnetic poly(2-hydroxyethyl methacrylate) (p (HEMA)) nanoparticles were synthesized by surfactant-free emulsion polymerization technique. Cibacron Blue F3GA was covalently attached to the magnetic p (HEMA) nanoparticles and Cu2+ ions were then chelated with dye molecules. Synthesized magnetic nanoparticles were spherical with the diameter of 80 nm and exhibited magnetic character. Incorporation rate of Cibacron Blue for magnetic nanoparticles was found to be 28.125-MUmol/g polymer. Loaded amount of Cu2+ ions was calculated as 10.229-MUmol/g polymer. These Cu2+-Cibacron Blue F3GA-derived magnetic p (HEMA) nanoparticles were used for urokinase adsorption under different conditions (i.e., pH, enzyme initial concentration, ionic strength, temperature). Maximum adsorption capacity was found to be 630.43-mg/g polymer, and it was observed that Langmuir adsorption isotherm was applicable in this adsorption process. The adsorbed urokinase was desorbed from the Cu2+-Cibacron Blue F3GA-derived magnetic p (HEMA) nanoparticles by using 1.0 M of NaCl with the desorption rate of 96%. It was also demonstrated that adsorption capacity did not change significantly after five adsorption/desorption cycles. PMID- 30417320 TI - Effect of Microalgae Polysaccharides on Biochemical and Metabolomics Pathways Related to Plant Defense in Solanum lycopersicum. AB - Microalgae are photosynthetic microorganisms that produce several bioactive molecules that have received considerable attention in scientific and industrial communities. Today, many plant biostimulants including seaweed extracts and polysaccharides are used in agriculture. However, microalgae have not been largely exploited in this field as a potential source of plant bio stimulants. This study investigated the biostimulatory effects of microalgae polysaccharides on different metabolomic and biochemical pathways related to plant defense. 0.2 mg mL-1 of crude polysaccharides extracted from four green microalgae strains was injected into tomato plants (Solanum lycopersicum). beta-1,3-glucanase activity, lipid remodeling, phenylalanine ammonia lyase (PAL), Lipoxygenase (LOX), and antioxidant enzyme (APX, POD and CAT) activities were evaluated 48 h after treatment. Plants treated with crude polysaccharides extracted from. C. vulgaris and C. sorokiniana exhibited a significant increase in beta-1,3-glucanase activity. Accordingly, C. sorokiniana crude polysaccharides had a significant stimulatory effect on PAL activity with a percentage increase of 188.73% compared to the control. GC/MS quantitative lipidomics analysis revealed that treatment with D. salina, C. sorokiniana, and C. reinhardtii crude polysaccharides increased PUFA content by 50.37%, 34.46%, and 33.37% respectively. Microalgae polysaccharides also enhanced stearic acid, palmitic acid, and VLCFA content, the optimal value of which increased by 45.50%, 32.83%, and 60.60% respectively under treatment with C. reinhardtii crude polysaccharides compared with the control. C. vulgaris and C. reinhardtii crude polysaccharides also exhibited higher APX and POD activity respectively. The present results therefore indicate the potentiality of microalgae crude polysaccharides as a promising renewable bio resource in the development plant bio stimulants. PMID- 30417321 TI - Withaferin A Protects Against High-Fat Diet-Induced Obesity Via Attenuation of Oxidative Stress, Inflammation, and Insulin Resistance. AB - Withaferin A (WA), a bioactive constituent derived from Withania somnifera plant, has been shown to exhibit many qualifying properties in attenuating several metabolic diseases. The current investigation sought to elucidate the protective mechanisms of WA (1.25 mg/kg/day) on pre-existing obese mice mediated by high-fat diet (HFD) for 12 weeks. Following dietary administration of WA, significant metabolic improvements in hepatic insulin sensitivity, adipocytokines with enhanced glucose tolerance were observed. The hepatic oxidative functions of obese mice treated with WA were improved via augmented antioxidant enzyme activities. The levels of serum pro-inflammatory cytokines and hepatic mRNA expressions of toll-like receptor (TLR4), nuclear factor kappaB (NF-kappaB), tumor necrosis factor-alpha (TNF-alpha), chemokine (C-C motif) ligand-receptor, and cyclooxygenase 2 (COX2) in HFD-induced obese mice were reduced. Mechanistically, WA increased hepatic mRNA expression of peroxisome proliferator activated receptors (PPARs), cluster of differentiation 36 (CD36), fatty acid synthase (FAS), carnitine palmitoyltransferase 1 (CPT1), glucokinase (GCK), phosphofructokinase (PFK), and phosphoenolpyruvate carboxykinase (PCK1) that were associated with enhanced lipid and glucose metabolism. Taken together, these results indicate that WA exhibits protective effects against HFD-induced obesity through attenuation of hepatic inflammation, oxidative stress, and insulin resistance in mice. PMID- 30417323 TI - Erratum. PMID- 30417322 TI - Class and status: on the misconstrual of the conceptual distinction and a neo Bourdieusian alternative. AB - In this article, we address the classical debate about the relationship between the economic and cultural aspects of social stratification, typically cast in terms of Weber's distinction between class and status. We discuss in particular Chan and Goldthorpe's influential, yet largely unchallenged, attempt to reinstate a strict version of the class-status distinction, mounted as an attack on 'Bourdieusian' accounts. We argue that this is unconvincing in two respects: There are fundamental problems with their conceptualization of status, producing a peculiar account where one expression of status honour explains the other; in addition, their portrayal of the Bourdieusian approach as one-dimensional is highly questionable. In contradiction of a reading of Bourdieu as discarding the class-status distinction, we develop an alternative, neo-Bourdieusian account that recognizes class and status as distinct aspects of stratification, thereby allowing for a subtle analysis of their empirical entwinement. The fruitfulness of this approach is demonstrated by analysing the homology between the space of lifestyles and the social space through Multiple Correspondence Analysis of unusually rich data about lifestyles. Importantly, we highlight the relative autonomy of these spaces: Although they exhibit a similar structure, they do not overlap completely. PMID- 30417324 TI - Phenotero: Annotate as you write. AB - In clinical genetics, the Human Phenotype Ontology as well as disease ontologies are often used for deep phenotyping of patients and coding of clinical diagnoses. However, assigning ontology classes to patient descriptions is often disconnected from writing patient reports or manuscripts in word processing software. This additional workload and the requirement to install dedicated software may discourage usage of ontologies for parts of the target audience. Here we present Phenotero, a freely available and simple solution to annotate patient phenotypes and diseases at the time of writing clinical reports or manuscripts. We adopt Zotero, a citation management software to create a tool which allows to reference classes from ontologies within text at the time of writing. We expect this approach to decrease the additional workload to a minimum while ensuring high quality associations with ontology classes. Standardized collection of phenotypic information at the time of describing the patient allows for streamlining the clinic workflow and efficient data entry. It will subsequently promote clinical and molecular diagnosis with the ultimate goal of better understanding genetic diseases. Thus, we believe that Phenotero eases the usage of ontologies and controlled vocabularies in the field of clinical genetics. PMID- 30417325 TI - A Challenge for Clinical Pharmacologists: How Can We Measure Scientific Impact of Publications in Drug Development and in Regulatory Decision Making? AB - Many articles in clinical pharmacology may highly influence drug development and regulatory decision making, far beyond the measure conveyed by the Journal Impact Factor. Quantifying impact from the grey content (e.g., nonpublished information) remains an evolving dilemma. A collaboration is proposed with library scientists and bioinformaticians to develop methods to measure the impact of grey content on drug development and regulatory decision making. Mechanisms to reward this impact are discussed. PMID- 30417327 TI - Population-based data registries suggest novel insight into malignancy and metabolism. AB - Malignancy and the metabolic syndrome are key challenges in modern health care. Population-based data registries are potent enablers for research into possible associations between them, providing primers for further studies, including the elucidation of molecular and cellular mechanisms underlying such links. PMID- 30417326 TI - Mosaic MECP2 variants in males with classical Rett syndrome features, including stereotypical hand movements. AB - Rett syndrome is rarely suspected in males because of the X-linked dominant inheritance. In the literature, only six male patients have been reported with methyl-CpG-binding protein 2 (MECP2) mosaicism. Next-generation sequencing (NGS) methods have enabled better detection of somatic mosaicism compared to conventional Sanger sequencing; however, mosaics can still be difficult to detect. We present clinical and molecular findings in two males mosaic for a pathogenic MECP2 variant. Both have been reexamined using deep sequencing of DNA isolated from four different cell tissues (blood, muscle, fibroblasts and oral mucosa). Deep sequencing of the different tissues revealed that the variants were present in all tissues. In one patient, the molecular diagnosis could only be established by reexamination after a normal whole exome sequencing, and the other case is an example of reverse genetic diagnostics. Rett syndrome should be considered in males with neurodevelopmental delay and stereotypical hand movements. Subsequent to clinical diagnosis males should be investigated with NGS based technologies of MECP2 with high read depth and a low threshold for variant calls. If the initial analysis on full blood derived DNA fails to confirm the suspicion, we recommend repeating the analysis on another tissue, preferentially fibroblasts to increase the diagnostic yield. PMID- 30417328 TI - We need to talk about Notch: Notch dysregulation as an epiphenomenon in inflammatory skin disease. PMID- 30417329 TI - What makes a good teacher? The relative importance of mathematics teachers' cognitive ability, personality, knowledge, beliefs, and motivation for instructional quality. AB - BACKGROUND: Teachers differ substantially in their instructional performance in the classroom. Thus, researchers and policymakers are interested in how these differences can be explained and how the instruction provided by low-performing teachers can be improved. Previous research has focused either on generic (cognitive ability and personality) or profession-specific (professional knowledge, beliefs, and motivation for teaching) teacher characteristics as predictors of instructional quality but their relative importance has not yet been tested. AIMS: Hardly any studies have combined central generic and profession-specific variables in ascertaining their relative importance for instructional quality. In the present study, we seek to close this research gap. SAMPLES: We investigated 209 German mathematics teachers and their 4,672 students attending grades 7-10 (13- to 16-year-old students). METHODS: Teacher characteristics (cognitive ability, personality, professional knowledge, beliefs about, and enthusiasm for teaching) were assessed using standardized tests and self-report measures. Instructional quality (learning support, classroom disruptions, and cognitive activation) was rated by the students. RESULTS: Using structural equation modelling, we found extraversion, enthusiasm for teaching, and pedagogical/psychological knowledge to be significant predictors of learning support (R2 = .31) and conscientiousness and enthusiasm for teaching to be significant predictors of classroom discipline (R2 = .21). We did not find significant predictors for cognitive activation. CONCLUSIONS: Our results indicate the relative significance of generic and profession-specific teacher variables for instructional quality. Overall, a substantial amount of variance in instructional quality is explained by teacher characteristics. PMID- 30417330 TI - Atopic dermatitis: the relationship to temperature and seasonality in the United States. AB - BACKGROUND: Climatologic factors may affect atopic dermatitis (AD), and there have been few explorations into this topic. Because of its size, the United States (US) has a broad range of climates. The objective of this study is to assess the relationship between ambulatory office visits physicians for AD with temperature and season. METHODS: US region-specific satellite-derived data air temperature from the North America Land Data Assimilation System from 1993 to 2011 were studied in relation with ambulatory AD visits to all physicians from the National Ambulatory Medical Care Survey. RESULTS: Over the 19-year study period, in no regional location in the US is there clear evidence of a winter flare of AD. The greatest numbers of visits occur in May and June, and smaller peaks also occur in January and October. As the ambient air temperature increases, the likelihood of an AD visit rises (P < .0001). In the South, the hottest US climate, summer is responsible for substantially more AD visits. In every other region and the US overall, the largest number of AD visits occur in spring. AD visits appear to display regional variation in comparing the Northeast, South, Midwest, and West. CONCLUSIONS: Increased temperatures predict increased likelihood of AD office visits. PMID- 30417331 TI - Adolescent overweight and obesity and the risk for pancreatic cancer among men and women: a nationwide study of 1.79 million Israeli adolescents. AB - BACKGROUND: There is growing concern regarding the impact of adolescent obesity on adult health. The objective of this study was to evaluate the association between body mass index (BMI) in late adolescence and the incidence of pancreatic cancer during adulthood. METHODS: The authors analyzed a cohort of 1087,358 Israeli Jewish men and 707,212 Jewish women who underwent a compulsory physical examination between ages 16 and 19 years from 1967 to 2002. Pancreatic cancer incidence through December 31, 2012 was identified by linkage to the national cancer registry. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HRs) for pancreatic cancer according to the US Centers for Disease Control and Prevention (CDC) BMI percentiles at baseline. RESULTS: Over a median 23 year follow-up, 551 incident cases of pancreatic cancer cases occurred (423 men; 128 women). Compared with normal weight (5th to-<85th percentile), obesity (>=95th percentile) was associated with an increased risk of cancer among both men (HR, 3.67; 95% confidence interval [CI], 2.52-5.34) and women (HR, 4.07; 95% CI, 1.78-9.29). Among men, compared with low-normal BMI (>=5th to <25th percentile), high-normal BMI (>=75th to <85th percentile) and overweight (85th to 95th percentile) also were associated with a higher risk for cancer(high-normal BMI: HR, 1.49; 95% CI, 1.05-2.13; overweight: HR, 1.97; 95% CI, 1.39-2.80). The estimated population-attributable fraction because of overweight and obesity was 10.9% (95% CI, 6.1%-15.6%). CONCLUSIONS: Men and women who were obese or overweight as adolescents are at an increased risk for subsequent pancreatic cancer. PMID- 30417333 TI - FERONIA Regulates Auxin-Mediated Lateral Root Development and Primary Root Gravitropism. AB - The Arabidopsis FERONIA (FER) receptor kinase is a key hub of cell signaling networks mediating various hormone, stress, and immune responses. Previous studies have shown that FER functions correlate with auxin responses, but the underlying molecular mechanism is unknown. Here, we demonstrate that the primary root of the fer-4 mutant displays increased lateral root branching and a delayed gravitropic response, which are associated with polar auxin transport (PAT). Our data suggest that aberrant PIN2 polarity is responsible for the delayed gravitropic response in fer-4. Furthermore, the diminished F-actin cytoskeleton in fer-4 implies that FER modulates F-actin-mediated PIN2 polar localization. Our findings provide new insights into the function of FER in PAT. This article is protected by copyright. All rights reserved. PMID- 30417332 TI - Preferences for in-person disclosure: Patients declining telephone disclosure characteristics and outcomes in the multicenter Communication Of GENetic Test Results by Telephone study. AB - Telephone disclosure of cancer genetic test results is noninferior to in-person disclosure. However, how patients who prefer in-person communication of results differ from those who agree to telephone disclosure is unclear but important when considering delivery models for genetic medicine. Patients undergoing cancer genetic testing were recruited to a multicenter, randomized, noninferiority trial (NCT01736345) comparing telephone to in-person disclosure of genetic test results. We evaluated preferences for in-person disclosure, factors associated with this preference and outcomes compared to those who agreed to randomization. Among 1178 enrolled patients, 208 (18%) declined randomization, largely given a preference for in-person disclosure. These patients were more likely to be older (P = 0.007) and to have had multigene panel testing (P < 0.001). General anxiety (P = 0.007), state anxiety (P = 0.008), depression (P = 0.011), cancer-specific distress (P = 0.021) and uncertainty (P = 0.03) were higher after pretest counseling. After disclosure of results, they also had higher general anxiety (P = 0.003), depression (P = 0.002) and cancer-specific distress (P = 0.043). While telephone disclosure is a reasonable alternative to in-person disclosure in most patients, some patients have a strong preference for in-person communication. Patient age, distress and complexity of testing are important factors to consider and requests for in-person disclosure should be honored when possible. PMID- 30417334 TI - Acute flaccid myelitis: an emerging clinical entity. PMID- 30417335 TI - MicroRNA-382 silencing induces a mitonuclear protein imbalance and activates the mitochondrial unfolded protein response in muscle cells. AB - Proper mitochondrial function plays a central role in cellular metabolism. Various diseases as well as aging are associated with diminished mitochondrial function. Previously, we identified 19 miRNAs putatively involved in the regulation of mitochondrial metabolism in skeletal muscle, a highly metabolically active tissue. In the current study, these 19 miRNAs were individually silenced in C2C12 myotubes using antisense oligonucleotides, followed by measurement of the expression of 27 genes known to play a major role in regulating mitochondrial metabolism. Based on the outcomes, we then focused on miR-382-5p and identified pathways affected by its silencing using microarrays, investigated protein expression, and studied cellular respiration. Silencing of miRNA-382-5p significantly increased the expression of several genes involved in mitochondrial dynamics and biogenesis. Conventional microarray analysis in C2C12 myotubes silenced for miRNA-382-5p revealed a collective downregulation of mitochondrial ribosomal proteins and respiratory chain proteins. This effect was accompanied by an imbalance between mitochondrial proteins encoded by the nuclear and mitochondrial DNA (1.35-fold, p < 0.01) and an induction of HSP60 protein (1.31 fold, p < 0.05), indicating activation of the mitochondrial unfolded protein response (mtUPR). Furthermore, silencing of miR-382-5p reduced basal oxygen consumption rate by 14% ( p < 0.05) without affecting mitochondrial content, pointing towards a more efficient mitochondrial function as a result of improved mitochondrial quality control. Taken together, silencing of miR-382-5p induces a mitonuclear protein imbalance and activates the mtUPR in skeletal muscle, a phenomenon that was previously associated with improved longevity. PMID- 30417336 TI - Inflammation and pericarditis: Are neutrophils actors behind the scenes? AB - The morbidity of acute pericarditis is increasing over time impacting on patient quality of life. Recent clinical trials focused especially on clinical aspects, with a modest interest in pathophysiological mechanisms. This narrative review, based on papers in English language obtained via PubMed up to April 2018, aims at focusing on the role of the innate immunity in pericarditis and discussing future potential therapeutic strategies impacting on disease pathophysiology. In developed countries, most cases of pericarditis are referred to as idiopathic, although etiological causes have been described, with autoreactive/lymphocytic, malignant, and infectious ones as the most frequent causes. Apart the known impairment of the adaptive immunity, recently a large body evidence indicated the central role of the innate immune system in the pathogenesis of recurrent pericarditis, starting from similarities with autoinflammatory diseases. Accordingly, the "inflammasome" has been shown to behave as an important player in pericarditis development. Similarly, the beneficial effect of colchicine in recurrent pericarditis confirms that neutrophils are important effectors as colchicine, which can block neutrophil chemotaxis, interferes with neutrophil adhesion and recruitment to injured tissues and abrogate superoxide production. Anyway, the role of the adaptive immune system in pericarditis cannot be reduced to a black or white issue as mechanisms often overlap. Therefore, we believe that more efficient therapeutic strategies have to be investigated by targeting neutrophil-derived mediators (such as metalloproteinases) and disentangling the strict interplay between neutrophils and platelets. In this view, some progress has been done by using the recombinant human interleukin-1 receptor antagonist anakinra. PMID- 30417337 TI - Metabolite systems profiling identifies exploitable weaknesses in retinoblastoma. AB - Retinoblastoma (RB) is a childhood eye cancer. Currently, chemotherapy, local therapy, and enucleation are the main ways in which these tumors are managed. The present work is the first study that uses constraint-based reconstruction and analysis approaches to identify and explain RB-specific survival strategies, which are RB tumor specific. Importantly, our model-specific secretion profile is also found in RB1-depleted human retinal cells in vitro and suggests that novel biomarkers involved in lipid metabolism may be important. Finally, RB-specific synthetic lethals have been predicted as lipid and nucleoside transport proteins that can aid in novel drug target development. PMID- 30417338 TI - Decreasing prevalence of cerebral palsy in birth cohorts in South Carolina using Medicaid, disability service, and hospital discharge data, 1996 to 2009. AB - AIM: Since cross-sectional trends of 8-year-old cerebral palsy (CP) birth prevalence based on record review were stable from 1985 to 2002 in Metropolitan Atlanta, we examined birth cohort trends using administrative data sets promptly. METHOD: Among 755 433 live births from 1996 to 2009 in South Carolina, 2080 received CP diagnosis by age 4 years from linked Medicaid claims with International Classification of Diseases, Ninth Revision codes 343.X (contributing 1061 [51%] unique cases), hospital discharge data (57 [3%] unique cases), and Department of Disabilities and Special Needs program (64 [3%] unique cases). Trends were assessed using negative binominal regression. RESULTS: Including 3.7 percent of cases who died before age 4 years, CP prevalence per 1000 live births decreased significantly from 3.6 in 1996 to 2.1 in 2006 (-3.0% average annual change; 95% confidence interval -4.4 to -1.6). The overall prevalence was 2.8 per 1000 live births, 46.0 per 1000 very-low-birthweight (VLBW) live births, and 53.0 per 1000 VLBW 1-year survivors. Disparities and downward trends persisted across subgroups with higher rates among non-Hispanic black infants than non-Hispanic white and among males compared to females. INTERPRETATION: Downward CP prevalence rates and persistent disparities remain in South Carolina. Further research should validate this methodology, including early deaths, and develop broad surveillance systems to inform clinical practices and etiology. WHAT THIS PAPER ADDS: Birth cohort cerebral palsy (CP) prevalence decreased in South Carolina from 1996 to 2009. CP prevalence was higher in very low-birthweight infants, non-Hispanic blacks, and males. Three administrative data sets captured 2080 patients with CP in South Carolina. Medicaid claims contributed 51% of unique cases of CP to the cohort. CP diagnoses included 76 patients who died before age 4 years. PMID- 30417339 TI - Understanding molecular biology of codon usage in mitochondrial complex IV genes of electron transport system: Relevance to mitochondrial diseases. AB - The mitochondrial cytochrome oxidase (CO) genes are involved in complex IV of the electron transport system, and dysfunction of CO genes leads to several diseases. However, no work has been reported on the codon usage pattern of these genes. We used bioinformatic methods to analyze the compositional properties and the codon usage pattern of the COI, COII, and COIII genes in fishes, birds, and mammals to understand the similarities and dissimilarities of codon usage in these genes, which gave an insight into the molecular biology of these genes. The effective number of codons (ENC) value of genes was high in different species of fishes, birds and mammals, which indicates that the codon bias of CO genes was low and the ENC values were significantly different among fishes, birds, and mammals, as revealed from the t test. The overall guanine and cytosine (GC) content in fishes, birds, and mammals was lower than 50% in all genes, indicating that the genes were AT-rich and significantly different among fishes, birds, and mammals. The TCA codon was overrepresented in fishes, birds, and mammals for the COI gene, in birds and mammals for the COII gene, but it was not overrepresented in others. Only three codons, namely CTA, CGA, and AAA, were overrepresented in all three groups for the COI, COII, and COIII genes, repectively. From the neutrality plot in fishes, birds, and mammals, it was observed that the slopes of the regression lines (regression coefficients) in the COI, COII, and COIII genes were <0.5, suggesting that natural selection played a major role, whereas mutation pressure played a minor role. PMID- 30417340 TI - Extended proliferation of chicken- and Okinawa rail-derived fibroblasts by expression of cell cycle regulators. AB - Although immortalized cultured cells are useful for various functional assays or transcriptome analysis, highly efficient and reproducible immortalization methods have not been developed in avian-derived cells. We introduced the simian virus 40 T antigen (SV40T) and human papillomavirus (HPV)-E6E7 to chick and Okinawa rail (endangered species)derived fibroblast. As a result, neither the SV40T nor E6E7 genes could induce avian cell immortality. Accordingly, we attempted to use a recently developed immortalization method, which involved the coexpression of mutant cyclin-dependent kinase 4 (CDK4), Cyclin D, and TERT (K4DT method) in these avian cells. Although the K4DT method could not efficiently induce the efficient immortalization in mass cell population, cellular division until the senescence was significantly extended by K4DT, we succeeded to obtain the immortalized avian cells (chick K4DT: one clone, Okinawa rail K4DT: three clones, Okinawa rail K4DT + telomerase RNA component: one clone) with K4DT expression. We conclude that K4DT expression is used to extend the cell division and immortalization of avian-derived cells. PMID- 30417341 TI - Guideline-concordant initiation of oral anticoagulant therapy for stroke prevention in older veterans with atrial fibrillation eligible for Medicare Part D. AB - OBJECTIVE: To characterize the rate of guideline-concordant initiation of oral anticoagulation (OAC) among elderly Veterans with atrial fibrillation (AF) and high stroke risk. DATA SOURCES/STUDY SETTING: Veterans Health Administration (VHA) Corporate Data Warehouse (CDW) linked with Medicare claims 2011-2015. STUDY DESIGN: We identified 6619 elderly, high stroke-risk patients with a new episode of AF initially diagnosed in the VHA during fiscal years 2012-2015. We used logistic regression to estimate marginal effects of associations between patient characteristics and OAC initiation within 90 days of the first AF episode. DATA EXTRACTION METHODS: We identified OACs using generic drug names. We calculated comorbidities and risk scores using diagnosis codes from 1 year of baseline data. PRINCIPAL FINDINGS: Overall, 66.5% of Medicare-eligible Veterans with AF at high risk of stroke initiated an OAC within 90 days. We found lower initiation rates for patients enrolled in Medicare Part D and those ineligible for drug co-payment subsidies. OAC initiation rates increased during the study among VHA-reliant patients but not among dual VHA-Part D enrollees. CONCLUSIONS: One-third of elderly Veterans at risk of stroke are not receiving recommended therapy. Increased coordination between Medicare and VHA providers may lead to improvements in anticoagulation quality and stroke prevention. PMID- 30417342 TI - Fusion with mesenchymal stem cells differentially affects tumorigenic and metastatic abilities of lung cancer cells. AB - Cell fusion plays a crucial role in cancer progression and leads to massive aberrant changes in chromosome and gene expression involved in tumor metastasis. Cancer cells can fuse with many cell types, including stromal cells, epithelial cells, macrophages, and endothelial cells. Mesenchymal stem cells (MSCs) have been reported to migrate and incorporate into tumor sites during cancer progression. However, the underlying mechanism of stem cell fusion in tumor metastasis has not been fully deciphered. In this research, we established a cell fusion model between lung cancer cells and MSCs in vitro. We found that the hybrid cells showed enhanced metastatic capacity with increased expression of MMP 2 and MMP-9, whereas the proliferation ability was inhibited and cell cycle was blocked in the G0 /G1 phase with elevated expression of p21, p27, and p53. Moreover, the hybrid cells lost epithelial morphology and exhibited an epithelial mesenchymal transition (EMT) change with downregulation of E-cadherin and upregulation of N-cadherin, Vimentin, alpha-SMA and Fibronectin1. Meanwhile, the expressions of EMT transcription factors, including Snail1, Slug, Twist1, Zeb1, and Zeb2, were also increased in hybrid cells. More important, the fusion hybrids acquired stem cell-like properties, which exhibited increased expression stem cell transcription factors Oct4, Sox2, Nanog, Kif4 as well as Bmi1. Taken together, our results suggested that cell fusion between lung cancer cells and MSCs offered enhanced metastatic capacity and characteristics of cancer stem cell by undergoing EMT. This study will contribute to explaning the origin of lung cancer stem cells and to elucidate the role of cell fusion in cancer metastasis. PMID- 30417343 TI - Autophagy in childhood neurological disorders. AB - Autophagy is a tightly modulated lysosomal degradation pathway. Genetic disorders of autophagy during nervous system development may lead to developmental delay, neurodegeneration, and other neurological signs in children. Here we aimed to summarize single gene disorders that perturb various steps of autophagy pathway and their roles in the causation of childhood neurological diseases. Numerous childhood-onset disorders are caused by mutations that impact the autophagy pathway. These can manifest with a range of features including ataxia, spastic paraplegia, and intellectual disability. Defective proteins causing such diseases can interfere with autophagy flux at different stages of the itinerary. Defective autophagy may be an important contributor to the pathological features of various childhood neurodegenerative diseases and lead to the accumulation of aberrant protein and dysfunctional organelles. Insights into the relevant cell biological processes may help understand pathophysiological mechanisms and inspire autophagy restoring therapeutic approaches. WHAT THIS PAPER ADDS: Numerous childhood-onset disorders are caused by mutations that impact the autophagy pathway. Defective autophagy is a feature of some mutations that cause ataxia, spastic paraplegia, and intellectual disability. PMID- 30417344 TI - Fascia thickness, aging and flexibility: is there an association? AB - The morphology of the connective tissue may play an important role in locomotor mechanics. Recent research has revealed an association between increased fascia thickness and reduced joint flexibility in patients with chronic pain. The present study aimed to examine the relationship of both factors in healthy individuals, additionally testing the hypothesis that older subjects display a higher fascia thickness. Young (n = 18, 22 +/- 1 years) and old (n = 17, 69 +/- 4 years) healthy females were recruited for a quasi-experimental, cross-sectional trial. All participants underwent standardized ultrasound-based thickness measurements of the deep fasciae of the trunk and lower limb. Flexibility was assessed using sit and reach testing (hamstring extensibility) and the Schober test (lumbar flexion and extension). Systematic between-group differences of fascia thickness and variable associations (i.e. fascia thickness and flexibility) were detected using non-parametric data analyses. Young adults exhibited higher fascia thickness of the anterior and posterior lower leg, anterior thigh and abdominal wall (+12.3-25.8%, P < 0.05). Conversely, older participants showed higher thickness in the lumbar spine (+40.0-76.7%, P < 0.05). Correlations of both body mass and fascia thickness (tau = 0.45-0.75, P < 0.05), as well as flexibility and fascia thickness (tau = 0.38-0.42, P < 0.05) were found. Age-related changes in fascia thickness may be a contributing factor of restrictions in joint range of motion. Further study delineating the cause-effect triangle of body mass index, flexibility and fascia thickness is necessary. PMID- 30417345 TI - Digest: Early exposure to facial cues facilitates facial learning in paper wasps. AB - Tibbetts et al. evaluated the influence of the rearing environment on the facial learning capacity of the paper wasp Polistes metricus. Wasps reared with cues signaling individual identity learned to discriminate faces more accurately than wasps reared in the absence of facial cues. These findings indicate that developmental plasticity plays a significant role in the evolution of animal communication systems. PMID- 30417346 TI - The role of DEAD-box RNA helicase p68 (DDX5) in the development and treatment of breast cancer. AB - RNA helicase p68 or DEAD (Asp-Glu-Ala-Asp) box polypeptide 5 (DDX5) is a unique member of the highly conserved protein family, which is involved in a broad spectrum of biological processes, including transcription, translation, precursor messenger RNA processing or alternative splicing, and microRNA (miRNA) processing. It has been shown that p68 is necessary for cell growth and participates in the early development and maturation of some organs. Interestingly, p68 is a transcriptional coactivator of numerous oncogenic transcription factors, including nuclear factor-kappabeta (NF-kappabeta), estrogen receptor alpha (ERalpha), beta-catenin, androgen receptor, Notch transcriptional activation complex, p53 and signal transducer, and activator of transcription 3 (STAT3). Recent studies on the role of p68 (DDX5) in multiple dysregulated cellular processes in various cancers and its abnormal expression indicate the importance of this factor in tumor development. Discussion of the precise role of p68 in cancer is complex and depends on the cellular microenvironment and interacting factors. In terms of the deregulated expression of p68 in breast cancer and the high prevalence of this cancer among women, it can be informative to review the precise function of this factor in the breast cancer. Therefore, an attempt will be made in this review to clarify the tumorigenic function of p68 in association with its targeting potential for the treatment of breast cancer. PMID- 30417347 TI - Outcome of paediatric acute flaccid myelitis associated with enterovirus D68: a case series. AB - Enterovirus D68 (EV-D68) is an emerging infection associated with acute flaccid myelitis (AFM). Cases of AFM associated with EV-D68 infection have increased in recent years and the evidence for a causal link is growing. However, our understanding of the epidemiology, clinical features, prognosis, and neurological sequelae of EV-D68 requires ongoing surveillance and investigation. We report five cases of AFM in previously typically developing children (2-6y) from South East Scotland during September and October 2016 after infection with EV-D68 (all detected in the nasopharyngeal aspirates). All cases presented with significant neurological symptoms, which were severe in two cases requiring intensive care support because of respiratory paralysis. At 18-month follow-up, two cases remain ventilator-dependent with other cases requiring ongoing community rehabilitation. These cases represent one of the largest reported paediatric cluster of AFM associated with EV-D68 in Europe. The epidemiology and clinical information add to the knowledge base and the 18-month outcome will help clinicians to counsel families. WHAT THIS PAPER ADDS: Nasopharyngeal aspirate is more sensitive for viral isolation and isolated in all cases. Clinical outcome at 18 months after enterovirus D68 with acute flaccid myelitis provides information on extent of recovery and level of disability. PMID- 30417348 TI - Quantifying the relative contributions of the X chromosome, autosomes, and mitochondrial genome to local adaptation. AB - During local adaptation with gene flow, some regions of the genome are inherently more responsive to selection than others. Recent theory predicts that X-linked genes should disproportionately contribute to local adaptation relative to other genomic regions, yet this prediction remains to be tested. We carried out a multigeneration crossing scheme, using two cline-end populations of Drosophila melanogaster, to estimate the relative contributions of the X chromosome, autosomes, and mitochondrial genome to divergence in four traits involved in local adaptation (wing size, resistance to heat, desiccation, and starvation stresses). We found that the mitochondrial genome and autosomes contributed significantly to clinal divergence in three of the four traits. In contrast, the X made no significant contribution to divergence in these traits. Given the small size of the mitochondrial genome, our results indicate that it plays a surprisingly large role in clinal adaptation. In contrast, the X, which represents roughly 20% of the Drosophila genome, contributes negligibly-a pattern that conflicts with theoretical predictions. These patterns reinforce recent work implying a central role of mitochondria in climatic adaptation, and suggest that different genomic regions may play fundamentally different roles in processes of divergence with gene flow. PMID- 30417349 TI - Cell viability in three ex vivo rat models of spinal cord injury. AB - Spinal cord injury (SCI) is a devastating disorder that has a poor prognosis of recovery. Animal models of SCI are useful to understand the pathophysiology of SCI and the potential use of therapeutic strategies for human SCI. Ex vivo models of central nervous system (CNS) trauma, particularly mechanical trauma, have become important tools to complement in vivo models of injury in order to reproduce the sequelae of human CNS injury. Ex vivo organotypic slice cultures (OSCs) provide a reliable model platform for the study of cell dynamics and therapeutic intervention following SCI. In addition, these ex vivo models support the 3R concept of animal use in SCI research - replacement, reduction and refinement. Ex vivo models cannot be used to monitor functional recovery, nor do they have the intact blood supply of the in vivo model systems. However, the ex vivo models appear to reproduce many of the post traumatic events including acute and secondary injury mechanisms. Several well-established OSC models have been developed over the past few years for experimental spinal injuries ex vivo in order to understand the biological response to injury. In this study, we investigated cell viability in three ex vivo OSC models of SCI: stab injury, transection injury and contusion injury. Injury was inflicted in postnatal day 4 rat spinal cord slices. Stab injury was performed using a needle on transverse slices of spinal cord. Transection injury was performed on longitudinal slices of spinal cord using a double blade technique. Contusion injury was performed on longitudinal slices of spinal cord using an Infinite Horizon impactor device. At days 3 and 10 post-injury, viability was measured using dual staining for propidium iodide and fluorescein diacetate. In all ex vivo SCI models, the slices showed more live cells than dead cells over 10 days in culture, with higher cell viability in control slices compared with injured slices. Although no change in cell viability was observed between time-points in stab- and contusion-injured OSCs, a reduction in cell viability was observed over time in transection-injured OSCs. Taken together, ex vivo SCI models are a useful and reliable research tool that reduces the cost and time involved in carrying out animal studies. The use of OSC models provides a simple way to study the cellular consequences following SCI, and they can also be used to investigate potential therapeutics regimes for the treatment of SCI. PMID- 30417350 TI - MiRNAs and inflammatory bowel disease: An interesting new story. AB - Inflammatory bowel disease (IBD), as a chronic and recurrent inflammatory disorder, is caused by a dysregulated and aberrant immune response to exposed environmental factors in genetically susceptible individuals. Despite huge efforts in determining the molecular pathogenesis of IBD, an increasing worldwide incidence of IBD has been reported. MicroRNAs (miRNAs) are a set of noncoding RNA molecules that are about 22 nucleotides long, and these molecules are involved in the regulation of the gene expression. By clarifying the important role of miRNAs in a number of diseases, their role was also considered in IBD; numerous studies have been performed on this topic. In this review, we attempt to summarize a number of studies and discuss some of the recent developments in the roles of miRNAs in the pathophysiology, diagnosis, and treatment of IBD. PMID- 30417351 TI - Ectopic nerve growth factor prevents proliferation in glioma cells by senescence induction. AB - OBJECTIVE: The neurotrophin nerve growth factor (NGF) affects survival, regulation and differentiation of both central and peripheral nervous system neurons. NGF exerts its effects primarily through tropomyosin receptor kinase A (TrkA), inducing a cascade of tyrosine kinase-initiated responses. In spite of its importance, the general behavior of NGF looks contradictory: its effects can be both stimulatory and inhibitory. The present study aims to explore the molecular mechanisms induced by NGF in glioma cancer cells. METHODS: The effects of NGF were investigated in high grade glioma and low grade pediatric glioma (PLGG) cell lines through comparative studies. In particular, we investigated TrkA-mediated cellular pathways, molecular signaling, proliferation, cell cycle and cellular senescence. RESULTS: We found that exposure of PLGG cells to NGF produced stable growth arrest with the features of a senescence phenotype but without the expression of anti-poly(ADP-ribose) polymerase cleavage, a marker of apoptosis. Moreover, NGF treatment promoted the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2), signal transducer and activator of transcription 3 (STAT3), and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling. In addition, K252a, a TrkA inhibitor, significantly reduced the phosphorylation of the aforementioned signaling pathways, suggesting that NGF activated ERK1/2 and AKT signaling take place downstream of TrkA-neurotrophin interaction. CONCLUSIONS: These findings provide the first evidence that NGF can induce senescence of PLGG cells in a receptor-mediated fashion, thus supporting the hypothesis that in the clinical setting NGF might be beneficial to pediatric glioma patients. PMID- 30417352 TI - Troxerutin attenuates myocardial cell apoptosis following myocardial ischemia reperfusion injury through inhibition of miR-146a-5p expression. AB - The aim of the current study was to investigate the effects and the underlying mechanisms of troxerutin on myocardial cell apoptosis during ischemia-reperfusion (I/R) injury. Hypoxia/reoxygenation (H/R) model in neonatal rat cardiomyocytes, and I/R model in rats, were established following troxerutin preconditioning. The quantitative real-time polymerase chain reaction analysis was performed to examine the messenger RNA miR-146a-5p expression in cardiomyocytes and myocardial tissues. Hemodynamic parameters and serum creatine kinase, lactate dehydrogenase, tumor necrosis factor-alpha, and interleukin-10 were evaluated. Infarct size was examined by 2,3,5-triphenyltetrazolium chloride staining. Besides, myocardial apoptosis was detected by terminal deoxynucleotidyl transferase (dUTP) nick end labeling (TUNEL) assay. Western blot analysis was performed to determine the protein levels of caspase-3, Bax, and Bcl-2. The results showed that, troxerutin decreased rat cardiomyocyte apoptosis during H/R injury. Furthermore, the antiapoptotic effect of troxerutin against I/R injury was mediated by miR-146a-5p downregulation. In vivo experiments suggested that troxerutin alleviated myocardial I/R injury in rats via inhibition of miR-146a-5p. In conclusion, troxerutin exerted cardioprotective effects during I/R injury by downregulating miR-146a-5p. PMID- 30417353 TI - Licochalcone A attenuates abdominal aortic aneurysm induced by angiotensin II via regulating the miR-181b/SIRT1/HO-1 signaling. AB - Licochalcone A (LA), a chalcone derived from liquorice, exhibits multiple biological activities, including anti-oxidation and anti-inflammation. This study aimed to investigate the role and underlying mechanism of LA in the abdominal aortic aneurysm (AAA). AAA model was established by continuous infusion of 1000 ng/kg/min of angiotensin II (AngII) in ApoE -/- mice for 4 weeks. At 7 days before AngII administration, 5 mg/kg/day or 10 mg/kg/day of LA was intraperitoneally administered to mice and continued for 4 weeks. The characteristics and quantification of AAAs were determined in situ. Real-time PCR or western blot was used to measure mRNA or protein levels of matrix metalloproteinase 2 and matrix metalloproteinase 9; pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6; apoptosis related proteins Bax, Bcl-2, and active caspase-3; miR-181b; Sirtuin 1 (SIRT1); and heme oxygenase-1 (HO-1). Mouse-aorta-origin vascular smooth muscle (MOVAS) cells were used to confirm the involved pathways in vitro. We found LA administration dose-dependently reduced the incidence of AngII-induced AAA, aneurysm diameter enlargement, elastin degradation, matrix metalloproteinase production, pro-inflammatory cytokines and miR-181b expression, and vascular smooth muscle cell apoptosis. It elevated SIRT1 and HO-1 expression that was suppressed by AngII. AngII enhanced miR-181b but reduced SIRT1 and HO-1 expression in MOVAS cells. In AngII-stimulated MOVAS cells, downregulation of miR 181b significantly upregulated the expression of SIRT1 and HO-1, the effect of which was abrogated by SIRT1 siRNA. Collectively, LA could attenuate AngII induced AAA by modulating the miR-181b/SIRT1/HO-1 signaling. LA might be a potential medical therapy for small AAA. PMID- 30417354 TI - Medical Cannabis: A plurimillennial history of an evergreen. AB - The history of Cannabis goes along that of humankind, as speculated based on geographical and evolutionary models together with historic data collected to date. Its medical use is several thousand years old, as attested both by archeobotanical evidence of Cannabis remains and written records found in ancient texts from the sacred Vedic foundational texts of Ayurvedic medicine (about 800 before current era [BCE]) to the first known Pharmacopoea, the Chinese "Shen Nung Pen Ts'ao Ching" (1 century BCE). In this paper, we retrace the history of Cannabis traveling through the key stages of its diffusion among the most important ancient cultures up to our days, when we are facing a renaissance of its medical employment. We report through the centuries evidence of its use in numerous pathologic conditions especially for its anti-inflammatory, antiseptic, and anticonvulsing properties that support the requirement to direct our present research efforts into the definitive understanding of its efficacy. PMID- 30417355 TI - A comparison of three strategies for biopanning of phage-scFv library against diphtheria toxin. AB - The biopanning process is a critical step in phage display for isolating peptides or proteins with specific binding properties. Conventional panning methods are sometimes not so effective and may result in nonspecific or low-yield positive results. In this study, three different strategies including soluble antibody capturing, pH-stepwise elution, and conventional panning were used for enrichment of specific clones against diphtheria toxoid. The reactivity of the selected clones was evaluated using an indirect enzyme-linked immunosorbent assay. The positive clones were screened using Vero cell viability assay. The neutralizing clones were expressed in HB2151 strain of Escherichia coli and soluble single chain fragment variable (scFv) fragments were purified by nickel-nitrilotriacetic acid affinity chromatography. Finally, the ability of scFv fragments for neutralizing diphtheria toxin (DT) were evaluated again using Vero cell viability assay. After four rounds of panning, the soluble antibody-capturing method yielded 15 positive phage-scFv clones against diphtheria toxoid. Conventional panning and pH-stepwise elution model resulted from nine and five positive phage scFv clones, respectively. Among all positive clones, three clones were able to neutralize DT in Vero cell viability assay. Two of these clones belonged to a soluble antibody-capturing method and one of them came from conventional panning. Three neutralizing clones were used for soluble expression and purification of scFvs fragments. It was found that these soluble scFv fragments possessed neutralizing activity ranging from 0.15 to 0.6 ug against two-fold cytotoxic dose 99% of DT. In conclusion, the results of our study indicate that soluble antibody capturing method is an efficient method for isolation of specific scFv fragments. PMID- 30417356 TI - Calpain-2 protects against heat stress-induced cardiomyocyte apoptosis and heart dysfunction by blocking p38 mitogen-activated protein kinase activation. AB - Cardiovascular dysfunction is a common complication among heatstroke patients, but its underlying mechanism is unclear. This study was designed to investigate the role of calpain-2 and its downstream signal pathway in heat stress-induced cardiomyocyte apoptosis and heart dysfunction. In cultured primary mouse neonatal cardiomyocytes (MNCs), heat stress (43 degrees C for 2 hr) induced a heat-shock response, as indicated by upregulated heat-shock protein 27 (HSP27) expression and cellular apoptosis, as indicated by increased caspase-3 activity, DNA fragmentation and decreased cell viability. Meanwhile, heat stress decreased calpain activity, which was accompanied by downregulated calpain-2 expression and increased phosphorylation of p38, extraceIIuIar signaI-reguIated protein kinase (ERK1/2) and c-Jun N-terminaI kinase (JNK). Calpain-2 overexpression abrogated heat stress-induced apoptosis and phosphorylation of p38 and JNK, but not of ERK1/2. Blocking only p38 prevented heat stress-induced apoptosis in MNCs. In cardiac-specific calpain-2 overexpressing transgenic mice, p38 phosphorylation and cardiomyocyte apoptosis were decreased in the heart tissue of heatstroke mice, as revealed by western blot and terminal deoxynucleotidyl transferase dUTP nick end labelling assays, respectively. M-mode echocardiography also demonstrated that calpain-2 overexpression significantly improved heatstroke induced decreases in ventricular end-diastolic volume and cardiac output. In conclusion, our study suggests that heat stress reduces calpain-2 expression, which then activates p38, leading to cardiomyocyte apoptosis and heart dysfunction. PMID- 30417357 TI - Estrogen deprivation aggravates intracellular calcium dyshomeostasis in the heart of obese-insulin resistant rats. AB - The incidence of cardiovascular disease and metabolic syndrome increases after the onset of menopause, giving evidence for the vital role of estrogen. Intracellular calcium [Ca2+ ]i regulation plays an important role in the maintenance of left ventricular (LV) contractile function. Although either estrogen deprivation or obesity has been shown to strongly affect the metabolic status and LV function, the effects of estrogen deprivation on the cardiometabolic status and cardiac [Ca 2+ ]i regulation in the obese-insulin resistant condition have never been investigated. Our hypothesis was that estrogen deprivation aggravates LV dysfunction through the increased impairment of [Ca 2+ ]i homeostasis in obese-insulin resistant rats. Female rats were fed on either a high-fat (HFD, 59.28% fat) or normal (ND, 19.77% fat) diet for 13 weeks. Then, rats were divided into sham (HFS and NDS) operated or ovariectomized (HFO and NDO) groups. Six weeks after surgery, metabolic status, LV function and incidence of [Ca 2+ ]i transients were determined. NDO, HFS, and HFO rats had evidence of obese-insulin resistance indicated by increased body weight with hyperinsulinemia and euglycemia. Although NDO, HFS, and HFO rats had markedly reduced %LV fractional shortening, E/A ratio and decreased [Ca 2+ ]i transient amplitude and decay rate, HFO rats had the most severe impairments. These findings indicate that estrogen deprivation had a strong impact on abnormal LV function through [Ca 2+ ]i regulation. In addition, evidence was found that in obese-insulin resistant rats, estrogen deprivation severely aggravates LV dysfunction via increased impairment of [Ca 2+ ]i homeostasis. PMID- 30417358 TI - A2a adenosine receptor agonist improves endoplasmic reticulum stress in MIN6 cell line through protein kinase A/ protein kinase B/ Cyclic adenosine monophosphate response element-binding protein/ and Growth Arrest And DNA-Damage-Inducible 34/ eukaryotic Initiation Factor 2alpha pathways. AB - Endoplasmic reticulum (ER) stress is one of the main molecular events underlying pancreatic beta cell (PBC) failure, apoptosis, and a decrease in insulin secretion. Recent studies have highlighted the fundamental role of A2a adenosine receptor (A2aR) in potentiation of insulin secretion and proliferation of PBCs. However, possible protective effects of A2aR signaling against ER stress have not been elucidated yet. Thus, in the present study, we aimed to investigate the effects of A2aR activation in MIN6 beta cells undergoing tunicamycin (TM) mediated ER stress. A2aR expression and activity were evaluated using real-time polymerase chain reaction and measurement of the cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), phospho-protein kinase B or Akt (p-Akt)/Akt, and phospho-Cyclic adenosine monophosphate response element-binding protein/CREB levels in response to a specific agonist (CGS 21680). Survival and proliferation in TM and CGS 21680 cotreated cells were evaluated using 3-(4,5-Dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide (MTT), annexin V-fluorescein isothiocyanate (FITC)/propidium iodide staining, colony formation, and 5-bromo-2'-deoxyuridine (Brdu) assays. In addition, the effects of A2aR stimulation on insulin secretion were evaluated using the enzyme-linked immunosorbent assay. B-cell lymphoma 2 (Bcl-2), phospho-eukaryotic Initiation Factor 2alpha (p-eIF2alpha)/eIF2alpha, growth arrest and DNA-damage-inducible 34 (GADD34), X-box binding protein 1 (XBP 1), spliced X-box binding protein 1 (XBP-1s), immunoglobulin heavy-chain-binding protein (BIP), and CCAAT-enhancer-binding protein homologous protein (CHOP) levels were evaluated using western blotting. Our results showed a decrease in A2aR expression and p-Akt/Akt and p-CREB/CREB levels in TM-pretreated cells. We also mentioned that CGS 21680 effectively increased cell survival, proliferation, and insulin secretion in TM-treated cells. The antiapoptotic effects were possibly mediated through Bcl-2 upregulation. Our western blotting results indicated that A2aR effectively downregulated p-eIF2alpha/eIF2alpha, XBP-1, XBP 1s, BIP, and CHOP levels, whereas GADD34 was upregulated. Altogether, the present study revealed that A2aR signaling through PKA/Akt/CREB mediators alleviated TM cytotoxicity effects in MIN6 beta cells. Thus, the stimulation of this receptor was seen as a new approach to control ER stress in the PBC cells. PMID- 30417359 TI - Prognostic value of a gene signature in clear cell renal cell carcinoma. AB - Renal cancer is a common urogenital system malignance. Novel biomarkers could provide more and more critical information on tumor features and patients' prognosis. Here, we performed an integrated analysis on the discovery set and established a three-gene signature to predict the prognosis for clear cell renal cell carcinoma (ccRCC). By constructing a LASSO Cox regression model, a 3 messenger RNA (3-mRNA) signature was identified. Based on the 3-mRNA signature, we divided patients into high- and low-risk groups, and validated this by using three other data sets. In the discovery set, this signature could successfully distinguish between the high- and low-risk patients (hazard ratio (HR), 2.152; 95% confidence interval (CI),1.509-3.069; p < 0.0001). Analysis of internal and two external validation sets yielded consistent results (internal: HR, 2.824; 95% CI, 1.601-4.98; p < 0.001; GSE29609: HR, 3.002; 95% CI, 1.113-8.094; p = 0.031; E MTAB-3267: HR, 2.357; 95% CI, 1.243-4.468; p = 0.006). Time-dependent receiver operating characteristic (ROC) analysis indicated that the area under the ROC curve at 5 years was 0.66 both in the discovery and internal validation set, while the two external validation sets also suggested good performance of the 3 mRNA signature. Besides that, a nomogram was built and the calibration plots and decision curve analysis indicated the good performance and clinical utility of the nomogram. In conclusion, this 3-mRNA classifier proved to be a useful tool for prognostic evaluation and could facilitate personalized management of ccRCC patients. PMID- 30417360 TI - Exosomes derived from acute myeloid leukemia cells promote chemoresistance by enhancing glycolysis-mediated vascular remodeling. AB - Acute myeloid leukemia (AML) is the most common type of leukemia in adults. AML cells secrete angiogenic factors to remodel vasculature and acquire chemoresistance; however, antiangiogenic drugs are often ineffective in AML treatment. Cancer cell-derived exosomes can induce angiogenesis, but their role in vascular remodeling during AML is unclear. Here, we found that exosomes secreted by AML cells promoted proliferation and migration and tube-forming activity of human umbilical vein endothelial cells (HUVECs), whereas HUVECs conferred chemoresistance to AML cells. AML cell-derived exosomes contained vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) messenger RNA and induced VEGFR expression in HUVECs. Furthermore, they enhanced glycolysis, which correlated with HUVEC proliferation, tube formation, and resistance to apoptosis. Thus, AML cells secrete VEGF/VEGFR-containing exosomes that induce glycolysis in HUVECs leading to vascular remodeling and acquisition of chemoresistance. These findings may contribute to the development of novel therapeutic strategies targeting exosomes in AML. PMID- 30417361 TI - Formation and activation induction of primordial follicles using granulosa and cumulus cells conditioned media. AB - Fertility preservation of prepubertal girls subjected to invasive cancer therapy necessitates defining protocols for activation of isolated primordial follicles. Granulosa (GCs) and cumulus cells (CCs) play pivotal role in oocyte development. Although GCs and CCs share some similarities, they differ in growth factors production. The current study was conducted to evaluate the effects of GCs, CCs and their conditioned media on mice primordial follicles activation. One-day-old mice ovaries were subjected to 6-day culture with base medium (BM), GC conditioned medium (GCCM), GC coculture (GCCC), CC conditioned medium (CCCM) or CC coculture (CCCC). Follicular growth and primordial to primary follicle transition was observed during 6-day culture, and follicular activation rate tended to be greater in GCCM than other groups (0.05

= 0.999) for all sensitivity measurements, including output as a function of tube current. Detector sensitivity was 2.41 MUC Gy-1 for the 220 kVp therapy beam, and it ranged from 1.21 to 1.32 MUC Gy-1 for the 40-80 imaging beams. Percentage difference in sensitivity between the therapy and imaging beams before sensitivity correction and after using the Birks quenching factors were 52.3% and 10.2%, respectively. Percentage differences between the therapy and imaging beam sensitivities after using the air kerma calibration method for in-air measurements was excellent and below 0.3%. In-air beam profile measurements agreed to MC simulations within a mean difference of 2.4% for the 5 x 5 and 3 x 3 mm2 field sizes, however, the scintillator showed signs of volume averaging at the penumbra edges. CONCLUSIONS: A small plastic scintillator was characterized for therapy and imaging energies of a small animal irradiator, with output corrected for using an in-house MC model of the irradiator. The characterization of the scintillator detector system for small fields presents steps towards implementing real-time measurements for quality assurance and small animal treatment and imaging dose verification. This article is protected by copyright. All rights reserved. PMID- 30417378 TI - Functions of adipose-resident immune subsets and the impact on metabolic syndrome. AB - There is a growing appreciation of the role in the aetiology of metabolic syndrome that is played by the interplay of diet, microbiota and the interactions of immune cells and adipose cells in visceral adipose tissue. Recent studies have highlighted the programmes, properties and roles of the specialized, resident immune subsets that are abundant in adipose tissue, which may be considered a newly identified lymphoid compartment for immunology research. The findings indicate important roles for resident T effector and regulatory cells, innate lymphoid cells (ILCs), invariant natural killer T (iNKT) cells and macrophages, among others. Immunologists are at the very beginning of trying to narrate a story of complex interactions, with the need to unravel cause from effect. The enterprise will require studies in humans as well as mice, and needs to bring together the collaborative efforts of scientists and clinicians from diverse spheres including metabolic disease, diet and microbiology. PMID- 30417379 TI - Marked interspecific differences in the neuroanatomy of the male olfactory system of honey bees (genus Apis). AB - All honey bee species (genus Apis) display a striking mating behavior with the formation of male (drone) congregations, in which virgin queens mate with many drones. Bees' mating behavior relies on olfactory communication involving queen but also drone pheromones. To explore the evolution of olfactory communication in Apis, we analyzed the neuroanatomical organization of the antennal lobe (primary olfactory center) in the drones of five species from the three main lineages (open-air nesting species: dwarf honey bees Apis florea and giant honey bees Apis dorsata; cavity-nesting species: Apis mellifera, Apis kochevnikovi, and Apis cerana) and from three populations of A. cerana (Borneo, Thailand, and Japan). In addition to differences in the overall number of morphological units, the glomeruli, our data reveal marked differences in the number and position of macroglomeruli, enlarged units putatively dedicated to sex pheromone processing. Dwarf and giant honey bee species possess two macroglomeruli while cavity-nesting bees present three or four macroglomeruli, suggesting an increase in the complexity of sex communication during evolution in the genus Apis. The three A. cerana populations showed differing absolute numbers of glomeruli but the same three macroglomeruli. Overall, we identified six different macroglomeruli in the genus Apis. One of these (called MGb), which is dedicated to the detection of the major queen compound 9-ODA in A. mellifera, was conserved in all species. We discuss the implications of these results for our understanding of sex communication in honey bees and propose a putative scenario of antennal lobe evolution in the Apis genus. PMID- 30417380 TI - Periodontitis is associated with systemic inflammation and vascular endothelial dysfunction in patients with lacunar infarct. AB - BACKGROUND: Periodontitis has been associated with lacunar infarct (LI), a type of cerebral small vessel disease. The objective of this study was to ascertain whether periodontitis is associated with increased circulating levels of systemic inflammation and endothelial dysfunction biomarkers in patients with LI. METHODS: One hundred twenty patients with LI and 120 healthy controls underwent a full mouth periodontal examination. The periodontal inflamed surface area (PISA) was calculated for each participant. Demographic, medical, and neurological information were recorded from all of them. In addition, blood samples were collected in order to investigate differences in terms of interleukin (IL)-6, IL 10, pentraxin (PTX) 3, soluble fragment of tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and amyloid-beta (Abeta) peptides (i.e., Abeta1-40 , and Abeta1-42 ) measured in serum. RESULTS: Periodontitis was independently associated with increased levels of IL-6 (R2 = 0.656, P < 0.001), PTX3 (R2 = 0.115, P < 0.001), sTWEAK (R2 = 0.527, P < 0.001), and Abeta1-40 (R2 = 0.467, P < 0.001) in patients with LI. Within patients with poor outcome, PISA positively correlated with IL-6 (r = 0.738, P < 0.001), PTX3 (r = 0.468, P = 0.008), sTWEAK (r = 0.771, P < 0.001), and Abeta1-40 (r = 0.745, P < 0.001). CONCLUSIONS: Our data suggest a link between periodontitis, systemic inflammatory response, and disruption of the vascular endothelial function in patients with LI. Experimental studies are needed to elucidate possible pathways through which periodontitis could lead to this systemic inflammatory state with impairment of the endothelial function in LI. Further longitudinal studies with large samples are warranted to confirm our findings. PMID- 30417381 TI - Impact of water exposure on skin barrier permeability and ultrastructure. AB - BACKGROUND: Skin occlusion due to use of diapers or sanitary napkins often results in irritant contact dermatitis. Furthermore, prolonged occlusion and exposure to body fluids are known to increase skin hydration and permeability, thus leading to irritant contact dermatitis. OBJECTIVE: The effects of water exposure on the skin and its barrier functions were investigated to get more insight into the mechanisms of irritant contact dermatitis. METHODS: Water patches were applied to the volar forearm skin of 10 human subjects for 3 hours. Permeability of the stratum corneum (SC) was examined using methyl nicotinate (MN). Alterations in the hydration and ultrastructure of the SC were measured by Raman spectroscopy and multiphoton microscopy, respectively. RESULTS: Water profiles found using Raman spectroscopy demonstrated notable increases in water content throughout the SC and skin surface. Multiphoton microscopy revealed morphological changes that were formed in the intercellular space of the SC. Emerged pools seemed to contribute to increased MN absorption. CONCLUSION: Excessive skin hydration leading to changes in the SC ultrastructure might result in increased skin permeability of skin irritants and allergens. PMID- 30417382 TI - Technical Note: EPID's response to 6 MV photons in a strong, parallel magnetic field. AB - PURPOSE: Electronic portal imaging devices (EPIDs) are potentially useful for dosimetric verification in integrated MRI-linac systems. This work presents the reproducibility, linearity image lag, and radiation field profiles in a conventional EPID, with and without a 0.5 T parallel magnetic field present in a 6MV photon beam. METHODS: An aS500 EPID was modified to function in strong magnetic fields. All measurements were made using the linac-MR installed at the Cross Cancer Institute. The EPID remained stationary on the couch between the measurements made with and without magnetic field. We measured short term reproducibility of dark and flood fields, signal linearity from 1 MU to 500 MU irradiations, and image lag post 100 MU irradiation. An ion chamber was used to measure any linac output variations to correct the EPID signal due to these variations for the duration of experiment. X-axis and Y-axis radiation field profiles were obtained from the EPID image resulting from a 10 x 10 cm2 radiation field delivery. RESULTS: The average pixel value (+/- standard deviation) of flood field with and without magnetic fields were 57876 +/- 379 and 57703 +/- 366 respectively, and the corresponding average dark field pixel values were -32.05 +/- 0.85 and -32.19 +/- 0.97. The maximum difference in image linearity data with and without magnetic field is 0.2% which is well within the measurement uncertainty of 0.65%. Similarly, the image lag curves, with and without the magnetic field, were nearly identical. The first measured point, with mean lag signal of 1.44% without and 1.41% with magnetic field, shows that the largest difference is well below the uncertainty in the EPID signal measurement. The radiation field profiles obtained with and without magnetic fields were nearly identical; 91.3% of the X-axis and 95.2% of the Y-axis profile points pass a gamma criterion of 1% and 1 mm. CONCLUSIONS: A conventional EPID imager with a 0.1 cm copper plate responds to 6 MV photons similarly irrespective of the strong magnetic field being off or on in the parallel orientation to the radiation beam. Thus, the EPID is a potentially useful tool for pre-treatment dosimetric verification in linac-MR systems using parallel magnetic field. This article is protected by copyright. All rights reserved. PMID- 30417383 TI - Is neighborhood poverty harmful to every child? Neighborhood poverty, family poverty, and behavioral problems among young children. AB - This longitudinal study investigates the association between neighborhood poverty and behavioral problems among young children. This study also examines whether social environments mediate the relationship between neighborhood poverty and behavioral problems. We used data from the third and fourth waves of the Fragile Families and Child Wellbeing study to assess behavioral problems separately for children who experienced no family poverty, moved out of family poverty, moved into family poverty, and experienced long-term family poverty. Regression models assessed the effect of neighborhood poverty on behavioral problem outcomes among children aged 5 years, after controlling for sociodemographic characteristics and earlier behavioral problems. Results showed an association between neighborhood poverty and lower social cohesion and safety, which lead to greater externalizing problems among children with long-term family poverty living in high-poverty neighborhoods compared with those in low-poverty neighborhoods. Policies and community resources need to be allocated to improve neighborhood social environments, particularly for poor children in high-poverty neighborhoods. PMID- 30417384 TI - Anterior laryngeal electrodes for recurrent laryngeal nerve monitoring during thyroid and parathyroid surgery: New expanded options for neural monitoring. AB - OBJECTIVES/HYPOTHESIS: Intraoperative neural monitoring is a useful adjunct for the laryngeal nerve function assessment during thyroid and parathyroid surgery. Typically, monitoring is performed by measurement of electromyographic responses recorded by endotracheal tube (ETT) surface electrodes. Tube position alterations during surgery can cause displacement of the electrodes relative to the vocal cords, leading to false positive loss of signal. Numerous reports have denoted monitoring equipment-related issues, especially endotracheal tube displacement, as the dominant source of false positive error. The false positive error may result in inappropriate decisions by the surgeon. This study tests the hypothesis that anterior laryngeal electrodes (ALEs) can help reduce this error. Placement of ALEs directly onto the thyroid cartilage represent an adjunctive and possible alternative method to standard ETT surface electrodes. STUDY DESIGN: Retrospective review. METHODS: Fifteen consecutive patients undergoing thyroid and parathyroid surgery with intraoperative neuromonitoring using both ETT electrodes and ALEs were studied. Data collected included site of neural stimulation, laterality, and electromyographic parameters. RESULTS: With vagal and recurrent laryngeal nerve stimulation, the ALEs recorded mean vocalis muscle waveform amplitude within 83% of that recorded with standard ETT electrodes. The latency measurements with the anterior laryngeal and endotracheal electrodes were similar, with both electrodes recording significantly longer latency for the left vagus nerve as compared to the right vagus nerve. With superior laryngeal nerve stimulation, the ALEs recorded a 800% greater mean amplitude than the ETT electrodes. The ALEs demonstrated similar sensitivity to stimulation at low current as ETT electrodes and provided stable intraoperative monitoring information. CONCLUSIONS: Compared to ETT surface electrodes, the ALEs provide similar and stable electromyographic responses with equal sensitivity for recording evoked responses during neural monitoring in thyroid and parathyroid surgery. The ALEs offer significantly more robust monitoring of the external branch of the superior laryngeal nerve. Furthermore, ALEs are contained within the operative field, are totally surgeon controlled, and are unaffected by the potential vicissitudes of ETT position during surgery. LEVEL OF EVIDENCE: 4 Laryngoscope, 2018. PMID- 30417385 TI - Resveratrol glucuronidation in vitro: potential implications of inhibition by probenecid. AB - OBJECTIVES: Resveratrol is a naturally occurring antioxidant with therapeutic potential in prevention and treatment of neoplastic disease and other human disorders. However, net clearance of resveratrol in humans is very high, mainly due to glucuronide conjugation. This leads to extensive presystemic extraction and low plasma concentrations after oral dosage. The present study evaluated the effect of probenecid, an inhibitor of glucuronide conjugation, on resveratrol metabolism in vitro. METHODS: Biotransformation of resveratrol to its 3-O glucuronide and 4'-O-glucuronide conjugates was studied in vitro using human liver microsomal preparations. The mechanism and inhibitory potency of probenecid were evaluated based on a mixed competitive-noncompetitive inhibition model. KEY FINDINGS: Probenecid inhibition of resveratrol 3-O-glucuronidation was predominantly noncompetitive, with an inhibition constant (Ki ) averaging 3.1 mm. CONCLUSIONS: The ratio of in vivo maximum concentration of probenecid [I] during usual clinical use to the in vitro Ki value ([I]/Ki ) exceeds the boundary value of 0.1, used by regulatory agencies to identify the possibility of clinical drug interactions. This finding, together with the known property of probenecid as an inhibitor of glucuronide conjugation in humans, suggests that probenecid could serve as a pharmacokinetic boosting agent to enhance systemic exposure to resveratrol in humans. PMID- 30417386 TI - Arabidopsis PLDs with C2-domain function distinctively in hypoxia. AB - Hypoxia (oxygen deprivation) causes metabolic disturbances at physiological, biochemical and genetic levels and results in decreased plant growth and development. Phospholipase D (PLD)-mediated signaling was reported for abiotic and biotic stress signaling events in plants. To investigate the participatory role of PLDs also in hypoxia signaling, we used wild type of Arabidopsis thaliana and 10 pld isoform mutants containing C2-domain. Hypoxia-induced changes in three major signaling players, namely, cytosolic free calcium (Ca2+ cyt ), reactive oxygen species (ROS) and phosphatidic acid (PA), were determined in mesophyll protoplasts. The Ca2+ cyt and ROS levels were monitored by fluorescence microscopy and confocal imaging, while PA levels were quantified by an enzymatic method. Our findings reveal that the elevations of cytosolic calcium and PA are reduced in all the 10 mutants dysfunctional in PLD isoforms. The hypoxia-related changes in both calcium and ROS show different kinetic patterns depending on the type of PLD studied. Pharmacological experiments confirm that both external and internal sources contribute to calcium and ROS accumulation under hypoxia. PLDalpha1-3, PLDbeta1 and PLDgamma1-3 are likely involved in calcium signaling under hypoxia as well as in PA production, while all investigated PLDs, except for PLDgamma3, take part in ROS elevation. PMID- 30417387 TI - Influence of the crosstalk on the intensity of HAADF-STEM images of quaternary semiconductor materials. AB - The influence of the neighbouring atomic-columns in determining the composition at atomic column scale of quaternary semiconductor compounds, using simulated HAADF-STEM images is evaluated. The InAlAsSb alloy, a promising material in the photovoltaic field, is considered. We find that the so called 'crosstalk' effect plays an important role for the aimed compositional determination. The intensity transfer is larger from neighbouring atomic columns with higher average Z, and towards atomic columns with smaller Z. Our results show that in order to obtain precise information on the column composition, the HAADF-STEM intensities of both columns need to be taken into account simultaneously. PMID- 30417388 TI - Proteomic analysis of the inhibitory effect of oligochitosan on the fungal pathogen, Botrytis cinerea. AB - BACKGROUND: The fungal pathogen, Botrytis cinerea, infects a broad range of horticultural plants worldwide, resulting in significant economic losses. A derivative of chitosan, oligochitosan, has been reported to be an eco-friendly alternative to synthetic fungicides. RESULTS: Oligochitosan can greatly inhibit B. cinerea spore germination and induce protein carbonylation. To further investigate the molecular mechanism underlying the inhibitory effect, a comparative proteome analysis was conducted of oligochitosan-treated vs. non treated B. cinerea spores. The cellular proteins were obtained from B. cinerea spore samples and subjected to two-dimensional gel electrophoresis. A total of 21 differentially expressed proteins (DEPs) were identified. Three DEPs were up regulated in the oligochitosan-treated vs. the untreated spores; including scytalone dehydratase and a serine carboxypeptidase III precursor. In contrast, 7 DEPs, including Hsp 88 and cell division cycle protein 48, were down-regulated by the oligochitosan treatment. Notably, 10 DEPs, including phosphatidylserine decarboxylase proenzyme and ATP-dependent molecular chaperone HSC82, were only detected in the control spores; while 1 DEP, a non-annotated, predicted protein, was only detected in the oligochitosan-treated spores. CONCLUSION: Oligochitosan may affect the spore germination of B. cinerea by impairing the protein function. These findings have practical implications for the use of oligochitosan to control fungal pathogens. This article is protected by copyright. All rights reserved. PMID- 30417389 TI - The PKCbeta-p66shc-NADPH oxidase pathway plays a crucial role in diabetic nephropathy. AB - OBJECTIVES: Oxidative stress plays a critical role in the pathogenesis of diabetic nephropathy (DN). p66shc is closely related to oxidative stress. However, the exact mechanism of its involvement in diabetic nephropathy is poorly understood. This study aimed to investigate the role of the p66shc-related pathway in diabetic nephropathy. METHODS: In an in-vivo experiment, rats were injected with streptozotocin to induce early diabetic nephropathy. The treatment groups were an aminoguanidine group and an enzastaurin group. In an in-vitro experiment, human renal proximal tubule epithelial cells (HK-2 cells) were cultured and incubated with high glucose. KEY FINDINGS: Upregulated protein expression of p66shc and p-p66shc was found in vivo and in vitro when cells were stimulated by high levels of glucose; this effect was accompanied by enhanced oxidative stress and damaged renal function, both of which were alleviated by p66shc siRNA. p66shc regulated NADPH oxidase, further promoting activation of oxidative stress. As an inhibitor of PKCbeta, enzastaurin reduced the abnormal expression of p66shc and NADPH oxidase and alleviated renal injury. CONCLUSIONS: This study demonstrated enzastaurin alleviated diabetic renal injury via modulation of the PKCbeta-p66shc-NADPH oxidase pathway, which provided a new perspective for the treatment of early DN. PMID- 30417390 TI - FIB-SEM imaging properties of Drosophila melanogaster tissues embedded in Lowicryl HM20. AB - Lowicryl resins enable processing of biological material for electron microscopy at the lowest temperatures compatible with resin embedding. When combined with high-pressure freezing and freeze-substitution, Lowicryl embedding supports preservation of fine structural details and fluorescent markers. Here, we analysed the applicability of Lowicryl HM20 embedding for focused ion beam (FIB) scanning electron microscopy (SEM) tomography of Drosophila melanogaster embryonic and larval model systems. We show that the freeze-substitution with per mill concentrations of uranyl acetate provided sufficient contrast and an image quality of SEM imaging in the range of similar samples analysed by transmission electron microscopy (TEM). Preservation of genetically encoded fluorescent proteins allowed correlative localization of regions of interest (ROI) within the embedded tissue block. TEM on sections cut from the block face enabled evaluation of structural preservation to allow ROI ranking and thus targeted, time-efficient FIB-SEM tomography data collection. The versatility of Lowicryl embedding opens new perspectives for designing hybrid SEM-TEM workflows to comprehensively analyse biological structures. LAY DESCRIPTION: Focused ion beam scanning electron microscopy is becoming a widely used technique for the three-dimensional analysis of biological samples at fine structural details beyond levels feasible for light microscopy. To withstand the abrasion of material by the ion beam and the imaging by the scanning electron beam, biological samples have to be embedded into resins, most commonly these are very dense epoxy-based plastics. However, dense resins generate electron scattering which interferes with the signal from the biological specimen. Furthermore, to improve the imaging contrast, epoxy embedding requires chemical treatments with e.g. heavy metals, which deteriorate the ultrastructure of the biological specimen. In this study we explored the applicability of an electron lucent resin, Lowicryl HM 20, for focused ion beam scanning electron microscopy. The Lowicryl embedding workflow operates at milder chemical treatments and lower temperatures, thus preserving the sub-cellular and sub-organellar organization, as well as fluorescent markers visible by light microscopy. Here we show that focus ion beam scanning electron microscopy of Lowicryl-embedded fruit flies tissues provides reliable imaging revealing fine structural details. Our workflow benefited from use of transmission electron microscopy for the quality control of the ultrastructural preservation and fluorescent light microscopy for localization of regions of interest. The versatility of Lowicryl embedding opens up new perspectives for designing hybrid workflows combining fluorescent light, scanning, and transmission electron microscopy techniques to comprehensively analyze biological structures. PMID- 30417391 TI - Mitochondrial quality control in cardiac cells: Mechanisms and role in cardiac cell injury and disease. AB - Mitochondria play an important role in maintaining cardiac homeostasis by supplying the major energy required for cardiac excitation-contraction coupling as well as controlling the key intracellular survival and death pathways. Healthy mitochondria generate ATP molecules through an aerobic process known as oxidative phosphorylation (OXPHOS). Mitochondrial injury during myocardial infarction (MI) impairs OXPHOS and results in the excessive production of reactive oxygen species (ROS), bioenergetic insufficiency, and contributes to the development of cardiovascular diseases. Therefore, mitochondrial biogenesis along with proper mitochondrial quality control machinery, which removes unhealthy mitochondria is pivotal for mitochondrial homeostasis and cardiac health. Upon damage to the mitochondrial network, mitochondrial quality control components are recruited to segregate the unhealthy mitochondria and target aberrant mitochondrial proteins for degradation and elimination. Impairment of mitochondrial quality control and accumulation of abnormal mitochondria have been reported in the pathogenesis of various cardiac disorders and heart failure. Here, we provide an overview of the recent studies describing various mechanistic pathways underlying mitochondrial homeostasis with the main focus on cardiac cells. In addition, this review demonstrates the potential effects of mitochondrial quality control dysregulation in the development of cardiovascular disease. PMID- 30417392 TI - Overexpression of novel lncRNA NLIPMT inhibits metastasis by reducing phosphorylated glycogen synthase kinase 3beta in breast cancer. AB - Long noncoding RNAs (lncRNAs) are considered as regulators of gene expression in cancers. However, cancer profiling has little focused on noncoding genes. Here, we reported that RP11-115N4.1 (here renamed novel lncRNA inhibiting proliferation and metastasis [NLIPMT]) was downregulated in breast cancer tissues. Ectopic expression of NLIPMT inhibited mammary cell proliferation, motility in vitro. Moreover, lnc-NLIPMT reduced the growth of implanted MDA-MB-231 cells in vivo. Mechanistically, glycogen synthase kinase 3beta (GSK3beta) was identified as an effector protein regulated by lnc-NLIPMT. Inhibition of GSK3beta activity restored NLIPMT-induced inhibition of proliferation and motility in breast cancer cells. These data reveal that lnc-NLIPMT functions as a driver of breast cancer progression and might serve as a potential target for antimetastatic therapies. PMID- 30417393 TI - A new enzymatic activity from elicitor-treated pear cell cultures converting trans-cinnamic acid to benzaldehyde. AB - Cell cultures of Asian pear (Pyrus pyrifolia) are known to produce benzoate derived biphenyl phytoalexins upon elicitor treatment. Although the downstream pathway for biphenyl phytoalexin biosynthesis is almost known, the upstream route of benzoic acid biosynthesis in pear has not been completely elucidated. In the present work, we report benzaldehyde synthase (BS) activity from yeast extract treated cell suspension cultures of P. pyrifolia. BS catalyzes the in vitro conversion of trans-cinnamic acid to benzaldehyde using a non-oxidative C2 -side chain cleavage mechanism. The enzyme activity was strictly dependent on the presence of a reducing agent, dithiothreitol being preferred. C2 -side chain shortening of the cinnamic acid backbone resembled the mechanisms catalyzed by 4 hydroxybenzaldehyde synthase (HBS) activity in Vanilla planifolia and salicylaldehyde synthase (SAS) activity in tobacco and apple cell cultures. A basal BS activity was also observed in the non-elicited cell cultures. Upon yeast extract-treatment, a 13-fold increase in BS activity was observed when compared to the non-treated control cells. Moreover, feeding of the cell cultures with trans-cinnamic acid, the substrate for BS, resulted in an enhanced level of noraucuparin, a biphenyl phytoalexin. Comparable accumulation of noraucuparin was observed upon feeding of benzaldehyde, the BS product. The preferred substrate for BS was found to be trans-cinnamic acid, for which the apparent Km and Vmax values were 0.5 mM and 50.7 pkat mg-1 protein, respectively. Our observations indicate the contribution of BS to benzoic acid biosynthesis in Asian pear via the CoA-independent and non-beta-oxidative route. PMID- 30417394 TI - Fixed drug eruption caused by fluconazole-An underdiagnosed but recurrent problem. PMID- 30417396 TI - Incidence and predictors of moderate to severe tricuspid regurgitation after dual chamber pacemaker implantation. AB - INTRODUCTION: The incidence and predictors of tricuspid regurgitation (TR) after permanent pacemaker (PM) implantations have not been well evaluated. We attempted to determine TR's natural course and predictors, especially focusing on the influence of atrial fibrillation (AF). METHODS: Data from 530 patients with dual chamber PMs were evaluated. The main study outcomes were moderate to severe TR and isolated TR (moderate to severe TR without other structural heart diseases [SHDs]) in follow-up echocardiography. RESULTS: Over a median follow-up period of 7.6 years, moderate to severe TR developed in 14.5% patients. Of those, concomitant SHD was observed in 51.9% of patients, and 48.1% presented with isolated TR. A multivariable analysis identified the independent predictors of moderate to severe TR (diabetes mellitus [DM], chronic lung disease, preexisting mild TR, peripheral artery disease, moderate to severe aortic regurgitation, and persistent AF [PeAF]) and isolated TR (DM, preexisting mild TR, and PeAF). PeAF (n = 67, 12.6%) was an independent predictor of both moderate to severe TR (hazard ratio [HR] 2.59, 95% confidence interval [CI]: 1.22-5.51) and isolated TR (HR 4.54, 95% CI: 1.60-12.90). The patients with PeAF exhibited a higher incidence of moderate to severe TR (21.8% vs 12.9% vs 11.6% PeAF, paroxysmal AF, and without AF, respectively) and isolated TR (18.6% vs 6.6% vs 4.2%, respectively) during the follow-up. CONCLUSION: Moderate to severe TR after PM implantations developed with or without the influence of concomitant SHD. Patients with PeAF exhibited a higher risk of moderate to severe TR after PM implantations. PMID- 30417395 TI - Noncoding transcribed ultraconserved region (T-UCR) UC.48+ is a novel regulator of high-fat diet induced myocardial ischemia/reperfusion injury. AB - Increasing evidence has suggested high-fat diet (HFD) is an independent risk factor for myocardial ischemia/reperfusion (MI/R) injury. Long noncoding RNAs (lncRNAs) recently attracted much attraction in the study of MI/R injury. However, the functional questions of specific lncRNAs in HFD-induced MI/R injury have not been well elucidated. Uc.48+ is a lncRNA from a transcribed ultraconserved region (T-UCR) of human, mouse, and rat genomes. Here, we explored the aggravating role of uc.48+and identified purinergic P2X7 receptor (P2X7R) as a downstream regulator of uc.48+ in HFD-induced MI/R vulnerability. We demonstrated uc.48+ expression was upregulated, accompanied by the corresponding upregulation of P2X7R in HFD I/R myocardium and HFD-induced MI/R vulnerability. Overexpression of uc.48+enhanced, whereas silencing of uc.48 + decreased the expression of P2X7R, cardiomyocyte apoptosis, and MI/R injury. The functional relevance of uc.48+ regulated P2X7R expression and the subsequent NF-kappaB signaling to promote cardiomyocyte apoptosis was supported by inhibition of P2X7R with its specific antagonist (A438079) as well as the inhibitor of NF-kappaB signaling (pyrrolidine dithiocarbamate, PDTC) in H9c2 hypoxia/reoxygenation (H/R) cells transfected with pcDNA3.0-uc.48 + plasmid, and RNA immunoprecipitation (RIP) suggested uc.48+ could interact with transcription factor Sp1. Importantly, Sp1 inhibitor (mithramycin, MIT) was found to suppress uc.48+ -induced P2X7R expression and the NF-kappaB signaling and cardiomyocyte apoptosis. Our findings provide a potential novel mechanism through which uc.48+ boosts cardiomyocyte apoptosis and MI/R vulnerability to HFD. Thus, uc.48+ is a novel regulator of HFD induced MI/R injury; targeting uc.48+ may be a novel therapeutic approach of MI/R vulnerability to HFD. PMID- 30417397 TI - Workers' compensation injury claims among workers in the private ambulance services industry-Ohio, 2001-2011. AB - BACKGROUND: Ambulance service workers frequently transfer and transport patients. These tasks involve occupational injury risks such as heavy lifting, awkward postures, and frequent motor vehicle travel. METHODS: We examined Ohio workers' compensation injury claims among state-insured ambulance service workers working for private employers from 2001 to 2011. Injury claim counts and rates are presented by claim types, diagnoses, and injury events; only counts are available by worker characteristics. RESULTS: We analyzed a total of 5882 claims. The majority were medical-only (<8 days away from work). The overall injury claim rate for medical-only and lost-time cases was 12.1 per 100 full-time equivalents. Sprains and strains accounted for 60% of all injury claims. Overexertion from patient handling was the leading injury event, followed by motor vehicle roadway incidents. CONCLUSIONS: Study results can guide the development or improvement of injury prevention strategies. Focused efforts related to patient handling and vehicle incidents are needed. PMID- 30417399 TI - Long-Term Survival for Hemodialysis Patients Differ in Japan Versus Europe and the USA. What Might the Reasons Be? PMID- 30417398 TI - Loss of paraspinal muscle mass is a gender-specific consequence of cirrhosis that predicts complications and death. AB - BACKGROUND: Loss of skeletal muscle mass is a recognised complication with a prognostic impact in patients with cirrhosis. AIM: To explore in a retrospective analysis which muscle compartment most reliably predicts the occurrence of cirrhosis-associated complications and if there are gender-related differences. METHODS: 795 patients with cirrhosis listed for liver transplantation between 2001 and 2014 met the inclusion and exclusion criteria including an abdominal CT scan (+/-200). Controls were 109 patients who underwent a CT scan after polytrauma. The paraspinal muscles index (PSMI), the abdominal wall muscles index (AWMI) and its combination skeletal muscle index (SMI) were assessed at L3/L4, normalised to the height (cm2 /m2 ). RESULTS: 62.0% of patients with cirrhosis had alcoholic liver disease, and 70.6% were male. As compared to controls, a reduction in PSMI and SMI but not AWMI was associated with high model of end stage liver disease (MELD) score, high Child-Pugh class, and the presence or history of cirrhosis-associated complications in males but not females. PSMI independently predicted the occurrence of bacterial infections (HR 0.932), spontaneous bacterial peritonitis (HR 0.901), hepatic encephalopathy (HR 0.961), and hepatorenal syndrome (HR 0.946) by multivariate Cox regression analysis in a gender-independent manner. Post-transplant survival was not associated with the PSMI; neither AWMI nor SMI predicted any clinical endpoints. CONCLUSIONS: This study links muscle wasting in patients with cirrhosis predominantly to males. However, the presence of a low PSMI mass is a gender-independent predictor of developing cirrhosis-associated complications and death. Scores combining the MELD with muscle parameters should be re-validated by utilizing the PSMI. PMID- 30417400 TI - Seasonal and spatial variation in the sediment bacterial community and diversity of Lake Bosten, China. AB - To explore the influence of seasonal and regional environmental factors on the bacterial community composition (BCC) and diversity in the sediments of Lake Bosten, the 16S rRNA gene of sediment bacteria in four samples from the lake center area and the macrophyte-dominated area were sequenced using 454 pyrosequencing. According to the operational taxonomic units (OTUs), diversity index, relative abundance, and redundancy analysis (RDA) of the bacteria, the results showed that (i) the bacterial diversity of the lake center area was lower than that of the macrophyte-dominated area, and it was higher in winter than that in summer as a whole; (ii) seasonal factors and geographical changes had obvious effects on the abundance of dominant bacteria, including Proteobacteria and Firmicutes; (iii) a large number of unclassified bacteria were detected in this study, and the dominant unclassified genera in both lake areas included unclassified Sva0485, unclassified Anaerolineaceae, and unclassified Nitrospiraceae; and (iv) TN and TOC were the main environmental factors influencing the sediment bacterial community in Lake Bosten, as determined by RDA analysis. The study provides a reference for the in-depth understanding the impact with the change of time and space on sediment microbes in Lake Bosten. PMID- 30417401 TI - Open Source 3D-printed focussing mechanism for cellphone-based cellular microscopy. AB - The need to improve access to microscopes in low-resource and educational settings coupled with the global proliferation of camera-enabled cellphones has recently led to an explosion in new developments in portable, low-cost microscopy. The availability of accurate ball lenses has resulted in many variants of van Leeuwenhoek-like microscopes. Combined with cellphones, they have the potential for use as portable microscopes in education and clinics. The need for reproducibility in such applications implies that control over focus is critical. Here, we describe a 3D-printed focussing mechanism based on a rack and pinion mechanism, coupled to a ball lens- based microscope. We quantify the time stability of the focussing mechanism through an edge-based contrast measure used in autofocus cameras and apply it to 'thin smear' blood sample infected with Plasmodium as well as onion skin cells. We show that stability of the z-focus is in the micrometre range. This development could, we believe, serve to further enhance the utility of a low-cost and robust microscope and encourage further developments in field microscopes based on the Open Source principle. LAY DESCRIPTION: The wide spread of cellphones with cameras makes them an attractive platform for digital microscopy. Such microscopes could help improve microscope access in clinics and classrooms in the form of 'field microscopes', if they could be adapted for imaging cells. We integrate a 3D printed focussing mechanism made with recyclable plastic with ball-lens microscope of the Leeuwenhoek type. We demonstrate how the device can help stabilise to a focal plane for acquiring movies of a thin-smear of blood infected with Plasmodium and onion skin cells using a cellphone. The stability of focus is expectedly less precise as compared to research-grade microscopes, but is of the range of a few micrometers. We believe, the focussing device demonstrates it is possible to obtain reliable and reproducible images of typical samples used in clinics and classrooms. By making the design files of this device open-source we believe it could serve as a small step in improved, affordable and accurate 'field microscopes'. PMID- 30417402 TI - Challenges and approaches in the discovery of human immunodeficiency virus type-1 non-nucleoside reverse transcriptase inhibitors. AB - The type I human immunodeficiency virus (HIV-1) pandemic affecting over 37 million people worldwide continues, with 1.8 million people newly infected each year. Highly active antiretroviral therapy is efficient at reducing viral load and nearly one-half of the infected population is on treatment. One of the most successful approaches for the treatment of HIV infections is the use of inhibitors for human immunodeficiency virus type-1 reverse transcriptase (HIV-1 RT). At present, there are six nonnucleoside reverse transcriptase inhibitors (NNRTIs) approved for clinical use: nevirapine (NVP), delavirdine (DLV), efavirenz (EFV), etravirine (ETV), rilpivirine (RPV), and elsulfavirine. In this review, we will cover the development of different classes of NNRTIs over the last two decades. We will give an overview of traditional medicinal chemistry strategies for structural modification as bioisosterism principles, scaffold hopping, substitute decoration, and molecular hybridization. Furthermore, computer-aid design as virtual screening, de novo design and free-energy perturbation will be described in details. PMID- 30417403 TI - CT automated exposure control using a generalized detectability index. AB - PURPOSE: Identifying an appropriate tube current setting can be challenging when using iterative reconstruction due to the varying relationship between spatial resolution, contrast, noise, and dose across different algorithms. This study developed and investigated the application of a generalized detectability index ( METHODS: This study proposes a task-based automated exposure control (AEC) method using a generalized detectability index ( RESULTS: The study of the ACR phantom with elliptical shell demonstrated reasonable agreement between the CONCLUSIONS: A novel AEC method, based on a generalized detectability index, was investigated. The proposed method can be used with some existing AEC systems to derive the tube current profile for iterative reconstruction algorithms. The results provide preliminary evidence that the proposed PMID- 30417404 TI - Factors associated with survival, laminitis and insulin dysregulation in horses diagnosed with equine pituitary pars intermedia dysfunction. AB - BACKGROUND: Pituitary pars intermedia dysfunction (PPID) is a commonly described endocrine disorder in higher latitudes of the Northern hemisphere but the description of the disease at lower latitudes and in the Southern hemisphere is limited. OBJECTIVES: Document the clinical features of PPID at different Australian latitudes and climates, and investigate factors associated with survival, laminitis and insulin dysregulation (ID). STUDY DESIGN: Retrospective study of 274 equids from eight institutions across Australia. METHODS: A diagnosis of PPID was based on endogenous ACTH, overnight dexamethasone suppression test, thyrotropin-releasing hormone stimulation test or necropsy. Clinical and clinicopathologic characteristics of PPID and therapeutic responses were investigated. Laminitis was diagnosed by radiographic or histologic changes and ID was diagnosed based on endogenous insulin, an oral glucose test or a 2 step insulin-response test. RESULTS: Being a pony, having a higher body condition score and pergolide administration were associated with survival. The clinical presentation of PPID changed with latitude and climate, with anhidrosis and polyuria/polydipsia more commonly recognised at lower latitudes. Laminitis was diagnosed in 89.9% of cases and ID was present in 76.5% of cases in which they were investigated. MAIN LIMITATIONS: Despite the sample size, the lack of uniform testing at all locations (primary or referral cases) and the incompleteness of data sets limited the power of the statistical analyses. CONCLUSIONS: PPID can present with variable signs at different latitudes and climates, and ID should be investigated in equids diagnosed with PPID. Adequate body condition and administration of pergolide are fundamental in PPID management. PMID- 30417405 TI - Glycyrrhizin, an HMGB1 inhibitor, exhibits neuroprotective effects in rats after lithium-pilocarpine-induced status epilepticus. AB - OBJECTIVES: It has been proven that extracellular HMGB1 is involved in progression of neurologic disorders, such as stroke, traumatic brain injury, meningitis and epilepsy. Glycyrrhizin (GL) is a direct inhibitor of HMGB1, and blocks HMGB1 release into the extracellular. We aim in this study to investigate the neuroprotective effects of GL in a rat model after lithium-pilocarpine induced status epilepticus (SE). METHODS: Adult male SD rats were divided into three groups: Sham group, SE-group and (SE + GL)-treated group. The HMGB1 expression in serum and hippocampus, the damage extent of blood brain barrier (BBB) and hippocampal neuronal damage were evaluated by enzyme-linked immunosorbent assay, immunohistochemistry, western blot and nissl's staining. KEY FINDINGS: Glycyrrhizin markedly reduced HMGB1 expression in serum and hippocampus, prevented HMGB1 translocation from nucleus to cytoplasm in hippocampal CA1, CA3 and hilus areas of SE rats. Meanwhile, GL significantly ameliorated neuronal damage in the CA1, CA3 and hilus areas of hippocampus, and protected BBB disruption after SE. The administration of GL significantly decreased the mortality from 25 to 8.9% in rats. CONCLUSIONS: Glycyrrhizin may exert neuroprotective effects via inhibiting HMGB1 and protect BBB permeability in lithium-pilocarpine-induced rats with SE. PMID- 30417407 TI - Documentation in the neonatal unit: the support given to parents and their participation in their baby's care. AB - AIMS: To explore how often the participation of parents in their infants' care and professionals' support for parents was documented in the clinical records and to determine how such participation and support were documented. BACKGROUND: Comprehensive documentation can facilitate collaboration between parents and health care professionals, supporting family-centered care, yet little is known about how this is reflected in practice. DESIGN: A prospective, mixed methods approach was used to analyse the clinical records of newborns. METHODS: The study was carried out in a large tertiary Neonatal Unit in the United Kingdom, from 2013-2014. We analysed the clinical records of 24 critically ill newborns using content analysis and thematic analysis, enabling us to determine the frequency of documented support and participation as well as how support and participation were documented. RESULTS: We identified four categories of support in the clinical records: 'emotional', 'spiritual', 'social' and 'practical support'. We also identified instances where parents were encouraged to participate in their infant's care. Frequency differences in the documentation of support between infants facing a redirection of care decision and infants receiving active treatment were found. Two organisational themes were identified: 'task focused documentation' and 'minimal documentation of parental role'. These were grouped together under the global theme 'professional accountability'. The perspectives and experiences of parents were minimally documented throughout. CONCLUSION: Documentation of support towards parents and parents' participation in their infants' care was limited in terms of frequency and content. Encouraging regular, detailed documentation of these aspects of care may facilitate family-centered care. This article is protected by copyright. All rights reserved. PMID- 30417406 TI - Decellularized Wharton's jelly extracellular matrix as a promising scaffold for promoting hepatic differentiation of human induced pluripotent stem cells. AB - Liver tissue engineering as a therapeutic option for restoring of damaged liver function has a special focus on using native decellularized liver matrix, but there are limitations such as the shortage of liver donor. Therefore, an appropriate alternative scaffold is needed to circumvent the donor shortage. This study was designed to evaluate hepatic differentiation of human induced pluripotent stem cells (hiPSCs) in decellularized Wharton's jelly (WJ) matrix as an alternative for native liver matrix. WJ matrices were treated with a series of detergents for decellularization. Then hiPSCs were seeded into decellularized WJ scaffold (DWJS) for hepatic differentiation by a defined induction protocol. The DNA quantitative assay and histological evaluation showed that cellular and nuclear materials were efficiently removed and the composition of extracellular matrix was maintained. In DWJS, hiPSCs-derived hepatocyte-like cells (hiPSCs Heps) efficiently entered into the differentiation phase (G1) and gradually took a polygonal shape, a typical shape of hepatocytes. The expression of hepatic associated genes (albumin, TAT, Cytokeratin19, and Cyp7A1), albumin and urea secretion in hiPSCs-Heps cultured into DWJS was significantly higher than those cultured in the culture plates (2D). Altogether, our results suggest that DWJS could provide a proper microenvironment that efficiently promotes hepatic differentiation of hiPSCs. PMID- 30417408 TI - Syringocystadenoma papilliferum of the cervix presenting as vulvar growth in an adolescent girl. AB - Syringocystadenoma papilliferum (SCP) is a rare, benign, adnexal tumour of apocrine or eccrine differentiation. It is commonly located on head and neck region. We report the case of an 18-year-old woman who presented with a vulvar lobulated growth that was found to arise from the posterior lip of cervix. Histopathological examination revealed the diagnosis of SCP. To our knowledge, SCP arising from the cervix has never been reported previously in the literature, thus we believe this to be the first case of SCP arising from the posterior lip of the cervix. PMID- 30417409 TI - Evaluation of Osteopontin and Pokemon genes expression in hepatitis C virus associated hepatocellular carcinoma. AB - Osteopontin and Pokemon genes may have an important role in the pathogenesis of different malignancies. Osteopontin is a glycoprotein of the extracellular matrix, and Pokemon is a regulator of transcription. Both have been hypothesized to be useful as therapeutic targets or diagnostic markers. We aim to assess the role of both in hepatocellular carcinoma and liver fibrosis due to hepatitis C virus (HCV) infection. We conducted our study on 50 patients and classified them into three groups-Group I: Patients with HCV-related hepatocellular carcinoma (HCC) (n = 30); Group II: Patients with hepatitis C cirrhosis (n = 10); and Group III: Patients with hepatitis C fibrosis (n = 10). We found high levels of Osteopontin and Pokemon gene expression in group I. Osteopontin levels were higher also in patients with liver fibrosis was correlated to high levels of parameters such as alpha fetoprotein and caspase. We conclude that HCC is associated with overexpression of both Osteopontin and Pokemon and that Osteopontin plays a significant role in liver fibrosis due to hepatitis C infection. PMID- 30417410 TI - Wnt/beta-catenin signaling enhances transcription of the CX43 gene in murine Sertoli cells. AB - Sertoli cells provide the nutritional and metabolic support for germ cells. Wnt/beta-catenin signaling is important for the development of the seminiferous epithelium during embryonic age, although after birth this pathway is downregulated. Cx43 gene codes for a protein that is critical during testicular development. The Cx43 promoter contains TCF/beta-catenin binding elements (TBEs) that contribute CX43 expression in different cell types and which may also be regulating the expression of this gene in Sertoli cells. In this study, we demonstrate that 42GPA9 Sertoli cells respond to treatments that result in accumulation of beta-catenin within the nucleus and in upregulation of CX43 gene transcription. beta-Catenin binds to TBEs located both upstream and downstream of the transcriptional start site (TSS). Luciferase reporter experiments revealed that TBEs located upstream of the TSS are necessary for beta-catenin-mediated upregulation. Our results also indicate that the Wnt/beta-catenin-dependent upregulation of the Cx43 gene in Sertoli cells is accompanied by changes in epigenetic parameters that may be directly contributing to generating a chromatin environment that facilitates the establishment of the transcriptional machinery at this promoter. PMID- 30417411 TI - The effect of VDR gene polymorphisms and vitamin D level on blood pressure, risk of preeclampsia, gestational age, and body mass index. AB - We investigated the influence of vitamin D receptor (VDR) polymorphisms and vitamin D level on the blood pressure and the risk of preeclampsia. In a case control study, 200 pregnant women, including 100 individuals with preeclampsia along with 100 healthy pregnant women, were studied for VDR FokI, TaqI, and BmsI polymorphisms and serum 25 (OH)-D level using polymerase chain reaction restriction fragment length polymorphism method and commercial kit, respectively. The mean level of 25 (OH)-D in preeclamptic patients was significantly lower (16.6 +/- 4.2 ng/mL, P < 0.001) compared with controls (19.6 +/- 3.8 ng/mL). Among all women, a significantly higher systolic blood pressure and before pregnancy body mass index and also lower gestational age were observed in the presence of 25 (OH)-D level < 20 ng/mL compared with the 20 to 30 ng/mL. A significantly higher frequency of VDR FokI C allele in preeclamptic patients (83%) than controls (74%) was associated with a 1.72-fold increased risk of preeclampsia. In all the studied individuals, the systolic and diastolic blood pressures were significantly higher in the presence of the FokI CC genotype compared with the TC and TT+TC genotypes. Neither VDR Taq1 nor VDR BmsI was associated with the risk of preeclampsia. The haplotype FokI C, TaqI C and BmsI A (CCA) compared with haplotype CTG increased the risk of preeclampsia by 1.4-fold (P = 0.33). Our study suggests an association between VDR FokI polymorphism and an insufficient serum level of 25 (OH)-D with the risk of preeclampsia and also the influence of insufficient 25 (OH)-D level and VDR FokI polymorphism on maternal factors, including blood pressure. PMID- 30417412 TI - Lycium barbarum polysaccharides promoted proliferation and differentiation in osteoblasts. AB - Osteoblasts have the capacity to differentiate into several different cell types, including adipocyte, chondrocyte, and muscle lineages. Therefore, osteoblast can be potentially applied in the treatment of bone diseases. The factors controlling osteoblast differentiation is complex. Recently, it has been reported that some natural products regulate the differentiation in osteoblasts and promote bone formation. Based on these findings, this study demonstrated that Lycium barbarum polysaccharides (LBP) could promote proliferation of osteoblast MC3T3-E1 cells through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Besides, expression of key proteins correlated with cellular proliferation such as proliferating cell nuclear antigen (PCNA) and Ki67 was enhanced in the presence of LBP. We also detected the increased expression of bone-specific matrix proteins such as morphogenetic protein 2 (BMP2), bone Gla protein (BGP), osteopontin (OPN), and alpha-1 type-I collagen (COL1A1) when treated with LBP. This process was mediated by some signals, such as smad1, smad8, Runt-related transcription factor 2 (RUNX2), and Osterix. Furthermore, RUNX2 silencing inhibited osteoblast differentiation by decreasing expression of bone-specific matrix proteins. Collectively, we proposed a previously unidentified function of LBP in osteoblast differentiation, suggesting its potential clinical role in bone disease treatment. PMID- 30417413 TI - Crosstalk of mTOR/PKM2 and STAT3/c-Myc signaling pathways regulate the energy metabolism and acidic microenvironment of gastric cancer. AB - Cancer cells consume large amounts of glucose to produce lactate, even in the presence of ample oxygen. This phenomenon is called the Warburg effect. c-Myc is an important member of the Myc gene family and is involved in the development of various tumors. It plays an important role in the regulation of tumor energy metabolism, which can regulate glycolysis to promote the Warburg effect in a tumor. Our study aimed to improve the malignant biological behavior by controlling the energy metabolism of gastric cancer through the mTOR/PKM2 and signal transduction and activator 3 (STAT3)/c-Myc signaling pathways through a series of in vitro experiments. Human gastric cancer AGS and HGC-27 cells were treated with PKM2 and c-Myc lentivirus, and the effects of the knockdown of PKM2 and/or c-Myc were analyzed on cell proliferation, cell apoptosis, the ability of cell migration, and the growth signaling pathway in vitro. The expressions of PKM2, c-Myc, LDHA, STAT3, P-STAT3, GLUT-1 gene were identified by the quantitative real-time polymerase chain reaction and Western blot analysis. Lactate and glucose levels were tested by the corresponding kit. Our findings showed that PKM2 and c-Myc were upregulated in human gastric cancer. Knockdown of c-Myc in gastric cancer cells suppressed cell proliferation capacity and glycolysis level, and the inhibitory effects on gastric cancer cells upon co knockdown of PKM2 and c-Myc were more obvious compared with knockout of PKM2 or c Myc alone. And there was a correlation between the mTOR/PKM2 and the STAT3/c-Myc signaling pathways. Our results suggested that c-Myc might be considered a potential therapeutic target for gastric cancer and PKM2 combined with c-Myc could better inhibit the malignant biological behaviors of gastric cancer. PMID- 30417414 TI - A note on tests for relevant differences with extremely large sample sizes. AB - A well-known problem in classical two-tailed hypothesis testing is that P-values go to zero when the sample size goes to infinity, irrespectively of the effect size. This pitfall can make the testing of data consisting of large sample sizes potentially unreliable. In this note, we propose to test for relevant differences to overcome this issue. We illustrate the proposed test a on real data set of about 40 million privately insured patients. PMID- 30417415 TI - The diagnostic accuracy of procalcitonin and C-reactive protein for sepsis: A systematic review and meta-analysis. AB - BACKGROUND: The objective of this study was to systematically evaluate the clinical value of procalcitonin and C-reactive protein in the diagnosis of adult patients with sepsis. METHOD: PubMed, Cochrane, Embase, Wanfang, China National Knowledge Infrastructure, and VIP database were searched by the index words to identify the qualified prospective studies, and relevant literature sources were also searched. The most recent research was done in the April 2017. The only languages included were English or Chinese. In the experiment group, patients were diagnosed with sepsis, severe sepsis, or septic shock; in the control group, the patients were of noninfectious origin or a systemic inflammatory response syndrome. The diagnostic accuracy was analyzed by heterogeneity, diagnostic odds ratio (DOR), sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and the summary receiver-operating characteristic curve. RESULTS: At least nine studies were involved in the meta-analysis with 495 patients in the sepsis group and 873 patients in the nonsepsis group. In terms of the diagnostic accuracy of C-reactive protein (CRP) for sepsis, the overall area under the summary receiver operator characteristic (SROC) curve was 0.73 (95% confidence interval [CI], 0.69-0.77), with a sensitivity and specificity of 0.80 (95% CI, 0.63-0.90) and 0.61 (95% CI, 0.50-0.72) respectively, and the DOR was 6.89 (95% CI, 3.86-12.31). In terms of the diagnostic accuracy of procalcitonin (PCT) for sepsis, the overall area under the SROC curve was 0.85 (95% CI, 0.82 0.88), with a sensitivity and specificity of 0.80 (95% CI, 0.69-0.87) and 0.77 (95% CI, 0.60-0.88) respectively, and the DOR was 12.50 (95% CI, 3.65-42.80). CONCLUSION: In this meta-analysis, our results together indicate a moderate degree of value of PCT and CRP for the diagnosis of sepsis in adult patients. The diagnosis accuracy and specificity of PCT are higher than those of CRP. PMID- 30417416 TI - Evidence supporting dual-process theory of medical diagnosis: a functional near infrared spectroscopy study. AB - PURPOSE: The objective of this study was to determine the extent to which the dual-process theory of medical diagnosis enjoys neuroscientific support. To that end, the study explored whether neurological correlates of system-2 thinking could be located in the brain. It was hypothesised that system-2 thinking could be observed as the activation of the prefrontal cortex. METHOD: An experimental paradigm was applied that consisted of a learning and a test phase. During the learning phase, 22 medical students were trained in diagnosing chest X-rays. Four of these eight cases were presented repeatedly, to develop a high level of expertise for these cases. During the test phase, all eight cases were presented and the participants' prefrontal cortex was scanned using functional near infrared spectroscopy. Response time and diagnostic accuracy were recorded as behavioural indicators. RESULTS: The results revealed that participants' diagnostic accuracy in the test phase was significantly higher for the trained cases as compared with the untrained cases (F[1, 21] = 138.80, p < 0.001, eta2 = 0.87). Also, their response time was significantly shorter for these cases (F[1, 21] = 18.12, p < 0.001, eta2 = 0.46). Finally, the results revealed that only for the untrained cases, could a significant activation of the anterolateral prefrontal cortex be observed (F[1, 21] = 21.00, p < 0.01, eta2 = 0.34). CONCLUSION: The fact that only untrained cases triggered higher levels of blood oxygenation in the prefrontal cortex is an indication that system-2 thinking is a cognitive process distinct from system 1. Implications of these findings for the validity of the dual-process theory are discussed. PMID- 30417417 TI - Usefulness of digital and optical refractometers for the diagnosis of failure of transfer of passive immunity in neonatal foals. AB - BACKGROUND: Neonatal foals with failure of transfer of passive immunity (FTPI) are at higher risk of morbidity and mortality. Successful treatment of FTPI is time-dependent, thus rapid and accurate measurement of serum IgG concentration is important for the management and care of neonatal foals. OBJECTIVES: To validate the use of digital and optical refractometers for assessing FTPI in neonatal foals and compare the diagnostic performance and level of agreement of the two refractometers to the reference standard radial immunodiffusion (RID) assay. STUDY DESIGN: A retrospective validation study. METHODS: Serum samples (n = 253) were collected from 230 foals admitted to the Veterinary Teaching Hospital and Ambulatory Equine Service between 2012 and 2017. The serum IgG concentrations were measured by the reference RID assay, digital Brix and optical refractometers. The correlation between results of two refractometers and RID assay was assessed. A receiver operating characteristic curve was created and used to identify the optimal cut-offs for evaluating sensitivity and specificity of the two refractometers to detect foals with complete and partial FTPI. RESULTS: The RID-IgG concentrations were positively correlated with the Brix scores obtained from a digital refractometer (r = 0.73, P = 0.001) and serum total protein obtained from an optical refractometer (r = 0.72, P = 0.001). The sensitivity and specificity of the digital Brix refractometer at optimal cut-off (<=7.8% Brix) were 88.1 (95% CI: 74.4-96.0) and 67.7% (95% CI: 60.6-74.3) to detect RID-IgG<4 g/L and 79.0 (95% CI: 68.5-87.3) and 77.3% (95% CI: 69.8-83.8) to detect RID-IgG<=8 g/L, respectively. The sensitivity and specificity of the optical refractometer at optimal cut-off (<=42 g/L) were 86.1 (95% CI: 72.1-94.7) and 70.9% (95% CI: 63.9-77.3) to detect RID-IgG<4 g/L and at cut-off (<=44 g/L) were 82.9 (95% CI: 73.0-90.3) and 72.7% (95% CI: 64.8-79.6) to detect RID-IgG<=8 g/L, respectively. MAIN LIMITATIONS: The number of diseased foals was small to investigate the validity of the selected cut-off values for assessing FTPI in sick foals. CONCLUSIONS: The two refractometers exhibit utility as rapid, inexpensive screening tests and have a good sensitivity for assessing FTPI in neonatal foals. PMID- 30417418 TI - CircABCB10 promotes nonsmall cell lung cancer cell proliferation and migration by regulating the miR-1252/FOXR2 axis. AB - Circular RNA (circRNA) is a key regulator in the development and progression of human cancers. Previous studies confirmed circRNA-0008717 (circABCB10) as an oncogene in osteosarcoma, but the regulatory effect of circABCB10 in nonsmall cell lung cancer (NSCLC) is still unclear. In the current study, we examined the expression of circABCB10 in different NSCLC cell lines. Bioinformatics analysis, Cell Counting Kit-8 assays, Transwell migration, fluorescein reporting experiments, and xenografts in mice were used to detect the effect of circABCB10 on NSCLC cell proliferation and migration in vitro and tumor growth in vivo. The results showed that the expression of circABCB10 in NSCLC cell lines was increased. Downregulation of circABCB10 suppressed NSCLC cell proliferation and migration by promoting microRNA miR-1252 expression and suppressing Forkhead box 2 (FOXR2). Fluorescein reporting experiments confirmed that circABCB10 expression increased FOXR2 levels by sponging miR-1252, and in vivo experiments found that knockdown of circABCB10 decreased tumor growth. These data suggested that circABCB10 acted as a tumor promoter through a novel miR-1252/FOXR2 axis, providing potential biomarkers and therapeutic targets for the management of NSCLC. PMID- 30417420 TI - The determination of the potential anticancer effects of Coriandrum sativum in PC 3 and LNCaP prostate cancer cell lines. AB - Coriander (Coriandrum sativum L.) is such an herb from the Apiaceae family, used both for its medicinal and nutritional properties for many centuries. In this study, the effects of C. sativum extract on gene expression, viability, colony formation, migration, and invasion of PC-3 and LNCaP prostate cancer cell lines have been investigated. The half maximal inhibitory concentration (IC50 ) dose in PC-3 and LNCaP cells was detected to be 2 and 5 mg/mL at the 24th hour, respectively. C. sativum extracts have been observed to cause a significant decrease in the expression of Akt and Bcl-2 in the PC-3 cells and just Akt in LNCaP cells while increasing in the expression of p53, caspase-9, caspase-10, PTEN, DR5, TRADD, PUMA, and NOXA. DR4 expression was increased in LNCaP cell line but not PC-3, and APAF and BID had increased expression in PC-3 but not the LNCaP cells. Our observations have shown that C. sativum extract decreased colony formation while inhibiting cell invasion and migration. Cell migration was hindered in PC-3 but not the LNCaP cells. In conclusion, this data present a valuable addition to the very limited data available out there on the potential use of C. sativum in prostate cancer treatment. PMID- 30417419 TI - Systematic review with meta-analysis: defecography should be a first-line diagnostic modality in patients with refractory constipation. AB - BACKGROUND: Defecography is considered the reference standard for the assessment of pelvic floor anatomy and function in patients with a refractory evacuation disorder. However, the overlap of radiologically significant findings seen in patients with chronic constipation (CC) and healthy volunteers is poorly defined. AIM: To systematically review rates of structural and functional abnormalities diagnosed by barium defecography and/or magnetic resonance imaging defecography (MRID) in patients with symptoms of CC and in healthy volunteers. METHODS: Electronic searches of major databases were performed without date restrictions. RESULTS: From a total of 1760 records identified, 175 full-text articles were assessed for eligibility. 63 studies were included providing data on outcomes of 7519 barium defecographies and 668 MRIDs in patients with CC, and 225 barium defecographies and 50 MRIDs in healthy volunteers. Pathological high-grade (Oxford III and IV) intussuscepta and large (>4 cm) rectoceles were diagnosed in 23.7% (95% CI: 16.8-31.4) and 15.9% (10.4-22.2) of patients, respectively. Enterocele and perineal descent were observed in 16.8% (12.7-21.4) and 44.4% (36.2-52.7) of patients, respectively. Barium defecography detected more intussuscepta than MRID (OR: 1.52 [1.12-2.14]; P = 0.009]). Normative data for both barium defecography and MRID structural and functional parameters were limited, particularly for MRID (only one eligible study). CONCLUSIONS: Pathological structural abnormalities, as well as functional abnormalities, are common in patients with chronic constipation. Since structural abnormalities cannot be evaluated using nonimaging test modalities (balloon expulsion and anorectal manometry), defecography should be considered the first-line diagnostic test if resources allow. PMID- 30417421 TI - Rab6A GTPase contributes to phenotypic modulation in pulmonary artery smooth muscle cells under hypoxia. AB - Previous studies have demonstrated that hypoxia can induce phenotypic modulation of pulmonary smooth muscle cells; however, the mechanisms remain unclear. The present study aimed to investigate the effect of the GTPase Rab6A-mediated phenotypic modulation and other activities of rat pulmonary artery smooth muscle cells (RPASMCs). We revealed that Rab6A was induced by hypoxia (1% O2 ) and was involved in a hypoxia-induced phenotypic switch and endoplasmic reticulum stress (ERS) in RPASMCs. After 48 hours of hypoxia, the expression of the phenotype marker protein smooth muscle actin was downregulated and vimentin (VIM) expression was upregulated. Rab6A was upregulated after 48 hours of hypoxia, and the level of glucose-regulated protein, 78 kDa (GRP78) after 12 hours of hypoxic stimulation was also increased. After transfection with a Rab6A short interfering RNA under hypoxic conditions, the expression levels of GRP78 and VIM in RPASMCs were downregulated. Overall, hypoxia-induced RPASMCs to undergo ERS followed by phenotypic transformation. Rab6A is involved in this hypoxia-induced phenotypic modulation and ERS in RPASMCs. PMID- 30417422 TI - Inactivation of ADAMTS18 by aberrant promoter hypermethylation contribute to lung cancer progression. AB - Lung cancer is the most frequently diagnosed cancer worldwide. Epigenetic regulation contributes to lung cancer pathogenesis. The ADAMTS18 tumor suppressor gene is inactivated in some cancers, but its involvement in lung cancer has not been shown. Immunohistochemistry, quantitative reverse-transcription polymerase chain reaction (qRT-PCR), and methylation-specific PCR were used to assay ADAMTS18 expression and promoter methylation in lung tumor tissues and adjacent tissues. Cell viability, transwell, and wound-healing assays, as well as flow cytometry were used to characterize the biological activity of ADAMTS18. The influence of ADAMTS18 on protein expression was assayed using western blots analysis, and its effect on chemosensitivity was assayed by the response to cisplatin. We found that ADAMTS18 was silenced in lung cancer cells by promoter methylation. Demethylation by the DNA methyltransferase inhibitor 5-aza-2' deoxycytidine, with or without the histone deacetylase inhibitor trichostatin A, restored ADAMTS18 expression. Compared with normal lung tissue, ADAMTS18 in lung tumors was frequently methylated. Overexpression of ADAMTS18 in lung cancer cells inhibited cell proliferation, migration, and invasiveness and induced G0/G1 cell cycle arrest. Furthermore, ADAMTS18 suppressed epidermal growth factor receptor/protein kinase B (EGFR/AKT) signaling, which sensitized lung cancer cells to cisplatin. Thus, our results demonstrated that the tumor suppressor gene ADAMTS18 was downregulated in lung cancer by promoter CpG methylation, and it promoted sensitivity to cisplatin via EGFR/AKT signaling. Our study suggests that ADAMTS18 promoter methylation is a potential epigenetic biomarker for early detection of lung cancer and warrants investigation as a therapeutic target for early-stage lung cancer. PMID- 30417423 TI - IGF-1 and BMP-7 synergistically stimulate articular cartilage repairing in the rabbit knees by improving chondrogenic differentiation of bone-marrow mesenchymal stem cells. AB - Knee injury is known as a frequently occurred damage related to sports, which may affect the function of cartilage. This study aims to explore whether Insulin-like growth factor 1 (IGF-1) and bone morphogenetic protein-7 (BMP-7)-modified bone marrow mesenchymal stem cells (BMSCs) affect the repair of cartilage damage found in the knee. Primarily, BMSCs were treated with a series of pEGFP-C1, IGF-1, and BMP-7, followed by determination of IGF-1 and BMP-7 expression. A rabbit cartilage defect model was also established. Afterfward, cell morphology, viability, cartilage damage repair effect, and expression of collagen I and collagen II at the 6th and the 12th week were measured. BMSCs treated with pEGFP C1/IGF-1, pEGFP-C1/BMP-7, and pEGFP-C1/BMP-7-IGF-1 exhibited elevated expression of BMP-7 and IGF-1. Besides, BMSCs in the P10 generation displayed decreased cell proliferation. Moreover, BMSCs treated with IGF-1, BMP-7, and IGF-1-BMP-7 showed reduced histological score and collagen I expression while elevated collagen II expression, as well as better repair effect, especially in those treated with IGF 1-BMP-7. Collectively, these results demonstrated a synergistic effect of IGF-1 and BMP-7 on the BMSC chondrogenic differentiation on the articular cartilage damage repair in the rabbit knees, highlighting its therapeutic potential for the treatment of articular cartilage damage. PMID- 30417424 TI - BET inhibitors reduce cell size and induce reversible cell cycle arrest in AML. AB - Inhibitors of the bromodomain and extraterminal domain family (BETi) offer a new approach to treat hematological malignancies, with leukemias containing mixed lineage leukemia rearrangements being especially sensitive due to a reliance on the regulation of transcription elongation. We explored the mechanism of action of BETi in cells expressing the t(8;21), and show that these compounds reduced the size of acute myeloid leukemia cells, triggered a rapid but reversible G0 /G1 arrest, and with time, cause cell death. Meta-analysis of PRO-seq data identified ribosomal genes, which are regulated by MYC, were downregulated within 3 hours of addition of the BETi. This reduction of MYC regulated metabolic genes coincided with the loss of mitochondrial respiration and large reductions in the glycolytic rate. In addition, gene expression analysis showed that transcription of BCL2 was rapidly affected by BETi but this did not cause dramatic increases in cell death. Cell cycle arrest, lowered metabolic activity, and reduced BCL2 levels suggested that a second compound was needed to push these cells over the apoptotic threshold. Indeed, low doses of the BCL2 inhibitor, venetoclax, in combination with the BETi was a potent combination in t(8;21) containing cells. Thus, BET inhibitors that affect MYC and BCL2 expression should be considered for combination therapy with venetoclax. PMID- 30417425 TI - Melatonin and its Metabolites as Chemical Agents Capable of Directly Repairing Oxidized DNA. AB - Oxidative stress mediates chemical damage to DNA yielding a wide variety of products. In this work, the potential capability of melatonin and several of its metabolites to repair directly (chemically) oxidative lesions in DNA was explored. It was found that all the investigated molecules are capable of repairing guanine-centered radical cations by electron transfer at very high rates, i.e., diffusion-limited. They are also capable of repairing C-centered radicals in the sugar moiety of 2'-deoxyguanosine (2dG) by hydrogen atom transfer. Although this was identified as a rather slow process, with rate constants ranging from 1.75 to 5.32 * 102 M-1 s-1 , it is expected to be fast enough to prevent propagation of the DNA damage. Melatonin metabolites 6 hydroxymelatonin (6OHM) and 4-hydroxymelatonin (4OHM) are also predicted to repair OH-adducts in the imidazole ring. In particular the rate constants corresponding to the repair of 8-OH-G adducts were found to be in the order of 104 s-1 , and is assisted by a water molecule. The results presented here strongly suggest that the role of melatonin in preventing DNA damage might be mediated by its capability, combined with that of its metabolites, to directly repair oxidized sites in DNA through different chemical routes. This article is protected by copyright. All rights reserved. PMID- 30417426 TI - Ameliorative effects of autophagy inducer, simvastatin on alcohol-induced liver disease in a rat model. AB - Alcoholic liver disease (ALD) encompasses a variety of liver injuries with various underlying mechanisms but still no effective treatment. So we aimed to monitor the influence of simvastatin on alcohol-induced liver injury and elucidate the underlying mechanisms of its cytoprotective effect. Thirty male albino rats were randomly divided into five equal groups. Group 1 (control): received a standard diet; group 2: received simvastatin (10 mg kg-1 day -1 ) once a day orally for 8 weeks; group 3: received 20% ethanol (7.9 g kg -1 day -1 ) daily orally for 8 weeks; group 4: received 20% ethanol along with same simvastatin dose daily for 8 weeks; group 5: received 20% ethanol orally for 8 weeks then received the same simvastatin dose for the next 8 weeks. Serum alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were measured. Liver tissue malondialdehyde, reduced glutathione levels, and superoxide dismutase activity were estimated. B-cell lymphoma 2 and C/EBP homologous protein levels were evaluated by enzyme linked immunosorbent assay (ELISA). Light chain 3-II and peroxisome proliferation-activated receptor gamma messenger RNA expression was assessed by real-time polymerase chain reaction. Immunohistochemical staining was performed using anti-rat tumor necrosis factor alpha antibody. Our results revealed that simvastatin treatment was able to ameliorate alcohol-induced liver damage; the improved biochemical data were confirmed by histopathological evaluation. Simvastatin being an autophagy inducer was able to prevent and reverse alcohol-induced liver changes via induction of autophagy, attenuation of oxidative stress, inflammation, and endoplasmic reticulum stress-induced apoptosis. Therefore, our findings suggest that treatment with simvastatin may be a useful approach in the management strategy of ALD. PMID- 30417427 TI - IL-36 receptor antagonistic antibodies inhibit inflammatory responses in preclinical models of psoriasiform dermatitis. AB - Psoriasis vulgaris (PV) results from activation of IL-23/Th17 immune pathway and is further amplified by cytokines/chemokines from skin cells. Among skin derived pro-inflammatory cytokines, IL-36 family members are highly upregulated in PV patients and play a critical role in general pustular psoriasis. However, there is limited data showing crosstalk between the IL-23 and IL-36 pathways in PV. Herein, potential attenuation of skin inflammation in the IL-23-induced mouse model of psoriasiform dermatitis by functional inhibition of IL-36 receptor (IL 36R) was interrogated. Anti-mouse IL-36R monoclonal antibodies (mAbs) were generated and validated in vitro by inhibiting IL-36alpha induced secretion of CXCL1 from NIH 3T3 cells. Antibody target engagement was demonstrated by inhibition of CXCL1 production in a novel acute model of IL-36alpha systemic injection in mice. In addition, anti-IL-36R mAbs inhibited tissue inflammation and inflammatory gene expression in an IL-36alpha ear injection model of psoriasiform dermatitis demonstrating engagement of the target in the ear skin. To elucidate the possible role of IL-36 signaling in IL-23/Th17 pathway, the ability of anti-IL-36R mAbs to inhibit skin inflammation in an IL-23 ear injection model was assessed. Inhibiting the IL-36 pathway resulted in significant attenuation of skin thickening and psoriasis-relevant gene expression. Taken together, this data suggests a role for IL-36 signaling in the IL-23/Th17 signaling axis in PV. This article is protected by copyright. All rights reserved. PMID- 30417428 TI - Microglial activation occurs late during preclinical Alzheimer's disease. AB - Sporadic Alzheimer's disease (AD) is marked by a lengthy preclinical phase during which patients are nonsymptomatic but show pathology in variable manifestations. Whether or not neuroinflammation occurs in such nondemented individuals is unknown. We evaluated the medial temporal lobe of 66 nondemented subjects, aged 42-93, in terms of tau pathology, Abeta deposition, and microglial activation. We show that 100% of subjects had neurofibrillary degeneration (NFD), 35% had Abeta deposits, and 8% revealed microglial activation in individuals where early amyloid formation was apparent by Congo Red staining. Amyloid-induced neuroinflammatory clusters of Iba1, CD68, and ferritin-positive microglia were evident in the immediate vicinity of aggregated Abeta. Microglia in the adjacent neuropil were nonactivated. Thus, neuroinflammation in AD represents a highly localized phagocyte reaction, essentially a foreign body response, geared toward removal of insoluble Abeta. Because clustered microglia in some amyloid plaques were dystrophic and ferritin-positive, we hypothesize that these cells were exhausted by their attempts to remove the aggregated, insoluble Abeta. Our findings show that the sequence of pathologic events in AD begins with tau pathology, followed by Abeta deposition, and then by microglial activation. Because only 8% of our subjects revealed all three hallmark pathologic features, we propose that these nondemented individuals were near the threshold of transitioning from nonsymptomatic to symptomatic disease. The onset of neuroinflammation in AD may thus represent a tipping point in AD pathogenesis. Our study suggests that the role of microglia in AD pathogenesis entails primarily the attempted removal of potentially toxic, extracellular material. PMID- 30417429 TI - Erratum. PMID- 30417430 TI - Major concerns about late hypothermia study. PMID- 30417432 TI - FtsA as a cidal target for Staphylococcus aureus: Molecular docking and dynamics studies. AB - Staphylococcus aureus infection is a healthcare problem to mankind for a considerable period of time. Once when it enters the bloodstream of an individual, it may potentially result in life-threatening conditions. The resistance of S. aureus to various drugs such as penicillin, methicillin, gentamicin, erythromycin, and tetracycline have been well documented. Presently vancomycin is the drug of choice for methicillin resistant S. aureus. Scientists believe that S. aureus would completely develop resistance to vancomycin as well. Therefore there is a commensurate need to develop a drug to replace vancomycin. In the current study, we have focussed on FtsA, an important and vital cell division protein, which is found only in S. aureus and in other prokaryotic cells. We have carried out virtual screening process for FtsA against ZINC database, the best hit molecules obtained from the preliminary docking studies were subjected to SYBYL X 2.0 docking. The molecules ZINC74432848, ZINC37769607, and ZINC96896268 displayed the highest C-score value of 4.89, 4.49, and 4.22, respectively. The top ranked molecule ZINC74432848 was observed to form 4 hydrogen bonds with FtsA. The simulation study reveals the greater stability of the FtsA-ZINC74432848 complex. If the in vitro and in vivo study turns out affirmative, then ZINC74432848 could be developed as a potent drug for FtsA. PMID- 30417431 TI - Erythropoietin reduces nerve demyelination, neuropathic pain behavior and microglial MAPKs activation through erythropoietin receptors on Schwann cells in a rat model of peripheral neuropathy. AB - Neuroprotective effects of erythropoietin (EPO) on peripheral nerve injury remain uncertain. This study investigated the efficacy of EPO in attenuating median nerve chronic constriction injury (CCI)-induced neuropathy. Animals received an intraneural injection of EPO at doses of 1,000, 3,000, or 5,000 units/kg 15 min before median nerve CCI. Afterwards, the behavioral and electrophysiological tests were conducted. Immunohistochemistry and immunoblotting were used for qualitative and quantitative analysis of microglial and mitogen-activated protein kinases (MAPKs), including p38, JNK, and ERK, activation. Enzyme-linked immunosorbent assay and microdialysis were applied to measure pro-inflammatory cytokine and glutamate responses, respectively. EPO pre-treatment dose dependently ameliorated neuropathic pain behavior, decreased microglial and MAPKs activation, and diminished the release of pro-inflammatory cytokines and glutamate in the ipsilateral cuneate nucleus after CCI. Moreover, EPO pre treatment preserved myelination of the injured median nerve on morphological investigation and suppressed injury-induced discharges. We also observed that EPO receptor (EPOR) expression was up-regulated in the injured nerve after CCI. Double immunofluorescence showed that EPOR was localized to Schwann cells. Furthermore, siRNA-mediated knockdown of EPOR expression eliminated the therapeutic effects of EPO on attenuating the microglial and MAPKs activation, pro-inflammatory cytokine responses, injury discharges, and neuropathic pain behavior in CCI rats. In conclusion, binding of EPO to its receptors on Schwann cells maintains myelin integrity and blocks ectopic discharges in the injured median nerve, that in the end contribute to attenuation of neuropathic pain via reducing glutamate release from primary afferents and inhibiting activation of microglial MAPKs and production of pro-inflammatory cytokines. PMID- 30417433 TI - Cyadox regulates the transcription of different genes by activation of the PI3K signaling pathway in porcine primary hepatocytes. AB - Cyadox, a new derivative of quinoxalines, has been ascertained as an antibiotic with significant growth promoting, low poison, quick absorption, swift elimination, brief residual period, and noncumulative effect. Seven differential expressed genes, including Insulin-like Growth Factor-1 ( IGF-1), Epidermal Growth Factor ( EGF), Poly ADP-ribose polymerase ( PARP), the Defender Against Apoptotic Death 1 ( DAD1), Complement Component 3 ( C3), Transketolase ( TK) and a New gene, were induced by cyadox in swine liver tissues by messenger RNA differential display reverse transcription polymerase chain reaction (DDRT-PCR) in our laboratory. However, the signal mechanism that cyadox altered these genes expression is not completely elucidated. The signaling pathways involved in the expressions of seven genes induced by cyadox were determined in porcine primary hepatocytes by RT-qPCR and the application of various signal pathway inhibitors. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that cyadox could stimulate proliferation of porcine primary hepatocytes in a time-dependent manner. In porcine primary cultured hepatocytes, phosphoinositide 3-kinase (PI3K) and transforming growth factor-beta (TGF-beta) signal pathways were the main signal pathways involved in the expressions of seven genes induced by cyadox. Taken together, these results demonstrate for the first time that seven cyadox-related genes expressions in porcine primary hepatocytes treated with cyadox are mediated mainly through the PI3K signaling pathway, potentially leading to enhanced cell growth and cell immunity. EGF might be the early response gene of cyadox, and a primary regulator of the other gene expressions such as IGF-1 and DAD1, playing an important role in cell proliferation promoted by cyadox. PMID- 30417434 TI - Adenosine protects pancreatic beta cells against apoptosis induced by endoplasmic reticulum stress. AB - Chronic exposure to high glucose induces endoplasmic reticulum (ER) stress in pancreatic beta cells (PBCs). The previous evidence showed that adenosine modulate PBCs viability and insulin secretion. The aim of this study was to evaluate possible involvement of adenosine in protection of MIN6 beta-cells from Tunicamycin (Tu)-induced ER stress. MIN6 cells were cotreated with Tu and different concentrations of adenosine. Cell viability, proliferation, and apoptosis were evaluated using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT), 5-bromo-2'-deoxyuridine (Brdu), and colony formation assays. Caspase-12 activity was assayed using the fluorometric method. Thioflavin T (ThT) staining was used for the evaluation of protein aggregation. Insulin secretion was evaluated using specific an ELISA kit. Ca2+ mobilization assayed using Fura2/AM probe. BIP, CHOP, XBP-1, and XBP-1s expression in both messenger RNA (mRNA) and protein levels were evaluated using the reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis, respectively. Bcl 2, p-eIF2alpha/eIF2alpha, and GADD34 levels also determined with Western blot analysis. Adenosine protected MIN6 cells against Tu-induced ER stress in a dose dependent manner and increased their proliferation. Decreased caspase-12 activity and upregulated Bcl-2 protein may explain antiapoptotic effects of adenosine. ThT staining indicated an attenuated aggregation of misfolded proteins. Adenosine effectively increased insulin secretion in Tu-treated cells. BIP, CHOP, XBP1, and sXBP1 expression were decreased significantly in cotreated cells, indicating alleviation of ER stress. However, adenosine potentiated the expression of GADD34 and decreased p-eIF2alpha/eIF2alpha ratio. Adenosine increased cytosolic Ca 2+ levels, which may promote adenosine triphosphate (ATP) synthesis in mitochondria, helping ER to preserve protein hemostasis. Taken together, adenosine upregulated Bcl-2 and GADD34 to protect PBCs against Tu-induced apoptosis and increase Insulin secretion. PMID- 30417435 TI - Dppa3 in pluripotency maintenance of ES cells and early embryogenesis. AB - Embryonic development is precisely regulated by a network of signal pathways and specific genes. Dppa3 (also known as Pgc7 or Stella) plays an important role in early embryonic development during the cleavage stage as a maternal effect gene. Dppa3 expresses in many species, and its homologous gene in human and rat genomes is located at the same chromosomal regions and have the same exon-intron structure. However, unlike mouse embryonic stem (ES) cells, in which the Dppa3 promoter maintains hypomethylation that allows a high transcription level, the DPPA3 promoter region in human ES cells is methylated, much like that of mouse epiblast stem cell. Dppa3 is essential for early embryogenesis and pluripotency maintenance; however, the precise mechanism and downstream passage remains unknown. In this review, we will summarize some important functions of Dppa3 in early embryogenesis and pluripotency maintenance of mouse ES cells. PMID- 30417436 TI - Midwifery presence in United States medical centers and labor care and birth outcomes among low-risk nulliparous women: A Consortium on Safe Labor study. AB - BACKGROUND: The presence of midwives in a health system may affect perinatal outcomes but has been inadequately described in United States settings. Our objective was to compare labor processes and outcomes for low-risk nulliparous women birthing in United States medical centers with interprofessional care (midwives and physicians) versus noninterprofessional care (physicians only). METHODS: We conducted a retrospective cohort study using Consortium on Safe Labor data from low-risk nulliparous women who birthed in interprofessional (n = 7393) or noninterprofessional centers (n = 6982). Unadjusted, adjusted (age, race, health insurance type), propensity-adjusted, and propensity-matched logistic regression models were used to compare outcomes. RESULTS: There was concordance across logistic regression models, the most restrictive and conservative of which were propensity-matched models. With this approach, women at interprofessional medical centers, compared with women at noninterprofessional centers, were 74% less likely to undergo labor induction (risk ratio [RR] 0.26; 95% CI 0.24-0.29) and 75% less likely to have oxytocin augmentation (RR 0.25; 95% CI 0.22-0.29). The cesarean birth rate was 12% lower at interprofessional centers (RR 0.88; 95% CI 0.79-0.98). Adverse neonatal outcomes occurred in only 0.3% of births and were thus too rare to be modeled. CONCLUSIONS: The care processes and birth outcomes at interprofessional and noninterprofessional medical centers differed significantly. Nulliparous women receiving care at interprofessional centers were less likely to experience induction, oxytocin augmentation, and cesarean than women at noninterprofessional centers. Labor care and birth outcome differences between interprofessional and noninterprofessional centers may be the result of the presence of midwives and interprofessional collaboration, organizational culture, or both. PMID- 30417437 TI - Site and species selection for religious release of non-native fauna. AB - In East and Southeast Asia, numerous non-native animal species are ceremonially released for spiritual merit (Severinghaus & Chi 1999; Yeo & Chia 2010; Liu et al. 2012; Su et al. 2016). Given the associated threat of biological invasions, such activities present a form of conservation conflict and need to be managed accordingly. Here, we propose a conservation management option for a value system that favours releasing animals for religious purposes. This article is protected by copyright. All rights reserved. PMID- 30417438 TI - Epitope-based immunoinformatics approach on RNA-dependent RNA polymerase (RdRp) protein complex of Nipah virus (NiV). AB - Persistent outbreaks of Nipah virus (NiV) with severe case fatality throw a major challenge on researchers to develop a drug or vaccine to combat the disease. With little knowledge of its molecular mechanisms, we utilized the proteome data of NiV to evaluate the potency of three major proteins (phosphoprotein, polymerase, and nucleocapsid protein) in the RNA-dependent RNA polymerase complex to count as a possible candidate for epitope-based vaccine design. Profound computational analysis was used on the above proteins individually to explore the T-cell immune properties like antigenicity, immunogenicity, binding to major histocompatibility complex class I and class II alleles, conservancy, toxicity, and population coverage. Based on these predictions the peptide 'ELRSELIGY' of phosphoprotein and 'YPLLWSFAM' of nulceocapsid protein were identified as the best-predicted T cell epitopes and molecular docking with human leukocyte antigen-C (HLA-C*12:03) molecule was effectuated followed by validation with molecular dynamics simulation. The B-cell epitope predictions suggest that the sequence positions 421 to 471 in phosphoprotein, 606 to 640 in polymerase and 496 to 517 in nucleocapsid protein are the best-predicted regions for B-cell immune response. However, the further experimental circumstance is required to test and validate the efficacy of the subunit peptide for potential candidacy against NiV. PMID- 30417439 TI - Electroactive Soft Photonic Devices for the Synesthetic Perception of Color and Sound. AB - Color, as perceived through the eye, transcends mere information in the visible range of electromagnetism and serves as an agent for communication and entertainment. Mechanochromic systems have thus far only aimed at satisfying the sense of vision and have overlooked the possibility of generating acoustic vibrations in concert with their visual color responses that would enable the simultaneous satisfaction of the auditory system. Transcending the boundaries of the two senses (i.e., sound and color), herein a strategy for their concurrent and synesthetic fulfillment is elucidated by electrically actuating an organogel photonic device, controlled by a single input signal. This new class of devices that integrate a color module with a speaker is fabricated from a mechanochromic layer that comprises close-packed photonic lattice with an organogel matrix pervading the void fraction. Exploiting a dielectric elastomer actuator, the system's mechanical response permits the simultaneous, yet independent, exploration of visible-light reflection alongside audible sound-wave generation. Large areal strains at low frequencies of actuation tune the photonic stop-band, whereas the layer remains incompressible and exhibits negligible strain when actuated at higher frequencies (e.g., tens of Hz), thereby making it amenable to modulate sound and color simultaneously yet independently. PMID- 30417440 TI - Clonal hematopoiesis: Genes and underlying mechanisms in cardiovascular disease development. AB - The clonal hematopoiesis when occurring without hematologic abnormalities is defined as clonal hematopoiesis of indeterminate potential (CHIP). Aging causes accumulation of somatic mutations, and hematopoietic stem cells (HSCs) can develop clonal expansion of different lineages by these mutations. CHIP has a correlation with cancer and cardiovascular disease (CVD) through acquired mutations in genes. DNMT3A, TET2, ASXL1, and JAK2 genes as well as other genes are the most common somatic mutations causing CHIP and CVD in an older age. Other factors such as cholesterol level, laboratory tests and indexes also affect CVD. In addition, mutations in adenosine triphosphate-binding cassette transporters and also chronic stress in nervous system can result in HSCs proliferation and CVD. However, laboratory tests and indexes are not sensitive for CVD diagnosis. But the therapeutic interventions can be helpful to prevent CVD cases by targeting somatic mutations, chemokine receptors, and growth factors in HSCs. Also, new drugs can control CVD by targeting of cells and their signaling pathways in HSCs. Therefore, more investigations are needed and more questions should be answered for the relationship between CHIP and CVD as a challenging issue in future. PMID- 30417441 TI - Strongly Coupled Nickel-Cobalt Nitrides/Carbon Hybrid Nanocages with Pt-Like Activity for Hydrogen Evolution Catalysis. AB - Designing non-precious-metal catalysts with comparable mass activity to state-of the-art noble-metal catalysts for the hydrogen evolution reaction (HER) in alkaline solution still remains a significant challenge. Herein a new strongly coupled nickel-cobalt nitrides/carbon complex nanocage (NiCoNzocage) is rationally designed via chemical etching of ZIF-67 nanocubes with Ni(NO3 )2 under sonication at room temperature, following nitridation. The as-prepared strongly coupled NiCoN/C nanocages exhibit a mass activity of 0.204 mA ug-1 at an overpotential of 200 mV for the HER in alkaline solution, which is comparable to that of commercial Pt/C (0.451 mA ug-1 ). The strongly coupled NiCoN/C nanocages also possess superior stability for the HER with negligible current loss under the overpotentials of 200 mV for 10 h. Density functional theory (DFT) calculations reveal that the excellent HER performance under alkaline condition arises from the robust Co2+ ->Co0 transformation achieved by strong (Ni, Co)?N bonding-induced efficient d-p-d coupled electron transfer, which is a key for optimal initial water adsorption and splitting. The high degree of amorphization urges the C-sites to be an electron-pushing bath to promote the inter-layer/sites electron-transfer with loss of the orbital-selection-forbidden-rule, which uniformly boosts the surface catalytic activities up to a high level independent of the individual surface active sites. PMID- 30417442 TI - Vitrification of equine expanded blastocysts following puncture with or without aspiration of the blastocoele fluid. AB - BACKGROUND: Historically, cryopreservation of equine embryos >300 MUm gave poor pregnancy rates until researchers collapsed the blastocoele cavity and aspirated the blastocoele fluid prior to vitrification. OBJECTIVE: To determine if aspiration of the blastocoele fluid prior to vitrification is essential for post warming survival. STUDY DESIGN: In vivo experiments. METHODS: Fifty embryos were recovered on day 7-8 and washed in holding medium (HM; M-199HEPES + 20% FBS + antibiotics). Embryos were punctured using a micromanipulator mounted 30 MUm biopsy needle; following this 28 had >90% of their blastocoelic fluid actively aspirated while the remaining 22 were not-aspirated. Embryos were then vitrified using a two-step process with increasing concentrations of DMSO and ethylene glycol (7.5-15% v:v), and 0.5 mol/L sucrose in the final solution before being loaded onto a Cryolock device and plunged into liquid nitrogen. The embryos were warmed by plunging the Cryolock tip into HM with 1 mol/L sucrose at 37 degrees C. After 1 min, the embryos were transferred to HM + 0.5 mol/L sucrose at RT for 4 min before transfer into HM for a further 4 min prior to transfer to a recipient mare. RESULTS: Mean (+/-s.e.) embryo diameter was not significantly different between the punctured and punctured plus aspirated group (646.4 +/- 61.7 vs. 754.8 +/- 59.1 MUm, respectively; P = 0.215). Nonaspirated and aspirated embryos gave pregnancy rates of 10/22 (45%) and 21/28 (75%) respectively (P = 0.061). Sub dividing embryos on the basis of size showed that vitrification of larger embryos (>550 MUm) yielded a significantly higher pregnancy rate when they were aspirated vs. not-aspirated (13/18 [72%] vs. 1/10 [10%], respectively; P = 0.006), whereas there was no difference for smaller embryos (8/10 [80%] vs. 9/12 [75%], respectively; P = 0.8). MAIN LIMITATIONS: Group sizes are limited. CONCLUSION: Aspiration of blastocoele fluid from embryos <=550 MUm is not a pre-requisite for successful vitrification. The Summary is available in Spanish - see Supporting Information. PMID- 30417443 TI - The absence of Rab27a accelerates the degradation of Melanophilin. AB - Melanophilin (Mlph) forms an interaction with Rab27a and the actin-based motor protein MyosinVa (MyoVa) on mature melanosome membranes and the tripartite complex regulates melanosome transport in melanocytes. In this study, we found that Rab27a siRNA decreased Mlph and Rab27a protein levels, but Mlph mRNA levels were not changed. Other Rab27a siRNA sequences also showed the same results. When Rab27a siRNA was treated with melan-a melanocytes, Rab27a protein was decreased within 6 h and Mlph protein was decreased within 24 h. To determine whether the absence of Rab27a promotes Mlph degradation, we inhibited protein degradation by treatment with proteasome (MG132) and lysosomal enzyme (E64D and Pepstatin A) inhibitors in melan-a melanocytes. MG132 inhibited the degradation of Mlph, but E64D and Pepstatin A had no effect on Mlph. The absence of Rab27a enhanced ubiquitination of Mlph and induced proteasomal degradation. From these results, we concluded that Mlph interaction with Rab27a is important for Mlph stability and melanosome transport. This article is protected by copyright. All rights reserved. PMID- 30417444 TI - The triptolide-induced apoptosis of osteoclast precursor by degradation of cIAP2 and treatment of rheumatoid arthritis of TNF-transgenic mice. AB - This study aims to discuss the effect of triptolide (TPL) on rheumatoid arthritis (RA) and the mechanism related to osteoclast precursor (OCP) and osteoclast (OC). TNF-transgenic RA mice were treated with different doses of TPL by gavage. After the administration was finished, the curative effects were evaluated and compared, and the OCP apoptosis rates, the OC number, and the OC differentiation ability in vitro were detected. Finally, splenocytes of wild-type mice were cultured in vitro and induced to differentiate into OCP, and the cell apoptosis rate, cIAP2, and apoptotic effectors expression level were detected after cIAP2 overexpression and TPL administration. After TPL administration, the RA symptoms in the TPL groups were all better, the apoptosis rate of OCP was higher, and the amount of OC in vitro were lower than that in the control group (all P < 0.05), and all of the changes in the high-dose group were more obvious than the low-dose group. In splenocytes cells cultured in vitro, cIAP2 overexpression could decrease the apoptosis rate of OCPs and increase the OC number, and TPL treatment could down-regulate the cIAP2 and promote OCP apoptosis and OC reduction. In conclusion, TPL could induce OCP apoptosis and inhibit OC formation to effectively treat RA by mediating cIAP2 degradation. PMID- 30417445 TI - Ionic-Liquid Doping Enables High Transconductance, Fast Response Time, and High Ion Sensitivity in Organic Electrochemical Transistors. AB - Organic electrochemical transistors (OECTs) are highly attractive for applications ranging from circuit elements and neuromorphic devices to transducers for biological sensing, and the archetypal channel material is poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate), PEDOT:PSS. The operation of OECTs involves the doping and dedoping of a conjugated polymer due to ion intercalation under the application of a gate voltage. However, the challenge is the trade-off in morphology for mixed conduction since good electronic charge transport requires a high degree of ordering among PEDOT chains, while efficient ion uptake and volumetric doping necessitates open and loose packing of the polymer chains. Ionic-liquid-doped PEDOT:PSS that overcomes this limitation is demonstrated. Ionic-liquid-doped OECTs show high transconductance, fast transient response, and high device stability over 3600 switching cycles. The OECTs are further capable of having good ion sensitivity and robust toward physical deformation. These findings pave the way for higher performance bioelectronics and flexible/wearable electronics. PMID- 30417446 TI - Candidate gene identification of existing or induced mutations with pipelines applicable to large genomes. AB - Bulked segregant analysis (BSA) is used to identify existing or induced variants that are linked to phenotypes. Although it is widely used in Arabidopsis and rice, it remains challenging for crops with large genomes, such as maize. Moreover, analysis of huge data sets can present a bottleneck linking phenotypes to their molecular basis, especially for geneticists without programming experience. Here, we identified two genes of maize defective kernel mutants with newly developed analysis pipelines that require no programing skills and should be applicable to any large genome. In the 1970s, Neuffer and Sheridan generated a chemically induced defective kernel (dek) mutant collection with the potential to uncover critical genes for seed development. To locate such mutations, the dek phenotypes were introgressed into two inbred lines to take advantage of maize haplotype variations and their sequenced genomes. We generated two pipelines that take fastq files derived from nextGen paired-end DNA and cDNA sequencing as input, call on several well established and freely available genomic analysis tools to call SNPs and INDELs, and generate lists of the most likely causal mutations together with variant index plots to locate the mutation to a specific sequence position on a chromosome. The pipelines were validated with a known strawberry mutation before cloning the dek mutants, thereby enabling phenotypic analysis of large genomes by next-generation sequencing. This article is protected by copyright. All rights reserved. PMID- 30417447 TI - Integrating self-determination theory and the theory of planned behaviour to predict intention to donate blood. AB - OBJECTIVES: The aim of this research was to test a model integrating self determination theory (SDT) and the theory of planned behaviour (TPB) to predict intention to donate blood. BACKGROUND: Social science research suggests that motivational orientations outlined by SDT can be usefully integrated with constructs from the TPB to collectively predict intention and behaviour. Such analysis has not yet been undertaken in the context of blood donation. METHODS: A total of 458 currently eligible donors completed measures of blood donor motivations, attitudes, subjective norms, perceived behavioural control (PBC) and intention. Path analyses modelled the direct and indirect effects (via TPB constructs) of motivational orientations on intention. RESULTS: SDT motivational orientations explained an additional 14% of the variance in blood donation intention, compared to a TPB-only model. Amotivation had a negative direct effect on intention; external regulation had no overall effect on intention; introjected regulation had positive direct and indirect effects on intention; and autonomous motivation predicted intention both directly as well as via attitudes, subjective norms and PBC. CONCLUSION: This research provides the first evidence that integrating SDT and the TPB is a useful approach in donor research, particularly for specifying plausible pathways through which motivational orientations impact intention to donate blood. PMID- 30417448 TI - Effect of high-density lipoprotein on oocyte maturation and bovine embryo development in vitro. AB - High-density lipoprotein (HDL) is the main lipoprotein in the follicular fluid and it has anti-inflammatory, antioxidant and cryoprotectant properties. The anti inflammatory and antioxidant potential are derived from its lipid composition, especially the apolipoprotein AI (ApoAI) and paraoxonase 1 (PON1). The aim of this study was to evaluate the effect of HDL during in vitro maturation (IVM) on oocyte maturation and early bovine embryo development. For this, cumulus oocyte complexes (COCs) were obtained from bovine ovaries collected at a local slaughterhouse. COCs (n=2250) were allocated into three groups (n=50 COCs/group) according to the addition of HDL protein (HDL-P) during IVM for 22 h: 0 mg/dL (control), 50 mg/dL and 150 mg/dL. After IVM, COCs were inseminated (IVF) and cultivated for 7 days. Total cholesterol concentration, total protein, triglycerides and ApoAI concentrations on IVM medium increased proportionally to HDL-P addition. However, PON1 activity was not detected in any treatment. The addition of HDL-P did not affect nuclear maturation rate, endogenous reactive oxygen species and glutathione levels in COCs (P > 0.05). The highest HDL-P concentration (150 mg/dL) decreased cleavage and blastocyst rate (P < 0.05). Moreover, the HDL-P 150 mg/dL group had lower cellular count/blastocyst than the 50 mg/dL group (P < 0.05). However, the addition of HDL-P did not affect relative gene expression of evaluated genes. In conclusion, the complex HDL/ApoAI obtained from human plasma, in absence of PON1 activity during in vitro oocyte maturation, decreased initial embryo development. This article is protected by copyright. All rights reserved. PMID- 30417449 TI - Selective synthesis in microdroplets of 2-phenyl-2,3-dihydrophthalazine-1,4-dione from phenyl hydrazine with phthalic anhydride or phthalic acid. AB - Pyridazine derivatives are privileged structures because of their potential biological and optical properties. Traditional synthesis methods usually require acid or base as a catalyst under reflux conditions with reaction times ranging from hours to a few days or require microwave assistance to induce the reaction. Herein, we present the accelerated synthesis of a pyridazine derivative, 2-phenyl 2,3-dihydrophthalazine-1,4-dione, PDHP, in electrosprayed microdroplets containing 1:1 v/v mixture of phenyl hydrazine and phthalic anhydride or phthalic acid. This reaction occurred on the submillisecond timescale with good yield (over 90% with the choice of solvent) without using an external catalyst at room temperature. In sharp contrast to the bulk reaction of obtaining a mixture of two products, the reaction in confined microdroplets yield only the important six membered heterocyclic product PDHP. Results indicated that surface reactions in microdroplets with low pH values cause selectivity, acceleration, and high yield. PMID- 30417450 TI - All-Optical Control of Shape. AB - Photoresponsive liquid crystal elastomers (LCEs) are a unique class of anisotropic materials capable of undergoing large-scale, macroscopic deformations when exposed to light. Here, surface-aligned, azobenzene-functionalized LCEs are prepared via a radical-mediated, thiol-acrylate chain transfer reaction. A long lived, macroscopic shape deformation is realized in an LCE composed with an o fluorinated azobenzene (oF-azo) monomer. Under UV irradiation, the oF-azo LCE exhibits a persistent shape deformation for >72 h. By contrasting the photomechanical response of the oF-azo LCE to analogs prepared from classical and m-fluorinated azobenzene derivatives, the origin of the persistent deformation is clearly attributed to the underlying influence of positional functionalization on the kinetics of cis->trans isomerization. Informed by these studies and enabled by the salient features of light-induced deformations, oF-azo LCEs are demonstrated to undergo all-optical control of shape deformation and shape restoration. PMID- 30417451 TI - How to Coat the Inside of Narrow and Long Tubes with a Super-Liquid-Repellent Layer-A Promising Candidate for Antibacterial Catheters. AB - Fouling of thin tubes is a major problem, leading to various infections and associated morbidities, while cleaning is difficult or even impossible. Here, a generic method is introduced to activate and coat the inside of meter-long and at the same time thin (down to 1 mm) tubes with a super-liquid-repellent layer of nanofilaments, exhibiting even antibacterial properties. Activation is facilitated by pumping an oxidative Fenton solution through the tubes. Subsequent pumping of a silane solution renders the surface of the tubes super-liquid repellent. The wide applicability of the method is demonstrated by coating stiff and flexible tubes made of polymers, inorganic/organic hybrids, metals, and ceramics. Coated medical catheters show excellent antibacterial properties. Notably, the nanofilaments retain their antibacterial properties even in the superhydrophilic state. These findings open new avenues toward the design of biocide-free, antibacterial tubings and catheters. PMID- 30417452 TI - Evaluation of pancreatic duct cannulation methods for human islet isolation. PMID- 30417453 TI - An Artificial Nocturnal Flower via Humidity-Gated Photoactuation in Liquid Crystal Networks. AB - Beyond their colorful appearances and versatile geometries, flowers can self shape-morph by adapting to environmental changes. Such responses are often regulated by a delicate interplay between different stimuli such as temperature, light, and humidity, giving rise to the beauty and complexity of the plant kingdom. Nature inspires scientists to realize artificial systems that mimic their natural counterparts in function, flexibility, and adaptation. Yet, many of the artificial systems demonstrated to date fail to mimic the adaptive functions, due to the lack of multi-responsivity and sophisticated control over deformation directionality. Herein, a new class of liquid-crystal-network (LCN) photoactuators whose response is controlled by delicate interplay between light and humidity is presented. Using a novel deformation mechanism in LCNs, humidity gated photoactuation, an artificial nocturnal flower is devised that is closed under daylight conditions when the humidity level is low and/or the light level is high, while it opens in the dark when the humidity level is high. The humidity gated photoactuators can be fueled with lower light intensities than conventional photothermal LCN actuators. This, combined with facile control over the speed, geometry, and directionality of movements, renders the "nocturnal actuator" promising for smart and adaptive bioinspired microrobotics. PMID- 30417454 TI - Mesoporous Silica as a Versatile Platform for Cancer Immunotherapy. AB - Immunotherapy has been recognized for decades as a promising therapeutic method for cancer treatment. To enhance host immune responses against cancer, antigen presenting cells (APCs; e.g., dendritic cells) or T cells are educated using immunomodulatory agents including tumor-associated antigens and adjuvants, and manipulated to induce a cascading adaptive immune response targeting tumor cells. Mesoporous silica materials are promising candidates to improve cancer immunotherapy based on their attractive properties that include high porosity, high biocompatibility, facile surface modification, and self-adjuvanticity. Here, the recent progress on mesoporous-silica-based immunotherapies based on two material forms is summarized: 1) mesoporous silica nanoparticles (MSNs), which can be internalized into APCs, and 2) micrometer-sized mesoporous silica rods (MSRs) that can form a 3D space to recruit APCs. Subcutaneously injected MSN based cancer vaccines can be taken up by peripheral APCs or by APCs in lymphoid organs to educate the immune system against cancer cells. MSR cancer vaccines can recruit immune cells into the MSR scaffold to induce cancer-specific immunity. Both vaccine systems successfully stimulate the adaptive immune response to eradicate cancer in vivo. Thus, mesoporous silica has potential value as a material platform for the treatment of cancer or infectious diseases. PMID- 30417455 TI - A Self-Organized Poly(vinylpyrrolidone)-Based Cathode Interlayer in Inverted Fullerene-Free Organic Solar Cells. AB - Herein, poly(vinylpyrrolidone) (PVP) is used as the cathode interlayer (CIL) through the self-organization method in inverted organic solar cells (OSCs). By coating a solution of PVP and active layer materials onto a glass/indium tin oxide (ITO) substrate, the PVP can segregate to the near ITO side due to its high surface energy and strong intermolecular interaction with the ITO electrode. The power conversion efficiency (PCE) of the obtained OSC device reaches 13.3%, much higher than that of the control device with a PCE of only 10.1%. The improvement results from the increased exciton dissociation efficiency and the depressed trap assisted recombination, which can be attributed to the reduced work function of the cathode by the self-organized PVP. Additionally, the molecular weight of the PVP has almost no influence on the device performance, and the PVP-modified device presents superior stability. This method can also be applied in other highly efficient fullerene-free OSCs, and with a fine selection of the active layer, a high PCE of 14.0% is obtained. Overall, this work demonstrates the great potential of the PVP-based CIL in inverted OSCs fabricated via the self organization method. PMID- 30417456 TI - Three vital RNA functions and interactions in the process of silk gland apoptosis in silkworm Bombyx mori. AB - The Silkworm Bombyx mori is an important insect in terms of economics and a model organism with a complete metamorphosis. The economic importance of silkworms is dependent on the functions of the silkgland, a specialized organ that synthesizes silk proteins. The silk gland undergoes massive degeneration during the larval to pupal stage, which involves in cell apoptosis. In this paper, high throughput sequencing was used to detect the expression of messenger RNA (mRNA), long noncoding RNA (lncRNA), and microRNA (miRNA) from silk glands of Day 3 in the fifth instar larvae (L5D3) and the spinning 36h (sp36h). We analyzed the Gene Ontology (GO) functions of target genes of the differentially expressed lncRNAs and miRNAs. We investigated the regulations of mRNA, lncRNA, and miRNA on silk gland apoptosis in L5D3 and sp36h. In total, 10,947 lncRNAs were detected in the silk gland and the index number TCONS-00021360 lncRNA may be involved in the process of apoptosis. In addition, 344 miRNAs targeted 285 mRNAs were related to the death process under GO entry. The results indicated that miRNAs play an important role in the molecular regulation of the silk gland apoptosis compared with that of lncRNAs. Finally, we screened 746 lncRNAs and 20 miRNAs that might interact with BmDredd, and drew an interaction network among them. PMID- 30417457 TI - Scavenging Materials to Stabilize LiPF6 -Containing Carbonate-Based Electrolytes for Li-Ion Batteries. AB - In conjunction with electrolyte additives used for tuning the interfacial structures of electrodes, functional materials that eliminate or deactivate reactive substances generated by the degradation of LiPF6 -containing electrolytes in lithium-ion batteries offer a wide range of electrolyte formulation opportunities. Herein, the recent advancements in the development of: (i) scavengers with high selectivity and affinity toward unwanted species and (ii) promoters of ion-paired LiPF6 dissociation are highlighted, showing that the utilization of the above additives can effectively mitigate the problem of electrolyte instability that commonly results in battery performance degradation and lifetime shortening. A deep mechanistic understanding of LiPF6 -containing electrolyte failure and the action of currently developed additives is demonstrated to enable the rational design of effective scavenging materials and thus allow the fabrication of highly reliable batteries. PMID- 30417458 TI - The effect of pH and biogenic ligands on the weathering of chrysotile asbestos; the pivotal role of tetrahedral Fe in dissolution kinetics and radical formation. AB - Chrysotile asbestos is a soil pollutant in many countries. It is a carcinogenic mineral, partly due to its surface chemistry. In chrysotile, FeII and FeIII substitute Mg octahedra (Fe[6]), whereas FeIII substitutes Si tetrahedra (Fe[4]). Fe on fiber surfaces can generate hydroxyl radicals (HO?) in Fenton reactions, which damage biomolecules. To better understand chrysotile weathering in soils, we determined net Mg and Si dissolution rates over the pH range 3.0 - 11.5, in the presence and absence of biogenic ligands. Also, we examined HO? generation and Fe bulk speciation of pristine and weathered fibers by EPR and Mossbauer spectroscopy. Dissolution rates were increased by ligands and inversely related to pH with complete inhibition at cement pH (11.5). Surface exposed Mg layers readily dissolved at low pH, but only within days at neutral pH. On longer timescales, the slow dissolution of Si layers became rate-determining. In absence of ligands, Fe[6] precipitated as Fenton-inactive Fe phases, whereas Fe[4] (7% of bulk-Fe) remained redox active throughout 2-week experiments and at pH 7.5 generated 50 +/- 10% of the HO? yield of Fe[6] at pristine fiber surfaces. Ligand promoted dissolution of Fe[4] (and potentially tetrahedral Al) labilized exposed Si layers. This increased Si and Mg dissolution rates and lowered HO? generation to near-background level. We conclude that Fe[4] surface species control long term HO? generation and dissolution rates of chrysotile at natural soil pH. PMID- 30417459 TI - Inhibition of PI3K/Akt/NF-kappaB signaling with leonurine for ameliorating the progression of osteoarthritis: In vitro and in vivo studies. AB - Osteoarthritis (OA) is characterized as the degeneration and destruction of articular cartilage. In recent decades, leonurine (LN), the main active component in medical and edible dual purpose plant Herba Leonuri, has been shown associated with potent anti-inflammatory effects in several diseases. In the current study, we examined the protective effects of LN in the inhibition of OA development as well as its underlying mechanism both in vitro and in vivo experiments. In vitro, interleukin-1 beta (IL-1beta) induced over-production of prostaglandin E2, nitric oxide, inducible nitric oxide synthase, cyclooxygenase-2, interleukin-6 and tumor necrosis factor alpha were all inhibited significantly by the pretreatment of LN at a dose-dependent manner (5, 10, and 20 uM). Moreover, the expression of thrombospondin motifs 5 (ADAMTS5) and metalloproteinase 13 (MMP13) was downregulated by LN. All these changes led to the IL-1beta induced degradation of extracellular matrix. Mechanistically, the LN suppressed IL-1beta induced activation of the PI3K/Akt/NF-kappaB signaling pathway cascades. Meanwhile, it was also demonstrated in our molecular docking studies that LN had strong binding abilities to PI3K. In addition, LN was observed exerting protective effects in a surgical induced model of OA. To sum up, this study indicated LN could be applied as a promising therapeutic agent in the treatment of OA. PMID- 30417460 TI - Clinicopathologic features of Anaplastic Myxopapillary Ependymomas. AB - Myxopapillary ependymomas (MPE) are considered benign (WHO grade I) neoplasms with favorable prognosis. However, malignant behavior occurs in a small subset. To our knowledge, only five anaplastic MPEs have been reported without consensus on diagnostic criteria. We retrieved fourteen anaplastic MPEs from the pathology archives of six institutions. Each tumor included at least two of the following features: > 5 mitoses per 10 high power fields, Ki-67 labeling index (LI) > 10%, microvascular proliferation (MVP), and spontaneous necrosis. These features were typically encountered in foci of hypercellularity and reduced mucin. There were 8 male and 6 female patients (age range 6-57 years, median=16.5). Ten tumors displayed anaplasia at initial resection, and four were anaplastic at a second surgery for recurrence (ranging from 9 months to 14 years following initial resection). The Ki-67 LI ranged between 8 and 40% in anaplastic foci and <3% in foci of classic MPE. There was documented CSF dissemination in seven cases, recurrence following an anaplastic diagnosis in three cases, and bone or soft tissue invasion in two cases. One patient suffered lung metastases. Two cases evaluated by targeted next-generation sequencing and one evaluated by FISH showed nonspecific chromosomal gains. We conclude that although rare, anaplastic MPE occurs in both pediatric and adult patients, similar to other ependymomas. At a minimum, closer follow-up is recommended, given the concern for aggressive biologic potential. Further study is needed to determine WHO grading criteria and genetic indicators of tumor progression. This article is protected by copyright. All rights reserved. PMID- 30417461 TI - Depilatory chemical thioglycolate affects hair cuticle and cortex, degrades epidermal cornified envelopes and induces proliferation and differentiation responses in keratinocytes. AB - Thioglycolate is a potent depilatory agent. In addition, it has been proposed to be useful as a penetration enhancer for transepidermal drug delivery. However, the effects on hair structure and stress responses it elicits in epidermal keratinocytes have not been fully characterized. We have used label-free confocal and fluorescence lifetime imaging supported by electron microscopy to demonstrate how thioglycolate damages hair cuticle cells by generating breakages along the endocuticle and leading to swelling of cortex cells. Maleimide staining of free SH-groups and a decrease in the average fluorescence lifetime of endogenous fluorophores demonstrate a specific change in protein structure in both hair cuticle and cortex. We found that the thioglycolate damages cornified envelopes isolated from the stratum corneum of the epidermis. However, thioglycolate treated epidermal equivalent cultures recover within 48 hours, which highlights the reversibility of the damage. HaCaT keratinocytes respond to thioglycolate by increased proliferation, onset of differentiation and expression of the chaperone protein Hsp 70, but not Hsp 27. Up-regulation of involucrin can be blocked by an application of c-Jun N-terminal kinase (JNK) inhibitor, but the up-regulation of Hsp 70 takes place regardless of the presence of the JNK inhibitor. This article is protected by copyright. All rights reserved. PMID- 30417462 TI - The alpha2A -adrenoceptor subtype plays a key role in the analgesic and sedative effects of xylazine. AB - Xylazine, the classical alpha2 -adrenoceptor (alpha2 -AR) agonist, is still used as an analgesic and sedative in veterinary medicine, despite its low potency and affinity for alpha2 -ARs. Previous pharmacological studies suggested that the alpha2A -AR subtype plays a role in mediating the clinical effects of xylazine; however, these studies were hampered by the poor subtype-selectivity of the antagonists used and a lack of knowledge of their bioavailability in vivo. Here, we attempted to elucidate the role of the alpha2A -AR subtype in mediating the clinical effects of xylazine by comparing the analgesic and sedative effects of this drug in wild-type mice with those in alpha2A -AR functional knockout mice using the hot-plate and open field tests, respectively. Hippocampal noradrenaline turnover in both mice was also measured to evaluate the contribution of alpha2A AR subtype to the inhibitory effect of xylazine on presynaptic noradrenaline release. In wild-type mice, xylazine (10 or 30 mg/kg) increased the hot-plate latency. Furthermore, xylazine (3 or 10 mg/kg) inhibited the open field locomotor activity and decreased hippocampal noradrenaline turnover. By contrast, all of these effects were abolished in alpha2A -AR functional knockout mice. These results indicate that the alpha2A -AR subtype is mainly responsible for the clinical effects of xylazine. PMID- 30417463 TI - Advanced Polymer Flocculants for Solid-Liquid Separation in Oil Sands Tailings. AB - The generation of tailings as a by product of the bitumen extraction process is one of the largest environmental footprints of oil sands operations. Most of the tailings treatment technologies use polymer flocculants to induce solid-liquid separation. However, due to the complex composition of tailings, conventional flocculants cannot reach the same performance achieved in other wastewater treatments. Over the last couple of decades, the oil sands industry has used acrylamide-based flocculants to treat tailings, achieving major progress in process optimization and integration with mechanical operations, but they still could not reach the required land reclamation targets. Over the last 5 years, the group designed, synthesized, and tested several novel polymer flocculants tailored for oil sands tailings treatment. This feature article communicates recent developments in these innovative polymers. The article first provides a background on tailings generation and treatment, followed by the description of advanced polymer flocculants categorized according to their microstructures such as linear, branched, and graft. The other tailings remediation technologies and one of the initial works on modeling of tailings flocculation is discussed. PMID- 30417464 TI - Trait discovery and editing in tomato. AB - Tomato (Lycopersicum esculentum), which is used for both processing and fresh markets, is a major crop species that is ranked the first vegetable produced over the world. Tomato is also a model species for research in genetics, fruit development and disease resistances. Genetic resources available in public repositories comprise the 12 wild related species and thousands of landraces, modern cultivars and mutants. In addition, high quality genome sequences are available for cultivated tomato and for several wild relatives, hundreds of accessions have been sequenced, and databases gathering sequence data together with genetic and phenotypic data are accessible to the tomato community. Major breeding goals are productivity, resistance to biotic and abiotic stresses and fruit sensorial and nutritional quality. New traits including resistance to various biotic and abiotic stresses and root architecture are increasingly being studied. Several major mutations and QTLs underlying traits of interest in tomato have been uncovered to date and, thanks to new populations and advances in sequencing technologies, the pace of trait discovery has considerably accelerated. In the recent years, CRISPR/Cas9 gene editing already proved its remarkable efficiency in tomato for engineering favorable alleles and for creating new genetic diversity by gene disruption, gene replacement and precise base editing. Here, we give insights into the major tomato traits and underlying causal genetic variations discovered so far and review the existing genetic resources and most recent strategies for trait discovery in tomato. Further, we explore the opportunities offered by CRISPR/Cas9 and their exploitation for trait editing in tomato. This article is protected by copyright. All rights reserved. PMID- 30417465 TI - Quaternization of a Polystyrene-block-poly(4-vinylpyridine) Isoporous Membrane: An Approach to Tune the Pore Size and the Charge Density. AB - Isoporous integral asymmetric membranes derived from the self-assembly of block copolymers combined with the non-solvent-induced phase separation (SNIPS) have gained great attention. To extend their utility, good control over pore size and surface functionality in a facile manner is highly desirable. Here, an approach is proposed to achieve this by quaternization of the poly(4-vinylpyridine) moiety of a polystyrene-block-poly(4-vinylpyridine) SNIPS membrane using alkyl iodides via a scalable gas-solid heterogeneous reaction. By changing the size of the alkyl groups of the quaternization agent and the degree of quaternization, the effective pore size of the membrane is tailored in a wide range from the ultrafiltration to the nanofiltration regime. A quaternization of approximately half of the 4VP repeating units of the membranes with methyl iodide, ethyl iodide, or 1-propyl iodide leads to a retention of methylene blue from a 10 mg L 1 aqueous solution of 96%, 87%, and 83%, respectively. PMID- 30417466 TI - Alternative RNA splicing of the GIT1 gene is associated with neuroendocrine prostate cancer. AB - Potent androgen receptor pathway inhibition (ARPI) therapies has given rise to a lethal, aggressive subtype of castration-resistant prostate cancer (CRPC) called treatment-induced neuroendocrine prostate cancer (t-NEPC). Now, t-NEPC poses a major clinical issue as ~20% of CRPC cases bear this subtype-a rate of occurrence that is predicted to rise with the widespread use of ARPI therapies. Unfortunately, there are no targeted therapies currently available to treat t NEPC, as the origin and molecular underpinnings of t-NEPC development remain unclear. In this study, we identify that the RNA splicing of the G protein coupled receptor kinase-interacting protein 1 (GIT1) gene is a unique event in t NEPC patients. Specifically, the up-regulation of the GIT1-A splice variant and down-regulation of the GIT1-C variant are associated with t-NEPC progression in patient tumors, as well as mouse and cell models, when compared to expression in the prostate adenocarcinoma subtype. RNA-binding assays reveal that the RNA splicing of GIT1 is directly driven by SRRM4 and is associated with its expression in CRPC cohorts. We show that GIT1-A and GIT1-C regulate differential transcriptomes in prostate cancer cells, where GIT1-A is enriched with genes associated with cell morphogenesis and neural functions. In summary, our study is the first to report that alternative RNA splicing of the GIT1 gene is associated with t-NEPC and may regulate transcriptomes implicated in t-NEPC progression. This article is protected by copyright. All rights reserved. PMID- 30417467 TI - Sn-Polyester/Polyimide Hybrid Flexible Free-Standing Film as a Tunable Dielectric Material. AB - Flexible films having high dielectric constants with low dielectric loss have promising application in the emerging area of high-energy-density materials. Here, for the first time, an organometallic, Sn-polyester-containing hybrid free standing film in polyimide matrix is reported. Polyimide, pBTDA-HDA, is used with poly(dimethyltin glutarate) and poly(dimethyltin-3,3-dimethyglutarate) (pDMTDMG) for having a processable film with tunable dielectric properties. Hybrid film with 60% pDMTDMG and 40% PI (HB2) is found to have improved dielectric features over previously synthesized organic polyimide and organometallic Sn-polyester homopolymers. These novel organometallic-organic hybrid systems expanded a new area of dielectrics for next-generation electronics with superior overall electrical performance. PMID- 30417468 TI - Between an ugly truth and a perfect lie: Wiping off fearful memories using beta adrenergic receptors antagonists. AB - Psychiatric disorders such as anxiety, phobias, and post-traumatic stress disorder are considered of high global prevalence. Currently, a therapeutic approach to treat these disorders using beta-blockers, which antagonize the beta adrenergic receptors (B1, B2, and B3) is being studied. This approach claims that beta-blockers, such as propranolol, inhibit fear memory reconsolidation. However, there are several studies refuting such claims by discrediting their experimental design and pointing out both the drugs pharmacokinetic properties and confounding factors. In this review, we explore the different effects of central beta adrenergic agonists and antagonists on the fear memory consolidation providing mixed-evidence, limitations, and future directions. PMID- 30417469 TI - Efficacy and safety of antiviral treatment on blocking the mother-to-child transmission of hepatitis B virus: a meta-analysis. AB - Nucleo(t)side analogues (NAs) have been administered as adjunctive therapy to interrupt the mother-to-child transmission (MTCT) of hepatitis B virus (HBV). The efficacy and safety of this method remain controversial. A Meta-analysis was conducted to evaluate the efficacy and safety of NAs treatment during pregnancy. The differences among different agents and initiation trimesters were analysed. A total of 9228 mother-infant-pairs in 59 studies (32 RCTs and 27 non-RCTs) were included in this meta-analysis. NAs significantly reduced the risk of MTCT, as indicated by seropositivity of hepatitis B surface antigen (HBsAg) (risk ratio (RR)=0.51, 95% confidence interval (CI) 0.45 to 0.57) and HBV DNA in newborns (RR=0.22, 95% CI 0.18 to 0.26). No differences in the efficacy of interrupting HBV MTCT were evident among lamivudine, telbivudine, and tenofovir disoproxil fumarate. NA was more effective when administered from the second than from the third trimester as indicated by HBV DNA (RR: the second vs. the third 0.08 vs. 0.22, P=0.010), but this effect was not evident as indicated by HBsAg (RR: the second vs. the third 0.46 vs. 0.53, P=0.596). Antiviral treatment initiated from the second trimester did not confer a higher risk of safety problems in the newborns compared with treatment from the third trimester, as indicated by weight (P=0.064), length (P=0.491), and malformation rate (P=0.635) of newborns. CONCLUSIONS: Lamivudine, telbivudine, and tenofovir disoproxil fumarate are equally effective in blocking HBV MTCT. Antiviral treatment can be applied from the second trimester, without obvious safety concerns. This article is protected by copyright. All rights reserved. PMID- 30417470 TI - Identification of TRA-1-60-positive cells as a potent refractory population in follicular lymphomas. AB - Despite receiving rituximab-combined chemotherapy, follicular lymphoma (FL) patients often suffer tumor recurrence, and understand the cause of relapse in FL would thus significantly ameliorate the tumor therapeutics. Here we demonstrate that the TRA-1-60-expressing cells are a unique population in FLs, converge to the conventional stem cell marker Oct3/4 and ALDH1-positive population, and resist current B-lymphoma agents. TRA-1-60 expression was observed only in scattered lymphoma cells in FL tissues as well as resting B-lymphocytes inside germinal centers. Retrospective comparison between the recurrent and cognate primary tissues revealed that the number of TRA-1-60-positive cells from R-CHOP treated FL had increased relative to primary tissue, a finding corroborated by assays on different rituximab-treated FL cell lines, FL-18 and DOHH2, wherein TRA positive cell numbers increased over ten-fold compared to the untreated sample. Concordantly, scanty TRA-1-60-positive FL-18 cells implanted subcutaneously into mice evinced potent tumor-initiating capacity in vivo, where tumors were twelve fold larger in volume (p=0.0021<0.005) and thirteen-fold heavier in weight (p=0.0015<0.005) compared to those xenografted from the TRA-negative cells. To explain these, gene expression profiling and the qPCR analysis indicated that the TRA-1-60-positive cells defined distinct population from that of the TRA-negative cells, with upregulation of multiple drug transporters and therapeutic resistance genes. Hence, TRA-1-60-expressing cells in FL are considered to be vigorously intractable against the conventional therapeutic agents, which may explain its refractory recurrence. This article is protected by copyright. All rights reserved. PMID- 30417471 TI - DEPDC1 predicts prognosis of hepatocellular carcinoma patients and regulates tumor proliferation and metastasis. AB - DEP domain containing 1 (DEPDC1) protein is a novel oncoantigen up-regulated in multi-type of cancers which presents oncogenic activity and high immunogenicity. However, the functional discovery and therapeutic potential of DEPDC1 in hepatocellular carcinoma (HCC) remain unclear. In this study, we demonstrated that DEPDC1 was frequently up-regulated in HCC and associated with cancer diagnosis and poor prognosis for HCC patients. Moreover, DEPDC1 promotes HCC cell proliferation in vitro as well as carcinogenesis in vivo. Notably, DEPDC1 overexpression also increases the neoplasm metastasis ability of HCC cells both in vivo and vitro. Gene Set Enrichment Analysis (GSEA) results showed that the DEPDC1 expression is positive correlated with K-RAS signal pathway, pathways in cancer and WNT/beta catenin signal pathway, all of which are closely associated with specific cancer-related gene sets. Our study provides the basis for further investigation of the molecular mechanism by which DEPDC1 promotes the development and metastasis of HCC. This article is protected by copyright. All rights reserved. PMID- 30417472 TI - Psychometric properties of the "Autonomous and Controlled Motivation for Treatment Questionnaire" in women with eating disorders. AB - OBJECTIVE: To validate the Autonomous and Controlled Motivation for Treatment Questionnaire (ACMTQ) for use in women with an eating disorder (ED). METHOD: Data were available for 463 individuals. We assessed factor structure, internal reliability, test-retest reliability, convergent/divergent validity, and incremental predictive validity. RESULTS: Our data showed acceptable fit to our hypothesized model (comparative fit index = 0.92, root mean square error of approximation = 0.09, standardized root mean square residual = 0.09). We found test-retest reliability of 0.73 for both the autonomous (alpha = 0.85) and controlled (alpha = 0.80) subscales. Autonomous scores were more strongly associated with motivation measures (beta = 0.37; 0.46) than with ED severity measures (beta = -0.10; -0.18). Associations between autonomous motivation and symptom improvement over time supported predictive validity. Controlled motivation was associated with lower motivation (beta = 0.02; -0.31) and with higher ED severity (beta = 0.12; 0.47). CONCLUSION: Our results suggest that the ACMTQ is valid for use in women with EDs and lend support to the validity of findings from previous ED studies that have used the ACMTQ. PMID- 30417473 TI - Effectiveness of a dissemination strategy on the uptake of an online menu planning program: A controlled trial. AB - ISSUE ADDRESSED: Online systems offer opportunities to provide effective, ongoing support to childcare services to implement dietary guidelines. The study aimed to assess the effectiveness of a dissemination strategy on childcare service: (i) adoption; and (ii) use of an online menu planning program designed to increase compliance with dietary guidelines. METHODS: A nonrandomised controlled trial was conducted with long day care services across Australia. All services received an email invitation to access an online evidence-based menu planning program. Services in the intervention also received training, telephone contact and provision of a portable computer tablet to encourage program adoption and use. Outcomes were assessed at the 6-month follow-up using analytics data recorded by the online program. Outcomes included the proportion of services having accessed the program (adoption) and the proportion of services with a current menu entered in the program (use as intended). RESULTS: Twenty-seven interventions and 19 control services took part. At the 6-month follow-up, 100% vs 58% of services had adopted the online menu planning program (OR: 14.67, 95% CI: 2.43-infinity; P < 0.01) and 41% vs 5% of services had a current menu entered in the program (OR: 9.99, 95% CI: 1.01-534.57; P < 0.01) in the intervention and control arms respectively. CONCLUSIONS: This study highlights the need for strategies to support adoption and use of an online menu planning program in childcare services if the potential benefits of such a program are to be achieved. Future research should explore the effectiveness of differing strategies to increase adoption and use of online programs at scale. SO WHAT?: Strategies to support childcare service uptake and use of online programs are required in order for the potential public health benefits of such technologies to be realised. PMID- 30417474 TI - Sequentially Controlled Deformations of Patterned Hydrogels into 3D Configurations with Multilevel Structures. AB - Sequential deformations of patterned hydrogels into 3D configurations with multilevel structures are reported, which are realized for the first time in self shaping materials. The periodically patterned single-layer hydrogels with different polymers are fabricated by multi-step photolithography. After swelling in water, the expansion of compartmentalized high-swelling gels is constrained by the dispersed non-swelling gels, resulting in out-of-plane buckling with high cooperativity and thus forming alternating concave-convex configuration. When the dispersed non-swelling gels are partly replaced by thermoresponsive ones, the preformed overall flat, yet locally undulant, hydrogel deforms further into dome , saddle-, or sandglass-like configurations at elevated temperature. As such, multilevel 3D structures can be achieved via prebuilt mechanical/geometric cues in a sequentially controlled manner. This conceptual design and sequential deformation of patterned hydrogels to form 3D configurations with multilevel structures should enrich the deformation/functioning modes of morphing materials and broaden their applications in diverse areas. PMID- 30417475 TI - Developmental stress and telomere dynamics in a genetically polymorphic species. AB - A central objective of evolutionary biology is understanding variation in life history trajectories and the rate of aging, or senescence. Senescence can be affected by trade-offs and behavioural strategies in adults but may also be affected by developmental stress. Developmental stress can accelerate telomere degradation, with long-term longevity and fitness consequences. Little is known regarding whether variation in developmental stress and telomere dynamics contributes to patterns of senescence during adulthood. We investigated this question in the dimorphic white-throated sparrow (Zonotrichia albicollis), a species in which adults of the two morphs exhibit established differences in behavioural strategy and patterns of senescence, and also evaluated the relationship between oxidative stress and telomere length. Tan morph females, which exhibit high levels of unassisted parental care, display faster reproductive senescence than white females, and faster actuarial senescence than all of the other morph-sex classes. We hypothesized that high oxidative stress and telomere attrition in tan female nestlings could contribute to this pattern, since tan females are small and potentially at a competitive disadvantage even as nestlings. Nestlings that were smaller than nest mates had higher oxidative stress, and nestlings with high oxidative stress and fast growth rates displayed shorter telomeres. However, we found no consistent morph-sex differences in oxidative stress or telomere length. Results suggest that oxidative stress and fast growth contribute to developmental telomere attrition, with potential ramifications for adults, but that developmental oxidative stress and telomere dynamics do not account for morph-sex differences in senescence during adulthood. PMID- 30417476 TI - Enablers of psychological well-being for refugees and asylum seekers living in transitional countries: A systematic review. AB - The purpose of this systematic review was to locate and synthesise existing peer reviewed quantitative and qualitative evidence regarding enablers of psychological well-being among refugees and asylum seekers living in transitional countries and for whom migration status is not final. Systematic searches were conducted in nine databases: Academic Search Premier, CINAHL, Embase, Emcare, Medline, Psychology and Behavioral Science, PsycINFO, Scopus, and Web of Science. Search terms were related to refugees and asylum seekers, enablers, and psychological well-being. Studies were limited to those conducted in the last 20 years, with participants who were refugees and asylum seekers with no legal residency status, aged 16 years and above, and living in transit host countries without UNHCR resettlement programmes. This systematic review was conducted between March and June 2018 and followed the PRISMA guidelines. Results were screened by two reviewers at two stages: title and abstracts, and full-text. Critical appraisal and data extraction were also completed by two reviewers. Initial database searching yielded 3,133 results. Following the addition of two records from relevant reference lists and the removal of duplicates, a total of 1,624 results were included for screening. A total of 16 articles were deemed eligible for inclusion in this review, reporting on a collective sample of 1,352 participants. Twelve qualitative and four quantitative studies identified eight enablers of psychological well-being: social support; faith, religion and spirituality; cognitive strategies; education and training opportunities; employment and economic activities; behavioural strategies; political advocacy; and environmental conditions. Despite many challenges associated with forced displacement and the transit period, this review highlights multiple factors that promote well-being and suggest areas for intervention development and resource allocation. PMID- 30417477 TI - Recent Developments in the Area of Click-Crosslinked Nanocarriers for Drug Delivery. AB - Click-crosslinking has been widely used for the fabrication of nanocarriers in recent years. Crosslinking can enhance the stability of nanocarriers that have served as an emerging platform for drug delivery to achieve cancer diagnosis and therapy. In crosslinking methods, click reactions have attracted increasing attention owing to their high reaction specificity and physiologically stable products. These reports on click-crosslinked nanocarriers are divided into four sections (nanogels, nanoparticles, micelles, and capsules) according to the types of nanocarriers. Click-crosslinked nanocarriers enhance the solubility of hydrophobic drugs and improve the efficacy of drug delivery owing to their good stability. Stimuli-responsive and targeted strategies can be introduced into click-crosslinked nanocarriers to enhance drug accumulation in tumors. PMID- 30417478 TI - Mechanoresponsive, Luminescent Polymer Blends Based on an Excimer-Forming Telechelic Macromolecule. AB - A well-known approach toward mechanochromic polymers relies on the incorporation of excimer-forming fluorophores into a matrix polymer and the disruption of aggregated chromophores when such materials undergo macroscopic mechanical deformation. However, the required aggregates and stress-transfer processes have so far only been realized with select dye/polymer combinations. As demonstrated here, the utility of this approach can be extended by tethering an excimer forming cyano-substituted oligo(p-phenylene vinylene) fluorophore to the two ends of a telechelic poly(ethylene-co-butylene) and blending small amounts (0.1-2 wt%) of the resulting aggregachromic macromolecule into polymer matrices such as poly(epsilon-caprolactone), poly(isoprene), or poly(styrene-b-butadiene-b styrene). All blends display mechanofluorochromic responses, and the ratio between the monomer and excimer emission intensities can be used to correlate the luminescence signal to the extent of deformation and to follow subsequent relaxation processes. The developed approach significantly expands the scope of blend-based mechanoresponsive luminescent materials. PMID- 30417479 TI - Ultrasensitive 2D Bi2 O2 Se Phototransistors on Silicon Substrates. AB - 2D materials are considered as intriguing building blocks for next-generation optoelectronic devices. However, their photoresponse performance still needs to be improved for practical applications. Here, ultrasensitive 2D phototransistors are reported employing chemical vapor deposition (CVD)-grown 2D Bi2 O2 Se transferred onto silicon substrates with a noncorrosive transfer method. The as transferred Bi2 O2 Se preserves high quality in contrast to the serious quality degradation in hydrofluoric-acid-assisted transfer. The phototransistors show a responsivity of 3.5 * 104 A W-1 , a photoconductive gain of more than 104 , and a time response in the order of sub-millisecond. With back gating of the silicon substrate, the dark current can be reduced to several pA. This yields an ultrahigh sensitivity with a specific detectivity of 9.0 * 1013 Jones, which is one of the highest values among 2D material photodetectors and two orders of magnitude higher than that of other CVD-grown 2D materials. The high performance of the phototransistor shown here together with the developed unique transfer technique are promising for the development of novel 2D-material-based optoelectronic applications as well as integrating with state-of-the-art silicon photonic and electronic technologies. PMID- 30417480 TI - Self-Organization and Charge Transport Properties of Selenium and Tellurium Analogues of Polythiophene. AB - A series of conjugated polymers comprising polythiophene, polyselenophene, and polytellurophene with branched 3,7-dimethyloctyl side chains, well-matched molecular weight, dispersity, and regioregularity is synthesized. The ionization potential is found to vary from 5.14 to 5.32 eV, with polytellurophene having the lowest potential. Field-effect transistors based on these materials exhibit distinct hole transport mobility that varies by nearly three orders of magnitude, with polytellurophene having the highest mobility (2.5 * 10-2 cm2 V-1 s-1 ). The large difference in mobility demonstrates the significant impact of heteroatom substitution. Although the series of polymers are very similar in structure, their solid-state properties are different. While the thin film microstructure of polythiophene and polyselenophene is identical, polytellurophene reveals globular features in the film topography. Polytellurophenes also appear to be the least crystalline, even though their charge transport properties are superior to other samples. The torsional barrier and degree of planarity between repeat units increase as one moves down group-16 elements. These studies show how a single atom in a polymer chain can have a substantial influence on the bulk properties of a material, and that heavy group-16 atoms have a positive influence on charge transport properties when all other variables are kept unchanged. PMID- 30417481 TI - TMEM206 promotes the malignancy of colorectal cancer cells by interacting with AKT and extracellular signal-regulated kinase signaling pathways. AB - BACKGROUND: The roles of TMEM206, a new transmembrane protein, in cancer, including colorectal cancer (CRC), are unknown. Related family members, including TMEM16A, TMEM132A, and TMEM176B, have been shown to be involved in various biological behaviors. In addition, TMEM88 has been reported to promote non-small cell lung cancer. In this study, we examined the roles of TMEM206 in CRC. METHOD: Real-time reverse transcription polymerase chain reaction was used to measure TMEM206 messenger RNA (mRNA) levels in clinical specimens and transfected cell lines. Immunohistochemistry was used to determine the relationship between TMEM206 expression levels and clinical data. Plasmids and small interfering RNA were used to upregulate and silence TMEM206, respectively. Protein expression levels and signaling pathway modulation were validated through western blot analysis. Colony formation, MTT, cell migration and invasion assays, and flow cytometry analyses were used to test the potential roles of TMEM206 in CRC. Co immunoprecipitation was used to evaluate the interaction between TMEM206 and AKT. RESULTS: Investigation of the clinical significance of TMEM206 expression in CRC tissues revealed that TMEM206 mRNA and protein levels were higher in CRC tissues than in paired normal adjacent tissues (p < 0.05). TMEM206 overexpression was positively associated with T stage of cancer and UICC stage ( p < 0.05) and negatively related to differentiation of CRC ( p = 0.015). Upregulation or silencing of TMEM206 promoted or inhibited the proliferation of CRC cells and positively or negatively regulated the levels of phospho-AKT and downstream signaling pathway components (phospho-glycogen synthase kinase 3beta and cyclin D1), respectively. Moreover, silencing of TMEM206 in cell lines arrested CRC cells in the G1 stage of the cell-cycle. In addition, upregulating or silencing TMEM206 increased or decreased cell invasion and migration in vitro and positively or negatively altered levels of the phospho-extracellular signal regulated kinase (ERK) and phospho-focal adhesion kinase 397, respectively. Co immunoprecipitation demonstrated that AKT and TMEM206 proteins interacted. Furthermore, TMEM206 promoted the development and progression of CRC by enhancing the interactions between the AKT and ERK signaling pathways. CONCLUSION: TMEM206 controlled the progression of CRC by accelerating CRC cell proliferation and promoting CRC cell migration and invasion. The target of TMEM206 may be AKT, which is known to be involved in modulating the biological behaviors of various cancers. PMID- 30417482 TI - Immunomodulatory in vitro effects of oclacitinib on canine T-cell proliferation and cytokine production. AB - BACKGROUND: Oclacitinib is a Janus kinase inhibitor used to control pruritus and skin lesions in canine allergic skin disease; its effect on canine T cells is not well-characterized. HYPOTHESIS/OBJECTIVES: To evaluate the impact of oclacitinib on cultured T cells using peripheral blood mononuclear cells from dogs. ANIMALS: Six bluetick coonhounds. METHODS AND MATERIALS: Lymphocyte-enriched cells were incubated with or without the T-cell mitogen concanavalin A (Con A), oclacitinib (0.5, 1 or 10 MUM), ciclosporin (200 ng/mL), Con A + oclacitinib 1 MUM and Con A + ciclosporin. We assessed both T-cell proliferation and the secretion of cytokines. RESULTS: Ciclosporin and oclacitinib both inhibited the spontaneous proliferation of T cells; this effect was significant only after incubation with oclacitinib at 10 MUM. At this concentration, oclacitinib significantly reduced the spontaneous secretion of clonal activator cytokines [interleukin (IL)-2, IL 15], pro-inflammatory cytokines (interferon-gamma (IFN-gamma), IL-18) and the regulatory cytokine IL-10; tumour necrosis factor alpha (TNF-alpha) and IL-6 cytokine production was mildly inhibited. After Con A stimulation, only T cells co-treated with ciclosporin achieved a significant proliferation inhibition and reduction of IL-2, IL-10, IL-15, IL-18, IFN-gamma and TNF-alpha. Surprisingly, oclacitinib at 1 MUM (337 ng/mL, corresponding to the oral dosage of 0.4-0.6 mg/kg) did not significantly affect Con A-stimulated T-cell proliferation nor cytokine production (IL-2, IL-10, IL-15, IL-18, IFN-gamma and TNF-alpha). CONCLUSIONS: Although a limited number of dogs were investigated, these preliminary results suggest that oclacitinib appears to have immunosuppressive properties, but only at dosages above those used to treat allergic pruritus in dogs. PMID- 30417483 TI - Gardner syndrome with maxillofacial manifestation: A case report. AB - Gardner syndrome is a hereditary disease in which patients develop gastrointestinal polyps, osteomas, desmoid tumors, epidermoid cysts, fibromas, lipomas, and retinal lesions. Dental abnormalities such as supernumerary or impacted teeth, odontomas and dentigerous cysts are also reported. The most serious concern in this syndrome is the extremely high risk of gastrointestinal polyps undergoing malignant transformation. Since the maxillofacial findings usually precede gastrointestinal polyps, the dentist plays a crucial role in the diagnosis of Gardner syndrome, and panoramic radiography is an important tool in the diagnosis of the disease. We report here a case of Gardner syndrome in a patient showing mandibular osteomas and impacted teeth. Also, cases of Gardner syndrome with maxillofacial manifestations reported in the literature were reviewed and compared with ours. According to the findings, osteomas are important manifestations of this syndrome, and regardless of the absence of family history of intestinal polyposis, their occurrence should prompt diagnostic evaluation for this disease. PMID- 30417484 TI - Choosing an accurate outcome metric for pediatric obesity care. AB - Thank you to Hagman et al for analyzing data from a past study to present the recent paper "Predictors of responses to clinic based childhood obesity care". This article is protected by copyright. All rights reserved. PMID- 30417485 TI - Single fraction carbon ion radiotherapy for colorectal cancer liver metastasis:A dose escalation study. AB - Prognosis is usually grim for those who cannot receive resection with liver metastasis from colorectal cancer (CRC). Radiation therapy can be an option for those unsuitable for resection, and carbon-ion radiotherapy (CIRT) would be expected higher effective and less toxic than X-ray due to its physio-biological characteristics. The objective of this study is to identify the optimal dose of single fraction CIRT for colorectal cancer liver metastasis. Thirty-one patients with liver metastasis from CRC were enrolled. Twenty-nine patients received a single-fraction CIRT, escalating dose from 36 Gy (RBE) in 5 to 10% increments until unacceptable incidence of dose-limiting toxicity is observed. Dose-limiting toxicity was defined as grade >= 3 acute toxicity attributed to radiotherapy. The prescribed doses were: 36 Gy (RBE) (3 cases), 40 (2), 44 (4), 46 (6), 48 (3), 53 (8), and 58 (3). Dose-limiting toxicity was not observed but late grade 3 liver toxicity due to biliary obstruction was observed in 2 patients at 53 Gy (RBE). Both cases had lesions close to the hepatic portal region, and therefore dose was escalated to 58 Gy (RBE) limited to peripheral lesions. Three-year actuarial overall survival rate of all 29 patients was 78%, and median survival time was 65 months. Local control improved significantly at >=53 Gy (RBE), with 3-year actuarial local control rate of 82%, compared to 28% in lower doses. Treatment for CRC liver metastasis with single-fraction CIRT appeared to be safe up to 58Gy (RBE) as long as the central hepatic portal region is avoided. This article is protected by copyright. All rights reserved. PMID- 30417486 TI - Integrative proteomics and immunochemistry analysis of the factors in the necrosis and repair in acetaminophen-induced acute liver injury in mice. AB - Acetaminophen (APAP) overdose-induced acute liver injury (AILI) is a significant clinical problem worldwide, the hepatotoxicity mechanisms are well elucidated, but the factors involved in the necrosis and repair still remain to be investigated. APAP was injected intraperitoneally in male Institute of Cancer Research (ICR) mice. Quantitative proteome analysis of liver tissues was performed by 2-nitrobenzenesulfenyl tagging, two-dimensional-nano high performance liquid chromatography separation, and matrix-assisted laser desorption/ionization-time of flight mass spectrometry analysis. Diffrenetial proteins were verified by the immunochemistry method. 36 and 44 differentially expressed proteins were identified, respectively, at 24 hr after APAP (200 or 300 mg.kg -1 ) administration. The decrease in the mitochondrial protective proteins Prdx6, Prdx3, and Aldh2 accounted for the accumulation of excessive reactive oxygen species (ROS) and aldehydes, impairing mitochondria structure and function. The Gzmf combined with Bax and Apaf-1 jointly contributed to the necrosis. The blockage of Stat3 activation led to the overexpression of unphosphorylated Stat3 and the overproduction of Bax. The overexpression of unphosphorylated Stat3 represented necrosis; the alternation from Stat3 to p Stat3 in necrotic regions represented hepatocytes from death to renewal. The high expressions of P4halpha1, Ncam, alpha-SMA, and Cygb were involved in the liver repair, they were not only the markers of activated HSC but also represented an intermediate stage of hepatocytes from damage or necrosis to renewal. Our data provided a comprehensive report on the profile and dynamic changes of the liver proteins in AILI; the involvement of Gzmf and the role of Stat3 in necrosis were revealed; and the role of hepatocyte in liver self-repair was well clarified. PMID- 30417487 TI - Hemophagocytic lymphohistiocytosis is a sign of poor outcome in pediatric Epstein Barr virus-associated post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation. AB - EBV-related PTLD developing after HSCT is a potentially life-threatening disease. HLH is uncommon after allogeneic HSCT. Data on outcome of patients with PTLD and concomitant HLH after allogeneic HSCT are limited. In this retrospective study, we collected demographic, clinical, laboratory, and outcome data for 408 patients who underwent allogeneic HSCT from 2006 to 2015. Graft source included CB (n = 135; 33.1%), PBSCs (n = 34; 8.3%), and BM (n = 239; 58.6%). Eight out of 408 patients (2%) developed EBV-PTLD with a median age at HSCT of 5.9 years (range: 2.3-17.3). All eight patients received ATG as part of the conditioning regimen. Graft source was PBSC in three patients (37.5%), BM in four patients (50%), and CB in one patient (12.5%). Donors were matched unrelated in five patients (62.5%) and matched sibling in three patients (37.5%). Seven out of eight patients developed EBV-PTLD within the first 100-day post-HSCT. Lymph node biopsy revealed early lesions in three patients, polymorphic in three patients, and monomorphic PTLD in two patients. Three patients (37.5%) died within 1 month of EBV-PTLD diagnosis. All deceased patients developed HLH manifestations with two of them meeting HLH diagnostic criteria and one having an incomplete workup. PTLD after allogeneic HSCT with manifestations of HLH is associated with high mortality. Early identification and treatment of EBV-PTLD seems imperative to control the disease, especially if signs of HLH are evolving. PMID- 30417488 TI - Mitochondrial dysfunction in diabetes and the regulatory roles of antidiabetic agents on the mitochondrial function. AB - The prevalence of type 2 diabetes mellitus (T2DM) is increasing rapidly with its associated morbidity and mortality. Many pathophysiological pathways such as oxidative stress, inflammatory responses, adipokines, obesity-induced insulin resistance, improper insulin signaling, and beta cell apoptosis are associated with the development of T2DM. There is increasing evidence of the role of mitochondrial dysfunction in the onset of T2DM, particularly in relation to the development of diabetic complications. Here, the role of mitochondrial dysfunction in T2DM is reviewed together with its modulation by antidiabetic therapeutic agents, an effect that may be independent of their hypoglycemic effect. PMID- 30417489 TI - Functionalized Boron Nitride Nanosheets: A Thermally Rearranged Polymer Nanocomposite Membrane for Hydrogen Separation. AB - Amino functionalized boron nitride nanosheets (FBN) were incorporated into a crosslinked, thermally rearranged polyimide (XTR) to fabricate FBN-XTR nanocomposite membrane. The FBN-XTR membrane exhibited a small decrease in H2 permeability but demonstrated a remarkably increased H2 gas selectivity over other gases, compared with XTR. The XTR membrane heat-treated at 425 degrees C had a H2 permeability of 210 Barrers and a H2 /CH4 separation factor of 24.1, whereas the nanocomposite membrane with 1 wt % FBN exhibited a H2 permeability of 110 Barrers and H2 /CH4 separation factor of 275, an order of magnitude greater. At 1 wt % FBN loading, the FBN-XTR membrane showed three times higher tensile strength and 60 % higher elongation than pristine XTR membrane. In addition, FBN XTR was found to be able to be readily processed into thin-film membranes for practical H2 separation applications. PMID- 30417490 TI - Corrigendum. PMID- 30417491 TI - Identification and tracking of addictovigilance signals in general practice: which interactions between the general practitioners and the French addictovigilance network? PMID- 30417492 TI - Ephenidine, diphenidine and methoxphenidine complications reported to the French Addictovigilance Network: another brick in the wall! PMID- 30417493 TI - The prevalence and outcome of children with failure to thrive after pediatric kidney transplantation. AB - BACKGROUND: Prior to transplantation, effects of advanced CKD contribute to malnutrition and impaired growth. After transplant, children are expected to thrive, however, in a subset of transplant recipients this does not occur. Factors associated with post-transplant FTT are poorly understood. OBJECTIVE: A retrospective cohort study was conducted to determine factors associated with FTT and association of FTT with infections and hospitalizations. METHODS: Records of 119 children transplanted between 2005 and 2016 were reviewed. FTT was defined by >=2 of the following post-transplant criteria: (a) low BMI or deceleration in BMI z-score, (b) poor growth velocity, and (c) chronic hypoalbuminemia at 1 or 3 years post-transplant. Association of FTT with deceased donor transplant, de novo DSA, intolerance to MMF, anemia, vitamin D deficiency, and CIC was investigated by logistic regression. Poisson regression was used to identify outcomes associated with FTT. RESULTS: Low pre-transplant BMI and post-transplant CIC dependence were independently associated with FTT after transplant. Odds of FTT at 1 year post-transplant decreased by 0.5 for each 1 unit increase in pre transplant BMI z-score. Requirement for CIC conferred 3.8 and 7.8 higher odds of FTT at 1 and 3 years. Patients with FTT had 2.7 and 2.6 times infections and hospitalizations during the first year, and 4.2 and 4.3 times infections and hospitalizations over 3 years post-transplant. CONCLUSIONS: Children with low BMI prior to transplant and those requiring CIC after transplant are at increased risk for post-transplant FTT. FTT is associated with adverse outcomes, evidenced by increased infections and hospitalizations. PMID- 30417494 TI - Pyruvic acid/ethyl pyruvate inhibits melanogenesis in B16F10 melanoma cells through PI3K/AKT, GSK3beta, and ROS-ERK signaling pathways. AB - Melanin is the main product of human melanocytes and functions to protect skin from ultraviolet (UV) radiation while conferring color to skin and hair. Tyrosinase is the rate-limiting enzyme for melanin synthesis along with tyrosinase-related protein (TRP)-1 and TRP-2. Microphthalmia-associated transcription factor regulates tyrosinase gene expression and is in turn regulated by extracellular signal-regulated kinase (ERK), phosphoinositide 3 kinase (PI3K)/AKT, and glycogen synthase kinase (GSK)3beta signaling pathways. Pyruvic acid (PA) is an energy source for ATP synthesis in the tricarboxylic acid cycle that also acts as a reactive oxygen species (ROS) scavenger. Since UV irradiation induces melanin synthesis and ROS generation, we speculated that PA or ethyl pyruvate (EP), a stable form of pyruvate, regulates melanogenesis. B16F10 melanoma cells served as a melanin synthesis model. Treatment with PA or EP suppressed melanin synthesis while increasing intracellular ROS levels, which was accompanied by increased ERK phosphorylation in the case of EP treatment. PA and EP induced GSK3beta phosphorylation and activated PI3K/AKT signaling, leading to decreased melanin synthesis. These results indicate that PA and EP inhibit melanogenesis via PI3K/AKT and GSK3beta signaling and targeting the ERK and GSK3beta pathways, respectively. Thus, PA and EP can potentially be used for treatment of hyperpigmentation disorders. This article is protected by copyright. All rights reserved. PMID- 30417495 TI - Door-to-balloon time and factors associated with delayed door-to-balloon time in ST-segment elevation myocardial infarction at Thailand's largest tertiary referral centre. AB - OBJECTIVE: To analyse door-to-balloon (DTB) time and to identify factors significantly associated with delayed DTB in patients with ST-segment elevation myocardial infarction (STEMI) at Thailand's largest tertiary referral centre. BACKGROUND: DTB time is considered an important measure of performance quality. METHODS: This observational study analysed DTB time in patients with STEMI who presented to our institute's emergency department and underwent primary percutaneous coronary intervention (PCI) during June 2008 to May 2011. DTB time greater than 90 minutes was considered delayed. Data were collected to determine which clinical variables were associated with delays. RESULTS: One hundred thirty three patients were included. The mean age of patients was 61.1 +/- 13.2 years, and 71.4% were male. Delayed DTB was observed in 70.7% of patients. Median DTB time was 117 (interquartile range [IQR], 86-168), 66 (IQR, 58-84), and 135 (IQR, 112-194) minutes in all patients, in nondelayed patients, and in delayed patients, respectively. Univariate analysis revealed triage to urgent care (P = 0.001) and presentation during on-call hours (P < 0.001) to be significantly associated with delayed DTB. Patients who were triaged to urgent care had a DTB time of 184 vs 105 minutes for triage to the emergency room. Patients who presented during on-call hours had a DTB time of 128 vs 86 minutes for work hour presentation. Presentation during on-call hours was the only significant predictor of DTB time >90 minutes in multivariate analysis (odds ratio [OR], 7.86; 95% confidence interval [CI], 3.39-18.22; P < 0.001). All patients that were triaged to urgent care were delayed; thus, association between urgent care triage and on-call hour service could not be determined. CONCLUSIONS: Delayed DTB time occurred in 70.7% of patients. Two key factors that significantly contributed to delayed DTB were patient mistriage to urgent care and presentation during on-call hours. PMID- 30417496 TI - Influence of different biological control agents and compost on total and nitrification driven microbial communities at rhizosphere and soil level in a lettuce - Fusarium oxysporum f. sp. lactucae pathosystem. AB - AIMS: The response of rhizosphere and bulk soil indigenous microbial communities focusing on nitrifiers was evaluated after the application of different biological control agents (BCAs) (Bacillus, Trichoderma, Pseudomonas) and compost in controlling lettuce Fusarium wilt. METHODS AND RESULTS: Experiments were conducted "in situ" over two lettuce cropping seasons. Total fungal, bacterial and archaeal populations and the nitrifiers were analysed using quantitative polymerase chain reaction (qPCR) method. The pathogen, Fusarium oxysporum forma specialis lactucae (FOL), Bacillus, Trichoderma and Pseudomonas and three antifungal genes (chiA, 2,4 - diacetylphloroglucinol - phlD and HCN synthase - hcnAB genes) were also assessed. Quantitative data were corroborated with disease severity, potential nitrification activity and soil chemical parameters. The application of BCAs and compost resulted in the disease reduction by as much as 69%, confirmed by significant negative correlations between Bacillus subtilis, Trichoderma and Pseudomonas spp. abundances and disease severity. The FOL presence in the untreated control resulted in the nitrifiers niche differentiation. CONCLUSIONS: The used treatments were efficient against Fusarium wilt and did not influence negatively the non - target microbial communities. SIGNIFICANCE AND IMPACT OF STUDY: The use of BCAs and compost appears as an effective and safe strategy to implement sustainable agricultural practices. This article is protected by copyright. All rights reserved. PMID- 30417497 TI - Fluid treatment for children with diabetic ketoacidosis: How do the results of the pediatric emergency care applied research network Fluid Therapies Under Investigation in Diabetic Ketoacidosis (FLUID) Trial change our perspective? AB - The optimal fluid treatment protocol for children with diabetic ketoacidosis (DKA) has long been a subject of controversy. Until recently, there was no high quality evidence from randomized clinical trials to support an optimal guideline, and recommendations were mainly based on theoretical considerations. As a consequence, fluid treatment protocols for children with DKA vary between institutions (and countries). In June 2018, the results from the Fluid Therapies Under Investigation in DKA Trial conducted in the Pediatric Emergency Care Applied Research Network were published. This large, factorial-designed randomized controlled trial assessed neurological outcomes of 1387 children with DKA who were treated with one of four fluid protocols that varied in infusion rate and sodium content. In this commentary, we review and discuss the results of this new study and the implications for clinical care of DKA in children. PMID- 30417498 TI - Tailoring Hydrocarbon Polymers and All-Hydrocarbon Composites for Circular Economy. AB - The world population will rapidly grow from 7 to 9 billion by 2050 and this will parallel a surging annual plastics consumption from today's 350 million tons to well beyond 1 billion tons. The switch from a linear economy with its throwaway culture to a circular economy with efficient reuse of waste plastics is therefore mandatory. Hydrocarbon polymers, accounting for more than half the world's plastics production, enable closed-loop recycling and effective product stewardship systems. High-molar-mass hydrocarbons serve as highly versatile, cost , resource-, eco- and energy-efficient, durable lightweight materials produced by solvent-free, environmentally benign catalytic olefin polymerization. Nanophase separation and alignment of unentangled hydrocarbon polymers afford 100% recyclable self-reinforcing all-hydrocarbon composites without requiring the addition of either alien fibers or hazardous nanoparticles. Recycling of durable hydrocarbons is far superior to biodegradation. The facile thermal degradation enables liquefaction and quantitative recovery of low molar mass hydrocarbon oil and gas. Teamed up with biomass-to-liquid and carbon dioxide-to-fuel conversions, powered by renewable energy, waste hydrocarbons serve as renewable hydrocarbon feedstocks for the synthesis of high molar mass hydrocarbon materials. Herein, an overview is given on how innovations in catalyst and process technology enable tailoring of advanced recyclable hydrocarbon materials meeting the needs of sustainable development and a circular economy. PMID- 30417499 TI - ISA Medal for Science for Gautam R. Desiraju / Dr. Hermann Schnell Fellowships. PMID- 30417500 TI - Establishment and characterization of CRISPR/Cas9-mediated NF2-/- human mesothelial cell line: Molecular insight into FGFR2 in MPM. AB - Malignant pleural mesothelioma (MPM), a highly refractory tumor, is currently incurable due to the lack of an early diagnosis method and medication, both of which are urgently needed to improve the survival and/or quality of life of patients. NF2 is a tumor suppressor gene and is frequently mutated in MPM. Using a CRISPR/Cas9 system, we generated an NF2-knockout human mesothelial cell line, MeT-5A (NF2-KO). In NF2-KO cell clones, cell growth, clonogenic activity, migration activity, and invasion activity significantly increased compared with those in NF2-WT cell clones. cDNA microarray analysis clearly revealed the differences in global gene expression profile between NF2-WT and NF2-KO cell clones. Quantitative PCR analysis and western blot analysis showed that the upregulation of FGFR2 was concomitant with the increases in phosphorylation levels of JNK, c-Jun, and Rb in NF2-KO cell clones. These increases were all abrogated by the exogenous expression of NF2 in the NF2-KO clone. In addition, the disruption of FGFR2 in the NF2-KO cell clone suppressed cell proliferation as well as the phosphorylation levels of JNK, c-Jun, and Rb. Notably, FGFR2 was found to be highly expressed in NF2-negative human mesothelioma tissues (11/12 cases, 91.7%) but less expressed in NF2-positive tissues. Collectively, these findings suggest that NF2 deficiency may play a role in the tumorigenesis of human mesothelium through mediating FGFR2 expression; FGFR2 would be a candidate molecule to develop therapeutic and diagnostic strategies for targeting MPM with NF2 loss. This article is protected by copyright. All rights reserved. PMID- 30417501 TI - The Combination of Benzaldehyde and Nickel-Catalyzed Photoredox sp3-C-H Alkylation/Arylation. AB - Herein we report a highly selective photoredox sp3-C-H alkylation/arylation of ethers via the combination of a photo-organocatalyst (benzaldehyde) and a transition metal catalyst (nickel). This methodology provides simple and general strategy for sp3-C-H alkylation/arylation of ethers, a selective late-stage modification of (-)-Ambroxide has also been conducted to demonstrate the applicability. PMID- 30417502 TI - miR-129-5p and -3p co-target WWP1 to suppress gastric cancer proliferation and migration. AB - Gastric cancer (GC) is a worldwide health problem. Uncovering the underlining molecular mechanisms of GC is of vital significance. Here, we identified a novel oncogene WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) in GC. WWP1 could promote GC cell proliferation and migration in vitro and expedite GC growth in vivo. We also found out two microRNAs (miRNAs): miR-129-5p and -3p could both target WWP1. Interestingly, miR-129-5p bound to the CDS region of WWP1 mRNA. The miR-129 pairs (miR-129-5p and -3p) play pivotal roles in GC to suppress its proliferation and migration in vitro and slow down GC growth in vivo by repressing WWP1. In summary, we identified two tumor suppressive miRNAs which share the same precursor that could regulate the same oncogene WWP1 in GC. Our finding would add new route for GC research and treatment. PMID- 30417503 TI - The roles of moonlight ribosomal proteins in the development of human cancers. AB - "Moonlighting protein" is a term used to define a single protein with multiple functions and different activities that are not derived from gene fusions, multiple RNA splicing, or the proteolytic activity of promiscuous enzymes. Different proteinous constituents of ribosomes have been shown to have important moonlighting extra-ribosomal functions. In this review, we introduce the impact of key moonlight ribosomal proteins and dependent signal transduction in the initiation and progression of various cancers. As a future perspective, the potential role of these moonlight ribosomal proteins in the diagnosis, prognosis, and development of novel strategies to improve the efficacy of therapies for human cancers has been suggested. PMID- 30417504 TI - A clinical prediction tool to determine the need for concurrent systematic sampling at the time of magnetic resonance imaging-guided biopsy. AB - OBJECTIVE: To develop a clinical prediction tool that characterises the risk of missing significant prostate cancer by omitting systematic biopsy in men undergoing transrectal ultrasonography/magnetic resonance imaging (TRUS/MRI) fusion-guided biopsy. PATIENTS AND METHODS: A consecutive sample of men undergoing TRUS/MRI-fusion-guided biopsy with the UroNav(r) system (Invivo International, Best, The Netherlands) who also underwent concurrent systematic biopsy was included. By comparing the grade of cancer diagnosed on targeted and systematic biopsy cores, we identified cases where clinically significant disease (Gleason score >=3+4) was only found on systematic and not targeted cores. Multivariable logistic regression analyses were used to identify predictive factors for finding significant cancer on systematic cores only. We then used these data to develop a nomogram and evaluated its utility using decision curve analysis. RESULTS: Of the 398 men undergoing TRUS/MRI-fusion-guided biopsy in our study, there were 46 (11.6%) cases in which clinically significant cancer was missed on targeted biopsy and detected on systematic biopsy. The clinical setting, number of MRI lesions identified, and the highest Prostate Imaging Reporting and Data System (PI-RADS) score of the lesions, were all found to be predictors of this. Our model had a good discriminative ability (concordance index = 0.70). The results from our decision curve analysis show that this model provides a higher net clinical benefit than either biopsying all men or omitting biopsy in all patients when the threshold probability is <30%. CONCLUSION: We found that omitting concurrent systematic biopsy in men undergoing TRUS/MRI fusion-guided biopsy would miss significant disease in more than one in 10 patients. We propose a prediction model with good discriminative ability that can be used to improve patient selection for performing concurrent systematic biopsy in order to minimise the number of missed significant cancers. It is important that our model is validated in external cohorts before being employed in routine clinical practice. PMID- 30417505 TI - Understanding the Roles of Oxygen Vacancy in Hematite based Photoelectrochemical Process. AB - Oxygen vacancy (VO) engineering is an effective method to tune the photoelectrochemical (PEC) performance, but the influence of Vo on photoelectrode is not well understood. Using hematite as a prototype, here we report that VO functions in a more complicate way in PEC process than previously reported. By comprehensive analysis of the key charge transfer and surface reaction steps in PEC process on hematite photoanode, we clarify that VO can facilitate surface electrocatalytic process but meanwhile leads to severe interfacial recombination at the semiconductor/electrolyte (S-E) interface, in addition to the well reported bulk conductivity improvement. The improved bulk conductivity and surface catalysis are beneficial for bulk charge transfer and surface charge consumption, however the interfacial charge transfer is deteriorated due to the recombination via VO induced trap states at the S-E interface. PMID- 30417506 TI - Osteoblast autophagy in glucocorticoid-induced osteoporosis. AB - Administration of glucocorticoids is an effective strategy for treating many inflammatory and autoimmune diseases. However, glucocorticoid treatment can have adverse effects on bone, leading to glucocorticoid-induced osteoporosis (GIO), the most common form of secondary osteoporosis. Although the pathogenesis of GIO has been studied for decades, over the past ten years the autophagy machinery has been implicated as a novel mechanism. Autophagy in osteoblasts, osteocytes, and osteoclasts plays a critical role in the maintenance of bone homeostasis. Herein, we specifically discuss how osteoblast autophagy responds to glucocorticoids and its role in the development of GIO. PMID- 30417507 TI - Regenerative Prophylaxis In Utero. AB - Technology advances have raised the outlook for regenerative solutions aimed at restoring organ health. Fetal surgery, implemented to reinstate early organ growth and restitute function in select congenital conditions, is increasingly considered with the prospect of improved postnatal outcomes. Herein, we highlight clinical prenatal interventions for rescue of fetal lung development in congenital diaphragmatic hernia and fetal neurological regeneration for spina bifida. Regenerative therapeutic care in utero is poised to transform management algorithms. PMID- 30417508 TI - Schistosoma haematobium cercarial infection alters subsequent systemic immune responses to eggs but has minimal impact on immune responses to egg injection of the bladder. AB - AIMS: Mouse bladder wall injection with Schistosoma haematobium eggs has been used to overcome limitations in animal models of urogenital schistosomiasis. However, the effect of the absence of cercarial infection on immune responses to eggs in this model is unknown. We hypothesized that cercarial infection would alter local bladder and systemic immune responses to eggs in this model. METHODS AND RESULTS: Mice were infected or not infected with S haematobium cercariae, and then, their bladder walls injected with S haematobium eggs or vehicle 5 weeks following cercarial infection. Three weeks later, mice were bled, sacrificed, perfused and their bladders harvested. Parasitological parameters and gross bladder pathology were not changed in egg-injected bladders by cercarial exposure. Figure S1 shows no changes in either granulomas or fibrosis. The only bladder cytokine upregulated in egg-injected bladders by cercarial exposure (vs no exposure) was leptin. Cercarial exposure, compared to no exposure, resulted in increased serum, IL-1alpha, IL-13 and TGF-beta in bladder egg-injected mice. CONCLUSION: Cercarial exposure altered systemic responses of several cytokines in bladder egg-injected mice, but surprisingly, only modified leptin expression in bladder tissue. This suggests that depending on the specific application, cercarial exposure may not be strictly necessary to model local immune responses in the bladder wall egg injection mouse model of urogenital schistosomiasis. PMID- 30417509 TI - Evaluation of the efficacy of microneedle fractional radiofrequency in Turkish patients with atrophic facial acne scars. AB - BACKGROUND: Scarring is an undesirable and severe complication of acne resulting in loss of self-esteem in young people. Although microneedle fractional radiofrequency (MFR) system has emerged as a good option to treat acne scars in recent years, it was examined in a few studies which were commonly from Asian countries. AIMS: We sought to evaluate the efficacy of MFR in Turkish patients with facial acne scars. METHODS: Nine patients with atrophic facial acne scars treated with MFR device were included in the study. The number of treatment sessions was varied from one to five (median three) with 4-week intervals. Demographic and basal clinical features were recorded. Efficacy of the device was evaluated by the physicians' global assessment and patients' self-assessment scales 4 weeks after the last treatment session. RESULTS: Of nine patients, two were male and seven were female (mean age, 31.33 years). Two patients had mild, four had moderate, and three had severe facial acne scars. Mean acne scar age was 13.22 +/- 8.79 years. According to the predominant scar subtype, three patients had V-shaped, three had U-shaped, and three had M-shaped atrophic acne scars. A clinical improvement of >25% has been reported in seven patients (77.7%) and eight patients (88.9%) by the physicians and patients, respectively. U-shaped atrophic acne scars responded better to the treatment than the other types, as statistically nonsignificant. There were no severe side effects. CONCLUSIONS: Microneedle fractional radiofrequency system showed a quite good efficacy and safety in the treatment of atrophic facial acne scars (Department of Dermato Cosmetology, Uludag University Medical School). PMID- 30417510 TI - A conceptual framework for clinicians working with artificial intelligence and health-assistive Smart Homes. AB - The Smart Home designed to extend older adults independence is emerging as a clinical solution to the growing ageing population. Nurses will and should play a key role in the development and application of Smart Home technology. Accordingly, conceptual frameworks are needed for nurse scientists who are collaborating with multidisciplinary research teams in developing an intelligent Smart Home that assists with managing older adults' health. We present a conceptual framework that is grounded in critical realism and pragmatism, informing a unique mixed methodological approach to generating, analyzing, and contextualizing sensor data for clinician-based machine learning. This framework can guide nurse scientists in knowledge construction as they participate in multidisciplinary health-assistive Smart Home and artificial intelligence research. In this paper, we review philosophical underpinnings and explicate how this framework can guide nurse scientists collaborating with engineers to develop intelligent health-assistive Smart Homes. It is critical that clinical nursing knowledge is integrated into Smart Home and artificial intelligence features. A conceptual framework and practical method will provide needed structure for knowledge construction by nurse scientists. PMID- 30417511 TI - Sentinel Node Biopsy in Clinical Stage I Testicular Cancer Enables Early Detection of Occult Metastatic Disease. AB - OBJECTIVES: To report the long-term results of the sentinel node approach in clinical stage I testicular tumour patients in our facility. PATIENTS AND METHODS: Analysis of 27 consecutive patients suspected of clinical stage I testicular germ cell tumour and treated with a sentinel node procedure at our tertiary referral centre. Sentinel nodes were identified using lymphoscintigraphy with or without single photo emission computed tomography with computed tomography. Patients underwent laparoscopic retroperitoneal sentinel node excision with inguinal orchiectomy. Patients with a tumour-positive sentinel node underwent adjuvant treatment. Follow-up was according to then current guidelines. RESULTS: In two patients, no sentinel nodes were visualized on scintigraphy. In the remaining twenty-five patients, a median of 3 sentinel nodes (range 1 - 4) per patient were removed. Two patients showed no malignancy on histopathological examination of the testis. Of the 23 patients diagnosed with testicular germ cell tumour (16 seminoma, 7 non-seminoma), 3 (13.0%) had occult metastatic disease. All 23 patients were without evidence of disease at a median follow-up of 63.9 months (range 29.0 - 143.4). CONCLUSION: The sentinel node procedure allows for early identification of patients with occult metastatic disease in clinical stage I testicular germ cell tumour, enabling early treatment. This article is protected by copyright. All rights reserved. PMID- 30417512 TI - Fast Deposition of Aligning Edge-On Polymers for High-Mobility Ambipolar Transistors. AB - Fast deposition of aligning ambipolar polymers for high-performance organic field effect transistors (OFETs) and inverter circuits are highly desired for both scientific studies and industry applications. Here, large-area and ordered polymer films are prepared by a bar-coating method at a rate of 120 mm s-1 in air. Atomic force microscopy and grazing-incidence wide-angle X-ray scattering analysis indicate uniform edge-on poly(fluoroisoindigo-difluorobithiophene fluoroisoindigo-bithiophene) (PFIBI-BT) in 11.7 +/- 1 nm film (~5 layers). The elongated, uniformly oriented grains can reduce the adverse effects of the grain boundaries and facilitate charge transport in polymers. Furthermore, OFETs based on parallel film show high hole/electron mobilities up to 5.5/4.5 cm2 V-1 s-1 , which are approximately nine times of the devices prepared by spin-coating. The gain of the inverter is as high as 174, which is one of the highest values in polymer inventers currently. These results demonstrate that the excellent bipolar performance of few-layer PFIBI-BT can be ensured while achieving the compatibility of the experimental process with industrial preparation. PMID- 30417513 TI - PPy-encapsulated SnS2 nanosheets stabilized by defects on TiO2 support as durable anode material for lithium ion battery. AB - Nanostructured alloy-type anodes have received great interests for high performance lithium ion batteries (LIBs). However, these anodes experience huge volume fluctuations during repeated lithiation/delithiation and are easily pulverized and subsequently form aggregates. Herein, an efficient method to stabilize alloy-type anodes by creating defects on the surface of metal oxide support is proposed. As a demonstration, PPy-encapsulated SnS2 nanosheets supported on defect-rich TiO2 nanotubes are produced and investigated as an anode material for LIBs. Both experimental results and theoretical calculations demonstrate that defect-rich TiO2 provides more chemical adhesions to SnS2 and to the discharge products compared to defect-poor TiO2 and then effectively stabilizes the electrode structure. As a result, the composite exhibits an unprecedented cycle stability. This work paves a way to design durable and active nanostructured alloy-type anodes on oxide supports. PMID- 30417514 TI - Accuracy of scleral transillumination techniques to identify infant ciliary body for sclerostomy and intravitreal injections. AB - IMPORTANCE: There is variation in the literature for sclerotomy and intravitreal injection placement in young children, ranging from 0.5-3.0mm from the limbus. We assess the accuracy of scleral transillumination to identify the ciliary body in infants for safe sclerotomy and intravitreal injections in young children. BACKGROUND: The study compares the perilimbal 'dark band' seen on scleral transillumination (STI) with the Ultrasound Biomicroscopy (UBM), and compares these measurements with the current guidelines for sclerotomy in infants. DESIGN: Prospective case series in a tertiary pediatric hospital. PARTICIPANTS: Children aged <= 36 months undergoing general anesthesia for eye procedures METHODS: Scleral transillumination was performed to measure the perilimbal dark band. Ultrasound biomicroscopy of the ciliary body region was then performed, and correlated with transillumination findings. MAIN OUTCOME MEASURES: The midpoints of STI and UBM were compared to current cadaver-based guidelines to assess the safe point for sclerotomy. RESULTS: Twenty children were recruited, 36 STI and 35 UBM measurements were obtained. The posterior edge of the dark band had good correlation with the posterior border of the ciliary body. Transillumination and UBM correlated well for midpoint measurements. The midpoint of the dark band on transillumination was confirmed to be in the ciliary body by UBM in all cases. CONCLUSIONS & RELEVANCE: The STI technique is a useful and fast technique to demonstrate the ciliary body. The mid-point of the dark band on STI correlates well with the UBM, and has a potential use for confirming safe-entry into the posterior segment if using current guidelines. The current cadaver-based pediatric guidelines safely avoid retinal injury. PMID- 30417515 TI - pH-Dependent Degradation of Layered Black Phosphorus: Essential Role of Hydroxide Ions. AB - The practical application of layered black phosphorus (LBP) was challenged by fast decomposition in the presence of H2O and/or O2, and the role of H2O was highly controversial. Herein, we proposed a hydroxide ion (OH-)-initiated degradation mechanism for LBP to elucidate the role of H2O. We found that LBP degraded faster in alkaline solutions than in neutral or acidic solutions with or without O2. Degradation rates of LBP increased linearly from pH 4 to 10. Density functional theory calculations showed that OH- initiated the decomposition of LBP through breaking the P-P bond and forming a P-O bond. The detection of hypophosphite, generated from OH- reacting with P atoms, confirmed the hypothesis. Protons acted in a way distinctive from OH-, by inducing deposition/aggregation or forming a cation-pi layer to protect LBP from degradation. This work revealed the exact degradation mechanism of LBP to facilitate the development of effective stabilization technologies. PMID- 30417516 TI - Reconstruction of global regulatory network from signaling to cellular functions using phosphoproteomic data. AB - Cellular signaling regulates various cellular functions via protein phosphorylation. Phosphoproteomic data potentially includes information for a global regulatory network from signaling to cellular functions, but a procedure to reconstruct this network using such data has yet to be established. In this paper we provide a procedure to reconstruct a global regulatory network from signaling to cellular functions from phosphoproteomic data by integrating prior knowledge of cellular functions and inference of the kinase-substrate relationships (KSRs). We used phosphoproteomic data from insulin-stimulated Fao hepatoma cells, and identified protein phosphorylation regulated by insulin specifically over-represented in cellular functions in the KEGG database. We inferred kinases for protein phosphorylation by KSRs, and connected the kinases in the insulin-signaling layer to the phosphorylated proteins in the cellular functions, revealing that the insulin signal is selectively transmitted via the Pi3k-Akt and Erk signaling pathways to cellular adhesions and RNA maturation, respectively. Thus, we provide a method to reconstruct global regulatory network from signaling to cellular functions based on phosphoproteomic data. This article is protected by copyright. All rights reserved. PMID- 30417518 TI - Controlled and Tunable Loading and Release of Vesicles by Using Gigahertz Acoustics. AB - Controllable exchange of molecules between the interior and the external environment of vesicles is critical in drug delivery and micro/nano-reactors. While many approaches exist to trigger release from vesicles, controlled loading remains a challenge. Herein, we show that gigahertz acoustic streaming generated by a nanoelectromechanical resonator can control the loading and release of cargo into and from vesicles. Polymer-shelled vesicles showed loading and release of molecules both in solution and on a solid substrate. We observed deformation of individual giant unilamellar vesicles and propose that the shear stress generated by gigahertz acoustic streaming induces the formation of transient nanopores, with diameters on the order of 100 nm, in the vesicle membranes. This provides a non-invasive method to control material exchange across membranes of different types of vesicles, which could allow site-specific release of therapeutics and controlled loading into cells, as well as tunable microreactors. PMID- 30417517 TI - Developing quality criteria for patient-directed knowledge tools related to clinical practice guidelines. A development and consensus study. AB - BACKGROUND: Patient-directed knowledge tools such as patient versions of guidelines and patient decision aids are increasingly developed to facilitate shared decision making. In this paper, we report how consensus was reached within the Netherlands on quality criteria for development, content and governance of these tools. METHOD: A 12-month development and consensus study. The consortium worked on four work packages: (a) reviewing existing criteria; (b) drafting the quality criteria; (c) safe-guarding the acceptability and feasibility of the draft criteria by participatory research in on-going tool development projects; and (d) gaining formal support from national stakeholders on the quality criteria. RESULTS: We reached consensus on a 8-step guidance; describing minimal quality criteria for (a) the team composition; (b) setting the scope; (c) identifying needs; (d) the content and format; (e) testing the draft; (f) finalizing and approval; (g) dissemination and application, and (h) ownership and revision. The participants of the on-going tool development projects were positive about the quality criteria in general, but divided as to the degree of detail. Whereas some expressed a clear desire for procedural standards, others felt that it would be sufficient to provide only general directions. Despite the different views as to the degree of detail, consensus was reached in three stakeholder meetings. DISCUSSION: We successfully collaborated with all stakeholders and achieved formal support from national stakeholders on a set of minimum criteria for the development process, content and governance of patient directed knowledge tools. PMID- 30417520 TI - The 60th Annual Meeting of the Japanese Society of Pediatric Hematology Society November 14-16. PMID- 30417519 TI - Meiosis-specific cohesin component, Rec8, promotes the localization of Mps3 SUN domain protein on the nuclear envelope. AB - Proteins in the nuclear envelope (NE) play a role in the dynamics and functions of the nucleus and of chromosomes during mitosis and meiosis. Mps3, a yeast NE protein with a conserved SUN domain, predominantly localizes on a yeast centrosome equivalent, spindle pole body (SPB), in mitotic cells. During meiosis, Mps3, together with SPB, forms a distinct multiple ensemble on NE. How meiosis specific NE localization of Mps3 is regulated remains largely unknown. In this study, we found that a meiosis-specific component of the protein complex essential for sister chromatid cohesion, Rec8, binds to Mps3 during meiosis, and controls Mps3 localization and proper dynamics on NE. Ectopic expression of Rec8 in mitotic yeast cells induced the formation of Mps3 patches/foci on NE. This required the cohesin regulator and WAPL ortholog, Rad61/Wpl1, suggesting that a meiosis-specific cohesin complex with Rec8 controls NE localization of Mps3. We also observed that two domains of the nucleoplasmic region of Mps3 are essential for NE-localization of Mps3 in mitotic as well as meiotic cells. We speculate that the interaction of Mps3 with the meiosis-specific cohesin in the nucleoplasm is a key determinant for NE-localization/function of Mps3. This article is protected by copyright. All rights reserved. PMID- 30417521 TI - Pattern associated leukemia immunophenotypes and measurable disease detection in acute myeloid leukemia or myelodysplastic syndrome with mutated NPM1. AB - BACKGROUND: The presence of measurable residual disease after therapy is a significant risk factor of relapse in patients with acute myeloid leukemia (AML). By detecting cells with leukemia-associated immunophenotype (LAIP), multiparameter flow cytometry (MFC) can detect residual leukemia at a level significantly lower than that detected by morphology. However, changes in LAIPs during or after therapy may pose a challenge to MRD testing. AML with mutated NPM1 represents the largest subtype of AML sharing a common leukemogenic mechanism and similar LAIPs. Here, we identified a common pattern of LAIPs in myeloid blasts with mutated NPM1, and studied its stability and limit of detection after therapy. METHODS: We summarized aberrancies of leukemic blasts with mutated NPM1 at diagnosis in 61 patients and paired relapse in 25 patients. In addition, we examined the detection of leukemic blasts in 590 specimens collected from 152 patients in complete remission after induction for AML/MDS-EB with mutated NPM1. RESULTS: Our findings demonstrate myeloid blasts with mutated NPM1 have a characteristic pattern of LAIPs that is present in nearly all cases of AML/MDS-EB with mutated NPM1 at initial diagnosis and relapse, regardless of morphologic variations, FLT3 ITD status, or karyotype abnormality. The myeloid blasts with mutated NPM1 can be detected at an approximate level of 0.1% of total leukocytes in morphologic remission with high specificity validated by clinical outcome. CONCLUSION: The characteristic pattern of LAIPs of myeloid blasts with mutated NPM1 is common and stable, and allows sensitive and specific detection of AML or MDS with mutated NPM1 after therapy. (c) 2018 International Clinical Cytometry Society. PMID- 30417522 TI - Long-term Psychosocial Outcomes after Nondirected Donation: A Single Center Experience. AB - Short-term studies have demonstrated that nondirected donors (NDDs) have similar psychosocial outcomes to those donating directly, but long-term studies have not been done. NDDs at our center were surveyed regarding motivation; support during donation; stresses related to donation; regret; financial resources used for donation; preferences about communication with the recipient; and cost reimbursement. Of 100 NDDs done at our center in the last 20 years, 95 remain in contact with us, and 77 responded to our survey (mean 6.7+/-4 years postdonation). The most common motivation for donation was the desire to help another (99%). Many NDDs received support from family, friends and employers. NDDs voiced stress about the possibility of recipient kidney rejection, physical consequences to themselves and financial burden. Only one donor expressed regret. Almost half wanted some recipient information at donation; 61% preferred routine recipient status updates; 56% believed meeting the recipient should occur at any mutually agreeable time; and 55% endorsed reimbursement for expenses. Stressors for NDDs are analogous to those of directed donors; NDDs prefer having some information about the recipient, and prefer to be given a choice regarding timing for communication with the recipient. NDDs supported donation being financially neutral. This article is protected by copyright. All rights reserved. PMID- 30417523 TI - Validation and IMRT/VMAT delivery quality of a pre-configured fast-rotating O ring linac system. AB - PURPOSE: A fast-rotating O-ring dedicated IMRT/VMAT delivery system, the Halcyon, is delivered by default with a fully pre-configured photon beam model in the TPS. This work reports on the validation and achieved IMRT/VMAT delivery quality on the system. METHODS: Acceptance testing followed the vendor's installation product acceptance and was supplemented with mechanical QA. The dosimetric calibration was performed according to the IAEA TRS-398 code of practice, delivering 600 cGy/min at 10 cm depth, a 90 cm source-surface distance and a 10x10 cm2 field size. The output factors, MLC transmission and dosimetric leaf gap (DLG) were validated by comparing measurements with the modelled values in the TPS. Validation of IMRT/VMAT was conducted following AAPM reports (MPPG 5.a, TG-119). Next, dose measurements were performed for end-to-end (E2E) checks in heterogeneous anthropomorphic phantoms using radiochromic film in multiple planes and using ionization chambers (IC) point measurements. E2E checks were performed for VMAT (cranial, rectum, spine and head&neck) and IMRT (lung). Additionally, IROC-Houston mailed dosimetry audits were performed for the beam calibration and E2E measurements using a thorax phantom (IMRT) and a head&neck phantom (VMAT). Lastly, extensive patient-specific QA was performed for the first patients of each new indication, 26 in total (nrectum =2, nspine =5, nlung =5, nesophagus =2, nhead&neck =7, ncranial =5), treated on the fast-rotating O-ring linac. The patient-specific QA followed the AAPM TG-218 guidelines and comprised of portal dosimetry, ArcCHECK diode array, radiochromic film dosimetry in a MultiCube phantom and IC point measurements. RESULTS: The measured output factors showed an agreement <1% for fields >= 3x3 cm2. Field sizes <= 2x2 cm2 had a difference of <2%. The measured single-layer MLC transmission was 0.42 +/- 0.01% and the measured DLG was 0.27 +/- 0.22 mm. The AAPM MPPG 5.a measurements were fully compliant with the guideline criteria. Dose differences larger than 2% were found for the PDD at large depths (>25 cm). TG-119's confidence limits were achieved for the VMAT point dose measurements and for both the IMRT and VMAT radiochromic film measurements. The TG-119 confidence limits were not achieved for IMRT point dose measurements in both the target (5.9%) and the avoidance structure (6.4%). All E2E tests had point differences below 2.3% and gamma agreement scores above 90.6%. The IROC beam calibration audit showed agreement of <1%. The IROC lung IMRT audit and head&neck VMAT audit had results compliant with the IROC-Houston's credentialing criteria. All IMRT and VMAT plans selected for patient-specific QA were within the action limits suggested by TG-218. CONCLUSIONS: The fast-rotating O-ring linac and its pre-configured TPS are compliant with the international commissioning criteria of AAPM MPPG 5.a and AAPM TG-119. E2E measurements on heterogeneous anthropomorphic phantoms were within clinically acceptable tolerances. IROC Houston's audits satisfied the credentialing criteria. This work comprises the first extensive dataset reporting on the pre-configured fast rotating O-ring linac. This article is protected by copyright. All rights reserved. PMID- 30417524 TI - A small marine biosphere in the Proterozoic. AB - The riverine supply of the globally limiting nutrient, phosphorus, to the ocean accounts for only a few percent of nutrient supply to photosynthetic organisms in surface waters. Recycling of marine organic matter by heterotrophic organisms provides almost all of the phosphorus that drives net primary production in the modern ocean. In the low-oxygen environments of the Proterozoic, the lack of free oxygen would have limited rates of oxic respiration, slowing the recycling of nutrients and thus limiting global rates of photosynthesis. A series of steady state mass balance calculations suggest that the rate of net primary production in the ocean was no more than 10% of its modern value during the Proterozoic eon, and possibly less than 1%. The supply of nutrients in such a world would be dominated by river input, rather than recycling within the water column, leading to a small marine biosphere found primarily within estuarine environments. PMID- 30417525 TI - Effects of microRNA-217 on proliferation, apoptosis, and autophagy of hepatocytes in rat models of CCL4-induced liver injury by targeting NAT2. AB - Liver injury is an important cause of serious liver disease. This study aims to explore the effects of miR-217 targeting NAT2 on hepatocyte proliferation, apoptosis, and autophagy following carbon tetrachloride (CCL4)-induced liver injury. Rat models of CCL4-induced liver injury were established. Healthy Wistar rats were randomized into the normal, blank, negative control (NC), microRNA-217 (miR-217) mimic, miR-217 inhibitor, small interfering RNA (siRNA)-N acetyltransferase 2 (NAT2), and miR-217 inhibitor + siRNA-NAT2 groups. NAT2 activity was evaluated with reversed-phase high-performance liquid chromatographic method. Immunohistochemistry was used to detect NAT2 protein positive rate. Reverse transcription quantitative polymerase chain reaction and western blot analysis were used to examine expressions of miR-217, NAT2, Bcl-2, Bax, p35, LC3-II, Becline-1, and the ratio of caspase-3/cleaved caspase-3. Autophagy, proliferation, and cell cycle distribution were determined by electron microscope, CCK-8, and flow cytometry. NAT2 protein positive rate and miR-217, NAT2, Bcl-2, and p35 expressions were higher and Bax, LC3-II, and Becline-1 expressions and the ratio of caspase-3/cleaved caspase-3 lower in the normal group than the other six groups. Compared with the blank and NC groups, in the miR-217 mimic and siRNA-NAT2 groups, Bax, LC3-II, and Becline-1 expressions and the ratio of caspase-3/cleaved caspase-3, and hepatocyte apoptosis and autophagy increased, while NAT2, Bcl-2, and p35 expressions and hepatocyte proliferation decreased; opposite results were observed in the miR-217 inhibitor group. Collectively, miR-217 targeting NAT2 inhibits proliferation and promotes apoptosis and autophagy of hepatocytes in CCL4-induced liver injury. PMID- 30417526 TI - CircRNA circPDSS1 promotes the gastric cancer progression by sponging miR-186-5p and modulating NEK2. AB - The aim of this study is to investigate the regulatory mechanism of circPDSS1/miR 186-5p/NEK2 axis on the viability and proliferation in gastric cancer (GC) cell line. Differentially expressed circRNAs, miRNAs, and mRNAs in GC tissues and paracarcinoma tissues were analyzed using gene chips GSE83521, GSE89143, and GSE93415. Then, the expression of circPDSS1, miR-186-5p, and NEK2 was analyzed via quantitative real-time polymerase chain reaction (qRT-PCR). Survival analysis was adopted to explore the association between the circPDSS1 expression and the prognosis of GC. The effect of circPDSS1 on GC cell cycle and apoptosis was verified with the flow cytometry. Targeting relationships among circPDSS1, miR 186-5p, and NEK2 were predicted via bioinformatics analysis and demonstrated by the dual-luciferase reporter assay. Our results showed that circPDSS1 and NEK2 were high-expressed whereas miR-186-5p was low-expressed in GC tissues and cells. CircPDSS1 promoted GC cell cycle and inhibited apoptosis by sponging miR-186-5p, while miR-186-5p inhibited cell cycle and promoted apoptosis by targeting NEK2. Thus, circPDSS1 acts as a tumor promoter by regulating miR-186-5p and NEK2, which could be a potential biomarker and therapeutic target for the management of GC. PMID- 30417527 TI - Betulinic acid induces apoptosis and suppresses metastasis in hepatocellular carcinoma cell lines in vitro and in vivo. AB - Hepatocellular carcinoma (HCC) is a high incidence and mortality malignant tumour globally. Betulinic acid (BA) is a pentacyclic triterpenoid with potential pro apoptotic activities which widely found in many plants. In this study, we determined the effects of BA on proliferation, apoptosis, invasion, and metastasis in HCC cell lines and on tumour growth and pulmonary metastasis in mice. The results suggested that BA could inhibit cell viability and proliferation of HCC cell lines including HepG2, LM3, and MHCC97H. In addition, BA induced apoptosis of HepG2 cells characterised condensed nuclei and nuclear fragmentation. Moreover, western blot analysis showed that BA-induced apoptosis associated with increasing of pro-apoptotic protein Bax and cleaved caspase-3 and decreasing of anti-apoptotic protein Bcl-2. Meanwhile, BA also reduced the reactive oxygen species (ROS) level. Furthermore, BA also significantly inhibited HCC growth in vivo and blocked pulmonary metastasis of HCC by regulating the metastasis-related proteins including MMP-2, MMP-9, and TIMP2 without obvious toxicity. In all, the present study suggested that BA might be a promising anti HCC drug candidate by inhibiting proliferation, inducing apoptosis, and blocking metastasis. PMID- 30417528 TI - Health benefits of an innovative model of care for chronic wounds patients in Queensland. AB - Wound management in Australia suffers from a lack of adequate coordination and communication between sectors that impacts patient outcomes and costs. Wound Innovations is a specialist service comprising of a transdisciplinary team that aims to streamline and improve patient care and outcomes. We compared patient experiences and outcomes prior to accessing this specialist service, and the 3 months following their enrolment at the clinic. Information on patient experiences, wound history, and outcomes was collected through interviews and a review of medical records for the 12 months prior to enrolment at the clinic. Wound progress, quality of life (QoL) outcomes, and service use were tracked during the 3-month prospective phase. A sample of 29 participants was recruited. 40% healed completely by 3 months, with the average time to healing being 8 weeks. The average QoL score at baseline was 0.69 (from a score of 1, being best health imaginable). At 3 months, the average QoL score increased significantly to 0.84 (P <=0.001). On average, participants attended the clinic 4.6 times. The average decrease in wound size was 85.4% (95% CI [75.7%, 95%]). Accessing wound care treatment at a specialist, multidisciplinary wound clinic leads to an increase in QoL and access to consistent evidence-based practices. PMID- 30417529 TI - Carbon Nanodots as Feedstock for a Uniform Hematite-Graphene Nanocomposite. AB - High degrees of dispersion are a prerequisite for functional composite materials for applications in electronics such as sensors, charge and data storage, and catalysis. The use of small precursor materials can be a decisive factor in achieving a high degree of dispersion. In this study, carbon nanodots are used to fabricate a homogeneous, finely dispersed Fe2 O3 -graphene composite aerogel in a one-step conversion process from a precursor mixture. The laser-assisted conversion of small size carbon nanodots enables a uniform distribution of 6.5 nm Fe2 O3 nanoparticles during the formation of a highly conductive carbon matrix. Structural and electrochemical characterization shows that the features of both material entities are maintained and successfully integrated. The presence of Fe2 O3 nanoparticles has a positive effect on the active surface area of the carbon aerogel and thus on the capacitance of the material. This is demonstrated by testing the performance of the composite in supercapacitors. Faradaic reactions are exploited in an aqueous electrolyte through the high accessible surface of the incorporated small Fe2 O3 nanoparticles boosting the specific capacitance of the 3D turbostratic graphene network significantly. PMID- 30417530 TI - 4 in 1: Antibody-free protocol for isolating the main hepatic cells from healthy and cirrhotic single rat livers. AB - Liver cells isolated from pre-clinical models are essential tools for studying liver (patho)physiology, and also for screening new therapeutic options. We aimed at developing a new antibody-free isolation method able to obtain the four main hepatic cell types (hepatocytes, liver sinusoidal endothelial cells [LSEC], hepatic macrophages [HMPhi] and hepatic stellate cells [HSC]) from a single rat liver. Control and cirrhotic (CCl4 and TAA) rat livers (n = 6) were perfused, digested with collagenase and mechanically disaggregated obtaining a multicellular suspension. Hepatocytes were purified by low revolution centrifugations while non-parenchymal cells were subjected to differential centrifugation. Two different fractions were obtained: HSC and mixed LSEC + HMPhi. Further LSEC and HMPhi enrichment was achieved by selective adherence time to collagen-coated substrates. Isolated cells showed high viability (80%-95%) and purity (>95%) and were characterized as functional: hepatocytes synthetized albumin and urea, LSEC maintained endocytic capacity and in vivo fenestrae distribution, HMPhi increased expression of inflammatory markers in response to LPS and HSC were activated upon in vitro culture. The 4 in 1 protocol allows the simultaneous isolation of highly pure and functional hepatic cell sub-populations from control or cirrhotic single livers without antibody selection. PMID- 30417531 TI - Dermatological conditions presenting to the emergency dermatological unit of a university hospital in Germany. AB - BACKGROUND AND OBJECTIVES: Recently, there have been increasing numbers of patients consulting emergency units in all medical disciplines. Our aim was to analyze the demographics, referral mode, symptoms, localization of lesions, prior treatment, diagnoses and hospitalization rate of dermatological patients. PATIENT AND METHODS: The study was conducted as a prospective single center survey over six months in the dermatology unit of a university hospital in Germany. 1552 consultations were included with consecutive sampling. RESULTS: The study cohort had a mean age of 41 years and included 53 % females. Nearly half of the patients lived less than 10 kilometers from the study center. 72 % of patients referred themselves. The main symptoms were itching and occurrence of a rash; these symptoms had been present for more than a week on average. A general manifestation was present on the skin in most cases. 55 % of patients were seen by a dermatologist or a general practitioner before the consultation. Prior treatment had been received in 49 % of cases. Eight percent of patients were hospitalized. Eczema was the most common diagnosis, followed by urticaria and scabies. CONCLUSIONS: This study confirms that a considerable number of patients present with non-urgent diagnoses. Careful prescreening and sensitization of the population may be necessary to reverse this trend. PMID- 30417532 TI - Oligo-Urea with No Alkylene Unit Self-Assembles into Rod-Like Objects in Water. AB - Long and rigid objects formed by self-assembly in water are useful as templates or for their rheological or biological properties. They are usually obtained by combining hydrogen bonding and strong hydrophobic interactions brought by an alkyl or alkylene chain. A simple access to well-defined rod-like assemblies in water is reported based on a penta-urea sticker directly connected to poly(ethylene oxide) side chains. These assemblies are characterized by an average length of several hundreds of nanometers and a monodisperse radius (4.5 nm) resulting from a reduced lateral aggregation of the stickers. PMID- 30417533 TI - Occurrence of Melibiose-containing Glycosphingolipids in a Sample of a Sponge coral Association (Desmapsamma anchorata/Carijoa riisei). AB - In our research on biologically active compounds from Vietnamese marine invertebrates, rare melibiose-containing glycosphingolipids were found in a sample of a sponge-coral association (Desmapsamma anchorata/Carijoa riisei). Melibiosylceramides were analyzed as constituents of some multi-component RP-HPLC fractions, and the structures of fourteen new (1b, 3b, 4a - c, 6a - c, 8b, 9a, 9b, 10b, 11a, 11b) and five known (2b, 5a - c, 7b) natural compounds were elucidated using NMR, mass spectrometry, optical rotation, and chemical transformations. These alpha-D-Galp-(1->6)-beta-D-Glcp-(1<->1)-ceramides (presumably sponge-derived compounds) were shown to contain phytosphingosine-type n-t17:0 (1), 6E-n-t17:1 (2), i-t17:0 (3), n-t18:0 (4), 6E-n-t18:1 (5), i-t18:0 (6), 6E-i-t18:1 (7), i-t19:0 (8), 6E-i-t19:1 (9), ai-t19:0 (10), and 6E-ai-t19:1 (11) backbones N-acylated with saturated straight-chain (2R)-2-hydroxy C21 (a), C22 (b), and C23 (c) acids. Characteristic trends in the fragmentations of the terminal parts of tetraacetylated normal-chain and iso- and anteiso- branched sphingoid bases were observed using GC-MS. The total sum of melibiosylceramides and compound 5b caused a reduction in colony formation of human melanoma cells. PMID- 30417534 TI - Could a national oral health promotion program improve the oral hygiene of persons attending special care establishments in France? Evaluation of a pilot program. AB - This study aimed to investigate the effectiveness of an oral health promotion intervention implemented in special care establishments by dentists trained online. Twenty-six dentists intervening in 27 French special care establishments undertook a standardised oral health promotion intervention, including a conference presentation for care staff and hands-on toothbrushing workshops. Oral hygiene status of the residents was performed at baseline and at 6 months, and were compared using the McNemar test. Mixed logistic regression was performed to identify the factors associated with an improvement of dental plaque removal. The oral health intervention was completed by 890 residents: 445 children, 373 adults and 72 elderly adults. At baseline, dental plaque was observed for 79.8% of the 797 dentate residents. Among the 691 dentate residents included in the final analysis, dental plaque removal was improved for 34%. Improvement in dental plaque removal was recorded more often for the group of 13 to 20-year-old residents (OR = 1.97; 95% CI = 1.15-3.38). The results indicate that this programme failed to significantly improve the dental plaque removal of the residents. More research is needed to understand the limiting factors of such interventions. PMID- 30417535 TI - RNA interference of muscle actin and ATP synthase beta increases mortality of the phytoplasma vector Euscelidius variegatus. AB - BACKGROUND: RNA interference (RNAi) techniques have emerged as powerful tools to develop novel management strategies for the control of insect pests. The leafhopper Euscelidius variegatus is a natural vector of chrysanthemum yellows phytoplasma and a laboratory vector of flavescence doree phytoplasma. Phytoplasmas are insect-borne bacterial plant pathogens that cause economically relevant crop losses worldwide. RESULTS: In the present study, we demonstrated that microinjection of muscle actin and ATP synthase beta dsRNAs in adult insects caused an exponential reduction in the expression of both genes, which began within 72 hours from the dsRNA administration and lasted for 14 days, leading to almost complete silencing of the target genes. Such silencing effects on muscle actin expression appeared to be both time- and dose-dependent. Our results also showed that the knockdown of both genes caused a significant decrease in survival rates in comparison with GFP dsRNA-injected control insects. CONCLUSION: The effectiveness of RNAi-based gene silencing in E. variegatus guarantees the availability of a powerful reverse genetic tool for the functional annotation of its genes and the identification of those potentially involved in the interaction with phytoplasmas. In addition, this study demonstrated that muscle actin and ATP synthase beta may represent candidate genes for RNAi-based control of E. variegatus. This article is protected by copyright. All rights reserved. PMID- 30417537 TI - Corrigendum. PMID- 30417536 TI - Sublethal effects from endosulfan on parasitization by the parasitoid wasp Leptopilina boulardi and specificity of nervous pathways involved. AB - BACKGROUND: Endosulfan is a semi-permanent pollutant that can be transported long distances through the atmosphere. Although phased out in many countries, it is still used in some populated areas and thus largely contributes to environmental pollution. It can impact non-target species such as Leptopilina boulardi, a hymenopteran parasitoid that is a beneficial insect because it controls the populations of its host. Only one L. boulardi egg can successfully develop in its host, a Drosophila larva. As a consequence, parasitoid females generally lay only one egg per host, except when they are infected by a virus (LbFV) that triggers a superparasitization behavior (laying more than one egg per host). The effects of an LC20 of endosulfan on the parasitization behavior of two L. boulardi strains, one infected by LbFV and the other not, were evaluated. RESULTS: The insecticide decreased the number of host larvae parasitized by both strains (decreased rate of parasitization) but had no impact on the number of eggs laid per host (i.e., the rate of superparasitization) whether or not the strain was infected by LbFV. CONCLUSIONS: Recent research1 has shown that the organophosphorus insecticide chlorpyrifos induced superparasitization in parasitoid females. Both endosulfan and chlorpyrifos are neurotoxic and induce nervous system hyperstimulation. The fact that endosulfan does not trigger superparasitization whereas chlorpyrifos does suggests that this effect is due to the specific pathway impacted by chlorpyrifos, the cholinergic nervous pathway. The consequences of these results in the context of awareness of environmental pollution by pesticides are discussed. This article is protected by copyright. All rights reserved. PMID- 30417538 TI - Corrigendum. PMID- 30417539 TI - Molecular phenotype of kidney transplant indication biopsies with inflammation in scarred areas. AB - In kidney transplant biopsies, inflammation in areas of atrophy-fibrosis (i-IFTA) is associated with increased risk of failure, presumably because inflammation is evoked by recent parenchymal injury from rejection or other insults, but some cases also have rejection. The present study explored the frequency of rejection in i-IFTA, by histology Banff 2015 and microarray-based molecular diagnostic system (MMDx). In unselected indication biopsies (108 i-IFTA, 73 uninflamed IFTA (i0-IFTA), and 53 no IFTA), i-IFTA biopsies were later, more scarred, and had more antibody-mediated rejection (ABMR) by histology (28%) and MMDx (45%). T cell mediated rejection (TCMR) was infrequent in i-IFTA by histology (8%) and MMDx (16%). Twelve i-IFTA biopsies (11%) had molecular TCMR not diagnosed by histology, although six were called Borderline and almost all had histologic TCMR lesions. The prominent feature of i-IFTA biopsies was molecular injury e.g. AKI transcripts. In multivariate analysis of biopsies>1 year post-transplant, the strongest associations with graft loss were AKI transcripts and histologic atrophy-scarring; i-IFTA was not significant when molecular AKI was included. We conclude that i-IFTA in indication biopsies reflects recent/ongoing parenchymal injury, often with concomitant ABMR but few with TCMR. Thus application of Banff i-IFTA in the population of late biopsies needs to be reconsidered. This article is protected by copyright. All rights reserved. PMID- 30417540 TI - A Versatile Metalloporphyrinic Framework Platform for Highly Efficient Bioinspired, Photo- and Asymmetric Catalysis. AB - Even though numerous bioinspired catalysts have been developed, there remain huge gaps between the artificial and natural catalysts, because it is very difficult to imitate simultaneously the complicated constituents, structures, and synergistic effect of enzymes. We report herein a versatile metalloporphyrinic framework platform, which exhibits high efficiency in bioinspired catalysis, photocatalysis, and asymmetric catalysis. The catalytic properties are highly dependent on the tunable constituents and their cooperation, and are significantly superior to the corresponding molecular catalyst systems which lack the synergistic effects. Since there are numerous functional moieties that can readily be incorporated into the metalloporphyrinic framework platform, a myriad of applications can be simply realized by embedding different functional moieties. PMID- 30417541 TI - Periocular scar sarcoidosis. PMID- 30417542 TI - On the analysis of microrheological responses of self-assembling RADA16-I peptide hydrogel. AB - This work aims to obtain a hydrogel based on self-assembling RADA16-I with proper rheological properties for hemostasis application. Response surface methodology (RSM) was performed to predict the gelation and stiffness of the hydrogel in different concentrations of peptide and NaCl in water and blood serum milieus. Particle tracking microrheology technique was used to evaluate Brownian motion of polystyrene particles in the peptide solutions to obtain their trajectories and measure the viscoelastic properties (G'', G", and tan delta). Formation of gel was influenced by the concentrations of peptide and salt and their interactions. Optimum response for maximizing elastic modulus was obtained in the presence of blood serum in comparison with water. Negative effect of excess amount of NaCl was predicted by RSM model and confirmed by animal study. Circular dichroism (CD) analysis showed formation of beta-sheet secondary structure in water. On the other hand, in the presence of blood serum, tertiary structure was formed. Dimensional characterization of peptide fibers was performed by means of AFM. Peptide self-assembly in blood serum (pH around 7) which contains different ions, led to enhancing bonds between fibers, caused increasing the fiber diameter and length by 20 and 10 times, respectively. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A:, 2018. PMID- 30417543 TI - B-cell follicular lymphoma presenting as facial papules. PMID- 30417544 TI - Sleep efficiency and neurophysiological patterns in middle-aged men are associated with cognitive change over their adult life course. AB - Disrupted sleep is a contributing factor to cognitive ageing, while also being associated with neurodegenerative disorders. Little is known, however, about the relation of sleep and the gradual cognitive changes over the adult life course. Sleep electroencephalogram (EEG) patterns are potential markers of the cognitive progress. To test this hypothesis, we assessed sleep architecture and EEG of 167 men born in the Copenhagen Metropolitan Area in 1953, who, based on individual cognitive testing from early (~18 years) to late adulthood (~58 years), were divided into 85 subjects with negative and 82 with positive cognitive change over their adult life. Participants underwent standard polysomnography, including manual sleep scoring at age ~58 years. Features of sleep macrostructure were combined with a number of EEG features to distinguish between the two groups. EEG rhythmicity was assessed by spectral power analysis in frontal, central and occipital sites. Functional connectivity was measured by inter-hemispheric EEG coherence. Group differences were assessed by analysis of covariance (p < 0.05), including education and severity of depression as potential covariates. Subjects with cognitive decline exhibited lower sleep efficiency, reduced inter hemispheric connectivity during rapid eye movement (REM) sleep, and slower EEG rhythms during stage 2 non-REM sleep. Individually, none of these tendencies remained significant after multiple test correction; however, by combining them in a machine learning approach, the groups were separated with 72% accuracy (75% sensitivity, 67% specificity). Ongoing medical screenings are required to confirm the potential of sleep efficiency and sleep EEG patterns as signs of individual cognitive progress. PMID- 30417545 TI - Neutrophil-to-lymphocyte ratio, mean platelet volume and platelet-to-lymphocyte ratio in Behcet's disease and their correlation with disease activity: A meta analysis. AB - AIM: We aimed to evaluate the relationship between mean platelet volume (MPV), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and Behcet's disease (BD). METHODS: We searched Medline, Embase, and Cochrane databases, and performed a meta-analysis to compare MPV, NLR, and PLR between patients with BD and healthy controls, and to evaluate these parameters in BD according to disease activity and thrombosis. RESULTS: In total, 14 studies were included. MPV was not higher in the BD group than in the control group (standardized mean difference [SMD], 0163; 95% confidence interval [CI], -0.125 to 0.451; P = 0.268), while NLR was significantly higher in the BD group than in the control group (SMD, 1.176; 95% CI, 0.392-1.960, P = 0.003) and PLR showed a non-significant trend of association with BD (SMD, 0.441; 95% CI, -0.025 to 0.907, P = 0.063). MPV did not differ between patients with active and inactive BD (SMD, -0.129; 95% CI, -0.323 to 0.085, P = 0.191), and between patients with BD with and without thrombosis (SMD, 0.231; 95% CI, -0.155 to 0.617, P = 0.241). Conversely, NLR was significantly higher in patients with active BD than in those with inactive BD (SMD, 1.774; 95% CI, 0.179-3.368, P = 0.029), but not significantly higher in patients with BD with thrombosis than in those without thrombosis (SMD, 0.258; 95% CI, -0.277 to 0.792, P = 0.345). CONCLUSIONS: This finding suggests that NLR may be a potential index to evaluate the disease activity of BD, although there are limitations of small number of studies and heterogeneity of individual characteristics. PMID- 30417546 TI - Cellular Composition and Proliferation Levels in the Hematopoietic Tissue of Black Scorpionfish (Scorpaena porcus L.) Head Kidney and Spleen During the Spawning and Wintering Periods. AB - To identify cells and analyze proliferative activity of hematopoietic tissue, black scorpionfish head kidney and spleen cells were characterized by light microscopy and flow cytometry. Hematopoiesis of black scorpionfish head kidney was formed by the following series: erythropoietic, granulopoietic, lymphopoietic, and thrombopoietic. Flow cytometric analysis allowed dividing blood cells in hematopoietic organs into subpopulations differing by size, granularity, and proliferative activity. Three distinct subpopulations were observed during the wintering period. The number of small low-granulated cells, identified as lymphocytes and thrombocytes, was 41% +/- 4% in both wintering and spawning fish. Proliferating subpopulation of blast (high-granulated) cells amounted to about 36% of the total cell count with 50% +/- 5% of proliferating cells; the largest low-granulated cells (10% of total cells) comprised maturing white blood cells, monocytes, and macrophages. The spawning period was accompanied with an increase of maturing neutrophils and enhancement of blast cell proliferation. In the spleen three distinct subpopulations were observed. The subpopulation of small low-granulated cells comprised lymphocytes and thrombocytes similar to the head kidney and amounted 33% +/- 4%. Other cells with larger diameter were identified as red blood cells. No proliferation was observed during the wintering period in the spleen, however, spawning induced cell proliferation of erythroblasts (small granulated cells) with the number of dividing cells 84% +/- 1%. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30417547 TI - Ecto-5'-nucleotidase (CD73) is a potential target of hepatocellular carcinoma. AB - High expression of ecto-5'-nucleotidase (CD73) has been reported in a number of epithelium origin malignancies. Here, we hypothesize that CD73 promotes hepatocellular carcinoma (HCC) growth and metastasis and that the effect is mediated by epithelial growth factor receptor (EGFR). HCC cells with different malignancies and Tissue microarrays of the tumor and peritumoral liver tissues from 30 independent patients were used to examine CD73 and EGFR expression. Then, MTT and Ki67 detection, together with cell adhesion, invasion, and migration assays were used to evaluate the effects of CD73 on cell growth and metastasis. The expression of EGFR in HCC cells was also tested after suppressing or overexpressing CD73. Lastly, tumor tissues from nude mice, which had been injected subcutaneously with HCC cells, were transplanted subcutaneously into CD73-/- and wild-type (WT) C57 mice. CD73 expression was higher in HCC cells with greater metastatic potentials and tumor tissues compared with low metastatic cells and peritumor tissues. CD73 and EGFR were coexpressed and positively correlated in tumor and peritumor liver tissues in HCC tissue microarrays. Up regulationof CD73 by plasmid transfection or by pharmacological agents promoted EGFR expression in HCC cells, whereas suppression of CD73 inhibited these effects. The growth of transplanted tumor tissues was dramatically slower in CD73 /- mice than in WT type mice in the in vivo experiments. CD73 promotes HCC growth and metastasis and upregulated the expression of EGFR in HCC. Thus, CD73 and EGFR are potential targets in the treatment of HCC. PMID- 30417548 TI - Social skills training shows comparable effectiveness with other interventions, including medications, for reducing negative symptoms in people with psychotic disorders. PMID- 30417549 TI - Mechanically stimulated osteocytes reduce the bone-metastatic potential of breast cancer cells in vitro by signaling through endothelial cells. AB - Bone metastases occur in 65% to 75% of patients with advanced breast cancer and significantly worsen their survival and quality of life. We previously showed that conditioned medium (CM) from osteocytes stimulated with oscillatory fluid flow, mimicking bone mechanical loading during routine physical activities, reduced the transendothelial migration of breast cancer cells. Endothelial cells are situated at an ideal location to mediate signals between osteocytes in the bone matrix and metastasizing cancer cells in the blood vessels. In this study, we investigated the specific effects of flow-stimulated osteocytes on the interaction between endothelial cells and breast cancer cells in vitro. We observed that CM from flow-stimulated osteocytes reduced endothelial permeability by 15% and breast cancer cell adhesion onto endothelial monolayers by 18%. The difference in adhesion was abolished with anti-intercellular adhesion molecule 1 (ICAM-1) neutralizing antibodies. Furthermore, CM from endothelial cells conditioned in CM from flow-stimulated osteocytes significantly altered the gene expression in bone-metastatic breast cancer cells, as shown by RNA sequencing. Specifically, breast cancer cell expression of matrix metallopeptidase 9 (MMP-9) was downregulated by 62%, and frizzled-4 (FZD4) by 61%, when the osteocytes were stimulated with flow. The invasion of these breast cancer cells across Matrigel was also reduced by 47%, and this difference was abolished by MMP-9 inhibitors. In conclusion, we demonstrated that flow-stimulated osteocytes downregulate the bone-metastatic potential of breast cancer cells by signaling through endothelial cells. This provides insights into the capability of bone mechanical regulation in preventing bone metastases; and may assist in prescribing exercise or bone loading regimens to patients with breast cancers. PMID- 30417551 TI - Shared neural and cognitive mechanisms in action and language: The multiscale information transfer framework. AB - This review compares how humans process action and language sequences produced by other humans. On the one hand, we identify commonalities between action and language processing in terms of cognitive mechanisms (e.g., perceptual segmentation, predictive processing, integration across multiple temporal scales), neural resources (e.g., the left inferior frontal cortex), and processing algorithms (e.g., comprehension based on changes in signal entropy). On the other hand, drawing on sign language with its particularly strong motor component, we also highlight what differentiates (both oral and signed) linguistic communication from nonlinguistic action sequences. We propose the multiscale information transfer framework (MSIT) as a way of integrating these insights and highlight directions into which future empirical research inspired by the MSIT framework might fruitfully evolve. This article is categorized under: Psychology > Language Linguistics > Language in Mind and Brain Psychology > Motor Skill and Performance Psychology > Prediction. PMID- 30417550 TI - Investigating the temporal and spatial distribution of foot-and-mouth disease virus serotype C in the Region of South America, 1968-2016. AB - This study investigates the historical temporal trend and geographical distribution of the foot-and-mouth disease virus (FMDv) serotype C in South America; discussing the findings within the context of the actions and strategies carried out for the elimination of foot-and-mouth disease (FMD). This is the first time that such a comprehensive historical compilation has been carried out in the Region; hence, the study is intended as a reference and source of evidence about the presence/absence of FMDv serotype C in South America. Data on the occurrence of FMD were sourced from the Weekly Epidemiological Reports submitted by the countries to Pan American Foot-and-Mouth Disease Center (PANAFTOSA PAHO/WHO) since 1972, and complemented with other sources of information from the 1968-1971 period. The temporal distribution was examined with local weighted regression (LOESS) to identify two temporal trends, that is, "smoothed" and "over adjusted", utilising the time-series with the total number of cases per year, at Regional level. Thereafter the outbreaks were aggregated by decades and mapped by the first subnational administrative level. As a result, two major peaks of occurrence were identified, one in the 70s, with up to 1,193 outbreaks, and another in the 80s, with 380. Overall, the investigations show a clear regressive trend in the occurrence of serotype C, with a reduction in the number of outbreaks over-time, and with the subsequent reduction of affected locations. This study illustrates the contrast between the very limited presence over the last 20 years - with only one event in 2004 - and the epidemic situation in the 1970s and 1980s, and suggests that serotype C of FMDv is no longer present in the Region. PMID- 30417552 TI - Second-generation antipsychotic long-acting injections in bipolar disorder: Systematic review and meta-analysis. AB - BACKGROUND: Non-adherence is a significant problem in bipolar disorder. Second generation antipsychotics (SGA) long-acting injections (LAIs) may improve adherence in bipolar disorder and may prevent relapses. However, the evidence is limited and conflicting. OBJECTIVE: The objective of this study was to evaluate efficacy and safety of SGA LAIs in bipolar disorder. METHOD: Systematic review and meta-analysis of randomised controlled trials (RCTs) (>=6 months duration) investigating safety and efficacy of SGA LAIs for bipolar disorder. We searched Pubmed, Embase, CINAHL, Cochrane, PsycINFO, LiLACS, www.clinicaltrials.gov up to October 2016. We also contacted the manufacturers of SGA LAIs. Primary efficacy and safety outcomes were relapse rate and all-cause discontinuation respectively. RESULTS: Total of seven RCTs (n = 1192) were included. SGA LAIs show superiority over placebo for study-defined relapse rate (RR = 0.58, 95% CI = 0.49-0.68, P < 0.00001) and all-cause discontinuation (RR = 0.72, 95% CI = 0.64-0.82, P < 0.00001). However, no significant difference was found between SGA LAIs and oral active control for relapse rate (RR = 0.92, P = 0.79) and all-cause discontinuation (RR = 1.2, P = 0.31). In terms of secondary outcomes, SGA LAIs performed better than placebo in relapse to mania/hypomania, young mania rating scales (YMRS), clinical global impression-severity (CGI-S), montgomery-asberg depression rating scale (MADRS). There was no significant difference between SGA LAIs and oral active control regarding relapse to mania/hypomania, YMRS, CGI-S, extra-pyramidal side effects (EPSEs), weight gain. However, the active control performed better than SGA LAIs in relapse to depression, MADRS, and prolactin related AEs. CONCLUSIONS: Current evidence is very limited to support the use of SGA LAIs (compared to oral medication) in bipolar disorder. Further high-quality studies, particularly comparing SGA LAIs with active control, are warranted. PMID- 30417553 TI - Long noncoding RNA MEG3 inhibits proliferation and migration but induces autophagy by regulation of Sirt7 and PI3K/AKT/mTOR pathway in glioma cells. AB - Glioma is a common primary brain tumor with high mortality rate and poor prognosis. Long noncoding RNA maternally expressed gene 3 (MEG3) is a tumor suppressor in diverse cancer types. However, the role of MEG3 in glioma remains unclear. We aimed to explore the effects of MEG3 on U251 cells as well as the underlying mechanisms. U251 cells were stably transfected with different recombined plasmids to overexpress or silence MEG3. Effects of aberrantly expressed MEG3 on cell viability, migration, apoptosis, expressions of apoptosis associated and autophagy-associated proteins, and phosphorylated levels of key kinases in the PI3K/AKT/mTOR pathway were all evaluated. Then, messenger RNA (mRNA) and protein expression of Sirt7 in cells abnormally expressing MEG3 were estimated. In addition, effects of abnormally expressed MEG3 and Sirt7 on U251 cells were determined to reveal the underlying mechanism of MEG3-associated modulation. Cell viability and migration were significantly reduced by MEG3 overexpression whereas cell apoptosis as well as Bax and cleaved caspase-3/-9 proteins were obviously induced. Beclin-1 and LC3-II/LC3-I were upregulated and p62 was downregulated in MEG3 overexpressed cells. In addition, the autophagy pharmacological inhibitor (3-methyladenine, 3-MA) affected the effect of MEG3 overexpression on cell proliferation. Furthermore, the phosphorylated levels of key kinases in the PI3K/AKT/mTOR pathway were all reduced by MEG3 overexpression. Sirt7 was positively regulated by MEG3 expression, and effects of MEG3 overexpression on U251 cells were ameliorated by Sirt7 silence. MEG3 suppressed cell proliferation and migration but promoted autophagy in U251 cells through positively regulating Sirt7, involving in the inhibition of the PI3K/AKT/mTOR pathway. PMID- 30417554 TI - What do undergraduate doctors really need to know about radiation oncology? PMID- 30417555 TI - Impact of knowledge, attitude and preceptor behaviour in pharmacovigilance education. AB - This study aimed to determine the level of pharmacovigilance (PV) education in pharmacy programs and to evaluate the predictive factors for the intent to report adverse drug reactions (ADRs) by pharmacy students in South Korea. Self administered questionnaires were collected from a regionally stratified nationwide convenience sample of pharmacy students in September 2017. The association between students' intent to report ADRs and their knowledge and attitude was evaluated by using multivariate logistic regression analysis. In total, 303 pharmacy students participated in the survey; the average age of students was 26.7 (standard deviation 2.9) years and 40.6% were males. Eighty eight students (29%) marked the degree of their intent as "strongly high." Increased knowledge of ADR reporting methods and positive attitude towards the need for ADR reporting were significant predictors of the intent to report ADRs. Further, witnessing reporting by the preceptor (adjusted odds ratio, 2.37; 95% confidence interval, 1.26-4.46; p < 0.01) was significantly correlated with the knowledge on and attitude towards ADR reporting of pharmacy students. The findings of our study indicated the need for improvements in PV curriculum, such as educational content focused on ADR reporting methods and demonstration of a preceptor's reporting in pharmacy practice experiential rotation, within Korean college of pharmacy curriculum. This article is protected by copyright. All rights reserved. PMID- 30417556 TI - A streamlined pathway for patients with unilateral tinnitus: our experience of 22 patients. AB - OBJECTIVES: Unilateral tinnitus must be investigated with an IAM MRI to rule out a rare but important finding of a cerebello-pontine angle lesion. A streamlined pathway was designed to uniquely enable GPs to make direct and concurrent referrals for an IAM MRI alongside an audiology-led one-stop tinnitus clinic. The primary aim was evaluating the efficacy of the streamlined pathway. The secondary aim was to identify defect measures and associated costs. Design A prospective, experimental non-randomised control study with retrospective controls was used. Setting Participants were selected from those presenting to the local NHS trust. PARTICIPANTS: There were 22 adult unilateral tinnitus patients in each of the experimental and control arms, presenting with no red flag or other otological signs/ symptoms or obvious treatable cause for their tinnitus. Main outcome measures Primary endpoints were referral to treatment times, number of patient healthcare visits, number of pathway steps, hand-off and lead time. Defect measures were ascertained to determine deviation from the intended pathway. The average cost of the new and old pathway were calculated. RESULTS: The streamlined pathway demonstrated a statistically significant reduction in referral received to treatment, number of patient healthcare visits, number of pathway steps, hand off and lead time. 50% of patients seen on the new pathway were redirected from other referrals, 18.2% lacked corresponding IAM MRI request and 54.5% of patients required additional ENT input. The streamlined pathway saved L80 per patient with unilateral tinnitus. CONCLUSIONS: The streamlined unilateral tinnitus patient pathway confers significant benefits to patients, the NHS and wider health economy. Future research should focus on the challenge of scaling and sustaining innovation. This article is protected by copyright. All rights reserved. PMID- 30417557 TI - Outbreak of Mycoplasmal Round Pneumonia in an Adult Population: a Case Series. AB - BACKGROUND: Mycoplasmal pneumonia is a common type of adult community-acquired pneumonia in China, but round/spherical pneumonia caused by mycoplasma pneumoniae has rarely been reported. Here we report an outbreak of mycoplasmal round pneumonia in a military dormitory in China. METHODS: We analysed epidemiological, clinical, imaging and laboratory data from a series of adults affected by an outbreak of mycoplasmal round pneumonia in the dormitory of a military hospital (Fuzhou General Hospital) in Fuzhou, China. The dormitory included 2 separate buildings. Mycoplasma antibody was detected using a passive agglutination assay. RESULTS: The first case in our series, a 23-year-old male intern, presented on July 16, 2015 with a 3-day history of low-grade fever, dizziness, fatigue and chest tightness. Chest computed tomography revealed spherical masses. Over the following four days, 11 individuals who had been in close contact with the first patient were found to have similar masses. All 12 cases were mildly symptomatic or asymptomatic, and fever was the only sign visible upon physical examination. Chest radiology revealed single, round consolidations in 3 cases and multiple round consolidations in 9 cases; consolidations ranged in size from 0.2 to 2.9 cm. Most cases had normal blood cell count, erythrocyte sedimentation rate and C reactive protein level. Nasopharyngeal swabs from all cases tested negative for 25 pathogens, including M. pneumoniae, in a PCR-based assay performed on August 1, 2015. All 12 patients showed a 4-fold increase in the titre of anti mycoplasmal pneumonia antibody in paired sera on August 13, 2015. Patients were given the antibiotic moxifloxacin or symptomatic treatment, and 11 of the 12 cases showed complete resolution of round pneumonia lesions within 4 weeks. CONCLUSION: This case series illustrates the diversity of clinical manifestations as well as imaging findings for mycoplasmal pneumonia, to which clinicians should pay more attention. Mycoplasmal round pneumonia should be included in differential diagnosis of multiple pulmonary nodules in adults in order to enable accurate clinical identification of disease and successful treatment and resolution. This article is protected by copyright. All rights reserved. PMID- 30417558 TI - General Nondestructive Passivation by 4-Fluoroaniline for Perovskite Solar Cells with Improved Performance and Stability. AB - Hybrid perovskite thin films are prone to producing surface vacancies during the film formation, which degrade the stability and photovoltaic performance. Passivation via post-treatment can heal these defects, but present methods are slightly destructive to the bulk of 3D perovskite due to the solvent effect, which hinders fabrication reproducibility. Herein, nondestructive surface/interface passivation using 4-fluoroaniline (FAL) is established. FAL is not only an effective antisolvent candidate for surface modification, but also a large dipole molecule (2.84 Debye) with directional field for charge separation. Density functional theory calculation reveals that the nondestructive properties are attributed to both the conjugated amine in aromatic ring and the para-fluoro substituent. A hot vapor assisted colloidal process is employed for the post treatment. The molecular passivation yields an ultrathin protection layer with a hydrophobic fluoro-substituent tail and thus enhances the stability and optoelectronic properties. FAL post-treated perovskite solar cell (PSC) delivers a 20.48% power conversion efficiency under ambient conditions. Micro photoluminescence reveals that passivation activates the dark defective state at the surface and interface, delivering the impact picture of boundary on the local carriers. This work demonstrates a generic nondestructive chemical approach for improving the performance and stability of PSCs. PMID- 30417559 TI - BrdU incorporation in multiparameter flow cytometry: A new cell cycle assessment approach in multiple myeloma. AB - BACKGROUND: Mutiple myeloma (MM) is a neoplasia characterized by the accumulation of malignant plasma cells (PC) in the bone marrow. Although proliferation markers have been studied in MM, none of the current staging systems include them. Moreover, approaches used to analyze proliferation do not separate MM cells (MMCs) from normal PC. METHODS: In this study, we combined multiparameter flow cytometry and BrdU incorporation or Ki67 staining to analyze MM cell proliferation in 44 monoclonal gammopathy of undetermined significance (MGUS), 153 newly diagnosed MM patients and 69 MM patients at relapse. The prognostic value of proliferation assessment was analyzed in 60 newly diagnosed patients treated with high-dose chemotherapy supported by autologous hematopoietic stem cell transplantation. RESULTS: The median number of proliferating malignant PC significantly increases during MM disease progression. MM patients with a percentage of proliferating MMCs greater than 1.42% using BrdU/DAPI or greater than 1.1% using ki67/DAPI, are associated with a significantly shorter event free survival compared with patients with a lower percentage of proliferating MMCs. CONCLUSIONS: Combination of flow cytometry with BrdU or ki67/DAPI staining could become a standard for the determination of MM cell proliferation. Furthermore, in the context of new effective myeloma treatment options, assessment of MM cell proliferation may be valuable, in clinical trials, to identify novel agents that could significantly affect the small proliferative compartment of MM cells. (c) 2018 International Clinical Cytometry Society. PMID- 30417560 TI - 2018 update on dermatologic laser therapy: Part 1 - epilation, vascular lesions and pigments. AB - Technical advances in recent years have led to new dermatologic laser systems, light sources, and treatment concepts. Commonly used wavelengths - generated today with LED-based devices - allow for the combination of various tissue effects and are associated with improved outcomes. Laser hair removal has become more efficient with the use of diode lasers that emit multiple wavelengths simultaneously. In the near future, novel LED-based lasers will also be introduced for the treatment of vascular lesions. Here, too, the combination of different wavelengths promises to be beneficial. Picosecond lasers have led to advances in the field of pigment removal (tattoos). PMID- 30417561 TI - Recent Advances in the Design and Development of Non-nucleoside Reverse Transcriptase Inhibitor Scaffolds. AB - Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have always been an important part of the anti-HIV-1 combination therapy known as combination antiretroviral therapy (cART) since 1996. The use of NNRTIs for about 22 years has led to some mutations in the residues that compose the reverse transcriptase active site, resulting in the emergence of drug-resistant viruses. Thus, the search for new potent NNRTIs with an improved safety profile and activity against drug-resistant HIV strains is indispensable, and many hit and lead NNRTIs have been discovered in the last decade. This review provides an overview of the development in this field from 2013 to August 2018. PMID- 30417562 TI - Tomato Tolerance and Pest Control Following Fumigation with Different Ratios of Dimethyl Disulfide and Chloropicrin. AB - BACKGROUND: The phaseout of methyl bromide (MeBr) continues to stimulate research into the use of other soil fumigants for controlling soilborne diseases and weeds. This research evaluated tomato (Solanum lycopersicum L.) tolerance, weed emergence and the recovery of Fusarium oxysporum f. sp. lycopersici (FOL) inoculum following fumigation with various combination ratios of dimethyl disulfide plus chloropicrin (DMDS + Pic). RESULTS: DMDS on its own did not effectively control purple nutsedge (Cyperus rotundus L.) as compared to DMDS + Pic. Control of C. rotundus and fusarium wilt increased with Pic based on weed emergence throughout the growing season and FOL inoculum recovery from soil. In all three growing seasons, 159 kg ha-1 DMDS + 379 kg ha-1 Pic provided season long control of C. rotundus. CONCLUSION: This research confirms that formulating DMDS + Pic containing a high percentage of Pic offers an effective alternative to MeBr for tomato production. This article is protected by copyright. All rights reserved. PMID- 30417563 TI - Comparison of urinary cytology and fluorescence in situ hybridization in the detection of urothelial neoplasia: An analysis of discordant results. AB - BACKGROUND: We examine the performance of cytology and FISH in the detection of urothelial carcinoma (UC), and explore the reasons for discrepant results, and potential clinical implications. METHODS: Urine samples from 89 patients were prospectively collected for simultaneous cytology and UroVysion FISH, and results correlated with concurrent biopsies and/or clinical or histologic follow-up data. Corresponding tissue biopsies, where available, were also evaluated by FISH. RESULTS: Sensitivity and specificity of cytology and FISH for the detection of UC was 54.8% and 92% and 50% and 88%, respectively. Only one of seven false-positive urinary FISH results proved to be an "anticipatory positive" on extended follow up. Five of eight (62.5%) high grade (HG) carcinomas with false-negative urinary FISH, were negative due to the absence/paucity of FISH-detectable changes in the tumor cells. In atypical cytology cases, the FISH result did not assist in identifying UC. There was no significant difference between an atypical cytology result and a positive FISH result, with respect to the identification of patients with UC. CONCLUSIONS: We found urinary cytology to be more sensitivity and specific than FISH in the detection of UC, though the difference was not statistically significant. Up to 24% of HG UCs are FISH negative due to an absence of FISH-detectable abnormalities in the tumor cells. Paucity of neoplastic cells in the urine also contributes to false-negative FISH results in both HG and low grade tumors. Negative urinary FISH cannot be taken alone as indicating the absence of significant disease in patients with atypical cytology. PMID- 30417564 TI - Reduced carbon use efficiency and increased microbial turnover with soil warming. AB - Global soil carbon (C) stocks are expected to decline with warming, and changes in microbial processes are key to this projection. However, warming responses of critical microbial parameters such as carbon use efficiency (CUE) and biomass turnover (rB) are not well understood. Here, we determine these parameters using a probabilistic inversion approach that integrates a microbial-enzyme model with 22 years of carbon cycling measurements at Harvard Forest. We find that increasing temperature reduces CUE but increases rB, and that two decades of soil warming increases the temperature sensitivities of CUE and rB. These temperature sensitivities, which are derived from decades-long field observations, contrast with values obtained from short-term laboratory experiments. We also show that long-term soil C flux and pool changes in response to warming are more dependent on the temperature sensitivity of CUE than that of rB. Using the inversion derived parameters, we project that chronic soil warming at Harvard Forest over six decades will result in soil C gain of <1.0% on average (1st and 3rd quartiles: 3.0% loss and 10.5% gain) in the surface mineral horizon. Our results demonstrate that estimates of temperature sensitivity of microbial CUE and rB can be obtained and evaluated rigorously by integrating multi-decadal datasets. This approach can potentially be applied in broader spatiotemporal scales to improve long-term projections of soil C feedbacks to climate warming. This article is protected by copyright. All rights reserved. PMID- 30417565 TI - Hypermethylated in cancer 1 (HIC1) suppresses bladder cancer progression by targeting yes-associated protein (YAP) pathway. AB - OBJECTIVES: Bladder cancer (BCa) is the most common malignant tumor in the urinary system. Growing evidence suggests that as a tumor suppressor gene, hypermethylated in cancer 1 (HIC1) is correlated with various malignancies in the modulation of tumor progression. This study aims to investigate the effect of HIC1 on regulating the proliferation, migration, and invasion of BCa. METHODS: Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot (WB) were used to evaluate the expression of HIC1 messenger RNA and protein in human BCa tissues and cells. Proliferation, migration and invasion assays, and flow cytometry assay were performed to assess the biological functional role of HIC1 in BCa. Co-immunoprecipitation (Co-IP) examined the protein-protein interaction. The signaling pathways involved in the mode of action of HIC1 in BCa were also investigated. RESULTS: HIC1 was found downregulated in tested samples. Cloning formation assay and cell-proliferation activity analysis showed that overexpression of HIC1 significantly inhibited the proliferation of BCa cells, while knockdown led to the opposite, namely the promotion of the proliferation. Flow cytometry assay confirmed the arrest of the cell cycle at the G1 phase with overexpression of HIC1 observed. Moreover, HIC1 inhibited migration and invasion of BCa. Co-IP showed the binding between YAP (yes-associated protein) and TEAD (TEA domain/transcription enhancer factor family members) as well as the cancerostatic activity of HIC1, partially manifested via its negative regulation of YAP signaling pathway. CONCLUSIONS: Our data unprecedently showed that HIC1 was responsible for the inhibition of proliferation, migration, and invasion of BCa via the YAP signaling pathway. These findings suggested that therapeutic strategies regulating HIC1 expression might provide effective treatments for BCa. PMID- 30417566 TI - Comparative volatile compounds and primary metabolites profiling of pitaya fruit peel after ozone treatment. AB - BACKGROUND: Ozone treatment can effectively inhibit fruit decay in many fruits during postharvest storage. However, little information was available for pitaya fruit. RESULTS: Ozone treatment significantly reduced decay rate, and induced enzyme activities of peroxidase and polyphenol oxidase, reduced the levels of reactive oxygen species. A total of 103 metabolites were detected and changed the content after ozone treatment, including 54 primary metabolites and 49 aromatic compounds. After significance and importance analysis, 37 metabolites were important. Some metabolites were induced by peel senescence to response to senescence stress, including D-fructose, D-glucose, mannose, inositol, galactonic acid, ethanedioic acid and stearic acid. Some metabolic products of peel senescence were reduced by ozone treatment, including D-arabinose, glucaric acid, galacturonic acid, 1-hexanol, 4-ethylcyclohexanol, beta-linalool, palmitoleic acid and 2-hydroxy-cyclopentadecanone. Some metabolites induced by ozone treatment might play a vital role in delaying the senescence and decay, mainly including malic acid, succinic acid, pentenoic acid, eicosanoic acid, 2-hexenal, hexanal, 2-heptenal, 4-heptenal, 2-octenal and nitro m-xylene. CONCLUSION: Ozone treatment significantly reduced decay and prolonged shelf-life without reducing fruit quality. A total of 37 metabolites might play important role in ozone delayed fruit decay. This article is protected by copyright. All rights reserved. PMID- 30417567 TI - Atherosclerosis as a predictor of transient exacerbation of overactive bladder symptoms after robot-assisted laparoscopic radical prostatectomy. AB - OBJECTIVES: To assess whether atherosclerosis is involved in the development of overactive bladder and the function of lower urinary tract after robot-assisted radical prostatectomy. METHODS: The present cohort consisted of 80 consecutive participants. The preoperative cardio-ankle vascular index was used to evaluate the presence of atherosclerosis. The present cohort was split into two groups, the atherosclerotic group, whose cardio-ankle vascular index was >=9.0, and the control group, whose index was <9.0. The overactive bladder symptom score and lower urinary tract function were compared for 12 months after surgery. RESULTS: The total score of the questionnaire was significantly higher at 6 and 9 months after surgery in the atherosclerosis group (P = 0.04, P = 0.03, respectively). Both the urgency and urgency incontinence subscores of the questionnaire showed a parallel tendency to that of the total score after surgery. At 3 months after surgery, there was a significant increase in the prevalence of de novo overactive bladder in the atherosclerosis group (P = 0.04). At 9 and 12 months after surgery, there was a significant decrease of voided volume in the atherosclerotic group (P < 0.01, P = 0.04, respectively). CONCLUSIONS: Atherosclerosis delays the improvement in both overactive bladder symptoms and storage function postoperatively, and it is involved in the transient increase in the prevalence of de novo overactive bladder. Atherosclerosis might be a predictor of the development of overactive bladder after robot-assisted radical prostatectomy. PMID- 30417568 TI - Revisiting the Origin of Bacterial Bioluminescence: QM/MM Study on Oxygenation Reaction of Reduced Flavin in Protein. AB - Bacterial bioluminescence is initiated by the oxygenation reaction of reduced flavin mononucleotide in luciferase. This enzymatic oxygenation occurs in a wide range of biological processes including cellular redox metabolism, biocatalysis, biosynthesis and homeostasis. However, little is known about the mechanism of the enzymatic reaction between singlet reduced flavin and triplet oxygen. To explore the enigmatic oxygenation, for the first time, the reaction of reduced flavin anion with oxygen was studied in bacterial luciferase by a combined quantum mechanics and molecular mechanics method as well as molecular dynamics simulation. The calculated results demonstrate that the reaction proceeds via a proton-coupled electron transfer (PCET) pathway, and the essential alphaHis44 acts as a catalytic acid to provide the proton. The currently proposed PCET mechanism clearly describes the initial steps of bacterial bioluminescence, and could be suitable for the other flavin oxygenation reactions in enzymes. PMID- 30417569 TI - A critical appraisal of the Milan system for reporting salivary gland cytology (MSRSGC) with histological correlation over a 3-year period: Indian scenario. AB - BACKGROUND: Fine needle aspiration cytology (FNAC) is the first line investigation for pre-operative diagnosis of salivary gland lesions, but due to its inherent limitations remains a challenge for the cytopathologists. The recently proposed international risk stratification scheme, the Milan System for Reporting Salivary Gland Cytology (MSRSGC) aims to promote and standardise the communication between cytopathologist and clinician thereby improving patient care. METHODS: A retrospective study of all salivary gland cytology cases was performed over a 3-year period, reviewed by pathologists and categorised into 1 of the 6 diagnostic categories according to MSRSGC, namely, non-diagnostic, non neoplastic, atypia of undetermined significance (AUS), benign neoplasm, and salivary gland neoplasm of undetermined significance (SUMP), suspicious for malignancy (SFM), and malignant neoplasm. Cyto- histological correlation was done wherever possible. Risk of malignancy (ROM) was calculated for each diagnostic category. RESULTS: Out of a total of 150 salivary FNAC cases, histopathology was available for 64 cases. The sensitivity of FNAC was 81.8%, specificity was 100% while the diagnostic accuracy was 96.9%. The positive and negative predictive values were 100% and 96.4% respectively. The ROM for non-diagnostic, non neoplastic, AUS, benign neoplasm, SUMP, SFM, and malignant categories were 0%, 10%, 50%, 2.5%, 50%, 100%, and 100% respectively. CONCLUSION: MSRSGC fulfils the critical need for a uniform, internationally acceptable reporting system with ROM specified for each category. However, large scale multi centre studies need to be conducted before its reliability and validity is proven. PMID- 30417570 TI - Molecular design, Circularly Polarized and Helical Self-Assembly of Chiral Aggregation Induced Emission Molecules. AB - Aggregation-induced emission luminogens (AIEgens) are a new class of luminophors, which are non-emissive in solutions, but emit intensively upon aggregation. By properly designing the chemical structures of the AIEgens, their aggregation process can be tuned towards desired direction to give the diverse novel luminescent architectures of micelles, rods and helical fibers. The AIEgens represent a kind of promising building blocks for the fabrication of luminescent micro/nanostructures with controllable morphologies. In this review, we describe our recent work in this research area, focusing on the molecular design, circularly polarized luminescence properties, and helical self-assembly behaviors of AIEgens. PMID- 30417571 TI - Whole-mount in situ hybridization of mouse brain to precisely locate mRNAs via fluorescence tomography. AB - Nucleic acids of intact biological tissues are rich in biological information. Whole-mount in situ hybridization is a powerful technique to mine the wealth of data contained in DNAs or RNAs, especially mRNAs. However, there are no simple, rapid approaches to precisely locate mRNAs in whole-mount tissues such as intact brains. By combining the penetration procedures of iDISCO with the signal amplification approach termed hybridization chain reaction, we herein developed a method for whole-brain in situ hybridization at cellular resolution. Based on fluorescence tomography instead of tissue clearing, this method provides a simple, rapid way to precisely locate mRNAs in the whole brain with cytoarchitectonic landmarks. As a proof of principle, we investigated the exact distribution of Cre mRNA in a Thy1-Cre mouse brain. We found high levels of Cre mRNA in most regions of the subcortical nuclei and the brain stem but comparatively low levels in major areas of the cerebral cortex. This method may have broad applications in studies of RNA function and its relations with diseases. This article is protected by copyright. All rights reserved. PMID- 30417572 TI - Morbidity and mortality conferences as medical student learning tools. PMID- 30417574 TI - Dynamic genome and transcriptional network-based biomarkers and drugs: precision in breast cancer therapy. AB - Despite remarkable progress in medium-term overall survival benefit in the adjuvant, neoadjuvant and metastatic settings, with multiple recent targeted drug approvals, acquired resistance, late relapse, and cancer-related death rates remain challenging. Integrated technological systems have been developed to overcome these unmet needs. The characterization of structural and functional noncoding genome elements through next-generation sequencing (NGS) systems, Hi-C and CRISPR/Cas9, as well as computational models, allows for whole genome and transcriptome analysis. Rapid progress in large-scale single-biopsy genome analysis has identified several novel breast cancer driver genes and oncotargets. The exploration of spatiotemporal tumor evolution has returned exciting while inconclusive data on dynamic intratumor heterogeneity (ITH) through multiregional NGS and single-cell DNA/RNA sequencing and circulating genomic subclones (cGSs) by serial circulating cell-free DNA NGS to predict and overcome intrinsic and acquired therapeutic resistance. This review discusses reliable breast cancer genome analysis data and focuses on two major crucial perspectives. The validation of ITH, cGSs, and intrapatient genetic/genomic heterogeneity as predictive biomarkers, as well as the valid discovery of novel oncotargets within patient-centric genomic trials, encouraging early drug development, could optimize primary and secondary therapeutic decision-making. A longer-term goal is to identify the individualized landscape of both coding and noncoding key mutations. This progress will enable the understanding of molecular mechanisms perturbating regulatory networks, shaping the pharmaceutical controllability of deregulated transcriptional biocircuits. PMID- 30417573 TI - Preparative separation of four isomers of synthetic anisodamine by HPLC and diastereomer crystallization. AB - Anisodamine (654-1), a well-known cholinergic antagonist, is marketed as synthetic anisodamine (mixture of four isomers, 654-2) in China. To preparative resolution and comparison of the bioactivities of the four isomers of synthetic anisodamine, current work explores an economic and effective separation method by using preparative high performance liquid chromatography (HPLC) and diastereomer crystallization. Their absolute configurations were established by single-crystal X-ray diffraction and circular dichroism method. The purities of each isomer were more than 95%. Among them, 654-2-A2 (6R, 2'S configuration) exhibited better effect on cabachol preconditioned small intestine tension more than 654-2 and other isomers. The direct separation method without using HPLC was tried as well, which was still on progress. This is the first report of the method for preparative separation of four isomers of synthetic anisodamine which could be used for large-scale production in industry. PMID- 30417575 TI - Process evaluation of a cluster-randomised controlled trial of multi-component weight management programme in adults with intellectual disabilities and obesity. AB - BACKGROUND: Providing effective weight management to adults with intellectual disabilities is necessary to challenge the high rates of obesity. The aim of this process evaluation was to explore the feasibility of conducting a full-scale clinical trial of the TAKE 5 multi-component weight management programme. METHODS: The study was a 12-month pilot cluster-randomised controlled trial. Adults with intellectual disabilities and obesity were randomised to either TAKE 5, which included an energy deficit diet (EDD) or Waist Winners Too, based on health education principles. A mixed-methods process evaluation was conducted focussing on the reach, recruitment, fidelity, implementation, dose (delivered/received) and context. RESULTS: The study successfully recruited adults with intellectual disabilities. Both weight management programmes were delivered with high fidelity and implemented as intended. Only one weight management programme, TAKE 5, demonstrated potential efficacy in reducing body weight and body composition. The effectiveness was largely attributed to the EDD and social support from carers. CONCLUSIONS: The extensive process evaluation illustrated that a full-scale trial of a multi-component programme including an EDD is feasible and an acceptable approach to weight management for adults with intellectual disabilities and obesity. PMID- 30417576 TI - Zbed3 promotes proliferation and invasion of lung cancer partly through regulating the function of Axin-Gsk3beta complex. AB - Our previous work showed that Zbed3 is overexpressed in nonsmall cell lung cancer and that down-regulation of Zbed3 inhibited beta-catenin expression and cancer cell proliferation and invasiveness. Here, we investigated Zbed3's ability to promote lung cancer cell proliferation and invasion and the involvement of the Axin/TPC/glycogen synthase kinase 3beta (Gsk-3beta) complex to the response. Coimmunoprecipitation assays showed that wild-type Zbed3 bound to Axin but a Zbed3 mutant lacking the Axin binding site did not. In A549 and H1299 lung cancer cells, Zbed3 overexpression promoted cancer cell proliferation and invasiveness, as well as Wnt signalling and expression of downstream mediators, including beta catenin, cyclin D1 and MMP7 (P < 0.05). In contrast, the Zbed3 mutant failed to enhance beta-catenin expression (P > 0.05), and its ability to promote cancer cell proliferation and invasiveness was much less than wild-type Zbed3 (P < 0.05). The ability of Zbed3 to increase beta-catenin levels was abolished by Axin knockdown in A549 cells (P > 0.05). Similarly, treating the cells with a GSK 3beta inhibitor abolished Zbed3's ability to increase beta-catenin levels and Wnt signalling. These results indicate that Zbed3 enhances lung cancer cell proliferation and invasiveness at least in part by inhibiting Axin/adenomatous polyposis coli/GSK-3beta-mediated negative regulation of beta-catenin levels. PMID- 30417577 TI - The growing demand for informatics in cytopathology. PMID- 30417578 TI - The fasting triglycerides and glucose (TyG) index is more suitable for the identification of metabolically unhealthy individuals of Chinese adult population: a nationwide study. AB - AIMS: Metabolic unhealth can be defined by the components of metabolic syndrome (MetS), which is closely connected to insulin resistance (IR). We aim to determine a simple index to identify the metabolic unhealth of the Chinese adult population. METHODS: A total of 30,291 individuals were screened from the China National Diabetes and Metabolic Disorders Study conducted from June 2007 to May 2008. Metabolic unhealth was defined using components of MetS, except waist circumference (WC). We compared the three surrogate indices of IR: TyG (the product of fasting triglycerides and glucose), TG/HDL (triglycerides divided by high-density lipoprotein cholesterol) and METS-IR (metabolic score for IR) for the evaluation of metabolic status. RESULTS: All indices had high sensitivity and specificity for the identification of metabolic unhealth, especially the TyG index with an area under the curve of 0.863 for men and 0.867 for women. Subjects were divided into subgroups to further analysis. The TyG index also showed high diagnostic values, especially for younger individuals and men with normal WC. Sex specific cutoffs for three indices were also used to define metabolic unhealth. The TyG index showed the highest agreement with kappa values of 0.603 and 0.605 for men and women between the components of MetS and three indices. CONCLUSION: We propose that the TyG index, just read in one blood laboratory test report, is simpler and more suitable for the identification of metabolically unhealthy individuals as well as who have high risk of cardiometabolic diseases of the Chinese adult population. This article is protected by copyright. All rights reserved. PMID- 30417579 TI - Clinical outcomes and management of patients with chronic hepatitis B and liver stiffness measurement in the grey zone. AB - BACKGROUND: A significant number of patients have liver stiffness measurements in the grey zone where liver biopsy is recommended. AIMS: To study chronic hepatitis B patients with initial liver stiffness measurements in the grey zone with regards to rates of liver biopsy, repeat liver stiffness measurements and outcomes. METHODS: Consecutive chronic hepatitis B patients who underwent transient elastography from August 2006 to July 2017 were retrospectively studied. Liver-related events were defined as hepatocellular carcinoma or cirrhotic complications. Grey zone was defined as liver stiffness measurements: 6.1-9.0 kPa (normal ALT) or 7.6-12.0 kPa (ALT 1-5 * upper limit of normal) on M probe and 6.9-10.0 kPa on XL-probe. RESULTS: Of the 3212 patients analysed, 837 (26%) had initial liver stiffness measurements in grey zone. Only 3.6% of grey zone patients proceeded to liver biopsy within 6 months of transient elastography, of which 33% had METAVIR F3-4 fibrosis. Repeat liver stiffness measurements was performed in 44% of grey zone patients. Liver biopsy and repeat liver stiffness measurements prompted change in management in 47% and 31% of patients respectively. Independent predictors for liver-related events in grey zone patients included increased age, low albumin and low platelet count. Liver related events rates were increased (9%-17%) in patients with METAVIR > F2 fibrosis on biopsy or repeat liver stiffness measurements which did not improve. CONCLUSIONS: Chronic hepatitis B patients with initial liver stiffness measurements in the grey zone rarely proceed to a clarifying liver biopsy which would reveal advanced fibrosis or cirrhosis in one-third of patients. Both liver biopsy and repeat liver stiffness measurements in grey zone patients have clinical utility in prompting changes in management and providing prognostic information. PMID- 30417580 TI - Time estimations by network of beta globin gene cluster haplotypes linked with Hb D-Los Angeles [beta121 (GH4) Glu -> Gln GAA -> CAA] mutation in the world populations. AB - BACKGROUND: beta-Globin gene cluster haplotypes associated with the Hb D-Los Angeles mutation have been reported in many different locations in different populations including Italy, Iran, Thailand, Belgium, Mexico, Holland, and Turkey. In this study, we have identified genetic relationships and formation periods between the haplotypes reported in the world regarding the Hb D-Los Angeles. METHODS: We comparatively analyzed the RFLP (restriction fragment length polymorphism) data in Denizli region and world populations using Arlequin 3.5 statistical software program. The data obtained from the Arlequin software were then entered into the Phylogenetic Network software to calculate the age estimates and to discover possible links between the haplotypes. RESULTS: We observed the frequencies of the beta-globin gene haplotypes for the seven polymorphic restriction sites around the world and calculated the estimated time of haplotypes using Network software on the basis of ancestral haplotypes. We performed the phylogenetic network analysis of the haplotypes linked with Hb D Los Angeles mutation by processing the data of frequency and age estimations with Network software. CONCLUSION: Our period of time results suggests that HAP1 was formed before modern human migration to Asia and/or independent origin of the Hb D-Los Angeles mutation from other populations. Considering that the population in Denizli region started the Hb D-Los Angeles mutation past about 40,000 years ago, it can be said that HAP1, HAP15, and HAP21 belong to the gene pool with an external effect. Our period of time results of HAP6 is compatible with published dating results. PMID- 30417581 TI - Virtual reality in dialysis: a new perspective on care. PMID- 30417583 TI - Enzymes inhibitors from natural sources with antidiabetic activity: A review. AB - Natural products have been extensively investigated for antidiabetic therapy. Many of the natural products have direct or indirect effect in diabetes pathways as enzyme inhibitors. The most involved mechanisms are inhibition of intestinal alpha-glucosidase and alpha-amylase, lens aldose reductase, oxidative stress protection, inhibition of formation of advanced glycation end products, inhibition of aldose reductase, lowering plasma glucose levels, altering enzyme activity of hexokinases and glucose-6-phosphate, synthesizing and releasing of insulin, postprandial hyperglycemia inhibition, stimulation of GLUT-4, decreasing activity of G6P, lowering the level of skeletal hexokinases, etc. The following medicinal plants products or extracts showed promising effects as enzyme inhibitors: Abelmoschus moschatus, Alangium salvifolium, Azadirachta indica, Bidens pilosa, Boerhaavia diffusa, Capsicum frutescens, Cassia alata, Eclipta alba, Embellica officinalis, Ficus carica, Gentiana Olivier, Glycyrrhiza glabra, Gymnema sylvestre, Hordeum vulgare, Ipomoea aquatica, Juniperus communis, Mangifera indica, Momordica charantia, Ocimum sanctum, Punica granatum, and Zingiber officinale. Some of the group of phytochemicals isolated with enzyme inhibition activities are Alkaloids, sesquiterpene and saponins, polysaccharides, flavonoids, dietary fibers, ferulic acid, tannins, limonene, and oleuropeoside. This review will provide very useful material to enhance the efficiency of rational antidiabetic drug design. PMID- 30417584 TI - Microglia shape presynaptic properties at developing glutamatergic synapses. AB - Deficient neuron-microglia signaling during brain development is associated with abnormal synaptic maturation. However, the precise impact of deficient microglia function on synaptic maturation and the mechanisms involved remain poorly defined. Here we report that mice defective in neuron-to-microglia signaling via the fractalkine receptor (Cx3cr1 KO) show reduced microglial branching and altered motility and develop widespread deficits in glutamatergic neurotransmission. We characterized the functional properties of CA3-CA1 synapses in hippocampal slices from these mice and found that they display altered glutamatergic release probability, maintaining immature properties also at late developmental stages. In particular, CA1 synapses of Cx3cr1 KO show (i) immature AMPA/NMDA ratio across developmental time, displaying a normal NMDA component and a defective AMPA component of EPSC; (ii) defective functional connectivity, as demonstrated by reduced current amplitudes in the input/output curve; and (iii) greater facilitation in the paired pulse ratio (PPR), suggesting decreased release probability. In addition, minimal stimulation experiments revealed that excitatory synapses have normal potency, but an increased number of failures, confirming a deficit in presynaptic release. Consistently, KO mice were characterized by higher number of silent synapses in comparison to WT. The presynaptic deficits were corrected by performing experiments in conditions of high release probability (Ca2+ /Mg2+ ratio 8), where excitatory synapses showed normal synaptic multiplicity, AMPA/NMDA ratio, and proportion of silent synapses. These results establish that neuron-microglia interactions profoundly influence the functional maturation of excitatory presynaptic function. PMID- 30417585 TI - Leucine aminopeptidase 3 promotes migration and invasion of breast cancer cells through upregulation of fascin and matrix metalloproteinases-2/9 expression. AB - Overexpression of leucine aminopeptidase 3 (LAP3) is involved in proliferation, migration, and invasion of several tumor cells and plays a crucial role in tumor metastasis. However, the related mechanism remains unknown. In this study, we used MDA-MB-231 and MCF7 breast cancer cell lines to explore the role of LAP3 in the regulation of cancer cell migration and invasion by employing the natural LAP3 inhibitor bestatin and a lentivirus vector that overexpresses or knocks down LAP3. Bestatin inhibited tumor cell migration and invasion in a dose-dependent manner. Western blot assay showed that bestatin and knockdown of LAP3 upregulated phosphorylation of Hsp27 and downregulated expression of fascin. Phosphorylation of Akt and expression of matrix metalloproteinase-2/9 can also be downregulated. LAP3 overexpression showed the opposite results. Immunohistochemistry analysis was conducted to detect expression levels of LAP3 in breast cancer tissues. High LAP3 expression was correlated with the grade of malignancy. Findings of this study uncovered the molecular mechanism of LAP3 on breast cancer metastasis and indicated that LAP3 may act as a potential antimetastasis therapeutic target. PMID- 30417586 TI - Progression-free survival (PFS) in oncology: caveat emptor! AB - Overall survival (OS) is the undisputed gold standard efficacy endpoint in cancer drug trials. It is with growing concern that we observe how progression-free survival (PFS) gains ground as surrogate endpoint in its place. PFS has appeal because it is resource-efficient, but it has severe shortcomings. Our concern is that uncritical use of PFS will harm the evidence-based evaluation of cancer drugs when considering them for standard use in publicly financed health care systems. PFS is only valid as a surrogate endpoint for OS if it correlates strongly with OS and if the cancer drug being investigated has the same effect on PFS and OS such that effects on one predicts effects on the other. The latter might be less obvious than the former but is no less critical. Research indicates that in a majority of cases, correlation between surrogate endpoints and OS is of medium strength or lower. PFS is therefore unreliable as a surrogate for OS. We do not find it justified to use PFS as surrogate for OS without first having assessed its validity. Stakeholders who take part in evaluating cancer drugs considered for standard use in a health care system must be particularly vigilant about this issue to minimize the risk of introducing cancer drugs that have an unacceptable cost-risk-benefit profile. This article is protected by copyright. All rights reserved. PMID- 30417587 TI - Quantification of Calcyclin and Heat Shock Protein 90 in Sera from Women with and without Preeclampsia by Mass Spectrometry. AB - PURPOSE: The objective of present study is to determine serum levels and placental distribution of two interacting proteins calcyclin and heat shock protein 90 in preeclampsia. EXPERIMENTAL DESIGN: Maternal serum levels of calcyclin and heat shock protein 90 are compared throughout pregnancy from the first trimester till term among women with preeclampsia (n = 43) and age-matched normotensive pregnant controls (n = 46). A serum-based 2D LC-MS assay using Parallel Reaction Monitoring is applied to quantify both calcyclin and heat shock protein 90. RESULTS: Serum levels of calcyclin are significantly lower in patients with preeclampsia in the second trimester of pregnancy as compared to controls (p < 0.05). Serum levels of heat shock protein 90 are significantly higher in patients with preeclampsia in the third trimester as compared to controls (p < 0.001). CONCLUSION AND CLINICAL RELEVANCE: Both interacting proteins calcyclin and heat shock protein 90 are notably changed in preeclamptic patients compared to controls. Calcyclin is already decreased before the onset of preeclampsia in the second trimester and HSP90 is strongly increased in the third trimester. This suggests that these proteins may play a role in the pathogenesis of preeclampsia and ought to be investigated in large cohort studies as molecular biomarkers. PMID- 30417590 TI - Author Guidelines. PMID- 30417588 TI - Estrogen Receptor Variant ER-alpha36 Promotes Tamoxifen Agonist Activity in Glioblastoma Cells. AB - Glioblastoma (GBM) is a highly infiltrative and malignant primary brain tumor. Despite aggressive therapy, patients with GBM have a dismal prognosis with median survival of about one year. Tamoxifen (TAM), a selective estrogen receptor modulator (SERM), has been used to treat GBM for many years. ER-alpha36 is a novel variant of estrogen receptor-alpha66 (ER-alpha66) and can mediate cell proliferation through estrogen or anti-estrogen signaling in different cancer cells. Previously, we found that ER-alpha36 was highly expressed in GBM and was involved in the tamoxifen-sensitivity of glioblastoma cells. However, the molecular mechanism responsible has not been well established. Here, we found that ER-alpha36 is highly expressed in glioblastoma specimens. We further found that ER-alpha36 knockdown increased sensitivity of the glioblastoma U87 cells to TAM and decreased autophagy in these cells. However, ER-alpha36 overexpression decreased TAM sensitivity and induced autophagy. We also established TAM resistant glioblastoma U251 cells by a long-term culture in TAM containing medium and found that TAM-resistant cells exhibited a six-fold increase of the ER alpha36 mRNA expression and elevated basal autophagy. ER-alpha36 knockdown in these TAM-resistant cells restored TAM sensitivity. In addition, we recapitulate the physiologically relevant tumor microenvironment in an integrated microfluidic device, and the U87 cells were treated with a gradient of TAM. We found ER alpha36 expression is consistent with autophagy protein P62 in a three dimensional microenvironment. In summary, these results indicate that ER-alpha36 contributes to tamoxifen resistance in glioblastoma cells presumably through regulation of autophagy. This article is protected by copyright. All rights reserved. PMID- 30417591 TI - Corrigendum. PMID- 30417592 TI - One-Step Access to Sequence-Controlled Block Copolymers by Self-Switchable Organocatalytic Multicomponent Polymerization. AB - A one-step procedure for the self-switchable block copolymerization of monomer mixtures of epoxides, cyclic anhydrides, and lactide (LA) was developed by using simple organocatalysts without an external stimulus. This multicomponent polymerization bridges two catalytic cycles involving ring-opening alternating copolymerization of epoxides with anhydrides and ring-opening polymerization (ROP) of LA, in which the presence/absence of anhydrides in mixed feedstocks switched the ROP of LA off/on. The self-switchable terpolymerization showed distinct noncoordinating and living nature, as well as perfect chemoselectivity. Different combinations of epoxides, anhydrides, and initiators enabled the generation of a variety of new block polyester polyols. PMID- 30417593 TI - A pilot randomized controlled trial examining the impact of a sleep intervention targeting home routines on young children's (3-6 years) physical activity. AB - BACKGROUND: Given evidence suggesting that sleep impacts on metabolic processes, interventions targeting sleep may improve child physical activity (PA). OBJECTIVES: To describe the potential effect of an intervention to increase sleep on young children's (3-6 years) moderate to vigorous PA (MVPA) and total PA. To determine adherence to the intervention, impact on sleep duration as well as feasibility, uptake and acceptability was also assessed. METHODS: Pilot randomized controlled trial with 76 parent-child dyads randomly allocated to an intervention (n = 38) or control group (n = 38). Parents in the intervention group received a 3-month theory-informed intervention consisting of an online video, a telephone call and two text messages. Child PA was assessed using accelerometers at baseline and approximately 3 months. Parents also completed a sleep log and a telephone interview. RESULTS: The consent rate was 41% (76/186). Estimated effect size for the intervention relative to control was 10.8 min/day for MVPA, 2.7 min/day for PA and 0.9 h for sleep. Sixteen (44%) parents accessed the video, and 18 (50%) received the telephone call. Over 40% of parents found the video and telephone call useful/very useful. CONCLUSIONS: This study reports promising effects that an intervention targeting sleep may improve child MVPA and sleep duration. Some modifications to data collection methods and intervention delivery are needed. PMID- 30417594 TI - Self-assembly of Amphiphilic Alternating Copolymers. AB - Polymer self-assembly has been the hot research topic for several decades. Different types of polymers with various architectures, like block copolymers, brush polymers, hyperbranched polymers and dendrimers, etc., are being deeply studied in this topic. Alternating copolymers, or alternating-structured copolymers (ASCPs) in a more general way, are regular copolymers with alternating monomeric unit structure in the polymer backbones. However, despite the great progress in the synthesis of ASCPs, the self-assembly of them is still in an infant stage. Very recently, our group has reported a new type of amphiphilic ASCPs through click copolymerization, and obtained spheres, vesicles, nanotubes and even hierarchical sea urchin-like aggregates through the self-assembly process. We also find some intriguing features in the self-assembly of ASCPs when compared with other copolymers, including the facile syntheses, readily functionalization, novel self-assembly structures, new folding-chain mechanisms, and uniform but ultrathin feature length. In this Concept article, we are going to present the ASCP self-assembly together with their unique features through reviewing our latest results, as well as some relating studies. Moreover, the future perspective on the self-assembly of ASCPs are also proposed. Our aim is to arouse the attentions and interests of chemists to this virgin but highly promising land. PMID- 30417595 TI - High resolution insight into recombination events at the SD1 locus in rice. AB - Recombination during meiosis plays an important role in genome evolution by reshuffling existing genetic variations into fresh combinations with the possibility of recovery of lost ancestral genotypes. While crossover (CO) events have been well-studied, gene conversion events (GCs), which represent non reciprocal information transfer between chromosomes, are poorly documented and difficult to detect due to their relatively small converted tract size. Here, we document these GC events and their phenotypic effects at an important locus in rice containing the SD1 gene, where multiple defective alleles contributed to the semi-dwarf phenotype of rice in the 'Green Revolution" of the 1960s. Here, physical separation of two defects allows recombination to generate the wild-type SD1 gene, for which plant height can then be used as a reporter. By screening 18,000 F2 progeny from a cross between two semi-dwarf cultivars which carry these different defective alleles, we detected 24 GC events, indicating a conversion rate of ~3.3 * 10-4 per marker per generation in a single meiotic cycle in rice. Furthermore, our data show that indels and SNPs do not differ significantly in GC rates, at least at the SD1 locus. Our results provide strong evidence that gene conversion by itself can regain an ancestral phenotype that was lost through mutation. This GC detection approach is likely to be broadly applicable to natural or artificial alleles of other phenotype-related functional genes which are abundant in other plant genomes. This article is protected by copyright. All rights reserved. PMID- 30417596 TI - Exendin-4 from Heloderma suspectum venom: From discovery to its latest application as Type II diabetes combatant. AB - Type II diabetes mellitus (T2DM) is a chronic non-communicable disease due to abnormal insulin actions causing uncontrolled hyperglycaemia. The treatment for T2DM, for instance, metformin and incretin mimetic, mainly focuses on the restoration of insulin sensitivity and secretion. Exendin-4 is a short incretin mimetic peptide consisting of 39 amino acids. It is discovered in the venom of Heloderma suspectum as a full agonist for the glucagon-like peptide 1 (GLP-1) receptor and produces insulinotropic effects. It is more resistant to enzymatic degradation by dipeptidyl-peptidase-4 and has a longer half-life than the endogenous GLP-1; thus, it is further developed as an incretin hormone analogue used to treat T2DM. The helical region of the peptide first interacts with the extracellular N-terminal domain (NTD) of GLP-1 receptor while the C-terminal extension containing the tryptophan cage further enhances its binding affinity. After binding to the NTD of the receptor, it may cause the receptor to switch from its auto-inhibited state of the receptor to its auto-activated state. Exendin-4 enhances the physiological functions of beta-cells and the up regulation of GLP-1 receptors, thus reducing the plasma glucose levels. Moreover, exendin-4 has also been found to ameliorate neuropathy, nephropathy and ventricular remodelling. The therapeutic effects of exendin-4 have also been extrapolated into several clinical trials. Despite exendin-4 has a reasonable subcutaneous bioavailability, its half-life is rather short. Therefore, several modifications have been undertaken to improve its pharmacokinetics and insulinotropic potency. This review focuses on the pharmacology of exendin-4 and the structure-function relationships of exendin-4 with GLP-1 receptor. The review also highlights some challenges and future directions in the improvement of exendin-4 as an anti-diabetic drug. This article is protected by copyright. All rights reserved. PMID- 30417597 TI - Corrigendum. PMID- 30417598 TI - Corrigendum. PMID- 30417600 TI - A survey of software tool utilization and capabilities for quantitative systems pharmacology: what we have and what we need. AB - Quantitative Systems Pharmacology is a rapidly emerging discipline with application across a spectrum of challenges facing the pharmaceutical industry, including mechanistically informed prioritization of target pathways and combinations in discovery, target population and dose expansion decisions early in clinical development, and analyses for regulatory authorities late in clinical development. Quantitative Systems Pharmacology's development has influences from physiologic modeling, systems biology, physiologically-based pharmacokinetic modeling, and pharmacometrics. Given a varied scientific heritage, a variety of tools to accomplish the demands of model development, application, and model based analysis of available data have been developed. We report the outcome from a community survey and resulting analysis of how modelers view the impact and growth of Quantitative Systems Pharmacology, how they utilize existing tools, and capabilities they need improved to further accelerate their impact on drug development. These results serve as a benchmark and roadmap for advancements to the Quantitative Systems Pharmacology tool set. This article is protected by copyright. All rights reserved. PMID- 30417601 TI - EBV-positive mucocutaneous ulcer on the penis. PMID- 30417599 TI - Enzymatic Reaction Generates Biomimic Nanominerals with Superior Bioactivity. AB - In vivo mineralization is a multistep process involving mineral-protein complexes and various metastable compounds in vertebrates. In this complex process, the minerals produced in the mitochondrial matrix play a critical role in initiating extracellular mineralization. However, the functional mechanisms of the mitochondrial minerals are still a mystery. Herein, an in vitro enzymatic reaction strategy is reported for the generation of biomimic amorphous calcium phosphate (EACP) nanominerals by an alkaline phosphatase (ALP)-catalyzed hydrolysis of adenosine triphosphate (ATP) in a weakly alkalescent aqueous condition (pH 8.0-8.5), which is partially similar to the mitochondrial environment. Significantly, the EACP nanomineral obviously promotes autophagy and osteogenic differentiation of human bone marrow-derived mesenchymal stem cells by activating an AMPK related pathway, and displays a high performance in promoting bone regeneration. These results provide in vitro evidence for the effect of ATP on the formation and stabilization of the mineral in the mineralization process, demonstrating a potential strategy for the preparation of the biomimic mineral for treating bone related diseases. PMID- 30417602 TI - Supramolecular Chiral Helical Ribbons of Tetraphenylethylene-Appended Naphthalenediimide Controlled by Solvent and Induced by l- and d-Alanine Spacers. AB - Naphthalenediimide-tetraphenylethylene conjugates with an alanine spacer (coded as: NDI-(Ala-TPE)2 ) were synthesized to study the influence of the chirality of the amino acid spacer on its self-assemblies. Here we particularly show that NDI Ala-TPE bearing l-alanine gives left-handed (M-type) helical superstructure, while d-alanine produces right-handed (P-type) helical ribbons in THF:H2 O at 40:60 % v/v ratio. However, particular aggregates were observed at 20:80 % v/v ratio. Circular dichroism was used to characterise the induction of chirality and the handedness of the helical superstructures, and the microstructure of the self assembled materials was visualised using scanning electron microscopy while DLS analysis confirmed the formation of particular aggregates in solution. PMID- 30417604 TI - Revealing structural modifications in thermomechanical reshaping of collagenous tissues using optical coherence elastography. AB - Moderate heating of such collagenous tissues as cornea and cartilages by IR-laser irradiation is an emerging technology for non-destructive modification of the tissue shape and microstructure for a variety of applications in ophthalmology, otolaryngology, etc. Post-irradiation high-resolution microscopic examination indicates the appearance of microscopic either spheroidal or crack-like narrow pores depending on the tissue type and irradiation regime. Such examinations usually require special tissue preparation (e.g., staining, drying that affect microstructure themselves) and are mostly suitable for studying individual pores, whereas evaluation of their averaged parameters, especially in situ, is challenging. Here, we demonstrate OCT's ability to visualize areas of pore initiation and evaluate their averaged properties by combining visualization of residual irradiation-induced tissue dilatation and evaluation of the accompanying Young-modulus reduction by OCT-based compressional elastography. We show that the averaged OCT-based data obtained in situ fairly well agree with the microscopic examination results. The results obtained develop the basis for effective and safe applications of novel non-destructive laser technologies of tissue modification in clinical practice. This article is protected by copyright. All rights reserved. PMID- 30417603 TI - Hybrid Architectures of Heterogeneous Carbon Nanotube Composite Microstructures Enable Multiaxial Strain Perception with High Sensitivity and Ultrabroad Sensing Range. AB - Low-dimensional nanomaterials are widely adopted as active sensing elements for electronic skins. When the nanomaterials are integrated with microscale architectures, the performance of the electronic skin is significantly altered. Here, it is shown that a high-performance flexible and stretchable electronic skin can be produced by incorporating a piezoresistive carbon nanotube composite into a hierarchical topography of micropillar-wrinkle hybrid architectures that mimic wrinkles and folds in human skin. Owing to the unique hierarchical topography of the hybrid architectures, the hybrid electronic skin exhibits versatile and superior sensing performance, which includes multiaxial force detection (normal, bending, and tensile stresses), remarkable sensitivity (20.9 kPa-1 , 17.7 mm-1 , and gauge factor of 707 each for normal, bending, and tensile stresses), ultrabroad sensing range (normal stress = 0-270 kPa, bending radius of curvature = 1-6.5 mm, and tensile strain = 0-50%), sensing tunability, fast response time (24 ms), and high durability (>10 000 cycles). Measurements of spatial distributions of diverse mechanical stimuli are also demonstrated with the multipixel electronic skin. The stress-strain behavior of the hybrid structure is investigated by finite element analysis to elucidate the underlying principle of the superior sensing performance of the electronic skin. PMID- 30417605 TI - Arterial adaptations in athletes of dynamic and static sports disciplines - a pilot study. AB - BACKGROUND: Structural and functional arterial adaptations with regard to the type and level of training in young athletes are understudied. Our research aimed at evaluating them in two types of exercise (dynamic and static) and two levels of engagement (high and recreational). METHODS: A total of 76 volunteers formed five groups. Group A included 17 high-level dynamic sports athletes 30.9 +/- 6.4 years old, group B 14 recreational ones aged 28.7 +/- 6.2 years, group C 15 high level static sports athletes 26.4 +/- 3.9 years old and group D 16 recreational ones, aged 25.8 +/- 4.8 years. Fourteen sedentary men 30 +/- 3.8 years old formed control group E. Structural indices of left cardiac chambers and thoracic aorta were echographically obtained, as well as common carotid intima-media thickness (cIMT). Furthermore, applanation tonometry was conducted, at rest and during a handgrip strength test, for the acquisition of central arterial pressure parameters, carotid-femoral pulse wave velocity (cfPWV) and total arterial compliance (Ctau ). RESULTS: No significant differences in structural arterial markers were observed. However, group A obtained the highest handgrip central systolic pressure values (13.1% compared to group D, P<0.05). Resting cfPWV was lower in group B by 13.8% (P<0.05) than C and by 16.7% (P<0.01) than E, whereas Ctau was higher in group Beta by 33.3% than C (P<0.05) and by 40.9% than E (P<0.01). CONCLUSION: Functional arterial exercise-induced adaptations become apparent at an early age, without being in conjunction with structural ones. Recreational dynamic exercise results in the most favourable arterial characteristics. PMID- 30417606 TI - Sixteen years of creatinine measurements among 460 000 individuals - The Funen Laboratory Cohort (FLaC), a population-based pharmacoepidemiological resource to study drug-induced kidney disease. AB - Register-based administrative data comprise the backbone of pharmacoepidemiological research.. However, information from these registers lack biochemical details.. The aim of our study was to describe the creation, coverage and content of the Funen Laboratory Cohort (FLaC). The Funen Laboratory Cohort (FLaC) is a database comprising all inhabitants of Funen, Denmark, who in the study period of January 2000 to December 2015 had their creatinine levels measured. Data were linked to the Danish nationwide registers with information on vital status, redeemed prescriptions, discharge diagnoses and socioeconomic status. A total of 693,843 individuals lived on Funen during the study period, and we included 460,365 (66.4%) individuals with a creatinine measurement. In total, 7,742,124 creatinine measurements were performed during the study period. The coverage increased with increasing age, reaching 90-100% of all 65-90+ year olds in 2015. We found that an overall coverage of individuals recorded in FLaC with at least one creatinine measured redeeming prescriptions from public pharmacies was 83% (Interquartile range [IQR] 75-89%) compared to the entire Funen population.. In total, 94.1% of all individuals with a discharge diagnosis of chronic kidney disease (CKD) were covered in FLaC, but only 16.5% (n=3,136) of all individuals with a laboratory-confirmed CKD also had a discharge diagnosis of CKD. We described the creation and content of the FLaC - a haven and a valuable resource for pharmacoepidemiological research using Danish nationwide administrative registers enriched with individual-level biochemical information in a population-based setting.. This article is protected by copyright. All rights reserved. PMID- 30417607 TI - Composition of gut microbiota and its association with body mass index and lifestyle factors in a cohort of 7-18 years old children from the American Gut Project. AB - BACKGROUND: The association between the gut microbiota and obesity in young children and adolescents is not fully studied. OBJECTIVES: This study investigated the associations between the gut microbiota and body mass index (BMI) level (underweight, normal, overweight, obese) and lifestyles (diet type and exercise frequency), controlling for demographic and clinical factors among children aged 7-18 years. METHODS: A cohort study was conducted on 267 children aged 7-18 years from the American Gut Project. 16S rRNA sequences were analysed by QIIME 2TM. Composition of gut microbiota and its associations with BMI level, weight change and lifestyles were analysed using linear decomposition model. RESULTS: Significant factors affecting the gut microbiota were BMI level (p = 0.009), exercise frequency (p = 0.003) and diet type (p = 0.01), controlling for age, sex and use of antibiotics and probiotics. More bacterial operational taxonomic units (OTUs) were associated with BMI level (120 OTUs) and diet type (122 OTUs) than exercise frequency (67 OTUs). Actinobacteria phylum had significantly depleted OTUs for BMI level, diet type and exercise frequency; Proteobacteria phylum had significantly enriched OTUs for higher BMI level and Firmicutes phylum had significantly enriched OTUs for more frequent exercise. CONCLUSIONS: Significant associations were found between the gut microbiota composition and BMI level and lifestyles controlling for demographic and clinical factors in children aged 7-18 years. PMID- 30417608 TI - [The disputes in the radiographic measurements of sagittal balance and how to deal with them]. AB - Objective: To review the process of radiographic measurements of sagittal balance and offer reference for the clinical practice. Methods: The related literature of spino-pelvic sagittal parameters and their clinical application was reviewed and analyzed from the aspects such as the clinical application, the advantages and disadvantages, and how to use them effectively. Results: All parameters have their advantages and disadvantages, and they are influenced by age and race. Sagittal vertical axis can only reflect the global balance, and T 1 pelvic angle which accounts for both spinal inclination and pelvic tilt can't be controlled in the surgery. The correction goal for western people may be not suitable for Chinese. Conclusion: The parameters should be used wisely when evaluating the sagittal balance, the global balance and local balance should be considered together and the different groups of people need different correction goals. PMID- 30417609 TI - [Comparison of accuracy between robot-assisted and fluoroscopy-guided percutaneous pedicle screw placement for treatment of lumbar spondylolisthesis]. AB - Objective: To explore the clinical application value of the spinal robot-assisted surgical system in mild to moderate lumbar spondylolisthesis and evaluate the accuracy of its implantation. Methods: The clinical data of 56 patients with Meyerding grade I or II lumbar spondylolisthesis who underwent minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) between January 2017 and December 2017 were retrospectively analysed. Among them, 28 cases were preoperatively planned with robotic arm and percutaneous pedicle screw placement according to preoperative planning (group A); the other 28 cases underwent fluoroscopy-guided percutaneous pedicle screw placement (group B). There was no significant difference in gender, age, body mass index, slippage type, Meyerding grade, and surgical segmental distribution between the two groups ( P>0.05). The screw insertion angle was measured by CT, the accuracy of screw implantation was evaluated by Neo's criteria, and the invasion of superior articular process was evaluated by Babu's method. Results: One hundred and twelve screws were implanted in the two groups respectively, 5 screws (4.5%) in group A and 26 screws (23.2%) in group B penetrated the lateral wall of pedicle, and the difference was significant ( chi 2=9.157, P=0.002); the accuracy of nail implantation was assessed according to Neo's criteria, the results were 107 screws of degree 0, 3 of degree 1, 2 of degree 2 in group A, and 86 screws of degree 0, 16 of degree 1, 6 of degree 2, 4 of degree 3 in group B, showing significant difference between the two groups ( Z=4.915, P=0.031). In group B, 20 (17.9%) screws penetrated the superior articular process, while in group A, 80 screws were removed from the decompression side, and only 3 (3.8%) screws penetrated the superior articular process. According to Babu's method, the degree of screw penetration into the facet joint was assessed. The results were 77 screws of grade 0, 2 of grade 1, 1 of grade 2 in group A, and 92 screws of grade 0, 13 of grade 1, 4 of grade 2, 3 of grade 3 in group B, showing significant difference between the two groups ( Z=7.814, P=0.029). The screw insertion angles of groups A and B were (23.5+/-6.6) degrees and (18.1+/-7.5) degrees respectively, showing significant difference ( t=3.100, P=0.003). Conclusion: Compared to fluoroscopy-guided percutaneous pedicle screw placement, robot-assisted percutaneous pedicle screw placement has the advantages such as greater accuracy, lower incidence of screw penetration of the pedicle wall and invasion of the facet joints, and has a better screw insertion angle. Combined with MIS-TLIF, robot-assisted percutaneous pedicle screw placement is an effective minimally invasive treatment for lumbar spondylolisthesis. PMID- 30417610 TI - [Atlantoaxial joint release through anterior retrophayngeal approach and staged posterior reduction fixation and fusion for irreducible atlantoaxial dislocation]. AB - Objective: To discuss the effectiveness of atlantoaxial joint release through anterior retrophayngeal approach and staged posterior reduction fixation and fusion for irreducible atlantoaxial dislocation (IAAD). Methods: Fifteen patients with IAAD (9 males, 6 females), aged 14-53 years (mean, 31.4 years) were included in the study. The disease duration was 3 months to 17 years (mean, 5.7 years). IAAD was attributed to trauma in 13 cases, and 2 cases were caused by congenital odontoid disconnection. Preoperative imaging examination showed atlantoaxial dislocation and could not be reset automatically in functional position. The preoperative visual analogue scale (VAS) score was 3-7 (mean, 4.1), and the preoperative Japanese Orthopaedic Association (JOA) score was 10-17 (mean, 13.8). All patients received atlantoaxial joint release through anterior retrophayngeal approach and staged posterior fixation and fusion. Results: Anatomical reduction was achieved in all 15 patients, and the alignment of atlantoaxial joints was restored. After operation, the neck pain and neurological symptom were partially or fully improved in all patients, without deterioration of neurological function. One patient developed pharyngeal discomfort and cough after one-stage operation, 4 patients developed pharyngeal discomfort and foreign body sensation after operation, and 2 patients developed pin-path lipstick swelling during skull traction. All patients were cured by symptomatic treatment. No pulmonary infection, pressure ulcers, venous thrombosis, and incision infection was found during the treatment. All 15 patients were followed up 24-36 months, with an average of 28.6 months. Bony fusion was achieved in all patients, and the fusion time was 3-5 months, with an average of 3.6 months. At last follow-up, the VAS score was 0-2 (mean, 0.5) and the JOA score was 13-17 (mean, 15.9). There was no dislocation, recurrence, or other abnormal sign in the cervical X-ray films and three-dimensional CT. Conclusion: Anatomical reduction can be achieved by atlantoaxial joint release through anterior retrophayngeal approach and staged posterior fixation and fusion for treating IAAD. It is an optional procedure for IAAD. PMID- 30417611 TI - [Mini locked-plate trans-carpometacarpal joint internal fixation for treating comminuted fracture of base of the fifth metacarpal]. AB - Objective: To evaluate the effectiveness of open reduction and trans carpometacarpal joint internal fixation with mini locked-plate for treatment of comminuted fracture of base of the fifth metacarpal. Methods: Between July 2015 and December 2017, 8 cases of comminuted fractures of base of the fifth metacarpals were treated with open reduction and trans-carpometacarpal joint internal fixation with mini locked-plate. There were 7 males and 1 female with an age of 19-45 years (mean, 32.5 years). The causes of injury included 2 cases of hitting hard objects while clenching fist, 6 cases of falling injury. There were 2 cases of subluxation of fifth carpal joints and 1 case of dislocation. The time from injury to operation was 1-5 days (mean, 3.5 days). The stability of fracture ends could not be maintained by preoperative evaluation without over articular fixation or short time over articular fixation. Postoperative complications and fracture healing were observed, and hand function was evaluated at last follow-up according to the total active motion (TAM) recommended by the Branch of Hand Surgery of Chinese Medicine Association. Results: All the incisions healed by first intention without complications such as wound infection, cutaneous necrosis, tendon or nerve injury. All the patients were followed up 6-18 months (mean, 12 months). All fractures healed with the healing time of 12-16 weeks (mean, 13 weeks). Within 4 months after operation, all patients were able to return to pre-injury job. At last follow-up, according to the TAM recommended by the Branch of Hand Surgery of Chinese Medicine Association, the results were excellent in 7 cases, good in 1 case, with the excellent and good rate of 100%. Conclusion: Applying of mini locked-plate for treatment of comminuted fractures of base of the fifth metacarpal, of which cannot obtain stable fixation through non-transarticular or short-time transarticular fixation, can achieve satisfactory functional results with very few complications through trans carpometacarpal joint approach, thus the procedure can be used as an alternative operation scheme. PMID- 30417612 TI - [Effectiveness comparison between Scarf osteotomy combined with Akin osteotomy fixed by absorbable screws and fixed by metal screws for the treatment of moderate to severe hallux valgus]. AB - Objective: To evaluate the effectiveness of Scarf osteotomy combined with Akin osteotomy in the treatment of moderate to severe hallux valgus with absorbable screws or metal screws fixation by clinical and radiological data. Methods: Between March 2014 and May 2016, the Scarf osteotomy combined with Akin osteotomy was used to treat 62 patients (83 feet) with moderate to severe hallux valgus. Twenty-five patients (35 feet) were fixed by absorbable screws (group A) and 37 patients (48 feet) were fixed by metal screws (group B). The difference in gender, age, affected side, etiology, severity, disease duration, preoperative hallux valgus angle (HVA) and first-second intermetatarsal angle (1-2IMA) measured in weight-bearing anteroposterior X-ray film, preoperative American Orthopaedic Foot and Ankle Society (AOFAS) scores and visual analogue scale (VAS) scores between 2 groups ( P>0.05). The complications and healing time of 2 groups were recorded and compared. At last follow-up, the AOFAS and VAS scores, and HVA, 1-2IMA measured by weight-bearing anteroposterior X-ray film were used to evaluate the effectiveness. Results: All incisions healed by first intention and no incision-related complication occurred in the two groups after operation. Both groups were followed up, the follow-up time in group A was 12-36 months (mean, 24.4 months) and in group B was 14-38 months (mean, 25.7 months). In group A, 1 foot was complicated with hallux varus, 2 feet had mild stiffness, 1 foot appeared metastatic metatarsal pain, and in group B was 2, 3, 2 feet, respectively. There was no recurrence of hallux valgus in both groups. The difference in the incidence of complications between the two groups after the first operation was not significant ( chi 2=0.275, P=0.843). The removal rate of internal fixator in group B was 89.2% (33 cases) during the second operation, among which 3 cases had screw slip and 1 case had screw fracture. And 10.8% (4 cases) refused the second removal operation due to their age. Postoperative X-ray films showed that both groups had good healing at the osteotomy site, and there was no significant difference in healing time between the two groups ( t=1.633, P=0.285). At last follow-up, the AOFAS score, VAS score, HVA, and 1-2IMA were significantly improved in the two groups when compared with preoperative ones ( P<0.05); but no significant difference was found between the two groups ( P>0.05). Conclusion: The effectiveness of Scarf osteotomy combined with Akin osteotomy in the treatment of moderate to severe hallux valgus is significant, with few complications. Compared with being fixed by metal screws, being fixed by absorbable screws has the same effectiveness, but can avoid the risk of second operation to remove the internal fixator. PMID- 30417613 TI - [Short-term effectiveness of Scarf osteotomy and Akin osteotomy combined with soft tissue procedures in treatment of hallux valgus associated with mild to moderate metatarsus adductus]. AB - Objective: To evaluate the short-term effectiveness of Scarf osteotomy and Akin osteotomy combined with soft tissue procedures for hallux valgus associated with mild to moderate metatarsus adductus. Methods: The clinical data of 30 patients (48 feet) who were diagnosised hallux valgus associated with mild to moderate metatarsus adductus and treated by Scarf osteotomy and Akin osteotomy combined with soft tissue procedures between February 2013 and May 2015 were analyzed retrospectively. There were 2 males (2 feet) and 28 females (46 feet) with an average age of 29.4 years (range, 18-50 years). The disease duration was 3-12 years (mean, 6.1 years). The degree of metatarsal adductus was assessed by Sgarlato's measurement and Yu et al classification criteria, and the degree of metatarsal adductus was mild in 20 feet and moderate in 28 feet. Preoperative X ray examination showed that the hallux valgus angle (HVA) was (39.4+/-5.6) degrees , the first-second intermetatarsal angle (1-2IMA) was (15.2+/-3.5) degrees , the metatarsus adductus angle (MAA) was (21.2+/-3.7) degrees . The American Orthopaedic Foot and Ankle Society (AOFAS) score was 51.7+/-10.0, and visual analogue scale (VAS) score was 4.9+/-2.7 before operation. Postoperative complications and the union time of osteotomies were recorded. At last follow-up, the HVA, 1-2IMA, and MAA were measured on X-ray films, and the AOFAS scores and VAS scores were recorded, then compared them with preoperative ones. Roles - Maudsley score was used to investigate patients' satisfaction. Results: All the incisions healed by first intention. Thirty patients were followed up 24-27 months (mean, 26.4 months). Three patients (4 feet) occured metatarsalgia, and the pain relieved after treated by Custom-Made Orthotics. All the osteotomies were unoin, the healing time was 2-4 months (mean, 2.7 months). At last follow up, the HVA and the 1-2IMA were (13.2+/-3.1) degrees and (5.1+/-2.3) degrees , respectively, showing significant differences when compared with preoperative ones ( t=14.606, P=0.000; t=22.356, P=0.000); the MAA was (21.0+/-3.4) degrees and there was no significant difference when compared with preoperative one ( t=0.789, P=0.434). The AOFAS and VAS scores were 91.8+/-7.5 and 1.1+/-1.0, respectively, showing signifiant differences when compared with preoperative ones ( t=13.787, P=0.000; t=14.781, P=0.000). Satisfaction survey showed that 28 patients were very satisfied and satisfied (93.3%), and 2 cases were not satisfied (6.7%). Conclusion: The short-term effectiveness of Scarf osteotomy and Akin osteotomy combined with soft tissue procedures for hallux valgus associated with mild to moderate metatarsus adductus is satisfactory, and no correction is required for metatarsal adductus. PMID- 30417614 TI - [Comparison of combined intravenous and topical use of tranexamic acid with different dosage in primary total knee arthroplasty]. AB - Objective: To compare the efficacy and safety of intra-articular combined with intravenous administration of tranexamic acid (TXA) with different dosage for reducing blood loss in primary total knee arthroplasty (TKA). Methods: Between January 2017 and June 2017, 90 patients suffering from unilateral osteoarthritis who underwent primary TKA were randomly scheduled to three interventions, named groups A, B, and C. Single dosage of TXA via intravenous injection (IV) and different dosages of TXA via intra-articular injection (IA) were utilized in three groups, respectively. All patients in three groups received 1 g TXA IV at 10 minutes preoperatively, and received 1, 2, and 3 g TXA IA diluted in 50 mL saline after wound closure in groups A, B and C, respectively. The age, gender, body mass index, affected side of the knee, grade of osteoarthritis, grade of America Society of Anesthesiologist, preoperative hemoglobin (Hb) concentration, platelet count, preoperative prothrombin time, and activated partial thromboplastin time were not significantly different between groups ( P>0.05). The postoperative wound blood drainage, Hb concentration at 1, 3, and 7 days after operation, transfusion rate, and thromboembolic complications were observed. All patients were routinely observed for deep vein thrombosis (DVT) by the color Doppler ultrasonography at 1 week, 1 month, and 3 months after operation, and the symptomatic pulmonary embolism (PE) were observed. Results: All patients in three groups were followed up 7-12 months (mean, 8.4 months). There was no significant difference in operation time between groups ( P>0.05). The postoperative wound blood drainage was significantly less in groups B and C than that in group A ( P<0.05), whereas no significant difference was found between group B and group C ( P>0.05). Incision skin necrosis occurred in 1 case of group B and fat liquefaction occurred in 1 case of group C. The other incisions of 3 groups healed by first intention. There was no significant difference in incision complication incidence between groups. The Hb concentration was significantly higher in groups B and C than that in group A at 1, 3, and 7 days after operation ( P<0.05). While between group B and group C, the significant difference of Hb concentration only existed at 1 day after operation ( P<0.05). The number of patients who got blood transfusion was significantly less in group B (4 cases, 13.3%) and group C (5 cases, 16.7%) than that in group A (9 cases, 30%) ( P< 0.05), but no significant difference was found between group B and group C ( P>0.05). The result of color Doppler ultrasonography showed that 1 case got DVT in the contralateral calf at 3 weeks in group B. And there was no symptomatic PE in 3 groups. Conclusion: Combined administration of IV and IA TXA in a clinically relevant reduction in blood loss was effective and safe in primary TKA, and no thromboembolic complication was observed. The combination of 1 g IV with 2 g IA could be the optional choice. PMID- 30417615 TI - [Effectiveness of double-plane high tibial osteotomy in treatment of medial compartment osteoarthritis]. AB - Objective: To investigate the effectiveness of double-plane high tibial osteotomy in treatment of medial compartment osteoarthritis. Methods: The clinical data of 65 patients with medial compartment osteoarthritis who were treated with double plane high tibial osteotomy between January 2014 and January 2017 was retrospectively analyzed. There were 28 males and 37 females. The age ranged from 46 to 75 years with an average of 53.2 years. There were 30 cases in the left knee and 35 cases in the right knee. The disease duration was 3-7 years (mean, 4.0 years). The patients had different degrees of pain in the knee joint and difficulty walking. The knee joint compression test was positive. The knee joint function was evaluated by Hospital for Special Surgery (HSS) score and knee society score (KSS) clinical and functional scores. The visual analogue scale (VAS) score was adopted to pain measurement. The healing of osteotomy was observed by X-ray films during follow-up; the femur tibia angle (FTA), posterior tibial slope (PTS), medial proximal tibial angle (MPTA), and knee varus angle (KVA) were also calculated. Results: All the incisions healed by first intention after operation. Only 1 case had numbness of the toe, and the symptoms disappeared after symptomatic treatment. All patients were followed up 13-18 months with an average of 15.4 months. X-ray examination showed that all patients had bone healing at 12 weeks after operation. There were significant differences in MPTA, FTA, PTS, and KVA between pre- and post-operation ( P<0.05). There was no significant difference in above parameters among 1 week, 6 months, and 12 months after operation ( P>0.05). There was no loosening and rupture of the fixator during the follow-up. The HSS score and KSS clinical and functional scores at 12 months after operation were significantly higher than those before operation ( P<0.05). The VAS scores at 1 week, 6 months, and 12 months after operation were significantly lower than that before operation ( P<0.05). Conclusion: Double-plane high tibial osteotomy for medial compartment osteoarthritis can effectively relieve pain symptoms and improve joint function. PMID- 30417616 TI - [Effectiveness comparison between proximal femoral nail anti-rotation and proximal femoral locking compression plate for intertrochanteric fracture in elderly patients combined with hemiplegia due to cerebral infarction]. AB - Objective: To investigate the difference in the effectiveness between proximal femoral nail anti-rotation (PFNA) and proximal femoral locking compression plate (PFLCP) for intertrochanteric fracture in elderly patients combined with hemiplegia due to cerebral infarction. Methods: The clinical data of 67 cases of intertrochanteric femoral fractures combined with hemiplegia due to cerebral infarction between October 2013 and January 2017 were retrospectively analyzed. Among them, 32 cases were treated with PFNA internal fixation (PFNA group), and 35 cases were treated with PFLCP internal fixation (PFLCP group). There was no significant difference in gender, age, injury side, modified Evans classification of fracture, preoperative medical disease, and interval from injury to operation between 2 groups ( P>0.05). The operation time, intraoperative blood loss, postoperative bed time, incidence of perioperative complications, time of fracture healing, and hip Harris score at 6 months and 1 year after operation were recorded and compared. Results: Both groups were followed up 12-24 months with an average of 14 months. Compared with the PFLCP group, the PFNA group had shorter operation time, less intraoperative blood loss, and shorter bed time, and the differences were significant ( P<0.05). X-ray films showed that the fractures healed in both groups. The fracture healing time of the PFNA group was shorter than that of the PFLCP group, but the difference was not significant ( t=0.743, P=0.460). During hospitalization, there were 3 cases of pulmonary infection, 2 cases of deep venous thrombosis of lower limbs, and 1 case of urinary tract infection in the PFNA group; and the incidence of perioperative complications was 18.8% (6/32). There were 4 cases of pulmonary infection, 6 cases of deep venous thrombosis of lower limbs, 1 case of recurrent cerebral infarction, and 1 case of stress ulcer in the PFLCP group; and the incidence of perioperative complications was 34.3% (12/35). There was no significant difference in the incidence of perioperative complications between 2 groups ( chi 2=2.053, P=0.152). At 6 months after operation, the Harris total score and individual scores in the PFNA group were higher than those in the PFLCP group ( P<0.05). At 1 year after operation, there was no significant difference in the Harris total score and pain score, life ability score, and walking ability score between the PFNA group and the PFLCP group ( P>0.05); However, the joint deformity and activity score of the PFNA group was significantly better than that of the PFLCP group ( t=4.112, P=0.000). Conclusion: For intertrochanteric fracture in elderly patients with cerebral infarction hemiplegia, the PFNA has shorter operative time, less intraoperative blood loss, shorter bed time after operation, and better short term hip function when compared with the PFLCP. PMID- 30417617 TI - [Effectiveness of F-shaped screw fixation technique in treatment of Pauwels type III femoral neck fractures]. AB - Objective: To summarize the effectiveness of F-shaped screw fixation technique in treatment of Pauwels type III femoral neck fractures. Methods: Between January 2013 and December 2016, 43 patients with Pauwels type III femoral neck fractures were treated with F-shaped screw fixation technique. There were 32 males and 11 females with an average age of 38.9 years (range, 20-55 years). The fractures located on the left side in 21 patients and on the right side in 22 patients. The cause of injury included traffic accident in 19 patients and falling from height in 24 patients. There were 25 patients of Garden type III and 18 of Garden type IV. The time from injury to operation was 2-3 days (mean, 2.2 days). These data were recorded, including operative time, fluoroscopy time, postoperative hospital stay, quality of reduction, postoperative complications (nonunion, varus deformity, femoral neck shortening, avascular necrosis of femoral head, screws back-out), and Harris scores. Results: The operative time was 28-45 minutes (mean, 37.5 minutes). The fluoroscopy time was 13-20 seconds (mean, 14.7 seconds). The postoperative hospital stay was 2-3 days (mean, 2.7 days). All incisions healed by first intention. All patients were followed up 18-58 months with an average of 38.7 months. All patients have anatomical reduction of fractures. Fracture healing occurred in 42 patients; the union time was 3-5 months with an average of 3.6 months. Nonunion occurred in 1 patient who was treated with total hip arthroplasty. Of the 42 patients with fracture healing, 11 cases had a femoral neck shortening, 9 cases had varus deformity, 3 cases had avascular necrosis of femoral head, and 8 cases had screws back-out. There was no significant difference in complication incidences between Garden type III fractures and Garden type IV fractures ( P>0.05). Conclusion: Treatment of femoral neck fractures by using the F-shaped screw fixation technique, can achieve satisfactory effectiveness with less postoperative complication. PMID- 30417618 TI - [Effect and mechanisms of vitamin E on early steroid-induced avascular necrosis of femoral head in rats]. AB - Objective: To investigate the possibility of mitochondria-dependent apoptosis as a mechanism of early steroid-induced avascular necrosis of femoral head (SANFH) in rats and vitamin E as a possible prevention strategy. Methods: Seventy-two male Sprague Dawley rats were randomly divided into control group, model group, and intervention group, with 24 rats in each group. The rats in control group were not treated as normal control. The rats in model group and intervention group were established early SANFH models by lipopolysaccharide combined with methylprednisolone injection. At the same time, the rats in intervention group were injected with vitamin E (40 mg/kg) every day for 7 days. At 2, 4, and 8 weeks after the final injection, the bilateral femoral heads were harvested and observed by HE staining, TUNEL assay, immunohistochemical staining, and Western blot. The rate of empty lacunae, apoptotic index, and the expressions of Caspase 9, Caspase-3, and cytochrome-c (Cyt-c) proteins were calculated. Results: According to histological staining, there were significant differences in the rate of empty lacunae between intervention group and control group at 8 weeks ( P<0.05) and between intervention group and model group at 4 and 8 weeks ( P<0.05). The apoptotic index of intervention group was significantly lower than that of model group at each time point ( P<0.05). And there was significant difference between the intervention group and the control group at 8 weeks ( P<0.05). According to immunohistochemistry staining and Western blot, the expressions of Cyt-c, Caspase-9, and Caspase-3 all significantly decreased in intervention group than those in model group at each time point ( P<0.05); and the differences were significant between intervention group and control group at 8 weeks ( P<0.05). Conclusion: Vitamin E can delay the progression of early SANFH by reducing mitochondrial dependent osteocyte apoptosis. PMID- 30417619 TI - [The role and mechanism of S100 calcium binding protein B in osteoarthritis cartilage damage repair]. AB - Objective: To investigate the role and mechanism of S100 calcium binding protein B (S100B) in osteoarthritis (OA) cartilage damage repair. Methods: Twenty New Zealand rabbits were randomly divided into control group and model group, with 10 rabbits in each group. Rabbits in the model group were injured by the right knee joint immobilization method to make the artilage injury model, while the control group did not deal with any injury. After 4 weeks, the levels of interleukin 1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) in synovial fluid were detected by ELISA method; the mRNA and protein expressions of S100B, fibroblast growth factor 2 (FGF-2), and FGF receptor 1 (FGFR1) in cartilage tissue were examined by real-time fluorescence quantitative PCR (qRT-PCR) and Western blot assay. Human synovial fibroblasts (SF) were isolated and cultured in vitro. The effects of S100B overexpression and knockdown on the levels of IL 1beta and TNF-alpha (ELISA method) and the expressions of FGF-2 and FGFR1 gene (qRT-PCR) and protein (Western blot) were observed. Moreover, the effects of FGFR1 knockdown in above S100 overexpression system on the levels of IL-1beta and TNF-alpha (ELISA method) and the expressions of FGF-2 and FGFR1 gene (qRT-PCR) and protein (Western blot) were observed. Results: ELISA detection showed that the expressions of IL-1beta and TNF-alpha in the synovial fluid of the model group were significantly higher than those of the control group ( P<0.05); qRT PCR and Western blot detection showed that the mRNA and protein expressions of S100B, FGF-2, and FGFR1 in cartilage tissue were significantly higher than those of the control group ( P<0.05). Overexpression and knockdown S100 could respectively significantly increase and decrease lipopolysaccharides (LPS) induced IL-1beta and TNF-alpha levels elevation and the mRNA and protein expressions of FGF-2 and FGFR1 ( P<0.05); whereas FGFR1 knockdown could significantly decrease LPS induced IL-1beta and TNF-alpha levels elevation and the mRNA and protein expressions of FGF-2 and FGFR1 ( P<0.05). Conclusion: S100B protein can regulate the inflammatory response of SF and may affect the repair of cartilage damage in OA, and the mechanism may be related to the activation of FGF 2/FGFR1 signaling pathway. PMID- 30417620 TI - [Selection principles and application status of surgical methods for hip fracture in the elderly]. AB - Objective: To summarize the selection criteria and clinical application of surgical methods for hip fractures (femoral neck fracture and intertrochanteric fracture) in the elderly. Methods: The related literature concerning the surgical methods for femoral neck fracture and intertrochanteric fracture in the elderly at home and abroad was extensively reviewed and summarized. Results: Among the elderly patients with femoral neck fracture, the closed reduction and internal fixation or dynamic hip screw (DHS), and total hip arthroplasty are recommended for patients under 65 years old and 65-80 years old respectively and without special surgical contraindication; whereas hemiarthroplasty is recommended for patients with poor physical conditions. Among the patients with intertrochanteric fracture, DHS or the 3rd generation of Gamma nails is recommended for patients with stable fracture while the intramedullary fixation systems (e.g., proximal femoral nail anti-rotation, intertrochanteric antegrade nail) and the extramedullary fixation systems (e.g., proximal femoral locking compression plate and less invasive stabilization system) can be applied to the patients with unstable fracture according to the fracture type and bone conditions. Notably, hip arthroplasty is recommended for elderly patients with comminuted fracture. Conclusion: The surgical method and internal fixator should be chosen according to the fracture type and bone condition in the elderly in order to improve the effectiveness and reduce the complication. PMID- 30417621 TI - [Clinical application of pedicled chimeric thoracoacromial artery perforator flap for circular hypopharyngeal reconstruction]. AB - Objective: To explore the effectiveness of pedicled chimeric thoracoacromial artery perforator (TAAP) flap as a reconstructive option for circular hypopharyngeal defects. Methods: Between January 2013 and December 2014, the pedicled chimeric TAAP flap was used to repair oncologic circular hypopharyngeal defects in 8 patients, included 6 males and 2 females, with an average age of 57 years (range, 45-80 years). All patients were treated in other hospitals before and recurrence was noted. The duration between latest treatment and recurrence ranged from 3 to 28 months (mean, 16.5 months). According to Union for International Cancer Control (UICC) TNM staged, 3 cases were T 2N 1M 0, 2 cases were T 3N 1M 0, 1 case was T 3N 2M 0, 2 cases were T 4N 1M 0. After laryngectomy, the size of circular hypopharyngeal defect ranged from 9.0 cm*8.5 cm to 12.0 cm*10.5 cm. The size of TAAP flap ranged from 7.0 cm*4.0 cm to 9.5 cm*6.0 cm.The size of pectoralis major flap ranged from 9.0 cm*5.0 cm to 14.5 cm*6.0 cm.The donor sites were closed directly in all cases. Results: Postoperatively all flaps survived smoothly, and all defects healed by first intention. No early complication was noted. The mean hospital stay period ranged from 12 to 22 days (mean, 14.5 days). All patients were followed up 12-45 months (mean, 18.7 months). Patients possessed good appearance of surgical sites. No recurrence, fistulas, stenosis/strictures, dehiscence, or swelling occurred. Only linear scars were left on the donor sites, and the pectoralis major muscle function was completely preserved in all patients. Conclusion: Patients with high comorbidities may not be suitable candidates for free flap reconstruction, especially when the recipient vessels are affected from disease or radiotherapy. Pedicled chimeric TAAP flap is a good choice for the reconstruction of hypopharyngeal defects in such conditions.. PMID- 30417622 TI - [Application of ipsilateral digital proper artery dorsal branch flap to repair mid-phalanx degloving injury with distal segment finger defect]. AB - Objective: To investigate the effectiveness of ipsilateral digital proper artery dorsal branch flap to repair mid-phalanx degloving injury with distal segment finger defect. Methods: Between February 2013 and July 2016, 11 cases (11 fingers) of mid-phalanx degloving injury with distal segment finger defect were treated. There were 9 males and 2 females with an average age of 33.6 years (range, 18-59 years). The injury caused by twisting in 8 cases and crushing in 3 cases. The injury located at index finger in 3 cases, middle finger in 6 cases, and ring finger in 2 cases. The skin avulsion was from proximal interphalangeal joint in 1 case, proximal 1/4 of mid-phalanx in 6 cases, and 1/2 of mid-phalanx in 4 cases. The area of wounds ranged from 4.0 cm*1.7 cm to 6.2 cm*2.6 cm. The interval between injury and operation was 2.5-6.0 hours (mean, 4.5 hours). All defects were repaired with the ipsilateral digital proper artery dorsal branch flaps. The size of flaps ranged from 4.4 cm*1.9 cm to 7.0 cm*2.9 cm. Nerve anastomose was carried between digital proper nerve dorsal branch in the flap and digital proper nerve stump in the wound. The donor sites were repaired by skin grafting. Results: Tension blisters of the flap and partial necrosis occurred in 1 case, and healed after dressing change. The other flaps and skin grafting survived, and wounds healed by first intention. All patients were followed up 6 18 months (mean, 16 months). The texture and appearance of all the flaps were satisfactory. At 6 months after operation, two-point discrimination of flaps ranged from 7 to 10 mm (mean, 8.5 mm). At last follow-up, according to the functional assessment criteria of upper limbs by the Branch of Hand Surgery of Chinese Medicine Association, the results were excellent in 10 cases and good in 1 case, with the excellent and good rate of 100%. Conclusion: The ipsilateral digital proper artery dorsal branch flap is a good method to repair mid-phalanx degloving injury with distal segment finger defect for the advantages of simple operation, less damage in donor site, high survival rate of the flap, and good feeling recovery of the finger. PMID- 30417623 TI - [Effectiveness of medial ankle branches propeller "Tennis racket-like" flap in repair of heel-ankle tissue defects]. AB - Objective: To investigate effectiveness of the medial ankle branches propeller "Tennis racket-like" flap in repair of heel-ankle tissue defect. Methods: Between June 2011 and June 2016, 50 patients with heel-ankle tissue defects were treated. There were 40 males and 10 females, with a median age of 35.6 years (range, 6-58 years). The defects were caused by trauma in 44 cases, scar deformity after trauma in 2 cases, chronic ulcer in 2 cases, and squamous cell carcinoma in 2 cases. The defects located at heel in 20 cases, ankle in 15 cases, and heel-ankle in 15 cases. The size of heel-ankle tissue defect ranged from 3.5 cm*2.0 cm to 13.0*10.0 cm. The course of disease ranged from 3 hours to 2 months (mean, 28 days). All wounds were repaired by the medial ankle branches propeller "Tennis racket-like" flap in a size of 3.8 cm*2.2 cm-13.4 cm*10.3 cm. The donor site was directly sutured in 5 cases or repaired by skin grafting in 45 cases. Results: All flaps survived and wounds healed by first intention. Partial necrosis of skin grafting occurred in 1 case, and the wound recovered by change dressing. The other skin grafting survived and wounds healed by first intention. Forty-eight patients were followed up 12 months after operation. The appearance, sensory, and function of repaired heel-ankle flaps were satisfactory. Conclusion: For heel ankle tissue defect repair, the medial ankle branches propeller "Tennis racket like" flap has advantages of the high survival rate, reliable blood supply, and sensory recovery. PMID- 30417624 TI - [Application of cavernosum reduction technology in glanuloplasty during repair of moderate-severe hypospadias]. AB - Objective: To investigate the application of cavernosum reduction technology in glanuloplasty during the repair of moderate-severe hypospadias and evaluate the effectiveness. Methods: The clinical data of 192 patients with moderate-severe hypospadias between November 2015 and May 2017 were retrospectively analyzed. Among them, 103 patients were treated with the cavernosum reduction technology in glanuloplasty during the repair (observation group), 88 patients were treated with repair and glanuloplasty without the cavernosum reduction technology (control group). There was no significant difference in maximum transverse diameter of glans and the height of glans between 2 groups ( t=1.652, P=0.152; t=1.653, P=0.077). The length of reconstructed urethra, complications (e.g. glans dehiscence and fistula), and the maximum flow rate at 3 months after operation in 2 groups were recorded. Results: The length of reconstructed urethra were (35.51+/-7.79) mm in observation group and (32.17+/-6.37) mm in control group. In observation group, the meatus location after the correction of chordee was proximal in 24 cases and scrotum-perineum in 79 cases. In control group, the meatus location after the correction of chordee was proximal in 21 cases and scrotum-perineum in 67 cases. There was no significant difference in the meatus location between 2 groups ( chi 2=0.008, P=0.920). All patients were followed up 6-12 months after operation (mean, 9 months). There were 3 cases of urethral fistula, 2 cases of glans dehiscence, and 3 cases of urethral orifice stricture in observation group, with the incidence of complications of 7.8%. There were 7 cases of urethral fistula, 3 cases of glans dehiscence, and 4 cases of urethral orifice stricture in control group, with the incidence of complications of 15.9%. There was a significant difference in the incidence of complications between 2 groups ( chi 2=4.027, P=0.040). The appearance of the penis was satisfactory, and the urethral orifice was fissured, which was close to the appearance of the normal urethral orifice. At 3 months after operation, the maximal flow rates were (6.23 +/- 0.54) mL/s in observation group and (5.44+/-0.92) mL/s in control group. There was significant difference in the maximum flow rate between 2 groups ( t=1.653, P=0.000). Conclusion: Cavernosum reduction technology being applied in the repair of moderate-severe hypospadias can reduce the probability of glans dehiscence, urethral fistula, urethrostenosis, and other postoperative complications, and improve the success and satisfaction of surgery. PMID- 30417625 TI - [Effectiveness of endoscopic nipple-sparing mastectomy combined with immediate breast reconstruction via axillary incision]. AB - Objective: To introduce an surgical technique of endoscopic nipple-sparing mastectomy (NSM) combined with immediate breast reconstruction through simple single-port access that placed in axillary incision. Methods: Between January 2017 and February 2018, 15 female patients with breast cancer (stageI in 5 cases and stage II in 10 cases) were treated with endoscopic NSM combined with immediate breast reconstruction through simple single-port access that placed in axillary incision. They were 27-45 years old (mean, 37.5 years). The disease duration ranged from 1 to 24 months (mean, 8 months). The tumor located at the left breast in 8 cases and at the right breast in 7 cases. The diameter of tumor ranged from 1.5 to 3.0 cm (mean, 2.6 cm). The distance between tumor and nipple was 1.8-4.0 cm (mean, 2.3 cm). Results: After operation, the nipple epidermal necrosis occurred in 1 case, and subcutaneous effusion in 1 case. No subcutaneous emphysema or skin flap necrosis occurred. Postoperative pathological examination showed that 1 case was nipple involvement and was treated with nipple resection. All patients were followed up 7-17 months (mean, 11 months). According to the Harris assessment criteria for appearance of reconstructed breast, there were 4 cases of excellent, 10 cases of good, and 1 case of poor. No tumor recurrence or metastasis occurred during follow-up. Conclusion: It is a safe and feasible method of endoscopic NSM combined with immediate breast reconstruction through simple single-port access that placed in axillary incision, and can obtain good cosmetic results. It is a new option to breast reconstruction. PMID- 30417626 TI - [Application progress of indocyanine green angiography in breast reconstruction]. AB - Objective: To summarize the application progress of indocyanine green (ICG) angiography in breast reconstruction. Methods: The literature about the application of ICG angiography in breast reconstruction was reviewed and analyzed, including its history, chemical composition, principles, usages, and attentions. Results: ICG is a kind of fluorescent substance used in medical diagnosis and various surgical fields, especially in intraoperative vascular angiography. ICG angiography and SPY system are gradually applied in breast reconstruction, including both prosthesis/tissue expander reconstruction and autologous reconstruction. Compared to clinical judgment, portable Doppler devices, tissue oximetry, and fluorescein angiography, ICG angiography obviously has more benefits and usages. Conclusion: ICG angiography can reveal the perfusion of flaps during the operation instantly and accurately, which refines the intraoperative strategy in order to decrease the incidence of flap-related complications. Besides, it has some economic benefits to some extent. PMID- 30417627 TI - [Osteogenic differentiation of bone marrow mesenchymal stem cells induced by gene loaded lipopolysaccharide-amine nanopolymersomes]. AB - Objective: To investigate the ability of gene-loaded lipopolysaccharide-amine nanopolymersomes (LNPs) in inducing osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) by in vitro gene transfection, where LNPs were used as a non-viral cationic carrier, and their properties were optimized during synthesis. Methods: LNPs were synthesized by a graft-copolymerization method, and the effects of different pH environments during synthesis on physicochemical properties of LNPs and LNPs/plasmid of bone morphogenetic protein 2-green fluorescent protein (pBMP-2-GFP) complexes were explored. Then, optimized LNPs with maximum transfection efficiency and safe cytotoxicity in rat BMSCs were identified by cytotoxicity and transfection experiments in vitro. Thereafter, the optimized LNPs were used to mediate pBMP-2-GFP to transfect rat BMSCs, and the influences of LNPs/pBMP-2-GFP on osteogenic differentiation of BMSCs were evaluated by monitoring the cell morphology, concentration of BMP-2 protein, activity of alkaline phosphatase (ALP), and the formation of calcium nodules. Results: The nitrogen content, particle size, and zeta potential of LNPs synthesized at pH 8.5 were lower than those of the other pH groups, with the lowest cytotoxicity (96.5%+/-1.4%) and the highest transfection efficiency (98.8%+/-0.1%). After transfection treatment, within the first 4 days, BMSCs treated by LNPs/pBMP-2-GFP expressed BMP-2 protein significantly higher than that treated by Lipofectamine2000 (Lipo)/pBMP-2-GFP, polyethylenimine 25K/pBMP-2-GFP, and the blank (non-treated). At 14 days after transfection, ALP activity in BMSCs treated by LNPs/pBMP-2-GFP was higher than that treated by Lipo/pBMP-2-GFP and the blank, comparable to that induced by osteogenic medium; with alizarin red staining, visible calcium nodules were found in BMSCs treated by LNPs/pBMP-2-GFP or osteogenic medium, but absent in BMSCs treated by Lipo/pBMP-2-GFP or the blank with apoptosis. At 21 days after transfection, transparent massive nodules were discovered in BMSCs treated by LNPs/pBMP-2-GFP, and BMSCs exhibited the morphologic features of osteoblasts. Conclusion: LNPs synthesized at pH 8.5 has optimal transfection efficiency and cytotoxicity, they can efficiently mediate pBMP-2-GFP to transfect BMSCs, and successfully induce their directional osteogenic differentiation, whose inducing effect is comparable to the osteogenic medium. The results suggest that gene transfection mediated by LNPs may be a convenient and effective strategy in inducing directional differentiation of stem cells. PMID- 30417628 TI - [The application of urine derived stem cells in regeneration of musculoskeletal system]. AB - Objective: To review the application of urine derived stem cells (USCs) in regeneration of musculoskeletal system. Methods: The original literature about USCs in the regeneration of musculoskeletal system was extensively reviewed and analyzed. Results: The source of USCs is noninvasive and extensive. USCs express MSCs surface markers with stable proliferative and multi-directional differentiation capabilities, and are widely used in bone, skin, nerve, and other skeletal and muscle system regeneration fields and show a certain repair capacity. Conclusion: USCs from non-invasive sources have a wide application prospect in the regeneration of musculoskeletal system, but the definite biological mechanism of its repair needs further study. PMID- 30417629 TI - [Research progress of graphene and its derivatives in repair of peripheral nerve defect]. AB - Objective: To review the research progress of graphene and its derivatives in repair of peripheral nerve defect. Methods: The related literature of graphene and its derivatives in repair of peripheral nerve defect in recent years was extensively reviewed. Results: It is confirmed by in vitro and in vivo experiments that graphene and its derivatives can promote cell adhesion, proliferation, differentiation and neurite growth effectively. They have good electrical conductivity, excellent mechanical properties, larger specific surface area, and other advantages when compared with traditional materials. The three dimensional scaffold can improve the effect of nerve repair. Conclusion: The metabolic pathways and long-term reaction of graphene and its derivatives in the body are unclear. How to regulate their biodegradation and explain the electric coupling reaction mechanism between cells and materials also need to be further explored. PMID- 30417630 TI - Over-the-scope-clips as primary and rescue therapy for non-variceal gastrointestinal bleeding: a systematic review and meta-analysis. AB - INTRODUCTION: Endoscopic hemostasis in patients with non-variceal bleeding (NVGIB) with standard therapy has improved outcomes. However, persistent bleeding and re-bleeding continues to drive morbidity and mortality. Use of Over-the-scope clips (OTSC) is an emerging treatment modality for managing gastrointestinal bleeding. We performed a systematic review and meta-analysis to evaluate the ability of OTSC to achieve primary hemostasis and re-bleeding rates as primary therapy and rescue endoscopic interventions in patients with NVGIB. EVIDENCE ACQUISITION: We searched articles in PubMed, Ovid Medline In- Process & Other Non Indexed Citations, Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus from inception to July 2017 using keywords such as "OTSC" and "NVGIB". EVIDENCE SYNTHESIS: A total of 16 studies which involved 475 patients met the inclusion criteria. 288 patients were treated with OTSC as primary therapy while 187 patients were treated with OTSC as rescue therapy. Primary hemostasis rate achieved with primary endoscopic therapy with OTSC was 0.93 (95% CI: 0.89-0.96). Similarly, primary hemostasis rate achieved with rescue endoscopic therapy with OTSC was 0.91 (95% CI: 0.84-0.95). Rebleeding rates after primary endoscopic therapy with OTSC was 0.21 (95% CI:0.08 0.43) and 0.25 (95%CI:0.17-0.34) with rescue therapy. There was a decreased risk of re-bleeding in patients treated with OTSC as primary therapy versus rescue therapy. RR=0.52 (95% CI: 0.31 -0.89). CONCLUSIONS: This meta-analysis demonstrates success on the use of OTSC as primary and rescue therapy in the management of NVGIB. Further trials should clarify the ideal setting for the use of OTSC and assess the cost of these devices as compared to standard therapy. PMID- 30417631 TI - Introduction: combat damage-control resuscitation/surgery and beyond PMID- 30417632 TI - Laparoscopic aortobifemoral bypass in a United States academic center. AB - BACKGROUND: Although aortoiliac occlusive disease (AIOD) is preferentially treated endovascularly, some patients are still better served with an aortobifemoral bypass (ABF). For those patients, surgical treatment options include both standard open operations as well as laparoscopic ABF (LapABF). Several European centers perform LapABF with favorable results instead of open surgery, but this has not been widely embraced in the United States. We reviewed our ten-year experience with LapABF, evolving from a completely laparoscopic to a standardized laparoscopic-assisted approach. METHODS: A retrospective review of all laparoscopic aortic operations performed at a single US academic institution from 2005 to 2015 was completed. Demographics, co-morbidities, intraoperative parameters and clinical outcomes were recorded. Patients were excluded from consideration for laparoscopic surgery if they had previous aortic surgery, aneurysmal disease or gastrointestinal pathology (e.g. diverticulitis or an enteric stoma). RESULTS: Thirty men and sixteen women were treated, (n=46) with a mean age of 55.7 (range 38-75 years). All operations were performed by a single surgeon. LapABF was successfully completed in 95.6%. A completely laparoscopic approach was undertaken in eight patients and a laparoscopic-assisted approach was used in the remaining 38 patients. Mean follow-up was 46 months (range 1 to 131). The indication for operation was claudication (n=35, 76%), rest pain (n=8, 17%) or tissue loss (n=3, 7%). Twenty-one limbs had a history of a prior failed aortoiliac endovascular intervention (23%). Median length of stay was 6 days (range 2-30). Within 30 days there were two myocardial infarctions (4.3%), one transient ischemic attack (2.2%) and one death (2.2%). Re-intervention was performed in 12 patients over the course of the study period (26.1%). Primary, primary-assisted and secondary patency was 79.4%, 93.9% and 94.9% at 60 months, respectively. Overall mortality was 17% with a mean duration of follow-up of 60 months (range 1-116). Multivariable analysis revealed coronary artery disease (CAD; p=0.03) conferred a sixteenfold risk for death during long-term follow-up. CONCLUSIONS: In this large US series of LapABF, we observed acceptable long-term patency, short length of stay and minimal morbidity. We suggest that this standardized approach for laparoscopicassisted ABF is a viable option for patients with AIOD not suitable for endovascular therapy. The use of laparoscopic assisted ABF affords practitioners the benefits of a completely laparoscopic approach while reducing the duration and complexity of the operation. Given the rate of re-interventions in the early era practitioners should be aware of the Learning curve with this approach. PMID- 30417633 TI - The endovascular revolution continues. PMID- 30417634 TI - Current aspects in the evolution of fenestrated and branched grafting: an editorial comment. PMID- 30417635 TI - Infectious etiology of chronic diarrhea in patients with primary immunodeficiency diseases. AB - Summary: Background.Primary immunodeficiency diseases (PIDs) are life-threatening disorders, which manifest commonly with gastrointestinal (GI) signs, mainly as chronic diarrhea. Objective. To investigate and compare infectious etiology of chronic diarrhea in different PIDs. Patients and methods. Assessing clinical features, obtaining immunological profiles, as well as characterizing infectious etiology of diarrhea were performed in 38 PID patients with chronic diarrhea. Stool samples and/or biopsy specimens were checked using culture, microscopic examination, RT-PCR, and PCR, as appropriate. The patients were diagnosed to have common variable immunodeficiency (CVID), severe combined immunodeficiency (SCID), X-linked agammaglobulinemia (XLA), and hyper-IgM (HIgM) syndrome. Results. In 32 patients we identified 41 infectious agents including 16 parasitic (39.0%, the most common Giardia lamblia), 11 bacterial (26.8%, the most common salmonella spp), 8 viral (19.5%, the most frequent group A rotavirus), and 6 fungal organisms (14.7%, the most common Candida albicans). From 6 of the patients, no infectious agent was isolated. In CVID bacteria and parasites, in SCID bacteria and viruses, in XLA parasites, and in individuals with HIgM syndrome parasites were the leading causes of chronic diarrhea. Infection with giardia and cryptosporidium were more frequent in XLA and HIgM, respectively. Conclusion. The current study suggests considering both usual and unusual pathogens in laboratory investigation and in the empiric treatment of chronic diarrhea. Opportunistic pathogens should be taken into account when no other pathogen is identified, especially in patients on long-term treatment or prophylaxis with antifungals/antibiotics and in those from geographical locations that favor pathogenicity of these organisms. PMID- 30417636 TI - Cost-effectiveness of the SQ HDM SLIT-tablet for the treatment of allergic asthma in three Eastern European Countries. AB - Summary: Background.The standardized quality (SQ(r)) house dust mite (HDM) sublingual immunotherapy (SLIT)-tablet (acarizax(r), ALK-Abello A/S, Horsholm, Denmark) is an allergy immunotherapy tablet for people with allergic respiratory disease. This analysis aims to assess the cost-effectiveness of the SQ HDM SLIT tablet from the perspective of three Eastern European countries: Czech Republic, Poland and Slovakia. Methods.A cost-utility model per country was developed, which compared the SQ HDM SLIT-tablet as add-on to pharmacotherapy with pharmacotherapy alone in patients with HDM allergic asthma (AA) over a five year time horizon. The effectiveness of the two interventions was based on the results from a large-scale randomised controlled trial. In the models, annual costs and quality-adjusted life year (QALY) scores from the trial were extrapolated over a five year period, and the incremental cost-effectiveness ratios (ICERs) were estimated. One-way deterministic sensitivity and scenario analyses were undertaken. Results.The SQ HDM SLIT-tablet is cost-effective in all three markets over the five year time horizon (ICERs of less than ? 10,000 per additional QALY). Treatment with the SQ HDM SLIT-tablet improves patient outcomes, with QALY gains of 0.35, versus pharmacotherapy only. In all three countries, the SQ HDM SLIT-tablet also incurs increased costs compared to pharma-cotherapy treatment only. The sensitivity analysis identified utility values from the clinical trial as the main driver of the model results. Conclusion.The SQ HDM SLIT-tablet is a cost-effective treatment option for people with HDM AA in three different health care settings in Eastern Europe. PMID- 30417637 TI - Hypersensitivity reactions to non-vitamin K oral anticoagulants - a review of literature and diagnostic work-up proposal. AB - Summary: Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly being used in hospital and outpatient settings as safe alternatives to warfarin. Hypersensitivity reactions have been described for NOACs and can be classified according to Gell and Coombs. We reviewed case reports of possible drug hypersensitivity reactions, noticing a predominance of delayed reactions (both mild and severe) and the absence of cross-reactions to warfarin and low molecu lar weight heparins. International experience on diagnostic tests is lacking. The vast majority of authors refer to probability scores and rely on biopsy to classify vasculitis and rule out differential diagnoses. We propose to adapt available tests to confirm the patient's reactivity to new anticoagulants. Among in vivo tests, patch testing revealed promising in delayed reactions. PMID- 30417639 TI - Care of victims of suicide bombing AB - Summary: Suicide bombers often target crowds. This commentary discusses the additional features required in a medical response beyond conventional mass casualty care, including forensic documentation, preservation of evidence, suspect tissue identification and viral status, victim counselling and postexposure prophylaxis. We propose a pathway for care of victims of a suicide bomb, adapting elements from protocols for child abuse, sexual assault and needle stick exposure. PMID- 30417638 TI - Proposed specifications of a mobile operating room for far-forward surgery AB - Summary: Provision of initial surgery to casualties within one hour of injury is associated with better survival. Where evacuation options are limited, surgery within the "golden hour" may have to occur close to the point of injury. Interventions close to the point of injury are limited by the adverse environment. Far-forward surgery has a long history going back to Dominique Larrey of the Napoleonic Army. We reviewed previous reports and used our own experience of far-forward surgery to describe the specifications of the ideal mobile operating room that would address some of these environmental barriers. PMID- 30417640 TI - Ce4+-Based Compounds Capable of Photoluminescence by Charge Transfer Excitation under Near-Ultraviolet-Visible Light. AB - Ce4+-based charge transfer phosphor is not common and has been reported mainly in Sr2CeO4 with an excitation band peaking at ~290 nm, mismatching with the near ultraviolet light emitting diodes. Herein, we report a new series of Ce4+-based compounds Sr4.4Ce2.6REZnO12 (RE = Y, La, and Eu) capable of photoluminescence induced by O2--Ce4+ charge transfer excitation under near-ultraviolet-visible light. The crystal structure of Sr4.4Ce2.6EuZnO12 was determined by single crystal X-ray diffraction. The RE = La and Y samples were confirmed to be iso structure compounds of the RE = Eu sample by powder X-ray diffraction. By introducing highly covalent Zn2+-O2- bonds into the framework, the Ce4+-O2- bonds are lengthened due to the effect of the Ce4+-O2--Zn2+ stretch. The lengthened Ce4+-O2- bond weakens the repulsion of the electrons between Ce4+ and O2-, thereby lowering the charge transfer energy to the visible light region. Incorporation of Eu3+ into the present compounds realized red emission under near ultraviolet-visible excitation by the O2--Ce4+ charge transfer followed by energy transfer to Eu3+. PMID- 30417641 TI - Synthesis and Characterization of meso-Substituted Cobalt Tetradehydrocorrin and Evaluation of Its Electrocatalytic Behavior Toward CO2 Reduction and H2 Evolution. AB - A meso-aryl substituted cobalt(II) tetradehydrocorrin complex (Co(II)TDHC) has been synthesized and investigated. The corrin framework, determined by X-ray crystallographic analysis, is found to be relatively planar except at the C1 and C19 positions. Cyclic voltammetry (CV) measurements indicate two positively shifted reversible redox couples at -0.53 and -1.70 V vs Fc/Fc+ for [CoII]+/[CoI] and [CoI]/([CoI]*- and/or [CoII]-) ([CoII] = Co(II)TDHC), respectively, compared with the previously reported cobalt porphyrin complex, because the tetradehydrocorrin ligand efficiently promotes the formation of low-valent metal species due to its monoanionic character. Furthermore, it is found that the current in the CV measurement is significantly enhanced upon addition of H2O under a CO2 atmosphere, indicating the progression of electroreductive catalysis by Co(II)TDHC. However, controlled-potential electrolysis (CPE) using Co(II)TDHC under the same conditions shows generation of H2 as a major product and only a small amount of CO as a CO2 reduction product; Faradaic efficiencies are calculated to be 66.8 and 4.5%, respectively. The CPE with a buffer solution under an N2 atmosphere reveals that the selective H2 generation is promoted by the moderate acidification of the solution under CO2 saturation conditions. The present study demonstrates that the significantly stabilized Co(I) species with the monoanionic ligand framework preferentially catalyzes the thermodynamically favored H2 evolution rather than CO2 reduction. PMID- 30417642 TI - 1 H-1,2,3-Triazol-5-ylidenes: Readily Available Mesoionic Carbenes. AB - Classical carbenes are usually described as neutral compounds featuring a divalent carbon with only six electrons in their valence shell. It was only in 1988 that our group prepared the first isolable example, in which the carbene center was stabilized by a push-pull effect, using a phosphino and a silyl substituent. In the last 30 years, a myriad of acyclic and cyclic push-pull and push-push carbenes, bearing different heteroatom substituents, have been isolated. Among them, the so-called N-heterocyclic carbenes (NHCs), which include cyclic (alkyl)(amino)carbenes (CAACs), are arguably the most popular. They have found a vast number of applications ranging from catalysis to material science, and even in medicine. In this Account, we focus on the synthesis, structure, electronic properties, coordination, and applications of a different class of stable cyclic carbenes, namely, 1 H-1,2,3-triazol-5-ylidenes. In contrast with NHCs and CAACs, these compounds have no reasonable canonical resonance forms that can be drawn showing a carbene without additional charges. According to the IUPAC, they belong to the family of mesoionic compounds and thus they are named mesoionic carbenes (MICs). In 2010, we prepared the first stable 1,2,3-triazol-5 ylidene, via a CuAAC reaction, followed by alkylation of the resulting 1,2,3 triazole, and deprotonation. Later, we synthesized more robust N3-arylated counterparts from 1,3-diarylated-1 H-1,2,3-triazolium salts. Both synthetic routes can be carried out in multigram scales, making these MICS readily available. Importantly, MICs do not dimerize which contrasts with NHCs that can give the corresponding Wanzlick-type olefin. This property leads to relaxed steric requirements for their isolation; even C-unsubstituted MICs can be stored for months in the solid state at room temperature. The practicality and easily scalable syntheses of MICs allow for the preparation of polycarbenes, such as bis(1,2,3-triazol-5-ylidenes) (i-bitz), the analogues of the well-known 2,2' bipyridines (bpy). MIC-transition metal complexes are excellent precatalysts for variety of chemical transformations, which include hydrohydrazination of alkynes, olefin metathesis, reductive formylation of amines with carbon dioxide and diphenylsilane, hydrogenation and dehydrogenation of N-heteroarenes in water, cycloisomerization of enynes, asymmetric Suzuki-Miyaura cross-coupling, and water oxidation (WO) reactions. Besides their catalytic applications, MIC-transition metal complexes have found applications in material sciences as exemplified by the preparation of the first iron(III) complex that is luminescent at room temperature. The peculiar properties of mesoionic triazolylidenes, combined with their enhanced stability, position them as excellent candidates to address some current challenges such as access to high-oxidation-state 3d metal complexes, the stabilization of highly reactive main group elements, the stabilization of nanoparticles, the preparation of efficient catalysts and photosensitizers based on earth-abundant transition metals, and the functionalization of self-assembled monolayers (SAMs) on gold. PMID- 30417643 TI - Glutathione Utilization in Lactobacillus fermentum CECT 5716. AB - Glutathione, a tripeptide antioxidant, has recently been shown to be either utilized or synthesized by Gram-positive bacteria, such as lactic acid bacteria. Glutathione plays an important role in countering environmental stress, such as oxidative stress. In this study, cellular activity regarding glutathione in Lactobacillus fermentum CECT 5716 is characterized. We demonstrate that L. fermentum CECT 5716 has a better survival rate in the presence of glutathione under both oxidative and metal stress. As L. fermentum CECT 5716 does not possess the ability to synthesize glutathione under the conditions tested, it shows the ability to uptake both reduced and oxidized glutathione from the environment, regenerate reduced glutathione from oxidized glutathione, and perform secretion of glutathione to the environment. PMID- 30417644 TI - Toward Understanding of Self-Electrophoretic Propulsion under Realistic Conditions: From Bulk Reactions to Confinement Effects. AB - Active matter concerns itself with the study of particles that convert energy into work, typically motion of the particle itself. This field saw a surge of interest over the past decade, after the first micrometer-sized, man-made chemical motors were created. These particles served as a simple model system for studying in a well-controlled manner complex motion and cooperative behavior as known from biology. In addition, they have stimulated new efforts in understanding out-of-equilibrium statistical physics and started a revolution in microtechnology and robotics. Concentrated effort has gone into realizing these ambitions, and yet much remains unknown about the chemical motors themselves. The original designs for self-propelled particles relied on the conversion of the chemical energy of hydrogen peroxide into motion via catalytic decomposition taking place heterogeneously over the surface of the motor. This sets up gradients of chemical fields around the particle, which allow it to autophorese. That is, the interaction between the motor and the heterogeneously distributed solute species can drive fluid flow and the motor itself. There are two basic designs: the first relies on redox reactions taking place between the two sides of a bimetal, for example, a gold-platinum Janus sphere or nanorod. The second uses a catalytic layer of platinum inhomogeneously vapor-deposited onto a nonreactive particle. For convenience's sake, these can be referred to as redox motors and monometallic half-coated motors, respectively. To date, most researchers continue to rely on variations of these simple, yet elegant designs for their experiments. However, there is ongoing debate on the exact way chemical energy is transduced into motion in these motors. Many of the experimental observations on redox motors were successfully modeled via self-electrophoresis, while for half-coated motors there has been a strong focus on self diffusiophoresis. Currently, there is mounting evidence that self-electrophoresis provides the dominant contribution to the observed speeds of half-coated motors, even if the vast majority of the reaction products are electroneutral. In this Account, we will summarize the most common electrophoretic propulsion model and discuss its strengths and weaknesses in relation to recent experiments. We will comment on the possible need to go beyond surface reactions and consider the entire medium as an "active fluid" that can create and annihilate charged species. This, together with confinement and collective effects, makes it difficult to gain a detailed understanding of these swimmers. The potentially dominant effect of confinement is highlighted on the basis of a recent study of an electro-osmotic pump that drives fluid along a substrate. Detailed analysis of this system allows for identification of the electro-osmotic driving mechanism, which is powered by micromolar salt concentrations. We will discuss how our latest numerical solver developments, based on the lattice Boltzmann method, should enable us to study collective behavior in systems comprised of these and other electrochemical motors in realistic environments. We conclude with an outlook on the future of modeling chemical motors that may facilitate the community's microtechnological ambitions. PMID- 30417645 TI - Evaluation of Inhibitory Activities of UK-2A, an Antimycin-Type Antibiotic, and Its Synthetic Analogues against the Production of Anti-inflammatory Cytokine IL 4. AB - The inhibitory activities of the antimycin-class antibiotics UK-2A, antimycin A, and splenocin B against the production of anti-inflammatory cytokine IL-4, which is related to IgE-mediated allergic responses in rat basophilic leukemia (RBL 2H3) cells, were evaluated. Although antimycin A and splenocin B showed cytotoxicity at concentrations at which IL-4 release from the cells was restricted, UK-2A was found to restrict IL-4 release without cytotoxicity. Three UK-2A analogues (4-6) were then synthesized and assessed. Compound 5 restricted IL-4 release dose-dependently without cytotoxicity, and its effect was more potent than that of UK-2A. PMID- 30417646 TI - Layered Hybrid Zincophosphites for Room Temperature Phosphorescent Emission. AB - Two layered zincophosphites constructed from an emissive linker molecule were prepared. The ligand connects zincophosphite chains or clusters to form two distinct two-dimensional hybrid frameworks in two compounds. The coordinating effect of an organic ligand to Zn centers increases the rigidity and results in room temperature phosphorescence. PMID- 30417647 TI - Elucidation and Heterologous Reconstitution of Chrodrimanin B Biosynthesis. AB - The biosynthetic gene cluster of the fungal meroterpenoid chrodrimanin B (4) was discovered in Penicillium verruculosum TPU1311, and the complete biosynthetic pathway of 4 has been elucidated by heterologous reconstitution of its biosynthesis in Aspergillus oryzae, as well as by in vitro characterizations of selected enzymes. The present study has identified the polyketide synthase that produces 6-hydroxymellein (3) and also provided a biosynthetic platform of chrodrimanins for further bioengineering. PMID- 30417649 TI - PPh3AuTFA Catalyzed in the Dearomatization of 2-Naphthols with Allenamides. AB - A new catalytic methodology for the direct dearomatization of substituted 2 naphthols via intermolecular condensation with allenamides is presented. PPh3AuTFA (5 mol %) promotes the formal allylating dearomative protocol under mild conditions, large scope (24 examples), and high regioselectivity and stereoselectivity. The synergistic catalytic role played by the [PPh3Au]+ (pi acid) and TFA- (Lewis base) is highlighted. PMID- 30417648 TI - Linking the Gastrointestinal Behavior of Ibuprofen with the Systemic Exposure between and within Humans-Part 2: Fed State. AB - Exploring the intraluminal behavior of an oral drug product in the human gastrointestinal (GI) tract remains challenging. Many in vivo techniques are available to investigate the impact of GI physiology on oral drug behavior in fasting state conditions. However, little is known about the intraluminal behavior of a drug in postprandial conditions. In a previous report, we described the mean solution and total concentrations of ibuprofen after oral administration of an immediate-release (IR) tablet in fed state conditions. In parallel, blood samples were taken to assess systemic concentrations. The purpose of this work was to statistically evaluate the impact of GI physiology (e.g., pH, contractile events) within and between individuals (intra and intersubject variability) for a total of 17 healthy subjects. In addition, a pharmacokinetic (PK) analysis was performed by noncompartmental analysis, and PK parameters were correlated with underlying physiological factors (pH, time to phase III contractions postdose) and study parameters (e.g., ingested amount of calories, coadministered water). Moreover, individual plasma profiles were deconvoluted to assess the fraction absorbed as a function of time, demonstrating the link between intraluminal and systemic behavior of the drug. The results demonstrated that the in vivo dissolution of ibuprofen depends on the present gastric pH and motility events at the time of administration. Both intraluminal factors were responsible for explaining 63% of plasma Cmax variability among all individuals. For the first time, an in-depth analysis was performed on a large data set derived from an aspiration/motility study, quantifying the impact of physiology on systemic behavior of an orally administered drug product in fed state conditions. The data obtained from this study will help us to develop an in vitro biorelevant dissolution approach and optimize in silico tools in order to predict the in vivo performance of orally administered drug products, especially in fed state conditions. PMID- 30417650 TI - Four new C19-diterpenoid alkaloids from Aconitum hemsleyanum var. circinatum. AB - Four new C19-diterpenoid alkaloids, hemaconitines A-D (1-4), were isolated from the roots of Aconitum hemsleyanum var. circinatum. Their structures were elucidated as 19R-hydroxyl-secoyunnaconitine (1), (3R)-hydroxyl-liwaconitine (2), 14-anisoyl-leucanthumsine E (3), and 19R -acetonyl-8-O-methyltalatisamine (4) by extensive spectroscopic analysis (IR, UV, HR-ESI-MS, 1D, and 2D NMR). PMID- 30417651 TI - Microstructural Findings in White Matter Associated with Cannabis and Alcohol Use in Early-Phase Psychosis: A Diffusion Tensor Imaging and Relaxometry Study. AB - Accumulating evidence suggests that brain white matter (WM) abnormalities may be central to the pathophysiology of psychotic disorders. In addition, there is evidence that cannabis use and alcohol use each is associated with WM abnormalities. However, there are very limited data on the effects of these substances on WM microstructure in patients with psychosis, especially for those at the early phase of illness. This project aimed to examine the impact of cannabis use and alcohol use on WM tissue in early-phase psychosis (EPP). WM was investigated in 21 patients with EPP using diffusion tensor imaging (DTI) and transverse relaxation time of tissue water (T2), with the primary outcomes being mean fractional anisotropy (FA) and T2. DTI analyses were performed at the full brain level using tract-based spatial statistics with both DTI and T2 analysis done within a WM volume of interest (VOI) implicated in psychosis (containing the left superior longitudinal fasciculus). Our findings revealed that younger age of onset of regular alcohol use (more than one drink per week) was associated with lower FA values in the left thalamic radiation and left parahippocampal and left amygdalar WM. More frequent lifetime cannabis use was correlated with increased mean full-brain FA. There was no significant relationship found between FA and alcohol or cannabis use within the VOI. Relaxometry analysis revealed trend-level evidence of shortened T2 with later onset of regular alcohol use and with more frequent cannabis use. This study provides novel data demonstrating cortical and subcortical WM findings related to alcohol use in EPP and is the first to combine DTI and relaxometry, relating to this patient population. PMID- 30417652 TI - Identification and integrated analysis of key differentially expressed circular RNAs in ER-positive subtype breast cancer. AB - AIM: To systematically profile and characterize the circular RNA (circRNA) expression pattern in estrogen receptor (ER)-positive breast cancer (BC). MATERIALS & METHODS: CircRNA expression profile was performed in ER-positive BC and adjacent nontumor tissues. The differentially expressed circRNAs (DECs) was analyzed by bioinformatics. The analysis findings were validated by quantitative real-time PCR. RESULTS: In total, 3653 DECs were detected in our ER-positive BC compared with the control. Bioinformatics analysis showed that some pathways related to cancer, especially BC, were significantly enriched. Additionally, hsa_circ_0087378 was validated to be downregulated in ER-positive BC and the hsa_circ_0087378-miR-1260b-SFRP1 axis was proposed to be a key regulatory pathway. CONCLUSION: This study revealed the general expression characteristics of specific DECs in ER-positive BC and hsa_circ_0087378 might be a promising candidate target. PMID- 30417653 TI - Conditioning on Parity in Studies of Perfluoroalkyl Acids and Time to Pregnancy: An Example from the Danish National Birth Cohort. AB - BACKGROUND: Previous studies have investigated the associations between perfluoroalkyl acids (PFAAs) in women and time to pregnancy (TTP). Inconsistent results may be explained by differences in conditioning on parity. OBJECTIVES: We used causal directed acyclic graphs to illustrate potential confounding related to previous pregnancies and exposure measurement error due to differences in the interpregnancy interval in pregnancy-based studies that include parous women. We exemplified the potential importance of these issues using data from the Danish National Birth Cohort. METHODS: We used discrete time survival models to estimate associations between maternal plasma PFAAs in early pregnancy and TTP in 638 nulliparous and 613 parous women. RESULTS: PFAA quartiles were not associated with the TTP in nulliparous women. In parous women, higher PFAA quartiles were associated with longer TTP. The strongest associations were estimated for perfluorohexane sulfonate and perfluorooctane sulfonate. PFAA concentrations were higher in women with longer interpregnancy intervals. Accounting for the interpregnancy interval attenuated the estimated associations. CONCLUSIONS: Associations between PFAAs and TTP in parous women may be biased by confounders related to previous pregnancies and exposure measurement error. To avoid these biases, studies that include parous women may need to condition on a) common causes of PFAAs and the TTP in the index pregnancy, b) previous births (a descendant of a collider), c) PFAA levels or common causes of PFAA levels and the TTP in the previous pregnancy (to alleviate collider stratification bias caused by conditioning on previous births), and d) the interpregnancy interval (in pregnancy-based studies). Alternatives would be to restrict studies to nulliparous women or to use toxicokinetic modeling to correct exposure estimates in parous women. These recommendations may be extended to studies of other chemicals with similar toxicokinetic properties. https://doi.org/10.1289/EHP1493. PMID- 30417654 TI - Chemical components of Hyssopus cuspidatus Boriss.: isolation and identification, characterization by HPLC-DAD-ESI-HRMS/MS, antioxidant activity and antimicrobial activity. AB - Eighteen compounds were isolated from the ethyl acetate fraction of the aerial part of Hyssopus cuspidatus. Their structures were established by analysis of mass and NMR data, as well as comparison with previous published data in the literatures. Among them, ten compounds were found from the Hyssopus genus for the first time, and one compound was isolated from H. cuspidatus for the first time. HPLC-DAD-ESI-HRMS/MS investigations was applied to further obtain the phenolic profiling of the ethyl acetate fraction, and nine derivatives of caffeic acid and ferulic or isoferulic acid were identified. Antioxidant activity against DPPH free radical and antibacterial activity against Candida albicans, Escherichia coli and Staphylococcus aureus were evaluated. The ethyl acetate fraction exhibited weak antioxidant activity and moderate antibacterial activity. The isolated compounds showed weak to potent antioxidant and antibacterial activity. To the best of our knowledge, this is the first report on the antioxidant and antibacterial activity of H. cuspidatus. PMID- 30417655 TI - Myocardial energy stress, autophagy induction and cardiomyocyte functional responses. AB - SIGNIFICANCE: Energy stress in the myocardium occurs in a variety of acute and chronic pathophysiologic contexts including ischemia, nutrient deprivation, and diabetic disease settings of substrate disturbance. Although the heart is highly adaptive and flexible in relation to fuel utilization and routes of ATP generation, maladaptations in energy stress situations confer functional deficit. An understanding of the mechanisms which link energy stress to impaired myocardial performance is crucial. Recent Advances: Emerging evidence suggests that, in parallel with regulated enzymatic pathways which control intracellular substrate supply, other processes of 'bulk' autophagic macromolecular breakdown may be important in energy stress conditions. Recent findings indicate that cargo specific autophagic activity may be important in different stress states. In particular, induction of glycophagy, a glycogen specific autophagy, has been described in acute and chronic energy stress situations. The impact of elevated cardiomyocyte glucose flux relating to glycophagy dysregulation on contractile function is unknown. CRITICAL ISSUES: Ischemic and diabetic related cardiac adverse events comprise the majority of cardiovascular disease morbidity and mortality. Current therapies involve management of systemic comorbidities. Cardiac-specific adjunct treatments targeted to manage myocardial energy stress responses are lacking. FUTURE DIRECTIONS: New knowledge is required to understand the mechanisms involved in selective recruitment of autophagic responses in the cardiomyocyte energy stress response. In particular, exploration of the links between cell substrate flux, activator Ca2+ flux and phagosomal cargo flux is required. Strategies to target specific fuel 'bulk' management defects in cardiac energy stress states may be of therapeutic value. PMID- 30417656 TI - Repertoire of bacterial species cultured from the human oral cavity and respiratory tract. AB - While the gut microbiota is currently in the spotlight, the airway microbiome has been recently associated with several pulmonary diseases and carcinogenesis. As there are several biases associated with high-throughput sequencing methods, cultivation techniques are crucial for the investigation of the human microbiome. We thus aimed to build an exhaustive database, including a list of microbes isolated by culture from respiratory specimens, by performing a review of the literature. Herein, we have listed a total of 756 species cultured from the human respiratory tract. This represents 27.23% of the overall bacterial richness captured from human being by culture methods. This repertoire could be valuable for the elucidation of the interactions between the respiratory microbiome and human health. PMID- 30417658 TI - Nitrite protects neurons against hypoxic damage through S-nitrosylation of caspase-6. AB - AIMS: The coordination of neurons to execute brain functions requires plenty of oxygen. Thus, it is not surprising that the chronic hypoxia resulting from chronic obstructive pulmonary diseases (COPD) can cause neuronal damage. Injury in the cortex can give rise to anxiety and cognitive dysfunction. This study investigated what causes hypoxia-induced neuronal injury and what strategies might be used to protect neurons against such damage. RESULTS: This study found that hypoxia in primary cortical neurons caused neurite retraction, a caspase-6 dependent process. The hypoxic stress activated caspase-6 within the neurite, leading to microtubule disassembly and neurite retraction. The effect of hypoxia on caspase-6 activation, microtubule disassembly and neurite retraction was alleviated by nitrite treatment. The protective role of nitrite was further supported by the observation that the active-site Cys146 of caspase-6 was S nitrosylated in hypoxic N2a cells treated with nitrite. We further validated the beneficial effect of nitrite on neuronal function against hypoxic stress in vivo. Using the wild-type or Apo E-/- mice exposed to chronic hypoxia as a model, we demonstrated that supplementing drinking water with nitrite suppressed active caspase-6 in the cortex of the brain, concomitant with the prevention of hypoxia induced anxiety in the animals. INNOVATION: These results are the first evidence of a new pathway for the activation of caspase-6 and the first to indicate that nitrite can protect neurons against chronic hypoxic insult. CONCLUSION: Our findings suggest that nitrite holds great potential for the treatment of diseases such as COPD associated with hypoxia-induced neuronal injury. PMID- 30417657 TI - Genetic diversity of rhinoviruses detected at a tertiary hospital in Catalonia (Spain) during the 2014-2017 seasons. AB - AIM: To describe the genetic diversity of rhinovirus (RV) from patients attended at a tertiary hospital in Barcelona (Spain) from October 2014 to May 2017. METHODS: RV detection was performed by real-time multiplex RT-PCR. A specific real-time quantitive retrotranscription PCR (qRT-PCR) was carried out to select those samples (Ct < 35) for molecular characterization based on partial VP4/2 protein. RESULTS: Phylogenetic characterization revealed proportions of 63% RV-A, 6% RV-B and 31% RV-C (119 different types). RV-A circulated throughout all the study period, with a minor circulation during winter, just when RV-C prevailed. Differences between age medians by RV-specie were reported. CONCLUSION: The large genetic diversity of RV detected in our area is described here. The variable cocirculation of multiple RV types is also reported, showing differences by age. PMID- 30417659 TI - Design, identification, antifungal evaluation and molecular modeling of chlorotetaine derivatives as new anti-fungal agents. AB - It is feasible to rationally modify existing bioactive components for new drug development, achieving molecules with improved biological activities. In this study, rational modification of chlorotetaine was carried out following in silico molecular modelling to enhance interactions between the fungal oligopeptide transmembrane transporter PTR22 and the ligand. The peptide obtained with the lowest docking energy, Lys-chlorotetaine (LC), displayed an improved antifungal effect compared with chlorotetaine. The lowest minimum inhibitory concentration observed against a tested pathogen was 1.47 ug/mL (Candida krusei CBS573), which was satisfactory. To thoroughly explore the detailed interactions between the transporter and LC, molecular dynamics simulation was also performed, which revealed that LC could bind to the transporter via different intermolecular interactions from chlorotetaine, and predicted electrostatic interactions (salt bridges) would enable the more efficient release of LC. This study provides a simple and reliable method for the rational modification of oligopeptide antibiotics. PMID- 30417660 TI - Two new polyketides isolated from a diethyl sulphate mutant of marine-derived Penicillium purpurogenum G59. AB - Two new polyketides, purpurofuranone (1) and purpuropyranone (2), were isolated along with the known polyketides, cillifuranone (3) and taiwapyrone (4), from a mutant BD-3n-1 derived from the diethyl sulfate (DES) mutagenesis of a marine derived Penicillium purpurogenum G59. The structures of 1 and 2 were elucidated by spectroscopic methods especially on the basis of X-ray diffraction and calculated optical rotations data. The plausible biosynthesis of 1 - 4 was also proposed and discussed. In preliminary MTT assay, 1 - 4 showed no notable inhibitory effects on the tested four human cancer cell lines. PMID- 30417661 TI - Two new chromene derivatives from Artemisia songarica. AB - Two new chromene derivatives, songaricachromenes A (1) and B (2), were isolated from Artemisia songarica, along with 10 known compounds (3-12). The structures and stereochemistry of the new compounds were elucidated by analyses of the NMR, MS, and electronic circular dichroism (ECD) data. All the isolates (1-12) were evaluated for their NO inhibitory effects on LPS-stimulated BV-2 microglial cells. [Formula: see text]. PMID- 30417662 TI - Low-dose rivaroxaban plus aspirin for the prevention of cardiovascular events: an evaluation of COMPASS. AB - The cardiovascular outcomes for people using anticoagulation strategies (NCT01776424) trial randomized 27,395 patients with stable coronary artery disease or peripheral artery disease (PAD) to receive rivaroxaban 5 mg twice daily alone, the combination of rivaroxaban 2.5 mg twice-daily and aspirin 100 mg daily, or aspirin 100 mg daily alone. The combination arm resulted in a 24% reduction in the primary end point of cardiovascular death, stroke or myocardial infarction, and an 18% reduction in mortality. Rivaroxaban alone did not produce any additional benefit compared with aspirin. The combination therapy also reduced major adverse limb events, including amputation, in patients with PAD. Based on these results, the addition of rivaroxaban to aspirin is expected to substantially reduce morbidity and mortality in patients with stable coronary or PAD. PMID- 30417663 TI - Santin inhibits influenza A virus replication through regulating MAPKs and NF kappaB pathways. AB - Influenza A virus (IAV) causes high morbidity and significant mortality worldwide. Given the limitations of existing vaccination and antiviral drugs, it is urgent to develop new anti-influenza drugs. Flavonoids are natural polyphenolic compounds with broad applications to treatments for influenza infection. In this study, we demonstrated that santin, a flavonoid compound, showed anti-influenza activity in MDCK and THP-1 cells. Mechanistic studies revealed that santin depressed the phosphorylation of p38 MAPK, JNK/SAPK, ERK, and NF-kappaB factor and subsequently attenuated the expression of inflammatory cytokines in IAV-infected cells. Thus, santin is a potential candidate for the future development of anti-IAV drugs. [Formula: see text]. PMID- 30417664 TI - EEG Resting-State Networks Responsible for Gait Disturbance Features in Idiopathic Normal Pressure Hydrocephalus. AB - Idiopathic normal pressure hydrocephalus (iNPH) is a neuropsychiatric disease characterized by gait disturbance, cognitive dysfunction, and urinary incontinence that affects a large population of elderly people. These symptoms, especially gait disturbance, can potentially be improved by cerebrospinal fluid (CSF) drainage, which is more effective if performed at an early stage of the disease. However, the neurophysiological mechanisms of these symptoms and their recovery by CSF drainage are poorly understood. In this study, using exact low resolution brain electromagnetic tomography-independent component analysis (eLORETA-ICA) with electroencephalography (EEG) data, we assessed activities of five EEG resting-state networks (EEG-RSNs) in 58 iNPH patients before and after drainage of CSF by lumbar puncture (CSF tapping). In addition, we assessed correlations of changes in these five EEG-RSNs activities with CSF tapping induced changes in iNPH symptoms. The results reveal that compared with 80 healthy controls, iNPH patients had significantly decreased activities in the occipital alpha rhythm, visual perception network, and self-referential network before CSF tapping. Furthermore, CSF tapping-induced changes in occipital alpha activity correlated with changes in postural sway and frontal lobe function. Changes in visual perception network activity correlated with changes in gait speed. In addition, changes in memory perception network activity correlated with changes in Parkinsonian gait features. These results indicate a recruitment of cognitive networks in gait control, and involvement of the occipital alpha activity in cognitive dysfunction in iNPH patients. Based on these findings, eLORETA-ICA with EEG data can be considered a noninvasive, useful tool for detection of EEG-RSN activities and for understanding the neurophysiological mechanisms underlying this disease. PMID- 30417665 TI - Neuroprotective terpenoids from the leaves of Viburnum odoratissimum. AB - As a part of our ongoing search for neuroprotective compounds from natural products, two new iridoid glycosides, vibsansuspenside A-B (1-2), along with five known terpenoids (3-7), were isolated from the dry leaves of Viburnum odoratissimum. Their chemical structures were well determined by means of NMR spectroscopic data as well as HRESIMS analysis. All compounds were detected for their neuroprotective effects against H2O2-induced damage in human dopaminergic neuroblastoma cells (SH-SY5Y). Among them, compound 3 displayed the most potent neuroprotective ability, and further investigation by Annexin V/PI and Western blot analysis demonstrated that compound 3 could protect SH-SY5Y cells from oxidative damage through inhibiting cell apoptosis. [Formula: see text]. PMID- 30417666 TI - Chemical composition and antioxidant activity of Phlomis leucophracta, an endemic species from Turkey. AB - The chemical composition, and antioxidant activity of the essential oils of the endemic Phlomis leucophracta P. H. Davis et Hub.-Mor. was investigated. The major compounds of the essential oil were linalool (36.4%), spathulenol (8.4%) and caryophyllene oxide (8.4%). The composition of the oil differs with published data, suggesting other chemotype. Moreover, the oil of this species was analysed for its antioxidant activity for the first time and results indicate it possess strong antioxidant activity comparable with already known antioxidants, such as ascorbic acid, BHT, or Trolox. Presented results suggest that this endemic species has strong potential to be used in food and pharmacological industries, and therefore they need to be further investigated. PMID- 30417667 TI - Sequence analysis of isolates of Aspergillus from patients with chronic and allergic aspergillosis reveals a spectrum of cryptic species. AB - AIM: To establish the prevalence and antifungal susceptibilities of Aspergillus cryptic species from respiratory samples. Methods: Retrospective susceptibility data on Aspergillus species cultured between 2015 and 2017 by 'high volume culture' (HVC) versus 'conventional' culture techniques. RESULTS: Fifty-six (2.5%) isolates were identified as Aspergillus cryptic species by sequencing of ITS, BenA and CalM gene loci. Recovery was higher in HVCs compared to conventional cultures. Common cryptic species were Aspergillus montevidensis (n = 15), A. creber (n = 11), A. sydowii (n = 5) and A. calidoustus (n = 4). Eighteen (32.1%) isolates had minimum inhibitory concentration (MIC) values >=4 mg/l to amphotericin B, and 19.1-60.1% had MIC values >=8 mg/l to the triazoles. CONCLUSION: HVC increases the likelihood of recovery of cryptic species. MIC values to antifungals were high. PMID- 30417668 TI - Geographical variations in the use of diagnostic imaging of musculoskeletal diseases in Norway. AB - BACKGROUND: There is a high prevalence of musculoskeletal disorders in the Norwegian population. A significant number of these patients are referred to diagnostic imaging. Geographical variations in the use of imaging for musculoskeletal disorders may display over- or underuse, and knowledge about these variations is required. PURPOSE: To investigate geographical variations in diagnostic imaging of the musculoskeletal system and analyze variations in the use of these examinations of all musculoskeletal diagnostic imaging, the specific modalities, and specific examinations. MATERIAL AND METHODS: Population rates from Statistics Norway and outpatient radiological procedures of the musculoskeletal system registered at the Norwegian Health Economics Administration (HELFO) the first half of 2016 were accessed. The HELFO data were age-adjusted; high/low ratios were calculated as rates in number of examinations per 1000 inhabitants. A high/low ratio of 1 = equal use, 1.5-1.9 = moderate variation (approximately 50% difference), and > 2 (twice as much) = high variation. RESULTS: Geographical variations were demonstrated at all levels, with an overall high/low ratio of 1.3. For specific modalities the highest variation was for ultrasound (3.2) and CT (2.2). For individual examinations, the highest high/low ratios were observed for MRI of the shoulder (2.4) and radiography of the lower back (1.9) and shoulder (1.8). CONCLUSION: We demonstrate a moderate to high geographical variation in the use of diagnostic imaging of the musculoskeletal system. This variation can indicate over- or underuse, which may violate basic principles of equity, priority, setting and appropriate care, and needs further attention. PMID- 30417669 TI - Metabolite profiling and in-vitro colon cancer protective activity of Cycas revoluta cone extract. AB - The methanolic extract of Cycas revoluta cone (MECR) was analyzed by GC-MS and UHPLC for metabolite profiling and was evaluated for anti-colon cancer property by using in vitro assays like Cell Viability Assay, Colony Formation Assay, ROS Determination, Flowcytometry, DAPI staining assay, Tunel assay. GC-MS and HPLC analysis confirmed the presence of different phytochemicals in the extract of Cycas revoluta cone. In-vitro studies showed MECR extract showed significant anti colon cancer activity by reducing proliferation and inducing apoptosis in colon cancer cell (HCT-8) line, but no such activity was seen in normal colon cell (CCD 18Co) line. The investigation confirms that MECR may be a promising candidate in colon cancer protection. PMID- 30417670 TI - Participation in Pulmonary Rehabilitation Following Hospitalization for COPD among Medicare Beneficiaries. AB - RATIONALE: Current guidelines recommend pulmonary rehabilitation (PR) after hospitalization for a COPD exacerbation, but little is known about its adoption or factors associated with participation. OBJECTIVES: To evaluate receipt of PR after a hospitalization for COPD exacerbation among Medicare beneficiaries and identify individual- and hospital-level predictors of PR receipt and adherence. METHODS: We identified individuals hospitalized for COPD during 2012 and recorded receipt, timing, and number of PR visits. We used generalized estimating equation models to identify factors associated with initiation of PR within 6 months of discharge and examined factors associated with number of PR sessions completed. RESULTS: Of 223,832 individuals hospitalized for COPD, 4,225 (1.9%) received PR within 6 months of their index hospitalization and 6,111 (2.7%) within 12 months. Median time from discharge until first PR session was 95 days (IQR 44 - 190) and median number of sessions completed was 16 (IQR 6-25). The strongest factor associated with initiating PR within 6 months was prior home oxygen use (OR: 1.49; 95% CI: 1.39 - 1.59). Individuals aged 75-84 and 85 and over (0R: 0.71; 95% CI: 0.66 - 0.76; OR: 0.25; 95% CI: 0.22 -0.29), those living over 10 miles from a PR facility (OR: 0.47; CI: 0.42 - 0.51) and those with lower SES (OR: 0.42; 95% CI 0.38 - 0.46) were less likely to receive PR. CONCLUSIONS: Two years after Medicare began providing coverage for PR, participation rates following hospitalization were extremely low. This highlights the need for strategies to increase participation. PMID- 30417671 TI - Chromatographic characterization on flavonoids and triterpenes of leaves and flowers of 15 crataegus L. species. AB - The Hawthorn (Crataegus L.) is the most commonly used herb for treating cardiovascular diseases. The purpose of this paper was the analysis and comparison of HPTLC chromatographic profiles of flavonoids and triterpenes of leaves and flowers of 15 Crataegus L. species occurring throughout Eurasia and North America, and determination of specific distinguishing markers of its fingerprints. The optimal chromatographical conditions for evaluation of flavonoids and triterpenes of 15 Hawthorn species were proposed, the specific HPTLC fingerprints were obtained. The flavonoids fingerprints were qualitatively much the same for the pharmacopoeial species C.laevigata/oxyacantha and C.monogyna and other related non-pharmacopoeial European and Asian Hawthorn species including C.curvisepala, C.pseudokyrtostyla, C.fallacina, C.leiomonogyna, C.ambigua, C.sanguinea, C.almaatensis, C.turkestanica. The specific distinctive features for Hawthorn species native to North America, including C.punctata var aurea, C.pringlei, C.festiva, C.douglasii and C.holmesiana, were determined. The evaluation of the triterpenes profiles showed that all 15 analyzed Hawthorn species had quite similar fingerprints. PMID- 30417672 TI - Acridone alkaloids from the rhizomes of Luvunga scandens (Roxb.) Buch. Ham. AB - The ethyl acetate extract of the rhizomes of Luvunga scandens (Roxb.) Buch. - Ham. ex Wight & Arn (Rutaceae) delivered one new acridone alkaloid named Luvungaside A (1) together with three known acridone alkaloids, namely 1,3 dihydroxy-2-methoxy-10-methyl-9-acridone (2), arborinine (3) and 1-hydroxy-3 methoxy-10-methyl-9-acridone (4). Compounds were reported for the first time from the species L. scandens applying various chromatography methods. Chemical structures were elucidated by IR, UV, HR-ESI-MS, NMR 1D & 2D experiments and comparison with the literature. The cytotoxicity and hepatoprotective activity of compounds 1-4 in human hepatoma cell line HepG2 was measured by MTT assay. At 10 100 MUM, compounds expressed significant hepatoprotective effect with prevention percentage ranging from 81.1% to 194.3%, compared to the positive control quercetin displaying 49.0%. PMID- 30417673 TI - Novel cyclohexene and benzamide derivatives from marine-associated Streptomyces sp. ZZ502. AB - Three new compounds and the known benzamides of 2-acetamido-3-hydroxybenzamide, 2 amino-3-hydroxybenzamide, and 2-aminobenzamide were isolated from the culture of a marine actinomycete Streptomyces sp. ZZ502. Structures of the new compounds were determined as 3-amino-2-carboxamine-6(R)-chloro-4(R),5(S)-dihydroxy-cyclohex 2-en-1-one, 3-amino-2-carboxamine-4(S),6(S)-dihydroxy-cyclohex-2-en-1-one, and 3 hydroxy-2-propionamidobenzamide based on extensive NMR spectroscopical analysis, HRESIMS data, ECD calculation, and X-ray diffraction analysis. None of these isolated compounds showed activity in inhibiting the proliferation of glioma cells nor the growth of methicillin-resistant Staphylococcus aureus, Escherichia coli, and Candida albicans. PMID- 30417674 TI - A new antimicrobial sesquiterpene isolated from endophytic fungus Cytospora sp. from the Chinese mangrove plant Ceriops tagal. AB - Chemical examination of Chinese mangrove Ceriops tagal endophytic Cytospora sp., yielded a new biscyclic sesquiterpene seiricardine D (1), and eight known metabolites, xylariterpenoid A (2a), xylariterpenoid B (2b) and regiolone (3) 4 hydroxyphenethyl alcohol (4), (22E, 24R)5, 8-epidioxy-5alpha, 8alpha-ergosta 6,22E-dien-3beta-ol (5), (22E, 24R)5, 8-epidioxy-5alpha, 8alpha-ergosta-6,9(11), 22-trien-3 beta-ol (6), beta-sitosterol (7) and stigmast-4-en-3-one (8). These structures were unambiguously elucidated on the basis of extensive NMR spectroscopic and mass spectrometric analyses. The antimicrobial activities of compounds 1-8 and their effects on a panel of plant and human pathogens were evaluated. PMID- 30417676 TI - Insecticidal, cytotoxic and anti-phytopathogenic fungal activities of chemical constituents from the aerial parts of Ferula sinkiangensis. AB - A new rare monoterpene coumarin (1) and its two known analogues (2-3), together with two sesquiterpenes (6-7) and ferulic acid (8) were isolated from the aerial parts of Ferula sinkiangensis. The structure of new compound was established on the basis of 1D and 2D NMR data and HRESIMS data interpretation. Insecticidal, cytotoxic and anti-phytopathogenic fungal activities of isolated compounds were evaluated against third-instar larvae of Spodoptera exigua and its cell line, and three plant pathogenic fungi respectively. Compounds 1-3 and 6-7 were found to be more effective contact toxicity to S. exigua with the corrected mortality values of 38.89%-58.89% at 10 MUg/larva doses for 24 h. Further studies showed that compounds 3 and 6 exhibited cell growth inhibitory activity against S. exigua cell line with the EC50 values of 22.78 and 14.64 uM for 72 h. In addition, compound 6 exhibited potent antifungal activity with MICs = 16-32 ug/mL. PMID- 30417675 TI - alpha-Mangostin exhibits antidepressant-like effects mediated by the modification of GABAergic, serotonergic and dopaminergic systems. AB - The present study explored the antidepressant-like activity of alpha-mangostin (alpha-MG) and the possible mechanism in this process in the tail suspension test (TST) in mice. The results revealed that alpha-MG (5 mg/kg, i.p.) exhibited markedly antidepressant-like activity, which could be reversed by pretreatment with haloperidol (a non-selective D2 receptor antagonist), bicuculline (a competitive GABA antagonist), p-chlorophenylalanine (an inhibitor of 5-HT synthesis). Meanwhile, alpha-MG also effectively increased the brain DA, 5-HT and GABA levels in mice exposed to TST, indicating that the antidepressant-like effect of alpha-MG might be mediated by the GABAergic, serotonergic and dopaminergic systems. [Formula: see text]. PMID- 30417677 TI - Two new tetralone glycosides from the green walnut husks of Juglans mandshurica Maxim. AB - Two new tetralone glycosides, 4(S)-5-methoxy juglanoside A (1), 4(S)-5-methoxy juglanoside D (2), together with ten known compounds (3-12) have been isolated from the green walnut husks of Juglans mandshurica Maxim. Their structures were elucidated on the basis of their ESI-MS, 1 D and 2 D NMR spectroscopic data. In addition, all compounds were evaluated for their cytotoxic activities against the cancer BGC-823 (human gastric carcinoma), HCT-15 (human colorectal carcinoma) and K562 (human chronic myeloid leukemia) cell lines. The results showed aglycones of naphthoquinones had stronger cytotoxic activities than glycosides of tetralone. PMID- 30417678 TI - Phytochemical compounds and antiradical, antimicrobial, and cytotoxic activities of the extracts from Hypericum scabrum L. Flowers. AB - Hypericum scabrum L. has been widely used in traditional medicine for the treatment of many diseases just as the other Hypericum species. In the present study, the antiradical, antimicrobial and cytotoxic activities of water and ethanol extracts of H. scabrum flowers were investigated. Their phytochemical contents and composition were also determined. The water and ethanol extracts are better scavenged ABTS (97.89 and 98.99%) and OH radicals (96.36 and 97.33%); the water extract is better scavenged DPPH radicals (91.66%) than the standard antioxidant BHA (94.33, 85.19, 90.16%, respectively). Flowers of H. scabrum contain flavonoids, phenolic acids, vitamins and phytosterols, dominated by catechin, vanillic acid, vitamin K and ergosterol. The extracts exhibit a strong cytotoxic activity against MCF-7, HCT-116, and LNCaP cancer cell lines. It is found that their antimicrobial activities are higher than the standard antibiotics. These results indicate that H. scabrum flowers have potent antiradical, antimicrobial and cytotoxic activities. PMID- 30417679 TI - Tracheal diverticulum as a rare cause of dysphagia. AB - Tracheal diverticula are rare benign entities characterized by small air-filled invaginations in the paratracheal area. They may be single or multiple, and usually present with nonspecific symptoms. Ideally, computed tomography imaging studies are used to confirm the diagnosis, followed by surgical resection as the treatment of choice. We present the case of a woman with an acquired tracheal diverticulum, with dysphagia as the only presenting symptom. PMID- 30417680 TI - Validity assessment of a simulation module for robot-assisted thoracic lobectomy. AB - BACKGROUND: Training for robot-assisted thoracic lobectomy remains an issue, prompting the development of virtual reality simulators. Our aim was to assess the construct and face validity of a new thoracic lobectomy module on the RobotiX Mentor, a robotic surgery simulator. We also aimed to determine the acceptability and feasibility of implementation into training. METHODS: This prospective, observational, and comparative study recruited novice (n = 16), intermediate (n = 9), and expert (n = 5) participants from King's College London, the 25th European Conference on General Thoracic Surgery, and the Society of Robotic Surgery conference 2018. Each participant completed two familiarization tasks followed by the Guided Robotic Lobectomy module and an evaluation questionnaire. Outcome measures were compared using Mann-Whitney U tests. RESULTS: Construct validity was demonstrated in 12/21 performance evaluation metrics. Significant differences between groups were found in all metrics including: time taken to complete module, vascular injury, respect for tissue, number of stapler firings, time instruments out of view, number of instrument collisions, and number of movements. Participants deemed aspects of the simulator (mean 3/5) and module (3/5) as realistic and rated the simulator as both acceptable (3.8/5) and feasible (3.8/5) for robotic surgical training. CONCLUSIONS: Face validity, acceptability, and feasibility were established for the thoracic lobectomy module of the RobotiX Mentor simulator. Moderate evidence of construct validity was also demonstrated. With further work, this simulation module could help to reduce the initial part of the learning curve for trainees and decrease the risk of errors during live training. PMID- 30417681 TI - Open insufflation: a novel technique for identifying the intersegmental border. AB - Segmentectomy is gaining popularity for the treatment of lung cancer, especially in the early stages. Comprehensive understanding of segmental and subsegmental anatomy is required for the procedure to be successfully completed from a technical and oncological point of view. We hereby present a novel technique for delineating the intersegmental border, which can be widely reproduced because it is not time-consuming and does not require special equipment. PMID- 30417683 TI - No ochronosis was seen at internal thoracic artery with alkaptonuria. AB - Alkaptonuria is a rare disorder of amino acid metabolism that causes premature large joint spine arthropathy and cardiac disease. We describe a case of aortic stenosis and coronary artery disease associated with ochronosis in a 76-year-old man who underwent aortic valve replacement and coronary artery bypass grafting. Although the ochronosis was extensive, no ochronosis was seen in the internal thoracic artery which used for coronary artery bypass grafting. Ochronosis with alkaptonuria is considered to accelerate the atherosclerotic process, so the internal thoracic artery may ensure a better long-term outcome. Long-term follow up may allow better understanding of this rare condition. PMID- 30417682 TI - Radiopathologic correlation of collision lung cancer with ground-glass opacity. AB - Pulmonary collision tumors have been described as a special entity of synchronous multiple lung cancer. There have been no reports detailing the chronological changes in primary collision lung cancers on chest computed tomography. We report a case of ground-glass lung nodules gradually colliding with each other. The collision tumors of the lung were composed of minimally invasive adenocarcinoma and adenocarcinoma in situ with epidermal growth factor mutations. Immunohistochemically, the Ki-67 labeling indices were different in the 2 components. Ki-67 staining was useful to distinguish the 2 components. The 2 dominant ground-glass tumors grew slowly with radiologic and pathologic heterogeneity. PMID- 30417684 TI - Analysis of achieving an "ideal" outcome following midline unifocalization. AB - OBJECTIVE: Pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries is a complex form of congenital heart disease. Midline unifocalization has been developed for the surgical treatment of this condition. There are 3 outcome measures that determine long-term success: patients are alive, patients have achieved complete repair (i.e. ventricular septal defect closure), and patients have a relatively low right ventricle-to aortic pressure ratio (<0.45). However, to date, no studies have combined these 3 outcome measures to analyze the likelihood of achieving an ideal outcome. METHODS: This was a retrospective review of 255 patients who underwent midline unifocalization for pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries. The median age at unifocalization was 4.5 months. RESULTS: Two hundred thirty-five (92%) patients were alive at a mean follow-up of 5.3 years. Two hundred and seventeen (85%) patients underwent single stage complete repair, and 38 (15%) had an initial unifocalization and shunt. Twenty-four of the 38 palliated patients have subsequently undergone repair. Thus 241 (94%) patients ultimately achieved complete repair. Of the 241 patients who were repaired, 219 (86%) had a right ventricle-to-aortic peak systolic pressure ratio <0.45. Combining these outcome measures, 77% of patients achieved an ideal outcome at one month, 73% at 6 months, 76% at one year, and 80% at 4 years. CONCLUSIONS: Most (80%) patients can achieve all 3 measures of favorable outcome at 4 years following midline unifocalization. We speculate that this will be a favorable portend for the future of these patients. PMID- 30417685 TI - Lung cancer risk stratification using methylation profile in the oral epithelium. AB - BACKGROUND: Assuming that the entire airway is affected by the same inhaled carcinogen, similar molecular alterations may occur in the lung and oral cavity. Thus, we hypothesized that DNA methylation profiles in the oral epithelium may be a promising biomarker for lung cancer risk stratification. METHODS: A methylation specific polymerase chain reaction was performed on oral epithelium from 16 patients with lung cancer and 32 controls without lung cancer. Genes showing aberrant methylation profiles in the oral epithelium were compared between patients and controls. RESULTS: The analysis revealed that HOXD11 and PCDHGB6 were methylated more frequently in patients than in controls ( p = 0.0055 and p = 0.0247, respectively). Combined analyses indicated that 8 of 16 (50%) patients and 3 of 32 (9.4%) controls showed DNA methylation in both genes ( p = 0.0016). Among the population limited to current and former smokers, 6 of 11 (54.5%) patients showed methylation in both genes, compared to 1 of 17 (5.9%) controls ( p = 0.0037). In a subgroup analysis limited to the population above 50-years old, 8 of 16 (50%) patients and 2 of 16 (12.5%) controls showed methylation in both genes ( p = 0.0221). CONCLUSIONS: The results of this study indicate that specific gene methylation in the oral epithelium might be a promising biomarker for lung cancer risk assessment, especially among smokers. Risk stratification through the analysis of DNA methylation profiles in the oral epithelium may be a useful and less invasive first-step approach in an efficient two-step lung cancer screening strategy. PMID- 30417686 TI - Arterialization of the Venous System for Acute and Chronic Ischemia of the Hand: A Case Series With Prospective Duplex Ultrasound Assessment. AB - BACKGROUND: Ischemia of the hand is a debilitating condition. In many cases, the cause of ischemia is diffuse atherosclerosis with no distal vessels available for bypass. In these situations, options are limited to restore perfusion, and there is a potential role for arterialization of the venous system to relieve ischemic pain and avoid amputation. METHODS: This is a retrospective review of all patients at our institution who underwent arterialization of the venous system between 2010 and 2014 by 4 surgeons for acute or chronic ischemia of the upper extremity not amenable to bypass procedures. Indications, preoperative and postoperative findings, and the requirement for future digital amputations were recorded. The patients were then evaluated prospectively for the patency of arteriovenous anastomosis and the pattern of perfusion by duplex ultrasound studies. RESULTS: Eight patients with 10 upper extremities underwent arterialization of the venous system. All patients with chronic ischemia went on to heal their ischemic ulcerations with relief of rest pain and avoided amputation. Eight upper extremities had arterial Doppler and duplex ultrasound signals showing arterialized dorsal veins demonstrating flow from the dorsal veins heading volar via the intrinsic compartments into the digital arteries. CONCLUSIONS: This study illustrates the successful use of arterialization of the venous system of the hand in both acute and chronic hand ischemia. It reports on prospective imaging and duplex ultrasound studies confirming patency of the anastomosis and objective evidence of distal arterial flow. Based on our experience, we believe that arterialization of the venous system may provide an effective salvage option in the setting where no distal bypass is available. PMID- 30417687 TI - Diagnostic value of lateral ventricle ratio: a retrospective case-control study of 112 acute subdural hematomas after non-severe traumatic brain injury. AB - PRIMARY OBJECTIVE: To evaluate correlation between the lateral ventricle ratio (LVR) and the risk of conservative treatment failure (CTF) among patients with acute subdural hematoma (ASDH) after non-severe traumatic brain injury (TBI), we retrieved from the hospital database and performed a retrospective analysis of 1339 cases with TBI treated during the 2008-2016 period. METHODS AND PROCEDURES: 112 patients with ASDH, GCS>= 9 and initial conservative treatment were enrolled. They were divided according to the final treatment method applied (surgical or conservative). Clinical and radiological data was evaluated. We used ROC curve analysis and multivariate logistic regression model to identify risk factors of CTF. MAIN OUTCOMES AND RESULTS: LVR higher than 1.48 calculated on admission CT scans was the strongest predictor of CTF, with sensitivity of 78.9% and specificity of 93.5% (AUC: 0.774-0.994). LVR, prolonged prothrombin time and coexisting traumatic subarachnoid hemorrhage were independent risk factors. CONCLUSIONS: Despite limitations, study results support the view that patients after non-severe TBI with ASDH and with lateral ventricle asymmetry, defined as LVR> 1.48, require surgical treatment. LVR seems to be indirect, but still the closest method to quantify intracranial compliance. Thus, in the selected group of patients without clinical symptoms of critically diminished compensatory reserve, LVR could indicate those who need a surgical decompression. PMID- 30417688 TI - The Direct and Indirect Costs to Society of Carpal Tunnel Release. AB - BACKGROUND: Carpal tunnel syndrome (CTS) is one of the most common compressive neuropathies and affects a large amount of individuals. We investigated the direct and indirect cost to society of operative versus nonoperative management of CTS. METHODS: A Monte Carlo simulation model was used to estimate the lifetime direct and indirect costs associated with nonoperative and operative treatment of CTS, and its utility to patients. RESULTS: Operative treatment of CTS had a lower total cost and a higher utility when compared with nonoperative treatment. CONCLUSIONS: CTS surgery is clearly a cost-effective treatment strategy that should be included in the societal perspective regarding evolving costs and savings associated with health care. PMID- 30417689 TI - Perceived Unfair Treatment by Police, Race, and Telomere Length: A Nashville Community-based Sample of Black and White Men. AB - Police maltreatment, whether experienced personally or indirectly through one's family or friends, represents a structurally rooted public health problem that disproportionately affects minorities. Researchers, however, know little about the physiological mechanisms connecting unfair treatment by police (UTBP) to poor health. Shortened telomeres due to exposure to this stressor represent one plausible mechanism. Using data from a community sample of black (n = 262) and white (n = 252) men residing in Nashville-Davidson County, we test four hypotheses: (1) Black men will be more likely to report UTBP than white men, (2) those reporting UTBP will have shorter telomeres than those not reporting UTBP, (3) this association will be more pronounced among black men, and (4) these hypotheses will extend to those who report vicarious UTBP. Results reveal support for all hypotheses. The implications for our findings are discussed as they pertain to debates on policing practices and health disparities research. PMID- 30417690 TI - Older recreational cross-country skiers adopt more even pacing strategies than their younger counterparts of similar performance level. AB - The aim of the present study was to examine the performance* age interaction on pacing in cross-country (XC) skiing. We analyzed all finishers (n = 79,722) who competed in "Vasaloppet" from 2012 to 2017 grouped in performance quartiles according to their race time with Q1 as the fastest and Q4 as the slowest. Women (44.1 +/- 10.2%) had larger pace range than men (40.9 +/- 11.8%; p < 0.001, eta2 = 0.014). The pace range ranged from 29.8 +/- 7.1% (Q1) to 49.0 +/- 10.1% (Q4; p < 0.001, eta2 = 0.179). In women and men, smaller differences in pace range among age groups for the faster performance groups were observed (p < 0.001, eta2 = 0.014, eta2 = 0.008, respectively). In summary, fast XC skiers adopted relatively even pacing independent of their age, and the older XC skiers adopted more even pacing than their younger counterparts of similar performance level suggesting that differences among age groups are performance-dependent. PMID- 30417691 TI - Secondary Effects of Radiation Therapy to the Hand for Benign Conditions. AB - BACKGROUND: Emerging literature introduces radiation therapy for benign hand conditions. However, hand surgeons are wary recommending radiation therapy for nonmalignant conditions. In our practice, we have used radiation therapy for patients who present with infiltrative or recurrent giant cell tumor of the tendon sheath (GCTTS) since 1998. The purpose of this study is to examine the secondary effects of radiation to the hand through the critical lens of a hand surgeon. METHODS: A case series of patients who received radiation therapy for GCTTS were reviewed. The Radiation Oncology/Toxicity Grading Late Radiation Morbidity Scoring Schema was used, and patients were questioned about symptoms and examined for physical findings involving their irradiated digits. RESULTS: A total of 8 patients with GCTTS presented for follow-up. The average patient age was 59.1 years, and the average time since radiation therapy was 5.4 years. Patients had an average of 2.3 surgeries on the affected digit prior to receiving radiation therapy. The average Disabilities of the Arm, Shoulder, and Hand score was 8.1. The most common sign of radiation was nail changes. All patients complained of sensibility changes, although only 2 of the 8 patients had abnormal moving 2-point discrimination tests. There were no confirmed recurrences of GCTTS and no skin cancers. CONCLUSIONS: Patients who received radiation therapy to the hand report high levels of satisfaction with the therapy. Radiation therapy is tolerated well by these patients and has a low level of morbidity in our population. PMID- 30417692 TI - Bilateral Metacarpal Hands: Reconstruction With 6 Toe Transfers. AB - BACKGROUND: Bilateral metacarpal hand injuries are extremely rare, but probably represent the most difficult reconstructive challenge in hand surgery. METHODS: We discuss the various options for metacarpal hand reconstruction, including the Krukenberg procedure, bionic prostheses, multiple toe-to-hand transfers, and possibly hand transplantation, and present the long-term functional outcomes, gait analysis, and psychological evaluation after a 4-stage reconstruction of bilateral metacarpal hands in a child using 6 toe-to-hand transfers-bilateral great toe transfers to reconstruct both thumbs and bilateral combined second third monobloc transfers to reconstruct 2 fingers in each hand. RESULTS: Reconstruction of bilateral metacarpal hands with 6 toe transfers yielded excellent functional results and patient satisfaction. CONCLUSIONS: Bilateral metacarpal hand injuries result in a devastating functional deficit and a major psychological impact. Multiple toe transfers (4, 5, or 6) provide an excellent reconstructive outcome with acceptable donor site morbidity. PMID- 30417693 TI - Long-term Patient-Reported Outcomes After Surgery for Hypothenar Hammer Syndrome. AB - BACKGROUND: This study aims to describe the long-term patient-reported outcomes after surgery for hypothenar hammer syndrome (HTHS) and to identify factors associated with inferior outcomes. METHODS: We retrospectively identified 27 patients who underwent surgical intervention for HTHS from 2002 to 2016. Fifteen patients (56%) completed outcome questionnaires: Quick Disabilities of the Arm, Shoulder, and Hand, Cold Intolerance Symptom Severity (CISS) survey, Patient Reported Outcomes Measurement Information System Upper Extremity Computer Adaptive Test, and Patient-Reported Outcomes Measurement Information System Pain Interference Computer Adaptive Test. The median questionnaire follow-up was 7.2 years (interquartile range, 3.1-9.9). Outcomes were compared across different surgical techniques, and the influence of patient-related factors on outcomes was also evaluated. RESULTS: Six (40%) patients experienced complete symptom resolution, 6 (40%) had improvement without complete resolution, 1 (7%) had resolution followed by recurrence, and 2 (13%) reported no improvement. The most common symptom after surgical intervention was cold intolerance. Questionnaire scores were similar across ligation, direct repair, and vein graft vascular reconstruction. Patients had better CISS scores if they had surgery on their nondominant hand (13.2 vs 38.6) and did not have a manual labor job (18.1 vs 40.5). CONCLUSIONS: Surgery for HTHS leads to moderate long-term improvement in patient-reported outcomes. Different surgical techniques yield similar symptomatic relief. Manual labor and surgery of the dominant hand are associated with worse CISS scores. PMID- 30417694 TI - The Use of Telemedicine Decreases Unnecessary Hand Trauma Transfers. AB - PURPOSE: The Arkansas Hand Trauma Telemedicine Program (AHTTP) is a novel telemedicine system that was developed in 2014 within a rural state to address the growing need of access to hand trauma care with one trauma center that cares for mangling hand injuries. The purpose is to compare transfers for hand injuries prior to and after the implementation of this system. METHODS: The hospital institutional database was queried for all transfers to a level 1 medical center in the state from 2012 to 2015, allowing the comparison of data prior to and after the institution of the AHTTP. Patient disposition from the emergency department was categorized to evaluate the impact of AHTTP. Distance, mode of transport, and transport cost were assessed. FINDINGS: There were 202 transfers for the treatment of isolated hand trauma (92 from 2012 to 2013 and 110 from 2014 to 2015). Prior to the institution of AHTTP, transfer patients were admitted 47.8% of the time compared with 68.2% of the time after the development of the program ( P = .02). The approximate cost of transport for patients who were discharged home directly from the emergency department was 38.5% (US $47,233) of the total costs for the 2012-2013 period and was 21.4% (US $34,017) of the costs for the 2014-2015 period ( P < .0001). CONCLUSIONS: There was a statistically significant decrease in the number of unnecessary transfers and transportation costs after the telemedicine program was started. The implementation of AHTTP in a rural state reduced health care costs and improved the efficiency of hand specialty care. PMID- 30417695 TI - Colonial surgeon Patrick Hill (1794-1852): unacknowledged pioneer of Australian mental healthcare. AB - Despite making a substantial contribution to the development of mental health services in colonial Australia, until now the story of Dr Patrick Hill's (1794 1852) life has been overlooked by historians. This paper reviews primary sources including clinical notes, patient lists, letters, government documents and newspaper articles which reveal that Dr Hill was a dedicated physician who played a vital role in the development of Australian mental healthcare. He was held in such esteem that by the time of his sudden death in 1852 he had been elevated to the most senior medical office in New South Wales. Dr Hill's career serves to exemplify how the local practice of individual colonial doctors helped build the reputation of medicine in the modern era. PMID- 30417696 TI - Periodontal sources of citrullinated antigens and TLR agonists related to RA. AB - Anti-citrullinated protein autoantibodies (ACPA) precede the onset of clinical and subclinical rheumatoid arthritis (RA). ACPA are frequently generated in further chronic inflammatory diseases, e.g. chronic obstructive pulmonary disease, lupus, periodontitis (PD), characterized by citrullination and mucosal as well as systemic autoimmunity against citrullinated proteins. PD is of particular interest, as it exhibits two sources of citrullination, namely peptidylarginine deiminase 4 (PAD4) of periodontal neutrophils and neutrophil extracellular traps (NETs) as well as the PAD of Porphyromonas gingivalis (PPAD). Whereas the PAD4-citrullinated host peptides and/or proteins occur physiologically, PPAD-citrullinated ones appear under pathological conditions as neo-antigens. Frequently, the oral pathogens P. gingivalis and A. actinomycetemcomitans directly and indirectly participate in synovitis in RA, providing topical citrullination: P. gingivalis via PPAD and A. actinomycetemcomitans via leukotoxin A-mediated ROS-independent NET formation. In addition, transient bacteraemia due to tooth brushing indicates the possibility that citrullinated peptides and/or proteins from periodontium regularly enter the blood circulation. In this way, the mucosal firewall is evaded and the systemic immune response against citrullinated peptides and/or proteins is facilitated. However, the role of swallowed PD-derived sludge for the induction of oral tolerance remains to be established. We hypothesize (I) PD-driven endotoxemia may increase the host responsiveness to autoantigens via TLR4 activation and (II) this participates in development and propagation of RA (III) circulating PD derived bacterial DNA is taken up by phagocytes, activates TLR9, and thus increases the responsiveness to autoantigens. PMID- 30417697 TI - A Prospective Evaluation of the Effect of Supervised Hand Therapy After Carpal Tunnel Surgery. AB - BACKGROUND: The objective of this investigation is to examine the effect of postoperative therapy after routine carpal tunnel release. Our hypothesis was that supervised hand therapy does not improve outcomes after routine carpal tunnel release. METHODS: Patients with carpal tunnel syndrome were randomly assigned to one of 3 groups based on the last digit of their medical record numbers to one of 3 groups: standard 6-week postoperative rehabilitation (standard therapy), expedited one-session postoperative rehabilitation group (expedited therapy), and no postoperative rehabilitation group (no therapy). The primary outcome measures were Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) and return to work. The outcome questionnaire was completed preoperatively, at the 2-week follow-up visit, and monthly to 6 months after surgery. RESULTS: All 3 treatment groups had similar mean QuickDASH scores preoperatively. At 1- to 6-month follow-up, all 3 groups had similar QuickDASH scores at each visit, and all showed a significant decline from baseline (preoperative) QuickDASH score. Overall, QuickDASH score decreased significantly from a preoperative visit mean of 42.7 to a final postoperative (visit 8) mean of 6.69. There was no significant difference in the mean QuickDASH score among all 3 groups at 6-month follow-up. There was no significance in the time of return to work among the 3 groups (standard therapy, 21.8 days; expedited therapy, 20.9 days; no therapy, 16.6 days). CONCLUSIONS: This investigation adds evidence that supervised hand therapy does not improve the outcomes of routine carpal tunnel surgery as measured by QuickDASH and return to work. PMID- 30417698 TI - Burning controversies in NETs and autoimmunity: The mysteries of cell death and autoimmune disease. AB - The causes and mechanisms of autoimmune disease pose continuing challenges to the scientific community. Recent clues implicate a peculiar feature of neutrophils, their ability to release nuclear chromatin in the form of neutrophil extracellular traps (NETs), in the induction or progression of autoimmune disease. Efforts to define the beneficial versus detrimental effects of NET release have, as yet, only partially revealed mechanisms that guide this process. Evidence suggests that the process of NET release is highly regulated, but the details of regulation remain controversial and obscure. Without a better understanding of the factors that initiate and control NET formation, the judicious modification of neutrophil behaviour for medically useful purposes appears remote. We highlight gaps and inconsistencies in published work, which make NETs and their role in health and disease a puzzle that deserves more focused attention. PMID- 30417699 TI - Revision Total Wrist Arthroplasty Due to Polyethylene Wear, Metallosis-Induced Carpal Tunnel Syndrome, Distal Ulnar Impingement, and Fourth Carpometacarpal Joint Pain: Case Report and Pitfalls to Avoid. AB - BACKGROUND: Total wrist arthroplasty (TWA) is indicated to alleviate pain secondary to arthritis while preserving wrist motion. Despite vigilant measures, TWAs are susceptible to complications. The current case illustrates an array of preventable complications which are addressed through operative technique in a revision setting. CASE PRESENTATION: The patient was a 72-year-old man who presented with chronic pain at the fourth carpometacarpal joint (CMCJ) and distal radioulnar joint with paresthesias in the median nerve distribution. Surgery was undertaken to address the following complications secondary to a previous TWA: impingement of the native distal ulna on the prosthesis, carpal tunnel due to metallosis and polyethylene synovitis, loose carpal component, and prominent screw at the fourth CMCJ. Surgical correction included open carpal tunnel release with extensive flexor tenosynovectomy, distal ulna resection and implant arthroplasty with shortening, revision of carpal component with bone grafting, and shortening of the ulnar screw to avoid crossing the fourth CMCJ. Within 6 months of the procedure, the patient reported resolution of neuropathic symptoms and pain-free motion of the wrist. DISCUSSION: Preventable complications associated with TWA are individually highlighted. In addition, we compare and contrast our approach and surgical technique to current reported literature. Overall, we provide education and guidance to avoid possible TWA pitfalls. CONCLUSION: With this case report, we hope to increase TWA knowledge with emphasis on the requirements of judicious patient selection, preoperative planning, meticulous surgical technique, and complication awareness for subsequent optimization of wrist function, stability, and durability. PMID- 30417700 TI - Impact of Handedness on Disability After Unilateral Upper-Extremity Peripheral Nerve Disorder. AB - BACKGROUND: Impairment of the dominant hand should lead to greater disability than impairment of the nondominant hand, but few studies have tested this directly, especially in the domain of upper-extremity peripheral nerve disorder. The aim of this study was to identify the association between hand dominance and standardized measures of disability and health status after upper-extremity peripheral nerve disorder. METHODS: An existing database was reanalyzed to identify the relationship between affected-side (dominant vs nondominant) on individuals with unilateral upper-extremity peripheral nerve disorder (N = 400). Primary measure of disability was the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire. RESULTS: We found no differences in standardized measures of disability or health status between patients with affected dominant hand and patients with an affected nondominant hand. However, a post hoc exploratory analysis revealed that patients with an affected dominant hand reported substantially reduced ability to perform 2 activities in the DASH questionnaire: "write" and "turn a key." CONCLUSIONS: Following unilateral upper-extremity peripheral nerve disorder, impairment of the dominant hand (compared with impairment of the nondominant hand) is associated with reduced ability to perform specific activities, but this reduced ability is not reflected in standardized measures of disability and health status. To adequately identify disability following unilateral impairment of the dominant hand with the DASH, individual items must be used instead of the total score. New or alternative measures are also recommended. PMID- 30417701 TI - Making the leap and finding your feet: A qualitative study of disclosure and social support in university students with type 1 diabetes. AB - University poses unique challenges surrounding disclosure for students living with type 1 diabetes, with implications for social support and self-management. Semi-structured interviews with students and peer interviewers living with type 1 diabetes explored university experiences of disclosure and social support. Thematic analysis identified three major themes: disclosure as a measured process, the need for lived experience for true understanding and personal growth and self-awareness. Findings emphasize the need to scaffold the university transition for individuals with type 1 diabetes as disclosure can elicit effective social support. In addition, the importance of lived experience suggests support from students with type 1 diabetes could considerably impact diabetes management. PMID- 30417702 TI - Outcomes of Distal Ulna Fractures Associated With Operatively Treated Distal Radius Fractures. AB - BACKGROUND: The purpose of this study was to report outcomes in patients with nonstyloid distal ulna fractures treated in conjunction with open reduction internal fixation (ORIF) of distal radius fractures. METHODS: A retrospective review of all patients who had undergone ORIF of a distal radius fracture over a 5-year period at a single institution was performed. Radiographic review was performed to identify patients with a concomitant fracture of the distal ulna. Radiographs were examined to determine whether and how the distal ulna fracture was stabilized and to assess healing of the distal ulna. Range of motion (ROM) was determined by review of the patients' charts. All skeletally mature patients with distal ulna fractures (not including isolated styloid fractures) undergoing surgical fixation of the distal radius fracture were included. Patients were excluded if follow-up was inadequate. There were 172 fractures of the distal ulna meeting the inclusion criteria. Seven patients were excluded. There were 91 patients treated without ulna fixation (ulna-no) and 74 patients treated with ulna fixation (ulna-yes). RESULTS: Seventy-two (97%) of the ulna-yes patients healed. All patients in the ulna-no group healed. The only significant difference in ROM was in pronation, although the magnitude of this difference was relatively small. CONCLUSIONS: Fractures of the distal ulna have high rates of healing and result in equivalent motion regardless of whether the distal ulna is treated operatively. Routine surgical fixation of concomitant distal ulna fractures during distal radius ORIF does not appear to be necessary. PMID- 30417703 TI - To Tie or Not to Tie: A Systematic Review of Postaxial Polydactyly and Outcomes of Suture Ligation Versus Surgical Excision. AB - BACKGROUND: Ulnar polydactyly is frequently encountered in the newborn nursery and is commonly treated with bedside suture ligation. However, growing concern about the complications associated with suture ligation has led some practitioners to advocate for primary surgical excision instead. Thus, we set out to compare outcomes of suture ligation and surgical excision by systematic appraisal of the literature. METHODS: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a systematic review was performed to identify studies published between 1950 and 2017 that described outcomes of suture ligation, surgical excision, or both. Baseline characteristics, complications, and study quality were extracted for each included article. RESULTS: A total of 900 articles were reviewed, of which 10 studies (8 case series, 2 comparative analyses) met the inclusion criteria. There was considerable heterogeneity among the studies with respect to patient characteristics and reported outcomes. There were 2 retrospective case series of suture ligation that reported no acute complications and a variable proportion of patients with residual remnants or neuromas. Studies evaluating surgical ligation reported no acute or long-term complications, with only 1 case series reporting a small percentage of residual remnants. However, in the largest cohort analysis, the difference in complication rate was reported to be as high as 23.5% for suture ligation compared with 3% for surgical excision. CONCLUSIONS: There is a paucity of literature limiting the comparison of suture ligation and surgical excision for ulnar polydactyly. Further studies are required to determine the optimal treatment. PMID- 30417704 TI - Ten years of HPV vaccination in the Netherlands: current evidence and future challenges in HPV-related disease prevention. AB - INTRODUCTION: Girls-only vaccination against human papillomavirus (HPV) type 16 and 18 was implemented in the Netherlands in 2009. Despite the evidence of the efficacy against precancerous lesions, cross-protection induced by the vaccine and a greater potential for cancer prevention than cervical cancer only, vaccine coverage in the girls-only program has remained below target levels. Areas covered: In this paper, we review the literature from the Netherlands on the effectiveness and cost-effectiveness of HPV vaccination since vaccine introduction, give an account of the coverage, safety and effectiveness of HPV vaccination as has been reported in the Dutch surveillance program and discuss challenges of the current HPV vaccination program. Expert commentary: Girls-only HPV vaccination may confer a substantial health gain in HPV-related disease prevention. However, vaccine coverage declined remarkably recently possibly related to safety concerns, limiting the benefits from girls' vaccination and increasing the potential additional benefit of sex-neutral HPV vaccination. Considering the emergence of novel vaccination and screening options and the change from cytology- to HPV-based screening in 2017, further research is required to inform decisions on the optimization of an integrated vaccination and screening program. PMID- 30417705 TI - Stereodirected synthesis of alkaloid-like quinolizidine systems. AB - New stereoselective methods for the chemical modification of cytisine based on T reactions are reported. A reaction of cytisine with 2-chloro-5-nitrobenzaldehyde and followed condensation with 1,3-dimethylbarbituric acid affords N-(5-nitro-2 {1,3-dimethylperhydropyrimidine-2,4,6-trione-5-methynyl})cytisine, which undergoes a cyclization with the tetrahydropyridine ring closure. The cyclization proceeds via two competing routes yielding 5,5-spirobarbituric acid derivatives with 11,19-diaza-pentacyclo[11.7.1.02,11.05,10.014,19]henicosane and 11,15 diazapentacyclo-[11.7.1.02,11.05,10.015,20]henicosane skeletons. The cyclization reaction in solutions afford either 24.25-trans and 15,16-trans isomers or trans and cis isomer mixtures, depending on the specific solvent. Meanwhile, 24,25-cis and 15,16-cis isomers are formed stereoselectively under heterogeneous conditions in water suspensions. Trans-5,5-spirobarbiturates under similar conditions undergo isomerization into more stable cis-analogs by the configuration inversion at the C7 atom. The synthesized 5,5-spirobarbituric acid derivatives were successfully converted into alkaloid-like quinolizidine systems (1R,2R,3R,13S)-7 nitro-18-oxo-11,19-diazapentacyclo[11.7.1.02,11.05,10.014,19]henicosa 5(10),6,8,14,16-pentaene-3-carboxylic acid and (1R,2S,3S,13S)-nitro-16-oxo-11,15 diazapentacyclo[11,7,1.02,11,05,10,015,20]henicosa-5,7,9,17,19-pentaene-3 carboxylic acid and their derivatives via the spiropyrimidine moiety removal by the stereoselective hydrolysis. The molecular and crystal structures of the target substances were elucidated by X-ray crystallography and NMR. PMID- 30417706 TI - Economic and epidemiological impact of dengue illness over sixteen years from a public health system perspective in Brazil to inform future health policies including the adoption of a dengue vaccine. AB - INTRODUCTION: Dengue is a serious global health problem endemic in Brazil. Consequently, our aim was to measure the costs and disease burden of symptomatic dengue infections in Brazil from the perspective of the Brazilian Public Health System (SUS) between 2000 and 2015, using Brazilian public health system databases. Specific age group incidence estimates were used to calculate the disability-adjusted life years (DALYs) to gain a better understanding of the disease burden. Areas covered: SUS spent almost USD159 million and USD10 million to treat dengue and severe dengue, respectively, between 2000-2015. This is principally hospitalization costs, with the majority of patients self-treated at home with minor symptoms. The average notification rate for dengue was 273 per 100,000 inhabitants and 3 per 100,000 for severe dengue, with annual DALYs estimates ranging between 72.35 to 6,824.45 during the 16 years. Expert commentary: The epidemiological and morbidity burden associated with dengue is substantial in Brazil, with costs affected by the fact that most patients self treat at home with these costs not included in SUS. The Brazilian government urgently needs to proactively evaluate the real costs and clinical benefits of any potential dengue vaccination program by the National Immunization Program to guide future decision making. PMID- 30417707 TI - Patterns of practice and pharmacoeconomic analysis of the management of patients with metastatic renal cell carcinoma (mRCC) in Greece--the CRISIS study. A retrospective analysis by the Hellenic Genitourinary Cancer Group (HGUCG). AB - BACKGROUND: Metastatic RCC (mRCC) treatment has been revolutionized with 11 approved targeted agents. We report patterns of practice, outcomes and pharmacoeconomic analyses after the introduction of targeted therapy. PATIENTS AND METHODS: CRISIS was a retrospective multicenter study of mRCCpatients who received targeted therapy . Results were related to the start of 1st-line therapy, with a cut off at 1 January 2011 in order to depict the impact of increased availability of effective options. RESULTS: 164 patients, were included. 70.1% and 44.5% received 2nd and 3rd-line therapy, respectively. More patients were treated in 2nd-line after 1 January 2011. After a median follow-up of 55.1 months, median progression-free (PFS) and overall survival (OS) were 10.7 (95% confidence intervals [CI]: 8.3-13.7), 7.3 (95% CI: 5.1-8.6), 5.8 (95% CI: 3.8-7.8) and 34 (95% CI: 28.5-39.8), 22.4 (95% CI: 16-32.1), 18.3 (95% CI: 12.4 26.4) months for first, second and third line, respectively. Efficacy of sunitinib and pazopanib in 1st-line were similar. The mean total cost/patient was 35,012.2 Euros (standard deviation [SD]: 28,971.5). CONCLUSIONS: Our study confirms previous real-world data suggesting that continuing advances in the treatment of mRCC produce favorable outcomes in everyday practice. Pharmacoeconomic analyses are important for cost-effective utilization of emerging novel therapies. PMID- 30417709 TI - The effects of strawberry tree (Arbutus unedo L.) water leaf extract and arbutin upon kidney function and primary DNA damage in renal cells of rats. AB - Although strawberry tree (Arbutus unedo L.) leaves have long been used as a herbal remedy, insufficient information is available on their nephrotoxicity. We assessed the safety of strawberry tree water leaf extract and its key component arbutin, administered per os to Lewis rats of both genders at 200 mg/kg b.w./day for 14 and 28 days. The effects of the tested compounds on DNA integrity in renal cells was evaluated using alkaline comet assay, while kidney function was studied using serum creatinine and urea levels. Strawberry tree water leaf extract showed high biocompatibility with kidney tissue. It did not impair DNA integrity of renal cells and kidney function, either in male or female rats. However, exposure to single arbutin affected the levels of primary DNA damage in renal cells which could be related to metabolic conversion of arbutin into hydroquinone, whose nephrotoxicity has previously been proven. PMID- 30417708 TI - Community Preceptors' Motivations and Views about Their Relationships with Medical Students During a Longitudinal Family Medicine Experience: A Qualitative Case Study. AB - Phenomenon: Although current evidence emphasizes various benefits of community oriented programs, little is still known about the nature of the relationships that students and family physicians develop in this educational setting. Our aim in this study was twofold: to identify family physicians' motivations to enroll as preceptors in a longitudinal undergraduate family medicine program and to explore the nature of the student-preceptor relationships built during the course. Approach: This was a qualitative exploratory case study. The case was the first edition of a longitudinal family medicine experience (LFME), a course that makes up part of the novel Medicinae Doctor et Chirurgiae Magister curriculum in place in a Canadian medical school since August 2013. All 173 family physician community preceptors of the academic year 2013-2014 were considered key informants in the investigation. Forty-three preceptors finally participated in one of six focus groups conducted in the spring of 2014. Several organizational documents relative to the LFME course were also gathered. Inductive semantic thematic analysis was performed on verbatim interview transcripts. Documents helped contextualize the major themes emerging from the focus groups discussions. Findings: Enjoying teaching, promoting family medicine, and improving medical education where salient motivations for family physicians to become LFME preceptors. The findings also pointed out the complexity of the student-preceptor exchanges that unfolded over the academic year, and the ambiguous and changing nature of the role that LFME preceptors adopted in their relationships with students: from simply being facilitators of students' clinical observership to behaving as their mentors. Insights: Family physicians were highly motivated to become LFME preceptors of 1st-year medical students. Whereas they consistently valued the relationships built during the academic year with the students assigned to them, they also considered that exchanges did not always happen without difficulties, and gauged the roles they played as complex, ambiguous, and necessarily evolving over time. PMID- 30417710 TI - Effect of HIV exposure and timing of antiretroviral therapy initiation on immune memory responses to diphtheria, tetanus, whole cell pertussis and hepatitis B vaccines. AB - OBJECTIVES: We evaluated memory responses and antibody persistence to diphtheria toxoid, tetanus-toxoid, whole-cell-pertussis (DTwP), and Hepatitis-B vaccines in HIV-unexposed, HIV-exposed-uninfected and HIV-infected children previously randomized to initiate time-limited ART at 6-10 weeks (ART-Immed) or when clinically/immunologically indicated (ART-Def). METHODS: All children received DTwP booster at 15-18 months. Antibodies were measured for pertussis-toxoid, filamentous haemagglutinin (FHA), diphtheria-toxoid, tetanus-toxoid, and hepatitis-B prior to booster, 1-2 weeks post-booster and at 24 months of age. RESULTS: Pre-booster antibody GMC were lower in HIV-infected groups than HIV unexposed children for all epitopes. Post-booster and at 24 months of age, the ART-Def group had lower GMCs and antibody proportion >=0.1 IU/ml for tetanus toxoid and diphtheria-toxoid compared to HIV-unexposed children. At 24 months of age, the ART-Immed group had higher GMCs, and more likely to maintain antibody titres >=1.0 IU/ml to tetanus-toxoid and diphtheria-toxoid compared to HIV unexposed children. Compared to HIV-unexposed children, at 15 and 24 months of age, persistence of antibody to HBsAg of >=10 mIU/ml was similar in the ART-Immed group but lower among the ART-Def group. Antibody kinetics indicated more robust memory responses in HIV-exposed-uninfected than HIV-unexposed children to diphtheria-toxoid and wP. CONCLUSION: HIV-infected children not on ART at primary vaccination had poorer memory responses, whereas HIV-exposed-uninfected children mounted robust memory responses. PMID- 30417712 TI - Characterization of drug delivery vehicles using atomic force microscopy: current status. AB - INTRODUCTION: The field of nanomedicine, utilizing nano-sized vehicles (nanoparticles and nanofibers) for targeted local drug delivery, has a promising future. This is dependent on the ability to analyze the chemical and physical properties of these drug carriers at the nanoscale and hence atomic force microscopy (AFM), a high-resolution imaging and local force-measurement technique, is ideally suited. Areas covered: Following a brief introduction to the technique, the review describes how AFM has been used in selected publications from 2015 to 2018 to characterize nanoparticles and nanofibers as drug delivery vehicles. These sections are ordered into areas of increasing AFM complexity: imaging/particle sizing, surface roughness/quantitative analysis of images, and analysis of force curves (to extract nanoindentation and adhesion data). Expert opinion: AFM imaging/sizing is used extensively for the characterization of nanoparticle and nanofiber drug delivery vehicles, with surface roughness and nanomechanical/adhesion data acquisition being less common. The field is progressing into combining AFM with other techniques, notably SEM, ToF-SIMS, Raman, Confocal, and UV. Current limitations include a 50 nm resolution limit of nanoparticles imaged within live cells and AFM tip-induced activation of cytoskeleton proteins. Following drug release real-time with AFM-spectroscopic techniques and studying drug interactions on cell receptors appear to be on the horizon. PMID- 30417711 TI - Debt, common mental disorders and mental health service use. AB - BACKGROUND: Uncertainty remains as to whether the effects of debt on common mental disorder (CMD) are persistent over time and what impact it has on mental health service use (MHSU). AIMS: To determine the distribution of debt across sociodemographic and socioeconomic statuses; to examine whether debt influences CMD recovery over time; and to determine the effects of episodic and/or long-term debt and CMD on MHSU outcomes. METHODS: Data were collected from phase 1 (N = 1698) and phase 2 (N = 1052) of the South East London Community Health (SELCoH) study, a population-based survey. RESULTS: 37.2% of participants who reported debt at SELCoH 1 and 46.6% at SELCoH 2 experienced concurrent CMD. Those with concurrent exposure to debt and CMD at SELCoH 1 were at greater risk of CMD at SELCoH 2. Debt accumulation was strongly associated with CMD cross-sectionally; however, this somewhat dissipated over time. Reporting any debt at SELCoH 2 or debt at both time-points were strongly associated with MHSU in the past year in the fully adjusted model adjusting for prior mental health. CONCLUSIONS: More focus is needed on concurrent exposure to debt and CMD with regards to subsequent psychological impact and consequences for MHSU. PMID- 30417713 TI - Controversies in the pharmacological treatment of Graves' disease in children. AB - INTRODUCTION: Graves' disease (GD) is a disorder, in which auto-immunity against the thyroid- stimulating hormone (TSH) receptor is the pivotal pathogenetic element. This disease may have different clinical manifestations, the most common being thyrotoxicosis. Treatment of this condition differs according to its etiology, but there is currently no evidence-based therapeutic strategy which is universally adopted in all countries. Areas covered: a systematic review of the updates on the management of pediatric GD was performed using the Pubmed data base until March 2018. Systematic reviews with or without meta-analysis were analyzed using the following terms: Antithyroid drugs, Childhood, Hyperthyroidism, Radioactive iodine, Thyroidectomy. Expert commentary: As the best way to manage children with GD remains a matter of debate among pediatric endocrinologists, and there is currently no evidence-based therapeutic strategy which is universally adopted, we confirm that the original and prolonged treatment with anti-thyroid drugs (ATDs) remains the mainstay of treatment for juvenile hyperthyroidism. Alternative treatments include radioiodine (RAI) therapy or surgery (total thyroidectomy). We recommend individualizing the therapeutic approach, without prejudices toward radical therapies that become necessary in case of relapse, adverse effects or poor compliance to ATDs. The optimal approach depends on patient or family preference, and specific patient clinical features. PMID- 30417714 TI - Antibacterial activity of native plants from Northwest Argentina against phytopathogenic bacteria. AB - Extracts from aerial parts of medicinal plants from northwest Argentina were screened for antibacterial activity against the phytopathogenic strains namely CECT 124 (Pseudomonas corrugata), CECT 126 (P. syringae pv. tomato), CECT 225 (Erwinia carotovora var. carotovora), CECT 472 (Agrobacterium tumefaciens) and CECT 792 (Xanthomonas campestres pv. vesicatoria). Leaves and stems of Aspidosperma quebracho-blanco, Schinus fasciculatus, S. gracilipes, Amphilophium cynanchoides and Tecoma stans were separately extracted with solvents of increasing polarity to obtain the dichloromethane (fCH2Cl2), ethyl acetate (fEtAc) and methanol extracts (fMeOH), respectively. Among the thirty extracts tested, only fEtAc from leaves and stems of S. fasciculatus reached the IC50 against the five bacterial strains tested (IC50 = 0.9 mg/ml). The fEtAc from the leaves contained kaempferol, quercetin and agathisflavone which had moderate to strong antibacterial activity. This extract and its identified flavonoids showed synergic (CECT 124,126 and 792) or additive effects (CECT 472 and 225) in mixtures with Kocide 3000. PMID- 30417715 TI - Persistent MOG-IgG positivity is a predictor of recurrence in MOG-IgG-associated optic neuritis, encephalitis and myelitis. AB - BACKGROUND:: MOG-IgG-associated optic neuritis, encephalitis and myelitis (MONEM) is a recently recognized group of inflammatory central nervous system (CNS) disorders distinct from multiple sclerosis and neuromyelitis optica spectrum disorders. Limited data are available regarding the predictors of relapse in this condition. OBJECTIVE:: We aimed to evaluate the longitudinal serostatus of patients with MOG-IgG and to correlate serostatus with long-term clinical outcomes. METHODS:: Of 574 consecutive patients who presented with demyelinating inflammatory CNS disorders, we included 31 patients who were MOG-IgG-positive. Patients with MOG-IgG were followed up from 2011 to 2017 at the School of Medicine, University of Sao Paulo, Brazil. RESULTS:: Relapsing disease occurred in 23 out of 31 patients (74%), while 8 (26%) exhibited a monophasic course. All monophasic patients, as well as the majority of relapsing patients, became seronegative during clinical remission. Patients exhibiting disease activity in the last 2 years were more likely to remain positive, with higher medium titres than those found in patients in clinical remission. CONCLUSION:: MOG-IgG patients usually present with a relapsing course, and the risk of relapse was associated with longitudinally persistent MOG-IgG seropositivity. In contrast, patients who experienced a single attack became spontaneously seronegative for MOG-IgG during long-term follow-up. PMID- 30417716 TI - Short-term outcome of the second twin during vaginal delivery is dependent on delivery time interval but not chorionicity. AB - The decrease in pH in monochorionic (MC) second twin may exceed that of dichorionic (DC) second twin during vaginal twin delivery. The aim of this study was to investigate the effect of chorionicity on the umbilical artery pH of the second twin in relation to increased twin-to-twin delivery time interval (DTI) from 30 weeks of gestation. A hospital based cohort of all twin deliveries after 30 completed weeks of gestation with the first twin delivered vaginally between 2007 and 2012 in four delivery units in Stockholm county was conducted. The changes of umbilical pH in MC twins compared to DC twins in relation to twin-to twin DTI was studied using linear regression. The predictors for acidosis (pH <= 7.10) in the second twin were studied by logistic regression. The cohort included 681 DC and 186 MC twin pairs. There was a correlation between the umbilical pH and the twin-to-twin DTI but independent of the chorionicity, the pH decreased in average by 0.0012 units/min (p < .001). Twin-to twin DTI was a predictor for acidosis of the second twin (p < .01). IMPACT STATEMENT What is already known on this subject? Vaginal twin deliveries are a major obstetrical challenge because of the increased risk for the second twin after the delivery of the first twin, and are suggested to increase among premature second twins. Previous studies report a continuous decline in the pH of the second twin during the second stage of labour, with an increased risk for acidosis (pH < 7.10) and Apgar scores <7 for twin-to-twin delivery time interval (DTI) as short as 15-30 min. Major studies have not discriminated between MC and DC vaginally delivered twins and the question rise if there is a reason for different delivery guidelines for MC diamniotic second twin compared to DC second twin. What do the results of this study add? The results of the present study show a correlation between umbilical pH and twin-to-twin DTI, but independent of chorionicity, from gestational week 30 to term. A main predictor for acidosis (pH <= 7.10) is the twin-to-twin DTI. What are the implications of these findings for clinical practice and/or future research? In cases of uneventful MC pregnancies, we find no support to suggest different vaginal delivery guidelines for MC diamniotic twins compared to DC twins. The risk for acidosis in the second twin increased with 1%/min during the second stage. Active management may be recommended after 15-30 min. PMID- 30417717 TI - The modulation of actin dynamics via atypical Protein Kinase-C activated Cofilin regulates metastasis of colorectal cancer cells. AB - Colorectal cancer (CRC) is the third most common cancer in the United States. The exact mechanism of CRC cells metastasis is poorly understood. Actin polymerization is thought to be an initial step in the cancer cell motility cycle which drives the formation of cell protrusions and defines the direction of migration. Cofilin, a significant actin-regulating molecule, regulates the migration of cancer cells by the formation of lamellipodia and filopodia, however, little is known about the upstream regulation of cofilin. In this study, the effect of atypical Protein Kinase C (atypical PKC) on Cofilin activity in CRC was studied. This study demonstrates that the atypical PKC inhibition impedes the metastasis of CRC cells by increasing phospho-Cofilin (S3) and changing actin organization.e. PMID- 30417718 TI - Cognitive-motor interference in persons with multiple sclerosis during five upper limb motor tasks with different complexity. AB - BACKGROUND:: Cognitive-motor interference in multiple sclerosis has been well examined during walking, but not during upper limb (UL) performance. OBJECTIVES:: To examine the dual-task cost (DTC) in persons with multiple sclerosis (pwMS) and healthy controls (HC) in various type and complexity of UL motor tasks. METHOD:: In total, 30 pwMS without major UL impairment and 30 HC performed five different UL tasks, in single condition and combined with the phonemic word list generation task. The percent change in performances was evaluated by the motor, cognitive, and combined DTC. The motor tasks consisted of four unimanual (sustained hand grip strength, box-and-block test, Purdue pegboard test, finger tapping task) and one bimanual task (Purdue pegboard test). Group and task differences were analyzed with unpaired and paired t-tests, respectively, and overall effect with a multivariate analysis of variance. RESULTS:: The motor DTC ranged between 10% (Purdue pegboard bimanual) and 35% (box-and-block test). The cognitive DTC ranged between -8% (finger tapping test) and +21% (bimanual Purdue pegboard). The magnitude of the combined DTC did not differ significantly between pwMS and HC in any task. CONCLUSION:: DTC is influenced by the complexity of the UL task, but was not significantly different between HC and cognitive intact, but mildly motor disabled pwMS. PMID- 30417719 TI - Preoperative smoking history is associated with decreased risk of early postoperative cognitive dysfunction in patients of advanced age after noncardiac surgery: a prospective observational cohort study. AB - OBJECTIVE: Prevention of postoperative cognitive dysfunction (POCD) in patients of advanced age remains unclear. Studies have shown that the cholinergic anti inflammatory pathway contributes to a decreased risk of POCD and that nicotine stimulates the cholinergic anti-inflammatory pathway. We investigated whether patients of advanced age with a preoperative smoking history have a decreased risk of POCD. METHODS: In total, 382 patients (190 smokers, 192 nonsmokers) aged >=60 years who underwent major noncardiac surgery were enrolled. Cognitive function was assessed, and multivariate logistic regression analyses were performed to identify risk factors. RESULTS: On postoperative days 5 and 7, 111 (29.05%) and 90 (23.56%) patients exhibited POCD, respectively. A preoperative smoking history was significantly correlated with a decreased risk of POCD. A high serum tumor necrosis factor-alpha (TNF-alpha) level on the operative day was significantly associated with an increased risk of POCD. Early POCD was significantly associated with the sufentanil dosage, age, and education level. The hospital stay in patients with and without POCD was 10.54 +/- 2.03 and 8.33 +/- 1.58 days, respectively. CONCLUSION: A preoperative smoking history was associated with a decreased risk of early POCD, and a high serum TNF-alpha level was significantly associated with an increased risk of POCD. PMID- 30417720 TI - A novel REBOA system: prototype and proof of concept AB - Background: Lower torso hemorrhage is a significant cause of death from injuries in combat. Resuscitative endovascular balloon occlusion of the aorta (REBOA) has been used to rescue patients successfully in the hospital setting, but its prehospital use is controversial. We designed a device that would be easy to use, safer in injured vessels, migration-resistant and amenable to a prehospital environment. Methods: We designed a novel, balloon-led device using common commercial materials. Thin latex rubber was reassembled in cylindrical conformation aligned to the shape of the aorta and invaginated into vinyl tubing. The catheter is placed into the femoral vessel, followed by expression of the balloon with CO2 inflation in a proximal direction to navigate and treat damaged pelvic vasculature, occluding the distal aorta. The system was tested on model aortas (both intact and injured cadaveric porcine aorta) with inline fluid flow and pressure monitoring to determine the maximum pressure the balloons could occlude. The device was also tested on a perfused human cadaveric model. Results: Flow was occluded with the balloon up to an average of 561.1 +/- 124.3 mm Hg. It always ruptured before causing damage to the porcine aorta and was able to occlude injured iliac vessels and proceed to occlude the distal aorta. The device was effective in occluding the distal aorta of a perfused human cadaver. Conclusion: This novel, high-volume, low-pressure device can occlude the distal aorta in a simulated human aorta model, cadaveric porcine model and perfused human cadaver. It can occlude fluid flow to supraphysiologic pressures. It is easy to use, migration-resistant, able to navigate and treat injured pelvic vessels, and amenable to prehospital care. PMID- 30417721 TI - Providing mental health peer support 2: Relationships with empowerment, hope, recovery, quality of life and internalised stigma. AB - OBJECTIVE:: Qualitative research has identified personal costs and benefits for peer supporters associated with their role; however, quantitative evidence is sparse. This study used quantitative methods to explore relationships in experiences of providing peer support with constructs of empowerment, hope, recovery, quality of life and internalised stigma. Differences were examined for those in statutory versus non-statutory services; who had themselves received peer support versus those who had not and who identified having had negative experiences in clinical teams versus those without such experiences. METHODS:: A cross-sectional online and postal survey was undertaken in tandem with a linked consensus study. In all, 147 peer supporters were recruited from a variety of organisations across the United Kingdom. Validated questionnaires were used to examine constructs. Instruments created for the study measured peer support experiences, and personal costs and benefits involved. Correlations were calculated and results informed further regression analysis. Chi-square tests and independent samples t-tests tested group differences. RESULTS:: Peer supporters indicated they experienced almost twice as many role-related personal benefits than personal costs. Benefits included improvements to mental health and well being, reduced use of services, increased social functioning and development of skills. Total number of personal costs experienced was significantly negatively related to peer supporters' empowerment and quality of life. There were no significant differences between the groups examined. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE:: An accumulation of personal costs may result in reduced quality of life; however, costs can be minimised by organisations. Limitations of the research are discussed and recommendations for future research are made including the need for longitudinal research. PMID- 30417722 TI - Sir Winston Churchill: acute ataxic stroke in June 1955 with excellent recovery. PMID- 30417723 TI - The review of results of foetal fibronectin at the Royal Cornwall Hospital Treliske. AB - The manufacturer of a popular qualitative fFN assay, changed to using a quantitative assay following results from EQUIPPE study. The objective of our study was to compare our hospital data collated from our qualitative fFN assay with EQUIPPE's data, with a view to establish its validity in our hospital. We undertook a retrospective study over a 22-month period to review the data of 432 preterm pregnant women at less than 34 weeks of gestation, who presented to the labour ward with symptoms of threatened preterm labour warranting a fFN test. None of the patient with results between 11 and 199 ng/mL delivered within 7 days. However, there was a rise in percentage of delivery at higher levels. For example, 73% of patients with levels greater or equal to 500 ng/mL delivered within 7 days. Our results are comparable with those of the EQUIPPE study. This has led to changes that could potentially save our hospital money. Impact statement What is already known on this subject? The fFN test is a well validated test used to diagnose a preterm delivery. Most units are changing from the qualitative assays that just show positive or negative results to quantitative assays that give specific numeric values. Manufacturers give a numeric range for positive and negative results. What do the results of this study add? Although our study is local to our population, our findings show that potentially more money could be saved and fewer women separated from their families, if the negative level of the fFN test is increased (following a review of their local practice). What are the implications of these findings for clinical practice and/or further research? More units should review or audit their fFN results and choose what levels to use as a cut off for the test locally. More importantly, a multicentre research is needed to validate if the negative level needs increasing from 49 ng/mL. PMID- 30417724 TI - Physiological Responses and Perceived Exertion During Robot-Assisted and Body Weight-Supported Gait After Stroke. AB - INTRODUCTION: Physiological responses are rarely considered during walking after stroke and if considered, only during a short period (3-6 minutes). The aims of this study were to examine physiological responses during 30-minute robot assisted and body weight-supported treadmill and overground walking and compare intensities with exercise guidelines. METHODS: A total of 14 ambulatory stroke survivors (age: 61 +/- 9 years; time after stroke: 2.8 +/- 2.8 months) participated in 3 separate randomized walking trials. Patients walked overground, on a treadmill, and in the Lokomat (60% robotic guidance) for 30 minutes at matched speeds (2.0 +/- 0.5 km/h) and matched levels of body weight support (BWS; 41% +/- 16%). Breath-by-breath gas analysis, heart rate, and perceived exertion were assessed continuously. RESULTS: Net oxygen consumption, net carbon dioxide production, net heart rate, and net minute ventilation were about half as high during robot-assisted gait as during body weight-supported treadmill and overground walking ( P < .05). Net minute ventilation, net breathing frequency, and net perceived exertion significantly increased between 6 and 30 minutes (respectively, 1.8 L/min, 2 breaths/min, and 3.8 units). During Lokomat walking, exercise intensity was significantly below exercise recommendations; during body weight-supported overground and treadmill walking, minimum thresholds were reached (except for percentage of heart rate reserve during treadmill walking). CONCLUSION: In ambulatory stroke survivors, the oxygen and cardiorespiratory demand during robot-assisted gait at constant workload are considerably lower than during overground and treadmill walking at matched speeds and levels of body weight support. Future studies should examine how robotic devices can be Future studies should examine how robotic devices can be exploited to induce aerobic exercise. PMID- 30417725 TI - Do you let me symptomatize? The potential role of cultural values in cross national variability of mental disorders' prevalence. AB - BACKGROUND:: Mental disorders may show inherent cross-national variability in their prevalence. A considerable number of meta-analyses attribute this heterogeneity to the methodological diversity in published epidemiological studies. Cultural values are characteristically not assessed in meta-regression models as potential covariates. AIM:: Our aim was to conduct a meta-regression analysis to explore to what extent certain cultural values and immigration rates (as indicator of cultural diversity) might be associated with the cross-national heterogeneity of prevalence rates. METHOD:: To minimize methodological differences that may exert a confounding effect, prevalence rates were obtained from the World Health Organization's (WHO) World Mental Health Survey Initiative. Cultural indices (overall emancipative values; overall secular values) were collected from the World Value Survey, while immigration rates were registered by utilizing the data of the United Nations' World Population Policies 2005 report. RESULTS:: Meta-regression analysis indicated that overall emancipative values (i.e. promoting self-expression, non-violent protest) showed significant connection with lifetime and last year prevalence of any mood disorders ( Z = 4.71, p = .001; Z = 2.35, p = .02) and any internalizing disorders (a merged category that combined mood and anxiety disorders; Z = 2.82, p = .004; Z = 2.34, p = .02). Overall secular values (i.e. rejecting authority and obedience) were negatively associated with last year prevalence of depression ( Z = -2.75, p = .06). Multistep regression analysis indicated that immigration rate moderated the connection between cultural values and mental disorders. Countries with higher immigration rates showed higher emancipative and secular values. CONCLUSION:: Our findings might function as potential foundation for formulating hypotheses regarding the cultural context's influence on the population's mental health. PMID- 30417726 TI - Furosemide unmasks inhibitory dysfunction following spinal cord injury in humans: implication for spasticity. AB - Spasticity after spinal cord injury has considerable quality of life implications, impacts on rehabilitation efforts and requires long-term multidisciplinary pharmacological and non-pharmacological management. The potassium chloride co-transporter (KCC2) plays a central role in intracellular chloride homeostasis and the inhibitory function of mature neurons. Animal studies have consistently demonstrated a down-regulation of KCC2 activity following spinal cord transection, causing a shift from the inhibitory action of gamma-aminobutyric acid and glycine to an excitatory effect. Furosemide, a recognised KCC2 antagonist in animals, blocks the formation of inhibitory postsynaptic potentials in spinal motoneurons without affecting excitatory postsynaptic potentials. Based on observations in animals studies, we hypothesized that furosemide may be used to unmask KCC2 down-regulation following spinal cord injury in humans which contributes to reflex hyperexcitability. We have previously shown that furosemide reduces both presynaptic and postsynaptic inhibition in healthy subjects without altering monosynaptic excitatory transmission. These findings provide evidence that furosemide may be used in humans to evaluate inhibitory synapses in the spinal cord. In this present study, we show that furosemide fails to modulate both pre- and postsynaptic inhibitions relayed to soleus spinal motor neurons in people with spinal cord injury. The lack of furosemide effect following spinal cord injury, suggests KCC2 dysfunction in humans, resulting in reduced inhibitory synaptic transmission in spinal neurons. Our findings suggest that KCC2 dysfunction may be an important aetiological factor in hyperreflexia following spinal cord injury. These observations may pave the way to novel therapeutic strategies against spasticity centred on chloride homeostasis. PMID- 30417727 TI - Changes in knee extensor strengths before and after medial patellofemoral ligament reconstruction. AB - OBJECTIVE: Quadriceps dysfunction has been suggested as a complication after medial patellofemoral ligament (MPFL) reconstruction. The purpose of this study was to investigate changes in knee extensor strength before and after MPFL reconstruction. METHODS: Twenty patients who underwent MPFL reconstruction for unilateral recurrent patellar dislocation (18 females and 2 males; mean age 20.8 +/- 7.6 years) were examined. The peak isometric torque at 60 degrees and 90 degrees of knee flexion and isokinetic knee extensor strength at speeds of 60 degrees /s and 90 degrees /s in operated and non-operated legs were measured using a dynamometer preoperatively and 6 months, 1 year, and 2 years postoperatively. The following parameters were evaluated: (1) body weight adjusted muscle strength, (2) improvement index (post-/preoperative value * 100) (%), and (3) extensor strength ratio (operated/non-operated value * 100) (%). RESULTS: The mean knee extensor strength in both operated and non-operated legs significantly increased 2 years after surgery compared with that before surgery. At 2 years postoperatively, the improvement indexes of the isometric knee extensor strength at 60 degrees and 90 degrees and of the isokinetic knee extensor strength at 60 degrees /s and 90 degrees /s were 237%, 192%, 318%, and 186%, respectively, in the operated legs and 144%, 124%, 140%, and 140%, respectively, in the non-operated legs. At 2 years postoperatively, the mean isometric knee extensor strength ratios at 60 degrees and 90 degrees and the isokinetic knee extensor strength ratios at 60 degrees /s and 180 degrees /s were 81%, 84%, 81%, 82%, respectively. CONCLUSIONS: Knee extensor strength was improved in most patients after MPFL reconstruction, at least compared with that before surgery, although an approximately 20% deficit against the non-operated legs remained even 2 years after surgery. PMID- 30417728 TI - Sir Winston Churchill: a left hemisphere stroke or possible focal seizure on 20 October 1956. PMID- 30417729 TI - Management of a pregnancy with underlying fibromuscular dysplasia with a history of stroke and carotid artery dissection. PMID- 30417730 TI - The progression of neuropathic pain after acute spinal cord injury: A meta analysis and framework for clinical trials. AB - The translation of therapeutic interventions to humans with spinal cord injury with the goal promoting growth and repair in the central nervous system could, inadvertently, drive mechanisms associated with the development of neuropathic pain. A framework is needed in order to evaluate the probability that a therapeutic intervention for acute spinal cord injury modifies the progression of neuropathic pain. We analyzed a large, longitudinal dataset from the European Multi-Center Study about Spinal Cord Injury (EMSCI) and compared these observations to a previously published Swedish/Danish cohort. A meta-analysis was performed to produce aggregate estimates for the transition period between 1-6 months and the transition period between 1-12 months after injury. A secondary analysis used logistic regression to explore associations between the progression of neuropathic pain and demographics, pain characteristics, and injury characteristics. For overall neuropathic pain, 72% presenting with pain symptoms at 1 month reported persisting symptoms at 6 months, and 23% who did not have neuropathic pain at 1-month later developed it. From 1-12 months, there was a similar likelihood of pain persisting (69%), and slightly higher rate of pain developing (36%). Characteristics that were significantly associated with the progression of pain included age and sensory and motor preservation. We provide historical benchmarks for estimating the progression of neuropathic pain during the first year after acute SCI. This information will be useful for comparison and evaluating safety during early phase acute spinal cord injury trials. PMID- 30417731 TI - Racial and ethnic differences in mental health service utilization among the Hawaii medicaid population. AB - BACKGROUND: Racial/ethnic differences have not been adequately addressed in the utilization of mental health services among Medicaid populations. AIM: This study aimed to examine racial/ethnic differences in the utilization of health services for mental disorders in a Medicaid adult population aged between 21 and 64 years. METHODS: Racial/ethnic differences in inpatient, outpatient and emergency department services utilization were assessed using 2010 Hawaii Medicaid data. Zero-inflated negative binomial regressions were employed adjusting for age, sex and residential area. RESULTS: Among 73,200 beneficiaries, 29.7% were Whites, 28.5% Asians, 34.7% Native Hawaiians and Pacific Islanders (NHPIs); 60.2% were younger (21-44 years) and 58.6% were females. The patterns of utilization of health services differed across race/ethnicity. Compared to Whites, Asians and NHPIs were less likely to use outpatient services and had lower rates of inpatient visits. NHPIs were also estimated to have lower rates of outpatient and emergency department visits. CONCLUSION: Variation in the utilization of health services emphasizes the importance of race/ethnicity in mental health management. Various factors, such as language barriers and cultural differences, should be considered in developing clinical interventions or integrative health programs that aim to reduce racial/ethnic disparities among people with mental disorders. PMID- 30417733 TI - Treating financial difficulty - the missing link in mental health care? PMID- 30417732 TI - Acute mitochondrial impairment underlies prolonged cellular dysfunction after repeated mild traumatic brain injuries. AB - Mild traumatic brain injuries (mTBI), accounting for over 80% of TBIs, can cause cognitive and behavioral impairments, the severity and duration of which increase after additional mTBIs. While mTBI does not cause widespread neuronal death, the mechanisms underlying increased cellular susceptibility to subsequent head impacts remain unknown. To investigate the hypothesis that altered mitochondrial bioenergetics underlie cellular vulnerability to repeated insults, we employed a mouse model of mild closed head injury (CHI) to examine mitochondrial function and oxidative stress, as these mechanisms are often intertwined. Mitochondrial respiration was assayed (Seahorse XFe24 Flux Analyzer) from cortex and hippocampus collected at 6h, 24h, 48h, and 96h post-injury. State III (ADP mediated) respiration was significantly decreased in the hippocampal mitochondria of the CHI group compared to sham at 48h post-injury. Furthermore, cortex-derived mitochondria exhibited a decrease in State III respiration at 24h and 48h post injury. No significant differences were observed at 6h or 96h post-injury in either region of interest. A second CHI repeated either 48h or 96h after the first did not worsen State III respiration at 48h after the final injury compared to a single CHI, but CHI repeated at a 48h interval prolonged cortical mitochondrial dysfunction to 96h after the final injury. Markers of oxidative stress were significantly elevated after two CHI delivered 48h apart, but not after single CHI or two CHI delivered 96h apart. This study establishes that mTBI results in early mitochondrial dysfunction, which may be a determinant for cellular vulnerability to repeated head impacts. Thus, therapies targeting mitochondrial impairment could improve outcomes after repeated mTBI. PMID- 30417734 TI - Patterns of structural lateralization in cortical language areas of older adolescents. AB - Structural lateralization of cortical language areas has been extensively studied in the past, with the conclusion that there is a predominant left lateralization in the majority of typically developing adolescents. However, lateralization in this age group has often been examined using cortical volumetric measures, without taking into account the independence of surface area and thickness. Utilizing structural MRI data in a relatively large sample size, the lateralization of cortical volume, surface area, and thickness was analysed across regions of interest (ROIs) known to support language processing in 118 typically developing adolescents, ages 13;9 to 18;9 using a laterality index. Results showed that the laterality index scores for volume and surface area were more strongly correlated than volume and thickness. Results also showed that not all language regions were left lateralized, with some ROIs being significantly right lateralized. Results also showed that surface area and thickness did not always share direction of lateralization. Taken together these results indicate that cortical ROIs supporting language are not all strongly left lateralized in adolescents. These data also show that cortical surface area and cortical thickness need to be treated independently in future studies characterizing language and lateralization in the adolescent brain. PMID- 30417736 TI - Information Needs Regarding Cognitive Late Effects of Caregivers of Central Nervous System Tumor Survivors. AB - Pediatric central nervous system (CNS) tumor survivors are at risk for experiencing cognitive late effects (CLEs). Caregivers of survivors may be unaware of these changes or receive untimely information regarding CLEs. Conversely, health care providers (HCPs) may face barriers to providing education. This study aims to (a) understand the knowledge and resource gap for caregivers regarding CLEs and (b) explore how HCPs currently provide education. Caregivers and HCPs were both interviewed. Qualitative analysis was performed using emergent coding. Fifteen caregivers and eight HCPs participated. Caregivers generally felt confident in assisting their survivor but experienced "information overload" during initial diagnosis and treatment. HCPs reported difficulties in determining appropriate timing for education and perceived that caregivers typically lack understanding of CLEs. Caregivers should be aware of and understand a survivor's risk for CLEs to help survivors manage changes. With increasing survival rates of pediatric CNS tumor patients, HCPs must be prepared to provide appropriate education and referrals regarding CLEs for long-term care. PMID- 30417735 TI - Comparison of PC and iPad administrations of the Cogstate Brief Battery in the Mayo Clinic Study of Aging: assessing cross-modality equivalence of computerized neuropsychological tests. AB - OBJECTIVE: Computerized neuropsychological assessments are increasingly used in clinical practice, population studies of cognitive aging and clinical trial enrichment. Subtle, but significant, performance differences have been demonstrated across different modes of test administration and require further investigation. METHOD: Participants included cognitively unimpaired adults aged 50 and older from the Mayo Clinic Study of Aging who completed the Cogstate Brief Battery and Cogstate's Groton Maze Learning Test (GMLT) on an iPad or a personal computer (PC) in the clinic. Mode of administration differences and test-retest reliability coefficients were examined across 3 cohorts: a demographically matched test-retest cohort completing PC and iPad administrations the same day (N = 168); a test naive cohort comparing baseline PC (n = 1820) and iPad (n =605) performance; and a demographically matched longitudinal cohort completing 3 Cogstate visits over 15 months on either the PC (n =63) or iPad (n =63). RESULTS: Results showed a small but statistically significant and consistent finding for faster performance on PC relative to iPad for several Cogstate Brief Battery measures. Measures of accuracy generally did not differ or differences were very small. The GMLT showed faster performance and higher total errors on iPad. Most Cogstate variables showed no difference in the rate of change across PC and iPad administrations. CONCLUSIONS: There are small, but significant, differences in performance when giving the same cognitive tests on a PC or an iPad. Future studies are needed to better understand if these small differences impact the clinical interpretation of results and research outcomes. PMID- 30417737 TI - Randomized Trial of Endoscopic or Open Vein-Graft Harvesting for Coronary-Artery Bypass. AB - BACKGROUND: The saphenous-vein graft is the most common conduit for coronary artery bypass grafting (CABG). The influence of the vein-graft harvesting technique on long-term clinical outcomes has not been well characterized. METHODS: We randomly assigned patients undergoing CABG at 16 Veterans Affairs cardiac surgery centers to either open or endoscopic vein-graft harvesting. The primary outcome was a composite of major adverse cardiac events, including death from any cause, nonfatal myocardial infarction, and repeat revascularization. Leg wound complications were also evaluated. RESULTS: A total of 1150 patients underwent randomization. Over a median follow-up of 2.78 years, the primary outcome occurred in 89 patients (15.5%) in the open-harvest group and 80 patients (13.9%) in the endoscopic-harvest group (hazard ratio, 1.12; 95% confidence interval [CI], 0.83 to 1.51; P=0.47). A total of 46 patients (8.0%) in the open harvest group and 37 patients (6.4%) in the endoscopic-harvest group died (hazard ratio, 1.25; 95% CI, 0.81 to 1.92); myocardial infarctions occurred in 34 patients (5.9%) in the open-harvest group and 27 patients (4.7%) in the endoscopic-harvest group (hazard ratio, 1.27; 95% CI, 0.77 to 2.11), and revascularization occurred in 35 patients (6.1%) in the open-harvest group and 31 patients (5.4%) in the endoscopic-harvest group (hazard ratio, 1.14; 95% CI, 0.70 to 1.85). Leg-wound infections occurred in 18 patients (3.1%) in the open-harvest group and in 8 patients (1.4%) in the endoscopic-harvest group (relative risk, 2.26; 95% CI, 0.99 to 5.15). CONCLUSIONS: Among patients undergoing CABG, we did not find a significant difference between open vein-graft harvesting and endoscopic vein-graft harvesting in the risk of major adverse cardiac events. (Funded by the Cooperative Studies Program, Office of Research and Development, Department of Veterans Affairs; REGROUP ClinicalTrials.gov number, NCT01850082 .). PMID- 30417738 TI - Clinical features of cats with aqueous tear deficiency: a retrospective case series of 10 patients (17 eyes). AB - OBJECTIVES: The aim of this study was to describe the clinical findings, diagnostic test results and response to therapy of cats with Schirmer tear test 1 (STT-1) values below the reference interval. METHODS: The medical records of three institutions were searched for cats with ocular surface disease and STT-1 values <9 mm/min, confirmed at two or more separate visits. RESULTS: Ten cats (17 eyes) were included. The mean +/- SD (range) age and STT-1 values in affected eye(s) were 6.1 +/- 5.7 (0.2-16) years and 2.4 +/- 3.1 (0-8) mm/min, respectively. Concurrent ocular surface disease was bilateral in 5/10 cats. Clinical signs included conjunctivitis (14/17 eyes), corneal ulceration (6/17 eyes), non-ulcerative keratitis (4/17 eyes), symblepharon (4/17 eyes), eosinophilic keratitis (3/17 eyes), corneal sequestrum (3/17 eyes), corneal fibrosis (2/17 eyes) and meibomitis (2/17 eyes). Management included topically applied lacrimomimetics, antiviral drugs, corticosteroids or immunomodulatory drugs; orally administered famciclovir; or surgical procedures, in various combinations. Response to therapy (defined as an increase in STT-1 value of ?5 mm/min) was transient (seen at a single reassessment) in 65% of eyes and sustained (seen at ?2 consecutive reassessments) in 18% of eyes. CONCLUSIONS AND RELEVANCE: Clinical features seen in cats with low STT-1 values are described, although the association between aqueous deficiency and the reported ocular changes is unknown at this time. We encourage clinicians to assess the tear film in cats with ocular surface disease, and initiate therapy with lacrimomimetics if STT-1 values are repeatedly below normal. Such information will further define aqueous tear deficiency in cats, providing a better understanding of disease prevalence, pathogenesis and treatment. PMID- 30417739 TI - Larval survival of Aelurostrongylus abstrusus lungworm in cat litters. AB - OBJECTIVES: The dehydrating power of cat litters may reduce the vitality of first stage larvae (L1s) of feline lungworms, limiting copromicroscopical diagnosis. This study assessed the effect of the most commonly used cat litters on Aelurostrongylus abstrusus L1 survival. METHODS: Four types of cat litters were used: clumpling clay (group A); non-clumpling clay (group B); silica crystals (group C); and biodegradable (group D). A control group without litter (group E) was also used. On study day 0 (T0), L1s were obtained by the Baermann-Wetzel technique from the faeces of a naturally infected cat and ~100 larvae were injected in each of the 20 lungworm larvae-free faecal samples (~2 g each). Thereafter, four faecal samples per group were transferred into plastic cups containing the four different types of cat litters, or into empty cups (group E). The survival of L1s was assessed in each group after 3 (T3), 6 (T6), 12 (T12) and 24 (T24) h, using the Baermann-Wetzel technique. RESULTS: A decreasing trend of L1 survival was observed in all groups, with highest significant values at T0 compared with T3, T6, T12 and T24 ( P <0.001). However, at T24, a significantly higher number ( P <0.05) of L1s was extracted from faeces of the control group compared with the four groups with cat litters. CONCLUSIONS AND RELEVANCE: This study demonstrates how the survival of A abstrusus L1s, and therefore diagnosis, may be negatively influenced by the litter. The effect is time dependent, with a reduction in the number of vital larvae according to the type of litter, over time. False-negative results may be obtained, especially in cases of low parasitic load or when the sample is collected many hours after the emission. PMID- 30417740 TI - Using the Brief-BESTest paired with a novel algorithm to provide targeted balance interventions for people with subacute stroke: a feasibility study. AB - BACKGROUND: Balance is a common mobility limitation following stroke, but determination of the most effective balance-related plan of care can be difficult due to multiple balance impairments that vary between individuals. The Brief BESTest is a validated outcome measure for balance based on six systems of postural control. It may also be a useful tool to guide clinicians in their balance plan of care design. OBJECTIVE: The objective of this study was to determine the feasibility of a quantitative balance plan of care for patients with subacute stroke, using a novel algorithm that utilizes the scoring design of the Brief-BESTest. The authors hypothesized that this plan of care could create targeted balance interventions among this population. METHODS: Eligible patients with subacute stroke at an inpatient rehab facility completed the Brief-BESTest within 1 week of admission. The subjects participated in specific interventions based on test section scores during their rehab stay. RESULTS: Five subjects completed testing and participated in targeted balance interventions, addressing three to five systems of postural control. Subjects demonstrated improved Brief BESTest overall scores by 2, 1, 7, 4, and 6 points from admission to discharge. Improvements in section scores were primarily seen in the systems of postural control identified by the algorithm. All subjects improved in Functional Independence Measure (FIMTM)30 scores for locomotion (walking and stairs) by 5, 6, 7, 6, and 9 points, respectively. All subjects were discharged to the community. CONCLUSION: Our observational study found this method of assessment and intervention to be feasible in the subacute stroke population and was associated with improved balance scores and improved functional mobility. Further study is warranted to determine effectiveness and efficiency. PMID- 30417741 TI - Location of multiple binding sites for testo and testo-Pt(II) with tRNA. AB - We report the binding of testo and testo-Pt(II) complexes (testosterone derivatives) with tRNA in aqueous solution at physiological pH. Thermodynamic parameter DeltaH0 -8 to -3 (kJ mol-1), DeltaS0 35 to 18 (J mol-1K-1) and DeltaG0 14 to -13 (kJ mol-1) and other spectroscopic results showed drug-tRNA binding occurs via ionic contacts with testo-Pt(II) forming more stable tRNA complexes in comparsion to testo: Ktesto-Pt(II)-tRNA = 3.2 ( +/- 0.9) x 105 M-1 > Ktesto-tRNA = 2.1 ( +/- 0.7) x 105 M-1. Molecular modeling showed multiple binding sites for testo and testo-Pt(II) on tRNA molecule. Some of the useful molecular descriptors are calculated. Major structural changes were observed for biopolymers upon drug complexation, while tRNA remains in the A-family structures. PMID- 30417743 TI - Network Analysis and Nursing Research: Challenging Opportunity. PMID- 30417742 TI - Pelvic and Lower Gastrointestinal Tract Anatomical Characterization of the Average Male. AB - OBJECTIVE: Colorectal surgeons report difficulty in positioning surgical devices in males, particularly those with a narrower pelvis. The objectives of this study were to (1) characterize the anatomy of the pelvis and surrounding soft tissue from magnetic resonance and computed tomography scans from 10 average males (175 cm, 78 kg) and (2) develop a model representing the mean configuration to assess variability. METHODS: The anatomy was characterized from existing scans using segmentation and registration techniques. Size and shape variation in the pelvis and soft tissue morphology was characterized using the Generalized Procrustes Analysis to compute the mean configuration. RESULTS: There was considerable variability in volume of the psoas, connective tissue, and pelvis and in surface area of the mesorectum, pelvis, and connective tissue. Subject height was positively correlated with mesorectum surface area (P = .028, R2 = 0.47) and pelvis volume ( P = .041, R2 = 0.43). The anterior-posterior distance between the inferior pelvic floor muscle and pubic symphysis was positively correlated with subject height ( P = .043, r = 0.65). The angle between the superior mesorectum and sacral promontory was negatively correlated with subject height ( P = .042, r = -0.65). The pelvic inlet was positively correlated with subject weight ( P = .001, r = 0.89). CONCLUSIONS: There was considerable variability in organ volume and surface area among average males with some correlations to subject height and weight. A physical trainer model created from these data helped surgeons trial and assess device prototypes in a controllable environment. PMID- 30417744 TI - Analysis of biochemical laboratory values to determine etiology and prognosis in patients with subarachnoid hemorrhage: a clinical study. AB - OBJECTIVES: The aim of this study was to establish prognostic and predictive markers in patients with subarachnoid hemorrhage (SAH) using simple laboratory methods. METHODS: A retrospective examination was made of patients with SAH diagnosed secondary to isolated head trauma, isolated anterior communicating artery aneurysm rupture, and angiography-negative SAH. Age, gender, Glasgow Coma Scale (GCS) scores, and Fisher's grade scores, Glasgow Outcome Scale (GOS) scores, leukocyte count, neutrophil count, lymphocyte count, platelet count, neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio results (PLR) were evaluated. RESULTS: NLR and PLR values, which were similar in patients with spontaneous SAH, were significantly high in patients with traumatic SAH. NLR and PLR values could be 80% sensitive and 75% specific for distinguishing traumatic SAH from spontaneous SAH. Eosinophil count was lower in patients with angiography negative SAH and patients with aneurysmal SAH than in patients with traumatic SAH. Initially measured GCS score, Fisher's grade score, eosinophil, neutrophil and lymphocyte counts could be prognostic in all patients with SAH. Moreover, it was concluded that the initially measured number of eosinophils might be directly related to patient prognosis. The eosinophil count was generally found to be high in traumatic SAH patients and it was observed that this parameter could be predictive for these patients. Lymphocyte count and NLR values could be prognostic markers in patients with angiography-negative SAH. CONCLUSION: NLR, PLR and eosinophil count values could be predictive for etiological factors (traumatic SAH or spontaneous SAH) of patients who were admitted unconscious to the emergency room with SAH detected on radiological imaging. PMID- 30417745 TI - On Factors Affecting Subharmonic-aided Pressure Estimation (SHAPE). AB - Subharmonic-aided pressure estimation (SHAPE) estimates hydrostatic pressure using the inverse relationship with subharmonic amplitude variations of ultrasound contrast agents (UCAs). We studied the impact of varying incident acoustic outputs (IAO), UCA concentration, and hematocrit on SHAPE. A Logiq 9 scanner with a 4C curvilinear probe (GE, Milwaukee, Wisconsin) was used with Sonazoid (GE Healthcare, Oslo, Norway) transmitting at 2.5 MHz and receiving at 1.25 MHz. An improved IAO selection algorithm provided improved correlations ( r from -0.85 to -0.95 vs. -0.39 to -0.98). There was no significant change in SHAPE gradient as the pressure increased from 10 to 40 mmHg and hematocrit concentration was tripled from 1.8 to 4.5 mL/L (Delta0.00-0.01 dB, p = 0.18), and as UCA concentration was increased from 0.2 to 1.2 mL/L (Delta0.02-0.05 dB, p = 0.75). The results for the correlation between the SHAPE gradient and hematocrit values for patients ( N = 100) in an ongoing clinical trial were also calculated showing a poor correlation value of 0.14. Overall, the SHAPE gradient is independent of hematocrit and UCA concentration. An improved algorithm for IAO selection will make SHAPE more accurate. PMID- 30417747 TI - Between-limb differences in running technique induces asymmetric negative joint work during running. AB - Negative work, which is mainly generated by eccentric muscle contraction, has an important influence on the associated muscle damage. Generally, mechanical parameters are determined for one side of a lower extremity on the assumption of negligible between-limb differences. However, between-limb differences in the negative work of lower extremity joints during running remain unclear. This study examines between-limb differences in negative work and associated mechanical parameters during the contact phase of running. Twenty-five young adult males voluntarily participated in this study. Each participant was asked to run on a straight runway at a speed of 3.0 m s-1. Negative work, amplitude, duration of negative power, moment, and angular velocity were computed for both sides of the lower extremities. Significant differences were found in negative work between limbs for the hip (18.9 +/- 11.7%), knee (13.6 +/- 10.4%), and ankle (11.8 +/- 8.5%) joints. For the hip joint, asymmetric negative work was attributable to the between-limb difference in the amplitude of negative power owing to a corresponding difference in the moment. The between-limb differences concerning the duration and amplitude of negative power could explain the asymmetric negative work in the knee joint. The asymmetric negative work of the ankle joint was attributable to the between-limb difference in the amplitude and duration of the negative power and the moment. These results indicate that asymmetric negative work was generated in each lower extremity joint; however, the major mechanical parameters corresponding to the negative work are not the same across the joints. PMID- 30417746 TI - Screening of Novel Histone Deacetylase 7 Inhibitors through Molecular Docking Followed by a Combination of Molecular Dynamics Simulations and Ligand-Based Approach. AB - Histone acetylation/deacetylation is a key mechanism for transcription regulation which plays an important role in control of gene expression, tissue growth and development. In particular, histone deacetylase 7 (HDAC7), a member of class IIa HDACs, is crucial to maintain cell homeostasis, and HDAC7 has emerged as a new target for cancer therapy. In this study, molecular docking was applied to screen candidate inhibitors and 21 compounds were found. Following the 50 ns molecular dynamics simulations and binding free energy calculation, ZINC00156160, ZINC01703144, ZINC04293665 and ZINC13900201 were identified as potential HDAC7 inhibitors, which would provide a sound starting point for further studies involving molecular modeling coupled with biochemical experiments. Meanwhile, similarity computation and substructure search were combined and then we found that compounds sharing common backbone "CC(=O)N[C@@H](CSc1ccccc1)C(=O)O" could be efficient to inhibit the bioactivity of HDAC7. Then CoMSIA techniques were implemented to investigate the relationship between properties of the substituent group and bioactivities of small molecules. The CoMSIA model exhibited powerful predictivity, with satisfactory statistical parameters such as q2 of 0.659, R2 of 0.952, and F of 268.448. Contour maps of the CoMSIA model gave insight into the feature requirements of the common backbone for the HDAC7 inhibitory activity. Finally, details of designing novel HDAC7 inhibitors were confirmed by a combination of receptor-based docking and ligand-based structure-activity relationship. PMID- 30417748 TI - Platypus Induced Pluripotent Stem Cells: the Unique Pluripotency Signature of a Monotreme. AB - The platypus (Ornithorhynchus anatinus) is an egg-laying monotreme mammal whose ancestors diverged approximately 166 million years ago from the evolutionary pathway that eventually gave rise to both marsupial and eutherian mammals. Consequently, its genome is an extraordinary amalgam of both ancestral reptilian and derived mammalian features. To gain insight into the evolution of mammalian pluripotency we have generated induced pluripotent stem cells (piPSCs) from the platypus. Deep sequencing of the piPSC transcriptome revealed that piPSCs robustly express the core eutherian pluripotency factors OCT4, SOX2 and NANOG. Given the more extensive role of SOX3 over SOX2 in avian pluripotency, our data indicate that between 315 million years and 166 million years ago primitive mammals replaced the role of SOX3 in the vertebrate pluripotency network with SOX2. DAX1/NR0B1 is not expressed in piPSCs and an analysis of the platypus DAX1 promoter revealed the absence of a proximal SOX2-binding DNA motif known to be critical for DAX1 expression in eutherian pluripotent stem cells, suggesting that the acquisition of SOX2 responsiveness by DAX1 has facilitated its recruitment into the pluripotency network of eutherians. Using the RNAseq data, we were also able to demonstrate that in both fibroblasts and piPSCs the expression ratio of X chromosomes to autosomes (X1-5 X1-5:AA) is approximately equal to 1 indicating that there is no upregulation of X-linked genes. Finally, the RNAseq data also allowed us to explore the process of X-linked gene inactivation in the platypus, where we determined that for any given gene there is no preference for silencing of the maternal or paternal allele; that is, within a population of cells the silencing of X-linked genes is not imprinted. PMID- 30417749 TI - Relationship between socioeconomic status and risk of sexually transmitted infections in Uganda: Multilevel analysis of a nationally representative survey. AB - Socioeconomic status (SES) appears to have positive and negative associations with sexually transmitted infection (STI) risk in resource-limited settings, but few studies have evaluated nationally representative data. We assessed multiple SES measures and their effect on STI risk. We conducted a secondary analysis of data from the Uganda Demographic and Health Survey (UDHS 2011). The primary outcome (STI risk) was self-reported STIs and/or symptoms in the prior 12 months. We examined associations between multiple SES measures and STI risk using a mixed effects Poisson regression model. The results showed that of the 9256 sexually active individuals, 7428 women and 1828 men were included in the analysis. At an individual level, middle wealth quintile and disposable income were associated with STI risk, whereas being in the richest wealth quintile was protective. Residence in wealthier regions (adjusted incidence rate ratio [aIRR] 3.92, 3.62, and 2.75, for Central, Western, and Eastern regions; p < 0.01) was associated with increased STI risk. Regional level analysis revealed stochastic variability of STI risk across geographical region (variance 0.03; p = 0.01). The bilateral association between SES and STI risk underscores the need for multi-sectoral interventions to address the upstream effects of poverty on STI risk and downstream effects of STIs on health and economic productivity. PMID- 30417750 TI - High burden of previously undiagnosed HIV infections and gaps in HIV care cascade for conflict-affected female sex workers in northern Uganda. AB - Given the disproportionate HIV burden faced by female sex workers FSWs and limited data regarding their engagement in the HIV cascade of care in conflict affected settings, we characterized the cascade of care and examined associations with new HIV diagnoses and antiretroviral therapy (ART) use in a community-based cohort of FSWs in conflict-affected Northern Uganda. Data were collected via FSW/peer-led time-location sampling and outreach, interview-administered questionnaires, and voluntary HIV testing. Of 400 FSWs, 33.5% were living with HIV, of whom 33.6% were new/previously undiagnosed infections and 32.8% were on ART. Unstable housing and heavy alcohol/drug use were independently associated with increased odds of new HIV diagnoses, whereas exposure to condom demonstrations and number of lifetime pregnancies were negatively associated. In subanalysis among known HIV-positive women, age and time since diagnosis were associated with ART use, whereas sexually transmitted infections were negatively associated. Findings suggest the need for FSW-tailored, peer-based, and integrated HIV and sexual and reproductive health programs to address gaps in HIV testing and treatment for FSWs in conflict-affected communities. PMID- 30417751 TI - Transcranial random noise stimulation (tRNS) over prefrontal cortex does not influence the evaluation of facial emotions. AB - Cerebral asymmetries for emotion processing are controversial, the right hemisphere being considered either superior in the recognition of all emotions, or superior in the recognition of negative emotions (together with the left hemispheric superiority for positive emotions). In a number of previous studies, tDCS was applied on the left/right prefrontal cortex (PFC) in order to disentangle this issue, but the results remain controversial. We applied hf tRNS/sham stimulation over the left/right PFC, during the presentation of neutral, angry and happy faces presented as broadband images (supraliminal condition), and as "hybrid" stimuli in which an emotional face in low spatial frequency is superimposed to the neutral expression of the same individual in high spatial frequency (subliminal condition), during a friendliness evaluation task. The results showed that angry and happy unfiltered stimuli were judged as the most unfriendly and friendly, respectively. Importantly, we found that hf tRNS applied over the left/right PFC did not influence friendliness evaluations for emotional faces. PMID- 30417752 TI - Biomechanical analysis of the "waiter's serve" on upper limb loads in young elite tennis players. AB - Waiter's serve (WS) is a specific tennis serve posture frequently observed in young players, and commonly considered as a technical error by tennis coaches. However, biomechanical impact of WS is unknown. The aims of this study were to identify the potential consequences of WS in young elite players relating to performance and injury risk, and to explain the kinematic causes of WS. Serve of 18 male junior elite players (Top 10 national French ranking, aged 12-15 years) was captured with a 20 camera, 200 Hz VICON MX motion analysis system. Depending on their serve technique, the players were divided into two groups (WS versus Normal Serve [NS]) by experienced coaches. Injury data were collected for each player during a 12-month-period following the motion capture. Normalized peak kinetic values of the dominant arm were calculated using inverse dynamics. In order to explain WS posture, upper limb kinematics were calculated during the cocking and the acceleration phases of the serve. Shoulder internal rotation torque, wrist proximal and anterior forces (P < .05) and elbow varus torque (P < .01) were significantly higher in WS group, with no difference from NS group concerning serve velocity. Moreover, significant lower shoulder abduction and higher wrist extension (P < .05) were observed for WS players during the cocking phase. Even if no significant difference was found between groups concerning injuries, higher upper limb joint loads suggested WS could be considered as pathomechanical in young elite players and could lead to upper limb joint injuries. PMID- 30417753 TI - Shifting Perspectives on Research Integrity. PMID- 30417754 TI - "Why Don't You Go Into Suburbs? Why Are You Targeting Us?": Trust and Mistrust in HIV Vaccine Trials in South Africa. AB - Trust is a key element of high-quality stakeholder relations, which are themselves essential for the success of HIV vaccine trials. Where trust is absent, community stakeholders might not volunteer to become involved in key trial activities, and potential participants might not volunteer for enrollment. We explored site staff and Community Advisory Board (CAB) members' experiences of trust/mistrust among community members and potential participants. We analyzed 10 focus group discussions with site staff and CAB members at two active South African HIV vaccine trial sites. We report on key characteristics perceived to contribute to the trustworthiness of communicators, as well as factors associated with mistrust. Attributes associated with trustworthy communicators included shared racial identity, competence, and independence (not being "captured"). Key foci for mistrust included explanations about site selection, stored samples, vaccination, and Vaccine Induced Sero-Positivity (VISP). Our findings suggest that community members' trust is not necessarily global, in which trials are trusted or not; rather, it appears fairly nuanced and is impacted by various perceived attributes of communicators and the information they provide. We make recommendations for clinical trial site stakeholders invested in building trust and for future research into trust at these sites. PMID- 30417755 TI - "Is This Class Hard?" Defining and Analyzing Academic Rigor from a Learner's Perspective. AB - Despite its value in higher education, academic rigor is a challenging construct to define for instructor and students alike. How do students perceive academic rigor in their biology course work? Using qualitative surveys, we asked students to identify "easy" or "hard" courses and define which aspects of these learning experiences contributed to their perceptions of academic rigor. The 100-level students defined hard courses primarily in affective terms, responding to stressors such as fast pacing, high workload, unclear relevance to their life or careers, and low faculty support. In contrast, 300-level students identified cognitive complexity as a contributor to course rigor, but course design elements alignment between instruction and assessments, faculty support, active pedagogy contributed to the ease of the learning process. Overwhelmingly, all students identified high faculty support, learner-centered course design, adequate prior knowledge, and active, well-scaffolded pedagogy as significant contributors to a course feeling easy. Active-learning courses in this study were identified as both easy and hard for the very reasons they are effective: they simultaneously challenge and support student learning. Implications for the design and instruction of rigorous active-learning college biology experiences are discussed. PMID- 30417756 TI - Can I Have Your Recipe? Using a Fidelity of Implementation (FOI) Framework to Identify the Key Ingredients of Formative Assessment for Learning. AB - For decades, formative assessment has been identified as a high-impact instructional practice that positively affects student learning. Education reform documents such as Vision and Change: A Call to Action expressly identify frequent, ongoing formative assessment and feedback as a key instructional practice in student-centered learning environments. Historically, effect sizes between 0.4 and 0.7 have been reported for formative assessment experiments. However, more recent meta-analyses have reported much lower effect sizes. It is unclear whether the variability in reported effects is due to formative assessment as an instructional practice in and of itself, differences in how formative assessment was enacted across studies, or other mitigating factors. We propose that application of a fidelity of implementation (FOI) framework to define the critical components of formative assessment will increase the validity of future impact studies. In this Essay, we apply core principles from the FOI literature to hypothesize about the critical components of formative assessment as a high-impact instructional practice. In doing so, we begin the iterative process through which further research can develop valid and reliable measures of the FOI of formative assessment. Such measures are necessary to empirically determine when, how, and under what conditions formative assessment supports student learning. PMID- 30417757 TI - Students Who Fail to Achieve Predefined Research Goals May Still Experience Many Positive Outcomes as a Result of CURE Participation. AB - Course-based undergraduate research experiences (CUREs) provide students opportunities to engage in research in a course. Aspects of CURE design, such as providing students opportunities to make discoveries, collaborate, engage in relevant work, and iterate to solve problems are thought to contribute to outcome achievement in CUREs. Yet how each of these elements contributes to specific outcomes is largely unexplored. This lack of understanding is problematic, because we may unintentionally underemphasize important aspects of CURE design that allow for achievement of highly valued outcomes when designing or teaching our courses. In this work, we take a qualitative approach and leverage unique circumstances in two offerings of a CURE to investigate how these design elements influence outcome achievement. One offering experienced many research challenges that increased engagement in iteration. This level of research challenge ultimately prevented achievement of predefined research goals. In the other offering, students experienced fewer research challenges and ultimately achieved predefined research goals. Our results suggest that, when students encounter research challenges and engage in iteration, they have the potential to increase their ability to navigate scientific obstacles. In addition, our results suggest roles for collaboration and autonomy, or directing one's own work, in outcome achievement. PMID- 30417758 TI - Probing the Relevance of Chemical Identity Thinking in Biochemical Contexts. AB - The solving of problems in biochemistry often uses concepts from multiple disciplines such as chemistry and biology. Chemical identity (CI) is a foundational concept in the field of chemistry, and the knowledge, thinking, and practices associated with CI are used to answer the following questions: "What is this substance?" and "How is it different from other substances?" In this study, we examined the relevance of CI in biochemical contexts and first explored the ways in which practicing biochemists consider CI relevant in their work. These responses informed the development of creative exercises (CEs) given to second- semester biochemistry students. Analysis of the student responses to these CEs revealed that students incorporated precursors to CI thinking in more than half of their responses, which were categorized by seven previously identified themes of CI relevant to the presented biochemical contexts. The prevalence of these precursors in student responses to the CEs, coupled with the examples provided by practicing biochemists of contexts in which CI is relevant, indicate that CI thinking is relevant for both students training to be biochemists and practicing biochemists. PMID- 30417759 TI - Patients' wishes, pregnancy and vascular access: When one size does not fit all. AB - Pregnancy in dialysis patients is a rare but important event that challenges our knowledge and demands re-thinking many aspects of our practice, including vascular access. This editorial briefly discusses some open questions on vascular access in this situation that challenge the motto 'fistula first' and underline the need for personalised approaches. Information on vascular access in pregnant women is scant. Different approaches may be considered between women on dialysis already on a well-functioning tunnelled catheter and newly placed catheters: while a tunnelled catheter in a woman already stabilised on outpatient dialysis, who has shown being able to take correct care of it and who has freely chosen this option, is a reasonable choice, central venous catheters placed during pregnancy, especially in the hospital setting, may have a high risk of complications. Conversely, pregnancy may increase the risk of development of fistula aneurysms, but the frequency of this complication is still unknown. The problem of whether or not shifting pregnant patients on peritoneal dialysis to daily haemodialysis sessions is still open, as well as the role of patients' preference for avoidance of an invasive procedure, or refuse of pain. In the wait for answers, reflecting on the problems encountered by pregnant women on dialysis should make us reflect on how to improve vascular access management for all our patients. PMID- 30417760 TI - Diets containing pomegranate polyphenol and soy isoflavone attenuate contact hypersensitivity in mice. AB - Contact hypersensitivity (CHS) is frequently used as an animal model for human allergic contact dermatitis (ACD). Diets of pomegranate polyphenols (PPs) or soy isoflavones (SIs) each alleviated CHS symptoms; however, the effect of diets containing a mixture of PPs and SIs on CHS is unclear. We investigated the CHS inhibitory effects of diets supplemented with a mixture of PPs and SIs at human physiologically relevant doses. Consuming the mixture of PPs and SIs attenuated ear swelling and reduced infiltration of Gr-1-positive cells. Ear swelling decreased in the PP and SI-treated mice compared to the SI-treated mice. The auricle tissues of the PP and SI-fed mice exhibited decreased production of CXCL2 and MCP-5 compared to the SI- and PP-treated mice, respectively. These results suggest that dietary supplementation with a mixture of PPs and SIs may have ACD preventive effects and may prove more beneficial than supplementation with PPs or SIs alone. PMID- 30417761 TI - Pregnancy and perinatal outcome among hypothyroid mothers: a population based cohort study. AB - BACKGROUND: Maternal hypothyroidism has been associated with adverse pregnancy outcomes. We established a large nationwide register-based cohort with data on medication purchases to study the associations between maternal hypothyroidism, levothyroxine use and pregnancy and perinatal complications. METHODS: Our data included all singleton births between 2004 and 2013 (N=571,785) in Finland. Hypothyroid mothers (N=16,364) were identified in the Finnish Medical Birth Register. Of these women 95.8% used levothyroxine medication and 37.5% had consistent levothyroxine use during pregnancy. Hypothyroid mothers were compared with mothers without thyroid disease (N=550,860) using logistic regression. Main outcome measures were pregnancy and perinatal complications. RESULTS: Maternal hypothyroidism associated with several pregnancy and perinatal complications including gestational diabetes mellitus (GDM) (OR 1.19, 95% CI 1.13-1.25), gestational hypertension (OR 1.20, 95% CI 1.10-1.30), severe preeclampsia (OR 1.38, 95% CI 1.15-1.65), caesarean sections (CS) (OR 1.22, 95% CI 1.17-1.27), preterm births (OR 1.25, 95% CI 1.16-1.34), large-for-gestational age newborns (LGA) (OR 1.30, 95% CI 1.19-1.42), major congenital anomalies (OR 1.14, 95% CI 1.06-1.22) and neonatal intensive care unit (NICU) admission (OR 1.23, 95% CI 1.17-1.29). However, among mothers with consistent levothyroxine purchases, only the associations between GDM (OR 1.12, 95% CI 1.03-1.22), CS (OR 1.13, 95% CI 1.06-1.21), NICU admission (OR 1.09, 95% CI 1.01-1.29) and LGA newborns (OR 1.26, 95% CI 1.10-1.45) and maternal hypothyroidism remained. CONCLUSIONS: Maternal hypothyroidism is associated with several pregnancy and perinatal complications but consistent levothyroxine use may reduce many of the risks. PMID- 30417762 TI - Association analysis of Glutathione S-transferase omega-1 and omega-2 genetic polymorphisms and ischemic stroke risk in a Turkish population. AB - OBJECTIVES: Oxidative stress is a known risk factor for the pathogenesis of atherosclerosis, the main cause of ischemic stroke. Glutathione S-transferase (GST) omega-1 and omega-2, members of phase II enzymes, play a role in the antioxidant system. The single nucleotide polymorphisms (SNPs), C419A and A424G in GST omega genes can cause a decrease in enzyme activity. The aim of this study was to investigate the possible association between these polymorphisms and ischemic stroke risk in a Turkish population. METHODS: The genotypes and allele frequencies for 239 patients and 130 controls were determined by the PCR/RFLP method. No significant differences were found between patients and controls in terms of genotype and allele frequencies. RESULTS: The frequency of the polymorphic 'A' allele was 0.358 in patients and 0.342 in controls for the C419A polymorphism in the GSTO1 gene. The frequency of the polymorphic 'G' allele for GSTO2 A424G SNP was 0.370 in patients and 0.404 in controls. The combined homozygous wild type genotype 'CCAG' was significantly higher in control group than in the patients. CONCLUSION: No significant difference was observed between the stroke patients and controls in terms of genotypes and allele distributions. Double combine haplotype CCAA was found to be protective against ischemic stroke when compare to other haplotypes. However, different genotypes of GSTO1 and GSTO2 were observed to have effects on stroke risk in subgroups of diabetics and smokers. In conclusion, the current study is the first to report this finding. PMID- 30417763 TI - Introduction of the Surgical Site Fire Risk Assessment at The Lister Hospital, part of HCA Healthcare UK. AB - INTRODUCTION: A surgical site fire within the operating theatres is a continuous risk in modern surgery. When such an event does happen, clinical personnel can feel stunned, because such events are rare, and often happen rapidly. At The Lister Hospital, part of HCA Healthcare UK, a Fire Risk Assessment Tool and Protocol was developed to reduce such risks. METHOD: Reviewing the scholarly literature and case studies relating to surgical site fires provides information and recommendations to highlight and improve such dangerous incidents from occurring in the future. CONCLUSION: From the review of literature, two extensively documented cases of surgical site fire concluded in the identification of the elements of the fire triangle that create risk. From the recommendations a Fire Risk Assessment Tool and Protocol were developed and implemented at The Lister Hospital, including an addition to the WHO five Steps to Safer Surgery Checklist. PMID- 30417764 TI - Postoperative stress and pain response applying fast-track protocol in patients undergoing hepatectomy. AB - AIM: To assess the clinical parameters and compare the stress and pain response between fast-track recovery protocol and conventional treatment in patients undergoing major liver resection. METHODS: Eighty-eight patients suffering from malignant liver tumours were surgically treated from May 2012 to March 2015. After randomisation, they were prospectively divided into two groups: group fast track patients (n = 46) and group conventional treatment patients (n = 42). Demographic and clinical data were collected and patients were assessed with pain scale (behavioural observation scale and visual analog scale), while depression levels were evaluated with Zung self-rating depression scale and three Numeric Analog Scale self-reported questions. Peripheral blood samples were collected at time points: T1 on the admission day, T2 on the day of surgery and T3 on the day of discharge examining serum levels of adrenocorticotropic hormone and cortisol. CONCLUSION: Fast-track recovery protocols seem to be associated with improvement in several clinical parameters, without compromising, biologic or emotional stress in patients undergoing major liver resection. PMID- 30417765 TI - Effect of music tempo on operating room preparation time. AB - Most operating rooms around the world play music, both during the surgeries and in between cases. We investigated whether music tempo (fast or slow) can affect the operating room preparation time in between surgeries (turnover time) in an ambulatory outpatient surgical centre setting. We compiled two playlists, one with fast upbeat tempo and the other with slow relaxing tempo. Each of the playlists was played throughout the workday in the operating room for one week with the same surgeon and nursing staff. The turnover times for each case were analysed. Inclusion criteria were standard cataract extraction with intraocular lens implant surgery. Exclusion criteria were any external reasons causing delays in the turnover time (such as anaesthesia team break time, computer system down, etc.). The turnover time from 32 cases in the slow group and 26 cases in the fast group were compared with Student's t test. The turnover time was significantly faster in the fast group versus the slow group (17.0 +/- 0.60 vs. 20.1 +/- 0.96, p < 0.03). Our study demonstrated that fast music tempo in the operating room can significantly reduce turnover time. This improved efficiency can potentially lead to significant cost savings in the healthcare sector. PMID- 30417766 TI - How can the presence of a surgical care practitioner improve training for staff who are learning how to scrub for robotics cases in a urology theatre? AB - AIM: This study examines how a surgical care practitioner can contribute to the learning needs of junior scrub staff learning to scrub for urological robotics cases. Key themes include education, technical training, non-technical skills, patient safety and the specialist practitioner as educator. METHODS: Data collection was via an online survey, distributed by a gatekeeper to 13 participants. These were junior scrub practitioners who had completed their robotic rotation. RESULTS: A 62% response rate was achieved. The majority of respondents indicated that there was a difference in interactions when a surgical care practitioner was assisting compared to a surgical trainee. Half of the respondents felt more confident when the surgical care practitioner was assisting. CONCLUSIONS: A range of approaches were proposed for how the surgical care practitioner could enhance learning. Structured input is likely to be more appropriate to avoid the surgical care practitioner being distracted from their own duties whilst assisting. There is scope for further research. PMID- 30417767 TI - Small Activating RNAs as Promising Agents for Biotechnological Use. PMID- 30417768 TI - Nanoparticle-Plasma Membrane interactions: thermodynamics, toxicity and cellular response. AB - Nanomaterials have become part of our daily lives, particularly nanoparticles contained in food, water, cosmetics, additives and textiles. Nanoparticles interact with organisms at the cellular level. The cell membrane is the first protective barrier against the potential toxic effect of nanoparticles. This first contact, including the interaction between the cell membranes -and associated proteins- and the nanoparticles is critically reviewed here. Nanoparticles, depending on their toxicity, can cause cellular physiology alterations, such as disruption in cell signaling or changes in gene expression, and they can trigger immune responses and even apoptosis. Additionally, the fundamental thermodynamics behind the nanoparticle-membrane and nanoparticle proteins-membrane interactions are discussed. The analysis is intended to increase our insight into the mechanisms involved in these interactions. Finally, consequences are reviewed and discussed. PMID- 30417769 TI - Isoliquiritigenin (ISL) and its formulations: potential antitumor agents. AB - Isoliquiritigenin (2',4',4-trihydroxychalcone, ISL) is one of the most important chalcone compound which mainly derived from licorice root and many other plants. It exhibits a remarkable range of potent biological and pharmacological activities such as antioxidative, antitumor, antiaging, anti-inflammatory, anti diabetic activities, etc. Numerous research teams have demonstrated that ISL process the ability to antigrowth and proliferation in various cancer cells in vitro and in vivo. Meanwhile, the underlying mechanisms of ISL inhibits cancer cell proliferation have not been well explored. However, the poor bioavailability and low water-soluble limits its clinical application. This review aims at providing a comprehensive overview of the pharmacology antitumor activity of ISL and its mechanisms in different malignancy especially in breast cancer cell line and summarize developments of formulation utilized to overcome the barrier between its delivery characteristics and application in clinical over the past 20 years. PMID- 30417770 TI - Structural and Bioactive Studies of Halogenated Constituents from Sponges. AB - Marine organisms are abundant sources of bioactive natural products. Among metabolites produced by sponges and their associated microbial communities, halogenated natural compounds accounted for an important part due to their potent biological activities. The present review updates and compiles a total of 258 halogenated organic compounds isolated in the past three decades, especially brominated derivatives derived from 31 genera of marine sponges. These compounds can be classified as the following classes: brominated polyunsaturated lipids, nitrogen compounds, brominated tyrosine derivatives and other halogenated compounds. These substances were listed together with their source organisms, structures and bioactivities. For this purpose, 84 references were consulted. PMID- 30417771 TI - Anthocyanins As Modulators of Cell Redox-Dependent Pathways in Non-Communicable Diseases. AB - Chronic noncommunicable diseases (NCDs), mostly represented by cardiovascular diseases, diabetes, chronic pulmonary diseases, cancers, and several chronic pathologies, are one of the main causes of morbidity and mortality, and are mainly related to the occurrence of metabolic risk factors. Anthocyanins (ACNs) posses a wide spectrum of biological activities, such as anti-inflammatory, antioxidant, cardioprotective, and chemopreventive properties, which are able to promote human health. Although ACNs present an apparent low bioavailability, their metabolites may play an important role in the in vivo protective effects observed. This article directly addresses the scientific evidences supporting that ACNs could be useful to protect human population against several NCDs not only acting as antioxidant but through their capability to modulate cell redox dependent signaling. In particular, ACNs interact with the NF-kappaB and AP-1 signal transduction pathways, which respond to oxidative signals and mediate a proinflammatory effect, and the Nrf2/ARE pathway and its regulated cytoprotective proteins (GST, NQO, HO-1, etc.), involved in both cellular antioxidant defenses and elimination/inactivation of toxic compounds, so countering the alterations caused by conditions of chemical/oxidative stress. In addition, supposed crosstalks could contribute to explain the protective effects of ACNs in different pathological conditions characterized by an altered balance among these pathways. Thus, this review underlines the importance of specific nutritional molecules for human health and focuses on the molecular targets and the underlying mechanisms of ACNs against various diseases. PMID- 30417772 TI - An Update On The Neurochemistry Of Essential Tremor. AB - BACKGROUND: The pathophysiology and neurochemical mechanisms of essential tremor (ET) are not fully understood, because only a few post-mortem studies have been reported, and the lack of a good experimental model for this disease. OBJECTIVE: The main aim of this review is to update data regarding the neurochemical features of ET. Alterations of certain catecholamine systems, the dopaminergic, serotonergic, GABAergic, noradrenergic, and adrenergic systems have been described, and are the object of this revision. METHODS: For this purpose, we performed a literature review on alterations of the neurotransmitter or neuromodulator systems (catecholamines, gammaaminobutyric acid or GABA, excitatory amino acids, adenosine, T-type calcium channels) in ET patients (both post-mortem or in vivo) or in experimental models resembling ET. RESULTS AND CONCLUSION: The most consistent data regarding neurochemistry of ET are related with the GABAergic and glutamatergic systems, with a lesser contribution of adenosine and dopaminergic and adrenergic systems, while there is not enough evidence of a definite role of other neurotransmitter systems in ET. The improvement of harmaline-induced tremor in rodent models achieved with T-type calcium channel antagonists, cannabinoid 1 receptor, sphingosine-1-phosphate receptor agonists, and gap-junction blockers, suggests a potential role of these structures in the pathogenesis of ET. PMID- 30417773 TI - Analytical Comparison of the Originator Granulocyte-colony Stimulating Factor Filgrastim and its Biosimilars. AB - BACKGROUND: Filgrastim, a recombinant human granulocyte colony-stimulating factor (rhG-CSF) produced in Escherichia coli, is indicated for treatment of neutropenia related conditions in cancer patients. It has been marketed as Neupogen since 1991. In 2006, biosimilar rhG-CSF products have been approved in the European Union (EU). OBJECTIVE: The aim of this study was to compare quality attributes of the originator filgrastim with its three biosimilars which came from the EU market in 2014 to verify whether their similarity is maintained since their market approval. METHODS: Spectrophotometric analysis was used to determine protein content in analyzed products. Chromatographic and electrophoretic analyses were applied to verify the presence of high and low-molecular weight impurities. Secondary and tertiary structure of the drugs were investigated with circular dichroism and intrinsic fluorescence. Finally, biological activity of the drugs was assessed using cell proliferation assay. RESULTS: All products displayed protein content close to the label concentration with a +/-6% variation. Two oxidized forms and a deamidated form were present at <0.5%. Levels of dimers and other high molecular-weight impurities were similar except for one product, which contained higher amount of the dimer. Profiles and levels of process-related impurities were comparable. The three-dimensional conformation of the molecules with respect to exposed tryptophan residues were similar. The relative potencies of the products were comparable to the reference standard with a +/-2% variation. CONCLUSIONS: This study shows that a high level of similarity is maintained among originator and three biosimilar filgrastims up to 5 years from their first registration in the EU. PMID- 30417774 TI - Advances in antidiabetic drugs targeting Insulin Secretion. AB - BACKGROUND: Diabetes mellitus (DM) is a disease of systemic metabolic disorders caused by the decrease of secretion or sensitivity of insulin. In recent years, the study of insulin-related drug targets and the development of new drugs have become the popular topic of current medical research, and studies have shown that multiple signaling pathways are associated with diabetes treatment. At present, some new drugs based on the new target design have been listed on the market and have achieved good hypoglycemic effect. However, most of the drugs are still in the clinical or pre-clinical stage. The efficacy and safety of the drugs need further clinical validation. OBJECTIVE: This article will introduce the advancements of targets and drugs to promote insulin secretion. PMID- 30417775 TI - Alternative routes of administration of the neuroprotective pituitary adenylate cyclase activating polypeptide. AB - Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with diverse actions, including strong neurotrophic and neuroprotective effects. The aim of our present review is to provide a summary of the different approaches how in vivo neuroprotective effects can be achieved, emphasizing the potential translational values for future therapeutic applications. In the central nervous system, PACAP has been shown to have in vivo protective effects in models of cerebral ischemia, Parkinson's and Alzheimer's disease, Huntington chorea, traumatic brain and spinal cord injury and different retinal pathologies. PACAP passes through the blood-brain barrier and therefore, systemic administration can affect the nervous system and lead to neuroprotective effects. This review summarizes results obtained in neuronal injury studies via local, such as intracerebral, intrathecal, intracerebroventricular, intravitreal and systemic treatments, such as intravenous, intraperitoneal and subcutaneous administration of PACAP. A few other options are summarized, like intranasal and eye drops treatments, as well as difficulties and side effects of different treatments are also discussed. PMID- 30417776 TI - Brain Peptides for the Treatment of Neuropsychiatric Disorders. AB - The realization of the importance of growth factors in adult CNS led to several studies investigating their roles in neuropsychiatric disorders. Based on the observations that chronic stress decreases brain-derived neurotrophic factor (BDNF) and antidepressant treatments reverse BDNF to normal levels, "neurotrophic hypothesis of depression" was proposed. Subsequent studies found that several other growth factors, including fibroblast growth factor (FGF), vascular endothelial growth factor, nerve growth factor were also decreased by chronic stress. Growth factors promote stem cell survival, angiogenesis and neurogenesis in addition to having anti-apoptotic and anti-inflammatory effects, all of which make them potential drug candidates as neuroprotective or neurorestorative agents. Indeed, certain peptides have consistently been shown to improve stroke outcome in experimental models of cerebral ischemia. Recent developments in nanothechnology appear promising in overcoming the blood-brain barrier and in delivering sufficient amounts of these large peptides to the brain after systemic administration. In addition to the translational potential resulting from application of nanotechnical approaches for delivering these large peptide growth factors, recent success obtained with small molecule and peptide antagonists of calcitonin gene-related peptide has created renewed enthusiasm to elucidate the role of neuropeptides in migraine headache, one of the most common health problems in the world. In this review, we will first focus on the role of FGF2 in mood disorders as well as in ischemic stroke. We will also introduce the nanomedicines developed to efficiently deliver FGF2 to the brain. In the last section, we will explore roles of the neuropeptides in migraine and its acute and prophylactic treatment. PMID- 30417777 TI - Cancer Biology Aspects of Computational Methods & Applications in Drug Discovery. AB - BACKGROUND: Cancer is one of the most debilitating diseases in the world. Even though advances in molecular and cellular biology have contributed to the decline of mortality associated with cancer, the procedure of drug discovery and development of cancer is time-consuming and expensive. However, with computer aided drug discovery (CADD) techniques, pharmaceutical firms can save production costs and reduce the time of introducing effective anticancer drugs to the market. CADD strategies like structure-based, ligand-based, and combined structure-based and ligand-based approaches also have the advantage of identifying target sites and discovering active compounds with high affinity for the target sites. In this article has been reviewed research carried out on cancer biology aspect of the computational methods in drug discovery. OBJECTIVE: The main objective of the study is to identity one of the most dangerous disease named cancer' causes and its development in human body. In addition to this, its recovery has also been discussed briefly. CONCLUSIONS: Our findings indicate that only a few studies have been carried out regarding this area of research. Hence, it is recommended that further research should be conducted on the computational methods for identifying candidate drugs cancers for colon cancer, prostate cancer, and other types of cancer. PMID- 30417778 TI - Convolutional neural networks for ATC classification. AB - BACKGROUND: Anatomical Therapeutic Chemical (ATC) classification of unknown compound has raised high significance for both drug development and basic research. The ATC system is a multi-label classification system proposed by the World Health Organization (WHO), which categorizes drugs into classes according to their therapeutic effects and characteristics. This system comprises five levels and includes several classes in each level; the first level includes 14 main overlapping classes. The ATC classification system simultaneously considers anatomical distribution, therapeutic effects, and chemical characteristics, the prediction for an unknown compound of its ATC classes is an essential problem, since such a prediction could be used to deduce not only a compound's possible active ingredients but also its therapeutic, pharmacological, and chemical properties. Nevertheless, the problem of automatic prediction is very challenging due to the high variability of the samples and the presence of overlapping among classes, resulting in multiple predictions and making machine learning extremely difficult. METHODS: In this paper, we propose a multi-label classifier system based on deep learned features to infer the ATC classification. The system is based on a 2D representation of the samples: first a 1D feature vector is obtained extracting information about a compound's chemical-chemical interaction and its structural and fingerprint similarities to other compounds belonging to the different ATC classes, then the original 1D feature vector is reshaped to obtain a 2D matrix representation of the compound. Finally a convolutional neural network (CNN) is trained and used as feature extractor. Two general purpose classifiers designed for multi-label classification are trained using the deep learned features and resulting scores are fused by the average rule. RESULTS: Experimental evaluation based on rigorous cross-validation demonstrates the superior prediction quality of this method compared to other state-of-the-art approaches developed for this problem. CONCLUSION: Extensive experiments demonstrate that the new predictor, based on CNN, outperforms other existing predictors in the literature in almost all the five metrics used to examine the performance for multi-label systems, particularly in the "absolute true" rate and the "absolute false" rate, the two most significant indexes. Matlab code will be available at https://github.com/LorisNanni. PMID- 30417779 TI - NAP protects against Tau hyperphosphorylation through GSK3. AB - BACKGROUND: The most common form of dementia is Alzheimer's disease (AD), which is characterized, in part, by the accumulation of neurofibrillary tangles (NFT), followed by synaptic and neuronal loss. NFTs are mainly composed of aggregated hyperphosphorylated Tau. It has been demonstrated that pathological concentrations of zinc induce 1] activation of a major Tau kinase - the glycogen synthase kinase-3beta (GSK-3beta), and 2] promote Tau aggregation and toxicity. Activity-dependent neuroprotective protein (ADNP) and its derived peptide NAP exhibit neuroprotective properties against a variety of toxic insults, including toxic zinc concentrations. ADNP deficiency results in increased content of the GSK-3beta active form, Tau hyperphosphorylation and NFT-like structure formation, all of which have been prevented by NAP treatment. Our previous experiments showed that NAP enhanced Tau-microtubule association in the face of zinc toxicity. Interestingly, NAP protection against zinc toxicity was rescued by Tau overexpression in NIH-3T3 fibroblast cells, which naturally do not express high amounts of Tau. OBJECTIVES AND METHODS: Pheochromocytoma cells (PC12), exposed to high concentration of zinc (400uM), were used to determine the protective effect of NAP on Tau phosphorylation and two Tau kinases (Fyn and GSK-3beta). Knockdown of Tau expression in PC12 cells by RNA silencing was used to determine Tau's requirement for the NAP protective activity under zinc intoxication. RESULTS: NAP treatment attenuated Tau hyperphosphorylation and GSK-3beta increased activity caused by zinc intoxication. Furthermore, Tau knockdown completely abolished NAP protective activity. CONCLUSION: These results together with previous findings strongly corroborated Tau's involvement in NAP/ADNP cellular activity. PMID- 30417780 TI - Neuroprotection with the Endozepine octadecaneuropeptide, ODN. AB - The term endozepines designates a family of astroglia-secreted proteins including the diazepam-binding inhibitor (DBI) and its processing products, which have been originally isolated and characterized as endogenous ligands of benzodiazepine receptors. It is now clearly established that the octadecaneuropeptide ODN (DBI33 50), acting through the central-type benzodiazepine receptor or a metabotropic receptor, exerts important functions such as proconflict behavior, induction of anxiety, inhibition of pentobarbital-provoked sleep, decrease of water consumption and reduction of food intake. To mediate its effects, ODN regulates both glial cell and neuronal activities by acting on neurosteroid biosynthesis and/or neuropeptide expression. In addition, ODN stimulates astrocyte proliferation and protects both neurons and astrocytes from oxidative stress induced cell death. The antiapoptotic effect of ODN on neural cells is mediated through activation of the ODN metabotropic receptor positively coupled to PKA, PKC and MAPK/ERK transduction pathways, which ultimately reduces the pro apoptotic gene Bax and stimulates Bcl-2 expressions, and inhibits intracellular reactive oxygen species accumulation. The imbalance in favor of Bcl2 promotes mitochondria functions and blocks in turn caspases activation while at the same time, ODN also activates the endogenous antioxidant system i.e. glutathione biosynthesis, and expression and activities of antioxidant enzymes. In cultured astrocytes, DBI expression is up-regulated during moderate oxidative stress, and authentic ODN production is increased, suggesting that ODN may act as a paracrine factor protecting neighboring neurons. Taken together, the remarkable effect of ODN on the apoptotic cascade suggests that innovative ODN derivatives could potentially be useful for treatment of cerebral injuries involving oxidative stress and neurodegeneration. PMID- 30417781 TI - Small molecules as PD-1/PD-L1 pathway modulators for cancer immunotherapy. AB - Blockade of PD-1/PD-L1 interaction using PD-1/PD-L1 inhibitors have demonstrated unprecedented clinical efficacy in various cancer types. Current PD-1/PD-L1 inhibitors approved by FDA are exclusively dominated by therapeutic antibodies. However, therapeutic antibodies also exhibit several disadvantages such as low tumor tissues penetration, difficult across physiological barriers, lacking oral bioavailability, immunogenicity, long half-life time and strong target occupancy, high manufacturing costs, inaccessible to intracellular targets. Modulation of PD 1/PD-L1 pathway using small molecules may be an alternative approach to mobilize immune system to fight with cancers. In this review, we focus on addressing the disclosed chemical structures and preliminary structure-activity relationships of small molecules in recent patents. PMID- 30417782 TI - The effects of coenzyme Q10 supplementation on metabolic profiles of patients with chronic kidney disease: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: This systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to determine the effects of coenzyme Q10 (CoQ10) supplementation on metabolic profiles of patients diagnosed with chronic kidney disease (CKD). METHODS: Two independent reviewers systematically searched online databases including PubMed, Cochrane Library, and Web of Science databases, Scopus, EMBASE until July 2018 to identify eligible clinical trials. The heterogeneity across included trials was assessed using Cochran's Q test and I square (I2) statistic. Cochrane Collaboration risk of bias tool was applied to evaluate the quality of selected RCTs. Standardized mean difference (SMD) and 95% Confidence Interval (CI) between two groups of intervention were used to determine pooled effect sizes. RESULTS: Out of 721 potential papers, 7 RCTs were appropriate to be included in our meta-analysis. The pooled results revealed that CoQ10 supplementation significantly reduced total-cholesterol (SMD=-0.58; 95% CI, -0.94, -0.21; P=0.002; I2: 54.9), LDL-cholesterol (SMD=-0.47; 95% CI, -0.78, 0.17; P=0.003; I2: 00.0), malondialdehyde (MDA) (SMD=-3.0; 95% CI, -5.10, -0.90; P=0.005; I2: 95.4) and serum creatinine levels (SMD=-1.65; 95% CI, -2.75, -0.54; P=0.003; I2: 95.0) in patients diagnosed with CKD. Triglycerides (SMD=-0.35; 95% CI, -0.82, 0.12; P=0.14; I2: 72.3), HDL-cholesterol (SMD=-0.00; 95% CI, -0.22, 0.21; P=0.97; I2: 47.3), fasting glucose (SMD=0.00; 95% CI, -0.60, 0.61; P=0.99; I2: 80.0), insulin (SMD=-0.02; 95% CI, -1.03, 1.00; P=0.97; I2: 86.2), homeostasis model assessment of insulin resistance (HOMA-IR) (SMD=0.11; 95% CI, 0.99, 1.22; P=0.84; I2: 88.3), and C-reactive protein (CRP) concentrations (SMD= 0.20; 95% CI, -0.44, 0.04; P=0.10; I2: 0.00) did not affect following CoQ10 supplementation. CONCLUSIONS: Overall, the current meta-analysis demonstrated that CoQ10 supplementation significantly improved metabolic profile in patients with CKD by reducing total-cholesterol, LDL-cholesterol, MDA and creatinine levels, yet it did not affect fasting glucose, insulin, HOMA-IR, and CRP concentrations. PMID- 30417784 TI - Effect of vinca alkaloids on the expression levels of microRNAs targeting apoptosis-related genes in breast cancer cell lines. AB - Background - Treatment of cancer with natural chemotherapeutic agents induces apoptosis along with remarkable alterations in the expression of apoptosis related genes. Deregulation of microRNA (miRNA) expression is implicated in several human malignancies. Vinca alkaloids compose a class of antimitotic drugs preventing cancer cells from dividing, leading to apoptosis. They are commonly used in clinical practice for breast cancer treatment. Objective - The present study focused on the effects of vinca alkaloids (vincristine, vinblastine, and vinorelbine) on miRNA expression of treated breast cancer cells. Methods - We investigated the effect of vincristine, vinblastine, and vinorelbine on the expression of oncogenic and tumor-suppressive miRNAs (miR-15a-5p, miR-16-5p, miR 21-5p, miR-25-3p, miR-29b-3p, miR-125b-5p, miR-148a-3p, miR-214-3p, miR-221-3p, miR-222-3p, and miR-421), as well as on the expression of the apoptosis-related genes BAX, BCL2, and TP53 in BT-20 and SK-BR-3 breast adenocarcinoma cells. Results - Treatment of BT-20 cells with vincristine, vinblastine, and/or vinorelbine resulted in upregulation of TP53 expression. However, no alterations in the mRNA levels of the pivotal BCL2 family members BAX and BCL2 were observed. On the other hand, treatment of SK-BR-3 cells with any of these vinca alkaloids led to an increase in the BAX/BCL2 mRNA ratio, implying the activation of the intrinsic apoptotic pathway. No concomitant alteration in TP53 expression was observed in treated SK-BR-3 cells. Regarding the miRNAs examined in this study, only miR-222-3p expression exhibited significant modulations in both treated cell lines. Conclusion - This study suggests the possible involvement of miR-222-3p expression in breast cancer cell apoptosis, triggered by vincristine, vinblastine, and vinorelbine. PMID- 30417783 TI - Cinnamate Hybrids: A unique family of compounds with multiple biological activities. AB - Cinnamic acid derivatives are widely distributed in nature presenting a wide range of biological activities: antiseptic, stimulant, carminative and insecticide activities. Hydroxy cinnamic acids especially caffeic, ferulic chlorogenic present various biological activities and they are synthesized in nature through the phenyl propanoid pathway. The cinnamic moiety is still present in various drugs such as a) Ozagrel, an imidazole pi-substituted cinnamic acid acting as a thromboxane A2 synthase inhibitor, used therapeutically for treating acute ischemic stroke, b) Cinnarizine, Cinanserin, Tranilasta series of antiallergic agents etc. During the last decade scientists have focused on multifunctional molecules instead of a single molecule hitting one target. Multi target drugs can be beneficial for the treatment of complex and multifunctional diseases.A variety of multi-target drugs contain the cinnamic acid moiety due to its biological importance and combination of biological activities e.g. antioxidant, antiiflammatory, anticancer, antituberculosis, antifungal, antimalarial, antiatherogenic, antimicrobial activities. Recently for the treatment of complex diseases hybrid drugs combining two pharmaceutical moieties in one molecule have been developed. These molecules are more medically effective than their individual components. In this review is given a survey of cinnamate hybrids, molecules that combine the cinnamic acid moiety with a second at least pharmacophore with or without a linker, acting as "multi-target" agents. The hybrids are listed in terms of their biological activity and applications as anti Alzheimer, anticancer agents as well as for cardiovascular diseases, as antivirals, antimalarials etc. PMID- 30417785 TI - Evidence for L-Dopa decarboxylase activity in cancer cell cytotoxicity induced by Docetaxel and Mitoxantrone. AB - Background - L-Dopa decarboxylase (DDC) expression has been implicated in the biochemistry of several human cancers. Docetaxel and Mitoxantrone are two widely used anticancer agents. Docetaxel is a semi-synthetic analogue of paclitaxel, an extract from the bark of the rare Pacific yew tree Taxus brevifolia, and Mitoxantrone is an anthracenedione anticancer agent. Objective - The purpose of the present study was to investigate the effect of chemotherapeutic agents on the expression of human DDC in human prostate and human breast cancer cell lines. Furthermore, the study focused on the effect of chemotherapeutics - particularly Docetaxel and Mitoxantrone - on the viability of mammalian cells expressing human DDC protein isoforms. Method - We investigated the effect of Docetaxel and Mitoxantrone on the expression of DDC in DU-145 (androgen-independent prostate cancer cell line) and MCF-7 (human breast adenocarcinoma cell line). In order to gain insight on the effect of DDC on cell viability following chemotherapeutic agent treatment, we investigated the cytotoxicity and apoptosis levels on CHO cells expressing different human DDC protein isoforms. Results - Our obtained data indicated that exposure of DU-145 and MCF-7 cells to Docetaxel and Mitoxantrone, enhances the expression of neural type DDC mRNA isoforms. Interestingly, DDC protein levels were not affected, despite of the cytotoxic events elicited by the chemotherapeutic agent treatment. Moreover, expression of DDC and its alternative protein isoforms, appear to enhance the cytotoxic and apoptotic events conferred by exposure to Docetaxel and Mitoxantrone. Conclusion This study suggests the possible involvement of DDC expression in Docetaxel and Mitoxantrone-induced cytotoxicity and apoptosis. PMID- 30417786 TI - In vitro bioaccessibility, bioavailability, and the plasma protein interaction of new oral anticoagulants in presence of macronutrients. AB - BACKGROUND: Over the last years, a new generation of oral anticoagulants (NOACs), including apixaban, rivaroxaban and dabigatran, has been developed for the control of thrombosis and related disorders.The presence of food within the gastrointestinal (GI) tract can potentially affect the oral bioavailability of drugs. OBJECTIVE: In the present paper we evaluated the stability of these drugs to in vitro GI digestion, with and without the main macronutrients such as proteins, lipids, carbohydrates, and fibers, and their ability to enter into the systemic circulation. In addition, we examined the percentage of the drug binding to plasma proteins, such as human serum albumin, high density- and low density lipoproteins. METHODS: The NOACs bioaccessibility was evaluated by an in vitro procedure simulating the gastrointestinal enzymatic system, while their bioavailability was studied by cell culture of Caco-2 cells and in vitro study of transepithelial transport. The in vitro transepithelial permeated NOACs were added to plasma protein solutions simulating the average fasting plasma protein concentrations. The NOACs detection was carried out by HPLC-DAD/ESI-MS analysis. RESULTS: GI digestion significantly reduces intestinal bioaccessibility and bioavailability of NOACs, especially as regards apixaban and dabigatran. Interestingly, the co-digestion of fibers led to a strong decrease of NOAC intestinal bioaccessibility and bioavailability, while the effects of the other macronutrients, as well as a low fiber standard meal, had no significant influence in this sense. CONCLUSION: Dabigatran, rivaroxaban and apixaban may be administered independently of a standard meal, provided that it does not include a high amount of dietary fibers. PMID- 30417787 TI - Molecular effects of treatment of human colorectal cancer cells with natural and classical chemotherapeutic drugs: alterations in the expression of apoptosis related BCL2 family members, including BCL2L12. AB - Background - Current chemotherapy regimens for the treatment of colorectal cancer include leucovorin, fluorouracil, oxaliplatin and/or irinotecan. Cytotoxicity involves the induction of programmed cell death. Objective - The purpose of the present study was to assess the molecular effects of doxorubicin (a 14-OH derivative of the natural product daunorubicin) and common chemotherapeutic drugs used in the clinical practice to treat colorectal cancer on the expression levels of the most prominent members of the BCL2 family, namely BCL2, BAX, BCLX, and MCL1. Moreover, we sought to define the role of BCL2L12, another member of the BCL2 family, the apoptotic role of which is ambiguous. Methods - The MTT cell proliferation assay was used to determine the IC50 of each chemotherapeutic drug at 72 hours of treatment of Caco-2 and DLD-1 colorectal cancer cells. Real-time PCR was used to quantify the antiapoptotic BCL2 (alpha), BLCX-L, and MCL1-L transcripts, the proapoptotic BAX, BLCX-S, BLCX-ES, MCL1-S, and MCL1-ES transcripts, and BCL2L12 expression in relation to GAPDH mRNA levels. Results - We constructed growth curves of Caco-2 and DLD-1 cells and determined the IC50 of each drug at 72 hours of treatment. Significant alterations in the expression levels of the studied BCL2-family genes and/or particular transcripts were observed. Conclusion - The intrinsic apoptotic pathway is activated during treatment of colorectal cancer cells with common chemotherapeutic drugs. Moreover, BCL2L12 mRNA expression increases progressively during treatment, similarly to the expression of other BCL2 family genes favoring apoptosis and/or particular proapoptotic transcripts, thus suggesting a proapoptotic role for BCL2L12 in chemotherapy-treated colorectal cancer. PMID- 30417788 TI - Epidemics and Peptide Vaccine Response - A Brief Review. AB - We briefly review the situations arising out of epidemics that erupt rather suddenly, threatening life and livelihoods of humans. Ebola, Zika and the Nipah virus outbreaks are recent examples where the viral epidemics have led to considerably high degree of fatalities or debilitating consequences. The problems are accentuated by a lack of drugs or vaccines against the new and emergent viruses, and the inordinate amount of temporal and financial resources that are required to combat the novel pathogen. Progress in computational. biological and informational sciences have made it possible to consider design of synthetic vaccines that can be rapidly developed and deployed to help stem the damages. In this review, we consider the pros and cons of this new paradigm and suggest a new system where the manufacturing process can be decentralized to provide even better vaccines to meet the urgent vaccination needs in case of a rampaging epidemic. PMID- 30417789 TI - Natural-based Antibiofilm and Antimicrobial Peptides from Microorganisms. AB - As the resistance to antimicrobial molecules increases among bacteria, the need for new antimicrobial molecules increases. Antimicrobial peptides (AMP), which may be a new generation of antibiotic candidates, are important in this respect. AMPs are small, cationic and amphipathic peptide sequences. In eukaryotes, they are synthesized as a part of the immune system. Substantially, AMPs are discovered all kingdoms of life such as bacteria, fungi and protozoa. Approximately 3,000 AMPs have been reported in the literature. However, most of these AMPs have been synthesized through chemical synthesis. Nature has a huge source of microorganisms, and in the literature there is a tendency to increase every year in the number of bacteria and fungus-derived AMPs thanks to their biotechnological importance. The explore of AMP and antibiofilm peptide (ABP) producer microorganisms brings with it a lot of challenges experimentally. In this review study, we want to stand out the importance and challenge of these natural peptides derived from microorganisms also we will proposed a new explanation for ABPs. PMID- 30417790 TI - Efficacy of beta-D-mannuronic acid [M2000] on pro-apoptotic process and inflammatory related molecules NF?B, IL-8 and Cd49d using healthy donor PBMC. AB - This investigation evaluates the pro-apoptotic and anti-inflammatory effects of beta-D-mannuronic acid [M2000] compared to diclofenac, based on gene expression involved in apoptosis and inflammation process [including Bcl2, NFkappaB, IL-8 and Cd49d] in peripheral blood mononuclear cells [PBMCs] of healthy donors under exvivo conditions. The venous blood of twelve healthy volunteers with aged 25-60 years, were collected in heparinized tubes. The healthy volunteers were selected from no smoking group and without using illicit drugs and suffering from diabetes. The PBMCs were separated and divided into untreated and treated groups. The PBMCs of each sample were cultured in 5 wells of culture plate, so that the first well consist of 2*106 cells exposed by LPS-EB [1MUg/ml] to stimulate PBMCs and absence of M2000 [untreated well]. The second, third, fourth and fifth wells containing 2*106 cells/well and LPS-EB, after 4 hours incubation at 37oC, received 5, 25 and 50 ug/well of M2000 and 5 ug/well of diclofenac, respectively as treated group. The PBMCs were separated and RNAs were then extracted and cDNAs synthesized and gene expression levels were assessed by qRT-PCR. Furthermore, we studied whether M2000 is able to facilitate apoptosis in PBMCs. Our findings represent that the high dose of M2000 could significantly decrease the expression level of NFkappaB gene compared to untreated group [p < 0.0001]. On the other hand, no significant change was observed in treated cells with diclofenac .All doses of M2000 could significantly augment apoptosis compared to untreated group [p < 0.0001]. Additionally, we observed the same apoptotic effects between medium dose of M2000 and diclofenac. Besides, no significant reduction was shown in expression levels of IL8, Bcl2 and Cd49d genes in all doses of M2000 and diclofenac compared to untreated group. This experiment demonstrates that M2000 as a new effective NSAID with immunosuppressive characteristic capable to stimulate apoptosis through lowering expression levels of NFkappaB gene, which might be probably considered as an appropriate drug for reducing the risk of developing inflammatory diseases and cancer. PMID- 30417791 TI - Maternal Serum Uric Acid as a Predictor of Severity of Hypertensive Disorders of Pregnancy: A Prospective Cohort Study. AB - OBJECTIVE: Assess the relationship between maternal serum uric acid and severity of Hypertensive disorders of pregnancy in a rural tertiary care centre. MATERIALS AND METHODS: Present study was conducted in Obstetrics and Gynaecology department of rural tertiary care centre of Northern India over seven months (October 2016 May 2017) on 110 women admitted with a Hypertensive disorder of pregnancy (Gestational hypertension, Pre-eclampsia, Eclampsia) at >=34 weeks gestation. Maternal serum uric acid levels were compared in three groups in relation to disease severity, mode of delivery, maternal outcome. RESULTS: Of total 110 women with a Hypertensive disorder of pregnancy; 35 (31.81%) had Gestational Hypertension, 49 (44.54%) preeclampsia and 26 (23.63%) had eclampsia. Mean+/-SD values for serum uric acid were 5.47+/-1.93 mg/dl in women with Gestational Hypertension; 6.72+/-2.15 mg/dl in Pre-eclampsia and 8.71+/-2.97 mg/dl in the eclamptic group. Of 110 women 34(97.14%) with gestational hypertension, 27(55.10%) with pre-eclampsia and one (3.85%) with eclampsia remained stable in post-partum period, 17 (34.69%) women with severe pre-eclampsia and 15 (57.69%) with eclampsia required intensive care in postpartum period and one (2.86%) women with gestational hypertension, five (10.20%) with pre-eclmapsia and ten (38.46%) with eclampsia required ventilator support and high dependency unit care. Of these 16 women with the severe disease, ten succumbed to death. Also, in women with serum uric acid,>6mg/dl, most common mode of delivery was a lower segment cesarean section (50.90%). CONCLUSION: Significant correlation was observed between maternal serum uric acid, disease severity and maternal outcome. PMID- 30417792 TI - Desensitization Of 5-Ht-1a Somatodentritic Receptors In Tryptophan Treated And Co Treated Rats Induced By Methylphenidate. AB - BACKGROUND: Psychostimulants can induce behavioral sensitization by their chronic use. The main target for the action of these drugs is dopamine, nor epinephrine and serotonin transporters. Serotonin is synthesized by the precursor L tryptophan. Tryptophan and methylphenidate being 5-HT agonists both increase the level of serotonin thereby may cause desensitization of 5-HT1a receptors. Present study investigated whether behavioral sensitization induced by Methylphenidate is decreased in tryptophan administrated animals. METHOD: Experiment was divided in 2 phases (1). Behavioral effects of repeated administration of TRP 100 mg/kg and MPD for 14 days in three groups; (i) water (ii) MPD 1.0 mg/kg (iii) TRP. To explore the locomotor effects of treatment, activity were monitored in familiar andnovel environment.(2) Behavioralconsequences of repeatedly administrated MPD (1.0 mg/kg) on pretreated TRP (100 mg/kg) and MPD (1.0 mg/kg) animals following Co-MPD and TRP for 14 day, rats were divided in three groups (i) water, (ii) MPD and (iii) TRP as mentioned in experiment no 1. After two weeks six sub groups were assigned i.e. (i) water-saline, (ii) water- MPD, (iii) TRP-saline (iv) TRP MPD (v) MPD-saline and (vi) MPD-MPD+TRP and treated for further 14 days.. Locomotorbehaviorwas monitored in familiar environment on next day and in novel environment on alternate days of each administration. RESULTS: Results from phase 1 showed the increased activity in both (TRP and MPD) treatment. However, the results of phase 2 showed significant decreases in methylphenidate induced behavioral sensitization by both pretreatment and co-administration with TRP. CONCLUSION: Present study suggests the potential of tryptophan to decrease the risk of behavioral sensitization induced by methylphenidate. PMID- 30417793 TI - Multiple Drug Intolerance Syndrome: An Underreported Distinct Clinical Entity. AB - Aim Multiple drug intolerance syndrome (MDIS) is a unique clinical entity distinct from other drug hypersensitivity syndromes. The aim of this review was to critically appraise the various aspects of MDIS. Methods A review was conducted to search for the causes, mechanism, clinical features, and management of MDIS. Results The most common cause of MDIS is antibiotics followed by non steroidal anti-inflammatory drugs (NSAIDs). Although some non-specific immunological mechanisms are involved, the immunological tests for MDIS are negative. Rashes, gastrointestinal reflux, headache, cough, muscle ache, fever, dermatitis, hypertension, and psychiatric symptoms are the usual manifestations. Treatment is mostly symptomatic with the withdrawal of the offending drug. Drug re-challenges and desensitization may be required for the management of this syndrome. Conclusion MDIS occurs by a nonimmune mechanism which requires a prompt withdrawal of the offending drug(s), and in some cases may require drug re challenge and desensitization. PMID- 30417794 TI - The cytotoxicity and synergistic potential of aspirin and aspirin analogues towards oesophageal and colorectal cancer. AB - BACKGROUND: Oesophageal cancer (OC) is a deadly cancer because of its aggressive nature with survival rates that have barely improved in decades. Epidemiologic studies have shown that low-dose daily intake of aspirin can decrease the incidence of OC. METHODS: The toxicity of aspirin and aspirin derivatives to OC and a colorectal cancer (CRC) cell line were investigated in the presence and absence of platins. RESULTS: The data in this study show the effects of a number of aspirin analogues and aspirin on OC cell lines that originally presented as squamous cell carcinoma (SSC) and adenocarcinoma (ADC). The aspirin analogues fumaryldiaspirin (PN517) and the benzoylsalicylates (PN524, PN528 and PN529), were observed to be more toxic against the OC cell lines than aspirin. Both quantitative and qualitative apoptosis experiments reveal that these compounds largely induce apoptosis, although some necrosis was evident with PN528 and PN529. Failure to recover following the treatment with these analogues emphasized that these drugs are largely cytotoxic in nature. The OE21 (SSC) and OE33 (ADC) cell lines were more sensitive to the aspirin analogues compared to the Flo-1 cell line (ADC). A non-cancerous oesophageal primary cells NOK2101, was used to determine the specificity of the aspirin analogues and cytotoxicity assays revealed that analogues PN528 and PN529 were selectively toxic to cancer cell lines, whereas PN508, PN517 and PN524 also induced cell death in NOK2101. In combination index testing synergistic interactions of the most promising compounds, including aspirin, with cisplatin, oxaliplatin and carboplatin against the OE33 cell line and the SW480 CRC cell line were investigated. Compounds PN517 and PN524, and to a lesser extent PN528, synergised with cisplatin against OE33 cells. Cisplatin and oxaliplatin synergised with aspirin and PN517 when tested against the SW480 cell line. CONCLUSION: These findings indicate the potential and limitations of aspirin and aspirin analogues as chemotherapeutic agents against OC and CRC when combined with platins. PMID- 30417795 TI - Peptide R18H from Brn-2 Transcription Factor POU Domain Displays Antitumor Activity In Vitro and In Vivo And Induces Apoptosis in B16F10-Nex2 Cells. AB - BACKGROUND: Brn-2 transcription factor is associated with the development of malignant melanoma. The cytotoxic activities and cell death mechanism against B16F10-Nex2 cells were determined with synthetic peptide R18H derived from the POU domain of the Brn-2 transcription factor. OBJECTIVE: To determine the cell death mechanisms and in vivo activity of peptide R18H derived from the POU domain of the Brn-2 transcription factor against B16F10-Nex2 cells. METHODS: Cell viability was determined by the MTT method. C57Bl/6 mice were challenged with B16F10-Nex2 cells and treated with R18H. To identify the type of cell death we used TUNEL assay, Annexin V and PI, Hoechst, DHE, and determination of caspase activation and cytochrome C release. Transmission electron microscopy was performed to verify morphological alterations after peptide treatment. RESULTS: Peptide R18H displays antitumor activity in the first hours of treatment and the EC50% was calculated for 2 and 24h, being 0.76 +/- 0.045 mM and 0.559 +/- 0.053 mM, respectively. After 24 h apoptosis is evident, based on DNA degradation, chromatin condensation, increase of superoxide anion production, phosphatidylserine translocation, activation of caspases 3 and 8, and release of extracellular cytochrome c in B16F10-Nex2 cells. The peptide cytotoxic activity was not affected by necroptosis inhibitors and treated cells did not release LDH into the extracellular medium. Moreover, in vivo antitumor activity was observed following treatment with peptide R18H. CONCLUSIONS: Peptide R18H from Brn-2 transcription factor induces apoptosis in B16F10-Nex2 and displays antitumor activity in vivo. PMID- 30417796 TI - Poly (ADP-Ribose) Polymerases (PARPs) and PARP Inhibitor-Targeted Therapeutics. AB - BACKGROUND: Poly-ADP-ribosylation, that is, adding ADP-ribose moieties to a protein, is a unique type of protein post-translational modification that regulates various cellular processes such as DNA repair, mitosis, transcription, and cell growth. Small-molecule inhibitors of poly-ADP-ribose polymerase 1 (PARP1) have been developed as anticancer agents because inhibition of PARP enzymes may be a synthetic lethal strategy for cancers with BRCA1 or BRCA2 mutations. However there are still questions surrounding PARP inhibitors Methods/results: Data were collected from Pubmed, Medline, through searching of these keywords: "PARP", "BRCA", "Synthetic lethal" and "Tankyrase inhibitors". We describe current knowledge of PARP inhibition and its effects on DNA damage; mechanisms of resistance to PARP inhibitors; the evolution of PARP inhibitors; and the potential use of PARP5a/b (tankyrases) inhibitors in cancer treatment. CONCLUSION: PARP inhibitors are already showing promise as therapeutic tools, especially in the management of BRCA-mutated breast and ovarian cancers but also in tumors with dysfunctional BRCA genes. Small-molecule tankyrase inhibitors are important for increasing our understanding of tankyrase biology. PMID- 30417797 TI - Determination of Usnic Acid Responsive miRNAs in Breast Cancer Cell Lines. AB - OBJECTIVE: Breast cancer (BC) is the most common type of cancer diagnosed in women. Since BC has heterogeneous molecular structure a common treatment strategy for BC is not available and most of the patients develop resistance through the course of treatment. Therefore, alternative medicine resources as new treatment options are determined to be used for the treatment of BC. Usnic acid (UA) that is one of the secondary metabolites of lichens has been used for different purposes in the field of medicine and its anti-proliferative effect has been mainly shown in some of the cancer types, which makes it a potential treatment molecule. METHODS: In this study, UA was isolated from the lichens and determination of anti-proliferative effect in BC cells (MDA-MB-231, MCF-7, BT 474) was performed by MTT analysis. Cells treated with the effective concentration of UA were conducted to microarray analysis to profile UA responsive miRNAs. After bioinformatics analysis cell specific miRNAs responsive to UA were identified. Their targets and the pathways they are taking part in were determined by using a miRNA target prediction tool. RESULTS: Microarray experiments showed that 67 miRNAs were specifically responsive to UA in MDA-MB 231 cells while it was 15 for BT-474 and 8 for MCF-7 cells. The targets of the miRNAs were found to be enriched commonly in Hedgehog signaling pathway. TGF Beta, MAPK and apoptosis pathways were also the prominent ones according to enrichment analysis. CONCLUSION: The pathway enrichment analysis results conducted with the UA responsive miRNAs together with the anti-proliferative effects of UA may make UA as one of the potential alternative therapeutics for treatment of BC. This study is the first study in the literature aiming to find out the molecular mechanism of UA at miRNA level by revealing the differentially expressed miRNAs, their targets and the molecular pathways that may have roles in the BC. PMID- 30417798 TI - Hybridized quinoline derivatives as anticancer agents: Design, Synthesis, biological evaluation and molecular docking. AB - OBJECTIVE: Conjugating quinolones with different bioactive pharmacophores to obtain potent anticancer active agents. METHODS: Fused pyrazolopyrimidoquinolines 3a-d, Schiff bases 5, 6a-e, two hybridized systems: pyrazolochromenquinoline 7 and pyrazolothiazolidinquinoline 8, different substituted thiazoloquinolines 13 15 and thiazolo[3,2-a]pyridine derivatives 16a-c were synthesized. Their chemical structures were characterized through spectral and elemental analysis, cytotoxic activity on five cancer cell lines, caspase-3 activation, tubulin polymerization inhibition and cell cycle analysis were evaluated. RESULTS: Four compounds 3b, 3d, 8 and 13 showed potent activity than doxorubicin on HCT116 and three compounds 3b, 3d and 8 on HEPG2. These promising derivatives showed increase in the level of caspase-3. The trifloromethylphenyl derivatives of pyrazolopyrimidoquinolines 3b and 3d showed considerable tubulin polymerization inhibitory activity. Both compounds arrested cell cycle at G2/M phase and induced apoptosis. CONCLUSION: Compounds 3b and 3d can be considered as promising anticancer active agents with 70% of colchicine activity on tubulin polymerization inhibition and represent hopeful leads that deserve further investigation and optimization. PMID- 30417799 TI - Synthesis of asymmetric 1-thiocarbamoyl pyrazoles as potent anti colon cancer, antioxidant and anti-inflammatory agent. AB - A novel series of 1-thiocarbamoyl pyrazole derivatives (4a-g) were accomplished by reacting pyrazolealdehyde 1 with appropriate aromatic ketone by using polyethylene glycol (PEG-300) as green reaction medium as well as catalyst to yield chalcone 2. The chalcones 2 reacted with thiosemicabazide 3 to yield asymmetric 1-thiocarbamoyl pyrazoles 4. The structural interpretations of newly synthesized compounds were based on chemical and spectroscopic evidences. The synthesized compounds were evaluated for their in vitro anticancer, antioxidant (H2O2, DPPH, SOR and NO radical scavenging activity) and anti-inflammatory activities. The anti-tumor activities of the synthesized compounds against Colon SW-620 cell line revealed that they possess high anti-tumor activities. Among them, compound 4c, 4d and 4e demonstrated potent activity against colon SW-620 cell line (LC50 <0.1, TGI <0.1 and GI50 <0.1 uM) as good as adriamycin <0.1 uM. All the synthesized compounds (4a-g) showed potent to demonstrate antioxidant activity as compared to the standard ascorbic acid. All the tested compounds exhibited moderate H2O2 scavenging activity as compared to ascorbic acid. All compounds showed excellent SOR scavenging activity, where as all the compounds showed better NO scavenging activity. DPPH scavenging activity result showed moderate to low activity. Additionally, all the synthesized compounds were screened for their in vitro anti-inflammatory activity. Compounds 4b, 4e and 4g showed potent anti-inflammatory activity while other four compounds 4a, 4c, 4d and 4f showed good to moderate anti-inflammatory activity as compared to diclofenac sodium as a standard reference. PMID- 30417800 TI - Is the efficacy of antibiotic prophylaxis for surgical procedures decreasing? Systematic review and meta-analysis of randomized control trials. AB - OBJECTIVE: Rising antibiotic resistance could reduce the effectiveness of antibiotics in preventing postoperative infections. We investigated trends in the efficacy of antibiotic prophylaxis regimens for 3 commonly performed surgical procedures-appendectomy, cesarean section, and colorectal surgery-and 1 invasive diagnostic procedure, transrectal prostate biopsy (TRPB). DESIGN: Systematic review and meta-analysis. METHODS: We searched PubMed and Cochrane databases (through October 31, 2017) for randomized control trials (RCTs) that measured the efficacy of antibiotic prophylaxis for 4 index procedures in preventing postoperative infections (surgical site infections [SSIs] following the 3 surgical procedures and a combination of urinary tract infections [UTIs] and sepsis following TRPB). RESULTS: Of 399 RCTs, 74 studies (9 appendectomy, 11 cesarean section, 39 colorectal surgery, and 15 TRPB) were included. Multilevel logistic regression models with random intercepts for each study showed no statistically significant increase in SSIs over time for appendectomy (adjusted odds ratio [aOR] per year, 1.03; 95% confidence interval [CI], 0.92-1.16; P=.57), cesarean section (aOR per year, 1.01; 95% CI, 0.96-1.05; P=.80), and TRPB (aOR per year, 0.95; 95% CI, 0.77-1.18; P=.67). However, there was a significant increase in SSIs proportion following colorectal surgery (aOR per year, 1.049; 95% CI, 1.03-1.07; P<.001). CONCLUSION: The efficacy of antibiotic prophylaxis agents in preventing SSIs following colorectal surgery has declined. Small number of RCTs and low infections rates limited our ability to assess true effect for simple appendectomy, cesarean section, or TRPB. PMID- 30417801 TI - Modified Visual Magnetic Resonance Rating Scale for Evaluation of Patients with Forgetfulness. AB - BACKGROUND: As cognitive impairment increases with age, sulcal atrophy (SA) and the enlargement of the ventricles also increase. Considering the measurements on the previously proposed visual scales, a new scale is proposed in this study that allows us to evaluate the atrophy, white matter hyperintensities (WMHs), basal ganglia infarct (BGI), and infratentorial infarct (ITI) together. Our aim of this study is to propose a practical and standardized MRI for the clinicians to be used in daily practice. METHODS: A total of 97 patients older than 60 years and diagnosed with depression or Alzheimer's disease (AD) are included. Cranial MRI, Mini Mental State Examination (MMSE), detailed neuropsychometric tests, and depression scales are applied to all patients. The SA, ventricular atrophy (VA), medial temporal lobe atrophy (MTA), periventricular WMH (PWMH), subcortical WMH (SCWMH), BGI, and ITI are scored according to the scale. The total score is also recorded. RESULTS: The average age of the patients was 74.53, and the mean MMSE score was 22.7 in the degenerative group and 27.8 in the non-degenerative group. Among the patients, 50 were diagnosed with AD. All parameters significantly increased with age. In the degenerative group, SA, VA, MTA, PWMH, SCWMH, and total scores were found to be significantly higher. Sensitivities of VA, PWMH, SCWMH, and total scores, as well as both sensitivity and specificities of MTA score, were observed to be high. When they were combined, sensitivities and specificities were found to be high. CONCLUSION: The scale is observed to be predictive in discriminating degenerative and non-degenerative processes. This discrimination is important, particularly in depressive patients complaining of forgetfulness. PMID- 30417802 TI - Atom Probe Compositional Analysis of Interphase Precipitated Nano-Sized Alloy Carbide in Multiple Microalloyed Low-Carbon Steels. AB - The composition of nano-sized alloy carbides formed by interphase precipitation in V-Nb and V-Ti multiple microalloyed low-carbon steels is analyzed by using three-dimensional atom probe. Carbide-forming alloying elements including V, Nb, and Ti, are simultaneously precipitated from the early stage of isothermal treatment, whose atoms are uniformly distributed in the carbide particles, even after prolonged holding. Cluster analysis by the maximum separation method, with parameters optimized using different methods, is carried out to extract alloy carbides from matrix. The composition of alloy carbides evaluated by site fraction of substitutional carbide-forming alloying elements indicates that at the early stage of their formation, Nb and Ti are more strongly enriched than V. PMID- 30417803 TI - Medical Spending for the 2001 Anthrax Letter Attacks. AB - : ABSTRACTIntroductionThis paper assesses the total medical costs associated with the US anthrax letter attacks of 2001. This information can be used to inform policies, which may help mitigate the potential economic impacts of similar bioterrorist attacks. METHODS: Journal publications and news reports were reviewed to establish the number of people who were exposed, were potentially exposed, received prophylactics, and became ill. Where available, cost data from the anthrax letter attacks were used. Where data were unavailable, high, low, and best cost estimates were developed from the broader literature to create a cost model and establish economic impacts. RESULTS: Medical spending totaled approximately $177 million. CONCLUSIONS: The largest expenditures stemmed from self-initiated prophylaxis (worried well): people who sought prophylactic treatment without any indication that they had been exposed to anthrax letters. This highlights an area of focus for mitigating the economic impacts of future disasters. (Disaster Med Public Health Preparedness. 2018;page 1 of 8). PMID- 30417804 TI - Anthrax Exposure, Belief in Exposure, and Postanthrax Symptoms Among Survivors of a Bioterrorist Attack on Capitol Hill. AB - BACKGROUND: Following chemical, biological, radiological, and nuclear disasters, medically unexplained symptoms have been observed among unexposed persons. OBJECTIVES: This study examined belief in exposure in relation to postdisaster symptoms in a volunteer sample of 137 congressional workers after the 2001 anthrax attacks on Capitol Hill. METHODS: Postdisaster symptoms, belief in exposure, and actual exposure status were obtained through structured diagnostic interviews and self-reported presence in offices officially designated as exposed through environmental sampling. Multivariate models were tested for associations of number of postdisaster symptoms with exposure and belief in exposure, controlling for sex and use of antibiotics. RESULTS: The sample was divided into 3 main subgroups: exposed, 41%; unexposed but believed they were exposed, 17%; and unexposed and did not believe that they were exposed, 42%. Nearly two-thirds (64%) of the volunteers reported experiencing symptoms after the anthrax attacks. Belief in anthrax exposure was significantly associated with the number of ear/nose/throat, musculoskeletal, and all physical symptoms. No significant associations were found between anthrax exposure and the number of postdisaster symptoms. CONCLUSIONS: Given the high incidence of these symptoms, these data suggest that even in the absence of physical injury or illness, there may be surges in health care utilization. (Disaster Med Public Health Preparedness. 2018;page 1 of 6). PMID- 30417805 TI - The Knowledge Level of Dentists in Turkey About Their Potential Role on the Disaster Victims Identification (DVI) Team. AB - OBJECTIVE: Although dentists are valuable assets in identification teams during disaster events, forensic dentistry is not used effectively in the identification studies conducted in Turkey, and the importance of dental data is ignored. The aim of this study was to determine the level of knowledge of dentists regarding their duties and responsibilities during major disasters. METHODS: This descriptive study was conducted between December 2015 and June 2016. Registered dentists (n=20.280) of the Turkish Dental Association were invited to complete the organization's online survey. A total of 539 dentists participated in the volunteer workshop. Data were analyzed using SPSS, version 22.0 (IBM Corp, Armonk, NY). The chi-square analysis was used to evaluate the knowledge level of dentists by group regarding disaster victim identification (DVI) - the process and procedure of recovering and identifying victims of major disasters (eg, earthquake, terrorist attack). RESULTS: The dentists included in the study consisted of 320 (59.4%) females and 219 (40.6%) males with a mean age of 37.4+/ 12.6 years. The number of specialists and general dentists were 249 (45.6%) and 297 (54.4%), respectively; 249 (69.71%) dentists who had knowledge about forensic dentistry stated that they received this information during their formal training. The percentage of dentists who were aware of the existence of an organization of a disaster response operation in Turkey was 74.2%, but only 20.5% (n=110) had knowledge about DVI. We found that 92.9% (n=104) of these dentists believed that dentists should be included in the team for the identification of disaster victims. On the other hand, only half (52.3%) of the dentists with knowledge of DVI wanted to work on the identification teams. The majority (99.1%) considered DNA analysis to be the safest method for identification. CONCLUSION: Our findings show that, although dentists know about the identification process, they do not have enough relevant knowledge. (Disaster Med Public Health Preparedness. 2018;page 1 of 6). PMID- 30417806 TI - A meta-analysis of low-intensity cognitive behavioral therapy-based interventions for dementia caregivers. AB - : ABSTRACTObjectives:This study aimed to review the effectiveness of low intensity cognitive behavioral therapy (CBT)-based interventions for informal dementia caregivers when compared to non-active control conditions. DESIGN: Literature searches were conducted in databases of published (PsycINFO, MEDLINE, CINAHL, Scopus) and unpublished (Open Grey, ISRCTN registry, ClinicalTrials.gov, ProQuest) literature. Individual meta-analyses were conducted for each outcome variable. Pooled intervention effect estimates were calculated as Hedge's g using a random-effects model. INCLUDED STUDIES: Studies examining the effect of low intensity CBT-based interventions for informal caregivers for people with any progressive dementia were included. Randomized controlled trials and controlled clinical trials were included. MEASUREMENTS: Outcomes included the psychological variables of anxiety, depression, burden, and distress (defined as stress or strain). RESULTS: A total of five studies reported anxiety outcomes, 12 reported on depression, three reported on burden, and six reported distress outcomes. Results demonstrated a significant effect of low-intensity CBT-based interventions in reducing all examined psychological difficulties. Small effect sizes were found for anxiety (g = 0.35), depression (g = 0.27), and distress (g = 0.33). A medium effect was found for burden (g = 0.53). CONCLUSIONS: The results provide initial support for low-intensity CBT-based interventions for dementia caregivers. Clinical implications and research recommendations are explored. Strengths and limitations of the study are discussed. PMID- 30417807 TI - ? PMID- 30417808 TI - ? PMID- 30417809 TI - [Early detection and treatment of breast cancer]. AB - Breast cancer is the most common cancer among Danish women. In Denmark, mammography screening has been implemented since 2010. The surgical approach has turned from mastectomy and axillary clearance to breast conserving surgery and sentinel node procedure. The development of radiotherapy is heading towards shorter treatment periods and more precise targeting leading to reduced toxicity. Genomic profiling aims at giving a more personalised adjuvant medical treatment with a high predictive chance of response. Nowadays, more women are offered neoadjuvant treatment, where the systemic treatment is delivered before surgery in order to downsize the disease and reduce surgical treatment. PMID- 30417810 TI - [Medical treatment of lung cancer]. AB - Lung cancer causes most cancer-related deaths in the western world. In Denmark, over 4,700 cases of lung cancer are diagnosed annually. The medical treatment of lung cancer has undergone a significant development over the past 20 years. Adjuvant chemotherapy is given to some patients after surgery, and patients with inoperable, non-metastatic disease can be treated with combinations of chemotherapy and radiation therapy. The large group of patients with metastatic disease can be offered different forms of medical treatment as chemotherapy, targeted treatment or immunotherapy. PMID- 30417811 TI - [Surgery in patients with lung cancer]. AB - This review is about the initial diagnostic workup and the surgical treatment of patients with lung cancer in Denmark. Due to the development of international and national clinical guidelines for diagnosis and treatment of lung cancer, survival has increased. Data from 2005-2016 in the National Danish Lung Cancer Registry show an increase in: 1) the number of women being diagnosed, 2) the part of surgical candidates being thoracoscopically treated, 3) the number of patients being referred to surgery and 4) the survival rate. PMID- 30417812 TI - [Prostate cancer - screening and early detection]. AB - The primary objectives of population screening for prostate cancer (PCa) are a reduction in mortality due to PCa and a maintained quality of life. Currently, screening for PCa is one of the most controversial topics in the urological literature, and findings have led to strong advice against systematic population based screening. PCa is usually suspected based on palpation and/or prostate specific antigen levels, and a definitive diagnosis depends on histopathological verification in biopsy cores. Multiparametric MRI is increasingly performed before prostate biopsy. PMID- 30417813 TI - [Prostate cancer surgery]. AB - Radical prostatectomy (RP) remains the preferred treatment option for men with localised prostate cancer (PCa). Following the introduction in 1995, approximately 1,100 procedures are performed annually in Denmark. Several studies have demonstrated the Danish standard of RP to be at an international level in terms of both functional and oncological outcomes. In order to reduce the risk of overtreatment, management of localised PCa should be organised in experienced multidisciplinary teams, where a constantly growing armamentarium of diagnostic and therapeutic options can be offered. PMID- 30417814 TI - [Medical treatment of patients with colorectal cancer in Denmark]. AB - In this review, the standard medical treatment of patients with colorectal cancer in Denmark is outlined in a pragmatic way. Three typical patient scenarios are described: the post-operative adjuvant setting, the patient with curable metastasis and the patient in palliative treatment. The biomedical knowledge about the disease and treatment options should always be combined with a patient centered approach in order to individualise the treatment according to the patient's values. Furthermore, suggestions for the timing of rehabilitation, palliative care and advance care planning are given. PMID- 30417815 TI - [Intended curative surgery of patients with colorectal cancer]. AB - The prognosis for patients with colorectal cancer has improved markedly in recent years due to standardisation of surgical procedures and incorporation of a multidisciplinary approach in treatment planning. Despite clinical advances, systemic disease recurrence following intended curative surgery remains the most prominent clinical challenge. Identification of patients with elevated perioperative risk of complications provides the opportunity for individualised, multimodal treatment strategies aimed at enhanced patient recovery and improved long-term patient outcomes. PMID- 30417816 TI - [Nuclear medical diagnostic and cancer precision medicine]. AB - Cancer therapy has taken a major leap forward in recent years. However, to fully unfold the concept of precision medicine, non-invasive methods for characterisation of tumours and metastases are needed. PET imaging offers this. Whereas 18F-fluorodeoxyglucose-PET is currently used in most cancer types for diagnosing or staging, we expect new tracers to become available in the clinical routine, supporting tailoring and monitoring of cancer therapies. PMID- 30417817 TI - [Parinaud syndrome caused by corpus pineale tumour in a 14-year-old boy]. AB - Parinaud syndrome (PS) can manifest in a pineal tumour. Major components of PS include restriction of gazing upwards, light-near dissociation and convergence retraction nystagmus. A 14-year-old boy presented with diplopia and restricted ability to gaze upwards. The objective examination revealed signs, which were compatible with the major manifestations of PS. A magnetic resonance scan (MRI) of cerebrum indicated pinealoma, and a pathological examination identified the lesion as a germ cell carcinoma. The patient received chemotherapy and stereotactic radiosurgery. The ophthalmic symptoms improved, and a follow-up MRI demonstrated complete regression of the tumour. PMID- 30417818 TI - [Nocturnal enuresis in children]. AB - Nocturnal enuresis is the most common type of urinary incontinence in children. The pathophysiology of the condition is complex with excess nocturnal urine production, bladder reservoir dysfunction and failure to wake up to the sensation of a full bladder, being important elements. The condition can be successfully treated in most children; desmopressin and the enuresis alarm are both effective first-line treatments. Tailoring the treatment based on the clinical characterisation of the patients can improve the outcome. PMID- 30417819 TI - [Asbestos and mesothelioma in Denmark 2017: status of a man-made cancer epidemic]. AB - Asbestos-induced cancer is an increasing problem in Denmark, and 32 years after the closure of the Danish Eternit Factory in Aalborg there are > 140 new mesothelioma cases diagnosed yearly, numbers rapidly increasing. Asbestos-induced lung cancer may be six times this number. The non-occupational exposure and even neighborhood exposure as a risk factor suggests, that compensation for mesothelioma should be universal. At the Aalborg University Hospital a multidisciplinary research team has been formed to do epidemiological, translational and clinical studies through national and international collaborations. Transformative research on asbestos cancer should be stimulated. PMID- 30417820 TI - [Acromegaly and symptoms of the motor apparatus]. AB - In this case report, a 72-year-old woman presented with symptoms attributed to arthritis, and MRI indicated sacroiliitis. However, the patient also experienced enlargement of hands and feet in addition to sweating and snoring, which in combination with coarse facial features suggested acromegaly. This diagnosis was biochemically confirmed, and MRI revealed a pituitary adenoma, which was successfully removed by transsphenoidal surgery. Symptom relief and reduced swelling occurred immediately post-operatively. Acromegaly can masquerade as arthritis or osteoarthritis, which may delay diagnosis. PMID- 30417821 TI - [Uterine lithiasis]. AB - This is a case report of multiple uterine lithiasis in a 66-year-old, healthy woman. The patient had postmenopausal bleeding but no other complaints. She underwent uneventful vaginal hysterectomy, and multiple loose pieces of detached uterine lithiasis in the uterine cavity were found. It is very rare to find stones in the human uterus without any intrauterine device, neoplasia or malignancy. PMID- 30417822 TI - [Successful treatment of KCNJ11 neonatal diabetes without insulin]. AB - In this case report a 40-year-old insulin-treated male patient presented with a KCNJ11 R201H mutation, which can cause neonatal diabetes. After initiation of treatment with high doses of the sulfonylurea glibencamide in combination with the glucagon-like peptide 1 receptor agonist liraglutide, insulin treatment of the patient could be terminated. The first nine months after termination of insulin treatment the glycated haemoglobin concentration was 48-54 mmol/mol (i.e. 6.5-7.1%). PMID- 30417823 TI - [Sports-related diving challenges the cardiovascular and pulmonary system]. AB - The underwater environment challenges human physiology in a unique way. Prolonged exposure to extreme conditions of immersion and increased ambient pressure can lead to injury and even death. Breath-hold and diving with self-contained underwater breathing apparatus (SCUBA diving) pose acute stress predominantly on the cardiovascular and pulmonary system. Currently there is no evidence of long term consequences of subclinical cardiovascular, neurological or pulmonary adverse effects, but diving has acute stresses on the human physiology. In this review, we aim to provide a basic understanding of the physiological changes related to diving and therapy in case of trauma. PMID- 30417824 TI - AutoAdaptive: A Noise Level-Sensitive Beamformer for MED EL Cochlear Implant Patients. AB - BACKGROUND: When cochlear implant (CI) listeners use a directional microphone or beamformer system to improve speech understanding in noise, the gain in understanding for speech presented from the front of the listener coexists with a decrease in speech understanding from the back. One way to maximize the usefulness of these systems is to keep a microphone in the omnidirectional mode in low noise and then switch to directional mode in high noise. PURPOSE: The purpose of this experiment was to assess the levels of speech understanding in noise allowed by a new signal processing algorithm for MED EL CIs, AutoAdaptive, which operates in the manner described previously. RESEARCH DESIGN: Seven listeners fit with bilateral CIs were tested in a simulation of a crowded restaurant with speech presented from the front and from the back at three noise levels, 45, 55, and 65 dB SPL. DATA COLLECTION AND ANALYSIS: The listeners were seated in the middle of an array of eight loudspeakers. Sentences from the AzBio sentence lists were presented from loudspeakers at 0 or 180 degrees azimuth. Restaurant noise at 45, 55, and 65 dB SPL was presented from all eight loudspeakers. The speech understanding scores (words correct) were subjected to a two-factor (speaker location and noise level), repeated measures, analysis of variance with posttests. RESULTS: The analysis of variance showed a main effect for level and location and a significant interaction. Posttests showed that speech understanding scores from front and back loudspeakers did not differ significantly at the 45- and 55-dB noise levels but did differ significantly at the 65-dB noise level-with increased scores for signals from the front and decreased scores for signals from the back. CONCLUSIONS: The AutoAdaptive feature provides omnidirectional benefit at low noise levels, i.e., similar levels of speech understanding for talkers in front of, and in back of, a listener and beamformer benefit at higher noise levels, i.e., increased speech understanding for signals from in front. The automatic switching feature will be of value to the many patients who prefer not to manually switch programs on their CIs. PMID- 30417825 TI - Bimodal Cochlear Implant Listeners' Ability to Perceive Minimal Audible Angle Differences. AB - BACKGROUND: Bilateral inputs should ideally improve sound localization and speech understanding in noise. However, for many bimodal listeners [i.e., individuals using a cochlear implant (CI) with a contralateral hearing aid (HA)], such bilateral benefits are at best, inconsistent. The degree to which clinically available HA and CI devices can function together to preserve interaural time and level differences (ITDs and ILDs, respectively) enough to support the localization of sound sources is a question with important ramifications for speech understanding in complex acoustic environments. PURPOSE: To determine if bimodal listeners are sensitive to changes in spatial location in a minimum audible angle (MAA) task. RESEARCH DESIGN: Repeated-measures design. STUDY SAMPLE: Seven adult bimodal CI users (28-62 years). All listeners reported regular use of digital HA technology in the nonimplanted ear. DATA COLLECTION AND ANALYSIS: Seven bimodal listeners were asked to balance the loudness of prerecorded single syllable utterances. The loudness-balanced stimuli were then presented via direct audio inputs of the two devices with an ITD applied. The task of the listener was to determine the perceived difference in processing delay (the interdevice delay [IDD]) between the CI and HA devices. Finally, virtual free-field MAA performance was measured for different spatial locations both with and without inclusion of the IDD correction, which was added with the intent to perceptually synchronize the devices. RESULTS: During the loudness balancing task, all listeners required increased acoustic input to the HA relative to the CI most comfortable level to achieve equal interaural loudness. During the ITD task, three listeners could perceive changes in intracranial position by distinguishing sounds coming from the left or from the right hemifield; when the CI was delayed by 0.73, 0.67, or 1.7 msec, the signal lateralized from one side to the other. When MAA localization performance was assessed, only three of the seven listeners consistently achieved above-chance performance, even when an IDD correction was included. It is not clear whether the listeners who were able to consistently complete the MAA task did so via binaural comparison or by extracting monaural loudness cues. Four listeners could not perform the MAA task, even though they could have used a monaural loudness cue strategy. CONCLUSIONS: These data suggest that sound localization is extremely difficult for most bimodal listeners. This difficulty does not seem to be caused by large loudness imbalances and IDDs. Sound localization is best when performed via a binaural comparison, where frequency-matched inputs convey ITD and ILD information. Although low-frequency acoustic amplification with a HA when combined with a CI may produce an overlapping region of frequency-matched inputs and thus provide an opportunity for binaural comparisons for some bimodal listeners, our study showed that this may not be beneficial or useful for spatial location discrimination tasks. The inability of our listeners to use monaural level cues to perform the MAA task highlights the difficulty of using a HA and CI together to glean information on the direction of a sound source. PMID- 30417826 TI - TrpV1 receptor activation rescues neuronal function and network gamma oscillations from Abeta-induced impairment in mouse hippocampus in vitro. AB - Amyloid-beta peptide (Abeta) forms plaques in Alzheimer's disease (AD) and is responsible for early cognitive deficits in AD patients. Advancing cognitive decline is accompanied by progressive impairment of cognition-relevant EEG patterns such as gamma oscillations. The endocannabinoid anandamide, a TrpV1 receptor agonist, reverses hippocampal damage and memory impairment in rodents and protects neurons from Abeta-induced cytotoxic effects. Here, we investigate a restorative role of TrpV1-receptor activation against Abeta-induced degradation of hippocampal neuron function and gamma oscillations. We found that the TrpV1 receptor agonist capsaicin rescues Abeta-induced degradation of hippocampal gamma oscillations by reversing both the desynchronization of AP firing in CA3 pyramidal cells and the shift in excitatory/inhibitory current balance. This rescue effect is TrpV1-receptor-dependent since it was absent in TrpV1 knockout mice or in the presence of the TrpV1-receptor antagonist capsazepine. Our findings provide novel insight into the network mechanisms underlying cognitive decline in AD and suggest TrpV1 activation as a novel therapeutic target. PMID- 30417827 TI - Reactivation of dormant/latent fungal infection. AB - OBJECTIVES: Latent infections are well-known for bacteria such as Mycobacterium tuberculosis and for viruses such as Herpesviridae and parasites like Leishmania spp. or Toxoplasma gondii. However, invasive fungi may also be latent and come to reactivate. The aim of this review is to clarify the reactivation concept in major fungal invasive diseases. METHOD: We have searched for PUBMED publications from 1980 to 2017 with the keywords "fungi", "reactivation", "latency", "dormancy", "granuloma", "Aspergillus", "Mucorales", "Dimorphic fungi", "Histoplasma", "Cryptococcus", "Pneumocystis", "Yeast", "Candida" and "Mold". RESULTS: After primary infection and immune control of the fungus, reactivation can occur following a period of latency. Two conditions must be present: dormancy/survival of the fungi and immunosuppression of the host. Fungal reactivation is easily demonstrated for dimorphic fungi when patients travelling in endemic areas are no longer exposed to fungi at the time they when develop the disease. For cosmopolitan fungi, such as Cryptococcus neoformans, Aspergillus or some emerging fungi, clinical data and animal models have brought some evidence of reactivation. Survival inside macrophages and granuloma formation appear to be predominant conditions to latency. Although granuloma may act as a reservoir for some fungi like Histoplasma or Cryptococcus, its role in mold reactivation has yet to be fully established. CONCLUSIONS: The risk of fungal reactivation should be taken into account in patient management, especially in cases of solid organ transplantation or long-term immunosuppressive treatment. PMID- 30417828 TI - Impact of the Use and Type of Antibiotics on Acute Graft-versus-Host Disease. AB - The intestinal microbiota plays an important role in the pathogenesis of acute graft-versus-host disease (aGVHD). During the course of hematopoietic stem cell transplantation (HSCT), the intestinal microbiota is influenced by the use of broad-spectrum antibiotics. However, the impact of the use and type of antibiotics on the microbiota composition and, subsequently, the onset of aGVHD remain poorly understood. We hypothesized that the use and type of antibiotics had an impact on the occurrence of aGVHD. We assessed 275 patients who underwent their first allogeneic HSCT between January 2005 and June 2015 at Kyoto University Hospital. We monitored the 6 most frequently administered antibiotics (fourth-generation cephalosporins, glycopeptides, piperacillin-tazobactam, carbapenems, aminoglycosides, and quinolones) administered between days -14 and +14 relative to HSCT and its duration. The primary endpoint was the cumulative incidence of grades II to IV aGVHD. The cumulative incidence of aGVHD was significantly higher in patients administered fourth-generation cephalosporins than in patients not receiving fourth-generation cephalosporins (grades II to IV: hazard ratio, 1.98; 95% confidence interval, 1.19 to 3.29; P = .0087; grades III to IV: hazard ratio, 8.03; 95% confidence interval, 1.07 to 60.51; P = .043). In contrast, there was no significant association between administration of other antibiotics and aGVHD incidence. As for organ-specific aGVHD, the cumulative incidence of gut aGVHD was significantly higher in patients who received fourth generation cephalosporins than in those who did not (31% versus 16%, P = .018). In conclusion, we demonstrated that the administration of fourth-generation cephalosporins had a strong impact on the development of aGVHD. PMID- 30417829 TI - Weight Evolution During Endocrine Therapy for Breast Cancer in Postmenopausal Patients: Effect of Initial Fat Mass Percentage and Previous Adjuvant Treatments. AB - BACKGROUND: Weight changes during adjuvant treatment for early-stage breast cancer has been associated with a poor prognosis. The long-term evolution of body composition during adjuvant treatment for breast cancer, in particular, endocrine therapy, is not well known, and new data on this topic are required. The present study assessed the evolution of weight and body composition among 33 postmenopausal breast cancer patients receiving endocrine therapy after standard adjuvant chemotherapy that included taxanes. PATIENTS AND METHODS: Dual-energy x ray absorptiometry was used to measure the fat and lean body mass. Body water was assessed using multifrequency bioelectrical impedance analysis. The Hospital Anxiety and Depression questionnaire and the short version of the International Physical Activity Questionnaire were also administered. RESULTS: During endocrine therapy, 5 of the 33 patients (15.2%) lost weight and 12 (36.4%) gained weight. The overall average gain was 2.0 +/- 5.5 kg (P = .04). During this period, the fat mass, lean body mass, and body water increased. The factors linked to fat mass gain included an excess fat mass (>= 36%) before treatment and weight loss during chemotherapy. In the overall period of adjuvant cancer treatment, 30% of the population gained > 5% of their initial weight. The average gain was the same as that during the endocrine therapy period (2.0 +/- 5.4 kg; P = .031) and was characterized by an increase in total lean body mass, mainly localized in the trunk region. CONCLUSION: Endocrine therapy appears as a pivotal period in weight and body composition management. Overfat and obese patients and those who lose weight during chemotherapy were more subject to weight and fat mass gain during endocrine therapy. PMID- 30417830 TI - Clinicians Should Actively Promote Exercise in Survivors of Breast Cancer. AB - Breast cancer is the most common cancer affecting women, causing 29% of all female cancers and afflicting 14% of all female cancer-related deaths worldwide. It remains a significant clinical, psychological, and financial burden. Exercise has been suggested to reduce cancer recurrence and cancer-related mortality from research in the past decade. Recent American and European guidelines advise on exercise for breast cancer survivors, not only to improve quality of life and decrease fatigue, but also to aid in decreasing recurrence and improve breast cancer related mortality. Nonetheless, adherence to guidelines remains low, with lack of awareness and fatigue related to chemotherapy as the most common barriers. It remains to be elucidated whether a particular type of exercise, or whether group or individualized activity is most effective. The importance of exercise in avoiding recurrence and improving quality of life needs to be recognized and taken into account in the management of breast cancer survivors. Further patient awareness and education is essential towards this goal, and the role of group exercise should be further explored. PMID- 30417831 TI - Neutrophil Gelatinase-Associated Lipocalin Significantly Correlates with Ischemic Damage in Patients Undergoing Laparoscopic Partial Nephrectomy. AB - BACKGROUND: Laparoscopic partial nephrectomy, minimizing renal function loss due to its nephron sparing nature, has become a standard technique among many experienced centers worldwide in the surgical treatment of localized kidney tumors. Although partial nephrectomy will remain the gold standard, we need to improve perioperative management and surgical method to prevent postoperative acute kidney injury. AIMS: We aimed to demonstrate the frequency of the development of postoperative acute kidney injury following laparoscopic partial nephrectomy in patients with healthy contralateral kidney and the early predictive effects of serum neutrophil gelatinase-associated lipocalin in ischemia reperfusion injury and its association with the warm ischemia time. STUDY DESIGN: Cross-sectional study. METHODS: Eighty patients were included in this study. We analyzed tumor size, operating time, duration of anesthesia and warm ischemia time. Serum samples were obtained for measurement of serum creatinine, estimated glomerular filtration rate and neutrophil gelatinase associated lipocalin preoperatively, at postoperative 2nd hour, on postoperative days 1 and 2. We used receiver operating characteristic curve for determining the cut-off point of neutrophil gelatinase-associated lipocalin to detect postoperative acute kidney injury. Correlation analysis was performed using the Spearman's test. RESULTS: 27 patients developed acute kidney injury on postoperative day 2, neutrophil gelatinase-associated lipocalin increased significantly higher at postoperative 2nd hour in acute kidney injury group (p=0.048). For a cut-off of 129.375 ng/ml neutrophil gelatinase-associated lipocalin, the test had 70.0% sensitivity and 68.3% specificity for the detection of at postoperative 2nd hour acute kidney injury. For a cut-off of 184.300 ng/ml neutrophil gelatinase-associated lipocalin, the test had 73.3% sensitivity and 63.3% specificity for the detection of on postoperative day 1 acute kidney injury. There was a significant correlation between warm ischemia time and neutrophil gelatinase-associated lipocalin at postoperative 2nd hour (r = 0.398, p = 0.003). Creatinine values were significantly higher and estimated glomerular filtration rate values were significantly lower on postoperative days 1 and 2 in acute kidney injury group compared to non-acute kidney injury group (p<0.001). CONCLUSION: Receiver operating curve analysis showed that the serum neutrophil gelatinase-associated lipocalin has a valuable diagnostic performance for detecting for AKI. We suggest that neutrophil gelatinase-associated lipocalin may be used as an alternative biomarker to serum creatinine in differentiation of ischemic damage in patients undergoing laparoscopic partial nephrectomy. PMID- 30417832 TI - The Turkish Version of the Rhinoplasty Outcomes Evaluation Questionnaire: Validation and Clinical Application. AB - BACKGROUND: An assessment of rhinoplasty (RP) from the patient's perspective, in terms of satisfaction and quality of life (QOL), is equally important because these are the predominant factors indicating the success of RP. AIMS: To translate the Rhinoplasty Outcomes Evaluation (ROE) into Turkish and then validate the new version for use in Turkish patients. STUDY DESIGN: Validation study. METHODS: We enrolled 30 participants who were able to read and write Turkish and underwent primary RP. The control group consisted of 58 healthy volunteers with no need for aesthetic or functional nasal surgery. The reliability of the ROE-T was analysed according to its internal consistency and test-retest reproducibility. Discriminant validity was calculated by comparing the ROE-T scores between the patient and control groups. Responsiveness and sensitivity to changes in RP outcomes were analysed by comparing the pre- and post-operative ROE-T scores of the patients. RESULTS: The scores for questions 1 6 of the ROE-T, and the total scores, were significantly lower in the patient group than in the control group (all p <0.05) . In the patient group, the scores for questions 1-6 of the ROE-T, and the total scores, were higher postoperatively than preoperatively (all p <0.05). The scores for each ROE-T question, and the total scores, did not significantly differ with respect to test-retest reproducibility (all p >0.05). The internal consistency of the ROE-T was high, as evidenced by Cronbach's alpha values of 0.887 preoperatively and 0.798 postoperatively. CONCLUSION: The ROE-T thus constitutes a validated instrument with which to measure RP outcomes among Turkish patients. As the ROE is the most well-validated tool for assessing the outcomes of RP, the ROE-T can be applied as a part of multi-national investigations. PMID- 30417833 TI - Validation of the "Mind the Gap" Scale to Assess Satisfaction with Health Care among Adolescents. AB - BACKGROUND: Today, more than 90% of adolescents with chronic conditions survive into adulthood as a user of health care and move pediatric to adult care with their chronic illness. Therefore, the need of satisfaction scales focuses specifically on transitional care and reflect youth and their parent's expectations is increasing. AIMS: The aim of this study is examining of validity and reliability of a Turkish version of Mind the Gap Scale. STUDY DESIGN: Methodological study. METHODS: Turkish version of Mind the Gap Scale and Patient Assessment of Choronic Illness Care Scale were applied to participants in two tertiary hospitals in Ankara.Validity was evaluated with factor analyses and content-scope validity; reliability was evaluated with item-total score correlation, internal consistency and continuity methods. RESULTS: A total of 109 adolescents and 157 parents completed the questionaire. Content validity were confirmed. Explatory Factor Analysis was used to determine the factor structure of the scale. Both adolescent and parent scale is formed of 3 sub dimensions and explained 71% and %73 of the variation respectively. Cronbach alpha reliability coefficient of MGS1 and MGS2 were found as .89 and .87; internal consistency of parent's scales were .92 and .90 respectively. The test-retest reliability coefficient was found .88 for adolescents and .85 for the parents. The suitability of the model were examined with Confirmatory Factor Analysis. x2/df and the other conformity indices were suited well. CONCLUSION: Turkish version of the MGS was decided to be a valid and reliable scale for evaluating the needs, expectations and satisfaction of adolescents and their parents with health care. PMID- 30417834 TI - A comparative study of gloved versus ungloved merocel(r) as nasal pack after septoplasty. AB - Introduction: Septoplasty or septal reconstruction is a corrective surgical procedure performed to straighten the nasal septum. It may be associated with numerous complications. To minimize these complications, both nasal cavities are frequently packed with different types of nasal packing. Materials and Methods: This prospective, observational, and comparative study was undertaken in the Department of ENT, Rajindra Hospital, Patiala, Punjab, India. A total of sixty patients fulfilling the inclusion criteria participated in the study. They were divided into two groups, Groups A and B. After septoplasty, the nasal cavity was packed with gloved Merocel(r) in Group A and ungloved Merocel(r) in control group (Group B). The efficacy and patient tolerance for both nasal packings were compared and assessed. The data collected were compiled and analyzed statistically. Results: In our study, it was demonstrated that gloved Merocel(r) produces less pain during pack insertion (P = 0.001) and produces less pain while insertion of pack in situ (P = 0.001) and during pack removal (P = 0.001). Saccharin transit time (STT) returned back to normal in gloved Merocel(r) group (P = 0.001) in most of patients (27) by the 2nd week, whereas STT in ungloved Merocel(r) group returned back to normal by the 4th week postoperatively. The differences in impairment in STT between the two groups were found to be statistically significant. There was no statistical significance between both groups for other parameters. Conclusion: Gloved Merocel(r) may be preferred over ungloved Merocel(r) as nasal packing following septoplasty since both types of packs had similar hemostatic, adhesion prevention properties and similar incidence in postoperative complications and gloved Merocel(r) produces less pain during its insertion, while it is in situ, during its removal with early recovery of nasal mucociliary clearance mechanism of nose. PMID- 30417835 TI - The economic burden of malignant and premalignant hematological diseases in Southern Nigeria. AB - Background: Hematological malignancies are a significant cause of morbidity and mortality. They constitute an economic burden for the patients, their relatives, and the society because of the cost associated with their management, which is usually long term. We aimed to determine the total direct cost of managing patients with premalignant hematological disorders (PMHDs) and malignant hematological disorders (MHDs). Materials and Methods: A hospital-based retrospective study was carried out between 1997 and 2015. Data were retrieved from the case notes of adult patients diagnosed with either PMHD or MHD. The total cost of medical care was calculated as the sum of in-patient and out patient direct cost associated with their management. Data were analyzed using Statistical Package for Social Sciences. Results: There was a total of 129 patients; 74 (57.4%) males and 55 (42.6%) females with mean age of 45.7 +/- 16.3 years and the majority (n = 76, 58.9%) being employed. Males were more affected than the females except in chronic lymphocytic leukemia, myelodysplastic syndrome, and paroxysmal nocturnal hemoglobinuria. The commonest MHD was chronic myeloid leukemia with 37 (28.7%) patients. Full blood count was the commonest investigation done, whereas free light chains were the least (n = 2; 1.6%). The total cost of care for the 129 patients was N30,041,900.00 ($82,306.58) with an average total cost of care per patient of N232,882.95 ($638.04). Patients with non-Hodgkin lymphoma had the highest mean cost of care per patient (N373,196.30; $1,022.46). The average monthly expenditure per patient was about N70,000 ($190). Conclusion: In our setting, management of CHDs constitutes an economic burden. PMID- 30417836 TI - Evaluation of normal tibial tubercle to trochlear groove distance in adult Turkish population. AB - Purpose: Many studies have confirmed the significance of tibial tuberosity trochlear groove (TTTG) distance measurement for the preoperative assessment of tibial tubercle osteotomy and refixation of the patients that need surgery. TTTG distance is being used as threshold value for surgery decision. The purpose is to determine the TTTG values for the adult Turkish population and compare this with the values of other studies and establish a possible index. Materials and Methods: This study was conducted on 200 patients (97 female, 103 male) aged between 18 and 65 years, retrospectively, who had magnetic resonance imaging at Istanbul Medipol Mega University Hospital Radiology Department. Individuals with no knee surgical history and deformation included to research group, any deformities related with knee were excluded. The scans were analyzed in Picture Archiving Communication System program and compared with other populations. Significance was evaluated with independent Student's t-test. Results: The mean TTTG distance was found 10.07 +/- 1.60 mm in males, 9.96 +/- 1.41 mm in females, and 10.02 +/- 1.51 mm for total cases. There was no statistically significant difference between sex (P > 0.05). However, overall TTTG distance of right and left knees found significantly different (P < 0.05). Conclusion: Obtained results are similar with the results of Caucasian population but different than Asian. It is believed that these results will be significant in evaluation of patellofemoral disorders and helpful in treatment. PMID- 30417837 TI - The relationship between fatigue and breastfeeding self-efficacy. AB - Background: Postpartum fatigue appears in the early weeks and after childbirth has a clear impact on maternal functioning and breastfeeding. Aim: This study aimed to examine the relationship between fatigue and breastfeeding self efficacy. Materials and Methods: This descriptive study was conducted at three family health centers (FHCs) in Izmir, Turkey, between June 2013 and March 2014. We used the Self-Description Form for Mothers, the Breastfeeding Self-Efficacy Scale Short Form (BSES-SF), and the Brief Fatigue Inventory (BFI) to collect data from 184 breastfeeding women during the postpartum period. Results: At week 1 postpartum, 98.9% of the mothers in this study experienced fatigue; of those, 12.6% had minor fatigue, 48.3% had moderate fatigue, 36.8% had excessive fatigue, and 0.7% had the highest level of fatigue. At week 8 postpartum, 46.7% of the mothers experienced fatigue, 50.0% of whom experienced fatigue on a minor level, 16.2% on a moderate level, and 2.5% on an excessive level. The present study found that 55.4% and 1.1% of the mothers had BSES-SF mean scores below 50 at weeks 1 and 8 postpartum, respectively. The mean BSES-SF score was 51.21 +/- 6.95 (min-max = 19.00-70.00) at week 1 postpartum, which increased to 64.54 +/- 9.65 (min-max = 15.00-70.00) at week 8 postpartum. The statistical results indicated that there were no significant relationships between the BSES-SF and the BFI at week 1 postpartum (r = 0.007, P > 0.05) and week 8 postpartum (r = 0.111, P > 0.05). Conclusion: In this study, the mothers' fatigue during the postpartum period was not associated with breastfeeding self-efficacy. Many of the variables identified may be considered modifiable and amenable to interventions. Targeted interventions should be directed toward improved breastfeeding outcomes among Turkish women. PMID- 30417839 TI - Determination of the relationship between patient satisfaction and some global economic indicators using multidimensional scaling. AB - Context: The importance of labor that contributes to the economy and economic power of the country is increasing recently. There is a strong link between health and economy. People are happier, more productive, and provide more contribution to the economy in communities of healthy individuals. In countries with strong economy, serious economic investments are made in the field of health to grow healthy individuals. Aim: The purpose of this study is to determine whether patient satisfaction in primary healthcare services is related to economic strength of countries. Materials and Methods: The data of European Patients Evaluate General/Family Practice (EUROPEP) scale from 2011 at 17 Organization for Economic Co-operation and Development (OECD) countries are used. The data were compiled from OECD reports and Republic of Turkey Ministry of Health Refik Saydam Hygiene Center Presidency School of Public Health patient satisfaction with primary healthcare services reports. Statistical Analysis Used: 17 OECD member countries in 2011 health expenditure data, some health indicators, and patient satisfaction are determined to show how grouping in two-dimensional space with the multidimensional scaling. Results: It was observed to vary by countries and groupings that they located in terms of all three criteria. In some countries' economic and health indicators, although quite high compared to the OECD average, citizen satisfaction of healthcare services was low. In some countries, although health expenditure and health indicators are far below the OECD average, citizens' satisfaction with health services has proved to be very high. Conclusion: Multidimensional scaling analysis findings reveal that countries have different positions and groups in terms of each three indicators. According to these results, it cannot be said that high expenditures in the field of health will affect patients satisfaction. Having a strong economy or spending too much money on health does not increase human satisfaction in health care. Effective expenditures on the field of health will increase healthcare service satisfaction. Policy-makers should consider international criteria and take the right steps according to citizens' expectation and satisfaction of healthcare service to implement effective spending. PMID- 30417838 TI - Comparison of the prevalence of adhesions at the time of diagnostic laparoscopy for infertility between patient who had open myomectomy and those who had no previous pelvic-abdominal surgery or pelvic inflammatory disease. AB - Objective: The aim of this study is to determine the prevalence and patterns of adhesions in infertile women with prior open myomectomy compared with women without prior pelvic-abdominal surgery. Methods: A nested case-control study of infertile women who had diagnostic laparoscopy after open myomectomy between January 2008 and June 2015 in Life Institute for Endoscopy Limited, Nnewi Nigeria, was conducted. At diagnostic laparoscopy, the presence, site, and quality (density) of adhesions was noted and recorded. Women with endometriosis and documented prior pelvic infections were excluded. Results: Of the 348 women who were eligible, 121 women had prior open myomectomy (study group) while 227 had none (control group). Of the 121 women, adhesions were detected in 97 women; thus, the prevalence of adhesion after open myomectomy was 80.2% versus 20.3% (46/227) in controls (odds ratio [OR] =15.90; 95% confidence interval [CI] =8.86 28.76; P < 0.001). Compared with controls, adhesions were statistically higher in these sites: uterus (68.6% vs. 14.5%), fallopian tubes (77.7% vs. 16.7%), ovaries (62.8% vs. 20.3%), cul-de-sac (66.1% vs. 16.3%), bladder (45.5% vs. 7.9%), and bowel (53.7% vs. 6.2%) (P < 0.001, for all). Cohesive form of adhesions was also statistically higher, 54 (44.6%) vs. 32 (14.1%) (P < 0.05). Conclusion: In infertile women, post-open myomectomy adhesions have a high prevalence of 80.2% with high predilection in fallopian tubes and uterus, compared with women without prior abdominopelvic surgery at 20.3%. Cohesive form of adhesion predominates. PMID- 30417840 TI - The prevalence of microalbuminuria and associated factors among patients with type 2 diabetes mellitus in Botswana. AB - Background: Microalbuminuria (MA) has been established as an early marker of both diabetic nephropathy and vascular disease in patients with diabetes mellitus (DM). Aims: This study was conducted to determine the prevalence of MA and associated factors among patients with type 2 DM in Botswana. Settings and Design: Outpatient tertiary clinic. Materials and Methods: A cross-sectional descriptive study involving 289 patients with type 2DM was conducted from January 2013 to June 2013 in Block 6 Reference Clinic, a tertiary clinic in Gaborone, Botswana. A random spot urine sample was collected from each patient with MA defined as urine albumin-to-creatinine ratio (ACR) between 3.0 and 30.0 mg/mmol. Statistical Analysis Used: Data analysis was done using STATA version 12 (College Station, TX, USA). Unpaired Student's t-test was used for compairing means and Chi-squared test was used for comparison of proportions between groups. A P value of <0.05 was considered statistically significant. Results: The majority of recruited patients (191, 66.1%) were females, and the median age (interquartile range) of the patients was 52 (42-53) years. The mean glycosylated hemoglobin (HbA1c) for the study population was 8.43% with 70.6% of the population having HbA1c over 7%. MA was found in 129 (44.6%) of study participants. The duration of diabetes of 6-10 years, estimated glomerular filtration rate, HbA1c, and higher serum trigerycides levels were significantly associated with presence of MA. Conclusion: High prevalence of MA raises an urgent need for changes in the management of patients with type 2 DM in Botswana, with emphasis on prevention and reduction of MA to avoid development of overt diabetic nephropathy and ensuing cardiovascular morbidity and mortality. PMID- 30417841 TI - Pattern of blood donation and characteristics of blood donors in Enugu, Southeast Nigeria. AB - Background: Despite increasing need for blood donation in medical practice, little is known about pattern of blood donation and characteristics of blood donors in some African populations like Nigeria. This information is necessary in designing strategies and policies for improving blood transfusion services in Africa. Aim: The aim of this study is to determine the pattern of blood donation and characteristics of blood donors in Enugu, Southeast, Nigeria. Materials and Methods: A cross-sectional study of 3377 blood donors at a tertiary hospital in Enugu, Nigeria from May 1, 2016 to April 30, 2017. Information sought included donors' sociodemographic characteristics; type of blood donor: Voluntary nonremunerated donor (VNRD), family replacement donor (FRD), or paid donor (PD); willingness to become VNRD in the future after counseling and education (at point of entry to blood bank) on its benefits to clinical practice; hemoglobin (Hb) level; and transfusion transmissible infections (TTIs). Results: Mean age of blood donors was 28.8 +/- 8.5 years, majority were male (3011, 89.2%) and students (1289, 32.8%). FRDs were the highest in number (1998, 59.2%), followed by PDs (746, 22.1%) and finally VNRDs (633, 18.7%). Of the 3377 persons that came for blood donation, 2537 (75.1%) were found eligible to donate while 840 (24.9%) were deferred on account of low Hb (602/3377, 17.8%) or positive infectious screening test (238/3377, 7.0%). The odds of a male donor being a VNRD were about one and half times that of a female donor (582/3011 [19.3%] vs. 51/366 [13.9%]; odds ratio: 1.48; 95% confidence interval: 1.09-2.02; P = 0.01). After counseling of FRDs and PDs, majority (54.3%) were willing to become VNRDs in the future. Donors' age >30 years, being of male sex, having tertiary level of education, and being employed were strongly associated with willingness to become VNRDs in the future (P < 0.001). Conclusion: VNRD made up <20% of the total number of donors in Enugu, Nigeria. There is a need for improvement in public enlightenment on the need for VNRDs and employment opportunities of the populace to improve voluntary blood donation. PMID- 30417843 TI - Incidence of pyramidal thyroid lobe in the university college hospital Ibadan. AB - Introduction: The pyramidal lobe of the thyroid gland is derived from remnant of the thyroglossal duct. Its presence may be missed clinically; however radiologic and intra-operative findings reveal its presence in up to 50% of cases. The incidence of pyramidal lobe is however not clearly known in Sub-Saharan Africa, particularly in Nigeria. Our aim is to determine the incidence and histological variation of pyramidal lobe of the thyroid gland among surgical patients who underwent thyroid surgery in the University College Hospital, Ibadan. Methodology: Consecutive surgical patients that underwent total thyroidectomy in the Endocrine Surgery Division, Department of Surgery, University College Hospital, Ibadan between April 2013 and April 2017 were recruited irrespective of age, sex and clinical diagnosis. The presence, anatomy and subsequent histological diagnosis of the pyramidal lobe were noted. Results: One hundred sixty thyroid surgeries were done. Pyramidal lobe was found in 70 patients (44.0%). The presence of the pyramidal lobe was most often associated with multinodular goitres 42 (61.8%) and least found in thyroids with malignant tumours 3 (4.4%). The pyramidal lobe originated commonly from the midline (50.0%) and least from the right (10.3%). The length of the pyramidal lobes ranged from 8 to 80 mm (average 50 mm) in males and 5 to 54 mm (average 42 mm) in females. Conclusion: The presence of a pyramidal lobe is not uncommon in people of southwestern Nigeria with its morphologic and histologic profile akin to what obtains in other geographical locations of the world. PMID- 30417842 TI - The efficacy of resin infiltrate on the treatment of white spot lesions and developmental opacities. AB - Objectives: The aim of this study was to evaluate the changes in opacities by applying resin infiltrate to developmental enamel opacities and applying resin infiltrate or fluoride varnish to white spot lesions (WSLs). Materials and Methods: A total of 132 teeth with WSLs and developmental enamel opacities were included in the study. WSLs were treated with resin infiltrate (Group 1) and fluoride varnish (Group 2), and developmental enamel opacities were treated with only resin infiltrate (Group 3). Lesions were evaluated in accordance with International Caries Detection and Assessment System (ICDAS II) criteria and DIAGNOdent Pen scores before applying the material (T0), just after the application (T1), and after 1 month (T2) and 3 months (T3). Results: A significant decrease in DIAGNOdent Pen scores was observed in all the groups and the most important decrease was seen in Group 2 (P < 0.05). A significant decrease in ICDAS II scores was observed in Groups 2 and 3 (T0-T1) and Group 1 (T1-T2) (P < 0.05). Conclusion: DIAGNOdent pen scores decreased and the lesion was partially masked after resin infiltrate was applied to treat developmental enamel opacities; the resin infiltrate application, however, was more successful than fluoride varnish on WSLs. Treating WSLs with resin infiltrate was a good option due to shorter term esthetic recovery and high patient satisfaction. PMID- 30417844 TI - Dental fear in primary school children and its relation to dental caries. AB - Background: Successful management of dental fear in children prevents its progression into adulthood. This study aimed to assess the level of dental fear among school children and to determine its relationship with dental caries. The study design was a cross-sectional analytical study. Materials and Methods: A sample of 1,546 primary school children were randomly selected. The Children's Fear Survey Schedule-Dental Subscale (CFSS-DS) was completed in class to assess child dental fear. Caries experience was measured as decayed, missed, and filled permanent and primary teeth (DMFT/dmft) according to the World Health Organization (WHO) criteria. Results: Approximately 24% of the participated children had high dental fear, and 12.50% of them had severe dental fear. Girls had higher rate of severe dental fear than boys (20% vs. 5%). The severity of caries was significantly increased in children who had higher fear scores (P = 0.035). Conclusion: About one quarter of 6- to 12-year-old children had dental fear; about half of them had severe dental fear. Dental fear has a direct relationship with decayed permanent teeth and an inverse relationship with restored permanent teeth. PMID- 30417845 TI - Comparison of sleep quality and quality of life indexes with sociodemographic characteristics in patients with chronic kidney disease. AB - Aims: Chronic kidney disease (CKD) is a serious health problem due to high mortality and morbidity, negative impact on the patients' quality of life (QOL), high diagnostic and therapeutic cost, and the burden on society. Sleep, which is one of the main needs of the human body, is important regarding the health and QOL in all ages. The objective of our study was to plan the quality of sleep and life quality in adults with CKD. Materials and Methods: Total 240 cases (91 healthy volunteers, 75 predialysis patients, and 74 hemodialysis (HD) patients) were included in our study. Our study was designed as a prospective survey with a face-to-face interview method. The sleep quality was evaluated with Pittsburgh Sleep Quality Index (PSQI). The WHO Quality of Life-short version (BREF) survey questions were used for QOL, and scoring was performed. Results: The analysis showed that the results of PSQI scores, QOL scores, and evaluation of the age variable were statistically significant (P = 0.001, P < 0.001, P < 0.001, respectively). Likewise, the PSQI scores were low in healthy volunteers but were the highest in predialysis patients. The scores of the HD patients were between the scores of predialysis and healthy volunteers. The score of the QOL increased with educational level. There was a positive correlation between Modification of Diet in Renal Disease (MDRD) level and QOL (P < 0.001; r = 0.260) and a negative correlation between MDRD level and PSQI score (P < 0.001, r = -0.202). Conclusion: Like in HD patients, close follow-up of predialysis patients with CKD is critical considering the resolution of the encountered problems. We believe that the increase in QOL and sleep in patients with CKD may decrease the morbidity. PMID- 30417846 TI - Parental monitoring and substance use among youths: A survey of high school adolescents in Lagos State, Nigeria. AB - Background: Risk behaviours including marijuana use, alcohol consumption and cigarette smoking have a significant impact on the present and future health of adolescents. There are limited studies in sub-Saharan Africa to show evidence, if it exists, of the relationship between parental monitoring practices and the prevalence of substance use among adolescents. The aim of this study is to assess the relationship between parental monitoring practices and alcohol consumption, cigarette smoking and marijuana use among in-school adolescents in Mushin Local Government Area of Lagos State, South-Western Nigeria. Methods: This was a cross sectional survey of 437 in-school adolescents randomly selected from two schools in Mushin Local Government Area of Lagos State, Nigeria. Information on socio demographic characteristics, the three domains of parental monitoring practices (Parental monitoring; negotiated unsupervised time and parental trust) and substance use were elicited using a modified version of parental monitoring practice scale and the Youth Risk Behaviour Surveillance System (YRBSS) questionnaire. Independent T tests and logistic regression models were used to assess relationship between parental monitoring practices and substance use. Results: The overall prevalence of use of any of the substance was 21.7%. Negotiated unsupervised time was significantly associated with use of alcohol (P < 0.05), marijuana (P < 0.05) and cigarette smoking (P < 0.05). After controlling for age and gender, one unit increase in parental monitoring reduced the odds of engaging in any substance use by 10% (AOR = 0.90, 95% CI = 0.81-0.99) while a similar increase in negotiated unsupervised time significantly increases the odds of any substance use by 7% (AOR = 1.07, 95% CI = 1.01-1.14). Conclusion: Of the three domains assessed, negotiated unsupervised time was consistently associated with substance use among these youth. Efforts to educate parents on the need to restrict unsupervised time of their wards may be warranted. PMID- 30417847 TI - Knowledge, risk perception and practices related to antibiotic resistance among patent medicine vendors in Sokoto metropolis, Nigeria. AB - Background: Resistance to antibiotics is now a serious threat to global health, and inappropriate use of drugs has been identified as a major contributing factor in the developing countries. Objectives: The aim of this study is to assess the knowledge, risk perception, and practices related to antibiotic resistance among patent medicine vendors (PMVs) in Sokoto metropolis, Nigeria. Materials and Methods: A cross-sectional study was conducted among 200 PMVs selected by multi stage sampling technique. Data were collected with a set of pretested, self administered, semi structured questionnaire. Results: A larger proportion (83, 42.1%) of the 197 respondents who completed the questionnaire were aged 20 29 years. Most of them were males (80.2%) and had tertiary education (80.7%). Most of the respondents had adequate knowledge of the causes of antibiotic resistance (94.9%), and its prevention (98.0%). Most of the respondents also perceived antibiotic resistance as a serious threat to their own health (95.4%), and the health of their clients (89.4%). Practices favorable to the development of antibiotic resistance were very prevalent among the respondents. Majority of respondents (59.9%) consistently sell antibiotics to clients without doctor's prescription, and close to half of them (49.2%) consistently practice self medication. Conclusion: Despite high levels of knowledge of the causes, prevention, and perception of the risks associated with antibiotics resistance, practices favorable to its development were very prevalent among PMVs in Sokoto, Nigeria. Government should regulate and closely monitor PMVs' practices in order to avert the looming crisis in medical practice that will become inevitable if there are no potent antibiotics. PMID- 30417848 TI - Preliminary data on clinical performance of bulk-fill restorations in primary molars. AB - Context: In pediatric clinic practice, bulk fill composite is gaining importance for shortened clinical time with a limited shrinkage. Aims: The present study evaluated the 1 year clinical performance of bulk fill composite and conventional composite material in occlusal caries of primary molars. Settings and Design: The study was designed as randomized single blind clinical trial and a total of 160 restorations were placed in the cavities of the 80 patients. Materials and Methods: Each patient received two restorations: one with Filtek Z250 (3M ESPE, St Paul, MN 55144, USA); the other restored with Filtek Bulk-Fill Restorative (FBF) (3M ESPE, St Paul, MN, USA). All restorations were clinically evaluated after baseline, 6 months, and 1 year in terms of retention, color matching, marginal discoloration, marginal adaptation, secondary caries, surface texture, anatomic form, and postoperative sensitivity. Statistical Analysis Used: Besides the descriptive statistical methods, the Friedman test and the Wilcoxon Signed Ranks were used. Results: Bulk fill was found to be worse compared to control with regard to postoperative sensitivity at baseline without statistical significance (P > 0.05). All of the evaluated restorations were retained and were still in function after 1 year (P > 0.05). With respect to marginal discoloration and marginal integrity, there were no significant differences between bulk fill and composite restorations at all intervals (P > 0.05). Conclusions: Based on this short term data, restoration of Class I cavities with both bulk fill and conventional composite restorations can be performed successfully. Postoperative sensitivity can be an issue with the restorations completed with Bulk fill restorative. PMID- 30417849 TI - Anisakiasis: The risks of seafood consumption. AB - Context and Aims: Japanese cuisine is now popular worldwide, and consumption of raw fish has thus increased at sushi bars and Japanese restaurants outside Japan. Anisakiasis, also known as herring-worm disease, is caused by ingesting larval nematodes in raw seafood and is a common illness in Japan. However, due to the rising popularity of Japanese food, gastroenterologists outside Japan need to be familiar with this disease. Subjects and Methods and Results: We treated 158 patients presenting with acute gastrointestinal manifestations caused by anisakiasis from April 1991 to April 2000. One or more nematodes were removed endoscopically within 48 h of presentation in 44% of these patients, which resulted in prompt resolution of symptoms. Major endoscopic findings were gastric ulcer accompanied by hemorrhage, erosion, redness, and edema of the gastric mucosa in areas penetrated by larvae and other areas. Conclusions: Endoscopy was valuable for the diagnosis and treatment of anisakiasis. We recommend endoscopy in suspected cases of anisakiasis. Moreover, it is desirable to combine complementary tests such as immunological tests/IgE measurement. As the popularity of Japanese cuisine increases, reports of anisakiasis are likely to be more frequent in countries other than Japan. PMID- 30417851 TI - Comparison of three different ketofol proportions in children undergoing dental treatment. AB - Aim and Background: Sedation is gaining popularity among dental procedures in children. Ketamine and propofol mixture, known as ketofol, is one of the promising choices in sedation protocols; however, there is no consensus on the exact ratio of ketamine plus propofol especially in dental practice. The aim of present study was to compare perioperative side effect profiles, recovery profiles, and satisfaction rates of both parents' and dentists' following three different ratio of ketofol mixtures in children undergoing dental treatment. Materials and. Methods: Three study groups each containing 30 children scheduled for dental treatment were created. Following anesthesia induction with 5% sevoflurane, 50% nitrous oxide mixture in 50% oxygen, 1 mg/kg bolus ketofol dose was administered. Patients in Group 1 received ketofol as a 1:1 mixture, patients in Group 2 received 1:2 ketofol while in Group 3; 1:4 ketofol was administered at a constant dose of 100 MUg/kg/min. Additional doses of the ketofol solution at the same concentration with infused solutions in groups (0.5 mg/kg from either 1:1, 1:2, or 1:4 proportions) were administered if required. Perioperative vital signs, side effects, postoperative side effects, recovery durations, parents' and dentists' satisfaction levels were compared between groups. Results: There were no significant differences between groups in terms of perioperative vital signs and side effects. Depth of sedation, dentists' satisfaction levels and postoperative side effects -myoclonus, hypersalivation and tachycardia were significantly higher in Group 1. Parents' satisfaction was highest in Group 3, however, necessity of additional doses and dissatisfaction of dentists' were found highest in this group. Mean duration of recovery recorded in Group 3 was shortest compared with other groups. Conclusion: Decreased ketamine doses in ketofol mixture was related with decreased side effect profile, high parents' satisfaction with fast recovery, however, dentists' satisfaction was lower. In this context, results of present study indicated that ketofol mixture of 1:2 ratio was more reliable choice than others when all investigated parameters evaluated simultaneously. PMID- 30417850 TI - Radiographic features associated with temporomandibular joint disorders among African, White, Chinese, Hispanic, and Indian racial groups. AB - Context: Various radiographic features have been associated with temporomandibular joint disorders (TMDs); however, these characteristics have not been compared among different racial groups. Aims: To radiographically evaluate and compare craniofacial patterns and condylar findings suggestive of TMD among African, White, Chinese, Hispanic, and Indian racial groups. Settings and Design: This multicenter retrospective study used data from three private orthodontic practices and a University Orthodontic Clinic. Subjects and Methods: Panoramic and lateral cephalometric radiographs were collected from 250 subjects who were equally divided into five racial groups: Africans, Whites, Chinese, Hispanics, and Indians. All radiographs were initial records from patients seeking orthodontic treatment. Linear and angular cephalometric measurements were used to evaluate and compare cephalometric characteristics associated with TMD among groups. Panoramic radiographs were analyzed to compare the presence of condylar abnormalities and antegonial notching among groups. Statistical Analysis Used: One-way analysis of variance, followed by Tukey's test. Results: African and Chinese groups had the smallest mean cranial base measurements, while the Indians had the largest. The mean Y-axis value was significantly larger in the Chinese group compared with the other groups. Increased mandibular plane angles were seen in the Chinese and African patients, compared with subjects from other groups. The mean percentage of condylar anomalies was higher in the Chinese subjects compared with all other groups. Conclusions: Chinese patients presented with more radiographic features suggestive of TMD, whereas the Indians showed the least, compared with subjects from the White, Black, and Hispanic racial groups. PMID- 30417852 TI - Tubal sterilization during cesarean section at a training hospital in Turkey: A clinical and demographic analysis. AB - Background: The total fertility rate is 2.1 children per women in Turkey. The population is expected to increase to 84 million by 2023. Maternal (19/100,000 live births), infant, and child mortality rates (20/100,000 live births) are still higher than desired levels in Turkey. We investigated factors affecting the choice of tubal sterilization (TS) after cesarean sections (CSs) and determined intraoperative and short-term postoperative maternal effects of this procedure. Materials and Methods: We compared 1,849 CSs for demographic characteristics and clinical parameters including obstetric outcomes between two patient groups who underwent CSs with or without TS. Intraoperative and short-term postoperative maternal effects of TS in these patients were also evaluated. Results: Twenty-one percent of women underwent both CSs and TS. A significantly higher ratio of TS was found in women with low education levels who had obstetric risk/systemic disease in their present pregnancy. Apart from a hemoglobin deficit and slightly higher duration of hospital stay, TS did not influence postoperative wound infection or heavy bleeding pattern that requires reoperation. Conclusion: These findings conclude that in developing countries TS can safely be applicable as a contraceptive method without additional cost at time of CSs and should be considered as an option for those women who desire or would benefit from it. PMID- 30417853 TI - Evaluation of content and cost of traditional eye medication in a resource-poor country - Implications for eye care practice and policy. AB - Background: Cataract, glaucoma, and conjunctivitis are common causes of ocular morbidity in Nigeria. A major obstacle in reducing the burden of ocular morbidity in rural areas is access to eye care services. Up to 80% of the population in developing countries use traditional medications for their primary healthcare needs because they are accessible, available, and affordable. The aim of this study is to evaluate the content and cost of commercialized traditional medications used in the treatment of common eye conditions in Nigeria. Patients and Methods: All the registered traditional healers (THs) at an International Trade Fair in Enugu who treated eye problems were identified. Data on their location and scope of their practice were collected by the researchers. Proxy patients consulted THs in the trade fair with simulated cataract, glaucoma, and bacterial conjunctivitis, and treatment was sought. Medication for the treatment of the simulated disorders was paid for and procured. The mode of administration and the cost of the drugs were recorded by proxy patients. Each medication was labeled with a code and sent to the laboratories of the National Agency for Drug Administration and Control for analysis. Data were entered into a database on Microsoft Access and transferred to STATA V12.1 (StataCorp) for analysis. Results: Cataract was treated by 87.5% of all the traditional eye healers interviewed. A total of 32 samples were collected and analyzed. These comprised mainly oral (53.1%) and topical traditional medications (43.8%). The pH of the topical samples ranged from 3.5 to 10, while the mean microbiological load per topical solution was 3.3 * 104 cfu/mL +/- 0.96. The cost of treatment of cataract ranged from 4 to 70 USD. Conclusion: The content of the majority of the samples of traditional eye medications in this study had high extremes of pH and/or had a high microbial content. The practice of THs should be regulated. PMID- 30417854 TI - The distribution and pattern of neurological disease in a neurology clinic in Ile Ife, Nigeria. AB - Background: Neurological disorders are common and contribute significantly to disease burden, disability-adjusted life years and death. Objective: To assess the distribution of neurological disease in patients presenting to our hospital. Methods: The records of the Adult Neurology Clinic in Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Osun state, Nigeria were reviewed retrospectively for the years 2003-2005 and 2010-2014, and diagnoses as made by the Consultant were obtained and analyzed. Results: The total number of complaints was 1,524 and 86.4% of these were neurological in nature. Episodic and paroxysmal disorders (ICD-10) accounted for 54.1% of the diagnoses, and epilepsy and stroke were the most common of these. Of the 1,226 patients seen during the period, 91.4% had neurological disorders. The peak occurrence of these disorders was within the first three decades of life. Conclusion: Epilepsy and stroke are the commonest neurological disorders in the outpatient setting and there should be more studies in the community on their prevalence and impact. PMID- 30417855 TI - Perceived social support and depression levels of women in the postpartum period in Hatay, Turkey. AB - Objectives: Postpartum depression is one of the major problems affecting the mother and baby's health. Inadequate social support system may affect the occurrence of this problem. This study was performed to determine the depression and social support in women at the postpartum period. Materials and Methods: This study was designed as a cross-sectional study. The research was conducted in Narlica No. 2 family health center located in the city center of Hatay with 177 women who have given birth at least 2-4 months before and agreed to participate in the study. Edinburgh Postpartum Depression Scale (EPDS), Multidimensional Scale of Perceived Social Support (MSPSS), and Sociodemographic Information Form was utilized for data collection. Results: It was determined that women's scores of EPDS and MSPSS were affected by the variables of intended pregnancy and obtained support for infant care (P < 0.05). A significant negative correlation (P < 0.01) was found between MSPSS and EPDS scales. Conclusion: This study concludes that as social support levels increase there is a decrease at postpartum depression risk. It is recommended that planning of interventions should be in accordance with the factors affecting the social support and depression levels at women in the postpartum period. PMID- 30417856 TI - Diagnostic values of diffusion tensor parameters in 3 T breast magnetic resonance imaging: Differentiation of breast tumors from bilateral healthy breast parenchyma. AB - Purpose: Our aim is to search diagnostic value of diffusion tensor parameters in the breast cancer. Materials and Methods: We included 46 patients with contrast enhanced magnetic resonance imaging of the breast between the dates of July 2015 and December 2016. We measured fractional anisotropy (FA), apparent diffusion coefficient (ADC), relative anisotropy (RA) and volume ratio (VR) values of the malignant mass, ipsilateral and contralateral healthy breast parenchyma in each patient. Results: ADC and VR values of the malignant lesions were significantly lower than normal parenchyma (P < 0.01). FA values were statistically higher in masses than normal breast parenchyma (P < 0.05). RA values were statistically higher in the mass than ipsilateral breast parenchyma (P < 0.01) but not significantly different from in contralateral breast parenchyma (P > 0.05). Only ADC values were statistically lower in contralateral side than ipsilateral breast parenchyma (P < 0.05) other parameters showed no statistical significance between parenchymas. Conclusion: DTI findings, such as FA, ADC, RA and VR, provide significant contribution in differentiating cancer from healthy breast tissue. PMID- 30417857 TI - Comparison of serum concentration of Ca, P, Mg, and Fe between hemifacial spasm patients and healthy controls; prospective randomized controlled study. AB - Purpose: In this study, we aimed to measure the serum vitamin D level in hemifacial spasmic (HFS) patients and show the role of HFS in the pathogenesis and place in etiology. Materials and Methods: This study included 43 prospective newly diagnosed HFS patients and 43 healthy volunteers in the neurology clinic. The serum (Ca, P, Mg, Fe) concentration of 4 essential elements was measured with a biochemical device. The groups were correlated in terms of four essential element concentrations. The severity of the disease was measured using Lee's Quality of Life Scale and correlated with the concentration of four trace elements. The results were compared using the independent t-test and Mann-Whitney U-test. Results: Concentration of serum Ca, P, and Mg in the HFS patients was found to be lower in the control group which was statistically significant (P < 0.05). There was no statistically difference between the groups in terms of Fe concentration (P > 0.05). There was no significant correlation between trace element concentration and severity of illness and daily life quality in the patient group. Conclusion: These results show us the role of HFS in the pathogenesis of these four trace elements and the importance of its location in etiology. We think that changes in the concentration of trace elements in HFS can lead to demyelinization, which may lead to spasm. PMID- 30417858 TI - Extrusion of ventriculoperitoneal shunt cathether through a herniotomy wound in an infant: Case report and review of literature. AB - Cerebrospinal fluid (CSF) diversion through the insertion of ventriculoperitoneal shunt (VPS) is the standard treatment for hydrocephalus. Many complications have been reported following VPS insertion. A case of extrusion of a VPS through a herniotomy wound is reported in a 4-month old male infant, who had a herniotomy performed on him by a General Practitioner (GP) for scrotal swelling. The extruded VPS was first externalized to the chest to aid healing of the groin wound and maintain CSF diversion. Later the VPS was removed to aid sepsis control. Although the parents did not comply with follow up instructions following their request for discharge, the patient remained well during telephonic communication 7 weeks after discharge. The case demonstrated higher risk for abdominal complications in the setting of background spina bifida and presence of intraperitoneal catheter. The need for optimal management of such complications by appropriate specialists cannot be over emphasised. PMID- 30417859 TI - Heat Shock Protein 70 (HSP70) Reduces Hepatic Inflammatory and Oxidative Damage in a Rat Model of Liver Ischemia/Reperfusion Injury with Hyperbaric Oxygen Preconditioning. AB - BACKGROUND Several clinical conditions can cause hepatic ischemia/reperfusion (I/R) injury. This study aimed to determine the mechanism of the protective effect of hyperbaric oxygen preconditioning (HBO2P) on hepatic ischemia/reperfusion (I/R) injury in a rat model, and to investigate the effects on HBO2P and I/R injury of blocking HSP70 using antibody (Ab) pretreatment. MATERIAL AND METHODS Male Sprague-Dawley rats underwent HBO2P for 60 min at 2.0 atmosphere absolute (ATA) pressure for five consecutive days before surgical hepatic I/R injury, performed by clamping the portal vein and hepatic lobe. Four groups studied included: the non-HBO2P+ non-I/R group, which underwent sham surgery (N=10); the non-HBO2P + I/R group (N=10); the HBO2P + I/R group (N=10); and the HBO2P + HSP70-Ab + I/R group (N=10) received one dose of HSP70 antibody one day before hepatic I/R injury. Serum lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and hepatic malondialdehyde (MDA) and myeloperoxidase (MPO) were measured biochemically. Rat liver tissues were examined histologically. RESULTS In rats with hepatic I/R injury without HSP70 antibody pre-treatment, HBO2P significantly reduced hepatic injury and levels of LDH, AST, ALT, TNF-alpha, IL-6, MDA, and MPO levels; in comparison, the group pre-treated with an antibody to inhibit HSP70 (the HBO2P + HSP70-Ab + I/R group) showed significant reversal of the beneficial effects of HBO2P on hepatic I/R injury (p<0.05). CONCLUSIONS In a rat model of hepatic I/R injury with HBO2P, HSP70 reduced hepatic inflammatory and oxidative damage. PMID- 30417860 TI - Fabrication of Schottky Diodes on Zn-polar BeMgZnO/ZnO Heterostructure Grown by Plasma-assisted Molecular Beam Epitaxy. AB - Heterostructure field effect transistors (HFETs) utilizing a two dimensional electron gas (2DEG) channel have a great potential for high speed device applications. Zinc oxide (ZnO), a semiconductor with a wide bandgap (3.4 eV) and high electron saturation velocity has gained a great deal of attention as an attractive material for high speed devices. Efficient gate modulation, however, requires high-quality Schottky contacts on the barrier layer. In this article, we present our Schottky diode fabrication procedure on Zn-polar BeMgZnO/ZnO heterostructure with high density 2DEG which is achieved through strain modulation and incorporation of a few percent Be into the MgZnO-based barrier during growth by molecular beam epitaxy (MBE). To achieve high crystalline quality, nearly lattice-matched high-resistivity GaN templates grown by metal organic chemical vapor deposition (MOCVD) are used as the substrate for the subsequent MBE growth of the oxide layers. To obtain the requisite Zn-polarity, careful surface treatment of GaN templates and control over the VI/II ratio during the growth of low temperature ZnO nucleation layer are utilized. Ti/Au electrodes serve as Ohmic contacts, and Ag electrodes deposited on the O2 plasma pretreated BeMgZnO surface are used for Schottky contacts. PMID- 30417861 TI - Oleic Acid-Injection in Pigs As a Model for Acute Respiratory Distress Syndrome. AB - The acute respiratory distress syndrome is a relevant intensive care disease with an incidence ranging between 2.2% and 19% of intensive care unit patients. Despite treatment advances over the last decades, ARDS patients still suffer mortality rates between 35 and 40%. There is still a need for further research to improve the outcome of patients suffering from ARDS. One problem is that no single animal model can mimic the complex pathomechanism of the acute respiratory distress syndrome, but several models exist to study different parts of it. Oleic acid injection (OAI)-induced lung injury is a well-established model for studying ventilation strategies, lung mechanics and ventilation/perfusion distribution in animals. OAI leads to severely impaired gas exchange, deterioration of lung mechanics and disruption of the alveolo-capillary barrier. The disadvantage of this model is the controversial mechanistic relevance of this model and the necessity for central venous access, which is challenging especially in smaller animal models. In summary, OAI-induced lung injury leads to reproducible results in small and large animals and hence represents a well-suited model for studying ARDS. Nevertheless, further research is necessary to find a model that mimics all parts of ARDS and lacks the problems associated with the different models existing today. PMID- 30417862 TI - Integrate Imaging Flow Cytometry and Transcriptomic Profiling to Evaluate Altered Endocytic CD1d Trafficking. AB - Populational analyses of the morphological and functional alteration of endocytic proteins are challenging due to the demand of image capture at a single cell level and statistical image analysis at a populational level. To overcome this difficulty, we used imaging flow cytometry and transcriptomic profiling (RNA-seq) to determine altered subcellular localization of the cluster of differentiation 1d protein (CD1d) associated with impaired endocytic gene expression in human dendritic cells (DCs), which were exposed to the common lipophilic air pollutant benzo[a]pyrene. The colocalization of CD1d and endocytic marker Lamp1 proteins from thousands of cell images captured with imaging flow cytometry was analyzed using IDEAS and ImageJ-Fiji programs. Numerous cellular images with co-stained CD1d and Lamp1 proteins were visualized after gating on CD1d+Lamp1+ DCs using IDEAS. The enhanced CD1d and Lamp1 colocalization upon BaP exposure was further demonstrated using thresholded scatterplots, tested with Mander's coefficients for co-localized intensity, and plotted based on the percentage of co-localized areas using ImageJ-Fiji. Our data provide an advantageous instrumental and bioinformatic approach to measure protein colocalization at both single and populational cellular levels, supporting an impaired functional outcome of transcriptomic alteration in pollutant-exposed human DCs. PMID- 30417863 TI - A Combinatorial Single-cell Approach to Characterize the Molecular and Immunophenotypic Heterogeneity of Human Stem and Progenitor Populations. AB - Immunophenotypic characterization and molecular analysis have long been used to delineate heterogeneity and define distinct cell populations. FACS is inherently a single-cell assay, however prior to molecular analysis, the target cells are often prospectively isolated in bulk, thereby losing single-cell resolution. Single-cell gene expression analysis provides a means to understand molecular differences between individual cells in heterogeneous cell populations. In bulk cell analysis an overrepresentation of a distinct cell type results in biases and occlusions of signals from rare cells with biological importance. By utilizing FACS index sorting coupled to single-cell gene expression analysis, populations can be investigated without the loss of single-cell resolution while cells with intermediate cell surface marker expression are also captured, enabling evaluation of the relevance of continuous surface marker expression. Here, we describe an approach that combines single-cell reverse transcription quantitative PCR (RT-qPCR) and FACS index sorting to simultaneously characterize the molecular and immunophenotypic heterogeneity within cell populations. In contrast to single cell RNA sequencing methods, the use of qPCR with specific target amplification allows for robust measurements of low-abundance transcripts with fewer dropouts, while it is not confounded by issues related to cell-to-cell variations in read depth. Moreover, by directly index-sorting single-cells into lysis buffer this method, allows for cDNA synthesis and specific target pre-amplification to be performed in one step as well as for correlation of subsequently derived molecular signatures with cell surface marker expression. The described approach has been developed to investigate hematopoietic single-cells, but have also been used successfully on other cell types. In conclusion, the approach described herein allows for sensitive measurement of mRNA expression for a panel of pre selected genes with the possibility to develop protocols for subsequent prospective isolation of molecularly distinct subpopulations. PMID- 30417864 TI - Antigenic Liposomes for Generation of Disease-specific Antibodies. AB - Antibody responses provide critical protective immunity to a wide array of pathogens. There remains a high interest in generating robust antibodies for vaccination as well as understand how pathogenic antibody responses develop in allergies and autoimmune disease. Generating robust antigen-specific antibody responses is not always trivial. In mouse models, it often requires multiple rounds of immunizations with adjuvant that leads to a great deal of variability in the levels of induced antibodies. One example is in mouse models of peanut allergies where more robust and reproducible models that minimize mouse numbers and the use of adjuvant would be beneficial. Presented here is a highly reproducible mouse model of peanut allergy anaphylaxis. This new model relies on two key factors: (1) antigen-specific splenocytes are adoptively transferred from a peanut-sensitized mouse into a naive recipient mouse, normalizing the number of antigen-specific memory B- and T-cells across a large number of mice; and (2) recipient mice are subsequently boosted with a strong multivalent immunogen in the form of liposomal nanoparticles displaying the major peanut allergen (Ara h 2). The major advantage of this model is its reproducibility, which ultimately lowers the number of animals used in each study, while minimizing the number of animals receiving multiple injections of adjuvant. The modular assembly of these immunogenic liposomes provides relatively facile adaptability to other allergic or autoimmune models that involve pathogenic antibodies. PMID- 30417865 TI - Fabrication and Testing of Photonic Thermometers. AB - In recent years, a push for developing novel silicon photonic devices for telecommunications has generated a vast knowledge base that is now being leveraged for developing sophisticated photonic sensors. Silicon photonic sensors seek to exploit the strong confinement of light in nano-waveguides to transduce changes in physical state to changes in resonance frequency. In the case of thermometry, the thermo-optic coefficient, i.e., changes in refractive index due to temperature, causes the resonant frequency of the photonic device such as a Bragg grating to drift with temperature. We are developing a suite of photonic devices that leverage recent advances in telecom compatible light sources to fabricate cost-effective photonic temperature sensors, which can be deployed in a wide variety of settings ranging from controlled laboratory conditions, to the noisy environment of a factory floor or a residence. In this manuscript, we detail our protocol for the fabrication and testing of photonic thermometers. PMID- 30417866 TI - Apparatus for Harvesting Tissue Microcolumns. AB - This manuscript describes the production process for a laboratory apparatus, made from off-the-shelf components, that can be used to collect microcolumns of full thickness skin tissue. The small size of the microcolumns allows donor sites to heal quickly without causing donor site scarring, while harvesting full-thickness tissue enables the incorporation of all cellular and extracellular components of skin tissue, including those associated with deeper dermal regions and the adnexal skin structures, which have yet to be successfully reproduced using conventional tissue engineering techniques. The microcolumns can be applied directly into skin wounds to augment healing, or they can be used as the autologous cell/tissue source for other tissue engineering approaches. The harvesting needles are made by modifying standard hypodermic needles, and they can be used alone for harvesting small amounts of tissue or coupled with a simple suction-based collection system (also made from commonly available laboratory supplies) for high-volume harvesting to facilitate studies in large animal models. PMID- 30417868 TI - Automation of a Positron-emission Tomography (PET) Radiotracer Synthesis Protocol for Clinical Production. AB - The development of new positron-emission tomography (PET) tracers is enabling researchers and clinicians to image an increasingly wide array of biological targets and processes. However, the increasing number of different tracers creates challenges for their production at radiopharmacies. While historically it has been practical to dedicate a custom-configured radiosynthesizer and hot cell for the repeated production of each individual tracer, it is becoming necessary to change this workflow. Recent commercial radiosynthesizers based on disposable cassettes/kits for each tracer simplify the production of multiple tracers with one set of equipment by eliminating the need for custom tracer-specific modifications. Furthermore, some of these radiosynthesizers enable the operator to develop and optimize their own synthesis protocols in addition to purchasing commercially-available kits. In this protocol, we describe the general procedure for how the manual synthesis of a new PET tracer can be automated on one of these radiosynthesizers and validated for the production of clinical-grade tracers. As an example, we use the ELIXYS radiosynthesizer, a flexible cassette-based radiochemistry tool that can support both PET tracer development efforts, as well as routine clinical probe manufacturing on the same system, to produce [18F]Clofarabine ([18F]CFA), a PET tracer to measure in vivo deoxycytidine kinase (dCK) enzyme activity. Translating a manual synthesis involves breaking down the synthetic protocol into basic radiochemistry processes that are then translated into intuitive chemistry "unit operations" supported by the synthesizer software. These operations can then rapidly be converted into an automated synthesis program by assembling them using the drag-and-drop interface. After basic testing, the synthesis and purification procedure may require optimization to achieve the desired yield and purity. Once the desired performance is achieved, a validation of the synthesis is carried out to determine its suitability for the production of the radiotracer for clinical use. PMID- 30417867 TI - Efficient and Scalable Directed Differentiation of Clinically Compatible Corneal Limbal Epithelial Stem Cells from Human Pluripotent Stem Cells. AB - Corneal limbal epithelial stem cells (LESCs) are responsible for continuously renewing the corneal epithelium, and thus maintaining corneal homeostasis and visual clarity. Human pluripotent stem cell (hPSC)-derived LESCs provide a promising cell source for corneal cell replacement therapy. Undefined, xenogeneic culture and differentiation conditions cause variation in research results and impede the clinical translation of hPSC-derived therapeutics. This protocol provides a reproducible and efficient method for hPSC-LESC differentiation under xeno- and feeder cell-free conditions. Firstly, monolayer culture of undifferentiated hPSC on recombinant laminin-521 (LN-521) and defined hPSC medium serves as a foundation for robust production of high-quality starting material for differentiations. Secondly, a rapid and simple hPSC-LESC differentiation method yields LESC populations in only 24 days. This method includes a four-day surface ectodermal induction in suspension with small molecules, followed by adherent culture phase on LN-521/collagen IV combination matrix in defined corneal epithelial differentiation medium. Cryostoring and extended differentiation further purifies the cell population and enables banking of the cells in large quantities for cell therapy products. The resulting high-quality hPSC-LESCs provide a potential novel treatment strategy for corneal surface reconstruction to treat limbal stem cell deficiency (LSCD). PMID- 30417870 TI - Conducting Multiple Imaging Modes with One Fluorescence Microscope. AB - Fluorescence microscopy is a powerful tool to detect biological molecules in situ and monitor their dynamics and interactions in real-time. In addition to conventional epi-fluorescence microscopy, various imaging techniques have been developed to achieve specific experimental goals. Some of the widely used techniques include single-molecule fluorescence resonance energy transfer (smFRET), which can report conformational changes and molecular interactions with angstrom resolution, and single-molecule detection-based super-resolution (SR) imaging, which can enhance the spatial resolution approximately ten to twentyfold compared to diffraction-limited microscopy. Here we present a customer-designed integrated system, which merges multiple imaging methods in one microscope, including conventional epi-fluorescent imaging, single-molecule detection-based SR imaging, and multi-color single-molecule detection, including smFRET imaging. Different imaging methods can be achieved easily and reproducibly by switching optical elements. This set-up is easy to adopt by any research laboratory in biological sciences with a need for routine and diverse imaging experiments at a reduced cost and space relative to building separate microscopes for individual purposes. PMID- 30417871 TI - A Method to Study Adaptation to Left-Right Reversed Audition. AB - An unusual sensory space is one of the effective tools to uncover the mechanism of adaptability of humans to a novel environment. Although most of the previous studies have used special spectacles with prisms to achieve unusual spaces in the visual domain, a methodology for studying the adaptation to unusual auditory spaces has yet to be fully established. This study proposes a new protocol to set up, validate, and use a left-right reversed stereophonic system using only wearable devices, and to study the adaptation to left-right reversed audition with the help of neuroimaging. Although individual acoustic characteristics are not yet implemented, and slight spillover of unreversed sounds is relatively uncontrollable, the constructed apparatus shows high performance in a 360 degrees sound source localization coupled with hearing characteristics with little delay. Moreover, it looks like a mobile music player and enables a participant to focus on daily life without arousing curiosity or drawing attention of other individuals. Since the effects of adaptation were successfully detected at the perceptual, behavioral, and neural levels, it is concluded that this protocol provides a promising methodology for studying adaptation to left-right reversed audition, and is an effective tool for uncovering the adaptability of humans to a novel environments in the auditory domain. PMID- 30417869 TI - Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method. AB - Hepatocytes are parenchymal cells of the liver and engage multiple metabolic functions, including synthesis and secretion of proteins essential for systemic energy homeostasis. Primary hepatocytes isolated from the murine liver constitute a valuable biological tool to understand the functional properties or alterations occurring in the liver. Herein we describe a method for the isolation and culture of primary mouse hepatocytes by performing a two-step collagenase perfusion technique and discuss their utilization for investigating protein metabolism. The liver of an adult mouse is sequentially perfused with ethylene glycol-bis tetraacetic acid (EGTA) and collagenase, followed by the isolation of hepatocytes with the density gradient buffer. These isolated hepatocytes are viable on culture plates and maintain the majority of endowed characteristics of hepatocytes. These hepatocytes can be used for assessments of protein metabolism including nascent protein synthesis with non-radioactive reagents. We show that the isolated hepatocytes are readily controlled and comprise a higher quality and volume stability of protein synthesis linked to energy metabolism by utilizing the chemo-selective ligation reaction with a Tetramethylrhodamine (TAMRA) protein detection method and western blotting analyses. Therefore, this method is valuable for investigating hepatic nascent protein synthesis linked to energy homeostasis. The following protocol outlines the materials and methods for the isolation of high-quality primary mouse hepatocytes and detection of nascent protein synthesis. PMID- 30417872 TI - Analysis of Cancer Cell Invasion and Anti-metastatic Drug Screening Using Hydrogel Micro-chamber Array (HMCA)-based Plates. AB - Cancer metastasis is known to cause 90% of cancer lethality. Metastasis is a multistage process which initiates with the penetration/invasion of tumor cells into neighboring tissue. Thus, invasion is a crucial step in metastasis, making the invasion process research and development of anti-metastatic drugs, highly significant. To address this demand, there is a need to develop 3D in vitro models which imitate the architecture of solid tumors and their microenvironment most closely to in vivo state on one hand, but at the same time be reproducible, robust and suitable for high yield and high content measurements. Currently, most invasion assays lean on sophisticated microfluidic technologies which are adequate for research but not for high volume drug screening. Other assays using plate-based devices with isolated individual spheroids in each well are material consuming and have low sample size per condition. The goal of the current protocol is to provide a simple and reproducible biomimetic 3D cell-based system for the analysis of invasion capacity in large populations of tumor spheroids. We developed a 3D model for invasion assay based on HMCA imaging plate for the research of tumor invasion and anti-metastatic drug discovery. This device enables the production of numerous uniform spheroids per well (high sample size per condition) surrounded by ECM components, while continuously and simultaneously observing and measuring the spheroids at single-element resolution for medium throughput screening of anti-metastatic drugs. This platform is presented here by the production of HeLa and MCF7 spheroids for exemplifying single cell and collective invasion. We compare the influence of the ECM component hyaluronic acid (HA) on the invasive capacity of collagen surrounding HeLa spheroids. Finally, we introduce Fisetin (invasion inhibitor) to HeLa spheroids and nitric oxide (NO) (invasion activator) to MCF7 spheroids. The results are analyzed by in-house software which enables semi-automatic, simple and fast analysis which facilitates multi-parameter examination. PMID- 30417873 TI - Functional Surface-immobilization of Genes Using Multistep Strand Displacement Lithography. AB - Immobilization of genes on lithographically structured surfaces allows the study of compartmentalized gene expression processes in an open microfluidic bioreactor system. In contrast to other approaches towards artificial cellular systems, such a setup allows for a continuous supply with gene expression reagents and simultaneous draining of waste products. This facilitates the implementation of cell-free gene expression processes over extended periods of time, which is important for the realization of dynamic gene regulatory feedback systems. Here we provide a detailed protocol for the fabrication of genetic biochips using a simple-to-use lithographic technique based on DNA strand displacement reactions, which exclusively uses commercially available components. We also provide a protocol on the integration of compartmentalized genes with a polydimethylsiloxane (PDMS)-based microfluidic system. Furthermore, we show that the system is compatible with total internal reflection fluorescence (TIRF) microscopy, which can be used for the direct observation of molecular interactions between DNA and molecules contained in the expression mix. PMID- 30417874 TI - High-resolution Patterned Biofilm Deposition Using pDawn-Ag43. AB - Spatial structure and patterning play an important role in bacterial biofilms. Here we demonstrate an accessible method for culturing E. coli biofilms into arbitrary spatial patterns at high spatial resolution. The technique uses a genetically encoded optogenetic construct-pDawn-Ag43-that couples biofilm formation in E. coli to optical stimulation by blue light. We detail the process for transforming E. coli with pDawn-Ag43, preparing the required optical set-up, and the protocol for culturing patterned biofilms using pDawn-Ag43 bacteria. Using this protocol, biofilms with a spatial resolution below 25 MUm can be patterned on various surfaces and environments, including enclosed chambers, without requiring microfabrication, clean-room facilities, or surface pretreatment. The technique is convenient and appropriate for use in applications that investigate the effect of biofilm structure, providing tunable control over biofilm patterning. More broadly, it also has potential applications in biomaterials, education, and bio-art. PMID- 30417875 TI - High-throughput Measurement of Gut Transit Time Using Larval Zebrafish. AB - Zebrafish are used as alternative model organisms for drug safety testing. The gastrointestinal (GI) tract of zebrafish has genetic, neuronal, and pharmacological similarities to that of the mammals. GI intolerance during clinical testing of drug candidates is common and may pose a serious threat to human health. Testing for GI toxicity in preclinical mammalian models can be expensive in terms of time, test compound, and labor. The high-throughput method presented here may be used to predict GI safety issues. Compared to mammalian models, this method allows for more expedient assessment of test compound effects on GI transit while using low quantities of compound. In this method, larval zebrafish (7 days post fertilization) are fed food containing a fluorescent label. After feeding, each larval fish is placed into a well of a 96-conical bottom-well plate and dosed with test compound (dissolved in water) or the vehicle. As gut transit occurs, fecal matter accumulates on the bottom of the wells, and the rate at which this happens is monitored by measuring fluorescence from the bottom of the well repeatedly over time using a plate spectrophotometer. The fluorescence from larvae in a given treatment group are averaged and these values are graphed along with standard error, for each measurement time, yielding a curve representing average transit of food over time. Effects on gut transit time are identified by comparing the area under the curve for each treatment group to that of the vehicle-treated group. This method detected changes in zebrafish GI transit time induced by drugs with known clinical GI effects; it can be employed to interrogate dozens of treatments for GI effects per day. As such, safer compounds can be quickly prioritized for mammalian testing, which expedites discovery and proffers 3Rs advancement. PMID- 30417876 TI - Molten-Salt Synthesis of Complex Metal Oxide Nanoparticles. AB - The development of feasible synthesis methods is critical for the successful exploration of novel properties and potential applications of nanomaterials. Here, we introduce the molten-salt synthesis (MSS) method for making metal oxide nanomaterials. Advantages over other methods include its simplicity, greenness, reliability, scalability, and generalizability. Using pyrochlore lanthanum hafnium oxide (La2Hf2O7) as a representative, we describe the MSS protocol for the successful synthesis of complex metal oxide nanoparticles (NPs). Furthermore, this method has the unique ability to produce NPs with different material features by changing various synthesis parameters such as pH, temperature, duration, and post-annealing. By fine-tuning these parameters, we are able to synthesize highly uniform, non-agglomerated, and highly crystalline NPs. As a specific example, we vary the particle size of the La2Hf2O7 NPs by changing the concentration of the ammonium hydroxide solution used in the MSS process, which allows us to further explore the effect of particle size on various properties. It is expected that the MSS method will become a more popular synthesis method for nanomaterials and more widely employed in the nanoscience and nanotechnology community in the upcoming years. PMID- 30417877 TI - A Loop-mediated Isothermal Amplification (LAMP) Assay for Rapid Identification of Bemisia tabaci. AB - The whitefly Bemisia tabaci (Gennadius) is an invasive pest of considerable importance, affecting the production of vegetable and ornamental crops in many countries around the world. Severe yield losses are caused by direct feeding, and even more importantly, also by the transmission of more than 100 harmful plant pathogenic viruses. As for other invasive pests, increased international trade facilitates the dispersal of B. tabaci to areas beyond its native range. Inspections of plant import products at points of entry such as seaports and airports are, therefore, seen as an important prevention measure. However, this last line of defense against pest invasions is only effective if rapid identification methods for suspicious insect specimens are readily available. Because the morphological differentiation between the regulated B. tabaci and close relatives without quarantine status is difficult for non-taxonomists, a rapid molecular identification assay based on the loop-mediated isothermal amplification (LAMP) technology has been developed. This publication reports the detailed protocol of the novel assay describing rapid DNA extraction, set-up of the LAMP reaction, as well as interpretation of its read-out, which allows identifying B. tabaci specimens within one hour. Compared to existing protocols for the detection of specific B. tabaci biotypes, the developed method targets the whole B. tabaci species complex in one assay. Moreover the assay is designed to be applied on-site by plant health inspectors with minimal laboratory training directly at points of entry. Thorough validation performed under laboratory and on-site conditions demonstrates that the reported LAMP assay is a rapid and reliable identification tool, improving the management of B. tabaci. PMID- 30417878 TI - An Experimental Protocol for Femtosecond NIR/UV - XUV Pump-Probe Experiments with Free-Electron Lasers. AB - This protocol describes key steps in performing and analyzing femtosecond pump probe experiments that combine a femtosecond optical laser with a free-electron laser. This includes methods to establish the spatial and temporal overlap between the optical and free-electron laser pulses during the experiment, as well as important aspects of the data analysis, such as corrections for arrival time jitter, which are necessary to obtain high-quality pump-probe data sets with the best possible temporal resolution. These methods are demonstrated for an exemplary experiment performed at the FLASH (Free-electron LASer Hamburg) free electron laser in order to study ultrafast photochemistry in gas-phase molecules by means of velocity map ion imaging. However, most of the strategies are also applicable to similar pump-probe experiments using other targets or other experimental techniques. PMID- 30417879 TI - Single-cell RNA Sequencing of Fluorescently Labeled Mouse Neurons Using Manual Sorting and Double In Vitro Transcription with Absolute Counts Sequencing (DIVA Seq). AB - Single-cell RNA sequencing (RNA-seq) is now a widely implemented tool for assaying gene expression. Commercially available single-cell RNA-sequencing platforms process all input cells indiscriminately. Sometimes, fluorescence activated cell sorting (FACS) is used upstream to isolate a specifically labeled population of interest. A limitation of FACS is the need for high numbers of input cells with significantly labeled fractions, which is impractical for collecting and profiling rare or sparsely labeled neuron populations from the mouse brain. Here, we describe a method for manually collecting sparse fluorescently labeled single neurons from freshly dissociated mouse brain tissue. This process allows for capturing single-labeled neurons with high purity and subsequent integration with an in vitro transcription-based amplification protocol that preserves endogenous transcript ratios. We describe a double linear amplification method that uses unique molecule identifiers (UMIs) to generate individual mRNA counts. Two rounds of amplification results in a high degree of gene detection per single cell. PMID- 30417880 TI - A Plate Competition Assay As a Quick Preliminary Assessment of Disease Suppression. AB - The goal was to develop and optimize a simple, affordable, and effective bioassay to detect disease suppressive ability of a specific compost against soilborne fungus Rhizoctonia solani. R. solani is a pathogen of a wide range of plant hosts worldwide. The fungus survives in soils as a saprophyte and grows rapidly on simple water agar media. The plate assay is a rapid method to compare composts for their ability to slow the growth of R. solani. The assay also correlates well with suppression of other soilborne fungal pathogens that survive as saprophytes in soils such as Alternaria early blights, Fusarium wilt, Phytophthora root rot, and Pythium root rot. PMID- 30417881 TI - Combined Genetic and Chemical Capsid Modifications of Adenovirus-Based Gene Transfer Vectors for Shielding and Targeting. AB - Adenovirus vectors are potent tools for genetic vaccination and oncolytic virotherapy. However, they are prone to multiple undesired vector-host interactions, especially after in vivo delivery. It is a consensus that the limitations imposed by undesired vector-host interactions can only be overcome if defined modifications of the vector surface are performed. These modifications include shielding of the particles from unwanted interactions and targeting by the introduction of new ligands. The goal of the protocol presented here is to enable the reader to generate shielded and, if desired, retargeted human adenovirus gene transfer vectors or oncolytic viruses. The protocol will enable researchers to modify the surface of adenovirus vector capsids by specific chemical attachment of synthetic polymers, carbohydrates, lipids, or other biological or chemical moieties. It describes the cutting-edge technology of combined genetic and chemical capsid modifications, which have been shown to facilitate the understanding and overcoming of barriers for in vivo delivery of adenovirus vectors. A detailed and commented description of the crucial steps for performing specific chemical reactions with biologically active viruses or virus derived vectors is provided. The technology described in the protocol is based on the genetic introduction of (naturally absent) cysteine residues into solvent exposed loops of adenovirus-derived vectors. These cysteine residues provide a specific chemical reactivity that can, after production of the vectors to high titers, be exploited for highly specific and efficient covalent chemical coupling of molecules from a wide variety of substance classes to the vector particles. Importantly, this protocol can easily be adapted to perform a broad variety of different (non-thiol-based) chemical modifications of adenovirus vector capsids. Finally, it is likely that non-enveloped virus-based gene transfer vectors other than adenovirus can be modified from the basis of this protocol. PMID- 30417882 TI - A Rat Methyl-Seq Platform to Identify Epigenetic Changes Associated with Stress Exposure. AB - As genomes of a wider variety of animals become available, there is an increasing need for tools that can capture dynamic epigenetic changes in these animal models. The rat is one particular model animal where an epigenetic tool can complement many pharmacological and behavioral studies to provide insightful mechanistic information. To this end, we adapted the SureSelect Target Capture System (referred to as Methyl-Seq) for the rat, which can assess DNA methylation levels across the rat genome. The rat design targeted promoters, CpG islands, island shores, and GC-rich regions from all RefSeq genes. To implement the platform on a rat experiment, male Sprague Dawley rats were exposed to chronic variable stress for 3 weeks, after which blood samples were collected for genomic DNA extraction. Methyl-Seq libraries were constructed from the rat DNA samples by shearing, adapter ligation, target enrichment, bisulfite conversion, and multiplexing. Libraries were sequenced on a next-generation sequencing platform and the sequenced reads were analyzed to identify DMRs between DNA of stressed and unstressed rats. Top candidate DMRs were independently validated by bisulfite pyrosequencing to confirm the robustness of the platform. Results demonstrate that the rat Methyl-Seq platform is a useful epigenetic tool that can capture methylation changes induced by exposure to stress. PMID- 30417883 TI - Manipulating Living Cells to Construct Stable 3D Cellular Assembly Without Artificial Scaffold. AB - Regenerative medicine and tissue engineering offer several advantages for the treatment of intractable diseases, and several studies have demonstrated the importance of 3-dimensional (3D) cellular assemblies in these fields. Artificial scaffolds have often been used to construct 3D cellular assemblies. However, the scaffolds used to construct cellular assemblies are sometimes toxic and may change the properties of the cells. Thus, it would be beneficial to establish a non-toxic method for facilitating cell-cell contact. In this paper, we introduce a novel method for constructing stable cellular assemblies by using optical tweezers with dextran. One of the advantages of this method is that it establishes stable cell-to-cell contact within a few minutes. This new method allows the construction of 3D cellular assemblies in a natural hydrophilic polymer and is expected to be useful for constructing next-generation 3D single cell assemblies in the fields of regenerative medicine and tissue engineering. PMID- 30417884 TI - Quantitative Analysis by Thermogravimetry-Mass Spectrum Analysis for Reactions with Evolved Gases. AB - During energy conversion, material production, and metallurgy processes, reactions often have the features of unsteadiness, multistep, and multi intermediates. Thermogravimetry-mass spectrum (TG-MS) is seen as a powerful tool to study reaction features. However, reaction details and reaction mechanics have not been effectively obtained directly from the ion current of TG-MS. Here, we provide a method of an equivalent characteristic spectrum analysis (ECSA) for analyzing the mass spectrum and giving the mass flow rate of reaction gases as precise as possible. The ECSA can effectively separate overlapping ion peaks and then eliminate the mass discrimination and temperature-dependent effect. Two example experiments are presented: (1) the decomposition of CaCO3 with evolved gas of CO2 and the decomposition of hydromagnesite with evolved gas of CO2 and H2O, to evaluate the ECSA on single-component system measurement and (2) the thermal pyrolysis of Zhundong coal with evolved gases of inorganic gases CO, H2, and CO2, and organic gases C2H4, C2H6, C3H8, C6H14, etc., to evaluate the ECSA on multi-component system measurement. Based on the successful calibration of the characteristic spectrum and relative sensitivity of specific gas and the ECSA on mass spectrum, we demonstrate that the ECSA accurately gives the mass flow rates of each evolved gas, including organic or inorganic gases, for not only single but multi-component reactions, which cannot be implemented by the traditional measurements. PMID- 30417886 TI - Visualization of Tangential Cell Migration in the Developing Chick Optic Tectum. AB - Time-lapse imaging is a powerful method to analyze migrating cell behavior. After fluorescent cell labeling, the movement of the labeled cells in culture can be recorded under video microscopy. For analyzing cell migration in the developing brain, slice culture is commonly used to observe cell migration parallel to the slice section, such as radial cell migration. However, limited information can be obtained from the slice culture method to analyze cell migration perpendicular to the slice section, such as tangential cell migration. Here, we present the protocols for time-lapse imaging to visualize tangential cell migration in the developing chick optic tectum. A combination of cell labeling by electroporation in ovo and a subsequent flat-mount culture on the cell culture insert enables detection of migrating cell movement in the horizontal plane. Moreover, our method facilitates detection of both individual cell behavior and the collective action of a group of cells in the long term. This method can potentially be applied to detect the sequential change of the fluorescent-labeled micro structure, including the axonal elongation in the neural tissue or cell displacement in the non-neural tissue. PMID- 30417887 TI - Veno-Venous Extracorporeal Membrane Oxygenation in a Mouse. AB - The use of extracorporeal membrane oxygenation (ECMO) has increased substantially in recent years. ECMO has become a reliable and effective therapy for acute as well as end-stage lung diseases. With the increase in clinical demand and prolonged use of ECMO, procedural optimization and prevention of multi-organ damage are of critical importance. The aim of this protocol is to present a detailed technique of veno-venous ECMO in a non-intubated, spontaneously breathing mouse. This protocol demonstrates the technical design of the ECMO and surgical steps. This murine ECMO model will facilitate the study of pathophysiology related to ECMO (e.g., inflammation,bleeding and thromboembolic events). Due to the abundance of genetically modified mice, the molecular mechanisms involved in ECMO-related complications can also be dissected. PMID- 30417888 TI - Large-scale Top-down Proteomics Using Capillary Zone Electrophoresis Tandem Mass Spectrometry. AB - Capillary zone electrophoresis-electrospray ionization-tandem mass spectrometry (CZE-ESI-MS/MS) has been recognized as a useful tool for top-down proteomics that aims to characterize proteoforms in complex proteomes. However, the application of CZE-MS/MS for large-scale top-down proteomics has been impeded by the low sample-loading capacity and narrow separation window of CZE. Here, a protocol is described using CZE-MS/MS with a microliter-scale sample-loading volume and a 90 min separation window for large-scale top-down proteomics. The CZE-MS/MS platform is based on a linear polyacrylamide (LPA)-coated separation capillary with extremely low electroosmotic flow, a dynamic pH-junction-based online sample concentration method with a high efficiency for protein stacking, an electro kinetically pumped sheath flow CE-MS interface with extremely high sensitivity, and an ion trap mass spectrometer with high mass resolution and scan speed. The platform can be used for the high-resolution characterization of simple intact protein samples and the large-scale characterization of proteoforms in various complex proteomes. As an example, a highly efficient separation of a standard protein mixture and a highly sensitive detection of many impurities using the platform is demonstrated. As another example, this platform can produce over 500 proteoform and 190 protein identifications from an Escherichia coli proteome in a single CZE-MS/MS run. PMID- 30417889 TI - Quasi-metagenomic Analysis of Salmonella from Food and Environmental Samples. AB - Quasi-metagenomics sequencing refers to the sequencing-based analysis of modified microbiomes of food and environmental samples. In this protocol, microbiome modification is designed to concentrate genomic DNA of a target foodborne pathogen contaminant to facilitate the detection and subtyping of the pathogen in a single workflow. Here, we explain and demonstrate the sample preparation steps for the quasi-metagenomics analysis of Salmonella enterica from representative food and environmental samples including alfalfa sprouts, ground black pepper, ground beef, chicken breast and environmental swabs. Samples are first subjected to the culture enrichment of Salmonella for a shortened and adjustable duration (4-24 h). Salmonella cells are then selectively captured from the enrichment culture by immunomagnetic separation (IMS). Finally, multiple displacement amplification (MDA) is performed to amplify DNA from IMS-captured cells. The DNA output of this protocol can be sequenced by high throughput sequencing platforms. An optional quantitative PCR analysis can be performed to replace sequencing for Salmonella detection or assess the concentration of Salmonella DNA before sequencing. PMID- 30417885 TI - The Unpredictable Chronic Mild Stress Protocol for Inducing Anhedonia in Mice. AB - Depression is a highly prevalent and debilitating condition, only partially addressed by current pharmacotherapies. The lack of response to treatment by many patients prompts the need to develop new therapeutic alternatives and to better understand the etiology of the disorder. Pre-clinical models with translational merits are rudimentary for this task. Here we present a protocol for the unpredictable chronic mild stress (UCMS) method in mice. In this protocol, adolescent mice are chronically exposed to interchanging unpredictable mild stressors. Resembling the pathogenesis of depression in humans, stress exposure during the sensitive period of mice adolescence instigates a depressive-like phenotype evident in adulthood. UCMS can be used for screenings of antidepressants on the variety of depressive-like behaviors and neuromolecular indices. Among the more prominent tests to assess depressive-like behavior in rodents is the sucrose preference test (SPT), which reflects anhedonia (core symptom of depression). The SPT will also be presented in this protocol. The ability of UCMS to induce anhedonia, instigate long-term behavioral deficits and enable reversal of these deficits via chronic (but not acute) treatment with antidepressants strengthens the protocol's validity compared to other animal protocols for inducing depressive-like behaviors. PMID- 30417890 TI - Using Clicker Training and Social Observation to Teach Rats to Voluntarily Change Cages. AB - Cage cleaning is a routinely performed husbandry procedure and is known to induce stress in laboratory rats. As stress can have a negative impact on well-being and can affect the comparability and reproducibility of research results, the amount of stress experienced by laboratory animals should be minimized and avoided when possible. Further, the direct contact between the rat and animal caretaker during the cage change bears hygiene risks and therefore possibly negatively impacts the well-being of the rats and the quality of the research. Our protocol aims to improve the routinely performed cage changing procedure. For this reason, we present a feasible protocol that enables rats to learn via clicker training and observation to voluntarily change to a clean cage. This training helps to reduce stress caused by the physical disturbance and handling associated with the cage changes and concurrently enables a reduction in direct contact between animal and animal caretaker after the training phase is completed. The implementation of clicker training to rats is fast and easy. Rats are generally interested in the training and efficiently learn the desired behavior, which entails changing cages through a pipe. Even without training, the rats learn to perform the desired behavior by observation, as 80% of the observational learning group successfully changed cages when tested. The training further helps to establish a relationship of trust between trainer and animal. As hygiene and well-being are both very important in animal experiments, this protocol might also help to improve high quality research. PMID- 30417891 TI - Morphology-Based Distinction Between Healthy and Pathological Cells Utilizing Fourier Transforms and Self-Organizing Maps. AB - The appearance and the movements of immune cells are driven by their environment. As a reaction to a pathogen invasion, the immune cells are recruited to the site of inflammation and are activated to prevent a further spreading of the invasion. This is also reflected by changes in the behavior and the morphological appearance of the immune cells. In cancerous tissue, similar morphokinetic changes have been observed in the behavior of microglial cells: intra-tumoral microglia have less complex 3-dimensional shapes, having less-branched cellular processes, and move more rapidly than those in healthy tissue. The examination of such morphokinetic properties requires complex 3D microscopy techniques, which can be extremely challenging when executed longitudinally. Therefore, the recording of a static 3D shape of a cell is much simpler, because this does not require intravital measurements and can be performed on excised tissue as well. However, it is essential to possess analysis tools that allow the fast and precise description of the 3D shapes and allows the diagnostic classification of healthy and pathogenic tissue samples based solely on static, shape-related information. Here, we present a toolkit that analyzes the discrete Fourier components of the outline of a set of 2D projections of the 3D cell surfaces via Self-Organizing Maps. The application of artificial intelligence methods allows our framework to learn about various cell shapes as it is applied to more and more tissue samples, whilst the workflow remains simple. PMID- 30417893 TI - Guest Editorial: Is your study reproducible? What "light" are you delivering to your specimens? PMID- 30417892 TI - In Vitro Method to Control Concentrations of Halogenated Gases in Cultured Alveolar Epithelial Cells. AB - Acute respiratory distress syndrome (ARDS) is a syndrome of diffuse alveolar injury with impaired alveolar fluid clearance and severe inflammation. The use of halogenated agents, such as sevoflurane or isoflurane, for the sedation of intensive care unit (ICU) patients can improve gas exchange, reduce alveolar edema, and attenuate inflammation during ARDS. However, data on the use of inhaled agents for continuous sedation in the ICU to treat or prevent lung damage is lacking. To study the effects of halogenated agents on alveolar epithelial cells under "physiologic" conditions, we describe an easy system to culture cells at the air-liquid interface and expose them to halogenated agents to provide precise controlled "air" fractions and "medium" concentrations for these agents. We developed a sealed air-tight chamber in which plates with human alveolar epithelial immortalized cells could be exposed to a precise, controlled fraction of sevoflurane or isoflurane using a continuous gas flow provided by an anesthetic machine circuit. Cells were exposed to 4% of sevoflurane and 1% of isoflurane for 24 hours. Gas mass spectrometry was performed to determine the concentration of halogenated agents dissolved in the medium. After the first hour, the concentrations of sevoflurane and isoflurane in the medium were 251 mg/L and 25 mg/L, respectively. The curves representing the concentrations of both sevoflurane and isoflurane dissolved in the medium showed similar courses over time, with a plateau reached at one hour after exposure. This protocol was specifically designed to reach precise and controlled concentrations of sevoflurane or isoflurane in vitro to improve our understanding of mechanisms involved in epithelial lung injury during ARDS and to test novel therapies for the syndrome. PMID- 30417894 TI - The Influence of Ceramic Re-pressing on Surface Properties, Bond Strength, and Color Stability of Leucite Ceramic. AB - PURPOSE: To evaluate the influence of recycling a pressed ceramic material on surface properties, color stability and bond strength to composite cement. MATERIALS AND METHODS: Forty-eight (48) ingots from a heat-pressed ceramic (PM9, Vita Zahnfabrik) were fabricated through the lost-wax technique and then polished with SiC sandpaper to standardize the dimensions (diameter: 12 mm; length: 4 mm). Leftover material from processing the pressed groups was retrieved and used to repeat heat pressing for the re-pressed groups. The ingots were randomly divided into 3 groups according to the number of injections - one, two, or three times. Ra, Rz, and RSm surface roughness parameters were evaluated through a contact rugosimeter. Topography was analyzed using SEM and the chemical constituents using EDS (energy dispersive spectroscopy). Color stability was evaluated according to CIE-Lab parameters to determine color variation (?E). Composite ingots with the same dimensions were cemented over each ceramic, then this set was cut into sticks with a 1-mm2 cross-sectional area. Half of the sticks were submitted to microtensile bond strength (uTBS) testing after 24 h. The other half was tested after thermocycling (5000 cycles, 5 degrees C-55 degrees C) and storage in water at 37 degrees C for 6 months. RESULTS: One-way ANOVA showed that the number of injections influenced both Rz and RSm roughness parameters (p = 0.00), but not Ra (p = 0.97). One injection exhibited higher (Rz) and grooves with less space between them (RSm) compared to the other groups. For color stability, the values of L*, a*, and b* were influenced by the number of injections (p = 0.00). ?E = 5 was found for 2 injections and ?E = 3 for 3 injections, using a control group as reference. One-way ANOVA showed that the number of injections significantly influenced wettability values: 1inj (63 +/- 5.3)A > 2inj (49 +/- 8.2)B > 3inj (45.8 +/- 15.8)B. However, the evaluated factor did not influence the bond strength of non-aged groups. Furthermore, aged groups showed that 1inj (21 +/- 37)a presented higher mean values than 2inj (10 +/- 8)b or 3inj (12 +/- 10.)b. CONCLUSION: Re-pressing the evaluated ceramic improves roughness and wettability, but compromises the color stability and decreases bond strengths after long-term aging. PMID- 30417895 TI - EDTA Conditioning Increases the Long-term Microtensile Bond Strength to Sclerotic Dentin Mediated by Self-etch Adhesives. AB - PURPOSE: To evaluate the immediate and 12-month microtensile bond strength (MUTBS) of two self-etch adhesives on sclerotic dentin with or without previous EDTA conditioning. The conditioning pattern and the relative area of open dentinal tubules were also evaluated. MATERIALS AND METHODS: Twenty-eight bovine incisors with naturally exposed sclerotic dentin were used. For MUTBS testing, 20 teeth were divided into 4 groups (n = 5) according to the combination of the main factors: 1. adhesive (Clearfil SE Bond [CSE, Kuraray] and Adper SE Plus [ADSE, 3M Oral Care]); 2. surface treatment (previous conditioning with EDTA and previous conditioning with distilled water [DW]). The sclerotic surfaces were conditioned with either 17% EDTA or DW for 2 min prior to adhesive application. Composite buildups were constructed. Specimens were sectioned to obtain composite-dentin sticks (0.8 mm2) to be tested immediately or after 12 months (distilled water at 37 degrees C) in tensile mode (0.5 mm/min). The conditioning pattern and the relative area of open dentinal tubules (OT) were evaluated in the remaining eight teeth. After adhesive application, the surfaces were rinsed off with acetone and ethanol. Then the surface was evaluated by SEM with image software. Data from MUTBS and OT were submitted to three-way repeated measures ANOVA and data from OT were submitted to one-way repeated measures ANOVA. After, for both tests, Tukey's post-hoc test was applied (alpha = 0.05). RESULTS: For both adhesives, EDTA resulted in the highest mean immediate MUTBS (p = 0.002), which remained stable after 12 months of water storage (p < 0.38). CSE showed higher MUTBS when compared to ADSE (p = 0.001). Degradation of the mean MUTBS was observed for both adhesives only in the DW groups. Adhesive application plus with EDTA conditioning increased the OT area in comparison with only adhesive application (p < 0.001). CONCLUSION: EDTA conditioning increased the immediate microtensile bond strength in sclerotic dentin substrate and prevented degradation when associated with a self-etch adhesive. PMID- 30417896 TI - Effects of Selective Phosphoric Acid Etching on Enamel Using "No-wait" Self etching Adhesives. AB - PURPOSE: To evaluate the effect of selective phosphoric acid etching on enamel using "no-wait" self-etching adhesives. MATERIALS AND METHODS: Clearfil Universal Bond Quick (UBQ, Kuraray Noritake) or G-Premio BOND (GPB, GC) was applied to ground human enamel surfaces. The adhesives were used in 3 modes: no-waiting self etching mode (UBQ-0 or GPB-0), 10-s self-etching mode (UBQ-10 or GPB-10), and the selective-etch mode with phosphoric acid etching (UBQ-PA or GPB-PA). After an acid-base challenge, the morphological attributes of the interface were examined using scanning electron microscopy (SEM) to characterize the acid-base resistant zone (ABRZ). Microshear bond strength (uSBS) testing to enamel and ultimate tensile strength (UTS) of the adhesive resin were carried out. RESULTS: ABRZ formation was confirmed in all groups. UBQ-PA and GPB-PA created thicker ABRZ with no funnel-shaped erosion beneath the adhesive-enamel interface. uSBS of UBQ PA was significantly higher than UBQ-0 and UBQ-10 (p < 0.05). However, there were no statistically signficant differences in uSBS among GPB-0, GPB-10, and GPB-PA. For the UTS, UBQ was significantly higher than GPB. CONCLUSION: Selective phosphoric acid etching created a stable adhesive-enamel interface. The no waiting self-etching concept adhesive led to a thinner ABRZ. The results of uSBS suggest that phosphoric acid etching effects on enamel are material dependent. PMID- 30417897 TI - Adhesion at 360 degrees - bond for less invasive dentistry. PMID- 30417898 TI - Size-controlled and water-soluble gold nanoparticles using UV-induced ligand exchange and phase transfer. AB - Oleylamine-capped gold nanoparticles (AuNPs) with sizes ranging from 5 to 13 nm and narrow size distributions (<10%) are synthesized by using a seeded growth approach. Water-solubility is achieved by using a UV-induced ligand exchange approach, resulting in transfer from the organic to an aqueous phase. PMID- 30417899 TI - Synergistic plasma-assisted electrochemical reduction of nitrogen to ammonia. AB - A nitrogen plasma was incorporated into the cathode side of an electrolyzer to provide energetically activated N2 species to the electrocatalyst surface. At an applied bias of ~3.5 V across the electrolyzer, plasma-assisted operation was observed to produce 47% more ammonia than the combination of plasma-without-bias and bias-without-plasma conditions. PMID- 30417900 TI - Quantification of the liquid window of deep eutectic solvents. AB - Deep eutectic solvents (DESs) have been considered as a new class of green solvents with tunable physical properties based on the selective combination of their individual components. As the liquid window of a DES identifies the range of feasible applications, it is essential to determine, quantify, and predict their phase behavior. Phase diagrams were measured for systems consisting of tetrapentylammonium bromide and erythritol or succinic acid. Regular solution theory is applied to quantitatively describe the liquid window of DESs. The succinic acid mixture shows a larger deviation from ideal behavior, caused by the stronger hydrogen bond forming acid groups. The interaction parameter between the two DES components in regular solution theory could be determined directly from the eutectic temperature of the mixture and this enables quantification of the degree of non-ideality of DESs. PMID- 30417901 TI - Nonadiabatic fragmentation of H2O+ and isotopomers. Wave packet propagation using ab initio wavefunctions. AB - The fragmentation of the water cation from its B[combining tilde] 2B2 electronic state, allowing the participation of the X[combining tilde] 2B1, A 2A1 and C[combining tilde] 2B1 states in the process, is simulated using the extended capabilities of the collocation GridTDSE code to account for the nonadiabatic propagation of wave packets in several potential energy surfaces connected by nonadiabatic couplings. Molecular data are calculated ab initio. Two initial wave packets are considered to reproduce two different experiments. The isotopic effect in the fragmentation of D2O+ and HDO+ is also studied and the results show very good agreement with the experimental cleavage preference in the fragmentation of HDO+. PMID- 30417902 TI - The generation and transport of reactive nitrogen species from a low temperature atmospheric pressure air plasma source. AB - The reactive chemical species generated by non-equilibrium plasma under atmospheric pressure conditions are key enablers for many emerging applications spanning the fields of biomedicine, manufacturing and agriculture. Despite showing great application potential, insight in to the underpinning reactive species generation and transport mechanisms remains scarce. This contribution focuses on the spatiotemporal behaviour of reactive nitrogen species (RNS) created and transported by an atmospheric pressure air surface barrier discharge (SBD) using both laser induced fluorescence and particle imaging velocimetry measurements combined with experimentally validated numerical modelling. It was observed that highly reactive species such as N are confined to the discharge region while less reactive species such as NO, NO2 and N2O closely followed the induced flow. The concentration of key RNS was found to be in the 10-100 ppm range at a position of 25 mm downstream of the discharge region. A close agreement between the experimental and computational results was achieved and the findings provide a valuable insight in to the role of electrohydrodynamic forces in dictating the spatiotemporal distribution of reactive chemical species beyond the plasma generation region, which is ultimately a key contributor towards downstream treatment uniformity and application efficacy. PMID- 30417903 TI - Structural isomers and low-lying electronic states of gas-phase M+(N2O)n (M = Co, Rh, Ir) ion-molecule complexes. AB - The structures of gas-phase group nine cation-nitrous oxide metal-ligand complexes, M+(N2O)n (M = Co, Rh, Ir; n = 2-7) have been determined by a combination of infrared photodissociation spectroscopy and density functional theory. The infrared spectra were recorded in the region of the N2O asymmetric (N[double bond, length as m-dash]N) stretch using the inert messenger technique and show spectroscopically distinct features for N- and O-bound isomers. The evolution of the spectra with increasing ligand number is qualitatively different for each of the metal ions studied here with only Co+(N2O)n complexes behaving similarly to the coinage metal complexes studied previously. The rich variety of electronic and isomeric structures identified make these species attractive targets for infrared-driven, isomer selective intra-complex chemistry. PMID- 30417904 TI - The sacrificial inactivation of the blue-light photosensor cryptochrome from Drosophila melanogaster. AB - Drosophila melanogaster cryptochrome functions as the primary blue-light receptor that mediates circadian photo entrainment. Absorption of a photon leads to reduction of the protein-bound FAD via consecutive electron transfer along a conserved tryptophan tetrad resembling the signalling state required for conformational changes and induction of subsequent signalling cascades. However, how the initial photochemistry and subsequent dark processes leading to downstream signalling are linked to each other at the molecular level is still poorly understood. Here, we investigated in detail the initial photochemical events in DmCRY by time-resolved and stationary absorption spectroscopy combined with quantum chemical and molecular dynamics calculations. We resolved the early events along the conserved tryptophan tetrad and the final deprotonation of the terminal tryptophanyl radical cation. These initial events lead to conformational changes, such as the known C-terminal tail release, Trp decomposition, and finally FAD release providing evidence that DmCRY does not undergo a photocycle. We propose that light is a negative regulator of DmCRY stability even under in vitro conditions where the proteasomal machinery is missing, that is in line with its biological function, i.e. entrainment of the circadian clock. PMID- 30417906 TI - Correlative light and electron microscopy for complex cellular structures on PDMS substrates with coded micro-patterns. AB - Fluorescence light microscopy (FLM) is commonly used for localizing specific cellular and subcellular targets. Electron microscopy (EM), on the other hand, can reveal ultrastructural details of cellular architectures beyond the limit of optical resolution. Correlative light and electron microscopy (CLEM) that combines the two techniques has proven valuable in various cell biological applications that require both specificity and resolution. Here, we report an efficient and easy-to-use CLEM system, and its applications in studying neuronal synapses. The system utilizes patterned symbols to encode coordinates on micro fabricated polydimethylsiloxane (PDMS) substrates, on which dissociated primary hippocampal neurons grow and form synaptic connections. After imaging and localizing specifically labeled synapses with FLM, samples are embedded in resin blocks and sectioned for EM analysis. The patterned symbols on PDMS substrates provide coordinate information, allowing efficient co-registration between FLM and EM images with high precision. A custom-developed software package achieves automated EM image collection, FLM/EM alignment, and EM navigation. With this CLEM system, we have obtained high quality electron tomograms of fluorescently labeled synapses along dendrites of hippocampal neurons and analyzed docking statistics of synaptic vesicles (SVs) in different subtypes of excitatory synapses. This technique provides an efficient approach to combine functional studies with ultrastructural analysis of heterogeneous neuronal synapses, as well as other subcellular structures in general. PMID- 30417907 TI - A comparative analysis of hydrosilative amide reduction catalyzed by first-row transition metal (Mn, Fe, Co, and Ni) N-phosphinoamidinate complexes. AB - A comparative study of the performance of (PN)M(N(SiMe3)2) (M = Mn, Fe, Co, and Ni) pre-catalysts supported by N-phosphinoamidinate ligation, as well as M(N(SiMe3)2)n (M = Li, Na, K, Mn, Fe, and Co) pre-catalysts, in the hydrosilative reduction of selected tertiary amide test substrates using PhSiH3 is reported. Encouraged by the performance observed herein for (PN)Ni(N(SiMe3)2) in the reduction of both N,N-dibenzylbenzamide and N,N-diisopropylbenzamide, further competitive testing involving the known complex (PN)Ni(NHdipp) (dipp = 2,6 diisopropylphenyl), as well as the new and crystallographically characterized mononuclear complexes (PN)Ni(OR) (R = 2,6-dimethylphenyl or tBu), revealed (PN)Ni(OtBu) to be particularly effective in such reduction chemistry, including transformations involving the secondary amides N-benzylbenzamide and caprolactam. PMID- 30417908 TI - Optimising the magnetic performance of Co ferrite nanoparticles via organic ligand capping. AB - Ferrofluids of CoFe2O4 nanoparticles are gaining increasing interest due to their enhanced heating performance in biomedical applications (e.g. in magnetic hyperthermia as mediators for cancer treatment) or in energy applications (e.g. magneto-thermo-electric applications). Until now, the effect of an organic surfactant on the magnetic particle behaviour has been unintentionally overlooked. Here, we present the counterintuitive magnetic effect of two representative organic ligands: diethylene glycol (DEG) and oleic acid (OA) bonded at the surface of small (~5 nm in size) CoFe2O4 particles. The combined results of the bulk dc susceptibility, local-probe Mossbauer spectroscopy and physical modelling, which is based on electronic structure calculations and Monte Carlo simulations, reveal the effect of different ionic distributions of the particles due to the different surfactant layers on their magnetic behaviour. They result in an unexpected increase of the saturation magnetisation and the blocking temperature, and a decrease of the coercive field of DEG coated CoFe2O4 nanoparticles. Our work provides a pathway for the production of colloidal assemblies of nanocrystals for the engineering of functional nano-materials. PMID- 30417909 TI - Synthesis and cycloaddition reactions of strained alkynes derived from 2,2' dihydroxy-1,1'-biaryls. AB - A series of strained alkynes, based on the 2,2'-dihydroxy-1,1'-biaryl structure, were prepared in a short sequence from readily-available starting materials. These compounds can be readily converted into further derivatives including examples containing fluorescent groups with potential for use as labelling reagents. The alkynes are able to react in cycloadditions with a range of azides without the requirement for a copper catalyst, in clean reactions with no observable side reactions. PMID- 30417913 TI - New nanoscale toughening mechanisms mitigate embrittlement in binary nanocrystalline alloys. AB - Nanocrystalline metals offer significant improvements in structural performance over conventional alloys. However, their performance is limited by grain boundary instability and limited ductility. Solute segregation has been proposed as a stabilization mechanism, however the solute atoms can embrittle grain boundaries and further degrade the toughness. In the present study, we confirm the embrittling effect of solute segregation in Pt-Au alloys. However, more importantly, we show that inhomogeneous chemical segregation to the grain boundary can lead to a new toughening mechanism termed compositional crack arrest. Energy dissipation is facilitated by the formation of nanocrack networks formed when cracks arrested at regions of the grain boundaries that were starved in the embrittling element. This mechanism, in concert with triple junction crack arrest, provides pathways to optimize both thermal stability and energy dissipation. A combination of in situ tensile deformation experiments and molecular dynamics simulations elucidate both the embrittling and toughening processes that can occur as a function of solute content. PMID- 30417915 TI - Near wall dynamics of a spherical particle in crowded suspensions of colloidal rods - dynamic information from TIRM revisited. AB - We performed total internal reflection microscopy (TIRM) experiments to determine the depletion potentials between probe spheres and a flat glass wall which are induced by long and thin, rod-shaped colloids (fd-virus), and probe the spatially resolved dynamics of the probe spheres. The dynamic information from the same raw TIRM intensity time traces is extracted in three different ways: by determining the spatially averaged diffusion constant of the probe sphere normal to the wall, by measuring the position dependence of the diffusion coefficient, and by measuring the particle's local drift velocity. Up to a concentration of about 6 times the overlap concentration of the rod-like colloids, the spatially averaged diffusion coefficient and the amplitude of the depletion potential are in surprisingly good agreement with theoretical predictions in which mutual interactions between the rods are neglected, that is, where the concentration is less than the overlap concentration. On increasing the depletant content even further, however, both the static and the averaged dynamic quantities begin to deviate from such theoretical predictions. In particular we find large deviations from the prediction by Mao, Cates, and Lekkerkerker [J. Chem. Phys., 1997, 106, 3721] based on the third order virial expansion for the rod concentration. It is shown that there are significant inaccuracies in TIRM measurements of diffusion coefficients due to the limited time range in which the mean squared displacements vary linearly in time, whereas mean displacements give much more accurate information concerning the probe sphere dynamics. PMID- 30417916 TI - Copper selenide (Cu3Se2 and Cu2-xSe) thin films: electrochemical deposition and electrocatalytic application in quantum dot-sensitized solar cells. AB - In this work, high crystallinity copper selenide thin films directly deposited onto conducting substrates were obtained through a potentiostatic electrodeposition approach. The as-deposited copper selenides involve annealing induced phase transformation from tetragonal Cu3Se2 to cubic Cu2-xSe. The annealing also leads to a remarkable morphology change from dendritic nanosheets to connected networks and separated particle shapes for the annealed (A-Cu2-xSe) and selenized (S-Cu2-xSe) samples, respectively. The copper selenide thin films were demonstrated to serve as efficient counter electrodes (CEs) in quantum dot sensitized solar cells (QDSCs) for electrocatalyzing polysulfide electrolyte regeneration. The CdS/CdSe QDSCs constructed with copper selenide CEs deliver considerable power conversion efficiencies (PCEs), especially an optimal value of 3.89% for the A-Cu2-xSe CE-based device. The enhanced photovoltaic performance benefits from the connected network microstructure of A-Cu2-xSe films which afford a large number of reaction sites and efficient charge transport pathways. The Tafel polarization characterization further indicates that, in contrast to the commonly used Cu2S and Pt CEs, the non-stoichiometric Cu2-xSe CE exhibits better electrochemical catalytic activity. This work highlights the great potential of electrodeposition for fabricating promising copper selenide CEs for high performance QDSCs. PMID- 30417917 TI - A mononuclear five-coordinate Co(ii) single molecule magnet with a spin crossover between the S = 1/2 and 3/2 states. AB - Although a great number of single-ion magnets (SIMs) and spin-crossover (SCO) compounds have been discovered, multifunctional materials with the combination of SCO and SIM properties are extremely scarce. Here magnetic studies have been carried out for a mononuclear, five-coordinate cobalt(ii) complex [Co(3,4 lut)4Br]Br (1) with square pyramidal geometry. Direct-current magnetic measurement confirms the spin transition between the S = 1/2 and 3/2 states in the range of 150-290 K with a small hysteresis loop. Frequency- and temperature dependent alternating-current magnetic susceptibility reveals slow magnetization relaxation under an applied dc field of 3000 Oe. The work here presents the first instance of the five-coordinate mononuclear cobalt(ii)-based SIM exhibiting the thermally induced complete SCO. PMID- 30417918 TI - Redox behaviour of the beta-dihydroporphycene cobalt complex: study on the effect of hydrogenation of the ligand. AB - The dihydrogenated porphycene cobalt(ii) complex was synthesized and electrochemical experiments were carried out. The one-electron reduction of the complex proceeded at the central metal to afford the Co(i) species; in contrast, for the non-hydrogenated porphycene cobalt(ii) complex, the one-electron reduction gave the ligand reduced radical anion species. The reactivity of the one-electron reduced species with alkyl halides showed clear differences between the complexes. Hydrogenation of the beta-position of the porphycene makes it possible to generate a central cobalt reduced species possessing a higher reactivity than the ligand reduced radical anion species. PMID- 30417919 TI - Modelling strategies for the covalent functionalization of 2D phosphorene. AB - This paper is a comparative outline of the potential acid-base adducts formed by an unsaturated main group or transition metal species and P atoms of phosphorene (Pn), which derives from black phosphorus exfoliation. Various possibilities of attaining a realistic covalent functionalization of the 2D material have been examined via DFT solid state calculations. The distribution of neighbor P atoms at one side of the sheet and the reciprocal directionalities of their lone pairs must be clearly understood to foreshadow the best possible acceptor reactants. Amongst the latter, the main group BH3 or I2 species have been examined for their intrinsic acidity, which favors the periodic mono-hapto anchoring at Pn atoms. The corresponding adducts are systematically compared with other molecular P donors from a phosphine to white phosphorus, P4. Significant variations emerge from the comparison of the band gaps in the adducts and the naked phosphorene with a possible electronic interpretation being offered. Then, the Pn covalent functionalization has been analyzed in relation to unsaturated metal fragments, which, by carrying one, two or three vacant sigma hybrids, may interact with a different number of adjacent P atoms. For the modelling, the concept of isolobal analogy is important for predicting the possible sets of external coligands at the metal, which may allow the anchoring at phosphorene with a variety of hapticities. Structural, electronic, spectroscopic and energy parameters underline the most relevant pros and cons of some new products at the 2D framework, which have never been experimentally characterized but appear to be reasonably stable. PMID- 30417920 TI - Facile synthesis of metal nanoparticles decorated magnetic hierarchical carbon microtubes with polydopamine-derived carbon layer for catalytic applications. AB - It is highly desirable but challenging to fabricate a unique hybrid material comprising nanosized copper/cobalt/nickel nanoparticles (NPs) uniformly distributed on magnetic supports. Herein in this work, hierarchical magnetic metal silicate hollow microtubes were prepared using silica coated magnetic N doped carbon microtubes (NCMTs@Fe3O4@SiO2) as a chemical template; then polydopamine (PDA) was employed to coat onto magnetic metal silicate carbon microtubes (NCMTs@Fe3O4@CuSNTs/CoSNTs/NiSNTs), which can be carbonized to form hierarchical hybrid composites with uniformly-dispersed metallic copper/cobalt/nickel NPs embedded in PDA-derived carbon layers (NCMTs@Fe3O4@SiO2@C/Cu-Co-Ni). Owing to its hierarchical structure, large specific surface area as well as the high density of metal NPs, the resultant NCMTs@Fe3O4@SiO2@C/Ni-Co-Cu could be applied as catalysts towards the reduction of 4-nitrophenol (4-NP). Furthermore, the NCMTs@Fe3O4@SiO2@C/Ni-Co-Cu catalysts could be easily collected and separated by applying an external magnetic field. In particular, it was found that NCMTs@Fe3O4@SiO2@C/Ni exhibited ultra-high catalytic activity on 4-NP reduction in comparison with Cu and Co supported catalysts. In addition, this unique hierarchical structure combined with magnetic recyclability make NCMTs@Fe3O4@SiO2@C/Ni a highly promising candidate for diverse applications. PMID- 30417921 TI - The coordination chemistry of lanthanide and actinide metal ions with hydroxypyridinone-based decorporation agents: orbital and density based analyses. AB - In the context of the mitigation of the biological effects of internal radionuclide contamination and for efficient decorporation, the design and development of efficient chelators for lanthanide and actinide metal ions has become a central issue. The pioneering work of Raymond and coworkers (Chem. Rev., 2003, 103, 4207-4282) led to the development of siderophore-related hydroxypyridinonate ligands for possible treatment of internalized radionuclides. However, the structure-function relationship of Ln/An bound to these ligands, particularly the bonding and coordination aspects are not clearly understood at the atomic level. Here, we have investigated the structure, binding and energetics of trivalent and tetravalent Ln/An (Sm3+, Eu3+, Am3+, Cm3+, Th4+, Pu4+) ions with spermine-based octadentate hydroxypyridinonate chelators, namely 3,4,3-LI(1,2-HOPO) and its 3,3,3 variant, using relativistic density functional theory (DFT). Furthermore, we have performed orbital and density based analyses to elucidate the nature of bonding in these complexes. In accordance with the experimental stability constant, we found the maximum binding free energy for An4+ (Pu4+, Th4+) as compared to trivalent metal ions. CDA and ECDA analyses along with orbital-based population analyses confirmed the higher ligand to metal charge transfer for An4+ than for trivalent metal ions. Furthermore, the aromaticity index analysis suggested the presence of crucial chelatoaromatic stabilization for all these metal ions with the maximum for An4+. QTAIM descriptors indicated that the binding of An/Ln with the hard oxygen donor of the ligands is of the donor-acceptor type but a higher degree of covalency exists for actinides as compared to lanthanides. Furthermore, QTAIM and molecular orbital analysis confirmed that such covalency is of the energy-driven type and strictly originates from the orbital mixing event of An-5f orbitals with the ligand orbitals. PMID- 30417922 TI - Infiltrated M2 tumour-associated macrophages in the stroma promote metastasis and poor survival in oesophageal squamous cell carcinoma. AB - Although M2 tumour-associated macrophages (M2 TAMs) have been shown to be associated with the progression and metastasis of breast cancer, their role in oesophageal squamous cell carcinoma (ESCC) remains less well understood. Therefore, to understand the clinicopathological significance of infiltrated M2 TAMs in ESCC, statistical analysis was performed after immunohistochemical evaluation of CD163 expression, a well-accepted surface marker of M2 TAMs in ESCC. To gain insight into the effect of M2 TAMs, ESCC cell lines Eca109 and KYSE150 cells were co-cultured with M2 TAMs artificially induced from THP-1 cells. The variations in the proliferation, migration and invasion were assessed using the MTT, wound-healing and Transwell assays, respectively. The variation in the typical biomarkers of the epithelial-mesenchymal transition (EMT) was evaluated using western blotting. Infiltrated M2 TAMs were confirmed to predominate in the stroma of ESCC relative to normal controls. Moreover, it turned out that M2 TAMs were shown to promote the migration and invasion of ESCC cells but not proliferation. Furthermore, M2 TAMs were observed to induce EMT in ESCC cells. Together, our results showed that infiltrated M2 TAMs in the stroma is a feature accompanying ESCC metastasis and that M2 TAMs can promote the migration and invasion, but not proliferation, of ESCC cells, thereby inducing EMT. Thus, M2 TAMs could be an alternative therapeutic target in ESCC. PMID- 30417924 TI - Spinal plasticity with motor imagery practice. AB - KEY POINTS: While a consensus has now been reached on the effect of motor imagery (MI) - the mental simulation of an action - on motor cortical areas, less is known about its impact on spinal structures. The current study, using H-reflex conditioning paradigms, examined the effect of a 20 min MI practice on several spinal mechanisms of the plantar flexor muscles. We observed modulations of spinal presynaptic circuitry while imagining, which was even more pronounced following an acute session of MI practice. We suggested that the small cortical output generated during MI may reach specific spinal circuits and that repeating MI may increase the sensitivity of the spinal cord to its effects. The short-term plasticity induced by MI practice may include spinal network modulation in addition to cortical reorganization. ABSTRACT: Kinesthetic motor imagery (MI) is the mental simulation of a movement with its sensory consequences but without its concomitant execution. While the effect of MI practice on cortical areas is well known, its influence on spinal circuitry remains unclear. Here, we assessed plastic changes in spinal structures following an acute MI practice. Thirteen young healthy participants accomplished two experimental sessions: a 20 min MI training consisting of four blocks of 25 imagined maximal isometric plantar flexions, and a 20 min rest (control session). The level of spinal presynaptic inhibition was assessed by conditioning the triceps surae spinal H-reflex with two methods: (i) the stimulation of the common peroneal nerve that induced D1 presynaptic inhibition (HPSI response), and (ii) the stimulation of the femoral nerve that induced heteronymous Ia facilitation (HFAC response). We then compared the effects of MI on unconditioned (HTEST ) and conditioned (HPSI and HFAC ) responses before, immediately after and 10 min after the 20 min session. After resting for 20 min, no changes were observed on the recorded parameters. After MI practice, the amplitude of rest HTEST was unchanged, while HPSI and HFAC significantly increased, showing a reduction of presynaptic inhibition with no impact on the afferent-motoneuronal synapse. The current results revealed the acute effect of MI practice on baseline spinal presynaptic inhibition, increasing the sensitivity of the spinal circuitry to MI. These findings will help in understanding the mechanisms of neural plasticity following chronic practice. PMID- 30417923 TI - Dermatological manifestations in Noonan syndrome: A prospective multicentric study of 129 mutation-positive patients. AB - BACKGROUND: Data on dermatological manifestations of Noonan syndrome (NS) remain heterogeneous and based on little dermatological expertise. OBJECTIVES: To describe the dermatological manifestations of NS, compare them with the literature findings, and test for dermatological phenotype-genotype correlations with or without the presence of PTPN11 mutations. METHODS: We performed a large, 4-year, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: One hundred and twenty-nine patients were enrolled, including 65 with PTPN11-NS, 34 with PTPN11-NS with multiple lentigines (NSML), and 30 without PTPN11-NS. Easy bruising was the most frequent dermatological finding in PTPN11 NS, present in 53.8%. Multiple lentigines and cafe-au-lait macules (>=3) were present in, respectively, 94% and 80% of NSML linked to specific mutations of PTPN11. Atypical forms of NSML could be associated with NS with RAF1 or NRAS mutations. In univariate analysis, patients without a PTPN11 mutation showed (i) a significantly higher frequency of keratinization disorders (P=0.001), including keratosis pilaris (P=0.005), ulerythema ophryogenes (P=0.0001) and palmar and/or plantar hyperkeratosis (P=0.06, trend association), and (ii) a significantly higher frequency of scarce scalp hair (P=0.035) and scarce or absent eyelashes (P=0.06, trend association) than those with PTPN11 mutations. CONCLUSIONS: Cutaneous phenotype of NS with a PTPN11 mutation is generally mild and non specific, whereas the absence of a PTPN11 mutation is associated with a high frequency of keratinization disorders and hair abnormalities. This article is protected by copyright. All rights reserved. PMID- 30417925 TI - Elevated fetal haemoglobin levels are associated with decreased incidence of retinopathy in adults with sickle cell disease. AB - Among the many vascular complications of sickle cell disease (SCD), retinopathy is the most prevalent and represents a leading cause of blindness. Hydroxycarbamide therapy ameliorates many symptoms of SCD, and high fetal haemoglobin (HbF) levels have been shown to protect against the development of retinopathy in children with HbSS. Its effect on adults with SCD, who are at a much higher risk of developing retinopathy, has not been studied. We aimed to investigate the effect of hydroxycarbamide use and HbF level on sickle cell retinopathy development in adults. We performed a retrospective cross-sectional study and collected demographics, comorbidities, and ocular and haematological data from 300 adult sickle cell subjects examined at the Henkind Eye Institute at Montefiore Medical Center during a 5-year period, from October 2012 to November 2017. The cohort was comprised mainly of Black and Hispanic subjects with all SCD genotypes, aged 18-71 years. Results show that in HbSS patients treated with hydroxycarbamide, those with retinopathy had significantly lower HbF levels compared to patients without retinopathy (P = 0.018). Our study identified the optimal HbF cut-off point for retinopathy protection to be 14.87%. Thus, a HbF level of 15% appears to be the threshold above which the odds for developing retinopathy in SS patients are reduced by 50%. PMID- 30417926 TI - Serenoa repens and N-acetyl glucosamine/milk proteins complex differentially affect the paracrine communication between endothelial and follicle dermal papilla cells. AB - Current treatments for hair follicle (HF) disruption are based on 5-alpha reductase inhibitors and prostaglandin modulators. Botanicals and nutraceutical compounds interfere with hair loss or stimulate its partial regrowth. Here, we used in vitro cocultures to investigate the activity of Serenoa repens ( SR) and N-acetyl glucosamine + milk proteins (NAG/Lac) on the paracrine interactions between human microvascular endothelial cells (HMVEC) and HF dermal papilla cells (FDPC). Both SR and NAG/Lac-induced endothelial tubulogenesis were enhanced by FDPC. SR promoted proliferation of both the cell types, while NAG/Lac was effective on endothelium. Vascular endothelial growth factor production, enhanced by SR, was further augmented by FDPC. In FDPC 5-alpha reductase-II and beta catenin expressions were modified by SR and less by NAG/Lac, with no additional effect by HMVEC. SR and NAG/Lac prevented lipid peroxidation, whereas NAG/Lac was effective on interleukin 1beta production. Finally, SR and NAG/Lac differentially affected HMVEC permeability and tight junction proteins content. These data provide a mechanistic background for the potential use of these compounds as promoters of HF vascularization. PMID- 30417927 TI - Success and survival of post-restorations: six-year results of a prospective observational practice-based clinical study. AB - AIM: This prospective, noninterventional, multi-centre, practice-based study aimed to evaluate the longevity of endodontically treated teeth (ETT) restored with posts and to analyse factors influencing the success and survival of endodontic posts. METHODOLOGY: Eight general dental practitioners each placed up to 27 endodontic posts without any restriction to size and material. Teeth were restricted to incisors, canines and premolars. Multi-level Cox proportional hazards models were used to evaluate the association between clinical factors and time until failure. RESULTS: A total of 195 endodontic posts were followed-up for up to 6.5 years in 195 patients. Of these, 140 posts were judged as successful [mean success time: 59 (55-63) months]; the mean annual failure rate was 8.6%. This decreased to 4.4% when excluding recementations. 152 posts survived [mean survival time: 64 (60-67) months]. Recemented restorations had an eight times higher failure rate compared with new restorations. Furthermore, restorations with glass fibre post had a significantly lower success rate compared with titanium posts. CONCLUSION: Relatively low success and survival rates occurred for restorations with posts after root canal treatment in a private practice setting after a follow-up of up to 6.5 years. Recemented crowns had a high risk of failure. PMID- 30417928 TI - Blood-brain barrier permeability measured using dynamic contrast-enhanced magnetic resonance imaging: a validation study. AB - KEY POINTS: The blood-brain barrier (BBB) is an important and dynamic structure which contributes to homeostasis in the central nervous system. BBB permeability changes occur in health and disease but measurement of BBB permeability in humans is not straightforward. Dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) can be used to model the movement of gadolinium contrast into the brain, expressed as the influx constant Ki . Here evidence is provided that Ki as measured by DCE-MRI behaves as expected for a marker of overall BBB leakage. These results support the use of DCE-MRI for in vivo studies of human BBB permeability in health and disease. ABSTRACT: Blood-brain barrier (BBB) leakage can be measured using dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) as the influx constant Ki . To validate this method we compared measured Ki with biological expectations, namely (1) higher Ki in healthy individual grey matter (GM) versus white matter (WM), (2) GM/WM cerebral blood volume (CBV) ratio close to the histologically established GM/WM vascular density ratio, (3) higher Ki in visibly enhancing multiple sclerosis (MS) lesions versus MS normal appearing white matter (NAWM), and (4) higher Ki in MS NAWM versus healthy individual NAWM. We recruited 13 healthy individuals and 12 patients with MS and performed whole-brain 3D DCE-MRI at 3 T. Ki and CBV were calculated using Patlak modelling for manual regions of interest (ROI) and segmented tissue masks. Ki was higher in control GM versus WM (P = 0.001). CBV was higher in GM versus WM (P = 0.005, mean ratio 1.9). Ki was higher in visibly enhancing MS lesions versus MS NAWM (P = 0.002), and in MS NAWM versus controls (P = 0.014). Bland-Altman analysis showed no significant difference between ROI and segmentation methods (P = 0.638) and an intra-class correlation coefficient showed moderate single measure consistency (0.610). Ki behaves as expected for a compound marker of permeability and surface area. The GM/WM CBV ratio measured by this technique is in agreement with the literature. This adds evidence to the validity of Ki measured by DCE-MRI as a marker of overall BBB leakage. PMID- 30417929 TI - T1 , T1 contrast, and Ernst-angle images of four rat-lung pathologies. AB - PURPOSE: To initiate the archive of relaxation-weighted images that may help discriminate between pulmonary pathologies relevant to acute respiratory distress syndrome. MRI has the ability to distinguish pathologies by providing a variety of different contrast mechanisms. Lungs have historically been difficult to image with MRI but image quality is sufficient to begin cataloging the appearance of pathologies in T1 - and T2 -weighted images. This study documents T1 and the use of T1 contrast with four experimental rat lung pathologies. METHODS: Inversion recovery and spoiled steady state images were made at 1.89 T to measure T1 and document contrast in rats with atelectasis, lipopolysaccharide-induced inflammation, ventilator-induced lung injury (VILI), and injury from saline lavage. Higher-resolution Ernst-angle images were made to see patterns of lung infiltrations. RESULTS: T1 -weighted images showed minimal contrast between pathologies, similar to T1 -weighted images of other soft tissues. Images taken shortly after magnetization inversion and displayed with inverted contrast highlight lung pathologies. Ernst-angle images distinguish the effects of T1 relaxation and spin density and display distinctive patterns. T1 for pathologies were: atelectasis, 1.25 +/- 0.046 s; inflammation from instillation of lipopolysaccharide, 1.24 +/- 0.015 s; VILI, 1.55 +/- 0.064 s (p = 0.0022 vs. normal lung); and injury from saline lavage, 1.90+/-0.080 s (p = 0.0022 vs. normal lung; p = 0.0079 vs. VILI). T1 of normal lung and erector spinae muscle were 1.25 +/- 0.028 s and 1.02 +/- 0.027 s, respectively (p = 0.0022). CONCLUSIONS: Traditional T1 -weighting is subtle. However, images made with inverted magnetization and inverted contrast highlight the pathologies and Ernst angle images aid in distinguishing pathologies. PMID- 30417930 TI - Retrospective artifact elimination in MEGA-PRESS using a correlation approach. AB - PURPOSE: To develop a method for retrospective artifact elimination of MRS data. This retrospective method was based on an approach that combines jackknife analyses with the correlation of spectral windows, and therefore termed "JKC." METHODS: Twelve healthy volunteers performed 3 separate measurement protocols using a 3T MR system. One protocol consisted of 2 cerebellar MEGA-PRESS measurements: 1 reference and 1 measurement including head movements. One-third of the artifact-influenced datasets were treated as training data for the implementation the JKC method, and the rest were used for validation. RESULTS: The implemented JKC method correctly characterized most of the validation data. Additionally, after elimination of the detected artifacts, the resulting concentrations were much closer to those computed for the reference datasets. Moreover, when the JKC method was applied to the reference data, the estimated concentrations were not affected, compared with standard averaging. CONCLUSION: The implemented JKC method can be applied without any extra cost to MRS data, regardless of whether the dataset has been contaminated by artifacts. Furthermore, the results indicate that the JKC method could be used as a quality control of a dataset, or as an indication of whether a shift in voxel placement has occurred during the measurement. PMID- 30417931 TI - Effects of preparation with the Self-Adjusting File, TRUShape and XP-Endo Shaper systems, and a supplementary step with XP-Endo Finisher R on filling material removal during retreatment of mandibular molar canals. AB - AIM: To compare the effects of three instrumentation systems, and a supplementary approach with a finishing instrument, on filling material removal during retreatment of mandibular molar canals. METHODS: Sixty mesial canals from mandibular molars (Vertucci's type IV anatomy) were instrumented, filled and subjected to retreatment. After initial removal of the root canal filling material using the D-RaCe system, the canals were randomly distributed into 3 groups (n=20) according to the instrument system used for preparation: the Self Adjusting File (SAF), TRUShape or XP-endo Shaper. The filling material volume in the apical 5 mm of the canals was assessed by means of micro-computed tomography (micro-CT) before and after retreatment. All specimens with residual filling material were subjected to a supplementary approach with the XP-endo Finisher R instrument and another micro-CT scan was taken. Data on the volumes of filling material and incidence of total removal were compared between groups by the general linear model for paired data and the Fisher's exact test. The effects of the refinement step were evaluated by the Wilcoxon Signed Ranks test. RESULTS: The amount of removed material was 92.4%, 96.9% and 96.9% for the SAF, TRUShape and XP-endo Shaper, respectively. There were no significant differences between them (p>0.05). Canals were completely cleaned of filling material in 70% of the specimens for XP-endo Shaper, 55% for SAF and 30% for TRUShape; the difference between XP-endo Shaper and TRUShape was significant (p=0.03). The supplementary step with the XP-endo Finisher R instrument was associated with additional filling material removal of 38% (p<0.001). Six more canals were rendered free of filling material after using this finishing instrument. CONCLUSIONS: The tested systems were equally effective in removing the mass of filling material from the apical 5 mm of molar canals. The supplementary step with the XP-endo Finisher R instrument enhanced filling material removal. This article is protected by copyright. All rights reserved. PMID- 30417932 TI - Accelerated, first-pass cardiac perfusion pulse sequence with radial k-space sampling, compressed sensing, and k-space weighted image contrast reconstruction tailored for visual analysis and quantification of myocardial blood flow. AB - PURPOSE: To develop an accelerated cardiac perfusion pulse sequence and test whether it is capable of increasing spatial coverage, generating high-quality images, and enabling quantification of myocardial blood flow (MBF). METHODS: We implemented an accelerated first-pass cardiac perfusion pulse sequence by combining radial k-space sampling, compressed sensing (CS), and k-space weighted image contrast (KWIC) filtering. The proposed and clinical standard pulse sequences were evaluated in a randomized order in 13 patients at rest. For visual analysis, 3 readers graded the conspicuity of wall enhancement, artifact, and noise level on a 5-point Likert scale (overall score index = sum of 3 individual scores). Resting MBF was calculated using a Fermi function model with and without KWIC filtering. Mean visual scores and MBF values were compared between sequences using appropriate statistical tests. RESULTS: The proposed pulse sequence produced greater spatial coverage (6-8 slices) with higher spatial resolution (1.6 * 1.6 * 8 mm3 ) and shorter readout duration (78 ms) compared to clinical standard (3-4 slices, 3 * 3 * 8 mm3 , 128 ms, respectively). The overall image score index between accelerated (11.1 +/- 1.3) and clinical standard (11.2 +/- 1.3) was not significantly different (P = 0.64). Mean resting MBF values with KWIC filtering (0.9-1.2 mL/g/min across different slices) were significantly lower (P < 0.0001) than those without KWIC filtering (3.1-4.3 mL/g/min) and agreed better with values reported in literature. CONCLUSION: An accelerated, first-pass cardiac perfusion pulse sequence with radial k-space sampling, CS, and KWIC filtering is capable of increasing spatial coverage, generating high-quality images, and enabling quantification of MBF. PMID- 30417933 TI - Predicting chemo-brain in breast cancer survivors using multiple MRI features and machine-learning. AB - PURPOSE: Breast cancer (BC) is the most common cancer in women worldwide. There exist various advanced chemotherapy drugs for BC; however, chemotherapy drugs may result in brain damage during treatment. When a patient's brain is changed in response to chemo drugs, it is termed chemo-brain. In this study, we aimed to construct machine-learning models to detect the subtle alternations of the brain in postchemotherapy BC patients. METHODS: Nineteen BC patients undergoing chemotherapy and 20 healthy controls (HCs) were recruited for this study. Both groups underwent resting-state functional MRI and generalized q-sampling imaging (GQI). RESULTS: Logistic regression (LR) with GQI indices in standardized voxel wise analysis, LR with mean regional homogeneity in regional summation analysis, decision tree classifier (CART) with generalized fractional anisotropy in voxel wise analysis, and XGBoost (XGB) with normalized quantitative anisotropy had formidable performances in classifying subjects into a chemo-brain group or an HC group. Classifying the brain MRIs of HC and postchemotherapy patients by conducting leave-one-out cross-validation resulted in the highest accuracy of 84%, which was attained by LR, CART, and XGB with multiple feature sets. CONCLUSIONS: In our study, we constructed the machine-learning models that were able to identify chemo-brains from normal brains. We are hopeful that these results will be helpful in clinically tracking chemo-brains in the future. PMID- 30417934 TI - Active smoking and macrocytosis in the general population: Two population-based cohort studies. PMID- 30417935 TI - iSEE: Interface structure, evolution, and energy-based machine learning predictor of binding affinity changes upon mutations. AB - Quantitative evaluation of binding affinity changes upon mutations is crucial for protein engineering and drug design. Machine learning-based methods are gaining increasing momentum in this field. Due to the limited number of experimental data, using a small number of sensitive predictive features is vital to the generalization and robustness of such machine learning methods. Here we introduce a fast and reliable predictor of binding affinity changes upon single point mutation, based on a random forest approach. Our method, iSEE, uses a limited number of interface Structure, Evolution, and Energy-based features for the prediction. iSEE achieves, using only 31 features, a high prediction performance with a Pearson correlation coefficient (PCC) of 0.80 and a root mean square error of 1.41 kcal/mol on a diverse training dataset consisting of 1102 mutations in 57 protein-protein complexes. It competes with existing state-of-the-art methods on two blind test datasets. Predictions for a new dataset of 487 mutations in 56 protein complexes from the recently published SKEMPI 2.0 database reveals that none of the current methods perform well (PCC < 0.42), although their combination does improve the predictions. Feature analysis for iSEE underlines the significance of evolutionary conservations for quantitative prediction of mutation effects. As an application example, we perform a full mutation scanning of the interface residues in the MDM2-p53 complex. PMID- 30417936 TI - Simultaneous B1 and T1 mapping using spiral multislice variable flip angle acquisitions for whole-brain coverage in less than one minute. AB - PURPOSE: Variable flip angle (VFA)-based T1 quantification techniques are highly sensitive to B1 inhomogeneities and to residual T2 dependency arising from incomplete spoiling. Here, a rapid spiral VFA acquisition scheme with high spoiling efficiency is proposed for simultaneous whole-brain B1 and T1 mapping. METHODS: VFA acquisitions at 2 different flip angles are performed to quantify T1 using a steady-state prepared spiral 2D multislice spoiled gradient-echo sequence with the acquisition of 10 and 20 spiral interleaves at 1.5T and 3T, respectively. Additionally, parallel imaging acceleration of factor 2 is investigated at 3T. The free induction decay induced by the preparation pulse is sampled by a single-shot spiral readout to quantify B1 . RESULTS: The in vitro and in vivo validations yielded good agreement between the derived spiral VFA B1 and the acquired reference B1 maps as well as between the B1 -corrected spiral VFA T1 and the reference T1 maps. The spiral VFA acquisitions in the human brain delivered artifact-free B1 and T1 maps and demonstrated high reproducibility at 1.5T and 3T. CONCLUSION: Reliable simultaneous spiral VFA B1 and T1 quantification was feasible with acquisition times of <1 min for whole-brain coverage at clinically relevant resolution. PMID- 30417937 TI - Robust retrospective frequency and phase correction for single-voxel MR spectroscopy. AB - PURPOSE: Subject motion and static field (B0 ) drift are known to reduce the quality of single voxel MR spectroscopy data due to incoherent averaging. Retrospective correction has previously been shown to improve data quality by adjusting the phase and frequency offset of each average to match a reference spectrum. In this work, a new method (RATS) is developed to be tolerant to large frequency shifts (>7 Hz) and baseline instability resulting from inconsistent water suppression. METHODS: In contrast to previous approaches, the variable projection method and baseline fitting is incorporated into the correction procedure to improve robustness to fluctuating baseline signals and optimization instability. RATS is compared to an alternative method, based on time-domain spectral registration (TDSR), using simulated data to model frequency, phase, and baseline instability. In addition, a J-difference edited glutathione in-vivo dataset is processed using both approaches and compared. RESULTS: RATS offers improved accuracy and stability for large frequency shifts and unstable baselines. Reduced subtraction artifacts are demonstrated for glutathione edited MRS when using RATS, compared with uncorrected or TDSR corrected spectra. CONCLUSIONS: The RATS algorithm has been shown to provide accurate retrospective correction of SVS MRS data in the presence of large frequency shifts and baseline instability. The method is rapid, generic and therefore readily incorporated into MRS processing pipelines to improve lineshape, SNR, and aid quality assessment. PMID- 30417938 TI - Integrated automated particle tracking microfluidic enables high-throughput cell deformability cytometry for red cell disorders. AB - Investigating individual red blood cells (RBCs) is critical to understanding hematologic diseases, as pathology often originates at the single-cell level. Many RBC disorders manifest in altered biophysical properties, such as deformability of RBCs. Due to limitations in current biophysical assays, there exists a need for high-throughput analysis of RBC deformability with single-cell resolution. To that end, we present a method that pairs a simple in vitro artificial microvasculature network system with an innovative MATLAB-based automated particle tracking program, allowing for high-throughput, single-cell deformability index (sDI) measurements of entire RBC populations. We apply our technology to quantify the sDI of RBCs from healthy volunteers, Sickle cell disease (SCD) patients, a transfusion-dependent beta thalassemia major patient, and in stored packed RBCs (pRBCs) that undergo storage lesion over 4 weeks. Moreover, our system can also measure cell size for each RBC, thereby enabling 2D analysis of cell deformability vs cell size with single cell resolution akin to flow cytometry. Our results demonstrate the clear existence of distinct biophysical RBC subpopulations with high interpatient variability in SCD as indicated by large magnitude skewness and kurtosis values of distribution, the "shifting" of sDI vs RBC size curves over transfusion cycles in beta thalassemia, and the appearance of low sDI RBC subpopulations within 4 days of pRBC storage. Overall, our system offers an inexpensive, convenient, and high-throughput method to gauge single RBC deformability and size for any RBC population and has the potential to aid in disease monitoring and transfusion guidelines for various RBC disorders. PMID- 30417939 TI - Changes in health-related quality of life with long-term eltrombopag treatment in adults with persistent/chronic immune thrombocytopenia: Findings from the EXTEND study. AB - Patients with persistent/chronic immune thrombocytopenia (cITP) have low platelet counts, increased risk of bleeding and bruising, and often suffer from reduced health-related quality of life (HRQoL). cITP treatments may either improve HRQoL by increasing platelet counts or decrease it because of side effects. The open label EXTEND study (June 2006 to July 2015) evaluated long-term safety, tolerability, and efficacy of eltrombopag (an oral thrombopoietin-receptor agonist) in adults with cITP who completed a previous eltrombopag ITP trial. The final results of EXTEND were published and used to assess changes in patient reported HRQoL over time and association between HRQoL and platelet response. Four validated HRQoL instruments were administered: SF-36v2 including physical component summary (PCS) and Mental Component Summary; Motivation and Energy Inventory Short Form (MEI-SF); Fatigue Subscale of FACIT (FACIT-Fatigue); and FACT-Thrombocytopenia Subscale Six-Item Extract (FACT-Th6). For the 302 patients enrolled, median duration of eltrombopag treatment was 2.37 years. All 4 HRQoL instruments demonstrated positive mean changes from baseline over time adjusted for patient baseline characteristics and rescue therapy use, and had positive association with platelet response (platelet count >=30 * 109 /L; >=50 * 109 /L; and >=50 * 109 /L and >2 times baseline). Improvements from baseline started within 3 months and persisted through 5 years of treatment for FACIT-Fatigue and FACT-Th6 (P <.05 for nearly all time points); through 2.5 years for SF-36v2 PCS and less consistently for the MEI-SF. In conclusion, in addition to eltrombopag increasing platelet counts and reducing bleeding/bruising, it also alleviated fatigue, concerns about bleeding and bruising, and improved physical function in many patients, especially responders. PMID- 30417940 TI - Real-time Triggered RAdial Single-Shot Inversion recovery for arrhythmia insensitive myocardial T1 mapping: motion phantom validation and in vivo comparison. AB - PURPOSE: Cardiac T1 mapping has become an increasingly important imaging technique, contributing novel diagnostic options. However, currently utilized methods are often associated with accuracy problems because of heart rate variations and cardiac arrhythmia, limiting their value in clinical routine. This study aimed to introduce an improved arrhythmia-related robust T1 mapping sequence called RT-TRASSI (real-time Triggered RAdial Single-Shot Inversion recovery). METHODS: All measurements were performed on a 3.0T whole-body imaging system. A real-time feedback algorithm for arrhythmia detection was implemented into the previously described pulse sequence. A programmable motion phantom was constructed and measurements with different simulated arrhythmias arranged. T1 mapping accuracy and susceptibility to artifacts were analyzed. In addition, in vivo measurements and comparisons with 3 prevailing T1 mapping sequences (MOLLI, ShMOLLI, and SASHA) were carried out to investigate the occurrence of artifacts. RESULTS: In the motion phantom measurements, RT-TRASSI showed excellent agreement with predetermined reference T1 values. Percentage scattering of the T1 values ranged from -0.6% to +1.9% in sinus rhythm and -1.0% to +3.1% for high-grade arrhythmias. In vivo, RT-TRASSI showed diagnostic image quality with only 6% of the acquired T1 maps including image artifacts. In contrast, more than 40% of the T1 maps acquired with MOLLI, ShMOLLI, or SASHA included motion artifacts. CONCLUSION: Accuracy issues because of heart rate variability and arrhythmia are a prevailing problem in current cardiac T1 mapping techniques. With RT-TRASSI, artifacts can be minimized because of the short acquisition time and effective real-time feedback, avoiding potential data acquisition during systolic heart phase. PMID- 30417941 TI - The Generation of Integration: The Early Experience of Implementing Bundled Care in Ontario, Canada. AB - : Policy Points: Policymakers interested in advancing integrated models of care may benefit from understanding how integration itself is generated. Integration is analyzed as the generation of connectivity and consensus-the coming together of people, practices, and things. Integration was mediated by chosen program structures and generated by establishing partnerships, building trust, developing thoughtful models, engaging clinicians in strategies, and sharing data across systems. This study provides examples of on-the-ground integration strategies in 6 programs, suggests contexts that better lend themselves to integration initiatives, and demonstrates how programs may be examined for the very thing they seek to implement-integration itself. CONTEXT: By bundling services and encouraging interprofessional and interorganizational collaboration, integrated health care models counter fragmented health care delivery and rising system costs. Building on a policy impetus toward integration, the Ministry of Health and Long-Term Care in the Canadian province of Ontario chose 6 programs, each comprising multiple hospital and community partners, to implement bundled care, also referred to as integrated-funding models. While research has been conducted on the facilitators and challenges of integration, there is less known about how integration is generated. This article explores the generation of integration through the dynamic interplay of contexts and mechanisms and of structures and subjects. METHODS: For this qualitative study, we conducted 48 interviews with program stakeholders, from organization leaders and managers to physicians and integrated care coordinators, across the hospital-community spectrum. We then used content analysis to explore the extent to which themes were shared across programs and to identify idiosyncrasies, followed by a realist evaluation approach to understand how integration was produced in structural and everyday ways in local program contexts. FINDINGS: Integration was generated through the successful production of connectivity and consensus-the coming together of people, practice, and things, as perceived and experienced by stakeholders. When able, the programs harnessed existing cultures of clinician engagement, and leveraged established partnerships. However, integration could be achieved even without these histories, by building trust, developing thoughtful models, using clinicians' existing engagement strategies, and implementing shared systems and technologies. The programs' structures (from their scale to their chosen patient population) also contextualized and mediated integration. CONCLUSIONS: This article has both practical and theoretical implications. It provides transferable insights into the strategies by which integration is generated. It also contributes conceptually to realist approaches to evaluation by advancing an understanding of mechanisms as contextually and temporally contingent, with the capacity to produce new contexts, which in turn generate new sets of mechanisms. PMID- 30417942 TI - Elderly do benefit from induction chemotherapy: High dose mitoxantrone-based ("5 + 1") induction chemotherapy regimen in newly diagnosed acute myeloid leukemia. AB - An intensive "5 + 1" regimen, which included bolus high dose cytarabine (HiDAC) at 3 g/m2 once daily over 3 hours on days 1-5 and high dose mitoxantrone (HDM) 80 mg/m2 on day 2, was evaluated in 101 consecutively treated newly diagnosed acute myeloid leukemia (AML) patients at a single center since 2009. The median age was 65 (range 18-90) years. The 4 and 8-week mortality in our cohort was 3/101 (2.9%) and 7/99 (7%), respectively. The overall response (complete remission [CR] + CRi) was 76.2% (77/101). The median overall survival (OS) stratified by age group <60, 60-69 and >=70 years were 56, 31 and 9 months respectively (log-rank, P = 0.02). 51.7% (45/84) of patients with intermediate/adverse risk category proceeded to allogeneic stem cell transplants. Among these 84 patients, the percentage of patients able to proceed to transplant in age groups <60, 60-69, and >= 70 years were 75% (18/24), 60.7% (17/28), and 31.2% (10/32), respectively. In conclusion, HDM-based chemotherapy regimen produces high CR rates, is well tolerated and more patients can undergo curative postremission therapy including stem cell transplant. PMID- 30417943 TI - Prognostic impact of trisomy 21 in follicular lymphoma. AB - The chromosomal abnormalities associated with follicular lymphoma (FL) prognosis are not fully elucidated. Here, we evaluated the pattern of chromosomal abnormalities in FL, and clarified the correlations between the cytogenetic features and clinical outcome. Cytogenetic analysis was performed using standard methods of Giemsa-banding at diagnosis for 201 FL patients admitted to our hospitals between 2001 and 2013. The identified chromosomal abnormalities were: t(14;18)(q32;q21) (59.2%), +X (17.9%), del(6)(q)/-6 (16.9%), +7 (14.4%), abnormality of 1q12-21/1q (12.9%), del(13)(q)/-13 (11.9%), abnormality of 3q27 (10.4%), abnormality of 10q22-24 (10.0%), +12/dup(12)(q) (10.0%), abnormality of 1p21-22/1p (9.0%), +18 (9.0%), del(17)(p)/-17 (5.0%), and a complex karyotype (54.7%). Patients with trisomy 21 had a significantly shorter progression-free survival (P = 0.00171) and overall survival (OS) (P < 0.001) than those without trisomy 21; additionally, patients with trisomy 21 in the rituximab-treated cohort also had a significantly shorter OS (P = 0.000428). Multivariate analysis identified trisomy 21 as an independent risk factor in our cohorts with or without t(14;18) (P = 0.015). In conclusion, the presence of trisomy 21 was an independent risk factor for in FL. Chromosomal analysis of FL patients at diagnosis can provide useful information about their expected survival. PMID- 30417944 TI - Social Networks of Children With Developmental Language Disorder in Inclusive Preschool Programs. AB - This study takes an ecological approach to examine how children with developmental language disorder (DLD) interact with their classmates within early childhood special education (ECSE) inclusive classrooms. Participants were 124 children with DLD, 56 children with other disabilities, and 247 typically developing children (Mage = 52.42 months, SD = 6.27) from 56 ECSE inclusive classrooms. Results of social network analysis showed that children with DLD had significantly smaller peer social networks and were more likely to be isolated. Children tended to interact with peers with the same DLD status. These effects of children's DLD status were above and beyond the effects of children's social pragmatics skills. PMID- 30417945 TI - No evidence for sibling or parent-offspring coadaptation in a wild population of blue tits, despite high power. AB - Parent and offspring behaviors are expected to act as both the agents and targets of selection. This may generate parent-offspring coadaptation in which parent and offspring behaviors become genetically correlated in a way that increases inclusive fitness. Cross-fostering has been used to study parent-offspring coadaptation, with the prediction that offspring raised by non-relatives, or parents raising non-relatives, should suffer fitness costs. Using long-term data from more than 400 partially crossed broods of blue tits (Cyanistes caeruleus), we show that there is no difference in mass or survival between crossed and non crossed chicks. However, previous studies for which the evidence for parent offspring coadaptation is strongest compare chicks from fully crossed broods with those from non-crossed broods. When parent-offspring coadaptation acts at the level of the brood then partial cross-fostering experiments are not expected to show evidence of coadaptation. To test this, we performed an additional experiment (163 broods) in which clutches were either fully crossed, non-crossed, or partially crossed. In agreement with the long-term data, there was no evidence for parent-offspring coadaptation on offspring fitness despite high power. In addition there was no evidence of effects on parental fitness, nor evidence of sibling coadaptation, although the power of these tests was more modest. PMID- 30417946 TI - The translational science of hodgkin lymphoma. AB - Hodgkin Lymphoma (HL) is an unusual B-cell lymphoma because the malignant cells exist as a minority population in a densely cellular microenvironment. The microenvironment is comprised predominately of inflammatory and immune cells with fibrosis in some cases. There are multiple dysregulated signalling pathways that sustain HL within this microenvironment, such as the Nuclear factor-kappaB and Janus kinase/signal transducers and activators of transcription pathways. Advances in genomic medicine have enabled a better characterisation of the rare tumour cells and improved our understanding of the signalling mechanisms that exist between the malignant cell and its microenvironment. Current therapy for HL produces excellent clinical outcomes in most younger patients. However, problems with current treatment approaches include poorer outcomes in the elderly, toxicity of highly-effective combination chemotherapy regimens and relapse in high-risk patients. Better understanding of disease biology aids in upfront prognostication of patients, defines new methods for treatment monitoring and assists in the recognition of novel targets for therapy. Biology-driven therapies, including anti-CD30 antibody conjugates, cellular immunotherapies and immune modulation, particularly with checkpoint inhibitors, have changed treatment algorithms for relapsed/refractory patients. Future challenges exist in incorporating immune-based therapies earlier in treatment algorithms to reduce toxicity and prevent relapse for patients with HL. PMID- 30417947 TI - A case study of gastric-type adenocarcinoma in situ of the uterine cervix. PMID- 30417948 TI - Peroral Endoscopic Myotomy for Complex Achalasia and the POEM Difficulty Score. AB - BACKGROUND: Peroral endoscopic myotomy (POEM) for achalasia is technically more challenging to perform in patients with type III, multiple prior treatments, prior myotomy, and sigmoid-type. Here we present a series of consecutive patients with complex achalasia and introduce the POEM Difficulty Score (PDS). AIM: To demonstrate the application and discuss the utility of the PDS, and present the feasibility, safety, and efficacy of POEM in complex achalasia patients. METHODS: 40 consecutive POEMs were performed with 28 meeting the criteria for complex achalasia. The primary outcome was clinical success (Eckardt score <3) at a minimum of 3 months' follow-up. Secondary outcomes included: adverse events, procedural velocity and PDS. RESULTS: 28 complex and 12 non-complex POEM procedures were performed with 100% and 92% clinical success, respectively without any major adverse events with a median follow-up of 15 months (complex) and 8 months (non-complex) months. The mean velocities for non-complex, type III, prior myotomy, >4 procedures and sigmoid-type were: 4.4+/-1.6minutes/cm, 4.8+/ 1.5 mins/cm, 5.9+/-2.2mins/cm, 6.9+/-2.2minutes/cm and 8.2+/-3.2minutes/cm, respectively. The median PDS for non-complex, type III, prior myotomy, >4 treatments and sigmoid-type were 1 (0-3), 2 (0-4), 2.5 (1-6), 3 (2-6) and 3.5 (1 6), respectively. The PDS was shown to correlate well with the procedural velocity with a correlation coefficient of 0.772 (Spearman's p < 0.001). CONCLUSIONS: The PDS identifies the factors that contribute to challenging POEM procedures and correlates well with procedural velocity. The order of increasing difficulty of POEM in complex achalasia appears to be type III, prior myotomy, >4 treatments and sigmoid-type. This article is protected by copyright. All rights reserved. PMID- 30417949 TI - Unravelling the genetic loci for growth and carcass traits in Chinese Bamaxiang pigs based on a 1.4 million SNP array. AB - Bamaxiang pig is from Guangxi province in China, characterized by its small body size and two-end black coat colour. It is an important indigenous breed for local pork market and excellent animal model for biomedical research. In this study, we performed genomewide association studies (GWAS) on 43 growth and carcass traits in 315 purebred Bamaxiang pigs based on a 1.4 million SNP array. We observed considerable phenotypic variability in the growth and carcass traits in the Bamaxiang pigs. The corresponding SNP based heritability varied greatly across the 43 traits and ranged from 9.0% to 88%. Through a conditional GWAS, we identified 53 significant associations for 35 traits at p value threshold of 10-6 . Among which, 26 associations on chromosome 3, 7, 14 and X passed a genomewide significance threshold of 5 * 10-8 . The most remarkable loci were at around 30.6 Mb on chromosome 7, which had growth stage-dependent effects on body lengths and cannon circumferences and showed large effects on multiple carcass traits. We discussed HMGA1 NUDT3, EIF2AK1, TMEM132C and AFF2 that near the lead SNP of significant loci as plausible candidate genes for corresponding traits. We also showed that including phenotypic covariate in GWAS can help to reveal additional significant loci for the target traits. The results provide insight into the genetic architecture of growth and carcass traits in Bamaxiang pigs. PMID- 30417950 TI - Does global drug innovation correspond to burden of disease? The neglected diseases in developed and developing countries. AB - Although it is commonly argued that there is a mismatch between drug innovation and disease burden, there is little evidence on the magnitude and direction of such disparities. In this paper, we measure inequality in innovation, by comparing research and development activity with population health and gross domestic product data across 493 therapeutic indications to globally measure: (a) drug innovation, (b) disease burden, and (c) market size. We use concentration curves and indices to assess inequality at two levels: (a) broad disease groups and (b) disease subcategories for both 1990 and 2010. For some top burden disease subcategories (i.e., cardiovascular and circulatory diseases, neoplasms, and musculoskeletal disorders), innovation is disproportionately concentrated in diseases with high disease burden and large market size, whereas for others (i.e., mental and behavioral disorders, neonatal disorders, and neglected tropical diseases) innovation is disproportionately concentrated in low burden diseases. These inequalities persisted over time, suggesting inertia in pharmaceutical research and development in tackling the global health challenges. Our results confirm quantitatively assertions about the mismatch between disease burden and pharmaceutical innovation in both developed and developing countries and highlight the disease areas for which morbidity and mortality remain unaddressed. PMID- 30417951 TI - Evaluation of varenicline usage on ventricular repolarization after smoking cessation. AB - BACKGROUND: Varenicline, which is a selective partial agonist of the alpha4-beta2 nicotinic acetylcholine receptor, is used for the smoking cessation pharmacotherapy. Cardiovascular adverse effects have been reported after varenicline usage in patients who stop smoking. We investigated the effect of varenicline usage on ventricular repolarization after smoking cessation. METHODS: In this prospective cohort study, we evaluated the cardiac arrhythmic effects of varenicline by comparing smoking patients (n = 214) before and after varenicline usage. Varenicline administered patients were also compared to ex-smoker individuals (n = 50) who quit smoking without varenicline usage in terms of ventricular repolarization parameters. RESULTS: After calculated according to Fridericia's and Framingham's formulas, QTc intervals were significantly increased when patients compared before and after smoking cessation with varenicline (402.9 +/- 24.5 ms vs. 409.1 +/- 25.0 ms p < 0.001 and 376.5 +/- 15.2 ms, vs. 380.6 +/- 13.5 ms; p < 0.001, respectively). There was no arrhythmic event during the follow-up. The change in Tp-e and QTc following varenicline usage was negatively correlated with the smoking packet/year. (rho: -0.443, p < 0.001 and rho = -0.601, p < 0.001) CONCLUSION: Varenicline usage was demonstrated to prolong ventricular repolarization parameters similar to animal studies. Varenicline may have a role to predispose cardiac dysrhythmias after utilization in smoking cessation. PMID- 30417952 TI - Chronic alcohol exposure induced gut microbiota dysbiosis and its correlations with neuropsychic behaviors and brain BDNF/Gabra1 changes in mice. AB - Alcohol addiction can cause brain dysfunction and many other diseases. Recently, increasing evidences have suggested that gut microbiota plays a vital role in regulating alcohol addiction. However, the exact mechanism has not yet been elucidated. Here, our study focused on the intestinal bacteria alternations and their correlations with alcohol-induced neuropsychic behaviors. When consuming alcohol over 3-week period, animals gradually displayed anxiety/depression-like behaviors. Moreover, 16S rRNA sequencing showed significant intestinal microflora dysbiosis and distinct community composition. Actinobacteria and Cyanobacteria were both increased at the phylum level. At the genus level, Adlercreutzia spp., Allobaculum spp., and Turicibacter spp. were increased whereas Helicobacter spp. was decreased. We also found that the distances in inner zone measured by open field test and 4% (v/v) alcohol preference percentages were significantly correlated with Adlercreutzia spp. The possible mechanisms were explored and we found the expression of brain-derived neurotrophic factor (BDNF) and alpha1 subunit of gamma-aminobutyric acid A receptor (Gabra1) were both decreased in prefrontal cortex (PFC). Especially, further correlation analyses demonstrated that decreased Adlercreutzia spp. was positively correlated with alcohol preference and negatively correlated with anxiety-like behavior and BDNF/Gabra1 changes in PFC. Similar relationships were observed between Allobaculum spp. and alcohol preference and BDNF changes. Helicobacter spp. and Turicibacter spp. were also correlated with PFC BDNF and hippocampus Gabra1 level. Taken together, our study showed that gut microbiota dysbiosis during chronic alcohol exposure was closely correlated with alcohol-induced neuropsychic behaviors and BDNF/Gabra1 expression, which provides a new perspective for understanding underlying mechanisms in alcohol addiction. (c) 2018 BioFactors, 2018. PMID- 30417953 TI - Low-level primary clarithromycin resistance of Helicobacter pylori in Burkina Faso: A prospective molecular study. PMID- 30417955 TI - Cytological features of Dyshormonogenetic Goitre: A diagnostic pitfall. AB - Dyshormonogenetic goitre, being rare, infrequently reaches the cytopathologist's desk. This letter reports a case of a child with dyshormonogenetic goitre, highlighting its cytological features and common differential diagnosis. Dyshormonogenetic goitre (DG) is a rare cause of congenital hypothyroidism, resulting from lack of enzymes necessary for biosynthesis/ transport of thyroid hormones. This article is protected by copyright. All rights reserved. PMID- 30417954 TI - Diagnostic utility and pitfalls of intraoperative pulmonary imprint cytology based on final pathological diagnoses. AB - OBJECTIVE: This study aimed to determine the reliability of imprint cytology (IC) for intraoperative diagnosis of pulmonary lesions. METHODS: We reviewed 113 cases of pulmonary lesion resection for which a scratch imprint was made intraoperatively. We divided the specimens into two groups (benign and malignant) and compared the scratch IC-based diagnoses against the final histopathological diagnoses in each group for concordance. We also analysed those cases in which the scratch IC preparation was classified as inadequate. RESULTS: The sensitivity, specificity, positive and negative predictive values, and accuracy of IC diagnoses among the patient cohort were 87.7% (72/82), 100% (7/7), 100% (72/72), 41.2% (7/17) and 88.8% (79/89), respectively. IC yielded some false negative results in terms of malignancy, although most of these imprints were of early cancer or cancer with mild cytological atypia. Five (41.6%) of 12 lesions for which the imprint was deemed inadequate were diagnosed histologically as granulomas with caseous necrosis. CONCLUSION: IC-based diagnoses of pulmonary lesions as malignant corresponded well with the final histopathological diagnoses, but IC-based diagnoses of negative (ie, without malignant cells) were not as reliable. Thus, pathologists should recognise the limitations of IC, especially for identifying malignant lesions. Also, the possibility of latent bacterial infection in a granuloma with caseous necrosis indicates that an IC preparation deemed inadequate for diagnosis should not be ignored. PMID- 30417956 TI - Adenosquamous carcinoma of the papilla of Vater: A phenotypic heterogeneity characterized by a common molecular landscape. PMID- 30417957 TI - Synovial sarcoma diagnosis on fine needle cytology sample confirmed by fluorescence in situ hybridisation. PMID- 30417958 TI - A model of cholinergic suppression of hippocampal ripples through disruption of balanced excitation/inhibition. AB - Sharp wave-ripples (140-220 Hz) are patterns of brain activity observed in the local field potential of the hippocampus which are present during memory consolidation. As rodents switch from memory consolidation to memory encoding behaviors, cholinergic inputs to the hippocampus from neurons in the medial septum-diagonal band of Broca cause a marked reduction in ripple incidence. The mechanism for this disruption in ripple power is not fully understood. In isolated neurons, the major effect of cholinergic input on hippocampal neurons is depolarization of the membrane potential, which affects both hippocampal pyramidal neurons and inhibitory interneurons. Using an existing model of ripple frequency oscillations that includes both pyramidal neurons and interneurons (Brunel and Wang, J Neurophysiol 2003; 90:415-30), we investigated the mechanism whereby depolarizing inputs to these neurons can affect ripple power and frequency. We observed that ripple power and frequency are maintained, as long as inputs to pyramidal neurons and interneurons are balanced. Preferential drive to pyramidal neurons or interneurons, however, affects ripple power and can disrupt ripple oscillations by pushing ripple frequency higher or lower. Thus, an imbalance in drive to pyramidal neurons and interneurons provides a means whereby cholinergic input can suppress hippocampal ripples. This article is protected by copyright. All rights reserved. PMID- 30417959 TI - The hippocampus is critical for value-based decisions guided by dissociative Inference. AB - The hippocampus supports flexible decision-making through memory integration: bridging across episodes and inferring associations between stimuli that were never presented together (associative inference). A pre-requisite for memory integration is flexible representations of the relationships between stimuli within episodes (AB) but also of the constituent units (A,B). Here we investigated whether the hippocampus is required for parsing experienced episodes into their constituents to infer their re-combined within-episode associations (dissociative inference). In three experiments male rats were trained on an appetitive conditioning task using compound auditory stimuli (AB+, BA+, CD-, DC ). At test either the compound or individual stimuli were presented as well as new stimuli. Rats with hippocampal lesions acquired and retained the compound discriminations as well as controls. Single constituent stimuli (A, B, C, D) were presented for the first time at test, so the only value with which they could be associated was the one from the compound to which they belonged. Controls inferred constituent tones' corresponding values while hippocampal rats did not, treating them as merely familiar stimuli with no associated value. This finding held whether compound training occurred before or after hippocampal lesions, suggesting that hippocampus-dependent inferential processes more likely occur at retrieval. The findings extend recent discoveries about the role of the hippocampus in intrinsic value representation, demonstrating hippocampal contributions to allocating value from primary rewards to individual stimuli. Importantly, we discovered that dissociative inferences serve to restructure or reparse patterns of directly acquired associations when animals are faced with environmental changes and need to extract relevant information from a multiplex memory. The hippocampus is critical for this fundamental flexible use of associations. This article is protected by copyright. All rights reserved. PMID- 30417960 TI - Massive His bundle injury current corresponds with acute trauma and slowing of conduction that has to subside before pacing threshold assessment. PMID- 30417961 TI - "Integrated diagnosis" of pilocytic astrocytoma: Molecular diagnostic procedure for an unusual case. AB - A 24 year-old female presented with a mass lesion in the right temporal lobe. This case was difficult to diagnose using histological and immunological methods and therefore molecular analyses were applied to provide a definitive diagnosis. The tumor was well-demarcated, partially cystic, and irregularly-enhanced on gadolinium-enhanced T1-weighted magnetic resonance images. Pathologically, a large part of the tumor consisted of cells with fine cytoplasmic processes on a myxoid and mucinous background. Cells formed a microcystic structure around the mucinous tissue. Numerous eosinophilic granular bodies, but not Rosenthal fibers, were present. The solid and compact regions of the tumor were composed of fasciculation of dense fibrous glial tissues and occasional multinucleated giant cells. Tumor cells and their fragmented cytoplasmic processes were positively stained with GFAP, while eosinophilic granular bodies were both positive and negative. Xanthomatous changes were not detected and the reticulin fibers were restricted to vascular tissues. The MIB1 index was scored as approximately 10%. In molecular analyses of BRAF, the KIAA1549-BRAF (K16-B9) fusion gene was detected in all tumor regions, whereas BRAF V600E mutation was not detected by either conventional Sanger sequencing or the Eprobe-PCR method. Based on the results of the molecular analyses, this case was diagnosed as pilocytic astrocytoma. PMID- 30417962 TI - Sensitivity of MG-ADL for generalized weakness in myasthenia gravis. AB - INTRODUCTION: MG-ADL (Myasthenia Gravis Activities of Daily Living) is a commonly used questionnaire in MG trials. To investigate whether MG-ADL is equally sensitive to oculobulbar and generalized weakness, we analyzed its correlation with the oculobulbar and generalized domain of the quantitative myasthenia gravis (QMG) score (QMGob and QMGgen, respectively). To test whether the sensitivity of MG-ADL for generalized weakness could be improved, we investigated whether adding questions on generalized weakness would increase its correlation with QMGgen. METHODS: We analyzed MG-ADL, QMG and ACTIVLIM, an ADL questionnaire focusing on generalized weakness, in a prospective cohort of 112 MG patients. We used a generalized linear model to calculate the correlation of MG-ADL with QMGob and QMGgen and to assess the additional value of ACTIVLIM on top of MG-ADL for its correlation with QMGgen. RESULTS: MG-ADL had a higher correlation with QMGob than with QMGgen (B=0.68; p<0.001 and B = 0.38; p<0.001, respectively). A similar trend was found for changes in the scores (B = 0.68; p = 0.132 and B = 0.39; p = 0.492, respectively). ACTIVLIM had a significant additional value on top of MG ADL in the prediction of QMGgen, both cross-sectionally (B = -0.61, p < 0.001) and for changes within individual patients (B = -0.93, p = 0.041). DISCUSSION: MG ADL has a lower sensitivity for generalized weakness than for oculobulbar weakness. Adding questions on generalized weakness would improve the sensitivity of the MG-ADL for generalized weakness. This article is protected by copyright. All rights reserved. PMID- 30417963 TI - Hydrogen-Bonded Networks: Molecular Recognition of Cyclic Alcohols in Enantiopure Alleno-Acetylenic Cage Receptors. AB - Enantiopure (P)4 - and (M)4 -alleno-acetylenic cage (AAC) receptors form circular fourfold hydrogen-bonding networks in their closed cage conformation. Theoretical studies reveal a preferential clockwise (cw) orientation of the H-bonding array for (P)4 -configured and counterclockwise (ccw) for (M)4 -configured receptors (DeltaEcw-ccw =-2.6 to -3.1 kcal mol-1 ). Solution and solid-state studies show how the H-bonding network of the receptor is expanded upon encapsulation of alcohol-containing guests. Topologies reminiscent of those found in isolated water clusters are observed: circular fourfold & docking, pentagonal, linear fivefold, and hexagonal boat-shaped. Expansion of the H-bonding network together with optimal space occupancy yields very high ligand affinities (DeltaG293 K = 9.0 kcal mol-1 for endo-tropine). The H-bonding network in the complexes also contributes substantially to the enantioselective complexation of chiral diols, such as (R,R)- and (S,S)-trans-cyclohexane-1,2-diol. PMID- 30417964 TI - Do we still need to demonstrate the survival benefit of pancreas transplantation? PMID- 30417965 TI - Improved Thermotolerance of Genome-Reduced Pseudomonas putida EM42 Enables Effective Functioning of the PL /cI857 System. AB - The higher intracellular ATP levels of genome-edited strains of P. putida that result from deleting various energy-consuming functions has been exploited for expanding the window of thermal tolerance of this bacterium. Unlike instant growth halt and eventual death of the naturally occurring strain P. putida KT2440 at 42 degrees C, the EM42 variant maintained growth and viability of most of the population at the higher temperature for at least 6 h. The authors took advantage of this quality for implementing a robust thermo-inducible heterologous expression device in this species. To this end, the cI857/PL pair of the lambda phage of Escherichia coli was reshaped as a functional cargo that followed the SEVA (Standard European Vector Architecture) format. Quantitation of the transcriptional output of the resulting expression device with GFP reporter technology in various gene dosages identified conditions of unprecedented induced/uninduced ratios (>300 folds) and very high total transcriptional capacity in this bacterial host. The broad-host range nature of the cognate replication origins makes expression vectors pSEVA2214 (low plasmid copy number), pSEVA2314 (medium), and pSEVA2514 (high) to cover a wide range of heterologous expression needs in P. putida and possibly other Gram-negative species. PMID- 30417967 TI - Fabrication and Characterization of Recombinant Silk-Elastin-Like-Protein (SELP) Fiber. AB - Silk-elastin-like-protein polymers (SELPs) are genetically engineered recombinant protein sequences consisting of repeating units of silk-like and elastin-like blocks. By combining these entities, it is shown that both the characteristic strength of silk and the temperature-dependent responsiveness of elastin can be leveraged to create an enhanced stimuli-responsive material. It is hypothesized that SELP behavior can be influenced by varying the silk-to-elastin ratio. If the responsiveness of the material at different ratios is significantly different, this would allow for the design of materials with specific temperature-based swelling and mechanical properties. This study demonstrates that SELP fiber properties can be controlled via a temperature transition dependent on the ratio of silk-to-elastin in the material. SELP fibers are experimentally wet spun from polymers with different ratios of silk-to-elastin and conditioned in either a below or above transition temperature (T t ) water bath prior to characterization. The fibers with higher elastin content showed more stimuli responsive behavior compared to the fibers with lower elastin content in the hot (57-60 degrees C) versus cold (4-7 degrees C) environment, both computationally and experimentally. This work builds a foundation for developing SELP materials with well-characterized mechanical properties and responsive features. PMID- 30417968 TI - Damaging Intermolecular Energy and Proton Transfer Processes in Alpha-Particle Irradiated Hydrogen-Bonded Systems. AB - Although the biological hazard of alpha-particle radiation is well-recognized, the molecular mechanisms of biodamage are still far from being understood. Irreparable lesions in biomolecules may not only have mechanical origin but also appear due to various electronic and nuclear relaxation processes of ionized states produced by an alpha-particle impact. Two such processes were identified in the present study by considering an acetylene dimer, a biologically relevant system possessing an intermolecular hydrogen bond. The first process is the already well-established intermolecular Coulombic decay of inner-valence-ionized states. The other is a novel relaxation mechanism of dicationic states involving intermolecular proton transfer. Both processes are very fast and trigger Coulomb explosion of the dimer due to creation of charge-separated states. These processes are general and predicted to occur also in alpha-particle-irradiated nucleobase pairs in DNA molecules. PMID- 30417969 TI - Nanographene Imides Featuring Dual-Core Sixfold [5]Helicenes. AB - A novel kind of nanographene imide, namely pentaperylene decaimides (PPD) featuring dual-core sixfold [5]helicenes and ten imide groups, was efficiently obtained. Among the possible 28 stereoisomers, which include 14 pairs of enantiomers, only one pair of enantiomers was obtained selectively which could be separated by chiral HPLC. Single-crystal X-ray diffraction analyses revealed that it exhibits a D2 -symmetric "four-bladed propeller" conformation composed of conjoined double "three-bladed propeller", which is very stable and could not convert into other conformations even when heated up to 200 degrees C. Meanwhile, enantiomerically pure PPD also exhibits an excellent resistance to thermally induced racemization, which makes it a promising candidate for various applications in chiral material science. PMID- 30417970 TI - Weight Trends in Veterans With and Without Diabetes, 2000 to 2014. AB - OBJECTIVE: The aim of this study was to assess weight trends and diabetes prevalence among US veterans. METHODS: Information from the Veterans Affairs Informatics and Computing Infrastructure Corporate Data Warehouse was used to construct data sets that included demographic data, diabetes status, and weight observations for males and females. Secular and longitudinal trends in mean weight were analyzed. RESULTS: A total of 4,527,865 patients born from 1915 to 1984 with weight data during 2000 to 2014 were included; 36.8% had diabetes. Mean weight at baseline was higher in men and women with diabetes (97 kg and 88 kg, respectively) than in men and women without diabetes (86 kg and 76 kg, respectively). Mean weight increased from 2000 to 2014 (P < 0.001) at rates of 0.36 kg/y in women without diabetes, 0.28 kg/y in men with diabetes, 0.25 kg/y in men without diabetes, and 0.22 kg/y in women with diabetes. Weight decreased in those born before 1940, was stable in those born between 1940 and 1949, and increased in those born since 1950. CONCLUSIONS: Among contemporary veterans, women without diabetes are gaining weight more rapidly than women with diabetes or men. Younger veterans are gaining weight more rapidly than older veterans. Further efforts are needed to prevent weight gain in veterans, especially among women. PMID- 30417972 TI - Mechanochemistry of gaseous reactants. AB - In recent years, the exertion of mechanical energy on chemical systems has repeatedly proven beneficial to facilitate chemical transformations in various areas in chemistry. Today, a systematic body of evidence indicates that mechanochemistry holds great promise to become a game-changer in chemical synthesis. Not only has mechanochemistry gained recognition for its ability to permit access to products that are inaccessible by established means such as purely thermal activation. It is also well acknowledged that mechanochemical reactions often outperform their solution-based counterparts in terms of sustainability. Intuitively, most mechanochemical reactions carried out by ball milling techniques are associated with transformations of solids and liquids. However, in recent times, the number of mechanochemical reactions that include gaseous reactants has increased. Thus, the aim of this minireview is to, first, provide an overview of recent chemical reactions involving gaseous samples by ball milling techniques, and second, to feature the advances in ball milling setups and technology that have enabled the safe handling of gaseous reagents by mechanochemistry. Additionally, examples of reactions proceeding at the interface of solid/liquid/gas-gas systems that led to significant improvements in reactivity or selectivity will be highlighted. Finally, we hope to stimulate future work tackling remaining challenges in the area of mechanochemistry. PMID- 30417971 TI - The Nigerian health information system policy review of 2014 : the need, content, expectations and progress. AB - BACKGROUND: Nigeria's national health information system (HIS) data sources are grouped into institutional and population based data that traverse many government institutions. Communication and collaboration between these institutions are limited, fraught with fragmentation and challenges national HIS functionality. OBJECTIVES: The objective of this paper was to share insights from and the implications of a recent review of Nigeria's HIS policy in 2014 that resulted in its substantial revision. We also highlight some subsequent enactments. REVIEW PROCESS AND OUTCOMES: In 2013, Nigeria's Federal Ministry of Health launched an inter-ministerial and multi-departmental review of the National Health Management Information System policy of 2006. The review was guided by World Health Organization's 'Framework and Standards for Country Health Information Systems'. The key finding was a lack of governance mechanisms in the execution of the policy, including an absent data management governance process. The review also found a multiplicity of duplicative, parallel reporting tools and platforms. CONCLUSION: Recommendations for HIS Policy revisions were proposed to and implemented by the Federal Government of Nigeria. The revised HIS policy now provides for a strong framework for the leadership and governance of the HIS with early results. PMID- 30417973 TI - Surfactant-assisted-water-exposed versus surfactant-aqueous-solution-exposed electrospinning of novel super hydrophilic polycaprolactone based fibers: Analysis of drug release behavior. AB - Surface hydrophilicity and scaffold integrity determine the drug release behavior of drug loaded electrospun fibrous mats. When mixture miscibility is acceptable, blend electrospinning of hydrophobic with hydrophilic polymers can improve scaffold hydrophilicity while the hydrophobic polymer maintains the mechanical strength of scaffold. Polycaprolactone (PCL) and Pluronic P123 (P123) blend electrospinning has been investigated. In routine blend electrospinning, surface enrichment of Pluronic sets a limit for P123 weight ratio in which exceeding from that limit causes the excess P123 to be accumulated within the electrospun fiber core. To overcome this setback, a method named surfactant assisted water exposed (SAWE) electrospinning was introduced which was proven to be effective for increasing the surface enrichment of Pluronic. In order to test the validity of this method, the electrospinning of solution containing PCL which is exposed to aqueous solution of P123 was investigated. This new method was named surfactant aqueous solution exposed (SASE) electrospinning. Myelin formation at the contact interface of aqueous solution and chloroform solution was studied and it was found that this layer can effectively barricade the migration of Pluronic chains between immiscible phases. For SASE, fiber surface coverage by P123 was uneven and loose. Electrospun scaffolds from SAWE and SASE were loaded with drug to investigate the effect of the exposure time during electrospinning on in vitro drug release. By increasing the exposure time, the abnormal two-stage phased release profile of SAWE became normal with moderate initial burst. Longer exposure time increased the initial burst of the drug loaded SASE fibers. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2018. PMID- 30417974 TI - Multi-Centre Ethics and Research Governance Review Can Impede Non-Interventional Clinical Research. AB - BACKGROUND: The Inter-jurisdictional National Mutual Acceptance (NMA) scheme for Human Research Ethics Committee (HREC) approvals of human research is designed to reduce the reported delays and costs of ethical review. Introduction of the NMA set forth an uncoupling of the ethics and governance review processes, permitting a single ethical review for multiple sites, whilst continuing separate governance review for each centre covering financial and operational aspects of the research project. AIM: Compare the time required to gain ethics and governance approvals in Australia for a non-interventional investigator-led study from December 2015, to approval times for an earlier pre-NMA study utilising a similar study design and study sites, and evaluate the effect that the NMA has had on total approval time for non-interventional multi-centre projects. METHODS: We recorded the time taken to obtain ethics and governance approval at 16 sites for our nationwide low risk non-interventional study looking at the prevalence and aetiology of non tuberculous mycobacterial infection in people with cystic fibrosis (CF) in Australia. RESULTS: Applications were submitted to three hospital and one university HREC to conduct our study at 16 hospital sites, HREC approval took from 16 - 79 days (median 28). Subsequent site-specific governance approval at 15 hospital sites took 23 - 225 days (median 83). The entire process of gaining ethical and governance approval to conduct the study at 16 sites took 24 months at an estimated cost of $AUD56000 ($USD 42000). CONCLUSIONS: Lengthy governance approval processes negate benefits gained from centralised ethics review under the NMA. This article is protected by copyright. All rights reserved. PMID- 30417975 TI - The Rising Cost of Diabetes: Can DiRECT Tip the Scales? AB - The cost of treating diabetes mellitus has risen sharply in recent years because of an increasing number of patients with type 2 diabetes and obesity and a rapidly expanding repertoire of expensive nongeneric medications. Despite the call for a new treatment paradigm by the American Diabetes Association to mitigate this cost, recent Medicare Part D expenditure data show that this call remains unanswered. The Diabetes Remission Clinical Trial, published in The Lancet, adds support to a different path, demonstrating success with intensive lifestyle intervention followed by structured support for long-term weight loss maintenance. Nearly half of patients enrolled were able to achieve remission of their diabetes with hemoglobin A1c < 6.5% and an improvement of their quality of life. Although only from one trial, and of limited duration, these results should provide optimism for providers and patients alike and support future work toward an evidence base for non-medication-based management of diabetes. PMID- 30417976 TI - Novel mutations identified in patients with tooth agenesis by whole-exome sequencing. AB - OBJECTIVES: To identify potentially pathogenic mutations for tooth agenesis by whole-exome sequencing. SUBJECTS AND METHODS: Ten Chinese families including five families with ectodermal dysplasia (syndromic tooth agenesis) and five families with selective tooth agenesis were included. Whole-exome sequencing was performed using genomic DNA. Potentially pathogenic mutations were identified after data filtering and screening. The pathogenicity of novel variants was investigated by segregation analysis, in silico analysis, and functional studies. RESULTS: One novel mutation (c.441_442insACTCT) and three reported mutations (c.252delT, c.463C>T, and c.1013C>T) in EDA were identified in families with ectodermal dysplasia. The novel EDA mutation was co-segregated with phenotype. A functional study revealed that NF-kappaB activation was compromised by the identified mutations. The secretion of active EDA was also compromised detection by western blotting. Novel Wnt10A mutations (c.521T>C and c.653T>G) and EVC2 mutation (c.1472C>T) were identified in families with selective tooth agenesis. The Wnt10A c.521T>C mutation and the EVC2 c.1472C>T mutation were considered as pathogenic for affecting highly conserved amino acids, co-segregated with phenotype and predicted to be disease-causing by SIFT and PolyPhen2. Moreover, several reported mutations in PAX9, Wnt10A, and FGFR3 were also detected. CONCLUSIONS: Our study expanded our knowledge on tooth agenesis spectrum by identifying novel variants. PMID- 30417977 TI - Susceptibility of European freshwater fish to climate change: Species profiling based on life-history and environmental characteristics. AB - Climate change is expected to strongly affect freshwater fish communities. Combined with other anthropogenic drivers, the impacts may alter species spatio temporal distributions and contribute to population declines and local extinctions. To provide timely management and conservation of fishes, it is relevant to identify species that will be most impacted by climate change and those that will be resilient. Species traits are considered a promising source of information on characteristics that influence resilience to various environmental conditions and impacts. To this end, we collated life-history traits and climatic niches of 443 European freshwater fish species and compared those identified as susceptible to climate change to those that are considered to be resilient. Significant differences were observed between the two groups in their distribution, life history, and climatic niche, with climate-change-susceptible species being distributed within the Mediterranean region, and being characterized by greater threat levels, lesser commercial relevance, lower vulnerability to fishing, smaller body and range size, and warmer thermal envelopes. Based on our results, we establish a list of species of highest priority for further research and monitoring regarding climate-change susceptibility within Europe. The presented approach represents a promising tool to efficiently assess large groups of species regarding their susceptibility to climate change and other threats, and to identify research and management priorities. PMID- 30417978 TI - Diagnostic role of cytology in serous effusions of patients with hematologic malignancies. AB - BACKGROUND: We investigated serous effusions occurring during the course of an already known hematologic neoplasia or as a first manifestation of it. We correlated cytology results with flow cytometry results, when available. In the absence of flow cytometry, our correlation was based on clinical follow up information obtained retrospectively. We evaluated our results in relation to the data of the literature and we considered some new suggestions for the improvement of cytology service. METHODS: Serous effusions in hematologic patients were retrieved from the files of the Department of Cytology, Laiko Hospital, for a period of 2 years. All patients had enrolled either a previous hematologic history, or a suspicious clinical and imaging status. Seventy-three serous effusions were included. Cytology reports consisting of morphology and immunocytochemistry assessment were correlated to flow cytometry results and, occasionally, to clinical follow-up. RESULTS: In the group of patients with previous history, sensitivity was 82.76%, positive predictive value was 100%, specificity 100%, and negative predictive value was 58.33%. In the group of patients without previous history, sensitivity and positive predictive value were both 91%, whereas specificity and negative predictive value could not be estimated. CONCLUSION: We provide evidence that the diagnostic accuracy of cytology with the adjunct of immunocytochemistry is high compared to flow cytometry for detecting hematologic malignancies. In order to improve clinical performance, it is suggested that a cytology triage of serous effusions in all patients with hematologic malignancy must be implemented. PMID- 30417979 TI - Holding Eternity in one's hand: First three-dimensional reconstruction and printing of the heart from 2700 years-old Egyptian mummy. AB - The heart in ancient Egyptian mummification procedure is the central organ that should stay in place in the chest and waiting for the afterlife judgment. Here we show the first case of three-dimensional (3D) CT scan reconstruction of a mummified heart from a person embalmed in Egypt around 2,700 years ago, and present a 3D printing of the same heart using a low-cost yet accurate 3D printer. A multi-slice computed tomography scanner was used to scan the mummy. We applied the following radiological protocol: 80 keV and 140 keV, 140 mAs, with a slice thickness of 0.9 mm. The mummified heart and ascending aorta were extracted with semi- automatic segmentation. We used a low-cost 3D printer (Up plus 2) using fusion deposition modelling technology. The 3D printed model was then painted with acrylic paint to color code structures of interest. The 3D CT multi resolution imaging allows us to identify the gross anatomy of the heart, the ascending aorta, the pulmonary arteries, and the presence of multiple atherosclerosis lesions. Using 3D printed model we recognized upper auricle, vein cave inferior, and the two coronary arteries. The brachiocephalic artery, common carotid artery, and left subclavian artery were clearly cut to dissociate the heart from surrounding tissues. This multi-3D approach allows for a better understanding of complex and distorted anatomy of the mummified heart, of paleopathology (arteriosclerosis), and of mummification techniques. This article is protected by copyright. All rights reserved. PMID- 30417980 TI - Factors associated with long-term mortality for stroke unit patients in Latvia. AB - AIM: The aim of this study was to evaluate how pre-stroke risk factors, neurological symptoms, and the level of disability shortly after stroke are associated with poststroke mortality during a 7-year period after stroke, for persons treated in a stroke unit. METHODS: The data of 231 patients were included in the study. Patients who were treated in the stroke unit at the Riga East University Hospital between February 1, 2009, and July 20, 2009, were included in this study. Three stepwise Cox proportional hazard analyses were performed to analyze mortality in the 7 years following stroke. Pre-stroke risk factors (type of stroke, arterial hypertension, diabetes mellitus, atrial fibrillation, smoking, alcohol abuse, obesity, recurrent stroke, age, gender), neurological symptoms (motor deficit, sensory disturbance, aphasia, poststroke urinary incontinence (PSUI), mental status), and limitations of activity (feeding, bathing, grooming, dressing, toilet use, transfers, mobility, stairs) were evaluated as factors associated with mortality after stroke. RESULTS: A total of 145 (62.8%) patients died during the study period. The final model for each group of factors included only one of the factors used for the analysis. Patients who had alcohol abuse were 40% more likely to die earlier. The hazard for those with PSUI is 1.72 times higher than those without PSUI. The independence in grooming showed a 39% lower likelihood of dying earlier. CONCLUSION: Alcohol abuse as a pre-stroke risk factor, poststroke urinary incontinence as a neurological symptom, and dependence in grooming as a factor of disability were associated with earlier mortality in the first seven years after stroke. PMID- 30417981 TI - Intraoperative liquid-based cytology of rinsed tissue fragments from head and neck lesions. AB - BACKGROUND: Intraoperative diagnosis is an essential tool for the rapid diagnostic assessment of clinically critical head and neck lesions. Thus, we assumed that a combination of frozen section histological and cytological diagnoses may be preferable. Here, we investigated a relatively new method called liquid-based cytology of rinsed tissue fragments (LBC-RTF) and compared this method with intraoperative histological diagnosis. METHODS: We used 68 tissue biopsies (9 brains, 8 lymph nodes, 22 salivary glands, and 29 thyroid samples). Samples submitted for intraoperative consultation were divided into two-halves: one was used to prepare frozen sections, and the other was prepared for LBC-RTF by washing with PreservCyt. We then compared the final diagnosis obtained from permanent sections with the intraoperative histological diagnosis based on frozen sections and examination of LBC-RTF preparations. RESULTS: The accuracy of LBC RTF was higher than that of intraoperative histological diagnosis alone, based on frozen sections of every organ (LBC-RTF: 91.2% vs intraoperative histological diagnosis: 80.9%). With LBC-RTF, artifacts that are commonly observed in frozen sections were not present. In addition, even with challenging cases from which it is impossible to prepare frozen sections, intraoperative diagnosis was possible using the LBC-RTF technique. CONCLUSION: Both histological and cytological intraoperative diagnoses were possible during a surgery if the LBC-RTF technique was used. Moreover, our findings suggest that LBC-RTF improved the diagnostic accuracy of traditional intraoperative diagnosis. PMID- 30417982 TI - Methylphenidate promotes the interaction between motor cortex facilitation and attention in healthy adults: A combined study using event-related potentials and transcranial magnetic stimulation. AB - OBJECTIVE: This study investigated simultaneously the impact of methylphenidate (MPH) on the interaction of inhibitory and facilitative pathways in regions processing motor and cognitive functions. METHOD: Neural markers of attention and response control (event-related potentials) and motor cortical excitability (transcranial magnetic stimulation) and their pharmacological modulation by MPH were measured simultaneously in a sample of healthy adults (n = 31) performing a cued choice reaction test. RESULTS: Methylphenidate modulated attentional gating and response preparation processes (increased contingent negative variation) and response inhibition (increased nogo P3). N1, cue- and go-P3 were not affected by MPH. Motor cortex facilitation, measured with long-interval cortical facilitation, was increased under MPH in the nogo condition and was positively correlated with the P3 amplitude. CONCLUSION: Methylphenidate seems particularly to enhance response preparation processes. The MPH-induced increased motor cortex facilitation during inhibitory task demands was accompanied by increased terminal response inhibition control, probably as a compensatory process. PMID- 30417983 TI - PIM3 Functions as Oncogenic Factor and Promotes the Tumor Growth and Metastasis in Colorectal Cancer. AB - Colorectal cancer (CRC) is one of the common human malignancies. Discovery and identification of novel therapeutic target is imperative to improve the prognosis of CRC patients. As a member of the PIM family, PIM3 has been found to be overexpressed in a variety of cancerous tumors. In this study, we evaluated the expression of PIM3 in CRC tissues and analyzed the role of PIM3 in CRC. Our results showed that PIM3 expression was significantly higher in CRC tissues compared with adjacent noncancerous tissues. The PIM3 expression level was found to be correlated with advanced disease stage and lymph node metastasis. Moreover, PIM3 was found to be able to predict poor prognosis in CRC patients as an independent factor. In vitro studies also showed that knockdown of PIM3 exhibited inhibitory effect on cell growth, promoted cell apoptosis and dampened invasive capability of HCT116 and SW620 cells. Moreover, PIM3 knockdown was able to delay tumor growth and suppress lung metastasis in xenograft model. Our results indicated that PIM3 is a potential therapeutic target for CRC. This article is protected by copyright. All rights reserved. PMID- 30417984 TI - Ultrasound-guided fine needle aspiration cytology in the diagnosis of hepatic and pancreatic perivascular epithelioid cell tumors: A case series. AB - Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors that can affect any part of the body. They can be sporadic or arise in the setting of tuberous sclerosis (TSC). In this article, we report a series of three hepatic and two pancreatic PEComas diagnosed preoperatively with ultrasound-guided fine needle aspiration (FNA). All patients were female (age range 28-70), had no personal history of TSC and presented with a single, localized painless mass. Rapid on-site evaluation (ROSE) of cytologic samples was performed for all cases to evaluate for cellular content and adequacy of specimens. Direct smears and cell block preparations revealed a proliferation of medium to large polygonal epithelioid cells, with abundant eosinophilic and vacuolated cytoplasm, arranged in sheets and nests. On immunohistochemistry (IHC), neoplastic cells showed co expression of melanocytic and smooth muscle markers and a diagnosis of PEComa was rendered. PEComas of the pancreas and liver are rare neoplasms, but should always be considered when examining "clear cell" neoplasms, especially in young female patients. If good quality cytologic samples are obtained by FNA, a correct diagnosis can be achieved with the help of IHC. This is of particular importance in order to plan adequate surgical strategy and to avoid overtreatment. PMID- 30417985 TI - A new heterozygous G duplicate in exon1 (c.100dupG) of gelsolin gene causes Finnish gelsolin amyloidosis in a Chinese family. AB - OBJECTIVES: In this study, we report a case of Finnish gelsolin amyloidosis (FGA) in a Chinese family. METHODS: The proband presented with a range of clinical symptoms that included epileptic seizures and multiple lesions in the brain. Whole exome sequencing of the Gelsolin (GSN) gene was performed, and the GSN mutation was identified through comparison with the known human genome sequences using Genetic Testing Intelligent Execution System. RESULTS: The GSN gene sequencing revealed that a heterozygous G duplicate in exon1 (c.100dupG) of the GSN gene, which caused a frameshift in GSN transcript translation in the proband, his mother and daughter, but his brother did not have it. CONCLUSION: We presented a new autosomal dominant heterozygous G duplicate mutation in exon1 of GSN gene, leading to FGA in a Chinese family. PMID- 30417986 TI - A Novel Understanding of Phocidae Hearing Adaptations Through a Study of Northern Elephant Seal (Mirounga angustirostris) Ear Anatomy and Histology. AB - The most conspicuous aural adaptation in northern elephant seals (NES) is complete absence of an auricle and a tortuous collapsed external acoustic meatus. The NES epitympanic recess contains massive ossicles immersed in the middle ear cavernous sinuses. Engorgement of the cavernous sinuses would make ossicles fully buoyant during deep diving. NES have a comparatively larger cochlear nerve, which carries a significantly larger number of axons than in terrestrial mammals, which would give them auditory ability similar to the obligate marine mammals such as cetaceans. Our calculations show that the traditional "air-dependent" impedance matching mechanism in NES functions to just half of the capacity compared with the one described in terrestrial mammals. Impedance matching would be further hindered in NES while diving due to fully collapsed external acoustic meatus. Thanks to similarities of acoustic impedance between the sea water, soft tissues, and blood sinuses, very little sound energy would be reflected and lost. When sound is generated underwater, the large ossicles, buoyant in the cavernous sinus, would not move due to oscillation of tympanic membrane. Rather, they would be oscillating due to their inertia and process of acoustic streaming. Our mathematical simulation shows that an increase in sound frequency would cause increased displacement of the stapedial footplate and thus transmit the sound energy to the inner ear. We contend that during diving, impedance matching and sound signal amplification in the middle ear courses through the cavernous sinuses and oscillates the enlarged ossicles, thus enabling a high-frequency ultrasonic hearing range in Phocidae. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30417988 TI - Concise Review: Lessons Learned from Islet Transplant Clinical Trials in Developing Stem Cell Therapies for Type 1 Diabetes. AB - We examined data and patterns in clinical islet transplant studies registered on clinicaltrials.gov (CTgov) for treatment of type 1 diabetes (T1D), with a goal of extracting insights to apply in the design of a pluripotent stem cell-derived islet therapy. Clinical islet transplantation, as a cell therapy (rather than solid organ transplant) is a unique precedent for stem cell-based islet therapies. Registration activity shows that the field is not growing significantly, and newer registrations suggest that the reasons for stagnation include need for a more optimal site of infusion/transplantation, and especially a need for better immune protective strategies to advance a more effective and durable therapy for T1D. Stem Cells Translational Medicine 2018. PMID- 30417987 TI - Transplantation of Olfactory Stem Cells with Biodegradable Hydrogel Accelerates Facial Nerve Regeneration After Crush Injury. AB - Olfactory mucosa contains neural stem cells, called olfactory stem cells (OSCs), which produce trophic support required for promoting axonal regeneration after nerve injury. However, the local tissue environment can reduce the viability/function of transplanted cells when placed directly on the injury. Although gelatin hydrogels have been shown to aid cell survival during transplantation, such OSC-hydrogel combinations have not been extensively tested, particularly during recovery from facial nerve palsy. In this study, OSCs were isolated from the olfactory mucosae of newborn mice and were shown to express neural stem cell markers before differentiation, as well as cell-type specific markers after differentiation, confirming their multipotency. The OSCs also secrete growth factors and various cytokines that promote nerve regeneration. To test the effects of OSC transplantation in vivo, Medgel, a biodegradable hydrogel sponge, was applied to retain OSCs around the injury site and to lessen the detrimental effects of the local environment in an established facial nerve palsy mouse model. When OSCs were transplanted into the injury site, accelerated recovery was observed for 1 week. When OSCs were transplanted with Medgel, a higher level and duration of accelerated recovery was observed. OSCs in Medgel also increased peripheral nerve function and increased the number of regenerated nerve fibers. These results suggest that OSCs implanted with Medgel accelerate and enhance recovery from facial palsy in mice. Because human OSCs can be easily obtained from olfactory mucosa biopsies with limited risk, this OSC-Medgel combination is a candidate treatment option for accelerating recovery after facial nerve injury. Stem Cells Translational Medicine 2018. PMID- 30417989 TI - Identification of Potential Metabolic Biomarkers in Yin Deficiency Syndrome Using LC-MS. AB - Yin and Yang are the two counter-balancing aspects in ancient Chinese philosophy. In traditional Chinese medicine, Yin deficiency syndrome (YDS) is a common sub health state with complex causes. While the syndrome may be treated to various degrees of effectiveness with traditional Chinese medicine, efficient modern methods are yet to be developed for diagnosing and treating the YDS. Here we performed a metabolomics study on YDS in rats. Serum metabolites in rats were analyzed using ultra-performance liquid chromatography-mass spectrometry (UPLC MS) method to identify potential biomarkers for YDS. The rats were divided randomly into the healthy control group, the untreated YDS group, and the anemarrhena treated YDS group. Compared with the control group, significant increase in the metabolites such as dihydrotestosterone (DHT) and 5beta-DHT, 4 imidazolone-5-propanoate, 4-(L-alanin-3-yl)-2-hydroxy-cis,cis-muconate 6 semialdehyde, and 5-(L-alanin-3-yl)-2-hydroxy-cis,cis-muconate 6-semialdehyde were observed in the serum of untreated YDS group, which returned to normal in the anemarrhena treated group. Therefore, these metabolites may serve as potential biomarkers for YDS, and may facilitate the diagnosis and treatment of YDS. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30417991 TI - Effects of Dietary Ximenia caffra Meal on Nutrient Intake, Digestibility, Nitrogen Balance and Growth Performance in Sprague Dawley Rats Modelling Monogastrics. AB - BACKGROUND AND OBJECTIVE: The sub-saharan livestock feed industry depends on imported soyabean meal (SBM) as a dietary protein source in feeds thus making livestock production costly. This calls for the search and development of local dietary protein sources. Using Sprague Dawley rats to model monogastric animals, this study evaluated the potential of Ximenia caffra kernel meal (XCKM) to substitute SBM as a dietary protein source in feeds. MATERIALS AND METHODS: Five diets were formulated wherein XCKM replaced SBM on a crude protein basis at 0, 25, 50, 75 and 100%. In the digestibility trial, 20 adult male SD rats were randomly assigned to the 5 diets. After a 12-day adaptation period feed and nutrient intake, faeces and urine output were determined over a 5-day collection period. Apparent Total Tract Digestibility (ATTD) of nutrients and nitrogen absorption and retention were determined. In the growth trial, 40 weanling male SD rats were randomly assigned to the five dietary treatments and fed for 38 days. The rats were weighed twice weekly. Following euthanasia, gastrointestinal viscera were harvested and their macro-morphometry determined. Linear growth was determined from tibiae and femora indices. RESULTS: In adult rats dietary XCKM had no (p>0.05) effect on ATTD of nutrients. At 100% substitution of SBM, XCKM increased (p<0.05) faecal nitrogen loss while at 75% substitution level it increased (p<0.05) nitrogen retention. In growing SD rats, although dietary XCKM had no effect (p>0.05) on the terminal body and empty carcass mass and viscera macro-morphometry, at 100% SBM substitution, it significantly compromised (p<0.05) body mass gain and average daily gain. Femora and tibiae mass and seed or index significantly decreased (p<0.05) with increased dietary XCKM. CONCLUSION: The XCKM could replace SBM as a dietary protein source in adult SD rat feeds without compromising ATTD digestibility of nutrients and nitrogen utilization thus it could be speculated that XCKM can be utilized as a dietary protein source in feeds of mature monogastrics. Caution must be exercised in using XCKM in grower rat diets as its use at higher inclusion levels compromised growth performance and long bone health. PMID- 30417992 TI - Foraging Behavior of an Aphidophagous Hoverfly, Sphaerophoria macrogaster (Thomson) on Insectary Plants. AB - BACKGROUND AND OBJECTIVE: Flower resources are prerequisites for survival and reproduction of aphidophagous hoverflies adults. It is, therefore, necessary to evaluate their foraging behavior with regards to different flowering species in order to utilize hoverflies to enhance conservation biological control (CBC) of aphids. MATERIALS AND METHODS: The foraging behavior of the female hoverfly, Sphaerophoria macrogaster (Thomson) was observed in coriander (Coriandrum sativum Linnaeus) and blue salvia (Salvia farinacea Bentham) flower patches using a focal sampling method combined with continuous recording. The sequences and durations of all foraging bouts were recorded during the residence of observed S. macrogaster in each flower patch. RESULTS: Significantly more transitions from searching to assessment of flowers were noted in coriander than in blue salvia flower patches (chi2 = 4.55, p<0.05). However, approaching to probing transitions were significantly more frequent in blue salvia than in coriander flower patches (chi2 = 9.59, p<0.05). Foragers showed significantly prolonged inter plant movement but shorter probing durations in coriander flower patches. Of interest, total duration of time spent in patches by S. macrogaster did not differ significantly between coriander and blue salvia. CONCLUSION: Results from the present study illustrated that both flowering plant species were apparently attractive to Sphaerophoria macrogaster females but these foragers preferred coriander flowers. This finding may form the basis of flower selection in and around the crop fields for enhancement of this aphidophagous natural enemy to maximize the biological control of aphids. PMID- 30417993 TI - Bacteriostatic and Bactericidal Activity of Deer Musk on Multidrug Resistance Bacteria. AB - BACKGROUND AND OBJECTIVE: Infecting agents (e.g., bacteria, fungi, virus and parasite) have comprised high levels of multidrug resistance (MDR) with increased morbidity and mortality; so the main aim of this study was to investigate and demonstrate the antimicrobial activity of deer musk on multidrug-resistance bacteria and to proof that musk had a bacteriostatic and bactericidal effects against MDR bacteria. MATERIALS AND METHODS: Deer musk evaluated 11 multi-drug resistance (MDR) species were selected, namely, Staphylococcus capitis, Staphylococcus aureus, Klebsiella pneumonia, Escherichia coli, Acinetobacter baumanni, Pseudomonas aeruginosa, Proteus mirabilis, Serratia marcescens, Streptococcus agalactiae, Streptococcus pyogenes and Enterococcus faecalis the MDR strain were tested by means of disk diffusion, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) by the time-kill method recommendation by CLSI. In addition, the antimicrobial susceptibility of 8 commonly used antimicrobials was examined on the same MDR bacterial strains. RESULTS: The minimum inhibitory concentration MIC and MBC values were <2% (v/v) against all MDR strains except Pseudomonas aeruginosa, but the deer musk has bacteriostatic and bactericidal activity against Pseudomonas aeruginosa at >2% (v/v), in addition changes was observed in the morphological form of the bacterial colonies in of most of MDR bacteria such as Staphylococcus aureus, Streptococcus agalactiae, Pseudomonas aeruginosa and Klebsiella baumanni and indicating that the musk had an effect on bacterial cellular membranes. CONCLUSION: The findings of this study indicated that deer musk has a bacteriostatic and bactericidal effects on the growth of all tested MDR bacteria. PMID- 30417994 TI - Therapeutic Efficacy of Melatonin Against Polycystic Ovary Syndrome (PCOS) Induced by Letrozole in Wistar Rat. AB - BACKGROUND AND OBJECTIVES: Polycystic ovary syndrome (PCOS) is a common heterogeneous endocrinological and metabolic disorder in women of reproductive age which leads to infertility/subfertility. The present study was commenced to elucidate the therapeutic efficacy of melatonin in the pathogenesis of letrozole induced polycystic ovary syndrome (PCOS) in Wistar rat. MATERIALS AND METHODS: Letrozole was administered orally (1 mg kg-1) to induce PCOS condition in Wistar female rats for a period of 2-3 weeks followed by a dose of melatonin (200 ug/100 g b.wt.) to PCOS induced rats. On the completion of experimental period the level of cytokines and expression level of different receptors was assessed. RESULTS: The PCOs rats showed down regulation in melatonin (MT1 and MT2), estrogen (ER alpha) and cytokine (IL-2R and IL-6R) receptors expression and high circulatory level of IL-6 and TNF-alpha during PCO condition. These anomalies in expression pattern and circulatory level of cytokines were restored following the treatment. CONCLUSION: Finding of present study showed the role of melatonin supplementation at receptor level and also suggesting a crosstalk between MT1R / MT2R via cytokine IL-2R and IL-6R resulting in modulation of ER-alpha receptors. PMID- 30417995 TI - Health Benefits of Fennel, Rosemary Volatile Oils and their Nano-Forms in Dyslipidemic Rat Model. AB - BACKGROUND AND OBJECTIVE: Dyslipidemia is a major health problem that may lead to cardiovascular diseases (CVDs). In the present research, a biological experiment was run on dyslipidemic rats to study the health benefits of the volatile oils (VOs) of fennel and rosemary in its original and nano-form using chitosan as carrier. MATERIALS AND METHODS: Rats were divided into 6 groups; normal control, dyslipidemic control and 4 test groups with dyslipidemia and treated by VOs of fennel and rosemary and their respective nano-forms separately. Glucose tolerance test was carried out after 4 weeks. Parameters reflecting oxidative stress/antioxidant plasma catalase, malondialdehyde (MDA) and blood uric acid, were assessed. Plasma lipid profile and tumor necrosis factor alpha (TNF-alpha) as inflammatory biomarker were determined. Liver and kidney function were assessed as determinant of the safety of the different VO forms. Twenty four hour urinary volume was measured to assess creatinine clearance and to evaluate the possible diuretic activity of the VOs. RESULTS: Dyslipidemic control rats showed dyslipidemia, increased CVDs risk, liver dysfunction, elevated MDA and TNF-alpha with marked increase in blood sugar after half an hour of glucose ingestion compared to normal control. Treatment with the four VOs forms improved the majority of the biochemical parameters. CONCLUSION: All treatment showed cardio and hepato- protective effect and safety towards kidney and blood sugar. Oxidative stress and inflammatory biomarkers were significantly improved by the different treatments; both VO forms of fennel were more efficient in ameliorating inflammation. PMID- 30417996 TI - Comparative Study of Orange and its Main Bioactive Constituents as Remedy for Non alcoholic Fatty Liver in Rats. AB - BACKGROUND AND OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is accused as inducer of both cardiovascular and chronic liver diseases. The aim of the present study was to evaluate the therapeutic effect of combined freeze dried orange juice with its dried pulp supplemented with methionine, as functional food, in comparison to orange bioactive constituents, as parallel formula, in NAFLD rat model. MATERIALS AND METHODS: Proximate composition, dietary fibers, minerals, total phenolics, fatty acids and phytosterols were determined in the orange functional food. The NAFLD was induced in rats through feeding high fructose diet. The prepared functional food and its parallel formula were evaluated in NAFLD rats through determination of liver fat and plasma lipid profile, malondialdehyde, tumor necrosis factor-alpha, leptin, insulin and glucose as well as liver and kidney function with histopathological examination of the liver. Insulin resistance (IR) and total cholesterol/high density lipoprotein cholesterol were calculated. RESULTS: Orange functional food was shown to contain 9.17% dietary fibers, 1.4% potassium, 1.4 phenolic content as mg gallic acid/g, oleic acid as the major fatty acid (29.75% of total fatty acids) and 11.97% phytosterols from unsaponifiable matter. The studied formulas produced reduction of liver and plasma lipids, inflammatory and oxidative stress biomarkers, IR and leptin with improving liver function and histopathology pointing to potential management of NAFLD. CONCLUSION: Orange functional food and its parallel formula were promising in management of NAFLD; with superiority to orange functional food. Phenolic compounds, dietary fibers, phytosterols and mono and poly-unsaturated fatty acids could be responsible to the bioactivity of orange formula. PMID- 30417997 TI - Synergistic Effect of the Extracts of Vernonia amygdalina and Solenostemon monostachyus on Gram-negative Bacteria. AB - BACKGROUND AND OBJECTIVES: Herbal medicines are getting more importance in the treatment of infections ailments because most of the synthetic drugs have side effects. A large proportion of the developing countries populations depend on herbal remedy for their physical and psychological health needs depend. Hence, the anti-bacterial activity of the mixture of the extracts of Solenostemon monostachyus and Vernonia amygdalina, common medicinal plants use in Africa, Asia and Europe on some Gram-negative bacteria was investigated. MATERIALS AND METHODS: The plants that were cultivated in a well-drained soil and the bacteria, Salmonella typhii, Escherichi coli and Enterobacter aerogenes freshly isolated from clinical samples were used for this study. The plant leaves were grounded separately into a powder and analyzed quantitatively for phytochemical composition and extracted using acetone. Similarly, equal volume of the two plants was homogenized. The sensitivity of the bacteria isolates was performed using disk diffusion method and the antimicrobial activity was determined by measuring the diameter zones of inhibition and for the sensitive measurement (inhibitory zones >20) and resistant measurement (inhibitory zones <17). RESULTS: Analysis of the plants revealed their phytochemical composition. The plant's extracts had high diameter zones of inhibition at the higher concentrations and the concoction treatment was more sensitive. In V. amygdalina, the zone of inhibition varied significantly between S. typhi and E. aerogenes (p<0.05, F = 7.2) and between E. coli and E. aerogenes (p<0.05, F = 6.7), while in S. monostachyus, it varid significantly between S. typhi and E. coli (p<0.05, F = 9.2) and between E. coli and E. aerogenes (p<0.05, F = 5.8). CONCLUSION: These plants were readily available at no cost therefore, they could be exploited to provide novel compounds that may be used as starting materials for the production of drug that can obliterate resistance bacteria. PMID- 30417998 TI - Protocol of in vitro Jojoba (Simmondsia chinensis (Link) Schneider) Callus Induction. AB - BACKGROUND AND OBJECTIVES: Presently, determination of optimum protocol for callus induction of any plant is an important issue in tissue culture technology. Therefore, the main objective of this study was to find out an optimum protocol for callus induction from in vitro cultured jojoba by determining the optimum explant and the best growth regulators mixture for callus induction. MATERIALS AND METHODS: The study used three variant explants namely the leaf disks, seeds and nodal segments for callus formation. Different culture media containing basic Murashige and Skoog (MS) medium components supplemented with various concentrations of 2,4-dichlorophenoxy acetic acid as an auxin (2,4-D) and Kinetin (Kin) as a cytokinin with various concentrations ranging from 0.0, 0.5, 1.0 and 2.0 mg L-1 were used. The total number of treatments were 16. The callus was induced from all explants on MS medium containing the lowest concentration of 2,4 D 0.5 mg L-1 with any concentration of Kin. RESULTS: The results showed that nodal segments were the best for callus formation followed by the leaf disks (leaves) and seeds, respectively. While, the best concentration of proliferation and development of the used explant was 2.00 followed in descending order by 1.00, 0.5 and 0.0 mg L-1, respectively. CONCLUSION: The study find out that the best concentration of 2,4-dichlorophenoxy acetic acid as an auxin (2,4-D) and Kinetin (Kin) as a cytokinin was 2.00 followed in descending order by 1.00, 0.5 and 0.0 mg L-1, respectively for callus induction. PMID- 30417999 TI - Estrus Detection Through Vaginal pH in Saanen Etawah Crossbreed Goats. AB - BACKGROUND AND OBJECTIVE: In goats, weak estrus behavior is potentially caused by a decline in reproductive efficiency. In the present study, aim was to measure the vaginal pH to determine the accuracy of lust detection in Saanen Etawah crossbreed goats. MATERIALS AND METHODS: Thirteen Saanen Etawah crossbred does (Capra hircus) with body condition score of 2-3 were used. The dose were fed concentrate, provided forage and water ad libitum. The experiment was conducted during the natural estrous cycle. Vaginal smears were collected from each dose every day over a 60 days period to determine the time of each phase of the estrous cycle. The vaginal pH was measured using pH indicator paper; simultaneously, the blood was sampled from the caudal vein into anticoagulant coated tubes following estrous cycle, covering estrus (E/day-0), metestrus (M/day 3), diestrus (D/day-12) and proestrus (P/day-15). The concentration of plasma estrogen and cortisol was determined by solid phase competitive enzyme-linked immune sorbent assay and the correlation between vaginal pH with each phase of estrous cycle and estrogen level was found. RESULTS: The changes in vaginal pH were confirmed with estrogen and cortisol profile at each estrous phase. The highest vaginal pH and estrogen content were found during estrus, whereas, the lowest vaginal pH and estrogen content was found during diestrus. Furthermore, the cortisol level was significantly different in each phase of the estrous cycle; the highest level of cortisol was observed during proestrus. CONCLUSION: The correlation between vaginal pH and estrous phase indicates that the vaginal pH can be a useful parameter for estrus detection. PMID- 30418000 TI - Physiological and Biochemical Response of Winter Triticale Crowns at Different Soil Moisture Levels. AB - BACKGROUND AND OBJECTIVE: The spring growth of winter cereals depends on the viability of the crowns as it is the key organ of the spring renewal of leaves, stems and roots. After the plants out of wintering, the impact of stressful conditions in the spring period negatively affects the viability of the crowns of winter cereals. The study was aimed at studying the physiological and biochemical reactions of the crowns of winter triticale, depending on the moisture level of the soil after wintering. MATERIALS AND METHODS: The physiological and biochemical reaction of crowns of winter triticale to the change of the soil moisture-30, 60, 90 of the field capacity (FC) was studied under the controlled conditions of the vegetation experience. The viability of crowns winter triticale, water content, free proline, water-soluble carbohydrates and the qualitative composition of dehydrins were investigated. RESULTS: Plant survival and steady water content during the first 10 days is associated with an increase in the concentration of free proline, high content of water-soluble carbohydrates and dehydrins in crowns, regardless of the soil moisture level. At later stages of spring growth resumption (20 and 30 days), a decrease in carbohydrates, dehydrins and proline was noted in the crowns of winter triticale at all the studied levels of soil moisture. These substances are likely playing an important role in the osmotic regulation and protection of the components of the cells of crowns at the initial stage (10 days) of the plants growth resumption. CONCLUSION: The higher content of proline and the low water content of the tissues of crowns were noted in plants in the variant with a lack of moisture. Water deficiency in the period of growth resumption after wintering has a negative effect on the survival of plants. PMID- 30418001 TI - Production of Healthy Functional Soft White Cheese Using Moringa oleifera Oil. AB - BACKGROUND AND OBJECTIVE: Moringa oleifera oil is composed of highly unsaturated fatty acids containing 80.4% polyunsaturated, mainly oleic acids 67.9% and had a low acid value and low free fatty acids composition, so it is acceptable for edible application. The objective of study was the feasibility of using Moringa oleifera oil in manufacture of cheese compared with other oils (olive, sun flower) and the effect of using Moringa oleifera oil in chemically; organoleptically and microbial content in cheese. MATERIALS AND METHODS: Fat was mechanically separated from buffalo's milk to reach 3% fat. Then the resultant milk divided into four portions. First let as control, then, the rest milk divided into three portions and fat substituted with 1, 1.5 and 3% of olive, moringa and sunflower oils. The resultant milk manufactured to soft white cheese and the resultant cheese was analyzed chemically, microbiologically and organoleptically. RESULTS: Findings showed that 1.5% of different oils are best ratio and had gained highest scores for appearance, body and texture and flavor. The soft white cheese manufactured by Moringa oleifera oil was a best treatment than control and other treatments and has antimicrobial properties. Acidity, fat, total nitrogen, soluble nitrogen, total volatile fatty acids (TVFA) and thiobarbituric acid (TBA) increased during cold storage at 5 degrees C+1 for 3 weeks cheese with Moringa oleifera oil had lower (PV) peroxide value than other treatments and pH took an opposite trend. CONCLUSION: It was concluded that Moringa oleifera oil in soft cheese improved body and texture, flavor, than olive and sunflower oils and also increased the shelf life of cheese. PMID- 30418002 TI - Formulation and Evaluation of Functional Cookies for Improving Health of Primary School Children. AB - BACKGROUND AND OBJECTIVE: School children especially in Egypt need a safe meal which is able to meet their daily nutrient needs and ameliorate cognition. So, the current study aimed to evaluate formula prepared as cookies to be served as a meal for primary school children. MATERIALS AND METHODS: Wheat, roasted chickpea, milk protein concentrate, cinnamon and brewer's yeast were used to prepare cookies which have been exposed to sensory, chemical and biological evaluation. Peroxide number, amino acids, vitamins (D, B12, folic acid and E) and minerals (calcium, zinc, iron and selenium) were determined. Twenty four rats of weaning age were used, 12 rats to estimate the true protein digestibility and 12 rats to estimate the protein efficiency ratio and the effect of feeding on cookies (28 days) on hemoglobin, glucose, total protein, liver and kidney functions and antioxidant status. RESULTS: Palatability and acceptability of cookies were insured via the sensory evaluation results. The value of peroxide number indicated that there is no possibility of rancidity during the storage. The cookies showed high contents of protein (14.88%), fat (16.83%) and carbohydrate (55.1%). Also cookies showed acceptable levels of amino acids, minerals and vitamins that meet a large amount of daily requirements of children. Results of the animal experiment declared the complete safety of the cookies and high nutritional and biological quality. CONCLUSION: Cookies can serve as a meal for the governmental school children to provide them with their needs from nutrients that reducing hunger and improving health benefits and scholastic achievement. PMID- 30418003 TI - Risk Factors and Microbiological Studies on Streptococcus pneumoniae Isolated from Pneumonia Patients of Quetta Balochistan. AB - BACKGROUND AND OBJECTIVE: Pneumococcal diseases remain a major cause of morbidity and mortality worldwide. Streptococcus Pneumoniae causing pneumonia in India, Pakistan, Bangladesh and Afghanistan in children under 5 years of age and older adults. Therefore; the present research was design to study the different microbiological aspects of Streptococcus pneumoniae. MATERIALS AND METHODS: A total of 480 sputum samples were collected from pneumonia patient at different government hospitals of Quetta. The detail of patient's gender, age, economical status and educational status were taken on performa. Sputum samples were inoculated into selective strep agar Streptococcus pneumonia colonies were observed on plates and confirmed through different biochemical tests and PCR. RESULTS: Total 480 samples were collected in which 36.6% were Streptococcus pneumoniae positive and 63.3% were negative. The sex wise ratio showed that female (24.10%) were more affected with pneumoniae as compare to male (12.50%). The pneumonia infection age wise distribution was 9% in 1-10 years old patients, 16% in 10-20 years old patients and 11% in 20-30 years old patients. The status wise distribution of pneumonia infection showed that lower class (16%) was more affected as compare to middle class and higher class of Quetta. The percentage of pneumonia infection in hazara race was 14%, in Pathan 8.30%, in Punjabi 7.60% and in Baloch 6.60%. It was seen that illiterate patients were more affected with pneumonia infection (28.3%) than literate (8.3%). The Streptococcus pneumoniae was confirmed through gram staining, different biochemical tests, different sugar fermentation tests and PCR. Whereas confirmed by PCR showed clear band of 329 kb of ply gene. CONCLUSION: It was concluded that the rate of pneumonia infection was high in female and lower class was more affected with pneumonia. PMID- 30418004 TI - Utilization profile of the Canadian-led coalition Role 2 Medical Treatment Facility in Iraq: the growing requirement for multinational interoperability AB - Background: The Canadian Armed Forces deployed a Role 2 Medical Treatment Facility (R2MTF) to Iraq in November 2016 as part of Operation IMPACT. We compared the multinational interoperability required of this R2MTF with that of similar facilities previously deployed by Canada or other nations. Methods: We reviewed data (Nov. 4, 2016, to Oct. 3, 2017) from the electronic Disease and Injury Surveillance Report and the Daily Medical Situation Report. Clinical activity was stratified by Global Burden of Diseases category, ICD-10 code, mechanism of injury, services used, encounter type, nationality and blood product usage. We reviewed the literature to identify utilization profiles for other MTFs over the last 20 years. Results: In total, 1487 patients were assessed. Of these, 5.0% had battle injuries requiring damage-control resuscitation and/or damage control surgery, with 55 casualties requiring medical evacuation after stabilization. Trauma and disease non-battle injuries accounted for 44% and 51% of patient encounters, respectively. Other than dental conditions, musculoskeletal disorders accounted for most presentations. Fifty-seven units of fresh frozen plasma and 64 units of packed red blood cells were used, and the walking blood bank was activated 7 times. Mass casualty activations involved coordination of health care and logistical resources from more than 12 countries. In addition to host nation military and civilian casualties, patients from 15 different countries were treated with similar frequency. Conclusion: The experience of the Canadian R2MTF in Iraq demonstrates the importance of multinational interoperability in providing cohesive medical care in coalition surgical facilities. Multinational interoperability derives from a unique relationship between higher medical command collaboration, international training and adherence to common standards for equipment and clinical practice. PMID- 30418005 TI - Effect of intraluminal thrombus on growth rate of abdominal aortic aneurysms. AB - BACKGROUND: Abdominal aortic aneurysm (AAA) includes variety of morphologies with changing properties. Growth rate is one of the most important factors directly linked to the risk of rupture. Intraluminal thrombus (ILT) covering aortic wall is found in majority of AAAs. Yet, its role in biomechanical processes in AAA remains unclear. From one point of view ILT can serve as protective factor in reducing wall stress of AAA and thus slow down the growth. Modern concept of multilayered ILT proved active inflammatory processes inside, that can significantly affect the quality of the wall and thus lead to the higher growth rate and higher risk of rupture. The goal of this study was to analyze effect of ILT on growth rate of AAA and support one these theories. METHODS: Retrospective study of CT angiography scans of AAA of 26 patients was performed. 40 pairs of consecutive scans have been analyzed. Periods between two scans varied. Maximal infrarenal diameter of AAA and size of ILT were measured. AAAs were split into 4 groups according to their intial diameter. Growth rate was calculated for each AAA and linked to the relative size of ILT These values were statistically evaluated. RESULTS: Negative correlation between relative size of ILT and growth rate was found (p=0.042062). This significant result proved that thicker thrombus slowed down the growth of AAA and vice versa, smaller relative size of ILT was linked to higher growth rate. CONCLUSIONS: This finding shows importance of ILT as one of the key factors influencing biomechanical processes inside an AAA. Results of this study may contribute to the further research of this topic. PMID- 30418006 TI - Real world experience of extracranial carotid artery interventions for atherosclerotic disease during a 10-year period. AB - BACKGROUND: The aim of this study was to assess the long-term outcome of carotid disease treatment with endarterectomy or stenting (CEA or CAS) in a real-world setting during a 10-year period. METHODS: A single center retrospective study with prospectively collected data including patients (symptomatic or asymptomatic) being treated with CEA or CAS. Survival, restenosis, stroke and major adverse cardiac events (MACE) were the outcomes. RESULTS: A total of 413 patients (mean age of 69+/-3.5 years; 80%, 333/413 males) were treated with CEA (83.7%, 346/413) or CAS (16.3%, 67/413). Most of the patients were asymptomatic (60%, 248/413). The incidence of in-hospital stroke and death was 0.5% (2/413) and 0.7% (3/413), respectively. The survival rate at 1, 3 and 5 years was 98%, 94.7% and 90.6%, respectively. The freedom of re-stenosis at 1, 3 and 5 years was 99%, 98% and 90.5%, respectively. The freedom of any stroke at 1, 3 and 5 years was 99%, 97% and 94.8%, respectively. The freedom of MACE at 1, 3 and 5 years was 97.6%, 91.5% and 86.3%, respectively. Symptomatic presentation was associated with higher rates of restenosis after CEA and higher rate of mortality (p=0.025) and MACE (p=0.022) after CAS. CONCLUSIONS: Carotid interventions remain durable treatment methods of carotid disease. Long-term outcomes regarding mortality, restenosis, and risk of stroke or MACE are similar between CAS and CEA for asymptomatic patients. Symptomatic presentation may be associated with higher rates of restenosis after CEA and higher rate of mortality and MACE after CAS, however larger studies are needed to clarify this issue. PMID- 30418007 TI - Impact of traumatic upper-extremity amputation on the outcome of injury caused by an antipersonnel improvised explosive device AB - Background: We have previously reported a higher than expected rate of upper extremity amputation (UEA) in victims of an antipersonnel improvised explosive device (AP-IED) compared with a similar cohort injured by antipersonnel mines (APM). The goal of this study was to describe the rate, severity and impact of UAE caused by an AP-IED. Methods: We analyzed a prospective database of 100 consecutive dismounted AP-IED victims with pattern 1 injuries to compare the outcomes of the cohort with UEA to that without. Results: We found that UEA (8 above elbow, 19 below elbow, 1 through elbow, 3 hand, 15 digit(s)) was much more prevalent with AP-IED than with APM (40% v. 6%, p < 0.001). In addition, UEA was associated with a higher rate of multiple amputations (39 [98%] v. 32 [53%], p < 0.001), bilateral lower-extremity amputation (LEA; 33 [82.5%] v. 30 [53.3%], p = 0.003) and facial injury (8 [20%] v. 4 [6.4%], p = 0.044), but not with pelvic disruption (10 [25%]), genitoperineal mutilation (19 [48%]), eye injury (6 [15%]), or skull fracture (6 [15%]). The fatality rate was higher in patients with UEA than in those without (12 [30%] v. 7 [12%], p = 0.022). Conclusion: Upper-extremity amputation is more prevalent with AP-IED than APM. Presence of UEA is associated with more severe injury and increased risk of death in AP-IED victims. Upper-limb injury has significant consequences forrehabilitation from LEA, which universally accompanies UEA in AP-IED victims. Upper-extremity injury should be amenable to prevention by innovative personal protective equipment designed to protect the flexed elbow. PMID- 30418008 TI - The effect of aerosolized indomethacin on lung inflammation and injury in a rat model of blunt chest trauma AB - Background: Acute lung contusion from blunt chest trauma (BCT) is characterized by an intense inflammatory response in the pulmonary parenchyma, which is associated with acute lung injury (ALI), acute respiratory distress syndrome and ventilator-associated pneumonia. We hypothesized that aerosolized indomethacin may reduce pulmonary inflammation and ALI in a rat model of BCT. Methods: Sprague Dawley rats were anesthetized and received a tracheotomy for administration of aerosolized medication through a catheter. The BCT procedure involved free dropping a hollow metal weight (200 g) from a height of 25.5, 38.3 or 51.2 cm onto the right thorax. We administered 1 mg/kg of indomethacin or 1 mL/kg of saline intratracheally 15 minutes after BCT. The sham group had a similar procedure without the exposure to BCT and treatment. Three hours postimpact, we obtained arterial blood gas and analyzed bronchoalveolar lavage for protein concentration, polymorphonuclear leukocytes (PMN) and cytokine levels, and lung tissue samples were taken for histopathological analysis. Results: The rats' mean arterial pressure and heart rate dropped immediately postimpact but recovered close to that of the sham group after 30 minutes in both control and treatment groups. Compared to BCT alone, indomethacin significantly reduced the total protein level in the lungs (1.06 +/- 0.39 mg/mL v. 3.75 +/- 1.95 mg/mL, p = 0.006) and alveolar FD-70 leak (0.23 +/- 0.19 MUg/mL v. 0.53 +/- 0.19 MUg/mL, p = 0.02). Indomethacin also significantly attenuated the acute inflammatory response in percent PMN (13.33 +/-7.5% v. 28.0 +/- 12.96%, p = 0.04). Tumour necrosis factor-alpha and interleukin-6 decreased in the indomethacin group, but the decreases were not significant compared with other groups. Conclusion: Aerosolized indomethacin has a protective effect against alveloar tissue permeability and inflammatory response induced by BCT. PMID- 30418009 TI - Reflections on recovery, rehabilitation and reintegration of injured service members and veterans from a bio-psychosocial-spiritualperspective AB - Medical interventions regarding trauma resuscitation have increased survivorship to levels not previously attained. Multiple examples from recent conflicts illustrate the potential return to high-level function of severely injured service members following medical and rehabilitative interventions. This review addresses the goals of rehabilitation, distills hard-won lessons of the last decade of military trauma and rehabilitation, and recommends the use of a bio psychosocial-spiritual approach to care that can be applied at all tiers of the health care system. Questions on enabling participation in meaningful life activities include the following: Why do some patients do well and others do not? What elements contribute to positive outcomes? What factors relate to suboptimal results? Lessons learned revolve around the importance of considering the physical, psychosocial and spiritual aspects of a person's well-being; empowering patients by fostering self-efficacy; and helping patients find meaning in life events and set high-level goals. A bio-psychosocial-spiritual model from the rehabilitation medicine literature - the Canadian Model of Occupational Performance and Engagement - is proposed as a guide to the provision of person centred care and the maximization of a person's functioning posttrauma. PMID- 30418010 TI - Novel use of FaceTime video calling in a deployed setting to assist with the care of a military working dog AB - Summary: In deployed settings, veterinary recourses are limited and nonveterinary medical providers frequently are required to provide medical treatment to military working dogs (MWDs) until veterinary specialty care can be provided. We present the case of a critically ill MWD who presented initially to a Canadian NATO Role II facility in Iraq that lacked immediate veterinary support. Through the use of FaceTime interactive video calling, the Role II medical providers were able to consult with the MWD unit's veterinarian in the United States and provide effective evaluation, treatment and prioritization of medical evacuation (MEDEVAC). FaceTime video calling was extremely effective and should be considered in future situations where specialist care is not immediately available and transmission of visual information would be beneficial. PMID- 30418011 TI - Ultrastructural histochemistry in biomedical research: Alive and kicking. AB - The high-resolution images provided by the electron microscopy has constituted a limitless source of information in any research field of life and materials science since the early Thirties of the last century. Browsing the scientific literature, electron microscopy was especially popular from the 1970's to 80's, whereas during the 90's, with the advent of innovative molecular techniques, electron microscopy seemed to be downgraded to a subordinate role, as a merely descriptive technique. Ultrastructural histochemistry was crucial to promote the Renaissance of electron microscopy, when it became evident that a precise localization of molecules in the biological environment was necessary to fully understand their functional role. Nowadays, electron microscopy is still irreplaceable for ultrastructural morphology in basic and applied biomedical research, while the application of correlative light and electron microscopy and of refined ultrastructural histochemical techniques gives electron microscopy a central role in functional cell and tissue biology, as a really unique tool for high-resolution molecular biology in situ. PMID- 30418012 TI - Immigrant patients in brief meetings with anaesthetist nurses - experiences from perioperative meetings in the orthopaedic setting. AB - Aim To explore the experience of anaesthetist nurses in brief meetings with immigrant patients in the perioperative setting. Methods The study was conducted through open individualised interviews using open-ended questions. Eighteen anaesthetist nurses (six men and twelve women) participated in the interviews. Their age varied between 35 and 65 and they had worked as anaesthetist nurses for a period between six and twenty eight years. The text was analysed using qualitative content analysis. Results Meetings with immigrant patients made nurses with less experience to prepare more, to study behaviour of these patients and to ask their older colleagues for advice. More experienced nurses acted on the basis of their previous experience and treated the patients in the same way as before. They also emphasised the great responsibility and wider scope of assistance needed by these patients than those born in Sweden. The majority of nurses begin the meetings with these patients by requesting an interpreter, while some nurses begin the meeting directly with the patient and, if they see it is not going well, they request an interpreter. Conclusion Nurses need better guidelines and education in how to deal with the legislation relating to immigrant patients in order to handle the situation more effectively. Training in cross-cultural care should be improved to help nurses deal with stress through co operation with the Migration Board and others. In order to provide for good communication and patient safety professional interpreters should be used. PMID- 30418013 TI - Stereocomplexation of Polymers in Micelle Nanoreactors As Studied by Multiple Detection Thermal Field-Flow Fractionation. AB - In this study the thermally induced in situ stereocomplexation (SC) of binary blends of symmetrical isotactic and syndiotactic polymethymethacrylates (i- and s PMMAs) inside micellar nanoreactors (MNR) with polystyrene (PS) shells is investigated using thermal field-flow fractionation (ThFFF) as a separation technique. The MNRs are prepared from three systematic binary blending ratios of pure micelles of i-PMMA-PS and s-PMMA-PS in a nonsolvent for PMMAs in order to produce mixed micelles with a binary microstructural composition of the interior PMMA cores. The SC of these stereoregular PMMA cores inside the MNRs is shown to be thermally induced as a function of annealing temperatures from room temperature up to 150 degrees C. This SC is initially confirmed by Fourier transform infrared spectroscopy (FTIR), whereby signal shifts are observed in the carbonyl absorption regions. These signal shifts are as a result of SC interactions between adjacent ester and alpha-methyl groups. Furthermore, temperature-dependent dynamic light scattering (DLS) results show that MNRs with more SC domains have a much more drastic reduction in size. Additional corroboration is provided by multiple detection ThFFF results which show significant differences in retentions and sizes between MNRs with stereocomplexed cores and those without. Ratios of i-PMMA:s-PMMA in the order of 1:1, 1:2, and 2:1 were investigated with all ratios exhibiting thermal annealing induced SC, of which the 1:2 ratio is shown to have the highest predisposition to SC. PMID- 30418014 TI - Metal-Organic Framework Template-Directed Fabrication of Well-Aligned Pentagon like Hollow Transition-Metal Sulfides as the Anode and Cathode for High Performance Asymmetric Supercapacitors. AB - Given the exceptional specific surface area, geometry, and periodic porosity, transition-metal sulfides derived from crystalline metal-organic frameworks have spurred great interest in energy storage systems. Herein, employing a different sulfurization process, well-aligned NiCo2S4 and CoS2 nanoarrays with a hollow/porous configuration derived from pentagon-like ZIF-67 are successfully designed and constructed on Ni foam. The hollow/porous structure grown on a conductive matrix can significantly improve electroactive sites, shorten charge/ion diffusion length, and enhance mass/electron transfer. Consequently, the obtained NiCo2S4 possesses an excellent specific capacitance of 939 C/g, a fast charge/discharge rate, and a favorable life span. An advanced asymmetrical supercapacitor is fabricated by engaging NiCo2S4 and CoS2 as cathode and anode materials, respectively, with a well-separated potential window. The obtained device delivers an exceptional energy density of 55.8 W h/kg at 695.2 W/kg, which is highly considerable to the recent transition metal sulfide-based devices. This facile tactic could be employed to construct other electrode materials with superior electrochemical properties. PMID- 30418015 TI - Simultaneously Porous Structure and Chemical Anchor: A Multifunctional Composite by One-Step Mechanochemical Strategy towards High-Performance and Safe Lithium Sulfur Battery. AB - lithium-sulfur (Li-S) battery has been regarded as one of most promising energy storage systems to meet requirements for high-energy-density in electric vehicles, advanced portable electronic devices, and so on. However, practical application of Li-S battery is restricted severely by easy dissolution of lithium polysulfides and high flammability of sulfur. Herein, we developed, for the first time, a multifunctional composite directly prepared by facile, green, low-cost and large-scale ball-milling method with fly ash and sulfur. Due to unique microstructure and sulfur-related components as chemical anchors, composites possessed good electron/ion transport, favorable resistance to volume change of sulfur, and strongly chemical affinity to polysulfides, which greatly facilitate redox kinetics, maintain structural integrity of cathode, and suppress polysulfide shuttling in electrolyte, hence significantly boosting electrochemical performance of Li-S battery with high initial discharge capacity, superior cycling stability, and satisfying rate capability. Typically, Li-S batteries based on composite with sulfur loading of 86.9% present initial discharge capacities of 969.8, 894.3 and 769.7 mAh g-1 as well as capacity decay rates of 0.068% (400 cycles), 0.1% and 0.042% per cycle (200 cycles) at 0.2 C, 0.5 C and 1 C, respectively. Moreover, average specific self-extinguishing time of composite-based cathode was clearly reduced to less than half of that of the pristine sulfur-based cathode, indicating significantly promoting safety of battery. PMID- 30418016 TI - Quantitative Interpretation of Intracellular Drug Binding and Kinetics Using the Cellular Thermal Shift Assay. AB - Evidence of physical interaction with the target protein is essential in the development of chemical probes and drugs. The cellular thermal shift assay (CETSA) allows evaluation of drug binding in live cells but lacks a framework to support quantitative interpretations and comparisons with functional data. We outline an experimental platform for such analysis using human kinase p38alpha. Systematic variations to the assay's characteristic heat challenge demonstrate an apparent loss of compound potency with an increase in duration or temperature, in line with expectations from the literature for thermal shift assays. Importantly, data for five structurally diverse inhibitors can be quantitatively explained using a simple model of linked equilibria and published binding parameters. The platform further distinguishes between ligand mechanisms and allows for quantitative comparisons of drug binding affinities and kinetics in live cells and lysates. We believe this work has broad implications in the appropriate use of the CETSA for target and compound validation. PMID- 30418017 TI - Quasi-Ballistic Heat Conduction due to Levy Phonon Flights in Silicon Nanowires. AB - Future of silicon-based microelectronics depends on solving the heat dissipation problem. A solution may lie in a nanoscale phenomenon known as ballistic heat conduction, which implies conduction of heat without heating the conductor. However, attempts to demonstrate this phenomenon experimentally are controversial and scarce, whereas its mechanism in confined nanostructures is yet to be fully understood. Here, we experimentally demonstrate quasi-ballistic heat conduction in silicon nanowires (NWs). We show that the ballisticity is the strongest in short NWs at low temperatures but weakens as the NW length or temperature is increased. Yet, even at room temperature, quasi-ballistic heat conduction remains visible in short NWs. To better understand this phenomenon, we probe directions and lengths of phonon flights. Our experiments and simulations show that the quasi-ballistic phonon transport in NWs is essentially the Levy walk with short flights between the NW boundaries and long ballistic leaps along the NW. Thus, we conclude that ballistic heat conduction is present in silicon even at room temperature in sufficiently small nanostructures and may yet improve thermal management in silicon-based microelectronics. PMID- 30418018 TI - Nuclear Resonance Vibrational Spectroscopy Definition of O2 Intermediates in an Extradiol Dioxygenase: Correlation to Crystallography and Reactivity. AB - The extradiol dioxygenases are a large subclass of mononuclear nonheme Fe enzymes that catalyze the oxidative cleavage of catechols distal to their OH groups. These enzymes are important in bioremediation, and there has been significant interest in understanding how they activate O2. The extradiol dioxygenase homoprotocatechuate 2,3-dioxygenase (HPCD) provides an opportunity to study this process, as two O2 intermediates have been trapped and crystallographically defined using the slow substrate 4-nitrocatechol (4NC): a side-on Fe-O2-4NC species and a Fe-O2-4NC peroxy bridged species. Also with 4NC, two solution intermediates have been trapped in the H200N variant, where H200 provides a second-sphere hydrogen bond in the wild-type enzyme. While the electronic structure of these solution intermediates has been defined previously as FeIII superoxo-catecholate and FeIII-peroxy-semiquinone, their geometric structures are unknown. Nuclear resonance vibrational spectroscopy (NRVS) is an important tool for structural definition of nonheme Fe-O2 intermediates, as all normal modes with Fe displacement have intensity in the NRVS spectrum. In this study, NRVS is used to define the geometric structure of the H200N-4NC solution intermediates in HPCD as an end-on FeIII-superoxo-catecholate and an end-on FeIII-hydroperoxo semiquinone. Parallel calculations are performed to define the electronic structures and protonation states of the crystallographically defined wild-type HPCD-4NC intermediates, where the side-on intermediate is found to be a FeIII hydroperoxo-semiquinone. The assignment of this crystallographic intermediate is validated by correlation to the NRVS data through computational removal of H200. While the side-on hydroperoxo semiquinone intermediate is computationally found to be nonreactive in peroxide bridge formation, it is isoenergetic with a superoxo catecholate species that is competent in performing this reaction. This study provides insight into the relative reactivities of FeIII-superoxo and FeIII hydroperoxo intermediates in nonheme Fe enzymes and into the role H200 plays in facilitating extradiol catalysis. PMID- 30418019 TI - Electric Field Effects on Bacterial Deposition and Transport in Porous Media. AB - Bacterial deposition and transport are key to microbial ecology and biotechnological applications. We therefore tested whether electrokinetic forces (electroosmotic shear force ( FEOF), electrophoretic drag force ( FEP)) acting on bacteria may be used to control bacterial deposition during transport in laboratory percolation columns exposed to external direct current (DC) electric fields. For different bacteria, yet similar experimental conditions we observed that DC fields either enhanced or reduced bacterial deposition efficiencies (alpha) relative to DC-free controls. By calculating the DLVO force of colloidal interactions, FEOF, FEP, and the hydraulic shear forces acting on single cells at a collector surface we found that DC-induced changes of alpha correlated to | FEOF| to | FEP| ratios: If | FEOF| > | FEP|, alpha was clearly increased and if | FEOF| < | FEP| alpha was clearly decreased. Our findings allow for better prediction of the forces acting on a bacterium at collector surface and, hence, the electrokinetic control of microbial deposition in natural and manmade ecosystems. PMID- 30418020 TI - Harnessing Cyanine Reactivity for Optical Imaging and Drug Delivery. AB - Optical approaches that visualize and manipulate biological processes have transformed modern biomedical research. An enduring challenge is to translate these powerful methods into increasingly complex physiological settings. Longer wavelengths, typically in the near-infrared (NIR) range (~650-900 nm), can enable advances in both fundamental and clinical settings; however, suitable probe molecules are needed. The pentamethine and heptamethine cyanines, led by prototypes Cy5 and Cy7, are among the most useful compounds for fluorescence based applications, finding broad use in a range of contexts. The defining chemical feature of these molecules, and the key chromophoric element, is an odd numbered polymethine that links two nitrogen atoms. Not only a light-harvesting functional group, the cyanine chromophore is subject to thermal and photochemical reactions that dramatically alter many properties of these molecules. This Account describes our recent studies to define and use intrinsic cyanine chromophore reactivity. The hypothesis driving this research is that novel chemistries that manipulate the cyanine chromophore can be used to address challenging problems in the areas of imaging and drug delivery. We first review reaction discovery efforts that seek to address two limitations of long wavelength fluorophores: undesired thiol reactivity and modest fluorescence quantum yield. Heptamethine cyanines with an O-alkyl substituent at the central C4' carbon were prepared through a novel N- to O-transposition reaction. Unlike commonly used C4'-phenol variants, this new class of fluorophores is resistant to thiol modification and exhibits improved in vivo imaging properties when used as antibody tags. We have also developed a chemical strategy to enhance the quantum yield of far-red pentamethine cyanines. Using a synthetic strategy involving a cross metathesis/tetracyclization sequence, this approach conformationally restrains the pentamethine cyanine scaffold. The resulting molecules exhibit enhanced quantum yield (PhiF = 0.69 vs PhiF = 0.15). Furthermore, conformational restraint improves interconversion between reduced hydrocyanine and intact cyanine forms, which enables super resolution microscopy. This Account then highlights efforts to use cyanine photochemical reactivity for NIR photocaging. Our approach involves the deliberate use of cyanine photooxidation, a reaction previously only associated with photodegradation. The uncaging reaction sequence is initiated by photooxidative chromophore cleavage (using wavelengths of up to 780 nm), which prompts a C-N bond hydrolysis/cyclization sequence resulting in phenol liberation. This approach has been applied to generate the first NIR activated antibody-drug conjugates. Tumor uptake can be monitored in vivo using NIR fluorescence, prior to uncaging with an external irradiation source. This NIR uncaging strategy can slow tumor progression and increase survival in a MDA-MB 468- luc mouse model. Broadly, the vantage point of cyanine reactivity is providing novel probe molecules with auspicious features for use in complex imaging and drug delivery settings. PMID- 30418021 TI - Designing an Excellent Deep-Ultraviolet Birefringent Material for Light Polarization. AB - Owing to their vital role in creating and controlling polarized light, birefringent materials are used extensively in various advanced optical systems which in turn impact a large, rapidly increasing range of applications in science and technology. Currently, the fairly small birefringence of MgF2 and the low transmittance of alpha-BaB2O4 (alpha-BBO) hinder their efficient application for wavelength below 200 nm. For example, deep-ultraviolet (DUV) birefringent materials for light polarization are urgently needed for DUV lithography. Here we demonstrate based on computational and experimental results that parallel chains of corner-connected planar sp2-hybridized BO3 groups found in Ca(BO2)2 effectively produce large birefringence. Ca(BO2)2 achieves three vital "best" properties including the shortest UV cutoff edge, the largest birefringence, and the highest laser-induced damage threshold (LIDT) compared to all the reported borate birefringent materials. On the basis of a Ca(BO2)2 single crystal, a DUV Glan polarizer has been realized and is more efficient than one constructed with commercially available MgF2. PMID- 30418022 TI - Spontaneous Electronic Band Formation and Switchable Behaviors in a Phase-Rich Superatomic Crystal. AB - Structural phase transitions run in families of crystalline solids. Perovskites, for example, feature a remarkable number of structural transformations that produce a wealth of exotic behaviors, including ferroelectricity, magnetoresistance, metal-insulator transitions and superconductivity. In superatomic crystals and other such materials assembled from programmable building blocks, phase transitions offer pathways to new properties that are both tunable and switchable. Here we describe [Co6Te8(PEt3)6][C70]2, a novel superatomic crystal with two separate phase transitions that drastically transform the collective material properties. A coupled structural-electronic phase transition triggers the emergence of a new electronic band in the fullerene sublattice of the crystal, increasing its electrical conductivity by 2 orders of magnitude, while narrowing its optical gap and increasing its spin density. Independently, an order-disorder transition transforms [Co6Te8(PEt3)6][C70]2 from a phonon crystal to a phonon glass. These results introduce a family of materials in which functional phase transformations may be manipulated by varying the constituent building blocks. PMID- 30418023 TI - Improved Modeling of Halogenated Ligand-Protein Interactions Using the Drude Polarizable and CHARMM Additive Empirical Force Fields. AB - Halogenated ligands can participate in nonbonding interactions with proteins via halogen bond (XB) or halogen-hydrogen bond donor (X-HBD) interactions. In the context of molecular dynamics (MD) simulations, the accuracy of the simulations depends strongly on the force field (FF) used. To ensure good reproduction of XB and X-HBD interactions with proteins, we optimized the previously developed additive CHARMM36/CHARMM General force field (CGenFF) and Drude polarizable force field by including atom pair-specific Lennard-Jones parameters for aromatic halogen-protein interactions. The optimization targeted quantum mechanical interaction energy surfaces with the developed parameters then examined for their ability to reproduce experimental halogen-containing ligand-protein interactions in MD simulations. The calculated halogenated ligand interaction geometries were in good overall agreement with the experimental crystal data for both the polarizable and additive FFs, showing that these models can accurately treat both XB and X-HBD interactions. Analysis of the ligand-protein interactions shows significant contributions of polarizability to binding occurring in the Drude FF, with self-polarization energy making both favorable and unfavorable contributions to binding. Further analysis of the dipole moments from aqueous solution to protein indicates the polarizable FF accounts for subtle changes of the environment of the ligands that can impact binding. The present work demonstrates the utility of the updated additive CHARMM36/CGenFF and polarizable Drude FFs for the study of halogenated ligand-protein interactions in computer-aided drug design. PMID- 30418024 TI - Bisphosphonate inhibitors of mammalian glycolytic aldolase. AB - The glycolytic enzyme aldolase is an emerging drug target in diseases such as cancer and protozoan infections which are dependent on a hyperglycolytic phenotype to synthesize ATP and metabolic precursors for biomass production. To date, structural information for the enzyme in complex with phosphate-derived inhibitors has been lacking. Thus, we determined the crystal structure of mammalian aldolase in complex with naphthalene 2,6-bisphosphate (1) that served as a template for the design of bisphosphonate-based inhibitors, namely 2 phosphate-naphthalene 6-bisphosphonate (2), 2-naphthol 6-bisphosphonate (3), and 1-phosphate-benzene 4-bisphosphonate (4). All inhibitors targeted the active site and the most promising lead, 2, exhibited slow-binding inhibition with an overall inhibition constant of ~38 nM. Compound 2 inhibited proliferation of HeLa cancer cells while HEK293 cells expressing a normal phenotype were not inhibited. The crystal structures delineated the essential features of high-affinity phosphate derived inhibitors and provide a template for the development of inhibitors with prophylaxis potential. PMID- 30418025 TI - Unique Surface Enhanced Raman Scattering Substrate for the Study of Arsenic Speciation and Detection. AB - In this study, a three-dimensional surface enhanced Raman scattering (SERS) substrate comprised of silver coated gold nanorods (Ag/AuNRs) decorated on electrospun polycaprolactone (PCL) fibers has been applied, for the first time, to quantitative analytical measurements on various arsenic species: p-arsanilic acid ( pAsA), roxarsone (Rox), and arsenate (AsV), with a demonstrated sensitivity below 5 ppb. AsV detection in a solution of common salt ions has been demonstrated, showing the tolerance of the substrate to more complex environments. pAsA adsorption behavior on the substrate surface has been investigated in detail using these unique SERS substrates. Calculations based on density functional theory (DFT) support the spectral observation for pAsA. This substrate also has been shown to serve as a platform for in situ studies of arsenic desorption and reduction. This SERS substrate is potentially an excellent environmental sensor for both fundamental studies and practical applications. PMID- 30418026 TI - Fluorofunctionalization of C?C Bonds with Selectfluor: Synthesis of beta Fluoropiperazines through a Substrate-Guided Reactivity Switch. AB - The halofunctionalization of alkene substrates remains an essential tool for synthetic chemists. Herein, we report regioselective ammoniofluorination of unactivated alkenes through photochemical means. A one-pot transformation of the ammonium fluoride products into pharmaceutically relevant beta-fluoropiperazines is highlighted. Furthermore, a substrate-guided reactivity switch is observed: certain alkenes are shown to react with the same fluorinating reagent to instead give the less-substituted fluoride. We hope that the ammoniofluorination reaction will be of utility in the area of medicinal chemistry, where nitrogen and fluorine are among the most important heteroatoms. PMID- 30418027 TI - Correction to Unveiling the Intrinsic Cycle Reversibility of a LiCoO2 Electrode at 4.8-V Cutoff Voltage through Subtractive Surface Modification for Lithium-Ion Batteries. PMID- 30418028 TI - Resonance Raman Spectroscopy of Conducting Polypyrrole Nanotubes: Disordered Surface versus Ordered Body. AB - Polypyrrole nanotubes rank among the most conducting forms of organic semiconductors. They are prepared by the oxidation of pyrrole in the presence of methyl orange. Other organic dyes, viz. ethyl orange, Acid Blue 25, and Acid Blue 129, have been used in the present study to prepare globules or nanofibers. The resulting polypyrroles were studied in detail by Raman spectroscopy. The apparent paradox when a dye contribution to spectra is absent with 785 nm excitation line and present with shorter wavelengths is explained by the resonance character of the Raman scattering, which allows the separation of the contributions from the polypyrrole surface and from the bulk. These differ depending on the laser excitation wavelength and the position of absorption maximum of the individual dyes in ultraviolet-visible spectra and affect both the laser-penetration depth and observation of the resonance effect. The spectra are discussed in terms of different ordering of polymer chains in individual morphologies. The correlation between conductivity, surface areas, and the proportions of ordered and disordered polypyrrole phases at the surface and in the interior of nanostructures is proposed and established using resonance Raman spectroscopy. PMID- 30418029 TI - QSAR Study of Biologically Active Essential Oils against Beetles Infesting the Walnut in Catamarca, Argentina. AB - Essential oils from six species of aromatic plants collected in the Catamarca Province of Argentina were evaluated for their chemical composition and repellent and insecticidal activities against beetles of the genus Carpophilus (Coleoptera: Nitidulidae) and Oryzaephilus (Coleoptera: Silvanidae) that infest the local walnut production. Experimental data were analyzed using generalized estimating equations, with normal distribution and the identity link function. From the spectral information from the tested essential oils, we worked their molecular modeling as mixtures by developing mixture descriptors ( Dmix) that combined the molecular descriptor of each component in the mixture ( d i) and its relative concentration ( x i), i.e., Dmix = f( d i, x i). The application of chemoinformatic approaches determined that a combination of mixture descriptors related to molecular size, branchedness, charge distribution, and electronegativity were useful to explain the bioactivity profile against Carpophilus spp. and Oryzaephilus spp. The reported models were rigorously validated using stringent statistical parameters and essential oils reported with repellent activity against other beetle species from the Nitidulidae and Silvanidae families. This model confirmed each essential oil as a repellent with a comparable performance to the experimental reports. PMID- 30418030 TI - Abnormal Rheological Phenomena in Newtonian Fluids in Electroosmotic Flows in a Nanocapillary. AB - Abnormal rheological phenomena arising in Tris-borate-ethylenediaminetetraacetic acid solutions (believed to be Newtonian fluids) were observed in direct current electroosmotic flows within a nanocapillary with a diameter of 200 nm under a low electric field of tens of volts per meter. In solutions with different concentrations and pH values, the flow behavior indices of the power-law fluids were calculated on the basis of current-voltage relations. When the electric field intensity was below a critical value of 6.7 V/m, the fluids exhibited dilatant (shear thickening) effects. Fluid viscosity changed with electric field intensity because the near-wall shear rate of an electroosmotic flow changes with electric field intensity via a power-law relation. When the electric field intensity surpasses the critical electric field, the fluid again becomes Newtonian and has constant viscosity. The investigation shows that in nanocapillaries, fluids commonly believed to be Newtonian can become non Newtonian near walls as a result of strong nanoscale interfacial effects. The results can also improve our understanding of electroosmosis-related transport phenomena in nanofluidics and biomedical science. PMID- 30418031 TI - Elucidation of Relative and Absolute Configurations of Highly Rearranged Diterpenoids and Evidence for a Putative Biosynthetic Intermediate from the Australian Nudibranch Goniobranchus geometricus. AB - A diterpene (1), previously isolated from a Japanese marine sponge, together with two undescribed (2, 3) diterpenes with highly rearranged carbon skeletons have been characterized from the Australian nudibranch species Goniobranchus geometricus. The structures and relative configuration were determined by spectroscopic analyses informed by detailed molecular modeling, as well as by DFT, DP4, and coupling constant predictions. A 13 R,14 R configuration was determined for secoshahamin (1) by chemical correlation with 12 desacetoxyshahamin C (4) and 12-desacetoxypolyrhaphin A (5); each metabolite (1, 4, and 5) was subjected to saponification and lactonization, yielding the same delta-lactone product (6). Secoshahamin has the same carbon skeleton as a putative precursor that may play a key role in the biosynthesis of highly rearranged diterpenoid scaffolds via C-9/C-11 cleavage of a spongian diterpene precursor. PMID- 30418032 TI - New Approach for Large-Area Thermoelectric Junctions with a Liquid Eutectic Gallium-Indium Electrode. AB - A challenge in organic thermoelectrics is to relate thermoelectric performance of devices to the chemical and electronic structures of organic components inside them on a molecular scale. To this end, a reliable and reproducible platform relevant to molecular-level thermoelectric measurements is essentially needed. This paper shows a new, efficient approach for thermoelectric characterization of a large area of molecular monolayers using liquid eutectic gallium-indium (EGaIn). A cone-shaped EGaIn microelectrode permits access to noninvasive, reversible top-contact formation onto organic surfaces in ambient conditions, high yields of working devices (up to 97%), and thus statistically sufficient thermoelectric data sets (~6000 data per sample in a few hours). We here estimated thermopowers of EGaIn (3.4 +/- 0.1 MUV/K) and the Ga2O3 layer (3.4 +/- 0.2 MUV/K) on the EGaIn conical tip and successfully validated our platform with widely studied molecules, oligophenylenethiolates. Our approach will open the door to thermoelectric large-area molecular junctions. PMID- 30418033 TI - Anthropometry and fitness profile, and their relationships with technical performance and perceived effort during small-sided basketball games. AB - The purpose of this study was to analyze the relationships between anthropometric (height and weight), fitness status (aerobic capacity, Yo-Yo Intermittent Recovery Test - level 1, YYIRT-L1; countermovement jump performance, CMJ) and perceived exertion (RPE) of twenty youth (under-14 and under-16) male basketball players and their technical actions (attacking balls-AB, shots-S, received balls RB, rebounds-R, conquered balls-CB, lost balls-LB) during five small-sided games (SSGs) formats (from 1v1 to 5v5). Pearson's product-moment correlation coefficients tested the relationships between the anthropometric and fitness variables and the technical actions and perceived exertion during SSGs. The results of this study revealed that both anthropometry and fitness variables are associated with technical performance during SSGs. However, correlations are not clear with the levels of perceived exertion reported by players. Coaches should be aware of such relationships to better design their SSGs format and implement basketball drills based on the specific players' characteristics. PMID- 30418034 TI - MCAT: Motif Combining and Association Tool. AB - De novo motif discovery in biological sequences is an important and computationally challenging problem. A myriad of algorithms have been developed to solve this problem with varying success, but it can be difficult for even a small number of these tools to reach a consensus. Because individual tools can be better suited for specific scenarios, an ensemble tool that combines the results of many algorithms can yield a more confident and complete result. We present a novel and fast tool ensemble MCAT (Motif Combining and Association Tool) for de novo motif discovery by combining six state-of-the-art motif discovery tools (MEME, BioProspector, DECOD, XXmotif, Weeder, and CMF). We apply MCAT to data sets with DNA sequences that come from various species and compare our results with two well-established ensemble motif-finding tools, EMD and DynaMIT. The experimental results show that MCAT is able to identify exact match motifs in DNA sequences efficiently, and it has a significantly better performance in practice. PMID- 30418035 TI - Mixed effects of restriction strategies in antimicrobial stewardship programs on antimicrobial use in 121 tertiary hospitals in China, 2013-2017. AB - BACKGROUND: The research evaluated the impact of intravenous antimicrobial restriction strategy (IARS) on different types of hospitals in China for evidence based management, for outpatients implemented in 2016. METHODS: Based on panel data on antimicrobial use in 121 tertiary hospitals in Zhejiang, China, segmented regression analysis was used to evaluate the impact of IARS in children's hospitals (CHs), obstetrics and gynecology hospitals (OGHs), women's and children's hospitals (WCHs), traditional Chinese medicine hospitals (TCMHs) and general hospitals (GHs). Antimicrobial use was measured using the percentage of total encounters with prescribing and the percentage of total drug expenditure relating to antimicrobials (APP and AEP). RESULTS: There was a downward baseline slope of APP in all types of hospitals and AEP in WCHs, TCMHs and GHs (P < 0.01). After IARS, a level reduction in AEP in CHs (-3.14%, 95% CI = -6.21 to 0.06), WCHs (-1.33%, 95% CI = -2.44 to 0.22) and TCMHs (-0.85%, 95%CI = -1.51 to 0.18). After IARS, the slope of AEP changed significantly in OGHs (-0.42%, 95%CI = -0.81 to 0.03) and WCHs (0.29%, 95% CI = 0.08 to 0.49), and the slope of APP changed significantly in CHs (2.35%, 95%CI = 1.20 to 3.49). CONCLUSIONS: IARS had the mixed effects including positive effect in AEP and no significant change in APP, and an unexpected rise in APP in CHs needs further study. PMID- 30418036 TI - The effect of sex, age and performance level on pacing of Ironman triathletes. AB - The aim of the present study was to examine the effect of sex, age and performance level on pacing of Ironman triathletes. Split times (i.e. swimming, cycling, and running) and overall race times of 343,345 athletes competing between 2002 and 2015 in 253 different Ironman triathlon races were analyzed. Participants were classified into nine performance groups according to their overall race time. Times in swimming, cycling, running and transition were expressed as percentage of the overall race time. Women spent relatively less time (%) in swimming, running and transition time, and more time (%) in cycling than men (p < 0.001). The fastest performance group was relatively faster in running (34.8 +/- 1.4 versus 40.3 +/- 3.0%, eta2= 0.098) and transition time (0.9 +/- 0.3 versus 2.2 +/- 0.6%, eta2= 0.178), and relatively slower in swimming (10.2 +/- 0.8 versus 9.8 +/- 1.5%, eta2= 0.018) and cycling (54.1 +/- 1.4 versus 47.8 +/- 2.8%, eta2= 0.138) than the slowest performance group (p < 0.001). The younger age groups were relatively faster in swimming, running and transition time, but relatively slower in cycling. In summary, the fastest Ironman triathletes were the relatively fastest in running and transition times. Thus, race tactics in an Ironman triathlon should focus on saving energy during swimming and cycling for the running split. PMID- 30418037 TI - Sulfamethoxazole derivatives complexed with metals: a new alternative against biofilms of rapidly growing mycobacteria. AB - Biofilms are considered important sources of infections on biomedical surfaces, and most infections involving biofilm formation are associated with medical device implants. Therefore, there is an urgent need for new antimicrobial compounds that can combat microbial resistance associated with biofilm formation. In this context, this work aimed to evaluate the antibiofilm action of sulfamethoxazole complexed with Au, Cd, Cu, Ni and Hg on rapidly growing mycobacteria (RGM), as well as to evaluate their safety through cytotoxic assays. The results demonstrate potentiation of the novel compounds in antibiofilm activity, mainly in the complex with Au, which was able to completely inhibit biofilm formation and had the capacity to destroy the biofilm at all the concentrations tested. All cytotoxic data suggest that the majority of sulfamethoxazole metallic derivatives are antimicrobial alternatives, as well as safe molecules, which could be used as potential therapeutic agents for bacterial and biofilm elimination. PMID- 30418038 TI - Transport of Domestic and Wild Animal Ovaries: A Review of the Effects of Medium, Temperature, and Periods of Storage on Follicular Viability. AB - Short-term storage of ovaries during their transport from the collection sites to the specialized laboratories allows the recovery of thousands of oocytes from females of high genetic value, endangered species, and companion or transgenic animals, which sometimes die unexpectedly in the field, or are ovariectomized for medical reasons. Therefore, several studies have been performed to find ideal protocols to preserve oocyte viability during ovarian tissue transport, thus ensuring the success of techniques that are performed after the storage, such as cryopreservation and/or in vitro follicle culture. To achieve this goal, some factors are essential to maintain oocyte quality, such as medium, temperature, and storage time. Currently, techniques for short-term storage of ovaries have been developed for several animal species. This review aims to present the state of the art with respect to the transport of domestic and wild animal ovaries, highlighting the advantages, limitations, and prospects. PMID- 30418039 TI - The Influence of Exposure to Smoking in Movies on Cigarette Cravings among Adolescents: A Contextual Quasi-Experimental Model. AB - This study explored the socio-contextual characteristics of adolescents that led them to have increased cigarette cravings when exposed to smoking scenes in films. We analyzed online survey data collected from a representative sample of 955 Korean adolescents. Our dependent variable was change in cigarette cravings after watching a smoking scene; independent variables included sex, age, school type, allowance, smoking experience, and parental smoking. We used paired t-tests to identify the differences in cigarette cravings modified by individual characteristics, and we performed logistic regression to explore the influences on these changes in cravings. The high school students investigated herein had significantly stronger cigarette cravings after they watched smoking scenes than they did prior to watching these scenes (t = -5.039, p < 0.001). The cravings were significantly higher after watching the clips among non-smokers (t = -4.264, p < 0.001) and participants who had at least one parent who smoked (t = -2.114, p < 0.05); non-smoking adolescents were also more likely to crave cigarettes after they watched smoking scenes than were smokers (odds ratio = 6.90, p < 0.001). Korean adolescents who did not smoke and those who had at least one parent who smoked showed the strongest cigarette cravings after being exposed to smoking in films. Consequently, more effective prevention strategies should be developed that recognize this tendency when regulating smoking scenes in movies or implementing related campaigns among adolescents. PMID- 30418040 TI - Pediatric ependymoma: current treatment and newer therapeutic insights. AB - Advances in genomic, transcriptomic and epigenomic profiling now identifies pediatric ependymoma as a defined biological entity. Molecular interrogation has segregated these tumors into distinct biological subtypes based on anatomical location, age and clinical outcome, which now defines the need to tailor therapy even for histologically similar tumors. These findings now provide reasons for a paradigm shift in therapy, which should profile future clinical trials focused on targeted therapeutic strategies and risk-based treatment. The need to diagnose and differentiate the aggressive variants, which include the posterior fossa group A and the supratentorial RELA fusion subtypes, is imperative to escalate therapy and improve survival. PMID- 30418041 TI - A Randomized Controlled Trial on the Role of Enthusiasm About Exergames Players' Perceptions of Exercise. AB - OBJECTIVE: Exergames are popular technology applications that encourage individuals to engage in exercise and create positive moods for players. However, little is known as to whether playing exergames makes players perceive to be more energetic and relaxed and whether enthusiasm about doing exercise moderates such perceptions. To answer these questions, we use the Flow Theory and the Self Determination Theory to develop the hypotheses. METHODS: We conducted a randomized controlled trial, which randomly assigned 337 participants to an intervention group and a control group. We asked the participants in the intervention group to play exergames for 2 weeks. We measured enthusiasm about doing exercise by asking the participants to evaluate themselves as having enthusiasm on doing exercise or not. We measured participants' perceptions of happiness, perceived energy (the perception of sufficient physical and mental resources), and relaxation before and after the 2-week exergame playing, generating scores to represent their changes. RESULTS: We found that playing exergames induces positive changes in happiness, perceived energy, and relaxation. Such changes were significant for participants who are enthusiastic about doing exercise, but not for those who are unenthusiastic about doing exercise. CONCLUSION: This study was the first using the Flow Theory and the Self Determination Theory to examine the impact of playing exergames on players' perceptions and to identify the moderator role of enthusiasm about doing exercise. These positive impacts of exergames can be used in rehabilitation settings in encouraging positive attitudes and behaviors toward exercise. PMID- 30418042 TI - Extended-Spectrum Beta-Lactamase-Producing Enterobacteriaceae in Dairy Farm Environments: A New Zealand Perspective. AB - Antimicrobial resistance (AMR) is a global issue for both human and animal health. Infections caused by antimicrobial-resistant bacteria present treatment option challenges and are often associated with heightened severity of infection. Antimicrobial use (AMU) in human and animal health is a main driver for the development of antimicrobial-resistant bacteria. Increasing levels of AMU and the development and spread of AMR in food-producing animals, especially in poultry and swine production, has been identified as a food safety risk, but dairy production systems have been less studied. A number of farm management practices may impact on animal disease and as a result can influence the use of antimicrobials and subsequently AMR prevalence. However, this relationship is multifactorial and complex. Several AMR transmission pathways between dairy cattle, the environment, and humans have been proposed, including contact with manure-contaminated pastures, direct contact, or through the food chain from contaminated animal-derived products. The World Health Organization has defined a priority list for selected bacterial pathogens of concern to human health according to 10 criteria relating to health and AMR. This list includes human pathogens such as the extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E), which can be associated with dairy cattle, their environment, as well as animal-derived food products. ESBL-E represent a potential risk to human and animal health and an emerging food safety concern. This review addresses two areas; first, the current understanding of the role of dairy farming in the prevalence and spread of AMR is considered, highlighting research gaps using ESBL-E as an exemplar; and second, a New Zealand perspective is taken to examine how farm management practices may contribute to on-farm AMU and AMR in dairy cattle. PMID- 30418043 TI - Iron deficiency anemia-related gut microbiota dysbiosis in infants and young children: A pilot study. AB - Nutritional iron deficiency (ID) causes not only anemia but also malfunction of the entire human organism. Recently, a role of the gut microbiota has been hypothesized, but limited data are available especially in infants. Here, we performed a pilot study to explore the gut microbiota in 10 patients with iron deficiency anemia (IDA) and 10 healthy controls aged 6-34 months. Fresh stool samples were collected from diapers, and the fecal microbiota was profiled by next-generation sequencing of the V3-V4 hypervariable region of the 16S rRNA gene. Except for diet diversity, the breastfeeding status at the enrollment, the exclusive breastfeeding duration, and the introduction of complementary foods did not differ between groups. Distinct microbial signatures were found in IDA patients, with increased relative abundance of Enterobacteriaceae (mean relative abundance, patients vs. controls, 4.4% vs. 3.0%) and Veillonellaceae (13.7% vs. 3.6%), and reduced abundance of Coriobacteriaceae (3.5% vs. 8.8%) compared to healthy controls. A decreased Bifidobacteriaceae/Enterobacteriaceae ratio was observed in IDA patients. Notwithstanding the low sample size, our data highlight microbiota dysbalance in IDA worth for further investigations, aimed at unraveling the ID impact on the microbiome trajectory in early life, and the possible long-term consequences. PMID- 30418045 TI - Correction. PMID- 30418044 TI - United States regulatory requirements for skin and eye irritation testing. AB - PURPOSE: Eye and skin irritation test data are required or considered by chemical regulation authorities in the United States to develop product hazard labeling and/or to assess risks for exposure to skin- and eye-irritating chemicals. The combination of animal welfare concerns and interest in implementing methods with greater human relevance has led to development of non-animal skin- and eye irritation test methods. To identify opportunities for regulatory uses of non animal replacements for skin and eye irritation tests, the needs and uses for these types of test data at U.S. regulatory and research agencies must first be clarified. METHODS: We surveyed regulatory and non-regulatory testing needs of U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) agencies for skin and eye irritation testing data. Information reviewed includes the type of skin and eye irritation data required by each agency and the associated decision context: hazard classification, potency classification, or risk assessment; the preferred tests; and whether alternative or non-animal tests are acceptable. Information on the specific information needed from non-animal test methods also was collected. RESULTS: A common theme across U.S. agencies is the willingness to consider non-animal or alternative test methods. Sponsors are encouraged to consult with the relevant agency in designing their testing program to discuss use and acceptance of alternative methods for local skin and eye irritation testing. CONCLUSIONS: To advance the implementation of alternative testing methods, a dialog on the confidence of these methods to protect public health and the environment must be undertaken at all levels. PMID- 30418046 TI - NFIX downregulation independently predicts poor prognosis in lung adenocarcinoma, but not in squamous cell carcinoma. AB - AIM: To study the expression profile of NFIX, its prognostic value and the mechanism of its dysregulation in lung adenocarcinoma (LUAD). Patients & materials: A retrospective study was performed by using data from the Cancer Genome Atlas and the Human Protein Atlas. RESULTS: High NFIX RNA expression was an independent prognostic factor of favorable overall survival (HR: 0.687, 95% CI: 0.496-0.951; p = 0.024) and recurrence-free survival (HR: 0.700, 95% CI: 0.493-0.994, p = 0.046) in LUAD, but not in lung squamous cell carcinoma. NFIX DNA hypermethylation was associated with significantly decreased NFIX expression and shorter overall survival and recurrence-free survival in LUAD. CONCLUSION: NFIX downregulation might independently predict poor prognosis in LUAD. DNA hypermethylation might be an important cause of the downregulation. PMID- 30418047 TI - Interleukin-1 (IL-1) Blockade Reduces Inflammation in Pulmonary Arterial Hypertension and Right Ventricular Failure: A Single-Arm, Open-Label, Phase IB/II Pilot Study. PMID- 30418048 TI - DNA methylation profiling as a tool for testicular germ cell tumors subtyping. AB - AIM: Assess differential patterns of selected five genes' promoter methylation among testicular germ cell tumors (TGCT) subtypes. MATERIALS & METHODS: CRIPTO, HOXA9, MGMT, RASSF1A and SCGB3A1 promoter methylation levels were evaluated by quantitative methylation-specific PCR in 161 TGCT and 16 controls. Associations between clinicopathological parameters and promoter methylation levels were assessed, and receiver operating characteristics curve analysis was performed. RESULTS: Promoter methylation of CRIPTO/HOXA9/SCGB3A1 panel and RASSF1A best discriminated between controls and nonseminomatous tumors or seminomas, respectively, whereas HOXA9/RASSF1A panel displayed the best discriminative performance between nonseminomatous tumor and seminomas. Significant differences in CRIPTO, MGMT and RASSF1A methylation levels were depicted between pure forms and matched mixed components of seminomas and embryonal carcinoma. HOXA9, RASSF1A and SCGB3A1 promoter methylation significantly associated with tumor stage. CONCLUSION: Different combinations of five genes' promoter methylation levels discriminate among TGCT subtypes. Methylation patterns may also assist in identification of more clinically aggressive tumors. PMID- 30418049 TI - Exploring patient-provider decision-making for use of anticoagulation for stroke prevention in atrial fibrillation: Results of the INFORM-AF study. AB - BACKGROUND:: Atrial fibrillation is associated with stroke, yet approximately 50% of patients are not treated with guideline-directed oral anticoagulants (OACs). AIMS:: Given that the etiology of this gap in care is not well understood, we explored decision-making by patients and physicians regarding OAC use for stroke prevention in atrial fibrillation. METHODS AND RESULTS:: We conducted a descriptive qualitative study among providers ( N=28) and their patients with atrial fibrillation for whom OACs were indicated ( N=25). We used purposive sampling across three outpatient settings in which atrial fibrillation patients are commonly managed: primary care ( n=14), geriatrics ( n=10), and cardiology ( n=4). Eligible patients were stratified by those prescribed OAC ( n=13) and not prescribed OAC ( n=12). Semi-structured, in-depth interviews assessed decision making regarding risk and OAC use. Classical content analysis was used to code narratives and identify themes. Results among patients consisted of the overarching theme of trust in provider recommendations. Sub-themes included: awareness of increased risk of stroke with atrial fibrillation; willingness to accept medications recommended by their physician; and low demand for explanatory decision aids. Among physicians, the overarching theme was decisional conflict regarding the balance between stroke and bleeding risk, and the optimal medication to prescribe. Subthemes included: absence of decision aids for communication; and misperceptions around the assessment and management of stroke risk with atrial fibrillation. CONCLUSIONS:: Patient involvement in decision making around OAC use did not occur in this study of patients with atrial fibrillation. Improved access to decision aids may increase patient engagement in the decision-making process of OAC use for stroke prevention. PMID- 30418050 TI - Pragmatic surgical studies. PMID- 30418051 TI - Salvage of failed osteosynthesis for an atypical subtrochanteric femoral fracture associated with long-term bisphosphonate treatment using a 95 degrees angled blade plate. AB - AIMS: The aim of this study was to evaluate the outcomes of a salvage procedure using a 95 degrees angled blade plate for failed osteosynthesis of atypical subtrochanteric femoral fractures associated with the long-term use of bisphosphonates. These were compared with those for failed osteosynthesis of subtrochanteric fractures not associated with bisphosphonate treatment. PATIENTS AND METHODS: Between October 2008 and July 2016, 14 patients with failed osteosynthesis of an atypical subtrochanteric femoral fracture were treated with a blade plate (atypical group). Their mean age was 67.8 years (60 to 74); all were female. During the same period, 21 patients with failed osteosynthesis of a typical subtrochanteric fracture underwent restabilization using a blade plate (typical group). Outcome variables included the time of union, postoperative complications, Harris Hip Score, and Sanders functional rating scale. RESULTS: In the atypical group, union was achieved in 12 patients (85.7%) at a mean of 8.4 months (4 to 12). The mean follow-up was 31.2 months (12 to 92) The plate broke in one patient requiring further stabilization with a longer plate and strut allograft. Another patient with failure of fixation and varus angulation at the fracture site declined further surgery. In the typical group, union was achieved in 18 patients (85.7%) at a mean of 7.9 months (4 to 12). There was no difference in the mean Harris Hip Score between the two groups (83.1 points vs 86.8 points; p = 0.522) at the time of final follow-up. Sanders functional rating scores were good or excellent in 78.6% of the atypical group and in 81.0% of the typical group. CONCLUSION: The 95 degrees angled blade plate was shown to be an effective fixation modality for nonunion of atypical subtrochanteric fractures with a high rate of union and functional improvement, comparable to those after fractures not associated with bisphosphonate treatment. Cite this article: Bone Joint J 2018;100-B:1511-17. PMID- 30418052 TI - The results of osteotomy at the base of femoral neck with osteoplasty in restoration of abductor function and strength in slipped capital femoral epiphysis. AB - AIMS: The aims of this study were to evaluate the abductor function in moderate and severe slipped capital femoral epiphysis (SCFE), comparing the results of a corrective osteotomy at the base of the femoral neck and osteoplasty with 1) in situ epiphysiodesis for mild SCFE, 2) contralateral unaffected hips, and 3) hips from healthy individuals. PATIENTS AND METHODS: A total of 24 patients (mean age 14.9 years (sd 1.6); 17 male and seven female patients) with moderate or severe SCFE (28 hips) underwent base of neck osteotomy and osteoplasty between 2012 and 2015. In situ epiphysiodesis was performed in seven contralateral hips with mild slip. A control cohort was composed of 15 healthy individuals (mean age 16.5 years (sd 2.5); six male and nine female patients). The abductor function was assessed using isokinetic dynamometry and range of abduction, with a minimum one year follow-up. RESULTS: We found no differences in mean peak abductor torque between the hips that underwent osteotomy and those that received in situ epiphysiodesis (p = 0.63), but the torque was inferior in comparison with contralateral hips without a slip (p < 0.01) and hips from control individuals (p < 0.001). The abduction strength was positively correlated with the range of hip abduction (R = 0.36; p < 0.001). CONCLUSION: Although the abductor strength was not restored to normal levels, moderate and severe SCFE treated with osteotomy at the base of the femoral neck and osteoplasty showed abductor function similar to in situ epiphysiodesis in hips with less severe displacement. Cite this article: Bone Joint J 2018;100-B:1524-32. PMID- 30418053 TI - Economic outcomes associated with deep surgical site infection in patients with an open fracture of the lower limb. AB - AIMS: The aim of this study was to estimate economic outcomes associated with deep surgical site infection (SSI) in patients with an open fracture of the lower limb. PATIENTS AND METHODS: A total of 460 patients were recruited from 24 specialist trauma hospitals in the United Kingdom Major Trauma Network. Preference-based health-related quality-of-life outcomes, assessed using the EuroQol EQ-5D-3L and the 6-Item Short-Form Health Survey questionnaire (SF-6D), and economic costs (L, 2014/2015 prices) were measured using participant completed questionnaires over the 12 months following injury. Descriptive statistics and multivariate regression analysis were used to explore the relationship between deep SSI and health utility scores, quality-adjusted life years (QALYs), and health and personal social service (PSS) costs. RESULTS: Deep SSI was associated with lower EQ-5D-3L derived QALYs (adjusted mean difference 0.102, 95% confidence interval (CI) -0.202 to 0.001, p = 0.047) and increased health and social care costs (adjusted mean difference L1950; 95% CI L1383 to L5285, p = 0.250) versus patients without deep SSI over the 12 months following injury. CONCLUSION: Deep SSI may lead to significantly impaired health-related quality of life and increased economic costs. Our economic estimates can be used to inform clinical and budgetary service planning and can act as reference data for future economic evaluations of preventive or treatment interventions. Cite this article: Bone Joint J 2018;100-B:1506-10. PMID- 30418054 TI - Cost-utility studies in upper limb orthopaedic surgery. AB - AIMS: The aim of this study was to assess the quality and scope of the current cost-effectiveness analysis (CEA) literature in the field of hand and upper limb orthopaedic surgery. MATERIALS AND METHODS: We conducted a systematic review of MEDLINE and the CEA Registry to identify CEAs that were conducted on or after 1 January 1997, that studied a procedure pertaining to the field of hand and upper extremity surgery, that were clinical studies, and that reported outcomes in terms of quality-adjusted life-years. We identified a total of 33 studies that met our inclusion criteria. The quality of these studies was assessed using the Quality of Health Economic Analysis (QHES) scale. RESULTS: The mean total QHES score was 82 (high-quality). Over time, a greater proportion of these studies have demonstrated poorer QHES quality (scores < 75). Lower-scoring studies demonstrated several deficits, including failures in identifying reference perspectives, incorporating comparators and sensitivity analyses, discounting costs and utilities, and disclosing funding. CONCLUSION: It will be important to monitor the ongoing quality of CEA studies in orthopaedics and ensure standards of reporting and comparability in accordance with Second Panel recommendations. Cite this article: Bone Joint J 2018;100-B:1416-23. PMID- 30418055 TI - Can a reverse shoulder arthroplasty be used to revise a failed primary reverse shoulder arthroplasty? AB - AIMS: Patients with a failed reverse shoulder arthroplasty (RSA) have limited salvage options. The aim of this study was to determine the outcome of revision RSA when used as a salvage procedure for a failed primary RSA. PATIENTS AND METHODS: We reviewed all revision RSAs performed for a failed primary RSA between 2006 and 2012, excluding patients with a follow-up of less than two years. A total of 27 revision RSAs were included in the study. The mean age of the patients at the time of revision was 70 years (58 to 82). Of the 27 patients, 14 (52% were female). The mean follow-up was 4.4 years (2 to 10). RESULTS: Six patients (22%) developed complications requiring further revision surgery, at a mean of 1.7 years (0.1 to 5.3) postoperatively. The indication for further revision was dislocation in two, glenoid loosening in one, fracture of the humeral component in one, disassociation of the glenosphere in one, and infection in one. The five-year survival free of further revision was 85%. Five additional RSAs developed complications that did not need surgery, including dislocation in three and periprosthetic fracture in two. Overall, patients who did not require further revision had excellent pain relief, and significant improvements in elevation and external rotation of the shoulder (p < 0.01). The mean postoperative American Shoulder and Elbow Surgeons (ASES), and simple shoulder test (SST) scores were 66 and 7, respectively. Radiological results were available in 26 patients (96.3%) at a mean of 4.3 years (1.5 to 9.5). At the most recent follow-up, six patients (23%) had glenoid lucency, which were classified as grade III or higher in three (12%). Smokers had a significantly increased risk of glenoid lucency (p < 0.01). CONCLUSION: Revision RSA, when used to salvage a failed primary RSA, can be a successful procedure. At intermediate follow-up, survival rates are reasonable, but dislocation and glenoid lucency remain a concern, particularly in smokers. Cite this article: Bone Joint J 2018;100-B:1493 98. PMID- 30418056 TI - Infographic: Replacing failed reverse shoulder arthroplasties as a reliable revision approach. PMID- 30418057 TI - A systematic review of local antibiotic devices used to improve wound healing following the surgical management of foot infections in diabetics. AB - AIMS: Local antibiotics are used in the surgical management of foot infection in diabetic patients. This systematic review analyzes the available evidence of the use of local antibiotic delivery systems as an adjunct to surgery. MATERIALS AND METHODS: Databases were searched to identify eligible studies and 13 were identified for inclusion. RESULTS: Overall, the quality of the studies was poor. A single trial suggested that wound healing is quicker when a gentamicin impregnated collagen sponge was implanted at time of surgery, with no difference in length of stay or rate of amputation. Results from studies with high risk of bias indicated no change in wound healing when a gentamicin-impregnated sponge was implanted during transmetatarsal amputation, but a reduction in the incidence of wound breakdown (8% vs 25%, not statistically significant) was identified. A significant cost reduction was identified when using an antimicrobial gel to deliver antibiotics and anti-biofilm agents (quorum-sensing inhibitors) compared with routine dressings and systemic antibiotics. Analyses of case series identified 485 patients who were treated using local antibiotic delivery devices. The rates of wound healing, re-operation, and mortality were comparable to those that have been previously reported for the routine management of these infections. CONCLUSION: There is a lack of good-quality evidence to support the use of local antibiotic delivery devices in the treatment of foot infections in patients with diabetes. Cite this article: Bone Joint J 2018;100-B:1409-15. PMID- 30418058 TI - The mean ten-year results of metal-on-metal hybrid hip resurfacing arthroplasty. AB - AIMS: This study presents the long-term survivorship, risk factors for prosthesis survival, and an assessment of the long-term effects of changes in surgical technique in a large series of patients treated by metal-on-metal (MoM) hip resurfacing arthroplasty (HRA). PATIENTS AND METHODS: Between November 1996 and January 2012, 1074 patients (1321 hips) underwent HRA using the Conserve Plus Hip Resurfacing System. There were 787 men (73%) and 287 women (27%) with a mean age of 51 years (14 to 83). The underlying pathology was osteoarthritis (OA) in 1003 (75.9%), developmental dysplasia of the hip (DDH) in 136 (10.3%), avascular necrosis in 98 (7.4%), and other conditions, including inflammatory arthritis, in 84 (6.4%). RESULTS: The mean follow-up time was 10.5 years (1 to 20). Using revision for any reason as the endpoint, the overall survivorship at 15 years was 89.4% (95% confidence interval (CI) 86.8 to 91.4). There was a substantial increase between the first and second generation of surgical technique (86.6% vs 90.1%; p = 0.05). Men with idiopathic OA had a 15-year survivorship of 94.5% and women, 82.2% (p = 0.001); gender was not a risk factor after stratification by component size and aetiology. Using revision for excessive wear (ion levels > 7 ug/l associated with symptoms or adverse local tissue reactions) as the endpoint, the 15-year survivorship was 98.5%. Risk factors for revision for all modes of failure were an underlying pathology of hip dysplasia, a contact patch to rim (CPR) distance of 7 mm or less, an age at surgery of 55 years or less, and a femoral component size of 46 mm or less. Specific risk factors for aseptic failure of the femoral component were early surgical technique, a cementless metaphyseal stem, and a body mass index of 24 kg/m2 or less. CONCLUSION: HRA is a viable concept; metal-on-metal bearings are well suited for this procedure when a well-designed device is properly implanted. The best results were obtained in men with OA, but survivorship was better for other underlying pathologies and for women after changes were made to the technique of implantation. Lifetime durability is a possible outcome for many patients despite a high level of activity. Cite this article: Bone Joint J 2018;100-B:1424-33. PMID- 30418059 TI - Management and outcome of acral soft-tissue sarcomas. AB - AIMS: The aim of this study was to evaluate the surgical management and outcome of patients with an acral soft-tissue sarcoma of the hand or foot. PATIENTS AND METHODS: We identified 63 patients with an acral soft-tissue sarcoma who presented to our tertiary referral sarcoma service between 2000 and 2016. There were 35 men and 28 women with a mean age of 49 years (sd 21). Of the 63 sarcomas, 27 were in the hands and 36 in the feet. The commonest subtypes were epithelioid sarcoma in the hand (n = 8) and synovial sarcoma in the foot (n = 11). RESULTS: In 41 patients (65%), the tumour measured less than 5 cm in its largest dimension (median size 3 cm (2 to 6)); 27 patients (43%) were diagnosed after inadvertent excision prior to their referral to the specialist sarcoma unit. After biopsy and staging, primary surgical intervention at the sarcoma unit was excision and limb salvage in 43 (68%), partial (digit or ray) amputation in 14 (22%), and more proximal amputation in six (10%). At final follow up, local recurrence had been treated by one partial amputation and six amputations, resulting in a partial amputation rate of 24% and a proximal amputation rate of 19%. The five-year survival rate was 82%. Patients who underwent inadvertent excision showed no statistically significant difference in survival or local recurrence, but were more likely to undergo amputation (p = 0.008). Large tumour size (> 5 cm) was associated with lower survival (p = 0.04) and a higher risk of local recurrence (p = 0.009;). CONCLUSION: Most acral soft-tissue sarcomas measure less than 5 cm at presentation, indicating that while size can be a useful prognostic factor, it should not be used as a diagnostic threshold for referral. Increased tumour size is associated with a higher rate of local recurrence and reduced survival. Sarcoma excision with limb preservation does not result in an increased risk of local recurrence. Cite this article: Bone Joint J 2018;100-B:1518-23. PMID- 30418060 TI - Long-term results of acetabular reconstruction using irradiated allograft bone. AB - AIMS: The management of acetabular defects at the time of revision hip arthroplasty surgery is a challenge. This study presents the results of a long term follow-up study of the use of irradiated allograft bone in acetabular reconstruction. PATIENTS AND METHODS: Between 1990 and 2000, 123 hips in 110 patients underwent acetabular reconstruction for aseptic loosening, using impaction bone grafting with frozen, irradiated, and morsellized femoral heads and a cemented acetabular component. A total of 55 men and 55 women with a mean age of 64.3 years (26 to 97) at the time of revision surgery are included in this study. RESULTS: At a mean follow-up of 16.9 years, there had been 23 revisions (18.7%), including ten for infection, eight for aseptic loosening, and three for dislocation. Of the 66 surviving hips (58 patients) that could be reassessed, 50 hips (42 patients; 75.6%) were still functioning satisfactorily. Union of the graft had occurred in all hips with a surviving implant. Survival analysis for all indications was 80.6% at 15 years (55 patients at risk, 95% confidence interval (CI) 71.1 to 87.2) and 73.7% at 20 years (eight patients at risk, 95% CI 61.6 to 82.5). CONCLUSION: Acetabular reconstruction using frozen, irradiated, and morsellized allograft bone and a cemented acetabular component is an effective method of treatment. It gives satisfactory long-term results and is comparable to other types of reconstruction. Cite this article: Bone Joint J 2018;100-B:1449-54. PMID- 30418061 TI - The serum level of C-reactive protein alone cannot be used for the diagnosis of prosthetic joint infections, especially in those caused by organisms of low virulence. AB - AIMS: The aim of this study was to determine the prevalence and characteristics of C-reactive protein (CRP)-negative prosthetic joint infection (PJI) and evaluate the influence of the type of infecting organism on the CRP level. PATIENTS AND METHODS: A retrospective analysis of all PJIs affecting the hip or knee that were diagnosed in our institution between March 2013 and December 2016 was performed. A total of 215 patients were included. Their mean age was 71 years (sd 11) and there were 118 women (55%). The median serum CRP levels were calculated for various species of organism and for patients with acute postoperative, acute haematogenous, and chronic infections. These were compared using the Kruskal-Wallis test, adjusting for multiple comparisons with Dunn's test. The correlation between the number of positive cultures and serum CRP levels was estimated using Spearman correlation coefficient. RESULTS: Preoperative CRP levels were normal (< 10 mg/l) in 77 patients (35.8%) with positive cultures. Low-virulent organisms were isolated in 66 PJIs (85.7%) with normal CRP levels. When grouping organisms by species, patients with an infection caused by Propionibacterium spp., coagulase-negative staphylococci (CNS), and Enterococcus faecalis had significantly lower median serum CRP levels (5.4 mg/l, 12.2 mg/l, and 23.7 mg/l, respectively), compared with those with infections caused by Staphylococcus aureus and Streptococcus spp. (194 mg/l and 89.3 mg/l, respectively; p < 0.001). Those with a chronic PJI had statistically lower median serum CRP levels (10.6 mg/l) than those with acute postoperative and acute haematogenous infections (83.7 mg/l and 149.4 mg/l, respectively; p < 0.001). There was a significant correlation between the number of positive cultures and serum CRP levels (Spearman correlation coefficient, 0.456; p < 0.001). CONCLUSION: The CRP level alone is not accurate as a screening tool for PJI and may yield high false-negative rates, especially if the causative organism has low virulence. Aspiration of the joint should be used for the diagnosis of PJI in patients with a chronic painful arthroplasty, irrespective of CRP level. Cite this article: Bone Joint J 2018;100-B:1482-86. PMID- 30418062 TI - The impact of older age on patient outcomes following primary total knee arthroplasty. AB - AIMS: As the population ages, there is projected to be an increase in the level of demand for total knee arthroplasty (TKA) in octogenarians. We aimed to explore whether those aged >= 80 years achieved similar improvements in physical function to younger patients while also comparing the rates of length of stay (LOS), discharge to rehabilitation, postoperative complications, and mortality following TKA in older and younger patients. PATIENTS AND METHODS: Patients from one institution who underwent primary elective TKA between 1 January 2006 and 31 December 2014 were dichotomized into those >= 80 years old (n = 359) and those < 80 years old (n = 2479) for comparison. Multivariable regression was used to compare the physical status component of the 12-Item Short-Form Health Survey (SF 12), LOS, discharge to rehabilitation, complications, and mortality between the two groups. RESULTS: Both age groups demonstrated a clinically meaningful improvement in their self-reported physical health relative to their baseline with no clinically relevant difference noted between them. Being >= 80 years old was associated with a 0.58-day increase in LOS and older patients were more likely to be discharged to rehabilitation (odds ratio (OR) 3.06, p < 0.001). Medical complications and mortality were higher in elderly patients (OR 1.92 for complications, p < 0.001; hazard ratio 3.40 for death, p < 0.001). There was no statistically significant association between age group and experiencing a postoperative surgical or wound-related complication. CONCLUSION: Those aged over 80 years achieved a statistically significant lower median SF-12 physical score than the younger group, after adjusting for the preoperative score, but this difference of 4.46 was not considered to be clinically meaningful. However, clinicians should be aware that the elderly are at a higher risk of experiencing longer hospital stays, postoperative medical complications, and mortality. Cite this article: Bone Joint J 2018;100-B:1463-70. PMID- 30418063 TI - Investigation of factors related to the occurrence of osteochondral lesions of the talus by 3D bone morphology of the ankle. AB - AIMS: The aims of this study were to evaluate the morphology of the ankle in patients with an osteochondral lesion of the talus using 3D CT, and to investigate factors that predispose to this condition. PATIENTS AND METHODS: The study involved 19 patients (19 ankles) who underwent surgery for a medial osteochondral lesion (OLT group) and a control group of 19 healthy patients (19 ankles) without ankle pathology. The mean age was significantly lower in the OLT group than in the control group (27.0 vs 38.9 years; p = 0.02). There were 13 men and six women in each group. 3D CT models of the ankle were made based on Digital Imaging and Communications in Medicine (DICOM) data. The medial malleolar articular and tibial plafond surface, and the medial and lateral surface area of the trochlea of the talus were defined. The tibial axis-medial malleolus (TMM) angle, the medial malleolar surface area and volume (MMA and MMV) and the anterior opening angle of the talus were measured. RESULTS: The mean TMM angle was significantly larger in the OLT group (34.2 degrees , sd 4.4 degrees ) than in the control group (29.2 degrees , sd 4.8 degrees ; p = 0.002). The mean MMA and MMV were significantly smaller in the OLT group than in the control group (219.8 mm2, sd 42.4) vs (280.5 mm2, sd 38.2), and (2119.9 mm3, sd 562.5) vs (2646.4 mm3, sd 631.4; p < 0.01 and p = 0.01, respectively). The mean anterior opening angle of the talus was significantly larger in the OLT group than in the control group (15.4 degrees , sd 3.9 degrees ) vs (10.2 degrees , sd 3.6 degrees ; p < 0.001). CONCLUSION: 3D CT measurements showed that, in patients with a medial osteochondral lesion of the talus, the medial malleolus opens distally, the MMA and MMV are small, and the anterior opening angle of the talus is large. This suggests that abnormal morphology of the ankle predisposes to the development of osteochondral lesions of the talus. Cite this article: Bone Joint J 2018;100-B:1487-90. PMID- 30418064 TI - Orthopaedic infection. PMID- 30418066 TI - Cup-cage reconstruction for severe acetabular bone loss and pelvic discontinuity. AB - AIMS: Severe acetabular bone loss and pelvic discontinuity (PD) present particular challenges in revision total hip arthroplasty. To deal with such complex situations, cup-cage reconstruction has emerged as an option for treating this situation. We aimed to examine our success in using this technique for these anatomical problems. PATIENTS AND METHODS: We undertook a retrospective, single centre series of 35 hips in 34 patients (seven male, 27 female) treated with a cup-cage construct using a trabecular metal shell in conjunction with a titanium cage, for severe acetabular bone loss between 2011 and 2015. The mean age at the time of surgery was 70 years (42 to 85) and all patients had an acetabular defect graded as Paprosky Type 2C through to 3B, with 24 hips (69%) having PD. The mean follow-up was 47 months (25 to 84). RESULTS: The cumulative five-year survivorship of the implant with revision for any cause was 89% (95% confidence interval (CI) 72 to 96) with eight hips at risk. No revision was required for aseptic loosening; however, one patient with one hip (3%) required removal of the ischial flange of the cage due to sciatic nerve irritation. Two patients (6%; two hips) suffered from hip dislocation, whereas one patient (one hip) required revision surgery with cement fixation of a dual-mobility acetababular component into a well-fixed cup-cage construct. Two patients (6%; two hips) developed periprosthetic infection. One patient was successfully controlled with a two stage revision surgery, while the other patient underwent excision arthroplasty due to severe medical comorbidities. For the whole series, the Harris Hip Score significantly improved from a mean of 30 (15 to 51) preoperatively to 71 (40 to 89) at the latest follow-up (p < 0.001). CONCLUSION: Our findings suggest that cup-cage reconstruction is a viable option for major segmental bone defects involving the posterior column and PD. It allows adequate restoration of the acetabulum centre with generally good stability and satisfactory postoperative function. Instability and infection remain drawbacks in these challenging revision cases. Cite this article: Bone Joint J 2018;100-B:1442-48. PMID- 30418065 TI - Radial head resection versus prosthetic arthroplasty in terrible triad injury: a retrospective comparative cohort study. AB - AIMS: The crucial role of the radial head in the stability of the elbow in terrible triad injury is acknowledged. This retrospective study aims to compare the results of resection of a severely comminuted radial head with or without prosthetic arthroplasty as part of the reconstruction for this injury. PATIENTS AND METHODS: The outcome of radial head resection was compared with prosthetic arthroplasty in 29 and 15 patients with terrible triad injuries, respectively. There were ten female patients (34.5%) in the resection group and six female patients (40%) in the prosthesis group. The mean age was 40.7 years (sd 13.6) in the resection group and 36 years (sd 9.4) in the prosthesis group. The mean follow-up of the patients was 24.4 months (sd 12) in the resection group and 45.8 months (sd 6.8) in the prosthesis group. Outcome measures included visual analogue scale (VAS) for pain, Mayo Elbow Performance Score (MEPS), Disabilities of Arm, Shoulder and Hand (DASH) Score, and range of movement. Postoperative radiological complications were also recorded. RESULTS: The mean ranges of extension, flexion, supination, and pronation were not significantly different between the two study groups (p = 0.75, p = 0.65, p = 0.82, and p = 0.68, respectively). The mean VAS score, DASH score, and MEPS of the two groups were also not statistically significantly different (p = 0.93, p = 0.19, and p = 0.32, respectively). At the final visit, the elbow was stable in all patients. No patient was found to have developed an Essex-Lopresti injury. Osteoarthritis grade I and II was observed in five and three patients of the resection group, respectively, and four and one patients of the arthroplasty group, respectively. CONCLUSION: The outcome of patients undergoing treatment for terrible triad injuries is similar whether the patient's radial head was excised or replaced. Cite this article: Bone Joint J 2018;100-B:1499-505. PMID- 30418067 TI - Irrigation and debridement with chronic antibiotic suppression for the management of infected total knee arthroplasty. AB - AIMS: The results of irrigation and debridement with component retention (IDCR) in the treatment of acutely infected total knee arthroplasties (TKAs) have been variable. The aim of this study was to assess the outcome after IDCR when combined with chronic antibiotic suppression. We also evaluated survivorship free from subsequent infection, removal of the components, and death, as well as the risk factors for failure. PATIENTS AND METHODS: This was a single-centre retrospective review of 134 infected primary TKAs that were treated with IDCR. Infections within four weeks of the procedure were defined as acute postoperative infections, and those occurring more than four weeks after the procedure with symptoms for less than three weeks were defined as acute haematogenous infections. Patients were treated with intravenous antibiotics for four to six weeks, followed by chronic oral antibiotic suppression. Estimates of survival were made using a competing risk analysis. The mean follow-up was five years (2.1 to 13). RESULTS: The infection was an acute postoperative infection in 23 TKAs and an acute haematogenous infection in 111 TKAs. The incidence of subsequent infection was 36% in those with an acute postoperative infection and 33% in those with a haematogenous infection, five years postoperatively (p = 0.40). Age < 60 years increased the risk of subsequent infection (hazard ratio (HR) 2.4; p = 0.009) and removal of the components (HR 2.8; p = 0.007). Infection with a staphylococcal species increased the risk of subsequent infection (HR 3.6; p < 0.001), and removal of the components (HR 3.2; p = 0.002). Musculoskeletal Infection Society host type and local extremity grade, body mass index (BMI), the duration of symptoms, gender, and the presence of a monoblock tibial component had no significant effect on the outcome. CONCLUSION: In a rigorously defined group of acute periprosthetic infections after TKA treated with IDCR and chronic antibiotic suppression, the infection-free survival at five years was 66%. The greatest risk factor for failure was an infection with a staphylococcal species, followed by age of < 60 years. Cite this article: Bone Joint J 2018;100-B:1471 76. PMID- 30418068 TI - Excellent results of large-diameter ceramic-on-ceramic bearings in total hip arthroplasty. AB - AIMS: This study reports the mid-term results of total hip arthroplasty (THA) performed using a monoblock acetabular component with a large-diameter head (LDH) ceramic-on-ceramic (CoC) bearing. PATIENTS AND METHODS: Of the 276 hips (246 patients) included in this study, 264 (96%) were reviewed at a mean of 67 months (48 to 79) postoperatively. Procedures were performed with a mini posterior approach. Clinical and radiological outcomes were recorded at regular intervals. A noise assessment questionnaire was completed at last follow-up. RESULTS: There were four re-operations (1%) including one early revision for insufficient primary fixation (0.4%). No hip dislocation was reported. The mean University of California, Los Angeles (UCLA) activity score, 12-Item Short-Form Health Survey (SF-12) Mental Component Summary (MCS) score, SF-12 Physical Component Summary (PCS) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and Forgotten Joint Score (FJS) were 6.6 (2 to 10), 52.8 (25.5 to 65.7), 53.0 (27.2 to 66.5), 7.7 (0 to 63), and 88.5 (23 to 100), respectively. No signs of loosening or osteolysis were observed on radiological review. The incidence of squeaking was 23% (n = 51/225). Squeaking was significantly associated with larger head diameter (p < 0.001), younger age (p < 0.001), higher SF-12 PCS (p < 0.001), and UCLA scores (p < 0.001). Squeaking did not affect patient satisfaction, with 100% of the squeaking hips satisfied with the surgery. CONCLUSION: LDH CoC THAs have demonstrated excellent functional outcomes at medium-term follow-up, with very low revision rate and no dislocations. The high incidence of squeaking did not affect patient satisfaction or function. LDH CoC with a monoblock acetabular component has the potential to provide long term implant survivorship with unrestricted activity, while avoiding implant impingement, liner fracture at insertion, and hip instability. Cite this article: Bone Joint J 2018;100-B:1434-41. PMID- 30418069 TI - Risk analysis of patients with an osteolytic acetabular defect after total hip arthroplasty using subject-specific finite-element modelling. AB - AIMS: Osteolysis, secondary to local and systemic physiological effects, is a major challenge in total hip arthroplasty (THA). While osteolytic defects are commonly observed in long-term follow-up, how such lesions alter the distribution of stress is unclear. The aim of this study was to quantitatively describe the biomechanical implication of such lesions by performing subject-specific finite element (FE) analysis on patients with osteolysis after THA. PATIENTS AND METHODS: A total of 22 hemipelvis FE models were constructed in order to assess the transfer of load in 11 patients with osteolysis around the acetabular component of a THA during slow walking and a fall onto the side. There were nine men and two women. Their mean age was 69 years (55 to 81) at final follow-up. Changes in peak stress values and loads to fracture in the presence of the osteolytic defects were measured. RESULTS: The von Mises stresses were increased in models of those with and those without defects for both loading scenarios. Although some regions showed increases in stress values of up to 100%, there was only a moderate 11.2% increase in von Mises stress in the series as a whole. The site of fracture changed in some models with lowering of the load to fracture by 500 N. The most common site of fracture was the pubic ramus. This was more frequent in models with larger defects. CONCLUSION: We conclude that cancellous defects cause increases in stress within cortical structures. However, these are likely to lead to a modest decrease in the load to fracture if the defect is large (> 20cm3) or if the patient is small with thin cortical structures and low bone mineral density. Cite this article: Bone Joint J 2018;100-B:1455-62. PMID- 30418070 TI - Patellar fractures are associated with an increased risk of total knee arthroplasty. AB - AIMS: The aim of this study was to investigate the incidence of knee arthroplasty and arthroscopy following patellar fractures, and to compare this with an age- and gender-matched group without a prior patellar fracture. PATIENTS AND METHODS: A national matched cohort study based on the Danish National Patient Register including all citizens of Denmark (approximately 5.3 million) was undertaken. A total of 6096 patients who sustained a patellar fracture in Denmark between 1 January 1996 and 31 December 2000 were included. The median age of these patients was 50.6 years (interquartile range (IQR) 28.5 to 68.9); 49.1% were women. Patients were followed-up until 31 December 2015, with regard to treatment with knee arthroplasty and/or knee arthroscopy. RESULTS: Patients with a patellar fracture had an increased risk of knee arthroplasty (hazard ratio (HR) 1.83, 95% confidence interval (CI) 1.57 to 2.13) compared with citizens without a patellar fracture, and the effect was strongest during the first five years (HR 3.02, 95% CI 2.26 to 4.03). Patients with a patellar fracture also had a higher risk of knee arthroscopy (HR 3.94, 95% CI 3.49 to 4.46), and the effect was highest during the first five years after the fracture (HR 7.40, 95% CI 6.32 to 8.66). CONCLUSION: Patellar fractures are associated with an increased risk of knee arthroplasty and knee arthroscopy. The consequences of a patellar fracture may be more severe than previously considered, and patients must expect a lifelong increased risk of knee arthroplasty. Cite this article: Bone Joint J 2018;100 B:1477-81. PMID- 30418071 TI - Evolution of innate immune sensors and responses during immune disorders and immunization against microbial infection. PMID- 30418072 TI - Recommendations for increasing research on co-occurring serious mental illness and gambling problems. AB - Psychiatric disorders frequently co-occur with gambling disorder. Although community and clinical samples show frequent co-occurrence between gambling and psychotic disorders, relatively little research has been conducted on this population. Here, we comment on a recent study conducted in Brazil on the clinical correlates of psychotic disorders in treatment-seeking individuals with gambling disorder, relate the findings to those from the northeastern region of the United States, and discuss implications with respect to promoting responsible gambling in the setting of the expansion of legalized gambling. PMID- 30418073 TI - Short version of the Smartphone Addiction Scale in Chinese adults: Psychometric properties, sociodemographic, and health behavioral correlates. AB - BACKGROUND AND AIMS: Problematic smartphone use (PSU) is an emerging but understudied public health issue. Little is known about the epidemiology of PSU at the population level. We evaluated the psychometric properties of the Smartphone Addiction Scale - Short Version (SAS-SV) and examined its associated sociodemographic factors and health behaviors in Chinese adults in Hong Kong. METHODS: A random sample of 3,211 adults aged >=18 years (mean +/- SD: 43.3 +/- 15.7, 45.3% men) participated in a population-based telephone survey in Hong Kong and completed the Chinese SAS-SV. Multivariable linear regressions examined the associations of sociodemographic factors, health behaviors, and chronic disease status with SAS-SV score. Data were weighted by age, sex, and education attainment distributions of the Hong Kong general population. RESULTS: The Chinese SAS-SV is internally consistent (Cronbach's alpha = .844) and stable over 1 week (intraclass correlation coefficient = .76, p < .001). Confirmatory factor analysis supported a unidimensional structure established by previous studies. The weighted prevalence of PSU was 38.5% (95% confidence interval: 36.9%, 40.2%). Female sex, younger age, being married/cohabitated or divorced/separated (vs. unmarried), and lower education level were associated with a higher SAS-SV score (all ps <.05). Current smoking, weekly to daily alcohol drinking, and physical inactivity predict greater PSU after controlling for sociodemographic factors and mutual adjustment. DISCUSSION AND CONCLUSIONS: The Chinese SAS-SV was found valid and reliable for assessing PSU in Hong Kong adults. Several sociodemographic and health behavioral factors were associated with PSU at the population level, which may have implication for prevention of PSU and future research. PMID- 30418074 TI - A cohort study of patients seeking Internet gaming disorder treatment. AB - BACKGROUND AND AIMS: Although Internet gaming disorder (IGD) is included as a condition in the fifth edition of Diagnostic and Statistical Manual of Mental Disorders, little is known about its nature or treatment response. This study is a follow-up of 755 patients who received professional treatment for IGD over a 5 year period. METHODS: The initial recommended treatment course lasted for 8 weeks, with additional care provided as needed. Treatment completion rates in the complete sample, as well as baseline predictors of treatment completion and long term recovery among the 367 patients who completed the follow-up, are reported. RESULTS: Nearly two thirds of patients who initiated treatment for IGD completed the 8-week psychotherapy. Of these, about two thirds who had not recovered completely by the end were offered additional care. Independent predictors of extended treatment were higher baseline scores on the Young Internet Addiction Scale, Beck Depression Inventory (BDI), and Korean-Attention Deficit Hyperactivity Disorder-Rating Scale (K-ADHD-RS). Between 1 and 5 years later, 33.5% of the complete sample was considered as recovered from IGD. Significant predictors of recovery from IGD were older age, earlier admission to the clinic, lower baseline scores on the BDI and K-ADHD-RS, and no offer of extended treatment. DISCUSSION AND CONCLUSIONS: The majority of the patients seeking treatment for IGD continued experiencing difficulties and randomized controlled trials of interventions, which are needed to be conducted to improve outcomes. Age, family, social factors, and psychological symptoms should be considered, while designing and evaluating interventions, because they impact initial and sustained response to treatment for IGD. PMID- 30418075 TI - A pilot study of a group mindfulness-based cognitive-behavioral intervention for smartphone addiction among university students. AB - BACKGROUND AND AIMS: Mindfulness-based intervention (MBI) has been applied in behavioral addiction studies in recent years. However, few empirical studies using MBI have been conducted for smartphone addiction, which is prevalent among Chinese university students. The aim of this study was to investigate the effectiveness of a group mindfulness-based cognitive-behavioral intervention (GMCI) on smartphone addiction in a sample of Chinese university students. METHODS: Students with smartphone addiction were divided into a control group (n = 29) and an intervention group (n = 41). The students in the intervention group received an 8-week GMCI. Smartphone addiction was evaluated using scores from the Mobile Phone Internet Addiction Scale (MPIAS) and self-reported smartphone use time, which were measured at the baseline (1st week, T1), post-intervention (8th week, T2), the first follow-up (14th week, T3), and the second follow-up (20th week, T4). RESULTS: Twenty-seven students in each group completed the intervention and the follow-up. Smartphone use time and MPIAS scores significantly decreased from T1 to T3 in the intervention group. Compared with the control group, the intervention group had significantly less smartphone use time at T2, T3, and T4 and significantly lower MPIAS scores at T3. DISCUSSION AND CONCLUSION: This pilot study demonstrated that the GMCI could significantly alleviate smartphone addiction among university students. PMID- 30418076 TI - The effect of loss-limit reminders on gambling behavior: A real-world study of Norwegian gamblers. AB - BACKGROUND: Over the past two decades, problem gambling has become a public health issue and research from many countries indicates that a small but significant minority of individuals are problem gamblers. In Norway, the prevalence of problem gambling among adults is estimated to be just less than 1%. To help minimize the harm from gambling, the Norwegian government's gambling operator (Norsk Tipping) has introduced several responsible gambling initiatives to help protect players from developing gambling problems (e.g., limit-setting tools, voluntary self-exclusion, personalized feedback, etc.). AIM: The aim of this study was to determine whether the receiving of personalized feedback exceeding 80% of a personally set monetary personal limit had an effect on subsequent playing behavior compared to those gamblers who did not receive personalized feedback. METHODS: Out of 54,002 players, a total of 7,884 players (14.5%) received at least one piece of feedback that they had exceeded 80% of their personal global monthly loss limit between January and March 2017. RESULTS: Using a matched-pairs design, results showed that those gamblers receiving personalized feedback in relation to limit-setting showed significant reductions in the amount of money gambled. CONCLUSION: The findings of this study will be of great value to many stakeholder groups including researchers in the gambling studies field, the gambling industry, regulators, and policymakers. PMID- 30418077 TI - Transcranial direct current stimulation for online gamers: A prospective single arm feasibility study. AB - AIM: Excessive use of online games can have negative influences on mental health and daily functioning. Although the effects of transcranial direct current stimulation (tDCS) have been investigated for the treatment of addiction, it has not been evaluated for excessive online game use. This study aimed to investigate the feasibility and tolerability of tDCS over the dorsolateral prefrontal cortex (DLPFC) in online gamers. METHODS: A total of 15 online gamers received 12 active tDCS sessions over the DLPFC (anodal left/cathodal right, 2 mA for 30 min, 3 times per week for 4 weeks). Before and after tDCS sessions, all participants underwent 18F-fluoro-2-deoxyglucose positron emission tomography scans and completed the Internet Addiction Test (IAT), Brief Self Control Scale (BSCS), and Beck Depression Inventory-II (BDI-II). RESULTS: After tDCS sessions, weekly hours spent on games (p = .02) and scores of IAT (p < .001) and BDI-II (p = .01) were decreased, whereas BSCS score was increased (p = .01). Increases in self-control were associated with decreases in both addiction severity (p = .002) and time spent on games (p = .02). Moreover, abnormal right-greater-than-left asymmetry of regional cerebral glucose metabolism in the DLPFC was partially alleviated (p = .04). CONCLUSIONS: Our preliminary results suggest that tDCS may be useful for reducing online game use by improving interhemispheric balance of glucose metabolism in the DLPFC and enhancing self-control. Larger sham-controlled studies with longer follow-up period are warranted to validate the efficacy of tDCS in gamers. PMID- 30418078 TI - Therapeutic Efficacy of Home-Use Photobiomodulation Devices: A Systematic Literature Review. AB - OBJECTIVE: Perform systematic literature review on photobiomodulation (PBM) devices used at home for nonesthetic applications. BACKGROUND: Home-use PBM devices have been marketed for cosmetic and therapeutic purposes. This is the first systematic literature review for nonesthetic applications. METHODS: A systematic literature search was conducted for PBM devices self-applied at home at least thrice a week. Two independent reviewers screened the articles and extracted the data. Treatment dosage appropriateness was compared to the World Association for Laser Therapy (WALT) recommendations. The efficacy was evaluated according to the relevant primary end-point for the specific indication. RESULTS: Eleven studies were suitable. Devices were applied for a range of indications, including pain, cognitive dysfunction, wound healing, diabetic macular edema, and postprocedural side effects, and were mostly based on near-infrared, pulsed light emitting diodes with dosages within WALT recommendations. Regarding efficacy, studies reported mostly positive results. CONCLUSIONS: Home-use PBM devices appear to mediate effective, safe treatments in a variety of conditions that require frequent applications. Conclusive evaluation of their efficacy requires additional, randomized controlled studies. PMID- 30418079 TI - Starvation reduces hyaluronan synthesis by suppressing TGF-beta1/IGF-I signaling in rat skin. AB - Although starvation has been reported to influence the functions of various tissues, its effects on the skin are not well understood. In this study, we investigated the effect of starvation on hyaluronan synthesis in rat skin. Starvation reduced hyaluronan synthesis in the skin. Starvation also decreased the skin mRNA expression of transforming growth factor (TGF)-beta1, which enhances the gene expression of rhas2 and rhas3. The serum levels of insulin-like growth factor (IGF)-I, which enhances rhas2, rhas3, and TGF-beta1 mRNA expression, in the starvation group were considerably lower than those in the control (CO) group. IGF-IR phosphorylation was substantially lower in the starvation group compared with the CO group. These findings suggest that starvation reduces hyaluronan synthesis in the skin by suppressing TGF-beta1/IGF I signaling. Abbreviations: HAS: hyaluronan synthase; IGF-I: insulin-like growth factor-I; IGFBP-1: insulin-like growth factor binding protein-1; TGF-beta1: transforming growth factor-beta1; TBST: tris buffered saline containing 0.5% (v/v) Tween 20; HABP: hyaluronic acid binding protein; GAPDH: glyceraldehyde-3 phosphate dehydrogenase. PMID- 30418080 TI - Response production during extinction training is not sufficient for extinction of evaluative conditioning. AB - Two high-powered experiments examined the role of evaluative response production in the extinction of evaluative conditioning (EC) by positioning EC in the procedural and conceptual framework of classical conditioning (CC). According to Rescorla's response inhibition hypothesis, more frequent responding during extinction training results in larger extinction during testing. Experiment 1 used three extinction conditions following response acquisition in an EC procedure: evaluative responses were measured only after extinction; after acquisition and after extinction; or were continuously measured after acquisition, during extinction and after extinction. Based on Rescorla's response inhibition hypothesis, we predicted that extinction of EC would be the highest in the third condition. Experiment 2 was aimed at further facilitating extinction of EC by encouraging participants to experience that their evaluation may change over the course of the experiment. To this end, half of the participants completed pre- and post-acquisition ratings prior to practicing continuous response expression in the extinction phase. Contrary to our predictions, no extinction of EC was observed in either of these experiments. We conclude that Rescorla's inhibition response hypothesis may not apply to EC and discuss the theoretical implications of this finding. PMID- 30418081 TI - Hormone deficient mutants have distinct flavonoid proportion fingerprints in response to abiotic stress. AB - Distinct flavonoid profiles (a.k.a. 'fingerprints') are produced in the vegetative tissues of plants in response to different abiotic stresses, yet it remained unknown whether flavonoid levels or their relative their proportions are more tightly regulated in response to stress. Here we show that the relative proportions of 19 flavonoids were more stringently controlled compared to their levels in response to variety of abiotic stresses. We screened mutants that are deficient in the biosynthesis of the stress response hormones ABA, Eth, JA, and GA by growing them in an abiotic stress condition that induces the biosynthesis of a wide variety of flavonoids and found that mutants deficient in a particular hormone generally had a distinct flavonoid proportion fingerprint. Our results suggest that flavonoid proportion fingerprints of uncharacterized mutants could be used to predict gene involvement in particular hormone pathways that signal responses to abiotic stress. PMID- 30418082 TI - Pulsed Transcranial Red/Near-Infrared Light Therapy Using Light-Emitting Diodes Improves Cerebral Blood Flow and Cognitive Function in Veterans with Chronic Traumatic Brain Injury: A Case Series. AB - OBJECTIVE: This study explored the outcome of applying red/near-infrared light therapy using light-emitting diodes (LEDs) pulsed with three different frequencies transcranially to treat traumatic brain injury (TBI) in Veterans. BACKGROUND: Photobiomodulation therapy (PBMT) using LEDs has been shown to have positive effects on TBI in humans and animal models. MATERIALS AND METHODS: Twelve symptomatic military Veterans diagnosed with chronic TBI >18 months post trauma received pulsed transcranial PBMT (tPBMT) using two neoprene therapy pads containing 220 infrared and 180 red LEDs, generating a power output of 3.3 W and an average power density of 6.4 mW/cm2 for 20 min, thrice per week over 6 weeks. Outcome measures included standardized neuropsychological test scores and qualitative and quantitative single photon emission computed tomography (SPECT) measures of regional cerebral blood flow (rCBF). RESULTS: Pulsed tPBMT significantly improved neuropsychological scores in 6 of 15 subscales (40.0%; p < 0.05; two tailed). SPECT analysis showed increase in rCBF in 8 of 12 (66.7%) study participants. Quantitative SPECT analysis revealed a significant increase in rCBF in this subgroup of study participants and a significant difference between pre-treatment and post-treatment gamma ray counts per cubic centimeter [t = 3.77, df = 7, p = 0.007, 95% confidence interval (95,543.21-21,931.82)]. This is the first study to report quantitative SPECT analysis of rCBF in regions of interest following pulsed tPBMT with LEDs in TBI. CONCLUSIONS: Pulsed tPBMT using LEDs shows promise in improving cognitive function and rCBF several years after TBI. Larger, controlled studies are indicated. PMID- 30418083 TI - Commentary Re: "Laparoscopic Roux-en-Y Gastric Bypass: Surgical Technique and Tips for Success"(J Laparoendosc Adv Surg Tech A 2018;28:938-943). PMID- 30418084 TI - Regulated Disorder: Posttranslational Modifications Control the RIN4 Plant Immune Signaling Hub. AB - RIN4 is an intensively studied immune regulator in Arabidopsis and is involved in perception of microbial features outside and bacterial effectors inside plant cells. Furthermore, RIN4 is conserved in land plants and is targeted for posttranslational modifications by several virulence proteins from the bacterial pathogen Pseudomonas syringae. Despite the important roles of RIN4 in plant immune responses, its molecular function is not known. RIN4 is an intrinsically disordered protein (IDP), except at regions where pathogen-induced posttranslational modifications take place. IDP act as hubs for protein complex formation due to their ability to bind to multiple client proteins and, thus, are important players in signal transduction pathways. RIN4 is known to associate with multiple proteins involved in immunity, likely acting as an immune-signaling hub for the formation of distinct protein complexes. Genetically, RIN4 is a negative regulator of immunity, but diverse posttranslational modifications can either enhance its negative regulatory function or, on the contrary, render it a potent immune activator. In this review, we describe the structural domains of RIN4 proteins, their intrinsically disordered regions, posttranslational modifications, and highlight the implications that these features have on RIN4 function. In addition, we will discuss the potential role of plasma membrane subdomains in mediating RIN4 protein complex formations. PMID- 30418085 TI - Systems Biology and Machine Learning in Plant-Pathogen Interactions. AB - Systems biology is an inclusive approach to study the static and dynamic emergent properties on a global scale by integrating multiomics datasets to establish qualitative and quantitative associations among multiple biological components. With an abundance of improved high throughput -omics datasets, network-based analyses and machine learning technologies are playing a pivotal role in comprehensive understanding of biological systems. Network topological features reveal most important nodes within a network as well as prioritize significant molecular components for diverse biological networks, including coexpression, protein-protein interaction, and gene regulatory networks. Machine learning techniques provide enormous predictive power through specific feature extraction from biological data. Deep learning, a subtype of machine learning, has plausible future applications because a domain expert for feature extraction is not needed in this algorithm. Inspired by diverse domains of biology, we here review classic systems biology techniques applied in plant immunity thus far. We also discuss additional advanced approaches in both graph theory and machine learning, which may provide new insights for understanding plant-microbe interactions. Finally, we propose a hybrid approach in plant immune systems that harnesses the power of both network biology and machine learning, with a potential to be applicable to both model systems and agronomically important crop plants. PMID- 30418086 TI - OsDRE2 contributes to chitin-triggered response through its interaction with OsRLCK185. AB - The rice receptor-like cytoplasmic kinase 185 (OsRLCK185) interacts with the chitin receptor complex OsCERK1/CEBiP and positively regulates chitin-induced immune responses including MAP kinase activation, ROS production and defense gene expression. To elucidate the regulatory mechanisms of OsRLCK185-mediated immunity, we searched for interactors of OsRLCK185. OsDRE2a, rice homologs of the yeast Dre2 protein, were identified as novel interactors of OsRLCK185. OsDRE2a interacted with OsRLCK185 at plasma membrane. The conserved cysteine residues in CIAPIN1 domain of OsDRE2a were essential for tight interaction of OsRLCK185. OsDRE2a was phosphorylated by OsRLCK185. The expression of OsDRE2a and OsDRE2b was induced after chitin treatment. Reduction of OsDRE2a and OsDRE2b mRNA levels by RNA interference resulted in the decreased chitin-induced ROS production. Thus, it is likely that OsDRE2 regulates OsRLCK185-mediated immune responses. PMID- 30418087 TI - Brain-Derived Neurotrophic Factor and Its Associations with Metabolism and Physical Activity in a Latino Sample. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) is associated with body weight and other health conditions but remains understudied in the Latino population. The aim of this study was to examine the associations of BDNF serum levels with body mass index (BMI), physical activity, and the rs6265 nonconservative polymorphism among 349 Latinos aged >=18 years enrolled in the Arizona Insulin Resistance Registry. MATERIALS AND METHODS: Data on physical activity were acquired using a self-reported questionnaire. BDNF serum levels were measured utilizing a modified ELISA method, and the rs6265 polymorphism was genotyped by the Assay-by-Design service. Two sample t-tests or chi-squared tests were employed to compare demographics and outcomes between physically active and nonactive groups as well as between rs6265 CC and CT+TT groups. RESULTS: BDNF levels and rs6265 polymorphism did not differ significantly between the physically active (N = 195) and nonactive group (N = 154). Participants with the rs6265 polymorphism did not show any significant difference in BDNF levels or BMI when compared with those with the normal functional variant. Higher BDNF levels were significantly associated with higher age (r = 0.11, P = 0.04) and higher 2 hr glucose level (r = 0.11, P = 0.04). CONCLUSIONS: In this cross-sectional study, the rs6265 polymorphism was not associated with a higher risk of obesity, or lower circulating levels of BDNF. Thus, the rs6265 polymorphism may have a different impact in Latinos as compared with other previously studied populations. PMID- 30418088 TI - A new resource for research and risk analysis: the updated European Food Safety Authority database of Xylella spp. host plant species. AB - Following a series of requests for scientific advice from the European Commission starting in 2013, the European Food Safety Authority (EFSA) conducted pest risk assessment and created a comprehensive Xylella fastidiosa host plant database. The last update of the database, published in September 2018, includes information on host plants of both X. fastidiosa and X. taiwanensis, together with details on botanical classification, infection conditions, geographic location, pathogen taxonomy including information on subspecies, strain and sequence type, detection techniques and tolerant/resistant response of the plant. This updated database of host plants of Xylella spp. reported world-wide provides a key tool for risk management, risk assessment and research on this generalist bacterial plant pathogen. PMID- 30418089 TI - Developing citrus Huanglongbing management strategies based on the severity of symptoms in HLB-endemic citrus-producing regions. AB - Citrus Huanglongbing (HLB), also known as greening, is a destructive disease caused by the fastidious, phloem-colonizing bacteria Candidatus Liberibacter spp.; Ca. Liberibacter asiaticus (Las) is the most prevalent of the species causing HLB. The Asian citrus psyllid (ACP, Diaphorina citri) transmits Las. HLB is threatening citrus production worldwide, and there is no cure for infected trees. Management strategies targeting diseased trees at different stages of colonization by Las are needed for sustainable citrus production in HLB-endemic regions. We evaluated the effect of the combinations of plant defense elicitors, nitrogen (N) fertilizer, and compost on mildly-diseased trees. We tested thermotherapy on severely-diseased trees and assessed tree protectors to prevent feeding by ACP, thus preventing Las from being transmitted to new plantings that replaced HLB-moribund trees. After four applications over two consecutive growing seasons we found that the combination of compost, urea, and plant defense elicitors beta-aminobutyric acid (BABA), plus Ascorbic acid (AA) and potassium phosphite with or without salicylic acid (SA), slowed down the progression of HLB and reduced disease severity by approximately 18%, compared to the untreated control. Our data showed no decline in fruit yield, indeed treatment resulted in a higher yield compared to the untreated control. Thermotherapy treatment (55 degrees C for 2 min) exhibited a suppressive effect on growth of Las and progress of HLB in severely diseased trees for two to three months after treatment. The tree protectors prevented feeding by ACP, and therefore young replant trees remained healthy and free from infection by Las over the two-year duration of the experiment. Taken together, these results may contribute to a basis for developing a targeted approach to control HLB based on stage of host colonization, application of plant defense elicitors, N fertilizer, compost, thermotherapy, and tree protectors. There is potential to implement these strategies in conjunction with other disease control measures to contribute to sustainable citrus production in HLB- endemic regions. PMID- 30418090 TI - Does Previous Failed Shockwave Lithotripsy Treatment Have an Influence on Retrograde Intrarenal Surgery Outcome? AB - BACKGROUND: The prevalence of urolithiasis is nearly 20% and patients with urolithiasis constitute an essential part of the patients referred to the urology clinic. Many parameters should be considered for the management of renal stones and authors recommend extracorporeal shockwave lithotripsy (SWL), retrograde intrarenal surgery (RIRS), and percutaneous nephrolithotripsy (PNL), as treatment options. Among these techniques, SWL does not require general anesthesia, has 89% success rate for renal pelvic stones: 83% for upper caliceal stones, 84% for middle caliceal stones, and 68% for lower caliceal stones. In this study, we aimed to investigate whether the previously failed SWL treatment affects RIRS outcome. METHODS: Patients who underwent RIRS for kidney stones between January 2012 and December 2017 in Diskapi Yildirim Beyazit Training and Research Hospital were reviewed retrospectively. Patients treated with primary RIRS (186 patients) were classified as Group 1. The outcomes of these patients were compared with those of 186 patients who underwent RIRS after failed SWL treatment using matched pair analysis, and these patients were classified as Group 2. RESULTS: The procedure success was defined as the sum of the stone-free and clinically insignificant residual fragments (CIRFs); final success rates were 90.3% and 91.9%, respectively. If we compare the final success rates, there was no statistically significant difference between both groups (P = .584). CONCLUSIONS: As a result, there is no negative effect of the previous unsuccessful SWL treatment on the RIRS success. Patients with CIRF should be followed up more carefully in terms of becoming symptomatic. PMID- 30418091 TI - Complexities of Addressing Food Insecurity in an Urban Population. AB - There is an association between food insecurity, poor health outcomes, and increased health care spending. The Temple Food Insecurity Program was initiated to screen patients for food insecurity as part of the post Temple University Hospital discharge process. The community is economically challenged and food insecurity is a significant problem. Food insecure patients were identified and referred to community-based resources, with a 30-day follow-up call. Screening was successful in 3655 patients, 27% (n = 987) of whom reported food insecurity. Of these patients, 66% (n = 647) were already receiving benefits through the Supplemental Nutrition Assistance Program (SNAP), but were still food insecure. All patients with food insecurity were referred to one of 2 resources for help. Despite significant need, less than a quarter of patients connected with these resources. Qualitative data revealed that some patients did not remember the information provided to them, were overwhelmed with poor health or other social determinants of health, had competing priorities, did not perceive the need for food assistance; and experienced system barriers. Health literacy also was an issue. Health care systems addressing food insecurity should consider the high prevalence of food insecurity in impoverished regions, the reality that SNAP benefits may not alleviate food insecurity for many patients, and the need for individualized, custom care plans that address barriers and reflect patient priorities and capabilities. Engaging patients differently may be aided by additional communication from community food resources directly to patients who provide permission for this added service. PMID- 30418092 TI - Importance of organoids for personalized medicine. AB - The establishment of organoid culture systems represents a milestone on the route toward successful personalized medicine. This mini review provides an update on the current status of organoid technology and summarizes their applications in personalized medicine. Organoids can be defined as 3D structures derived either from pluripotent or organ restricted stem cells harboring the ability to mimic in vivo architecture and multi lineage differentiation of terminally differentiated tissues. Due to their unique ability of virtually unlimited self-renewal, organoid cultures should be distinguished from previous 'sphere'-culture assays, for example, 'tumor spheres' that have already been described and applied over the last decades. PMID- 30418093 TI - Health Professionals' Perspectives on the Nature of Distress and Low Mood in Young People with Cancer. AB - PURPOSE: Young people with cancer are at increased risk of depression, yet evidence-based psychological interventions that are tailored to the specific needs of young people with cancer are scarce, and depression in this group may be particularly challenging to recognize and treat. The aims of this study were to (1) explore the views of health professionals in recognizing and treating low mood in young people with cancer and (2) identify the key components of an effective online treatment package for depression in this population. METHODS: Eighteen NHS health professionals with a range of professional backgrounds working directly with young people with cancer were interviewed using a semi structured interview schedule. Responses were analyzed using thematic analysis. RESULTS: Five themes emerged: (1) one size doesn't fit all-the nature of depression is complex and varied, and symptoms fluctuate greatly in relation to physical health; (2) distress is completely understandable-it is important not to pathologize a normal reaction; (3) a stepping stone intervention-online interventions may promote engagement with face-to-face therapy; (4) connecting with others-the intervention should promote sharing experiences with others to reduce isolation; and (5) ownership and empowerment-lack of independence may be a cause of distress, and young people should have control of the intervention. CONCLUSION: The nature of depression in young people with cancer is complex and multifaceted. Online guided self-help may be useful when added as a component or first step of a treatment package including face-to-face talking therapies. PMID- 30418095 TI - Massive femur defect after Ewing's sarcoma resection reconstructed with a free vascularised fibular graft in a four-year-old girl. AB - BACKGROUND: Ewing's sarcoma is the second most common primary malignant bone tumour in children. Depending on localisation and extent, massive bone defects remain when curative surgery is performed. Whereas in the past, limb amputation was often unavoidable to obtain curative resection, nowadays different limb saving reconstructive options are available. CASE REPORT: We report the successful reconstruction of a massive femur defect with a free vascularised fibular graft (FVFG) after Ewing's sarcoma resection in a four-year-old girl. Both the age of the patient and the extensive graft hypertrophy makes this case exceptional. CONCLUSION: Femur reconstruction with a FVFG is a rarely performed and complex procedure in young children. It is an excellent reconstructive technique for large long bone defects, which can avoid limb amputation without compromising oncologic outcome. PMID- 30418094 TI - Empower Seriously Ill Older Adults to Formulate Their Goals for Medical Care in the Emergency Department. AB - BACKGROUND: Most seriously ill older adults visit the emergency department (ED) near the end of life, yet no feasible method exists to empower them to formulate their care goals in this setting. OBJECTIVE: To develop an intervention to empower seriously ill older adults to formulate their future care goals in the ED. DESIGN: Prospective intervention development study. SETTING: In a single, urban, academic ED, we refined the prototype intervention with ED clinicians and patient advisors. We tested the intervention for its acceptability in English speaking patients >=65 years old with serious illness or patients whose treating ED clinician answered "No" to the "surprise question" ("would not be surprised if died in the next 12 months"). We excluded patients with advance directives or whose treating ED clinician determined the patient to be inappropriate. MEASUREMENTS: Our primary outcome was perceived acceptability of our intervention. Secondary outcomes included perceived main intent and stated attitude toward future care planning. RESULTS: We refined the intervention with 16 mock clinical encounters of ED clinicians and patient advisors. Then, we administered the refined intervention to 23 patients and conducted semistructured interviews afterward. Mean age of patients was 76 years, 65% were women, and 43% of patients had metastatic cancer. Most participants (n = 17) positively assessed our intervention, identified questions for their doctors, and reflected on how they feel about their future care. CONCLUSION: An intervention to empower seriously ill older adults to understand the importance of future care planning in the ED was developed, and they found it acceptable. PMID- 30418096 TI - Modified Uniportal Video-Assisted Thoracic Surgery Versus Three-Port Approach for Lung Nodule Biopsy in Pediatric Cancer Patients. AB - BACKGROUND: Uniportal video-assisted thoracic surgery (VATS) is gaining popularity among thoracic surgeons, but the limited space in the thorax of children makes uniportal VATS difficult to perform. The purpose of this study was to evaluate procedural and outcome differences between a modified uniportal VATS (MU-VATS) and three-port VATS (TP-VATS) for peripheral lung nodule biopsy in pediatric cancer patients. MATERIALS AND METHODS: This is an Institutional Review Board-approved retrospective analysis of all consecutive MU-VATS and TP-VATS peripheral lung nodule biopsies performed at a single institution between June 2014 and December 2016. Patients with diffuse lung disease who underwent a lung biopsy were excluded. RESULTS: Over a 30-month period, 22 patients with a median age of 12 years (range, 7-21) underwent MU-VATS or TP-VATS for excisional biopsy of a peripheral lung nodule. MU-VATS lung biopsy was attempted in 11 patients and TP-VATS lung biopsy in the remaining 11. Both groups were comparable with regard to demographics, primary diagnosis, purpose of biopsy, and lung nodule location. MU-VATS demonstrated no difference when compared with TP-VATS lung biopsy in operative time (54 versus 62 min, P = .899), estimated blood loss (14 versus 15 mL, P = .587), pain score (2.8 versus 2.9, P = .717), and discharge day (1.3 versus 1.2 days, P = .572). No difference existed between groups with regard to conversion, need for intraoperative blood transfusion, and duration of chest tube. Complications including pneumothorax (n = 2) and subcutaneous emphysema (n = 1) were only seen in the TP-VATS group. CONCLUSIONS: MU-VATS can be safely utilized for biopsy of peripheral lung nodules in pediatric cancer patients without increasing procedural duration, hospitalization, pain scores, or need for intraoperative blood transfusion. Further studies need to evaluate the theoretical cosmetic advantage from a single surgical scar. PMID- 30418097 TI - The freeze-drying does not influence the proteomic profiles of human milk. AB - PURPOSE: Human milk (HM) proteins are known as important factors in growing and development of neonates. For longer and easier storage of HM, freeze-drying is suggested as one of the promising methods for HM banks. However, the effects of freeze-drying on HM proteins were not evaluated yet. The purpose of this study is to analyze and compare proteomic data before and after the freeze-drying. MATERIAL AND METHODS: Totally nine fresh HM samples were collected from three healthy mothers at 15 and 60 days of lactation period. The samples were freeze dried and the proteomic analysis was performed by shotgun proteomic method with mass spectrometry. The results were compared between samples of different lactation periods, and before and after the freeze-drying using Wilcoxon signed rank test for paired comparisons. Moreover, the functional grouping and analysis were performed for the detected proteins by bioinformatics analysis. RESULTS: Totally, 245 proteins were detected in the HM samples. The expression of proteins was not affected by both of the different lactation periods and the freeze-drying status (P>.050). Moreover, the functional analysis of proteomic data revealed no significant difference between both groups as well. CONCLUSION: HM proteins were found not to be significantly affected by the lactation periods (15 and 60 days) and freeze-drying status. As significant changes of HM proteins were not found after the freeze-drying, we hope that the present study would support introducing freeze-drying in the HM banks. However, the number of samples was quite small to provide strong evidence. Moreover, the evaluation of the safe storage length in the view of infectious agents and the composition changes after freeze-drying is warranted in the further study. PMID- 30418098 TI - Statistical analysis plan for pooled individual patient data from two landmark randomized trials (INTERACT2 and ATACH-II) of intensive blood pressure lowering treatment in acute intracerebral hemorrhage. AB - BACKGROUND: There is persistent uncertainty over the benefits of early intensive systolic blood pressure lowering in acute intracerebral hemorrhage. In particular, over the timing, target, and intensity of systolic blood pressure control for optimum balance of potential benefits (i.e. functional recovery) and risks (e.g. cerebral ischemia). AIMS: To determine associations of early systolic blood pressure lowering parameters and outcomes in patients with a hypertensive response in acute intracerebral hemorrhage. Secondary aims are to identify the modifying effects of patient characteristics and an optimal systolic blood pressure lowering profile. METHODS: Individual participant data pooled analyses of two large, multicenter, randomized controlled trials specifically undertaken to assess the effects of early intensive systolic blood pressure reduction on clinical outcomes in acute intracerebral hemorrhage: the Intensive Blood Pressure in Acute Intracerebral Hemorrhage Trial (INTERACT2) and the Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH-II) trial. Combined data will include baseline characteristics; systolic blood pressure in the first 24 h; process of care measures; and key efficacy and safety outcomes. OUTCOMES: The primary outcome is functional recovery, defined by an ordinal distribution of scores on the modified Rankin scale at 90 days post-randomization. Secondary outcomes include various standard binary cut-points for disability-free survival on the modified Rankin scale, and health-related quality of life at 90 days. Safety outcomes include symptomatic hypotension requiring corrective therapy and early neurologic deterioration within 24 h, and deaths, any serious adverse event, and cardiac and renal serious adverse events, within 90 days. DISCUSSION: A pre-determined protocol was developed to facilitate successful collaboration and reduce analysis bias arising from prior knowledge of the findings. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifiers for INTERACT2 (NCT00716079) and ATACH-II (NCT01176565). PMID- 30418099 TI - A Randomized Trial to Compare the Conventional Three-Port Laparoscopic Appendectomy Procedure to Single-Incision and One-Puncture Procedure That Was Safe and Feasible, Even for Surgeons in Training. AB - BACKGROUND: Single-incision laparoscopic surgery has emerged; however, the procedures might be complicated for trainees. We compared the clinical outcomes of conventional three-port laparoscopic appendectomy (CLA) and single-incision and one-puncture laparoscopic appendectomy (SIOPLA) by attending pediatric surgeons (APSs) and surgeons in training (SITs). MATERIALS AND METHODS: We reviewed the clinical outcomes of 72 randomized laparoscopic appendectomies that were consecutively performed by SITs and APSs for a 2-year period. The cases were categorized according to type of surgeon. Finally, 10 CLA and 18 SIOPLA procedures were performed by SITs, and 24 CLA and 20 SIOPLA procedures were performed by APSs. The operative time, blood loss, analgesic use, complications, and hospital stay were analyzed. RESULTS: There were no significant differences in any of the evaluation points between CLA and SIOPLA. CONCLUSIONS: SIOPLA is not inferior operation to CLA, and the postoperative outcomes of SIOPLA were satisfactory. Thus, SIOPLA was safe and feasible for young surgeons to perform. PMID- 30418100 TI - Brachial artery intima-media thickness and grayscale texture changes in patients with peripheral artery disease receiving supervised exercise training in the PROPEL randomized clinical trial. AB - We performed an exploratory analysis to evaluate the effects of a treadmill exercise program on brachial artery (BA) intima-media thickness (IMT) and three BA grayscale ultrasound measures that may indicate subclinical arterial injury. Data were from a clinical trial in individuals with peripheral artery disease who were randomly assigned to treadmill exercise training or attention control. B mode ultrasonography was performed at baseline and after 26 weeks. BA IMT, grayscale median (GSM), entropy, and gray-level difference statistic-contrast (GLDS-CON) were measured by a single reader. The 184 participants were (mean (SD)) 66.7 (8.2) years old and had an ankle-brachial index of 0.70 (0.18). Exercise training was associated with a 0.01 (0.06) mm ( p = 0.025) reduction in BA IMT compared to 0.00 (0.05) mm ( p = 0.807) in the control group (between group p = 0.061). BA GSM, entropy, and GLDS-CON did not change significantly with exercise. Improvements in the 6-minute walk distance correlated with increases in resting BA blood flow ( r = 0.23, p = 0.032), flow-mediated dilation ( r = 0.24, p = 0.022), diameter ( r = 0.29, p = 0.005), entropy ( r = 0.21, p = 0.047), and GLDS-CON ( r = 0.22, p = 0.041). In a post hoc analysis, BA IMT improved significantly with treadmill exercise training but did not change with attention control; however, the between-group difference did not reach statistical significance. With exercise, improvements in the 6-minute walk distance were associated with improved endothelial function, increased resting blood flow, and BA dilation, as well as higher grayscale entropy and GLDS-CON, indicating that lower extremity exercise is associated with salutary changes in upper-extremity arterial wall structure and function. ClinicalTrials.gov Identifier: NCT01408901. PMID- 30418101 TI - A Randomized Controlled Trial Comparing Telehealth Self-Management to Standard Outpatient Management in Underserved Black and Hispanic Patients Living with Heart Failure. AB - BACKGROUND: Although the American Heart Association promotes telehealth models to improve care access, there is limited literature on its use in underserved populations. This study is the first to compare utilization and quality of life (QoL) for underserved black and Hispanic heart failure (HF) patients assigned to telehealth self-monitoring (TSM) or comprehensive outpatient management (COM) over 90 days. METHODS: This randomized controlled trial enrolled 104 patients. Outcomes included emergency department (ED) visits, hospitalizations, QoL, depression, and anxiety. Binary outcomes for utilization were analyzed using chi square or Fisher's exact test. Poisson or negative binomial regression, repeated measures analysis of variance, or generalized estimating equations were also used as appropriate. RESULTS: Of 104 patients, 31% were Hispanic, 69% black, 41% women, and 72% reported incomes of <$10,000/year. Groups did not differ regarding binary ED visits (relative risk [RR] = 1.37, confidence interval [CI] = 0.83 2.27), hospitalization (RR = 0.92, CI = 0.57-1.48), or length of stay in days (TSM = 0.54 vs. COM = 0.91). Number of all-cause hospitalizations was significantly lower for COM (TSM = 0.78 vs. COM = 0.55; p = 0.03). COM patients reported greater anxiety reduction from baseline to 90 days (TSM = 50-28%; COM = 57-13%; p = 0.05). CONCLUSIONS: These findings suggest that TSM is not effective in reducing utilization or improving QoL for underserved patients with HF. Future studies are needed to determine whether TSM can be effective for populations facing health care access issues. PMID- 30418102 TI - Removal of ethanethiol using a biotrickling filter with nitrate as an electron acceptor. AB - Many studies have discussed the biotreatment of ethanethiol (ET) under aerobic conditions. However, O2 free conditions offer bio-conversion of ET gas into elemental sulphur and/or sulphate using [Formula: see text] as electron acceptor, and this has been not studied. In this study, an anoxic biotrickling filter was tested in lab-scale conditions with ET/[Formula: see text] ratio 0.74 and 0.34 mole/mole to remove malodorous ET waste gas. The study examined the effect of three operational parameters: ET inlet concentrations (150, 300, 800, and 1500 mg/m3), trickling velocities (0.12, 0.18, 0.24, 0.3, and 0.45 m/h), and empty bed residence times (30, 60, 90, and 120 s). It found that the effect of trickling velocity on removal efficiency depended on inlet concentrations; 0.24 m/h trickling velocity resulted in efficient ET removal (higher than 90.8% for 150 mg/m3 of inlet concentration) while 0.45 m/h trickling velocity could only achieve a removal of 80.6% for 1500 mg/m3 of inlet concentration at fixed EBRT 60 s. Increasing the EBRT up to 60 s was adequate to achieve removal efficiency, i.e. 92 and 80% for ET inlet concentrations 150 and 1500 mg/m3 respectively, and the maximum elimination capacity was 75.18 g/m3/h at 0.45 m/h. Overall, the anoxic conditions enhanced the low oxidation rates of ET in an anoxic biotrickling filter despite mass transfer limitations and poor solubility of ET. PMID- 30418103 TI - Denaturing Gradient Gel Electrophoresis Analysis of Bacteria in Italian Ticks and First Detection of Streptococcus equi in Rhipicephalus bursa from the Lazio Region. AB - Tick-borne diseases are an increasing problem for the community. Ticks harbor a complex microbial population acquired while feeding on a variety of animals. Profiling the bacterial population by 16S rDNA amplification and denaturing gradient gel electrophoresis enables detection of the broad spectrum of bacteria that settles in the ticks. This study identified known and unknown tick-infecting bacteria in samples from Italy. Seven adult ticks from different hosts and origins were analyzed: two Rhipicephalus sanguineus ticks from dogs (Lombardia), two Rhipicephalus bursa ticks from bovines (Lazio), and three Ixodes ricinus ticks from humans (Marche). The major result was the first report of the zoonotic agent Streptococcus equi in ticks. S. equi is a species complex of highly contagious pathogens. Subsequent to S. equi detection in a R. bursa tick removed from a bovine of Lazio in 2012, we studied 95 R. bursa samples collected from 3 bovines, 3 ponies, and 1 sheep grazing in the same area in 2012 and from 6 ponies grazing there in 2017. The results of a specific PCR assay indicated a not sporadic occurrence of S. equi in ticks. This finding provides a basis for assessing the potential of ticks to harbor and disperse S. equi. PMID- 30418104 TI - Resting Heart Rate Variability: Exploring Associations With Symptom Severity in Adults With Substance Use Disorders and Posttraumatic Stress. AB - OBJECTIVE: Substance use disorders and posttraumatic stress symptoms are commonly comorbid. Previous studies have established that those with substance use disorders or posttraumatic stress disorder (PTSD) have lower high frequency-heart rate variability (HF-HRV) compared to controls, suggesting that low HF-HRV may be a biomarker of a common physiological mechanism underlying both disorders. We evaluated HF-HRV as a potential biomarker of a common underlying process by testing whether lower HF-HRV related to greater severity of substance use and PTSD symptoms in individuals with both substance use disorders and at least four symptoms of PTSD. METHODS: HF-HRV was measured in 49 adults with substance use disorders and at least four symptoms of PTSD. We performed a series of regressions controlling for age to test whether low HF-HRV was associated with greater substance use disorder and PTSD symptom severity. Substance use disorder symptoms were measured by the Addiction Severity Index and PTSD symptoms were measured by the Clinician-Administered PTSD Scale and the PTSD Checklist. RESULTS: After controlling for age, low resting HF-HRV was significantly associated with drug and alcohol symptom severity but not PTSD symptom severity. CONCLUSIONS: HF-HRV may be more sensitive to the severity of drug and alcohol use rather than PTSD. Findings may suggest that in PTSD populations, HF-HRV may primarily index comorbid substance use disorder symptoms. HF-HRV could serve as an objective measure of substance use severity and should be further investigated as a predictor of outcomes in treatment for substance use disorders. PMID- 30418105 TI - An Interrogation of Shared and Unique Copy Number Variants Across Genetically Distinct Zebrafish Strains. AB - Zebrafish (Danio rerio) are a widely utilized model system for human disorders, but common laboratory strains have distinct behavioral and physiological differences. Accompanying these known strain differences, commonly used "wildtype" zebrafish strains have both shared and unique suites of single nucleotide polymorphisms and copy number variants (CNVs). Despite this, genomic variation is often ignored in study design, and the actual strain used is often not adequately reported. The goal of this study was to assess CNVs across three common laboratory strains of zebrafish-AB, Tubingen (TU), and WIK-and provide these data as a tool for the zebrafish community. Herein we identified 1351 CNV regions within the most recent genome assembly (GRCz11) covering 1.9% of the zebrafish genome (31.7 Mb). CNVs were found across all chromosomes, and 2200 genes (5121 transcripts) lie within +/-5 kb of identified CNVs, pointing to likely cis regulatory actions of CNVs on nearby gene neighbors. We have created a Public Session accessible on the UCSC Genome Browser to view CNVs from this study titled "danRer11 zebrafish CNV across strains" as a tool for the zebrafish community. PMID- 30418106 TI - Emergence of staphylococcal scalded skin syndrome associated with a new toxinogenic, methicillin-susceptible Staphylococcus aureus clone. AB - A sharp increase in staphylococcal scalded skin syndrome (SSSS) cases has been recorded in our settings since 2015, with 31 cases having been documented during the period 2014-2017. The molecular investigation of strains from the above period showed the emergence of a methicillin-susceptible, mupirocin- and fusidic acid-resistant Staphyloccocus aureus clone that belongs to the ST121 complex and carries both epidermolysin (eta/etb) genes. We concluded that the SSSS caused by the newly emerged, highly virulent community-associated-methicillin sensitive S. aureus strains that have been encountered lately is more severe than impetigo. Physicians should be aware of the probability of SSSS epidemics from strains that are resistant to mupirocin and fusidic acid, which have been used irrationally and excessively. PMID- 30418107 TI - Evaluation of an in-house MALDI-TOF MS rapid diagnostic method for direct identification of micro-organisms from blood cultures. AB - PURPOSE: Bloodstream infections are major causes of morbidity and mortality among hospitalized patients worldwide. Early identification of micro-organisms from blood culture can facilitate earlier optimization of treatment. The objective of this study was to assess an in-house method based on a new matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) platform (Clin-TOF MS) for direct organism identification. METHODOLOGY: We studied the performance of the in-house method for direct identification and the conventional sub-culture method in parallel. Identification from subcultures was analysed with Bruker MS as the reference method. RESULTS: A total of 666 blood cultures with a single micro-organism that flagged positive after no more than a 3-day incubation period were collected. The identification accuracy of the in-house Clin-TOF MS method for direct identification and the sub-culture method was 88.6 and 100 %, respectively. The in-house method exhibited better performance for Gram-negative bacteria than for Gram-positive bacteria (93.3 vs 81.6 %). The accuracy rate for anaerobes was 100 % (3/3). The lowest accurate identification rate was for yeast; this was only 20 %. Lytic Anaerobic/F (LAF) and Plus Aerobic/F (PAF) provided the highest accurate identification rates, and it was noteworthy that the accuracy rate for FAN Aerobic (FA) was 82 %, which is higher than previously reported and showed that the method was effective. CONCLUSION: Our study provides an effective sample preparation method for the direct identification of pathogens from positive blood culture vials via Clin-TOF MS at a very low cost of about $0.5 per sample and with a short turnaround time of about 20 min. This will help clinicians make precise diagnoses and provide targeted prescriptions, reducing the risk of the potential development of resistance. PMID- 30418108 TI - Molecular characterization of Staphylococcus argenteus in Myanmar: identification of novel genotypes/clusters in staphylocoagulase, protein A, alpha-haemolysin and other virulence factors. AB - PURPOSE: Staphylococcus argenteus is a novel emerging species of coagulase positive staphylococcus that is genetically closely related to Staphylococcus aureus. To elucidate the molecular differences in the virulence factors (staphylocoagulase, protein A, alpha-haemolysin, enterotoxin-like toxin and staphylokinase) between these staphylococcal species, S. argenteus that had recently been isolated in Myanmar (five nasal isolates and four clinical isolates) were analysed. METHODOLOGY: The nucleotide sequences of the virulence factors were determined by PCR and direct sequencing, followed by phylogenetic analysis by mega6 and multiple alignment by clustalw using the published sequence data for S. aureus and S. argenteus. RESULTS: Six S. argenteus isolates belonged to MLST sequence type (ST) 2250, while others belonged to ST4625, ST2198 and ST2854. The novel staphylocoagulase (coa) genotype XIV and the novel coa-XI subtype (XId) were identified in an ST2198 isolate and all other isolates, respectively. Among the S. argenteus isolates, the protein A and alpha-haemolysin genes showed high sequence identity (96-98 % and >99 %, respectively), while lower identity was observed between S. argenteus and S. aureus (88-91 % and 86 %, respectively), with both species showing phylogenetically distinct clusters. Similar findings were found for the staphylococcal enterotoxin (SE)-like toxin genes selw, selx and sely. In contrast, the staphylokinase genes were almost identical between these two species. All of the coa-XId isolates had a CRISPR/Cas locus at the site of orfX without having SCCmec, whereas an ST2198 isolate lacked this locus. CONCLUSION: The primary virulence factors (staphylocoagulase, protein A andalpha-haemolysin) as well as the SE-like toxins of S. argenteus were genetically discriminated from those of S. aureus, revealing the presence of the novel coa-type/subtype (coa-IXd, XIV) in S. argenteus. PMID- 30418109 TI - The endosphere of the salt marsh plant Halimione portulacoides is a diversity hotspot for the genus Salinicola: description of five novel species Salinicola halimionae sp. nov., Salinicola aestuarinus sp. nov., Salinicola endophyticus sp. nov., Salinicola halophyticus sp. nov. and Salinicola lusitanus sp. nov. AB - Seven endophytic strains were isolated from the halophyte Halimione portulacoides, collected from Ria de Aveiro, Portugal. To determine their exact taxonomic position, comparative analyses were performed with these strains and closely related type strains of Salinicola species. Genome sequencing and comparison indicated that five of the seven isolated strains comprised distinct and novel species (average nucleotide identity <0.95; in silico DNA-DNA hybridization <70 %; G+C difference >1 %). Multilocus sequence analysis was performed using gyrB, rpoD and 16S rRNA gene sequences from the novel and type strains to determine their phylogenetic positions. The novel strains are facultative anaerobes, mesophilic, facultative alkaliphic and halophilic, test positive for catalase and oxidase activities, for hydrolysis of Tween 20 and phosphate, for production of indole-3-acetic acid, but do not produce H2S. Ubiquinone UQ-9 is present in major amounts in all strains. The major fatty acids include C16 : 0 and the summed feature containing C18 : 1omega7c and/or C18 : 1omega6c. The DNA G+C content ranges from 60.6 to 65.8 mol%. Five strains were confirmed as new species belonging to the genus Salinicola, for which the names Salinicolahalimionae sp. nov. (type strain CPA60T=CECT 9338T=LMG 30107T), Salinicolaaestuarinus sp. nov. (type strain CPA62T=CECT 9339T=LMG 30108T), Salinicolaendophyticus sp. nov. (type strain CPA92T=CECT 9340T=LMG 30109T), Salinicolahalophyticus sp. nov. (type strain CR45T=CECT 9341T=LMG 30105T) and Salinicola lusitanus sp. nov. (type strain CR50T=CECT 9342T=LMG 30106T) are proposed. PMID- 30418110 TI - Diagnostic accuracy of dual-energy computed tomography and joint aspiration: a prospective study in patients with suspected gouty arthritis. AB - OBJECTIVES: To validate the diagnostic benefit of dual-energy computed tomography (DECT) and synovial fluid aspiration in suspected gout. METHODS: A total of 43 patients with suspected gout underwent aspiration and DECT (320-row CT; Canon Medical Systems, Japan). The patients were assessed (gout vs. non-gout) based on the 2015 ACR/EULAR gout classification criteria using clinical and laboratory findings. The results were analysed by comparing two scenarios using McNemar test: Scenario A: ACR/EULAR criteria, followed by DECT results and aspiration findings. Scenario B: ACR/EULAR criteria, followed by aspiration and DECT results. RESULTS: 15/43 patients (34.9%) were positive for MSU crystals, and 16/43 patients (37.2%) for gouty tophi (DECT). 26/43 patients (60.5%) were diagnosed with gout and fulfilled the ACR/EULAR criteria. The diagnostic performance of either synovial fluid aspiration or DECT was similar with sensitivity of 58% and specificity of 100% and 94%, respectively. Combination of both modalities (at least one of them positive), resulted in increased sensitivity of 85% and unchanged specificity (94%). Based only on clinical and laboratory findings, 13/43 patients (30.2%) were classified as gout according to ACR/EULAR criteria. In scenario A, additional 8 out of 30 (26.7%) patients were diagnosed as gout by DECT findings, and another 5/22 (22.7%) patients by aspiration findings. In scenario B, initial consideration of aspiration findings resulted in 10 out of 30 (33.3%) additionally identified patients, and another 3 (15%) patients by DECT findings. There was no relevant difference between scenarios A and B (p=0.508). CONCLUSIONS: Combination of joint aspiration and DECT improves the diagnostic algorithm for gout. In our attempt to establish an optimal sequence of diagnostic tests, we did not identify an advantage for either synovial fluid analysis or DECT as the initially better modality after clinical examination and analysis of blood tests. PMID- 30418111 TI - Analysis of NLRP3, MVK and TNFRSF1A variants in adult Greek patients with autoinflammatory symptoms. AB - OBJECTIVES: Autoinflammatory diseases are characterised by abnormal hyperactivity of the innate immune system, causing systemic inflammation. The cryopyrin associated periodic syndrome (CAPS), the hyper IgD syndrome (HIDS) and the TNF receptor-associated periodic syndrome (TRAPS), are autoinflammatory conditions associated with mutations in the NLRP3, MVK and TNFRSF1A genes, respectively. We present the experience of our Department with these rare syndromes analysing genetic and clinical data of adult patients encountered between January 2011 and September 2017. METHODS: Eighty-eight adult patients with clinical suspicion of CAPS, HIDS and TRAPS were sequentially recruited and genetically tested for specific mutations in NLRP3, MVK and TNFRSF1A using Sanger sequencing. Clinical picture of mutation carriers was reviewed. Allele frequencies were compared to those described for the normal population by the 1000 Genomes project. RESULTS: Seventy-two of the 88 adult patients were found to be positive for mutations or polymorphisms. One patient carried two pathogenic MVK mutations (pV377I/c.1129G>A and c.850delG) and another one carried a pathogenic heterozygous pAlpha439V/c.1316C>T NLRP3 mutation. Seventeen patients carried variants of uncertain significance. The pS434S/c.1302C>T NLRP3 mutation is slightly increased in our patients compared to the reference population and seems to correlate with severe symptom presentation. CONCLUSIONS: In rare cases, periodic fever and inflammatory symptoms in adults can be attributed to mutations in NLRP3, MVK and TNFRSF1A. Clinical assessment and genetic analysis are critical for proper diagnosis and treatment of autoinflammatory diseases. PMID- 30418112 TI - Which definition should be used to determine colchicine resistance among patients with familial Mediterranean fever? AB - OBJECTIVES: Colchicine is the main therapy for familial Mediterranean fever (FMF); however, 5-10% of patients are colchicine-resistant. There is no standard and validated definition for colchicine resistance. We aimed to compare the existing definitions for colchicine resistance in both adult and paediatric FMF patients to find out the best definition to determine colchicine-resistant patients. METHODS: 385 FMF patients were evaluated and patients receiving anti interleukin-1 treatment were included. The anti-IL-1 therapy had been initiated by the experts in the past based on their experience. Eleven different definitions (found out after PubMed search for colchicine resistance in FMF) were applied to all patients. Results were re-analysed after excluding the patients who had no clinical attacks but persistently high acute phase reactants (APRs) and/or amyloidosis. RESULTS: Sixty patients (40 adults/20 children) who had been using anti-IL-1 therapy were included into this study as colchicine-resistant patients. The highest percentage of patients fulfilled definition 5 (93.3%). Definition 9 had the poorest performance (26%). Significantly, a higher percentage of adult patients met definitions 4 and 6 than paediatric patients (87.5% vs. 50%, p=0.002; 75% vs. 40%, p=0.008, respectively). After excluding patients without clinical attacks, the highest percentage of patients fulfilled definition 2 (94.4%). We combined the attack frequency (>1 typical episode/3 months) in definition 2 and presence of amyloidosis/APR increase (increase in >=2/3 APRs) in definition 5 to create a new definition which was met by 59 (98.3%) colchicine-resistant FMF patients. CONCLUSIONS: Definition of colchicine resistance is still controversial. Definitions with both clinical and laboratory criteria were met by a higher percentage of resistant patients than those without laboratory criteria. However, the proper definitions for the attack-free period and persistence of APRs are still lacking. PMID- 30418113 TI - Agreement between semiquantitative and quantitative Doppler scoring systems for the assessment of synovial pathological vascularisation in rheumatoid arthritis. AB - OBJECTIVES: To compare colour Doppler (CD) versus power Doppler (PD) semiquantitative and quantitative scoring of synovial vascularisation and to evaluate the relationship between semiquantitative and quantitative scores in patients with rheumatoid arthritis (RA). METHODS: One hundred RA patients underwent B-mode, PD, and CD assessments of 12 joints at two European centres. Each joint with synovial hypertrophy (SH) detected on B-mode was semiquantitatively scored (0-3) for PD (SPD score) and CD (SCD score) synovial signal. PD and CD synovial signal were also quantitatively scored (0-100%) (QPD and QCD scores, respectively) using a software integrated in the US equipment for counting the colour fraction. RESULTS: We found SH in 184 joints. SPD and SCD agreed in 92.3% (95%CI: 88.4; 96.2%) of paired scores, with Kendall rank correlation coefficient tau-b=0.95. QPD and QCD scores were highly correlated (Pearson's coefficient=0.70) but Blamd-Altman plot showed insufficient agreement, being the QCD scores systematically slightly higher than the QPD scores. The comparison of mean values of QPD and QCD between scores of SPD and SCD, respectively, showed significant differences between grade 0 and grade 1 (p<0.001), and grade 2 and grade 3 (p=0.042 and p=0.007, respectively) but not between grade 1 and 2 (p=0.154 and p=0.150, respectively). CONCLUSIONS: The SPD and SCD scores were concordant and the QPD and QCD scores highly correlated but were not concordant. There was an overlap between SPD and SCD mild and moderate scores regarding QPD and QCD scores. PMID- 30418114 TI - The clinical significance of ubiquitin carboxyl hydrolase L1 and its autoantibody in neuropsychiatric systemic lupus erythematosus. AB - OBJECTIVES: To identify specific cerebrospinal fluid (CSF) biomarkers for the diagnosis and disease severity evaluation of neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: Patients presented with neuropsychiatric symptoms were recruited and categorised as 36 NPSLE, 19 SLE controls, 4 other connective tissue disease (CTD) controls and 10 nervous system disorder (NSD) controls. The NPSLE group consisted of severe NPSLE (sNPSLE) and mild NPSLE (mNPSLE). Potential biomarkers were determined by Luminex multiplex assay and enzyme-linked immunosorbent assay. RESULTS: 1) Among a variety of neurological disease-related proteins, only ubiquitin carboxyl hydrolase L1 (UCH-L1) levels were significantly elevated in the CSF samples of sNPSLE patients compared with those of mNPSLE patients (p=0.020) and SLE controls (p=0.037). CSF UCH-L1 levels were significantly positively correlated with SLE disease activity index and overlap number of NPSLE manifestations. 2) CSF anti-UCH-L1 autoantibodies were significantly elevated in patients with NPSLE in comparison to all of the control groups, with a sensitivity of 53% and a specificity of 91% for NPSLE. CSF anti UCH-L1 levels were associated with organ involvement and were positively correlated with serum anti-UCH-L1 levels in the NPSLE patients (r=0.4551, p=0.0382). CONCLUSIONS: Anti-UCH-L1 is a promising CSF biomarker for NPSLE diagnosis with high specificity, and the elevated levels of CSF UCH-L1 reflect the clinical severity of NPSLE. The elevation of UCH-L1 and its autoantibody in NPSLE patients showed us novel aetiological insights on NPSLE. PMID- 30418115 TI - Utility of administrative and clinical data to predict major change in medical treatment in US Veterans enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry. AB - OBJECTIVES: To examine factors associated with major therapeutic changes (MTC) among US Veterans with moderate/severe rheumatoid arthritis (RA) based on Disease Activity Score based on 28 joints (DAS28). METHODS: We used data from patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry from 1/1/2006 through 12/31/2014. The index date was a clinic visit with DAS28 >3.2 (moderate/severe disease) following an 18-month pre-index period that included >=2 DAS28 measurements >=60 days apart. The patients were followed for MTC from 7 days pre-index through 90 days post-index. Poisson multivariable regression models were used to identify associations with MTC. Chart review of a subset of randomly selected patients explored factors that impacted therapeutic decisions. RESULTS: Among 941 patients, 396 (42.1%) had MTC. Of these, 369 (39.2%) patients had worsening DAS28 at index, 118 (12.5%) had DAS28 improvements, and 454 (48.2%) patients had no change in DAS28 versus pre-index DAS28. Of the patients with worsening DAS28, no change in DAS28, and improved DAS28, respectively, 50.5%, 62.6%, and 70.3% had no MTC. Regression analyses showed index DAS28, oral steroid or non-biologic disease-modifying anti-rheumatic drug (nbDMARD) use in the previous year were associated with an increased likelihood of MTC; use of nbDMARDs in the previous 90 days was associated with a decreased likelihood of MTC. The most common reason for not modifying therapy despite DAS28 >3.2 was a judgement of mild disease. CONCLUSIONS: Clinicians frequently do not institute major therapeutic changes despite DAS28 indicating moderate/severe disease activity; multiple factors are involved in real-world treatment decisions. PMID- 30418116 TI - Effect of adding medical cannabis to analgesic treatment in patients with low back pain related to fibromyalgia: an observational cross-over single centre study. AB - OBJECTIVES: Low back pain (LBP) occurs in many patients with fibromyalgia (FM). The current study aimed to assess the possible pain and function amelioration associated with medical cannabis therapy (MCT) in this setting. METHODS: 31 patients were involved in an observational cross-over study. The patients were screened, treated with 3 months of standardised analgesic therapy (SAT): 5 mg of oxycodone hydrochloride equivalent to 4.5 mg oxycodone and 2.5 mg naloxone hydrochloride twice a day and duloxetine 30 mg once a day. Following 3 months of this therapy, the patients could opt for MCT and were treated for a minimum of 6 months. Patient reported outcomes (PRO's) included: FIQR, VAS, ODI and SF-12 and lumbar range of motion (ROM) was recorded using the modified Schober test. RESULTS: While SAT led to minor improvement as compared with baseline status, the addition of MCT allowed a significantly higher improvement in all PRO's at 3 months after initiation of MCT and the improvement was maintained at 6 months. ROM improved after 3 months of MCT and continued to improve at 6 months. CONCLUSIONS: This observational cross-over study demonstrates an advantage of MCT in FM patients with LBP as compared with SAT. Further randomised clinical trial studies should assess whether these results can be generalised to the FM population at large. PMID- 30418118 TI - Aromatic hydrocarbon receptor provides a link between smoking and rheumatoid arthritis in peripheral blood mononuclear cells. AB - OBJECTIVES: Epidemiology shows that smoking plays a central role in rheumatoid arthritis (RA). The aim of this study was to evaluate the potential relationship between smoking, aromatic hydrocarbon receptor (AHR) and RA susceptibility. METHODS: We performed a hospital-based, case-control study of patients with RA and healthy controls. Expressions of AHR, cytochrome P4501A1(CYP1A1), aromatic hydrocarbon receptor repressor (AHRR) genes were assessed in peripheral blood mononuclear cells (PBMCs) and cultured cells using real-time PCR. The response of PBMCs to the AHR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and cigarette smoke extract (CSE) were cultured in vitro. RESULTS: AHR and its downstream gene expressions were demonstrated in smoking rheumatoid PBMCs and non smoking patients with significantly higher expression in smoking patients. The observation was consistent with the sensitivity of RA PBMCs to TCDD and CSE stimulation demonstrated in vitro. CONCLUSIONS: Our study shows that smoking may be involved in the pathogenesis of RA by the AHR pathway. PMID- 30418117 TI - The VICM biomarker is released from activated macrophages and inhibited by anti GM-CSFRalpha-mAb treatment in rheumatoid arthritis patients. AB - OBJECTIVES: Macrophages possess widespread pro-inflammatory, destructive, and remodelling capabilities that can critically contribute to acute and chronic diseases, such as rheumatoid arthritis (RA). Continuous monitoring and measurement of selective counteraction of macrophage activity in patients require a sensitivity and non-invasive marker. We characterised the VICM (citrullinated and MMP degraded vimentin fragment) biomarker by investigating the release from in vitro activated macrophages and by monitoring the change in serum levels after treatment with the anti-GM-CSFRalpha-mAb (mavrilimumab). METHODS: Peripheral blood mononuclear cells were isolated, and lipopolysaccharide (LPS) was used to activate the macrophages and calcium chloride (CaCl2) was used to facilitate the citrullination process of vimentin. Supernatants, cell lysates, was collected and analysed by ELISA, and western blotting. RA patients were treated with mavrilimumab+methotrexate or methotrexate alone in a phase 2b study (NCT01706926) once every two weeks for 24 weeks. Serum levels of VICM were measured at baseline and multiple time points post-treatment. In addition, whole blood expression of peptidylarginine deiminase-2 (PAD-2) and matrix metalloproteinase-9 (MMP-9) transcripts were tested by quantitative reverse transcriptase PCR assays at day 0 and day 169 post-treatment. RESULTS: VICM levels were significantly higher at day 5 and 8 in supernatants of activated macrophages compared to controls (p<0.01), which was confirmed by Western blot. In RA patients, VICM correlated with disease activity (DAS28), modified total sharp score (mTSS), joint space narrowing (JSN), joint erosions and CRP at baseline. VICM was dose-dependently and significantly (p<0.01) inhibited by mavrilimumab. This suppression of VICM serum levels was supported by a decreased expression of PAD2 and MMP9 transcripts in patients treated with mavrilimumab. CONCLUSIONS: These data verified that VICM is released by activated macrophages. Treatment of RA patients with mavrilimumab significantly reduced release of VICM and peptidylarginine deiminases-2 (PAD-2) gene expression indicating that mavrilimumab indeed is targeting activated macrophages and that VICM may be a novel blood-based marker of anti-GM-CSF response. PMID- 30418119 TI - Hepatitis B virus vaccination in an Australian pre-biologic population with rheumatoid arthritis. PMID- 30418121 TI - alpha-enolase is an antigenic target in primary Sjogren's syndrome. AB - OBJECTIVES: Although anti-cyclic citrullinated peptides antibodies are specific markers for rheumatoid arthritis (RA), they might be present in other diseases. Our aim was to assess the native or citrullinated antigens recognised by patients with primary Sjogren's syndrome (pSS) and to evaluate their association with clinical and serological features. METHODS: In an initial screening, we assessed the serum reactivity of 12 patients with pSS against native or in vitro citrullinated antigens of HEp-2 cells by immunoblotting. We identified a 47kDa band, which was preferentially recognised and corresponded to alpha-enolase. Thus, levels of IgA and IgG anti-native and citrullinated alpha-enolase antibodies were measured in 50 pSS patients, 20 RA patients and 20 healthy subjects (HS) by ELISA. RESULTS: We identified alpha-enolase as predominant antigen recognised in pSS. These patients had higher levels of anti-citrullinated alpha-enolase IgG antibodies compared with RA or HS (p=0.003 and p<0.0001, respectively). Furthermore, there was an increase of IgG anti-citrullinated alpha enolase vs IgG anti-non-citrullinated alpha-enolase antibodies in pSS patients (p=0.001), by contrast no difference was found in RA. The presence of IgA and IgG anti-non-citrullinated and anti-citrullinated alpha-enolase antibodies were not associated with any clinical manifestation whatsoever, including non-erosive arthritis among pSS, but an association of IgA anti-citrullinated alpha-enolase with anti-Ro/SSA antibodies was found. CONCLUSIONS: We characterised alpha enolase as a dominant antigen in lysates of HEp- 2 cells in pSS. Nevertheless, their precise role in pSS remains to be elucidated. PMID- 30418120 TI - Body mass index and persistence of conventional DMARDs and TNF inhibitors in rheumatoid arthritis. AB - OBJECTIVES: Obese patients with rheumatoid arthritis (RA) may be more likely to discontinue therapy than non-obese patients, possibly signifying a more refractory phenotype. The purpose of this study was to examine the association between body mass index (BMI) and discontinuation rates for different RA treatments accounting for confounding factors. METHODS: Veterans Affairs administrative databases were used to define initial courses of methotrexate (MTX), hydroxychloroquine, sulfasalazine, prednisone, and self-injectable tumour necrosis factor inhibitors (TNFi). Discontinuation was defined as a lapse in drug refill >90 days. Using overweight BMI (25-30 kg/m2) as the referent group, multivariable Cox proportional hazards models were used to evaluate associations between BMI category and time to treatment discontinuation. RESULTS: There were 46,970 initial RA treatment courses identified from 2005-2014 among 23,669 Veterans with RA. In multivariable models, severe obesity (BMI >35 kg/m2), compared to overweight BMI, was not associated with treatment discontinuation with the exception of prednisone [HR 1.10 (1.04, 1.17) p<0.001]. Patients with low (<20 kg/m2) and normal BMI (20-25 kg/m2) were more likely to discontinue MTX, TNFi, and HCQ compared to overweight patients. Other factors associated with earlier MTX and/or TNFi discontinuation included female sex, black race, greater comorbidity, depression, malignancy, congestive heart failure, current smoking, and more recent calendar year. CONCLUSIONS: Obesity was not associated with therapy discontinuation among veterans with RA after accounting for confounding factors, suggesting that obesity is not a biological mediator of more refractory disease. Conversely, low BMI, comorbidity, and depression were identified as important predictors of drug discontinuation. PMID- 30418122 TI - Secukinumab produces a quick increase in WNT signalling antagonists in patients with psoriatic arthritis. AB - OBJECTIVES: Interleukin-17 (IL-17) is an important cytokine involved in the pathogenesis of bone lesions of psoriatic arthritis (PsA). The aim of our study was to explore the short-term effects (<=6 months) of secukinumab (an anti-IL-17 antibody) on the serum levels of bone turnover markers (BTMs) and on the inhibitors of the WNT signalling pathway. METHODS: The study sample consisted of patients with PsA starting treatment with secukinumab 150 mg every month, and healthy controls (HCs). For the PsA group, the DAS28 score was recorded, and serum samples were collected at baseline, and then at Month 1, 3 and 6 of therapy. As for the HCs, a single observation was performed, with the relevant serum collection. Intact N-terminal propeptide of type I collagen (PINP), C terminal telopeptide of type I collagen (CTX-I-I), Dickkopf-related protein-1 (Dkk-1) and sclerostin were administered. RESULTS: 28 patients with PsA and 43 HCs were enrolled. Neither PINP nor CTX-I serum levels showed any significant variation during the observation period. Baseline mean Dkk-1 serum levels for the PsA arm were significantly lower than in the HC (p<0.05). Dkk-1 and sclerostin serum levels increased at Month 6 during the treatment with secukinumab (p<0.05 vs. baseline). When the PsA arm was compared to the HC, the difference between the serum levels of Dkk-1 lost significance at Month 6. CONCLUSIONS: Treatment with secukinumab does not have any significant short-term effect on BTMs, but may influence some fine regulators of the bone cell activity, such as the WNT inhibitors. PMID- 30418123 TI - The frequency of juvenile spondyloarthropathies in childhood familial Mediterranean fever. AB - OBJECTIVES: The aim of this study is to evaluate the frequency of juvenile spondyloarthropathies (JSpA) in childhood familial Mediterranean fever (FMF) patients from a single tertiary centre. Additionally, we aimed to investigate the main clinical characteristics of FMF patients with coexistence of JSpA clinical features. METHODS: We evaluated 323 paediatric FMF patients who were followed at our clinic. All of the patients were evaluated by three different investigators (EO, DS, ET) for the presence of JSpA clinical signs, according to the recently proposed JSpA criteria. Patients preliminary diagnosed as FMF+JSpA were further evaluated by the experienced paediatric rheumatologist (OK) who made the final decision on the diagnosis of the patients. RESULTS: The female/male ratio was 1.13 (n =172/151). Preliminarily, 33 (10.2%) out of 323 paediatric FMF patients had been classified as FMF+JSpA. An experienced paediatric rheumatologist re evaluated the classified patients and all of them were diagnosed as definitive FMF+JSpA. The M694V mutation was the most common mutation, seen in (n=18/32) (56.3%) FMF+JSpA and in (n=152/251) (61.1%) FMF patients without JSpA/JIA. CONCLUSIONS: Apart from acute monoarthritis of the lower extremities, the chronic arthritis should be kept on mind among FMF patients with articular involvement. The JSpA should be considered in FMF patients with oligoarthritis, inflammatory back pain and enthesopathy complaints with onset over 6 years. Newly proposed JSpA criteria can be used to spondyloarthropathies in childhood FMF. PMID- 30418124 TI - Rapid beneficial effect of the IL-6 receptor blockade on insulin resistance and insulin sensitivity in non-diabetic patients with rheumatoid arthritis. AB - OBJECTIVES: In patients with rheumatoid arthritis (RA), insulin resistance (IR), a component of the metabolic syndrome, is closely linked to the systemic inflammation induced by proinflammatory cytokines such as tumor necrosis factor alpha and interleukin (IL)-6. In the present study, we aimed to assess if an intravenous administration of the anti-IL-6 receptor tocilizumab may yield a rapid improvement of IR in RA. METHODS: 50 consecutive non-diabetic patients with RA refractory to methotrexate, undergoing periodic treatment with tocilizumab, were studied. Besides disease activity, serum insulin, insulin/glucose ratio, insulin resistance (HOMA-IR) and insulin sensitivity (QUICKI) indexes were assessed immediately before and 1 hour after the end of an intravenous administration of tocilizumab (given in saline solution over 60 minutes). RESULTS: When comparing baseline data (immediately before) and 1 hour after finishing tocilizumab administration, we observed a dramatic decrease of the serum insulin levels and insulin/glucose ratio. Also, a statistically significant reduction of IR (HOMA-IR: mean+/- standard deviation immediately before: 2.62+/ 2.03 vs. 1.65+/-1.15 1 hour after the end of the infusion (p<0.01) and a statistically significant increase of insulin sensitivity (QUICKI immediately before 0.34+/-0.03 vs. 0.37+/-0.04 1 hour after the end of tocilizumab infusion (p<0.01) was observed. CONCLUSIONS: The intravenous administration of tocilizumab yields a rapid beneficial effect on IR and insulin sensitivity in non-diabetic RA patients. These findings support the potential beneficial effect of the IL-6 blockade on the mechanisms associated with the development of metabolic syndrome and cardiovascular disease in patients with RA. PMID- 30418125 TI - Polyarteritis nodosa: lessons from 25 years of experience. AB - OBJECTIVES: Polyarteritis nodosa is a necrotising vasculitis of predominantly medium size vessels. The present study aimed to summarise the characteristics of PAN patients, and also analyse the trend of decreasing PAN frequency in the last 25 years. METHODS: PAN patients followed up between 1990 and 2015 were included. The demographics, clinical findings and outcomes were retrospectively evaluated. RESULTS: One hundred thirty-three patients, including 66 children, were enrolled in the study. Among 133 patients, 86 (64.7%) had fever, 108 (81.2%) had skin involvement, 54 (40.6%) had renal involvement, 43 (32.3%) had neurological involvement, 32 (24.1%) had gastrointestinal involvement, 10 (7.5%) had cardiac involvement, 6 (4.5%) had pulmonary involvement. The median (minimum-maximum) leukocyte count, erythrocyte sedimentation rate and C-reactive protein levels at the time of diagnosis were 10400 (6100-32000)/mm3, 58 (2-132) mm/h and 5.22 (0 46) mg/dL, respectively. All patients were ANCA negative. Hepatitis serology was analysed in 121 patients and found positive in 13 of them. MEFV mutations were screened among 65 patients, 24 of them had mutations in at least one allele. Biopsy was performed in 109 patients and angiography was performed in 92 patients. The number of PAN patients declined significantly after 2010. 9 patients were re-categorised as DADA2 after 2014 and no patient were diagnosed with FMF+PAN after 2008. CONCLUSIONS: Our results suggest a decrease in PAN in our country which may be due to improved healthcare and dissecting mimicking diseases. Further prospective studies with prolonged follow-up could help us to better understand the disease characteristics. PMID- 30418126 TI - Multifactorial explanatory model of depression in patients with rheumatoid arthritis: a structural equation approach. AB - OBJECTIVES: Depressive symptoms are common among patients with rheumatoid arthritis (RA). This study was aimed at developing a multifactorial explanatory model that evaluated the influence of personality traits, disease activity, perceived disease impact, and comorbidities. METHODS: This cross-sectional study used structural equation modelling estimation to analyse the associations between these dimensions, pursuing three hypotheses. Depressive symptoms were assessed using the Hospital Anxiety and Depression Scale, disease impact by the Rheumatoid Arthritis Impact of Disease score, personality by the Ten Item Personality Inventory and the disease activity through the Disease Activity Score 28 joints. The influence of comorbidities was investigated by multigroup analysis. RESULTS: The final model derived from data of 254 patients presented a good fit. Disease activity had an indirect relation with depressive symptoms mediated by disease impact (beta=0.17, p<0.001), but the direct relationship between disease activity and depressive symptoms was not significant (beta=0.09; p=0.07). "Positive" personality had a strong negative direct relation with depressive symptoms as well as an indirect relationship mediated by disease impact (total effect beta= 0.61, p<0.001). The final proposed model explained 58% of the variance of depressive symptoms. Multigroup analysis showed an invariant model when comparing patients with and without comorbidities (dchi2=9.03; df=12; p=0.70). CONCLUSIONS: Personality characteristics seem to have a major influence upon the impact of disease and the patient's adjustment to RA, including the vulnerability or resilience to depression. Individual personality traits deserve attention in tailored assessment and treatment of patients with RA, in order to optimise outcomes. PMID- 30418127 TI - Reply to: Vaccination for hepatitis B virus in an Australian pre-biologic population with rheumatoid arthritis. PMID- 30418128 TI - Prevention and management of acute reactions to intravenous iron in surgical patients. AB - Absolute or functional iron deficiency is the most prevalent cause of anaemia in surgical patients, and its correction is a fundamental strategy within "Patient Blood Management" programmes. Offering perioperative oral iron for treating iron deficiency anaemia is still recommended, but intravenous iron has been demonstrated to be superior in most cases. However, the long-standing prejudice against intravenous iron administration, which is thought to induce anaphylaxis, hypotension and shock, still persists. With currently available intravenous iron formulations, minor infusion reactions are not common. These self-limited reactions are due to labile iron and not hypersensitivity. Aggressively treating infusion reactions with H1-antihistamines or vasopressors should be avoided. Self limited hypotension during intravenous iron infusion could be considered to be due to hypersensitivity or vascular reaction to labile iron. Acute hypersensitivity reactions to current intravenous iron formulation are believed to be caused by complement activation-related pseudo-allergy. However, though exceedingly rare (<1:250,000 administrations), they should not be ignored, and intravenous iron should be administered only at facilities where staff is trained to evaluate and manage these reactions. As preventive measures, prior to the infusion, staff should inform all patients about infusion reactions and identify those patients with increased risk of hypersensitivity or contraindications for intravenous iron. Infusion should be started at a low rate for a few minutes. In the event of a reaction, the very first intervention should be the immediate cessation of the infusion, followed by evaluation of severity and treatment. An algorithm to scale the intensity of treatment to the clinical picture and/or response to therapy is presented. PMID- 30418129 TI - Transfused platelets enhance alloimmune responses to transfused KEL-expressing red blood cells in a murine model. AB - BACKGROUND: Factors influencing the development of alloantibodies against blood group antigens on transfused red blood cells are poorly defined. We hypothesised that transfused platelets may act as a danger signal to recipients and affect humoral immune responses to transfused red blood cells. MATERIALS AND METHODS: Platelet-rich plasma prepared from wild-type C57BL/6 or CD40L knockout donors was transfused into wild-type or CD40L knock-out recipients. Leucoreduced red blood cells from transgenic donors expressing high levels of the human KEL glycoprotein in an erythrocyte-specific manner (KELhi donors) were transfused after the platelets, and anti-KEL responses were measured longitudinally. In some experiments, recipients were treated with poly (I:C), monoclonal CD40L-blocking antibody, or CD4-depleting antibody prior to transfusion. RESULTS: Transfusion of wild-type C57BL/6 platelets or treatment with poly (I:C) prior to KELhi red blood cell transfusion led to an anti-KEL alloimmune response in wild-type recipients. Transfusion of platelets from wild-type but not CD40L knock-out donors prior to KELhi red blood cell transfusion led to an IgG anti-KEL alloimmune response in CD40L knock-out recipients; unexpectedly, transfusion of platelets from CD40L knock-out donors prior to KELhi red blood cell transfusion led to a robust anti KEL alloimmune response in wild-type recipients. Recipient treatment with MR1 CD40L-blocking antibody or CD4-depleting antibody prevented KEL alloimmunisation altogether. DISCUSSION: Transfused platelets serve as an adjuvant in this T dependent murine model of anti-KEL red blood cell alloimmunisation, with CD40/CD40L interactions being involved to some degree but with additional mechanisms also playing a role. These findings raise questions about the role that transfused or endogenous platelets may play in other innate/adaptive immune responses. PMID- 30418130 TI - Platelet cut-off for anticoagulant therapy in thrombocytopenic patients with blood cancer and venous thromboembolism: an expert consensus. AB - BACKGROUND: Management of venous thromboembolism (VTE) in patients with haematologic malignancies and thrombocytopenia is clinically challenging due to the related risks. No prospective studies or clinical trials have been carried out and, therefore, no solid evidence on this compelling issue is available. METHODS: Given this, an expert panel endorsed by the Gruppo Italiano Malattie Ematologiche dell'Adulto Working Party on Thrombosis and Haemostasis was set up to produce a formal consensus, according to the RAND method, in order to issue clinical recommendations about the platelet (PLT) cut-off for safe administration of low molecular weight heparin (LMWH) in thrombocytopenic (PLT <100*109/L) adult patients with haematologic malignancies affected by acute (<1 month) or non-acute VTE. RESULTS: In acute VTE, the panel suggests safe anticoagulation with LMWH at therapeutic doses for PLT between 50<100*109/L and at 50% dose reduction for PLT 30<50*109/L. In acute VTE for PLT <30*109/L, the following interventions are recommended: positioning of an inferior vena cava (IVC) filter with prophylactic LMWH administration and platelet transfusion. In non-acute VTE, anticoagulation with LMWH at therapeutic doses for PLT between 50<100*109/L or over and at 50% dose reduction for PLT 30<50*109/L is considered appropriate. The discontinuation of full or reduced therapeutic dose of LMWH is recommended for PLT <30*109/L, both in acute and non-acute VTE. DISCUSSION: We suggest using dose-adjusted LMWH according to PLT to optimise anticoagulant treatment in patients at high bleeding risk. PMID- 30418131 TI - Identification of novel mutations in patients with fibrinogen disorders and genotype/phenotype correlations. AB - BACKGROUND: Congenital fibrinogen disorders are caused by variants occurring within the fibrinogen gene cluster. We describe ten subjects with disease causative variants, adding information on such disorders. MATERIALS AND METHODS: Ten subjects were referred to our Centre because of likely hypo/dysfibrinogenaemia. We evaluated the function and quantity of fibrinogen, using Clauss and immunoreactive assays, and performed genetic investigations by direct sequencing of alpha, beta and gamma chain-encoding genes. Mutations were analysed using SIFT and Polyphen-2 algorithms. RESULTS: We identified one afibrinogenaemic patient (alpha p.Arg178* homozygote) with bleeding/thrombotic events, three heterozygous patients with hypo/dysfibrinogenaemia (gamma p.Thr47ILeu combined with beta IVS7+1G>T; beta p.Cys95Ser; beta p.Arg196Cys) referred for bleeding or thrombotic episodes and six heterozygous subjects with hypofibrinogenaemia (alpha p.Glu41Lys; gamma p.Gly191Val; beta p.Gly288Ser; gamma p.His333Arg; gamma p.Asp342Glu and p.343-344 duplication; gamma p.Asp356Val), of whom four were symptomatic. Five novel missense changes and one novel duplication variant were found, all in hypofibrinogenaemic subjects: p.Glu41Lys (SIFT score 0, Polyphen-2 score 0.986) was identified in a woman with bleeding after major orthopaedic surgery; p.Gly191Val (SIFT score 0.02, Polyphen-2 score 1) in an asymptomatic woman; p.His333Arg (SIFT score 0, Polyphen-2 score 1) in a woman with a post-partum haemorrhage; and p.Asp342Glu (SIFT score 0.23, Polyphen-2 score 0.931); and an Asn-343 and Asp-344 duplication in a child who developed a haematoma following a fall. DISCUSSION: All but one of the novel mutations were in symptomatic subjects and are predicted to be deleterious. Our findings shed more light on genotype-phenotype relationships in congenital fibrinogen disorders. PMID- 30418132 TI - Cost of pathogen reduction for platelets: reply to Cicchetti et al. Blood Transfus 2018; 16: 483-9. PMID- 30418133 TI - Comprehensive phenotypic and molecular investigation of RhD and RhCE variants in Moroccan blood donors. AB - BACKGROUND: To date, more than 650 (weak and partial) Rh variants have been reported. Nature and frequency of these variants are known to be ethnodependent. In transfusion medicine, their identification is important to ensure blood safety. The aim of this study is to investigate and describe the nature and estimate the frequency of Rh variants in blood donors in Morocco by serological tests and molecular analysis. MATERIALS AND METHODS: Blood samples from 4,458 blood donors were collected and typed for Rh antigens (D, C, c, E and e) by an automated system with monoclonal antibodies. RhD-negative samples were tested for weak D expression by indirect antiglobulin test (IAT), as well as weak C, c, E, and e expression with monoclonal antibodies, by column agglutination technique. All samples exhibiting a weak D agglutination by the automated system and IAT were tested for partial D. RHD and RHCE genes were analysed by quantitative multiplex PCR of short fluorescent fragments (QMPSF) and/or Sanger sequencing. RESULTS: 4,038 (90.58%) and 420 (9.42%) samples were respectively typed serologically as D-positive and D-negative, including 23 (0.52%) presenting with a weak D phenotype. In 21 weak D samples investigated by molecular analysis, RHD*weak D type 4.0 was found to be the most prevalent variant allele (n=11), and a novel RHD(V270A) missense allele was found once. Variant Rh CcEe antigen expression was observed in 17 samples carrying 20 variant RHCE alleles, including a novel RHCE*ce(499G) missense allele (p.M167V). DISCUSSION: For the first time, molecular genetics of the Rh system was investigated in the Moroccan population. On the basis of our data and in order to optimise donor/recipient matching to prevent from a potential risk of alloimmunisation in recipients, we suggest that 1) quality control of serological reagents and screening strategies must be reviewed in Morocco, and 2) molecular analysis should be implemented and performed in blood donor centers. PMID- 30418134 TI - Fibrinogen measurement in liver disease: validation of the functional fibrinogen thromboelastography assay and a novel mathematical predictive model. AB - BACKGROUND: Fibrinogen is produced in the liver and tends to be reduced in liver cirrhosis. Quantitative and qualitative tests exist to measure fibrinogen. We aimed to validate the functional fibrinogen thromboelastography assay (FF-TEG) and propose a new model to estimate fibrinogen levels via the Clauss method (Clauss) using data from a prothrombin time-derived fibrinogen assay (PT-Fg) in patients with liver cirrhosis. MATERIALS AND METHODS: Clauss, PT-Fg, fibrinogen antigen (Fib-Ag) and FF-TEG were studied in 55 patients with liver cirrhosis (26 with Child-Turcotte-Pugh [CTP]-A disease, 14 with CTP-B and 15 CTP-C) and 20 healthy individuals. RESULTS: The results of all four assays correlated strongly with each other, but gave significantly different mean levels in all cohorts. PT Fg gave the highest levels whereas the Clauss gave the lowest levels. The FF-TEG performed well with results which were in between the Clauss and the PT-Fg. Significant differences were only observed between CTP-A and CTP-C for the Clauss, PT-Fg and Fib-Ag but not functional fibrinogen level. We devised a simple linear regression model in order to estimate Clauss from the PT-Fg. DISCUSSION: The results of the FF-TEG correlate well with those of routine fibrinogen assays in patients with liver cirrhosis. However, the FF-TEG assay does not discriminate between early and late stages of disease, pointing to a preserved fibrin clot strength in cirrhosis. Through linear regression models, fibrinogen levels can be accurately estimated using the Clauss method based on fibrinogen levels obtained in the cheaper PT-Fg. PMID- 30418135 TI - [Human movement: from motor units to muscle force]. PMID- 30418136 TI - [Diagnostic odyssey at the heart of the 3rd National Initiative for Rare Disorders]. PMID- 30418137 TI - [Non-verbal communication in patients with DM1 and FSHD]. PMID- 30418138 TI - [Legal aspects of genetic testing for diagnostic purposes in France]. PMID- 30418139 TI - [Can acupuncture help relieve muscle pain in muscular dystrophy?] PMID- 30418140 TI - [Towards an harmonization of diagnosis by NGS of neuromuscular diseases - Actions of the Molecular Genetics sub-group of FILNEMUS]. PMID- 30418141 TI - [Multidisciplinary Concertation Meetings (RCP): objectives and operating procedures]. PMID- 30418142 TI - [Tubular aggregate myopathy and Stormorken syndrome]. AB - Calcium (Ca2+) is an essential regulator for a large number of cellular functions in various tissues and organs, and small disturbances of Ca2+ homeostasis can severely compromise normal physiology. Intracellular Ca2+ balance is mainly controlled by the reticular Ca2+ sensor STIM1 and the plasma membrane Ca2+ channel ORAI1 through a mechanism known as store-operated Ca2+ entry (SOCE). Gain of-function mutations in STIM1 or ORAI1 cause excessive extracellular Ca2+ influx, resulting in tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK). Both disorders are spectra of the same disease and involve muscle weakness, miosis, thrombocytopenia, hyposplenism, ichthyosis, dyslexia, and short stature. Here we summarize the clinical and histological characteristics of both disorders, provide an overview on the genetic causes, and recapitulate the current knowledge on the pathomechanisms leading to the multi-systemic phenotype of tubular aggregate myopathy and Stormorken syndrome. PMID- 30418143 TI - [SMA in France, how many patients ?] PMID- 30418144 TI - [The effect of interferon-gamma on skeletal muscle cell biology]. AB - Dysimmune and inflammatory myopathies (DIMs) affect around 14/100,000 people worldwide. Based on immupour nopathological criteria, DIMs are divided in four groups: (1) polymyositis (PM)/inclusion body myositis (IBM), (2) dermatomyositis (DM), (3) immune-mediated necrotizing myopathies (IMNM) and (iv) overlapping myositis including anti-synthetase syndrome (ASS). ASS and PM/IBM are characterized by the activation of inflammation with lymphocytic infiltrations. Recently, we showed that an expression of the major histocompatibility complex class 2 (MHC2) was present in myofibers from ASS and IBM muscle biopsies. Interestingly, MHC2 expression is known to be stimulated by Interferon-gamma (IFNgamma) in myogenic cells. LTCD8 cells, which are well-known producers of IFNgamma, are commonly found in close vicinity to MHC2 positive myofibers. This inflammatory cytokine also inhibits myogenic differentiation in vitro by CIITA myogenin interaction. The mechanisms involved in the lymphocyte-driven muscle toxicity in DIMs are unclear. The objectives of this project are to characterize IFNgamma effects on the biology of human myogenic cells by morphological, molecular and cellular approaches. Then, we aim to investigate the role of IFNgamma in these myopathies and its impact during muscular regeneration. In vitro preliminary studies have been performed using human and mouse myoblasts treated or not with IFNgamma. Our results should lead to a better understanding of the role of IFNgamma in the pathophysiology of DIMs, and would hopefully help identify new therapeutic targets. PMID- 30418145 TI - [Genotype-phenotype correlations of pathogenic variants in the FLNC gene]. PMID- 30418146 TI - [Skin cells for use as an alternate diagnostic method for Duchenne muscular dystrophy]. PMID- 30418147 TI - [DM1 with severe fatigue: a cognitive behavioural therapy trial]. PMID- 30418148 TI - [The burden of pain, fatigue and mental health on quality of life in neuromuscular disorders]. PMID- 30418149 TI - [An overview of Duchenne muscular dystrophy in Martinique]. PMID- 30418150 TI - [GLeaned On the Web]. PMID- 30418151 TI - [Outcomes measures used in clinical trials in neuromuscular diseases]. PMID- 30418152 TI - Global warming reduces leaf-out and flowering synchrony among individuals. AB - : The temporal overlap of phenological stages, phenological synchrony, crucially influences ecosystem functioning. For flowering, among-individual synchrony influences gene flow. For leaf-out, it affects interactions with herbivores and competing plants. If individuals differ in their reaction to the ongoing change in global climate, this should affect population-level synchrony. Here, we use climate-manipulation experiments, Pan-European long-term (>15 years) observations, and common garden monitoring data on up to 72 woody and herbaceous species to study the effects of increasing temperatures on the extent of leaf-out and flowering synchrony within populations. Warmer temperatures reduce in situ leaf-out and flowering synchrony by up to 55%, and experiments on European beech provide a mechanism for how individual differences in day-length and/or chilling sensitivity may explain this finding. The rapid loss of reproductive and vegetative synchrony in European plants predicts changes in their gene flow and trophic interactions, but community-wide consequences remain largely unknown. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter). PMID- 30418153 TI - Subunit exchange enhances information retention by CaMKII in dendritic spines. AB - Molecular bistables are strong candidates for long-term information storage, for example, in synaptic plasticity. Calcium/calmodulin dependent protein Kinase II (CaMKII) is a highly expressed synaptic protein which has been proposed to form a molecular bistable switch capable of maintaining its state for years despite protein turnover and stochastic noise. It has recently been shown that CaMKII holoenzymes exchange subunits among themselves. Here we used computational methods to analyze the effect of subunit exchange on the CaMKII pathway in the presence of diffusion in two different micro-environments, the post synaptic density (PSD) and spine cytosol. We show that CaMKII exhibits multiple timescales of activity due to subunit exchange. Further, subunit exchange enhances information retention by CaMKII both by improving the stability of its switching in the PSD, and by slowing the decay of its activity in the spine cytosol. The existence of diverse timescales in the synapse has important theoretical implications for memory storage in networks. PMID- 30418155 TI - Adjuvants in allergen-specific immunotherapy: modulating and enhancing the immune response. AB - Allergen-specific immunotherapy (AIT) is the only treatment that may affect the natural course of allergic diseases such as allergic asthma, allergic rhinitis, and IgEmediated food allergy. Adjuvants are used to induce a quicker, more potent, and longer-lasting AIT immune response. Up to now, only four compounds are used as adjuvants in currently marketed AIT products: aluminum hydroxide, calcium phosphate, microcrystalline tyrosine (MCT), and monophosphoryl lipid A (MPL). The three first adjuvants are delivery systems with depot effect, although they also may have immunomodulatory properties. These firstgeneration adjuvants are still widely used, especially aluminum hydroxide. However, aluminum has some limitations. MCT is the depot formulation of L-tyrosine; it enhances IgG production withoutinducing a significant IgE increase, is biodegradable and has good local and systemic tolerability. In turn, MPL is an immunostimulatory agent that is the only second-generation adjuvant currently used for AIT. In addition, there are multiple adjuvants under research, including immunostimulatory sequences (ISS), nanoparticles (liposomes, virus-like particlesand biodegradable polymers), and phosphatidylserine derivatives. In a murine model of allergic bronchial inflammation by sensitization to olive pollen, specific IgE level was significantly higher in sensitized mice treated with olive pollen and aluminum hydroxide. However, sensitized mice treated with olive pollen and bacterial derivatives (MPL or ISS) showed a significant reduction of specific IgE levels and a significant improvement of bronchial hyperreactivity. PMID- 30418154 TI - Correction: Non-invasive detection of urothelial cancer through the analysis of driver gene mutations and aneuploidy. PMID- 30418156 TI - Early outcomes of percutaneous pulmonary valve implantation using the Edwards SAPIEN 3 transcatheter heart valve system. AB - AIMS: Multiple surgical revisions are often necessary in individuals with congenital heart defects affecting the RVOT or pulmonary valve. There are no multicentre data on the feasibility and safety of percutaneous pulmonary valve implantation using the SAPIEN 3 (S3) transcatheter heart valve. METHODS AND RESULTS: Pulmonic S3 is an observational registry of patients undergoing PPVI with the S3 valve across centres in Europe and Canada. Data for 82 patients (mean age 27.3 years) was obtained. The most common underlying diagnosis was Tetralogy of Fallot (ToF) (58.5%), with 16.0% of patients having native RVOT anatomy. 90.2% received pre-stenting. Prosthesis dislodgement occurred in one patient and conduit perforation in another. Both were successfully resolved without need for open surgery. Peak systolic gradient over the RVOT fell from 46.3 mmHg to 17.2 mmHg, moderate/severe pulmonary regurgitation from 86.3% to 0.0% and NYHA >=II from 86.0% to 15.2%. During follow-up valve-thrombosis was observed in two patients which resolved with adequate anticoagulation. No other procedural complications, endocarditis, stent fracture or death were reported within two years. CONCLUSIONS: PPVI with the S3 valve appears feasible and safe in a wide range of patients with congenital heart defects, with good short-term haemodynamic and functional outcomes. PMID- 30418157 TI - Intracoronary Tenecteplase versus Abciximab as Adjunctive Treatment during Primary Percutaneous Coronary Intervention in Patients with Anterior Myocardial Infarction. AB - AIMS: We sought to compare the effects of intracoronary administration of a fibrinolytic drug (tenecteplase) to those of a glycoprotein IIb/IIIa inhibitor (abciximab) in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). METHODS AND RESULTS: In this pilot trial, 76 patients (59 male) with anterior STEMI were randomised to intracoronary infusion of reduced-dose tenecteplase or abciximab during PPCI. Angiography was repeated at 48 hours to assess corrected TIMI frame count (cTFC) and TIMI myocardial perfusion grade (TMPG). The primary end-point was infarct size as assessed by cardiac-MRI. Abciximab-group showed lower cTFC (median 14.1 [IQR 9.4-17.1]) than tenecteplase-group (18.2 [10.0-28.2]) (p=0.02), and the proportion of patients with TMPG grade 2/3 was higher in the abciximab group (90.3% vs. 67.7%; p= 0.03). Major cardiac and cerebrovascular event rates did not differ but, notably, 2/38 patients in the tenecteplase-group experienced subacute stent thrombosis. At 4 months, there were no significant differences in infarct size between the tenecteplase and abciximab groups (17.0 g. [9.6-27.5] vs. 21.1 g. [11.3-35.0], p=0.33). CONCLUSIONS: Intracoronary administration of tenecteplase did not reduce infarct size compared to abciximab in STEMI patients undergoing PPCI. Tenecteplase exhibited poorer myocardial reperfusion and might be associated with increased subacute stent thrombosis. PMID- 30418158 TI - Bioabsorbable Magnesium scaffold in complex PCI in nickel allergy patient one year follow-up: no disease, no scaffolds. PMID- 30418159 TI - Prosthesis-Patient Mismatch after Transcatheter Aortic Valve Implantation: Prevalence and Prognostic Impact under Consideration of Baseline Left Ventricular Function. AB - AIMS: We aimed to assess prevalence and features of PPM following transcatheter aortic valve implantation (TAVI) and its prognostic impact considering baseline left ventricular ejection fraction (LVEF). METHODS AND RESULTS: Data from 1,309 patients undergoing TAVI for severe aortic stenosis was derived from a single center dedicated TAVI registry. PPM was assessed according to echocardiography at discharge and was defined in accordance with VARC2. Follow-up time was 2.03 years. Moderate and severe PPM was detected in 22.9% and 12.9%, respectively. Patients with severe PPM had smaller annuli and received more often transcatheter heart valve (THV) sizes <=23 mm. Supraannular THV design showed the lowest rate of PPM. In patients with LVEF <40%, but not in those with LVEF >=40%, severe PPM was associated with increased 3-year mortality rate (no vs. severe PPM for LVEF >=40%: 34.6% vs. 29.5%, p=0.96; LVEF <40%: 45.1% vs. 68.0%, p=0.041) and was independently predictive for all-cause mortality according to multivariate analysis in these patients (HR 2.97; 95%CI 1.58-5.59, p<0.001). CONCLUSIONS: The presence of severe PPM depends on annular dimensions and THV size and design and is an independent predictor for mortality in patients with reduced LVEF. Hence, the risk of PPM should be considered within the process of THV selection. PMID- 30418160 TI - ImpellaCP or VA-ECMO in profound cardiogenic shock: left ventricular unloading and organ perfusion in a large animal model. AB - Aims/ To evaluate ImpellaCP over Veno-Arterial Extracorporeal Membrane Oxygenation (VA-ECMO) and their impact on left ventricular (LV) unloading and end organ perfusion. Methods and results: cardiogenic shock (CS) was induced by injecting microspheres into the left coronary artery in fourteen adult female swine. ImpellaCP or VA-ECMO was initiated in the presence of CS and evaluated after 60 minutes. LV pressure-volume area (PVA, total mechanical work) was obtained from a conductance catheter. Results are presented as mean [95% CI] and rank sum test was used to assess differences between devices. Compared to the CS state PVA was unaffected by ImpellaCP and increased on VA-ECMO (from 2548 [2193, 2904] mmHg x mL during CS to 5775 [4451; 7099], between device p-value = 0.02). Arterial lactate increased during CS and decreased on support with no difference between devices. Renal venous oxygen saturation decreased during CS and increased on support with no difference between devices. Cerebral venous oxygen saturation increased to 33% [25, 40] on ImpellaCP and to 69% [49, 89] on VA-ECMO, p=0.04. Conclusions: In this porcine model of profound cardiogenic shock ImpellaCP unloaded the LV compared to VA-ECMO. Both devices improved end-organ perfusion, with a tendency towards higher venous oxygen saturations on VA-ECMO. PMID- 30418161 TI - Surgical Application of Viable Cryopreserved Placental Membrane for the Treatment of Chronic Wounds in 12 High-risk Patients. AB - Treatment of lower extremity ulcers remains a challenge to physicians and surgeons. These wounds lead to an increased risk of amputation and increased mortality rate and must be treated aggressively, in many cases requiring surgical debridement, to prevent these complications. The objective of this retrospective case series is to evaluate the safety and efficacy of a viable cryopreserved placental membrane (vCPM) in 12 patients with 16 wounds of mixed etiologies when surgically debrided and augmented with vCPM 1 time, followed by standard of care (nonadherent dressing, gauze, and compression) until healed. The results of this case series demonstrate that the surgical application of vCPM can be used as an alternative treatment for high-risk patients with chronic lower extremity wounds. PMID- 30418162 TI - Platelet-rich Plasma and Other Hemocomponents in Veterinary Regenerative Medicine. AB - Platelet-rich plasma, platelet-rich fibrin, fibrin glue, and platelet lysate are the most widely used nontransfusional hemocomponents that, as biological and therapeutic aids, enhance the physiological reactions after an injury to facilitate the repair and regeneration processes. Recently, this type of therapy also has significantly expanded in veterinary medicine. Due to many similarities, the animal patient could be a good reference as a study model for humans, especially for chronic and difficult-to-heal injuries. This review discusses the current state of hemocomponent use for topical application in veterinary medicine, with a comparison with human medicine. PMID- 30418163 TI - Time to Abandon Antimicrobial Approaches in Wound Healing: A Paradigm Shift. AB - Antimicrobial approaches (eg, antibiotics and antiseptics) have been used for decades in the treatment of infected wounds, ulcers, and burns. However, an increasing number of meta-analyses have raised questions regarding the therapeutic value of these approaches. Newer findings show that the body actively hosts an ecosystem of bacteria, fungi, viruses, and mites on its outer surfaces, known as the microbiome, as part of its defense against pathogens. Antimicrobials would disrupt this system and thereby work against the strategy the body has chosen. Recently, a new technology, micropore particle technology (MPPT), has been identified; it is not an antimicrobial but instead acts as a passive immunotherapy that disrupts the weaponry bacteria and fungi use to inhibit the immune system, allowing the immune system to recover. Clinical findings show MPPT removes wound infections 60% quicker than antibiotics and antiseptics and promotes the healing of chronic wounds that have not responded to antimicrobials. These effects are achieved without antimicrobial action and, considering the limited therapeutic benefits of antibiotics and antiseptics for wound infections, it is valid to question the use of antimicrobial approaches in wound care and the dogma that a reduction in microbial burden will lead to a reduction in infection. Instead, it may be time to consider a paradigm shift in wound healing away from antimicrobials and towards therapies that support the immune system and the microbiome. This review covers the increasing evidence that infections on external surfaces have to be treated fundamentally differently to internal infections. PMID- 30418164 TI - OCT Analysis of Very Early Strut Coverage of the Synergy Stent in Non-ST Segment Elevation Acute Coronary Syndrome Patients. AB - OBJECTIVES: Early endothelialization of drug-eluting stent (DES) is a major challenge to reduce the risk of stent thrombosis and the duration of dual antiplatelet therapy (DAPT) in high bleeding-risk patients. The aim of the present study is to evaluate very early strut coverage with optical coherence tomography (OCT) of the Synergy stent (Boston Scientific) at 1 month in non-ST segment elevation acute coronary syndrome (NSTE-ACS) patients. METHODS: This substudy of the EARLY trial prospectively included NSTE-ACS patients treated with the Synergy DES. OCT analysis of the Synergy stent was performed during a staged PCI of additional lesions at 1 month. The primary endpoint was the percentage of covered struts assessed with OCT at 1 month. RESULTS: Twenty-four patients were included, with a mean stent length of 35.9 +/- 10.1 mm per patient. The rate of covered struts was 78.5% out of 3839 struts analyzed. Nineteen patients (79.2%) had at least 70% of their struts covered. The average neointimal thickness was 0.0508 +/- 0.016 mm. CONCLUSIONS: In NSTE-ACS patients undergoing culprit percutaneous coronary intervention with the Synergy stent, the rate of covered struts at 1 month was 78.5%. This rapid coverage is in line with the results of clinical trials demonstrating the safety of short-duration DAPT in selected patients who are at high bleeding risk and treated with new-generation DES options. PMID- 30418165 TI - Immediate Improvement in Left Atrial Function After Transcatheter Aortic Valve Replacement on Doppler Echocardiography. AB - BACKGROUND: More than 50% of embolic strokes occur >24 hours after transcatheter aortic valve replacement (TAVR) and are therefore not directly procedure related. We aimed to determine immediate changes in left atrial (LA) function after TAVR, that may alter short-term and long-term stroke risk after TAVR. METHODS: Transesophageal and transthoracic echocardiography were performed before and immediately after TAVR to evaluate left atrial appendage (LAA) velocities and Doppler echocardiographic markers of LA function. RESULTS: Eighty-five patients (mean age, 83.1 +/- 7.5 years; 54% male) underwent TAVR. Patients in sinus rhythm (n = 57) during TAVR had immediate improvement of LA function, with an increase in A-wave velocity (92.3 +/- 33.7 cm/s to 104.9 +/- 34.6 cm/s), mitral inflow velocity time integral (VTI; 27.8 +/- 3.6 to 29.6 +/- 9.5), A-wave VTI (10.8 +/- 4.1 to 12.8 +/- 4.2), and lateral A' velocity (8.8 +/- 3.6 cm/s to 9.7 +/- 3.6 cm/s; P<.05 for all), and a decrease in E/A ratio (1.2 +/- 0.73 to 1.05 +/- 0.59; P<.01) after TAVR. Low baseline LAA emptying velocities were common (53%), and velocities significantly increased after TAVR (mean change, +4.9 cm/s; P<.01). We identified several clinical and echocardiographic determinants of low LAA emptying velocity at baseline (<35 cm/s). CONCLUSIONS: There is immediate improvement in LA function and an increase in LAA velocities after TAVR. This improvement may benefit hemodynamics immediately after TAVR, but may also increase the short-term stroke risk (as recently shown in two independent studies) in patients with LAA thrombus or low emptying velocities. Therefore, evaluation of LA function and LAA thrombus may be warranted to identify patients at high risk for periprocedural stroke and guide the need for anticoagulation therapy. PMID- 30418167 TI - Low-intensity microcurrent therapy promotes regeneration of atrophied calf muscles in immobilized rabbits. AB - The purpose of this study was to investigate the intensity-specific regenerative effects of microcurrent therapy on gastrocnemius muscle atrophy induced by cast immobilization in rabbits. Fifteen rabbits were randomly allocated to 3 groups after cast removal: cast-immobilization and sham microcurrent therapy for 2 weeks (group 1); cast-immobilization and microcurrent therapy (25 MUA) for 2 weeks (group 2); cast-immobilization and microcurrent therapy (5,000 MUA) for 2 weeks (group 3). Clinical parameters [calf circumference, compound muscle action potential (CMAP) of the tibial nerve, thickness of gastrocnemius muscle], cross sectional area of gastrocnemius muscle fibres, and immunohistochemistry was evaluated. The clinical parameters representing mean atrophic changes in group 2 were significantly lower than those in group 3. The cross sectional area of the gastrocnemius muscle fibres and immunohistochemical parameters in group 2 were significantly greater than those in group 3. The results showed that low intensity microcurrent therapy can more effectively promote regeneration in atrophied gastrocnemius muscle than high-intensity microcurrent therapy. PMID- 30418168 TI - Effect of restoration technique on resistance to fracture of endodontically treated anterior teeth with flared root canals. AB - This study was designed to compare the impact of post and core systems on resistance to fracture of endodontically treated anterior teeth with flared root canals and to assess their fracture pattern. Sixty central incisors were cut horizontally 2 mm coronal to the cementoenamel junction (CEJ). After root canal therapy, teeth were assigned into 6 groups (n=10 each) based on a post system and used as follows: Group C, non-flared root received size #1 glass fiber posts (Control); Group AP, flared root restored with anatomical post; Group RC, flared root restored with size #1 fiber post and cemented with thick layer of resin cement; Group CR, flared root restored with size #1 and reinforced with composite resin; Group CM, cast post-core; Group CP, CAD?/CAM polymer-infiltrated ceramic post and core. Following post cementation, core build-up and crown insertion, the specimens were thermo-cycled up to 10,000 cycles (5C/55C; 30 seconds dwell time, 6 seconds transition time) and then statically loaded at 1 mm/minute crosshead speed using a universal testing machine. One-way ANOVA and Tukey HSD post hoc test (alpha=0.05) were used for data analysis. Group C recorded significantly higher resistance to fracture values [(826.9+/-39.1) N] followed by group CP [(793.8+/-55.6) N] while group RC yielded the lowest fracture resistance values [(586.7+/-51.4) N]. The resistance to fracture of wide root canals can be enhanced by using one-piece CAM/CAM post and core as an alternative to the use of either glass fiber post, relined with composite resin increasing the thickness of luting cement or the use of cast post and core system. However, this was an in vitro investigation and further in vivo studies are necessary. PMID- 30418166 TI - Comparison Between Traditional and Guide-Catheter Extension Reverse Controlled Antegrade Dissection and Retrograde Tracking: Insights From the PROGRESS-CTO Registry. AB - OBJECTIVES: The most common re-entry technique during retrograde chronic total occlusion (CTO) percutaneous coronary intervention (PCI) is reverse controlled antegrade and retrograde tracking (rCART). The use of guide-catheter extensions can facilitate rCART, but has received limited study. METHODS: We compared the clinical and procedural characteristics and outcomes of traditional rCART vs guide-catheter extension rCART vs cases in which both techniques were used (combined rCART) in patients with successful retrograde CTO crossing in a contemporary multicenter CTO-PCI registry. RESULTS: Between 2012 and 2018, rCART was used in 467 of 1336 retrograde CTO-PCI cases. Guide-catheter extension rCART was used in 60/467 cases (13%; use increased from 0% in 2012 to 26% in 2017). The traditional rCART group, guide-catheter extension rCART group, and combined rCART group had similar target lesion J-CTO scores (3.3 +/- 1.1 vs 3.2 +/- 1.2 vs 3.6 +/- 0.8, respectively; P=.28), technical success rates (99% vs 100% vs 96.4%, respectively; P=.36), procedural success rates (93.2% vs 93.8% vs 96.3%, respectively; P=.82), and major in-hospital adverse cardiac event (MACE) rates (6.4% vs 9.4% vs 3.6%, respectively; P=.66). Total procedural time was longer in the combined rCART group (196 min [IQR, 146-256 min] vs 200 min [IQR, 164-293 min] vs 255 min [IQR, 195-280 min], respectively; P<.01), with a trend for lower patient air kerma radiation dose in the guide-catheter extension groups (4.11 Gray [IQR, 2.49-5.77 Gray] vs 3.19 Gray [IQR, 1.29-4.74 Gray] vs 3.47 Gray [IQR, 2.89-5.56 Gray]; P=.07). CONCLUSIONS: Guide-catheter extension rCART is increasingly being used for retrograde CTO crossing and is associated with similar success and MACE rates as traditional rCART. PMID- 30418169 TI - Maxillary denture flange and occlusal discrepancies of Vertex ThermoSens in comparison with conventional heat-cured denture base materials. AB - This study was conducted to investigate the maxillary denture bases and occlusal discrepancies using the Vertex Thermosens in comparison with the conventional polymethyl-methacrylate materials. Twenty maxillary denture bases were prepared from the Vertex ThermoSens and a conventional heat-cured denture base materials. Acrylic maxillary second molars were arranged in their respective positions on the ridge. After curing of both types of denture bases, they were deflasked with their respective master casts. Reference points were prepared for measurements of the antero-posterior and cross-arch dimensions at the denture borders using caliper device. Furthermore, the teeth discrepancies were measured between reference points in the ligual aspect of the second maxillary molars. The recorded data was analyzed using SPSS statistical software version 20. The results showed initial shrinkage of both denture bases in the antero-posterior and cross-arch dimensions immediately after decasting. This contraction was compensated gradually during storage in water up to 2 weeks. Regarding the variable time, there was a significant difference between the tested materials. Moreover, the results revealed occlusal discrepancies and shifting of teeth inward immediately after decasting, followed by outward movement after storage in water for 2 weeks. Regarding the variables time and materials, there were significant differences. Both materials exhibited inward shrinkage in the antero posterior and cross-arch dimensions immediately after decasting. Both denture bases showed inward shifting of teeth immediately after decasting, followed by outward movement after storage in water up to 2 weeks. PMID- 30418170 TI - STAT3: a link between CaMKII-betaIV-spectrin and maladaptive remodeling? AB - betaIV-Spectrin, along with ankyrin and Ca2+/calmodulin-dependent kinase II (CaMKII), has been shown to form local signaling domains at the intercalated disc, while playing a key role in the regulation of Na+ and K+ channels in cardiomyocytes. In this issue of the JCI, Unudurthi et al. show that under chronic pressure overload conditions, CaMKII activation leads to betaIV-spectrin degradation, resulting in the release of sequestered STAT3 from the intercalated discs. This in turn leads to dysregulation of STAT3-mediated gene transcription, maladaptive remodeling, fibrosis, and decreased cardiac function. Overall, this study presents interesting findings regarding the role of CaMKII and betaIV spectrin under physiological as well as pathological conditions. PMID- 30418172 TI - A protective role for microRNA-688 in acute kidney injury. AB - Ischemia-reperfusion (I/R) sets off a devastating cascade of events, leading to cell death and possible organ failure. Treatments to limit I/R-associated damage are lacking, and the pathways that drive injury are poorly understood. In this issue of the JCI, Wei and colleagues identify microRNA-668 (miR-668) as a protective factor in acute kidney injury (AKI). miR-668 was shown to repress mitochondrial fission-associated protein MTP18, thereby inhibiting pathogenic mitochondrial fragmentation. In murine models of I/R-induced AKI, treatment with a miR-668 mimetic reduced mitochondrial fragmentation and improved renal function. Moreover, HIF-1alpha was shown to be required for miR-688 expression in response to I/R. Importantly, Wei et al. show miR-668 upregulation in a cohort of human patients with AKI. Together, these results identify a HIF-1alpha/miR 668/MTP18 axis that may have potential as a therapeutic target for AKI. PMID- 30418171 TI - Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel-associated retinopathy. AB - Mutations in CNGA3 and CNGB3, the genes encoding the subunits of the tetrameric cone photoreceptor cyclic nucleotide-gated ion channel, cause achromatopsia, a congenital retinal disorder characterized by loss of cone function. However, a small number of patients carrying the CNGB3/c.1208G>A;p.R403Q mutation present with a variable retinal phenotype ranging from complete and incomplete achromatopsia to moderate cone dysfunction or progressive cone dystrophy. By exploring a large patient cohort and published cases, we identified 16 unrelated individuals who were homozygous or (compound-)heterozygous for the CNGB3/c.1208G>A;p.R403Q mutation. In-depth genetic and clinical analysis revealed a co-occurrence of a mutant CNGA3 allele in a high proportion of these patients (10 of 16), likely contributing to the disease phenotype. To verify these findings, we generated a Cngb3R403Q/R403Q mouse model, which was crossbred with Cnga3-deficient (Cnga3-/-) mice to obtain triallelic Cnga3+/- Cngb3R403Q/R403Q mutants. As in human subjects, there was a striking genotype-phenotype correlation, since the presence of 1 Cnga3-null allele exacerbated the cone dystrophy phenotype in Cngb3R403Q/R403Q mice. These findings strongly suggest a digenic and triallelic inheritance pattern in a subset of patients with achromatopsia/severe cone dystrophy linked to the CNGB3/p.R403Q mutation, with important implications for diagnosis, prognosis, and genetic counseling. PMID- 30418173 TI - Why are diabetics prone to kidney infections? AB - People with diabetes mellitus are at higher risk of developing serious ascending infections of the urinary tract. The traditional explanation has focused on the role of glycosuria in promoting bacterial growth. Using mouse models, Murtha et al. demonstrate that when the intracellular insulin signaling pathway is compromised, antimicrobial defenses are compromised too, and the mice are unable to effectively handle uropathogenic E. coli introduced experimentally into the urinary tract. These observations strongly support the hypothesis that the antimicrobial defenses of the kidney are dependent on insulin, and the urinary tract infections associated with diabetes occur due to reduced expression of these key effectors of innate immunity. PMID- 30418174 TI - Fbxo22-mediated KDM4B degradation determines selective estrogen receptor modulator activity in breast cancer. AB - The agonistic/antagonistic biocharacter of selective estrogen receptor modulators (SERMs) can have therapeutic advantages, particularly in the case of premenopausal breast cancers. Although the contradictory effects of these modulators have been studied in terms of crosstalk between the estrogen receptor alpha (ER) and coactivator dynamics and growth factor signaling, the molecular basis of these mechanisms is still obscure. We identify a series of regulatory mechanisms controlling cofactor dynamics on ER and SERM function, whose activities require F-box protein 22 (Fbxo22). Skp1, Cullin1, F-box-containing complex (SCFFbxo22) ubiquitylated lysine demethylase 4B (KDM4B) complexed with tamoxifen-bound (TAM-bound) ER, whose degradation released steroid receptor coactivator (SRC) from ER. Depletion of Fbxo22 resulted in ER-dependent transcriptional activation via transactivation function 1 (AF1) function, even in the presence of SERMs. In living cells, TAM released SRC and KDM4B from ER in a Fbxo22-dependent manner. SRC release by TAM required Fbxo22 on almost all ER-SRC bound enhancers and promoters. TAM failed to prevent the growth of Fbxo22 depleted, ER-positive breast cancers both in vitro and in vivo. Clinically, a low level of Fbxo22 in tumor tissues predicted a poorer outcome in ER-positive/human epidermal growth factor receptor type 2-negative (HER2-negative) breast cancers with high hazard ratios, independently of other markers such as Ki-67 and node status. We propose that the level of Fbxo22 in tumor tissues defines a new subclass of ER-positive breast cancers for which SCFFbxo22-mediated KDM4B degradation in patients can be a therapeutic target for the next generation of SERMs. PMID- 30418175 TI - Insulin receptor signaling regulates renal collecting duct and intercalated cell antibacterial defenses. AB - People with diabetes mellitus have increased infection risk. With diabetes, urinary tract infection (UTI) is more common and has worse outcomes. Here, we investigate how diabetes and insulin resistance impact the kidney's innate defenses and urine sterility. We report that type 2 diabetic mice have increased UTI risk. Moreover, insulin-resistant prediabetic mice have increased UTI susceptibility, independent of hyperglycemia or glucosuria. To identify how insulin resistance affects renal antimicrobial defenses, we genetically deleted the insulin receptor in the kidney's collecting tubules and intercalated cells. Intercalated cells, located within collecting tubules, contribute to epithelial defenses by acidifying the urine and secreting antimicrobial peptides (AMPs) into the urinary stream. Collecting duct and intercalated cell-specific insulin receptor deletion did not impact urine acidification, suppressed downstream insulin-mediated targets and AMP expression, and increased UTI susceptibility. Specifically, insulin receptor-mediated signaling regulates AMPs, including lipocalin 2 and ribonuclease 4, via phosphatidylinositol-3-kinase signaling. These data suggest that insulin signaling plays a critical role in renal antibacterial defenses. PMID- 30418176 TI - Comparing assessments of physical functional independence in older adults with mobility limitations. AB - OBJECTIVES: 1) To assess the agreement and correlation between self-reported functional independence and observations of family caregivers in a heterogeneous population of community-dwelling older adults with disabilities. 2) To determine how self- and caregiver-reports correlate with evaluator rated functional independence over time. DESIGN: Data were drawn from a larger, randomized controlled trial examining the effects of a caregiver-inclusive intervention on outcomes of care recipients and their family caregivers. Functional independence measures were obtained using a self-report version of the Functional Independence Measure (care recipient FIM-SR, caregiver FIM-SR) and the Functional Autonomy Measurement System (evaluator perspective). They were administered at baseline (pre-intervention), and following the intervention at 6-, 22-, and 58-weeks. RESULTS: Bivariate correlation analyses of ninety dyads consisting of older care recipients and their family caregivers reported moderate to very strong correlations between the three functional independence measures across all time points (rS=0.45-0.91; P<0.01). Bland-Altman analyses revealed a small systematic bias between care recipient- and caregiver-assessments of functional independence, with participants reporting higher scores across all time points (mean difference=2.00-2.97). CONCLUSION: There is substantial consistency among the self-assessed, caregiver-assessed, and evaluator assessed functional independence of older adults. Caregivers may be used as proxies for community dwelling older adults without severe cognitive impairments with functional limitations. PMID- 30418177 TI - Cochrane Corners to Enhance Access to Evidence-Based Physiatry (EBP). PMID- 30418178 TI - A Phase Ib Study of the FGFR/VEGFR Inhibitor Dovitinib With Gemcitabine and Capecitabine in Advanced Solid Tumor and Pancreatic Cancer Patients. AB - OBJECTIVES: Preclinical studies demonstrated antitumor activity of dovitinib in pancreatic cancer models. This phase Ib study aimed to determine the maximum tolerated dose (MTD) of dovitinib in combination with gemcitabine and capecitabine and to characterize the safety and pharmacokinetic profile in patients with advanced pancreatic and biliary tract cancers and solid malignancies. MATERIALS AND METHODS: Patients received gemcitabine 1000 mg/m2 intravenously on days 1 and 8, capecitabine 1300 mg/m2 oral daily from day 1 to 14, and dovitinib oral daily 5 days on and 2 days off, every 21-day cycle. The standard 3+3 dose escalation design was utilized and the study expanded to treat an additional 20 advanced pancreatic and biliary tract cancers patients at MTD. RESULTS: A total of 29 patients were enrolled. One patient experienced dose limiting grade 3 colitis. Two patients developed clinically significant neuropathy after the first cycle requiring dose reduction. The MTD was not reached and dovitinib 300 mg was declared the recommended dose for expansion. The most frequent grade 2 or worse adverse events were fatigue (45%), neutropenia (41%), thrombocytopenia (34%), anemia (24%), nausea (24%), and palmer-plantar erythrodysaesthesia syndrome (21%). Partial responses were observed in 5 patients. Pharmacokinetic studies showed no drug-drug interaction between dovitinib, capecitabine and gemcitabine. Fibroblast growth factor 23 plasma level increased in 4 of 5 patients during the first cycle of treatment. CONCLUSIONS: Dovitinib 300 mg daily is the recommended dose when combined with gemcitabine and capecitabine, achieving clinically relevant plasma concentrations. The study combination demonstrated encouraging efficacy signals in advanced pancreatic cancer. PMID- 30418179 TI - Role of Stereotactic Body Radiation Therapy in Early Stage Small Cell Lung Cancer in the Era of Lung Cancer Screening: A Systematic Review. AB - With the obvious benefit from low dose computed tomography to reduce the lung cancer-specific mortality, lung cancer screening is on the rise. With the implementation of the screening programs, diagnosis of early stage lung cancer is expected to increase, and small cell lung cancer (SCLC) would account for 10% of screen-detected lung cancer. Apart from Concurrent chemoradiation (CRT), the present guidelines virtually do not support other options for radiation (RT). There is a paucity of data addressing the role of Stereotactic Body Radiation Therapy (SBRT) in SCLC and we conducted the current systematic review on this topic. We systematically searched literature using the electronic databases PubMed and Embase with no language, year or publication status restrictions. After removal of duplicate records, 3469 screened, 3446 excluded with reasons, 23 full-text articles were assessed for eligibility, and 7 studies (8 reports) were included. Unsuitability for surgery or refusal for surgery was the most common reason for the use of SBRT in early stage SCLC in the included studies. Variable patterns of SBRT-chemotherapy (CT) sequencing including concurrent, pre-CT and post-CT and radiation doses were noted. Within the reported studies overall survival (OS) at 1 year, 2 year and 3 year varied from 63% to 87%, 37% to 72%, and 35% to 72%, respectively. Distant metastasis was the most common pattern of failure ranging from 38% to 53%. There was no increase in the reported grade III toxicity. SBRT could be a potential option in stage I SCLC with comparable outcomes with no added toxicity. Acknowledging the limitations and absence of high-quality data, presently cautious interpretation is warranted and further studies are needed to establish the role of SBRT in SCLC. PMID- 30418180 TI - What's New in Dermatopathology: Inflammatory Dermatoses. AB - Inflammatory skin diseases encompass a vast array of conditions. The field continues to expand and evolve with resurgence of conditions, through newly recognized medication adverse effects, and via more detailed descriptions of known dermatoses. The importance of clinicopathologic correlation and an up to date knowledge of dermatologic conditions cannot be overstated. This review focuses on an array of recent important developments in the histologic diagnosis of inflammatory conditions that affect the skin. PMID- 30418181 TI - Discontinuation of Long-Term Proton Pump Inhibitor Therapy. PMID- 30418182 TI - CE: Original Research: Advance Care Planning: An Exploration of the Beliefs, Self Efficacy, Education, and Practices of RNs and LPNs. AB - : : Objective: This study compared the advance care planning (ACP)-related beliefs, sense of self-efficacy, education, and practices of RNs and LPNs. METHODS: Data were extrapolated from a larger multisite study that was conducted across seven counties in one midwestern state. The sample consisted of RNs and LPNs working in 29 urban skilled nursing facilities in zip code areas with greater than 10% African American residents. The survey tool, a self-administered written questionnaire, gathered data on participants' demographics and ACP related beliefs, sense of self-efficacy, education, and practices. The two main outcome variables were the percentage of residents with whom a nurse discussed ACP and the timing of the most recent such discussion. RESULTS: A total of 136 RNs and 178 LPNs completed the survey. Multivariate mixed-model analysis of the two main outcome variables showed that negative beliefs were not significantly associated with the percentage of residents with whom nurses discussed ACP but were significantly associated with the timing of the most recent ACP discussion. Having higher levels of ACP-related self-efficacy and education were significantly and positively associated with both outcome variables. RNs and LPNs did not differ significantly in their ACP-related beliefs, but RNs reported significantly higher levels of self-efficacy and education than LPNs did. CONCLUSIONS: There has been a paucity of research comparing RNs and LPNs regarding their ACP practices in skilled nursing facilities. Better education and policies that empower nurses to take a more active role are critical to increasing conversations about ACP. Further research exploring how the complementary roles of RNs and LPNs can be used to improve ACP processes and inform ACP policies is needed. PMID- 30418183 TI - CE: Managing Movement Disorders: A Clinical Review. AB - : Neuromuscular disorders are complex, difficult both to differentiate and to manage. Yet nurses, who encounter a symptomatically diverse neuromuscular patient population in various practice settings, are expected to be well versed in managing the variable associated symptoms of these disorders. Here the authors discuss how to assess such neuromuscular conditions as muscle tightness, spasticity, and clonus; the pathophysiology underlying each; and the available recommended treatments, an understanding of which is necessary for successful symptom management and clear provider-patient communication. PMID- 30418185 TI - "Fat-rich" (Spindle Cell-poor) Variants of Atypical Spindle Cell Lipomatous Tumors Show Similar Morphologic, Immunohistochemical and Molecular Features as "Dysplastic Lipomas" Are They Related Lesions? PMID- 30418184 TI - The Spectrum of EBV-positive Mucocutaneous Ulcer: A Study of 9 Cases. AB - We describe a series of 9 patients with Epstein-Barr virus (EBV)-positive mucocutaneous lymphoproliferative lesions that broadens the concept of EBV positive mucocutaneous ulcer. We report 5 female and 4 male patients, with an average age of 74 years (range, 55 to 87 y), 2 of whom were HIV-positive. The lesions were located in the oropharynx, skin, and rectal and/or genital mucosa. Histopathologically, 6 cases showed a polymorphic pattern and 3 had a monomorphic and diffuse one, with angiotropism in 4 cases (2 each with the polymorphic and monomorphic patterns). Three of the cases expressed PDL1. In addition to its presence in the neoplastic lymphoid cells, EBV was also detected in adjacent epithelial cells in an oropharyngeal lesion. All cases responded to local therapy or adapted systemic chemotherapy in selected cases. This series extends the spectrum of this disorder to include some HIV-positive cases, patients with multiple lesions confined to a single anatomic area, lesions with an angiocentric pattern, and some cases with monomorphous large-cell cytology. We discuss the differential clinicopathologic diagnosis of this disorder and that of classic EBV large B-cell lymphoma. PMID- 30418186 TI - Papillary Adenomas and Other Small Epithelial Tumors in the Kidney: An Autopsy Study. AB - The aim of this work was to study small neoplasms of the epithelium of the renal tubules; kidneys from 402 unselected autopsies were sectioned at 1 to 2 mm intervals. All lesions were examined histologically. A total of 232 papillary adenomas were found in 76 patients (19%), ranging from 1 to 35 adenomas/patient (mean: 3, median: 2). Patients with papillary adenomas were older (range: 27 to 90 y) (P<0.0001), more commonly smokers (P=0.01), and more frequently had glomerulosclerosis (P=0.0001) than those without. Papillary adenomas ranged in size from 0.5 to 5 mm (mean: 1.4, median: 1) and were morphologically classified in 4 subtypes. Type A adenomas consisting of papillae and/or tubules covered by cells with scant cytoplasm, often with psammoma bodies, were the most common (149 adenomas). In 30, the papillae were broad with lymphocytes in the cores (type B). Thirty were more cystic lined by columnar cells and contained macrophages and psammoma bodies (type C). Sixteen were composed of large eosinophilic cells with pseudostratified nuclei, occasionally near the apical membrane (type D). Four were unclassified. Mixtures of types were observed only once (3 adenomas in one patient, each composed of a mixture of types B and D). Other epithelial lesions included 31 adrenal rests, 5 oncocytomas, 2 clear cell papillary renal cell carcinomas, 2 tubulocystic renal cell carcinomas, and 2 acquired cystic disease associated renal cell carcinomas. In conclusion, papillary adenoma was the most common small epithelial neoplasm. The first type of papillary adenoma (type A) closely resembles papillary renal cell carcinoma, type 1, and the fourth (type D) resembles type 2. No other type of renal cell neoplasm was found (including clear cell renal cell carcinoma and chromophobe renal cell carcinoma). No nephrogenic rest was found. Angiomyolipomas and renomedullary interstitial cell tumors were found, and these findings have been reported in earlier papers. PMID- 30418187 TI - Central control of gastrointestinal motility. AB - PURPOSE OF REVIEW: This review summarizes the organization and structure of vagal neurocircuits controlling the upper gastrointestinal tract, and more recent studies investigating their role in the regulation of gastric motility under physiological, as well as pathophysiological, conditions. RECENT FINDINGS: Vagal neurocircuits regulating gastric functions are highly plastic, and open to modulation by a variety of inputs, both peripheral and central. Recent research in the fields of obesity, development, stress, and neurological disorders highlight the importance of central inputs onto these brainstem neurocircuits in the regulation of gastric motility. SUMMARY: Recognition of the pivotal role that the central nervous system exerts in the regulation, integration, and modulation of gastric motility should serve to encourage research into central mechanisms regulating peripheral motility disorders. PMID- 30418188 TI - Gastrointestinal hormones and regulation of gastric emptying. AB - PURPOSE OF THE REVIEW: This review examines the hormonal regulation of gastric emptying, a topic of increasing relevance, given the fact that medications that are analogs of some of these hormones or act as agonists at the hormonal receptors, are used in clinical practice for optimizing metabolic control in the treatment of type 2 diabetes and in obesity. FINDINGS: The major effects on gastric emptying result from actions of incretins, particularly gastric inhibitory polypeptide, glucagon-like peptide-1, and peptide tyrosine-tyrosine, the duodenal and pancreatic hormones, motilin, glucagon, and amylin, and the gastric orexigenic hormones, ghrelin and motilin. All of these hormones delay gastric emptying, except for ghrelin and motilin which accelerate gastric emptying. These effects on gastric emptying parallel the effects of the hormones on satiation (by those retarding emptying) and increase appetite by those that accelerate emptying. Indeed, in addition to the effects of these hormones on hypothalamic appetite centers and glycemic control, there is evidence that some of their biological effects are mediated through actions on the stomach, particularly with the glucagon-like peptide-1 analogs or agonists used in treating obesity. SUMMARY: Effects of gastrointestinal hormones on gastric emptying are increasingly recognized as important mediators of satiation and postprandial glycemic control. PMID- 30418189 TI - Pre, peri and posttransplant diabetes mellitus. AB - PURPOSE OF REVIEW: The leading cause of death in both chronic kidney disease (CKD) and renal transplant patients is cardiovascular events. Post-transplant diabetes mellitus (PTx-DM), which is a major cardiovascular risk factor, is a metabolic disorder that affects 5.5-60.2% of renal allograft recipients by 1-year posttransplant (PTx). PTx-DM has been associated with a negative impact on patient and graft outcomes and survival. RECENT FINDINGS: Individuals who develop PTx-DM are usually prone to this condition prior to and/or after developing CKD. Genetic factors, obesity, inflammation, medications and CKD all are risk factors for PTx-diabetes mellitus. The path to development of disease continues PTx frequently augmented by the use of diabetogenic maintenance immunosuppressive and some nonimmunosuppressive medications. These risk factors are usually associated with an increase in insulin resistance, a decrease in insulin gene expression and/or beta-cell dysfunction and apoptosis. SUMMARY: Some new anti-diabetes mellitus medications may help to improve the overall outcome; however, there is a real need for developing a preventive strategy. Identifying and targeting PTx-DM risk factors may help to guide the development of an effective programme. This could include the adoption of nondiabetogenic immunosuppressive protocols for high-risk patients. PMID- 30418190 TI - Extracorporeal Technologies Within the Social Media Labyrinth. PMID- 30418191 TI - Calcium Priming of the Central Venous Catheter Prevents a Drop in Ionized Calcium Concentration During Regional Citrate Anticoagulation. AB - During citrate-based Continuous Renal Replacement Therapy (CRRT), an infusion of calcium is necessary to replace the calcium lost in the effluent. The replacement takes place through a central venous catheter (CVC) that is primed with saline solution. Thus, we hypothesized a potential systemic anticoagulation because of unchelated citrate reaching the patient at the start of CRRT because of 0.42 ml of line dead space. In this pilot study, two subpopulations of 7 patients who underwent Continuous Veno-Venous Hemodiafiltration (150 ml/min of blood flow, 1500 ml/h dialysate, 1500 ml/h of citrate predilution) were studied. One had the CVC primed with saline, the second with calcium chloride. Calcium replacement rate was 6.3 +/- 0.2 ml/h. Ionized calcium concentration was studied over time in the two groups, in the group with saline priming we detected a transient period of hypocalcemia (ionized calcium concentration [iCa] < 1.00 mmol/L for the first 2 hours). In the subpopulation with the calcium priming, this was not present. No significant effect on filter life emerged. Priming of the catheter with calcium seems effective in avoiding a potential issue regarding citrate accumulation at the start of CRRT. More studies are needed to assess the clinical significance of this finding. PMID- 30418192 TI - Biomarkers for immune checkpoint inhibitors in advanced nonsmall cell lung cancer. AB - PURPOSE OF REVIEW: Immune checkpoint inhibitors have been established as a new class of anticancer drugs for patients with advanced nonsmall cell lung cancer. Predictive biomarkers might help to select those patients who will derive the greatest benefit from these expensive drugs. This review summarizes the current status of predictive biomarkers for immune checkpoint inhibitors in advanced nonsmall cell lung cancer. RECENT FINDING: Programmed death ligand 1 (PD-L1) staining on tumor cells and immune cells has been studied as a predictive biomarker for immune checkpoint inhibitors. Higher PD-L1 levels appeared to be associated with greater benefit from these drugs in many studies, although such an association was absent in some studies. Tumor mutational load was associated with benefit from the combination of nivolumab plus ipilimumab. Immune checkpoint inhibitors combined with first-line chemotherapy improved survival compared to chemotherapy alone. These improvements were clinically relevant also in patients with PD-L1 expression in less than 1% of tumor cells. SUMMARY: PD-L1 expression on tumor and immune cells and tumor mutational load allow better selection of patients for treatment with immune checkpoint inhibitors as single agents. The role of PD-L1 for the selection of patients for chemoimmuntherapy remains to be seen. PMID- 30418193 TI - Hydroxychavicol sensitizes imatinib-resistant chronic myelogenous leukemia cells to TRAIL-induced apoptosis by ROS-mediated IAP downregulation. AB - The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of cytokine superfamily, induces apoptosis in a number of tumor cells through the activation of extrinsic apoptotic pathway but shows little or no cytotoxicity toward normal cells. However some tumor cells are inherently resistant to TRAIL mediated apoptosis, which needs to be addressed to establish TRAIL as a potential chemotherapeutic drug. In this study, our aim was to manipulate TRAIL-apoptosis pathway by hydroxychavicol (HCH), a polyphenol from Piper betel leaf, for the induction of apoptosis in TRAIL resistant chronic myeloid leukemia cell. When imatinib-resistant K562 cells were treated with HCH, it made these K562 cells sensitive to TRAIL. It was observed that HCH downregulated antiapoptotic proteins XIAP and FLIP, whereas the expression of TRAIL receptors, DR4 and DR5, remains unchanged. Moreover, we observed that reactive oxygen species or ROS played a crucial role in the downregulation of FLIP and XIAP because ROS scavenger significantly reversed the decrease of XIAP, and FLIP. Ubiquitin-proteasome pathway was observed to play a crucial role in the downregulation of XIAP and FLIP, as proteasomal inhibitor MG132 significantly reversed the downregulation of XIAP and FLIP. In conclusion, this study demonstrates the combinatorial treatment of TRAIL and HCH as promising alternative therapeutic approach to treat the imatinib-resistant leukemia, which are also resistant to TRAIL. PMID- 30418194 TI - Clinicopathological significance of miR-27b targeting Golgi protein 73 in patients with hepatocellular carcinoma. AB - Using five bioinformatics analysis software, we identified Golgi protein 73 (GP73) as a putative target of microRNA-27b (miR-27b), which is closely related to various biological processes or diseases such as bone metabolism disease, adipose cell and muscle cell development, pulmonary hypertension, cervical cancer, and breast cancer. However, the clinical significance of miR-27b in hepatocellular carcinoma (HCC) is still unclear. The differential expression of miR-27b in HCC and adjacent normal liver tissues was measured by quantitative reverse transcription PCR. Our results showed that the expression of miR-27b in tumor tissues is lower than that in adjacent nontumor tissues. The expression of miR-27b was significantly lower in HCC tissues with high expression of GP73, when compared with adjacent nontumor tissues. Moreover, down-regulated expression of miR-27b was closely correlated with serum GP73, tumor-node-metastasis stage, tumor size, and portal vein thrombosis. GP73 mRNA might be a target of miR-27b. The 5-year overall survival rate of the low miR-27b expression group was significantly lower than that of the high miR-27b expression group. Moreover, multivariate analysis of prognostic factors, with a Cox proportional hazards model, showed that low miR-27b expression was a significant and independent predictor of poor survival in HCC. Hence, the abnormal expression of miR-27b might be related to the occurrence and development of tumors. Similarly, a study in the Cancer Genome Atlas database demonstrated that the expression of miR-27b in 50 normal individuals was 1.6 times higher than that of 372 patients with liver cancer. The overall survival rate of the low GP73 expression group (275 liver cancer patients) was significantly longer than that of the high GP73 expression group (90 normal individuals). MiR-27b suppresses the expression of GP73 and is therefore a potential prognostic biomarker and therapy target in HCC. PMID- 30418195 TI - Nonshaven Follicular Unit Extraction: Personal Experience. AB - Nonshaven follicular unit extraction (NS-FUE) is the most state-of-the-art surgical technique in the field of follicular unit hair transplantation. It is particularly appealing because donor area shaving, one of the most serious impediments for the patient, can be omitted. In this article, we present our surgical approach for NS-FUE. We selectively used the direct or the pretrimming method of NS-FUE according to indication, determined by considering the location and purpose of transplantation, the condition of the recipient site, and the patient's preference. A total of 658 patients underwent NS-FUE. Of these, 17 had pubic atrichia, 2 had pubic atrichia and also received hairline correction surgery, 6 received eyebrow transplantation, 19 had female pattern hair loss, 362 had male pattern baldness (MPB), 2 had MPB and also required eyebrow transplantation, 3 received hair transplantation for MPB and scalp scar, 9 underwent male hairline correction surgery, 192 underwent female hairline surgery, and 46 received hair transplantation for scalp scar. The average numbers of transplanted grafts were 573 for atrichia, 1300 for atrichia and hairline correction performed successively, 240 for eyebrow transplantation, 996 for female pattern hair loss, 1408 for MPB (with a maximum of 3000), 1050 for MPB and eyebrow transplantation, 998 for female pattern hair loss (with a maximum of 1910), and 141 for scalp scar. On average, the total transection rate was 8.2%, and the calculated density was 2.2.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30418196 TI - Update on obstructive sleep apnea for neuro-ophthalmology. AB - PURPOSE OF REVIEW: Obstructive sleep apnea (OSA) is increasing in prevalence. The intermittent hypoxia of OSA has wide-ranging effects on a patient's general health outcomes. However, gold-standard investigations and treatment are expensive and a significant burden on patients. Therefore, OSA research remains focused on improving the means of diagnosing and treating OSA, in high-risk associated conditions. This review is to provide an update on the advances in the field of OSA. RECENT FINDINGS: There has been recent debate about the best practice for diagnosis and treatment of OSA. Further work has been done on conditions associated with OSA including hypertension, atherosclerosis, various types of dementia and intracranial aneurysms. Inflammatory and vascular risk factors associated with OSA increase stroke risk and alter outcomes for recovery. OSA should definitely be considered in patients presenting with nonarteritic anterior ischemic optic neuropathy, and perhaps those with intracranial hypertension. SUMMARY: Newer home-based sleep-apnea testing can be implemented via physician clinics, with oversight by a certified sleep physician. Although continuous positive airway pressure (CPAP) is the gold-standard, management should include diet and exercise. It is important to test for, and treat OSA in patients with a range of neurological diseases. However, further studies into the long-term impact of CPAP on health outcomes are still needed. PMID- 30418197 TI - The role of optical coherence tomography in the evaluation of compressive optic neuropathies. AB - PURPOSE OF REVIEW: Optical coherence tomography (OCT) is a noninvasive imaging tool routinely used in ophthalmology that provides cross-sectional images of the retina. Compression of the anterior visual pathways results in progressive thinning of the retinal nerve fiber layer (RNFL) and macular ganglion cell complex (GCC) and this review will highlight the utility of OCT in evaluating patients with this condition. RECENT FINDINGS: The RNFL and macular GCC have been found to highly correlate with visual function in patients with compressive optic neuropathies. Preoperative RNFL and macular GCC thickness have emerged as the most reliable and consistent prognostic factors for visual recovery after surgery. Patients with an otherwise normal neuroophthalmic examination, including automated perimetry, may have macular GCC or RNFL thinning as the only manifestation of compression, enabling compressive optic neuropathies to be diagnosed at an earlier stage and managed accordingly. SUMMARY: Recent findings indicate that OCT is an important tool in the evaluation of patients with compressive optic neuropathies, particularly for prognosis in patients with visual field defects and diagnosis in patients with preserved or mildly reduced visual function. Anatomical changes detected by OCT may precede visual loss and allow for earlier diagnosis and presumably better visual outcomes. PMID- 30418198 TI - Effectiveness of Field-Based Resistance Training Protocols on Hip Muscle Strength Among Young Elite Football Players. AB - OBJECTIVE: The objective of this study was to examine the effects of an 8-week progressive resistance training program on hip joint muscles' strength measures, using the Copenhagen adduction (CA) and the sliding hip (SH) exercises. DESIGN: Prospective randomized controlled trial. SETTING: Sport training and medical centers. PARTICIPANTS: Forty-two young male football athletes (age 17.5 +/- 1.1 years; height 178.3 +/- 3.2 cm; body mass 66.1 +/- 8.6 kg) allocated to a CA, SH, and matched control (C) group. INTERVENTIONS: Two weekly sessions of CA and SH. MAIN OUTCOMES MEASURES: Maximal eccentric strength test for the hip adductor (EHAD) and maximal eccentric strength test for the hip abductor (EHAB) muscles, and the relative EHAD/EHAB ratio assessed through a break test in the side-lying position. RESULTS: No significant differences between groups were found at baseline for any of the assessed variables (all P > 0.053). The CA group had a significant strength increase in the right and left leg (d = 2.11, d = 1.9, respectively). The SH group also had a significant strength increase in the right and left leg (d = 1.68 and d = 1.67, respectively). The CA group presented EHAD/EHAB improvements in the right and left leg (d = 0.84 and d = 1.14, respectively). The SH group also presented EHAD/EHAB improvements in the right and left leg (d = 1.34 and d = 1.44, respectively). CONCLUSIONS: Both exercises' protocols were effective in inducing significant increases on EHAD, EHAB, and EHAD/EHAB ratio when compared with the control group. Practitioners should be aware of the training effectiveness of both protocols. PMID- 30418199 TI - Practical Management: Brief Physical Examination for Sport-Related Concussion in the Outpatient Setting. AB - This article presents a brief, focused physical examination [PE, the Buffalo Concussion Physical Examination (BCPE)] for sport-related concussion (SRC) to be considered for use in the outpatient setting by sports medicine physicians, pediatricians, and primary-care physicians. This companion paper describes how to perform the PE, which was derived in a separate study presented in this journal. It is envisioned for use at the initial and follow-up outpatient visits both for acute concussions and in patients with prolonged symptoms. A pertinent PE, combined with other assessments, can help identify specific treatment targets in those with persistent symptoms after SRC. The BCPE includes orthostatic vital signs and examinations of the cranial nerves, oculomotor/ophthalmologic, cervical, and vestibular systems. Supplementary tests, including testing for exercise tolerance and neurocognitive function, may be performed if indicated. It is recommended that a PE be performed at the initial visit and every 1 to 2 weeks after SRC. On return of symptoms, cognition, and the PE to baseline, as well as normalization of any supplementary tests, patients can begin a return to play program. PMID- 30418200 TI - The pharmacology of executive functioning: part 2: research reports. PMID- 30418201 TI - Announcement of Special Issues for 2019: Stress and Neuroinflammation. PMID- 30418202 TI - Response: "Early Acute Mesenteric Ischemia: Many Rivers to Cross". PMID- 30418204 TI - Reply. PMID- 30418203 TI - Association of MRI T2 Signal Intensity With Desmoid Tumor Progression During Active Observation: A Retrospective Cohort Study. AB - OBJECTIVE: The aim of this study was to identify predictors of desmoid progression during observation. SUMMARY OF BACKGROUND DATA: Untreated desmoids can grow, remain stable, or regress, but reliable predictors of behavior have not been identified. METHODS: Primary or recurrent desmoid patients were identified retrospectively from an institutional database. In those managed with active observation who underwent serial magnetic resonance imaging (MRIs) with T2 weighted sequences, baseline tumor size was recorded, and 2 radiologists independently estimated the percentage of tumor volume showing hyperintense T2 signal at baseline. Associations of clinical or radiographic characteristics with progression-free survival (PFS; by RECIST) were evaluated by Cox regression and Kaplan-Meier statistics. RESULTS: Among 160 patients with desmoids, 72 were managed with observation, and 37 of these had serial MRI available for review. Among these 37 patients, median age was 35 years and median tumor size was 4.7 cm; all tumors were extra-abdominal (41% in abdominal wall). Although PFS was not associated with size, site, or age, it was strongly associated with hyperintense T2 signal in >=90% versus <90% of baseline tumor volume (as defined by the "test" radiologist; hazard ratio = 11.3, P = 0.003). For patients in the >=90% group (n = 20), 1-year PFS was 55%, compared with 94% in the <90% group (n = 17). The percentage of baseline tumor volume with hyperintense T2 signal defined by a validation radiologist correlated with results of the test radiologist (rho = 0.75). CONCLUSION: The percent tumor volume characterized by hyperintense T2 signal is associated with desmoid progression during observation and may help distinguish patients who would benefit from early intervention from those who may be reliably observed. PMID- 30418205 TI - Feasibility and Value of the Critical View of Safety in Difficult Cholecystectomies. PMID- 30418206 TI - Multimodal Patient Blood Management Program Based on a Three-pillar Strategy: A Systematic Review and Meta-analysis. AB - OBJECTIVES: To determine whether a multidisciplinary, multimodal Patient Blood Management (PBM) program for patients undergoing surgery is effective in reducing perioperative complication rate, and thereby is effective in improving clinical outcome. BACKGROUND: PBM is a medical concept with the focus on a comprehensive anemia management, to minimize iatrogenic (unnecessary) blood loss, and to harness and optimize patient-specific physiological tolerance of anemia. METHODS: A systematic review and meta-analysis was performed. Eligible studies had to address each of the 3 PBM pillars with at least 1 measure per pillar, for example, preoperative anemia management plus cell salvage plus rational transfusion strategy. The study protocol has been registered with PROSPERO (CRD42017079217). RESULTS: Seventeen studies comprising 235,779 surgical patients were included in this meta-analysis (100,886 pre-PBM group and 134,893 PBM group). Implementation of PBM significantly reduced transfusion rates by 39% [risk ratio (RR) 0.61, 95% confidence interval (CI) 0.55-0.68, P < 0.00001], 0.43 red blood cell units per patient (mean difference -0.43, 95% CI -0.54 to -0.31, P < 0.00001), hospital length of stay (mean difference -0.45, 95% CI -0.65 to 0.25, P < 0,00001), total number of complications (RR 0.80, 95% CI 0.74-0.88, P <0.00001), and mortality rate (RR 0.89, 95% CI 0.80-0.98, P = 0.02). CONCLUSIONS: Overall, a comprehensive PBM program addressing all 3 PBM pillars is associated with reduced transfusion need of red blood cell units, lower complication and mortality rate, and thereby improving clinical outcome. Thus, this first meta analysis investigating a multimodal approach should motivate all executives and health care providers to support further PBM activities.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0. PMID- 30418207 TI - Evolution of a Schmorl's Node and a Degenerative Osteophyte on Sequential 68Ga DOTATATE PET/CT Scans: Potential Pitfalls in Neuroendocrine Tumor Imaging. AB - Schmorl's node (SN) arises from the herniation of the nucleus pulposus of the disc through the cartilaginous endplate into the body of the vertebra. Our report describes a patient with carcinoid tumor who underwent a series of Ga-DOTATATE PET/CT scans for follow-up, demonstrating gradually increasing focal vertebral uptake in absence of CT abnormality, suspicious for a metastasis. Both CT and MRI eventually revealed classical findings of a SN. Also observed in the same vertebra is a degenerative osteophyte showing intense Ga-DOTATATE uptake. This interesting case shows 2 benign spinal lesions, which potentially can simulate bone metastasis in patients with neuroendocrine tumors. PMID- 30418208 TI - Synchronous Metastatic Breast Carcinoma and Parathyroid Adenoma on 18F-FDG PET/CT and 99mTc-Sestamibi Imaging. AB - In addition to nuclear cardiac and breast imaging, Tc-sestamibi scintigraphy is often used to localize parathyroid adenomas. F- fluorodeoxyglucose (FDG) PET is heavily utilized in oncology, although its use in identifying parathyroid adenomas is limited. We describe a case of a 57-year-old woman who underwent parathyroid scintigraphy and F-FDG PET/CT in the same week due to hyperparathyroidism and an enlarging breast mass, respectively. A right paratracheal mediastinal mass that otherwise would be suspicious for nodal metastases by CT alone was correctly identified to be an ectopic parathyroid adenoma using a combination of the nuclear medicine studies performed. PMID- 30418209 TI - Sentinel Lymph Node Biopsy in Small Papillary Thyroid Cancer: A Meta-analysis. AB - PURPOSE: The aim of this study was to compare reported results on available techniques for sentinel lymph node detection rate (SDR) in papillary thyroid cancer (PTC). METHODS: The MEDLINE database was searched via a PubMed interface to identify original articles regarding sentinel lymph node biopsy (SNB) in thyroid cancer. Studies were stratified according to the sentinel lymph node (SLN) detection technique: vital-dye (VD), Tc-nanocolloid planar lymphoscintigraphy with the use of intraoperative hand-held gamma probes (LS), both Tc-nanocolloid planar lymphoscintigraphy with intraoperative use of hand held gamma probe and VD (LS + VD), Tc-nanocolloid planar lymphoscintigraphy with the additional contribution of preoperative SPECT/CT, and intraoperative use of hand-held gamma probe (LS-SPECT/CT). Pooled SDR values were presented with a 95% confidence interval (CI) for each SLN detection techniques. A Z-test was used to compare pooled SDR estimates. False-negative rates were summarized for each method. RESULTS: Forty-five studies were included. Overall SDRs for the VD, LS, LS + VD, and LS-SPECT/CT techniques were 83% (95% CI, 77%-88%; I = 78%), 96% (95% CI, 90%-98%; I = 68%), 87% (95% CI, 65%-96%; I = 75%), and 93% (95% CI, 86%-97%; I = 0%), respectively. False-negative rates were 0% to 38%, 0% to 40%, 0% to 17%, and 7% to 8%, respectively. CONCLUSIONS: In patients with PTC, Tc-nanocolloids offer a higher SDR than that of the VD technique. The addition of SPECT/CT improved identification of metastatic SLNs outside the central neck compartment. PMID- 30418210 TI - Two Cases of 188Re Microspheres for Inoperable Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most lethal malignancies. Often, patients present with inoperable and advanced disease. Selective internal radionuclide therapy offers prolonged survival and improved quality of life by delivering high radiation dose to the tumor with minimal complications. We report 2 inoperable cases of HCC treated with therapeutic dose of indigenously developed Re microspheres delivered to the hepatic lesions by transarterial catheterization. Follow-up CT revealed necrosis within the lesion, suggesting response to selective internal radionuclide therapy. Re microspheres may be a potential treatment option for inoperable HCC with or without portal vein thrombosis. PMID- 30418211 TI - A Diagnostic Algorithm That Combines Quantitative 18F-FDG PET Parameters and Contrast-Enhanced CT Improves Posttherapeutic Locoregional Restaging and Prognostication of Survival in Patients With Esophageal Cancer. AB - PURPOSE: The aim of this study was to determine whether the combination of contrast-enhanced CT (CE-CT) and quantitative F-FDG PET parameters improves locoregional restaging in esophageal cancer (EC) after neoadjuvant therapy. METHODS: Eighty-eight consecutive patients with locally advanced esophageal cancer, who underwent restaging after neoadjuvant chemotherapy or chemoradiotherapy before esophagectomy, were included in this retrospective study. The diagnostic accuracy of CE-CT, visual F-FDG PET/CT (vPET/CT), and quantitative PET parameters was assessed for T and N staging. Histopathology was used as the reference standard. The prognostic value for recurrence-free survival, cancer-specific survival, and overall survival was assessed using Cox regression analysis. RESULTS: Sensitivity, positive predictive value, and accuracy were 78.8%, 70.2%, and 59.0% (CE-CT), and 81.1%, 81.1%, and 68.2% (vPET/CT) for T staging as well as 59.5%, 75.9%, and 50.0% (CE-CT), and 70.2%, 93.7%, and 67.0% (vPET/CT) for N staging, respectively. Tumor length and metabolic tumor volume (MTV) exhibited an incremental increase with advancing T stages (P = 0.002 and 0.038). Contrast-enhanced CT had the highest sensitivity to differentiate advanced T stages (T3/4 vs 0-2; area under the receiver operating curve [AUC], 0.86; P < 0.001), whereas MTV at a threshold of 5.8 mL had the highest sensitivity to detect complete response (T0 vs 1-4; AUC, 0.77; P = 0.002). Contrast-enhanced CT and MTV combined had an even superior accuracy to predict complete response (AUC, 0.82; P < 0.001). The imaging American Joint Committee on Cancer stage provided a better prognostication of recurrence-free survival, cancer-specific survival, and overall survival than either T stage, N stage derived from CE-CT or vPET/CT, or quantitative PET parameters alone. CONCLUSIONS: Combined CE-CT and MTV had the highest diagnostic accuracy to identify the posttherapeutic T stage, allowing for robust prediction of recurrence and survival. PMID- 30418212 TI - Contribution of Baroreceptor Function to Pain Perception and Perioperative Outcomes. AB - Baroreceptors are mechanosensitive elements of the peripheral nervous system that maintain homeostasis by coordinating physiologic responses to external and internal stimuli. While it is recognized that carotid and cardiopulmonary baroreceptor reflexes modulate autonomic output to mitigate excessive fluctuations in arterial blood pressure and to maintain intravascular volume, increasing evidence suggests that baroreflex pathways also project to key regions of the central nervous system that regulate somatosensory, somatomotor, and central nervous system arousal. In addition to maintaining autonomic homeostasis, baroreceptor activity modulates the perception of pain, as well as neuroimmune, neuroendocrine, and cognitive responses to physical and psychologic stressors. This review summarizes the role that baroreceptor pathways play in modulating acute and chronic pain perception. The contribution of baroreceptor function to postoperative outcomes is also presented. Finally, methods that enhance baroreceptor function, which hold promise in improving postoperative and pain management outcomes, are presented. PMID- 30418213 TI - Low Incidence of Biphasic Allergic Reactions in Patients Admitted to Intensive Care after Anaphylaxis. AB - BACKGROUND: Biphasic allergic reactions-recurrence of allergy symptoms after a symptom-free period-are reported to occur in 1 to 23% of allergic reactions. Patients admitted to an intensive care unit after anaphylaxis potentially have more severe reactions and a higher risk of biphasic allergic reactions. The purpose of this study was to examine incidence, triggers, symptoms, and treatment of biphasic allergic reactions, in patients admitted to an intensive care unit. METHODS: Records of patients admitted to intensive care units with anaphylaxis from 2011 to 2014 were reviewed. Only patients with a reaction fulfilling internationally accepted criteria for anaphylaxis were included. Potential biphasic allergic reactions, defined as renewed allergy symptoms 1 to 72 h after initial symptoms had resolved, without further exposure to the trigger, were identified. RESULTS: A total of 83 cases of anaphylaxis were identified, and the most frequent triggers were medications (58 of 83 [70%]). Skin symptoms occurred in 69 (83%) cases, and circulatory and respiratory symptoms in 48 (58%) and 45 (54%) cases, respectively. In total, 82 (99%), 80 (96%), and 66 (80%) were treated with antihistamines, corticosteroids, and epinephrine, respectively. Only 10 patients presented with one or more relevant symptoms after the initial allergic reaction. Of these, three were possible, and one was a probable biphasic allergic reaction, giving a total incidence of 4 of 83 (4.8% [95% CI, 1.6 to 12.5]) or 1 of 83 (1.2% [95% CI, 0.1 to 7.46]), respectively. All cases were mild, presenting with skin symptoms only, occurring on average 14 h after initial reactions. CONCLUSIONS: The authors observed a low incidence of biphasic reactions in patients admitted to an intensive care unit after anaphylaxis, at a rate equivalent to that reported in other patient groups. PMID- 30418214 TI - Analgesic Effects of Hydromorphone versus Buprenorphine in Buprenorphine maintained Individuals. AB - WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Managing acute pain in buprenorphine-maintained individuals in emergency or perioperative settings is a significant challenge. This study compared analgesic and abuse liability effects of adjunct hydromorphone and buprenorphine using quantitative sensory testing, a model of acute clinical pain, in persons maintained on 12 to 16 mg sublingual buprenorphine/naloxone. METHODS: Participants (N = 13) were enrolled in a randomized within-subject, double-blind, placebo-controlled three-session experiment. Each session used a cumulative dosing design with four IV injections (4, 4, 8, and 16 mg of hydromorphone or 4, 4, 8, and 16 mg of buprenorphine); quantitative sensory testing and abuse liability assessments were measured at baseline and after each injection. The primary analgesia outcome was change from baseline cold pressor testing; secondary outcomes included thermal and pressure pain testing, as well as subjective drug effects and adverse events. RESULTS: A significant two-way interaction between study drug condition and dose was exhibited in cold pressor threshold (F10,110 = 2.14, P = 0.027) and tolerance (F10,110 = 2.69, P = 0.006). Compared to after placebo, participants displayed increased cold pressor threshold from baseline after cumulative doses of 32 mg of IV hydromorphone (means +/- SD) (10 +/- 14 s, P = 0.035) and 32 mg of buprenorphine (3 +/- 5 s, P = 0.0.39) and in cold pressor tolerance after cumulative doses of 16 mg (18 +/- 24 s, P = 0.018) and 32 mg (48 +/- 73 s, P = 0.041) IV hydromorphone; cold pressor tolerance scores were not significant for 16 mg (1 +/- 15 s, P = 0.619) or 32 mg (7 +/- 16 s, P = 0.066) buprenorphine. Hydromorphone and buprenorphine compared with placebo showed greater ratings on subjective measures of high, any drug effects, good effects, and drug liking. Adverse events were more frequent during the hydromorphone compared with buprenorphine and placebo conditions for nausea, pruritus, sedation, and vomiting. CONCLUSIONS: In this acute clinical pain model, high doses of IV hydromorphone (16 to 32 mg) were most effective in achieving analgesia but also displayed higher abuse liability and more frequent adverse events. Cold pressor testing was the most consistent measure of opioid related analgesia. PMID- 30418215 TI - Morphine Exacerbates Postfracture Nociceptive Sensitization, Functional Impairment, and Microglial Activation in Mice. AB - WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Emerging evidence suggests that opioid use immediately after surgery and trauma may worsen outcomes. In these studies, the authors aimed to determine whether morphine administered for a clinically relevant time period (7 days) in a tibia fracture orthopedic surgery model had adverse effects on postoperative recovery. METHODS: Mice were given morphine twice daily for 7 days after unilateral tibial fracture and intramedullary pin fixation to model orthopedic surgery and limb trauma. Mechanical allodynia, limb-specific weight bearing, gait changes, memory, and anxiety were measured after injury. In addition, spinal cord gene expression changes as well as glial activation were measured. Finally, the authors assessed the effects of a selective Toll-like receptor 4 antagonist, TAK 242, on nociceptive and functional changes after injury. RESULTS: Tibial fracture caused several weeks of mechanical nociceptive sensitization (F(1, 216) = 573.38, P < 0.001, fracture + vehicle vs. sham + vehicle, n = 10 per group), and this change was exacerbated by the perioperative administration of morphine (F(1, 216) = 71.61, P < 0.001, fracture + morphine vs. fracture + vehicle, n = 10 per group). In additional testing, injured limb weight bearing, gait, and object location memory were worse in morphine-treated fracture mice than in untreated fracture mice. Postfracture expression levels of several genes previously associated with opioid-induced hyperalgesia, including brain-derived neurotrophic factor and prodynorphin, were unchanged, but neuroinflammation involving Toll like receptor 4 receptor-expressing microglia was observed (6.8 +/- 1.5 [mean +/- SD] cells per high-power field for fracture + vehicle vs. 12 +/- 2.8 fracture + morphine, P < 0.001, n = 8 per /group). Treatment with a Toll-like receptor 4 antagonist TAK242 improved nociceptive sensitization for about 2 weeks in morphine-treated fracture mice (F(1, 198) = 73.36, P < 0.001, fracture + morphine + TAK242 vs. fracture + morphine, n = 10 per group). CONCLUSIONS: Morphine treatment beginning at the time of injury impairs nociceptive recovery and other outcomes. Measures preventing glial activation through Toll-like receptor 4 signaling may reduce the adverse consequences of postoperative opioid administration. PMID- 30418216 TI - Endovascular Retrieval of Broken Arterial Cannulas. PMID- 30418217 TI - Long-term Impact of Crystalloid versus Colloid Solutions on Renal Function and Disability-free Survival after Major Abdominal Surgery. AB - WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: The authors recently demonstrated that administration of balanced hydroxyethyl starch solution as part of intraoperative goal-directed fluid therapy was associated with better short-term outcomes than administration of a balanced crystalloid solution in patients having major open abdominal surgery. In the present study, a 1-yr follow-up of renal and disability outcomes in these patients was performed. METHODS: All patients enrolled in the earlier study were followed up 1 yr after surgery for renal function and disability using the World Health Organization Disability Assessment Schedule 2.0 (WHODAS). The main outcome measure was the estimated glomerular filtration rate. Other outcomes were serum creatinine, urea, pruritus, and WHODAS score. Groups were compared on a complete case analysis basis, and modern imputation methods were then used in mixed-model regressions to assess the stability of the findings taking into account the missing data. RESULTS: Of the 160 patients enrolled in the original study, follow up data were obtained for renal function in 129 and for WHODAS score in 114. There were no statistically significant differences in estimated glomerular filtration rate at 1 yr (ml min 1.73 m): 80 [65 to 92] for crystalloids versus 74 [64 to 94] for colloids; 95% CI [-10 to 7], P = 0.624. However, the WHODAS score (%) was statistically significantly lower in the colloid than in the crystalloid group (2.7 [0 to 12] vs. 7.6 [1.3 to 18]; P = 0.015), and disability-free survival was higher (79% vs. 60%; 95% CI [2 to 39]; P = 0.024). CONCLUSIONS: In patients undergoing major open abdominal surgery, there was no evidence of a statistically significant difference in long-term renal function between a balanced hydroxyethyl starch and a balanced crystalloid solution used as part of intraoperative goal-directed fluid therapy, although there was only limited power to rule out a clinically significant difference. However, disability-free survival was significantly higher in the colloid than in the crystalloid group. PMID- 30418218 TI - Timing of Muscle Activation Is Altered During Single-Leg Landing Tasks After Anterior Cruciate Ligament Reconstruction at the Time of Return to Sport. AB - OBJECTIVES: It is well known that alterations in landing mechanics persist for years after anterior cruciate ligament reconstruction (ACL-R). Nevertheless, existing literature is controversial in reporting successful or unsuccessful recovery of prelanding muscle activation timing after ACL-R. The study aimed at comparing myoelectric and kinematic patterns during landing tasks between ACL-R and healthy subjects. DESIGN: Cross-sectional study. SETTING: Institutional research laboratory. PATIENTS AND INTERVENTION: Fifteen male athletes after ACL-R using patellar tendon and 11 using hamstrings autograft at the time of return to sport were recruited. Fifteen healthy athletes served as control group. Participants performed 4 different single-leg landing tasks arriving onto a force plate. MAIN OUTCOME MEASURES: Electromyographic (EMG) activity of knee extensors and flexors, normalized vertical ground reaction force (vGRF), and knee angular displacement were recorded. RESULTS: In all the tasks, preimpact EMG duration was longer in ACL-R (112 +/- 28 ms in the knee extensors; 200 +/- 34 ms in the knee flexors) compared with healthy participants (74 +/- 19 ms in the knee extensors; 153 +/- 29 ms in the knee flexors; P < 0.05). Initial contact (IC) and maximum postimpact knee angle were lower in ACL-R (9 +/- 7 degrees at IC; 39 +/- 12 degrees at maximum flexion) compared with healthy participants (17 +/- 9 degrees at IC; 52 +/- 15 degrees at maximum flexion; P < 0.05). Normalized vGRF was higher in ACL-R compared with healthy participants (3.4 +/- 0.5 and 2.7 +/- 0.6; P < 0.05). CONCLUSIONS: At the time of return to sport, ACL-R subjects showed altered motor control strategies of single-leg landings. These alterations may lead to uncoordinated movement, hence increasing the risk of reinjury. PMID- 30418219 TI - Derivation of a Focused, Brief Concussion Physical Examination for Adolescents With Sport-Related Concussion. AB - OBJECTIVE: To describe the derivation of a brief but pertinent physical examination (PE) for adolescents who have sustained sport-related concussion (SRC). DESIGN: Prospective cohort. SETTING: University concussion management clinic. PARTICIPANTS: Acutely concussed (AC, n = 52, 15.5 +/- 1.4 years, 4.4 +/- 2 days since injury, 26.2 +/- 38 days to recovery, 71% males) and healthy control (HC) adolescents (n = 30, 15.8 +/- 1.4 years, 73% males). INTERVENTION: Acutely concussed had a PE on visit 1 and were retested at visit 2 (13.6 +/- 1 day after visit 1). Acutely concussed were further characterized as normal recovery (NR, n = 41, 15.5 +/- 1.5 years, recovery time 13.0 +/- 7 days) and delayed recovery (DR, n = 11, 15.5 +/- 1.2 years, recovery time 75.4 +/- 63 days). MAIN OUTCOME MEASURE: Physical examination findings, including cervical, vestibular, and oculomotor systems. RESULTS: Visit 1 abnormal PE signs were significantly greater in AC versus HC (2.79 +/- 2.13 vs 0.07 +/- 0.37, P < 0.0001) but not in NR versus DR (2.61 +/- 2.2 vs 3.45 +/- 1.8, P = 0.246). Visit 2 abnormal PE signs differentiated NR versus DR (0.17 +/- 0.7 vs 2.45 +/- 2.1, P < 0.0001). CONCLUSIONS: A brief focused PE can help to diagnose SRC, establish recovery, and may have prognostic value. PMID- 30418222 TI - Isolated Bilateral Ear and Scalp Rash After Cytarabine Therapy for Acute Myelogenous Leukemia: A Report and Literature Review. PMID- 30418220 TI - Disagreement Between Clinicians and Score in Decision-Making Capacity of Critically Ill Patients. AB - OBJECTIVES: To compare the assessment of decision-making capacity of ICU patients by attending clinicians (physicians, nurses, and residents) with a capacity score measured by the Mini-Mental Status Examination, completed by Aid to Capacity Evaluation if necessary. The primary outcome was agreement between physicians' assessments and the score. Secondary outcomes were agreement between nurses' or residents' assessments and the score and identification of factors associated with disagreement. DESIGN: A 1-day prevalence study. SETTING: Nineteen ICUs in France. SUBJECTS: All patients hospitalized in the ICU on the study day and the attending clinicians. INTERVENTIONS: The decision-making capacity of patients was assessed by the attending clinicians and independently by an observer using the score. MEASUREMENTS AND MAIN RESULTS: A total of 206 patients were assessed by 213 attending clinicians (57 physicians, 97 nurses, and 59 residents). Physicians designated more patients as having decision-making capacity (n = 92/206 [45%]) than score (n = 34/206 [17%]; absolute difference 28% [95% CI, 20-37%]; p = 0.001). There was a high disagreement between assessments of all clinicians and score (Kappa coefficient 0.39 [95% CI, 0.29-0.50] for physicians; 0.39 [95% CI, 0.27-0.52] for nurses; and 0.46 [95% CI, 0.35-0.58] for residents). The main factor associated with disagreement was a Glasgow Coma Scale score between 10 and 15 (odds ratio, 2.92 [1.18-7.19], p = 0.02 for physicians; 4.97 [1.50-16.45], p = 0.01 for nurses; and 3.39 [1.12-10.29], p = 0.03 for residents) without differentiating between the Glasgow Coma Scale scores from 10 to 15. CONCLUSIONS: The decision-making capacity of ICU patients was largely overestimated by all attending clinicians as compared with a score. The main factor associated with disagreement was a Glasgow Coma Scale score between 10 and 15, suggesting that clinicians confused consciousness with decision-making capacity. PMID- 30418221 TI - Effect of beta-Lactam Plus Macrolide Versus Fluoroquinolone on 30-Day Readmissions for Community-Acquired Pneumonia. AB - BACKGROUND: Antibiotic therapy with a macrolide and beta-lactam or a fluoroquinolone for the empirical treatment of community-acquired pneumonia (CAP) in an inpatient non-intensive care setting is recommended per guidelines. Studies show that these treatments have similar outcomes, including death, adverse effects, and bacterial eradication. However, a comparison of 30-day readmission rates between these treatments is limited. STUDY QUESTION: To determine whether 30-day readmissions for patients treated for CAP in a regional hospital differed between a fluoroquinolone monotherapy and a beta-lactam plus macrolide combination therapy. STUDY DESIGN: Retrospective cohort study of patients aged >=18 years with a CAP diagnosis who were admitted to the same regional hospital from December 1, 2011, through December 1, 2016. MEASURES AND OUTCOMES: Patients receiving a third-generation cephalosporin plus macrolide were compared with those receiving a respiratory fluoroquinolone. Exclusion criteria were concurrent or recent use of the study antibiotics; death, transfer, or transition to hospice; and diagnosis of hospital-acquired pneumonia or health care-associated pneumonia. The collected data were 30-day readmission rates, antibiotic regimens, demographic characteristics, and pneumonia severity index and comorbidity scores. Association between treatment group and readmissions was assessed with logistic regression. Association between readmissions and individual data points between the 2 treatment groups was calculated with multivariate regression and odds ratio (95% confidence interval). RESULTS: Of 432 patients, 171 met inclusion criteria (fluoroquinolone group, n = 101; beta-lactam plus macrolide group, n = 70). Thirty-day readmissions were not significantly different between the fluoroquinolone group and beta-lactam plus macrolide group (P = 0.58). Increased 30-day readmissions were independently associated with male sex and hospital length of stay (P < 0.05). Length of stay was approximately 3 days and did not differ between treatment groups. CONCLUSIONS: No difference was seen in 30-day readmissions between CAP patients who received fluoroquinolone monotherapy and those who received beta-lactam plus macrolide combination therapy. PMID- 30418223 TI - Symptomatic Bradycardia on Propafenone After Discontinuation of Amiodarone. PMID- 30418224 TI - Flurbiprofen-Associated Hemolytic Anemia. PMID- 30418225 TI - Combination of Quetiapine Immediate Release and XR for H1-Antihistamine Refractory Chronic Spontaneous Urticaria Comorbid With Depressive Disorder: A Case Report. PMID- 30418226 TI - Correlation of Cardiovascular Risk Factors and Biomarkers With Platelet Reactivity in Coronary Artery Disease. AB - BACKGROUND: Low response to aspirin, aspirin resistance, and high platelet reactivity on aspirin treatment are similar names for lack of response to block arachidonic acid-induced aggregation with aspirin therapy and have an important role in the evolution of coronary artery disease (CAD) with thromboembolic events. STUDY QUESTION: Was to evaluate the correlation between cardiovascular risk factors, biomarkers, and low response to aspirin in patients (pts) with CAD. STUDY DESIGN: Four hundred pts with CAD were divided into 8 groups of study, consistent with the type of CAD and low response to aspirin. Cardiovascular risk factors and biomarkers-including some of high platelet reactivity, endothelial dysfunction, hypercoagulability, and oxidative stress-were evaluated in correlation with low response to aspirin, defined as on treatment aspirin test (ASPItest) >30U by multiple electrode platelet aggregometry. RESULTS: In patients with CAD, low response to aspirin was significantly correlated with age older than 65 years, smoking, presence of diabetes mellitus, body mass index >25, hypertension, previous aspirin treatment, low response to clopidogrel, high mean platelets volume and von Willebrand factor activity, low flow-mediated vasodilation, and total antioxidant status (P < 0.01). In unstable angina patients, low response to aspirin was significantly correlated with male sex (P < 0.03). Incidence of other hypercoagulability biomarkers-S Protein, C Protein, Antithrombin III, and V Factor Leiden resistance to activated protein C-was low and not correlated with low response to aspirin. CONCLUSIONS: In CAD, low response to aspirin was significantly correlated with age older than 65 years, smoking, presence of diabetes mellitus, body mass index I >25, hypertension, previous aspirin treatment, and only in unstable angina with male sex. Low response to aspirin was also statistically associated with low response to clopidogrel, high mean platelets volume, high von Willebrand factor activity, low flow-mediated vasodilation, and low total antioxidant status values. PMID- 30418227 TI - Preventive Effect of L-Carnitine on Scar Formation During Acute Pyelonephritis: A Randomized Placebo-Controlled Trial. AB - BACKGROUND: Urinary tract infection and pyelonephritis are clinical problems that frequently occur in children. Several factors are responsible for renal tissue injury, morbidity, and renal scarring after pyelonephritis. The aim of this study was to evaluate the preventive effect of L-carnitine on renal scarring in acute pyelonephritis. METHODS: A randomized double-blind clinical trial was conducted on 65 children aged 6 months to 10 years. Patients were randomized into 2 groups to receive 7-day treatment with only antibiotics without L-carnitine (control group; n = 32) and 7-day treatment with L-carnitine (case group; n = 33) during the acute phase of infection. Technetium-99m-labeled dimercaptosuccinic acid (DMSA) scintigraphy was performed for all children during the acute phase (in 2-7 days of hospitalization) and late phase. P-value less than 0.05 was statistically significant. RESULTS: We recruited 65 participants in the study: 32 children in control group and 33 children in case group. Three children in the control group and 2 children in the case group refused to perform the second DMSA scan. Overall, data analysis at the end of the study was done on 60 patients. Age distribution of girl patients with upper urinary infection was 6.5% in girl children aged between 6 months and 12 months, 41.1% aged between 1 and 5 years, 33.3% aged between 5 and 10 years, respectively. There was no significant difference between 2 groups in age and sex. There was no significant difference between 2 groups in systolic blood pressure, diastolic blood pressure, the lab data including urine white blood cells and serum erythrocyte sedimentation rate, and antibiogram profiles. Voiding dysfunction was detected in 10% of the participants. The baseline DMSA was not significantly difference in 2 groups, but worsening of kidney lesions was significantly higher in control group after 6 months (P = 0.012). CONCLUSION: Our study showed that L-carnitine significantly decreased renal scarring because of acute pyelonephritis. PMID- 30418228 TI - Paralytic Ileus and Syndrome of Inappropriate Antidiuretic Hormone Secretion Potentially due to an Interaction Between Vincristine and Voriconazole/Posaconazole. PMID- 30418229 TI - Step-wise Drug Therapy for Comorbid Bipolar and Obsessive-Compulsive Disorders. PMID- 30418230 TI - Typical Versus Atypical Antipsychotics for Acute Mania. AB - BACKGROUND: Mania is challenging to treat. Typical antipsychotics may be more efficient compared with atypical antipsychotics, however, with unfavorable side effects. STUDY QUESTION: To investigate the courses of acute manic episodes and correlations between changes of severity during manic episodes and type of antipsychotic treatment. STUDY DESIGN: This case record study included patients admitted with mania (International Classification of Diseases 10th revision code F30, F31.0, F31.1, F31.2 or F31.6) at the Department of Affective Disorders, Aarhus University Hospital from June 1, 2013 to April 1, 2016. MEASURES AND OUTCOMES: The doses of typical and atypical antipsychotics were standardized as defined daily dose according to the World Health Organization's guidelines. The severity of mania was measured up to 3 times daily with the Modified Bech Rafaelsen Mania Scale (MAS-M), a nurse administered scale. We applied a linear regression in a mixed model approach to compare MAS-M score over time under the influence of typical plus atypical antipsychotics and atypical antipsychotics only. We further analyzed by mania with and without psychosis and by concomitant use of lithium and/or antiseizure medication. RESULTS: We included 56 admissions on 46 patients. The courses of the manic episodes measured by MAS-M varied between patients-both daily variations and changes over time. Patients receiving typical antipsychotics had higher baseline MAS-M, more recent admissions, and were mechanically constrained more often compared with patients receiving atypical antipsychotics only. Adjusted for age, gender, mechanical constraint, and dosage of antipsychotics, the difference in reduction of mania was -0.02 MAS M points/d (95% confidence interval, -0.05 to 0.01) higher in the group receiving atypical antipsychotics only; however, it is not statistically or clinically significant. CONCLUSIONS: The rate of improvement of mania was similar in the two groups which supports that atypical antipsychotics can be recommended over typical antipsychotics to reduce risk of severe side effects. PMID- 30418231 TI - Is antidyslipidemic statin use for cancer prevention a promising drug repositioning approach? AB - Novel pharmacological therapies are in development for cancer, ranging from conventional chemotherapeutic drugs to molecular targeted drugs, antibody-based drugs, and immune checkpoint inhibitors, which are developed using new technologies. However, the increasing cost of new drug development is increasing the costs of national healthcare and putting pressure on government finances worldwide. Under these circumstances, drug repositioning (i.e. discovering novel effects of existing drugs, thereby allowing their use to treat other diseases) has become a major focus because of reliability and cost reduction. It is becoming increasingly clear that statins (currently used for treating dyslipidemia) can be effective in the prevention of coronary disease, heart failure, and arrhythmia. Epidemiological as well as basic research studies and epidemiological surveys have showed that statins have a suppressive effect on cancers and that they have an antitumor effect on colorectal, prostate, breast, cervical, endometrial, and ovarian cancers. Given the pharmacological mechanism of action of statins, they may have an antitumor effect on cancer types in which the mevalonate pathway is activated as well as on tumors with p53 mutations. To investigate this further, it would be necessary to conduct a large-scale survey after confirming the clinical background of patients as well as their mutational status, and therefore, great hope has been placed on the role of academia and public institutions. Thus, there is an urgent need for researchers to be actively involved in investigator-initiated clinical trials. PMID- 30418232 TI - Acute Kidney Injury and Risk of Death After Elective Surgery: Prospective Analysis of Data From an International Cohort Study. AB - BACKGROUND: Postoperative acute kidney injury (AKI) is associated with a high mortality rate. However, the relationship among AKI, its associations, and mortality is not well understood. METHODS: Planned analysis of data was collected during an international 7-day cohort study of adults undergoing elective in patient surgery. AKI was defined using Kidney Disease Improving Global Outcomes criteria. Patients missing preoperative creatinine data were excluded. We used multivariable logistic regression to examine the relationships among preoperative creatinine-based estimated glomerular filtration rate (eGFR), postoperative AKI, and hospital mortality, accounting for the effects of age, major comorbid diseases, and nature and severity of surgical intervention on outcomes. We similarly modeled preoperative associations of AKI. Data are presented as n (%) or odds ratios (ORs) with 95% confidence intervals. RESULTS: A total of 36,357 patients were included, 743 (2.0%) of whom developed AKI with 73 (9.8%) deaths in hospital. AKI affected 73 of 196 (37.2%) of all patients who died. Mortality was strongly associated with the severity of AKI (stage 1: OR, 2.57 [1.3-5.0]; stage 2: OR, 8.6 [5.0-15.1]; stage 3: OR, 30.1 [18.5-49.0]). Low preoperative eGFR was strongly associated with AKI. However, in our model, lower eGFR was not associated with increasing mortality in patients who did not develop AKI. Conversely, in older patients, high preoperative eGFR (>90 mL.minute.1.73 m) was associated with an increasing risk of death, potentially reflecting poor muscle mass. CONCLUSIONS: The occurrence and severity of AKI are strongly associated with risk of death after surgery. However, the relationship between preoperative renal function as assessed by serum creatinine-based eGFR and risk of death dependent on patient age and whether AKI develops postoperatively. PMID- 30418233 TI - Invasive Respiratory or Vasopressor Support and/or Death as a Proposed Composite Outcome Measure for Perioperative Care Research. AB - BACKGROUND: There is a need for a clinically relevant and feasible outcome measure to facilitate clinical studies in perioperative care medicine. This large scale retrospective cohort study proposed a novel composite outcome measure comprising invasive respiratory or vasopressor support (IRVS) and death. We described the prevalence of IRVS in patients undergoing major abdominal surgery and assessed the validity of combining IRVS and death to form a composite outcome measure. METHODS: We retrospectively collected perioperative data for 2776 patients undergoing major abdominal surgery (liver, colorectal, gastric, pancreatic, or esophageal resection) at Kyoto University Hospital. We defined IRVS as requirement for mechanical ventilation for >=24 hours postoperatively, postoperative reintubation, or postoperative vasopressor administration. We evaluated the prevalence of IRVS within 30 postoperative days and examined the association between IRVS and subsequent clinical outcomes. The primary outcome of interest was long-term survival. Multivariable Cox proportional regression analysis was performed to adjust for the baseline patient and operative characteristics. The secondary outcomes were length of hospital stay and hospital mortality. RESULTS: In total, 85 patients (3.1%) received IRVS within 30 postoperative days, 15 of whom died by day 30. Patients with IRVS had a lower long-term survival rate (1- and 3-year survival probabilities, 66.1% and 48.5% vs 95.2% and 84.0%, respectively; P < .001, log-rank test) compared to those without IRVS. IRVS was significantly associated with lower long-term survival after adjustment for the baseline patient and operative characteristics (adjusted hazard ratio, 2.72; 95% confidence interval, 1.97-3.77; P < .001). IRVS was associated with a longer hospital stay (median [interquartile range], 65 [39-326] vs 15 [12-24] days; adjusted P < .001) and a higher hospital mortality (24.7% vs 0.5%; adjusted P < .001). Moreover, IRVS was adversely associated with subsequent clinical outcomes including lower long-term survival (adjusted hazard ratio, 1.78; 95% confidence interval, 1.21-2.63; P = .004) when the analyses were restricted to 30-day survivors. CONCLUSIONS: Patients with IRVS can experience ongoing risk of serious morbidity and less long-term survival even if alive at postoperative day 30. Our findings support the validity of using IRVS and/or death as a composite outcome measure for clinical studies in perioperative care medicine. PMID- 30418234 TI - Side Effect Rates of Opioids in Equianalgesic Doses Via Intravenous Patient Controlled Analgesia: A Systematic Review and Network Meta-analysis. AB - BACKGROUND: Side effects of opioids used for the treatment of acute pain frequently limit their analgesic quality. Many studies have compared opioid side effects in patient-controlled analgesia (PCA), but it remains unclear whether there are specific side effect profiles that can be exploited when choosing an opioid for a patient. In this review, we wanted to determine the risk ratios (RRs) for the most common side effects when using different opioids for intravenous PCA in equianalgesic doses and rank the substances accordingly. METHODS: A search of MEDLINE, EMBASE, the Cochrane Library (CENTRAL), and Web of Science identified 63 randomized controlled trials comparing opioids under equianalgesic conditions. Inclusion criteria were comparable pain stimulus between groups, equal coanalgesic treatment, and comparable resulting pain scores. Quality of studies was assessed using the Cochrane risk of bias tool with 6 items. Frequentistic network meta-analysis was conducted with morphine as the comparator. This method not only summarizes all estimated effects from direct comparisons of different interventions but also allows for indirect comparisons between interventions that can be linked via the common comparator, in which case the indirect evidence can be used to enhance the precision of the direct comparisons. Primary end points of this study were RRs for nausea and vomiting, pruritus, and events of sedation, as well as mean differences for scores of sedation. Events of respiratory depression were counted. Secondary end point was patient satisfaction (mean difference). The study protocol was registered at PROSPERO (CRD42017062355). RESULTS: Sixteen opioid interventions were compared in the largest network (nausea and vomiting outcome) and 7 opioid interventions in the smallest network (sedation events outcome). Most interventions did not differ from morphine on the primary outcomes (side effects), with some exceptions. Buprenorphine had a significantly higher RR of nausea and vomiting, whereas fentanyl had a lower RR of nausea and vomiting. Nalbuphine, butorphanol, methadone, and pethidine/meperidine had a lower risk of pruritus. Respiratory depression was rare (22 of 2452 patients). Pethidine/meperidine, fentanyl, and oxymorphone caused significantly lower sedation scores. Tramadol caused significantly lower satisfaction scores, whereas oxycodone, alfentanil, remifentanil, fentanyl, and pethidine/meperidine caused significantly higher satisfaction scores. CONCLUSIONS: The opiate chosen for treatment most likely has little effect on the incidence of pruritus and nausea/vomiting, although considerable differences exist in terms of better and worse opioids in the presented rankings. Larger differences between drugs were observed with regard to sedation and patient satisfaction, and choosing the appropriate opioid may help to improve PCA in this regard. PMID- 30418235 TI - Analgesic Efficacy and Safety of Intravenous Meloxicam in Subjects With Moderate to-Severe Pain After Open Abdominal Hysterectomy: A Phase 2 Randomized Clinical Trial. AB - BACKGROUND: An intravenous (IV) formulation of meloxicam was developed for moderate-to-severe pain management. This study evaluated the safety and efficacy of meloxicam IV after open abdominal hysterectomy. Meloxicam IV is an investigational product not yet approved by the US Food and Drug Administration. METHODS: Women (N = 486) with moderate-to-severe pain after open abdominal hysterectomy were enrolled in this multicenter, randomized, double-blind, placebo and active-controlled trial. Subjects were randomized to receive a single dose of meloxicam IV (5-60 mg), placebo, or morphine (0.15 mg/kg) in <=6 hours after morphine dosing on postoperative day 1 and were evaluated for 24 hours. Rescue morphine (~0.15 mg/kg IV) was available if needed for pain not relieved by the study medication. In an open-label extension (N = 295), meloxicam IV was administered once daily for the remaining hospital stay (or per the investigator's discretion). The coprimary efficacy end points were the summed pain intensity difference (SPID24) and total pain relief (TOTPAR24) from hour 0 to 24 hours after dosing. Effect size, the standardized difference between means reported in standard deviation (SD) units, was calculated to indicate the magnitude of the difference in the mean analgesic effect measured for different intervention groups. RESULTS: Subjects who received morphine or meloxicam IV had a median time to first perceptible pain relief within 6-8 minutes. Morphine and meloxicam IV 5-60 mg produced statistically significant differences than placebo in SPID24 and TOTPAR24. SPID24 (standard error [SE]) for meloxicam IV 5-60 mg ranged from -56276.8 (3926.46) to -33517.1 (3930.1; P < .001); SPID24 (SE) for morphine and placebo were -29615.8 (3869.2; P < .001) and 4555.9 (3807.1), respectively. SPID24 effect sizes (95% confidence intervals) for the 60, 30, 15, 7.5, and 5 mg meloxicam IV doses and morphine were 1.93 (1.61-2.25), 2.00 (1.65 2.35), 1.70 (1.35-2.05), 1.28 (0.95-1.60), 1.25 (0.90-1.61), and 1.12 (0.77-1.45) SDs, respectively. TOTPAR24 (SE) for meloxicam IV 5-60 mg ranged from 3104.5 (155.28) to 4130.4 (191.17; P < .001); TOTPAR24 (SE) for morphine and placebo were 2723.3 (188.4; P < .001) and 1100.6 (185.4), respectively. TOTPAR24 effect sizes (95% confidence interval) for the 60, 30, 15, 7.5, and 5 mg meloxicam IV doses and morphine were 2.03 (1.70-2.35), 2.05 (1.70-2.40), 1.78 (1.43-2.13), 1.35 (1.03-1.67), 1.37 (1.01-1.72), and 1.10 (0.75-1.45) SDs, respectively. The mean total opioid consumed (SD) during the double-blind phase was 4.6 (8.17), 5.3 (8.85), 5.9 (7.85), 8.5 (9.67), 9.3 (9.47), 9.6 (8.12), and 16.0 (10.15) mg for patients in the 60, 30, 15, 7.5, and 5 mg meloxicam IV, morphine, and placebo groups, respectively. Generally, meloxicam IV was well tolerated, evidenced by the incidence of adverse events compared to placebo and lack of deaths and treatment-related serious adverse events. CONCLUSIONS: A meloxicam IV dose of 5 60 mg was generally well tolerated and appeared to reduce opioid consumption in subjects with moderate-to-severe pain after open abdominal hysterectomy. Once daily administration of meloxicam IV produced analgesic effect within 6-8 minutes postdose that was maintained over a 24-hour dosing interval.This is an open access article distributed under the terms of the Creative Commons Attribution Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30418236 TI - An Observational Study of Cerebral Blood Flow Velocity Evaluation in the Prone Position During Posterior Lumbar Surgery. AB - BACKGROUND: Prone positioning (PP) is necessary for surgical access during posterior spine procedure. However, physiological changes occur in the PP. Typical findings are a decrease in arterial blood pressure and in cardiac output that could potentially lead to an alteration in cerebral perfusion. Therefore, we decided to study cerebral blood flow velocity (CBFV) with transcranial Doppler ultrasonography to evaluate the effect of the PP on cerebral hemodynamics. METHODS: Twenty-two patients undergoing spine surgery in the PP were studied. General anesthesia was induced using 250 MUg of fentanyl, 2 mg/kg of propofol, and 0.1 mg/kg of vecuronium, and was maintained with 0.25%-0.5% isoflurane, 50% nitrous oxide in oxygen, continuous infusion of 100 MUg/kg/min of propofol, 1.5 MUg/kg/h of fentanyl, and 0.15 mg/kg/h of ketamine. Continuous invasive arterial blood pressure, heart rate, electrocardiogram, and end-tidal carbon dioxide were monitored. CBFV with transcranial Doppler in the middle cerebral artery was first measured with the patients under general anesthesia in the supine position. Patients were then placed in the PP and remained in this position throughout surgery. CBFV, end-tidal carbon dioxide, heart rate, and blood pressure were measured continuously for 75 minutes after initiation of PP. This coincided with surgical exposure and minimal blood loss. Data were analyzed every 15 minutes for statistical significant change over time. RESULTS: Mean arterial blood pressure decreased 15 minutes after the installation of the PP and onward, but this decrease was not statistically significant. CBFVsyst (the maximal CBFV during the systolic phase of a cardiac cycle) and CBFVmean (the time averaged value of the maximal velocity envelope over 1 cardiac cycle) did not vary at any time points. CBFVdiast (the CBFV just before the acceleration phase [systole] of the next waveform) was lower at T3 (30 minutes after PP) compared to T1 (value derived averaging the first measure in the PP with the ones at 5 and 10 minutes) (P = .01), and the pulsatility index was higher at T5 (60 minutes after PP) compared to T0 (baseline, patient supine under general anesthesia) (P = .04). Data were analyzed at specific time points (T0 and T1). This value was derived by computing an average of the CBFV values collected at the first measure in the PP and at 5 and 10 minutes thereafter: T2, 15 minutes after PP; T3, 30 minutes after PP; T4, 45 minutes after PP; T5, 60 minutes after PP; and T6, 75 minutes after PP. CONCLUSIONS: Our data on CBFV during PP for spine surgery demonstrate preservation of cerebral perfusion during stable systemic hemodynamic conditions. The present results do not allow us to determine whether the PP would be similarly tolerated with increasing length of surgery, variations in systemic hemodynamics, and in different patient populations. PMID- 30418237 TI - Trends in Authorship in Anesthesiology Journals. AB - Despite increasing representation in medicine, women continue to be a minority in academic practice and leadership, especially in male-dominated fields like anesthesiology. Differences in compensation and participation in leadership may represent barriers to career advancement for women in anesthesiology. Key factors for promotion in academic anesthesiology are research, funding, and publication. As such, designation as a first or senior author on a publication in a professional journal may act as currency for promotion. Here, we examine the prevalence of female first and senior authorship of original research articles published in Anesthesiology and Anesthesia & Analgesia during the years 2002, 2007, 2012, and 2017. Other manuscript characteristics assessed in relation to author gender included study type, subspecialty topic, and total number of authors. Of 2600 manuscripts studied, analysis of authorship by year demonstrated an increase in female first authorship, senior authorship, and editorial board membership by 10%, 9%, and 6%, respectively. Women made up a higher percentage of first authors on manuscripts with female senior authors. More nonexperimental studies had female senior authors than experimental studies. Female first authors had greater representation in the subspecialties of neuroanesthesia, obstetrical anesthesia, pain management, and pediatric anesthesia. Median number of authors was unrelated to senior author gender. This study shows increasing female first and senior authorship, as well as editorial board composition in 2 popular, high impact anesthesiology journals. Recognizing gender-based trends in publications is important to develop strategies for the recruitment, retention, and advancement of women in anesthesiology. PMID- 30418238 TI - Distribution of Extreme Vital Signs and Complete Blood Count Values of Healthy Parturients: A Retrospective Database Analysis and Review of the Literature. AB - BACKGROUND: The impact of physiological adjustments throughout pregnancy on maternal vital signs and laboratory values has yet to be fully defined. The present study was designed to determine the normal range of these parameters among healthy pregnant women during the peripartum period. METHODS: This is a retrospective analysis of data collected during real-time deliveries in a single medical center. Vital signs and laboratory results from the 24 hours preceding delivery room admission and up to 72 hours postpartum were collected. Only pregnant women at term (37 to 41 weeks' gestation) with a liveborn, singleton gestation, and no chronic disease or obstetric complication that could affect the physiological parameters under study were included. The mean, range, and standard deviations of the extremes of all parameters at 3 distinct time points (prelabor, intrapartum, and postpartum) were calculated. The 2.5 and 97.5 percentiles for each parameter were reported as the normal range. RESULTS: A total of 32,161 cases fulfilled inclusion criteria. The average gestational age at delivery was 39 weeks +/- 8 days, and one-third of the cases were primiparous. During labor and after delivery, the upper limits of normal blood pressure values were 147/94 and 145/94 mm Hg, respectively. The lower limits were 83/43 and 83/42 mm Hg, respectively. Normal heart rates were 60-115 beats/min prelabor, 51-120 beats/min intrapartum, and 50-120 beats/min postpartum. Lowest normal temperatures ranged between 36.0 degrees C and 36.3 degrees C in the 3 study time points, and highest normal temperatures were 37.2 degrees C prelabor and 37.6 degrees C intra- and postpartum. The normal ranges of white blood cell counts were 6.1-16.8 prelabor, 6.5-22.5 intrapartum, and 6.4-23.9 K/uL postpartum. Normal low values of hemoglobin were 9.7, 8.7, and 7.1 g/dL and of platelets were 117, 113, and 105 K/uL, respectively. CONCLUSIONS: Our findings justify the practice of using >=2 repeated measurements for diagnosing hypertensive disorders of pregnancy. Lower normal blood pressure limits may be below those defining hypotensive shock. Normal heart rates exceed the accepted definitions of both tachy- and bradycardia. Normal temperatures at all times have a more narrow range than previously thought, and the normal range of white blood cell count has outliers exceeding the current definitions of leukocytosis or leukopenia at all times. The normal lower range of hemoglobin was constantly below 10 g/dL, and normal platelet counts were considerably lower than those previously described. The vital signs and complete blood count values thus far considered normal for the peripartum period may require some adjustment. New definitions for hypotension, tachy- and bradycardia, fever, and leukocyte quantitative disorders should be considered. PMID- 30418239 TI - Relationship Between Preoperative Antidepressant and Antianxiety Medications and Postoperative Hospital Length of Stay. AB - BACKGROUND: Patients on antidepressant or antianxiety medications often have complex perioperative courses due to difficult pain management, altered coping mechanisms, or medication-related issues. This study examined the relationship between preoperative antidepressants and antianxiety medications on postoperative hospital length of stay while controlling for confounding variables. METHODS: From an administrative database of 48,435 adult patients who underwent noncardiac surgery from 2011 to 2014 at a single, large urban academic institution, multivariable zero-truncated negative binomial regression analyses controlling for age, sex, medical comorbidities, and surgical type were performed to assess whether preoperative exposure to antidepressant or antianxiety medication use was associated with postoperative hospital length of stay. RESULTS: There were 5111 (10.5%) patients on antidepressants and 4912 (10.1%) patients on antianxiety medications. The median length of stay was 3 days (interquartile range = 2-6). After controlling for confounding variables, preoperative antidepressant medication was associated with increased length of stay with an incidence rate ratio of 1.04 (99% confidence interval, 1.0-1.08, P < .001) and antianxiety medication with an incidence rate ratio of 1.1 (99% confidence interval, 1.06 1.14; P < .001). CONCLUSIONS: The association between antidepressants or antianxiety medications and increased postoperative length of stay suggests that these patients may require greater attention in the perioperative period to hasten recovery, which may involve integrating preoperative counseling, postoperative psychiatric consults, or holistic recovery approaches into enhanced recovery protocols. PMID- 30418240 TI - Clockwise Versus Counterclockwise Rotation of Endotracheal Tube When Using Videolaryngoscopy in Children. PMID- 30418241 TI - Intravascular Cooling Device Versus Esophageal Heat Exchanger for Mild Therapeutic Hypothermia in an Experimental Setting. AB - BACKGROUND: Targeted temperature management is a standard therapy for unconscious survivors of cardiac arrest. To date, multiple cooling methods are available including invasive intravascular cooling devices (IVDs), which are widely used in the clinical setting. Recently, esophageal heat exchangers (EHEs) have been developed providing cooling via the esophagus that is located close to the aorta and inferior vena cava. The objective was to compare mean cooling rates, as well as differences, to target temperature during maintenance and the rewarming period of IVD and EHE. METHODS: The study was conducted in 16 female domestic pigs. After randomization to either IVD or EHE (n = 8/group), core body temperature was reduced to 33 degrees C. After 24 hours of maintenance (33 degrees C), animals were rewarmed using a target rate of 0.25 degrees C/h for 10 hours. All cooling phases were steered by a closed-loop feedback system between the internal jugular vein and the chiller. After euthanasia, laryngeal and esophageal tissue was harvested for histopathological examination. RESULTS: Mean cooling rates (4.0 degrees C/h +/- 0.4 degrees C/h for IVD and 2.4 degrees C/h +/- 0.3 degrees C/h for EHE; P < .0008) and time to target temperature (85.1 +/- 9.2 minutes for IVD and 142.0 +/- 21.2 minutes for EHE; P = .0008) were different. Mean difference to target temperature during maintenance (0.07 degrees C +/- 0.05 degrees C for IVD and 0.08 degrees C +/- 0.10 degrees C for EHE; P = .496) and mean rewarming rates (0.2 degrees C/h +/- 0.1 degrees C/h for IVD and 0.3 degrees C/h +/- 0.2 degrees C/h for EHE; P = .226) were similar. Relevant laryngeal or esophageal tissue damage could not be detected. There were no significant differences in undesired side effects (eg, bradycardia or tachycardia, hypokalemia or hyperkalemia, hypoglycemia or hyperglycemia, hypotension, overcooling, or shivering). CONCLUSIONS: After insertion, target temperatures could be reached faster by IVD compared to EHE. Cooling performance of IVD and EHE did not significantly differ in maintaining target temperature during a targeted temperature management process and in active rewarming protocols according to intensive care unit guidelines in this experimental setting. PMID- 30418242 TI - Melatonin attenuates cardiac reperfusion stress by improving OPA1-related mitochondrial fusion in a Yap-Hippo pathway-dependent manner. AB - The role of OPA1-related mitochondrial fusion in cardiac reperfusion stress has remained elusive. The aim of our study is to explore whether melatonin alleviates cardiac IR injury by modulating OPA1-related mitochondrial fusion. We found that melatonin reduced infarct area, sustained myocardial function and suppressed cardiomyocyte death during cardiac reperfusion stress. Biological studies have revealed that IR-inhibited mitochondrial fusion was largely reversed by melatonin via upregulated OPA1 expression. Knocking down OPA1 abrogated the protective effects of melatonin on mitochondrial energy metabolism and mitochondrial apoptosis. In addition, we also found that melatonin modified OPA1 expression via the Yap-Hippo pathway; blockade of the Yap-Hippo pathway induced cardiomyocyte death and mitochondrial damage despite treatment with melatonin. Altogether, our data demonstrated that cardiac IR injury is closely associated with defective OPA1-related mitochondrial fusion. Melatonin supplementation enhances OPA1 related mitochondrial fusion by activating the Yap-Hippo pathway, ultimately reducing cardiac reperfusion stress. PMID- 30418243 TI - Procalcitonin and antibiotics in moderate-severe acute exacerbation of chronic obstructive pulmonary disease: to use or not to use. AB - PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Acute exacerbations of COPD (AECOPD) are major driver for healthcare utilization with each exacerbation begetting the next exacerbation. It is, therefore, important to treat each episode effectively to prevent the next. However, this can be challenging as AECOPD result from complex interactions between host, environment and infective agents. The benefits of starting antibiotics in AECOPD, which are not life-threatening (e.g. not requiring mechanical ventilation) or not complicated by pneumonia remain controversial. RECENT FINDINGS: The use of procalcitonin to guide antibiotic therapy in AECOPD has gained interest in recent years. The main advantage of this approach is a safe reduction in antibiotic use in a large group of patients, which may potentially translate to several other benefits. These include reduced antibiotic-related side-effects, reduced risk of developing antibiotic-resistant organisms and cost savings. This approach is associated with no increase in mortality or morbidity such as treatment failure, re-admission, admission to ICU. SUMMARY: Procalcitonin-guided antibiotic therapy in AECOPD is a promising and safe approach, which may be ready for the prime time. PMID- 30418244 TI - The role of statins in chronic obstructive pulmonary disease: is cardiovascular disease the common denominator? AB - PURPOSE OF REVIEW: The pleiotropic anti-inflammatory effects of statins that have proven to improve outcomes in cardiovascular disease have also been of interest in the treatment of COPD, a disease with considerable morbidity and little available treatment that improves mortality. In-vitro and animal studies have supported biologic plausibility of statin therapy for lung health and function. Retrospective observational studies in humans have echoed this potential as well but confirmatory data from randomized studies are limited and somewhat disappointing. RECENT FINDINGS: Despite discouraging clinical trial results, the possibility remains that statins can help patients with COPD characterized by systemic inflammation. At the same time, increasing recognition of the considerable cardiovascular disease burden and its suboptimal treatment in patients with COPD has also contributed to continued enthusiasm for statin use in COPD. SUMMARY: When it comes to defining the role for statins as a disease modifying therapy, the jury is still out; however, the importance of more careful cardiovascular risk stratification that includes assessing levels of inflammatory markers in patients with COPD and the benefit of statins in those with increased risk is gaining increasing recognition. PMID- 30418245 TI - Using Nursing Information and Data Mining to Explore the Factors That Predict Pressure Injuries for Patients at the End of Life. AB - This study investigated the association between patient characteristics and the occurrence of pressure injuries for patients at the end of life. A retrospective study was conducted using data collected from 2062 patients at the end of life between January 2007 and October 2015. In addition to demographic data and pressure injury risk assessment scale scores, injury history, disease type, and length of hospitalization were revealed as the major independent variables for predicting the occurrence of pressure injuries. Both chi tests and t tests were employed for binary variable analysis, and logistic regression was used to conduct multivariate analysis. Classification models were formulated through decision tree analysis, backpropagation neural network, and support vector machine algorithms. The rules obtained using the decision tree algorithm were analyzed and interpreted. The accuracy rate, sensitivity, and specificity of the decision tree, backpropagation neural network, and support vector machine algorithms were 77.15%, 79.54%, and 74.76%; 78.12%, 81.37%, and 74.85%; and 79.32%, 81.03%, and 78.75%, respectively. The predictive factors, ranked in order of importance, were history of pressure injuries, without cancer, excretion, activity/mobility, and skin condition/circulation. These were the primary shared risk factors among the four models used in this study. PMID- 30418246 TI - Implementation of High-Sensitivity Cardiac Troponin: Challenges From the International Experience. AB - OBJECTIVE: Implementation of the newly approved high-sensitivity cardiac troponin (hs-cTn) in the United States presents a challenge for clinical practice. Sex specific cutoffs, clinical protocols, and workflows will likely require modifications before implementation. METHODS: We conducted a cross-sectional survey of international physicians and laboratorians already utilizing hs-cTn for the evaluation of acute myocardial infarction. RESULTS: Twenty-two of 54 (41%) eligible participants completed the survey, representing 9 countries and 18 hospitals. All reported successful hs-cTn implementation and diagnostic utility (mean 8.6 + 1.2 out of 10 for best implementation). The major perceived benefit was more rapid evaluation of acute myocardial infarction (14/19, 74%), and the most frequently cited limitation was an increase in the number of measurable hs cTn values that required further evaluation (8/18, 44%). Institutions using the hs-cTnI assay favored sex-specific cutoffs (5/6, 83%), whereas institutions employing the hs-cTnT assay favored a combined cutoff (12/12, 100%). Timing of serial hs-cTn measurements varied, with 0-3 hours (8/17, 47%) most frequent, followed by 0-2 hours (4/17, 24%), 0-1 hour (3/17, 18%), and other (2/17, 12%). CONCLUSIONS: Our survey of hs-cTn implementation at international institutions reveals satisfaction with new assays but reflects important variations in clinical practice. The use of sex-specific vs. combined cutoffs and timing of serial hs-cTn measurements varies across institutions and are subjects that United States centers must define without consensus from international practices. PMID- 30418247 TI - Prognostic Utility of the HEART Score in the Observation Unit. AB - The evaluation of individuals with possible acute myocardial infarction (AMI) is time consuming and costly. Risk stratification early during an acute care encounter presents an opportunity for increased delivery of high-value care. We sought to evaluate if the HEART score could be used in the triage of low-risk versus high-risk patients directly home without cardiac testing. Retrospective review of 838 patients placed in an observation unit for evaluation of AMI was done at a single-center, tertiary care teaching hospital. Primary outcome was major adverse cardiac event-death, AMI, or revascularization-at 30 days from the index encounter. Participants' average age was 60.1 years, 40% were male, and 67% were African American. Complete data were available for all 838 patients, including 30-day follow-up at study completion. The primary endpoint was met in 14 patients (1.7%), all of whom were in the high-risk group, with HEART score >=4. Of the low-risk patients, 8 (2.8%) had a positive functional study, 5 underwent subsequent coronary angiography, with none (0%) found to have obstructive coronary disease. In conclusion, our results suggest that patients with a HEART score <=3 being evaluated for chest pain are at extremely low risk for major adverse cardiac events and may be safely discharged without provocative testing. Positive cardiac testing in this population is more likely to represent a false-positive finding, resulting in unnecessary testing. These findings should be prospectively validated. PMID- 30418248 TI - Incorporation of the HEART Score Into a Low-risk Chest Pain Pathway to Safely Decrease Admissions. AB - Chest pain can be a challenging complaint to manage in the emergency department. A missed diagnosis can result in significant morbidity or mortality, whereas avoidable testing and hospitalizations can lead to increased health care costs, contribute to hospital crowding, and increase risks to patients. The HEART score is a validated decision aid to identify patients at low risk for acute coronary syndrome who can be safely discharged without admission or objective cardiac testing. In the largest and one of the longest studies to date (N = 31,060; 30 months), we included the HEART score into a larger, newly developed low-risk chest pain decision pathway, using a retrospective observational pre/post study design with the objective of safely lowering admissions. The modified HEART score calculation tool was incorporated in our electronic medical record. A significant increase in discharges of low-risk chest pain patients (relative increase of 21%; p < 0.0001) in the postimplementation period was observed with no significant difference in the rates of major adverse cardiac events between the pre and post periods. There was a decrease in the amount of return admissions for 30 days (4.65% fewer; p = 0.009) and 60 days (3.78% fewer; p = 0.020). No significant difference in length of stay was observed for patients who were ultimately discharged. A 64% decrease in monthly coronary computed tomography angiograms was observed in the post period (p < 0.0001). These findings support the growing consensus in the literature that the adoption of the HEART pathway or similar protocols in emergency departments, including at large and high-volume medical institutions, can substantially benefit patient care and reduce associated health care costs. PMID- 30418249 TI - Implementation of the HEART Pathway: Using the Consolidated Framework for Implementation Research. AB - OBJECTIVE: The HEART Pathway is an evidence-based decision tool for identifying emergency department (ED) patients with acute chest pain who are candidates for early discharge, to reduce unhelpful and potentially harmful hospitalizations. Guided by the Consolidated Framework for Implementation Research, we sought to identify important barriers and facilitators to implementation of the HEART Pathway. STUDY SETTING: Data were collected at 4 academic medical centers. STUDY DESIGN: We conducted semi-structured interviews with 25 key stakeholders (e.g., health system leaders, ED physicians). We conducted interviews before implementation of the HEART Pathway tool to identify potential barriers and facilitators to successful adoption at other regional academic medical centers. We also conducted postimplementation interviews at 1 medical center, to understand factors that contributed to successful adoption. DATA COLLECTION: Interviews were recorded and transcribed verbatim. We used a Consolidated Framework for Implementation Research framework-driven deductive approach for coding and analysis. PRINCIPAL FINDINGS: Potential barriers to implementation include time and resource burden, challenges specific to the electronic health record, sustained communication with and engagement of stakeholders, and patient concerns. Facilitators to implementation include strength of evidence for reduced length of stay and unnecessary testing and iatrogenic complications, ease of use, and supportive provider climate for evidence-based decision tools. CONCLUSIONS: Successful dissemination of the HEART Pathway will require addressing institution specific barriers, which includes engaging clinical and financial stakeholders. New SMART-FHIR technologies, compatible with many electronic health record systems, can overcome barriers to health systems with limited information technology resources. PMID- 30418250 TI - Facilitators and Barriers to Reducing Emergency Department Admissions for Chest Pain: A Qualitative Study. AB - BACKGROUND: Chest pain of possible cardiac etiology is a leading reason for emergency department (ED) visits and hospitalizations nationwide. Evidence suggests outpatient management is safe and effective for low-risk patients; however, ED admission rates for chest pain vary widely. To identify barriers and facilitators to outpatient management after ED visits, we performed a multicenter qualitative study of key stakeholders. METHODS AND RESULTS: We identified Massachusetts hospitals with below-average admission rates for adult ED chest pain visits from 2010 to 2011. We performed a qualitative case study of 27 stakeholders across 4 hospitals to identify barriers and facilitators to outpatient management. Clinicians cited ability to coordinate follow-up care, including stress testing and cardiology consultation, as key facilitators of ED discharge. When these services are unavailable, or inconsistently available, they present a barrier to outpatient management. Clinicians identified pressure to maintain throughput and the lack of observation units as barriers to ED discharge. At 3 of 4 hospitals without observation units, clinicians did not use clinical protocols to guide the admission decision. At the site with a dedicated ED observation unit, low ED admission rates were attributed to clinician adherence to clinical protocols. CONCLUSIONS: In conclusion, most participants have not adopted protocols focused on reducing variation in ED chest pain admissions. Robust systems to ensure follow-up care after ED visits may reduce admission rates by mitigating the perceived risk of discharging ED patients with chest pain. Greater use of observation protocols may promote adoption of clinical guidelines and reduce admission rates. PMID- 30418251 TI - Are Prior Aspirin Users With ST-Elevation Myocardial Infarction at Increased Risk of Adverse Events and Worse Angiographic Features? AB - Despite its clinical benefits, aspirin has been considered one of the predictors of worse outcomes in patients with unstable angina/non-ST-segment-elevation myocardial infarction. Nevertheless, such association has not been demonstrated in patients with ST-elevation myocardial infarction (STEMI). Five hundred eighty six STEMI patients undergoing primary percutaneous coronary intervention were evaluated including 116 prior aspirin users. Angiographic characteristics and 1 year major adverse cardiac events (MACE) were then compared between the 2 groups. Adjusted analysis showed that the prior aspirin users had a significantly higher rate of totally occluded infarct-related artery before primary percutaneous coronary intervention (odds ratio: 1.859; P = 0.019). Postprocedural Thrombolysis in Myocardial Infarction flow grade 3 was less often demonstrated in the prior aspirin users (odds ratio: 1.512; P = 0.059). Aspirin consumption was associated with increased long-term mortality and MACE. Prior aspirin users had higher rate of MACE and worse pre- and postprocedural angiographic features. We suppose that patients who develop STEMI despite long-term aspirin intake probably reflect more vulnerable pre-existing coronary plaques with more thrombogenicity, which could negatively affect long-term cardiovascular outcomes. PMID- 30418252 TI - Acceptance of the Chest Pain Unit Certification Process: Current Status in Germany. AB - The nationwide German certification process of specialized chest pain units is unique in Europe. By February 2018, 269 units had already been successfully certified. With that number, more than half of all catheter laboratories across the country offering service on a 24/7 basis for interventional treatment in myocardial infarction take part in that certified chest pain program - with still increasing tendency. Currently, those units provide a mean of one chest pain unit bed per 65,000 inhabitants. Thereby, a high percentage of recertification of about 95% reflects a high acceptance of the concept by the health care providers. Structured in-hospital procedures, increasing awareness within the community and among the emergency medical services as well as increasing numbers of self referrals guarantee higher work-flow, improving performance and an even increasing demand for those units. Complimentary patient awareness campaigns focusing on early symptom recognition might further improve, expand and redirect patient flow, shorten patient-related delay and have to become the next level in chest pain patient care in Germany. Transferring the idea of early heart attack care to the community as a new way of thinking might be able to more significantly decrease future symptoms-to-therapy times as the current chest pain unit program can solely achieve. PMID- 30418253 TI - Development and evaluation of a home nocturnal blood pressure monitoring system using a wrist-cuff device. AB - OBJECTIVE: The conventional nocturnal blood pressure monitoring (NBPM) systems can disturb sleep and lead to false measurements. The present study compared the validity and acceptability of a newly developed wrist-cuff system with that of the conventional upper arm-cuff system for NBPM. PARTICIPANTS AND METHODS: Home blood pressure (BP) and pulse rate (PR) were measured in hypertensive patients (n=57) every 30 min at night using a wrist-cuff system and at 2 am (fixed time) and 4 h after going to bed (flexible time) using an upper arm-cuff system. The nocturnal BPs with the wrist-cuff system at 2 am and at 4 h after going to bed were selected from the measurements taken every 30 min at night. The same systems were used to measure the morning and evening home BP and PR, after rising and before going to bed. Measurements were taken for two nights separately for each system. BP, PR, sleep quality, and the perception of several stimuli during NBPM were compared between the two systems. Systolic BP/diastolic BP (DBP) in the supine position at 2 am and at 4 h after going to bed were corrected by the mean difference between the wrist-cuff and the arm-cuff systems. RESULTS: Compared with the arm-cuff system, the wrist-cuff system had significantly lower systolic BP (mean+/-SD: 106.3+/-13.4 vs. 109.8+/-10.8 mmHg, P<0.05), DBP (59.4+/-11.0 vs. 64.5+/-7.8 mmHg, P<0.005), and PR (53.8+/-7.1 vs. 60.5+/-8.1 bpm, P<0.0005) at 2 am and significantly lower DBP (60.2+/-10.3 vs. 66.0+/-9.8 mmHg, P<0.005) and PR (53.6+/-7.4 vs. 60.9+/-8.5 bpm, P<0.0005) at 4 h after going to bed. Among the participants, sleep disturbance during NBPM was reported in less than 20% with the wrist-cuff system and in 70% with the arm-cuff system. A significantly higher rate of participants who wore the wrist-cuff system reported that they were not bothered by various stimuli, such as noise, during NBPM. DISCUSSION: The newly developed wrist-cuff home NBPM system provided information on BP as a function of time, especially at night, with minimal sleep disturbance and with more frequent BP measurements. PMID- 30418254 TI - Two Manic Episodes Related to a Levetiracetam-Based Treatment in a 34-Year-Old Female Patient: A Case Report. PMID- 30418255 TI - Clozapine Addition Following Brain Surgery in Severe Primary Obsessive-Compulsive Disorder With Tardive Movement Disorder. PMID- 30418256 TI - Effect of WeChat and short message service on bowel preparation: an endoscopist blinded, randomized controlled trial. AB - OBJECTIVE: Adequate bowel preparation is essential for a successful colonoscopy; clinical studies suggest reinforced education can improve the preparation process. However, there have been no trials to compare WeChat directions (the most widely used social media app in China) with those of the short message service (SMS). This study was aimed to assess the effect of WeChat and SMS on the bowel preparation quality. PARTICIPANTS AND METHODS: This was a single-center, prospective, endoscopically blinded, randomized, controlled study. Patients in reinforced education groups received additional reminder messages by WeChat and SMS 2 days before colonoscopy. The primary outcome was bowel preparation quality evaluated by the Boston bowel preparation scale (BBPS) score and the rate of adequacy (BBPS score >=6). Secondary outcomes included polyp detection rate, adenoma detection rate, and mean total adenomas detected. Patient tolerance level and subjective feelings were also evaluated. RESULTS: The total BBPS score and the percentage of adequacy were significantly higher in the reinforced education groups compared with the control (WeChat vs. control, P<0.001; SMS vs. control, P<0.001). Moreover, statistically significant differences between the two interventions were found in the total BBPS score but not in the rate of adequacy (P=0.007 and 0.561, respectively). The detection of adenomas, using multiplicity detection rate, advanced adenoma detection rate, and mean total adenomas detected, was much higher in the intervention groups (P=0.039, 0.037, and 0.019, respectively). CONCLUSION: WeChat was superior to SMS for bowel preparation, although both of them may help improving the detection of adenomas. PMID- 30418257 TI - Cardiovascular Diseases and Long-Term Self-Reported Exposure to Pollution: RESULTS OF A NATIONAL EPIDEMIOLOGICAL STUDY IN LEBANON. AB - BACKGROUND: Cardiovascular diseases (CVDs) are linked to high mortality and morbidity, particularly in developing countries. Some studies have linked indoor and outdoor pollution to CVD, but results are inconsistent. Our objective was to assess this association in Lebanon, a Middle Eastern country. METHODS: A national cross-sectional study was conducted across Lebanon. CVD prevalence, which included prevalent ischemic heart and cerebrovascular diseases, was assessed. Moreover, in addition to self-reported items of pollution exposure, we assessed potential predictors of CVD, including sociodemographic characteristics, self reported health information, and biological measurements. RESULTS: We assessed the dose-effect relationship of pollution items in relation with CVD. Self reported indoor and outdoor pollution exposures were associated with CVD, with or without taking biological values into account. Moreover, we found a dose-effect relationship of exposure with risk of disease (44% increase in risk of CVD for every additional pollution exposure item), after adjustment for sociodemographic and biological characteristics. CONCLUSION: Although additional studies would be necessary to confirm these findings, interventions should start to sensitize the population about the effect of pollution on chronic diseases and the work of reducing pollution and improving air quality should be implemented to decrease the disease burden on the population and health system. PMID- 30418258 TI - Modern imaging techniques in urinary stone disease. AB - PURPOSE OF REVIEW: Radiological imaging techniques are a fast developing field in medicine. Therefore, the purpose of this review was to identify and discuss the latest changes of modern imaging techniques in the management of urinary stone disease. RECENT FINDINGS: The introduction of iterative image reconstruction enables low-dose and ultra-low-dose (ULD) protocols. Although current guidelines recommend their utilization in nonobese patients recent studies indicate that low dose imaging may be feasible in obese (<30 kg/m) but not in bariatric patients. Use of dual energy computed tomography (CT) technologies should balance between additional information and radiation dose aspects. If available on a dose neutral basis, dual energy imaging and analysis should be performed. Current guidelines recommend measuring the largest diameter for clinical decision making; however, recent studies suggest a benefit from measuring the volume based on multiplanar reformation. Quantitative imaging is still an experimental approach. SUMMARY: The use of low-dose and even ULD CT protocols should be diagnostic standard, even in obese patients. If dual energy imaging is available, it should be limited to specific clinical questions. The stone volume should be reported in addition to the largest diameter for treatment decision and a more valid comparability of upcoming studies. PMID- 30418259 TI - Are Temporal Trends Important Measures of Opioid-prescribing Risk? PMID- 30418261 TI - Clinical Magnetic Resonance Imaging of the Knee at 7 T: Optimization of Fat Suppression. AB - PURPOSE: The aim of this study was to evaluate the efficiency and performance of different fat suppression techniques for clinical 7 T knee magnetic resonance imaging including the slice-selective gradient reversal (SSGR) technique. MATERIALS AND METHODS: This article is an ethical board-approved prospective study with written informed consent from 8 volunteers (mean, 31 +/- 4 years). It included fat phantom and knee magnetic resonance imaging at 3 T (Magnetom Skyra; Siemens Healthcare) and at 7 T (Achieva, Philips Healthcare). At 3 T, an axial proton density-weighted turbo spin echo sequence with spectral adiabatic inversion recovery (SPAIR) was acquired. At 7 T, a series of 5 proton density weighted turbo spin echo sequences was acquired: (a) without fat suppression, (b) with spectral presaturation with inversion recovery (SPIR), (c) with SPAIR, (d) with SSGR, and (e) with the combination of SSGR + SPIR. Additional noise scans allowed pixelwise calculation of signal-to-noise ratio and contrast-to-noise ratio maps. Quantitative data at 7 T were compared with each other but not to 3 T. Two independent radiologists evaluated overall image quality, homogeneity and grade of fat suppression, and the delineation between 2 adjacent structures. Results were compared using Wilcoxon signed rank and paired sample t tests. RESULTS: Relative signal-to-noise ratios of fat demonstrated that the SPIR technique reduced the fat signal to 45% +/- 5.4%; SPAIR, 18% +/- 1.2%; SSGR, 14% +/- 1.1%; and SSGR + SPIR, 11% +/- 0.3%. Contrast-to-noise ratio showed superior contrast between muscle-fat (P < 0.001) and fluid-fat (P <= 0.001) for SSGR and SSGR + SPIR. The radiologists rated the overall image quality higher at 7 T than 3 T. The homogeneity and grade of fat suppression as well as the delineation between 2 different (adjacent) structures were rated best for SSGR + SPIR. CONCLUSIONS: At 7 T, fat saturation for clinical knee imaging using SSGR and the combination of SSGR + SPIR was superior compared with standard methods based on spectrally selective radiofrequency pulses. PMID- 30418260 TI - Escalating Opioid Dose Is Associated With Mortality: A Comparison of Patients With and Without Opioid Use Disorder. AB - OBJECTIVE: Prescription Drug Monitoring Programs (PDMPs) are intended to help reduce prescription drug misuse and opioid overdose, yet little is known about the longitudinal patterns of opioid prescribing that may be associated with mortality. This study investigated longitudinal opioid prescribing patterns among patients with opioid use disorder (OUD) and without OUD in relation to mortality using PDMP data. METHODS: Growth modeling was used to examine opioid prescription data from the California PDMP for a 4-year period before death or a comparable period ending in 2014 for those remaining from a sample of 7728 patients (2576 with OUD, and 5152 matched non-OUD controls) treated in a large healthcare system. RESULTS: Compared to controls, individuals with OUD (alive and deceased) had received significantly more opioid prescriptions, greater number of days' supply, and steeper increases of opioid dosages over time. For morphine equivalents (ME, in grams), the interaction of OUD and mortality was significant at both intercept (beta = 10.4, SE = 4.4, P < 0.05) and slope (beta = 6.0, SE = 1.1, P < 0.001); deceased OUD patients demonstrated the sharpest increase (ie, an average yearly increment of 7.84 grams over alive patients without OUD) and ended with the highest level of opioids prescribed before they died (ie, 20.2 grams higher). Older age, public health insurance, cancer, and chronic pain were associated with higher number and dose of opioid prescriptions. CONCLUSIONS: Besides the amount of prescriptions, clinicians must be alert to patterns of opioid prescription such as escalating dosage as critical warning signals for heightened mortality risks, particularly among patients with OUD. PMID- 30418262 TI - Prediction of Lumbar Disk Herniation and Clinical Outcome Using Quantitative Magnetic Resonance Imaging: A 5-Year Follow-Up Study. AB - OBJECTIVES: The aim of this study was to assess the predictive value of T2 mapping at baseline with regard to the development of disk herniation and clinical outcome at a 5-year follow-up in patients with low back pain. MATERIALS AND METHODS: Twenty-five symptomatic patients (13 male; mean age, 44.0 years; range, 24-64 years at baseline) were examined at 3 T magnetic resonance imaging, with a 5-year follow-up. Region of interest analysis was performed on 125 lumbar intervertebral disks on 2 central sagittal T2 maps. Absolute T2 relaxation times and a T2 value ratio of the posterior annulus fibrosus as a percentage of the nucleus pulposus (NPAF) were evaluated for each disk. All disks were graded morphologically using the Pfirrmann score. Roland-Morris Disability Questionnaires (RMDQ) and a visual analogue scale (VAS) were assessed for each patient at follow-up as a clinical end point and compared with diagnosed lumbar disk herniation. Statistical analysis was conducted by a biomedical statistician. RESULTS: Using the baseline NPAF ratio, follow-up development of herniation was predicted with an area under the curve (AUC) of 0.893 in a receiver operating characteristic curve. The same was done using the baseline nucleus pulposus T2, resulting in an AUC of 0.901. Baseline and follow-up NPAF, as well as baseline and follow-up nucleus pulposus T2, differed significantly (P < 0.001) between disks with no herniation, disks with herniation at baseline, and disks with new herniation at follow-up. Difference was still significant (all P < 0.001), when only testing for difference in degenerated discs with Pfirrmann score III to V. Calculating sensitivity and specificity for herniation prediction only in discs with Pfirmann III to V using a receiver operating characteristic, AUC was 0.844 with baseline herniations excluded.The lowest baseline nucleus pulposus T2 per patient correlated significantly with follow-up RMDQ (r = -0.517; P = 0.008) and VAS (r = -0.494; P = 0.012). The highest baseline NPAF correlated significantly with RMDQ (r = 0.462; P = 0.020), but not VAS (r = 0.279; P = 0.177). CONCLUSIONS: Quantitative T2 mapping may serve as a clinically feasible, noninvasive imaging biomarker that can indicate disks at risk for herniation and correlates with clinical outcome and subjective patient burden in a representative cohort of patients with low back pain. PMID- 30418263 TI - Tamsulosin to Prevent Postoperative Urinary Retention After Female Pelvic Reconstructive Surgery. AB - OBJECTIVE: This study aimed to determine the effect of tamsulosin on postoperative urinary retention in female patients after pelvic reconstructive surgery. METHODS: Data were obtained from a retrospective, matched cohort of female patients who were admitted after pelvic reconstructive surgery at a single academic institution. Patients who received tamsulosin were compared with those who did not at a 1:4 ratio, matched by surgical procedure. Patients were excluded if they were discharged on the day of surgery or if an intraoperative complication necessitated prolonged postoperative bladder drainage. Information on demographics, preoperative diagnoses, prolapse stage, preoperative voiding dysfunction, urodynamic findings, intraoperative details, postoperative complications, and voiding outcomes up to 6 weeks after surgery was gathered. The primary outcome was postoperative urinary retention, defined by failure of an active voiding trial. RESULTS: Patients underwent surgery between January 2016 and March 2018. We identified 35 patients who received tamsulosin and matched to 140 controls. Patients in the tamsulosin group were younger; groups were otherwise similar. Patients who received tamsulosin after surgery were less likely to develop postoperative urinary retention (2.9% vs 24.3%, P = 0.004). After controlling for confounders, multivariable logistic regression identified tamsulosin use as the only independent predictor of postoperative urinary retention with a significant protective effect (odds ratio, 0.09; 95% confidence interval, 0.01-0.67; P = 0.03). CONCLUSIONS: Prophylactic tamsulosin use may be effective in preventing postoperative urinary retention in female patients undergoing pelvic reconstructive surgery. PMID- 30418264 TI - Cerebral Microbleeds and the Safety of Anticoagulation in Ischemic Stroke Patients: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: The objective of this study was to investigate the safety of anticoagulation in ischemic stroke (IS) patients with cerebral microbleeds (CMBs). METHODS: PubMed, Web of Science, Elsevier Clinical Key, Google Scholar, and Cochrane Library from 1996 to July 2018 were searched to identify relevant studies that included IS patients, underwent T2*-weighted gradient recalled echo, or susceptibility-weighted imaging for detection CMBs and used anticoagulants during follow-up. Primary outcome of interest was intracerebral hemorrhage (ICH). Secondary outcomes were hemorrhage transformation, IS, total mortality, and new developed CMBs. We critically appraised studies and conducted a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance. RESULTS: We included 7 observational studies. Cerebral microbleeds were associated with a significantly elevated risk of anticoagulation related ICH (odds ratio, 4.01; 95% confidence interval, 1.82-8.81; P = 0.001). It was significant for warfarin (odds ratio, 8.02; 95% confidence interval, 1.51 42.62; P = 0.015). New developed CMBs in patients on warfarin treatment were associated with baseline CMBs, and the appearance of hemorrhagic transformation did not have a significant relationship with baseline CMBs. CONCLUSIONS: The presence of CMBs increases the risk of ICH during anticoagulant treatment (especially warfarin) in IS patients. Further studies with larger numbers of patients are needed to confirm our conclusions. PMID- 30418265 TI - Index: Authors of Abstracts. PMID- 30418266 TI - Analysis of Movement-Related Beta Oscillations in the Off-Medication State During Subthalamic Nucleus Deep Brain Stimulation Surgery. AB - PURPOSE: Local field potential recordings from deep brain stimulation (DBS) leads provide insight into the pathophysiology of Parkinson disease (PD). We recorded local field potential activity from DBS leads within the subthalamic nucleus in patients with PD undergoing DBS surgery to identify reproducible pathophysiological signatures of the disease. METHODS: Local field potentials were recorded in 11 hemispheres from patients with PD undergoing subthalamic nucleus-DBS. Bipolar recordings were performed off medication for 2 minutes at rest and another 2 minutes with continuous repetitive opening-closing of the contralateral hand. Spectral analysis and bicoherence were performed and compared between the two testing conditions. RESULTS: In all hemispheres, predominance of the beta band frequency (13-30 Hz) was observed at rest and during movement. Beta peak energy was significantly (P < 0.05) increased during movement compared with rest in 6 of 10 hemispheres. Significant beta bicoherence was observed at rest and during movement in 5 of 10 hemispheres. The most robust local field potential recordings were observed at the DBS contact(s) independently chosen for programming in 9 of the 10 hemispheres. CONCLUSIONS: In patients with PD, beta activity that increases with repetitive movement may be a signature of the "off" medication state. These findings provide new data on beta oscillatory activity during the Parkinsonian "off" state that may help further define the local field potential signatures of PD. PMID- 30418267 TI - Quantitative EEG After Subarachnoid Hemorrhage Predicts Long-Term Functional Outcome. AB - PURPOSE: Delayed cerebral ischemia is a major complication after subarachnoid hemorrhage. Our previous study showed that alpha power reduction in continuous quantitative EEG predicts delayed cerebral ischemia. In this prospective cohort, we aimed to determine the prognostic value of alpha power in quantitative EEG for the long-term outcome of patients with subarachnoid hemorrhage. METHODS: Adult patients with nontraumatic subarachnoid hemorrhage were included if admitted early enough for EEG to start within 72 hours after symptom onset. Continuous six channel EEG was applied. Unselected EEG signals underwent automated artifact rejection, power spectral analysis, and detrending. Alpha power decline of >=40% for >=5 hours was defined as critical EEG event based on previous findings. Six month outcome was obtained using the modified Rankin scale. RESULTS: Twenty-two patients were included (14 male; mean age, 59 years; Hunt and Hess grade I-IV; duration of EEG monitoring, median 14 days). Poor outcome (modified Rankin scale, 2-5) was noted in 11 of 16 patients (69%) with critical EEG events. All six patients (100%) without EEG events achieved an excellent outcome (modified Rankin scale 0, 1) (P = 0.0062; sensitivity 100%, specificity 54.5%). Vasospasm detected with transcranial Doppler/Duplex sonography appeared 1.5 days after EEG events and showed weaker association with outcome (P = 0.035; sensitivity 100%, specificity 45.5%). There was no significant association between EEG events and ischemic lesions on imaging (P = 0.1). Also, no association between ischemic lesions and outcome was seen (P = 0.64). CONCLUSIONS: Stable alpha power in quantitative EEG reflects successful therapy and predicts good functional outcome after subarachnoid hemorrhage. Critical alpha power reduction indicates an increased risk of poor functional outcome. PMID- 30418268 TI - Mycotic coronary aneurysms. AB - : Mycotic coronary aneurysm is a rare infective disease of arterial vessel walls. Their development could be linked to the presence of an infective endocarditis or could represent a primary infection at the site of an implanted intracoronary stent. Bacterial agents, particularly Staphylococcus aureus, are the most common etiological agents. Due to an aspecific clinical presentation and examination, diagnosis could be challenging. Multiple imaging techniques (both invasive and noninvasive) are often required to reach the final diagnosis. Prognosis is characterized by high morbidity and mortality rates and, in fact, a tempestive treatment is required, although, to date, scanty data concerning the optimal treatment choice are present in literature. PMID- 30418269 TI - Congenital Tibial Deficiency. AB - Congenital tibial deficiency is a rare condition characterized by partial to complete absence of the tibia, an intact but frequently overgrown fibula, variable degrees of knee deformity and function, and an abnormal equinovarus foot. It can occur in isolation but also presents concurrently with other orthopaedic anomalies and syndromic conditions. Among these, congenital abnormalities of the hand and femur are most commonly observed. Many theories exist regarding its etiology and some genetic mutations have been identified; however, the underlying mechanism remains unknown. The prognosis and treatment differ based on the clinical severity. The goal of treatment is always to create a stable, functional limb, most commonly with amputation and use of prosthetics. Controversy exists over the level of amputation and the usefulness of reconstructive procedures to preserve the foot and limb length. Current investigation on this complex disorder is focused on identifying its origins and further developing a classification-based treatment algorithm to improve patient outcomes. PMID- 30418270 TI - Insurance Status Affects Complication Rates After Total Hip Arthroplasty. AB - INTRODUCTION: Previous studies have examined the relationship between total hip arthroplasty (THA) and insurance status in small cohorts. This study evaluates the effect of patient insurance status on complications after primary elective THA using the Nationwide Inpatient Sample. METHODS: All patients undergoing primary elective THA from 1998 to 2011 were included. Patient demographics, comorbidities, and complications were collected and compared based on insurance type. Multivariable logistic regression and a matched cohort analysis were performed. RESULTS: About 515,037 patients (53.7% Medicare, 40.1% private insurance, 3.9% Medicaid/uninsured, and 2.2% other) were included, who underwent elective THA. Privately insured patients had fewer medical complications (odds ratio, 0.80; P < 0.001), whereas patients with Medicaid or no insurance demonstrated no notable difference (odds ratio, 1.03; P = 0.367) compared with Medicare patients. Similar trends were found for both surgical complications and mortality, favoring lower complication rates for privately insured patients. Furthermore, patients with private insurance tend to go to higher volume hospitals for total hip replacement surgery compared to those with Medicare insurance. DISCUSSION: Patients with government-sponsored insurance (Medicare or Medicaid) or no insurance have higher risk of medical complications, surgical complications, and mortality after primary elective THA compared with privately insured patients. Insurance status should be considered an independent risk factor for stratifying patients before THA procedures. PMID- 30418271 TI - AAOS Appropriate Use Criteria: The Management of Developmental Dysplasia of the Hip in Infants up to Six Months of Age: Intended for Use by Orthopaedic Specialists. PMID- 30418272 TI - AAOS Appropriate Use Criteria: The Management of Developmental Dysplasia of the Hip in Infants up to 6 Months of Age: Intended for Use by General Pediatricians and Referring Physicians. PMID- 30418273 TI - Cross-Country Transportation Efficacy and Clinical Outcomes of Preloaded Large Diameter Ultra-Thin Descemet Stripping Automated Endothelial Keratoplasty Grafts. AB - PURPOSE: To evaluate the clinical outcomes of preloaded large-diameter ultra-thin grafts for Descemet stripping automated endothelial keratoplasty (UT-DSAEK) after cross-country shipment. METHODS: A laboratory study in an eye bank and a clinical cohort study in an academic tertiary care center were performed. UT-DSAEK (9.5 mm diameter) grafts (n = 7) were prepared, loaded into a commercial device (iGlide; Eurobio, Les Ulis, France), preserved for 4 days at room temperature in transport medium, and analyzed. In a retrospective study, preloaded tissues (n = 39) for clinical use were prepared, transported from Italy to the United Kingdom, and surgically delivered into the eyes of patients undergoing UT-DSAEK. Central and peripheral endothelial cell density (ECD) and viability were measured before and after loading and storage of the grafts in the laboratory study. Clinically, best corrected visual acuity, ECD before and at final follow-up, dislocation rate, primary graft failure, and surgical time were recorded. RESULTS: In the laboratory study, postcut central graft thickness was 93.3 +/- 17.2 MUm. ECD and cell mortality did not change significantly before and after preservation (P = 0.8). Cell loss after 4 days of preservation was 1.7% +/- 1.6%. Clinically, 39 eyes of 39 patients at final follow-up showed a mean central graft thickness of 88 +/- 22 MUm and a best-corrected visual acuity of 0.34 +/- 0.24 logMAR. Nine of 39 cases (23%) needed rebubbling, and 28% cell loss was observed at final follow up. CONCLUSIONS: Large-diameter UT-DSAEK grafts can be prepared and preloaded in the eye bank using the iGlide and transported to the surgical center facilitating surgery for patients undergoing UT-DSAEK, potentially reducing tissue wastage, surgical time, and costs related to surgery. PMID- 30418274 TI - Minimizing Endothelial Cell Loss Caused by Orientation Stamps on Preloaded Descemet Membrane Endothelial Keratoplasty Grafts. AB - PURPOSE: To quantify endothelial cell loss (ECL) caused by orientation stamps on prestripped and preloaded Descemet membrane endothelial keratoplasty (DMEK) grafts, and to examine a method for reducing ECL using a smaller stamp. METHODS: Ten prestripped and 10 preloaded DMEK grafts were prepared with S-stamps. Ten additional preloaded DMEK grafts were prepared with both an S-stamp and a smaller F-stamp in different paracentral areas of the graft. The footprint of each stamp was measured using ink on cardstock. DMEK grafts were stored in viewing chambers filled with 20 mL of Optisol-GS for 3 days at 4 degrees C. ECL was quantified using Calcein-AM staining and FIJI Weka Segmentation. RESULTS: S-stamps on prestripped DMEK grafts contributed an average ECL of 1.1% +/- 0.5% (range: 0.6% 2.2%) toward total graft damage, whereas S-stamps on preloaded DMEK grafts contributed approximately twice that amount (average ECL: 2.0% +/- 0.7%, range: 1.3%-3.1%, P = 0.004). Overall ECL for prestripped grafts (average: 7.1% +/- 3.3%, range: 3.3%-13.7%) and preloaded grafts (average: 11.3% +/- 4.2%, range: 6.9%-19.4%) was similar to previous reports. The footprint of the S-stamp was approximately 45% larger than that of the F-stamp. In 10 preloaded grafts marked with both stamps, the S-stamp caused an average ECL of 1.9% +/- 0.6% (range: 1.2% 3.2%), whereas the smaller F-stamp caused an average ECL of 1.0% +/- 0.2% (range: 0.8%-1.4%, P = 0.0002). CONCLUSIONS: Loss of endothelial cells associated with graft-stamping was greater in preloaded tissue than in prestripped tissue and was less with a smaller F-stamp than with a larger S-stamp. Using a smaller stamp could help minimize ECL in prestripped and preloaded DMEK grafts. PMID- 30418275 TI - Bilateral Ulcerative Keratitis Associated With Afatinib Treatment for Non-Small Cell Lung Carcinoma. AB - PURPOSE: To report a case of afatinib-related bilateral ulcerative keratitis. METHODS: An 85-year-old female patient on treatment with afatinib for non-small cell lung carcinoma presented with progressive redness, pain, and decreased vision in both eyes. Four weeks before the onset of symptoms, afatinib therapy had been commenced at a dose of 40 mg, once daily. Clinical examination, OCT imaging, photographs, and corneal scrapes were completed at presentation. Afatinib was discontinued. Topical and oral therapy were commenced to treat ulcerative keratitis with close monitoring for signs of progression or corneal perforation. RESULTS: Significant stromal thinning was detected in the inferior cornea of both eyes with an overlying epithelial defect and no infiltrate. No organisms were identified from the corneal scrapes. The patient responded well to treatment, and her vision returned to baseline 4 months after presentation. CONCLUSIONS: To the best of our knowledge, this is the first case in the literature that reports afatinib-related ulcerative keratitis. Careful monitoring for signs of ocular adverse events is recommended during treatment with afatinib for non-small-cell lung carcinoma. PMID- 30418276 TI - Multicenter Study of Intense Pulsed Light Therapy for Patients With Refractory Meibomian Gland Dysfunction. PMID- 30418277 TI - Zirconium Nitride Coating Reduced Staphylococcus epidermidis Biofilm Formation on Orthopaedic Implant Surfaces: An In Vitro Study. AB - BACKGROUND: One of the most commonly identified pathogens responsible for orthopaedic implant infection is Staphylococcus epidermidis, which can form biofilms on surfaces. Currently, orthopaedic implants made of various surface materials are available, each with features influencing osseointegration, biocompatibility, and adherence of bacteria to the surface, which is the first step in biofilm formation. The aim of this experimental study was to investigate the effect of a high tribologic-resistant 2.5-um zirconium nitride top coat on an antiallergic multilayer ceramic-covered cobalt-chromium-molybdenum surface on the formation of S. epidermidis biofilm compared with other commonly used smooth and rough orthopaedic implant surface materials. QUESTIONS/PURPOSES: (1) When evaluating the surfaces of a cobalt-chromium-molybdenum (CoCrMo) alloy with a zirconium (Zr) nitride coating, a CoCrMo alloy without a coating, titanium alloy, a titanium alloy with a corundum-blasted rough surface, and stainless steel with a corundum-blasted rough surface, does a Zr coating reduce the number of colony forming units of S. epidermidis in an in vitro setting? (2) Is there quantitatively less biofilm surface area on Zr-coated surfaces than on the other surfaces tested in this in vitro model? METHODS: To determine bacterial adhesion, five different experimental implant surface discs were incubated separately with one of 31 different S. epidermidis strains each and subsequently sonicated. Twenty test strains were obtained from orthopaedic patients undergoing emergency hip prosthesis surgeries or revision of implant infection and 10 further strains were obtained from the skin of healthy individuals. Additionally, one reference strain, S. epidermidis DSM 3269, was tested. After serial dilutions, the number of bacteria was counted and expressed as colony-forming units (CFUs)/mL. For biofilm detection, discs were stained with 0.1% Safranin-O for 15 minutes, photographed, and analyzed with computer imaging software. RESULTS: The lowest bacterial count was found in the CoCrMo + Zr surface disc (6.6 x 10 CFU/mL +/- 4.6 x 10 SD) followed by the CoCrMo surface (1.1 x 10 CFU/mL +/- 1.9 x 10 SD), the titanium surface (1.36 x 10 CFU/mL +/- 1.8 x 10 SD), the rough stainless steel surface (2.65 x 10 CFU/mL +/- 3.8 x 10 SD), and the rough titanium surface (2.1 x 10 CFU/mL +/- 3.0 x 10 SD). The mean CFU count was lower for CoCrMo + Zr discs compared with the rough stainless steel surface (mean difference: 2.0 x 10, p = 0.021), the rough titanium alloy surface (mean difference: 1.4 x 10, p = 0.002), and the smooth titanium surface (mean difference: 7.0 x 10, p = 0.016). The results of biofilm formation quantification show that the mean covered area of the surface of the CoCrMo + Zr discs was 19% (+/- 16 SD), which was lower than CoCrMo surfaces (35% +/- 23 SD), titanium alloy surface (46% +/- 20 SD), rough titanium alloy surface (66% +/- 23 SD), and rough stainless steel surface (58% +/ 18 SD). CONCLUSIONS: These results demonstrate that a multilayer, ceramic covered, CoCrMo surface with a 2.5-um zirconium nitride top coat showed less S. epidermidis biofilm formation compared with other surface materials used for orthopaedic implants. CLINICAL RELEVANCE: CoCrMo with a 2.5-um zirconium nitride top coat seems to be a promising surface modification technology able to reduce bacterial attachment on the surface of an implant and, hence, may further prevent implant infection with S. epidermidis biofilm formation. PMID- 30418278 TI - Translation and Validation of the German New Knee Society Scoring System. AB - BACKGROUND: In 2011 the Knee Society Score (KSS) was revised to include patient expectations, satisfaction, and physical activities as patient-reported outcomes. Since the new KSS has become a widely used method to evaluate patient status after TKA, we sought to translate and validate it for German-speaking populations. QUESTIONS/PURPOSES: After translation of the new KSS into German using established guidelines, we sought to test the new German version for (1) validity; (2) responsiveness; and (3) reliability. METHODS: The new KSS form was translated and adapted according to the available guidelines. The final version was used to validate the German version of the new KSS (GNKSS) in 133 patients undergoing TKA, of which 100 patients were included in the study as per inclusion criteria. Patients completed the GNKSS form along with the German WOMAC and the German SF-36 scores preoperatively and at the 2-year postoperative followup. Construct validity was tested by comparing domain scores of the GNKSS with domain scores of the German WOMAC and the SF-36. Responsiveness was evaluated by comparing pre- and postoperative scores in all questionnaires in all patients using standardized response means. To evaluate reliability, every second patient (n = 50) in the whole group was asked to complete the GNKSS form a second time 1 week after their 2-year followup; 39 patients responded. This sample group was considered representative after testing the difference among age, sex, body mass index, operation side, preoperative or postoperative GNKSS, and WOMAC scores with the original group. Intraclass correlation coefficients (ICCs) were used to assess reliability and Cronbach's alpha was an indicator of internal consistency of each domain score. RESULTS: Construct validity was excellent pre- and postoperatively between the GNKSS and the WOMAC for domains including symptoms, satisfaction, total functional score, and total score and activity subdomains, except the expectation domain and advanced and discretionary subdomains of the GNKSS and the stiffness domain of WOMAC. The expectation domain showed either no significant correlation or only weak correlations with the domains of WOMAC pre- as well as postoperatively (r ranging between -0.19 and -0.34). Correlation of the function section of the GNKSS as well as the physical function and role physical domains of the SF-36 pre- and postoperatively were moderate to strong, respectively, with statistically significant (p < 0.001) r values of 0.49 and 0.48 preoperatively and 0.73 and 0.65 postoperatively. Correlation of the symptom section of the GNKSS and bodily pain domain of the SF-36 was also strong pre- and postoperatively. Regarding responsiveness, all domains of the GNKSS showed large changes except the expectation domain. The symptom and functional sections of the GNKSS showed higher responsiveness than the corresponding pain and function domains of the WOMAC and bodily pain and physical function domains of the SF-36. Also, the total score changes were larger for the GNKSS compared with the WOMAC. No floor or ceiling effect was observed. Reliability was excellent with ICCs of 0.83 to 0.97 as an indicator of test-retest reliability and Cronbach's alpha values of 0.78 to 0.85 preoperatively and 0.92 to 0.94 postoperatively as an indicator of internal consistency for all domains and subdomains. CONCLUSIONS: The GNKSS is a valid, responsive, reliable, and consistent outcome measurement tool that may be used to evaluate the outcome of TKA. LEVEL OF EVIDENCE: Level II, diagnostic study. PMID- 30418279 TI - Are Complications After the Bernese Periacetabular Osteotomy Associated With Subsequent Outcomes Scores? AB - BACKGROUND: The Bernese periacetabular osteotomy (PAO) continues to be a commonly performed nonarthroplasty option to treat acetabular dysplasia, but only a few short-term studies have evaluated complications rigorously after PAO. QUESTIONS/PURPOSES: (1) What complications are observed at 10-year mean followup of the Bernese PAO in patients with symptomatic acetabular dysplasia? (2) What factors are associated with these complications? (3) Do these complications affect clinical outcome scores? METHODS: We reviewed 238 hips in 206 patients treated with PAO from July 1994 to August 2008. Only PAOs performed for symptomatic acetabular dysplasia and those that had at a minimum 4-year followup were included. Patients who went on to THA before 4 years were included in the study. Patients with hip pain who presented with a clinical presentation of symptomatic acetabular dysplasia, radiographic evidence of femoral head uncovering, and a lateral center-edge angle < 25 degrees were considered for PAO and no other juxtaacetabular osteotomy was offered other than PAO. Sixty-two hips had diagnoses other than acetabular dysplasia and 22 were lost to followup. The remaining 154 hips (129 patients) were evaluated by chart review at a mean of 10 years (range, 1.7-20.5 years) using the UCLA Activity Score, modified Harris hip score (mHHS), WOMAC, and radiographic analysis. The mean age at PAO was 26 years (range, 10-60 years) and consisted of 113 female patients (132 hips [86%]) and 16 male patients (22 hips [14%]). Complications were graded using the validated Clavien-Dindo system. Complications were assessed for each hip and the highest complication grade was assigned to the hip if multiple complications occurred. We divided complication grades into three groups for analysis: no complications, Grade 1 complications, and complications that deviated from the standard postoperative course (Grades 2, 3, and 4). There were no Grade 5 complications. Variables with significant (p < 0.05) univariable associations with complications were considered for inclusion in a multivariable model. Outcome variables (mHHS and WOMAC) at the most recent followup visit were analyzed using a generalized estimating equation approach. Analysis of variance was used to compare UCLA at the most recent followup among the complication classes. RESULTS: Major complications defined as Clavien-Dindo Grade 3/4 occurred in 14 hips (9%). After controlling for potential confounding variables, we found that increasing body mass index (BMI) (odds ratio [OR], 1.16; 95% confidence interval, 1.05-1.25; p = 0.004) was associated with increased risk of complication. In contrast, greater surgeon experience was associated with a decreased risk (OR, 0.3; p = 0.002). Complications were associated with postoperative pain and activity, WOMAC (mean +/- SD: 0 complications = 1.5 +/- 15.1, 1 complication = 4.3 +/- 4.1, 2-3 complications = 3.8 +/- 4.6; p = 0.020) and UCLA scores (mean +/- SD: 0 complications = 7.8 +/- 2, 1 complication = 6.7 +/- 2.1, 2-3 complications = 6.5 +/- 2; p = 0.003). CONCLUSIONS: Most hips undergoing PAO have few complications. The most common major surgical complication is nonunion. Increasing BMI was a predictor of having a complication, and surgeon experience decreased complication risk. Having a complication adversely affected long-term pain and activity. To minimize complications and maximize outcomes, a patient's BMI should be assessed preoperatively and those with excessive BMI should be counseled on the increased risk of complications. In an experienced surgeon's hands, PAO has few complications at mean 10-year followup and a low risk of permanent disability. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 30418280 TI - Introductory Note to Special Issue for World Association for Plastic Surgeons of Chinese Descent. PMID- 30418281 TI - Periauricular Purse-String Reinforced with SMAS plication and Malaria Fat Pad Elevation for Mid-and Lower Facial Rejuvenation: FACE-Q Report. AB - BACKGROUND: Facial aging is a complex process influencing every layer of the facial structure. Most accepted surgical techniques for facial rejuvenation involve certain manipulation of the superficial musculoaponeurotic system (SMAS). Out of these SMAS-based techniques, SMAS plication or suspension provides excellent outcomes with shorter convalescence and fewer potential complications. Herein, we would like to present our own technique combining SMAS plication, periauricular purse-string, and malar fat pad elevation technique for mid and lower facelift. METHODS: Through a classical periauricular and temporal incision, a periauricular permanent purse-string suture was woven into the SMAS to suspend sagging soft tissue of the mid and lower face after superficial undermining, then plication of inner and outer SMAS of the purse-string loop was performed to further secure suspension, and at last the malar fat pad was elevated for midface rejuvenation. The shape of the loop varies with patients' age; for younger patients, the loop is more vertical, and for older patients, the loop is more horizontal. Patient-reported outcomes were described using the FACE-Q questionnaire. RESULTS: From January 2010 to June 2015, a total of 138 patients were treated with this technique by a same surgeon. Follow-up duration ranged from 1 to 6 years. Preoperative and postoperative photographs were recorded and analyzed. The complications rates were low, and satisfaction rates were high. Patients felt that they appeared 7.3 years younger than their actual age on average and were most satisfied with the appearance of their lower face and jawline. CONCLUSIONS: Periauricular purse-string reinforced with SMAS plication and malar fat pad elevation technique produces esthetically pleasing outcomes, besides being simple, safe, and personalized. PMID- 30418282 TI - Speech-in-Noise and Quality-of-Life Measures in School-Aged Children With Normal Hearing and With Unilateral Hearing Loss. AB - OBJECTIVES: (1) Measure sentence recognition in co-located and spatially separated target and masker configurations in school-aged children with unilateral hearing loss (UHL) and with normal hearing (NH). (2) Compare self reported hearing-related quality-of-life (QoL) scores in school-aged children with UHL and NH. DESIGN: Listeners were school-aged children (6 to 12 yrs) with permanent UHL (n = 41) or NH (n = 35) and adults with NH (n = 23). Sentence reception thresholds (SRTs) were measured using Hearing In Noise Test-Children sentences in quiet and in the presence of 2-talker child babble or a speech shaped noise masker in target/masker spatial configurations: 0/0, 0/-60, 0/+60, or 0/+/-60 degrees azimuth. Maskers were presented at a fixed level of 55 dBA, while the level of the target sentences varied adaptively to estimate the SRT. Hearing-related QoL was measured using the Hearing Environments and Reflection on Quality of Life (HEAR-QL-26) questionnaire for child subjects. RESULTS: As a group, subjects with unaided UHL had higher (poorer) SRTs than age-matched peers with NH in all listening conditions. Effects of age, masker type, and spatial configuration of target and masker signals were found. Spatial release from masking was significantly reduced in conditions where the masker was directed toward UHL subjects' normal-hearing ear. Hearing-related QoL scores were significantly poorer in subjects with UHL compared to those with NH. Degree of UHL, as measured by four-frequency pure-tone average, was significantly correlated with SRTs only in the two conditions where the masker was directed towards subjects' normal-hearing ear, although the unaided Speech Intelligibility Index at 65 dB SPL was significantly correlated with SRTs in four conditions, some of which directed the masker to the impaired ear or both ears. Neither pure tone average nor unaided Speech Intelligibility Index was correlated with QoL scores. CONCLUSIONS: As a group, school-aged children with UHL showed substantial reductions in masked speech perception and hearing-related QoL, irrespective of sex, laterality of hearing loss, and degree of hearing loss. While some children demonstrated normal or near-normal performance in certain listening conditions, a disproportionate number of thresholds fell in the poorest decile of the NH data. These findings add to the growing literature challenging the past assumption that one ear is "good enough." PMID- 30418283 TI - Evaluation of a New Algorithm to Optimize Audibility in Cochlear Implant Recipients. AB - OBJECTIVES: A positive relation between audibility and speech understanding has been established for cochlear implant (CI) recipients. Sound field thresholds of 20 dB HL across the frequency range provide CI users the opportunity to understand soft and very soft speech. However, programming the sound processor to attain good audibility can be time-consuming and difficult for some patients. To address these issues, Advanced Bionics (AB) developed the SoftVoice algorithm designed to remove system noise and thereby improve audibility of soft speech. The present study aimed to evaluate the efficacy of SoftVoice in optimizing AB CI recipients' soft-speech perception. DESIGN: Two studies were conducted. Study 1 had two phases, 1A and 1B. Sixteen adult, AB CI recipients participated in Study 1A. Acute testing was performed in the unilateral CI condition using a Harmony processor programmed with participants' everyday-use program (Everyday) and that same program but with SoftVoice implemented. Speech recognition measures were administered at several presentation levels in quiet (35 to 60 dB SPL) and in noise (60 dB SPL). In Study 1B, 10 of the participants compared Everyday and SoftVoice at home to obtain feedback regarding the use of SoftVoice in various environments. During Study 2, soft-speech perception was acutely measured with Everyday and SoftVoice for 10 participants using the Naida CI Q70 processor. Results with the Harmony (Study 1A) and Naida processors were compared. Additionally, Study 2 evaluated programming options for setting electrode threshold levels (T-levels or Ts) to improve the usability of SoftVoice in daily life. RESULTS: Study 1A showed significantly higher scores with SoftVoice than Everyday at soft presentation levels (35, 40, 45, and 50 dB SPL) and no significant differences between programs at a conversational level (60 dB SPL) in quiet or in noise. After take-home experience with SoftVoice and Everyday (Study 1B), 5 of 10 participants reported preferring SoftVoice over Everyday; however, 6 reported bothersome environmental sound when listening with SoftVoice at home. Results of Study 2 indicated similar soft-speech perception between Harmony and Naida processors. Additionally, implementing SoftVoice with Ts at the manufacturer's default setting of 10% of Ms reduced reports of bothersome environmental sound during take-home experience; however, soft-speech perception was best with SoftVoice when Ts were behaviorally set above 10% of Ms. CONCLUSIONS: Results indicate that SoftVoice may be a potential tool for optimizing AB users' audibility and, in turn, soft-speech perception. To achieve optimal performance at soft levels and comfortable use in daily environments, setting Ts must be considered with SoftVoice. Future research should examine program parameters that may benefit soft-speech perception when used in combination with SoftVoice (e.g., increased input dynamic range). PMID- 30418284 TI - Lesions of the Parotid Gland and Buccal Artery After Buccal Fat Pad Reduction. AB - The significant increase in esthetic surgery, especially buccal fat pad reduction, has led to a corresponding increase in lesions and postoperatory after effects from this surgical procedure. The aim of this study is to discuss the immediate and mediate risks of removing the Bichat ball, as well as describing a clinical study in which this surgical procedure resulted in lesions of the parotid gland and buccal artery, which was confirmed via nuclear magnetic resonance. The facial lesions were remedied via exploratory surgery by opening a new orifice of the glandular duct in the buccal cavity followed by drainage and compressive surgical bandages. PMID- 30418285 TI - Temporomandibular Disorders Clinical and Anatomical Outcomes After Fat-Derived Stem Cells Injection. AB - Temporomandibular disorders (TMD) are common disorders that usually involve temporomandibular joint (TMJ), masticatory muscles, and other relevant structures. The symptoms may vary limiting the patients' quality of life. Many treatment options were proposed during the last years with the aim to treat the pathology. In this article, we analyze the effect of the injection of the fat derived stem cell in the joint as a new treatment option. PMID- 30418286 TI - Technique of The Buccal Fat Pad Flap as an Alternative for the Surgical Defect of Pleomorphic Adenoma. AB - Pleomorphic adenoma (PA) is the most common benign salivary gland neoplasm, and its malignant transformation rarely occurs. Diagnosis is based on clinical features of local or regional malignancy or distant metastasis, and histological identification of invasion and cellular atypia. Buccal fat pad, also called Bichat fat pad, is an excellent option to create tissue coverage over surgically treated areas, providing great blood supply. Thus, this study aims to report a surgical treatment of a patient who reported to the Oral and Maxillofacial Surgery and Traumatology service of a hospital in the city of Fortaleza, presenting a large lesion in the right side of the palate. Clinical examination revealed a nodular volume increase with smooth surface, sessile insertion, firm to palpation and coloration similar to the mucosa, no pain complaints, and 2 years of evolution. Orthopantomographic examination did not reveal alterations in the adjacent anatomical structures. After clinical and radiographic evaluation, an incisional biopsy was performed and histopathological diagnosis was PA. Patient was submitted to surgery for tumor excision with narrow surgical margins, including oral lining mucosa to reduce recurrence chances. In the same surgical act, after the excision of the lesion, the right buccal fat pad pedicle flap was sutured onto the residual mucosa in order to act as a framework for re epithelialization of the palatal mucosa, phenomenon of metaplasia, and reduction of patient's morbidity. Surgical piece obtained was sent to anatomopathological study, confirming initial diagnosis. After 12-month follow-up, patient is esthetically and functionally rehabilitated, and satisfied with clinical and surgical plans executed. PMID- 30418287 TI - Rare Median Cleft-Lip Repair With Novel Surgical Procedures Using Bilateral Cleft Margin Flaps. AB - Reports of median cleft lip with nasal anomalies are few, and descriptions of concomitant surgical repair of a median cleft lip and bifid nose deformity are similarly rare. These surgical repair techniques mainly involve the use of normal neighboring structures. Reconstruction of the columella and nasal base is especially important. A new surgical procedure was examined using bilateral cleft margin flaps for patients with a rare median cleft lip. Two patients with a rare median cleft lip were indicated for the procedure. One patient was 3 months old at surgery, and the other patient was 6 months old. These patients underwent single-stage reconstruction of the lip and nose. The new surgical procedure is characterized by the reconstruction of the columella, which involves creating a supportive structure using a cleft margin flap; subsequently, an anterior covering is created using a hinge flap from the nasal tip. Upper lip formation is performed by repair of the orbicularis oris muscle and rotation advancement of a cutaneous and mucosal flap from the lateral segments. The postoperative follow-up period was 4 to 5 years. The postoperative appearance was satisfactory in both patients. Furthermore, no significant complications were observed postoperatively. In conclusion, the surgical procedure with bilateral cleft margin flaps described in this report allows for successful reconstruction of a median cleft lip. This procedure is effectively tissue saving and results in satisfactory outcomes, which are maintained over a long term. PMID- 30418288 TI - Posterior Distraction First or Fronto-Orbital Advancement First for Severe Syndromic Craniosynostosis. AB - PURPOSE: Posterior calvarial vault expansion using distraction osteogenesis is performed for syndromic craniosynostosis as the first choice. This procedure allows far greater intracranial volume than fronto-orbital advancement (FOA). This study aimed to determine the most suitable timing of posterior distraction or FOA to sufficiently increase the intracranial volume and remodel the skull shape. PATIENTS AND METHODS: From 2014 to 2017, the authors performed posterior distraction in 13 patients with syndromic craniosynostosis. Data on premature suture fusion, age at first visit, age at surgery, skull thickness, and complications were collected. RESULTS: Five patients underwent posterior distraction at approximately 12 months of age and had no complications, including cerebrospinal fluid leakage or gull wing deformity. However, during the waiting period for the operation, the skull deformity continues to extend upward (turribrachycephaly). To prevent progress of the skull deformity, the authors performed the operation at approximately 6 months of age in 7 patients. However, in 3 of 7 patients whose lambdoid sutures were opening, gull wing deformity occurred. From these results, in a patient with severe Beare-Stevenson syndrome, the authors performed FOA first at 5 months of age, followed by posterior distraction at 12 months of age, and achieved favorable results. CONCLUSIONS: Treatment patterns are patient specific and should be tailored to premature suture fusion, specific skull deformity, and required intracranial volume of each patient. PMID- 30418289 TI - Perinasal Osteotomy With Distraction Osteogenesis for a Mild Syndromic Craniosynostosis. AB - Le Fort II and III procedures have generally been performed for syndromic craniosynostosis with midfacial hypoplasia and skeletal class III malocclusion. However, some patients have midfacial hypoplasia without malocclusion. Perinasal osteotomy was performed with distraction osteogenesis to move the midface forward in 2 patients (a 17-year old female patient with Crouzon-like disease and a 15 year-old female patient with Antely-Bixler syndrome) with mild midface hypoplasia without malocclusion. The success of the procedure was assured by 3 features: the intermaxillary sutures were fixed by a mini metal plate to prevent separation during distraction; the distraction wires were fixed through the bone of the piriform aperture with the mini metal plates to prevent the wires from coming off; and the osteotomy line was designed in front of the palatomaxillary suture to avoid suture damage. These were expected to secure the procedure. Perinasal osteotomy with distraction osteogenesis is considered one of the recommended procedures for mild midfacial hypoplasia as seen in mild syndromic craniosynostosis without malocclusion. PMID- 30418290 TI - Epidemiologic Assessment of Microtia in Over 23 Million Consecutive United States Births. AB - PURPOSE: Conflicting data exist regarding the incidence, demographics, and abnormalities associated with microtia. Using a large national cohort database, a comprehensive evaluation of microtia in the United States was performed. METHODS: The Kids' Inpatient Database was reviewed over a 15-year consecutive period. Information regarding patient demographics, comorbidities, postoperative complications, and hospital setting was collected. Statistical tests were analyzed using independent t tests and chi analysis. RESULTS: A total of 23,479,792 births over 15 consecutive years from 1997 to 2012 were included in the study. Microtia was identified in 1563 births. Incidence of microtia was higher in males (P<0.01) and patients of Asian or Hispanic race (P<0.01). Patients with microtia had significantly more congenital anomalies relative to the rest of the population (P<0.01). Specifically, cardiac and genitourinary anomalies were 51 and 19 times, respectively, more likely in microtia patients. Risk of associated congenital anomalies with microtia was highest in female and Black patients. 12.6% of all microtia patients had an associated craniofacial syndrome with a comparable postsurgical course to the nonsyndromic population. CONCLUSION: This study represents the largest national, longitudinal study of microtia allowing for demographic, socioeconomic, and comorbidity commentary. By quantifying relative risk of associated congenital anomalies, it can help inform the type and utility of screening modalities when evaluating microtia patients. PMID- 30418291 TI - The benefits of agreeing on what matters most: Team cooperative norms mediate the effect of co-leaders' shared goals on safety climate in neonatal intensive care units. AB - BACKGROUND: Safety climate research suggests that a corresponding climate in work units is crucial for patient safety. Intensive care units are usually co-led by a nurse and a physician, who are responsible for aligning an interprofessional workforce and warrant a high level of safety. Yet, little is known about whether and how these interprofessional co-leaders jointly affect their unit's safety climate. PURPOSE: This empirical study aims to explain differences in the units' safety climate as an outcome of the nurse and physician leaders' degree of shared goals. Specifically, we examine whether the degree to which co-leaders share goals in general fosters a safety climate by pronouncing norms of interprofessional cooperation as a behavioral standard for the team members' interactions. METHODOLOGY/APPROACH: A cross-sectional design was used to gather data from 70 neonatal intensive care units (NICUs) in Germany. Survey data for our variables were collected from the unit's leading nurse and the leading physician, as well as from the unit's nursing and physician team members. Hypotheses testing at unit level was conducted using multivariate linear regression. RESULTS: Our analyses show that the extent to which nurse-physician co-leaders share goals covaries with safety climate in NICUs. This relationship is partially mediated by norms of interprofessional cooperation among NICU team members. Our final model accounts for 54% of the variability in safety climate of NICUs. CONCLUSION: Increasing the extent to which co-leaders share goals is an effective lever to strengthen interprofessional cooperation and foster a safety climate among nursing and physician team members of hospital units.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30418292 TI - Variability in skilled nursing facility screening and admission processes: Implications for value-based purchasing. AB - BACKGROUND: Hospitalized older adults are increasingly admitted to skilled nursing facilities (SNFs) for posthospital care. However, little is known about how SNFs screen and evaluate potential new admissions. In an era of increasing emphasis on postacute care outcomes, these processes may represent an important target for interventions to improve the value of SNF care. PURPOSE: The aim of this study was to understand (a) how SNF clinicians evaluate hospitalized older adults and make decisions to admit patients to an SNF and (b) the limitations and benefits of current practices in the context of value-based payment reforms. METHODS: We used semistructured interviews to understand the perspective of 18 clinicians at three unique SNFs-including physicians, nurses, therapists, and liaisons. All transcripts were analyzed using a general inductive theme-based approach. RESULTS: We found that the screening and admission processes varied by SNF and that variability was influenced by three key external pressures: (a) inconsistent and inadequate transfer of medical documentation, (b) lack of understanding among hospital staff of SNF processes and capabilities, and (c) hospital payment models that encouraged hospitals to discharge patients rapidly. Responses to these pressures varied across SNFs. For example, screening and evaluation processes to respond to these pressures included gaining access to electronic medical records, providing inpatient physician consultations prior to SNF acceptance, and turning away more complex patients for those perceived to be more straightforward rehabilitation patients. CONCLUSIONS: We found facility behavior was driven by internal and external factors with implications for equitable access to care in the era of value-based purchasing. PRACTICE IMPLICATIONS: SNFs can most effectively respond to these pressures by increasing their agency within hospital-SNF relationships and prioritizing more careful patient screening to match patient needs and facility capabilities. PMID- 30418293 TI - Diverting dementia: Reducing the risk of cognitive loss. AB - As the population ages, more adults in the United States are living with dementia. Younger family members often are concerned that they too may develop dementia, but the general public is largely unaware that strategies exist to slow or delay onset of dementia. In fact, by implementing a number of healthful strategies throughout their lifespans, patients may be able to reduce the likelihood of developing dementia or at least delay its onset. These strategies include eating a high-quality diet; keeping physically, socially, and intellectually active; preventing or treating hearing loss; avoiding obesity, hypertension, and diabetes; and avoiding or stopping tobacco smoking. This article reviews the recent scientific literature for dementia risk-reduction strategies and offers suggestions to healthcare professionals who wish to help their patients stave off cognitive loss. PMID- 30418294 TI - Colorectal cancer rates are rising in younger adults. PMID- 30418295 TI - Commonly Held Beliefs About Myopia That Lack a Robust Evidence Base. AB - PURPOSE: To subject a number of commonly held beliefs or areas of confusion in the myopia field to scientific scrutiny. METHOD: A collection of statements about myopia are provided with references to demonstrate that a section of the research or clinical community supports the statement. The topics under discussion are reviewed critically with reference to the literature. RESULTS: The following statements are considered to lack sufficient supporting data to be considered as evidence-based: low-dose (0.01%) atropine slows myopia progression; relative peripheral hyperopia leads to myopia development and progression in children; undercorrection slows myopia progression; percentage treatment effect remains constant with continuing treatment; percentage treatment effect applies across the progression range; hand-held digital devices contribute to the myopia epidemic; more time outdoors slows myopia progression; the impact of outdoor activity on myopia incidence is due to daylight; subclassifications for myopia are effective; and myopia is a condition with a negative dioptric number. CONCLUSION: There are many hypotheses proposed to explain phenomena in the myopia field. Caution should be exercised in adopting conjecture until a robust evidence base is provided in support. PMID- 30418296 TI - Surgical Factors Affecting Changes in Ocular Surface Dynamics in the Early Postoperative Period After 25-Gauge Vitrectomy. AB - OBJECTIVES: Because vitrectomy-associated postoperative ocular surface changes are not well known, we evaluated such changes before and after vitrectomy in eyes with posterior segment diseases and investigated their associations with patients' characteristics and surgical procedures. METHODS: Thirty-five eyes of 32 consecutive patients (16 women; average age 66.6+/-11.1 years) were included in this prospective, noncomparative case series from tertiary care university hospital. Contact lens wearers and patients with history of ocular surgery or regular use of topical eyedrops were excluded. Patients had undergone primary 25 gauge vitrectomy at Osaka University Hospital in Japan between July and December 2016. Tear break-up time (TBUT), corneal and conjunctival fluorescein staining score (FSS), and tear meniscus height (TMH) were evaluated before, 1 week after, and 1 month after vitrectomy. RESULTS: Conjunctival FSS and TMH were significantly higher at 1 week after vitrectomy than preoperatively. However, they decreased significantly 1 month after. Changes in TBUT and corneal FSS showed a similar course at 1 week, but this was not statistically significant. Multiple linear regression analysis showed no significant correlation between significantly increased ocular parameters and patients' characteristics. By contrast, surgical time and combined cataract surgery significantly contributed to increased and decreased conjunctival FSS, respectively (P=0.011 and 0.033, respectively). Sclerotomy site suturing significantly contributed to increased TMH (P=0.025). CONCLUSIONS: We showed associations between ocular surface changes and specific surgical procedures. Caution should be exercised to minimize the effect of surgical procedures on the ocular surface during vitrectomy. PMID- 30418297 TI - SEAPI Incontinence Classification System: 1-Year Postoperative Results Following Midurethral Sling Placement. AB - OBJECTIVE: There are limited long-term data that has examined postoperative quality-of-life measures following placement of midurethral sling (MUS) for stress urinary incontinence (SUI). The SEAPI incontinence questionnaire includes 5 data points that rate severity of specific urinary symptoms. Our aim was to describe changes in SEAPI questionnaire outcomes 1 year following sling placement. METHODS: We retrospectively reviewed women who underwent MUS for SUI from 2005 to 2012. We included those women who had completed preoperative and postoperative (>12 months) SEAPI scores. Individual S, E, A, P, I score cure was defined as postoperative score of 0 (>0 preoperative). Logistic regression analysis was used to model the effects of patient characteristics on incontinence cure and S, E, A, P, I scores. RESULTS: A total of 584 women were included. Median follow-up was 25.4 months (12-126.8 months). Follow-up duration and baseline S, P, and I scores were associated with significantly lower odds of overall incontinence cure, whereas rectocele grade has positive association (odds ratio, 1.31; P = 0.040). Type of sling did not impact overall incontinence cure or cure of individual SEAPI scores. CONCLUSIONS: Preoperative S, P, and I scores had negative association with stress incontinence cure. Cure of individual S, E, A, P, I scores was impacted differently by various patient factors. The SEAPI questionnaire provides a unique profile of patient-reported and functional measures in women with SUI and may be helpful in those who undergo MUS. PMID- 30418298 TI - Interest of Youth Living with HIV in Long-Acting Antiretrovirals. AB - OBJECTIVES: This study's primary objective was to characterize attitudes to long acting antiretrovirals (LAARV), among youth aged 13 to 24 years living with perinatally- and non-perinatally-acquired HIV (PHIV and NPHIV, respectively). Secondary objectives included: assessing whether those with detectable HIV RNA PCR viral load had higher enthusiasm for LAARV compared to those with suppressed viral load, and examining characteristics associated with LAARV enthusiasm. METHODS: A cross-sectional survey of 303 Youth Living with HIV (YHIV) followed at four pediatric/adolescent HIV clinics in the USA was performed to determine interest in LAARV, using a modified survey instrument previously used in adults. Interest in LAARV across groups was compared. Poisson regression with robust variance was used to determine the impact of various characteristics on interest in LAARV. FINDINGS: Overall, 88% of YHIV reported probable or definite willingness to use LAARV. The enthusiasm level was similar between PHIV and NPHIV youth (p=0.93). Youth with HIV viral load >1000 copies/mL had significantly higher interest than youth with suppressed viral load (PR 1.12 [95% CI: 1.03 - 1.20]; p= 0.005). Female youth participants who had had past experience with implantable contraceptive methods had a significantly higher interest in LAARV (100% vs 85.5%; p=0.002). Proportion of respondents endorsing definite willingness to use was significantly higher with decreased injection frequency compared to increased injection frequency. INTERPRETATION: YHIV at four urban US pediatric/adolescent HIV clinics had high levels of enthusiasm for LAARV. LAARV should be given high priority as a potentially viable treatment option to improve clinical outcomes in YHIV. PMID- 30418299 TI - Concomitant Left Atrial Reduction in Rheumatic Mitral Valve Disease With Giant Left Atrium: Our Technique With Midterm Results. AB - OBJECTIVE: The giant left atrium is a frequent finding with rheumatic heart disease. The enlarged left atrium was found to be a risk factor for early mortality and postoperative higher thromboembolic events, but its management remains controversial. Most of the surgeons just do the mitral valve procedure without any intervention for enlarged left atrium. We present our center's experience of patients with giant left atrium who underwent a newer technique of left atrium reduction concomitant with mitral valve procedure. METHODS: Between January 2012 and February 2015, 25 patients, who underwent surgery for concomitant left atrium reduction with mitral valve disease, were included in the study after institute's ethics committee clearance. Patients having combined aortic and mitral valve disease were excluded. Preoperative, intraoperative, and postoperative data were collected. All the patients were also followed up clinically and echocardiographically in postoperative period. RESULTS: There were 15 (60%) females. The mean +/- SD age of the patients was 36.92 +/- 5.4 years. Preoperatively, all patients were in long-standing persistent atrial fibrillation. The mean +/- SD bypass and aortic cross-clamp time were 74.56 +/- 3.85 and 51.72 +/- 4.32 minutes, respectively. There was a significant reduction of left atrium diameter and volume from 94.48 +/- 11.0 mm to 40.08 +/- 1.35 mm and 348.3 +/- 121.1 to 26.57 +/- 2.9 mL/m, respectively. There was no early or late mortality. At a mean +/- SD follow-up of 42.28 +/- 12.1 months, all patients were in New York Heart Association I or II class and 24 (96%) patients were in normal sinus rhythm. CONCLUSIONS: Concurrent left atrium reduction with mitral valve procedure is a feasible and effective technique for event-free survival of the patients having giant left atrium with mitral disease. PMID- 30418300 TI - Multidisciplinary Approach to Improve Sepsis Outcomes. AB - Severe sepsis and septic shock cause significant morbidity and mortality with health care costs approximating $17 billion annually. The Surviving Sepsis Campaign 2012 recommended time-sensitive care bundles to improve outcomes for patients with sepsis. At our community teaching hospital, a review of sepsis management for patients admitted to a medical intensive care unit (ICU) between December 2015 and March 2016 found 70.8% compliance with timing of lactate draw, 65.3% compliance for blood cultures, and 51.4% compliance with antibiotic administration recommendations. Thus, a quality improvement initiative to improve detection and time to bundle completion for ICU-level patients was designed. Previous studies suggest that utilization of sepsis alert systems and sepsis response teams in the emergency department setting is associated with improved compliance with recommended sepsis bundles and improved hospital mortality. Therefore, a "sepsis alert" protocol was implemented that used both an electronic alert and an overhead team alert that mobilized nursing, pharmacy, phlebotomy, and a senior internal medicine resident to bedside. In addition, a template to document sepsis diagnosis and bundle adherence was created. After implementation, we noted improvement in appropriately timed serum lactate, 88.6% versus 70.8% (p = .008) with no significant improvements in blood cultures, antibiotic administration, or mortality. PMID- 30418301 TI - Differences in Performance on Developmental Tasks in Young Children Across Digital and Paper-Based Modalities: A Feasibility Trial. AB - OBJECTIVE: To determine whether use of digital-based screening is a feasible approach to monitoring child development, it is necessary to assess young children's abilities to interface with touch screen technology. The primary objectives of this exploratory feasibility study with a randomized experimental design were to determine (1) whether young children respond differently to developmental tasks on paper versus tablet device and (2) whether responses to items presented digitally differed according to hours of weekly exposure to touch screen technology in the home. METHODS: Eighty children attending 18-, 24-, 36-, or 48-month pediatrician well-child checks were randomly assigned to complete a series of 70 examiner-facilitated, developmental tasks across 7 domains (receptive language, expressive language, early literacy, early numeracy, social emotional, cognition, and fine motor) presented either digitally or on paper. Parents provided information about use of technology in the home. A series of t tests assessed for main effects of presentation modality (digital vs paper) on each of the domains. RESULTS: Raw scores across the 7 domains did not differ by presentation modality. Hours of technology use per week was not related to raw scores among children in the digital condition. CONCLUSION: Young children do not respond differentially to items when presented in a digital format in comparison to a paper-based format. Use of manipulatives for assessing developmental skills may be needed for children 2 years and younger, as they displayed a limited range of responses to items in both conditions at these age groups. PMID- 30418302 TI - The management of partial zoen II intrasynovial flexor tendon lacrations: A literature review of biomechanics, clinical outcomes and complications. PMID- 30418303 TI - Response: Questions on "Accessory Nerves of the Forehead: A Newly Discovered Frontotemporal Neurovascular Bundle". PMID- 30418304 TI - An New Photogrammetry of Nasal Morphology for Asian Patients with Unilateral Secondary Cleft Lip Nasal Deformity. PMID- 30418305 TI - "No Protractor, No Problem: A different angle on z-plasties." PMID- 30418306 TI - "Factors Affecting Women's Success in Academic and Private Practice Plastic Surgery". PMID- 30418307 TI - Intercostal Artery Perforator Flap for Vascularized Lymph Node Transfer in Post Breast Cancer Upper Extremity Lymphedema. PMID- 30418308 TI - The Lateral Thigh Perforator Propeller Flap: A Reliable Back-Up Plan For Loco Regional Reconstruction In Case Of Missing Or Unreliable Alt Perforators. PMID- 30418310 TI - Questions on "Accessory Nerves of the Forehead: A Newly Discovered Frontotemporal Neurovascular Bundle". PMID- 30418309 TI - Submitting Appropriately for Breast Surgery in Transmasculine Patients. PMID- 30418311 TI - "Global Interest in Gender Affirmation Surgery: A Google Trends Analysis." PMID- 30418312 TI - Reply to: The Lateral Thigh Perforator Propeller Flap: A Reliable Back-Up Plan For Loco-Regional Reconstruction In Case Of Missing Or Unreliable Alt Perforators. PMID- 30418314 TI - Response to "letter to the editor" PRS-D-18-00605, entitled Minimal Pain with Prepectoral implant based breast reconstruction, by Dr Raghavan Vidya. PMID- 30418313 TI - Motiva Ergonomix Round SilkSurface Silicone Breast Implants - The tale of Goldilocks: never be afraid of exploring unknown territory. PMID- 30418315 TI - "The tale of Goldilocks: the middle is the place to be". PMID- 30418316 TI - The Management of Partial Zone II Intrasynovial Flexor Tendon Lacerations: A Literature Review of Biomechanics, Clinical Outcomes, and Complications. PMID- 30418317 TI - Reply: Letter to the Editor. PMID- 30418318 TI - Effects of Botulinum Toxin on Improving Facial Surgical Scars: A Prospective, Split-Scar, Double-Blind, Randomized Controlled Trial'. PMID- 30418319 TI - Design and Usability Testing of the Stroke Caregiver Support System: A Mobile Friendly Website to Reduce Stroke Caregiver Burden. AB - PURPOSE: The purpose of this study was to design a mobile-friendly, Internet based website, modeled on previously described websites for Alzheimer caregivers, to equip stroke caregivers and potentially reduce caregiver burden. DESIGN: A mixed-methods study was performed to design and test the usability of the Stroke Caregiver Support System (SCSS). METHODS: An iterative, user-centered design approach was employed in three phases: (I) Focus Groups, (II) Structured Interviews, and (III) Usability Testing. Phase I and Phase II provided information for the development of the SCSS website, whereas Phase III helped in gathering data regarding the usability and efficacy of the newly implemented SCSS website. FINDINGS: Qualitative data on caregiving and the content and design of the SCSS were obtained from focus groups and interviews. In the usability test, the nine caregivers who completed Phase III (78% women, mean age = 46, SD = 17) exhibited a high level of burden and depressive symptoms (median [Q1, Q3] Zarit burden score = 18 [16, 23], Center of Epidemiologic Studies-Depression Scale = 15 [8, 17]). Caregivers conveyed the usability of the SCSS but also expressed several needed improvements. CONCLUSIONS: Participants reported the value of the SCSS, but further refinements are needed to maximize its usability and potential efficacy. CLINICAL RELEVANCE: The SCSS has potential to reduce caregiver burden in stroke. PMID- 30418320 TI - Screening for orthostatic hypotension using home blood pressure measurements. AB - OBJECTIVE: Orthostatic hypotension is a common condition associated with adverse cardiovascular and cognitive prognosis. Screening for orthostatic hypotension consists of blood pressure measurements in supine (or sitting) and standing position during clinical consultations. As orthostatic hypotension is a poorly reproducible clinical condition, it is likely that the simple measurement carried out during consultations underestimates the true prevalence of the condition. The objective of this study is, therefore, to determine whether screening for orthostatic hypotension with home blood pressure measurements (HBPM) may improve orthostatic hypotension diagnosis without compromising the quality of the blood pressure readings. MATERIALS AND METHODS: We asked all patients with indications for HBPM in the hypertension unit and in a general medical practice to perform a series of home blood pressure measurements, ending each series with a measurement in standing position. RESULTS: We recruited 505 patients of mean age 68 years of which 93% were hypertensive patients. The success rate of HBPM complying with the ESH criteria (12 out of 18 measurements) was 94.5%, which is comparable with previously published series of measurements. Ninety-one percent of patients measured their blood pressure at least once in standing position, and 88% of patients recorded all six standing measurements. Orthostatic hypotension prevalence defined as the presence of one episode of orthostatic hypotension was 37.47%, much higher than orthostatic hypotension prevalence measured in the same cohort in a clinic setting (15%). CONCLUSION: The measurement of blood pressure in standing position during HBPM is feasible without altering the quality of the blood pressure readings in seated position. Our findings show that orthostatic hypotension is significantly more often detected at home by the patient than at the doctor's office, which may allow quicker initiation of preventive and therapeutic strategies. PMID- 30418321 TI - Eplerenone improves endothelial function and arterial stiffness and inhibits Rho associated kinase activity in patients with idiopathic hyperaldosteronism: a pilot study. AB - OBJECTIVE: Primary aldosteronism is one of the most common cause of secondary hypertension. It is well known that the incidence of cardiovascular events is higher in patients with primary aldosteronism than in patients with essential hypertension. In a previous study, we showed that aldosterone-producing adenoma is associated with vascular function and structure. The aim of this study was to evaluate the effects of eplerenone on vascular function in the macrovasculature and microvasculature, arterial stiffness and Rho-associated kinase (ROCK) activity in patients with idiopathic hyperaldosteronism (IHA). METHODS: Vascular function, including reactive hyperemia index (RHI), flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID), arterial stiffness including brachial-ankle pulse wave velocity (baPWV) and brachial intima-media thickness (IMT) and ROCK activity in peripheral leukocytes were measured before and after 12 weeks of treatment with eplerenone in 50 patients with IHA. RESULTS: After 12 weeks, eplerenone decreased the aldosterone renin ratio but did not alter SBP and DBP. Eplerenone treatment increased log RHI from 0.56 +/- 0.25 to 0.69 +/- 0.25 (P < 0.01) and NID from 12.8 +/- 5.8 to 14.9 +/- 6.9% (P = 0.02) and it decreased baPWV from 1540 +/- 263 to 1505 +/- 281 (P = 0.04) and ROCK activity from 1.20 +/ 0.54 to 0.89 +/- 0.42 (P < 0.01), whereas there was no significant change in FMD (increase from 4.6 +/- 3.4 to 4.6 +/- 3.6%, P = 0.99) or brachial IMT (decrease from 0.28 +/- 0.07 to 0.28 +/- 0.04 mm, P = 0.14). CONCLUSION: Eplerenone improves microvascular endothelial function, vascular smooth muscle function, arterial stiffness and ROCK activity in patients with IHA. CLINICAL TRIAL REGISTRATION INFORMATION: URL for Clinical Trial: http://UMIN; Registration Number for Clinical Trial: UMIN000003409. PMID- 30418322 TI - Excess Mortality Among Adults Hospitalized With Traumatic Brain Injury in Australia: A Population-Based Matched Cohort Study. AB - OBJECTIVE: To quantify and describe excess mortality attributable to traumatic brain injury (TBI) during the 12 months after hospitalization. DESIGN: Population based matched cohort study using linked hospital and mortality data. SETTING: Australia. PARTICIPANTS: Individuals 18 years and older who were hospitalized with a principal diagnosis of TBI in 2009 (n = 6929) and matched noninjured individuals randomly selected from the electoral roll (n = 6929). MAIN MEASURES: Survival distributions were compared using a Kaplan-Meier plot with a log-rank test. Mortality rate ratios (MRRs) were computed using Cox proportional hazard regression with and without controlling for demographic characteristics and preexisting health status. RESULTS: Individuals with TBI experienced significantly worse survival during the 12 months after hospitalization (chi = 640.9, df = 1, P < .001), and were more than 7.5 times more likely to die compared with their noninjured counterparts (adjusted MRR, 7.76; 95% confidence interval, 6.07-9.93). TBI was likely to be a contributory factor in 87% of deaths in the TBI cohort. Excess mortality was higher among males, younger age groups, and those with more severe TBI. CONCLUSION: Excess mortality is high among individuals hospitalized with TBI and most deaths are attributable to the TBI. Increased primary and secondary preventive efforts are warranted to reduce the mortality burden of TBI. PMID- 30418323 TI - Primary care for survivors of colorectal cancer. AB - Colorectal cancer survivorship has risen in recent years because of earlier detection and advances in treatment. Primary care providers (PCPs) may see more of these patients in their daily practices. This article discusses some of the most common issues patients face after completing treatment for colorectal cancer and describes how PCPs can help. PMID- 30418324 TI - Radiation-Induced Multiphasic Demyelination. PMID- 30418325 TI - Intracranial Hypertension in Transgender Patients. PMID- 30418326 TI - Neuro-Ophthalmology in South India. PMID- 30418327 TI - Influence of Physical Fitness on Special Judo Fitness Test Performance: A Multiple Linear Regression Analysis. AB - Lopes-Silva, JP, Panissa, VLG, Julio, UF, and Franchini, E. Influence of physical fitness on Special Judo Fitness Test performance: a multiple linear regression analysis. J Strength Cond Res XX(X): 000-000, 2018-The purpose of this study was to identify the physical fitness variables that best predict Special Judo Fitness Test (SJFT) performance. Thirty-five male experienced judo athletes took part in this study. All athletes performed 5 tests: upper- and lower-body cycle ergometer graded exercise tests; upper- and lower-body Wingate tests; and SJFT. The peak oxygen consumption (V[Combining Dot Above]O2peak), maximum heart rate (HRmax), maximum aerobic power, and the variables corresponding to onset blood lactate accumulation (OBLA) were determined during the graded exercise tests. For the Wingate tests, peak power (PP) and mean power were used. Furthermore, the total number of throws, heart rate (HR) immediately and 1 minute after, and SJFT index were calculated. Four separated forward multiple linear regressions (forward model) were used to identify the physical fitness variables that best explained the SJFT variables. Upper-body V[Combining Dot Above]O2peak (ml.min.kg) explained 27% of variance in the total number of throws, whereas an additional 7% was explained by upper-body PP. Upper-body HRmax explained 46% of the variance in the HR immediately after the SJFT, whereas lower-body HR at OBLA accounted for an additional 8%. Lower-body HRmax explained 21% of the variance in the HR 1 minute after the SJFT, whereas peak lactate ([La]peak) after the lower-body graded exercise test accounted for an additional 12%. Upper-body V[Combining Dot Above]O2peak (ml.min.kg) alone accounted for 15% of the variance in the SJFT index. Based on these results, the data suggest that physical fitness variables, derived from upper- and lower-body aerobic and anaerobic tests, have a small ability to predict the SJFT variables. PMID- 30418328 TI - Normative Reference Values for High School-Aged American Football Players: Proagility Drill and 40-Yard Dash Split Times. AB - McKay, BD, Miramonti, AA, Gillen, ZM, Leutzinger, TJ, Mendez, AI, Jenkins, NDM, and Cramer, JT. Normative reference values for high school-aged American football players: Proagility drill and 40-yard dash split times. J Strength Cond Res XX(X): 000-000, 2018-The purpose of this short report was to provide test- and position-specific normative reference values for the 10- and 20-yd split times (10YD and 20YD) during the 40-yd dash (40YD) as well as 10-yd split times during the proagility drill (PA) based on a large, nationally representative sample of high school-aged American football players in their freshman, sophomore, and junior classes. Cross-sectional performance data were obtained from 12 different high school American football recruiting combines between March 7, 2015, and January 9, 2016, across the United States. The sample included (n = 7,478) high school-aged American football athletes in their freshman (n = 1,185), sophomore (n = 2,514), and junior (n = 3,779) classes. Each player self-classified their American football positions as defensive back, defensive end, defensive linemen, linebacker, offensive linemen (OL), quarterback (QB), running back, tight end, or wide receiver. The results of the freshman, sophomore, and junior class were aggregated to generate test- and position-specific normative values. Mean differences were found among classes for all positions and all measurements (p <= 0.05) except for OL and QB PA split time (p > 0.05). Greater percent differences for all 3 variables were observed between freshman and sophomore years than between sophomore and junior years. These normative reference values will be useful for athletes, parents, coaches, and high school strength and conditioning professionals to set realistic goals for young American football athletes. PMID- 30418329 TI - Meliora! PMID- 30418330 TI - T-Cell Acute Lymphoblastic Lymphoma Presenting as Dissecting Cellulitis and Cavernous Sinus Syndrome. PMID- 30418331 TI - Methods to Assess Ocular Motor Dysfunction in Multiple Sclerosis. AB - : BACKGROUND:: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system causing the immune-mediated demyelination of the brain, optic nerve, and spinal cord and resulting in ultimate axonal loss and permanent neurological disability. Ocular motor dysfunction is commonly observed in MS but can be frequently overlooked or underappreciated by nonspecialists. Therefore, detailed and quantitative assessment of eye movement function has significant potential for optimization of patient care, especially for clinicians interested in treating visual symptoms or tracking disease progression. METHODS:: A brief history of eye tracking technology followed by a contextualized review of the methods that can be used to assess ocular motor dysfunction in MS-including a discussion of each method's strengths and limitations. We discuss the rationale for interest in this area and describe new tools capable of tracking eye movements as a possible means of monitoring disease. RESULTS/CONCLUSIONS:: This overview should inform clinicians working with patients with MS of how ocular motor deficits can best be assessed and monitored in this population. It also provides a rationale for interest in this field with insights regarding which techniques should be used for studying which classes of eye movements and related dysfunction in the disease. PMID- 30418332 TI - The International Multiple Sclerosis Visual System Consortium: Advancing Visual System Research in Multiple Sclerosis. AB - BACKGROUND: The International Multiple Sclerosis Visual System Consortium (IMSVISUAL) was formed in November 2014 with the primary goal of improving research, care, and education regarding the role of the visual system in multiple sclerosis (MS) and related disorders. METHODS: In this review, we describe the formation, goals, activities, and structure of IMSVISUAL, as well as the relationship of IMSVISUAL with the Americas Committee for Treatment and Research in MS (ACTRIMS). Finally, we provide an overview of the work IMSVISUAL has completed to date, as well as an outline of research projects ongoing under the auspices of IMSVISUAL. RESULTS: IMSVISUAL has 140 members worldwide and continues to grow. Through IMSVISUAL-related research, optical coherence tomography (OCT) derived peripapillary retinal nerve fiber layer (pRNFL) thinning has been established as a predictor of future disability in MS. IMSVISUAL has also developed guidelines for reporting OCT studies in MS. Moreover, a systematic review performed by IMSVISUAL found that not only are pRNFL and ganglion cell + inner plexiform layer (GCIPL) thicknesses reduced in patients with MS (particularly in eyes with prior optic neuritis [ON]), but that inner nuclear layer measures may be higher among MS ON eyes, relative to healthy control eyes. Currently, there are several ongoing IMSVISUAL projects that will establish a role for visual outcomes in diagnosing MS and quantifying the effects of emerging therapies in clinical trials. CONCLUSIONS: The development of IMSVISUAL represents a major collaborative commitment to defining the role of visual outcomes in high-quality, large-scale studies that generate definitive and instructive findings in the field of MS. As a consortium, IMSVISUAL has completed several international collaborative projects, is actively engaged in numerous ongoing research studies, and is committed to expanding the role of vision research in MS and related disorders. PMID- 30418333 TI - Patterns of Cortical Visual Field Defects From Embolic Stroke Explained by the Anastomotic Organization of Vascular Microlobules. AB - The cerebral cortex is supplied by vascular microlobules, each comprised of a half dozen penetrating arterioles that surround a central draining venule. The surface arterioles that feed the penetrating arterioles are interconnected via an extensively anastomotic plexus. Embolic occlusion of a small surface arteriole rarely produces a local infarct, because collateral blood flow is available through the vascular reticulum. Collateral flow also protects against infarct after occlusion of a single penetrating arteriole. Cortical infarction requires blockage of a major arterial trunk, with arrest of blood flow to a relatively large vascular territory. For striate cortex, the major vessels compromised by emboli are the inferior calcarine and superior calcarine arteries, as well as the distal branches of the middle cerebral artery. Their vascular territories have a fairly consistent relationship with the retinotopic map. Consequently, occlusion by emboli results in stereotypical visual field defects. The organization of the arterial supply to the occipital lobe provides an anatomical explanation for a phenomenon that has long puzzled neuro-ophthalmologists, namely, that of the myriad potential patterns of cortical visual field loss, only a few are encountered commonly from embolic cortical stroke. PMID- 30418334 TI - Surgical stabilisation improves 30-day mortality in patients with traumatic flail chest: A comparative case series at a Major Trauma Centre. AB - OBJECTIVES: To evaluate the outcomes including early mortality following surgical rib fixation using a locking plate system as part of a newly introduced chest trauma pathway. DESIGN: Prospective cohort study with retrospective case controlled matching with a minimum of one year follow up. SETTING: Regional Level 1 Trauma Centre. PATIENTS/PARTICIPANTS: Consecutive patients undergoing surgical rib fixation were prospectively recruited over a three year period (56 patients), and matched to similar patients managed non-operatively (89 patients) using our local trauma registry. Matching was based on injury severity scores and patient demographics. INTERVENTION: Surgical rib fixation with locking plates. MAIN OUTCOME MEASUREMENTS: The primary outcome measure was 30-day mortality with secondary outcomes of hospital length of stay (HLOS), intensive care unit length of stay (ICULOS), and patient-reported outcome measures including quality of life (EuroQol - EQ-5D-5L). Official causes of death were obtained from the Coroner including post mortem results. RESULTS: There was a significant reduction in 30 day mortality in the fixed patients with 1.8% (1/56) compared to 12.4% (11/89) of the non-fixed patients (p=0.03). This difference remained significant after further exclusion of other non-survivable injuries (p=0.046). Although HLOS was significantly longer in the fixed group, there was no difference on multivariable analysis. Other secondary outcomes were comparable between the groups with no significant differences in any patient-reported measures. CONCLUSIONS: Mortality was significantly lower in patients who underwent rib stabilisation. Quality of life and other patient-reported measures were similar, demonstrating no evidence of detrimental longer term effects of rib stabilisation. LEVEL OF EVIDENCE: Prospective cohort study with retrospective case-controlled matching. Level II. PMID- 30418335 TI - Correlates of Treatment Retention and Opioid Misuse Among Postpartum Women in Methadone Treatment. AB - OBJECTIVES: The postpartum period is a particularly challenging time for women in methadone treatment. Unfortunately, this is also the time when women are vulnerable to treatment discontinuation and opioid misuse. The purpose of the present exploratory study was to examine demographic, treatment, and delivery factors that may be associated with postbirth retention in treatment and opioid misuse. METHODS: A chart review was conducted among postpartum women (n = 81) receiving opioid agonist treatment during pregnancy. RESULTS: Results revealed that treatment discharge and postbirth opioid misuse were common after delivery. Longer treatment duration before delivery was associated with a lower likelihood of opioid misuse in the month after delivery. Women who delivered via cesarean section and received a discharge opioid medication were also more likely to engage in opioid misuse (ie, providing an opioid-positive urine toxicology screen outside the window of detection for the discharge opioid prescription) in the month after delivery. CONCLUSIONS: Increasing support to minimize the likelihood of treatment discontinuation or opioid misuse may be particularly important in this period, especially for this vulnerable group. PMID- 30418336 TI - Utility of Urine Drug Testing in Outpatient Addiction Evaluations. AB - OBJECTIVE: Data examining usefulness of urine drug testing in addiction settings for accurately establishing diagnoses and informing treatment is limited. In this retrospective-cohort study we examined the utility of performing urine drug testing in patients presenting for an outpatient addiction assessment. METHODS: Urine drug testing and patient-reported substance use history were obtained from the medical record of patients who presented for an outpatient addiction evaluation. Patients who denied use of a substance within the window of detection but tested positive were considered to have misrepresented their use. Differences between patients accurately representing versus misrepresenting their use were evaluated. Sensitivity/specificity of drug tests were calculated from self-report and changes to treatment recommendations and diagnoses assessed. RESULTS: One hundred and seventy-four patients (mean age = 43.35 +/- 15.68 years) were included and the sample was majority male (67%). Ninety-four (54%) patients reported use of a substance within the window of detection. Of 80 patients denying recent use, 14 tested positive (8%). There were no differences in sex (P = 0.78) or age (P = 0.12); referral sources differed significantly between correct and incorrect responders (P = 0.01). Specificity varied between 96% and 99%, while sensitivity had a wider range (17%-87%). Treatment recommendations and diagnoses were altered after review of drug testing results in 1 patient (0.5%). However, in the remainder, all patients were already diagnosed with a severe substance use disorder and had received recommendations to initiate residential/outpatient substance use treatment. CONCLUSIONS: Among patients completing urine drug testing during outpatient substance use disorder evaluation positive screens alerted providers to undisclosed persistent substance use and potential withdrawal in 8% of the cohort and resulted in a change in diagnoses and/or treatment in 1 patient. PMID- 30418337 TI - Trends and Related Factors of Cannabis-Associated Emergency Department Visits in the United States: 2006-2014. AB - OBJECTIVES: To examine national trends and contributing factors of cannabis associated emergency department visits in the United States. METHODS: This pooled serial cross-sectional study used a hierarchical multivariable analysis on emergency department visit adjusting for year, patient and hospital characteristics. We analyzed 2006 to 2014 National Emergency Department Sample data that identified cannabis-associated emergency department visits among patients aged 12 years or older (n = 265,128). RESULTS: Cannabis-associated emergency department visits per 100,000 emergency department discharges increased monotonically (annually by 7%). As compared with privately insured patients, Medicare, and Medicaid, uninsured patients were over 40% more likely to visit emergency department. The age group 12 to 17 had the highest risk of emergency department visits and the risk monotonically declined as the age increased. Hospitals in the South region showed the highest cannabis-associated emergency department utilization, yet trends of cannabis-associated emergency department visits increased in the West region from 15.4% to 26% over time. CONCLUSIONS: Cannabis-associated emergency department visits increase monotonically over time. Although vulnerable persons were identified, additional policy or regional factors should explore risks of emergency department visits associated with cannabis use. PMID- 30418338 TI - Outcomes and Patterns of Health Care Utilization After Hospitalization for Pediatric Critical Illness Due to Respiratory Failure. AB - OBJECTIVES: To quantify home care needs, healthcare utilization, and 2-year mortality after pediatric critical illness due to respiratory failure, and evaluate the impact of new morbidity and abnormal function at hospital discharge on resource use and outcomes. DESIGN: Retrospective cohort study. SETTING: Quaternary care PICU. PATIENTS: Patients less than or equal to 18 years with respiratory failure from January 1, 2013, to December 31, 2014. MEASUREMENTS AND MAIN RESULTS: Patient demographics, hospitalization characteristics, and healthcare utilization were quantified and compared according to morbidity development and discharge functional status. Multivariable regression methods evaluated 2-year readmission rates and mortality by morbidity development and discharge functional status. Of 163 patients, the median age was 2.1 years (interquartile range, 0.6-10.9 yr), 61 (37.4%) had a comorbidity, and 73 (44.8%) had abnormal function at admission. Median ventilation duration was 6.0 days (interquartile range, 3.0-11.7 d), and median PICU and hospital length of stay were 8 (interquartile range, 4-15) and 14 days (interquartile range, 8-23 d), respectively. At hospital discharge, eight of 163 (4.9%) had died, and 14 of 163 (8.6%) had a new morbidity. Of the surviving 155 patients at hospital discharge, 87 (56.1%) had abnormal function, 120 (77.4%) had new medications, 24 (15.5%) had new medical devices, and 43 (27.7%) had new home care equipment. Cumulative 2 year mortality was 14 of 163 (8.6%) with six of 163 (3.7%) occurring after discharge. Within 2 years, 81 of 155 of patients (52.2%) were readmitted, often (58/81, 71.6%) to the PICU. Abnormal function at discharge was associated with elevated odds of readmission to the hospital (odds ratio, 1.49; 1.28-1.74; p < 0.0001) and PICU (odds ratio, 1.47; 1.27-1.71; p < 0.0001) within 2 years. CONCLUSIONS: After critical illness, children have significant new healthcare burdens heretofore unrecognized. Abnormal functional status at hospital discharge was associated with increased healthcare utilization up to 2 years thereafter. PMID- 30418339 TI - A Cross-Sectional Analysis of Compassion Fatigue, Burnout, and Compassion Satisfaction in Pediatric Critical Care Physicians in the United States. AB - OBJECTIVES: To determine the prevalence of compassion fatigue, burnout, and compassion satisfaction and identify potential personal and professional predictors of these phenomena in pediatric critical care providers. DESIGN: Cross sectional, online survey. SETTING: Pediatric critical care practices in the United States. SUBJECTS: Pediatric critical care fellows and attending physicians. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: A modified Compassion Fatigue and Satisfaction Self-Test for Helpers and a questionnaire of personal and professional characteristics were distributed electronically to pediatric critical care physicians nationally. Prevalence of these phenomena was calculated. Hierarchical linear regression models for compassion fatigue, burnout, and compassion satisfaction as a function of potential risk factors were constructed. The survey response rate was 35.7%. The prevalence of compassion fatigue, burnout, and compassion satisfaction was 25.7%, 23.2%, 16.8%, respectively. Burnout score, emotional depletion, and distress about a patient and/or the physical work environment were each significant determinants of higher Compassion Fatigue scores. Preparing for didactics, Compassion Fatigue score, distress about administrative issues and/or coworkers, and "self-care is not a priority" were each significant determinants of higher burnout scores, whereas female sex, Compassion Satisfaction score, and distress about the physical work environment were each significant determinants of lower burnout scores. Prayer/meditation, talking with colleagues, senior faculty level, and student and/or chaplain involvement when delivering bad news were each significant predictors of higher Compassion Satisfaction scores, whereas female sex, burnout score, emotional depletion, and distress about coworkers were each significant predictors of lower Compassion Satisfaction scores. CONCLUSIONS: In our population, chronic exposure to distress in patients and families puts pediatric critical care physicians at risk for compassion fatigue and low compassion satisfaction. Awareness of compassion fatigue, burnout, and compassion satisfaction and their predictors may benefit providers both personally and professionally by allowing them to proactively manage their distress. PMID- 30418340 TI - Effect of Physical Activity on the Quality of Life in Osteoporotic Females Living in Residential Facilities: Randomized Controlled Trial. AB - BACKGROUND AND PURPOSE: The study aimed to assess the effect of a program of modified Sinaki exercises and Nordic Walking on the life quality in osteoporotic and osteopenic females living in residential care facilities, taking into account their baseline level of activity and risk of falling. The study was designed as a randomized controlled trial. METHODS: A sample of 91 females 65 to 98 years of age, the residents of Upper Silesian residential care facilities, was randomized into 4 groups. All groups received the same pharmacological treatment. In group 1 (control group), drugs were the only therapy; in group 2, the therapy was enhanced by program of modified Sinaki exercises; group 3 participated in Nordic Walking workout; and group 4 did both Sinaki exercises and Nordic Walking. Locomotor activity of the participants was estimated from pedometer readings. The risk of falling was assessed with the "Timed Up and Go" Test and the Functional Reach Test. With the QUALEFFO-41 questionnaire, the life quality of the participants was evaluated at baseline and after 12 months of intervention. RESULTS AND DISCUSSION: The study revealed that the studied women were at high risk of falling and that their physical activity was relatively low, likewise the quality of their lives. Their satisfaction with life was reduced by poor health, limited mobility, and the lack of social activities. Life quality improved in all 3 intervention groups, but in the control group, it decreased. The results of Bonferroni's post hoc test pointed to statistically significantly better quality of life in groups 2 (P = .01) and 4 (P = .00). CONCLUSION: Both modified Sinaki exercises and Nordic Walking significantly improved the participants' quality of life, but the most effective therapeutically was the combination of both these forms of physical activity. PMID- 30418341 TI - An Investigation of the Predictors of Comfortable and Fast Gait Speed in Community-Dwelling Older Adults. AB - BACKGROUND/PURPOSE: To identify the unique predictors of comfortable and fast gait speed in community-dwelling older adults using measures of physical performance (eg, lower extremity strength and balance), self-reported balance confidence, and global cognitive function. METHODS: Demographic information was collected from 60 healthy, community-dwelling older adults older than 60 years. Participants completed the following assessments: Mini-Mental State Examination; Activities-Specific Balance Confidence Scale; 30-second Chair Stand (30-SCS); Functional Reach (FR); and gait speed (comfortable and fast) using the GAITRite system. Hierarchical linear regression was used to examine the relationship of both fast and comfortable gait speeds with functional performance (CST and FR), cognition (Mini-Mental State Examination), Activities-Specific Balance Confidence Scale, and demographic information (age, gender, and body mass index). RESULTS AND DISCUSSION: Functional performance measures (30-SCS and FR) explained 55.4% and 64.7%, respectively, of the variance in comfortable and fast gait speed. Unique predictors for comfortable gait speed included 30-SCS, FR, and body mass index. Unique predictors of fast gait speed included 30-SCS, FR, gender, body mass index, and Activities-Specific Balance Confidence Scale score. These predictors explained 68.5% and 80.4% of the total variance in comfortable and fast gait speed, respectively. Global cognition was not a unique predictor of gait speed when performance measures were statistically controlled. However, the current study measured global cognitive status rather than the specific cognitive constructs, such as processing speed or executive function. Further research is needed to determine the role of cognition in the composition of gait speed. CONCLUSIONS: Gait speed is an important indicator for many outcomes such as fall risk, mortality, and functional status. Understanding that key variables of strength and balance comprise a large portion of gait speed allows clinicians to better direct their care and optimize rehabilitation outcomes. This study specifically used functional measures of strength and balance that can be easily implemented in the clinical setting. PMID- 30418342 TI - Extern Programs Promote Confidence and Reduce Anxiety With Clinical Decision Making in Nursing Students. AB - BACKGROUND: Clinical decision making (CDM), expected of professional nurses, affects patient outcomes but is arduous for nursing students to learn. Psychological barriers (low self-confidence [SC] and high anxiety with CDM) have an impact on its achievement. Externship programs help mitigate these barriers. PURPOSE: The aim was to examine the impact of summer employment (nurse extern [NE], nursing assistant, and non-health care employed) on students' confidence and anxiety with CDM. METHODS: The study used a quasi-experimental before-and after design using the Nursing Anxiety and Self-Confidence with Clinical Decision Making scale. Associate and baccalaureate degree students (N = 134) from 2 nursing and 2 extern programs were included. RESULTS: The NEs reported significantly increased SC (F = 14.02, P < .001) and reduced anxiety (F = 8.64, P < .001). Nonsignificant improvements were noted in other groups. CONCLUSIONS: Externships appear to enhance students' SC and lessen their anxiety with CDM. PMID- 30418343 TI - A Protocol-Driven Assessment Promotes a More Accurate Diagnosis of Irritable Bowel Syndrome. AB - A diverse range of conditions share symptoms commonly identified with irritable bowel syndrome. The objective of this study was to examine the diagnostic process in identifying additional diagnoses in women who are attending a clinic for evaluation of symptoms suggestive of irritable bowel syndrome. A retrospective audit was conducted of anonymous data gathered on consecutive female patients presenting to a specialist nurse-led service in Christchurch, New Zealand, with a provisional diagnosis of irritable bowel syndrome. A protocol containing routine pathology investigations and physical examination was used. Alarm features were identified and pertinent investigations were implemented. Rectocele was detected on rectal examination. Final diagnosis was noted and compared with baseline symptom data. Of 231 patients, 187 initially met Rome III criteria for irritable bowel syndrome. Red flags and abnormal investigations led to an alternate diagnosis in a further 27 patients. Of the 160 patients with irritable bowel syndrome, 31% were found to have a rectocele. They were seven times more likely to report a symptom associated with pelvic floor dysfunction (p < .0001) and four times more likely to report constipation (p = .0003). The use of a protocol including routine investigations and physical examination improves diagnostic yield. Pelvic floor dysfunction should be considered in those with unique symptom patterns and rectocele in the setting of irritable bowel syndrome. PMID- 30418345 TI - Anti-TNF and Physiologic Measures of Metabolic Disease in Rheumatoid Arthritis. PMID- 30418344 TI - Abnormal Liver Enzymes. AB - Abnormal liver enzymes are frequently encountered in primary care offices and hospitals and may be caused by a wide variety of conditions, from mild and nonspecific to well-defined and life-threatening. Terms such as "abnormal liver chemistries" or "abnormal liver enzymes," also referred to as transaminitis, should be reserved to describe inflammatory processes characterized by elevated alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. Although interchangeably used with abnormal liver enzymes, abnormal liver function tests specifically denote a loss of synthetic functions usually evaluated by serum albumin and prothrombin time. We discuss the entities that most commonly cause abnormal liver enzymes, specific patterns of enzyme abnormalities, diagnostic modalities, and the clinical scenarios that warrant referral to a hepatologist. PMID- 30418346 TI - Association of High-Sensitivity Troponin T With Left Ventricular Dysfunction in Ankylosing Spondylitis. AB - BACKGROUND: Ankylosing spondylitis (AS) is a systemic inflammatory disease, and cardiac dysfunction has not been clearly described clinically. High-sensitivity cardiac troponin T (hs-cTnT) is a noninvasive marker for subclinical myocardial injury. OBJECTIVE: In this study, we aimed to investigate any relationship between hs-cTnT and left ventricular (LV) function evaluated via tissue Doppler imaging in AS patients with no known cardiac risk factor. METHODS: Our study used a cross-sectional case protocol design and was conducted between January 2016 and June 2016. In total, 40 AS patients (17 females and 23 males) were age and sex matched with healthy volunteers (20 females and 20 males) and enlisted for this study. Detailed transthoracic echocardiography was performed, and tissue Doppler imaging was used to assess systolic and diastolic functions. High-sensitivity cardiac troponin T levels were measured and compared between 2 groups. RESULTS: Compared with control subjects, AS patients had lower early (Em)/late (Am) diastolic myocardial velocities, mitral annular plane systolic excursion, and end diastolic distance from the mitral annulus to the LV apex. Conversely, they had greater systolic myocardial velocity (Sm), isovolumetric relaxation time, and displacement index (p < 0.001, for all). Higher hs-cTnT levels were measured in AS patients (0.45 +/- 0.22 vs. 1.11 +/- 0.27, p < 0.001), and multivariate logistic regression analyses revealed that hs-cTnT was an independent predictor of LV diastolic dysfunction in AS patients. CONCLUSIONS: These data show that AS patients had impaired LV functions and increased hs-cTnT levels. Tissue Doppler imaging may be a useful tool for detection of early functional LV abnormalities, and hs-cTnT may be valuable biomarker of diastolic LV dysfunction in AS patients. PMID- 30418347 TI - Up-regulation of CD64 Expression on Monocytes in Patients With Active Adult-Onset Still Disease: A Possible Biomarker of Disease Activity. AB - OBJECTIVES: In this study, we investigated whether monocyte CD64 (mCD64) expression is correlated with disease activity in patients with adult-onset Still disease (AOSD) and whether it could be used to distinguish between active and inactive disease states. METHODS: We reviewed a series of 10 patients with a definite diagnosis of AOSD, recruited from January 2013 to December 2016. We used flow cytometry to quantitatively measure mCD64 expression levels in patients presenting with active and inactive disease states and statistically analyzed the corresponding changes. RESULTS: The mean +/- SD values of mCD64 expression levels in patients with active and inactive disease states were 77,148.3 +/- 39,066.3 and 19,225.8 +/- 7006.2 molecules/cell, respectively, indicating significantly higher mCD64 expression in the active state than in the inactive state (p = 0.005). Receiver operating characteristic analysis with a cutoff value of 31,796.0 molecules/cell was applied to distinguish active from inactive disease states; the sensitivity and specificity were both 100%. In these patients, only the mCD64 expression levels changed in parallel with disease activity under tocilizumab treatment; other conventional biomarkers measured showed no changes. CONCLUSIONS: Monocyte CD64 expression could be used to clearly distinguish between active and inactive AOSD. Thus, mCD64 could be a promising biomarker for evaluating the disease activity of AOSD, even in patients receiving tocilizumab treatment. PMID- 30418348 TI - The Value of Histology in the Diagnosis of Tuberculous Spondylodiscitis. AB - BACKGROUND: Tuberculous spondylodiscitis (TS) is the most common form of musculoskeletal tuberculosis. Currently, histology is widely used to distinguish tuberculous from nontuberculous disease. OBJECTIVES: The aim of the present study was to assess the accuracy of histology compared with bacteriology in the diagnosis of TS. METHODS: This is a single-center case series carried out from January 2014 to February 2018 in a pathology department. It included 121 discovertebral biopsies of infective spondylodiscitis. The measures of diagnostic accuracy of histology were determined taking bacteriology as criterion standard. RESULTS: Among the 121 cases, 55 (45.4%) were diagnosed as TS by histological and/or bacteriological findings, 17 (30.9%) were classified as definite TS by bacteriology, and the remaining 38 (69.1%) had positive histology and negative bacteriology. There were 2 false-negatives, which histologically displayed suppuration without granuloma, and 3 false-positives; in one case, histology displayed granulomas without necrosis and culture isolated Brucella. In the 2 others, histology revealed granulomas with caseous-like necrosis and microbiology isolated fungal species. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of histology in the diagnosis of TS were 88.2%, 93.4%, 83.3%, 95.5%, and 92%, respectively. CONCLUSIONS: Histology is proved to be an accurate diagnostic tool in TS. Suppurative forms of TS without granuloma are rare and represent the main cause of false-negative histology. Suggestive histology of TS does not rule out fungal and brucellar spondylodiscitis. Caseous necrosis is not pathognomonic of tuberculosis. Fungal infection can also exhibit such type of necrosis. PMID- 30418349 TI - Assessing the Quality of Global Clinical Practice Guidelines on Gout Using AGREE II Instrument. AB - OBJECTIVE: The aim of this study was to assess the quality of global clinical practice guidelines (CPGs) on gout. METHODS: We systematically searched MEDLINE, CBM (Chinese Biomedical Literature database), GIN (Guidelines International Network), NICE (National Institute for Health and Clinical Excellence), NGC (National Guideline Clearinghouse), WHO (World Health Organization), SIGN (Scottish Intercollegiate Guidelines Network), DynaMed, UpToDate, and Best Practice databases from their inception until January 2017 to identify and select CPGs related to gout. Two reviewers independently assessed the eligible gout CPGs using the AGREE II instrument. RESULTS: We evaluated 15 CPGs published between 2007 and 2017, produced by 13 different developers. Quality of evidence and strength of recommendations were presented in 14 (93%) and 13 (87%) CPGs, respectively. The mean scores (+/-SD) for each AGREE II domain were as follows: (i) scope and purpose: 75% (+/-17%), (ii) stakeholder involvement: 39% (+/-19%), (iii) rigor of development: 43% (+/-17%), (iv) clarity and presentation: 82% (+/ 14%), (v) applicability: 31% (+/-12%), and (vi) editorial independence: 23% (+/ 29%). CONCLUSIONS: The quality of gout CPGs was suboptimal, and various incompatible grading systems of quality of evidence and strength of recommendations were used. The use of a standardized international grading system is essential to ensure high methodological quality of gout CPGs. Tools such as AGREE II could substantially improve the development and update of future gout CPGs. PMID- 30418350 TI - Localized Provoked Vulvodynia: Association With Nerve Growth Factor and Transient Receptor Potential Vanilloid Type 1 Genes Polymorphisms. AB - OBJECTIVE: The aim of the study was to study the associations between localized provoked vulvodynia (LPV) and several single-nucleotide polymorphisms (SNPs) in the transient receptor potential vanilloid type 1 (TRPV1), nerve growth factor (NGF), and the heparanase (HPSE) genes. MATERIALS AND METHODS: Prevalence of SNPs among 65 women with moderate or severe primary LPV (initial symptoms occur with first provoking physical contact) and 126 healthy, ethnically matched controls was analyzed in an observational case-control study. Each participant answered a questionnaire addressing familial LPV occurrence and comorbid pain conditions. RESULTS: Familial occurrences of LPV, temporomandibular joint (TMJ) symptoms, recurrent vaginitis, and irritable bowel syndrome were significantly higher among LPV women than healthy controls. Genotyping analyses revealed a novel, statistically significant high prevalence of polymorphism c.945G>C (rs222747) of TRPV1 and a SNP in the promoter region of NGF (rs11102930) in LPV women compared with controls. A logistic regression model for rs222747 and rs11102930 frequent alleles indicates significant LPV association within the entire study group and Ashkenazi Jewish women, respectively. Comparison of pain conditions with frequent alleles showed the rs222747 "CC" genotype of TRPV1 associated with women with TMJ, recurrent vaginitis, and LPV. CONCLUSIONS: Our results suggest novel genetic susceptibility to primary LPV associated with specific alleles in genes TRPV1 and NGF and propose the rs222747 "C" allele of TRPV1 as a common genetic predisposition for other pain syndromes. PMID- 30418351 TI - Importance of Colposcopy Impression in the Early Diagnosis of Posthysterectomy Vaginal Cancer. AB - OBJECTIVE: The aim of the study was to investigate the value of cytology, high risk human papillomavirus (hrHPV) status and colposcopy in the early diagnosis of vaginal cancer after hysterectomy. MATERIALS AND METHODS: A retrospective study was performed in the Obstetrics and Gynecology Hospital of Fudan University. Posthysterectomy patients who were diagnosed with vaginal high-grade intraepithelial lesion (HSIL) by colposcopy-directed biopsy with colposcopy impression of extensive HSIL or suspicion of cancer and underwent upper or total vaginectomy from January 2009 to December 2017 were included. RESULTS: Eighty-six posthysterectomy vaginal HSIL patients were included. Available abnormal cytology and positive hrHPV were observed in 90.7% (49/54) and 96.2% (51/53) of the patients, respectively. A total of 18.6% (16/86) of the patients were diagnosed with squamous cell cancer by vaginectomy, and the average interval between hysterectomy and vaginectomy was 3.5 years. Among them, 62.5% (10/16) cancers occurred after hysterectomy for cervical cancer, 31.2% (5/16) after hysterectomy for cervical precancer, and 6.3% (1/16) after hysterectomy for myoma. An indication for hysterectomy (cervical cancer vs HSIL, odds ratio = 7.2, 95% CI = 1.9-28.0, p = .004) and colposcopy impression of vaginal cancer (vaginal cancer vs HSIL, odds ratio = 5.9, 95% CI = 1.3-26.8, p = .021) were high-risk factors of cancer confirmed by vaginectomy in colposcopy-directed biopsy vaginal intraepithelial neoplasia 2/3 posthysterectomy in multiple logistic regression analysis. CONCLUSIONS: Colposcopy is pivotal in the evaluation of abnormal cytology/hrHPV tests in follow-up of cervical cancer patients after hysterectomy and decision-making for vaginectomy in detecting early cancer.This is an open access article distributed under the terms of the Creative Commons Attribution Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30418352 TI - Longitudinal pattern of pain medication utilization in peripheral neuropathy patients. AB - We aimed to investigate the pattern and utilization of neuropathic pain medications in peripheral neuropathy patients. Using a privately-insured, healthcare claims database from 2001-2014, we identified a retrospective cohort of incident peripheral neuropathy patients (validated ICD-9 definition) after excluding other chronic pain conditions. Outcome measures included opioid prescriptions, chronic opioid therapy (greater than or equal to 90 days of continuous supply), guideline-recommended medications for painful peripheral neuropathy (serotonin reuptake inhibitors, tricyclic antidepressants, and gabapentinoids), and pain specialists (neurologists, physiatrists, and anesthesiologists). Multivariable logistic regression was used to evaluate associations of patient-level factors with these outcomes. The peripheral neuropathy population included 14,426 individuals with a mean (SD) age of 43.1 years (2.8) and 52.4% men followed for 3.1 (1.7) years before and 4.5 (1.4) years after the diagnosis. In this population, 65.9% received >= 1 opioid prescription, and 8.8% received chronic opioid therapy. Of those receiving chronic opioid therapy, only 26.4% received a guideline-recommended medication prior to chronic opioid status. For guideline-recommended medications, 35.7% received >=1, 12.4% >=2, and 3.8% >=3 different medications. No patient level factors were associated with both high opioid utilization (initiation and chronic use) and low guideline recommended medication utilization. Pain specialists were associated with high opioid utilization and high guideline-recommended medication utilization. In conclusion, opioid initiation and transition to chronic opioid therapy is frequent in a peripheral neuropathy population despite few patients receiving more than one guideline-recommended medication. Efforts to decrease opioid utilization and increase guideline-recommended medication use are needed to improve current neuropathic pain treatment. PMID- 30418353 TI - Nursing Professional Development's Spirit of Inquiry Focus Areas. AB - An Association for Nursing Professional Development (ANPD) task force was charged with redesigning the association's small research grant process. One step in this process included identifying focus areas for the specialty's spirit of inquiry. Using input from a round table discussion with ANPD annual convention attendees, the Journal for Nurses in Professional Development Editorial Board, and the convention evaluation query, 10 spirit of inquiry focus areas were identified that align with the Nursing Professional Development Practice Model. PMID- 30418354 TI - Spatiotemporal Analysis and Epidemiology of Kawasaki Disease in Western New York: A Sixteen Year Review of Cases Presenting to a Single Tertiary Care Center. AB - BACKGROUND: Kawasaki Disease (KD) is one of the leading causes of acquired heart disease in children in developed nations. Epidemiologic evidence suggests KD is related to an infectious agent; however, the cause remains unknown. Yearly incidence in Japan has been steadily increasing but few long-term databases of KD cases from North America have been reviewed. METHODS: We reviewed the epidemiology of local cases over a 16 year period to study incidence with time and temporal and geographic clustering of cases in a representative cohort in North America. RESULTS: The yearly incidence in cases per population < 5 years old per 100,000 was 20.2 and 15.9, using ICD9 and detailed chart review, respectively. Using ICD9 alone overestimates our incidence by 27%. We show a distinct seasonality of cases with winter predominance. Applying Kulldorff's spatial scan statistic revealed no significant clustering of cases with either purely spatial or space-time analyses. On purely non-constrained temporal SaTScan analysis, there was a significant clustering of cases in a 67-68 week period in 2000-2001. CONCLUSIONS: Our analysis reveals an apparent outbreak of KD in our region in 2000-2001. In contrast to Japan, for the last 14 years, the incidence in our region has been stable. PMID- 30418355 TI - Specimen Pooling as a Diagnostic Strategy for Microbiologic Confirmation in Children With Intrathoracic Tuberculosis. AB - 304 young children with suspected pulmonary tuberculosis had a gastric aspirate, induced sputum and nasopharyngeal aspirate collected on each of two consecutive weekdays. Specimens collected on the second day were pooled in the laboratory for each child individually. The diagnostic yield by Xpert and culture from pooled specimens was not significantly different to a single gastric aspirate. PMID- 30418356 TI - Compromised Growth among HIV Exposed Uninfected Compared to Unexposed Children in Nigeria. AB - BACKGROUND: HIV exposed but uninfected (HEU) children may be at an increased risk of impaired growth when compared to their unexposed and uninfected (HUU) counterparts. We compared the growth patterns of HEU to HUU children in Nigeria. METHODS: Pregnant women with and without HIV infection were enrolled at the Plateau State Specialist Hospital (PSSH), Jos, Nigeria. Infants born to these mothers were recruited at birth and the mother-infant pairs followed up for 18 months. Weight, length, and head circumference of the infants were measured at each visit. Age- and sex-standardized z-scores were generated for each anthropometric measure using the World Health Organization Child Growth Standards. Children with length-for-age (LAZ), weight-for-age (WAZ) and weight for-length (WLZ) z-scores <-2 were classified as stunted, underweight, and wasted respectively. RESULTS: Of 415 children (307 HEU and 108 HUU) recruited for this study, 117 (28.4%), 9 (2.2%) and 32 (7.8%) infants were stunted, underweight and wasted, respectively, at birth. In a multivariable longitudinal analysis, the odds of stunting were higher among HEU as compared to HUU children (adjusted odds ratio (aOR): 2.4 [95% CI: 1.4, 4.1]). Similarly, odds of being underweight were higher among the HEU children (aOR: 1.6 [95% CI: 1.1, 2.2]). CONCLUSION: Linear and ponderal growth were more impaired among HEU as compared to HUU children in Nigeria during the first 18 months of life. Further studies are needed to explore the causal basis for these differences. PMID- 30418357 TI - A Prospective, Open-label Study to Assess the Safety, Tolerability, and Efficacy of Anidulafungin in the Treatment of Invasive Candidiasis in Children 2 to <18 Years of Age. AB - BACKGROUND: Treatment with an echinocandin is recommended as first-line therapy for patients with invasive candidiasis including candidemia (ICC). Little is known about the efficacy and safety of anidulafungin in children with ICC. METHODS: Eligible patients with ICC aged 2-<18 years were enrolled into this prospective, open-label, non-comparative, international study (NCT00761267), and received anidulafungin for 10-35 days (3 mg/kg on Day 1, 1.5 mg/kg daily thereafter). Safety was assessed through Week 6 follow-up. Efficacy, measured by global response (based on clinical and microbiologic responses), was assessed at: end of intravenous treatment (EOIVT); end of treatment; Weeks 2 and 6 follow-up. RESULTS: Forty-nine patients (n=19, 2-<5 years; n=30, 5-<18 years) received >=1 dose of anidulafungin (median 11 days; range 1-35 days) and were assessed for safety. Among 48 patients with a Candida spp. isolated, C. albicans (37.5%), C. parapsilosis (25.0%), C. tropicalis (14.6%), and C. lusitaniae (10.4%) were the most frequent Candida spp. All patients reported >=1 treatment-emergent adverse event (AE), with diarrhea (22.4%), vomiting (24.5%), and pyrexia (18.4%) being most frequent. Five patients discontinued treatment due to AEs, of which 4 discontinuations were considered related to anidulafungin. All-cause mortality was 8.2% (4/49) by EOIVT and 14.3% (7/49) by Week 6 follow-up. None of 7 deaths during the study period were considered treatment-related. Global response success rate was 70.8% at EOIVT. CONCLUSIONS: These data support the use of anidulafungin as a treatment option for ICC in children aged 2-<18 years at the studied dose.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30418358 TI - Determinants of Influenza and Pertussis Vaccination Uptake in Pregnancy: A Multi Centre Questionnaire Study of Pregnant Women and Healthcare Professionals. AB - INTRODUCTION: Uptake rates of antenatal vaccination remain suboptimal. Our aims were to determine: (1) the acceptability of routine vaccination among pregnant women, (2) the confidence of maternity healthcare professionals (HCPs) discussing vaccination and (3) HCP opinion regarding the optimum healthcare site for vaccine administration. METHODS: Separate questionnaires for pregnant women and HCPs were distributed within four NHS trusts in South England (July 2017-January 2018). RESULTS: Responses from 314 pregnant women and 204 HCPs (18% obstetricians, 75% midwives, 7% unidentified) were analysed. Previous/intended uptake of influenza and pertussis vaccination was 78% and 92%, respectively. The commonest reason for declining vaccination was feared side-effects for their child. White British women (79%) were significantly more accepting of influenza (85% vs. 61%, OR 3.25, 95% CI: 1.67-6.32) and pertussis vaccination (96% vs. 83%, OR 4.83, 95% CI: 1.77 13.19) compared with non-white-British women. Among HCPs, 25% were slightly or not-at-all confident discussing vaccination. Obstetricians felt significantly more confident discussing pertussis vaccination than midwives (68% vs. 55% were very/moderately confident, OR 2.05, 95% CI: 1.02-4.12). Among HCPs, 53%, 25% and 16% thought vaccines should be administered in primary care (general practice), community midwifery and in hospital, respectively. CONCLUSION: Misconceptions exist regarding safety/efficacy of antenatal vaccination, and framing information towards the child's safety may increase uptake. Education of HCPs is essential, and vaccine promotion should be incorporated into routine antenatal care, with an emphasis on women from ethnic minorities. Administration of vaccines in primary care presents logistical barriers however support for alternative sites appears low among HCPs. PMID- 30418359 TI - Pertussis Morbidity in Children 12 to 59 Months of Age: A NSW Public Health Network Study. AB - BACKGROUND: Pertussis continues to be a significant public health problem despite high levels of vaccination. Although hospitalizations and deaths among children older than 12 months are much less frequent than among infants less than 6 months of age, only limited information is available for this age group on other measures of morbidity. METHODS: A cross sectional study with a 6 week follow-up component was conducted in New South Wales, Australia in 2017 to measure morbidity among children 12 to 59 months of age notified to health authorities. Measures used included cough duration, cough severity, constitutional symptoms and impacts upon the family. Associations between these outcomes and age group, vaccination status, asthma, treatment and family structure were explored. RESULTS: Three hundred and five of 472 (65%) notified cases were interviewed at baseline with approximately 20% having a severe cough with no trend in prevalence across age groups. Forty eight percent of cases had experienced 3 or more constitutional symptoms with rates significantly higher among younger children. Children who had received an 18 month booster vaccination were significantly less likely to experience 3 or more constitutional symptoms (OR 0.46, 0.22-0.97). Fifty one percent of cases were still coughing at 6 weeks. One third of carers initially reported having disrupted sleep 4 or more nights per week with substantial disruption to carers' sleep still recorded at 6 weeks. CONCLUSIONS: Substantial morbidity was observed in this age group with some evidence that the reintroduction of an 18 month acellular pertussis booster lessened disease severity. PMID- 30418360 TI - Editorial. PMID- 30418361 TI - Thomas A. LaVeist, PhD, Dean, Tulane University School of Public Health and Tropical Medicine. PMID- 30418362 TI - Physician and Nurse Well-Being: Seven Things Hospital Boards Should Know. PMID- 30418363 TI - Healthcare, Disrupt Thyself: How Ascension Makes Changes Today to Thrive Tomorrow. PMID- 30418365 TI - PRACTITIONER APPLICATION: Spending Patterns Among Medicare ACOs That Have Reduced Costs. PMID- 30418364 TI - Spending Patterns Among Medicare ACOs That Have Reduced Costs. AB - EXECUTIVE SUMMARY: This study aimed to examine whether specific cost categories were disproportionately affected by accountable care organizations (ACOs) in the Medicare Shared Savings Program (MSSP) achieving overall spending reductions, and whether there were demonstrable differences in spending patterns between "low"- or "high"-cost ACOs. Using financial data obtained from the Centers for Medicare & Medicaid Services for ACOs launched between 2012 and 2015, and employing a cross-sectional study design, we determined which cost categories were associated with overall reductions in ACO spending. Linear regressions were conducted to discern whether reductions in inpatient and skilled nursing facility (SNF) costs were driven by reductions in the number of admissions or in the cost per admission. Results showed that ACOs that reduced total per capita spending saw the largest percentage decreases in inpatient (-9%), hospice (-11%), and SNF ( 16%) per capita costs, compared to ACOs that were unable to decrease costs between 2014 and 2015 (p < .05). Reductions in SNF and inpatient spending were driven by declines in the number of patients admitted, not the cost per hospitalization or SNF admission (p < .05). In 2015, ACOs in the highest decile of per capita spending spent more than double on each beneficiary compared to ACOs in the lowest decile ($16,672 versus $8,030, respectively; p < .05). ACOs in the lowest-cost decile spent more proportionally on outpatient and physician/supplier costs (p < .05). Thus, we determined that initial success in reducing the cost of care has been driven by reductions in inpatient costs due to a decline in the volume of patients admitted. Future studies should further investigate specific interventions that allow high-performing ACOs to achieve these cost reductions. PMID- 30418366 TI - Military Hospital Spending on Environmental Services and Inpatient Satisfaction Ratings. AB - EXECUTIVE SUMMARY: To assess the impact of military hospital expenditures on environmental services (EVS) on inpatient satisfaction, the authors collected Defense Health Agency TRICARE Inpatient Satisfaction Survey data from fiscal years 2011 through 2013, military hospital EVS spending and workload data, facility construction/renovation data, and military health system inpatient administrative claims data. Multivariate logistic regression for panel data was performed independently for medical/surgical and obstetric product lines and each satisfaction question. A statistically significant positive relationship was found between hospital EVS spending and patient satisfaction, with the highest expenditure levels generally exhibiting a greater association with satisfaction. Statistically significant increases in satisfaction with cleanliness were associated with higher levels of hospital expenditures on EVS. PMID- 30418367 TI - Practitioner Application: Military Hospital Spending on Environmental Services and Inpatient Satisfaction Ratings. PMID- 30418368 TI - Examining the Healthcare Administrator's Perspective on "Teamness" in Primary Care. AB - EXECUTIVE SUMMARY: Team-based care has been identified as an important element of effective primary care practice. While there is a growing body of literature supporting the value of team-based care, research on best practices in team-based care has suffered from the lack of a widely accepted framework with common definitions. We used qualitative interviews to explore healthcare administrators' perspectives regarding team-based care descriptions, their decisions regarding composition of a team, and how they identify characteristics of a well functioning team. Interviewees discussed six broad themes: (1) definitions of team-based care, (2) team structure and roles, (3) team goals, (4) monitoring team effectiveness, (5) challenges to implementing team-based care, and (6) the influence of healthcare policy on team-based care. The study findings can be used to identify further ways to assess the notion of "teamness." PMID- 30418369 TI - PRACTITIONER APPLICATION: Examining the Healthcare Administrator's Perspective on "Teamness" in Primary Care. PMID- 30418370 TI - Behavioral Integrity, Engagement, Organizational Citizenship Behavior, and Service Quality in a Healthcare Setting. AB - EXECUTIVE SUMMARY: In response to increased competition and outcomes transparency, healthcare delivery organizations must rely on their employees to provide superior care quality and patient service. Healthcare managers seeking to motivate employees to this end have an abundance of leadership theories, many of which are broad and overlapping, on which to base their initiatives. In this study, we looked at a relatively narrow construct: behavioral integrity (BI)-that is, the extent to which employees view their managers' words and actions as congruent (whether they "walk their talk"). We collected data from self-reported surveys completed by 3,605 employees of a large, integrated, religiously affiliated healthcare system in the mid-Atlantic region of the United States. Using correlational and hierarchical regression, we tested whether employees who perceived their direct managers as exhibiting more BI were more engaged in their jobs; reported their coworkers as performing more organizational citizenship behaviors; and had more favorable views both of the service quality of their unit and hospital or other entity in which they worked. We found positive relationships between perceived BI and all of those desirable outcomes. Employee engagement also was positively related to individuals' perceptions of their unit's organizational citizenship, as evidenced by discretionary effort, and with their perceptions of the quality of care delivered by both unit and organizational entity. Engagement partially mediated the relationships between BI and those variables. We discuss the implications for individual managers seeking practical advice for self-improvement as well as for organizations striving to improve employee engagement and performance through leadership development. PMID- 30418371 TI - PRACTITIONER APPLICATION: Behavioral Integrity, Engagement, Organizational Citizenship Behavior, and Service Quality in a Healthcare Setting. PMID- 30418372 TI - Qualifications and Skills Required for Performance Improvement: A Content Analysis of Job Postings. AB - EXECUTIVE SUMMARY: Healthcare reform and the implementation of a national quality strategy in the United States have increased emphasis on quality improvement. Additionally, as healthcare organizations focus on value, they are paying more attention to quality in the context of cost and seeking to address these concerns through various performance improvement initiatives. Given the importance of these initiatives, this study analyzed the improvement job positions posted by U.S. healthcare organizations, specifically with respect to the qualifications and skills required. The author conducted a content analysis of improvement job postings using an inductive approach to capture and categorize core information about each posting and a deductive approach to evaluate skills required for selected job areas. The results show that healthcare organizations have invested in a breadth of improvement positions across all levels of the organization. Many positions are tied to strategic initiatives. The greatest number of positions posted were in the performance improvement area, followed by quality improvement, process improvement, Lean, Six Sigma, and Lean Six Sigma. These research results may be useful to healthcare organizations for strategic resource planning purposes and to educators and professional associations to target programs that offer students and members the opportunity to gain needed qualifications and skills. PMID- 30418373 TI - Practitioner Application: Qualifications and Skills Required for Performance Improvement: A Content Analysis of Job Postings. PMID- 30418374 TI - The Effect of the Magnet Recognition Signal on Hospital Financial Performance. AB - EXECUTIVE SUMMARY: The objective of this study was to investigate the effect of the Magnet Recognition (MR) signal on hospital financial performance. MR is a quality designation granted by the American Nurses Credentialing Center (ANCC). Growing evidence shows that MR hospitals are associated with various interrelated positive outcomes that have been theorized to affect hospital financial performance.In this study, which covered the period from 2000 to 2010, we applied a pre-post research design using a longitudinal, unbalanced panel of MR hospitals and hospitals that had never received MR designation located in urban areas in the United States. We obtained data for this analysis from Medicare's Hospital Cost Report Information System, the American Hospital Association Annual Survey Database, the Health Resources & Services Administration's Area Resource File, and the ANCC website. Propensity score matching was used to construct the final study sample. We then applied a difference-in-difference model with hospital fixed effects to the matched hospital sample to test the effect of the MR signal, while controlling for both hospital and market characteristics.According to signaling theory, signals aim to reduce the imbalance of information between two parties, such as patients and providers. The MR signal was found to have a significant positive effect on hospital financial performance. These findings support claims in the literature that the nonfinancial benefits resulting from MR lead to improved financial performance. In the current healthcare environment in which reimbursement is increasingly tied to delivery of quality care, healthcare executives may be encouraged to pursue MR to help hospitals maintain their financial viability while improving quality of care. PMID- 30418375 TI - Practitioner Application: The Effect of the Magnet Recognition Signal on Hospital Financial Performance. PMID- 30418376 TI - Balancing Quality Healthcare Services and Costs Through Collaborative Leadership. AB - EXECUTIVE SUMMARY: This review assesses the effectiveness of collaborative leadership strategies in balancing quality healthcare services and costs. Quantitative analysis of 39 studies answered research questions to identify collaborative leadership strategies employed by healthcare managers to address the cost of care, determine the most effective strategies for managing this cost, and evaluate how collaborative leadership's cost-reduction strategies affect quality of care. The intrahospital collaboration strategy was noted to be the most frequently used strategy (53.8%). The other strategies included patient based collaboration (41.0%) and interorganizational collaboration (17.9%). The patient-based collaborative strategy offered significantly higher cost-reduction effectiveness (31.9% +/- 6.005). The cost effectiveness of the intrahospital collaboration (25.3% +/- 2.014) and interorganizational collaboration strategy (20.2% +/- 4.229) were also significant. The adoption of the patient-based collaboration strategy was associated with enhanced quality of healthcare (62.5%), while the interorganizational collaboration strategy had a greater proportion of noneffect on quality of services (71.4%). Therefore, healthcare leaders should facilitate the adoption of patient-based and interorganizational collaboration strategies to manage healthcare costs. PMID- 30418377 TI - Practitioner Application: Balancing Quality Healthcare Services and Costs Through Collaborative Leadership. PMID- 30418378 TI - Correlation of Appointment Times and Subspecialty With the No-Show Rates in an Orthopedic Ambulatory Clinic. AB - EXECUTIVE SUMMARY: Unexpectedly missed appointments ("no-shows") cause clinic inefficiency, lost time and revenue, wasted healthcare resources, and provider dissatisfaction. No-shows can be associated with miscommunication, transportation difficulties, employment status, age, race, and socioeconomic status. This study investigates the association between no-show rates and patient, appointment time, and provider characteristics. Data for all scheduled appointments in a single orthopedic multispecialty institution during calendar year 2016 were obtained. Data points included patient age, gender, and race; hour; month; and subspecialty. Chi-square testing was used to compare no-show and kept appointments with respect to patient and appointment characteristics. Logistic regression was used to calculate differences in no-show rates between orthopedic subspecialties. The overall no-show rate was 11.5%. Race, age, and subspecialties were all found to be associated with higher no-show rates. No significant differences were observed for gender, appointment time, or month of appointment. The authors suggest that patients at higher risk of not showing up for scheduled appointments may need extra effort from providers to accommodate the patients' schedules when making appointments, to confirm their appointments a few days before, and/or to incentivize patients to minimize no-shows. PMID- 30418379 TI - Practitioner Application: Correlation of Appointment Times and Subspecialty With the No-Show Rates in an Orthopedic Ambulatory Clinic. PMID- 30418380 TI - Diastolic dysfunction can precede systolic dysfunction on MUGA in cancer patients receiving trastuzumab-based therapy. AB - BACKGROUND: Trastuzumab (T) and anthracycline (A)-based chemotherapy is considered the standard of care in human epidermal growth factor receptor-2+ overexpressing breast cancer, but requires monitoring for known cardiotoxicity using left ventricular (LV) ejection fraction (EF) every 3-4 months during treatment. It is not conclusively established whether diastolic dysfunction (DD) precedes LVEF decrease in patients developing trastuzumab-induced cardiotoxicity (TIC). OBJECTIVE: The aim was to elucidate whether DD precedes LVEF decrease in trastuzumab-treated patients being monitored with radionuclide multigated acquisition for TIC. PATIENTS AND METHODS: Patients treated with T+/-A-based chemotherapy who had undergone multigated acquisition were selected by date range (January 2006-September 2015). Up to four scans were analyzed per patient: (a) pre-A therapy, (b) pre-T therapy, (c) 4 months into T therapy, and (d) at end of T therapy. Baseline referred to the first scan of each patient (i.e. pre-A or pre T). LV systolic and DD were defined as follows: EF less than 50% or a 10-point decrease from baseline and LV peak filling rate (PFR) less than 2.5 end-diastolic volume/s and time to peak LV filling rates (TPFR) greater than 180 ms, respectively. RESULTS: A total of 202 patients were screened for this study, of whom 153 had received A therapy (5.1+/-4.1 months duration) before T, 192 had 4 months of follow-up data, and 146 had 4 months of follow-up data and beyond (10.5+/-5.0 months). LVEF decreased with A and T therapy (P<0.005), but remained stable between 4 months and the final exam (P=0.26). In patients with normal diastolic function at baseline (45.5%), PFR decreased with A and T, and DD preceded SD by 73 days on average. In the remaining patients, with abnormal diastolic function at baseline (54.5%), PFR did not change over the course of treatment (P>0.1), nor did TPFR (P>0.3). CONCLUSION: Patients with normal diastolic function at baseline receiving trastuzumab+/-anthracycline adjuvant therapy may develop DD before SD, therefore offering an opportunity for early referral to cardiologists to optimize cardiovascular risk factors and manage cardiotoxicity. PMID- 30418381 TI - Myocardial perfusion imaging detects mechanical dyssynchrony in left ventricular infarcted and noninfarcted areas early after acute myocardial infarction in a porcine model. AB - BACKGROUND: Left ventricular mechanical dyssynchrony (LVMD) is closely associated with left ventricular dysfunction and poor prognosis in patients with acute myocardial infarction (AMI). However, whether mechanical dyssynchrony is present in the noninfarcted areas remains controversial. This research aimed to quantitatively evaluate the global and regional mechanical dyssynchrony early after AMI by phase analysis of single-photon emission computed tomography (SPECT) gated myocardial perfusion imaging (GMPI) and to further explore the related influencing factors. MATERIALS AND METHODS: Of 11 Bama suckling pigs, eight animals were successfully subjected to left anterior descending artery occlusion by balloon to generate porcine AMI models and completed the study. SPECT GMPI was performed before AMI and at 1 day, 1 week, and 4 weeks after AMI. The global bandwidth (BW), SD, entropy, total perfusion deficit, summed rest score, regional BW, regional summed motion score, and regional summed thickening score were measured by SPECT GMPI. RESULTS: The global BW, SD, and entropy values significantly increased after AMI and showed no significant change among the three time points after AMI. The BW in the infarcted area (left anterior descending artery-dominated area) at 1 day, 1 week, and 4 weeks after AMI was significantly higher than that before AMI, as was the BW in the noninfarcted areas (left circumflex artery-dominated and right coronary artery-dominated areas), which revealed that there was less dyssynchrony in the noninfarcted areas than in the infarcted area at the three time points after AMI. The global BW was positively correlated with the scar burden measured by summed rest score (r=0.709 0.832, all P<0.05), whereas the regional BW in the noninfarcted areas after AMI showed moderate to good correlation with regional summed motion score (r=0.733 0.875, all P<0.05) and regional summed thickening score (r=0.713-0.889, all P<0.05). CONCLUSION: LVMD occurs early on the first day after AMI, with no significant worsening over the next 4 weeks. Mechanical dyssynchrony was present in both the infarcted and noninfarcted areas. The global LVMD is mainly influenced by the scar burden, and the regional mechanical dyssynchrony in the noninfarcted areas is closely associated with the abnormal regional wall thickening and motion, which are indicative of reduced myocardial contractility. PMID- 30418382 TI - Characteristic Reconstitution of the Spinal Langerhans Cell Histiocytosis in Young Children. AB - BACKGROUND: Pediatric Langerhans cell histiocytosis (LCH) often results in vertebral compression fracture. However, few reports have reported vertebral remodeling during the course of LCH. We aimed to investigate the longitudinal reconstitution and transformation of the affected vertebrae and the adjacent structures in young children with spinal LCH. METHODS: We recruited 13 patients, including 16 affected vertebrae, diagnosed with LCH via biopsy. The average age at first visit was 3.6 years. The average follow-up period was 10.2 years. Vertebral lesions involved L2 in 3 cases; T12, L1, or L5 in 2 cases; and C4, C5, C7, T5, T8, T9, or L3 in 1 case. We measured the ratios of the height of the affected vertebra and 1 vertebra above the affected one to that of the second vertebra above the affected one, local kyphotic angles, and the ratio of the height of the center of the adjacent disk to that of one disk above it. RESULTS: The collapse of the affected vertebra was most severe after 1 year of disease onset. The rate of reconstitution accelerated at 2 years or later of disease onset. The recovery speed of the anterior wall was faster than that of the center height. While the height of the affected vertebrae was restored, the thickness of the adjacent disk also increased. Further, the height of the adjacent vertebrae increased in a similar manner. The average local kyphosis angle shifted to lordosis within the first 3 years. CONCLUSIONS: The heights of not only the disk but also the adjacent vertebra increased during the vertebral collapse phase in pediatric spinal LCH patients. These transformations may affect the realignment of the sagittal spinal balance at the earlier stage of the disease. During the collapse phase, the heights of the adjacent vertebrae and disks increase but after the affected vertebrae reconstituted, the augmentation of adjacent vertebrae and disks diminished. LEVEL OF EVIDENCE: Level IV.This is an open access article distributed under the terms of the Creative Commons Attribution Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/. PMID- 30418383 TI - Functional and Oncological Outcome After Treatment of Chondroblastoma With Intralesional Curettage. AB - BACKGROUND: Chondroblastoma is a rare cartilaginous benign bone tumor that commonly arises in long bones of young people. Surgical management is the primary treatment of choice for chondroblastoma and it entails adequate intralesional curettage alone or in combination with adjuvants. This study was performed to describe the epidemiological characteristics and clinical and radiologic results of intralesional curettage of chondroblastoma. METHODS: This was a retrospective study which included an analysis of 91 patients with chondroblastoma who were treated with intralesional curettage and were followed up between 1994 and 2014 for at least 3 years. Epidemiological data, clinical symptoms, radiologic and histologic investigations, surgery, functional outcomes, complications, and local recurrence rate were analyzed. RESULTS: There were 60 males (65.9%) and 31 females (34.1%) with a mean age of 16.4 years. The most commonly involved bone was the proximal tibia in 24 patients (26.4%), followed by distal femur in 20 patients (22%), proximal humerus in 17 patients (18.7%) and proximal femur in 15 patients (16.6%). All patients underwent intralesional curettage. High-speed burr was used in 66 patients (72.5%). The resultant cavity was filled with autogenous bone graft, bone substitute, bone cement or a combination of bone graft and cement. Four patients (4.4%) had complications. Three patients (3.3%) developed local recurrence. Age, site, history of previous intervention or pathologic fracture had no impact on the rate of recurrence. The mean Musculoskeletal Tumor Society (MSTS) score was 28.88 (range, 24 to 30) points. CONCLUSIONS: Thorough curettage using high-speed burr and bone-grafting or bone cement in the treatment of chondroblastoma has good local control, low recurrence rate and excellent functional long-term outcome. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 30418384 TI - The Pediatric Orthopaedic Society of North America (POSNA) Adopts a Member Health and Wellness Charter. AB - The Pediatric Orthopaedic Society of North America took actions to address the well-being of its members. The epidemic of physician burnout interferes with the delivery of high-quality care that our patients and families need and deserve, and at the same time places the care-providers at an increased risk of depression and suicide. The actions taken by Pediatric Orthopaedic Society of North America serve as a model for other professional medical societies to emulate. PMID- 30418385 TI - Hospital Physician Engagement: A Scoping Review. AB - BACKGROUND: Literature on health system transformation highlights the importance of physician engagement, suggesting that it is a critical factor for lowering costs while improving efficiency, quality of care, patient safety, physician satisfaction and retention. "Engagement" in health care is often defined as a positive, fulfilling work-related state of mind, which is characterized by vigor, dedication and absorption. The aim of this scoping review is to identify factors associated with, and tools used to measure physician engagement. METHODS: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and gray literature were searched. Supplementary articles were obtained by searching article references. All quantitative and qualitative study designs were eligible that described factors associated with, and tools used to measure, hospital physician engagement. Quantitative and qualitative analyses were conducted. Groupings and clustering were conducted to determine dominant groups or cluster of characteristics. Conceptual mapping was then conducted to identify patterns. RESULTS: A total of 15 studies fulfilled the eligibility criteria. All were published between 2012 and 2017. Studies were predominantly conducted in Germany (n=8). Factors associated with physician engagement were synthesized into individual characteristics (n=7), work environment characteristics (n=7), and work outcomes (n=5). The Utrecht Work Engagement Scale was the most commonly used tool (n=14). CONCLUSIONS: This scoping review provides a strong evidence-based platform to further advance knowledge in the area of physician engagement. The identification of environmental factors assists hospital administrative leaders in understanding how they might intervene to affect engagement, while the identification of individual characteristics enable identification of vulnerable physicians, permitting identification of the most pertinent targeted areas for focus. PMID- 30418386 TI - Going Beyond Clinical Care to Reduce Health Care Spending: Findings From the J CHiP Community-based Population Health Management Program Evaluation: Erratum. PMID- 30418387 TI - CORRELATION OF GENE EXPRESSION PROFILE STATUS AND AMERICAN JOINT COMMISSION ON CANCER STAGE IN UVEAL MELANOMA. AB - PURPOSE: To study the relationship between gene expression profile (GEP) subclass and American Joint Committee on Cancer (AJCC) stage in patients with uveal melanoma (UM). METHODS: A retrospective, multicenter study was undertaken with patients entered from nine major ocular oncology centers from across the United States. Three hundred sixty eligible patients had UM and underwent I-125 plaque brachytherapy with concurrent tumor biopsy with GEP testing between January 1, 2010, and October 28, 2014. Patient demographics and UM features were analyzed by both GEP and AJCC status. RESULTS: Gene expression profile class divided the cohort into three groups: Class 1a (n = 186), Class 1b (n = 77), and Class 2 (n = 113). When classified using AJCC staging criteria, we found the following: Stage I in 91 cases (25.3%), Stage IIA in 143 cases (39.7%), Stage IIB in 89 cases (24.7%), Stage IIIA in 36 cases (10%), and Stage IIIB in 1 case (0.3%). There were no Stage IV cases, as lymph node and metastatic data were not collected as a part of this study. Among Stage I tumors, both high tumor height and high largest basal diameter were associated with a higher frequency of Class 2 status (P < 0.05). As UMs progress to a larger AJCC tumor group (T1-T4), the odds ratio of having a worse prognosis based on GEP class was 1.75 (95% CI, 1.36-2.25; P < 0.001). Similarly, as UMs progress to a higher AJCC stage, the odds ratio of having a worse prognosis based on GEP class was 1.69 (95% CI, 1.36-2.10; P < 0.001). CONCLUSION: This report details the differences in clinical features between GEP subclasses and how they are distributed among the AJCC stages. When the tumors were grouped by AJCC staging criteria, both larger AJCC tumor (T) group and worsening AJCC stage were associated with worsening predicted prognosis, based on GEP subclass. PMID- 30418389 TI - Correspondence. PMID- 30418388 TI - Perfluorodecalin as Medium-Term Tamponade in the Case of Retinal Detachment Recurrence With an Inferior Retinal Break, Which Lies Posteriorly to an Encircling Band. PMID- 30418390 TI - Correspondence. PMID- 30418391 TI - OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY CHANGES AFTER SUBTHRESHOLD MICROPULSE YELLOW LASER IN DIABETIC MACULAR EDEMA. AB - PURPOSE: To assess changes on optical coherence tomography (OCT) angiography in diabetic macular edema (DME) treated with subthreshold micropulse yellow laser (SMPL) over a period of 6 months. METHODS: Thirty-five eyes (35 consecutive patients) with treatment-naive DME prospectively underwent (at baseline, 3 and 6 months) best-corrected visual acuity, swept-source OCT angiography/OCT, and fundus autofluorescence. Following parameters were evaluated on OCT angiography in the superficial capillary plexus (SCP) and deep capillary plexus (DCP): the area of foveal avascular zone, number of microaneurysms (MA), area of cysts, and presence of capillary network alterations. Microaneurysm change was also evaluated in 15 fellow eyes, not needing treatment over 6 months. Vessel and perfusion densities were evaluated in the SCP, DCP, and choriocapillaris, with image J. Retina thickness, number of hyperreflective retinal spots, and external limiting membrane integrity were evaluated on OCT. All measurements were performed by two masked graders, independently. RESULTS: All patients had diabetes mellitus Type 2 (mean age, 69.4 +/- 10.9 years; duration of diabetes mellitus, 15.7 +/- 8.7 years; and HbA1c 7.7 +/- 1.2%). Mean best-corrected visual acuity at baseline was 69.7 +/- 12.0 letters ETDRS, 72.7 +/- 10.7 at 3 months (gain 3.1 +/- 4.3, P = 0.0049) and 74.3 +/- 9.5 at 6 months (gain 4.6 +/- 7.2, P < 0.0001). Foveal avascular zone area decreased in the DCP at 6 months (P = 0.01). Area of cysts decreased in the SCP at 3 months and 6 months (P = 0.038; P = 0.049), and in the DCP at 6 months (P = 0.0071). Number of MA decreased at 6 months in the SCP (P = 0.0007) and at 3 months and 6 months in the DCP (P = 0.048; P < 0.0001) in treated eyes. No significant change in number of MA was found in nontreated eyes. There was no statistically significant change in any other OCT angiography/OCT parameter. CONCLUSION: Subthreshold micropulse yellow laser induces more pronounced changes in the DCP than in the SCP in DME. These changes occurred as early as 3 months after treatment. The evaluation of specific parameters in the DCP may help in determining treatment response. PMID- 30418392 TI - Reply. PMID- 30418393 TI - Reply. PMID- 30418394 TI - Reply. PMID- 30418395 TI - Self-directed Continuing Medical Education for Ophthalmic Plastic and Reconstructive Surgery. PMID- 30418396 TI - Posterior Ischemic Optic Neuropathy Following Contralateral Endoscopic Orbital Decompression. PMID- 30418397 TI - The Use of Long-Acting Liposomal Bupivacaine (Exparel) for Postoperative Pain Control Following Enucleation or Evisceration. PMID- 30418399 TI - Antiglaucoma Medications Complicating the Management of Graves' Ophthalmopathy. PMID- 30418398 TI - Endoscopic Features of a Granuloma Within a Lacrimal Sac Diverticulum. PMID- 30418400 TI - Use of Cyanoacrylate Glue for Replacing Orbital Bone After Lateral Orbitotomy: A Pilot Study. PMID- 30418401 TI - Kinesio Tape for Treatment of Lower Eyelid Festoons. PMID- 30418402 TI - Stenotrophomonas maltophilia Causing Recurrent Acute Canaliculitis. PMID- 30418403 TI - Re: "Autologous Fat Graft for the Treatment of Sighted Posttraumatic Enophthalmos and Sunken Upper Eyelid". PMID- 30418404 TI - Reply re: "Autologous Fat Graft (AFG) for the Treatment of Sighted Posttraumatic Enophthalmos and Sunken Upper Eyelid". PMID- 30418405 TI - Unusual Location for a Periorbital Dermoid Cyst. AB - Dermoid cysts in the orbit classically present in children as a mass in the superotemporal or superonasal orbit along the zygomatico-frontal or fronto ethmoidal suture lines. The presence of a dermoid cyst in the superficial eyelid, not associated with the tarsus, has only been reported once previously. The authors present a case of a 60-year-old man with a painless right lower eyelid mass inferonasally that was completely excised and found to be a dermoid cyst. The presence of a dermoid cyst involving the superficial lower eyelid is very rare. Furthermore, dermoid cysts in adults typically present in the setting of trauma, which was absent in this case. Therefore, it is important to consider dermoid cysts in the differential diagnosis of eyelid lesions in adults. PMID- 30418406 TI - Early Onset Scoliosis: Is there an Improvement in Quality of Life With Conversion From Traditional Growing Rods to Magnetically Controlled Growing Rods? AB - BACKGROUND: Modern treatment of early onset scoliosis (EOS) includes implantation of traditional growing rods (TGR) or magnetically controlled growing rods (MCGR) for posterior-based distraction if nonoperative treatment plans failed. The recent MCGR innovation has largely been expected to improve patient and family burden by avoiding frequent return to the operating room. At least one study has shown no HRQoL difference between TGR and MCGR, but none have specifically investigated a cohort of conversion patients whose families have experienced both. METHODS: An EOS database was queried for all patients treated with TGR, MCGR, and those converted from TGR to MCGR who had at least 1 pretreatment and 1 posttreatment HRQoL assessment (EOSQ-24). Data on demographics, diagnoses, and major curve size, as well as EOSQ-24 domain scores were studied. RESULTS: There were 156 TGR, 114 MCGR, and 32 conversion patients, with an average of 2.0 years between first and final EOSQ-24 surveys. There was no significant difference in outcome in any EOSQ-24 domain between the converts and the other 2 treatment groups. There was a significant post-op improvement in MCGR versus TGR in transfers and energy level (P=0.01; P=0.01). CONCLUSIONS: Although patient families and their surgeons may subjectively report improved HRQoL after conversion from TGR lengthenings to in-office MCGR lengthenings, these improvements were seen in transfer and fatigue domains, not burden or satisfaction. Although the EOSQ-24 is a well-validated EOS metric, it may not be sensitive enough to overcome the QoL floor-effect associated with the diagnosis itself, or perhaps the improvement in QoL must be assessed over a longer interval to assess meaningful change. LEVEL OF EVIDENCE: Level III-retrospective comparative study. PMID- 30418407 TI - The Plumb Line and Hand Surgery. PMID- 30418408 TI - Esophageal Compliance Quantifies Epithelial Remodeling in Pediatric Patients with Eosinophilic Esophagitis. AB - BACKGROUND: The management of eosinophilic esophagitis (EoE) relies on the severity of esophageal eosinophilia, yet there is poor evidence of its prediction of esophageal fibrotic remodeling and subsequent complications such as dysphagia, food impactions, or strictures. Functional Luminal Impedance (FLIP) has had limited use in pediatric patients to evaluate esophageal tissue mechanics. We aimed to standardize the FLIP technique and to measure esophageal compliance in children with EoE in comparison to controls. METHODS: Subjects were enrolled into a prospective observational study and had FLIP performed at the time of endoscopy. We calculated esophageal distensibility and compliance for the total and segmental esophagus independently (i.e., proximal, middle and distal esophageal segments). We evaluated esophageal biopsies for eosinophilia and epithelial remodeling, calculated endoscopy scores, and documented patient symptoms. RESULTS: We enrolled 11 EoE and 12 controls subjects, aged 5-18 years old. While EoE subjects had lower esophageal compliance (p = 0.004) than controls, the difference in distensibility did not reach significance (p = 0.151). Epithelial remodeling severity was more strongly correlated with compliance than with distensibility. Epithelial remodeling scores >=2 had a significant association with lower compliance both segmentally and in the entire esophagus (p = 0.029), but not with distensibility. Compliance measures were more sensitive in detecting subjects with remodeling score >=2 than distensibility (79% versus 64%). CONCLUSION: Compliance is a more sensitive measure of esophageal epithelial remodeling in children compared to distensibility, and a more appropriate measure of esophageal tissue mechanics. Standardized placement of the FLIP catheter is important to accurately assess esophageal compliance. PMID- 30418409 TI - Bacteriophage Therapy Testing against Shigella flexneri in a Novel Human Intestinal Organoid-Derived Infection Model. AB - OBJECTIVE: Enteric bacterial pathogens cause diarrheal disease and mortality at significant rates throughout the world, particularly in children under the age of 5 years. Our ability to combat bacterial pathogens has been hindered antibiotic resistance, a lack of effective vaccines, and accurate models of infection. With the renewed interest in bacteriophage therapy, we sought to use a novel human intestinal model to investigate the efficacy of a newly isolated bacteriophage against Shigella flexneri. METHODS: A S. flexneri 2457T-specific bacteriophage was isolated and assessed through kill curve experiments and infection assays with colorectal adenocarcinoma HT-29 cells and a novel human intestinal-derived organoid monolayer model. In our treatment protocol, organoids were generated from intestinal crypt stem cells, expanded in culture, and seeded onto transwells to establish two-dimensional monolayers that differentiate into intestinal cells. RESULTS: The isolated bacteriophage efficiently killed S. flexneri 2457T, other S. flexneri strains, and a strain of 2457T harboring an antibiotic resistance cassette. Analyses with laboratory and commensal Escherichia coli strains demonstrated that the bacteriophage was specific to S. flexneri, as observed under co-culture conditions. Importantly, the bacteriophage prevented both S. flexneri 2457T epithelial cell adherence and invasion in both infection models. CONCLUSIONS: Bacteriophages offer feasible alternatives to antibiotics for eliminating enteric pathogens, confirmed here by the bacteriophage-targeted killing of S. flexneri. Furthermore, application of the organoid model has provided important insight into Shigella pathogenesis and bacteriophage-dependent intervention strategies. The screening platform described herein provides proof of-concept analysis for the development of novel bacteriophage therapies to target antibiotic-resistant pathogens. PMID- 30418410 TI - Eculizumab Is Safe and Effective as a Long-term Treatment for Protein-losing Enteropathy Due to CD55 Deficiency. AB - OBJECTIVES: Loss of the complement inhibitor CD55 leads to a syndrome of early onset protein-losing enteropathy (PLE), associated with intestinal lymphangiectasia and susceptibility to large-vein thrombosis. The in vitro and short-term treatment benefits of eculizumab (C5-inhibitor) therapy for CD55 deficiency have been previously demonstrated. Here we present the 18-months treatment outcomes for 3 CD55-deficiency patients with sustained therapeutic response. METHODS: Three CD55-deficiency patients received off-label eculizumab treatment. Clinical and laboratory treatment outcomes included frequency and consistency of bowl movements, weight, patient/parent reports of overall well being, and serum albumin and total protein levels. Membrane attack complex deposition on leukocytes was tested by flow cytometry, before and during eculizumab treatment. RESULTS: Marked clinical improvement was noted in all 3 patients with resolution of PLE manifestations, that is, diarrhea, edema, malabsorption, overall well-being, growth, and quality of life. In correlation with the clinical observations, we observed progress in all laboratory outcome parameters, including increase in albumin and total protein levels, and up to 80% reduction in membrane attack complex deposition on leukocytes (P < 0.001). The progress persisted over 18 months of treatment without any severe adverse events. CONCLUSIONS: CD55-deficiency patients present with early-onset diarrhea, edema, severe hypoalbuminemia, abdominal pain, and malnutrition. Targeted therapy with the terminal complement inhibitor eculizumab has positive clinical and laboratory outcomes in PLE related to CD55 loss-of-function mutations, previously a life threatening condition. Our results demonstrate the potential of genetic diagnosis to guide tailored treatment, and underscore the significant role of the complement system in the intestine. PMID- 30418411 TI - Prevalence of Celiac Disease in a Long-Term Study of a Spanish At-Genetic-Risk Cohort from the General Population. AB - OBJECTIVES: To perform long-term celiac disease (CD) screening in an HLA-DQ2 (+) cohort from the general population and to assess the influence of risk genotypes on its development. METHODS: In 2004, an HLA-DQ2 (+) cohort was selected. After the first CD screening at age 2-3 years, we performed a follow-up screening 8-10 years later. Anti-TG2 antibodies were determined using a rapid test kit. Results were confirmed by serum IgA anti-TG2 and IgA EMA determination. CD diagnosis was carried out by intestinal biopsies. Four HLA-DQ2 genotypic groups were used: G1: DQ2.5/DQ2.5 (G1A) or DQ2.5/ DQ2.2 (G1B); G2: DQ2.2/DQ7.5 (DQ2.5 trans); G3: DQ2.5/ X; G4: DQ2.2/X. RESULTS: CD prevalence after 10 years of follow-up was 5.8% (95%CI 3.8-8.7). One of every three HLA-DQ2(+) children carried at least one haplotype DQ2.2 or DQ7. The homozygous genotype DQ2.5/DQ2.5 and the HLA-DQ2.5 trans genotype increased CD risk 4- and 3-fold, respectively. The homozygous genotype DQ2.5/ DQ2.2 did not increase the CD risk. Children carrying G1 or G2 genotypes were diagnosed with CD earlier and more frequently during the follow-up compare with those carrying G3 or G4 genotypes. 81% of children with spontaneous antibody negativization after the first screening maintained negative antibodies. CONCLUSIONS: A repeated screening of at-risk children during their follow-up allowed us to diagnose new CD cases. In our cohort, HLA- DQ2.5 trans genotype conferred a higher risk in the development of CD than HLA- DQ2.5/DQ2.2. The majority of children with potential CD and CD autoimmunity at 10 years of age remained healthy. PMID- 30418412 TI - Shared Decision Making About Starting anti-TNFs: A Pediatric Perspective. AB - Shared decision making (SDM) is central to patient-centered medicine and has the potential to improve outcomes for pediatric patients with inflammatory bowel diseases. We surveyed specialists about their use of SDM in the decision to start a tumor necrosis factor-alpha inhibitor in pediatric patients. Results were compared between those who reported using SDM and those who did not. Of 209 respondents, 157 (75%) reported using SDM. Physician/practice characteristics were similar between users and non-users. There were no statistically significant differences between groups in the components deemed important to the decision making process nor the number of barriers or facilitators to SDM. Exploratory analyses suggested that physicians using SDM were more accepting of adolescent involvement in the decision-making process. Our results question the effectiveness of using reported barriers and facilitators to guide interventions to improve use of SDM, and suggest further work is needed to understand the adolescent role in decision-making. PMID- 30418413 TI - Can Pediatric Endoscopists Accurately Assess Their Clinical Competency? A Comparison Across Skill Levels. AB - BACKGROUND: Assessment is critical to support pediatric endoscopy training. Although trainee engagement in assessment is encouraged, the use of self assessment and its accuracy among pediatric endoscopists is not well described. We aimed to determine the self-assessment accuracy of novice, intermediate and experienced pediatric endoscopists. METHODS: Novice (performed <50 previous colonoscopies), intermediate (50-500), and experienced (>1000) pediatric endoscopists from 3 North American academic teaching hospitals each performed a clinical colonoscopy. Endoscopists were assessed in real-time by two experienced endoscopists using the Gastrointestinal Endoscopy Competency Assessment Tool for Pediatric Colonoscopy (GiECATKIDS). In addition, participants self-assessed their performance using the same instrument. Self-assessment accuracy between the externally assessed and self-assessed scores was evaluated using absolute difference scores, intraclass correlation coefficients (ICCs), and Bland-Altman analyses. RESULTS: 47 endoscopists participated (21 novices, 16 intermediates and 10 experienced). There was moderate agreement of externally assessed and self assessed GiECATKIDS total scores with an ICC of 0.72 (95% confidence interval [CI], 0.55-0.83). The absolute difference scores among the three groups were significantly different (P = 0.005), with experienced endoscopists demonstrating a more accurate self-assessment compared to novices (P = 0.003). Bland-Altman plots revealed that novice endoscopists' self-assessed scores tended to be higher than their externally-assessed scores, indicating they overestimated their performance. CONCLUSIONS: We found that endoscopic experience was positively associated with self-assessment accuracy among pediatric endoscopists. Novices were inaccurate in assessing their endoscopic competence and were prone to overestimation of their performances. Our findings suggest novices may benefit from targeted interventions aimed at improving their insight and self-awareness. PMID- 30418414 TI - Recanalization of Chronic Extrahepatic Portal Vein Obstruction in Pediatric Patients Using A Minilaparotomy Approach. AB - PURPOSE: Extrahepatic portal vein obstruction (EHPVO) is the most frequent cause of portal hypertension in children. Some patients are not amenable to meso-Rex bypass and alternative surgeries don't restore physiologic flow. We aim to demonstrate the feasibility and safety of minilaparotomy for recanalization of chronic EHPVO. METHODS: This 2013-2015 single-center, retrospective review included pediatric patients with chronic EHPVO who underwent minilaparotomy, mesenteric vein access, and attempted recanalization of the occluded portal vein. Outcomes included portal patency, resolution of variceal bleeding, size and number of varices, spleen size, and platelet count. RESULTS: There were 6 EHPVO patients. The median age was 9.9 years and median duration of EHPVO was 7 years (3-16 years). EHPVO etiologies were liver transplantation (50%), idiopathic (33%), and umbilical vein catheterization (17%). Four patients (67%) had successful portal vein recanalization and stenting. At last follow-up [median 3.1 years (2.2-4.3 years)] all successfully recanalized patients had patent portal vein stents and resolution of varices and variceal bleeding. The median reduction in spleen size was 26%, with improvement in platelet counts (50 to 310/MUL). The 2 patients with an idiopathic etiology may have never had a main extrahepatic portal vein based on imaging, and both were unable to be recanalized. CONCLUSIONS: Recanalization and stenting of a prolonged occlusion of the portal vein via a minilaparotomy approach is feasible, safe, and may provide an alternative to shunt surgery or endoscopic therapy in selected patients. PMID- 30418415 TI - Steps Forward in the Management of Familial Cholestasis. PMID- 30418416 TI - Inflammatory Bowel Diseases and School Absenteeism. AB - OBJECTIVES: Inflammatory Bowel Diseases (IBD) are chronic diseases which negatively affect the schooling of children. The aim is to analyze school absenteeism and its causes in children followed for IBD. METHODS: A prospective multicenter study of IBD patients aged from 5 to 18 years old, from September 2016 to June 2017. Data on absenteeism and its causes were collected via a monthly questionnaire completed by patients or their family by mail. The results were compared with existing data supplied by the school authorities (497 students without IBD divided by class). RESULTS: 106 patients (62 boys), median age of 14 (5 to 18), were included. The global response rate was 83.1%. The IBD patients were absent an average of 4.8 +/- 5.5% of school days during the school year, against 3.2 +/- 1.6% for non IBD group (p = 0.034). Digestive disorders accounted for 34% of the causes of absenteeism. 27% of the absences were due to scheduled events (hospitalizations, endoscopy, or consultations). By excluding the absences for scheduled care, the rate of school absenteeism of IBD patients is significantly lower than that of non-IBD group. CONCLUSION: Children with IBD are more frequently absent from school than non IBD group. The main cause of school absenteeism appears to be associated with the disease itself. The share of scheduled absenteeism is quite large. The organization and scheduling of the patients' care path must be a priority to maximally limit the negative impact of their disease on the patients' schooling. PMID- 30418417 TI - Note: High interest in doxycycline for sexually transmitted infection post exposure prophylaxis (doxycycline-PEP) in a multi-city survey of men who have sex with men (MSM) using a social-networking app. AB - Current strategies to prevent sexually-transmitted infections (STI) are not controlling the epidemic. Doxycycline STI post-exposure prophylaxis' efficacy (doxycycline-PEP) shows promise in pilot studies, but wider acceptability is unknown. A majority (84%) of diverse individuals using a gay social-networking app were interested in doxycycline-PEP. Doxycycline-PEP should be examined in larger trials. PMID- 30418418 TI - Text Messaging after HIV and STI Screening: Do Patients' Profiles Matter? AB - BACKGROUND: Text messaging after STI/HIV screening may be a cost-effective means of improving patient care, but it may not be appropriate for all patients. This study aimed to explore the profiles of patients who did not participate in an SMS program after STI/HIV testing. METHODS: During October 2016, 396 patients in Paris were screened for STI/HIV and were invited to complete an anonymous self administered questionnaire. Patients were offered the possibility of being notified by SMS after testing and 68% accepted (SMS group) whereas 32% did not (no-SMS group). Each of the 100 patients from the no-SMS group who had completed the questionnaire was matched with the next patient from the SMS group. Factors associated with non-participation in the SMS program were studied using conditional logistic regression models. RESULTS: Participation in the SMS program was not related to STI screening characteristics (screening results and seriousness of the diseases screened), but appeared to be related to patient characteristics. In multivariate analysis, compared with patients in the SMS group, those in the no-SMS group were more often older, socially less favoured (born in Africa or Asia, no university diploma, living outside Paris). They also more often declined to answer sexual questions, which could reflect a need for privacy and discretion. CONCLUSIONS: Although SMS after STI/HIV screening is well accepted, it does not suit all patients. Several contact options should be proposed in order to comply with patients' preferences and to reduce the risk of non-delivery of STI screening results.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. PMID- 30418419 TI - Preseptal Upper Eyelid Lipoma. AB - Superficial subcutaneous lipomas are benign, slow-growing neoplasms comprised mature adipose cells that may be surrounded by a fibrous tissue capsule. While found commonly on the body, simple lipomas are rarely described in the eyelids. Reports of two eyelid lipomas in the literature describe the anatomy to be posterior to the orbital septum. The presenting authors report the case of a simple lipoma of the eyelid found fully in the preseptal plane. Lipomas can occur anterior to the orbital septum and should be considered in the differential when presented with a painless, slow-growing eyelid mass in adults. PMID- 30418420 TI - The role of transient receptor potential vanilloid receptor 1 and peroxisome proliferator-activated receptors-alpha in mediating the antinociceptive effects of palmitoylethanolamine in rats. AB - Palmitoylethanolamine (PEA) is a ligand at peroxisome proliferator-activated receptors-alpha (PPARalpha), a nuclear receptor that has anti-inflammatory effects. Herein, complete Freund's adjuvant (CFA)-induced inflammatory pain model in rats and in-vitro calcium imaging studies were used to evaluate the mechanisms that underlie the antinociceptive effects of PEA, including modulating the activity of the transient receptor potential vanilloid receptor 1, which is a key receptor involved in the development of inflammatory pain. Adult male Sprague Dawley rats (180-250 g) received subcutaneous injections of CFA (0.1 ml) into the plantar surface of the left hind paw. Von Frey filaments were used to determine the paw withdrawal threshold. PEA (50 ug), WY14643 (50 ug, a selective PPARalpha agonist) were injected into the plantar surface of the left hind paw at day 7 after CFA injection, and behavioral tests were repeated 6 h after drug administration. Rats were killed and dorsal root ganglia neurons were dissected and prepared for calcium imaging. Neurons were loaded with the calcium-sensitive ratiometric dye Fura-2AM. Changes in [Ca]i were measured as ratios of peak florescence at excitation wavelengths of 340 and 380 nm and expressed as a percentage of the KCl (60 mM) response. Both PEA and WY14643 significantly restored the paw withdrawal threshold in a PPARalpha-dependent fashion (P<0.01). Capsaicin of 15 nM produced 63.9+/-13.4% of KCl response. Preincubation of dorsal root ganglia neurons with PEA 6 h before stimulation with capsaicin, significantly reduce capsaicin-evoked calcium responses (42.9+/-6.4% of KCl response, n=54, P<0.001). In conclusion, modulating transient receptor potential vanilloid receptor 1 activity could provide the mechanism that underlies PEA antinociceptive effects observed in vivo. PMID- 30418421 TI - Comparison of Unilateral With Bilateral Metal Stenting for Malignant Hilar Biliary Obstruction. AB - PURPOSE: The main purpose of this study was to compare the clinical effectiveness between unilateral and bilateral metal stenting for malignant hilar biliary obstruction (MHBO). METHODS: From January 2012 to October 2017, consecutive patients with MHBO underwent unilateral or bilateral stent insertion at our center. Technical and clinical success, stent patency, and survival were compared between these 2 groups. RESULTS: A total of 110 patients with MHBO were included in this study. Technical successful rates of unilateral and bilateral stenting were 93.1% (54/58) and 90.4% (47/52), respectively (P=0.864). Clinical successful rates of unilateral and bilateral stenting were 96.4% (53/55) and 97.9% (46/47), respectively (P=1.000). There was no significant difference in stent patency period (unilateral, 182 d; bilateral, 198 d; P=0.999) and survival (unilateral, 189 d; bilateral, 199 d; P=0.867) between 2 groups. CONCLUSIONS: Unilateral and bilateral metal stenting had similar clinical effectiveness and long-term outcomes in patients with MHBO. PMID- 30418422 TI - Comparison of Immune Reconstitution After Allogeneic Versus Autologous Stem Cell Transplantation in 182 Pediatric Recipients. AB - Hematopoietic stem cell transplantation (HSCT) is a life-saving procedure for children with a variety of malignant and nonmalignant conditions. However, even if immune reconstitution after HSCT has been studied extensively, until now, data on the comparison of immune reconstitution after autologous versus allogeneic HSCT are scarce, but might provide important clinical implications. We examined immune reconstitution (T cells, B cells, and NK cells) at defined timepoints in 147 children who received 182 HSCTs. Differences in the time course of immune reconstitution were analyzed in autologous versus allogeneic HSCT. We identified a quicker immune reconstitution in the T-cell compartment, especially in the CD4 and naive subset after autologous HSCT, whereas recipients of allogeneic transplants showed a higher TCRgd proportion. B-cell reconstitution showed a delayed immune reconstitution after allogeneic HSCT in the first 2 years after HSCT. However, a reconstitution of all lymphocyte subsets after HSCT could be achieved in all patients. Children undergoing an HSCT show a different pattern of immune reconstitution in the allogeneic and autologous setting. This might influence the outcome and should affect the clinical handling of infectious prophylaxis and revaccinations. PMID- 30418423 TI - An Easy and Sensitive Method to Profile the Antibody Specificities of HLA Specific Memory B Cells. AB - BACKGROUND: Pre-transplant immunological risk assessment is currently based on donor-specific HLA antibodies in serum. Despite being an excellent source for antibodies produced by bone marrow-residing plasma cells, serum analysis does not provide information on the memory B cell compartment. While B cell culture supernatants can be used to detect memory B cell derived HLA antibodies, low IgG concentrations can preclude detectability of HLA antibodies in luminex single antigen bead (SAB) assays. METHOD: Culture supernatants of polyclonally activated B cells from alloantigen exposed (n=13) or non-exposed (n=10) individuals were either concentrated 10-fold, or IgG was isolated by using a protein G affinity purification method to increase the IgG concentration. These processed culture supernatants, as well as paired serum samples were tested for the presence of HLA antibodies using luminex SAB analysis. RESULTS: In immunized individuals, 64% were found to have HLA-specific B cell memory in concentrated supernatants, whereas 82% showed HLA-specific B cell memory when IgG isolated supernatants were used for HLA antibody detection. IgG isolated supernatants showed higher MFI values compared to concentrated supernatants without increased background. In some individuals, HLA-specific B cell memory was detected in the absence of accompanying serum antibody specificities. CONCLUSIONS: We developed a novel, highly sensitive method to assess the HLA-specific memory B cell compartment using luminex SAB technology. This assay, allows direct comparison to the serum compartment and may therefore provide a more complete picture of the humoral alloimmune response in patients with a history of alloantigen exposure.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30418424 TI - Validating a Trigger Tool for Detecting Adverse Drug Events in Elderly Patients With Multimorbidity (TRIGGER-CHRON). AB - PURPOSE: The aims of the study were to evaluate the performance of an initial list developed to detect adverse drug events (ADEs) in elderly patients with multimorbidity in clinical practice, to explore the possibility of shortening the list, and to use this tool to study the incidence and characteristics of the ADEs among this population. METHODS: This observational study was conducted at 12 Spanish hospitals. A random sample of five charts from each hospital was selected weekly for retrospective review for a 12-week period. We included patients aged 65 years and older with multimorbidity, hospitalized more than 48 hours. Adverse drug events were detected using a list of 51 triggers previously selected by an expert panel by means of a modified Delphi method. The number of triggers identified and ADEs detected were recorded. The severity and preventability of the ADEs were evaluated. The positive predictive value (PPV) of each trigger was calculated and used to select the most efficient triggers. RESULTS: In 720 charts reviewed, 1430 positive triggers were identified that led to detect 215 ADEs in 178 patients (24.7%), of which 13% were serious. One hundred nineteen ADEs (55.3%) were preventable and mainly related to inadequate treatment monitoring and prescribing errors. Triggers with a PPV of 5% or less were eliminated, resulting in a final list of 32 triggers (TRIGGER-CHRON) with a PPV of 22.1%, which accounted for 98.9% of all ADEs detected and 98.6% of the preventable ADEs. CONCLUSIONS: The shorter final validated TRIGGER-CHRON tool is an efficient list for identifying ADEs in elderly patients with multimorbidity, detecting ADEs in one-fourth of hospitalized patients in internal medicine or geriatric units. PMID- 30418425 TI - Dissecting Communication Barriers in Healthcare: A Path to Enhancing Communication Resiliency, Reliability, and Patient Safety. AB - Suboptimal exchange of information can have tragic consequences to patient's safety and survival. To this end, the Joint Commission lists communication error among the most common attributable causes of sentinel events. The risk management literature further supports this finding, ascribing communication error as a major factor (70%) in adverse events. Despite numerous strategies to improve patient safety, which are rooted in other high reliability industries (e.g., commercial aviation and naval aviation), communication remains an adaptive challenge that has proven difficult to overcome in the sociotechnical landscape that defines healthcare. Attributing a breakdown in information exchange to simply a generic "communication error" without further specification is ineffective and a gross oversimplification of a complex phenomenon. Further dissection of the communication error using root cause analysis, a failure modes and effects analysis, or through an event reporting system is needed. Generalizing rather than categorizing is an oversimplification that clouds clear pattern recognition and thereby prevents focused interventions to improve process reliability. We propose that being more precise when describing communication error is a valid mechanism to learn from these errors. We assert that by deconstructing communication in healthcare into its elemental parts, a more effective organizational learning strategy emerges to enable more focused patient safety improvement efforts. After defining the barriers to effective communication, we then map evidence-based recovery strategies and tools specific to each barrier as a tactic to enhance the reliability and validity of information exchange within healthcare. PMID- 30418426 TI - Impact of Donor Hepatectomy Time during Organ Procurement in Donation after Circulatory Death Liver Transplantation: The United Kingdom Experience. AB - BACKGROUND: No data exists to evaluate how hepatectomy time (HT), in the context of donation after cardiac death (DCD) procurement, impacts on short and long-term outcomes following liver transplantation (LT). In this study we analyse the impact of the time from aortic perfusion to end of hepatectomy on outcomes following DCD LT in the UK. METHODS: An analysis of 1112 DCD donor LT across all UK transplant centres between 2001 and 2015 was performed, using data from the UK Transplant Registry. Donors were all Maastricht Category III. Graft survival after transplantation was estimated using Kaplan-Meier method and logistic regression to identify risk factors for PNF and short and long-term graft survival after LT. RESULTS: Incidence of PNF was 4% (40) and in multivariate analysis only CIT >8 hrs. (HR 2.186 (1.113-4.294, p=0.023) and HT > 60 mins (HR 3.669 (1.363-9.873, p=0.01) were correlated with PNF. Overall 90-day, 1 year, 3 year and 5 year graft survival in DCD LT was 91.2%, 86.5%, 80.9% and 77.7% (compared to a DBD cohort in the same period (n=7221) 94%, 91%, 86.6%, and 82.6% respectively (p<0.001)). In multivariate analysis the factors associated with graft survival were HT > 60mins, donor age >45 yrs., CIT> 8 hours and recipient previous abdominal surgery. CONCLUSIONS: There is a negative impact of prolonged HT on outcomes on DCD LT and although HT > 60 mins is not a contraindication for utilisation it should be part of a multifactorial assessment with established prognostic donor factors such as age (>45yrs) and CIT (>8hrs) for an appropriately selected recipient. PMID- 30418427 TI - Ethnic and Age Disparities in Outcomes among Liver Transplant Waitlist Candidates. AB - BACKGROUND: Despite the increasing prevalence of end-stage liver disease in older adults, there is no consensus to determine suitability for liver transplantation (LT) in the elderly. Disparities in LT access exist, with a disproportionately lower percentage of African Americans (AAs) receiving LT. Understanding waitlist outcomes in older adults, specifically AAs, will identify opportunities to improve LT access for this vulnerable population. METHODS: All adult, liver-only white and AA LT waitlist candidates (1/1/2003-10/1/2015) were identified in the Scientific Registry of Transplant Recipients. Age and race categories were defined: younger (age <60) white, younger AA, older white (age >=60), and older AA. Outcomes were delisting, transplantation, and mortality and were modeled using Fine and Gray competing risks. RESULTS: Among 101,805 candidates, 58.4% underwent transplantation, 14.7% died while listed, and 21.4% were delisted. Among those delisted, 36.1% died, while 7.4% were subsequently relisted. Both older AAs and older whites were more likely than younger whites to be delisted and to die after delisting. Older whites had higher incidence of waitlist mortality than younger whites (sdHR 1.07; 95%CI:1.01-1.13). All AAs and older whites had decreased incidence of LT, compared with younger whites. CONCLUSIONS: Both older age and AA race were associated with decreased cumulative incidence of transplantation. Independent of race, older candidates had increased incidences of delisting and mortality following delisting than younger whites. Our findings support the need for interventions to ensure medical suitability for LT among older adults and to address disparities in LT access for AAs. PMID- 30418428 TI - First Report of siRNA Uptake During Ex Vivo Hypothermic and Normothermic Liver Machine Perfusion. PMID- 30418429 TI - Patient selection and ethical considerations - justifying combined lung AND liver transplantation. PMID- 30418430 TI - Pretransplant cancer in kidney recipients in relation to recurrent and de novo cancer incidence posttransplantation and implications for graft and patient survival. AB - BACKGROUND: Whether kidney transplant recipients who were treated for a malignant tumor prior to transplantation are at an increased risk of developing a tumor post transplantation has not been adequately quantified and characterized. METHODS: We studied more than 270 000 patients on whom pre and posttransplant malignancy data were reported to the Collaborative Transplant Study. More than 4000 of these patients were treated for pretransplant malignancy. The posttransplant tumor incidence in these patients was compared to that in recipients without a pretransplant tumor. Cox regression considering multiple confounders was applied. RESULTS: Significant increases in posttransplant tumor incidence with HR ranging from 2.10 to 5.47 (all P<0.001) were observed for tumors in the site-specific pretransplant locations, suggesting tumor recurrences. There were also significantly increased de novo tumors in new locations with HR ranging from 1.28 to 1.89. Pretransplant basal cell carcinoma of the skin and male genital cancer were associated with significantly increased death-censored graft survival, suggesting impaired immune responsiveness against transplanted kidneys. Time interval from pretransplant tumor occurrence to transplantation and posttransplant mTOR inhibitor treatment were not found to be of significant relevance in this study. CONCLUSIONS: Patients who experienced a pretransplant tumor are at significant risk of tumor recurrence, regardless of the length of interval between tumor treatment and transplantation. There is also some increased risk for de novo tumors, suggesting impaired immune surveillance. Impaired tumor immunity appears to extend to a lower rate of transplant rejection because patients with pretransplant tumors tended to show improved death-censored graft survival. PMID- 30418431 TI - Steatosis in Liver Transplantation: Current Limitations and Future Strategies. AB - In parallel with the pandemic of obesity and diabetes, the prevalence of nonalcoholic fatty liver disease (NAFLD) has progressively increased. Non alcoholic steatohepatitis (NASH), a subtype of NAFLD has also augmented considerably being currently cirrhosis due to NASH the second indication for liver transplantation in USA. Innovative treatments for NASH have shown promising results in phase-2 studies and are being presently evaluated in phase-3 trials.On the other hand, the high mortality on the liver transplant wait list and the organ shortage has obligated the transplant centres to consider suboptimal grafts, such as steatotic livers for transplantation. Fatty livers are vulnerable to preservation injury resulting in a higher rate of primary non-function, early allograft dysfunction and post-transplant vascular and biliary complications. Macrosteatosis of more than 30% in fact is an independent risk factor for graft loss. Therefore, it needs to be considered into the risk assessment scores. Growing evidence supports that moderate and severe macrosteatotic grafts can be successfully used for liver transplantation with careful recipient selection. Protective strategies, such as machine-based perfusion have been developed in experimental setting to minimize preservation related injury and are now on the verge to move into the clinical implementation.This review focuses on the current and potential future treatment of NASH and the clinical practice in fatty liver transplantation, highlights its limitations and optimal allocation, and summarizes the advances of experimental protective strategies, and their potential for clinical application to increase the acceptance and improve the outcomes after liver transplantation with high-grade steatotic livers. PMID- 30418432 TI - ClampFISH detects individual nucleic acid molecules using click chemistry-based amplification. AB - Methods for detecting single nucleic acids in cell and tissues, such as fluorescence in situ hybridization (FISH), are limited by relatively low signal intensity and nonspecific probe binding. Here we present click-amplifying FISH (clampFISH), a method for fluorescence detection of nucleic acids that achieves high specificity and high-gain (>400-fold) signal amplification. ClampFISH probes form a 'C' configuration upon hybridization to the sequence of interest in a double helical manner. The ends of the probes are ligated together using bio orthogonal click chemistry, effectively locking the probes around the target. Iterative rounds of hybridization and click amplify the fluorescence intensity. We show that clampFISH enables the detection of RNA species with low magnification microscopy and in RNA-based flow cytometry. Additionally, we show that the modular design of clampFISH probes allows multiplexing of RNA and DNA detection, that the locking mechanism prevents probe detachment in expansion microscopy, and that clampFISH can be applied in tissue samples. PMID- 30418433 TI - High-throughput determination of the antigen specificities of T cell receptors in single cells. AB - We present tetramer-associated T-cell receptor sequencing (TetTCR-seq) to link T cell receptor (TCR) sequences to their cognate antigens in single cells at high throughput. Binding is determined using a library of DNA-barcoded antigen tetramers that is rapidly generated by in vitro transcription and translation. We applied TetTCR-seq to identify patterns in TCR cross-reactivity with cancer neoantigens and to rapidly isolate neoantigen-specific TCRs with no cross reactivity to the wild-type antigen. PMID- 30418434 TI - Ligand field effects on the ground and excited states of reactive FeO2+ species. AB - High-valent Fe(iv)-oxo species have been found to be key oxidizing intermediates in the mechanisms of mononuclear iron heme and non-heme enzymes that can functionalize strong C-H bonds. Biomimetic Fe(iv)-oxo molecular complexes have been successfully synthesized and characterized, but their catalytic reactivity is typically lower than that of the enzymatic analogues. The C-H activation step proceeds through two competitive mechanisms, named sigma- and pi-channels. We have performed high-level wave function theory calculations on bare FeO2+ and a series of non-heme Fe(iv)-oxo model complexes in order to elucidate the electronic properties and the ligand field effects on those channels. Our results suggest that a coordination environment formed by a weak field gives access to both competitive channels, yielding more reactive Fe(iv)-oxo sites. In contrast, a strong ligand environment stabilizes only the sigma-channel. Our concluding remarks will aid the derivation of new structure-reactivity descriptors that can contribute to the development of the next generation of functional catalysts. PMID- 30418435 TI - Atmospheric chemistry of hexa- and penta-fluorobenzene: UV photolysis and kinetics and mechanisms of the reactions of Cl atoms and OH radicals. AB - Photochemical reactors were used to study the kinetics and mechanisms of reactions of Cl atoms and OH radicals with hexa- and penta-fluorobenzene (C6F6, C6F5H) in 700 Torr total pressure of N2, air, or O2 diluent at 296 +/- 2 K. C6F6 and C6F5H undergo ring-opening following 254 nm UV irradiation, but with small quantum yields (phi < 0.03). Reaction of Cl atoms with C6F6 proceeds via adduct formation, while the reaction of Cl atoms with C6F5H proceeds via hydrogen abstraction and adduct formation. C6F6-Cl and C6F5H-Cl adducts decompose rapidly (k ~ 105-106 s-1) reforming the reactants, and react with Cl atoms to form products. The fraction of adduct reacting with Cl atoms increases with steady state Cl atom concentration, resulting in an increasing apparent effective Cl atom rate constant. The rate constant for the H-abstraction channel for Cl + C6F5H is estimated at (7.3 +/- 5.7) * 10-16 cm3 molecule-1 s-1. Establishment of the equilibrium between the adducts and the aromatic reactant + Cl occurs rapidly with equilibrium constants of K([adduct]/[aromatic][Cl]) = (1.96 +/- 0.11) * 10 16 and (9.28 +/- 0.11) * 10-17 cm3 molecule-1 for C6F6 and C6F5H, respectively. Reaction of the adducts with O2 occurs slowly with estimated rate constants of <7 and <4 * 10-18 cm3 molecule-1 s-1 for C6F6-Cl and C6F5H-Cl, respectively. The rate constants for reaction of OH radicals with C6F6 and C6F5H were determined to be (2.27 +/- 0.49) * 10-13 and (2.56 +/- 0.62) * 10-13 cm3 molecule-1 s-1, respectively. UV and IR spectra of C6F6 and C6F5H at 296 +/- 1 K were collected and calibrated. Results are discussed in the context of available literature data for reactions of Cl atoms and OH radicals with halogenated aromatic compounds. PMID- 30418436 TI - On the molecular optical nonlinearity of halogen-bond-forming azobenzenes. AB - We study hyper-Rayleigh scattering and computed molecular hyperpolarizability in a series of azobenzene chromophores in chloroform and dimethylformamide as solvents. The chromophores form halogen or hydrogen bonds of varying strength with dimethylformamide molecules, differently from what is expected for chloroform. We show that hyperpolarizability is unaffected or sligthly lower with the azobenzene forming the strongest halogen bond. Solid supramolecular polymers with the same chromophores have previously demonstrated clearly higher second order nonlinear responses when a halogen-bond-accepting polymer is used, the larger increase being associated with the stronger halogen bond. The present study proves that the higher optical nonlinearity in polymers lies in the better ordering of the chromophores instead of changes in molecular hyperpolarizability, highlighting the unique properties of halogen bonding in supramolecular chemistry. PMID- 30418437 TI - Towards a dissociative SPC-like water model II. The impact of Lennard-Jones and Buckingham non-coulombic forces. AB - The dissociative water model developed by Garofalini and coworkers provides a versatile and effective approach to model proton transfer in a liquid water environment. This work presents the continuation of a previous study aiming at improving the transferability of this model, thereby enabling its application via third party simulation programs. In particular it is probed, whether a re formulation of the non-coulombic interaction potential in the framework of the more common Lennard-Jones (LJ) and Buckingham formulation is feasible. In order to minimise the deviation of the structural properties between the original and modified models, while at the same time the rovibrational spectrum and proton transfer characteristics are optimised to best match experimental data, a hierarchical optimisation strategy is applied to adjust the parameters of the associated three-body interaction potential. While the application of the Lennard Jones potential resulted in a slight overstructuring of the liquid typical for LJ based simple-point charge models, the Buckingham formulation provides a virtually unmodified description of the liquid structure, while the overall proton diffusion coefficient of 0.96 A2 ps-1 and the average proton-donor lifetime of 1.39 ps are found in good agreement with the respective reference values of 0.93 A2 ps-1 and 1.24 to 1.70 ps obtained via experiment and Car-Parrinello molecular dynamics simulations, respectively. Comparison of the pair distribution functions and the vibrational spectra with their experimental counterpart highlight that the proposed potential model provides a state-of-the-art description of liquid water in addition to the comparably rare capability of adequately describing proton transfer events in aqueous solution. Due to the widespread use of the Lennard-Jones and Buckingham non-coulombic potentials in simulations relevant for life and material sciences, the re-formulated dissociative water potentials can be combined with established force-field models in a straight-forward way. PMID- 30418438 TI - Self-sterilizing antibacterial silver-loaded microneedles. AB - Microneedle patches have become an exciting means for transdermal delivery of various therapeutics. Herein, we report on self-sterilizing dissolving nanosilver loaded microneedle patches created from carboxymethylcellulose capable of suppressing microbial pathogen growth at the insertion site. PMID- 30418439 TI - Pillararene-based supramolecular polymers. AB - Pillararenes, as a new type of macrocyclic hosts, possess columnar structures and electron-rich cavities. Pillararenes not only recognize suitable cations, but also bind many neutral molecules. Due to the easy modification of pillararenes, various functional groups can be conveniently attached to the rim of pillararenes to provide suitable interaction sites, and the modified pillararenes even bind anionic guests. Thus, pillararenes and their derivatives have presented intriguing and unique host-guest recognition nature in the past few years, which make them ideal building blocks for the preparation of supramolecular polymers. Pillararene-based supramolecular polymers (PSPs) not only possess many merits of traditional covalent polymers but also have many specific properties, such as self-reparability, degradability, and self-adaptation. This feature paper gives an overview of the preparation of PSPs and covers recent research advance and future trends of pillararene-based host-guest pairs, assembly methods, topological architectures, stimuli-responsiveness, and functional features. We expect that the review will be helpful to researchers working in the fields of supramolecular chemistry and polymer science. PMID- 30418440 TI - Copper-catalyzed oxidative intermolecular 1,2-alkylarylation of styrenes with ethers and indoles. AB - A new copper-catalyzed oxidative three-component intermolecular 1,2 alkylarylation of styrenes with ethers and indoles is disclosed. This method utilizes TBPB as an oxidant to efficiently construct C(sp3)-C(sp3) and C(sp3) C(sp2) bonds in one step through probable radical and electrophilic alkylation processes, respectively, and a variety of functional groups are well tolerated. PMID- 30418441 TI - Native chemical ligation in protein synthesis and semi-synthesis. AB - Native chemical ligation (NCL) provides a highly efficient and robust means to chemoselectively link unprotected peptide and protein segments to generate proteins. The ability to incorporate non-proteinogenic amino acids (e.g. d-amino acids or fluorescent labels) and post-translational modifications into proteins by stitching together peptide fragments has driven extremely important developments in peptide and protein science over the past 20 years. Extensions of the original NCL concept (including the development of thiol- and selenol-derived amino acids and desulfurisation and deselenisation methods), improved access to peptide thioesters, and the use of the methodology in combination with recombinantly expressed polypeptide fragments (termed Expressed Protein Ligation, EPL) have helped to further expand the utility of the methodology. Over the past five years, there has been a dramatic increase in the number of proteins that have been accessed by total chemical synthesis and semi-synthesis, including a large range of modified proteins; new records have also been set with regards to the size of proteins that can now be accessed via ligation chemistry. Together these efforts have not only contributed to a better understanding of protein structure and function, but have also driven innovations in protein science. In this tutorial review, we aim to provide the reader with the latest developments in NCL- and EPL-based ligation technologies as well as illustrated examples of using these methods, together with synthetic logic, to access proteins and modified proteins for biological study. PMID- 30418442 TI - Orientation of nitro-group governs the fluorescence lifetime of nitrobenzoxadiazole (NBD)-labeled lipids in lipid bilayers. AB - Nitrobenzoxadiazole (NBD) labeled lipids are popular fluorescent probes of membrane structure and dynamics, and have been widely used in both model systems and living cells. Irrespective of attachment to the lipid head group or hydrocarbon chains, the NBD fluorophore generally adopts a transverse bilayer location near the host lipid carbonyl/glycerol moieties. Still, considerable variability is observed in the measured fluorescence lifetimes, indicating that overall fluorophore location is not the determinant of NBD fluorescence properties. Combining fluorescence experiments and molecular dynamics simulations, we show that for two almost identical NBD probes, significant differences in fluorophore orientation and fluorescence lifetime are observed. Integrating these findings with literature data, we demonstrate a correlation between NBD orientation and fluorescence lifetime. The latter is longer when the NBD nitro group is predominantly oriented towards the bilayer interior, compared to probes for which it points to the water medium. PMID- 30418443 TI - Identification and computational characterization of isomers with cis and trans amide bonds in folate and its analogues. AB - Folate and its synthetic analogues, called antifolates, are known to have diverse bio-applications, for example as cell proliferation stimulators or anticancer drugs. Their molecular structure is important for performing the required biological activity. Since all folate-derived ligands contain a peptide-like amide bond, its configuration is one of the key components for the functional fitness of such compounds. During the modelling of folate and three of its derivatives - methotrexate, 5-methyl tetrahydrofolate, and pteroyl ornithine, we registered significant population of the cis isomers along the amide bond. The properties of the cis and trans forms of the ligands in saline are studied in detail by classical atomistic molecular dynamics and by quantum chemical methods. The calculations predict high probability for coexistence of the cis isomers for two of the ligands. The energetic instability of the cis form is explained with a sigma-character admixture into the C[double bond, length as m-dash]O(pi) bond, while its magnitude is attributed to the pattern of local electron density redistribution. The cis forms of all molecules have markedly slower structural dynamics than the trans ones, which might affect their behavior in vivo. PMID- 30418444 TI - Polymeric micro- and nanoparticles for immune modulation. AB - New advances in biomaterial-based approaches to modulate the immune system are being applied to treat cancer, infectious diseases, and autoimmunity. Particulate systems are especially well-suited to deliver immunomodulatory factors to immune cells since their small size allows them to engage cell surface receptors or deliver cargo intracellularly after internalization. Biodegradable polymeric particles are a particularly versatile platform for the delivery of signals to the immune system because they can be easily surface-modified to target specific receptors and engineered to release encapsulated cargo in a precise, sustained manner. Micro- and nanoscale systems have been used to deliver a variety of therapeutic agents including monoclonal antibodies, peptides, and small molecule drugs that function to activate the immune system against cancer or infectious disease, or suppress the immune system to combat autoimmune diseases and transplant rejection. This review provides an overview of recent advances in the development of polymeric micro- and nanoparticulate systems for the presentation and delivery of immunomodulatory agents targeted to a variety of immune cell types including APCs, T cells, B cells, and NK cells. PMID- 30418446 TI - Intrinsic photophysics of nitrophenolate ions studied by cryogenic ion spectroscopy. AB - The intrinsic photophysics of nitrophenolate isomers (meta, para, and ortho) was studied at low temperature using photodissociation mass spectrometry in a cryogenic ion trap instrument. Each isomer has distinct photophysics that affects the excited state lifetimes, as observed experimentally in their spectroscopic linewidths. Visible-light-induced excitation of m-nitrophenolate gives rise to well-resolved vibronic features in the spectrum of the S1 state. The para and ortho isomers have broad spectra - even at cryogenic temperatures - due to their shorter excited state lifetimes and spectral congestion. We present computational evidence for mixing of the first and second excited states of o-nitrophenolate, leading to significant additional broadening in the experimental spectrum. PMID- 30418447 TI - Novel electronic structures and enhanced optical properties of boron phosphide/blue phosphorene and F4TCNQ/blue phosphorene heterostructures: a DFT + NEGF study. AB - Blue phosphorene (Blue-p), an allotrope of black phosphorene, has attracted extensive interest due to its hexagonal crystal with a flat arranged layer of phosphorus atoms. However, the indirect band gap of Blue-p greatly hinders its applications in optoelectronics. By stacking both boron phosphide (BP) and the organic molecule 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F4TCNQ) with Blue-p, we construct BP/Blue-p and F4TCNQ/Blue-p heterostructures. We reveal that the BP/Blue-p heterostructure possesses a direct band gap of 0.605 eV and is tunable via in-plane strain and an external electric field. Moreover, it also has remarkable optical absorption in the UV region and enhanced transport properties. Furthermore, by doping with F4TCNQ, the F4TCNQ/Blue-p heterojunction displays type-II semiconducting properties with a flat valence band and Van Hove singularities at the Fermi level, which can be used to achieve extremely low in band tunneling, yielding low static power dissipation and large drive currents in the ON regime of transistors. Due to the superior electronic, optical and transport properties, Blue-p-based heterostructures are promising candidates for electronic and optical device applications. PMID- 30418449 TI - Neuromorphic computation with spiking memristors: habituation, experimental instantiation of logic gates and a novel sequence-sensitive perceptron model. AB - Memristors have been compared to neurons and synapses, suggesting they would be good for neuromorphic computing. A change in voltage across a memristor causes a current spike which imparts a short-term memory to a memristor, allowing for through-time computation, which can do arithmetical operations and sequential logic, or model short-time habituation to a stimulus. Using simple physical rules, simple logic gates such as XOR, and novel, more complex, gates such as the arithmetic full adder (AFA) can be instantiated in sol-gel TiO2 plastic memristors. The adder makes use of the memristor's short-term memory to add together three binary values and outputs the sum, the carry digit and even the order they were input in, allowing for logically (but not physically reversible) computation. Only a single memristor is required to instantiate each gate, as additional input/output ports can be replaced with extra time-steps allowing a single memristor to do a hitherto unexpectedly large amount of computation, which may mitigate the memristor's slow operation speed and may relate to how neurons do a similarly large computation with slow operation speeds. These logic gates can be understood by modelling the memristors as a novel type of perceptron: one which is sensitive to input order. The memristor's short-term memory can change the input weights applied to later inputs, and thus the memristor gates cannot be accurately described by a single perceptron, requiring either a network of time invariant perceptrons, or a sequence-sensitive self-reprogrammable perceptron. Thus, the AFA is best described as a sequence-sensitive perceptron that sorts binary inputs into classes corresponding to the arithmetical sum of the inputs. Co-development of memristor hardware alongside software (sequence-sensitive perceptron) models in trained neural networks would allow the porting of modern deep-neural networks architecture to low-power hardware neural net chips. PMID- 30418448 TI - Influence of alcoholic solvent and acetate anion coordination mode variations on structures and magnetic properties of heterometallic Zn2Dy2 tetranuclear clusters. AB - The present work clarifies how slight modifications of the synthetic conditions (e.g., employment of different alcoholic solvents) can result in the variation of the coordination mode of an acetate anion yielding two structurally similar heterometallic Zn2Dy2 tetranuclear clusters with formulas [Zn2Dy2(L)4(CH3COO)2(CH3CH2OH)2].2CH2Cl2.0.5H2O (1) and [Zn2Dy2(L)4(CH3COO)2(CH3OH)2].4CH2Cl2.2CH3OH.0.1H2O (2), where H2L is (E)-4-(tert butyl)-2-((2-hydroxy-3-methoxybenzylidene)amino)phenol. Complexes 1 and 2 were synthesized by varying the alcoholic solvent employed in the synthesis. The ethanol solvent in 1 led to the acetate anion being coordinated to the DyIII ion in bidentate chelating mode while the methanol solvent in 2 generated the acetate anion coordinated to the DyIII ion in bridging mode. Such a subtle change of the coordination mode of the acetate anion on the DyIII ion imposes a significant effect on the distinct dynamic relaxation in 1 and 2. The magnetic properties of 1 and 2 were characterized through SQUID magnetometry and theoretical calculations to determine the effective energy barrier, energy levels, magnetic anisotropy and intracluster magnetic exchange coupling parameters. Both tetramers show frequency dependence of the out-of-phase ac magnetic susceptibility signal under zero applied dc field associated with single-molecule magnetic behaviour. The effective energy barriers of 1 and 2 are 115.4 and 104.2 cm-1, respectively. Theoretical calculations suggest that the different magnetic behaviours between 1 and 2 are mainly due to the coordination mode variations of the acetate anion on the DyIII site. The present result highlights how a subtle modification in the reaction alcoholic solvent resulted in two structurally similar tetranuclear Zn2Dy2 examples with different magnetic behaviours. PMID- 30418450 TI - Probing the dynamic self-assembly behaviour of photoswitchable wormlike micelles in real-time. AB - Understanding the dynamic self-assembly behaviour of azobenzene photosurfactants (AzoPS) is crucial to advance their use in controlled release applications such as drug delivery and micellar catalysis. Currently, their behaviour in the equilibrium cis- and trans-photostationary states is more widely understood than during the photoisomerisation process itself. Here, we investigate the time dependent self-assembly of the different photoisomers of a model neutral AzoPS, tetraethylene glycol mono(4',4-octyloxy,octyl-azobenzene) (C8AzoOC8E4) using small-angle neutron scattering (SANS). We show that the incorporation of in situ UV-Vis absorption spectroscopy with SANS allows the scattering profile, and hence micelle shape, to be correlated with the extent of photoisomerisation in real time. It was observed that C8AzoOC8E4 could switch between wormlike micelles (trans native state) and fractal aggregates (under UV light), with changes in the self-assembled structure arising concurrently with changes in the absorption spectrum. Wormlike micelles could be recovered within 60 seconds of blue light illumination. To the best of our knowledge, this is the first time the degree of AzoPS photoisomerisation has been tracked in situ through combined UV-Vis absorption spectroscopy-SANS measurements. This technique could be widely used to gain mechanistic and kinetic insights into light-dependent processes that are reliant on self-assembly. PMID- 30418451 TI - Alcohol induced gelation of TEMPO-oxidized cellulose nanofibril dispersions. AB - Solvent-induced physical hydrogels of TEMPO-oxidized cellulose nanofibrils (OCNFs) were obtained from aqueous/alcoholic dispersions of fibrils in lower alcohols, namely, methanol, ethanol, 1-propanol and 2-propanol. The sol-gel transition occurs above a critical alcohol concentration of ca. 30 wt% for all alcohols tested. The rheological properties of the hydrogels depend on the nature of the alcohol: for ethanol, 1-propanol and 2-propanol the magnitude of the shear storage modulus follows the alcohol hydrophilicity, whilst methanol produces the weakest gels in the group. Above a second critical concentration, ca. 60 wt% alcohol, phase separation is observed as the gels undergo syneresis. Analysis of small-angle X-ray scattering data shows that the OCNFs may be modelled as rigid rods. In the presence of lower alcohols, attractive interactions between nanofibrils are present and, above the alcohol concentration leading to gelation, an increase of the OCNF cross-section is observed, suggesting alcohol induced aggregation of nanofibrils. PMID- 30418452 TI - A Viedma ripening route to an enantiopure building block for Levetiracetam and Brivaracetam. AB - A simple route to enantiomerically pure (S)-2-aminobutyramide - the chiral component of the anti-epileptic drugs Levetiracetam and Brivaracetam has been developed. This approach is based on the rational design and application of a Viedma ripening process. The practical potential of the process is demonstrated on a large scale. PMID- 30418453 TI - Capillary imbibition in a square tube. AB - When a square tube is brought in contact with bulk liquid, the liquid wets the corners of the tube and creates finger-like wetted regions. The wetting of the liquid then takes place with the growth of two parts, the bulk part where the cross section is entirely filled with the liquid and the finger part where the cross section of the tube is partially filled. In previous works, the growth of these two parts has been discussed separately. Here we conduct the analysis by explicitly accounting for the coupling of the two parts. We propose coupled equations for liquid imbibition in both parts and show that (a) the length of each part, h0 and h1, both increases in time t following Lucas-Washburn's law, h0 ~ t1/2 and h1 ~ t1/2, but that (b) the coefficients are different from those obtained in the previous analysis which ignored the coupling. PMID- 30418454 TI - Membrane nanotube pearling restricted by confined polymers. AB - Increasing evidence showed that membrane nanotubes readily undergo pearling in response to external stimuli, while long tubular membrane structures have been observed connecting cells and functioning as channels for intercellular transport, raising a fundamental question of how the stability of membrane nanotubes is maintained in the cellular environment. Here, combining dissipative particle dynamics simulations, free energy calculations, and a force analysis, we propose and demonstrate that nanotube pearling can be restricted by confined polymers, which can be DNA and protein chains transported through the nanotubes, or actin filaments participating in tube formation and elongation. Thermodynamically, nanotube pearling releases the membrane surface energy, but costs bending energies of both the membrane and the confined polymers. Following the mechanism, the pearling of nanotubes confining longer and stiffer polymers is more difficult as it costs larger polymer bending energies. In dynamics, nanotube pearling occurs by repelling polymers from the region of nanotube shrinking to that of swelling. Shorter polymers can be readily repelled owing to the unbalanced force exerted by the shrinking tube region, whereas longer polymers tend to be trapped at the shrinking region to retard the nanotube pearling. Besides the low surface tension maintained by lipid reservoirs kept in living cells, our results supplement the explanation for the stability of membrane nanotubes, and open up a new avenue to manipulate the shape deformation of tubular membrane structures for study of many biological processes. PMID- 30418455 TI - Information transmission by Marangoni-driven relaxation oscillations at droplets. AB - Marangoni-driven relaxation oscillations can be observed in many systems where concentration gradients of surface-active substances exist. In the present paper, we describe the experimentally observed coupling between relaxation oscillations at neighboring droplets in a concentration gradient. By a numerical parameter study, we evaluate the oscillation characteristics depending on relevant material parameters and the pairwise droplet distance. Based on these findings, we demonstrate that hydrodynamic interaction in multidroplet configurations can lead to a synchronization of the oscillations over the whole ensemble. This effect has the potential to be used as a novel approach for information transmission in microfluidic applications. PMID- 30418456 TI - New tetralactam hosts for squaraine dyes. AB - The photophysical properties of a deep-red fluorescent squaraine dye can be improved by encapsulating it within a tetralactam macrocycle. Three new tetralactams are described with different substituents (methyl, methoxy, methylenedioxy) on the macrocycle aromatic sidewalls. The capability of each tetralactam to encapsulate a squaraine dye in chloroform solution was determined experimentally using absorption, fluorescence, and NMR spectroscopy. Two of the tetralactams were found to thread a squaraine dye with association constants on the order of 106 M-1, while a third macrocycle exhibited no squaraine affinity. An X-ray crystal structure of the third tetralactam showed that the substituents sterically blocked squaraine association. Of the two tetralactams that encapsulate a squaraine, one induces an increase in squaraine fluorescence quantum yield, while the other quenches the squaraine fluorescence. The results suggest that these new squaraine binding systems will be useful for biological imaging and diagnostics applications. PMID- 30418459 TI - Chemoselective synthesis of m-teraryls through ring transformation of 2H-pyran-2 ones by 2-(1-arylethylidene)-malononitriles. AB - We have developed a simple, efficient and chemoselective approach for the synthesis of m-teraryls by the reaction of 6-aryl-2-oxo-4-(sec.amino)-2H-pyran-3 carbonitriles and 2-(1-arylethylidene)malononitriles under basic conditions. We used 6-aryl-2-oxo-4-methylsulfanyl-2H-pyran-3-carbonitriles as precursors and successfully afforded 5'-methylsulfanyl-[1,1';3',1'']teraryl-4'-carbonitriles. We tried to understand the difference in the reactivity of structurally symmetrical molecules, such as allyl cyanide, 2-cyanomethylbenzonitrile and 2-(1 arylethylidene)malononitrile. The structure of 4''-methyl-5'-(piperidin-1-yl) [1,1':3',1''-terphenyl]-4'-carbonitrile was confirmed by single crystal X-ray diffraction analysis. PMID- 30418460 TI - N,O-Bidentate ligand-tunable copper(ii) complexes as a catalyst for Chan-Lam coupling reactions of arylboronic acids with 1H-imidazole derivatives. AB - An efficient procedure for Chan-Lam coupling reactions of arylboronic acids with 1H-imidazole derivatives using N,O-bidentate ligand-tunable copper(ii) complexes as a catalyst under base-free conditions has been developed. This protocol features mild reaction conditions, high yields and compatibility with different functional groups, providing a direct and facile strategy for the construction of C-N bonds and synthesis of heterocyclic compounds. PMID- 30418461 TI - Templated direct growth of ultra-thin double-walled carbon nanotubes. AB - Double-walled carbon nanotubes (DWCNTs) combined the advantages of multi-walled (MW-) and single-walled (SW-) CNTs can be obtained by transforming the precursors (e.g. fullerene, ferrocene) into thin inner CNTs inside SWCNTs as templates. However, this method is limited since the DWCNT yield is strongly influenced by the filling efficiency (depending on the type of the filled molecules), opening and cutting the SWCNTs, and the diameter of the host SWCNTs. Therefore, it cannot be applied to all types of SWCNT templates. Here we show a universal route to synthesize ultra-thin DWCNTs via making SWCNTs stable at high temperature in vacuum. This method applies to different types of SWCNTs including metallicity sorted ones without using any precursors since the carbon sources were from the reconstructed SWCNTs and the residue carbons. The resulting DWCNTs are with high quality and the yield of inner tubes is comparable to/higher than that of the DWCNTs made from the transformation of ferrocene/fullerene peapods. PMID- 30418462 TI - Total synthesis of (+/-)-antroquinonol. AB - We report the total synthesis of (+/-)-antroquinonol based on a concise and efficient route. Key features include two different strategies to install the required three contiguous stereogenic centers, which not only furnish the desired natural product but also provide natural product congeners for further biological studies. PMID- 30418463 TI - Charge polarization, local electroneutrality breakdown and eddy formation due to electroosmosis in varying-section channels. AB - We characterize the dynamics of an electrolyte embedded in a varying-section channel under the action of a constant external electrostatic field. By means of molecular dynamics simulations we determine the stationary density, charge and velocity profiles of the electrolyte. Our results show that when the Debye length is comparable to the width of the channel bottlenecks a concentration polarization along with two eddies sets inside the channel. Interestingly, upon increasing the external field, local electroneutrality breaks down and charge polarization sets leading to the onset of net dipolar field. This novel scenario, that cannot be captured by the standard approaches based on local electroneutrality, opens the route for the realization of novel micro and nano fluidic devices. PMID- 30418464 TI - Nanoclusters of crystallographically aligned nanoparticles for magnetic thermotherapy: aqueous ferrofluid, agarose phantoms and ex vivo melanoma tumour assessment. AB - Magnetic hyperthermia is an oncological therapy where magnetic nanostructures, under a radiofrequency field, act as heat transducers increasing tumour temperature and killing cancerous cells. Nanostructure heating efficiency depends both on the field conditions and on the nanostructure properties and mobility inside the tumour. Such nanostructures are often incorrectly bench-marketed in the colloidal state and using field settings far off from the recommended therapeutic values. Here, we prepared nanoclusters composed of iron oxide magnetite nanoparticles crystallographically aligned and their specific absorption rate (SAR) values were calorimetrically determined in physiological fluids, agarose-gel-phantoms and ex vivo tumours extracted from mice challenged with B16-F0 melanoma cells. A portable, multipurpose applicator using medical field settings; 100 kHz and 9.3 kA m-1, was developed and the results were fully analysed in terms of nanoclusters' structural and magnetic properties. A careful evaluation of the nanoclusters' heating capacity in the three milieus clearly indicates that the SAR values of fluid suspensions or agarose-gel-phantoms are not adequate to predict the real tissue temperature increase or the dosage needed to heat a tumour. Our results show that besides nanostructure mobility, perfusion and local thermoregulation, the nanostructure distribution inside the tumour plays a key role in effective heating. A suppression of the magnetic material effective heating efficiency appears in tumour tissue. In fact, dosage had to be increased considerably, from the SAR values predicted from fluid or agarose, to achieve the desired temperature increase. These results represent an important contribution towards the design of more efficient nanostructures and towards the clinical translation of hyperthermia. PMID- 30418465 TI - Organocatalytic asymmetric syntheses of 3-fluorooxindoles containing vicinal fluoroamine motifs. AB - An organocatalytic Mannich reaction of 3-fluorooxindoles has been developed. Using a commercially available cinchona alkaloid catalyst, a wide range of 3 fluorooxindoles was successfully reacted with N-sulfonyl aldimines to give biologically important 3-fluorooxindoles containing vicinal fluoroamine motifs with high efficiency and good enantioselectivity. This protocol uses readily available reactants and cheap organocatalysts, and it is operationally simple. PMID- 30418466 TI - Recent advances in one-dimensional halide perovskites for optoelectronic applications. AB - Metal-halide perovskites have emerged as efficient, low-cost energy materials owing to their remarkable optoelectronic properties. In particular, the dimensionality and morphology of crystallites may have a striking influence on their chemical and physical properties and therefore affect their optoelectronic applications. One-dimensional halide perovskites have superior carrier transportation in one dimension, high crystalline quality, and consequently, high quantum efficiencies and long carrier diffusion lengths, which are important for the performance of perovskite-based nanoscale optoelectronic and photonic devices. In this review, we highlight recent advances in the synthesis of one dimensional halide perovskites and their unique properties as well as their novel optoelectronic applications. This review aims to provide an overview of the achievements in synthesis techniques and nanoscale optoelectronic applications based on one-dimensional perovskite nanocrystals. PMID- 30418467 TI - Risk Factors, Causes, and Costs of Hospital Readmission After Head and Neck Cancer Surgery Reconstruction. AB - Importance: Thirty-day hospital readmissions have substantial direct costs and are increasingly used as a measure of quality care. However, data regarding the risk factors and reasons for readmissions in head and neck cancer surgery reconstruction are lacking. Objective: To describe the rate, risk factors, and causes of 30-day readmission in patients with head and neck cancer following free or pedicled flap reconstruction. Design, Setting, and Participants: This retrospective, population-based cohort study analyzed medical records from the Nationwide Readmissions Database of 9487 patients undergoing pedicled or free flap reconstruction of head and neck oncologic defects between January 1, 2010, and December 31, 2014. Data analysis was performed in October 2017. Exposures: Pedicled or free flap reconstruction of an oncologic head and neck defect. Main Outcomes and Measures: The primary outcome was 30-day all-cause readmissions. Secondary outcomes included risk factors, causes, and costs of readmission. Multivariate regression analyses were conducted to determine factors independently associated with 30-day readmissions. Results: Among 9487 patients included in the study (6798 male; 71.7%), the median age was 63 years (interquartile range, 55-71 years), and the 30-day readmission rate was 19.4% (n = 1839), with a mean cost per readmission of $15 916 (standard error of the mean, $785). The most common indication for readmission was wound complication (26.5%, n = 487). On multivariate regression, significant risk factors for 30-day readmission were median household income in the lowest quartile (vs highest quartile: odds ratio [OR], 1.58; 95% CI, 1.18-2.11), congestive heart failure (OR, 1.68; 95% CI, 1.14-2.47), liver disease (OR, 2.02; 95% CI, 1.22- 3.33), total laryngectomy (OR, 1.40; 95% CI, 1.12-1.75), pharyngectomy (OR, 1.47; 95% CI, 1.08-2.01), blood transfusion (OR, 1.30; 95% CI, 1.04-1.64), discharge to home with home health care (vs routine: OR, 1.32; 95% CI, 1.04-1.67), and discharge to a nursing facility (vs routine: OR, 1.77; 95% CI, 1.30-2.40). Conclusions and Relevance: Using the Nationwide Readmissions Database, we demonstrate that approximately 1 in 5 patients undergoing head and neck cancer surgery reconstruction is readmitted within 30 days of surgery. Readmissions are most commonly associated with wound complications. Socioeconomic status, complex ablative procedures, and patient comorbidities are independent risk factors for readmission. These findings may be useful to clinicians in developing perioperative interventions aimed to reduce hospital readmissions and improve quality of patient care. PMID- 30418468 TI - Effectiveness of Transconjunctival Fat Removal and Resected Fat Grafting for Lower Eye Bag and Tear Trough Deformity. AB - Importance: The main treatment of lower eye bags is changing from fat removal techniques to fat repositioning techniques. However, fat repositioning techniques have potential complications because of disruption of the middle lamellae, leading to contracture and shortening. Objective: To determine whether transconjunctival fat removal followed by resected fat grafting is an effective alternative method of eye bag treatment. Design, Setting, and Participants: This retrospective study of 229 consecutive patients who underwent transconjunctival fat removal followed by resected fat grafting from November 1, 2011, to October 31, 2017, was conducted by review of medical records from the Seoul H Dermatology Clinic in Seoul, Korea. Main Outcomes and Measures: Comparison of patient satisfaction and modified Goldberg scores before and after surgery. Results: A total of 229 patients (mean [SD] age, 41.24 [11.11] years; range, 20-69 years; 164 [71.6%] female) underwent transconjunctival fat removal followed by resected fat grafting. Of the 229 patients, 224 (97.8%) were satisfied with their surgical results, and major improvements were seen in the mean (SD) preoperative and postoperative scores for orbital fat prolapse (preoperative: 1.94 [0.63]; postoperative: 0.07 [0.21]), tear trough depression (preoperative: 1.61 [0.75]; postoperative: 0.33 [0.42]), skin transparency (preoperative: 1.15 [0.97]: postoperative: 0.22 [0.37]), and triangular malar mound (preoperative: 0.37 [0.61]; postoperative: 0.34 [0.58]). Although the orbicularis prominence worsened after surgery, this outcome should be interpreted as a good result for Asian patients. Skin elasticity deteriorated postoperatively. Conclusions and Relevance: The findings suggest that transconjunctival fat removal followed by resected fat grafting is an effective and safe technique to treat lower eyelid fat herniation without increased complication rates and provides good patient and surgeon satisfaction. Level of Evidence: 4. PMID- 30418469 TI - New Physical Activity Guidelines: A Call to Activity for Clinicians and Patients. PMID- 30418470 TI - Middle-Aged Man With Bilateral Subretinal Fluid. PMID- 30418471 TI - The Physical Activity Guidelines for Americans. AB - Importance: Approximately 80% of US adults and adolescents are insufficiently active. Physical activity fosters normal growth and development and can make people feel, function, and sleep better and reduce risk of many chronic diseases. Objective: To summarize key guidelines in the Physical Activity Guidelines for Americans, 2nd edition (PAG). Process and Evidence Synthesis: The 2018 Physical Activity Guidelines Advisory Committee conducted a systematic review of the science supporting physical activity and health. The committee addressed 38 questions and 104 subquestions and graded the evidence based on consistency and quality of the research. Evidence graded as strong or moderate was the basis of the key guidelines. The Department of Health and Human Services (HHS) based the PAG on the 2018 Physical Activity Guidelines Advisory Committee Scientific Report. Recommendations: The PAG provides information and guidance on the types and amounts of physical activity to improve a variety of health outcomes for multiple population groups. Preschool-aged children (3 through 5 years) should be physically active throughout the day to enhance growth and development. Children and adolescents aged 6 through 17 years should do 60 minutes or more of moderate to-vigorous physical activity daily. Adults should do at least 150 minutes to 300 minutes a week of moderate-intensity, or 75 minutes to 150 minutes a week of vigorous-intensity aerobic physical activity, or an equivalent combination of moderate- and vigorous-intensity aerobic activity. They should also do muscle strengthening activities on 2 or more days a week. Older adults should do multicomponent physical activity that includes balance training as well as aerobic and muscle-strengthening activities. Pregnant and postpartum women should do at least 150 minutes of moderate-intensity aerobic activity a week. Adults with chronic conditions or disabilities, who are able, should follow the key guidelines for adults and do both aerobic and muscle-strengthening activities. Recommendations emphasize that moving more and sitting less will benefit nearly everyone. Individuals performing the least physical activity benefit most by even modest increases in moderate-to-vigorous physical activity. Additional benefits occur with more physical activity. Both aerobic and muscle-strengthening physical activity are beneficial. Conclusions and Relevance: The Physical Activity Guidelines for Americans, 2nd edition, provides information and guidance on the types and amounts of physical activity that provide substantial health benefits. Health professionals and policy makers should facilitate awareness of the guidelines and promote the health benefits of physical activity and support efforts to implement programs, practices, and policies to facilitate increased physical activity and to improve the health of the US population. PMID- 30418472 TI - Th17 cells were recruited and accumulated in the cerebrospinal fluid and correlated with the poor prognosis of anti-NMDAR encephalitis. AB - Anti-N-methyl-D-aspartate-receptor (NMDAR) encephalitis is an autoimmune disorder characterized by memory deficits, psychiatric symptoms, and autonomic instability. The lack of suitable biomarkers targeting anti-NMDAR encephalitis makes the immunotherapy and prognosis challenging. In this study, we found that the Th17 cells were significantly accumulated in the cerebrospinal fluid (CSF) of anti-NMDAR encephalitis patients than that of control individuals. The concentration of the cytokines and chemokines including interleukin (IL)-1beta, IL-17, IL-6, and CXCL-13 were significantly increased in the CSF of anti-NMDAR encephalitis patients. IL-6 and IL-17 were found to promote the differentiation of CD4+ T cells into Th17 lineage. The chemotaxis assay showed that CCL20 and CCL22 play essential roles in the migration of Th17 cells. Notably, the correlation between the expression of IL-17 and the outcome of anti-NMDAR encephalitis patients was analyzed. The data showed that high level of IL-17 was significantly correlated with the limited response to the treatment and relapse of anti-NMDAR encephalitis patients. Our results suggested the potential important involvement of IL-17 in anti-NMDAR encephalitis. PMID- 30418473 TI - Physical Activity Guidelines for Health and Prosperity in the United States. PMID- 30418474 TI - Error in Figure. PMID- 30418475 TI - Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk: The CARMELINA Randomized Clinical Trial. AB - Importance: Type 2 diabetes is associated with increased cardiovascular (CV) risk. Prior trials have demonstrated CV safety of 3 dipeptidyl peptidase 4 (DPP 4) inhibitors but have included limited numbers of patients with high CV risk and chronic kidney disease. Objective: To evaluate the effect of linagliptin, a selective DPP-4 inhibitor, on CV outcomes and kidney outcomes in patients with type 2 diabetes at high risk of CV and kidney events. Design, Setting, and Participants: Randomized, placebo-controlled, multicenter noninferiority trial conducted from August 2013 to August 2016 at 605 clinic sites in 27 countries among adults with type 2 diabetes, hemoglobin A1c of 6.5% to 10.0%, high CV risk (history of vascular disease and urine-albumin creatinine ratio [UACR] >200 mg/g), and high renal risk (reduced eGFR and micro- or macroalbuminuria). Participants with end-stage renal disease (ESRD) were excluded. Final follow-up occurred on January 18, 2018. Interventions: Patients were randomized to receive linagliptin, 5 mg once daily (n = 3494), or placebo once daily (n = 3485) added to usual care. Other glucose-lowering medications or insulin could be added based on clinical need and local clinical guidelines. Main Outcomes and Measures: Primary outcome was time to first occurrence of the composite of CV death, nonfatal myocardial infarction, or nonfatal stroke. Criteria for noninferiority of linagliptin vs placebo was defined by the upper limit of the 2-sided 95% CI for the hazard ratio (HR) of linagliptin relative to placebo being less than 1.3. Secondary outcome was time to first occurrence of adjudicated death due to renal failure, ESRD, or sustained 40% or higher decrease in eGFR from baseline. Results: Of 6991 enrollees, 6979 (mean age, 65.9 years; eGFR, 54.6 mL/min/1.73 m2; 80.1% with UACR >30 mg/g) received at least 1 dose of study medication and 98.7% completed the study. During a median follow-up of 2.2 years, the primary outcome occurred in 434 of 3494 (12.4%) and 420 of 3485 (12.1%) in the linagliptin and placebo groups, respectively, (absolute incidence rate difference, 0.13 [95% CI, -0.63 to 0.90] per 100 person-years) (HR, 1.02; 95% CI, 0.89-1.17; P < .001 for noninferiority). The kidney outcome occurred in 327 of 3494 (9.4%) and 306 of 3485 (8.8%), respectively (absolute incidence rate difference, 0.22 [95% CI, -0.52 to 0.97] per 100 person-years) (HR, 1.04; 95% CI, 0.89-1.22; P = .62). Adverse events occurred in 2697 (77.2%) and 2723 (78.1%) patients in the linagliptin and placebo groups; 1036 (29.7%) and 1024 (29.4%) had 1 or more episodes of hypoglycemia; and there were 9 (0.3%) vs 5 (0.1%) events of adjudication-confirmed acute pancreatitis. Conclusions and Relevance: Among adults with type 2 diabetes and high CV and renal risk, linagliptin added to usual care compared with placebo added to usual care resulted in a noninferior risk of a composite CV outcome over a median 2.2 years. Trial Registration: ClinicalTrials.gov Identifier: NCT01897532. PMID- 30418477 TI - Genetic polymorphisms in Hypertension: are we missing the Immune Connection? PMID- 30418476 TI - A Multimethod Analysis of Pragmatic Skills in Children and Adolescents With Fragile X Syndrome, Autism Spectrum Disorder, and Down Syndrome. AB - Purpose: Pragmatic language skills are often impaired above and beyond general language delays in individuals with neurodevelopmental disabilities. This study used a multimethod approach to language sample analysis to characterize syndrome- and sex-specific profiles across different neurodevelopmental disabilities and to examine the congruency of 2 analysis techniques. Method: Pragmatic skills of young males and females with fragile X syndrome with autism spectrum disorder (FXS-ASD, n = 61) and without autism spectrum disorder (FXS-O, n = 40), Down syndrome (DS, n = 42), and typical development (TD, n = 37) and males with idiopathic autism spectrum disorder only (ASD-O, n = 29) were compared using variables obtained from a detailed hand-coding system contrasted with similar variables obtained automatically from the language analysis program Systematic Analysis of Language Transcripts (SALT). Results: Noncontingent language and perseveration were characteristic of the pragmatic profiles of boys and girls with FXS-ASD and boys with ASD-O. Boys with ASD-O also initiated turns less often and were more nonresponsive than other groups, and girls with FXS-ASD were more nonresponsive than their male counterparts. Hand-coding and SALT methods were largely convergent with some exceptions. Conclusion: Results suggest both similarities and differences in the pragmatic profiles observed across different neurodevelopmental disabilities, including idiopathic and FXS-associated cases of ASD, as well as an important sex difference in FXS-ASD. These findings and congruency between the 2 language sample analysis techniques together have important implications for assessment and intervention efforts. PMID- 30418478 TI - Pan-genomic analysis provides novel insights into the association of E. coli with human host and its minimal genome. AB - Motivation: Bacteria can usually acquire certain advantageous genes that enable the bacteria to adapt to rapidly changing niches, thereby leading to a wide range of intraspecific genome content and genetic redundancy. The minimal genome of E. coli, which is the most important bacterial species, and the association between E. coli and its human host are worthy of further exploration. Results: We used gene prediction and phylogenetic analysis to reveal a rich phylogenetic diversity among 491 E. coli strains and to reveal substantial differences between these strains with respect to gene number and genome length. We used pan-genomic analysis to accurately identified 867 core genes, in which only 243 genes are shared by essential genes. This analysis revealed that core genes mainly provide essential functions to the basic lifestyle of E. coli, and accessory genes are likely to confer selective advantages such as niche adaptation or the ability to colonize specific hosts. By association analysis, we found that E. coli strains in nonhuman hosts may more easily utilize foreign genetic materials to adapt to their surroundings, but the population in human hosts has higher demands for the control of population density, indicating that highly accurate quorum-sensing behavior is very important for harmony between E. coli and its human host. By considering core genes and previous deletions together, we propose a potential direction for further reduction of the E. coli genome. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30418480 TI - BayMAP: A Bayesian hierarchical model for the analysis of PAR-CLIP data. AB - Motivation: Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation (PAR-CLIP) is a biochemical method for detecting interaction sites of proteins with mRNA. This method introduces T-to-C substitutions at sequenced cDNA that help to detect binding sites on mRNA. However, T-to-C substitutions can also occur due to other reasons such as mismatches or SNPs. Only few statistical procedures exist for detecting binding sites in PAR-CLIP data. Most of these methods do not account for other types of substitutions than those induced by PAR-CLIP, and therefore, also report positions with high T-to-C substitution rates, e.g., SNPs, as binding sites. Moreover, none of these procedures allow to include additional information, e.g., the type of mRNA region, relevant for the biology of microRNA binding sites. Results: We have developed BayMAP, a procedure based on a fully Bayesian hierarchical model that takes other sources of substitutions into account. Furthermore, this model enables the incorporation of additional information into the analysis of PAR-CLIP data. This incorporation does not only permit a better detection of binding sites, but also a better understanding of the data and the biology of binding sites. In applications to simulated PAR-CLIP data, BayMAP distinguishes binding sites from noise better than existing methods. Additionally, it yields good estimates of the influence of the additional information. We here demonstrate BayMAP's usability for real data sets even when noisy data is present. Availability: BayMAP is freely available as an R package at http://stat.math.uni duesseldorf.de/baymap. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30418479 TI - Riding on the wind: volatile compounds dictate selection of grassland seedlings by snails. AB - Background and Aims: Seedling herbivory is an important selective filter in many plant communities. The removal of preferred food plants by both vertebrate and, more commonly, invertebrate herbivores can destroy entire seedling cohorts, and consequently dictate plant community assembly. Nevertheless, our understanding of how and why some seedlings are more prone to herbivore attack than their neighbours remains limited. For seedlings, where even minor tissue damage is fatal, avoiding contact with herbivores is probably advantageous and, on this basis, volatile organic compounds (VOCs) are strong candidates to fulfil a primary defensive role. Methods: We quantified seedling selection by snails (Cornu aspersum) for 14 common, European grassland species. Seedling acceptability was subsequently compared with species-specific expression of constitutive secondary defence metabolites (CSDMs), and VOCs to determine their relative influence on seedling selection. Results: We found no relationship between seedling acceptability and CSDMs, but seedling selection was strongly associated with VOC profiles. Monoterpenes (specifically beta-ocimene) were identified as likely attractants, while green leaf volatiles (GLVs) (3-hexen-1-ol acetate) were strongly associated with low seedling acceptability. Conclusions: By elucidating a relationship between VOCs and seedling acceptability, we contradict a long-held, but poorly tested, assumption that seedling selection by herbivores in (semi-)natural plant communities centres on CSDMs. Instead, our results corroborate recent work showing how GLVs, including 3-hexen-1-ol acetate, deter crop seedling selection by molluscs. Although our failure to establish any early-ontogenetic relationship between VOCs and CSDMs also suggests that the former do not 'advertise' possession of the latter, we nevertheless reveal the role that VOCs play in defending seedlings against herbivory before lethal damage occurs. PMID- 30418481 TI - MAGpy: a reproducible pipeline for the downstream analysis of metagenome assembled genomes (MAGs). AB - Motivation: Metagenomics is a powerful tool for assaying the DNA from every genome present in an environment. Recent advances in bioinformatics have enabled the rapid assembly of near complete metagenome-assembled genomes (MAGs), and there is a need for reproducible pipelines that can annotate and characterise thousands of genomes simultaneously, to enable identification and functional characterisation. Results: Here we present MAGpy, a scalable and reproducible pipeline that takes multiple genome assemblies as FASTA and compares them to several public databases, checks quality, suggests a taxonomy and draws a phylogenetic tree. Availability: MAGpy is available on github: https://github.com/WatsonLab/MAGpy. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30418482 TI - A Novel Extended Deep Plane Facelift Technique for Jawline Rejuvenation and Volumization. AB - Background: Jawline aging is a complex process. We believe loss of posterior jawline definition and volume depletion is an underappreciated factor in the aging face. Objectives: The aim of this study is to describe a novel composite, rotational flap modification of an extended deep-plane rhytidectomy. We evaluate long term efficacy on improving jawline contour and volumization of the posterior mandibular region overlying the gonial angle. Methods: We performed a prospective study on patients undergoing our modification of extended deep-plane rhytidectomy. We define and introduce the Mandibular Defining Line (MDL), a new anatomic metric in evaluating the mandibular contour. We define the area of the posterior lower face overlying the gonion and mandibular angle as the gonial area. Using 3D photography, we quantify contour changes along the mandibular border and volume change along the gonial area. Results: Eighty-nine patients (178 hemifaces) were analyzed. The mean gonial area volume gained was 3.5 cc. Average follow-up was 19 months. There was a statistically significant change in the mean MDL from 7.1 cm preoperatively to 9.8 cm postoperatively. This represents a lengthening of the visual perspective of the mandibular contour of 2.7 cm. Conclusions: Composite, rotational flap modification of extended deep plane rhytidectomy provides significant long-term augmentation of volume to the posterior mandibular region and lengthens the visual perspective of the inferior mandibular contour creating a more youthful jawline. In selected cases, this may obviate the need for other volumization procedures used to improve jawline contour, such as autologous fat grafting. PMID- 30418483 TI - Multi-segment indexes of arterial stiffness show lower repeatability than carotid femoral pulse-wave velocity or systolic blood pressure. AB - Background: We investigated the inter-day repeatability of newly-proposed indexes of cardiovascular health based on the absolute (PWVABS) or relative (PWVRATIO) difference in pulse wave velocity between the carotid-femoral (PWVCF) and carotid radial (PWVCR) segments compared with PWVCF alone and with systolic blood pressure (BPSYST) over multiple days. Methods: All variables were measured in triplicates in a group of 16 young, healthy individuals (8 males/8 females, 66 +/ 14 kg, 1.7 +/- 0.1 m, 27 +/- 3 years old) on six different occasions, always at the same time of the day (+/- 1 h) and with at least 48h between assessments. Results: Values did not differ significantly over the six different visits for any of the parameters (all p > 0.08). Intra-class coefficients (ICC) ranged from 0.52 (PWVRATIO) to 0.8 (PWVCF). The ICC 95% confidence interval of PWVRATIO (0.30 - 0.77) and PWVABS (0.33 - 0.78) did not overlap with that of PWVCF (0.79 - 0.95), indicating lower repeatability. The coefficient of variation (CV) of PWVABS was over 5-fold larger than the next largest one (46.7 vs. 8.1 % for PWVABS and PWVRATIO respectively), while PWVCF and BPSYST showed the lowest CVs (4.6 and 4.0 %, respectively). Conclusion: Between PWVABS and PWVRATIO, the relative method showed better repeatability and might be more sensitive to longitudinal changes in patients. Nonetheless, indexes of arterial stiffness based PWV gradients between different segments show lower inter-day repeatability compared with PWVCF or BPSYST, suggesting that the latter are still preferable in clinical practice. PMID- 30418484 TI - Abscisic acid (ABA) and low temperatures synergistically increase the expression of CBF/DREB1 transcription factors and cold-hardiness in grapevine dormant buds. AB - Background and Aims: It has been reported that low temperatures (LTs) and the plant hormone abscisic acid (ABA) induce the expression of CBF/DREB1 transcription factors in vegetative tissues and seedlings of Vitis vinifera and Vitis riparia and that foliar applications of ABA to V. vinifera increase the freezing tolerance or cold-hardiness of dormant buds. However, the combined effect of ABA and LTs on the expression of CBF/DREB1 transcription factors and on the acquisition of freezing tolerance in dormant grapevine buds has not been investigated. The objective of this study was to analyse the combined effect of ABA and LT treatments on the expression of CBF/DREB transcription factors and the acquisition of freezing tolerance. Methods: In vitro experiments with single-bud cuttings of grapevines were used to analyse the effect of ABA, ABA + LT and LT on the expression of CBF/DREB transcription factors, dehydrin and antioxidant genes, the acquisition of freezing tolerance and the endogenous content of ABA. Gene expression analysis was performed by quantitative real-time PCR and freezing tolerance was determined by measuring the low-temperature exotherm by differential thermal analysis. ABA levels were determined by gas chromatography coupled to an electron capture detector. Key Results: The LT treatment and exogenous application of ABA to grapevine dormant buds increased the expression of the CBF/DREB1 transcription factors VvCBF2, VvCBF3, VvCBF4 and VvCBF6. The joint application of LT and ABA produced a huge increase in the expression of these transcription factors, which was greater than the sum of the increases produced by them individually, which indicates the existence of a synergistic effect between ABA and LT on the activation of these transcription factors. This synergic effect was also observed on the increase in bud cold-hardiness and on the expression of antioxidant and dehydrin genes. Conclusions: The synergy between ABA and LT on the expression of CBF/DREB1 transcription factors VvCBF2, VvCBF3, VvCBF4 and VvCBF6 plays a key role in cold acclimatization of grapevine buds. The results highlight the importance of the combination of stimuli in the improvement of genetic and physiological responses and help us to understand the adaption of plants to complex environments. PMID- 30418485 TI - Identifying Antimicrobial Peptides using Word Embedding with Deep Recurrent Neural Networks. AB - Motivation: Antibiotic resistance constitutes a major public health crisis, and finding new sources of antimicrobial drugs is crucial to solving it. Bacteriocins, which are bacterially-produced antimicrobial peptide products, are candidates for broadening the available choices of antimicrobials. However, the discovery of new bacteriocins by genomic mining is hampered by their sequences' low complexity and high variance, which frustrates sequence similarity-based searches. Results: Here we use word embeddings of protein sequences to represent bacteriocins, and apply a word embedding method that accounts for amino acid order in protein sequences, to predict novel bacteriocins from protein sequences without using sequence similarity. Our method predicts, with a high probability six yet unknown putative bacteriocins in Lactobacillus. Generalized, the representation of sequences with word embeddings preserving sequence order information can be applied to peptide and protein classification problems for which sequence similarity cannot be used. Availability: Data and source code for this project are freely available at: https://github.com/nafizh/Bacteriocin_paper. Supplementary Information: Supplementary data are available at Bioinformatics online. PMID- 30418486 TI - Comparison of Biomechanical Properties and Microstructure of Trabeculae Carneae, Papillary muscles, and Myocardium in Human Heart. AB - Trabeculae carneae account for a significant portion of human ventricular mass, despite being considered embryologic remnants. Recent studies have found trabeculae hypertrophy and fibrosis in hypertrophied left ventricles with various pathological conditions. The objective of this study was to investigate the passive mechanical properties and microstructural characteristics of trabeculae carneae and papillary muscles compared to the myocardium in human hearts. Uniaxial tensile tests were performed on samples of trabeculae carneae and myocardium strips, while biaxial tensile tests were performed on samples of papillary muscles and myocardium sheets. The experimental data were fit to a Fung type strain energy function and material coefficients were determined. The secant moduli at given diastolic stress and strain levels were determined and compared among the tissues. Following the mechanical testing, histology examinations were performed to investigate the microstructural characteristics of the tissues. Our results demonstrated that the trabeculae carneae were significantly stiffer (Secant modulus SM2=80.06+/-10.04 KPa) and had higher collagen content (16.10+/ 3.80%) than the myocardium (SM2=55.14+/-20.49 KPa, collagen content=10.06+/ 4.15%) in the left ventricle. The results of the present study improve our understanding of the contribution of trabeculae carneae to left ventricular compliance and will be useful for building accurate computational models of human hearts. PMID- 30418487 TI - Depletion of thiols leads to redox deregulation, production of 4-hydroxinonenal and sperm senescence: a possible role for GSH regulation in spermatozoa. AB - Although redox regulation and oxidative stress are important concepts in spermatology, the molecular mechanisms behind these processes are poorly understood. Recent research has revealed that redox homeostasis is extremely important for the maintenance of sperm functionality in the stallion due to the high mitochondrial activity in the spermatozoa of this species. We hypothesized that thiols and particularly glutathione (GSH) are essential for the regulation of stallion sperm functionality. To test this hypothesis, we initially investigated the relationship between sperm function and GSH content, revealing highly significant correlations between GSH, sperm viability, motility and velocity parameters (p < 0.001). Furthermore, the deleterious effects of GSH depletion using menadione and 1,3 Dimethoxy 1,4, naphtoquinone (DMNQ) were able to be prevented by the addition of cysteine, but no other antioxidant. Pre incubation with cysteine prevented menadione and DMNQ induced damage to sperm membranes after 1 h (viable sperm in control: 80%; menadione treated: 56%; both p < 0.001; pre-incubation with cysteine and treatment with menadione: 80%, controls 62%, DMNQ 44% and pre-incubation with cysteine and treatment with DMNQ 55% p < 0.05) and after 3 h of incubation (control: 78%; menadione: 30%; both p < 0.001, and pre-incubation with cysteine and treatment with menadione: 83%, controls 52.6%, DMNQ 45% and pre-incubation with cysteine and treatment with DMNQ 50% p < 0.05). Similar patterns were also observed for motility and sperm velocity parameters, and pre-incubation with cysteine ameliorated both the menadione- and DMNQ-induced increase in 4-hydroxynonenal (p < 0.001). As cysteine is a pre cursor of GSH, we hypothesized that stallion spermatozoa are able to synthesize this tri-peptide using exogenous cysteine. To test this hypothesis we investigated the presence of two enzymes required to synthesize GSH (Glutathione Synthetase and glutamate-cysteine ligase) and using western blotting and immunocytochemistry approaches we detected both enzymes in stallion spermatozoa. The inhibition of glutamate cysteine ligase reduced the recovery of GSH by addition of cysteine after depletion, suggesting that stallion spermatozoa may use exogenous cysteine to regulate GSH. Other findings supporting this hypothesis were changes in sperm functionality after BSO treatment and changes in GSH and GSSG validated using HPLC-MS, showing that BSO prevented the increase in GSH in presence of cysteine, although important stallion to stallion variability occurred and suggested differences in expression of glutamate cysteine ligase. Mean concentration of GSH in stallion spermatozoa was 8.2 +/- 2.1 MUM/109 spermatozoa, well above the nanomolar ranges per billion spermatozoa reported for other mammals. These novel findings reveal new avenues for the treatment of stallion infertility and for the development of better stallion sperm preservation technologies based on a more comprehensive understanding of redox regulation in these highly specialized cells. PMID- 30418488 TI - Zinc mediates the action of androgen in acting as a downstream effector of LH on oocyte maturation in zebrafish. AB - The role of androgenic steroids on ovarian development has attracted much attention in recent years, but the molecular mechanism is still largely unknown. In this study, using zebrafish as a model, we found that the trace metal zinc mediates the action of androgen on oocyte maturation. The ovarian and serum testosterone is transiently stimulated by LH during oocyte maturation. Testosterone could mimic the action of LH on oocyte maturation, and its action appears to be independent of the classical nuclear androgen receptor. Consistent with a recent finding that a zinc transporter (Zip9) has been suggested as a novel androgen receptor, we found the labile zinc concentration could be induced by testosterone in the ovarian follicular cells, and zinc could mimic the action of testosterone on oocyte maturation and signaling. Moreover, the action of testosterone on oocyte maturation could be abolished by the chelation of zinc. Thus, the evidence support the notion that zinc could mediate the action of androgen on oocyte maturation in zebrafish. This finding would shed light on understanding the role of androgen in ovary development and the molecular mechanism of oocyte maturation in fish. PMID- 30418489 TI - TGF beta promotes repair of bulky DNA damage through increased ERCC1/XPF and ERCC1/XPA interaction. AB - Transforming growth factor beta (TGFbeta) is multi-functional cytokine that is involved in the co-ordination and regulation of many cellular homeostatic processes. Compromised TGFbeta activity has been attributed to promotion of human cancers. Recent studies have identified a role for TGFbeta in response to radiation-induced DNA damage, suggesting a link between TGFbeta and the DNA damage response with implications for cancer development. In the present study the effects of TGFbeta on promoting the repair of bulky DNA damage, through modulation of nucleotide excision repair (NER), was investigated. We show that treatment of cells with exogenous TGFbeta leads to enhanced repair of DNA damage formed by polycyclic aromatic hydrocarbons and UV-C radiation; similarly cells with constitutively activated endogenous TGFbeta signaling show comparable responses. This effect of TGFbeta is independent of the cell cycle. The response to TGFbeta is decreased in cells that have compromised TGFbeta signaling through RNA interference of Smad4, and is decreased in NER deficient cells and cells with compromised NER through RNA interference of ERCC1. Increased interaction and nuclear localization of ERCC1/XPF and ERCC1/XPA proteins is observed after TGFbeta treatment. Our study represents the first experimental evidence of a role for TGFbeta in the repair of bulky DNA damage resulting from promotion of the interaction and localization of repair protein complexes involved in the incision step of NER. PMID- 30418490 TI - Introduction to the Research Symposium Forum. AB - Purpose: The purpose of this introduction is to provide an overview of the articles contained within this research forum of JSLHR. Each of these articles is based upon presentations from the 2017 ASHA Research Symposium. PMID- 30418491 TI - Changing Developmental Trajectories of Toddlers With Autism Spectrum Disorder: Strategies for Bridging Research to Community Practice. AB - Purpose: The need for community-viable, evidence-based intervention strategies for toddlers with autism spectrum disorder (ASD) is a national priority. The purpose of this research forum article is to identify gaps in intervention research and needs in community practice for toddlers with ASD, incorporate published findings from a randomized controlled trial (RCT) of the Early Social Interaction (ESI) model (Wetherby et al., 2014) to illustrate community-based intervention, report new findings on child active engagement from the ESI RCT, and offer solutions to bridge the research-to-community practice gap. Method: Research findings were reviewed to identify gaps in the evidence base for toddlers with ASD. Published and new findings from the multisite ESI RCT compared the effects of two different ESI conditions for 82 toddlers with ASD to teach parents how to support active engagement in natural environments. Results: The RCT of the ESI model was the only parent-implemented intervention that reported differential treatment effects on standardized measures of child outcomes, including social communication, developmental level, and adaptive behavior. A new measure of active engagement in the natural environment was found to be sensitive to change in 3 months for young toddlers with ASD and to predict outcomes on the standardized measures of child outcomes. Strategies for utilizing the Autism Navigator collection of web-based courses and tools using extensive video footage for families and professional development are offered for scaling up in community settings to change developmental trajectories of toddlers with ASD. Conclusions: Current health care and education systems are challenged to provide intervention of adequate intensity for toddlers with ASD. The use of innovative technology can increase acceleration of access to evidence-based early intervention for toddlers with ASD that addresses health disparities, enables immediate response as soon as ASD is suspected, and rapidly bridges the research-to-practice gap. PMID- 30418492 TI - SMARTer Approach to Personalizing Intervention for Children With Autism Spectrum Disorder. AB - Purpose: This review article introduces research methods for personalization of intervention. Our goals are to review evidence-based practices for improving social communication impairment in children with autism spectrum disorder generally and then how these practices can be systematized in ways that personalize intervention, especially for children who respond slowly to an initial evidence-based practice. Method: The narrative reflects on the current status of modular and targeted interventions on social communication outcomes in the field of autism research. Questions are introduced regarding personalization of interventions that can be addressed through research methods. These research methods include adaptive treatment designs and the Sequential Multiple Assignment Randomized Trial. Examples of empirical studies using research designs are presented to answer questions of personalization. Conclusion: Bridging the gap between research studies and clinical practice can be advanced by research that attempts to answer questions pertinent to the broad heterogeneity in children with autism spectrum disorder, their response to interventions, and the fact that a single intervention is not effective for all children. Presentation Video: https://doi.org/10.23641/asha.7298021. PMID- 30418493 TI - Executive Function Skills in School-Age Children With Autism Spectrum Disorder: Association With Language Abilities. AB - Purpose: This article reviews research on executive function (EF) skills in children with autism spectrum disorder (ASD) and the relation between EF and language abilities. The current study assessed EF using nonverbal tasks of inhibition, shifting, and updating of working memory (WM) in school-age children with ASD. It also evaluated the association between children's receptive and expressive language abilities and EF performance. Method: In this study, we sought to address variables that have contributed to inconsistencies in this area of research-including task issues, group comparisons, and participant heterogeneity. EF abilities in children with ASD (n = 48) were compared to typically developing controls (n = 71) matched on age, as well as when statistically controlling for group differences in nonverbal cognition, socioeconomic status, and social communication abilities. Six nonverbal EF tasks were administered-2 each to evaluate inhibition, shifting, and WM. Language abilities were assessed via a standardized language measure. Language-EF associations were examined for the ASD group as a whole and subdivided by language status. Results: Children with ASD exhibited significant deficits in all components of EF compared to age-mates and showed particular difficulty with shifting after accounting for group differences in nonverbal cognition. Controlling for social communication-a core deficit in ASD-eliminated group differences in EF performance. A modest association was observed between language (especially comprehension) and EF skills, with some evidence of different patterns between children on the autism spectrum with and without language impairment. Conclusions: There is a need for future research to examine the direction of influence between EF and language. It would be beneficial for EF interventions with children with ASD to consider language outcomes and, conversely, to examine whether specific language training facilitates aspects of executive control in children on the autism spectrum. Presentation Video: https://doi.org/10.23641/asha.7298144. PMID- 30418494 TI - Lexical Development in Young Children With Autism Spectrum Disorder (ASD): How ASD May Affect Intake From the Input. AB - Purpose: Most children with autism spectrum disorder (ASD) have below-age lexical knowledge and lexical representation. Our goal is to examine ways in which difficulties with social communication and language processing that are often associated with ASD may constrain these children's abilities to learn new words and to explore whether minimizing the social communication and processing demands of the learning situation can lead to successful learning. Method: In this narrative review of recent work on lexical development in ASD, we describe key findings on children's acquisition of nouns, pronouns, and verbs and outline our research program currently in progress aimed at further elucidating these issues. Conclusion: Our review of studies that examine lexical development in children with ASD suggests that innovative intervention approaches that take into account both the social communication and processing demands of the learning situation may be particularly beneficial. Presentation Video: https://doi.org/10.23641/asha.7324013. PMID- 30418495 TI - Early Motor and Communicative Development in Infants With an Older Sibling With Autism Spectrum Disorder. AB - Purpose: A recent approach to identifying early markers of risk for autism spectrum disorder (ASD) has been to study infants who have an older sibling with ASD. These infants are at heightened risk (HR) for ASD and for other developmental difficulties, and even those who do not receive an eventual ASD diagnosis manifest a high degree of variability in trajectories of development. The primary goal of this review is to summarize findings from research on early motor and communicative development in these HR infants. Method: This review focuses on 2 lines of inquiry. The first assesses whether delays and atypicalities in early motor abilities and in the development of early communication provide an index of eventual ASD diagnosis. The second asks whether such delays also influence infants' interactions with objects and people in ways that exert far-reaching, cascading effects on development. Results: HR infants who do and who do not receive a diagnosis of ASD vary widely in motor and communicative development. In addition, variation in infant motor and communicative development appears to have cascading effects on development, both on the emergence of behavior in other domains and on the broader learning environment. Conclusions: Advances in communicative and language development are supported by advances in motor skill. When these advances are slowed and/or when new skills are not consolidated and remain challenging for the infant, the enhanced potential for exploration afforded by new abilities and the concomitant increase in opportunities for learning are reduced. Improving our understanding of communicative delays of the sort observed in ASD and developing effective intervention methods requires going beyond the individual to consider the constant, complex interplay between developing communicators and their environments. Presentation Video: https://doi.org/10.23641/asha.7299308. PMID- 30418496 TI - The Shape Bias in Children With Autism Spectrum Disorder: Potential Sources of Individual Differences. AB - Purpose: Children with autism spectrum disorder (ASD) demonstrate many mechanisms of lexical acquisition that support language in typical development; however, 1 notable exception is the shape bias. The bases of these children's difficulties with the shape bias are not well understood, and the current study explored potential sources of individual differences from the perspectives of both attentional and conceptual accounts of the shape bias. Method: Shape bias performance from the dataset of Potrzeba, Fein, and Naigles (2015) was analyzed, including 33 children with typical development (M = 20 months; SD = 1.6), 15 children with ASD with high verbal abilities (M = 33 months; SD = 4.6), and 14 children with ASD with low verbal abilities (M = 33 months; SD = 6.6). Lexical predictors (shape-side noun percentage from the MacArthur-Bates Communicative Development Inventory; Fenson et al., 2007) and social-pragmatic predictors (joint attention duration during play sessions) were considered as predictors of subsequent shape bias performance. Results: For children in the low verbal ASD group, initiation of joint attention (positively) and passive attention (negatively) predicted subsequent shape bias performance, controlling for initial language and developmental level. Proportion of child's known nouns with shape defined properties correlated negatively with shape bias performance in the high verbal ASD group but did not reach significance in regression models. Conclusions: These findings suggest that no single account sufficiently explains the observed individual differences in shape bias performance in children with ASD. Nonetheless, these findings break new ground in highlighting the role of social communicative interactions as integral to understanding specific language outcomes (i.e., the shape bias) in children with ASD, especially those with low verbal abilities, and point to new hypotheses concerning the linguistic content of these interactions. Presentation Video: https://doi.org/10.23641/asha.7299581. PMID- 30418498 TI - Maternal L-proline supplementation enhances fetal survival, placental development and nutrient transport in mice. AB - L-Proline (proline) in amniotic fluid was markedly increased during pregnancy in both pigs and sheep. However, in vivo data to support a beneficial effect of proline on fetal survival are not available. In this study, pregnant C57BL/6J mice were fed a purified diet supplemented with or without 0.50% proline from embryonic day 0.5 (E0.5) to E12.5 or term. Results indicated that dietary supplementation with proline to gestating mice enhanced fetal survival, reproductive performance, the concentrations of proline, arginine, aspartic acid, and tryptophan in plasma and amniotic fluid, while decreasing the concentrations of ammonia and urea in plasma and amniotic fluid. Placental mRNA levels for amino acid transporters, including Slc36a4, Slc38a2, Slc38a4, Slc6a14, and Na+/K+ ATPase subunit-1alpha (Atp1a1), fatty acid transporter Slc27a4 and glucose transporter Slc2a1 and Slc2a3, were augmented in proline-supplemented mice, compared with the control group. Histological analysis showed that proline supplementation enhanced labyrinth zone in the placenta of mice at E12.5, mRNA levels for Vegf, Vegfr, Nos2, and Nos3, compared with the controls. Western blot analysis showed that proline supplementation increased protein abundances of phosphorylated (p)-mTORC1, p-ribosomal protein S6 kinase (p70S6K), and p eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), as well as the protein level of GCN2 (a negative regulator of mTORC1 signaling). Collectively, our results indicate a novel functional role of proline in improving placental development and fetal survival by enhancing placental nutrient transport, angiogenesis, and protein synthesis. PMID- 30418499 TI - The co-administration of estradiol/17alpha-methyltestosterone leads to male fate in the protogynous orange-spotted grouper, Epinephelus coioides. AB - Estrogen plays a pivotal role in the sex differentiation of teleosts, whereas the precise function of androgens is more controversial. In this study, orange spotted grouper (Epinephelus coioides) fry were treated with letrozole (an aromatase inhibitor, AI), 17alpha-methyltestosterone (MT), or MT and 17beta estradiol (E2) simultaneously, during the period of gonadal formation and sex differentiation. MT-feeding at 50 days after hatching resulted in gonadal dysgenesis, which could be rescued by E2 supplementation. Different doses of AI treatment led to different phenotypes: undifferentiated gonads were maintained in the AI group fed a low dose (5mg/kg diet) whereas female to male sex reversal was observed in the AI group fed a high dose (100mg/kg diet). MT, and MT + E2, treatment could induce female to male sex reversal during sex differentiation (90 days after hatching). The expression of female pathway genes was suppressed while the expression of genes in the male pathway was up-regulated in the MT + E2 group. Consistent with the expression of sex-related genes, the serum 11- ketotestosterone level was also up-regulated in MT and MT + E2 group. Finally, we examined the expression of male specific mark (DMRT1), and proliferating cell nuclear antigen (PCNA) in MT and MT + E2 induced sex reversal, and the result indicated that male germ cells and somatic cells may origin from the gonium and proliferative somatic cells surrounding the efferent duct, respectively. Overall, our data suggested that estrogen acts as a natural inducer of female differentiation, and that the co-administration of estrogen and androgen during sex differentiation leads to a male sex fate in the protogynous orange-spotted grouper. PMID- 30418500 TI - Commentary on: Modified Composite-Flap Facelift Combined with Finger-Assisted Malar Elevation (FAME): A Cadaver Study. PMID- 30418501 TI - Predicting Mortality in Nursing Home Residents with Dementia and Pneumonia Treated with Antibiotics: Validation of a Prediction Model in a More Recent Population. AB - Background: We aimed to find the best predictive model for 14-day mortality in antibiotic-treated nursing home residents with dementia and pneumonia by first applying an existing model to the recent PneuMonitor study. Second, we evaluated whether model performance improved by revising variables or adding variables related to recent changes in the care for older people. Methods: The original prognostic model included gender, respiratory rate, respiratory difficulty, pulse rate, decreased alertness, fluid intake, eating dependency and pressure sores. This model was applied to 380 recent pneumonia episodes in nursing home residents with dementia, updated by considering revising and/or adding variables, internally validated using bootstrapping, and transformed into a simplified risk score that can be used in clinical practice. Model performance was evaluated by Hosmer-Lemeshow statistics (HL) and calibration graphs to assess calibration; and area under the receiver operating characteristic curve (AUC) to assess discrimination. Results: The newer cohort had lower 14-day mortality and was less often dehydrated or malnourished. Median AUC of the original model over the imputed datasets was 0.76 (IQR: 0.76-0.77), compared to 0.80 in the old cohort. Extending the model with dehydration, bowel incontinence, increase in eating dependency and cardiovascular history, while removing pressure sores, improved AUC: 0.80 (IQR: 0.80-0.81) after internal validation. Calibration remained adequate (HL: p=0.67). Conclusions: In the newer cohort with less severe illness, model performance of the existing model was adequate, but a new extended model distinguished better between residents at low and high mortality risk. PMID- 30418502 TI - Erratum: Vitamin D and skeletal health during growth: the functional muscle-bone unit. PMID- 30418503 TI - Neuropsychological And Psychopathological Profile Of Anti-Nmdar Encephalitis: A Possible Pathophysiological Model For Pediatric Neuropsychiatric Disorders. AB - Objective: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a severe, but treatable, autoimmune disorder, characterized by autoantibodies causing hypofunction of blocking NMDA receptors leading to a unique constellation of cognitive, motor, and psychiatric symptoms. Neuropsychological and psychopathological outcome has not been fully explored, particularly in children. Aim of this study was to investigate pediatric anti-NMDAR encephalitis as a model of impairment of the complex frontal-subcortical circuits who are implicated in several of the childhood neuropsychiatric disorders. Method: Seven children diagnosed with anti-NMDAR encephalitis at our department underwent an evaluation of the global mental functioning before discharge, a neuropsychological and psychological/behavioral standardized examination within one month after discharge and subsequently were followed up longitudinally for mean 35 months (range 24-48 months). Collected neuropsychological data were evaluated retrospectively. Results: Deficits in attention, executive functions and/or visual motor functions involving executive functions were seen in all children within one month after discharge. These deficits were long lasting in about a half of the patients. In addition, four patients developed persistent psychopathological dysfunctions: difficulties to regulate their own behavior, impulsivity, hyperactivity, irritability, apathy, and obsessive-compulsive symptoms. Conclusions: Our data are in line with research suggesting a crucial role of the executive functions impairments in cognitive outcome disturbance of anti-NMDAR encephalitis. We found also behavioral and psychological deficits pointing to a more comprehensive framework of frontal-subcortical dysfunction, in which the NMDA mediated transmission appear to have a role, as suggested by neurobiological, pharmacological, and neuroimaging studies. PMID- 30418504 TI - Erratum: Infant breastfeeding and childhood general, visceral, liver, and pericardial fat measures assessed by magnetic resonance imaging. PMID- 30418506 TI - Erratum: Differential effects of medium- and long-chain saturated fatty acids on blood lipid profile: a systematic review and meta-analysis. PMID- 30418505 TI - Erratum: Validation of rapid 4-component body composition assessment with the use of dual-energy X-ray absorptiometry and bioelectrical impedance analysis. PMID- 30418507 TI - Neurocognition in Post-Treatment Lyme Disease and Major Depressive Disorder. AB - Objective: Neurocognitive dysfunction in patients with residual or emergent symptoms after treatment for Lyme Disease is often attributed to comorbid depression. In this study, patients with Post-Treatment Lyme Disease Syndrome (PTLDS) were compared to patients with Major Depressive Disorder (MDD), as well as healthy comparison subjects (HC), on neurocognitive measures administered through the same laboratory, to determine if patterns of performance were similar. Methods: Two analyses were conducted. First, performance on the Wechsler Adult Intelligence Scale (WAIS-III) and on subtests from the Wechsler Memory Scale (WMS-III) was compared among the groups. Second, comparable subgroups of PTLDS and MDD patients with at least one low WMS-III score were compared on an additional set of measures assessing motor function, psychomotor performance, attention, memory, working memory, and language fluency, to determine if the overall profile of performance was similar in the two subgroups. Results: In the first analysis, PTLDS patients performed more poorly than both MDD and HC on tasks assessing verbal abilities, working memory, and paragraph learning. Processing speed in the two patient groups, however, was equally reduced. In the second analysis, MDD patients with low WMS-III exhibited concomitantly greater difficulties in psychomotor speed and attention, while low-WMS-III PTLDS patients exhibited greater difficulties in language fluency. Conclusions: MDD and PTLDS can be confused neuropsychologically because both exhibit similar levels of psychomotor slowing. However, problems on memory-related tasks, though mild, are more pronounced in PTLDS. PTLDS patients with poorer memory also exhibit poorer language fluency, and less deficit in processing speed and attention compared to MDD. PMID- 30418508 TI - Anterior Segment Optical Coherence Tomography Angiography in a Patient With Persistent Pupillary Membrane. PMID- 30418509 TI - Penetrating Injury With Foreign Body in the Angle of the Left Eye. PMID- 30418510 TI - Long-term Minocycline Therapy With Scleral Pigmentation Simulating Melanocytosis. PMID- 30418511 TI - Retinal Angiography Findings in Male Infant With Incontinentia Pigmenti and Sickle Cell Trait. PMID- 30418513 TI - JAMA Ophthalmology. PMID- 30418514 TI - Erratum: The physiologic and phenotypic significance of variation in human amylase gene copy number. PMID- 30418515 TI - Erratum: Dairy matrix effects: response to consumption of dairy fat differs when eaten within the cheese matrix-a randomized controlled trial. PMID- 30418517 TI - AlphaE expression in IBD: a biomarker for the use of Etrolizumab? PMID- 30418516 TI - Validity of the ImPACT Post-Concussion Symptom Scale (PCSS) Affective Symptom Cluster as a Screener for Depression in Collegiate Athletes. AB - Objective: The relationship between depression and sports-related concussion is complex and has implications both pre- and post-injury. The current study established the construct validity, convergent and discriminant, of the affective symptom cluster of The Immediate Post-Concussion Assessment and Cognitive Test (ImPACT) post-concussion symptom scale (PCSS) as a screening tool for depression. Method: Nine hundred and thirty (M = 695, F = 235) college athletes were assessed at baseline using the ImPACT PCSS and Beck-Depression Inventory-Fast Screen (BDI FS). Previous factor analysis identified four symptom clusters on the PCSS: affective, physical, cognitive, and sleep. Clinically significant depression was operationalized as a BDI-FS score >=4. Receiver Operating Characteristic curves (ROC) were used to determine the ideal cutoff, Chi-square tests of independence were calculated to establish convergent validity, and Fisher's r-to-z comparisons were used to establish discriminant validity of the affective symptom cluster. Results: The 90th percentile cutoff yielded the highest sensitivity and specificity on the affective symptom cluster for males (4) and females (6). The correlation between BDI-FS and the 90th percentile cutoff was statistically significantly higher in females (phi = .96) than males (phi = .83), Z = 9.49, p < .001. When correlating the BDI-FS with each PCSS symptom cluster, the correlation with the affective symptom cluster was stronger than its correlation with cognitive, sleep, and physical clusters across gender. Discussion: By utilizing a measure of depression within an existing and commonly used assessment, clinicians can easily screen for depression and identify athletes at risk for complicated recovery even in the absence of a supplemental depression assessment. PMID- 30418518 TI - Five-year prospective evaluation of cytology, HPV testing, and biomarkers for detection of anal precancer in HIV+ MSM. AB - Background: Human papillomavirus (HPV)-related biomarkers have shown good cross sectional performance for anal precancer detection in HIV-positive (HIV+) men who have sex with men (MSM). However, the long-term performance and risk stratification of these biomarkers are unknown. Here, we prospectively evaluated high-risk (HR) HPV DNA, HPV16/18 genotyping, HPV E6/E7 mRNA, and p16/Ki-67 dual stain in a population of HIV+ MSM. Methods: We enrolled 363 HIV+ MSM between 2009 2010 with passive follow-up through 2015. All had anal cytology and high resolution anoscopy at baseline. For each biomarker, we calculated the baseline sensitivity and specificity for a combined endpoint of high grade squamous intraepithelial lesion (HSIL) and anal intraepithelial neoplasia grade 2 or more severe diagnoses (HSIL/AIN2+), and we estimated the 2- and 5-year cumulative risks of HSIL/AIN2+ using logistic and Cox regression models. Results: One hundred twenty-nine men were diagnosed with HSIL/AIN2+ during the study. HR-HPV testing had the highest positivity and sensitivity, but the lowest specificity of all assays. HPV16/18 and HPV E6/E7 mRNA had high specificity, but lower sensitivity. Two- and 5-year risks of HSIL/AIN2+ were highest for testing HPV16/18- or HPV E6/E7 mRNA-positive, followed by dual stain-positive. Testing HR HPV- or dual stain-negative had the lowest 2- and 5-year risks of HSIL/AIN2+. Conclusions: HPV-related biomarkers provide long-term risk stratification for anal precancers. HR-HPV- and dual stain-negativity indicate low risk of HSIL/AIN2+ for at least 2 years compared with negative anal cytology; however, the high positivity of HR-HPV in HIV+ MSM may limit its utility for surveillance and management in this population. PMID- 30418519 TI - Soluble Urokinase Plasminogen Activator Receptor (suPAR) is predictive of Non AIDS Events during Antiretroviral Therapy-mediated Viral Suppression. AB - Background: Despite effective antiretroviral therapy (ART), HIV infection remains associated with higher morbidity/mortality, driven- in part -by increased inflammation. The objective of this study is to identify associations between levels of plasma biomarkers of chronic inflammation, microbial translocation, and monocyte activation, measured prior to and during suppressive ART, with occurrence of non-AIDS events. Methods: Participants (141 cases, 310 matched controls) were selected from the longitudinal observational ACTG ALLRT trial; all were virally suppressed on ART at year 1, and thereafter. Soluble urokinase plasminogen activator receptor (suPAR), lipopolysaccharide binding protein (LBP), beta-D-glucan (BDG), intestinal fatty acid binding protein (I-FABP), oxidized (ox)LDL, and soluble CD163 (s)CD163 were measured pre-ART, after 1-year of ART, and pre-event. At each timepoint, conditional logistic regression analysis assessed associations of the biomarkers with events, and adjusted for relevant covariates to calculate odds ratios (OR) according to one interquartile range (IQR) differences. Results: At all time points, higher levels of suPAR were associated with increased risk of non-AIDS events (OR per one IQR 1.7 before ART initiation, OR 2.0 after 1-year of suppressive ART and OR 2.1 pre-event). Higher levels of BDG and LBP at year one and pre-event (but not at baseline) were associated with increased risk of non-AIDS events. No associations were observed for other biomarkers. Conclusions: Elevated levels of suPAR were strongly, consistently and independently predictive of non-AIDS events at every measured time point. Interventions that target the suPAR pathway should be investigated to explore its role in the pathogenesis of non-AIDS-related outcomes in HIV infection. PMID- 30418520 TI - Imaging primary mitral regurgitation: the whole is better than the sum of its parts. PMID- 30418521 TI - A Web-Delivered Multicomponent Intervention for Adolescents with Poorly Controlled Type 1 Diabetes: A Pilot Randomized Controlled Trial. AB - Background: Type 1 diabetes is associated with significant mortality and economic cost. Management of type 1 diabetes involves completing multiple daily adherence behaviors, and many adolescents struggle with self-management and show poor glycemic control. Purpose: The purpose was to conduct an unblinded pilot randomized controlled parallel-group study of a web-delivered multicomponent intervention targeting self-monitoring of blood glucose, working memory, and parent supervision of diabetes care among adolescents with type 1 diabetes. Intervention components included high magnitude incentives for adolescents and parents, motivational and cognitive behavioral therapy and working memory training for adolescents, and training in contingency contracting for parents. Methods: Adolescents (N = 114) with poorly controlled type 1 diabetes were screened, and N = 61 were randomized using minimum likelihood allocation to usual care (usual care, N = 31) or to a 25-week/15-session web-delivered intervention (WebRx, N = 30). Results: At the end of treatment, adolescents in WebRx had higher self-monitoring of blood glucose (d = 0.58) (primary outcome), better visual spatial working memory (d = 0.48) and inhibition (d = 0.98), and lower HbA1c (d = 0.45) than those in usual care. WebRx parents reported more frequent review of the adolescent's glucometer (d = 1.30) and reduced family conflict (d = 0.56). Between-condition differences were maintained 6 months later in self monitoring of blood glucose (d = 0.42), visual spatial working memory (d = 0.76), family conflict (d = 0.50), and HbA1c (d = 0.44). Conclusions: Results showing sustained effects on self-monitoring of blood glucose and HbA1c support moving forward with a larger trial to test this innovative web-delivered and multicomponent intervention. ClinicalTrials.gov Number (NCT01722643). PMID- 30418523 TI - The Influence of University Students' Stress Mindsets on Health and Performance Outcomes. AB - Background: Emerging evidence indicates that holding particular stress mindsets has favorable implications for peoples' health and performance under stress. Purpose: The aim of the current study was to examine the processes by which implicit and explicit stress mindsets relate to health- and performance-related outcomes. Specifically, we propose a stress beliefs model in which somatic responses to stress and coping behaviors mediate the effect of stress mindsets on outcomes. Methods: Undergraduate university students (N = 218, n = 144 females) aged 17- 25 years completed measures of stress mindset, physical and psychological wellbeing, perceived stress, perceived somatic responses to stress, proactive behaviors under stress, and an implicit association test assessing an implicit stress mindset. At the end of the semester, students' academic performance was collected from university records. Results: Path analysis indicated significant indirect effects of stress mindset on psychological wellbeing and perceived stress through proactive coping behaviors and perceived somatic symptoms. Stress mindset directly predicted perceived stress and physical wellbeing, and physical wellbeing and academic performance were predicted by stress mindset through perceived somatic symptoms. Implicit stress mindset did not predict proactive behavior as anticipated. Conclusions: Current findings indicate that behaviors with the goal of proactively meeting demands under stress and perceived somatic symptoms are important mediators of the effect of stress mindset on health- and performance-related outcomes. The findings from this study provide formative data that can inform the development of future interventions aiming to encourage more adaptive responses to stress. PMID- 30418524 TI - Are Cardiovascular Risk Factors Stronger Predictors of Incident Cardiovascular Disease in U.S. Adults With Versus Without a History of Clinical Depression? AB - Background: Several mechanisms underlying the depression-to-cardiovascular disease (CVD) relationship have been proposed; however, few studies have examined whether depression promotes CVD through potentiating traditional cardiovascular risk factors. Purpose: To test the combined influence of three cardiovascular risk factors and lifetime depressive disorder on incident CVD in a large, diverse, and nationally representative sample of U.S. adults. Methods: Respondents were 26,840 adults without baseline CVD who participated in Waves 1 (2001-2002) and 2 (2004-2005) of the National Epidemiologic Survey on Alcohol and Related Conditions. Lifetime depressive disorder, tobacco use, hypertension, and incident CVD were determined from structured interviews, and body mass index (BMI) was computed from self-reported height and weight. Results: Logistic regression models predicting incident CVD (1,046 cases) revealed evidence of moderation, as the interactions between lifetime depressive disorder and current tobacco use (p = .002), hypertension (p < .001), and BMI (p = .031) were significant. The Former Tobacco Use * Lifetime Depressive Disorder interaction was not significant (p = .85). In models stratified by lifetime depressive disorder, current tobacco use (OR = 1.78, 95% CI = 1.36-2.32, p < .001 vs. OR = 1.41, 95% CI = 1.24-1.60, p < .001), hypertension (OR = 2.46, 95% CI = 1.98-3.07, p < .001 vs. OR = 1.39, 95% CI = 1.28-1.51, p < .001), and BMI (OR = 1.10, 95% CI = 1.01-1.20, p = .031 vs. OR = 1.03, 95% CI = 0.99-1.07, p = .16) were stronger predictors of incident CVD in adults with versus without a lifetime depressive disorder. Conclusions: Our findings suggest that amplifying the atherogenic effects of traditional cardiovascular risk factors may be yet another candidate mechanism that helps to explain the excess CVD risk of people with depression. PMID- 30418522 TI - Religious and Spiritual Coping and Risk of Incident Hypertension in the Black Women's Health Study. AB - Background: The few studies of the relationship between religion and/or spirituality (R/S) and hypertension are conflicting. We hypothesized that R/S may reduce the risk of hypertension by buffering adverse physiological effects of stress. Methods: We prospectively assessed the association of R/S with hypertension within the Black Women's Health Study (BWHS), a cohort study initiated in 1995 that follows participants through biennial questionnaires. The 2005 questionnaire included four R/S questions: (i) extent to which one's R/S is involved in coping with stressful situations, (ii) self-identification as a religious/spiritual person, (iii) frequency of attending religious services, and (iv) frequency of prayer. Incidence rate ratios (IRRs) and 95% confidence intervals were calculated for each R/S variable in relation to incident hypertension using Cox proportional hazards regression models, controlling for demographics, known hypertension risk factors, psychosocial factors, and other R/S variables. Results: During 2005-2013, 5,194 incident cases of hypertension were identified. High involvement of R/S in coping with stressful events compared with no involvement was associated with reduced risk of hypertension (IRR: 0.87; 95% CI: 0.75, 1.00). The association was strongest among women reporting greater levels of perceived stress (IRR: 0.77; 95% CI: 0.61, 0.98; p interaction = .01). More frequent prayer was associated with increased risk of hypertension (IRR: 1.12; 95% CI: 0.99, 1.27). No association was observed for the other R/S measures. Conclusion: R/S coping was associated with decreased risk of hypertension in African American women, especially among those reporting higher levels of stress. Further research is needed to understand the mechanistic pathways through which R/S coping may affect health. PMID- 30418525 TI - Cannabis, cannabinoids and the endocannabinoid system - is there therapeutic potential for inflammatory bowel disease? AB - Cannabis sativa and its extracts have been used for centuries both medicinally and recreationally. There is accumulating evidence that exogenous cannabis and related cannabinoids improve symptoms associated with inflammatory bowel disease such as pain, loss of appetite, and diarrhoea. In vivo, exocannabinoids have been demonstrated to improve colitis, mainly in chemical models.Exocannabinoids signal through the endocannabinoid system, an increasingly understood network of endogenous lipid ligands and their receptors, together with a number of synthetic and degradative enzymes and the resulting products. Modulating the endocannabinoid system using pharmacological receptor agonists, genetic knockout models, or inhibition of degradative enzymes have largely shown improvements in colitis in vivo. Despite these promising experimental results, this has not translated into meaningful benefits for human IBD in the few clinical trials which have been conducted to date. The largest study to date being limited by poor medication tolerance due to the Delta9-tetrahydrocannabinol component.This review article synthesises the current literature surrounding the modulation of the endocannabinoid system and administration of exocannabinoids in experimental and human IBD. Findings of clinical surveys and studies of cannabis use in IBD are summarised. Discrepancies in the literature are highlighted together with identifying novel areas of interest. PMID- 30418526 TI - Beyond Prevention of Influenza: The Value of Flu Vaccines. PMID- 30418527 TI - Development and Validation of a Deep Learning-Based Automatic Detection Algorithm for Active Pulmonary Tuberculosis on Chest Radiographs. AB - Background: Detection of active pulmonary tuberculosis (TB) on chest radiographs (CR) is critical for the diagnosis and screening of TB. An automated system may help streamline the TB screening process and improve diagnostic performance. Methods: We developed a deep-learning-based automatic detection (DLAD) algorithm, using 54,221 normal CRs and 6,768 CRs with active pulmonary TB, which were labeled and annotated by 13 board-certified radiologists. The performance of DLAD was validated using six external multi-center, multi-national datasets. To compare the performances of DLAD with physicians, an observer performance test was conducted by 15 physicians including non-radiology physicians, board certified radiologists, and thoracic radiologists. Image-wise classification and lesion-wise localization performances were measured using area under the receiver operating characteristic (ROC) curves, and area under the alternative free response ROC curves, respectively. Sensitivities and specificities of DLAD were calculated using two cutoffs [high sensitivity (98%) and high specificity (98%)] obtained through in-house validation. Results: DLAD demonstrated classification performances of 0.977-1.000 and localization performance of 0.973-1.000. Sensitivities and specificities for classification were 94.3-100% and 91.1-100% using the high sensitivity cutoff and 84.1-99.0% and 99.1-100% using the high specificity cutoff. DLAD showed significantly higher performance in both classification (0.993 vs. 0.746-0.971) and localization (0.993 vs. 0.664-0.925) compared to all groups of physicians. Conclusion: Our DLAD demonstrated excellent and consistent performance in the detection of active pulmonary TB on CR, outperforming physicians including thoracic radiologists. PMID- 30418528 TI - Measles immunity at 4.5 years of age following vaccination at 9 and 15-18 months of age among HIV-infected, HIV-exposed-uninfected and HIV-unexposed children. AB - Background: HIV-infected and HIV-exposed-uninfected (HEU) children may be at increased risk of measles infection due to waning of immunity following vaccination. We evaluated persistence of antibodies to measles vaccination at 4.5 years of age in HIV-unexposed, HEU, and HIV-infected children with CD4+>=25% previously randomised to immediate antiretroviral therapy interrupted at 12 months (HIV/Immed-ART-12), 24 months (HIV/Immed-ART-24), or when clinically/immunologically indicated (HIV/Def-ART). The HIV/Def-ART group had ART initiated by median 5.8 (interquartile range 4.4-10.3) months of age. Methods: This cohort study followed participants from 6-12 weeks through 4.5 years of age. HIV-unexposed (n=95), HEU (n=84), HIV/Immed-ART-12 (n=70), HIV/Immed-ART-24 (n=70), and HIV/Def-ART (n=62) children were scheduled to receive measles vaccination at 9 and 15-18 months of age. Anti-measles serum IgG titres were quantified using enzyme-linked immunosorbent assay at 4.5 years. Results: Compared with HIV-unexposed children (2860 mIU/ml; 95% confidence interval [CI] 2373-3446), measles antibody geometric mean titres (GMTs) were significantly lower in both HIV/Immed-ART-12 (571; 95%CI 409-796; p<0.001) and HIV/Immed-ART-24 (1136; 95%CI 791-1633; p<0.001), but similar in the HIV/Def-ART (2777; 95%CI 2008 3841); p=0.675) and HEU (3242; 95%CI 2617-4014; p=0.525) groups. Furthermore, compared with HIV-unexposed, antibody titres >=330 mIU/mL (i.e. presumed sero correlate for protection; 99%) were also significantly lower in HIV/Immed-ART-12 (70%; p<0.001) and HIV/Immed-ART-24 (83%; p<0.001); but similar in the HIV/Def ART (90%) and HEU (98%) groups. Conclusions: HIV-infected children in whom ART was interrupted at either 12 or 24 months of age had lower GMTs and lower proportions with seroprotective titres than HIV-unexposed children; indicating a potential downside of ART treatment interruption. PMID- 30418529 TI - Subdistribution hazard models for competing risks in discrete time. AB - A popular modeling approach for competing risks analysis in longitudinal studies is the proportional subdistribution hazards model by Fine and Gray (1999. A proportional hazards model for the subdistribution of a competing risk. Journal of the American Statistical Association94, 496-509). This model is widely used for the analysis of continuous event times in clinical and epidemiological studies. However, it does not apply when event times are measured on a discrete time scale, which is a likely scenario when events occur between pairs of consecutive points in time (e.g., between two follow-up visits of an epidemiological study) and when the exact lengths of the continuous time spans are not known. To adapt the Fine and Gray approach to this situation, we propose a technique for modeling subdistribution hazards in discrete time. Our method, which results in consistent and asymptotically normal estimators of the model parameters, is based on a weighted ML estimation scheme for binary regression. We illustrate the modeling approach by an analysis of nosocomial pneumonia in patients treated in hospitals. PMID- 30418530 TI - 17-beta estradiol and 17alpha-ethinyl estradiol exhibit immunologic and epigenetic regulatory effects in NZB/WF1 female mice. AB - 17alpha-ethinyl estradiol (EE), a synthetic analog of natural estrogen 17-beta estradiol (E2), is extensively used in hormonal contraceptives and estrogen replacement therapy, and has also been found in sewage effluents. Given that E2 is a well-known immunomodulator, surprisingly there has been only limited information on the cellular and molecular immunologic consequences of exposure to EE. To address this fundamental gap, we directly compared the effects of EE with E2 on splenic leukocytes of NZB/WF1 mice during the pre-autoimmune period. We found that EE and E2 have common, as well as distinctive, immunologic effects, with EE exposure resulting in more profound effects. Both EE and E2 increased numbers of splenic neutrophils, enhanced neutrophil serine proteases and myeloperoxidase expression, promoted the production of nitric oxide (NO) and monocyte chemoattractant protein (MCP-1), and altered adaptive immune T cell subsets. However, activation of splenic leukocytes through TCR or TLR4 revealed not only common (IL-10), but also hormone-specific alterations of cytokines (IFNgamma, IL-1beta, TauNuFalpha, IL-2). Further, in EE-exposed mice, TLR9 stimulation suppressed IFNalpha, in contrast to increased IFNalpha from E2 exposed mice. EE and E2 regulated common and hormone-specific expression of immune-related genes. Further, EE exposure resulted in more marked alterations in miRNA expression levels than E2. Only EE was able to reduce global DNA methylation significantly in splenic leukocytes. Together, our novel data revealed that EE and E2 exposure confers more similar effects in innate immune system related cell development and responses, but has more differential regulatory effects in adaptive immune related cell development and responses. PMID- 30418531 TI - Non-linear multidimensional flow cytometry analyses delineate NK cell phenotypes in normal and HIV-infected chimpanzees. AB - Natural killer cells are primary immune effector cells with both innate and potentially adaptive functions against viral infections, but commonly become exhausted or dysfunctional during chronic diseases such as HIV. Chimpanzees are the closest genetic relatives of humans and have been previously used in immunology, behavior, and disease models. Due to their similarities to humans, a better understanding of chimpanzee immunology, particularly innate immune cells, can lend insight into the evolution of human immunology, as well as response to disease. However, the phenotype of NK cells has been poorly defined. In order to define NK cell phenotypes, we unbiasedly quantified NK cell markers among mononuclear cells in both naive and HIV-infected chimpanzees by flow cytometry. We identified NKG2D and NKp46 as the most dominant stable NK cells markers using multidimensional data reduction analyses. Other traditional NK cell markers such as CD8alpha, CD16, and perforin fluctuated during infection, while some such as CD56, NKG2A and NKp30 were generally unaltered by HIV infection, but did not delineate the full NK cell repertoire. Taken together these data indicate that phenotypic dysregulation may not be pronounced during HIV infection of chimpanzees, but traditional NK cell phenotyping used for both humans and other nonhuman primate species may need to be revised to accurately identify chimpanzee NK cells. PMID- 30418532 TI - Programmed death ligand 1 and CD8+ immune cell infiltrates in resected primary tracheal malignant neoplasms. AB - OBJECTIVES: Many patients with primary malignant tracheal neoplasms are not surgical candidates nor do they experience residual or recurrent disease after surgery and may benefit from alternative therapies. This study explores the expression of programmed death ligand 1 (PD-L1) in patients with primary tracheal malignancy as a biomarker for candidacy for treatment with immune checkpoint inhibitors. METHODS: We conducted a retrospective review of the medical records of 23 patients with resected primary tracheal malignant tumours from 2010 to 2016. Paraffin-embedded blocks of tumour tissue were evaluated immunohistochemically to determine the expression of PD-L1 and infiltration by CD8+ immune cells. RESULTS: We identified 14 (61%) adenoid cystic carcinomas, 4 (17%) squamous cell carcinomas (SCC), 4 (17%) mucoepidermoid carcinomas and 1 adenosquamous carcinoma. PD-L1 expression was observed in 3 (75%) cases of SCC and 1 (100%) case of adenosquamous carcinoma, but it was absent in cases of adenoid cystic carcinomas and mucoepidermoid carcinomas. PD-L1 expression was significantly higher in tumours with a SCC component than in salivary-type tumours (P = 0.001). The presence of CD8+ immune cells in the tumour or peritumoural stroma was significantly higher in cases of tracheal tumours with a SCC component than in salivary-type tumours. CONCLUSIONS: Salivary-type primary malignant tracheal tumours do not significantly express PD-L1. In contrast, most primary tracheal tumours with a SCC component show membranous expression of PD-L1 and larger numbers of infiltrating CD8+ immune cells. PD-L1 expression may serve as a biomarker in patients with primary tracheal squamous cell malignant neoplasms when the patients are being considered for alternative treatments and inclusion in clinical trials. IRB Approval: Protocol No. 2017P000415 (22 March 2017). PMID- 30418533 TI - Sensitive Period for Cognitive Repurposing of Human Visual Cortex. AB - Studies of sensory loss are a model for understanding the functional flexibility of human cortex. In congenital blindness, subsets of visual cortex are recruited during higher-cognitive tasks, such as language and math tasks. Is such dramatic functional repurposing possible throughout the lifespan or restricted to sensitive periods in development? We compared visual cortex function in individuals who lost their vision as adults (after age 17) to congenitally blind and sighted blindfolded adults. Participants took part in resting-state and task based fMRI scans during which they solved math equations of varying difficulty and judged the meanings of sentences. Blindness at any age caused "visual" cortices to synchronize with specific frontoparietal networks at rest. However, in task-based data, visual cortices showed regional specialization for math and language and load-dependent activity only in congenital blindness. Thus, despite the presence of long-range functional connectivity, cognitive repurposing of human cortex is limited by sensitive periods. PMID- 30418534 TI - Development and Validation of a Deep Learning System for Detection of Active Pulmonary Tuberculosis on Chest Radiographs: Clinical and Technical Considerations. PMID- 30418535 TI - Ribose-5-Phosphate Isomerase A Overexpression Promotes Liver Cancer Development in Transgenic Zebrafish via Activation of ERK and beta-catenin Pathways. AB - Dysregulation of the enzymes involved in the pentose phosphate pathway (PPP) is known to promote tumorigenesis. Our recent study demonstrated that ribose-5 phosphate isomerase (RPIA), a key regulator of the PPP, regulates hepatoma cell proliferation and colony formation. Our studies in zebrafish reveal that RPIA mediated hepatocarcinogenesis requires extracellular signal-regulated kinase (ERK) and beta-catenin signaling. To further investigate RPIA-mediated hepatocarcinogenesis, two independent lines of transgenic zebrafish expressing human RPIA in the liver were generated. These studies reveal that RPIA overexpression triggers lipogenic factor/enzyme expression, steatosis, fibrosis and proliferation of the liver. In addition, the severity of fibrosis and the extent of proliferation are positively correlated with RPIA expression levels. Furthermore, RPIA-mediated induction of hepatocellular carcinoma (HCC) requires the ERK and beta-catenin signaling pathway but is not dependent upon transaldolase levels. Our study presents a mechanism for RPIA-mediated hepatocarcinogenesis and suggests that RPIA represents a valuable therapeutic target for the treatment of HCC. PMID- 30418536 TI - Disseminated gonococcal infections in patients receiving eculizumab: a case series. AB - Background: Gonorrhea is the second most commonly reported notifiable condition in the United States (U.S.). Infrequently, Neisseria gonorrhoeae can cause disseminated gonococcal infection (DGI). Eculizumab, a monoclonal antibody, inhibits terminal complement activation which impairs the ability of the immune system to respond effectively to Neisseria infections. This series describes cases of N. gonorrhoeae infection among patients receiving eculizumab. Methods: Pre- and postmarketing safety reports of N.gonorrhoeae infection in patients receiving eculizumab worldwide were obtained from FDA safety databases and the medical literature, including reports from the start of pivotal clinical trials in 2004 through December 31, 2017. Included patients had at least one eculizumab dose within the three months prior to N. gonorrhoeae infection. Results: Nine cases of N. gonorrhoeae infection were identified; eight were classified as disseminated (89%). Of the disseminated cases, eight patients required hospitalization, seven had positive blood cultures, and two required vasopressor support. One patient required mechanical ventilation. N. gonorrhoeae may have contributed to complications prior to death in one patient; however, the fatality was attributed to underlying disease per the reporter. Conclusion: Patients receiving eculizumab may be at higher risk for DGI than the general population. Prescribers are encouraged to educate patients receiving eculizumab on their risk for serious gonococcal infections and perform screening for sexually transmitted diseases (STDs) per Centers for Disease Control and Prevention STD treatment guidelines or in suspect cases. If antimicrobial prophylaxis is used during eculizumab therapy, prescribers should consider trends in gonococcal antimicrobial susceptibility due to emerging resistance concerns. PMID- 30418537 TI - Risk of neuropsychiatric adverse events associated with the use of oseltamivir: a nationwide population-based case-crossover study. AB - Background: Although the potential risk of neuropsychiatric adverse events (NPAEs) upon administration of oseltamivir has been raised in case reports, the association between the use of oseltamivir and the risk of NPAEs is unclear. Objectives: We aimed to evaluate whether the use of oseltamivir triggers NPAEs. Patients and methods: We conducted a population-based case-crossover study using the National Sample Cohort data from the National Health Insurance Service in South Korea. From a total of 236 348 incident patients with NPAEs as either a primary or secondary diagnosis, our final case series included 5322 patients with a prior prescription for oseltamivir between 2009 and 2013. Exposure to oseltamivir was assessed during 2, 7, 14, 28 and 56 day hazard periods prior to each patient's NPAE. Three pre-consecutive control periods were matched using the same time windows. Conditional logistic regression analysis was used to estimate adjusted ORs (aORs), adjusting for time-variant diagnosis of influenza and concomitant medications. Results: Matched analyses found a consistently increased risk of NPAEs associated with the use of oseltamivir in the 2 day (aOR 1.90, 95% CI 1.29-2.81), 7 day (aOR 1.32, 95% CI 1.00-1.74), 14 day (aOR 1.28, 95% CI 1.03 1.60), 28 day (aOR 1.25, 95% CI 1.06-1.47) and 56 day (aOR 1.13, 95% CI 0.99 1.29) hazard periods compared with use in the three control periods. Conclusions: This study found that the short-term use of oseltamivir triggers the incidence of NPAEs. Early monitoring of NPAEs may be required when prescribing oseltamivir with careful consideration of the risk-benefit balance of oseltamivir. PMID- 30418538 TI - Transfemoral versus transapical transcatheter aortic valve implantation: a single centre experience. AB - OBJECTIVES: Transapical transcatheter aortic valve implantation (TAVI) is associated with increased mortality as compared to the transfemoral (TF) access. Possible mechanisms include different patient risk profiles as well as an intrinsic injury caused by the access route itself. METHODS: All consecutive patients scheduled for TAVI between January 2009 and June 2016 at a single centre were evaluated. A comparison of 30-day mortality and morbidity rates for patients undergoing TF or transapical (TA) TAVI was performed according to the criteria of the Valve Academic Research Consortium 2. RESULTS: During the investigated period, 1130 patients (TF: n = 619, TA: n = 511) were scheduled for TAVI. TA patients had a higher operative risk profile (logistic EuroSCORE: 24% vs 17%; P < 0.001). Unadjusted 30-day mortality rate was higher in TA than in TF patients, albeit this difference was not significant [TA: 6.7%, TF: 4.8%; odds ratio (OR) 1.3 (0.8-2.3); P = 0.216]. The multivariate logistic regression analysis revealed the logistic EuroSCORE and institutional experience, but not the access mode as independent predictors of 30-day mortality. Major access-site complications occurred with a similar frequency in both groups [TA: 9.4%; TF: 9.2%; OR 1.02 (0.68-1.53); P = 0.915]. Unadjusted long-term mortality rate was higher after TA TAVI. After adjustment, the Cox regression analysis revealed similar long-term mortality rates after TF and TA TAVI [hazard ratio 1.1 (0.88-1.36)]. CONCLUSIONS: The increased mortality of patients undergoing TA TAVI is associated with the patient risk profile and the institutional experience but not with the access mode itself. PMID- 30418539 TI - Long-term impact of oral vancomycin, ciprofloxacin and metronidazole on the gut microbiota in healthy humans. AB - Objectives: The impact of combination antibiotic therapy on the composition of the intestinal microbiota remains ill-defined. We aimed to assess the effect of a 1 week antibiotic regimen on the intestinal microbiota of healthy humans for a period of up to 31 months. Patients and methods: Thirteen healthy adult men received either no treatment or oral broad-spectrum antibiotics (ciprofloxacin, vancomycin and metronidazole) for 7 days. At four timepoints (prior to treatment, on day 9, day 49 and 8-31 months later) faecal samples were collected and analysed using 16S RNA gene sequencing. Results: The short-term impact of broad spectrum antibiotics on the gut microbiota was profound, with a loss of diversity and drastic shifts in community composition. In addition, antibiotics significantly reduced the abundance of bacterial taxa with important metabolic functions, such as the production of butyrate. The microbiota showed a remarkable return towards baseline after 8-31 months, but community composition often remained altered from its initial state. Conclusions: These findings suggest that combined treatment with vancomycin, ciprofloxacin and metronidazole has a profound and long-lasting effect on microbiota composition, the consequences of which remain largely unknown. PMID- 30418540 TI - Autonomic dysfunction and chronic disease. AB - Introduction: The majority of chronic diseases are accompanied by symptoms of more or less pronounced dysautonomia, which frequently and noticeably deteriorate the quality of patients' life. Sources of data: Pubmed. Areas of agreement: Functional disorders in the autonomic nervous system (ANS) require very precise diagnostics; frequently involving several specialists and a number of diagnostic tests. Areas of controversy: Dysautonomia symptoms are of a very discrete nature and may develop much earlier than symptoms specific for a given chronic disease, significantly influencing the treatment process itself. Growing points: ANS dysfunctions should be considered at each stage of the diagnostic and treatment processes, as a predictor for the patient's clinical condition. Areas timely for developing research: Many researchers indicate that a decrease in dysautonomia intensity has a direct effect on the progress of the underlying disease and undoubtedly contributes to the improvement of the general health condition or to symptoms remission. PMID- 30418541 TI - Selective effects of temperature on the sensory irritation but not taste of NaCl and citric acid. AB - This study investigated the effect of temperature on taste and chemesthetic sensations produced by the prototypical salty and sour stimuli NaCl and citric acid. Experiment 1 measured the perceived intensity of irritation (burning, stinging) and taste (saltiness, sourness) produced on the tongue tip by brief (3 sec) exposures to suprathreshold concentrations of NaCl and citric acid at 3 different temperatures (12, 34, 42 degrees C). No significant effects of temperature were found on the taste or sensory irritation of either stimulus. Experiment 2 investigated the potential effects of temperature on sensory irritation at peri-threshold concentrations and its sensitization over time. Measurements were again made on the tongue tip at the same 3 temperatures. Heating was found to enhance the perception of irritation at peri-threshold concentrations for both stimuli, whereas cooling suppressed sensitization of irritation for NaCl but not for citric acid. These results (i) confirm prior evidence that perception of suprathreshold salty and sour tastes are independent of temperature; (ii) demonstrate that heat has only weak effects on sensory irritation produced by brief exposures to NaCl and citric acid; and (iii) suggest that sensitization of the irritation produced by NaCl and citric acid occur via different peripheral mechanisms that have different thermal sensitivities. Overall the results are consistent with involvement of the heat-sensitive channel TRPV1 in the sensory irritation of both stimuli together with one or more additional channels (e.g. ASIC, ENaC, TRPA1) that are insensitive to heat and may possibly be sensitive to cooling. PMID- 30418542 TI - Anticoccidial efficacy of Canary rue (Ruta pinnata) extracts against the caprine apicomplexan Eimeria ninakohlyakimovae. AB - Continuous use of anticoccidial treatments against Eimeria infections has resulted in the development of drug resistance. This study aimed to evaluate the anticoccidial efficacy of a methanolic extract derived from the endemic Canary rue (Ruta pinnata) plant of the Canary Islands, Spain, against Eimeria ninakohlyakimovae using in vitro assays. Freshly unsporulated oocysts were exposed to different concentrations of R. pinnata extract and thereafter evaluated for sporulation inhibition. Additionally, anticoccidial activity was examined by testing the viability of the E. ninakohlyakimovae sporozoites and their ability to infect bovine colonic epithelial cells after incubation with different concentrations of R. pinnata plant extract. The inhibition of oocyst sporulation by the extract was both time and concentration dependent, with certain combinations affording the same levels of sporulation inhibition as formaldehyde used as positive control (P < 0.001). Moreover, concentrations >0.1 mg/mL also affected not only the viability of the sporozoites but also their cell invasion capacity (P < 0.001). Altogether, these results show that methanolic fruit extracts from R. pinnata have important anticoccidial activity against oocysts and sporozoites of Eimeria. The potential efficacy of the extracts against other animal/human parasites remains to be elucidated, and further studies are needed to better understand its mode of action against coccidian parasites. PMID- 30418543 TI - Emergent Functional Network Effects in Parkinson Disease. PMID- 30418544 TI - Comprehensive plasma and tissue profiling reveals systemic metabolic alterations in cardiac hypertrophy and failure. AB - Aims: Heart failure is characterized by structural and metabolic cardiac remodelling. The aim of the present study is to expand our understanding of the complex metabolic alterations in the transition from pathological hypertrophy to heart failure and exploit the results from a translational perspective. Methods and results: Mice were subjected to transverse aortic constriction (TAC) or sham surgery and sacrificed 2, 4, or 6 weeks after the procedure. Samples from plasma, liver, skeletal muscle, and heart were collected and analysed using metabolomics. Cardiac samples were also analysed by transcriptional profiling. Progressive alterations of key cardiac metabolic pathways and gene expression patterns indicated impaired mitochondrial function and a metabolic switch during transition to heart failure. Similar to the heart, liver and skeletal muscle revealed significant metabolic alterations such as depletion of essential fatty acids and glycerolipids in late stages of heart failure. Circulating metabolites, particularly fatty acids, reflected cardiac metabolic defects and deteriorating heart function. For example, inverse correlation was found between plasma and the heart levels of triacylglycerol (C18:1, C18:2, C18:3), and sphingomyelin (d18:1, C23:0) already at an early stage of heart failure. Interestingly, combining metabolic and transcriptional data from cardiac tissue revealed that decreased carnitine shuttling and transportation preceded mitochondrial dysfunction. We, thus, studied the therapeutic potential of OCTN2 (Organic Cation/Carnitine Transporter 2), an important factor for carnitine transportation. Cardiac overexpression of OCTN2 using an adeno-associated viral (AAV) vector significantly improved ejection fraction and reduced interstitial fibrosis in mice subjected to TAC. Conclusions: Comprehensive plasma and tissue profiling reveals systemic metabolic alterations in heart failure, which can be used for identification of novel biomarkers and potential therapeutic targets. PMID- 30418545 TI - The profile of human milk metabolome, cytokines and antibodies in inflammatory bowel diseases versus healthy mothers and potential impact on the newborn. AB - Background and Aims: For women with inflammatory bowel disease (IBD), it is not very well known how IBD or IBD treatment impacts their breastmilk components. We aimed to investigate whether breastmilk composition differs in healthy control (HC) versus IBD mothers in terms of antibodies, cytokines and metabolites to identify potential impact of IBD breastmilk on neonatal immune system. Methods: Breastmilk specimens from HC (n=17) and IBD (n=31 for Crohn's disease (CD); n=41 for ulcerative colitis (UC)) were collected at 3 and 6 months post-partum (PP3) and (PP6), respectively. Fecal samples were also collected. Cytokines and immunoglobulins (IgA/IgG/IgE) were analyzed by multiplex Meso Scale Discovery (MSD) and commercial kits. Moreover, breastmilk metabolites were analyzed by 1H nuclear magnetic resonance (NMR). Results: We found breastmilk from IBD mothers showed significantly lower levels of IgA, sugar metabolite (lactose) and 2 aminobutyrate. In contrast, we observed breastmilk from mothers with IBD had increased levels of pro-inflammatory cytokines and higher energy metabolites (lactate and succinate) than milk from healthy mothers. In addition, we noticed that the type of treatment (5-ASA versus Biologics) influenced the milk cytokines and metabolites profile. Conclusions: The reduction in immunoprotective components of IBD breastmilk such as sIgA and lactose theoretically may modulate the potential protective effects of breastfeeding. On the other hand, presence of higher levels of pro-inflammatory cytokines, lactate and succinate may predispose the offspring to an inflammatory condition or impact the gut microbiome. Better understanding the role of succinate in infants and its potential effects on microbiome or mucosal immunity merits further investigations. PMID- 30418546 TI - Bitter taste receptor ligand improves metabolic and reproductive functions in a murine model of PCOS. AB - Polycystic ovary syndrome (PCOS) results from functional ovarian hyperandrogenism due to dysregulation of androgen secretion. Cultured theca cells from polycystic ovaries of women with the most common form of PCOS overexpress most androgen producing enzymes, particularly CYP450c17. This study used a murine model of PCOS induced by chronic feeding with high fat content diet that exhibits the reproductive, hyperandrogenic, and metabolic constellation of symptoms of PCOS seen in women. Oral administration of KDT501, a hops-derived bitter taste receptor (Tas2R 108) isohumulone ligand resulted in resolution of PCOS-associated endocrine and metabolic disturbances and restored reproductive function. Pioglitazone, a PPARgamma agonist, also improved metabolic and reproductive function, though not to the same degree as KDT501. Specifically, treatment of the murine PCOS model with KDT 501 resulted in reduced testosterone and androstenedione in the absence of significant changes in luteinizing or follicle stimulating hormones, improved glucose tolerance, improved lipid metabolism, a reduction in hepatic lipid infiltration and a reduction in adiposity. There was a significant improvement in estrous cyclicity and an increase in the number of ovarian corpora lutea indicative of improved reproductive function after exposure to KDT 501. Finally, ex vivo exposure of murine ovaries to KDT 501 attenuated androgen production and ovarian expression of CYP450c17. Interestingly, the ovaries were found to express Tas2R 108 suggesting a potential regulation of ovarian steroidogenesis through this chemosensory receptor family. In summary, this study suggests that a therapeutic strategy for PCOS can include direct influences on ovarian steroidogenesis that are independent from gonadotrophic hormone regulation. PMID- 30418547 TI - Functional Connectivity of the Anterior Cingulate Cortex in Depression and in Health. AB - The first voxel-level resting-state functional connectivity (FC) neuroimaging analysis of depression of the anterior cingulate cortex (ACC) showed in 282 patients with major depressive disorder compared with 254 controls, some higher, and some lower FCs. However, in 125 unmedicated patients, primarily increases of FC were found: of the subcallosal anterior cingulate with the lateral orbitofrontal cortex, of the pregenual/supracallosal anterior cingulate with the medial orbitofrontal cortex, and of parts of the anterior cingulate with the inferior frontal gyrus, superior parietal lobule, and with early cortical visual areas. In the 157 medicated patients, these and other FCs were lower than in the unmedicated group. Parcellation was performed based on the FC of individual ACC voxels in healthy controls. A pregenual subdivision had high FC with medial orbitofrontal cortex areas, and a supracallosal subdivision had high FC with lateral orbitofrontal cortex and inferior frontal gyrus. The high FC in depression between the lateral orbitofrontal cortex and the subcallosal parts of the ACC provides a mechanism for more non-reward information transmission to the ACC, contributing to depression. The high FC between the medial orbitofrontal cortex and supracallosal ACC in depression may also contribute to depressive symptoms. PMID- 30418548 TI - Functional Connectivity Changes of Key Regions for Motor Initiation in Parkinson's Disease. AB - Akinesia, a cardinal symptom of Parkinson's disease, has been linked to abnormal activation in putamen and posterior medial frontal cortex (pMFC). However, little is known whether clinical severity of akinesia is linked to dysfunctional connectivity of these regions. Using a seed-based approach, we here investigated resting-state functional connectivity (RSFC) of putamen, pMFC and primary motor cortex (M1) in 60 patients with Parkinson's disease on regular medication and 72 healthy controls. We found that in patients putamen featured decreases of connectivity for a number of cortical and subcortical areas engaged in sensorimotor and cognitive processing. In contrast, the pMFC showed reduced connectivity with a more focal cortical network involved in higher-level motor cognition. Finally, M1 featured a selective disruption of connectivity in a network specifically connected with M1. Correlating clinical impairment with connectivity changes revealed a relationship between akinesia and reduced RSFC between pMFC and left intraparietal lobule (IPL). Together, the present study demonstrated RSFC decreases in networks for motor initiation and execution in Parkinson's disease. Moreover, results suggest a relationship between pMFC-IPL decoupling and the manifestation of akinetic symptoms. PMID- 30418549 TI - Intervention effect estimates in cluster randomized versus individually randomized trials: a meta-epidemiological study. AB - Background: Cluster (CRTs) and individually randomized trials (IRTs) are often pooled together in meta-analyses (MAs) of randomized trials. However, the potential systematic differences in intervention effect estimates between these two trial types has never been investigated. Therefore, we conducted a meta epidemiological study comparing intervention effect estimates between CRTs and IRTs. Methods: All Cochrane MAs including at least one CRT and one IRT, published between 1 January 2010 and 31 December 2014, were included. For each MA, we estimated a ratio of odds ratios (ROR) for binary outcomes or a difference of standardized differences (DSMD) for continuous outcomes, where less than 1 (or 0, respectively) indicated a greater intervention effect estimate with CRTs. Results: Among 1301 screened reviews, we selected 121 MAs, of which 76 had a binary outcome and 45 had a continuous outcome. For binary outcomes, intervention effect estimates did not differ between CRTs and IRTs [ROR 1.00, 95% confidence interval (0.93 to 1.08)]. Subgroup and adjusted analyses led to consistent results. For continuous outcomes, the DSMD was 0.13 (0.06 to 0.19). It was lower for MAs with a pharmacological intervention [-0.03, (-0.12 to 0.07)], an objective outcome [0.05, (-0.08 to 0.17)] or after adjusting for trial size [0.06, (-0.01 to 0.15)]. Conclusion: For binary outcomes, CRTs and IRTs can safely be pooled in MAs because of an absence of systematic differences between effect estimates. For continuous outcomes, the results were less clear although accounting for trial sample sizes led to a non-significant difference. More research is needed for continuous outcomes and, meanwhile, MAs should be completed with subgroup analyses (CRTs vs IRTs). PMID- 30418550 TI - Urolithin A gains in anti-proliferative capacity by reducing the glycolytic potential via the p53/TIGAR axis in colon cancer cells. AB - Polyphenols have shown promising bioactivity in experimental in vitro and in vivo models for cancer chemoprevention. However, consumed orally they are often transformed by gut microbes into new active principles with so far incompletely deciphered molecular mechanisms. Here enterolacton, S-equol and urolithin A as representatives of metabolites of lignans, isoflavones and ellagitannins, respectively, were examined for their impact on HCT116 colon cancer cell growth, cooperativity with oxaliplatin and p53 dependency in vitro. Whereas enterolacton and S-equol (<= 60 uM) did not elicit growth inhibition or positive cooperativity with oxaliplatin, urolithin A showed an IC50 value of 19 uM (72 h) and synergism with oxaliplatin. Urolithin A induced p53 stabilization and p53 target gene expression, and absence of p53 significantly dampened the antiproliferative effect of urolithin A (IC50(p53-/-)= 38 uM). P53 was dispensable for the G2/M arrest in HCT116 cells, but required for induction of a senescence-like phenotype upon long-term exposure and for the observed synergism with oxaliplatin. Moreover, extracellular flux analyses and knockdown approaches uncovered a reduced glycolytic potential via the p53/TIGAR axis which was linked to the higher susceptibility of wildtype cells to urolithin A. Overall, the p53 status turned out to be an important determinant for the potential benefit of dietary ellagitannins in cancer chemoprevention or use in adjuvant therapy. PMID- 30418551 TI - Detection and characterization of ESBL-producing Escherichia coli expressing mcr 1 from dairy cows in China. AB - Objectives: To investigate the prevalence and molecular characteristics of ESBL producing Escherichia coli (ESBL-EC) in faecal samples from dairy cows in China. Methods: In total, 651 faecal samples were collected from cows distributed among the 10 provinces of China. Potential ESBL-EC isolates were cultured on selective medium. The clonal relatedness of the ESBL-EC isolates was assessed using MLST. WGS was conducted on 3 mcr-positive isolates and 14 additional randomly selected ESBL-EC isolates. Southern blot, S1-PFGE and conjugation were performed for mcr-1 carrying isolates. The genetic environment of the pMCR-JLF4 plasmid was also analysed. Results: In total, 290 unique ESBL-EC isolates were detected from 284 cows (43.6%). Alleles of CTX-M were observed in 94.1% (273/290) of all isolates. The most prevalent genotypes observed in this study were blaCTX-M-14, blaCTX-M 15, blaCTX-M-17 and blaCTX-M-55. Differentiation of 79 STs with a polyclonal structure was accomplished using MLST. Clonal complex 10 was the most prevalent major complex detected here. Furthermore, the mcr-1 gene was detected in three isolates. The complete sequence of the mcr-1-containing pMCR-JLF4 was determined. The plasmid was 66.7 kb in length, with a genetic structure of nikA-nikB-mcr-1 pap2. Conjugation analysis confirmed that the mcr-1 gene in pMCR-JLF4 was transferable without the assistance of the ISApl1 gene. Conclusions: The data presented here suggest high prevalence of ESBL-EC in Chinese cow farms. Furthermore, it was clearly demonstrated that commensal E. coli strains can be reservoirs of blaCTX-M genes, potentially contributing to the dissemination and transfer of the mcr-1 gene to pathogenic bacteria among cows. PMID- 30418552 TI - No good deed goes unpunished: eculizumab and invasive neisserial infections. PMID- 30418553 TI - An entirely leadless cardiac resynchronization therapy. PMID- 30418554 TI - Compassionate use of cefiderocol as adjunctive treatment of native aortic valve endocarditis due to XDR-Pseudomonas aeruginosa. AB - Serious infections such as endocarditis due to XDR-Gram-negative bacteria are an increasing challenge. This article presents successful adjunctive use of cefiderocol for a patient with persistently bacteremic healthcare-associated native aortic valve endocarditis due to an ESBL-positive P. aeruginosa susceptible in vitro only to colistin, following failure of conventional therapeutic options. PMID- 30418555 TI - Hormone production by human first-trimester gonads in a functional in vitro system. AB - In the past, explant tissue-culture methodologies have been used to grow gonads and study their development. Results from in vitro cultures of human gonads showed limited progress towards gonadal cell differentiation and were focused mainly on germ-cell differentiation. Thus, detailed studies focusing on human first-trimester gonadal tissue functionality in vitro are still missing.In this study we investigated the endocrine function of human first-trimester gonads in vitro. We included 27 female and 28 male gonadal samples, derived from in total 55 cases, at post-conceptional ages of 4.5-10.5 weeks. Tissues were cultured using an explant tissue-culture system for 14 days. Assays for testosterone (LC MS/MS), AMH (ELISA) and inhibin B (ELISA) were performed using media collected after seven and 14 days of culture. We demonstrated sex- and age-dependent secretion profiles of testosterone, AMH and inhibin B in the culture media, which resemble the pattern of hormone production in human gonads in vivo, from the few available studies at the same age range.Our study shows that explant tissue culture conditions are robust for culture of human first-trimester gonadal somatic cells. Thus it can be used to study human gonadal development and related diseases as well as the effect of potentially hormone disturbing substances in human gonads during development. However, detailed molecular studies are needed for better understanding of the mechanistic control of the endocrine function of human first trimester gonads. PMID- 30418556 TI - Regional Body Fat Changes and Metabolic Complications in Children with Dunnigan Lipodystrophy-causing LMNA Variants. AB - Context: Familial partial lipodystrophy, Dunnigan variety (FPLD2) is a rare autosomal dominant disorder due to heterozygous missense LMNA mutations. FPLD2 subjects gradually lose fat from the upper and lower extremities but gain fat in the face and neck around puberty. However, the precise onset of body fat changes and metabolic complications during childhood remains unknown. Objective: To compare metabolic parameters and regional body fat in children with FPLD2 with the sex- and age-matched controls from the National Health and Nutrition Examination Survey (NHANES) 2005-2010. Methods: We measured fasting serum triglycerides and glucose, and skinfold thicknesses in all children (age 1-18 years) harboring FPLD2-causing LMNA mutations; and determined regional body fat by dual energy X-ray absorptiometry in those aged >= 8 years. Results: Thirty-two affected females and 14 males participated. The lower limb fat in all affected females, except one, was <= 1st percentile; and in two affected males was < 5th percentile for NHANES. One FPLD2 female subject followed from age 6-16 years revealed marked loss of extremity fat much before thelarche. Serum triglycerides were higher in FPLD2 females age 7-18 years compared to controls (median 208 vs. 70 mg/dL; p < 0.0001); and showed inverse correlation with extremity skinfolds. Serum triglycerides in FPLD2 males were not significantly different than controls. Conclusions: The onset of fat loss from the extremities, especially in girls with FPLD2, occurs much before the onset of puberty. Higher serum triglycerides are seen in young FPLD2 females with more severe loss of fat from the extremities. PMID- 30418557 TI - Sequential intravenous-to-oral outpatient antibiotic therapy for MRSA bacteraemia: one step closer. AB - Background: Published guidelines call for prolonged courses of intravenous (iv) antibiotics for the treatment of MRSA bloodstream infection (BSI) to ensure eradication of deep foci and decrease relapse risk. Sequential iv-to-oral antibiotic therapy has been successfully applied to other serious infections but has not been evaluated for MRSA BSI. Objectives: To compare outcomes in adults completing MRSA BSI therapy with oral versus parenteral antibiotics in the outpatient setting [oral outpatient antibiotic therapy (OOAT) versus outpatient parenteral antibiotic therapy (OPAT)]. Methods: This was a single-centre, retrospective, cohort study between 2008 and 2018. The primary outcome was 90 day clinical failure (MRSA BSI recurrence, deep-seated MRSA infection or all-cause mortality). Analyses were adjusted for confounding using inverse probability of treatment weighting (IPTW). Results: A total of 492 patients were included (70 OOAT, 422 OPAT). In general, OOAT patients had characteristics consistent with a lower risk of poor outcomes; however, after IPTW key prognostic factors were balanced. In IPTW-adjusted analysis, there was non-significant reduction in the rate of 90 day clinical failure in the OOAT group compared with the OPAT group [adjusted HR (aHR) 0.379, 95% CI 0.131-1.101]. In analyses restricted to pre specified subgroups defined by index infection complexity and comorbidity burden, findings were consistent with the main analysis. Furthermore, OOAT patients had a significantly reduced rate of 90 day hospital readmission (aHR 0.603, 95% CI 0.388-0.937). Conclusions: We provide preliminary evidence that selected patients with MRSA BSI may have at least equivalent clinical outcomes with OOAT versus OPAT and provide support to ongoing and future studies evaluating oral antibiotics for MRSA BSI. PMID- 30418558 TI - Value-Based Health Care in Inflammatory Bowel Disease. AB - Inflammatory bowel disease (IBD) is a chronic inflammatory disease associated with significant resource utilization and health care burden. It is emerging as a global disease affecting an increasing proportion of the population. Along with evolving epidemiological trends, the paradigm of managing IBD has also changed. With a burgeoning repertoire of therapeutic options, improved use of health informatics, and emphasis on health care value, the treatment paradigm for IBD has experienced seismic shifts. In this review, we focused on value-based health care (VBHC)-a health care model that emphasizes monitoring outcomes to emphasize patient-centered, cost-effective IBD patient care. Several quality initiatives have been developed worldwide, and successful models of care were created for proper implementation of these initiatives. Although there are significant challenges to scale these models to a national level, it is still possible to successfully implement VBHC models within health systems to improve the quality of care provided to patients with IBD. PMID- 30418559 TI - A false pleural effusion. PMID- 30418560 TI - Vegetarian Diets Are Associated with Selected Cardiometabolic Risk Factors among Middle-Older Aged South Asians in the United States. AB - Background: Following a vegetarian diet is considered to be beneficial for overall health and is associated with a lower risk of chronic disease. Objective: This study examined whether South Asians in the United States who consume a vegetarian diet have a lower prevalence of cardiometabolic risk factors. Methods: Data from the Mediators of Atherosclerosis in South Asians Living in America study, which included 892 South Asians (47% women), with an age range of 40-83 y and a mean +/- SD age of 55 +/- 9.4 y, were used. Participants were classified as vegetarian if they reported no consumption of meat, poultry, or fish in the previous year on a validated and culturally appropriate food-frequency questionnaire. Adjusted linear and logistic regression models were used to examine associations of a vegetarian diet with cardiometabolic risk factors. Results: Thirty-eight percent of the cohort participants were classified as vegetarian. Vegetarians reported more frequent weekly eating occasions of whole grains (median frequency/wk: 10 compared with 9, P = 0.012) and beans and legumes (median frequency/wk: 8.5 compared with 5.1, P < 0.001), and less frequent weekly eating occasions of sweets and desserts (median frequency/wk: 1.9 compared with 2.3, P < 0.001). Consuming a vegetarian diet was associated with lower body mass index (P = 0.023), fasting glucose (P = 0.015), insulin resistance (P = 0.003), total cholesterol (P = 0.027), and LDL cholesterol (P = 0.004) and lower odds of fatty liver (OR: 0.43; 95% CI: 0.23, 0.78, P = 0.006). The odds of having any coronary artery calcium were lower for vegetarian men (OR: 0.53; 95% CI: 0.32, 0.87, P = 0.013); however, no significant associations were observed among women. Conclusions: Among US South Asians, a vegetarian diet was associated with fewer cardiometabolic risk factors overall and with less subclinical atherosclerosis among men. PMID- 30418561 TI - Release of the Flightless Strain of Harmonia axyridis (Coleoptera: Coccinellidae) Against Two Aphid Species on Komatsuna (Brassica rapa var. perviridis) in Open Fields. AB - Myzus persicae (Sulzer) (Hemiptera: Aphididae) and Lipaphis erysimi (Kaltenbach) are important pests of Brassica leafy vegetables, especially in Japan, the United States, and India. In Japan, because most of the nonheading Brassica vegetables are considered minor crops, the number of commercially available pesticides against these aphids is limited. Here, we evaluated the effect of releasing adults of a flightless strain of the multicolored Asian ladybird, Harmonia axyridis Pallas, on these aphid species on a nonheading Brassica cultivar in open fields. Three weeks after, ladybirds were released onto aphid-infested plants at a rate of two adults per m2, only 4-12% equal numbers of aphids were found on plants with ladybirds as without ladybirds in all three trials. The result indicates that H. axyridis adults are the effective biocontrol agents against aphids on the plants. PMID- 30418562 TI - Bacterial diversity in the marine sponge Halichondria panicea from Icelandic waters and host-specificity of its dominant symbiont "Candidatus Halichondribacter symbioticus". AB - Marine sponges can harbour diverse bacteria that contribute to host metabolism and defence. Identifying these stable members of sponge bacterial communities remains a necessary step in understanding their ecological roles and underlying co-evolutionary processes. In this study, we applied high-throughput sequencing of 16S rRNA gene amplicons, ribosomal nucleotide variant analysis and fluorescence in situ hybridisation to characterise the core members of the bacterial community in the marine sponge Halichondria panicea from Icelandic waters. We show that the core bacterial community across all samples consisted of a single, dominant bacterial taxon, for which we propose a candidate status 'Candidatus Halichondribacter symbioticus'. Comparison against public databases showed that 'Ca. H. symbioticus' is both a highly abundant specialist in H. panicea and a low abundant opportunist in other sponge species. Additionally, H. panicea with and without 'Ca. H. symbioticus' co-exist in similar locations in the North Atlantic. This dichotomy paired with the presence of geographically distinct ribosomal sequence variants of the symbiont make H. panicea an interesting sponge species for studying sponge-symbiont co-evolution and functional interactions. PMID- 30418563 TI - Renal tubular dysfunction fully accounts for plasma biochemical abnormalities in Type 1A Pseudohypoparathyroidism. AB - Context: Type 1A Pseudohypoparathyroidism (PHP-1A) is characterized by target organ resistance to parathyroid hormone (PTH). Patients can show various dysmorphic features, but renal failure is not classically described. Case Description: A female patient came to our attention at the age of seven years with characteristic signs of PTH resistance, namely hypocalcemia, hyperphosphatemia and high serum PTH levels. She also presented hypothyroidism, early-onset obesity, short metacarpal bones and multiple subcutaneous ossifications leading to a clinical diagnosis of pseudohypoparathyroidism In addition to her genetic condition, she had bilateral renal hypodysplasia slowly progressing to end-stage kidney disease. She received a kidney transplant at the age of sixteen and after transplantation rapidly normalized calcium, phosphate and PTH levels, allowing withdrawal of vitamin D supplementation. Conclusions: This the first report of a patient with PHP-1A undergoing kidney transplantation. Normalization of biochemical parameters after the procedure demonstrates that renal tubular resistance to PTH is sufficient to explain the calcium/phosphate abnormalities observed in PHP-1A. PMID- 30418564 TI - NAT/NCS2-hound: A webserver for the detection and evolutionary classification of prokaryotic and eukaryotic nucleobase-cation symporters of the NAT/NCS2 family. AB - Nucleobase transporters are important for supplying the cell with purines and/or pyrimidines, for controlling the intracellular pool of nucleotides and for obtaining exogenous nitrogen/carbon sources for the metabolism. Nucleobase transporters are also evaluated as potential targets for antimicrobial therapies, since several pathogenic microorganisms rely on purine/pyrimidine salvage from their hosts. The majority of known nucleobase transporters belong to the evolutionarily conserved and ubiquitous NAT/NCS2 protein family. Based on a large scale phylogenetic analysis that we performed on thousands of prokaryotic proteomes, we have developed a webserver that can detect and distinguish this family of transporters from other homologous families that recognize different substrates. We can further categorize these transporters to certain evolutionary groups with distinct substrate preferences. The webserver scans whole proteomes and graphically displays which proteins are identified as NAT/NCS2, to which evolutionary groups and subgroups they belong to and which conserved motifs they have. For key subgroups and motifs, the server displays annotated information from published crystal-structures and mutational studies pointing to key functional amino acids that may help experts assess the transport capability of the target sequences. The server is 100% accurate in detecting NAT/NCS2 family members. We also used the server to analyze 9109 prokaryotic proteomes and identified Clostridia, Bacilli, beta- and gamma-Proteobacteria, Actinobacteria and Fusobacteria as the taxa with the largest number of NAT/NCS2 transporters per proteome. An analysis of 120 representative eukaryotic proteomes also demonstrates the server's capability of correctly analyzing this major lineage, with plants emerging as the group with the highest number of NAT/NCS2 members per proteome. PMID- 30418565 TI - Assessment of aneuploidy concordance between clinical trophectoderm biopsy and blastocyst. AB - STUDY QUESTION: Is a clinical trophectoderm (TE) biopsy a suitable predictor of chromosomal aneuploidy in blastocysts? SUMMARY ANSWER: In the analyzed group of blastocysts, a clinical TE biopsy was an excellent representative of blastocyst karyotype in cases of whole chromosome aneuploidy, but in cases of only segmental (sub-chromosomal) aneuploidy, a TE biopsy was a poor representative of blastocyst karyotype. WHAT IS KNOWN ALREADY: Due to the phenomenon of chromosomal mosaicism, concern has been expressed about the possibility of discarding blastocysts classified as aneuploid by preimplantation genetic testing for aneuploidy (PGT-A) that in fact contain a euploid inner cell mass (ICM). Previously published studies investigating karyotype concordance between TE and ICM have examined small sample sizes and/or have utilized chromosomal analysis technologies superseded by Next Generation Sequencing (NGS). It is also known that blastocysts classified as mosaic by PGT-A can result in healthy births. TE re-biopsy of embryos classified as aneuploid can potentially uncover new instances of mosaicism, but the frequency of such blastocysts is currently unknown. STUDY DESIGN, SIZE, DURATION: For this study, 45 patients donated 100 blastocysts classified as uniform aneuploids (non-mosaic) using PGT-A by NGS (n = 93 whole chromosome aneuploids, n = 7 segmental aneuploids). In addition to the original clinical TE biopsy used for PGT-A, each blastocyst was subjected to an ICM biopsy as well as a second TE biopsy. All biopsies were processed for chromosomal analysis by NGS, and karyotypes were compared to the original TE biopsy. PARTICIPANTS/MATERIALS, SETTING, METHODS: The setting for this study was a single IVF center with an in-house PGT-A program and associated research laboratory. MAIN RESULTS AND THE ROLE OF CHANCE: When one or more whole chromosomes were aneuploid in the clinical TE biopsy, the corresponding ICM was aneuploid in 90 out of 93 blastocysts (96.8%). When the clinical TE biopsy contained only segmental (sub-chromosomal) aneuploidies, the ICM was aneuploid in three out of seven cases (42.9%). Blastocysts showing aneuploidy concordance between clinical TE biopsy and ICM were also aneuploid in a second TE biopsy in 86 out of 88 cases (97.7%). In blastocysts displaying clinical TE-ICM discordance, a second TE biopsy was aneuploid in only two out of six cases (33.3%). LIMITATIONS, REASONS FOR CAUTION: All embryos in this study had an initial classification of 'aneuploid' and not 'euploid' or 'mosaic'. Therefore, the findings of this study refer specifically to a TE biopsy predicting aneuploidy in the remaining blastocyst, and cannot be extrapolated to deduce the ability of a TE biopsy to predict euploidy in the blastocyst. No conclusions should be drawn from this study about the ability of a mosaic TE biopsy to predict the karyotype of the corresponding blastocyst. Caution should be exercised in generalizing the findings of the sample group of this study to the general IVF blastocyst population. The segmental aneuploidy group only contained seven samples. WIDER IMPLICATIONS OF THE FINDINGS: The high rate of intra-blastocyst concordance observed in this study concerning whole chromosome aneuploidy contributes experimental evidence to the validation of PGT-A at the blastocyst stage. Concomitantly, the results suggest potential clinical value in reassessing blastocysts deemed aneuploid by TE re-biopsy in select cases, particularly in instances of segmental aneuploidies. This could impact infertility treatment for patients who only have blastocysts classified as aneuploid by PGT-A available. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Zouves Foundation for Reproductive Medicine and Zouves Fertility Center. The authors have no competing interest to disclose. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 30418566 TI - Advanced Dietary Patterns Analysis Using Sparse Latent Factor Models in Young Adults. AB - Background: Principal components analysis (PCA) has been the most widely used method for deriving dietary patterns to date. However, PCA requires arbitrary ad hoc decisions for selecting food variables in interpreting dietary patterns and does not easily accommodate covariates. Sparse latent factor models can be utilized to address these issues. Objective: The objective of this study was to compare Bayesian sparse latent factor models with PCA for identifying dietary patterns among young adults. Methods: Habitual food intake was estimated in 2730 sedentary young adults from the Training Interventions and Genetics of Exercise Response (TIGER) Study [aged 18-35 y; body mass index (BMI; in kg/m2): 26.5 +/- 6.1] who exercised <30 min/wk during the previous 30 d without restricting caloric intake before study enrollment. A food-frequency questionnaire was used to generate the frequency intakes of 102 food items. Sparse latent factor modeling was applied to the standardized food intakes to derive dietary patterns, incorporating additional covariates (sex, race/ethnicity, and BMI). The identified dietary patterns via sparse latent factor modeling were compared with the PCA derived dietary patterns. Results: Seven dietary patterns were identified in both PCA and sparse latent factor analysis. In contrast to PCA, the sparse latent factor analysis allowed the covariate information to be jointly accounted for in the estimation of dietary patterns in the model and offered probabilistic criteria to determine the foods relevant to each dietary pattern. The derived patterns from both methods generally described common dietary behaviors. Dietary patterns 1-4 had similar food subsets using both statistical approaches, but PCA had smaller sets of foods with more cross-loading elements between the 2 factors. Overall, the sparse latent factor analysis produced more interpretable dietary patterns, with fewer of the food items excluded from all patterns. Conclusion: Sparse latent factor models can be useful in future studies of dietary patterns by reducing the intrinsic arbitrariness involving the choice of food variables in interpreting dietary patterns and incorporating covariates in the assessment of dietary patterns. PMID- 30418568 TI - Fluorescence In Situ Hybridization, a complementary molecular tool for the clinical diagnosis of infectious diseases by intracellular and fastidious bacteria. AB - Many obligate or facultative intracellular bacteria pose a critical problem in clinical microbiology diagnosis as a result of their fastidious growth or lack of growth in conventional culture media. Molecular diagnosis is based on the analysis and demonstration of nucleic acids (DNA and RNA). In the field of infectiology, it combines laboratory medicine with the technology of molecular genetics to identify infectious pathogens. Fluorescence In Situ Hybridization (FISH) is used for the detection and localization of nucleotide sequences in various samples while preserving cell integrity. For more than 30 years, FISH methods have in constant evolution with the development of rRNA-targeted probes and synthetic molecules, such as PNA, which have contributed to the development of this technique in various fields by research and diagnostic laboratories. We describe here a panel of infectious diseases due to intracellular bacteria for which FISH diagnosis has proven its effectiveness. FISH techniques were applied in cases of blood culture negative endocarditis, respiratory infections, gastrointestinal diseases, mycobacterial infections, highly pathogenic microorganisms and other fastidious bacteria such as spirochetes. FISH has been proven to be applicable to various samples and for diverse infectious diseases, it can be used as a complementary tool for the diagnosis of infectious diseases by intracellular and fastidious bacteria. PMID- 30418567 TI - Usefulness of guideline recommendations for prognosis in patients with candidemia. AB - We aimed to analyze whether the lack of inclusion of specific recommendations for the management of candidemia is an independent risk factor for early and overall mortality. Multicenter study of adult patients with candidemia in 13 hospitals. We assessed the proportion of patients on whom nine specific ESCMID and IDSA guidelines recommendations had been applied, and analyzed its impact on mortality. 455 episodes of candidemia were documented. Patients who died within the first 48 hours were excluded. Sixty-two percent of patients received an appropriate antifungal treatment. Either echinocandin or amphotericin B therapy were administered in 43% of patients presenting septic shock and in 71% of those with neutropenia. Sixty-one percent of patients with breakthrough candidemia underwent a change in antifungal drug class. Venous catheters were removed in 79% of cases. Follow-up blood cultures were performed in 72% of cases. Ophthalmoscopy and echocardiogram were performed in 48% and 50% of patients, respectively. Length of treatment was appropriate in 78% of cases. Early (2-7 days) and overall (2-30 days) mortality were 8% and 27.7%, respectively. Inclusion of less than 50% of the specific recommendations was independently associated with a higher early (HR = 7.02, 95% CI: 2.97-16.57; P < .001) and overall mortality (HR = 3.55, 95% CI: 2.24-5.64; P < .001). In conclusion, ESCMID and IDSA guideline recommendations were not performed on a significant number of patients. Lack of inclusion of these recommendations proved to be an independent risk factor for early and overall mortality. PMID- 30418569 TI - Paracoccidioidomycosis: characterization of subpopulations of macrophages and cytokines in human mucosal lesions. AB - Mucosal lesions of paracoccidioidomycosis (PCM) are frequently described and clinically important. Macrophages are classified as M1 or M2. M1 are proinflammatory and M2 are related to chronicity. Dectin-1 recognizes beta-glucan and plays an important role against fungal cells. The objective was to verify the presence of M1, M2, and dectin-1 and a possible correlation with Th1/Th2 cytokines in mucosal PCM lesions. In sum, 33 biopsies of oral PCM were submitted to histological and immunohistochemistry analysis, and positive cells were quantified. Eleven biopsies were characterized by compact granulomas (G1), 12 with loose granulomas (G2), and 10 with both kind of granulomas (G3). pSTAT-1 was equally increased in the three groups. G1 was characterized by an increased number of CD163+ macrophages. G2 presented similar number of arginase 1, iNOS, and CD163 expressing cells. G3 presented an increased number of cells expressing arginase 1 and CD163 over iNOS. G1 and G3 presented high number of cells expressing interferon (IFN)-gamma; interleukin (IL) 5 was increased in G2 and G3; the expression of IL10 was similar among the three groups, and the expression of tumor necrosis factor (TNF)-alpha was higher in G3. G1 correlates to Th1 cytokines and pSTAT-1 and G2 correlates to Th2 cytokines. G3 presents both kinds of cytokines. We could not associate the expression of arginase-1, CD163, iNOS, and dectin-1 with the pattern of cytokines or kind of granuloma. PMID- 30418570 TI - Efficient and accurate detection of splice junctions from RNA-Seq with Portcullis. AB - Next generation sequencing (NGS) technologies enable rapid and cheap genome-wide transcriptome analysis, providing vital information about gene structure, transcript expression and alternative splicing. Key to this is the the accurate identification of exon-exon junctions from RNA sequenced (RNA-Seq) reads. A number of RNA-Seq aligners capable of splitting reads across these splice junctions (SJs) have been developed, however, it has been shown that while they correctly identify most genuine SJs available in a given sample, they also often produce large numbers of incorrect SJs. Herein we describe the extent of this problem using popular RNA-Seq mapping tools, and present a new method, called Portcullis, to rapidly filter false SJs junctions derived from spliced alignments. We show that Portcullis distinguishes between genuine and false positive junctions to a high-degree of accuracy across different species, samples, expression levels, error profiles and read lengths. Portcullis is portable, efficient and to our knowledge is currently the only SJ prediction tool that reliably scales for use with large RNA-Seq datasets and large, highly fragmented genomes, whilst delivering accurate SJs. PMID- 30418571 TI - Estimation of standardized mineral availabilities in feedstuffs for broilers. AB - Two experiments were conducted to estimate standardized mineral (Ca, P, Cu, Fe, Mn and Zn) availabilities (SMA) in commonly used feedstuffs and verify the additivity of SMA for diet formulation of broilers. In Exp. 1, after 3 d of acclimation, a total of 96 22-d-old Arbor Acres male broilers were fasted for 24 h. Then the broilers were fed a mineral-free, corn, soybean meal (SBM), or corn soybean meal (C-SBM) diet for 4 h and the excreta samples were collected for 48 h after feed withdrawal (totally 52 h). The results showed that the endogenous losses of Ca, P, Cu, Fe, Mn and Zn for chickens fed the mineral-free diet were 13.7, 113, 0.064, 0.593, 0.094 and 0.132 mg/52 h per bird, respectively. The standardized availability values of Ca, P, Cu, Fe, Mn and Zn were 20.8, 39.6, 37.8, 47.4, 10.7 and 45.2% in corn as well as 54.3, 51.1, 39.7, 27.6, 26.1 and 51.0% in SBM, respectively. The determined values of SMA in C-SBM diet were close (P > 0.09) to the predicted summations of SMA from corn and SBM (Ca, 48.6 vs 48.1%; P, 44.9 vs 46.0%; Cu, 41.7 vs 39.1%; Fe, 35.3 vs 33.2%; Mn, 22.7 vs 22.2%; Zn, 46.2 vs 48.4%). In Exp. 2, a total of 144 22-d-old Arbor Acres male broilers were used to estimate the SMA values in 6 feedstuffs by using the above procedure. The results showed that the standardized availability values in wheat, wheat bran, corn distillers dried grains with solubles, cottonseed meal, rapeseed meal and corn gluten meal diets were 24.7-55.8% for Ca, 35.6-46.6% for P, 24.5 45.7% for Cu, 21.6-43.5% for Fe, 9.3-34.5% for Mn, and 22.9-52.9% for Zn, respectively. The results from the present study indicated that the mineral-free diet could be used for estimating the endogenous losses of the above minerals and SMA values of feedstuffs for broilers, and the estimates of SMA in feedstuffs for the C-SBM diet formulation were additive. PMID- 30418572 TI - Left ventricular end-systolic volume is a more sensitive marker of acute response to cardiac resynchronization therapy than contractility indices: insights from an experimental study. AB - Aims: There are conflicting data and no consensus on how to measure acute response to cardiac resynchronization therapy (CRT). This study investigates, which contractility indices are best markers of acute CRT response. Methods and results: In eight anaesthetized dogs with left bundle branch block, we measured left ventricular (LV) pressure by micromanometer and end-diastolic volume (EDV) and end-systolic volume (ESV) by sonomicrometry. Systolic function was measured as LV ejection fraction (EF), peak rate of LV pressure rise (LV dP/dtmax) and as a gold standard of contractility, LV end-systolic elastance (Ees), and volume axis intercept (V0) calculated from end-systolic pressure-volume relations (ESPVR). Responses to CRT were compared with inotropic stimulation by dobutamine. Both CRT and dobutamine caused reduction in ESV (P < 0.01) and increase in LV dP/dtmax (P < 0.05). Both interventions shifted the ESPVR upwards indicating increased contractility, but CRT which reduced V0 (P < 0.01), caused no change in Ees. Dobutamine markedly increased Ees, which is the typical response to inotropic stimulation. Preload (EDV) was decreased (P < 0.01) by CRT, and there was no change in EF. When adjusting for the reduction in preload, CRT increased EF (P = 0.02) and caused a more marked increase in LV dP/dtmax (P < 0.01). Conclusion: Increased contractility by CRT could not be identified by Ees, which is a widely used reference method for contractility. Furthermore, reduction in preload by CRT attenuated improvement in contractility indices such as EF and LV dP/dtmax. These results suggest that changes in LV volume may be more sensitive markers of acute CRT response than conventional contractility indices. PMID- 30418573 TI - Pharmacological inhibition of pigmentation in Cryptococcus. AB - Melanin formation is a promising target for antifungal development. We screened a collection of 727 compounds that were previously approved for clinical use in humans for inhibition of pigmentation in Cryptococcus gattii, a lethal fungal pathogen that causes damage to both immunocompetent and immunocompromised hosts. The pyrimidine analogues flucytosine (5-fluorocytosine [5-FC]), 5-fluorouracil (5 FU) and carmofur were identified as efficient inhibitors of pigmentation in the C. gattii model. Since melanin synthesis is enzymatically catalyzed by laccase in Cryptococcus, we investigated whether inhibition of pigmentation by the pyrimidine analogues was laccase-mediated. Enzyme activity and expression of LAC genes were not involved in the effects of the pyrimidine analogues, suggesting alternative cellular targets for inhibition of pigmentation. To address this hypothesis, we screened a collection of approximately 8000 mutants of C. gattii that were produced by insertional mutation after incubation with Agrobacterium tumefaciens and identified a gene product required for the anti-pigmentation activity of 5-FC as a beta-DNA polymerase. Reduced expression of this gene affected capsule formation and urease activity, suggesting essential roles in the cryptococcal physiology. These results demonstrate a previously unknown antifungal activity of 5-FC and reveal a promising target for the development of novel antifungals. PMID- 30418574 TI - Central Nervous System and Peripheral Hormone Responses to a Meal in Children. AB - Context: Behavioral studies suggest that responses to food consumption are altered in children with obesity. Objective: To test central nervous system and peripheral hormone response by functional magnetic resonance imaging (fMRI) and satiety-regulating hormone levels before and after a meal. Design and Setting: Cross-sectional study comparing children with obesity (OB) and children of healthy weight (HW) recruited from across the Puget Sound region of Washington. Participants: Children (9-11-year-old, OB n=54, HW n=22), matched for age and sex. Intervention and Outcome Measures: Neural activation to images of high- and low-calorie food and objects was evaluated across a set of a priori appetite processing regions that included the ventral and dorsal striatum, amygdala, substantia nigra/ventral tegmental area, insula and medial orbitofrontal cortex. Pre- and post-meal hormones (insulin, peptide YY, glucagon-like peptide-1, active ghrelin) were measured. Results: In response to a meal, average brain activation by high-calorie food cues vs. objects in a priori regions was reduced post-meal in HW children (z=-3.5, P<0.0001), but not in OB children (z=0.28, P=0.78) despite appropriate meal responses by gut hormones. Although pre-meal average brain activation by high-calorie food cues was lower in OB vs HW children, post meal activation was higher in OB children (z=-2.1, P=0.04; z=2.3, P=0.02, respectively). An attenuated central response to a meal was associated with greater degree of insulin resistance. Conclusions: Our data suggest that children with obesity exhibit an attenuated central, as opposed to gut hormone, response to a meal, which may predispose them to overconsumption of food or difficulty with weight loss. PMID- 30418576 TI - An open-source high-speed infrared videography database to study the principles of active sensing in freely navigating rodents. AB - Background: Active sensing is crucial for navigation. It is characterized by self generated motor action controlling the accessibility and processing of sensory information. In rodents, active sensing is commonly studied in the whisker system. As rats and mice modulate their whisking contextually, they employ frequency and amplitude modulation. Understanding the development, mechanisms, and plasticity of adaptive motor control will require precise behavioral measurements of whisker position. Findings: Advances in high-speed videography and analytical methods now permit collection and systematic analysis of large datasets. Here, we provide 6,642 videos as freely moving juvenile (third to fourth postnatal week) and adult rodents explore a stationary object on the gap crossing task. The dataset includes sensory exploration with single- or multi whiskers in wild-type animals, serotonin transporter knockout rats, rats received pharmacological intervention targeting serotonergic signaling. The dataset includes varying background illumination conditions and signal-to-noise ratios (SNRs), ranging from homogenous/high contrast to non-homogenous/low contrast. A subset of videos has been whisker and nose tracked and are provided as reference for image processing algorithms. Conclusions: The recorded behavioral data can be directly used to study development of sensorimotor computation, top-down mechanisms that control sensory navigation and whisker position, and cross species comparison of active sensing. It could also help to address contextual modulation of active sensing during touch-induced whisking in head-fixed vs freely behaving animals. Finally, it provides the necessary data for machine learning approaches for automated analysis of sensory and motion parameters across a wide variety of signal-to-noise ratios with accompanying human observer determined ground-truth. PMID- 30418575 TI - Prevalence of pretreatment HIV drug resistance in West African and Southeast Asian countries. AB - Background: ART in the developing world has moved to a new era with the WHO recommendation to test and immediately treat HIV-positive individuals. A high frequency of pretreatment HIV drug resistance (PDR) can compromise ART efficacy. Our study presents updated estimates of PDR in seven countries from West Africa (Burkina Faso, Cameroon, Cote d'Ivoire, Mali and Togo) and Southeast Asia (Thailand and Vietnam). Methods: Eligible study participants were adult ART initiators, recruited from December 2015 to November 2016 in major ART clinics in each country. HIV drug resistance (HIVDR) tests were performed for all specimens and interpretation was done using the Stanford algorithm. Results: Overall, 1153 participants were recruited and 1020 nt sequences were generated. PDR frequency among all initiators was 15.9% (95% CI: 13.8%-18.3%) overall, ranging from 9.6% and 10.2% in Burkina Faso and Thailand, respectively, 14.7% in Vietnam, 15.4% in Mali, 16.5% in Cote d'Ivoire and 19.3% in Cameroon, to 24.6% in Togo. The prevalence of NNRTI resistance mutations was 12%; NRTI and PI PDR prevalences were 4% and 3%, respectively. Conclusions: Our study shows that in most countries PDR exceeded 10%, warranting the conduct of nationally representative surveys to confirm this trend. In the meantime, actions to prevent drug resistance, including transition from NNRTIs to more robust drug classes should be urgently implemented. PMID- 30418577 TI - A rapid and non-pathogenic assay for association of Mycobacterium tuberculosis gyrBA mutations and fluoroquinolone resistance using recombinant Mycobacterium smegmatis. AB - We developed a method involving recombinant Mycobacterium bovis bacillus Calmette Guerin (BCG) and recombinant Mycobacterium smegmatis to determine which mutations in Mycobacterium tuberculosis (Mtb) gyrBA are associated with fluoroquinolone (FQ) resistance. The minimal inhibitory concentration (MIC) for FQ for recombinant strains with wild-type Mtb gyrBA was equivalent to that for strains with intrinsic gyrBA. Among 27 gyrBA mutations, the fold-changes in FQ MIC for M. smegmatis and M. bovis BCG backgrounds were comparable and were in part equivalent to those previously reported for recombinant Mtb strains. Mutations at position 90 or 94 of gyrA conferred strong and synergistic FQ resistance, which may be associated with the clinical observation that isolates carrying these mutations are the most or second most frequent. Sitafloxacin hydrate had the lowest MIC among the FQs tested in this study, which is similar to findings from a previous in vivo animal study. Most gyrBA mutations detected in clinical Mtb isolates could confer FQ resistance, but several mutations reduced bacterial growth rates. Overall, recombinant M. smegmatis appears to be a beneficial surrogate system to evaluate FQ susceptibility of virulent mycobacteria. PMID- 30418579 TI - Fish Oil Supplementation in Pregnancy Increases Gestational Age, Size for Gestational Age, and Birth Weight in Infants: A Randomized Controlled Trial. AB - Background: Randomized trials have reported that supplementation with n-3 long chain polyunsaturated fatty acids (LCPUFAs) in pregnancy can prolong pregnancy and thereby increase birth weight. Objective: We aimed to examine the relations of n-3 LCPUFA supplementation in pregnancy with duration of pregnancy, birth weight, and size for gestational age (GA). Methods: This was a double-blind randomized controlled trial conducted in 736 pregnant women and their offspring, from the Copenhagen Prospective Studies on Asthma in Childhood2010cohort. They were recruited between weeks 22 and 26 in pregnancy and randomly assigned to either of 2.4 g n-3 LCPUFA or control (olive oil) daily until 1 wk after birth. Exclusion criteria were endocrine, cardiovascular, or nephrologic disorders and vitamin D supplementation intake >600 IU/d. In this study we analyzed secondary outcomes, and further excluded twin pregnancies and extrauterine death. The primary outcome for the trial was persistent wheeze or asthma. Results: The random assignment ran between 2008 and 2010. Six hundred and ninety-nine mother infant pairs were included in the analysis. n-3 LCPUFA compared with control was associated with a 2-d prolongation of pregnancy [median (IQR): 282 (275-288) d compared with 280 (273-286) d, P = 0.02], a 97-g higher birth weight (mean +/- SD: 3601 +/- 534 g compared with 3504 +/- 528 g, P = 0.02), and an increased size for GA according to the Norwegian population-based growth curves-Skjaerven (mean +/- SD: 49.9 +/- 28.3 percentiles compared with 44.5 +/- 27.6 percentiles, P = 0.01). Conclusion: Supplementing pregnant women with n-3 LCPUFAs during the third trimester is associated with prolonged gestation and increased size for GA, leading to a higher birth weight in this randomized controlled trial. This trial was registered at clinicaltrials.gov as NCT00798226. PMID- 30418578 TI - Comprehensive evaluation of RNA-seq analysis pipelines in diploid and polyploid species. AB - Background: The usual analysis of RNA sequencing (RNA-seq) reads is based on an existing reference genome and annotated gene models. However, when a reference for the sequenced species is not available, alternatives include using a reference genome from a related species or reconstructing transcript sequences with de novo assembly. In addition, researchers are faced with many options for RNA-seq data processing and limited information on how their decisions will impact the final outcome. Using both a diploid and polyploid species with a distant reference genome, we have tested the influence of different tools at various steps of a typical RNA-seq analysis workflow on the recovery of useful processed data available for downstream analysis. Findings: At the preprocessing step, we found error correction has a strong influence on de novo assembly but not on mapping results. After trimming, a greater percentage of reads could be used in downstream analysis by selecting gentle quality trimming performed with Skewer instead of strict quality trimming with Trimmomatic. This availability of reads correlated with size, quality, and completeness of de novo assemblies and with number of mapped reads. When selecting a reference genome from a related species to map reads, outcome was significantly improved when using mapping software tolerant of greater sequence divergence, such as Stampy or GSNAP. Conclusions: The selection of bioinformatic software tools for RNA-seq data analysis can maximize quality parameters on de novo assemblies and availability of reads in downstream analysis. PMID- 30418580 TI - Homology modeling and in vivo functional characterization of the zinc permeation pathway in a heavy metal P-type ATPase. AB - The P1B ATPase heavy metal ATPase 4 (HMA4) is responsible for zinc and cadmium translocation from roots to shoots in Arabidopsis thaliana. It couples ATP hydrolysis to cytosolic domain movements, enabling metal transport across the membrane. The detailed mechanism of metal permeation by HMA4 through the membrane remains elusive. Here, homology modeling of the HMA4 transmembrane region was conducted based on the crystal structure of a ZntA bacterial homolog. The analysis highlighted amino acids forming a metal permeation pathway, whose importance was subsequently investigated functionally through mutagenesis and complementation experiments in plants. Although the zinc pathway displayed overall conservation among the two proteins, significant differences were observed, especially in the entrance area with altered electronegativity and the presence of a ionic interaction/hydrogen bond network. The analysis also newly identified amino acids whose mutation results in total or partial loss of the protein function. In addition, comparison of zinc and cadmium accumulation in shoots of A. thaliana complemented lines revealed a number of HMA4 mutants exhibiting different abilities in zinc and cadmium translocation. These observations could be instrumental to design low cadmium-accumulating crops, hence decreasing human cadmium exposure. PMID- 30418581 TI - HuR biological function involves RRM3-mediated dimerization and RNA binding by all three RRMs. AB - HuR/ELAVL1 is an RNA-binding protein involved in differentiation and stress response that acts primarily by stabilizing messenger RNA (mRNA) targets. HuR comprises three RNA recognition motifs (RRMs) where the structure and RNA binding of RRM3 and of full-length HuR remain poorly understood. Here, we report crystal structures of RRM3 free and bound to cognate RNAs. Our structural, NMR and biochemical data show that RRM3 mediates canonical RNA interactions and reveal molecular details of a dimerization interface localized on the alpha-helical face of RRM3. NMR and SAXS analyses indicate that the three RRMs in full-length HuR are flexibly connected in the absence of RNA, while they adopt a more compact arrangement when bound to RNA. Based on these data and crystal structures of tandem RRM1,2-RNA and our RRM3-RNA complexes, we present a structural model of RNA recognition involving all three RRM domains of full-length HuR. Mutational analysis demonstrates that RRM3 dimerization and RNA binding is required for functional activity of full-length HuR in vitro and to regulate target mRNAs levels in human cells, thus providing a fine-tuning for HuR activity in vivo. PMID- 30418582 TI - Tethered imidazole mediated duplex stabilization and its potential for aptamer stabilization. AB - Previous investigations of the impact of an imidazole-tethered thymidine in synthetic DNA duplexes, monitored using UV and NMR spectroscopy, revealed a base context dependent increase in thermal stability of these duplexes and a striking correlation with the imidazolium pKa. Unrestrained molecular dynamics (MD) simulations demonstrated the existence of a hydrogen bond between the imidazolium and the Hoogsteen side of a nearby guanosine which, together with electrostatic interactions, form the basis of the so-called pKa-motif responsible for these duplex-stabilizing and pKa-modulating properties. Here, the robustness and utility of this pKa-motif was explored by introducing multiple imidazole-tethered thymidines at different positions on the same dsDNA duplex. For all constructs, sequence based expectations as to pKa-motif formation were supported by MD simulations and experimentally validated using NOESY. Based on the analysis of the pKa values and melting temperatures, guidelines are formulated to assist in the rational design of oligonucleotides modified with imidazolium-tethered thymidines for increased thermal stability that should be generally applicable, as demonstrated through a triply modified construct. In addition, a proof-of principle study demonstrating enhanced stability of the l-argininamide binding aptamer modified with an imidazole-tethered thymidine in the presence and absence of ligand, demonstrates its potential for the design of more stable aptamers. PMID- 30418583 TI - Association Between Triglyceride Level and Glycemic Control Among Insulin-treated Patients With Type 2 Diabetes. AB - Context: Elevated blood triglyceride levels are known to increase the risk of diabetes and prediabetes. However, it is still unclear whether elevated triglyceride levels are associated with inadequate glycemic control in type 2 diabetic patients. Objective: To investigate the association between elevated triglyceride levels and inadequate glycemic control among insulin-treated patients with type 2 diabetes. Design, Setting, and Patients: We recruited 20,108 type 2 diabetic patients who were treated with a sufficient dose of insulin. These patients were from the 2013 China National HbA1c Surveillance System study, which was a multi-center study conducted in Mainland China. Multivariate logistic regressions were used to assess the association of the triglyceride level with the inadequate glycemic control. Results: Overall, 56.0% of the included study subjects had elevated triglyceride levels (>=1.70mmol/L), and prevalence of HbA1c >=7.0% (53 mmol/mol) and >=6.5% (48 mmol/mol) was 67.2% and 83.4%, respectively. The adjusted odds ratios of HbA1c >=7.0% were 1.06 (0.98-1.15), 1.35 (1.23-1.48) and 3.12 (2.76-3.53), respectively, for those with triglyceride levels in ranges of 1.70-2.29, 2.30-3.39 and >=3.40 mmol/L compared to those with triglyceride levels of <1.70 mmol/L. There was a similar association between triglyceride levels and HbA1c >=6.5%. This positive association was confirmed by subgroup analyses among different subpopulations. There was also a strong nonlinear dose response relationship between the triglyceride level and inadequate glycemic control. Conclusions: Elevated triglyceride levels were strongly associated with inadequate glycemic control, thus suppressing triglyceride levels might benefit in attaining a more optimal glycemic control in type 2 diabetic patients. PMID- 30418584 TI - Circulating irisin levels in children with growth hormone (GH) deficiency before and after 1 year of GH treatment. AB - PURPOSE: To evaluate circulating irisin levels in children with growth hormone deficiency (GHD) and any relation with clinical and metabolic parameters. PATIENTS: Fifty-four prepubertal children (mean age 7.4 +/- 0.8 years) with idiopathic GHD treated with GH for at least 12 months and 31 healthy short children as controls. METHODS: Body height, body mass index (BMI), waist circumference (WC), insulin-like growth factor (IGF)-I, HbA1c, lipid profile, fasting and after-OGTT glucose and insulin, insulin sensitivity indices and irisin levels were evaluated at baseline and after 12 months of growth hormone replacement (GHR). RESULTS: At baseline, GHD children, in addition to having lower growth velocity (p<0.001), GH peak after stimulation tests (both p<0.001) and IGF-I (p<0.001), showed significantly lower irisin (p<0.001) and higher BMI (p<0.001) and WC (p=0.001), without any difference in metabolic parameters, than controls. After GHR, GHD children showed a significant increase in height (p<0.001), growth velocity (p<0.001), IGF-I (p<0.001), fasting glucose (p=0.002) and insulin (p<0.001), HOMA-IR (p<0.001) and irisin (p=0.005), with a concomitant decrease in BMI (p=0.001) and WC (p=0.003). In multivariate analysis, the independent variables significantly associated with irisin were BMI (p=0.002) and GH peak (p=0.037) at baseline, and BMI (p=0.005), WC (p=0.018) and IGF-I (p<0.001) during GHR. CONCLUSIONS: We report for the first time that GHR leads to an increase in irisin levels, strongly related to a decrease in BMI and WC, and an increase in IGF-I, changes which are among the main goals of GHR. These data confirm the favorable effects of GHR in children. PMID- 30418585 TI - Applying Machine Vision Techniques to Neuroimaging. PMID- 30418587 TI - Peristent Dyslipidemia in Hypothyroid Patients: a Good Marker For Personalized Replacement Therapy? PMID- 30418588 TI - Individual and household influences on food security and dietary diversity in seven Dominican batey communities. AB - Background: To identify individual and household characteristics associated with food security and dietary diversity in seven Haitian-Dominican bateyes. Methods: A cross-sectional sample of 667 households were surveyed. Novel household food security scores were calculated from components of the Household Food Insecurity Assessment Scale, while the Food and Agricultural Organization's Household Dietary Diversity Score was utilized to calculate individual dietary diversity scores. Multivariable analyses were performed using ordinal logistic regression models to estimate the association between these scores and the covariate variables. Secondary dietary diversity analyses were performed after removing non nutritious food groups. Results: Food security was significantly associated with being above the poverty line (OR 3.14, 95% CI 1.92 to 5.14), living in a rural batey (OR 1.44, 95% CI 1.02 to 2.03), receiving gifts and/or donations (OR 1.76, 95% CI 1.03 to 3.00) and having a salaried job (i.e., not being paid hourly; OR 1.67, 95% CI 1.05 to 2.64). Dietary diversity was significantly associated with living in a semi-urban batey (OR 1.70, 95% CI 1.26 to 2.30), living with a partner (OR 1.47, 95% CI 1.08 to 2.00), growing at least some of one's own food (OR 1.62, 95% CI 1.17 to 2.23), and receiving gifts and/or donations (OR 1.72, 95% CI 1.08 to 2.73). Conclusions: Food insecurity and low dietary diversity are highly prevalent in Haitian-Dominican bateyes. The inclusion of sweets and non milk beverages in dietary diversity calculations appear to skew scores towards higher levels of diversity, despite limited nutritional gains. PMID- 30418586 TI - How right hemisphere damage after stroke can impair speech comprehension. AB - Acquired language disorders after stroke are strongly associated with left hemisphere damage. When language difficulties are observed in the context of right hemisphere strokes, patients are usually considered to have atypical functional anatomy. By systematically integrating behavioural and lesion data from brain damaged patients with functional MRI data from neurologically normal participants, we investigated when and why right hemisphere strokes cause language disorders. Experiment 1 studied right-handed patients with unilateral strokes that damaged the right (n = 109) or left (n = 369) hemispheres. The most frequently impaired language task was: auditory sentence-to-picture matching after right hemisphere strokes; and spoken picture description after left hemisphere strokes. For those with auditory sentence-to-picture matching impairments after right hemisphere strokes, the majority (n = 9) had normal performance on tests of perceptual (visual or auditory) and linguistic (semantic, phonological or syntactic) processing. Experiment 2 found that these nine patients had significantly more damage to dorsal parts of the superior longitudinal fasciculus and the right inferior frontal sulcus compared to 75 other patients who also had right hemisphere strokes but were not impaired on the auditory sentence-to-picture matching task. Damage to these right hemisphere regions caused long-term speech comprehension difficulties in 67% of patients. Experiments 3 and 4 used functional MRI in two groups of 25 neurologically normal individuals to show that within the regions identified by Experiment 2, the right inferior frontal sulcus was normally activated by (i) auditory sentence-to picture matching; and (ii) one-back matching when the demands on linguistic and non-linguistic working memory were high. Together, these experiments demonstrate that the right inferior frontal cortex contributes to linguistic and non linguistic working memory capacity (executive function) that is needed for normal speech comprehension. Our results link previously unrelated literatures on the role of the right inferior frontal cortex in executive processing and the role of executive processing in sentence comprehension; which in turn helps to explain why right inferior frontal activity has previously been reported to increase during recovery of language function after left hemisphere stroke. The clinical relevance of our findings is that the detrimental effect of right hemisphere strokes on language is (i) much greater than expected; (ii) frequently observed after damage to the right inferior frontal sulcus; (iii) task dependent; (iv) different to the type of impairments observed after left hemisphere strokes; and (v) can result in long-lasting deficits that are (vi) not the consequence of atypical language lateralization. PMID- 30418589 TI - Social-Emotional Interventions with Children and Youth Who are Deaf or Hard of Hearing: A Research Synthesis. AB - To be successful in school and life individuals need to learn to understand and manage their emotions, get along with others and exercise good judgment. Children and youth who are deaf or hard of hearing have long been considered a population at risk for not developing age-appropriate social-emotional skills. The purpose of this study was to identify, review, and summarize the intervention research addressing social and emotional learning with children and youth who are deaf or hard of hearing. We examined the research published in professional peer-reviewed journals between the years 1996 and 2017. Eight hundred and nineteen articles on the topic were reviewed. A total of 11 intervention studies were identified. A summary of each study as well as recommendations for future research are provided. PMID- 30418590 TI - BREX system of Escherichia coli distinguishes self from non-self by methylation of a specific DNA site. AB - Prokaryotes evolved numerous systems that defend against predation by bacteriophages. In addition to well-known restriction-modification and CRISPR-Cas immunity systems, many poorly characterized systems exist. One class of such systems, named BREX, consists of a putative phosphatase, a methyltransferase and four other proteins. A Bacillus cereus BREX system provides resistance to several unrelated phages and leads to modification of specific motif in host DNA. Here, we study the action of BREX system from a natural Escherichia coli isolate. We show that while it makes cells resistant to phage lambda infection, induction of lambda prophage from cells carrying BREX leads to production of viruses that overcome the defense. The induced phage DNA contains a methylated adenine residue in a specific motif. The same modification is found in the genome of BREX carrying cells. The results establish, for the first time, that immunity to BREX system defense is provided by an epigenetic modification. PMID- 30418591 TI - HumanNet v2: human gene networks for disease research. AB - Human gene networks have proven useful in many aspects of disease research, with numerous network-based strategies developed for generating hypotheses about gene disease-drug associations. The ability to predict and organize genes most relevant to a specific disease has proven especially important. We previously developed a human functional gene network, HumanNet, by integrating diverse types of omics data using Bayesian statistics framework and demonstrated its ability to retrieve disease genes. Here, we present HumanNet v2 (http://www.inetbio.org/humannet), a database of human gene networks, which was updated by incorporating new data types, extending data sources and improving network inference algorithms. HumanNet now comprises a hierarchy of human gene networks, allowing for more flexible incorporation of network information into studies. HumanNet performs well in ranking disease-linked gene sets with minimal literature-dependent biases. We observe that incorporating model organisms' protein-protein interactions does not markedly improve disease gene predictions, suggesting that many of the disease gene associations are now captured directly in human-derived datasets. With an improved interactive user interface for disease network analysis, we expect HumanNet will be a useful resource for network medicine. PMID- 30418592 TI - Comprehensive Approach to Diagnosis and Treatment of Newly Diagnosed Primary CNS Lymphoma. AB - Primary central nervous system (CNS) lymphoma (PCNSL) is a rare form of non Hodgkin lymphoma that affects the brain parenchyma, spinal cord, eyes, and cerebrospinal fluid without evidence of systemic, non-CNS involvement. PCNSL is uncommon and only a few randomized trials have been completed in the first-line setting. Over the past decades, the prognosis of PCNSL has improved mainly due to the introduction and wide-spread use of high-dose methotrexate, which is now the backbone of all first-line treatment polychemotherapy regimens. Despite this progress, durable remission is recorded in only 50% of patients, and therapy can be associated with significant late neurotoxicity. Here, we overview the epidemiology, clinical presentation, staging evaluation, prognosis and current up to-date treatment of immunocompetent PCNSL patients. PMID- 30418593 TI - Comparative efficacy of artemether-lumefantrine and dihydroartemisinin piperaquine for the treatment of uncomplicated malaria in Ugandan children. AB - Background: In Uganda, artemether-lumefantrine (AL) and dihydroartemisinin piperaquine (DHA-PQ) showed excellent treatment efficacy for uncomplicated malaria in prior trials. As resistance to artemisinins and piperaquine is increasing in southeast Asia, and as prevalence of Plasmodium falciparum polymorphisms associated with resistance has changed, we reassessed treatment efficacies at 3 sites in Uganda. Methods: For this randomized, single blinded clinical trial, children aged 6-59 months with uncomplicated falciparum malaria were assigned treatment with AL or DHA-PQ and followed for 42 days. Primary endpoints were risks of recurrent parasitemia, either unadjusted or adjusted to distinguish recrudescence from new infection. We assessed selection by study regimens of relevant P. falciparum genetic polymorphisms associated with drug resistance. Results: Of 599 patients enrolled, 578 completed follow-up. There were no early treatment failures. The risk of recurrent parasitemia was lower with DHA-PQ compared to AL at all 3 sites at 42 days (26.0% vs 47.0%, p<0.001). Recrudescent infections were uncommon in both the DHA-PQ and AL arms (1.1% vs 2.2%, p=0.25). Neither regimen selected for pfcrt or pfmdr1 polymorphisms associated with drug resistance. Conclusions: AL and DHA-PQ remain effective for the treatment of malaria in Uganda. Neither regimen selected for genetic polymorphisms associated with drug resistance. PMID- 30418594 TI - Bacterial superantigens expand and activate, rather than delete or incapacitate, preexisting antigen-specific memory CD8+ T cells. AB - Superantigens (SAgs) released by common Gram-positive bacterial pathogens have been reported to delete, anergize or activate mouse T cells. However, little is known about their effects on preexisting memory CD8 + T cell (TCD8) pools. Furthermore, whether SAgs manipulate human memory TCD8 responses to cognate antigens is unknown. We employed a human peripheral blood mononuclear cell culture system and a non-transgenic mouse model in which the impact of stimulation by two fundamentally distinct SAgs, staphylococcal enterotoxin B and Mycoplasma arthritidis mitogen, on influenza- and/or cytomegalovirus-specific memory TCD8 could be monitored. Bacterial SAgs surprisingly expanded antiviral memory TCD8 generated naturally through infection or artificially through vaccination. Mechanistically, this was a T cell-intrinsic and TCR Vbeta-dependent phenomenon. Importantly, SAg-expanded TCD8 displayed an effector memory phenotype and were capable of producing interferon-gamma and destroying target cells ex vivo or in vivo. These findings have clear implications for antimicrobial defense and rational vaccine design. PMID- 30418595 TI - Novel methods to diagnose leptomeningeal metastases in breast cancer. AB - Leptomeningeal metastases (LM) in breast cancer patients are rare but often accompanied by devastating neurological symptoms and carries a very poor prognosis, even if treated. To date, two diagnostic methods are clinically used to diagnose LM: gadolinium MRI of the brain and/or spinal cord and cytological examination of cerebrospinal fluid (CSF). Both techniques are however hampered by limited sensitivities, often leading to a long diagnostic process requiring repeated lumbar punctures and MRI examinations. To improve the detection rate of LM, numerous studies have assessed new techniques. In this review, we present the current diagnostic work-up to diagnose LM, set out an overview of novel techniques to diagnose LM and give recommendations for future research. PMID- 30418597 TI - Oral Susceptibility of Japanese Culicoides (Diptera: Ceratopogonidae) Species to Akabane Virus. AB - To test their virus susceptibility and capacity as transmission vectors, Japanese Culicoides species were artificially fed a mixture of Akabane virus (AKAV) and bovine blood, and virus recovery was attempted from infected midges 9-11 d post exposure. Culicoides tainanus, C. punctatus, C. humeralis, C. jacobsoni, C. oxystoma, and C. asiana were found to be orally susceptible to AKAV. Virus titers in single infected midges of C. tainanus, C. oxystoma, C. punctatus, and C. jacobsoni ranged from 100.75 to 104.0 TCID50 (tissue culture infectious dose). The titers in the infected C. oxystoma were significantly higher than those in the other infected species. Viral RNA was detected from both midges testing positive and those testing negative for infectious virus particles, but the viral RNA copies in the infectious virus-negative midges were significantly lower than those in the infectious virus-positive midges. Lower viral amplification, limited dissemination or both caused by tissue barriers might occur in infected midges from which infectious viruses were undetectable. A fully disseminated infection was developed in orally infected C. oxystoma and C. tainanus. This finding indicates their capacity to transmit AKAV, assuming that salivary gland barriers have limited effects on viral entry to and replication in salivary gland tissue. This result also suggests that the other orally susceptible species are potentially competent for AKAV transmission and would be considered active vectors of its spread. PMID- 30418596 TI - Lessons Learned Over More than 500 Stroke Thrombectomies Using ADAPT With Increasing Aspiration Catheter Size. AB - BACKGROUND: Endovascular thrombectomy is currently the standard of care for acute ischemic stroke (AIS). Although earlier trials on endovascular thrombectomy were performed using stent retrievers, recently completed the contact aspiration vs stent retriever for successful revascularization (ASTER) and a comparison of direct aspiration versus stent retriever as a first approach (COMPASS) trials have shown the noninferiority of direct aspiration. OBJECTIVE: To report the largest experience with ADAPT thrombectomy and compare the impact of advancement in reperfusion catheter technologies on outcomes. METHODS: We reviewed a retrospective database of AIS patients who underwent ADAPT thrombectomy between January 2013 and November 2017 at the Medical University of South Carolina. Demographics and baseline characteristics, technical variables, and radiological and clinical outcomes were reviewed. RESULTS: Among 510 patients (mean age: 67.7, 50.6% females), successful recanalization at first pass was achieved in 61.8%, and with aspiration only in 77.5%. Mean procedure time was 27.4 min, and the rate of good outcomes (mRS 0-2) at 90 d was 42.9%. The rate of recanalization with aspiration only was significantly higher, and procedure time was significantly lower in patients treated with larger catheters (ACE 064 and ACE 068) compared to smaller catheters (5 MAX and ACE, P < .05). There were no differences in complication rates or postoperative parenchymal hemorrhage across groups (P > .05); however, use of ACE 068 was an independent predictor of good outcomes at 90 d on multivariate regression analysis (odds ratio = 1.6, P < .05). CONCLUSION: Refinement of ADAPT thrombectomy by incorporating reperfusion catheters with higher inner diameters and thus higher aspiration forces is associated with better outcomes, shorter procedure times, and lower likelihood of using additional devices without impacting complication rates. PMID- 30418598 TI - Evaluating for human herpesvirus 6 in the liver explants of children with liver failure of unknown etiology. AB - Background: Liver failure of unknown etiology (LFUE) has a transplant-free survival rate of less than 25%. Human herpesvirus 6 (HHV-6) may be associated with LFUE, but existing studies are limited by small sample size. Methods: We identified all children who underwent liver transplant for LFUE at a single quaternary children's hospital. 51/65 cases were able to be age-matched with controls (children who underwent liver transplant for metabolic liver disease). Quantitative polymerase chain reaction (PCR) for HHV-6 was performed on DNA from formalin-fixed paraffin-embedded liver explant tissue. Results: HHV-6 was detected in 34/51 cases (66.7%), and 19/51 controls (37.3%) (p=0.005). Average HHV-6 viral load was 213,207 copies/10 6 cells in positive cases (range: 7,293 1,102,030), and 38,115 copies/10 6 cells in positive controls (range: 1,382 122,375) (p=0.0008). HHV-6 was present significantly more often in cases compared to controls in patients less than 6 years in age; in particular, in patients less than 3 years in age, HHV-6 was present in 13/27 cases (48.1%), and 2/27 controls (7.4%) (p=0.0009). Conclusions: HHV-6 was detected in liver explants significantly more often and in higher quantities in children transplanted for LFUE compared to controls. This suggests HHV-6 should be evaluated for in young children who present with LFUE. PMID- 30418599 TI - Reduced Forced Vital Capacity among HIV-infected middle-aged individuals. AB - Introduction: Pulmonary function impairments are more common among people living with HIV (PWH), as are contributing risk behaviors. To understand the effects of HIV infection independent of risk behaviors, pulmonary function was evaluated in lifestyle comparable HIV-positive and -negative AGEhIV-cohort participants. Methods: Prevalence of obstructive lung disease in 544 HIV-positive and 529 HIV negative participants was determined using spirometry. Logistic regression was used to assess HIV as a determinant of obstructive lung disease. Additional explanatory models were constructed to explain observed differences. Results: The unadjusted obstructive lung disease prevalence was similar in HIV-positive (23.0%) and -negative (23.4%) participants. Multivariable logistic regression analysis showed an effect modification whereby obstructive lung disease prevalence among persons with limited smoking experience was notably lower among HIV-positive compared to HIV-negative participants. This resulted from a lower Forced Vital Capacity (FVC) in HIV-positive participants, but similar 1-second Forced Expiratory Volume (FEV1), especially in those with limited smoking experience. Discussion: The lower FVC in HIV-positive participants could indicate HIV-related restrictive or fibrotic pulmonary changes. Factors that decrease the FVC could obscure emphysematous changes in the lungs of PWH when using the FEV1/FVC ratio as single diagnostic measure. PMID- 30418600 TI - Long-Term Outcomes of Endovascular Treatment of Indirect Carotid Cavernous Fistulae: Superior Efficacy, Safety, and Durability of Transvenous Coiling Over Other Techniques. AB - BACKGROUND: Endovascular surgery is the first-line treatment for indirect cavernous carotid fistulae (CCFs). This study compares multiple treatment techniques. OBJECTIVE: To compare endovascular techniques for indirect CCF treatment. METHODS: Retrospective analysis was performed of prospectively maintained records at 4 centers, identifying patients undergoing indirect CCF embolization. Demographics, symptoms, and lesion characteristics were recorded. Medical records were reviewed for changes in symptoms, delayed complications, and angiographically proven recurrence. Univariate and multivariate analyses were performed to identify impacts of the above characteristics on outcomes. RESULTS: Sufficient records were available for 267 patients treated between January 1987 and December 2016. Obliteration was achieved in 86.5% patients, occurring in 86.9% of exclusively transvenous treatments and 79.5% of other treatments. Obliteration rates were highest following transvenous embolization using coils compared to all other materials (likelihood ratio [LR] 5.0, P = .024). Complications were less common with coil embolization compared to other materials (LR 0.070, P < .001). Embolization with liquid embolics resulted in higher complication rates (LR 10.2, P = .002), although risk was reduced when used in conjunction with coils. Angiographically confirmed recurrence was more common following embolization with polyvinyl alcohol (LR 9.9, P = .004) and when multiple embolic agents were used (LR 6.6, P = .018). Delayed development of symptoms following embolization was less common following embolization with coils (LR 0.20, P = .030) and more common following embolization with liquids (LR 6.5, P = .014). CONCLUSION: To treat indirect CCFs, transvenous coil embolization is the safest and most effective technique. Liquid embolics are less effective and have more complications and should be carefully considered only in extenuating circumstances. PMID- 30418601 TI - Electropenetrography Monitoring of the Neotropical Brown-Stink Bug (Hemiptera: Pentatomidae) on Soybean Pods: An Electrical Penetration Graph-Histology Analysis. AB - The Neotropical brown-stink bug Euschistus heros (F.) (Hemiptera: Pentatomidae) is the most important pest damaging soybean in the Neotropics, the world largest production area. The alternating current-direct current (AC-DC) electropenetrography (EPG) technology was used to develop an EPG waveform library of adult females feeding on soybean (Glycine max (L.) Merr.) pods at different input resistor (Ri) levels. Thirteen waveform types/subtypes were identified and described. They were divided into non-probing (Z, Np, Dw1, and Dw2), and probing waveforms (Eh1, Eh2, Eh3, Eh4, and Eh5). Probing waveforms were grouped into three phases: 1) pathway (Eh1a, Eh1b, Eh1c, and Eh1w), 2) ingestion (Eh2, Eh3a, Eh3b, and Eh4), and 3) interruption (Eh5). Correlations between waveforms Eh1b, Eh1c, Eh2, Eh3, and Eh4 and stylets tip position and/or salivary sheath in the pod tissue were determined via histological studies. Non-probing waveforms, Z and Np were visually associated with the bug resting and walking on pod surface, respectively. Waveform Dw1 was correlated with egestion, and the ingestion of fluids (droplets) was proposed for Dw2. Eh1a and Eh1b corresponded to initial and deep stylet penetration through pod tissue, and secretion of a salivary sheath. In Eh1c, stylets penetrated the rigid cell layer of sclerenchyma, and during Eh1w they were withdrawn. Eh2 represents sustained xylem sap ingestion. Eh3a corresponded to lacerate and macerate cell rupture feeding behavior in seed endosperm, whereas Eh3b corresponded to ingestion of cellular contents. Eh4 represented short ingestion from an unknown site, and Eh5 represented short interruptions during xylem sap ingestion. PMID- 30418602 TI - Commentary: Radiological Characteristics and Natural History of Adult IDH Wild Type Astrocytomas With TERT Promoter Mutations. PMID- 30418603 TI - Left Transsylvian-Transinsular Approach for Radiation-Induced Cavernous Malformation: 3-Dimensional Operative Video. AB - De novo cavernous malformation (CM) formation after radiation therapy for brain tumors is well known, but CM formation adjacent to a radiosurgically treated arteriovenous malformation (AVM) is rare.1 This video demonstrates the microsurgical resection of a de novo CM adjacent to a previously treated high grade AVM and clipping of a middle cerebral artery (MCA) aneurysm. A 70-yr-old male with history of radiosurgery for AVM presented with aphasia and confusion. Preoperative angiography showed complete occlusion of the AVM. MRI showed multiple cystic lesions suspicious for radiation-induced necrosis and CM.IRB approval and patient consent was obtained. A pterional craniotomy was performed with transsylvian exposure of the insula. The radiated feeding arteries were followed to the occluded AVM nidus. A CM was noted deep to this candelabra of the MCA vessels, which were mobilized to access and resect the CM. A small incision was made in this insular cortex underneath the malformation circumferentially freeing it of adhesions. The sclerotic AVM nidus was circumferentially dissected and removed en bloc. Thorough exploration of the resection cavity revealed no residual CM or AVM nidus. Attention was then turned to the M2-MCA bifurcation aneurysm, which was occluded with a straight clip. Postoperative imaging confirmed complete CM resection. The patient recovered from his aphasia.This case demonstrates the management of a radiation-induced de novo CM following treatment of a high-grade AVM. Radiographic follow-up for radiosurgically treated AVM is needed to rule out long-term complications. Bleeding from a de novo CM mimics bleeding from residual AVM nidus, requiring careful angiographic evaluation. PMID- 30418604 TI - Viral Load Dynamics and Clinical Disease Severity in Infants with Respiratory Syncytial Virus Infection. AB - INTRODUCTION: The association between RSV loads (VL) and clinical outcomes in children remains to be defined. In most studies VL were evaluated in hospitalized children and at a single time-point. We investigated the relationship between VLs and disease severity in both outpatients and inpatients with RSV infection. METHODS: We enrolled previously healthy children with RSV infection. Disease severity was defined by level of care (outpatients vs ward vs PICU), and a clinical disease severity score (CDSS). Nasopharyngeal VL by PCR and CDSSs were measured at enrollment and daily in inpatients. VL decay according to disease severity was analyzed using linear mixed modeling. RESULTS: From 2/2015 to 3/2017 we enrolled 150 infants: 39 outpatients and 111 inpatients. VLs were higher in outpatients vs age-matched inpatients. Among inpatients initial VLs were comparable in ward and PICU patients, and preceded the peak CDSS. However, after excluding infants treated with steroids, those hospitalized in the ward had higher VLs than infants requiring PICU care (p<0.001). Dynamic analyses showed that VL decay was delayed in PICU patients, especially in those treated with steroids. CONCLUSIONS: Higher VLs at presentation, and a faster and consistent VL decline were both associated with less severe RSV disease in children. PMID- 30418605 TI - Alu insertion variants alter mRNA splicing. AB - RNA splicing is a highly regulated process dependent on sequences near splice sites. Insertions of Alu retrotransposons can disrupt splice sites or bind splicing regulators. We hypothesized that some common inherited polymorphic Alu insertions are responsible for splicing QTLs (sQTL). We focused on intronic Alu variants mapping within 100 bp of an alternatively used exon and screened for those that alter splicing. We identify five loci, 21.7% of those assayed, where the polymorphic Alu alters splicing. While in most cases the Alu promotes exon skipping, at one locus the Alu increases exon inclusion. Of particular interest is an Alu polymorphism in the CD58 gene. Reduced CD58 expression is associated with risk for developing multiple sclerosis. We show that the Alu insertion promotes skipping of CD58 exon 3 and results in a frameshifted transcript, indicating that the Alu may be the causative variant for increased MS risk at this locus. Using RT-PCR analysis at the endogenous locus, we confirm that the Alu variant is a sQTL for CD58. In summary, altered splicing efficiency is a common functional consequence of Alu polymorphisms including at least one instance where the variant is implicated in disease risk. This work broadens our understanding of splicing regulatory sequences around exons. PMID- 30418606 TI - Middle Meningeal Artery Embolization for Chronic Subdural Hematoma: A Series of 60 Cases. AB - BACKGROUND: Chronic subdural hematoma (SDH) is a particularly challenging pathology due to high recurrence rates (2%-37%) and complex medical comorbidities that tend to afflict the patient population. Recently, there have been several case series published describing the use of middle meningeal artery (MMA) embolization as an alternative to surgery for treatment of new or recurrent chronic SDH. OBJECTIVE: To describe our first 60 cases of MMA embolization for chronic SDH. METHODS: MMA embolization was performed using angiography, selective microcatheterization of the MMA, and infusion of polyvinyl alcohol particles. Outcomes were assessed clinically and with interval imaging studies at 1 d, 2 wk, and 6 wk postprocedure, and additional intervals as indicated. RESULTS: MMA embolization was performed successfully on 60 total SDHs in 49 patients. This includes upfront treatment for new (not previously treated) SDH in 42, for recurrence in 8, and prophylaxis (soon after surgical evacuation) in 10. There were 3 mortalities (unrelated to the procedure), and no procedural complications. Of the 50 nonprophylactic cases, there were 4 (8.9%) cases of recurrence requiring surgical evacuation, and 31 (68.9%) that had resolution or reduction in size >50% of SDH at longest follow-up. Overall, 41 (91.1%) were stable or decreased in size and able to avoid surgery. CONCLUSION: MMA embolization may represent a minimally-invasive alternative to surgery for new or recurrent chronic SDH, or as prophylaxis to reduce the risk of recurrence after surgery. Given our encouraging results with a 91% long-term success rate, a large scale clinical trial is warranted. PMID- 30418607 TI - Next-generation sequencing reveals two populations of damage-induced small RNAs at endogenous DNA double-strand breaks. AB - Recent studies suggest that transcription takes place at DNA double-strand breaks (DSBs), that transcripts at DSBs are processed by Drosha and Dicer into damage induced small RNAs (diRNAs), and that diRNAs are required for DNA repair. However, diRNAs have been mostly detected in reporter constructs or repetitive sequences, and their existence at endogenous loci has been questioned by recent reports. Using the homing endonuclease I-PpoI, we have investigated diRNA production in genetically unperturbed human and mouse cells. I-PpoI is an ideal tool to clarify the requirements for diRNA production because it induces DSBs in different types of loci: the repetitive 28S locus, unique genes and intergenic loci. We show by extensive sequencing that the rDNA locus produces substantial levels of diRNAs, whereas unique genic and intergenic loci do not. Further characterization of diRNAs emerging from the 28S locus reveals the existence of two diRNA subtypes. Surprisingly, Drosha and its partner DGCR8 are dispensable for diRNA production and only one diRNAs subtype depends on Dicer processing. Furthermore, we provide evidence that diRNAs are incorporated into Argonaute. Our findings provide direct evidence for diRNA production at endogenous loci in mammalian cells and give insights into RNA processing at DSBs. PMID- 30418608 TI - Wearable and implantable diagnostic monitors in early assessment of atrial tachyarrhythmia burden. AB - Atrial fibrillation (AF) is the cause of substantial direct patient morbidity and a frequent cause of emergency room visits. Even when asymptomatic, AF remains a major cause of stroke, particularly among the elderly. As the risk of both AF and stroke increase with age, the importance of AF-related stroke is growing as a result of demographic shifts in many countries. Oral anticoagulation is highly effective at preventing stroke due to AF; however, AF remains undetected in a large number of individuals. The last decade has witnessed the development of many new technologies to detect AF. Screening studies using single-time point or repeated discrete screening methods have uncovered previously undiagnosed AF in 1 3% of asymptomatic individuals. However, continuous monitoring with implanted devices demonstrates short-lasting AF in over one-third of older individuals with cardiovascular risk factors. Debate remains regarding the minimum burden of AF that is associated with an increase in stroke risk, and the threshold for using oral anticoagulation. Over the next 5 years, ongoing studies will help clarify how wearable and implantable technology can be used to improve outcomes in patients with previously unrecognized AF. PMID- 30418609 TI - In Reply: Tailored Extended Bifrontal Craniotomy for Anterior Skull Base Tumors: Anatomic Description of a Modified Surgical Technique and Case Series. PMID- 30418610 TI - eggNOG 5.0: a hierarchical, functionally and phylogenetically annotated orthology resource based on 5090 organisms and 2502 viruses. AB - eggNOG is a public database of orthology relationships, gene evolutionary histories and functional annotations. Here, we present version 5.0, featuring a major update of the underlying genome sets, which have been expanded to 4445 representative bacteria and 168 archaea derived from 25 038 genomes, as well as 477 eukaryotic organisms and 2502 viral proteomes that were selected for diversity and filtered by genome quality. In total, 4.4M orthologous groups (OGs) distributed across 379 taxonomic levels were computed together with their associated sequence alignments, phylogenies, HMM models and functional descriptors. Precomputed evolutionary analysis provides fine-grained resolution of duplication/speciation events within each OG. Our benchmarks show that, despite doubling the amount of genomes, the quality of orthology assignments and functional annotations (80% coverage) has persisted without significant changes across this update. Finally, we improved eggNOG online services for fast functional annotation and orthology prediction of custom genomics or metagenomics datasets. All precomputed data are publicly available for downloading or via API queries at http://eggnog.embl.de. PMID- 30418611 TI - Characterization of Two Growth Period QTLs Reveals Modification of PRR3 Genes during Soybean Domestication. AB - Soybean yield is largely dependent on growth period. We characterized two growth period quantitative trait loci, Gp11 and Gp12, from a recombinant inbred population generated from a cross of wild (W05) and cultivated (C08) soybean. Lines carrying Gp11C08 and Gp12C08 tend to have shorter growth period and higher expression of GmFT2a and GmFT5a. Furthermore, multiple interval mapping suggests that Gp11 and Gp12 maybe genetically interacting with E2 locus. This is consistent with the observation GmFT2a and GmFT5a are activated by Gp11C08 and Gp12C08 at ZT4 in the recessive e2 but not the dominant E2 background. Gp11 and Gp12 are duplicated genomic regions each containing a copy of the soybean orthologue of PSEUDO RESPONSE REGULATOR 3 (GmPRR3A and GmPRR3B). GmPRR3A and GmPRR3B from C08 carry mutations that delete the CCT domain in the encoded proteins. These mutations were selected during soybean improvement and these mutations alter the subcellular localization of GmPRR3A and GmPRR3B. Furthermore, GmPRR3A and GmPRR3B can interact with TOPLESS-Related transcription factors suggesting that they function in a transcription repressor complex. This study addresses previously unexplored components of the genetic network that probably controls growth period of soybean and puts these loci into context with the well characterized growth period regulating E loci. PMID- 30418612 TI - Breakfast Skipping Is Associated with Increased Risk of Type 2 Diabetes among Adults: A Systematic Review and Meta-Analysis of Prospective Cohort Studies. AB - Background: Epidemiologic studies have indicated that breakfast skipping is associated with risk of type 2 diabetes. However, the shape of the dose-response relation and the influence of adiposity on this association have not been reported. Objective: We investigated the association between breakfast skipping and risk of type 2 diabetes by considering the influence of the body mass index (BMI). Methods: In this systematic review and meta-analysis, PubMed and Web of Science were searched up to August 2017. Prospective cohort studies on breakfast skipping and risk of type 2 diabetes in adults were included. Summary RRs and 95% CIs, without and with adjustment for BMI, were estimated with the use of a random effects model in pairwise and dose-response meta-analyses. Results: In total 6 studies, based on 96,175 participants and 4935 cases, were included. The summary RR for type 2 diabetes comparing ever with never skipping breakfast was 1.33 (95% CI: 1.22, 1.46, n = 6 studies) without adjustment for BMI, and 1.22 (95% CI: 1.12, 1.34, n = 4 studies) after adjustment for BMI. Nonlinear dose-response meta analysis indicated that risk of type 2 diabetes increased with every additional day of breakfast skipping, but the curve reached a plateau at 4-5 d/wk, showing an increased risk of 55% (summary RR: 1.55; 95% CI: 1.41, 1.71). No further increase in risk of type 2 diabetes was observed after 5 d of breakfast skipping/wk (P for nonlinearity = 0.08). Conclusions: This meta-analysis provides evidence that breakfast skipping is associated with an increased risk of type 2 diabetes, and the association is partly mediated by BMI. PMID- 30418613 TI - Exploring the effects of cosolutes and crowding on the volumetric and kinetic profile of the conformational dynamics of a poly dA loop DNA hairpin: a single molecule FRET study. AB - We investigated the volumetric and kinetic profile of the conformational landscape of a poly dA loop DNA hairpin (Hp) in the presence of salts, osmolytes and crowding media, mimicking the intracellular milieu, using single-molecule FRET methodology. Pressure modulation was applied to explore the volumetric and hydrational characteristics of the free-energy landscape of the DNA Hp, but also because pressure is a stress factor many organisms have to cope with, e.g. in the deep sea where pressures even up to the kbar level are encountered. Urea and pressure synergistically destabilize the closed conformation of the DNA Hp due to a lower molar partial volume in the unfolded state. Conversely, multivalent salts, trimethylamine-N-oxide and Ficoll strongly populate the closed state and counteract deteriorating effects of pressure. Complementary smFRET measurements under immobilized conditions at ambient pressure allowed us to dissect the equilibrium data in terms of folding and unfolding rate constants of the conformational transitions, leading to a deeper understanding of the stabilization mechanisms of the cosolutes. Our results show that the free-energy landscape of the DNA Hp is a rugged one, which is markedly affected by the ionic strength of the solution, by preferential interaction and exclusion of cosolvents as well as by pressure. PMID- 30418615 TI - Reduced oxygenation but not fibrosis defined by functional magnetic resonance imaging predicts the long-term progression of chronic kidney disease. AB - Background: Although chronic hypoxia and fibrosis may be a key to the progression of chronic kidney disease (CKD), a noninvasive means of measuring these variables is not yet available. Here, using blood oxygen level-dependent (BOLD) and diffusion-weighted (DW) magnetic resonance imaging (MRI), we assessed changes in renal tissue oxygenation and fibrosis, respectively, and evaluated their correlation with prognosis for renal function. Methods: The study was conducted under a single-center, longitudinal, retrospective observational design. We examined the prognostic significance of T2* values of BOLD-MRI and apparent diffusion coefficient (ADC) values on DW-MRI and other clinical parameters. The rate of decline in estimated glomerular filtration rate (eGFR) was calculated by linear regression analysis using changes in eGFR during the observation period. Results: A total of 91 patients were enrolled, with a mean age of 55.8 +/- 15.6 years. Among patients, 51 (56.0%) were males and 38 (41.8%) had diabetes mellitus. The mean eGFR was 49.2 +/- 28.9 mL/min/1.73 m2 and the mean observation period was 5.13 years. ADC values of DW-MRI but not T2* values of BOLD-MRI were well correlated with eGFR at the initial time point. The mean annual rate of decline in eGFR during the 5-year observation period was -1.92 +/- 3.00 mL/min/1.73 m2. On multiple linear regression analysis, the rate of decline in eGFR was significantly correlated with eGFR at the start point, period average amount of proteinuria and T2* values, but not with ADC values (t = 2.980, P = 0.004). Conclusions: Reduced oxygenation as determined by low T2* values on BOLD MRI is a clinically useful marker of CKD progression. PMID- 30418616 TI - Too much nephrology? The CKD epidemic is real and concerning. A CON view. AB - The prevalence of chronic kidney disease (CKD) clearly depends on its definition, and the definition used most often is the one proposed by the Kidney Disease: Improving Global Outcomes guidelines in 2012: 'CKD is defined as abnormalities of kidney structure or function, present for >3 months, with implications for health.' Abnormality of kidney function is a glomerular filtration rate (GFR) <60 mL/min/1.73 m2, and the most frequently used marker of kidney damage is the presence of albuminuria [albumin excretion rate >30 mg/24 h or albumin/creatinine ratio (ACR) >30 mg/g (or 3 mg/mmol)]. However, two major aspects of this definition could explain why CKD prevalence is, in our view, overstated in most epidemiological studies. First, the fixed threshold at 60 mL/min/1.73 m2 is questionable because normal GFR decreases with age. This and the profound consequence it has on CKD epidemiology will be illustrated. The second aspect of the definition is the criterion of chronicity, which is ignored by the vast majority of epidemiological studies. In other words, confirming CKD (low GFR and/or high ACR) is mandatory. Indeed, a large proportion of subjects with a low first GFR level has a normal GFR level when tested a second time. The prevalence of CKD may hence, in fact, be considerably lower although still neither negligible nor irrelevant. PMID- 30418614 TI - Association of plasma vitamin D metabolites with incident type 2 diabetes: EPIC InterAct case-cohort study. AB - Background: Existing evidence for the prospective association of vitamin D status with type 2 diabetes (T2D) is focused almost exclusively on circulating total 25 hydroxyvitamin D [25(OH)D] without distinction between its subtypes: non-epimeric and epimeric 25(OH)D3 stereoisomers; and 25(OH)D2, the minor component of 25(OH)D. We aimed to investigate the prospective associations of circulating levels of the sum and each of these three metabolites with incident T2D. Methods: This analysis in the EPIC-InterAct case-cohort study for T2D included 9671 incident T2D cases and 13562 subcohort members. Plasma vitamin D metabolites were quantified by liquid-chromatography mass-spectrometry. We used multivariable Prentice-weighted Cox regression to estimate hazard ratios (HRs) of T2D for each metabolite. Analyses were performed separately within country, and estimates combined across countries using random-effects meta-analysis. Results: The mean concentrations (standard deviation) of total 25(OH)D, non-epimeric 25(OH)D3, epimeric 25(OH)D3 and 25(OH)D2 were 41.1 (17.2), 40.7 (17.3), 2.13 (1.31), and 8.16 (6.52) nmol/L, respectively. Plasma total 25(OH)D and non-epimeric 25(OH)D3 were inversely associated with incident T2D [multivariable-adjusted HR per 1 SD=0.81 (95%CI: 0.77, 0.86) for both variables], while epimeric 25(OH)D3 was positively associated: per 1-SD HR=1.16 (1.09, 1.25). There was no statistically significant association with T2D for 25(OH)D2 [per 1-SD HR=0.94 (0.76, 1.18)]. Conclusions: Plasma non-epimeric 25(OH)D3 was inversely associated with incident T2D, consistent with it being the major metabolite contributing to total 25(OH)D. The positive association of the epimeric form of 25(OH)D3 with incident T2D provides novel information to assess the biological relevance of vitamin D epimerization and vitamin D subtypes in diabetes etiology. PMID- 30418617 TI - Burnout, depression and paranoid ideation: a cluster-analytic study. AB - Background: A link between burnout and paranoid ideation has long been suspected. However, systematic research on the association has been scarce. Aims: We investigated the relationship between burnout and paranoid ideation. Because burnout overlaps with depression, depression was also examined. Methods: A total of 218 Swiss schoolteachers participated in the study (58% female; mean age: 47). Burnout symptoms were assessed with the emotional exhaustion (EE) and depersonalization (DP) subscales of the Maslach Burnout Inventory-Educators Survey, depressive symptoms with the PHQ-9 and paranoid ideation with the Green et al. Paranoid Thought Scales. Results: Burnout, depression and their subdimensions showed raw correlations ranging from 0.42 to 0.55 with paranoid ideation. Burnout, depression and paranoid thoughts were found to cluster together. Lower levels of burnout and depression coexisted with lower levels of paranoid ideation and higher levels of burnout and depression coexisted with higher levels of paranoid ideation. When corrected for measurement error, the correlations of EE with depression and DP were 0.96 and 0.57, respectively. A principal component analysis confirmed that EE was indistinguishable from depression. Conclusions: Burnout is substantially associated with paranoid ideation. Interestingly, EE correlated as strongly with paranoid ideation as it correlated with DP. Moreover, if burnout is a syndrome of EE and DP that excludes depression, then the EE-depression correlation should not be close to 1 and EE should not correlate more strongly with depression than with DP. These basic requirements for construct distinctiveness and syndromal unity were not satisfied. PMID- 30418618 TI - 3D organization of chicken genome demonstrates evolutionary conservation of topologically associated domains and highlights unique architecture of erythrocytes' chromatin. AB - How chromosomes are folded, spatially organized and regulated in three dimensions inside the cell nucleus are among the longest standing questions in cell biology. Genome-wide chromosome conformation capture (Hi-C) technique allowed identifying and characterizing spatial chromatin compartments in several mammalian species. Here, we present the first genome-wide analysis of chromatin interactions in chicken embryonic fibroblasts (CEF) and adult erythrocytes. We showed that genome of CEF is partitioned into topologically associated domains (TADs), distributed in accordance with gene density, transcriptional activity and CTCF-binding sites. In contrast to mammals, where all examined somatic cell types display relatively similar spatial organization of genome, chicken erythrocytes strongly differ from fibroblasts, showing pronounced A- and B- compartments, absence of typical TADs and formation of long-range chromatin interactions previously observed on mitotic chromosomes. Comparing mammalian and chicken genome architectures, we provide evidence highlighting evolutionary role of chicken TADs and their significance in genome activity and regulation. PMID- 30418619 TI - Sources of erroneous sequences and artifact chimeric reads in next generation sequencing of genomic DNA from formalin-fixed paraffin-embedded samples. AB - Tissues used in pathology laboratories are typically stored in the form of formalin-fixed, paraffin-embedded (FFPE) samples. One important consideration in repurposing FFPE material for next generation sequencing (NGS) analysis is the sequencing artifacts that can arise from the significant damage to nucleic acids due to treatment with formalin, storage at room temperature and extraction. One such class of artifacts consists of chimeric reads that appear to be derived from non-contiguous portions of the genome. Here, we show that a major proportion of such chimeric reads align to both the 'Watson' and 'Crick' strands of the reference genome. We refer to these as strand-split artifact reads (SSARs). This study provides a conceptual framework for the mechanistic basis of the genesis of SSARs and other chimeric artifacts along with supporting experimental evidence, which have led to approaches to reduce the levels of such artifacts. We demonstrate that one of these approaches, involving S1 nuclease-mediated removal of single-stranded fragments and overhangs, also reduces sequence bias, base error rates, and false positive detection of copy number and single nucleotide variants. Finally, we describe an analytical approach for quantifying SSARs from NGS data. PMID- 30418620 TI - Predictors of risk-reducing surgery intentions following genetic counseling for hereditary breast and ovarian cancer. AB - Risk-reducing mastectomy (RRM) and salpingo-oophorectomy (RRSO) are increasingly used to reduce breast and ovarian cancer risk following BRCA1/BRCA2 testing. However, little is known about how genetic counseling influences decisions about these surgeries. Although previous studies have examined intentions prior to counseling, few have examined RRM and RRSO intentions in the critical window between genetic counseling and test result disclosure. Previous research has indicated that intentions at this time point predict subsequent uptake of surgery, suggesting that much decision-making has taken place prior to result disclosure. This period may be a critical time to better understand the drivers of prophylactic surgery intentions. The aim of this study was to examine predictors of RRM and RRSO intentions. We hypothesized that variables from the Health Belief Model would predict intentions, and we also examined the role of affective factors. Participants were 187 women, age 21-75, who received genetic counseling for hereditary breast and ovarian cancer. We utilized multiple logistic regression to identify independent predictors of intentions. 49.2% and 61.3% of participants reported intentions for RRM and RRSO, respectively. Variables associated with RRM intentions include: newly diagnosed with breast cancer (OR = 3.63, 95% CI = 1.20-11.04), perceived breast cancer risk (OR = 1.46, 95% CI = 1.17-1.81), perceived pros (OR = 1.79, 95% CI = 1.38-2.32) and cons of RRM (OR = 0.81, 95% CI = 0.65-0.996), and decision conflict (OR = 0.80, 95% CI = 0.66-0.98). Variables associated with RRSO intentions include: proband status (OR = 0.28, 95% CI = 0.09-0.89), perceived pros (OR = 1.35, 95% CI = 1.11-1.63) and cons of RRSO (OR = 0.72, 95% CI = 0.59-0.89), and ambiguity aversion (OR = 0.79, 95% CI = 0.65-0.95). These data provide support for the role of genetic counseling in fostering informed decisions about risk management, and suggest that the role of uncertainty should be explored further. PMID- 30418621 TI - Cochlear Implantation and Social-Emotional Functioning of Children with Hearing Loss. AB - This study examined the contribution of cochlear implants (CIs) to the social emotional functioning of children who are deaf or hard of hearing (dhh). Sixty three parents of children who are dhh participated in the study. Thirty children were CI users and 32 used hearing aids (HAs). They completed the Strengths and Difficulties Questionnaire and a background questionnaire. Parents of children with CIs reported lower levels of hyperactivity/inattention and higher levels of pro-social behavior compared to parents of children with HAs. Additionally, older age when hearing loss was detected was related to more pro-social behavior, and age at implantation among CI users was negatively correlated with children's hyperactivity/inattention and conduct problems. These findings add to the existing knowledge about the many benefits of CIs for individuals with hearing loss and emphasize the possible impact of early implantation to children's social emotional functioning. PMID- 30418622 TI - Abdominal Epilepsy Treated With Vagal Nerve Stimulation: A Case Report. AB - BACKGROUND AND IMPORTANCE: Abdominal epilepsy is a rare seizure disorder characterized by episodic gastrointestinal symptoms with electroencephalogram abnormalities. It is typically well treated with anti-epileptic medications; however, little is known about treatment of refractory cases. CLINICAL PRESENTATION: The patient is a 16-yr-old male who began experiencing episodic abdominal pain and distension at the age of 2. After undergoing an extensive negative gastrointestinal workup, he was referred for neurological examination. The patient's examination and brain magnetic resonance imaging were normal, but epileptiform discharges were noted on the electroencephalogram. He initially failed treatment with several anti-epileptic medications but achieved seizure control with lamotrigine for 10 yr. However, his seizure frequency increased at age 15 and vagal nerve stimulation (VNS) was proposed for treatment. He underwent VNS placement surgery and experienced significant seizure reduction. By 22 mo postsurgery, he had experienced 11 total seizures compared to his preoperative seizure frequency of 16 seizures per month. Additionally, the patient's neuropsychological testing postsurgery demonstrated improvements in verbal reasoning and reading comprehension in comparison to presurgical testing. CONCLUSION: VNS has been used to treat intractable, nonfocal epilepsy although the therapeutic mechanism remains poorly understood. This case demonstrates utility of VNS for the treatment of abdominal epilepsy that remains refractory to pharmacotherapy. PMID- 30418623 TI - Podoplanin expression is a prognostic biomarker but may be dispensable for the malignancy of glioblastoma. AB - Background: Treatment options of glioblastoma, the most aggressive primary brain tumor with frequent relapses and high mortality, are still very limited urgently calling for novel therapeutic targets. Expression of the glycoprotein podoplanin correlates with poor prognosis in various cancer entities including glioblastoma. Furthermore, podoplanin has been associated with tumor cell migration and proliferation in vitro; however, experimental data on its function in gliomagenesis in vivo is still missing. Hence, we have functionally investigated the impact of podoplanin on glioblastoma in a preclinical mouse model to evaluate its potential as a therapeutic target. Methods: FACS, genome-wide expression analysis and CRIPSR/Cas9-mediated deletion of podoplanin in patient-derived human glioblastoma cells were combined with organotypic brain slice cultures and intracranial injections into mice. Results: We defined a malignant gene signature in tumor cells with high podoplanin expression. The increase and/or maintenance of high podoplanin expression in serial transplantations and in podoplanin low sorted glioblastoma cells during outgrowth indicated the association of high podoplanin expression and poor outcome. Unexpectedly, similar rates of proliferation, apoptosis, angiogenesis, and invasion were observed in control and podoplanin-deleted tumors. Accordingly, neither tumor growth nor survival was affected upon podoplanin loss. Conclusion: We report that tumor progression occurs independently of podoplanin. Thus, in contrast to previous suggestions, blocking of podoplanin does not represent a promising therapeutic approach. However, as podoplanin is associated with tumor aggressiveness and progression, we propose the cell surface protein as a biomarker for poor prognosis. PMID- 30418624 TI - Stoichiometry of triple-sieve tRNA editing complex ensures fidelity of aminoacyl tRNA formation. AB - Aminoacyl-tRNA synthetases catalyze the attachment of cognate amino acids onto tRNAs. To avoid mistranslation, editing mechanisms evolved to maintain tRNA aminoacylation fidelity. For instance, while rejecting the majority of non cognate amino acids via discrimination in the synthetic active site, prolyl-tRNA synthetase (ProRS) misactivates and mischarges Ala and Cys, which are similar in size to cognate Pro. Ala-tRNAPro is specifically hydrolyzed by the editing domain of ProRS in cis, while YbaK, a free-standing editing domain, clears Cys-tRNAPro in trans. ProXp-ala is another editing domain that clears Ala-tRNAPro in trans. YbaK does not appear to possess tRNA specificity, readily deacylating Cys tRNACysin vitro. We hypothesize that YbaK binds to ProRS to gain specificity for Cys-tRNAPro and avoid deacylation of Cys-tRNACys in the cell. Here, in vivo evidence for ProRS-YbaK interaction was obtained using a split-green fluorescent protein assay. Analytical ultracentrifugation and native mass spectrometry were used to investigate binary and ternary complex formation between ProRS, YbaK, and tRNAPro. Our combined results support the hypothesis that the specificity of YbaK toward Cys-tRNAPro is determined by the formation of a three-component complex with ProRS and tRNAPro and establish the stoichiometry of a 'triple-sieve' editing complex for the first time. PMID- 30418625 TI - Commentary: Double-Barrel Extracranial-Intracranial Bypass and Trapping of Dolichoectatic Middle Cerebral Artery Aneurysms: 3-Dimensional Operative Video. PMID- 30418626 TI - dbPTM in 2019: exploring disease association and cross-talk of post-translational modifications. AB - The dbPTM (http://dbPTM.mbc.nctu.edu.tw/) has been maintained for over 10 years with the aim to provide functional and structural analyses for post-translational modifications (PTMs). In this update, dbPTM not only integrates more experimentally validated PTMs from available databases and through manual curation of literature but also provides PTM-disease associations based on non synonymous single nucleotide polymorphisms (nsSNPs). The high-throughput deep sequencing technology has led to a surge in the data generated through analysis of association between SNPs and diseases, both in terms of growth amount and scope. This update thus integrated disease-associated nsSNPs from dbSNP based on genome-wide association studies. The PTM substrate sites located at a specified distance in terms of the amino acids encoded from nsSNPs were deemed to have an association with the involved diseases. In recent years, increasing evidence for crosstalk between PTMs has been reported. Although mass spectrometry-based proteomics has substantially improved our knowledge about substrate site specificity of single PTMs, the fact that the crosstalk of combinatorial PTMs may act in concert with the regulation of protein function and activity is neglected. Because of the relatively limited information about concurrent frequency and functional relevance of PTM crosstalk, in this update, the PTM sites neighboring other PTM sites in a specified window length were subjected to motif discovery and functional enrichment analysis. This update highlights the current challenges in PTM crosstalk investigation and breaks the bottleneck of how proteomics may contribute to understanding PTM codes, revealing the next level of data complexity and proteomic limitation in prospective PTM research. PMID- 30418627 TI - Commentary: The Experience With Flow Diverters in the Treatment of Posterior Inferior Cerebellar Artery Aneurysms. PMID- 30418628 TI - Tegumentary leishmaniasis and sandflies in a border area between Argentina and Bolivia. AB - Background: Some sand flies are of medical importance because they are vectors of Leishmania parasites that are responsible for leishmaniasis. The aim of this study was to make a retrospective epidemiological analysis of tegumentary leishmaniasis (TL), to identify Leishmania spp. from patient isolates and to describe the diversity of sand flies from a border area between Bolivia and Argentina. Methods: TL cases included in the study were diagnosed in an endemic area of the north of Argentina from 1985 to 2017. The parasites isolated were characterized by the cytochrome B method. Sandflies were captured with Centers for Disease Control traps in Aguas Blancas and Media Luna-Algarrobito localities. Results: A total of 118 cases of TL were analysed. Eight isolates were characterized as Leishmania (Viannia) braziliensis. A total of 1291 sandflies were captured, including Nyssomyia neivai, Cortelezzii complex, Evandromyia sallesi, Migonemyia migonei and Micropygomyia quinquefer. Within the area, sandflies were found in the backyards of houses. Conclusions: In this region there exists the possibility of peridomestic transmission of TL in the neighbourhoods peripheral to the urban area and in rural environments as well as the risk of transmission to travellers that pass through the customs offices. PMID- 30418629 TI - Incisional Seeding of Metastatic Squamous Cell Carcinoma Following Carotid Endarterectomy: An Unusual Case of an Unknown Primary Cancer Presenting as a Presumed Neck Abscess. AB - BACKGROUND: Carotid endarterectomy (CEA) is a safe and effective procedure, with a low risk of complications when performed by experienced surgeons. Postoperative infections are particularly rare, reportedly affecting less than 1% of cases. Incisional metastases have not been described. OBJECTIVE: To describe a previously unreported complication, the incisional seeding of metastatic squamous cell carcinoma (SCC) during neck dissection, which presented and was treated as a presumed postoperative neck abscess. METHODS: Clinical records were reviewed regarding a 73-yr-old female who underwent routine CEA and presented 2 mo postoperatively with neck induration and erythema. Tissue submitted during the initial CEA was reexamined given the updated clinical history. RESULTS: Postoperatively, a complex, multi-cystic fluid collection beneath the incision was identified and percutaneously drained. Although cultures were negative, an infection was favored and antibiotic therapy initiated. The patient's symptoms worsened prompting surgical exploration, and tissue sent for pathological examination was consistent with metastatic SCC. Retrospective analysis of a lymph node excised during the initial dissection also revealed tumor deposits, indicating that the surgical site had been seeded during exposure. A primary origin was not identified. CONCLUSION: The time from initial presentation of postoperative complications to a final diagnosis of metastatic SCC was 2 mo, during which time the patient was treated as having a postoperative infection. Further investigations were consistent with diffuse and incurable metastatic disease. This report highlights the diagnostic challenges and potential avoidance strategies when dealing with rare complications following CEA. PMID- 30418630 TI - Hereditary spherocytosis presenting with branch retinal artery occlusion. PMID- 30418631 TI - IRES-dependent ribosome repositioning directs translation of a +1 overlapping ORF that enhances viral infection. AB - RNA structures can interact with the ribosome to alter translational reading frame maintenance and promote recoding that result in alternative protein products. Here, we show that the internal ribosome entry site (IRES) from the dicistrovirus Cricket paralysis virus drives translation of the 0-frame viral polyprotein and an overlapping +1 open reading frame, called ORFx, via a novel mechanism whereby a subset of ribosomes recruited to the IRES bypasses 37 nucleotides downstream to resume translation at the +1-frame 13th non-AUG codon. A mutant of CrPV containing a stop codon in the +1 frame ORFx sequence, yet synonymous in the 0-frame, is attenuated compared to wild-type virus in a Drosophila infection model, indicating the importance of +1 ORFx expression in promoting viral pathogenesis. This work demonstrates a novel programmed IRES mediated recoding strategy to increase viral coding capacity and impact virus infection, highlighting the diversity of RNA-driven translation initiation mechanisms in eukaryotes. PMID- 30418632 TI - Effects of feed form and particle size, and pellet binder on performance, digestive tract parameters, intestinal morphology, and cecal microflora populations in broilers. AB - This study was conducted to assess the effects of feed form (FF), particle size (PS), and pellet binder (PB) on performance, digestive tract parameters, intestinal morphology, and cecal microflora populations in broiler chicks. Two FF (mash and pellet), two feed PS (fine and coarse), and two levels of PB (0 and 3%) were evaluated in a completely randomized design with a 2 * 2 * 2 factorial arrangement of treatments. A total of 256 one-day-old male Ross 308 chicks were allocated into 8 treatments consisting of 8 replicates (4 birds/cage) with equal weight from 25 to 42 d of age. The results showed a three-way interaction among FF, PS, and PB for growth performance in broilers. The growth performance parameters were significantly improved by feeding the pellet-coarse PS-3% PB diet in comparison to the other treatments (P < 0.05). Birds fed pelleted diets had lower relative weight of the gizzard and pancreas, goblet cell (GC) number of the duodenum, crypt depth (CD) of the jejunum, higher villus height (VH) of the duodenum, and cecal spore-forming bacteria population (P < 0.05). Coarse PS resulted in lower jejunum CD and higher cecal count of lactic acid bacteria (LAB) and spore-forming bacteria (P < 0.05). Adding PB significantly improved pellet durability index (PDI) (P < 0.05). In addition, coarse PS-3% PB diets had higher pellet hardness. Also, adding PB to diets significantly (P < 0.05) decreased cecal spore-forming bacteria population. Pellet-coarse PS-3% PB diets fed broilers had a lower (P < 0.05) cecal Clostridium spp. bacterial population. The main factors had no significant effect (P > 0.05) on cecal Coliform spp. levels. Birds fed pellet-3% PB diets had higher VH:CD ratio both in the duodenum and jejunum, and those fed mash-3% PB diets had significantly (P < 0.05) lower VH in the jejunum than other treatments. Overall, pellet-coarse PS-3% PB diets improved growth performance through the positive changes on intestinal morphology of broilers under short-term conditioning (STC). PMID- 30418633 TI - Human Coronavirus in Hospitalized Children with Respiratory Tract Infections: A Nine-year-long, Population-based Study from Norway. AB - Background: The burden of Human Coronavirus- (HCoV) associated respiratory tract infections (RTIs) in hospitalized children is poorly defined. We studied the occurrence and hospitalization rates of HCoV over nine years. Methods: Children from Sor-Trondelag County, Norway, hospitalized with RTIs and asymptomatic controls, were prospectively enrolled from 2006 to 2015. Nasopharyngeal aspirates were analyzed with semi-quantitative polymerase chain reaction (PCR) tests for HCoV subtypes OC43, 229E, NL63 and HKU1, and 13 other respiratory pathogens. Results: HCoV was present in 9.1% (313/3458) of all RTI episodes: 46.6% OC43, 32.3% NL63, 16.0% HKU1 and 5.8% 229E. Hospitalization rates for HCoV-positive children with lower RTIs were 1.5 and 2.8 per 1,000 <5 and <1 years of age, respectively. The detection rate among controls was 9.4% (60/639). Co-detections occurred in 68.1% of the patients and 73.3% of the controls. In a logistic regression analysis, high HCoV genomic loads (cycle threshold <28 in PCR analysis) were associated with RTIs (OR = 2.16, P = .032) adjusted for relevant factors. Conclusions: HCoVs occurred in one out of 11 hospitalized children with RTIs and asymptomatic controls. A high HCoV genomic load was associated with RTI. HCoVs are associated with a substantial burden of RTIs in need of hospitalization. PMID- 30418634 TI - Is smoking cessation in young adults associated with tobacco retailer availability in their activity space? AB - Introduction: The presence of tobacco retailers in residential neighbourhoods has been inversely associated with residents' likelihood of quitting smoking. Few studies have yet explored whether this association holds when accounting for tobacco retailers found in the multiple environments where people conduct their daily activities, i.e., their activity space. Methods: We analyzed cross sectional data from 921 young adults (18-25 years-old) participating in the Interdisciplinary Study of Inequalities in Smoking (Montreal, Canada). Respondents self-reported socio-demographic, smoking, and activity location data. Log-binomial regression was used to estimate prevalence ratios for the association between smoking cessation and (1) the number of tobacco retailers (counts), and (2) the distance to the closest retailer (proximity) in participants' residential neighbourhood and activity space. Results: Smoking cessation was positively associated with low and intermediate tertile levels of tobacco retailer counts in both the residential neighbourhood and activity space, and with the furthest distance level in the activity space (PR and 95% CI of 1.21 (1.02, 1.43)). Conclusions: Individuals encounter resources in the course of their regular daily activities which may hamper smoking cessation. This study highlights the relevance of considering the tobacco retail environment of both individuals' residential neighbourhood and activity space to understand its association with smoking cessation. Implications: This article contributes to the literature on the association between the tobacco retail environment and smoking cessation in young adults by moving beyond the residential neighbourhood to also assess individuals' access to tobacco retailers in the multiple areas where they regularly spend time, i.e., their activity space. Findings suggest that lower numbers of tobacco retailers in both the residential neighbourhood and activity space, and further distance to tobacco retailers in the activity space are associated with increased smoking cessation. PMID- 30418635 TI - Early spatial attention deployment toward and away from aggressive voices. AB - Salient vocalizations, especially aggressive voices, are believed to attract attention due to an automatic threat detection system. However, studies assessing the temporal dynamics of auditory spatial attention to aggressive voices are missing. Using event-related potential markers of auditory spatial attention (N2 ac and LPCpc), we show that attentional processing of threatening vocal signals is enhanced at two different stages of auditory processing. As early as 200 ms post stimulus onset, attentional orienting/engagement is enhanced for threatening as compared to happy vocal signals. Subsequently, as early as 400 ms post stimulus onset, the reorienting of auditory attention to the center of the screen (or disengagement from the target) is enhanced. This latter effect is consistent with the need to optimize perception by balancing the intake of stimulation from left and right auditory space. Our results extend the scope of theories from the visual to the auditory modality by showing that threatening stimuli also bias early spatial attention in the auditory modality. Attentional enhancement was only present in female and not in male participants. PMID- 30418636 TI - Cloning and Expression Profile of Glyceraldehyde-3-Phosphate Dehydrogenase in Haemaphysalis flava (Acari: Ixodidae). AB - Haemaphysalis flava (Acari: Ixodidae) harbors pathogenic microorganisms and transfers these to hosts during blood feeding. Proteomic analysis in the midgut contents of H. flava detected glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and contig 1683 was retrieved as a GAPDH gene fragment by searching our previous transcriptomic library. In the study, the 5' and 3' ends of contig 1683 were cloned by rapid amplification of cDNA ends (RACE) and a full length, 1340 bp cDNA of Hf-GAPDH was obtained. The open-reading frame had 999 bp and coded for 333 amino acids. Hf-GAPDH was predicted to have an N-terminal NAD binding domain and a C-terminal glyceraldehyde dehydrogenase catalytic domain. The molecular structure of Hf-GAPDH was analyzed and the evolutionary relationship also established. The GAPDH protein sequence was conserved among ticks. The expression pattern of Hf-GAPDH, analyzed by real-time PCR, significantly differed among life phases, feeding stages, and tissues. As the ticks grew, the expression level of Hf-GAPDH was up-regulated. The expression levels of Hf-GAPDH in salivary glands and midguts from half-engorged ticks were lower than the same tissues from engorged ticks. This study will provide reference data for the follow-up verification of the GAPDH-related function and the feasibility as a potential anti-tick vaccine. PMID- 30418637 TI - Longitudinal relationship between sleep deficiency and pain symptoms among community-dwelling older adults in Japan and Singapore. AB - The association of sleep with pain is well documented among adult populations. Even though both sleep problems and pain are prevalent in older adults, the longitudinal and bidirectional relationship between sleep deficiency (i.e., insufficient and poor sleep) and pain is less well established. This study investigated the association between sleep deficiency and pain among community dwelling adults aged 65 years and older across a 2-3 year period. We analyzed cross-country data from the Nihon University Japanese Longitudinal Study of Aging (N = 2888) and the Panel on Health and Aging of Singaporean Elderly (N = 2111). Sleep deficiency was operationalized as self-reported short sleep duration (< 6 hours), frequent restlessness during the night, and/or non-restorative sleep. Pain was characterized in terms of any pain, multiple pain locations, and pain related disability. Demographics, smoking, nap duration, depressive symptoms, chronic conditions, and body mass index were included as covariates. Baseline sleep deficiency was associated with any pain, multiple pain locations, and pain related disability among older adults at follow-up, although differences by country of residence were observed. In Singaporeans, sleep deficiency predicted the new onset of any pain, and any pain also predicted the new emergence of sleep deficiency. Improving sleep of older adults may improve pain-related symptoms and help intervene on the vicious cycle of pain and sleep deficiency. PMID- 30418639 TI - Nearly Neutral Evolution across the Drosophila melanogaster Genome. AB - Under the nearly neutral theory of molecular evolution, the proportion of effectively neutral mutations is expected to depend upon the effective population size (Ne). Here, we investigate whether this is the case across the genome of Drosophila melanogaster using polymorphism data from North American and African lines. We show that the ratio of the number of nonsynonymous and synonymous polymorphisms is negatively correlated to the number of synonymous polymorphisms, even when the nonindependence is accounted for. The relationship is such that the proportion of effectively neutral nonsynonymous mutations increases by ~45% as Ne is halved. However, we also show that this relationship is steeper than expected from an independent estimate of the distribution of fitness effects from the site frequency spectrum. We investigate a number of potential explanations for this and show, using simulation, that this is consistent with a model of genetic hitchhiking: Genetic hitchhiking depresses diversity at neutral and weakly selected sites, but has little effect on the diversity of strongly selected sites. PMID- 30418638 TI - Deducing putative ancestral forms of GNRA/receptor interactions from the ribosome. AB - Stable RNAs rely on a vast repertoire of long-range interactions to assist in the folding of complex cellular machineries such as the ribosome. The universally conserved L39/H89 interaction is a long-range GNRA-like/receptor interaction localized in proximity to the peptidyl transferase center of the large subunit of the ribosome. Because of its central location, L39/H89 likely originated at an early evolutionary stage of the ribosome and played a significant role in its early function. However, L39/H89 self-assembly is impaired outside the ribosomal context. Herein, we demonstrate that structural modularity principles can be used to re-engineer L39/H89 to self-assemble in vitro. The new versions of L39/H89 improve affinity and loop selectivity by several orders of magnitude and retain the structural and functional features of their natural counterparts. These versions of L39/H89 are proposed to be ancestral forms of L39/H89 that were capable of assembling and folding independently from proteins and post transcriptional modifications. This work demonstrates that novel RNA modules can be rationally designed by taking advantage of the modular syntax of RNA. It offers the prospect of creating new biochemical models of the ancestral ribosome and increases the tool kit for RNA nanotechnology and synthetic biology. PMID- 30418640 TI - Host Range and Genetic Plasticity Explain the Coexistence of Integrative and Extrachromosomal Mobile Genetic Elements. PMID- 30418641 TI - Report of the 112th Annual Meeting of the Association of Physicians of Great Britain and Ireland. PMID- 30418643 TI - Partial Transcondylar Approach for Ventral Foramen Magnum Neurenteric Cyst: 2 Dimensional Operative Video. AB - The anterior foramen magnum area, ventral to the brainstem is one of the most difficult regions to access surgically, and the extent of osseous drilling through the far-lateral or transcondylar approach should be planned in each case based on the tumor extension.1,2 This video, reproduced after informed consent of the patient, demonstrates a case of a ventral foramen magnum neurenteric cyst surgically treated using the partial transcondylar approach. A 27-yr-old woman presented with gait disturbance, oscillopsia, and transient arm numbness. Neuroimaging revealed a ventral foramen magnum cystic tumor involving the basilar and bilateral vertebral arteries. The tumor extended inferiorly from the middle clivus to the C1 level, and occupied the whole premedullary cistern compressing the bilateral lower cranial nerves. The left partial transcondylar approach was performed with drilling the condylar fossa, superior part of the occipital condyle, C1 posterior arch, and posterior part of the jugular process to achieve the sufficient surgical view from the inferolateral side. The drilling of the occipital condyle was minimized so that the articular facet of the occipital condyle was preserved. The tumor on the bilateral side was completely removed as enabled by the sufficient surgical field without new neurological deficits. Three dimensional reconstructed images based on the postoperative computed tomography scans demonstrated the appropriate extent of the osseous drilling. PMID- 30418644 TI - Commentary: Surgical Resection of Cervical Meningioma: 3-Dimensional Operative Video. PMID- 30418645 TI - The MemProtMD database: a resource for membrane-embedded protein structures and their lipid interactions. AB - Integral membrane proteins fulfil important roles in many crucial biological processes, including cell signalling, molecular transport and bioenergetic processes. Advancements in experimental techniques are revealing high resolution structures for an increasing number of membrane proteins. Yet, these structures are rarely resolved in complex with membrane lipids. In 2015, the MemProtMD pipeline was developed to allow the automated lipid bilayer assembly around new membrane protein structures, released from the Protein Data Bank (PDB). To make these data available to the scientific community, a web database (http://memprotmd.bioch.ox.ac.uk) has been developed. Simulations and the results of subsequent analysis can be viewed using a web browser, including interactive 3D visualizations of the assembled bilayer and 2D visualizations of lipid contact data and membrane protein topology. In addition, ensemble analyses are performed to detail conserved lipid interaction information across proteins, families and for the entire database of 3506 PDB entries. Proteins may be searched using keywords, PDB or Uniprot identifier, or browsed using classification systems, such as Pfam, Gene Ontology annotation, mpstruc or the Transporter Classification Database. All files required to run further molecular simulations of proteins in the database are provided. PMID- 30418646 TI - Too much nephrology? The CKD epidemic is real and concerning. A PRO view. AB - After decades of Babylonian confusion, we finally have a clear, uniform and widely accepted definition of chronic kidney disease (CKD). Based on evidence, and in accordance with other diseases, this definition is independent of age. This has made it possible to study the relevance and prevalence of CKD. We now know that CKD is associated with a myriad of health problems. We have also learned that studying the prevalence of CKD is difficult from a methodological perspective. But whatever the exact prevalence may be, we can safely conclude that CKD is common and that the crude prevalence of treated end-stage kidney disease is increasing, as is the importance of morbidity and mortality caused by CKD. The CKD epidemic is therefore real and concerning. It is now time to move forwards from debate about the semantics of the definition of CKD to the challenges of disseminating this newly obtained knowledge to patients, the medical community and health care policymakers and to develop strategies for CKD prevention and treatment. PMID- 30418647 TI - Potassium: poison or panacea in chronic kidney disease? PMID- 30418648 TI - Trypanosomes can initiate nuclear export co-transcriptionally. AB - The nuclear envelope serves as important messenger RNA (mRNA) surveillance system. In yeast and human, several control systems act in parallel to prevent nuclear export of unprocessed mRNAs. Trypanosomes lack homologues to most of the involved proteins and their nuclear mRNA metabolism is non-conventional exemplified by polycistronic transcription and mRNA processing by trans-splicing. We here visualized nuclear export in trypanosomes by intra- and intermolecular multi-colour single molecule FISH. We found that, in striking contrast to other eukaryotes, the initiation of nuclear export requires neither the completion of transcription nor splicing. Nevertheless, we show that unspliced mRNAs are mostly prevented from reaching the nucleus-distant cytoplasm and instead accumulate at the nuclear periphery in cytoplasmic nuclear periphery granules (NPGs). Further characterization of NPGs by electron microscopy and proteomics revealed that the granules are located at the cytoplasmic site of the nuclear pores and contain most cytoplasmic RNA-binding proteins but none of the major translation initiation factors, consistent with a function in preventing faulty mRNAs from reaching translation. Our data indicate that trypanosomes regulate the completion of nuclear export, rather than the initiation. Nuclear export control remains poorly understood, in any organism, and the described way of control may not be restricted to trypanosomes. PMID- 30418642 TI - Scientific Business Abstracts of the 112th Annual Meeting of the Association of Physicians of Great Britain and Ireland. PMID- 30418649 TI - Exploring and Visualising Spaces of Tree Reconciliations. AB - Tree reconciliation is the mathematical tool that is used to investigate the coevolution of organisms, such as hosts and parasites. A common approach to tree reconciliation involves specifying a model that assigns costs to certain events, such as cospeciation, and then tries to find a mapping between two specified phylogenetic trees which minimises the total cost of the implied events. For such models, it has been shown that there may be a huge number of optimal solutions, or at least solutions that are close to optimal. It is therefore of interest to be able to systematically compare and visualise whole collections of reconciliations between a specified pair of trees. In this paper, we consider various metrics on the set of all possible reconciliations between a pair of trees, some that have been defined before but also new metrics that we shall propose. We show that the diameter for the resulting spaces of reconciliations can in some cases be determined theoretically, information that we use to normalise and compare properties of the metrics. We also implement the metrics and compare their behaviour on several host parasite datasets, including the shapes of their distributions. In addition, we show that in combination with multidimensional scaling, the metrics can be useful for visualising large collections of reconciliations, much in the same way as phylogenetic tree metrics can be used to explore collections of phylogenetic trees.Implementations of the metrics can be downloaded from: https://team.inria.fr/erable/en/team members/blerina-sinaimeri/reconciliation-distances/. PMID- 30418650 TI - Commentary: A Pilot Comparison of Multispectral Fluorescence to Indocyanine Green Videoangiography and Other Modalities for Intraoperative Assessment in Vascular Neurosurgery. PMID- 30418651 TI - Commentary: Multicenter Study of Pipeline Flex for Intracranial Aneurysms. PMID- 30418653 TI - Ventral Precentral Fiber Intersection Area: A Central Hub in the Connectivity of Perisylvian Associative Tracts. AB - BACKGROUND: The ventral part of the precentral gyrus is considered one of the most eloquent areas. However, little is known about the white matter organization underlying this functional hub. OBJECTIVE: To analyze the subcortical anatomy underlying the ventral part of the precentral gyrus, ie, the ventral precentral fiber intersection area (VPFIA). METHODS: Eight human hemispheres from cadavers were dissected, and 8 healthy hemispheres were studied with diffusion tensor imaging tractography. The tracts that terminate at the ventral part of the precentral gyrus were isolated. In addition, 6 surgical cases with left side gliomas close to the VPFIA were operated awake with intraoperative electrical stimulation mapping. RESULTS: The connections within the VPFIA are anatomically organized along an anteroposterior axis: the pyramidal pathway terminates at the anterior bank of the precentral gyrus, the intermediate part is occupied by the long segment of the arcuate fasciculus, and the posterior bank is occupied by the anterior segment of the arcuate fasciculus. Stimulation of the VPFIA elicited speech arrest in all cases. CONCLUSION: The present study shows strong arguments to sustain that the fiber organization of the VPFIA is different from the classical descriptions, bringing new light for understanding the functional role of this area in language. The VPFIA is a critical neural epicenter within the perisylvian network that may represent the final common network for speech production, as it is strategically located between the termination of the dorsal stream and the motor output cortex that directly control speech muscles. PMID- 30418654 TI - COORDINATION OF MANAGEMENT OF THE ACUTE RADIATION SYNDROME. AB - The acute radiation syndrome (ARS) constitutes the most challenging, immediate medical consequence of exposure to high doses of ionizing radiation in an emergency situation. This report highlights some of the currently available medical guidelines and recommendations on the clinical management of ARS, comments recent trends regarding the approval of targeted pharmaceuticals for ARS, and suggests further initiatives for international collaboration aiming at continuously updating the medical knowledge base of this syndrome. PMID- 30418652 TI - Is there long-term value of pathology scoring in immunoglobulin A nephropathy? A validation study of the Oxford Classification for IgA Nephropathy (VALIGA) update. AB - Background: It is unknown whether renal pathology lesions in immunoglobulin A nephropathy (IgAN) correlate with renal outcomes over decades of follow-up. Methods: In 1130 patients of the original Validation Study of the Oxford Classification for IgA Nephropathy (VALIGA) cohort, we studied the relationship between the MEST score (mesangial hypercellularity, M; endocapillary hypercellularity, E; segmental glomerulosclerosis, S; tubular atrophy/interstitial fibrosis, T), crescents (C) and other histological lesions with both a combined renal endpoint [50% estimated glomerular filtration rate (eGFR) loss or kidney failure] and the rate of eGFR decline over a follow-up period extending to 35 years [median 7 years (interquartile range 4.1-10.8)]. Results: In this extended analysis, M1, S1 and T1-T2 lesions as well as the whole MEST score were independently related with the combined endpoint (P < 0.01), and there was no effect modification by age for these associations, suggesting that they may be valid in children and in adults as well. Only T lesions were associated with the rate of eGFR loss in the whole cohort, whereas C showed this association only in patients not treated with immunosuppression. In separate prognostic analyses, the whole set of pathology lesions provided a gain in discrimination power over the clinical variables alone, which was similar at 5 years (+2.0%) and for the whole follow-up (+1.8%). A similar benefit was observed for risk reclassification analyses (+2.7% and +2.4%). Conclusion: Long-term follow-up analyses of the VALIGA cohort showed that the independent relationship between kidney biopsy findings and the risk of progression towards kidney failure in IgAN remains unchanged across all age groups and decades after the renal biopsy. PMID- 30418655 TI - Letter to Editor - Seasonal Hypercalcaemia (Response). PMID- 30418656 TI - A drama movie activates brains of holistic and analytical thinkers differentially. AB - People socialized in different cultures differ in their thinking styles. Eastern culture people view objects more holistically by taking context into account, whereas Western-culture people view objects more analytically by focusing on them at the expense of context. Here we studied whether participants, who have different thinking styles but live within the same culture, exhibit differential brain activity when viewing a drama movie. A total of 26 Finnish participants, who were divided into holistic and analytical thinkers based on self-report questionnaire scores, watched a shortened drama movie during functional magnetic resonance imaging. We compared intersubject correlation (ISC) of brain hemodynamic activity of holistic vs analytical participants across the movie viewings. Holistic thinkers showed significant ISC in more extensive cortical areas than analytical thinkers, suggesting that they perceived the movie in a more similar fashion. Significantly higher ISC was observed in holistic thinkers in occipital, prefrontal and temporal cortices. In analytical thinkers, significant ISC was observed in right-hemisphere fusiform gyrus, temporoparietal junction and frontal cortex. Since these results were obtained in participants with similar cultural background, they are less prone to confounds by other possible cultural differences. Overall, our results show how brain activity in holistic vs analytical participants differs when viewing the same drama movie. PMID- 30418659 TI - Lower-grade gliomas: the wrong target for bevacizumab. PMID- 30418657 TI - Estimating survival for renal cell carcinoma patients with brain metastases: an update of the Renal Graded Prognostic Assessment tool. AB - Background: Brain metastases are a common complication of renal cell carcinoma (RCC). Our group previously published the Renal Graded Prognostic Assessment (GPA) tool. In our prior RCC study (n = 286, 1985-2005), we found marked heterogeneity and variation in outcomes. In our recent update in a larger, more contemporary cohort, we identified additional significant prognostic factors. The purpose of this study is to update the original Renal-GPA based on the newly identified prognostic factors. Methods: A multi-institutional retrospective institutional review board-approved database of 711 RCC patients with new brain metastases diagnosed from January 1, 2006 to December 31, 2015 was created. Clinical parameters and treatment were correlated with survival. A revised Renal GPA index was designed by weighting the most significant factors in proportion to their hazard ratios and assigning scores such that the patients with the best and worst prognoses would have a GPA of 4.0 and 0.0, respectively. Results: The 4 most significant factors were Karnofsky performance status, number of brain metastases, extracranial metastases, and hemoglobin. The overall median survival was 12 months. Median survival for GPA groups 0-1.0, 1.5-2.0, 2.5-3, and 3.5-4.0 (% n = 25, 27, 30 and 17) was 4, 12, 17, and 35 months, respectively. Conclusion: The updated Renal GPA is a user-friendly tool that will help clinicians and patients better understand prognosis, individualize clinical decision making and treatment selection, provide a means to compare retrospective literature, and provide more robust stratification of future clinical trials in this heterogeneous population. To simplify use of this tool in daily practice, a free online application is available at brainmetgpa.com. PMID- 30418660 TI - Letter to Editor - Seasonal Hypercalcaemia. PMID- 30418661 TI - Family Politics: Campaigning for Child Benefits in the 1980s. AB - Child benefit was seen by some to encourage the sort of welfare dependency that the moralistic individualism of Thatcherism opposed. Yet, surprisingly, the benefit survived the Thatcher years. Its survival reveals the conundrum the Conservative party have had regarding benefits for the family and family policy more broadly. Neo-liberals were supportive of the family as a vehicle for reinforcing Conservative values. Yet, the late 1970s and 1980s were periods of social change where the traditional family of the Conservative imagination was breaking down and consequently 'family policy' became a key political theme. By emphasizing the utility of child benefit as being fair to families, rather than its role in poverty alleviation, the Child Poverty Action Group (CPAG) was able to draw on this increased concern. As a result, their campaigns to save child benefit profited from increased support from across Conservatism. In tracing the development of CPAG's campaign, this article will demonstrate the cautiousness of Conservatives, even in the neo-liberal era, to changing some aspects of social policy. It will also highlight the challenge changing family patterns posed to the male breadwinner model that had long been embedded within the welfare policy prescriptions of both main parties. PMID- 30418662 TI - Homology-independent genome integration enables rapid library construction for enzyme expression and pathway optimization in Yarrowia lipolytica. AB - Yarrowia lipolytica is an important oleaginous industrial microorganism used to produce biofuels and other value-added compounds. Although several genetic engineering tools have been developed for Y. lipolytica, there is no efficient method for genomic integration of large DNA fragments. In addition, methods for constructing multi-gene expression libraries for biosynthetic pathway optimization are still lacking in Y. lipolytica. In this study, we demonstrate that multiple and large DNA fragments can be randomly and efficiently integrated into the genome of Y. lipolytica in a homology-independent manner. This homology independent integration generates variation in the chromosomal locations of the inserted fragments and in gene copy numbers, resulting in expression differences in the integrated genes or pathways. Because of these variations, gene expression libraries can be easily created through one-step integration. As proof of concept, a LIP2 (producing lipase) expression library and a library of multiple genes in the beta-carotene biosynthetic pathway were constructed, and high production strains were obtained through library screening. Our work demonstrates the potential of homology-independent genome integration for library construction, especially for multivariate modular libraries for metabolic pathways in Y. lipolytica, and will facilitate pathway optimization in metabolic engineering applications. This article is protected by copyright. All rights reserved. PMID- 30418663 TI - Early Miocene CO2 estimates from a Neotropical fossil leaf assemblage exceed 400 ppm. AB - PREMISE OF THE STUDY: The global climate during the early Miocene was warmer than the present and preceded the even warmer middle Miocene climatic optimum. The paleo-CO2 records for this interval suggest paradoxically low concentrations (<450 ppm) that are difficult to reconcile with a warmer-than-present global climate. METHODS: In this study, we use a leaf gas-exchange model to estimate CO2 concentrations using stomatal characteristics of fossil leaves from a late early Miocene Neotropical assemblage from Panama that we date to 18.01 +/- 0.17 Ma via 238 U/206 Pb zircon geochronology. We first validated the model for Neotropical environments by estimating CO2 from canopy leaves of 21 extant species in a natural Panamanian forest and from leaves of seven Neotropical species in greenhouse experiments at 400 and 700 ppm. KEY RESULTS: The results showed that the most probable combined CO2 estimate from the natural forests and 400 ppm experiments is 475 ppm, and for the 700 ppm experiments is 665 ppm. CO2 estimates from the five fossil species exhibit bimodality, with two species most consistent with a low mode (528 ppm) and three with a high mode (912 ppm). CONCLUSIONS: Despite uncertainties, it is very likely (at >95% confidence) that CO2 during the late early Miocene exceeded 400 ppm. These results revise upwards the likely CO2 concentration at this time, more in keeping with a CO2 -forced greenhouse climate. PMID- 30418664 TI - Jagged1-expressing adenovirus-infected dendritic cells induce expansion of Foxp3+ regulatory T cells and alleviate T helper type 2-mediated allergic asthma in mice. AB - Dendritic cells (DCs) are professional antigen-presenting cells that play a key role in directing T-cell responses. Regulatory T (Treg) cells possess an immunosuppressive ability to inhibit effector T-cell responses, and Notch ligand Jagged1 (Jag1) is implicated in Treg cell differentiation. In this study, we evaluated whether bone marrow-derived DCs genetically engineered to express Jag1 (Jag1-DCs) would affect the maturation and function of DCs in vitro and further investigated the immunoregulatory ability of Jag1-DCs to manipulate T helper type 2 (Th2) -mediated allergic asthma in mice. We produced Jag1-DCs by adenoviral transduction. Overexpression of Jag1 by ovalbumin (OVA) -stimulated Jag1-DCs exhibited increased expression of programmed cell death ligand 1 (PD-L1) and OX40L molecules. Subsequently, co-culture of these OVA-pulsed Jag1-DCs with allogeneic or syngeneic CD4+ T cells promoted the generation of Foxp3+ Treg cells, and blocking PD-L1 using specific antibodies partially reduced Treg cell expansion. Furthermore, adoptive transfer of OVA-pulsed Jag1-DCs to mice with OVA induced asthma reduced allergen-specific immunoglobulin E production, airway hyperresponsiveness, airway inflammation, and secretion of Th2-type cytokines (interleukin-4, interleukin-5, and interleukin-13). Notably, an increased number of Foxp3+ Treg cells associated with enhanced levels of transforming growth factor-beta production was observed in Jag1-DC-treated mice. These data indicate that transgenic expression of Jag1 by DCs promotes induction of Foxp3+ Treg cells, which ameliorated Th2-mediated allergic asthma in mice. Our study supports an attractive strategy to artificially generate immunoregulatory DCs and provides a novel approach for manipulating Th2 cell-driven deleterious immune diseases. PMID- 30418665 TI - Sex bias in preclinical research and an exploration of how to change the status quo. AB - There has been a revolution within clinical trials to include females in the research pipeline. However, there has been limited change in the preclinical arena; yet the research here lays the ground work for the subsequent clinical trials. Sex bias has been highlighted as one of the contributing factors to the poor translation and replicability issues undermining preclinical research. There have been multiple calls for action and the funders of biomedical research are actively pushing the inclusion of sex as a biological variable. Here we consider the current standard practice within the preclinical research setting, why there is a movement to include females, and why the imbalance exists. We explore organisational change theory as a tool to shape strategies needed at an individual and institute level to change the status quo. The ultimate goal is to create a scientific environment in which our preclinical research automatically implements sex sensitive approaches. PMID- 30418667 TI - The contribution of gustatory input to larval acceptance and female oviposition choice of potential host plants in Papilio hospiton (Gene). AB - The Lepidopteran Papilio hospiton uses only plants belonging to the Apiaceae and the Rutaceae families as hosts. Both adult females and larvae are equipped with gustatory receptor neurons (GRNs) capable of detecting sugars, bitters and salts, thus providing information for evaluating the chemical composition of the plant. Since the activation of these neurons may affect insect behavior, the aim of this study were: (a) to study the gustatory sensitivity of both females and larvae to the sap of two Apiaceae, Foeniculum vulgare (fennel) and Daucus carota (carrot), that are not used as host plants; (b) to cross-compare the spike activity evoked from these two plants with that evoked by Ferula communis (ferula), the host plant preferred by ovipositing females of P. hospiton and where the larvae perform best; (c) finally, to confirm that the gustatory system can provide the central nervous system with the necessary information to evaluate differences between plant saps. The results show that: (a) fennel and carrot both evoke a higher neural activity from the bitter-sensitive neurons and lower from the sugar sensitive neurons with respect to ferula, in both adult females and larvae; (b) on the basis of the different patterns of neural activity generated in tarsal, lateral and medial sensilla by fennel and carrot versus ferula, both adult and larvae possess enough information to discriminate among these plants; (c) adult females of P. hospiton lay eggs where the larvae have the greatest growth success and this confirms the importance of taste sensitivity in host plants selection. PMID- 30418666 TI - GABAB receptors modulate Ca2+ but not G protein-gated inwardly rectifying K+ channels in cerebrospinal-fluid contacting neurones of mouse brainstem. AB - KEY POINTS: Medullo-spinal CSF contacting neurones (CSF-cNs) located around the central canal are conserved in all vertebrates and suggested to be a novel sensory system intrinsic to the CNS. CSF-cNs receive GABAergic inhibitory synaptic inputs involving ionotropic GABAA receptors but the contribution of metabotropic GABAB receptors (GABAB -Rs) was not studied yet. Here, we indicate that CSF-cNs express functional GABAB -Rs that inhibit postsynaptic calcium channels but fail to activate inhibitory potassium channel of the kir3-type. We further show that GABAB -Rs localize presynaptically on GABAergic and glutamatergic synaptic inputs contacting CSF-cNs where they inhibit the release of GABA and glutamate. Our data are the first to address the function of GABAB Rs in CSF-cNs and show that on the presynaptic side they exert a classical synaptic modulation whereas at the postsynaptic level they have an atypical action by modulating calcium signalling without inducing potassium-dependent inhibition. ABSTRACT: Medullo-spinal neurones that contact the cerebrospinal fluid (CSF-cNs) are a population of evolutionary conserved cells located around the central canal. CSF-cNs activity was shown to be regulated by inhibitory synaptic inputs involving ionotropic GABAA receptors, but the contribution of the G-protein coupled GABAB receptors was not studied yet. Here, we used a combination of immunofluorescence, electrophysiology and calcium imaging to investigate the expression and function of GABAB -Rs in CSF-cNs of the mouse brainstem. We found that CSF-cNs express GABAB -Rs, but their selective activation failed to induce G protein-coupled inwardly-rectifying potassium (GIRK) currents. Instead, CSF-cNs express primarily N-type voltage-gated calcium (CaV 2.2) channels and GABAB -Rs recruit Gbetagamma subunits to inhibit Cav channels activity induced by membrane voltage steps or under physiological conditions by action potentials. Moreover, electrical stimulation evoked in CSF cNs GABAergic inhibitory (IPSCs) but also glutamatergic excitatory (EPSCs) synaptic currents, showing that mammalian CSF-cNs are also under excitatory control by glutamatergic synaptic inputs. We further demonstrate that baclofen reversibly reduced the amplitudes of both IPSCs and EPSCs evoked in CSF-cNs through a presynaptic mechanism of regulation. In summary, these results are the first to demonstrate the existence of functional postsynaptic GABAB -Rs in medullar CSF-cNs as well as presynaptic GABAB auto- and heteroreceptors regulating the release of GABA and glutamate. Remarkably, postsynaptic GABAB -Rs associate with CaV but not GIRK channels indicating that GABAB -Rs function as a calcium signalling modulator without GIRK-dependent inhibition in CSF-cNs. This article is protected by copyright. All rights reserved. PMID- 30418669 TI - Associations of Organizational Justice and Job Characteristics with Work Engagement Among Nurses in Hospitals in China. AB - Work engagement of nurses has a great effect on their productivity, patient outcomes, and organizational performance. It is important to explore what can be done to facilitate nurse engagement. In this study, we surveyed a total of 1,065 nurses chosen from seven hospitals in China by random cluster sampling to explore the state of nurse engagement and its associations with organizational justice and job characteristics. The mean score for nurse engagement was 3.5 (SD = 1.5) on a 0-6 scale, and in hierarchical multiple regression analyses we found that nurse engagement had statistically significant relationships with the two organizational justice dimensions of distributive justice (beta = 0.13, p < .01) and informational justice (beta = 0.17, p < .05); and the three job characteristic dimensions of task significance (beta = 0.15, p < .01), job feedback (beta = 0.10, p < .01), and skill variety (beta = .08, p < .05). Hence, work engagement of nurses was not at a high level, and nursing leaders should consider enhancing their engagement through creating motivational job characteristics and improving nurses' perception of organizational justice. PMID- 30418668 TI - Altered function of the glutamate-aspartate transporter GLAST, a potential therapeutic target in glioblastoma. AB - In glioma patients, high levels of glutamate can cause brain edema and seizures. GLAST, a glutamate-aspartate transporter expressed by astrocytes with a role in glutamate uptake, is highly expressed on the plasma membrane of glioblastoma (GBM) cells, and its expression significantly correlates with shortened patient survival. Here, it was demonstrated that inhibition of GLAST expression limited the progression and invasion of GBM xenografts. Magnetic resonance spectroscopy was used to measure glutamate in GLAST-expressing gliomas showing that these tumors exhibit increased glutamate concentration compared to GLAST-depleted glioma. Despite their GLAST expression, GBM stem-like cells (GSCs) released rather than taking up glutamate due to their lack of Na+/K+-ATPase. Overexpression of Na+/K+-ATPase in these cells restored glutamate uptake and induced apoptosis. The therapeutic relevance of targeting GLAST in gliomas was assessed using the inhibitor UCPH-101. In glioma-bearing mice, a single intratumoral injection of UCPH-101 significantly increased survival by decreasing GLAST expression and inducing apoptosis. Thus, GLAST has a novel role in GBM that appears to have crucial relevance in glutamate trafficking and may thus be a new therapeutic target. This article is protected by copyright. All rights reserved. PMID- 30418670 TI - Time interval between antibody investigations among patients who demonstrate serial red cell antibody formation. AB - BACKGROUND: Current national standards for pretransfusion testing do not address the frequency or optimal time interval to repeat antibody identification testing for patients in whom antibodies have been previously detected. STUDY DESIGN AND METHODS: A retrospective review was performed of patients with existing red blood cell (RBC) antibodies who subsequently developed new antibody specificities. Data were drawn from a single institution where the antibody investigation was repeated if the screen suggested a new antibody or if 14 days had elapsed since the previous investigation. Clinically insignificant or drug-dependent antibodies were excluded. Among cases in which new antibodies were detected within 30 days of a previous sample that already demonstrated existing antibodies, the median and lower 95% confidence intervals for the number of days between the detection of the existing and new antibodies were determined. RESULTS: Over a 9-year period, among 2114 patients with more than 1 antibody, 699 (33%) had serially detected antibodies from separate samples. Among 152 patients whose subsequent antibody was detected within 30 days of the existing antibodies, the median time interval to detection of the new antibody was 13 days. The lower 95% confidence interval was 1 day. By Day 3, 18% of the new antibodies had already appeared. CONCLUSION: In patients who form multiple antibodies, the serial emergence of clinically significant antibodies is common. In some patients, detection of a new specificity occurs in a sample drawn shortly after the sample that demonstrated the first antibody. These results have implications for the frequency of pretransfusion testing. PMID- 30418671 TI - Dental appliance therapy in pantothenate kinase-associated neurodegeneration: Case report. AB - Pantothenate kinase-associated neurodegeneration (PKAN) is a rare condition associated with severe protrusive lingual dystonia, a form of oromandibular dystonia. Dental appliance therapy has been described for oromandibular dystonia however there is a lack of literature regarding its application specifically to PKAN. In this report, the authors describe the use of an appliance in conjunction with botulinum toxin injections for the symptomatic treatment of this condition. A satisfactory outcome is achieved which suggests this technique may be of use to other clinicians. PMID- 30418672 TI - Metallochaperone Function of the Self-Subunit Swapping Chaperone Involved in the Maturation of Subunit-Fused Cobalt Type Nitrile Hydratase. AB - The transition metal (iron or cobalt) is a mandatory part that constitute the catalytic center of Nitrile hydratase (NHase). The incorporation of cobalt ion into cobalt containing NHase (Co-NHase) was reported to depend on self-subunit swapping, and the activator of the Co-NHase acts as a self-subunit swapping chaperone for subunit exchange. Here we discovered that the activator acted as a metallochaperone transferred cobalt ion into subunit-fused Co-NHase. We successfully isolated two activators, P14K and NhlE, which were the activators of NHases from Pseudomonas putida NRRL-18668 and the activator of low-molecular-mass NHase from Rhodococcus rhodochrous J1 respectively. Cobalt content determination demonstrated that NhlE and P14K were two cobalt-containing proteins. Substitution of the amino acids involved in the C-terminus of the activators affected the activity of the two NHases, indicating that the potential cobalt-binding sites might be located at the flexible C-terminal region. The cobalt-free NHases could be activated by either of the two activators, and both the two activators activated their cognate NHase more efficiently than non-cognate ones. This study brought insights into the maturation of subunit-fused NHases and confirmed the metallochaperone function of the self-subunit swapping chaperone. This article is protected by copyright. All rights reserved. PMID- 30418673 TI - Interleukin-1 beta influences functional regeneration following nerve injury in mice through NF-kappa B signaling pathway. AB - OBJECTIVE: This study focuses on investigating the role of interleukin-1 beta (IL 1beta) in functional regeneration following nerve injury in mice. METHODS: A microarray-based mRNA profiling study was used to analyze the expression level of IL-1beta in peripheral nerve regeneration. QRT-PCR and western blot were applied to assess the IL-1beta expressions of C57BL/6J-crush and C57BL/6J-crush+IL-1beta mice at different post-injury time points after the standard sciatic nerve crush injury. The outcomes of nerve regeneration were evaluated by behavioral tests. RESULTS: IL-1beta was found to be upregulated in peripheral nerve regeneration, and significantly raised on the 3rd days and returned on 14th days after nerve injury. Compared with C57BL/6J-crush+IL-1beta mice, the nerve regeneration of C57BL/6J-crush mice was worse after nerve crush injury. IL-1beta increased mechanical sensitivity and stimulated amplitude. CONCLUSIONS: IL-1beta could benefit the recovery of sciatic nerve crush injury by facilitating nerve regeneration. This article is protected by copyright. All rights reserved. PMID- 30418674 TI - Texture analysis for automated evaluation of Jaszczak phantom SPECT system tests. AB - PURPOSE: Routine quarterly quality assurance (QA) assessment of single photon emission computed tomography (SPECT) systems includes analysis of multipurpose phantoms containing spheres and rods of various sizes. When evaluated by accreditation agencies, criteria applied to assess image quality are largely subjective. Determining a quantified image characteristic metric that emulates human reader impressions of image quality could be quite useful. Our investigation was conducted to ascertain whether image texture analysis metrics, such as those applied to PET scans to detect neoplasms, could prove helpful in linking qualitative statements of phantom sphere and rod visibility to quantified parameters. Because it is not obvious whether it is preferable to submit reconstructions to accrediting agencies performed using typical clinical (CLIN) protocol processing parameters or to follow agencies' filtered backprojection (FBP) suggestions, we applied texture analysis metrics to determine the degree to which these choices affect equipment capability assessment. METHODS AND MATERIALS: Data were processed retrospectively for 125 different Tc-99 m SPECT scans of standardized phantoms for 14 rotating Anger detector systems as part of routine quarterly QA. Algorithms were written to compute several classes of image metrics: quantile curve metrics, image texture analysis gray-level co-occurrence matrix (GLCM) metrics, contrast metrics, and count histogram metrics. For qualitative image scores, two experienced physicists independently graded sphere and rod visibility on a 5-level scale and assigned dichotomous visibility scores, without knowledge of quantified texture analysis metrics or each other's readings. The same phantom was used to collect 15 additional data sets with two dual-detector SPECT/CT systems, reconstructed both by FBP parameters that have been suggested by accrediting agencies and by manufacturers' default settings for CLIN SPECT/CT bone imaging protocols by ordered subsets expectation maximization (OSEM), incorporating attenuation correction using the CT scan. Image characteristics metrics were compared for FBP and CLIN reconstructions. RESULTS: For spheres, the metric with the strongest rank correlation with 5-level scale readings was the quantile curve slope (rho = 0.83, P < 0.0001), while for rods it was GLCM Energy normalized to the maximum GLCM Energy value (EnergyNorm) (rho = 0.88, P < 0.0001). Compared to dichotomous readings, the metric with the highest ROC area under curve (AUC) for spheres was the quantile curve slopes (AUC = 96 +/ 1%, sensitivity = 91%, specificity = 90%), and for rods was EnergyNorm (AUC = 98 +/- 1%, sensitivity = 92%, specificity = 95%). Image contrast was higher for all sphere sizes and rod EnergyNorm was lower for sectors of intermediate-sized rods for FBP compared to CLIN reconstructions, in agreement with more rods judged to be visible from FBP than CLIN reconstructions (47% vs 33%, P = 0.002). CONCLUSIONS: When preparing to submit quality assurance images of standardized phantoms to accrediting agencies, a reliable gauge of sphere and rod visibility can be predicted accurately using quantified reader-independent image texture analysis metrics, which also provide a useful basis for choosing among alternative image reconstruction options. PMID- 30418675 TI - Quantification of DNA Double Strand Breaks using Geant4-DNA. AB - PURPOSE: This study aims to standardize the simulation procedure in measuring DNA Double Strand Breaks (DSBs), by using advanced Monte Carlo toolkits, and newly introduced experimental methods for DNA DSB measurement. METHODS: For the experimental quantification of DNA DSB, an innovative DNA dosimeter was used to produce experimental data. GATE in combination with Geant4-DNA toolkit were exploited to simulate the experimental environment. The PDB4DNA example, of Geant4-DNA was upgraded and investigated. Parameters of the simulation such energy threshold (ET) for a strand break and base pair threshold (BPT) for a DSB were evaluated, depending on the dose. RESULTS: Simulations resulted to minimum differentiation in comparison to experimental data for ET=19+/-1 eV and BPT=10 bp, and high differentiation for ET<17.5 eV or ET>22.5 eV and BPT=10 bp. There was also small differentiation for ET=17.5 eV and BPT=6 bp. Uncertainty has been kept lower than 3%. CONCLUSIONS: This study includes first results on the quantification of DNA double-strand breaks. The energy spectrum of a LINAC was simulated and used for the first time to irradiate DNA molecules. Simulation outcome was validated on experimental data that were produced by a prototype DNA dosimeter. This article is protected by copyright. All rights reserved. PMID- 30418676 TI - Comparative foliar metabolomics of a tropical and a temperate forest community. AB - Plant enemies that attack chemically similar host species are thought to mediate competitive exclusion of chemically similar plants and select for chemical divergence among closely related species. This hypothesis predicts that plant defenses should diverge rapidly, minimizing phylogenetic signal. To evaluate this prediction, we quantified metabolomic similarity for 203 tree species that represent >89% of all individuals in large forest plots in Maryland and Panama. We constructed molecular networks based on mass spectrometry of all 203 species, quantified metabolomic similarity for all pairwise combinations of species, and used phylogenetically independent contrasts to evaluate how pairwise metabolomic similarity varies phylogenetically. Leaf metabolomes exhibited clear phylogenetic signal for the temperate plot, which is inconsistent with the prediction. In contrast, leaf metabolomes lacked phylogenetic signal for the tropical plot, with particularly low metabolomic similarity among congeners. In addition, community wide variation in metabolomes was much greater for the tropical community, with single tropical genera supporting greater metabolomic variation than the entire temperate community. Our results are consistent with the hypothesis that stronger plant-enemy interactions lead to more rapid divergence and greater metabolomic variation in tropical than temperate plants. Additional community-level foliar metabolomes will be required from tropical and temperate forests to evaluate this hypothesis. PMID- 30418677 TI - Comparative screening of recombinant antigen thermostability for improved leptospirosis vaccine design. AB - Recombinant antigens exhibit targeted protectiveproperties and offer important opportunities in the development of therapeutic technologies. Biophysical and structural methods have become important tools for the rational design and engineering of improved antigen-based vaccines. Vaccines containing Leptospira immunoglobulin-like (Lig) protein-derived antigens are currently the most promising candidates for protective immunity against the globally prevalent bacterial pathogen, Leptospira interrogans; however, vaccine trials using these domains have produced inconsistent results. Here, we compare the thermostability of domains from the main immunogenic regions from major leptospiral antigens, LigA and LigB. By measuring temperature-dependent fluorescence decay of the hydrophobic core tryptophan, 17 individual Lig protein immunoglobulin-like (Ig like) domains were shown to display a broad range of unfolding temperatures. For a majority of the domains, stability issues begin to occur at physiologically relevant temperatures. A set of chimeric Ig-like domains was used to establish the ability of transplanted domain regions to enhance thermostability. Further insights into the determinants for domain stabilization were explored with nuclear magnetic resonance dynamics and mutational analysis. The current study has yielded a set of thermostable Ig-like domain scaffolds for use in engineering antigen-based vaccines and demonstrates the importance of incorporating thermostability screening as a design parameter. PMID- 30418678 TI - Evaluation of the impact of a clinical pathway on the progression of acute urinary retention. AB - AIMS: The management of acute urinary retention (AUR) revolves around trial without catheter (TWOC) after prescription of an alpha-blocker. This study evaluates the implementation of a clinical pathway for AUR. METHODS: Specific clinical pathways for AUR was established between the Emergency Department and the Department of Urology in order to reduce the duration of bladder drainage that included standard prescriptions, an information sheet, and a note to be faxed to scheduling nurses to organize the trial without catheter (TWOC). The main endpoint was the reduction in the time between the AUR episode and TWOC, without decreasing urination. RESULTS: Between April 2015 and December 2016, 248 patients were treated in the Emergency Department, and externally, for AUR. One hundred and seventy patients were enrolled in the pathway group and 78 in the control group. The mean duration of urinary catheterization decreased by 5.5 days as did the number of patients lost to follow-up (32% vs 76%), without decreasing the successful voiding (46% vs 36%). The duration of the urinary catheterization was not related to the chance of successful voiding regardless of the urine volume and a drainage time of over 10 days significantly reduced the chance of success (68%, n = 26 versus 42%, n = 76; P = 0.0038). CONCLUSION: The implementation of a clinical pathway for AUR reduced the number of patients lost to follow-up and the catheterization duration, thus optimizing the management of these patients. PMID- 30418679 TI - Patterns and predictors of fleshy fruit phenology at five international botanical gardens. AB - PREMISE OF THE STUDY: To improve our understanding of the patterns and drivers of fleshy fruit phenology, we examined the sequence, patterns across years and locations, and drivers of fruiting times at five botanical gardens on three continents. METHODS: We monitored four stages of fruit phenology for 406 temperate, fleshy-fruited, woody plant species in 2014 and 2015. KEY RESULTS: Across all gardens, ripe fruits were present from May to March of the following year, with peak fruiting durations ranging from under 1 week to over 150 days. Species-level first fruiting and onset of peak fruiting dates were strongly associated with one another within sites and were more consistent between years and sites than the end of peak fruiting and last fruiting date. The order of fruiting among species between years and gardens was moderately consistent, and both peak fruiting times and fruiting durations were found to be phylogenetically conserved. CONCLUSIONS: The consistent order of fruiting among species between years and locations indicates species-specific phenological responses to environmental conditions. Wide variation in fruiting times across species and in the duration of peak fruiting reinforces the importance of understanding how plant phenology impacts dispersers and monitoring the health and consistency of these interactions. PMID- 30418680 TI - A sparse representation-based radiomics for outcome prediction of higher grade gliomas. AB - PURPOSE: Accurately predicting outcome (i.e., overall survival (OS) time) for higher grade glioma (HGG) has great clinical value and would provide optimized guidelines for treatment planning. Radiomics focuses on revealing underlying pathophysiological information in biomedical images for disease analysis and demonstrates promising prognostic clinical performance. In this paper, we propose a novel sparse representation-based radiomics framework to predict if HGG patients would have long or short OS time. METHODS: First, taking advantages of the scale invariant feature transform (SIFT) feature in image characterizing, we developed a sparse representation-based method to convert a local SIFT descriptor into a global tumor feature. Next, because preserving sample structure is beneficial for feature selection, we proposed a locality preserving projection and sparse representation-combined feature selection method to select more discriminative features for tumor classification. Finally, we employed a multifeature collaborative sparse representation classification to combine the information of multimodal images to classify OS time. RESULTS: Three experiments were performed on the two datasets provided by different institutions. Specifically, the proposed model was trained and independently tested on dataset 1 (135 subjects), on dataset 2 (86 subjects), and on the combination of dataset 1 and dataset 2, respectively. Experimental results demonstrated that the proposed method achieved encouraging prediction performance, exhibiting a testing accuracy of 93.33% on dataset 1 (one modality), 92.31% on dataset 2 (two modalities), and 87.93% on the combined dataset (one modality). CONCLUSIONS: The sparse representation theory provides reasonable solutions to feature extraction, feature selection, and classification for radiomics. This study provides a promising tool to enhance the prediction performance of HGG patient's outcome. PMID- 30418681 TI - ON EXACTITUDE IN SCIENCE: A MAP OF THE EMPIRE THE SIZE OF THE EMPIRE. AB - In the service of children's best interests, we argue for a sharpening of the evidentiary standards used in family court decision making, from preponderance of (occasionally substandard) evidence to "beyond a reasonable doubt." Second, we call for a move in child protection cases from static diagnoses (e.g., attachment classifications) to assessments of the potential for enhanced parenting. Finally, informed by the implications of the replication crisis in the biomedical and psychological sciences, we applaud the move of the attachment field forward to large-scale, collective research agendas and goals. PMID- 30418682 TI - Massive release of the histamine-degrading enzyme diamine oxidase during severe anaphylaxis in mastocytosis patients. AB - BACKGROUND: Histaminolytic activity mediated by diamine oxidase (DAO) is present in plasma after induction of severe anaphylaxis in rats, guinea pigs and rabbits. Heparin released during mast cell degranulation in the gastrointestinal tract might liberate DAO from heparin-sensitive storage sites. DAO release during anaphylaxis has not been demonstrated in humans. METHODS: Plasma DAO, tryptase and histamine concentrations of four severe anaphylaxis events were determined at multiple serial time points in two patients with systemic mastocytosis. The histamine degradation rates were measured in anaphylaxis samples and in pregnancy sera and plasma with comparable DAO concentrations. RESULTS: Mean DAO (132 ng/ml) and tryptase (304 ng/ml) concentrations increased 187- and 4.0-fold respectively over baseline values (DAO 0.7 ng/ml, tryptase 76 ng/ml) during severe anaphylaxis. Under non-anaphylaxis conditions DAO concentrations were not elevated in 29 mastocytosis patients compared to healthy volunteers and there was no correlation between DAO and tryptase levels in mastocytosis patients. The histamine degradation rate of DAO in plasma from mastocytosis patients during anaphylaxis is severely compromised compared to DAO from pregnancy samples. CONCLUSIONS: During severe anaphylaxis in mastocytosis patients DAO is likely released from heparin-sensitive gastrointestinal storage sites. The measured concentrations can degrade histamine, but DAO activity is compromised compared to pregnancy samples. For accurate histamine measurements during anaphylaxis DAO inhibition is essential to inhibit further histamine degradation after blood withdrawal. Determination of DAO antigen levels might be of clinical value to improve the diagnosis of mast cell activation. This article is protected by copyright. All rights reserved. PMID- 30418683 TI - Six-month prevalence and correlates of Generalized Anxiety Disorder among primary care patients aged 70 years and over: Results from the ESA-services study. AB - OBJECTIVES: To estimate the 6-month prevalence of Generalized Anxiety Disorder (GAD) in primary care patients aged 70 years and over and to describe their clinical profile, including types of worries. METHODS/DESIGN: Participants (N=1193) came from the ESA-services study conducted in Quebec, Canada. An in person structured interview was used to identify GAD and other anxiety/depressive disorders as well as to identify types of worries. Three groups were created (i.e., patients with GAD, patients with another anxiety disorder, and patients without anxiety disorders) and compared on several sociodemographic and clinical characteristics using multinomial logistic regression analyses. RESULTS: The 6 month prevalence of GAD was 2.7%. Findings also indicated that the most common types of worries were about health, being a burden for loved ones, and losing autonomy. Compared to respondents without anxiety disorders, older patients with GAD were more likely to be women, be more educated, suffer from depression, use antidepressants, be unsatisfied with their lives, and use health services. In comparison to respondents with another anxiety disorder, those with GAD were 4.5 times more likely to suffer from Minor Depression. CONCLUSIONS: GAD has a high prevalence in primary care patients aged 70 years and over. Clinicians working in primary care settings should screen for GAD, since it remains underdiagnosed. In addition, it may be associated with depression and life dissatisfaction. Screening tools for late-life GAD should include worry themes that are specific to aging. PMID- 30418684 TI - Current practices in the management of adenovirus infection in allogeneic hematopoietic cell transplant recipients in Europe: The AdVance study. AB - OBJECTIVE: Adenovirus (AdV) infections are potentially life-threatening for allogeneic hematopoietic cell transplant (allo-HCT) recipients. The AdVance study aimed to evaluate the incidence management and outcomes of AdV infections in European allo-HCT recipients. METHODS: As part of the study physician surveys were conducted to determine current AdV screening and treatment practices at their center. RESULTS: All of the 28 respondents who treat pediatric patients reported routine AdV screening practices with 93% screening all allo-HCT recipients and others screening those with transplant-related risk factors. Nearly all centers take a pre-emptive approach to AdV treatment in both high- (89%) and low-risk patients (75%). Among the 14 respondents who treat adult patients 5/14 (36%) reported routine screening practices and few (21%) screen all allo-HCT recipients unless risk factors are present. In adults, pre-emptive AdV treatment is uncommon and quantitative AdV thresholds are rare. Typical treatment for all patients with symptomatic AdV infection is off-label intravenous cidofovir. CONCLUSIONS: Our findings confirm that screening for AdV is more common in pediatric patients. Antiviral treatment is employed in both pediatric and adult patients, although adults are generally treated when AdV disease is diagnosed. The approach to AdV screening and treatment is risk-based and consistent with clinical guidelines. This article is protected by copyright. All rights reserved. PMID- 30418685 TI - Parsing Redox Potentials of the Five Ferredoxins found within Thermotoga maritima. AB - Most organisms contain multiple soluble protein-based redox carriers such as members of the ferredoxin (Fd) family, that contain one or more iron-sulfur clusters. The potential redundancy of Fd proteins is poorly understood, particularly in connection to the ability of Fd proteins to deliver reducing equivalents to members of the "radical SAM", or S-adenosylmethionine radical enzyme (ARE) superfamily, where the activity of all known AREs requires that an essential iron-sulfur cluster bound by the enzyme be reduced to the catalytically relevant [Fe4 S4 ]1+ oxidation state. As it is still unclear whether a single Fd in a given organism is specific to individual redox partners, we have examined the five Fd proteins found within Thermotoga maritima via direct electrochemistry, to compare them in a side-by-side fashion for the first time. While a single [Fe4 S4 ]-cluster bearing TM0927 has a potential of -420 mV, the other four 2x[Fe4 S4 ]-bearing Fds (TM1175, TM1289, TM1533, TM1815) have potentials that vary significantly, including cases where the two clusters of the same Fd are essentially coincident (e.g. TM1175) and those where the potentials are well separate (TM1815). This article is protected by copyright. All rights reserved. PMID- 30418686 TI - Simultaneous four-channel recording of bilateral cervical and ocular vestibular evoked myogenic potentials in response to stimulation by forehead bone-conducted vibration: Our experience in 20 healthy adults. PMID- 30418687 TI - Actin and actin-rich structures are part of the fabric of The Anatomical Record. PMID- 30418688 TI - Sex-specific influence of the vacuolar adenosine triphosphatase a2 isoform on outcome in twin pregnancies. AB - PROBLEM: The influence of fetal sex on immune responses in multifetal pregnancies remains incompletely elucidated. The a2 isoform of vacuolar adenosine triphosphatase (a2V) is expressed on the cell membrane of maternal lymphoid cells and contributes to down-regulation of pro-inflammatory immune responses during gestation. The association between fetal sex and a2V expression on peripheral blood mononuclear cells (PBMCs) from mothers with twin gestations was assessed. METHOD OF STUDY: Patients in this prospective study were 93 women with twin pregnancies in their mid-second or early third trimester-27 with two male, 30 with two female and 36 with one male and one female fetus. PBMCs were isolated and a2V was measured by ELISA in cell lysates. Demographic and clinical data were subsequently obtained and correlations between a2V and fetal sex, birthweight and pregnancy outcome were assessed by the Mann-Whitney and Spearman rank correlation tests. RESULTS: The mean a2V level was highest when both fetuses were male (2.0 ng/mL) and lowest when both were female (1.5 ng/mL; P = 0.0184). Only when both fetuses were female did the a2V concentration negatively correlate with birthweight of the 1st (P = 0.0011) and 2nd (P = 0.0044) born fetus and with gestational age at delivery (P = 0.0018). There were no associations between a2V and these outcomes in male only or mixed twin pregnancies. CONCLUSION: We conclude that the a2V-mediated regulation of maternal immunity during twin pregnancies is influenced by fetal sex. PMID- 30418689 TI - Muscle-induced loading as an important source of variation in craniofacial skeletal shape. AB - The shape of the craniofacial skeleton is constantly changing through ontogeny, and reflects a balance between developmental patterning and mechanical-load induced remodeling. Muscles are a major contributor to producing the mechanical environment that is crucial for "normal" skull development. Here we use an F5 hybrid population of Lake Malawi cichlids to characterize the strength and types of associations between craniofacial bones and muscles. We focus on four bones/bone complexes, with different developmental origins, alongside four muscles with distinct functions. We used micro-computed tomography to extract 3D information on bones and muscles. 3D geometric morphometrics and volumetric measurements were used to characterize bone and muscle shape, respectively. Linear regressions were performed to test for associations between bone shape and muscle volume. We identified three types of associations between muscles and bones: weak, strong direct (i.e., muscles insert directly onto bone), and strong indirect (i.e., bone is influenced by muscles without a direct connection). In addition, we show that whereas the shape of some bones are relatively robust to muscle-induced mechanical stimulus, others appear to be highly sensitive to muscular input. Our results imply that the roles for muscular input on skeletal shape extend beyond specific points of origin or insertion, and hold significant potential to influence broader patterns of craniofacial geometry. Thus, changes in the loading environment, either as a normal course of ontogeny or if an organism is exposed to a novel environment, may have predicable effects on skeletal shape via near and far-ranging effects of muscular loading. This article is protected by copyright. All rights reserved. PMID- 30418691 TI - Cobalt-Catalyzed Reductive Alkylation of Amines with Carboxylic Acids. AB - Direct reductive alkylation of amines with carboxylic acid is carried out by using an inexpensive, air-stable cobalt/triphos catalytic system with molecular hydrogen as the reductant. This efficient synthetic method proceeds through reduction and condensation, followed by reduction of the in situ-generated imine into the amine in a green catalytic process. PMID- 30418690 TI - Germination of pollen grains in the esophagus of individuals with eosinophilic esophagitis. AB - BACKGROUND: Eosinophilic esophagitis (EoE) is characterized by esophageal dysfunction and, histologically, by eosinophilic inflammation. There is no a clear etiologic treatment. EoE exacerbations are often seasonal. We hypothesized that the inflammatory response of the esophageal mucosa in patients with high levels of antibodies to pollen allergens and worsened seasonal EoE might be due to swallowing airborne pollen and the intrusion into the esophageal mucosa of pollen allergens and pollen tubes, which encounter a pH and humidity resembling the stigma at pollination. OBJECTIVE: The aim of our study was to demonstrate the possible pathogenic role of environmental allergens in EoE through molecular and anatomopathological studies. METHODS: 129 patients with EoE were tested for environmental and food allergens. Component resolved diagnosis (CRD), histological and botanical analysis was performed. Microscopic examination of esophageal biopsies of 129 adults patients with EoE, 82 of them with seasonal exacerbation, and 100 controls, with gastroesophageal reflux without eosinophilic infiltrate, were made to verify the presence of callose (polysaccharide abundant in pollen tubes but absent in animal tissues) in the esophagus. RESULTS: CRD detected pollen allergens in 87.6% of patients with EoE. The predominant allergens were group 1 grass (55%), Art v 3 (11.3%) and lipid transfer proteins (LTPs) (19.4%) of common Mediterranean foods such as peach, hazelnuts, walnuts and wheat. Callose from pollen tubes was found in 65.6% of biopsies. CONCLUSION: Alteration of the mucosal barrier in EoE might cause the penetration of pollen grains into the esophageal tissues. In EoE patients, anatomopathological studies searching for intrusion to plant foods and pollen, and specific-guided diet and immunotherapy after plant structures detection in biopsies, might be effective. This article is protected by copyright. All rights reserved. PMID- 30418692 TI - Performance of a recombinant fusion protein linking coagulation factor IX with recombinant albumin in one-stage clotting assays. AB - BACKGROUND: Measuring factor IX activity (FIX:C) with one-stage clotting (OSC) assays, based on the activated partial thromboplastin time (aPTT), is the current mainstay of diagnostic techniques for hemophilia B. Assessing the performance of new recombinant FIX (rFIX) products in OSC assays is essential as aPTT reagents from different manufacturers yield different potency estimates for rFIX. OBJECTIVES: To evaluate the extent to which choice of reagent composition influences rFIX potency measurements of recombinant FIX-albumin fusion protein (rIX-FP, IDELVION(r) ) activity in OSC assays. METHODS: rIX-FP was added to FIX deficient plasma and FIX:C assessed centrally and locally in a multicenter international field study with a variety of commercial OSC aPTT reagents. Paired sample analysis of clinical samples compared values of FIX:C from local and central laboratories. In-house bioanalytic investigations with spiked samples were conducted to compare the aPTT-reagent dependent variability of rIX-FP with unmodified rFIX and rFIX Fc fusion protein (rFIXFc). RESULTS: Central and local assessments of FIX:C from 10 countries and 21 participating centers showed comparable results to the central laboratory across the majority of 18 different aPTT reagents from both clinical and spiked samples. There was a consistent underestimation in rIX-FP activity of approximately 50% with OSC assays using Actin(r) FS or kaolin-based aPTT reagents. In the bioanalytical study, rIX-FP showed comparable variability in OSC assays to unmodified rFIX and rFIXFc. CONCLUSIONS: rIX-FP activity can be accurately measured using OSC assays with the majority of commercial reagents. Actin(r) FS or kaolin-based reagents will likely lead to 50% underestimation in activity. This article is protected by copyright. All rights reserved. PMID- 30418693 TI - Diffusion weighted magnetic resonance imaging is a feasible method for characterizing regional lymph nodes in canine patients with head and neck disease. AB - In dogs diagnosed with solid tumors, regional lymph node involvement or evidence of distant metastasis can predict worse prognoses and significantly decreased survival. Lymph node size alone has been shown to be insufficient as a predictor for the accurate clinical staging of some canine neoplasia. However, certain regional lymph nodes (including those of the oral cavity) are difficult to access for routine tissue sampling. Diffusion weighted magnetic resonance imaging (MRI) has demonstrated the ability to differentiate metastatic from inflammatory/benign lymph nodes in clinical studies with human cancer patients through the calculation of quantitative values of diffusion termed apparent diffusion coefficients (ADC). The objective of this prospective, exploratory study was to evaluate diffusion-weighted MRI and ADC as potential methods for detecting metastatic lymph nodes in dogs with naturally occurring disease. We hypothesized that diffusion-weighted MRI would identify significantly different ADC values between benign and metastatic lymph nodes in a group of canine patients with head or neck disease. Our study population consisted of eight client-owned canine patients, with a total of 20 lymph nodes evaluated (six metastatic, 14 benign). Our results demonstrated that two of four observers identified a significant difference between the mean ADC values of the benign and metastatic lymph nodes. When data from all four observers were pooled, the difference between the mean apparent diffusion coefficients values of the benign and metastatic lymph nodes did not reach significance (P-value = 0.0566). Findings indicated that diffusion weighted MRI is a feasible method for further characterizing enlarged lymph nodes in dogs with head and neck disease, however measured ADC values did not differ for benign vs. metastatic lymph nodes in this small sample of dogs. PMID- 30418694 TI - Diversity and enzymatic profiles of indigenous yeasts isolated from three types of palm wines produced in Cote d'Ivoire. AB - AIMS: To investigate the genotypic diversity and enzymatic activity of yeast flora isolated from spontaneous fermenting saps of warious palm trees (Borassus aethiopum, Raphia hookeri, Elaeis guineensis) tapped for palm wines. METHODS AND RESULTS: PCR-RFLP of ITS-5.8S rDNA combined to 26S rRNA gene and/or the partial ACT1 gene sequencing were applied for yeast characterization, and their enzymatic profiles assessed by using API ZYM kits. Thirteen genera and 23 species were identified, with the highest diversity (14 species) in raffia wine. Saccharomyces cerevisiae was dominant and common to all palm wines. Some potentially pathogenic yeasts were also isolated. The majority of tested strains displayed high amylo peptidase, phosphatase, beta-glucosidase and alpha-glucosidase activities and esterase activity. CONCLUSIONS: Diverse yeast species colonized palm wines, among which some were related to a specific type of wine and the majority of them have the ability to digest starch, sugar, protein or lipid. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is a first step in understanding the significance of indigenous yeast flora of palm wines from Cote d'Ivoire. This knowledge is important as a tool for establishing new indigenous yeast collection; which could be used for the product quality improvement and as enzyme sources for biotechnological purposes. This article is protected by copyright. All rights reserved. PMID- 30418695 TI - Photocatalysis Enables Visible Light Uncaging of Bioactive Molecules in Live Cells. AB - The photomanipulation of bioactive molecules provides unique advantages with the high temporal and spatial precision of light. Here we report the first visible light uncaging reaction by photocatalytic deboronative hydroxylation in live cells. Using the fluorescein and rhodamine derivatives as photocatalysts and ascorbates as reductants, transient hydrogen peroxides were generated from molecular oxygen to uncage phenol, alcohol and amine functional groups on bioactive molecules in bacteria and mammalian cells including neurons. The effective visible light uncaging reaction enabled the light-inducible protein expression, the photomanipulation of membrane potentials, and the subcellular specific photorelease of small molecules. PMID- 30418696 TI - Another record in submissions to Acta Physiologica. PMID- 30418697 TI - Lipidomic profile as a noninvasive tool to predict endometrial receptivity. AB - For the present study we asked whether the endometrial fluid lipidomic may be a useful approach to predict endometrial receptivity in freeze-all cycles. For this case-control study, endometrial fluid samples were collected from 41 patients undergoing freeze-all cycles. Samples were split depending on the pregnancy outcome: positive group (n = 24) and negative group (n = 17). Data were acquired by the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were applied. A list of potential biomarker ion ratios was obtained and the values were used to build a receiver operating characteristic (ROC) curve to predict pregnancy success. The lipid categories were attributed by LIPID MAPS database. Ion ratios were established according to their correlations and used for the analysis. The PCA showed a tendency of separation between the studied groups, whereas the PLS-DA was able to clearly distinguish them. Fifteen ratios (13 hyper-represented in the negative and two hyper-represented in the positive group) were selected according to their importance for model prediction. These ratios were used to build the ROC curve, which presented an area under curve of 84.0% (95%CI: 69.2-97.4%; p = 0.009). These findings suggest that lipidomic profiling of endometrial fluid may be a valuable tool for identifying the time interval comprising the window of implantation. PMID- 30418698 TI - Is successful treatment of depression in dialysis patients an achievable goal? AB - Depression is undisputedly common among individuals with End-Stage Kidney Failure and associated with adverse outcomes. It is well recognized that effective treatments for depression are needed within routine dialysis care. But, are we any closer to successfully treating depression in dialysis patients? We consider this question here with respect to two common treatments, antidepressant medication and cognitive behavioural therapy (CBT). Currently, there are limited data from randomized placebo-controlled trials regarding the acceptability and efficacy of antidepressants. CBT trials appear to show more consistent treatment effects, albeit the feasibility of routine delivery remains unknown. No studies in dialysis patients has evaluated the combined effects of CBT with antidepressants. There is a need to consider pragmatic depression treatment trials in dialysis patients in order to increase study recruitment in order to have more reliable data from which to evaluate the evidence base. Furthermore, we need to understand why treatments work, and for whom do they work? Lastly, addressing issues surrounding treatment acceptability and implementation as part of regular care remain as key challenges that require attention if we are to improve the mental health of individuals on dialysis. PMID- 30418700 TI - Efficient Light Harvesting Systems with Tunable Emission through Controlled Precipitation in Confined Nanospace. AB - Light harvesting is a key step in photosynthesis but creation of synthetic light harvesting systems (LHSs) with high efficiency has been challenging. When donor and acceptor dyes with aggregation-induced emission were trapped inside the interior of cross-linked reverse vesicles, LHSs were obtained readily through spontaneous hydrophobically driven aggregation of the dyes in water. Aggregation in the confined nanospace was critical to the energy transfer and the light harvesting efficiency. The efficiency of the excitation energy transfer (EET) reached 95% at a donor/acceptor ratio of 100:1 and the energy transfer was clearly visible even at a donor/acceptor ratio of 10,000:1. Multicolor emission was achieved simply by tuning the donor/acceptor feed ratio in the preparation and the quantum yield of white light emission from the system was 0.38, the highest reported for organic materials in water to date. PMID- 30418699 TI - Flower-visitor communities of an arcto-alpine plant- global patterns in species richness, phylogenetic diversity and ecological functioning. AB - Pollination is an ecosystem function of global importance. Yet, who visits the flower of specific plants, how the composition of these visitors varies in space and time, and how such variation translates into pollination services is hard to establish. The use of DNA barcodes allows us to address ecological patterns involving thousands of taxa that are difficult to identify. To clarify the regional variation in the visitor community of a wide-spread flower resource, we compared the composition of the arthropod community visiting species in the genus Dryas (mountain avens, family Rosaceae), throughout Arctic and high-alpine areas. At each of 15 sites, we sampled Dryas visitors with 100 sticky flower mimics, and identified specimens to Barcode Index Numbers (BINs) using a partial sequence of the mitochondrial COI-gene. As a measure of ecosystem functioning, we quantified variation in the seed set of Dryas. To test for an association between phylogenetic and functional diversity, we characterized the structure of local visitor communities with both taxonomic and phylogenetic descriptors. In total, we detected 1,360 different BINs, dominated by Diptera and Hymenoptera. The richness of visitors at each site appeared to be driven by local temperature and precipitation. Phylogeographic structure seemed reflective of geological history, and mirrored trans-Arctic patterns detected in plants. Seed set success varied widely among sites, with little variation attributable to pollinator species richness. This pattern suggests idiosyncratic associations, with function dominated by few and potentially different taxa at each site. Taken together, our findings illustrate the role of post-glacial history in the assembly of flower visitor communities in the Arctic, and offer insights for understanding how diversity translates into ecosystem functioning. This article is protected by copyright. All rights reserved. PMID- 30418702 TI - Morphological Alterations and Increased Gelatinase Activity in the Superficial Digital Flexor Tendon of Chickens During Growth and Maturation. AB - The superficial digital flexor tendon (SDFT) connects the superficial digital flexor muscle to the digits and its main function is to participate in digit flexion. The SDFT presents different regions along its length, which adapt to different biomechanical forces. During growth and maturation, the tendon may present changes in the regions subjected to compression and tension, with variations in the composition of the extracellular matrix (ECM), in the arrangement of collagen fibers and cellularity. With the purpose of analyzing the morphological and biochemical alterations of ECM of tendons during the growth and maturation, Gallus domesticus were euthanized at 1, 5, and 8 months of age and their SDFT were divided into regions of tension/compression (Sp) and tension (Sd). From 1 month of age, the Sp region already presented fibrocartilage characteristics with cells similar to chondrocytes. At 5 and 8 months, the Sd region displayed formation of a new structure similar to bone matrix, and intense metachromasia. The animals of 5 and 8 months presented an increase in MMP-2 and 9 activities and a lower number of cells when compared with the animals of 1 month, in both regions. In conclusion, structural and biochemical alterations occur during the maturation process of the SDFT, involving a decrease in the number of cells and changes in the degradation and composition of the ECM. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30418701 TI - A study of positioning orientation effect on segmentation accuracy using convolutional neural networks for rectal cancer. AB - PURPOSE: Convolutional neural networks (CNN) have greatly improved medical image segmentation. A robust model requires training data can represent the entire dataset. One of the differing characteristics comes from variability in patient positioning (prone or supine) for radiotherapy. In this study, we investigated the effect of position orientation on segmentation using CNN. METHODS: Data of 100 patients (50 in supine and 50 in prone) with rectal cancer were collected for this study. We designed three sets of experiments for comparison: (a) segmentation using the model trained with data from the same orientation; (b) segmentation using the model trained with data from the opposite orientation; (c) segmentation using the model trained with data from both orientations. We performed fivefold cross-validation. The performance was evaluated on segmentation of the clinical target volume (CTV), bladder, and femurs with Dice similarity coefficient (DSC) and Hausdorff distance (HD). RESULTS: Compared with models trained on cases positioned in the same orientation, the models trained with cases positioned in the opposite orientation performed significantly worse (P < 0.05) on CTV and bladder segmentation, but had comparable accuracy for femurs (P > 0.05). The average DSC values were 0.74 vs 0.84, 0.85 vs 0.88, and 0.91 vs 0.91 for CTV, bladder, and femurs, respectively. The corresponding HD values (mm) were 16.6 vs 14.6, 8.4 vs 8.1, and 6.3 vs 6.3, respectively. The models trained with data from both orientations have comparable accuracy (P > 0.05), with average DSC of 0.84, 0.88, and 0.91 and HD of 14.4, 8.1, and 6.3, respectively. CONCLUSIONS: Orientation affects the accuracy for CTV and bladder, but has negligible effect on the femurs. The model trained from data combining both orientations performs as well as a model trained with data from the same orientation for all the organs. These observations can offer guidance on the choice of training data for accurate segmentation. PMID- 30418703 TI - Risk of Ocular Anomalies in Children Exposed in Utero to Antimalarials: A Systematic Literature Review. AB - OBJECTIVE: To determine if SLE offspring exposed in utero to antimalarials have an increased risk of ocular anomalies during childhood versus unexposed SLE offspring. METHODS: We systematically performed searches of PubMed, Embase, and Web of Science databases for original human data on fetal and/or child ocular outcomes following exposure to antimalarials during pregnancy and/or lactation, from their inception until March 2017. RESULTS: 10 cohort studies and 2 randomized controlled trials, ranging in size from 6 to 444 exposed infants studied, and 3 case reports met the inclusion criteria for our systematic review. Collectively, 1477 infants were studied, 789 of which were exposed to hydroxychloroquine or chloroquine. 563 of exposed infants had follow-up visits after delivery (ranging from less than 3 months to 19 years), and 331 of these exposed infants underwent ophthalmological exams during the follow-up period. Our review of the literature suggests a low to nonexistent risk of visual abnormalities in offspring exposed to antimalarials. CONCLUSION: In children exposed to appropriate doses of antimalarials antenatally, the risk of ocular toxicity appears low to nonexistent. The potential benefits and risks of antimalarials should be discussed in all SLE pregnancies, and high dosages should continue to be avoided. This article is protected by copyright. All rights reserved. PMID- 30418705 TI - Effect of disease activity at three and six months on long-term outcomes in ANCA associated vasculitis. AB - INTRODUCTION: The treatment of ANCA associated vasculitis (AAV) aims to suppress disease activity and prevent subsequent disease flare. We explored the association of early disease control with long-term outcomes to validate early disease control as end-points for future clinical trials. METHODS: Data from four inception trials (CYCAZAREM, NORAM, MEPEX & CYCLOPS) and subsequent long-term registry data were studied. Clinical parameters at baseline, three and six months were assessed to study the risk of death and end stage renal failure (ESRF). At six months, outcomes were defined as: sustained remission (remission by three, sustained to six months), late remission (remission after three and by six months), relapsing disease (remission by three months but relapse by six months), or refractory disease (no remission by six months). RESULTS: Of 354 patients followed for a median of 5.7 years, 46(13%) developed ESRF, 66(18.6%) died and 89(25.1%) suffered either death or ESRF. At six months, age (HR=1.02(1-1.05), p=0.012*), eGFR (HR=0.94(0.92-0.95), p=0.001*), disease status at six months: late remission (HR=2.94(1.1-7.85), p=0.031*), relapsing disease (HR=8.21(2.73 24.65), p=0.001*), refractory disease (HR=4.89(1.96-12.18), p=0.001*), predicted the composite end-point of death or ESRF. Similar results were observed when these analyses were performed separately for death and ESRF. CONCLUSIONS: This study suggests that disease status at three and six months may predict the risk of long-term mortality and ESRF in AAV, and that these time points may be valid end-points for induction trials in AAV. These results need to be validated in a larger dataset. This article is protected by copyright. All rights reserved. PMID- 30418704 TI - Sensitivity and specifity of autoantibodies against CD74 in axial spondyloarthritis. AB - OBJECTIVES: Autoantibodies against CD74 (anti-CD74) are associated with ankylosing spondylitis. InterSpA is a multicenter study conducted to compare sensitivity and specificity of anti-CD74 and HLA-B27 in patients with non radiographic axial spondyloarthritis (nr-axSpA). METHODS: Patients aged 18-45 years with inflammatory back pain of <=2 years duration and clinical suspicion of axSpA were recruited. HLA-B27 genotyping and MRI of sacroiliac joints were performed in all patients. 149 patients with chronic back pain not caused by axSpA (CBP) served as controls, furthermore 50 patients with ankylosing spondylitis (AS) and 100 blood donors were analyzed. RESULTS: 100 patients with IBP received the diagnosis of axSpA by the investigators and fulfilled the ASAS criteria. Their mean age was 29 years and the mean symptom duration 12.5 months. The sensitivity of IgA and IgG anti-CD74 related to the 100 axSpA patients was 47% and 17%. The specificity, per definition, was 95.3%, respectively. The sensitivity of HLA-B27 was 81%. The positive likelihood ratios (LR+) were 10.0 (IgA anti-CD74), 3.6 (IgG anti-CD74) and 8.1 (HLA-B27). Assuming a 5% pretest probability of axSpA in CBP patients of 5%, the posttest probability after consideration of the respective positive test results was 33.3% for IgA, 15.3% for IgG antibodies against CD74 and 28.8% for HLA-B27. Combination of IgA antibodies against CD74 and HLA-B27 provides posttest probabilities of 80.2%. CONCLUSIONS: IgA anti-CD74 may be a useful tool for identifying axSpA. The diagnostic value of the test needs to be further proven in daily practice. This article is protected by copyright. All rights reserved. PMID- 30418706 TI - Flow Cytometry Method Validation Protocols. AB - Analytical method validation provides a means to ensure that data are credible and reproducible. This unit will provide a brief introduction to analytical method validation as applied to cellular analysis by flow cytometry. In addition, the unit will provide practical procedures for three different types of validation. The first is a limited validation protocol that is applicable for research settings and non-regulated laboratories. The second is validation protocol that presents the minimum validation requirements in regulated laboratories. The third is a transfer validation protocol to be used when methods are transferred between laboratories. The recommendations presented in this unit are consistent with the white papers published by the American Association of Pharmaceutical Scientists and the International Clinical Cytometry Society, as well as with Clinical Laboratory Standards Institute Guideline H62: Validation of Assays Performed by Flow Cytometry (currently in preparation). (c) 2018 by John Wiley & Sons, Inc. PMID- 30418707 TI - Association of diabetes mellitus and biomarkers of abnormal glucose metabolism with incident radiographic knee osteoarthritis. AB - OBJECTIVE: Whether diabetes mellitus (DM) is associated with increased risk of knee osteoarthritis is uncertain. We evaluated associations of DM and biomarkers of abnormal glucose metabolism with incident radiographic knee osteoarthritis (RKOA), controlling for body mass index (BMI). METHODS: Participants (mean age 60.6+/-7.8 years; mean BMI 29.1+/-4.9 kg/m2 ) were from the Multicenter Osteoarthritis Study (MOST) study and did not have RKOA at baseline (Kellgren and Lawrence [KL] grade <2 bilaterally). A random sample (n=987) stratified by BMI was selected. Baseline serum fasting glucose and insulin resistance (homeostasis model of assessment [HOMA-IR]) were measured. Participants were categorized as having DM based on self-report, use of medication or fasting glucose >126 mg/dL. Incident RKOA (KL grade > 2 or knee replacement) was assessed at 3 follow up visits (30, 60, 84 months). Knee level pooled logistic regression analysis was performed to obtain odds ratios (95% CI) for associations of DM status and biomarkers of abnormal glucose metabolism with incident RKOA. RESULTS: After adjustment for BMI, the odds of incident RKOA were not associated with baseline DM status nor with levels of fasting glucose and HOMA-IR overall and in men. In women, HOMA-IR was inversely associated with odds of incident RKOA (adjusted OR 0.80, 95% CI 0.69-0.94; p=0.005). CONCLUSION: DM and higher levels of biomarkers of abnormal glucose metabolism were not associated with increased odds of incident RKOA after adjusting for BMI in this cohort overall. A possible protective association of higher HOMA-IR with incident RKOA in women deserves further investigation. This article is protected by copyright. All rights reserved. PMID- 30418708 TI - Multidetector Computed Tomographic Anatomy of the Lungs in the Loggerhead Sea Turtle (Caretta caretta). AB - Multidetector computed tomographic (CT) anatomy was used to evaluate the lungs of 10 loggerhead sea turtle (Caretta caretta) without pulmonary disease, in order to provide a baseline of turtle lung anatomy by CT imaging. In all patients, in this retrospective anatomic study, the CT datasets were carefully evaluated for assessment of the bronchial tree morphology and branching pattern, of the arborization pattern of pulmonary arteries and veins and of the bronchoarterial bronchovenous diameter ratios. Imaging anatomy was compared with previous published data based on dissection and microscopic anatomy. With the increasing availability of advanced imaging tools for wildlife animal patients, a detailed CT anatomy background is required to decipher correctly the pathologic respiratory conditions of sea turtles. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30418709 TI - Care of Youth in Their First Emergency Presentation for Psychotic Disorder: A Population-Based Retrospective Cohort Study. AB - OBJECTIVE: Emergency departments (EDs) are often the first point of care for youth with psychotic disorders; however, the care and aftercare they receive have not been well described. The aim of this study was to examine care and aftercare following first ED visit for psychotic disorder among youth. METHODS: We conducted a population-based retrospective cohort study of first ED presentations for psychotic disorder among youth 16 to 24 years old (N = 2,875) in Ontario, Canada. The youth were diagnosed with a psychotic disorder according to ICD-10 coding. We captured all first visits for psychotic disorder between April 2010 and March 2013. Our primary outcome was rate of outpatient mental health care within 30 days. We also examined factors associated with timely psychiatric aftercare, rates of outpatient mental health follow-up by provider type, ED revisit, and psychiatric admission within 30 days and 1 year. RESULTS: Forty percent of youth discharged to the community from their first ED presentation for psychotic disorder received no outpatient mental health care within 30 days. Factors associated with psychiatric aftercare included higher neighborhood income (income quintile 5 vs 1, hazard ratio [HR] = 1.48; 95% CI, 1.05-2.09; P = .026), rural residence (HR = 0.46; 95% CI, 0.31-0.70; P < .001), and mental health care in the 1 year before presentation (outpatient psychiatrist visit: HR = 1.89; 95% CI, 1.50-2.37; P < .001; psychiatric admission: HR = 0.71; 95% CI, 0.52-0.98; P = .038). CONCLUSIONS: Many youth do not receive timely follow-up after their first ED visit for psychotic disorder. There is an urgent need to improve service access for this vulnerable population. PMID- 30418710 TI - Access to Psychotropic Medication via Prescription Is Associated With Choice of Psychotropic Medication as Suicide Method: A Retrospective Study of 27,876 Suicide Attempts. AB - OBJECTIVE: Whether physical access to psychotropic medication via prescription (ie, prescribed access) is associated with use of psychotropic medication as a means of subsequent suicide attempt remains unclear. In a population of suicide attempters, we investigated whether prescribed access to any psychotropic medication increased the likelihood of using any psychotropic drug in a suicide attempt and whether prescribed access to a specific psychotropic drug type increased the likelihood of using that specific psychotropic drug type in an attempt. METHODS: Case-control study design was used. We identified individuals receiving care for a suicide attempt (fatal or nonfatal) in emergency department and inpatient settings from a US insurance claims dataset (2006-2013) using relevant ICD-9-CM codes. Cases used a psychotropic drug in their suicide attempt, while controls used another method. Exposed individuals filled a psychotropic drug prescription within 90 days prior to the attempt. Multivariable logistic regression estimated odds ratios. RESULTS: A population of 27,876 (cases = 10,158, controls = 17,718) was included. Anxiolytics were used most in attempts (n = 6,037, 59.4%), followed by antidepressants (n = 3,573, 35.2%), antipsychotics or mood stabilizers (n = 1,168, 11.5%), and stimulants (n = 368, 3.6%). Thirteen percent (n = 1,316) used more than 1 type of psychotropic drug in the attempt. Across all psychotropic drug groups evaluated, individuals using psychotropic medication in a suicide attempt were significantly more likely to have had prescribed access (adjusted odds ratio [aOR] = 1.7; 95% CI, 1.6-1.9), with the highest drug type-specific odds ratios for antipsychotics or mood stabilizers (aOR = 6.5; 95% CI, 5.4-7.7) and stimulants (aOR = 7.6; 95% CI, 5.5 10.5). CONCLUSIONS: Individuals at high risk for suicide with prescribed access to any psychotropic medication should be targeted for means safety interventions. PMID- 30418734 TI - Beyond the Roles in Biomimetic Chemistry: An Insight into the Intrinsic Catalytic Activity of an Enzyme for Tumor-Selective Phototheranostics. AB - Protein-assisted biomimetic synthesis has been an emerging offshoot of nanofabrication in recent years owing to its features of green chemistry, facile process, and ease of multi-integration. As a result, many proteins have been used for biomimetic synthesis of varying kinds of nanostructures. Although the efforts on exploring new proteins and investigating their roles in biomimetic chemistry are increasing, the most essential intrinsic properties of proteins are largely neglected. Herein we report a frequently used enzyme (horseradish peroxidase, HRP) to demonstrate the possibility of enzymatic activity retaining after accomplishing the roles in biomimetic synthesis of ultrasmall gadolinium (Gd) nanodots and stowing its substrate 2,2'-Azinobis (3-ethylbenzothiazoline-6 sulfonic acid ammonium salt) (ABTS), denoted as Gd@HRPABTS. It was found that ca. 70% of the enzymatic activity of HRP was preserved. The associated changes of protein structure with chemical treatments were studied by spectroscopic analysis. Leveraging on the highly retained catalytic activity, Gd@HRPABTS exerts strong catalytic oxidation of peroxidase substrate ABTS into photoactive counterparts in the presence of intrinsic H2O2 inside the tumor, therefore enabling tumor-selective catalytic photoacoustic (PA) imaging and photothermal therapy (PTT). In addition, the MR moiety of Gd@HRPABTS provides guidance for PTT and further diagrams that Gd@HRPABTS is clearable from the body via kidneys. Preliminary toxicity studies show no observed adverse effects by administration of them. This study demonstrates beyond the well-known roles in biomimetic chemistry that HRP can also preserve its enzymatic activity for tumor catalytic theranostics. PMID- 30418733 TI - Zr2N2O Coating-Improved Corrosion Resistance for the Anodic Dissolution Induced by Cathodic Transient Potential. AB - Developing a corrosion-resistant and electrically conductive coating on metallic bipolar plates is essential to mitigate the performance degradation induced by the high cathodic transient potentials (CTPs) in the start-up/shut-down (SU/SD) processes of polymer electrolyte membrane fuel cells (PEMFCs). Herein, a zirconium oxynitride (Zr2N2O) coating prepared by atomic layer deposition was used to improve the corrosion resistance of 304 stainless steel (304 SS) toward anodic dissolution at various CTPs. Triangular potential pulses were applied to the specimens to simulate potential variations at the cathode side of the PEMFCs at SU/SD stages. Results show that the Zr2N2O coating can provide effective protection at a CTP as positive as 1.1 V versus Ag/AgCl. At all CTPs examined, the peak current density ( ipeak) extracted from the pulse test of the coated specimen (Zr2N2O/SS) is 2 orders of magnitude lower than that of uncoated 304 SS, indicating that the presence of the Zr2N2O coating remarkably increases the corrosion resistance for the anodic dissolution induced by CTPs. More importantly, upon increasing the CTPs, 304 SS experiences severe intergranular corrosion after 4050 pulses, whereas Zr2N2O/SS shows slight pitting corrosion. The quite low ipeak and the mitigated corrosion morphologies of Zr2N2O/SS confirm that incorporating oxygen into the protective coating for achieving a high oxidation resistance is a feasible way to restrain the anodic dissolution caused by high CTPs. Analysis of the electron energy level diagrams of the passive film suggests a protective coating with a wider valence band contributing to the improved corrosion resistance toward the transpassive dissolution. PMID- 30418735 TI - Ethanol and Naltrexone Have Distinct Effects on the Lateral Nano-organization of Mu and Kappa Opioid Receptors in the Plasma Membrane. AB - The complex spatiotemporal organization of proteins and lipids in the plasma membrane is an important determinant of receptor function. Certain substances, such as ethanol, can penetrate into the hydrophobic regions of the plasma membrane. By altering protein-lipid and protein-protein interactions, these substances can modify the dynamic lateral organization and the function of plasma membrane receptors. To assess changes in plasma membrane receptor organization, we used photoactivated localization microscopy (PALM). This single molecule localization microscopy technique was employed to quantitatively characterize the effects of pharmacologically relevant concentrations of ethanol and naltrexone (an opioid receptor antagonist and medication used to treat alcohol use disorders) on the lateral nano-organization of mu and kappa opioid receptors (MOR and KOR, respectively). Ethanol affected the lateral organization of MOR and KOR similarly: It reduced the size and occupancy of opioid receptor nanodomains and increased the fraction of opioid receptors residing outside of nanodomains. In contrast, naltrexone affected MOR and KOR lateral organization differently. It significantly increased KOR surface density, nanodomain size, and the occupancy of KOR nanodomains. However, naltrexone marginally affected these parameters for MOR. Pretreatment with naltrexone largely protected against ethanol-induced changes in MOR and KOR lateral organization. Based on these data, we propose a putative mechanism of naltrexone action that operates in addition to its canonical antagonistic effect on MOR- and KOR-mediated signaling. PMID- 30418736 TI - Simultaneous Observation of Kinesin-Driven Microtubule Motility and Binding of Adenosine Triphosphate Using Linear Zero-Mode Waveguides. AB - Single-molecule fluorescence observation of adenosine triphosphate (ATP) is a powerful tool to elucidate the chemomechanical coupling of ATP with a motor protein. However, in total internal reflection fluorescence microscopy (TIRFM), available ATP concentration is much lower than that in the in vivo environment. To achieve single-molecule observation with a high signal-to-noise ratio, zero mode waveguides (ZMWs) are utilized even at high fluorescent molecule concentrations in the micromolar range. Despite the advantages of ZMWs, the use of cytoskeletal filaments for single-molecule observation has not been reported because of difficulties in immobilization of cytoskeletal filaments in the cylindrical aperture of ZMWs. Here, we propose linear ZMWs (LZMWs) to visualize enzymatic reactions on cytoskeletal filaments, specifically kinesin-driven microtubule motility accompanied by ATP binding/unbinding. Finite element method simulation revealed excitation light confinement in a 100-nm-wide slit of LZMWs. Single-molecule observation was then demonstrated with up to 1 MUM labeled ATP, which was 10-fold higher than that available in TIRFM. Direct observation of binding/unbinding of ATP to kinesins that propel microtubules enabled us to find that significant fraction of ATP molecules bound to kinesins were dissociated without hydrolysis. This highlights the advantages of LZMWs for single molecule observation of proteins that interact with cytoskeletal filaments such as microtubules, myosin filaments, or intermediate filaments. PMID- 30418737 TI - UV-Protective TiO2 Thin Films with High Transparency in Visible Light Region Fabricated via Atmospheric-Pressure Plasma-Enhanced Chemical Vapor Deposition. AB - This article focuses on control of film thickness and roughness to improve the ultraviolet (UV)-protective performance of TiO2 films prepared by atmospheric pressure plasma-enhanced chemical vapor deposition using titanium(IV) isopropoxide (TTIP) as the precursor and argon as the plasma working gas. The relationship between the film morphology and UV-protective performance suggested that a decrease in roughness is the key factor to achieve performance improvement. The effects of substrate temperature and precursor concentration were investigated, and the results showed that an increase in both substrate temperature and precursor concentration reduced the roughness and improved the transparency to visible light without reducing the ability to block UV light. Finally, a TiO2 film with greater than 99% UV light blockage and greater than 95% transmittance of visible light was obtained. PMID- 30418738 TI - Scaling Atomic Layer Deposition to Astronomical Optic Sizes: Low-Temperature Aluminum Oxide in a Meter-Sized Chamber. AB - Atomic Layer Deposition (ALD) is very attractive for producing optical quality thin films, including transparent barrier films on metal-coated astronomical mirrors. To date, ALD of mirror coatings has been limited to relatively small sized substrates. A new ALD tool has been designed, constructed, and tested to apply uniform protective coatings over a 0.9 m diameter substrate in a 1 m diameter scale deposition plane. The new tool, which we have named the meter scale ALD system (MSAS), employs a unique chamber design that isolates a large substrate surface to be coated by utilizing the substrate as a wall of the reaction chamber. The MSAS is mechanically designed to be rapidly reconfigurable for selective area coating of custom substrates with arbitrary shape, size, and permanent backside hardware attachments. The design, implementation, results, and future applications of this new tool are discussed for coating large-area optical substrates, specifically protective coatings for silver mirrors, and other future large astronomical optics. To demonstrate the potential of this new design, aluminum oxide was deposited by thermal ALD using trimethylaluminum and water at a low reaction temperature of 60 degrees C. Growth rate and uniformity, which are dependent on precursor pulse times and chamber purge times, show that the two half-reactions occur in a saturated regime, matching typical characteristics of ideal ALD behavior. Aluminum oxide deposition process parameters of the MSAS are compared with those of a conventional 100 mm wafer-scale ALD tool, and saturated ALD growth over the 0.9 m substrate is realized with a simple scaling factor applied to precursor pulse and purge times. This initial test shows that lateral thickness uniformity across a 0.9 m substrate is within 2.5% of the average film thickness, and simple steps to realize 1% uniformity have been identified for next growths. Results show promising application of transparent robust dielectric films as uniform coatings across large optical components scaled to meter-sized substrates. PMID- 30418739 TI - A Hydrophilic/Hydrophobic Janus Inverse-Opal Actuator via Gradient Infiltration. AB - Janus/gradient actuating materials have become promising candidates for actuating devices. The fabrication of functional Janus gradient actuators remains a challenge. This paper presents a facile fabrication of a hydrophilic/hydrophobic Janus inverse opal actuator via gradient infiltration. The Janus characteristics of the fabricated actuator were attributed to gradient infiltration along the thickness of the film caused by the gradient light intensity and the distinct polymerization behavior of ionic liquids and methyl methacrylate in the methanol system. The Janus film demonstrated directional bending upon water vapor adsorption, with a bending angle approaching 1440 degrees in 4 s, accompanied by structure color/optic signal alteration. The actuating behaviors were effectively modulated by changing the composition of the film and the solvent system. Promising applications of this Janus solvent actuator were demonstrated in two sets of tests: driving an engine and lifting cargo. This work provides insight into the design and fabrication of multifunctional humidity-actuating materials. PMID- 30418740 TI - Direct Patterning of p-Type-Doped Few-layer WSe2 Nanoelectronic Devices by Oxidation Scanning Probe Lithography. AB - Direct, robust, and high-resolution patterning methods are needed to downscale the lateral size of two-dimensional materials to observe new properties and optimize the overall processing of these materials. In this work, we report a fabrication process where the initial microchannel of a few-layer WSe2 field effect transistor is treated by oxygen plasma to form a self-limited oxide layer on top of the flake. This thin oxide layer has a double role here. First, it induces the so-called p-doping effect in the device. Second, it enables the fabrication of oxide nanoribbons with controlled width and depth by oxidation scanning probe lithography (o-SPL). After the removal of the oxides by deionized H2O etching, a nanoribbon-based field-effect transistor is produced. Oxidation SPL is a direct writing technique that minimizes the use of resists and lithographic steps. We have applied this process to fabricate a 5 nm thick WSe2 field-effect transistor, where the channel consists in an array of 5 parallel 350 nm half-pitch nanoribbons. The electrical measurements show that the device presents an improved conduction level compared to the starting thin-layer transistor and a positive threshold voltage shift associated to the p-doping treatment. The method enables to pattern devices with sub-50 nm feature sizes. We have patterned an array of 10 oxide nanowires with 36 nm half-pitch by oxidation SPL. PMID- 30418741 TI - Effect of Growth Temperature during the Atomic Layer Deposition of the SrTiO3 Seed Layer on the Properties of RuO2/SrTiO3/Ru Capacitors for Dynamic Random Access Memory Applications. AB - The atomic layer deposition process of SrTiO3 (STO) films at 230 degrees C was studied with Sr(iPr3Cp)2 and Ti(CpMe5)(OMe)3 (Pr, Cp, and Me are propyl, cyclopentadienyl, and methyl groups, respectively) on Ru substrates. The growth behavior and properties of STO films grown at 230 degrees C were compared with those deposited at 370 degrees C. With the limited over-reaction of the Sr precursor during the initial growth stage at a lower temperature, the cation composition was more controllable, and the surface morphology after crystallization annealing at 650 degrees C had more uniform grains with fewer defects. Here, the excess reaction of the Sr precursor means the chemical-vapor deposition-like growth of the SrO component mediated through the thermal decomposition of the adsorbed Sr precursor molecules. It was by the reaction of the Sr precursor with the oxygen supplied from the partly oxidized Ru substrate. The second STO was grown at 370 degrees C (main layer) on the annealed first STO layer (crystallized seed layer) to lead to the in situ crystallization of the main layer. Due to the improved microstructure of STO films induced by the seed layer deposited at 230 degrees C, the bulk dielectric constant of 167 was obtained for the main layer, which was higher than the value of 101 where the seed layer was deposited at 370 degrees C, even though the crystallization annealing condition of the seed layer and the deposition condition of the main layer were consistent. The seed layer grown at 230 degrees C, however, had a lower dielectric constant of only ~49, whereas the high-temperature seed layer had a dielectric constant of ~106. Therefore, the low-temperature seed layer posed a severe limitation in acquiring an advanced capacitor property with the involvement of a low-dielectric interfacial layer. PMID- 30418742 TI - Ultrathin Polyamide Membrane with Decreased Porosity Designed for Outstanding Water-Softening Performance and Superior Antifouling Properties. AB - Poly(piperazine-amide)-based nanofiltration membranes exhibit a smooth surface and superior antifouling properties but often have lower Ca2+ and Mg2+ rejection due to their larger inner micropore and thus cannot be extensively used in water softening applications. To decrease the pore size of poly(piperazine-amide) membranes, we designed and synthesized a novel monomer, 1,2,3,4-cyclobutane tetracarboxylic acid chloride (BTC), which possesses a smaller molecular conformation than trimesoyl chloride (TMC). The thickness of the prepared BTC piperazine (PIP) polyamide nanofilm via interfacial polymerization is as thin as 15 nm, significantly lower than the 50 nm thickness of the TMC-PIP nanofilm. The surface characterization reveals that the BTC-PIP polyamide membrane exhibits an enhanced hydrophilicity, a smooth surface, and a decreased surface-negative charge. The desalination performance (both rejection and water flux) of these membranes in terms of Ca2+ and Mg2+ exceeds that of the current commercial water softening membranes. In addition, the BTC-PIP polyamide membrane also exhibits superior antifouling properties compared to the TMC-based polyamide membrane. More importantly, molecular simulations show that the BTC-PIP membrane has a lower average pore size than that of the TMC-PIP membrane, which demonstrates an enhanced steric hindrance effect, as confirmed by desalination performance. Our results demonstrate that in the household and industrial water-softening market, BTC-PIP membrane with decreased porosity, enhanced hydrophilicity, and smooth surface is preferred alternative to the conventional TMC-based polyamide membranes. PMID- 30418743 TI - Confining Redox Electrolytes in Functionalized Porous Carbon with Improved Energy Density for Supercapacitors. AB - It is a big challenge to improve the energy density of the carbon-based supercapacitors for wide applications. In this work, considering the properties of redox electrolytes, functionalized porous carbon has been synthesized with interconnected pores and oxygen functional groups, which is employed to well hold the redox electrolyte ions. As a result, the functionalized porous carbon shows a high capacitance of 454 F g-1 at a current density of 1 A g-1 and can maintain 88% of the initial capacitance after 10 000 charge-discharge cycles at 10 A g-1. Especially, the as-prepared asymmetric supercapacitor obtains high energy density of 36.9 W h kg-1 at the power density of 225 W kg-1. This new design strategy by coordinating carbon materials with the redox electrolytes will guide the development of high-energy density supercapacitors. PMID- 30418744 TI - Luminescent Carrier, Tb3+-Doped Layered Yttrium Hydroxide, for Delivery Systems. AB - Layered rare-earth hydroxides (LRHs) with high anion exchangeability between the hydroxocation layers, where a large variety of organic anions can be sheltered, are employed to construct hybrid systems that slowly release active organic ingredients. More importantly, it is possible to endow LRHs with a photoluminescence capability by doping activator ions such as Ce3+, Eu3+, and Tb3+ into matrices. In the present work, we explored Tb3+-doped layered yttrium hydroxide Y1.80Tb0.20(OH)5Cl. nH2O (LYH:Tb) nanosheets as a luminescent carrier for sustained release of salicylic acid (2-hydroxybenzoic acid), an example of nonsteroidal anti-inflammatory drugs and antimicrobial agents. Salicylate (sal) was intercalated into the interlayer gallery of LYH:Tb via a direct ion-exchange reaction. An observed variation in basal spacing suggested that salicylate anions are arranged in an interdigitated bilayer manner in the interlayer space of LYH:Tb. As generally observed in organic/inorganic hybrid systems, the thermal and photostabilities of salicylate were significantly improved after intercalation compared to its free state. The release kinetics of salicylate from sal-LYH:Tb hybrids in a saline solution at pH = 7.4 showed a highly sustained release of salicylate. Among various examined mathematical models, the parabolic diffusion equation best described the cumulative salicylate release. In particular, the salicylate intercalation led to the characteristic 5D4 -> 7F J ( J = 6, 5, and 4) green emission of Tb3+ by its sensitization followed by the energy transfer to sal-LYH:Tb, whereas typical blue emission of salicylate was recovered after its release from the interlayer gallery of the LYH:Tb carrier. This green/blue luminescence change behavior provides a useful technique for in situ monitoring of the delivery and release of salicylate at target sites. The sal-LYH:Tb hybrid, with antimicrobial properties, was readily dispersed into a biodegradable polymer, polyvinyl alcohol, to prepare a transparent, UV-shielding, and luminescent composite that is applicable as an antimicrobial polymer to retard or prevent microbial growth. PMID- 30418745 TI - Unusual Methylenediolate Bridged Hexanuclear Ruthenium(III) Complexes: Syntheses and Their Application. AB - Three structurally analogous hexanuclear ruthenium(III) complexes were isolated with the general molecular formula of [Ru6III(O)2(MU4-eta2-eta2-CH2O2)( t BuCO2)12(L)2] where L = pyridine (1) or 4-dimethylamino pyridine (DMAP; 2) or 4 cyanopyridine (3). Complexes 1 and 3 were solved in the tetragonal I4c2 and P41212 space group, respectively, while 2 crystallized in the monoclinic system with P21 /c space group. In all three complexes, two oxo-centered Ru(III) triangles were bridged by a unique and a rare methylenediolate (CH2O2)2-) ligand. This (CH2O2)2- group is reported to be an intermediate, which is not isolated in its metal-free form, to date, as it is unstable. Control experiments performed evidently reveal that the unique reaction condition followed is mandatory to isolate 1-3 and the origin of (CH2O2)2- is unknown at the moment, as no precursor was used to form this intermediate. The presence of (CH2O2)2- identified through X-ray diffraction was further unambiguously confirmed by various 1D (1H and 13C) and 2D-NMR (HSQC, TOCSY, NOESY, and DEPT) spectroscopies. Direct current (dc) magnetic susceptibility measurements performed on 1 and 2 reveal the predominant antiferromagnetic exchange interaction between the Ru(III) centers result in a diamagnetic ground state at 2.0 K. The paramagnetic influence of 1-3 at room temperature evidently felt by the 1H nuclei of the (CH2O2)2- unit predominates compared to other NMR active nuclei in the complexes. The presence of an electron donating or withdrawing substituent on the terminal pyridine results in significant change in the dihedral angle of two oxo-centered triangular (Ru3O-) planes. The change in the structural parameters of 1-3 due to the substituents markedly reflected on the absorption profile and redox behavior, which are systematically investigated. Preliminary galvanostatic charge/discharge cycling experiments performed on a representative complex (3) suggest that 3 can be a promising candidate to employ as an effective multiple electron charge carrier in a nonaqueous redox flow battery. PMID- 30418746 TI - Selective Synthesis of Site-Differentiated Fe4S4 and Fe6S6 Clusters. AB - Obtaining rational control over the structure and nuclearity of metalloclusters is an ongoing challenge in synthetic Fe-S cluster chemistry. We report a new family of tridentate imidazolin-2-imine ligands L(NImR)3 that can bind [Fe4S4]2+ or [Fe6S6]3+ clusters, depending on the steric profile of the ligand and the reaction stoichiometry. A high-yielding synthetic route to L(NImR)3 ligands (where R is the imidazolyl N substituents) from trianiline and 2 chloroimidazolium precursors is described. For L(NImMe)3 (tris(1,3,5-(3-( N, N dimethyl-4,5-diphenylimidazolin-2-imino)phenylmethyl))benzene), metalation with 1 equiv of [Ph4P]2[Fe4S4Cl4] and 3 equiv of NaBPh4 furnishes a mixture of products, but adjusting the stoichiometry to 1.5 equiv of [Ph4P]2[Fe4S4Cl4] provides (L(NImMe)3)Fe6S6Cl6 in high yield. Formation of an [Fe6S6]3+ cluster using L(NImTol)3 (tris(1,3,5-(3-( N, N-bis(4-methylphenyl)-4,5-diphenylimidazolin-2 imino)phenylmethyl))benzene) is not observed; instead, the [Fe4S4]2+ cluster [(L(NImTol)3)(Fe4S4Cl)][BPh4] is cleanly generated when 1 equiv of [Ph4P]2[Fe4S4Cl4] is employed. The selectivity for cluster nuclearity is rationalized by the orientation of the imidazolyl rings whereby long N-imidazolyl substituents preclude formation of [Fe6S6]3+ clusters but not [Fe4S4]2+ clusters. Thus, the structure and nuclearity of L(NImR)3-bound Fe-S clusters may be selectively controlled through rational modification the ligand's substituents. PMID- 30418747 TI - Processing Lignocellulose-Based Composites into an Ultrastrong Structural Material. AB - Natural lignocellulose has been a significant renewable raw material attributable to its high specific mechanical performance, compared to the benefits of traditional reinforcing fibers. However, the unsatisfactory mechanical performance of lignocellulose-based materials has limited applications in many advanced engineering domains. Herein, we demonstrate that layered bulk delignified nanolignocellulose/brushite composites with a multifold increase in strength and toughness. Our procedure contains the partially removable lignin and hemicellulose from the nanolignocellulose and the precipitating process of brushite on the nanolignocellulose surface via the mechanochemical process and flow-directed assembly followed by hot-pressing, resulting in the complete toppling of cell walls and the densification of the nanolignocellulose/brushite composites with highly ordered layered structures. This composite exhibits an ultrastrong specific strength 1.8-4.4 times higher than that of modified lignocellulose-based materials, which surpasses that of most natural structural materials and some metals and alloys, opening a path for production of ultrastrong lignocellulose-based load-bearing materials in practical applications by various farming and forestry surplus operations. PMID- 30418748 TI - Sustainability analysis of microalgae production systems - A review on resource with unexploited high-value reserves. AB - Sustainability, at present, is a prominent aspect in the development of any production system that aims to provide the energy resources of the future. Developing sustainable bioenergy production technologies is no mean task. Microalgae appear to be a promising feedstock, however, the sustainability of algae based production systems is still on debate. Commercial market volumes of algae derived products are still narrow. The extraction and conversion of primary metabolites to biofuels requires cultivation at large scales; cost-effective methods are therefore highly desirable. This review sets the attention on sustainability analysis of microalgae production systems, focusing majorly on techno-economic constrains and challenges, life cycle analysis and socio environmental impacts, both in medium-scale cultivars intended for the production of high added value secondary metabolites and/or in large-scale plants for biofuel production derived from primary metabolites. PMID- 30418749 TI - Acidity/Reducibility Dual-Responsive Hollow Mesoporous Organosilica Nanoplatforms for Tumor-Specific Self-Assembly and Synergistic Therapy. AB - Featured with a large surface area, uniform interpenetrating mesopores, diverse organic framework hybridization, and well-defined surface properties, the hollow mesoporous organosilica nanoparticle (HMON) represents a promising paradigm in drug delivery systems with excellent biocompatibility. However, effective tumor accumulation and precise cancer theranostics of the HMON still remain a challenge. In this study, an "ammonia-assisted hot water etching" method is applied for the successful construction of sub-50 nm thioether/phenylene dual hybridized HMON with low hemolytic effect. Particularly, the surface modification with Mo(VI)-based polyoxometalate (POM) clusters drives the self-assembly of HMON in the mild acidic tumor microenvironment (TME) to achieve enhanced tumor retention and accumulation. More importantly, the reducibility-activated Mo(VI) to-Mo(V) conversion within POM not only endows the POM-anchored HMON with outstanding TME-responsive photoacoustic (PA) imaging contrast and photothermal therapy (PTT) performance but also plays an indispensable role in controllably triggering the decomposition of the Mn2(CO)10 payload for CO release, which gives rise to remarkable synergistic PTT-enhanced CO gas therapy for complete tumor eradication. By harnessing the unique acidic and redox properties of TME, the judiciously designed smart POM-anchored HMON nanoplatform is expected to act as a "magic bomb" to selectively destroy cancer without damaging normal tissues. This nanoplatform holds significant potential in realizing TME-responsive self assembly for enhanced tumor accumulation and precise tumor-specific synergistic therapy, which is very promising for clinical translation. PMID- 30418750 TI - Switching the Spin-Crossover Phenomenon by Ligand Design on Imidazole Diazineiron(II) Complexes. AB - The iron(II) complexes of two structural isomers of 2-(1 H-imidazol-2-yl)diazine reveal how ligand design can be a successful strategy to control the electronic and magnetic properties of complexes by fine-tuning their ligand field. The two isomers only differ in the position of a single diazinic nitrogen atom, having either a pyrazine (Z) or a pyrimidine (M) moiety. However, [Fe(M)3](ClO4)2 is a spin-crossover complex with a spin transition at 241 K, whereas [Fe(Z)3](ClO4)2 has a stable magnetic behavior between 2 and 300 K. This is corroborated by temperature-dependent Mossbauer spectra showing the presence of a quintet and a singlet state in equilibrium. The temperature-dependent single-crystal X-ray diffraction results relate the spin-crossover observed in [Fe(M)3](ClO4)2 to changes in the bond distances and angles of the coordination sphere of iron(II), hinting at a stronger sigma donation of ligand Z in comparison to ligand M. The UV/vis spectra of both complexes are solved by means of the multiconfigurational wave-function-based method CASPT2 and confirm their different spin multiplicities at room temperature, as observed in the Mossbauer spectra. Calculations show larger stabilization of the singlet state in [Fe(Z)3]2+ than in [Fe(M)3]2+, stemming from the slightly stronger ligand field of the former (506 cm-1 in the singlet). This relatively weak effect is indeed capable of changing the spin multiplicity of the complexes and causes the appearance of the spin transition in the M complex. PMID- 30418751 TI - Exceptional Adsorption and Binding of Sulfur Dioxide in a Robust Zirconium-Based Metal-Organic Framework. AB - We report a record-high SO2 adsorption capacity of 12.3 mmol g-1 in a robust porous material, MFM-601, at 298 K and 1.0 bar. SO2 adsorption in MFM-601 is fully reversible and highly selective over CO2 and N2. The binding domains for adsorbed SO2 and CO2 molecules in MFM-601 have been determined by in situ synchrotron X-ray diffraction experiments, giving insights at the molecular level to the basis of the observed high selectivity. PMID- 30418752 TI - Mitochondria-Targeted DNA Nanoprobe for Real-Time Imaging and Simultaneous Quantification of Ca2+ and pH in Neurons. AB - Herein, a single highly selective DNA nanoprobe was designed and created for the real-time imaging and simultaneous quantification of two kinds of biological species using Ca2+ and pH; the molecules were selected as models because of their close relationship with cellular functions and diseases. A Ca2+ fluorescent probe was synthesized and assembled onto a DNA nanostructure together with pH responsive, inner-reference, and mitochondria-targeted molecules. This nanoprobe with high spatial resolution, together with long-term fluorescent and structural stability, powerfully tracked pH and Ca2+ dynamics at the same localization in mitochondria in response to O2*--induced oxidative stress and aggregated amyloid beta (Abeta) stimulation with a temporal resolution of milliseconds. Using this tool, we discovered that O2*- and Abeta triggered transitory cytoplasmic acidosis and then activated acid-sensing ion channel 1a (ASIC1a) in the mitochondrial membrane, leading to mitochondrial Ca2+ overload and pH abnormalities, which contribute to neuron death. Moreover, psalmotoxin 1 effectively protected against O2*-- and Abeta-induced neuron injury. PMID- 30418753 TI - Cell-Based Biosensor with Dual Signal Outputs for Simultaneous Quantification of Phenylacetic Acid and Phenylethylamine. AB - Despite the importance of 2-phenylacetic acid, a plant hormone in the endogenous auxin family, its biosynthesis pathway has yet to be elucidated. In this study, we developed a novel whole-cell biosensor for the simultaneous quantification of 2-phenylacetic acid (PA) and 2-phenylethylamine (PEA) through the regulation of bacterial catabolism of aromatic compounds. We used the PA regulon to enable the recognition of PA and PEA. Differentiation of PEA from PA involves the incorporation of the FeaR regulon within the same whole-cell biosensor to report the presence of aromatic amines. The proposed system is highly sensitive to PA as well as PEA. PMID- 30418754 TI - Environmental DNA Metabarcoding Supporting Community Assessment of Environmental Stressors in a Field-Based Sediment Microcosm Study. AB - Conventional ecological risk assessment on toxic stressors in sediment is limited to a small and selected fraction of benthic communities. Ecogenomic approaches provide unprecedented capacity to monitor the changes of biodiversity and community composition in the field, but how to utilize it to assess ecological impact by contaminates remains largely unexplored. Here, an environmental DNA (eDNA) metabarcoding approach was used to assess the effect of copper on changes in biodiversity and community composition across the tree of life (including bacteria, protists, algae, fungi, and metazoa) in a field-based microcosm. Many microorganisms across a broad range of taxa groups changed their relative abundance in response to increased copper concentrations in sediments. Changes in community structure of microbiota appeared to be more sensitive to copper than survival of laboratory-bred organisms and indigenous macroinvertebrates. Copper caused a significant shift in prokaryotic community composition via substitution of dominant species. Network heterogeneity and Shannon diversity of the bacterial community decreased in the high copper treatments. eDNA metabarcoding assessed the effects of copper-contaminated sediment with less effort than manually processing samples. Our study highlighted the value of community profiling by an eDNA-based approach in prospective and retrospective risk assessment of environmental stressors. PMID- 30418755 TI - Paramagnetism and Fluorescence of Zinc(II) Tripyrrindione: A Luminescent Radical Based on a Redox-Active Biopyrrin. AB - The ability of bilins and other biopyrrins to form fluorescent zinc complexes has been known for more than a century; however, the exact identity of the emissive species remains uncertain in many cases. Herein, we characterize the hitherto elusive zinc complex of tripyrrin-1,14-dione, an analogue of several orange urinary pigments. As previously observed for its Pd(II), Cu(II), and Ni(II) complexes, tripyrrindione binds Zn(II) as a dianionic radical and forms a paramagnetic complex carrying an unpaired electron on the ligand pi-system. This species is stable at room temperature and undergoes quasi-reversible ligand-based redox chemistry. Although the complex is isolated as a coordination dimer in the solid state, optical absorption and electron paramagnetic resonance spectroscopic studies indicate that the monomer is prevalent in a tetrahydrofuran solution. The paramagnetic Zn(II) tripyrrindione complex is brightly fluorescent (lambdaabs = 599 nm, lambdaem = 644 nm, PhiF = 0.23 in THF), and its study provides a molecular basis for the observation, made over several decades since the 1930s, of fluorescent behavior of tripyrrindione pigments in the presence of zinc salts. The zinc-bound tripyrrindione radical is thus a new addition to the limited number of stable radicals that are fluorescent at room temperature. PMID- 30418756 TI - Cinnamaldehyde-Based Poly(ester-thioacetal) To Generate Reactive Oxygen Species for Fabricating Reactive Oxygen Species-Responsive Nanoparticles. AB - Due to the high oxidative stress of the tumor microenvironment, more and more researchers have been devoted to reactive oxygen species (ROS)-responsive nanodrug delivery systems for anticancer therapy. Herein, a ROS-responsive moiety, thioacetal, was synthesized, and cinnamaldehyde (CA) was introduced in the polymer chain to trigger the generation of ROS to expect the enhancement of the ROS-responsive effect. The poly(ester-thioacetal) mPEG2k - b-(NTA-HD)12 polymer, its self-assembled micelles, and the ROS-responsive behavior were characterized by 1H NMR and DLS. The anticancer drug doxorubicin (DOX) was adopted to prepare DOX-loaded poly(ester-thioacetal) micelles. The intracellular ROS detection indicated that the mPEG2k - b-(NTA-HD)12 polymer could degrade via the high concentration of ROS in cancer cells, and the released CA stimulated mitochondria to regenerate additional ROS. The flow cytometry results indicated that the ROS-responsive polymeric micelles showed faster cellular uptake compared to the control mPEG2k - b-PCL5k micelles. The ROS responsive DOX/mPEG2k - b-(NTA HD)12 micelles exhibited much better anticancer efficiency on both 4T1 and HeLa cancer cells than DOX/mPEG2k - b-PCL5k micelles. PMID- 30418757 TI - Inhibiting APOBEC3 Activity with Single-Stranded DNA Containing 2' Deoxyzebularine Analogues. AB - APOBEC3 enzymes form part of the innate immune system by deaminating cytosine to uracil in single-stranded DNA (ssDNA) and thereby preventing the spread of pathogenic genetic information. However, APOBEC mutagenesis is also exploited by viruses and cancer cells to increase rates of evolution, escape adaptive immune responses, and resist drugs. This raises the possibility of APOBEC3 inhibition as a strategy for augmenting existing antiviral and anticancer therapies. Here we show that, upon incorporation into short ssDNAs, the cytidine nucleoside analogue 2'-deoxyzebularine (dZ) becomes capable of inhibiting the catalytic activity of selected APOBEC variants derived from APOBEC3A, APOBEC3B, and APOBEC3G, supporting a mechanism in which ssDNA delivers dZ to the active site. Multiple experimental approaches, including isothermal titration calorimetry, fluorescence polarization, protein thermal shift, and nuclear magnetic resonance spectroscopy assays, demonstrate nanomolar dissociation constants and low micromolar inhibition constants. These dZ-containing ssDNAs constitute the first substrate like APOBEC3 inhibitors and, together, comprise a platform for developing nucleic acid-based inhibitors with cellular activity. PMID- 30418758 TI - Correction to "Nonviral Genome Editing Based on a Polymer-Derivatized CRISPR Nanocomplex for Targeting Bacterial Pathogens and Antibiotic Resistance". PMID- 30418759 TI - Experimental evaluation of coevolution in a self-assembling particle. AB - Protein evolution occurs via restricted evolutionary paths that are influenced by both previous and subsequent mutations. This effect, termed epistasis, is critical in population genetics, drug resistance, and immune escape; however, the effect of epistasis on the level of protein fitness is less well characterized. We generated and characterized a 6,615-member library of all two amino acid combinations in a highly mutable loop of a virus-like particle. This particle is a model of protein self-assembly and a promising vehicle for drug delivery and imaging. In addition to characterizing the effect of all double mutants on assembly, thermostability, and acid stability, we observed many instances of epistasis, where combinations of mutations are either more deleterious or more beneficial than expected. These results were used to generate rules governing the effects of multiple mutations on the self-assembly of the virus-like particle. PMID- 30418760 TI - Ultrasensitive Detection of DNA Based on Exonuclease III-Assisted Recycling Amplification and DNAzyme Motor. AB - Herein, we have developed a dual amplification strategy for ultrasensitive detection of DNA combining exonuclease III (Exo III)-assisted reaction and DNAzyme motor. DNA probes are carefully designed; thus, target recognition and the first amplification cycle are accomplished simultaneously, which makes the operation very convenient. Moreover, the self-powered DNAzyme motor may translate a single binding event into cleavage of multiple fluorescence probes, which significantly heightens the signal intensity. As a result, the limit of detection as low as 21 fM is achieved. The fluorescence intensity is found to have a linear relationship with respect to the logarithm of DNA concentration in a wide range from 100 fM to 10 nM. This proposed method shows great potential for the applications of biological studies and clinical diagnosis. PMID- 30418761 TI - Molecular Thorium Compounds with Dichalcogenide Ligands: Synthesis, Structure, 77Se NMR Study, and Thermolysis. AB - A series of dimeric thorium disulfides and diselenides have been prepared with sterically undemanding ancillary ligands. Five complexes, (py)6Th2I4(MU2-S2)2, (py)6Th2Br2(SC6F5)2(MU2-S2)2, (py)6Th2I4(MU2-Se2)2, (py)6Th2I2(SC6F5)2(MU2-Se2)2, and (py)6Th2Br2(SC6F5)2(MU2-Se2)2, were isolated in high yields by first reducing mixtures of I2, F5C6SSC6F5, PhSeSePh, or PhSSPh, and PhSeBr with elemental Th, followed by in situ ligand-based redox reactions with elemental sulfur or selenium. These are the first examples of thorium compounds with bridging dichalcogenide ligands. Attempts to prepare chloride derivatives gave mixtures of (py)4ThCl4 and either (py)6Th2Cl2(SC6F5)2(MU2-S2)2 or (py)8Th4Se4(SePh)4(SC6F5)4. All products were characterized by single-crystal and powder X-ray diffraction and IR, UV-visible, and NMR spectroscopy. A computational analysis of experimental 77Se NMR chemical shifts reveals that the solvated dimeric structures with two bridging dichalcogenides are maintained in solution. Thermolysis of (py)6Th2I4(MU2-Se2)2 leads to reduction of the bridging Se22- moieties, oxidation of the I- ligand, and formation of solid-state ThSe2 and I2. PMID- 30418762 TI - Amino Acid Misincorporation Propensities Revealed through Systematic Amino Acid Starvation. AB - Elevated amino acid misincorporation levels during protein translation can cause disease and adversely impact biopharmaceutical product quality. Our previous work, along with that of others, identified numerous low-level unintended sequence variants. However, because of the limited analytical detection efficiency, we believed that these observations represented only a fraction of biologically relevant outcomes. Because amino acid misincorporation can be exacerbated by amino acid starvation, we believed that a more comprehensive set of sequence variants could be derived through systematic starvation. Our goals for this study were therefore (1) to systematically characterize misincorporation patterns under amino acid starvation and (2) to elucidate the major misincorporation mechanisms and propensities for cultured mammalian cells. To the best of our knowledge, this is the first study to use controlled systematic starvation to maximize the observation of unique sequence variants to provide a more holistic perspective of amino acid misincorporation. Our findings bridge the two prevailing lines of research and propose that both base mismatches during codon recognition (especially G/U and wobble mismatches) and misacylation are common and major amino acid misincorporation mechanisms. This proposal is also supported by the observation of mechanistic additivity between the base mismatch and misacylation mechanisms. In addition, we observed significant overlap in misincorporation mechanisms and propensities among cell lines and organisms. Lastly, we explored factors that can lead to codon-associated misincorporation behavior. PMID- 30418763 TI - Puromycins B-E, Naturally Occurring Amino-Nucleosides Produced by the Himalayan Isolate Streptomyces sp. PU-14G. AB - The isolation and structure elucidation of four new naturally occurring amino nucleoside [puromycins B-E (1-4)] metabolites from a Himalayan isolate ( Streptomyces sp. PU-14-G, isolated from the Bara Gali region of northern Pakistan) is reported. Consistent with prior reports, comparative antimicrobial assays revealed the need for the free 2"-amine for anti-Gram-positive bacteria and antimycobacterial activity. Similarly, comparative cancer cell line cytotoxicity assays highlighted the importance of the puromycin-free 2"-amine and the impact of 3'-nucleoside substitution. These studies extend the repertoire of known naturally occurring puromycins and their corresponding SAR. Notably, 1 represents the first reported naturally occurring bacterial puromycin-related metabolite with a 3'- N-amino acid substitution that differs from the 3'- N tyrosinyl of classical puromycin-type natural products. This discovery suggests the biosynthesis of 1 in Streptomyces sp. PU-14G may invoke a uniquely permissive amino-nucleoside synthetase and/or multiple synthetases and sets the stage for further studies to elucidate, and potentially exploit, new biocatalysts for puromycin chemoenzymatic diversification. PMID- 30418764 TI - Addressing Multiple Resistive States of Polyoxovanadates: Conductivity as a Function of Individual Molecular Redox States. AB - The sustainable development of IT-systems requires a quest for novel concepts to address further miniaturization, performance improvement, and energy efficiency of devices. The realization of these goals cannot be achieved without an appropriate functional material. Herein, we target the technologically important electron modification using single polyoxometalate (POM) molecules envisaged as smart successors of materials that are implemented in today's complementary metal oxide-semiconductor (CMOS) technology. Lindqvist-type POMs were physisorbed on the Au(111) surface, preserving their structural and electronic characteristics. By applying an external voltage at room temperature, the valence state of the single POM molecule could be changed multiple times through the injection of up to 4 electrons. The molecular electrical conductivity is dependent on the number of vanadium 3d electrons, resulting in several discrete conduction states with increasing conductivity. This fundamentally important finding illustrates the far reaching opportunities for POM molecules in the area of multiple-state resistive (memristive) switching. PMID- 30418765 TI - Hinge-Linker Elements in the AAA+ Protein Unfoldase ClpX Mediate Intersubunit Communication, Assembly, and Mechanical Activity. AB - The ClpXP protease plays important roles in protein homeostasis and quality control. ClpX is a ring-shaped AAA+ homohexamer that unfolds target proteins and translocates them into the ClpP peptidase for degradation. AAA+ modules in each ClpX subunit-consisting of a large AAA+ domain, a short hinge-linker element, and a small AAA+ domain-mediate the mechanical activities of the ring hexamer. Here, we investigate the roles of these hinge-linker elements in ClpX function. Deleting one hinge-linker element in a single-chain ClpX pseudohexamer dramatically decreases unfolding and degradation activity, in part by compromising the formation of closed rings, protein-substrate binding, and ClpP binding. Covalently reclosing the broken hinge-linker interface rescues activity. Deleting one hinge-linker element from a single-chain dimer or trimer prevents assembly of stable hexamers. Mutationally disrupting a hinge-linker element preserves closed-ring assembly but reduces ATP-hydrolysis cooperativity and degradation activity. These results indicate that hinge-linker length and flexibility are optimized for efficient substrate unfolding and support a model in which the hinge-linker elements of ClpX facilitate efficient degradation both by maintaining proper ring geometry and facilitating subunit-subunit communication. This model informs our understanding of ClpX as well as the larger AAA+ family of motor proteins, which play diverse roles in converting chemical into mechanical energy in all cells. PMID- 30418766 TI - Kinase and Histone Deacetylase Hybrid Inhibitors for Cancer Therapy. AB - Histone deacetylases (HDACs), encompassing at least 18 members, are promising targets for anticancer drug discovery and development. To date, five histone deacetylase inhibitors (HDACis) have been approved for cancer treatment, and numerous others are undergoing clinical trials. It has been well validated that an agent that can simultaneously and effectively inhibit two or more targets may offer greater therapeutic benefits over single-acting agents in preventing resistance to treatment and in potentiating synergistic effects. A prime example of a bifunctional agent is the hybrid HDAC inhibitor. In this perspective, the authors review the majority of reported kinase/HDAC hybrid inhibitors. PMID- 30418767 TI - A Modified Shifted Force Approach to the Wolf Summation. AB - The Wolf method for calculation of electrostatic interactions in molecular simulations is known to describe the energy well, whereas the forces have discontinuities. For a more reliable description of the forces this method can be extended with a shifted force approach. This leads to a good description of the forces and precise molecular dynamics simulation, but the description of the energy becomes poorer. In this study we propose a modification of a shifted force extension to describe the energy as well as the forces in better agreement to reference data as determined from the Ewald summation. We show that vapor-liquid phase equilibria (VLE) calculated with Monte Carlo simulations in the grand canonical ensemble and dynamic properties calculated with molecular dynamics simulations can be calculated reliably using this modification to describe the electrostatic interactions. PMID- 30418768 TI - Advancing the Development of Highly-Functionalizable Glucose-Based Polycarbonates by Tuning of the Glass Transition Temperature. AB - Fundamental studies that gain an understanding of the tunability of physical properties of natural product-based polymers are vital for optimizing their performance in extensive applications. Variation of glass transition temperature ( Tg) was studied as a function of the side chain structure and molar mass for linear poly(glucose carbonate)s. A remarkable range of Tg values, from 38 to 125 degrees C, was accomplished with six different alkyloxycarbonyl side chains. The impact of molar mass on Tg was investigated for two series of polymers and discrete oligomers synthesized and fractionated with precise control over the degrees of polymerization. The Tg was found to be greatly influenced by a synergistic effect of the flexibility and bulkiness of the repeating unit side chain, as well as the chain end relative free volume. This work represents an important advance in the development of glucose-based polycarbonates, as materials that possess high degrees of functionalizability to be capable of exhibiting diversified physicochemical and thermal properties by simple side chain modification. PMID- 30418769 TI - Improved Speed and Scaling in Orbital Space Variational Monte Carlo. AB - In this work, we introduce three algorithmic improvements to reduce the cost and improve the scaling of orbital space variational Monte Carlo (VMC). First, we show that, by appropriately screening the one- and two-electron integrals of the Hamiltonian, one can improve the efficiency of the algorithm by several orders of magnitude. This improved efficiency comes with the added benefit that the cost of obtaining a constant error per electron scales as the second power of the system size O( N2), down from the fourth power O( N4). Using numerical results, we demonstrate that the practical scaling obtained is, in fact, O( N1.5) for a chain of hydrogen atoms. Second, we show that, by using the adaptive stochastic gradient descent algorithm called AMSGrad, one can optimize the wave function energies robustly and efficiently. Remarkably, AMSGrad is almost as inexpensive as the simple stochastic gradient descent but delivers a convergence rate that is comparable to that of the Stochastic Reconfiguration algorithm, which is significantly more expensive and has a worse scaling with the system size. Third, we introduce the use of the rejection-free continuous time Monte Carlo (CTMC) to sample the determinants. Unlike the first two improvements, CTMC does come at an overhead that the local energy must be calculated at every Monte Carlo step. However, this overhead is mitigated to a large extent because of the reduced scaling algorithm, which ensures that the asymptotic cost of calculating the local energy is equal to that of updating the walker. The resulting algorithm allows us to calculate the ground state energy of a chain of 160 hydrogen atoms using a wave function containing ~2 * 105 variational parameters with an accuracy of 1 mEh/particle at a cost of just 25 CPU h, which when split over 2 nodes of 24 processors each amounts to only about half hour of wall time. This low cost coupled with embarrassing parallelizability of the VMC algorithm and great freedom in the forms of usable wave functions, represents a highly effective method for calculating the electronic structure of model and ab initio systems. PMID- 30418770 TI - Glufosinate Resistance Level is Proportional to Phosphinothricin Acetyltransferase Gene Expression in Glufosinate-Resistant Maize. AB - Phosphinothricin acetyltransferase ( pat) gene confers resistance to glufosinate by transforming this herbicide into N-acetyl-l-glufosinate (NAG). The pat gene was inserted in six maize hybrids (Herculex, Agrisure TL, Herculex Yieldgard, Leptra, Viptera 3, Power Core) as a selectable marker, and its expression was evaluated by qPCR in comparison with the maize glufosinate-susceptible cultivar VTPRO. In addition, the levels of NAG, glufosinate degradation, ammonia accumulation, electron transport rate (ETR), visual injury, and biomass were also investigated. The VTPRO, Herculex, Agrisure, and Viptera showed lower pat gene expression, and consequently lower NAG contents and glufosinate degradation, as well as reduced ETR and biomass accumulation. In contrast, greater ammonia accumulation and higher visual injury were observed. The ranking of pat gene expression was Leptra > Power Core > Herculex Yieldgard ? Herculex > Agrisure TL = Viptera 3 > VTPRO. This gene expression was proportional to the glufosinate resistance level observed in each maize hybrid. PMID- 30418771 TI - Bioinspired Surface Functionalization for Improving Osteogenesis of Electrospun Polycaprolactone Nanofibers. AB - Electrospun nanofibers, with a typical interconnected porous structure mimicking the extracellular matrix, are commonly used in bone tissue engineering. However, to the best of our knowledge, few studies have been reported to investigate the enhancement of osteogenesis capability of electrospun polycaprolactone (PCL) nanofibers based on bioinspired surface functionalization. In this study, a universal and versatile approach was proposed to spontaneously modify the electrospun PCL nanofibers with bioactive nano-hydroxyapatite (nHA), using dopamine as an effective bioadhesive agent. The evaluation of scanning electron microscopy, energy-dispersive spectroscopy, Fourier transform infrared spectroscopy, thermogravimetric analysis, and surface wettability indicated that nHA was successfully coated onto electrospun nanofibers (PCL-PDHA). Furthermore, in vitro cell experiment including adhesion, proliferation, and osteogenic capability and in vitro biomineralization test in simulated body fluid revealed that the PCL-PDHA nanofibers were biocompatible to MC3T3-E1 cells, and the osteogenesis and biomineralization capabilities were greatly improved in comparison with that of PCL nanofibers. In summary, the facile bioinspired surface functionalization method introduced in the present study, due to its universality and versatility, not only can be used to improve osteogenesis of electrospun nanofibers but also can be regarded as an avenue to achieve other predesigned purposes in biomedical engineering. PMID- 30418772 TI - Metabolic Alternations of Amino Acids, gamma-Aminobutyric Acid, and Salicylic Acid in Solanum lycopersicum (L.) Following Preplanting Seedling Spray with Salicylic Acid. AB - Preplanting foliar spray of salicylic acid (SA) (0.0, 5.0, and 10.0 MUg/mL) to Solanum lycopersicum (L.) altered the metabolite profile of amino acids, gamma aminobutyric acid (GABA), and SA in leaf, root, and fruits. Free amino acid pools increased; bound amino acid pools reduced. In vegetative tissues, amino acid biosyntheses linked to osmo-compatibility (Pro, Leu, Val and GABA); N (Arg, Asn, Asp, Gln, and Glu); C (Pro, Ser, and Tyr); S (Cys) assimilation; stress tolerance (Ala, Gly, Hyp, His, Lys, Met, and Thr); and central metabolism (Phe, Trp, and Tyr) enhanced for 60-120 days. Concentrations of Ala, Arg, Gln, Gly, Leu, and Ser in leaf and of Asp, Cys, Glu, His, Hyp, Lys, Met, Pro, and Val in root predominated. In planta SA and GABA biosynthesis increased concurrently. SA affected GABA biosynthesis via Glu, Pro, and Arg metabolism. SA, GABA, Glu, and Pro were key canonical variables. This study first reported SA-induced metabolites promoting health (SA/GABA; Cys/Met) and palatability (Glu/Asp; Gln) in table tomato. PMID- 30418773 TI - Computation Revealed Mechanistic Complexity of Low-Valent Cobalt-Catalyzed Markovnikov Hydrosilylation. AB - We explored the mechanism of Markovnikov-selective hydrosilylation of phenylacetylene catalyzed by N-N-N Pincer-cobalt complex with density functional theory (DFT) calculations. In contrast to the previously proposed Co(I) mechanism, computational results suggest a Co(0) pathway, which is further supported by experimental studies. At the same time, our study reveals unexpected complexity in terms of the origin of regioselectivity. First, different orientations between the phenyl group in the substrate and the ligand plane lead to two possible transition states responsible for the branched product. However, the favored one varies according to ligand substitution pattern. Second, both entropy and solvation effects (rather than the conventional approach that considers electronic energies) have to be considered to explain regioselectivity, where the dominant factor also varies from case to case. Despite this complexity, computations predict a general overall ligand structure-regioselectivity relationship. In addition to increasing steric hindrance, introduction of an electron-withdrawing group to the ligands will also increase regioselectivity, which unveils a new dimension of ligand design. PMID- 30418774 TI - Radical S-Adenosyl-l-methionine Tryptophan Lyase (NosL): How the Protein Controls the Carboxyl Radical *CO2- Migration. AB - The radical S-adenosyl-l-methionine tryptophan lyase uses radical-based chemistry to convert l-tryptophan into 3-methyl-2-indolic acid, a fragment in the biosynthesis of the thiopeptide antibiotic nosiheptide. This complex reaction involves several successive steps corresponding to (i) the activation by a specific hydrogen-atom abstraction, (ii) an unprecedented *CO2- radical migration, (iii) a cyanide fragment release, and (iv) the termination of the radical-based reaction. In vitro study of this reaction is made more difficult because the enzyme produces a significant amount of a shunt product instead of the natural product. Here, using a combination of X-ray crystallography, electron paramagnetic resonance spectroscopy, and quantum and hybrid quantum mechanical/molecular mechanical calculations, we have deciphered the fine mechanism of the key *CO2- radical migration, highlighting how the preorganized active site of the protein tightly controls this reaction. PMID- 30418775 TI - Effect of Heat Treatment on the Antitumor Activity of Lactoferrin in Human Colon Tumor (HT29) Model. AB - To investigate the effect of heat treatment on the antitumor activity of lactoferrin in colon cancer cells and colon tumors, the HT-29 (human intestinal epithelial tumor cell) cell line was exposed to lactoferrin and various heat treatments. The impacts on cell proliferation, invasion, and migration were observed in vitro, and nude mice bearing HT29 tumors were administered lactoferrin and underwent various heat treatments in vivo. In the HT29 cell proliferation test using transwell and scratch analyses, lactoferrin (20 mg/mL) without or with heat treatment (50 and 70 degrees C) significantly inhibited cell proliferation, migration, and invasion (compared with the control, p < 0.05), while lactoferrin with heat treatment (100 degrees C) did not affect these parameters. In vivo, HT29 tumor weight was significantly reduced in the lactoferrin (without heat treatment and with 50 and 70 degrees C treatment) groups (1.59 +/- 0.20, 1.67 +/- 0.25, and 2.41 +/- 0.42 g, compared with the control, p < 0.05), and there was no significant difference between the control (3.73 +/- 0.33 g) and the 100 degrees C treatment group (3.58 +/- 0.29 g). Moreover, 100 degrees C heat treatment reduced inhibition of the VEGFR2/VEGFA/PI3K/Akt/Erk1/2 angiogenesis pathway by lactoferrin. In summary, HT29 tumors were effectively suppressed by lactoferrin via inhibition of VEGFR2/VEGFA/PI3K/Akt/Erk1/2 pathway, and heat treatment affected the antitumor activity of lactoferrin in a temperature-dependent manner. PMID- 30418776 TI - Conjugation with Phenylalanine Enhances Autophagy-Inducing Activity of (-) Epigallocatechin Gallate in Hepatic Cells. AB - Given the importance of (-)-epigallocatechin gallate (EGCG) as an autophagy enhancing and thereby lipid-lowering agent, optimization of its activity warrants its therapeutic potential in the treatment of hepatic diseases as well as metabolic disorders. On the basis of our previous observations that structural modifications provided substantial improvements in the bioactivity of EGCG, we investigated the autophagy-enhancing activity of EGCG derivatives. Among 14 EGCG derivatives, E10 with a phenylalanine attached to the D ring of EGCG exhibited the most promising effects in stimulating autophagy in Huh7 cells, which was supported by several lines of evidence: (1) stimulation of autophagy revealed by an increased amount of LC3B-II (4.1 +/- 0.8-fold compared to the control) as well as the 2.0 +/- 0.1-fold activation of adenosine monophosphate-activated protein kinase in the presence of E10 and (2) E10-stimulated autophagic flux demonstrated by a 1.6 +/- 0.4-fold increase in LC3B-II upon co-treatment with chloroquine, 38.1 +/- 5.6% reduction of p62/SQSTM1, and an increase in the formation of autophagic compartments visualized by both CYTO-ID staining (3.0 +/- 0.1-fold) and tandem RFP-GFP-LC3 fluorescence (2.7 +/- 0.4- and 3.2 +/- 0.3-fold for green and red fluorescence, respectively). Finally, the autophagy-inducing activity of E10 culminated in a 5.3-fold reduction of hepatic lipid accumulation caused by fatty acids. In all of the assay settings, E10 was consistently 1.3-3.5-fold more potent than EGCG. Taken together, we demonstrated a significant increase in autophagy-stimulating activity of EGCG through structural modifications. PMID- 30418777 TI - Engineering Titanium Dioxide Nanostructures for Enhanced Lithium-Ion Storage. AB - Various kinds of nanostructured materials have been extensively investigated as lithium ion battery electrode materials derived from their numerous advantageous features including enhanced energy and power density and cyclability. However, little is known about the microscopic origin of how nanostructures can enhance lithium storage performance. Herein, we identify the microscopic origin of enhanced lithium storage in anatase TiO2 nanostructure and report a reversible and stable route to achieve enhanced lithium storage capacity in anatase TiO2. We designed hollow anatase TiO2 nanostructures composed of interconnected ~5 nm sized nanocrystals, which can individually reach the theoretical lithium storage limit and maintain a stable capacity during prolonged cycling (i.e., 330 mAh g-1 for the initial cycle and 228 mAh g-1 for the 100th cycle, at 0.1 A g-1). In situ characterization by X-ray diffraction and X-ray absorption spectroscopy shows that enhanced lithium storage into the anatase TiO2 nanocrystal results from the insertion reaction, which expands the crystal lattice during the sequential phase transition (anatase TiO2 -> Li0.55TiO2 -> LiTiO2). In addition to the pseudocapacitive charge storage of nanostructures, our approach extends the utilization of nanostructured TiO2 for significantly stabilizing excess lithium storage in crystal structures for long-term cycling, which can be readily applied to other lithium storage materials. PMID- 30418778 TI - How Do Enzymes Orient When Trapped on Metal-Organic Framework (MOF) Surfaces? AB - Enzyme immobilization in metal-organic frameworks (MOFs) offers retained enzyme integrity and activity, enhanced stability, and reduced leaching. Trapping enzymes on MOF surfaces would allow for catalysis involving large substrates. In both cases, the catalytic efficiency and selectivity depend not only on enzyme integrity/concentration but also orientation. However, it has been a challenge to determine the orientation of enzymes that are supported on solid matrices, which is even more challenging for enzymes immobilized/trapped in MOFs due to the interferences of the MOF background signals. To address such challenge, we demonstrate in this work the utilization of site-directed spin labeling in combination with Electron Paramagnetic Resonance spectroscopy, which allows for the first time the characterization of the orientation of enzymes trapped on MOF surfaces. The obtained insights are fundamentally important for MOF-based enzyme immobilization design and understanding enzyme orientation once trapped in solid matrices or even cellular confinement conditions. PMID- 30418779 TI - Excitation Energies of Localized Correlated Defects via Quantum Monte Carlo: A Case Study on Mn4+ Doped Phosphors. AB - Accurate excitation energies of localized open-shell defects have been a long standing problem for electronic structure calculation methods. Using Mn4+ doped solids as our proof of principle case, we show that diffusion quantum Monte Carlo (DMC) is able to predict phosphorescence emission energies within statistical error. We make charge density analyses using DMC and density functional theory (DFT), to demonstrate the generality of our DMC approach on other possible localized defects. We also identify a new material with an emission energy 1.97(8) eV, which is close to the optimum of 2.03 eV, for a red emitting phosphor. To our knowledge, our work is the first report on studying excitation energies of a transition metal impurity using an ab-initio many-body electronic structure method. In contrast, semi-local and hybrid-DFT largely underestimates and fails to reproduce some of the trends in the emission energies. Our work underscores the importance of an accurate account of exchange, correlation and excitonic effects for localized excitations in defective solids. PMID- 30418780 TI - Progress Toward a Semi-Synthetic Organism with an Unrestricted Expanded Genetic Alphabet. AB - We have developed a family of unnatural base pairs (UBPs), exemplified by the pair formed between dNaM and dTPT3, for which pairing is mediated not by complementary hydrogen bonding but by hydrophobic and packing forces. These UBPs enabled the creation of the first semisynthetic organisms (SSOs) that store increased genetic information and use it to produce proteins containing noncanonical amino acids. However, retention of the UBPs was poor in some sequence contexts. Here, to optimize the SSO, we synthesize two novel benzothiophene-based dNaM analogs, dPTMO and dMTMO, and characterize the corresponding UBPs, dPTMO-dTPT3 and dMTMO-dTPT3. We demonstrate that these UBPs perform similarly to, or slightly worse than, dNaM-dTPT3 in vitro. However, in the in vivo environment of an SSO, retention of dMTMO-dTPT3, and especially dPTMO dTPT3, is significantly higher than that of dNaM-dTPT3. This more optimal in vivo retention results from better replication, as opposed to more efficient import of the requisite unnatural nucleoside triphosphates. Modeling studies suggest that the more optimal replication results from specific internucleobase interactions mediated by the thiophene sulfur atoms. Finally, we show that dMTMO and dPTMO efficiently template the transcription of RNA containing TPT3 and that their improved retention in DNA results in more efficient production of proteins with noncanonical amino acids. This is the first instance of using performance within the SSO as part of the UBP evaluation and optimization process. From a general perspective, the results demonstrate the importance of evaluating synthetic biology "parts" in their in vivo context and further demonstrate the ability of hydrophobic and packing interactions to replace the complementary hydrogen bonding that underlies the replication of natural base pairs. From a more practical perspective, the identification of dMTMO-dTPT3 and especially dPTMO dTPT3 represents significant progress toward the development of SSOs with an unrestricted ability to store and retrieve increased information. PMID- 30418781 TI - Geometrically Enhanced Thermoelectric Effects in Graphene Nanoconstrictions. AB - The influence of nanostructuring and quantum confinement on the thermoelectric properties of materials has been extensively studied. While this has made possible multiple breakthroughs in the achievable figure of merit, classical confinement, and its effect on the local Seebeck coefficient has mostly been neglected, as has the Peltier effect in general due to the complexity of measuring small temperature gradients locally. Here we report that reducing the width of a graphene channel to 100 nm changes the Seebeck coefficient by orders of magnitude. Using a scanning thermal microscope allows us to probe the local temperature of electrically contacted graphene two-terminal devices or to locally heat the sample. We show that constrictions in mono- and bilayer graphene facilitate a spatially correlated gradient in the Seebeck and Peltier coefficient, as evidenced by the pronounced thermovoltage Vth and heating/cooling response Delta TPeltier, respectively. This geometry dependent effect, which has not been reported previously in 2D materials, has important implications for measurements of patterned nanostructures in graphene and points to novel solutions for effective thermal management in electronic graphene devices or concepts for single material thermocouples. PMID- 30418782 TI - Hydroxy Group Directed Catalytic Hydrosilylation of Amides. AB - Chemo- and site-selective hydrosilylation of alpha- or beta-hydroxy amides using organocatalyst B(C6F5)3 and commercially available hydrosilanes is described. This transformation is operative under mild conditions and tolerates a wide range of functional groups. The reaction was applied for selective reduction of a specific amide group of the therapeutically important cyclic peptide cyclosporin A, demonstrating the potential usefulness of this catalytic method in late-stage structural transformations of drug lead molecules. PMID- 30418783 TI - Correction to "Influence of Electronic Polarization on the Structure of Ionic Liquids". PMID- 30418784 TI - Palladium-Catalyzed Intermolecular Dehydrogenative Carboamination of Alkenes with Amines and N-Substituted Isatin. AB - The first intermolecular dehydrogenative carboamination of alkenes with aromatic amines and N-substituted isatin has been developed using palladium as a catalyst. This multicomponent reaction is a valuable synthetic tool for difunctionalization of the alkene with retention of the C-C double bond. This reaction has two very distinguishing features: (1) the formation of the C-N and C-C bonds with retention of the double bond and (2) high regioselectivity. Thus, this strategy has opened up a new area in chemistry. PMID- 30418785 TI - Suppressing Ambient Degradation of Exfoliated InSe Nanosheet Devices via Seeded Atomic Layer Deposition Encapsulation. AB - With exceptional charge carrier mobilities and a direct bandgap at most thicknesses, indium selenide (InSe) is an emerging layered semiconductor that has generated significant interest for electronic and optoelectronic applications. However, exfoliated InSe nanosheets are susceptible to rapid degradation in ambient conditions, thus limiting their technological potential. In addition to morphological changes upon ambient exposure, the mobilities and current modulation on/off ratios of InSe transistors, as well as the responsivities of InSe photodetectors, decrease by over 3 orders of magnitude within 12 h of ambient exposure. In an effort to mitigate these deleterious effects, here we present an encapsulation scheme based on seeded atomic layer deposition that provides pinhole-free growth of alumina without compromising the intrinsic electronic properties of the underlying InSe. In particular, this encapsulation provides reproducible InSe field-effect transistor characteristics and InSe photodetector responsivities in excess of 107 A/W following ambient exposure for time periods on the order of months. Because atomic layer deposition is a highly scalable and manufacturable process, this work will accelerate ongoing efforts to integrate InSe nanosheets into electronic and optoelectronic technologies. PMID- 30418786 TI - Modeling crowd dynamics through coarse-grained data analysis. AB - Understanding and predicting the collective behaviour of crowds is essential to improve the efficiency of pedestrian flows in urban areas and minimize the risks of accidents at mass events. We advocate for the development of crowd traffic management systems, whereby observations of crowds can be coupled to fast and reliable models to produce rapid predictions of the crowd movement and eventually help crowd managers choose between tailored optimization strategies. Here, we propose a Bi-directional Macroscopic (BM) model as the core of such a system. Its key input is the fundamental diagram for bi-directional flows, i.e. the relation between the pedestrian fluxes and densities. We design and run a laboratory experiments involving a total of 119 participants walking in opposite directions in a circular corridor and show that the model is able to accurately capture the experimental data in a typical crowd forecasting situation. Finally, we propose a simple segregation strategy for enhancing the traffic efficiency, and use the BM model to determine the conditions under which this strategy would be beneficial. The BM model, therefore, could serve as a building block to develop on the fly prediction of crowd movements and help deploying real-time crowd optimization strategies. PMID- 30418787 TI - Dynamical analysis for a hepatitis B transmission model with immigration and infection age. AB - Hepatitis B virus (HBV) is responsible for an estimated 378 million infections worldwide and 620, 000 deaths annually. Safe and effective vaccination programs have been available for decades, but coverage is limited due to economic and social factors. We investigate the effect of immigration and infection age on HBV transmission dynamics, incorporating age-dependent immigration flow and vertical transmission. The mathematical model can be used to describe HBV transmission in highly endemic regions with vertical transmission and migration of infected HBV individuals. Due to the effects of immigration, there is no disease-free equilibrium or reproduction number. We show that the unique endemic equilibrium exists only when immigration into the infective class is measurable. The smoothness and attractiveness of the solution semiflow are analyzed, and boundedness and uniform persistence are determined. Global stability of the unique endemic equilibrium is shown by a Lyapunov functional for a special case. PMID- 30418788 TI - Modeling the control of infectious diseases: Effects of TV and social media advertisements. AB - Public health information through media plays an important role to curb the spread of various infectious diseases as most of the populations rely on what media projects to them. Social media and TV advertisements are important mediums to communicate people regarding the spread of any infectious disease and methods to prevent its spread. Therefore, in this paper, we propose a mathematical model to see how TV and social media advertisements impact the dynamics of an infectious disease. The susceptible population is assumed vulnerable to infection as well as information (through TV and social media ads). It is also assumed that the growth rate of TV and social media ads is proportional to the number of infected individuals with decreasing function of aware individuals. The feasibility of possible equilibria and their stability properties are discussed. It is shown that the increment in growth rate of TV and social media ads destabilizes the system and periodic oscillations arise through Hopf-bifurcation. It is also found that the increase in dissemination rate of awareness among susceptible population also gives rise interesting dynamics about the stability of endemic equilibrium and causes stability switch. It is observed that TV and social media advertisements regarding the spread of infectious diseases have the potential to bring behavioral changes among the people and control the spread of diseases. Numerical simulations also support analytical findings. PMID- 30418789 TI - Early and late stage profiles for a chemotaxis model with density-dependent jump probability. AB - In this paper, we derive a chemotaxis model with degenerate diffusion and density dependent chemotactic sensitivity, and we provide a more realistic description of cell migration process for its early and late stages. Different from the existing studies focusing on the case of non-degenerate diffusion, this model with degenerate diffusion causes us some essential difficulty on the boundedness estimates and the propagation behavior of its compact support. In the presence of logistic damping, for the early stage before tumour cells spread to the whole domain, we first estimate the expanding speed of tumour region as O(t^beta) for 0 < beta < 1/2 . Then, for the late stage of cell migration, we further prove that the asymptotic profile of the original system is just its corresponding steady state. The global convergence of the original weak solution to the steady state with exponential rate O(e^(-ct)) for some c < 0 is also obtained. PMID- 30418790 TI - Ebola: Impact of hospital's admission policy in an overwhelmed scenario. AB - Infectious disease outbreaks sometimes overwhelm healthcare facilities. A recent case occurred in West Africa in 2014 when an Ebola virus outbreak overwhelmed facilities in Sierra Leone, Guinea and Liberia. In such scenarios, how many patients can hospitals admit to minimize disease burden? This study considers what type of hospital admission policy during a hypothetical Ebola outbreak can better serve the community, if overcrowding degrades the hospital setting. Our result shows that which policy minimizes loss to the community depends on the initial estimation of the control reproduction number, R0. When the outbreak grows extremely fast (R0 ? 1) it is better (in terms of total disease burden) to stop admitting patients after reaching the carrying capacity because overcrowding in the hospital makes the hospital setting ineffective at containing infection, but when the outbreak grows only a little faster than the system's ability to contain it (R0 ? 1), it is better to admit patients beyond the carrying capacity because limited overcrowding still reduces infection more in the community. However, when R0 is no more than a little greater than 1 (for our parameter values, 1.012), both policies result the same because the number of patients never exceeds the maximum capacity. PMID- 30418791 TI - Dynamics of a stochastic delayed Harrison-type predation model: Effects of delay and stochastic components. AB - This paper investigates the complex dynamics of a Harrison-type predator-prey model that incorporating: (1) A constant time delay in the functional response term of the predator growth equation; and (2) environmental noise in both prey and predator equations. We provide the rigorous results of our model including the dynamical behaviors of a positive solution and Hopf bifurcation. We also perform numerical simulations on the effects of delay or/and noise when the corresponding ODE model has an interior solution. Our theoretical and numerical results show that delay can either remain stability or destabilize the model; large noise could destabilize the model; and the combination of delay and noise could intensify the periodic instability of the model. Our results may provide us useful biological insights into population managements for prey-predator interaction models. PMID- 30418792 TI - Impact of behavioral change on the epidemic characteristics of an epidemic model without vital dynamics. AB - The epidemic characteristics of an epidemic model with behavioral change in [V. Capasso, G. Serio, A generalizaition of the Kermack-McKendrick deterministic epidemic model, Math. Bios., 42 (1978), 43-61] are investigated, including the epidemic size, peak and turning point. The conditions on the appearance of the peak state and turning point are represented clearly, and the expressions determining the corresponding time for the peak state and turning point are described explicitly. Moreover, the impact of behavioral change on the characteristics is discussed. PMID- 30418793 TI - Enhancement of chemotherapy using oncolytic virotherapy: Mathematical and optimal control analysis. AB - Oncolytic virotherapy has been emerging as a promising novel cancer treatment which may be further combined with the existing therapeutic modalities to enhance their effects. To investigate how virotherapy could enhance chemotherapy, we propose an ODE based mathematical model describing the interactions between tumour cells, the immune response, and a treatment combination with chemotherapy and oncolytic viruses. Stability analysis of the model with constant chemotherapy treatment rates shows that without any form of treatment, a tumour would grow to its maximum size. It also demonstrates that chemotherapy alone is capable of clearing tumour cells provided that the drug efficacy is greater than the intrinsic tumour growth rate. Furthermore, virotherapy alone may not be able to clear tumour cells from body tissue but would rather enhance chemotherapy if viruses with high viral potency are used. To assess the combined effect of virotherapy and chemotherapy we use the forward sensitivity index to perform a sensitivity analysis, with respect to chemotherapy key parameters, of the virus basic reproductive number and the tumour endemic equilibrium. The results from this sensitivity analysis indicate the existence of a critical dose of chemotherapy above which no further significant reduction in the tumour population can be observed. Numerical simulations show that a successful combinational therapy of the chemotherapeutic drugs and viruses depends mostly on the virus burst size, infection rate, and the amount of drugs supplied. Optimal control analysis was performed, by means of the Pontryagin's maximum principle, to further refine predictions of the model with constant treatment rates by accounting for the treatment costs and sides effects. Results from this analysis suggest that the optimal drug and virus combination correspond to half their maximum tolerated doses. This is in agreement with the results from stability and sensitivity analyses. PMID- 30418794 TI - State feedback impulsive control of computer worm and virus with saturated incidence. AB - A state feedback impulsive model is set up to discuss the spreading and control of the computer worm and virus. Considering the transmission features, saturated infectious is adopted to describe the spreading in the model, and all the treatment measures, such as patching operating system and updating antivirus software, are assumed to take effect instantly. Then the model is analyzed with a novel method, and the existence and stability of order-1 limit cycle are discussed. Finally, the numerical simulation is listed to verify the result of the paper. PMID- 30418795 TI - Coexistence of a cross-diffusive West Nile virus model in a heterogenous environment. AB - This paper is concerned with a strongly-coupled elliptic system, which describes a West Nile virus (WNv) model with cross-diffusion in a heterogeneous environment. The basic reproduction number is introduced through the next generation infection operator and some related eigenvalue problems. The existence of coexistence states is presented by using a method of upper and lower solutions. The true positive solutions are obtained by monotone iterative schemes. Our results show that a cross-diffusive WNv model possesses at least one coexistence solution if the basic reproduction number is greater than one and the cross-diffusion rates are small enough, while if the basic reproduction number is less than or equal to one, the model has no positive solution. To illustrate the impact of cross-diffusion and environmental heterogeneity on the transmission of WNv, some numerical simulations are given. PMID- 30418796 TI - Review of stability and stabilization for impulsive delayed systems. AB - This paper reviews some recent works on impulsive delayed systems (IDSs). The prime focus is the fundamental results and recent progress in theory and applications. After reviewing the relative literatures, this paper provides a comprehensive and intuitive overview of IDSs. Five aspects of IDSs are surveyed including basic theory, stability analysis, impulsive control, impulsive perturbation, and delayed impulses. Then the research prospect is given, which provides a reference for further study of IDSs theory. PMID- 30418797 TI - Gender-specific associations between polymorphisms in the Toll-like receptor (TLR) genes and lung function among workers in swine operations. AB - Workers in swine operations are exposed to dust, bacteria, and virus, and are at increased risk of respiratory problems. Toll-like receptors (TLR) play an important role in human immune responses to respiratory hazards. Worker gender and age may significantly modify the involvement of TLR in the etiology of these respiratory outcomes. The aim of this study was to investigate whether modification effects of worker gender and age altered associations between polymorphisms in the TLR genes and lung function. This study included 374 full time workers from large swine operations from Saskatchewan. Information on demography, lifestyle, pulmonary function, and blood samples were obtained. Multiple linear regression and decision tree model were used in the analysis. Among females aged <45.8 years, workers with polymorphisms of rs4696480 in the TLR2 gene exhibited markedly better lung function than workers with wild-type. These associations were not observed among female workers aged >=45.8 years and males. Among males, workers with polymorphisms of rs187084 in the TLR9 gene displayed significantly lower lung function than those with wild-type. This male specific association was not dependent on worker age. This is the first study to report gender-specific correlations between lung function and polymorphisms of TLR genes, and modification effects of worker age on these associations, suggesting the importance of considering gender and age in genetic association studies of airway diseases due to exposure of high concentration of respiratory hazards. PMID- 30418798 TI - Epithelial-Stromal Interactions in Pancreatic Cancer. AB - Pancreatic cancer is characterized by an extensive fibroinflammatory reaction that includes immune cells, fibroblasts, extracellular matrix, vascular and lymphatic vessels, and nerves. Overwhelming evidence indicates that the pancreatic cancer microenvironment regulates cancer initiation, progression, and maintenance. Pancreatic cancer treatment has progressed little over the past several decades, and the prognosis remains one of the worst for any cancer. The contribution of the microenvironment to carcinogenesis is a key area of research, offering new potential targets for treating the disease. Here, we explore the composition of the pancreatic cancer stroma, discuss the network of interactions between different components, and describe recent attempts to target the stroma therapeutically. We also discuss current areas of active research related to the tumor microenvironment. Expected final online publication date for the Annual Review of Physiology Volume 81 is February 10, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30418799 TI - People Make the Same Bayesian Judgment They Criticize in Others. AB - When two individuals from different social groups exhibit identical behavior, egalitarian codes of conduct call for equal judgments of both individuals. However, this moral imperative is at odds with the statistical imperative to consider priors based on group membership. Insofar as these priors differ, Bayesian rationality calls for unequal judgments of both individuals. We show that participants criticized the morality and intellect of someone else who made a Bayesian judgment, shared less money with this person, and incurred financial costs to punish this person. However, participants made unequal judgments as a Bayesian statistician would, thereby rendering the same judgment that they found repugnant when offered by someone else. This inconsistency, which can be reconciled by differences in which base rate is attended to, suggests that participants use group membership in a way that reflects the savvy of a Bayesian and the disrepute of someone they consider to be a bigot. PMID- 30418800 TI - Inexpensive High-Throughput Screening of Kinase Inhibitors Using One-Step Enzyme Coupled Fluorescence Assay for ADP Detection. AB - Protein kinases are attractive targets for both biological research and drug development. Several assay kits, especially for the detection of adenosine diphosphate (ADP), which is universally produced by kinases, are commercially available for high-throughput screening (HTS) of kinase inhibitors, but their cost is quite high for large-scale screening. Here, we report a new enzyme coupled fluorescence assay for ADP detection, which uses just 10 inexpensive, commercially available components. The assay protocol is very simple, requiring only the mixing of test solutions with ADP detection solution and reading the fluorescence intensity of resorufin produced by coupling reaction. To validate the assay, we focused on CDC2-like kinase 1 (CLK1), a dual-specificity kinase that plays an important role in alternative splicing, and we used the optimized assay to screen an in-house chemical library of about 215,000 compounds for CLK1 inhibitors. We identified and validated 12 potent inhibitors of CLK1, including a novel inhibitory scaffold. The results demonstrate that this assay platform is not only simple and cost-effective, but also sufficiently robust, showing good reproducibility and giving similar results to those obtained with the widely used ADP-Glo bioluminescent assay. PMID- 30418801 TI - Severe Obesity, Obesity, and Cardiometabolic Risk in Children 0 to 6 Years of Age. AB - BACKGROUND: The prevalence of obesity in children has been shown to be plateauing or decreasing in some countries. However, the burden of severe obesity is often not assessed. Children with severe obesity may be at an increased risk for cardiovascular disease and diabetes. The objective is to determine the prevalence of severe obesity in young children and to examine the association with cardiometabolic risk factors. METHODS: A longitudinal study was conducted through The Applied Research Group for Kids! (TARGet Kids!), a practice-based research network in Toronto, Canada. Healthy children from birth to 6 years of age were recruited and followed through middle childhood. The main outcomes of the study were as follows: total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and non-HDL cholesterol, triglycerides, glucose, systolic blood pressure (SBP), and diastolic blood pressure (DBP). BMI was age and sex standardized based on the WHO growth standards. A BMI z-score >3 was used to define obesity for children <5 years of age, and severe obesity for children >=5 years of age. RESULTS: Among 5738 children <5 years, 0.8% had a zBMI >3. In 626 children who were 5 and 6 years old, 2.1% had a zBMI >3. In the multivariable analysis adjusted for age, sex, maternal ethnicity, and family history, using repeated measures, children with a zBMI >3 had significantly higher odds of having abnormal SBP [odds ratio (OR) 6.4, 95% confidence interval (CI) 1.5-27.9; p = 0.01] and DBP (OR, 3.6 95% CI 1.2-10.6; p = 0.02), respectively, as compared with healthy-weight children. Trends demonstrating an association between a zBMI >3 and abnormal lipid levels were also identified. CONCLUSION: Young children with a zBMI >3 have significantly higher blood pressure measures and trends toward worse lipid profiles than children at lower zBMIs. PMID- 30418802 TI - Canine Cancer Genomics: Lessons for Canine and Human Health. AB - Dogs are second only to humans in medical surveillance and preventative health care, leading to a recent perception of increased cancer incidence. Scientific priorities in veterinary oncology have thus shifted, with a demand for cancer genetic screens, better diagnostics, and more effective therapies. Most dog breeds came into existence within the last 300 years, and many are derived from small numbers of founders. Each has undergone strong artificial selection, in which dog fanciers selected for many traits, including body size, fur type, color, skull shape, and behavior, to create novel breeds. The adoption of the breed barrier rule-no dog may become a registered member of a breed unless both its dam and its sire are registered members-ensures a relatively closed genetic pool within each breed. As a result, there is strong phenotypic homogeneity within breeds but extraordinary phenotypic variation between breeds. One consequence of this is the high level of breed-associated genetic disease. We and others have taken advantage of this to identify genes for a large number of canine maladies for which mouse models do not exist, particularly with regard to cancer. Expected final online publication date for the Annual Review of Animal Biosciences Volume 7 is February 15, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30418803 TI - Meeting Global Feed Protein Demand: Challenge, Opportunity, and Strategy. AB - Feed protein supplements are one of the most expensive and limiting feed ingredients. This review offers a comprehensive analysis of how the expected expansion of animal production, driven by the rising world population and living standards for more animal-sourced foods, is creating a global shortage of feed protein supply. Because ruminants, chickens, and pigs contribute to 96% of the global supply of animal protein and aquaculture is growing fast, means of meeting the feed protein requirements of these species are elaborated. Geographic variation and interdependence among China, Europe, and North America in the demand and supply of feed protein are compared. The potential and current state of exploration into alternative feed proteins, including microalgae, insects, single-cell proteins, and coproducts, are highlighted. Strategic innovations are proposed to upgrade feed protein processing and assessment, improve protein digestion by exogenous enzymes, and genetically select feed-efficient livestock breeds. An overall successful and sustainable solution in meeting global feed protein demands will lead to a substantial net gain of human-edible animal protein with a minimal environmental footprint. Expected final online publication date for the Annual Review of Animal Biosciences Volume 7 is February 15, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30418804 TI - New Insights on Intermediary Metabolism for a Better Understanding of Nutrition in Teleosts. AB - The rapid development of aquaculture production throughout the world over the past few decades has led to the emergence of new scientific challenges to improve fish nutrition. The diet formulations used for farmed fish have been largely modified in the past few years. However, bottlenecks still exist in being able to suppress totally marine resources (fish meal and fish oil) in diets without negatively affecting growth performance and flesh quality. A better understanding of fish metabolism and its regulation by nutrients is thus mandatory. In this review, we discuss four fields of research that are highly important for improving fish nutrition in the future: ( a) fish genome complexity and subsequent consequences for metabolism, ( b) microRNAs (miRNAs) as new actors in regulation of fish metabolism, ( c) the role of autophagy in regulation of fish metabolism, and ( d) the nutritional programming of metabolism linked to the early life of fish Expected final online publication date for the Annual Review of Animal Biosciences Volume 7 is February 15, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30418805 TI - The One Health Leadership Experience at the University of Saskatchewan, Canada. AB - Competency in One Health (OH) leadership was emphasized in the Roadmap for Veterinary Medical Education in the 21st Century in 2011. Since then, several educational interventions have been aimed at increasing awareness and capacity for inter-professional collaboration. At the University of Saskatchewan, Canada, a 3-day event, the One Health Leadership Experience (OHLE), was initiated in 2012 and continues to the present. The event targets students entering their first year of a health professional program and consists of presentations by invited OH guest speakers, networking sessions, small-group case discussions of OH scenarios, and leadership development through panel discussions and interactive small-group dialogues. Post-conference surveys, a 5-year follow-up survey, and two focus groups were conducted to evaluate the impact of participation in the OHLE. After the event, the proportion of students who said they clearly understood OH and its goals was substantially higher than before: 86% versus 14% in 2012, 91% versus 23% in 2013, and 69% versus 24% in 2014. In the 5-year follow up survey, most respondents (90%) indicated that attending the OHLE increased their interaction with other students from health sciences colleges or schools on campus. Also, most (81%) believed that OH should be formally taught in their program and 80% anticipated implementing, or had already implemented, OH practices after graduation. The OHLE increased participants' awareness of the importance of interdisciplinary approaches and is a successful educational model that can be adapted to health professional curricula at other institutions. PMID- 30418806 TI - Flipped Classroom Use in Veterinary Education: A Multinational Survey of Faculty Experiences. AB - Active teaching approaches such as the flipped classroom are linked to better quality student learning outcomes across healthcare disciplines, with the potential to support students' preparedness for practice. In the flipped classroom instructional approach, students engage in significant pre-class preparation to learn foundational knowledge and skills, then undertake instructional activities in the classroom which require them to integrate, apply and extend their learning to new contexts. This study reports the results of a multinational survey of flipped classroom use in veterinary education. Participants' (n = 165) familiarity with and extent of use of the flipped classroom technique were investigated, together with the teaching strategies used and the perceived benefits and barriers to implementation. Relationships between respondent characteristics and flipped classroom use were also explored. The results indicated that 95% of participants were familiar with the flipped classroom technique, although fewer (64%) used it in their teaching. Pre-class activities included reviewing online and printed material, and engaging in preparatory learning activities such as quizzes, case analyses, reflective assignments and group activities. A variety of active learning strategies were used in class, including discussions, presentations, quizzes, group activities, problem solving and laboratory/practical exercises. Most participants perceived that the flipped classroom technique benefited student learning, with some also identifying benefits for the faculty involved. A range of student-, faculty- and institution-related barriers to implementing the flipped classroom technique were identified. These barriers need to be addressed by teachers and administrators seeking to improve students' preparedness for practice by implementing flipped classrooms in veterinary education. PMID- 30418807 TI - Construction of the Equine Digestive System: A Tool for Teaching Topographical Anatomy. AB - Anatomy is traditionally regarded as a difficult, non-motivating course involving a large body of theoretical and practical content, and it is often associated with high levels of dropout and failure. Given the relevance of the topic, we propose an alternative active multisensory teaching tool consisting of the construction of a low-fidelity anatomical model assembled into an articulated equine skeleton. Model construction and assembly assists students in the recognition of the topography and anatomical boundaries of the equine abdominal digestive system. Digestive system organs (liver, pancreas, stomach, small and large intestines) were constructed using common, easily available materials, such as newspaper, balloons, laminated rubber sheets, and polyethylene cylinders. The method described in this study is a low-cost, user-friendly teaching tool that is potentially applicable across different academic disciplines and that can also be used to construct models of other systems and species. However, it should be combined with other anatomy teaching methods because it does not provide detailed representation of specific digestive system organ features. PMID- 30418808 TI - One Health-One Education: Medical and Veterinary Inter-Professional Training. AB - Physicians and veterinarians are increasingly expected to collaborate across disciplines; however, in most cases their education and training remain isolated within their respective professions. Medical and veterinary students are rarely provided with opportunities for inter-professional learning during their coursework and clinical training. One Health serves as an ideal framework for developing problem-focused curricula that promote inter-professional teamwork. One Health issues (e.g., zoonotic diseases, water pollution, toxic waste, impact of climate change, food safety and security) not only engage students across disciplines, but require faculty and senior leadership across various health related fields to share knowledge and balance perspectives throughout curriculum development and implementation. In this article, we report on one of several interactive, small-group, case-based One Health curricular exercises developed collaboratively by students and faculty in our Schools of Medicine and Veterinary Medicine to ensure that all students, regardless of background or intended specialty, would receive a basic introduction to inter-professional collaboration in the context of a One Health clinical problem of the sort they might encounter in their future practice. Toxoplasmosis (Toxoplasma gondii infection) was selected as the first case because of the potentially different perspectives that medical and veterinary practitioners may have on advising a pregnant woman with regard to risk factors, prevention, testing, and treatment. Our goal was to develop an evidenced-based approach to this clinical case that could be used by both professions to assess environmental and zoonotic risk factors for T. gondii in human pregnancies. PMID- 30418809 TI - Impact of Team Communication Training on Performance and Self-Assessment of Team Functioning during Sophomore Surgery. AB - Collaboration and teamwork are important skills for veterinary professionals that affect relationship development, health and well-being, financial success, and clinical outcomes. This study explores the impact of team communication training on performance and assessment of team functioning during second-year surgery by comparing two different classes. The class of 2017 (control group) received no formal training in team communication before their participation in surgery, and the class of 2018 (treatment group) participated in training offered through a dedicated team communication course. Results showed that team training increased surgical preparation times and had a positive impact on perceptions of competence in some teamwork behaviors. Both cohorts identified similar challenges and solutions associated with teamwork, although the team-trained students responded to challenges differently than the control group. Team communication training had a positive impact on students' ability to plan and organize their experiences, navigate team dynamics in the moment, and respond to stress in a positive manner. These findings suggest that team training does, in fact, make a difference in students' abilities to navigate a team task productively. PMID- 30418810 TI - Australian and New Zealand Veterinary Students' Opinions on Animal Welfare and Ethical Issues Concerning Animal Use within Sport, Recreation, and Display. AB - Animals used for sport, recreation and display are highly visible and can divide community attitudes. The study of animal welfare and ethics (AWE) as part of veterinary education is important because it is the responsibility of veterinarians to use their scientific knowledge and skills to promote animal welfare in the context of community expectations. To explore the attitudes of veterinary students in Australia and New Zealand to AWE, a survey of the current cohort was undertaken. The survey aimed to reveal how veterinary students in Australia and New Zealand rate the importance of five selected AWE topics for Day One Competences in animals used in sport, recreation and display and to establish how veterinary students' priorities were associated with gender and stage of study. The response rate (.=851) across the seven schools was just over 25%. Results indicated little variation on ratings for topics. The topics were ranked in the following order (most to least important): Pushing of animals to their physiologic/behavioral limits; ownership/responsibility; euthanasia; educating the public; and behavior, selection, and training for sport and recreation displays. In contrast to related studies, ratings were not associated with stage of study and there were few differences associated with gender. More females rated the pushing of animals to physiologic/behavioral limits as extremely important than did males (.<.001). The role of veterinarians in advocating for and educating the public about the welfare of animals used in sport, recreation and display merits further discussion. PMID- 30418812 TI - Twitter in the Veterinary Diagnostic Imaging Classroom: Examination Outcomes and Student Views. AB - Radiographic lesion identification and differential diagnosis list generation can be difficult for veterinary students; thus, a novel means of distributing cases for study could improve students' engagement and learning. The goal of this study was to determine whether using Twitter as an adjunct means of studying diagnostic imaging would improve student outcomes on the final exam for a radiology course. A secondary goal was to determine students' preferred means of accessing additional cases for study. Twitter was used in a third-year veterinary radiology course to provide additional optional radiographic cases that were relevant to the topics covered in the course. At the end of the semester, students completed a survey to report their prior and current use of Twitter and to give preferences as to further distribution of optional cases. Mean final examination scores were compared between students who used Twitter in their studies and those who did not. No significant difference was found between the mean final examination score for each group (22.2; p = .98). Only 3% of respondents (n = 2/79) preferred Twitter as a means of receiving additional radiographic cases; Moodle (the Web platform for classwork used at this institution) and Facebook were the most preferred platforms for further cases, receiving 41% (n = 32/79) and 23% (n = 18/79) of votes, respectively. Educational use of Twitter did not improve student examination performance in diagnostic imaging, and other media platforms may be more beneficial than Twitter for encouraging student use of additional resources. PMID- 30418811 TI - Exploring the Effects of Participation in a Shelter Medicine Externship on Student Knowledge and Self-Confidence. AB - With the recognition of shelter medicine as sub-discipline of veterinary medicine, many veterinary programs are including clinical shelter experiences in their curricula. A concurrent mixed-methods study was designed with the aim to determine the effectiveness of a 4-week clinical shelter medicine program on students' perception of canine and feline surgical proficiency and shelter medicine knowledge as well as gain information on student attitudes toward shelter medicine and interest in pursuing this career path. Year 4 veterinary students at Western University of Health Sciences who were enrolled in a shelter medicine externship from 2014 to 2016 were invited to complete pre- and post course online surveys. Of the 168 enrolled students, 77.4% were invited to participate, and 114 completed the survey. There was no statistically significant difference in student veterinary career interest before and after completing the externship. There was an overall increase in student rating of their ability to perform six shelter medicine tasks as well as ovariohysterectomy/ovariectomy (OVH/OE) and castration surgeries after completing their externship; all were statistically significant (p < .001). There was a statistically significant difference in the proportion of students who were familiar with the Asilomar Accords and the Association of Shelter Veterinarians (ASV) Guidelines for Standards of Care in Animal Shelters after completion of their externship (p < .001). Students largely supported pediatric spay and neuter, stating it was an effective means of population control. Based on the themes that emerged from the qualitative analysis, it appeared most students had an accurate understanding of the term no-kill. PMID- 30418813 TI - Innovative, Simple Models for Teaching Neuroanatomy Using the Elnady Technique. AB - Plastination is a valuable tool for the teaching of neuroanatomy. However, the high cost of the process and the complexity of sheet plastination for brain slices remains a challenge. This article describes an innovative, simple, and inexpensive method, called the Elnady Technique, to develop brain slices of various domestic animals. The slices are either enveloped in lamination sheets using an electric iron, or enveloped in transparent plastic using an impulse sealer. This fast, effortless process results in realistic, durable, odorless, soft, flexible slices. The models provide accurate three-dimensional (3D) reference guides for demonstration of neuroanatomical structures that show soft tissue contrast between the gray and white matter. This makes them invaluable for interpretation of clinical imaging modalities, such as computed tomography (CT) and magnetic resonance imaging (MRI). These ethically sourced models can provide a replacement for the killing of animals for practical classes. PMID- 30418814 TI - Challenges and Issues Surrounding Promotion and Tenure of Faculty with Clinical Service Responsibilities in Veterinary Medicine. AB - Mentoring, assessing, and rewarding faculty who have clinical service responsibilities with promotion and tenure can be challenging in many respects. Clinical service responsibilities can limit the time that faculty have available to participate in scholarly activities, especially if the scholarship required for promotion is restricted to traditional research efforts where an individual faculty member is assessed in terms of the number of scientific publications in high-tiered journals with senior authorship and the amount of extramural funding garnered. Even if other forms of scholarship are recognized, metrics used to evaluate research efforts are often inappropriately applied to other scholarly activities. This challenge is not unique to veterinary medicine. This literature review reveals information regarding barriers and recommended solutions from other healthcare and service professions as recognizing scholarly engagement in academic veterinary medicine is just beginning. Opportunities and examples of how faculty can derive scholarship from their clinical service activities are provided. In addition, an approach for mentoring faculty in the prospective planning and documenting of scholarly engagement efforts is suggested. Lastly, challenges and guidance for assessing such scholarship in academic veterinary medicine are recommended as one step toward encouraging colleges of veterinary medicine to develop methods to assess scholarly engagement within their promotion and tenure processes. A change in approach to the promotion and tenure process can result in more faculty being rewarded for their clinical, diagnostic, and scholarly excellence, which positively impacts patient care, career fulfillment, institutional reputation, the veterinary profession, and society as a whole. PMID- 30418815 TI - Use of Three-Dimensional Printing Models for Veterinary Medical Education: Impact on Learning How to Identify Canine Vertebral Fractures. AB - Vertebral fractures and luxations are common causes of neurological emergencies in small-animal patients. The objective of this study was to evaluate the impact of three-dimensional printing (3Dp) models on how veterinary students understand and learn to identify canine spinal fractures and to compare 3Dp models to computed tomography (CT) images and three-dimensional CT (3D-CT) reconstructions. Three spinal fracture models were generated by 3Dp. Sixty first-year veterinary students were randomized into three teaching module groups (CT, 3D-CT, or 3Dp) and asked to answer a multiple-choice questionnaire with 12 questions that covered normal spinal anatomy and the identification of vertebral fractures. We used four additional questions to evaluate the overall learning experience and knowledge acquisition. Results showed that students in the 3Dp group performed significantly better than those in the CT (p < .001) and the 3D-CT (p < .001) groups. Students in the 3Dp and 3D-CT groups answered all questions more quickly than the CT group (3Dp versus CT, p < .001; 3D-CTversus CT, p < .001), with no significant differences between the 3Dp and 3D-CT groups (p = .051). Only the degree of knowledge acquisition that the students considered they had acquired during the session showed significant differences between groups (p = .01). In conclusion, across first-year veterinary students, 3Dp models facilitated learning about normal canine vertebral anatomy and markedly improved the identification of canine spinal fractures. Three-dimensional printing models are an easy and inexpensive teaching method that could be incorporated into veterinary neuroanatomy classes to improve learning in undergraduate students. PMID- 30418817 TI - Turkish Undergraduate Veterinary Students' Attitudes to Use of Animals and Other Teaching Alternatives for Learning Anatomy. AB - This study aimed to investigate the views of first-year veterinary students in Turkey from six veterinary faculties on their anatomy courses and to evaluate their perceptions of the uses of animals and other teaching alternatives from an ethical perspective. The study sample included a total of 293 veterinary students studying in the provinces of Ankara, Burdur, Diyarbakir, Kars, Konya, and Tekirdag. The 38-item instrument tool developed by the researchers consisted of three sections and was administered to volunteer student participants. All the data were statistically analyzed, and normal distribution of the scores obtained in the attitude scales was determined using the Kolmogorov-Smirnov Z test (KSZ). The 20 items in the Anatomy Scale had an arithmetic mean of 3.48 and thus indicated an average rating of agree. The most challenging topic was found by 40.9% to be "the nervous system." The most useful material in facilitating the learning process was rated by 24.1% to be "the anatomy book." The 11 items in the Cadaver Scale had an arithmetic mean of 3.77, indicating an average rating of agree. The highest arithmetic mean score was for the item "Using cadavers is a must for the anatomy course" with a mean of 4.66, indicating their strong agreement with this view. The veterinary students' perspective emphasized that the combination of cadavers and the anatomy book contributed to their learning of anatomy. PMID- 30418816 TI - Mucous Membrane Color Assessment Variability of Veterinary Students Using Either Colorimetric or Word-Based Scales. AB - A colorimetric scale has the potential to be very useful as a training tool for students in veterinary training programs. The authors of this report hypothesized that clinically active, graduate level veterinary students would assess mucous membrane color with greater consistency using an image-based system than with traditional word-based techniques. Third- and fourth-year veterinary students were asked to evaluate 10 canine gingival mucosa images and rate them with either an image-based scale designed by the authors or a word-based system. Although the mean absolute deviations from the median values were greater for the word scale (0.22) than for the image scale (0.20) indicating increased variation, mixed model analysis did not demonstrate these differences were significant (p = .120). Based on this data it is possible that prior image and word-based instruction made it easier for the students to differentiate mucous membrane colors, or that the majority of the students were multimodal learners rather than single-type learners, making previous instruction techniques effective regardless of whether they were visual or read/write based. The authors recommend that future investigators both evaluate previous student instruction and consider administering visual, auditory, read/write, kinesthetic (VARK) tests when investigating potential learning aids in veterinary medicine. PMID- 30418818 TI - End-stage liver disease: critical care escalation or palliative care. PMID- 30418819 TI - Medical and surgical advances in World War I. PMID- 30418820 TI - Will direct oral anticoagulants completely replace warfarin? PMID- 30418821 TI - Warfarin-resistant left ventricular thrombus completely dissolved by rivaroxaban. PMID- 30418822 TI - Medical and surgical care for patients with Parkinson's disease. PMID- 30418823 TI - The contribution of hospital doctors to public health. PMID- 30418824 TI - Can surgical research improve health? PMID- 30418825 TI - Assessing and treating adult patients with hearing loss. AB - Hearing loss is a very common presentation both in primary and secondary care. In addition to causing significant morbidity, it can make communication with patients very challenging, and thus impact other aspects of their care. This article presents an approach to the assessment and management of this condition. PMID- 30418826 TI - Calcific myonecrosis: imaging and radiographic findings. PMID- 30418827 TI - Assessing antibiotic stewardship using the surgical site infection prevention bundle. AB - BACKGROUND:: Antibiotic prophylaxis is crucial in head and neck surgery to prevent infection from clean contaminated wounds. Scottish Intercollegiate Guidelines Network (SIGN) guidance, the gold standard of practice, recommends that administration of broad spectrum antibiotics is discontinued after 24 hours post-operation. A three-audit cycle quality improvement project was conducted to assess clinical practice against SIGN guidance at a large London teaching hospital. METHODS:: Three change initiatives were implemented to improve antibiotic stewardship. First, an update of Trust guidelines with an associated poster campaign to educate staff and improve awareness. Second, introduction of a specific 'prophylactic antibiotics in head and neck surgery' bundle on the electronic hospital-wide prescribing system. Third, an update to an antibiotic prescribing guide (Microguide). RESULTS:: Over a 3-year study period the number of patients receiving antibiotics beyond 24 hours declined significantly (88% in 2015, 76% in 2016, 25% in 2018), demonstrating improved compliance with SIGN guidelines overall. Despite this, staff documentation of indications for extended antibiotic use remains suboptimal (58% in 2016 and 44% in 2018) as does the number of specimens sent for microbiological analysis (52% in 2016 and 0% in 2018). CONCLUSIONS:: Appropriate prophylactic antibiotic prescribing can improve morbidity and mortality rates in head and neck cancer patients. Three change initiatives have been demonstrated which can help to improve prescribing compliance in line with SIGN guidance. Ongoing auditing is required to maintain the longevity of improvements made and encourage staff documentation of indications for extended antibiotic use and microbiology specimen analysis. PMID- 30418828 TI - Traumatic abdominal mass in a young boy. PMID- 30418829 TI - The bariatric airway. AB - The prevalence of obesity in the UK is increasing. Airway management in the obese patient can be challenging. Face mask ventilation is frequently difficult, and while the incidence of difficult laryngoscopy is only marginally raised, the consequences of failed intubation and the rate at which the obese patient desaturates makes this an unforgiving population. Emergence from anaesthesia requires particular care and attention. This article addresses the problems of airway management in the obese patient and looks at measures which can be taken to overcome them. PMID- 30418830 TI - Stress-induced hyperglycaemia. AB - Stress-induced hyperglycaemia is an important clinical entity. It is an adaptive immune-neurohormonal response to physiological stress in an attempt to increase metabolic substrates to struggling organs during a time of crisis. However, this acute hyperglycaemia is also responsible for a number of detrimental effects implying that treatment is necessary. Hence, admission hyperglycaemia is not necessarily equivalent to a diagnosis of diabetes mellitus but the blood glucose level needs to be interpreted in context of the patient's presenting complaint and previous glycaemic status. Stress-induced hyperglycaemia is associated with increased morbidity and short-term mortality. Thus prompt recognition of stress induced hyperglycaemia and high risk hyperglycaemic patients with the stress hyperglycaemia ratio can help improve inpatient management. Patients with stress induced hyperglycaemia who have recovered from their acute illness should be followed up as they remain at risk for incident diabetes. This review focuses on the definition, pathophysiology, targets, management and significance of stress induced hyperglycaemia. PMID- 30418831 TI - Clinical audits can work if they are followed up correctly. PMID- 30418832 TI - Clinical News. PMID- 30418833 TI - Gastrointestinal bleeding in a patient on multiple medications including edoxaban. PMID- 30418834 TI - The junior doctor contract 2 years on: one trust's experience of exception reporting. AB - The new junior doctor contract allows trainees to exception report when they breach safe working hours. After a full year of foundation year 1 rotations, analysis from a large NHS trust in London showed that exception reporting works to highlight rota and working issues. It is unsurprising that trainees are busy but simple things such as competent infrastructure and senior support could go a long way to improving working conditions. In addition, results from a local survey suggest that trainees think the new contract is less safe for both doctors and patients, with inflexibility of rota patterns having a significant impact on the ability to take annual and study leave. A drive to modernise the way health care is delivered in hospitals is needed as a shortage of doctors will only worsen the situation. PMID- 30418835 TI - The clinical assessment of low mood. PMID- 30418836 TI - Apixaban for stroke prevention in a patient with a mechanical heart valve. PMID- 30418837 TI - Giant hydronephrosis presenting as acute pyelonephritis. PMID- 30418838 TI - The role of high flow nasal oxygen therapy in anaesthesia. AB - The delivery of oxygen is a key component of anaesthetic practice. High flow nasal oxygen therapy is a relatively new addition to more traditional means of oxygenation which provides heated and humidified flows of controlled oxygen/air mixes achieving rates of up to 120 litres/min. The physiological benefits include nasopharyngeal dead space washout, reduced work of breathing, alveolar recruitment, maintained mucociliary function and the ability to provide apnoeic oxygenation. This article considers the current evidence for high flow nasal oxygen therapy in perioperative anaesthetic care during pre-oxygenation and intubation, management of the difficult airway, oxygenation for shared airway surgery, extubation and postoperative support, obstetric and paediatric anaesthesia. PMID- 30418840 TI - SICKLE as a holistic treatment approach to sickle cell disease related ulcers. AB - This article introduces a simple approach to adopt in the treatment of sickle cell disease (SCD) related ulcerations based on the acronym SICKLE, standing for Skin assessment, Infection control, Compression, Keep moving keep debriding, Local strapping and Endless support. This case report explains and describes each step used in the treatment of this challenging disease in a 24-year-old patient, achieving complete healing in 6 months in long-lasting SCD ulceration previously treated without results with many other treatments. It has been replicated in further patients with excellent results. The SICKLE approach is an attempt to deliver a holistic way of treating patients with SCD-related leg ulcers. More studies are needed to better define the scientific validity of this method or to demonstrate any inconsistencies. PMID- 30418841 TI - Hand hygiene and handwashing: key to preventing the transfer of pathogens. AB - Claire Ford, Lecturer, Adult Nursing ( claire.ford@northumbria.ac.uk ), and Laura J Park, Graduate Tutor, of Northumbria University, describe how to maintain good skin health to reduce the risk of infection. PMID- 30418842 TI - Influencing building design in care for older people. AB - A Florence Nightingale Foundation travel scholarship was used to support a nurse's journey to gather information and knowledge on aspects of building design for older people in emergency care. Evidence on the effect of the environment on senior care is well established and some areas have carefully considered this when planning facilities for older people. The travel opportunity was used to explore how large-scale building design was carried out, and to understand how mindsets, models of care and built environments influence the result of large scale changes to building design to meet the needs of older people in hospital. Furthermore, this enabled an understanding of how demographic data, clinical evidence, outcomes and quality data were embedded into the processes of informing specific building design. The intention of this scholarship was for the author to be able to influence hearts and minds in her sphere so every opportunity can be taken to embrace a better, more informed approach to the therapeutic built environment, specifically for older people in hospital and community settings. PMID- 30418844 TI - From staff nurse to nurse consultant. AB - The reasons why nurses may want to study for a master's or PhD are many and varied, as is the choice of courses on offer. John Fowler, Educational Consultant, looks at the benefits of undertaking advanced study, but warns that it will require good organisational skills and the support of family, friends and employers. PMID- 30418843 TI - Understanding sepsis. AB - This article provides information on sepsis, which can be life threatening and is often difficult to identify due to subtle signs and symptoms. It is the body's response to infection resulting in injury to the tissues and organs. Assessment tools can be used to assess risk of sepsis and include considering a source of infection along with a NEWS 2 or qSOFA score. However, it is important to be aware of other subtle changes including cold or clammy skin and changes in the patient's behaviour such as new confusion. Within 1 hour from diagnosis supportive treatments need to be administered, including the most appropriate antibiotic for the source of infection, fluid and oxygen. Blood cultures, bloods including lactate and urine measurement are all needed to support management of the patient. PMID- 30418845 TI - Managing vascular compromise of hand and digit replantation following traumatic amputation. AB - Hands are anatomically complex and have great social, physical and emotional importance. Hand or digit replantation following traumatic partial or complete amputation is a complex injury for nursing staff to understand and manage. The absence of clear guidance, combined with a lack of consensus in the literature gives rise to ambiguity and insufficient understanding of appropriate and effective management. This article aims to outline nursing care of the patient in the first few days following hand or digit reattachment, particularly focusing on the recognition and management of arterial and venous compromise. Complications must be recognised and acted on quickly to give the best chance of survival so it is essential for nurses to have an accurate understanding of the signs, symptoms and management options of vascular compromise. Leech therapy, also discussed, has long been used as a nonsurgical option in the management of venous congestion and is a simple and minimally invasive method of managing congestion. PMID- 30418846 TI - The use of debridement in the healing of diabetic foot ulcers. PMID- 30418847 TI - Report of the proceedings of a UK skin safety advisory group. AB - Moisture-associated skin damage, especially incontinence-associated dermatitis, continues to present significant health challenges and requires multidisciplinary input to provide effective prevention and treatment. In the absence of mandatory reporting such damage is under- or wrongfully reported, resulting in a lack of accurate data on prevalence and costs of associated care. In March this year, a multidisciplinary team of experts met in the UK to seek to determine measures to improve patient skin care. They aimed to identify activities to increase awareness and education, collect data, and improve prevention and treatment regimes. This article describes that discussion and the conclusions made by the group, such as the key actions required to effect policy changes. PMID- 30418848 TI - Impact of clinical placements on graduates' choice of first staff-nurse post. AB - Quality clinical placements for pre-registration nursing students are particularly important at a time when there is a recruitment crisis within nursing. A study was conducted to identify what impact clinical placements have on pre-registration adult nursing students' choice of clinical specialty as a newly qualified nurse (NQN). Data were collected from students on their final day of a BSc (Hons) programme at two campus sites at a university in the east of England. Participants judged the desirability of a clinical placement on the basis of the quality of the learning, working and clinical environment and the nature of the specialty. The influence of clinical placements on the choice of first destination of NQNs more than doubles within the final year of study. Clinical placements generate vivid experiences, which exert a strong influence on the first employment destination decisions of NQNs. PMID- 30418849 TI - Is wraparound care the future? PMID- 30418850 TI - Bespoke dressings for discerning practitioners. PMID- 30418851 TI - Neuromuscular electrostimulation on lower limb wounds. AB - The gekoTM is a disposable neuromuscular electrostimulation (NMES) device intended to increase blood circulation and promote wound healing in a range of lower limb conditions. The purpose of this case series was to evaluate the therapeutic effect of the geko device on wound healing outcomes over an 8-week period. Thirty patients with non-healing wounds (>= 12-week duration) of either venous leg ulceration (VLU), mixed leg ulceration (MLU) or diabetic foot ulceration aetiology were recruited from a local outpatient wound clinic in the South Wales area. Over the 8 weeks 2 participants (8%) achieved complete re epithelialisation between baseline and endpoint. Mean wound surface area decreased (7.6 cm2) and there was an increase of 21% in the mean percentage of granulation tissue in the wound bed. Pain levels reduced in 52% of patients who completed the study, but the extent of oedema reduction was difficult to establish given that 76% of the cohort were treated with a form of compression as part of standard care. The findings support the use of the therapy in patients with painful VLUs and MLUs, but further research needs to be conducted to establish the generalisability of the findings to the wider population of patients living with chronic wounds of differing aetiology in the lower limb. PMID- 30418854 TI - Care Quality Commission spotlights effective quality improvement initiatives. AB - Emeritus Professor Alan Glasper, from the University of Southampton, discusses a recent report showing how trusts rated as outstanding by the regulator have embedded a culture of change that involves all staff. PMID- 30418852 TI - Nurses: catalysts for change. PMID- 30418853 TI - Swept under the carpet? PMID- 30418855 TI - Communication breakdown in healthcare settings. AB - John Tingle, Associate Professor (Teaching and Scholarship), Nottingham Trent University, discusses a report by NHS Improvement, the patient safety initiative group, on spoken communication and patient safety in the NHS. PMID- 30418856 TI - Optimising nutritional intake in people with dementia on hospital wards. AB - It is important that nurses are aware of potential problems individuals with dementia may face in unfamiliar environments and adopt strategies to ensure their patients get enough to eat and drink, says Aysha Mendes. PMID- 30418857 TI - T-levels: a skills-based qualification. AB - Sam Foster, Chief Nurse, Oxford University Hospitals, describes preparations under way for T-levels-the latest qualification that young people interested in a career in health care will be able to take. PMID- 30418858 TI - Compression systems used in lymphoedema management. PMID- 30418859 TI - Health care in a technological world. AB - Ongoing innovation in the field of mobile health (mHealth) has the potential to change the landscape of healthcare practice both inside and outside formal clinical settings. mHealth could enhance patient education, prevent disease, improve diagnosis and research-based treatment, reduce healthcare costs and enable patients to manage long-term conditions. In addition, unimpeded by geographical distance, smartphone-linked wearable sensors, built around real-time connectivity, will improve communication between health professionals and improve the understanding of physiological variability, thereby improving clinical decisions and quality of care. However, despite the potential of mHealth, there are still significant information gaps regarding its long-term effects, acceptability, costs and risks. There is therefore a significant need for continued research to evaluate the functions and appropriateness of these medical devices that are slowly entering the healthcare arena, while not neglecting the rights of the individual. PMID- 30418860 TI - Encouraging patients with lymphoedema to self-care. PMID- 30418861 TI - Letting the stars of nursing shine. AB - Paul Steiner, Communications Manager, Cavell Nurses' Trust(PaulS@cavellnursestrust.org), describes the Cavell Star Awards programme, which recognises nurses who bring something extra to their team. PMID- 30418862 TI - Recognition and management of febrile convulsions in children. AB - Febrile convulsions (FCs) are characterised by convulsions associated with fever in children aged between 6 months and 6 years. FCs are relatively common and affect 3-4% of children in western countries. This is the most common seizure disorder seen in children. The cause of febrile illness in FC is usually benign and most frequently due to acute viral infection. Convulsions secondary to an intracranial infection (e.g. meningitis, encephalitis) or from acute electrolyte imbalance should not be labelled as FCs. The diagnosis is based mainly on clinical history, and further investigations are generally unnecessary; management is largely symptomatic. Prolonged FC may need anticonvulsant medication to stop the seizure. Referral to paediatric neurologists may be considered in cases of complex or recurrent FC or in children where there is a pre-existing neurological disorder. One third of children with a first FC will develop a further FC during subsequent febrile illness; the likelihood increases in presence of other risk factors. This article outlines the presentation, management, investigations and prognosis for FC, and highlights how nurses in different clinical settings can provide education, support and counselling to help families return to normality after the event. An illustrative case study is also included to highlight the challenges faced by health professionals while managing children with this condition. PMID- 30418863 TI - The Trojan War inside nursing: an exploration of compassion, emotional labour, coping and reflection. AB - Compassionate care is fundamental to nursing. However, when delivering compassionate care, the expected emotional state may not always spontaneously arise, risking a dissonance between authentic and displayed emotions. Nurses may therefore be required to engage in some form of emotional regulation strategy, to conform with assumed professional rules on emotional display. In both the dissonance and emotional regulation, there are risks on which nurses need to reflect. In this article, the end of the Trojan War as depicted in Homer's The Iliad and Virgil's The Aeneid is used as an allegory to illustrate the dangers and advantages of using response- or antecedent-focused strategies for emotional regulation. Response-focused strategies are reactive in nature-they could build resilience over time but may leave students and newly qualified nurses feeling exposed. An 'emotional curriculum' to include emotional intelligence in nurse education could equip the students with a more proactive approach to developing resilience rather than defensive practice. Using a narrative as an allegory may help to explore the application of these concepts in nursing practice. PMID- 30418864 TI - Use of dermal gel pads in preventing and managing pressure ulcers in ICU: an audit. AB - Most of the pressure ulcers (PUs) that developed in the intensive care unit (ICU) of an acute trust were medical-device related. While use of a dermal pad was recommended as part of its pressure ulcer prevention strategy, staff were concerned that it tended to tear or split while in use. An alternative gel pad (Dermisplus(r) Prevent, Frontier Medical), that was cost-effective and appeared to be more robust, was identified. A 4-week non-comparative audit involving 37 patients was therefore undertaken to investigate the effect of this alternative gel pad on PU incidence in the ICU. With the exception of the change in the gel pad used, there was no difference to the overall PU prevention strategy. No new PUs developed during the audit period with the new gel pad, although there was also no reduction in incidence compared with the previous 3 months. None of the four patients (11%) with blanching erythema developed category 1 PUs. There were also no reports of tearing or splitting with the new gel pad. The ICU staff commented that they found the new gel pad simpler to use, easier to clean and more robust than the previous product used. Following the audit, the ICU incorporated the new gel pad into its PU prevention strategy. PMID- 30418865 TI - Wound Expo 2018 highlights. PMID- 30418866 TI - BJN Awards: Runner up 2018. PMID- 30418867 TI - Wound Exudate. PMID- 30418868 TI - SynerClust: a highly scalable, synteny-aware orthologue clustering tool. AB - Accurate orthologue identification is a vital component of bacterial comparative genomic studies, but many popular sequence-similarity-based approaches do not scale well to the large numbers of genomes that are now generated routinely. Furthermore, most approaches do not take gene synteny into account, which is useful information for disentangling paralogues. Here, we present SynerClust, a user-friendly synteny-aware tool based on synergy that can process thousands of genomes. SynerClust was designed to analyse genomes with high levels of local synteny, particularly prokaryotes, which have operon structure. SynerClust's run time is optimized by selecting cluster representatives at each node in the phylogeny; thus, avoiding the need for exhaustive pairwise similarity searches. In benchmarking against Roary, Hieranoid2, PanX and Reciprocal Best Hit, SynerClust was able to more completely identify sets of core genes for datasets that included diverse strains, while using substantially less memory, and with scalability comparable to the fastest tools. Due to its scalability, ease of installation and use, and suitability for a variety of computing environments, orthogroup clustering using SynerClust will enable many large-scale prokaryotic comparative genomics efforts. PMID- 30418869 TI - Comparative serum proteome analysis reveals potential early pregnancy-specific protein biomarkers in pigs. AB - In this study, the comparative serum proteome profile of Day 5, 12 and 16 of gestation, representing three early embryonic events, namely formation, elongation and implantation of blastocysts, and non-pregnant control were explored by a label-free quantitation-based mass spectrometric approach to identify early pregnancy biomarkers in pigs. A total of 131 proteins were identified with respect to different groups, out of which 105 were found to be differentially expressed proteins (DEPs). Among the DEPs, 54 and 66 proteins were found to be up and downregulated respectively in early pregnancy groups (fold change >2) and the maximum number of upregulated proteins was observed in the Day 12 pregnancy stage. Functional classification and pathway analysis of the DEPs revealed involvement of most of the proteins in complement and coagulation cascades, metabolic processes and immune and inflammatory responses. Proteins such as glutathione peroxidise (GPX), pregnancy zone protein (PZP), thrombospondin-1 (THBS1), alpha-1-antitrypsin (AAT) and mannose-binding lectin C (MBLC) were differentially expressed during early pregnancy and actively involved in different pregnancy-related activities. To the best of our knowledge, this is the first report on comparative serum protein profiling of different early pregnancy stages in pigs and our results provide a set of proteins that can be used as potential biomarkers for early pregnancy diagnosis in pigs. PMID- 30418870 TI - New functions for old factors: the role of polyamines during the establishment of pregnancy. AB - Implantation is essential for the establishment of a successful pregnancy, and the preimplantation period plays a significant role in ensuring implantation occurs in a timely and coordinated manner. This requires effective maternal embryonic signalling, established during the preimplantation period, to synchronise development. Although multiple factors have been identified as present during this time, the exact molecular mechanisms involved are unknown. Polyamines are small cationic molecules that are ubiquitously expressed from prokaryotes to eukaryotes. Despite being first identified over 300 years ago, their essential roles in cell proliferation and growth, including cancer, have only been recently recognised, with new technologies and interest resulting in rapid expansion of the polyamine field. This review provides a summary of our current understanding of polyamine synthesis, regulation and function with a focus on recent developments demonstrating the requirements for polyamines during the establishment of pregnancy up to the implantation stage, in particular the role of polyamines in the control of embryonic diapause and the identification of an alternative pathway for their synthesis in sheep pregnancy. This, along with other novel discoveries, provides new insights into the control of the peri implantation period in mammals and highlights the complexities that exist in regulating this critical period of pregnancy. PMID- 30418872 TI - ScAlN Thick-Film Ultrasonic Transducer in 40-80 MHz. AB - A medical ultrasound diagnostic system and an ultrasonic microscope are generally used in the frequency range of 1-20 MHz and 100 MHz-2 GHz, respectively. Ultrasonic transducers in the frequency range of 20-100 MHz are, therefore, not well developed because of less application into ultrasonic imaging or suitable piezoelectric materials with this frequency range. Polyvinylidene difluoride (PVDF) is usually used for ultrasonic transducers in the 10-50-MHz ranges. However, their electromechanical coupling coefficient of 4% is not enough for the practical uses. In order to excite the ultrasonic wave in the 20-100 MHz range, a 125-25- -thick piezoelectric film is required when the longitudinal velocity of the material is assumed to be 5000 m/s. However, it is difficult to grow such a thick piezoelectric film without a crack being caused by the internal stress during the dry deposition technique. We achieved a stress-free film growth by employing the unique hot target sputtering technique without heating the substrate. High-efficient 81- ( .5%) and 43-MHz ( %) ultrasonic generation by using the 43- and 90- extremely thick ScAlN (Sc: 39%) films were demonstrated, respectively. We discussed the advantage of ScAlN thick-film transducers by comparing them with the conventional PVDF transducer for the water medium. PMID- 30418873 TI - Noncontact Transportation of Planar Object in an Ultrasound Waveguide. AB - This paper investigates acoustic levitation and noncontact transportation techniques for use with planar objects. An acoustic levitation system was developed which consists of a 1-mm-thick and 400-mm-long bending plate along with two bolt-clamped Langevin-type transducers (BLTs) that have stepped horns. A plane reflector was installed parallel to the vibrating plate to generate an ultrasound standing wave between the reflector and the plate. The sound pressure distribution in the ultrasound waveguide was calculated via finite-element analysis to investigate the effects of levitation of a planar object in the standing-wave field. A 1-mm-thick polystyrene plate was levitated along the nodal line of the acoustic standing wave in the waveguide. By controlling the driving phase difference between the two BLTs, the position at which flexural vibration occurs on the vibrating plate could be shifted along the length direction, and the trapped planar object could be moved by 9 mm along the same direction when the phase difference was varied from 0 degrees to 360 degrees . PMID- 30418874 TI - Adaptive Spatiotemporal Filtering for Coronary Ultrafast Doppler Angiography. AB - The heart's supply of oxygen and nutrients relies on the coronary vasculature, which branches from millimeter-sized arteries down to micrometer-sized capillaries. To date, imaging technologies can only detect large epicardial coronary vessels, whereas the intramural coronary vasculature remains invisible due to cardiac motion. We recently introduced coronary ultrafast Doppler angiography, a noninvasive vascular imaging technology based on ultrafast ultrasound that enables the visualization of epicardial and intramural coronary vasculature in humans. In this letter we describe, using an open-chest swine data set, the adaptive spatiotemporal filtering method that was developed for the detection of slow blood flows embedded in rapid myocardial motion. PMID- 30418875 TI - Permanent and Transient Electrophysiological Effects During Cardiac Cryoablation Documented by Optical Activation Mapping and Thermal Imaging. AB - OBJECTIVE: Cardiac catheter cryoablation is a safer alternative to radiofrequency ablation for arrhythmia treatment, but electrophysiological (EP) effects during and after freezing are not adequately characterized. The goal of this study was to determine transient and permanent temperature induced EP effects, during and after localized tissue freezing. METHODS: Conduction in right (RV) and left ventricles (LV) was studied by optical activation mapping during and after cryoablation in paced, isolated Langendorff-perfused porcine hearts. Cryoablation was performed endocardially (n=4) or epicardially (n=4) by a cryoprobe cooled to 120 degrees C for 8 minutes. Epicardial surface temperature was imaged with an infrared camera. Viability staining was performed after ablation. Motion compensation and co-registration was performed between optical mapping data, temperature image data, and lesion images. RESULTS: Cryoablation produced lesions 14.9 +/- 3.1 mm in diameter and 5.8 +/- 1.7 mm deep. A permanent lesion was formed in tissue cooled below -5 +/- 4 degrees C. Transient EP changes observed at temperatures between 17 and 37 degrees C during cryoablation surrounding the frozen tissue region directly correlated with local temperature, and include action potential (AP) duration prolongation, decrease in AP magnitude, and slowing in conduction velocity (Q10=2.0). Transient conduction block was observed when epicardial temperature reached <17 degrees C, but completely resolved upon tissue rewarming, within 5 minutes. CONCLUSION: Transient EP changes were observed surrounding the permanent cryo lesion (<-5 degrees C), including conduction block (-5 to 17 degrees C), and reduced conduction velocity (>17 degrees C). SIGNIFICANCE: The observed changes explain effects observed during clinical cryoablation, including transient increases in effective refractory period, transient conduction block, and transient slowing of conduction. The presented quantitative data on temperature dependence of EP effects may enable the prediction of the effects of clinical cryoablation devices. PMID- 30418871 TI - Cerebellar learning using perturbations. AB - The cerebellum aids the learning of fast, coordinated movements. According to current consensus, erroneously active parallel fibre synapses are depressed by complex spikes signalling movement errors. However, this theory cannot solve the credit assignment problem of processing a global movement evaluation into multiple cell-specific error signals. We identify a possible implementation of an algorithm solving this problem, whereby spontaneous complex spikes perturb ongoing movements, create eligibility traces and signal error changes guiding plasticity. Error changes are extracted by adaptively cancelling the average error. This framework, stochastic gradient descent with estimated global errors (SGDEGE), predicts synaptic plasticity rules that apparently contradict the current consensus but were supported by plasticity experiments in slices from mice under conditions designed to be physiological, highlighting the sensitivity of plasticity studies to experimental conditions. We analyse the algorithm's convergence and capacity. Finally, we suggest SGDEGE may also operate in the basal ganglia. PMID- 30418876 TI - Capturing Dynamic Connectivity from Resting State fMRI using Time-Varying Graphical Lasso. AB - Functional connectivity (FC) within the human brain evaluated through functional magnetic resonance imaging (fMRI) data has attracted increasing attention and has been employed to study the development of the brain or health conditions of the brain. Many different approaches have been proposed to estimate FC from fMRI data, whereas many of them rely on an implicit assumption that functional connectivity should be static throughout the fMRI scan session. Recently, the fMRI community has realized the limitation of assuming static connectivity and dynamic approaches are more prominent in the resting state fMRI (rs-fMRI) analysis. The sliding window technique has been widely used in many studies to capture network dynamics, but has a number of limitations. In this study, we apply a time-varying graphical lasso (TVGL) model, an extension from the traditional graphical lasso, to address the challenge, which can greatly improve the estimation of FC. The performance of estimating dynamic FC is evaluated with the TVGL through both simulated experiments and real rs-fMRI data from the Philadelphia Neurodevelopmental Cohort (PNC) project. Improved performance is achieved over the sliding window technique. In particular, group differences and transition behaviours between young adults and children are investigated using the estimated dynamic connectivity networks, which help us to better unveil the mechanisms underlying the evolution of the brain over time. PMID- 30418877 TI - Non-invasive Seizure Localization with Ictal Single-Photon Emission Computed Tomography is Impacted by Preictal/Early Ictal Network Dynamics. AB - OBJECTIVE: More than one third of children with epilepsy have medically intractable seizures. Promising therapies, including targeted neurostimulation and surgery, depend on accurate localization of the epileptogenic zone. Ictal perfusion Single-Photon Emission Computed Tomography (SPECT) can localize the seizure focus noninvasively, with comparable accuracy to that of invasive EEG. However, multiple factors including seizure dynamics may affect its spatial specificity. METHODS: Using subtracted ictal from interictal SPECT and scalp EEG from 118 pediatric epilepsy patients (40 of whom had surgery after the SPECT studies), information theoretic measures of association and advanced statistical models, this study investigated the impact of preictal and ictal brain network dynamics on SPECT focality. RESULTS: Network dynamics significantly impacted the SPECT localization ~30 s before to ~45 s following ictal onset. Distributed early ictal connectivity changes, indicative of a rapidly evolving seizure, were negatively associated with SPECT focality. Spatially localized connectivity changes later in the seizure, indicating slower seizure propagation, were positively associated with SPECT focality. In the first ~60 s of the seizure, significantly higher network connectivity was estimated in an area overlapping with the area of hyperperfusion. Finally, ~75% of patients with Engel class 1a/1b outcomes had SPECTs that were concordant with the resected area. CONCLUSION: Slowly evolving seizures are more likely to be accurately imaged with SPECT, and the identified focus may overlap with brain regions where significant topological changes occur. SIGNIFICANCE: Measures of preictal/early ictal network dynamics may help optimize the SPECT localization, leading to improved surgical and neurostimulation outcomes in refractory epilepsy. PMID- 30418878 TI - Discontinuity Preserving Liver MR Registration with 3D Active Contour Motion Segmentation. AB - OBJECTIVE: The sliding motion of the liver during respiration violates the homogeneous motion smoothness assumption in conventional non-rigid image registration and commonly results in compromised registration accuracy. This paper presents a novel approach, registration with 3D active contour motion segmentation (RAMS), to improve registration accuracy with discontinuity-aware motion regularization. METHODS: A Markov random field-based discrete optimization with dense displacement sampling and self-similarity context metric is used for registration, while a graph cuts-based 3D active contour approach is applied to segment the sliding interface. In the first registration pass, a mask-free L1 regularization on an image-derived minimum spanning tree is performed to allow motion discontinuity. Based on the motion field estimates, a coarse segmentation finds the motion boundaries. Next, based on MR signal intensity, a fine segmentation aligns the motion boundaries with anatomical boundaries. In the second registration pass, smoothness constraints across the segmented sliding interface are removed by masked regularization on a minimum spanning forest and masked interpolation of the motion field. RESULTS: For in vivo breath-hold abdominal MRI data, the motion masks calculated by RAMS are highly consistent with manual segmentations in terms of Dice similarity and bidirectional local distance measure. These automatically obtained masks are shown to substantially improve registration accuracy for both the proposed discrete registration as well as conventional continuous non-rigid algorithms. CONCLUSION/SIGNIFICANCE: The presented results demonstrated the feasibility of automated segmentation of the respiratory sliding motion interface in liver MR images and the effectiveness of using the derived motion masks to preserve motion discontinuity. PMID- 30418879 TI - Real-time Temperature Measurements of HMEC-1 Cells during Inflammation Production and Repair detected by Wireless Thermometry. AB - : Cell inflammation process is reflected through real-time in situ cellular temperature changes. METHODS: A wireless thermometry system for in situ cellular temperature measurements was used in an incubator to detect the HMEC-1 cellular temperature under lipopolysaccharide inflammation production and norepinephrine for inflammation repair. Combining the changes in cell viability, inflammatory factor levels and ATP content caused by different lipopolysaccharide or norepinephrine doses, an obvious inflammatory response and repair effect was obtained. Temperature variations were correlated with ATP content. RESULTS: An obvious inflammatory response with a lipopolysaccharide concentration of 0.1 mg/L and an optimal repair effect with 1 MUM norepinephrine were obtained. The relationship between temperature changes and ATP content were quite different during the production of inflammation in HMEC-1 cells, having an approximately linear relationship, while under conditions of inflammation repair in HMEC-1 cells, there was an obvious nonlinear relationship. CONCLUSION: During cell damage, cell thermogenesis has a linear correlation with intracellular energy. While during cell repair, there is a gradual saturation relationship between the temperature (small range) and ATP, which may be because the thermogenesis capacity of the cell is enhanced compared to conditions during cell energy storage. Additionally, there is an optimal drug concentration for cell action during cell injury and cell repair, which is not dose-dependent. SIGNIFICANCE: Whether in inflammation production or treatment, there is an optimal drug concentration. The relationship between cell thermogenesis and intracellular energy reserves is related to cell processes. Quick analysis of the energy changes in different physiological process can be realized. PMID- 30418880 TI - A multi-channel approach for cortical stimulation artefact suppression in depth EEG signals using time-frequency and spatial filtering. AB - OBJECTIVE: The stereo electroencephalogram (SEEG) recordings are the sate of the art tool used in pre-surgical evaluation of drug-unresponsive epileptic patients. Coupled with SEEG, electrical cortical stimulation (CS) offer a complementary tool to investigate the lesioned/healthy brain regions and to identify the epileptic zones with precision. However, the propagation of this stimulation inside the brain masks the cerebral activity recorded by nearby multi-contact SEEG electrodes. The objective of this paper is to propose a novel filtering approach for suppressing the CS artifact in SEEG signals using time, frequency as well as spatial information. METHODS: The method combines spatial filtering with tunable-Q wavelet transform (TQWT). SEEG signals are spatially filtered to isolate the CS artifacts within a few number of sources/components. The artifacted components are then decomposed into oscillatory background and sharp varying transient signals using tunable-Q wavelet transform (TQWT). The CS artifact is assumed to lie in the transient part of the signal. Using prior known time-frequency information of the CS artifacts, we selectively mask the wavelet coefficients of the transient signal and extract out any remaining significant electrophysiological activity. RESULTS: We have applied our proposed method of CS artifact suppression on simulated and real SEEG signals with convincing performance. The experimental results indicate the effectiveness of the proposed approach. CONCLUSION: The proposed method suppresses CS artifacts without affecting the background SEEG signal. SIGNIFICANCE: The proposed method can be applied for suppressing both low and high frequency CS artifacts and outperforms current methods from the literature. PMID- 30418881 TI - eFESTA: Ensemble Feature Exploration with Surface Density Estimates. AB - We propose surface density estimate (SDE) to model the spatial distribution of surface features-isosurfaces, ridge surfaces, and streamsurfaces-in 3D ensemble simulation data. The inputs of SDE computation are surfaces represented as polygon meshes, and no field datasets are required. The SDE is defined as the kernel density estimate of the infinite set of points on the input surfaces and is approximated by accumulating the surface densities of triangular patches. We also propose an algorithm to guide the selection of a proper kernel bandwidth for SDE computation. An ensemble Feature Exploration method based on Surface densiTy EstimAtes (eFESTA) is then proposed to extract and visualize the major trends of ensemble surface features. For an ensemble of surface features, each surface is first transformed into a density field based on its contribution to the SDE, and the resulting density fields are organized into a hierarchical representation based on the pairwise distances between them. The hierarchical representation is then used to guide visual exploration of the density fields as well as the underlying surface features. We demonstrate the application of our method using isosurface in ensemble scalar fields, Lagrangian coherent structures in uncertain unsteady flows, and streamsurfaces in ensemble fluid flows. PMID- 30418882 TI - Technology-assisted ankle rehabilitation improves balance and gait performance in stroke survivors: A randomized controlled study with 1-month follow-up. AB - Many stroke survivors have limited ankle range of motion (ROM) caused by weak dorsiflexors and stiff plantarflexors. Passive ankle stretching exercises with physical therapists or a stretching board are usually recommended, but these treatments have some limitations (e.g., cost, availability of physical therapists, etc.). In this paper, we assessed the results of ankle stretching exercises delivered by a robotic ankle stretching system called Motorized Ankle Stretcher (MAS) that we developed or by a stretching board on ankle ROM, balance control, and gait performance. Sixteen stroke survivors were randomly assigned to an intervention group (IG) or a control group (CG), and participated in seven sessions of dorsiflexion stretching exercises for three-and-a-half consecutive weeks. Laboratory assessments included pre-assessment (baseline at the beginning of the first exercise session), post-assessment (at the end of the seventh exercise session), and retention-assessment (one month after the seventh exercise session). All assessments included ankle ROM for the affected side, static/dynamic balance control with a Sensory Organization Test (SOT), walking speed, walking cadence, and step length for the affected and unaffected sides. During seven sessions of ankle stretching exercises, the IG performed them using the MAS, and the CG used a stretching board. The IG significantly improved ankle ROM, SOT scores (i.e., static/dynamic balance control), walking speeds, walking cadences, and step lengths for the unaffected side after completing the seven exercise sessions of ankle stretching exercises, and maintained the enhancements at the retention-assessment. The CG did not significantly improve across the majority of outcome measures except for the SOT scores between the pre- and retention-assessments. Future work will investigate the ideal intensity, frequency, and duration of exercising with the MAS. Our research on technology assisted ankle rehabilitation, which can ascertain the level of persistent improvement, long-term performance retention, and carry-over effects in stroke survivors, can be used to inform future designs. PMID- 30418883 TI - Electronics of a Wearable ECG with Level Crossing Sampling and Human Body Communication. AB - In this paper, the human body communication (HBC) and level crossing sampling (LCS) are combined to design electronics for a wearable ECG. The ECG signals acquired by capacitively coupled electrodes are sampled with LCS in place of conventional synchronous sampling. In order to transmit signals through HBC at low frequencies (100 kHz, 1 MHz), an electric field sensor with high input impedance is adopted as the front end of the HBC receiver. The HBC channel gain is enhanced by more than 30 dB with the electric field sensor. An LCS structure based on the send-on-delta concept is implemented with several discrete components to convert the ECG signals into binary impulses. The converted impulses are modulated by an on-off keying (OOK) modulator and then transmitted via the human body to the receiver. A prototype ECG waist belt is developed with commercially available components and experimentally evaluated. The results indicate that the acquired ECG waveforms exhibit good agreement with regular Ag/AgCl ECG methods. The heartbeat detection using a technique based on the Kadane's algorithm and the power consumption performance of the proposed system are also discussed. PMID- 30418884 TI - Neuromorphic LIF Row-by-Row Multi-convolution Processor for FPGA. AB - Deep Learning algorithms have become state-of-the-art methods for multiple fields, including computer vision, speech recognition, natural language processing and audio recognition, among others. In image vision, convolutional neural networks (CNN) stand out. These kind of networks are expensive in terms of computational resources due to the large number of operations required to process a frame. In recent years, several frame-based chip solutions to deploy CNN for real time have been developed. Despite the good results in power and accuracy given by these solutions, the number of operations is still high, due the complexity of the current network models. However, it is possible to reduce the number of operations using different computer vision techniques other than frame based, e.g. neuromorphic event-based techniques. There exist several neuromorphic vision sensors whose pixels detect changes in luminosity. Inspired in the Leaky Integrate-and-Fire neuron, we propose in this manuscript an event-based FPGA multiconvolution system. Its main novelty is the combination of a memory arbiter for efficient memory access to allow row-by-row kernel processing. This system is able to convolve 64 filters across multiple kernel sizes, from 1x1 to 7x7, with latencies of 1.3MUs and 9.01MUs, respectively, generating a continuous flow of output events. The proposed architecture will easily fit spike-based CNNs. PMID- 30418885 TI - A Chronically-Implanted Neural Coprocessor for Exploring Treatments for Neurological Disorders. AB - Developing new tools to better understand disorders of the nervous system, with a goal to more effectively treat them, is an active area of bioelectronic medicine research. Future tools must be flexible and configurable, given the evolving understanding of both neuromodulation mechanisms and how to configure a system for optimal clinical outcomes. We describe a system, the RC+S "neural coprocessor," that attempts to bring the capability and flexibility of a microprocessor to a prosthesis embedded within the nervous system. The paper describes the updated system architecture for the RC+S system, the five custom integrated circuits required for bi-directional neural interfacing, the supporting firmware/software ecosystem, and the verification and validation activities to prepare for human implantation. Emphasis is placed on design changes motivated by experience with the CE-marked Activa PC+S TM research tool; specifically, enhancement of sense-stim performance for improved bi-directional communication to the nervous system, implementation of rechargeable technology to extend device longevity, and application of MICS-band telemetry for algorithm development and data management. The technology was validated in a chronic treatment paradigm for canines with naturally-occurring epilepsy, including free ambulation in the home environment, which represents a typical use case for future human protocols. PMID- 30418886 TI - Two-Dimensional Quaternion PCA and Sparse PCA. AB - Benefited from quaternion representation that is able to encode the cross-channel correlation of color images, quaternion principle component analysis (QPCA) was proposed to extract features from color images while reducing the feature dimension. A quaternion covariance matrix (QCM) of input samples was constructed, and its eigenvectors were derived to find the solution of QPCA. However, eigen decomposition leads to the fixed solution for the same input. This solution is susceptible to outliers and cannot be further optimized. To solve this problem, this paper proposes a novel quaternion ridge regression (QRR) model for two dimensional QPCA (2D-QPCA). We mathematically prove that this QRR model is equivalent to the QCM model of 2D-QPCA. The QRR model is a general framework and is flexible to combine 2D-QPCA with other technologies or constraints to adapt different requirements of real-world applications. Including sparsity constraints, we then propose a quaternion sparse regression model for 2D-QSPCA to improve its robustness for classification. An alternating minimization algorithm is developed to iteratively learn the solution of 2D-QSPCA in the equivalent complex domain. In addition, 2D-QPCA and 2D-QSPCA can preserve the spatial structure of color images and have a low computation cost. Experiments on several challenging databases demonstrate that 2D-QPCA and 2D-QSPCA are effective in color face recognition, and 2D-QSPCA outperforms the state of the arts. PMID- 30418887 TI - Shared Nearest-Neighbor Quantum Game-Based Attribute Reduction With Hierarchical Coevolutionary Spark and Its Application in Consistent Segmentation of Neonatal Cerebral Cortical Surfaces. AB - The unprecedented increase in data volume has become a severe challenge for conventional patterns of data mining and learning systems tasked with handling big data. The recently introduced Spark platform is a new processing method for big data analysis and related learning systems, which has attracted increasing attention from both the scientific community and industry. In this paper, we propose a shared nearest-neighbor quantum game-based attribute reduction (SNNQGAR) algorithm that incorporates the hierarchical coevolutionary Spark model. We first present a shared coevolutionary nearest-neighbor hierarchy with self-evolving compensation that considers the features of nearest-neighborhood attribute subsets and calculates the similarity between attribute subsets according to the shared neighbor information of attribute sample points. We then present a novel attribute weight tensor model to generate ranking vectors of attributes and apply them to balance the relative contributions of different neighborhood attribute subsets. To optimize the model, we propose an embedded quantum equilibrium game paradigm (QEGP) to ensure that noisy attributes do not degrade the big data reduction results. A combination of the hierarchical coevolutionary Spark model and an improved MapReduce framework is then constructed that it can better parallelize the SNNQGAR to efficiently determine the preferred reduction solutions of the distributed attribute subsets. The experimental comparisons demonstrate the superior performance of the SNNQGAR, which outperforms most of the state-of-the-art attribute reduction algorithms. Moreover, the results indicate that the SNNQGAR can be successfully applied to segment overlapping and interdependent fuzzy cerebral tissues, and it exhibits a stable and consistent segmentation performance for neonatal cerebral cortical surfaces. PMID- 30418888 TI - A Cross-Domain Recommender System With Kernel-Induced Knowledge Transfer for Overlapping Entities. AB - The aim of recommender systems is to automatically identify user preferences within collected data, then use those preferences to make recommendations that help with decisions. However, recommender systems suffer from data sparsity problem, which is particularly prevalent in newly launched systems that have not yet had enough time to amass sufficient data. As a solution, cross-domain recommender systems transfer knowledge from a source domain with relatively rich data to assist recommendations in the target domain. These systems usually assume that the entities either fully overlap or do not overlap at all. In practice, it is more common for the entities in the two domains to partially overlap. Moreover, overlapping entities may have different expressions in each domain. Neglecting these two issues reduces prediction accuracy of cross-domain recommender systems in the target domain. To fully exploit partially overlapping entities and improve the accuracy of predictions, this paper presents a cross domain recommender system based on kernel-induced knowledge transfer, called KerKT. Domain adaptation is used to adjust the feature spaces of overlapping entities, while diffusion kernel completion is used to correlate the non overlapping entities between the two domains. With this approach, knowledge is effectively transferred through the overlapping entities, thus alleviating data sparsity issues. Experiments conducted on four data sets, each with three sparsity ratios, show that KerKT has 1.13%-20% better prediction accuracy compared with six benchmarks. In addition, the results indicate that transferring knowledge from the source domain to the target domain is both possible and beneficial with even small overlaps. PMID- 30418889 TI - Efficient Multispike Learning for Spiking Neural Networks Using Probability Modulated Timing Method. AB - Error functions are normally based on the distance between output spikes and target spikes in supervised learning algorithms for spiking neural networks (SNNs). Due to the discontinuous nature of the internal state of spiking neuron, it is challenging to ensure that the number of output spikes and target spikes kept identical in multispike learning. This problem is conventionally dealt with by using the smaller of the number of desired spikes and that of actual output spikes in learning. However, if this approach is used, information is lost as some spikes are neglected. In this paper, a probability-modulated timing mechanism is built on the stochastic neurons, where the discontinuous spike patterns are converted to the likelihood of generating the desired output spike trains. By applying this mechanism to a probability-modulated spiking classifier, a probability-modulated SNN (PMSNN) is constructed. In its multilayer and multispike learning structure, more inputs are incorporated and mapped to the target spike trains. A clustering rule connection mechanism is also applied to a reservoir to improve the efficiency of information transmission among synapses, which can map the highly correlated inputs to the adjacent neurons. Results of comparisons between the proposed method and popular the SNN algorithms showed that the PMSNN yields higher efficiency and requires fewer parameters. PMID- 30418890 TI - An Adaptive, Data-Driven Personalized Advisor for Increasing Physical Activity. AB - In recent years, there has been growing interest in the use of fitness trackers and smartphone applications for promoting physical activity. Most of these applications use accelerometers to measure the level of activity that users engage in and provide descriptive, interactive reports of a user's step counts. While these reports are data-driven and personalized, any recommendations, if provided, are limited to popular health advice. In our work, we develop an approach for providing data-driven and personalized recommendations for intraday activity planning. We generate an hour-by-hour activity plan that is informed by the user's probability of adhering to the plan. The user's probability of adherence to the plan is personalized, based on his/her past activity patterns and current activity target. Using this approach, we can tailor notifications (e.g., reminders, encouragement) based on the user's adherence to the plan. We can also dynamically update the user's activity plan mid-day, if his/her actual activity deviates sufficiently from the original plan such that the original plan becomes unrealistic for the user to achieve. In this paper we describe an implementation of our approach and report our technical findings with respect to identifying typical activity patterns from historical data, predicting whether an activity target will be achieved, and adapting an activity plan based on a user's actual performance throughout the day. PMID- 30418891 TI - A Lightweight Multi-section CNN for Lung Nodule Classification and Malignancy Estimation. AB - The size and shape of a nodule are the essential indicators of malignancy in lung cancer diagnosis. However, effectively capturing the nodule's structural information from CT scans in a Computer-aided system is a challenging task. Unlike previous models which proposed computationally intensive deep ensemble models or 3D CNN models, we propose a lightweight, multiple view sampling based Multi-section CNN architecture. The model obtains a nodule's cross-sections from multiple view angles and encodes the nodule's volumetric information into a compact representation by aggregating information from its different cross sections via a view pooling layer. The compact feature is subsequently used for the task of nodule classification. The method does not require nodule's spatial annotation and works directly on the crosssections generated from volume enclosing the nodule. We evaluated the proposed method on LIDC-IDRI dataset. It achieved state-of-the-art performance with a mean 93.18% classification accuracy. The architecture could also be used to select the representative cross-sections determining nodule's malignancy which facilitates in the interpretation of results. Because of being lightweight the model could be ported to mobile devices which brings the power of AI driven application directly into practitioner's hand. PMID- 30418892 TI - Heart Rate and Heart Rate Variability from Single-Channel Video and ICA Integration of Multiple Signals. AB - Unobtrusive monitoring of vital signs is relevant for both medical (patient monitoring) and non-medical applications (e.g. stress and fatigue monitoring). In this work, we focus on the use of imaging photoplethysmography (iPPG). High frame rate videos were acquired by using a monochrome camera and an op- tical band-pass filter (560 +/- 20 nm). To enhance iPPG signal, we investigated the use of Independent Component Analysis (ICA) pre-processing applied to iPPG signal from different regions of the face. Methodology was tested on 30 healthy volunteers. Heart rate (HR) and standard time and frequency domain descriptors of heart rate variability (HRV), simultaneously extracted from videos and ECG data, were compared. A mean absolute error (MAE) about 3.812 ms was observed for normal-to normal in- tervals with or without ICA pre-processing. Smaller MAE values of frequency domain descriptors were observed when ICA pre- processing is used. The impact of both video frame rate and video signal interval were also analyzed. All the results support the conclusion that proposed ICA pre-processing can effectively improve the HR and HRV assessment from iPPG. PMID- 30418893 TI - Multiview Semantic Representation for Visual Recognition. AB - Due to interclass and intraclass variations, the images of different classes are often cluttered which makes it hard for efficient classifications. The use of discriminative classification algorithms helps to alleviate this problem. However, it is still an open problem to accurately model the relationships between visual representations and human perception. To alleviate these problems, in this paper, we propose a novel multiview semantic representation (MVSR) algorithm for efficient visual recognition. First, we leverage visually based methods to get initial image representations. We then use both visual and semantic similarities to divide images into groups which are then used for semantic representations. We treat different image representation strategies, partition methods, and numbers as different views. A graph is then used to combine the discriminative power of different views. The similarities between images can be obtained by measuring the similarities of graphs. Finally, we train classifiers to predict the categories of images. We evaluate the discriminative power of the proposed MVSR method for visual recognition on several public image datasets. Experimental results show the effectiveness of the proposed method. PMID- 30418894 TI - Weighted Hierarchical Grammatical Evolution. AB - Grammatical evolution (GE) is one of the most widespread techniques in evolutionary computation. Genotypes in GE are bit strings while phenotypes are strings, of a language defined by a user-provided context-free grammar. In this paper, we propose a novel procedure for mapping genotypes to phenotypes that we call weighted hierarchical GE (WHGE). WHGE imposes a form of hierarchy on the genotype and encodes grammar symbols with a varying number of bits based on the relative expressive power of those symbols. WHGE does not impose any constraint on the overall GE framework, in particular, WHGE may handle recursive grammars, uses the classical genetic operators, and does not need to define any bound in advance on the size of phenotypes. We assessed experimentally our proposal in depth on a set of challenging and carefully selected benchmarks, comparing the results of the standard GE framework as well as two of the most significant enhancements proposed in the literature: 1) position-independent GE and 2) structured GE. Our results show that WHGE delivers very good results in terms of fitness as well as in terms of the properties of the genotype-phenotype mapping procedure. PMID- 30418895 TI - Intraspectrum Discrimination and Interspectrum Correlation Analysis Deep Network for Multispectral Face Recognition. AB - Multispectral images contain rich recognition information since the multispectral camera can reveal information that is not visible to the human eye or to the conventional RGB camera. Due to this characteristic of multispectral images, multispectral face recognition has attracted lots of research interest. Although some multispectral face recognition methods have been presented in the last decade, how to fully and effectively explore the intraspectrum discriminant information and the useful interspectrum correlation information in multispectral face images for recognition has not been well studied. To boost the performance of multispectral face recognition, we propose an intraspectrum discrimination and interspectrum correlation analysis deep network (IDICN) approach. Multiple spectra are divided into several spectrum-sets, with each containing a group of spectra within a small spectral range. The IDICN network contains a set of spectrum-set-specific deep convolutional neural networks attempting to extract spectrum-set-specific features, followed by a spectrum pooling layer, whose target is to select a group of spectra with favorable discriminative abilities adaptively. IDICN jointly learns the nonlinear representations of the selected spectra, such that the intraspectrum Fisher loss and the interspectrum discriminant correlation are minimized. Experiments on the well-known Hong Kong Polytechnic University, Carnegie Mellon University, and the University of Western Australia multispectral face datasets demonstrate the superior performance of the proposed approach over several state-of-the-art methods. PMID- 30418896 TI - Outlier Detection Using Structural Scores in a High-Dimensional Space. AB - Outlier detection has drawn significant interest from both academia and industry, such as network intrusion detection. Most existing methods implicitly or explicitly rely on distances in Euclidean space. However, the Euclidean distance may be incapable of measuring the similarity among high-dimensional data due to the curse of dimensionality, thus leading to inferior performance in practice. This paper presents an innovative approach for outlier detection from the view of meaningful structure scores. If two points have similar features, the difference between their structural scores is small and vice versa. The scores are calculated by measuring the variance of angles weighted by data representation, which takes the global data structure into the measurement. Thus, it could consistently rank more similar points. Compared with existing methods, our structural scores could be better to reflect the characteristics of data in a high-dimensional space. The proposed method consistently ranks more similar points. Experiments on synthetic and several real-world datasets have demonstrated the effectiveness and efficiency of our proposed methods. PMID- 30418897 TI - Inverse Visual Question Answering: A New Benchmark and VQA Diagnosis Tool. AB - In this paper we propose the inverse problem of VQA (iVQA). The iVQA task is to generate a question that corresponds to a given image and answer pair. We propose a variational iVQA model that can generate diverse, grammatically correct and content correlated questions that match the given answer. Based on this model, we show that iVQA is an interesting benchmark for visuo-linguistic understanding, and a more challenging alternative to VQA because an iVQA model needs to understand the image better to be successful. As a second contribution, we show how to use iVQA in a novel reinforcement learning framework to diagnose any existing VQA model by way of exposing its belief set: the set of question-answer pairs that the VQA model would predict true for a given image. This provides a completely new window into what VQA models 'believe' about images. We show that existing VQA models have more erroneous beliefs than previously thought, revealing their intrinsic weaknesses. Suggestions are then made on how to address these weaknesses going forward. PMID- 30418898 TI - Open Set Domain Adaptation for Image and Action Recognition. AB - Since annotating and curating large datasets is very expensive, there is a need to transfer the knowledge from existing annotated datasets to unlabelled data. Data that is relevant for a specific application, however, usually differs from publicly available datasets since it is sampled from a different domain. While domain adaptation methods compensate for such a domain shift, they assume that all categories in the target domain are known and match the categories in the source domain. Since this assumption is violated under real-world conditions, we propose an approach for open set domain adaptation where the target domain contains instances of categories that are not present in the source domain. The proposed approach achieves state-of-the-art results on various datasets for image classification and action recognition. Since the approach can be used for open set and closed set domain adaptation, as well as unsupervised and semi-supervised domain adaptation, it is a versatile tool for many applications. PMID- 30418899 TI - Backprojection Filtration Image Reconstruction Approach for Reducing High-density Object Artifacts in Digital Breast Tomosynthesis. AB - While an accurate image reconstruction of digital breast tomosynthesis (DBT) is fundamentally impossible due to its limited data, the DBT is increasingly used in clinics for its rich image information at a relatively low dose. One of the dominant image artifacts in DBT that hinders a faithful diagnosis is highdensity object artifact in conjunction with a limited angle problem. In this work, we developed a very efficient method for reconstructing DBT images with much reduced high-density object artifacts. The method is based on backprojection filtration reconstruction algorithm, voting strategy, and image blending. Data derivatives were backprojected with appropriate weights to reduce ripple artifacts by use of the voting strategy. We generated another differentiated backprojection volume where edges of high-density objects are replaced by the background. After Hilbert transform, we blended the two images to reduce undershoot artifacts. Physical phantoms were scanned and we compared conventional filtered backprojection, filtered backprojection with weighted backprojection, and our proposed method. Ripple artifacts were dramatically suppressed and undershoot artifacts were also greatly suppressed in the proposed method. PMID- 30418900 TI - Learning Domain Shift in Simulated and Clinical Data: Localizing the Origin of Ventricular Activation from 12-Lead Electrocardiograms. AB - Building a data-driven model to localize the origin of ventricular activation from 12-lead electrocardiograms (ECG) requires addressing the challenge of large anatomical and physiological variations across individuals. The alternative of a patientspecific model is, however, difficult to implement in clinical practice because training data must be obtained through invasive procedures. Here, we present a novel approach that overcomes this problem of the scarcity of clinical data by transferring the knowledge from a large set of patient-specific simulation data while utilizing domain adaptation to address the discrepancy between simulation and clinical data. The method that we have developed quantifies non-uniformly distributed simulation errors, which are then incorporated into the process of domain adaptation in the context of both classification and regression. This yields a quantitative model that, with the addition of 12-lead ECG data from each patient, provides progressively improved patientspecific localizations of the origin of ventricular activation. We evaluated the performance of the presented method in localizing 75 pacing sites on three in-vivo premature ventricular contraction (PVC) patients. We found that the presented model showed an improvement in localization accuracy relative to a model trained on clinical ECG data alone or a model trained on combined simulation and clinical data without considering domain shift. Further, we demonstrated the ability of the presented model to improve the real-time prediction of the origin of ventricular activation with each added clinical ECG data, progressively guiding the clinician towards the target site. PMID- 30418901 TI - An Augmented Linear Mixing Model to Address Spectral Variability for Hyperspectral Unmixing. AB - Hyperspectral imagery collected from airborne or satellite sources inevitably suffers from spectral variability, making it difficult for spectral unmixing to accurately estimate abundance maps. The classical unmixing model, the linear mixing model (LMM), generally fails to handle this sticky issue effectively. To this end, we propose a novel spectral mixture model, called the augmented linear mixing model (ALMM), to address spectral variability by applying a data-driven learning strategy in inverse problems of hyperspectral unmixing. The proposed approach models the main spectral variability (i.e., scaling factors) generated by variations in illumination or typography separately by means of the endmember dictionary. It then models other spectral variabilities caused by environmental conditions (e.g., local temperature and humidity, atmospheric effects) and instrumental configurations (e.g., sensor noise), as well as material nonlinear mixing effects, by introducing a spectral variability dictionary. To effectively run the data-driven learning strategy, we also propose a reasonable prior knowledge for the spectral variability dictionary, whose atoms are assumed to be low-coherent with spectral signatures of endmembers, which leads to a well-known low-coherence dictionary learning problem. Thus, a dictionary learning technique is embedded in the framework of spectral unmixing so that the algorithm can learn the spectral variability dictionary and estimate the abundance maps simultaneously. Extensive experiments on synthetic and real datasets are performed to demonstrate the superiority and effectiveness of the proposed method in comparison with previous state-of-the-art methods. PMID- 30418902 TI - Single Image Reflection Removal Using Convolutional Neural Networks. AB - When people take a picture through glass, the scene behind the glass is often interfered by specular reflection. Due to relatively easy implementation, most studies have tried to recover the transmitted scene from multiple images rather than single image. However, the use of multiple images is not practical for common users in real situations due to the critical shooting conditions. In this paper, we propose single image reflection removal using convolutional neural networks. We provide a ghosting model that causes reflection effects in captured images. First, we synthesize multiple reflection images from the input single one based on ghosting model and relative intensity. Then, we construct an end-to-end network that consists of encoder and decoder. To optimize the network parameters, we use a joint training strategy to learn the layer separation knowledge from the synthesized reflection images. For the loss function, we utilize both internal and external losses in optimization. Finally, we apply the proposed network to single image reflection removal. Compared with the previous work, the proposed method does not need handcrafted features and specular filters for reflection removal. Experimental results show that the proposed method successfully removes reflection from both synthetic and real images as well as achieves the highest scores in PSNR, SSIM and FSIM. PMID- 30418903 TI - A Second Order Multi-Stencil Fast Marching Method with a Non-Constant Local Cost Model. AB - The Fast Marching method is widely employed in several fields of image processing. Some years ago a Multi-Stencil version (MSFM) was introduced to improve its accuracy by solving the equation for a set of stencils and choosing the best solution at each considered node. The following work proposes a modified numerical scheme for MSFM to take into account the variation of the local cost, which has proven to be second order. The influence of the stencil set choice on the algorithm outcome with respect to stencil orthogonality and axis swapping is also explored, where stencils are taken from neighborhoods of varying radius. The experimental results show that the proposed schemes improve the accuracy of their original counterparts, and that the use of permutation-invariant stencil sets provides robustness against shifted vector coordinates in the stencil set. PMID- 30418904 TI - VRSA Net: VR Sickness Assessment Considering Exceptional Motion for 360 degrees VR Video. AB - The viewing safety is one of the main issues in viewing virtual reality (VR) content. In particular, VR sickness could occur when watching immersive VR content. To deal with the viewing safety for VR content, objective assessment of VR sickness is of great importance. In this paper, we propose a novel objective VR sickness assessment (VRSA) network based on deep generative model for automatically predicting the VR sickness score. The proposed method takes into account motion patterns of VR videos in which an exceptional motion is a critical factor inducing excessive VR sickness in human motion perception. The proposed VRSA network consists of two parts, which are VR video generator and VR sickness score predictor. By training the VR video generator with common videos with non exceptional motion, the generator learns the tolerance of VR sickness in human motion perception. As a result, the difference between the original and the generated videos by the VR video generator could represent exceptional motion of VR video causing VR sickness. In the VR sickness score predictor, the VR sickness score is predicted by projecting the difference between the original and the generated videos onto the subjective score space. For the evaluation of VR sickness assessment, we built a new dataset which consists of 360 degrees videos (stimuli), corresponding physiological signals, and subjective questionnaires from subjective assessment experiments. Experimental results demonstrated that the proposed VRSA network achieved a high correlation with human perceptual score for VR sickness. PMID- 30418905 TI - Robust Reflection Removal Based on Light Field Imaging. AB - In daily photography, it is common to capture images in the reflection of an unwanted scene. This circumstance arises frequently when imaging through a semi reflecting material such as glass. The unwanted reflection will affect the visibility of the background image and introduce ambiguity that perturbs the subsequent analysis on the image. It is a very challenging task to remove the reflection of an image since the problem is severely ill-posed. In this paper, we propose a novel algorithm to solve the reflection removal problem based on light field (LF) imaging. For the proposed algorithm, we first show that the strong gradient points of an LF epipolar plane image (EPI) are preserved after adding to the EPI of another LF image. We can then make use of these strong gradient points to give a rough estimation of the background and reflection. Rather than assuming that the background and reflection have absolutely different disparity ranges, we propose a sandwich layer model to allow them to have common disparities, which is more realistic in practical situations. Then, the background image is refined by recovering the components in the shared disparity range using an iterative enhancement process. Our experimental results show that the proposed algorithm achieves superior performance over traditional approaches both qualitatively and quantitatively. These results verify the robustness of the proposed algorithm when working with images captured from real-life scenes. PMID- 30418906 TI - FastDeRain: A Novel Video Rain Streak Removal Method Using Directional Gradient Priors. AB - Rain streaks removal is an important issue in outdoor vision systems and has recently been investigated extensively. In this paper, we propose a novel video rain streak removal approach FastDeRain, which fully considers the discriminative characteristics of rain streaks and the clean video in the gradient domain. Specifically, on the one hand, rain streaks are sparse and smooth along the direction of the raindrops, whereas on the other hand, clean videos exhibit piecewise smoothness along the rain-perpendicular direction and continuity along the temporal direction. Theses smoothness and continuity results in the sparse distribution in the different directional gradient domain, respectively. Thus, we minimize 1) the l1 norm to enhance the sparsity of the underlying rain streaks, 2) two l1 norm of unidirectional Total Variation (TV) regularizers to guarantee the anisotropic spatial smoothness, and 3) an l1 norm of the time-directional difference operator to characterize the temporal continuity. A split augmented Lagrangian shrinkage algorithm (SALSA) based algorithm is designed to solve the proposed minimization model. Experiments conducted on synthetic and real data demonstrate the effectiveness and efficiency of the proposed method. According to comprehensive quantitative performance measures, our approach outperforms other state-of-the-art methods, especially on account of the running time. The code of FastDeRain can be downloaded at https://github.com/TaiXiangJiang/FastDeRain. PMID- 30418907 TI - A Convex Optimization Framework for Video Quality and Resolution Enhancement From Multiple Descriptions. AB - Transmission and compression technologies advancement over the past decade led to a shift of multimedia content towards cloud systems. Multiple copies of the same video are available through numerous distribution systems. Different compression levels, algorithms and resolutions are used to match the requirements of particular applications. As 4k display technologies are rapidly adopted, resolution enhancement algorithms are of vital importance. Current solutions do not take into account the particularities of different video encoders, while video reconstruction methods from compressed sources do not provide resolution enhancement. In this paper, we propose a multi source compressed video enhancement framework, where each description can have a different compression level and resolution. Using a variational formulation based on a modern proximal dual splitting algorithm, we efficiently combine multiple descriptions of the same video. Two applications are proposed: combining two compressed low resolution (LR) descriptions of a video sequence into a high resolution (HR) description and enhancing a compressed HR video using a LR compressed description. Tests are performed over multiple video sequences encoded with high efficiency video coding, at different compression levels and resolutions obtained through multiple down-sampling methods. PMID- 30418908 TI - A Novel Scheme Based on the Diffusion to Edge Detection. AB - A novel scheme of edge detection based on the physical law of diffusion is presented in this paper. Though the most current studies are using data based methods such as deep neural networks, these methods on machine learning need big data of labeled ground truth as well as a large amount of resources for training. On the other hand, the widely used traditional methods are based on the gradient of the grayscale or color of images with using different sorts of mathematical tools to accomplish the mission. Instead of treating the outline of an object in an image as a kind of gradient of grayscale or color, our scheme deals with the edge detection as a character of an energy diffusing in the space of media such as charge-coupled device. By using the characteristic function of diffusion, the information of the energy will be extracted. The scheme preserves the structural information of images very well. Because it comes from the inhere law of images' physical property, it has a unified mathematical framework for images' edge detection under different conditions, for example, multiscales, diferent light conditions, and so on. Moreover, it has low computational complexity. PMID- 30418909 TI - Image Inpainting Using Nonlocal Texture Matching and Nonlinear Filtering. AB - Nonlocal texture similarity and local intensity smoothness are both essential for solving most image inpainting problems. In this paper, we propose a novel image inpainting algorithm that is capable of reproducing the underlying textural details using a nonlocal texture measure and also smoothing pixel intensity seamlessly in order to achieve natural-looking inpainted images. For matching texture, we propose a Gaussian-weighted nonlocal texture similarity measure to obtain multiple candidate patches for each target patch. To compute the pixel intensity, we apply the -trimmed mean filter to the candidate patches to inpaint the target patch pixel-by-pixel. The proposed algorithm is compared with four current image inpainting algorithms under different scenarios, including object removal, texture synthesis, and error concealment. Experimental results show that the proposed algorithm outperforms the existing algorithms when inpainting large missing regions in images with texture and geometric structures. PMID- 30418910 TI - FlowNet: A Deep Learning Framework for Clustering and Selection of Streamlines and Stream Surfaces. AB - For effective flow visualization, identifying representative flow lines or surfaces is an important problem which has been studied. However, no work can solve the problem for both lines and surfaces. In this paper, we present FlowNet, a single deep learning framework for clustering and selection of streamlines and stream surfaces. Given a collection of streamlines or stream surfaces generated from a flow field data set, our approach converts them into binary volumes and then employs an autoencoder to learn their respective latent feature descriptors. These descriptors are used to reconstruct binary volumes for error estimation and network training. Once converged, the feature descriptors can well represent flow lines or surfaces in the latent space. We perform dimensionality reduction of these feature descriptors and cluster the projection results accordingly. This leads to a visual interface for exploring the collection of flow lines or surfaces via clustering, filtering, and selection of representatives. Intuitive user interactions are provided for visual reasoning of the collection with ease. We validate and explain our deep learning framework from multiple perspectives, demonstrate the effectiveness of FlowNet using several flow field data sets of different characteristics, and compare our approach against state-of-the-art streamline and stream surface selection algorithms. PMID- 30418911 TI - Survey of Markov Chain Monte Carlo Methods in Light Transport Simulation. AB - Two decades have passed since the introduction of Markov chain Monte Carlo (MCMC) into light transport simulation by Veach and Guibas, and numerous follow-up works have been published since then. However, up until now no survey has attempted to cover majority of these methods. The aim of this paper is therefore to offer a first comprehensive survey of MCMC algorithms for light transport simulation. The methods presented in this paper are categorized by their objectives and properties, while we point out their strengths and weaknesses. We discuss how the methods handle the main issues of MCMC and how they could be combined or improved in the near future. To make the paper suitable for readers unacquainted with MCMC methods, we include an introduction to general MCMC and its demonstration on a simple example. PMID- 30418912 TI - Data-driven Indoor Scene Modeling from a Single Color Image with Iterative Object Segmentation and Model Retrieval. AB - We propose a new method for modeling the indoor scene from a single image. With our system, the user only needs to drag a few bounding boxes surrounding the objects of interest. Our system then automatically finds the most similar models from the ShapeNet repository and aligns them with the corresponding objects of interest. To achieve this, each 3D model is represented as a group of view dependent representations generated from a set of synthesized views. We iteratively conduct object segmentation and 3D model retrieval, based on the observation that good segmentation of the objects of interest can significantly improve the accuracy of model retrieval and make it robust to cluttered background and occlusion, and in turn, the retrieved models can be used to assist with segmentation. Segmentation of all objects of interest is achieved simultaneously under a unified multi-labeling framework which fully utilizes the correspondences between the objects and retrieved model images. Besides, we propose a new method to estimate the scene layout of the input image, which helps compose the resulting scene and further improves the modeling result. We verify the effectiveness of our approach through experimenting with a variety of indoor images and comparing against the relevant methods. PMID- 30418913 TI - Conceptual Design of a Fully Passive Transfemoral Prosthesis to Facilitate Energy Efficient Gait. AB - In this study, we present the working principle and conceptual design towards the realization of a fully-passive transfemoral prosthesis that mimics the energetics of the natural human gait. The fundamental property of the conceptual design consists of realizing an energetic coupling between the knee and ankle joints of the mechanism. Simulation results show that the power flow of the working principle is comparable to that in human gait and a considerable amount of energy is delivered to the ankle joint for the push-off generation. An initial prototype in half scale is realized to validate the working principle. The construction of the prototype is explained together with the test setup that has been built for the evaluation. Finally, experimental results of the prosthesis prototype during walking on a treadmill show the validity of the working principle. PMID- 30418914 TI - Two New Heuristic Methods for Protein Model Quality Assessment. AB - Protein tertiary structure prediction is an important open challenge in bioinformatics and requires effective methods to accurately evaluate the quality of protein 3-D models generated computationally. Many quality assessment (QA) methods have been proposed over the past three decades. However, the accuracy or robustness is unsatisfactory for practical applications. In this paper, two new heuristic QA methods are proposed: MUfoldQA_S and MUfoldQA_C. The MUfoldQA_S is a quasi-single-model QA method that assesses the model quality based on the known protein structures with similar sequences. This algorithm can be directly applied to protein fragments without the necessity of building a full structural model. A BLOSUM-based heuristic is also introduced to help differentiate accurate templates from poor ones. In MUfoldQA_C, the ideas from MUfoldQA_S were combined with the consensus approach to create a multi-model QA method that could also utilize information from existing reference models and have demonstrated improved performance. Extensive experimental results of these two methods have shown significant improvement over existing methods. In addition, both methods have been blindly tested in the CASP12 world-wide competition in the protein structure prediction field and ranked as top performers in their respective categories. PMID- 30418915 TI - Adaptive Particle Filtering for Fault Detection in Partially-Observed Boolean Dynamical Systems. AB - We propose a novel methodology for fault detection and diagnosis in partially observed Boolean dynamical systems (POBDS). These are stochastic, highly nonlinear, and derivative- less systems, rendering difficult the application of classical fault detection and diagnosis methods. The methodology comprises two main approaches. The first addresses the case when the normal mode of operation is known but not the fault modes. It applies an innovations filter (IF) to detect deviations from the nominal normal mode of operation. The second approach is applicable when the set of possible fault models is finite and known, in which case we employ a multiple model adaptive estimation (MMAE) approach based on a likelihood-ratio (LR) statistic. Unknown system parameters are estimated by an adaptive expectation- maximization (EM) algorithm. Particle filtering techniques are used to reduce the computational complexity in the case of systems with large state-spaces. The efficacy of the proposed methodology is demonstrated by numerical experiments with a large gene regulatory network (GRN) with stuck-at faults observed through a single noisy time series of RNA-seq gene expression measurements. PMID- 30418916 TI - Inference of model parameters using particle filter algorithm and Copula distributions. AB - It is widely accepted that experimental data often include noise because of the limitation in experimental conditions. In addition, biological systems inside the cells also contain uncertainty due to small copy molecular numbers. To address this issue, it was proposed that experimental data include both real system state and a noise term whose variance is a constant. An additional assumption is that the observation data of different variables are independent to each other. However, recent research works showed that noise in experimental data might not be the white noise. In addition, the observed values of different variables may be correlated. This work designs a new algorithm to infer the unknown model parameters based on noisy data. The innovation of this method includes a new noise model, in which the variance of noise is dependent on the system state, and a copula particle filter algorithm that uses the copula density functions to describe the dependence of different variables. The proposed algorithm is evaluated by using two deterministic models for gene networks and a stochastic model. Numerical results show that the accuracy of our proposed method is better than that of the widely used Liu-West filter and copula particle filter algorithms. PMID- 30418917 TI - A 430-MHz Wirelessly Powered Implantable Pulse Generator with Intensity/Rate Control and Sub-1 A Quiescent Current Consumption. AB - This work presents a miniaturized W-level implantable pulse generator (IPG) inductively powered at 430 MHz. Notches are intentionally applied to the incident power, which are replicated to precisely control the timing of the output pulses. Fabricated in 180 nm CMOS process, the concise circuitry occupies a pad-included footprint of 850 m 450 m and achieves a quiescent current consumption of 950 nA. To reduce the form factor, 401-457 MHz MedRadio-band is utilized to realize the induction link. The finalized assembly achieves one of the smallest dimensions (4.6 mm 7.0 mm) for near-field IPGs with the Rx coil size of 4.5 mm 3.6 mm. Co design of the rectifier and Rx coil accommodates the possible resonant frequency drifts in biological tissues. In the benchtop measurement, a 430 MHz Tx coil is demonstrated to operate the IPG at 4.5 cm and 4 cm proximities in the air and through water, respectively. An in vivo experiment has been performed, in which the IPG was implanted on the hindlimb muscle belly of an anesthetized rat with the connective tissue and skin sutured. The electrical stimuli induced the isolated ankle flexion at specific strengths and rates, and the experiment complies with the specific absorption rate (SAR) regulations. This work shows the potential for applications requiring stringent form factors and high sensitivities. PMID- 30418918 TI - A Sub-MUW/Ch Analog Front-End for -Neural Recording with Spike-Driven Data Compression. AB - We present a fully implantable neural recording IC with a spike-driven data compression scheme to improve the power efficiency and preserve crucial data for monitoring brain activities. A difference between two consecutive neural signals, -neural signal, is sampled in each channel to reduce the full dynamic range and the required resolution of an analog-to-digital converter (ADC), enabling the whole analog chain to be operated at a 0.5-V supply. A set of multiple -signals are stored in analog memory to extract the magnitude and frequency features of the incoming neural signals, which are utilized to discriminate spikes in these signals instantaneously after the acquisition in the analog domain. The energy- and area- efficient successive approximation ADC is implemented and only converts detected spikes, decreasing the power dissipation and the amount of neural data. A prototype 16-channel neural interface IC was fabricated using a 0.18-MUm CMOS process, and each component in the analog front-end was fully characterized. We successfully demonstrated precise spike detection through both in vitro and in vivo acquisition of the neural signal. The prototype chip consumed 0.88 MUW/channel at a 0.5-V supply for the recording and compressed about 89% of neural data, saving the power consumption and bandwidth in the system. PMID- 30418919 TI - A 0.086-mm 12.7-pJ/SOP 64k-Synapse 256-Neuron Online-Learning Digital Spiking Neuromorphic Processor in 28nm CMOS. AB - Shifting computing architectures from von Neumann to event-based spiking neural networks (SNNs) uncovers new opportunities for low-power processing of sensory data in applications such as vision or sensorimotor control. Exploring roads toward cognitive SNNs requires the design of compact, low-power and versatile experimentation platforms with the key requirement of online learning in order to adapt and learn new features in uncontrolled environments. However, embedding online learning in SNNs is currently hindered by high incurred complexity and area overheads. In this work, we present ODIN, a 0.086-mmMU 64k-synapse 256 neuron online-learning digital spiking neuromorphic processor in 28nm FDSOI CMOS achieving a minimum energy per synaptic operation (SOP) of 12.7pJ. It leverages an efficient implementation of the spike-driven synaptic plasticity (SDSP) learning rule for high-density embedded online learning with only 0.68MUm2 per 4 bit synapse. Neurons can be independently configured as a standard leaky integrate-and-fire (LIF) model or as a custom phenomenological model that emulates the 20 Izhikevich behaviors found in biological spiking neurons. Using a single presentation of 6k 16*16 MNIST training images to a single-layer fully connected 10-neuron network with on-chip SDSP-based learning, ODIN achieves a classification accuracy of 84.5% while consuming only 15nJ/inference at 0.55V using rank order coding. ODIN thus enables further developments toward cognitive neuromorphic devices for low-power, adaptive and low-cost processing. PMID- 30418920 TI - Enabling Ultrasound In-Body Communication: FIR Channel Models and QAM Experiments. AB - Ultrasound waves pose a promising alternative to the commonly used electromagnetic waves for intra-body communication. This due to the lower ultrasound wave attenuation, the reduced health risks and the reduced external interference. Current state-of-the-art ultrasound designs, however, are limited in their practical in-body deployment and reliability. This stems from their use of bulky, focused transducers, the use of simple modulation schemes or the absence of a realistic test environment and corresponding realistic channel models. Therefore, this work proposes a new, ultrasound, static emulation test bed consisting of small, omnidirectional transducers and custom gelatin phantoms with additional scattering materials. Using this test bed, we investigate different in-body communication scenarios. Multiple communication channels were extracted and mapped onto FIR channel models, which are verified and open sourced for future research. Furthermore, a basic QAM modem was built to assess the communication performance under various modulation schemes. A link was established using 4-QAM and 200kbit/s resulting in a BER <1e-4 at received Eb/No of 13dB. Identical results were obtained by computer simulations on the FIR channels, which makes the extracted FIR channels suitable for the design of future ultrasound in-body communication schemes. PMID- 30418921 TI - Integrated Optoelectronic Device for Detection of Fluorescent Molecules. AB - This work presents the development of a compact optoelectronic device suitable for on-chip detection of fluorescent molecules. In order to obtain a highly integrated device, a long-pass multi-dielectric filter has been integrated with thin film amorphous silicon photosensors on a single glass substrate. Filter rejects the excitation light, allowing the reduction of the distance between the source and the fluorescent site and avoiding the use of external optical component. The compatibility of the technological processes determined the materials and the temporal sequence of the device fabrication. The developed device has been designed for the fluorescence detection of ruthenium complex based molecules and tested, as a proof of concept, for the detection of double stranded DNA down to 0.5 ng. Results demonstrate the correct operation of the integrated system in both rejecting the excitation light and in detecting the fluorescent signal, demonstrating the suitability of this optoelectronic platform in practical biomedical applications. PMID- 30418922 TI - Impedance Spectroscopy and Electrophysiological Imaging of Cells with a High density CMOS Microelectrode Array System. AB - A monolithic multi-functional CMOS microelectrode array system was developed that enables label-free electrochemical impedance spectroscopy of cells in-vitro at high spatiotemporal resolution. The electrode array includes 59,760 platinum microelectrodes, densely packed within a 4.5 mm*2.5 mm sensing region at a pitch of 13.5 MUm. 32 on-chip lock-in amplifiers can be used to measure the impedance of any arbitrarily chosen subset of electrodes in the array. A sinusoidal voltage, generated by an on-chip waveform generator with a frequency range from 1 Hz to 1 MHz, was applied to the reference electrode. The sensing currents through the selected recording electrodes were amplified, demodulated, filtered and digitized to obtain the magnitude and phase information of the respective impedances. The circuitry consumes only 412 MUW at 3.3 V supply voltage and occupies only 0.1 mm2, for each channel. The system also included 2048 extracellular action-potential recording channels on the same chip. Proof of concept measurements of electrical impedance imaging and electrophysiology recording of cardiac cells and brain slices are demonstrated in this paper. Optical and impedance images showed a strong correlation. PMID- 30418923 TI - The Boundedness Conditions for Model-Free HDP(lambda). AB - This paper provides the stability analysis for a model-free action-dependent heuristic dynamic programing (HDP) approach with an eligibility trace long-term prediction parameter (lambda). HDP(lambda) learns from more than one future reward. Eligibility traces have long been popular in Q-learning. This paper proves and demonstrates that they are worthwhile to use with HDP. In this paper, we prove its uniformly ultimately bounded (UUB) property under certain conditions. Previous works present a UUB proof for traditional HDP [HDP(lambda=0)], but we extend the proof with the lambda parameter. By using Lyapunov stability, we demonstrate the boundedness of the estimated error for the critic and actor neural networks as well as learning rate parameters. Three case studies demonstrate the effectiveness of HDP(lambda). The trajectories of the internal reinforcement signal nonlinear system are considered as the first case. We compare the results with the performance of HDP and traditional temporal difference [TD(lambda)] with different lambda values. The second case study is a single-link inverted pendulum. We investigate the performance of the inverted pendulum by comparing HDP(lambda) with regular HDP, with different levels of noise. The third case study is a 3-D maze navigation benchmark, which is compared with state action reward state action, Q(lambda), HDP, and HDP(lambda). All these simulation results illustrate that HDP(lambda) has a competitive performance; thus this contribution is not only UUB but also useful in comparison with traditional HDP. PMID- 30418924 TI - L1-Norm Batch Normalization for Efficient Training of Deep Neural Networks. AB - Batch normalization (BN) has recently become a standard component for accelerating and improving the training of deep neural networks (DNNs). However, BN brings in additional calculations, consumes more memory, and significantly slows down the training iteration. Furthermore, the nonlinear square and sqrt operations in the normalization process impede low bit-width quantization techniques, which draw much attention to the deep learning hardware community. In this paper, we propose an L1-norm BN (L1BN) with only linear operations in both forward and backward propagations during training. L1BN is approximately equivalent to the conventional L2-norm BN (L2BN) by multiplying a scaling factor that equals (pi/2)1/2. Experiments on various convolutional neural networks and generative adversarial networks reveal that L1BN can maintain the same performance and convergence rate as L2BN but with higher computational efficiency. In real application-specified integrated circuit synthesis with reduced resources, L1BN achieves 25% speedup and 37% energy saving compared to the original L2BN. Our hardware-friendly normalization method not only surpasses L2BN in speed but also simplifies the design of deep learning accelerators. Last but not least, L1BN promises a fully quantized training of DNNs, which empowers future artificial intelligence applications on mobile devices with transfer and continual learning capability. PMID- 30418925 TI - Robust Subspace Clustering by Cauchy Loss Function. AB - Subspace clustering is a problem of exploring the low-dimensional subspaces of high-dimensional data. State-of-the-art approaches are designed by following the model of spectral clustering-based method. These methods pay much attention to learn the representation matrix to construct a suitable similarity matrix and overlook the influence of the noise term on subspace clustering. However, the real data are always contaminated by the noise and the noise usually has a complicated statistical distribution. To alleviate this problem, in this paper, we propose a subspace clustering method based on Cauchy loss function (CLF). Particularly, it uses CLF to penalize the noise term for suppressing the large noise mixed in the real data. This is due to that the CLF's influence function has an upper bound that can alleviate the influence of a single sample, especially the sample with a large noise, on estimating the residuals. Furthermore, we theoretically prove the grouping effect of our proposed method, which means that highly correlated data can be grouped together. Finally, experimental results on five real data sets reveal that our proposed method outperforms several representative clustering methods. PMID- 30418926 TI - Adaptive Neural Control of Underactuated Surface Vessels With Prescribed Performance Guarantees. AB - This paper presents adaptive neural tracking control of underactuated surface vessels with modeling uncertainties and time-varying external disturbances, where the tracking errors consisting of position and orientation errors are required to keep inside their predefined feasible regions in which the controller singularity problem does not happen. To provide the preselected specifications on the transient and steady-state performances of the tracking errors, the boundary functions of the predefined regions are taken as exponentially decaying functions of time. The unknown external disturbances are estimated by disturbance observers and then are compensated in the feedforward control loop to improve the robustness against the disturbances. Based on the dynamic surface control technique, backstepping procedure, logarithmic barrier functions, and control Lyapunov synthesis, singularity-free controllers are presented to guarantee the satisfaction of predefined performance requirements. In addition to the nominal case when the accurate model of a marine vessel is known a priori, the modeling uncertainties in the form of unknown nonlinear functions are also discussed. Adaptive neural control with the compensations of modeling uncertainties and external disturbances is developed to achieve the boundedness of the signals in the closed-loop system with guaranteed transient and steady-state tracking performances. Simulation results show the performance of the vessel control systems. PMID- 30418927 TI - Multistability of Switched Neural Networks With Piecewise Linear Activation Functions Under State-Dependent Switching. AB - This paper is concerned with the multistability of switched neural networks with piecewise linear activation functions under state-dependent switching. Under some reasonable assumptions on the switching threshold and activation functions, by using the state-space decomposition method, contraction mapping theorem, and strictly diagonally dominant matrix theory, we can characterize the number of equilibria as well as analyze the stability/instability of the equilibria. More interesting, we can find that the switching threshold plays an important role for stable equilibria in the unsaturation regions of activation functions, and the number of stable equilibria of an n-neuron switched neural network with state dependent parameters increases to 3n from 2n in the conventional one. Furthermore, for two-neuron switched neural networks, the precise attraction basin of each stable equilibrium point can be figured out, and its boundary is composed of the stable manifolds of unstable equilibrium points and the switching lines. Two simulation examples are discussed in detail to substantiate the effectiveness of the theoretical analysis. PMID- 30418928 TI - Gait Evaluation using Procrustes and Euclidean Distance Matrix Analysis. AB - Objective assessment of gait is important in the treatment and rehabilitation of patients with different diseases. In this paper, we propose a gait evaluation system using Procrustes and Euclidean distance matrix analysis. We design and develop an android app to collect real time synchronous accelerometer and gyroscope data from two Inertial Measurement Unit (IMU) sensors through Bluetooth connectivity. The data is collected from 12 young (10 for modelling and 2 for validation) and 20 older subjects. We analyse the data collected from real world for stride, step, stance and swing gait features. We validate our method with measurements of gait features. Generalized Procrustes analysis is used to estimate a standard normal mean gait shape (NMGS) for 10 young subjects. Each gait feature of both young and older subjects is then converted to find the best match with the NMGS using ordinary Procrustes analysis. The shape distance between the NMGS and each gait shape is estimated using Riemannian shape distance, Riemannian size-and-shape distance, Procrustes size-and-shape distance and Root mean square deviation. A t-test is performed to provide statistical evidence of gait shape differences between young and older gaits. A mean form which is considered as a standard normal mean gait form (NMGF) and inter-feature distances are estimated from the set of 10 young subjects. The form difference is estimated between the NMGF and individual gaits of young and older. The degree of abnormality is then estimated for individual features and the result is plotted to visualize the feature in a gait. Experimental results demonstrate the performance of the proposed method. PMID- 30418929 TI - 3D convolutional neural networks for automatic detection of pulmonary nodules in chest CT. AB - Deep 2D convolutional neural networks (CNNs) have been remarkably successful in producing record-breaking results in a variety of computer vision tasks. It is possible to extend CNNs to three dimensions using 3D kernels to make them suitable for volumetric medical imaging data such as CT or MRI, but this increases the processing time as well as the required number of training samples (due to the higher number of parameters that need to be learned). In this work, we address both of these issues for a 3D CNN implementation through the development of a two-stage computer-aided detection system for automatic detection of pulmonary nodules. The first stage consists of a 3D fully convolutional network (FCN) for fast screening and generation of candidate suspicious regions. The second stage consists of an ensemble of 3D CNNs trained using extensive transformations applied to both the positive and negative patches to augment the training set. To enable the second stage classifiers to learn differently, they are trained on false positive patches obtained from the screening model using different thresholds on their associated scores as well as different augmentation types. The networks in the second stage are averaged together to produce the final classification score for each candidate patch. Using this procedure, our overall nodule detection system called DeepMed is fast and can achieve 91% sensitivity at 2 false positives per scan on cases from the LIDC dataset. PMID- 30418930 TI - Finite-Time Stability of Delayed Memristor-Based Fractional-Order Neural Networks. AB - This paper studies one type of delayed memristor-based fractional-order neural networks (MFNNs) on the finite-time stability problem. By using the method of iteration, contracting mapping principle, the theory of differential inclusion, and set-valued mapping, a new criterion for the existence and uniqueness of the equilibrium point which is stable in finite time of considered MFNNs is established when the order alpha satisfies 00.05) and females worse (~43s, P<0.05) performance with DP versus CLASSIC. Flat and undulating terrain favored DP in males, while uphill favored CLASSIC in females (~60s). Uphill sections showed the greatest group differences. Greater RPE was found in arms during DP, whereas RPE was greater in legs using CLASSIC. VO2peak in DP was ~95% of VO2max. CONCLUSION: Male skiers demonstrated superior performance with exclusively using DP on a F.I.S. regulations compliant XCS track, while junior males achieved similar, and females weaker performance using DP versus CLASSIC. The greatest potential in females is in uphill sections where they distinctly lose time. Exclusive DP might only be beneficial in athletes with high upper-body capacity, and double-pole specific training and technique. In order to generalize the findings of the current study, further analysis of snow conditions and course topography is required.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30418964 TI - Up-Regulation of Phosphatase in Regenerating Liver-3 (PRL-3) Contributes to Malignant Progression of Hepatocellular Carcinoma by Activating Phosphatase and Tensin Homolog Deleted on Chromosome Ten (PTEN)/Phosphoinositide 3-Kinase (PI3K)/AKT Signaling Pathway. AB - BACKGROUND The purpose of the study was to investigate the functional roles of phosphatase in regenerating liver-3 (PRL-3) in hepatocellular carcinoma (HCC), as well as the related molecular mechanisms. MATERIAL AND METHODS HCC tissues and adjacent normal tissues were collected from 124 HCC patients. The mRNA and protein levels of PRL-3 were detected using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot assays, respectively. The relationship between PRL-3 expression and clinical characteristics of HCC patients was evaluated by chi-square test. MTT and Transwell assays were performed to estimate cell proliferation and motility, respectively. RESULTS The expression of PRL-3 was significantly increased in HCC tissues and cells at both protein and mRNA levels (P<0.01 for all). Furthermore, the up-regulation of PRL-3 was positively correlated with hepatic vascular invasion (P=0.019), lymph node metastasis (P=0.012), and TNM stage (P=0.001). The knockdown of PRL-3 suppressed HCC cell proliferation, migration, and invasion, and PR3K/AKT pathway activity was also obviously inhibited in HCC cells with PRL-3 deficiency. The levels of PTEN were negatively associated with PRL-3 expression. PRL-3 might inhibit the protein level of PTEN through enhancing its phosphorylation level. The transfection of si PTEN can reverse the anti-tumor action caused by PRL-3 knockdown in HCC cells. CONCLUSIONS Up-regulation of PRL-3 may activate the PI3K/AKT signaling pathway and enhance malignant progression of HCC through targeting PTEN. PMID- 30418965 TI - Single-cell RNA-sequencing reveals transcriptional dynamics of estrogen-induced dysplasia in the ovarian surface epithelium. AB - Estrogen therapy increases the risk of ovarian cancer and exogenous estradiol accelerates the onset of ovarian cancer in mouse models. Both in vivo and in vitro, ovarian surface epithelial (OSE) cells exposed to estradiol develop a subpopulation that loses cell polarity, contact inhibition, and forms multi layered foci of dysplastic cells with increased susceptibility to transformation. Here, we use single-cell RNA-sequencing to characterize this dysplastic subpopulation and identify the transcriptional dynamics involved in its emergence. Estradiol-treated cells were characterized by up-regulation of genes associated with proliferation, metabolism, and survival pathways. Pseudotemporal ordering revealed that OSE cells occupy a largely linear phenotypic spectrum that, in estradiol-treated cells, diverges towards cell state consistent with the dysplastic population. This divergence is characterized by the activation of various cancer-associated pathways including an increase in Greb1 which was validated in fallopian tube epithelium and human ovarian cancers. Taken together, this work reveals possible mechanisms by which estradiol increases epithelial cell susceptibility to tumour initiation. PMID- 30418966 TI - Arabidopsis class I formins control membrane-originated actin polymerization at pollen tube tips. AB - A population of dynamic apical actin filaments is required for rapid polarized pollen tube growth. However, the cellular mechanisms driving their assembly remain incompletely understood. It was postulated that formin is a major player in nucleating apical actin assembly, but direct genetic and cytological evidence remains to be firmly established. Here we found that both Arabidopsis formin 3 (AtFH3) and formin 5 (AtFH5) are involved in the regulation of apical actin polymerization and actin array construction in pollen tubes, with AtFH3 playing a more dominant role. We found that both formins have plasma membrane (PM) localization signals but exhibit distinct PM localization patterns in the pollen tube, and loss of their function reduces the amount of apical actin filaments. Live-cell imaging revealed that the reduction in filamentous actin is very likely due to the decrease in filament elongation. Furthermore, we found that the rate of tip-directed vesicle transport is reduced and the pattern of apical vesicle accumulation is altered in formin loss-of-function mutant pollen tubes, which explains to some extent the reduction in pollen tube elongation. Thus, we provide direct genetic and cytological evidence showing that formin is an important player in nucleating actin assembly from the PM at pollen tube tips. PMID- 30418967 TI - Comparative transcriptome analysis and RNA interference reveal CYP6A8 and SNPs related to pyrethroid resistance in Aedes albopictus. AB - Wide and improper application of pyrethroid insecticides for mosquito control has resulted in widespread resistance in Aedes albopictus mosquitoes, an important dengue vector. Therefore, understanding the molecular regulation of insecticide resistance is urgently needed to provide a basis for developing novel resistance diagnostic methods and vector control approaches. We investigated the transcriptional profiles of deltamethrin-resistant and -susceptible Ae. albopictus by performing paired-end sequencing for RNA expression analysis. The analysis used 24 independent libraries constructed from 12 wild-caught resistant and 12 susceptible Ae. albopictus female adults. A total of 674,503,592 and 612,512,034 reads were obtained, mapped to the Ae. albopictus genome and assembled into 20,091 Ae. albopictus transcripts. A total of 1,130 significantly differentially expressed genes included 874 up-regulated genes and 256 down regulated genes in the deltamethrin-resistant individuals. These differentially expressed genes code for cytochrome P450s, cuticle proteins, glutathione S transferase, serine proteases, heat shock proteins, esterase, and others. We selected three highly differentially expressed candidate genes, CYP6A8 and two genes of unknown function (CCG013931 and CCG000656), to test the association between these 3 genes and deltamethrin resistance using RNAi through microinjection in adult mosquitoes and oral feeding in larval mosquitoes. We found that expression knockdown of these three genes caused significant changes in resistance. Further, we detected 1,162 single nucleotide polymorphisms (SNPs) with a frequency difference of more than 50%. Among them, 5 SNPs in 4 cytochrome P450 gene families were found to be significantly associated with resistance in a genotype-phenotype association study using independent field-collected mosquitoes of known resistance phenotypes. Altogether, a combination of novel individually based transcriptome profiling, RNAi, and genetic association study identified both differentially expressed genes and SNPs associated with pyrethroid resistance in Ae. albopictus mosquitoes, and laid a useful foundation for further studies on insecticide resistance mechanisms. PMID- 30418968 TI - Estimating the elimination feasibility in the 'end game' of control efforts for parasites subjected to regular mass drug administration: Methods and their application to schistosomiasis. AB - Progress towards controlling and eliminating parasitic worms, including schistosomiasis, onchocerciasis, and lymphatic filariasis, is advancing rapidly as national governments, multinational NGOs, and pharmaceutical companies launch collaborative chemotherapeutic control campaigns. Critical questions remain regarding the potential for achieving elimination of these infections, and analytical methods can help to quickly estimate progress towards-and the probability of achieving-elimination over specific timeframes. Here, we propose the effective reproduction number, Reff, as a proxy of elimination potential for sexually reproducing worms that are subject to poor mating success at very low abundance (positive density dependence, or Allee effects). Reff is the number of parasites produced by a single reproductive parasite at a given stage in the transmission cycle, over the parasite's lifetime-it is the generalized form of the more familiar basic reproduction number, R0, which only applies at the beginning of an epidemic-and it can be estimated in a 'model-free' manner by an estimator ('epsilon'). We introduce epsilon, demonstrate its estimation using simulated data, and discuss how it may be used in planning and evaluation of ongoing elimination efforts for a range of parasitic diseases. PMID- 30418969 TI - Growth and adaptation of Zika virus in mammalian and mosquito cells. AB - The recent emergence of Zika virus (ZIKV) in the Americas coincident with increased caseloads of microcephalic infants and Guillain-Barre syndrome has prompted a flurry of research on ZIKV. Much of the research is difficult to compare or repeat because individual laboratories use different virus isolates, growth conditions, and quantitative assays. Here we obtained three readily available contemporary ZIKV isolates and the prototype Ugandan isolate. We generated stocks of each on Vero mammalian cells (ZIKVmam) and C6/36 mosquito cells (ZIKVmos), determined titers by different assays side-by-side, compared growth characteristics using one-step and multi-step growth curves on Vero and C6/36 cells, and examined plaque phenotype. ZIKV titers consistently peaked earlier on Vero cells than on C6/36 cells. Contemporary ZIKV isolates reached peak titer most quickly in a multi-step growth curve when the amplifying cell line was the same as the titering cell line (e.g., ZIKVmam titered on Vero cells). Growth of ZIKVmam on mosquito cells was particularly delayed. These data suggest that the ability to infect and/or replicate in insect cells is limited after growth in mammalian cells. In addition, ZIKVmos typically had smaller, more homogenous plaques than ZIKVmam in a standard plaque assay. We hypothesized that the plaque size difference represented early adaptation to growth in mammalian cells. We plaque purified representative-sized plaques from ZIKVmos and ZIKVmam. ZIKVmos isolates maintained the initial phenotype while plaques from ZIKVmam isolates became larger with passaging. Our results underscore the importance of the cells used to produce viral stocks and the potential for adaptation with minimal cell passages. In addition, these studies provide a foundation to compare current and emerging ZIKV isolates in vitro and in vivo. PMID- 30418970 TI - Identification of Elg1 interaction partners and effects on post-replication chromatin re-formation. AB - Elg1, the major subunit of a Replication Factor C-like complex, is critical to ensure genomic stability during DNA replication, and is implicated in controlling chromatin structure. We investigated the consequences of Elg1 loss for the dynamics of chromatin re-formation following DNA replication. Measurement of Okazaki fragment length and the micrococcal nuclease sensitivity of newly replicated DNA revealed a defect in nucleosome organization in the absence of Elg1. Using a proteomic approach to identify Elg1 binding partners, we discovered that Elg1 interacts with Rtt106, a histone chaperone implicated in replication coupled nucleosome assembly that also regulates transcription. A central role for Elg1 is the unloading of PCNA from chromatin following DNA replication, so we examined the relative importance of Rtt106 and PCNA unloading for chromatin reassembly following DNA replication. We find that the major cause of the chromatin organization defects of an ELG1 mutant is PCNA retention on DNA following replication, with Rtt106-Elg1 interaction potentially playing a contributory role. PMID- 30418972 TI - Genetic characteristics of Bacillus anthracis isolated from northwestern China from 1990 to 2016. AB - Anthrax is a global re-emerging zoonotic disease and is an endemic disease in China, especially in rural regions. In this study, the general characteristics of human anthrax outbreaks that occurred in areas of northwestern China over the past decade have been described. Meanwhile, the genetic characteristics of Bacillus anthracis isolated from these areas from 1990 to 2016 were analyzed by means of canonical single-nucleotide polymorphism (canSNP) analysis and multilocus variable-number tandem repeat analysis (MLVA) with 15 markers. Five sublineages/subgroups, namely, A.Br.001/002, A.Br.Vollum, A.Br.Aust94, A.Br.Ames and A.Br.008/009, were detected by using 13 canSNP sites. All of the sublineages were found in Xinjiang province, while one sublineage was found in Shaanxi, two in Gansu, three in Qinghai and four in Inner Mongolia. However, the geographical distribution of the B. anthracis populations exhibited different canSNP characteristics from those of the strains isolated before 1990 in China. In contrast to previous data, the A.Br.Ames subgroup was also observed to be scattered from Inner Mongolia to other provinces. All 106 strains were assigned to 36 MLVA15 genotypes, and 21 of these types were first observed in this study. The strains collected from anthrax outbreaks in recent decade were classified as subgroups A.Br.001/002 and A.Br.Ames and identified as genotypes MLVA15-28, MLVA15-30, MLVA15-31, MLVA15-38, MLVA15-CHN3, and MLVA15-CHN18. By canSNP analysis and MLVA, we found that the diversification of MLVA genotypes and the geographical distribution of B. anthracis populations is gradually becoming balanced across northwestern China. This study also provides preliminary survey results regarding the population diversity of B. anthracis in China, which will help promote the prevention and control of this important disease. PMID- 30418971 TI - Use of anthropophilic culicid-based xenosurveillance as a proxy for Plasmodium vivax malaria burden and transmission hotspots identification. AB - Vector-borne diseases account for more than 17% of all infectious diseases, causing more than one million deaths annually. Malaria remains one of the most important public health problems worldwide. These vectors are bloodsucking insects, which can transmit disease-producing microorganisms during a blood meal. The contact of culicids with human populations living in malaria-endemic areas suggests that the identification of Plasmodium genetic material in the blood present in the gut of these mosquitoes may be possible. The process of assessing the blood meal for the presence of pathogens is termed 'xenosurveillance'. In view of this, the present work investigated the relationship between the frequency with which Plasmodium DNA is found in culicids and the frequency with which individuals are found to be carrying malaria parasites. A cross-sectional study was performed in a peri-urban area of Manaus, in the Western Brazilian Amazon, by simultaneously collecting human blood samples and trapping culicids from households. A total of 875 individuals were included in the study and a total of 13,374mosquito specimens were captured. Malaria prevalence in the study area was 7.7%. The frequency of households with at least one culicid specimen carrying Plasmodium DNA was 6.4%. Plasmodium infection incidence was significantly related to whether any Plasmodium positive blood-fed culicid was found in the same household [IRR 3.49 (CI95% 1.38-8.84); p = 0.008] and for indoor-collected culicids [IRR 4.07 (CI95%1.25-13.24); p = 0.020]. Furthermore, the number of infected people in the house at the time of mosquito collection was related to whether there were any positive blood-fed culicid mosquitoes in that household for collection methods combined [IRR 4.48 (CI95%2.22-9.05); p<0.001] or only for indoor-collected culicids [IRR 4.88 (CI95%2.01-11.82); p<0.001]. Our results suggest that xenosurveillance can be used in endemic tropical regions in order to estimate the malaria burden and identify transmission foci in areas where Plasmodium vivax is predominant. PMID- 30418973 TI - Estimation of HTLV-1 vertical transmission cases in Brazil per annum. AB - BACKGROUND: Brazil has at least 800,000 HTLV-1 infected individuals. HTLV-1 can be transmitted via sexual intercourse, contact with blood and from mother to child, mainly by breastfeeding. Treatments for the high morbidity/mortality associated diseases (ATL and HAM/TSP) are limited, therefore, infection prevention is of utmost importance. However, antenatal screening is not routinely performed in Brazil. A lack of data regarding the number of individuals infected via breastfeeding impairs the development of government policies. The objective is to estimate the number of HTLV-1 infections occurring annually due to mother to child transmission (MTCT) in Brazil, nationally and regionally. METHODOLOGY: To estimate HTLV-1 MTCT in Brazil the following variables are modelled: number of births, prevalence of HTLV-1 infection in pregnant women, breastfeeding duration rate and transmission risk according to breastfeeding period. The number of cases of HAM/TSP and ATL attributable to MTCT are also estimated. PRINCIPAL FINDINGS: In 2008, there were 2,934,828 live births in Brazil. HTLV prevalence in pregnant women in Brazil ranges between 0.1-1.05% by region. An estimated 16,548 HTLV-1 infected women are pregnant each year. According to the breastfeeding pattern and HTLV-1 prevalence of each region there are an estimated 3,024 new cases of HTLV-1 infection due to MTCT annually of which 2,610 are preventable through infant feeding advice. These 3,024 transmissions will result in 120-604 cases of ATL and 8-272 of HAM/TSP. North-East region comprises the high number of MTCT cases, followed by South-East. CONCLUSIONS/SIGNIFICANCE: A high number of new HTLV-1 infections due to MTCT occur every year in Brazil. Antenatal screening and avoiding breastfeeding are essential to prevent subsequent development of HTLV-1 associated diseases. PMID- 30418974 TI - Molecular analysis of clinical Burkholderia pseudomallei isolates from southwestern coastal region of India, using multi-locus sequence typing. AB - BACKGROUND: The Gram-negative soil dwelling bacterium Burkholderia pseudomallei is the etiological agent of melioidosis. The disease is endemic in most parts of Southeast Asia and northern Australia. Over last few years, there has been an increase in number of melioidosis cases from India; however the disease epidemiology is less clearly understood. Multi-locus sequence typing (MLST) is a powerful genotypic method used to characterize the genetic diversity of B. Pseudomallei both within and across the geographic regions. METHODS: In this study, MLST analysis was performed on 64 B. pseudomallei clinical isolates. These isolates were obtained between 2008-2014 from southwestern coastal region of India. Broad population patterns of Indian B. pseudomallei isolates in context with isolates of Southeast Asia or global collection was determined using in silico phylogenetic tools. RESULTS: A total of 32 Sequence types (STs) were reported among these isolates of which 17 STs (53%) were found to be novel. ST1368 was found as group founder and the most predominant genotype (n = 11, 17%). Most of the B. pseudomallei isolates reported in this study (or other Indian isolates available in MLST database) clustered in one major group suggesting clonality in Indian isolates; however, there were a few outliers. When analyzed by measure of genetic differentiation (FST) and other phylogenetic tools (e.g. PHYLOViZ), Indian STs were found closer to Southeast Asian isolates than Australian isolates. The phylogenetic analysis further revealed that within Asian clade, Indian isolates grouped more closely with isolates from Sri Lanka, Vietnam, Bangladesh and Thailand. CONCLUSIONS: Overall, the results of this study suggest that the Indian B. pseudomallei isolates are closely related with lesser heterogeneity among them and cluster in one major group suggesting clonality of the isolates. However, it appears that there are a few outliers which are distantly related to the majority of Indian STs. Phylogenetic analysis suggest that Indian isolates are closely related to isolates from Southeast Asia, particularly from South Asia. PMID- 30418975 TI - Serological evidence of inter-epizootic/inter-epidemic circulation of Rift Valley fever virus in domestic cattle in Kyela and Morogoro, Tanzania. AB - BACKGROUND: Tanzania is among the Rift Valley fever (RVF) epizootic/endemic countries in sub Saharan Africa, where RVF disease outbreaks occur within a range of 3 to 17-year intervals. Detection of Rift Valley fever virus (RVFV) antibodies in animals in regions with no previous history of outbreaks raises the question of whether the disease is overlooked due to lack-of effective surveillance systems, or if there are strains of RVFV with low pathogenicity. Furthermore, which vertebrate hosts are involved in the inter-epidemic and inter-epizootic maintenance of RVFV? In our study region, the Kyela and Morogoro districts in Tanzania, no previous RVF outbreaks have been reported. METHODOLOGY: The study was conducted from June 2014 to October 2015 in the Kyela and Morogoro districts, Tanzania. Samples (n = 356) were retrieved from both the local breed of zebu cattle (Bos indicus) and Bos indicus/Bos Taurus cross breed. RVFV antibodies were analyzed by two enzyme-linked immunosorbent assay (ELISA) approaches. Initially, samples were analyzed by a RVFV multi-species competition ELISA (cELISA), which detected both RVFV IgG and IgM antibodies. All serum samples that were positive with the cELISA method were specifically analysed for the presence of RVFV IgM antibodies to trace recent infection. A plaque reduction neutralization assay (PRNT80) was performed to determine presence of RVFV neutralizing antibodies in all cELISA positive samples. FINDINGS: Overall RVFV seroprevalence rate in cattle by cELISA in both districts was 29.2% (104 of 356) with seroprevalence rates of 33% (47/147) in the Kyela district and 27% (57/209) in the Morogoro district. In total, 8.4% (30/356) of all cattle sampled had RVFV IgM antibodies, indicating current disease transmission. When segregated by districts, the IgM antibody seroprevalence was 2.0% (3/147) and 12.9% (27/209) in Kyela and Morogoro districts respectively. When the 104 cELISA positive samples were analyzed by PRNT80 to confirm that RVFV-specific antibodies were present, the majority (89%, 93/104) had RVFV neutralising antibodies. CONCLUSION: The results provided evidence of widespread prevalence of RVFV antibody among cattle during an inter epizootic/inter-epidemic period in Tanzania in regions with no previous history of outbreaks. There is a need for further investigations of RVFV maintenance and transmission in vertebrates and vectors during the long inter-epizootic/inter epidemic periods. PMID- 30418976 TI - Exploring the parasite load and molecular diversity of Trypanosoma cruzi in patients with chronic Chagas disease from different regions of Brazil. AB - Chagas disease is still a major public health issue in many Latin American countries. One of the current major challenges is to find an association between Trypanosoma cruzi discrete typing units (DTUs) and clinical manifestations of the disease. In this study, we used a multilocus conventional PCR and quantitative real time PCR (qPCR) approaches to perform the molecular typing and parasite load quantification directly from blood specimens of 65 chronic Chagas disease patients. All patients were recruited at the same health center, but their place of birth were widely distributed in different geographic regions of Brazil. Of the 65 patients, 35 (53.8%) presented positive amplification by real time qPCR, being 20 (30.7%) with the clinical indeterminate form and 15 (23.1%) with the cardiac form of the disease. The parasite load median for all positive patients was 2.54 [1.43-11.14] parasite equivalents/mL (par. Eq./mL), with the load ranging from 0.12 to 153.66 par. Eq./mL. Noteworthy, the parasite load was significantly higher in patients over 70 years old (median 20.05 [18.29-86.86] par. Eq./mL). Using guanidine-EDTA blood samples spiked with reference T. cruzi strains, belonging to the six DTUs, it was possible to genotype the parasite up to 0.5 par. Eq./mL, with high specificity. Of the patients with positive qPCR, it was possible to identify the T. cruzi DTU in 28 patients (80%). For the remaining patients (20%), at least a partial result was obtained. Analysis of specimens showed prevalences of TcVI, TcII and mixed infection TcVI+TcII equal to 40%, 17.1% and 14.3%, respectively. In addition, two patients were infected by TcV, and one patient was coinfected by TcIII+TcVI, These last three patients were in stage A of chronic chagasic cardiomyopathy (CCC), and they were born at the Bahia State (northeast region of Brazil). When T. cruzi genotypes were compared with the parasite load, more elevated parasite loads were observed in patients infected by TcII in general (parasite load median of 7.56 par. Eq./mL) in comparison to patients infected by TcVI (median of 2.35 par. Eq./mL). However, while the frequency of CCC was 50% in patients infected by TcVI and TcV, only 16.7% of patients infected by TcII evolved to CCC. Taking together, our results contribute to update the epidemiological knowledge of T. cruzi DTUs in Brazil, and highlight the age of patient and infection by TcII as important features that lead to the observation of higher parasitemia levels. PMID- 30418977 TI - Validation of the blood gas analyzer for pH measurements in IVF culture medium: Prevent suboptimal culture conditions. AB - Measurement of pH in IVF-media using the blood gas analyzer (BGA) requires validation, because IVF-media is outside the intended scope of the BGA. To determine whether the Siemens Rapidpoint 500 BGA is suitable for pH measurements in IVF-media this study will validate the BGA and assess its accuracy. In this method comparison study, the pH of over three hundred IVF-media samples was measured with the BGA and a pH electrode (Hanna pH checker). The precision of both the BGA and the pH electrode were excellent (coefficient variation <1.4%). However, the closeness of agreement between measured values of both devices were not equivalent to each other in the tested IVF-media, showing 15% to 85% accordance between devices. The pH measured with the blood gas analyzer was also significantly higher in the tested media, compared to that measured by the pH electrode. One of the tested media did not reach its target pH when it was measured with the BGA, even at 9% CO2. The results show that the validated blood gas analyzer produces excellent results in terms of precision but not in terms of accuracy. Inaccurate measurement may lead to misinterpretation of results and consequently to suboptimal culture conditions. Therefore, each laboratory is encouraged to perform a validation of their BGA. PMID- 30418979 TI - Correction: Manganese-porphyrin-enhanced MRI for the detection of cancer cells: A quantitative in vitro investigation with multiple clinical subtypes of breast cancer. AB - [This corrects the article DOI: 10.1371/journal.pone.0196998.]. PMID- 30418978 TI - Differences in self-rated health and work ability between self-employed workers and employees: Results from a prospective cohort study in the Netherlands. AB - BACKGROUND: With the increase of the statutory retirement age, the number of self employed older workers will most likely increase. Therefore, this study aimed to explore: 1) the differences in self-rated health and work ability of self employed workers and employees, 1) whether self-employment is associated with better self-rated health and work ability across three years, than employment, and 3) the role of sociodemographic, health- and work-related characteristics (e.g., mental load, physical load, and autonomy) in these relationships. METHODS: Data was used from the Study on Transitions in Employment, Ability and Motivation, where self-employed (n = 1,029) and employees (n = 12,055) aged 45-64 years were followed during 2010-2013. Linear regression and generalized estimating equations analyses were carried out to study the differences in self rated health and work ability (i.e., self-assessed work ability in relation to an individual's resources and work demands) of self-employed and employees. To explore the role of sociodemographic, health-and work-related characteristics in these associations, we included interaction terms between these characteristics and employment status. RESULTS: The self-employed had better work ability (8.3 versus 8.2), and better self-rated health (3.4 versus 3.3) than employees. Work ability of self-employed improved over time, compared to the changes over time in work ability among employees, but not no difference in change over time in self rated health was found. None of the interaction terms were statistically significant (p>0.05). CONCLUSION: We observed higher scores in self-rated health and work ability among the self-employed than employees. Being self-employed leads to an increase in work ability across three years. The differences in work ability can be considered small, and more research is needed to establish the role of self-employment as a potential facilitator for sustainable employment. PMID- 30418980 TI - Low coverage of HPV vaccination in the national immunization programme in Brazil: Parental vaccine refusal or barriers in health-service based vaccine delivery? AB - BACKGROUND: The World Health Organization has recommended the introduction of HPV vaccines into national immunization programme (NIP), but vaccination coverage remains low worldwide. We assessed the coverage and the parental acceptance of female and male HPV vaccination in Brazil after its introduction into the NIP. METHODS: We conducted a random-digit-dial survey of parents in seven major Brazilian cities from July-2015 to October-2016. A knowledge, attitude and practices questionnaire was developed and validated by expert analysis, semantic analysis, and pre-testing. RESULTS: 826 out of 2,324 (35.5%) eligible parents completed the interview. Parental acceptance of the HPV vaccine for daughters and sons 18 years of age or less was high (92% and 86%, respectively). Parents refusing vaccination were less likely to know that: HPV is sexually transmitted and causes genital warts, HPV vaccination is more beneficial before sexual debut, and HPV vaccine reactions are minor, and they were more likely to believe HPV vaccination can cause severe adverse events. Parents accepting HPV vaccine for daughters but not forsons were more likely to ignore that the vaccine is recommended for boys. Attitudes associated with HPV vaccine acceptance included: general belief in vaccines, trust in the NIP and in the HPV vaccine efficacy. Among girls eligible for HPV vaccination through the NIP, 58.4% had received a two-dose scheme and 71.1% at least one dose. "No vaccination/missed vaccination at school" was the most common reason for missed HPV vaccination in theNIP. CONCLUSIONS: One year after introduction in the NIP, most parents surveyed in Brazil accepted HPV vaccination for their daughters and sons. Low coverage in the NIP seemed to be due to challenges in adolescent vaccine delivery and HPV vaccination barriers at health-care centers, rather than to vaccine refusal. PMID- 30418982 TI - Clustering time series based on dependence structure. AB - The clustering of time series has attracted growing research interest in recent years. The most popular clustering methods assume that the time series are only linearly dependent but this assumption usually fails in practice. To overcome this limitation, in this paper, we study clustering methods applicable to time series with a general and dependent structure. We propose a copula-based distance to measure dissimilarity among time series and consider an estimator for it, where the strong consistency of the estimator is guaranteed. Once the pairwise distance matrix for time series has been obtained, we apply a hierarchical clustering algorithm to cluster the time series and ensure its consistency. Numerical studies, including a large number of simulations and analysis of practical data, show that our method performs well. PMID- 30418981 TI - Short-lived AUF1 p42-binding mRNAs of RANKL and BCL6 have two distinct instability elements each. AB - Regulation of mRNA stability by RNA-protein interactions contributes significantly to quantitative aspects of gene expression. We have identified potential mRNA targets of the AU-rich element binding protein AUF1. Myc-tagged AUF1 p42 was induced in mouse NIH/3T3 cells and RNA-protein complexes isolated using anti-myc tag antibody beads. Bound mRNAs were analyzed with Affymetrix microarrays. We have identified 508 potential target mRNAs that were at least 3 fold enriched compared to control cells without myc-AUF1. 22.3% of the enriched mRNAs had an AU-rich cluster in the ARED Organism database, against 16.3% of non enriched control mRNAs. The enrichment towards AU-rich elements was also visible by AREScore with an average value of 5.2 in the enriched mRNAs versus 4.2 in the control group. Yet, numerous mRNAs were enriched without a high ARE score. The enrichment of tetrameric and pentameric sequences suggests a broad AUF1 p42 binding spectrum at short U-rich sequences flanked by A or G. Still, some enriched mRNAs were highly unstable, as those of TNFSF11 (known as RANKL), KLF10, HES1, CCNT2, SMAD6, and BCL6. We have mapped some of the instability determinants. HES1 mRNA appeared to have a coding region determinant. Detailed analysis of the RANKL and BCL6 3'UTR revealed for both that full instability required two elements, which are conserved in evolution. In RANKL mRNA both elements are AU-rich and separated by 30 bases, while in BCL6 mRNA one is AU-rich and 60 bases from a non AU-rich element that potentially forms a stem-loop structure. PMID- 30418983 TI - The estimated cost of dementia in Japan, the most aged society in the world. AB - OBJECTIVE: Dementia has become a global critical issue. It is estimated that the global cost of dementia was 818 billion USD in 2015. The situation in Japan, which is the most aged country in the world, should be critical. However, the societal cost of dementia in Japan has not yet been estimated. This study was designed to estimate cost of dementia from societal perspective. DESIGN: We estimated the cost from societal perspective with prevalence based approach. SETTING, PARTICIPANTS AND MEASURES: Main data sources for the parameters to estimate the costs are the National Data Base, a nationwide representative individual-level database for healthcare utilization, the Survey of Long-Term Care Benefit Expenditures, a nationwide survey based on individual-level secondary data for formal long-term care utilization, and the results of an informal care time survey for informal care cost. We conducted the analyses with 'probabilistic modeling' using the parameters obtained to estimate the costs of dementia. We also projected future costs. RESULTS: The societal costs of dementia in Japan in 2014 were estimated at JPY 14.5 trillion (se 66.0 billion). Of these, the costs for healthcare, long-term care, and informal care are JPY 1.91 trillion (se 4.91 billion), JPY 6.44 trillion (se 63.2 billion), and JPY 6.16 trillion (se 12.5 billion) respectively. The cost per person with dementia appeared to be JPY5.95 million (se 27 thousand). The total costs would reach JPY 24.3 trillion by 2060, which is 1.6 times higher than that in 2014. CONCLUSIONS: The societal cost of dementia in Japan appeared to be considerable. Interventions to mitigate this impact should be considered. PMID- 30418984 TI - Burnout syndrome among medical residents: A systematic review and meta-analysis. AB - BACKGROUND: Burnout is a psychological syndrome that is very common among medical residents. It consists of emotional exhaustion (EE), depersonalization (DP) and reduced personal accomplishment (PA). OBJECTIVE: To estimate burnout among different medical residency specialties. METHODS: A systematic review with meta analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A search of bibliographic databases and grey literature was conducted, from inception to March 2018. The following databases were accessed: Embase, PubMed, Web of Science, Google Scholar and Scopus, and 3,575 studies were found. Methodological quality was evaluated by Agency for Healthcare Research and Quality Methodology Checklist for Cross Sectional/Prevalence Study. In the final analysis, 26 papers were included. Their references were checked for additional studies, but none were included. RESULTS: 4,664 medical residents were included. High DP, EE and low PA proportions were compared. Specialties were distributed into three groups of different levels of burnout prevalence: general surgery, anesthesiology, obstetrics/gynecology and orthopedics (40.8%); internal medicine, plastic surgery and pediatrics (30.0%); and otolaryngology and neurology (15.4%). Overall burnout prevalence found for all specialties was 35.7%. CONCLUSION: The prevalence of burnout syndrome was significantly higher among surgical/urgency residencies than in clinical specialties. PROSPERO REGISTRATION: CRD42018090270. PMID- 30418985 TI - Prognostic impact of adjuvant chemotherapy treatment intensity for ovarian cancer. AB - OBJECTIVE: We aimed to investigate the prognostic impact of duration of first line chemotherapy administration in patients with epithelial ovarian cancer (EOC). METHODS: Chemotherapy records were abstracted from the electronic medical record. Patients with on-time completion (105 days) were compared to patients finishing early (<105 days), delays of 1-4 weeks, or >4 weeks. For 222 women with stage IIIC/IV, stage-stratified estimates of progression-free survival (PFS) and overall survival (OS) were compared. A delay sub-study was performed with outliers removed. Each week of delay was correlated with the change in PFS and OS to identify time points associated with change in outcome. RESULTS: Most women had on-time completion of chemotherapy (23.6%) or a treatment delay of <=4 weeks (21.8%); 21.6% of women experienced a delay longer than 4 weeks. R0 resection at initial debulking (OR = 1.99, 95%CI: 1.18-3.36, p = 0.010) and RECIST complete response (OR = 4.88, 95%CI: 2.47-10.63, p<0.001) were strongly associated with on time completion. Patients with on-time completion and < 1 month delay had similar median survivals of 43.1 months (lower 95% CI bound 33.7 months) and 44.5 months (lower bound 37.0, p = 0.93). Women with >1 month delay had decreased median survival of 18.1 months (14.7-24.9 months), while women with short intervals survived 35.0 months (95%CI: 21.8-49.8 months). Short-term delays lead to progressively decreasing OS. This was significantly different from the on schedule survival estimate after 6 weeks of delay. CONCLUSIONS: On-time completion of chemotherapy correlates with increased survival and higher complete response rates. Increasing delays in chemotherapy completion were associated with decreased survival. PMID- 30418987 TI - A prospective clinical study of Primo-Lacto: A closed system for colostrum collection. AB - BACKGROUND: Colostrum is the first nutritional liquid that comes out of the breast during lactation. Colostrum collection can be challenging due to the small volume produced, and because breast pumps are not designed for colostrum collection. Besides pumping colostrum, the generally accepted practice is to use any available container to hand-express colostrum. Transfer between containers may lead to contamination, higher chance of infection and loss of colostrum. Our aim was to understand if a dedicated colostrum collection system (Primo-Lacto, Maternal Life, LLC, Palo Alto, CA) is more effective than standard hospital practice. METHODS: Mothers who delivered preterm infants < 34 weeks gestation and mothers with non-latching infants were approached within 24 hours of delivery. Surveys were distributed to participating patients (n = 67), and nurses or lactation consultants (n = 89). Mothers compared ease of use, their confidence level and satisfaction with the amount collected during standard practice vs. the colostrum collection system. Nurses or lactation consultants compared ease of use, differences in colostrum loss and time invested collecting. Quantitative data were analyzed using the Wilcoxon signed rank test and qualitative data were analyzed with grounded theory methods. RESULTS: For mothers, ease of use and confidence were significantly better when they used the colostrum collection system than when they used the standard collection procedure, and this difference was true for both hand and pump expression (p<0.01). Nurses and lactation consultants perceived that ease of use was better, and percent of colostrum lost was significantly less with the colostrum collection system for both hand and pump expression. The collection times were not significantly different between the colostrum collection system and standard practice. CONCLUSION: The colostrum collection system is a tool to help facilitate successful colostrum collection and improve the experience both for clinicians and patients. PMID- 30418986 TI - Carvacrol reduces adipogenic differentiation by modulating autophagy and ChREBP expression. AB - OBJECTIVE: Obesity is the result of white adipose tissue accumulation where excess of food energy is stored to form triglycerides. De novo lipogenesis (DNL) is the continuous process of new fat production and is driven by the transcription factor ChREBP. During adipogenesis, white adipocytes change their morphology and the entire cell volume is occupied by one large lipid droplet. Recent studies have implicated an essential role of autophagy in adipogenic differentiation, cytoplasmic remodelling and mitochondria reorganization. The phenolic monoterpenoid carvacrol (2-methyl-5-[1-methylethyl]phenol), produced by numerous aromatic plants, has been shown to reduce lipid accumulation in murine 3T3-L1 cells during adipogenic differentiation by modulating genes associated with adipogenesis and inflammation. Therefore, the aim of this study was to evaluate whether carvacrol could affect autophagy and ChREBP expression during adipogenic differentiation. METHODS: The study was carried on by using the murine 3T3-L1 and the human WJ-MSCs (Wharton's jelly-derived mesenchymal stem cells) cell lines. Cells undergoing adipogenic differentiation were untreated or treated with carvacrol. Adipogenic differentiation was assessed by analyzing cellular lipid accumulation with Oil-Red O staining and by ultrastructural examination with TEM. Autophagy was evaluated by western immunoblotting of autophagy markers LC3B and p62/SQSTM and by ultrastructural examination of autophagic bodies. Autophagic flux was evaluated by using autophagy inhibitor cloroquine (CQ). ChREBP expression levels was assessed by both western blotting and immunoelectron microscopy and ChREBP activity by analysis of adipogenic target genes expression. RESULTS: We found that carvacrol reduced adipogenic differentiation of about 40% and 30% in, respectively, 3T3-L1 and in WJ-MSCs cells. The effect of carvacrol on adipogenic differentiation correlated with both reduction of autophagy and reduction of ChREBP expression. CONCLUSION: The results support the notion that carvacrol, through its effect on autophagy (essential for adipocyte maturation) and on ChREBP activity, could be used as a valuable adjuvant to reduce adipogenic differentiation. PMID- 30418988 TI - Prenatal treatment with rosiglitazone attenuates vascular remodeling and pulmonary monocyte influx in experimental congenital diaphragmatic hernia. AB - INTRODUCTION: Extensive vascular remodeling causing pulmonary hypertension (PH) represents a major cause of mortality in patients with congenital diaphragmatic hernia (CDH). The chemokine monocyte chemoattractant protein-1 (MCP-1) is a biomarker for the severity of PH and its activation is accompanied by pulmonary influx of monocytes and extensive vascular remodeling. MCP-1 activation can be reversed by application of rosiglitazone (thiazolidinedione). We performed this study to evaluate the role of MCP-1 for the pathogenesis of PH in experimental CDH. We hypothesized that vascular remodeling and MCP-1 activation is accompanied by pulmonary influx of fetal monocytes and can be attenuated by prenatal treatment with rosiglitazone. METHODS: In a first set of experiments pregnant rats were treated with either nitrofen or vehicle on gestational day 9 (D9). Fetal lungs were harvested on D21 and divided into CDH and control. Quantitative real-time polymerase chain reaction, Western blot (WB), and immunohistochemistry (IHC) were used to evaluate MCP-1 expression, activation, and localization. Quantification and localization of pulmonary monocytes/macrophages were carried out by IHC. In a second set of experiments nitrofen-exposed dams were randomly assigned to prenatal treatment with rosiglitazone or placebo on D18+D19. Fetal lungs were harvested on D21, divided into control, CDH+rosiglitazone, and CDH+placebo and evaluated by WB as well as IHC. RESULTS: Increased thickness of pulmonary arteries of CDH fetuses was accompanied by increased systemic and perivascular MCP-1 protein expression and significantly higher amounts of pulmonary monocytes/macrophages compared to controls (p<0.01). These effects were reversed by prenatal treatment with rosiglitazone (p<0.01 vs. CDH+P; control). CONCLUSION: Prenatal treatment with rosiglitazone has the potential to attenuate activation of pulmonary MCP-1, pulmonary monocyte influx, and vascular remodeling in experimental CDH. These results provide a basis for future research on prenatal immunomodulation as a novel treatment strategy to decrease secondary effects of PH in CDH. PMID- 30418989 TI - Comparison of early effects of pneumococcal conjugate vaccines: PCV7, PCV10 and PCV13 on Streptococcus pneumoniae nasopharyngeal carriage in a population based study; The Palestinian-Israeli Collaborative Research (PICR). AB - BACKGROUND: Pneumococcal conjugate vaccines (PCVs), PCV10 and PCV13, are currently used in different countries. We have previously reported the effectiveness of PCV7, following its introduction in Israel and before PCVs were introduced in Palestine. Here, we extended the study and compared the initial impact of PCV10 to that of PCV7/13. METHODS: Four cross-sectional surveys of S. pneumoniae carriage among children <5y through 2009-2014 were preformed among two proximate populations, living under two distinct health authorities, with different vaccination policies. In East-Jerusalem (EJ), PCV7 was implemented in 2009 and replaced by PCV13 in late 2010, while in Palestine (PA), PCV10 was implemented in 2011. RESULTS: A total of 1267 and 2414 children from EJ and PA were screened. In 2014, S. pneumoniae was detected in 30.7% and 28.6% of the children in EJ and PA respectively Implementation of both PCV7 (in EJ) and PCV10 (in PA) did not affect overall S. pneumoniae carriage, but resulted in a significant decrease in the prevalence of vaccine-type strains. In the pre vaccine era, VT7/VT13 strains consisted 47.0%/62.0% and 41.2%/54.8% of pneumococci in EJ and PA, respectively. A 48.6% and 53.9% decrease in VT7 strains was observed within 3 years of PCV7 implementation in EJ (p = 0.001) and PCV10 in PA (p<0.0001), respectively. These vaccination policies also resulted in ~50% reduction in VT13-added serotypes especially 6A (from 11.0% to 0.0% (EJ) and 9.5% to 4.9% (PA)). Three years after PCV13 implementation in EJ, an additional 67% decrease in VT13 strains was observed, yet an increase in serotype 3 was observed (0.0% to 3.4%, p = 0.056). While the prevalence of VT13 strains decreased significantly during the study period, the overall carriage rate didn't change significantly due to replacement with non-VT13 strains which comprised 89.8% and 70.7% of all pneumococci, in EJ and in PA respectively in the last study year. CONCLUSIONS: Within the first three years following PCV implementation, we observed similar reductions in carriage of VT10 and VT13 strains with either vaccination policies, with no effect on overall carriage. Further follow-up is needed to compare the long-term effects. PMID- 30418991 TI - Growth dynamics of different half-sib families of Melia azedarach Linn. AB - The genetic diversity and growth dynamics of fifty-three half-sib families of eleven provenance sources and one bulk seed mixed population of fast growing forest tree species i.e. Melia azedarach were studied at two stand ages viz., fourth year (mid-rotation) and eighth year (end-rotation) to determine the selection stage in northern India. Significant variations were reported between and within seed provenances in all growth characters at both rotational ages. The broad sense heritability was higher at mid-rotational age. This revealed the growth is genetically controlled but with the time environmental effects escort the growth pattern. Growth pattern was different at each stand age. Growth is diameter dependent and the pattern was crown growth type. Families maintained their superiority over the time for tree height, basal diameter and diameter at breast height, which indicated a strong potential to identify good performing families for future plantation program. This study concluded that early stage selection is appropriate that later stage selection for all parameters studied except clear bole height that is much influenced by management practice and environment factors also. Neighbor-joining clustering with similarity index revealed that it is not necessary that the families, originated in one region were distributed in one cluster, indicating that families with same geographic origin could have undergone changes for different characters under selection. PMID- 30418990 TI - Time and frequency dependent changes in resting state EEG functional connectivity following lipopolysaccharide challenge in rats. AB - Research has shown that inflammatory processes affect brain function and behavior through several neuroimmune pathways. However, high order brain functions affected by inflammation largely remain to be defined. Resting state functional connectivity of synchronized oscillatory activity is a valid approach to understand network processing and high order brain function under different experimental conditions. In the present study multi-electrode EEG recording in awake, freely moving rats was used to study resting state connectivity after administration of lipopolysaccharides (LPS). Male Wistar rats were implanted with 10 cortical surface electrodes and administered with LPS (2 mg/kg) and monitored for symptoms of sickness at 3, 6 and 24 h. Resting state connectivity and power were computed at baseline, 6 and 24 h. Three prominent connectivity bands were identified using a method resistant to spurious correlation: alpha (5-15 Hz), beta-gamma (20-80 Hz), and high frequency oscillation (150-200 Hz). The most prominent connectivity band, alpha, was strongly reduced 6 h after LPS administration, and returned to baseline at 24 h. Beta-gamma connectivity was also reduced at 6 h and remained reduced at 24 h. Interestingly, high frequency oscillation connectivity remained unchanged at 6 h and was impaired 24 h after LPS challenge. Expected elevations in delta and theta power were observed at 6 h after LPS administration, when behavioral symptoms of sickness were maximal. Notably, gamma and high frequency power were reduced 6 h after LPS and returned to baseline by 24 h, when the effects on connectivity were more evident. Finally, increases in cross-frequency coupling elicited by LPS were detected at 6 h for theta-gamma and at 24 h for theta-high frequency oscillations. These studies show that LPS challenge profoundly affects EEG connectivity across all identified bands in a time-dependent manner indicating that inflammatory processes disrupt both bottom-up and top-down communication across the cortex during the peak and resolution of inflammation. PMID- 30418992 TI - We miss the opportunity: Pretreament of osteoporosis in a German trauma center. AB - Osteoporosis remains a major health concern due to high incidence of fragility fractures followed by higher mortality and morbidity. Implementation of guidelines for diagnosis and treatment of osteoporosis is critically discussed internationally. Aim of this study was to evaluate implementation of these guidelines regarding diagnosis and therapy of osteoporosis in a developed western country. We hypothesized that (a) prior diagnosis of osteoporosis in patients with low-energy fractures is higher than the estimated incidence and (b) diagnosis and therapy of osteoporosis in patients with prior low-energy fractures is higher than in patients without prior low-energy fractures. 399 patients >60 years suffering low-energy-fractures of their spine, femur, humerus or forearm between 03/2014 and 04/2015 were recruited in a German trauma center. All received a standardized interview. In 21% (84/399) of all patients, osteoporosis was diagnosed prior to current admission. 34% (136/399) suffered a prior risk fracture after age of 50. Of these, only 54% (73/136) reported about following dual-energy X-ray absorptiometry (DXA) to test for decreased bone-marrow-density with positive results in 68% (50/73). 38% (19/50) of these patients with fragility fractures and prior osteoporosis diagnosis received anti-osteoporotic medication. 66% (263/399) of all patients had no prior risk-fracture and were tested for osteoporosis by DXA in 36% (95/263), leading to positive results in 34% (32/95). 44% (14/32) of these patients received anti-osteoporotic medication. Applying FRAX, 33% of all patients showed a calculated 10-year-risk >20% for suffering a major osteoporotic fracture. 61% (83/136) of patients with a prior fracture had a 10-year-risk >20% of which 47% (39/83) patients received no prior DXA. Although guidelines recommend diagnosis and treatment of patients with low energy fractures, opportunity for early treatment following risk fractures seems rarely used. Expedient risk assessment is necessary to indicate further diagnostics and therapy of osteoporosis to ensure adequate and efficient treatment for osteoporotic fractures. PMID- 30418993 TI - Design and development of a gait training system for Parkinson's disease. AB - BACKGROUND: Rhythmic Auditory Stimulation (RAS) is an effective technique to improve gait and reduce freezing episodes for Persons with Parkinson's Disease (PwPD). The BeatHealth system, which comprises a mobile application, gait sensors, and a website, exploits the potential of the RAS technique. This paper describes the tools used for co-designing and evaluating the system and discusses the results and conclusions. METHODS: Personas, interviews, use cases, and ethnographic observations were used to define the functional requirements of the system. Low fidelity prototypes were created for iterative and incremental evaluation with end-users. Field trials were also performed with the final system. The process followed a user centered design methodology defined for this project with the aim of building a useful, usable, and easy-to-use system. RESULTS: Functional requirements of the system were produced as a result of the initial exploration phase. Building upon these, mock-ups for the BeatHealth system were created. The mobile application was iterated twice, with the second version of it achieving a rating of 75 when assessed by participants through the System Usability Scale (SUS). After another iteration field trials were performed and the mobile application was rated with an average 78.6 using SUS. Participants rated two website mock-ups, one for health professionals and another for end users, as good except from minor issues related to visual design (e.g. font size), which were resolved in the final version. CONCLUSION: The high ratings obtained in the evaluation of the BeatHealth system demonstrate the benefit of applying a user centered design methodology which involves stakeholders from the very beginning. Other important lessons were learned through the process of design and development of the system, such as the importance of motivational aspects, the techniques which work best, and the extra care that has to be taken when evaluating non-functional mock-ups with end users. PMID- 30418994 TI - Inferring individual sexual action dispositions from egocentric network data on dyadic sexual outcomes. AB - In this paper we present a family of models that allows us to estimate egos' unobserved action dispositions from a joint behavioural outcome of a dyadic social interaction process of both egos' and alters' action dispositions. The method is put to test on a data set containing two different types of dyadic activities of high relevance for the spread of sexually transmitted infections (STI), condom use and anal sex. The data consists of individuals older than 15 years old who visited one of the nine youth clinics in the Vastra Gotaland region of Sweden between February 2010 and March 2011 for STI testing. This is hence a group of special interest for STI interventions. We cannot find any difference in condom disposition between women and men. Condoms are initially used more often in less risky types of relationships, especially if the partner ends up as a main partner. When studying the disposition towards anal sex we do however find a difference between men and women. Women are more against practising anal sex than men while the majority of men are neutral towards anal sex. PMID- 30418995 TI - What accounts for individual differences in susceptibility to the McGurk effect? AB - The McGurk effect is a classic audiovisual speech illusion in which discrepant auditory and visual syllables can lead to a fused percept (e.g., an auditory /balpha/ paired with a visual /galpha/ often leads to the perception of /dalpha/). The McGurk effect is robust and easily replicated in pooled group data, but there is tremendous variability in the extent to which individual participants are susceptible to it. In some studies, the rate at which individuals report fusion responses ranges from 0% to 100%. Despite its widespread use in the audiovisual speech perception literature, the roots of the wide variability in McGurk susceptibility are largely unknown. This study evaluated whether several perceptual and cognitive traits are related to McGurk susceptibility through correlational analyses and mixed effects modeling. We found that an individual's susceptibility to the McGurk effect was related to their ability to extract place of articulation information from the visual signal (i.e., a more fine-grained analysis of lipreading ability), but not to scores on tasks measuring attentional control, processing speed, working memory capacity, or auditory perceptual gradiency. These results provide support for the claim that a small amount of the variability in susceptibility to the McGurk effect is attributable to lipreading skill. In contrast, cognitive and perceptual abilities that are commonly used predictors in individual differences studies do not appear to underlie susceptibility to the McGurk effect. PMID- 30418996 TI - Actual European forest management by region, tree species and owner based on 714,000 re-measured trees in national forest inventories. AB - BACKGROUND: European forests have a long record of management. However, the diversity of the current forest management across nations, tree species and owners, is hardly understood. Often when trying to simulate future forest resources under alternative futures, simply the yield table style of harvesting is applied. It is now crucially important to come to grips with actual forest management, now that demand for wood is increasing and the EU Land Use, Land Use Change and Forestry Regulation has been adopted requiring 'continuation of current management practices' as a baseline to set the Forest Reference Level carbon sink. METHODS: Based on a large dataset of 714,000 re-measured trees in National Forest inventories from 13 regions, we are now able to analyse actual forest harvesting. CONCLUSIONS: From this large set of repeated tree measurements we can conclude that there is no such thing as yield table harvesting in Europe. We found general trends of increasing harvest probability with higher productivity of the region and the species, but with important deviations related to local conditions like site accessibility, state of the forest resource (like age), specific subsidies, importance of other forest services, and ownership of the forest. As a result, we find a huge diversity in harvest regimes. Over the time period covered in our inventories, the average harvest probability over all regions was 2.4% yr-1 (in number of trees) and the mortality probability was 0.4% yr-1. Our study provides underlying and most actual data that can serve as a basis for quantifying 'continuation of current forest management'. It can be used as a cornerstone for the base period as required for the Forest Reference Level for EU Member States. PMID- 30418997 TI - Maintaining vs. milking good reputation when customer feedback is inaccurate. AB - In Internet transactions, customers and service providers often interact once and anonymously. To prevent deceptive behavior a reputation system is particularly important to reduce information asymmetries about the quality of the offered product or service. In this study we examine the effectiveness of a reputation system to reduce information asymmetries when customers may make mistakes in judging the provided service quality. In our model, a service provider makes strategic quality choices and short-lived customers are asked to evaluate the observed quality by providing ratings to a reputation system. The customer is not able to always evaluate the service quality correctly and possibly submits an erroneous rating according to a predefined probability. Considering reputation profiles of the last three sales, within the theoretical model we derive that the service provider's dichotomous quality decisions are independent of the reputation profile and depend only on the probabilities of receiving positive and negative ratings when providing low or high quality. Thus, a service provider optimally either maintains a good reputation or completely refrains from any reputation building process. However, when mapping our theoretical model to an experimental design we find that a significant share of subjects in the role of the service provider deviates from optimal behavior and chooses actions which are conditional on the current reputation profile. With respect to these individual quality choices we see that subjects use milking strategies which means that they exploit a good reputation. In particular, if the sales price is high, low quality is delivered until the price drops below a certain threshold, and then high quality is chosen until the price increases again. PMID- 30418998 TI - Skin lesion monitoring at slaughter on heavy pigs (170 kg): Welfare indicators and ham defects. AB - In order to evaluate at the slaughterhouse external carcass lesions on heavy pigs (170 kg) as potential welfare indicators, and the prevalence of ham defects determining ham exclusion from Protected Designation of Origin (PDO) markets, 732 pig batches from northern Italy were monitored during a 12-month period, and then processed analysing the effect of slaughter season, overnight lairage, and production type. On the slaughter line, skin scratches were separately scored in the posterior region (defined as the area including the hind legs and the tail) and the anterior one (as the remaining area), while the whole carcass was examined for external hematomas. Chronic ear and tail lesions referable to the rearing phase, and bursitis were recorded as retrospective welfare indicators. The annual median prevalence of carcasses per batch with severe anterior scratches was 64% while 46.4% had severe posterior scratches. The highest autumn score for both skin scratches (P < 0.001) and traumatic ham defects (P = 0.005) is reflected in the positive correlation between severe posterior scratches and ham hematomas (r2 = 0.27; P < 0.001). Overnight lairage batches resulted in higher prevalence for scratches, while among ham defects only veining increased. Among binary records, only ear lesions were frequently recorded (annual median = 10%). A comparison analysis between pigs in and out of PDO circuit was performed to evaluate the variation related to the different genetics, showing differences for ear and tail lesions and for almost all the considered ham defects. The present study confirms that skin lesions represent a problem also for heavy pigs and that overnight lairage and season can affect their prevalence, with the associated possibility to give ham defects. Ear lesions are suitable to be used as retrospective welfare indicator, while tail lesions usage is nowadays limited by the extensive use of tail docking. PMID- 30418999 TI - Demographic risk factors for mid-urethral sling failure. Do they really matter? AB - Age, obesity and vaginal deliveries (VD) are recognized risk factors for stress urinary incontinence (SUI). According to many authors, the abovementioned risk factors for incontinence also increase the risk of mid-urethral sling (MUS) failure. Our aim was to evaluate the objective and subjective effectiveness of retropubic MUS in 12 months observation, relative to the three potential risk factors of failure: obesity, age and VDs. A prospective observational study including 238 women who underwent retropubic MUS implantation was performed. Patients were divided into subgroups: obese vs non-obese, <65 vs >=65 years old and no history of VD vs >=1 VD. Follow-up took place between 6 and 12 months post surgery. Cough test, 1-hour pad test, pelvic floor ultrasound examination, and Incontinence Impact Questionnaire 7 (IIQ-7) results were assessed pre- and post operatively. Of the 238 patients, 208 (86.3%) completed a minimum follow-up period of 12 months. Significant improvement in the pad test was observed in all patients (83.2 +/- 78.6 g vs 0.7 +/- 3.3 g). Negative cough test results were obtained in over 94% of patients. Significant improvement in the IIQ7 results was observed in all patients (74.2 +/- 17.7 vs 5.5 +/- 13.4). No significant differences in all the analyzed parameters with regard to BMI, age and parity were observed. No combination of risk factors influenced the objective and subjective cure rates. Our study demonstrated that older age, obesity and history of VDs have no impact on objective and subjective sling effectiveness in a short term observation. There is no influence of combined demographic features on the failure risk. PMID- 30419000 TI - Effects of ambient temperature on ambulance emergency call-outs in the subtropical city of Shenzhen, China. AB - The associations between meteorological factors and mortality have been well documented worldwide, but limited evidence is available for the non-fatal health impacts of ambient temperature, particularly there are few population-based investigations on the impacts of emergency ambulance dispatches in Asia. In this study, based on 809,906 ambulance emergency call-outs (AECOs) for the total population from 2010-2016 in the subtropical city of Shenzhen, China, a Poisson regression combined with a distributed lag nonlinear model was used to simultaneously assess the nonlinear and lag effects of daily mean temperature on AECOs. Stratified analyses by age and sex were performed to identify vulnerable subpopulations. A U-shaped relationship was found between temperature and AECOs. Cold effects were delayed and persisted for 3-4 weeks, with a cumulative relative risk (RR) and 95% confidence interval (CI) of 1.23 (1.10-1.38) and 1.25 (1.16 1.35) over lag 0-28 when comparing the 1st and 5th percentile of the temperature distribution to the optimal (i.e. minimum AECOs) temperature, respectively. Hot effects were immediate and diminished quickly in 5 days, with an increase of 19% (RR = 1.19, 95%CI: 1.14-1.23) and 21% (RR = 1.21, 95%CI: 1.16-1.26) in AECOs over lag 0-5 when comparing the 95th and 99th percentile of temperature to the optimal temperature. Children and the elderly were more vulnerable to cold effects. The youth and middle-aged people suffered more from high temperature. The effects of temperature were similar between males and females. In summary, significant increases were observed in the frequency of AECOs during cold and hot days, and the weather-associated increases in AECOs are different among age groups. This information has valuable implications in ambulance demand prediction and service provision planning. PMID- 30419001 TI - High myopia induced by form deprivation is associated with altered corneal biomechanical properties in chicks. AB - The cornea is a soft, transparent, composite organic tissue, which forms the anterior outer coat of the eyeball. Although high myopia is increasing in prevalence worldwide and is known to alter the structure and biomechanical properties of the sclera, remarkably little is known about its impact on the biomechanics of the cornea. We developed and validated a novel optical-coherence tomography-indentation probe-to measure corneal biomechanical properties in situ, in chicks having experimentally-induced high myopia, while maintaining intraocular pressure at levels covering the physiological range. We found that the cornea of highly myopic chicks was more steeply curved and softer, at all tested intraocular pressures, than that in contralateral, non-myopic eyes, or in age-matched normal, untreated eyes. These results indicate that the biomechanical properties of the cornea are altered in chicks developing experimentally-induced myopia. PMID- 30419002 TI - Malaria in children under-five: A comparison of risk factors in lakeshore and highland areas, Zomba district, Malawi. AB - BACKGROUND: In Malawi, children under the age of five living in different geographical areas may experience different malaria risk factors. We compare the risk factors of malaria experienced by children under the age of five from Zomba district, who reside in lakeshore and highland areas. METHODS: We conducted a case control study of 765 caregivers, cases being children under-five who were diagnosed with malaria, and obtained matched controls from local health facilities and communities. We used a multivariate logistic regression to identify individual and household risk factors. RESULTS: In lakeshore areas, risk factors were households located one kilometer or less away from stagnant water (AOR: 2.246 95% CI: 1.269 to 3.975 P-value: 0.005); or if the household had obtained a mosquito bed net more than one year ago (AOR: 1.946 95% CI: 1.073 to 3.529 P-value: 0.028). In highland areas, risk factors were households which used a borehole/unprotected well (AOR: 1.962 95% CI: 1.001 to 3.844 P-value 0.050), communal standpipe (AOR: 3.293 95% CI: 1.301 to 8.332 P-value 0.012), and un protected dug well in their yards (AOR: 16.195 95% CI: 2.585 to 101.464 P-value 0.003) as their drinking water sources. In highland areas, caregivers not attending health talks on malaria prevention messages was a risk factor (AOR: 2.518 95% CI: 1.439 to 4.406 P-value: 0.001). CONCLUSION: Children under the age of five living in highland areas experience different malaria risk factors compared to children living in lakeshore areas. Settling away from stagnant/open water source in lakeshore and encouraging caregivers to attend health talks on malaria prevention in highlands can help reduce malaria transmission. Nevertheless, using a mosquito bed net that is more than one year old is a common risk factor in both locations. Using new mosquito bed nets can significantly reduce the risk of contracting malaria in children under the age of five. PMID- 30419003 TI - The phosphorylation of sorting nexin 5 at serine 226 regulates retrograde transport and macropinocytosis. AB - Sorting nexin 5 (SNX5), a member of sorting nexin family, plays an important role in membrane trafficking, including the retrograde trafficking of the cation independent mannose 6-phosphate receptor (CI-M6PR) and macropinocytosis. Using ESI-LCMS/MS analysis, we confirmed that SNX5 serine 226 is phosphorylated. Since SNX5 forms heterodimers with SNX1 or SNX2, we examined the effect of phosphorylation at S226 on the heterodimer formations. Wild-type and mutants of SNX5, in which S226 was mutated to a glutamic acid or an alanine, were expressed in 8505C cells. In pull-down assays using SNX5 as bait, only the S226E mutant failed to precipitate both SNX1 and SNX2. Confocal microscopy data indicated that the wild type and S226A mutant were colocalized with SNX1 and SNX2 in endosomes, but the S226E was not. SNX5 and SNX6 support each other's functions and are involved with CI-M6PR retrograde trafficking. In SNX5 and SNX6 double knockdown cells, CI-M6PR was dispersed and colocalized with the endosomal marker EEA1. In a rescue experiment using SNX5 mutants, the S226A rescued CI-M6PR localization, similar to control cells, but S226E did not. Furthermore, the decrease in the uptake of dextran by macropinocytosis in SNX5 knockdown cells was recovered by the expression of rescue-wild type or S226A mutant, but not by the rescue-S226E mutant. These observations indicate that SNX5 constitutive phosphorylation that mimics the mutant S226E decreases the active SNX5 in these cells. The phosphorylation of SNX5 regulates the dimerization with SNX1 or SNX2, and this suggests that it controls membrane trafficking and protein sorting. PMID- 30419004 TI - Emergence of genotype Cosmopolitan of dengue virus type 2 and genotype III of dengue virus type 3 in Thailand. AB - Dengue is a mosquito-borne disease that has spread to over 100 countries. Dengue fever is caused by dengue virus (DENV), which belongs to the Flavivirus genus of the family Flaviviridae. DENV comprises 4 serotypes (DENV-1 to DENV-4), and each serotype is divided into distinct genotypes. Thailand is an endemic area where all 4 serotypes of DENV co-circulate. To understand the current genotype distribution of DENVs in Thailand, we enrolled 100 cases of fever with dengue like symptoms at the Bamrasnaradura Infectious Diseases Institute during 2016 2017. Among them, 37 cases were shown to be dengue-positive by real-time PCR. We were able to isolate DENVs from 21 cases, including 1 DENV-1, 8 DENV-2, 4 DENV-3, and 8 DENV-4. To investigate the divergence of the viruses, RNA was extracted from isolated DENVs and viral near-whole genome sequences were determined. Phylogenetic analysis of the obtained viral sequences revealed that DENV-2 genotype Cosmopolitan was co-circulating with DENV-2 genotype Asian-I, the previously predominating genotype in Thailand. Furthermore, DENV-3 genotype III was found instead of DENV-3 genotype II. The DENV-2 Cosmopolitan and DENV-3 genotype III found in Thailand were closely related to the respective strains found in nearby countries. These results indicated that DENVs in Thailand have increased in genotypic diversity, and suggested that the DENV genotypic shift observed in other Asian countries also might be taking place in Thailand. PMID- 30419005 TI - Correction: Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness. AB - [This corrects the article DOI: 10.1371/journal.pone.0132546.]. PMID- 30419006 TI - Correction: Chronic kidney disease (CKD) patients are exposed to more proton pump inhibitor (PPI)s compared to non-CKD patients. AB - [This corrects the article DOI: 10.1371/journal.pone.0203878.]. PMID- 30419007 TI - Correction: HJURP antagonizes CENP-A mislocalization driven by the H3.3 chaperones HIRA and DAXX. AB - [This corrects the article DOI: 10.1371/journal.pone.0205948.]. PMID- 30419008 TI - Correction: Examining food intake and eating out of home patterns among university students. AB - [This corrects the article DOI: 10.1371/journal.pone.0197874.]. PMID- 30419009 TI - HIV-1 capsids from B27/B57+ elite controllers escape Mx2 but are targeted by TRIM5alpha, leading to the induction of an antiviral state. AB - Elite controllers (ECs) are a rare subset of HIV-1 slow progressors characterized by prolonged viremia suppression. HLA alleles B27 and B57 promote the cytotoxic T lymphocyte (CTL)-mediated depletion of infected cells in ECs, leading to the emergence of escape mutations in the viral capsid (CA). Whether those mutations modulate CA detection by innate sensors and effectors is poorly known. Here, we investigated the targeting of CA from B27/B57+ individuals by cytosolic antiviral factors Mx2 and TRIM5alpha. Toward that aim, we constructed chimeric HIV-1 vectors using CA isolated from B27/B57+ or control subjects. HIV-1 vectors containing B27/B57+-specific CA had increased sensitivity to TRIM5alpha but not to Mx2. Following exposure to those vectors, cells showed increased resistance against both TRIM5alpha-sensitive and -insensitive HIV-1 strains. Induction of the antiviral state did not require productive infection by the TRIM5alpha sensitive virus, as shown using chemically inactivated virions. Depletion experiments revealed that TAK1 and Ubc13 were essential to the TRIM5alpha dependent antiviral state. Accordingly, induction of the antiviral state was accompanied by the activation of NF-kappaB and AP-1 in THP-1 cells. Secretion of IFN-I was involved in the antiviral state in THP-1 cells, as shown using a receptor blocking antibody. This work identifies innate activation pathways that are likely to play a role in the natural resistance to HIV-1 progression in ECs. PMID- 30419011 TI - Function and regulation of the Caenorhabditis elegans Rab32 family member GLO-1 in lysosome-related organelle biogenesis. AB - Cell type-specific modifications of conventional endosomal trafficking pathways lead to the formation of lysosome-related organelles (LROs). C. elegans gut granules are intestinally restricted LROs that coexist with conventional degradative lysosomes. The formation of gut granules requires the Rab32 family member GLO-1. We show that the loss of glo-1 leads to the mistrafficking of gut granule proteins but does not significantly alter conventional endolysosome biogenesis. GLO-3 directly binds to CCZ-1 and they both function to promote the gut granule association of GLO-1, strongly suggesting that together, GLO-3 and CCZ-1 activate GLO-1. We found that a point mutation in GLO-1 predicted to spontaneously activate, and function independently of it guanine nucleotide exchange factor (GEF), localizes to gut granules and partially restores gut granule protein localization in ccz-1(-) and glo-3(-) mutants. CCZ-1 forms a heterodimeric complex with SAND-1(MON1), which does not function in gut granule formation, to activate RAB-7 in trafficking pathways to conventional lysosomes. Therefore, our data suggest a model whereby the function of a Rab GEF can be altered by subunit exchange. glo-3(-) mutants, which retain low levels of GLO-3 activity, generate gut granules that lack GLO-1 and improperly accumulate RAB-7 in a SAND-1 dependent process. We show that GLO-1 and GLO-3 restrict the distribution of RAB-7 to conventional endolysosomes, providing insights into the segregation of pathways leading to conventional lysosomes and LROs. PMID- 30419010 TI - Highly competent, non-exhausted CD8+ T cells continue to tightly control pathogen load throughout chronic Trypanosoma cruzi infection. AB - Trypanosoma cruzi infection is characterized by chronic parasitism of non lymphoid tissues and is rarely eliminated despite potent adaptive immune responses. This failure to cure has frequently been attributed to a loss or impairment of anti-T. cruzi T cell responses over time, analogous to the T cell dysfunction described for other persistent infections. In this study, we have evaluated the role of CD8+ T cells during chronic T. cruzi infection (>100 dpi), with a focus on sites of pathogen persistence. Consistent with repetitive antigen exposure during chronic infection, parasite-specific CD8+ T cells from multiple organs expressed high levels of KLRG1, but exhibit a preferential accumulation of CD69+ cells in skeletal muscle, indicating recent antigen encounter in a niche for T. cruzi persistence. A significant proportion of CD8+ T cells in the muscle also produced IFNgamma, TNFalpha and granzyme B in situ, an indication of their detection of and functional response to T. cruzi in vivo. CD8+ T cell function was crucial for the control of parasite burden during chronic infection as exacerbation of parasite load was observed upon depletion of this population. Attempts to improve T cell function by blocking PD-1 or IL-10, potential negative regulators of T cells, failed to increase IFNgamma and TNFalpha production or to enhance T. cruzi clearance. These results highlight the capacity of the CD8+ T cell population to retain essential in vivo function despite chronic antigen stimulation and support a model in which CD8+ T cell dysfunction plays a negligible role in the ability of Trypanosoma cruzi to persist in mice. PMID- 30419012 TI - Population genomics of grey wolves and wolf-like canids in North America. AB - North America is currently home to a number of grey wolf (Canis lupus) and wolf like canid populations, including the coyote (Canis latrans) and the taxonomically controversial red, Eastern timber and Great Lakes wolves. We explored their population structure and regional gene flow using a dataset of 40 full genome sequences that represent the extant diversity of North American wolves and wolf-like canid populations. This included 15 new genomes (13 North American grey wolves, 1 red wolf and 1 Eastern timber/Great Lakes wolf), ranging from 0.4 to 15x coverage. In addition to providing full genome support for the previously proposed coyote-wolf admixture origin for the taxonomically controversial red, Eastern timber and Great Lakes wolves, the discriminatory power offered by our dataset suggests all North American grey wolves, including the Mexican form, are monophyletic, and thus share a common ancestor to the exclusion of all other wolves. Furthermore, we identify three distinct populations in the high arctic, one being a previously unidentified "Polar wolf" population endemic to Ellesmere Island and Greenland. Genetic diversity analyses reveal particularly high inbreeding and low heterozygosity in these Polar wolves, consistent with long-term isolation from the other North American wolves. PMID- 30419014 TI - Functional mechanisms underlie the emergence of a diverse range of plasticity phenomena. AB - Diverse plasticity mechanisms are orchestrated to shape the spatiotemporal dynamics underlying brain functions. However, why these plasticity rules emerge and how their dynamics interact with neural activity to give rise to complex neural circuit dynamics remains largely unknown. Here we show that both Hebbian and homeostatic plasticity rules emerge from a functional perspective of neuronal dynamics whereby each neuron learns to encode its own activity in the population activity, so that the activity of the presynaptic neuron can be decoded from the activity of its postsynaptic neurons. We explain how a range of experimentally observed plasticity phenomena with widely separated time scales emerge from learning this encoding function, including STDP and its frequency dependence, and metaplasticity. We show that when implemented in neural circuits, these plasticity rules naturally give rise to essential neural response properties, including variable neural dynamics with balanced excitation and inhibition, and approximately log-normal distributions of synaptic strengths, while simultaneously encoding a complex real-world visual stimulus. These findings establish a novel function-based account of diverse plasticity mechanisms, providing a unifying framework relating plasticity, dynamics and neural computation. PMID- 30419013 TI - Visual physiology of the layer 4 cortical circuit in silico. AB - Despite advances in experimental techniques and accumulation of large datasets concerning the composition and properties of the cortex, quantitative modeling of cortical circuits under in-vivo-like conditions remains challenging. Here we report and publicly release a biophysically detailed circuit model of layer 4 in the mouse primary visual cortex, receiving thalamo-cortical visual inputs. The 45,000-neuron model was subjected to a battery of visual stimuli, and results were compared to published work and new in vivo experiments. Simulations reproduced a variety of observations, including effects of optogenetic perturbations. Critical to the agreement between responses in silico and in vivo were the rules of functional synaptic connectivity between neurons. Interestingly, after extreme simplification the model still performed satisfactorily on many measurements, although quantitative agreement with experiments suffered. These results emphasize the importance of functional rules of cortical wiring and enable a next generation of data-driven models of in vivo neural activity and computations. PMID- 30419016 TI - A regularity index for dendrites - local statistics of a neuron's input space. AB - Neurons collect their inputs from other neurons by sending out arborized dendritic structures. However, the relationship between the shape of dendrites and the precise organization of synaptic inputs in the neural tissue remains unclear. Inputs could be distributed in tight clusters, entirely randomly or else in a regular grid-like manner. Here, we analyze dendritic branching structures using a regularity index R, based on average nearest neighbor distances between branch and termination points, characterizing their spatial distribution. We find that the distributions of these points depend strongly on cell types, indicating possible fundamental differences in synaptic input organization. Moreover, R is independent of cell size and we find that it is only weakly correlated with other branching statistics, suggesting that it might reflect features of dendritic morphology that are not captured by commonly studied branching statistics. We then use morphological models based on optimal wiring principles to study the relation between input distributions and dendritic branching structures. Using our models, we find that branch point distributions correlate more closely with the input distributions while termination points in dendrites are generally spread out more randomly with a close to uniform distribution. We validate these model predictions with connectome data. Finally, we find that in spatial input distributions with increasing regularity, characteristic scaling relationships between branching features are altered significantly. In summary, we conclude that local statistics of input distributions and dendrite morphology depend on each other leading to potentially cell type specific branching features. PMID- 30419015 TI - Oscillations in working memory and neural binding: A mechanism for multiple memories and their interactions. AB - Neural oscillations have been recorded and implicated in many different basic brain and cognitive processes. For example, oscillatory neural activity has been suggested to play a role in binding and in the maintenance of information in working memory. With respect to the latter, the majority of work has focused primarily on oscillations in terms of providing a "code" in working memory. However, oscillations may additionally play a fundamental role by enabling or facilitating essential properties and behaviors that neuronal networks must exhibit in order to produce functional working memory and the processes it supports, such as combining items in memory into bound objects or separating bound objects into distinct items. In the present work, we present a biologically plausible working memory model and demonstrate that specific types of stable oscillatory dynamics that arise may play critical roles in providing mechanisms for working memory and the cognitive functions that it supports. Specifically, these roles include (1) enabling a range of different types of binding, (2) both enabling and limiting capacities of bound and distinct items held active in working memory, and (3) facilitating transitions between active working memory states as required in cognitive function. Several key results arise within the examinations, such as the occurrence of different network capacities for working memory and binding, differences in processing times for transitions in working memory states, and the emergence of a combinatorially rich and complex range of oscillatory states that are sufficient to map onto a wide range of cognitive operations supported by working memory, such as variable binding, reasoning, and language. In particular, we show that these oscillatory states and their transitions can provide a specific instantiation of current established connectionist models in representing these functions. Finally, we further characterize the dependence of the relevant oscillatory solutions on certain critical parameters, including mutual inhibition and synaptic timescales. PMID- 30419017 TI - Invasion and effective size of graph-structured populations. AB - Population structure can strongly affect evolutionary dynamics. The most general way to describe population structures are graphs. An important observable on evolutionary graphs is the probability that a novel mutation spreads through the entire population. But what drives this spread of a mutation towards fixation? Here, we propose a novel way to understand the forces driving fixation by borrowing techniques from evolutionary demography to quantify the invasion fitness and the effective population size for different graphs. Our method is very general and even applies to weighted graphs with node dependent fitness. However, we focus on analytical results for undirected graphs with node independent fitness. The method will allow to conceptually integrate evolutionary graph theory with theoretical genetics of structured populations. PMID- 30419018 TI - Replicative and non-replicative mechanisms in the formation of clustered CNVs are indicated by whole genome characterization. AB - Clustered copy number variants (CNVs) as detected by chromosomal microarray analysis (CMA) are often reported as germline chromothripsis. However, such cases might need further investigations by massive parallel whole genome sequencing (WGS) in order to accurately define the underlying complex rearrangement, predict the occurrence mechanisms and identify additional complexities. Here, we utilized WGS to delineate the rearrangement structure of 21 clustered CNV carriers first investigated by CMA and identified a total of 83 breakpoint junctions (BPJs). The rearrangements were further sub-classified depending on the patterns observed: I) Cases with only deletions (n = 8) often had additional structural rearrangements, such as insertions and inversions typical to chromothripsis; II) cases with only duplications (n = 7) or III) combinations of deletions and duplications (n = 6) demonstrated mostly interspersed duplications and BPJs enriched with microhomology. In two cases the rearrangement mutational signatures indicated both a breakage-fusion-bridge cycle process and haltered formation of a ring chromosome. Finally, we observed two cases with Alu- and LINE-mediated rearrangements as well as two unrelated individuals with seemingly identical clustered CNVs on 2p25.3, possibly a rare European founder rearrangement. In conclusion, through detailed characterization of the derivative chromosomes we show that multiple mechanisms are likely involved in the formation of clustered CNVs and add further evidence for chromoanagenesis mechanisms in both "simple" and highly complex chromosomal rearrangements. Finally, WGS characterization adds positional information, important for a correct clinical interpretation and deciphering mechanisms involved in the formation of these rearrangements. PMID- 30419019 TI - A fast and agnostic method for bacterial genome-wide association studies: Bridging the gap between k-mers and genetic events. AB - Genome-wide association study (GWAS) methods applied to bacterial genomes have shown promising results for genetic marker discovery or detailed assessment of marker effect. Recently, alignment-free methods based on k-mer composition have proven their ability to explore the accessory genome. However, they lead to redundant descriptions and results which are sometimes hard to interpret. Here we introduce DBGWAS, an extended k-mer-based GWAS method producing interpretable genetic variants associated with distinct phenotypes. Relying on compacted De Bruijn graphs (cDBG), our method gathers cDBG nodes, identified by the association model, into subgraphs defined from their neighbourhood in the initial cDBG. DBGWAS is alignment-free and only requires a set of contigs and phenotypes. In particular, it does not require prior annotation or reference genomes. It produces subgraphs representing phenotype-associated genetic variants such as local polymorphisms and mobile genetic elements (MGE). It offers a graphical framework which helps interpret GWAS results. Importantly it is also computationally efficient-experiments took one hour and a half on average. We validated our method using antibiotic resistance phenotypes for three bacterial species. DBGWAS recovered known resistance determinants such as mutations in core genes in Mycobacterium tuberculosis, and genes acquired by horizontal transfer in Staphylococcus aureus and Pseudomonas aeruginosa-along with their MGE context. It also enabled us to formulate new hypotheses involving genetic variants not yet described in the antibiotic resistance literature. An open-source tool implementing DBGWAS is available at https://gitlab.com/leoisl/dbgwas. PMID- 30419021 TI - Novel protein signatures suggest progression to muscular invasiveness in bladder cancer. AB - Patients with bladder cancer need frequent controls over long follow-up time due to high recurrence rate and risk of conversion to muscle invasive cancer with poor prognosis. We identified cancer-related molecular signatures in apparently healthy bladder in patients with subsequent muscular invasiveness during follow up. Global proteomics of the normal tissue biopsies revealed specific proteome fingerprints in these patients prior to subsequent muscular invasiveness. In these presumed normal samples, we detected modulations of proteins previously associated with different cancer types. This study indicates that analyzing apparently healthy tissue of a cancer-invaded organ may suggest disease progression. PMID- 30419020 TI - The zinc finger protein DCM1 is required for male meiotic cytokinesis by preserving callose in rice. AB - Meiotic cytokinesis influences the fertility and ploidy of gametes. However, limited information is available on the genetic control of meiotic cytokinesis in plants. Here, we identified a rice mutant with low male fertility, defective callose in meiosis 1 (dcm1). The pollen grains of dcm1 are proved to be defective in exine formation. Meiotic cytokinesis is disrupted in dcm1, resulting in disordered spindle orientation during meiosis II and formation of pollen grains with varied size and DNA content. We demonstrated that meiotic cytokinesis defect in dcm1 is caused by prematurely dissolution of callosic plates. Furthermore, peripheral callose surrounding the dcm1 pollen mother cells (PMCs) also disappeared untimely around pachytene. The DCM1 protein contains five tandem CCCH motifs and interacts with nuclear poly (A) binding proteins (PABNs) in nuclear speckles. The expression profiles of genes related to callose synthesis and degradation are significantly modified in dcm1. Together, we propose that DCM1 plays an essential role in male meiotic cytokinesis by preserving callose from prematurely dissolution in rice. PMID- 30419022 TI - Spore-autonomous fluorescent protein expression identifies meiotic chromosome mis segregation as the principal cause of hybrid sterility in yeast. AB - Genome-wide sequence divergence between populations can cause hybrid sterility through the action of the anti-recombination system, which rejects crossover repair of double strand breaks between nonidentical sequences. Because crossovers are necessary to ensure proper segregation of homologous chromosomes during meiosis, the reduced recombination rate in hybrids can result in high levels of nondisjunction and therefore low gamete viability. Hybrid sterility in interspecific crosses of Saccharomyces yeasts is known to be associated with such segregation errors, but estimates of the importance of nondisjunction to postzygotic reproductive isolation have been hampered by difficulties in accurately measuring nondisjunction frequencies. Here, we use spore-autonomous fluorescent protein expression to quantify nondisjunction in both interspecific and intraspecific yeast hybrids. We show that segregation is near random in interspecific hybrids. The observed rates of nondisjunction can explain most of the sterility observed in interspecific hybrids through the failure of gametes to inherit at least one copy of each chromosome. Partially impairing the anti recombination system by preventing expression of the RecQ helicase SGS1 during meiosis cuts nondisjunction frequencies in half. We further show that chromosome loss through nondisjunction can explain nearly all of the sterility observed in hybrids formed between two populations of a single species. The rate of meiotic nondisjunction of each homologous pair was negatively correlated with chromosome size in these intraspecific hybrids. Our results demonstrate that sequence divergence is not only associated with the sterility of hybrids formed between distantly related species but may also be a direct cause of reproductive isolation in incipient species. PMID- 30419023 TI - Re-assessing causality between energy consumption and economic growth. AB - The energy consumption-growth nexus has been widely studied in the empirical literature, though results have been inconclusive regarding the direction, or even the existence, of causality. These inconsistent results can be explained by two important limitations of the literature. First, the use of bivariate models, which fail to detect more complex causal relations, or the ad hoc approach to selecting variables in a multivariate framework; and, second, the use of linear causal models, which are unable to capture more complex nonlinear causal relationships. In this paper, we aim to overcome both limitations by analysing the energy consumption-growth nexus using a Flexible Fourier form due to Enders and Jones (2016). The analysis focuses on the US over the period 1949 to 2014. From our results we can conclude that, where the linear methodology supports the neutrality hypothesis (no causality between energy consumption and growth), the Flexible Fourier form points to the existence of causality from energy consumption to growth. This is contrary to the linear analysis, suggesting that lowering energy consumption would adversely affect US economic growth. Thus, by employing the Flexible Fourier form we find the conclusions can be quite different. PMID- 30419024 TI - Human-pathogenic Anaplasma spp., and Rickettsia spp. in animals in Xi'an, China. AB - In China, thirteen species of tick-borne rickettsiales bacteria pathogenic to human have been reported in ticks and host animals, and human patients caused by them also has been identified. However, investigation for rickettsiales bacteria circulating in Xi'an wasn't performed although diseases resembling human diseases caused by these organisms have been found. In this study, domestic animals and ticks in Xi'an, China, were tested for the presence of rickettsiales bacteria pathogenic to humans. Besides A. ovis, a high prevalence of A. capra was observed suggesting a high public health risk exists. In addition, two novel Anaplasma species closely related to A. phagocytophilum were identified and formed distinct lineages in the phylogenetic trees, with more than 98.3% identities for rrs gene, while divergences up to 20.2% and 37.0% for groEL and gltA genes, respectively. Both of these two novel Anaplasma species were found to circulate in goats and further assessment of their pathogenicity is needed. Ca. R. jingxinensis, with potential pathogenicity, was also detected in H. longicomis ticks with high prevalence. However, other causative agents were not identified although they were distributed in other areas of China. PMID- 30419025 TI - The prevalence of lymphatic filariasis infection and disease following six rounds of mass drug administration in Mandalay Region, Myanmar. AB - Lymphatic filariasis is widely endemic in Myanmar. Despite the establishment of an elimination program in 2000, knowledge of the remaining burden of disease relies predominantly on programmatic information. To assist the program, we conducted an independent cross-sectional household cluster survey to determine the prevalence of filariasis infection, morbidity and mass-drug administration coverage in four townships of the Mandalay Region: Amarapura, Patheingyi, Tada-U and Wundwin. The survey included 1014 individuals from 430 randomly selected households in 24 villages. Household members one year and older were assessed for antigenaemia using immunochromatographic test cards and if positive, microfilaraemia by night-time thick blood smear. Participants 15 years and older were assessed for filariasis morbidity by ultrasound-assisted clinical examination. The overall prevalence of infection was 2.63% by antigenaemia (95% confidence interval (CI) 1.71-4.04%) and 1.03% by microfilaraemia (95%CI 0.59 1.47%). The prevalence of hydrocoele in adult males was 2.78% (95%CI 1.23-6.15%) and of lymphoedema in both genders was 0% (95%CI 0-0.45%). These results indicate the persistence of filarial infection and transmission despite six rounds of annual mass drug administration and highlight the need for further rounds as well as the implementation of morbidity management programs in the country. PMID- 30419027 TI - The effect of attachment and environmental manipulations on cooperative behavior in the prisoner's dilemma game. AB - Cooperation and competition are vital for human survival and for social progress. In this study we examine the impact of external (environmental) and internal (individual differences) factors on the tendency to cooperate or compete in social conflicts. To this end, 53 young adults played blocks of the repeated Prisoner's Dilemma Game with each other or with a computer. The environmental context was manipulated across blocks, by introducing uncertainty, randomly losing or gaining money. Individual differences were assessed by participants' attachment style. We found that participants cooperated more when randomly losing money compared to when randomly winning or in the neutral condition. Moreover, in a negative uncertain environment, individuals with higher anxious and avoidant attachment styles cooperated less. The above effects were only observed when playing against a human and not a computer. Overall, the findings highlight the dependency of cooperative behavior on the context as driven by external and internal factors. PMID- 30419026 TI - The structure of resilience in irritable bowel syndrome and its improvement through hypnotherapy: Cross-sectional and prospective longitudinal data. AB - BACKGROUND: Resilience refers to a class of variables that are highly relevant to wellbeing and coping with stress, trauma, and chronic adversity. Despite its significance for health, resilience suffers from poor conceptual integration. Irritable bowel syndrome (IBS) is a functional disorder with altered psychological stress reactivity and a brain-gut-microbiota axis, which causes high levels of chronic strain. Gut-directed Hypnotherapy (GHT) is a standardized treatment for IBS aimed at improving resilience. An improvement of resilience as a result of GHT has been hypothesized but requires further investigation. The aims of the study were to validate the construct and develop an integrational measure of various resilience domains by dimensional reduction, and to investigate changes in resilience in IBS patients after GHT. METHOD: A total of N = 74 gastroenterology outpatients with IBS (Rome III criteria) were examined in 7 resilience domains, quality of life, psychological distress and symptom severity. Of these, n = 53 participated in 7 to 10 GHT group sessions (Manchester protocol). Post-treatment examinations were performed on average 10 months after last GHT session. RESULTS: Resilience factors proved to be unidimensional in the total sample. Greater resilience (composite score of resilience domains) and quality of life, and lower symptom severity and psychological distress were found after treatment (n = 16). Similar differences were present in cross-sectional comparisons of n = 37 treated vs. n = 37 untreated patients. CONCLUSION: Resilience factors share a common psychological dimension and are functionally connected. The absence of maladaptive behaviours contributes to resilience. Improvements in resilience after hypnotherapy with parallel increases in quality of life and reduced psychological distress and symptom severity were observed. Independent replications with larger sample sizes and randomized controlled trials are needed. PMID- 30419028 TI - Annotation of enhanced radiographs for medical image retrieval with deep convolutional neural networks. AB - The number of images taken per patient scan has rapidly increased due to advances in software, hardware and digital imaging in the medical domain. There is the need for medical image annotation systems that are accurate as manual annotation is impractical, time-consuming and prone to errors. This paper presents modeling approaches performed to automatically classify and annotate radiographs using several classification schemes, which can be further applied for automatic content-based image retrieval (CBIR) and computer-aided diagnosis (CAD). Different image preprocessing and enhancement techniques were applied to augment grayscale radiographs by virtually adding two extra layers. The Image Retrieval in Medical Applications (IRMA) Code, a mono-hierarchical multi-axial code, served as a basis for this work. To extensively evaluate the image enhancement techniques, five classification schemes including the complete IRMA code were adopted. The deep convolutional neural network systems Inception-v3 and Inception ResNet-v2, and Random Forest models with 1000 trees were trained using extracted Bag-of-Keypoints visual representations. The classification model performances were evaluated using the ImageCLEF 2009 Medical Annotation Task test set. The applied visual enhancement techniques proved to achieve better annotation accuracy in all classification schemes. PMID- 30419029 TI - Improving counterfactual reasoning with kernelised dynamic mixing models. AB - Simulation-based approaches to disease progression allow us to make counterfactual predictions about the effects of an untried series of treatment choices. However, building accurate simulators of disease progression is challenging, limiting the utility of these approaches for real world treatment planning. In this work, we present a novel simulation-based reinforcement learning approach that mixes between models and kernel-based approaches to make its forward predictions. On two real world tasks, managing sepsis and treating HIV, we demonstrate that our approach both learns state-of-the-art treatment policies and can make accurate forward predictions about the effects of treatments on unseen patients. PMID- 30419031 TI - Development and validation of a HPLC/FLD method combined with online derivatization for the simple and simultaneous determination of trace amino acids and alkyl amines in continental and marine aerosols. AB - A method was developed for simultaneous determination of 15 amino acids and 7 alkyl amines. The method was based on the employment of high performance liquid chromatography/fluorescence detection and online derivatization with o phthaldiadehyde. The 22 derivatives were separated within 30 min including the equilibration time and detected by a fluorescence detector at an excitation wavelength of 230 nm and emission wavelength of 450 nm. The analysis procedure was satisfactorily validated by the reproducibility, recovery, linearity and detection limit of the analytes. The relative standard deviations (RSDs) of retention time and peak area for individual amino acids and alkyl amines were consistently less than 0.30% and 2.35%, respectively. Good recovery values ranging from 70% to 109% were obtained. The proposed method showed good linearity (R2>=0.99) in the range of 0.125-125 MUM/L for amino acids and 2.5-5000 ng/L for alkyl amines. The detection limit ranged from 0.13 pM to 0.37 pM for individual amino acids and from 0.9 ng to 7.2 ng for individual alkyl amines. The developed and validated method was successfully applied to the quantitative analysis of amino acids and alkyl amines in continental and marine aerosols in China. Among the identified organic nitrogen compounds, 7 amino acids and 6 alkyl amines were detected in every aerosol sample. Glycine was the dominant amino acid, with the average of 130.93 pmol/m3 (accounting for 83% of the total amino acids) and 137.22 pmol/m3 (accounting for 66% of the total amino acids) in continental and marine aerosols in China, respectively. Methylamine and ethanolamine were the most abundant alkyl amines, contributing 87% and 64% to the total alkyl amines in continental and marine aerosols in China, respectively. This work provided an accurate, sensitive and simple method to determine simultaneously amino acids and alkyl amines, and applied the proposed method to the first investigation of amino acids in Shanghai and amino acids and alkyl amines in Huaniao Island in China. The finding of considerable amino acids and alkyl amines in continental and marine aerosols may exert significant implications on nitrogen cycling and atmospheric chemistry. PMID- 30419030 TI - The public health benefit and burden of mass drug administration programs in Vietnamese schoolchildren: Impact of mebendazole. AB - BACKGROUND: Mass anthelmintic drug administration is recommended in developing countries to address infection by soil-transmitted helminthiases (STH). We quantified the public health benefit of treatment with mebendazole in eight million Vietnamese children aged 5-14 years from 2006 to 2011. This was compared to the environmental impact of the pharmaceutical supply chain of mebendazole, as the resource use and emissions associated with pharmaceutical production can be associated with a public health burden, e.g. through emissions of fine particulate matter. METHODOLOGY: Through Markov modelling the disability due to STH was quantified for hookworm, Ascaris lumbricoides and Trichuris trichiura. For each worm type, four levels of intensity of infection were included: none, light, medium and heavy. The treatment effect on patients was quantified in Disability-Adjusted Life Years (DALYs). The public health burden induced by the pharmaceutical supply chain of mebendazole was quantified in DALYs through Life Cycle Assessment. PRINCIPAL FINDINGS: Compared to 'no treatment', the modelled results of five-year treatment averted 116,587 DALYs (68% reduction) for the three worms combined and largely driven by A. lumbricoides. The main change in DALYs occurred in the first year of treatment, after which the results stabilized. The public health burden associated with the pharmaceutical supply chain was 6 DALYs. CONCLUSIONS: The public health benefit of the Mass Drug Administration (MDA) averted substantially more DALYs than those induced by the pharmaceutical supply chain. These results were verified in a sensitivity analysis. The starting prevalence for each worm was the most sensitive model parameter. This methodology is useful for policymakers interested in a holistic approach towards the public health performance of MDA programs, enveloping both the treatment benefit received by the patient and the public health burden associated with the resource consumption and environmental emissions of the pharmaceutical production and supply chain. PMID- 30419032 TI - Mapping the structure of perceptions in helping networks of Alaska Natives. AB - This paper introduces a new method for acquiring and interpreting data on cognitive (or perceptual) networks. The proposed method involves the collection of multiple reports on randomly chosen pairs of individuals, and statistical means for aggregating these reports into data of conventional sociometric form. We refer to the method as "perceptual tomography" to emphasize that it aggregates multiple 3rd-party data on the perceived presence or absence of individual properties and pairwise relationships. Key features of the method include its low respondent burden, flexible interpretation, as well as its ability to find "robust intransitive" ties in the form of perceived non-edges. This latter feature, in turn, allows for the application of conventional balance clustering routines to perceptual tomography data. In what follows, we will describe both the method and an example of the implementation of the method from a recent community study among Alaska Natives. Interview data from 170 community residents is used to ascribe 4446 perceived relationships (2146 perceived edges, 2300 perceived non-edges) among 393 community members, and to assert the perceived presence (or absence) of 16 community-oriented helping behaviors to each individual in the community. Using balance theory-based partitioning of the perceptual network, we show that people in the community perceive distinct helping roles as structural associations among community members. The fact that role classes can be detected in network renderings of "tomographic" perceptual information lends support to the suggestion that this method is capable of producing meaningful new kinds of data about perceptual networks. PMID- 30419033 TI - Improved islet recovery and efficacy through co-culture and co-transplantation of islets with human adipose-derived mesenchymal stem cells. AB - Islet transplantation is an established clinical procedure for select patients with type 1 diabetes and severe hypoglycemia to stabilize glycemic control. Post transplant, substantial beta cell mass is lost, necessitating multiple donors to maintain euglycemia. A potential strategy to augment islet engraftment is the co transplantation of islets with multipotent mesenchymal stem cells to capitalize upon their pro-angiogenic and anti-inflammatory properties. Herein, we examine the in vitro and in vivo effect of co-culturing murine islets with human adipose derived mesenchymal stem cells (Ad-MSCs). Islets co-cultured with Ad-MSCs for 48 hours had decreased cell death, superior viability as measured by membrane integrity, improved glucose stimulated insulin secretion and reduced apoptosis compared to control islets. These observations were recapitulated with human islets, albeit tested in a limited capacity. Recipients of marginal mouse islet mass grafts, co-transplanted with Ad-MSCs without a co-culture period, did not reverse to normoglycemia as efficiently as islets alone. However, utilizing a 48 hour co-culture period, marginal mouse islets grafts with Ad-MSCs achieved a superior percent euglycemia rate when compared to islets cultured and transplanted alone. A co-culture period of human islets with human Ad-MSCs may have a clinical benefit improving engraftment outcomes. PMID- 30419034 TI - Risk factors for childhood enteric infection in urban Maputo, Mozambique: A cross sectional study. AB - BACKGROUND: Enteric infections are common where public health infrastructure is lacking. This study assesses risk factors for a range of enteric infections among children living in low-income, unplanned communities of urban Maputo, Mozambique. METHODS & FINDINGS: We conducted a cross-sectional survey in 17 neighborhoods of Maputo to assess the prevalence of reported diarrheal illness and laboratory confirmed enteric infections in children. We collected stool from children aged 1 48 months, independent of reported symptoms, for molecular detection of 15 common enteric pathogens by multiplex RT-PCR. We also collected survey and observational data related to water, sanitation, and hygiene (WASH) characteristics; other environmental factors; and social, economic, and demographic covariates. We analyzed stool from 759 children living in 425 household clusters (compounds) representing a range of environmental conditions. We detected >=1 enteric pathogens in stool from most children (86%, 95% confidence interval (CI): 84-89%) though diarrheal symptoms were only reported for 16% (95% CI: 13-19%) of children with enteric infections and 13% (95% CI: 11-15%) of all children. Prevalence of any enteric infection was positively associated with age and ranged from 71% (95% CI: 64-77%) in children 1-11 months to 96% (95% CI: 93-98%) in children 24-48 months. We found poor sanitary conditions, such as presence of feces or soiled diapers around the compound, to be associated with higher risk of protozoan infections. Certain latrine features, including drop-hole covers and latrine walls, and presence of a water tap on the compound grounds were associated with a lower risk of bacterial and protozoan infections. Any breastfeeding was also associated with reduced risk of infection. CONCLUSIONS: We found a high prevalence of enteric infections, primarily among children without diarrhea, and weak associations between bacterial and protozoan infections and environmental risk factors including WASH. Findings suggest that environmental health interventions to limit infections would need to be transformative given the high prevalence of enteric pathogen shedding and poor sanitary conditions observed. TRIAL REGISTRATION: ClinicalTrials.gov NCT02362932. PMID- 30419035 TI - Differential regulation of actin-activated nucleotidyl cyclase virulence factors by filamentous and globular actin. AB - Several bacterial pathogens produce nucleotidyl cyclase toxins to manipulate eukaryotic host cells. Inside host cells they are activated by endogenous cofactors to produce high levels of cyclic nucleotides (cNMPs). The ExoY toxin from Pseudomonas aeruginosa (PaExoY) and the ExoY-like module (VnExoY) found in the MARTX (Multifunctional-Autoprocessing Repeats-in-ToXin) toxin of Vibrio nigripulchritudo share modest sequence similarity (~38%) but were both recently shown to be activated by actin after their delivery to the eukaryotic host cell. Here, we further characterized the ExoY-like cyclase of V. nigripulchritudo. We show that, in contrast to PaExoY that requires polymerized actin (F-actin) for maximum activation, VnExoY is selectively activated by monomeric actin (G-actin). These two enzymes also display different nucleotide substrate and divalent cation specificities. In vitro in presence of the cation Mg2+, the F-actin activated PaExoY exhibits a promiscuous nucleotidyl cyclase activity with the substrate preference GTP>ATP>=UTP>CTP, while the G-actin activated VnExoY shows a strong preference for ATP as substrate, as it is the case for the well-known calmodulin activated adenylate cyclase toxins from Bordetella pertussis or Bacillus anthracis. These results suggest that the actin-activated nucleotidyl cyclase virulence factors despite sharing a common activator may actually display a greater variability of biological effects in infected cells than initially anticipated. PMID- 30419036 TI - Hospital based surveillance of congenital rubella syndrome cases in the pre vaccine era in Amhara Regional State, Ethiopia: A base line information for the country. AB - BACKGROUND: Rubella virus infection in early pregnancy lead to serious multi organ birth defects known as congenital rubella syndrome (CRS). The incidence of CRS varies in different populations and the highest burden is found in developing countries in which rubella vaccination is not included in their national immunization programs. In Ethiopia, there is scarcity of data about congenital rubella syndrome. Therefore, the aim of this study was to determine the burden of CRS-related birth defects and its incidence in the pre-vaccine era in Amhara Regional State, Ethiopia. MATERIALS AND METHODS: A cross sectional study was conducted in Dessie, Felege-Hiwot and University of Gondar Referral Hospitals, from December 2015 to August 2017. After getting informed assent from each parent/guardian, blood was collected from infants < 1 year of age for laboratory determination of anti-rubella virus antibodies. Their socio-demographic data and clinical information compatible with congenital rubella syndrome were collected using WHO guideline. RESULTS: During the study period, a total of 50 infants suspected for congenital rubella syndrome were included in the study. All infants suspected for CRS were tested against rubella specific IgM and IgG [for infants >= 6 months of age] antibodies using ELISA method. Of these, 9/50 (18%) and 4/14 (28.6%) of them were laboratory confirmed and potential CRS cases, respectively. In the present study, the most common laboratory confirmed defect was ocular manifestations 6 (66.7%) followed by heart related problems 5 (55.6%). In the present study, most of the laboratory confirmed cases (66.7%) were reported among 1-5 months of age infants. In addition, 5 (55.6%) of the infants with laboratory confirmed CRS cases were male and 6 (66.7%) of them were from urban settings. In this study, the incidence of CRS was 0.4 per 1000 live births. CONCLUSION: In this study, nearly one fifth of the infants had laboratory confirmed congenital rubella syndrome and most of them had multiple rubella associated congenital defects at a time. Most of these congenital anomalies were reported among infants >= 1 month of age. Based on our result, the incidence of the CRS was line with the global incidence of the CRS in the pre-vaccine era. Therefore, establishing strong rubella/CRS surveillance system as well as introducing the rubella containing vaccine in the national immunization program might be important to reduce the burden of rubella and CRS in the country. PMID- 30419037 TI - Role of truncated oxidized phospholipids in acute endothelial barrier dysfunction caused by particulate matter. AB - Particulate matter (PM) air pollution is a global environmental health problem contributing to more severe lung inflammation and injury. However, the molecular and cellular mechanisms of PM-induced exacerbation of lung barrier dysfunction and injury are not well understood. In the current study, we tested a hypothesis that PM exacerbates vascular barrier dysfunction via ROS-induced generation of truncated oxidized phospholipids (Tr-OxPLs). Treatment of human pulmonary endothelial cells with PM caused endothelial cell barrier disruption in a dose dependent fashion. Biochemical analysis showed destabilization of cell junctions by PM via tyrosine phosphorylation and internalization of VE-cadherin. These events were accompanied by PM-induced generation of Tr-OxPLs, detected by mass spectrometry analysis. Furthermore, purified Tr-OxPLs: POVPC, PGPC and lyso-PC alone, caused a rapid increase in endothelial permeability and augmented pulmonary endothelial barrier dysfunction induced by submaximal doses of PM. In support of a role of TR-OxPLs-dependent mechanism in mediation of PM effects, ectopic expression of intracellular type 2 platelet-activating factor acetylhydrolase (PAFAH2), which specifically hydrolyzes Tr-OxPLs, significantly attenuated PM-induced endothelial hyperpermeability. In summary, this study uncovered a novel mechanism of PM-induced sustained dysfunction of pulmonary endothelial cell barrier which is driven by PM-induced generation of truncated products of phospholipid oxidation causing destabilization of cell junctions. PMID- 30419038 TI - Economic evaluation of brief cognitive behavioural therapy for social activation in recent-onset psychosis. AB - BACKGROUND: In schizophrenia spectrum disorders, negative symptoms (e.g. social withdrawal) may persist after initial treatment with antipsychotics, much affecting the quality of life (QOL) of patients. This health-economic study evaluated if a dedicated form of cognitive behaviour therapy for social activation (CBTsa) would reduce negative symptoms and improve QOL in an economically sustainable way. METHODS: A health-economic evaluation was conducted alongside a single-blind randomised controlled trial in two parallel groups: guideline congruent treatment as usual (TAU; n = 50) versus TAU augmented with adjunct CBTsa (n = 49). Outcomes were PANSS negative symptom severity and EQ-5D quality adjusted life years (QALYs) gained. The health-economic evaluation was conducted both from the societal and the health sector perspective. RESULTS: Both conditions showed improvement in the respective outcomes over the follow-up period of six months, but QALY gains were significantly higher in the CBTsa condition compared to the TAU condition. Treatment response rate (i.e. >= 5-point decrease on the PANSS) was not significantly different. However, the add-on CBT intervention was associated with higher costs. This did not support the idea that CBTsa is a cost-effective adjunct. Various sensitivity analyses attested to the robustness of these findings. CONCLUSIONS: In the Dutch context where TAU for psychosis is guideline congruent and well implemented there appears no added value for adjunct CBTsa. In other settings where the treatment for the schizophrenia spectrum disorders solely relies on antipsychotics, add-on CBTsa may lead to clinically superior outcomes, but it should still be evaluated if adjunct CBTsa therapy is a cost-effective alternative. TRIAL REGISTRATION: ClinicalTrials.gov registry under NCT03217955. PMID- 30419039 TI - Can emotional content be extracted under interocular suppression? AB - Previous studies showed that emotional faces break through interocular suppression more easily compared to neutral faces under the continuous flash suppression (CFS) paradigm. However, there is controversy over whether emotional content or low-level properties contributed to the results. In this study, we directly manipulated the meaningfulness of facial expression to test the role of emotional content in breaking CFS (b-CFS). In addition, an explicit emotion judgment for different facial expressions (happy, neutral, and fearful) used in the b-CFS task was also conducted afterwards to examine the relationship between b-CFS time and emotion judgment. In Experiment 1, face orientation and luminance polarity were manipulated to generate upright-positive and inverted-negative faces. In Experiment 2, Asian and Caucasian faces were presented to Taiwanese participants so that these stimuli served as own-race and other-race faces, respectively. We found robust face familiarity effects in both experiments within the same experimental framework: upright-positive and own-race faces had shorter b-CFS times than inverted-negative and other-race faces, respectively. This indicates potential involvement of high-level processing under interocular suppression. In Experiment 1, different b-CFS times were found between emotional and neutral faces in both upright-positive and inverted-negative conditions. Furthermore, with sufficient duration (1000 ms) participants could still extract emotional content in explicit valence judgment even from inverted-negative faces, though with a smaller degree than upright-positive faces. In Experiment 2, differential b-CFS times were found between emotional and neutral faces with own race but not other-race faces. Correlation analyses from both experiments showed that the magnitude of emotion judgment was correlated with b-CFS time only for familiar (upright-positive / own-race) but not unfamiliar (inverted-negative / other-race) faces. These results suggest that emotional content can be extracted under interocular suppression with familiar faces, and low-level properties in unfamiliar faces may play a major role in the b-CFS time. PMID- 30419041 TI - Anti-plasminogen antibodies in ANCA-associated vasculitis: An optimized anti plasminogen assay. AB - Anti-plasminogen antibodies (alpha-PLG) were previously detected in a subpopulation of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patients, showing a relation to renal lesions and outcome. Several studies showed different proportions of alpha-PLG positive AAV patients, possibly due to differences in the assays used. We here present a new, optimized alpha-PLG Enzyme-Linked Immuno Sorbent Assay (ELISA) and validate the presence of alpha-PLG in AAV. Different ELISA set-ups were tested regarding plasminogen (PLG) antigen, concentrations, coating buffers, blocking agents, and environmental conditions. Purified lysine-PLG (lys-PLG) showed better differentiation between positive samples and negative samples than glutamic acid-PLG (glu-PLG). Therefore, lys-PLG was used as coating antigen. With the optimized alpha-PLG ELISA we found alpha-PLG in 14.3% of the myeloperoxidase (MPO)-ANCA patients, whereas all our proteinase-3 (PR3)-ANCA patients tested in our new assay were negative. Concluding, in this study we have combined important technical findings and methods from previous studies to optimize the alpha-PLG assay, which can be used for future research purposes and will aid in uniform reporting of alpha-PLG status of patients. PMID- 30419040 TI - Safety of azithromycin in infants under six months of age in Niger: A community randomized trial. AB - BACKGROUND: Mass azithromycin distribution reduces under-5 child mortality. Trachoma control programs currently treat infants aged 6 months and older. Here, we report findings from an infant adverse event survey in 1-5 month olds who received azithromycin as part of a large community-randomized trial in Niger. METHODS AND PRINCIPAL FINDINGS: Active surveillance of infants aged 1-5 months at the time of treatment was conducted in 30 randomly selected communities from within a large cluster randomized trial of biannual mass azithromycin distribution compared to placebo to assess the potential impact on child mortality. We compared the distribution of adverse events reported after treatment among azithromycin-treated versus placebo-treated infants. From January 2015 to February 2018, the caregivers of 1,712 infants were surveyed. Approximately one-third of caregivers reported at least one adverse event (azithromycin: 29.6%, placebo: 34.3%, risk ratio [RR] 0.86, 95% confidence interval [CI] 0.68 to 1.10, P = 0.23). The most commonly reported adverse events included diarrhea (azithromycin: 19.3%, placebo: 28.1%, RR 0.68, 95% CI 0.49 to 0.96, P = 0.03), vomiting (azithromycin: 15.9%, placebo: 21.0%, RR 0.76, 95% CI 0.56 to 1.02, P = 0.07), and skin rash (azithromycin: 12.3%, placebo: 13.6%, RR 0.90, 95% CI 0.59 to 1.37, P = 0.63). No cases of infantile hypertrophic pyloric stenosis were reported. CONCLUSIONS: Azithromycin given to infants aged 1-5 months appeared to be safe. Inclusion of younger infants in larger azithromycin based child mortality or trachoma control programs could be considered if deemed effective. TRIAL REGISTRATION: ClinicalTrials.gov NCT02048007. PMID- 30419042 TI - Decreasing cost of public sector first-line ART services in India from 2007-2008 to 2015-2016. AB - INTRODUCTION: India has scaled-up antiretroviral treatment (ART) in public sector facilities, but data to understand time trends of average cost of ART are limited. MATERIALS AND METHODS: Cost and output data were collected at all public sector ART centres in undivided Andhra Pradesh (high-HIV burden state) and Rajasthan (low-HIV burden state) in India from fiscal year 2007-2008 to 2012 2013. Average cost per patient for first-line ART, and its relation with scale of services, were assessed. Using data on scale of services, the average cost was estimated up to 2015-2016. Break-even point was estimated from average and marginal cost functions. Costs were adjusted to 2015 constant price. RESULTS: The average cost per patient alive and on ART in 2015-2016 was US$162 in undivided Andhra Pradesh and US$186 in Rajasthan, which was 51.4% and 35.8% lower than in 2007-2008, respectively. Average ART drug cost declined by 27.2% during this period, and was 70.9% and 61.5% of the total ART cost in the two states in 2015 2016. The average cost other than ART drugs declined by 73.1% and 45.7%, with the number of patients served increasing 7 and 14.2 times, respectively. Average cost other than ART drugs had a significant negative relation with scale (R2 = 86.4% 82.8%, p<0.001). Break-even analysis suggested that 47.5% and 58.8% of the ART centres in undivided Andhra Pradesh and Rajasthan, respectively, were functioning below optimal scale in 2015-2016. The estimated total economic cost of first-line ART services provided in the public sector in India in fiscal year 2015-2016 was US$ 151 million; it would be US$ 216.1 million to provide this to all eligible persons in India. CONCLUSION: The average cost of providing first-line ART has declined in India, and further reduction is possible if the optimal scale of services is achieved. These findings can inform resource requirement for the ART programme in India. PMID- 30419043 TI - Regulating transcriptional activity by phosphorylation: A new mechanism for the ARX homeodomain transcription factor. AB - Aristaless-related homeobox (ARX) gene encodes a paired-type homeodomain transcription factor with critical roles in development. Here we identify that ARX protein is phosphorylated. Using mass spectrometry and in vitro kinase assays we identify phosphorylation at serines 37, 67 and 174. Through yeast-2-hybrid and CoIP we identified PICK1 (Protein interacting with C kinase 1) binding with the C terminal region of ARX. PICK1 is a scaffold protein known to facilitate phosphorylation of protein partners by protein kinase C alpha (PRKCA). We confirm that ARX is phosphorylated by PRKCA and demonstrate phosphorylation at serine 174. We demonstrate that phosphorylation is required for correct transcriptional activity of the ARX protein using transcriptome-wide analysis of gene expression of phospho-null mutants (alanines replacing serines) compared to ARX wild-type (ARX-WT) overexpressed in pancreatic alpha TC cells. Compared to untransfected cells, ARX-WT overexpression significantly altered expression of 70 genes (Log2FC >+/-1.0, P-value <0.05). There were fewer genes with significantly altered expression compared to untransfected cells with the double phospho-null mutant Ser37Ala+Ser67Ala (26%) and Ser174Ala (39%), respectively. We demonstrate that the c-terminal region of ARX required to bind PICK1 causes a shift in PICK1 subcellular localisation to the nucleus to co-locate with the ARX protein, and truncation of this C-terminal region leads to the same loss of transcriptional activation as S174A mutant. In conclusion, we show that ARX is phosphorylated at several sites and that this modification affects its transcriptional activity. PMID- 30419044 TI - Effect of metformin exposure on growth and photosynthetic performance in the unicellular freshwater chlorophyte, Chlorella vulgaris. AB - Many pharmaceuticals have negative effects on biota when released into the environment. For example, recent work has shown that the commonly prescribed antidiabetic drug, metformin (N,N-dimethylbiguanide), has endocrine disrupting effects on fish. However, effects of metformin on aquatic primary producers are poorly known. We exposed cultured isolates of a freshwater chlorophyte, Chlorella vulgaris, to a range of metformin concentrations (0-767.9 mg L-1) to test the hypothesis that exposure negatively affects photosynthesis and growth. A cessation of growth, increase in non-photochemical quenching (NPQ, NPQmax), and reduced electron transport rate (ETR) were observed 24 h after exposure to a metformin concentration of 767.8 mg L-1 (4.6 mM). By 48 h, photosynthetic efficiency of photosystem II (Fv/Fm), alpha, the initial slope of the ETR irradiance curve, and Ek (minimum irradiance required to saturate photosynthesis) were reduced. At a lower concentration (76.8 mg L-1), negative effects on photosynthesis (increase in NPQ, decrease in ETR) were delayed, occurring between 72 and 96 h. No negative effects on photosynthesis were observed at an exposure concentration of 1.5 mg L-1. It is likely that metformin impairs photosynthesis either through downstream effects from inhibition of complex I of the electron transport chain or via activation of the enzyme, SnRK1 (sucrose non-fermenting related kinase 1), which acts as a cellular energy regulator in plants and algae and is an ortholog of the mammalian target of metformin, AMPK (5' adenosine monophosphate-activated protein kinase). PMID- 30419045 TI - Use of physician billing claims to identify infections in children. AB - While medical records have detailed information, they are limited in reach to the availability and accessibility of those records. On the other hand, administrative data while limited in scope, have a much further reach in coverage of an entire population. However, few studies have validated the use of administrative data for identifying infections in pediatric populations. Pediatric patients from Ontario, Canada aged <18 years were randomly sampled from the Electronic Medical Record Administrative data Linked Database (EMRALD). Using physician diagnoses from the electronic medical record (EMR) as the reference standard, we determined the criterion validity of physician billing claims in administrative data for identifying infectious disease syndromes from 2012 to 2014. Diagnosis codes were assessed by infection category (respiratory, skin and soft tissue, gastrointestinal, urinary tract and otitis externa) and for all infections combined. Sensitivity analyses assessed the performance if patients had more than one reason to visit the physician. We analysed 2,139 patients and found 33.3% of all visits were for an infection, and respiratory infections accounted for 67.6% of the infections. When we combined all infection categories, sensitivity was 0.74 (95% CI 0.70-0.77), specificity was 0.95 (95% CI 0.93-0.96), positive predictive value (PPV) was 0.87 (95% CI 0.84-0.90), and negative predictive value (NPV) was 0.88 (95% CI 0.86-0.89). For respiratory infections, sensitivity was 0.77 (95% CI 0.73-0.81), specificity was 0.96 (95% CI 0.95-0.97), PPV was 0.85 (95% CI 0.81-0.88), and NPV was 0.94 (95% CI 0.92-0.95). Similar performance was observed for skin and soft tissue, gastrointestinal, urinary tract, and otitis externa infections, but with lower sensitivity. Performance measures were highest when the patient visited the physician with only one health complaint. We found when using linked EMR data as the reference standard, administrative billing codes are reasonably accurate in identifying infections in a pediatric population. PMID- 30419046 TI - The impact of functional and social value on the price of goods. AB - According to hedonic pricing theory (HPT) market forces operate on individual characteristics of a good, and the price of a product is the aggregate of the price across those characteristics. The relationship between price and characteristics remains poorly understood because characteristic qualities are hard to quantify, people have varying levels of information about characteristics, and people have heterogeneous preferences over characteristics. By analyzing data from a large, market-driven virtual world we are able to test HPT, while largely avoiding these pitfalls. We find that a linear model with functional characteristics predicts the prices poorly, but a log-linear model performs quite well. Adding social characteristics to this log-linear model improves the predictions substantially. This work strongly supports HPT and demonstrates a "rational" calculus including social value. PMID- 30419047 TI - Fecal bacterial microbiota of Canadian commercial mink (Neovison vison): Yearly, life stage, and seasonal comparisons. AB - The gastrointestinal microbiome is known to play a critical role in animal health but has been relatively poorly characterized in commercial mink, an obligate carnivore. Whether the microbiota can be manipulated in mink to improve pelt quality, health, and well-being is unknown. The objectives of this study were to characterize the fecal microbiota of commercial mink, and to evaluate potential changes due to year (2014 vs 2015), life stage (adult female vs weaned kit), season (summer vs winter), and between Canadian farms. Pooled fecal samples were collected from adult females and weaned kits in the summers of 2014 (n = 173) and 2015 (n = 168), and from females in the winter of 2016 (n = 39), a time when females undergo marked calorie restriction, from 49 mink farms in Ontario. Bacterial DNA was extracted and the V4 region of the 16S rRNA gene was amplified. Approximately 22 million sequences were identified following quality control filtering. A total of 31 bacterial phyla were identified; however, only 3 comprised >1% of the total sequences identified, with Firmicutes and Proteobacteria together comprising 95% of the total sequences. Comparisons were made by life stage, season and year; no differences were found in the relative abundance of any taxa between samples collected from adult females and weaned kits from the same year and the greatest number of differences at each taxonomic level were noted between 2014 and 2015. Significantly more operational taxonomic units (OTUs) were found in 2014 than 2015 or 2016 (p<0.05) and samples from 2014 were more even, but less diverse than in 2015 (p = 0.002 and 0.001, respectively). There were significant differences in community population and structure by year and season (all p-values <0.001). The predominant phyla and genera at the farm level were similar from year to year. Together, these indicate that mink environment, season, and time are important factors in the stability of gastrointestinal microbiota, once mink reach maturity. PMID- 30419048 TI - Predictors of alcohol consumption among in-school adolescents in the Central Region of Ghana: A baseline information for developing cognitive-behavioural interventions. AB - BACKGROUND AND PURPOSE: Despite a recent shift in school going adolescents' engagement in health compromising behaviours and their related socio-economic implications on developing societies, it is surprising that baseline information for planned interventions is sparse. The purpose of this study was to investigate the prevalence of alcohol drinking and related behaviours among in-school adolescents in the Junior High Schools (JHS) in the Central Region of Ghana. METHODS AND RESULTS: Descriptive cross-sectional design was employed with multistage sampling procedures to sample 1400 school going adolescents in JHS in the Central Region. Preliminary findings using simple frequencies and percentages revealed 42% alcohol drinking prevalence in the region. High prevalence of drunkenness (73%, n = 406) and early exposure to alcohol drinking when students were in primary school (52%, n = 286) were noted. Community festivals and use of alcohol as a form of medicine were enabling factors of alcohol consumption in the region. Binary logistic regression analysis also showed that geographical location was a significant predictor of alcohol drinking among school going adolescents, with students in the southern and central part of the region at greater risks of drinking alcohol than those from the northern part (OR = .696, 95% CI = 0.52-926, p = .013). However, no statistical significant variations were found in the odds of drinking alcohol for age (OR = 1.13, 95% CI = 0.86-1.48, p = .370), gender (OR = .81, 95% CI = 0.65-1.01, p = .06), religious affiliation (OR = 1.33, 95% CI = 0.94-1.89, p = .10), parental communication (OR = .86, 95% CI = 0.66-1.06, p = .13), academic performance (OR = 1.07, 95% CI = 0.79-1.45, p = .05) and socioeconomic status (OR = 1.20, 95% CI = 0.95-1.53, p = .12). CONCLUSIONS: With this baseline data, it was recommended that schools' curricula should include preventive cognitive-behavioural interventions that teach drug resistance skills and anti-drug norms. These interventions would foster the development of requisite knowledge and social skills (e.g., developing competence) for resisting social and peer influences that may trigger alcohol use and perhaps other drugs. Potentially, the motivation for alcohol use among school going adolescents in the region would be minimized, if not prevented. PMID- 30419049 TI - Novel chromaticity similarity based color texture descriptor for digital pathology image analysis. AB - Pathology images are color in nature due to the use of chemical staining in biopsy examination. Aware of the high color diagnosticity in pathology images, this work introduces a compact rotation-invariant texture descriptor, named quantized diagnostic counter-color pattern (QDCP), for digital pathology image understanding. On the basis of color similarity quantified by the inner product of unit-length color vectors, local counter-color textons are indexed first. Then the underlined distribution of QDCP indexes is estimated by an image-wise histogram. Since QDCP is computed based on color difference directly, it is robust to small color variation usually observed in pathology images. This study also discusses QDCP's extraction, parameter settings, and feature fusion techniques in a generic pathology image analysis pipeline, and introduces two more descriptors QDCP-LBP and QDCP/LBP. Experimentation on public pathology image sets suggests that the introduced color texture descriptors, especially QDCP-LBP, outperform prior color texture features in terms of strong descriptive power, low computational complexity, and high adaptability to different image sets. PMID- 30419050 TI - Inducing gender/professional identity compatibility promotes women's compensation requests. AB - In this paper, I examine whether inducing gender/professional identity compatibility prior to a self-advocacy negotiation, may enhance women's assertiveness in a compensation negotiation and mitigate potential social backlash concerns for assertiveness. In two experimental lab studies where women negotiated with a male counterpart as sellers and job candidates, I found evidence supporting the causal link between state gender/profession identity integration and higher levels of assertiveness in women's self-advocacy compensation negotiations. PMID- 30419051 TI - Use of Geographically Weighted Poisson Regression to examine the effect of distance on Tuberculosis incidence: A case study in Nam Dinh, Vietnam. AB - OBJECTIVES: This study aimed to examine the potential of combining routine tuberculosis (TB) surveillance and demographic and socioeconomic variables into the Geographic Information System (GIS) to describe the geographical distribution of TB notified incidence in relation to distances to health services as well as local demographic and socioeconomic factors, including population density, urban/rural status, and household poverty rates in Nam Dinh, Vietnam. It also aimed to compare the conventional Generalized Linear Models (GLM) Poisson regression model and Geographically Weighted Poisson Regression (GWPR) models in order to determine the best fitting model that can be used to investigate the relationship between TB notified incidence and distances and the social risk factors. METHODS: The data of new and relapse patients with all forms of TB aged >=15 years residing in Nam Dinh (Vietnam) from 2012 to 2015 were collected from the Administration of Medical Services' (Ministry of Health of Vietnam) TB surveillance database. Data on the population and household poverty rates from 2012 to 2015 were gathered from the Nam Dinh Statistical Office. Distances between communes and the nearest TB diagnostic facilities in districts were computed. The TB notified incidence per 100,000 population was denoted by indirect age and sex standardized incidence ratio. GLM Poisson regression and GWPR were performed to assess the relationship between distance and TB incidence. RESULTS: The average notified TB incidence level measured from 2012 to 2015 is 82 per 100,000 population (range: 79-84/100,000). The distance to the nearest TB diagnosis presents a negative effect on TB notified incidence. By capturing spatial heterogeneity, the GWPR may be better at fitting data (corrected Aikake information criterion [AICc] = 245.71, residual deviance = 221.12) than the traditional GLM (AICc = 251.53, residual deviance = 241.21). CONCLUSIONS: GIS technologies benefit TB surveillance system. Distances should be considered when planning methods of improving access for those who live far from TB diagnostic services, thereby improving TB detection. Additional studies must confirm the association between geographic distance and TB case detection and must explore other factors that may affect TB notified incidence. PMID- 30419052 TI - Functional principal component analysis for identifying multivariate patterns and archetypes of growth, and their association with long-term cognitive development. AB - For longitudinal studies with multivariate observations, we propose statistical methods to identify clusters of archetypal subjects by using techniques from functional data analysis and to relate longitudinal patterns to outcomes. We demonstrate how this approach can be applied to examine associations between multiple time-varying exposures and subsequent health outcomes, where the former are recorded sparsely and irregularly in time, with emphasis on the utility of multiple longitudinal observations in the framework of dimension reduction techniques. In applications to children's growth data, we investigate archetypes of infant growth patterns and identify subgroups that are related to cognitive development in childhood. Specifically, "Stunting" and "Faltering" time-dynamic patterns of head circumference, body length and weight in the first 12 months are associated with lower levels of long-term cognitive development in comparison to "Generally Large" and "Catch-up" growth. Our findings provide evidence for the statistical association between multivariate growth patterns in infancy and long term cognitive development. PMID- 30419053 TI - The compensation for nonlinear friction of DDVC flange-type rotary vane steering gear. AB - This study reports on the direct drive volume control flange-type rotary vane steering gear (DDVC-FRVSG), a promising component with superior advantages of compact structure, powerful vibration absorption, and simple control for application in the controlling course and posture of a vessel. The ability of the DDVC-FRVSG to satisfy the accuracy requirement of the vessel is limited by nonlinear friction. This study proposes two compensation methods to compensate for the nonlinear friction. We establish the mathematical model and the transfer function of the steering gear system and the mathematical model of nonlinear friction on the DDVC-FRVSG system based on the principle of the DDVC-FRVSG. A high-gain proportional-integral-derivative control strategy and another method using the self-adaption robust control strategy is proposed and studied both theoretically and experimentally to suppress the nonlinear friction. With the "no compensation state" as a benchmark, our measured results by prototype testing has proved that both methods can compensate for the nonlinear friction, with the second method showing a better performance of up to 78.85% increase compared to that of the 41.65% shown by the first one. The outcome of this research will contribute to the rapidity and stability of the DDVC-FRVSG. PMID- 30419054 TI - Lestaurtinib is a potent inhibitor of anaplastic thyroid cancer cell line models. AB - Anaplastic thyroid cancer (ATC) is a rare and lethal human malignancy with no known effective therapies in the majority of cases. Despite the use of conventional treatments such as chemotherapy, radiation and surgical resection, this disease remains almost universally fatal. In the present study, we identified the JAK2 inhibitor Lestaurtinib as a potent compound when testing against 13 ATC cell lines. Lestaurtinib demonstrated a potent antiproliferative effect in vitro at nanomolar concentrations. Furthermore, Lestaurtinib impeded cell migration and the ability to form colonies from single cells using scratch wound and colony formation assays, respectively. Flow cytometry was used for cell cycle analysis following drug treatment and demonstrated arrest at the G2/M phase of the cell cycle, indicative of a cytostatic effect. In vivo studies using the chick chorioallantoic membrane xenograft models demonstrated that treatment with Lestaurtinib resulted in a significant decrease in endpoint tumor volume and vascularity using power Doppler ultrasound imaging. Overall, this study provides evidence that Lestaurtinib is a potent antiproliferative agent with potential antiangiogenic activity that warrants further investigation as a targeted therapy for ATC. PMID- 30419055 TI - The importance of culture in predicting environmental behavior in middle school students on Hawai'i Island. AB - Researchers have investigated the factors that influence environmental behavior for decades. Two often-investigated phenomena, connectedness to nature and self efficacy, often correlate with environmental behavior, yet researchers rarely analyze those correlations along with underlying cultural factors. We suggest that this is a substantial oversight and hypothesize that cultural factors affect environmental behavior, particularly through an interplay with the connectedness to nature and self-efficacy constructs. To test this hypothesis, we surveyed eighth-grade students on the island of Hawai'i. The instrument included items to assess connectedness to nature and self-efficacy (both frequently measured in environmental behavior studies) and multiple measures of behavior. Most of the behavior measures are commonly used in studies of environmental behavior, and one was developed in collaboration with local partners to reflect more culturally specific modes of environmental behavior. With those partners, we also developed a construct reflecting the relevance of local culture. We explored the relative influence of the more commonly investigated constructs (connectedness to nature, behavioral variables) along with the newer construct (cultural relevance). We found that, when we took those considerations into account, cultural relevance significantly predicted connectedness to nature, self-efficacy, and a commonly used behavioral measure. Our results thus suggest that many models of environmental behavior may be misspecified when they omit critical culture- and ethnicity-related factors. This may be particularly important in contexts with high cultural, racial, and ethnic diversity or in contexts where mainstream Western environmental approaches are non-dominant. Our results emphasize the importance of addressing ethnicity and culture in environmental thought and action. PMID- 30419056 TI - The cut-off values of surrogate measures for insulin resistance in the Korean population according to the Korean Genome and Epidemiology Study (KOGES). AB - OBJECTIVE: The current methods available for determining insulin resistance are complicated; hence, they are only applicable to small-scale studies. Therefore, this study aimed to classify the characteristics of surrogate measures for insulin resistance and establish valid cut-off values for predicting the development of type 2 diabetes mellitus (DM) in Korean populations. METHODS: This prospective study included 7,643 participants aged 40-69 years from the Ansung Ansan cohort database (2001-2012). Four surrogate measures, namely homeostasis model assessment-insulin resistance (HOMA-IR), visceral adiposity index (VAI), lipid accumulation product (LAP), and triglycerides and glucose (TyG) index, were analyzed. We analyzed each measure using receiver operating characteristic (ROC) curve for the development of type 2 DM. The cut-off value was determined as the value with the highest Youden index score in the specificity dominant area. RESULTS: The area under the curve (AUC) was 0.566 (95% confidence interval [CI], 0.548-0.583) for HOMA-IR, 0.622 (95% CI, 0.605-0.639) for VAI, 0.642 (95% CI, 0.625-0.658) for LAP, and 0.672 (95% CI, 0.656-0.687) for TyG index. The AUC of TyG index was significantly higher than that of HOMA-IR, VAI, and LAP (p < 0.001). The cut-off value was 2.54 (sensitivity 36.8%; specificity 73.1%; hazard ratio [HR], 1.41, 95% CI, 1.25-1.59) for HOMA-IR, 2.54 (sensitivity 50.4%; specificity 68.8%; HR, 1.75, 95% CI, 1.55-1.96) for VAI, 36.6 (sensitivity 59.2%; specificity 63.9%; HR, 1.87, 95% CI, 1.64-2.14) for LAP, and 4.69 (sensitivity 62.1%; specificity 63.1%; HR, 2.17, 95% CI, 1.92-2.45) for TyG index. CONCLUSIONS: The TyG index was a better predictor for DM than HOMA-IR. VAI and LAP showed the modest predictability for DM. The TyG index could be a useful supplementary method for identifying individuals at risk for insulin resistance and DM development. PMID- 30419057 TI - Perfect metamaterial absorber with high fractional bandwidth for solar energy harvesting. AB - A new perfect metamaterial absorber (PMA) with high fractional bandwidth (FBW) is examined and verified for solar energy harvesting. Solar cells based on perfect metamaterial give a chance to increase the efficiency of the system by intensifying the solar electromagnetic wave that incident on the device. The designed structure is mostly offered in the visible frequency range so as to exploit the solar's energy efficiently. Parametric investigations with regard to the measurements of the design structure are fulfilled to characterize the absorber. The finite-difference time-domain (FDTD) method-based CST simulator was used to keep the pattern parameters and absorbance analysis. The metamaterial shows almost 99.96% and 99.60% perfect absorption at 523.84 THz and 674.12 THz resonance frequencies. Moreover, absorption's FBW is studied, and 39.22% FBW is found. The results confirm that the designed PMA can attain very high absorption peak at two modes such as transverse electric (TE) and transverse magnetic (TM) mode. Other than the numerical outcomes demonstrated that the suggested configuration was also polarization angle insensitive. In addition, the change of absorbance of the structure has provided a new kind of sensor applications in these frequency ranges. Therefore, the suggested metamaterial absorber offers perfect absorption for visible frequency ranges and can be used for renewable solar energy harvesting applications. PMID- 30419058 TI - Dosimetric and radiobiological comparison in different dose calculation grid sizes between Acuros XB and anisotropic analytical algorithm for prostate VMAT. AB - To investigate feasible treatment planning parameters, we aimed to evaluate the dosimetric and radiobiological impact of the dose calculation algorithm and grid size in the volumetric modulated arc therapy (VMAT) plan for prostate cancer. Twenty patients were selected, and the treatment plans were initially generated with anisotropic analytical algorithm (AAA) and recalculated with Acuros XB (AXB) algorithm. Various dose grids were used for AXB (1, 2, and 3 mm) and AAA (1, 3, and 5 mm) plan. Dosimetric parameters such as homogeneity index (HI) and conformity index (CI), and radiobiological parameters such as tumor control probability (TCP) and normal tissue complication probability (NTCP) were calculated. Significant differences were observed in the planning target volume (PTV) coverage between both algorithms, and the V95%, HI, and CI of AAA were significantly affected by grid (p < 0.01). On 1 mm grid, the mean rectal dose difference between both algorithms was 2.87% of the prescription dose (p < 0.01), which was the highest among the critical organs. The TCP and NTCP of the AAA were higher than those of AXB (p < 0.01). Compared to AXB with 1 mm grid, the 2 mm grid showed comparable dose calculation accuracy with short calculation time. This study found that the PTV and rectum show significant differences according to dose calculation algorithm and grid. Considering the dose calculation performance for heterogeneous area, we recommend AXB with 2 mm grid for improving treatment efficiency of prostate VMAT. PMID- 30419060 TI - Automatic detection of mind wandering in a simulated driving task with behavioral measures. AB - Mind wandering (MW) is extremely common during driving and is often accompanied by performance losses. This study investigated the use of driving behavior measurements to automatically detect mind wandering state in the driving task. In the experiment, participants (N = 40) performed a car-following task in a driving simulator and reported, upon hearing a tone, whether they were experiencing mind wandering or not. Supervised machine learning techniques were applied to classify MW-absent versus MW-present state, using both driver-independent and driver dependent modeling methods. In the driver-independent modeling, we separately built models for participants with high or low MW and participants with medium MW. The optimal models can not offer a significant improvement than other models. So building effective driver-independent models with the leave-one-participant out cross-validation method is challenging. In the driver-dependent modeling, we built models for each participant with medium MW. The best models of some participants were effective. The results indicate the development of mind wandering detecting system should take into account both inter-individual and intra-individual difference. This study provides a step toward minimizing the negative impacts of mindless driving and should benefit other fields of psychological research. PMID- 30419059 TI - A systematic review on the impact of gestational Lyme disease in humans on the fetus and newborn. AB - Lyme disease (LD), caused by bacteria of the Borrelia burgdorferi sensu lato species complex, is the most common vector-borne disease in North America and Europe. A systematic review (SR) was conducted to summarize the global literature on adverse birth outcomes associated with gestational LD in humans. The SR followed an a priori protocol of pretested screening, risk of bias, and data extraction forms. Data were summarized descriptively and random effects meta analysis (MA) was used where appropriate. The SR identified 45 relevant studies, 29 describing 59 cases reported as gestational LD in the United States, Europe, and Asia (1969-2017). Adverse birth outcomes included spontaneous miscarriage or fetal death (n = 12), newborn death (n = 8), and newborns with an abnormal outcome (e.g. hyperbilirubinemia, respiratory distress and syndactyly) at birth (n = 16). Only one report provided a full case description (clinical manifestations in the mother, negative outcome for the child, and laboratory detection of B. burgdorferi in the child) that provides some evidence for vertical transmission of B. burgdorferi that has negative consequences for the fetus. The results of 17 epidemiological studies are included in this SR. Prevalence of adverse birth outcomes in an exposed population (defined by the authors as: gestational LD, history of LD, tick bites or residence in an endemic area) was compared to that in an unexposed population in eight studies and no difference was reported. A meta-analysis of nine studies showed significantly fewer adverse birth outcomes in women reported to have been treated for gestational LD (11%, 95%CI 7-16) compared to those who were not treated during pregnancy (50%, 95%CI 30-70) providing indirect evidence of an association between gestational LD and adverse birth outcomes. Other risk factors investigated; trimester of exposure, length of LD during pregnancy, acute vs. disseminated LD at diagnosis, and symptomatic LD vs. seropositive women with no LD symptoms during pregnancy were not significantly associated with adverse birth outcomes. This SR summarizes evidence from case studies that provide some limited evidence for transplacental transmission of B. burgdorferi. There was inconsistent evidence for adverse birth outcomes of gestational LD in the epidemiological research, and uncommon adverse outcomes for the fetus may occur as a consequence of gestational LD. The global evidence does not fully characterize the potential impact of gestational LD, and future research that addresses the knowledge gaps may change the findings in this SR. Given the current evidence; prompt diagnosis and treatment of LD during pregnancy is recommended. PMID- 30419062 TI - Association of specific gene mutations derived from machine learning with survival in lung adenocarcinoma. AB - Lung cancer is the second most common cancer in the United States and the leading cause of mortality in cancer patients. Biomarkers predicting survival of patients with lung cancer have a profound effect on patient prognosis and treatment. However, predictive biomarkers for survival and their relevance for lung cancer are not been well known yet. The objective of this study was to perform machine learning with data from The Cancer Genome Atlas of patients with lung adenocarcinoma (LUAD) to find survival-specific gene mutations that could be used as survival-predicting biomarkers. To identify survival-specific mutations according to various clinical factors, four feature selection methods (information gain, chi-squared test, minimum redundancy maximum relevance, and correlation) were used. Extracted survival-specific mutations of LUAD were applied individually or as a group for Kaplan-Meier survival analysis. Mutations in MMRN2 and GMPPA were significantly associated with patient mortality while those in ZNF560 and SETX were associated with patient survival. Mutations in DNAJC2 and MMRN2 showed significant negative association with overall survival while mutations in ZNF560 showed significant positive association with overall survival. Mutations in MMRN2 showed significant negative association with disease free survival while mutations in DRD3 and ZNF560 showed positive associated with disease-free survival. Mutations in DRD3, SETX, and ZNF560 showed significant positive association with survival in patients with LUAD while the opposite was true for mutations in DNAJC2, GMPPA, and MMRN2. These gene mutations were also found in other cohorts of LUAD, lung squamous cell carcinoma, and small cell lung cancer. In LUAD of Pan-Lung Cancer cohort, mutations in GMPPA, DNAJC2, and MMRN2 showed significant negative associations with survival of patients while mutations in DRD3 and SETX showed significant positive association with survival. In this study, machine learning was conducted to obtain information necessary to discover specific gene mutations associated with the survival of patients with LUAD. Mutations in the above six genes could predict survival rate and disease free survival rate in patients with LUAD. Thus, they are important biomarker candidates for prognosis. PMID- 30419061 TI - Rapidly evolving changes and gene loss associated with host switching in Corynebacterium pseudotuberculosis. AB - Phylogenomics and genome scale positive selection analyses were performed on 29 Corynebacterium pseudotuberculosis genomes that were isolated from different hosts, including representatives of the Ovis and Equi biovars. A total of 27 genes were identified as undergoing adaptive changes. An analysis of the clades within this species and these biovars, the genes specific to each branch, and the genes responding to selective pressure show clear differences, indicating that adaptation and specialization is occurring in different clades. These changes are often correlated with the isolation host but could indicate responses to some undetermined factor in the respective niches. The fact that some of these more rapidly evolving genes have homology to known virulence factors, antimicrobial resistance genes and drug targets shows that this type of analysis could be used to identify novel targets, and that these could be used as a way to control this pathogen. PMID- 30419063 TI - Predicting functional networks from region connectivity profiles in task-based versus resting-state fMRI data. AB - Intrinsic Connectivity Networks, patterns of correlated activity emerging from "resting-state" BOLD time series, are increasingly being associated with cognitive, clinical, and behavioral aspects, and compared with patterns of activity elicited by specific tasks. We study the reconfiguration of brain networks between task and resting-state conditions by a machine learning approach, to highlight the Intrinsic Connectivity Networks (ICNs) which are more affected by the change of network configurations in task vs. rest. To this end, we use a large cohort of publicly available data in both resting and task-based fMRI paradigms. By applying a battery of different supervised classifiers relying only on task-based measurements, we show that the highest accuracy to predict ICNs is reached with a simple neural network of one hidden layer. In addition, when testing the fitted model on resting state measurements, such architecture yields a performance close to 90% for areas connected to the task performed, which mainly involve the visual and sensorimotor cortex, whilst a relevant decrease of the performance is observed in the other ICNs. On one hand, our results confirm the correspondence of ICNs in both paradigms (task and resting) thus opening a window for future clinical applications to subjects whose participation in a required task cannot be guaranteed. On the other hand it is shown that brain areas not involved in the task display different connectivity patterns in the two paradigms. PMID- 30419064 TI - SSR-Linkage map of interspecific populations derived from Gossypium trilobum and Gossypium thurberi and determination of genes harbored within the segregating distortion regions. AB - Wild cotton species have significant agronomic traits that can be introgressed into elite cultivated varieties. The use of a genetic map is important in exploring, identification and mining genes which carry significant traits. In this study, 188 F2mapping individuals were developed from Gossypium thurberi (female) and Gossypium trilobum (male), and were genotyped by using simple sequence repeat (SSR) markers. A total of 12,560 simple sequence repeat (SSR) markers, developed by Southwest University, thus coded SWU were screened out of which only 994 were found to be polymorphic, and 849 markers were linked in all the 13 chromosomes. The map had a length of 1,012.458 cM with an average marker distance of 1.193 cM. Segregation distortion regions (SDRs) were observed on Chr01, Chr02, Chr06, Chr07 Chr09, Chr10 and Chr11 with a large proportion of the SDR regions segregating towards the heterozygous allele. There was good syntenic block formation that revealed good collinearity between the genetic and physical map of G. raimondii, compared to the Dt_sub genome of the G. hirsutum and G. barbadense. A total of 2,496 genes were mined within the SSR related regions. The proteins encoding the mined genes within the SDR had varied physiochemical properties; their molecular weights ranged from 6.586 to 252.737 kDa, charge range of -39.5 to 52, grand hydropathy value (GRAVY) of -1.177 to 0.936 and isoelectric (pI) value of 4.087 to 12.206. The low GRAVY values detected showed that the proteins encoding these genes were hydrophilic in nature, a property common among the stress responsive genes. The RNA sequence analysis revealed more of the genes were highly upregulated in various stages of fiber development for instance; Gorai.002G241300 was highly up regulated at 5, 10, 20 and 25 day post anthesis (DPA). Validation through RT-qPCR further revealed that these genes mined within the SDR regions might be playing a significant role under fiber development stages, therefore we infer that Gorai.007G347600 (TFCA), Gorai.012G141600 (FOLB1), Gorai.006G024500 (NMD3), Gorai.002G229900 (LST8) and Gorai.002G235200 (NSA2) are significantly important in fiber development and in turn the quality, and further researches needed to be done to elucidate their exact roles in the fiber development process. The construction of the genetic map between the two wild species paves away for the mapping of quantitative trait loci (QTLs) since the average distance between the markers is small, and mining of genes on the SSR regions will provide an insight in identifying key genes that can be introgressed into the cultivated cotton cultivars. PMID- 30419065 TI - An urgent need for HIV testing among men who have sex with men and transgender women in Bamako, Mali: Low awareness of HIV infection and viral suppression among those living with HIV. AB - Despite the high HIV prevalence among men who have sex with men (MSM) and transgender women (TGW), there are limited data on progress on their respective HIV antiretroviral treatment (ART) cascades to identify progress and gaps in meeting UNAIDS 90-90-90 targets. We conducted a respondent-driven sampling survey of MSM and TGW in Bamako, Mali from October 2014 to February 2015. We describe the HIV treatment cascade for MSM and TGW, identify correlates of being unaware of HIV-infected status and having unsuppressed viral load levels, and estimate proportion of recent infections. We enrolled 387 MSM and 165 TGW. HIV prevalence was 13.7%. Of those living with HIV, 10.4% were aware of their serostatus, 61.2% of them self-reported being on treatment, and of them, 100% were virally suppressed. In multivariate analysis, factors associated with being unaware of HIV infection included not using free condoms in the last six months (aOR: 5.7, 95% CI: 1.1-29.5) and not having comprehensive knowledge of HIV (aOR: 6.5, 95% CI: 1.4-29.9). Having unsuppressed viral load was associated with identifying as a transgender woman (aOR: 4.8, 95% CI: 1.1-20.7) and not having comprehensive knowledge of HIV (aOR: 6.5, 95% CI: 1.0-40.9). Of the 79 HIV-positive participants, 5.1% had recent infections. While the proportion aware of their HIV status was low despite adjusting for viral load biomarkers, all MSM and TGW on treatment were virally suppressed. Improved testing strategies are urgently needed to achieve the first 90 of the HIV cascade among MSM and TGW in Bamako. PMID- 30419066 TI - Exposure to a musically-enriched environment; Its relationship with executive functions, short-term memory and verbal IQ in primary school children. AB - BACKGROUND: Previous literature has shown a putative relationship between playing a musical instrument and a benefit in various cognitive domains. However, to date it still remains unknown whether the exposure to a musically-enriched environment instead of playing an instrument yourself might also increase cognitive domains such as language, mathematics or executive sub-functions such as for example planning or working memory in primary school children. DESIGN: Cross-sectional. METHOD: Exposure to a musically-enriched environment like listening to music at home, during play or when attending concerts was assessed using a comprehensive intake questionnaire administered to a sample of 176 primary school children. Furthermore, participants completed the verbal intelligence section of the Wechsler Intelligence Scale (WISC III), performed executive sub-function tasks such as planning (Tower of London), working memory (Klingberg Matrix backward span) and inhibition (Go/no-Go task), and a short-term memory task (Klingberg Matrix forward span). RESULTS: Linear and multiple regression analyses showed no significant relationship between exposure to a musically-enriched environment, executive sub-functions (planning, inhibition and working memory), and short-term memory. The relationship between an enriched musical environment and verbal IQ has revealed trends. DISCUSSION: Experiencing a musically enriched environment does not serve as predictor for higher performance on executive sub-functions, however, can influence verbal IQ. PMID- 30419067 TI - Emerging Shiga-toxin-producing Escherichia coli serogroup O80 associated hemolytic and uremic syndrome in France, 2013-2016: Differences with other serogroups. AB - To generate hypotheses on possible sources of Shiga toxin-producing Escherichia coli (STEC) serogroup O80 associated hemolytic-uremic syndrome (HUS), we explored differences in factors associated with STEC O80 associated HUS, compared with STEC O157 or STEC of other serogroups, in France during 2013-16. STEC was isolated from 153/521 (30%) reported HUS cases: 45 serogroup O80, 46 O157 and 62 other serogroups. Median ages were 1.1 years, 4.0 years and 1.8 years, respectively. O80 infected patients were less likely to report ground beef consumption (aOR [adjusted Odds Ratio] 0.14 95% CI [Confidence Interval] 0.02 0.80) or previous contact with a person with diarrhea or HUS (aOR 0.13 95%CI 0.02 0.78) than patients infected with STEC O157. They were also less likely to report previous contact with a person presenting with diarrhea/HUS than patients infected with other serogroups (aOR 0.13 95%CI 0.02-0.78). STEC O80 spread all over France among young children less exposed to known risk factors of O157 or other STEC infections, suggesting the existence of different reservoirs and transmission patterns. PMID- 30419068 TI - Lack of modulatory effect of the SCN5A R1193Q polymorphism on cardiac fast Na+ current at body temperature. AB - SCN5A encodes the main subunit of the NaV1.5 channel, which mediates the fast Na+ current responsible for generating cardiac action potentials. The single nucleotide polymorphism SCN5A(R1193Q), which results in an amino acid replacement in the subunit, is common in East Asia. SCN5A(R1193Q) is often identified in patients with type 3 long QT syndrome and Brugada syndrome. However, its linkage to arrhythmic disorders is under debate. Previous electrophysiological studies performed at room temperature inconsistently reported the gain- or loss-of function effect of SCN5A(R1193Q) on the NaV1.5 channel. More recently, it was theoretically predicted that SCN5A(R1193Q) would exert a loss-of-function effect at body temperature. Here, we experimentally assessed whether SCN5A(R1193Q) modulates the NaV1.5 channel at various temperatures including normal and febrile body temperatures. We compared voltage-gated Na+ currents in SCN5A(R1193Q) transfected and wild-type SCN5A-transfected HEK293T cells using a whole-cell voltage-clamp technique. First, we made comparisons at constant temperatures of 25 degrees C, 36.5 degrees C, and 38 degrees C, and found no difference in the conductance density, voltage dependence of gating, or time dependence of gating. This suggested that SCN5A(R1193Q) does not modulate the NaV1.5 channel regardless of temperature. Second, we made comparisons while varying the temperature from 38 degrees C to 26 degrees C in 3 min, and again observed no difference in the time course of the amplitude or time dependence of gating during the temperature change. This also indicated that SCN5A(R1193Q) does not modulate the NaV1.5 channel in response to an acute body temperature change. Therefore, SCN5A(R1193Q) may not be a monogenic factor that triggers arrhythmic disorders. PMID- 30419070 TI - Deletion of a conserved transcript PG_RS02100 expressed during logarithmic growth in Porphyromonas gingivalis results in hyperpigmentation and increased tolerance to oxidative stress. AB - The oral obligate anaerobe Porphyromonas gingivalis possesses a small conserved transcript PG_RS02100 of unknown function we previously identified using small RNA-seq analysis as expressed during logarithmic growth. In this study, we sought to determine if PG_RS02100 plays a role in P. gingivalis growth or stress response. We show that a PG_RS02100 deletion mutant's (W83Delta514) ability to grow under anaerobic conditions was no different than wildtype (W83), but it was better able to survive hydrogen peroxide exposure when cultured under heme limiting growth conditions, and was more aerotolerant when plated on enriched whole blood agar and exposed to atmospheric oxygen. Together, these results indicate that PG_RS02100 plays a role in surviving oxidative stress in actively growing P. gingivalis and that P. gingivalis' response to exogenous hydrogen peroxide stress is linked to heme availability. Relative qRT-PCR expression analysis of oxyR, trx-1, tpx, sodB, ahpC, dinF, cydB, and frd, in W83Delta514 and W83 in response to 1 h exogenous dioxygen or hydrogen peroxide exposure, when cultured with varying heme availability, support our phenotypic evidence that W83Delta514 has a more highly primed defense system against exogenous peroxide, dioxygen, and heme generated ROS. Interestingly, W83Delta514 turned black faster than W83 when cultured on whole blood agar, suggesting it was able to accumulate heme more rapidly. The mechanism of increased heme acquisition observed in W83Delta514 is not yet known. However, it is clear that PG_RS02100 is involved in modulating the P. gingivalis cell surface in a manner related to survival, particularly against oxidative stress. PMID- 30419069 TI - C/VDdb: A multi-omics expression profiling database for a knowledge-driven approach in cardiovascular disease (CVD). AB - The cardiovascular disease (C/VD) database is an integrated and clustered information resource that covers multi-omic studies (microRNA, genomics, proteomics and metabolomics) of cardiovascular-related traits with special emphasis on coronary artery disease (CAD). This resource was built by mining existing literature and public databases and thereafter manual biocuration was performed. To enable integration of omic data from distinct platforms and species, a specific ontology was applied to tie together and harmonise multi level omic studies based on gene and protein clusters (CluSO) and mapping of orthologous genes (OMAP) across species. CAD continues to be a leading cause of death in the population worldwide, and it is generally thought to be an age related disease. However, CAD incidence rates are now known to be highly influenced by environmental factors and interactions, in addition to genetic determinants. With the complexity of CAD aetiology, there is a difficulty in research studies to elucidate general elements compared to other cardiovascular diseases. Data from 92 studies, covering 13945 molecular entries (4353 unique molecules) is described, including data descriptors for experimental setup, study design, discovery-validation sample size and associated fold-changes of the differentially expressed molecular features (p-value<0.05). A dedicated interactive web interface, equipped with a multi-parametric search engine, data export and indexing menus are provided for a user-accessible browsing experience. The main aim of this work was the development of a data repository linking clinical information and molecular differential expression in several CVD-related traits from multi-omics studies (genomics, transcriptomics, proteomics and metabolomics). As an example case of how to query and identify data sets within the database framework and concomitantly demonstrate the database utility, we queried CAD-associated studies and performed a systems-level integrative analysis. URL: www.padb.org/cvd. PMID- 30419071 TI - Blood-stage Plasmodium vivax antibody dynamics in a low transmission setting: A nine year follow-up study in the Amazon region. AB - Plasmodium vivax remains a global health problem and its ability to cause relapses and subpatent infections challenge control and elimination strategies. Even in low malaria transmission settings, such as the Amazon basin, where progress in malaria control has caused a remarkable reduction in case incidence, a recent increase in P. vivax transmission demonstrates the continued vulnerability of P.vivax-exposed populations. As part of a search for complementary approaches to P.vivax surveillance in areas in which adults are the majority of the exposed-population, here we evaluated the potential of serological markers covering a wide range of immunogenicity to estimate malaria transmission trends. For this, antibodies against leading P. vivax blood-stage vaccine candidates were assessed during a 9 year follow-up study among adults exposed to unstable malaria transmission in the Amazon rainforest. Circulating antibody levels against immunogenic P. vivax proteins, such as the Apical Membrane Antigen-1, were a sensitive measure of recent P. vivax exposure, while antibodies against less immunogenic proteins were indicative of naturally acquired immunity, including the novel engineered Duffy binding protein II immunogen (DEKnull-2). Our results suggest that the robustness of serology to estimate trends in P.vivax malaria transmission will depend on the immunological background of the study population, and that for adult populations exposed to unstable P.vivax malaria transmission, the local heterogeneity of antibody responses should be considered when considering use of serological surveillance. PMID- 30419073 TI - Functional diversity and nutritional content in a deep-sea faunal assemblage through total lipid, lipid class, and fatty acid analyses. AB - Lipids are key compounds in marine ecosystems being involved in organism growth, reproduction, and survival. Despite their biological significance and ease of measurement, the use of lipids in deep-sea studies is limited, as is our understanding of energy and nutrient flows in the deep ocean. Here, a comprehensive analysis of total lipid content, and lipid class and fatty acid composition, was used to explore functional diversity and nutritional content within a deep-sea faunal assemblage comprising 139 species from 8 phyla, including the Chordata, Arthropoda, and Cnidaria. A wide range of total lipid content and lipid class composition suggested a diversified set of energy allocation strategies across taxa. Overall, phospholipid was the dominant lipid class. While triacylglycerol was present in most taxa as the main form of energy storage, a few crustaceans, fish, jellyfishes, and corals had higher levels of wax esters/steryl esters instead. Type and amount of energy reserves may reflect dietary sources and environmental conditions for certain deep-sea taxa. Conversely, the composition of fatty acids was less diverse than that of lipid class composition, and large proportions of unsaturated fatty acids were detected, consistent with the growing literature on cold-water species. In addition, levels of unsaturation increased with depth, likely suggesting an adaptive strategy to maintain normal membrane structure and function in species found in deeper waters. Although proportions of n-3 fatty acids were high across all phyla, representatives of the Chordata and Arthropoda were the main reservoirs of these essential nutrients, thus suggesting health benefits to their consumers. PMID- 30419074 TI - Determining minimal output sets that ensure structural identifiability. AB - The process of inferring parameter values from experimental data can be a cumbersome task. In addition, the collection of experimental data can be time consuming and costly. This paper covers both these issues by addressing the following question: "Which experimental outputs should be measured to ensure that unique model parameters can be calculated?". Stated formally, we examine the topic of minimal output sets that guarantee a model's structural identifiability. To that end, we introduce an algorithm that guides a researcher as to which model outputs to measure. Our algorithm consists of an iterative structural identifiability analysis and can determine multiple minimal output sets of a model. This choice in different output sets offers researchers flexibility during experimental design. Our method can determine minimal output sets of large differential equation models within short computational times. PMID- 30419072 TI - REM1.3's phospho-status defines its plasma membrane nanodomain organization and activity in restricting PVX cell-to-cell movement. AB - Plants respond to pathogens through dynamic regulation of plasma membrane-bound signaling pathways. To date, how the plant plasma membrane is involved in responses to viruses is mostly unknown. Here, we show that plant cells sense the Potato virus X (PVX) COAT PROTEIN and TRIPLE GENE BLOCK 1 proteins and subsequently trigger the activation of a membrane-bound calcium-dependent kinase. We show that the Arabidopsis thaliana CALCIUM-DEPENDENT PROTEIN KINASE 3 interacts with group 1 REMORINs in vivo, phosphorylates the intrinsically disordered N-terminal domain of the Group 1 REMORIN REM1.3, and restricts PVX cell-to-cell movement. REM1.3's phospho-status defines its plasma membrane nanodomain organization and is crucial for REM1.3-dependent restriction of PVX cell-to-cell movement by regulation of callose deposition at plasmodesmata. This study unveils plasma membrane nanodomain-associated molecular events underlying the plant immune response to viruses. PMID- 30419075 TI - Activation of trigeminal ganglion satellite glial cells in CFA-induced tooth pulp pain in rats. AB - This study further investigated the mechanisms underlying the rat model of tooth pulp inflammatory pain elicited by complete Freund's adjuvant (CFA), in comparison to other pulpitis models. Pulps of the left maxillary first molars were accessed. In the CFA group, the pulps were exposed, and CFA application was followed by dental sealing. In the open group, the pulps were left exposed to the oral cavity. For the closed group, the pulps were exposed, and the teeth were immediately sealed. Naive rats were used as negative controls. Several parameters were evaluated at 1, 2, 3 and 8 days. There was no statistical significant difference among the groups when body weight variation, food or water consumption were compared. Analysis of serum cytokines (IL-1beta, TNF or IL-6) or differential blood cell counts did not reveal any evidence of systemic inflammation. The CFA group displayed a significant reduction in the locomotor activity (at 1 and 3 days), associated with an increased activation of satellite glial cells in the ipsilateral trigeminal ganglion (TG; for up to 8 days). Amygdala astrocyte activation was unaffected in any experimental groups. We provide novel evidence indicating that CFA-induced pulp inflammation impaired the locomotor activity, with persistent activation of ipsilateral TG satellite cells surrounding sensory neurons, without any evidence of systemic inflammation or amygdala astrogliosis. PMID- 30419077 TI - The localized surface plasmon resonance induced edge effect of gold regular hexagonal nanoplates for reaction progress monitoring. AB - Clear doughnut-shaped far-field scattering patterns (DNSPs) for gold regular hexagonal nanoplates (AuHNPs) larger than 500 nm (distance between the two opposite edges) have been observed by dark-field microscopy imaging. This phenomenon was attributed to the edge effect, which can be further applied for reaction process monitoring. PMID- 30419076 TI - Lassa virus activates myeloid dendritic cells but suppresses their ability to stimulate T cells. AB - Lassa virus (LASV) is responsible for a viral hemorrhagic fever in humans and the death of 3,000 to 5,000 people every year. The immune response to LASV is poorly understood, but type I interferon (IFN-I) and T-cell responses appear to be critical for the host. We studied the response of myeloid dendritic cells (mDC) to LASV, as mDCs are involved in both IFN-I production and T-cell activation. We compared the response of primary human mDCs to LASV and Mopeia virus (MOPV), which is similar to LASV, but non-pathogenic. We showed that mDCs produced substantial amounts of IFN-I in response to both LASV and MOPV. However, only MOPV-infected mDCs were able to activate T cells. More surprisingly, coculture with T cells completely inhibited the activation of LASV-infected mDCs. These differences between LASV and MOPV were mostly due to the LASV nucleoprotein, which has major immunosuppressive properties, but the glycoprotein was also involved. Overall, these results suggest that mDCs may be important for the global response to LASV and play a role in the outcome of Lassa fever. PMID- 30419078 TI - Wide Complex Tachycardia and Syncope in a Middle-Aged Woman. PMID- 30419079 TI - Moving Precision Oncology Forward Amid Myths and Misconceptions. PMID- 30419081 TI - Moving Precision Oncology Forward Amid Myths and Misconceptions. PMID- 30419080 TI - Moving Precision Oncology Forward Amid Myths and Misconceptions-Reply. PMID- 30419082 TI - Comparative Evaluation of 5 Validated Symptom Questionnaires as Screening Instruments for Dry Eye Disease. PMID- 30419083 TI - Idiopathic Retinal Vasculitis, Aneurysms, and Neuroretinitis (IRVAN) in a Patient Without IRVAN History. PMID- 30419084 TI - Association of Macular Visual Field Measurements With Glaucoma Staging Systems. AB - Importance: Macular function is important for daily activities but is underestimated when tested with 24-2 visual fields, which are often used to classify glaucoma severity. Objective: To test the hypothesis that current glaucoma staging systems underestimate glaucoma severity by not detecting macular damage. Design, Setting, and Participants: This cross-sectional study was carried out in a glaucoma referral practice. The eyes of participants with manifest glaucoma and 24-2 mean deviation (MD) better than -6 dB were included. All participants were tested with 24-2, 10-2 visual fields, and spectral-domain optical coherence tomography of the optic disc and macula. Exposures: Macular damage was based on the topographic agreement between visual field results and retinal ganglion cell plus inner plexiform layer probability plots. Classifications from the Hodapp-Parrish-Anderson (HPA), visual field index (VFI), and Brusini staging systems were examined and compared with visual field and spectral-domain optical coherence tomography results. Main Outcomes and Measures: The association between the presence of macular damage and glaucoma severity scores. Results: Fifty-seven eyes of 57 participants were included; 33 participants (57%) were women, and 43 (75%) were white. Their mean (SD) age was 57 (14) years. Forty-eight of the eyes (84% [95% CI, 72%-92%]) had macular damage by the study definition. These had a 24-2 MD mean (SD) of -2.5 (1.8); corresponding results for the 10-2 MD were -3.0 (2.4) dB and for the VFI were 94.2% (4.5%). The HPA system classified 70% (95% CI, 55%-83%) of eyes with macular damage as having early defects; the VFI system classified 81% (95% CI, 67%-91%) of eyes with macular damage as having early defects, and the Brusini system 68% (95% CI, 53%-81%). Conclusions and Relevance: These findings suggest that current glaucoma staging systems based on 24-2 (or 30-2) visual fields underestimate disease severity and the presence of macular damage. If these results are confirmed and generalizable to other participants, new systems using macular measures (from 10-2 and spectral-domain optical coherence tomography results) might improve staging of glaucoma severity. PMID- 30419085 TI - Association of Concussion With the Risk of Suicide: A Systematic Review and Meta Analysis. AB - Importance: Concussion is the most common form of traumatic brain injury (TBI). While most patients fully recover within 1 week of injury, a subset of patients might be at a higher risk of suicide. Objective: To assess the risk of suicide after concussion. Data Sources: We performed a systematic search of Medline (PubMed), Embase, PsycINFO, and Published International Literature on Traumatic Stress (PILOTS) from 1963 to May 1, 2017. We also searched Google Scholar and conference proceedings and contacted experts in the field to seek additional studies. Study Selection: Studies that quantified the risk of suicide, suicide attempt, or suicidal ideation after a concussion and/or mild TBI were included. Studies that included children and adults, including military and nonmilitary personnel, were included. Two authors independently reviewed all titles and abstracts to determine study eligibility. Data Extraction and Synthesis: Study characteristics were extracted independently by 2 trained investigators. Study quality was assessed using the Newcastle-Ottawa Scale. Study data were pooled using random-effects meta-analysis. Main Outcomes and Measures: The primary exposure was concussion and/or mild TBI, and the primary outcome was suicide. Secondary outcomes were suicide attempt and suicidal ideation. Results: Data were extracted from 10 cohort studies (n = 713 706 individuals diagnosed and 6 236 010 individuals not diagnosed with concussion and/or mild TBI), 5 cross-sectional studies (n = 4420 individuals diagnosed and 11 275 individuals not diagnosed with concussion and/or mild TBI), and 2 case-control studies (n = 446 individuals diagnosed and 8267 individuals not diagnosed with concussion and/or mild TBI). Experiencing concussion and/or mild TBI was associated with a 2-fold higher risk of suicide (relative risk, 2.03 [95% CI, 1.47-2.80]; I2 = 96%; P < .001). In 2 studies that provided estimates with a median follow-up of approximately 4 years, 1664 of 333 118 individuals (0.50%) and 750 of 126 114 individuals (0.59%) diagnosed with concussion and/or mild TBI died by suicide. Concussion was also associated with a higher risk of suicide attempt and suicide ideation. The heightened risk of suicide outcomes after concussion was evident in studies with and without military personnel. Conclusions and Relevance: Experiencing concussion and/or mild TBI was associated with a higher risk of suicide. Future studies are needed to identify and develop strategies to decrease this risk. PMID- 30419086 TI - Association of Blepharitis and Ectropion With Tumor Necrosis Factor alpha Inhibitor Treatment in Crohn Disease. PMID- 30419087 TI - Association of Cerebrospinal Fluid Neurofilament Light Protein With Risk of Mild Cognitive Impairment Among Individuals Without Cognitive Impairment. AB - Importance: Accumulating data suggest that elevated cerebrospinal fluid (CSF) neurofilament light (NfL) and neurogranin (Ng) levels are associated with cognitive decline and may be useful markers of neurodegeneration. However, to our knowledge, previous studies have not assessed these CSF markers in the community, evaluated them with regards to risk of mild cognitive impairment (MCI), or compared their prognostic value with CSF total tau (T-tau) or phosphorylated tau (P-tau). Objective: To determine (1) whether CSF NfL and Ng levels were associated with risk of MCI, (2) the effect size of these markers compared with CSF T-tau or P-tau for risk of MCI, and (3) whether CSF amyloid-beta (Abeta42) modified these associations. Design, Setting and Participants: The analyses included 648 participants without cognitive impairment who were enrolled into the prospective population-based Mayo Clinic Study of Aging between January 2004 and December 2015 with available CSF data and at least 1 follow-up visit. Participants were followed up for a median of 3.8 years (interquartile range, 2.6 5.4 years). The CSF NfL and Ng levels were measured using an in-house sandwich enzyme-linked immunosorbent assay. The CSF Abeta42, T-tau, and P-tau levels were measured with automated electrochemiluminescence immunoassays. Cox proportional hazards models, with age as the timescale, were used to assess the association between CSF NfL, Ng, Abeta42, T-tau, or P-tau with risk of MCI after adjusting for sex, education, apolipoprotein E genotype, and the Charlson comorbidity index. To examine CSF Abeta42 as an effect modifier, it was categorized into tertiles; the bottom tertile was defined as having elevated brain amyloid. Main Outcomes and Measures: Risk of MCI. Results: At baseline, the median age of the 648 participants without cognitive impairment was 72.3 years (range, 50.7-95.3 years) and 366 (56.5%) were men; 96 (14.8%) developed incident MCI. Compared with the bottom quartile, the top quartile of CSF NfL was associated with a 3.1-fold increased risk of MCI (hazard ratio, 3.13; 95% CI, 1.36-7.18) in multivariate models. Neither CSF T-tau, P-tau, nor Ng was associated with risk of MCI. There was no interaction between Abeta42 and CSF NfL for risk of MCI. Conclusions and Relevance: Elevated CSF NfL levels but not CSF T-tau, P-tau or Ng are a risk factor for MCI in a community population and are independent of brain amyloid. PMID- 30419088 TI - Comparison of Local Control of Brain Metastases With Stereotactic Radiosurgery vs Surgical Resection: A Secondary Analysis of a Randomized Clinical Trial. AB - Importance: Brain metastases are a common source of morbidity for patients with cancer, and limited data exist to support the local therapeutic choice between surgical resection and stereotactic radiosurgery (SRS). Objective: To evaluate local control of brain metastases among patients treated with SRS vs surgical resection within the European Organization for the Research and Treatment of Cancer (EORTC) 22952-26001 phase 3 trial. Design, Setting, and Participants: This unplanned, exploratory analysis of the international, multi-institutional randomized clinical trial EORTC 22952-26001 (conducted from 1996-2007) was performed from February 9, 2017, through July 25, 2018. The EORTC 22952-26001 trial randomized patients with 1 to 3 brain metastases to whole-brain radiotherapy vs observation after complete surgical resection or before SRS. Patients in the present analysis were stratified but not randomized according to local modality (SRS or surgical resection) and treated per protocol with 1 to 2 brain metastases and tumors with a diameter of no greater than 4 cm. Interventions: Surgical resection or SRS. Main Outcomes and Measures: The primary end point was local recurrence of treated lesions. Cumulative incidence of local recurrence was calculated according to modality (surgical resection vs SRS) with competing risk regression to adjust for prognostic factors and competing risk of death. Results: A total of 268 patients were included in the analysis (66.4% men; median age, 60.7 years [range, 26.9-81.1 years]); 154 (57.5%) underwent SRS and 114 (42.5%) underwent surgical resection. Median follow-up time was 39.9 months (range, 26.0-1982.0 months). Compared with the SRS group, patients undergoing surgical resection had larger metastases (median 28 mm [range, 10-40 mm] vs 20 mm [range, 4-40 mm]; P < .001), more frequently had 1 brain metastasis (112 [98.2%] vs 114 [74.0%]; P < .001), and differed in location (parietal, 21 [18.4%] vs 61 [39.6%]; posterior fossa, 30 [26.3%] vs 12 [7.8%]; P < .001). In adjusted models, local recurrence was similar between the SRS and surgical resection groups (hazard ratio [HR], 1.15; 95% CI, 0.72-1.83). However, when stratified by interval, patients with surgical resection had a much higher risk of early (0-3 months) local recurrence compared with those undergoing SRS (HR, 5.94; 95% CI, 1.72-20.45), but their risk decreased with time (HR for 3-6 months, 1.37 [95% CI, 0.64-2.90]; HR for 6-9 months, 0.75 [95% CI, 0.28-2.00]). At 9 months or longer, the surgical resection group had a lower risk of local recurrence (HR, 0.36; 95% CI, 0.14-0.93). Conclusions and Relevance: In this exploratory analysis, local control of brain metastases was similar between SRS and surgical resection groups. Stereotactic radiosurgery was associated with improved early local control of treated lesions compared with surgical resection, although the relative benefit decreased with time. Trial Registration: ClinicalTrials.gov Identifier: NCT00002899. PMID- 30419089 TI - A Potential Link Between Ambient Air Pollution and Intraocular Pressure. PMID- 30419090 TI - From Puppy to Patient: Translational Oncology. PMID- 30419091 TI - Errors in Number at Risk and Author Email Address. PMID- 30419094 TI - Severe Nasal Swelling. PMID- 30419095 TI - Incidental Pulmonary Nodules Detected on CT Images. PMID- 30419096 TI - Effect of Exercise Intervention on Functional Decline in Very Elderly Patients During Acute Hospitalization: A Randomized Clinical Trial. AB - Importance: Functional decline is prevalent among acutely hospitalized older patients. Exercise and early rehabilitation protocols applied during acute hospitalization can prevent functional and cognitive decline in older patients. Objective: To assess the effects of an innovative multicomponent exercise intervention on the functional status of this patient population. Design, Setting, and Participants: A single-center, single-blind randomized clinical trial was conducted from February 1, 2015, to August 30, 2017, in an acute care unit in a tertiary public hospital in Navarra, Spain. A total of 370 very elderly patients undergoing acute-care hospitalization were randomly assigned to an exercise or control (usual-care) intervention. Intention-to-treat analysis was conducted. Interventions: The control group received usual-care hospital care, which included physical rehabilitation when needed. The in-hospital intervention included individualized moderate-intensity resistance, balance, and walking exercises (2 daily sessions). Main Outcomes and Measures: The primary end point was change in functional capacity from baseline to hospital discharge, assessed with the Barthel Index of independence and the Short Physical Performance Battery (SPPB). Secondary end points were changes in cognitive and mood status, quality of life, handgrip strength, incident delirium, length of stay, falls, transfer after discharge, and readmission rate and mortality at 3 months after discharge. Results: Of the 370 patients included in the analyses, 209 were women (56.5%); mean (SD) age was 87.3 (4.9) years. The median length of hospital stay was 8 days in both groups (interquartile range, 4 and 4 days, respectively). Median duration of the intervention was 5 days (interquartile range, 0); there was a mean (SD) of 5 (1) morning and 4 (1) evening sessions per patient. No adverse effects were observed with the intervention. The exercise intervention program provided significant benefits over usual care. At discharge, the exercise group showed a mean increase of 2.2 points (95% CI, 1.7-2.6 points) on the SPPB scale and 6.9 points (95% CI, 4.4-9.5 points) on the Barthel Index over the usual-care group. Hospitalization led to an impairment in functional capacity (mean change from baseline to discharge in the Barthel Index of -5.0 points (95% CI, -6.8 to -3.2 points) in the usual-care group, whereas the exercise intervention reversed this trend (1.9 points; 95% CI, 0.2-3.7 points). The intervention also improved the SPPB score (2.4 points; 95% CI, 2.1-2.7 points) vs 0.2 points; 95% CI, -0.1 to 0.5 points in controls). Significant intervention benefits were also found at the cognitive level of 1.8 points (95% CI, 1.3-2.3 points) over the usual-care group. Conclusions and Relevance: The exercise intervention proved to be safe and effective to reverse the functional decline associated with acute hospitalization in very elderly patients. Trial Registration: ClinicalTrials.gov identifier: NCT02300896. PMID- 30419097 TI - Vaccines as an Integral Component of Cancer Immunotherapy. PMID- 30419098 TI - Intensive Intervention to Improve Outcomes for Patients With COPD. PMID- 30419099 TI - Errors in Corresponding Authors Section. PMID- 30419102 TI - Proportion of Violent Injuries Unreported to Law Enforcement. PMID- 30419103 TI - Effect of a Program Combining Transitional Care and Long-term Self-management Support on Outcomes of Hospitalized Patients With Chronic Obstructive Pulmonary Disease: A Randomized Clinical Trial. AB - Importance: Patients hospitalized for chronic obstructive pulmonary disease (COPD) exacerbations have high rehospitalization rates and reduced quality of life. Objective: To evaluate a hospital-initiated program that combined transition and long-term self-management support for patients hospitalized due to COPD and their family caregivers. Design, Setting, and Participants: This single site randomized clinical trial was conducted in Baltimore, Maryland, with 240 participants. Participants were patients hospitalized due to COPD, randomized to intervention or usual care, and followed up for 6 months after hospital discharge. Enrollment occurred from March 2015 to May 2016; follow-up ended in December 2016. Interventions: The intervention (n = 120) was a comprehensive 3 month program to help patients and their family caregivers with long-term self management of COPD. It was delivered by COPD nurses (nurses with special training on supporting patients with COPD using standardized tools). Usual care (n = 120) included transition support for 30 days after discharge to ensure adherence to discharge plan and connection to outpatient care. Main Outcomes and Measures: The primary outcome was number of COPD-related acute care events (hospitalizations and emergency department visits) per participant at 6 months. The co-primary outcome was change in participants' health-related quality of life measured by the St George's Respiratory Questionnaire (SGRQ) at 6 months after discharge (score, 0 [best] to 100 [worst]; 4-point difference is clinically meaningful). Results: Among 240 patients who were randomized (mean [SD] age, 64.9 [9.8] years; females, 61.7%), 203 (85%) completed the study. The mean (SD) baseline SGRQ score was 63.1 (19.9) in the intervention group and 62.6 (19.3) in the usual care group. The mean number of COPD-related acute care events per participant at 6 months was 0.72 (95% CI, 0.45-0.97) in the intervention group vs 1.40 (95% CI, 1.01-1.79) in the usual care group (difference, 0.68 [95% CI, 0.22 to 1.15]; P = .004). The mean change in participants' SGRQ total score at 6 months was -1.53 in the intervention and +5.44 in the usual care group (adjusted difference, -6.69 [95% CI, -12.97 to -0.40]; P = .04). During the study period, there were 15 deaths (intervention: 7; usual care: 8) and 337 hospitalizations (intervention: 135; usual care: 202). Conclusions and Relevance: In a single-site randomized clinical trial of patients hospitalized due to COPD, a 3-month program that combined transition and long-term self-management support resulted in significantly fewer COPD-related hospitalizations and emergency department visits and better health-related quality of life at 6 months after discharge. Further research is needed to evaluate this intervention in other settings. Trial Registration: ClinicalTrials.gov Identifier: NCT02036294. PMID- 30419105 TI - Is Precision Medicine an Oxymoron? PMID- 30419104 TI - Risk of Malignant Ovarian Cancer Based on Ultrasonography Findings in a Large Unselected Population. AB - Importance: The risk of malignant ovarian cancer associated with simple cysts is unknown. Objective: To quantify the risk of ovarian cancer based on ultrasonographic characteristics of ovarian masses, including simple cysts, in a large unselected population. Design, Setting, and Participants: This was a nested case-control study of patients enrolled in Kaiser Permanente Washington, a large integrated health care system in Washington State. Participants were 72 093 women who underwent pelvic ultrasonography between January 1, 1997, and December 31, 2008. Analysis was completed in April 2017. Exposures: Ultrasonographic characteristics of ovarian masses measured in 1043 women, and also, using weights derived from the sampling strategy, estimated frequencies for the entire cohort. Main Outcomes and Measures: Malignant ovarian cancer, identified through December 31, 2011, by cancer registry linkage. Results: Among 210 women who were diagnosed as having ovarian cancer, 49 were younger than 50 years, and 161 were 50 years or older. Ultrasonography findings were predictive of cancer (C statistic, 0.89). The risk of cancer was significantly elevated in women with complex cysts or solid masses, with likelihood ratios relative to women with normal ovaries ranging from 8 to 74 and the 3-year risk of cancer ranging from 9 to 430 cases per 1000 women based on patient age and ultrasonography findings. In contrast, the 23.8% of women younger than 50 years and the 13.4% of women 50 years or older with simple cysts were not at a significantly increased risk of ovarian cancer compared with women with normal ovaries. Likelihood ratios associated with the detection of a simple cyst were 0.00 in women younger than 50 years (no cancers were identified) and 0.10 (95% CI, 0.01-0.48) in women 50 years or older, and the absolute 3-year risk of cancer ranged from 0 to 0.5 cases per 1000 women. Conclusions and Relevance: According to this study, the ultrasonographic appearance of ovarian masses is strongly associated with a woman's risk of ovarian cancer. Simple cysts are not associated with an increased risk of ovarian cancer, whereas complex cysts or solid masses are associated with a significantly increased risk of ovarian cancer. PMID- 30419106 TI - Palliative Care. PMID- 30419107 TI - On the Link Between Concussions and Suicide. PMID- 30419108 TI - Effectiveness of the Tacrolimus Swish-and-Spit Treatment Regimen in Patients With Geographic Tongue. PMID- 30419109 TI - Role Models, Allies, and Diversity-Global Issues for Female Cardiology Trainees. PMID- 30419110 TI - Staging Systems to Predict Metastatic Cutaneous Squamous Cell Carcinoma: Unsatisfactory for Clinical Use, but Some Less So? PMID- 30419112 TI - Evaluating an Asymptomatic Adnexal Cyst Found on Pelvic Ultrasonography. PMID- 30419111 TI - Notice of Retraction and Replacement: Roscher et al. Validating 4 Staging Systems for Cutaneous Squamous Cell Carcinoma Using Population-Based Data: A Nested Case Control Study. JAMA Dermatol. 2018;154(4):428-434. PMID- 30419113 TI - Influence of Cardiovascular Risk Communication Tools and Presentation Formats on Patient Perceptions and Preferences. AB - Importance: Practice guidelines recommend that clinicians engage patients in treatment decisions and explain atherosclerotic cardiovascular disease (ASCVD) risk but do not describe how to communicate this risk most effectively. Objective: To determine how the ASCVD risk time horizon, outcome, and presentation format influence risk perceptions and treatment preferences. Design, Setting, and Participants: From May 27, 2015, through November 12, 2015, participants from the Patient and Provider Assessment of Lipid Management Registry at 140 US cardiology, primary care, and endocrinology practices were presented 3 independent scenarios (representing the same hypothetical patient) and asked to rate their perceived risk and willingness to take medication to lower risk in light of (1) a 15% 10-year ASCVD event risk, (2) a 4% 10-year cardiovascular disease (CVD) death risk, and (3) a 50% lifetime ASCVD event risk. Exposures: Participants were randomized to receive risk estimates using numbers only, a bar graph, or a face pictogram. Results: Of 3566 eligible participants, 2708 (76.9%) responded (median age, 67 years [interquartile range, 61-76 years]; 280 [10.3%] African American; 1491 men [55.1%]). When shown the lifetime ASCVD risk, respondents were more likely to consider the risk "high to very high" than when presented the 10-year ASCVD risk or the CVD death risk (70.1% vs 31.4% vs 25.7%, respectively; both P < .001). Treatment willingness was also the highest for lifetime ASCVD risk (77.9% very willing) followed by 10-year ASCVD risk (68.1%) and 10-year CVD death risk (63.1%; both P < .001). Compared with participants who were shown a bar graph or no graphic, those who were shown the risk information with a pictogram had the lowest perception of disease severity and the lowest willingness to consider therapy. These findings were robust across demographic and socioeconomic subgroups. Conclusions and Relevance: The format, time horizon, and outcome used for risk estimation influence patient perceptions and should be considered when designing risk communication tools. When shown lifetime risk estimates, patients had higher risk perception and willingness for therapy than when shown 10-year estimates. Pictogram risk displays may decrease risk perception and consideration for treatment. PMID- 30419114 TI - Antibiotic Treatment of Nonsevere Pneumonia With Fast Breathing-Is the Pendulum Swinging? PMID- 30419115 TI - Association of Age-Related Hearing Loss With Multiple Adverse Health Outcomes. PMID- 30419116 TI - Video Assessment of the Frequency and Evaluations of Head Collision Events During the 2018 World Cup Tournament. PMID- 30419117 TI - Incomplete Data in Cutaneous Squamous Cell Carcinoma Staging System Analysis Reply. PMID- 30419118 TI - Epigenetic Hallmarks of Fetal Early Atherosclerotic Lesions in Humans. AB - Importance: Although increasingly strong evidence suggests a role of maternal total cholesterol and low-density lipoprotein cholesterol (LDLC) levels during pregnancy as a risk factor for atherosclerotic disease in the offspring, the underlying mechanisms need to be clarified for future clinical applications. Objective: To test whether epigenetic signatures characterize early fetal atherogenesis associated with maternal hypercholesterolemia and to provide a quantitative estimate of the contribution of maternal cholesterol level to fetal lesion size. Design, Setting, and Participants: This autopsy study analyzed 78 human fetal aorta autopsy samples from the Division of Human Pathology, Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy. Maternal levels of total cholesterol, LDLC, high-density lipoprotein cholesterol (HDLC), triglycerides, and glucose and body mass index (BMI) were determined during hospitalization owing to spontaneous fetal death. Data were collected and immediately processed and analyzed to prevent degradation from January 1, 2011, through November 30, 2016. Main Outcomes and Measurements: Results of DNA methylation and messenger RNA levels of the following genes involved in cholesterol metabolism were assessed: superoxide dismutase 2 (SOD2), low-density lipoprotein receptor (LDLR), sterol regulatory element binding protein 2 (SREBP2), liver X receptor alpha (LXRalpha), and adenosine triphosphate binding cassette transporter 1 (ABCA1). Results: Among the 78 fetal samples included in the analysis (59% male; mean [SD] fetal age, 25 [3] weeks), maternal cholesterol level explained a significant proportion of the fetal aortic lesion variance in multivariate analysis (61%; P = .001) independently by the effect of levels of HDLC, triglycerides, and glucose and BMI. Moreover, maternal total cholesterol and LDLC levels were positively associated with methylation of SREBP2 in fetal aortas (Pearson correlation, 0.488 and 0.503, respectively), whereas in univariate analysis, they were inversely correlated with SREBP2 messenger RNA levels in fetal aortas (Pearson correlation, -0.534 and -0.671, respectively). Epivariations of genes controlling cholesterol metabolism in cholesterol-treated human aortic endothelial cells were also observed. Conclusions and Relevance: The present study provides a stringent quantitative estimate of the magnitude of the association of maternal cholesterol levels during pregnancy with fetal aortic lesions and reveals the epigenetic response of fetal aortic SREBP2 to maternal cholesterol level. The role of maternal cholesterol level during pregnancy and epigenetic signature in offspring in cardiovascular primary prevention warrants further long-term causal relationship studies. PMID- 30419119 TI - Preventing Late-Life Depression Through Task Sharing: Scope of Translating Evidence to Practice in Resource-Scarce Settings. PMID- 30419120 TI - Placebo vs Amoxicillin for Nonsevere Fast-Breathing Pneumonia in Malawian Children Aged 2 to 59 Months: A Double-blind, Randomized Clinical Noninferiority Trial. AB - Importance: Pneumonia is the leading infectious killer of children. Rigorous evidence supporting antibiotic treatment of children with nonsevere fast breathing pneumonia in low-resource African settings is lacking. Objective: To assess whether treatment with placebo for nonsevere fast-breathing pneumonia is substantively less effective than 3 days of treatment with amoxicillin. Design, Setting, and Participants: This double-blind, 2-arm, randomized clinical noninferiority trial with follow-up of 14 days screened 1343 HIV-uninfected children aged 2 to 59 months with nonsevere fast-breathing pneumonia at outpatient departments of hospitals in Lilongwe, Malawi, Africa, between June 2016 and June 2017. Interventions: Placebo or amoxicillin dispersible tablets administered twice daily for 3 days. Main Outcomes and Measures: The primary end point was the proportion of children failing treatment by day 4 with a relative noninferiority margin of 1.5 times the failure rate in the amoxicillin group. Primary analyses were performed based on the intention-to-treat principle. Planned secondary analyses included treatment failure or relapse by day 14. Results: In total, 1126 children were randomized to 3 days of amoxicillin (n = 564) or placebo (n = 562) therapy. Baseline demographic and clinical characteristics were similar between the groups. For the entire study population, the mean (SD) age was 21.3 (15.1) months, and 601 (53.4%) were female. After an interim analysis, the data safety monitoring board stopped the study because children receiving amoxicillin had a 4.0% (22 of 552 with outcome data) treatment failure rate by day 4, whereas children receiving placebo had a 7.0% (38 of 543) treatment failure rate (adjusted relative risk, 1.78; 95% CI, 1.07%-2.97%; adjusted absolute difference, 3.0%; 95% CI, 0.4%-5.7%). Among children with known day 14 outcomes, 56 of 552 (10.1%) receiving amoxicillin and 64 of 543 (11.8%) receiving placebo had either treatment failure by day 4 or relapse by day 14 (relative risk, 1.16; 95% CI, 0.83%-1.63%; absolute difference, 1.6%; 95% CI, 2.1% to 5.4%). There were no deaths. Conclusions and Relevance: In HIV-uninfected children aged 2 to 59 months in a malaria-endemic region of Malawi, placebo treatment of nonsevere fast-breathing pneumonia was significantly inferior to treatment with amoxicillin. However, by day 4, approximately 93% of children receiving placebo were without treatment failure, and there was no significant difference between groups in treatment failure or relapse by day 14. The number of children with nonsevere fast-breathing pneumonia that needed amoxicillin treatment for 1 child to benefit was 33. Trial Registration: ClinicalTrials.gov Identifier: NCT02760420. PMID- 30419121 TI - Disseminated Vegetating Plaques and Pustules. PMID- 30419122 TI - Epidemiologic, Imaging, Audiologic, Clinical, Surgical, and Prognostic Issues in Common Cavity Deformity: A Narrative Review. AB - Importance: Common cavity deformity is a rare congenital inner ear malformation associated with profound hearing loss and attributed to an early developmental arrest of the cochlear-vestibular structures. This narrative review highlights the need to identify reliable indicators of hearing rehabilitation outcome. Observations: Despite its relatively simple definition, common cavity deformity varies widely in morphologic features, presence of cochlear nerve fibers and remnants of Corti organ, and outcome after cochlear or brainstem implant. Conclusions and Relevance: Cochlear implant has been shown to be a valid option for common cavity deformity, but its outcome remains variable and poor. Identification of specific neuroradiologic, audiologic, and neurophysiologic prognostic features; tailoring of the surgical approach; and standardization of outcome measures are needed to optimize the management of common cavity deformity and hearing rehabilitation after implant. PMID- 30419124 TI - Role Models, Allies, and Diversity-Global Issues for Female Cardiology Trainees Reply. PMID- 30419123 TI - Cutaneous Sensitization to Peanut in Children With Atopic Dermatitis: A Window to Prevention of Peanut Allergy. PMID- 30419125 TI - Effect of Platelet-Rich Plasma Injection for Rejuvenation of Photoaged Facial Skin: A Randomized Clinical Trial. AB - Importance: There remains little experimental evidence and no randomized clinical trial to date to confirm the benefit of platelet-rich plasma (PRP) for facial rejuvenation. Objective: To investigate whether PRP injection improves the visual appearance, including texture and color, of photodamaged facial skin. Design, Setting, and Participants: In this randomized clinical trial, participants and raters were masked to groupings. The setting was an academic-based, urban outpatient dermatology practice in Chicago, Illinois. Participants were adults aged 18 to 70 years with bilateral cheek rhytids of Glogau class II or greater. The duration of the study was August 21, 2012, to February 16, 2016. Interventions: Each participant received 3 mL intradermal injections of PRP to one cheek and sterile normal saline to the contralateral cheek. Main Outcomes and Measures: Primary outcomes were photoaging scores (with subscores for fine lines, mottled pigmentation, roughness, and sallowness) as rated by 2 masked dermatologists. Secondary outcomes included participant self-assessment scores of improvement on a 5-point scale (worsening, no change, mild improvement, moderate improvement, or significant improvement), participant overall satisfaction scores on a 4-point scale (not satisfied, slightly satisfied, moderately satisfied, or very satisfied), and participant-reported or investigator-observed adverse events. Results: Of 27 enrolled participants, 19 (mean [SD] age, 46.37 [10.88] years; 17 female) were analyzed. Reported adverse events, which were not associated with the study agent, included redness (n = 18), swelling (n = 16), bruising (n = 14), pruritus (n = 1), skin scaling (n = 1), and dryness of skin (n = 1). No participants reported any adverse events at 12 months. Mean (SD) photoaging scores rated by 2 dermatologists showed no significant difference between PRP and normal saline for fine lines (baseline, 1.00 [0.75] vs 1.05 [0.78]; 2 weeks, 0.95 [0.71] vs 0.95 [0.71]; 3 months, 0.95 [0.71] vs 0.95 [0.71]; 6 months, 0.95 [0.71] vs 0.95 [0.71]), mottled pigmentation (baseline, 1.21 [0.53] vs 1.21 [0.54]; 2 weeks, 1.16 [0.60] vs 1.16 [0.60]; 3 months, 1.00 [0.47] vs 1.11 [0.46]; 6 months, 1.16 [0.69] vs 1.16 [0.69]), skin roughness (baseline, 0.47 [0.61] vs 0.47 [0.61]; 2 weeks, 0.47 [0.61] vs 0.47 [0.61]; 3 months, 0.47 [0.61] vs 0.47 [0.61]; 6 months, 0.37 [0.60] vs 0.37 [0.68]), and skin sallowness (baseline, 1.11 [0.88] vs 1.11 [0.88]; 2 weeks, 0.95 [0.85] vs 0.95 [0.85]; 3 months, 0.58 [0.61] vs 0.58 [0.61]; 6 months, 0.37 [0.68] vs 0.37 [0.68]). At 6 months after a single treatment, participants rated the PRP-treated side as significantly more improved compared with normal saline for texture (mean [SD] self-assessment score, 2.00 [1.20] vs 1.21 [0.54]; P = .02) and wrinkles (mean [SD] self-assessment score, 1.74 [0.99] vs 1.21 [0.54]; P = .03). Conclusions and Relevance: Masked participants noted that both fine and coarse texture improved significantly more with a single treatment of PRP than with normal saline. Both participants and raters found PRP to be nominally but not significantly superior to normal saline. Trial Registration: ClinicalTrials.gov Identifier: NCT01372566. PMID- 30419126 TI - Errors in Statistical Test Results, Figure 2, and eFigure 3. PMID- 30419127 TI - Incomplete Data in Cutaneous Squamous Cell Carcinoma Staging System Analysis. PMID- 30419128 TI - Association of Long-term Ambient Black Carbon Exposure and Oxidative Stress Allelic Variants With Intraocular Pressure in Older Men. AB - Importance: Elevated intraocular pressure is a major risk factor for glaucoma, a leading cause of irreversible blindness worldwide. Environmental air pollution has been suggested as a potential contributor to elevated intraocular pressure; however, no studies have demonstrated such an association to date. Objective: To investigate the association of long-term ambient black carbon exposure with intraocular pressure in community-dwelling older adults. Design, Setting, and Participants: This population-based analysis, conducted from October 18, 2017, through March 22, 2018, used data from the all-male, New England-based Normative Aging Study of the US Department of Veterans Affairs. The analysis included 419 older men with a total of 911 follow-up study visits between January 1, 2000, and December 30, 2011. Intraocular pressure was measured by Goldmann applanation tonometry during the study visits. Validated spatiotemporal models were used to generate 1-year black carbon exposure levels at the addresses of the participants. Main Outcomes and Measures: An independently developed genetic score approach was used to calculate allelic risk scores for 3 pathways associated with black carbon toxicity: endothelial function, oxidative stress, and metal processing. The associations among black carbon exposure, allelic risk scores, and intraocular pressure were explored using linear mixed-effects models. Results: All 419 participants were men with a mean (SD) age of 75.3 (6.9) years. The mean (SD) 1-year black carbon exposure was 0.51 (0.18) MUg/m3, and the mean (SD) intraocular pressure for the left eye was 14.1 (2.8) mm Hg and for the right eye was 14.1 (3.0) mm Hg. Of the 911 visits, 520 (57.1%) had a high endothelial function allelic risk score, 644 (70.7%) had a high metal-processing allelic risk score, and 623 (68.4%) had a high oxidative stress allelic risk score. In fully adjusted linear mixed-effects models, the association of black carbon with intraocular pressure was greater in individuals with a high oxidative stress allelic score (beta = 0.36; 95% CI, 0.003-0.73) compared with individuals with a low score (beta = -0.35; 95% CI, -0.86 to 0.15). Conclusions and Relevance: Ambient black carbon exposure may be a risk factor for increased intraocular pressure in individuals susceptible to other biological oxidative stressors. If additional studies confirm these results, monitoring ambient black carbon exposure and physiological oxidative stress may prevent the development and progression of intraocular pressure-related disease. PMID- 30419130 TI - A Novel Exercise Intervention and Functional Status in Very Elderly Patients During Acute Hospitalization. PMID- 30419129 TI - Performance of a Multigene Genomic Classifier in Thyroid Nodules With Indeterminate Cytology: A Prospective Blinded Multicenter Study. AB - Importance: Approximately 20% of fine-needle aspirations (FNA) of thyroid nodules have indeterminate cytology, most frequently Bethesda category III or IV. Diagnostic surgeries can be avoided for these patients if the nodules are reliably diagnosed as benign without surgery. Objective: To determine the diagnostic accuracy of a multigene classifier (GC) test (ThyroSeq v3) for cytologically indeterminate thyroid nodules. Design, Setting, and Participants: Prospective, blinded cohort study conducted at 10 medical centers, with 782 patients with 1013 nodules enrolled. Eligibility criteria were met in 256 patients with 286 nodules; central pathology review was performed on 274 nodules. Interventions: A total of 286 FNA samples from thyroid nodules underwent molecular analysis using the multigene GC (ThyroSeq v3). Main Outcomes and Measures: The primary outcome was diagnostic accuracy of the test for thyroid nodules with Bethesda III and IV cytology. The secondary outcome was prediction of cancer by specific genetic alterations in Bethesda III to V nodules. Results: Of the 286 cytologically indeterminate nodules, 206 (72%) were benign, 69 (24%) malignant, and 11 (4%) noninvasive follicular thyroid neoplasms with papillary like nuclei (NIFTP). A total of 257 (90%) nodules (154 Bethesda III, 93 Bethesda IV, and 10 Bethesda V) had informative GC analysis, with 61% classified as negative and 39% as positive. In Bethesda III and IV nodules combined, the test demonstrated a 94% (95% CI, 86%-98%) sensitivity and 82% (95% CI, 75%-87%) specificity. With a cancer/NIFTP prevalence of 28%, the negative predictive value (NPV) was 97% (95% CI, 93%-99%) and the positive predictive value (PPV) was 66% (95% CI, 56%-75%). The observed 3% false-negative rate was similar to that of benign cytology, and the missed cancers were all low-risk tumors. Among nodules testing positive, specific groups of genetic alterations had cancer probabilities varying from 59% to 100%. Conclusions and Relevance: In this prospective, blinded, multicenter study, the multigene GC test demonstrated a high sensitivity/NPV and reasonably high specificity/PPV, which may obviate diagnostic surgery in up to 61% of patients with Bethesda III to IV indeterminate nodules, and up to 82% of all benign nodules with indeterminate cytology. Information on specific genetic alterations obtained from FNA may help inform individualized treatment of patients with a positive test result. PMID- 30419131 TI - Trends in Health Care Costs and Utilization Associated With Untreated Hearing Loss Over 10 Years. AB - Importance: Nearly 38 million individuals in the United States have untreated hearing loss, which is associated with cognitive and functional decline. National initiatives to address hearing loss are currently under way. Objective: To determine whether untreated hearing loss is associated with increased health care cost and utilization on the basis of data from a claims database. Design, Setting, Participants: Retrospective, propensity-matched cohort study of persons with and without untreated hearing loss based on claims for health services rendered between January 1, 1999, and December 31, 2016, from a large health insurance database. There were 154 414, 44 852, and 4728 participants at the 2-, 5-, and 10-year follow-up periods, respectively. The study was conceptualized and data were analyzed between September 2016 and November 2017. Exposures: Untreated hearing loss (ie, hearing loss that has not been treated with hearing devices) was identified via claims measures. Main Outcomes and Measures: Medical costs, inpatient hospitalizations, total days hospitalized, 30-day hospital readmission, emergency department visits, and days with at least 1 outpatient visit. Results: Among 4728 matched adults (mean age at baseline, 61 years; 2280 women and 2448 men), untreated hearing loss was associated with $22 434 (95% CI, $18 219-$26 648) or 46% higher total health care costs over a 10-year period compared with costs for those without hearing loss. Persons with untreated hearing loss experienced more inpatient stays (incidence rate ratio, 1.47; 95% CI, 1.29-1.68) and were at greater risk for 30-day hospital readmission (relative risk, 1.44; 95% CI, 1.14-1.81) at 10 years postindex. Similar trends were observed at 2- and 5-year time points across measures. Conclusions and Relevance: Older adults with untreated hearing loss experience higher health care costs and utilization patterns compared with adults without hearing loss. To further define this association, additional research on mediators, such as treatment adherence, and mitigation strategies is needed. PMID- 30419132 TI - A More Balanced Approach to Dietary Supplement Data. PMID- 30419133 TI - Analysis of Clinical Features of Mammary Analog Secretory Carcinoma Using the Surveillance, Epidemiology, and End Results Database. PMID- 30419134 TI - Incident Hearing Loss and Comorbidity: A Longitudinal Administrative Claims Study. AB - Importance: Because hearing loss is highly prevalent and treatable, determining its association with morbidity has major public health implications for disease prevention and the maintenance of health in adults with hearing loss. Objective: To investigate the association between the diagnosis of incident hearing loss and medical comorbidities in adults 50 years or older. Design, Setting, and Participants: Retrospective, propensity-matched cohort study using administrative claims data from commercially insured and Medicare Advantage members in a geographically diverse US health plan. Adults 50 years or older with claims for services rendered from January 1, 2000, to December 31, 2016, were observed for 2 (n = 154 414), 5 (n = 44 852), and 10 (n = 4728) years. This research was conceptualized and data were analyzed between September 2016 and November 2017. Exposures: A claim for incident hearing loss is defined as 2 claims for hearing loss within 2 consecutive years without evidence of hearing device use, excluding claims for sudden hearing loss or hearing loss secondary to medical conditions. Main Outcomes and Measures: Incident claims for dementia, depression, accidental falls, nonvertebral fractures, acute myocardial infarction, and stroke. Results: After cohort matching, 48% of participants were women (n = 74 464), 61% were white (n = 93 442), and 31% (n = 48 056) were Medicare Advantage insured, with a mean (SD) age of 64 (10) years. In a multivariate-adjusted modified Poisson regression with robust standard errors, relative associations were strongest for dementia (relative risk at 5 years, 1.50; 95% CI, 1.38-1.64) and depression (relative risk at 5 years, 1.41; 95% CI, 1.26-1.58). The absolute risk of all outcomes was greater in persons with hearing loss than in those without hearing loss at all times, with the greatest risk difference observed at 10 years for all outcomes. The 10-year risk attributable to hearing loss was 3.20 per 100 persons (95% CI, 1.76-4.63) for dementia, 3.57 per 100 persons (95% CI, 1.67-5.47) for falls, and 6.88 per 100 persons (95% CI, 4.62-9.14) for depression. Conclusions and Relevance: In this large observational study using administrative claims data, incident untreated hearing loss was associated with greater incident morbidity than no hearing loss across a range of health conditions. Future studies are needed to elucidate the mechanisms underlying these associations and to determine if treatment for hearing loss could reduce the risk of comorbidity. PMID- 30419135 TI - A Wide Complex Tachycardia in a Woman During Exercise: Did She Tread Into Dangerous Territory? PMID- 30419137 TI - Trends in Opioid Prescription in Children and Adolescents in a Commercially Insured Population in the United States, 2004-2017. PMID- 30419136 TI - A More Balanced Approach to Dietary Supplement Data-Reply. PMID- 30419139 TI - The Invisible Costs of Hearing Loss. PMID- 30419140 TI - Oncology in Transition: Changes, Challenges, and Opportunities. PMID- 30419141 TI - Participant Protection in Phase 1 Pediatric Cancer Trials. PMID- 30419138 TI - Association of Nurse Workload With Missed Nursing Care in the Neonatal Intensive Care Unit. AB - Importance: Quality improvement initiatives demonstrate the contribution of reliable nursing care to gains in clinical and safety outcomes in neonatal intensive care units (NICUs); when core care is missed, outcomes can worsen. Objective: To evaluate the association of NICU nurse workload with missed nursing care. Design, Setting, and Participants: A prospective design was used to evaluate associations between shift-level workload of individual nurses and missed care for assigned infants from March 1, 2013, through January 31, 2014, at a 52-bed level IV NICU in a Midwestern academic medical center. A convenience sample of registered nurses who provided direct patient care and completed unit orientation were enrolled. Nurses reported care during each shift for individual infants whose clinical data were extracted from the electronic health record. Data were analyzed from January 1, 2015, through August 13, 2018. Exposures: Workload was assessed each shift with objective measures (infant-to-nurse staffing ratio and infant acuity scores) and a subjective measure (the National Aeronautics and Space Administration Task Load Index [NASA-TLX]). Main Outcomes and Measures: Missed nursing care was measured by self-report of omission of 11 essential care practices. Cross-classified, multilevel logistic regression models were used to estimate associations of workload with missed care. Results: A total of 136 nurses provided reports of shift-level workload and missed nursing care for 418 infants during 332 shifts of 12 hours each. When workload variables were modeled independently, 7 of 12 models demonstrated a significant worsening association of increased infant-to-nurse ratio with odds of missed care (eg, nurses caring for >=3 infants were 2.51 times more likely to report missing any care during the shift [95% credible interval, 1.81-3.47]), and all 12 models demonstrated a significant worsening association of increased NASA-TLX subjective workload ratings with odds of missed care (eg, each 5-point increase in a nurse's NASA-TLX rating during a shift was associated with a 34% increase in the likelihood of missing a nursing assessment for his or her assigned infant[s] during the same shift [95% credible interval, 1.30-1.39]). When modeling all workload variables jointly, only 4 of 12 models demonstrated significant association of staffing ratios with odds of missed care, whereas the association with NASA-TLX ratings remained significant in all models. Few associations of acuity scores were observed across modeling strategies. Conclusions and Relevance: The workload of NICU nurses is significantly associated with missed nursing care, and subjective workload ratings are particularly important. Subjective workload represents an important aspect of nurse workload that remains largely unmeasured despite high potential for intervention. PMID- 30419142 TI - Characterization of mitochondrial proteomes of nonbilaterian animals. AB - Mitochondria require ~1,500 proteins for their maintenance and proper functionality, which constitute the mitochondrial proteome (mt-proteome). Although a few of these proteins, mostly subunits of the electron transport chain complexes, are encoded in mitochondrial DNA (mtDNA), the vast majority are encoded in the nuclear genome and imported to the organelle. Previous studies have shown a continuous and complex evolution of mt-proteome among eukaryotes. However, there was less attention paid to mt-proteome evolution within Metazoa, presumably because animal mtDNA and, by extension, animal mitochondria are often considered to be uniform. In this analysis, two bioinformatic approaches (Orthologue-detection and Mitochondrial Targeting Sequence prediction) were used to identify mt-proteins in 23 species from four nonbilaterian phyla: Cnidaria, Ctenophora, Placozoa, and Porifera, as well as two choanoflagellates, the closest animal relatives. Our results revealed a large variation in mt-proteome in nonbilaterian animals in size and composition. Myxozoans, highly reduced cnidarian parasites, possessed the smallest inferred mitochondrial proteomes, while calcareous sponges possessed the largest. About 513 mitochondrial orthologous groups were present in all nonbilaterian phyla and human. Interestingly, 42 human mitochondrial proteins were not identified in any nonbilaterian species studied and represent putative innovations along the bilaterian branch. Several of these proteins were involved in apoptosis and innate immunity, two processes known to evolve within Metazoa. Conversely, several proteins identified as mitochondrial in nonbilaterian phyla and animal outgroups were absent in human, representing cases of possible loss. Finally, a few human cytosolic proteins, such as histones and cytosolic ribosomal proteins, were predicted to be targeted to mitochondria in nonbilaterian animals. Overall, our analysis provides the first step in characterization of mt-proteomes in nonbilaterian animals and understanding evolution of animal mt-proteome. (c) 2018 IUBMB Life, 70(12):1289-1301, 2018. PMID- 30419143 TI - Absorption and distribution of lupeol in CD-1 mice evaluated by UPLC-APCI+ MS/MS. AB - Lupeol is a dietary triterpene that shows limited water solubility, which affects its bioavailability. It is well known that poor oral bioavailability is one of the major causes of therapeutic variability. Lupeol has been reported to have multiple biological activities; however, there are no reports about its bioavailability. Therefore, the objective of this research was to evaluate the systemic bioavailability of lupeol. An experimental strategy with three groups of female CD-1 strain mice was proposed (control, olive oil and lupeol in olive oil), at six experimental times (0.5, 2, 4, 8, 12 and 24 h) with four animals per experimental point. Mice were sacrificed for organs, urine, feces and blood collection. Lupeol was extracted from samples and analyzed by UPLC-APCI+ -MS/MS, obtaining the pharmacokinetics parameters time to peak concentration 6.444 +/- 0.851 h and peak concentration 8.071 +/- 2.930 MUg/mL. Study of direct digestion and absorption in various organs showed important concentrations of lupeol at earlier post-administration times (stomach, 137.25 +/- 19.94 ng/mg and small intestine, 99.00 +/- 12.99 ng/mg). The main excretion route was fecal, with a peak at 12 h post-administration (163.28 +/- 9.83 MUg/mg). Absorption of lupeol by the animals was better than expected despite its nonpolar nature (extent of absorption F = 0.645 +/- 0.0581). PMID- 30419144 TI - Design principles for cationic, astrocyte-targeted probes. AB - The brain's astrocytes play key roles in normal and pathological brain processes. Targeting small molecules to astrocytes in the presence of the many other cell types in the brain will provide useful tools for their visualization and manipulation. Here, we explore the functional consequences of synthetic modifications to a recently described astrocyte marker composed of a bright rhodamine-based fluorophore and an astrocyte targeting moiety. We altered the nature of the targeting moiety to probe the dependence of astrocyte targeting on hydrophobicity, charge, and pKa when exposed to astrocytes and neurons isolated from the mouse cortex. We found that an overall molecular charge of +2 and a targeting moiety with a heterocyclic aromatic amine are important requirements for specific and robust astrocyte labeling. These results provide a basis for engineering astrocyte-targeted molecular tools with unique properties, including metabolite sensing or optogenetic control. PMID- 30419145 TI - Diel Activity and Effect of Carcass Decomposition on the Attractiveness to the Forensically Important Species Oxelytrum Discicolle (Coleoptera: Silphidae)?. AB - Oxelytrum discicolle is a carrion beetle commonly found in the Neotropical region, mainly associated with cadavers and carcasses. Information on behavior related to the likelihood of cadaver colonization is scarce. We performed two field experiments in peri-urban forest in Brazil in order to strengthen our knowledge on O. discicolle behavior. In the first experiment, we assessed the preference for piglet carcasses at different stages of decomposition offered simultaneously in two seasons, dry and rainy, while in the second experiment we investigated the diel activity of adults. A total of 493 adults were collected in the experiments. A significantly higher abundance was detected in the rainy season. There was a marked preference for carcasses at advanced stages. Adults exhibited a typical nocturnal behavior, the number trapped at night was 17 times greater than those collected during the day. Oxelytrum discicolle is nocturnal species that prefers carcasses in advanced stage of decomposition. PMID- 30419146 TI - Heart valve tissue-derived hydrogels: Preparation and characterization of mitral valve chordae, aortic valve, and mitral valve gels. AB - Heart valve (HV) diseases are among the leading causes of death and continue to threaten public health worldwide. The current clinical options for HV replacement include mechanical and biological prostheses. However, an ongoing problem with current HV prostheses is their failure to integrate with the host tissue and their inability grow and remodel within the body. Tissue engineered heart valves (TEHVs) are a promising solution to these problems, as they are able to grow and remodel somatically with the rest of the body. Recently, decellularized HVs have demonstrated great potential as valve replacements because they are tissue specific, but recellularization is still a challenge due to the dense HV extracellular matrix (ECM) network. In this proof-of-concept work, we decellularized porcine mitral valve chordae, aortic valve leaflets, and mitral valve leaflets and processed them into injectable hydrogels that could accommodate any geometry. While the three valvular ECMs contained various amounts of collagen, they displayed similar glycosaminoglycan contents. The hydrogels had similar nanofibrous structures and gelation kinetics with various compressive strengths. When encapsulated with NIH 3 T3 fibroblasts, all the hydrogels supported cell survivals up to 7 days. Decellularized HV ECM hydrogels may show promising potential HV tissue engineering applications. (c) 2018 Wiley Periodicals, Inc. J. Biomed. Mater. Res. Part B: 1-9, 2018. PMID- 30419147 TI - MicroRNA-98 attenuates cardiac ischemia-reperfusion injury through inhibiting DAPK1 expression. AB - Cardiovascular ischemic disease is a large class of diseases that are harmful to human health. The significant role of microRNAs (miRNAs) in terms of controlling cardiac injury has been reported in latest studies. MiR-98 is very important in regulating the apoptosis, the differentiation, the growth as well as the metastasis of cells. Nevertheless, the effect of miR-98 in the cardiac ischemia reperfusion (I/R) injury has rarely been investigated. In the current research, we found that the miR-98 expression was down-regulated in the cardiomyocytes subjected to hypoxia/reoxygenation (H/R) and in the myocardium of the I/R rats. In addition, over-expression of miR-98 could significantly reduce the myocardial oxidative stress and ischemic injury as well as cell apoptosis. In agreement, similar findings were demonstrated in H9c2 cells subjected to H/R injury. Bioinformatic analysis using MiRanda and TargetScan and luciferase activity assay confirmed death-associated protein kinase 1 (DAPK1) as a direct target of miR-98. These findings suggest that miR-98 may be exploited as a novel molecular marker or therapeutic target for myocardial I/R injury. (c) 2018 IUBMB Life, 1-11, 2018. PMID- 30419148 TI - A Multi-Doped Electrocatalyst for Efficient Hydrazine Oxidation. AB - We report an efficient electrocatalyst for the oxidation of hydrazine, a promising fuel for fuel cells and an important analyte for health and environmental monitoring. To design this material, we emulated natural nitrogen cycle enzymes, focusing on designing a cooperative, multi-doped active site. The catalytic oxidation occurs on Fe2 MoC nanoparticles and on edge-positioned nitrogen dopants, all well-dispersed on a hierarchically porous, graphitic carbon matrix that provides active site exposure to mass-transfer and charge flow. The new catalyst is the first carbide with HzOR activity. It operates at the most negative onset potentials reported for carbon-based HzOR catalysts at pH 14 (0.28 V vs. RHE), and has good-to-excellent activity at pH values down to 0. It shows high faradaic efficiency for oxidation to N2 (3.6 e- /N2 H4 ), and is perfectly stable for at least 2000 cycles. PMID- 30419149 TI - Application of Physical Gas Absorbers in Manipulating the CO2 Pressure of Kimchi Package. AB - Physical gas absorption and release of activated carbon or zeolite were used to attain the desired CO2 concentration profile inside a package of kimchi for its dynamic storage and consumption environment. The CO2 adsorption/desorption behavior of different combinations of physical scavengers in the microporous Tyvek sachet was measured at 0, 10 and 20 degrees C. A combination of highly permeable microporous Tyvek and much less permeable nylon/polyethylene laminate was also examined as a variable to help control the access of CO2 to the physical CO2 absorber. The composition of the absorber and its packing density in the sachet affected the CO2 absorption rate and capacity. Increased zeolite in the Tyvek sachet showed higher CO2 absorption followed by higher CO2 release concomitant with moisture sorption, while activated carbon itself had low CO2 absorption and little subsequent CO2 desorption. Lower temperatures increased the capacity of CO2 absorption and release along with lower CO2 absorption and release rates. A reduction in Tyvek area could decrease the absorption and release rates. An application of a physical CO2 absorber to the kimchi package was tested at 10 degrees C to show potential for keeping the desired CO2 pressure profile for carbonic cool flavor under tolerable pressure during storage and use. PRACTICAL APPLICATIONS: Physical carbon dioxide absorbers consisting of zeolite and activated carbon inside the gas-permeable sachet can be placed in kimchi packages for time-dependent absorption and release of carbon dioxide, which responds in harmony with the fermentation profile of kimchi. Its practical potential is both to provide a carbonic cool taste of the product and to avoid excessive overpressure in the package through its shelf life when used in kimchi packaging. Its intelligent use may resolve the problem of a dull kimchi taste, which occurs when incorporating calcium hydroxide as the chemical scavenger in the package. PMID- 30419150 TI - A hard push to help protect survivors of childhood cancer. PMID- 30419151 TI - Treatment of intractable oral ulceration with an oral mucosa equivalent. AB - The current use of steroids or pharmacological immunomodulators for the treatment of intractable oral ulceration is ineffective, necessitating newer cell-based therapeutic approaches. We examined the potential efficacy of an oral mucosa equivalent developed in this study in an in vivo model of repeat major oral ulceration mimicking the intractable oral ulceration observed clinically. Oral mucosal samples and plasma fibrin were obtained from Sprague-Dawley rats. The oral mucosa equivalents were prepared with cultured mucosal keratinocytes and plasma fibrin mixed with cultured fibroblasts. Ulcers were chemically induced on the rat buccal mucosa thrice in 3 weeks and covered with or without mucosa equivalents. Gross and microscopic findings and mRNA expression levels were compared between the ulcer control and mucosa equivalent groups. Oral mucosal keratinocytes and fibroblasts were cultured in vitro to achieve high viability and colony-forming efficiency. The equivalents showed epithelial and subepithelial structures similar to those of oral mucosa and exhibited high p63 positivity. In the in vivo study, ulceration was resolved earlier without significant granulation or scarring in the equivalent group than in control group (p < 0.05). Microscopic examinations revealed rapid re-epithelialization and less fibrosis in the equivalent group than in the control group (p < 0.05). Mucosa equivalent-covered ulcers showed histological characteristics similar to those of the normal buccal mucosa and exhibited lower expression of TGFB1, ACTA2, and FN1 mRNAs than the control group. The in vitro-engineered oral mucosa equivalent promotes ulcer healing without scarring and functional deficits. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res B Part B: Appl Biomater, 2018. PMID- 30419152 TI - Non-invasive liver fibrosis assessment correlates with collagen and elastic fiber quantity in patients with hepatitis C. AB - BACKGROUND AND AIMS: Elastic fiber deposition is a cause of irreversibility of liver fibrosis. However, to date, its relevance to clinical features has not yet been clarified. This study aimed to clarify the correlation between non-invasive markers of fibrosis and fiber quantity, including elastic fiber, obtained from computational analysis. METHODS: This retrospective study included 270 patients evaluated by non-invasive liver fibrosis assessment prior to liver biopsy. Of these patients, 95 underwent magnetic resonance elastography (MRE) and 244 were assessed with Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+ -M2BP). Using whole-slide imaging of Elastica van Gieson-stained liver biopsy sections, the quantity of collagen, elastin, and total fiber (elastin + collagen) was determined. RESULTS: The total fiber quantity showed significant linear correlation with fibrosis stage F0-F4. While collagen fiber quantity increased from stage F0 to F4, elastic fiber quantity increased significantly only from stage F2 to F3. Spearman's rank correlation test revealed that non-invasive liver fibrosis assessment significantly correlates with each fiber quantity, including correlation between total fiber quantity and FIB-4 index (r=0.361, p<0.001), WFA+ -M2BP values (r=0.404, p<0.001), and liver stiffness value by MRE (r=0.615, p<0.001). Receiver operating characteristic (ROC) curve analyses revealed that the area under ROC for predicting higher elastic fiber (>3.6%) is 0.731 by FIB-4 index, 0.716 by WFA+ -M2BP, and 0.822 by liver stiffness by MRE. CONCLUSION: Liver fibrosis correlates with fiber quantity through non-invasive assessment regardless of fiber type, including elastic fiber. Moreover, MRE is useful for predicting high amounts of elastic fiber. PMID- 30419153 TI - Heterogeneity of Treatment Dropout: PTSD, Depression and Alcohol Use Disorder Reductions in PTSD and AUD/SUD Treatment Non-Completers. AB - Treatment dropout is often assumed to be due to worsening or lack of symptom improvement, despite minimal research examining symptom change among treatment dropouts. Thus, the present study examined symptom change in veterans who discontinued evidence-based treatment for comorbid posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD). Participants were veterans who completed at least 1 session of a 12-session Concurrent Treatment of PTSD and Substance Use Disorders using Prolonged Exposure (COPE) for comorbid PTSD/AUD. The study analyses investigated the forty three percent of the sample (n = 22) that did not complete the full 12-session protocol and were therefore considered treatment dropouts. Symptom changes in PTSD, AUD and depression were examined among dropouts using two methods: 1) clinically significant change criteria and 2) good end-state criteria. Results indicated that a significant proportion of treatment dropouts displayed clinically significant improvement and/or met good end-state criteria for PTSD (40-59%), AUD (66%) and depression (45-68%) prior to dropping out. The results revealed that participants who displayed symptom improvement attended more treatment sessions and completed more imaginal exposures than participants who did not experience significant improvement. Together, the findings add to a growing body of literature suggesting that a large proportion of treatment dropouts may actually improve. Although preliminary, the findings challenge the notion that treatment dropout is always associated with negative outcomes. PMID- 30419154 TI - Chronicling the Risk and Risk Communication by Governmental Officials During the Zika Threat. AB - The unique circumstances surrounding Zika, including the fact that it is both mosquito-borne and sexually transmissible, brought to the fore concerns about optimal ways to communicate risk in an environment characterized by rapidly evolving knowledge. The difficulty in doing so is magnified by the fact that science-based health messages from governmental agencies must be developed in an evidence-based, audience-participative, and collaborative manner. A recent reminder in JAMA asserted the importance of preparing now for future threats. Understanding how the knowledge and messaging about Zika changed across time should help public health officials prepare for such challenges. PMID- 30419155 TI - Searching for the value of accountable care organizations in cancer care. PMID- 30419156 TI - Stereocontrolled Synthesis of 1,4-Dicarbonyl Compounds by Photochemical Organocatalytic Acyl Radical Addition to Enals. AB - We report a visible-light-mediated organocatalytic strategy for the enantioselective acyl radical conjugate addition to enals, leading to valuable 1,4-dicarbonyl compounds. The process capitalizes upon the excited-state reactivity of 4-acyl-1,4-dihydropyridines that, upon visible-light absorption, can trigger the generation of acyl radicals. By means of a chiral amine catalyst, iminium ion activation of enals ensures a stereoselective radical trap. We also demonstrate how the combination of this acylation process with a second catalyst controlled bond-forming event allows to selectively access the full matrix of all possible stereoisomers of the resulting 2,3-substituted 1,4-dicarbonyl products. PMID- 30419157 TI - Information Hazards in Biotechnology. AB - With the advance of biotechnology, biological information, rather than biological materials, is increasingly the object of principal security concern. We argue that both in theory and in practice, existing security approaches in biology are poorly suited to manage hazardous biological information, and use the cases of Mousepox, H5N1 gain of function, and Botulinum toxin H to highlight these ongoing challenges. We suggest that mitigation of these hazards can be improved if one can: (1) anticipate hazard potential before scientific work is performed; (2) consider how much the new information would likely help both good and bad actors; and (3) aim to disclose information in the manner that maximally disadvantages bad actors versus good ones. PMID- 30419158 TI - Living Well in Times of Threat: The Importance of Adjustment Processes to Explain Functional Adaptation to Uncertain Security in Expatriates Deployed in the Sudan. AB - The present study investigated expatriate humanitarian aid workers' perceptions and responses to uncertain security while deployed in the Sudan. Interviews conducted in Khartoum (n = 7) and Darfur (n = 17) focused on risk perception, concern for personal security, and strategies used to function well in an insecure environment. Despite a high perceived general risk, as well as broad knowledge and experience with security incidents, participants often expressed low concern. General adjustment processes were drawn on to explain this finding, while different constellations of processes resulted in different patterns of adjustment. Functional adjustment, resulting in adequate risk perception, protective behavior, protection, and low concern, was characterized by a constellation of complementary activation of accommodation and assimilation processes. PMID- 30419159 TI - Polymeric ionically conductive composite matrices and electrical stimulation strategies for nerve regeneration: In vitro characterization. AB - Stem cell strategies and the use of electrical stimulation (ES) represent promising new frontiers for peripheral nerve regeneration. Composite matrices were fabricated by coating electrospun polycaprolactone/cellulose acetate micro nanofibers with chitosan and ionically conductive (IC) polymers including, sulfonated polyaniline, and lignin sulfonate. These composite matrices were characterized for surface morphology, coating uniformity, ionic conductivity, and mechanical strength to explore as scaffold materials for nerve regeneration in conjunction with ES. Composite matrices measured conductivity in the range of 0.0049-0.0068 mS/m due to the uniform coating of sulfonated polymers on the micro nanofibers. Thin films (2D) and composite fiber matrices (3D) of IC polymers seeded with human mesenchymal stem cells (hMSCs) were electrically stimulated at 0.5 V, 20 Hz for 1 h daily for 14 days to study the changes in cell viability, morphology, and expression of the neuronal-like phenotype. In vitro ES lead to changes in hMSCs' fibroblast morphology into elongated neurite-like structures with cell bodies for ES-treated and positive control growth factor-treated groups. Immunofluorescent staining revealed the presence of neuronal markers including beta3-tubulin, microtubule-associated protein 2, and nestin in response to ES. (c) 2018 Wiley Periodicals, Inc. J. Biomed. Mater. Res. Part B: 1-9, 2018. PMID- 30419161 TI - Comment on "Ionic Conductivity, Diffusion Coefficients, and Degree of Dissociation in Lithium Electrolytes, Ionic Liquids, and Hydrogel Polyelectrolytes". PMID- 30419160 TI - No wonder it itches: quick bedside visualization of a scabies infestation using reflectance confocal microscopy. PMID- 30419162 TI - Surface Engineering of Room Temperature-Grown Inorganic Perovskite Quantum Dots for Highly Efficient Inverted Light-Emitting Diodes. AB - Inorganic cesium lead bromide quantum dots (CsPbBr3 QDs) are usually synthesized via a high-temperature process (hot injection, HI). This process is similar to that used for the synthesis of other semiconductor QDs (i.e., CdSe@ZnS), which limits their potential cost advantage. CsPbBr3 QDs can also be synthesized at room temperature (RT) in a low cost and easily scalable process, which, thus, is one of the greatest advantages of the CsPbBr3 QDs. However, light-emitting diodes (LEDs) fabricated using RT-QDs exhibit poor performance compared to those of HI QDs. In fact, QDs are surrounded by insulating ligands to maintain their colloidal stability but these ligands need to be removed to obtain high performance LEDs. Here, we show that ligand removal techniques used for HI-QDs are not sufficient in the case of RT-QDs. Additional ligand engineering and annealing steps are necessary to remove the excess of ligands from RT-QD films while preventing the coalescence of the QDs. The eventual surface defects induced by annealing can be healed by a subsequent photoactivation step. Moreover, the use of solution processable inorganic charge transport layers can reduce the fabrication costs of LEDs. We fabricated an inverted LED based on a metal oxide electron transport layer and a RT-QD emitting layer which exhibited a maximum current efficiency of 17.61 cd A-1 and a maximum luminance of 22 825 cd m-2. PMID- 30419163 TI - Evaluating charge equilibration methods to generate electrostatic fields in nanoporous materials. AB - Charge equilibration (Qeq) methods estimate the electrostatic potential of molecules and periodic frameworks by assigning point charges to each atom, using only a small fraction of the resources needed to compute density functional (DFT) derived charges. This makes possible the computational screening of thousands of microporous structures to assess their performance for the adsorption of polar molecules. Recently, different variants of the original Qeq scheme were proposed to improve the quality of the computed point charges. One focus of this research was improving the gas adsorption predictions in Metal Organic Frameworks (MOFs), for which many different structures are available. In this work, we review the evolution of the original Qeq scheme, understanding the role of these modifications on the final output. We evaluated the result of combining different variant and set of parameters, by comparing the Qeq charges with high quality DFT derived DDEC charges for 2338 MOF structures. We focused on the systematic errors that are attributable to specific atom types to quantify the final precision that one can expect from Qeq methods in the context of gas adsorption where the electrostatic potential plays a significant role, namely CO2 and H2S adsorption. In conclusion, both the type of algorithm and the input parameters have a large impact on the resulting charges and we draw some guidelines to help the user to choose the proper combination of the two for obtaining a meaningful set of charges. We show that, considering this set of MOFs, the accuracy of the original Qeq scheme is often still comparable with the most recent variants, even if it clearly fails in the presence of certain atom types, such as alkali metals. PMID- 30419164 TI - Intestinal Villi Model with Blood Capillaries Fabricated Using Collagen-Based Bioink and Dual-Cell-Printing Process. AB - The human intestine, a vital organ in our digestive system, shows an anatomically complex architecture. The fabrication of three-dimensional (3D) intestinal models containing villus structures has been an important topic for intestine regeneration or organ-on-a-chip, because a 3D model can provide broad surface area and help absorption and transportation of digested nutrients. In this study, we developed a 3D intestinal villi model containing an epithelium layer and a blood capillary structure, using an innovative cell-printing process. The epithelium and capillary network of the 3D model were fabricated using two collagen-based bioinks laden with Caco-2 cells and human umbilical vein endothelial cells (HUVECs). The fabricating conditions were optimized to obtain a unique 3D villus structure, with capillary in the core and high cell viability. A fabricated single villus was 183 +/- 12 MUm in diameter and 770 +/- 42 MUm in height, which means the aspect ratio of the structure was 4.2 +/- 0.3. The results indicate that the cell-laden intestinal villi successfully mimicked the 3D geometry of human intestinal villi. In vitro cellular activity of the 3D villi model containing epithelium and capillary demonstrated significantly higher cell growth and expression of enzymes and MUC17, compared to those of 2D models and a 3D villi model without the capillary network. The suggested 3D intestinal villi also exhibited the enhancement of the barrier function as compared to those of the others, and even demonstrated an increase of the permeability coefficient of FITC-dextran and glucose uptake ability (FITC, fluorescein isothiocyanate). These results indicate that a 3D intestinal villi model would be a highly promising for mimicking the human intestine. PMID- 30419165 TI - Diffusion-Coupled Degradation of Chlorinated Ethenes in Sandstone: An Intact Core Microcosm Study. AB - Matrix diffusion must be considered when assessing natural attenuation and remediation of chlorinated ethenes in fractured porous bedrock aquifers. In this study, intact sandstone rock and groundwater from a trichloroethene (TCE) contaminated site were used in microcosms (maintained for approximately 600 days) to simulate a single fracture-matrix system with a chamber at the top of the core allowing advection to represent fracture flow. Diffusion-coupled degradation with and without biostimulation were evaluated and compared to crushed-rock, batch microcosms. In the diffusion-transport microcosms, lactate stimulated reductive dechlorination of TCE to cis-1,2-dichloroethene (cDCE) and sulfate reduction. Reduction of TCE to cDCE led to a higher rate of chlorinated ethene removal from the cores, likely due to higher concentration gradients, along with lower sorption and a higher diffusion coefficient for cDCE relative to TCE. Reduction of cDCE to vinyl chloride or ethene did not occur as in crushed rock microcosms, inferring an absence of Dehalococcoides in the intact cores. Abiotic transformation was evident in the core microcosms based on the appearance of acetylene and enrichment in delta13C-TCE and delta13C-cDCE. Core microcosms permit a more realistic representation of the behavior of chlorinated ethenes in water-saturated fractured porous rock by incorporating the combined influence of fracture flow and matrix diffusion on transport and transformation. PMID- 30419166 TI - Microbiome-Triggered Transformations of Trace Organic Chemicals in the Presence of Effluent Organic Matter in Managed Aquifer Recharge (MAR) Systems. AB - It is widely assumed that biodegradation of trace organic chemicals (TOrCs) in managed aquifer recharge (MAR) systems occurs via a cometabolic transformation with dissolved organic carbon serving as primary substrate. Hence, the composition facilitating bioavailability of the organic matter seems to have a great impact on TOrCs transformation in MAR systems. The aim of this study was to elucidate the character of effluent organic matter present in the feedwater of a simulated sequential MAR system throughout the infiltration by use of FT-ICR-MS analyses as well as spectroscopic methods. Furthermore, compositional changes were correlated with TOrCs targeted throughout the system as well as the abundance of different microbial phyla. On the basis of their behavior throughout the infiltration system in which different redox and substrate conditions prevailed, TOrCs were classified in four groups: easily degradable, redox insensitive, redox sensitive, and persistent. Masses correlating with persistent TOrCs were mainly comprised of CHNO-containing molecules but also of CHO which are known as carboxyl-rich alicyclic molecules, while CHOS and CHNOS can be neglected. Easily degradable TOrCs could be associated with CHNO-, CHO-, and CHOS containing compounds. However, a shift of molecular compounds to mostly CHOS was observed for redox-insensitive TOrCs. Three hundred thirty eight masses correlated with removal of redox-sensitive TOrCs, but no distinct clustering was identified. PMID- 30419167 TI - ZINClick v.18: Expanding Chemical Space of 1,2,3-Triazoles. AB - In the last years, we have investigated the click-chemical space covered by molecules containing the triazole ring and generated a database of 1,2,3 triazoles called ZINClick, starting from literature-reported alkynes and azides synthesizable in no more than three synthetic steps from commercially available products. This combinatorial database contains millions of 1,4-disubstituted 1,2,3-triazoles that are easily synthesizable. The library is regularly updated and can be freely downloaded from http://www.ZINClick.org . In this communication, the new implementation of ZINClick will be discussed as well as our new strategy for clustering the chemical space covered by 1,4-disubstituted 1,2,3-triazoles around their availability: from direct purchase to different degrees of synthetic feasibility of the compounds. PMID- 30419168 TI - Reply to "Comment on 'Ionic Conductivity, Diffusion Coefficients and Degree of Dissociation in Lithium Electrolytes, Ionic Liquids and Hydrogel Polyelectrolytes'". PMID- 30419169 TI - Fully Coupled Quantum Treatment of Nanoconfined Systems: A Water Molecule inside a Fullerene C60. AB - We implemented a systematic procedure for treating the quantal rotations by including all translational and vibrational degrees of freedom for any triatomic bent molecule in any embedded or confined environment, within the MCTDH framework. Fully coupled quantum treatments were employed to investigate unconventional properties in nanoconfined molecular systems. In this way, we facilitate a complete theoretical analysis of the underlying dynamics that enables us to compute the energy levels and the nuclear spin isomers of a single water molecule trapped in a C60 fullerene cage. The key point lies in the full 9D description of both nuclear and electronic degrees of freedom, as well as a reliable representation of the guest-host interaction. The presence of occluded impurities or inhomogeneities due to noncovalent interactions in the interfullerene environment could modify aspects of the potential, causing significant coupling between otherwise uncoupled modes. Using specific n-mode model potentials, we obtained splitting patterns that confirm the effects of symmetry breaking observed by experiments in the ground ortho-H2O state. Further, our investigation reveals that the first rotationally excited states of the encapsulated ortho- and para-H2O have also raised their 3-fold degeneracy. In view of the complexity of the problem, our results highlight the importance of accurate and computational demanding approaches for building up predictive models for such nanoconfined molecules. PMID- 30419170 TI - A Novel Arthroscopic Technique for Intraoperative Mobilization of Synovial Mesenchymal Stem Cells. AB - BACKGROUND:: Mesenchymal stem cells (MSCs) have emerged as a promising candidate for tissue regeneration and restoration of intra-articular structures such as cartilage, ligaments, and menisci. However, the routine use of MSCs is limited in part by their low numbers and the need for methods and procedures outside of the joint or surgical field. PURPOSE:: To demonstrate feasibility of a technique in which minimally manipulated synovial MSCs can be mobilized during knee arthroscopy, thereby showing proof of concept for the future evaluation and clinical use of native joint resident MSCs in single-stage joint repair strategies. STUDY DESIGN:: Descriptive laboratory study. METHODS:: Patients (n = 15) undergoing knee arthroscopy who were free from synovitis or active inflammation were selected. Three samples of irrigation fluid were collected from each patient at inception of the procedure, after an initial inspection of the joint, and after agitation of the synovium. MSC numbers were evaluated by colony forming unit-fibroblastic assay. The phenotype of synovial fluid resident and synovial-mobilized MSCs was determined by flow cytometry, and their functionality was determined by trilineage differentiation. Adhesion of culture-expanded mobilized MSCs to fibrin scaffolds was also evaluated to ascertain whether mobilized MSCs might concentrate at sites of bleeding. RESULTS:: Normal irrigation during arthroscopy depleted resident synovial fluid MSCs (4-fold decrease, n = 15). Numbers of MSCs mobilized through use of a purpose-made device were significantly higher (105-fold) than those mobilized through use of a cytology brush (median of 5763 and 54 colonies, respectively; P = .001; n = 15). The mobilized cellular fraction contained viable MSCs with proliferative potential and trilineage differentiation capacity for bone, cartilage, and fat lineages, and cultured daughter cells exhibited the standard MSC phenotype. Following culture, mobilized synovial MSCs also adhered to various fibrin scaffolds in vitro. The technique was simple and convenient to use and was not associated with any complications. CONCLUSION:: Numbers of functional MSCs can be greatly increased during arthroscopy through use of this technique to mobilize cells from the synovium. CLINICAL RELEVANCE:: This study highlights a novel, single-stage technique to increase joint-specific, synovial-derived MSCs and thereby increase the repair potential of the joint. This technique can be undertaken during many arthroscopic procedures, and it supports the principle of integrating mobilized MSCs into microfracture sites and sites of bleeding or targeted repair through use of fibrin-based and other scaffolds. PMID- 30419171 TI - In Revision Hip Arthroscopy, Labral Reconstruction Can Address a Deficient Labrum, but Labral Repair Retains Its Role for the Reparable Labrum: A Matched Control Study. AB - BACKGROUND:: Revision hip arthroscopy is increasingly common and often addresses acetabular labrum pathology. There is a lack of consensus on indications or outcomes of revision labral repair versus reconstruction. PURPOSE:: To report clinical outcomes of labral reconstruction during revision hip arthroscopy at minimum 2-year follow-up as compared with pair-matched labral repair during revision hip arthroscopy (control group) and to suggest a decision-making algorithm for labral treatment in revision hip arthroscopy. STUDY DESIGN:: Cohort study; Level of evidence, 3. METHODS:: Patients who underwent revision hip arthroscopy with labral reconstruction were matched 1:2 with patients who underwent revision arthroscopic labral repair. Patients were matched according to age, sex, and body mass index. Outcome scores, including the modified Harris Hip Score (mHHS), Non-Arthritic Hip Score, Hip Outcome Score-Sport-Specific Subscale, and a visual analog scale for pain, were collected preoperatively and at minimum 2-year follow-up. At latest follow-up, patient satisfaction on a 0-10 scale and the abbreviated International Hip Outcome Tool (iHOT-12) were collected. Complications, subsequent arthroscopies, and conversion to total hip arthroplasty were collected as well. RESULTS:: A total of 15 revision labral reconstructions were pair matched to 30 revision labral repairs. The reconstructions had fewer isolated Seldes type I detachments ( P = .008) and lower postoperative lateral center-edge angle, but there were otherwise no significant differences in demographics, radiographics, intraoperative findings, or procedures. Both groups demonstrated significant improvements in all outcomes and visual analog scale at minimum 2-year follow-up. The revision repairs trended toward better preoperative scores: mHHS (mean +/- SD: 59.3 +/- 16.5 vs 54.2 +/- 16.0), Non-Arthritic Hip Score (61.0 +/- 16.7 vs 51.2 +/- 17.6), Hip Outcome Score-Sport-Specific Subscale (39.6 +/- 25.1 vs 30.5 +/- 22.1), and visual analog scale (5.8 +/- 1.8 vs 6.2 +/- 2.2). At follow-up, the revision repair group had significantly higher mHHS (84.1 +/- 14.8 vs 72.0 +/- 18.3, P = .043) and iHOT-12 (72.2 +/- 23.3 vs 49.0 +/- 27.6, P = .023) scores than the reconstruction group. The magnitudes of pre- to postoperative improvement between the groups were comparable. The groups also had comparable rates of complications: 1 case of numbness in each group ( P > .999), subsequent arthroscopies (repair: n = 2, 6.5%; revision: n = 3, 20%; P = .150), and conversion to total hip arthroplasty (1 patient in each group, P > .999). CONCLUSION:: Labral reconstruction safely and effectively treats irreparable labra in revision hip arthroscopy. However, labral repair is another treatment option for reparable labra, yielding similar magnitude of improvement. A proposed algorithm may assist in surgical decision making to achieve optimal outcomes based on the condition and history of each patient's acetabular labrum. PMID- 30419172 TI - Biceps Detachment Preserves Joint Function in a Chronic Massive Rotator Cuff Tear Rat Model. AB - BACKGROUND:: Lesions of the long head of the biceps tendon are often associated with massive rotator cuff tears (MRCTs), and biceps tenotomy is frequently performed for pain relief and functional reservation. However, the efficacy and safety of biceps tenotomy regarding the effects on the surrounding tissues in chronic MRCT are unclear. HYPOTHESIS:: Biceps tenotomy would result in improved mechanical and histological properties of the intact subscapularis tendon and improved in vivo shoulder function while not compromising glenoid cartilage properties. STUDY DESIGN:: Controlled laboratory study. METHODS:: Right supraspinatus and infraspinatus tendons were detached in 25 male Sprague-Dawley rats, followed by 4 weeks of cage activity to create a chronic MRCT condition. Animals were randomly divided into 2 groups and received either biceps tenotomy (n = 11) or sham surgery (n = 14) and were sacrificed 4 weeks thereafter. Forelimb gait and ground-reaction forces were recorded 1 day before the tendon detachment (baseline), 1 day before the surgical intervention (biceps tenotomy or sham), and 3, 7, 10, 14, 21, and 28 days after the intervention to assess in vivo shoulder joint function. The subscapularis tendon and glenoid cartilage were randomly allocated for mechanical testing or histologic assessment after the sacrifice. RESULTS:: Compared with sham surgery, biceps tenotomy partially restored the in vivo shoulder joint function, with several gait and ground reaction force parameters returning closer to preinjury baseline values at 4 weeks. With biceps tenotomy, mechanical properties of the subscapularis tendons were improved, while mechanical properties and histological Mankin scores of the glenoid cartilage were not diminished when compared with the sham group. CONCLUSION:: Biceps tenotomy in the presence of chronic MRCT partially preserves overall shoulder function and potentially restores subscapularis tendon health without causing detrimental effects to joint cartilage. This laboratory study adds to the growing literature regarding the protective effects of biceps tenotomy on the shoulder joint in a chronic MRCT model. CLINICAL RELEVANCE:: This study provides important basic science evidence supporting the use of biceps tenotomy in patients with massive rotator cuff tears. PMID- 30419173 TI - Validity and Responsiveness of the Single Alpha-numeric Evaluation for Shoulder Patients. AB - BACKGROUND:: There is an ever-increasing demand for widespread implementation of patient-reported outcomes. However, adoption is slow owing to limitations in clinical infrastructure and resources within busy orthopaedic practices. Prior studies showed the single alpha-numeric evaluation (SANE) score to correlate at a single point in time with the American Shoulder and Elbow Surgeons (ASES) score. However, no study has validated the SANE in terms of test-retest reliability, responsiveness, or clinical utility. PURPOSE:: To validate SANE with the ASES across a sample of patients with common orthopaedic shoulder diagnoses. STUDY DESIGN:: Cohort study (diagnosis); Level of evidence, 2. METHODS:: Patients undergoing rotator cuff repair (n = 77), total shoulder replacement (n = 55), or physical therapy (n = 80) for signs and symptoms of subacromial impingement syndrome (n = 61) or adhesive capsulitis (n = 19) were administered the SANE and ASES at baseline and again at their 3-month follow-up from initial care or surgery (N = 212, mean +/- SD age = 52.6 +/- 1.2 years, n = 145 women). Interclass correlation coefficient (ICC2,1) and standard error of the measurement (SEm) were used to evaluate the test-retest reliability of the SANE and the validity between the SANE and ASES scores. Analysis of variance (treatment group * time) was used to evaluate the responsiveness to treatment, and a receiver operating characteristic curve was used to establish the minimal clinically important difference (MCID) for the SANE as compared with the ASES (alpha = .05). Floor and ceiling effects were evaluated as the percentage of patients who scored the highest or lowest score on each tool. RESULTS:: The SANE demonstrated good pretreatment reliability (ICC2,1 = 0.84, SEM = 3.8), similar to the ASES (ICC2,1 = 0.82, SEM = 3.4). The SANE also showed good agreement with the ASES before and after treatment across all treatment groups (rotator cuff repair, ICC2,1 = 0.85, SEM = 3.4; total shoulder replacement, ICC2,1 = 0.72, SEM = 5.2; physical therapy: ICC2,1 = 0.82, SEM = 2.9). The SANE and ASES displayed similar responsiveness after treatment, with similar mean change and SD within each treatment group. The receiver operating characteristic curve revealed an area under the curve of 0.79 (SE, 0.62; P < .001) and a cutoff of 15% on the SANE, with a sensitivity of 85% to establish the MCID. Acceptable and similar floor and ceiling effects were observed for the ASES (4%) and SANE (9%). CONCLUSION:: The study demonstrates that the SANE is valid for a range of common shoulder diagnoses to assess patient outcomes across operative and nonoperative treatment for shoulder complaints. The MCID of 15% is similar to that of the ASES (11%), suggesting that the SANE is a simple and efficient tool to assess treatment effects for shoulder disorders. Future studies are warranted to confirm these results and compare across other body parts and diagnoses. PMID- 30419174 TI - Femoral Tunnel Drilling Method: Risk of Reoperation and Revision After Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND:: The femoral tunnel in anterior cruciate ligament reconstruction (ACLR) can be created by the transtibial (TT) or tibial-independent (TI) methods. An anatomically located femoral tunnel can be more consistently achieved by TI methods, which include the anteromedial portal and lateral (outside-in, retrodrill) techniques. Nonanatomic graft placement in ACLR can result in postoperative instability and meniscal or chondral injury. An anatomically located graft is subjected to higher postoperative physiologic forces than one placed nonanatomically. PURPOSE:: To examine isolated primary ACLR and determine the risk of aseptic revision and reoperation based on femoral tunnel drilling method. STUDY DESIGN:: Cohort study; Level of evidence, 2. METHODS:: The ACLR registry of an integrated US health care system was used to identify primary isolated unilateral ACLRs from 2009 to 2014. Multivariable Cox proportional hazard regression models were used to evaluate risk for aseptic revision for graft failure and aseptic reoperation for meniscal or chondral injury according to femoral tunnel drilling method: TI versus TT. Models included age, sex, body mass index (BMI), race, graft type, and femoral fixation type as covariates. RESULTS:: The cohort included 19,059 patients with primary ACLR. The mean age was 28.9 years (SD, 11.5), 6991 patients (36.8%) were younger than 22 years, 11,795 patients (61.9%) were male, 7648 patients (40.1%) had a BMI less than 25 kg/m2, 8913 patients (46.8%) were white, and 7357 patients (38.6%) received an allograft. Median follow-up was 2.30 years (interquartile range, 1.08-3.77). TI techniques were used for 12,342 (64.8%) of the ACLRs, and the TT method was used for 6717 (35.2%). Use of TI techniques increased from 33.6% of all ACLRs in 2009 to 83.4% in 2014. After adjustment for covariates, the TI group had a higher risk for aseptic revision than the TT group (hazard ratio [HR], 1.28; 95% CI, 1.04 1.56), and this risk was 1.41 times higher in patients younger than 22 years specifically. The 5-year cumulative reoperation probability was lower in the TI group (4.50%; 95% CI, 3.78%-5.36%) compared with the TT group (5.06%; 95% CI, 4.31-5.94%). After adjustment for the covariates, no difference in risk for aseptic reoperation was observed (HR, 1.08; 95% CI, 0.85-1.39). CONCLUSION:: In the largest known study of its type examining femoral tunnel drilling method for primary ACLR, after adjustment for age, sex, BMI, race, graft type, and femoral fixation, TI techniques were found to carry higher risk of aseptic revision compared with the TT method, while no difference was observed in risk for aseptic reoperation. PMID- 30419175 TI - Timeline for Maximal Subjective Outcome Improvement After Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND:: Anterior cruciate ligament (ACL) tears are one of the most common traumatic knee injuries experienced by athletes. Return to sport is considered the pinnacle endpoint among patients receiving ACL reconstruction. However, at the time of return to sport, patients may not be participating at their previous levels of function, as defined by clinical metrics. PURPOSE:: To establish when patients perceive maximal subjective medical improvement according to patient reported outcome measures (PROMs). STUDY DESIGN:: Systematic review. METHODS:: A systematic review of the PubMed database was conducted to identify studies that reported sequential PROMs up to a minimum of 2 years after ACL reconstruction. Pooled analysis was conducted for PROMs at follow-up points of 3 months, 6 months, 1 year, and 2 years. Clinically significant improvement was determined between pairs of intervals with the minimal clinically important difference. RESULTS:: This review contains 30 studies including 2253 patients who underwent ACL reconstruction. Clinically significant improvement in the KOOS (Knee injury and Osteoarthritis Outcome Score) was seen up to 1 year after ACL reconstruction, but no clinical significance was noted from 1 to 2 years. Clinically significant improvement in the IKDC (International Knee Documentation Committee) and Lysholm questionnaires was seen up to 6 months postoperatively, but no clinical significance was noted beyond that. CONCLUSION:: After ACL reconstruction, maximal subjective medical improvement is established 1 year postoperatively, with no further perceived clinical improvement beyond this time point according to current PROMs. The KOOS may be a more responsive metric to subjective improvements in this patient cohort than other patient-reported outcomes, such as the IKDC and Lysholm. CLINICAL RELEVANCE:: After ACL reconstruction, patients perceive interval subjective improvements until 1 year postoperatively. PMID- 30419176 TI - Human Subacromial Bursal Cells Display Superior Engraftment Versus Bone Marrow Stromal Cells in Murine Tendon Repair. AB - BACKGROUND:: Bone marrow aspirate is a primary source for cell-based therapies with increasing value in the world of orthopaedic surgery, especially in revision cases of tendon and ligament repairs. However, cells within peritendinous structures, such as the paratenon and surrounding bursa, contribute to the native tendon-healing response and offer promising cell populations for cell-based repair strategies. Therefore, the purpose of this study is to investigate the efficacy of cells derived from human subacromial bursa as compared with the current gold standard, bone marrow stromal cells (BMSCs), for tendon repairs in an established in vivo immunodeficient murine patellar tendon defect model. HYPOTHESIS:: Subacromial bursal cells will show superior survival and engraftment into the host tissue as compared with BMSCs. STUDY DESIGN:: Controlled laboratory study. METHODS:: Human subacromial bursal and bone marrow aspirate were harvested from the same donor undergoing rotator cuff repair. Cells were transfected with a fluorescent lentiviral vector to permanently label the cells, encapsulated into fibrin gel, and implanted into bilateral full-length central-width patellar tendon defects of immunodeficient mice. Additional surgery was performed on control mice comparing fibrin without cells and natural healing. At the time of sacrifice, all limbs were scanned on a multiphoton microscope to monitor the engraftment of the human donor cells. Afterward, limbs were assigned to either immunohistochemical or biomechanical analysis. RESULTS:: As compared with BMSCs, implanted subacromial bursal cells displayed superior tissue engraftment and survival. The main healing response in this defect model was the creation of new healing tissue over the anterior surface of the defect space. The implantation of cells significantly increased the thickness of the anterior healing tissue as compared with control limbs that did not receive cells. Cell proliferation was also increased in limbs that received implanted cells, suggesting that the donor cells stimulated a more robust healing response. Finally, these changes in the healing response did not lead to significant changes in mechanical properties. CONCLUSION:: The subacromial bursa, while often removed during rotator cuff repair, may harbor a more suitable cell source for tendon repair than BMSCs, as bursal cells display superior engraftment and survival in tendon tissue. In addition, the subacromial bursa may be a more accessible cell source than bone marrow aspirate. CLINICAL RELEVANCE:: The subacromial bursa contains a cell population that responds to tendon injury and may provide a more optimal cell source for tendon repair and regeneration strategies. Therefore, cells could be harvested from this tissue in the future, as opposed to the current practice of bursectomy and debridement. PMID- 30419177 TI - Performance on a Single-Legged Drop-Jump Landing Test Is Related to Increased Risk of Lateral Ankle Sprains Among Male Elite Soccer Players: A 3-Year Prospective Cohort Study. AB - BACKGROUND:: Soccer has a high injury rate, with lateral ankle sprains being a common injury. Therefore, an approach to prevent or at least reduce the occurrence is warranted. Injury prevention can be improved by identifying specific risk factors and individuals at risk. PURPOSE:: To assess drop-jump landing performance as a potential predictor of lateral ankle sprain within 3 year follow-up. STUDY DESIGN:: Case-control study; Level of evidence, 3. METHODS:: Single-legged drop-jump landing tests were performed by 190 elite soccer players. Based on ground-reaction forces, 6 outcome measures were calculated that aim to reflect the impact and stabilization phase. Lateral ankle sprains were registered during up to 3 years of follow-up. Following a z score correction for age, a multivariate regression analysis was performed. RESULTS:: During follow-up, 45 players (23.7%) suffered a primary lateral ankle sprain. Of those, 34 were regarded as severe (absence >7 days). Performance was related to increased risk of ankle sprain ( P = .005 for all sprains and P = .001 for severe sprains). Low mediolateral stability for the first 0.4 seconds after landing (a larger value indicates more force exerted in the mediolateral direction, resulting in rapid lateral stabilization) and high horizontal ground-reaction force between 3.0 and 5.0 seconds (a smaller value indicates less sway in the stabilization phase) were identified as risk factors. A player that scored 2 SD below average for both risk factors had a 4.4-times-higher chance of sustaining an ankle sprain than a player who scored average. CONCLUSION:: The current study showed that following a single-legged drop-jump landing, mediolateral force over 0 to 0.4 seconds and/or mean resultant horizontal ground-reaction force over 3 to 5 seconds has predictive value with regard to the occurrence of an ankle sprain among male elite soccer players within 3 years. PMID- 30419178 TI - Primary Stability of an Acromioclavicular Joint Repair Is Affected by the Type of Additional Reconstruction of the Acromioclavicular Capsule. AB - BACKGROUND:: The synergistic effect of the acromioclavicular (AC) capsule and coracoclavicular (CC) ligaments on AC joint stability has gained recent recognition for its importance. Biomechanical and clinical studies have shown the benefit of combined reconstruction with multiple variations of surgical techniques for AC capsule augmentation. The ideal configuration remains unknown for such capsular repair aimed at achieving optimal stability with anatomic reconstruction. HYPOTHESIS:: Primary AC joint stability can be restored by AC capsule augmentation, while position of the additional suture construct is critical. It was hypothesized that techniques that reconstruct the anterior capsular structures would restore native stability against rotations and translations. STUDY DESIGN:: Controlled laboratory study. METHODS:: Thirty fresh frozen human cadaveric shoulders were used. Each sample was tested in the native state and served as its own control. After complete capsulotomy, 1 of 5 AC capsular repair configurations was performed: anterior, superior, posterior, O frame, and X-frame. After testing of the AC capsular repair configurations, the tests were repeated after dissection of the CC ligaments and after CC ligament reconstruction with a suture button system. AC joint stability was immediately tested after each step under rotation and horizontal translation. To accomplish this, the AC joints were anatomically positioned on a custom fixture linked to a servohydraulic testing system. A 3-dimensional optical measuring system was used to evaluate the 3-dimensional joint motion. Clavicle posterior translation in relation to the acromion, rotation around the long axis of the clavicle, and displacement of the lateral clavicle in relation to the center of rotation were measured. The torques and forces required to rotate and translate the clavicle were recorded. RESULTS:: In terms of translational testing, after the complete capsulotomy, a significant reduction of resistance force was found across all groups, with a mean 13% to 20% remaining ( P < .05). All AC suture augmentations were able to significantly increase the average resistance force as compared with the native ( P = .01) against posterior translation. Subsequent cutting of the CC ligaments did not result in a significant change in any of the groups ( P = .23). The synergistic effect of AC capsule augmentation and CC ligament reconstruction could be demonstrated without exception. In terms of rotational testing, the complete capsulotomy resulted in a significant reduction of resistance torque in all groups ( P < .05), with a remaining torque ranging between 2% and 11% across the groups. However, all AC suture constructs significantly increased the resistance torque as compared with the capsulotomy ( P = .01). The subsequent cutting of the CC ligaments resulted in a significant change in 2 of the 5 groups (O-frame, P = .01; X-frame, P = .02) and an overall remaining torque reduction ranging from 3% and 42%. The combined reconstruction of the AC capsule and CC ligaments achieved the highest percentage of regained resistance torque but remained significantly weaker than the native specimen ( P = .01). CONCLUSION:: Native translational stability could be restored by the addition of AC capsule augmentation, while partial rotational instability remained. The tested constructs revealed no significant individual differences. CLINICAL RELEVANCE:: Combined stabilization of the AC capsule and CC ligaments demonstrated the greatest capacity to restore the native stability against translational and rotational loads, with the specific configuration of the AC capsule repair to be chosen according to the personal preferences of the surgeon. PMID- 30419179 TI - Arthroscopic Capsular Plication in Patients With Labral Tears and Borderline Dysplasia of the Hip: Analysis of Risk Factors for Failure. AB - BACKGROUND:: Hip arthroscopy for the treatment of instability in the setting of borderline dysplasia is controversial. Capsular management in such cases is an important consideration, and plication has been described as a reliable technique, with good midterm outcomes reported when indications are appropriate. HYPOTHESIS:: Patients with borderline dysplasia who have a lower lateral center edge angle (LCEA) and greater age will be at a higher risk of failure after arthroscopic capsular plication. STUDY DESIGN:: Case-control study; Level of evidence, 3. METHODS:: Data were retrospectively reviewed for all patients between 15 and 40 years of age who underwent hip arthroscopy from November 2008 to January 2015. Inclusion criteria were an LCEA between 18 degrees and 25 degrees , Tonnis grade <=1, primary case with capsular plication, and minimum 2 year follow-up. Patients were excluded if they had any history of ipsilateral hip procedure or conditions such as Legg-Calve-Perthes disease, slipped capital femoral epiphysis, rheumatologic disease, and Tonnis grade >=2. Age, sex, and body mass index data were retrieved for each patient. Patient-reported outcomes (PROs)-including modified Harris Hip Score (mHHS), Non-Arthritic Hip Score (NAHS), Hip Outcome Score-Sports Specific Subscale, and a visual analog scale (VAS) for pain (0-10)-were obtained preoperatively and at a minimum of 2 years postoperatively, in addition to the postoperative International Hip Outcome Tool 12. The "success" group consisted of all patients who achieved the patient acceptable symptomatic state of mHHS >=74 and had no ipsilateral hip surgery subsequent to their index arthroscopy. The "failure" group was composed of patients who were below the patient acceptable symptomatic state at latest follow up or required secondary arthroscopy or conversion to total hip arthroplasty. Patient satisfaction and minimal clinically important difference were also calculated. Mean age for the failure group was applied as a cutoff age for subanalysis, and relative risk for failure was determined. RESULTS:: Ninety patients (97 hips; 79.5%) met criteria for the success group, and 25 patients (25 hips) met criteria for the failure group. No significant differences in preoperative baseline scores or VAS were found. However, there did appear to be a trend that the failure group had lower mean preoperative scores for all PRO measures and a higher VAS score. The differences in preoperative mHHS and NAHS closely approached significance ( P = .053). Postoperative PRO, VAS, and patient satisfaction scores of the success group were significantly higher than the failure group. The failure group was significantly older than the success group (28.5 +/- 7.8 vs 23.5 +/- 7.5 years, P = .005). Patients >35 years old were 2.25 times more likely to fail according to relative risk (95% CI, 1.10-4.60; P = .0266). LCEA did not differ between the groups, and no other risk factors for failure were identified. CONCLUSION:: Stringent criteria for patient selection and meticulous repair or augmentation of the static stabilizers of the hip yielded favorable clinical outcomes in this study cohort with borderline dysplasia. Within this carefully selected group, the analysis revealed that increased age was the main risk factor for failure in the management of borderline hip dysplasia via isolated primary arthroscopic hip surgery with capsular plication. PMID- 30419180 TI - High prevalence of congenital heart disease at high altitudes in Tibet. AB - BACKGROUND: Previous small sample studies suggested that elevated altitudes might be associated with the incidence of cardiovascular diseases. However, it remains uncertain whether high altitudes (over 3000 m above sea level) are related to congenital heart disease. We therefore explored the prevalence of congenital heart disease in a large cohort of students in the world's largest prefecture level city with the highest altitude. METHODS: This cross-sectional study included 84,302 student participants (boys 52.12%, girls 47.88%, with an average age of 10.62 +/- 3.33 years). Data were extracted from the screening results among different altitude area schools in Nagqu from June 2016 to August 2017. Students were first screened by performing a physical examination consisting of cardiac auscultations and clinical manifestation screenings. An echocardiography was performed to confirm and identify the subtype of congenital heart disease. RESULTS: The prevalence of congenital heart disease among students in Nagqu, Tibet, was 5.210/00 (439 cases). The most common congenital heart disease type was patent ductus arteriosus, representing 66.3% of congenital heart diseases diagnosed in this study, followed by atrial septal defect and ventricular septal defect, representing 20.3% and 9.1% of congenital heart diseases, respectively. Students living in higher altitudes were significantly more prone to have congenital heart disease than students in locations with lower altitudes. The prevalence of congenital heart disease in girls was found to be higher than that of boys. CONCLUSIONS: The correlation between congenital heart disease and increased altitude is noteworthy. This study's results are the first big data epidemiological investigation to confirm that high altitude is a significant environmental risk factor for congenital heart disease, especially patent ductus arteriosus. Furthermore, the results provide additional support to make a diagnostic and treatment plan to prevent congenital heart disease in high altitude areas. PMID- 30419182 TI - Care needs of people with dementia in the peri-operative environment: A systematic review. AB - The care of people with dementia within the hospital setting is challenging for healthcare professionals. Hospital design and services are not optimized for people with dementia, owing to the lack of preparation of healthcare professionals and the busy environment of the acute hospital. The peri-operative environment may present particular difficulties but little is known about the experience and care of people with dementia in this setting. The aim of this review was to examine the care of surgical patients who have dementia and their family members in peri-operative environments and describe strategies adopted by healthcare professionals. A systematic search of the following databases was completed: BNI, CINAHL, PubMED and PsychINFO in accordance with PRISMA guidelines. Data were extracted and analysed within a thematic analysis framework as described by Braun and Clarke . Ten papers based on eight studies were included, five (n = 355,010 participants) containing quantitative data and five reporting qualitative data (n = 395 participants). People with dementia who go undergo surgery experienced higher adverse post-operative outcomes such as respiratory problems or urinary tract infections. The key elements in surgical care for people with dementia included: health assessment throughout the surgical trajectory (pre-, intra- and post-operative) and the resources used by healthcare professionals in the peri-operative care. Healthcare professionals reported difficulties in the completion of health assessments due to the cognitive status of people with dementia and a lack of skills in dementia management. The use of restraints was still a common practice and a source of conflict. Dementia specific training and guidelines focused on the care of surgical patients who have dementia in peri-operative environments are required to improve care and post-operative outcomes. More research is required to develop effective interventions to improve care and decrease the risk of complications for people with dementia in the peri-operative care environment. PMID- 30419181 TI - Bone Marrow-Harvesting Technique Influences Functional Heterogeneity of Mesenchymal Stem/Stromal Cells and Cartilage Regeneration. AB - BACKGROUND:: Connective tissue progenitors (CTPs) from native bone marrow (BM) or their culture-expanded progeny, often referred to as mesenchymal stem/stromal cells, represents a promising strategy for treatment of cartilage injuries. But the cartilage regeneration capacity of these cells remains unpredictable because of cell heterogeneity. HYPOTHESIS:: The harvest technique of BM may highly influence stem cell heterogeneity and, thus, cartilage formation because these cells have distinct spatial localization within BM from the same bone. STUDY DESIGN:: Controlled laboratory study. METHODS:: CTPs obtained from the femur of patients undergoing total hip replacement by 2 harvest techniques-BM aspiration and BM collection-after bone rasping were immunophenotyped by flow cytometry and evaluated for chondrogenic ability. The spatial localization of different CTP subsets in BM was verified by immunohistochemistry. RESULTS:: Cells from the BM after rasping were significantly more chondrogenic than the donor-matched aspirate, whereas no notable difference in their osteogenic or adipogenic potential was observed. The authors then assessed whether distinct immunophenotypically defined CTP subsets were responsible for the different chondrogenic capacity. Cells directly isolated from BM after rasping contained a higher percentage (mean, 7.2-fold) of CD45-CD271+CD56+ CTPs as compared with BM aspirates. The presence of this subset in the harvested BM strongly correlated with chondrogenic ability, showing that CD271+CD56+ cells are enriched in chondroprogenitors. Furthermore, evaluation of these CTP subsets in BM revealed that CD271+CD56+ cells were localized in the bone-lining regions whereas CD271+CD56- cells were found in the perivascular regions. Since the iliac crest remains a frequent site of BM harvest for musculoskeletal regeneration, the authors also compared the spatial distribution of these subsets in trabeculae of femoral head and iliac crest and found CD271+CD56+ bone-lining cells in both tissues. CONCLUSION:: Chondrogenically distinct CTP subsets have distinct spatial localization in BM; hence, the harvest technique of BM determines the efficiency of cartilage formation. CLINICAL RELEVANCE:: The harvest technique of BM may be of major importance in determining the clinical success of BM mesenchymal stem/stromal cells in cartilage repair. PMID- 30419184 TI - Measuring Blood Pressure in Clinical Practice: We Can and Must Do Better. PMID- 30419183 TI - Impact of aortic stent-graft oversizing on outcomes of the chimney endovascular technique based on a new analysis of the PERICLES Registry. AB - OBJECTIVE: Chimney endovascular aortic aneurysm repair is gaining ever greater acceptance. However, persistent gutters leading to type IA endoleaks represent an unsolved issue. The aim of the current study was to analyze the impact of abdominal endograft oversizing to the occurrence of this phenomenon. METHODS: The PERformance of the snorkel/chImney endovascular teChnique in the treatment of compLex aortic PathologiesES registry includes the largest experience with chimney endovascular aortic aneurysm repair from 13 vascular centers in Europe and the U.S. Prospectively collected data from centers with standard use of the Endurant stent-graft and balloon-expandable covered stents as chimney grafts only were included in the present analysis. The parameter which varied was the degree of oversizing of the aortic stent-graft classifying the cohort in two groups, group A (20% and less oversizing) and group B (>20% of oversizing). The primary endpoint was the incidence of persistent type IA endoleak needed reintervention. Secondary endpoints were all-cause mortality and freedom from reintervention. RESULTS: Group A included 21 patients while group B 144. The mean preoperative pathology's neck length and diameter was 5.8 mm (+/-4.4) versus 4.9 mm (+/-3.8) and 27.6 mm (+/-4.7) versus 24.9 mm (+/-3.7) for group A and group B, respectively. The mean length of the new sealing zone after chimney graft placement was similar for both groups (group A versus group B; 17.9 mm versus 18.3 mm, respectively, P = .21). The percentage of oversizing of the aortic stent graft ranged between 13.8 and 20% versus 22.2 and 30%, for group A and group B, respectively. Patients of group A had more type 1A endoleaks, (14.3%) versus patients of group B (2.1%) based on the first follow-up imaging, P = .02. The incidence of persistent type IA endoleaks needing a reintervention was 14.3 and 1.4% for the group A and group B, respectively, P = .01. The mean volume of contrast medium used was greater in group A versus group B with 239 ml versus150 ml, P = .05. Additionally, 14.3% of patients of group A experienced acute renal failure compared to those in group B which was 1.0%, P = .01. CONCLUSIONS: Oversizing of ideally 30% of the Endurant stent-graft is associated with significant lower incidence of type IA endoleaks requiring reintervention for patients treated by chimney endovascular aortic aneurysm repair. PMID- 30419185 TI - Going digital: a narrative overview of the effects, quality and utility of mobile apps in chronic disease self-management. AB - Objective Smartphone health applications (apps) are being increasingly used to assist patients in chronic disease self-management. The effects of such apps on patient outcomes are uncertain, as are design features that maximise usability and efficacy, and the best methods for evaluating app quality and utility.Methods In assessing efficacy, PubMed, Cochrane Library and EMBASE were searched for systematic reviews (and single studies if no systematic review was available) published between January 2007 and January 2018 using search terms (and synonyms) of 'smartphone' and 'mobile applications', and terms for each of 11 chronic diseases: asthma, chronic obstructive lung disease (COPD), diabetes, chronic pain, serious mental health disorders, alcohol and substance addiction, heart failure, ischaemic heart disease, cancer, cognitive impairment, chronic kidney disease (CKD). With regard to design features and evaluation methods, additional reviews were sought using search terms 'design', 'quality,' 'usability', 'functionality,' 'adherence', 'evaluation' and related synonyms.Results Of 13 reviews and six single studies assessing efficacy, consistent evidence of benefit was seen only with apps for diabetes, as measured by decreased glycosylated haemoglobin levels (HbA1c). Some, but not all, studies showed benefit in asthma, low back pain, alcohol addiction, heart failure, ischaemic heart disease and cancer. There was no evidence of benefit in COPD, cognitive impairment or CKD. In all studies, benefits were clinically marginal and none related to morbid events or hospitalisation. Twelve design features were identified as enhancing usability. An evaluation framework comprising 32 items was formulated.Conclusion Evidence of clinical benefit of most available apps is very limited. Design features that enhance usability and maximise efficacy were identified. A provisional 'first-pass' evaluation framework is proposed that can help decide which apps should be endorsed by government agencies following more detailed technical assessments and which could then be recommended with confidence by clinicians to their patients.What is known about the topic? Smartphone health apps have attracted considerable interest from patients and health managers as a means of promoting more effective self-management of chronic diseases, which leads to better health outcomes. However, most commercially available apps have never been evaluated for benefits or harms in clinical trials, and there are currently no agreed quality criteria, standards or regulations to ensure health apps are user-friendly, accurate in content, evidence based or efficacious.What does this paper add? This paper presents a comprehensive review of evidence relating to the efficacy, usability and evaluation of apps for 11 common diseases aimed at assisting patients in self-management. Consistent evidence of benefit was only seen for diabetes apps; there was absent or conflicting evidence of benefit for apps for the remaining 10 diseases. Benefits that were detected were of marginal clinical importance, with no reporting of hard clinical end-points, such as mortality or hospitalisations. Only a minority of studies explicitly reported using behaviour change theories to underpin the app intervention. Many apps lacked design features that the literature identified as enhancing usability and potential to confer benefit. Despite a plethora of published evaluation tools, there is no universal framework that covers all relevant clinical and technical attributes. An inclusive list of evaluation criteria is proposed that may overcome this shortcoming.What are the implications for practitioners? The number of smartphone apps will continue to grow, as will the appetite for patients and clinicians to use them in chronic disease self-management. However, the evidence to date of clinical benefit of most apps already available is very limited. Design features that enhance usability and clinical efficacy need to be considered. In making decisions about which apps should be endorsed by government agencies and recommended with confidence by clinicians to their patients, a comprehensive but workable evaluation framework needs to be used by bodies assuming the roles of setting and applying standards. PMID- 30419186 TI - From Pretending to Truly Being OK: A Journey From Illness to Health With Postinfection Irritable Bowel Syndrome: The Provider's Perspective. PMID- 30419187 TI - LncRNA NKILA regulates endothelium inflammation by controlling a NF-kappaB/KLF4 positive feedback loop. AB - Endothelium inflammation, a key event in vascular pathological process, can lead to endothelial activation and subsequent vascular disorders. Long non-coding RNA NKILA plays an important regulatory role in pro-inflammatory response. However, the underlying molecular basis by which NKILA regulates endothelial inflammation is poorly understood. In this study, we identify NKILA as a critical repressor to protect the endothelium from inflammation. Mechanistically, we show that NKILA is able to positively mediate the expression of KLF4, an anti-inflammatory atheroprotective regulator in endothelial cells (ECs), by a NF-kappaB-mediated DNA methylation mechanism. Moreover, NF-kappaB is found to help recruit DNMT3A to the CpG island of KLF4 promoter, facilitating KLF4 promoter DNA methylation and transcriptional repression. More importantly, we find KLF4 can inversely attenuate NF-kappaB transcriptional activity via establishing a NF-kappaB/KLF4 positive feedback loop, which is under the control of NKILA. Hence, sustained endothelium inflammation will occur, once the NKILA becomes dysfunctional. These studies revealed that NKILA can function as a vital regulator to protect the endothelium from inflammatory lesions and related vascular diseases. PMID- 30419188 TI - Analysis of oxygen-18 labeled phosphate to study positional isotope experiments using LC-QTOF-MS. AB - A method is proposed in this paper for the determination of oxygen-18 labeled phosphate so that positional isotope experiments using sensitive and rapid liquid chromatography-QTOF-mass spectrometry (LC-QTOF-MS) experiments can be carried out. The positional isotope exchange technique is a useful tool in understanding the mechanisms and kinetics of many enzyme-catalyzed reactions. Detection of the positions and concentration of these exchanged isotopes is the key. Gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance imaging are commonly used analytical techniques for measurement of 18O/16O, 31P and 15N isotope enrichment. Since these techniques either require a time-consuming derivatization step or have a limited sensitivity, an LC and accurate mass-based method for monitoring 18O/16O exchange was developed and compared with a standard GC-MS method. Our results showed that the LC-QTOF-MS method developed was not only as accurate as the standard GC-MS method, but also a sensitive and robust analytical platform for the simultaneous determination of isotope enrichment and the analysis of positional isotopes without chemical derivation. The LC-QTOF-MS method developed was successfully applied to the measurement of 18O/16O in the reversibility study of ATP hydrolysis by Lon proteases. PMID- 30419189 TI - E2P-like states of plasma membrane Ca2+-ATPase characterization of vanadate and fluoride-stabilized phosphoenzyme analogues. AB - The plasma membrane Ca2+-ATPase (PMCA) belongs to the family of P-type ATPases, which share the formation of an acid-stable phosphorylated intermediate as part of their reaction cycle. The crystal structure of PMCA is currently lacking. Its abundance is approximately 0.1% of the total protein in the membrane, hampering efforts to produce suitable crystals for X-ray structure analysis. In this work we characterized the effect of beryllium fluoride (BeFx), aluminium fluoride (AlFx) and magnesium fluoride (MgFx) on PMCA. These compounds are known inhibitors of P-type ATPases that stabilize E2P ground, E2.P phosphoryl transition and E2.Pi product states. Our results show that the phosphate analogues BeFx, AlFx and MgFx inhibit PMCA Ca2+-ATPase activity, phosphatase activity and phosphorylation with high apparent affinity. Ca2+-ATPase inhibition by AlFx and BeFx depended on Mg2+ concentration indicating that this ion stabilizes the complex between these inhibitors and the enzyme. Low pH increases AlFx and BeFx but not MgFx apparent affinity. Eosin fluorescent probe binds with high affinity to the nucleotide binding site of PMCA. The fluorescence of eosin decreases when fluoride complexes bind to PMCA indicating that the environment of the nucleotide binding site is less hydrophobic in E2P-like states. Finally, measuring the time course of E -> E2P-like conformational change, we proposed a kinetic model for the binding of fluoride complexes and vanadate to PMCA. In summary, our results show that these fluoride complexes reveal different states of phosphorylated intermediates belonging to the mechanism of hydrolysis of ATP by the PMCA. PMID- 30419191 TI - Surgeon-Specific Quality Monitoring System for Coronary Artery Bypass Grafting. AB - BACKGROUND: We developed a multidimensional quality monitoring system using an electronic healthcare records-derived database, and mobile-based reports for individual cardiovascular surgeons. METHODS: This study included surgeons who performed coronary artery bypass grafting (CABG) at a single center in China from January to December 2015. Patient data were automatically derived from structured electronic health records. Surgeon-specific quality measures included in-hospital mortality and morbidity, transfusion-free procedure, use of internal mammary artery, postoperative length of stay, and hospitalization cost. The Technique for Order of Preference by Similarity to Ideal Solution method was used to create a composite quality measure and rank surgeons on performance. Surgeons were rated into 3 categories: the top 20%, middle 20% to 80%, and the bottom 20%. Quality data were delivered to surgeons through mobile-based reports. RESULTS: Forty surgeons performed 4288 CABG surgeries in 2015. For surgeons in the top, middle, and bottom performance categories, there was a trend of increase in risk adjusted in-hospital morbidity rate (2.66%, 2.89%, and 3.07%, respectively; P=0.5101). There were significant differences in the use of internal mammary artery (94.65%, 95.8%, 90.14%, respectively; P<0.0001), risk adjusted postoperative length of stay (7.01 days, 7.99 days, and 8.69 days, respectively; P<0.0001), and hospitalization cost (81.27 thousand yuan, 88.36 thousand yuan, and 102.77 thousand yuan, respectively; P<0.0001). CONCLUSIONS: We developed a surgeon specific quality monitoring system using structured electronic health records derived database, multidimensional measures, and mobile-based reporting. This system will facilitate quality reporting and peer comparison, and strengthen the effect of quality improvement. PMID- 30419190 TI - Financial analysis of free lung cancer screening program shows profitability using broader NCCN Guidelines. AB - BACKGROUND: Lung cancer screening with low-dose CT (LDCT) chest scans in high risk populations has been established as an effective measure of preventive medicine by the National Lung Screening Trial (NLST). However, the sustainability of funding a program is still controversial. We present a 2.5 year profitability analysis of our screening program using the broader National Comprehensive Cancer Network (NCCN) criteria. METHODS: Retrospective chart review was performed on the initial 2.5 year data set of a free LDCT chest scan program targeting the underserved Southeastern United States. Patients were selected by the NCCN high risk criteria, screening twice as many patients compared to CMS criteria. LDCT scans were performed during the off-service hours of our PET-CT scanner. Analysis of fiscal years 2015-2017 was done to evaluate indirect cost, direct cost, and adjusted net margin per case after factoring downstream revenue from positive scans and other findings. RESULTS: A total of 705 scans were performed with 418 patients referred for subsequent procedures or specialist evaluations. The mean overhead cost over total cost was 42.3%. The adjusted net margin per case was $ 212 in the first year but turned positive to $177 in the third fiscal year. The total break-even point of adjusted net margin was between 6-7% of indirect cost as a function of charges. Of the 60 new patients introduced to the hospital system, a gross margin per case of $211 was found. CONCLUSIONS: Free lung cancer screening can demonstrate profitability from downstream revenue with a lag time of 2 years. PMID- 30419192 TI - Contrasting effects of IGF binding protein-3 expression in mammary tumor cells and the tumor microenvironment. AB - IGFBP-3 has both stimulatory and inhibitory effects on cancer progression. The growth of EO771 mammary carcinoma cells as syngeneic tumors in C57BL/6 mice is reduced in Igfbp3-null (BP3KO) mice, suggesting that systemic IGFBP-3 enhances tumor progression. In this study we assessed the growth of EO771 cells expressing human IGFBP-3 in BP3KO mice. Cells expressing hIGFBP-3 showed decreased proliferation in vitro and increased levels of IGF-1 receptor (IGF1R) protein but not mRNA, consistent with sequestration of endogenous IGF by IGFBP-3. The growth rate of these cells was restored by exposure to IGF-1 or analogues with reduced affinity for IGFBP-3 (long Arg3-IGF-1) or IGF1R (Leu24-IGF-1). In EO771 cells implanted orthotopically into mice, hIGFBP-3 expression by the cells inhibited tumor establishment in BP3KO but not wild-type mice. For tumors that successfully established, final weight was not affected significantly by hIGFBP-3 expression. However, final tumor weight was inversely related to intratumoral T cell counts, and sera from BP3KO mice with tumors showed low-titer immunoreactivity against IGFBP-3. The contrasting effects on tumor establishment and progression of IGFBP 3 expressed by mammary carcinoma cells, compared to systemic stromal and circulating IGFBP-3, highlights the complexity of growth regulation by IGFBP-3 in mammary tumors. PMID- 30419193 TI - Orbital Lymphoma - An International Multicenter Retrospective Study. AB - PURPOSE: To investigate and characterize the clinical features of subtype specific orbital lymphoma. DESIGN: Retrospective, interventional case series. METHODS: The study included 7 international eye cancer centers. Patient data were collected from January 1, 1980 through December 31, 2017. A total of 797 patients with a histologically verified orbital lymphoma were included. The primary end points were overall survival, disease-specific survival and progression-free survival. RESULTS: The median age was 64 years, and 51% of patients were male. The majority of lymphomas were of B-cell origin (98%, n = 779). Extranodal marginal zone B-cell lymphoma (EMZL) was the most frequent subtype (57%, n = 452), followed by diffuse large B-cell lymphoma (DLBCL) (15%, n = 118), follicular lymphoma (FL) (11%, n = 91), and mantle cell lymphoma (MCL) (8%, n = 66). Localized Ann Arbor stage IE EMZL and FL were frequently treated with external beam radiation therapy. DLBCL, MCL and disseminated EMZL and FL were primarily treated with chemotherapy. EMZL and FL patients had a markedly better prognosis (10-year disease-specific survival of 92% and 71%, respectively) than DLBCL and MCL patients (10-year disease-specific survival of 41% and 32%, respectively). CONCLUSIONS: and Relevance: Four lymphoma subtypes were primarily found in patients with orbital lymphoma: EMZL, DLBCL, FL, and MCL. The histological subtype was found to be the main predictor for outcome, with EMZL and FL patients having a markedly better prognosis than DLBCL and MCL. PMID- 30419195 TI - Characterization of the T Cell Response to Polypropylene Mesh in Women with Complications. AB - BACKGROUND: Polypropylene mesh is widely used for surgical treatment of pelvic organ prolapse and stress urinary incontinence. While these surgeries demonstrate favorable functional and anatomical outcomes, their use has been limited by complications, the two most common being exposure and pain. Growing evidence suggests T lymphocytes play a critical role in regulating the host response to biomaterials. OBJECTIVES: To define and characterize the T cell response and correlate the response to collagen deposition in fibrotic capsules in mesh tissue complexes removed for the complications of pain versus exposure. STUDY DESIGN: Patients who were scheduled to undergo a surgical excision of mesh for pain or exposure at Magee-Women's Hospital were offered enrollment. Forty- two mesh vagina tissue complexes were removed for the primary complaint of exposure (n=24) versus pain (n=18). Twenty-one patients agreed to have an additional vaginal biopsy away from the site of mesh and served as control tissue. T cells were examined via immunofluorescent labeling for cell surface markers CD4+ (T helper), CD8+ (cytotoxic) and foxp3 (T regulatory cell). Frozen sections were stained with H&E for gross morphology and picrosirius red for collagen fiber analysis. Interrupted sodium-dodecyl sulfate gel electrophoresis was used to quantify the content of collagens type I and III, and the collagen III/I ratio. Growth factors TGF-Beta and CTGF implicated in the development of fibrosis were measured via enzyme-linked immunosorbent assays. Data were analyzed using Student's t-tests, mixed effects linear regression, and Spearman's correlation coefficients. RESULTS: Demographic data were not different between groups except for BMI, which was 31.7 for the exposure group and 28.2 for pain (P=0.04). Tissue complexes demonstrated a marked, but highly localized foreign body response. We consistently observed a teardrop shaped fibroma encapsulating mesh fibers in both pain and exposure groups, with the T cells localized within the tip of this configuration away from the mesh-tissue interface. All three T cell populations were significantly increased relative to control - CD4+ Thelper (P<0.001), foxp3+ Treg (P<0.001) and CD8+ cytotoxic T cell (P=0.034) in the exposure group. In the pain group, only Thelper (P<0.001) and Treg cells (P<0.001) were increased, with cytotoxic T cells (P=0.520) not different from control. Picrosirius red staining showed a greater area of green (thin) fibers in the exposure group (P=0.025) and red (thick) fibers in the pain group (P<0.001). The ratio of area green/(yellow + orange + red) representing thin vs. thick fibers was significantly greater in the exposure group (P=0.005). Analysis of collagen showed that collagen type I was increased by 35% in samples with mesh complications (exposure and pain) when compared to controls (P=0.043). Strong correlations between the pro-fibrosis cytokine TGF-beta and collagen type I and III were found in patients with pain (r>0.833; P=0.01) but not exposure (P>0.7). CONCLUSION: T cells appear to play a critical role in the long-term host response to mesh and may be a central pathway leading to complications. The complexity of this response warrants further investigation and has the potential to broaden our understanding of mesh biology and clinical outcomes. PMID- 30419194 TI - Amniotic Membrane Transplantation in Acute Severe Ocular Chemical Injury: A Randomized Clinical Trial. AB - PURPOSE: To compare the outcomes of conventional medical treatment versus combined medical treatment and amniotic membrane transplantation (AMT) in the management of patients with Roper-Hall grade IV ocular chemical injury. DESIGN: Randomized, parallel-controlled clinical trial METHODS: Setting: Single tertiary referral hospital. PATIENTS: 60 eyes of 60 patients with Roper-Hall grade IV ocular chemical injury with a minimum follow-up of 12 months were enrolled in the study. INTERVENTION: Patients were randomly assigned to two groups; Group 1 (30 eyes) received topical preservative-free lubricating gel and drops, chloramphenicol, betamethasone, homatropine, oral vitamin C, and doxycycline. Group 2 (30 eyes) received amniotic membrane transplant (AMT) on the entire ocular surface in addition to the medical treatment provided in Group 1. MAIN OUTCOME MEASURES: The main outcome measure was time to complete corneal epithelialization. Secondary outcome measures were best-corrected visual acuity (BCVA) and neovascularization in the central 5 mm of the cornea. RESULTS: Mean follow-up time was 20.3 +/- 2.5 months (13-24 months). Corneal epithelial defects healed within 72.6 +/- 30.4 days (21 to 180) in Group 1 versus 75.8 +/- 29.8 days (46 to 170) in Group 2 (P=0.610). Mean BCVA was 2.06 +/- 0.67 logMAR (0.4 to 2.6) versus 2.06 +/- 0.57 logMAR (1 to 2.9) in Groups 1 and 2, respectively (P=0.85). Group 1 developed more central corneal neovascularization (22 eyes; 73.3%) compared to Group 2 (16 eyes; 53.3%), however, it was not statistically significant (P=0.108). CONCLUSIONS: In comparison to conventional medical therapy, combined amniotic membrane transplantation and medical therapy does not accelerate corneal epithelialization or affect final visual acuity in severe chemical injuries. PMID- 30419196 TI - Complete molar pregnancy coexisting with a normal fetus in the third trimester. PMID- 30419197 TI - Re: Magnetic resonance imaging is often misleading when used as an adjunct to ultrasound in the management of placenta accrete spectrum disorders. PMID- 30419198 TI - Uterine Structural Abnormality and IUD Malposition: Analysis of Ultrasonographic and Demographic Variables of 517 Patients. AB - BACKGROUND: Intrauterine devices are currently one of the leading forms of reversible contraception in the world. However, in approximately 10 to 25% of women, intrauterine devices can become malpositioned, leading to consequences including pain, bleeding, as well as possible decreased contraceptive efficacy. OBJECTIVE: We sought to determine if certain reproductive and uterine characteristics are associated with an increased risk of intrauterine device malposition. We hypothesized that anatomical characteristics such as the presence of any uterine anomalies, particularly congenital anomalies and fibroids that may lead to cavitary distortion, will be associated with higher incidence of intrauterine device malposition. STUDY DESIGN: We conducted a retrospective case control study in an academic medical center. All patients presenting for scheduled ultrasound appointments for gynecologic indication between June 2004 and February 2016 were included (1,253 ultrasound reports identified). Of these, 236 demonstrated malpositioned intrauterine devices. With a control group of 281 patients with normal intrauterine device location, a total of 517 patients were included in the study. Transabdominal and transvaginal ultrasounds were performed followed by 3-dimensional rendering (as per our institution's protocol for patients with intrauterine devices) using Voluson 730 and Voluson E8 (GE Healthcare) ultrasound machines. Demographic and reproductive characteristics, indication for ultrasound, intrauterine device, and uterine characteristics were all extrapolated from the electronic medical record. STATISTICAL ANALYSIS: Chi square tests were performed with categorical variables. Generalized linear models for Poisson distributed variables, and multiple logistic regression were used to ascertain significant independent predictors of IUD malposition. Ninety-five percent confidence intervals and effect sizes were calculated and p<0.05 was considered statistically significant. RESULTS: In this study, we found a cumulative IUD malposition rate of 19%. In patients with malpositioned intrauterine devices, there was increased incidence of retroflexed uterine positions (7.6% vs. 1.8%, p=0.001), and all uterine anomalies (this includes septate and bicornuate uteri and fibroids, 31.9% vs. 23.5%, p=0.02) compared to controls. The anterior midline uterine position was more commonly noted in controls (28.5% vs. 11%, p<0.001). A higher total number of fibroids was noted in the malpositioned group (3.7% vs. 1.8%, p=0.01), however fibroid size was not statistically significant. In particular, there was an increased incidence of submucosal fibroids in women with malpositioned intrauterine devices (p=0.01). Multivariable logistic regression revealed that anterior midline position (OR 0.33, 95% CI 0.20-0.57) and absence of uterine anomalies (OR 0.59, 95% CI 0.38 0.93) were factors associated with a lower risk of IUD malposition; whereas vaginal bleeding (OR 2.25, 95% CI 1.38-3.67), pain (OR 2.85, 95% CI 1.84-4.44), or missing IUD strings at time of presentation (OR 3.58, 95% CI 1.88-6.82) were associated with an increased risk of malposition. CONCLUSIONS: Retroflexed uterine positions and all uterine malformations are associated with higher incidence of malpositioned intrauterine devices. Presence of increased number of fibroids and specifically submucosal fibroids showed a positive association with intrauterine device malposition, as did symptoms of bleeding, pain, and missing IUD strings at time of presentation. These findings pertain to women presenting for gynecologic ultrasound evaluation and may not be generalizable to all women with IUDs. PMID- 30419200 TI - Achieving High-Value in the Surgical Approach to Hysterectomy. AB - Value-based care, best clinical outcome relative to cost, is a priority in correcting the high costs for average clinical outcomes of health care delivery in the United States. Hysterectomy represents the most common and identifiable non-obstetric major surgical procedure among women. Surgical approaches to hysterectomy in the United States have changed in recent decades. For benign indications, clinical evidence identifies the superiority of vaginal hysterectomy to all other routes. These conclusions rest on clinical outcomes; however, cost differentials also exist across hysterectomy approach with the vaginal approach consistently possessing the lowest overall costs. Taken together, vaginal hysterectomy possesses the highest value, while the robotic (given high costs) and abdominal approaches (given less favorable clinical outcomes) possess less value. Traditional laparoscopic hysterectomy holds an intermediate value. Increasing the utilization of high-value hysterectomy approaches can be achieved by adopting multimodal strategies with changes in the payment models being the most important. PMID- 30419199 TI - Depressive symptoms among women with endometriosis: a systematic review and meta analysis. AB - OBJECTIVE: To evaluate whether endometriosis is associated with depressive symptoms, and whether the association is modulated by pelvic pain. DATA SOURCES: PubMed, Embase, PsychINFO, and the Cochrane Library, were systematically searched through September 2017. STUDY ELIGIBILITY CRITERIA: The following eligibility criteria applied: full-text original article; quantitative data about depressive symptoms or depression; comparing women with and without endometriosis, or women with endometriosis with and without pelvic pain. Articles reporting duplicated data were excluded. STUDY APPRAISAL AND SYNTHESIS METHODS: Two reviewers selected and reviewed the studies. Disagreements were resolved through discussion or a third opinion. Qualitative synthesis was performed through tabulation and assessment using a modified version of the Newcastle-Ottawa Scale. Effect sizes were pooled through meta-analysis and moderator analyses were performed to identify potential confounders with several variables: region of the sample, method of ascertainment of endometriosis, method of measurement of depression, year of publication, quality score. RESULTS: A meta-analysis of 24 studies (99,614 women) showed higher levels of depression among women with endometriosis compared to controls (standardized mean difference [SMD] =0.22, 95%CI:0.12-0.32). The heterogeneity in this analysis (I2=68%) was not explained by any of the moderating variables. When only healthy controls were considered, a larger endometriosis-depression effect was found (11 studies, SMD=0.49, 95%CI:0.24-0.73; I2=69%). Endometriosis patients reporting pelvic pain had significantly higher levels of depression compared to those without pain (4 studies, SMD=1.01, 95%CI:0.71-1.31; I2=0%). No significant difference was found between women with pelvic pain and endometriosis and those with pelvic pain but without endometriosis (11 studies, SMD=-0.11, 95%CI:-0.25-0.04; I2=0%). CONCLUSIONS: The association between endometriosis and depressive symptoms is largely determined by chronic pain but may also be modulated by individual and context vulnerabilities. Awareness of the complex relationship between endometriosis and depressive symptoms informs tailored care and patient-centred research outcomes. PMID- 30419201 TI - Clarifications in reply to Rottenstreich and colleagues. PMID- 30419202 TI - Molecular mechanism of metabolic NAD(P)H-dependent electron-transfer systems: The role of redox cofactors. AB - NAD(P)H-dependent electron-transfer (ET) systems require three functional components: a flavin-containing NAD(P)H-dehydrogenase, one-electron carrier and metal-containing redox center. In principle, these ET systems consist of one-, two- and three-components, and the electron flux from pyridine nucleotide cofactors, NADPH or NADH to final electron acceptor follows a linear pathway: NAD(P)H -> flavin -> one-electron carrier -> metal containing redox center. In each step ET is primarily controlled by one- and two-electron midpoint reduction potentials of protein-bound redox cofactors in which the redox-linked conformational changes during the catalytic cycle are required for the domain domain interactions. These interactions play an effective ET reactions in the multi-component ET systems. The microsomal and mitochondrial cytochrome P450 (cyt P450) ET systems, nitric oxide synthase (NOS) isozymes, cytochrome b5 (cyt b5) ET systems and methionine synthase (MS) ET system include a combination of multi domain, and their organizations display similarities as well as differences in their components. However, these ET systems are sharing of a similar mechanism. More recent structural information obtained by X-ray and cryo-electron microscopy (cryo-EM) analysis provides more detail for the mechanisms associated with multi domain ET systems. Therefore, this review summarizes the roles of redox cofactors in the metabolic ET systems on the basis of one-electron redox potentials. In final Section, evolutionary aspects of NAD(P)H-dependent multi-domain ET systems will be discussed. PMID- 30419203 TI - Probiotics for Treating Irritable Bowel Syndrome: Are Bugs the Best Drugs? PMID- 30419205 TI - How to Approach a Patient With Ampullary Lesion. PMID- 30419206 TI - Is Liver Injury an Affordable Risk of Immune Checkpoint Inhibitor Therapy for Cancer? PMID- 30419207 TI - Reply. PMID- 30419208 TI - From Pretending to Truly Being OK: A Journey from Illness to Health with Post Infection IBS: The Provider's Perspective. PMID- 30419209 TI - Refining Classification of Pancreatic Cancer Subtypes to Improve Clinical Care. PMID- 30419210 TI - Even When You Know Everything, There Is Still More to Learn About Hirschsprung Disease. PMID- 30419211 TI - How Effective Are Secretagogues for Irritable Bowel Syndrome With Constipation. PMID- 30419212 TI - Macrophages Steal STING From the Infectious Disease Playbook to Promote Nonalcoholic Fatty Liver Disease. PMID- 30419213 TI - Do Sex Hormones Cause, or Are They Only Associated With, Microscopic Colitis? PMID- 30419214 TI - Next Steps for Immune Checkpoints in Hepatocellular Carcinoma. PMID- 30419216 TI - The vasodilating effect of glucose differs among vessels at different branching level in the porcine retina ex vivo. AB - Diabetic retinopathy is characterized by retinal lesions related to disturbances in retinal blood flow. The metabolic dysregulation in diabetes involves hyperglycemia which in both clinical and experimental studies has been shown to induce dilatation of larger retinal vessels, which has been suggested to be mediated by nitric oxide (NO). However, the effects of glucose on the diameter of smaller retinal vessels that are the site of development of diabetic retinopathy are unknown. Diameter changes in porcine retinal arterioles, pre-capillary arterioles and capillaries were studied ex vivo during acute changes in intraluminal glucose concentrations that mimicked changes in plasma glucose in diabetic patients. The experiments were repeated during blocking of NO-synthesis. Intravascular application of 2 mM glucose dilated arterioles and capillaries significantly, while 20 mM glucose dilated precapillary arterioles significantly. Intravascular application of 20 mM glucose dilated precapillary arterioles previously exposed to 2 mM glucose, while no significant diameter changes were observed after application of 2 mM glucose in vessels previously exposed to 20 mM glucose. No diameter changes were observed after application of 5.5 mM glucose in vessels previously exposed to both 2 mM and 20 mM glucose in either order. There was no significant difference between the diameter responses in the absence and presence of NO-synthesis blocker. Glucose induced dilatation of porcine precapillary arterioles ex vivo differs from the response in larger arterioles and capillaries, and the response is unaffected by the blocking of NO-synthesis. This may have implications for understanding the pathophysiology of diseases in the retinal microcirculation, such as diabetic retinopathy. PMID- 30419217 TI - Psychrotolerant bacteria isolated from the leaf apoplast of cold-adapted wild plants improve the cold resistance of bean (Phaseolus vulgaris L.) under low temperature. AB - We have isolated psychrotolerant bacteria from the leaf apoplast of cold-adapted wild plants and aimed to investigate their effect on the cold resistance of bean (Phaseolus vulgaris L.). Based on the findings of 16S rRNA gene sequence analysis, 20 isolates belonging to 5 bacteria species (Pseudomonas fragi, P. chloropaphis, P. fluorescens, P. proteolytica and Brevibacterium frigoritolerans) were identified in the leaf apoplastic fluid of Draba nemorosa, Galanthus gracilis, Colchicum speciousum, Scilla siberica, Erodium cicutarium, respectively. We have determined that 6 of the 20 isolates have exhibited ACC (1 aminocyclopropane-1-carboxylate) deaminase activity and secreted different extracellular proteins under cold condition (+4 degrees C) compared to normal growth condition (28 degrees C). The six isolates were then inoculated independently of each other to the leaves of 10-day-old bean seedlings growing under normal conditions (25/22 degrees C, 16/8 h photoperiod), and the inoculated and uninoculated (control) seedlings were transferred to cold (9/5 degrees C, 16/8 h photoperiod) for 3 days. The bacterial inoculations have decreased freezing injury, ice nucleating activity and lipid peroxidation content in parallel with the decrease of reactive oxygen species level such as O2.- and H2O2 in the inoculated seedlings compared to the control. In addition, the inoculations of the isolates have stimulated the activity of apoplastic antioxidant enzymes including superoxide dismutase, catalase, peroxidase, and glutathione reductase. The results show that the inoculations improve the cold resistance of bean seedlings and the psychrotolerant bacterial isolates can be evaluated within the group of plant growth promoting bacteria (PGPB) which can increase tolerance of cold-sensitive crops. PMID- 30419218 TI - Blue-light imaging has an additional value to white-light endoscopy in visualization of early Barrett's neoplasia. an international multicenter cohort study. AB - BACKGROUND AND AIMS: Endoscopic features of early neoplasia in Barrett's esophagus (BE) are subtle. Blue-light imaging (BLI) may improve visualization of neoplastic lesions. The aim of this study was to evaluate BLI in visualization of Barrett's neoplasia. METHODS: Corresponding whit- light endoscopy (WLE) and BLI images of 40 BE lesions were obtained prospectively and assessed by 6 international experts in 3 assessments. Each assessment consisted of overview and magnification images. Assessments were as follows: Assessment 1: WLE only; Assessment 2: BLI only; and Assessment 3: corresponding WLE and BLI images. Outcome parameters were as follows: (1) appreciation of macroscopic appearance and surface relief (VAS-scores); (2) ability to delineate lesions (VAS-scores); (3) preferred technique for delineation (ordinal scores); and (4) quantitative agreement on delineations (AND/OR scores). RESULTS: Experts appreciated BLI significantly better than WLE for visualization of macroscopic appearance (median 8.0 vs 7.0, P<0.001) and surface relief (8.0 vs 6.0, P<0.001). For both overview and magnification images, experts appreciated BLI significantly better than WLE for ability to delineate lesions (8.0 vs 6.0, P<0.001 and 8.0 vs 5.0, P<0.001). There was no overall significant difference in AND/OR scores of WLE+BLI when compared with WLE, yet agreement increased significantly with WLE+BLI for cases with a low baseline AND/OR score on WLE, both in overview (mean difference 0.15, P=0.015) and magnification (mean difference 0.10, P=0.01). CONCLUSIONS: BLI has additional value for visualization of BE neoplasia. Experts appreciated BLI better than WLE for visualization and delineation of BE neoplasia. Quantitative agreement increased significantly when BLI was offered next to WLE for lesions that were hard to delineate with WLE alone. PMID- 30419219 TI - Altered electrical properties with controlled copper doping in ZnO nanoparticles infers their cytotoxicity in macrophages by ROS induction and apoptosis. AB - The present study reports the regulation of cytotoxicity of Cu doped ZnO nanoparticles in macrophages (RAW 264.7) due to altered physiochemical properties changes like electrical properties by controlled doping of Cu in ZnO. Cu-doped ZnO nanoparticles were prepared by High Energy Ball Milling technique (HEBM) and formed single phase Zn1-xCuxO (x = 0.0, 0.01, 0.02, 0.03) were called as pure ZnO, Cu1%, 2%, 3% respectively. Hexagonal wurtzite structure with size range of 22-26 nm was verified. FE-SEM with EDX analysis indicated the Cu doping effect on the surface morphology of ZnO. Zeta potential of Zn1-xCuxO was found to be elevated with increase in doping percentage of Cu (-36.6 mV to +18.2 mV). Dielectric constant was found to be decreased with increasing doping percentage. Increase in doping percentage enhanced cytotoxicity of Zn1-xCuxO in macrophages with LC50 of 62 MUg/ml, 51 MUg/ml, 40 MUg/ml, 32 MUg/ml. Granularity change of macrophages suggested doping influenced cellular uptake as consequence of zeta potential and dielectric properties changes. 3% Cu doped ZnO shown a higher ROS signal and apoptosis than 2% and 1% Cu doping with exhibition of ROS scavenging nature leading to apoptosis of prepared Cu doped ZnO nanoparticles. Our findings revealed mechanism of cytotoxicity of Zn1-xCuxO as a consequence of alteration in electric properties eliciting ROS scavenging leading to higher apoptosis with increasing doping percentage of Cu in ZnO. PMID- 30419220 TI - A novel mixed hemimicelles dispersive micro-solid phase extraction using ionic liquid functionalized magnetic graphene oxide/polypyrrole for extraction and pre concentration of methotrexate from urine samples followed by the spectrophotometric method. AB - Methotrexate (MTX) is an anticancer drug that is widely used in a variety of cancers including primary central nervous system lymphoma. It is also administrated in the treatment of some autoimmune diseases. A simple, accurate, sensitive, and precise mixed hemimicelles dispersive micro-solid phase extraction was proposed for MTX quantification in human urine samples. MTX was quantified by spectrophotometer after dispersive micro-solid phase extraction using ionic liquid functionalized magnetic graphene oxide/polypyrrole. Interactions of adsorbent and MTX were modeled by molecular docking and the interaction energy was predicted to be -8.35 kcal/mol. A larger absolute value of binding energy represents larger adsorption strength, indicating that graphene oxide nanosheets could perform higher adsorption strength toward MTX. The concentrations of MTX were proportional to analytical response in amounts ranging from 10 to 1000 ng/mL with a good correlation (R2 = 0.99). Inter- and intra-day precisions and accuracies were within the acceptable limit according to FDA guideline (15% for biological determination). The recoveries were ranging from 89 to 93% and the method was specific for routine analysis of MTX. This protocol was applied to the urine of two patients under MTX therapy received an intravenous administration of 1 mg/kg/dose of MTX with acute lymphoblastic leukemia. The accuracy of the method was confirmed by HPLC measurements. PMID- 30419221 TI - Exosomes in inflammation and role as biomarkers. AB - Exosomes are endosomal-derived nano-vesicles. They are considered vehicles through which donor cells transfer proteins, lipids and nucleic acids to target cells thus influencing their metabolism. Exosomes are involved in inflammatory processes that play a pivotal role in a large number of pathologic states including cancer, inflammatory bowel diseases, type 2 diabetes, obesity, rheumatoid arthritis and neurodegenerative diseases. The association between inflammation and change in nature or expression level of some exosomal cargos is the fundamental step for identifying possible novel biomarkers of inflammatory based diseases. A novel interesting exosome cargo is the SLC22A5 transport protein whose level in exosomes is regulated by the pro-inflammatory cytokine INF gamma. The advantage of using exosomes as a biomarker vehicle consists of their ease of collection from body fluids such as urine and saliva as they may represent a non-invasive means for screening human pathology. PMID- 30419222 TI - Cerebral Blood Flow Features in Chronic Subcortical Stroke: Lesion Location Dependent Study. AB - We investigated the influence of lesion location on cerebral blood flow (CBF) in chronic subcortical stroke patients. Three-dimensional pseudocontinuous arterial spin labeling was employed to obtain CBF images in normal controls (NC) and patients with left hemisphere subcortical infarctions involving motor pathways. Stroke patients were divided into two subgroups based on the infarction location (basal ganglia (BS) or pontine (PS). We mapped CBF alterations in a voxel-wise manner and compared them to detect differences among groups with height-level false discovery rate correction. Regions with significant group differences were extracted to perform post hoc analyses among the BS, PS and NC groups using a general linear model with age, gender, years of education, and interval after stroke as covariates. The BS group displayed significantly increased CBF in the contralesional putamen relative to NC and significantly decreased CBF in the ipsilesional sensorimotor cortex, ipsilesional thalamus and contralesional cerebellum. The PS group displayed significantly increased CBF in the contralesional inferior frontal gyrus relative to both the NC and BS groups. Nevertheless, the PS group showed significantly decreased CBF mainly in the cerebellum. Our results suggest different alteration patterns of CBF in chronic stroke patients with different infarct locations within subcortical motor pathways, potentially providing important information for the initiation of individualized rehabilitation strategies for subcortical stroke patients involving different infarct types. PMID- 30419223 TI - The Inhibitory Effect of Different Patterns of Low Frequency Stimulation on Neuronal Firing following Epileptiform Activity in Rat Hippocampal Slices. AB - Low frequency stimulation (LFS) has inhibitory effect on hyperexcitability during epileptic states. However, knowledge is lacking about LFS patterns that can exert an optimal antiepileptic effect. In this study, the effect of different numbers of pulses and current intensities of 1 Hz LFS applied at various time points of epileptiform activity was evaluated in high-K+ model of epileptiform activity (EA). LFS was applied to the Schaffer collaterals, and changes in the excitability of CA1 pyramidal neurons were measured using whole-cell patch-clamp recording. Six hundred and 900 pulses of LFS at two current intensities (equal to and 1.5 times greater than the current intensity sufficient to elicit a 5 mV EPSP) administered at the beginning of EA revealed a stronger LFS inhibitory effect on EA-induced neuronal hyperexcitability when applied at higher pulse number and current intensity. LFS900 (high intensity) significantly hyperpolarized the membrane potential after a high-K+ ACSF washout, reduced the frequency of spontaneous action potentials during EA, and attenuated neuronal firing frequency after high-K+ ACSF washout. Moreover, applying LFS900 (high intensity) before EA induction and 8-10 min after EA initiation could not significantly affect neuronal hyperexcitability, compared to its application at the beginning of EA. This study's findings also offered long-term depression (LTD) as a probable mechanism for LFS' inhibitory role on EA-induced neuronal hyperexcitability. Therefore, the application of LFS (1 Hz) at 900 pulses and greater current intensity at the beginning of EA can exert a strong inhibitory effect on EA-induced neuronal hyperexcitability. PMID- 30419224 TI - Cannabis legalization does not influence patient compliance with opioid therapy. AB - BACKGROUND: Prescription opioid use and opioid related deaths continue to increase nationwide. Several states have adopted legislation allowing for recreational use of cannabis. Little is known about how recreational cannabis law impacts compliance in chronic pain patients prescribed opioid therapy. The goals of this study were to: 1) Retrospectively assess the effect of cannabis use on compliance with opioid therapy in a high-risk patient population and 2) Determine the impact that legalization of recreational cannabis had on patients prescribed therapeutic opioids. METHODS: We conducted a retrospective cohort study on results from a "high-risk" urine drug testing panel. Results from one year before and one year after initiation of recreational cannabis legislation were analyzed. This testing panel included qualitative assays for cannabinoids and nine other common drugs of abuse, in addition to a quantitative LC-MS/MS assay for 23 different opioids and metabolites. Opioid compliance was assigned by reviewing pathologist's interpretations. RESULTS: In the pre-legalization period 1,776 panels were performed and post-legalization, 1,648 panels were performed. An increase (6%) in the rate of positive cannabinoid results was observed after legalization of recreational cannabis, however the overall compliance rate was consistent. CONCLUSIONS: This study suggests that legalization of recreational cannabis does not affect compliance rate in patients treated with opioid therapy for chronic pain. PMID- 30419225 TI - Divisions, Departments, and the 2018 Red Sox Baseball Team: Qualities of Leadership That Lead to Success. PMID- 30419226 TI - Altitude Sickness Prevention with Ibuprofen Relative to Acetazolamide. AB - BACKGROUND: Acute mountain sickness is a common occurrence for travel to high altitudes. Although previous studies of ibuprofen have shown efficacy for the prevention of acute mountain sickness, recommendations have been limited, as ibuprofen has not been compared directly with acetazolamide until this study. METHODS: Before their ascent to 3810 m on White Mountain in California, adult volunteers were randomized to ibuprofen (600 mg, 3 times daily, started 4 hours before the ascent), or to acetazolamide (125 mg, twice daily, started the night before the ascent). The main outcome measure was acute mountain sickness incidence, using the Lake Louise Questionnaire (LLQ), with a score of >3 with headache. Sleep quality and headache severity were measured with the Groningen Sleep Quality Survey (GSQS). This trial was registered at ClinicalTrials.gov: NCT03154645 RESULTS: Ninety-two participants completed the study: 45 (49%) on ibuprofen and 47 (51%) on acetazolamide. The total incidence of acute mountain sickness was 56.5%, with the incidence for the ibuprofen group being 11% greater than that for acetazolamide, surpassing the predetermined 26% noninferiority margin (62.2% vs 51.1%; 95% confidence interval [CI], -11.1 to 33.5). No difference was found in the total LLQ scores or subgroup symptoms between drugs (P = .8). The GSQS correlated with LLQ sleep (r = 0.77; 95% CI, 0.67-0.84)=%. The acetazolamide group had higher peripheral capillary oxygen saturation than the ibuprofen group (88.5% vs 85.6%; P = .001). CONCLUSION: Ibuprofen was slightly inferior to acetazolamide for acute mountain sickness prevention and should not be recommended over acetazolamide for rapid ascent. Average symptoms and severity were similar between drugs, suggesting prevention of disease. PMID- 30419227 TI - Risk Estimation in Type 2 Myocardial Infarction and Myocardial Injury: The TARRACO Risk Score. AB - BACKGROUND: Despite adverse prognoses of type 2 myocardial infarction and myocardial injury, an effective, practical risk stratification method remains an unmet clinical need. We sought to develop an efficient clinical bedside tool for estimating the risk of major adverse cardiovascular events at 180 days for this patient population. METHODS: The derivation cohort included patients with type 2 myocardial infarction or myocardial injury admitted to a tertiary hospital between 2012 and 2013 (n = 611). The primary outcome was a major adverse cardiovascular event (death or readmission for heart failure or myocardial infarction). The score included clinical variables significantly associated with the outcome. External validation was conducted using the UTROPIA cohort (n = 401). RESULTS: The TARRACO Score included cardiac troponin (cTn) concentrations and 5 independent clinical predictors of adverse cardiovascular events: age, hypertension, absence of chest pain, dyspnea, and anemia. The score exhibited good discriminative accuracy (area under the curve = 0.74; 95% CI, 0.70-0.79). Patients were classified into low-risk (score 0-6) and high-risk (score >=7) categories. Major adverse cardiovascular events rates were 5 times more likely in high-risk patients compared with those at low risk (78.9 vs 15.4 events/100 patient-years, respectively; logrank P < .001). The external validation showed equivalent prognostic capacity (area under the curve=0.71, 0.65-0.78). CONCLUSION: A novel risk score based on bedside clinical variables and cTn concentrations allows risk stratification for death and cardiac-related rehospitalizations in patients with type 2 myocardial infarctions and myocardial injury. This score identifies patients at the highest risk of adverse events, a subset of patients who may benefit from close observation, medical intensification, or both. PMID- 30419228 TI - Learnings about the complexity of extracellular tau aid development of a blood based screen for Alzheimer's disease. AB - INTRODUCTION: The tau protein plays a central role in Alzheimer's disease (AD), and there is huge interest in measuring tau in blood and cerebrospinal fluid (CSF). METHODS: We developed a set of immunoassays to measure tau in specimens from humans diagnosed based on current best clinical and CSF biomarker criteria. RESULTS: In CSF, mid-region- and N-terminal-detected tau predominated and rose in disease. In plasma, an N-terminal assay (NT1) detected elevated levels of tau in AD and AD-mild cognitive impairment (MCI). Plasma NT1 measurements separated controls from AD-MCI (area under the curve [AUC] = 0.88) and AD (AUC = 0.96) in a discovery cohort and in a Validation Cohort (with AUCs = 0.79 and 0.75, respectively). DISCUSSION: The forms of tau in CSF and plasma are distinct, but in each specimen type, the levels of certain fragments are increased in AD. Measurement of plasma NT1 tau should be aggressively pursued as a potential blood based screening test for AD/AD-MCI. PMID- 30419229 TI - Regular handling reduces corticosterone stress responses to handling but not condition of semi-precocial mottled petrel (Pterodroma inexpectata) chicks. AB - Handling of avian study species is common in ecological research, yet few studies account for the impact of handling in nestlings where exposure to stress may result in negative lifetime fitness consequences. As a result, our understanding of stress reactivity in free-living avian young is limited. In this study we examined the cumulative impact of three levels of research-relevant handling (control, daily and every three days) on the development of the stress response, growth and condition of semi-precocial seabird chicks from near-hatching to near fledging. By measuring corticosterone concentrations in plasma, we found that mottled petrel (Pterodroma inexpectata) chicks were capable of mounting a stress response comparable to adults from near-hatching. There were no differences in plasma corticosterone concentrations in initial samples (<4 min) between groups at six weeks of age, though by 12 weeks of age plasma corticosterone concentrations in initial samples collected from chicks handled daily were lower than chicks that were handled once every three days, and from control chicks. Corticosterone responses to handling were lower in chicks handled daily at six and 12 weeks of age when compared to other handling groups. Handling chicks daily or every three days had no negative effect on the growth or condition of chicks when compared to control chicks. These findings indicate that daily handling results in chicks became accustomed to handling, with no evidence that regular handling was detrimental to mottled petrel chicks. However, given the unique life history characteristics of mottled petrels relative to closely related species, we caution that this finding may be species-specific, and wider testing is recommended. PMID- 30419230 TI - Effects of green light on the growth of spotted halibut, Verasper variegatus, and Japanese flounder, Paralichthys olivaceus, and on the endocrine system of spotted halibut at different water temperatures. AB - We have previously shown that the somatic growth of barfin flounder, Verasper moseri, was promoted by green light. The present study was undertaken to elucidate whether growth-promoting effect of green light can be observed in other flatfishes and to understand the roles of endocrine systems in green light induced growth. Herein, we demonstrated facilitation of growth by green light in the spotted halibut, Verasper variegatus, and Japanese flounder, Paralichthys olivaceus. Blue and blue-green light showed potencies that were similar to that of green light, while the potencies of red and white light were equivalent to that of ambient light (control). We also examined the effects of green light on growth and endocrine systems of V. variegatus at various water temperatures. Growth of the fish was facilitated by green light at four different water temperatures examined; the fish were reared for 31 days at 12 and 21 degrees C, and 30 days at 15 and 18 degrees C. Increase in condition factor was observed at 15 and 18 degrees C. Among the genes encoding hypothalamic hormones, expression levels of melanin-concentrating hormone 1 (mch1) were enhanced by green light at the four water temperatures. Expression levels of other genes including mch2 increased at certain water temperatures. No difference was observed in the expression levels of pituitary hormone genes, including those of growth hormone and members of proopiomelanocortin family, and in plasma levels of members of the insulin family. The results suggest that green light may generally stimulate growth of flatfishes. Moreover, it is conceivable that MCH, production of which is stimulated by green light, is a key hormone; it augments food intake, which is intimately coupled with somatic growth. PMID- 30419231 TI - Implementation of pressure injury prevention best practices across six Canadian rehabilitation sites: results from the Spinal Cord Injury Knowledge Mobilization Network. AB - OBJECTIVE: To utilize the theoretical frameworks of implementation science to implement pressure injury (PI) prevention best practices in spinal cord injury (SCI) rehabilitation. DESIGN: Quality Improvement SETTING: Six Canadian SCI rehabilitation centers PARTICIPANTS: Inpatients admitted 2011-2015 INTERVENTIONS: The SCI Knowledge Mobilization Network (SCI KMN) selected and implemented two PI prevention best practices at six Canadian SCI rehabilitation centers: (1) completing a comprehensive PI risk assessment comprised of a structured risk assessment instrument followed by an individualized, interprofessional risk factor determination and prevention plan; and (2) providing structured and individualized PI prevention patient education. Active Implementation Frameworks provided a systematic approach to best practice implementation. OUTCOME MEASURES: Implementation indicators (completion rates) and patient outcomes (PI incidence; patient education survey). RESULTS: Following implementation, risk assessment completion rates improved from 46% to 82% (p<0.05). Between initial (2012-13) and full (2014-15) implementation stages, completion rates improved for both interprofessional risk factor determination (67% to 96%) and prevention plans (67% to 94%). Documentation of patient education also increased to 86% (71% pre implementation). The incidence of PIs at rehabilitation admission was 22%, with 14% of individuals developing new PIs during rehabilitation. The overall PI prevalence was 30%. Considering only PIs of stage 2 or greater, prevalence was 21% and incidence 7%. There were no statistically significant differences in PI incidence between pre- and post-implementation. Patient education surveys indicated that PI education improved patients' knowledge of prevention strategies. CONCLUSIONS: Active Implementation Frameworks supported successful implementation of PI prevention best practices across the six participating SCI KMN sites. Achieving a reduction in PI incidence will require additional measures, and there is an ongoing need to strengthen the evidence base underpinning PI prevention guidelines. PMID- 30419232 TI - Improvement of upper limb motor control and function after competitive and non competitive volleyball exercises in chronic stroke survivors: A randomized clinical trial. AB - OBJECTIVES: To investigate the effects of competitive and non-competitive volleyball exercises on the functional performance and motor control of the upper limbs in chronic stroke survivors. DESIGN: Randomized clinical trial. SETTING: Outpatient rehabilitation center. PARTICIPANTS: Forty-eight chronic stroke survivors. INTERVENTIONS: Participants were randomly assigned to competitive (n=16) or non-competitive (n=16) volleyball exercise groups (60 min/day volleyball exercise + 30 min/day traditional rehabilitation, 3 day/week for 7 weeks) and control group (n=16). MAIN OUTCOME MEASURES: Reach and grasp motor control measures were evaluated through kinematic analysis. Functional outcomes were assessed via Motor Activity Log, Wolf Motor Function Test, Box and Block Test, as well as, Wrist Position Sense Test. RESULTS: Significant improvement of functional performance was observed in both competitive (P <0.0001) and non competitive volleyball exercise groups (P <0.01), but not in the control group (P >0.05), with the exception of Wolf Motor Function Test score. Volleyball training, in general, resulted in more efficient spatiotemporal control of reach and grasp functions, as well as less dependence on feedback control as compared to the control group. Moreover, the competitive volleyball exercise group exhibited greater improvement in both functional performance and motor control levels. CONCLUSIONS: Volleyball team exercises, especially in a competitive format, resulted in enhancing the efficacy of the pre-programming and execution of reach and grasp movements, as well as a shift from feedback to feedforward control of the affected upper limb in chronic stroke survivors. This may well be a potential underlying mechanism for improving functional performance. PMID- 30419233 TI - Trends in Hospitalization and In-Hospital Mortality from Venous Thromboembolism, 2007 to 2016, in China. AB - BACKGROUND: Venous thromboembolism (VTE) has emerged as a major public health problem. However, data on VTE burden in China is seldom reported. METHODS: We collected data on patients with principal diagnose of VTE, pulmonary embolism (PE), or deep vein thrombosis (DVT) using the International Classification of Diseases, 10th Revision (ICD-10) from 90 hospitals across China. The trends in hospitalization rate, mortality, length of stay (LOS), and comorbidities from 2007 to 2016 were analyzed. RESULTS: In total, 105,723 patients with VTE were identified. For patients with VTE, age-sex-adjusted hospitalization rate increased from 3.2 to 17.5 per 100,000 population and in-hospital mortality decreased from 4.7% to 2.1% (P<0.001). The mean LOS declined from 14 days to 11 days (P<0.001). And the data in 2016 showed that the hospitalization rate of VTE was higher in elderly male patients (males vs. females, 155.3 vs. 125.4 per 100,000 population in patients aged >=85 years old, P<0.001) and northern China (north vs. south, 18.4 vs. 13.4 per 100,000 population, P<0.001). Higher mortality rates were found in patients with cancer and Charlson Comorbidity Index (CCI) >2. Similar trends were also observed in patients with PE and those with DVT. The hospitalization rate in China was much lower than that of the United States or selected sites in Canada and Europe, the LOS was much longer, and the in-hospital mortality were similar. CONCLUSIONS: The hospitalization of VTE increased steadily, while the mortality sustained a decline. This study provides important information on disease burden of VTE in China. PMID- 30419234 TI - Charge Reductions Associated With Shorter Time to Recovery in Septic Shock. AB - BACKGROUND: Septic shock therapies that shorten the time to physiologic and clinical recovery may result in financial savings. However, the financial implications of improving these nonmortal outcomes are not well characterized. Therefore, we quantified hospital charges associated with four outcomes: ICU length of stay, duration of invasive mechanical ventilation, duration of vasopressor use, and new renal replacement therapy. METHODS: This was an observational study using administrative data from a large academic hospital in the United States. The analysis included adults treated with vasopressors for septic shock in a medical ICU. Linear regression modeling with ordinary least square was used to estimate the incremental hospital charges associated with 1 day of ICU length of stay, 1 day of mechanical ventilation, 1 day of vasopressor use, and new renal replacement therapy. RESULTS: The study population included 587 adults with septic shock, including 180 (30.7%) who died in the hospital. The median charge for a septic shock hospitalization was $98,583 (interquartile range [IQR], $61,177-$136,672). Decreases in ICU length of stay, mechanical ventilation duration, and vasopressor duration of 1 day were associated with charge reductions of $15,670 (IQR, $15,023-$16,317), $15,284 (IQR, $13,566-$17,002), and $17,947 (IQR, $16,344-$19,549), respectively. Avoidance of new renal replacement therapy was associated with a charge reduction of $36,051 (IQR, $22,353-$49,750). CONCLUSIONS: Septic shock therapies that reduce the duration of organ support and ICU care have the potential to lead to substantial financial savings. PMID- 30419236 TI - The Landscape of United States Lung Cancer Screening Services. AB - BACKGROUND: Low adoption of lung cancer screening is potentially due to inadequate access to a comprehensive lung cancer screening registry (LCSR), currently a requirement for reimbursement by the Centers for Medicare and Medicaid Services. However, variations in LCSR facilities have not been extensively studied. METHODS: We applied a hierarchical clustering method to a comprehensive database integrating state-level LCSR facility density, defined as the number of facilities per 100, 000 at-risk persons, lung cancer outcomes including mortality and stage specific incidence, as well as socio-economic and behavioral factors. RESULTS: We found three distinct clusters of LCSR facilities roughly corresponding to the northern states (Cluster 1), southeastern (Cluster 2), and southwestern (Cluster 3). The southeastern states had the lowest total number of facilities (67+/-44 in Cluster 2 < 74+/-69 in Cluster 1 < 80+/-100 in Cluster 3), and the slowest increase in facilities (23+/-20 in Cluster 2 < 26+/ 28 in Cluster 1 < 27+/-32 in Cluster 3) between 2016 and 2018, and the highest lung cancer burden and current smokers. They ranked second in terms of facility density (2.9+/-1.0 in Cluster 3 < 3.8+/-1.3 in Cluster 2 < 6.3+/-2.8 in Cluster 1) and increase in facility density (1.1+/-0.3 in Cluster 3 < 1.3+/-0.7 in Cluster 2 < 2.5+/-2.5 in Cluster 1). CONCLUSIONS: We found substantial state level variability in LCSR facilities tied to lung cancer burden, socioeconomic and behavioral characteristics. Given known risk factors of lung cancer, correcting a suboptimal distribution of screening programs will likely lead to improved lung cancer outcomes. PMID- 30419235 TI - Air Pollution and Non-Communicable Diseases: A Review by the Forum of International Respiratory Societies' Environmental Committee, Part 1: The damaging effects of air pollution. AB - Air pollution poses a great environmental risk to health. Outdoor fine particulate matter (PM2.5) exposure is the fifth leading risk factor for death in the world, accounting for 4.2 million deaths and more than a hundred million disability-adjusted-life-years lost according to the Global Burden of Disease Report. The World Health Organization attributes 3.8 million additional deaths to Indoor air pollution. Air pollution can harm acutely, usually manifested by respiratory or cardiac symptoms, as well as chronically, potentially affecting every organ in the body. It can cause, complicate, or exacerbate many adverse health conditions. Tissue damage may result directly from pollutant toxicity, because fine and ultrafine particles can gain access to organs, or indirectly through systemic inflammatory processes. Susceptibility is partly under genetic and epigenetic regulation. Although air pollution affects people of all regions, ages, and social groups, it is likely to cause greater illness in those with heavy exposure and greater susceptibility. Persons are more vulnerable to air pollution if they have other illnesses or less social support. Harmful effects occur on a continuum of dosage and even at levels below air quality standards previously considered to be safe. PMID- 30419237 TI - Air Pollution and Non-Communicable Diseases: A review by the Forum of International Respiratory Societies' Environmental Committee. Part 2: Air pollution and organ systems. AB - Although air pollution is well-known to be harmful to the lung and airways, it can also damage most other organ systems of the body. It is estimated that about 500,000 lung cancer deaths and 1.6 million chronic obstructive pulmonary disease (COPD) deaths can be attributed to air pollution, but air pollution may also account for 19% of all cardiovascular deaths and 21% of all stroke deaths. Air pollution has been linked to other malignancies, such as bladder cancer and childhood leukemia. Lung development in childhood is stymied with exposure to air pollutants, and poor lung development in children predicts lung impairment in adults. Air pollution is associated with reduced cognitive function and increased risk of dementia. Particulate matter in the air (PM2.5) is associated with delayed psychomotor development and lower child intelligence. Studies link air pollution with diabetes mellitus prevalence, morbidity, and mortality. Pollution affects the immune system and is associated with allergic rhinitis, allergic sensitization, and autoimmunity. It is also associated with osteoporosis and bone fractures, conjunctivitis, dry eye disease, and blepharitis, inflammatory bowel disease, increased intravascular coagulation, and decreased glomerular filtration rate. Atopic and urticarial skin disease, acne, and skin aging are linked to air pollution. Air pollution is controllable and, therefore, many of these adverse health effects can be prevented. PMID- 30419238 TI - Oxymatrine prevents the development of monocrotaline-induced pulmonary hypertension via regulation of the NG, NG-dimethyl-L-arginine metabolism pathways in rats. AB - The purpose of this study was to investigate the potential effect of oxymatrine in monocrotaline-induced pulmonary hypertension and its possible influence on the NG,NG-dimethyl-L-arginine (ADMA) metabolism pathway. Pulmonary hypertension was induced in rats by a single-dose injection of monocrotaline (60 mg/kg). Daily oral administration of oxymatrine (25, 50 and 100 mg/kg) was started on the day following the monocrotaline injection for 28 days. Oxymatrine (50 and 100 mg/kg) significantly attenuated monocrotaline-induced lung and right ventricular hypertrophy, right ventricular systolic pressure elevation, and right ventricular dysfunction. Oxymatrine also reduced the thickening of monocrotaline-induced pulmonary arterial medial wall. Meanwhile, oxymatrine normalized the level of pulmonary asymmetric ADMA and attenuated the upregulated expression of protein arginine methyltransferase 1 (PRMT1). Oxymatrine had no effect on the expression of protein arginine methyltransferase 2 (PRMT2) and NG,NG-Dimethylarginine dimethylaminohydrolase 1 (DDAH1), which were upregulated in monocrotaline-induced pulmonary arterial hypertensive rats. However, the expression of the protein NG,NG-Dimethylarginine dimethylaminohydrolase 2 (DDAH2) did not differ among all groups (all P>0.05). These results suggest that oxymatrine may offer protective effects on the development of pulmonary hypertension by ameliorating pulmonary remodeling and modulating the ADMA metabolism pathway. PMID- 30419239 TI - Protective effects of VGX-1027 in PM2.5-induced airway inflammation and bronchial hyperresponsiveness. AB - Fine particulate matter (PM2.5) can penetrate into alveolar spaces and induce airway inflammation. Recent evidence suggests that the activation of Toll-like receptor 4 (TLR4) signaling may participate in PM2.5-induced acute lung injury. We investigated the effect of VGX-1027, a TLR4 blocker, on PM2.5-induced airway inflammation and bronchial hyperresponsiveness (BHR) in a murine model in vivo and on inflammatory mechanisms in vitro in human airway epithelial cells. Mice were injected intraperitoneally with vehicle (PBS) or VGX-1027 (25 mg/kg) one hour before intranasal instillation of vehicle (PBS) or PM2.5 (7.8 mg/kg) for two consecutive days and inflammatory events and BHR studied 24 h later. Human airway epithelial Beas-2b cells were pretreated with vehicle or VGX-1027 (50 MUM) in vitro one hour before incubation with vehicle or PM2.5 (150 ng/ml) for 24 h and effects on inflammatory mediators and mechanisms studied. VGX-1027 pretreatment attenuated PM2.5-induced BHR and elevated total and neutrophils, macrophages, lymphocytes and eosinophils numbers in bronchoalveolar lavage (BAL) fluid in vivo. PM2.5-induced BAL fluid inflammatory mediator levels including TNF-alpha, chemokine (C-X-C motif) ligand1, IL-1beta, IL-6 and IL-18 were reduced by VGX 1027. PM2.5-induced increases in TNF-alpha, IL-1beta, IL-6 and IL-18 mRNA levels in Beas-2b cells were also reduced by VGX-1027. Mechanistically, VGX-1027 inhibited PM2.5-induced activation of the TLR4-NF-kappaB-p38 MAPK and NLRP3 caspase-1 pathways as well as the dysregulation of mitochondrial fusion/fission proteins in vivo and in vitro. VGX-1027 may be a potential prophylactic treatment for PM2.5-induced acute lung injury that has airway inflammation, BHR and mitochondrial damage. PMID- 30419240 TI - Involvement of the annexin A1-Fpr anti-inflammatory system in the ocular allergy. AB - Annexin A1 (ANXA1)-formyl peptide receptor (Fpr) system is potent effective mediators in the control of the inflammatory response. In this study, we evaluate the potential involvement of the Fpr family in the protective effect of the mimetic peptide of ANXA1 (ANXA12-26) using an experimental allergic conjunctivitis (AC) model in mice. Ovalbumin (OVA)/Alum-immunized wild-type (WT) and ANXA1-null (ANXA1-/-) Balb/c mice (days 0 and 7) were challenged by eye drops containing OVA on days 14-16, and two groups received ANXA12-26 alone or with Fpr antagonist Boc2 intraperitoneally during challenged days. As expected, plasma IgE anti-OVA levels increased significantly in the OVA-immunized WT and ANXA1-/- mice, supporting the efficacy of AC model. AC increased Fpr1 and Fpr2 levels in the conjunctiva and the lack of endogenous ANXA1 exacerbated Fpr2 expression only. In contrast, administering ANXA12-26 in the WT mice diminished Fpr2 levels in the conjunctiva, and the effect was reverted by Boc2. Ultrastructural analysis showed the co-localization of Fpr2 and ANXA1 in the plasma membrane of mast cells (MCs), eosinophils and neutrophils, supporting this system as being operative in the AC. Boc2 abrogated the ANXA12-26 effect by increasing the MC degranulation and the eosinophil influx in the conjunctiva, and these findings were supported by peroxidase eosinophil, eotaxin and MC protease levels. Additionally, the ANXA12-26-Fpr system in the AC was associated with the activation of ERK and JNK. Collectively, the data provided in vivo supports the anti-allergic effects of the ANXA1-Fpr system and may serve as a therapeutic target in this ocular disorder. PMID- 30419241 TI - Amphetamine activates non-receptor tyrosine kinase Fyn and stimulates ERK phosphorylation in the rat striatum in vivo. AB - The psychostimulant amphetamine (AMPH) has an impact on a variety of cellular activities in striatal neurons, although underlying signaling mechanisms are incompletely understood. The Src family kinase (SFK) is among key signaling molecules enriched in striatal neurons and is involved in the regulation of a set of discrete downstream targets. Given the likelihood that AMPH may regulate SFKs, we investigated and characterized the effect of AMPH on SFK phosphorylation and enzymatic activity in rat striatal neurons in vivo. We found that AMPH elevated SFK Y416 phosphorylation in striatal slices and the adult rat striatum. This elevation was concentration- and time-dependent and occurred in all subdivisions of the striatum, including the caudate putamen and nucleus accumbens (core and shell). The dopamine D1 receptor antagonist SCH23390 blocked the effect of AMPH. Between Fyn and Src, AMPH elevated phosphorylation of immunoprecipitated Fyn but not Src and increased Fyn kinase activity in the striatum. In parallel with SFKs, striatal ERK phosphorylation was increased by AMPH. This increase in ERK phosphorylation was reduced by the SFK inhibitor PP2. These results demonstrate that AMPH is able to activate SFKs (mainly Fyn) in striatal neurons via a D1 receptor-dependent mechanism. Activated SFKs participate in processing the concomitant ERK response to AMPH. PMID- 30419242 TI - Biovisualization of the Genome, from Data Analysis and Hypothesis Generation to Communication and Learning. AB - Genome discoveries at the core of biology are made by visual description and exploration of the cell, from microscopic sketches and biochemical mapping to computational analysis and spatial modeling. We outline the experimental and visualization techniques that have been developed recently which capture the three-dimensional interactions regulating how genes are expressed. We detail the challenges faced in integration of the data to portray the components and organization and their dynamic landscape. The goal is more than a single data driven representation as interactive visualization for de novo research is paramount to decipher insights on genome organization in space. PMID- 30419243 TI - Structural Variability of EspG Chaperones from Mycobacterial ESX-1, ESX-3, and ESX-5 Type VII Secretion Systems. AB - Type VII secretion systems (ESX) are responsible for transport of multiple proteins in mycobacteria. How different ESX systems achieve specific secretion of cognate substrates remains elusive. In the ESX systems, the cytoplasmic chaperone EspG forms complexes with heterodimeric PE-PPE substrates that are secreted from the cells or remain associated with the cell surface. Here we report the crystal structure of the EspG1 chaperone from the ESX-1 system determined using a fusion strategy with T4 lysozyme. EspG1 adopts a quasi 2-fold symmetric structure that consists of a central beta-sheet and two alpha-helical bundles. In addition, we describe the structures of EspG3 chaperones from four different crystal forms. Alternate conformations of the putative PE-PPE binding site are revealed by comparison of the available EspG3 structures. Analysis of EspG1, EspG3, and EspG5 chaperones using small-angle X-ray scattering reveals that EspG1 and EspG3 chaperones form dimers in solution, which we observed in several of our crystal forms. Finally, we propose a model of the ESX-3 specific EspG3-PE5-PPE4 complex based on the small-angle X-ray scattering analysis. PMID- 30419244 TI - Ethanol and a rapid-acting antidepressant produce overlapping changes in exon expression in the synaptic transcriptome. AB - Alcohol use disorder (AUD) and major depressive disorder (MDD) are prevalent, debilitating, and highly comorbid disorders. The molecular changes that underlie their comorbidity are beginning to emerge. For example, recent evidence showed that acute ethanol exposure produces rapid antidepressant-like biochemical and behavioral responses. Both ethanol and fast-acting antidepressants block N-methyl D-aspartate receptor (NMDAR) activity, leading to synaptic changes and long lasting antidepressant-like behavioral effects. We used RNA sequencing to analyze changes in the synaptic transcriptome after acute treatment with ethanol or the NMDAR antagonist, Ro 25-6981. Ethanol and Ro 25-6981 induced differential, independent changes in gene expression. In contrast with gene-level expression, ethanol and Ro 25-6981 produced overlapping changes in exons, as measured by analysis of differentially expressed exons (DEEs). A prominent overlap in genes with DEEs indicated that changes in exon usage were important for both ethanol and Ro 25-6981 action. Structural modeling provided evidence that ethanol-induced exon expression in the NMDAR1 amino-terminal domain could induce conformational changes and thus alter NMDAR function. These findings suggest that the rapid antidepressant effects of ethanol and NMDAR antagonists reported previously may depend on synaptic exon usage rather than gene expression. PMID- 30419245 TI - Arrestin recruitment and signaling by G protein-coupled receptor heteromers. AB - G protein-coupled receptors (GPCR) have a long history of being considered a prime target for drug development to treat a plethora of diseases and disorders. In fact in 1827, the first approved therapeutic in the United States was morphine, a drug that targets a GPCR, namely the mu opioid receptor. However, with the rise in biologics over the last two decades, the market share of small molecules targeting GPCRs has declined. Still, two phenomena concerning GPCR pharmacology, specifically heteromerization and biased signaling, have bolstered new interests in this particular class of drug targets. Heteromerization, the process by which two distinct GPCRs come together to form a unique signaling complex, has been demonstrated between many different GPCRs and has spurred efforts to discover heteromer selective drugs. Additionally, the discovery of biased signaling, a concept by which a GPCR can transduce intracellular signaling by favoring a specific pathway (e.g. G-protein) over another pathway (e.g. arrestin), has led to the development of signal-biased drugs with potentially fewer side effects. Our goal for this review is to highlight studies that have investigated the interplay of these two phenomena by providing an overview of the current literature describing instances where GPCR heteromers have distinct arrestin recruitment profiles when compared to the individual GPCRs, with a focus on those GPCRs expressed in the central nervous system. PMID- 30419246 TI - Dissociating between the N2pc and attentional shifting: An attentional blink study. AB - The N2pc is routinely used as an electrophysiological index of attentional shifting. Its absence is thus taken as evidence that no shift of attention occurred. We provide evidence in contrast to this notion using a variant of the attentional blink (AB) paradigm. Two target letters, embedded in two streams of distractor letters and defined by their color, were separated by either 300 or 800 ms. The second target was preceded by a distractor frame of the same color (cue). As expected, identification of the second target was poorer at the short than at the long lag (the AB effect). The AB did not affect attentional capture by the cue, but suppressed and delayed the N2pc associated with it. This result suggests that the N2pc does not reflect attentional shifting. Instead, we conclude that the N2pc indexes the transient enhancement that occurs at the spatial focus of attention and promotes high-level processing such as identification. This conclusion calls for a reinterpretation of findings from the attentional capture literature that relied on the N2pc as an index of attentional shifting. Our results also inform contemporary models of the AB. PMID- 30419247 TI - Influence of different processing techniques on the toxicity and biochemical characteristics of Tityus serrulatus scorpion venom. AB - Studies of scorpion venoms have used different venom drying methods: lyophilization, desiccation, lyophilization after mixing with 0.9% saline or purified water and centrifugation. The aim of this study was to see if these different approaches cause some alteration in the composition of the venom or interfere with its biological effects. Mice were injected (i.p.) with T. serrulatus scorpion venom in the liquid form (G-liq) or dried by different methods (lyophilized - G-lyo; centrifuged and the supernatant lyophilized - G cen; desiccated - G-des), and observed regarding the occurrence of the symptoms respiratory difficulty, convulsion and death. The occurrence of seizures, although occurring in all groups and with the various doses used, did not prove to be effective to determine differences between the different handling techniques. Respiratory distress appeared to be useful in analyzing differences between groups, where this effect was less pronounced in the G-liq and G-des groups. In general, death occurred in a certain proportion with increasing dose for all groups. G-liq and G-des seemed to be more "active" at lower doses and G cen and G-lyo at higher doses. The electrophoretic and chromatographic profile demonstrated main differences between G-liq and the dried groups. In the electrophoretic profile, the liquid venom showed bands of proteins of higher concentration and greater number of major bands and the three dried venom had the lowest number of protein bands. The HPLC profile and densitometry of the electrophoretic profiles showed some differences that may be associated with different protein conformation/aggregation. Our data indicated that lyophilization is the most suitable method for processing T. serrulatus scorpion venom after extraction. PMID- 30419248 TI - Potential immunomodulatory effect of allelochemical juglone in mice vaccinated with BCG. AB - Juglone, a naphthoquinone is a known phytotoxic and cytotoxic allelochemical. Various anticancer studies suggest that pharmacological ROS insult and enzymes inhibited by juglone could be of therapeutic utility. In this study, we show that juglone induces immunomodulation in BCG-vaccinated mice. We have shown that juglone treatment leads to the generation of Th1 cytokines which develops an M1 phenotype in splenic macrophages. These findings were supported by a decrease in Treg population in BCG-vaccinated mice treated with juglone. Additionally, we observed juglone significantly increases CD8+ and T-helper memory population in BCG-vaccinated mice under immunomodulation. Further, BCG-challenge test showed that juglone enhances effector immune functions. Our finding was demonstrated by estimating ex-vivo Th1 and Th2 cytokines, flow cytometric analysis of Treg, T helper memory, and CD8+ cells and determining serum IgG2a/IgG1 titer shift in BCG vaccinated animals treated with juglone. Collectively, our findings provide evidence that juglone may act as immunomodulator when used at a low dose, metronomically. PMID- 30419249 TI - Predicting the ligand-binding properties of Borrelia burgdorferi s.s. Bmp proteins in light of the conserved features of related Borrelia proteins. AB - Bacteria of the genus Borrelia cause vector-borne infections like the most important hard tick-borne disease in the northern hemisphere, Lyme borreliosis (LB), and soft tick or louse transmitted relapsing fevers (RF), prevalent in temperate and tropical areas. Borrelia burgdorferi sensu lato (s.l.) includes several genospecies and causes LB in humans. In infected patients, Borrelia burgdorferi sensu stricto (s.s.) expresses the BmpA, BmpB, BmpC and BmpD proteins. The role of these proteins in the pathogenesis of LB remains incompletely characterized, but they are, however, closely related to Treponema pallidum PnrA (Purine nucleoside receptor A), a substrate-binding lipoprotein of the ATP-binding cassette (ABC) transporter family preferentially binding purine nucleosides. Based on 3D homology modeling, the Bmp proteins share the typical fold of the substrate-binding protein family and the ligand-binding properties of BmpA, BmpB and BmpD are highly similar, whereas those of BmpC differ markedly. Nevertheless, these residues are highly conserved within the genus Borrelia and the inferred phylogenetic tree also reveals that the RF Borrelia lack BmpB proteins but has an additional Bmp protein (BmpA2) missing in LB-causing Borrelia burgdorferi s.l. Our results indicate that the Bmp proteins could bind nucleosides, although BmpC might have a different ligand-binding specificity and, therefore, a distinct function. Furthermore, the work provides a means for classifying the Bmp proteins and supports further elucidation of the roles of these proteins. PMID- 30419250 TI - Revisiting the association of HLA alleles and haplotypes with CYP21A2 mutations in a large cohort of patients with congenital adrenal hyperplasia. AB - The CYP21A2 gene encoding 21-hydroxylase is on chromosome 6p21.3 within the human leukocyte antigen (HLA) class III major histocompatibility complex and an association between congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency and HLA class I and II alleles has been shown in genetically isolated populations. One-third of CAH causing alleles are 30-kb deletions due to homologous recombination events between active and pseudogenes resulting in chimeric genes. The aim of this study was to re-visit the association between the CYP21A2 variants and HLA polymorphisms in a large ethnically diverse cohort of patients with CAH who underwent comprehensive CYP21A2 genotyping, including specification of chimeric gene subtypes (CAH CH-1 through CH-9 of CYP21A1P/CYP21A2 chimeras; CAH-X CH-1 through CH-3 of TNXA/TNXB chimeras) in alleles with 30-kb deletions. The study population included 201 patients (86 males, 115 females, age 3-75 years) with CAH due to 21-hydroxylase deficiency (159 classic, 42 nonclassic) and 194 parents. Based on the availability of parental genotype, we determined the haplotypes of CYP21A2 mutations and HLA types in 95 probands (190 alleles). Five prevalent haplotype associations were found: p.V281L and B*14-C*08 (P < 0.0001); p.I172N and DQB1*03 (P = 0.035); and of the chimeric genes caused by 30-kb deletions: CH-1 and A*03 (P = 0.033); CH-5 and C*06-DRB1*07 (P < 0.0001); and CAH-X CH-1 and DQB1*03 (P = 0.004). Our findings show that a number of associations between HLA alleles and haplotypes and CYP21A2 mutations, including large 30-kb deletions, exist commonly across ethnicities. These HLA associations may have clinical implications for patients with CAH and may provide insight into the genetics of this highly complex region of the human genome. PMID- 30419251 TI - The role of EGFR overexpression on the recurrence of basal cell carcinomas with positive surgical margins. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) expression may have role on recurrence of basal cell carcinoma (BCC) with positive surgical margin(s). OBJECTIVE: The aim was to investigate the role of genetic expression changes of EGFR on recurrence rates in patients in follow up with surgically excised BCC with positive surgical margin(s). METHODS: Thirty-four surgical margin-positive BCC lesions that were closely followed up without an immediate reoperation were included in this study. Real-time polymerase chain reaction (PCR) was performed from the both healthy and tumoral tissue samples. RESULTS: EGFR was expressed at a significantly higher rate in tumoral tissues compared to healthy tissues (p < 0,05). In patients with recurrence lesions, EGFR expression was 6,66 times higher compared to patients with non-recurrent. Also, there was statistically significant difference EGFR expression for infiltrative subtypes (p < 0,05). CONCLUSION: Our study focuses on the role of EGFR overexpression specifically and outcomes for recurrent and infiltrative subtyped lesions are significant for both clinic and pathogenesis of BCC. Similar studies have to be performed with high numbered patient groups. PMID- 30419252 TI - Adaptive homeostasis of the vitamin D-vitamin D nuclear receptor axis in 8 methoxypsoralen-induced hepatotoxicity. AB - 8-methoxypsoralen (8-MOP) with ultraviolet A radiation therapy (PUVA) is the standard therapy for patients with psoriasis, despite the reported potential risks of 8-MOP-induced cholestatic liver injury in both humans and animals. Usually, patients with chronic cholestasis exhibit lower serum 25-hydroxy vitamin D (25(OH)D) levels. But those patients receiving PUVA for psoriasis showed an increase in serum 25(OH)D levels, probably highlighting that the vitamin D vitamin D nuclear receptor (VD-VDR) axis play a protective role in 8-MOP-induced hepatotoxicity. The present study confirmed 8-MOP could increase serum 25(OH)D levels in conventional lighting and diet (CLD) and vitamin D deficient (VDD) Sprague-Dawley rats. Potential liver risks were also found in CLD and VDD rats after 8-MOP treatment. We proved that 8-MOP could be a potent ligand for VDR using molecular docking and luciferase report assay. Effect of 8-MOP on VDR subcellular distribution was determined using human liver cell line L02. We found 8-MOP could increase VDR protein expression in the nuclear and cytosol extracts and also total cell extracts in L02. siRNAs for VDR were used to determine the role of VDR in protecting 8-MOP-induced cholestasis and potential cellular mechanisms. The results showed 8-MOP could affect the CYP7A1, SHP and MRP3 expression via VDR, and such effects could be reversed by knockdown of VDR expression, suggesting a vital role of VDR involved in 8-MOP-regulated bile acid synthesis and transportation. In conclusion, these results revealed activation of VD-VDR axis may play a beneficial role in 8-MOP-mediated regulation of bile acid synthesis and transportation. PMID- 30419253 TI - A bispecific broadly neutralizing antibody against enterovirus 71 and coxsackievirus A16 with therapeutic potential. AB - Enterovirus 71 (EV71) and coxsackievirus A16 (CA16) are the major pathogens of hand, foot and mouth disease (HFMD), which affects children worldwide and is often associated with neurological complications. At present, there is no vaccine or cure available for simultaneous EV71 and CA16 infection, posing a great need to develop novel strategies for the treatment of this disease. Here, we engineered four bispecific antibodies using variable fragments of monoclonal antibodies (mAbs) from EV71- and CA16-specific neutralizing antibodies. The engineered bispecific antibody Bs(scFv)4-IgG-1 exhibits remarkable cross reactivity against EV71 and CA16 and has a more potent cross-neutralization than its parental antibodies. Furthermore, we showed that Bs(scFv)4-IgG-1 conferred 100% therapeutic efficacy against single or mixed EV71 and CA16 infections in mice. Our study provides important insights into bispecific antibody engineering against enterovirus and will inform new curative treatment options for HFMD. PMID- 30419254 TI - Longitudinal associations of family functioning with body mass index in Mexican origin adolescents living in the U.S. AB - Mexican-origin adolescents have a high prevalence of obesity. Research is needed to understand how family context may shape adolescent BMI. This study examined longitudinal associations of family functioning variables with the Centers for Disease Control and Prevention's modified BMI z-score (BMIaz) in 1175 Mexican origin adolescents, and explored interactions with acculturation. Adolescents (50% female, aged 11-13 y in 2005-06) were identified from an ongoing cohort study of Mexican-origin adults in Houston, TX, and were assessed three times from 2005-06 to 2010-11. In multivariate linear mixed models stratified by gender, we assessed longitudinal associations of family cohesion and family conflict with adolescent BMIaz and explored interactions with language acculturation. We disaggregated the between- (mean) and within-person (individual deviation) components of family cohesion and family conflict to assess the effects on BMIaz. Approximately one-third of adolescents were obese at baseline, and BMIaz declined during the study. In girls, higher mean family cohesion and conflict were associated with steeper declines in BMIaz. Parental linguistic acculturation modified the relationship between within-person deviation in family cohesion and BMIaz in girls, such that high parental U.S. acculturation was associated with a stronger inverse association. There were no significant associations in boys. These findings highlight the potential importance of the family context to female adolescent BMI and the promise of addressing family context in obesity-related interventions. PMID- 30419255 TI - Behavioral tests predicting striatal dopamine level in a rat hemi-Parkinson's disease model. AB - Parkinson's disease (PD) is a frequent neurodegenerative disease causing bradykinesia, tremor, muscle rigidity and postural instability. Although its main pathology is progressive dopaminergic (DArgic) neuron loss in the substantia nigra, motor deficits are thought not to become apparent until most DArgic neurons are lost, probably due to compensatory mechanisms that overcome the decline of DA level in the striatum. Even in animal PD models, it is difficult to detect motor deficits when most DArgic neurons are functional. In this study, we performed various behavioral tests (apomorphine-induced rotation, cylinder, forepaw adjustment steps (FAS), beam walking, rota-rod, and open-field), using 6 hydroxydopamine (OHDA) and lipopolysaccharide (LPS)-induced hemi-PD model rats with various striatal DA levels, to find the best way to predict the DA level from earlier disease stages. Different from the 6-OHDA-induced model, reduction in the striatal DA levels in the LPS-model was less significant. Among the behavioral tests, data from cylinder and FAS tests, which evaluate forelimb movements, best correlated with decline of the DA level. They also correlated well with decreased body weight gain. The beam and apomorphine tests showed less significant correlation than the cylinder and FAS tests. Open-field and rota-rod tests were not useful. Expressional levels of mRNA encoding tyrosine hydroxylase (TH), a marker of DArgic neurons, correlated well with the DA level. Metabotropic glutamate receptor 4 mRNA expression correlated with the striatal DA level and may be related to compensatory mechanisms. These results suggest that motor impairments of PD should be evaluated by forelimb movements, or hands and forearms in clinical settings, rather than movement of the body or large joints. The combination of cylinder and FAS tests may be the best to evaluate the rat PD models, in which many DArgic neurons survive. PMID- 30419256 TI - Mature Extraterrestrial Biology in Astrophysical Phenomena - Reply to critical numerical analysis of R Duggleby (2018) on Steele et al (2018) "Cause of Cambrian Explosion: Terrestrial or Cosmic?" PMID- 30419257 TI - Depletion of thiol reducing capacity impairs cytosolic but not mitochondrial iron sulfur protein assembly machineries. AB - Iron-sulfur (Fe/S) clusters are versatile inorganic cofactors that play central roles in essential cellular functions, from respiration to genome stability. >30 proteins involved in Fe/S protein biogenesis in eukaryotes are known, many of which bind clusters via cysteine residues. This opens up the possibility that the thiol-reducing glutaredoxin and thioredoxin systems are required at both the Fe/S biogenesis and target protein level to counteract thiol oxidation. To address the possible interplay of thiol redox chemistry and Fe/S protein biogenesis, we have characterized the status of the mitochondrial (ISC) and cytosolic (CIA) Fe/S protein assembly machineries in Saccharomyces cerevisiae mutants in which the three partially redundant glutathione (Glr1) and thioredoxin (Trr1 and Trr2) oxidoreductases have been inactivated in either mitochondria, cytosol, or both compartments. Cells devoid of mitochondrial oxidoreductases maintained a functional mitochondrial ISC machinery and showed no altered iron homeostasis despite a non-functional complex II of the respiratory chain due to redox specific defects. In cells that lack either cytosolic or total cellular thiol reducing capacity, both the ISC system and iron homeostasis were normal, yet cytosolic and nuclear Fe/S target proteins were not matured. This dysfunction could be attributed to a failure in the assembly of [4Fe-4S] clusters in the CIA factor Nar1, even though Nar1 maintained robust protein levels and stable interactions with later-acting CIA components. Overall, our analysis has uncovered a hitherto unknown thiol-dependence of the CIA machinery and has demonstrated the surprisingly varying sensitivity of Fe/S proteins to thiol oxidation. PMID- 30419258 TI - The role of DNA methylation in epigenetics of aging. AB - Recent research suggests that epigenetics, especially DNA methylation, plays a mechanistic role in aging. Epigenetic clocks, which measure changes in a few hundred specific CpG sites, can accurately predict chronological age in a variety of species, including humans. These clocks are currently the best biomarkers for predicting mortality in humans. Additionally, several studies have characterized the effects of aging across the methylome in a wide variety of tissues from humans and mice. A small fraction (~2%) of the CpG sites show age-related changes, either hypermethylation or hypomethylation with aging. Evaluation of non CpG site methylation has only been examined in a few studies, with about ~0.5% of these sites showing a change with age. Therefore, while only a small fraction of cytosines in the genome show changes in DNA methylation with age, this represents 2 to 3 million cytosines in the genome. Importantly, the only study to compare the effect of aging on DNA methylation in male and female mice and humans found that >95% of the age-related changes in DNA methylation in the hippocampus were sexually divergent, i.e., the methylation did not differ between males and females at young age but age-related changes occurred in one sex but not the other. The age-related changes in DNA methylation tend to be enriched and under represented in specific genomic contexts, with some commonalities between tissues and species that require further investigation. The strongest evidence that the age-related changes in DNA methylation play a role in aging comes from studies of anti-aging interventions (e.g., caloric restriction, dwarfism, and rapamycin treatment) in mice. These anti-aging interventions deaccelerate the epigenetic clocks and reverse/prevent 20 to 40% of the age-related changes in DNA methylation. It will be important in the future to demonstrate that at least some of the age-related changes in DNA methylation directly lead to alterations in the transcriptome of cells/tissues that could potentially contribute to aging. PMID- 30419260 TI - Serotonin in retina. AB - The expression of serotonin (5-HT) in the retina was first reported in the sixties. The detection of vesicular monoamine transporter and serotonin receptors in several retinal cells confirm that 5-HT is playing a neuromodulatory role in this structure. Whereas signaling pathways activated by 5-HT receptor binding has been poorly investigated so far, numerous data demonstrated that 5-HT is involved in retinal physiology, retinal physiopathology and photoreceptor survival. PMID- 30419259 TI - Neural Correlates of Social Perception in Children with Autism: Local versus Global Preferences. AB - The Weak Central Coherence account of autism spectrum disorders posits that individuals with ASD utilize a detail-oriented information processing bias. While this local bias is helpful in visual search tasks, ASD individuals falter in social cognition tasks where coherence is advantageous. The present study examined the neural correlates of Weak Central Coherence in ASD during visual and social processing. Fifteen ASD and sixteen typically developing children/adolescents completed a social/visual information processing task in an fMRI scanner. The stimuli consisted of human characters, composed of geometrical shapes, displaying different emotions. In the locally oriented Shape condition, participants indicated whether a given shape was present in a figure. In the Emotion condition, participants identified the emotion conveyed by the character in the figure at the global level. Whole-brain within- and between-group activation and seed-to-voxel functional connectivity analyses were conducted in SPM12 and the CONN toolbox. The ASD group was significantly faster in shape identification, but less accurate in emotion identification. The TD group showed significantly increased areas of activity over the ASD group in the Shape task in regions associated with executive control, such as the medial prefrontal cortex and middle frontal gyrus, suggesting increased interference from the global/social information. During the Emotion condition, the ASD group showed decreased connectivity between frontal and posterior regions and between body perception and motor networks, suggesting a possible difference in mirroring. The findings suggest that social cognitive factors, not visual processing biases, underlie the observed behavioral differences. PMID- 30419261 TI - The cell secretome in personalized and regenerative medicine. PMID- 30419262 TI - A novel uORF-based regulatory mechanism controls translation of the human MDM2 and eIF2D mRNAs during stress. AB - Short upstream open reading frames (uORFs) are the most prevalent cis-acting regulatory elements in the mammalian transcriptome which can orchestrate mRNA translation. Apart from being "passive roadblocks" that decrease expression of the main coding regions, particular uORFs can serve as specific sensors for changing conditions, thus regulating translation in response to cell stress. Here we report a novel uORF-based regulatory mechanism that is employed under conditions of hyperosmotic stress by at least two human mRNAs, coding for translation reinitiation/recycling factor eIF2D and E3 ubiquitin ligase MDM2. This novel mode of translational control selectively downregulates their expression and requires as few as one uORF. Using a set of reporter mRNAs and fleeting mRNA transfection (FLERT) technique, we provide evidence that the phenomenon does not rely on delayed reinitiation, altered AUG recognition, ribosome stalling, mRNA destabilization or other known mechanisms. Instead, it is based on events taking place at uORF stop codon or immediately downstream. Functional aspects and implications of the novel regulatory mechanism to cell physiology are discussed. PMID- 30419263 TI - MULTI-INSTITUTIONAL EVALUATION OF PRODUCING AND TESTING A NOVEL 3D-PRINTED LAPAROSCOPIC TRAINER. AB - OBJECTIVE: To create, distribute, and evaluate the efficacy of a portable, cost effective 3D-printed laparoscopic trainer for surgical skills development. METHODS: The UCI Trainer (UCiT) laparoscopic simulator was developed via computer aided designs (CAD), which were used to 3D-print the UCiT. Once assembled, a tablet computer with a rear-facing camera was attached for video and optics. Four institutions were sent the UCiT CAD files with a 3D-printer and instructions for UCiT assembly. For a comparison of the UCiT to a standard trainer, peg transfer and intracorporeal knot tying skills were accessed. These tasks were scored, and participants were asked to rate their experience with the trainers. Lastly, a questionnaire was given to individuals who 3D-printed and assembled the UCiT. RESULTS: We recruited 25 urologists; none had any 3D-printing experience. The cost of printing each trainer was $26.50 USD. Each institution used the Apple iPad for optics. Six of eight participants assembled the UCiT in < 45 minutes, and rated assembly as somewhat easy. On objective scoring, participants performed tasks equally well on the UCiT vs. the conventional trainer. On subjective scoring, the conventional trainer provided a significantly better experience vs. the UCiT; however, all reported that the UCiT was useful for surgical education. CONCLUSIONS: The UCiT is a low cost, portable training tool that is easy to assemble and use. UCiT provided a platform whereby participants performed laparoscopic tasks equal to performing the same tasks on the more expensive, non portable standard trainer. PMID- 30419264 TI - The genetics, structure and function of the M1 aminopeptidase oxytocinase subfamily and their therapeutic potential in immune-mediated disease. AB - The oxytocinase subfamily of M1 aminopeptidases plays an important role in processing and trimming of peptides for presentation on major histocompatibility (MHC) Class I molecules. Several large-scale genomic studies have identified association of members of this family of enzymes, most notably ERAP1 and ERAP2, with immune-mediated diseases including ankylosing spondylitis, psoriasis and birdshot chorioretinopathy. Much is now known about the genetics of these enzymes and how genetic variants alter their function, but how these variants contribute to disease remains largely unresolved. Here we discuss what is known about their structure and function and highlight some of the knowledge gaps that affect development of drugs targeting these enzymes. PMID- 30419265 TI - Ancistrobrevines E-J and related naphthylisoquinoline alkaloids from the West African liana Ancistrocladus abbreviatus with inhibitory activities against Plasmodium falciparum and PANC-1 human pancreatic cancer cells. AB - From the roots of the West African liana Ancistrocladus abbreviatus (Ancistrocladaceae), ten new naphthylisoquinoline alkaloids (7a, 7b, 8a, 8b, and 9-14), displaying three different coupling types (5,1', 5,8', and 7,8'), were isolated, among them a series of five 5,1'-linked representatives and four metabolites belonging to the rare group of 7,8'-coupled alkaloids. Two of the alkaloids, the ancistrobrevines I (13) and J (14), are only the fourth and fifth examples of 7,8'-linked naphthyldihydroisoquinolines ever found in nature. The stereostructures of the new plant metabolites were determined by spectroscopic, chemical (oxidative degradation), and chiroptical (electronic circular dichroism) methods. For the assignment of the axial configuration of 13 and 14 relative to the stereocenter at C-3, which is too far away for significant NOE long-range interactions, these 7,8'-coupled naphthyldihydroisoquinolines were stereoselectively converted into the respective cis-configured tetrahydroisoquinoline analogs. The newly generated 'auxiliary' stereocenter at C 1 permitted decisive NOE interactions between the isoquinoline and the naphthalene parts, and thus a reliable attribution of the axial configuration of 13 and 14. In addition, five known compounds (3, 5, 16, 17, and 20), previously discovered in related African and Asian Ancistrocladus species, have now for the first time been identified in A. abbreviatus. All of these alkaloids are S configured at C-3 and bear an oxygen function at C-6, and are, thus, typical Ancistrocladaceae-type compounds. Some of the alkaloids of A. abbreviatus exhibited promising activities against the malaria parasite Plasmodium falciparum and PANC-1 human pancreatic cancer cells. PMID- 30419266 TI - Perfect anomalous transport of subdiffusive cargos by molecular motors in viscoelastic cytosol. AB - Multiple experiments show that various submicron particles such as magnetosomes, RNA messengers, viruses, and even much smaller nanoparticles such as globular proteins diffuse anomalously slow in viscoelastic cytosol of living cells. Hence, their sufficiently fast directional transport by molecular motors such as kinesins is crucial for the cell operation. It has been shown recently that the traditional flashing Brownian ratchet models of molecular motors are capable to describe both normal and anomalous transport of such subdiffusing cargos by molecular motors with a very high efficiency. This work elucidates further an important role of mechanochemical coupling in such an anomalous transport. It shows a natural emergence of a perfect subdiffusive ratchet regime due to allosteric effects, where the random rotations of a "catalytic wheel" at the heart of the motor operation become perfectly synchronized with the random stepping of a heavily loaded motor, so that only one ATP molecule is consumed on average at each motor step along microtubule. However, the number of rotations made by the catalytic engine and the traveling distance both scale sublinearly in time. Nevertheless, this anomalous transport can be very fast in absolute terms. PMID- 30419267 TI - Controlled release strategy designed for intravitreal protein delivery to the retina. AB - Therapeutic protein delivery directly to the eye is a promising strategy to treat retinal degeneration; yet, the high risks of local drug overdose and cataracts associated with bolus injection have limited progress, requiring the development of sustained protein delivery strategies. Since the vitreous humor itself is a gel, hydrogel-based release systems are a sensible solution for sustained intravitreal protein delivery. Using ciliary neurotrophic factor (CNTF) as a model protein for ocular treatment, we investigated the use of an intravitreal, affinity-based release system for protein delivery. To sustain CNTF release, we took advantage of the affinity between Src homology 3 (SH3) and its peptide binding partners: CNTF was expressed as a fusion protein with SH3, and a thermogel of hyaluronan and methylcellulose (HAMC) was modified with SH3 binding peptides. Using a mathematical model, the hydrogel composition was successfully designed to release CNTF-SH3 over 7 days. The stability and bioactivity of the released protein were similar to those of commercial CNTF. Intravitreal injections of the bioengineered thermogel showed successful delivery of CNTF-SH3 to the mouse retina, with expected transient downregulation of phototransduction genes (e.g., rhodopsin, S-opsin, M-opsin, Gnat 1 and 2), upregulation of STAT1 and STAT3 expression, and upregulation of STAT3 phosphorylation. This constitutes the first demonstration of intravitreal protein release from a hydrogel. Immunohistochemical analysis of the retinal tissues of injected eyes confirmed the biocompatibility of the delivery vehicle, paving the way towards new intravitreal protein delivery strategies. PMID- 30419268 TI - Single bead investigation of a clinical drug delivery system - A novel release mechanism. AB - Microgels, such as polymeric hydrogels, are currently used as drug delivery devices (DDSs) for chemotherapeutics and/or unstable drugs. The clinical DDS DC bead(r) was studied with respect to loading and release, measured as relative bead-volume, of six amphiphilic molecules in a micropipette-assisted microscopy method. Theoretical models for loading and release was used to increase the mechanistic understanding of the DDS. It was shown that equilibrium loading was independent of amphiphile concentration. The loading model showed that the rate determining step was diffusion of the molecule from the bulk to the bead surface ('film control'). Calculations with the developed and applied release model on the release kinetics were consistent with the observations, as the amphiphiles distribute unevenly in the bead. The rate determining step of the release was the diffusion of the amphiphile molecule through the developed amphiphile-free depletion layer. The release rate is determined by the diffusivity and the tendency for aggregation of the amphiphile where a weak tendency for aggregation (i.e. a large cacb) lead to faster release. Salt was necessary for the release to happen, but at physiological concentrations the entry of salt was not rate determining. This study provides valuable insights into the loading to and release from the DDS. Also, a novel release mechanism of the clinically used DDS is suggested. PMID- 30419269 TI - Associations between clinical symptoms, plasma norepinephrine and deregulated immune gene networks in subgroups of adolescent with Chronic Fatigue Syndrome. AB - BACKGROUND: Chronic Fatigue Syndrome (CFS) is one of the most important causes of disability among adolescents while limited knowledge exists on genetic determinants underlying disease pathophysiology. METHODS: We analyzed deregulated immune-gene modules using Pathifier software on whole blood gene expression data (29 CFS patients, 18 controls). Deconvolution of immune cell subtypes based on gene expression profile was performed using CIBERSORT. Supervised consensus clustering on pathway deregulation score (PDS) was used to define CFS subgroups. Associations between PDS and immune, neuroendocrine/autonomic and clinical markers were examined. The impact of plasma norepinephrine level on clinical markers over time was assessed in a larger cohort (91 patients). RESULTS: A group of 29 immune-gene sets was shown to differ patients from controls and detect subgroups within CFS. Group 1P (high PDS, low norepinephrine, low naive CD4+ composition) had strong association with levels of serum C-reactive protein and Transforming Growth Factor-beta. Group 2P (low PDS, high norepinephrine, high naive CD4+ composition) had strong associations with neuroendocrine/autonomic markers. The corresponding plasma norepinephrine level delineated 91 patients into two subgroups with significant differences in fatigue score. CONCLUSION: We identified 29 immune-gene sets linked to plasma norepinephrine level that could delineate CFS subgroups. Plasma norepinephrine stratification revealed that lower levels of norepinephrine were associated with higher fatigue. Our data suggests potential involvement of neuro-immune dysregulation and genetic stratification in CFS. PMID- 30419270 TI - The offspring of rats selected for high or low ethanol intake at adolescence exhibit differential ethanol-induced Fos immunoreactivity in the central amygdala and in nucleus accumbens core. AB - Adolescents exhibit, when compared to adults, altered responsivity to the unconditional effects of ethanol. It is unclear if this has a role in the excessive ethanol intake of adolescents. Wistar rats from the third filial generation (F3) of a short-term breeding program which were selected for high (STDRHI) vs. low (STDRLO) ethanol intake during adolescence, were assessed for ethanol-induced (0.0, 1.25 or 2.5 g/kg) Fos immunoreactivity (Fos-ir) in the central (Ce), basolateral (BLA) and medial (Me) amygdaloid nuclei; nucleus accumbens core and shell (AcbC, AcbSh), ventral tegmental area (VTA), as well as prelimbic and infralimbic (PrL, IL) prefrontal cortices. Following i.p. administration of saline, and across the structures measured, Fos-ir was significantly greater in STDRHI than in STDRLO rats. Across both lines, baseline Fos-ir was significantly lower in BLA than in any other structure, whereas PrL, IL and Shell did not differ between each other and exhibited significantly greater level of baseline neural activation than Ce, Me, AcbC and VTA. STDRLO, but not STDRHI, rats exhibited ethanol-induced Fos-ir in Ce. STRDHI, but not STDRLO, rats exhibited an ethanol-induced Fos-ir depression in AcbC. Key maternal care behaviors (i.e., grooming of the pups, latency to retrieve the pups, time spent in the nest and time adopting a kiphotic posture) were fairly similar across lines. There were significant intergenerational variations in the amount self-licking behaviors in STDRHI dams as well as an increased amount of exploration of the cage in these animals, when compared to STDRLO counterparts. These results indicate that short term selection for differential alcohol intake during adolescence yields heightened neural activity at baseline (i.e., after vehicle) in STRDHI vs. STDRLO adolescent rats, and differential sensitivity to ethanol-induced Fos immunoreactivity in Ce and in AcbC. It is unlikely that rearing patterns explained the neural differences reported, between STDRHI and STDRLO rats. PMID- 30419271 TI - mS-11, a mimetic of the mSin3-binding helix in NRSF, ameliorates social interaction deficits in a prenatal valproic acid-induced autism mouse model. AB - Growing evidence suggests pivotal roles for epigenetic mechanisms in both animal models of and individuals with autism spectrum disorders (ASD). Neuron restrictive silencer factor (NRSF) binds to neuron-restrictive silencing elements in neuronal genes and recruits co-repressors, such as mSin3, to epigenetically inhibit neuronal gene expression. Because dysregulation of NRSF is related to ASD, here we examined the effects of mS-11, a chemically optimized mimetic of the mSin3-binding helix in NRSF, on the behavioral and morphological abnormalities found in a mouse model of valproic acid (VPA)-induced ASD. Chronic treatment with mS-11 improved prenatal VPA-induced deficits in social interaction. Additionally, we found that NRSF mRNA expression was greater in the somatosensory cortex of VPA exposed mice than of controls. Agreeing with these behavioral findings, mice that were prenatally exposed to VPA showed lower dendritic spine density in the somatosensory cortex, which was reversed by chronic treatment with mS-11. These findings suggest that mS-11 has the potential for improving ASD-related symptoms through inhibition of mSin3-NRSF binding. PMID- 30419272 TI - Persistent attenuation of nicotine self-administration in rats by co administration of chronic nicotine infusion with the dopamine D1 receptor antagonist SCH-23390 or the serotonin 5-HT2C agonist lorcaserin. AB - Tobacco addiction each year causes millions of deaths worldwide. Brain nicotinic acetylcholine receptors have been shown to be central to tobacco addiction. Nicotine replacement therapy aids tobacco cessation, but the success rate is still far too low. This may in part be due to the fact that neurons with nicotinic receptors are not the only neural systems involved in tobacco addiction. Interacting neural systems also play important roles in tobacco addiction. Nicotine increases the release of a variety of neurotransmitters, including dopamine and serotonin. Dopamine, in particular dopamine D1 receptors, has been shown to be involved in the reinforcing action of nicotine. Serotonin through its actions on 5-HT2C receptors has been shown to play a key role in modulating the reinforcement of addictive drugs, including nicotine and alcohol. Combination of treatments could provide greater treatment efficacy. These studies were conducted to evaluate combination therapies utilizing nicotine replacement therapy in conjunction with either a dopamine D1 receptor antagonist SCH-23390 or a serotonin 5-HT2C receptor agonist, lorcaserin. Female Sprague-Dawley rats were given access to self-administer nicotine via IV infusions. Osmotic pumps were implanted to reproduce the kinetic of chronic nicotine patch therapy. SCH-23390 (0.02 mg/kg) or lorcaserin (0.6 mg/kg) were administered prior to nicotine self administration sessions. Reproducing earlier findings SCH-23390, lorcaserin and nicotine replacement therapy were effective at reducing IV nicotine self administration. 5HT2C agonist treatment had additive effects with chronic nicotine infusion for significantly lowering nicotine self-administration. This study demonstrates the feasibility of combination of chronic nicotine with therapies targeting non-nicotinic receptors as treatment options for tobacco addiction. PMID- 30419273 TI - Quantification of intracellular accumulation and retention of lysosomotropic macrocyclic compounds by high throughput imaging of lysosomal changes. AB - Many marketed pharmaceuticals reach extremely high tissue concentrations due to accumulation in lysosomes (lysosomotropism). Quantitative prediction of intracellular concentrations of accumulating drugs is challenging, especially for macrocyclic compounds which mainly do not fit in current in silico models. We tested a unique library of 47 compounds (containing 39 macrocycles) specifically designed to cover the entire range of accumulation intensities observed with pharmaceuticals so far. For the first time, we show that intracellular concentration of compounds measured by LC-MS/MS correlates with the induction of phospholipidosis and inhibition of autophagy, but the highest correlation was observed with the increase of lysosomal volume (R=0.95), all measured by high throughput imaging assays. Based only on imaging data, we developed a 5-class in vitro model for the prediction of compound accumulation with the accuracy of 81%. The measured change of total lysosomal volume can thus be used in high throughput screening for determination of the actual intensity of intracellular accumulation of new macrocyclic compounds. The models are largely based on macrocycles, greatly improving the screening and prediction of intracellular accumulation of this challenging class. However, all tested non-macrocyclic compounds fitted well in the models, indicating potential use of the models in broader chemical space. PMID- 30419274 TI - Electrostatically Mediated Protein-Protein Interactions for Monoclonal Antibodies: a Combined Experimental and Coarse-Grained Molecular Modeling Approach. AB - Electrostatically mediated protein-protein interactions (PPI) can influence key product properties such as solubility, solution viscosity, and aggregation rates. Predictive models would allow for candidates / formulations to be screened with little or no protein material. Three monoclonal antibodies (MAbs) that display qualitatively different experimental PPI were evaluated at a range of pH and ionic strength conditions that are typical of product formulations. PPI parameters (kD, B22, and G22) were obtained from static and dynamic light scattering measurements, and spanned from strongly repulsive to strongly attractive net interactions. Coarse-grained (CG) molecular simulations of PPI (specifically, B22) were compared against experimental PPI parameters across multiple pH and salt conditions, using a CG model that treats each amino acid explicitly. Predicted B22 values with default model parameters matched experimental B22 values semi-quantitatively for some cases; others required parameter tuning to account for effects such as ion binding. Experimental PPI values were also analyzed for each MAb within the context of single-protein properties such as net charge, and domain-based and global dipole moments. The results show that PPI predicted qualitatively and semi-quantitatively by CG molecular modeling of B22 can be an effective computational tool for molecule and/or formulation assessment. PMID- 30419275 TI - Solution Stability of Poloxamer 188 Under stress Conditions. AB - Poloxamer 188 (P188) is a triblock copolymer of the form polyethylene oxide polypropylene oxide-polyethylene oxide (PEO-PPO-PEO). The center PPO block is hydrophobic and the side PEO blocks are hydrophilic, resulting in surface-active properties. P188 has been used in the pharmaceutical industry as an excipient in various formulations and drug delivery systems. Although the chemical stability of P188 in the solid state has been reported there are very few reports detailing the solution state stability. In this work, we report the solution state stability of P188 conducted to evaluate the effects of P188 concentration, temperature, pH and buffer type and trace metals on chemical stability. The degradation chemistry of P188 and identification of degradation products formed was studied using various analytical techniques (UV, GC-MS and LC-MS). The degradation of P188 in solution was found to be strongly dependent on temperature, P188 concentration and buffer type. For the first time we report that in histidine buffer, oxidation of both P188 and histidine may occur at pharmaceutically relevant conditions. We observed degradation of both histidine and P188 as well as species formed from the mutual interactions of the degradation products from the two types of molecules. PMID- 30419276 TI - Nepeta angustifolia attenuates responses to vascular inflammation in high glucose induced human umbilical vein endothelial cells through heme oxygenase-1 induction. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The traditional folk medicine Nepeta angustifolia C. Y. Wu (NA) reportedly possesses various biological activities, such as anti inflammatory, analgesic, antihypoxia, and antifatigue effects. In this study, we evaluated the anti-vascular inflammation effects of N. angustifolia extract in human umbilical vein endothelial cells (HUVECs) induced by high glucose (HG) as well as the underlying mechanisms and verified its activity in diabetic rats. MATERIALS AND METHODS: HUVECs were exposed to 25 mM glucose to induce endothelial dysfunction. Adhesion molecule expression and reactive oxygen species (ROS) were assayed. IkappaB and IkappaB phosphorylation, nuclear factor-kappaB (NF-kappaB), HO-1 and nuclear factor erythroid 2-related factor 2 (Nrf2) were examined by Western blot. Nuclear localisation of Nrf2 was also examined using immunofluorescence. The in vivo study of NA was tested in diabetic rats in which the thoracic aorta and serum were collected to observe aorta histological change, and evaluate endothelial function and vascular inflammation. RESULTS: The results revealed that HG can significantly promote the generation of ROS, the expression of cell adhesion molecules (CAMs), and the phosphorylation and degradation of IkappaB and NF-kappaB activation in HUVECs. These HG-induced phenomena were suppressed by NA-induced heme oxygenase (HO)- 1 expression in a dose- and time dependent manner by activating Nrf2. The HO-1 inhibitor tin protoporphyrin also dramatically reversed the NA-induced inhibition of CAM expression and the reduction in ROS production. Furthermore, NA also elicited anti-vascular dysfunction effects in diabetic rats, where endothelial function was improved and vascular inflammation was alleviated. CONCLUSION: All these findings indicated that NA attenuated high glucose-induced vascular dysfunction in vitro and in vivo. PMID- 30419277 TI - Rapid and sensitive detection of Amphidinium carterae by loop-mediated isothermal amplification combined with a chromatographic lateral-flow dipstick. AB - Frequent outbreaks of toxic algal blooms devastate marine ecosystems, marine fisheries, and public health. Monitoring toxic algae is crucial to reduce losses caused by imminent algal blooms. However, traditional detection techniques relying on morphological examination are tedious and time-consuming. Therefore, the development of convenient strategies to detect toxin-producing microalgae is necessary. In this study, a novel method for the rapid, sensitive detection of Amphidinium carterae by loop-mediated isothermal amplification (LAMP) combined with a chromatographic lateral-flow dipstick (LFD) was established. The partial internal transcribed spacer gene was PCR amplified, cloned, and sequenced to design four LAMP primers and a detection probe for A. carterae detection. The LAMP detection conditions were optimized, and the optimum parameters were determined to be the following: dNTP concentration, 1.2 mM; betaine concentration, 1.2 M; magnesium ion concentration, 8 mM; ratio of inner primer to outer primer, 8:1; amplification temperature, 59 degrees C; and amplification time, 60 min. The specificity of LAMP-LFD was confirmed by cross-reactivity tests with other algal species. LAMP-LFD was 100 times more sensitive than regular PCR and similarly sensitive as LAMP and SYBR Green I. LAMP-LFD can be completed within 70 min and did not require special detection equipment. The convenience of the established LAMP-LFD assay was further validated by tests with simulated field-water samples. In conclusion, the developed LAMP-LFD assay can be used as a reliable and simple method of detecting A. carterae. PMID- 30419278 TI - Hydrazone covalent adaptable networks modulate extracellular matrix deposition for cartilage tissue engineering. AB - Cartilage tissue engineering strategies often rely on hydrogels with fixed covalent crosslinks for chondrocyte encapsulation, yet the resulting material properties are largely elastic and can impede matrix deposition. To address this limitation, hydrazone crosslinked poly(ethylene glycol) hydrogels were formulated to achieve tunable viscoelastic properties and to study how chondrocyte proliferation and matrix deposition vary with the time-dependent material properties of covalent adaptable networks. Hydrazone equilibrium differences were leveraged to produce average stress relaxation times from hours (4.01 * 103 s) to months (2.78 * 106 s) by varying the percentage of alkyl-hydrazone (aHz) and benzyl-hydrazone (bHz) crosslinks. Swelling behavior and degradation associated with adaptability were characterized to quantify temporal network changes that can influence the behavior of encapsulated chondrocytes. After four weeks, mass swelling ratios varied from 36 +/- 3 to 17 +/- 0.4 and polymer retention ranged from 46 +/- 4% to 92 +/- 5%, with higher aHz content leading to loss of network connectivity with time. Hydrogels were formulated near the Flory-Stockmayer bHz percolation threshold (17% bHz) to investigate chondrocyte response to distinct levels of covalent architecture adaptability. Four weeks post-encapsulation, formulations with average relaxation times of 3 days (2.6 * 105s) revealed increased cellularity and an interconnected articular cartilage-specific matrix. Chondrocytes embedded in this adaptable formulation (22% bHz) deposited 190 +/- 30% more collagen and 140 +/- 20% more sulfated glycosaminoglycans compared to the 100% bHz control, which constrained matrix deposition to pericellular space. Collectively, these findings indicate that incorporating highly adaptable aHz crosslinks enhanced regenerative outcomes. However, connected networks containing more stable bHz bonds were required to achieve the highest quality neocartilaginous tissue. STATEMENT OF SIGNIFICANCE: Covalently crosslinked hydrogels provide robust mechanical support for cartilage tissue engineering applications in articulating joints. However, these materials traditionally demonstrate purely elastic responses to deformation despite the dynamic viscoelastic properties of native cartilage tissue. Here, we present hydrazone poly(ethylene glycol) hydrogels with tunable viscoelastic properties and study covalent adaptable networks for cartilage tissue engineering. Using hydrazone equilibrium and Flory-Stockmayer theory we identified average relaxation times leading to enhanced regenerative outcomes and showed that extracellular matrix deposition was biphasic as a function of the hydrazone covalent adaptability. We also showed that the incorporation of highly adaptable covalent crosslinks could improve cellularity of neotissue, but that a percolating network of more stable bonds was required to maintain scaffold integrity and form the highest quality neocartilaginous tissue. PMID- 30419279 TI - A 12-item short form of the Hip disability and Osteoarthritis Outcome Score (HOOS 12): tests of reliability, validity and responsiveness. AB - OBJECTIVE: To evaluate reliability, validity and responsiveness of Hip disability and Osteoarthritis Outcome Score (HOOS)-12, a 12-item short form of the 40-item HOOS. HOOS-12 provides Pain, Function and Quality of Life (QOL) scale scores and a summary hip impact score. DESIGN: Data from 1,273 FORCE-TJR hip osteoarthritis (OA) patients who completed HOOS before and six and 12 months after total hip replacement (THR) were analyzed. HOOS-12 includes a pain frequency item and three items measuring pain during increasingly difficult (sitting/lying, walking, stairs) activities; function items about standing, rising from sitting, getting in/out of a car, and walking on an uneven surface; and the 4-item HOOS QOL scale. Percent computable scale scores, floor and ceiling effects, internal consistency reliability, validity (scale correlations, tests of known groups validity using one-way analysis of variance (ANOVA)) and responsiveness (effect sizes, standardized response means) were compared for HOOS-12, full-length HOOS, HOOS-PS and HOOS, JR. RESULTS: Internal consistency reliability was above 0.70 for all HOOS-12 scales and above 0.90 for the HOOS-12 Summary score. Validity and responsiveness of HOOS-12 Pain, Function and QOL scales were satisfactory and reached similar conclusions as comparable full-length HOOS scales. The HOOS-12 Summary score was highly responsive in discriminating between groups who differed in global ratings of post-THR change in physical capabilities and had high effect sizes and standardized response means (SRM). CONCLUSIONS: HOOS-12 was a reliable and valid alternative to HOOS in THR patients with moderate to severe OA and provided three domain-specific and summary hip impact scores with substantially reduced respondent burden. PMID- 30419280 TI - ERK and miRNA-1 target Cx43 expression and phosphorylation to modulate the vascular protective effect of angiotensin II. AB - AIMS AND METHODS: We previously reported that angiotensin II (AngII) restores the vascular reactivity diminished by hemorrhagic shock. In this study, we investigated whether the beneficial effects of AngII are related to regulation of gap junctions (GJs) and connexin43 (Cx43), and the implication of MAPK signaling and microRNA (miR-1) in this process. KEY FINDINGS: Our results show that after hemorrhagic shock or hypoxia, the blockade of GJs or knockdown of Cx43 inhibits the AngII-induced increase in vascular reactivity of superior mesenteric arteries and the contractile response of vascular smooth muscle cells (VSMCs). AngII treatment increases Cx43 expression and phosphorylation at Ser262, and restores gap-junctional communication (GJIC) between VSMCs after hypoxia. The AngII induced up-regulation of Cx43 expression and phosphorylation is blocked in cells transduced with ERK-siRNA, but is not blocked in cells transduced with p38-siRNA. miR-1 levels are elevated after hypoxia; AngII treatment reverses the up regulation of miR-1, while ERK-siRNA abolishes that effect of AngII. In hypoxic cells, transfection of a miR-1 mimic into VSMCs decreases Cx43 expression and VSMC reactivity, whereas a miR-1 inhibitor increases both. Also in hypoxic cells, miR-1 eliminates the restoration effects of AngII on Cx43 expression and VSMC reactivity. SIGNIFICANCE: AngII provides protection of vascular function through the restoration of the expression and phosphorylation of Cx43 and its mediated GJIC in VSMCs. It is ERK that mediates the AngII-induced phosphorylation of Cx43 at Ser262. Additionally, miR-1 is involved in this process, and AngII may exert its protective effect partially by inhibiting miR-1 elevation via ERK signaling. PMID- 30419281 TI - Integrative proteomic analysis reveals potential high-frequency alternative open reading frame-encoded peptides in human colorectal cancer. AB - Identification of alternative open reading frame-encoded peptides (AEPs) for the diagnosis of colorectal cancer at the proteome level is largely unexplored because of a lack of comprehensive proteomics data. Here, we performed a comprehensive integrative analysis of mass spectral data published by Clinical Proteomic Tumor Analysis Consortium and characterized 93 high-confident AEPs encoded within 75 genes. There are four cancer-related genes appeared to have AEPs identified frequently in >20 out of 95 colorectal cancer samples, including ABCF2, AR, RBM10 and NRG1. Further network analysis of the identified AEPs found the enrichment of novel AEPs within hormone androgen receptor and a highly modularised network with 42 genes associated with patient survival. Our results not only suggested a mechanistic view of how AEPs work in cancer progression, but also shed light on somatic amino acid mutations in AEPs, which might be overlooked previously because of their low frequencies. In particular, potential high-frequency mutations in 77 samples associated with EDARADD may contribute to the discovery of new biomarkers and the development of innovative therapeutic approaches. PMID- 30419282 TI - Cardioprotective and anti-apoptotic effects of Potentilla reptans L. root via Nrf2 pathway in an isolated rat heart ischemia/reperfusion model. AB - BACKGROUND: Previous studies have shown that proanthocyanidins have cardioprotective effects which are mediated via the release of nitric oxide (NO) ultimately resulting in increasing the antioxidant activity. We have investigated to show whether 1) the total extract and ethyl acetate fraction (Et) of Potentilla reptans root have an ischemic preconditioning (IPC) effect, 2) P. reptans has antioxidant and cardioprotective effects mediated by nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and scavenging of reactive oxygen species (ROS), 3) NO, caspase-3 and Bcl-2/Bax are involved in the IPC effect of P. reptans. METHODS: Male Wistar rats were divided into 10 groups. The isolated hearts were subjected to 30 min of ischemia and 100 min of reperfusion. The P. reptans was applied before the main ischemia. The infarct size was estimated by triphenyl-tetrazolium chloride staining. The hemodynamic parameters and ventricular arrhythmias were calculated during the reperfusion. Antioxidant markers and immunohistochemistry assays were determined at the end of the protocol. RESULTS: The Et significantly decreased the infarct size, arrhythmia scores, ventricular fibrillation incidence, and enhanced the hemodynamic parameters in a concentration-dependent manner against the ischemia/reperfusion group. SOD and CAT activity were increased and MDA level was decreased in response to the Et. Meanwhile, Et attenuated the suppression of Nrf2 expression and reduced the apoptotic indexes. The cardioprotective effect of P. reptans was abrogated by L-NAME. CONCLUSIONS: P. reptans demonstrated that the cardioprotective preconditioning effects via NO release, Nrf2 pathway, and antioxidant activity lead to a decrease in the apoptotic index. PMID- 30419283 TI - MicroRNA-499-5p regulates skeletal myofiber specification via NFATc1/MEF2C pathway and Thrap1/MEF2C axis. AB - AIMS: This study aimed to investigate the role of microRNA-499-5p (miR-499-5p) in the regulation of skeletal myofiber specification and its underlying mechanisms. MAIN METHODS: Mouse C2C12 cells were used in this study. Cyclosporin A and siRNA targeting Thrap1 (si-Thrap1) were used to inhibit NFATc1/MEF2C pathway and knockdown Thrap1, respectively. The expressions of miR-499-5p and genes were evaluated by real-time quantitative PCR and western blot analysis. KEY FINDINGS: Overexpression of miR-499-5p promoted oxidative fiber gene expression and repressed glycolytic fiber gene expression, affecting several factors associated with fiber specification including NFATc1/MEF2C pathway, PGC-1alpha, FoxO1 and Wnt5a. Inhibition of NFATc1/MEF2C pathway partly reduced the effect of miR-499-5p overexpression on muscle fiber gene expression. MiR-499-5p targeted Thrap1 in proliferating and differentiating C2C12 cells. Knockdown of Thrap1 showed a parallel function with miR-499-5p overexpression on muscle fiber gene expression and NFATc1/MEF2C pathway, accompanied by an increase of miR-499-5p level. The effects of miR-499-5p inhibitor on muscle fiber type specific gene expression and NFATc1/MEF2C pathway were effectively reversed by Thrap1 knockdown. SIGNIFICANCE: MiR-499-5p regulated skeletal myofiber specification and affected several factors associated with fiber specification. MiR-499-5p regulated muscle gene expression partly through NFATc1/MEF2C pathway. We also showed a clue that miR-499-5p regulates skeletal muscle fiber specification in C2C12 cells through targeting Thrap1, thereby, promoting NFATc1/MEF2C pathway and then triggering a series of oxidative muscle fiber gene expression. PMID- 30419284 TI - Successful amphiphiles as the key to crystallization of membrane proteins: Bridging theory and practice. AB - BACKGROUND: Membrane proteins constitute a major group of proteins and are of great significance as pharmaceutical targets, but underrepresented in the Protein Data Bank. Particular reasons are their low expression yields and the constant need for cautious and diligent handling in a sufficiently stable hydrophobic environment substituting for the native membrane. When it comes to protein crystallization, such an environment is often established by detergents. SCOPE OF REVIEW: In this review, 475 unique membrane protein X-ray structures from the online data bank "Membrane proteins of known 3D structure" are presented with a focus on the detergents essential for protein crystallization. By systematic analysis of the most successful compounds, including current trends in amphiphile development, we provide general insights for selection and design of detergents for membrane protein crystallization. MAJOR CONCLUSIONS: The most successful detergents share common features, giving rise to favorable protein interactions. The hydrophile-lipophile balance concept of well-balanced hydrophilic and hydrophobic detergent portions is still the key to successful protein crystallization. Although a single detergent compound is sufficient in most cases, sometimes a suitable mixture of detergents has to be found to alter the resulting protein-detergent complex. Protein crystals with a high diffraction limit involve a tight crystal packing generally favored by detergents with shorter alkyl chains. GENERAL SIGNIFICANCE: The formation of well-diffracting membrane protein crystals strongly depends on suitable surfactants, usually screened in numerous crystallization trials. The here-presented findings provide basic criteria for the assessment of surfactants within the vast space of potential crystallization conditions for membrane proteins. PMID- 30419285 TI - Interaction of the anticancer p28 peptide with p53-DBD as studied by fluorescence, FRET, docking and MD simulations. AB - BACKGROUND: The p28 peptide, derived from the blue copper protein Azurin, exerts an anticancer action due to interaction with the tumor suppressor p53, likely interfering with its down-regulators. Knowledge of both the kinetics and topological details of the interaction, could greatly help to understand the peptide anticancer mechanism. METHODS: Fluorescence and Forster resonance energy transfer (FRET) were used to determine both the binding affinity and the distance between the lone tryptophan (FRET donor) of DNA Binding Domain (DBD) of p53 and the Iaedens dye (FRET acceptor) bound to the p28 peptide. Docking, Molecular Dynamic simulations and free energy binding calculations were used to single out the best complex model, compatible with the distance measured by FRET. RESULTS: Tryptophan fluorescence quenching provided a 105 M-1 binding affinity for the complex. Both FRET donor fluorescence quenching and acceptor enhancement are consistent with a donor-acceptor distance of about 2.6 nm. Docking and molecular dynamics simulations allowed us to select the best complex, enlightening the contact regions between p28 and DBD. CONCLUSIONS: p28 binds to DBD partially engaging the L1 loop, at the same region of the p53 down-regulator COP1, leaving however the DNA binding site available for functional interactions. GENERAL SIGNIFICANCE: Elucidation of the DBD-p28 complex gets insights into the functional role of p28 in regulating the p53 anticancer activity, also offering new perspectives to design new drugs able to protect the p53 anticancer function. PMID- 30419286 TI - Role of leucine zipper-like motifs in the oligomerization of Pseudomonas putida phasins. AB - BACKGROUND: Phasins are low molecular mass proteins that accumulate strongly in bacterial cells in response to the intracellular storage of polyhydroxyalkanoates (PHA). Although lacking catalytic activity, phasins are the major components of the surface of the PHA granules and could be potentially involved in the formation of a network-like protein layer surrounding the polyester inclusions. Structural models revealed phasins to possess coiled-coil regions that might be important in the establishment of protein-protein interactions. However, there is not experimental evidence of a coiled-coil mediated oligomerization in these proteins. METHODS: Structure prediction analyses were used to characterize the coiled-coil motifs of phasins PhaF and PhaI -produced by the model bacterium Pseudomonas putida KT2440-. Their oligomerization was evaluated by biolayer interferometry and the in vivo two-hybrid (BACTH) system. The interaction ability of a series of coiled-coil mutated derivatives was also measured. RESULTS: The formation of PhaF and PhaI complexes was detected. A predicted short leucine zipper-like coiled-coil (ZIP), containing "ideal" residues located within the hydrophobic core, was shown responsible for the oligomers stability. The substitution of key residues (leucines or valines) in PhaI ZIP (ZIPI) for alanine reduced by four fold the oligomerization efficiency. CONCLUSIONS: These results indicate that coiled-coil motifs are essential for phasin interactions. Correct oligomerization requires the formation of a stable hydrophobic interface between both phasins. GENERAL SIGNIFICANCE: Our findings elucidate the oligomerization motif of PhaF and PhaI. This motif is present in most phasins from PHA accumulating bacteria and offers a potentially important target for modulating the PHA granules stability. PMID- 30419287 TI - Distinct phosphorylation sites/clusters in the carboxyl terminus regulate alpha1D adrenergic receptor subcellular localization and signaling. AB - The human alpha1D-adrenergic receptor is a seven transmembrane-domain protein that mediates many of the physiological actions of adrenaline and noradrenaline and participates in the development of hypertension and benign prostatic hyperplasia. We recently reported that different phosphorylation patterns control alpha1D-adrenergic receptor desensitization. However, to our knowledge, there is no data regarding the role(s) of this receptor's specific phosphorylation residues in its subcellular localization and signaling. In order to address this issue, we mutated the identified phosphorylated residues located on the third intracellular loop and carboxyl tail. In this way, we experimentally confirmed alpha1D-AR phosphorylation sites and identified, in the carboxyl tail, two groups of residues in close proximity to each other, as well as two individual residues in the proximal (T442) and distal (S543) regions. Our results indicate that phosphorylation of the distal cluster (T507, S515, S516 and S518) favors alpha1D AR localization at the plasma membrane, i. e., substitution of these residues for non-phosphorylatable amino acids results in the intracellular localization of the receptors, whereas phospho-mimetic substitution allows plasma membrane localization. Moreover, we found that T442 phosphorylation is necessary for agonist- and phorbol ester-induced receptor colocalization with beta-arrestins. Additionally, we observed that substitution of intracellular loop 3 phosphorylation sites for non-phosphorylatable amino acids resulted in sustained ERK1/2 activation; additional mutations in the phosphorylated residues in the carboxyl tail did not alter this pattern. In contrast, mobilization of intracellular calcium and receptor internalization appear to be controlled by the phosphorylation of both third-intracellular-loop and carboxyl terminus-domain residues. In summary, our data indicate that a) both the phosphorylation sites present in the third intracellular loop and in the carboxyl terminus participate in triggering calcium signaling and in turning-off alpha1D-AR-induced ERK activation; b) phosphorylation of the distal cluster appears to play a role in receptor's plasma membrane localization; and c) T442 appears to play a critical role in receptor phosphorylation and receptor-beta-arrestin colocalization. PMID- 30419288 TI - Cloning, SNP detection, and growth correlation analysis of the 5' flanking regions of two myosin heavy chain-7 genes in Mandarin fish (Siniperca chuatsi). AB - Myosin heavy chains (MYHs) play important roles in muscle growth and contraction. In fish, MYHs contribute to hyperplasia and hypertrophy of muscle fibers, which can continue into adult life and thus result in indeterminate growth in some species. We previously identified two MYH genes, MYH-7a and MYH-7b, that are differentially expressed in Mandarin fish (Siniperca chuatsi) and appear to function in early growth. However, the regulatory role of their 5' flanking regions is unknown. To examine the effects of single nucleotide polymorphisms (SNPs) in these regions, we used genome walking to amplify their flanking sequences and analyzed the regulatory elements and binding sites. A single SNP locus was found in the flanking sequence of each gene. These SNP loci are located in the conserved glucocorticoid receptor binding region (MYH-7a: G-614A; Allele frequency: G:A = 94.9:5.1; GG (89.76) and AG (10.24) genotypes) and the LIM homeobox domain transcription factor binding sequence (MYH-7b: C-1933A; Allele frequency: C:A = 54.8:45.2; AA (20.82), AC (48.81), and CC (30.37) genotypes). At the G-614A loci, the GG genotype exhibited more superior growth traits (total length, body length, body height, etc.) than the AG genotype, with the exception of caudal peduncle length. Alternatively, at the C-1933A loci, the AC and AA genotypes showed significant differences in all growth traits, except for head length, with AC exhibiting superior traits. The AA and CC genotypes showed significant differences in caudal peduncle length and height, while no differences were observed between the AC and CC genotypes. Thus, these SNPs in the 5' flanking regions of MYH-7a and MYH-7b are correlated with superior growth and can be used for selecting Mandarin fish during breeding. PMID- 30419289 TI - Intrinsic functional clustering of anterior cingulate cortex in the common marmoset. AB - The common marmoset (Callithrix jacchus) has garnered recent attention as a potentially powerful preclinical model and complement to other canonical mammalian models of human brain diseases (e.g., rodents and Old World non-human primates). With a granular frontal cortex and the advent of transgenic modifications, marmosets are well positioned to serve as neuropsychiatric models of prefrontal cortex dysfunction. A critical step in the development of marmosets for such models is to characterize functional network topologies of frontal cortex in healthy, normally functioning marmosets. Here, we sought to characterize the intrinsic functional connectivity of anterior cingulate cortex (ACC) in marmosets using resting state functional magnetic resonance imaging (RS fMRI). Seven lightly anesthetized marmosets were imaged at ultra-high field (9.4 T) and hierarchical clustering was employed to extract functional clusters of ACC from the RS-fMRI data. The data demonstrated three functionally discrete clusters within ACC. The functional connectivity between these clusters with the rest of the brain was also found to be distinct, supporting the hypothesis that ACC subregions serve different circuits and their concomitant functions. In a separate seed-based analysis, we also sought to delineate finer-grained patterns of ACC connectivity between marmoset primary motor area 4ab and putative eye movement areas (8aD and 8aV). This analysis demonstrated distinct patterns of ACC functional connectivity between motor and eye movement regions that overlapped well with what has been shown in humans and macaques. Overall, these results demonstrate that marmosets have a network topology of ACC that resembles that of Old World primates, giving further credence to the use of marmosets for preclinical studies of intractable human brain diseases. PMID- 30419290 TI - Iliac screws may not be necessary in long-segment constructs with L5-S1 anterior lumbar interbody fusion: cadaveric study of stability and instrumentation strain. AB - BACKGROUND CONTEXT: Lumbosacral pseudoarthrosis and instrumentation failure is common with long-segment constructs. Optimizing lumbosacral construct biomechanics may help to reduce failure rates. The influence of iliac screws and interbody type on range of motion (ROM), rod strain (RS), sacral screw strain (SS) is not well-established. PURPOSE: Investigate the effects of transforaminal lumbar interbody fusion (TLIF), anterior lumbar interbody fusion (ALIF), and iliac screws on long-segment lumbosacral construct biomechanics. STUDY DESIGN: Biomechanical study. PATIENT SAMPLE: Fourteen human cadaveric spine specimens. OUTCOME MEASURES: Lumbosacral ROM, RS, and SS. METHODS: Specimens were potted at L1 and the ilium. Specimens were equally divided into either an L5-S1 ALIF or TLIF group and underwent testing in the following conditions: (1) intact (2) L2 S1 pedicle screw rod fixation (PSR-S) (3) L2-ilium (PSR-I) (4) PSR-S+ALIF (ALIF S) or TLIF (TLIF-S) (5) PSR-I + ALIF (ALIF-I) or TLIF (TLIF-I). Pure moment bending (7.5 Nm) in flexion, extension, lateral bending, axial rotation, and compressive loads (400N) were applied and ROM, SS, and RS were measured. Comparisons were performed using a one-way ANOVA (p<.05). RESULTS: ALIF-S and TLIF-S provided similar decreases in ROM as TLIF-I (p>.05). Compared to PSR-S, PSR-I significantly decreased SS during bending in all directions (p<.02) but increased RS in flexion and extension (p<=.02). Anterior lumbar interbody fusion S provided similar decreases in SS as TLIF-I in all directions (p>.40) but had significantly less RS than TLIF-I in flexion, extension, compression (p<.01). TLIF-S had more SS than TLIF-I in flexion, extension, axial rotation (p<.02), while TLIF-S had less RS only in flexion (p=.03). Compared to PSR-I, ALIF-I decreased the RS (p<.02) but TLIF-I did not (p>.67). CONCLUSIONS: Iliac screws were protective of SS but increased RS at the lumbosacral junction. Constructs with ALIF and no iliac screws result in comparable SS as constructs with TLIF and iliac screws with significantly reduced RS. If iliac screws are utilized, ALIF but not TLIF reduces the iliac screw-induced RS. CLINICAL SIGNIFICANCE: There is a relatively high incidence of lumbosacral instrumentation failure in adult spinal deformity. Optimizing lumbosacral construct biomechanics may help to reduce failure rates. Iliac screws induce lumbosacral rod strain and may be responsible for instrumentation failure. Constructs with lumbosacral ALIF reduce iliac-screw induced rod strain and may obviate the need for fixation to the ilium. PMID- 30419291 TI - A general theory of genital homologies for the Hexapoda (Pancrustacea) derived from skeletomuscular correspondences, with emphasis on the Endopterygota. AB - No consensus exists for the homology and terminology of the male genitalia of the Hexapoda despite over a century of debate. Based on dissections and the literature, genital skeletomusculature was compared across the Hexapoda and contrasted with the Remipedia, the closest pancrustacean outgroup. The pattern of origin and insertion for extrinsic and intrinsic genitalic musculature was found to be consistent among the Ectognatha, Protura, and the Remipedia, allowing for the inference of homologies given recent phylogenomic studies. The penis of the Hexapoda is inferred to be derived from medially-fused primary gonopods (gonopore bearing limbs), while the genitalia of the Ectognatha are inferred to include both the tenth-segmental penis and the ninth-segmental secondary gonopods, similar to the genitalia of female insects which comprise gonopods of the eighth and ninth segments. A new nomenclatural system for hexapodan genitalic musculature is presented and applied, and a general list of anatomical concepts is provided'. Novel and refined homologies are proposed for all hexapodan orders, and a series of groundplans are postulated. Emphasis is placed on the Endopterygota, for which fine-grained transition series are hypothesized given observed skeletomuscular correspondences. PMID- 30419292 TI - Contribution of NHE3 and dietary phosphate to lithium pharmacokinetics. AB - Lithium is one of the mainstays for the treatment of bipolar disorder despite its side effects on the endocrine, neurological, and renal systems. Experimentally, lithium has been used as a measure to determine proximal tubule reabsorption based on the assumption that lithium and sodium transport go in parallel in the proximal tubule. However, the exact mechanism by which lithium is reabsorbed remains elusive. The majority of proximal tubule sodium reabsorption is directly or indirectly mediated by the sodium-hydrogen exchanger 3 (NHE3). In addition, sodium-phosphate cotransporters have been implicated in renal lithium reabsorption. In order to better understand the role of sodium-phosphate cotransporters involved in lithium (re)absorption, we studied lithium pharmacokinetics in: i) tubule-specific NHE3 knockout mice (NHE3loxloxPax8Cre), and ii) mice challenged with low or high phosphate diets. Intravenous or oral administration of lithium did not result in differences in lithium bioavailability, half-life, maximum plasma concentrations, area under the curve, lithium clearance, or urinary lithium/creatinine ratios between control and NHE3loxloxPax8Cre mice. After one week of dietary phosphate challenges, lithium bioavailability was ~30% lower on low versus high dietary phosphate, possibly the consequence of a smaller area under the curve after oral administration. This was associated with higher apparent lithium clearance after oral administration and lower urinary lithium/creatinine ratios on low versus high dietary phosphate. Collectively, renal NHE3 does not play a role in lithium pharmacokinetics; however, dietary phosphate could have an indirect effect on lithium bioavailability and lithium disposition. PMID- 30419293 TI - Dynamic time-kill curve characterization of spectinamide antibiotics 1445 and 1599 for the treatment of tuberculosis. AB - Spectinamides are a novel class of antibiotics under development for the treatment of MDR- and XDR-tuberculosis, with 1599 and 1445 as early lead candidates within this group. In order to evaluate and differentiate the pharmacological properties of these compounds and assist in candidate selection and design of optimal dosing regimens in animal models of Mtb infection, time kill curve assessments were performed in a previously established in vitro PK/PD model system. The performed studies and subsequent pharmacometric analysis indicate that the anti-mycobacterial activity of 1599 exhibits concentration dependent killing whereas 1445 shows time-dependent killing. These findings are supported by the fact that the PKPD index that best describes bacterial killing is T > MIC for 1445, but fCmax/AUC for 1599. The differential killing behavior among the lead candidates can be rationalized by the differences in post antibiotic effect: 15.7 h for 1445 compared the 133 h for 1599. Overall, the PK/PD based analysis of the in vitro pharmacologic killing profile of spectinamides 1599 and 1445 on mycobacteria provided valuable insights that contributed to lead candidate selection and preclinical development of these compounds. PMID- 30419295 TI - Paving the Right Road? PMID- 30419294 TI - A regulatory module controlling GA-mediated endosperm cell expansion is critical for seed germination in Arabidopsis. AB - A key component of seed germination is the interplay of mechanical forces governing embryo growth and the surrounding restraining endosperm tissue. Endosperm cell separation is therefore thought to play a critical role in the control of this developmental transition. Here we demonstrate that in Arabidopsis thaliana seeds, endosperm cell expansion is a key component of germination. Endosperm cells expand to accommodate embryo growth prior to germination. We show that this is an actively regulated process supported by spatiotemporal control of the cell expansion gene EXPANSIN 2 (EXPA2). The NAC transcription factors NAC25 and NAC1L were identified as upstream regulatory effectors of EXPA2 expression, GA-mediated endosperm expansion and seed germination. The DELLA protein RGL2 repressed activation of EXPA2 promoter by NAC. Our findings demonstrate a key role of this gene network in regulating endosperm cell-expansion to control the seed to seedling transition. PMID- 30419296 TI - The effect of different feed frame components on the powder behavior and the residence time distribution with regard to the continuous manufacturing of tablets. AB - The present study focused on the effect of different feed frame components on the residence time distribution of a three-chamber feed frame system (Fill-O-Matic). A production-scale rotary tablet press was used to simulate the industrial manufacture of tablets. The powder residence time distribution was used to characterize the powder behavior in the Fill-O-Matic. Therefore, two powder blends based on microcrystalline cellulose, one of them serving as a plain powder blend (MCC blend) and the other blend (tracer blend) spray colored with an indigo carmine solution by a fluid bed granulator, were used. With these powder blends, the effect of the reduction of the Fill-O-Matic volume with a perspex disc on the residence time distribution was compared with the standard configuration of the Fill-O-Matic. Furthermore, the filling wheel design with regard to the rod shape and different gap size configurations between the feed frame and the die disc were investigated. Interestingly, the reduction of the feed frame volume led to a remarkable decrease of the mean residence time and the mean centered variance. Moreover, the results of the filling wheel design showed that the rod shape of the filling wheels had a high influence on the intermixing of the powder particles in the filling chamber, whereas the corresponding tablet weights and their relative standard deviation were not affected. The gap size between the feed frame and the die disc had low influence on the residence time distribution but an effect on the tablet weights and their standard deviation. PMID- 30419297 TI - Rhegmatogenous Retinal Detachment In Children: Clinical Factors Predictive Of Successful Surgical Repair. AB - OBJECTIVE: To describe presenting clinical features and surgical techniques that are associated with successful surgical repair of pediatric rhegmatogenous retinal detachment (RRD). DESIGN: Retrospective interventional case series. SUBJECTS: 212 eyes of 191 patients, aged 0-18 years, undergoing surgical repair for RRD between 2001 and 2015 with a minimum follow up of 3 months. METHODS: Patients were divided into three age groups (0-6 years, 7-12 years, 13-18 years) and comparisons were made using bivariate and multivariable generalized estimating equation models. A mixed means model was used to examine visual acuity in each age group over time. MAIN OUTCOME MEASURES: Complete reattachment of the retina at final follow up. RESULTS: Of a total of 212 eyes, 166 (78%) achieved total reattachment at final follow up. Mean follow up was 36.3 months. RRD associated with Stickler syndrome was more likely to occur in the younger cohorts (odds ratio [OR] 0.45, 95 % confidence interval [CI] 0.22 - 0.91), while RRD associated with blunt trauma was more likely to occur in the oldest cohort (OR 2.3, 95% CI 1.2 - 4.4). Subtotal RRD was more likely to be successfully repaired than total RRD (OR 3.6, 95% CI 1.5 - 8.4, p = 0.0100), and eyes with previous vitreoretinal surgery were less likely to have successful repair (OR 0.30, 95% CI 0.12 - 0.78, p = 0.0258). There was no significant difference between age groups in the rate of surgical success (p = 0.55). There was a significantly higher success rate with primary scleral buckle (SB) (63%, OR 2.2, 95% CI 1.1- 4.5) and combined scleral buckle/vitrectomy (SB/PPV) (68%, OR 2.3 95% CI 1.1-5.1) compared to vitrectomy (PPV) alone (51%). CONCLUSIONS: Most pediatric patients with RRD achieved complete reattachment with surgery. Success was more common in patients with a subtotal RRD at presentation. Previous vitreoretinal surgery was a risk factor for failure. Younger patients were more likely to present with RRD involving the macula but there was no difference between age groups in successful reattachment at final follow up. Primary PPV had a lower rate of success than SB or combined SB/PPV. PMID- 30419298 TI - Durability of Diabetic Retinopathy Improvement with As-Needed Ranibizumab: Open label Extension of RIDE and RISE Studies. AB - OBJECTIVE: To evaluate durability of diabetic retinopathy (DR) improvements after a change in ranibizumab dosing from monthly to individualized pro re nata (PRN) therapy. DESIGN: Pooled analysis of the open-label extension (OLE) of RIDE/RISE (NCT00473382/NCT00473330) patients with DR and diabetic macular edema (DME). PARTICIPANTS: Patients who completed 36-month participation in RIDE/RISE and entered the OLE. METHODS: In the RIDE/RISE studies, patients (N = 759) were randomized 1:1:1 to ranibizumab 0.3 mg monthly, 0.5 mg monthly, or monthly sham injections with rescue macular laser available after 6 months, per protocol specified criteria. After 24 months, sham patients crossed over to ranibizumab 0.5 mg monthly. After 36 months in the core studies, patients in the OLE (n = 500) could receive ranibizumab 0.5 mg through an individualized PRN dosing regimen based on predefined DME re-treatment criteria. DR severity was evaluated photographically using the Early Treatment Diabetic Retinopathy Study DR severity scale. MAIN OUTCOME MEASURE: Change in DR severity from months 36 to 48 by re treatment status. RESULTS: Among patients who entered the OLE, 121/500 (24%) did not require additional ranibizumab injections. In total, 442 patients had evaluable DR outcomes during the OLE; 367 had evaluable DR at months 36 and 48. Among patients not requiring ranibizumab re-treatment from months 36 to 48 (88/367), 57% to 78%, 0% to 7%, and 22% to 36% experienced DR severity stability, >=2-step improvement, and >=2-step worsening, respectively. Among patients requiring ranibizumab re-treatment (279/367), 84% to 94%, 2%, and 3% to 14% experienced DR severity stability, >=2-step improvement, and >=2-step worsening, respectively. On average, vision improvements were maintained during the OLE regardless of change in DR severity. CONCLUSIONS: DR severity improvements with ranibizumab were maintained in the majority of patients in the OLE after switching from ranibizumab monthly to an individualized best-corrected visual acuity- and optical coherence tomography-based ranibizumab 0.5 mg PRN dosing regimen. Because nearly one-third of OLE patients not requiring further therapy for DME experienced DR worsening, once DME resolves, patients should be watched carefully for worsening of DR and possible need for more frequent follow-up and/or treatment of vision-threatening disease with anti-VEGF or other modalities. PMID- 30419299 TI - Lung allograft donors with excessive alcohol use have increased levels of human antimicrobial peptide LL-37. AB - The relatively low long-term survival rate of lung transplants as compared to other organ recipients serves as an impetus to identify potential lung dysfunction as early as possible. There is an association between donor heavy alcohol use and acute lung injury in the lung allograft after transplant, known as primary graft dysfunction. Excessive alcohol use (EAU) can induce pulmonary immune dysregulation in response to an infection. Antimicrobial peptides (AMPs) are an important component of the innate immune response to pulmonary infections, but the impact of EAU on AMPs in the allograft lung has not been evaluated. Our hypothesis is that specific lung AMPs, LL-37, alpha-defensin-1,2,3, and beta defensin-2, are dysregulated in the lungs from organ donors who had EAU. In this prospective observational investigation, we measured AMPs via ELISA and inflammatory cytokines via multiplex bead array, in bronchoalveolar lavage (BAL) fluid of lung allograft donors, comparing results based on their alcohol consumption. LL-37 levels in lung donors with EAU were found to be increased compared to nondrinker (ND) donors [median 7.7 ng/ml (IQR 4.1-37.0) vs 2.3 ng/ml (IQR 1.1-7.9), p=0.004] whereas alpha-defensins-1,2,3 was decreased only in the presence of an infection in donors with EAU compared to ND donors [median 2.2 ng/ml (IQR 1.6-2.4) vs 3.2 ng/ml (IQR 2.3-3.8), p=0.049]. There was no difference in beta-defensin-2 levels. Gene expression levels of these AMPs were not different. Elevated levels of CXCL8 were noted in bronchial washings of donors with EAU compared to ND donors, [median 4372 pg/ml (IQR 3352-13180) vs 867.3 pg/ml (IQR 163.6-3675), p=0.04] suggesting a potentially heightened inflammatory response. At 1 month post-transplant, LL-37 and CXCL8 levels are decreased compared to levels at time of transplant. In lung donors with EAU, LL-37 and alpha-defensins-1,2,3 dysregulated levels in the presence of an infection may be a harbinger of dysfunction of the lungs through the transplant process. PMID- 30419300 TI - Alcohol and Cannabis Use Alter Pulmonary Innate Immunity. AB - PURPOSE: Cannabis use is increasing due to recent legislative changes. In addition, cannabis is often used in conjunction with alcohol. The airway epithelium is the first line of defense against infectious microbes. Toll-like receptors (TLR) recognize airborne microbes and initiate the inflammatory cytokine response. How cannabis use in conjunction with alcohol affects pulmonary innate immunity mediated by TLRs is unknown. METHODS: Samples and data from an existing cohort of individuals with alcohol use disorders (AUDs), along with samples from additional participants with cannabis use alone and with AUD were utilized. Subjects were categorized into the following groups: no alcohol use disorder (AUD) or cannabis use (Control) (n=46), AUD only (n=29), Cannabis use only (n=39) and AUD and Cannabis use (n= 29). The participants underwent bronchoscopy with bronchoalveolar lavage (BAL) and airway epithelial brushings. We measured IL-6, IL-8, TNF? and IL-10 levels in BAL fluid, and performed real time PCR for TLR1-9 on the airway epithelial brushings. RESULTS: We found significant increases in TLR2 with AUD alone, cannabis use alone and cannabis use with AUD compared to control. TLR5 was increased in cannabis users compared to control, TLR6 was increased in cannabis users and cannabis users with AUD compared to control, TLR7 was increased in cannabis users compared to control, and TLR9 was increased compared to control. In terms of cytokine production, IL-6 was increased in cannabis users compared to control. IL-8 and IL-10 were increased in AUD only. CONCLUSIONS: AUD and cannabis use have complex effects on pulmonary innate immunity that promote airway inflammation. PMID- 30419301 TI - Genetic variation in TCF7L2 rs7903146 and history of GDM negatively and independently impact on diabetes-associated metabolic traits. AB - AIMS: Gestational diabetes (GDM) is recognized as a major risk factor for the development of type 2 diabetes (T2DM) later in life. Risk allele carriers at TCF7L2 rs7903146 have increased susceptibility for both GDM and T2DM. We hypothesized that carrying TCF7L2 risk alleles would further aggravate the negative impact of a positive history for GDM on metabolic traits related to T2DM later in life. METHODS: 210 women with a confirmed history of gestational diabetes and 810 controls without evidence for GDM underwent standardized 75 g oral glucose tolerance tests (OGTT). Liver fat was quantified in a subset of subjects (n = 444) using magnetic resonance spectroscopy. RESULTS: 504 women were homozygous or heterozygous risk allele carriers. The risk allele carriers had a higher risk for GDM (p = 0.0076, OR 1.52, 95% CI 1.11-2.06). Multivariable regression analysis demonstrated that both a history of GDM, or carrying a TCF7L2 risk allele resulted in lower insulin secretion, impaired proinsulin processing and higher fasting and 2-hour glucose levels. Liver fat content was not associated with either a history of GDM or a TCF7L2 risk genotype. There was no significant interaction (all p > 0.05) between history of GDM and TCF7L2 risk alleles on all diabetes-associated metabolic traits tested. CONCLUSION: The TCF7L2 rs7903146 polymorphism is a risk factor for gestational diabetes. However, the additional presence of TCF7L2 rs7903146 risk alleles does not further aggravate the negative impact of a history of gestational diabetes on metabolic traits related to T2DM. PMID- 30419302 TI - Factors associated with undiagnosed diabetes among adults with diabetes: Results from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). AB - AIMS: To investigate sociodemographic and health factors associated with undiagnosed diabetes among adults with diabetes in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). METHODS: Among 3384 adults with self-reported diabetes or undiagnosed diabetes in the baseline HCHS/SOL, we estimated odds ratios (OR) of being undiagnosed for demographic, cultural, access to care, and health factors. RESULTS: Among individuals with diabetes, 37.0% were undiagnosed. After adjustment and compared to people of Mexican heritage, people of Cuban and South American heritage had 60% (OR = 1.60, 95% CI = 1.02-2.50) and 91% (OR = 1.91, 1.16-3.14) higher odds of being undiagnosed, respectively. Individuals with a higher odds of being undiagnosed were women (OR = 1.64, 1.26-2.13), those with no health insurance (OR = 1.31, 1.00-1.71), individuals who received no healthcare in the past year (OR = 3.59, 2.49-5.16), those who were overweight (vs. normal weight) (OR = 1.60, 1.02-2.50), and those with dyslipidemia (OR = 1.38, 1.10-1.74). Individuals with lower odds of being undiagnosed were those with a family history of diabetes (OR = 0.54, 0.43-0.68), and those with hypertension (OR = 0.46, 0.36-0.58). CONCLUSIONS: Variation by Hispanic heritage group, sex, and access to medical care highlight where concentrated efforts are need to improve diabetes awareness. Our findings will inform clinical and public health practices to improve diabetes awareness among vulnerable populations. PMID- 30419303 TI - The impact of dry eye disease treatment on patient satisfaction and quality of life: A review. AB - Several aspects of the quality of life (QoL) and treatment satisfaction of patients with dry eye disease (DED) may be underestimated. Ocular symptoms, which are assessed by validated patient-reported questionnaires and may include stinging, burning, itchiness, grittiness, dryness and discomfort, reduce QoL by affecting daily activities and work productivity. Self-reported symptoms do not always correlate with post-treatment improvements in clinical measures such as tear film break-up time, inflammation and osmolarity. Thus, treatments may improve clinical ocular features without improving symptoms that affect daily life. This review explores 1500 abstracts from congress presentations and peer reviewed journals for QoL and treatment satisfaction data on the use of active lubricants, osmoprotectants, secretagogues, and immunomodulators present in topical formulations for DED treatment, and validated symptom questionnaires. Patient-reported symptoms of DED are generally improved after treatment with topical formulations for tear replacement, tear stimulation or anti-inflammatory therapy compared with baseline or a control treatment. However, more data are required to compare the performance of active ingredients. It is fundamental to diagnose patients with DED accurately, recognising the major cause behind their dry eyes. Studies are also necessary to identify how patient satisfaction and QoL may be improved through long-term use of topical preparations. We conclude that careful and thorough consideration of patient-reported symptoms should be integrated into DED management to help tailor treatment to patient needs. PMID- 30419304 TI - Neurostimulation in dry eye disease-past, present, and future. AB - Neuromodulation is a novel approach that utilizes electrical signals, pharmaceutical agents, or other forms of energy to modulate abnormal neural function through neurostimulation. Neurostimulation is a novel technique that uses electrical currents to stimulate the nervous system. During the recent few decades, neuromodulation has gained significant attention, in particular for the treatment of chronic neurological diseases, due to its success in treating patients unresponsive to conventional pharmacological therapies. Dry eye disease (DED) is a chronic, multifactorial disease that affects millions of people worldwide. Recent data have demonstrated that neurosensory abnormalities contribute to the pathogenesis of DED. Current mainstays of dry eye therapy include lubrication, tear retention, and anti-inflammatory therapies, among others. The recent development of intranasal neurostimulation therapy for DED utilizes the nasolacrimal reflex as an alternative pathway, not only to increase tear production via increased lacrimation, but also to target other tear film components, such as mucin and meibum secretion, promoting tear film homeostasis. This review aims to describe the different types of neuromodulation devices available and their application for non-ocular diseases, as well as to review recent advances and literature on ocular neurostimulation. PMID- 30419305 TI - Conformal Radiation Therapy for Pediatric Patients with Low-Grade Glioma: Results from the Children's Oncology Group Phase II Study XXXX. AB - PURPOSE: To determine the rate of marginal relapse, progression-free survival (PFS), and overall survival (OS) in patients with pediatric low-grade glioma (PLGG) treated with conformal radiation therapy (CRT) with a clinical target volume (CTV) margin of 5 mm in the Children's Oncology Group trial XXXX. METHODS AND MATERIALS: Children (age 3-21 years) with unresectable progressive, recurrent, or residual PLGG were eligible for this study. Patients younger than 10 years were required to have received at least 1 chemotherapy course. Patients with neurofibromatosis type I were not eligible. All patients underwent MRI-based planning and received CRT 54 Gy in 30 fractions with a 5-mm CTV margin. RESULTS: Of 85 eligible patients (median age 13.6 years) treated between March 2006 and December 2010, 14 were younger than 10 years and 36 received prior chemotherapy. Sixty-six had pilocytic astrocytoma (PA); 15 had other histologic subtypes, and 4 had unbiopsied chiasmatic lesions. Events included 23 relapses - 19 central 4 distant, and no marginal - and 7 deaths. At a median follow-up of 5.15 years, 5 year PFS was 71%+/-6% and OS was 93%+/-4%. Male gender (P=.068) and large tumor size (P=.050) trended toward significance for association with decreased PFS. Age, histology, tumor location, time between diagnosis and study entry, and MIB-1 status were not associated with PFS. OS was negatively associated with male gender (P=.064), non-PA histology (P=.010), and large tumor size (P=.0089). CONCLUSIONS: For patients with PLGG, CRT with a CTV margin of 5 mm yields an acceptable PFS and does not lead to a high rate of marginal relapse. PMID- 30419306 TI - Rapid Multi-Site Remote Surface Dosimetry for Total Skin Electron Therapy: Scintillator Target Imaging. AB - PURPOSE: The goal of this work is to produce a surface dosimetry method capable of accurately and remotely measuring skin dose for patients undergoing total skin electron therapy (TSET) without the need for post-exposure dosimeter processing. A rapid and wireless surface dosimetry system was developed to improve clinical workflow. Scintillator surface dosimetry was conducted on patients undergoing TSET by imaging scintillator targets with an intensified camera during TSET delivery. METHODS: & Materials: Disc-shaped scintillator targets were attached to the skin surface of patients undergoing TSET and imaged with an intensified, time gated, and linac-synchronized camera. Optically Stimulated Luminescence Dosimeters (OSLDs) were placed directly adjacent to scintillators at several dosimetry sites to serve as an absolute dose reference. Real-time image processing methods were used to produce background-subtracted intensity maps of Cherenkov and scintillation emission. Rapid conversion of scintillator light output to dose was achieved by using a custom fitting algorithm and calibration factor. Surface doses measured by scintillators were compared to those from of OSLDs. RESULTS: Absolute surface dose measurements for 99 dosimetry sites were evaluated. Based on paired OSLD estimates, scintillator dosimeters were able to report dose with < 3% and < 5% difference in 88/99 and 98/99 observed dosimetry sites, respectively. Fitting a linear regression to dose data reported by scintillator versus OSLD, per dosimetry site, yielded an R2 = 0.94. CONCLUSION: Scintillators were able to report dose within < 3% accuracy of OSLDs. Imaging of calibrated scintillator targets via an intensified, linac-synchronized, camera, provides rapid absolute surface dosimetry measurements for patients treated with TSET. This technique has the potential to reduce the amount of time and effort necessary to conduct full-body dosimetry and can be adopted for use in any surface dosimetry setting where the region of interest is observable throughout treatment. PMID- 30419307 TI - Nomogram predicting locoregional recurrence to assist decision-making of postmastectomy radiotherapy in patients with T1-2N1 breast cancer. AB - PURPOSE: Postmastectomy radiotherapy (PMRT) showed heterogeneous effects on survival outcome of patients with T1-2N1 breast cancer. A reliable model to estimate individuals' risk of locoregional recurrence (LRR) and the potential benefit derived from PMRT is in need. METHODS AND MATERIALS: We retrospectively analyzed 1141 patients with T1-2N1 breast cancer who underwent mastectomy between January 2001 and December 2012. Based on the Fine and Gray competing risks regression in 623 unirradiated patients, a nomogram predicting LRR was conducted for risk quantification. Decision tree analysis was performed for patient grouping. The impact of PMRT was evaluated among three subgroups. RESULTS: With a median follow-up of 74.9 months, the five-year cumulative incidence of LRR, distant recurrence (DR) and breast cancer mortality (BCM) were 3.9%, 8.8% and 6.0% for the entire cohort. Based on nomogram scores, patients were classified into three risk groups in decision tree analysis. In high-risk group, PMRT was found to be associated with a 12.7% risk reduction of 5-year LRR, 9.2% risk reduction of 5-year DR and 7.0% risk reduction of 5-year BCM, while it was not significantly associated with LRR, DR or BCM in low- and intermediate-risk groups. CONCLUSIONS: The nomogram performed individualized risk quantification of LRR in patients with T1-2N1 breast cancer. A newly identified patient subgroup with high risk of LRR were found to derive survival benefit from PMRT. PMID- 30419308 TI - A Nomogram for Testosterone Recovery Following Combined Androgen Deprivation and Radiation Therapy for Prostate Cancer. AB - PURPOSE: Testosterone recovery (TR) after androgen deprivation therapy (ADT) and radiation therapy (RT) is not well characterized. We studied TR in men who received RT and either short-term (ST) or long-term (LT) ADT and aimed to create a nomogram to predict TR. METHODS AND MATERIALS: We identified consecutive localized PC patients treated with ADT-RT at two academic medical centers from 1/2011-10/2016 with documented baseline testosterone (T). TR was time from last ADT injection to T normalization. The Kaplan-Meier method was used to estimate time to TR. Cox proportional hazards models identified TR predictors. A nomogram was trained with site one and externally validated with site two. RESULTS: 340 patients were included. 69.7% received STADT, median duration 6 months; 30.3% received LTADT, median duration 24.3 months. Median follow-up was 26.7 months. Median time for TR was 17.2 months for STADT and 24.0 months for LTADT patients (p = 0.004). The 2-year cumulative incidence of TR was 53.1% after LTADT vs 65.7% after STADT (p=0.004). On multivariate analysis, shorter duration ADT (HR = 0.96, p = 0.004), higher pre-treatment T (HR = 1.004, p<0.001), and lower BMI (HR = 0.95, p = 0.002) were associated with shorter time to TR. Older age (HR = 0.97, p = 0.09) and white race (HR = 0.67, p = 0.06) trended as longer TR predictors. A nomogram was generated to predict probability of TR at 1, 2, and 3 years. The c index was 0.71 (95%CI 0.64-0.78) for the validation cohort. CONCLUSIONS: In this population of localized PC patients, TR following ADT-RT was variable. Using baseline T, ADT duration, BMI, age, and race, a predictive nomogram can estimate the likelihood of TR. PMID- 30419309 TI - Risk factors for ureteral stricture following radiochemotherapy including image guided adaptive brachytherapy in cervical cancer: results from the XXXXXXX studies. AB - BACKGROUND: and purpose: Ureteral stricture is a rare but severe side effect, after radiotherapy for locally advanced cervical cancer (LACC). This report describes the incidence and predictive factors for ureteral stricture in a large patient cohort treated with 3D image guided adaptive brachytherapy (IGABT) and radiochemotherapy within the XXXXXXX studies. MATERIAL AND METHODS: A total of 1860 patients were included. Treatment consisted of external beam radiotherapy (45-50 Gy in 25-30 fx), concomitant Cisplatin and IGABT. Grade 3-4 ureteral strictures were assessed with CTCAE v. 3.0. Predictive factors for grade 3-4 ureteral stricture were analysed. These factors included: age, hydronephrosis on imaging at time of diagnosis, TNM stage, CTVHR volume, laparoscopic staging, chemotherapy, radiotherapy doses to targets and organs at risk, applicator type, intracavitary (IC) versus intracavitary/interstitial (IC/IS) technique, and dose rate. RESULTS: At a median follow up of 34 (2-163) months, 31 patients were diagnosed with grade 3-4 ureteral stricture. Actuarial 3 and 5-year risk for ureteral stricture grade 3-4 was 1.7% and 2.1% for all patients. Advanced tumor stage T3-4 with hydronephrosis at diagnosis was the only independent risk factors for ureteral stricture (p=0.01). Patients with TNM stage T1 (n=359) and T2 (n=1085) had a low risk of 0.4%/1.0% and 1.0%/1.0% at 3/5 years, respectively. Patients (n=274) with T3-T4 without hydronephrosis at diagnosis had a 3/5 year risk of 2.2%/4.8%, compared to 11.5%/11.5% in T3-T4 patients (n=142) with baseline hydronephrosis. CONCLUSION: Severe to life threatening ureteral stricture occurs rarely in LACC patients with T1-2 tumors. The risk for ureteral stricture is significantly increased in patients with T3-T4 tumors with hydronephrosis at diagnosis. PMID- 30419310 TI - Dancing from bottoms up - Roles of the POZ-ZF transcription factor Kaiso in Cancer. AB - The POZ-ZF transcription factor Kaiso was discovered two decades ago as a binding partner for p120ctn. Since its discovery, roles for Kaiso in diverse biological processes (epithelial-to-mesenchymal transition, apoptosis, inflammation) and several signalling pathways (Wnt/beta-catenin, TGFbeta, EGFR, Notch) have emerged. While Kaiso's biological role in normal tissues has yet to be fully elucidated, Kaiso has been increasingly implicated in multiple human cancers including colon, prostate, ovarian, lung, breast and chronic myeloid leukemia. In the majority of human cancers investigated to date, high Kaiso expression correlates with aggressive tumor characteristics including proliferation and metastasis, and/or poor prognosis. More recently, interest in Kaiso stems from its apparent correlation with racial disparities in breast and prostate cancer incidence and survival outcomes in people of African Ancestry. This review discusses Kaiso's role in various cancers, and Kaiso's potential for driving racial disparities in incidence and/or outcomes in people of African ancestry. PMID- 30419311 TI - Neural regulation of drug resistance in cancer treatment. AB - The treatment of cancer has made great progress. However, drug resistance remains problematic. Multiple physiologic processes of tumor development can be dominated by central and sympathetic nervous systems. The interactions between the nervous system, immune system, and tumor occur consistently and dynamically. Recent evidence suggests that nerves and neural signals are intimately involved in the development of resistance to cancer therapies. In this review, we will provide an overview of the recent progress in this rapidly growing area and discuss the potential new strategies for targeting the neural signaling pathway to improve the effectiveness of chemotherapies, targeted therapies, and immunotherapies. PMID- 30419312 TI - Role of tumor-derived exosomes in cancer metastasis. AB - The highlights of cancer research include the discovery of exosomes, which are small (30-100 nm) sized vesicular nanoparticles released virtually by all cells. Tumor-derived exosomes (TDEs) are notoriously known for orchestrating the invasion-metastasis cascade via systemic pathways that we have previously proposed (1), resulting in a paradigm shift of our understanding about the pathobiology of metastases. In principle, exosomes serve as transport medium for proteins, mRNAs and miRNAs to transmit targeted cues from the primary cell to distant sites via horizontal transfer or cell-receptor interaction. In this chapter, we seek to explore in-depth the mechanisms engendering TDE in the metastatic cascade, along with experimental models to augment our understanding. The aforementioned has also paved way for parallel advancements in the therapeutic armamentarium, as evident from pronounced efforts to exploit the metastatic process for therapeutic targeting. In this light, we aim to examine potential anti-metastatic therapeutic opportunities derived from exosomal research. Lastly, exosomes may play a crucial role in the contemporary era of "liquid biopsies", given the array of molecular information with diagnostic and predictive indications. We thus intend to end this chapter off by exploring future applications of exosomes that could illuminate shortcomings and propel advancements in biomarker research. PMID- 30419313 TI - Functions and clinical implications of exosomes in pancreatic cancer. AB - Pancreatic cancer is one of the most aggressive human malignancies and is associated with a dismal prognosis, which can be contributed to its atypical symptoms, metastatic propensity, and significant chemoresistance. Emerging evidence shows that pancreatic cancer cell-derived exosomes (PEXs) play critical roles in tumorigenesis and tumor development, as they are involved in drug resistance, immune evasion and metabolic reprograming, and distant metastasis of pancreatic cancer. Their numerous differentially expressed and functional contents make PEXs promising screening tools and therapeutic targets, which require further exploration. In this review, we focus on the functions of PEX contents and their clinical implications in pancreatic cancer. PMID- 30419314 TI - Unraveling the journey of cancer stem cells from origin to metastasis. AB - Cancer biology research over recent decades has given ample evidence for the existence of self-renewing and drug-resistant populations within heterogeneous tumors, widely recognized as cancer stem cells (CSCs). However, a lack of clear understanding about the origin, existence, maintenance, and metastatic roles of CSCs limit efforts towards the development of CSC-targeted therapy. In this review, we describe novel avenues of current CSC biology. In addition to cell fusion and horizontal gene transfer, CSCs are originated by mutations in somatic or differentiated cancer cells, resulting in de-differentiation and reprogramming. Recent studies also provided evidence for the existence of distinct or heterogeneous CSC populations within a single heterogeneous tumor. Our analysis of the literature also opens the doors for a novel hypothesis that CSC populations with specific phenotypes, metabolic profiles, and clonogenic potential metastasize to specific organs. PMID- 30419315 TI - EMT: A mechanism for escape from EGFR-targeted therapy in lung cancer. AB - Epithelial mesenchymal transition (EMT) is a reversible developmental genetic programme of transdifferentiation of polarised epithelial cells to mesenchymal cells. In cancer, EMT is an important factor of tumour cell plasticity and has received increasing attention for its role in the resistance to conventional and targeted therapies. In this paper we provide an overview of EMT in human malignancies, and discuss contribution of EMT to the development of the resistance to Epidermal Growth Factor Receptor (EGFR)-targeted therapies in non small cell lung cancer (NSCLC). Patients with the tumours bearing specific mutations in EGFR have a good clinical response to selective EGFR inhibitors, but the resistance inevitably develops. Several mechanisms responsible for the resistance include secondary mutations in the EGFR gene, genetic or non mutational activation of alternative survival pathways, transdifferentiation of NSCLC to the small cell lung cancer histotype, or formation of resistant tumours with mesenchymal characteristics. Mechanistically, application of an EGFR inhibitor does not kill all cancer cells; some cells survive the exposure to a drug, and undergo genetic evolution towards resistance. Here, we present a theory that these quiescent or slow-proliferating drug-tolerant cell populations, or so called "persisters", are generated via EMT pathways. We review the EMT-activated mechanisms of cell survival in NSCLC, which include activation of ABC transporters and EMT-associated receptor tyrosine kinase AXL, immune evasion, and epigenetic reprogramming. We propose that therapeutic inhibition of these pathways would eliminate pools of persister cells and prevent or delay cancer recurrence when applied in combination with the agents targeting EGFR. PMID- 30419316 TI - The cornerstone of integrating circulating tumor DNA into cancer management. AB - Recent circulating tumor DNA (ctDNA) research has demonstrated its potential as a non-invasive biomarker for cancer. However, the deployment of ctDNA assays in routine clinical practice remains challenging owing to variability in analytical approaches and the assessment of clinical significance. A well-developed, analytically valid ctDNA assay is a prerequisite for integrating ctDNA into cancer management, and an appropriate analytical technology is crucial for the development of a ctDNA assay. Other determinants including pre-analytical procedures, test validation, internal quality control (IQC), and continual proficiency testing (PT) are also important for the accuracy of ctDNA assays. In the present review, we will focus on the most widely used ctDNA detection technologies and the key quality management measures used to assure the accuracy of ctDNA assays. The aim of this review is to provide useful information for technology selection during ctDNA assay development and assure a reliable test result in clinical practice. PMID- 30419317 TI - NF-kappaB-inducing kinase in cancer. AB - Dysregulation of the alternative NF-kappaB signaling has severe developmental consequences that can ultimately lead to oncogenesis. Pivotal for the activation of the alternative NF-kappaB pathway is the stabilization of the NF-kappaB inducing kinase (NIK). The aim of this review is to focus on the emerging role of NIK in cancer. The documented subversion of NIK in cancers highlights NIK as a possible therapeutic target. Recent studies show that the alterations of NIK or the components of its regulatory complex are manifold including regulation on the transcript level, copy number changes, mutations as well as protein modifications. High NIK activity is associated with different human malignancies and has adverse effects on tumor patient survival. We discuss here research focusing on deciphering the contribution of NIK towards cancer development and progression. We also report that it is possible to engineer inhibitors with high specificity for NIK and describe developments in this area. PMID- 30419318 TI - Roles of DDX5 in the tumorigenesis, proliferation, differentiation, metastasis and pathway regulation of human malignancies. AB - The DEAD-box RNA helicase DDX5 is a member of a family of highly conserved proteins involved in gene-expression regulation and ATP-dependent RNA helicase activities. Recently, it has been reported to be aberrantly expressed in many tumors, and is linked to the regulation of many cancer-related pathways. It co activates many transcription factors, with profound implications for cancer development, and the de-regulation of its functions is ultimately associated with tumor formation and progression. Moreover, it is strongly implicated in the tumorigenesis, invasiveness and metastasis, as well as the proliferation of several cancer types. In this review, we seek to elucidate the role of DDX5 in the development and progression of human malignancies and put forward its prospective applications in future cancer research. PMID- 30419319 TI - Correlations between gene expression and mineralization in the avian leg tendon. AB - Certain avian tendons have been studied previously as a model system for normal mineralization of vertebrates in general. In this regard, the gastrocnemius tendon in the legs of turkeys mineralizes in a well-defined temporal and spatial manner such that changes in the initial and subsequent events of mineral formation can be associated with time and specific locations in the tissue. In the present investigation, these parameters and mineral deposition have been correlated with the expression of several genes and the synthesis and secretion of their related extracellular matrix proteins by the composite tenocytes of the tendon. Quantitative polymerase chain reaction analysis demonstrates that mRNA expression of the non-collagenous genes of bone sialoprotein, osteopontin, and osteocalcin corresponds well with the temporal and spatial onset and progression of mineralization. Immunolocalization separately confirms the synthesis and secretion of these matrix molecules. The expression of other non-collagenous genes such as decorin does not show strong correlation with turkey leg tendon mineralization, and expression of vimentin, a cytoskeletal component which may be regulated by biomechanical factors in the tendon, may lead to inhibition of osteocalcin expression during the development and mineralization of the tissue. The overall results of this work provide insight into direct temporal and spatial relations between the genes and proteins of interest as well as the formation and deposition of mineral in the avian tendon model. PMID- 30419320 TI - Schizophrenia and gut-flora related epigenetic factors. AB - BACKGROUND: Schizophrenia (SZ) is a complex psychiatric disorder and the exact mechanisms that underpin SZ remain poorly understood despite decades of research. Genetic, epigenetic, and environmental factors are all considered to play a role. The importance of gut flora and its influence on the central nervous system has been recognized in recent years. We hypothesize that gut flora may be a converging point where environmental factors interact with epigenetic factors and contribute to SZ pathogenesis. AIM: To summarize the current understanding of genetic and epigenetic factors and the possible involvement of gut flora in the pathogenesis of schizophrenia. RESULTS: We searched PubMed and Medline with a combination of the key words schizophrenia, microbiome, epigenetic factors to identify studies of genetic and epigenetic factors in the pathogenesis of schizophrenia. Numerous genes that encode key proteins in neuronal signaling pathways have been linked to SZ. Epigenetic modifications, particularly, methylation and acetylation profiles, have been found to differ in individuals that present with SZ from those that don't. Gut flora may affect epigenetic modifications by regulation of key metabolic pathway molecules, including methionine, florate, biotin, and metabolites that are acetyl group donors. Despite a lack of direct studies on the subject, it is possible that gut flora may influence genetic and epigenetic expression and thereby contribute to the pathogenesis of SZ. CONCLUSION: Gut flora is sensitive to both internal and environmental stimuli and the synthesis of some key molecules that participate in the epigenetic modulation of gene expression. Therefore, it is possible that gut flora is a converging point where environmental factors interact with genetic and epigenetic factors in the pathogenesis of SZ. PMID- 30419321 TI - Neuroimaging research in posttraumatic stress disorder - Focus on amygdala, hippocampus and prefrontal cortex. AB - Neuroimaging research reflects the complexity of post-traumatic stress disorder and shares some common difficulties of post-traumatic stress disorder research, such as the different classifications of the disorder over time, changes in diagnostic criteria, and extensive comorbidities, as well as precisely delineated and prevailing genetic and environmental determinants in the development of the disorder and its clinical manifestations. Synthesis of neuroimaging findings in an effort to clarify causes, clinical manifestations, and consequences of the disorder is complicated by a variety of applied technical approaches in different brain regions, differences in symptom dimensions in a study population, and typically small sample sizes, with the interplay of all of these consequently bringing about divergent results. Furthermore, combinations of the aforementioned issues serve to weaken any comprehensive meta-analytic approach. In this review, we focus on recent neuroimaging studies and those performed on larger samples, with particular emphasis on research concerning the amygdala, hippocampus, and prefrontal cortex, as these are the brain regions postulated by the core research to play a prominent role in the pathophysiology of post-traumatic stress disorder. Additionally, we review the guidelines for future research and list a number of new intersectional and cross-sectional approaches in the area of neuroimaging. We conclude that future neuroimaging research in post-traumatic stress disorder will certainly benefit from a higher integration with genetic research, better profiling of control groups, and a greater involvement of the neuroimaging genetics approach and from larger collaborative studies. PMID- 30419322 TI - Quorum quelling efficacy of marine cyclic dipeptide -cyclo(L-leucyl-L-prolyl) against the uropathogen Serratia marcescens. AB - In the current study, the anti-quorum sensing (QS) efficacy of cyclic dipeptide cyclo(L-leucyl-L-prolyl) (CLP) of marine origin was explored against Serratia marcescens. Minimal -inhibitory (MIC) and -bactericidal concentrations (MBC) of CLP against both reference as well as a clinical isolate of S. marcescens was identified to be 200 and 400 ug/mL, respectively. CLP proficiently inhibited the QS controlled prodigiosin production in S. marcescens, which affirm its anti-QS efficacy towards S. marcescens. At sub-MIC (100 ug/mL), CLP exhibited a phenomenal inhibitory propensity towards the production of virulence traits viz. biofilm, exopolymeric substance, protease and lipase to the level of 81, 77, 71 and 92%, respectively. Further, the confocal and scanning electron microscopic analyses validated the antibiofilm efficacy of CLP. Besides, CLP effectively modified the hydrophobic and motility characteristics of S. marcescens. Furthermore, the in vivo assay using C. elegans revealed the non-toxic and anti adherence propensity of CLP. Concomitantly, the down regulation of QS controlled virulence genes (unveiled through qPCR analysis) are in accordance with the data of phenotypic and in vivo assays. Therefore, this study exemplifies that CLP could plausibly be a convincing alternative over conventional antibiotics in preventing the QS associated pathogenesis of uropathogens. PMID- 30419323 TI - Biological, chemical and toxicological perspectives on aerial and roots of Filago germanica (L.) huds: Functional approaches for novel phyto-pharmaceuticals. AB - We investigated into the effects of methanol and dichloromethane extracts from aerial and roots of Filago germanica (L.) Huds (Astearaceae) on key enzymes (cholinesterases, alpha-glucosidase and urease), antioxidant capabilities, cytotoxic potential and secondary metabolomics profile. Total phenolic and flavonoids were determined by spectrophotometric technique and secondary metabolites composition by UHPLC-MS. Antioxidant activities were assessed employing free radical scavenging, ferric reducing power and phosphomolybdenum assays. The cell-toxicity was evaluated by MTT assay against breast (MCF-7, MDA MB-231), cervix (CaSki) and prostate (DU-145) cancers. Overall, methanol extracts were found to have higher total bioactive contents and antioxidant potential. UHPLC-MS analysis revealed significant variation in the secondary metabolites in the methanol extracts. The most common derivatives belong to seven groups i.e. alkaloids, benzoic acids, flavones, flavonols, flavan-3-ols, terpenoids and saponins. The major polyphenolic compounds were found to be kampferol, robinin, luteolin, ferulic acid, benzoic acid and salicylic acid. All the extracts showed moderate cholinesterases inhibition, whereas methanol extracts exhibited highest urease inhibition and all extracts presented a relatively high inhibition against alpha-glucosidase. Similarly, all extracts showed strong to moderate cytotoxicity with IC50 values ranging from 53.02 to 382.7 MUg/mL. Overall, results have suggested F. germanica to be a lead source for novel natural products. PMID- 30419325 TI - Beneficial contribution of a safflower (Carthamus tinctorius L.) polysaccharide on steroid-induced avascular necrosis of the femoral head in rats. AB - A water-soluble polysaccharide (SPS) was purified from dried safflower (Carthamus tinctorius L.) and its structure was identified using a combination of chemical and instrumental analysis. SPS has a repeating backbone of 1,4,6-beta-Glcp, which was attached with T-beta-Glcp at its C6 position along the main chain in the molar ratio of 1:1. A steroid-induced avascular necrosis of the femoral head (SANFH) model was established in mice injected with dexamethasone (50 mg/kg) twice per week for 6 weeks. Following SPS treatment at 25 and 100 mg/kg for 60 days, the decreased bone mineral density, abnormal histopathological changes, the increased rate of empty lacunae and apoptosis rate of osteocytes of femoral head in mice induced by dexamethasone was significantly reversed. Meanwhile, increased serum hydroxyproline (HOP) and decreased serum hexosamine (HOM) concentration in mice were turned to the opposite trend with increasing dosage of SPS, thus leading to a high rate of HOM/HOP. In conclusion, SPS may serve as a potential agent for the treatment of SANFH. PMID- 30419324 TI - Risk assessment for migration of styrene oligomers into food from polystyrene food containers. AB - Regulation EU 10/2011 requires a risk assessment of Non Intentionally Added Substances (NIAS) migrating into food for food contact plastics within the EU. Styrene oligomers are important potential components of NIAS in polystyrene used for food packaging and so far only dimers and trimers have been identified. They are not genotoxic in vitro, and there is good evidence that they are not endocrine disruptors. Hazard characterization to establish "safe" exposure levels is based on 1. The No Adverse Effect Level (NOAEL) of 1 mg/kg bw/d in an oral rat study during pregnancy and lactation and 2. The concept of Threshold of Toxicological Concern (TTC). Likely human exposure is derived from 1. The concentrations of dimers and trimers in food simulants or 2. Food and 3. The probabilistic FACET exposure estimation based on dimer and trimer concentrations in polystyrene and their potential for migration. The Margin of Safety as the relation of potential consumer exposure and the "safe" exposure level was always above 1 (apart from migration with 95% ethanol which is no longer recommended as an official food simulant for overall migration into fatty food) demonstrating that dimers and trimers in PS food packaging present a low risk for consumers. PMID- 30419326 TI - Understanding the nano-bio interactions using real-time surface plasmon resonance tool. AB - Our current understanding of the biophysicochemical interactions at nano-bio interfaces is still very limited. Surface plasmon resonance (SPR) is a powerful tool for understanding the real-time kinetics of protein binding on the surface of nanoparticles (NPs) but has been least exploited for this purpose. In this study, we demonstrated the interaction of negatively charged poly lactic-co glycolic acid (PLGA) NPs and positively charged chitosan oligosaccharide (COS) coated PLGA NPs with two model proteins, namely bovine serum albumin (BSA) and hen egg white lysozyme (LYZ), at the physiological pH of 7.4. Various biophysical characterization techniques were employed to elucidate the influence of surface charge of NPs on protein interaction. SPR investigations revealed the binding affinity and binding kinetics involved in nanoparticle-protein interactions. These results confirmed that the affinity of both types of NPs towards positively charged LYZ was much greater than that for negatively charged BSA, which was also in accordance with the results of the adsorption studies. Our results demonstrate that the surface properties of the interacting species play a dominant role during protein-nanoparticle interactions, apart from the net charge on their individual surfaces. The information obtained from this study adds significant value to the biophysicochemical toolbox for characterization of nano-bio interactions. PMID- 30419327 TI - In vitro digestibility and quality attributes of white salted noodles supplemented with pullulanase-treated flour. AB - This study aimed to develop a noodle with slow digestibility by adding pullulanase-treated wheat flour (PF). PF was prepared from normal wheat flour (NF) by pullulanase treatment, then its characteristics were compared with NF. Varying proportions (0%, 3%, 6%, 9%, 12% and 15%) of PF were substituted for NF to produce white salted noodles (WSN). The rheological, digestive, cooking, color and textural properties of WSN were evaluated. This showed that the amylose content of PF (83 wt%, total starch) was 62% higher than that of NF. After pullulanase treatment, the pasting temperature increased from 62.7 to 75.0 degrees C and the crystal structure of the starch changed from a mixture of A- and V-types to one of B- and V-types. Microstructure graphs showed that the structure of PF was more compact than that of NF. PF substitution produced noodles of acceptable quality with increased water absorption, cooking loss, L* value, hardness, and resilience and decreased cooking yield compared with the control (100% NF). In vitro digestibility tests showed that k (the kinetic constant) for cooked WSN decreased from 0.405 to 0.168 as substitution levels of PF increased from 0% to 15%, indicating that PF still exhibited slow digestibility after cooking. PMID- 30419328 TI - Sulfated polysaccharide isolated from Globularia alypum L.: Structural characterization, in vivo and in vitro anticoagulant activity, and toxicological profile. AB - A sulfated polysaccharide from Globularia alypum L. (GASP) was extracted with a yield of 14.2%. GASP is composed mostly of sulfate and total sugars (13.29% and 71.56%, respectively) with small amount of proteins and lipids. The chemical and structural characterization was studied by Infra-Red spectroscopic and gas chromatography-mass spectrometry (GC-MS). GASP composed of eight carbohydrates where galactose, glucose, and mannose are the major compounds (33.47%, 26.71% and 18.21%, respectively). The in vitro and in vivo anticoagulant activities in rats were tested using the standard coagulation assays activated partial thromboplastin time (aPTT), prothrombine time (TT) and thrombin time (PT) tests. Both doses of GASP (200 and 500 mg/kg b.w) displayed a significant in vitro (1.22 and 1.33-fold, 1.17 and 1.27-fold, and 1.21 and 1.26-fold, respectively) and in vivo (1.47 and 2.52-fold; 1.20 and 1.43-fold; 1.21 and 1.40-fold, respectively) compared with the control. Toxicity studies on liver performed by the catalytic activity of transaminases in plasma, oxidative stress markers and hepatic morphological changes indicated that GASP at both doses are not toxics. The important pharmacological and toxicological profile of GASP revealed that this compound may be used as a novel and effective drug. PMID- 30419329 TI - Influences of different pectins on the emulsifying performance of conjugates formed between pectin and whey protein isolate. AB - The effects of different pectins on the conjugates formed between pectin and whey protein isolate (WPI) under the dry-heating condition (80 degrees C, 79% relative humidity) were investigated in this study. The different pectin samples were sugar beet pectin (SBP), high methyl-esterified citrus pectin (HMCP) and low methyl-esterified citrus pectin (LMCP). The covalent linkage between pectin and WPI was proved by SDS-PAGE. As the incubation time was prolonged, the degree of glycosylation (DG) of WPI-pectin conjugate gradually increased, but its solubility decreased gradually. The glycosylated speed between WPI and SBP was the fastest, while the DG between WPI and LMCP was the highest. Even so, the 24 h incubated WPI-HMCP conjugate sample had the best emulsifying properties in all of the prepared conjugates. All the results revealed that the HMCP was the most suitable pectin sample for preparing the WPI-pectin conjugate with a superior emulsifying performance. PMID- 30419330 TI - Chitosan-functionalized nanofibers: A comprehensive review on challenges and prospects for food applications. AB - Chitosan exhibits outstanding properties, which allow a wide range of applications. For this reason, chitosan-based biomaterials have been developed over the years and, among these biomaterials, chitosan-based nanomaterials may significantly change the material properties, which could result in some exceptional features. Indeed, chitosan-based nanofibers have a larger surface area:volume ratio than the bulk materials at macro scale. Moreover, chitosan based nanofibers could lead to enhanced porosity and mechanical properties, which could also improve surface functionalities, and consequently, the range of applications. However, the diversity in sources of raw materials and the production processes for the development of chitosan might provide distinct physicochemical characteristics. Because the varieties of chitosan have been limited in the most part the nanofibers synthesis, the current review describes an extensive research concerning the development of chitosan-based nanofibers and summarizes the different techniques for the nanofibers production; in addition to point out the effects of chitosan characteristics on the spinnability of the solution. Furthermore, the present review explores some potential studies in relation to the chitosan-based nanofibers applied to food technology, including active food packaging, nanofood carrier and enzyme immobilization. PMID- 30419331 TI - The development of a near infrared inulin optical probe for measuring glomerular filtration rate. AB - The polysaccharide, inulin, is considered the clinical gold standard for measuring glomerular filtration rate (GFR), an assessment of kidney filtering capacity and renal function, and therefore, is a prognostic indicator of chronic kidney disease (CKD). The classic method of measuring GFR is laborious, tedious and invasive. Therefore, estimated GFR (eGFR) has become the favoured measurement, but unfortunately suffers in its accuracy. Here, we describe the development of a near infrared dye-labeled inulin, Cy7.5-inulin conjugate, for use as an optical probe to accurately and non-invasively measure GFR in patients by transcutaneous pulse dye densitometer (TPDD). We have characterized the modifications made to inulin and the dye-polysaccharide conjugate by a number of analytical techniques and demonstrated that it is stable under experimental in vivo conditions. To this end, the probe has been successfully used in a pig model to accurately measure GFR non-invasively. PMID- 30419332 TI - Injectable and self-healing polysaccharide-based hydrogel for pH-responsive drug release. AB - Injectable hydrogels with self-healing and pH-responsive property are appealing for biomedical applications. Herein, we developed a facile and green method to prepare a multifunctional polysaccharide-based hydrogel as a new carrier of drug. The hydrogels were prepared by forming reversible chemical bond between carboxyethyl-modified chitosan (CEC) and aldehyde modified hyaluronic acid (A HA). The morphology and rheological property of the hydrogels with different solid content were systematically characterized. Owing to the dynamic equilibrium of the Schiff base bonds between amine groups on CEC and aldehyde groups on A-HA, the rapid self-healing performance of hydrogels was confirmed through qualitative and quantitative methods without any external stimulus. The pH-responsive behaviour was demonstrated by equilibrium swelling and in vitro Doxorubicin (Dox) release in PBS medium with various pH. In acidic condition, Dox can be release more rapidly compared with weak alkaline medium. Furthermore, the kill effect of Dox released from hydrogels for cancer cells was investigated. In vitro degradation and cytotoxicity examinations showed that the hydrogel is biodegradable and biocompatible. Therefore, such polysaccharide-based injectable self-healing and pH-responsive hydrogel is a promising candidate as drug delivery carrier. PMID- 30419333 TI - Towards improving proximity labeling by the biotin ligase BirA. AB - The discovery and validation of protein-protein interactions provides a knowledge base that is critical for defining protein networks and how they underpin the biology of the cell. Identification of protein interactions that are highly transient, or sensitive to biochemical disruption, can be very difficult. This challenge has been met by proximity labeling methods which generate reactive species that chemically modify neighboring proteins. The most widely used proximity labeling method is BioID, which features a mutant biotin ligase BirA(Arg118Gly), termed BirA*, fused to a protein of interest. Here, we explore how amino acid substitutions at Arg118 affect the biochemical properties of BirA. We found that relative to wild-type BirA, the Arg118Lys substitution both slightly reduced biotin affinity and increased the release of reactive biotinyl 5'-AMP. BioID using a BirA(Arg118Lys)-Lamin A fusion enabled identification of PCNA as a lamina-proximal protein in HEK293T cells, a finding that was validated by immunofluorescence microscopy. Our data expand on the concept that proximity labeling by BirA fused to proteins of interest can be modulated by amino acid substitutions that affect biotin affinity and the release of biotinyl-5'-AMP. PMID- 30419334 TI - Analysis of RNA 5' ends: Phosphate enumeration and cap characterization. AB - The function and fate of cellular RNAs are often governed by the phosphorylation state at the 5' end or the identity of whatever cap may be present there. Here we describe methods for examining these important 5'-terminal features on any cellular or synthetic RNA of interest that can be detected by Northern blotting. One such method, PABLO, is a splinted ligation assay that makes it possible to accurately quantify the percentage of 5' ends that are monophosphorylated. Another, PACO, is a capping assay that reveals the percentage of 5' ends that are diphosphorylated. A third, boronate gel electrophoresis in conjunction with deoxyribozyme-mediated cleavage, enables different types of caps (e.g., m7Gppp caps versus NAD caps) to be distinguished from one another and the percentage of each to be determined. After completing all three tests, the percentage of 5' ends that are triphosphorylated can be deduced by process of elimination. Together, this battery of assays allows the 5' terminus of an RNA to be profiled in unprecedented detail. PMID- 30419335 TI - Fluorescence-based quantification of nucleocytoplasmic transport. AB - The sequestration of DNA within the membrane-bound nucleus is a defining characteristic of eukaryotic cells. Replication and transcription are therefore restricted to the nucleus, however, the regulation of these events relies on cytoplasmic processes including protein synthesis and signal transduction pathways. Because a variety of cellular activities depend on nuclear transport, researchers from diverse fields have found it useful to examine the nuclear localization of proteins of interest. Here we present some important technical considerations for studying nuclear and cytoplasmic localization, and provide guidance for quantifying protein levels using fluorescence microscopy and ImageJ software. We include discussion of the use of regions of interest and image segmentation for quantification of protein localization. Nucleocytoplasmic transport is fundamentally important for controlling protein levels and activity in the nucleus or cytoplasm, and quantitative analysis can provide insight into how biological output is achieved. PMID- 30419336 TI - HiPLA: High-throughput imaging proximity ligation assay. AB - Protein-protein interactions are essential for cellular structure and function. To delineate how the intricate assembly of protein interactions contribute to cellular processes in health and disease, new methodologies that are both highly sensitive and can be applied at large scale are needed. Here, we develop HiPLA (high-throughput imaging proximity ligation assay), a method that employs the well-established antibody-based proximity ligation assay in a high-throughput imaging screening format as a novel means to systematically visualize protein interactomes. Using HiPLA with a library of antibodies targeting nuclear proteins, we probe the interaction of 60 proteins and associated post translational modifications (PTMs) with the nuclear lamina in a model of the premature aging disorder Hutchinson-Gilford progeria syndrome (HGPS). We identify a subset of proteins that differentially interact with the nuclear lamina in HGPS. Using HiPLA in combination with quantitative indirect immunofluorescence, we find that the majority of differential interactions are accompanied by corresponding changes in expression of the interacting protein. Taken together, HiPLA offers a novel approach to probe cellular protein-protein interaction at a large scale and reveals mechanistic insights into the assembly of protein complexes. PMID- 30419337 TI - Cause or casualty: The role of mitochondrial DNA in aging and age-associated disease. AB - The mitochondrial genome (mtDNA) represents a tiny fraction of the whole genome, comprising just 16.6 kilobases encoding 37 genes involved in oxidative phosphorylation and the mitochondrial translation machinery. Despite its small size, much interest has developed in recent years regarding the role of mtDNA as a determinant of both aging and age-associated diseases. A number of studies have presented compelling evidence for key roles of mtDNA in age-related pathology, although many are correlative rather than demonstrating cause. In this review we will evaluate the evidence supporting and opposing a role for mtDNA in age associated functional declines and diseases. We provide an overview of mtDNA biology, damage and repair as well as the influence of mitochondrial haplogroups, epigenetics and maternal inheritance in aging and longevity. PMID- 30419338 TI - Pharmacologic IL-6Ralpha inhibition in cholangiocarcinoma promotes cancer cell growth and survival. AB - Biliary tract cancer (BTC) represents a malignant tumor of the biliary tract including cholangiocarcinoma (CCA) and the carcinoma of the gallbladder (GBC) with a 5-year survival rate between 5 and 18% due to late diagnosis and rapid disease progression. Chronic inflammation is one of the main risk factors for CCA and GBC in particular. IL-6, as a mediator of inflammation, can act through a membrane-bound receptor alpha-chain (mIL-6R, "IL-6 classic signaling") or via soluble forms (sIL-6R, "IL-6 trans-signaling"). However, little is known about the impact on cellular responses of IL-6 trans-signaling on BTC. We analyzed primary tumors as whole sections and as tissue microarrays, and also searched The Cancer Genome Atlas database. Compared to non-neoplastic, non-inflamed gallbladder tissue, IL-6Ralpha was downregulated in GBC, and this correlated with the patients' overall survival. Furthermore, different CCA cell lines and compounds for activation (IL-6 and Hyper-IL-6) or inhibition (Tocilizumab and sgp130Fc) of IL-6 classic signaling and trans-signaling were used to determine their effects on cellular processes between the two modes of IL-6 signaling. Inhibition of IL-6 trans-signaling by sgp130Fc reduced CCA cell line viability and apoptosis, whereas migration and proliferation were increased. We conclude that IL-6Ralpha expression is a good prognostic marker for GBC, and that the blocking of IL-6 trans-signaling and activation of IL-6 classic signaling have tumor promoting activity. These findings warrant the exclusion of patients with GBC or other malignancies associated with bile metabolism from IL-6R inhibitor therapy. PMID- 30419339 TI - Acute pancreatic beta cell apoptosis by IL-1beta is responsible for postburn hyperglycemia: Evidence from humans and mice. AB - BACKGROUND: Acute hyperglycemia is regarded as a risk factor for critically ill patients; however, insufficient understanding of its nature and underlying mechanisms hinders widespread adoption of glycemic control in critical care units. METHODS: A single center, prospective cohort study recruiting 107 burn patients and 62 controls was conducted to characterize the early phase of acute hyperglycemia in burn patients. A total of 1643 blood samples were collected and analyzed over the entire postburn 200 h. A mouse severe burn model was used to study the underlying mechanisms of acute hyperglycemia postburn. RESULTS: The dynamic change of postburn blood glucose represented a distinctive pattern in amplitude and duration that was in parallel with the degree of burn injury. Multiple linear regressions revealed that serum insulin, glucagon and glucocorticoid were the major factors affecting blood glucose postburn. Particularly, extensive burns impaired capacity and responsiveness of pancreatic insulin secretion, which was associated with increased serum IL-1beta in burn patients. Mechanistically, acute IL-1beta elevation specifically induced pancreatic beta cell apoptosis and dampened capacity of insulin secretion, leading to postburn hyperglycemia in burned mice. More importantly, inhibition of IL-1beta not only alleviated pancreatic beta cell apoptosis, but also attenuated hyperglycemia and improved survival of burned mice. CONCLUSIONS: Our findings reveal a novel mechanism of acute hyperglycemia postburn in which impaired insulin secretory capacity mediated by IL-1beta leads to acute hyperglycemia. These data suggest that targeting IL-1beta to restore endogenous insulin secretory function may be a novel glycemic control strategy to improve outcomes for burn patients. PMID- 30419340 TI - Stemming retinal regeneration with pluripotent stem cells. AB - Cell replacement therapy is a promising treatment for irreversible retinal cell death in diverse diseases, such as age-related macular degeneration (AMD), Stargardt's disease, retinitis pigmentosa (RP) and glaucoma. These diseases are all characterized by the degeneration of one or two retinal cell types that cannot regenerate spontaneously in humans. Aberrant retinal pigment epithelial (RPE) cells can be observed through optical coherence tomography (OCT) in AMD patients. In RP patients, the morphological and functional abnormalities of RPE and photoreceptor layers are caused by a genetic abnormality. Stargardt's disease or juvenile macular degeneration, which is characterized by the loss of the RPE and photoreceptors in the macular area, causes central vision loss at an early age. Loss of retinal ganglion cells (RGCs) can be observed in patients with glaucoma. Once the retinal cell degeneration is triggered, no treatments can reverse it. Transplantation-based approaches have been proposed as a universal therapy to target patients with various concomitant diseases. Both the replacement of dead cells and neuroprotection are strategies used to rescue visual function in animal models of retinal degeneration. Diverse retinal cell types derived from pluripotent stem cells, including RPE cells, photoreceptors, RGCs and even retinal organoids with a layered structure, provide unlimited cell sources for transplantation. In addition, mesenchymal stem cells (MSCs) are multifunctional and protect degenerating retinal cells. The aim of this review is to summarize current findings from preclinical and clinical studies. We begin with a brief introduction to retinal degenerative diseases and cell death in diverse diseases, followed by methods for retinal cell generation. Preclinical and clinical studies are discussed, and future concerns about efficacy, safety and immunorejection are also addressed. PMID- 30419341 TI - The roles of flp1 and tadD in Actinobacillus pleuropneumoniae pilus biosynthesis and pathogenicity. AB - Pili have been demonstrated to contribute to the pathogenicity of many bacterial pathogens. Flp pilus encoded by the tad locus belongs to the type IVb pilus. Our previous study has revealed that the intact tad locus is essential for Flp pilus formation in Actinobacillus pleuropneumoniae, a very important porcine respiratory pathogen. To further investigate the functions of Flp pilus in A. pleuropneumoniae pathogenesis, the flp1 and tadD single deletion mutants were constructed by homologous recombination. Both of the mutant strains lost pilus on their cell surfaces. The abilities of biofilm formation, cell adhesion, resistance to phagocytosis, survival in swine whole blood, and in vivo colonization of the two mutants were significantly reduced compared with those of the parental strain. The corresponding complemented strains recovered the phenotypes. These results demonstrated that flp1 and tadD were essential for the biosynthesis of Flp pilus and that the pilus played important roles during infection of A. pleuropneumoniae. PMID- 30419342 TI - Canine visceral leishmaniasis: Detection of Leishmania spp. genome in peripheral blood of seropositive dogs by real-time polymerase chain reaction (rt-PCR). AB - Visceral leishmaniasis (VL) is a zoonosis caused by the protozoa of the genus Leishmania. Among the species, L. infantum and/or L. infantum (chagasi) are the most important species affecting the Americas. Domestic dogs are the main reservoir of the parasite and participate effectively in the parasite' transmission cycle. The Canine Visceral Leishmaniasis Control Program (PCLV) adopted in Brazil present as strategies the vector control, health education and serological diagnosis of CVL in dogs followed by culling of the seropositive ones. The resolution to eliminate seropositive dogs by euthanasia, when necessary, are the most controversial and least accepted by society. The diagnostic methods for canine visceral leishmaniasis, currently indicated and approved in Brazil by the Ministry of Health from Brazil are the Dual Path Platform (DPP)(r) as a screening test and the Enzyme immunoassay test (ELISA(r)). This study aimed to verify the presence of Leishmania spp. DNA in peripheral blood samples of dogs presenting positive serological results byDPP(r) and ELISA(r) tests,throughreal-time polymerase chain reaction (rt-PCR), using the pair of primers 150-152 already described. For this purpose, were collected blood samples from 185 seropositive dogs among them, 41 (22%) exhibited some clinical signal of disease, whereas 144 (78%) was asymptomatic. The animals were also analyzed according to gender, race and hair size. According to the results of rt PCR, it was observed that among the185 seropositive dogs analyzed, only 132 (71%) presented positive results for CVL and 53 (29%) presented negative results. From this, 41/41 symptomatic dogs were positive (100%), while among the asymptomatic dogs, 91/144 were positive (63, 2%) and 53/144 were negative (36, 8%). Concerning the hair size of seropositive dogs, we found that 41 (22%) had long hair, while 144 (78%) had short hair. No statistical significance occurred between the results of rt-PCR, ELISA and DPP tests and the profile of the animals (gender, size of the dogs and hair size), probably due to the small number of samples and the sampling differences of each profile. But statistical significance occurred between the results of rt-PCR and the clinical evaluation, since the rt-PCR was positive in all symptomatic dogs. Thus, through these results, we reached at the following question, which may contribute to an important current debate: the dogs presenting CVL seropositive diagnosis confirmed by tests distributed by the Ministry of Health were in reality ill or were they seropositive by living in an endemic area of the disease? Would these asymptomatic seropositive dogs spread the disease to the inhabitants even presenting a low parasite charge circulating in the blood. PMID- 30419343 TI - Spectrum-effect relationships between high-performance liquid chromatography fingerprints and anti-inflammatory activities of Leontopodium leontopodioides (Willd.) Beauv. AB - Leontopodium leontopodioides (Willd.) Beauv. is used therapeutically to prevent numerous diseases. Historically, L. leontopodioides extracts have been used to treat influenza infections, bronchitis, acute and chronic nephritis, proteinuria, hematuria, and diabetes. However, the bioactive compounds that are responsible for the associated therapeutic effects have not yet been characterized. In this study, high-performance liquid chromatography was utilized to study the anti inflammatory properties of L. leontopodioides through analysis of spectrum-effect relationships. The bioactive compounds that correlated with anti-inflammatory activities were partially identified. Following aqueous extraction, a variety of different polar organic solvents including petrol ether extracts, ethyl acetate extracts, n-butanol extracts, and residual aqueous extracts were successfully isolated from L. leontopodioides. These extracts were analyzed using high performance liquid chromatography to generate HPLC fingerprints. A total of 32 common peaks were selected following a similarity analysis (SA). The spectrum effect relationship was subsequently studied and inflammatory factors were identified following acute inflammatory experiments. The results revealed that the main peaks associated with anti-inflammatory activities were x1, x3, x4, x13, x14, x16 for interleukin-1 (IL-1), x5, x8, x9, x18, x26, x27, x30, x31, x32 for interleukin-6 (IL-6), and x28 and x29 for leukotriene B4 (LTB4). Following analysis of HPLC data, peaks x9 and x14 were identified as chlorogenic acid and ferulic acid, respectively. The current study utilized HPLC and pharmacological analyses to formulate a spectrum-effect relationship and identify bioactive compounds in L. leontopodioides. PMID- 30419344 TI - Myeloid-derived suppressor cells induce multiple myeloma cell survival by activating the AMPK pathway. AB - Multiple Myeloma (MM) is an incurable malignancy of terminally differentiated plasma cells, which are predominantly localized in the bone marrow. Myeloid derived suppressor cells (MDSC) are described to promote MM progression by immunosuppression and induction of angiogenesis. However, their direct role in drug resistance and tumor survival is still unknown. In this study, we performed co-culture experiments of myeloma cells with 5TMM derived MDSC in vitro, leading to increased survival and proliferation of MM cells. Co-culture experiments resulted in MDSC-induced AMPK phosphorylation in MM cells, which was associated with an increase in the anti-apoptotic factors MCL-1 and BCL-2, and the autophagy marker LC3II. In addition, 5TMM cells inoculated in mice showed a clear upregulation of AMPK phosphorylation in vivo. Targeting the AMPK pathway by Compound C resulted in apoptosis of human myeloma cell lines, primary MM cells and 5TMM cells. Importantly, we observed that the tumor-promoting effect of MDSC was partially mediated by AMPK activation. In conclusion, our data clearly demonstrate that MDSC directly increase the survival of MM cells, partially through AMPK activation, identifying this pathway as a new target in the treatment of MM patients. PMID- 30419345 TI - Immunological therapy: A novel thriving area for triple-negative breast cancer treatment. AB - Triple-negative breast cancer (TNBC) refers to cancers that are low in expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC tends to behave more aggressively than other types of breast cancer. Unlike other breast cancer subtypes (ie, ER positive, HER2-positive subtypes), there are no approved targeted treatments available, other than the administration of chemotherapy. Immunotherapy is a new kind of treatment approach for TNBC when compared with the surgical treatment, chemotherapy, endocrine therapy, and molecular targeting therapy. The present article reviews the research progresses of immunotherapy for TNBC in recent years. The full text structure covers molecular classification of TNBC, active immunotherapy of TNBC, passive immunotherapy of TNBC, oncolytic immunotherapy and the prospect of immunotherapy for TNBC. PMID- 30419346 TI - A novel circular RNA, circFAT1(e2), inhibits gastric cancer progression by targeting miR-548g in the cytoplasm and interacting with YBX1 in the nucleus. AB - In the present study, two circular RNA (circRNA) expression profiles in paired gastric cancer (GC) tissues from the GEO database were examined. We identified a novel circRNA, has_circ_0001461, which we termed circFAT1(e2). We verified that circFAT1(e2) was significantly downregulated in GC tissues and cell lines and was correlated with overall survival of GC patients. Fluorescence in situ hybridization (FISH) analysis showed that circFAT1(e2) was distributed in the cytoplasm of GC cells, as well as in the nucleus. Functional assays indicated that overexpression of circFAT1(e2) inhibited GC cell proliferation, migration and invasion. Then, we investigated whether circFAT1(e2) acts as a sponge of microRNA-549g(miR-548g) and regulates the expression of tumor suppressor RUNX1 in GC cells. Moreover, we found that nucleus-located circFAT1(e2) could directly interact with Y-box binding protein-1 (YBX1) and inhibit its function. In conclusion, circFAT1(e2) may play a role as a tumor suppressor in GC cells by regulating the miR-548g/RUNX1 axis in the cytoplasm and targeting YBX1 in the nucleus. PMID- 30419347 TI - Estrogen-independent Myc overexpression confers endocrine therapy resistance on breast cancer cells expressing ERalphaY537S and ERalphaD538G mutations. AB - Approximately 30% of metastatic breast cancers harbor estrogen receptor alpha (ERalpha) mutations associated with resistance to endocrine therapy and reduced survival. Consistent with their constitutive proliferation, T47D and MCF7 cells in which wild-type ERalpha is replaced by the most common mutations, ERalphaY537S and ERalphaD538G, exhibit partially estrogen-independent gene expression. A novel invasion/dissociation/rebinding assay demonstrated that the mutant cells have a higher tendency to dissociate from invasion sites and rebind to a second site. Compared to ERalphaD538G breast tumors, ERalphaY537S tumors exhibited a dramatic increase in lung metastasis. Transcriptome analysis showed that the ERalphaY537S and ERalphaD538G mutations each elicit a unique gene expression profile. Gene set enrichment analysis showed Myc target pathways are highly induced in mutant cells. Moreover, chromatin immunoprecipitation showed constitutive, fulvestrant resistant, recruitment of ERalpha mutants to the Myc enhancer region, resulting in estrogen-independent Myc overexpression in mutant cells and tumors. Knockdown and virus transduction showed Myc is necessary and sufficient for ligand independent proliferation of the mutant cells but had no effect on metastasis related phenotypes. Thus, Myc plays a key role in aggressive proliferation related phenotypes exhibited by breast cancer cells expressing ERalpha mutations. PMID- 30419348 TI - Exosomes derived from human umbilical cord mesenchymal stromal cells deliver exogenous miR-145-5p to inhibit pancreatic ductal adenocarcinoma progression. AB - The roles of miRNAs in the development of cancer have made them promising tools for novel therapeutic approaches. However, the successful delivery of miRNAs to cancer cells has been hampered by difficulties in developing an effective and sustainable delivery mechanism. Exosomes are small endogenous membrane vesicles that mediate communication between cells by delivering genetic materials. Thus, given their intrinsic properties, exosomes have been a focus for use as biological delivery vehicles for miRNAs transfer. Whether exosomes can effectively deliver exogenous miRNAs to pancreatic ductal adenocarcinoma (PDAC) cells has not been thoroughly investigated. Here, we used exosomes from human umbilical cord mesenchymal stromal cells (hucMSCs) to deliver exogenous miR-145 5p, which inhibited PDAC cell proliferation and invasion and increased apoptosis and cell cycle arrest, concomitant with decreased Smad3 expression in vitro. Using a mouse model, we also demonstrated that overexpressing miR-145-5p significantly reduced the growth of xenograft tumors in vivo. Our findings provide novel insights that exosomes might be an attractive therapeutic vehicle for the clinical administration of miRNAs in patients with PDAC. PMID- 30419349 TI - DEPDC1, negatively regulated by miR-26b, facilitates cell proliferation via the up-regulation of FOXM1 expression in TNBC. AB - Triple negative breast cancer (TNBC), characterized by lack of estrogen receptors, progesterone hormone receptors, and HER2 overexpression, is a more aggressive high grade tumor and not sensitive to current targeted drugs. The clinical prognosis of TNBC is poorer than other types of breast cancer, and there is no effective therapy strategy until now. Thus, it is necessary to determine important factors involved in regulating the progression of TNBC. In this study, we found DEPDC1 was up-regulated in the tissues of TNBC compared with their paired peritumoral tissues. DEPDC1 over-expression facilitated cell proliferation and tumor growth through increasing the expression of FOXM1 in TNBC cells. Conversely, knockdown of DEPDC1 had the opposite effects. Moreover, miR-26b, acting as a tumor suppressor in TNBC, directly repressed the expression of DEPDC1 and mitigated its promotive effects on cell growth and colony formation. These results indicate that DEPDC1, negatively regulated by miR-26b, promotes cell proliferation and tumor growth via up-regulating FOXM1 expression, implying an important underlying mechanism of regulating the progression of TNBC. PMID- 30419350 TI - Beyond the PD-L1 horizon: In search for a good biomarker to predict success of immunotherapy in gastric and esophageal adenocarcinoma. AB - Gastric adenocarcinoma and esophageal adenocarcinoma are aggressive cancers with a poor prognosis. Therefore, new therapeutic strategies are needed, especially for patients refractory to conventional treatment. Cancer immunotherapy (CIT), is a promising new treatment option and is effective in a proportion of patients with gastroesophageal malignancies. Biomarkers for selecting patients likely to benefit from CIT in gastroesophageal malignancies remain unproven. Programmed cell death ligand-1 (PD-L1), which is a validated biomarker in non-small cell lung cancer (NSCLC), is often also used to select patients for CIT in the context of gastroesophageal cancer, although this marker has not been validated for this purpose. We question the use of PD-L1 as a biomarker in gastroesophageal cancers, as there are fundamental differences in PD-L1 expression between NSCLC and gastroesophageal cancers. This review discusses the value of PD-L1 in selecting patients for CIT in esophageal and gastric cancer. Potential alternatives, especially microsatellite instability and Epstein-Barr virus positivity, are discussed. PMID- 30419351 TI - Insights into Streptococcus agalactiae PI-2b pilus biosynthesis and role in adherence to host cells. AB - The core PI-2b pilus present in "hypervirulent" ST-17 Streptococcus agalactiae strains consists of three pilin subunits (Spb1, Ap1 and Ap2) assembled by sortase SrtC1 and cell-wall anchored by Srt2. Spb1 was shown to be the major pilin and Ap2 the anchor pilin. Ap1 is a putative adhesin. Two additional genes, orf and lep, are part of this operon. The contribution of Lep and Ap1 to the biogenesis of the PI-2b pilus was investigated. Concerning the role of PI-2b, we found that higher PI-2b expression resulted in higher adherence to human brain endothelial cells and higher phagocytosis by human THP1 macrophages. PMID- 30419352 TI - A touching Sight: EEG/ERP correlates for the vicarious processing of affectionate touch. AB - Observers can simulate aspects of other people's tactile experiences. We asked whether they do so when faced with full-body social interactions, whether emerging representations go beyond basic sensorimotor mirroring, and whether they depend on processing goals and inclinations. In an EEG/ERP study, we presented line-drawn, dyadic interactions with and without affectionate touch. In an explicit and an implicit task, participants categorized images into touch versus no-touch and same versus opposite sex interactions, respectively. Modulations of central Rolandic rhythms implied that affectionate touch displays engaged sensorimotor mechanisms. Additionally, the late positive potential (LPP) being larger for images with as compared to without touch pointed to an involvement of higher order socio-affective mechanisms. Task and sex modulated touch perception. Sensorimotor responding, indexed by Rolandic rhythms, was fairly independent of the task but appeared less effortful in women than in men. Touch induced socio affective responding, indexed by the LPP, declined from explicit to implicit processing in women and disappeared in men. In sum, this study provides first evidence that vicarious touch from full-body social interactions entails shared sensorimotor as well as socio-affective experiences. Yet, mental representations of touch at a socio-affective level are more likely when touch is goal relevant and observers are female. Together, these results outline the conditions under which touch in visual media may be usefully employed to socially engage observers. PMID- 30419353 TI - Pacemaker Lead Surveillance and Failure: Is There a Signal in the Noise? PMID- 30419354 TI - New insights into immune cells cross-talk during IgG4-related disease. AB - Immunoglobulin G4-related disease (IgG4-RD) is a newly acknowledged entity, characterized by an immune-mediated fibro-inflammatory process affecting virtually all organs, with infiltration of IgG4+ bearing plasma cells. Until today the pathogenesis of IgG4-RD remains unknown. Treatment with anti-CD20 monoclonal antibodies efficiently induced remission and attenuated the secretory phenotype of myofibroblasts responsible of uncontrolled collagen deposition. This supports the pathogenic role of the adaptive immunity, particularly B cell compartment and B cell/T cell interaction. Latest studies have also highlighted the importance of innate immune system that has been underestimated before and the key role of a specific T cell subset, T follicular helper cells that are involved in IgG4-class-switching and plasmablast differentiation. In this review, we aim to review the most recent knowledge of innate immunity, T and B cells involvement in IgG4-RD, and introduce tertiary lymphoid organs (TLO) as a potential marker of relapse in this condition. PMID- 30419356 TI - Surveillance and public health response for travelers returning from MERS-CoV affected countries to Gyeonggi Province, Korea, 2016-2017. PMID- 30419355 TI - Tick- and flea-borne rickettsioses in Tizi-Ouzou, Algeria: Implications for travel medicine. AB - BACKGROUND: In Algeria, Mediterranean spotted fever (MSF), caused by Rickettsia conorii conorii and transmitted by Rhipicephalus sanguineus, is endemic. However, the documentation of cases is rare due to a lack of laboratory facilities. Our aim was to screen for rickettsioses in patients with fever, rash and a possible inoculation eschar. MATERIALS AND METHODS: Between 2013 and 2015, patients with a fever and a rash presenting at hospitals in the Tizi-Ouzou region were prospectively included in our study. Sera were screened using Indirect Immunofluorescence Assay (IFA) and qPCR was performed on swab samples from eschars. RESULTS: One hundred and sixty-six patients were included. For 57 patients, MSF due to R. conorii conorii was diagnosed by serology and qPCR on a swab eschar sample. Three patients were diagnosed with murine typhus, a flea borne rickettsiosis. In addition, two patients had a positive serology in IgM for R. felis. For nine patients, serology for rickettsiosis was positive, but the specific rickettsia involved could not be determined. Nine patients had a severe disease with neurological involvement or multi-organ failure. CONCLUSION: Clinicians should routinely screen for rickettsioses in patients and travellers presenting with a rash upon return from Algeria. Doxycycline treatment must be given promptly because the prognosis can be severe. PMID- 30419357 TI - Allosteric regulation of pyruvate kinase from Mycobacterium tuberculosis by metabolites. AB - Mycobacterium tuberculosis (Mtb) causes both acute tuberculosis and latent, symptom-free infection that affects roughly one-third of the world's population. It is a globally important pathogen that poses multiple dangers. Mtb reprograms its metabolism in response to the host niche, and this adaptation contributes to its pathogenicity. Knowledge of the metabolic regulation mechanisms in Mtb is still limited. Pyruvate kinase, involved in the late stage of glycolysis, helps link various metabolic routes together. Here, we demonstrate that Mtb pyruvate kinase (Mtb PYK) predominantly catalyzes the reaction leading to the production of pyruvate, but its activity is influenced by multiple metabolites from closely interlinked pathways that act as allosteric regulators (activators and inhibitors). We identified allosteric activators and inhibitors of Mtb PYK originating from glycolysis, citrate cycle, nucleotide/nucleoside inter conversion related pathways that had not been described so far. Enzyme was found to be activated by fructose-1,6-bisphosphate, ribose-5-phosphate, adenine, adenosine, hypoxanthine, inosine, L-2-phosphoglycerate, l-aspartate, glycerol-2 phosphate, glycerol-3-phosphate. On the other hand thiamine pyrophosphate, glyceraldehyde-3-phosphate and L-malate were identified as inhibitors of Mtb PYK. The detailed kinetic analysis indicated a morpheein model of Mtb PYK allosteric control which is strictly dependent on Mg2+ and substantially increased by the co presence of Mg2+ and K+. PMID- 30419358 TI - Structural and biochemical characterization of citrate binding to AtPPC3, a plant type phosphoenolpyruvate carboxylase from Arabidopsis thaliana. AB - Phosphoenolpyruvate carboxylase (PEPC) is a tightly regulated cytosolic enzyme situated at a crucial branch point of central plant metabolism. The structure of AtPPC3, a C3 PEPC isozyme of the model plant Arabidopsis thaliana, in complex with the inhibitors aspartate and citrate was solved at 2.2-A resolution. This represents the first PEPC structure with citrate bound. Aspartate and citrate binding sites are in close proximity (5.1-5.3 A) and interactions between citrate and specific residues were identified. Citrate functions as a mixed (allosteric) inhibitor as it reduced AtPPC3's Vmax while increasing Km(PEP) values. The PEP saturation data gave an excellent fit to the mixed inhibition model, yielding Ki and Ki' (citrate) values of 9.3 and 42.5 mM, respectively. Citrate and aspartate inhibition of AtPPC3 was non-additive, likely due to their closely positioned binding sites, their similar negative charge, and type of binding residues. Fewer interactions and lower affinity for citrate support its observed weaker inhibition of AtPPC3 relative to aspartate. Citrate does not appear to induce further conformational change beyond aspartate owing to the similar structural mechanism of inhibition. AtPPC3 largely exhibits root-specific expression in Arabidopsis, where it is markedly upregulated during stresses such as excessive salinity or nutritional Pi deprivation that necessitate large increases in anaplerotic PEP carboxylation. The cytosolic citrate concentration of potato tubers suggests that AtPPC3's inhibition by citrate may be physiologically relevant. Our results provide novel insights into the structural basis of allosteric PEPC control and the kinetic effects brought about upon inhibitor binding. PMID- 30419359 TI - Long-term exposure to waterborne nonylphenol alters reproductive physiological parameters in economically important marine fish. AB - Low concentrations of nonylphenol (NP) in aquatic environment can induce drastic effects on the endocrine system in animals. In this study, we examined the modulatory effects of NP on reproductive and physiological parameters in juveniles of the red seabream and black rockfish following waterborne NP exposure (0, 1, 10, and 50 MUg L-1) for 60 days. In red seabream exposed to 50 MUg L-1 NP, plasma levels of 17beta-estradiol (E2) and 11-ketotestosterone (11-KT) were significantly lower at 30 and 60 days, while E2 levels were slightly higher in 10 MUg L-1-exposed individuals at day 30. Similarly, significantly lower levels of E2 and 11-KT were observed in 10 and 50 MUg L-1-exposed black rockfish at 60 days, whereas the E2 level was higher in 1 MUg L-1-exposed individuals at day 30. After exposure to NP, plasma and mRNA levels of vitellogenin (VTG) were significantly higher in both species at 30 and 60 days, similar to the inducible effects from synthetic estrogen. Plasma cortisol levels were significantly elevated by relatively higher concentrations of NP (10 and 50 MUg L-1) at 30 and 60 days. Finally, 60 days of exposure of 50 MUg L-1 NP significantly decreased the gonadosomatic index (GSI) and increased the hepatosomatic index (HSI) in both species. The results obtained from this study provide an evidence of the endocrine disrupting potential of waterborne NP on early stages of economically important marine fish. The NP-triggered endocrine modulation can induce effects on the development of reproductive and metabolic organs in fish species. PMID- 30419361 TI - Exposure to environmentally relevant cadmium concentrations negatively impacts early life stages of channel catfish (Ictalurus punctatus). AB - Cadmium is a persistent contaminant of surface waters. The effects of cadmium on early life stages of fish are not well understood, although they are often disproportionately affected by contaminants. The objectives of this study were to examine effects of chronic exposure to environmentally relevant concentrations on growth, development, cellular stress, and glucose metabolism of channel catfish, Ictalurus punctatus. Eggs were wet-fertilized in treatment water at concentrations of 0.4 (control), 2.2 (low), or 8.5 (high) MUg L-1 and monitored through swim-up, black fry stage. Eggs and fry accumulated cadmium dose dependently. Fertilization rates were unaffected, yet hatch rate was significantly reduced in the high treatment. Survival to black fry and overall size and condition factor were not affected; however, differences in yolk sac size, and presumably energetics of yolk fry, was detected. Physiological pathways were also affected, demonstrated by altered gene expression, most notably in genes related to carbohydrate metabolism. Elevated expression of HK and G6PD, rather than G6P and GADPH, suggests glucose may be shunted towards the pentose phosphate pathway. Overall, observations indicate cadmium negatively affects development in early life stages of channel catfish, which could lead to shifts in population structure and life history patterns in exposed populations of wild fish. PMID- 30419360 TI - The protective effect exerted by dietary borax on toxicity metabolism in rainbow trout (Oncorhynchus mykiss) tissues. AB - The aim of this study was to evaluate the effectiveness of borax (BX) against heavy metal exposure on the transcriptional and biochemical reaction in vivo and alleviating effect on gill and liver tissues of rainbow trout. Due to this aim, fish were fed with different level of BX and/or copper (Cu) (1.25, 2.5 and 5 mg/kg of BX; 500 and 1000 mg/kg of Cu) for 21.days in pre- and co-treatment options. The transcriptional parameters [(heat-shock protein 70 (hsp70), and cytochromes P450 (cyp1a), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT))], antioxidant enzyme activities (SOD, CAT and GPx), malondialdehyde (MDA), oxidative DNA damage (8-hydroxy-2'-deoxyguanosine (8-OHdG) and caspase-3 levels were investigated in different tissues samples of treated and control fish. Our results revealed that antioxidant enzyme activity was increased and levels of 8-OHdG, Caspase-3 and MDA were decreased in the BX and BX combined groups as compared to the copper combination group and to copper-only application during pre- and co-treatment (p < 0.05). Similarly, hsp70 and cyp1a gene expressions were decreased after treatment with BX. As conclusion, we suggest that borax itself is not an antioxidant it supportes antioxidant defense mechanism of fish disrupted by heavy metals. PMID- 30419362 TI - Intratumoral delivery of antigen with complement C3-bound liposomes reduces tumor growth in mice. AB - Antigen presenting cells (APCs) initiate the immune response against cancer by engulfing and presenting tumor antigen to T cells. Our lab has recently developed a liposomal nanoparticle that binds complement C3 proteins, allowing it to bind to the complement C3 receptors of APCs and directly deliver antigenic peptides. APCs were shown to internalize and process complement C3-bound liposomes containing ovalbumin (OVA), resulting in a significant increase in activated T cells that recognize OVA. Mice bearing A20-OVA lymphoma tumors were treated with OVA-loaded C3-liposomes, which led to reduced tumor growth in both treated and distal tumors in all mice. Peripheral blood from treated mice had a lower percentage of immunosuppressive myeloid derived suppressor cells (MDSCs), a higher percentage of B cells, and increased anti-OVA IgG1 levels compared to control mice. These results indicate that C3-liposome delivery of tumor antigen to APCs initiates a potent and systemic antitumor immune response. PMID- 30419363 TI - A gentle approach to investigate the influence of LRP-1 silencing on the migratory behavior of breast cancer cells by atomic force microscopy and dynamic cell studies. AB - The aim of the study was to get more insight into the role of LRP-1 in the mechanism of tumor progression in triple negative breast cancer. Atomic force microscopy, videomicroscopy, confocal microscopy and Rho-GTPAse activity assay were used on MDA-MB-231 and LRP-1-silenced cells. Silencing of LRP-1 in MDA-MB 231 cells was shown to led to a dramatic increase in the Young's modulus in parallel to a spectacular drop in membrane extension dynamics as well as a decrease in the cells migration abilities on both collagen I and fibronectin substrates. These results were perfectly correlated to a corresponding change in cell morphology and spreading capacity as well as in Rho-GTPases activity. By a multi-technique approach, it was demonstrated that LRP-1 played a crucial role in the migration of MDA-MB-231 cells by modulating the membrane extension dynamic. The originality of this AFM investigation lies in the non-invasive aspect of the measurements. PMID- 30419364 TI - Ursolic acid loaded-mesoporous bioglass/chitosan porous scaffolds as drug delivery system for bone regeneration. AB - Bioglass scaffolds have great application potentials in orthopedics, and Ursolic acid (UA) can effectively promote in vivo new bone formation. Herein, we for the first time developed the mesoporous bioglass/chitosan porous scaffolds loaded with UA (MBG/CS/UA) for enhanced bone regeneration. The MBG microspheres with particle sizes of ~300 nm and pore sizes of ~3.9 nm were uniformly dispersed on the CS films. The mesoporous structure within the MBG microspheres and the hydrogen bonding between the scaffolds and UA drugs made the MBG/CS/UA scaffolds have controlled drug release performances. The as-released UA drugs from the scaffolds increased remarkably the alkaline phosphatase activity, osteogenic differentiation related gene type I collagen, runt-related transcription factor 2 expression, and osteoblast-associated protein expression. Moreover, the results of micro-CT images, histomorphological observations demonstrated that the MBG/CS/UA scaffolds improved new bone formation ability. Therefore, the MBG/CS/UA porous scaffolds can be used as novel bone tissue engineering materials. PMID- 30419365 TI - A Framework for Data-Driven Adaptive GUI Generation Based on DICOM. AB - Computer applications for diagnostic medical imaging provide generally a wide range of tools to support physicians in their daily diagnosis activities. Unfortunately, some functionalities are specialized for specific diseases or imaging modalities, while other ones are useless for the images under investigation. Nevertheless, the corresponding Graphical User Interface (GUI) widgets are still present on the screen reducing the image visualization area. As a consequence, the physician may be affected by cognitive overload and visual stress causing a degradation of performances, mainly due to unuseful widgets. In clinical environments, a GUI must represent a sequence of steps for image investigation following a well-defined workflow. This paper proposes a software framework aimed at addressing the issues outlined before. Specifically, we designed a DICOM based mechanism of data-driven GUI generation, referring to the examined body part and imaging modality as well as to the medical image analysis task to perform. In this way, the self-configuring GUI is generated on-the-fly, so that just specific functionalities are active according to the current clinical scenario. Such a solution provides also a tight integration with the DICOM standard, which considers various aspects of the technology in medicine but does not address GUI specification issues. The proposed workflow is designed for diagnostic workstations with a local file system on an interchange media acting inside or outside the hospital ward. Accordingly, the DICOMDIR conceptual data model, defined by a hierarchical structure, is exploited and extended to include the GUI information thanks to a new Information Object Module (IOM), which reuses the DICOM information model. The proposed framework exploits the DICOM standard representing an enabling technology for an auto-consistent solution in medical diagnostic applications. In this paper we present a detailed description of the framework, its software design, and a proof-of-concept implementation as a suitable plug-in of the OsiriX imaging software. PMID- 30419366 TI - Decreased fractal dimension of heart rate variability is associated with early neurological deterioration and recurrent ischemic stroke after acute ischemic stroke. AB - Acute ischemic stroke (AIS) may experience early neurological deterioration (END) and have high risks of recurrent ischemic strokes (RIS), which are often associated with a poor outcome. Post-stroke prognosis is associated with autonomic status. Recently, studies showed that heart rate variability (HRV) is an early outcome predictor in acute stroke patients. The purpose of our study was to investigate association decreased HRV by fractal dimension (FD) with early END within 72 h of admission and 1-year RIS. In this study, we assessed autonomic function of ischemic stroke patients within 24 h from symptom onset by FD. Receiver operating characteristic (ROC) curve was utilized to determine the optimal cut point of FD for END and RIS. 516 patients (mean age 66.14 +/- 10.11) with acute ischemic stroke underwent a comprehensive clinical investigation and FD test. According to the data of FD, we investigated association with END within 72 h of admission and the 1-year RIS. ROC curve analysis shown that the optimal cut point of FD for END and RIS were FD <= 1.05 and FD <= 1.15 respectively. In fully adjusted models, there was an association between FD <= 1.05 and END (adjusted odds ratio, 2.64; 95% confidence interval, 1.55-4.49; P < 0.001), there was an association between FD <= 1.15 and RIS (adjusted odds ratio,5.40; 95% confidence interval, 3.02-9.64; P < .001). These findings indicate that FD <= 1.05 and FD <= 1.15 were independently associated with increased risk of END and RIS respectively, which may have predictive value in END and RIS. PMID- 30419367 TI - Adult CSF total protein: Higher upper reference limits should be considered worldwide. A web-based survey. AB - BACKGROUND: The cerebrospinal fluid total protein level (CSF-TP) is commonly used as a potential marker of infectious or immune disease of the CNS and PNS. Recent laboratory reference studies indicate that the antiquated single upper reference limit of 0.45 g/L commonly used by hospital laboratories and widely quoted in medical literature is a significant underestimation. METHODS: We distributed worldwide a web-based survey comprised of three questions: 1. What is the CSF-TP upper limit used at your institution? 2. What is the source of this upper limit? 3. Do you adjust your upper limit according to age? RESULTS: A total of 473 unique responses were obtained from North America (37.5%), South America (5.5%), Europe (29.4%), Africa (4%), Asia (21.6%) and Oceania (1.7%). A strong preponderance (86.8%) of institutions reported an upper limit of 0.45 g/L or less. Only 4% reported making age-partitioned adjustments. CONCLUSIONS: Worldwide, a strong majority of hospital laboratories presently use an underestimation of CSF-TP upper reference value, particularly for older adults. Recent well powered laboratory reference studies support higher values with age adjustment. PMID- 30419368 TI - Huntington disease: A quarter century of progress since the gene discovery. AB - Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor, behavioral, and cognitive manifestations. It is caused by an expansion of a trinucleotide repeat in the huntingtin gene (HTT) on chromosome 4. Although disease onset is currently clinically defined by motor signs, the presence of non-motor symptoms prior to motor diagnosis is increasingly recognized. Complex multimodal symptoms adversely affect quality of life and longevity of patients. Thoughtful interdisciplinary symptomatic care can make a major positive impact for patients and families. A variety of symptomatic treatments are currently available, and new symptomatic and potentially disease modifying therapies are being actively developed. Functional and quality of life outcome measures can be used to assess efficacy of clinical interventions. These outcomes along with clinical data and novel longitudinal biomarkers are increasingly utilized in clinical trials, particularly those testing disease modifying therapeutics. Recent advances in novel therapeutic strategies, including targeting mutant huntingtin (HTT) and the HTT gene, promise another wave of disease-modifying trials in the near future. Better appreciation of heterogeneous clinical phenomenology and immediate tractable treatment goals coupled with advances in new therapeutics heralds a golden age of HD treatment that will positively impact quality of life and longevity of HD patients and inform advances in other inherited and neurodegenerative neurological disorders. PMID- 30419369 TI - Influence of the circle of Willis on leptomeningeal collateral flow in anterior circulation occlusive stroke: Friend or foe? AB - BACKGROUND: Clinical outcome after large vessel occlusion (LVO) stroke depends on collateral integrity. We aimed to evaluate whether the completeness of the circle of Willis (CoW) and anterior temporal artery (ATA) determines the status of leptomeningeal collaterals (LC) in patients with acute LVO (internal carotid artery (ICA) and middle cerebral artery M1 (MCA) occlusion) treated with endovascular thrombectomy. PATIENTS AND METHODS: LC, cross-flow through the anterior communicating artery (ACoA), presence of the ipsilateral posterior communicating artery (IpsiPCoA) and presence of the ATA were evaluated using CT angiography. LC was graded as good when >=50% collateral filling was noted compared to the unaffected hemisphere. RESULTS: We included 159 patients with a median age of 75 years (IQR 63-82), MCA M1 occlusion in 96 (60%) and good outcome in 68 (45.6%). The LC were good in 129 (81.1%) patients. Complete IpsiPCoA and incomplete ACoA status was inversely associated with good LC in LVO (OR 0.51 (95% CI 0.02-0.07)). A complete CoW was associated with good LC in ICA occlusions, OR 8.4 (p = .025). Good outcome (modified Rankin scale 0-2 at 3 months) was associated with good LC (OR 5.63 (95% CI 1.11-28.4)), small ischemic lesion volume (OR 0.94 (95% CI 0.97-0.98)) and absence of the ACoA and IpsiPCoA (OR 4.47 (95% CI 1.09-18.3)). CONCLUSIONS: ATA presence was associated with good leptomeningeal collaterals in LVO (OR 8.13 (95% CI 1.69-39.0)) and in MCA M1 patients (OR 7.9 (95% CI 1.7-36.4)). The effect of ATA was most pronounced in MCA M1 occlusions, and that of ACoA was most pronounced in ICA occlusions. PMID- 30419370 TI - EBV-NMDA double positive encephalitis in an immunocompromised patient. PMID- 30419371 TI - Surfactant-free exfoliation of multilayer molybdenum disulfide nanosheets in water. AB - In this study, we report a potentially scalable method for producing multilayer molybdenum disulfide (MoS2) nanosheets. The addition of a small amount of ammonia solution can improve the exfoliation of MoS2 nanosheets in water. The surface charge induced by spontaneous adsorption of hydroxyl ions on MoS2 surfaces favors the exfoliation process. The edge charge generated by the ionization of edge attached groups facilities the dispersion of exfoliated nanosheets in water. It is also found that smaller MoS2 nanosheets show an improved photocatalytic performance, which stems from enhanced edge effects and a reduced flake thickness. This work opens a new vista on preparation and application of multilayer MoS2 nanosheets. PMID- 30419372 TI - Study of the synergic effect between mica and biosurfactant to stabilize Pickering emulsions containing Vitamin E using a triangular design. AB - HYPOTHESIS: Vitamin E has interesting biological functions for the cosmetic and pharmaceutical industry because it can act as a fat-soluble antioxidant, as well as peroxyl radical scavenger. However, this vitamin is formed by a group of compounds that include tocopherols (gamma-tocopherols, alpha-tocopherol) characterized by their poor solubility in water, what implies the need of using stabilizing agents such as biosurfactants or minerals, in order to make them soluble or stable in formulations composed by water and oil. EXPERIMENTS: In this work, it has been evaluated the synergic effect between a mining silicate mineral (mica) and a biosurfactant extract, obtained from corn steep liquor, to stabilize emulsions containing water and a non-aqueous soluble antioxidant consisting of Vitamin E, through the use of a triangular design. FINDINGS: The results show that the presence of biosurfactant extract improves the emulsion volume up to 70% after 22 days, for an emulsion composed of Vitamin E and biosurfactant, whereas the mica component was able to increase the emulsion stability until values of 80% after 30 days of experiment, for those emulsions containing 10% of mica. Hence, both novel ingredients produce a synergistic effect on the Pickering emulsions carried out in the study. PMID- 30419373 TI - Withdrawal of plasma estradiol is associated with increased anxiety reported by women in the first 12 hours after delivery. AB - The aim of this study was to verify if the fall of plasma concentrations of steroid hormones in the first 12 h postpartum would be associated with changes in the same period in the emotional state of healthy women. Subjective and hormonal data were collected from 14 women (28.5 +/- 7.1 years old) at zero (only hormones), 1, 2, 6 and 12 h after delivery. Subjective measures were taken using the Visual Analogue Mood Scale (VAMS), which consists of four factors (anxiety, sedation, discomfort, and cognitive impairment). Cortisol was measured by radioimmunoassay and estradiol and progesterone by chemiluminescence immunoassay. Women reported a significant increase in anxiety (relative increase: 43.8%+/ 77.6) and discomfort (125.9%+/-218.5) within the 12 h postpartum. There were also significant decreases in the plasma concentration of estradiol (relative decrease: 96.5%+/-3.1), progesterone (78.1%+/-8.7) and cortisol (71.7%+/-18.0). The relative decrease in estradiol concentrations was significantly correlated with the relative increase in anxiety. No significant associations between progesterone and cortisol concentrations and subjective measures were observed. Changes of estradiol but not of progesterone and cortisol concentrations were associated with changes in the reported emotional state of healthy women in the immediate postpartum period. The role of this association as a predictor of mood disorders in the postpartum period should be explored in further studies. PMID- 30419374 TI - Cross-sectional relationship between kynurenine pathway metabolites and cognitive function in major depressive disorder. AB - OBJECTIVE: Cognitive impairment is common among patients with major depressive disorder (MDD), but its pathological mechanism is complex and not fully understood. Evidence suggests that the kynurenine (KYN) pathway may be implicated in the pathophysiology of depression, but few studies have explored the association between the KYN pathway and cognitive impairment in MDD. Our aim was to examine the relationship between cognitive impairment and KYN pathway metabolites in patients with MDD. METHODS: A total of 146 patients with MDD according to DSM-V and 72 healthy controls (HCs) were enrolled, and the severity of depressive symptoms using the 17-item Hamilton Depression Rating Scale (HAMD 17) and cognitive performance including speed of processing, working memory, visual learning and verbal learning were assessed. Blood samples were collected, and serum concentrations of tryptophan (TRP), kynurenine (KYN) and kynurenic acid (KYNA) were measured by liquid chromatography-tandem mass spectrometry. RESULTS: In females with MDD, there was a significant negative association between the KYN level and verbal learning (B=-0.039, adjusted p = 0.018), and the KYN/TRP ratio was negatively correlated with speed of processing (B=-470.086, adjusted p = 0.029), verbal learning (B=-544.251, adjusted p = 0.002) and visual learning (B= 513.777, adjusted p = 0.004). Those associations were not present in male individuals with MDD or in HCs, except for a significant negative correlation between the KYNA/KYN ratio and category fluency (B=-0.373, adjusted p = 0.039) in female HCs. CONCLUSION: Our results suggest that learning function and speed of processing in female MDD were associated with KYN serum level and the KYN/TRP ratio, potentially implicating the KYN pathway in the pathological mechanism of cognitive function in female MDD. PMID- 30419375 TI - Study on neurotoxicity of dinotefuran, thiamethoxam and imidacloprid against Chinese lizards (Eremias argus). AB - The neurotoxicity of dinotefuran, thiamethoxam and imidacloprid against Chinese lizards (Eremias argus) were evaluated in acute oral exposure and 28d subchronic exposure. Dinotefuran was not easily metabolized and showed strong persistence in the lizard brain. Thiamethoxam and imidacloprid were rapidly absorbed and excreted in lizards, and were not easily enriched in the lizard brain. Dinotefuran and thiamethoxam could directly increase the concentrations of acetylcholine in the brain and blood by up-regulating the expression of the ach gene, which in turn enhanced the binding of acetylcholine and acetylcholinesterase receptors, eventually causing the release of dopamine. The effect of dinotefuran was more pronounced than thiamethoxam. Clothianidin was a major metabolite of thiamethoxam in the brain and aggravated the neurotoxic effects of thiamethoxam. Imidacloprid desnitro olefin was the only metabolite of imidacloprid that enriched in the brain. The protonation effect of imidacloprid desnitro olefin was stronger than that of the parent imidacloprid, which increased its binding ability to lizard acetylcholinesterase receptors. Competitive inhibition of imidacloprid desnitro olefin and acetylcholine led to the down-regulation of ach gene expression. Although neonicotinoids caused the opening of ligand-gated ion channel through the activation of acetylcholinesterase receptors, the body would alleviate these effects by the inhibition of voltage-dependent channel activity for compensatory mechanisms. This study provided a new perspective on the neotoxic effects of neonicotinoids. PMID- 30419376 TI - Source identification of arsenic contamination in agricultural soils surrounding a closed Cu smelter, South Korea. AB - Arsenic sources were identified in As-contaminated soils 4 km-7 km from a closed Cu smelter. Host rocks, heavy minerals in contaminated soils, ore minerals in quartz veins (geogenic sources) and bottom ash from the Cu smelter (an anthropogenic source) were investigated as potential sources. As a result, heavy minerals and bottom ash were found to contain higher As concentrations than the contaminated soils. Some of the host rock samples also showed higher As levels than the contaminated soils. Arsenopyrite was one of the frequently detected ore minerals in quartz veins. The As concentrations in soils did not decrease with soil depth or distance from the smelter. These results imply that the atmospheric emission from the smelter was not a major arsenic source. Based on the geochemical investigation and Pb isotopic analysis, the As contamination was affected by both regional ore mineralization and the host rock, and the influence of the smelter was limited. The spatial analysis of As concentrations and Pb isotopic ratios suggested that As contamination was mainly due to regional ore mineralization. The 206Pb/207Pb and 206Pb/204Pb ratios of the contaminated soils were plotted on the mixing line between background soils and ore minerals. The source apportionment results indicated a significant contribution of regional ore mineralization (average 52.9 +/- 30.3%) to the As contamination. The contribution of this study is that we identified that the major source of soil contamination was of geologic origin despite an anthropogenic source nearby using geochemical and Pb isotopic investigation. PMID- 30419377 TI - Organotins in the aquatic media of secondary anabranches in the Three Gorges Reservoir Region, China. AB - The Three Gorges Reservoir Region (TGRR) is one of the most sensitive areas of ecological environment in China. As vital backwater areas, the secondary anabranches of the TGRR were prone to eutrophication in Spring which would affect the distribution and transfer of organotins (OTs) among aquatic media. This study quantified the concentrations of butyltins (BTs) and phenyltins (PhTs) in water columns and aquatic media of two anabranches of the TGRR, the Daning River (DR) and the Xiaojiang River (XR) during the state of eutrophication. Our results showed that the average concentrations of BTs and PhTs in surface water are 43.91, 81.25 ng Sn L-1 in the DR, and 63.49, 69.21 ng Sn L-1 in the XR, respectively, and there were no obvious differences in the concentrations of BTs and PhTs across the water columns in the DR and XR. PhTs, especially monophenyltin (MPhT), are predominated in the dissolved phase, whereas BTs, especially dibutyltin (DBT), are predominated in both suspended particulate matter (SPM) and the sediment. Shipping and agricultural activity were likely the sources of OTs in both the DR and XR. High concentrations of tributyltin (TBT) and triphenyltin (TPhT) are still present in the aquatic media of the TGRR, and pose a significant risk to aquatic organisms due to the potential for bioaccumulation. Therefore, it is necessary to further monitor and assess OTs especially PhTs in surface water, and to continue to restrict the use of OTs to protect the aquatic environment of the TGRR. PMID- 30419378 TI - Quasi-QSAR for predicting the cell viability of human lung and skin cells exposed to different metal oxide nanomaterials. AB - A quasi-QSAR model was developed to predict the cell viability of human lung (BEAS-2B) and skin (HaCaT) cells exposed to 21 types of metal oxide nanomaterials. A wide range of toxicity datasets obtained from the S2NANO (www.s2nano.org) database was used. The data of descriptors representing the physicochemical properties and experimental conditions were coded to quasi SMILES. In particular, hierarchical cluster analysis (HCA) and min-max normalization method were respectively used in assigning alphanumeric codes for numerical descriptors (e.g., core size, hydrodynamic size, surface charge, and dose) and then quasi-QSAR model performances for both methods were compared. The quasi-QSAR models were developed using CORAL software (www.insilico.eu/coral). Quasi-QSAR model built using quasi-SMILES generated by means of HCA showed better performance than the min-max normalization method. The model showed satisfactory statistical results (Radj2 for the training dataset: 0.71-0.73; Radj2 for the calibration dataset: 0.74-0.82; and Radj2 for the validation dataset: 0.70-0.76). PMID- 30419379 TI - Tetracycline removal from aqueous solutions using zeolitic imidazolate frameworks with different morphologies: A mathematical modeling. AB - Concerns about environment pollution by antibiotics raised notable attention. In this context, metal-organic frameworks (MOFs) can produce an excellent platform for toxicant removal from water environments. In the current investigation, eight MOFs (ZIF-67-NO3, ZIF-67-Cl, ZIF-67-SO4, ZIF-67-OAC, ZIF-8-Octahedron, ZIF-8 Leaf, ZIF-8-Cuboid, and ZIF-8-Cube) with different chemical and textural compositions were synthesized, and furthermore, the adsorption of Tetracycline (TC) by them was evaluated. Also, the key experimental conditions were modeled using response surface methodology (RSM). Among the prepared MOFs, the highest tendency for TC removal was nominated to ZIF-67- Acetate (ZIF-67-OAC). By model optimization approach, the optimum system conditions as contact time, adsorbent dosage, pH and adsorbed antibiotic concentration were reported as 26.8 min, 0.63 g/L, 5.9, and 74.6 mg/L, respectively. The proposed equilibrium model showed that the TC accumulated on ZIF-67-OAC surface is reversible in multilayer with the highest monolayer capacity of 446.9 mg/g. Furthermore, based on separation factor (KL), TC adsorption is more favorable at a higher amount of MOFs added. Moreover, according to the fitted kinetic model, the process was controlled by chemisorption. ZIF-67-OAC shows excellent structural stability during mechanical agitation in an aqueous environment, and the TC removal capacities of regenerated adsorbent did not change considerably at the end of cycle 4 compared to the first cycle. Considering the findings among the examined MOFs, the ZIF-67-OAC can be approached as a promising adsorbent for the removal of antibiotics from aqueous environments. PMID- 30419380 TI - Where has the pollution gone? A survey of organic contaminants in Ho Chi Minh city / Saigon River (Vietnam) bed sediments. AB - A wide range of persistent organic chemicals, including polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), some insecticides, as well as polybrominated diphenyl ethers (PBDEs) and some perfluoroalkyl substances (PFASs) were analyzed in 17 bed sediments collected along the Saigon River and at adjacent canal mouths from upstream to downstream in Ho Chi Minh City (Vietnam). Concentrations were rather low for PAHs, as well as for legacy PCBs and dichloro diphenyl-trichlorethane and metabolites (DDTs), or below detection limits for several PFASs and all PBDEs measured. Several insecticides (chlorpyrifos-ethyl, and the pyrethroids cypermethrin and lambda-cyhalothrin) displayed rather high concentrations at a few sites within the city. There was no distinct upstream - downstream trend for PAHs, (DDTs) or PCBs. Although adjacent canal sediments tended to be more contaminated than Saigon River sediments, the differences were not significant. Emissions are almost certainly substantial for PAHs, and probably also for other contaminants such as PBDEs and some PFASs. During the dry season, contaminants are presumably stored in the city, either in canals or on urban surfaces. Heavy rainfall during the monsoon period carries away contaminated particle flows into the canals and then the Saigon River. The strong tidal influence in the river channel hinders the accumulation of contaminated particles. Contaminated deposits should accordingly be investigated further downstream in depositional environments, such as the mangrove. PMID- 30419381 TI - Efficient adsorption of diclofenac sodium from aqueous solutions using magnetic amine-functionalized chitosan. AB - In this study, we prepared a magnetic composite based on amine-functionalized chitosan (aminochitosan; AmCS) and Fe3O4 to remove diclofenac sodium (DS) from water. The fabricated AmCS@Fe3O4 composite was characterized using Fourier transform infrared spectroscopy, transmission electron microscopy, scanning electron microscopy, vibrating sample magnetometry, X-ray diffraction, and thermogravimetric analysis. Furthermore, we investigated the influence of pH, initial DS concentration, and adsorbent dosage on the adsorption of DS. Through thermodynamic analysis, we found that the data corresponded with the Langmuir adsorption isotherm model. The maximum adsorption capacity reached 469.48 mg g-1, and the adsorption process followed the pseudo-second-order kinetic model. Finally, the AmCS@Fe3O4 composite retained good adsorption characteristics after four consecutive cycles, with removal efficiency exceeding 70%. Therefore, the developed adsorbent could be used for efficient adsorptive removal of trace drugs and personal care products from water bodies. PMID- 30419382 TI - Anammox granule as new inoculum for start-up of anaerobic sulfide oxidation (ASO) process and its reverse start-up. AB - The feasibility of implementing anaerobic ammonium oxidation (anammox) granules to start up high-loading anaerobic sulfide oxidation (ASO) in an upflow anaerobic sludge bed (UASB) reactor was investigated. An innovation method of the reverse start-up of anammox was also validated. Firstly, the reactor was operated to treat sulfide-rich wastewaters into which nitrite was introduced as an electron acceptor. An high-rate performance with sulfide and nitrate removal rates of 105.5 +/- 0.11 kg S m-3 d-1 and 28.45 +/- 3.40 kg N m-3 d-1, respectively, was accomplished. Sulfurovum were enriched with the increase of the substrate load and then conquered Candidatus Kuenenia to be the predominant bacteria. Excitation emission matrix (EEM) spectroscopy showed that the intensities of fluorescence decreased and protein-like substrates were the main components associated with the process of start-up. FT-IR analysis found that the main functional groups indicator were O-H groups. Secondly, the reverse start-up of anammox (achieving 90% TN removal) was achieved immediately when the substrate changed. 16S rRNA analysis indicated the successfully enrichment of anammox bacteria (Candidatus Kuenenia). These results suggest that anammox granules can act as inoculum of high-loading ASO process and the reverse start-up provides a new perspective for the fast initiation of anammox process. PMID- 30419383 TI - Growth, antioxidant capacity, intestinal morphology, and metabolomic responses of juvenile Oriental river prawn (Macrobrachium nipponense) to chronic lead exposure. AB - Understanding the mechanisms of metal toxicity to organisms farmed for food may suggest mitigation strategies. We determined the 24-, 48-, 72-, and 96-h median lethal concentrations of lead in juvenile oriental river prawn (Macrobrachium nipponense). The prawns were then exposed to sub-lethal concentrations (13.13 and 26.26 MUg/L) of lead for 60 days and growth, antioxidant enzyme activity, intestinal morphology, and metabolite profiles were assessed. Prawns exposed to 26.26 MUg/L but not to 13.13 MUg/L lead exhibited lower weight gain than controls. The lead burden in muscle was 0.067 and 0.25 MUg/g of dry weight exposed to 13.13 and 26.26 MUg/L, respectively. Levels of glutamic oxaloacetic transaminase and glutamic-pyruvic transaminase were not altered following exposure. Exposure increased malondialdehyde activity in the hepatopancreas and decreased superoxide dismutase and glutathione peroxidase activities. Catalase activity first increased and then decreased as lead concentrations increased. Some intestinal epithelial cells disassociated from the basement membrane in prawns exposed to 13.13 MUg/L lead. Intestinal epithelial cells in prawns exposed to 26.26 MUg/L lead separated completely from the basement membrane. Gas chromatography-mass spectrometry metabolomics assays showed the 13.13-MUg/L exposure did not elicit significant metabolic alterations. Exposure to 26.26 MUg/L lead differentially up-regulated 58 metabolites and down-regulated 21 metabolites. The metabolites identified were involved in galactose, purine, glutathione, and carbon metabolism, biosynthesis of amino acids and steroids, and neuroactive ligand-receptor interaction. These data indicate that chronic lead exposure can adversely affect growth, increase accumulation in muscle, impair intestinal morphology, and induce oxidant stress or neurotoxicity-related effects in M. nipponense. PMID- 30419384 TI - A multimedia fugacity model to estimate the fate and transport of polycyclic aromatic hydrocarbons (PAHs) in a largely urbanized area, Shanghai, China. AB - Increasing PAHs pollution is creating more complex urban pollution system. However, the availability of sufficient monitoring activities for PAHs in multicompartment and corresponding multi-interface migration processes is still not well understood. In this study, a Level III steady state fugacity model was validated to evaluate the detailed local variations, and mass fluxes of PAHs in various environmental compartments (i.e., air, soil, sediment, water, vegetation and organic film). This model was applied to a region of Shanghai in 2012 based on a large number of measured data and brings model predictions in 2020. The model results indicate that most of the simulated concentrations agreed with the observed values within one order of magnitude with a tendency of underestimation for vegetation. Direct emission is the main input pathway of PAHs entering the atmosphere, whereas advection is the main outward flow from Shanghai. Organic film was achieved the highest concentration of PAHs compared to other compartments up to 58.17 g/m3. The soil and sediment served as the greatest sinks of PAHs and have the longest retention time (2421.95-78642.09 h). Importantly, a decreasing trend of PAHs was observed in multimedia from 2012 to 2020 and the transfer flux from the air to vegetation to soil was the dominant pathways of BaP intermedia circulation processes. A sensitivity analysis showed that temperature was the most influential parameter, especially for Phe. A Monte Carlo simulation emphasized heavier PAHs were overpredicted in film and sediment, but lighter PAHs in air and water were generally underestimated. PMID- 30419385 TI - Exposure to nitrate alters the histopathology and gene expression in the liver of Bufo gargarizans tadpoles. AB - Nitrate is a ubiquitous component in aquatic environment and the concentrations of anthropogenic nitrate-nitrogen (NO3N) can exceed 25 mg/L in surface waters and 100 mg/L in ground waters. The exceed nitrate has adverse effects on survival, development, and metamorphosis of amphibian. Liver is the hub of many biological processes, including lipid metabolism and bile salts secretion. However, there is little information about the effects of nitrate on the liver in amphibians during metamorphosis. In this study, B. gargarizans was exposed to different concentrations of nitrate from embryo to metamorphosis climax to investigate the effects of nitrate on the liver. The survival rate, metamorphosis percent, body mass, total length, and hind-limb length were measured. The histopathological changes and transcriptome responses in the liver of B. gargarizans to nitrate were examined. Results indicated exposure to 50 and 100 mg/L NO3N delayed the metamorphosis and decreased the metamorphosis percent of B. gargarizans. The body size of B. gargarizans at 10 and 50 mg/L NO3N groups were decreased while it was increased at 100 mg/L NO3N group. In addition, exposure to 100 mg/L NO3N caused severe histopathological changes, including cellular atrophy, increased intercellular areas, degraded lipid droplets, hepatic fibrosis, bile canaliculus contraction and degraded mitochondria in liver. The results of RNA-seq and qRT PCR interpreted the molecular responses, which might be the factors to induce histopathological changes in the liver of B. gargarizans under the pressure of nitrate exposure. PMID- 30419386 TI - Is blood a reliable indicator of trace metal concentrations in organs of small mammals? AB - In wildlife ecotoxicology, the rationale for using blood rather than other body fluids or tissues is that sampling blood is a minimally invasive technique without animal mortality, providing both ethical and scientific benefits. To date, few studies are available on the relationships between blood and organ metal concentrations of small mammals living in contaminated sites. The present work aimed to study the relationships between the concentrations of 18 essential and nonessential metals in blood and their concentrations in the liver and kidneys, two accumulation and target organs, in wood mice from a former lead and zinc smelter, Metaleurop Nord, in northern France. The results from Se, Pb and Tl indicate that blood levels may be used to predict concentrations in organs of small mammals. Conversely, for Cd, Cu, Fe, Mo, Ti and Zn, blood concentrations were poorly or not related to liver and kidney concentrations. In addition to accurately predicting the concentrations of some metals in target organs, blood can provide important information about the physiological and biochemical status of organisms, but further toxicokinetic research is required to develop the use of blood sampling as a minimally invasive biomonitoring and ecotoxicological method in wildlife. PMID- 30419387 TI - The risk of neonicotinoid exposure to shrimp aquaculture. AB - Widespread agricultural use of systemic neonicotinoid insecticides has resulted in the unintended contamination of aquatic environments. Water quality surveys regularly detect neonicotinoids in rivers and waterways at concentrations that could impact aquaculture stock. The toxicity of neonicotinoids to non-target aquatic insect and crustacean species has been recognised, however, there is a paucity of information on their effect on commercial shrimp aquaculture. Here, we show that commercially produced shrimp are likely to be exposed to dietary, sediment and waterborne sources of neonicotinoids; increasing the risks of disease and accidental human consumption. This review examines indicators of sublethal neonicotinoid exposure in non-target species and analyses their potential usefulness for ecotoxicology assessment in shrimp. The identification of rapid, reliable responses to neonicotinoid exposure in shrimp will result in better decision making in aquaculture management. PMID- 30419388 TI - Bioaccumulation and acute toxicity of As(III) and As(V) in Nile tilapia (Oreochromis niloticus). AB - The distribution of arsenic in the different tissues of tilapia fish is determined by the exposure time and the depuration rate. The mechanisms of toxicity/carcinogenicity depend on the arsenic species involved in the biotransformation processes. After a 7-day exposure period, the accumulation of inorganic arsenic (iAs) in the tilapia tissues studied was in the order: liver > stomach > gills > muscles. In bioaccumulation assays, the values of the organ uptake constant (ka) ranged from 0.06 to 0.51 mL g-1 d-1, while the depuration rate constant (kd) values were in the range 0.03-1.15 d-1. Higher iAs bioaccumulation factor (BCF) values were observed for the stomach (3.1 mL g-1) and the liver (1.6 mL g-1), reflecting their high capacity to accumulate iAs species. These organs act as long-term storage sites for iAs, following chronic exposure. The LC50 values were determined considering the average iAs concentration and the cumulative fish mortality. For As(III), the LC50 values indicated fish mortality at concentrations above 30 mg L-1. The fish showed greater tolerance to exposure to As(V), compared to As(III), with fish mortality after the second day of exposure requiring an As(V) concentration 7-fold higher than As(III). PMID- 30419389 TI - Formation of iodinated trihalomethanes during chlorination of amino acid in waters. AB - Chlorination is essential to provide safe drinking water. However, this process leads to the formation of disinfection byproducts (DBPs). In this study, tryptophan (Trp) has been selected as a precursor to conduct the chlorine disinfection. Moreover, the factors that affect the formation of trihalomethanes (THMs) and iodinated trihalomethanes (I-THMs) are investigated. The formation pathway of Trp chlorination is proposed based on the intermediate products identified. According to the experimental results, the formation of THMs and I THMs during Trp chlorination fitted a new first-order kinetic model. The dosage of chlorine, temperature, pH and the ratio of bromide and iodide had major influence on the formation of THMs and I-THMs during chlorination. In addition, the inhibition of luminescent bacteria Vibrio fischeri in the water sample increased during Trp chlorination. PMID- 30419390 TI - Nitrogen removal of anaerobically digested swine wastewater by pilot-scale tidal flow constructed wetland based on in-situ biological regeneration of zeolite. AB - Dispersed swine wastewater has increasingly aggravated water pollution in China. Anaerobically digested dispersed swine wastewater was targeted and treated by a pilot-scale zoning tidal flow constructed wetland (TFCW) with a bottom wastewater saturation layer. The long-term application of in-situ biological regeneration of biozeolite, nitrogen removal performance, nitrogen removal pathways and microbial community of TFCW were investigated. Results showed that with the surface loads of 0.079, 0.022 and 0.024 kg/(m2.d), TFCW could decrease COD, NH4N and TN by 84.75%, 74.13% and 67.13% respectively. Influent COD, NH4N, TN and nitrates/nitrites produced by bioregeneration of NH4N were mostly removed in zeolite layer and the remaining nitrates/nitrites could be further denitrified in bottom saturation layer. Theory of dynamic process of rapid-adsorption and bioregeneration for NH4N removal was proposed. When this process reached dynamic equilibrium, the mass of adsorbed NH4N onto zeolites remained relatively stable. When ambient temperature decreased to 16 degrees C, TFCW could still remove COD, NH4N and TN by 73.79%, 72.99% and 70.71% with the surface loads of 0.103, 0.056 and 0.054 kg/(m2.d) respectively. Nitrification-denitrification which accounted for 80.32% of TN removal was the main nitrogen removal pathway. Dominant nitrifiers (Nitrosospira and Rhizomicrobium) and denitrifiers (Ottowia, Thauera and Rhodanobacteria) in biozeolite layer verified the existence of simultaneous nitrification and denitrification. PMID- 30419391 TI - Redox mediators and irradiation improve fenton degradation of acesulfame. AB - Widely recognized as a promising approach to degrading recalcitrant pollutants, Advanced Oxidation Processes (AOPs) have drawn much attention for their effectiveness and efficiency. Among all the AOPs, the Fenton system has been widely applied for oxidation and mineralization of micropollutants due to its ease of implementation and high catalytic efficiency. However, the necessity of preceding acidification, together with rapid consumption and slow regeneration of Fe(II) resulting in deterioration of reactivity, has reduced its competitiveness as a practical option for water treatment. Acknowledging the above drawbacks, this study investigates the potential viable option to enhance the Fenton system. Acesulfame was chosen as the model compound due to its ubiquitous occurrence and persistence in the environment. UV-assisted photo-Fenton treatment was found to remove the parent compound effectively; the transformation profile of acesulfame was identified and elucidated with the ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Prolonged UV photo Fenton treatment was effective for mineralization of the majority of the transformation products, without increasing the overall toxicity as indicated by Vibrio fischeri bioluminescence assay. The positive effects of the addition of redox mediators to Fenton systems at neutral pH were confirmed in this study. The results could be the basis for further development of homogeneous catalytic degradation techniques for the oxidation of environmental contaminants at circumneutral pHs to neutral pHs. PMID- 30419392 TI - Adverse effects of a synthetic pyrethroid insecticide cypermethrin on life parameters and antioxidant responses in the marine copepods Paracyclopina nana and Tigriopus japonicus. AB - To find the adverse effects induced by cypermethrin, the ecotoxicological model copepods Tigriopus japonicus and Paracyclopina nana were exposed under cypermethrin, which is a widely used type-II pyrethroid insecticide in agriculture. Despite its large-scale application as insecticide in agriculture, little information is available on its adverse effects on aquatic invertebrates. In this study, the toxicity of cypermethrin on two copepods was assessed based on life parameters (growth rate and reproduction), oxidative stress and consequent antioxidant enzymatic activities, and gene expression profiles of antioxidants. The acute toxicity alone demonstrated that P. nana is less tolerant and sensitive against cypermethrin, compared to T. japonicus. However, under chronic exposure, life parameters of both P. nana and T. japonicus were severely affected by cypermethrin. Among antioxidant enzymatic activities, superoxide dismutase (SOD) and glutathione S-transferase (GST), in particular, demonstrated significant increase in response to cypermethrin. Furthermore, temporal-mRNA expression profile showed modulations in antioxidant related genes in response to cypermethrin. Our results provide the underlying toxic mechanism of cypermethrin and the oxidative stress defense mechanism and species-specific tolerance against cypermethrin in two model copepods species. PMID- 30419393 TI - Parental transfer of ethylhexyl methoxy cinnamate and induced biochemical responses in zebrafish. AB - Ethylhexyl methoxy cinnamate (EHMC) is one of the major organic ultraviolet (UV) filter pollutants in the environment. The purpose of this study was to investigate the parental transfer of EHMC and induced biochemical responses in zebrafish (Danio rerio). Zebrafish embryos were exposed to EHMC solution (1, 10, and 100 MUg/L) for 4 months until sexual maturation. Then male and female parents were paired to lay eggs. F1 generations were divided into 2 categories: with and without continued EHMC exposure. EHMC was detected in both F0 parents and F1 eggs, indicating that EHMC can accumulate in zebrafish and transfer to offspring through reproduction. The hatching rate decreased and malformation rate increased significantly among parents and progeny embryos in the high concentration exposure group. For 40 dpf (days post-fertilisation) F0 generations, estradiol hormone and vitellogenin (Vtg) contents, the expression levels of Vtg1, P450 aromatase (Cyp19a and Cyp19b), 17beta-hydroxysteroid dehydrogenase (Hsd17b1, Hsd17b3), estrogen receptor-alpha and progesterone receptor in all concentration groups decreased significantly, while androgen receptor increased significantly in 10 and 100 MUg/L exposure groups compared with the corresponding control group, showing anti-estrogen and androgen effects. For 120 dpf F0 generations, acetylcholinesterase activity was significantly decreased and glutathione and malondialdehyde levels, superoxide dismutase, catalase and glutathione reductase activities were significantly increased in all treatment groups compared with the corresponding control group. In addition, F1 offspring with or without continued exposure to EHMC suffered similar or stronger oxidative stress compared with their parents. DNA breakage and apoptosis also occurred in 120 dpf parental liver cells in all treatment groups as a result of oxidative damage. Results suggested that EHMC have transfer effects between parents and offspring, which may cause negative effects on growth and development of zebrafish and induce biochemical responses in both parents and offspring. PMID- 30419394 TI - Molecular bionics - engineering biomaterials at the molecular level using biological principles. AB - Life and biological units are the result of the supramolecular arrangement of many different types of molecules, all of them combined with exquisite precision to achieve specific functions. Taking inspiration from the design principles of nature allows engineering more efficient and compatible biomaterials. Indeed, bionic (from bion-, unit of life and -ic, like) materials have gained increasing attention in the last decades due to their ability to mimic some of the characteristics of nature systems, such as dynamism, selectivity, or signalling. However, there are still many challenges when it comes to their interaction with the human body, which hinder their further clinical development. Here we review some of the recent progress in the field of molecular bionics with the final aim of providing with design rules to ensure their stability in biological media as well as to engineer novel functionalities which enable navigating the human body. PMID- 30419395 TI - Native nanodiscs from blood inhibit pulmonary fibrosis. AB - Blood is a treasure trove whose constituents have attracted increasing attention for use in understanding and controlling disease. However, the functions of blood, especially with regard to its composition at the nanoscale, remain largely unknown. Inspired by exosomes and lipoproteins, the present work isolated and characterized biotic nanodiscs from human blood (BNHBs) using multiple techniques. The isolated BNHBs had diameters of 10-30 nm and a thicknesses of approximately 2.9 nm. The BNHB concentration in blood peaked at 34.5 +/- 5.19 mg/mL (20-fold higher than that of high-density lipoproteins and exosomes). BNHBs had high biocompatibility, facile cell internalization and strong biological control of pulmonary fibrosis. The BNHBs were hybrids of many metalloproteins and metabolites and contained a few functional proteins similar to lipoproteins or exosomal proteins. BNHBs inhibited transforming growth factor-beta 1 (TGF-beta1) induced fibrosis damage in human embryonic lung fibroblasts (HELFs) by inhibiting the expression of alpha-smooth muscle actin and collagen-1 protein. BNHBs also intensively bound TGF-beta1 to inhibit TGF-beta1 activity in fibrogenesis. BNHBs successfully reduced pulmonary inflammation and collagen deposition in a mouse model, preventing pulmonary fibrosis. Applying the protective properties of nanodiscs may be a novel therapeutic approach for pulmonary and other diseases. PMID- 30419396 TI - Multiple-strain probiotics appear to be more effective in improving the growth performance and health status of white shrimp, Litopenaeus vannamei, than single probiotic strains. AB - The probiotic efficiencies of the mixed probiotics containing Lactobacillus pentosus BD6, Lac. fermentum LW2, Bacillus subtilis E20, and Saccharomyces cerevisiae P13 for shrimp growth and health status improvement were better than those when using single probiotics. The probiotic mixture at a level of 108 colony-forming units (cfu) (kg diet)-1 and the diets containing BD6 and E20 at 109 cfu (kg diet)-1 significantly improved the growth and health status of shrimp, whereas the diets containing P13 or LW2 did not significantly affect the growth of shrimp. No significant difference in the carcass composition was recorded among the control and treatments. After 56 days of feeding, shrimp fed the diet containing the probiotic mixture (107~109 cfu (kg diet)-1) had higher survival after injection with the V. alginolyticus, but 109 cfu (kg diet)-1 of single probiotics (except for S. cerevisiae P13) had to be administered to improve shrimp survival. The better disease resistance of shrimp in groups fed the probiotic mixture might have been due to increased phenoloxidase activity, respiratory bursts, and lysozyme activity of hemocytes. Therefore, we considered that the probiotic mixture could adequately provide probiotic efficiency for white shrimp, and a diet containing 108 cfu (kg diet)-1 probiotic mixture is recommended. PMID- 30419397 TI - Effects of Bacillus aryabhattai TBRC8450 on vibriosis resistance and immune enhancement in Pacific white shrimp, Litopenaeus vannamei. AB - The use of probiotics in aquaculture is a practical alternative to promote animal health and disease prevention. Meanwhile, this practice can also reduce the use of prophylactic antibiotics. The purpose of this study was to identify candidate probiotics that could control pathogen populations in host's gastrointestinal (GI) tract and stimulate host immunity in shrimp aquaculture. Bacillus aryabhattai TBRC8450, a bacterial strain isolated from the environment in a shrimp farm, has an antimicrobial activity against many pathogenic strains of Vibrio harveyi and V. parahaemolyticus. Supplementation of B. aryabhattai to Pacific white shrimp (Litopenaeus vannamei) not only decreased the abundance of Vibrio populations, but also shifted the bacterial community in the shrimp GI tract. We found that supplementation of B. aryabhattai triggered shrimp innate immunity and antioxidant activities. mRNA expression of genes encoding microbial peptides and antioxidant enzymes, including C-type lectin, penaeidin-3, heat shock protein 60, thioredoxin, and ferritin, was significantly upregulated in the hepatopancreas of shrimp fed B. aryabhattai. Furthermore, phenoloxidase activity in the hemocytes and the total antioxidant activity in the plasma were increased, indicating enhanced immune and antioxidant responses at the systemic level. In contrast, supplementation of B. aryabhattai had no effect on the total hemocyte count and superoxide dismutase activity in the plasma and hepatopancreas. Importantly, a pathogen challenge test using V. harveyi 1562 showed a significant increase in survival rates of shrimp fed B. aryabhattai compared to the control group. Our findings suggest that B. aryabhattai TBRC8450 can likely be used as a probiotic to reduce the population of V. harveyi in the shrimp GI tract and to enhance shrimp innate immunity and antioxidant capacity for vibriosis resistance in shrimp aquaculture. PMID- 30419398 TI - Characterization and functional analysis of grouper (Epinephelus coioides) MEK1 and MEK2. AB - MEK dual-specificity protein kinases are a group of mitogen-activated protein kinase kinases, which act as an integration point by transferring extracellular signals to the nucleus. To investigate the function of MEK in teleost fish, we cloned MEK1 and MEK2 cDNA sequences from the orange-spotted grouper (Epinephelus coioides). EcMEK1 and EcMEK2 shared 80% amino acid identity with each other. EcMEK1 had 89-99% amino acid identity with teleosts or mammals, whereas EcMEK2 shared 85-97% amino acid identity. The exon structures of the grouper MEK1/2 genes were conserved with zebrafish and human MEK1/2. Tissue distribution analysis showed that EcMEK1 and EcMEK2 had a similar expression pattern in grouper tissues and was mainly transcribe in systemic immune organs. Both EcMEK1 and EcMEK2 were distributed throughout the cytoplasm of transfected GS or HEK293T cells. Overexpression of EcMEK1 or EcMEK2 activated Activator protein 1 dependent luciferase. The phosphorylation levels of EcMEK1/2 and EcERK1/2 were significantly increased in head kidney leukocytes by stimulation with PMA treatment. The grouper MEK1/2-ERK1/2 axis was activated in Cryptocaryon irritans infection and showed an enhanced phosphorylation after immunization. PMID- 30419399 TI - Surgery of Small Anterior Skull Base Meningiomas by Endoscopic 5-Aminolevulinic Acid Fluorescence Guidance: First Clinical Experience. AB - BACKGROUND: Minimally invasive surgery of small skull base meningiomas is technically challenging. We report the role of endoscopic 5-aminolevulinic acid fluorescence guidance (e-5-ALA-FGS) for small and deep-seated anterior skull base meningiomas. METHODS: We report the cases of 2 patients. The first case was a small olfactory groove meningioma resected via a trans-eyebrow, subfrontal approach. The second case was a clinoid meningioma with invasion of the optic canal resected via a small frontolateral approach. Intraoperative documentation demonstrated the usefulness of 5-ALA endoscopy. In either case, residual fluorescing tumor tissue was detected. No complication was encountered. The clinical and radiological outcomes were good. No regrowth had occurred after 54 and 17 months of follow-up, respectively. RESULTS: Residual meningioma tissue on the far side of a keyhole approach (e.g., in the olfactory groove or at the optic canal) can be difficult to visualize. Visualization can be improved by use of an endoscope. To date, fluorescence guidance with a microscope was limited by insufficient fluorescence signals in deep corridors. With a specially equipped 5 ALA fluorescence endoscope, one can combine the advantages of both endoscopic vision and fluorescence guidance. The results of present report have demonstrated the usefulness of 5-ALA endoscopy for difficult to visualize areas. CONCLUSION: Endoscopic 5-ALA fluorescence guidance was shown to be feasible when resecting small and deep-seated skull base meningiomas via minimally invasive approaches. Based on this proof of principle, we encourage its evaluation for the middle or posterior fossa (e.g., internal auditory canal) and other difficult areas (e.g., behind neurovascular structures or the brainstem). The sensitivity and specificity of this method should be prospectively and systematically investigated. PMID- 30419400 TI - Thalamus Stimulation for Myoclonus-Dystonia Syndrome: Five Cases and Long-term Follow-up. AB - BACKGROUND: Myoclonic dystonia syndrome (MDS) is a rare inherited movement disorder characterized by the coexistence of myoclonic jerks and dystonia. Deep brain stimulation (DBS) is a promising treatment for MDS patients targeting the globus pallidus internus (GPi) or ventral intermediate nucleus (Vim) of the thalamus. However, there are few studies regarding the long-term effects of Vim DBS in MDS patients and even fewer in those without gene mutations. METHODS: Two positive and three negative SGCE mutation patients presenting with predominant myoclonus underwent Vim DBS. The unified myoclonus rating scale (UMRS) and the Burke-Fahn-Marsden dystonia rating scale (BFMDRS) were assessed pre- and post operation. RESULTS: Over an average follow-up period of 50 months, the myoclonus improvement rate was 92.7%. The average improvement in the BFMDRS motor score was 71.4% and the average improvement in the BFMDRS disabling score was 75.8%. CONCLUSIONS: This study suggests that Vim DBS can be a safe and effective treatment option for MDS patients. Vim DBS alone may be preferable for myoclonus dominated MDS patients regardless of the identification of an SGCE mutation. Additional GPi DBS may be used for progressive dystonia after Vim DBS. PMID- 30419401 TI - Iatrogenic lumbar artery injury in spine surgery: a literature review. AB - OBJECTIVE: To review the literature related to iatrogenic lumbar artery injury (ILAI) in spine surgery with a focus on which iatrogenic operation may cause lumbar artery (LA) injury. METHODS: We conducted a comprehensive search in the Web of Science, PubMed, EMBASE and Chinese biomedical databases in July 2018. RESULTS: A total of 20 articles on ILAI were selected in this study, most of which were published as case reports involving a total of 26 cases. The causes of ILAI were as follows: puncture injury in 9 cases, transforaminal endoscopic operation in 5 cases, pedicle screw injury in 3 cases, intervertebral foramen decompression in 2 cases, disc rongeur injury during discectomy in 2 cases, LA tear caused by transverse process fracture in 1 case, vertebral fracture restoration in 1 case, retractor injury in 1 case, cage insertion or pedicle screw injury in 1 case, and drainage tube stimulation in 1 case. The treatment methods included transarterial embolization (TAE) in 20 cases, percutaneous embolization in 2 cases, surgical ligation in 1 case, and steroid and cyclophosphamide treatment in 1 case; all patients were treated successfully. One patient died during anti-shock therapy, and another patient died because her family refused any further intervention. CONCLUSION: We should pay attention to surgical procedures that are likely to cause ILAI, such as percutaneous vertebroplasty/percutaneous kyphoplasty, vertebral biopsy, pedicle screw implantation, discectomy, transforaminal endoscopic operation, and intervertebral foramen decompression. Once a diagnosis of ILAI is confirmed, selective endovascular TAE is the preferred treatment. PMID- 30419402 TI - Deep brain stimulation versus peripheral denervation for cervical dystonia: a systematic review and meta-analysis. AB - BACKGROUND: Cervical dystonia is a disabling medical condition that drastically decreases quality of life. Surgical treatment consists of peripheral nerve denervation procedures with or without myectomies or deep brain stimulation (DBS). The current objective was to compare the efficacy of peripheral denervation versus DBS in improving severity of cervical dystonia through a systematic review and meta-analysis. METHODS: A search of PubMed, MEDLINE, EMBASE and Web of Science electronic databases was conducted in accordance with PRISMA guidelines. Pre- and post-operative Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total scores were used to generate standardized mean differences and 95% confidence intervals, which were combined in a random-effects model. Both mean percentage and absolute reduction in TWSTRS scores were calculated. Absolute reduction was used for forest plots. RESULTS: Eighteen studies met inclusion criteria, comprising 870 patients with 180 (21%) undergoing DBS and 690 (79%) undergoing peripheral denervation procedures. Mean follow-up was 31.5 months (range 12-38 months). In assessing efficacy of each intervention, forest plots revealed significant absolute reduction in total post-operative TWSTRS scores for both peripheral denervation (standardized mean difference 1.54; 95% CI 1.42-1.66) and DBS (standardized mean difference 2.07; 95% CI 1.43-2.71). On subgroup analysis, DBS therapy was significantly associated with improvement in post operative TWSTRS severity (standardized mean difference 2.08; 95% CI 1.66-2.50) and disability (standardized mean difference 2.12; 95% CI 1.57-2.68), but not pain (standardized mean difference 1.18; 95% CI 0.80-1.55). CONCLUSIONS: Both peripheral denervation and DBS are associated with a significant reduction in absolute TWSTRS total score, with no significant difference in the magnitude of reduction observed between the two treatments. Further comparative data are needed to better evaluate the long-term results of both interventions. PMID- 30419403 TI - Hepatitis C virus genotype diversity and distribution among methadone maintenance treatment patients in Jiangsu, China. AB - BACKGROUND: Heroin users are vulnerable and represent a highly-infected reservoir for hepatitis C virus (HCV) infection. This study investigated HCV prevalence and genotypes distribution among heroin users who received methadone maintenance treatment (MMT) in Jiangsu. METHODS: From June to December in 2016, a total of 534 patients among nine MMT clinics in six regions of Jiangsu were enrolled, with their demographic characteristics collected and serum samples tested for HCV antibody. 395 samples were seropositive and furthered to RNA extraction. HCV NS5B region fragments were amplified and subsequently sequenced. RESULTS: Among HCV seropositive samples, 240 were characterized by NS5B partial sequences and classified into four genotypes (GPs) and eight subtypes. HCV GP3 predominated and accounted for 66.3%, followed by GP1 (27.5%), GP6 (4.2%) and GP2 (2.1%). HCV subtypes 3b (41.7%) and 3a (24.6%) were the most common subtypes. None of the demographic characteristics showed a significant difference when comparing with HCV genotypes. The geographic feature shown GPs in six regions were the same, but the frequency of subtypes exhibited regional divergence. Phylogenetic analyses demonstrated that 3b had become a local endemic in Jiangsu. CONCLUSION: The distribution of HCV subtypes among heroin users in Jiangsu province was complex. The data could provide more precise estimates for HCV prevalence and genotype distribution as well as heroin users of Jiangsu province. PMID- 30419404 TI - Alcohol consumption and S-Klotho plasma levels in sedentary healthy middle-aged adults: A cross sectional study. AB - INTRODUCTION: Alcohol consumption is related to several diseases and injuries that accelerate the ageing process and increase the mortality and morbidity risk. The soluble form of the alpha-Klotho gene (called S-Klotho) is widely considered as a powerful anti-ageing biomarker. AIM: The aim of the present study was to analyze the association between alcohol consumption and S-Klotho plasma levels in sedentary middle-aged adults. METHODS: 74 (39 women) middle-aged sedentary adults (40-65 years old) participated in the present study. Alcohol consumption was assessed with a food frequency questionnaire previously validated and with three non-consecutive 24-hours recall. The S-Klotho plasma levels were measured by ELISA using a soluble alpha-Klotho ELISA assay kit. RESULTS: Total alcoholic drinks consumption was negatively associated with S-Klotho plasma levels (beta= 17.031; R2 = 0.096, P = 0.013). Furthermore, we observed that higher consumption of total alcoholic drinks is associated with lower S-Klotho plasma levels in middle-aged sedentary adults controlling for BMI (beta=-16.372; R2 = 0.201, P = 0.011), LMI (beta=-31.854; R2 = 0.305, P = 0.010) and for FMI beta=-13.337; R2 = 0.075, P = 0.049). CONCLUSION: In conclusion, our study shows that total alcoholic drinks consumption is negatively associated with the S-Klotho plasma levels in middle-aged sedentary adults. PMID- 30419405 TI - The event-level impact of one's typical alcohol expectancies, drinking motivations, and use of protective behavioral strategies. AB - INTRODUCTION: Much of the past research on the excessive consumption of alcohol by college students has focused on the interplay of individual factors and typical drinking patterns, but this is not adequate to understand behavior as it occurs. The need to understand drinking at the event-level is critical in order to develop event-level prevention. To this end, this study examined a conceptual model of college students' drinking events in order to determine the potential mediating effect of drinking motives and protective behavioral strategies (PBS) in the relationship between alcohol expectancies and event-level alcohol use and consequences. METHODS: An existing data set containing information about 2279 college student drinking events were analyzed for this study. Students completed surveys during the administration of a commercial online alcohol course during 2010 and 2011. A theoretical model was analyzed with structural equation modeling. RESULTS: Both typical use of PBS and drinking motives mediated the relationship between expectancies and event-level alcohol use and problems. Positive expectancies were associated with greater positive motives, greater motives were associated with less use of PBS, and less PBS use was then, in turn, associated with higher event-level intoxication. Lastly, higher intoxication was associated with more serious consequences during the event. CONCLUSION: This is the first study to simultaneously explore the relationship between these factors and event-level drinking. There is a great need to continue to further explore the dynamic nature of drinking at the event-level to illuminate potential leverage points amendable to change. PMID- 30419406 TI - Longitudinal patterns of amphetamine use from adolescence to adulthood: A latent class analysis of a 20-year prospective study of Australians. AB - BACKGROUND: To examine the longitudinal patterns of amphetamine use over twenty years from adolescence to the mid-thirties; and identify adolescent antecedents of future problematic patterns of use. DESIGN: Ten-wave longitudinal study following participants from age 15 to age 35 in Victoria, Australia. Participants (N = 1755; 47% males) first enrolled in the Victoria Adolescent Health Cohort Study in 1992. MEASUREMENTS: Outcome: Self-reported frequency of amphetamine use. PREDICTORS: Gender, depression and anxiety, peer alcohol and tobacco use; self reported alcohol, tobacco and cannabis use, self-reported adolescent antisocial behavior. FINDINGS: Three different longitudinal patterns were identified: Non user (83.7%); Occasional user (14.5%); Regular user (1.8%). Among the two user patterns, amphetamine use was commonly initiated in late teenage years or early 20s, peaked at mid-20s, and declined substantially by mid-30s. Participants who used cannabis and had smoking peers during adolescence were at significantly more likely to become an occasional or regular user (p < .05). CONCLUSION: Regular cannabis use and peer tobacco use during adolescence were the two strongest predictors of a longitudinal pattern of regular amphetamine use in the mid-30s. This suggests that prevention programs could be implemented around or before mid adolescence and interventions to reduce amphetamine harms focus on high-risk individuals in their 20s when amphetamine use was at its peak. PMID- 30419407 TI - Associations of the Stoptober smoking cessation program with information seeking for smoking cessation: A Google trends study. AB - INTRODUCTION: The national smoking cessation program Stoptober was introduced in October 2012 in England and in October 2014 in the Netherlands. There is little evidence on the extent to which the Stoptober program has an impact on smoking related outcomes at national levels. We aimed to measure the magnitude and timing of the associations of the Dutch Stoptober program with searching for smoking cessation on the internet. METHODS: An interrupted time series analysis was used on Google search queries. Data were seasonally adjusted and analyzed using autoregressive integrated moving average (ARIMA) modelling. To examine the magnitude and timing of the program, nine potential intervention periods around early October were analyzed simultaneously, with control for national tobacco control policies. Parallel analyses were made of Belgium as a control group. RESULTS: The 2014-2016 Dutch Stoptober programs were associated with a significant increase in relative search volume (RSV) in the week the challenge starts (11%, 95% CI: 1-21), the next week (22%, 95% CI: 12-33) and the week afterward (17%, 95% CI: 8-27). A smaller, non-significant increase was observed in the two weeks before the challenge. No substantial increases were found in the Belgian control group. CONCLUSIONS: In the Netherlands, the Stoptober program was associated with a substantial short-term increase in information seeking for smoking cessation. This suggests that Stoptober may be able to affect smoking related outcomes in national populations at large. PMID- 30419408 TI - Episodic memory in mild cognitive impairment inversely correlates with the global modularity of the cerebral blood flow network. AB - Cerebral blood flow (CBF) SPECT is an interesting methodology to study brain connectivity in mild cognitive impairment (MCI) since it is accessible worldwide and can be used as a biomarker of neuronal injury in MCI. In CBF SPECT, connectivity is grounded in group-based correlation networks. Therefore, topological metrics derived from the CBF correlation network cannot be used to support diagnosis and prognosis individually. However, methods to extract the individual patient contribution to topological metrics of group-based correlation networks were developed although not yet applied to MCI patients. Here, we investigate whether the episodic memory of 24 amnestic MCI patients correlates with individual patient contributions to topological metrics of the CBF correlation network. We first compared topological metrics of the MCI group network with the network corresponding to 26 controls. Metrics that showed significant differences were then used for the individual patient contribution analysis. We found that the global network modularity was increased while global efficiency decreased in the MCI network compared to the control. Most importantly, we found that episodic memory inversely correlates with the patient contribution to the global network modularity, which highlights the potential of this approach to develop a CBF connectivity-based biomarker at the individual level. PMID- 30419409 TI - The health risks of informal waste workers in the Kathmandu Valley: a cross sectional survey. AB - OBJECTIVE: To describe the health and occupational risks of informal waste workers (IWWs) in the Kathmandu Valley and explore the factors associated with not using personal protective equipment (PPE). STUDY DESIGN: This is a cross sectional survey of IWWs. METHODS: Data were collected on the health and occupational risks of adult IWWs working on waste sites in the Kathmandu Valley and in the adjacent Nuwakot district, Nepal, in November 2017, through convenience sampling. Using a standardized health assessment questionnaire, face to-face interviews were undertaken to record sociodemographic data, indicators of general and occupational health, data on healthcare access and use, physical risks, perception of occupational risks and use of PPE. Associations between use of PPE and gender, age, education, country of origin, injury and perception of occupational risks were examined using multivariate logistic regression analyses. RESULTS: In 1278 surveyed IWWs, prevalent physical risks included injuries (66.2% in the previous 12 months), and the main reported symptoms were respiratory in nature (69.9% in the previous 3 months). Most prevalent injuries were glass cuts (44.4%) and metal cuts (43.9%). Less than half of the IWWs (46.8%) had been vaccinated against tetanus and 7.5% against hepatitis B. The work was considered as 'risky' by 72.5% of IWWs, but 67.6% did not use PPE. Non-use of PPE was independently associated with male gender (odds ratio [OR] 2.19; P < 0.001), Indian origin (OR 1.35; P = 0.018), older age (OR 2.97 for more than the age of 55 years; P = 0.007) and low perception of occupational risks (OR 2.41; P < 0.001). Low perception of occupational risk was associated with older age (55 + years) and the lack of receipt of information on the risks. CONCLUSIONS: IWWs are at increased risk of injury in their work, yet are poorly protected in relation to vaccine-preventable infections and workwear. The results suggest that information is important in relation to perception of occupational risk, which in turn is associated with the use of PPE. There is a need for policymakers and public health practitioners to have a robust understanding of the needs and vulnerabilities of this group, as well as identify effective interventions that can be taken to safeguard the health and welfare of IWWs. PMID- 30419410 TI - Dynamic postural stability, is associated with competitive level, in youth league soccer players. AB - OBJECTIVES: To assess the effect of competitive level on dynamic postural stability in young elite and sub-elite soccer players. DESIGN: Cross-sectional study. SETTING: Laboratory. PARTICIPANTS: Fifty-four male soccer players of Under 16 and Under 17 categories (mean age 15.9 +/- 0.6), divided into two groups who regularly compete at national (n = 28) and regional (n = 26) levels. MAIN OUTCOME MEASURES: Dynamic Postural Stability Index (DPSI) and vertical Time to Stabilization (vTTS) for a forward-jump landing. Static postural sway was calculated on the basis of center-of-pressure trajectories for a 20 s one-legged stance. RESULTS: Players at national level exhibit better dynamic postural control than those at regional level, as indicated by the significantly lower DPSI (0.327 vs. 0.373, p < 0.001) and vTTS (0.887 vs. 1.158 s, p = 0.003). In contrast, no differences between groups were found in any of the postural sway parameters for the static test. CONCLUSIONS: Young soccer players at national level are characterized by better balance performance in terms of faster and more efficient stabilization after a forward jump, while one-leg static standing tests appear not challenging enough to reveal differences in balance abilities associated with the combination of superior technical and physical features. PMID- 30419411 TI - Funiculosone, a substituted dihydroxanthene-1,9-dione with two of its analogues produced by an endolichenic fungus Talaromyces funiculosus and their antimicrobial activity. AB - An undescribed substituted dihydroxanthene-1,9-dione, named funiculosone, was isolated together with its two analogues identified as mangrovamide J and ravenelin, from the culture filtrates of Talaromyces funiculosus (Thom) Samson, Yilmaz, Frisvad & Seifert (Trichocomaceae), an endolichenic fungus isolated from lichen thallus of Diorygma hieroglyphicum (Pers.) Staiger & Kalb (Graphidaceae), in India. Funiculosone was characterized, essentially by spectroscopic methods, as 4,8,9a-trihydroxy-3,4a-dimethyl-4a,9a-dihydro-4H-xanthene-1,9-dione. Its relative stereochemistry was deduced by single crystal X-ray analysis while the absolute configuration was assigned as 4S,4aS,9aS by ECD spectra in comparison to that of the closely related mangrovamide J. This latter, to which, not being an amide, an inappropriate common name was given, was only recently isolated, together with undescribed and known prenylatedindole alkaloids and chromone derivatives from an unidentified Penicillium sp. X-ray structural analysis of the isolated mangrovamide J, for which no biological activity was previously reported, revealed polymorphism and a new crystalline phase is described. All the compounds displayed antibacterial activity with an IC50 range 23-104 MUg/mL when assayed against Escherichia coli Escherich and Staphylococcus aureus Ogston. Funiculosone also showed anticandidal activity against Candida albicans Berkhout with an IC50 35 MUg/mL. PMID- 30419412 TI - PgUGT95B2 preferentially metabolizes flavones/flavonols and has evolved independently from flavone/flavonol UGTs identified in Arabidopsis thaliana. AB - UDP-dependent glycosyltransferases (UGTs) convert aglycones into more stable, bioactive, and structurally diverse glycosylated derivatives. Pomegranate (Punica granatum L.) produces various glycosylated phenolic metabolites, e.g. hydrolyzable tannins (HTs), anthocyanins, and flavonoids, and constitutes an excellent system for investigating the corresponding UGT activities. Here we report the cloning and functional characterization of a pomegranate UGT, PgUGT95B2, which is highly active towards flavones and flavonols and can glycosylate at more than one position in the substrate molecule. Particularly, PgUGT95B2 has the strongest activity towards tricetin (flavone with a tri hydroxylated B-ring) and can act at the 4'-O position of its B-ring. In addition, PgUGT95B2 was able to glycosylate flavones present in pomegranate metabolite extracts. Conversely, PgUGT95B2 did not produce a galloylglucose ester (precursor for HT biosynthesis) or anthocyanins in enzyme assays. Our phylogenetic analysis suggested an independent evolution of PgUGT95B2 and flavone/flavonol UGTs identified in the model plant Arabidopsis thaliana through convergent evolution or gene loss. PMID- 30419413 TI - Recurrent desmoid tumor arising from latissimus dorsi flap: A case report. AB - Fibromatosis or desmoid tumor in the breast is a very rare benign soft tissue tumor. We report a case of recurrent desmoid tumor arising from latissimus dorsi flap after lumpectomy for breast carcinoma. To our knowledge, this is the first case of desmoid tumor arising from the latissimus dorsi flap. Despite its benignity, desmoid tumor is often locally aggressive, therefore timely diagnosis and proper management are very important. Imaging and pathological diagnosis as well as treatment management are discussed. High clinical suspicion and multidisciplinary approach are essential for prompt diagnosis and management. Wide surgical resection is required, but there is no consensus regarding treatment due to limited data. PMID- 30419414 TI - Relationship between current smoking, visual CT findings and emphysema index in cigarette smokers. AB - PURPOSE: To evaluate whether visual CT findings could account for the effect of current smoking. METHODS: 500 CT scans were visually evaluated within each lobe. A multivariate model for emphysema index was constructed containing previously described confounders in addition to the visual components associated with smoking status. RESULTS: Current smokers displayed 23% less visual emphysema, 19% more airway wall thickening, and 188% more centrilogular nodule than former smokers (all p < 0.001). The effect of current smoking on the emphysema index decreased after adjustment with confounders and visual parameters. CONCLUSIONS: Visual CT findings could partially account for the effect of current smoking. PMID- 30419415 TI - Early TIPS failure in association with left mesenterico-gonadal spontaneous portosystemic venous shunt; a case report. AB - Transjugular intrahepatic portosystemic shunt (TIPS) periprocedural thrombosis rates have fallen significantly since the introduction of polytetrafluoroethylene covered stent grafts. We present a case of a cirrhotic patient with portal hypertension presenting with early TIPS thrombosis in association with an underlying competing spontaneous left mesenterico-gonadal venous shunt, an uncommon variant of spontaneous portal systemic shunt (SPSS). The patient presented with bleeding distal duodenal varices refractory to endovascular therapy, and although a successful TIPS procedure was performed for this indication, early thrombosis was determined by follow-up abdominopelvic computed tomographic angiography (CTA) scan. Despite undergoing a standard TIPS revision procedure, blood flow through the TIPS remained hepatofugal. During a TIPS revision, portal vein angiography revealed competing large inferior mesenteric vein (IMV) varices shunting into the left renal vein via the left gonadal vein. The initial abdominal CTA was later reviewed by a non-invasive cardiovascular radiologist, and the presence of the competing left mesenterico-gonadal shunt was retrospectively identified. Radiologists interpreting CTA exams should be aware of SPSS generally and mesenterico-gonadal shunts specifically. Pre-procedural knowledge of underlying SPSS can affect post procedural outcomes and should be emphasized in the final CTA report. PMID- 30419416 TI - Factors influencing the process of learning mathematics among visually impaired and blind people. AB - Effective instruction and comprehension of mathematics are important for achieving academic and professional success but are especially difficult for visually impaired individuals because of the inherent difficulty in managing structural information included in math formulae. An evaluation of an alternative for computer-aided math instruction and comprehension among visually impaired students was developed, and the evaluation included seven detailed categories of factors: behavioral, emotional, cognitive, social, distracting, motivational, and modeling factors. Then, the proposed method was used to compare the alternative teaching method, including problem decomposition and vector knowledge, to the classical teaching method with a teacher. The assessment of the impact of the developed approach on improving the process of teaching mathematics in a group of blind and visually impaired students was carried out by the completion of a questionnaire prepared by a psychologist. The alternative teaching method achieved significantly better results in six of the seven proposed assessment categories. These experiments extend the knowledge base on the limitations and challenges associated with teaching and learning mathematics among blind people. PMID- 30419417 TI - A new nonparametric statistical approach to detect lumen and Media-Adventitia borders in intravascular ultrasound frames. AB - Intravascular ultrasound (IVUS) imaging is widely known as a powerful interventional imaging modality for diagnosing atherosclerosis, and for treatment planning. In this regard, the detection of lumen and media-adventitia (MA) borders is considered to be a vital process. However, the manual detection of these two borders by the physician is cumbersome due to the large number of frames in a sequence. In addition, no approved universal automatic method has been presented so far due to the great diversity in the appearance of the coronary artery in the images acquired by different IVUS systems. To this end, the present study aimed to provide a new border search theory on the radial profile, based upon the nonparametric statistical approach, and to develop a generic and fully automatic three-step process for extracting the lumen and MA borders in IVUS frames based on the proposed theory. Thereafter, the proposed theory and three-step process were evaluated on synthetic images, as well as on a test set of standard publicly available images, respectively. The results showed that our three-step process could segment the borders with >=0.82 and with >=0.75 Jaccard measure (JM) to manual borders in IVUS frames acquired by the 20 MHz and 40 MHz probes, respectively. Based on the results, the lumen and MA borders can be extracted automatically, and the border extraction process can be implemented in parallel for a polar image due to the capability of the present proposed method to estimate the borders for each angle independently. PMID- 30419418 TI - 'It was all in your voice' - Tertiary student perceptions of alternative feedback modes (audio, video, podcast, and screencast): A qualitative literature review. AB - BACKGROUND: Feedback is an integral part of teaching and learning with written comments being one of the most widely used methods of providing student feedback. From the student perspective, written feedback has been seen as limited in terms of its quality, vague nature and lack of clear examples with feed-forward. Alternative feedback modes (including audio, video, podcasts, and screencast feedback) have been suggested as a means of enhancing feedback. OBJECTIVE: The purpose of this qualitative literature review is to synthesise the views of tertiary students on alternative feedback modes. REVIEW METHODS: Searches were carried out in five online scientific databases (ERIC, Education Source, PsycINFO, Teacher Reference Center, and CINAHL Complete). Potentially relevant studies were screened against the inclusion/exclusion criteria. Data were extracted using customised data extraction forms. The qualitative findings section of each included study underwent thematic synthesis. RESULTS: A total of 450 studies were identified through the search strategy. Ten studies met the inclusion criteria. Five themes were identified: belonging; greater comprehension from non-verbal aspects of communication; individualised and personal; technical/practical technology aspects; and circumstances and context. CONCLUSION: Alternative feedback modes help students achieve a greater level of comprehension of feedback, with feedback that was more personalised. The alternative feedback modes promote a sense of belonging in relation to the programme of study and in relation to teaching staff. Educators should consider the use of innovative media approaches which could enhance and improve the quality of the student feedback experience. PMID- 30419419 TI - The impact of combining concept-based learning and concept-mapping pedagogies on nursing students' clinical reasoning abilities. AB - BACKGROUND: Integrating contemporary teaching strategies into the nursing curriculum is an effective approach to enhance undergraduate clinical-judgment and reasoning abilities. OBJECTIVE: This study aims to document the impact of blending the teaching strategies of concept-based learning and concept-mapping to enhance nursing students' clinical-reasoning abilities. DESIGN: A quasi experimental design is used to guide data collection from second year students. SETTING AND PARTICIPANTS: A consecutive sample of all students undertaking adult health nursing courses at a private university in Jordan and meeting the eligibility criteria resulted in (N = 40). METHOD: Data was collected via a questionnaire and observation to reveal students' independence in both clinical reasoning and clinical-judgment. General Clinical-Reasoning Behavior Scale, Independence in Clinical-Reasoning and Clinical-Judgment scales were completed by the students at the beginning and end of the courses. RESULTS: Despite requesting extensive preparation time, concept-based learning and concept-mapping as student centered approaches enabled the move away from a content laden approach towards constructing criteria against which various patients' encounters were reflected. This study documented enhancement in students' independence in clinical-reasoning and clinical-judgment as they learned to take command of the elements of their clinical-reasoning. Significant improvement in students' general clinical reasoning behavior was also documented. CONCLUSION: The data collection tools utilized in this study can be used as clinical teaching aides, hence maximizing the impact of blended teaching strategies by providing the faculty with specific feedback regarding students' clinical reasoning and judgment abilities. Institutionalizing these processes by initiating relevant policies and guidelines is essential to help students take command of their clinical-reasoning, maturity, and responsibility in a practice area that is constantly changing and evolving. PMID- 30419420 TI - The Spanish version of the Cultural Competence Assessment (CCA-S): Transcultural validation study and proposed refinement. AB - BACKGROUND: Cultural competence (CC) is becoming an essential component of healthcare professionals. There is a gap in the research evaluating CC in order to develop competency-based approach programs. Spain has become a multicultural society and it is necessary to evaluate and promote CC attitudes to reduce the disparity of care for vulnerable and minority groups. OBJECTIVES: To adapt and validate the Cultural Competence Assessment (CCA) of Schim et al. (2003), to get evidence-based data of CC in Spanish healthcare professionals. METHOD: A process of translation/back-translation and cultural adaptation was carried out in accordance with international standards. An on-line cross-sectional survey questionnaire was used. Statistical and metrical analysis was based in a sample of 568 healthcare professionals who worked daily with patients in a health care institution in South Catalonia in 2018. RESULTS: The results of the exploratory factorial analysis and subsequent confirmatory analysis showed that the data had an adequate fit for a four-factor model. The reliability analysis results confirm an acceptable consistency for each subscale: active behaviour (0.86), seeking information (0.86), awareness (0,94), and sensitivity (0.69). ANOVA showed no differences between healthcare professionals, age and gender. The scores showed a normal distribution and it was proposed a standardization of scores. CONCLUSIONS: The translation and transcultural-validation process of the CCA resulted in a Spanish-language for the 25 items, like the original. The psychometric analysis proved that the Spanish version is a reliable and valid instrument. This scale is going to be useful to analyze healthcare professional's attitudes to create effectiveness training programs focused on specific needs. The four-factor model and the standardization of the scores will be useful to achieve future objectives about research in cultural competence in healthcare professionals. PMID- 30419421 TI - Do body checking and avoidance behaviours explain variance in disordered eating beyond attitudinal measures of body image? AB - Body checking and body avoidance, considered to be behavioural manifestations of core attitudinal disturbances of body image, are theorized to be important contributors to the development and maintenance of eating disorder symptoms. Currently, however, it is unclear whether body checking and body avoidance accounts for variance in disordered eating behaviours beyond core attitudinal components of body image (i.e., over-evaluation, preoccupation, dissatisfaction). This was the objective of the present study. Cross-sectional data were analysed from 320 females recruited through undergraduate psychology programs and throughout the community. Bivariate correlations demonstrated that body checking and avoidance were significantly and positively correlated with each attitudinal component and with each measure of disordered eating (overeating, objective binge eating, and disinhibition). However, body checking and avoidance did not contribute variance (all R2changes <= 0.01) to each disordered eating behaviour beyond the variance accounted for by attitudinal components. Future research should aim to identify what specific and unique function these body image behaviours serve. Overall, eating disorder prevention and early intervention programs may benefit from ensuring that all facets of body image concerns are targeted and addressed. PMID- 30419423 TI - Fisher discriminant analysis for classification of autism spectrum disorders based on folate-related metabolism markers. AB - Autism spectrum disorders (ASDs) are neurodevelopmental disorders with an increasing prevalence but lack reliable biomarkers for early diagnosis. The present study investigated 13 serological metabolites and 2 genetic variants related to folate metabolism in a total of 89 ASD cases and 89 matched controls. Fisher discriminant analysis was used to establish the classification model to recognize ASD cases and controls. Ten metabolites were significantly different between the groups, of which six metabolites were used as predictors to determine the discriminant prediction model: vitamin B12, 5-methylene-tetrahydrofolate, methonine, the ratio of S-adenosylmethionine/S-adenosylhomocysteine, methionine synthase and transcobalamin II. The model had statistical significance (lambda=0.520, chi2=113.103, df=6, P<.001) and correctly identified 84.3% of ASD and normal cohorts. The area under the receiver operating characteristic curve was 0.913, with a sensitivity of 86.5% and a specificity of 85.4%. Overall, the results indicated that folate-related metabolism contributed to predisposition of ASD and the combined detection of folate-related metabolism biomarkers could be effective in distinguishing ASD from healthy controls, and provide new insights for the early diagnosis of ASD in the future. PMID- 30419422 TI - BPTF promotes hepatocellular carcinoma growth by modulating hTERT signaling and cancer stem cell traits. AB - Bromodomain PHD finger transcription factor (BPTF), a core subunit of nucleosome remodeling factor (NURF) complex, plays an important role in chromatin remodeling. However, its precise function and molecular mechanism involved in hepatocellular carcinoma (HCC) growth are still poorly defined. Here, we demonstrated the tumor-promoting role of BPTF in HCC progression. BPTF was highly expressed in HCC cells and tumor tissues of HCC patients compared with normal liver cells and tissues. Knockdown of BPTF inhibited cell proliferation, colony formation and stem cell-like traits in HCC cells. In addition, BPTF knockdown effectively sensitized the anti-tumor effect of chemotherapeutic drugs and induced more apoptosis in HCC cells. Consistently, knockdown of BPTF in a xenograft mouse model also suppressed tumor growth and metastasis accompanied by the suppression of cancer stem cells (CSC)-related protein markers. Moreover, the mechanism study showed that the tumor-promoting role of BPTF in HCC was realized by transcriptionally regulating the expression of human telomerase reverse transcriptase (hTERT). Furthermore, we found that HCC patients with high BPTF expression displayed high hTERT expression, and high BPTF or hTERT expression level was positively correlated with advanced malignancy and poor prognosis in HCC patients. Collectively, our results demonstrate that BPTF promotes HCC growth by targeting hTERT and suggest that the BPTF-hTERT axis maybe a novel and potential therapeutic target in HCC. PMID- 30419424 TI - Clinical and genetical study of a familial form of REM sleep behavior disorder. AB - OBJECTIVE: We report a kindred with a genetic form of REM behaviour disorder (RBD) with autosomal dominant transmission. PATIENTS AND METHODS: Clinical, polysomnography study, genetic study and brain MRI were performed to evaluate the index patients. The genetic study included exome sequencing of the index cases that detected 60,869 variants in the individuals examined. RESULTS: The kindred has a RBD with autosomal dominant transmission starting in second decade of life. After filtering out the exome variants shared by two affected cases the pool of variants could be reduced to thirteen; one of them is in PVALB, a calcium-binding albumin protein present in gabaergic interneurons in the nervous system that inhibit the pyramidal cell during REM sleep. CONCLUSIONS: RBD can have a genetic origin. The results of the exome study in this kindred suggest that gabaergic circuits may be altered in patients with RBD. Further studies in this family or in other pedigrees with familial RBD may clear the role of this gene in this disorder. PMID- 30419426 TI - Well-differentiated papillary mesothelioma: A 17-year single institution experience with a series of 75 cases. AB - We present our experience with 75 cases of well-differentiated papillary mesothelioma (WDPM) that were diagnosed at our institution between 2000 and 2017. The patients included 58 females and 17 males with age ranging from 18 to 69 years (mean, 42 years). Clinically, the vast majority of WDPMs were incidental findings during laparotomy or laparoscopic surgery for a variety of benign or malignant disease. The lesion manifested as either a small solitary nodule or multiple miliary nodules on the peritoneum or serosal surfaces of internal organs. Histologically, 67 cases were consistent with a classical WDPM, of which 6 cases contained microinvasive foci and 1 case had malignant transformation. Eight cases were hybrid tumors with variable combined component of adenomatoid tumor (n = 4), multicystic mesothelioma (n = 2), and both (n = 2). By immunohistochemistry, besides calretinin, D2-40, CK5/6 and WT1, 94% (29/31) of cases also showed immunostaining for PAX8. In comparison, PAX8 staining was only present in 12% (6/50) of epithelioid malignant mesothelioma selected as control cases. Follow-up information available in 46 cases revealed no signs of tumor progression or local recurrence except for the case that showed transformation to a fully malignant mesothelioma after a period of 15 years. Our comprehensive study further expanded the clinical and histopathological spectrum of WDPM. Compared with epithelioid malignant mesothelioma, PAX8 staining is highly sensitive and specific for WDPM (P < 0.001). PMID- 30419425 TI - Early neutropenia with thrombocytopenia following alemtuzumab treatment for multiple sclerosis: case report and review of literature. AB - Alemtuzumab is a monoclonal antibody targeting the CD52 antigen used in the treatment of relapsing-remitting multiple sclerosis (RRMS). CD52 is expressed by lymphocytes and monocytes but less by neutrophils and not by platelets. We present a case of a 38-year-old woman with RRMS who developed early neutropenia with thrombocytopenia after alemtuzumab infusion. She had no fever or symptoms of infection or purpura. After two weeks her haematological disorders spontaneously resolved. We reported the first case of neutropenia and thrombocytopenia as a possible event occurring after alemtuzumab infusion in MS patients, even if in a mild grade. So, we recommend to not underestimate these two conditions. PMID- 30419427 TI - Thyroid tumors with follicular architecture. AB - Thyroid tumors with follicular architecture encompass a considerable array of distinct entities. These lesions share significant morphologic overlap, but portend different prognostic and therapeutic implications. Due to their similar growth patterns, distinction between these tumors can be difficult; remarkable interobserver variability exists, even between expert endocrine pathologists. Given the diagnostic challenges associated with these lesions, establishment of the correct diagnosis requires adequate gross examination protocol, careful attention to morphologic features and pathologic context, as well as-increasingly adjunct molecular findings. In this review, we summarize the salient features of various follicular thyroid tumors, with special emphasis on the recently defined category of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), as well as the molecular pathology of these lesions. PMID- 30419428 TI - Gene and protein expression of E-cadherin and NCAM markers in non-functioning pituitary adenomas. AB - Non-functioning pituitary adenomas (NFPA) are classified as benign tumors of slow growth, but 40% of them present local invasion, a characteristic of behavior still unpredictable with the use of current tumor markers. This work aims to evaluate the tissue markers E-cadherin and NCAM, which act on cell adhesion, in tumor tissue samples of NFPA and its relationship with the degree of local invasiveness. Gene expression of E-cadherin (CDH1) and NCAM (NCAM1) was assessed by real-time PCR and tissue expression by immunohistochemistry. Fifty-three patients with macroadenomas were submitted to transsphenoidal surgery, presented grade II invasive adenomas in 16 cases (30.2%), grade III in 7 (13.2%) and grade IV in 30 (56.6%). In the immunohistochemistry, one case was negative for E cadherin, 7 showed weak immunostaining, 17 moderate and 28 strong, whereas for NCAM, 5 showed negative, 28 weakly, 14 moderate and 6 strong. Regarding gene expression, 43.3% showed expression for CDH1 (mean of 2.12) and 50% for NCAM1 (mean of 1.86). There was no significant correlation between the immunohistochemical expression of the markers, as well as the gene expression, the degree of invasiveness and clinical data. The results suggest that E-cadherin and NCAM markers are not directly related to the invasiveness in NFPA. PMID- 30419429 TI - What Saudi teachers know about epilepsy: A cross-sectional study of Tabuk City. AB - PURPOSE: This study was conducted to evaluate awareness, knowledge, and attitudes of teachers toward the disease in Tabuk City in north Saudi Arabia and identify areas in which training and education are required. METHOD: Data were collected from 349 school teachers using a structured 28-item questionnaire. Data were collected between December 2017 and May 2018 in Tabuk City. RESULTS: In general, the study shows a negative trend in knowledge and attitude toward epilepsy. The majority of the participants (84%) have read or heard about epilepsy, and more than half (67%) had witnessed a seizure. Epilepsy was considered contagious and psychological by 1.7% and 56%, respectively. Regarding attitude, 68% would not approve a son/daughter marriage to a person with epilepsy. This attitude correlates to the level of education as the percentage is higher for those who hold a Bachelor's or Master's degree, p < 0.05. Even though 84% of the participants reported knowing how to help a patient during a seizure, the majority of the participants had incorrect procedures, holding the legs and arms and believing that smelling onions is helpful to end the seizure. Moreover, almost half of the participants (46%) believed that a person with epilepsy cannot be successful in high-ranking professions. This belief was found to be more common in females than their counterparts, p < 0.05. CONCLUSION: School teachers' knowledge about epilepsy needs improvement. A focus on educational interventions about epilepsy are needed to develop a well-informed and tolerant community. PMID- 30419430 TI - Decarbromodiphenyl ether (BDE-209) promotes monocyte-endothelial adhesion in cultured human aortic endothelial cells through upregulating intercellular adhesion molecule-1. AB - There is growing evidence that exposure to persistent organic pollutants (POPs) is statistically associated with incidence of cardiovascular disease (CVD) or its risk factors. Decarbromodiphenyl ether (BDE-209) is a new POP which exists extensively in human tissues, but its potential effects on CVD have so far received less focus. The adhesion of circulating monocytes to endothelial cells is one of the critical underlying steps in the initiation and development of CVD. In the present study, we investigated the effect of BDE-209 on the adhesion of THP-1 monocytes to human aortic endothelial cells (HAECs) and identified the molecular mechanisms involved. Our results showed that 6.25, 12.5 and 25 uM of BDE-209 exposures caused significant increases in monocyte-endothelial cell adhesion, in a dose-dependent manner. Mechanistically, BDE-209 exposure increased the expression of intercellular adhesion molecule-1 (ICAM-1). Moreover, the up regulation of ICAM-1 was accompanied by a decrease in the expression of microRNA 141 (miR-141). Furthermore, the up-regulation of ICAM-1 and the increased adhesion induced by BDE-209 could be reversed by miR-141 supplement. Taken together, our results show that BDE-209 potentiates monocyte-endothelial cell interaction via miR-141/ICAM-1 pathway in HAECs. PMID- 30419431 TI - Global burden of late-stage chronic kidney disease resulting from dietary exposure to cadmium, 2015. AB - Chronic exposures to cadmium (Cd) are associated with reduced glomerular filtration rate (GFR), increasing the risk of chronic kidney disease (CKD). In support of the World Health Organization (WHO)'s initiative to estimate the global burden of foodborne diseases, a risk assessment was performed to estimate the Disability-Adjusted Life Years (DALYs) due to late-stage CKD associated with dietary exposures to cadmium. Using the distribution of population GFRs, the prevalence of CKD was calculated as the proportion of humans whose GFR fall in the ranges corresponding to Stage 4 or Stage 5 CKD. The increase in the CKD prevalence due to cadmium exposure was simulated based on a previously reported pharmacokinetic model describing the relationship between dietary cadmium intake and urinary cadmium (UCd), as well as a previously published dose-response relationship between UCd and GFR. Cadmium-related incidence rate, calculated as the change in the prevalence during a one-year period, were used to compute the mortality and DALY in all WHO regions. It is estimated that dietary cadmium would result in a median of 12,224 stage 4 and stage 5 new CKD cases per year worldwide, resulting in 2064 global deaths and 70,513 DALYs. These data translate into a median global burden of 1.0 DALY per 100,000 population, which account for 0.2% of the global DALYs of CKD. While these results suggest that the overall impact of dietary cadmium exposure on global CKD is low, they do indicate that reasonable efforts to reduce dietary exposure will result a positive public health impact. This would be particularly the case in areas with elevated levels of dietary cadmium. PMID- 30419432 TI - Formation of gold nanoparticles in a free-standing ionic liquid triggered by heat and electron irradiation. AB - Ionic liquids (ILs) feature negligibly low vapor pressures and can thus be freely introduced into the high vacuum of a transmission electron microscope. With this extraordinary property, the ILs offer a powerful tool for in situ transmission electron microscopy (TEM) in window-free liquid media at very high resolution. In this work, we use the IL 1-butyl-3-methylimidazolium chloride in order to study nucleation and growth of gold nanoparticles (NPs) in free-standing liquid droplets by scanning TEM (STEM). The results confirm that the used IL allows for generating Au NPs in situ, triggered by electron irradiation and heat. Firstly, the isotropic growth of small, spherical Au NPs was initiated and monitored, whereas different growth mechanisms were observed, i.e. growth by monomer attachment, growth through particle coalescence and possible Ostwald ripening events. After the initial growth phase, a second, anisotropic growth process was induced by a moderate temperature increase and continued electron irradiation. As a result, larger, faceted crystals, such as tetrahedra, octahedra or decahedra, were formed. As all these polymorphs are terminated by {111}-facets, the IL might not only act as liquid medium but in addition as a surfactant which preferentially attaches on the {100}-facets. PMID- 30419433 TI - Considerations for imaging thick, low contrast, and beam sensitive samples with liquid cell transmission electron microscopy. AB - Transmission electron microscopy of whole cells is hindered by the inherently large thickness and low atomic contrast intrinsic of cellular material. Liquid cell transmission electron microscopy allows samples to remain in their native hydrated state and may permit visualizing cellular dynamics in-situ. However, imaging biological cells with this approach remains challenging and identifying an optimal imaging regime using empirical data would help foster new advancements in the field. Recent questions about the role of the electron beam inducing morphological changes or damaging cellular structure and function necessitates further investigation of electron beam-cell interactions, but such comparisons are complicated by variability in imaging techniques used across various studies currently present in literature. The necessity for using low electron fluxes while imaging biological samples requires finding an imaging strategy which produces the strongest contrast and signal to noise ratio for the electron flux used. Here, we experimentally measure and evaluate signal to noise ratios and damage mechanisms between liquid and cryogenic samples of intact cells using multiple electron imaging modalities all on the same instrument and with equivalent beam parameters to standardize the comparison. We also discuss considerations for optimal electron microscopy imaging conditions for future studies on whole cells within liquid environments. PMID- 30419434 TI - Removal of Sr2+ using high-surface-area hydroxyapatite synthesized by non additive in-situ precipitation. AB - Owing to their high-risk factor, many attempts have been made to remove radionuclides from water. Sr2+ ions are the target of removal by synthesized hydroxyapatite in this research. A facile method for synthesizing high-surface area hydroxyapatite by in-situ precipitation using excess diammonium phosphate solution and without any additive was developed. The highest surface area achieved using this method was 177.00 m2/g, and the synthesized hydroxyapatite was also mesoporous. The effects of different pH, temperatures, and ion concentrations during synthesis on the properties of the hydroxyapatite were assessed, and it was found that a low temperature and high pH were optimal for synthesizing high-surface-area hydroxyapatite. The maximum strontium removal capacity of 28.51 mg/g was achieved when the pH-7.5 solution was used. This performance is competitive in comparison with previously developed synthesized materials. Synthesized hydroxyapatite could effectively remove radioactive strontium from an aqueous solution for nuclear waste management. PMID- 30419435 TI - The influence of environmental background on tourists' environmentally responsible behaviour. AB - Previous research on the environmentally responsible behaviour (ERB) of tourists has primarily focused on the personal psychological factors of tourists. However, the studies overlook the effect of contextual factors of a tourist site. According to the broken window theory, a disorderly, unkempt environment might lead more people to be involved in environmental destruction, which would form a vicious cycle. Therefore, it can be deduced that the environmental background (EB) of a tourist site is an important contextual factor. In this paper, the effect of the EB of a tourist site on the ERB was examined by the theory of planned behaviour (TPB) adopting structural equation model (SEM) multi-group analysis (MGA). The results show the following: first, both the attitude toward environmental behaviour (ATT) of tourists and their subjective norm (SN) have a positive impact on the environmentally responsible behavioural intention (ERBI) of tourists. In addition, perceived behavioural control (PBC) exerts a remarkable influence on the ERB of tourists and their behavioural intention. Second, the relationship between the ERBI and ERB of tourists is positively regulated by the EB of a tourist site. Additionally, this paper presents policy proposals for the environmental management of tourist sites. PMID- 30419436 TI - Reclamation of an arsenic-bearing gypsum via acid washing and CaO-As stabilization involving svabite formation in thermal treatment. AB - As one of the biggest hazardous solid waste in the metallurgical industry, arsenic-bearing gypsum (ABG) is a great threat to environmental safety owing to possible leakage and diffusion contamination. However, the reclamation of ABG suffers great challenges due to its worthless constituents and high arsenic leaching. In this study, an ABG was reclaimed as more valuable bassanite (CaSO4?0.5H2O) and anhydrite (CaSO4). Firstly, the overmuch arsenic in ABG was removed to below 150 mg/kg (Japan standard value) using acid extraction. Then, the sludge was mixed with a small amount of CaO and heated at 150 degrees C and 900 degrees C to produce bassanite and anhydrite, respectively. In this calcination, gypsum dehydration and arsenic stabilization were combined. In Japan standard leaching test (JSLT), the arsenic leaching concentrations from bassanite (5.1 MUg/L) and anhydrite (1.3 MUg/L) satisfied the environmental criteria (<10 MUg/L) set by Japan government and remained stable for three months. In toxicity characteristic leaching procedure (TCLP), arsenic leaching concentrations remained at 1.61 and 0.61 mg/L, much lower than the limitation (<5 mg/L). Moreover, the arsenic leaching behavior implied that higher temperature was benefited to arsenic stability, which indicated that the arsenic stabilization process was temperature dependent. By XRD analyses, it was found that heating (over 100 degrees C) could effectively promote arsenic immobilization through reducing the carbonation influence. And the temperature dependence was attributed to the formation of insoluble svabite (Ca5(AsO4)3OH) at high temperature (300-900 degrees C). PMID- 30419437 TI - Concurrent production of sodium lignosulfonate and ethanol from bagasse spent liquor. AB - This study was done with the aim of lignosulfonate and ethanol production from different spent liquors of bagasse pulping process. For this purpose, alkali lignin from bagasse alkali liquor was separated and was sulfomethylated to produce soda lignosulfonate (SLig). Furthermore, raw bagasse was directly treated with sodium sulfite in acidic and neutral conditions to produce BLig and NLig bagasse lignosulfonate, respectively. In addition, the pentoses and hexoses impurities in lignosulfonates were fermented to ethanol using Candida guilliermondii. Results showed that the molecular weight of NLig lignosulfonate was considerably high comparing to the SLig and BLig lignosulfonates. A high level of thermal resistance was found in case of SLig regarding to the other samples at 500 degrees C. Fermentation of the spent liquors with Candida guilliermondii led to a maximum ethanol yield of 7.0, 1.0 and 5.1 g L-1 in NLig, SLig and BLig, respectively. PMID- 30419438 TI - Living biomass supported on a natural-fiber biofilter for lead removal. AB - Living biomass biofilters constitute an excellent alternative for heavy metal bioremediation. In situ biomass and exopolysaccharides production involve a crucial advantage over other bioremediation alternatives such as lignocellulosic biomass-based materials. In this study, a biofilm-forming bacterium was isolated from an ambient exposed to heavy metals. Bacterial biomass was inoculated on a biofilter packed with Furcraea andina fibers. The goal was to develop a continuous low-cost biofilter to remove low-to-moderate concentrations of Pb2+. Adsorption equilibrium and kinetics were determined for the fibers and the biofilm developed on the fibers. Biofilm presence had positive effects on the maximum adsorption capacity and the process kinetics. Biofilters packed with 20 g of F. andina fibers, with and without living biomass biofilm, were evaluated under continuous inflow of Pb2+ (325 mg/day) at a concentration of 50 mg/L. The best results were obtained with the biofilm-fiber biofilter where total adsorption on Pb2+ were observed for 72 h. Maximum absorption capacity was 48.75 mg/g at pH = 7. PMID- 30419439 TI - Volatile fatty acids and biogas recovery using thermophilic anaerobic membrane distillation bioreactor for wastewater reclamation. AB - The effects of bioreactor temperatures and salinities of an anaerobic membrane distillation bioreactor (anMDBR) on the permeation performance and their potential recovery of bioresources were fully examined in this study. To the best of our knowledge, this is the first study of a lab-scale anMDBR process utilizing sub-merged hollow fiber membranes. The hybrid system utilizing both membrane distillation (MD) and anaerobic bioreactors achieved 99.99% inorganic salt rejection regardless the operation temperatures and high initial flux from (2-4 L m-2 h-1) at 45-65 degrees C. However, after 7-day operation, the flux dropped by 16-50% proportional to the bioreactor temperatures. It was found that the effects of bioreactor temperatures had strong impacts on both the permeation performance and fouling behavior while salinity had insignificant effect. A compact non porous fouling layer was observed on the membrane surface from the bioreactor operated at 65 degrees C while only a few depositions was found on the membrane from 45 degrees C bioreactor. In the present study, the optimal anMDBR temperature was found to be 45 degrees C, showing a balanced biogas production and membrane permeation performance including less fouling formation. At this bioreactor temperature (45 degrees C), the biogas yield was 0.14 L/g CODremoval, while maintaining a methane recovery of 42% in the biogas, similar recovery to those at bioreactor temperatures of 55 and 65 degrees C. The potential recovery of volatile fatty acids made anMDBR a more economically efficient system, in addition to its lower operation cost and smaller footprint compared with most other technologies for on-site wastewater treatment. PMID- 30419441 TI - Increasing resilience of smallholder farmers to climate change through multiple adoption of proven climate-smart agriculture innovations. Lessons from Southern Africa. AB - Conservation agriculture, drought tolerant maize, and improved legume varieties are key climate change management strategies for smallholder farmers in southern Africa. Their complementary efforts in adaptation to climate change are sternly important for farm productivity and income. This study evaluates factors explaining individual and multiple adoption of climate change management strategies and their differential impacts on productivity and income using a sample of 1172 smallholder farmers from Malawi and Zimbabwe. The study employs multinomial logistic regression to evaluate factors of individual and multiple adoption and regression adjustment with inverse probability weighting to evaluate impacts of the different adoption regimes on farm productivity and income. The results show that multiple adoption of innovations is mostly explained by access to key resources (credit, income and information), level of education and size of land owned by the farmer. More so, the concurrent adoption of conservation agriculture, stress adapted legume varieties and drought tolerant maize has far greater dividends on productivity and income than when considered individually. However, impacts of multiple adoption of the practices are not entirely uniform across different geographic regions and gender. Results suggest that effective institutional and policy efforts targeted towards reducing resource constraints that inhibit farmers' capacity to adopt complementary climate-smart agriculture packages such as conservation agriculture, drought tolerant maize and improved legume varieties must be gender sensitive and context specific. PMID- 30419440 TI - Tales of transforming cities: Transformative climate governance capacities in New York City, U.S. and Rotterdam, Netherlands. AB - Climate change actions in cities worldwide are driving deep changes in urban governance. We ask whether new capacities for transformative climate governance are emerging in two cities that have experimented with urban climate governance: Rotterdam, the Netherlands, and New York City (NYC), United States. Transformative climate governance creates the conditions for developing integrated and innovative climate mitigation and adaptation policies and interventions that respond to and shape urban transformation dynamics and contribute to sustainability and resilience. The comparison of capacities for transformative climate governance in Rotterdam and NYC offers insights into the emerging features of urban climate governance vis-a-vis existing urban governance regimes: how urban climate governance is driven and delivered, what new governance conditions emerge, and whether these conditions enable transformative climate governance. In both cities, an integrated, experimental and inclusive approach to climate governance is emerging, which crosses multiple policy sectors and domains (e.g. transport, energy, health, justice), involves a variety of actors and facilitates innovative solutions. Envisioning, long-term goal and knowledge integration, experimentation and tapping into coalitions for change help to provide the basis (including guiding principles, urgency, actor networks, innovative solutions) for transformative climate governance. However, these transformative approaches tend to be still subordinate to business-as-usual interests and policy and planning approaches, which favour isolated, incremental and short-term responses. The challenge for strengthening transformative climate governance will be to develop rigorous institutional and organisational conditions that decisively stipulate a prioritisation of climate change across scales and sectors, provide action mandates and enable wider coordination, collaboration and learning. PMID- 30419442 TI - Understanding scuba divers' response to coral bleaching: An application of Protection Motivation Theory. AB - Coral reefs are important to the dive experience, suggesting the expected increase in coral bleaching events has the potential to alter global flows of dive tourists. There are a growing number of studies that suggest taking people's estimation of their options and ability to react to a threat into account provides a clearer picture of the decision to respond to a threat. This study applied Protection Motivation Theory (PMT) to help understand the motivational factors associated with intended adaptation to coral bleaching. Multiple regression analysis was used to analyze the effects of threat and coping appraisal variables. This study provided the first empirical evidence of scuba divers' response to marginal reef conditions, indicating that the majority of respondents would significantly alter their behavior in some way. PMT was able to explain between 12.8% and 47.7% of the variance in adaptation intentions, with response efficacy and self-efficacy consistently emerging as the strongest significant predictors. Consideration of multiple adaptation responses demonstrates the variability of model performance and highlights the need to consider the context of adaptation when interpreting results. Implications for future research and the dive tourism industry are discussed. PMID- 30419443 TI - Impact of culvert flooding on carnivore crossings. AB - Along many roads worldwide, drainage culverts are the only structures wildlife can safely use to cross. However, culverts inundate and can become unavailable to terrestrial fauna during rainy periods. We conducted a field study over wet and dry seasons in southern Portugal to assess the effect of culvert flooding on crossings by medium-sized carnivores. We set up track stations inside 30 culverts along intermediate-level traffic roads to evaluate complete crossings (n = 1211) and used mixed-effects models to quantify the effects. Carnivores were more likely to cross and crossed more frequently if the culvert had a natural dry pathway at the time of the crossing. Carnivores were also more likely to cross culverts with streams running through them. Moreover, culverts with flowing streams during the wet season were still more likely to be crossed during the dry season when the streams were dry. The significance of the difference in crossing rates between wet and dry seasons was species-specific. Our study reveals that flowing water and dry pathways jointly contribute to promoting crossings by this carnivore community. Culverts including streams may act as a continuation of riparian corridors, being incorporated into carnivores' movement routes. Our results lend empirical support to recommendations advising the implementation of dry pathways to provide crossing paths. Interventions to offset the transient impacts of water flooding in new or existing culverts can be a cost-effective solution promoting connectivity across roads allowing movement of individuals. PMID- 30419444 TI - Phytoremediation of highly contaminated mining soils by Jatropha curcas L. and production of catalytic carbons from the generated biomass. AB - This paper deals with the removal of heavy metals from marginal soil mixtures from the Cobre Las Cruces and Aznalcollar mining areas containing high concentrations of metals (Cr, Fe, Ni, Cu, Zn, Cd, Hg, Pb and As) by means of phytoremediation using Jatropha curcas L., and the subsequent production of biocatalysts from the plant biomass. First, J. curcas L. was sowed in eight mixtures of these mining soils to study its adaption to these high-contaminated soils and its growth during 60 days in a greenhouse under conditions simulating the South of Spain's spring climate. Later, the most suitable soil mixtures for plant growth were used for 120-day phytoremediation under the same conditions. Heavy metal concentration in soils, roots, stems and leaves were measured by ICP OES at the beginning, at the middle and at the end of the phytoremediation period, thus calculating the translocation and bioaccumulation factors. J. curcas L. was found to absorb great amounts of Fe (>3000 mg kg-1 plant) as well as notable amounts of Pb, Zn, Cu, Cr and Ni, and traces of As. Other metals with lower initial concentrations such as Cd, Hg and Sn were completely removed from soils. Finally, the plant biomass was subjected to pyrolysis to obtain catalytic biocarbons, assessing the optimal temperature for the pyrolytic process by means of thermogravimetric analysis and Raman spectroscopy. PMID- 30419445 TI - Arthrospira maxima OF15 biomass cultivation at laboratory and pilot scale from sugarcane vinasse for potential biological new peptides production. AB - An environmental friendly process was developed to produce Arthrospira maxima's biomass from sugarcane vinasse, which was generated in a bioethanol production chain, at laboratory and pilot scale. Peptides fractions were than obtained from enzymatically hydrolyzed biomass. High microalgae biomass productivities were reached (0.150 g L-1 day-1) coupled with a significant reduction of BOD and COD (89.2 and 81%, respectively). Three peptide fractions were obtained from microalgae biomass through single or sequential enzymatic hydrolysis. Antioxidant, antimicrobial, anti-inflammatory, and/or anti-collagenase activities of biopetides' fractions were observed. The PHS showed multi-biological activities. The three peptides fractions could be potential candidates for different applications in pharmaceutical, cosmetic and food industry. PMID- 30419446 TI - Evaluation of inhibitory effect and feasible utilization of dilute acid pretreated rice straws on succinate production by metabolically engineered Escherichia coli AS1600a. AB - This work demonstrated a pioneer work in the pre-treatment of rice straw by phosphoric acid (H3PO4) for succinate production. The optimized pre-treatment condition of rice straw was at 121 degrees C for 30 min with 2 N H3PO4. With this condition, total sugar concentration of 31.2 g/L with the highest hemicellulose saccharification yield of 94% was obtained. The physicochemical analysis of the pre-treated rice straw showed significant changes in its structure thus enhancing enzymatic saccharification. Succinate concentrations of 78.5 and 63.8 g/L were produced from hydrolysate liquor (L) and solid fraction (S) of the pre-treated rice straw respectively, with a comparable yield of 86% by E. coli AS1600a. Use of a combined L + S fraction in simultaneous saccharification and fermentation (LS + SSF) further improved succinate production at a concentration and yield of 85.6 g/L and 90% respectively. The results suggested that H3PO4 pre-treated rice straw may be utilized for economical succinate production by E. coli AS1600a. PMID- 30419447 TI - Role of Health Technology Assessment in Drug Policies: Korea. AB - South Korea is the first Asian country to mandate the submission of pharmacoeconomic data for reimbursement decision making. For a new drug to be listed, it must demonstrate its value in terms of comparative effectiveness and cost effectiveness. The Health Insurance Review and Assessment Service (HIRA) judges the submitted drug's value and decides whether its coverage is appropriate on the basis of the recommendation of the Pharmaceutical Benefit Coverage Assessment Committee. Once the drug has been accepted by HIRA, the National Health Insurance Service and the sponsoring company negotiate the price and expected sales volume. Even if HIRA acknowledges the value of the drug, it cannot be listed if the negotiation fails. In the off-patent market, generic and original branded drugs are treated equally in terms of pricing. Once generics enter the market, both drug prices should be lowered to 53.55% or less of the on patent price. Since the current system was implemented, concerns have been raised about a decline in the accessibility of new drugs, especially for high-priced drugs used to treat serious diseases. In 2013, several measures had been introduced aimed at improving the accessibility of these drugs. A risk-sharing scheme and an increase in the maximum acceptable cost-effectiveness ratio were subsequently initiated. Although these schemes have been successful in improving access to high-priced drugs, they are often criticized for reducing transparency in pricing. Finding a balance between accessibility and efficiency is still a challenge in Korea. PMID- 30419448 TI - Medication Adherence and Diabetes Self-Care Activities among Patients with Type 2 Diabetes Mellitus. AB - BACKGROUND: The prevalence of type 2 diabetes mellitus (T2DM) is increasing at an alarming rate in developing countries. The accompanying complications of T2DM can be reduced by maintaining a good adherence to medication and self-care activities. OBJECTIVES: To evaluate medication adherence and self-care behaviors among patients with T2DM. METHODS: A total of 497 subjects with T2DM were recruited from three hospitals and a government clinic in the state of Selangor, Malaysia. Previously validated scales were used to measure medication adherence (Morisky Medication Adherence Scale) and diabetes self-care activities (Summary of Diabetes Self-Care Activities). Pearson correlation coefficient was used to investigate the relationship between the risk factors and medication adherence. Pearson chi2 test of association was used to test significant association. RESULTS: The mean age of the subjects was 55.5 years. The mean Morisky Medication Adherence Scale score was 5.65 +/- 1.97, indicating a moderate adherence level to medication. Among the subjects who had low adherence level, 50.9% were Malays, followed by 34.2% Indians. The Pearson chi2 test of association indicated a significant association (P = 0.000) between ethnicity and medication adherence. The subjects had better self-care behaviors in their general diet (mean 5.04 +/- 1.88) and poor self-care behaviors in blood sugar testing (mean 2.13 +/- 2.34). CONCLUSIONS: The Malaysians had a moderate medication adherence level, whereas they were nonadherent to blood glucose testing. Emphasis on self-care activities and medication adherence is relevant to improve outcomes in the management of T2DM. PMID- 30419449 TI - Assessing the Burden of Type 2 Diabetes in China Considering the Current Status Quo Management and Implications of Improved Management Using a Modeling Approach. AB - BACKGROUND: Recent estimates from the International Diabetes Federation Diabetes Atlas have quantified the total annual expenditure for diabetes in China to be between 354 and 611 billion Chinese yuan (Y) (2015). OBJECTIVES: To use a modeling approach to assess the current and possible future diabetes burden in China on the basis of the current standard of type 2 diabetes (T2D) management (status quo [SQ]) and a series of hypothetical improved management strategies. METHODS: The IQVIA CORE Diabetes Model was used to evaluate the economic burden of T2D in China on the basis of assumptions reflecting the current SQ of T2D management and a number of stepwise improvements. SQ was defined as a scenario in which T2D diagnosis is delayed by 4 years, treatment escalation to maintain glucose control occurs at a 9% glycated hemoglobin (HbA1c) threshold, and there is an overall 60% adherence rate. Stepwise improvements considered immediate diagnosis, declining levels of HbA1c escalation thresholds to 7.0%, and improvements in adherence rate to 80% and 100%. The CORE Diabetes Model was applied on per-capita level to project lifetime costs and clinical outcomes of newly diseased T2D individuals in the Chinese setting. Model outcomes were subsequently annualized and extrapolated to Chinese national level considering the total number of diagnosed individuals with T2D in China. RESULTS: The total annual direct costs attributable to diagnosed T2D in China reflecting current SQ management were estimated at Y621 billion. Scenarios exploring stepwise improvements from SQ estimated annual net savings of Y35, Y35, Y60, Y71, Y75, and Y106 billion for scenarios exploring immediate diagnosis, HbA1c threshold reductions to 8.0% and 7.0%, adherence rate increase to 80% and 100%, and cardiovascular risk factor control in concordance with clinical guidelines, respectively. Net savings resulted from reduced costs to treat diabetes complications (Y38, Y67, Y124, Y141, Y161, and Y212 billion) and excess treatment costs alongside stepwise management improvements (Y4, Y32, Y65, Y69, Y86, and Y107 billion). Per-capita life expectancy was increased by 0.26, 0.68, 1.33, 1.47, 1.69, and 3.21 years, respectively. CONCLUSIONS: Improved T2D management strategies can help to decrease the financial burden of the disease and increase life expectancy of individuals with T2D. PMID- 30419450 TI - Neuroprotective effects of Astilbin on MPTP-induced Parkinson's disease mice: Glial reaction, alpha-synuclein expression and oxidative stress. AB - Astilbin (AST), a dihydro-flavonol glycoside, is a major bioactive ingredient in Astilbe thunbergii, Engelhardia roxburghiana, Smilax corbularia and Erythroxylum gonocladum, and has been shown to have anti-inflammatory, antioxidative and neuroprotective effects, suggesting potential therapeutic value in the treatment of Parkinson's disease (PD). We explored the neuroprotective effects of AST in 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease mice. Mice were administered with MPTP (30 mg/kg, i.p) daily for 5 days, to establish a subacute Parkinson's disease model, followed by daily treatment with AST or saline for 7 days. Pole and traction tests showed that AST ameliorated the impaired motor functions in MPTP-induced Parkinson's disease mice. High performance liquid chromatography analysis revealed that AST treatment prevented MPTP-induced decreases in striatal dopamine levels. Immunofluorescence assays showed that AST reduced the loss of dopaminergic neurons and the activation of microglia and astrocytes in the substantia nigra. Western blot analyses revealed that AST suppressed alpha-synuclein overexpression and activated PI3K/Akt in the striatum following MPTP treatment. AST also prevented the MPTP-induced reduction in total superoxide dismutase and glutathione activity in the striatum. AST exerts neuroprotective effects on MPTP-induced PD mice by suppressing gliosis, alpha-synuclein overexpression and oxidative stress, suggesting that AST could serve as a therapeutic drug to ameliorate PD. PMID- 30419451 TI - Effect of recombinant Trichinella spiralis cysteine proteinase inhibitor on TNBS induced experimental inflammatory bowel disease in mice. AB - Inflammatory bowel disease (IBD) is a chronic autoimmune disease with a high recurrence rate. Ulcerative colitis (UC) and Crohn's disease (CD) are two types of IBD. At present, parasite-derived cysteine protease inhibitors have received extensive attention from researchers, and experiments have confirmed that these protease have an effect on certain autoimmune diseases. So we conducted experiments to investigate the effect of Trichinella spiralis cysteine protease inhibitors on TNBS-induced mouse CD models. In this experiment, 72 male BALB/c mice aged 6-8 weeks were randomly divided into two groups: prevention group and therapy group. The mice were sacrificed and harvested on the 7th day after the model was established to measure the changes of various indicators of colitis. The comparison of the TsCystatin + TNBS group with the PBS + TNBS group showed that the DAI score, MPO activity, and colonic macroscopic and microscopic damage significantly reduced, IFN-gamma significantly decreased, IL-4 expression increased, and NF-kappaB expression decreased. The percentage of CD4+CD25+Foxp3+ Treg and CD8+CD28- Treg in spleen, and the proportion of CD4+/CD8+ Treg cells decreased. In the therapy group, we found no significant difference between the TNBS+PBS group and TNBS + TsCystatin group. Treatment with TsCystatin exerted a good intervention effect on the TNBS-induced mouse CD model. TsCystatin possibly induced a Th2-type immune response in the body, which balanced the Th1-type immune response induced by TNBS administration, thereby relieving colitis. PMID- 30419452 TI - Methyl helicterte ameliorates liver fibrosis by regulating miR-21-mediated ERK and TGF-beta1/Smads pathways. AB - Methyl helicterate (MH) has been reported to have protective effects against CCl4 induced hepatic injury and fibrosis in rats, but its protective mechanism, especially on hepatic stallete cells (HSCs), remains unclear. Recently, our pilot experiment showed that MH could inhibit miR-21 expression in HSC-T6 cells, suggesting that miR-21 may be one of the targets of MH to intervene liver fibrosis. To verify the hypothesis, the present study would focus on the regulatory effect of MH on the miR-21-mediated ERK and TGF-beta1/Smads pathways. Briefly, rats were intraperitoneally injected with 0.5 ml porcine serum (PS) twice a week for 24 weeks to induce liver fibrosis, and meanwhile, the rats were treated with MH from weeks 16 to 24. In vitro experiment, miR-21 expression in HSC-T6 cells was up- or down-regulated using lentiviral transfection assay. Collagen accumulation, inflammatory cytokines, cell apoptosis, miR-21 expression, and activation of the ERK and TGF-beta1/smad2/3 pathways were then assessed. The results showed that MH treatment markedly alleviated PS-induced liver injury, as evidenced by the attenuation of histopathological changes and the decrease in serum alanine and aspartate aminotransferases activity. MH significantly decreased the content of inflammatory cytokines and recruited the anti-oxidative defense system. Moreover, MH treatment significantly decreased miR-21 expression and inhibited the activation of the ERK and TGF-beta1/smad2/3 pathways in liver tissues. In vitro experiments showed that MH strongly inhibited HSC-T6 cell activation and reduced collagen accumulation. Interestingly, miR-21 overexpression significantly promoted HSC-T6 cell proliferation, reduced HSC apoptosis, and increased collagenation, while these abnormal changes induced by miR-21overexpression were significantly reversed by MH treatment. Furthermore, miR-21 overexpression notably activated the ERK and TGF-beta1/Smads pathways via repressing SPRY2 and Smad7 expression respectively, however, these effects were largely abolished by MH treatment. In conclusion, our study demonstrates that MH significantly alleviates PS-induced liver injury and fibrosis by inhibiting miR 21-mediated ERK and TGF-beta1/Smads pathways. PMID- 30419453 TI - Spectroscopy approach to methanol detection in waste fat methyl esters. AB - Second-generation biodiesel manufactured from waste cooking oils (WCO) and inedible animal fats (AF) are one of the alternatives to the first generation (1G) vegetable oil-based biodiesel. In this study, a quality control method is proposed to evaluate methanol content in waste fat methyl esters and is based on near infrared spectroscopy (NIR) combined with multivariate analysis. More specifically, calibration models are constructed using partial least squares regression (PLS) for the prediction of methanol content in rapeseed oil methyl ester (ROME), waste cooking oil methyl ester (WCOME), chicken fat methyl ester (CFME) and pork fat methyl ester (PFME) by Vis-NIR spectrometer. The calibration models are based on the absorbance spectra and computed data from five wavelength regions of 400-2170 nm, 780-2170 nm, 1400-2170 nm, 1400-1600 nm and 1970-2170 nm. For the cases with the highest prediction ability obtained in this study, the coefficient of determination of the model's goodness-of-fit for methanol concentrations range 0-5% (v/v) was R2 > 0.990, and for concentrations 0-1% (v/v) was R2 > 0.994, indicating the spectroscopic approach effectiveness in methanol content detection relevant to the biofuel quality assessment. A pseudo-univariate limits of detection (LODpu) and quantification (LOQpu) as well as ratio of performance to deviation (RPD) were used to confirm the validity and to evaluate the practical applicability of developed models. In addition, the obtained results indicate the possibility of developing a transmission sensor for online monitoring of the production process and the quality of biofuel. PMID- 30419454 TI - Biodegradation of triphenylmethane dye crystal violet by Cedecea davisae. AB - The present study focuses on the biodegradation of triphenylmethane dye crystal violet (CV) by Cedecea davisae. The degradation of CV was evaluated via ultraviolet absorbance at 254 nm (UV254) and chemical oxygen demand (COD) removal, and the kinetics was used to evaluate the degradation efficiency. Intermediate products were analyzed via UV-vis spectroscopy (UV), Fourier transform infrared spectroscopy (FTIR), and high-performance liquid chromatography (HPLC). Results showed that C. davisae was able to decolorize the CV, and the maximum decolorization ratio reached 97%. COD reduction was observed after decolorization, with average removal rates of >90% after 48 h. Moreover, 50% of UV254 can be removed after 14 h. The removal efficiency of CV by C. davisae followed first- and second-order reaction kinetics at temperature ranged from 20 degrees C to 40 degrees C and pH 4.0 to 6.0, respectively. By using UV, the peak representing the CV disappeared 14 h after CV decolorization, and the degradation of aromatic and naphthalene rings was attributed to the formation of a new metabolite. The FTIR spectra of metabolites showed that a new functional group of OH, CH, CH2, CH3, NH, CN, CN, or CO was produced. The chromatograms of HPLC recorded at 589 nm at retention time decreased and were not detected following incubation for 8 h by C. davisae. PMID- 30419455 TI - Relative efficiency calibration for determining isotopic composition and age of HEU items by passive non-destructive gamma spectrometry. AB - The observation of the 239 keV gamma line from 232U decay in high-enriched uranium (HEU) samples prompted us to utilize 232U (with main gamma energies of its daughters at 239, 583, 763, and 860 keV) as a mediator isotope for performing relative (intrinsic) efficiency calibration among 232U, 234U, 235U, 238U, and 214Bi isotopes. By this way, the isotopic composition and age of HEU samples can be derived from activity ratios constituted between pairs of these isotopes on the basis of a common relative efficiency calibration curve. The method proved to be a useful tool for gamma-spectrometric characterization of HEU items, especially of weapon grade, shielded uranium material. PMID- 30419456 TI - Novel epileptogenic positive rolandic sharp waves in an adult: an unusual case of post-hypoxic myoclonus. PMID- 30419457 TI - Fly-ash-incorporated electrospun zinc oxide nanofibers: Potential material for environmental remediation. AB - Fly ash (FA), a solid waste generated in thermal power plants, is considered an environmental pollutant. Therefore, measures must be taken to dispose of FA in an environmentally friendly manner. In this paper, an electrospinning technique was employed to incorporate FA particles onto zinc oxide nanofibers (ZnO NFs), and the product (FA/ZnO composite) was used for the removal of methylene blue (MB) from the water. Herein, ZnO NFs may serve as effective semiconductor photocatalysts and provide sufficient surface area for FA, while the FA particles serve as an effective adsorbent. The adsorption capacity and photocatalytic efficiency of the as-synthesized nanocomposite fibers were enhanced compared to those of the pristine ZnO NFs, and this result is attributed to the uniform distribution of FA on the surface of the ZnO NFs. The as-synthesized nanocomposite could have great significance in wastewater treatment. PMID- 30419458 TI - Atmospheric deposition of antimony in a typical mercury-antimony mining area, Shaanxi Province, Southwest China. AB - Mercury-antimony (HgSb) mining activities are important anthropogenic sources of Hg and Sb to the local environment. The Xunyang HgSb mine situated in Shaanxi Province is an active Hg mine in China. To understand the emission, transportation, and deposition of Sb through HgSb mining activities, current study systematically monitored the Sb concentration in precipitation in the Xunyang HgSb mining district. Five groups of experimental pots were carefully designed to further investigate the influence of HgSb mining activities on the Sb contamination in the local surface soil. Based on the overtime increasing of the Sb concentrations in soil from experimental pots, for the first trial, we estimated the atmospheric deposition flux/mass of Sb in the Xunyang HgSb mining district. Our results showed that the concentrations of Sb in precipitation in the Xunyang HgSb mining district ranged from 0.71 MUg L-1 to 19 MUg L-1 (mean = 4.2 +/- 4.5 MUg L-1), which was orders of magnitude higher than that at the control site. As expected, the concentration of Sb in precipitation was highly elevated near of the HgSb smelter and gradually decreased with distance from the smelter. After 12 months exposure, Sb concentrations in soil of experimental pots were increased by 1.2-8.5 times. The average atmospheric wet and dry deposition flux of Sb in the Xunyang HgSb mining district were 7.2 +/- 6.9 MUg m-2 day-1 and 2.1 +/- 4.7 mg m-2 day-1, respectively; the annual wet and dry deposition mass of Sb through HgSb mining activities were estimated to be 1.6 t y-1 and 158 t y-1, respectively, indicating that dry deposition was the dominant pathway (98 +/- 1.2%) for the removal of Sb from the atmosphere. Our results confirmed that the ongoing HgSb mining activities resulted to serious Sb contamination to terrestrial ecosystems, posing a potential threat to local residents in the Xunyang HgSb mining district. PMID- 30419459 TI - Dose-response relationships between polycyclic aromatic hydrocarbons exposure and platelet indices. AB - The relations of polycyclic aromatic hydrocarbons (PAHs) exposure with platelet indices remain unclear. Based on the baseline data from the Wuhan-Zhuhai Cohort Study, we used generalized linear model, multivariate logistic regression analysis and restricted cubic splines (RCS) to assess linear and nonlinear relationship of PAHs exposure with platelet indices. The results showed that among Wuhan individuals, there were the non-linear relations between total hydroxynaphthalene (SigmaOHNa) and mean platelet volume (MPV) or ratio of mean platelet volume to platelet count (MPVP), total hydrophenanthrene (SigmaOHPh) and MPV or platelet distribution width (PDW), the sum concentration of urinary monohydroxylated metabolites of PAHs (SigmaOH-PAHs) and ratio of platelet count to lymphocyte count (PLR) or MPVP, 1-hydropyrene (1-OHP) and PLR or PDW. But among Zhuhai individuals, neither linear nor non-linear relations were found between each of OH-PAHs or SigmaOH-PAHs and platelet indices. The findings indicate that serum MPV and MPVP may be independent biomarkers of effects of exposing to environmental PAHs on human bodies. PMID- 30419460 TI - Wetland plant microbial fuel cells for remediation of hexavalent chromium contaminated soils and electricity production. AB - The plant microbial fuel cell (PMFC) is a novel technology which integrates plants, microbes, and electrochemical elements together to create renewable energy. However, information regarding using the PMFC system to remediate metal contaminated soils is still limited. In this study, we evaluate the potential of PMFC systems to remediate soils polluted by Cr(VI). We compare different plants and different electrode materials with regard to their electricity generation and Cr(VI) removals under different soil Cr(VI) concentrations. In PMFC systems, the soil pH was transformed from slightly acidic to neutral, and the electrical conductivity was reduced during operation. The removal efficiency of Cr(VI) in soils could reach 99%, and the total Cr of soils could also be reduced. The closed circuit voltage of PMFC systems of Chinese pennisetum using the graphite carbon felt as the electrodes could reach the daily average value of 469.21 mV. PMFC systems have successfully demonstrated the ability to remove Cr(VI) from soils collected from actual metal-contaminated sites. Our results suggest that using PMFCs to remediate contaminated soils is promising, and the effects of decontamination are mostly contributed by bioelectrochemical processes and plant uptake. PMID- 30419461 TI - Efficiency and mechanism of atenolol decomposition in Co-FeOOH catalytic ozonation. AB - Co-incorporated alpha-FeOOH nanocrystal (Co-FeOOH) was synthesized and applied for the ozonation of atenolol (ATL) in water. The compound was characterized and recognized as a transitional structure from FeOOH to CoFeO4. The presence of Co FeOOH was observed to support the formation of *OH by promoting ozone decomposition, and the degradation of ATL and TOC was significantly improved during the catalytic ozonation. Catalytic reactions were rationally designed in different water matrices, efficient and simultaneous removal of ATL and natural organic contaminants was achieved. It was found that the reactions kinetics depend strongly on the solution pH which could alter the surface properties of catalyst and influence the ozone-decomposition. Based on the 19 organic intermediates identified by UPLC/Q-TOF-mass spectrometry, possible reaction pathways were accordingly proposed to elucidate the mechanism of atenolol degradation by ozone molecular and *OH. Three positions of ATL structure were concluded as the most vulnerable sites to be attacked by oxygen species to initiate the degradation path. PMID- 30419462 TI - Degradation of diclofenac using palladized anaerobic granular sludge: Effects of electron donor, reaction medium and deactivation factors. AB - Biogenic nanopalladium (Bio-Pd) was formed by Anaerobic Granular Sludge (AGS). The Bio-Pd hosted in AGS (Pd-AGS) was used to degrade a pharmaceutical compound diclofenac (DCF) under the conditions of various electron donors, Pd loadings and reaction media. Results showed that hydrogen was the most effective electron donor for the Pd-AGS, followed by formate, glucose and acetate. The Pd-AGS was able to produce effective hydrogen/electron donors from organic compounds via microbial metabolism to initiate Pd activity. Over 96% of DCF (initial concentration of 20 mg L-1) was removed using the Pd-AGS within 90 min, and a maximum specific activity Kobs of 1.53 L g-1 min-1 was obtained at 3.0 wt% Pd loading, in the presence of hydrogen. The Pd-AGS exhibited a relatively high activity in the medium of PBS or Na2SO4 (25 mM) at pH = 7-7.5, but lost activity in the medium of Na2CO3 (40 mM) or NaOH (40 mM). The Pd-AGS was more resistant to deactivation by chloride or sulphide comparing to free Pd nanoparticles. The Pd AGS could reduce DCF and nitrate simultaneously with high nitrogen selectivity. The Pd-AGS, as a novel form of Pd catalyst with AGS, shows promise for applications in reducing chlorinated organic compounds in contaminated water. PMID- 30419463 TI - Experimental and numerical simulation study of the thermal hazards of four azo compounds. AB - Azo compounds (azos) possess diverse exothermic properties that enable their application in numerous industrial processes, but these properties also engender a corresponding diversity of thermal hazard profiles. This study employed an innovative approach to determine the specific thermal reactions and decomposition hazard profiles of azos. Four typical azos (AIBN, AMBN, ABVN, and AIBME) were assessed using three thermal calorimetry techniques, and results were subsequently analyzed using a nonlinear optimization model. Thermal hazard analysis of small-scale experiments indicated that AIBN had a heat decomposition of 1247 J/g and a maximum pressure increase of 367 psig and thus exhibited more hazardous characteristics than did AMBN, ABVN, and AIBME. This study also obtained the relevant process safety parameters, time to maximum rate, onset and peak temperature, adiabatic temperature rise, and rate of pressure increase to use for later scaled-up applications. The findings of this study can be used to develop a predictive model for the thermal behavior of azos and to provide the necessary basis for the design and selection of precise treatment and appropriate safety systems. PMID- 30419464 TI - Lignin synthesis and accumulation in barley cultivars differing in their resistance to lodging. AB - Since lignin greatly affects stem strength, which is an important agronomical trait, understanding the relationship between lodging resistance and lignin synthesis is important in barley breeding and selection processes. The aim of the study was to reveal the connection between physiological aspects of lignin synthesis and genetic background of barley cultivars with different lodging phenotype. Three barley cultivars Astor, Scarlett and Jaran were compared by measuring lignin, cellulose and total soluble phenolics content, phenylalanine ammonia-lyase activity (PAL) and expression of cinnamoyl-CoA reductase (CCR) and cinnamyl-alcohol dehydrogenase (CAD) in three lower internodes at flowering and grain filling stage. To assess their genetic background simple sequence repeats (SSR) markers, connected to lodging resistance and plant height, were analyzed. Compared to lodging susceptible cultivars Scarlett and Jaran, a lodging resistant cultivar Astor revealed different dynamics of lignin synthesis and deposition, showing higher PAL activity and total soluble phenolics content as well as higher expression of CCR and CAD genes in the second internode at grain filling stage. Analysis of SSR markers associated with quantitative trait loci (QTL) for lodging resistance revealed that Astor discriminates from Scarlett and Jaran by marker Bmag337 connected with elongation of the second internode. Lignification process is under a strong influence of genotype and environmental factors which determine lignin synthesis dynamics and deposition of lignin in the cell walls of barley. PMID- 30419465 TI - Chlorella vulgaris enhance the photodegradation of chlortetracycline in aqueous solution via extracellular organic matters (EOMs): Role of triplet state EOMs. AB - Algae, which are ubiquitous in surface waters (e.g., lakes, ponds, wetlands) may play an important role in sunlight-driven transformation of compounds. This study is to investigate the role of algae (Chlorella Vulgaris) in chlortetracycline (CTC) photolysis and explore the photosensitive mechanism. The algae were found to significantly accelerate the photodegradation rate of CTC and extracellular organic matters (EOMs) were confirmed to be the major active substances. Triplet state EOMs (3EOMs*) were verified to be the dominant reactive species with 93% contribution to the indirect photodegradation rate of CTC, while .OH and 1O2 contributed minor (7%). The steady-state concentration of 3EOMs* was determined by probe compounds (2,4,6-trimethylphenol) to be 3.50 * 10-14-1.88 * 10-13 M with the increase of EOMs from 2.0 to 8.0 mg L-1. The rate constant for reaction of 3EOMs* with CTC was calculated to be 3.17 * 109 M-1s-1. 3EOMs* were found to react with CTC mainly via electron transfer, on basis of susceptible reaction of 3EOMs* with the hydroxyl and amidogen groups in CTC. In addition, the energy transfer of 3EOMs* to CTC was possible according to the higher energy of 3EOMs* than that of triplet CTC. PMID- 30419466 TI - Carbon dioxide and organic waste valorization by microbial electrosynthesis and electro-fermentation. AB - Carbon-rich waste materials (solid, liquid, or gaseous) are largely considered to be a burden on society due to the large capital and energy costs for their treatment and disposal. However, solid and liquid organic wastes have inherent energy and value, and similar as waste CO2 gas they can be reused to produce value-added chemicals and materials. There has been a paradigm shift towards developing a closed loop, biorefinery approach for the valorization of these wastes into value-added products, and such an approach enables a more carbon efficient and circular economy. This review quantitatively analyzes the state-of the-art of the emerging microbial electrochemical technology (MET) platform and provides critical perspectives on research advancement and technology development. The review offers side-by-side comparison between microbial electrosynthesis (MES) and electro-fermentation (EF) processes in terms of principles, key performance metrics, data analysis, and microorganisms. The study also summarizes all the processes and products that have been developed using MES and EF to date for organic waste and CO2 valorization. It finally identifies the technological and economic potentials and challenges on future system development. PMID- 30419467 TI - Kinetics studies and mechanistic considerations on the reactions of superoxide radical ions with dissolved organic matter. AB - Superoxide ion (O2*-) is one of the short lived reactive oxygen species (ROS) formed in aquatic environments. The reactions of O2*- with the model dissolved organic matter (DOM) were studied using a chemiluminescent analysis method under relevant environmental conditions. The reaction of O2*- with DOM produced reduced DOM (DOM*-) by fast one-electron-transfer in the initial stage. This process resulted an initial "loss" in the O2*- decay kinetics. DOM*- is unstable which will continue react with O2*- generating H2O2 to complete a catalytic dismutation cycle. Based on analyzing the observed pseudo-first order O2*- decay rates (kpseudo), the quasi-steady-state concentration of DOM*- is found to be equal to the initial loss of O2*-. Thus, the rate constant for DOM*- with HO2*/O2*- is derived to be (1.1-1.9) * 106 M-1 s-1 in the temperature range of 7.8-41.4 degrees C. Meanwhile, the apparent rate constant for DOM with O2*- in a flow cell during a short time (2.25 s) is measured as (1.5-3.3) * 103 MC-1 s-1 in the temperature range of 8.2-38.6 degrees C. These temperature dependent O2*- reaction rate constants present an apparent activation energy of (19.6 +/- 2.9) kJ molC-1 for DOM, while that of DOM*- (12.5 +/- 3.5 kJ mol-1) is lower. For the pseudo-first order decay rate of O2*-, the catalyzed-dismutation by metal components ranges from 13 to 23%; the contribution by aromatic ketones of DOM is estimated to be 10-13% by using NaBH4 reduction method. The residual contribution might mainly occur at the quinone-like groups, which contributed 64%-77% to the total dismutation. The pH effects on the apparent catalytic rate constants dominate the reaction of O2*- with DOM. The present work suggests that DOM is an important sink for O2*- in aquatic environments. Furthermore, we proposed that the reaction of O2*- with DOM could be a potential source of DOM*- in natural water. PMID- 30419468 TI - Evaluating membrane fouling potentials of dissolved organic matter in brackish water. AB - Isolating dissolved organic matter (DOM) is a preliminary step that improves the accuracy of its characterization. In this study, DOM in brackish water was clearly separated and evaluated by multiple characterization analyses. The sample was divided into three fractions by preparative high-performance liquid chromatography (preparative HPLC) according to molecular size. The homogeneity of each fraction was estimated by analytical size exclusion chromatography (SEC) and fluorescence excitation-emission matrix (FEEM). Pyrolysis gas chromatography-mass spectrometry (Py-GC/MS) and liquid chromatography-organic carbon detection (LC OCD) were used to characterize the physicochemical properties of each fraction. Py-GC/MS revealed that Fraction 1 consisted of evenly distributed organic matter in order polysaccharides, proteins, polyhydroxy aromatics, lignins, and lipids. However, Fraction 2 was primarily composed of dominant lipids and low portion of proteins, and Fraction 3 was composed predominantly of lignins and lipids. The LC OCD results showed that Fractions 1 and 2 had similar organic carbon (OC) compositions: a humic substance (ca. 37%), building blocks (ca. 10%), and neutrals (ca. 37%), whereas Fraction 3 contained a high proportion of neutrals (62%). In the fouling experiments, the distinct DOM characteristics in each fraction resulted in different declining flux behaviors, ranked as: Fraction 2 > Fraction 1 > Fraction 3. PMID- 30419469 TI - Response and recovery of microbial communities subjected to oxidative and biological treatments of 1,4-dioxane and co-contaminants. AB - Microbial community dynamics were characterized following combined oxidation and biodegradation treatment trains for mixtures of 1,4-dioxane and chlorinated volatile organic compounds (CVOCs) in laboratory microcosms. Bioremediation is generally inhibited by co-contaminate CVOCs; with only a few specific bacterial taxa reported to metabolize or cometabolize 1,4-dioxane being unaffected. Chemical oxidation by hydrogen peroxide (H2O2) as a non-selective treatment demonstrated 50-80% 1,4-dioxane removal regardless of the initial CVOC concentrations. Post-oxidation bioaugmentation with 1,4-dioxane metabolizer Pseudonocardia dioxanivorans CB1190 removed the remaining 1,4-dioxane. The intrinsic microbial population, biodiversity, richness, and biomarker gene abundances decreased immediately after the brief oxidation phase, but recovery of cultivable microbiomes and a more diverse community were observed during the subsequent 9-week biodegradation phase. Results generated from the Illumina Miseq sequencing and bioinformatics analyses established that generally oxidative stress tolerant genus Ralstonia was abundant after the oxidation step, and Cupriavidus, Pseudolabrys, Afipia, and Sphingomonas were identified as dominant genera after aerobic incubation. Multidimensional analysis elucidated the separation of microbial populations as a function of time under all conditions, suggesting that temporal succession is a determining factor that is independent of 1,4-dioxane and CVOCs mixtures. Network analysis highlighted the potential interspecies competition or commensalism, and dynamics of microbiomes during the biodegradation phase, in line with the shifts of predominant genera and various developing directions during different steps of the treatment train. Collectively, this study demonstrated that chemical oxidation followed by bioaugmentation is effective for treating 1,4-dioxane, even in the presence of high levels of CVOC mixtures and residual peroxide, a disinfectant, and enhanced our understanding of microbial ecological impacts of the treatment train. These results will be valuable for predicting treatment synergies that lead to cost savings and improved remedial outcomes in short-term active remediation as well as long-term changes to the environmental microbial communities. PMID- 30419470 TI - Characterising the two-phase flow and mixing performance in a gas-mixed anaerobic digester: Importance for scaled-up applications. AB - This study aimed to characterise the gas-liquid flow and mixing behaviour in a gas-mixed anaerobic digester by improving phase interaction modelling using Computational Fluid Dynamics (CFD). A 2D axisymmetric model validated with experimental data was set up using an Eulerian-Eulerian method. Uncertainty factors, including bubble size, phase interaction forces and liquid rheology were found to significantly influence the flow field. A more reliable and complete validation was obtained by critical comparison and assessment of the referred experimental data, compared to the models reported in other studies. Additionally, justifiable corrections and predictions in detail were obtained. Mixing was evaluated by trajectory tracking of a large number of particles based on an Euler-Lagrange method. The mixing performance approximated to a laminar flow reactor (LFR) that distinctly deviated from expected continuous stirred tank reactor (CSTR) design, indicating limited enhancement from the applied gas sparging strategy in the studied digester. The study shows the importance of a proper phase-interaction description for a reliable hydrodynamic characterisation and mixing evaluation in gas-mixed digesters. Validations, bend to experimental data without a critical assessment, may lead to an inaccurate model for further scaled-up applications. PMID- 30419471 TI - Ninety-day prognosis of patients receiving direct oral anticoagulants in the early phase of non valvular atrial fibrillation-related acute ischemic stroke: The real life evidence. PMID- 30419472 TI - Serotonin release assay (SRA)-negative HIT, a newly recognized entity: Implications for diagnosis and management. PMID- 30419473 TI - Aversion center blackening of muskmelon fruit caused by Pseudomonas oryzihabitans, an opportunistic pathogen of humans and warm-blooded animals. AB - This is the first report of bacterial center blackening in muskmelon fruit caused by Pseudomonas oryzihabitans, which is known as an opportunistic pathogen of humans and warm-blooded animals. The aim of this study was to investigate the microbiological characteristics of this infection. Bacterial center blackening, which can cause aversion in consumers, was observed in muskmelon fruit in South Korea in the fall of 2017. Symptoms included severe black pigmentation in the pulp surrounding the seeds inside muskmelon fruit. Dark brown pigmentation and gram-negative, non-spore-forming, rod-shaped pseudomonads were consistently recovered from the black pigmented pulp tissue of muskmelons. The symptoms after artificial inoculation were the same as those of the natural infection, while the control fruit exhibited no symptoms of infection. Using pathogenicity tests, analytical profile index (API) tests, whole-cell matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), and 16S rRNA gene and gyrB region sequencing, the dominant species was identified as P. oryzihabitans. The recent outbreak indicates that P. oryzihabitans poses a potential threat to the global production and transportation of muskmelon as well as food safety. PMID- 30419474 TI - Impact of some environmental factors on growth and ochratoxin A production by Aspergillus niger and Aspergillus welwitschiae. AB - Ochratoxin A (OTA) is a nephrotoxic mycotoxin which may contaminate various foods and feed products worldwide. Aspergillus niger is one of the species responsible for OTA contamination in grapes and derived products. This species has recently been split into A. niger and Aspergillus welwitschiae. Both species can not be distinguished by phenotypic or extrolite profiles and to date there is no ecophysiological information of A. welwitschiae. The aim of this study was to determine the effects of water activity (aw) (0.90; 0.95 and 0.98-0.99), culture media (Yeast Extract Sucrose Broth (YESB); Synthetic Grape Juice Medium (SGM); White grape juice (WGJ)) and temperature (15 degrees C, 25 degrees C and 35 degrees C) on the growth and OTA production of four strains of A. niger and six strains of A. welwitschiae. The assay was performed in microtiter plates, determining the absorbance at 530 nm and the concentration of OTA at 1, 2, 4 and 10 days. No significant differences were observed in absorbance and OTA values between the two species under study. The highest absorbance values were recorded in YESB, followed by SGM and WGJ. Absorbance values increased with increasing aw and temperature. The highest OTA values were obtained at 0.98-0.99 aw and the best culture media for OTA production was YESB, followed by WGJ and SGM. The studied strains of A. niger produced the highest mean OTA level at 25 degrees C whereas A. welwitschiae strains produced the highest mean OTA concentration at 15 degrees C, although not differing significantly from concentration produced at 25 degrees C. To our knowledge, this is the first report on the impact of some environmental factors on growth and OTA production by A. welwitschiae. PMID- 30419475 TI - Hepatitis E virus was not detected in feces and milk of cows in Hebei province of China: No evidence for HEV prevalence in cows. AB - Hepatitis E virus (HEV) is an important human pathogen, with pigs and other species serving as natural animal reservoirs. Recently, the report of detection of genotype 4 HEV in dairy milk with high positive rate in Yunnan province of China has attracted extensive attention. To assess the zoonotic risk of cows as HEV reservoir and transmission of HEV through dairy milk, 467 fecal samples of cows, 276 fresh milk samples, and 140 retail milk samples were collected across Hebei Province, China, from March 2017 to May 2018, and detected for HEV RNA. Fecal samples of rabbit or pig were also collected for HEV detection from farms of mixed farming with cows or farms neighboring cow farms. HEV RNA was not detected in any cow feces or in any milk samples, but 9.3% feces of pigs and 18.9% feces of rabbits were positive for HEV RNA. In addition, all of the dairy milk samples undergone HEV antigen and anti-HEV antibody detections, but none was positive. Phylogenetic analysis showed that all of the HEV isolates from pigs belonged to genotype 4 and those from rabbits were genotype 3-rabbit HEV. The results indicate that, currently in Hebei province of China, HEV is not apparently prevalent in cows and hence there is no zoonotic transmission risk through dairy milk towards humans, albeit the genotype 4 and 3 (rabbit) HEV are prevalent in pigs and rabbits respectively. PMID- 30419476 TI - Polydopamine reinforced hemostasis of a graphene oxide sponge via enhanced platelet stimulation. AB - Graphene oxide (GO) is a promising hemostatic material because of its platelet stimulatory activity. However, our previous studies on cross-linked graphene sponges demonstrated that those sponges lost the GO function of platelet stimulation due to the pristine GO was reduced under the harsh reaction conditions. Accordingly, a mild cross-linking strategy is expected to preserve the oxygen-containing groups to further increase the hemostatic performance of the sponges. Here, we present a polydopamine (PDA) cross-linked GO sponge (DCGO) by using mild and facile wet chemistry. The obtained DCGO possessed a high surface charge (-31.3 +/- 0.3 mV) and showed strong platelet stimulation. Moreover, this method strengthened the mechanical properties of the DCGO, which supported 350 times its own weight without deformation, thus ensuring its absorbability. For the synergy of platelet stimulation and physical absorption, DCGO achieved outstanding hemostatic performance. Bleeding stopped within 105 +/- 15 s, which was 165 s faster than that of the un-cross-linked GO aerogel and 96 s faster than that of the cross-linked graphene sponge (CGS). The DCGO combines the advantages of both PDA and GO, thus supplying a new material and method for the field of trauma hemostasis. PMID- 30419477 TI - Excess of nutrient-induced morphofunctional adaptation and inflammation degree in a Caco2/HT-29 in vitro intestinal co-culture. AB - OBJECTIVES: The intestinal cell function can be modulated by the type and quantity of nutrients. The aim of this study was to evaluate the effects of an excess of nutrients on intestinal morphofunctional features and a possible association of inflammation in a 70/30 Caco2/HT-29 intestinal in vitro co culture. METHODS: An excess of nutrients (EX) was obtained by progressively increasing the medium change frequency with respect to standard cell growth conditions (ST) from confluence (T0) to 15 d after confluence (T15). RESULTS: In comparison with the ST group, the EX group revealed a maintenance in the number of microvilli, an increase in follicle like-structures and mucus production, and a decrease in the number of tight junction. The specific activity of markers of intestinal differentiation, alkaline phosphatase and aminopeptidase N, and of the enterocyte differentiation specific marker, dipeptidyl peptidase-IV, were progressively raised. The transepithelial electrical resistance, indicative of the co-culture barrier properties, decreased, whereas Lucifer yellow Papp evaluation, an index of the paracellular permeability to large molecules, showed an increase. Reactive oxygen species and nitric oxide production, indicative of an oxidative status, together with interleukin-6, interleukin-8, indicative of a low-grade inflammation, and peptide YY secretion were higher in the EX group than in the ST group. The differences between ST and EX were particularly evident at T15. CONCLUSION: These data support the suitability of our in vitro gut model for obesity studies at the molecular level and the necessity to standardize the medium frequency change in intestinal culture. PMID- 30419478 TI - Endomyocardial fibrosis and myocardial infarction leading to diastolic and systolic dysfunction requiring transplantation. AB - Endomyocardial fibrosis (EMF) is an endemic disease in tropical areas, characterized by restrictive physiology due to endocardial fibrous thickening of the ventricular chambers. We report the case of a 25-year-old man of African origin who presented with end-stage heart failure due to both diastolic and systolic dysfunction and extensive endocavitary thrombosis as proven by echocardiography and cardiac magnetic resonance. EMF diagnosis was confirmed by endomyocardial biopsy and the patient had eventually cardiac transplantation. The explanted heart revealed, besides features consistent with EMF, transmural post- myocardial infarction scarring, in the absence of significant coronary artery disease, most probably thromboembolic in origin. PMID- 30419479 TI - Expression of tenascin C in cardiovascular lesions of Kawasaki disease. AB - BACKGROUND/OBJECTIVE: To examine tenascin C (TN-C) expression in coronary artery lesions (CALs) and myocardial lesions (MLs) in Kawasaki disease (KD). METHODS AND RESULTS: Twenty-five KD autopsy cases (post-KD-onset range of 6 days to 17 years) were examined in this study. Time-course analysis based on the disease day was performed of the histological findings for the CALs and MLs, as well as the localization and intensity of expression of TN-C. TN-C expression was observed to coincide with the areas where inflammatory cell infiltration was present in both coronary arteries and myocardium during the acute stage of KD, and the intensity of its expression correlated with the degree of inflammation. Obvious TN-C expression persisted in the thickened intima and media of CALs even after Disease Day 27. However, in spite of the presence of inflammatory cell infiltration, TN-C expression became weaker in the adventitia and surrounding connective tissue. After 8 months or more, TN-C was not expressed in the vasculitis scars of most cases, but expression was observed around newly formed vessels in the thickened intima and around recanalized vessels after thrombotic occlusion. CONCLUSIONS: The findings suggest a correlation between the degree of inflammation and TN-C expression in the cardiovascular lesions of acute-stage Kawasaki disease. PMID- 30419480 TI - A neurodynamic approach to nonlinear optimization problems with affine equality and convex inequality constraints. AB - This paper presents a neurodynamic approach to nonlinear optimization problems with affine equality and convex inequality constraints. The proposed neural network endows with a time-varying auxiliary function, which can guarantee that the state of the neural network enters the feasible region in finite time and remains there thereafter. Moreover, the state with any initial point is shown to be convergent to the critical point set when the objective function is generally nonconvex. Especially, when the objective function is pseudoconvex (or convex), the state is proved to be globally convergent to an optimal solution of the considered optimization problem. Compared with other neural networks for related optimization problems, the proposed neural network in this paper has good convergence and does not depend on some additional assumptions, such as the assumption that the inequality feasible region is bounded, the assumption that the penalty parameter is sufficiently large and the assumption that the objective function is lower bounded over the equality feasible region. Finally, some numerical examples and an application in real-time data reconciliation are provided to display the well performance of the proposed neural network. PMID- 30419481 TI - Transcriptional shifts during juvenile Coho salmon (Oncorhynchus kisutch) life stage changes in freshwater and early marine environments. AB - There is a paucity of information on the physiological changes that occur over the course of salmon early marine migration. Here we aim to provide insight on juvenile Coho salmon (Oncorhynchus kisutch) physiology using the changes in gene expression (cGRASP 44K microarray) of four tissues (brain, gill, muscle, and liver) across the parr to smolt transition in freshwater and through the first eight months of ocean residence. We also examined transcriptome changes with body size as a covariate. The strongest shift in the transcriptome for brain, gill, and muscle occurred between summer and fall in the ocean, representing physiological changes that we speculate may be associated with migration preparation to feeding areas. Metabolic processes in the liver were positively associated with body length, generally consistent with enhanced feeding opportunities. However, a notable exception to this metabolic pattern was for spring post-smolts sampled soon after entry into the ocean, which showed a pattern of gene expression more likely associated with depressed feeding or recent fasting. Overall, this study has revealed life stages that may be the most critical developmentally (fall post-smolt) and for survival (spring post-smolt) in the early marine environment. These life stages may warrant further investigation. PMID- 30419482 TI - Transcriptional effects of dietary chlorpyrifos-methyl exposure in Atlantic salmon (Salmo salar) brain and liver. AB - Elevated levels of chlorpyrifos-methyl have been detected in plant-based Atlantic salmon feeds. To evaluate the potential negative effects of long-term and continuous dietary exposure to chlorpyrifos-methyl in fish, we fed juvenile Atlantic salmon three concentrations (0.1, 1.0 and 8.0 mg/kg) of the pesticide for about two months. Brain and liver tissues were collected after 30 and 67 days of exposure. Homogenized brain tissue was examined for effects on acetylcholinesterase, and brain and liver tissue from fish exposed to 8.0 mg/kg were used for transcriptional analysis (RNA-seq). The results showed a transient accumulation of chlorpyrifos-methyl in the brain with lower levels after 67 days of exposure compared to after 30 days of exposure. In contrast, the liver showed a time-dependent accumulation pattern. No effect on acetylcholinesterase activity, the primary target of chlorpyrifos-methyl, was seen in the brain. However, after 30 days of exposure, 98 significantly differentially expressed genes (DEGs) were found in brain tissue and 239 DEGs in liver tissue. After 67 days of exposure, two and 258 DEGs were found in brain and liver tissue, respectively. Continuous dietary exposure of chlorpyrifos-methyl most profoundly affected mechanisms associated with protein degradation and lipid metabolism in both brain and liver. Specific for the brain, many of the significant DEGs encode proteins involved in neuron function. In conclusion, this study shows that chlorpyrifos-methyl affects the transcription of genes involved in neurological function in Atlantic salmon brain, even at exposure concentrations below the threshold for systemic toxicity as seen from brain acetylcholinesterase inhibition. PMID- 30419483 TI - Quantifying appendicular muscle mass in geriatric inpatients: Performance of different single frequency BIA equations in comparison to dual X-ray absorptiometry. AB - BACKGROUND: Quantification of skeletal muscle mass is mandatory for diagnosing sarcopenia, a highly prevalent geriatric syndrome. While dual energy X-ray absorptiometry (DXA) is the reference method in a clinical context, bioimpedance analysis (BIA) is more readily applicable on a broad scale. Recently BIA equations for the prediction of appendicular skeletal muscle mass in higher age groups have been published, but data on their performance in geriatric inpatients are lacking. METHODS: In 144 geriatric inpatients (86 women and 58 men, mean age 80.7 +/- 5.6 years) appendicular skeletal muscle mass was predicted by 4 different BIA equations and measured by DXA. Results were compared by linear regression analysis and Bland Altmann plots. The agreement with DXA in classifying subjects to have normal or reduced muscle mass was calculated for the BIA based approaches. RESULTS: The 4 BIA equations showed only minor differences in regression analysis, but major differences in mean error (range -0.98 kg to + 0.19 kg in women and -2.47 kg to -0.58 kg in men). Considering regression parameters and mean error, the equation of Scafoglieri et al. performed best, resulting in an agreement with DXA of more than 83%. Sensitivity to detect subjects with reduced muscle mass was <70% in the whole group for all BIA equations. CONCLUSION: The BIA equation of Scafoglieri et al. performs best in geriatric inpatients, with more than 83% of subjects classified correctly as having normal or reduced muscle mass compared to DXA. Low sensitivity to detect subjects with reduced muscle mass in geriatric inpatients remains a limitation of BIA. PMID- 30419484 TI - Roles of functional strain and capsule compression on mandibular cyst expansion and cortication. AB - OBJECTIVE: Cyst expansion in bone involves bone resorption but is often accompanied by adjacent bone formation with cortication. The mechanisms for these two apparently opposite processes remain unclear. From a mechanobiological perspective, functional strain drives bone remodeling, which involves both bone apposition and resorption. In this study, we explore the role of functional strain in cyst growth. DESIGN: Using a three-dimensional finite element analysis model of a simulated cyst at the of right first mandibular molar mesial apex, we examined three loading conditions, representing biting on the right molar, left molar and incisors, respectively. Comparison was made with an identical finite element model without the simulated cyst. RESULTS: Under all loading conditions, finite element analysis revealed higher strain energy density within the bone lining the cyst compared with the non-cyst model, which is consistent with bone formation and cortication observed clinically. Further analysis demonstrated overall compression of the simulated cyst capsule under all loading conditions.We interpret compression of the capsule as indicating resorption of the adjacent bone surface. CONCLUSIONS: We conclude that functional stress results in dominant compression of the soft tissue capsules of bony cysts, contributing to cyst expansion. Also, functional strain becomes elevated in the bone immediately adjacent to the soft tissue cyst capsule, which may drive bone formation and cortication. PMID- 30419485 TI - Insulin-like growth factor-1 engaged in the mandibular condylar cartilage degeneration induced by experimental unilateral anterior crossbite. AB - OBJECTIVE: To investigate the changes in insulin-like growth factor-1 (IGF-1) expression levels in the degenerative mandibular condylar cartilage. DESIGN: Thirty-six rats were divided into the unilateral anterior crossbite and control groups. The expression levels of IGF-1; IGF-1 receptor (IGF-1R); IGF-binding protein-3 and -5 (IGFBP-3 and -5); proliferating cell nuclear antigen (PCNA); aggrecan; type-I, -II, -VI, and -X collagen; tissue inhibitor of metalloproteinases-1 and -3 (TIMP-1 and -3); metalloproteinases of matrix metalloproteinases-3 and-13 (MMP-3 and -13); a disintegrin and metalloproteinase thrombospondin-4 and -5 (ADAMTS-4 and -5); alkaline phosphatase (ALP); beta glucuronidase; and N-acetyl-beta-glucosaminidase in the mandibular condylar cartilage were assessed. RESULTS: The protein expression levels of IGF-1and IGF 1R were increased from week 4 in the unilateral anterior crossbite group. The mRNA expression level of IGFBP-3 and -5 was upregulated from week 4 and week 2, respectively; that of IGFBP-3 was downregulated at week 8; and that of PCNA, type II collagen, type-X collagen, aggrecan, TIMP-1, and TIMP-3 was downregulated, whereas that of MMP-3, MMP-13, ADAMTS-4, ADAMTS-5, beta-glucuronidase, and N acetyl-beta-glucosaminidase were upregulated from week 2. The positive area size of type-I collagen was increased and that of type VI collagen was decreased from week 2. The positive area size of type X collagen was increased at week 2 but decreased at week 8. The percentage of ALP-positive cells was increased from week 4. CONCLUSIONS: Unilateral anterior crossbite stimulated the multifarious expression of IGF-1 and IGFBP, which may be linked to chondrocyte proliferation and differentiation in the mandibular condylar cartilage that showed progressive degeneration. PMID- 30419486 TI - Deregulated phospholipase D2/mammalian target of rapamycin/hypoxia-inducible factor 1 alpha in peripheral T lymphocytes of oral lichen planus correlated with disease severity. AB - OBJECTIVE: Oral lichen planus (OLP) is a common T lymphocyte-mediated autoimmune disease of unknown etiology. The mammalian target of rapamycin (mTOR) can regulate proliferation, apoptosis, and autophagy of T lymphocytes, therefore impacting the T lymphocyte-mediated immunity. The present study was aimed to investigate the possible association between Akt/mTOR/4E-BP1 (eIF4E-binding protein 1) signaling, phospholipase D (PLD) and hypoxia-inducible factor 1 alpha (Hif-1alpha) in peripheral T lymphocytes of OLP and the correlation of their expression with the disease severity. DESIGN: RAE (reticular, atrophic and erosive lesion) scores were used to assess the disease severity of OLP. Akt, mTOR, 4E-BP1, PLD1, PLD2 and Hif-1alpha expression in peripheral T lymphocytes were measured by using quantitative real-time polymerase chain reaction. Associations of Akt/mTOR/4E-BP1 expression with PLD1, PLD2 and Hif-1alpha expression were also assessed, respectively. Moreover, correlations of their expression with RAE scores were analyzed. RESULTS: Expressions of mTOR, 4E-BP1, PLD2 and Hif-1alpha mRNA were significantly reduced in peripheral T lymphocytes of OLP patients, especially in erosive form. mTOR expression was positively correlated with PLD2 and Hif-1alpha expression in OLP. Moreover, mTOR, PLD2 and Hif-1alpha expression were negatively correlated with RAE scores, respectively. CONCLUSIONS: Deregulated PLD2/mTOR/Hif-1alpha may contribute to the development of OLP and reflect the severity of the disease. PMID- 30419487 TI - Activity of quercetin and kaemferol against Streptococcus mutans biofilm. AB - OBJECTIVE: Nidus Vespae (NV) is the honeycomb of Polistes Olivaceous, P. Japonicus Saussure, and Parapolybiavaria Fabricius. Previously, we have shown the extract and chemical fractions from NV demonstrated remarkable capacities of inhibiting the acid production of oral bacteria at sub-minimum inhibitory concentration (MIC) concentrations. In searching the most potent anti-caries compounds in NV, we further separated the NV Chl/MeOH fraction and obtained two purified compounds: quercetin and kaemferol. The objective of this study was to assess the effectiveness of quercetin and kaemferol against S. mutans biofilm formation. METHODS: The MIC, minimum biofilm inhibition concentration (MBIC50) and minimum biofilm reduction concentration (MBRC50) against Streptococcus mutans were examined for NV-derived of quercetin and kaemferol. The effectiveness of inhibiting S. mutans biofilm formation was further examined using in vitro biofilm model. RESULTS: Both quercetin and kaemferol compounds demonstrated anti biofilm activities when compared to the negative control. They are capable of reducing biofilm dry-weight, total protein, viable cells measured by colony forming unit (CFU), insoluble and soluble glucans formation. The in situ culture pH was less acidic when the biofilms were treated by quercetin and kaemferol. The quercetin and kaemferol demonstrated comparable capability of S. mutans killing in biofilms, compared to chlorhexidine. CONCLUSIONS: The results of this study showed inhibitory activity of quercetin and kaemferol against S. mutans biofilms, suggesting that quercetin and kaemferol might be considered as alternative anti caries agents in searching novel anti-caries therapeutics. PMID- 30419488 TI - Comparison of treatment options for depression in heart failure: A network meta analysis. AB - BACKGROUND: Depression independently predicts poor outcomes in heart failure (HF) patients, including increased mortality, morbidity and 30-day re-hospitalization. In this network meta-analysis, we compared different interventions designed to treat depression in HF. MATERIALS AND METHODS: Electronic searches were conducted using Ovid MEDLINE, EMBASE, CINAHL, Web of Science, and PsycINFO up to November 2016. Included randomized clinical trials (RCTs) compared interventions (Exercise therapy (ET), cognitive behavioral therapy (CBT) or antidepressant (AD) medications) for depression in heart failure patients. The primary outcome was change in depressive symptoms based on validated measures of depression. Network meta-analysis based on random effects model estimating standardized mean difference (SMD) with 95% confidence interval (CI), compared the effects of the 3 classes of interventions with respect to usual care or placebo control conditions. RESULTS: A total of 21 RCTs (including 4563 HF patients) reporting the effects of treating depression in HF patients were included in the analysis. In comparison to placebo or usual standard of care, ET (SMD -0.38; 95% CI -0.54 to -0.22) and CBT (SMD -0.29; 95% CI -0.58 to -0.01) were associated with reduction in depressive symptoms whereas AD (SMD -0.16; 95% CI -0.44 to 0.11) was less effective. CONCLUSIONS: This meta-analysis is suggestive of therapeutic benefit of ET and CBT in comparison to usual standard of care in treating depression in HF patients. However, comparison among the three interventions was not conclusive. Future randomized clinical trials are warranted to compare the therapeutic effects of ET, CBT and AD in such patients. PMID- 30419489 TI - Hypertension prevalence in early breast cancer patients undergoing primary surgery. AB - PURPOSE: Treatment with chemotherapy and targeted drugs may results in elevated risk of cardiac and renal toxicity as well as hypertension. However, data on prevalence of chronic kidney disease and hypertension in subjects with early breast cancer undergoing primary surgery are very limited. PATIENTS AND METHODS: The study aimed to assess the prevalence of chronic kidney disease and hypertension (evaluated as a preoperative assessment and defined according to ESC/ESH guidelines) in a cohort of 100 consecutive female patients with early breast cancer treated with primary surgery with curative intent. RESULTS: Patients with breast cancer were 53 +/- 14 years of age, with serum creatinine of 0.68 +/- 0.14 mg/dl and estimated glomerular filtration rate by chronic kidney disease-epidemiological collaboration formula of 99 +/- 18 mL/min/1.72 m2. Hypertension was present in 37%, but in the elderly patients (over 65 years) the prevalence was 74%. Hypertensive females had worse kidney function as reflected by higher serum creatinine and lower estimated glomerular filtration rate, higher body mass index and fibrinogen, which reflects general inflammatory state. When we divided the patients according to age (<= vs >65 years) and the presence of hypertension, the elderly hypertensive females had significantly worse kidney function, higher fibrinogen and fasting glucose. CONCLUSIONS: The prevalence of hypertension in patients with breast cancer raises with age, and presence of comorbidities, including chronic kidney disease. Hypertension should be treated promptly to prevent cardiovascular complications during oncological therapy. PMID- 30419490 TI - Hierarchical segmentation using equivalence test (HiSET): Application to DCE image sequences. AB - Dynamical contrast enhanced (DCE) imaging allows non invasive access to tissue micro-vascularization. It appears as a promising tool to build imaging biomarkers for diagnostic, prognosis or anti-angiogenesis treatment monitoring of cancer. However, quantitative analysis of DCE image sequences suffers from low signal to noise ratio (SNR). SNR may be improved by averaging functional information in a large region of interest when it is functionally homogeneous. We propose a novel method for automatic segmentation of DCE image sequences into functionally homogeneous regions, called DCE-HiSET. Using an observation model which depends on one parameter a and is justified a posteriori, DCE-HiSET is a hierarchical clustering algorithm. It uses the p-value of a multiple equivalence test as dissimilarity measure and consists of two steps. The first exploits the spatial neighborhood structure to reduce complexity and takes advantage of the regularity of anatomical features, while the second recovers (spatially) disconnected homogeneous structures at a larger (global) scale. Given a minimal expected homogeneity discrepancy for the multiple equivalence test, both steps stop automatically by controlling the Type I error. This provides an adaptive choice for the number of clusters. Assuming that the DCE image sequence is functionally piecewise constant with signals on each piece sufficiently separated, we prove that DCE-HiSET will retrieve the exact partition with high probability as soon as the number of images in the sequence is large enough. The minimal expected homogeneity discrepancy appears as the tuning parameter controlling the size of the segmentation. DCE-HiSET has been implemented in C++ for 2D and 3D image sequences with competitive speed. PMID- 30419491 TI - Translation, cross-cultural adaptation and psychometric properties of the Sleep Related Breathing Disordered-Pediatric Sleep Questionnaire for obese Thai children with obstructive sleep apnea. AB - OBJECTIVE: Obstructive sleep apnea (OSA) is a comorbid condition with obesity that can produce deleterious effects on children's health and well-being. Unfortunately, valid instruments for screening OSA in obese Thai children are limited. This study aimed to translate and cross-culturally adapt, from English to Thai, the Sleep-Related Breathing Disordered-Pediatric Sleep Questionnaire (SRBD-PSQ) and to determine its psychometric properties. METHODS: The SRBD-PSQ was translated into Thai and cross-culturally adapted. It was administered to 62 parents of obese children and adolescents 7-18 years of age who had polysomnographically confirmed OSA. The psychometric properties including validity, reliability, and diagnostic accuracy were examined. RESULTS: The Thai SRBD-PSQ possessed excellent content validity index for scale (S-CVI = 0.95). An acceptable internal consistency (cronbach's alpha >= 0.7) and good to excellent test-retest reliability (intraclass correlation coefficients [ICCs] = 0.82-0.90) of the Thai SRBD-PSQ and subdomain were observed. There was a significant correlation between the SRBD scale and polysomnography (PSG) indices: apnea hypopnea index (AHI) and oxygen desaturation index (ODI) (r = 0.35, p < 0.01, and r = 0.27, p < 0.05, respectively). The Thai SRBD-PSQ had an area under the curve of 0.71 (p < 0.05) with a sensitivity of 72% and a specificity of 54%. CONCLUSION: The Thai SRBD-PSQ is a reliable and valid instrument for use in obese children with OSA. However, the Thai SRBD-PSQ should be used in combination with other investigations. PMID- 30419492 TI - Synthesis of new ent-labdane diterpene derivatives from andrographolide and evaluation of their anti-inflammatory activities. AB - Two series of andrographolide derivatives with nitrogen-containing heterocycles, phenols and aromatic acids as bioisostere moiety of lactone ring were synthesized. 8 from 18 tested compounds showed stronger inhibitory effect on LPS induced NO production in RAW264.7 macrophage than hydrocortisone. Among them, compound 8m exhibited the most potent inhibition with IC50 of 3.38 +/- 1.03 MUM. The structure-activity relationships (SARs) suggested that the replacement of lactone ring with small-molecule phenols could improve the anti-inflammatory efficacy. Furthermore, compound 8m significantly reduced the levels of pro inflammatory cytokine IL-1beta and IL-6 with no influence on cell survival, decreased the expression of iNOS and COX-2, and down-regulated the level and phosphorylation of IkappaBalpha, as well as the expression of NF-kappaB. Also it blocked the nuclear translocation of NF-kappaB in LPS-induced macrophage. Therefore, the anti-inflammation mechanism of compound 8m was related to the inhibition of COX-2, iNOS and NF-kappaB signal pathway. PMID- 30419493 TI - Asymmetric synthesis and biological evaluation of imidazole- and oxazole containing synthetic lipoxin A4 mimetics (sLXms). AB - Lipoxins (LXs) are endogenously generated eicosanoids with potent bio-actions consistent with attenuation of inflammation. The costly synthesis and metabolic instability of LXs may limit their therapeutic potential. Here we report the synthesis and characterization of novel imidazole-/oxazole-containing synthetic LX-mimetics (sLXms). The key steps of asymmetric synthesis of putative sLXms include a Suzuki reaction and an asymmetric ketone reduction. The effect of the novel compounds on inflammatory responses was assessed using a human monocyte cell line stably expressing a Nuclear Factor Kappa B (NFkB) reporter gene, by investigating downstream cytokine secretion. The potential interaction of the imidazoles/oxazoles with the molecular target of LXs, i.e. G-protein coupled receptor (GPCR) Formyl Peptide Receptor 2 (ALX/FPR2) was investigated using a cell system where ALX/FPR2 is coupled to the Galphaq subunit and receptor interaction determined by mobilisation of intracellular calcium. In vivo anti inflammatory effects were assessed using a murine zymosan-induced peritonitis model. Overall, structure-activity relationship (SAR) studies demonstrated that the (R)-epimer of 6C-dimethyl-imidazole (1R)-11 was the most potent and efficient anti-inflammatory agent, among the ten compounds tested. This molecule significantly attenuated LPS-induced NFkB activity, reduced the release of several pro-inflammatory cytokines and inhibited peritonitis-associated neutrophil infiltration in vivo. The underlying mechanism for those actions appeared to be through FPR2 activation. These data support the therapeutic potential of imidazole-containing sLXms in the context of novel inflammatory regulators. PMID- 30419494 TI - Forensic microbiology applications: A systematic review. AB - According to the Human Microbiome Project (HMP), a healthy human body contains ten times more microbes than human cells. Microbial communities colonize different organs of the body, playing fundamental roles both in human health and disease. Despite the vast scientific knowledge of the role of microbial communities in a living body, little is known at present about microbial changes occurring after death, thus leading many authors to investigate the composition of the thanatomicrobiome and its potential applications in the forensic field. The aim of the following review is to provide a general overview of the advances of postmortem microbiology research, mainly focusing on the role of microbiological investigations carried out on internal organs and fluids. To this end, a total of 19 studies have been sistematically reviewed, each one chosen according to specific inclusion/exclusion criteria. The selected studies assess the contribution of contamination, postmortem transmigration and agonal spread to microbial isolation from dead body samples, and shed light on the role of postmortem microbiological investigations in several forensic fields, such as cause of death or PMI determination. PMID- 30419495 TI - The impact of Ethiopia's pilot community based health insurance scheme on healthcare utilization and cost of care. AB - In June 2011, the Government of Ethiopia introduced a pilot Community Based Health Insurance (CBHI) scheme in rural parts of the country. Based on a fixed effects analysis of household panel data, this paper assesses the impact of the scheme on utilization of modern healthcare and the cost of accessing healthcare. It adds to the relatively small body of work that provides a rigorous evaluation of CBHI schemes. We find that in the case of public health facilities, enrolment leads to a 30-41% increase in utilization of outpatient care, a 45-64% increase in the frequency of visits and at least a 56% decline in the cost per visit. The impact on utilization and costs combined with a high uptake rate of almost 50% within two years of scheme establishment underlines the relative success of the Ethiopian scheme. While there are several reasons for this success, a comparative analysis of the design and execution of the Ethiopia CBHI with the existing body of work yields two distinct features. First, the Ethiopian scheme is embedded within existing government administrative structures and to signal government commitment, scheme performance and uptake is used as a yardstick to measure the success of the administration. Second, an existing social protection scheme was used to spread information, raise scheme awareness and encourage uptake of health insurance. The alignment of the interests of administrators with scheme performance and interlinking of social protection schemes are innovative design features that are worth considering as developing countries strive to enhance access to health care through voluntary insurance schemes. PMID- 30419496 TI - The effect of school sports facilities on physical activity, health and socioeconomic status in adulthood. AB - This paper focuses on the long-term impacts of attending a high school with inadequate sports facilities. We use prospective data from the British National Child Development Study, a continuing panel of a cohort of 17,634 children born in Great Britain during a single week of March 1958. Our empirical approach exploits the educational system they were exposed to: children were sorted by educational ability at age 11, but conditional on educational ability, attended their closest school. This produces quasi-random variation in the quality of the school sports facilities across respondents. We use this variation between cohort members residing within the same local authority area, and focus on outcome measures of physical activity, health, health-related lifestyle activities, and socioeconomic status, collected at ages between 33 and 50 years. We control for any potential links between the inadequacy of sports facilities and inadequacy of other facility types, and test that allocation to school type is random with respect to pre-high school observables. We find that attending a school with inadequate sports facilities led to a statistically significant, modest decrease in the likelihood of physical activity participation during adulthood. In contrast, we find no evidence that inadequate sports facilities worsened adulthood measures of physical and mental health, lifestyle or socioeconomic status. PMID- 30419497 TI - Synthesis and carbonic anhydrase inhibitory properties of novel 4-(2 aminoethyl)benzenesulfonamide-dipeptide conjugates. AB - Thirty novel sulfonamide derivatives incorporating dipeptide were synthesized by facile acylation through benzotriazole mediated reactions and their structures were identified by 1H NMR, 13C NMR, MS and FT-IR spectroscopic techniques and elemental analysis. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was assessed against four human (h) isoforms, hCA I, hCA II, hCA IV and hCA XII. Most of the synthesized compounds showed excellent in vitro carbonic anhydrase inhibitory properties comparable to those of the clinically used drug acetazolamide (AAZ). The new unprotected dipeptide-sulfonamide conjugates showed very effective inhibitory activity, in the low nanomolar range against II and XII, being less effective as hCA I and IV inhibitors. Four of the thirty compounds also showed strong inhibitory activity against hCA XII compared to AAZ. PMID- 30419498 TI - Effects of cholecalciferol supplementation on inflammatory markers and muscle damage indices of soccer players after a simulated soccer match. AB - OBJECTIVES: Soccer-induced muscle damage and inflammation lead to a reduction in athletic performance. The aim of this study was to determine whether supplementation with cholecalciferol would reduce inflammation and muscle damage in soccer players after a simulated soccer match. METHODS: Twenty-two soccer players (median age 27 y, interquartile range 5 y) were divided randomly into two groups, as follows: a cholecalciferol group (n = 11) and a placebo group (n = 11). Cholecalciferol supplements (50 000 IU/wk) or placebos were administered to the groups by an independent co-worker. After 8 wk, the athletes participated in a simulated soccer match, and perceived exertion and heart rates were measured during the trial. Blood samples were obtained presupplementation, postsupplementation, immediately after, and 2- and 24-h postexercise for measurement of lactate dehydrogenase, creatine phosphokinase, C-reactive protein (CRP), and interleukin (IL)-6. RESULTS: The intervention group demonstrated a significant increase in serum 25-hydroxyvitamin D levels (53.93, 10.68 ng/mL, P < 0.0001), which is the best indicator of vitamin D levels in the body, with no change in the circulating markers of muscle damage and CRP (P ? 0.05) but showed increased IL-6 (P = 0.034). In addition, the ratings of perceived exertion and heart rates were not altered by vitamin D compared with placebo ingestion (P = 0.155 versus P = 0.261; P = 0.600 versus P = 0.983). CONCLUSION: The study showed that 50 000 IU/wk of cholecalciferol supplementation for 8 wk increased the 25 hydroxyvitamin D levels, with no effect on muscle damage indices or CRP. However, The IL-6 concentration was generally higher in the intervention group. PMID- 30419499 TI - Methods for data analysis of resting energy expenditure measured using indirect calorimetry. AB - OBJECTIVES: The aim of this study was to test the accuracy of different methods of resting energy expenditure (REE) data analysis using indirect calorimetry (IC) during traditional (30 min) and abbreviated (10 min) protocols. METHODS: Fifteen women and 15 men (21-34 y of age) completed two consecutive 30-min IC measurements. Body composition was measured using dual-energy x-ray absorptiometry. The reference method for REE analysis was 5 min in steady state (SS) during 30 min (first 5 min discarded). REE measurements were randomized to define a reference or testing method. An interval method was defined using 25, 20, and 15 min (with first 5, 10, and 15 min discarded, respectively), during 30 min, and 5 min (first 5 min discarded) during 10-min intervals. The SS method was defined using 5 min in SS (first 5 min discarded) during 30 min, 5, 4, and 3 min in SS during 10-min (first 5 min discarded) intervals. RESULTS: Interval methods during 30 min and SS and interval methods during 10 min demonstrated large bias with significantly high REEs compared to the reference method (78.8-109.0 kcal/d, all P < 0.001). Testing methods demonstrated large upper limits of agreement between 225.2 and 322.8 kcal/d. No mean differences (P > 0.05), small bias (14.3 kcal/d), and narrow limits of agreement (-125.8 to 154.4 kcal/d) were observed between 5-min SS during 30 min and the reference method. CONCLUSIONS: All interval methods and SS methods during 10 min overestimated REE. We recommend using 5-min SS during 30 min. The measurement may be repeated until all participants achieve SS. PMID- 30419500 TI - Body composition evaluation with computed tomography: Contrast media and slice thickness cause methodological errors. AB - OBJECTIVE: Although computed tomography (CT) is frequently used to determine body composition, the effects of using different CT protocols is not well known. The aim of this study was to determine whether contrast media phase, radiation dose, and slice thickness in CT affect body composition segmentation. METHODS: Clinically indicated perfusion CTs of the upper abdomen in 20 patients (seven women) between 40 and 87 y of age with high suspicion of hepatocellular carcinoma were analyzed retrospectively. Axial images from the L3 level with varying imaging delay were reconstructed after contrast media injection (18 images per patient), slice thickness (5 images, 2-10 mm), and radiation dose (4 images with one-third to four-thirds of standard dose). Muscle and fat areas were segmented semiautomatically by drawing regions of interests and using established cutoff thresholds. Skeletal muscle index (SMI), steatotic muscle area, and adipose tissue index, as well as muscle attenuation and fat attenuation, were evaluated. RESULTS: Average SMI increased by up to 2.8% after contrast media injection. Steatotic muscle area decreased by <=13.8%, and adipose tissue index decreased by <=6.5%. Muscle attenuation increased after contrast media injection, whereas fat attenuation decreased (all P < 0.001). SMI decreased by 1.9% on average when increasing slice thickness from 2 to 10 mm. Steatotic muscle area increased by <=3.3%, and adipose tissue index increased by <=1.5% (all P < 0.05). Muscle attenuation did not change significantly with reconstruction thickness. Radiation dose had no effect on estimated area of spinal muscle, fatty spinal muscle, or visceral fat. CONCLUSIONS: Contrast media have a strong effect on the evaluation of body composition, whereas the influence of slice thickness is less pronounced. Radiation dose can be reduced by >=66% without significantly affecting segmentation. PMID- 30419501 TI - Current evidence on omega-3 fatty acids in enteral nutrition in the critically ill: A systematic review and meta-analysis. AB - Fish oil exerts anti-inflammatory and immunomodulatory properties that may be beneficial for critically ill patients, thus multiple randomized controlled trials and meta-analyses have been performed. However, controversy remains as to whether fish oil-enriched enteral nutrition can improve clinical outcomes in adult critically ill patients in intensive care units (ICUs). The aim of this study was to provide an up-to-date systematic review and meta-analysis of all randomized controlled trials of fish oil-containing enteral nutrition addressing relevant clinical outcomes in critically ill patients. A systematic literature search was conducted. The primary outcome was 28-d mortality. Secondary outcomes were ICU and hospital mortality, ICU and hospital length of stay (LOS), ventilation duration, and infectious complications. Predefined subgroup and sensitivity analyses were performed. Twenty-four trials, enrolling 3574 patients, met the inclusion criteria. The assessment of risk for bias showed that most of included studies were of moderate quality. The overall results revealed no significant effects of enteral fish oil supplementation on 28-d, ICU or hospital mortality. However, ICU LOS and ventilation duration were significantly reduced in patients receiving fish oil supplementation. Furthermore, subgroup analysis revealed a significant reduction in 28-d mortality, ICU LOS, and ventilation duration in patients with acute respiratory distress syndrome but not in other subgroups. When comparing high- and low-quality trials, significant reductions in 28-d mortality and ventilation duration in low-quality trials only were observed. Regarding ICU LOS a significant reduction was observed in high-quality trials; whereas only a trend was observed in low-quality trials. No significant effects on hospital LOS or infectious complications were observed in overall or subgroup analyses. Enteral fish oil supplementation cannot be recommended for critically ill patients, as strong scientific evidence for improved clinical benefits was not found. There is a signal of mortality benefit in patients with acute respiratory distress syndrome; however, results are based on low-quality studies. Further research should focus on the relation between the individual critically ill patients' immune response, the administration of fish oil, and clinical outcomes. PMID- 30419502 TI - The electrodiagnosis of Guillain-Barre syndrome subtypes: Where do we stand? AB - It is controversial as to whether the electrophysiological Guillain-Barre syndrome (GBS) subtypes can be diagnosed on the basis of a single study and which criteria sets and cut-offs should be used. Serial electrophysiologic studies have shown that a significant number of patients changed electrodiagnostic subtype largely because of the recognition of reversible conduction failure as a possible evidence of axonal pathology. However, other reports concluded that electrodiagnosis can be made by a single study, the subtypes depending on the characteristic of the criteria set applied. Such divergent views, although explicable by the different methodology employed, can be confusing in the everyday practice. We argue that the pathophysiology of GBS is dynamic and that serial studies allow a more accurate diagnosis of subtypes. A second study, although not always practicable, is recommended in patients showing no clear demyelinating features, low amplitude distal compound muscle action potentials or conduction block without temporal dispersion. For practical purposes, we propose that at a first study Uncini's or Rajabally's criteria sets can be employed for an indicative subtype diagnosis. Finally, although the GBS subtype diagnosis has currently no impact on treatment, we believe that is important for understanding the underlying pathophysiology and prognostication. PMID- 30419503 TI - Intestinal Snakeskin Limits Microbial Dysbiosis during Aging and Promotes Longevity. AB - Intestinal barrier dysfunction is an evolutionarily conserved hallmark of aging, which has been linked to microbial dysbiosis, altered expression of occluding junction proteins, and impending mortality. However, the interplay between intestinal junction proteins, age-onset dysbiosis, and lifespan determination remains unclear. Here, we show that altered expression of Snakeskin (Ssk), a septate junction-specific protein, can modulate intestinal homeostasis, microbial dynamics, immune activity, and lifespan in Drosophila. Loss of Ssk leads to rapid and reversible intestinal barrier dysfunction, altered gut morphology, dysbiosis, and dramatically reduced lifespan. Remarkably, restoration of Ssk expression in flies showing intestinal barrier dysfunction rescues each of these phenotypes previously linked to aging. Intestinal up-regulation of Ssk protects against microbial translocation following oral infection with pathogenic bacteria. Furthermore, intestinal up-regulation of Ssk improves intestinal barrier function during aging, limits dysbiosis, and extends lifespan. Our findings indicate that intestinal occluding junctions may represent prolongevity targets in mammals. PMID- 30419504 TI - Pergola: Boosting Visualization and Analysis of Longitudinal Data by Unlocking Genomic Analysis Tools. AB - The growing appetite of behavioral neuroscience for automated data production is prompting the need for new computational standards allowing improved interoperability, reproducibility, and shareability. We show here how these issues can be solved by repurposing existing genomic formats whose structure perfectly supports the handling of time series. This allows existing genomic analysis and visualization tools to be deployed onto behavioral data. As a proof of principle, we implemented the conversion procedure in Pergola, an open source software, and used genomics tools to reproduce results obtained in mouse, fly, and worm. We also show how common genomics techniques such as principal component analysis, hidden Markov modeling, and volcano plots can be deployed on the reformatted behavioral data. These analyses are easy to share because they depend on the scripting of public software. They are also easy to reproduce thanks to their integration within Nextflow, a workflow manager using containerized software. PMID- 30419505 TI - Nostoc entophytum cell response to cadmium exposure: A possible role of chaperon proteins GroEl and HtpG in cadmium-induced stress. AB - The present study is pursuing our previous research, focused on some aspects of Nostoc entophytum ISC32 cell response to the stress caused by exposure to cadmium at the cellular and molecular levels. Variations in the antioxidant system (catalase and ascorbate peroxidase activity) of N. entophytum ISC32 exposed to varying concentrations of Cd (2, and 5 mg/L) resulted in a significant increase in the activity of both catalase and peroxidase. Activity of these enzymes was, however, not significantly changed in the presence of Cd concentrations of 10 and 20 mg/L. Levels of lipid peroxidation, as measured by malondialdehyde (MDA) assay, were observed in response to exposure to Cd (20 mg/L). There was, however, a sharp drop in both antioxidant and lipid peroxidation activities of Cd treated cells after 5 days exposure, likely in consequence of cellular damage. The content of chlorophyll a and phycobiliproteins of living cells were altered under Cd-induced conditions. TEM images of cyanobacterial cells treated with Cd showed cell surface alteration and modification along with altered cellular microcompartments. Cyanobacterial cells treated with Cd at concentrations below the minimum inhibitory concentration (MIC) remained with no apparent structural changes. However, at a higher concentration of Cd (30 mg/L), a clear detachment effect was observed between the mucilage external layer and cell membrane which may be attributed to cell plasmolysis due to toxic effects of Cd. Subsequently, the thickness of the ring-shaped mucilage external layer increased likely as a result of the cell defense mechanisms against toxic concentrations of Cd. Characterization of cells treated with Cd (30 and 150 mg/L) by scanning electron microscopy (SEM) indicated cell shrinkage with varying degrees of distortion and surface wrinkling. Energy-dispersive X-ray spectrometry (EDS) analysis suggested that Cd was not present as nanoparticles within the cell, but in the form of salt or other molecular structures. The up-regulation of chaperons was confirmed for GroEL and HtpG using real-time PCR and northern blot analyses. Interestingly, the expression of GroEL was markedly increased at lower Cd concentration (5 mg/L). However, the ISC32 strain accrued higher levels of HtpG transcript in response to an elevated concentration of Cd (15 mg/L). This pattern seems to be related to the fast and early induction of GroEL, which may be necessary for induction of other factors and heat shock proteins such as HtpG in Cd-treated Nostoc cells. The result of this study paves the way for a more detailed exploration of Cd effects on the defense mechanisms of cyanobacteria. Our research also shed some light on how cyanobacterial cells have evolved to respond to the heavy metal toxicity at the cellular, molecular and ultrastructural levels. PMID- 30419506 TI - Integrative moringa and licorice extracts application improves Capsicum annuum fruit yield and declines its contaminant contents on a heavy metals-contaminated saline soil. AB - Green approaches for improving plant performance using natural supplementations are highly seeking. Following a preliminary study conducted on contaminated saline (EC = 7.75 dS m-1) and normal (EC = 1.4 dS m-1) soils, two main field trials were conducted to study the potential effects of licorice root (LRE; 0.5%) and moringa seed (MSE; 0.5%) extracts, supplemented to soil through irrigation water (SA) and/or as foliar spray (FS), on performance, physio-biochemical components, antioxidant defense system, and contaminants contents of Capsicum annuum plants grown on heavy metals-contaminated saline soil. Both extracts were applied in single treatments such as LRE-SA, MSE-SA, LRE-FS, and MSE-FS or in integrations like LRE-SA+LRE-FS, LRE-SA+MSE-FS, MSE-SA+LRE-FS, and MSE-SA+MSE-FS. The preliminary study results showed significant reductions in plant performance (growth and yield), chlorophylls content and significant increase in Cd content due to heavy metals and salt stress. However, LRE and MSE applied singly or in combinations positively modified these parameters compared to the control (SA and FS were applied with tap water). On the other hand, these parameters were not responded to LRE and/or MSE applications on the normal soil. The main studies results showed that all single or integrative treatments significantly increased plant growth and yield, leaf contents of leaf photosynthetic pigments, free proline, total soluble sugars, N, P, and K+, ratio of K+/Na+, and activities of CAT, POX, APX, SOD, and GR. In contrast, contaminants; Na+, Cd, Cu, Pb and Ni contents in plant leaves and fruits were significantly reduced on heavy metals contaminated saline soil compared to the control. Additionally, all integrative treatments significantly exceeded all single treatments in this concern. The integrative MSE-SA+LRE-FS was the best treatment that is recommended to be used to maximize pepper plant performances and minimize plant contaminant contents on contaminated saline soils. PMID- 30419507 TI - Effects of cypermethrin (pyrethroid), glyphosate and chlorpyrifos (organophosphorus) on the endocrine and immune system of Salvator merianae (Argentine tegu). AB - Several geographical areas where Salvator merianae is distributed in Argentina are included in regions with agricultural activity and exposed to pesticide formulations. Some pesticides could affect defense mechanisms being able alter structures of some components of immune and endocrine systems. To assess the potential effects of pesticides in this reptile under seminatural conditions, on the immune system and endocrine responses in S. merianae we analyzed several blood parameters. Total (TWBCC), differential (DWBCC) white blood cells count, heterophils/lymphocytes index (H/L), lobularity index (LI), natural antibodies (NAbs) titres, complement system (CS), and corticosterone concentration were analyzed in animals exposed to a mixture of cypermethrin (25%), glyphosate (66.2%) and chlorpyrifos (48%) formulations. In addition, body size was considered in these analyzes. TWBCC and NAbs revealed lower values in organisms exposed to pesticides respect to a control indicating a possible immunosuppression effect. Besides, the LI showed a greater number of lobes in organism exposed demonstrating symptoms of chronic infection. In addition, we observed a reduced growth in these animals possibly related to a less energy investment in body mass to maintain an active defense against pesticides. Finally, we found high levels of plasma corticosterone in animals exposed to mix formulation that could demonstrate neuroendocrine axis activation. Other parameters like DWBCC, H/L index and activity of CS showed no differences in treated animals respect to control group, which could indicate low sensibility of these parameters to the concentration of pesticides used. Our results provide evidence of the toxic effects of pesticides on different immune system parameters, but also a trade-off among these parameters, corticosterone levels and growth. In this way, we can conclude that the formulated pesticides applied widely and constantly in the areas occupied by S. merianae, would be affecting its immune and endocrine systems and therefore its ability to defend against external agents. This kind of studies is of great interest to know the possible responses of wild species to anthropogenic disturbances such as pesticide contamination. PMID- 30419508 TI - A model for discovering 'containment' relations. AB - Rapid developments in the fields of learning and object recognition have been obtained by successfully developing and using methods for learning from a large number of labeled image examples. However, such current methods cannot explain infants' learning of new concepts based on their visual experience, in particular, the ability to learn complex concepts without external guidance, as well as the natural order in which related concepts are acquired. A remarkable example of early visual learning is the category of 'containers' and the notion of 'containment'. Surprisingly, this is one of the earliest spatial relations to be learned, starting already around 3 month of age, and preceding other common relations (e.g., 'support', 'in-between'). In this work we present a model, which explains infants' capacity of learning 'containment' and related concepts by 'just looking', together with their empirical development trajectory. Learning occurs in the model fast and without external guidance, relying only on perceptual processes that are present in the first months of life. Instead of labeled training examples, the system provides its own internal supervision to guide the learning process. We show how the detection of so-called 'paradoxical occlusion' provides natural internal supervision, which guides the system to gradually acquire a range of useful containment-related concepts. Similar mechanisms of using implicit internal supervision can have broad application in other cognitive domains as well as artificial intelligent systems, because they alleviate the need for supplying extensive external supervision, and because they can guide the learning process to extract concepts that are meaningful to the observer, even if they are not by themselves obvious, or salient in the input. PMID- 30419509 TI - Impact of early diagnosis on clinical characteristics of an Italian sample of people with multiple sclerosis recruited online. AB - BACKGROUND: In order to anticipate the diagnosis of Multiple Sclerosis (MS), the diagnostic criteria had been reviewed several times in the last years. OBJECTIVE: We wanted to understand whether earlier diagnoses of MS have impacted on therapeutic management of the disease. METHODS: We designed a 22-item survey posted on SMsocialnetwork, a webplatform with a medical supervision, dedicated to Italian MS patients. We collected socio-demographic data, disease and treatment related information of 1000 patients. RESULTS: The median age at diagnosis significantly decreased over years. In the last decades the time delay between disease onset and diagnosis reduced, the disease phenotypes at diagnosis shifted from progressive form to relapsing ones and clinically isolated syndrome, the number of early treated patients increased over time. CONCLUSION: We showed, verifying a large sample of patients in a reallife setting, that the improvement of the diagnostic process allowed the anticipation of MS diagnosis over years and had a huge impact in terms of treatment approach. PMID- 30419510 TI - Treating the ineligible: Disease modification in people with multiple sclerosis beyond NHS England commissioning policies. AB - BACKGROUND: Whilst there is a broad selection of drugs licensed as disease modifying treatments (DMTs) for people with relapsing multiple sclerosis (pwRMS), access to DMTs remains restricted, particularly for people with progressive MS (pwPMS). Cladribine has shown efficacy at all stages of MS. Following withdrawal from the market of oral cladribine in 2011, partly due to issues associated with lymphopenia, and following a thorough risk assessment, we started using subcutaneously injected cladribine (Litak(r)) to treat both pwRMS and pwPMS. Here, we report on the real life safety and tolerability of this treatment option. METHODS: Cladribine was offered to (i) pwRMS as a choice despite fulfilling NHS England (NHSE) criteria for licensed DMTs, and (ii) pwRMS and pwPMS not eligible for NHSE approved DMTs. To avoid lymphocyte depletion lower than 0.5 * 109/l (WHO grade 2) cladribine was administered using a personalised dosing scheme (30-40 mg in week 1; and another 0-30 mg in week 5 pending total lymphocyte count at week 4). Anti-viral prophylaxis was given from day 1 for 60 days. Patients approaching week 48 were given a second treatment cycle. Data collection included side effects, relapses, change in disability and MRI indices. RESULTS: Seventy-one pwMS (40 female, 31 male; 36 RMS, 35 PMS,) received at least one treatment cycle. Mean age for starting cladribine was 44 years (range 22-72 years), median EDSS was 5 (range 1-8.5). Maximum follow-up was 28 months. 35/71 pwMS were followed up for at least 20 weeks. These patients had a median EDSS of 5.0 (range 1.0-7.5) at baseline and 5.5 (range 1.0-8.0) after a mean follow-up of 11 months (range 5-28). Cladribine was well tolerated with very few treatment related adverse events observed. Personalised dosing led to grade 1-2 lymphopenia in 50% of cases. A single patient developed transient grade 3 lymphopenia. No cases of varicella or other infections were observed. Four/17 people with relapsing MS, experienced a total of six relapses during a mean follow-up of 13 months (range 5-28 months). In people with PMS (n = 18) median EDSS was 5.5 (2.0 7.5) at baseline and 6.0 (2.5-7.5) after a median of 10 months (range 5-18). In pwPMS MRI showed that 25% had active scans at baseline, and 0% at follow-up. CONCLUSION: Personalised dosing of cladribine avoided severe lymphopenia in all but one patients and was very well tolerated across a large spectrum of disease severity. Our data suggests cladribine may offer benefit people with relapsing and progressive MS alike. The personalised protocol used appears safe, however warrants controlled studies to more definitively assess efficacy and safety, particularly in groups of pwMS who are not eligible for licensed DMT including oral cladribine (Mavenclad(r)). PMID- 30419511 TI - Disruption of blood-brain barrier integrity associated with brain lesions in Chinese neuromyelitis optica spectrum disorder patients. AB - OBJECTIVE: The aims of this study were to report brain characteristic abnormalities and to evaluate the relationship of blood-brain barrier (BBB) disruption and brain lesions in Chinese patients with NMOSD. METHODS: Brain magnetic resonance imaging characteristics and cerebrospinal fluid (CSF) laboratory tests of 121 patients with NMOSD at acute attack were reviewed retrospectively. Qalb (CSF albumin/serum albumin) was used for assessment of disruption of BBB. RESULTS: Brain MRI abnormalities were observed in 36.4% (44/121) of the NMOSD patients. Thirty patients (25%) showed typical-NMOSD abnormalities, including dorsal medulla lesions (n = 16, 13.2%), brainstem/cerebellum (n = 11, 9.1%), thalamus/hypothalamus (n = 3, 2.5%), periventricular white matter lesions (n = 4, 3.3%) hemispheric white matter (n = 4, 3.3%). Twenty-five patients (20.7%) had nonspecific lesions. Compared to the NMOSD patients without brain lesion, the proportion of patients who had abnormal BBB permeability was significantly higher in the abnormal brain MRI group (47.7% vs. 27.3%, P < 0.05). BBB permeability was not correlated to distribution of brain lesions or enhancement lesions. Qalb was associated with higher Expanded Disability Status Scale scores (r = 0.689, P < 0.05). CONCLUSIONS: Brain lesions are common in NMOSD patients. Marker of BBB permeability is associated with brain lesion and EDSS scores of NMOSD. PMID- 30419512 TI - Manual wheelchair users gradually face fewer postural stability and control challenges with increasing rolling resistance while maintaining a rear-wheel wheelie. AB - Teaching manual wheelchair users to perform wheelies using various rolling resistances is expected to facilitate learning of this advanced wheelchair skill. However, limited scientific evidence is available to support this approach. This study aimed to measure and compare postural stability and control requirements when maintaining a stationary wheelie on different rolling resistances. Eighteen manual wheelchair users with a spinal cord injury performed in a random order and maintained four 30-second wheelies on four rolling resistances: natural hard floor (NAT), 5-cm thick soft foam (LOW), 5-cm thick memory foam (MOD), and rear wheels blocked by wooden blocks (HIGH). All wheelies were performed over a large instrumented force plate to continuously record the center of pressure (CoP). To quantify postural stability, resultant and directional time- and frequency-domain CoP measures were computed and compared across all four rolling resistances. All resultant time-domain measures confirmed increased postural stability from NAT to LOW and from MOD to HIGH rolling resistances. Most time-domain measures confirmed a shift in postural control from an anticipatory to a predominantly compensatory strategy, accompanied by increased reliance on proprioceptive feedback, especially from NAT to LOW and from MOD to HIGH rolling resistances. Postural stability gradually increased with various rolling resistances while maintaining a stationary wheelie, whereas the postural control strategy shifted from an anticipatory to a reactive strategy. Blocking the rear wheels is recommended when first teaching this advanced wheelchair skill. Rapid progression on foam and natural surfaces is advocated to refine learning and enhance proper postural control strategies. PMID- 30419513 TI - Understanding cutting maneuvers - The mechanical consequence of preparatory strategies and foot strike pattern. AB - OBJECTIVES: This study investigated the relation of different previously reported preparatory strategies and musculo-skeletal loading during fast preplanned 90 degrees cutting maneuvers (CM). The aim was to increase the understanding of the connection between whole body orientation, preparatory actions and the solution strategy to fulfil the requirements of a CM. METHODS: Three consecutive steps of anticipated 90 degrees CMs were investigated in a 3D movement analysis setup. Pelvis orientation clustered the subjects in two groups, with minor and major pre orientation. To understand the impact of body orientation on the specific movement strategy, joint angles, moments and energy as well as spatio-temporal parameters of the movement were analysed. RESULTS: Early rotation of the body was initiated by a small step width during braking resulting in a more constant path velocity of the centre of mass and less demands on the hip- and knee surrounding muscles. Minor pre-orientation required increased work of the hip muscles to decelerate, reaccelerate and in particular to rotate the body. This resulted in an increase of contact time. While pre-orientation in combination with fore-foot striking led to a strategy where energy absorption and generation is mainly generated by the ankle plantar flexors, less pre-orientation and rear-foot striking resulted in a knee- and hip dominant strategy. CONCLUSION: Step width before transition strongly determined pre-orientation and overall body position. Both strategies fulfil the requirements of a CM but induce different demands regarding muscular capacities. Pelvis orientation and step width are easy-to-use assessment parameters in the practical field. PMID- 30419514 TI - Motor learning in children with developmental coordination disorder: The role of focus of attention and working memory. AB - Effective motor learning paradigms are essential for children with motor difficulties to enhance their motor skills and facilitate performance in physical activities and in daily life. This study aimed to examine the effect of feedback with an internal or external focus of attention on motor learning of children with probable Developmental Coordination Disorder (pDCD). In addition, the role of working memory capacity was examined. Children were recruited via physical therapists, who integrated the experimental procedures within therapy sessions. We analyzed data of 25 children between 5 and 11 years old. They practiced a novel motor task of throwing a 'slingerball' over three weeks, while receiving feedback with an internal or external focus of attention. Results showed that children improved throwing accuracy regardless of the type of feedback they received. Visuospatial working memory capacity enhanced learning, especially for children receiving feedback with an external focus of attention. These findings corroborate clinical recommendations stating that children with DCD benefit from task specific training and feedback, which is promoted with both foci of attention. However, the findings contrast the expected benefits of practice with an external focus of attention. It highlights that the exact mechanisms and task constraints that influence the learning processes with an internal and external focus among children are not yet understood and warrant further study. PMID- 30419515 TI - Peroxisome proliferator-activated receptor gamma coactivator family members competitively regulate hepatitis b virus biosynthesis. AB - Transcriptional coactivators represent critical components of the transcriptional pre-initiation complex and are required for efficient gene activation. Members of the peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1) family differentially regulate hepatitis b virus (HBV) biosynthesis. Whereas PGC1alpha has been shown to be a potent activator of HBV biosynthesis, PGC1beta only very poorly activates HBV RNA and DNA synthesis in human hepatoma (HepG2) and embryonic kidney (HEK293T) cells. Furthermore, PGC1beta inhibits PGC1alpha mediated HBV biosynthesis. These observations suggest that a potential competition between human hepatoma (HepG2) and embryonic kidney (HEK293T) cells PGC1alpha and PGC1beta for common transcription factor target(s) may regulate HBV transcription and replication in a context and signal transduction pathway dependent manner. PMID- 30419516 TI - From next generation sequencing to now generation sequencing in forensics. AB - In contrast to genetic diagnostic disciplines such as Oncogenetics and Cinical Genetics, where worldwide, since 2010, tens of thousands of DNA samples are routinely screened annually using either targeted genome sequencing or whole genome sequencing using massively parallel sequencing (MPS), the forensic use of MPS is still far from being a routine diagnostic tool. This perspectives focusses on issues that are essential in order to fully understand (i) why MPS of short tandem repeats (STRs) is very different from the capillary electrophoresis (CE) based genotyping of STRs, (ii) what we, DNA experts, should know before explaining MPS-based evidence in court, and (iii) what information should be present in a forensic investigation report that is MPS-based. Here one has to keep in mind that the forensic use of CE was first introduced in 1992-1993 and that it took some time to fully appreciate all intricacies. Obviously, I might be biased in my opinion, having worked on this topic since 2008, but I sincerely hope that MPS will soon be widely accepted and used because, especially in case of mixed-source DNA samples, MPS is much better in the deconvolution of the individual contributors and invariably reveals genetic information that cannot be inferred otherwise. PMID- 30419517 TI - The generalisability of artificial neural networks used to classify electrophoretic data produced under different conditions. AB - Previous work has shown that artificial neural networks can be used to classify signal in an electropherogram into categories that have interpretational meaning (such as allele, baseline, pull-up or stutter). The previous work trained the neural networks on a single data type, produced under a single laboratory condition and applied it to data that was matched in these factors. In this work we investigate the ability of neural networks to be trained on data of different types (i.e. single sourced profiles or mixed DNA profiles) and from different laboratory conditions (specifically the model of electrophoresis instrument) to determine whether a set of neural networks is required for each different type of data produced or whether a single neural network can be used for a broad range of data and still achieve the same level of performance. The results of our study have implications as to how a laboratory would choose to train and apply neural networks to classify data in electropherograms produced in their laboratory. PMID- 30419518 TI - Rapidly mutating Y-STRs in rapidly expanding populations: Discrimination power of the Yfiler Plus multiplex in northern Africa. AB - The male-specific northern African genetic pool is characterised by a high frequency of the E-M81 haplogroup, which expanded in very recent times (2-3 kiloyears ago). As a consequence of their recent coalescence, E-M81 chromosomes often cannot be completely distinguished on the basis of their Y-STR profiles, unless rapidly-mutating Y-STRs (RM Y-STRs) are analysed. In this study, we used the Yfiler(r) Plus kit, which includes 7 RM Y-STRs and 20 standard Y-STR, to analyse 477 unrelated males coming from 11 northern African populations sampled from Morocco, Algeria, Libya and Egypt. The Y chromosomes were assigned to monophyletic lineages after the analysis of 72 stable biallelic polymorphisms and, as expected, we found a high proportion of E-M81 subjects (about 46%), with frequencies decreasing from west to east. We found low intra-population diversity indexes, in particular in the populations that experienced long-term isolation. The AMOVA analysis showed significant differences between the countries and between most of the 11 populations, with a rough differentiation between northwestern Africa and northeastern Africa, where the Egyptians Berbers from Siwa represented an outlier population. The comparison between the Yfiler(r) and the Yfiler(r) Plus network of the E-M81 Y chromosomes confirmed the high power of discrimination of the latter kit, thanks to higher variability of the RM Y-STRs: indeed, the number of chromosomes sharing the same haplotype was drastically reduced from 201 to 81 and limited, in the latter case, to subjects from the same population. PMID- 30419519 TI - Facile synthetic Photoluminescent Graphene Quantum dots encapsulated beta cyclodextrin drug carrier system for the management of macular degeneration: Detailed analytical and biological investigations. AB - Drug administration by effective nano-carriers is an emerging and growing technology in the field of bio-medicine and particularly Age -related macular degeneration (AMD). This developed nanomaterials based methods with drug administration maximizes the biocompatibility and systemically increases drug delivery profile for the drugs. Herein, we described the effective drug molecules delivery profiles by the hydrothermally synthesized graphene quantum dots (GQDs) encapsulated with supramolecular beta-cyclodextrin (beta-CD) as a drug delivery system for AMD. The drug release profiles were analysed and plotted by two different types of drugs ((Bevacizumab (Bev) and Ranibizumab (Ran))) and compounds displayed an initial burst delivery percentage of 55.7 +/- 1.6% and 52.2 +/- 2.6, respectively, within 15 min. After 1 h, 94.2% (Ran) and 93.1% (Bev) of loaded drug molecules were released from the beta-CD encapsulated GQDs in sustained manner. The biocompatibility of the synthesized carriers was investigated quantitatively and qualitatively with the mouse Fibroblast L929 cell line. The biological cell analysis observed by calculated cell count and green fluorescence visualization has been clearly confirmed the samples are non-toxic and highly compatible to the cells with more than 90% cell viability after 5 days cell culture. The observed material properties and biological results demonstrated that the suitability of the developed nano-carriers for the drug delivery system in the AMD. PMID- 30419520 TI - Ameliorative effect of berberine coated bio-active nanoparticles in acetaminophen induced hepato-renal damage in diabetic rats. AB - The current investigation was performed for the detailed analysis of protective effect of biofabricate berberine coated nano-silver ameliorate (BBR-AgNPs) on acetaminophen (APAP) induced hepato-renal damages in diabetic rats by blood biochemistry, tissue biochemistry, histopathological and immunohistochemical analysis. The spherical shaped BBR-AgNPs were synthesized by the Biofabrication technique and its physico-chemical characterizations done by different spectroscopic (UV-vis spectrophotometer, XRD spectroscopy, FTIR spectroscopy EDAX & DLS analyses) and microscopic (FE-SEM) techniques. The diabetic developed rats were administrated with APAP (2.0 g/5 mL/kg) and scrutinize its hepato-renal injuries. The synthesized BBR-AgNPs (75 mg/kg p.o) was administrated orally to the APAP-induced diabetic rats. The result of biochemical markers and lipid peroxidation were significantly (P ? 0.05) increased in APAP-induced diabetic rats but decreased the level of antioxidants (P ? 0.05), which results obtained in liver and kidney compared to the control group. Immunohistochemical studies result showed that the APAP-induced diabetic rats expressed a high immunoreactivity of nuclear transcription factor (NF-kB). Whereas, the acetaminophen-induced diabetic rats were treated with BBR-AgNPs renovated the changes in the above parameters analyzed. The results of the study clearly indicated that the BBR-AgNPs possess the antioxidant properties as well as anti diabetic effects, furthermore, the acetaminophen-induced liver and kidney damage was probably inhibited by the inhibition of proinflammatory factor & NF-kB factors. PMID- 30419521 TI - Efficient discrimination of natural stereoisomers of chicoric acid, an HIV-1 integrase inhibitor. AB - Plants from the Asteraceae family are known to contain a wide spectrum of phytochemicals with various nutraceutical properties. One important phytochemical, chicoric acid (CA), is reported to exist in plants, such as Sonchus oleraceus and Bidens pilosa, as stereoisomers. These CA molecules occur either as the naturally abundant RR-chicoric acid (RR-CA), or the less abundant RS-chicoric acid (RS-CA), also known as meso-chicoric acid. To date, little is known about the biological activity of RS-CA, but there is evidence of its anti human immunodeficiency virus (HIV) properties. In this study, a reliable analytical method was developed to distinguish between the two stereoisomers detected in S. oleraceus and B. pilosa. For structure identification and characterization of CA molecules, liquid chromatography-mass spectrometry (LC-MS) was used in combination with ultraviolet radiation (UV)-induced geometrical isomerization, molecular dynamics (MD) simulations, and density functional theory (DFT) models. Optimized structures from DFT calculations were used for docking studies against the HIV-1 integrase enzyme. Different retention times on the reverse phase chromatograms revealed that the plants produce two different CA stereoisomers: S. oleraceus produced the RR-CA isomer, while B. pilosa produced the RS-CA isomer. DFT results demonstrated the RR-CA molecule was more stable than RS-CA due to the stabilizing force of intra-molecular hydrogen bonding. Differences in the HIV-1 integrase enzyme binding modes were observed, with the RR-CA being a more potent inhibitor than the RS-CA molecule. The results highlight the significance of plant metabolite structural complexity from both chemical and biological perspectives. Furthermore, the study demonstrates that induced-formation of geometrical isomers, in combination with the predictive ability of DFT models and the resolving power of the LC-MS, can be exploited to distinguish structurally closely related compounds, such as stereoisomers. PMID- 30419522 TI - Bio-synthesis of Barleria gibsoni leaf extract mediated zinc oxide nanoparticles and their formulation gel for wound therapy in nursing care of infants and children. AB - Bio-synthesis of nano-metal oxide particles is gaining lot of significance and recommended as promising substitute not only physical methods but also chemical methods. Here in, we demonstrate the nano-zinc oxide (nano-ZnO) particles were successfully prepared by an eco-friendly process using plant Barleria gibsoni (B. gibsoni) aqueous leaf extract. The water leaf extract of B. gibsoni responsible for not only reducing source but also protective agent. The prepared nano-ZnO particles were studied by UV-Vis diffuse reflectance (UV-DRS), Photoluminescence (PL), Fourier transform (FT-IR) infrared spectroscopy, X-ray diffraction spectroscopy (X-RD), transmission electron microscopy (TEM), thermal stability was studied by thermogravimetric and differential thermal (TG-DTA) analysis and particle size by zeta sizer, dynamic light scattering (DLS). UV-DRS spectrum of nano-ZnO particles showed below at wave length 400 nm. FT-IR spectra showed that plant metabolites like polyphenols, flavonoids and amino acids etc., are act as reducing and protective agent. X-RD studies revealed the formed nano-ZnO particles have hexagonal (wurtzite) structure. TEM analysis confirmed the range of nanoparticles between 30 and 80 nm, which is supported by DLS analysis. The antibacterial property of synthesized nano-ZnO particles was tested with bacterial pathogens showed good results. The developed nano-ZnO gel act as an efficient and superior another tropical antimicrobial formulations for healing of burn infections. Moreover, the formulated nano-ZnO gel exhibited a remarkable wound healing potential in rats. PMID- 30419523 TI - Heavy metals concentrations in some commercially key species from Sicilian coasts (Mediterranean Sea): Potential human health risk estimation. AB - Trace elements were measured in the edible tissues of target marine species (Sardina pilchardus, Mullus barbatus, Mullus surmuletus, Merluccius merluccius and Parapenaeus longirostris) collected in some of the main ports of the Sicilian coast (southern Italy) in order to evaluate the potential human health risk associated to their consumption. Cadmium, Pb and Hg were below the tolerable limits reported by the European Union in foodstuffs (Commission Regulation (EC) 1881/2006) except for Hg in P. longirostris from one sampling site. The health risk for consumers was assessed both for adults and children calculating the estimated weekly intake (EWI), the target hazard quotient (THQ) and the lifetime cancer risk (CR) for each element. The EWI did not exceed the provisional tolerable weekly intake (PTWI) recommended by the European Food Safety Authority and THQs were < 1 in most cases. Further, the probabilistic distributions of health hazard were evaluated through Monte-Carlo simulation which confirmed a non carcinogenic risk. With some exceptions related to As exposure, the results obtained definitively confirm the goodness of the fishery commercial resources in one of the most important seafood market of the central Mediterranean Sea and represent a positive data for the assessment of the good environmental status for descriptor 9 of the Marine Strategy Framework Directive in this area of the basin. PMID- 30419524 TI - Augmenting Buried in Treasures with in-home uncluttering practice: Pilot study in hoarding disorder. AB - Hoarding disorder is characterized by difficulty parting with possessions and by clutter that impairs the functionality of living spaces. Cognitive behavioral therapy conducted by a therapist (individual or in a group) for hoarding symptoms has shown promise. For those who cannot afford or access the services of a therapist, one alternative is an evidence-based, highly structured, short-term, skills-based group using CBT principles but led by non-professional facilitators (the Buried in Treasures [BIT] Workshop). BIT has achieved improvement rates similar to those of psychologist-led CBT. Regardless of modality, however, clinically relevant symptoms remain after treatment, and new approaches to augment existing treatments are needed. Based on two recent studies - one reporting that personalized care and accountability made treatments more acceptable to individuals with hoarding disorder and another reporting that greater number of home sessions were associated with better clinical outcomes, we tested the feasibility and effectiveness of adding personalized, in-home uncluttering sessions to the final weeks of BIT. Participants (n = 5) had 15 sessions of BIT and up to 20 hours of in-home uncluttering. Reductions in hoarding symptoms, clutter, and impairment of daily activities were observed. Treatment response rate was comparable to rates in other BIT studies, with continued improvement in clutter level after in-home uncluttering sessions. This small study suggests that adding in-home uncluttering sessions to BIT is feasible and effective. PMID- 30419525 TI - Increased expression of inwardly rectifying Kir4.1 channel in the parietal cortex from patients with major depressive disorder. AB - BACKGROUND: The inwardly rectifying K+ channel subtype Kir4.1 has been well studied in the astrocyte within brain; however, the precise role of this protein in psychiatric disorders is unknown. Kir4.1 is also known to interact with GABAB receptors which may be implicated in psychiatric disorders. Here we studied whether expression of Kir4.1 and GABAB receptors was altered in the postmortem brain samples (parietal cortex and cerebellum) from patients with major psychiatric disorders. METHODS: Protein expression of Kir4.1 and GABAB receptors in the parietal cortex and cerebellum from control, major depressive disorder (MDD), schizophrenia (SZ), and bipolar disorder (BD) groups was measured. RESULTS: Levels of Kir4.1 in the parietal cortex from MDD group, but not SZ and BD groups, were significantly higher than the control group. Furthermore, levels of GABAB receptor subunit 1 in the parietal cortex from MDD group and SZ group, but not BD group, were also significantly higher than the control group. Interestingly, there was a positive correlation between Kir4.1 protein and GABAB receptor subunit 1 in the parietal cortex from control group, but not MDD group. LIMITATIONS: The small number in each group may limit our interpretation. Only two brain regions were analyzed. CONCLUSIONS: Abnormalities in the interaction of Kir4.1 and GABAB receptor in the parietal cortex might play a role in the pathophysiology of MDD. PMID- 30419526 TI - The relationships between health anxiety, online health information seeking, and cyberchondria: Systematic review and meta-analysis. AB - BACKGROUND: Cyberchondria refers to an abnormal behavioral pattern in which excessive or repeated online searches for health-related information are distressing or anxiety-provoking. Health anxiety has been found to be associated with both online health information seeking and cyberchondria. The aims of the present systematic review and meta-analysis were to examine the magnitude of these associations and identify any moderator variables. METHODS: A systematic literature search was performed across several databases (PsycINFO, PubMed, Embase) and reference lists of included studies. RESULTS: Twenty studies were included across two independent meta-analyses, with 7373 participants. Random effects meta-analyses showed that there was a positive correlation between health anxiety and online health information seeking [r = 0.34, 95% CI (0.20, 0.48), p < .0001], and between health anxiety and cyberchondria [r = 0.62, 95% CI (0.52, 0.71), p < .0001]. A meta-regression indicated that the age of study participants [Q(1) = 4.58, p = .03] was partly responsible for the heterogeneity found for the relationship between health anxiety and cyberchondria. LIMITATIONS: The generalizability and validity of our findings are restricted by the methodological limitations of the primary studies, namely, an over-reliance on a single measure of cyberchondria, the Cyberchondria Severity Scale. CONCLUSIONS: Our review found a positive correlation between health anxiety and online health information seeking, and between health anxiety and cyberchondria. Further research should aim to explore the contexts for these associations as well as address the identified limitations of the extant literature. PMID- 30419527 TI - Predominant polarity classification and associated clinical variables in bipolar disorder: A machine learning approach. AB - BACKGROUND: Bipolar disorder (BD) is a severe psychiatric disorder characterized by periodic episodes of manic and depressive symptomatology. Predominant polarity (PP) appears to be an important specifier of BD. The present study employed machine learning (ML) algorithms to accurately determine a patient's PP without the inclusion of number and polarity of past episodes, while exploring associations between PP and demographic and clinical variables. METHODS: From a cohort of 148 BD patients, demographic and clinical variables were collected using a customized questionnaire and the SCID-CV. The algorithm employed was the Random-Forest method. The algorithm was programed to classify patients into either depressive or manic predominant polarities and to reveal which variables were associated to the specifier. RESULTS: The algorithm attained an AUC ROC of 74.72% (95% CI = 72.29-77.15%) in classifying patients into either manic or depressive PP. The variables selected by the algorithm were: (1) age at first depressive episode; (2) number of hospitalizations; (3) BD Type II; (4) manic onset; (5) delusions; (6) psychotic features at onset; (7) tobacco addiction; (8) family history of BD; (9) hallucinations; and (10) comorbid anxiety disorders, (11) alcohol dependence, (12) eating disorders and (13) substance dependence. LIMITATIONS: The study is limited due to the small sample size, the inclusion of only self-reported and clinician-observed clinical variables and its cross sectional design. DISCUSSION: The results suggest that the ML approach could be effective in determining a patient's PP. Furthermore, although not previously reported, some variables, such as tobacco use and comorbid eating disorders, appear to be closely associated with PP. PMID- 30419528 TI - Subjective neurocognition and quality of life in patients with bipolar disorder and siblings. AB - BACKGROUND: Bipolar disorder (BD) is associated with significant neurocognitive and functional impairment, which may progress across stages. However, the potential progression of subjective cognitive complaints and quality of life (QoL) has not been addressed. Our main objective was to assess subjective cognitive complaints and QoL on euthymic patients with BD and their healthy siblings. METHODS: Four groups were compared: euthymic patients with type I BD in the early (n = 25) and late (n = 23) stages, their healthy siblings (latent stage; n = 23) and healthy controls (n = 21). Cognitive complaints and QoL were assessed using the COBRA and WHO-QoLBREF questionnaires, respectively. RESULTS: Late-stage patients had greater number of subjective cognitive complaints and reported a worse QoL compared to the other groups. Early-stage patients also had more cognitive complaints than controls and siblings, although differences were not significant. Siblings and controls reported similar QoL. LIMITATIONS: the most important limitation of this study is the criterion used to define the early and late stages of BD, as currently there is no consensus and previous studies have used different criteria. CONCLUSIONS: This is the first study to examine subjective cognition and QoL in patients with BD and siblings. Our results raise the possibility that burden of cognitive complaints increase with disorder progression, in tandem with deterioration in subjective QoL. That would support a clinical staging model of BD. This hypothesis remains to be confirmed by a longitudinal analysis. PMID- 30419529 TI - Do affective episodes modulate moral judgment in individuals with bipolar disorder? AB - BACKGROUND: Bipolar disorder (BD) patients experience altered emotional states and deficits in social adaptation that may also be involved in deontological moral judgments in which participants have to choose whether to sacrifice one person in order to save the lives of a greater number. METHODS: In the present study we compared the utilitarian responses of BD patients in their different states (euthymia, mania, depression) and healthy controls to moral dilemmas with low (impersonal dilemma) and high (personal dilemma) emotional saliency. RESULTS: Our findings revealed an increased tendency to utilitarian judgments in the three groups of BD patients in impersonal dilemmas relative to healthy individuals. In addition, utilitarian responses were increased during manic and depressive episodes in personal moral dilemmas relative to control group. Furthermore, we found no differences in social adaptation between utilitarian and deontological BD responders, though the depressive BD had a lower adaptation than the euthymic individuals. LIMITATIONS: The recording of response times, the exhaustive control of medication effect, or the inclusion of a non-moral condition in the battery of moral dilemmas would provide a better characterization of moral judgment in BD. CONCLUSIONS: For impersonal dilemmas, BD patients exhibited more utilitarian reasoning, which is also affected by emotional engagement for personal dilemmas during acute episodes of mania and depression. Social adaptation is not associated to utilitarian reasoning, but is rather influenced by mood state. PMID- 30419530 TI - Intimate partner violence and incidence of depression in married women: A longitudinal study of a nationally representative sample. AB - BACKGROUND: Intimate partner violence (IPV) has a serious detrimental effect on mental health outcomes. We aimed to investigate the association of verbal or physical IPV with incidence of depressive symptoms in both married women and men according to the victim-perpetrator role. The potential mediating role of verbal or physical IPV in the association between satisfaction level with family relationships or childhood adversity and the incidence of depressive symptoms in married adults was also explored. METHODS: The Korea Welfare Panel Study (KOWEPS) in 2006 and 2007 dataset was analyzed for 9217 married respondents aged 19 years or older. Physical and verbal IPV was assessed according to victim-perpetrator role in 2006. Depressive symptoms were evaluated by the Center for Epidemiologic Studies Depression Scale, 11-item version in 2006 and 2007. Association of IPV with incidental depressive symptoms was investigated with logistic regression analysis fully-adjusted for all potential confounding factors. RESULTS: The bidirectional role of verbal IPV and victimization by physical IPV led to incidence of depressive symptoms in married women. Verbal IPV significantly mediated the association between satisfaction level with the family relationship and incidental depressive symptoms in women. LIMITATIONS: We did not investigate the influence of premorbid depressive symptoms on new-onset IPV. CONCLUSIONS: This study is the first to demonstrate that gender and the victim-perpetrator role are critical moderating factors in the association between IPV and depressive symptom incidence using a nationally representative sample. PMID- 30419531 TI - Preliminary study: Factor structure and psychometric properties of Affective Lability Scale-18 in pregnant and postpartum women. PMID- 30419532 TI - Protective factors do not moderate risk for past-year suicide attempts conferred by recent NSSI. AB - BACKGROUND: NSSI is a robust predictor of suicide attempts but little is known about what factors may serve protective functions in this relationship. METHODS: This study used a subsample of 828 young adults with past year NSSI. Participants were recruited from two universities to complete an on-line survey that included assessments of past year NSSI frequency and total NSSI methods used (versatility), past year suicide attempts, life satisfaction, subjective happiness, and resilience. RESULTS: Bootstrapping logistic regression models were used to test the protective factors as moderators between NSSI frequency, versatility and past year suicide attempts. Greater NSSI versatility and past year frequency were significantly associated with greater likelihood of past year suicide attempts in all models. Life satisfaction and subjective happiness were associated with decreased likelihood of past year suicide attempts in all models. Resilience was not associated with past year suicide attempts, and all moderation analyses were non-significant. LIMITATIONS: Our sample had limited heterogeneity, focused on a college-age population with lower severity relative to clinical samples, and all data were collected on-line. CONCLUSIONS: NSSI emerged as a robust predictor of recent suicide attempts as the strength of the relationship did not change in the presence of protective factors. Our results highlight the strong relationship between NSSI and suicide attempts that occur within the same time frame (past year in this study), and the need for future research to identify factors that do serve protective functions between NSSI and suicide attempts. PMID- 30419533 TI - Long-lasting antidepressant-like activity of the GPR39 zinc receptor agonist TC-G 1008. AB - BACKGROUND: The discovery of the zinc-sensing receptor, has provided new possibilities for explaining the neurobiology of zinc. Recent studies indicate that the GPR39 zinc receptor may play an important role in the pathogenesis of depression as well as in the antidepressant mechanism of action. METHODS: In this study we evaluated the time-course of the antidepressant response of the GPR39 agonist (TC-G 1008), imipramine, ZnCl2 and MK-801 in the forced swim test in mice 30 min, 3 h, 6 h and 24 h after acute drug administration as well as after 14-day treatment. Zinc level was measured in serum of mice. BDNF protein level was evaluated in hippocampus following both acute and chronic TC-G 1008 treatment. RESULTS: A single administration of the GPR39 agonist caused an antidepressant like effect lasting up to 24 h following the injection, which is longer than the effect of imipramine, ZnCl2 and MK-801. Chronic treatment with these compounds caused a decrease in immobility time in the FST. Serum zinc concentrations showed an increased level following chronic ZnCl2 administration, but not following administration of TC-G 1008, imipramine or MK-801. We also observed some tendencies for increased BDNF following acute TC-G 1008 treatment. LIMITATIONS: TC-G 1008 is new drug designed to study GPR39 therefore additional pharmacodynamic and pharmacokinetic properties in preclinical studies are required. CONCLUSION: This study shows for the first time the long-lasting antidepressant effect of the GPR39 agonist in comparison with imipramine, ZnCl2 and MK-801. Our findings suggest that GPR39 should be considered as a target in efforts to develop new antidepressant drugs. PMID- 30419534 TI - Risks of bipolar disorder, depressive disorder, and traumatic brain injury among siblings of patients with attention-deficit hyperactivity disorder. AB - BACKGROUND: Previous studies have suggested that the unaffected siblings of patients with attention-deficit hyperactivity disorder (ADHD) experience deficits in attention, impulsivity control, and behavior inhibition, which are associated with health-risk behaviors. However, risks to mental and physical health among the unaffected siblings of ADHD probands have rarely been investigated. METHODS: Using the Taiwan National Health Insurance Research Database, 5128 unaffected siblings of ADHD probands born between 1980 and 2000 were included in our study along with 20,512 age- and sex-matched controls, and they were followed from 1996 or birth until the end of 2011. Mental and physical health risks, including affective disorders, traumatic brain injury (TBI), and sexually transmitted infection were identified during the follow-up period. RESULTS: Logistic regression analyses with adjustments for demographic data showed that the unaffected siblings were more likely to develop unipolar depression (odds ratio [OR]: 1.76, 95% confidence interval [CI]: 1.39-2.22), bipolar disorder (OR: 2.10, 95% CI: 1. 09-4.05), and TBI (OR: 1.24, 95% CI: 1.14-1.36) than were the control group. DISCUSSION: The unaffected siblings of patients with ADHD were prone to developing unipolar depression, bipolar disorder, and TBI later in life. PMID- 30419535 TI - A key for perinatal depression early diagnosis: The body dissatisfaction. AB - OBJECTIVE: To test if the evaluation of body dissatisfaction by images could be an interesting tool to detect perinatal depression early in pregnancy, questioning patients about their body image instead of their depressive symptoms. METHODS: A sample of 457 women was recruited in a longitudinal study. Three evaluations were performed at the 4th and 8th months of pregnancy and during post partum. During these evaluations, sociodemographic data were collected and psychiatric scales were completed, including Edinburgh Postnatal Depression Scale (EPDS), Eating Disorder Examination-Questionnaire (EDE-Q), Pictorial Body Image Scale (PBIS) and Body Shape Questionnaire (BSQ). RESULTS: 33% of the women who were unsatisfied with their body image suffered from perinatal depression vs. 11.3% of the women who were not (p < 0.0001). The risk of perinatal depression was 4 times higher in women dissatisfied with their body image (p < 0.001) if unintended pregnancy and age are taken into account and is 3 times significantly higher in women with higher levels of eating disorders symptoms (p < 0.001) if unintended pregnancy and age are taken into account. Our sample was a privileged population, as often in the literature. CONCLUSION: The administration of a simple scale (PBIS) during an early visit during pregnancy allows detecting perinatal depression. This should prevent the stigmatization of women during pregnancy and reduce the risk of not diagnosing depression during pregnancy and post-partum. PMID- 30419536 TI - Sugar-sweetened beverages consumption and the risk of depression: A meta-analysis of observational studies. AB - BACKGROUND: It remains inconsistent whether sugar-sweetened beverages (SSBs) consumption increases the risk of depression. Thus, we carried out a meta analysis to evaluate the association between SSBs consumption and the risk of depression. METHODS: PubMed and Web of Science were searched for relevant articles published up to June 2018. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated by the fixed-effects model or random effect model based on heterogeneity test. RESULTS: 10 observational studies involving 37,131 depression cases among 365,289 participants were included. The combined risk of depression for the highest versus lowest consumption of SSBs was 1.31 (95% CI 1.24-1.39). The findings were consistent in the cross-sectional studies (RR = 1.38; 95% CI 1.26-1.52) as well as in the cohort studies (RR = 1.30; 95% CI 1.19-1.41) A nonlinear dose-response relationship was found (Pnonlinearity = 0.0103) for depression risk and SSBs consumption. Compared with SSBs nondrinkers, those who drank the equivalent of 2 cups/day of cola might increase the risk of depression by 5% (RR = 1.05; 95% CI 1.01-1.09). And the equivalent of 3cans/day of cola might have approximately 25% higher risk of depression. LIMITATIONS: 10 studies were included in this meta-analysis, of which only 4 were cohort studies, and more cohort studies need to be performed in the future. CONCLUSIONS: This meta-analysis indicates that SSBs consumption might be associated with a modestly higher risk of depression. The results need to be further confirmed in the future. PMID- 30419537 TI - Ensemble machine learning prediction of posttraumatic stress disorder screening status after emergency room hospitalization. AB - Posttraumatic stress disorder (PTSD) develops in a substantial minority of emergency room admits. Inexpensive and accurate person-level assessment of PTSD risk after trauma exposure is a critical precursor to large-scale deployment of early interventions that may reduce individual suffering and societal costs. Toward this aim, we applied ensemble machine learning to predict PTSD screening status three months after severe injury using cost-effective and minimally invasive data. Participants (N = 271) were recruited at a Level 1 Trauma Center where they provided variables routinely collected at the hospital, including pulse, injury severity, and demographics, as well as psychological variables, including self-reported current depression, psychiatric history, and social support. Participant zip codes were used to extract contextual variables including population total and density, average annual income, and health insurance coverage rates from publicly available U.S. Census data. Machine learning yielded good prediction of PTSD screening status 3 months post hospitalization, AUC = 0.85 95% CI [0.83, 0.86], and significantly outperformed all benchmark comparison models in a cross-validation procedure designed to yield an unbiased estimate of performance. These results demonstrate that good prediction can be attained from variables that individually have relatively weak predictive value, pointing to the promise of ensemble machine learning approaches that do not rely on strong isolated risk factors. PMID- 30419538 TI - Effect of light-curing protocols on the mechanical behavior of bulk-fill resin composites. AB - OBJECTIVE: To investigate the effect of two light-curing protocols on mechanical behavior of three bulk-fill resin composites (BFRC) considering their optical properties. METHODS: One increment of 4 mm thickness of the bulk-fill resin composites Opus Bulk Fill, Tetric N-Ceram and Filtek Bulk Fill Flow were submitted to two different light-curing protocols: Sp - irradiance of 1000 mW/cm2 (20 s); Xp - irradiance of 3200 mW/cm2 (6 s). To assess the influence on the mechanical behavior it was studied polymerization shrinkage by X-ray microtomography (n = 3), Vickers hardness (n = 10) at the top and bottom surfaces of the samples, irradiance reaching the bottom surface (n = 3) and absorbance spectrum during the light-curing time interval (n = 3). Data were analyzed by two way ANOVA test for parametric data and Kruskal Wallis test, followed by Wilcoxon or Mann-Whitney U post-test, for non-parametric data. RESULTS: All BFRCs contracted when light-cured, with greater contraction for Xp. Filltek Bulk Fill Flow showed highest polymerization shrinkage, for both Sp and Xp. All BFRCs showed minor hardness values on the bottom surface, with greater reduction for Xp. All BFRCs exhibited a decrease in irradiance at 4 mm depth. A decrease in absorbance intensity throughout the light-cure was observed, except for Opus Bulk Fill. CONCLUSIONS: Regardless BFRCs composition, the light-curing protocol with lower irradiance and longer exposure time results in lower polymerization shrinkage and higher hardness. The higher irradiance in a shorter time interval compromises the mechanical behavior of the resin composites, which may result in undesirable clinical outcomes. PMID- 30419539 TI - Engagement in a Community Physical Activity Program and Its Effects Upon the Health-Related Quality of Life of Elderly People: A Cross-Sectional Study. AB - BACKGROUND: Aging is related to an increase in the prevalence of noncommunicable diseases and impairments in health-related quality of life. Physical activity is a nonpharmacological intervention that is known to prevent and manage noncommunicable diseases and improve quality of life. OBJECTIVES: To compare the quality of life, as measured by the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), of elderly participants and nonparticipants in a community physical activity program. METHODS: One hundred elderly men and women (age > 60 years) who were either sedentary (sedentary [S] group; n = 50, 30 men) or physically active and attended a community physical activity program (physical activity [PA] group; n = 50, 30 men) took part in the study. All participants completed the SF-36 subscales to assess their quality of life. RESULTS: The PA group reported higher values on the functioning capacity and general health perceptions subscales of the SF-36 when compared with the S group. Conversely, scores on the following SF-36 subscales did not differ between the groups: role limitations due to physical problems, pain, vitality, social functioning, role limitations due to emotional problems, and mental health. A ceiling effect was evident in both groups for all SF-36 subscales. CONCLUSIONS: The SF-36 subscales were not sufficiently sensitive to detect differences between the S and PA groups (except for functioning capacity and general health perceptions), probably because of ceiling effects. PMID- 30419541 TI - Investigation of health literacy and affecting factors of nursing students. AB - Health literacy (HL) is a concept that concerns individuals, as well as health systems and health professionals. This study was conducted to determine health literacy and affecting factors of nursing students. A descriptive-cross sectional design was used. First and fourth year nursing students were included in the study (n = 303). A questionnaire and the Adult Health Literacy Scale were used for collection of the data. Most (84.8%) of the students were female and 60.4% were studying in their first year. The mean Adult Health Literacy Scale score of the student nurses was 15.9 +/- 3.2. The fourth year nursing students who have health insurance, have chronic disease, use drugs regularly, and have difficulties in reading had higher mean Adult Health Literacy Scale scores (p < 0.05). Although this study indicates that the HL level of the nursing students was found as adequate, it is thought that the higher HL level acquired in the undergraduate education the more competent nursing workforce. The HL concept should be integrated into the nursing curriculum to improve the HL levels of the nursing students. Nurse educators should emphasize the importance of health literacy and patient empowerment in the curriculum. PMID- 30419542 TI - Calix[4]arene urea derivatives: The pathway from fundamental studies to the selective removal of fluorides and phosphates from water. AB - Wet processes of phosphoric acids produce untreated wastewater containing large amounts of fluoride leading to serious environmental problems. This paper reports fundamental studies on two lower rim functionalised calix[4]arene based receptors namely 5, 11, 17, 23 tetra-tert-butyl, 25, 27 bis [diethylphenylurea]ethoxy, 26, 28 dihydroxycalix[4]arene, 1 and 25, 27 bis[diethylphenylurea]ethoxy, 26, 28 dihydroxycalix[4]arene, 2 and their ionic interactions. It is shown that these receptors only interact with fluoride and phosphate in acetonitrile. Their receptive properties are higher for phosphate (2:1 anion:receptor complex) relative to fluoride (1:1 complex). However, thermodynamics shows that these receptors are more selective for fluoride relative to phosphate in the formation of the 1:1 complex. The pathway from fundamental studies to the use of these receptors for removing these anions from water has been tested. The receptive properties of 1 for phosphate are held when the extraction involves aqueous solutions containing individual ions. However, in mixtures containing both anions, the kinetics of the process and the selectivity of 1 for fluoride predominate and as a result, fluoride is better extracted than phosphate. The counter-ion effect on the removal process is assessed from Molecular Simulation studies. The removal of fluoride from phosphate is discussed taking into account existing technologies. PMID- 30419540 TI - Multi-Spectral Fluorescence Imaging of Colon Dysplasia InVivo Using a Multi Spectral Endoscopy System. AB - BACKGROUND AND STUDY AIM: To develop a molecular imaging endoscopic system that eliminates tissue autofluorescence and distinguishes multiple fluorescent markers specifically on the cancerous lesions. METHODS: Newly developed multi-spectral fluorescence endoscope device has the potential to eliminate signal interference due to autofluorescence and multiplex fluorophores in fluorescent probes. The multiplexing capability of the multi-spectral endoscope device was demonstrated in the phantom studies and multi-spectral imaging with endoscopy and macroscopy was performed to analyze fluorescence signals after administration of fluorescent probe that targets cancer in the colon. Because of the limitations in the clinical application using rigid-type small animal endoscope, we developed a flexible channel insert-type fluorescence endoscope, which was validated on the colonoscopy of dummy and porcine model. RESULTS: We measured multiple fluorescent signals simultaneously, and the fluorescence spectra were unmixed to separate the fluorescent signals of each probe, in which multiple fluorescent probes clearly revealed spectral deconvolution at the specific targeting area in the mouse colon. The positive area of fluorescence signal for each probe over the whole polyp was segmented with analyzing software, and showed distinctive patterns and significantly distinguishable values: 0.46 +/- 0.04, 0.39 +/- 0.08 and 0.73 +/- 0.12 for HMRG, CET-553 and TRA-675 probes, respectively. The spectral unmixing was finally demonstrated in the dummy and porcine model, corroborating the targeted multi-spectral fluorescence imaging of colon dysplasia. CONCLUSION: The multi-spectral endoscopy system may allow endoscopists to clearly identify cancerous lesion that has different patterns of various target expression using multiple fluorescent probes. PMID- 30419543 TI - Optimization of Direct Blue-14 dye degradation by Bacillus fermus (Kx898362) an alkaliphilic plant endophyte and assessment of degraded metabolite toxicity. AB - Alkaliphilic bacteria possesses the ability to survive in the extreme conditions with high salt concentrations. The adaptability of alkaliphilic bacteria to extreme conditions has made them predominant degrader in the field of biodegradation. A moderately alkaliphilic endophyte was isolated from Centella asiatica with a potential to degrade a di-azo dye Direct Blue-14(DB-14). The isolate was identified as Bacillus fermus with 97% similarity strain Xmb064. On optimization, maximum of 92.76% biodegradation was attained with dye concentration at 68.78 ppm supplemented with 1 g of sucrose and 2.5% (v/v) of inoculum for 72 h incubation. Characterization of the biodegraded product carried out using UV-vis spectrophotometry, FT-IR and LC-MS confirmed the destabilization of di-azo bond followed with the degradation of DB-14. Cytogenotoxicity studies revealed the biodegraded products to be less toxic. The current study is the first report on the optimization, biotransformation and cytogenotoxicity of DB-14 by B. fermus strain Centella. PMID- 30419544 TI - An analysis of homeless patients in the United States requiring ICU admission. AB - PURPOSE: To assess how homelessness impacts mortality and length of stay (LOS) among select the intensive care unit (ICU) patients. METHODS: We used ICD-9 code V60.0 to identify homeless patients using the Premier Perspective Database from January 2010 to June 2011. We identified three subpopulations who received critical care services using ICD-9 and Medicare Severity Diagnosis Related Groups (MS-DRG) codes: patients with a diagnosis of sepsis who were treated with antibiotics by Day 2, patients with an alcohol or drug related MS-DRG, and patients with a diabetes related MS-DRG. We used multivariable logistic regression to predict mortality and multivariable generalized estimating equations to predict hospital and ICU LOS. RESULTS: 781,540 hospitalizations met inclusion criteria; 2278 (0.3%) were homeless. We found homelessness had no significant adjusted association with mortality among sepsis patients, but was associated with substantially longer hospital LOS: (3.7 days longer; 95% CI (1.7, 5.7, p < .001). LOS did not differ in the Diabetes or Alcohol and Drug related DRG groups. CONCLUSIONS: Critically ill homeless patients with sepsis had longer hospital LOS but similar ICU LOS and mortality risk compared to non-homeless patients. Homelessness was not associated with increased LOS in the diabetes or alcohol and drug related groups. PMID- 30419545 TI - Acinetobacter etiology respiratory tract infections associated with mechanical ventilation: what impacts on the prognosis? A retrospective cohort study. AB - INTRODUCTION: Acinetobacter species treatment often represents a challenge. The main objective of this study is identify predictors of ICU mortality in patients submitted to mechanical ventilation (MV). MATERIALS AND METHODS: Retrospective cohort study. Patients with MV > 48 h who developed a respiratory tract positive culture for Acinetobacter were included, and distinguished among colonized, ventilator-associated pneumonia (VAP) or ventilator-associated tracheobronchitis (VAT) patients. Primary outcome was ICU mortality. RESULTS: 153 patients were in MV and presented positive culture for Acinetobacter calcoaceticus-baumanii complex, 70 of them with VAP, 59 with VAT and 24 patients were colonized. The factors related to ICU mortality were VAP (OR 2.2, 95% CI 1.1-4.5) and shock at the time of diagnosis (OR 4.8, 95% CI 1.8-2.3). In multivariate analysis, only SOFA score at the time of diagnosis (OR 1.06, 95% CI 1.03-1.09) was related with ICU mortality. A paired-matched analysis was performed to assess effect of dual therapy on outcomes, and no effect was found in terms of clinical cure, ICU or hospital mortality or duration of antimicrobial therapy. CONCLUSIONS: Previous comorbidities and degree of associated organic injury seem to be more important factors in the prognosis than double antibiotic therapy in patients with Acinetobacter-related respiratory infection. PMID- 30419546 TI - Impact of maintenance, resuscitation and unintended fluid therapy on global fluid load after elective coronary artery bypass surgery. AB - INTRODUCTION: Standardized protocols are provided for maintenance and replacement fluid therapy in critically ill patients. However, unintended fluid sources (analgesics, antibiotics and other drugs) are not always taken into account when prescribing intravenous fluid therapy. We evaluated the extent to which maintenance, resuscitation and unintended fluids contributed to total fluid load in elective coronary artery bypass graft patients during their ICU stay. METHODS: Data on intravenous and oral fluid input and output were retrospectively collected from the electronic medical files. RESULTS: Sixty patients were included. Maintenance fluids represented 1435 +/- 570mL (49%) and 2214 +/- 657mL (71%), resuscitation fluids 847 +/- 542mL (29%) and 338 +/- 559mL (11%), unintended fluids 639 +/- 162mL (22%) and 576 +/- 285mL (18%) respectively on day 1 and day 2. Mean oral intake increased almost fourfold (from 258mL to 1017mL) on the second day. CONCLUSION: Postoperative maintenance and resuscitation fluids are responsible for most of the observed total fluid load on the first two days after elective coronary artery bypass graft surgery. Unintended fluid load is underestimated and has to be taken into account during fluid prescription. PMID- 30419547 TI - Measuring quality indicators to improve pain management in critically ill patients. AB - PURPOSE: To evaluate the quality of pain assessment in Dutch ICUs and its room for improvement. MATERIALS AND METHODS: We used a modified RAND method to develop pain assessment indicators. We measured performance on the indicators using retrospectively collected pain measurement data from Dutch ICUs, which are all mixed medical - surgical, of three months within October 2016-May 2017. We assessed the room for improvement, feasibility of data collection, and reliability of the indicators. RESULTS: We defined four pain assessment indicators. We analyzed 45,688 patient-shift observations from 15 ICUs. In 69.2% (IQR 58.7-84.9) of the patient-shifts pain was measured at least once (indicator 1); in 56.7% (IQR 49.6-73.5) pain scores were acceptable (indicator 2); in 11.7% (IQR 5.6-26.4) pain measurements with unacceptable scores were repeated within 1 h (indicator 3); and in 10.9% (IQR 5.1-20.1) unacceptable scores normalized within 1 h (indicator 4). We found data collection feasible because data were available for >79.3% of the admissions, and all indicators reliable as they produced consistent performance scores. CONCLUSIONS: There is substantial variation in pain assessment across Dutch ICUs, and ample room for improvement. With this study we took a first step towards quality assurance of pain assessment in Dutch ICUs. PMID- 30419548 TI - MXD1 regulates the imatinib resistance of chronic myeloid leukemia cells by repressing BCR-ABL1 expression. AB - Tyrosine kinase inhibitors have achieved unprecedented efficacy in the treatment of chronic myeloid leukemia (CML); however, imatinib resistance has emerged as a major problem in the clinic. Because the overexpression of BCR-ABL1 critically contributes to CML pathogenesis and drug resistance, targeting the regulation of BCR-ABL1 gene expression may be an alternative therapeutic strategy. In this study, we found that the transcriptional repressor MXD1 showed low expression in CML patients and was negatively correlated with BCR-ABL1. Overexpression of MXD1 markedly inhibited the proliferation of K562 cells and sensitized the imatinib resistant K562/G01 cell line to imatinib, with decreased BCR-ABL1 mRNA and protein expression. Further investigation using reporter gene analysis showed that MXD1 significantly inhibited the transcriptional activity of the BCR-ABL1 gene promoter. Taken together, these data show that MXD1 functions as a negative regulator of BCR-ABL1 expression and subsequently inhibits proliferation and sensitizes CML cells to imatinib treatment. PMID- 30419549 TI - LMO2 functional and transcriptional regulatory profiles in hematopoietic cells. PMID- 30419550 TI - Hydroxyurea prior to intensive chemotherapy in AML with moderate leukocytosis. PMID- 30419552 TI - Changing effect of GABA B receptor antagonist CGP46381 after status epilepticus in immature rats. AB - Possible proconvulsant action of GABAB receptor antagonist CGP46381 was studied 3 and 13 days after status epilepticus elicited in 12-day-old rats. GABAA-dependent activity was tested by pentylenetetrazol administration and found different in 15 day-old rats after status epiolepticus but not in the older group. The interaction of the two GABAergic systems should be studied in detail. PMID- 30419551 TI - A single-center, single-blind study to evaluate the clinical sensitivity, specificity, and agreement between Elecsys Anti-HBc II and Elecsys Anti-HBc in a Korean population. AB - BACKGROUND: Anti-HBc IgG is almost always detected in hepatitis B virus (HBV) infected individuals and persists in resolved infections. In certain cases, anti HBc IgG is the only serological marker and anti-HBc-positive result generally means anti-HBc total positivity. OBJECTIVES: To evaluate the clinical sensitivity and specificity of an investigational medical device, Elecsys Anti-HBc II, using samples from the Korean population. Agreement between Elecsys Anti-HBc II and its widely utilized predecessor Elecsys Anti-HBc was also evaluated. STUDY DESIGN: Residual serum or plasma samples stored at below -20 degrees C without individual identifiers were used in this study. This study had 106 randomly selected HBV deoxyribonucleic acid (DNA)-positive samples used for evaluating clinical sensitivity. For clinical specificity, a total of 239 both HBV DNA and hepatitis B surface antigen-negative samples, which were anti-HBc-negative by Elecsys Anti-HBc, were used. Agreement between Elecsys Anti-HBc and Elecsys Anti HBc II was evaluated in total 345 samples. The Architect Anti-HBc II was used as a confirmatory test regarding discrepancies between Elecsys Anti-HBc and Elecsys Anti-HBc II results. RESULTS: The clinical sensitivity and specificity of Elecsys Anti-HBc II were found to be 99.06% and 100%, respectively. In total, 345 samples showed 100% agreement. Both positive and negative agreements were also 100%. CONCLUSIONS: The clinical performance of Elecsys Anti-HBc II was confirmed as sufficient in Korean samples. Elecsys Anti-HBc II demonstrated an exceptional performance, exceeding the requirements of the Ministry of Food and Drug Safety and confirming its reliability as an in vitro diagnostic device for HBV diagnosis in Korea. PMID- 30419553 TI - Efficacy of Carboplatin/Paclitaxel-Based Radiochemotherapy in Locally Advanced Squamous Cell Carcinoma of Head and Neck. AB - BACKGROUND: Cisplatin-based chemotherapy (CTX) is commonly used concurrently with radiotherapy for head and neck cancer. The value of CTX regimens other than cisplatin for locally advanced squamous cell carcinoma of head and neck (LASCCHN) has not been well established. Here we compare the outcome of patients treated with different platinum-based chemotherapy regimens. METHODS: Medical records from 104 patients with LASCCHN treated with radiochemotherapy (RCTX) between February 2013 and August 2016 were analyzed. RESULTS: All patients were treated with intensity-modulated radiation therapy (51 definitive, 53 postoperative). The median total dose was 66.6 Gy and the median fraction dose was 1.8 Gy. 81 (78%) patients were administered cisplatin CTX, 23 (22%) patients received carboplatin and paclitaxel (CarboTaxol). The rate of recurrence was 38% in patients treated with cisplatin and 30% in CarboTaxol-treated patients (p = 0.6). Regarding the CTX regimens, event-free survival (EFS) was 37 versus 30 months (p = 0.6) and overall survival (OS) was 35 versus 28 months (p = 0.5) in cisplatin group versus CarboTaxol group, respectively. Significantly higher grade 3/4 acute toxicity in terms of dysphagia was observed following cisplatin-based RCTX (p = 0.002). In multivariable analysis, females and patients with early primary tumors (T1-2) have longer EFS and OS, regardless the CTX regimen. CONCLUSIONS: Primary or adjuvant RCXT with CarboTaxol is a safe and effective treatment alternative for LASCCHN patients with contraindication to cisplatin-based RCTX. PMID- 30419554 TI - MALAT1 Activates the P53 Signaling Pathway by Regulating MDM2 to Promote Ischemic Stroke. AB - BACKGROUND/AIMS: This study focused on evaluating the effect of MALAT1 and MDM2 on ischemic stroke through regulation of the p53 signaling pathway. MATERIALS: Bioinformatics analysis was performed to identify abnormally expressed lncRNAs, mRNAs and their associated pathways. Oxygen-glucose deprivation/reoxygenation (OGD/R) in cells and middle cerebral artery occlusion/reperfusion (MCAO/R) in mice were performed to simulate an ischemic stroke environment. Western blot and qRT-PCR were used to examine lncRNA expression and mRNA levels. Fluorescence in situ hybridization (FISH) LncRNA was used to locate mRNA. MTT and flow cytometry were performed to examine cell proliferation and apoptosis. Finally, immunohistochemistry was used to observe the expression of genes in vivo. RESULTS: MALAT1 and MDM2, which exhibit strong expression in stroke tissues, were subjected to bioinformatics analysis, and the p53 pathway was chosen for further study. MALAT1, MDM2 and p53 signaling pathway-related proteins were all up regulated in OGD/R cells. Furthermore, Malat1, Mdm2 and p53 pathway related proteins were also up regulated in MCAO/R mice. Both MALAT1 and MDM2 were localized in the nuclei. Down regulation of MALAT1 and MDM2 enhanced cell proliferation ability and reduced apoptosis, resulting in decreased infarct size in MCAO/R brains. CONCLUSION: These results indicate that MALAT1/MDM2/p53 signaling pathway axis may provide more effective clinical therapeutic strategy for patients with ischemic stroke. PMID- 30419555 TI - A New Physiologic Mouse Model of One Anastomosis Gastric Bypass. AB - BACKGROUND: One anastomosis gastric bypass (OAGB) is a modern metabolic operation that has been demonstrated to be a rapid, safe, and effective procedure. As for other bariatric operations, the mechanisms and long-term effects of this procedure remain largely unknown and are difficult to address in human studies. Here, we present a new physiologic mouse model for mechanistic and long-term investigations. METHODS: Six-week-old C57Bl/6 mice were fed a high-fat diet for 12 weeks and scheduled for OAGB or sham operation. Mice were observed for 2 weeks after the operation, and weight and metabolic condition were monitored. RESULTS: Six mice were used to adapt the surgical technique. Afterwards, another 7 mice were scheduled for OAGB without further complications. The newly established OAGB procedure resulted in significant weight loss and improvement of glucose metabolism 2 weeks after the operation. CONCLUSIONS: The operation presented here is an easy-to-learn and physiologic mouse model of OAGB that can be used for further studies in mice. PMID- 30419557 TI - Risk Factors for Lymph Node Metastasis among Lymphovascular Space Invasion Positive Women with Endometrioid Endometrial Cancer Clinically Confined to the Uterus. AB - INTRODUCTION: We aimed to assess risk factors for lymph node (LN) metastasis among lymphovascular space invasion(LVSI)-positive women with pure endometrioid endometrial cancer (EC) clinically confined to the uterus. METHODS: Medical records of women who underwent primary surgery for EC between 2007 and 2016 at either of 2 gynecological oncology centers were retrospectively reviewed. Patient data were analyzed with respect to LN involvement, and predictive factors for LN metastasis were investigated. RESULTS: 280 patients with surgically staged endometrioid-type EC with LVSI were identified. LN involvement was detected in 88 patients (31.4%) with a systematic LN dissection. In multivariate analysis, elevated baseline serum CA 125 levels, deep myometrial invasion (MMI), adnexal involvement and positive peritoneal cytology were found to be independent risk factors for LN metastasis. In women without deep MMI and elevated baseline serum CA 125 levels, the rate of LN metastasis was 19%. The presence of solely deep MMI increased this probability up to 29.1%. The rate of LN metastasis was found to be 46.8% for women with both deep MMI and elevated baseline serum CA 125 levels. CONCLUSION: These findings may be useful in the decision-making process for LVSI positive women who are unstaged. PMID- 30419556 TI - Increased Risk for Cancer in Young Patients with Severe Obstructive Sleep Apnea. AB - BACKGROUND: Several studies in animal models and human with obstructive sleep apnea syndrome (OSAS) demonstrated an increase in cancer aggressiveness and mortality. However, there is a need for further clinical evidence supporting a correlation between OSAS and cancer incidence. OBJECTIVES: To reveal whether OSAS presence and severity is correlated with cancer incidence in a large homogenous patients' cohort. METHODS: We analyzed a cohort of over 5,000 concurrently enrolled patients, age > 18, with suspected OSAS, from a tertiary medical academic center. Patients underwent whole night polysomnography, the gold standard diagnostic tool for OSAS, and were classified for severity according to the Apnea Hypopnea Index (AHI). Data on cancer incidence were obtained from the Israel National Cancer Registry. A multivariate Cox proportional-hazards analysis, adjusted for age, gender, and BMI, was performed to estimate the hazard ratio of new cancer incidence. RESULTS: Among 5,243 subjects with a median follow up of 5.9 years, 265 were diagnosed with cancer. The most prevalent cancers were prostate (14.7%), hematological (12.8%), urothelial (9.4%), colorectal (9%), and breast (8.3%). In subjects who were diagnosed at age below 45 years (n = 1,533), a high AHI (> 57/h) was significantly associated with cancer (HR 3.7, CI 1.12 12.45, p = 0.008). CONCLUSIONS: Patients younger than 45 with severe OSAS have a significantly higher all-type cancer incidence than the general population. These results should encourage clinicians to detect and diagnose young patients with suspected OSAS and to recommend cancer screening methods in this high-risk population. PMID- 30419558 TI - Neutrophil to Lymphocyte Ratio as a Prognostic Factor in European Patients with Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer Treated with Tyrosine Kinase Inhibitors. AB - BACKGROUND: A high neutrophil to lymphocyte ratio (NLR) has been associated with adverse outcomes in non-small cell lung cancer (NSCLC). However, information on epidermal growth factor receptor (EGFR)-mutant advanced NSCLC is scarce, and most of the studies published have been conducted in Asian populations. We aimed to assess the influence of pretreatment NLR on progression-free survival (PFS) and overall survival (OS) in Western European patients treated with EGFR tyrosine kinase inhibitors (TKIs). METHODS: A retrospective evaluation of 41 patients with EGFR-mutant advanced NSCLC treated with EGFR TKIs between June 2010 and May 2016 was carried out. The association between several prognostic factors including pretreatment NLR and survival was analyzed. RESULTS: Median PFS and OS were 10.58 and 20.84 months, respectively. OS for patients with a high NLR was 7.4 months, compared to 24.6 months for patients with a low NLR (p = 0.0122). In multivariate analysis, poor performance status (ECOG PS >= 2) and presence of >= 3 metastatic locations were identified as significant independent prognostic factors for worse PFS. For OS, unfavorable prognostic factors were a high NLR and central nervous system metastasis at diagnosis. CONCLUSION: Pretreatment NLR is an independent prognostic factor for OS in Western European patients with EGFR-mutant NSCLC treated with EGFR TKIs. PMID- 30419559 TI - Letter to the Article by Maus et al.: "Order of Treatment Matters in Ischemic Stroke: Mechanical Thrombectomy First, Then Carotid Artery Stenting for Tandem Lesions of the Anterior Circulation". PMID- 30419560 TI - Isoform-Dependent Changes in Cytochrome P450-Mediated Drug Metabolism after Portal Vein Ligation in the Rat. AB - BACKGROUND: Surgical removal of complicated liver tumors may be realized in two stages via selective portal vein ligation, inducing the atrophy of portally ligated lobes and the compensatory hypertrophy of nonligated liver lobes. Unlike morphological changes, functional aspects such as hepatic cytochrome P450 (CYP) mediated drug metabolism remain vaguely understood, despite its critical role in both drug biotransformation and hepatic functional analysis. Our goal was the multilevel characterization of hepatic CYP-mediated drug metabolism after portal vein ligation in the rat. METHODS: Male Wistar rats (n = 24, 210-230 g) were analyzed either untreated (controls; n = 4) or 24/48/72/168/336 h (n = 4 each) following portal vein ligation affecting approximately 80% of the liver parenchyma. Besides the weights of ligated and nonligated lobes, pentobarbital (30 mg/kg)-induced sleeping time, CYP1A(2), CYP 2B(1/2), CYP2C(6/11/13), CYP3A(1) enzyme activities, and corresponding isoform mRNA expressions, as well as CYP3A1 protein expression were determined by in vivo sleeping test, CYP isoform selective assays, polymerase chain reaction, and immunohistochemistry, respectively. RESULTS: Portal vein ligation triggered atrophy in ligated lobes and hypertrophy nonligated lobes. Sleeping time was transiently elevated (p = 0.0451). After an initial rise, CYP1A, CYP2B, and CYP3A enzyme activities dropped until 72 h, followed by a potent increase only in the nonligated lobes, paralleled by an early (24-48 h) transcriptional activation only in nonligated lobes. CYP2C enzyme activities and mRNA levels were bilaterally rapidly decreased, showing a late reconvergence only in nonligated lobes. CYP3A1 immunohistochemistry indicated substantial differences in positivity in the early period. CONCLUSIONS: Beyond the atrophy-hypertrophy complex, portal vein ligation generated a transient suppression of global and regional drug metabolism, re established by an adaptive, CYP isoform-dependent transcriptional response of the nonligated lobes. PMID- 30419561 TI - Challenge of Attaining Flow Arrest in Anterior Circulation Tandem Occlusions in Large Vessel Ischemic Stroke: Wedged SAVE Technique. PMID- 30419562 TI - Fatal Umbilical Cord Strangulation in the Remaining Co-Twin after Selective Foeticide with Radiofrequency Ablation for Twin-Twin Transfusion Syndrome. AB - We report a case of a monochorionic diamniotic twin diagnosed with twin-twin transfusion syndrome (TTTS; stage 3) with co-existing severe cerebral damage in the donor twin at 18 + 4 weeks' gestation. After counselling, the parents opted for selective foeticide of the donor twin. For the procedure, radiofrequency ablation (RFA) was used. Serial ultrasound examinations at 20 + 1 and 21 + 1 weeks' gestation showed good recovery of the ex-recipient, after which the patient was sent back to the referring hospital. At 29 + 5 weeks' gestation, an unexpected foetal death was diagnosed. On macroscopic placental examination, (iatrogenic) monoamnionicity was detected. In addition, the umbilical cord of the recipient was found to be constricted by the macerated umbilical cord of the ex donor. This case demonstrates that iatrogenic monoamnionicity can be a serious complication of RFA in monochorionic twins complicated by TTTS, with a subsequent risk for cord entanglement leading to a fatal outcome for the remaining co-twin. Although the actual incidence of iatrogenic monoamnionicity after RFA remains unknown, increased attention to the intactness of the inter-twin membrane even weeks after the RFA may be required. PMID- 30419563 TI - Machado de Assis' Original Sin. AB - Machado de Assis (1839-1908) suffered from temporal lobe epilepsy, probably with origin in the non-dominant hemisphere. The evidence for this is provided by the detailed reports of the characteristics of his seizures by his contemporaries and by his correspondence with other writers. He was treated with bromides and homeopathy. It is unclear whether his neurological disorder influenced his artistic performance. What is evident is that he was deeply ashamed of the disease - he avoided the word "epilepsy" and just wrote about it in his personal correspondence with friends in the last years of his life. Though controversial, he had no clear traces of personality disorders linked to his temporal lobe epilepsy. Despite all his adversities, including being "mulatto," having a stutter, being of humble origins, and epileptic in a period when there was no efficacious therapy and a profound stigma associated with the disease, Machado de Assis became one of the most important Brazilian writers of all times. PMID- 30419564 TI - Transoral Robotic Surgery and the Unknown Primary. AB - Carcinoma of unknown primary (CUP) comprises approximately 1%-5% of all head and neck malignancies. Primary site detection rates for metastatic cervical squamous cell carcinoma (SCC) remain variable, with current diagnostic imaging unable to identify all tumours. Prevailing evidence suggests that most head and neck CUP are located in the oropharynx. Diagnostic surgical efforts have been directed at sampling the entire oropharynx. Present techniques that make this possible include transoral robotic surgery (TORS). TORS Lingual tonsillectomy or tongue base mucosectomy performed in the setting of head and neck CUP increases the detection rate of occult tumour. The indication, surgical technique, evidence base, and controversies of performing TORS in the context of the unknown primary are presented. PMID- 30419565 TI - Reliability of Symptom-Based Diagnosis of Uncomplicated Cystitis. AB - BACKGROUND AND OBJECTIVES: Acute uncomplicated cystitis (AC) is common among women. Acute onset of specific typical symptoms may serve as reliable criteria for developing a cost-effective strategy to make an accurate diagnosis of AC. We aimed to evaluate the diagnostic values of most common symptoms and signs of AC depending on their presence and severity. METHODS: The current trial was designed as a case-control study. Data derived from the Acute Cystitis Symptom Score (ACSS) database were analyzed. Diagnostic values of the symptoms and their severity were assessed via the calculations of the sensitivity and specificity, odds ratio, positive and negative likelihood ratios. The strength of associations was estimated by the coefficient of correlation (Pearson's R). RESULTS: Data from 819 female subjects (423 Patients, 396 controls) with the mean age of 37.1 +/- 15.3 were analyzed. Highest diagnostic values for AC in this study belonged to dysuria, urgency, and frequency. Interestingly, complaints of vaginal discharge was not found to decrease the odds for having AC in the study population. CONCLUSIONS: The severity of the symptom is even more essential than just its presence for an accurate diagnosis. The ACSS is an accurate tool and may be recommended for clinical practice and studies for diagnosis of AC in women. Further studies and unification of terms are need. PMID- 30419566 TI - Patients' Perspective: What has Changed in Deciding about Breast-Conserving Surgery for Early-Stage Breast Cancer in Turkey? AB - BACKGROUND: This study aims to describe patients' perception of early breast cancer, factors influencing the choice of operation, patients' sources of information about the disease and the seriousness with which this information is considered, and to address what surgeons can do to enlighten their patients prior to decision-making. METHODS: Patients were asked to complete a questionnaire consisting of 3 sections: The first section addressed influential factors during the decision-making process; the second pertained to the role of surgeons or health facilities in the process; and the third asked patients to revisit their initial choice of surgery. RESULTS: 237 patients were included in the study. Statistical analyzes regarding demographic features showed that nulliparous, younger than 50 years, never or <5 years married, highly educated, business owning, employed, and stage I breast cancer patients preferred breast-conserving surgery (BCS) to mastectomy. CONCLUSION: Although the rate of BCS is a technical quality indicator for breast cancer centers, providing sufficient patient counseling, involving the patient in the decision-making process, and offering every possible surgical option are key to improving quality of life. Systematic counseling should be provided to breast cancer patients who have primary tumors that are eligible for BCS. PMID- 30419567 TI - Letter to His Father by Franz Kafka: Literary Reconstruction of a Traumatic Childhood? AB - Franz Kafka's Letter to His Father is one of the greatest examples in world literature of memory of a traumatic childhood. In it, the author takes a retrospective journey through his life, recollecting and analyzing the reasons for the estrangement and hostility between a father and a son. This essay considers Letter to His Father in the light of current knowledge about autobiographical memory. The essay first sets forth basic aspects of Kafka's life in order to place Letter to His Father in the context of Kafka's biography, and then presents Kafka's relevance to the literature and thought of the twentieth and twenty-first centuries. The essay then considers the different forms of childhood abuse and their consequences in light of evidence from neurodevelopmental psychology. We present evidence about the relationship between trauma and the construction of self-image. Furthermore, we discuss the subjectivity of Kafka's recollections from the perspective of recent advances in neurobiology. Memory is shown to be dynamic, selective, inherently malleable and dependent on perception, which is a subjective construction, in which the brain interprets and gives coherence to experienced stimuli. We consider the inaccuracy of memory, which is related to neuroplastic changes in the brain that take place over time: consolidation, reconsolidation and transformation. Finally, the relationship between literature and autobiography in the Kafkaesque universe is considered. PMID- 30419568 TI - Outcome of Infants with Therapeutic Hypothermia after Perinatal Asphyxia and Early-Onset Sepsis. AB - BACKGROUND: Animal models suggest that neuroprotective effects of therapeutic hypothermia (TH) after perinatal asphyxia are reduced in infants with early-onset sepsis. OBJECTIVES: To assess the outcome of infants with perinatal asphyxia, neonatal encephalopathy, and TH in the presence of early-onset sepsis. METHODS: In a retrospective cohort of 1,084 infants with perinatal asphyxia and TH, the outcome of 42 infants (gestational age 36.1-42.6 weeks and birth weight 2,280 5,240 g) with proven sepsis (n = 14) and probable sepsis (n = 28) was analyzed. Death, cerebral palsy, or a delayed development at 2 years was considered an adverse outcome. RESULTS: Sepsis was caused mostly by group B streptococci (n = 17), other Gram-positive bacteria (n = 5), and Candida albicans (n = 1). Of the 42 infants, 9 (21.4%) died, and 5 (11.9%) showed impairments on follow-up. The outcome is comparable to the previously reported outcome of infants with TH without early-onset sepsis. CONCLUSION: A good outcome was reported in the majority of infants with perinatal asphyxia, TH, and early-onset sepsis. Cooling should not be withheld from these infants. PMID- 30419569 TI - Clinical Study on Complications of Intracranial Ruptured Aneurysm Embolization by Stent-Assisted Coil. AB - BACKGROUND The aim of this study was to retrospectively analyze the incidence of complications of intracranial complex aneurysms embolization by stent-assisted coils, and to investigate the causes of complications and corresponding treatment methods. MATERIAL AND METHODS A total of 71 patients with subarachnoid hemorrhage (SAH) underwent stent-assisted coil embolization from 2015 to 2018 were enrolled in this study. Among them, 59 cases were single aneurysm, 12 cases were multiple aneurysms (11 cases with 2 aneurysms and 1 case with 3 aneurysms), for a total of 84 aneurysms. All enrolled patients received stent angioplasty except for 1 case. RESULTS There were 62 aneurysms (73.81%) treated with complete tamponade, 21 aneurysms (25.00%) treated with near-total tamponade and 1 aneurysm (1.19%) treated with partial tamponade. All aneurysms were evaluated based on GOS (Glascow outcome scale): 55 cases had GOS of 5 scores, 12 cases had GOS of 4 scores, 3 cases had GOS of 3 scores, and 1 case had GOS of 1 score. There were 67 SAH patients with good prognosis (GOS of 4-5 scores). In our study, the incidence of complications was 12.7%. Three cases experienced acute thrombosis, 2 cases experienced aneurysm rupture during embolization, and 1 case experienced postoperative focal ischemic changes with mild neurological deficits. CONCLUSIONS Stent-assisted coil embolization is safe, effective, and feasible for the treatment of intracranial ruptured aneurysms. Patients had a favorable outcome of as high as 94.4%. However, clinical skills should be improved to reduce the occurrence of complications. Prompt and timely treatment for complications of intracranial ruptured aneurysm is also of great significance. PMID- 30419570 TI - A Child with Central Variant Posterior Reversible Encephalopathy Syndrome. PMID- 30419571 TI - Artifact Properties of Dental Ceramic and Titanium Implants in MRI. AB - AIM: Assessment of the visualization of titanium and ceramic dental implants using various isotropic three-dimensional magnetic resonance imaging (MRI) methods. MATERIALS AND METHODS: 21 dental implants (7 ceramic, 14 titanium) were scanned in vitro with a spatially isotropically resolved three-dimensional gradient echo (FFE), a turbo spin echo (SE) and an ultra-short-echo time (UTE) imaging technique. The resulting absolute volumes of the implants were quantified and the relative error to the theoretical volume was calculated. RESULTS: Ceramic implants and their periphery could be displayed well in all cases. The observed mean relative error results were 5.4 +/- 2.3 % (UTE) to 6.5 +/- 4.3 % (FFE). No significant difference was observed between the investigated MRI methods. The transition between implant and surrounding agarose could be shown in all cases without artifacts. Titanium implants resulted in mean relative errors between 1314 +/- 350 % (FFE) and 2157 +/- 810 % (SE). Here, significant differences were observed between the FFE and the SE and between the UTE and the SE sequence. The periphery of the implants could not be displayed in any case. CONCLUSION: Use of the MRI technique for the diagnosis of peri-implantitis, the assessment of anatomical structures and planning of dental implantation is currently very limited but could be used more frequently, provided there are no disturbing or imaging-disturbing materials in the region of interest. MRI technology is not suitable in case of titanium implants. When using ceramic implants, MRI technology is an option. KEY POINTS: . MRI allows the artifact free depiction of dental ceramic implants.. . Titanium implants cause the greatest relative errors in SE techniques.. . The UTE technique shows no significant improvements with respect to artifact behavior over the FFE technique.. CITATION FORMAT: . Geibel M, Gelibetaen B, Bracher A et al. Artefakt Verhalten von dentalen Keramik- und Titanimplantaten im MRT. Fortschr Rontgenstr 2019; DOI: 10.1055/a-0755-2374. PMID- 30419572 TI - Whole-Body CT in Multiple Trauma Patients: Clinically Adapted Usage of Differently Weighted CT Protocols. AB - PURPOSE: Whole-body CT (wbCT) has been established as an internationally accepted diagnostic modality in multiple trauma. Until 2011, a uniform CT scanning protocol was used for all multiple trauma patients (pat.) at our hospital (OLD protocol = OP). In 2011, 2 new differently weighted protocols were introduced: TIME protocol (TP) for hemodynamically unstable pat. and DOSE protocol (DP) for pat. with stable vital parameters. The aim of this study was to compare the original "One-fits-all-concept" with the new, clinically oriented approach to wbCT. MATERIALS AND METHODS: This study retrospectively evaluated 3 distinct wbCT protocols, looking at automatic exposure control variation (AEC; OP/TP) and arm positioning close to the body/overhead (TP/DP). The analysis included waist circumference (WC, cm), injury severity score (ISS), examination time (ET, min), image noise (IN), and effective dose (E, mSv). Normality of distribution was assessed with the Kolmogorov-Smirnov test. Data are given as median and range. Test of significance with Kruskal-Wallis test or Mann-Whitney-U test. Level of significance: 0.05. RESULTS: 308 pat. were included in the study (77 % m; age: 46 a, 18 - 90 a; WC: 93 cm, 66 - 145 cm). ISS was 14 (OP; n = 104; 0 - 75), 18 (TP; n = 102; 0 - 75) and 9 (DP; n = 102; 0 - 50). ET was 3.9 min (OP; 3.3 - 5.6 min), 4.1 min (TP; 2.8 - 7.2 min) and 7.7 min (DP; 6 - 10 min). IN showed no significant differences when comparing OP/TP but was significantly reduced in DP. For a wbCT (vertex to ischium), E could be reduced from 49.7 mSv to 35.4 mSv by optimizing AEC (OP/TP). Through the overhead repositioning of the arms in DP, a further reduction to 28.2 mSv was achieved. CONCLUSION: AEC and arm repositioning have a crucial influence on image quality and dose. The presented clinical approach is superior to the original concept. KEY POINTS: . The use of 2 differently weighted wbCT protocols allows a more flexible approach to the patient's clinical presentation.. . The clinically adapted concept presented in this study allows trauma care centers to reduce the collective dose.. . Whole-body CT is leading to exposure to relevant radiation doses - further multicenter research is required.. CITATION FORMAT: . Reske SU, Braunschweig R, Reske AW et al. Whole-Body CT in Multiple Trauma Patients: Clinically Adapted Usage of Differently Weighted CT Protocols. Fortschr Rontgenstr 2018; 190: 1141 - 1151. PMID- 30419573 TI - Intraosseous Lipoma of the Lateral Cuneiform. PMID- 30419574 TI - Tubulointerstitial Nephritis and Uveitis Syndrome with unilateral enthesopathy of the knee joint. PMID- 30419575 TI - Fasciotomy for Lateral Lower-leg Chronic Exertional Compartment Syndrome. AB - Exercise-induced lower leg pain may be caused by chronic exertional compartment syndrome (CECS). Anterior or deep posterior compartments are usually affected. Knowledge about CECS of the lateral compartment (lat-CECS) is limited and outcome after fasciotomy is unknown. The purpose of this study is to report on success rates of fasciotomy in patients with lat-CECS. Surgical success rates in patients with lat-CECS diagnosed with a dynamic intracompartmental pressure (ICP) measurement were studied using a questionnaire (success: excellent or good as judged by the patient; unsuccessful: moderate, fair or poor). We conducted ICP measurements in 247 patients for suspected lat-CECS, of whom 78 were positively diagnosed. Following exclusion (n=11), 30 of the eligible 67 patients completed the questionnaire. Bilateral (70%, n=21/30) exertional pain (97%, n=29) and a feeling of tightness (93%, n=28) were the most frequently reported symptoms. Four years after fasciotomy, severity and frequency of symptoms had dropped significantly. Long-term surgical success was reported by 33% (n=10; excellent n=4, good n=6). Seventy-three percent (n=22) had resumed sports activities (9 same level, 13 lower level). In conclusion, a fasciotomy for lat-CECS was successful in the long term in just one of three operated patients in this retrospective study. PMID- 30419576 TI - Impact Loading During Distracted Running Before and After Auditory Gait Retraining. AB - Visual feedback gait retraining has been reported to successfully reduce impact loading in runners, even when the runners were distracted. However, auditory feedback is more feasible in real life application. Hence, this study compared the peak positive acceleration (PPA), vertical average (VALR) and instantaneous (VILR) loading rate during distracted running before and after a course of auditory feedback gait retraining in 16 runners. The runners were asked to land with softer footfalls with and without auditory feedback. Low or high sound pitch was generated according to the impact of particular footfall, when compared with the preset target. Runners then received a course of auditory gait retraining, and after the gait retraining, runners completed a reassessment. Runners before gait retraining exhibited lower PPA, VALR and VILR with augmented auditory feedback (p<0.049). We found a reduction in PPA, VALR and VILR after gait retraining, regardless of the presence of feedback (p<0.018). However, runners after gait retraining did not demonstrate further reduction in PPA and VALR with auditory feedback (p>0.104). A small effect of auditory feedback on VILR in runners after gait retraining was observed (p=0.032). Real time auditory feedback gait retraining is effective in impact loading reduction, even when the runners were distracted. PMID- 30419577 TI - Circulating Inflammatory Cytokine Responses to Endurance Exercise in Female Rowers. AB - This investigation examined the effects of acute rowing exercise on a panel of 12 different inflammatory cytokines. Fifteen female rowers (18.3+/-1.6 yrs; 172.0+/ 5.0 cm; 67.5+/-8.8 kg; maximal oxygen consumption [VO2max]: 47.2+/-7.9 ml.min. 1kg-1) completed a 1-h endurance exercise (distance: 12.1+/-1.1 km; energy expenditure [EE]: 639+/-69 kcal; heart rate: 151+/-7 beats.min-1; intensity: 79.6+/-3.5% of the second ventilatory turn point). Venous blood samples were analysed for interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, vascular endothelial growth factor (VEGF), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), IL-1alpha, IL-1beta, monocyte chemoattractant protein-1 (MCP-1) and epidermal growth factor (EGF) concentrations. Rowing exercise resulted increment (P<0.05) in IL-6, IL-8, VEGF and MCP-1. Exercise metabolic demand variables such as rating of perceived exertion (r=0.61), distance covered (r=0.60) and EE (r=0.57) were related (P<0.05) to changes in VEGF concentration. Cardiorespiratory fitness as measured by VO2max was correlated with changes in IL 6 (r=-0.55; P<0.05) level. In conclusion, acute exercise-induced inflammatory reaction was induced by a significant increase in IL-6, IL-8, VEGF and MCP-1 concentrations. Variance in exercise-induced increases in inflammatory cytokines in response to prolonged endurance exercise was characterised by exercise metabolic demand and cardiorespiratory fitness measures in female rowers. PMID- 30419578 TI - [Endoscopic submucosal dissection for mucosal low-risk early gastric cancer - a retrospective, unicentric study]. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) is the standard-procedure in Asia for the treatment of early gastric cancer (EGC) within defined criteria. In Europe, this technique is being used more and more frequently. In the context of risk constellations (submucosal invasion, lymphangioinvasion, poorly differentiated carcinoma), the occurrence of lymph node metastases is possible. We defined a low-risk group (differentiated, mucosal EGC without ulceration and vascular infiltration, size independent) to investigate the endoscopic outcome and the long-term course of this special group with excellent prognosis. PATIENTS AND METHODS: Patients with untreated low-risk EGC were included in this retrospective evaluation. Patient data (age, gender distribution), carcinoma parameters (number, size, location, Paris-Classification), histological parameters, resection data (including en bloc resection, R-status), follow-up (including local recurrence, survival) and complication data were evaluated. RESULTS: In 55 patients, ESD was used to remove 61 low-risk EGC. In 93.4 %, the En-bloc resection succeeded, in 91.8 % of cases, an R0 status was documented. In 8 cases (13.1 %), intervention-dependent complications occurred: 5 delayed bleeding (8.2 %), two microperforations (3.3 %, no surgery required) and one non ST-elevated myocardial infarciation (1.6 %). During the follow-up (mean: 54.3 months) there were 4 cases (6.6 %) of local recurrences, of which at least 2 could be successfully treated endoscopically. The other 2 patients died after repeated endoscopy before the first control. Overall, 4 patients (7.8 %) died during the follow up, none of them tumor-associated. In 9 patients (16.4 %) syn- or metachronous lesions were detected, all of which could be treated endoscopically. Lymphnode metastases did not occur. CONCLUSION: In the low-risk group that we defined, a high rate of en bloc and R0 resections were achieved with ESD; the detected local recurrences could be treated endoscopically. Metastases were not detected, no tumor-associated patient deaths occured. ESD is, therefore, recommended for this group as a standard therapy. The study provides no data on the endoscopic and clinical follow up in the presence of risk factors of both mucosal and other EGCs from the so-called Expanded Group (including lymphangio-invasion, submucosal invasive EGC, poorly differentiated G3 carcinomas). PMID- 30419579 TI - Endoscopic suturing as a less invasive approach for the treatment of anastomotic leakage after esophagogastrostomy - a case report. AB - Anastomotic leakage is a frequent complication after gastrointestinal (GI) surgery and is associated with high morbidity and mortality. Endoluminal therapy offers numerous advantages compared to surgical revision. We present the case of a 74-year-old female patient with anastomotic leakage after esophagogastrostomy. The defect was closed using the OverStitch endoscopic suturing system with immediate technical and clinical success. Hereby, an example of the feasibility of this novel technique in a case of anastomotic leakage is presented and provides an outlook for the rising importance of endoscopic therapy. PMID- 30419580 TI - [Advances in the diagnosis and treatment of Clostridioides [Clostridium] difficile infections in inflammatory bowel disease]. AB - Patients with chronic inflammatory bowel disease (IBD) have a significantly increased risk of clinically relevant clostridial infection (CDI). In turn, CDI can increase IBD activity. Therefore, rapid diagnosis and therapy is required. Many diagnostic and treatment studies on patients with CDI without inflammatory bowel disease are not congruent with IBD patients. This overview summarizes the everyday data of recent years and condenses these into four guiding principles. 1) patients with IBD present a risk population for a CDI. A CDI not only worsens the disease activity in the short term, but also causes increased morbidity and mortality in the long term. 2) If a CDI is suspected, glutamate-dehydrogenase (GDH) detection should be carried out quickly. If this is positive, and the disease activity is high, a therapy against C. difficile already may be initiated and-if necessary-terminated in cases of negative confirmation tests. 3) IBD patients with a proven CDI should be treated primarily with vancomycin. 4) In a relapsing CDI, fecal microbiome transfer is an effective therapeutic measure. However, activation of the IBD must be expected in about 15 % of cases. Consistent adherence to these guidelines may help treat a CDI in IBD patients. PMID- 30419582 TI - [Over-The-Scope-Clips: First Choice of Therapy for Recurrent Ulcer Bleeding?] PMID- 30419581 TI - [Interpretation und performance of high-resolution esophageal manometry: Recommendations of the German Association of Neurogastroenterology and Motility (DGNM) and the German Association of Gastroenterology, Digestive and Metabolic Diseases (DGVS)]. AB - Esophageal manometry provides a detailed evaluation of esophageal contractility and, therefore, represents the reference method for diagnosis of esophageal motility disorders. Significance and clinical relevance have been further increased by implementation of high-resolution esophageal manometry (HRM), which reveals the functional anatomy of the esophagus in a visually-intuitive manner. The current 3 rd version of the international Chicago Classification (CC v3.0) gives standardized recommendations on performance and interpretation of HRM and serves as the basis for much of this expert consensus document. However, CC v3.0 gives only limited information with regards to the function of the lower and upper esophageal sphincters, the use of adjunctive tests including solid test meals and long-term ambulatory HRM measurements. In this expert consensus, we describe how to perform and interpret HRM on the basis of the CC v3.0 with additional recommendations based on the results of recent, high-quality clinical studies concerning the use of this technology to assess the causes of esophageal symptoms in a variety of clinical scenarios. PMID- 30419583 TI - [Risk factors for hypertensive and cerebral amyloid angiopathy associated intracerebral hemorrhage: a retrospective comparison]. AB - INTRODUCTION: The aim of this study was to compare possible risk factors for the most common forms of spontaneous intracerebral hemorrhage (ICH), namely hypertensive and cerebral amyloid angiopathy (CAA) associated ICH. METHODS: Retrospectively, different parameters and factors were compared in patients with hypertensive ICH (n = 141) and patients with a CAAassociated ICH (n = 95). These included age, INR value and blood pressure at admission, cardiovascular risk factors as well as pre-medication. The Chi-square test with the Yates' continuity correction and the t-test were used as test methods. RESULTS: Patients of the group with CAA-associated ICH were significantly older than patients with a hypertensive ICH (p = 0.001). In addition, there was a significantly higher incidence of acetylsalicylic acid prior treatment (p = 0.042) and a previous stroke (p = 0.048) in the CAA patients. Patients of both groups had a high proportion of arterial hypertension as pre-diagnosis, which was significantly more common in patients with hypertensive ICH (p < 0,001). Patients with a hypertensive ICH also had significantly higher systolic and diastolic blood pressure values (p < 0.001) and higher INR values (p = 0.005) at admission. A subgroup analysis of all patients without anticoagulation (ZAA group: n = 78, hypertensive ICB group: n = 99) showed similar results. However, there was no significant difference (p = 0.037) for a previous stroke, but there was a significant difference in premedication with a statin (p = 0.032). DISCUSSION: Arterial hypertension is a relevant risk factor in both forms of intracerebral hemorrhage and should therefore receive adequate prophylaxis. For a more detailed classification of the other risk factors, further studies with larger cases are necessary. PMID- 30419584 TI - [Update - Lithium in the Long-Term Treatment of Bipolar Disorders]. AB - Lithium is the gold standard in the long-term treatment of bipolar disorders and the only substance with a convincing antisuicidal effect in affective disorders. Under regular monitoring, lithium represents mostly a well-tolerated and safe medication. Balancing risk and benefits shows that lithium can also be an off label therapeutic option during pregnancy and breast feeding. Lithium may exhibit neuroprotective effects and has been linked to a reduced risk of Alzheimer's disease and stroke. In the future, biomarkers of lithium response may be available that enable development of more personalized therapies. PMID- 30419585 TI - Differences in Ankle ROM Between Young Men and Women With a History of Ankle Sprain. AB - BACKGROUND: Ankle injuries are the most common injuries in sports. However, very little is known about sex differences in ankle range of motion (ROM) between ankle joints with an episode of ankle sprain (ASE) and those without an episode of ankle sprain (non-ASE). This study aimed to investigate the differences of ankle ROM between men and women with and without ASE. METHODS: 26 ASE had at least one episode of ankle injury in the last 6 to 12 months. 35 non-ASE served as a control group. All subjects were examined in supine position and the ankle ROM was calculated by the sum of inversion (IV), eversion (EV), plantar flexion (PF) and dorsiflexion (DF) in both ankles. RESULTS: Subjects with ASE had a significantly smaller ROM regarding EV than non-ASE subjects in both ankles. The male subjects with ASE had a significantly higher EV and IV compared with the female subjects. However, ROM in PF was significantly lower among men compared with women who had ASE. CONCLUSIONS: Our findings suggest that the ROM after ASE affects PF in male and EV in female patients. This could point to sex-based prevention and rehabilitation after ankle injury. PMID- 30419586 TI - [Timing of kyphoplasty influences the outcome: a prospective study]. AB - The aim of this prospective study was to evaluate the efficiency of early versus delayed treatment of vertebral fractures by balloon kyphoplasty with regard to fracture age. A total of 106 patients (37 male and 69 female) with 128 vertebral body fractures, an average age of 67.5 years (21 to 92) and a body mass index of 26.4 (16 to 40.4) were recorded. All fractures were evaluated radiologically and clinically. Pain intensity (visual analogue scale 0 - 10), analgesics consumption (WHO steps 1 to 3) and the relevant surgery data (operating time, cement consumption, complications) were recorded. 37 A 1.1, 43 A 1.2, 43 A 1.3, 4 A 3.1 and 1 A 2.3 classifications were collected. Fracture age in days was less than 23 days in 75 patients; the mean time of surgery was 43 minutes. Analgesics consumption was reduced from 1.8 +/- 0.8 preoperatively to 1.0 +/- 0.6 postoperatively. A significant improvement was found in pain intensity, which fell significantly from 8.2 +/- 0.9 preoperatively to 3.9 +/- 0.8 postoperatively. In relation to fracture age and pain intensity, a significantly higher pain reduction was achieved with timing of kyphoplasty between 0 and 23 days. Here, pain intensity decreased to 2.5 +/- 0.5 postoperatively, compared with 4.5 +/- 0.4 for fractures treated later. Fracture age had no influence on vertebral body alignment or improvement of the kyphotic angle. In summary, it can be stated that balloon kyphoplasty is a sufficient method to treat vertebral body fractures, to improve the kyphotic angle and reduce pain significantly. PMID- 30419587 TI - Back Pain in Rowers: A Cross-sectional Study on Prevalence, Pain Characteristics and Risk Factors. AB - OBJECTIVES: To establish the prevalence of back pain in rowers at different competition levels and rowing typologies compared with a non-rowing control group; to determine different time periods, the location on the spine, and different pain characteristics. Additionally to evaluated different risk factors that might be responsible for back pain. METHODS: A standardized and validated online back pain questionnaire was sent to elite and non-elite rowers of different rowing typologies, and a physically active non-rowing control group. RESULTS: Responses from 156 rowers (104 elite and 52 non-elite/ 49 scull and 76 sweep rowers) and 166 controls were received. Back pain prevalence and severity was significantly higher among rowers compared with controls, and among scull compared with sweep rowers. The lower back was the main location of back pain in rowers of all competition levels and typologies, and in controls. Age, sex, and training volume influenced the prevalence of back pain. Rowing kinematics, strength, and ergometer training were the main associated risk factors for back pain in rowers. CONCLUSIONS: Back pain in different spinal locations is a common complaint in rowers of different typologies and competition levels. Rowing kinematics, strength, and ergometer training are the main associated risk factors for developing back pain in rowers. Thus, the spinal load due to rowing kinematics and different types of training should be investigated in future studies. Additionally, training should be monitored by experienced coaches to prevent back pain due to technical mistakes or too-heavy loads. PMID- 30419588 TI - [Intraoperative Imaging in Pelvic Surgery]. AB - Pelvic fractures may range from highly severe, life-threatening injuries to less acute clinical entities. There are several sub-entities that are summed up as pelvic injuries. Anatomically, there are fractures of the anterior or posterior pelvic ring. Apart from these, there are fractures of the acetabulum that make up about one fifth of all pelvic injuries. The indication for surgical treatment of pelvic ring injuries depends on the type of injury, involvement of anterior and/or posterior elements of the pelvic ring, demands and the general condition of the patient. In acetabular fractures, indications depend on the dislocation of the fracture and of course also the needs of the patient and his general condition. An intraarticular step-off of more than 2 mm is usually considered as an indication for open reduction and osteosynthesis. Usually in all these injuries, a preoperative CT scan is mandatory to allow precise planning of the operative approach and technique. Intraoperatively, the surgeon should be familiar with the acquisition of the 2D standard views, including 2D imaging of the pelvic ring and the acetabulum. These consist of the anteroposterior view for both pelvic ring and acetabular osteosyntheses. For further assessment of pelvic ring treatments, inlet and outlet views are achievable by angulating the C-arm cranially and caudally. To assess aspects of the anterior and posterior column of the acetabulum, iliac oblique views are used. Here, the C-arm is rotated laterally. As evaluation of 2D views can be limited due to anatomy and superposing structures, intraoperative 3D imaging has become common in the last decade. Special C-arms allow the automatic acquisition of large numbers of projections and create CT-like views of the central volume. Although this method has significantly widened the possibilities of intraoperative imaging, some issues remain. Depending on the amount of implants placed in the imaging field, assessment can be seriously impaired due to artefacts caused by the implants. Intraoperative CT imaging promises enhanced image quality for artefacts and allows a considerably larger field of view. The use of radiation-free navigation facilitates implant placement in minimally invasive procedures like screw placement in the sacroiliacal joint or the acetabulum by visualisation of instruments and implants in a pre- or intraoperative 3D data set. PMID- 30419589 TI - Epidemiology and Treatment of Patients with Haemophilia in Austria-Update from the Austrian Haemophilia Registry. AB - The Austrian Haemophilia Registry collects epidemiological data on patients with haemophilia, on treatment modalities and potential side effects. The Registry covers more than 85% of the assumed total number of haemophilia patients in Austria. This report summarizes data on 753 patients: 84.3% (635) have haemophilia A and 15.7% (118) have haemophilia B. Patients' median age is 34 years (range: 1-93 years). Of the total cohort, 39.0% (294) patients have severe haemophilia, 11.3% (85) moderate haemophilia, and 49.4% (372) mild haemophilia. Of the patients with severe haemophilia, 38.4% (113) have been infected with hepatitis C virus (HCV) and 12.6% (37) are human immunodeficiency virus (HIV) positive. Overall, 10.6% (67) of patients with haemophilia A and 1.7% (2) of those with haemophilia B have had an inhibitor in their history. Among patients with severe haemophilia, 68.4% (201) receive prophylaxis and 28.6% (84) receive on-demand therapy. There are 65.0% (191) patients with severe haemophilia who are treated with recombinant products. In conclusion, most patients with severe haemophilia receive prophylactic treatment. HCV and HIV infections are still important issues in the Austrian haemophilia population. PMID- 30419591 TI - ? PMID- 30419590 TI - Cofactor-Independent Antiphospholipid Antibodies: Implications for Pathogenesis, Diagnosis, and Treatment of Antiphospholipid Syndrome. AB - The antiphospholipid syndrome (APS) has occupied haemostaseologists, rheumatologists and obstetricians since its initial description 35 years ago. Its name has been coined because of the antibodies against phospholipids which were the common property of affected patients. In particular, the pathogenesis of APS has been intensively studied after the early discovery that it was possible to induce the clinical manifestations in animals by transfer of antiphospholipid antibodies (aPL). In recent years, it has become clear that aPL are not only structurally heterogeneous but also have different pathogenic properties. This review will focus on the relevance of antigenic specificity of aPL in terms of pathogenesis, diagnosis, and perhaps treatment of APS. PMID- 30419592 TI - Fifth World Veterinary Orthopaedic Congress: An Outstanding Success. PMID- 30419593 TI - Rudolf "Tass" Dueland (1933-2018). PMID- 30419594 TI - Pierre M. Montavon (1949-2018). PMID- 30419595 TI - Neutrophil-Mediated Proteolysis of Thrombospondin-1 Promotes Platelet Adhesion and String Formation. AB - Thrombospondin-1 (TSP-1) is primarily expressed by platelets and endothelial cells (ECs) and rapidly released upon their activation. It functions in haemostasis as a bridging molecule in platelet aggregation, by promoting platelet adhesion to collagen and by protecting von Willebrand factor strings from degradation. In blood of patients undergoing surgery and in co-cultures of neutrophils with platelets or ECs, we observed proteolysis of the 185 kDa full length TSP-1 to a 160-kDa isoform. We hypothesized that TSP-1 processing may alter its haemostatic properties. Selective enzyme inhibitors in co-cultures revealed that neutrophil proteases elastase and cathepsin G mediate TSP-1 processing. The cut site of cathepsin G was mapped to TSP-1 amino acids R237/T238 by Edman sequencing. Formation of neutrophil extracellular traps protected TSP-1 from complete degradation and promoted controlled processing to the 160-kDa isoform. Haemostatic properties were tested by platelet aggregation, adhesion, coagulation and string formation under flow. Platelets from TSP-1 deficient mice did not differ from wild-type in platelet aggregation but showed severe impairment of platelet adhesion to collagen and string formation under flow. Reconstitution experiments revealed that the 160-kDa TSP-1 isoform was markedly more potent than the 185-kDa full-length molecule in restoring function. Thus, TSP-1 processing by neutrophil proteases yields a 160-kDa isoform which shows enhanced potency to promote platelet adhesion and string formation. This finding reveals a novel mechanism of neutrophil-mediated thrombus formation and provides first evidence for the impact of TSP-1 proteolysis on its haemostatic properties. PMID- 30419596 TI - Plasma Phospholipid Transfer Protein Promotes Platelet Aggregation. AB - It remains unclear whether plasma phospholipid transfer protein (PLTP) is involved in hyper-coagulation or hypo-coagulation. This study investigated the direct effect of PLTP on platelet aggregation and the underlying mechanism. Washed platelets from humans or mice and mouse platelet-rich plasma and human recombinant PLTP were isolated. PLTP is present in human platelets. We assessed adenosine diphosphate (ADP)-, collagen- and thrombin-induced platelet aggregation, phosphatidylserine externalization and photothrombosis-induced cerebral infarction in mice. PLTP over-expression increased platelet aggregation, while PLTP deficiency had the opposing reaction. Human recombinant PLTP increased both mouse and human platelet aggregation in a dose-dependent manner. Phosphatidylserine externalization provides a water/lipid surface for the interaction of coagulation factors, which accelerates thrombosis. Compared with wild-type controls, platelets from PLTP transgenic mice had significantly more phosphatidylserine on the exterior surface of the plasma membrane, whereas platelets from PLTP-deficient mice had significantly less phosphatidylserine on the surface, thus PLTP influences fibrinogen binding on the plasma membrane. Moreover, recombinant PLTP together with ADP significantly increased phosphatidylserine exposure on the plasma membrane of PLTP-deficient platelets, thereby increasing fibrinogen binding. PLTP over-expression significantly accelerated the incidence of photothrombosis-induced infarction in mice, whereas PLTP deficiency significantly reduced the frequency of infarction. We concluded that PLTP promotes phosphatidylserine externalization at the plasma membrane of platelets and accelerates ADP- or collagen-induced platelet aggregation. This effect plays an important role in the initiation of thrombin generation and platelet aggregation under sheer stress conditions. Thus, PLTP is involved in hyper-coagulation. Therefore, PLTP inhibition could be a novel approach for countering thrombosis. PMID- 30419597 TI - Asymptomatic Deep Vein Thrombosis is Associated with an Increased Risk of Death: Insights from the APEX Trial. AB - AIM: Asymptomatic deep vein thrombosis (DVT) diagnosed with compression ultrasound (CUS) is a common endpoint in trials assessing the efficacy of anticoagulants to prevent venous thromboembolism (VTE), but the relationship of asymptomatic thrombus to mortality remains uncertain. METHODS: In the APEX trial (ClinicalTrials.gov: NCT01583218), 7,513 acutely ill hospitalized medical patients were randomly assigned to extended-duration betrixaban (35-42 days) or enoxaparin (10 +/- 4 days). Asymptomatic DVT was assessed once with CUS between day 32 and 47, and mortality was assessed through 77 days. RESULTS: A total of 309 asymptomatic DVTs were detected through CUS. Of these, 133 (4.27%) subjects were in the betrixaban group, and 176 (5.55%) subjects were in the enoxaparin group (relative risk = 0.77, 95% confidence interval [CI] = 0.62-0.97, p = 0.025, number needed to treat = 79). With respect to all-cause mortality due to cardiovascular diseases, non-cardiovascular diseases and unknown causes, the number of the deaths was 5 (1.67%), 4 (1.34%) and 1 (0.33%) in the asymptomatic DVT group and 25 (0.42%), 33 (0.56%) and 11 (0.19%) in the no DVT group, respectively. Subjects with an asymptomatic DVT had an almost threefold increase in the risk of all-cause mortality compared with subjects without DVT (hazard ratio = 2.87, 95% CI = 1.48-5.57, p = 0.001). A positive linear trend was observed between greater thrombus burden and mortality during the follow-up (p = 0.019). CONCLUSION: Asymptomatic DVT was associated with approximately threefold increased risk of short-term all-cause mortality in patients hospitalized with an acute medical illness within the prior 77 days. A positive linear trend was observed between greater thrombus burden and mortality during the follow-up. PMID- 30419598 TI - Proline 36 of the Factor XIII Activation Peptide Plays a Crucial Role in Substrate Recognition and Zymogen Activation. AB - The activation peptide of blood coagulation factor XIII (AP-FXIII) has important functions in stabilizing the FXIII-A2 dimer and regulating FXIII activation. Contributions of many of its 37 amino acids to these functions have been described. However, the role of proline 36, which is adjacent to the thrombin cleavage site at Arg37, has not yet been studied in detail. We approached this question when we came across a patient with congenital FXIII deficiency in whom we detected a novel Pro36Ser mutation. We expressed the mutant FXIII-A Pro36Ser protein in Chinese hamster ovary cells and found that this mutation does not influence FXIII-A expression but significantly inhibits proteolytic activation by thrombin. The enzymatic transglutaminase activity is not affected as it can be induced in the presence of high Ca2+ concentrations. We performed nuclear magnetic resonance analysis to investigate AP-FXIII-thrombin interactions, which showed that the mutant Ser36 peptide binds less well to the thrombin surface than the native Pro36 peptide. The Arg37 at the P1 position still makes strong interactions with the active site cleft but the P4-P2 residues (34VVS36) appear to be less well positioned to contact the neighbouring thrombin active site region. In conclusion, we have characterized a novel mutation in AP-FXIII representing only the fourth case of the rare FXIII-A type II deficiency. This case served as a perfect in vivo model to shed light on the crucial role of Pro36 in the proteolytic activation of FXIII-A. Our results contribute to the understanding of structure-function relationship in FXIII. PMID- 30419599 TI - Erratum to: Prothrombin Complex Concentrate for Major Bleeding on Factor Xa Inhibitors: A Prospective Cohort Study. PMID- 30419600 TI - The Urokinase Plasminogen Activator System in Human Cancers: An Overview of Its Prognostic and Predictive Role. AB - Urokinase plasminogen activator (uPA) system regulates extracellular matrix remodelling by activating ubiquitous protease plasmin in many important physiological processes. The system components include uPA, plasminogen activator inhibitors (PAIs) and uPA receptor (uPAR). Besides its role in physiological processes, uPA system is active in most tumour types where its aberrant regulation has been associated with the development of metastatic phenotype. In vitro and in vivo studies have shown that the over-expression of uPA, PAI-1 and uPAR not only enhances tumour cell invasion capacity and metastasis, but also corresponds to a higher risk of disease correlating with traditional clinicopathological features which makes them potential prognostic biomarkers and therapeutic targets in a wide range of human malignancies. This review focuses on uPA system's prognostic and predictive role in several types of human cancers, summarizing its activities in cancer development and highlighting the importance of addressing all unanswered questions before bridging the gap between laboratory findings to clinic use of uPA system's components as cancer biomarkers. PMID- 30419602 TI - Neonatal outcomes of pregnancy-associated breast cancer: Population-based study on 11 million births. AB - BACKGROUND: As the age at first pregnancy continues to rise in the United States so does the incidence of breast cancer diagnosed during pregnancy. Our objective was to evaluate temporal trends in the incidence of pregnancy-associated breast cancer (PABC) and to measure neonatal outcomes associated with PABC. METHODS: We conducted a population-based cohort study using the 1999-2012 Healthcare Cost and Utilization Project-Nationwide Inpatient Sample (HCUP-NIS) from the United States. Logistic regression models, adjusted for maternal baseline characteristics, examined the effect of PABC on neonatal outcomes. RESULTS: There were 11 846 300 deliveries between 1999 and 2012, of which 772 cases of PABC were identified, resulting in an overall incidence of 6.5 cases/100 000 pregnancies. There was a significant increase in the incidence of PABC during the study period (P < 0.05). Women with PABC tended to be older, of white ethnicity, belong to a higher income quartile and to be treated in an urban teaching hospital. In pregnancies complicated by breast cancer, there was a greater risk of preterm delivery (OR 4.84, 95% CI 4.05-5.79) and preterm premature rupture of membranes (OR 1.79, 95% CI 1.06-3.05). No associations were observed between PABC and intrauterine growth restriction, congenital anomalies or intrauterine fetal demise. CONCLUSION: There is an uptrend in the incidence of PABC and therefore, the need for counseling these patients is also increasing. Although pregnancies with the diagnosis of maternal breast cancer are more prone to premature births, it is encouraging that these babies do not appear to be at increased risk for congenital anomalies, growth restriction, or fetal demise. PMID- 30419601 TI - Should the Presence or Extent of Coronary Artery Disease be Quantified in the CHA2DS2-VASc Score in Atrial Fibrillation? A Report from the Western Denmark Heart Registry. AB - BACKGROUND: Patients with atrial fibrillation (AF) have an increased risk of ischaemic stroke. The risk can be predicted by the CHA2DS2-VASc score, in which the vascular component refers to previous myocardial infarction, peripheral artery disease and aortic plaque, whereas coronary artery disease (CAD) is not included. OBJECTIVES: This article explores whether CAD per se or extent provides independent prognostic information of future stroke among patients with AF. MATERIALS AND METHODS: Consecutive patients with AF and coronary angiography performed between 2004 and 2012 were included. The endpoint was a composite of ischaemic stroke, transient ischaemic attack and systemic embolism. The risk of ischaemic events was estimated according to the presence and extent of CAD. Incidence rate ratios (IRR) were calculated in reference to patients without CAD and adjusted for parameters included in the CHA2DS2-VASc score and treatment with anti-platelet agents and/or oral anticoagulants. RESULTS: Of 96,430 patients undergoing coronary angiography, 12,690 had AF. Among patients with AF, 7,533 (59.4%) had CAD. Mean follow-up was 3 years. While presence of CAD was an independent risk factor for the composite endpoint (adjusted IRR, 1.25; 1.06 1.47), extent of CAD defined as 1-, 2-, 3- or diffuse vessel disease did not add additional independent risk information. CONCLUSION: Presence, but not extent, of CAD was an independent risk factor of the composite thromboembolic endpoint beyond the components already included in the CHA2DS2-VASc score. Consequently, we suggest that significant angiographically proven CAD should be included in the vascular disease criterion in the CHA2DS2-VASc score. PMID- 30419604 TI - Spontaneous coronary artery dissection treated with magnesium-made bioresorbable scaffold: 1-Year angiographic and optical coherence tomography follow-up. AB - A young woman admitted with a diagnosis of NSTE-ACS underwent coronary angiography which showed LAD spontaneous coronary artery dissection treated with magnesium-made bioresorbable scaffold. We report 1-year angiographic and OCT findings. PMID- 30419603 TI - Implantation of the Melody transcatheter pulmonary valve PB1016 in patients with dysfunctional right ventricular outflow tract conduits. AB - OBJECTIVES: This study describes procedural and 1-year outcomes of the 16 mm Melody PB1016 valve in patients with dysfunctional RVOT conduits. BACKGROUND: The Melody PB1016 is a standard Melody valve produced from a 16 mm bovine jugular vein and is intended for deployment up to 20 mm. METHODS: This is a prospective, non-randomized, multicenter study of the procedural and short-term outcomes of Melody PB1016 TPV replacement within dysfunctional RVOT conduits. Data from eight centers were included in the analysis. RESULTS: During the study period, 39 patients underwent attempted Melody TPVR. Of the 39 patients, 30 underwent successful Melody TPVR. The majority of patients underwent placement of one or more stents prior to TPVR. There was a significant reduction in peak conduit pressure gradient following TPVR (38 mmHg vs. 11 mmHg, P < 0.001). There were three cases of confined conduit tears successfully treated with covered stents or the valve itself. Repeat catheterization was performed in one patient for early re-obstruction that was successfully treated with balloon valvuloplasty. At recent follow-up, there were no cases of more than mild valve regurgitation and the mean pulmonary valve gradient by echocardiogram remained reduced relative to pre-TPVR implant measurements (33.5 mmHg vs. 15.2 mmHg). There were no cases of valve stent fracture or endocarditis reported at the 1-year follow-up. CONCLUSIONS: Our analysis of TPVR with the PB1016 valve in RVOT conduits showed it to be safe and effective and can be performed in a wide range of conduit sizes with preserved valve function. ClinicalTrials.gov Identifier: NCT02347189. PMID- 30419605 TI - Spectrum of mutations of cystic fibrosis in the 22 Arab countries: A systematic review. AB - Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the CFTR gene, with various clinical manifestations that affect pulmonary, digestive, exocrine and male reproductive functions as well as the bones and kidneys. This study aimed to reveal the spectrum of CFTR gene mutations in Arab CF patients and their corresponding clinical phenotypes among the 22 Arab countries. We searched four literature databases (PubMed, Science Direct, Web of Science and Scopus) from their times of inception to January 2018. All possible search terms were used to encompass the different clinical phenotypes, disease incidences, CFTR mutations, ages and consanguinity rates of CF patients in the 22 Arab countries. Our search strategy identified 678 articles; of these, 72 were eligible for this systematic review. We retrieved data from 18 Arab countries; only 1766 Arab patients with CF were identified, even after additional searches using Google and Google Scholar. The search uncovered a wide spectrum of mutations, some of which are shared with other ethnic groups and some unique to Arab patients. Although the clinical phenotypes of Arab patients were typical of CF, several distinct phenotypes were reported. Despite the rarity of genetic epidemiological studies of CF patients among the 22 Arab nations, the disease is frequently reported in Arab countries where consanguineous marriage is common. Therefore, significant attention should be paid to this problem by implementing carrier and premarital screening, newborn screening and genetic counselling. PMID- 30419606 TI - Tuning surface-cross-linking of molecularly imprinted cross-linked micelles for molecular recognition in water. AB - Molecular recognition in water is an important challenge in supramolecular chemistry. Surface-core double cross-linking of template-containing surfactant micelles by the click reaction and free radical polymerization yields molecularly imprinted nanoparticles (MINPs) with guest-complementary binding sites. An important property of MINP-based receptors is the surface-cross-linking between the propargyl groups of the surfactants and a diazide cross-linker. Decreasing the number of carbons in between the two azides enhanced the binding affinity of the MINPs, possibly by keeping the imprinted binding site more open prior to the guest binding. The depth of the binding pocket can be controlled by the distribution of the hydrophilic/hydrophobic groups of the template and was found to influence the binding in addition to electrostatic interactions between oppositely charged MINPs and guests. Cross-linkers with an alkoxyamine group enabled two-stage double surface-cross-linking that strengthened the binding constants by an order of magnitude, possibly by expanding the binding pocket of the MINP into the polar region. The binding selectivity among very similar isomeric structures also improved. PMID- 30419607 TI - Intraoperative palpation of sentinel lymph nodes can accurately predict axilla in early breast cancer. AB - Recent randomized trials have shown that completion axillary lymph node dissection (ALND) is not required in all patients with a positive sentinel lymph node (SLN) who will receive radiation therapy. Although routine intraoperative pathologic assessment (IPA) becomes unnecessary and less indicated by breast surgeons in the United States and some European countries, it is still widely used all around the world. In this prospective study, the feasibility of intraoperative nodal palpation (INP) as opposed to IPA of the SLN has been analyzed. Between March 2014 and June 2015, 305 patients with clinical T1-2/N0 breast cancer from two different breast clinics (cohort A; [n = 225] and cohort B; [n = 80]) who underwent any breast surgery with sentinel lymph node biopsy (SLNB) were included in this study. Surgeons evaluated the SLNs by manual palpation before sending for IPA, and findings compared with the final pathology. The positive predictive values (PPV) of INP and IPA were 81.8% and 97.9%, respectively, whereas the negative predictive values (NPV) of INP and IPA were 83% and 92.4%. The accuracies of INP and IPA were 82.6% and 94.1%, respectively. If patients with SLNB including micrometastasis were also considered in the final pathologic assessment (FPA) (-) group that would not require a further axillary dissection, the revised NPV of INP and FPA were found to be 92.6% and 98.1%, respectively. The revised accuracy of INP also found to be increase to 86.9%. Our study, which is the only prospective one about palpation of dissected SLNs in the literature, suggests that INP can help to identify patients who do not need ALND, which encourages omitting IPA in cT1-2 N0 breast cancer. PMID- 30419608 TI - Measuring the effects of bronchial thermoplasty using oscillometry. AB - BACKGROUND AND OBJECTIVE: Bronchial thermoplasty (BT) has been consistently shown to reduce symptoms, exacerbations and the need for reliever medication in patients with severe asthma. Paradoxically, no consistent improvement in spirometry has been demonstrated. It has been suggested that this is due to a reduction in peripheral resistance in small airways, not captured by spirometry. Therefore, in this study, we evaluate the response to BT using oscillometry. METHODS: A total of 43 patients with severe asthma from two centres were evaluated at baseline, 6 weeks and 6 months post BT, using spirometry, plethysmography and oscillometry, in addition to medication usage, exacerbation frequency and the Asthma Control Questionnaire (5-item version) (ACQ-5). RESULTS: The mean age was 58.4 +/- 11.2 years, forced expiratory volume in 1 s (FEV1 ) 55.5 +/- 20.1% predicted, forced expiratory ratio 53.0 +/- 14.5% and FEV1 response to salbutamol was 14.0 +/- 14.5%. Following BT, the group responded to treatment with an improvement in ACQ-5 from 2.9 +/- 0.9 at baseline to 1.7 +/- 1.1 at 6 months (P < 0.005). There was an 81% reduction in exacerbation frequency (P < 0.001) and 50% of patients were weaned completely from maintenance oral corticosteroids. No changes after treatment were observed in spirometry but the residual volume reduced from 147 +/- 38% to 139 +/- 39% predicted (P < 0.01). Baseline oscillometry demonstrated high levels of resistance at 5 Hz with normal resistance at 20 Hz, indicating resistance in the small airways was elevated, but no changes were observed in any oscillometry parameter after BT treatment. CONCLUSION: Lung impedance measured with oscillometry did not change following BT despite marked clinical improvements in patients with severe asthma. PMID- 30419609 TI - ComPAS: A Bayesian drug combination platform trial design with adaptive shrinkage. AB - Combining different treatment regimens provides an effective approach to induce a synergistic treatment effect and overcome resistance to monotherapy. The challenge is that, given the large number of existing monotherapies, the number of possible combinations is huge and new potentially more efficacious compounds may become available any time during drug development. To address this challenge, we propose a flexible Bayesian drug combination platform design with adaptive shrinkage (ComPAS), which allows for dropping futile combinations, graduating effective combinations, and adding new combinations during the course of the trial. A new adaptive shrinkage method is developed to adaptively borrow information across combinations and efficiently identify the efficacious combinations based on Bayesian model selection and hierarchical models. Simulation studies show that ComPAS identifies the effective combinations with higher probability than some existing designs. ComPAS provides an efficient and flexible platform to accelerate drug development in a seamless and timely fashion. PMID- 30419610 TI - Hybrid transcatheter tricuspid valve-in-valve placement of an Edwards Sapien XT valve in palliated hypoplastic left heart syndrome. AB - Tricuspid regurgitation in the context of hypoplastic left heart syndrome (HLHS) carries a significant burden of both mortality and morbidity. We report successful hybrid trans-atrial implantation of an Edwards Sapien XT valve into a dysfunctional bioprosthetic valve in the tricuspid position of a 9-year-old patient with HLHS. There was an immediate fall in the Fontan pressures combined with significant clinical improvement and the valve continues to function well nearly 3 years post implant. To the best of our knowledge, this is the first described implantation of a transcatheter valve in this specific position and anatomy. PMID- 30419611 TI - Feasibility, safety and midterm follow-up of patients after nonsurgical closure of atrial septal defects using very large 40-46 mm nitinol septal occluders. AB - OBJECTIVES: To study the feasibility of closure of large atrial septal defects (ASDs) using occluder devices >38 mm and assess the midterm complications. BACKGROUND: Feasibility and safety of large occluders >38 mm and their follow-up are largely unknown. METHODS: All patients with ASDs closed using devices >38 mm were retrospectively analyzed. Since outcome of patients receiving 40 mm devices were known before, patients receiving 40 mm devices were compared with those receiving 42-46 mm devices on demographic, hemodynamic parameters and procedural characteristics. RESULTS: A total of 17 patients with 40-mm device and 31 patients with >40-mm device formed the cohort. The mean echocardiographic defect size was 36.3 +/- 3.7 mm. In total 19 patients had deficient retroaortic margin; inferior margin was deficient in one. Larger defects needed special deployment techniques more often. There was acute technical success in all patients. Two procedures failed; one device embolization next day in a patient with deficient inferior margin needed surgery. Another elderly patient with restrictive left ventricular physiology died of multiorgan dysfunction. Two late deaths on follow up were unrelated to the procedure. All other patients had symptom improvement. There were no erosions, thromboembolism or valvar regurgitation at a median follow-up of 39 (1-60) months. Apart from late-onset atrial flutter in one, there were no arrhythmias on follow-up. CONCLUSIONS: Occluders larger than 38 mm in appropriately selected patients are feasible, successful and safe in majority and often require special deployment techniques. Complications during and after the procedure were infrequent. Very large defects with any deficient margin except retroaortic rim should be excluded from device closure. PMID- 30419612 TI - A Real-time Color Doppler Marker for Echocardiographic Guidance of an Acoustically Active Extracorporeal Membrane Oxygenation Cannula. AB - B-mode ultrasound imaging guidance of cannulas can be compromised by noise, artifacts, and echogenicity that is not distinctive from that of surrounding anatomy. We have modified a venovenous extracorporeal membrane oxygenation cannula by embedding piezoelectric crystals into each of its 3 blood flow ports. Each vibrating crystal acoustically interacts with a Doppler imaging signal and produces an instantaneous color marker. The aim of this study was to compare identification of the extracorporeal membrane oxygenation cannula ports by B-mode imaging versus the color Doppler marker. Unlike B-mode imaging, the color Doppler marker identified the corresponding port even in highly challenging closed-chest scans in anesthetized pigs. The method could improve guidance accuracy of cannulas by ultrasound scans. PMID- 30419613 TI - Pre-treatment wait time for head and neck cancer patients in Western Australia: description of a new metric and examination of predictive factors. AB - BACKGROUND: Prolonged pre-treatment wait times in head and neck cancer are associated with increased morbidity and reduced survival. Traditional metrics exclude delays prior to biopsy, which represents an important and measurable period of time. This study aims to describe total wait time for head and neck cancer patients in our institution, to define a more accurate representation of the clinically relevant pre-treatment wait time, and to evaluate predictive factors for prolonged wait times. METHODS: A retrospective review of head and neck cancer patients treated over 2 years in a tertiary referral centre was conducted. Patient demographics, referral symptoms, tumour details, treatment plan and key dates were analysed to identify total wait time and factors predictive of increased wait time. RESULTS: Two hundred and ninety-four patients were included. Mean total wait time from initial referral to treatment initiation was 71.6 (median 61) days. The period from referral to biopsy represented 29% of mean total wait time. Factors predictive of increased wait time included presenting symptom of hoarseness, laryngeal cancer and treatment with definitive radiotherapy. CONCLUSIONS: This study demonstrates that time from referral to biopsy represents a significant portion of total wait time, and we suggest that this be incorporated into future wait time metrics for improved clinical relevance. Furthermore, we have identified factors predicting increased wait time which can be targeted for future service improvement. PMID- 30419614 TI - Determinants of angiographic thrombus burden and impact of thrombus aspiration on outcome in young patients with ST-segment elevation myocardial infarction. AB - OBJECTIVES: We aimed to investigate the determinants of thrombus burden (TB) and the impact of thrombus aspiration (TA) on outcome in young adults with ST segment elevation myocardial infarction (STEMI). BACKGROUND: The determinants of TB in young STEMI patients are not fully understood now. METHODS: The 182 young (age <= 45 years) STEMI patients, who underwent coronary angiography and percutaneous coronary intervention (PCI) in our hospital from January 2013 to September 2016, were included. Angiographic TB and impact of TA on major adverse cardiac events (MACEs) were evaluated. Median clinical follow-up period was 875 (641-1,052) days. RESULTS: All patients were male, mean age was 40 +/- 5 years. High thrombus burden (HTB) was evidenced in 100 (54.9%) patients. TA was performed in 62 out 100 (62%) patients with high TB (HTB) during PCI. The prevalence of hypertension was significantly higher in the HTB group than in the low thrombus burden (LTB) group (75 vs. 17%, P < 0.001). The proportion of smoking, alcohol consumption, and family history of premature coronary artery disease were similar between HTB and LTB groups. During follow-up, 2 patients died and 31 patients underwent repeat PCI. MACE rate was significantly higher in the HTB group than in the LTB group (24.0 vs. 9.8%, P = 0.012) and significantly lower in HTB patients with TA than HTB patients without TA (14.5 vs. 39.5%, P = 0.018). CONCLUSIONS: Hypertension is an independent determinant of HTB and TA could be considered as an effective therapeutic option in young male STEMI patients with HTB. PMID- 30419615 TI - Distribution of hepatitis C virus genotypes and subtypes in Croatia: 2008-2015. AB - OBJECTIVE: Hepatitis C virus (HCV) genotyping is an important part of pre treatment diagnostic algorithms as it guides the choice of therapeutic regimens. The aim of this study was to analyse the distribution of HCV genotypes in patients with chronic hepatitis C from Croatia in the period 2008-2015. METHODS: The study enrolled 3,655 anti-HCV positive patients with available results of HCV genotyping from the three largest national HCV genotyping laboratories. RESULTS: The majority of HCV-infected individuals enrolled in the study were male (70.7%). Analysis of age distribution in a subset of 2,164 individuals showed a mean age of 40.9 years (SD 11.77 years). Croatian patients were mostly infected with HCV genotype 1 (56.6%), followed by genotype 3 (37.3%), genotype 4 (4.2%) and genotype 2 (1.8%). Genotype 1 subtyping in a subset of 1,488 patients showed 54% (803/1,488) of 1b infections and 46% (685/1,488) of 1a infections. Percentages of genotype 1 were the highest in Central/Northwestern and Eastern Croatia and the lowest in the Central/Southern Adriatic Region. Genotype 3 was most frequently found in the Central/Southern Adriatic Region (49.1%) but represented only 17.5% of infections in Eastern Croatia (p < 0.001). CONCLUSIONS: The results of this nine-year retrospective analysis on the distribution of HCV genotypes and subtypes in 3,655 HCV-infected individuals from Croatia showed that the majority of infections can be attributed to genotypes 1 and 3 with absence of major changes in the molecular epidemiology of the two most frequent HCV genotypes infection in Croatia in the past 20 years. PMID- 30419616 TI - Continued smoking versus spontaneous quitting among pregnant women living in a high risk environment. AB - OBJECTIVES: In Hungary, 37% of women living in poverty were smokers in 2012. There are no valid data of pregnant women's spontaneous smoking cessation. METHODS: Our retrospective cohort study (2009-2012) targeted the most underdeveloped regions with an estimated 6-8.5% of Roma population. The sample (N = 12,552) represented 76% of the target population i.e. women in four counties in a year delivering live born babies. Chi-square probe and multivariable logistic regression model (p < 0.05) were used to assess relationship between socio demographic characteristics and spontaneous cessation. RESULTS: Prior to pregnancy, the overall smoking rate was 36.8%. That of women in deep poverty and Roma was 49.7% and 51.1%, respectively. 70.3% of smokers continued smoking during the pregnancy. Among them 80.6% lived in deep poverty. Spontaneous quitting rate was 23.0%. Factors correlated with continued smoking included being Roma (OR = 1.95), undereducated (OR = 2.66), living in homes lacking amenities (OR = 1.48), and having regularly smoking partner (OR = 2.07). Cessation was promoted by younger age (<= 18 years) (OR = 0.18), being married (OR = 0.50), and the first pregnancy. CONCLUSIONS: Tailored cessation programmes are needed for Roma, older, low-income, and multiparous women who are less likely to quit on their own. Engaging husbands/partners is essential to reduce smoking among pregnant women and second-hand smoke exposure. PMID- 30419617 TI - Community-based survey as a basis for evidence-based public health: children living in Upper Silesian Industrial Zone. AB - OBJECTIVE: The aim of the study was to estimate changes in the prevalence of respiratory diseases and disorders between 2003/2004 and 2011/2012 in 13-16 years old children living in Bytom, one of the biggest cities in the Silesia agglomeration and provide the evidence for local policy makers. METHODS: Data from two cross-sectional surveys, based on the Polish version of the International Study of Allergy and Asthma in Childhood (ISAAC) questionnaire, conducted in 2003/2004 and 2011/2012 was used. Response rate in the first and the second survey was 68% and 35%, respectively. The number of analyzed observations was 4,041 and 707 from the first and the second survey. The selection bias was controlled with the propensity score matching and potential determinants of analyzed respiratory diseases and disorders were controlled in the multivariable logistic regression model. RESULTS: We found statistically significant increase in asthma ever diagnosed by medical doctor (4.5% vs. 9.6%; p < 0.01), seizures of dyspnea (8.2% vs. 27.7%; p < 0.01), and chest wheeze (9.6% vs. 19.2%; p < 0.01). CONCLUSION: Our study revealed significant increase in the prevalence of respiratory diseases and disorders after 8 years in adolescents living in the Upper Silesian Industrial Zone. This is a relevant finding which provides the evidence for decision makers in the scope of local public health policies. PMID- 30419618 TI - Respiratory toxicity of TiO2 nanoparticles after intravenous instillation: an experimental study. AB - OBJECTIVE: Nanomaterials are materials consisting of particles having one or more dimensions smaller than 100 nm. Nanoparticles (NP) have different properties and effects in comparison with the same particle materials of larger size. They can penetrate through various membranes and get from the bloodstream to other organs in the body. Therefore, in our experiment we have dealt with the impact of nanoparticles TiO2 instilled intravenously (i.v.) (to a tail vein of an animal) on the selected parameters of bronchoalveolar lavage (BAL). The aim of our study was to determine whether TiO2 nanoparticles do pass through the vascular system to the respiratory tract, and if so, how they affect the selected inflammatory and cytotoxic parameters of bronchoalveolar lavage. METHODS: Wistar rats were intravenously given a suspension of TiO2 nanoparticles in saline solution. This suspension contained 10% volume of rat serum in dose: 1.0% from LD50 = 0.592 mg/kg of animal body weight. After the time intervals 1, 7, 14 and 28 days, the animals were sacrificed under anaesthesia; bronchoalveolar lavage was performed and the BAL cells were isolated. We have examined these markers: differential count of BAL cells - alveolar macrophages (AM), polymorphonuclear leukocytes (PMNL), lymphocytes (Ly); viability and phagocytic activity of AM; proportion of immature cells and cathepsin D enzyme levels. RESULTS: Regarding the respiratory toxicity of TiO2 nanoparticles we have found that TiO2 nanoparticles are relatively inert. BAL examined parameters (except the immature form of AM) were not significantly changed after 28 days of instillation compared to the control group. We found that the TiO2 nanoparticles used in our study were transferred from the bloodstream to the respiratory tract, but in a 28-day phase after i.v. instillation have been largely eliminated by the defence mechanism from the respiratory tract. CONCLUSIONS: We suggest low biopersistence and relatively rapid elimination of TiO2 nanoparticles from the lung under used experimental conditions. PMID- 30419619 TI - Psychosocial and physiological risks of shift work in nurses: a cross-sectional study. AB - OBJECTIVES: Many jobs are associated with psychological or social risk factors. Knowledge of occupational diseases is essential for adopting rational control measures. The aim was to study and describe frequent social, psychological and physiological risk factors for nurses. METHODS: Psychological and social risks were evaluated in nurses with regular or irregular shifts. In addition, differences between nurses or nursing assistants were studied. The Copenhagen Psychosocial Questionnaire, Eating Attitudes Test, Profile of Mood State, Athens Insomnia Scale, Trait Anxiety Inventory, and Minnesota Leisure Time were administered. RESULTS: Nursing assistants presented higher levels of body mass index and food restriction than nurses, nevertheless, nurses showed increasing tension in work. In nursing, shift work increases psychosocial risks, insomnia, eating disorders, and trait anxiety. CONCLUSIONS: In conclusion, nurses and nursing assistants in health centres and hospitals show high levels of exposure to psychological and psychosocial risks that are unfavourable to their health. PMID- 30419620 TI - A new potential biomarker in early diagnosis of firefighter lung function impairment: dynamic thiol/disulphide homeostasis. AB - OBJECTIVES: The aim of this study was to investigate the associations between urinary arsenic, oxidative stress, assessed by thiol/disulphide homeostasis, and lung diseases in firefighters. METHODS: The study conducted among the municipality-based male firefighters (n = 100) who were admitted to occupational diseases clinic for periodic medical examination. The control group consisted of non-exposed male office workers (n = 50). Urinary arsenic levels, thiol/disulphide homeostasis parameters of participants were determined. Also, lung diseases were assessed by chest X-ray and pulmonary function tests. RESULTS: The mean age and work year did not differ in the study and control group. The median urinary arsenic concentration of firefighters was significantly higher than in the control group: 15.65 (2.5-246) MUg/L and 3 (0.10-6) MUg/L, respectively (p < 0.001). The parameters of pulmonary function tests (PFT) FVC (%), FEV1 (%), FEV1/FVC ratio and FEF 25-75 (%) were all significantly lower in firefighters compared to controls. A significant increase in mean serum disulphide concentration (17.10 +/- 8.31 MUmol/L vs. 7.48 +/- 5.91) (Fig. 1) and disulphide/native thiol % ratio: 3.63 (0.53-11.43) vs. 1.51 (0.03-7.65) (p < 0.001) were found between exposed group and controls. The Spearman's correlation analysis revealed a positive correlation between urinary arsenic and disulphide (r = 0.422, p < 0.001), disulphide/native thiol % ratio (r = 0.409, p < 0.001). Nevertheless, urinary arsenic correlated negatively with all PFT parameters including FVC (%), FEV1 (%), FEV1/FVC and FEF 25-75 (%) (p < 0.001). CONCLUSION: We showed the arsenic-induced oxidative stress in firefighters with impairments of several lung functions determined by thiol/disulphide homeostasis using a novel method. PMID- 30419621 TI - Risk indicators for road accident in Poland for the period 2004-2017. AB - OBJECTIVE: The aim of the research was to assess the prevalence, effects and risk factors for motor vehicle accidents (MVA) in the years 2004-2017 in Poland. METHOD: We merged secondary data from the Prevention and Analysis Office of Road Traffic Headquarters of Police and Central Statistical Office of Poland. RESULTS: Our results suggest that several thousand people are killed on Polish roads annually, and tens of thousands are injured. Road crashes represent the leading cause of death for Polish men up to 44 years of age. The most common causes of road crashes in Poland include failure to comply with the road traffic rules and low driving skills. We also found drivers who poorly assessed road situations, roads characterized by a lack of adequate road infrastructure, and many vehicles in poor condition. Road crashes have become a significant public health and social problem globally. Drivers caused most MVA in Poland in the years 2004 2017, whereas the underlying cause was inadequate speed regarding the road traffic condition as well as not respecting the right-of-way. Despite various measures that are being taken to improve safety on Polish roads, the number of the dead and wounded as a result of road accidents is still high and the losses to the society are considerable as well. CONCLUSION: It is necessary to continue multidirectional actions to improve safety on the roads in Poland resulting in a systematic increase in the level of road traffic security. PMID- 30419622 TI - Evaluation of oral health status of children in pretreatment and after treatment for 18 month. AB - OBJECTIVE: Dental caries is an important public health issue worldwide. In developing countries preventive dentistry is not common; hence, oral and dental health problems continue to generate serious economic and social issues. The aim of this study was to assess oral health and the incidence of dental caries in systemically healthy children aged 3-14 years, provide education on oral hygiene motivation, conduct the necessary preventive and restorative procedures, and reassess caries development at the 6-, 12-, and 18-month post-treatment follow up. METHODS: Systemically healthy children aged 3-14 years who applied to the Paediatric Dentistry Clinic, Faculty of Dentistry, Adnan Menderes University (ADU) were included in the study. The subjects were evaluated for oral health status and incidence of dental caries based on surveys and clinical examination, motivation for oral hygiene with necessary training, completion of preventive and restorative treatments, and development of dental caries at the 6-, 12-, and 18 month post-treatment follow-up. RESULTS: The study included 320 patients, aged 3 14 years (mean age 8.08 +/- 3.45 years). In children included in the study, the average decayed (d), missing (m) and filled (f) primary teeth (dmft) value was 3.81 (min-max: 0-16), decayed (D), missing (M) and filled (F) permanent teeth (DMFT) value, 1.49 (min-max: 0-6), decayed (d), missing(m) and filled(f) primary teeth surface (dmfs) value, 10.11 (min-max: 0-40), and decayed (D), missing (M) and filled (F) permanent teeth surface (DMFS) value, 2.09 (min-max: 0-12). CONCLUSIONS: For the protection and maintenance of oral and dental health in dentistry, preventive approaches should be the first concern and conservative therapeutic methods should be given priority after occurrence of any dental pathology. In addition, one-time examinations are not sufficient, and children should be examined at least twice a year. This study showed that the incidence of dental caries declined in children who underwent periodical examination and preventive dental treatment. PMID- 30419623 TI - Test-retest reliability of selected HBSC items measuring problem behaviour among Slovak and Czech adolescents. AB - OBJECTIVES: The purpose of this study was to assess the test-retest reliability of selected items based on self-reports, measuring problem behaviour in the Slovak and Czech version of the HBSC survey questionnaire. METHODS: The data from test-retest study, based on an international Health Behaviour in School-aged Children (HBSC) study and consistent with its methodology, were analysed. A sample of 580 primary school pupils (51.2% of boys), grades five and nine participated in a test and retest with a four-week interval. Six items concerning problem behaviour were evaluated overall and stratified by gender and age. RESULTS: Analyses of test-retest reliability indicated modest (0.30 to 0.49), moderate (0.50 to 0.69), or high (0.70 to 1.00) reliability across nearly all questions, with some reliability differences in analyses by gender and age. In general, findings of present study suggest the moderate reliability of measures of smoking, drunkenness, fighting and negative relationship to school, modest reliability of measures of bullying behaviour, and low reliability of measure of truancy. CONCLUSIONS: The overall findings of this study suggest that most of selected indicators in the HBSC survey questionnaire have satisfactory test retest reliability. Further test-retest studies in a large and diverse sample, as well as validity studies, should be considered for the future HBSC study. PMID- 30419624 TI - Association between computer game type, playing time and sense of coherence in Lithuanian adolescents. AB - OBJECTIVE: As an excessive gaming is the addiction of the 21th century, purpose of our study was to investigate how sense of coherence interacts with gaming time, choice of various games types, age and gender characteristics. Our task was to evaluate relationship between computer gaming and an adolescent's sense of coherence. METHODS: A cross-sectional study based on a self-reported questionnaire was performed among the representative samples of 1,806 adolescents aged 13-18 years. Adolescents reported the amount of time spent gaming computer games, types of games, as well as sense of coherence. The relations between the choice of computer games type, time spent gaming computer games and sense of coherence of respondents were assessed by odds ratio using multivariate regression analysis. RESULTS: 32.9% of boys and 81.1% of girls reported gaming computer games less than 5 hours per day during the last month (p < 0.001). 30.9% of boys and 4.1% of girls reported gaming computer games more than 10 hours per day during the last month (p < 0.001). Boys and girls aged 13-15 with a weak sense of coherence had significantly higher probability to play action or combat computer games for 5 or more hours per day in comparison to the respondents who had a strong sense of coherence. Also, this probability was 2 times higher among boys than among girls. CONCLUSION: Sense of coherence is a useful tool to identify adolescents who are at risk of excessive gaming. Game playing time is linked to the sense of coherence. Adolescent with a weak sense of coherence had a higher probability to play more times, especially in younger age. PMID- 30419625 TI - A study on stress, depression and suicidal ideation according to sexual behaviours among Korean adolescents. AB - OBJECTIVE: The purpose of this study was to examine stress, depression and suicidal ideation in Korean adolescents according to their sexual behaviours, such as experience of sexual intercourse, time of first sexual intercourse, and sexual intercourse after alcohol drinking. METHODS: This study was conducted as a secondary data analysis using the raw data of the 9th Korea Youth Risk Behaviour Web-based Survey (KYRBWS-IX) conducted in 2013. The survey sampled 75,149 secondary school students, and 72,435 of them were included in this analysis. RESULTS: Stress level, depression and suicidal ideation were significantly higher in adolescents with experience of sexual intercourse than in those without it. Adolescents with experience of sexual intercourse after drinking had a 1.415 times higher odds ratio depression than those without it. When the time of first sexual intercourse was delayed by one year, the odds of stress increased by 1.022 times and the odds of suicidal ideation increased by 1.014 times. CONCLUSIONS: Adolescents with experience of sexual intercourse showed significantly higher stress, depression and suicidal ideation, the latter of which was particularly higher among low-grade female students that had experienced first sexual intercourse at a young age. Suicidal ideation was more common when first sexual intercourse was early. Adolescents with experience of sexual intercourse after drinking showed higher stress, depression and suicidal ideation than those without drinking. PMID- 30419626 TI - Assessment of changes in somatic characteristics based on the level of physical activity in women who undertook weight reduction course. AB - OBJECTIVE: Obesity is a chronic disease in modern age and finding approach to the prevention, diagnosis and treatment of obesity has its place among the priorities of modern medicine and related fields. Important component in programmes to reduce overweight and obesity is regular physical activity (PA), which plays vital role in the comprehensive approach to the treatment of obesity. Primary objective of our study was to assess changes in somatic characteristics following eleven weeks of PA in overweight and obese women aged 30 to 60 years. METHODS: Our research sample consisted of 221 women who were classified according to the level of PA carried out, namely 1st, 2nd and 3rd category. STOB (STop OBesity) course participants underwent PA monitoring and diagnosis of the body composition, which is a modern multifaceted cognitive behavioural method. RESULTS: Younger highly active women (PA 3) achieved higher average differences in body fat than did women with the typical daily activity (PA 1), however, significant differences have not been found. Statistically significant differences in visceral fat between the 1st (PA 1) and 3rd PA category (PA 3) have been observed in older women. CONCLUSION: Given the significantly higher increase of fat-free mass percentage in older highly active women (PA 3), we may assess the course results positively. Our study demonstrated positive correlation between carrying out the recommended level of PA and its impact on the body composition's health risk indicators. Obese women should walk at least 10,000 steps per day to improve their health. PMID- 30419627 TI - Gender-associated differences in the prevalence of central obesity using waist circumference and waist-to-height ratio, and that of general obesity, in Slovak adults. AB - OBJECTIVES: Central obesity represents an increased risk to develop cardiovascular diseases. Guidelines of international societies suggest estimating central obesity by measuring waist circumference (WC). Robust statistical data in literature provide evidence on the superiority of waist-to-height ratio (WHtR) over WC and body mass index (BMI) for detecting cardiometabolic risk in both genders. Based on measurements of weight, height and waist circumference we compared the prevalence of central obesity using both the above mentioned criteria in the apparently healthy Slovak adults, and compared the prevalence of central obesity to that of general obesity (BMI). METHODS: Data collected from 5,184 individuals (45% males) aged >=18 years in four cross-sectional studies carried out between the years 2009-2012 were subjected to secondary analysis. RESULTS: Waist circumference underestimated central obesity in males and overestimated in females: 37.3% of males and 41.8% of females presented central obesity according to WC, 54.2% males and 34.9% females according to WHtR. 17.3% of males centrally obese according to WC present WHtR < 0.5; while 7.8% of females centrally obese according to their WHtR do not display increased WC. The frequency of central obesity increased with age. According to BMI, the prevalence of overweight was 39% in males and 22% in females; that of obesity was 17% and 15%, respectively. CONCLUSION: The prevalence of central obesity estimated using WC vs. WHtR differs significantly in Slovak adults. WHtR is considered superior for detection of the risk of future development of cardiovascular afflictions. Thus, further studies addressing the gender-associated discordance of central obesity measures are required to determine whether our results are consistent across geographical regions and ethnic groups. PMID- 30419628 TI - Low health literacy and excess body weight: a systematic review. AB - OBJECTIVE: There is recent evidence that poor health literacy (HL) could be implicated in the aetiology of obesity and could be an important reason behind obese people's inability to encounter difficulties in overcoming obesity issues. The current study reviews the recent scientific evidence investigating the possible link between poor HL levels and excess body weight in adults and children. METHODS: The authors performed a thorough systematic computer-assisted literature search from 1 January 2005 up to 31 May 2017. Only English original studies in healthy people, investigating the relationship between HL and excess body weight, were included. RESULTS: Twenty-two studies in total were included in this literature review, 17 studies were conducted in adults and 5 in children. In 17 out of 22 studies reviewed, low HL was significantly associated with increased body mass index, overweight and obesity. In case of children and adolescents, the above association seems to be more consistent compared to adults. CONCLUSION: There is good evidence that low levels of HL are associated with excess body weight, particularly in children. Initiatives to improve health literacy levels could be a useful tool in the management of the obesity epidemic. PMID- 30419629 TI - Expansion of lactation support services to neonatal intensive care unit. PMID- 30419630 TI - Current Definition of and Controversial Issues Regarding Postoperative Pancreatic Fistulas. AB - The International Study Group for Pancreatic Fistula (ISGPF) made the first attempt to standardize the outcome measure of fistulas in the field of pancreatic surgery by publishing the definition and classification of postoperative pancreatic fistulas (POPFs) in 2005. POPFs were determined by any measurable volume of fluid output via an operatively placed drain with amylase activity greater than three times the upper normal serum value. Taking into account more than 10 years of reported experience worldwide, the updated definition published in 2016 by the reconvened International Study Group for Pancreatic Surgery (ISGPS) attempted to overcome the limits of the previous classification. The crucial concept of POPF clinical significance was introduced by eliminating grade A from the fistula scenario. The wider use of interventional procedures has also made it necessary to recode grade C POPFs, which now have clearer boundaries, toward the worst end of the severity scale. Grade B still represents the most prevalent and heterogeneous category of POPFs, both in terms of clinical burden and management. In the near future, further efforts will be required to better stratify grade B POPFs to standardize treatment strategies and compare outcomes among institutions. PMID- 30419631 TI - Association between Types of Usual Source of Care and User Perception of Overall Health Care Service Quality in Korea. AB - Background: Patients' perceptions of care tend to correlate with the quality of care provided. Different health care systems and service environments may show different associations between types of usual source of care (USC) and overall service quality assessment. We attempted to analyze this association as a benefit of having a USC. Methods: This study used the 2012 Korea Health Panel data version 1.1 as representative national household survey data. The total number of subjects aged 18 years or more was 12,708. The number of subjects in the final analysis was 10,665. Multiple logistic regression analysis was used to assess the association between types of USC and overall health care service quality. The main outcome variable was users' ratings of the quality of health care service. Results: People having a usual doctor (n=1,796) were more likely to positively assess the quality of health care they received than those not having a USC (n=7,920; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.20-1.60) or with those having only a place as a USC without a usual doctor (n=949; OR, 1.29; 95% CI, 1.05-1.58) after adjustment for demographic characteristics and health related variables. Conclusion: People having a usual doctor rated overall health care service quality as high, which might be due to benefits of primary care attributes related to usual doctors. Further studies are needed to elucidate the causal relationship. This finding implies that health policies encouraging people to have a usual doctor are needed in Korea. PMID- 30419632 TI - Serum Alanine Aminotransferase Level as a Risk Factor for Coronary Heart Disease Prediction in Koreans: Analysis of the Korea National Health and Nutrition Examination Survey (V-1, 2010 and V-2, 2011). AB - Background: The blood level of alanine aminotransferase (ALT) is associated with increased coronary heart disease (CHD) risk. However, its use as an independent factor for CHD risk prediction remains unclear in Asian populations. The purpose of this study was to examine the association between serum ALT levels and CHD risk in Koreans. Methods: This was a cross-sectional study using data from the Korea National Health and Nutrition Examination Survey (V-1, 2010 and V-2, 2011). The ALT levels of 3,215 individuals were analyzed. The Framingham Risk Score (FRS) modified by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) was used to compute the 10-year CHD risk prediction. Results: Positive correlations were established between log-transformed ALT concentration and FRS (r=0.433, P<0.001). After adjusting for body mass index, low-density lipoprotein cholesterol, the amount of alcohol intake, and gamma glutamyl transferase, the odds ratio (95% confidence interval) for intermediate or greater risk of 10- year CHD prediction (10-year risk >=10%) for the lowest quartile of participants was 2.242 (1.405-3.577) for the second quartile, 2.879 (1.772-4.679) for the third quartile, and 3.041 (1.789-5.170) for the highest quartile. Conclusion: In Koreans, a higher serum ALT concentration was significantly correlated with 10-year CHD risk prediction according to NCEP ATP III guidelines. PMID- 30419633 TI - Isolation of MLL1 Inhibitory RNA Aptamers. AB - Mixed lineage leukemia proteins (MLL) are the key histone lysine methyltransferases that regulate expression of diverse genes. Aberrant activation of MLL promotes leukemia as well as solid tumors in humans, highlighting the urgent need for the development of an MLL inhibitor. We screened and isolated MLL1-binding ssRNAs using SELEX (Systemic Evolution of Ligands by Exponential enrichment) technology. When sequences in sub-libraries were obtained using next generation sequencing (NGS), the most enriched aptamers-APT1 and APT2-represented about 30% and 26% of sub-library populations, respectively. Motif analysis of the top 50 sequences provided a highly conserved sequence: 5? A[A/C][C/G][G/U][U/A]ACAGAGGG[U/A]GG[A/C]GAGUGGGU-3?. APT1, APT2, and APT5 embracing this motif generated secondary structures with similar topological characteristics. We found that APT1 and APT2 have a good binding activity and the analysis using mutated aptamer variants showed that the site information in the central region was critical for binding. In vitro enzyme activity assay showed that APT1 and APT2 had MLL1 inhibitory activity. Three-dimensional structure prediction of APT1-MLL1 complex indicates multiple weak interactions formed between MLL1 SET domain and APT1. Our study confirmed that NGS-assisted SELEX is an efficient tool for aptamer screening and that aptamers could be useful in diagnosis and treatment of MLL1-mediated diseases. PMID- 30419634 TI - The Inhibitory Mechanism on Acetylcholine-Induced Contraction of Bladder Smooth Muscle in the Streptozotocin-Induced Diabetic Rat. AB - Most diabetic patients experience diabetic mellitus (DM) urinary bladder dysfunction. A number of studies evaluate bladder smooth muscle contraction in DM. In this study, we evaluated the change of bladder smooth muscle contraction between normal rats and DM rats. Furthermore, we used pharmacological inhibitors to determine the differences in the signaling pathways between normal and DM rats. Rats in the DM group received an intraperitoneal injection of 65 mg/kg streptozotocin and measured blood glucose level after 14 days to confirm DM. Bladder smooth muscle contraction was induced using acetylcholine (ACh, 10-4 M). The materials such as, atropine (a muscarinic receptor antagonist), U73122 (a phospholipase C inhibitor), DPCPX (an adenosine A1 receptor antagonist), udenafil (a PDE5 inhibitor), prazosin (an alpha1-receptor antagonist), papaverine (a smooth muscle relaxant), verapamil (a calcium channel blocker), and chelerythrine (a protein kinase C inhibitor) were pre-treated in bladder smooth muscle. We found that the DM rats had lower bladder smooth muscle contractility than normal rats. When prazosin, udenafil, verapamil, and U73122 were pre-treated, there were significant differences between normal and DM rats. Taken together, it was concluded that the change of intracellular Ca2+ release mediated by PLC/IP3 and PDE5 activity were responsible for decreased bladder smooth muscle contractility in DM rats. PMID- 30419635 TI - Purpurogallin Protects Keratinocytes from Damage and Apoptosis Induced by Ultraviolet B Radiation and Particulate Matter 2.5. AB - Purpurogallin, a natural phenol obtained from oak nutgalls, has been shown to possess antioxidant, anticancer, and anti-inflammatory effects. Recently, in addition to ultraviolet B (UVB) radiation that induces cell apoptosis via oxidative stress, particulate matter 2.5 (PM2.5) was shown to trigger excessive production of reactive oxygen species. In this study, we observed that UVB radiation and PM2.5 severely damaged human HaCaT keratinocytes, disrupting cellular DNA, lipids, and proteins and causing mitochondrial depolarization. Purpurogallin protected HaCaT cells from apoptosis induced by UVB radiation and/or PM2.5. Furthermore, purpurogallin effectively modulates the pro-apoptotic and anti-apoptotic proteins under UVB irradiation via caspase signaling pathways. Additionally, purpurogallin reduced apoptosis via MAPK signaling pathways, as demonstrated using MAPK-p38, ERK, and JNK inhibitors. These results indicate that purpurogallin possesses antioxidant effects and protects cells from damage and apoptosis induced by UVB radiation and PM2.5. PMID- 30419636 TI - Successful transition from pediatric to adult care in inflammatory bowel disease: what is the key? AB - The incidence of pediatric-onset inflammatory bowel disease (IBD) is on the rise, accounting for up to 25% of IBD cases. Pediatric IBD often has extensive bowel involvement with aggressive and rapidly progressing behavior compared to adult IBD. Because IBD has a high morbidity rate and can have a lifelong impact, successful transition from pediatric to adult care is important to maintain the continuity of care. Furthermore, successful transition facilitates appropriate development and psychosocial well-being among patients, as well as comprehensive and harmonious healthcare delivery amongst stakeholders. However, there are various obstacles related to patients, family, providers, and organizations that interfere with successful transition. Successful transition requires a flexible and tailored plan that is made according to the patient's developmental abilities and situation. This plan should be established through periodic interviews with the patient and family and through close collaboration with other care providers. Through a stepwise approach to the transition process, patients' knowledge and self-management skills can be improved. After preparation for the transition is completed and the obstacles are overcome, patients can be gradually moved to adult care. Finally, successful transition can increase patients' adherence to therapy, maintain the appropriate health status, improve patients' self management, and promote self-reliance among patients. PMID- 30419637 TI - Recent advance in very early onset inflammatory bowel disease. AB - Recent studies on pediatric inflammatory bowel disease (IBD) have revealed that early-onset IBD has distinct phenotypic differences compared with adult-onset IBD. In particular, very early-onset IBD (VEO-IBD) differs in many aspects, including the disease type, location of the lesions, disease behavior, and genetically attributable risks. Neonatal or infantile-onset IBD develops in less than 1% of pediatric patients. Children with infantile-onset IBD have high rates of affected first-degree relatives and severe disease course. The suspicion of a monogenic cause of VEO-IBD was first confirmed by the discovery of mutations in the genes encoding the interleukin 10 (IL-10) receptors that cause impaired IL-10 signaling. Patients with such mutations typically presented with perianal fistulae, shows a poor response to medical management, and require early surgical interventions in the first year of life. To date, 60 monogenic defects have been identified in children with IBD-like phenotypes. The majority of monogenic defects presents before 6 years of age, and many present before 1 year of age. Next generation sequencing could become an important diagnostic tool in children with suspected genetic defects especially in children with VEO-IBD with severe disease phenotypes. VEO-IBD is a phenotypically and genetically distinct disease entity from adult-onset or older pediatric IBD. PMID- 30419638 TI - Health-related quality of life of patients with inflammatory bowel disease in Singapore. AB - Background/Aims: Inflammatory bowel disease (IBD) is associated with considerable impairment of patients' health-related quality of life (HRQoL). Knowledge of factors that significantly affect IBD patients' HRQoL can contribute to better patient care. However, the HRQoL of IBD patients in non-Western countries are limited. Hence, we assessed the HRQoL of Singaporean IBD patients and identified its determinants. Methods: A prospective, cross-sectional study was conducted at Singapore General Hospital outpatient IBD Centre. The HRQoL of IBD patients was assessed using the short IBD questionnaire (SIBDQ), Short Form-36 physical and mental component summary (SF-36 PCS/MCS) and EuroQol 5-dimensions 3-levels (EQ-5D 3L) and visual analogue scale (VAS). Independent samples t-test was used to compare HRQoL between Crohn's disease (CD) and ulcerative colitis (UC). Determinants of HRQoL were identified through multiple linear regression. Results: A total of 195 IBD patients (103 UC, 92 CD) with a mean disease duration of 11.2 years were included. There was no significant difference in HRQoL between patients with UC and CD. Factors that significantly worsened HRQoL were presence of active disease (b=-6.293 [SIBDQ], -9.409 [PCS], -9.743 [MCS], -7.254 [VAS]), corticosteroids use (b=-7.392 [SIBDQ], -10.390 [PCS], -8.827 [MCS]), poor medication adherence (b=-4.049 [SIBDQ], -1.320 [MCS], -8.961 [VAS]), presence of extraintestinal manifestations (b=-13.381 [PCS]), comorbidities (b=-4.531 [PCS]), non-employment (b=-9.738 [MCS], -0.104 [EQ-5D-3L]) and public housing (b=-8.070 [PCS], -9.207 [VAS]). Conclusions: The HRQoL is impaired in this Asian cohort of IBD. The magnitude of HRQoL impairment was similar in UC and CD. Clinical characteristics were better determinants of patients' HRQoL than socio demographic factors. Recognizing the factors that impact patients' HRQoL would improve the holistic management of IBD patients. PMID- 30419639 TI - WITHDRAWN:Knowledge and viewpoints on biosimilar monoclonal antibodies from members of the Asian Organization of Crohn's and Colitis: comparison with European Crohn's and Colitis members. AB - Ahead of Print article withdrawn by publisher. PMID- 30419640 TI - Association of visceral adiposity and insulin resistance with colorectal adenoma and colorectal cancer. AB - Background/Aims: To examine whether visceral adiposity serves as a risk factor for colorectal cancer (CRC) and colorectal adenomas. Methods: Two hundred healthy subjects, 200 patients with colorectal adenoma, and 151 patients with CRC (46 with early-stage and 105 with advanced-stage cancers) were enrolled at a tertiary referral hospital. All subjects underwent colonoscopy, and had laboratory data, and computed tomography (CT) scan available for abdominal fat measurement. An abdominal CT scan taken 1 to 4 years (mean interval, 20.6 months) before the diagnosis of CRC was also available in the 42 CRC patients. Results: The mean areas of visceral adipose tissue (VAT) areas in the control, adenoma, early- and advanced-stage CRC groups were 94.6, 116.8, 110.4, and 99.7 cm2 , respectively (P<0.001). The risk of adenoma positively correlated with VAT area and the visceral-to-total fat ratio (P for trend <0.01), but the risk of CRC did not (P>0.05). The risk of both adenoma and CRC positively correlated with fasting plasma glucose levels (P for trend <0.05). In patients with early-stage cancer (n=17), VAT area decreased when the CT scan at diagnosis was compared with that taken before the diagnosis of CRC, but superficial adipose tissue area did not, so visceral-to-total fat ratio significantly decreased (46.6% vs. 50.7%, respectively, P=0.018). Conclusions: VAT area is related to the risk of colorectal adenoma. However, VAT decreases from the early stages of CRC. Impaired fasting glucose has a role in colorectal carcinogenesis. PMID- 30419641 TI - [Gender Difference in Functional Gastrointestinal Disorders]. AB - Functional gastrointestinal diseases (FGIDs) are known to be influenced more by a lowering of the quality of life, such as mental health and sleep quality, compared to organic diseases. Genetic, microbiological, molecular biological, and social environmental factors are involved in the pathophysiology of FGIDs. In particular, mental factors, such as depression and anxiety, play a major role in the development of FGIDs. The prevalence of most FGIDs is higher in women. Gender needs to be analyzed in patients with FGIDs because it can have a great influence on the onset of FGIDs. Because there are differences in the treatment response according to gender, further research in the development of therapeutic drugs considering this gender difference will be needed, and ultimately it will be possible to lower the prevalence of FGIDs and improve the quality of life of patients. PMID- 30419642 TI - [Guideline Recommendation for Endpoints Used in Clinical Trials for Functional Dyspepsia]. AB - Functional dyspepsia is a disease, in which there is no organic lesion but chronic and repetitive postprandial fullness, early satiation, epigastric pain, and epigastric burning. Functional dyspepsia is not life-threatening but its symptoms are relapsing and remitting and persist over a lifetime, limiting the social life and reducing the quality of life. Therefore, the treatment for acute relapsing period may help improve the short-term symptoms. Continuous medication may be needed to improve the long-term symptoms. Research designs to demonstrate the short-term efficacy of therapeutic agents may differ from clinical trials to demonstrate long-term efficacy. There are many difficulties in clinical trial design, implementation, and screening because there are no international standards of clinical trials for functional dyspepsia. The purpose of this guideline recommendation is to develop a standard for clinical trials, such as clinical trial subjects and evaluation methods, in the development of therapeutic agents for functional dyspepsia. The ultimate aim is to enhance the safety and efficacy of therapeutic agents for functional dyspepsia and promote the development of new therapeutic agents. PMID- 30419643 TI - Risk Factors and On-site Rescue Treatments for Endoscopic Variceal Ligation Failure. AB - Background/Aims: The success rate of endoscopic variceal ligation (EVL) is about 85-94%. There is only a few studies attempting to determine the cause of EVL failure, and to date, on-site rescue treatments remains unestablished. This study aimed to elucidate the risk factors for EVL failure and the effectiveness of on site rescue treatment. Methods: Data of 454 patients who underwent emergency EVL at Chonnam National University Hospital were retrospectively analyzed. Enrolled patients were divided into two groups: the EVL success and EVL failure groups. EVL failures were defined as inability to ligate the varices due to poor endoscopic visual field, or failure of hemostasis after band ligation for the culprit lesion. Results: Forty-seven patients experienced EVL failure. In the multivariate analysis, male patients, initial hypovolemic shock, active bleeding on endoscopy, and history of previous EVL were independent risk factors for EVL failure. During endoscopic procedure, we came across the common causes of EVL failure, including unsuctioned varix due to previous EVL-induced scars followed by insufficient ligation of the stigmata and inability to ligate the varix due to poor endoscopic visual field. Endoscopic variceal obturation using N-butyl-2 cyanoacrylate (48.9%) was the most commonly used on-site rescue treatment method, followed by insertion of Sangstaken Blakemore tube (14.9%), and EVL retrial (12.8%). The rescue treatments successfully achieved hemostasis in 91.7% of those in the EVL failure group. Conclusions: The risk factors of EVL failure should be considered before performing EVL, and in case of such scenario, on-site rescue treatment is needed. PMID- 30419644 TI - The Efficacy and Safety of Direct-acting Antiviral Treatment for Chronic Hepatitis C Patients: A Single Center Study. AB - Background/Aims: Direct-acting antiviral (DAA) therapy has been shown to achieve a high rate of sustained virologic response (SVR) and favorable outcomes in chronic hepatitis C (CHC) patients. We investigated the virologic response and its clinical impact in CHC patients. Methods: CHC patients with compensated liver function treated with DAAs between 2016 and 2017 were included for retrospective analysis. We analyzed baseline characteristics and virologic and biochemical responses at on-treatment 4 weeks, end of treatment, and post-treatment 12 weeks. Fibrosis was measured as liver stiffness measurement by transient elastography (FibroScan). Adverse events were monitored during the treatment period. Results: A total of 135 patients (61.5% with genotype [GT] 1b and 38.5% with GT 2a) were enrolled 47.4% were male, 79.3% were treatment naive, and 30.4% had cirrhosis. SVR 12 was observed in 97.6% (81/83) in the GT 1b and 98.1% (51/52) in the GT 2a; treatment with daclatasvir+asunaprevir was the most commonly used in GT 1b (55/83), and sofosbuvir+ribavirin was the most commonly used in GT 2a (49/52). The median change of liver stiffness measurement at two time points using the signed rank test was -3.2 kPa in patients who underwent transient elastography before treatment and at SVR 12 (n=25). The most common adverse events were anemia, dyspepsia, and insomnia. One GT 2a patient treated with sofosbuvir+ribavirin stopped the treatment at 8 weeks due to symptomatic bradyarrhythmia; however, he recovered spontaneously and achieved SVR 12. Conclusions: DAA treatment of chronic hepatitis C genotype 1b and 2a resulted in a high rate of sustained virologic response and improvement of liver fibrosis score. PMID- 30419645 TI - A Ruptured Metastatic Hepatic Gastrointestinal Stromal Tumor Treated by Angiographic Embolization. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal tract and occur most frequently in the stomach. The liver is the most common metastatic site of a GIST, and spontaneous rupture of the hepatic metastasis of a malignant gastric GIST is rare. We report the case of a 70-year old man who presented with sudden right lower quadrant abdominal pain and was diagnosed with a spontaneously ruptured hepatic metastasis of a malignant gastric GIST. The patient was successfully managed with transcatheter arterial embolization of the hepatic artery. PMID- 30419646 TI - Asymptomatic Splenic Cysts in an Immunocompromised Patient: Should They Be Investigated. AB - Splenic abscess is a rare disease that generally occurs in immunocompromised patients. It is difficult to distinguish between splenic abscesses and cysts using imaging studies, especially if they are asymptomatic. A 50-year-old asymptomatic man who had received steroid therapy for underlying rheumatoid arthritis was referred to a university hospital due to presence of several splenic cysts, with the largest being 3.5 cm in diameter. Percutaneous aspiration was performed, and fluid analysis showed cysts infected by extended-spectrum, beta-lactamase-producing Escherichia coli. The patient was treated with ertapenem for four weeks, and the lesion disappeared on follow-up imaging studies. Splenic abscess should be included as a differential diagnosis of splenic cystic lesions in immunocompromised patients. PMID- 30419647 TI - [Heterotopic Salivary Gland Tissue at the Hepatic Flexure of the Large Intestine: A Case Report]. AB - The occurrence of heterotopic tissue in the large intestine is unusual. The most common heterotopic tissue type described is gastric-type mucosa. On the other hand, heterotopic salivary gland tissue in the large intestine is extremely rare. To the best of the authors' knowledge, only five cases of heterotopic salivary gland in the large intestine have been reported, and all cases arose in the left colon. One out of five cases arose in the sigmoid colon, and the four other cases were found in the rectum-anal canal region. Endoscopically, they usually appeared as a polyp. The presentation of the patients was rectal bleeding or asymptomatic. Heterotopic salivary gland tissue in the colon has not been reported in Korea. This paper reports a case of heterotopic salivary gland tissue at the hepatic flexure of the colon and reviews the literature on similar cases. A 55-year-old male underwent large bowel endoscopy for colorectal carcinoma screening. The colonoscopy revealed five polyps. A sessile polyp at the hepatic flexure, 0.6 cm in size, was resected in a piecemeal manner. The histopathologic findings revealed a salivary gland with mixed mucinous-serous features and ducts. The other four polyps all were diagnosed as tubular adenoma with low-grade dysplasia. PMID- 30419648 TI - Endoscopic Papillectomy for Synchronous Major and Minor Duodenal Papilla Neuroendocrine Tumors. AB - Neuroendocrine tumor (NET) of the major duodenal papilla is a rare occurrence. However, that of the minor duodenal papilla is even rarer. To date, only a few cases have been reported. Herein, we present a rare case of NETs detected at the major and minor duodenal papilla synchronously, which were successfully treated with endoscopic papillectomy without procedure-related complication. To the best of our knowledge, this is the first report of this kind in the world. Photomicrograph of the biopsy specimen stained immunohistochemically for synaptophysin showed a positive reaction of tumor cells. All resection margins were negative. Further experience with more cases will be needed to establish the exact indication of endoscopic papillectomy for duodenal papillary NETs. PMID- 30419649 TI - Influence of hepatic steatosis on the outcomes of patients with chronic hepatitis B treated with entecavir and tenofovir. AB - Background/Aims: The influence of hepatic steatosis (HS) on chronic hepatitis B (CHB) is unclear. We evaluated the influence of the degree of HS, assessed using the controlled attenuation parameter (CAP) of transient elastography (TE), on treatment outcomes in CHB patients initiated on antiviral therapy. Methods: A total of 334 patients who were initiated on entecavir or tenofovir between 2007 and 2016 with available TE results were recruited. Results: Of the total study population, 146 (43.7%) patients had HS (CAP > 238 dB/m). Three-hundred-three patients (90.7%) achieved complete virological response (CVR) (hepatitis B virus DNA<12 IU/L), and 25 patients (7.5%) developed hepatocellular carcinoma (HCC). Among hepatitis B e antigen (HBeAg)-positive patients (n=172, 51.5%), 37 (21.5%) experienced HBeAg loss. On univariate analysis, CAP value was not associated with the probability of HCC development (P=0.380). However, lower CAP value was independently associated with higher probability of HBeAg loss among HBeAg positive patients (hazard ratio [HR]=0.991, P=0.026) and with CVR achievement in the entire study population (HR=0.996, P=0.004). The cumulative incidence of HBeAg loss among HBeAg-positive patients was significantly higher in patients without HS than in those with HS (log-rank, P=0.022). Conclusions: CAP values were not correlated with HCC development in patients initiated on entecavir and tenofovir. However, CAP values were negatively correlated with the probability of HBeAg loss among HBeAg-positive patients and with CVR achievement. PMID- 30419650 TI - [Clinical follow-up observation of 84 cases of implant-retained/supported prostheses in edentulous patients]. AB - Objectives: To evaluate the long-term clinical results and patient satisfaction of implant-retained/supported prostheses in edentulous patient based on retrospectively summary of the clinical data of implant-retained/supported prostheses patients. Methods: Edentulous patients who received implant denture treatment between 01/2005 and 12/2016 was included in this study. Soft tissue health, clinical examination, X-ray observation, patient satisfaction with implant-retained/supported prostheses were evaluated. Results: A total of 400 implants in 84 cases (96 jaws), 35 fixed bridges and 61 overdentures. The follow up time was (34.3+/-25.5) months. The 3- and 5-year implant cumulative survival rate of implant-supported overdenture was 95.0% and 92.1%, and the 3- and 5- year survival rate of implant-supported fixed denture was both 99.9%. The prevalence of peri-implantitis was 2.8% (11/400). A total of 44% (27/61) of the overdenture and 23%(8/35) of the fixed denture were repaired due to the complications of prosthesis. The mean repair frequency was (1.4+/-1.2) in overdenture and (1.3+/ 0.9) in fixed denture (t=0.490, P=0.600). The average probing depth around implant recorded in the overdenture group [(2.2+/-1.1) mm] was significantly greater than that in the fixed denture group [(1.4+/-1.2) mm] (t=3.300, P=0.002). Patient satisfaction with an average of (6.5+/-4.9) in implant-support overdenture group was significantly higher than that in implant-support fixed denture group (3.2+/-2.8) (t=3.218, P=0.006). Conclusions: The complication rate of the prosthesis was high in edentulous patients with implant-retained/supported prostheses. Besides, the patients with implant supported denture expressed more satisfaction with their prostheses. And there was a relatively high implant cumulative survival rate of implant-retained/supported prostheses in edentulous patient. PMID- 30419651 TI - [A comparative study on early childhood caries detection by using international caries detection and assessment system-II and WHO criteria]. AB - Objective: To investigate and compare the sensitivities of early childhood caries detection by using international caries detection and assessment system (ICDAS) II and WHO criteria. Methods: A total of 449 3-year-old children from four day care kindergartens in Beijing were enrolled in this study. Both ICDAS-II and WHO criteria were used to assess the prevalence of caries in the given subjects. The decayed, missing, and filled teeth (dmft) index scores were calculated. In ICDAS II system, four cut-off points (D1, D2, D3 and D4) were employed to differentiate sound and decayed teeth: D1 (score 0 as sound, scores 1-6 as caries); D2 (0-1 sound, 2-6 caries); D3 (0-2 sound, 3-6 caries) and D4 (0-3 sound, 4-6 caries). SPSS software was used to analyze the data to decide the significance of differences. Results: The caries prevalence using ICDAS-II were 76.6% (344/449), 71.3% (320/449), 52.8% (237/449) and 46.1% (207/449) for D1 to D4, respectively; the corresponding mean dmft scores were 4.95+/-4.85, 4.41+/-4.77, 2.54+/-3.69 and 1.97+/-3.10. The sites with highest caries prevalence were occlusal surface of mandibular molars in groups of D1 and D2 and proximal surface of maxillary anterior teeth in groups D3 and D4. In contrast, the caries prevalence was 48.8% (219/449) and the mean dmft was 2.27+/-3.54 when using WHO criteria, significantly lower than the detection rates by using ICDAS-II (D1-D2) (P=0.00). This suggested that ICDAS-II system was a more sensitive method in detecting early childhood caries. Conclusions: ICDAS-II system might be superior in detection of incipient caries and be of specific value in prevention of early childhood caries. PMID- 30419652 TI - [Prevalence of Candida albicans and its relationship with early childhood caries among children of three ethnic groups (Han, Uygur, Mongolian) in Bortala Mongol Autonomous Prefecture of Xinjiang Uygur Autonomous Region]. AB - Objective: To investigate the distributions of Candida albicans (Ca), which are closely associated to early childhood caries (ECC) of young children, in 3-5-year old children of Mongolian, Uygur and Han ethnic groups in Bortala Mongol Autonomous Prefecture of Xinjiang Urgur Autonomous Region, so as to provide scientific basis for the early prediction and prevention of caries locally. Methods: Totally 1 089 healthy children aged 3 to 5 years old (Mongolian 136, Uygur 403 and Han 550; 568 males and 521 females) were randomly selected by stratified and cluster sampling method. The children in early childhood caries group were 786 and in caries free group were 303. Dental plaque samples were collected from the carious tooth tissues and supragingival sites, respectively. Samples were isolated and cultured by different media. Ca were identified by Gram stain, germ tube test, PCR method and internal transcribed spacer region sequencing methods. Ca isolated were further typed by using PCR-25SrDNA genotype method. Pearson chi(2) test and Spearman rank correlation were used to analyze the differences in genotypes of Ca amongst three ethnic groups and the relationship between decayed missing filled tooth (dmft) classification and detection of Ca. Results: The Ca was significantly higher in the ECC group [14.4% (113/786)] than in the caries free group [7.6% (23/303)] (P=0.002). The identified rate of Ca in Mongolian group was [11.8% (16/136)], which was significantly lower than that of Uygur group [17.9% (72/403)] and higher than that of Han group [8.7% (48/550)] (chi(2)=10.192, P=0.006). Among the male children, the identified rate of Ca in Mongolian group was [10.0% (8/80)], which was significantly lower than that of Uygur group [21.7% (44/203)] and higher than that of Han group [8.4% (24/285)] (chi(2)=18.887, P=0.000). Among the female children, the detection rates of Ca were [14.3% (8/56)] in Mongolian group, [14.0% (28/200)] in Uygur group and [9.1% (24/265)] in Han group. There were no significant differences among the three ethnic groups (chi(2)=3.206, P=0.201). The identification rates of oral Ca in Uygur and Han ECC groups were correlated with the decayed, missing and filled teeth (Uygur r=0.195, P=0.001; Han r=0.145, P=0.004). Totally 136 Ca samples were divided into 3 types by PCR-25SrDNA method, and the predominant type was type A [55.1% (75/136)]. Conclusions: The distribution of oral Ca among children were ethnically different. Uygur male children carrying Ca were more susceptible to dental caries. Ca might be a risk factor for ECC. There was no specific cariogenic genotype in Ca isolated. There were no associations between ethnic factors and the genotypes of Ca isolated. PMID- 30419653 TI - [A retrospective clinical study on autotransplantation of teeth with complete root formation]. AB - Objective: To evaluate the 5-year survival and success rates of transplanted autologous teeth with complete root formation. Methods: A total of 32 patients admitted to the hospital for 36 cases of tooth autotransplantation with complete root formation from November 2008 to October 2012 were enrolled in this study. Clinical and radiographic examinations were performed during the post-operative follow up periods of 1 month, 3 months, 6 months, 9 months and 12 months, respectively. Survival analysis was then conducted and the predictive factors influencing prognosis from the aspects of age, sex and root canal treatment status were investigated. Kaplan-Meier survival curve was adopted for survival analysis and Log-Rank test was used to compare the survival rate and success rate of each single factor. Results: According to each case's last follow-up, the 5 year survival rate of autotransplanted teeth with complete root formation was 83%. Within these cases, the 5-year success rate of the autotransplanted teeth with no apparent periodontitis or apical periodontitis, and the crown to root ratio being less than 1 was 65%. Factors of age and sex of the patients showed no correlation with the prognosis of autotransplantation (P>0.05). Root canal treatment was crucial in preventing transplanted teeth from apical periodontitis and root resorption, and accordingly increased the success rate (P=0.028) of autotransplantation. Conclusions: Autotransplantation with complete root formation has a high 5-year survival rate, and is a viable and alternative method for restoration of tooth loss. Post-operative follow-up should be thoroughly planned and root canal treatment should be performed in order to increase the survival rate and success rates of autotransplantation. PMID- 30419654 TI - [Comparison of the secretory related molecules expression in stem cells from the pulp of human exfoliated deciduous teeth and dental pulp stem cells]. AB - Objective: To compare the general biological characteristics and the expressions of proteins involved in secretion in stem cells from the pulp of human exfoliated deciduous teeth (SHED) and dental pulp stem cells (DPSC). Methods: SHED and DPSC were cultured and collected at passage 4 (P4) and P7. The submandibular gland epithelial and interstitial cells were cultured with tissue culture method. The cell morphology was observed using a phase contrast microscope. Flow cytometry was used to detect stem cell surface markers. Cell counting kit-8 (CCK-8) and IncuCyte ZOOM were used to evaluate cell proliferation. Quantitative real-time PCR (qPCR) was performed to examine the mRNA expressions of proteins involved in fluid and protein secretion. Results: P4 and P7 SHED and DPSC were spindle shaped. There was no difference in cell morphology among the 4 group cells. P4 and P7 SHED and DPSC expressed CD29, CD44, CD73, and CD90, the mesenchymal stem cell markers, while, CD49f and CD117, the epithelium markers were undetected. There was no difference in cell proliferation among the 4 group cells. Compared with P4 SHED, the expressions of muscarinic cholinergic receptor 1 (MR1), MR3, aquaporin 5 (AQP5), beta1-adrenoceptor (beta1-AR), alpha-amylase, and mucin 5B in SHED were not different, while beta2-AR expression was decreased (P<0.05). Compared with P4 DPSC, the expressions of MR3, beta2-AR, and alpha-amylase in P7 DPSC were not different, while, the expressions of MR1, AQP5, beta1-AR, and mucin 5B were decreased (P<0.05). Compared with primary cultured submandibular gland epithelial cells and gland tissues from a child, the expressions of proteins involved in secretion were all decreased. Compared with submandibular epithelial cells from adults, the expression of AQP5 in P4 DPSC was decreased (P<0.05), while other proteins were not different. The expressions of AQP5, beta1-AR, alpha amylase and mucin 5B in P7 DPSC were increased (P<0.05), while other proteins were not different. In P4 and P7 DPSC, all the protein expression levels were decreased, compared with those in submandibular gland tissues (P<0.01). Conclusions: Compared with DPSC, SHED have stable growth and the expressions of protein involved fluid and protein secretion are low. Based on its extensive sources and easy separation, SHED can be used as the ideal seed cell for salivary gland tissue engineering and the treatment of salivary gland hypofunction, and the P4 to P7 SHED can be used for experimental study. PMID- 30419655 TI - [Study on radiation dose in different field of views of oral and maxillofacial cone-beam CT]. AB - Objective: To analyze the absorptive radiation dose of non-target sensitive organs under the NewTomVGi oral and maxillofacial cone-beam CT scanning in different view fields. Methods: The thermoluminescence dosimeter chip was placed in the non-target sensitive organ of the simulated radiology head model, and 6 scanning fields were measured and analyzed (standard resolution: scanning range was 15 cm*15 cm, 15 cm*12 cm, 12 cm*8 cm, 8 cm*8 cm respectively). High definition resolution: the radiation absorption dose of thermoluminescence with the scanning range of 12 cm*8 cm, 8 cm*8 cm, respectively. Results: Under the same resolution, the absorptive dose increased with the expansion of scanning field, and the amount of absorbent during high resolution scanning was higher than that during the standard resolution with the same scanning field. Conclusions: New TomVGi oral and maxillofacial cone-beam CT has sighificant difference in radiation dose in different view fields. The appropriate view field should be selected according to the patient's clinical needs, so as to reduce unnecessary radiation dose during medical imaging examination. PMID- 30419656 TI - [microRNA-146a reverses the inhibitory effects of Porphyromonas gingivalis lipopolysaccharide on osteogenesis of human periodontal ligament cells]. AB - Objective: To investigate the effects and mechanisms of microRNA-146a (miR-146a) on osteogenic differentiation of human periodontal ligament cells (hPDLC) stimulated by lipopolysaccharide (LPS) of Porphyromonas gingivalis (Pg). Methods: hPDLC were cultured in vitro and induced to the phase of osteogenic differentiation. These cells were divided into five groups: non-osteogenic differentiation cells, osteogenic differentiation cells, osteogenic differentiation cells treated with Pg LPS, osteogenic differentiation cells treated with Pg LPS and miR-146a mimic, osteogenic differentiation cells treated with Pg LPS and miR-146a negative control. Osteogenic markers and mineralization were detected via quantitative real-time PCR (qPCR) and alizarin red staining, respectively. Meanwhile, non-radioactive transcription factor assay was applied to explore the nuclear activity of nuclear factor kappa B (NF-kappaB) p65 in nuclear extracts of hPDLC. Results: Compared with cells of osteogenic differentiation in non-LPS-stimulated groups, Pg LPS could decrease the markers of osteogenic differentiation of hPDLC such as collagen I (Col-I), alkaline phosphatase (ALP), Runt-related transcription factor-2 (RUNX2) and osteocalcin (OCN) (P<0.05), inhibit mineralization, and stimulate NF-kappaB p65 nuclear activity expression (non-LPS stimulated group: 1.023+/-0.217, LPS stimulated group: 6.252+/-0.613, P=0.008). However, compared with cells in Pg LPS/miR-146a negative control group, miR-146a increased Col-I (P=0.007) and OCN (P=0.049) mRNA expression, rather than ALP (P=0.167) and RUNX2 (P=0.580) at day 3; miR-146a also upregulated mRNA levels of Col-I, ALP, RUNX2 and OCN (P<0.05) at day 7 and day 14, and enhance mineralization. Meanwhile, miR-146a mimic could decrease the nuclear activity of NF-kappaB p65 induced by Pg LPS in hPDLC (miR-146a: 2.427+/ 0.354, negative control: 5.863+/-0.482, P=0.019). Conclusions: miR-146a could reverse the inhibitory effects of Pg LPS on osteogenic differentiation of hPDLC through enhancing the expression of osteogenic markers and decreasing inflammatory pathway in hPDLC. PMID- 30419657 TI - [Effect of long non-coding RNA highly upregulated in liver cancer on the biological behavior of oral squamous cell carcinoma]. AB - Objective: To investigate the effect of long non-coding RNA highly upregulated in liver cancer (lncRNA HULC) on the biological behavior of oral squamous cell carcinoma (OSCC) cell lines. Methods: A total of thirty patients with oral squamous cell carcinoma at Peking University Shenzhen Hospital from March 2017 to March 2018 were enrolled in this study. OSCC and adjacent tissues were extracted during tumor extensive resection. Quantitative real-time PCR (qPCR) was used to detect the expression levels of lncRNA HULC in OSCC and paracancerous tissues and OSCC cell lines. SCC15 and SCC25 cells were transfected with siRNA, and the effects of the gene on the biological behavior of OSCC cells were detected by cell counting assay, scratch assay, Transwell assay and Western blotting. Results: The expression of lncRNA HULC in OSCC tissues (10.98+/-0.31, n=30) was significantly higher than that in paracancerous tissues (8.39+/-0.31, n=30) (t=5.93, P<0.001), the expression of lncRNA HULC in OSCC cells (SCC15: 28.58+/ 2.74; SCC25: 16.56+/-0.87; SCC9: 11.18+/-1.32; CAL27: 13.92+/-0.99, n=5) was significantly higher than that in human keratinocytes (1.01+/-0.00, n=5) (t(SCC15)=10.08, t(SCC25)=17.96, t(SCC9)=7.71, t(CAL27)=13.09, P<0.001). Down regulation of lncRNA HULC in SCC15 and SCC25 cells can inhibit the proliferation, migration and invasion of tumor cells and promote tumor cell apoptosis. Conclusions: lncRNA HULC is highly expressed in OSCC and can enhance the proliferation, migration and invasion of cancer cells and inhibit tumor cell apoptosis. PMID- 30419658 TI - [Influence of fracture resistance of prosthesis with different thickness of ferrule restored with fiber post and resin core and crown]. AB - Objective: To evaluate the influence of fracture resistance of endodontically treated teeth with different thickness of ferrule by mechanical fatigue test and static loading test, and so as to provide a reference for the clinical treatment planning. Methods: Fifty bovine incisors were divided into 5 groups by random number table method (n=10). Group A was the control group in which the incisors were prepared without a ferrule design (0 mm). The other four groups (B, C, D, E) were experimental groups, and the thickness of the dentin ferrule prepared for specimens in each group was 0.5, 1.0, 1.5, and 2.0 mm. The height of ferrules in all the specimens was 2 mm. Cyclic fatigue loading (2.33 Hz, 50 N) was applied on each specimen until either the specimen was dislodged/fractured or the 300 000 cycles were finished. After fatigue loading, the mode of failure was observed. Those intact specimen after fatigue loading were tested under a gradually increasing force using a universal testing machine (0.05 mm/min) until fracture occurred. The forces required to fracture and failure model was recorded. Results: The results of cyclic loading tests showed that: all specimens survived the 300 000 cycles of intermittent loading. The results of static loading tests showed that: the fracture force of A, B, C, D and E groups respectively were (226.4+/-67.7), (369.7+/-34.5), (400.7+/-48.2), (528.1+/-56.3), and (555.4+/ 98.5) N (F=15.227, P=0.000). There was a significant difference in fracture resistance between group A and the other four groups, and between group B, C and group D, E (P<0.05). No statistical difference were found in fracture resistance among the other groups (P>0.05). There was strong correlation between the thickness of ferrule and the fracture force by Pearson correlation analysis (r=0.973, P=0.002). Conclusions: Within the limitations of this study, the following conclusions can be drawn: The different thickness of ferrule can influence the fracture resistance of the teeth, and when the height of the ferrule is 2.0 mm, the fracture force increased significantly with an increasing ferrule thickness. PMID- 30419659 TI - [Osteogenic potential of different adipose derived stem cells in rats]. AB - Objective: To compare the in vitro osteogenic ability of brown adipose stem cells (BADSC) and white adipose stem cells (WADSC), and to provide evidence for further research and clinical application of adipose-derived stem cells. Methods: The brown fat under the scapula of SD rats and the white adipose tissue in the groin were isolated and obtained BADSC and WADSC. The morphology of the cells was observed by an inverted phase contrast microscope, and the cell count was used to detect the proliferative ability. After osteogenic induction, alkaline phosphatase (ALP) staining and alizarin red staining were performed. The expression of the osteogenic marker gene [Runt-related transcription factor-2 (RUNX2), osteocalcin] was detected by quantitative real-time PCR (qPCR). Results: Both BADSC and WADSC were osteogenic. The ALP activity of BADSC was significantly greater than that of WADSC at each time point after osteogenic induction. After 5 weeks of osteogenic induction, BADSC formed a larger area of calcium nodules (accumulated optical density was 92 558+/-1 507), which was significantly greater than WADSC (accumulated optical density was 52 319+/-1 786) (t=29.81, P<0.05). The expression of BADSC osteogenic marker genes (RUNX2 and osteocalcin) was significantly higher than that of WADSC (P<0.05). Conclusions: Both BADSC and WADSC have the potential for osteogenic differentiation, but BADSC has better osteogenic differentiation ability than WADSC. PMID- 30419660 TI - [Digital duplication of mock-up in the restorations of severe dental fluorosis cases]. PMID- 30419661 TI - [The research progress in gingival invagination]. AB - Gingival invagination is a type of gingival cleft that occurs during orthodontic space closure in some of the orthodontic patients who received tooth extraction. Clinical manifestations may be fine folds in attached gingiva surface, or deep cleft that penetrates the interdental papilla from the buccal to the lingual alveolar process. Gingival invagination can affect the health of local periodontal tissues, the effect and stability of orthodontic treatment. This article reviews the research progress of gingival invagination studies, including the definition, manifestations, causes, influencing factors and effects. PMID- 30419662 TI - [Various scaffolds for dentine-pulp complex regeneration]. AB - With the rapid development of cell biology and biological materials, the dentine pulp complex regeneration research has gone further. Scaffolds play important roles in the construction of tissue engineered dentine-pulp complex. At present, scaffolds used in dentine-pulp complex regeneration include not only natural biological materials and synthetic biomaterials, but also various composite materials and cell- or body-based carrier materials. In this paper, the latest research status of various scaffolds for dentine-pulp complex regeneration were reviewed. The advantages and problems of these scaffolds were analyzed. The future development direction was predicted. PMID- 30419663 TI - [Regulation of dentin remineralization progress by non-collagenous protein analogues]. AB - The use of various biomimetic methods to achieve remineralization of demineralized dentin and the formation of an organic matrix-inorganic mineral complex with a certain mechanical strength has been a research hotspot in recent years in the field of stomatology, and it also provides a new idea for the restoration of dentin defect. Dentin biomineralization is a process that simulates the mineralization of biological tissue in nature in which the remineralization of dentin collagen is induced and regulated by organic macromolecules. This review summarizes the process of remineralization of decalcified dentin regulated by non-collagenous protein analogues in vitro. PMID- 30419664 TI - [Research on the influence factors of the carrying system]. AB - Objective: To investigate surface electromyography signal (sEMG) of the major back muscle group and subjective fatigue assessment under different experimental combinations during walk with weight on both shoulders, as well as the functional status and fatigue property of human muscles. Methods: From October to December, 2017, 10 college students were recruited to participate in shoulder weight bearing work and walk under the combinations of different shoulder strap widths, weights, and hardness of waist cushion. The subjects were required to complete 12 sets of experiments, with each set lasting for 15 minutes, and the rest time between work was 30 minutes. The sEMG signals of the upper trapezius and the erector spinae were measured during the experiment, and subjective fatigue assessment was performed during rest. The time domain evaluation index (average amplitude, aEMG) , the frequency domain evaluation index (median frequency, MF) , and the data of subjective assessment were processed and analyzed. Results: Weight and shoulder strap width had a significantly effect on fatigue (P<0.01) , and the change in the hardness of waist cushion had no significant effect on fatigue (P>0.05) . There was an interaction effect between weight and shoulder strap width (P<0.01) , and there was no interaction effect between weight, shoulder strap width, and hardness of waist cushion (P>0.05) . For the backpack carrying system, the combination of 10% weight and 50 mm shoulder strap width was the best one for relieving fatigue. The subjective test also showed that subjective feelings of muscle fatigue were associated with the weight and width, which was consistent with sEMG results. Conclusion: The results of this experiment show that the combination of 10% weight and 50 mm shoulder strap width can help to relieve muscle fatigue during walk with weight on both shoulders, and weight-bearing walking is more likely to cause the fatigue of the erector spinae. PMID- 30419665 TI - [Effect of long-term crotonaldehyde exposure on heart damage in male rats]. AB - Objective: To observe the effect of long term crotonaldehyde exposure on heart damage in male rats, and to explore the possible mechanism of toxic action. Methods: 24 specific pathogen free healthy male wistar rats were randomly divided into 4 groups with 6 rats in each group. Rats were treated with with 8.5, 4.5, 2.5 and 0.0 mg/kg body weight crotonaldehyde by gavage, once a day for consecutive 150 days. After the last treatment, they were anesthetized and collected blood samples by cardiac puncture. The heart was rapidly separated after cervical dislocation. The cardiac organ coefficient was calculated and the histopathology changes in heart were observed by HE staining. At the same time, the activities of creatine kinase (CK) , lactate dehydrogenase-L (LDH-L) in serum were determined by automatic biochemical analyzer. Moreover, the levels of cardiac troponin (cTnT) , Angiotensin II (Ang II) , Brain natriuretic peptide (BNP) , Aldosterone (ALD) and interleukin (IL) -6, 8, 1beta, interferon (IFN) gamma and tumor necrosis factor (TNF) -alpha in heart were determined by enzyme linked immunosorbent assay. Results: At the 90d, 120 d, and 150 d exposure, compared with the control group, the body weight gain in 4.5 and 8.5 mg/kg groups were decreased. Moreover, the heart weight in 4.5 and 8.5 mg/kg groups, and heart coefficient in 8.5 mg/kg group were decreased (P<0.05) . With the increasing dosage of crotonaldehyde, the degree of pathological changes in the heart of exposed rats were aggravated. The major pathological changes of heart in 4.5 and 8.5 mg/kg groups could be summarized as lymphocyte infiltration, abnormal cardiac muscle fiber arrangements, necrosis and fibrous connective tissue hyperplasia. Compared with the control group, the serum CK activity in 4.5 mg/kg group, CK and LDH-L activitivies in 8.5 mg/kg group were increased (P<0.05) ; Compared with the control group, the levels of ALD and ANGII in the heart of 4.5 and 8.5 mg/kg groups were increased, BNP level were decreased, and cTNT level in 8.5 mg/kg group were increased (P<0.05) . Compared with the control group, the levels of IL 1beta,IL-6,IL-8 in 4.5 mg/kg group and IL-1beta,IL-6,IL-8,TNF-alpha,IFN-gamma in 8.5 mg/kg group were increased (P<0.05) . Conclusion: Crotonaldehyde could up regulate cardiac inflammatory cytokines and alter the balance ofangiotensin aldosterone-brain natriuretic peptide causing heart damage. PMID- 30419666 TI - [The Role of TSP-1-CD47 in ROS-mediated Pulmonary Fibrosis Induced by Paraquat]. AB - Objective: Taking human A549 cells as the research object, to construct the paraquat-induced pulmonary fibrosis model in vitro, and to explore the role of TSP-1 (Thrombospondin-1, TSP-1) and its receptor CD47 in PQ-induced pulmonary fibrosis. Methods: Human A549 cells were cultured in vitro, divided into normal control group, PQ group, Anti-TSP1 group (PQ with neutralizing anti-TSP1 antibody at a final concentration of 10 MUg/ml) . A549 cells were stimulated with different concentrations (50, 100, 200, 400, 600, 800, 1 000 MUmol/L) for different time (12, 24, 48 h) , and then CCK8 method was used to detect the cell viability to screen out the concentration and time of half cell viability. The subsequent test will be performed at this concentration point.The morphology of the cells was observed under inverted microscope. The expression levels of Fibronectin (FN) and type I collagen were determined by Enzyme Linked Immunosorbent Assay (ELISA) . Immunocytochemistry (ICC) and Immunofluorescence (IF) were used to observe the expression of TSP-1 and CD47 protein and the co expression.The mRNA expression of TSP-1 and CD47 was detected by Real Time PCR (RT-PCR) . The protien expression of TSP-1 and CD47 was detected by Western Blot (WB) . The levels of Reactive Oxygen Species (ROS) were measured by flow cytometry. Results: Before neutralizing anti-TSP1 antibody intervention: (1) When the time of PQ was constant, the cell viability decreased with the increase of PQ concentration. (2) The cells in the control group were closely connected, cobble like, arranged neatly; with the increase of PQ concentration, the cell gap of PQ group gradually increased, spindle shape or long spindle shape. (3) With the increase of PQ concentration, the relative expression of FN and I collagen in PQ group was gradually increased compared with the control group in a concentration dependent manner, and 200 MUmol/L is the most obvious. (4) Compared with the control group, the mRNA level and the protein expression of TSP-1 and CD47 in PQ group was significantly increased, and 200 MUmol/L is the most obvious, and Immunofluorescence showed they were co-expression in cytoplasm. (5) Compared with the normal group, the level of ROS in A549 cells was significantly increased at 24 h after PQ stimulation. (6) Compared with PQ group, the cell viability of Anti TSP1 group was significantly increased, and the morphology changed to normal cell morphology, and the mRNA level and the protein expression of TSP-1 and CD47 decreased, and the overexpression of ROS was inhibited, and the relative expression of FN and I collagen decreased. Conclusion: PQ stimulation induced morphological changes of A549 cells, increased expression of TSP-1, CD47, FN and type I collagen, and increased production of ROS.Neutralizing anti-TSP1 antibodies against TSP-1 can partially improve the above lesions. TSP-1-CD47 may be associated with oxidative stress-mediated PQ-induced pulmonary fibrosis. PMID- 30419667 TI - [The spatial distribution and epidemic trend of silicosis in Guangdong province]. AB - Objective: To investigate the characteristics, temporal trend of silicosis, and provide basis for risk assessment and precise prevention and control of occupational diseases. Methods: Using descriptive statistics to analyze the reported cases of silicosis by SPSS 20.0 software. Reported silicosis cases, the constituent ratio, the incidence age and the working age at onset were analyzed by a linear trend test. Analyzing the variation trends of regional, industry, economic type and enterprise scale distributions by the chi-square trend test. Moreover, using Moran's I method for spatial autocorrelation analysis and trend surface analysis. Results: (1) During 2006 to 2015, Guangdong province had reported 1, 428 cases of silicosis, mainly gathered in Foshan, Zhongshan, Guangzhou, Shenzhen, which included 1391 male cases accounting for 97.41%. And the average incidence age was 45 (39, 51) . The average working age of onset was 9 (5.5, 15) . In economic type distribution, the private economy took the main part, accounting for 59.1%. In enterprise scale distribution, it was dominated by small and medium enterprises (SMEs) , accounting for 32.4% and 37.3% respectively. In industry distribution, most cases were gathered in materials and mining industry, accounting for 32.1% and 22.9% respectively. (2) The number of silicosis cases, the incidence age and the working age of onset showed a rising trend (P<0.01) . Meanwhile, the constituent ratios of medium-sized enterprises and building materials industry were increasing (P<0.05) . The annual variation trends of regional, economic type and age distributions were not statistically significant (P> 0.05) . (3) The spatial distribution trend showed an inverted U type, which was firstly raised and then declined from south to north and from east to west. The distribution characteristic demonstrated some high-high cluster areas, including Chancheng, Nanhai, Shunde, Panyu, Dongguan, Pengjiang, and Zhongshan. While Wuhua showed a high-low outlier form (P<0.01) . Conclusion: Silicosis cases, age and working age of onset were on the rise, as well as the industry and enterprise scale distributions of occupational diseases presented a certain trend in Guangdong province from 2006 to 2015. There were high-high cluster and high-low outlier phenomena in spatial distribution with spatial correlation. Therefore, our work of silicosis epidemic trend and distribution may provide some bases for the occupational disease risk assessment and control. PMID- 30419668 TI - [The Occupational and Procreation Health of Road Sweeping Female Sanitation Workers in a District of a City]. AB - Objective: To investigate occupational and procreation health of roadsweeping female sanitation workers in a city district. Methods: Using cross-sectional survey methods, all 303 the road sweeping female sanitation workers of one company were selected and interviewed face to face with questionnaires in june 2017. Data were analysed by SPSS22.0 statistical software. Results: The total prevalence of reproduction tract infection was 21.47%. The prevalence of uterine fibroids was 6.38%, and menstruation abnormal rate was 25.17%. The sanitation worker of menstruation abnormal rate was 31.03%, which were exposed low temperature, automobile exhaust and air contaminant at the same time, or else was 19.61%. There were statistical significance between them. (chi(2)=5.161, P<0.05) The sanitation worker of menstruation abnormal rate was 28.81%, which were not satisfied with women/s rights protection, or else was 11.67%. There were statistical significance between them. (chi(2)=7.435, P<0.01) . Conclusion: Female sanitation workers in the city district were exposed to many occupational hazards. The status of procreation health among road sweeping female sanitation workers in the city district is not optimistic. Occupational health protection and laborers's rights protection should be emphasized to improve health status of female sanitation workers. PMID- 30419669 TI - [Study on the correlation between work-related musculoskeletal disorders and work ability among nurses at three level general hospital in Xinjiang]. AB - Objective: To investigate the correlation between work-related musculoskeletal disorders (WMSDs) and work ability (WA) among nurses in Xinjiang. Methods: A total of 1 873 nursing staff in the Departments of Internal Medicine, Surgery, Emergency and ICU Department, Operating Room and Supply Room of 6 Grade 3 General Hospitals in Xinjiang Beijiang Region were randomly selected by means of random sampling, and revised Nordic National Musculoskeletal Disorders Standard Questionnaire and Work Ability Index Scale were used to evaluate the status of nursing WMSDs and WA. Results: (1) The symptom incidence of work-related musculoskeletal disorders among nursing staff in the past year was 77.42%; The highest symptom incidence in all parts of the body was waist, neck, shoulder and back, and the symptom incidence was 63.59%, 59.80%, 47.78% and 37.32%, respectively; (2) The total score of nursing staff's work ability was (35.91+/ 5.143) ; The proportion of "poor" , "middle" , "good" and "excellent" were 5.23%, 47.41%, 41.43% and 5.93% respectively; (3) The total working capacity of the sick group was (35.11+/-5.044) , The working ability of the non-diseased group was (38.64+/-4.507) , The difference between the two groups was statistically significant (t=13.773, P<0.01) ; There was a significant difference in the level of work ability between the two groups (z=-12.335, P<0.01) ; The working ability of "poor" and medium in the injury group was significantly higher than that of the non injury group, while the working ability was "better" and "excellent" than that of the non injury group; (4) The working ability of nursing staff of different age in WMSDs injury group was lower than that in non injury group, the difference was statistically significant (P<0.01) ; There was a negative correlation between the working ability of the injury group and the length of service, that is, with the increase of the length of service, the working ability index decreased (P<0.01) ; There was a positive correlation between the working ability of the non injury group and the length of service, that is, with the increase of the length of service, the work ability index increased gradually, but the correlation was not statistically significant (r=0.063, P=0.195) ; (5) The working ability of nursing staff of different departments in WMSDs injury group was lower than that in non injury group, the difference was statistically significant (P<0.01) . (6) Multiple linear regression analysis showed that the factors influencing the working ability of nursing staff were: past medical history, WMSDs disease, length of service and night shift frequency; Conclusion: The symptom incidence of WMSDs was high among nurses; Work Ability at a moderate level; work-related musculoskeletal disorders is associated with reduced ability of nursing staff; work-related musculoskeletal disorders are associated with reduced working capacity of nursing staff. PMID- 30419670 TI - [Investigations on occupational hazards in a kitchen waste treatment plant]. AB - Objective: To explore the distribution and intensity of kitchen waste treatment plant, providing scientific basis for occupational diseases prevention and treatment in that industry. Methods: 30 operating personnel in a kitchen waste disposal enterprise were selected as the research group and 16 non-operating personnel as the control group. The epidemiological survey was carried out in June 2015 and July 2016, and the results of occupational hazards and occupational health monitoring during 2015 to 2017 were analyzed. Results: The results of various occupational hazards factors during 2015 to 2017 were all in accordance with the occupational health limit, but the results of occupational health examination were abnormal. The occupational correlation could not be ruled out by the abnormality of electrical audiometry, electrocardiogram and Department of Dermatology examination. Conclusion: Workers in kitchen waste treatment plant are likely to suffer low-intensity, continuous health damage. There is occupational health risk in that industry. The accumulation of basic information and the improvement of relevant standards and methods are needed for further study. PMID- 30419671 TI - [Voxel-based morphometry (VBM) MRI analysis of gray matter in patients with occupational noise-induced hearing loss]. AB - Objective: To investigate the changes of brain gray matter volume in patients with occupational noise-induced hearing loss by voxel based morphometry (VBM) . Methods: 16 age-and education-matched healthy controls and 42 patients with occupational noise induced hearing loss, including 27 in mild group and 15 in severe group, received MRI 3D-FSPGR sequence T1WI sagittal scan, and then underwent VBM of brain gray matter volume data analysis. Results: The brain gray matter volume of the left occipitotemporal lateral gyrus, the anterior cingulate gyrus, the bilateral angular gyrus, the precuneus and the near midline area of cerebellum differed between experimental group and control group (P<0.01) . Conclusion: The volume of gray matter in specific brain areas of patients with occupational noise-induced hearing loss was changed, and the effect of noise on brain structure was revealed from the perspective of imaging. PMID- 30419672 TI - [Delphy expert survey on diagnosis of chronic obstructive pulmonary disease caused by occupational irritant chemicals]. AB - Objective: o explore the problems encountered in the application of GBZ/T 237 2011 edition of "Diagnosis of Chronic Obstructive Pulmonary Disease Caused by Occupational Stimulating Chemicals" , and to provide reference for the revision of the new standard. Methods: Delphi expert survey method was used to consult experts on the reasonableness of six primary indicators (scope of application, diagnostic principles, diagnostic indicators, treatment principles, diagnostic grading, appendix A) and their corresponding secondary indicators in the Diagnosis of Chronic Obstructive Pulmonary Disease (COPD) caused by Occupational Stimulant Chemicals. Results: The results of the first round of Delphi method showed that the reasonable mean of the diagnostic criteria about long-term occupational history, smoking history and clinical diagnostic criteria was less than 7, and the coefficient of variation was greater than 0.25, indicating that the experts disagreed with the scope of application of the original criteria; the average of smoking history and 3-year working age were 1.78 and 3.43 (less than 7) respectively, which indicated that the experts agreed that the two diagnostic indexes were not conducive to the practical work of occupational disease clinicians; among the diagnostic indicators, smoking history and smoking volume were taken into account in a comprehensive way, and the average values were 7.61 and 7.61 (greater than 7) , respectively. the coefficient of variation was less than 0.25, indicating that the experts had concentrated their opinions and agreed that such indicators could be considered into the diagnostic index system. Conclusion: "Diagnosis of Chronic Obstructive Pulmonary Disease Caused by Occupational Stimulating Chemicals" should be improved by expanding the scope of occupational irritant gases. Smoking problems can be considered in combination with clinical practice, and occupational exposure history can be considered to reduce appropriately. PMID- 30419674 TI - [A case of severe organophosphorus poisoning complicated with rhabdomyolysis]. PMID- 30419673 TI - [Electromyography analysis in 13 patients with acute trimethyltin chloride poisoning]. AB - Objective: To investigate the electromyography (EMG) characteristics and clinical significance in patients with acute trimethyltin chloride (TMT) poisoning. Methods: Retrospectively analyze the EMG results of major limb nerves and muscles of 13 patients with acute TMT poisoning. Results: Among the 13 patients, 10 cases had abnormal and the abnormal rate was 76.9%. The same degree of involvement of upper and lower limbs is the most common. And distal peripheral nerve damage is the most common, mainly manifested as sensory damage or mixed sensory and motor damage, with axonal injury and demyelinating lesions to almost the same degree. The peroneal nerve and median nerve were the most vulnerable, with an abnormal rate of 39.1% and 35.9%, respectively. The peroneal nerve and median nerve were damaged first but recovered slowly.The ulnar nerve first appeared damaged and recovered quickly. The sural nerve was damaged later. Conclusion: Acute TMT poisoning can cause limb peripheral nerve damage. This damage is a slow, gradual process, and its recovery is also a slow process. PMID- 30419675 TI - [A case of acute toxic encophatopathy after uninfentio ally antifreeze ingestion]. PMID- 30419676 TI - [Diagnosis discussion of two case's occupational tumor]. PMID- 30419677 TI - [Experience of rescue froma occupational acute mercury poisoning accident]. PMID- 30419678 TI - [Management of patient burned by sulfuric acid naphthalene]. PMID- 30419679 TI - [8 cases of pulmonary edema caused by clozapine poisoning]. PMID- 30419680 TI - [Report on a subacute 1,2-dichloroethane mild poisoning]. PMID- 30419681 TI - [Acute severe ammonia intoxication: a case report]. PMID- 30419682 TI - [Analysis of a death case on the misdiagnosis and improper treatments of propoxur poisoning]. PMID- 30419683 TI - [Determination of p-Phenylene diamine in workplace air by elution solution-liquid chromatography]. AB - Objective: To establish a elution solution-liquid chromatography method for determination of p-Phenylene diamine (PPD) in workplace air. Methods: p-Phenylene diamine (PPD) in the air of workplace was collected with glass fiber filters coated with dilute sulfuric acid and extracted with an aqueous EDTA solution. The target toxicant was separated with the C(18) column and analyzed with UV detector, identified by retention time, and quantified by peak area. Results: The linear range of PPD in the air of workplace was 2.00~10.00 MUg/ml, with a correlation coefficient of 0.999 96. The limit of detection was 0.07 MUg/ml. The lower limit of quantification was 0.23 MUg/ml. The minimum detectable concentration was 0.003 1 mg/m(3) under 45.0 L sampling volume and 2.0 ml extraction solution volume. The within-run precision of different PPD concentrations was 0.15%~2.3% and the between-run precisions was 1.4%~2.6%; The extraction efficiencies was 91.4%~95.4%; The average collection efficiencies was 96.6%; The samples could be stored for 7 days isolation of air. The potential coexistence of m-Phenylene diamine and o-Phenylene diamine with p-Phenylene diamine (PPD) in the air did not interfere with the results of determination. Conclusion: This method has high sensitivity, precision, accuracy and lower limit of detection and it is applicable for determination of p-Phenylene diamine (PPD) in workplace air. PMID- 30419684 TI - [Evaluation uncertainty of power frequency electric field for a Power Project in inner Mongolia]. AB - Objective: With the measurement and uncertainty analysis of the power frequency electric field of the main transformer in the power station, the source of uncertainty, its quantitative calculation, the synthetic assessment method and the reporting method of the measurement results are described to ensure the reliability of the power frequency electric field measurement data. Methods: Referring to the "Measurement of power frequency electric field in the workplace" (GBZ/T189.3-2007) , "Labour environment monitoring technological specification of electric power industry Partt7: Monitoring of power frequency electromagnetic fields" (DL/T 799.7-2010) and "Evaluation and Expression of Uncertainty in Measurement" (JJF 1059.1-2012) , the uncertainty of power frequency electric field measurement data of the main transformer of a power plant was analyzed and the extended uncertainty was obtained. Results: The main source of the uncertainty of power frequency electric field measurement was the measurement of repetitive operation, and the expanded uncertainty of power frequency electric field was 0.09 kV/m. Conclusion: When reporting the results of power frequency electric field measurement, the measurement uncertainty should be used simultaneously to quantify the quality of the measurement results. This method has strong practicability and operability, which can meet the requirements of uncertainty evaluation of power frequency electric field measurement results. PMID- 30419685 TI - [Review of the application of health promotion model]. PMID- 30419686 TI - [Research progress on toxictiy of methyl iolide]. PMID- 30419687 TI - [Experimental research advances in toxic effects of silica nanoparticles on cardiovascular system]. PMID- 30419689 TI - [mTOR signaling pathway and its research progress in embryo implantation]. PMID- 30419688 TI - [Application of Cobinamide in the treatment of toxic diseases]. PMID- 30419690 TI - [Developmental origin mechanism of non-communicable disease and its prevention and control in childhood]. PMID- 30419691 TI - [Framework for human health risk assessment of washing product ingredients in China]. PMID- 30419693 TI - [Scientific consensus on coffee and health]. PMID- 30419692 TI - [Technical guidelines for seasonal influenza vaccination in China (2018-2019)]. AB - Seasonal influenza vaccination is the most effective way to prevent influenza virus infection and complications from infection. Currently, China has licensed trivalent inactivated influenza vaccine (IIV3) and quadrivalent inactivated influenza vaccine (IIV4), including split-virus influenza vaccine and subunit vaccine. Except for a few major cities, influenza vaccine is a category II vaccine, which means influenza vaccination is voluntary, and recipients must pay for it. To strengthen the technical guidance for prevention and control of influenza and operational research on influenza vaccination in China, the National Immunization Advisory Committee (NIAC) Influenza Vaccine Technical Working Group (TWG), updated the 2014 technical guidelines and compiled the "Technical guidelines for seasonal influenza vaccination in China (2018-2019)" . The main updates in this version include: epidemiology, disease burden, types of influenza vaccines, northern hemisphere influenza vaccination composition for the 2018-2019 season, IIV3 and IIV4 immune response, durability of immunity, immunogenicity, vaccine efficacy, effectiveness, safety, cost-effectiveness and cost-benefit. The influenza vaccine TWG provided the recommendations for influenza vaccination for the 2018-2019 influenza season based on existing scientific evidence. The recommendations described in this report include the following: Points of Vaccination clinics (PoVs) should provide influenza vaccination to all persons aged 6 months and above who are willing to be vaccinated and do not have contraindications. No preferential recommendation is made for one influenza vaccine product over another for persons for whom more than one licensed, recommended, and appropriate product is available. To decrease the risk of severe infections and complications due to influenza virus infection among high risk groups, the recommendations prioritize seasonal influenza vaccination for children aged 6-59 months, adults >=60 years of age, persons with specific chronic diseases, healthcare workers, the family members and caregivers of infants <6 months of age, and pregnant women or women who plan to become pregnant during the influenza season. Children aged 6 months through 8 years require 2 doses of influenza vaccine administered a minimum of 4 weeks apart during their first season of vaccination for optimal protection. If they were vaccinated in 2017-2018 influenza season or a prior season, 1 dose is recommended. People more than 8 years old require 1 dose of influenza vaccine. It is recommended that people receive their influenza vaccination by the end of October. Influenza vaccination should be offered as soon as the vaccination is available. For the people unable to be vaccinated before the end of October, influenza vaccination will continue to be offered for the whole season. Influenza vaccine is also recommended for use in pregnant women during any trimester. These guidelines are intended for use by staff members of the Centers for Disease Control and Prevention at all levels who work on influenza control and prevention, PoVs staff members, healthcare workers from the departments of pediatrics, internal medicine, and infectious diseases, and staff members of maternity and child care institutions at all levels. PMID- 30419694 TI - [The baseline characteristics of School-based Cardiovascular and Bone Health Promotion Program in Beijing]. AB - Objective: To describe the baseline characteristics of School-based Cardiovascular and Bone Health Promotion Program(SCVBH) in Beijing. Methods: Children and adolescents were selected in 30 schools (8 primary schools, 21 middle schools and one 12-year education school) from Dongcheng, Tongzhou, Fangshan and Miyun districts of Beijing by using a stratified cluster sampling method. 15 391 students in grade 1 to 4 from primary schools, grade 1 from junior and senior high schools were enrolled in the investigation with an exclusion of students who were not able to participate due to trauma or other uncomfortable physical conditions. The baseline survey including a questionnaire survey, physical examination and blood biochemical test was conducted from September 2017 to January 2018. Obesity, blood pressure, fasting blood glucose, lipid, bone density and grip were evaluated. Results: The prevalence of obesity, hypertension, hyperglycemia (impaired fasting glucose and diabetes), dyslipidemia, lower bone density were 22.3%(3 394), 14.8%(2 248), 10.4%(1 490), 20.3%(2 919) and 2.1%(316) in total respectively, and 27.2%(2 081), 16.3%(1 244), 12.8%(922), 22.2%(1 595) and 1.2%(94) for boys, 17.3%(1 313), 13.3% (1 004), 7.9%(568), 18.4%(1 324) and 2.9%(229) for girls. Boys had higher prevalence of obesity, hypertension, hyperglycemia, and dyslipidemia and lower prevalence of low bone density than girls (all P values <0.05) The mean of body mass index, systolic blood pressure, fasting plasma glucose and grip of boys were significantly higher than that of girls (all P values <0.05).The mean of body mass index, systolic blood pressure, fasting plasma glucose and grip of boys were significantly higher than that of girls (all P values <0.05), the mean of fat mass percentage, total cholesterol, triglyceride, high density lipoprotein cholesterol and low density lipoprotein-cholesterol of boys were significantly lower than those of girls (all P values <0.05). Conclusion: The prevalence of risk factors of chronic cardiovascular disease was high and the low bone density was appearing in children and adolescents in this study. The promotion of cardiovascular and bone health should be implemented in children and adolescents. PMID- 30419695 TI - [Characteristics of cardiovascular health of children and adolescents aged 6-16 years in Beijing during 2017-2018]. AB - Objective: To describe the status of cardiovascular health (CVH) of children and adolescents aged 6-16 years in Beijing during 2017-2018. Methods: The school based Cardiovascular and Bone Health Promotion Program(SCVBH) was conducted from November 2017 to January 2018. 15 391 children and adolescents aged 6-16 years were selected from grade 1 to 4 in 8 primary schools, grade 1 in 21 middle schools and senior grade 1 in one twelve-year education school in Dongcheng, Fangshan, Miyun and Haidian Districts of Beijing by using a cluster sampling method. Seven cardiovascular health indicators, including smoking, body mass index, dietary intake, physical activity, blood pressure, blood glucose, and total cholesterol, were categorized as poor, intermediate, and ideal according to American Heart Association (AHA) criteria. The status of CVH was evaluated according to the criteria of the ideal CVH related behaviors and factors defined by AHA. Results: The proportion of children and adolescents with an ideal smoking, dietary intake and physical activity indicators reached 99.2%(4 982/15 108), 19.7%(2 921/14 805), 17.8% (2 499/14 056), respectively. The proportion of children and adolescents with 7 and 4-5 ideal cardiovascular health indicators was 1.7%(209/12 560) and 65.1%(8 176/12 560). The proportion of children and adolescents with 4-7 ideal cardiovascular health indicators, 2-4 ideal health behavior indicators and 2-3 ideal health factors was significantly higher in urban than that in rural all P values<0.001. The proportion of females with 4-7 ideal cardiovascular health indicators, 2-4 ideal health behavior indicators and 2-3 ideal health factors was significantly higher than that in males (all P values<0.001). Conclusion: The prevalence of ideal cardiovascular health of children and adolescents aged 6-16 years in Beijing during 2017-2018 was very low, particularly for healthy dietary intake and physical activity. Effective public health interventions should be implemented to improve the status of cardiovascular health of them. PMID- 30419696 TI - [Characteristics of cardiometabolic risk factors of children and adolescents aged 6-17 years in seven cities in China from 2013 to 2015]. AB - Objective: To describe characteristics of cardiometabolic risk factors of children and adolescents aged 6-17 years in 7 cities in China from 2013 to 2015. Methods: Data was from the China Child and Adolescent Cardiovascular Health (CCACH) study. 12 590 children and adolescents were selected from 24 schools (3 kindergartens, 7 primary schools, 7 junior high schools and 7 senior high schools) in seven cities (Changchun, Yinchuan, Beijing, Jinan, Shanghai, Chongqing and Tianjin) during 2013-2015 by using a stratified cluster random sampling method. The demographic characteristics, e.g. birth date, feed status and history of disease, were collected by questionnaires. Anthropometric measurements, i.e. weight, height, waistline, blood pressure, total cholesterol, fasting plasma glucose, triglyceride and high-density lipoprotein, were also collected. The detection rate of metabolic syndrome was calculated respectively according to "international diabetes federation standard " and "definition and prevention of metabolic syndrome in Chinese children and adolescents " . Results: The prevalence of cardiometabolic risk factors such as obesity, hypertension, hyperglycemia and dyslipidemia was 12.0%(1 497/12 491), 18.2%(2 193/12 035), 24.4%(3 028/12 422) and 15.8%(1 977/12 490), respectively. The prevalence of these four cardiometabolic risk factors in males was significantly higher than that in females (all P values<0.05). The prevalence of metabolic syndrome was 3.3%(272/8 328) with international diabetes federation 2007 definition and 5.4% (453/8 325) with Chinese definition among children above 10 years old. The prevalence of hypertension, hyperglycemia, hypertriglyceridemia, high total cholesterol, low high-density lipoproteincholesterol and dyslipidemia increased with the change of obesity type from non-obesity to complex obesity (all P values<0.001). Conclusion: The prevalence of cardiometabolic risk factors was still high in children and adolescents, which has become an important factor threatening the healthy growth of children and adolescents. PMID- 30419697 TI - [The analysis of the association of sleep with high blood pressure among children and adolescents aged 6-16 years in Beijing]. AB - Objective: To investigate the sleep status in children and adolescents and explore the relationship between the sleep and high blood pressure in them. Methods: Data was from the Schoolbased Cardiovascular and Bone Health Promotiow Program (SCVBH) in Beijing. And 13 471 children and adolescents aged 6-16 years were selected from grades 1 to 4 in 8 primary schools, grade 1 in 21 middle schools and senior grade 1 in one twelve-year education school in Dongcheng, Fangshan, Miyun and Tongzhou Districts of Beijing during 2017-2018 by using a cluster sampling method. Self-reported questionnaires were used to collect the demographic characteristics, lifestyle habits of children and adolescents. The blood pressure was measured by electronic sphygmomanometer. Multiple logistic regression model was used to analyze the association between sleep and hypertension risk. Results: The sleep duration was (8.4+/-1.1) hours. The prevalence of high blood pressure was 15.0%(2 021/13 471). The incidence of mouth breathing, slobber, snoring, and suffocate was 28.4%(3 823/13 471), 23.6%(3 184/13 471) and 18.7%(2 513/13 471), 2.8%(378/13 471) respectively. After adjusting for age, gender, snoring, mouth breaking, slobber, suffocate, the time for bed and sleep duration, we found that snoring and sleep duration (5.0-6.9 h) were both associated with high blood pressure (OR=1.49, 95%CI:1.32-1.69; OR=1.53, 95%CI: 1.28-1.81). Conclusion: Snoring and sleep duration were positively associated with high blood pressure in this study. Interventions focusing on sleep status should be developed to reduce the incidence of high blood pressure in children and adolescents. PMID- 30419698 TI - [Influence of change in blood pressure status from childhood to adulthood on renal dysfunction: a cohort study]. AB - Objective: To investigate the influence of change in blood pressure status from childhood to adulthood on renal damage. Methods: Data were obtained from Beijing Blood Pressure Cohort initiated from 1987. 3 198 children and adolescents aged 6 18 years from 6 primary and 6 middle schools in Chaoyang, Xicheng and Haidian Districts of Beijing were enrolled at baseline by using a cluster random sampling method, and 1 222 participants were followed up during 2010-2012. The measurements included weight, height, and blood pressure at baseline and microalbumin, serum creatinine, cystatin C and blood pressure at follow-up. Based on blood pressure status in childhood and adulthood, the participants were divided into four groups: participants with normal blood pressure in both childhood and adulthood, participants with elevated blood pressure in childhood but normal blood pressure in adulthood, participants with normal blood pressure in childhood but elevated blood pressure in adulthood, and participants with elevated blood pressure in both childhood and adulthood. Multivariate linear regression model was used to investigate the association of change in blood pressure from childhood to adulthood on renal dysfunction. Results: The prevalence of elevated blood pressure in childhood and adulthood was 17.9% and 39.9%, respectively. The P(50) (P(25)-P(75)) of microalbumin was 5.7(3.0-12.0) mg/L, and the concentration of eGFR and cystatin C were (118.0+/-19.8)% and (0.734+/-0.184)mg/L, respectively. With adjustment for sex, baseline age and follow-up years, compared with participants with persistently normal blood pressure from childhood to adulthood, participants with normal blood pressure in childhood but elevated blood pressure in adulthood had significantly higher levels of microalbumin (beta=0.502, 95%CI: 0.320-0.684) and cystatin C (beta=0.049, 95%CI: 0.025-0.073). After adjustment for sex, baseline age, follow up duration, and adult BMI, smoking and drinking, participants with normal blood pressure in childhood and elevated blood pressure in adulthood had higher levels of adult urine microalbumin (beta=0.322, 95%CI: 0.128-0.516) and cystatin C (beta=0.032, 95%CI:0.007-0.057). Conclusion: An increase in blood pressure during childhood and adulthood has an adverse impact on renal functional damage in adulthood. These findings underscore the importance of maintaining normal blood pressure during life course to prevent the development of chronic kidney disease. PMID- 30419699 TI - [The associations between nighttime sleep duration, bedtime and preschool children's obesity]. AB - Objective: To examine the relationship of nighttime sleep duration and bedtime with preschool children's obesity, and to explore possible early life risk factors for childhood obesity. Methods: A total of 14 946 valid children from 16 439 pre-school children aged 3-6 years in 91 kindergartens in Ma'anshan city participated in the study. The body mass index cut-offs for overweight and obesity in Chinese children and adolescents aged 2-18 years was used as the criterion for judging overweight and obesity, and pathological and secondary causes of obesity were excluded. The associations of nighttime sleep duration and bedtime with preschool children's obesity was analyzed by using non-conditional multivariate binary logistic regression model. Results: Among the preschool children, 22.4% (n=3 345) had shorter sleep duration. 9.5% (n=1 415) had bedtimes after 22:00 on weekdays and 21.8% (n=3 260) had bedtimes after 22:00 on weekends. The prevalence of overweight and obesity were 16.5% (n=2 466) and 10.5% (n=1 562), respectively. After the adjustent of age, gender, whether or not only child, residence in the last six months, parents' body mass index parents' educational level, diet preference, outdoor activities, TV viewing duration, sleep duration, bedtime on weekdays and weekends, only the shorter sleep duration (OR=1.25, 95%CI: 1.03-1.51) was still positively associated with the prevalence of obesity in preschool children. Conclusion: Shorter sleep duration was positively associated with the prevalence of obesity among preschool children. PMID- 30419700 TI - [Analysis on epidemiological characteristics and related factors of dyslipidemia among adult residents of Xinjiang Uygur Autonomous Region during 2013-2014]. AB - Objective: To study the epidemiological characteristics and related factors of dyslipidemia among adult residents in Xinjiang Uygur Autonomous Region (Xinjiang) in 2013-2014. Methods: A total of 4 120 adult residents consisting of Han and Uygur group aged over 18 years old were selected by using a stratified cluster random sampling method in 8 counties of Xinjiang from 2013 to 2014. The related factors of dyslipidemia were collected by questionnaire and physical measurement. The total cholesterol, triglyceride, high-density lipoprotein cholesterol and low density lipoprotein cholesterol were detected by enzyme method. Factors associated with dyslipidemia were analyzed by chi-squared test and a multivariate unconditioned logistic regression model adjusted for gender, urban or rural area, age-group, body mass index (BMI), central obesity, smoking, drinking, education attainment, diabetes mellitus and hypertension. Results: The prevalence of dyslipidemia was 45.00% (1 854 cases). The prevalence of dyslipidemia was higher in Uygur group (47.80% (977/2 044)) than that in Han group (42.24% (877/2 076)) (chi(2)=12.84, P<0.001). The analysis showed that dyslipidemia was related with gender (OR=0.41, 95%CI: 0.33-0.51), urban area (OR=0.54, 95%CI: 0.39-0.76), BMI (overweight group (OR=1.52, 95%CI: 1.18-1.96); obesity group (OR=2.20, 95%CI: 1.64-2.96)), central obesity (OR=1.66, 95%CI: 1.29-2.14) and diabetes mellitus (OR=1.49, 95%CI: 1.06-2.11) in Uygur group. The analysis also showed that dyslipidemia was related with BMI (overweight group (OR=1.72, 95%CI: 1.32-2.25), obesity group (OR=2.60, 95%CI: 1.85-3.64)), central obesity (OR=1.45, 95%CI: 1.13 1.87), smoking (OR=1.46, 95%CI: 1.09-1.95), diabetes mellitus (OR=1.77, 95%CI: 1.38-2.25) and hypertension (OR=1.62, 95%CI: 1.31-2.00) in Han group. Conclusions: The prevalence of dyslipidemia in Xinjiang was higher than the national average prevalence. The prevalence of dyslipidemia in Uygur group was significantly higher than that in Han group. The gender, living area, BMI, central obesity and diabetes mellitus were risk factors of dyslipidemia in Uygur group, and BMI, central obesity, smoking, diabetes mellitus and hypertension were risk factors of dyslipidemia in Han group in Xinjiang. PMID- 30419701 TI - [Expression of type 1 and type 2 cytokines from serum of coal miners and the evaluation in surveillance of coal workers' pneumoconiosis at earlier stage]. AB - Objectives: To explore the expression regulation of type 1 and type 2 (Th1 and Th2) cytokines from serum of coal miners and the evaluation in surveillance of coal workers' pneumoconiosis, 630 coal miners were studied. Methods: A total of 90 male patients diagnosed as coal workers' pneumoconiosis (CWP) in a institute for occupational health and 19 male workers newly diagnosed as CWP patients was chosen as CWP group with simple random sampling method from a coal mine group from January 2013 to December in 2015. 180 male coal miners with abnormal but not diagnosed as CWP were selected as CWP suspected group with simple random sampling methods, meanwhile 180 male coal miners with normal chest X-ray photograph was as dust-exposed group by 1?1 matched as age. And 161 healthy males accepted pre employed examination were selected as control group, CWP suspected group, dust exposed group and control group called as non-CWP group. According to screening test and diagnosis test, the basic information and occupational history of all subjects were collected, and cytokines including IL-1beta, IL-8, IFN-gamma, IL-6 and IL-10 of serum were detected. Receiver operator characteristic (ROC) curve was used to determine the optimal cutoff value of each cytokine. Area under curve (AUC), the validity and reliability were calculated and judged. Results: The average age of control group, dust-exposed group, CWP suspected group and CWP group were (27.4+/-5.0) , (43.4+/-10.7) , (48.2+/-6.2) , (64.7+/-7.0) years old, respectively. The median level of IL-1beta, IL-8, IFN-gamma and IL-6 in cases group (1 638.30, 2 099.49, 815.18,140.32 pg/ml) were higher than that of non cases group (1 445.57, 1 402.26, 736.38, 95.73 pg/ml) (P<0.05) . The level of IL 8 (1 503.99 pg/ml) in CWP suspected group was higher than that of control group (1 295.67 pg/ml) and dust-exposed group (1 376.94 pg/ml) , but the level of IL-10 (654.08 pg/ml) was lower than that of control group (596.64 pg/ml) . The ratio of IFN-gamma/IL-6 ranged from 5 to 8, and the ratio in CWP group (5.87) was lower than that of non-CWP group (7.61) . The IL-6 and IL-8 among the subjects of dust exposed group in terms of the age distribution of among had reached statistical significance. According to ROC, the cutoff value of IL-1beta, IL-6, IL-8, IL-10 and INF-gamma reached 1 582.65, 116.53, 1 791.54, 581.08 and 792.69 pg/ml, respectively. The AUC was 0.668, 0.895, 0.859, 0.716 and 0.637, respectively. It was found that IL-6 and IL-8 could be used as biomarkers in detecting CWP, the sensitivity and specificity was 82.6% and 84.6%, 78.0% and 84.8%, respectively; Youden's index was 0.674 and 0.628 and the consistency rate was 84.3% and 83.7%, while Kappa value was 0.55 and 0.52. Conclusion: There was Type 1 and type 2 cytokine dysregulation in CWP patients. IL-6 and IL-8 can be used as effective biomarkers to forecast lung injury before X-ray changes. PMID- 30419702 TI - [Laboratory diagnosis and molecular tracing of dengue bordline cases in Henan Province, 2017]. AB - Objective: To confirm the laboratory diagnosis of dengue bordline cases reported in Henan Province and trace its origin from molecular level in 2017. Methods: The study samples were blood samples (3-5 ml), which came from 8 suspected cases of dengue fever reported in the 2017 direct reporting system of Henan provincial infectious disease monitoring network. Meanwhile, case investigation was conducted according to National dengue fever surveillance programme. Serum were separated from blood samples and tested for Dengue NS1 antigen, IgM & IgG antibodies, and dengue RNA. According to dengue diagnosis criteria, confirmed cases were identified by testing results. Samples carried dengue RNA performed for real-time PCR genotyping and amplification of E gene. Then, the amplicons were sequenced and homological and phylogenetic analyses were constructed. Results: 8 serum samples of suspected dengue cases were collected in Henan Province, 2017. Six of them were diagnosed as dengue confirmed cases. All the dengue confirmed cases belonged to outside imported cases, 5 of them were positive by dengue RNA testing. Genotyping results showed there were 1 DENV1 case, 2 DENV2 cases and 2 DENV3 cases. A DENV2 case and a DENV3 case of this study were traced its origin successfully. The sequence of Pakistan imported DENV2 case belongs to cosmopolitan genotype, which was the most consistent with Pakistan's DENV2 KJ010186 in 2013 (identity 99.0%). The sequence of Malaysia imported DENV3 case belongs to genotype I, which was the most consistent with Singapore's DENV3 KX224276 in 2014(identity 99.0%). Conclusion: The laboratory diagnosis and molecular traceability of dengue cases in Henan Province in 2017 confirmed that all cases were imported and did not cause local epidemics. PMID- 30419703 TI - [Etiology and clinical analysis of central nervous system infection caused by Coxsackievirus B5 in severe hand, foot and mouth disease in Qingdao City, 2013 2014]. AB - Objective: To illuminate the gene characteristics and clinical characterization of Coxsackievirus B5 (CV-B5) strains isolated from patients with sevre hand, foot and mouth disease (HFMD) in Qingdao city. Methods: A total of 1 844 patients of HFMD were consecutively admitted to Qingdao Women and Children's Hospital from 2013 to 2014. Information of the study population described above was collected retrospectively. The samples were collected from at least 1 site (throat swab, cerebrospinal fluid), which viral nucleic acid extracted and the entire VP1 gene sequences of CV-B5 isolates were amplified and sequenced, then the homology and phylogeny analysis were conducted by MEGA7.0. The prototype Faulkner strain and other VP1 amino acid sequences were derived from the GenBank database. Results: A total of 8 CV-B5 positive cases were obtained, including 4 males and 4 females; 6 severe hospitalized cases and 2 outpatients. The age of 6 hospitalized patients ranged from 3 to 48 months, with a median of 26 months. For the six inpatients, fever, convulsions vomiting, diarrhea and rash were the main clinical manifestation, and all combined with viral encephalitis. Compared with the prototype strain Faulkner, in the VP1 region,the nucleotide and the amino acid homologies was 77.3%-78.8% and 95.5%-97.0% respectively. Five out of the six severe cases with substitution of serine (S) to asparagine (N) at amino acid site 95 in the VP1 region. The sequences of 8 CV-B5 strains were classified into genogroup D. Conclusion: Hand, foot and mouth disease associated with CV-B5 virus infection can result in nervous system involvement and the main complication was viral encephalitis. The CV-B5 strains associated with severe hand, foot and mouth disease had high nucleotide homology and present a certain regional aggregation. PMID- 30419705 TI - [The role of heme oxygenase-1 on oxidative stress injury induced by zinc oxide nanoparticles in human umbilical vein endothelial cells line EA.hy926 cells]. AB - Objective: To explore the effect of heme oxygenase-1 (HO-1) on level of reactive oxygen species (ROS) induced by zinc oxide nanoparticles (ZnO-NPs) in Human umbilical vein endothelial cells line EA.hy926. Methods: The EA.hy926 cells in logarithmic growth phase were incubated with 0.0, 2.5, 5.0, 10.0 and 15.0 mg/L ZnO-NPs respectively. The ROS level, reflected by mean fluorescence intensity (MFI), was examined by flow cytometer after 4 hours exposure, the protein expression of HO-1 which was determined by Western Blot after exposed to ZnO-NPs for 24 hours. Cells incubated with 15.0 mg/L were set as the ZnO-NPs group; a blank control group was set at the same time. Cells were pretreated with HO-1 inhibitor zinc protoporphyrin (ZnPPIx) and HO-1 activator cobalt protoporphyrin (CoPPIx), they were classified as ZnPPIx group and CoPPIx group. 15 mg/L ZnO-NPs was chosen to conduct the experiment of HO-1 activation and inhibition. Cells were classified as ZnPPIX+ ZnO-NPs group and CoPPIx+ ZnO-NPs group after pretreated with 10 MUmol/L ZnPPIx or CoPPIx for 1 h, added 15 mg/L ZnO-NPs to cell culture medium. In all groups ROS levels were detected after exposed to ZnO NPs for 4 hours, the protein expression of HO-1 was detected after exposed to ZnO NPs for 24 hours. Results: With the increased dose of ZnO-NPs, levels of ROS and HO-1 in EA.hy926 cells were clearly elevated (the MFI of 0.0, 2.5, 5.0, 10.0 and 15.0 mg/L ZnO-NPs incubated groups was 22 627.22+/-718.27, 24 726.47+/-568.52, 31 141.75+/-1 312.24, 39 824.82+/-4 774.74, 50 569.03+/-1 497.63 respectively, and HO-1 relative expression were 0.16+/-0.01, 0.19+/-0.02, 0.16+/-0.01, 0.23+/-0.02, 0.92+/-0.06 respectively). HO-1 expression in ZnPPIx pretreatment group decreased compared with ZnO-NPs group (1.05+/-0.05 vs. 1.12+/-0.01, P<0.05), meanwhile ROS level enhanced (62 683.95+/-2 589.59 vs. 53 654.53+/-2 229.01, P<0.05). However, CoPPIx pretreatment had higher HO-1 level and lower level of ROS compared with ZnO-NPs group (HO-1: 1.74+/-0.11 vs. 0.22+/-0.03, P<0.05; ROS: 32 845.04+/-993.48 vs. 53 654.53+/-2 229.01, P<0.05). Conclusions: Exposure to ZnO-NPs significantly induced ROS generation in EA.hy926 cells in a dose-dependent manner. HO-1 regulated ZnO-NPs-induced oxidative stress. PMID- 30419706 TI - [Effects of endoplasmic reticulum stress-induced apoptosis in thyroid injury caused by fluoride in rat]. AB - Objective: To explore the effects of endoplasmic reticulum stress-induced apoptosis in thyroid injury of rats caused by excessive fluoride intake. Methods: All 40 Wistar rats were randomly divided into four groups, control group, low fluoride group, medium fluoride group and high fluoride group. The rats in control group were fed with tap water (fluoride concentration=0.344 mg/L) and the experimental rats were fed with the water contaminated fluoride with the dose of 5, 10 and 20 mg/L. 10 rats (female: male=1?1) in each group were sacrificed after 8 months of exposure through drinking water. The contents of urine fluoride were detected by fluorine ion selective electrode method. Morphology of thyroid was observed through light microscope and apoptosis in thyroid were detected by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. The mRNA and protein expressions of glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) were analyzed by RT-PCR and immunohistochemistry respectively, and results were compared among groups. Results: The contents of urine fluoride in all fluoride treated groups were separately (4.74+/-1.88), (7.70+/-2.82) and (10.50+/-2.92) mg/L, which were gradually higher than that of control group (2.23+/-0.54) mg/L (P<0.05). Morphological changes were found in thyroid tissues of fluoride treated groups, thyroid follicular hyperplasia or even no cavity cell clusters were observed. Apoptosis in thyroid were notably increased in fluoride treated groups. The mRNA expression levels of GRP78 in all fluoride treated groups were separately 1.30+/ 0.42, 1.39+/-0.29 and 1.50+/-0.27, which were significantly higher than that of control group (0.93+/-0.24) (P<0.05). And the mRNA expression levels of CHOP in medium and high fluoride groups were separately 1.17+/-0.29 and 1.30+/-0.26, which were significantly higher than that of control group (0.91+/-0.20) (P<0.05). The protein expression levels of GRP78 and CHOP in medium and high fluoride groups were respectively 29.68+/-4.04, 29.90+/-3.74 and 4.05+/-1.62, 4.44+/-1.81, which were significantly higher than those in the control group (separately 23.80+/-6.36, 2.27+/-0.89) (P<0.05). Conclusion: Excessive-fluoride intake can induce thyroid injury, and endoplasmic reticulum stress-induced apoptosis might be involved in the injury. PMID- 30419704 TI - [Investigation on the cold-chain temperature of vaccine in some areas of Zhejiang Province]. AB - Objective: To investigation the situation of cold chain on vaccine in parts of Zhejiang Province and to provide recommendations for the management. Methods: From October to December, 2016, we each selected an immunization clinic in Cangnan County of Wenzhou, Yongkang City of Jinhua, Jianggan District of Hangzhou. Temperature recorder and vaccine viral monitor (VVM) labels were used to monitor the cold chain during all the storage and transportation process. In Jianggan District, we use optical density sensor to detected 20 VVM labels every time when the vaccine was stock in and out. Results: In total, 54 958 records were collected by temperature recording devices in all the three immunization clinic. 275 records exceeded the temperature limit required for store and transportation, of which 270 (98.2%) were above 8 C and 5 (1.9%) were under 2 C. Excessive temperature exposure mainly occurred during the transportation (38.2%, n=105), followed by storage process in CDCs at different levels (26.2%, n=72), stock in and out (20.7%, n=50) and storage in the refrigerators in immunization clinics (14.9%, n=41). The average optical density difference between VVM labels and the reference circular decreased from 0.404 to 0.344 when the vaccines were delivered from the Zhejiang provincial CDC to immunization clinics. The color of VVMs did not significantly changed before use. Conclusions: The potential risk of vaccine cold chain in the monitoring sites is over-temperature. The weak links of cold chain management include the transportation, storage process, and stock in and out. PMID- 30419707 TI - [A comparative study on the three methods of concentration of norovirus from water]. PMID- 30419708 TI - [Analysis of surveillance on iodine deficiency disorders in the interim of readjustment of salt iodine in Sichuan Province]. PMID- 30419709 TI - [Monitoring of the first imported Zika case in Henan Province]. PMID- 30419710 TI - [Advances on antimicrobial resistance research of Salmonella enterica Serovar Indiana]. AB - Salmonella enterica Serovar Indiana is a common serotype of Salmonella isolated from food especially from poultry meat. Recently it demonstrated a raising tendency of infection cases and isolate numbers with high antimicrobial resistant rate against many common antimicrobials, including quinolones and cephalosporin which were regarded as the first line drug for the treatment of Salmonella infections, and this kind of Salmonella serotype was always carrying complex resistance mechanisms and also a variety of mobile elements, all of these features made the very clinical infections caused by Salmonella hard to treat and brought great difficulties and risks. Here, we review the prevalence of Samonella Indiana on national and international view, and we also anticipate the research progress on antimicrobial drug classes, multi drug resistance, co-resistance and resistance mechanism. We discuss the resistant genotypes, phenotypes, mechanism and transmission of Salmonella Indiana strains isolated from different origins. By introducing the resistance of Salmonella Indiana, we want to attract people's attention to this bacteria and its hazard, and offer some idea to evaluate and treat infections in clinical. PMID- 30419711 TI - [The compilation, content and dissemination of Jian Yao Ji Zhong Fang]. AB - Jian Yao Ji Zhong Fang(Brief collectanea of prescriptions which are benefit to common people)<<>> was the 4th medical formulary promulgated by the Song government. Zhou Ying, the medical officer of the Hanlin Academy, was called to compile this book.The content of it mainly came from Tai Ping Sheng Hui Fang, compiled by Wang Huaiyin under the order of the Emperor, and the collection of various effective prescriptions. But this book was lost in the late Ming Dynasty. The primary edition of Jian Yao Ji Zhong Fang was published in the third year of Huangyou(1051 AD). It was not only given to the counties by the Song government at that time, but also effectively handed down and applied in Jin, Yuan, Ming and Qing Dynasties. Besides, this book has been spread to such places as Korea and Japan. The extant content of Jian Yao Ji Zhong Fang was mainly preserved in such medical books as The classified collection of medical prescriptions <>>> collected by Kim Ye-mong in Korea; Da Guan Jing Shi Zheng Lei Beiji Bencao<<>>originally edited by medical expert Tang Shenwei,proofread and supplemented by Ai Sheng; Chong Xiu Zheng He Jing Shi Zheng Lei Bei Yong Ben Cao <<>>originally edited by Tang Shenwei,proofread and supplemented by Cao Xiaozhong, revised and enlarged by Zhang Cunhui; Mananpou<<>>edited by Kajiwara Senzen; Zatsubyou kouyou<<>> edited by Tanba Motokata. It contained various categories of symptoms and signs, like liver, heart, spleen, lung, kidney, sanjiao, stroke, defecation and children, as well as hundreds of therapeutic prescriptions to heal different kinds of internal and surgical diseases and plague. PMID- 30419712 TI - [Review Joseph Needham's study on Ge Hong and western view of the history of Traditional Chinese Medicine]. AB - Ge Hong(), from Joseph Needham's view, is a historical figure with multiple characters, for example: he was a priest, a scientific researcher, a pioneer in the research of chemical medicines, a successor of the "prevention prior to cure" theory, an early explorer of immunotherapy. He was a man who detailedly recorded the infectious diseases, an ascetic with a strong individual spirit. Ge Hong was also a collector of the new knowledge, and his writings can be regarded as the typical Chinese ancient literature. Needham's viewpoints on Ge Hong represent a different perspective of western society on ancient Chinese science and technology, especially on the development of Chinese medicine. PMID- 30419713 TI - [The analysis of "Wasting-and-Thirst" disease from Wei-Jin to Tang Dynasty]. AB - Huangdi Neijing ()considered that "wasting-and-thirst" patients should not take mineral drugs. The period from Wei-Jin to Tang Dynasty, to meet the need for mildly strengthening Yang by tonic, people no longer considered that "wasting-and thirst" patients can't take mineral drugs. It was popular to take mineral elixir. The rich people who consumed mineral elixir were susceptible of diabetes. The practitioners observed that taking mineral elixir and sexual behaviors were related to "wasting-and-thirst" , and therefore, they realized that taking mineral elixir was main cause of getting it. They inferred that "mineral heat" deposited in kidney and "kidney deficiency" resulted in "wasting-and-thirst" . Therefore, many cure medicines presented. Among the group of rich people from Wei Jin to Tang Dynasty, many were patients of elixir poisoning and diabetes, also including its many complications. Some experiences and ideas of treating "wasting and-thirst" patients from Wei-Jin to Tang are still helpful clinically to cure diabetes today. PMID- 30419714 TI - [Evidential research on the source of term "wine"]. AB - During Shang Dynasty, there appeared the wine(Chinese:, Jiuji), a clarified liquid preparation extracted from crude medicine with distilled liquor.The wine had many alternative names in history.In Yuan Dynasty, the connotation of "wine" was completely same as its modern meaning. It was as a specific term of drug types during the Republic of China. In Chinese Traditional Medicine and Materia Medica Subject Headings, the "wine" became a formal subject term. In Chinese Terms in Traditional Chinese Medicine and Pharmacy, "wine" was issued as a standardized name, which considered to be consistent, scientific and concise under scientific naming rules. PMID- 30419715 TI - [The rise of "Artificial Plasma" , nutritional medicines and the social trend of health care]. AB - Chinese companies made "artificial plasma" by learning the experience of artificial nutritional medicine at western drugs companies. A lot advertising presented typical models for modern medicines. The producers tried to convince the customers of artificial plasma's functions by utilizing famous person advertising effect and the customers' assured talking about it. And the theories of traditional Chinese medicines and western medicines experiments were hired to note the functions "artificial plasma" , but it is very difficult to evaluate its real functions. "Artificial plasma" was fashionable on the market, because the customers joyfully have requirements of nourishing live psychologically, fear being "sick man of Asia" and hopefully strengthen the race and country. After the Revolution of 1911, the companies wanted to meet not only the need and requirement of the ruler class, but also of the common people. The popularity of "artificial plasma" , to some extent, pushed medical knowledge to spread among common people, expanded influence of Chinese nation medical industry. From later Qing Dynasty, health care and preventive medicine became more popular. Artificial nutritional medicine played an important role in this process. PMID- 30419716 TI - [The investigation on the historical remains related to medical, healthy and hygienical activities in Zhejiang]. AB - Aiming to protect and utilize the historical remains related to medical, healthy, and hygienical activities, we have to get the information of those remains. From 2003 to 2018, we investigated and documented those remains before 1949 by checking various literatures, archives, and collected the information supplied by the traditional Chinese medicine practitioners and scholars. Total remains 167 recorded and documented as following: historical event remains 17; temple and shrine 12; medical institutions remains 43; research institutions remains 2; traditional Chinese medical factory remains 1; western and traditional Chinese medicine stores 15; western and Chinese medical education institutions remains 5; famous medical person residence remains 16; tombs 14; inscription 7; sites of wells 35, also including 1950s historical remains 2. PMID- 30419717 TI - [Discrimination on a disease of Foot-Taiyang Meridian named "Chong head()" or "Chong headache()"]. AB - In various versions of Mai Shu(), "Chong head()" or "Chong headache()" is a disease of Foot-Taiyang Meridian. "Chong()" cannot be interchanged with "swell()" , and it does not have the meaning of "upward" . In ancient medical records, the headache due to "reversing Qi uprush" has nothing to do with Foot-Taiyang Meridian. The word "Chong()" is commonly used before the Han Dynasty as "collide" or "strike" . "Chong head()" or "Chong headache()" can be interpreted as a striking pain in head. which can reasonably solve the problems of disparate explanations in all versions of Mai Shu(), as well as the some internal problems of traditional medical principles. PMID- 30419718 TI - [A study on Wu Jinshou]. AB - Wu Jinshou()[(1785-1795)-(1844-1851)]once wanted to take the imperial examination, but in late Qing Dynasty, under the depressed situation of economics and politics, he was trapped in countryside as many lower intellectuals, and chose medicine as another way to earn a living. In fact, he was both a doctor and a literatus. He kept friends with scholars, such as Zhang Tingji, Yao Wentian, Lu Changchun, Wei Guangfu, and scholar-physicians like Chen XIshu, Lu zeng and also Xu Jin's family, famous doctors at that time. He changed status Flexibly. To some extent, he represented the basic appearance of the traditional Chinese practitioner. In Daoguang 11 years(1831), Wu Jinshou published Medincal Cases Records of Three physicians(<<>>), Yi Xiao Mi Chuan(<<>>), Wen Re Zhui Yan(<<>>). This naturally have business purpose and was market-oriented. He had influenced on the spread of Wuzhong(the name of Suzhou and its surrounding area in Ming and Qing Dynasty) medical books, and provided some topics to the study of the Wenbing academic history. PMID- 30419719 TI - Waiting and Hope: Optimal Time Interval for Surgery After Long-Course Neoadjuvant Chemoradiotherapy in Patients With Locally Advanced Rectal Cancer. PMID- 30419720 TI - Lateral Lymph Node Dissection With the Focus on Indications, Functional Outcomes, and Minimally Invasive Surgery. AB - The lateral lymph node dissection (LLND) is still a subject of great debate as to the appropriate treatment for patients with mid to low advanced rectal cancer. The guidelines of the Japanese Society for Cancer of the Colon and Rectum recommend a LLND for patients with T3/4 rectal cancer below the peritoneal reflection. However, in most Western countries, a routine LLND is not recommended unless a node or nodes are clinically suspicious for metastasis. Even after preoperative chemoradiotherapy (CRT), an 8% to 12% lateral pelvic recurrence was noted. The size of the lateral lymph node and responsiveness to preoperative CRT should be the main factors for selecting appropriate patients to undergo a LLND. In addition, from the recent literature, a laparoscopic LLND is safe and oncologically feasible and might have some advantages in short-term outcomes. PMID- 30419721 TI - Optimal Time Interval for Surgery After Neoadjuvant Chemoradiotherapy in Patients With Locally Advanced Rectal Cancer: Analysis of Health Insurance Review and Assessment Service Data. AB - PURPOSE: Pathologic downstaging of rectal cancer has been suggested to be associated with the time interval from chemoradiotherapy (CRT) completion to surgery. We aimed to evaluate the effect of this time interval for patients with rectal cancer on the pathologic response. METHODS: All patients with rectal cancer undergoing neoadjuvant CRT with evaluable data were selected from among the Health Insurance Review and Assessment Service data. Patients were divided into groups according to the time between CRT and surgery. CRT responses were analyzed. RESULTS: Two hundred forty-nine patients were included, of whom 86 (34.5%) were in the 5- to 7-week interval, 113 (45.4%) in the 7- to 9-week interval, 38 (15.3%) in the 9- to 11-week interval, and 12 (4.8%) in the >11-week interval. The median time interval between CRT completion and surgery was 7.4 weeks (range: 5-22.7 weeks; interquartile range, 6.7-8.7 weeks). Surgery 9-11 weeks after CRT completion resulted in the highest, but not statistically significant, pathologic complete response (pCR) rate (3 patients, 8.6%; P = 0.886), no pCR was noted in the >11-week interval group. Results for downstaging in the 9- to 11-week interval group were as follows: T downstaging, 38.2% (P = 0.735); N downstaging, 50.0% (P = 0.439); and TN downstaging, 52.9% (P = 0.087). The 3-year overall survival rates for the 5- to 7-week, 7- to 9-week, 9- to 11 week, and >11-week interval groups were 93.0%, 85.0%, 81.6%, and 91.7%, respectively (P = 0.326). CONCLUSION: Delaying surgery by 9 to 11 weeks may increase TN downstaging, but delaying for over 11 weeks may not increase additional tumor downstaging from long-course CRT. PMID- 30419722 TI - Discrepancy of Medical Terminology Regarding Colorectal Surgery Between South and North Korea. AB - PURPOSE: We aimed to investigate the extent of heterogeneity in medical terminology between South and North Korea by comparing medical terms related to the colorectal system. METHODS: North Korean medical terms were collected from the sections on diseases of the small intestine and colon in a surgery textbook from North Korea, and those terms were compared with their corresponding terms in a South Korean medical terminology textbook. The terms were categorized as either identical, similar, showing disparity, or not used in South Korea. In a subsection analysis, the terms were allocated to pathophysiology, diagnosis, symptoms and examination, drugs, testing, treatment, or others according to the categorization used in the textbook. RESULTS: We found 705 terms in the North Korean textbook, most of which were pathophysiological terms (206, 29.2%), followed by diagnostic terms (165, 23.4%) and symptom and examination terms (122, 17.3%). Treatment-, drug-, and testing-related terms constituted 15.5%, 5.8%, and 4.1% of the 705 terms, respectively. There were 331 identical terms (47.0%) and 146 similar terms (20.7%); 126 terms (17.9%) showed disparity. Another 102 terms (14.5%) were not used in South Korea. The pathophysiological terms were the least heterogeneous, with 61.2% being identical terms used in both countries. However, 26.8% of the terms in the drug category were not used in South Korea. CONCLUSION: The present study showed that less than 50% of the terms for the colorectal system used in South and North Korea were identical. As the division between South and North Korea persists, the heterogeneity of medical terminology is expected to increase. PMID- 30419723 TI - Patient-Controlled Nutrition After Abdominal Surgery: Novel Concept Contrary to Surgical Dogma. AB - PURPOSE: According to surgical dogma, patients who are recovering from general anesthesia after abdominal surgery should begin with a clear liquid diet, progress to a full liquid diet and then to a soft diet before taking regular meals. We propose patient-controlled nutrition (PCN), which is a novel concept in postoperative nutrition after abdominal surgery. METHODS: A retrospective pilot study was conducted to evaluate the feasibility and effects of PCN. This study was carried out with a total of 179 consecutive patients who underwent a laparoscopic appendectomy between August 2014 and July 2016. In the PCN group, diet was advanced depending on the choice of the patients themselves; in the traditional group, diet was progressively advanced to a full liquid or soft diet and then a regular diet as tolerated. The primary endpoints were time to tolerance of regular diet and postoperative hospital stay. RESULTS: Time to tolerance of a regular diet (P < 0.001) and postoperative hospital stay (P < 0.001) showed statistically significant differences between the groups. Multivariate analysis using linear regression showed that the traditional nutrition pattern was the only factor associated with postoperative hospital stay (P < 0.001). Multivariate analysis using logistic regression showed that traditional nutrition was the only risk factor associated with prolonged postoperative hospital stay (>=3 days). CONCLUSION: After abdominal surgery, PCN may be a feasible and effective concept in postoperative nutrition. In our Early Recovery after Surgery program, our PCN concept may reduce the time to tolerance of a regular diet and shorten the postoperative hospital stay. PMID- 30419724 TI - Clinical Outcomes of a Redo for a Failed Colorectal or Coloanal Anastomosis. AB - PURPOSE: Redo surgery in patients with a persistent anastomotic failure (PAF) is a rare procedure, and data about this procedure are lacking. This study aimed to evaluate the surgical outcomes of redo surgery in such patients. METHODS: Patients who underwent a redo anastomosis for PAF from January 2004 to November 2016 were retrospectively evaluated. Data from a prospective colorectal database were analyzed. Success was defined as the combined absence of any anastomosis related complications and a stoma at the last follow-up. RESULTS: A total of 1,964 patients who underwent curative surgery for rectal cancer during this study period were included. Among them, 32 consecutive patients underwent a redo anastomosis for PAF. Thirteen patients of those 32 had major anastomotic dehiscence with a pelvic sinus, 12 had a recto-vaginal fistula, and 7 had anastomosis stenosis. There were no postoperative deaths. The median operation time was 255 minutes (range, 80-480 minutes), and the median blood loss was 80 mL (range, 30-1,000 mL). The overall success rate was 78.1%, and the morbidity rate was 40.6%. Multivariable analyses showed that the primary tumor height at the lower level was the only statistically significant risk factor for redo surgery (P = 0.042; hazard ratio, 2.444). CONCLUSION: In our experience, a redo anastomosis is a feasible surgical option that allows closure of a stoma in nearly 80% of patients. Lower tumor height (<5 cm from the anal verge) is the only independent risk factor for nonclosure of defunctioning stomas after primary rectal surgery. PMID- 30419725 TI - Prevention and Control Strategies for Parasitic Infections in the Korea Centers for Disease Control and Prevention. AB - Korea is successfully controlled intestinal parasitic infections owing to economic development and high health consciousness. The Division of Vectors and Parasitic Diseases (formerly the Division of Malaria and Parasitology) is in the Center for Laboratory Control of Infectious Diseases of the Korea Centers for Disease Control and Prevention. It has been the governmental agency responsible for controlling and leading scientific research on parasitic diseases. The Division of Vectors and Parasitic Diseases has conducted and funded basic research and disseminated the research results to various medical fields, ultimately promoting public health in Korea. Among the noteworthy achievements of this division are the national surveillance of healthcare-associated parasitic infections, prevention and control for parasitic infections, and the elimination of lymphatic filariasis from Korea. On a broader scale, the division's research programs and academic supports were influential in preventing and treating infectious parasitic diseases through public policies and laws. In this review, we summarize the past and present role of the Division of Vectors and Parasitic Diseases in preventing and treating infectious parasitic diseases in Korea. PMID- 30419726 TI - Molecular and Biochemical Properties of a Cysteine Protease of Acanthamoeba castellanii. AB - Acanthamoeba spp. are free-living protozoa that are opportunistic pathogens for humans. Cysteine proteases of Acanthamoeba have been partially characterized, but their biochemical and functional properties are not clearly understood yet. In this study, we isolated a gene encoding cysteine protease of A. castellanii (AcCP) and its biochemical and functional properties were analyzed. Sequence analysis of AcCP suggests that this enzyme is a typical cathepsin L family cysteine protease, which shares similar structural characteristics with other cathepsin L-like enzymes. The recombinant AcCP showed enzymatic activity in acidic conditions with an optimum at pH 4.0. The recombinant enzyme effectively hydrolyzed human proteins including hemoglobin, albumin, immunoglobuins A and G, and fibronectin at acidic pH. AcCP mainly localized in lysosomal compartment and its expression was observed in both trophozoites and cysts. AcCP was also identified in cultured medium of A. castellanii. Considering to lysosomal localization, secretion or release by trophozoites and continuous expression in trophozoites and cysts, the enzyme could be a multifunctional enzyme that plays important biological functions for nutrition, development and pathogenicity of A. castellanii. These results also imply that AcCP can be a promising target for development of chemotherapeutic drug for Acanthamoeba infections. PMID- 30419727 TI - Development of Molecular Diagnosis Using Multiplex Real-Time PCR and T4 Phage Internal Control to Simultaneously Detect Cryptosporidium parvum, Giardia lamblia, and Cyclospora cayetanensis from Human Stool Samples. AB - This study aimed to develop a new multiplex real-time PCR detection method for 3 species of waterborne protozoan parasites (Cryptosporidium parvum, Giardia lamblia, and Cyclospora cayetanensis) identified as major causes of traveler's diarrhea. Three target genes were specifically and simultaneously detected by the TaqMan probe method for multiple parasitic infection cases, including Cryptosporidium oocyst wall protein for C. parvum, glutamate dehydrogenase for G. lamblia, and internal transcribed spacer 1 for C. cayetanensis. Gene product 21 for bacteriophage T4 was used as an internal control DNA target for monitoring human stool DNA amplification. TaqMan probes were prepared using 4 fluorescent dyes, FAMTM, HEXTM, Cy5TM, and CAL Fluor Red(r) 610 on C. parvum, G. lamblia, C. cayetanensis, and bacteriophage T4, respectively. We developed a novel primer probe set for each parasite, a primer-probe cocktail (a mixture of primers and probes for the parasites and the internal control) for multiplex real-time PCR analysis, and a protocol for this detection method. Multiplex real-time PCR with the primer-probe cocktail successfully and specifically detected the target genes of C. parvum, G. lamblia, and C. cayetanensis in the mixed spiked human stool sample. The limit of detection for our assay was 2*10 copies for C. parvum and for C. cayetanensis, while it was 2*103 copies for G. lamblia. We propose that the multiplex real-time PCR detection method developed here is a useful method for simultaneously diagnosing the most common causative protozoa in traveler's diarrhea. PMID- 30419728 TI - Virus-Like Particles Expressing Toxoplasma gondii Rhoptry Protein 18 Induces Better Protection Than Rhoptry Protein 4 against T. gondii Infection. AB - Toxoplasma gondii is a ubiquitous protozoan parasite responsible for causing toxoplasmosis. Preventive measures for toxoplasmosis are currently lacking and as such, development of novel vaccines are of urgent need. In this study, we generated 2 virus-like particles (VLPs) vaccines expressing T. gondii rhoptry protein 4 (ROP4) or rhoptry protein 18 (ROP18) using influenza matrix protein (M1) as a core protein. Mice were intranasally immunized with VLPs vaccines and after the last immunization, mice were challenged with ME49 cysts. Protective efficacy was assessed and compared by determining serum antibody responses, body weight changes and the reduction of cyst counts in the brain. ROP18 VLPs immunized mice induced greater levels of IgG and IgA antibody responses than those immunized with ROP4 VLPs. ROP18 VLPs immunization significantly reduced body weight loss and the number of brain cysts in mice compared to ROP4 VLPs post challenge. These results indicate that T. gondii ROP18 VLPs elicited better protective efficacy than ROP4 VLPs, providing important insight into vaccine design strategy. PMID- 30419729 TI - Tissue Fluid Enzyme-Linked Immunosorbant Assay for Piglets Experimentally Infected with Toxoplasma gondii and Survey on Local and Imported Pork in Korean Retail Meat Markets. AB - To investigate the prevalence of Toxoplasma gondii in pork on the market in Korea, an in-house enzyme-linked immunosorbent assay for tissue fluid (CAU-tf ELISA) was developed using a soluble extract of T. gondii RH strain tachyzoites. As the standard positive controls, the piglets were experimentally infected with T. gondii: Group A (1,000 cysts-containing bradyzoites), Group B (500 cysts containing bradyzoites) and Group C (1.0*103 or 1.0*104 tachyzoites). The CAU-tf ELISA demonstrated infection intensity-dependent positivity toward tissue fluids with average cut-off value 0.15: 100% for Group A, 93.8% for Group B and 40.6% for Group C. When tissue-specific cut-off values 0.066-0.199 were applied, CAU-tf ELISA showed 96.7% sensitivity, 100% specificity, 100% positive and 90.0% negative predictive values. When compared with the same tissue fluids, performance of CAU-tf-ELISA was better than that of a commercial ELISA kit. Of the 583 Korea domestic pork samples tested, anti-T. gondii antibodies were detected from 9.1% of whole samples and 37.9% from skirt meat highest among pork parts. In the 386 imported frozen pork samples, 1.8% (skirt meat and shoulder blade) were positive for anti-T. gondii antibodies. In Korea, prevalence of anti T. gondii antibodies in the pork on retail markets appeared high, suggesting that regulations on pig farming and facilities are necessary to supply safe pork on the tables. PMID- 30419730 TI - Comparative Assessment of Diagnostic Performances of Two Commercial Rapid Diagnostic Test Kits for Detection of Plasmodium spp. in Ugandan Patients with Malaria. AB - Prompt diagnosis of malaria cases with rapid diagnostic tests (RDTs) has been widely adopted as an effective malaria diagnostic tool in many malaria endemic countries, primarily due to their easy operation, fast result output, and straightforward interpretation. However, there has been controversy about the diagnostic accuracy of RDTs. This study was conducted to evaluate the diagnostic performances of the 2 commercially available malaria RDT kits, RapiGEN Malaria Ag Pf/Pv (pLDH/pLDH) and Asan EasyTestTM Malaria Ag Pf/Pv (HRP-2/pLDH) for their abilities to detect Plasmodium species in blood samples collected from Ugandan patients with malaria. To evaluate the diagnostic performances of these 2 RDT kits, 229 blood samples were tested for malaria infection by microscopic examination and a species-specific nested polymerase chain reaction. The detection sensitivities for P. falciparum of Malaria Ag Pf/Pv (pLDH/pLDH) and Asan EasyTestTM Malaria Ag Pf/Pv (HRP-2/pLDH) were 87.83% and 89.57%, respectively. The specificities of the 2 RDTs were 100% for P. falciparum and mixed P. falciparum/P. vivax infections. These results suggest that the 2 RDT kits showed reasonable levels of diagnostic performances for detection of the malaria parasites from Ugandan patients. However, neither kit could effectively detect P. falciparum infections with low parasitaemia (<500 parasites/MUl). PMID- 30419731 TI - Distribution Status of Hybrid Types in Large Liver Flukes, Fasciola Species (Digenea: Fasciolidae), from Ruminants and Humans in Vietnam. AB - The aim of this study is to delineate 'admixed hybrid' and 'introgressive' Fasciola genotypes present in the Fasciola population in Vietnam. Adult liver flukes collected from ruminants in 18 Provinces were morphologically sorted out by naked eyes for small (S), medium (M) and large (L) body shapes; and human samples (n=14) from patients. Nuclear ribosomal (rDNA) ITS1 and ITS2, and mitochondrial (mtDNA) nad1 markers were used for determination of their genetic status. Total 4,725 worm samples of ruminants were tentatively classified by their size: 6% (n=284) small (S)-, 13% (n=614) medium (M)-, and 81% (n=3,827) large (L)-forms. All the representative (n=120, as 40 each group) and 14 human specimens, possessed maternal mtDNA of only F. gigantica and none of F. hepatica. Paternally, all (100%) of the L-(n=40) and 77.5% (n=31) of the M-flukes had single F. gigantica rDNA indicating 'pure' F. gigantica. A majority (90%, n=36) of the S- and 15% (n=6) of the M-worms had single F. hepatica rDNA, indicating their introgressive; the rest (10%, n=4) of the S- and 7.5% (n=3) of the M-flukes had mixture of both F. gigantica and F. hepatica rDNAs, confirming their admixed hybrid genetic status. Fourteen human samples revealed 9 (64%) of pure F. gigantica, 3 (22%) of introgressive and 2 (14%) of admixed hybrid Fasciola spp. By the present study, it was confirmed that the small worms, which are morphologically identical with F. hepatica, are admixed and/or introgressive hybrids of Fasciola spp., and able to be the pathogens of human fascioliasis. PMID- 30419732 TI - Morphological Studies of Developmental Stages of Oculotrema hippopotami (Monogenea: Polystomatidae) Infecting the Eye of Hippopotamus amphibius (Mammalia: Hippopotamidae) Using SEM and EDXA with Notes on Histopathology. AB - The present study was performed to observe histopathological effects of Oculotrema hippopotami Stunkard, 1924 infection in the eye of Hippopotamus amphibius, as well as to reveal new details of morphology and structural features of this monogenean and its comparison between 2 age stages of the parasite. This was done using both light and scanning electron microscopy, energy dispersive X ray analysis (EDXA) and histopathology. The presence of a mixture of different generations (adult and sub-adult) in one host individual is common for Oculotrema Stunkard, 1924 in contrast to Polystoma Zeder, 1800. New metrical and graphical information obtained for adults and sub-adults compared with the previous studies. Here we show the presence of genital papillae in adults, metrical data on the distal part of the vas deferens. SEM micrographs of sperm ejaculatory structures and information about the flattened dorsal side of the body provided for the first time. Histopathological changes, such as necrosis and hemorrhage in host tissues as a result of O. hippopotami attachment structures are described. Structural analysis of different body parts of O. hippopotami of both age groups are also included. We show qualitative differences in the presence of hardening ions (S, P, Ca) in attachment structures (oral and haptor suckers) that increase with the age of the worm. The presence of sub-adults and adults on the same host, together with high levels of infection without high pathogenicity may account for Oculotrema being one of the most successful parasites among the Monogenea. PMID- 30419733 TI - Analysis of Five Arboviruses and Culicoides Distribution on Cattle Farms in Jeollabuk-do, Korea. AB - Arthropod-borne viruses (Arboviruses) are transmitted by arthropods such as Culicoides biting midges and cause abortion, stillbirth, and congenital malformation in ruminants, apparently leading to economic losses to farmers. To monitor the distribution of Culicoides and to determine their relationship with different environmental conditions (temperature, humidity, wind speed, and altitude of the farms) on 5 cattle farms, Culicoides were collected during summer season (May-September) in 2016 and 2017, and analyzed for identification of species and detection of arboviruses. About 35% of the Culicoides were collected in July and the collection rate increased with increase in temperature and humidity. The higher altitude where the farms were located, the more Culicoides were collected on inside than outside. In antigen test of Culicoides against 5 arboviruses, only Chuzan virus (CHUV) (2.63%) was detected in 2016. The Akabane virus (AKAV), CHUV, Ibaraki virus and Bovine ephemeral fever virus (BEFV) had a positive rate of less than 1.8% in 2017. In antigen test of bovine whole blood, AKAV (12.96%) and BEFV (0.96%) were positive in only one of the farms. As a result of serum neutralization test, antibodies against AKAV were generally measured in all the farms. These results suggest that vaccination before the season in which the Culicoides are active is probably best to prevent arbovirus infections. PMID- 30419734 TI - Phthirus pubis Infestation of the Scalp: A Case Report and Review of The Literature. AB - Phthirus pubis usually infests the pubis, groin, buttocks and perianal region. It can sometimes infest the thighs, abdomen, chest, axillae and beard. Eyelashes and eyebrows may be involved in children. The involvement of the scalp is very rare. We describe a case of P. pubis infestation located exclusively on the scalp in an adult woman. Neither lice/nits nor skin lesions were observed elsewhere, including eyebrows, eyelashes, axillae, pubis, buttocks and perianal region (the patient was hairless in the axillae and pubis). A review of the literature is enclosed. PMID- 30419735 TI - Effect of 2, 6-Dichlorobenzonitrile on Amoebicidal Activity of Multipurpose Contact Lens Disinfecting Solutions. AB - Multipurpose contact lens disinfecting solutions (MPDS) are widely used to cleanse and disinfect microorganisms. However, disinfection efficacy of these MPDS against Acanthamoeba cyst remain insufficient. 2, 6-dichlorobenzonitrile (DCB), a cellulose synthesis inhibitor, is capable of increasing the amoebical effect against Acanthamoeba by inhibiting its encystation. In this study, we investigated the possibility of DCB as a disinfecting agent to improve the amoebicidal activity of MPDS against Acanthamoeba cyst. Eight commercial MPDS (from a to h) were assessed, all of which displayed insufficient amoebicidal activity against the mature cysts. Solution e, f, and h showed strong amoebicidal effect on the immature cysts. Amoebicidal efficacy against mature cysts remained inadequate even when the 8 MPDS were combined with 100 MUM DCB. However, 4 kinds of MPDS (solution d, e, f, and h) including 100 MUM DCB demonstrated strong amoebicidal activity against the immature cysts. The amoebicidal activity of solution d was increased by addition of DCB. Cytotoxicity was absent in human corneal epithelial cells treated with either DCB or mixture of DCB with MPDS. These results suggested that DCB can enhance the amoebicical activity of MPDS against Acanthamoeba immature cyst in vitro. PMID- 30419736 TI - Prevalence and Phylogenetic Analyses of Trichuris suis in Pigs in Hunan Province, Subtropical China. AB - Trichuris suis infection in pigs is ubiquitous in intensive and extensive farms, which causes potential threat to human health. The objective of this research was to investigate the prevalence of T. suis in pigs in Hunan province. Total 2,267 fresh fecal samples distributed in 28 pig farms from 7 different administrative regions (Hunan province) were evaluated for the existence of T. suis eggs using saturated NaCl floating method. The average infection rate of T. suis in pigs was 8.91% in Hunan province. To determine genetic variation of the gained T. suis isolates in the present study, the internal transcribed spacer (ITS) regions from nuclear ribosomal DNA (rDNA) of 7 T. suis isolates were cloned and analyzed. Nucleotide diversities were 1.0-3.5% and 0-3.8% for ITS-1 and ITS-2, respectively. Phylogenetic analyses indicated that all isolates collected in the present study and T. suis available in Genbank generated a monophyletic clade. The present investigation revealed high infection rates of T. suis in pigs in Hunan province, which shed light on making effective measures to prevent and control T. suis infection in pigs in Hunan province. PMID- 30419737 TI - Morphological Characteristics and Fish Hosts of Isoparorchis sp. (Digenea: Isoparorchiidae) in Korea. AB - We described here the morphological characteristics for the species identification and fish hosts of Isoparorchis sp. (Digenea: Isoparorchiidae) in the Republic of Korea (Korea). Total 1,371 freshwater fishes collected in Yangcheon (Stream) in Sancheong-gun, Gyeongsangnam-do were examined by the artificial digestion methods to survey the infection status of digenetic trematode metacercariae for 4 years (2013-2016). Adult and larval worms of Isoparorchis sp. were detected in 38 (8.4%) out of 451 fish in 4 species, i.e., Pungtungia herzi, Acheilognathus koreensis, Squalidus japonicus coreanus and Odontobutis platycephala, examined. The infection density was 1.1 worm per fish infected. They were mainly found in the subcutaneous tissues and abdominal cavities. Nodules with worms in the subcutaneous tissues were revealed as the blue ink-colored bulges. Adults leaf-like, 21.6*9.84 mm in average size. The ratio of body length to body width was 2.20: 1. Oral sucker subterminal, 1.03*1.22 mm. Pharynx muscular, 0.55*0.54 mm. Esophagus very short. Ceca convoluted, terminated near the posterior end. Ventral sucker anterior 1/3.75, 1.99*2.10 mm. The ratio of ventral sucker to oral sucker was 1.74: 1. Testes round to elliptical, both sides of ventral sucker, 1.43*1.33 mm. Vitellaria highly dendritic, posterior 1/3 level. Eggs operculated, embryonated, 52*32 MUm in size. By the present study, 4 fish species aforementioned are to be listed as the fish hosts of Isoparorchis sp. in Korea and additionally the morphological characteristics are to be described for the species identification. PMID- 30419738 TI - Infections with Digenean Trematode Metacercariae in Two Invasive Alien Fish, Micropterus salmoides and Lepomis macrochirus, in Two Rivers in Chungcheongbuk do, Republic of Korea. AB - Present study was performed to survey infection status of digenetic trematode metacercariae in 2 alien fish species, Micropterus salmoides (largemouth bass) and Lepomis macrochirus (bluegill), in 2 rivers draining Chungcheongbuk-do, Republic of Korea. A total of 107 largemouth bass and 244 bluegills were caught in Daecheong-ho (ho=lake) and Musim-cheon (a branch of Geum-gang), in Chungcheongbuk-do April-July 2015. Additionally, 68 native fish of 5 species, i.e., Zacco platypus, Hemibarbus longirostris, Carassius auratus, Pseudogobio esocinus and Puntungia herzi, were caught from the same water bodies. All of the fish collected were examined by artificial digestion method. The metacercariae of Centrocestus armatus, Clinostomum complanatum, Metagonimus sp. and Diplostomum spp. were detected from 4 out of 5 native fish species in Daecheong-ho. However, any metacercariae were not found from 87 M. salmoides and 177 L. macrochirus in Daecheong-ho. In Musim-cheon, metacercariae of Exorchis oviformis and Metacercaria hasegawai were detected from 78% Z. platypus and 34% L. macrochirus, but any metacercariae not found in M. salmoides. We report here that the 2 alien fish species were less infected with the metacercariae than the native ones. Surveys on the metacercariae in the alien fish species in geographically various rivers should be undertaken for better understanding on the role of alien fish species in the trematode infections in Republic of Korea. PMID- 30419739 TI - Complete Mitochondrial Genome of the Chagas Disease Vector, Triatoma rubrofasciata. AB - Triatoma rubrofasciata is a wide-spread vector of Chagas disease in Americas. In this study, we completed the mitochondrial genome sequencing of T. rubrofasciata. The total length of T. rubrofasciata mitochondrial genome was 17,150 bp with the base composition of 40.4% A, 11.6% G, 29.4% T and 18.6% C. It included 13 protein coding genes, 22 tRNA genes, 2 rRNA genes and one control region. We constructed a phylogenetic tree on the 13 protein-coding genes of T. rubrofasciata and other 13 closely related species to show their phylogenic relationship. The determination of T. rubrofasciata mitogenome would play an important role in understanding the genetic diversity and evolution of triatomine bugs. PMID- 30419741 TI - Early monitoring of fatty acid profile in children with attention deficit and/or hyperactivity disorder under treatment with omega-3 polyunsaturated fatty acids. AB - BACKGROUND: Cognitive effects of omega-3 polyunsaturated fatty acids (omega-3 PUFAs) might make them helpful in attention deficit / hyperactivity disorder (ADHD). However, the results derived from supplementation studies in children depend on the respective combinations and the study period. We aimed to investigate the serum fatty acid profile, attention scores and the tolerability in a group of ADHD children after receiving methylphenidate (MPH) and omega-3 PUFAs for 1 month. METHODS: A combination of MPH (1 mg/kg/day) and eicosapentaenoic (EPA, 70 mg/day) + docosahexaenoic acids (DHA, 250 mg/day) was administered to 40 ADHD children (7-15 years). An analysis of serum fatty acids by gas chromatography and an assessment of attention by using the Magallanes Scale of Visual Attention (MSVA) were carried out before and after 1 month of treatment. RESULTS: Our data revealed significant decreases of several omega-6 PUFAs, like arachidonic acid (p < .0259). EPA and DHA concentrations increased by 27% and 3% respectively, and the omega-6/omega-3 index slightly decreased. The quality of attention significantly increased (p < .026) and an improvement of ADHD core symptoms was reported both by parents and by teachers. No severe side effects occurred. CONCLUSIONS: Results demonstrate that the combination of MPH and EPA+DHA at the tested doses has positive clinical effects and an adequate safety profile. Therefore, our study suggests that omega-3 PUFAs may represent a feasible and a safe adjuvant therapy in children with ADHD and might enhance the effects of MPH. Further long-term follow-up studies are required to confirm these initial findings. PMID- 30419740 TI - Survey and Phylogenetic Analysis of Rodents and Important Rodent-Borne Zoonotic Pathogens in Gedu, Bhutan. AB - Rodents are well-known reservoirs and vectors of many emerging and re-emerging infectious diseases, but little is known about their role in zoonotic disease transmission in Bhutan. In this study, a cross-sectional investigation of zoonotic disease pathogens in rodents was performed in Chukha district, Bhutan, where a high incidence of scrub typhus and cases of acute undifferentiated febrile illness had been reported in people during the preceding 4-6 months. Twelve rodents were trapped alive using wire-mesh traps. Following euthanasia, liver and kidney tissues were removed and tested using PCR for Orientia tsutsugamushi and other bacterial and rickettsial pathogens causing bartonellosis, borreliosis, human monocytic ehrlichiosis, human granulocytic anaplasmosis, leptospirosis, and rickettsiosis. A phylogenetic analysis was performed on all rodent species captured and pathogens detected. Four out of the 12 rodents (33.3%) tested positive by PCR for zoonotic pathogens. Anaplasma phagocytophilum, Bartonella grahamii, and B. queenslandensis were identified for the first time in Bhutan. Leptospira interrogans was also detected for the first time from rodents in Bhutan. The findings demonstrate the presence of these zoonotic pathogens in rodents in Bhutan, which may pose a risk of disease transmission to humans. PMID- 30419742 TI - Intrasphincteric BoTox injections in Hirschsprung's disease: indications and outcome in 64 procedures over a ten-year period. AB - BACKGROUND: Intrasphincteric Botulinum toxin (BoTox) injection for symptomatic postoperative anal achalasia in Hirschsprung's disease (HSCR) has found wide application in the last twenty years. The aim of this study is to describe effectiveness and functional outcome of a series of patients treated over a 10 year period. METHODS: All consecutive HSCR patients who received intrasphincteric BoTox injections between January 2007 and December 2016 were included. Demographic data and clinical features were collected. A detailed questionnaire focusing on outcome in the medium and long term was administered to all families. RESULTS: In the study period 64 intrasphincteric BoTox injections were performed in 31 patients. Completed questionnaires were returned by 27 out of 28 eligible patients (96%) reporting improvement or symptoms resolution in 16 (59%). The highest success rates were experienced by patients younger than 4, with long HSCR forms and with recurrent enterocolitis (75%, 100% and 100% of success rates, respectively). No major complications occurred. Minor complications were described by 7 patients (26%). CONCLUSIONS: Intrasphincteric BoTox injection proved to be feasible, safe and reasonably effective in children with HSCR and postoperative anal achalasia. Infants and toddlers with long HSCR forms and recurrent bouts of enterocolitis are those who would benefit most from this treatment. PMID- 30419743 TI - Targeting bacterial biofilms in pulmonary diseases in pediatric population. PMID- 30419744 TI - Steroid- and immunosuppressant-based protocol of Henoch-Schonlein purpura nephritis without angiotensin inhibitors in the acute phase: case series with correlation to histology. AB - BACKGROUND: The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines suggest initially using angiotensin-converting-enzyme inhibitors (ACE-Is) and/or angiotensin receptor blockers (ARBs) to treat Henoch-Schonlein purpura nephritis (HSPN). However, these guidelines might overlook the potential benefits of aggressive therapy. Therefore, we evaluated the efficacy of an HSPN protocol that primarily uses steroids and immunosuppressants, without ACE-Is or ARBs. METHODS: We determine treatment intensity based on International Study of Kidney Diseases in Children (ISKDC) grading. Fifty-one patients were treated with our protocol that primarily uses steroids and immunosuppressants. ACE-Is and ARBs were not used in the acute phase, including before renal biopsy. We evaluated the proteinuria disappearance rate, duration to proteinuria disappearance, and estimated glomerular filtration rate (eGFR) at the time of last observation and compared them to those in previous reports. RESULTS: Proteinuria disappeared in 49 patients (96%) within a median of 5 months. The median eGFR was 116.0 mL/min/1.73 m2 at the time of last observation. Six of 51 patients had acute kidney injury (eGFR <90 mL/min/1.73 m2) before treatment, but all recovered during the observation period (median 52 months). CONCLUSIONS: Our steroid- and immunosuppressant-based protocol without ACE-Is or ARBs in the acute phase of HSPN had almost equivalent efficacy to that in previous studies that used ACE-Is and/or ARBs with steroids and immunosuppressants. PMID- 30419745 TI - Comparison of the Fitbit(r) Charge and polysomnography for measuring sleep quality in children with sleep disordered breathing. AB - BACKGROUND: Due to the cost and inconvenience of polysomnography (PSG), wristworn accelerometers have been explored as an alternative method to measure sleep efficacy in children with obstructive sleep apnea (OSA) or sleep-disordered breathing (SDB). We compared the measurement of sleep quality with the Fitbit(r) Charge compared to PSG in children presenting for sleep studies. METHODS: Children ages 3 to 18 years, presenting for PSG with persistent SDB symptoms were enrolled. During PSG, the Fitbit(r) Charge was placed on the wrist and timesynchronized with sleep laboratory devices, which were worn while a single night PSG was performed. Bias and concordance in measurements of total sleep time (TST), total wake time (TWT), and number of awakenings were assessed using paired t-tests, sign-rank tests, and Lin's concordance coefficient. RESULTS: The study cohort included 22 patients (9 boys and 13 girls; 9 +/- 3 years). TST was significantly overestimated using the Fitbit(r) Charge (difference in means = 30 min; 95% confidence interval [CI] of difference: 3, 58; p = 0.031), while TWT was underestimated (difference = 23 min; 95% CI: 4, 42; p=0.018). All measures showed a lack of concordance between the Fitbit(r) Charge and PSG. CONCLUSIONS: The current prospective study confirms that the Fitbit(r) Charge overestimates time spent asleep compared to PSG in children with OSA/SDB symptoms, limiting the validity of sleep monitoring with wearable activity trackers appears in these patients. PMID- 30419746 TI - Dynamic and Electronic Polarization Corrections to the Dielectric Constant of Water. AB - The standard approach to calculating the dielectric constant from molecular dynamics (MD) simulations employs a variant of the Kirkwood-Frohlich methodology. Many popular nonpolarizable models of water, such as TIPnP, give a reasonable agreement with the experimental value of 78. However, it has been argued in the literature that the dipole moments of these models are effective, being smaller than the real dipole of a liquid water molecule by about a factor of [Formula: see text], or roughly [Formula: see text]. If the total or corrected dipole moment is used in calculations, the dielectric constant comes out nearly twice as large, i.e., in the range of 160, which is twice as high as the experimental value. Here we discuss possible reasons for such a discrepancy. One approach takes into account dynamic corrections due to the dependence of the dielectric response of the medium producing the reaction field on the time scale of dipole fluctuations computed in the Kirkwood-Frohlich method. When dynamic corrections are incorporated into the computational scheme, a much better agreement with the experimental value of the dielectric constant is found when the corrected (real) dipole moment of liquid water is used. However, a formal analysis indicates that the static properties, such as dielectric constant, should not depend on dynamics. We discuss the resulting conundrum and related issues of simulations of electrostatic interactions using periodic boundary conditions in the context of our findings. PMID- 30419747 TI - Origin of Flowback and Produced Waters from Sichuan Basin, China. AB - Shale gas extraction through hydraulic fracturing and horizontal drilling is increasing in China, particularly in Sichuan Basin. Production of unconventional shale gas with minimal environmental effects requires adequate management of wastewater from flowback and produced water (FP water) that is coextracted with natural gas. Here we present, for the first time, inorganic chemistry and multiple isotope (oxygen, hydrogen, boron, strontium, radium) data for FP water from 13 shale gas wells from the Lower Silurian Longmaxi Formation in the Weiyuan gas field, as well as produced waters from 35 conventional gas wells from underlying (Sinian, Cambrian) and overlying (Permian, Triassic) formations in Sichuan Basin. The chemical and isotope data indicate that the formation waters in Sichuan Basin originated from relics of different stages of evaporated seawater modified by water-rock interactions. The FP water from shale gas wells derives from blending of injected hydraulic fracturing water and entrapped saline (Cl ~ 50,000 mg/L) formation water. Variations in the chemistry, delta18O, delta11B, and 87Sr/86Sr of FP water over time indicate that the mixing between the two sources varies with time, with a contribution of 75% (first 6 months) to 20% (>year) of the injected hydraulic fracturing water in the blend that compose the FP water. Mass-balance calculation suggests that the returned hydraulic fracturing water consisted of 28-49% of the volume of the injected hydraulic fracturing water, about a year after the initial hydraulic fracturing. We show differential mobilization of Na, B, Sr, and Li from the shale rocks during early stages of operation, which resulted in higher Na/Cl, B/Cl, Li/Cl, and 87Sr/86Sr and lower delta11B of the FP water during early stages of FP water formation relative to the original saline formation water recorded in late stages FP water. This study provides a geochemical framework for characterization of formation waters from different geological strata, and thus the ability to distinguish between different sources of oil and gas wastewater in Sichuan Basin. PMID- 30419748 TI - Nanoscale Near-Field Tomography of Surface States on (Bi0.5Sb0.5)2Te3. AB - Three-dimensional topological insulators (TIs) have attracted tremendous interest for their possibility to host massless Dirac Fermions in topologically protected surface states (TSSs), which may enable new kinds of high-speed electronics. However, recent reports have outlined the importance of band bending effects within these materials, which results in an additional two-dimensional electron gas (2DEG) with finite mass at the surface. TI surfaces are also known to be highly inhomogeneous on the nanoscale, which is masked in conventional far-field studies. Here, we use near-field microscopy in the mid-infrared spectral range to probe the local surface properties of custom-tailored (Bi0.5Sb0.5)2Te3 structures with nanometer precision in all three spatial dimensions. Applying nanotomography and nanospectroscopy, we reveal a few-nanometer-thick layer of high surface conductivity and retrieve its local dielectric function without assuming any model for the spectral response. This allows us to directly distinguish between different types of surface states. An intersubband transition within the massive 2DEG formed by quantum confinement in the bent conduction band manifests itself as a sharp, surface-bound, Lorentzian-shaped resonance. An additional broadband background in the imaginary part of the dielectric function may be caused by the TSS. Tracing the intersubband resonance with nanometer spatial precision, we observe changes of its frequency, likely originating from local variations of doping or/and the mixing ratio between Bi and Sb. Our results highlight the importance of studying the surfaces of these novel materials on the nanoscale to directly access the local optical and electronic properties via the dielectric function. PMID- 30419749 TI - Trimethylphosphate as a Methylating Agent for Cross Coupling: A Slow-Release Mechanism for the Methylation of Arylboronic Esters. AB - A methyl group on an arene, despite its small size, can have a profound influence on biologically active molecules. Typical methods to form a methylarene involve strong nucleophiles or strong and often toxic electrophiles. We report a strategy for a new, highly efficient, copper and iodide co-catalyzed methylation of aryl- and heteroarylboronic esters with the mild, nontoxic reagent trimethylphosphate, which has not been used previously in coupling reactions. We show that it reacts in all cases tested in yields that are higher than those of analogous copper catalyzed reactions of MeOTs or MeI. The combination of C-H borylation and this methylation with trimethylphosphate provides a new approach to the functionalization of inert C-H bonds and is illustrated by late-stage methylation of four medicinally active compounds. In addition, reaction on a 200 mmol scale demonstrates reliability of this method. Mechanistic studies show that the reaction occurs by a slow release of methyl iodide by reaction of PO(OMe)3 with iodide catalyst, rather than the typical direct oxidative addition to a metal center. The low concentration of the reactive electrophile enables selective reaction with an arylcopper intermediate, rather than nucleophilic groups on the arylboronate, and binding of tert-butoxide to the boronate inhibits reaction of the electrophile with the tert-butoxide activator to form methyl ether. PMID- 30419750 TI - Investigation of Microstructure Effect on NO2 Sensors Based on SnO2 Nanoparticles/Reduced Graphene Oxide Hybrids. AB - The microstructures of metal oxide-modified reduced graphene oxide (RGO) are expected to significantly affect room-temperature (RT) gas sensing properties, where the microstructures are dependent on the synthesis methods. Herein, we demonstrate the effect of microstructures on RT NO2 sensing properties by taking typical SnO2 nanoparticles (NPs) embellished RGO (SnO2 NPs-RGO) hybrids as examples. The samples were synthesized by growing SnO2 NPs on RGO through hydrothermal reduction (SnO2 NPs-RGO-PR), which display the advantages such as high reactivity of the SnO2 surface with NO2, more oxygen vacancies (OV) and chemisorbed oxygen (OC), close contact between SnO2 NPs and RGO, and large surface area, compared to the samples prepared by one-pot hydrothermal synthesis from Sn4+ and GO (SnO2 NPs-RGO-IS), and the assembly of SnO2 NPs on RGO (SnO2 NPs RGO-SA). As expected, the SnO2 NPs-RGO-PR-based sensor presents high sensitivity towards 5 ppm NO2 (65.5%), but 35.0% for the SnO2 NPs-RGO-IS-based sensor and 32.8% for the SnO2 NPs-RGO-SA-based sensor at RT. Meanwhile, the corresponding response time and recovery time calculated by achieving 90% of the current change of the SnO2 NPs-RGO-PR-based sensor for exposure to NO2 is 12 s and to air is 17 s, respectively, whereas 74/42 s for the SnO2 NPs-RGO-IS-based sensor and 77/90 s for the SnO2 NPs-RGO-SA-based sensor. The results can prove the tailoring sensing behavior of the gas sensor according to different structures of materials. PMID- 30419751 TI - Superlubricity of Black Phosphorus as Lubricant Additive. AB - Superlubricity is defined as a sliding regime in which friction, or the resistance to sliding of two relatively moving surfaces, almost vanishes. From a practical point of view, the development and use of new materials that can enable superlubricity (coefficient of friction, COF < 0.01) in moving mechanical systems will have huge positive impact on energy-saving and emission reduction. In this work, the use of a new two-dimensional material, black phosphorus (BP) as a high performance water-based lubricant additive that can significantly reduce friction and achieve superlubricity has been explored. A lowest COF value of 0.0006 ever measured by an application-orientated ball-on-plate tribometer has been found. Robust superlubricity in the aqueous solution with ultrafine BP nanosheets modified by NaOH (BP-OH) has been observed for a wide range of additive concentrations, contact pressures, and sliding velocities owing to the very low shear resistance of the water layer retained by BP-OH nanosheets. This finding has the potential of opening up a new approach to dramatically reduce or even eliminate friction by using BP nanomaterials as lubricant additives. PMID- 30419752 TI - Trends in Sedentary and Physical Activity Behaviors in Incarcerated Adolescent Boys During a Sports, Play, and Recreation for Kids Program. AB - PURPOSE:: To examine the trends in total and segmented sedentary and physical activity behaviors during a Sports, Play, and Recreation for Kids (SPARK) program in incarcerated adolescent boys. DESIGN:: Longitudinal trend analysis. SETTING:: Two juvenile justice facilities. SUBJECTS:: Eighty-six adolescent boys (mean age = 17.1 +/- 1.0 years). INTERVENTION:: Sports, Play, and Recreation for Kids implemented over 36 weeks. MEASURES:: Sedentary times and physical activity were examined at baseline and at 3 follow-up time points at 12, 24, and 36 weeks after SPARK implementation. Physical activity was assessed using the percentage of accelerometer wear time within each segment for sedentary (%SED) and moderate-to vigorous physical activity (%MVPA). ANALYSIS:: Trends in %SED and %MVPA were assessed using 2 * 4 doubly multivariate analysis of variance tests. RESULTS:: For the total week, there was a significantly lower %SED (mean difference = 10.6%, P < .001) and significantly higher %MVPA (mean difference = +3.0%, P < .001) at the 24-week follow-up compared to baseline. There were also significantly lower %SED and higher %MVPA before school, after school, and during the weekends at 24-week follow-up compared to baseline ( P < .01). CONCLUSION:: There were significantly lower sedentary times and higher levels of physical activity during the middle portions of the SPARK intervention in incarcerated adolescent boys, highlighting the potential of this intervention to affect sedentary and physical activity behaviors in the population. PMID- 30419753 TI - Designing Prison-Based Parenting Programs to Maximize Their Outcomes. AB - Parenting programs are increasingly being offered in prison as governments seek to reduce the negative consequences of parental imprisonment and encourage desistance from crime. However, little is known about the design and delivery of such programs and how this may shape program effectiveness. This article seeks to address this gap by examining how the design and delivery of the Families Matter program for imprisoned adult fathers in Northern Ireland affected its ability to achieve its goals of improving family relationships and fathers' parenting skills. Examples of good practice are offered, as well as challenges that remain to be overcome. It is argued that more attention needs to be paid to the design and delivery of these programs if their ability to achieve long-term improvements in family relationships and parenting skills are to be improved. PMID- 30419754 TI - De-Escalation of Antiplatelet Therapy in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: A Meta-Analysis of Randomized Clinical Trials. AB - AIMS:: Patients with acute coronary syndrome undergoing percutaneous coronary intervention (PCI) are recommended to be placed on potent P2Y12 blockade. However, the long-term bleeding risk is high. Therefore, despite no definitive evidence, switching to clopidogrel beyond the acute phase is common. We aimed to evaluate the clinical outcomes of antiplatelet de-escalation compared with continuation in patients treated with PCI. METHODS:: We searched databases for randomized clinical trials (RCTs) that evaluated the safety and efficacy of antiplatelet de-escalation compared with continuation in patients treated with PCI. Pooled summary estimates were calculated. RESULTS:: We included 3 RCTs with 3391 patients (median follow-up: 12 months). Compared with the continued group, the net clinical outcome (composite of bleeding or thrombotic events) was significantly reduced in the group switched to clopidogrel (8.7% vs 12.1%; risk ratio [RR]: 0.64; 95% confidence interval [CI]: 0.43-0.97; P = .03). However, there were similar clinical outcomes between groups for major adverse cardiovascular events (MACE; RR: 0.78; 95% CI: 0.55-1.11; P = .17), all Bleeding Academic Research Consortium (BARC) types bleeding (RR: 0.61; 95% CI: 0.33-1.11; P = .10), or BARC types >=2 bleeding (RR: 0.49; 95% CI: 0.19-1.26; P = .14). CONCLUSIONS:: Our results suggest a net clinical benefit of de-escalation therapy shortly after PCI, without increased risk of MACE. Larger randomized trials will be necessary to confirm these findings. PMID- 30419755 TI - Health Workers' and Villagers' Perceptions of Young Child Health, Growth Monitoring, and the Role of the Health System in Remote Thailand. AB - BACKGROUND:: In Thailand, despite widespread improvements in child nutrition, stunting is still highly prevalent among northern hill tribe children. OBJECTIVE:: To understand how villagers and health workers (volunteers and officials) gauge health of children younger than 5 years, whether growth monitoring is salient, and the relationships of villagers with the health system in this remote location. METHODS:: Qualitative research was undertaken with 8 hill tribe villages. A workshop on infant and young child health and nutrition was held with 8 village health volunteers, 2 per village, selected by a public health officer. In-depth interviews were conducted with 20 villagers and 2 volunteers who had children 0 to 5 years. Eight other health workers were also interviewed. All dialogue was conducted in Thai through bilingual facilitators and recorded, transcribed, and translated into English. Transcripts were coded and analyzed thematically within and across participant groups. RESULTS:: Overall, villagers considered strength and independence of children to be hallmarks of health; the size of children featured rarely. Volunteers did not perceive local benefits of growth monitoring, and the extent of child malnutrition was unclear to them. Nutrition counseling was seldom mentioned by villagers or health workers. Across all accounts, and considering silences, relationships of villagers with the health system seemed fragile. CONCLUSION:: Villagers understand child health in terms of functional abilities rather than size. Volunteer health workers in this remote location have limited resources and support. Together this helps explain why, against a background of poverty and food insecurity, growth monitoring does not translate to improvements in child nutrition. PMID- 30419756 TI - Clinical Characteristics and Outcomes in Asian Patients With Premature Coronary Artery Disease: Insight From the FOCUS Registry. AB - OBJECTIVES:: Premature coronary artery disease (PCAD) is increasingly common in Asian countries; however, less is known regarding its characteristics and clinical outcomes. This study aims to describe clinical characteristics and investigate clinical outcomes in real-world Asian patients with PCAD. METHODS:: A total of 4700 Asian patients undergoing drug-eluting stent implantation were included in our study and divided into PCAD group and mature CAD (MCAD) group according to their onset age. All patients were followed up for 3 years to observe their clinical outcomes. RESULTS:: Patients with PCAD were more likely to be associated with acute coronary syndrome (ACS; P = .03) and acute occlusive lesion ( P < .001). Reference diameter ( P < .001) and lesion diameter stenosis ( P = .001) were significantly greater in PCAD group. Conversely, the MCAD group was more likely to be associated with left main disease, severe calcification lesion and small vessel involvement. The cumulative incidences of major adverse cardiovascular event (MACE; P = .007), cardiovascular death ( P < .001), and all cause death ( P < .001) were significantly lower in PCAD group than those in MCAD group. CONCLUSIONS:: Although more often manifested as ACS, PCAD is associated with lower risks of MACE and cardiovascular death than MCAD in real-world Asian population. PMID- 30419757 TI - Clinical significance of proximal interphalangeal joint pain in patients with trigger fingers. AB - We investigated incidence, clinical features and surgical outcomes of trigger finger accompanied by proximal interphalangeal joint pain. One-hundred and seventy-nine consecutive patients with trigger finger who had A1 pulley release were recruited. Forty-two patients (24%) complained of proximal interphalangeal joint pain at the time of surgery. Symptom duration was investigated, and tenderness at the proximal interphalangeal joint was palpated. Range of motion and pain score of the affected finger were measured pre- and post-operatively. Bone scan was performed to identify joint lesions. A comparison of the results between the proximal interphalangeal joint pain group and the non-proximal interphalangeal joint pain group shows that the proximal interphalangeal joint pain seemed to result from long symptom duration and consequent joint pathology. The proximal interphalangeal joint pain was incompletely resolved after A1 pulley release. Thus, the surgical outcomes might be worse than expected in spite of resolution of painful clicking, especially when there was additional joint tenderness on palpation. Level of evidence: IV. PMID- 30419758 TI - Incidence of tenolysis and features of adhesions in the digital flexor tendons after multi-strand repair and early active motion. AB - We report seven patients requiring tenolysis after primary or delayed primary flexor tendon repair and early active mobilization out of 148 fingers of 132 consecutive patients with Zone 1 or 2 injuries from 1993 to 2017. Three fingers had Zone 2A, two Zone 2B, and two Zone 2C injuries. Two fingers underwent tenolysis at Week 4 or 6 after repair because of suspected repair rupture. The other five fingers had tenolysis 12 weeks after repair. Adhesions were moderately dense between the flexor digitorum superficialis and profundus tendons or with the pulleys. According to the Strickland and Tang criteria, the outcomes were excellent in one finger, good in four, fair in one, and poor in one. Fingers requiring tenolysis after early active motion were 5% of the 148 fingers so treated. Indications for tenolysis were to achieve a full range of active motion in the patients rated good or improvement of range of active motion of the patients rated poor or fair. Not all of our patients with poor or fair outcomes wanted to have tenolysis. Level of evidence: IV. PMID- 30419759 TI - Access and Health System Impact of an Early Intervention Treatment Program for Emerging Adults with Mood and Anxiety Disorders. AB - OBJECTIVES:: Early intervention programs are effective for improving outcomes in first-episode psychosis; however, less is known about their effectiveness for mood and anxiety disorders. We sought to evaluate the impact of an early intervention program for emerging adults with mood and anxiety disorders in the larger health system context, relative to standard care. METHODS:: Using health administrative data, we constructed a retrospective cohort of cases of mood and anxiety disorders among emerging adults aged 16 to 25 years in the catchment of the First Episode Mood and Anxiety Program (FEMAP) in London, Ontario, between 2009 and 2014. This cohort was linked to primary data from FEMAP to identify service users. We used proportional hazards models to compare indicators of service use between FEMAP users and a propensity score-matched group of nonusers receiving care elsewhere in the health system. RESULTS:: FEMAP users ( n = 490) had more rapid access to a psychiatrist relative to nonusers (hazard ratio [HR], 2.82; 95% confidence interval, 2.45 to 3.26; median time, 16 vs. 71 days). In the year following admission, FEMAP users also had lower rates of emergency department use for mental health reasons (HR, 0.73; 95% CI, 0.53 to 0.99). We did not observe differences in psychiatric hospitalization rates. CONCLUSIONS:: An early intervention model of care for mood and anxiety disorders is associated with better access to psychiatric care and lower use of the emergency department. Our findings suggest that early intervention services for mood and anxiety disorders may be beneficial from a health systems perspective, and further research on the effectiveness of this model of care is warranted. PMID- 30419761 TI - Using Theory to Understand the Barriers to Engagement in Group Offending Behavior Programs. AB - Noncompletion of group offending behavior programs is a common problem, indicating barriers to engagement. While existing theoretical models have accounted for determinants of motivation, little focus has been directed towards barriers to engagement. The authors developed the program engagement theory (PET) which not only accounts for the determinants of engagement and the engagement process, it also considers the barriers to engagement. Interviews and session observations were used to collect data from 23 program facilitators and 28 offenders, which were analyzed using grounded theory. The barriers to engagement were classified as program and referral factors (uninformative referrals, offense focused programs, rigid and abstract content, didactic delivery, and homework), facilitator characteristics (lack of control: contentious and nonassertive), and group member characteristics (unmotivated, pre-contemplative, and blaming others and young, chaotic, and disruptive). Suggestions as to the design and facilitation of group offending behavior programs, and facilitator training and supervision to overcome barriers to engagement are proposed. PMID- 30419762 TI - Comparison of Clostripain and Neutral Protease as Supplementary Enzymes for Human Islet Isolation. AB - Although human islet transplantation has been established as valid and safe treatment for patients with type 1 diabetes, the utilization rates of human pancreases for clinical islet transplantation are still limited and substantially determined by the quality and composition of collagenase blends. While function and integrity of collagenase has been extensively investigated, information is still lacking about the most suitable supplementary neutral proteases. The present study compared islet isolation outcome after pancreas digestion by means of collagenase used alone or supplemented with either neutral protease (NP), clostripain (CP), or both proteases. Decent amounts of islet equivalents (IEQ) were isolated using collagenase alone (3090 +/- 550 IEQ/g), or in combination with NP (2340 +/- 450 IEQ/g) or CP (2740 +/- 280 IEQ/g). Nevertheless, the proportion of undigested tissue was higher after using collagenase alone (21.1 +/ 1.1%, P < 0.05) compared with addition of NP (13.3 +/- 2.2%) or CP plus NP (13.7 +/- 2.6%). Likewise, the percentage of embedded islets was highest using collagenase only (13 +/- 2%) and lowest adding NP plus CP (4 +/- 1%, P < 0.01). The latter combination resulted in lowest post-culture overall survival (42.7 +/- 3.9%), while highest survival was observed after supplementation with CP (74.5 +/ 4.8%, P < 0.01). An insulin response toward glucose challenge was present in all experimental groups, but the stimulation index was significantly decreased using collagenase plus NP (2.0 +/- 0.12) compared with supplementation with CP (3.16 +/ 0.4, P < 0.001). This study demonstrates for the first time that it is possible to isolate significant numbers of human islets combining collagenase only with CP. The supplementation with CP is an effective means to substantially reduce NP activity, which significantly decreases survival and viability after culture. This will facilitate the manufacturing of enzyme blends with less harmful characteristics. PMID- 30419760 TI - An In Vitro Model of Charcot-Marie-Tooth Disease Type 4B2 Provides Insight Into the Roles of MTMR13 and MTMR2 in Schwann Cell Myelination. AB - Charcot-Marie-Tooth Disorder Type 4B (CMT4B) is a demyelinating peripheral neuropathy caused by mutations in myotubularin-related (MTMR) proteins 2, 13, or 5 (CMT4B1/2/3), which regulate phosphoinositide turnover and endosomal trafficking. Although mouse models of CMT4B2 exist, an in vitro model would make possible pharmacological and reverse genetic experiments needed to clarify the role of MTMR13 in myelination. We have generated such a model using Schwann cell dorsal root ganglion (SC-DRG) explants from Mtmr13-/- mice. Myelin sheaths in mutant cultures contain outfoldings highly reminiscent of those observed in the nerves of Mtmr13-/- mice and CMT4B2 patients. Mtmr13-/- SC-DRG explants also contain reduced Mtmr2, further supporting a role of Mtmr13 in stabilizing Mtmr2. Elevated PI(3,5)P2 has been implicated as a cause of myelin outfoldings in Mtmr2 /- models. In contrast, the role of elevated PI3P or PI(3,5)P2 in promoting outfoldings in Mtmr13-/- models is unclear. We found that over-expression of MTMR2 in Mtmr13-/- SC-DRGs moderately reduced the prevalence of myelin outfoldings. Thus, a manipulation predicted to lower PI3P and PI(3,5)P2 partially suppressed the phenotype caused by Mtmr13 deficiency. We also explored the relationship between CMT4B2-like myelin outfoldings and kinases that produce PI3P and PI(3,5)P2 by analyzing nerve pathology in mice lacking both Mtmr13 and one of two specific PI 3-kinases. Intriguingly, the loss of vacuolar protein sorting 34 or PI3K-C2beta in Mtmr13-/- mice had no impact on the prevalence of myelin outfoldings. In aggregate, our findings suggest that the MTMR13 scaffold protein likely has critical functions other than stabilizing MTMR2 to achieve an adequate level of PI 3-phosphatase activity. PMID- 30419763 TI - Historical Review: Opiate Addiction and Opioid Receptors. AB - Substance use disorders (SUDs), defined as a collection of symptoms including tolerance and withdrawal, are chronic illnesses characterized by relapse and remission. In the United States, billions of dollars have been lost due to SUDs. In the past 30 years, effective medications and behavioral interventions have played a major role in preventing relapse and facilitating longer periods of abstinence. From the late 1990s to the present, the opioid epidemic or opioid crisis in the United States has raised public awareness of SUDs. Methadone, buprenorphine, and naloxone have proven their effectiveness in treating addicted individuals, and each of them has different effects on different opioid receptors. Methadone and buprenorphine target mu opioid receptors (MORs) in the brain to treat opioid dependence by reducing withdrawal and craving, whereas naloxone is an opioid antagonist used to treat opioid overdose. Mu, kappa, and delta are opioid receptor subtypes with common analgesic effects, and each also has unique effects and distribution in the brain. MORs in distinct brain regions, such as the nucleus accumbens and basolateral amygdala, trigger the euphoria and incentive properties of rewarding stimuli. Kappa opioid receptors can trigger anti-reward effects and produce dysphoric effects. Delta opioid receptors can induce anxiolytic effects. Though effective medications are available, relapse is still common due to neurobiological changes in brain pathways and tolerance of opioid receptors with repeated abuse of substances. In this article, I summarize the biological mechanisms of opioid dependence and opioid receptors and review previous articles about medications used to treat SUDs and their clinical effects. PMID- 30419764 TI - Association Studies Between Regulatory Regions of IRF6/ TP63 Genes and Nonsyndromic Oral Clefts. AB - OBJECTIVE:: To evaluate genetic variants within the regulatory regions of interferon regulatory factor 6 ( IRF6) and TP63 for the etiology of nonsyndromic oral clefts risk factors. DESIGN:: We performed allelic transmission disequilibrium test analysis on 5 eligible single-nucleotide polymorphisms (SNPs) and SNP haplotypes using the Family-Based Association Test. PARTICIPANTS:: The study sample consisted of 334 case-parent trios of nonsyndromic oral clefts from Taiwanese population, separated into nonsyndromic cleft lip/palate (NSCL/P) and nonsyndromic cleft palate only (NSCPO) groups. RESULTS:: We found all 3 selected SNPs of the IRF6 gene show significant association with nonsyndromic oral clefts (rs2235371, P = 5.10E-07; rs642961, P = .00194; and rs77542756, P = 9.08E-07). Haplotype analyses identified 3 possible SNP combination haplotypes in the IRF6 gene and found that C-G-G showed significant undertransmission ( P = .058), whereas 2 other haplotypes, T-G-A and C-A-G ( P = 2.71E-06 and P = 5.00E-04, respectively), were significantly overtransmitted to the NSCL/P children but not to the NSCPO children. For the TP63 gene, we failed to detect evidence of nonsyndromic oral cleft association in the 2 SNPs within the TP63 large intron 1 region. CONCLUSIONS:: We used a family-based analysis in 334 Taiwanese case parent trios to evaluate selected SNPs of IRF6 genes and TP63 genes for a risk of orofacial clefting. This study provides additional evidence for an association between IRF6 and NSCL/P, including the genetic variants within the 5'-noncoding region of the gene. We also confirmed that NSCL/P and NSCPO individuals belong to different groups. For the TP63, our data did not favor the direct involvement of TAp63 isoforms during orofacial development. PMID- 30419765 TI - The Levels of Neonatal Care Practices at Health Facilities and Home Deliveries in Rural Sidama Zone, Southern Ethiopia. AB - BACKGROUND: Globally, there has been progress in reducing maternal and under-5 child deaths in the past 2 decades; however, the progress in reducing newborn mortality has been slower with estimated 3 million neonatal deaths per year. In Ethiopia, unhealthy newborn care is common at home deliveries compared with institutional births that might be associated with neonatal deaths. The purpose of the current study was to assess the practices of immediate newborn care at home and institutional deliveries in rural Sidama Zone, 2017. METHODS: A population-based cross-sectional survey was used. The study was conducted in 5 districts of Sidama Zone, from January 21 to February 4, 2017. A total of 2300 mothers who gave live births in the past 6 months were selected using a 2-stage cluster sampling methods. Data were entered, cleaned, and recoded using Epi Data and SPSS for analysis. Accordingly, descriptive and bivariate analyses were done, and the results are presented using P values. RESULTS: The response rate was 99% (2279/2300). About one-third of the mothers are in the age group of 20 to 24 years, and 94.6% of them had at least 1 antenatal care follow-up. Most (72%) mothers delivered at health facilities. The practices of skin to skin care of the babies was 52% (61% at health facilities, 28% at home; P < .002). Baby bathing delay for at least 24 hours was 78% and clean cord care was 73% overall (home 21% vs health institution 93.6%). The cord was not tied in 11.6% of cases all of whom were home births ( P < .001). As to immediate breastfeeding of the child, most (78%) of the babies were put to the breast within an hour of birth with no significant difference between the 2 places of births ( P = .75). CONCLUSION: In this study, giving birth at health facilities did not make immediate newborn care practices universal, but unhealthy practices were more common among home births. Therefore, more efforts to promote community-based immediate newborn care are needed with great emphasis to proper thermal care. PMID- 30419766 TI - Profiling Heparin-Induced Thrombocytopenia (HIT) Antibodies in Hospitalized Patients With and Without Diabetes. AB - Heparin (H) anticoagulation in populations characterized by elevated platelet factor 4 (PF4) frequently elicits PF4/H antibodies, presenting a risk of heparin induced thrombocytopenia. Recent studies have shown that anti-PF4/H enzyme-linked immunosorbent assays (ELISAs) detect antibodies in individuals never exposed to heparin. Platelet factor 4/H cross-reactive antibodies may result from PF4 mediated defense responses to injury or infection. This study questioned whether patients with diabetes are more likely to develop the endogenous cross-reactive antibodies. A comparison of healthy volunteers versus hospitalized patients with or without diabetes showed no significant differences in the prevalence of PF4/H ELISA-positive results. However, the group of patients who had both diabetes and an infectious condition had higher median antibody titer compared to other patients with or without diabetes regardless of reason for hospitalization. Higher PF4/H titers were also associated with patients with diabetes who were not on any medical therapy. In the future, determining whether PF4/H cross-reactive antibodies sensitize patients to respond adversely to heparin anticoagulation or predispose patients to other complications may be relevant to diabetes care. PMID- 30419768 TI - Cetirizine versus diphenhydramine in the prevention of chemotherapy-related hypersensitivity reactions. AB - OBJECTIVE: This study evaluated the role of cetirizine compared to diphenhydramine as premedications for patients receiving paclitaxel, cetuximab, and rituximab infusions. Historically, diphenhydramine has been linked with more sedation in comparison to cetirizine; however, it is unknown if cetirizine can replace diphenhydramine in the prevention of hypersensitivity reactions in patients receiving chemotherapy. METHODS: This is a retrospective study designed to assess infusion reactions occurring in patients receiving diphenhydramine or cetirizine premedication for rituximab, paclitaxel, or cetuximab therapies. Infusion reactions were defined as various symptoms such as flushing, itching, alterations in heart rate and blood pressure, and dyspnea plus the clinical setting of a concurrent or very recent infusion. RESULTS: A total of 207 patients were evaluated in this study with 83 patients receiving cetirizine and 124 diphenhydramine patients. Overall, the percentage of patients with at least one chemotherapy-related infusion event in the cetirizine group was 19.3% (95% CI 11.4-29.4) compared to diphenhydramine group 24.2% (95% CI 17.0-32.7), P = 0.40. Of the patients who received cetirizine and then experienced an event in the first cycle, 41.7% (95% CI 13.7-74.3) of the events were due to paclitaxel, 50.0% (95% CI 19.4-80.6) were due to rituximab, and 8.3% (95% CI 0.1-43.6) were due to cetuximab. Of the patients who received diphenhydramine and then experienced an event in the first cycle, 26.1% (95% CI 5.7-51.4) were due to paclitaxel, 73.9% (95% CI 48.6-94.3) were due to rituximab and none due to cetuximab. CONCLUSION: Cetirizine appears to be a viable substitute for diphenhydramine for the prevention of infusions reactions with cetuximab, paclitaxel, and rituximab infusions in adults. Prospective studies are needed to determine the efficacy and safety of cetirizine compared with diphenhydramine in the prevention of chemotherapy-related infusion reactions. PMID- 30419767 TI - Coagulation phenotype of wild-type mice on different genetic backgrounds. AB - Genetically engineered mouse models are used to investigate beneficial treatment in haemophilia by comparison with wild-type mice. It has been recognized that wild-type and haemophilic mice of different genetic backgrounds show different bleeding phenotypes. We assessed ex-vivo coagulation parameters in nine wild-type substrains of 129S1/Sv, BALB/c and C57BL/6 mice applying thromboelastography (TEG), activated partial thromboplastin time (aPTT), prothrombin time (PT) and fibrinogen levels. The comprehensive ex-vivo data are discussed in view of results from a tail-tip bleeding assay. Time to first clot formation ( R-time) showed higher within-substrain (CV range: 28-54%) and higher between-substrain (median range: 25.53-42.60 min) variation for BALB/c than for C57BL/6 mice (CV range: 14-31%; median range: 22.45-24.93 min). Median R-time for 129S1/Sv mice was 30.42 min (CV: 33%). No distinct strain differences were observed for maximum amplitude (MA), aPTT, or PT, but males generally showed higher MA and shorter aPTT than females. Males of all substrains had higher fibrinogen levels than females. The heightened in-vivo variability (CV range: 81-171%; median range: 36.00-469.50 mg) in the tail-tip bleeding assay and increased blood loss in wild type C57BL/6 male mice was not reflected in ex-vivo coagulation parameters. In general, ex-vivo coagulation results appeared consistent within substrains, but showed substrain and sex differences of variable magnitudes. We conclude that alignment of the mouse substrain genetic background to the experimental model is critical to reduce data variability and animal numbers. PMID- 30419769 TI - A case of severe, irreversible hypocalcemia after one dose of pamidronate administered for hypercalcemia of malignancy. AB - This is a case report of a patient who developed severe, irreversible hypocalcemia after receiving one dose of pamidronate 90 mg for hypercalcemia of malignancy. Hypocalcemia is a known risk of bisphosphonate treatments, but the incidence of severe hypocalcemia is rare, and the risk factors are well established. However, in the treatment of hypercalcemia of malignancy, the treatment objective is to reduce the elevated serum calcium level, and the bisphosphonate is usually given as one time dose only. The potential for developing severe hypocalcemia may not be considered a significant concern in this setting compared to the setting of the treatment of bone metastasis, where the baseline serum calcium level is not elevated and the bisphosphonate is administered at a regular interval of every three to four weeks. Furthermore, there is unawareness of prevalence of vitamin D deficiency in cancer patients, especially in those with advanced cancer, which may lead to inadvertent, severe hypocalcemia from bisphosphonate treatment. The objective of this case report is to bring awareness to the risk of severe hypocalcemia in patients with hypercalcemia of malignancy and the high prevalence of unrecognized vitamin D deficiency in cancer patients. PMID- 30419770 TI - Two Rapid Screens for Detecting Probable Post-Traumatic Stress Disorder and Interpersonal Violence Exposure: Predictive Utility in a Juvenile Justice Sample. AB - The Trauma-Related Symptoms and Impairment Rapid Screen (TSIRS) and the Dimensions of Violence Exposure Rapid Screen (DVERS) are two new tools designed to detect traumatic stress symptoms and high-risk characteristics of trauma exposure. Each screen contains 10 yes-or-no questions and is estimated to take approximately 2 min to complete. The rapid screens were developed to address the demand for efficient, effective, and user-friendly tools for use in settings where universal screening of trauma and related symptoms is recommended, but training and expertise in clinical assessment are generally lacking or absent. The purpose of the current study was to examine the predictive utility of the TSIRS and DVERS in detecting probable post-traumatic stress disorder and poly victimization assessed via a validated self-report instrument. Data were collected on a sample of 218 detained adolescents. Results provide initial support for the predictive utility of the TSIRS and DVERS in a justice-involved sample. PMID- 30419771 TI - Discovering a double murder through skeletal remains: A case report. AB - Forensic examination of human remains is a complex process that relies on the contribution of multidisciplinary forensic medicine specialties. Here we present a complex forensic case regarding a double murder whose victims were found almost completely skeletonized. Post-mortem investigations allowed us to define the biological profile of the two bodies (ancestry, sex, age and stature), to discover their identity through forensic DNA analysis, and to detect peri-mortem injuries caused by firearms and stabbing weapons. Three men were recognized as involved in the crime and two of them were condemned to life imprisonment for homicide. The judges accepted the reconstruction of the crime promoted by the Prosecutor (double firearm murder). PMID- 30419772 TI - Surface tyre imprints caused by a motorcycle collision rather than by being run over. AB - Tyre imprints on the skin are usually considered to be the result of being run over by a motor vehicle. This article reports a traffic accident in which tyre marks on the victim's skin were caused by a collision rather than by being run over. The mechanism of the injury in this case is analysed and discussed. A 23 year-old male drove a motorcycle while under the influence of alcohol and collided with a sign pillar on the side of the road. Both the victim and the motorcycle careened into the bottom of a tractor-trailer. No witnesses or surveillance videos could confirm the process of the accident. Because tyre imprints were found on the victim's skin, traffic police believed that he had been run over during the accident. However, forensic autopsy and analysis of the accident process revealed that the true cause of the imprints was a collision between the victim's body and a tyre. PMID- 30419773 TI - Overactive bladder symptom bother and health-related quality of life in patients with systemic lupus erythematosus and primary Sjogren syndrome. AB - OBJECTIVE: The objective of this paper is to assess overactive bladder (OAB) symptom bother (SB) and health-related quality of life (HRQL) among patients with systemic lupus erythematosus (SLE) and primary Sjogren syndrome (pSS). METHODS: We recruited adult SLE and pSS patients and two groups of age- and sex-matched controls. We applied the OAB questionnaire-short form (OABq-SF) to all participants to assess SB and HRQL and collected clinical information relevant for OAB. We compared the OABq-SF scores for SB and HRQL between patients and controls using univariate and multivariate linear regression analysis. RESULTS: We recruited 95 rheumatic patients (68 SLE, 27 pSS) and 231 controls. Compared to controls SLE patients showed higher OABq-SF SB scores (22.6 +/- 20.4 vs 14.7 +/- 17.0, p = 0.004) and lower HRQL scores (89.8 +/- 15.8 vs 93.8 +/- 11.4, p = 0.044). On multivariate analysis SLE was significantly associated with a higher SB score (beta-coefficient 7.13, p = 0.008) and tended to be associated with worse HRQL values (beta-coefficient -3.53, p = 0.055). Patients with pSS had numerically higher mean SB scores (22.8 +/- 22.5 vs 16.2 +/- 18.0, respectively, p = 0.107) and lower HRQL scores (91.0 +/- 10.7 vs 93.2 +/- 11.6, respectively, p = 0.369), although these differences were not statistically significant. Diagnosis of pSS was not significantly associated with SB or HRQL scores on univariate or multivariate analysis. CONCLUSIONS: Patients with SLE have significantly worse OAB-SB and poorer HRQL compared to controls. A similar trend was seen for pSS patients, especially for SB. These findings suggest that clinically subtle OAB symptoms may be present in rheumatic patients for whom, later on, bladder pain syndrome may occur. PMID- 30419774 TI - Associations between Community-Acquired Pneumonia and Proton Pump Inhibitors in the Laryngeal/Voice-Disordered Population. AB - OBJECTIVES: To examine the relationship between community-acquired pneumonia (CAP) and proton pump inhibitor (PPI) treatment among patients with laryngeal/voice disorders. STUDY DESIGN: Retrospective cohort analysis. SETTING: Large national administrative US claims database. SUBJECTS AND METHODS: Patients were included if they were >=18 years old; had outpatient treatment for a laryngeal/voice disorder from January 1, 2010, to December 31, 2014 (per International Classification of Diseases, Ninth Revision, Clinical Modification codes); had 12 months of continuous enrollment prior to the index date (ie, first diagnosis of laryngeal/voice disorder); had no preindex diagnosis of CAP; and had prescription claims captured from 1 year preindex to end of follow-up. Patient demographics, comorbid conditions, index laryngeal diagnosis, number of unique preindex patient encounters, and CAP diagnoses during the postindex 3 years were collected. Two models-a time-dependent Cox regression model and a propensity score-based approach with a marginal structural model-were separately performed for patients with and without pre-index date PPI prescriptions. RESULTS: A total of 392,355 unique patients met inclusion criteria; 188,128 (47.9%) had a PPI prescription. The 3-year absolute risk for CAP was 4.0% and 5.3% among patients without and with preindex PPI use, respectively. For patients without and with pre-index date PPI use, the CAP occurrence for a person who had already received a PPI is 30% to 50% higher, respectively, than for a person who had not yet had a PPI but may receive one later. CONCLUSIONS: Patients without and with pre-index date PPI use experienced a roughly 30% to 50% increased likelihood of CAP, respectively, as compared with patients who had not had PPI prescriptions. PMID- 30419775 TI - Ophthalmomyiasis externa due to sheep nasal botfly in rural Jamaica. AB - We present the case of a young male patient who presented with pain, redness and foreign body sensation in his left eye. There was no associated decrease in vision. Three live larvae were removed from his left conjunctival sac and sent to the laboratory for identification. The patient was treated symptomatically and his symptoms were mostly resolved by the following day. The larvae were later identified as the first instar of the sheep nasal botfly. Poor sanitation and exposure to livestock were among the identified risk factors in this case. Physicians must have this as a differential diagnosis for conjunctivitis in patients with risk factors. This is the first reported case of ophthalmomyiasis from Jamaica. PMID- 30419776 TI - Unmet need for contraception among HIV-positive women in Ile-Ife, Nigeria. AB - As mother-to-child transmission of HIV is difficult to predict and also hard to prevent in practice, pregnancy among women living with HIV/AIDS (WHA) needs to be taken with considerable aforethought. The prevention of unwanted pregnancy among WHA is therefore a public health issue. The aim of our study was to determine the unmet need for contraception among HIV-positive women and the associated factors. Ours was a cross-sectional study involving 425 non-pregnant WHA attending an adult HIV clinic in Nigeria. Interviewer-administered, structured questionnaires designed for the study were used to obtain data. The contraceptive uptake was 47% while the unmet need for contraception was 20%. There were significant associations between unmet need for contraception and age group ( P < 0.001), religion ( P < 0.001), ethnic group ( P < 0.001), knowledge about contraceptives ( P = 0.02), educational status ( P = 0.01) and partners' retroviral status ( P = 0.008) The unmet need for contraception was high. Advocacy programs should perhaps be focused on older women, Christians and those with little or no education. PMID- 30419777 TI - The burden of chronic elbow dislocations in Cambodia and early results of a cost effective surgical approach. AB - Chronic elbow dislocation presents a surgical challenge and there is difficulty in balancing stability with early mobilisation. We present a series of 103 patients treated with open reduction via a posterior approach and provide early results of an alternative combined medial and lateral approach (Soddo technique, Anderson et al.). Of the 103 patients, 81% initially consulted a traditional healer and the mean dislocation period was 11 weeks. There was significant loss to follow-up. Only 12 patients having undergone the posterior approach had complete datasets. The mean preoperative arc of movement was 10 degrees and the postoperative arc was 65 degrees at a mean follow-up of 16 weeks. Five patients treated with the Soddo technique had sufficient follow-up data. The mean preoperative arc was 20 degrees and the mean postoperative arc was 95 degrees (mean follow-up of 20 days). Those having undergone the Soddo technique achieved a 20 degrees greater increase in range of movement and no re-dislocations. PMID- 30419778 TI - Aboriginal women have a higher risk of cervical abnormalities at screening; South Australia, 1993-2016. AB - OBJECTIVE: Cervical cancer mortality has halved in Australia since the national cervical screening program began in 1991, but elevated mortality rates persist for Aboriginal and Torres Strait Islander women (referred to as Aboriginal women in this report). We investigated differences by Aboriginal status in abnormality rates predicted by cervical cytology and confirmed by histological diagnoses among screened women. METHODS: Using record linkage between cervical screening registry and public hospital records in South Australia, we obtained Aboriginal status of women aged 20-69 for 1993-2016 (this was not recorded by the registry). Differences in cytological abnormalities were investigated by Aboriginal status, using relative risk ratios from mixed effect multinomial logistic regression modelling. Odds ratios were calculated for histological high grade results for Aboriginal compared with non-Aboriginal women. RESULTS: Of 1,676,141 linkable cytology tests, 5.8% were abnormal. Abnormal results were more common for women who were younger, never married, and living in a major city or socioeconomically disadvantaged area. After adjusting for these factors and numbers of screening episodes, the relative risk of a low grade cytological abnormality compared with a normal test was 14% (95% confidence interval 5-24%) higher, and the relative risk of a high grade cytological abnormality was 61% (95% confidence interval 44 79%) higher, for Aboriginal women. The adjusted odds ratio of a histological high grade was 76% (95% confidence interval 46-113%) higher. CONCLUSIONS: Ensuring that screen-detected abnormalities are followed up in a timely way by culturally acceptable services is important for reducing differences in cervical cancer rates between Aboriginal and non-Aboriginal women. PMID- 30419779 TI - The decision to biopsy in a lung cancer screening program: Potential impact of risk calculators. AB - OBJECTIVE: The National Lung Screening Trial demonstrated the benefits of lung cancer screening, but the potential high incidence of unnecessary invasive testing for ultimately benign radiologic findings causes concern. We aimed to review current biopsy patterns and outcomes in our community-based program, and retrospectively apply malignancy prediction models in a lung cancer screening population, to identify the potential impact these calculators could have on biopsy decisions. METHODS: Retrospective review of lung cancer-screening program participants from 2013 to 2016. Demographic, biopsy, and outcome data were collected. Malignancy risk calculators were retrospectively applied and results compared in patients with positive imaging findings. RESULTS: From 520 individuals enrolled in the screening program, pulmonary nodule(s) >=6 mm were identified in 166, with biopsy in 30. Malignancy risk probabilities were significantly higher (Brock p < 0.00001; Mayo p < 0.00001) in those undergoing diagnostic sampling than those not undergoing sampling. However, there was no difference in the Brock ( p = 0.912) or Mayo ( p = 0.435) calculators when discriminating a final diagnosis of cancer from not cancer in those undergoing sampling. CONCLUSIONS: In our screening program, 5.7% of individuals undergo invasive testing, comparable with the National Lung Screening Trial (6.1%). Both Brock and Mayo calculators perform well in indicating who may be at risk of malignancy, based on clinical and radiologic factors. However, in our invasive testing group, the Brock and Mayo calculators and Lung Cancer Screening Program clinical assessment all lacked clarity in distinguishing individuals who have a cancer from those with a benign abnormality. PMID- 30419780 TI - Transcriptional processes: Models and inference. AB - Many biochemical events involve multistep reactions. One of the most important biological processes that involve multistep reaction is the transcriptional process. Models for multistep reaction necessarily need multiple states and it is a challenge to compute model parameters that best agree with experimental data. Therefore, the aim of this work is to design a multistep promoter model which accurately characterizes transcriptional bursting and is consistent with observed data. To address this issue, we develop a model for promoters with several OFF states and a single ON state using Erlang distribution. To explore the combined effects of model and data, we combine Monte Carlo extension of Expectation Maximization (MCEM) and delay Stochastic Simulation Algorithm (DSSA) and call the resultant algorithm as delay Bursty MCEM. We apply this algorithm to time-series data of endogenous mouse glutaminase promoter to validate the model assumptions and infer the kinetic parameters. Our results show that with multiple OFF states, we are able to infer and produce a model which is more consistent with experimental data. Our results also show that delay Bursty MCEM inference is more efficient. PMID- 30419781 TI - Introduction to JBCB Special Issue on BICOB-2018. PMID- 30419782 TI - Minimizing the deep coalescence cost. AB - Metagenomic studies identify the species present in an environmental sample usually by using procedures that match molecular sequences, e.g. genes, with the species taxonomy. Here, we first formulate the problem of gene-species matching in the parsimony framework using binary phylogenetic gene and species trees under the deep coalescence cost and the assumption that each gene is paired uniquely with one species. In particular, we solve the problem in the cases when one of the trees is a caterpillar. Next, we propose a dynamic programming algorithm, which solves the problem exactly, however, its time and space complexity is exponential. Next, we generalize the problem to include non-binary trees and show the solution for caterpillar trees. We then propose time and space-efficient heuristic algorithms for solving the gene-species matching problem for any input trees. Finally, we present the results of computational experiments on simulated and empirical datasets consisting of binary tree pairs. PMID- 30419783 TI - Adjusted likelihood-ratio test for variants with unknown genotypes. AB - Association tests performed with the Likelihood-Ratio Test (LR Test) can be an alternative to [Formula: see text], which is often used in population genetics to find variants of interest. Because the LR Test has several properties that could make it preferable to [Formula: see text], we propose a novel approach for modeling unknown genotypes in highly-similar species. To show the effectiveness of this LR Test approach, we apply it to single-nucleotide polymorphisms (SNPs) associated with the recent speciation of the malaria vectors Anopheles gambiae and Anopheles coluzzii and compare to [Formula: see text]. PMID- 30419784 TI - A systematic exploration of [Formula: see text] cutoff ranges in machine learning models for protein mutation stability prediction. AB - Discerning how a mutation affects the stability of a protein is central to the study of a wide range of diseases. Mutagenesis experiments on physical proteins provide precise insights about the effects of amino acid substitutions, but such studies are time and cost prohibitive. Computational approaches for informing experimentalists where to allocate wet-lab resources are available, including a variety of machine learning models. Assessing the accuracy of machine learning models for predicting the effects of mutations is dependent on experiments for amino acid substitutions performed in vitro. When similar experiments on physical proteins have been performed by multiple laboratories, the use of the data near the juncture of stabilizing and destabilizing mutations is questionable. In this work, we explore a systematic and principled alternative to discarding experimental data close to the juncture of stabilizing and destabilizing mutations. We model the inconclusive range of experimental [Formula: see text] values via 3- and 5-way classifiers, and systematically explore potential boundaries for the range of inconclusive experimental values. We demonstrate the effectiveness of potential boundaries through confusion matrices and heat map visualizations. We explore two novel metrics for assessing viable cutoff ranges, and find that under these metrics, a lower cutoff near [Formula: see text] and an upper cutoff near [Formula: see text] are optimal across multiple machine learning models. PMID- 30419785 TI - Protein secondary structure prediction improved by recurrent neural networks integrated with two-dimensional convolutional neural networks. AB - Protein secondary structure prediction (PSSP) is an important research field in bioinformatics. The representation of protein sequence features could be treated as a matrix, which includes the amino-acid residue (time-step) dimension and the feature vector dimension. Common approaches to predict secondary structures only focus on the amino-acid residue dimension. However, the feature vector dimension may also contain useful information for PSSP. To integrate the information on both dimensions of the matrix, we propose a hybrid deep learning framework, two dimensional convolutional bidirectional recurrent neural network (2C-BRNN), for improving the accuracy of 8-class secondary structure prediction. The proposed hybrid framework is to extract the discriminative local interactions between amino-acid residues by two-dimensional convolutional neural networks (2DCNNs), and then further capture long-range interactions between amino-acid residues by bidirectional gated recurrent units (BGRUs) or bidirectional long short-term memory (BLSTM). Specifically, our proposed 2C-BRNNs framework consists of four models: 2DConv-BGRUs, 2DCNN-BGRUs, 2DConv-BLSTM and 2DCNN-BLSTM. Among these four models, the 2DConv- models only contain two-dimensional (2D) convolution operations. Moreover, the 2DCNN- models contain 2D convolutional and pooling operations. Experiments are conducted on four public datasets. The experimental results show that our proposed 2DConv-BLSTM model performs significantly better than the benchmark models. Furthermore, the experiments also demonstrate that the proposed models can extract more meaningful features from the matrix of proteins, and the feature vector dimension is also useful for PSSP. The codes and datasets of our proposed methods are available at https://github.com/guoyanb/JBCB2018/ . PMID- 30419786 TI - Gene multifunctionality scoring using gene ontology. AB - Multifunctional genes are important genes because of their essential roles in human cells. Studying and analyzing multifunctional genes can help understand disease mechanisms and drug discovery. We propose a computational method for scoring gene multifunctionality based on functional annotations of the target gene from the Gene Ontology. The method is based on identifying pairs of GO annotations that represent semantically different biological functions and any gene annotated with two annotations from one pair is considered multifunctional. The proposed method can be employed to identify multifunctional genes in the entire human genome using solely the GO annotations. We evaluated the proposed method in scoring multifunctionality of all human genes using four criteria: gene disease associations; protein-protein interactions; gene studies with PubMed publications; and published known multifunctional gene sets. The evaluation results confirm the validity and reliability of the proposed method for identifying multifunctional human genes. The results across all four evaluation criteria were statistically significant in determining multifunctionality. For example, the method confirmed that multifunctional genes tend to be associated with diseases more than other genes, with significance [Formula: see text]. Moreover, consistent with all previous studies, proteins encoded by multifunctional genes, based on our method, are involved in protein-protein interactions significantly more ([Formula: see text]) than other proteins. PMID- 30419787 TI - Identification of jointly correlated gene sets. AB - Associations between expressions of genes play a key role in deciphering their functions. Correlation score between pairs of genes is often utilized to associate two genes. However, the relationship between genes is often more complex; multiple genes might collaborate to control the transcription of a gene. In this paper, we introduce the problem of searching pairs of genes, which collectively correlate with another gene. This problem is computationally much harder than the classical problem of identifying pairwise gene associations. Exhaustive search is infeasible for transcriptomic datasets also; since for [Formula: see text] genes, there are [Formula: see text] possible gene combinations. Our method builds three filters to avoid computing the association for a large fraction of the gene combinations, which do not produce high correlation. Our experiments on a synthetic dataset and a prostate cancer dataset demonstrate that our method produces accurate results at the transcriptome level in practical time. Moreover, our method identifies biologically novel results which classical pairwise gene association studies are unlikely to discover. PMID- 30419789 TI - 1947-1952: UNESCO's division for science & its popularization. PMID- 30419788 TI - Surgical Loupe at 4.0* Magnification in Pancreaticoduodenectomy-Does It Affect the Surgical Outcomes? A Propensity Score-Matched Study. AB - BACKGROUND: There is paucity of data about the impact of using magnification on rate of pancreatic leak after pancreaticoduodenectomy (PD). The aim of this study was to show the impact of using magnifying surgical loupes 4.0* EF (electro focus) on technical performance and surgical outcomes of PD. PATIENTS AND METHOD: This is a propensity score-matched study. Thirty patients underwent PD using surgical loupes at 4.0* magnification (Group A), and 60 patients underwent PD using the conventional method (Group B). The primary outcome was postoperative pancreatic fistula. Secondary outcomes included operative time, intraoperative blood loss, postoperative complications, mortality, and hospital stay. RESULTS: The total operative time was significantly longer in the loupe group ( P = .0001). The operative time for pancreatic reconstruction was significantly longer in the loupe group ( P = .0001). There were no significant differences between both groups regarding hospital stay, time to oral intake, total amount of drainage, and time of nasogastric tube removal. Univariate and multivariate analyses demonstrated 3 independent factors of development of postoperative pancreatic fistula: pancreatic duct <3 mm, body mass index >25, and soft pancreas. CONCLUSION: Surgical loupes 4.0* added no advantage in surgical outcomes of PD with regard to improvement of postoperative complications rate or mortality rate. PMID- 30419790 TI - Executive Functions and Social Cognition in Juveniles Who Have Sexually Offended. AB - Although neuropsychological assessments provide valuable information for those working in forensic mental health, few neuropsychological studies concern persons who sexually offend, particularly juveniles who have sexually offended (JSO). It has been suggested that, contrary to current theories, executive function in JSO, as a group, is no more impaired than it is in juvenile delinquents in general. However, JSO with child victims seem to be more impulsive than JSO whose victims are peers or adults. To verify this potentially important (and unexpected) finding, a sample of adolescent males ( N = 134; 15.6 +/- 1.5 years old) that included JSO, general delinquents, and underprivileged nondelinquents was assessed using a battery of behavioral and psychological tests that focus on impulsivity. No difference was found between groups regarding higher order executive functions as measured with the Wisconsin Card Sorting Task but JSO with child victims were found to be the most impulsive subgroup as evidenced with the Iowa Gambling Task, the Stop-Signal Reaction Task, and the Impulsive scale of the Social Problem Solving Inventory. They also had the highest number of prescriptions for attention deficit hyperactivity disorder (ADHD) medication. These results, which contradict hypotheses derived from assessment of adult sex offenders, illustrate an important difference between the cognitive profiles of adult and juvenile males who sexually offended. They also confirm that JSO whose victims are children appear to be more impulsive. PMID- 30419791 TI - Feasibility Study of a Newly Developed Hybrid Energy Device Used During Laparoscopic Liver Resection in a Porcine Model. AB - BACKGROUND: Although various devices have been clinically used for laparoscopic liver resection (LLR), the best device for liver parenchymal transection remains unknown. Olympus Corp (Tokyo, Japan) developed a laparoscopic hybrid pencil (LHP) device, which is the first electric knife to combine ultrasound and electric energy with a monopolar output. We aimed to evaluate the feasibility of using the LHP device and to compare it with the laparoscopic monopolar pencil (LMP) and laparoscopic ultrasonic shears (LUS) devices for LLR in a porcine model. METHODS: Nine male piglets underwent laparoscopic liver lobe transections using each device. The operative parameters were evaluated in the 3 groups (n = 24 lobes) during the acute study period. The imaging findings from contrast-enhanced computed tomography and histopathological findings of autopsy on postoperative day 7 were compared among groups (n = 6 piglets) during the long-term study. RESULTS: The transection time was shorter ( P = .001); there was less blood loss ( P = .018); and tip cleaning ( P < .001) and instrument changes were less often required ( P < .001) in the LHP group than in the LMP group. The LHP group had fewer instances of bleeding ( P < .001) and coagulator usage ( P < .001) than did the LUS group. In the long-term study, no postoperative adverse events occurred in the 3 groups. The thermal spread and depth of the LHP device were equivalent to those of the LMP and LUS devices (vs LMP: P = .226 and .159; vs LUS: P = 1.000 and .574). CONCLUSIONS: The LHP device may be an efficient device for LLR if it can be applied to human surgery. PMID- 30419792 TI - Validation of a claims-based algorithm to identify patients with chronic thromboembolic pulmonary hypertension using electronic health record data. AB - This study aimed to validate an algorithm developed to identify chronic thromboembolic pulmonary hypertension (CTEPH) among patients with a history of pulmonary embolism. Validation was halted because too few patients had gold standard evidence of CTEPH in the administrative claims/electronic health records database, suggesting that CTEPH is underdiagnosed. PMID- 30419793 TI - EXPRESS: Development of acquired intrapulmonary venous anastomosis contributing to establishment of Fontan circulation. PMID- 30419794 TI - Reduced free-living activity levels in pulmonary arterial hypertension patients. AB - We conducted a survey of pulmonary arterial hypertension (PAH) patients and healthy controls who use either a smartphone or wearable fitness device that tracks daily step count. We found that PAH patients have markedly reduced activity levels compared to controls, after controlling for confounders. PMID- 30419795 TI - Late onset cardiac cirrhosis and portal hypertensive ascites after atrial fibrillation ablation. AB - Pulmonary vein stenosis is a potential complication following catheter ablation of atrial fibrillation (AF). We report the case of a patient with refractory ascites late after multiple catheter ablation procedures for AF. This is the first case report of portal hypertensive ascites due to acquired multiple pulmonary vein stenoses resulting in pulmonary hypertension (PH) and cardiac cirrhosis late after AF ablation. Despite extensive surgical reconstruction of the affected pulmonary veins, the patient has PH and right heart failure with persistent ascites and lower extremity edema. PMID- 30419797 TI - EXPRESS: Hemodynamics of the diastolic pressure gradients in acute heart failure: Implications for the diagnosis of pre-capillary pulmonary hypertension in left heart disease. PMID- 30419796 TI - Hemodynamic changes after acute fluid loading in patients with systemic sclerosis without pulmonary hypertension. AB - A fluid challenge with a rapid infusion of saline helps to discriminate between pre- and post-capillary pulmonary hypertension (PH) and allows unmasking hidden post-capillary PH. Systemic sclerosis (SSc) patients may present with biventricular systolic and diastolic dysfunction. The aim of this study was to evaluate the hemodynamic changes of the pulmonary circulation in SSc patients without PH after a fluid challenge. Twenty-five SSc patients and 25 controls underwent right heart catheterization in basal conditions and after volume loading with saline infusion of 7 mL/kg over 5-10 min. At baseline, there was no difference in hemodynamics between SSc patients and controls. Rapid volume loading resulted in a significant increase in pressures and flows in both groups. Increases in right atrial pressure (3 +/- 1 vs. 2 +/- 1 mmHg, P = 0.03), mean pulmonary artery pressure (5 +/- 1 vs. 3 +/- 1 mmHg, P < 0.001), and pulmonary artery wedge pressure (PAWP; 5 +/- 2 vs. 3 +/- 1 mmHg, P < 0.001) were larger in SSc patients than in controls. Conversely, cardiac index (0.4 +/- 0.2 vs. 0.6 +/- 0.3 L/min/m2, P = 0.005) increased less in SSc patients than in controls. Pulmonary vascular resistance did not differ between groups before and after volume loading. Four SSc patients and only one of the controls reached a PAWP > 18 mmHg suggesting latent left heart failure. Even if differences are small and not diagnostic for heart failure, SSc patients without PH have a larger increase in pulmonary vascular pressures and a smaller increase in cardiac output than controls after an acute volume loading, probably due to subclinical left ventricular diastolic dysfunction. PMID- 30419798 TI - Right ventricular function in infants with bronchopulmonary dysplasia and pulmonary hypertension: a pilot study. AB - Premature birth and bronchopulmonary dysplasia (BPD) are risk factors for the development of echocardiographic signs of pulmonary hypertension (PH) and are associated with changes in cardiac structure and function. It is unclear whether this association persists beyond early infancy. The aims of this study are to prospectively investigate the prevalence of PH in children with severe BPD and to investigate the effect of BPD and PH on myocardial structure and function at six months corrected age. Preterm infants (gestational age <= 32 weeks) with severe BPD were included. Echocardiography was used to define PH and to measure speckle tracking derived longitudinal and circumferential strain of the left ventricle (LV) and right ventricle (RV). Sixty-nine infants with a median (interquartile range [IQR]) gestational age of 25.6 (24.9-26.4) weeks and a median birthweight of 770 (645-945) gram were included. Eight (12%) infants had signs of PH at six months corrected age. RV fractional area change was lower in infants with severe BPD and PH at six months compared to infants without PH (35% +/- 9% vs. 43% +/- 9%, P = 0.03). RV mean longitudinal systolic strain was lower in infants with severe BPD and PH compared to infants without PH (17.6% [-19.5%/-16.1%] vs. 20.9% [-25.9%/-17.9%], P = 0.04). RV size and LV longitudinal and circumferential strain in children with BPD with or without PH were similar. Signs of PH were found in 12% of infants with severe BPD at six months corrected age and the presence of PH is associated with reduced RV systolic function. PMID- 30419799 TI - The Association of Maternal Age With Fetal Growth and Newborn Measures: The Mumbai Maternal Nutrition Project (MMNP). AB - BACKGROUND:: Young maternal age is associated with poorer birth outcomes, but the mechanisms are incompletely understood. Using data from a prospective cohort of pregnant women living in Mumbai slums, India, we tested whether lower maternal age was associated with adverse fetal growth. METHODS:: Fetal crown-rump length (CRL) was recorded at a median (interquartile range, IQR) of 10 weeks' gestation (9-10 weeks). Head circumference (HC), biparietal diameter (BPD), femur length (FL), and abdominal circumference (AC) were recorded at 19 (19-20) and 29 (28-30) weeks. Newborns were measured at a median (IQR) of 2 days (1-3 days) from delivery. Gestation was assessed using prospectively collected menstrual period dates. RESULTS:: The sample comprised 1653 singleton fetuses without major congenital abnormalities, of whom 1360 had newborn measurements. Fetuses of younger mothers had smaller CRL (0.01 standard deviation [SD] per year of maternal age; 95% confidence interval CI: 0.00-0.02 1 ; P = .04), and smaller HC, FL, and AC at subsequent visits. Fetal growth of HC (0.04 cm; 95% CI: 0.02-0.05; P < .001), BPD (0.01 cm; 95% CI: 0.00-0.01; P = .009), FL (0.04 cm; 95% CI: 0.02 0.06; P < .001), and AC (0.01 cm; 95% CI: 0.00-0.01; P = .003) up to the third trimester increased with maternal age. Skinfolds, head, and mid-upper arm circumferences were smaller in newborns of younger mothers. Adjusting for maternal prepregnancy socioeconomic status, body mass index, height, and parity attenuated the associations between maternal age and newborn size but did not change those with fetal biometry. CONCLUSION:: Fetuses of younger mothers were smaller from the first trimester onward and grew slower, independently of known confounding factors. PMID- 30419800 TI - The Role of Endometrial Volume and Endometrial and Subendometrial Vascularization Parameters in a Frozen Embryo Transfer Cycle. AB - The role of three-dimensional power Doppler ultrasonography of the endometrium in assisted reproduction is still far from clear. In this retrospective cohort study, transvaginal three-dimensional power Doppler examinations were performed 30 min before frozen-thawed embryo transfer. After pregnancy tests, two cohorts were established: P (pregnant, n = 31) and NP (nonpregnant, n = 31). The study only included nullipara with no uterine abnormalities who were undergoing infertility treatment at the Department of Gynecology, Obstetrics and Gynecological Endocrinology, Kepler University Hospital, Linz, Austria. The main outcome measures were the vascularization flow index (VFI), flow index (FI), and vascularization index (VI) in the endometrium/subendometrium, assessed using Virtual Organ Computer-aided AnaLysis (VOCALTM), and the endometrial volume. A total of 62 patients were enrolled in the study, forming two cohorts (pregnant, P; nonpregnant, NP). There were no significant differences between the two cohorts with regard to demographic data, numbers of embryos transferred, or embryo grading, but there was a significant difference in endometrial volume (cohort P, 3.17 +/- 0.84 mL; cohort NP, 2.36 +/- 0.9 mL; P = 0.001) and the pregnancy rate rises with larger volume. No differences were observed in the vascularization parameters FI, VFI, and VI in the endometrium and subendometrium. In the cohort of pregnant patients, there were 26 (41.9%) live births, with 21 term deliveries (80.8%). The endometrial volume was larger in the cohort of pregnant patients. Measurements were performed 30 min before embryo transfer, and no differences were observed in vascularization parameters in the subendometrium and endometrium. PMID- 30419801 TI - Dysregulated cancer cell transdifferentiation into erythrocytes is an additional metabolic stress in hepatocellular carcinoma. AB - A number of human and canine hepatocellular carcinoma tissues showed clear signs of hypoxia indicated by HIF1alpha-activation and the presence of large clusters of cells resembling erythrocytes at different stages of nuclear elimination without any defined endothelial cell lining or blood vessel walls. Differentiated erythrocytic identity of such cells in hepatocellular carcinoma tissues was apparent from their non-nucleated and evolving basophilic to eosinophilic staining characteristics. In addition to the fully differentiated non-nucleated mesenchymal cell clusters, the onset of erythroblastic transdifferentiation was apparent from the activation of Glycophorin A, a marker of erythrocytic progenitors, in some epithelial cancer cells. Activation of canonical Wnt signalling in such tumours was apparent from the expression of Wnt2 ligand and active beta-catenin translocation into the nucleus indicating Wnt signalling to be one of the key signalling pathways participating in such cell transdifferentiation. Sonic hedgehog and bone morphogenetic protein signalling along with Sulf1/Sulf2 activation was also observed in such hepatocellular carcinoma tissue samples. The presence of stem cell markers and the cell signalling pathways associated with erythropoiesis, and the detection of messenger RNAs for both alpha and beta haemoglobins, support the assumption that hepatocellular carcinoma cells have the potential to undergo cell fate change despite this process being dysregulated as indicated by the lack of simultaneous generation of endothelial cell lining. Lack of blood vessel walls or endothelial cell lining around erythrocytic clusters was confirmed by non-detection of multiple blood vessel markers such as vWF, CD146 and smooth muscle alpha-actin that were clearly apparent in normal and unaffected adjacent regions of hepatocellular carcinoma livers. In addition to the activation of Glycophorin A, transdifferentiation of some hepatocellular carcinoma hepatocytes into other cell fates was further confirmed by the activation of some stem cell markers, for example, NANOG and OCT4 transcription factors, not only by reverse transcription polymerase chain reaction but also by their restricted expression in such cells at protein level. PMID- 30419803 TI - People of Diverse Genders and/or Sexualities Caring For and Protecting Animal Companions in the Context of Domestic Violence. AB - This article reports on a thematic analysis of open-ended questions about how humans respond to violence directed toward animals in the context of violent human relationships, derived from an Australian-U.K. survey of people of diverse genders and/or sexualities. From the 137 responses, three major themes were identified: (a) animals are an important source of support, (b) humans actively protect animal companions, and (c) witnessing animal abuse can trigger leaving violent relationships. The findings offer unique insights for practitioners into the help-seeking needs of people of diverse genders and/or sexualities who live with animal companions in the context of domestic violence. PMID- 30419802 TI - The relationship between chemokines CCL2, CCL3, and CCL4 with the tumor microenvironment and tumor-associated macrophage markers in colorectal cancer. AB - A complex network of chemokines can influence cancer progression with the recruitment and activation of hematopoietic cells, including macrophages to the supporting tumor stroma promoting carcinogenesis and metastasis. The aim of this study was to investigate the relation between tissue and plasma chemokine levels involved in macrophage recruitment with tumor-associated macrophage profile markers and clinicopathological features such as tumor-node-metastases stage, desmoplasia, tumor necrosis factor-alpha, and vascular endothelial growth factor plasma content. Plasma and tumor/healthy mucosa were obtained from Chilean patients undergoing colon cancer surgery. Chemokines were evaluated from tissue lysates (CCL2, CCL3, CCL4, CCL5, and CX3CL1) by Luminex. Statistical analysis was performed using Wilcoxon match-paired test ( p < 0.05). Macrophage markers (CD68, CD163, and iNOS) were evaluated by immunohistochemistry samples derived from colorectal cancer patients. Correlation analysis between chemokines and macrophage markers and clinicopathological features were performed using Spearman's test. Plasmatic levels of chemokines and inflammatory mediators' vascular endothelial growth factor and tumor necrosis factor-alpha were evaluated by Luminex. Tumor levels of CCL2 (mean +/- standard deviation = 530.1 +/- 613.9 pg/mg), CCL3 (102.7 +/- 106.0 pg/mg), and CCL4 (64.98 +/- 48.09 pg/mg) were higher than those found in healthy tissue (182.1 +/- 116.5, 26.79 +/- 22.40, and 27.06 +/- 23.69 pg/mg, respectively p < 0.05). The tumor characterization allowed us to identify a positive correlation between CCL4 and the pro-tumor macrophages marker CD163 ( p = 0.0443), and a negative correlation of iNOS with desmoplastic reaction ( p = 0.0467). Moreover, we identified that tumors with immature desmoplasia have a higher CD163 density compared to those with a mature/intermediated stromal tissue ( p = 0.0288). Plasmatic CCL4 has shown a positive correlation with inflammatory mediators (tumor necrosis factor-alpha and vascular endothelial growth factor) that have previously been associated with poor prognosis in patients. In conclusion High expression of CCL4 in colon cancer could induce the infiltration of tumor-associated macrophages and specifically a pro-tumor macrophage profile (CD163+ cells). Moreover, plasmatic chemokines could be considered inflammatory mediators associated to CRC progression as well as tumor necrosis factor-alpha and vascular endothelial growth factor. These data reinforce the idea of chemokines as potential therapeutic targets or biomarker in CRC. PMID- 30419804 TI - Laser speckle flowgraphy can also be used to show dynamic changes in the blood flow of the skin of the foot after surgical revascularization. AB - OBJECTIVES: Laser speckle flowgraphy is a new method that enables the rapid evaluation of foot blood flow without contact with the skin. We used laser speckle flowgraphy to evaluate foot blood flow in peripheral arterial disease patients before and after surgical revascularization. MATERIALS AND METHODS: A prospective single-center study. Thirty-one patients with 33 limbs that underwent surgical revascularization for peripheral arterial disease were included. Pre- and postoperative foot blood flows were measured on the plantar surface via laser speckle flowgraphy and skin perfusion pressure. The laser speckle flowgraphy device was used to visualize the blood flow distribution of the target skin and processed the pulse wave velocity of synchronized heart beats. The mean blood flow, which was expressed as the area of the pulse wave as the beat strength of skin perfusion on laser speckle flowgraphy converted into a numerical value, was assessed as dynamic changes following surgery. Beat strength of skin perfusion was also investigated in non-peripheral arterial disease controls (23 patients/46 limbs). RESULTS: The suitability of beat strength of skin perfusion in non peripheral arterial disease controls was achieved; the beat strength of skin perfusion value was significantly higher in every area of interest in non peripheral arterial disease controls compared to that in peripheral arterial disease limbs at the preoperative stage (105.8 +/- 8.2 vs. 26.3 +/- 8.2; P < 0.01). Although the pulse wave before surgery was visually flat in peripheral arterial disease patients, the pulse wave was remarkably and immediately improved through surgical revascularization. Beat strength of skin perfusion showed a dynamic change in foot blood flow (26.3 +/- 8.2 at preoperation, 98.5 +/- 6.7 immediately after surgery, 107.6 +/- 5.7 at seven days after surgery, P < 0.01 for each compared to preoperation) that correlated with an improvement in skin perfusion pressure. CONCLUSIONS: Laser speckle flowgraphy is a noninvasive, contact-free modality that is easy to implement, and beat strength of skin perfusion is a useful indicator of foot circulation during the perioperative period. Further analysis with a larger number of cases is necessary to establish appropriate clinical use. PMID- 30419806 TI - Perampanel inhibits calcitonin gene-related peptide release from rat brainstem in vitro. AB - BACKGROUND: Perampanel is a novel antiepileptic drug acting via non-competitive antagonism on glutamatergic AMPA receptors, and the subsequent inhibition of ion calcium influx. Since it was recently postulated that the antagonists of glutamate receptors might play a role in the treatment of migraine, in this study we investigated the putative anti-migraine activity of perampanel in an in vitro animal model involving the static incubation of rat brainstem explants and the subsequent measurement of immune-reactive calcitonin gene-related peptide released into the incubation medium. METHODS: Acute rat brainstem explants were incubated in plain medium or in medium containing graded concentrations of perampanel. The release into the medium was assessed by radioimmunoassay either under baseline conditions or after stimulation by such secretagogues as high K+ concentrations, veratridine or capsaicin. RESULTS: We found that: 1) under baseline conditions perampanel, given in the range 0.01-100 MUM, inhibited in a concentration-dependent manner calcitonin gene-related peptide's release compared to controls; the decrease was statistically significant as from 10 MUM; 2) a significant and consistent increase in calcitonin gene-related peptide's secretion was induced by all depolarizing stimuli after 1 h of incubation; 3) under these conditions, calcitonin gene-related peptide's release stimulated by 56 mM KCl was significantly reduced by perampanel from 0.1 MUM onward, whereas secretion stimulated by veratridine was significantly reduced as from 1 MUM; 4) on the contrary, perampanel had no effect on capsaicin-induced calcitonin gene related peptide's release up to 100 MUM. CONCLUSIONS: Here we provided preliminary in vitro evidence suggesting that perampanel might control pain transmission under conditions of activated trigeminal system, in a preclinical model mimicking the pathophysiology of human migraine. PMID- 30419805 TI - SNP markers associated with body size and pelt length in American mink (Neovison vison). AB - BACKGROUND: Identification of genes underlying production traits is a key aim of the mink research community. Recent availability of genomic tools have opened the possibility for faster genetic progress in mink breeding. Availability of mink genome assembly allows genome-wide association studies in mink. RESULTS: In this study, we used genotyping-by-sequencing to obtain single nucleotide polymorphism (SNP) genotypes of 2496 mink. After multiple rounds of filtering, we retained 28,336 high quality SNPs and 2352 individuals for a genome-wide association study (GWAS). We performed the first GWAS for body weight, behavior, along with 10 traits related to fur quality in mink. CONCLUSIONS: Combining association results with existing functional information of genes and mammalian phenotype databases, we proposed WWC3, MAP2K4, SLC7A1 and USP22 as candidate genes for body weight and pelt length in mink. PMID- 30419807 TI - PIAS1 protects against myocardial ischemia-reperfusion injury by stimulating PPARgamma SUMOylation. AB - BACKGROUND: Myocardial ischemia-reperfusion injury (IRI) has become one of the most serious complications after reperfusion therapy in patients with acute myocardial infarction. Small ubiquitin-like modification (SUMOylation) is a reversible process, including SUMO E1-, E2-, and E3-mediated SUMOylation and SUMO specific protease-mediated deSUMOylation, with the latter having been shown to play a vital role in myocardial IRI previously. However, little is known about the function and regulation of SUMO E3 ligases in myocardial IRI. RESULTS: In this study, we found dramatically decreased expression of PIAS1 after ischemia/reperfusion (I/R) in mouse myocardium and H9C2 cells. PIAS1 deficiency aggravated apoptosis and inflammation of cardiomyocytes via activating the NF kappaB pathway after I/R. Mechanistically, we identified PIAS1 as a specific E3 ligase for PPARgamma SUMOylation. Moreover, H9C2 cells treated with hypoxia/reoxygenation (H/R) displayed reduced PPARgamma SUMOylation as a result of down-regulated PIAS1, and act an anti-apoptotic and anti-inflammatory function through repressing NF-kappaB activity. Finally, overexpression of PIAS1 in H9C2 cells could remarkably ameliorate I/R injury. CONCLUSIONS: Collectively, our findings demonstrate the crucial role of PIAS1-mediated PPARgamma SUMOylation in protecting against myocardial IRI. PMID- 30419808 TI - Effect of IAPP on the proteome of cultured Rin-5F cells. AB - BACKGROUND: Islet amyloid polypeptide (IAPP) or amylin deposits can be found in the islets of type 2 diabetes patients. The peptide is suggested to be involved in the etiology of the disease through formation of amyloid deposits and destruction of beta islet cells, though the underlying molecular events leading from IAPP deposition to beta cell death are still largely unknown. RESULTS: We used OFFGELTM proteomics to study how IAPP exposure affects the proteome of rat pancreatic insulinoma Rin-5F cells. The OFFGELTM methodology is highly effective at generating quantitative data on hundreds of proteins affected by IAPP, with its accuracy confirmed by In Cell Western and Quantitative Real Time PCR results. Combining data on individual proteins identifies pathways and protein complexes affected by IAPP. IAPP disrupts protein synthesis and degradation, and induces oxidative stress. It causes decreases in protein transport and localization. IAPP disrupts the regulation of ubiquitin-dependent protein degradation and increases catabolic processes. IAPP causes decreases in protein transport and localization, and affects the cytoskeleton, DNA repair and oxidative stress. CONCLUSIONS: Results are consistent with a model where IAPP aggregates overwhelm the ability of a cell to degrade proteins via the ubiquitin system. Ultimately this leads to apoptosis. IAPP aggregates may be also toxic to the cell by causing oxidative stress, leading to DNA damage or by decreasing protein transport. The reversal of any of these effects, perhaps by targeting proteins which alter in response to IAPP, may be beneficial for type II diabetes. PMID- 30419809 TI - WebNetCoffee: a web-based application to identify functionally conserved proteins from Multiple PPI networks. AB - BACKGROUND: The discovery of functionally conserved proteins is a tough and important task in system biology. Global network alignment provides a systematic framework to search for these proteins from multiple protein-protein interaction (PPI) networks. Although there exist many web servers for network alignment, no one allows to perform global multiple network alignment tasks on users' test datasets. RESULTS: Here, we developed a web server WebNetcoffee based on the algorithm of NetCoffee to search for a global network alignment from multiple networks. To build a series of online test datasets, we manually collected 218,339 proteins, 4,009,541 interactions and many other associated protein annotations from several public databases. All these datasets and alignment results are available for download, which can support users to perform algorithm comparison and downstream analyses. CONCLUSION: WebNetCoffee provides a versatile, interactive and user-friendly interface for easily running alignment tasks on both online datasets and users' test datasets, managing submitted jobs and visualizing the alignment results through a web browser. Additionally, our web server also facilitates graphical visualization of induced subnetworks for a given protein and its neighborhood. To the best of our knowledge, it is the first web server that facilitates the performing of global alignment for multiple PPI networks. AVAILABILITY: http://www.nwpu-bioinformatics.com/WebNetCoffee. PMID- 30419810 TI - The crowns have eyes: multiple opsins found in the eyes of the crown-of-thorns starfish Acanthaster planci. AB - BACKGROUND: Opsins are G protein-coupled receptors used for both visual and non visual photoreception, and these proteins evolutionarily date back to the base of the bilaterians. In the current sequencing age, phylogenomic analysis has proven to be a powerful tool, facilitating the increase in knowledge about diversity within the opsin subclasses and, so far, at least nine types of opsins have been identified. Within echinoderms, opsins have been studied in Echinoidea and Ophiuroidea, which do not possess proper image forming eyes, but rather widely dispersed dermal photoreceptors. However, most species of Asteroidea, the starfish, possess true eyes and studying them will shed light on the diversity of opsin usage within echinoderms and help resolve the evolutionary history of opsins. RESULTS: Using high-throughput RNA sequencing, we have sequenced and analyzed the transcriptomes of different Acanthaster planci tissue samples: eyes, radial nerve, tube feet and a mixture of tissues from other organs. At least ten opsins were identified, and eight of them were found significantly differentially expressed in both eyes and radial nerve, with R-opsin being the most highly expressed in the eye. CONCLUSION: This study provides new important insight into the involvement of opsins in visual and nonvisual photoreception. Of relevance, we found the first indication of an r-opsin photopigment expressed in a well developed visual eye in a deuterostome animal. Additionally, we provided tissue specific A. planci transcriptomes that will aid in future Evo Devo studies. PMID- 30419811 TI - Identification and validation of QTL and their associated genes for pre-emergent metribuzin tolerance in hexaploid wheat (Triticum aestivum L.). AB - BACKGROUND: Herbicide tolerance is an important trait that allows effective weed management in wheat crops. Genetic knowledge of metribuzin tolerance in wheat is needed to develop new cultivars for the industry. Here, we evaluated metribuzin tolerance in a recombinant inbred line (RIL) mapping population derived from Synthetic W7984 and Opata 85 over two consecutive years to identify quantitative trait loci (QTL) contributing to the trait. Herbicide tolerance was measured by two chlorophyll traits, SPAD chlorophyll content index (CCI) and visual senescence score (SNS). The markers associated with major QTL from Synthetic W7984, positively contributing to reduced phytotoxic effects under herbicide treatment were validated in two F3/4 recombinant inbred populations developed from crosses of Synthetic W7984 * Westonia and Synthetic W7984 * Lang. RESULTS: Composite interval mapping (CIM) identified four QTL, two on chromosome 4A and one each on chromosomes 2D and 1A. The chromosomal position of the two QTL mapped on 4A within 10 cM intervals was refined and validated by multiple interval mapping (MIM). The major QTL affecting both measures of tolerance jointly explained 42 and 45% of the phenotypic variation by percentage CCI reduction and SNS, respectively. The identified QTL have a pure additive effect. The metribuzin tolerant allele of markers, Xgwm33 and Xbarc343, conferred lower phytotoxicity and explained the maximum phenotypic variation of 28.8 and 24.5%, respectively. The approximate physical localization of the QTL revealed the presence of five candidate genes (ribulose-bisphosphate carboxylase, oxidoreductase (rbcS), glycosyltransferase, serine/threonine-specific protein kinase and phosphotransferase) with a direct role in photosynthesis and/or metabolic detoxification pathways. CONCLUSION: Metribuzin causes photo-inhibition by interrupting electron flow in PSII. Consequently, chlorophyll traits enabled the measure of high proportion of genetic variability in the mapping population. The validated molecular markers associated with metribuzin tolerance mediating QTL may be used in marker-assisted breeding to select metribuzin tolerant lines. Alternatively, validated favourable alleles could be introgressed into elite wheat cultivars to enhance metribuzin tolerance and improve grain yield in dryland farming for sustainable wheat production. PMID- 30419812 TI - Characterization of Streptococcus pluranimalium from a cattle with mastitis by whole genome sequencing and functional validation. AB - BACKGROUND: Streptococcus pluranimalium is a new member of the Streptococcus genus isolated from multiple different animal hosts. It has been identified as a pathogen associated with subclinical mastitis, valvular endocarditis and septicaemia in animals. Moreover, this bacterium has emerged as a new pathogen for human infective endocarditis and brain abscess. However, the patho-biological properties of S. pluranimalium remain virtually unknown. The aim of this study was to determine the complete genome sequence of S. pluranimalium strain TH11417 isolated from a cattle with mastitis, and to characterize its antimicrobial resistance, virulence, and carbon catabolism. RESULTS: The genome of S. pluranimalium TH11417, determined by single-molecule real-time (SMRT) sequencing, consists of 2,065,522 base pair (bp) with a G + C content of 38.65%, 2,007 predicted coding sequence (CDS), 58 transfer RNA (tRNA) genes and five ribosome RNA (rRNA) operons. It contains a novel ISSpl1 element (a memeber of the IS3 family) and a F11417.1 prophage that carries the mef(A), msr(D) and lnu(C) genes. Consistently, our antimicrobial susceptibility test confirmed that S. pluranimalium TH11417 was resistant to erythromycin and lincomycin. However, this strain did not show virulence in murine pneumonia (intranasal inoculation, 107 colony forming unit - CFU) and sepsis (intraperitoneal inoculation, 107 CFU) models. Additionally, this strain is able to grow with glucose, lactose or galactose as the sole carbon source, and possesses a lactose-specific phosphoenolpyruvate-dependent phosphotransferase system (PTS). CONCLUSIONS: We reported the first whole genome sequence of S. pluranimalium isolated from a cattle with mastitis. It harbors a prophage carrying the mef(A), msr(D) and lnu(C) genes, and is avirulent in the murine infection model. PMID- 30419814 TI - Abstracts of the 6th Meeting of the Neapolitan Brain Group. PMID- 30419813 TI - The validation of the Hungarian version of the ID-migraine questionnaire. AB - BACKGROUND: Despite its high prevalence, migraine remains underdiagnosed and undertreated. ID-Migraine is a short, self-administrated questionnaire, originally developed in English by Lipton et al. and later validated in several languages. Our goal was to validate the Hungarian version of the ID-Migraine Questionnaire. METHODS: Patients visiting two headache specialty services were enrolled. Diagnoses were made by headache specialists according to the ICHD-3beta diagnostic criteria. There were 309 clinically diagnosed migraineurs among the 380 patients. Among the 309 migraineurs, 190 patients had only migraine, and 119 patients had other headache beside migraine, namely: 111 patients had tension type headache, 3 patients had cluster headache, 4 patients had medication overuse headache and one patient had headache associated with sexual activity also. Among the 380 patients, 257 had only a single type headache whereas 123 patients had multiple types of headache. Test-retest reliability of the ID-Migraine Questionnaire was studied in 40 patients. RESULTS: The validity features of the Hungarian version of the ID-Migraine questionnaire were the following: sensitivity 0.95 (95% CI, 0.92-0.97), specificity 0.42 (95% CI, 0.31-0.55), positive predictive value 0.88 (95% CI, 0.84-0.91), negative predictive value 0.65 (95% CI, 0.5-0.78), missclassification error 0.15 (95% CI, 0.12-0.19). The kappa coefficient of the questionnaire was 0.77. CONCLUSION: The Hungarian version of the ID-Migraine Questionnaire had adequate sensitivity, positive predictive value and misclassification error, but a low specificity and somewhat low negative predictive value. PMID- 30419815 TI - Double maternal-effect: duplicated nucleoplasmin 2 genes, npm2a and npm2b, with essential but distinct functions are shared by fish and tetrapods. AB - BACKGROUND: Nucleoplasmin 2 (npm2) is an essential maternal-effect gene that mediates early embryonic events through its function as a histone chaperone that remodels chromatin. Recently, two npm2 (npm2a and npm2b) genes have been annotated in zebrafish. Thus, we examined the evolution of npm2a and npm2b in a variety of vertebrates, their potential phylogenetic relationships, and their biological functions using knockout models via the CRISPR/cas9 system. RESULTS: We demonstrated that the two npm2 duplicates exist in a wide range of vertebrates, including sharks, ray-finned fish, amphibians, and sauropsids, while npm2a was lost in coelacanth and mammals, as well as some specific teleost lineages. Using phylogeny and synteny analyses, we traced their origins to the early stages of vertebrate evolution. Our findings suggested that npm2a and npm2b resulted from an ancient local gene duplication, and their functions diverged although key protein domains were conserved. We then investigated their functions by examining their tissue distribution in a wide variety of species and found that they shared ovarian-specific expression, a key feature of maternal-effect genes. We also demonstrated that both npm2a and npm2b are maternally-inherited transcripts in vertebrates, and that they play essential, but distinct, roles in early embryogenesis using zebrafish knockout models. Both npm2a and npm2b function early during oogenesis and may play a role in cortical granule function that impact egg activation and fertilization, while npm2b is also involved in early embryogenesis. CONCLUSION: These novel findings will broaden our knowledge on the evolutionary history of maternal-effect genes and underlying mechanisms that contribute to vertebrate reproductive success. In addition, our results demonstrate the existence of a newly described maternal-effect gene, npm2a, that contributes to egg competence, an area that still requires further comprehension. PMID- 30419816 TI - Novel insights into the genetic basis of buffalo reproductive performance. AB - BACKGROUND: Fertility is a complex trait that has a major impact on the development of the buffalo industry. Genome-wide association study (GWAS) has increased the ability to detect genes influencing complex traits, and many important genes related to reproductive traits have been identified in ruminants. However, reproductive traits are influenced by many factors. The development of the follicle is one of the most important internal processes affecting fertility. Genes found by GWAS to be associated with follicular development may directly affect fertility. The present study combined GWAS and RNA-seq of follicular granulosa cells to identify important genes which may affect fertility in the buffalo. RESULTS: The 90 K Affymetrix Axiom Buffalo SNP Array was used to identify the SNPs, genomic regions, and genes that were associated with reproductive traits. A total of 40 suggestive loci (related to 28 genes) were identified to be associated with six reproductive traits (first, second and third calving age, calving interval, the number of services per conception and open days). Interestingly, the mRNA expressions of 25 of these genes were also observed in buffalo follicular granulosa cells. The IGFBP7 gene showed high level of expression during whole antral follicle growth. The knockdown of IGFBP7 in buffalo granulosa cells promoted cell apoptosis and hindered cell proliferation, and increased the production of progesterone and estradiol. Furthermore, a notable signal was detected at 2.3-2.7 Mb on the equivalent of bovine chromosome 5 associated with age at second calving, calving interval, and open days. CONCLUSIONS: The genes associated with buffalo reproductive traits in this study may have effect on fertility by regulating of follicular growth. These results may have important implications for improving buffalo breeding programs through application of genomic information. PMID- 30419817 TI - Patient-centred access to health care: a framework analysis of the care interface for frail older adults. AB - BACKGROUND: The objective of this study was to explore the issues surrounding access to health and social care services for frail older adults with Polish stakeholders, including healthy and frail/pre-frail older adults, health care providers, social care providers, and caregivers, in order to determine their views and perspectives on the current system and to present suggestions for the future development of a more accessible and person-centred health and social care system. METHODS: Focus groups were used to gather qualitative data from stakeholders. Data were analysed using framework analysis according to five dimensions of accessibility to care: approachability, acceptability, availability and accommodation, affordability and appropriateness. RESULTS: Generally services were approachable and acceptable, but unavailable. Poor availability related to high staff turnover, staff shortages and a lack of trained personnel. There were problems of long waiting times for specialist care and rehabilitation services, and geographically remote clinics. Critically, there were shortages of long-term inpatient care places, social care workers and caregivers. The cost of treatments created barriers to care and inequities in the system. Participants described a lack of integration between health and social care systems with differing priorities and disconnected budgets. They described an acute medical system that was inappropriate for patients with complex needs, alongside a low functioning social care system, where bureaucratisation caused delays in providing services to the vulnerable. An integrated system with a care coordinator to improve connections between services and patients was suggested. CONCLUSIONS: There is an immediate need to improve access to health and social care systems for pre-frail and frail patients, as well as their caregivers. Health and social care services need to be integrated to reduce bureaucracy and increase the timeliness of treatment and care. PMID- 30419818 TI - Novel human monoclonal antibodies targeting the F subunit of leukocidins reduce disease progression and mortality caused by Staphylococcus aureus. AB - BACKGROUND: Staphylococcus aureus is a leading cause of Gram-positive bacterial infections worldwide; however, the treatment of S. aureus infection has become increasingly difficult due to the prevalence of methicillin-resistant S. aureus strains, highlighting the urgent need for the development of novel strategies. The complexity of S. aureus pathogenesis relies on virulence factors. Recent studies have demonstrated that leukocidins expressed by the majority of clinical isolates play important roles in the pathogenesis of S. aureus. RESULTS: In this study, we developed three human monoclonal antibodies against all F-components of leukocidins HlgABC, LukSF, and LukED with high affinity. These antibodies were found to be capable of blocking leukocidin-mediated cell lysis in vitro. Furthermore, the antibodies dramatically reduced disease progression and mortality after S. aureus infection in vivo. CONCLUSIONS: Our findings revealed that neutralizing bicomponent leukocidins may be a promising strategy to combat infections caused by S. aureus. PMID- 30419819 TI - "You've got to look after yourself, to be able to look after them" a qualitative study of the unmet needs of caregivers of community based primary health care patients. AB - BACKGROUND: There is growing reliance on unpaid caregivers to provide support to people with care needs. Integrated care approaches that aim to coordinate primary care with community care known as community based primary health care (CBPHC) has been a key policy initiative across health systems; however most attention has been paid to the needs of patients and not caregivers. The objective of this paper was to explore the unmet needs of caregivers of older adults with complex care needs receiving CBPHC. METHODS: This qualitative descriptive study entailed one-to-one interviews with 80 caregivers from Canada and New Zealand where roles, experiences and needs were explored. Interview text related to unmet need was reviewed inductively and core themes identified. RESULTS: Three themes were identified across CBPHC sites: unrecognized role; lack of personal resources; and no breaks even when services are in place. CONCLUSIONS: To support caregivers, models of care such as CBPHC need to look beyond the patient to meaningfully engage caregivers, address their needs and recognize the insight they hold. This knowledge needs to be valued as a key source of evidence to inform developments in health and social care. PMID- 30419820 TI - Chemical fingerprinting of single glandular trichomes of Cannabis sativa by Coherent anti-Stokes Raman scattering (CARS) microscopy. AB - BACKGROUND: Cannabis possesses a rich spectrum of phytochemicals i.e. cannabinoids, terpenes and phenolic compounds of industrial and medicinal interests. Most of these high-value plant products are synthesised in the disk cells and stored in the secretory cavity in glandular trichomes. Conventional trichome analysis was so far based on optical microscopy, electron microscopy or extraction based methods that are either limited to spatial or chemical information. Here we combine both information to obtain the spatial distribution of distinct secondary metabolites on a single-trichome level by applying Coherent anti-Stokes Raman scattering (CARS), a microspectroscopic technique, to trichomes derived from sepals of a drug- and a fibre-type. RESULTS: Hyperspectral CARS imaging in combination with a nonlinear unmixing method allows to identify and localise Delta9-tetrahydrocannabinolic acid (THCA) in the secretory cavity of drug-type trichomes and cannabidiolic acid (CBDA)/myrcene in the secretory cavity of fibre-type trichomes, thus enabling an easy discrimination between high-THCA and high-CBDA producers. A unique spectral fingerprint is found in the disk cells of drug-type trichomes, which is most similar to cannabigerolic acid (CBGA) and is not found in fibre-type trichomes. Furthermore, we differentiate between different cell types by a combination of CARS with simultaneously acquired two photon fluorescence (TPF) of chlorophyll a from chloroplasts and organic fluorescence mainly arising from cell walls enabling 3D visualisation of the essential oil distribution and cellular structures. CONCLUSION: Here we demonstrate a label-free and non-destructive method to analyse the distribution of secondary metabolites and distinguish between different cell and chemo-types with high spatial resolution on a single trichome. The record of chemical fingerprints of single trichomes offers the possibility to optimise growth conditions as well as guarantee a direct process control for industrially cultivated medicinal Cannabis plants. Moreover, this method is not limited to Cannabis related issues but can be widely implemented for optimising and monitoring all kinds of natural or biotechnological production processes with simultaneous spatial and chemical information. PMID- 30419821 TI - RRAD, IL4I1, CDKN1A, and SERPINE1 genes are potentially co-regulated by NF-kappaB and p53 transcription factors in cells exposed to high doses of ionizing radiation. AB - BACKGROUND: The cellular response to ionizing radiation involves activation of p53-dependent pathways and activation of the atypical NF-kappaB pathway. The crosstalk between these two transcriptional networks include (co)regulation of common gene targets. Here we looked for novel genes potentially (co)regulated by p53 and NF-kappaB using integrative genomics screening in human osteosarcoma U2 OS cells irradiated with a high dose (4 and 10 Gy). Radiation-induced expression in cells with silenced TP53 or RELA (coding the p65 NF-kappaB subunit) genes was analyzed by RNA-Seq while radiation-enhanced binding of p53 and RelA in putative regulatory regions was analyzed by ChIP-Seq, then selected candidates were validated by qPCR. RESULTS: We identified a subset of radiation-modulated genes whose expression was affected by silencing of both TP53 and RELA, and a subset of radiation-upregulated genes where radiation stimulated binding of both p53 and RelA. For three genes, namely IL4I1, SERPINE1, and CDKN1A, an antagonistic effect of the TP53 and RELA silencing was consistent with radiation-enhanced binding of both p53 and RelA. This suggested the possibility of a direct antagonistic (co)regulation by both factors: activation by NF-kappaB and inhibition by p53 of IL4I1, and activation by p53 and inhibition by NF-kappaB of CDKN1A and SERPINE1. On the other hand, radiation-enhanced binding of both p53 and RelA was observed in a putative regulatory region of the RRAD gene whose expression was downregulated both by TP53 and RELA silencing, which suggested a possibility of direct (co)activation by both factors. CONCLUSIONS: Four new candidates for genes directly co-regulated by NF-kappaB and p53 were revealed. PMID- 30419822 TI - Modulation of auxin and cytokinin responses by early steps of the phenylpropanoid pathway. AB - BACKGROUND: The phenylpropanoid pathway is responsible for the synthesis of numerous compounds important for plant growth and responses to the environment. In the first committed step of phenylpropanoid biosynthesis, the enzyme phenylalanine ammonia-lyase (PAL) deaminates L-phenylalanine into trans-cinnamic acid that is then converted into p-coumaric acid by cinnamate-4-hydroxylase (C4H). Recent studies showed that the Kelch repeat F-box (KFB) protein family of ubiquitin ligases control phenylpropanoid biosynthesis by promoting the proteolysis of PAL. However, this ubiquitin ligase family, alternatively named Kiss Me Deadly (KMD), was also implicated in cytokinin signaling as it was shown to promote the degradation of type-B ARRs, including the key response activator ARR1. Considering that ubiquitin ligases typically have narrow target specificity, this dual targeting of structurally and functionally unrelated proteins appeared unusual. RESULTS: Here we show that the KFBs indeed target PAL but not ARR1. Moreover, we show that changes in early phenylpropanoid biosynthesis alter cytokinin sensitivity - as reported earlier - but that the previously documented cytokinin growth response changes are primarily the result of altered auxin signaling. We found that reduced PAL accumulation decreased, whereas the loss of C4H function increased the strength of the auxin response. The combined loss of function of both enzymes led to a decrease in auxin sensitivity, indicating that metabolic events upstream of C4H control auxin sensitivity. This auxin/phenylpropanoid interaction impacts both shoot and root development and revealed an auxin-dependent stimulatory effect of trans-cinnamic acid feeding on leaf expansion and thus biomass accumulation. CONCLUSIONS: Collectively, our results show that auxin-regulated plant growth is fine-tuned by early steps in phenylpropanoid biosynthesis and suggest that metabolites accumulating upstream of the C4H step impact the auxin response mechanism. PMID- 30419823 TI - Downregulation of calcium-dependent NMDA receptor desensitization by sodium calcium exchangers: a role of membrane cholesterol. AB - BACKGROUND: The plasma membrane Na+/Ca2+-exchanger (NCX) has recently been shown to regulate Ca2+-dependent N-methyl-D-aspartate receptor (NMDAR) desensitization, suggesting a tight interaction of NCXs and NMDARs in lipid nanoclasters or "rafts". To evaluate possible role of this interaction we studied effects of Li+ on NMDA-elicited whole-cell currents and Ca2+ responses of rat cortical neurons in vitro before and after cholesterol extraction by methyl-beta-cyclodextrin (MbetaCD). RESULTS: Substitution Li+ for Na+ in the external solution caused a concentration-dependent decrease of steady-state NMDAR currents from 440 +/- 71 pA to 111 +/- 29 pA in 140 mM Na+ and 140 mM Li+, respectively. The Li+ inhibition of NMDAR currents disappeared in the absence of Ca2+ in the external solution (Ca2+-free), suggesting that Li+ enhanced Ca2+-dependent NMDAR desensitization. Whereas the cholesterol extraction with MbetaCD induced a decrease of NMDAR currents to 136 +/- 32 pA in 140 mM Na+ and 46 +/- 15 pA in 140 mM Li+, the IC50 values for the Li+ inhibition were similar (about 44 mM Li+) before and after this procedure. In the Ca2+-free Na+ solution the steady-state NMDAR currents after the cholesterol extraction were 47 +/- 6% of control values. Apparently this amplitude decrease was not Ca2+-dependent. In the Na+ solution containing 1 mM Ca2+ the Ca2+-dependent NMDAR desensitization was greater when cholesterol was extracted. Obviously, this procedure promoted its development. In agreement, Li+ and KB-R7943, an inhibitor of NCX, both considerably reduced NMDA activated Ca2+ responses. The cholesterol extraction itself caused a decrease of NMDA-activated Ca2+ responses and, in addition, abolished the effects of Li+ and KB-R7943. The cholesterol loading into the plasma membrane caused a recovery of the KB-R7943 effects. CONCLUSIONS: Taken together our data suggest that NCXs downregulate the Ca2+-dependent NMDAR desensitization. Most likely, this is determined by a tight functional interaction of NCX and NMDAR molecules because of their co-localization in membrane lipid rafts. The destruction of these rafts is accompanied by an enhancement of NMDAR desensitization and a loss of NCX selective agent effects on NMDARs. PMID- 30419824 TI - Transcriptome analysis of human heart failure reveals dysregulated cell adhesion in dilated cardiomyopathy and activated immune pathways in ischemic heart failure. AB - BACKGROUND: Current heart failure (HF) treatment is based on targeting symptoms and left ventricle dysfunction severity, relying on a common HF pathway paradigm to justify common treatments for HF patients. This common strategy may belie an incomplete understanding of heterogeneous underlying mechanisms and could be a barrier to more precise treatments. We hypothesized we could use RNA-sequencing (RNA-seq) in human heart tissue to delineate HF etiology-specific gene expression signatures. RESULTS: RNA-seq from 64 human left ventricular samples: 37 dilated (DCM), 13 ischemic (ICM), and 14 non-failing (NF). Using a multi-analytic approach including covariate adjustment for age and sex, differentially expressed genes (DEGs) were identified characterizing HF and disease-specific expression. Pathway analysis investigated enrichment for biologically relevant pathways and functions. DCM vs NF and ICM vs NF had shared HF-DEGs that were enriched for the fetal gene program and mitochondrial dysfunction. DCM-specific DEGs were enriched for cell-cell and cell-matrix adhesion pathways. ICM-specific DEGs were enriched for cytoskeletal and immune pathway activation. Using the ICM and DCM DEG signatures from our data we were able to correctly classify the phenotypes of 24/31 ICM and 32/36 DCM samples from publicly available replication datasets. CONCLUSIONS: Our results demonstrate the commonality of mitochondrial dysfunction in end-stage HF but more importantly reveal key etiology-specific signatures. Dysfunctional cell-cell and cell-matrix adhesion signatures typified DCM whereas signals related to immune and fibrotic responses were seen in ICM. These findings suggest that transcriptome signatures may distinguish end-stage heart failure, shedding light on underlying biological differences between ICM and DCM. PMID- 30419825 TI - Improvement in tuberculosis infection control practice via technical support in two regions of Ethiopia. AB - BACKGROUND: Globally recommended measures for comprehensive tuberculosis (TB) infection control (IC) are inadequately practiced in most health care facilities in Ethiopia. The aim of this study was to assess the extent of implementation of TB IC measures before and after introducing a comprehensive technical support package in two regions of Ethiopia. METHODS: We used a quasi-experimental design, whereby a baseline assessment of TB IC practices in 719 health care facilities was conducted between August and October 2013. Based on the assessment findings, we supported implementation of a comprehensive package of interventions. Monitoring was done on a quarterly basis, and one-year follow-up data were collected on September 30, 2014. We used the Student's t-test and chi-squared tests, respectively, to examine differences before and after the interventions and to test for inter-regional and inter-facility associations. RESULTS: At baseline, most of the health facilities (69%) were reported to have separate TB clinics. In 55.2% of the facilities, it was also reported that window opening was practiced. Nevertheless, triaging was practiced in only 19.3% of the facilities. Availability of an IC committee and IC plan was observed in 29.11 and 4.65% of facilities, respectively. Health care workers were nearly three times as likely to develop active TB as the general population. After 12 months of implementation, availability of a separate TB room, TB IC committee, triage, and TB IC plan had increased, respectively, by 18, 32, 44, and 51% (p < 0.001). CONCLUSIONS: After 1 year of intervention, the TB IC practices of the health facilities have significantly improved. However, availability of separate TB rooms and existence of TB IC committees remain suboptimal. The burden of TB among health care workers is higher than in the general population. TB IC measures must be strengthened to reduce TB transmission among health workers. PMID- 30419826 TI - General control non-repressible 20 (GCN20) functions in root growth by modulating DNA damage repair in Arabidopsis. AB - BACKGROUND: Most ABC transporters are engaged in transport of various compounds, but its subfamily F lacks transmembrane domain essential for chemical transportation. Thus the function of subfamily F remains further elusive. RESULTS: Here, we identified General Control Non-Repressible 20 (GCN20), a member of subfamily F, as new factor for DNA damage repair in root growth. While gcn20-1 mutant had a short primary root with reduced meristem size and cell number, similar primary root lengths were assayed in both wild-type and GCN20::GCN20 gcn20-1 plants, indicating the involvement of GCN20 in root elongation. Further experiments with EdU incorporation and comet assay demonstrated that gcn20-1 displays increased cell cycle arrest at G2/M checkpoint and accumulates more damaged DNA. This is possible due to impaired ability of DNA repair in gcn20-1 since gcn20-1 seedlings are hypersensitive to DNA damage inducers MMC and MMS compared with the wild type plants. This note was further supported by the observation that gcn20-1 is more sensitive than the wild type when subjected to UV treatment in term of changes of both fresh weight and survival rate. CONCLUSIONS: Our study indicates that GCN20 functions in primary root growth by modulating DNA damage repair in Arabidopsis. Our study will be useful to understand the functions of non-transporter ABC proteins in plant growth. PMID- 30419827 TI - Hypothesis testing in Bayesian network meta-analysis. AB - BACKGROUND: Network meta-analysis is an extension of the classical pairwise meta analysis and allows to compare multiple interventions based on both head-to-head comparisons within trials and indirect comparisons across trials. Bayesian or frequentist models are applied to obtain effect estimates with credible or confidence intervals. Furthermore, p-values or similar measures may be helpful for the comparison of the included arms but related methods are not yet addressed in the literature. In this article, we discuss how hypothesis testing can be done in a Bayesian network meta-analysis. METHODS: An index is presented and discussed in a Bayesian modeling framework. Simulation studies were performed to evaluate the characteristics of this index. The approach is illustrated by a real data example. RESULTS: The simulation studies revealed that the type I error rate is controlled. The approach can be applied in a superiority as well as in a non inferiority setting. CONCLUSIONS: Test decisions can be based on the proposed index. The index may be a valuable complement to the commonly reported results of network meta-analyses. The method is easy to apply and of no (noticeable) additional computational cost. PMID- 30419828 TI - Subgroups of lifestyle patterns among hypertension patients: a latent-class analysis. AB - BACKGROUND: Hypertension remains one of the most important preventable risk factors for diseases and death. Identifying clustered patterns of modifiable lifestyle risk factors for hypertension and demographics factors related to these clustered patterns allows for targeting health prevention interventions. Therefore, this study aims to identify latent classes of hypertensive patients' lifestyle risk factors based on the clustering of four modifiable lifestyle risk factors: eating, physical activity patterns, smoking habits, and blood pressure control. METHODS: A total of 750 patients (Mage = 65.38 years, SDage = 9.2 years) with diagnosed hypertension in urban and rural primary health care centers in Takab (Iran) were recruited randomly from August 2016 to February 2017. Latent class analysis was performed by using proc. LCA in SAS 9.2. RESULTS: Three classes of lifestyle patterns were identified. About 14.4% of hypertensive patients were categorized in a low-risk class (I), 54.6% in an intermediate-risk class (II), and 31% in a high-risk class (III) of lifestyle. A one-year increase in age significantly increases the risk of membership in classes II and III. Similarly, being widowed or divorced increases the risk of membership in classes II and III. Also, having a higher education level decreases the risk of membership in classes II and III. CONCLUSIONS: This study contributes to the literature on lifestyle behaviors among older adults and provides evidence that there are considerable differences in lifestyle behaviors between subgroups of older adult patients. The three profiles of hypertensive patients' conditions suggest that because behaviors often occur simultaneously within an individual level, a latent-class approach helps cluster co-occurrence risk behaviors and focuses on interventions targeted to several healthy behaviors among high-risk patients. PMID- 30419829 TI - Natural variation in tolerance to sub-zero temperatures among populations of Arabidopsis lyrata ssp. petraea. AB - BACKGROUND: Temperature is one of the most important abiotic factors limiting plant growth and productivity. Many plants exhibit cold acclimation to prepare for the likelihood of freezing as temperatures decrease towards 0 degrees C. The physiological mechanisms associated with enabling increased tolerance to sub-zero temperatures vary between species and genotypes. Geographically and climatically diverse populations of Arabidopsis lyrata ssp. petraea were examined for their ability to survive, maintain functional photosynthetic parameters and cellular electrolyte leakage integrity after being exposed to sub-zero temperatures. The duration of cold acclimation prior to sub-zero temperatures was also manipulated (2 and 14 days). RESULTS: We found that there was significant natural variation in tolerances to sub-zero temperatures among populations of A. petraea. The origin of the population affected the acclimation response and survival after exposure to sub-zero temperatures. Cold acclimation of plants prior to sub-zero temperatures affected the maximum quantum efficiency of photosystem II (PSII) (Fv/Fm) in that plants that were cold acclimated for longer periods had higher values of Fv/Fm as a result of sub-zero temperatures. The inner immature leaves were better able to recover Fv/Fm from sub-zero temperatures than mature outer leaves. The Irish population (Leitrim) acclimated faster, in terms of survival and electrolyte leakage than the Norwegian population (Helin). CONCLUSION: The ability to survive, recover photosynthetic processes and cellular electrolyte leakage after exposure to sub-zero temperatures is highly dependent on the duration of cold acclimation. PMID- 30419830 TI - Clinical characteristics of hepatic Arterioportal shunts associated with hepatocellular carcinoma. AB - BACKGROUND: Hepatic arterioportal shunt (A-P shunt) is defined as the direct blood flow established between hepatic artery and portal venous system; it is frequently observed in patients with hepatocellular carcinoma (HCC). Clinically, it is important to diagnose HCC associated A-P shunts, as it may impact the treatment strategy of the patients. In the present study, we described the imaging findings of the HCC associated A-P shunts and discussed the treatments strategy of such patients. From the findings, we also discussed the potential cause of A-P shunts. METHODS: Clinical data of HCC patients (n = 560), admitted to the hospital between April 2012 to April 2014, were reviewed. Hepatic angiography was used to examine the presence of A-P shunts. Of the 137 patients with A-P shunts, grading of the A-P shunts was performed, and statistical analysis of the different grades of A-P shunts and clinical characteristics was performed. RESULTS: The hepatic angiography confirmed that 99 patients had typical A-P shunts (Grade 1-3), and 38 patients had atypical A-P shunts. Embolization was the main strategy used to treat A-P shunts, in which liquid embolic agents appeared to provide a better treatment outcome. The correlation analysis showed that the grading of portal vein tumor thrombus was significantly associated with the grading of A-P shunt (p = < 0.001, Spearman correlation coefficient was 0.816 +/- 0.043). CONCLUSIONS: We characterized A-P shunts and proposed treatment strategy for treating HCC patients with various levels of A-P shunts. The findings supported the hypothesis that the formation of HCC associated A-P shunts was caused by tumor thrombus. PMID- 30419831 TI - Development of novel EST-SSR markers in the macauba palm (Acrocomia aculeata) using transcriptome sequencing and cross-species transferability in Arecaceae species. AB - BACKGROUND: The macauba palm is a novel feedstock for oil production suitable for multiple uses, including as biodiesel and in the food and cosmetic industries. As an efficient alternative, the macauba palm has limited genomic resources, particularly expressed sequence tag (EST) markers. We report a comprehensive set of validated EST-simple sequence repeat (SSR) markers by using transcriptome sequencing, its application in genetic diversity analysis and cross transferability in other palm trees with environmental and economic importance. RESULTS: In this study, a total of 418 EST-SSRs were identified to be unique for one transcript and region; 232 EST-SSRs were selected, with trinucleotide repeats being the most frequent motif, representing 380 (90.9%), followed by composited (4.5%), di- (3.6%), and hexanucleotides (3.6%). A total of 145 EST-SSRs (62.5%) were validated for consistent amplification in seventeen macauba palm samples, and 100 were determined to be polymorphic with PIC values ranging from 0.25 to 0.77. Genetic diversity analysis was performed with the 20 most informative EST SSR markers showing a distinct separation of the different groups of macauba palm. Additionally, these 145 markers were transferred in six other palm species resulting in transferability rates of 99% (144) in Acrocomia intumescens, 98% (143) in Acrocomia totai, 80.7% (117 EST-EST) in African oil palm (Elaeis guineensis) and peach palm (Bactris gasipaes) samples, 70% (102) in the jucara palm (Euterpe edulis) and 71.7% (104) in the hat palm (Sabal causiarum). Analysis of genetic distance showed a high separation in accordance with geographic location, establishing distinct groups by genera. CONCLUSIONS: The EST markers identified in our study are a valuable resource and provide a genomic tool for genetic mapping and further genetic studies, as well as evaluation of co-location between QTLs and functionally associated markers. PMID- 30419832 TI - Surgical outcomes of infectious spondylitis after vertebroplasty, and comparisons between pyogenic and tuberculosis. AB - BACKGROUND: Infection after vertebroplasty (VP) is a rare but serious complication. Previous literatures showed most pathogens for infection after VP were bacteria; tuberculosis (TB) induced infection after VP was extremely rare. We reported our treatment experiences of cases with infectious spondylitis after VP, and compared the differences between developed pyogenic and TB spondylitis. METHODS: From January 2001 to December 2015, 5749 patients had undergone VP at our department were reviewed retrospectively. The causative organisms were obtained from tissue culture of revision surgery. Parameters including type of surgery, the interval between VP and revision surgery, neurologic status, and visual analog scale (VAS) of back pain were recorded. Laboratory data at the time of VP and revision surgery were collected. Charlson comorbidity index (CCI), preoperative bacteremia, urinary tract infection (UTI), pulmonary TB history were also analyzed. RESULTS: Eighteen patients were confirmed with developed infectious spondylitis after VP (0.32%, 18/5749). Two were male and 16 were female. The median age at VP was 73.4 years. Nine patients were TB and the other nine patients were pyogenic. The interval between VP and revision surgery ranged from 7 to 1140 days (mean 123.2 days). The most common type of revision surgery was anterior combined with posterior surgery. Seven patients developed neurologic deficit before revision surgery. Three patients died within 6 months after revision surgery, with a mortality of 16.7%. Finally, VAS of back pain was improved from 7.4 to 3.1. Seven patients could walk normally, the other 8 patients had some degree of disability. Both pyogenic and TB group had similar age, sex, and CCI distribution. The interval between VP and revision surgery was shorter in the patients with pyogenic organisms (75.9 vs 170.6 days). At revision surgery, WBC and CRP were prominently elevated in the pyogenic group. Five in the pyogenic group had UTI and bacteremia; five in TB group had a history of lung TB. CONCLUSIONS: Infection spondylitis after VP required major surgery for salvage with a relevant part of residual disability. Before VP, any bacteremia/UTI or history of pulmonary TB should be reviewed rigorously; any elevation of infection parameters should be scrutinized strictly. PMID- 30419833 TI - Soluble fibrinogen-like protein 2 levels in patients with hepatitis B virus related liver diseases. AB - BACKGROUND: Clinical progression of HBV-related liver diseases is largely associated with the activity of HBV-specific T cells. Soluble fibrinogen-like protein 2 (sFGL2), mainly secreted by T cells, is an important effector molecule of the immune system. METHODS: sFGL2 levels were determined by ELISA assays in sera of 296 HBV patients clinically classified into the subgroups of acute hepatitis B (AHB), chronic hepatitis B (CHB), liver cirrhosis (LC), hepatocellular carcinoma (HCC) and patients with LC plus HCC. As control group, 158 healthy individuals were included. FGL2 mRNA was quantified by qRT-PCR in 32 pairs of tumor and adjacent non-tumor liver tissues. RESULTS: sFGL2 levels were elevated in HBV patients compared to healthy controls (P < 0.0001). In the patient group, sFGL2 levels were increased in AHB compared to CHB patients (P = 0.017). sFGL2 levels were higher in LC patients compared to those without LC (P = 0.006) and were increased according to the development of cirrhosis as staged by Child-Pugh scores (P = 0.024). Similarly, HCC patients had increased sFGL2 levels compared to CHB patients (P = 0.033) and FGL2 mRNA was up-regulated in tumor tissues compared to adjacent non-tumor tissues (P = 0.043). In addition, sFGL2 levels were positively correlated with HBV-DNA loads and AST (Spearman's rho = 0.21, 0.25 and P = 0.006, 0.023, respectively), but reversely correlated with platelet counts and albumin levels (Spearman's rho = - 0.27, - 0.24 and P = 0.014, 0.033, respectively). CONCLUSIONS: sFGL2 levels are induced by HBV infection and correlated with the progression and clinical outcome of HBV-related liver diseases. Thus, sFGL2 may serve as a potential indicator for HBV-related liver diseases. PMID- 30419834 TI - Clinical and genetic factors associated with increased risk of severe liver toxicity in a monocentric cohort of HIV positive patients receiving nevirapine based antiretroviral therapy. AB - BACKGROUND: Nevirapine has been used as antiretroviral agent since early '90. Although nevirapine is not currently recommended in initial anti-HIV regimens, its use remains consistent in a certain number of HIV-1-positive subjects. Thus, our aim was to determine clinical and genetic factors involved in the development of severe nevirapine induced liver toxicity. METHODS: We retrospectively analyzed all HIV positive patients who were followed at the Infectious Diseases Unit, DIBIC Luigi Sacco, University of Milan from May 2011 to December 2015. All patients treated with nevirapine who underwent a genotyping for the functional variants mapping into ABCB1, CYP2B6, CYP3A4 and CYP3A5 genes were included in the analysis. Severe hepatotoxicity was defined as ACTG grade 3-4 AST/ALT increase during the first three months of nevirapine treatment. The causality assessment between NVP exposure and drug-induced liver injury was performed by using the updated Roussel Uclaf Causality Assessment Methods. Hardy Weinberg equilibrium was tested by chi2 test. A multivariable logistic regression model was constructed using a backward elimination method. RESULTS: Three hundred and sixty two patients were included in the analysis, of which 8 (2.2%) experienced a severe liver toxicity. We observed no differences between patients with and without liver toxicity as regards gender, ethnicity, age and immune-virological status. A higher prevalence of HCV coinfection (75.0% vs 30.2%; p = .0013) and higher baseline AST (58 IU/L vs 26 IU/L; p = 0.041) and ALT (82 IU/L vs 27 IU/L; p = 0.047) median levels were observed in patients with liver toxicity vs those without toxicity. The genotypes CT/TT at ABCB1 rs1045642 single nucleotide polymorphism (SNP), showed a protective effect for liver toxicity when compared with genotype CC (OR = 0.18, 95%CI 0.04-0.76; p = 0.020) in univariate analysis. In the multivariate model, HCV coinfection was independently associated with higher risk of developing liver toxicity (aOR = 8.00, 95%CI 1.27-50.29; p = 0.027), whereas ABCB1 rs1045642 CT/TT genotypes (aOR = 0.10, 95%CI 0.02-0.47; p = 0.004) was associated with a lower risk. CONCLUSIONS: According to our findings HCV coinfection and ABCB1 rs1045642 SNP represent independent determinants of severe liver toxicity related to nevirapine. This genetic evaluation could be included as toxicity assessment in HIV-1-positive subjects treated with nevirapine. PMID- 30419835 TI - Posterior reversible encephalopathy syndrome with extensive cytotoxic edema after blood transfusion: a case report and literature review. AB - BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is described as a clinical-radiological disease entity with good prognosis. In brain MRI, PRES generally presents with vasogenic edema. Although PRES is induced by various causes, a small number of PRES cases have occurred after red cell blood transfusion. It is unclear whether there are characteristic features in PRES after blood transfusion. CASE PRESENTATION: Here, we report a case of 75-year-old Japanese woman who had acute exacerbation of subacute anemia by bleeding from gastric ulcer. After receiving a red cell blood transfusion, she showed disturbance of consciousness with extensive cytotoxic and small vasogenic edema in the occipitoparietal area on brain MRI. She was diagnosed as PRES and suffered irreversible impairments of visual acuity and fields in both eyes. We summarized and discussed clinical features of cases with PRES after blood transfusion. CONCLUSIONS: A total of 21 cases including the present one have been reported as PRES after blood transfusion. Of the cases, 20 of 21 were female, and 15 of 17 developed PRES in the course of chronic anemia lasting over 1 month. Anemia was severe in 15 of 20 cases, with hemoglobin levels < 3.5 g/dl. In 14 of 17 cases, hemoglobin levels increased to 5 g/dl by red cell blood transfusion until the onset of PRES. On brain MRI, 2 of 21 cases showed cytotoxic edema and 3 of 21 cases showed irreversible neurological disturbance. In this patient, the occurrence of PRES in subacute anemia and the presence of extensive cytotoxic brain edema with irreversible neurological deficits were characteristic points. When treating severe anemia, even with a subacute progression, we should consider a possibility that PRES occurs after blood transfusion with extensive cytotoxic brain edema and irreversible neurological changes. PMID- 30419837 TI - The relationship between care burden and quality of life in caregivers of hemodialysis patients. AB - BACKGROUND: Caregivers of hemodialysis patients endure a significant caring pressure as a result of caring for patients with chronic illness, which can affect their quality of life. Disruptions in the quality of life of these caregivers impose double pressure on them and disrupt the care process. Therefore, the present study aimed to determine the level of care burden and its relationship with quality of life of caregivers of hemodialysis patients. METHODS: In this descriptive-analytical study, 246 caregivers of hemodialysis patients were enrolled by census method, so that, all patients and caregivers who attended the study environment at morning, evening and night participated in the study. The study tool was a three-part questionnaire, which included personal information, Novak & Guest Care burden Questionnaire, and WHOQOL-BREF Quality of Life Questionnaire. Data were analyzed by descriptive, statistical and inferential tests. RESULTS: In total, 37.4% of caregivers were experiencing high and very high levels of care burden and 42.7% of them were experiencing a moderate level of care burden. The mean and standard deviation of the quality of life of caregivers was 76.27 +/- 13.67 out of 130. There was a significant and negative correlation between the total scores of care burden and quality of life (r = - 0. 436, P < 0.001). The factors influencing care burden included variables such as; level of patient's caring capability, the patient's incidence of other chronic diseases, and the age of the caregiver. So that, in case of reduced patient's capability in self-care, the patient's incidence of other chronic diseases, and the increased age of the caregiver, the level of care burden on the caregivers would be increased. CONCLUSIONS: The caregivers of hemodialysis patients endure high level of care burden and this pressure has a negative effect on their quality of life. Therefore, it is recommended to pay more attention to the needs of caregivers and provide adequate social, economic, physical and psychological support for them. PMID- 30419836 TI - Low-dose Bacillus Calmette-Guerin versus full-dose for intermediate and high-risk of non-muscle invasive bladder cancer: a Markov model. AB - BACKGROUND: To compare the efficacy of low dose (27 mg) Bacillus Calmette-Guerin (BCG) and a full dose (81 mg) BCG immunotherapy for patients with intermediate and high-risk non-muscle invasive bladder cancer (NMIBC) after a typical transurethral bladder resection. METHODS: We constructed a Markov model for a 20 year simulation of the disease to compare the overall survival of patients with intermediate and high-risk of NMIBC between the full-dose therapy (FD group) and the low-dose therapy (LD group). Base case analysis, one-way and two-way sensitivity analysis and a second-order Monte Carlo analysis were performed based on data from 15 published articles. RESULTS: The expected overall survivals were 9.56 (9.55-9.57) years for FD group and 9.63 (9.61-9.64) years for LD group(P < 0.001). The estimated mortality in the FD group at 5, 10, and 20 years were 34.23%, 57.51% and 83.14%, respectively. The corresponding values in the LD group were 34.11%, 57.17%, 82.16%, respectively. Age-specific mortality and metastatic rate after undergoing radical cystectomy (RC) were the most two sensitive parameters in both groups. The rate of disease recurrence with disease worsening is the determining factor when choosing the optimal dose of BCG treatment. CONCLUSIONS: A low-dose BCG treatment may act slightly better than a full-dose BCG treatment for patients with intermediate and high-risk of NMIBC. This finding will require further high-quality studies to validate. PMID- 30419838 TI - Calcium-activated chloride channel regulator 1 as a prognostic biomarker in pancreatic ductal adenocarcinoma. AB - BACKGROUND: In a previous study utilizing mass spectrometry-based proteomics, we identified calcium-activated chloride channel regulator 1 (CLCA1) as a potential tumor suppressor in pancreatic cancer and the expression was inversely correlated with patient survival. The aim of the study was to further validate the prognostic significance of CLCA1 in pancreatic cancer. METHODS: CLCA1 expression was evaluated with tissue microarrays and immunohistochemistry in 140 patients with pancreatic ductal adenocarcinoma that underwent surgical resection at Skane University Hospital, Sweden. Kaplan-Meier and Cox proportional hazards modeling were used to explore the association between CLCA1 and clinicopathological factors and survival. RESULTS: CLCA1 expression was denoted as positive in 90 tumors (64.3%), with positive staining being limited to the tumor cells. There were no significant association between CLCA1 expression and established clinicopathological parameters. Low CLCA1 expression correlated significantly with shorter disease-free survival (11.9 vs 17.5 months, P = 0.042). Multivariable Cox regression analysis confirmed the results (HR 0.61, 95% CI-0.40 0.92, P = 0.019). CONCLUSIONS: Low CLCA1 expression is an independent factor of poor disease-free survival in pancreatic cancer. PMID- 30419839 TI - Monoclonal light chain crystalline podocytopathy and tubulopathy associated with monoclonal gammopathy of renal significance: a case report and literature review. AB - BACKGROUND: Monoclonal gammopathy of renal significance (MGRS) is a recently defined group of renal diseases caused by monoclonal immunoglobulin secreted by nonmalignant proliferative B cell or plasma cell. Monoclonal immunoglobulin can form different types of structures deposited in renal tissue, including fibrils, granules, microtubules, crystals and casts, and has mostly been reported in multiple myeloma patients. Here we report a rare case with kappa light chain crystals in both podocytes and tubular epithelial cells associated with MGRS, which adds more information to the spectrum of MGRS-related renal diseases. CASE PRESENTATION: A 53-year old woman presented with albumin-predominant moderate proteinuria and renal failure. She had monoclonal IgGkappa in the serum and monoclonal IgGkappa plus free kappa in the urine. Multiple myeloma and lymphoproliferative disorders were excluded. Renal biopsy confirmed kappa restricted crystal-storing renal disease involving the podocytes and proximal tubular epithelial cells. The patient was treated with bortezomib followed by lenalidomide-based chemotherapy, and renal function was stable after 1 year of follow-up. CONCLUSIONS: This is a rare case of combined crystalline podocytopathy and tubulopathy associated with MGRS, in which diagnosis was dependent on electron and immuno-electron microscopy. PMID- 30419840 TI - Analysis of oncogenic activities of protein kinase D1 in head and neck squamous cell carcinoma. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cause of cancer death in the US. The protein kinase D (PKD) family has emerged as a promising target for cancer therapy with PKD1 being most intensively studied; however, its role in HNSCC has not been investigated. METHODS: The expression of PKD was evaluated in human HNSCC by quantitative RT-PCR, Western blot and immunohistochemistry. Cell proliferation, wound healing, and matrigel invasion assays were performed upon siRNA-mediated knockdown of PKD1 in HNSCC cells, and subcutaneous xenograft mouse model was established by implantation of the stable doxycycline (Dox)-inducible PKD1 expression cell lines for analysis of tumorigenic activity in vivo. RESULTS: PKD1 was frequently downregulated in HNSCC cell lines at both transcript and protein levels. In human HNSCC tissues, PKD1 was significantly down-regulated in localized tumors and metastases, and in patient-paired tumor tissues as compared to their normal counterparts, which was in part due to epigenetic modification of the PRKD1 gene. The function of PKD1 in HNSCC was analyzed using stable doxycycline-inducible cell lines that express native or constitutive-active PKD1. Upon induction, the rate of proliferation, survival, migration and invasion of HNSCC cells did not differ significantly between the control and PKD1 overexpressing cells in the basal state, and depletion of endogenous PKD1 did not impact the proliferation of HNSCC cells. However, the median growth rate of the subcutaneous HNSCC tumor xenografts over time was elevated with PKD1 induction, and the final tumor weight was significantly increased in Dox-induced vs. the non-induced tumors. Moreover, induced expression of PKD1 promoted bombesin-induced cell proliferation of HNSCC and resulted in sustained ERK1/2 activation in response to gastrin-releasing peptide or bombesin stimulation, suggesting that PKD1 potentiates GRP/bombesin induced mitogenic response through the activation of ERK1/2 in HSNCC cells. CONCLUSIONS: Our study has identified PKD1 as a frequently downregulated gene in HNSCC, and functionally, under certain cellular context, may play a role in GRP/bombesin-induced oncogenesis in HNSCC. PMID- 30419841 TI - Persistent candidemia in very low birth weight neonates: risk factors and clinical significance. AB - BACKGROUND: The prevalence and risk factors for persistent candidemia among very low birth weight infants are poorly understood. This study aimed to investigate the epidemiology of persistent candidemia over a 4-year period in a neonatal intensive care unit (NICU) in Liuzhou, China. METHODS: We retrospectively extracted demographic data, risk factors, microbiological results and outcomes of very low birth weight infants with candidemia in our hospital between January 2012 and November 2015. Persistent candidemia was defined as a positive blood culture for > 5 days. Logistic regression was used to identify risk factors associated with persistent candidemia. RESULTS: Of 48 neonates with candidemia, 28 had persistent candidemia. Both mechanical ventilation and intubation were significantly associated with increased rates of persistent candidemia (P = 0.044 and 0.004, respectively). The case fatality rate for the persistent candidemia group was 14.3%. CONCLUSION: The rate of persistent candidemia was high among very low birth weight neonates. Mechanical ventilation and intubation were the major factors associated with the development of persistent candidemia. This study highlights the importance of intensive prevention and effective treatment among neonates with persistent candidemia. PMID- 30419842 TI - Associations between social support, mental wellbeing, self-efficacy and technology use in first-time antenatal women: data from the BaBBLeS cohort study. AB - BACKGROUND: Information and communication technologies are used increasingly to facilitate social networks and support women during the perinatal period. This paper presents data on how technology use affects the association between women's social support and, (i) mental wellbeing and, (ii) self-efficacy in the antenatal period. METHODS: Data were collected as part of an ongoing study - the BaBBLeS study - exploring the effect of a pregnancy and maternity software application (app) on maternal wellbeing and self-efficacy. Between September 2016 and February 2017, we aimed to recruit first-time pregnant women at 12-16 gestation weeks in five maternity sites across England and asked them to complete questionnaires. Outcomes included maternal mental wellbeing (Warwick-Edinburgh Mental Wellbeing Scale), and antenatal self-efficacy (antenatal version of the Tool to Measure Parenting Self-Efficacy). Other variables assessed were perceived social support (Multidimensional Scale of Perceived Social Support), general technology use (adapted from Media and Technology Usage and Attitudes Scale). Potential confounders were age, ethnicity, education, socioeconomic deprivation, employment, relationship status and recruitment site. Linear regression models were developed to analyse the relationship between social support and the outcomes. RESULTS: Participants (n = 492, median age = 28 years) were predominantly white British (64.6%). Half of them had a degree or higher degree (49.3%), most were married/living with a partner (83.6%) and employed (86.2%). Median (LQ-UQ) overall scores were 81.0 (74.0-84.0) for social support (range 12 84), 5.1 (4.7-5.4) for technology use (range 1-6), 54.0 (48.0-60.0) for mental well-being (range 14-70), and 319.0 (295.5-340) for self-efficacy (range 0-360). Social support was significantly associated with antenatal mental well-being adjusting for confounders [adj R2 = 0.13, p < .001]. The addition of technology use did not alter this model [adj R2 = 0.13, p < .001]. Social support was also significantly associated with self-efficacy after adjustment [adj R2 = 0.14, p < .001]; technology had limited impact on this association [adj R2 = 0.13, p < .001]. CONCLUSIONS: Social support is associated with mental well-being and self efficacy in antenatal first-time mothers. This association was not significantly affected by general technology use as measured in our survey. Future work should investigate whether pregnancy-specific technologies yield greater potential to enhance the perceived social support, wellbeing and self-efficacy of antenatal women. PMID- 30419843 TI - Multimodal imaging in a pedigree of X-linked Retinoschisis with a novel RS1 variant. AB - BACKGROUND: To describe the clinical phenotype and genetic cause underlying the disease pathology in a pedigree (affected n = 9) with X-linked retinoschisis (XLRS1) due to a novel RS1 mutation and to assess suitability for novel therapies using multimodal imaging. METHODS: The Irish National Registry for Inherited Retinal Degenerations (Target 5000) is a program including clinical history and examination with multimodal retinal imaging, electrophysiology, visual field testing and genetic analysis. Nine affected patients were identified across 3 generations of an XLRS1 pedigree. DNA sequencing was performed for each patient, one carrier female and one unaffected relative. Pedigree mapping revealed a further 4 affected males. RESULTS: All affected patients had a history of reduced visual acuity and dyschromatopsia; however, the severity of phenotype varied widely between the nine affected subjects. The stage of disease was classified as previously described. Phenotypic severity was not linearly correlated with age. A novel RS1 (Xp22.2) mutation was detected (NM_000330: c.413C > A) resulting in a p.Thr138Asn substitution. Protein modelling demonstrated a change in higher order protein folding that is likely pathogenic. CONCLUSIONS: This family has a novel gene mutation in RS1 with clinical evidence of XLRS1. A proportion of the older generation has developed end-stage macular atrophy; however, the severity is variable. Confirmation of genotype in the affected grandsons of this pedigree in principle may enable them to avail of upcoming gene therapies, provided there is anatomical evidence (from multimodal imaging) of potentially reversible early stage disease. PMID- 30419844 TI - Neutrophil, lymphocyte and platelet ratio as a predictor of postoperative acute kidney injury in major abdominal surgery. AB - BACKGROUND: Surgery is one of the leading causes of acute kidney injury (AKI) in hospitalized patients. Major abdominal surgery has the second higher incidences of AKI, after cardiac surgery. AKI results from a complex interaction between hemodynamic, toxic and inflammatory factors. The pathogenesis of AKI following major abdominal surgery is distinct from cardiac and vascular surgery. The neutrophil, lymphocytes and platelets (N/LP) ratio has been demonstrated as an inflammatory marker and an independent predictor for AKI and mortality after cardiovascular surgery. The aim of this study was to evaluate the prognostic ability of the post-operative N/LP ratio after major abdominal surgery. METHODS: We cross-examined data of a retrospective analysis of 450 patients who underwent elective or urgent major nonvascular abdominal surgery at the Department of Surgery II of Centro Hospitalar Lisboa Norte from January 2010 to February 2011. N/LP ratio was determined using maximal neutrophil counts and minimal lymphocyte and platelet counts in the first 12 h after surgery. AKI was considered when developed within 48 h after surgery. RESULTS: One-hundred and one patients (22.4%) developed AKI. Patients with higher N/LP ratio had an increased risk of developing postoperative AKI (6.36 +/- 7.34 vs 4.33 +/- 3.36, p < 0.001; unadjusted OR 1.1 (95% CI 1.04-1.16), p = 0.001; adjusted OR 1.05 (95% CI 1.00 1.10), p = 0.048). Twenty-nine patients died (6.44%). AKI was an independent predictor of mortality (20.8 vs 2.3%, p < 0.0001; unadjusted OR 11.2, 95% CI 4. 8 26.2, p < 0.0001; adjusted OR 3.56, 95% CI 1.0 2-12.43, p = 0.046). In a multivariate analysis higher N/LP ratio was not associated with increased in hospital mortality. CONCLUSION: Postoperative N/LP ratio was independently associated with AKI after major abdominal surgery, although there was no association with in-hospital mortality. PMID- 30419845 TI - Anti-colorectal cancer effects of anti-p21Ras scFv delivered by the recombinant adenovirus KGHV500 and cytokine-induced killer cells. AB - BACKGROUND: Colorectal cancer (CRC) is the most common type of gastrointestinal cancer. CRC gene therapy mediated by adenovirus holds great promise for the treatment of malignancies. However, intravenous delivery of adenovirus exhibits limited anti-tumor activity in vivo when used alone. METHODS: In this study, the antitumor activity of the recombinant adenovirus KGHV500 was assessed with the MTT, TUNEL, Matrigel invasion and cell migration assays. To enhance the intravenous delivery of KGHV500 in vivo, cytokine-induced killer (CIK) cells were used as a second vector to carry KGHV500. We explored whether CIK cells could carry the recombinant adenovirus KGHV500 containing the anti-p21Ras single chain fragment variable antibody (scFv) gene into tumors and enhance antitumor potency. RESULTS: Our results showed that KGHV500 exhibited significant antitumor activity in vitro. In the nude mouse SW480 tumor xenograft model, the combination of CIK cells with KGHV500 could induce higher antitumor activity against colorectal cancer in vivo than that induced by either CIK or KGHV500 alone. After seven days of treatment, adenovirus and scFv were detected in tumor tissue but were not detected in normal tissues by immunohistochemistry. Therefore, KGHV500 replicates in tumors and successfully expresses anti-p21Ras scFv in a colorectal cancer xenograft model. CONCLUSIONS: Our study provides a novel strategy for the treatment of colorectal cancer by combining CIK cells with the recombinant adenovirus KGHV500 which carried anti-p21 Ras scFv. PMID- 30419846 TI - MiR-10a and HOXB4 are overexpressed in atypical myeloproliferative neoplasms. AB - BACKGROUND: Atypical Myeloproliferative Neoplasms (aMPN) share characteristics of MPN and Myelodysplastic Syndromes. Although abnormalities in cytokine signaling are common in MPN, the pathophysiology of atypical MPN still remains elusive. Since deregulation of microRNAs is involved in the biology of various cancers, we studied the miRNome of aMPN patients. METHODS: MiRNome and mutations in epigenetic regulator genes ASXL1, TET2, DNMT3A, EZH2 and IDH1/2 were explored in aMPN patients. Epigenetic regulation of miR-10a and HOXB4 expression was investigated by treating hematopoietic cell lines with 5-aza-2'deoxycytidine, valproic acid and retinoic acid. Functional effects of miR-10a overexpression on cell proliferation, differentiation and self-renewal were studied by transducing CD34+ cells with lentiviral vectors encoding the pri-miR-10a precursor. RESULTS: MiR-10a was identified as the most significantly up-regulated microRNA in aMPN. MiR-10a expression correlated with that of HOXB4, sitting in the same genomic locus. The transcription of these two genes was increased by DNA demethylation and histone acetylation, both necessary for optimal expression induction by retinoic acid. Moreover, miR-10a and HOXB4 overexpression seemed associated with DNMT3A mutation in hematological malignancies. However, overexpression of miR-10a had no effect on proliferation, differentiation or self-renewal of normal hematopoietic progenitors. CONCLUSIONS: MiR-10a and HOXB4 are overexpressed in aMPN. This overexpression seems to be the result of abnormalities in epigenetic regulation mechanisms. Our data suggest that miR-10a could represent a simple marker of transcription at this genomic locus including HOXB4, widely recognized as involved in stem cell expansion. PMID- 30419847 TI - Mononeuritis multiplex: an uncommon neurological manifestation of cytomegalovirus reactivation in an HIV-infected patient. AB - BACKGROUND: Cytomegalovirus (CMV) reactivation with neurological involvement in patients with acquired immunodeficiency syndrome (AIDS) is increasingly rare since the introduction of antiretroviral therapy (ART). Manifestations include encephalitis, myelitis, polyradiculopathy and, less commonly, mononeuritis multiplex (MNM). We report a case of disseminated CMV disease with gastrointestinal and peripheral and central nervous system involvement in a patient with AIDS, manifesting primarily as MNM. CASE PRESENTATION: A 31-year old woman with AIDS presented with a clinical picture of MNM. Electromyography confirmed the clinical findings. CMV DNA was detected in cerebrospinal fluid (CSF) and blood. Gastrointestinal involvement was histologically documented. HIV RNA was also detected in CSF and brain MRI was consistent with HIV encephalopathy. A diagnosis of disseminated CMV disease (with esophagitis, colitis, encephalitis and MNM) and HIV encephalopathy was made. Treatment consisted of ganciclovir and foscarnet, followed by maintenance therapy with valganciclovir. Evolution was favorable and valganciclovir was stopped after sustained immune recovery following ART initiation. CONCLUSION: We discuss the diagnostic approach to CMV neurological disease, with a focus on MNM and CMV encephalitis. Combination therapy with ganciclovir and foscarnet should be considered for all forms of neurological involvement, although available data are scarce. Since there is significant overlap between CMV encephalitis and HIV encephalopathy, ART drugs with higher CSF penetration may have to be considered. ART and immune recovery are essential to improve outcomes. PMID- 30419848 TI - The effect of exercise during pregnancy on gestational diabetes mellitus in normal-weight women: a systematic review and meta-analysis. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is one of the most common complications during pregnancy, and it has both short- and long-term adverse effects on the health of mothers and fetuses. To investigate the effect of exercise during pregnancy on the occurrence of GDM among normal-weight pregnant women. METHODS: We searched for studies published between January 1994 and June 2017 that appeared in the Web of Science, Scopus, ClinicalTrials.gov or Cochrane library databases. Randomized controlled trials that investigated the preventive effect of exercise on GDM in normal-weight women were included. Interventions including any confounding factors (e.g., dietary) were excluded. We extracted maternal characteristics, the diagnostic criteria of GDM, and basic information for intervention and obstetric outcomes. The primary outcome was the occurrence of GDM, and the secondary outcomes included gestational weight gain, gestational age at birth, birth weight, and the odds of cesarean section. A meta-analysis was conducted based on calculations of pooled estimates using the random-effects model. RESULTS: Eight studies were included in this systematic review and meta analysis. Exercise during pregnancy was shown to decrease the occurrence of GDM [RR = 0.58, 95% CI (0.37, 0.90), P = 0.01 and RR = 0.60, 95% CI (0.36, 0.98), P = 0.04 based on different diagnosis criteria, respectively] in normal-weight women. Regarding secondary outcomes, exercise during pregnancy can decrease gestational weight gain [MD = - 1.61, 95% CI (- 1.99, - 1.22), P<0.01], and had no significant effects on gestational age at birth [MD = - 0.55, 95% CI (- 1.57, 0.47), P = 0.29], birth weight [MD = - 18.70, 95% CI (- 52.49, 15.08), P = 0.28], and the odds of caesarean section [RR = 0.88, 95% CI (0.72, 1.08), P = 0.21], respectively. CONCLUSIONS: Exercise during pregnancy can ostensibly decrease the occurrence of GDM without reducing gestational age at delivery and increasing the odds of cesarean section in normal-weight women. PMID- 30419849 TI - Preoperative diagnosis and prediction of hepatocellular carcinoma: Radiomics analysis based on multi-modal ultrasound images. AB - BACKGROUND: This study aims to establish a radiomics analysis system for the diagnosis and clinical behaviour prediction of hepatocellular carcinoma (HCC) based on multi-parametric ultrasound imaging. METHODS: A total of 177 patients with focal liver lesions (FLLs) were included in the study. Every patient underwent multi-modal ultrasound examination, including B-mode ultrasound (BMUS), shear wave elastography (SWE), and shear wave viscosity (SWV) imaging. The radiomics analysis system was built on sparse representation theory (SRT) and support vector machine (SVM) for asymmetric data. Through the sparse regulation from the SRT, the proposed radiomics system can effectively avoid over-fitting issues that occur in regular radiomics analysis. The purpose of the proposed system includes differential diagnosis between benign and malignant FLLs, pathologic diagnosis of HCC, and clinical prognostic prediction. Three biomarkers, including programmed cell death protein 1 (PD-1), antigen Ki-67 (Ki 67) and microvascular invasion (MVI), were included and analysed. We calculated the accuracy (ACC), sensitivity (SENS), specificity (SPEC) and area under the receiver operating characteristic curve (AUC) to evaluate the performance of the radiomics models. RESULTS: A total of 2560 features were extracted from the multi modal ultrasound images for each patient. Five radiomics models were built, and leave-one-out cross-validation (LOOCV) was used to evaluate the models. In LOOCV, the AUC was 0.94 for benign and malignant classification (95% confidence interval [CI]: 0.88 to 0.98), 0.97 for malignant subtyping (95% CI: 0.93 to 0.99), 0.97 for PD-1 prediction (95% CI: 0.89 to 0.98), 0.94 for Ki-67 prediction (95% CI: 0.87 to 0.97), and 0.98 for MVI prediction (95% CI: 0.93 to 0.99). The performance of each model improved when the viscosity modality was included. CONCLUSIONS: Radiomics analysis based on multi-modal ultrasound images could aid in comprehensive liver tumor evaluations, including diagnosis, differential diagnosis, and clinical prognosis. PMID- 30419850 TI - Are comorbidities associated with long-term survival of lung cancer? A population based cohort study from French cancer registries. AB - BACKGROUND: Survival rates of lung cancer remains poor and the impact of comorbidities on the prognosis is discussed. The objective of this study was to assess if the Charlson Comorbidity Index (CCI) was associated with 8-year survival rates by histological type. METHODS: A cohort study was conducted using randomly selected cases from 10 French cancer registries. Net survival rates were computed using the Pohar-Perme estimator of the net cumulative rate. Three Cox models were independently built for adenocarcinomas, squamous cell and small cell cancers to estimate prognostic factors including CCI grade. RESULTS: A total of 646 adenocarcinomas, 524 squamous cell and 233 small cell cancers were included in the analysis. The net 8-year survival rate ranged from 12.6% (95% CI: 9.8 15.4%) for adenocarcinomas and 13.4% (95% CI: 10.1-16.7%) for squamous cell carcinomas, to 3.7% (95% CI: 1.1-6.3%) for small cell cancers. Observed and net survival rates decreased for CCI grades >=3 for all histological group considered. After adjustment for sex, age group, stage and diagnostic mode, CCI grades 1 (HR = 1.6 [95% CI: 1.1-2.3]), 2 (HR = 1.7 [95% CI: 1.1-2.7]) and >= 3 (HR = 2.7 [95% CI: 1.7-4.4]) were associated with lower survival rates only for small cell cancers. CONCLUSION: After adjustment for age, sex, stage and diagnostic mode, the presence of comorbidity based on CCI grades 1-2 and >= 3 was associated with lower survival rates for small cell cancers whereas no differences were observed for adenocarcinomas and squamous cell cancers. PMID- 30419851 TI - Neo-adjuvant treatment of adenocarcinoma and squamous cell carcinoma of the cervix results in significantly different pathological complete response rates. AB - BACKGROUND: Previous studies on cervical cancer reported a worse outcome for adenocarcinoma (AC) compared with squamous cell carcinoma (SCC). Nevertheless, standard treatment remains identical. Insight in the impact of histological types on biological behavior and pathological complete response rates might result in a treatment paradigm shift. METHODS: Clinicopathological characteristics, survival rates and relapse patterns were compared between AC (n = 36) and SCC (n = 143) cervical cancer patients. Pathological response to treatment was evaluated in the patient subgroup treated with neo-adjuvant chemoradiation followed by surgery (NA CRT group; n = 84). RESULTS: In the entire cohort, 5y Disease Specific Survival (DSS) was 97.1 and 84% for AC and SCC respectively (p = 0.150). In the NA-CRT group 5y DSS was 100 and 75.5% for AC and SCC respectively (p = 0.059). Relapse patterns did not differ significantly between AC and SCC in the entire cohort, or in the NA-CRT group. Adenocarcinoma patients treated with NA-CRT showed significantly less pathological complete response compared with SCC patients (AC = 7%, SCC = 43%, p = 0.027). CONCLUSIONS: There were no statistically significant differences regarding relapse and DSS rates between SCC and AC in the entire cohort, or the NA-CRT group. However, a trend to better 5y DSS of AC in the NA CRT group was observed. This analysis showed significant differences in treatment responses after NA-CRT: patients with AC responded remarkably less to chemoradiation, resulting in a significantly lower pathological complete response rate. These findings imply a need for a paradigm shift in the treatment of cervical AC patients. PMID- 30419852 TI - Epithelial cell adhesion molecule (EpCAM) is involved in prostate cancer chemotherapy/radiotherapy response in vivo. AB - BACKGROUND: Development of chemo-/radioresistance is a major challenge for the current prostate cancer (CaP) therapy. We have previously demonstrated that epithelial cell adhesion molecule (EpCAM) is associated with CaP growth and therapeutic resistance in vitro, however, the role of EpCAM in CaP in vivo is not fully elucidated. Here, we aimed to investigate how expression of EpCAM is involved in CaP growth and chemo-/radiotherapy response in NOD/SCID mouse models in vivo and to validate its role as a therapeutic target for CaP therapy. METHODS: EpCAM was knocked down in PC-3 CaP cell line using short hairpin RNA (shRNA). The effect of EpCAM-knockdown (KD) on tumour growth, chemo-/radiotherapy response and animal survival was evaluated on subcutaneous (s.c) and orthotopic mouse models. RESULTS: We found that KD of EpCAM significantly inhibited tumour growth, increased xenograft sensitivity to chemotherapy/radiotherapy, and prolonged the survival of tumour-bearing mice. In addition, we demonstrated that KD of EpCAM is associated with downregulation of the PI3K/Akt/mTOR pathway. CONCLUSIONS: In conclusion, our data confirms that CaP growth and chemo /radioresistance in vivo is associated with over-expression of EpCAM, which serves both a functional biomarker and promising therapeutic target. PMID- 30419853 TI - Attitude, knowledge and informed choice towards prenatal screening for Down Syndrome: a cross-sectional study. AB - BACKGROUND: Down Syndrome screening test is a bridge between knowledge and uncertainty, safety and risk, unpredictability and desire to know in order to gain control. It may be accepted either not to have a baby with Down syndrome, or to prepare to have a baby with this condition. Every woman should understand that it is an option and should be encouraged to make their own decisions based on information and personal values. The implications and possible subsequent scenarios differentiate this type of test from the common biochemical tests performed during pregnancy, of paramount importance being the right to make informed choices. The aim of this study was to investigate the knowledge and attitude towards prenatal Down syndrome screening in order to asses to what extent the Romanian women make informed choices in this area. METHODS: A cross sectional study was carried out that included 530 postpartum women, clients of Romania' south-east region maternities, during April-September 2016. The level of knowledge and the attitude concerning the Down syndrome screening were evaluated using a questionnaire. Data were analyzed using SPSS version 20.0. RESULTS: 48.1% of the women have never heard about any tests for Down Syndrome and from those 51.9% who have heard, only 14.2% made an informed choice, 78.9% had a positive attitude for screening, 88% were classified as having insufficient knowledge and 68.3% made a value-consistent decision to accept or decline prenatal screening. A higher knowledge level was associated with a higher education level and the urban residence. The information satisfaction and confidence in the overall value of screening were predictive factors of positive attitude. More informed choices were made by women monitored by an obstetrician in a private practice. CONCLUSIONS: The prenatal screening tests for Down Syndrome were mostly unknown and the women who accepted or not to perform a test were insufficiently knowledgeable that means that the ethical concept of the informed choice wasn't followed. In our opinion the Romanian Health System needs to improve the antenatal policy by developing an adequate information strategy at the reproductive population level based on a network of trained specialists. PMID- 30419854 TI - Successful response to the combination of immunotherapy and chemotherapy in cholangiocarcinoma with high tumour mutational burden and PD-L1 expression: a case report. AB - BACKGROUND: Cholangiocarcinoma, or bile duct cancer, is a gastrointestinal cancer with limited therapeutic options and a poor outcome. Studies have revealed that some major driver genes are associated with cholangiocarcinoma, but no targeted therapies have been approved. Immune checkpoint inhibitors, which are represented by inhibitors of programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD L1), have emerged as a potential therapy for multiple types of solid cancers. CASE PRESENTATION: A 53-year-old female presented with postoperative recurrence of PD-L1-positive intrahepatic cholangiocarcinoma with a high tumour mutational burden. This patient exhibited a marked response to the combination of anti-PD-1 immunotherapy and chemotherapy. CONCLUSIONS: As far as we know, this is the first case report on the success of the combination of immunotherapy and chemotherapy for advanced cholangiocarcinoma with PD-L1 positivity and a high tumour mutational burden. PMID- 30419856 TI - Oncogenic potential of N-terminal deletion and S45Y mutant beta-catenin in promoting hepatocellular carcinoma development in mice. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide with limited treatment options. Mutation of beta-catenin is one of the most frequent genetic events along hepatocarcinogenesis. beta catenin mutations can be in the form of point mutation or large N-terminal deletion. Studies suggested that different beta-catenin mutations might have distinct oncogenic potential. METHODS: We tested the oncogenic activity of beta cateninS45Y, one of the most frequent point mutations of beta-catenin, and ?N90 beta-catenin, a form of beta-catenin with a large N-terminal deletion, in promoting HCC development in mice. Thus, we co-expressed beta-cateninS45Y or ?N90 beta-catenin together with c-Met into the mouse liver using hydrodynamic injection. RESULTS: We found that both beta-catenin mutations were able to induce HCC formation in combination with c-Met at the same latency and efficiency. Tumors showed similar histological features and proliferation rates. However, immunohistochemistry showed predominantly nuclear staining of beta-catenin in c Met/?N90-beta-catenin HCC, but membrane immunoreactivity in c-Met/beta cateninS45Y HCC. qRT-PCR analysis demonstrated that both ?N90-beta-catenin and beta-cateninS45Y induced the same effectors, although at somewhat different levels. In cultured cells, both ?N90-beta-catenin and beta-cateninS45Y were capable of inducing TCF/LEF reporter expression, promoting proliferation, and inhibiting apoptosis. CONCLUSIONS: Our study suggests that beta-cateninS45Y and ?N90-beta-catenin, in combination with the c-Met proto-oncogene, have similar oncogenic potential. Furthermore, nuclear staining of beta-catenin does not always characterize beta-catenin activity. PMID- 30419855 TI - The effect of occipital nerve field stimulation on the descending pain pathway in patients with fibromyalgia: a water PET and EEG imaging study. AB - BACKGROUND: Fibromyalgia is a chronic disorder characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory, and mood problems. Recently, occipital nerve field stimulation (ONS) has been proposed as an effective potential treatment for fibromyalgia-related pain. The aim of this study is to unravel the neural mechanism behind occipital nerve stimulation's ability to suppress pain in fibromyalgia patients. MATERIALS AND METHODS: Seven patients implanted with subcutaneous electrodes in the C2 dermatoma were enrolled for a Positron Emission Tomography (PET) H215O activation study. These seven patients were selected from a cohort of 40 patients who were part of a double blind, placebo-controlled study followed by an open label follow up at six months. The H215O PET scans were taken during both the "ON" (active stimulation) and "OFF" (stimulating device turned off) conditions. Electroencephalogram (EEG) data were also recorded for the implanted fibromyalgia patients during both the "ON" and "OFF" conditions. RESULTS: Relative to the "OFF" condition, ONS stimulation resulted in activation in the dorsal lateral prefrontal cortex, comprising the medial pain pathway, the ventral medial prefrontal cortex, and the bilateral anterior cingulate cortex as well as parahippocampal area, the latter two of which comprise the descending pain pathway. Relative deactivation was observed in the left somatosensory cortex, constituting the lateral pain pathway as well as other sensory areas such as the visual and auditory cortex. The EEG results also showed increased activity in the descending pain pathway. The pregenual anterior cingulate cortex extending into the ventral medial prefrontal cortex displayed this increase in the theta, alpha1, alpha2, beta1, and beta2 frequency bands. CONCLUSION: PET shows that ONS exerts its effect via activation of the descending pain inhibitory pathway and the lateral pain pathway in fibromyalgia, while EEG shows activation of those cortical areas that could be responsible for descending inhibition system recruitment. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov , number NCT00917176 (June 10, 2009). PMID- 30419857 TI - The pace and prognosis of peripheral sensory loss in advanced age: association with gait speed and falls. AB - BACKGROUND: Peripheral sensory loss is considered one of many risk factors for gait impairments and falls in older adults, yet no prospective studies have examined changes in touch sensation in the foot over time and their relationship to mobility and falls. Therefore, we aimed to determine the prevalence and progression of peripheral sensory deficits in the feet of older adults, and whether sensory changes are associated with the slowing of gait and development of falls over 5 years. METHODS: Using baseline, and 18 and 60 month followup data from the Maintenance Of Balance, Independent Living, Intellect, and Zest in the Elderly (MOBILIZE) Study in Boston, MA, we determined changes in the ability to detect stimulation of the great toe with Semmes Weinstein monofilaments in 351 older adults. We used covariate-adjusted repeated measures analysis of variance to determine relationships between sensory changes and gait speed or fall rates. RESULTS: Subjects whose sensory function was consistently impaired over 5 years had a significantly steeper decline in gait speed (- 0.23 m/s; 95% CI: -0.28 to - 0.18) compared to those with consistently intact sensory function (- 0.12 m/s; 95% CI: -0.15 to - 0.08) and those progressing from intact to impaired sensory function (- 0.13 m/s; - 0.16 to - 0.10). Compared to subjects with consistently intact sensation, those whose sensory function progressed to impairment during followup had the greatest risk of falls (adjusted risk ratio = 1.57 (95% confidence interval = 1.12 to 2.22). CONCLUSIONS: Our longitudinal results indicate that a progressive decline in peripheral touch sensation is a risk factor for mobility impairment and falls in older adults. PMID- 30419858 TI - Intra-patient and inter-patient comparisons of DNA damage response biomarkers in Nasopharynx Cancer (NPC): analysis of NCC0901 randomised controlled trial of induction chemotherapy in locally advanced NPC. AB - BACKGROUND: Inter-patient heterogeneity in radiation-induced DNA damage responses is proposed to reflect intrinsic variations in tumour and normal tissue radiation sensitivity, but the prediction of phenotype by a molecular biomarker is influenced by clinical confounders and assay reproducibility. Here, we characterised the intrapatient and inter-patient heterogeneity in biomarkers of DNA damage and repair and radiation-induced apoptosis. METHODS: We enrolled 85 of 172 patients with locally advanced nasopharynx cancer from a randomised controlled phase II/III trial of induction chemotherapy added to chemo radiotherapy. G0 blood lymphocytes were harvested from these patients, and irradiated with 1, 4, and 8 Gy ex vivo. DNA damage induction (1 Gy 0.5 h) and repair (4 Gy 24 h) were assessed by duplicate gammaH2AX foci assays in 50-100 cells. Duplicate FLICA assays performed at 48 h post-8 Gy were employed as surrogate of radiation-induced apoptosis; %FLICA-positive cells were quantified by flow cytometry. RESULTS: We observed limited intrapatient variation in gammaH2AX foci and %FLICA readouts; median difference of duplicate foci scores was - 0.37 (IQR = - 1.256-0.800) for 1 Gy 0.5 h and 0.09 (IQR = - 0.685-0.792) for 4 Gy 24 h; ICC of >=0.80 was observed for duplicate %FLICA0Gy and %FLICA8Gy assays of CD4+ and CD8+ T lymphocytes. As expected, we observed wide inter patient heterogeneity in both assays that was independent of intrapatient variation and clinical covariates, with the exception of age, which was inversely correlated with %FLICAbackground-corrected (Spearman R = - 0.406, P < 0.001 [CD4+]; R = - 0.220, P = 0.04 [CD8+]). Lastly, an exploratory case-control analysis indicates increased levels of gammaH2AX foci at 4 Gy 24 h in patients with severe late radiotherapy-induced xerostomia (P = 0.05). CONCLUSION: Here, we confirmed the technical reproducibility of DNA damage response assays for clinical implementation as biomarkers of clinical radiosensitivity in nasopharynx cancer patients. PMID- 30419859 TI - Porphyrins are increased in the faeces of patients with prostate cancer: a case control study. AB - BACKGROUND: Experimental models of prostate cancer have demonstrated increased levels of protoporphyrin IX (PpIX) in the blood and faeces of mice. Hence, the quantification of these autofluorescent molecules could be hypothesized to be a potential marker for this type of tumour. In this case-control study, the autofluorescence of porphyrins in human faeces from patients with prostate cancer and control subjects was analysed using fluorescence spectroscopy. METHODS: First, 3 mL of analytical-grade acetone was added to 0.3 g of faeces, and the mixture was macerated and centrifuged at 4000 rpm for 15 min. The supernatant was analysed spectroscopically. The emission spectra from 550 to 750 nm were obtained by exciting the samples at 405 nm. RESULTS: A significant difference between the samples from control and cancer subjects was established in the spectral region of 670-675 nm (p = 0.000127), which corresponds to a significant increase in faecal porphyrins in patients with cancer. There was no statistically significant correlation between PSA levels and faecal porphyrins. CONCLUSION: In this preliminary study conducted in humans, the results show a simple and non-invasive method to assess faecal porphyrins, which have the potential to function as a tumour biomarker in patients with prostate cancer. This approach has improved sensitivity and specificity over PSA testing. Additional prospective studies with larger sample sizes are required to validate these findings. PMID- 30419860 TI - Triptolide as a novel agent in pancreatic cancer: the validation using patient derived pancreatic tumor cell line. AB - BACKGROUND: Triptolide induces apoptosis and DNA damage followed by inhibition of DNA repair associated gene expression. However, there is the limited data for biomarker to predict the benefit to triptolide in various cancers including pancreatic cancer. METHODS: We investigated the anti tumor efficacy of triptolide in various pancreatic cancer cell lines (Capan-1, Capan-2, SNU-213, SNU-410, HPAFII, and Hs766T) and patient derived cells (PDCs) from metastatic pancreatic cancer patients. RESULTS: In vitro cell viability assay for triptolide in 6 PC cell lines, the IC50 was 0.01 uM, 0.02 uM, 0.0096 uM for triptolide in Capan-1, Capan-2 and SNU-213. However, the growth of tumor cells was not significantly reduced by triptolide in Hs766T, SNU-410 and HPAFII. The distinct difference of gene expression was also observed between Capan-1, Capan-2 and SNU-213 and Hs766T, SNU-410 and HPAFII. In analysis of pathway using gene expression profiles, the integrin mediated RAS signaling pathway was associated with the sensitivity of the triptolide in PC cell lines. Immunoblot assay showed that Chk2 phosphorylation after triptolide was distinctively observed in SNU-213 sensitive to triptolide but, not in SNU-410 insensitive to triptolide. This finding in immunoblot assay was also reproduced in PDCs originated from pancreatic cancer patients. CONCLUSIONS: Our findings might be helpful to completely capture the subset of patients who may benefit to tripolide (minnelide). More robust biomarkers such as KRAS mutation and Chk2 phosphorylation and careful clinical trial design using triptolide (minnelide) are warranted. PMID- 30419861 TI - Testing for minimal residual disease in adults with acute lymphoblastic leukemia in Europe: a clinician survey. AB - BACKGROUND: In acute lymphoblastic leukemia (ALL), the presence of minimal residual disease (MRD) after induction/consolidation chemotherapy is a strong prognostic factor for subsequent relapse and mortality. Accordingly, European clinical guidelines and protocols recommend testing patients who achieve a complete hematological remission (CR) for MRD for the purpose of risk stratification. The aim of this study was to provide quantitative information regarding real-world clinical practice for MRD testing in five European countries. METHODS: A web-based survey was conducted in March/April 2017 in France, Germany, Italy, Spain, and the UK. The survey was developed after consultation with specialist clinicians and a review of published literature. Eligible clinicians (20 per country; 23 in Spain) were board-certified in hemato oncology or hematology, had at least five years' experience in their current role after training, had treated at least two patients with B-cell precursor ALL in the 12 months before the survey or at least five patients in the last five years, and had experience of testing for MRD in clinical practice. RESULTS: MRD testing is now standard practice in the treatment of adult ALL across the five European countries, with common use of recent treatment protocols which specify testing. Respondents estimated that, among clinicians in their country who conduct MRD testing, 73% of patients in first CR (CR1) and 63% of patients in second or later CR (CR2+) are tested for MRD. The median time point reported as most commonly used for the first MRD test, to establish risk status and to determine a treatment plan was four weeks after the start of induction therapy. The timing and frequency of tests is similar across countries. An average of four or five post-CR1 tests per patient in the 12 months after the first MRD test were reported across countries. CONCLUSIONS: This comprehensive study of MRD testing patterns shows consistent practice across France, Germany, Italy, Spain, and the UK with respect to the timing and frequency of MRD testing, aligning with use of national protocols. MRD testing is used in clinical practice also in patients who reach CR2 + . PMID- 30419862 TI - Finding the right BCR-ABL1 tyrosine kinase inhibitor: a case report of successful treatment of a patient with chronic myeloid leukemia and a V299L mutation using nilotinib. AB - BACKGROUND: Chronic myeloid leukemia can be effectively treated with BCR-ABL1 tyrosine kinase inhibitors. However, BCR-ABL1 mutations can develop and cause secondary resistance to these inhibitors. For each of the available BCR-ABL1 inhibitors, certain mutations are known to be associated with resistance, although most mutations that confer resistance to one tyrosine kinase inhibitor remain sensitive to one or more of the other available inhibitors. For patients displaying poor response or loss of response to frontline treatment, the possibility that they have developed a new BCR-ABL1 mutation must be considered, and selection of a second-line treatment must consider the patient's mutational profile. Here we describe a case in which a patient developed a V299L mutation; although this mutation is known to be associated with resistance to dasatinib while remaining sensitive to nilotinib, limited information is currently available regarding the use of second-line nilotinib following development of a V299L mutation while receiving dasatinib. CASE PRESENTATION: A 73-year-old man presenting with fatigue and drenching night sweats lasting for 2 weeks was diagnosed with chronic myeloid leukemia based on an analysis of a bone marrow biopsy and detection of the BCR-ABL1 fusion gene in peripheral blood. The patient initiated frontline treatment with dasatinib. A good treatment response was seen initially, with a complete hematologic response by month 2 of treatment. By month 20 however, BCR-ABL1 transcript levels rose markedly, and a mutational analysis revealed a BCR-ABL1 V299L mutation. Based on the identification of this specific mutation, the patient switched treatment to nilotinib; by month 18 of nilotinib treatment, the patient achieved a deeper reduction in BCR-ABL1 transcript levels than was seen with dasatinib. To date, in month 34 of treatment with nilotinib, the patient has shown good tolerance of the drug and has no clinical evidence of disease progression. CONCLUSIONS: Our case report illustrates the benefit of having multiple drugs available to treat chronic myeloid leukemia, each with the ability to inhibit a distinct set of BCR-ABL1 mutations. This patient's case suggests that switching to nilotinib can be an effective treatment option for patients who develop a BCR-ABL1 V299L mutation while receiving dasatinib. PMID- 30419863 TI - Prognostic value of inflammation-based scores in patients receiving radical resection for colorectal cancer. AB - BACKGROUND: The modified Glasgow Prognostic Score (mGPS) and the neutrophil-to lymphocyte ratio (NLR) are conventional inflammation-based scores for colorectal cancer (CRC). The systemic inflammation score (SIS) has been shown to be more informative than the mGPS in CRC. The albumin-NLR, composed of albumin and the NLR, can also be a candidate for a valuable inflammation score. However, about the utility of the mGPS, SIS, and albumin-NLR for CRC patients who have received radical resections remains unclear. METHODS: This study enrolled 877 CRC patients, who underwent radical surgical resection between January 1, 2007 and December 31, 2014. The prognostic values of the mGPS, SIS, and albumin-NLR were compared by the Kaplan-Meier survival analysis, multivariate Cox regression modelling, and the time-dependent receiver operating characteristic curve analysis (ROC). RESULTS: In the Kaplan-Meier analysis, all three inflammation scores were significantly associated with overall survival (OS) in the group including all the patients (mGPS, p = 0.016; SIS, p < 0.001; albumin-NLR, p = 0.007) and in the left-sided colon tumour subgroup (mGPS, p = 0.029; SIS p = 0.0013; albumin-NLR, p = 0.001). In the right-sided colon tumour subgroup, only the albumin-NLR was associated with OS (p = 0.048). The albumin-NLR was the only independent prognostic factor of the three scores for OS in the multivariate survival analysis. CONCLUSIONS: The albumin-NLR outperformed both the SIS and mGPS in predicting OS in CRC patients undergoing radical resection. PMID- 30419864 TI - Elevated platelet count is a negative predictive and prognostic marker in locally advanced rectal cancer undergoing neoadjuvant chemoradiation: a retrospective multi-institutional study on 965 patients. AB - BACKGROUND: In patients with locally advanced rectal cancer treated by neoadjuvant chemoradiation, pathological complete response in the surgical specimen is associated with favourable long-term oncologic outcome. Based on this observation, nonoperative management is being explored in the subset of patients with clinical complete response. Whereas, patients with poor response have a high risk of local and distant recurrence, and appear to receive no benefit from standard neoadjuvant chemoradiation. Therefore, in order to develop alternative treatment strategies for non responding patients, predictive and prognostic factors are highly needed. Accumulating clinical observations indicate that elevated platelet count is associated with poor outcome in different type of tumors. In this study we investigated the predictive and prognostic impact of elevated platelet count on pathological response and long-term oncologic outcome in patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiation. METHODS: A total of 965 patients were selected from prospectively maintained databases of seven Centers within the SICO Colorectal Cancer Network. Patients were divided into two groups based on a pre-neoadjuvant chemoradiation platelet count cut-off value of 300 * 109/L identified by receiver operating characteristic curve considering complete pathological response as the outcome. RESULTS: Complete pathological response rate was lower in patients with elevated platelet count (12.8% vs. 22.1%, p = 0.001). Mean follow-up was 50.1 months. Comparing patients with elevated platelet count with patients with not elevated platelet count, 5-year overall survival was 69.5% vs.76.5% (p = 0.016), and 5 year disease free survival was 63.0% vs. 68.9% (p = 0.019). Local recurrence rate was higher in patients with elevated platelet count (11.1% vs. 5.3%, p = 0.001), as higher was the occurrence of distant metastasis (23.9% vs. 16.4%, p = 0.007). At multivariate analysis of potential prognostic factors EPC was independently associated with worse overall survival (HR 1.40, 95% CI 1.06-1.86), and disease free survival (HR 1.37, 95% CI 1.07-1.76). CONCLUSIONS: In locally advanced rectal cancer elevated platelet count before neoadjuvant chemoradiation is a negative predictive and prognostic factor which might help to identify subsets of patients with more aggressive tumors to be proposed for alternative therapeutic strategies. PMID- 30419865 TI - Reduced RBM3 expression is associated with aggressive tumor features in esophageal cancer but not significantly linked to patient outcome. AB - BACKGROUND: RBM3 expression has been suggested as prognostic marker in several cancer types. The purpose of this study was to assess the prevalence and clinical significance of altered RBM3 expression in esophageal cancer. METHODS: RBM3 protein expression was measured by immunohistochemistry using tissue microarrays containing samples from 359 esophageal adenocarcinoma (EAC) and 254 esophageal squamous cell cancer (ESCC) patients with oncological follow-up data. RESULTS: While nuclear RBM3 expression was always high in benign esophageal epithelium, high RBM3 expression was only detectable in 66.4% of interpretable EACs and 59.3% of ESCCs. Decreased RBM3 expression was linked to a subset of EACs with advanced UICC stage and presence of distant metastasis (P = 0.0031 and P = 0.0024). In ESCC, decreased RBM3 expression was associated with advanced UICC stage, high tumor stage, and positive lymph node status (P = 0.0213, P = 0.0061, and P = 0.0192). However, RBM3 expression was largely unrelated to survival of patients with esophageal cancer (EAC: P = 0.212 and ESCC: P = 0.5992). CONCLUSIONS: In summary, the present study shows that decreased RBM3 expression is associated with unfavourable esophageal cancer phenotype, but not significantly linked to patient prognosis. PMID- 30419866 TI - Thirty-month results after the treatment of post-LASIK ectasia with allogenic lenticule addition and corneal cross-linking: a case report. AB - BACKGROUND: To report a first case of lenticule addition and corneal cross linking for post-LASIK ectasia with associated corneal thinning. CASE PRESENTATION: Lenticule addition followed by corneal cross-linking was performed on the left eye of a patient with post-LASIK ectasia. Postoperatively, the corneal power and elevation were stable with a remarkable improvement in corneal thickness, and the lenticule had merged with the adjacent corneal stroma at 30 months follow-up. The patient's corrected distance visual acuity gained two lines. CONCLUSIONS: This case provides a potential treatment option for patients with keratectasia and keratoconus in association with thin corneal thickness (less than 400 MUm) and may provide the benefit of delaying or avoiding the need for keratoplasty, which has its own associated complications and is limited by the availability of donor corneas. PMID- 30419867 TI - A retrospective study of neonatal case management and outcomes in rural Rwanda post implementation of a national neonatal care package for sick and small infants. AB - BACKGROUND: Despite worldwide efforts to reduce neonatal mortality, 44% of under five deaths occur in the first 28 days of life. The primary causes of neonatal death are preventable or treatable. This study describes the presentation, management and outcomes of hospitalized newborns admitted to the neonatal units of two rural district hospitals in Rwanda after the 2012 launch of a national neonatal protocol and standards. METHODS: We retrospectively reviewed routinely collected data for all neonates (0 to 28 days) admitted to the neonatal units at Rwinkwavu and Kirehe District Hospitals from January 1, 2013 to December 31, 2014. Data on demographic and clinical characteristics, clinical management, and outcomes were analyzed using median and interquartile ranges for continuous data and frequencies and proportions for categorical data. Clinical management and outcome variables were stratified by birth weight and differences between low birth weight (LBW) and normal birth weight (NBW) neonates were assessed using Fisher's exact or Wilcoxon rank-sum tests at the alpha = 0.05 significance level. RESULTS: A total of 1723 neonates were hospitalized over the two-year study period; 88.7% were admitted within the first 48 h of life, 58.4% were male, 53.8% had normal birth weight and 36.4% were born premature. Prematurity (27.8%), neonatal infection (23.6%) and asphyxia (20.2%) were the top three primary diagnoses. Per national protocol, vital signs were assessed every 3 h within the first 48 h for 82.6% of neonates (n = 965/1168) and 93.4% (n = 312/334) of neonates with infection received antibiotics. The overall mortality rate was 13.3% (n = 185/1386) and preterm/LBW infants had similar mortality rate to NBW infants (14.7 and 12.2% respectively, p = 0.131). The average length of stay in the neonatal unit was 5 days. CONCLUSIONS: Our results suggest that it is possible to provide specialized neonatal care for both LBW and NBW high-risk neonates in resource-limited settings. Despite implementation challenges, with the introduction of the neonatal care package and defined clinical standards these most vulnerable patients showed survival rates comparable to or higher than neighboring countries. PMID- 30419868 TI - Does improvement towards a normal cervical sagittal configuration aid in the management of cervical myofascial pain syndrome: a 1- year randomized controlled trial. AB - BACKGROUND: There is a growing interest concerning the understanding of and rehabilitation of the sagittal configuration of the cervical spine as a clinical outcome. However, the literature on the topic specific to conservative treatment outcomes of patients with chronic myofascial cervical pain syndrome (CMCPS) has not adequately addressed the relationship between cervical sagittal alignment and improved pain, disability and range of motion. METHODS: A randomized controlled study with a 1-year follow-up. Here, 120 (76 males) patients with chronic CMCPS and defined cervical sagittal posture abnormalities were randomly assigned to the control or an intervention group. Both groups received the Integrated neuromuscular inhibition technique (INIT); additionally, the intervention group received the denneroll cervical traction device. Alignment outcomes included two measures of sagittal posture: cervical angle (CV), and shoulder angle (SH). Patient relevant outcome measures included: neck pain intensity (NRS), neck disability (NDI), pressure pain thresholds (PPT), cervical range of motion using the CROM. Measures were assessed at three intervals: baseline, 10 weeks, and 1 year after the 10 week follow up. RESULTS: After 10 weeks of treatment, between group statistical analysis, showed equal improvements for both the intervention and control groups in NRS (p = 0.36) and NDI (p = 0.09). However, at 10 weeks, there were significant differences between groups favoring the intervention group for PPT (p<0.001) and all measures of CROM (p<0.001). Additionally, at 10 weeks the sagittal alignment variables showed significant differences favoring the intervention group for CV p<0.001 and SH (p<0.001) indicating improved CSA. Importantly, at the 1-year follow-up, between group analysis identified a regression back to baseline values for the control group for the non-significant group differences (NRS and NDI) at the 10-week mark. Thus, all variables were significantly different between groups favoring the intervention group at 1-year follow up: NRS (p<0.001), NDI (p<0.001), PPT p<0.001), CROM (p<0.001), CV (p<0.001), SH (p<0.001). CONCLUSION: The addition of the denneroll cervical orthotic to a multimodal program positively affected CMCPS outcomes at long term follow up. We speculate the improved sagittal cervical posture alignment outcomes contributed to our findings. TRIAL REGISTRATION: Pan African Clinical Trial Registry Clinical Trial Registry: PACTR201801002968301 , registered 11 January 2018 (retrospectively registered). PMID- 30419869 TI - Ready to run the wards? - A descriptive follow-up study assessing future doctors' clinical skills. AB - BACKGROUND: Recent studies have shown that clinical tasks only represent a small percentage in the scope of final-year medical students' activities and often lack sufficient supervision. It appears that final-year medical students are frequently deployed to perform "routine tasks" and show deficits in the performance of more complex activities. This study aimed to evaluate final-year students' clinical performance in multiple impromptu clinical scenarios using video-based assessment. METHODS: We assessed final-year medical students' clinical performance in a prospective, descriptive, clinical follow-up study with 24 final-year medical students during their Internal Medicine rotation. Participating students were videotaped while practicing history taking, physical examination, IV cannulation, and case presentation at the beginning and end of their rotation. Clinical performance was rated by two independent, blinded video assessors using binary checklists, activity specific rating scales and a five point global rating scale for clinical competence. RESULTS: Students' performance, assessed by the global rating scale for clinical competence, improved significantly during their rotation. However, their task performance was not rated as sufficient for independent practice in most cases. Analysis of average scores revealed that overall performance levels differed significantly, whereby average performance was better for less complex and more frequently performed activities. CONCLUSIONS: We were able to show that students' performance levels differ significantly depending on the frequency and complexity of activities. Hence, to ensure adequate job preparedness for clinical practice, students need sufficiently supervised and comprehensive on-ward medical training. PMID- 30419871 TI - Corneal higher-order aberrations of the anterior surface, posterior surface, and total cornea after small incision lenticule extraction (SMILE): high myopia versus mild to moderate myopia. AB - BACKGROUND: To investigate corneal higher-order aberrations (HOAs) of the anterior surface, posterior surface, and total cornea after small incision lenticule extraction (SMILE) in high myopic and mild to moderate myopic patients. METHODS: This retrospective study included 197 eyes (101 patients) undergoing SMILE surgery. According to the preoperative spherical equivalent (SE), treated eyes were divided into two groups: a high myopic group (more than - 6.0 D, Group H) and a mild to moderate myopic group (less than - 6.0 D, Group M). Corneal HOAs of the anterior surface, posterior surface, and total cornea were measured using a Scheimpflug camera preoperatively and 3 months postoperatively. Pearson's correlation analysis was conducted to determine relationships between corneal aberrations and the SE. RESULTS: There were no significant differences in third order to eight-order aberrations (RMS HOAs) of the anterior surface, posterior surface, and total corneal between the two groups before SMILE surgery. However, after SMILE, anterior and total corneal HOAs, especially vertical coma and spherical aberrations, significantly increased in both groups (p < 0.0167), whereas posterior corneal HOAs remained relatively stable (p > 0.0167). The induction of HOAs was significantly greater in Group H than Group M postoperatively (p < 0.0167). Changes in anterior surface and total corneal HOAs, especially vertical coma and spherical aberrations, were related to the SE (p < 0.05). CONCLUSIONS: Anterior and total corneal HOAs, particularly vertical coma and spherical aberrations, significantly increased after SMILE in both groups, whereas posterior corneal HOAs remained stable. Aberration changes were related to SE. TRIAL REGISTRATION: Retrospectively registered. ChiCTR-ORC-17011040 . Registered 1 April 2017. Name of registry: The observation of clinical results after corneal refractive surgery. Data of enrolment of the first participant to the trial: 15 December 2016. PMID- 30419870 TI - Impact of maternal ART on mother-to-child transmission (MTCT) of HIV at six weeks postpartum in Rwanda. AB - BACKGROUND: In 2010, Rwanda adopted ART for prevention of mother to child transmission of HIV from pregnant women living with HIV during pregnancy and breasfeeding period. This study examines rates of mother-to-child-transmission of HIV at 6-10 weeks postpartum and risk factors for mother-to-child transmission of HIV (MTCT) among HIV infected women on ART during pregnancy and breastfeeding. METHODS: A cross-sectional survey study was conducted between July 2011-June 2012 among HIV-exposed infants aged 6-10 weeks and their mothers/caregivers. Stratified multi-stage, probability proportional to size and systematic sampling to select a national representative sample of clients. Consenting mothers/caregivers were interviewed on demographic and program interventions. Dry blood spots from HIV-exposed infants were collected for HIV testing using DNA PCR technique. Results are weighted for sample realization. Univariable analysis of socio-demographic and programmatic determinants of early mother-to-child transmission of HIV was conducted. Variables were retained for final multivariable models if they were either at least of marginal significance (p value < 0.10) or played a confounding role (the variable had a noticeable impact > 10% change on the effect estimate). RESULTS: The study sample was 1639 infants with HIV test results. Twenty-six infants were diagnosed HIV-positive translating to a weighted MTCT estimate of 1.58% (95% CI 1.05-2.37%). Coverage of most elimination of MTCT (EMTCT) program interventions, was above 80, and 90.4% of mother-infant pairs received antiretroviral treatment or prophylaxis. Maternal ART and infant antiretroviral prophylaxis (OR 0.01; 95%CI 0.001-0.17) and maternal age older than 25 years were significantly protective (OR 0.33; 95%CI 0.14-0.78). No disclosure of HIV status, not testing for syphilis during pregnancy and preterm birth were significant risk factors for MTCT. Factors suggesting higher socio-demographic status (flush toilet, mother self-employed) were borderline risk factors for MTCT. CONCLUSION: ART for all women during pregnancy and breastfeeding was associated with the estimated low MTCT rate of 1.58%. Mothers who did not receive a full package of anti-retroviral therapy according to the Rwanda EMTCT protocol, and young and single mothers were at higher risk of MTCT and should be targeted for support in preventing HIV infection. PMID- 30419873 TI - Sleep and its relationship to health in parents of preterm infants: a scoping review. AB - BACKGROUND: Sleep is essential for human health and functioning. Parents of preterm infants are susceptible to sleep disturbances because of stress related to the preterm birth. Poor sleep has the potential to affect parental health and well-being. The aim of this study was to identify and map evidence on sleep and its relationship to health in parents of preterm infants. No review has summarized the evidence on this topic. METHODS: A scoping review was conducted. Seven health and medical electronic research databases were searched for relevant quantitative and qualitative primary studies, including grey literature. The search was performed March 2-7, 2017. RESULTS: Ten American studies and one Australian study were included in the review. Most research was quantitative and focused on maternal sleep and mental health within the first two weeks after the childbirth. Both objective and subjective sleep measures were used to study sleep at the hospital; actigraphs were not used after discharge. Maternal sleep was poor early postpartum, and this was associated with negative health outcomes. Two cohort studies compared sleep in mothers of preterm and term infants, but the results were conflicting. In one qualitative study, fathers described their inability to catch up on sleep after homecoming with a preterm baby. CONCLUSIONS: Quantitative studies reporting on maternal sleep early postpartum was most frequently occurring in the results. Qualitative research on the topic was identified as a knowledge gap. More cultural and geographical breadth, including research on fathers' sleep, is recommended in future research. PMID- 30419872 TI - Stromal fibroblast activation protein alpha promotes gastric cancer progression via epithelial-mesenchymal transition through Wnt/ beta-catenin pathway. AB - BACKGROUND: To investigate the influence of fibroblast activation protein alpha (FAP) derived from cancer-associated fibroblasts (CAFs), as well as potential mechanism of epithelial mesenchymal transition (EMT), on gastric cancer (GC) progression. METHODS: Correlation between CAFs-derived FAP and clinical results has been studied by using 60 GC cases. To confirm this relationship, SGC7901 cells were co-cultured with pre-established FAP-overexpressed fibroblasts in vitro and the characteristics including proliferation, migration, invasion and apoptosis abilities were detected subsequently. Meanwhile, SGC and GES1 cells cocultured with FAP-overexpressed fibroblasts were treated with cis-platinum for apoptotic analysis. The underlying EMT was detected by analyzing expression level of E-cadherin, ZO-1, N-cadherin, Vimentin, alpha-SMA, DKK1 and LEF-1 through western blot and immunofluorescence staining assay. Finally, the tumor-promoting ability of FAP was investigated by utlizing a xenograft gastric cancer nude mouse model. RESULTS: It show that FAP has a high-risk correlation with the malignant level of clinical outcomes in GC patients. FAP promotes the ability of proliferation, migration, invasion, apoptosis-inhibition of SGC7901 cells and induces apoptosis of GES1 cells in vitro. The mechanism study shows that epithelial markers have been down-regulated and mesenchymal markers and Wnt/beta catenin signal pathway related proteins have been up-regulated. Animal assay suggests that tumor burden has been enhanced by FAP significantly in vivo. CONCLUSIONS: Stromal FAP could be a potential prognostic biomarker in GC by promoting cancer progression via EMT through Wnt/ beta-catenin signal pathway. PMID- 30419874 TI - Association between diabetic retinopathy in type 2 diabetes and the ICAM-1 rs5498 polymorphism: a meta-analysis of case-control studies. AB - BACKGROUND: Genetic studies have reported contradictory results on the association between the intercellular adhesion molecule-1 (ICAM-1) rs5498 polymorphism and diabetic retinopathy (DR) risk in type 2 diabetic patients. We aimed to perform a systematic literature search and conduct random-effects meta analysis to provide a quantitative evaluation. METHODS: We searched Pubmed, Embase, Scopus, Web of Science and Wanfang databases from inception up to January 2018. Allelic and genotype frequencies of rs5498 was compared between DR cases and controls. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using a random effects model. RESULTS: Nine studies involving a total of 1792 cases and 1400 controls met our inclusion criteria. We did not find any significant association between rs5498 and DR risk at the dominant model (GG + GA versus AA, OR = 1.00, 95% CI: 0.66-1.50, P = 0.987), the recessive model (GG versus GA + AA, OR = 1.24, 95% CI: 0.86-1.77, P = 0.245), the GG versus AA contrast (OR = 1.14, 95% CI: 0.68-1.92, P = 0.611), and the G allele versus A allele contrast (OR = 1.08, 95% CI: 0.81-1.45, P = 0.592). Subgroup analysis by ethnicity showed no association in Asian populations (G allele versus A allele: OR = 1.05, 95% CI: 0.76-1.44, P = 0.790). Subgroup analysis by DR subtype also did not reveal any association of rs5498 with proliferative DR (G allele versus A allele: OR = 1.34, 95% CI: 0.71-2.52, P = 0.364) and non-proliferative DR (G allele versus A allele: OR = 0.71, 95% CI: 0.43-1.17, P = 0.180). CONCLUSION: Our meta-analyses provide no evidence of the association of rs5498 with DR in type 2 diabetic patients. PMID- 30419875 TI - Identifying the most suitable treatment for depression based on patients' attachment: study protocol for a randomized controlled trial of supportive expressive vs. supportive treatments. AB - BACKGROUND: In the absence of one intervention that can cure all patients with major depressive disorder (MDD), the leading cause of disability worldwide, increased attention has been focused on selecting the best treatment based on patient characteristics. Theory-driven hypotheses for selecting the best treatments have not yet been adequately investigated. The present study tested the a priory hypothesis that attachment orientations may determine whether patients benefit more from a treatment where alliance provides a facilitative environment for the treatment to work, as in the case of supportive-expressive psychotherapy, vs. where alliance is conceptualized as an active ingredient in itself, as in the case of supportive psychotherapy. METHOD/DESIGN: To test the hypothesis that attachment orientation moderates the effect of treatment condition on outcome, we conduct a randomized controlled trial (RCT). One hundred patients are randomized to 16 sessions of either supportive-expressive or supportive psychotherapy for MDD, conducted by experienced psychologists. The primary outcome is change in the Hamilton Rating Scale for Depression. Secondary outcome measures include self-reported depressive and other symptoms, psychological and interpersonal functioning, quality of life, and the presence of the diagnosis of depression. Additional measures include hormonal levels, motion synchrony, and acoustic attributes, performance on cognitive tasks, and narrative material (collected from the sessions and from interviews). DISCUSSION: The RCT will expand our understanding of how the outcome of treatment can be optimized by identifying the most promising role of alliance in treatment, based on patients' pre-treatment attachment orientation. Results will contribute to the ongoing theoretical debate concerning the differential efficacy of various psychotherapeutic approaches for patients with different attachment orientations. The RCT will also contribute to progress toward personalized treatment by informing therapists about which of two approaches are most effective with patients based on their attachment styles. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02728557 submitted on the 15.3.16. FUNDING: The Israel Science Foundation. Trial status: Recruitment is ongoing. PMID- 30419876 TI - Exploring the timing of medical student research internships: before or after clerkships? AB - BACKGROUND: The objective of this study was to determine the optimal positioning of the research internship, either before clinical clerkships, at the beginning of the medical Master's programme, or at the end. METHODS: A mixed methods study was carried out. We compared characteristics such as duration, location and grades for internships performed and students' motives for choosing to perform their research internship before or after clinical clerkships. We analysed students' answers to open-ended questions about the reasons for their choices, using the Self-Determination Theory of motivation. RESULTS: Students performing their research internship before clinical clerkships (n = 338) opted more often for an extended internship (OR = 3.16, 95% CI = 2.32-4.31) and an international location (OR = 2.22, 95% CI = 1.46-3.36) compared to those performing their research internships after clinical clerkships (n = 459). Neither the internship grades nor the number of international publications differed significantly between the two groups. Most of the students' motives (102 participants) were classified as extrinsic motivation for research. Students performing research before clinical clerkships more often showed intrinsic motivation for research, students performing research after clinical clerkships were mainly motivated by their career choice. CONCLUSION: To accommodate both groups of students, offering research internships before and after clinical clerkships, is recommended. PMID- 30419878 TI - Diagnosis of somatoform disorders in primary care: diagnostic agreement, predictors, and comaprisons with depression and anxiety. AB - BACKGROUND: To investigate (a) the diagnostic agreement between diagnoses of somatoform disorders, depressive and anxiety disorders obtained from a structured clinical interview and diagnoses reported from primary care physicians (PCPs) and (b) to identify patient and PCP-related predictors for the diagnostic agreement regarding the presence of a somatoform disorder. METHODS: Data from a cross sectional study comprising 112 primary care patients at high risk for somatoform disorders were analyzed. Diagnoses according to International Classification of Diseases, 10th revision (ICD-10) for somatoform, depressive and anxiety disorders were obtained from the Composite International Diagnostic Interview (CIDI) and compared with the diagnoses of the patients' PCPs documented in their medical records. Using multiple regression analyses, predictors for the PCPs' diagnosis of a somatoform disorder were analyzed. RESULTS: The agreement between PCP diagnoses and CIDI diagnoses was 32.3% for somatoform disorders, 48.0% for depressive disorders and 25.0% for anxiety disorders. Multiple regression analyses revealed the likelihood of being diagnosed with a somatoform disorder by PCP increased with somatic symptom severity (OR = 1.22, 95% CI 1.03-1.44). Regarding PCP-related characteristics, a specialization in internal medicine (OR = 5.95, 95% CI 1.70-20.80) and working in a solo practice (OR = 2.92, 95% CI 1.02 8.38) increased the likelihood that patients were diagnosed with a somatoform disorder. CONCLUSIONS: The present results indicate that the process of diagnosing somatoform disorders in primary care needs to be improved. Findings further underline the necessity to implement appropriate strategies to improve early detection of patients. TRIAL REGISTRATION: ISRCTN ISRCTN55870770 . Registered 22 October 2014. Retrospectively registered. PMID- 30419877 TI - Association of Glutathione S-transferase gene polymorphism with bladder Cancer susceptibility. AB - BACKGROUND: We conducted a meta-analysis to evaluate the relationship between the glutathione S-transferase MU1 (GSTM1)- and glutathione S-transferase theta1 (GSTT1)- null genotypes and susceptibility to bladder cancer. METHODS: We identified association reports from the databases of PubMed, Embase, the Cochrane Library and the China Biological Medicine Database (CBM disc) on July 1, 2017 and synthesized eligible investigations. Results were expressed using odds ratios (ORs) for dichotomous data, and we also calculated 95% confidence intervals (CIs). RESULTS: In this meta-analysis, we found that the GSTM1-null genotype was associated with bladder cancer risk in the overall population, and individually in whites, Africans and Asians (overall population: OR = 1.40, 95% CI: 1.31-1.48, P<0.00001; whites: OR = 1.39, 95% CI: 1.26-1.54, P<0.00001; Africans: OR = 1.54, 95% CI: 1.16-2.05, P = 0.003; Asians: OR = 1.45, 95% CI: 1.33-1.59, P<0.00001). The GSTT1-null genotype was associated with bladder cancer risk in the overall population, but not in whites, in Africans or Asians (overall population: OR = 1.11, 95% CI: 1.01-1.22, P = 0.03; whites: OR = 1.16, 95% CI: 0.99-1.36, P = 0.07; Africans: OR = 1.07, 95% CI: 0.65-1.76, P = 0.79; Asians: OR = 1.05, 95% CI: 0.91-1.22, P = 0.51). Interestingly, a dual-null GSTM1-GSTT1 genotype was associated with bladder cancer risk in the overall population and in Asians (overall population: OR = 1.48, 95% CI: 1.15-1.92, P = 0.002; Asians: OR = 1.62, 95% CI: 1.15-2.28, P = 0.006). In conclusion, the GSTM1-null, GSTT1-null and dual null GSTM1-GSTT1 genotypes might be associated with the onset of bladder cancer, but additional genetic-epidemiological studies should be conducted to explore this association further. PMID- 30419879 TI - Short stature as a presenting symptom of attenuated Mucopolysaccharidosis type I: case report and clinical insights. AB - BACKGROUND: Mucopolysaccharidosis type I (MPS I) results in significant disease burden and early treatment is important for optimal outcomes. Recognition of short stature and growth failure as symptoms of MPS I among pediatric endocrinologists may lead to earlier diagnosis and treatment. CASE PRESENTATION: A male patient first began experiencing hip pain at 5 years of age and was referred to an endocrinologist for short stature at age 7. Clinical history included recurrent respiratory infections, sleep apnea, moderate joint contractures, mild facial dysmorphic features, scoliosis, and umbilical hernia. Height was more than - 2 SD below the median at all time points. Growth velocity was below the 3rd percentile. Treatment for short stature included leuprolide acetate and recombinant human growth hormone. The patient was diagnosed with MPS I and began enzyme replacement therapy with laronidase at age 18. CONCLUSIONS: The case study patient had many symptoms of MPS I yet remained undiagnosed for 11 years after presenting with short stature. The appropriate path to MPS I diagnosis when patients present with short stature and/or growth failure plus one or more of the common signs of attenuated disease is described. Improved awareness regarding association of short stature and growth failure with attenuated MPS I is needed since early identification and treatment significantly decreases disease burden. PMID- 30419880 TI - Emotional experiences of medical students during cadaver dissection and the role of memorial ceremonies: a qualitative study. AB - BACKGROUND: It has been well reported that the emotional experiences of medical students in the gross anatomy laboratory could have significant impacts on their professional identity formation. This qualitative study aimed to investigate students' emotions towards cadaver dissection and the educational role of memorial ceremonies. METHODS: A total of 37 students from eight teams were recruited in the team-based dissection course during two consecutive academic years (2016 and 2017) at one medical school. In focus group interviews, students were encouraged to express and discuss their emotions regarding cadaver dissection and memorial ceremonies. RESULTS: The participants described their apprehension and anxiety during their first encounter with cadavers that diminished through gradual exposure. Unfortunately, their positive emotions such as gratitude and responsibility also tended to decline under the pressure of excessive workloads and frequent examinations. Memorial ceremonies, including not only large-scale events but also daily rituals, had educational effects that they prevented the decline of students' responsibility and respect during the dissection course. CONCLUSION: Educators should assist medical students in overcoming their initial distress and maintaining respectful attitudes throughout the dissection course. Memorial ceremonies can be effective educational tools for fostering appropriate attitudes and ethical practice in the gross anatomy laboratory. PMID- 30419881 TI - Splenic embolization for a giant splenic hemangioma in a child: a case report. AB - BACKGROUND: Splenic hemangioma is the most common benign tumor of the spleen. However, it remains a rare medical condition in children. Although the natural course of splenic hemangioma is slow growth, treatment for large splenic hemangiomas has been recommended due to the risk of spontaneous rupture causing life-threating hemorrhage. However, the optimal treatment for splenic hemangioma in children is unclear. CASE PRESENTATION: An 11-year-old girl had an enhancing mass, 61 * 54 * 65 mm in size and numerous daughter nodules throughout the entire spleen on a contrast-enhanced computed tomography scan of the abdomen and angiography. The patient was treated by complete embolization at the distal level of splenic artery, which resulted in total splenic infarction. Treatment-related complications were thrombocytosis and postembolization syndrome, including abdominal pain and, intermittent fever below 39 degrees C. There were no other serious complications, including bleeding. CONCLUSION: Splenic embolization may be a safe and less invasive intervention for children with a large splenic hemangioma. Further studies are needed to confirm the effectiveness of our approach. PMID- 30419882 TI - Hepatic artery pseudoaneurysm, bronchobiliary fistula in a patient with liver trauma. AB - BACKGROUND: Bronchobiliary fistula and hepatic artery pseudoaneurysm are rare complications of hepatic trauma. There are isolated case reports for both pseudoaneurysm and bronchobiliary fistula following hepatic trauma but there aren't reports of both conditions developing in a single patient. CASE PRESENTATION: This case describes an 18 year old hindu male who developed right hepatic artery pseudoaneurysm and bronchobiliary fistula following blunt abdominal trauma. Patient was managed with exploratory laparotomy followed by coil embolization and Endoscopic retrograde cholangiopancreatography stenting respectively. CONCLUSION: Rare complications of liver trauma include pseudoaneurysm and bronchobiliary fistula. These complications can rarely co- exist in a single patient. PMID- 30419883 TI - E-learning for chest x-ray interpretation improves medical student skills and confidence levels. AB - BACKGROUND: Radiology is an important aspect of medicine to which medical students often do not receive sufficient exposure. The aim of this project was to determine whether the integration of an innovative e-learning module on chest x ray interpretation of the heart would enhance the radiological interpretive skills, and improve the confidence, of first year graduate entry medical students. METHODS: All first-year graduate entry (all students had a prior university degree) medical students at the University of Limerick (n = 152) during academic year 2015-16 were invited to participate in this study. An assessment instrument was developed which consisted of 5 radiological cases to be interpreted over a designated and supervised 15-min time period. Students underwent a pre-, mid- and post-intervention assessment of their radiology interpretative skills. An online e-module was provided following the pre-test and additional practice cases were provided following the mid-intervention test. Assessment scores and confidence levels were compared pre-, mid- and post intervention. RESULTS: The overall performance (out of a total score of 25) for the 87 students who completed all three assessments increased from 13.2 (SD 3.36) pre-intervention to 14.3 (SD 2.97) mid-intervention to 15.8 (SD 3.40) post intervention. This change over time was statistically significant (p < 0.001) with a medium effect size (eta-squared = 0.35). Increases from pre- to post intervention were observed in each of the five areas assessed, although performance remained poor in diagnosis post-intervention. Of the 118 students who provided feedback after the intervention, 102 (86.4%) stated that they would recommend the resource to a colleague to improve their interpretative skills. CONCLUSIONS: This study suggests that early exposure to e-learning radiology modules is beneficial in undergraduate medical school curricula. Further studies are encouraged to assess how long the improvement may last before attrition. PMID- 30419884 TI - Impact of electronic and blended learning programs for manual perineal support on incidence of obstetric anal sphincter injuries: a prospective interventional study. AB - BACKGROUND: Obstetric anal sphincter injuries (OASIS) are associated with anal incontinence, dyspareunia and perineal pain. Bimanual perineal support technique (bPST) prevents OASIS. The aim of this study was to assess the effect of two different bPST training-methods on OASIS incidence. METHODS: This is a prospective-interventional quality improvement study conducted in two Palestinian maternity units between June 1 2015 and December 31 2016. Women having spontaneous or operative vaginal-delivery at >=24 gestational-weeks or a birthweight of >=1000 g (n = 1694) were recruited and examined vaginally and rectally immediately after vaginal birth by a trained assessor. Data on baseline OASIS incidence were collected during Phase-1 of the study. Subsequently, birth attendants in both maternity units were trained in bPST using two training modalities. A self-directed electronic-learning (e-learning) using an animated video was launched in phase-2 followed by a blended learning method (the animated e-learning video+ structured face-to-face training) in phase-3. OASIS incidence was monitored during phases-2 and 3. Variations in OASIS incidence between the three phases were assessed using Pearson-chi2-test (or Fisher's-Exact-test). The impact of each training-method on OASIS incidence was assessed using logistic regression analysis. RESULTS: A total of 1694 women were included; 376 in phase 1, 626 in phase-2 and 692 in phase-3. Compared to Phase-1, OASIS incidence was reduced by 45% (12.2 to 6.7%, aOR: 0.56, CI; 0.35-0.91, p = 0.018) and 74% (12.2 to 3.2%, aOR, 0.29, CI; 0.17-0.50, p < 0.001) in phases-2 and 3, respectively. There was also a significant reduction in OASIS incidence by 52% from phase-2 to phase-3 (6.7% (42/626) to 3.2% (22/692), p = 0.003). These reductions reached statistical significance among parous-women only (aOR: 0.18, CI; 0.07-0.49, p = 0.001) after the first training method tested in phase-2. However, the reduction was significant among both primiparous (aOR: 0.39, CI; 0.21-0.74, p = 0.004) and parous-women (aOR: 0.11, CI; 0.04-0.32, p < 0.001) after implementing the blended learning method in phase-3. CONCLUSION: The animated e-learning video had a positive impact on reducing OASIS incidence. However, this reduction was enhanced by the use of a blended learning program combining both e- learning and face-to face training modalities. STUDY REGISTRATION NUMBER: ClinicalTrialo.gov identifier: NCT02427854 , date: 28 April 2015. PMID- 30419885 TI - Treatment of deep cavities using a perforator-based island flap with partial de epithelization. AB - BACKGROUND: The perforator-based island flap is a popular option for defect coverage. In cases with deep cavities, however, the classical island flap may not be a suitable option. By de-epithelization of the peripheral portion of a perforator-based island flap, the distal part of the flap can be used to fill deep spaces, as the flap can be folded and inserted into the spaces. METHODS: From June 2015 to April 2017, 21 cases of deep internal defects were reconstructed with perforator-based island flaps with peripheral de epithelization. A fasciocutaneous flap was elevated and rotated with the pivot point on the perforator. After performing de-epithelization on the periphery of the flap, the de-epithelized portion of the flap was inserted and anchored into the internal defect. Demographic information about the patients, the size of the defects, the perforators that were used, and complications were recorded. RESULTS: During the follow-up period (mean, 14.2 months) of total 21 cases, no major complications such as flap loss occurred. In 2 cases, a minor complication was observed. Temporary flap congestion was seen in 1 case, and was treated with a short period of leech therapy, and the other case was partial necrosis on the flap margin, which was cured with minimal debridement and conservative treatment. No major problems have occurred, especially on the de-epithelized part of the flap and in the occupied space. CONCLUSIONS: With performing careful procedure, a perforator-based island flap with partial de-epithelization can be a useful option for the surgical treatment of deep cavities. TRIAL REGISTRATION: This study was retrospectively registered in the institutional review board on human subjects research and the ethics committee, Hanyang University Guri Hospital (Institutional Review Board File No. 2018-01-003-002 https://www.e irb.com:3443/devlpg/nlpgS200.jsp ). PMID- 30419886 TI - Cyclodextrin enhanced the soluble expression of Bacillus clarkii gamma-CGTase in Escherichia coli. AB - BACKGROUND: Cyclodextrin glycosyltransferases (CGTases) catalyze the synthesis of cyclodextrins, which are circular alpha-(1,4)-linked glucans used in many applications in the industries related to food, pharmaceuticals, cosmetics, chemicals, and agriculture, among others. Economic use of these CGTases, particularly gamma-CGTase, requires their efficient production. In this study, the effects of chemical chaperones, temperature and inducers on cell growth and the production of soluble gamma-CGTase by Escherichia coli were investigated. RESULTS: The yield of soluble gamma-CGTase in shake-flask culture approximately doubled when beta-cyclodextrin was added to the culture medium as a chemical chaperone. When a modified two-stage feeding strategy incorporating 7.5 mM beta cyclodextrin was used in a 3-L fermenter, a dry cell weight of 70.3 g.L- 1 was achieved. Using this cultivation approach, the total yield of gamma-CGTase activity (50.29 U.mL- 1) was 1.71-fold greater than that observed in the absence of beta-cyclodextrin (29.33 U.mL- 1). CONCLUSIONS: Since beta-cyclodextrin is inexpensive and nontoxic to microbes, these results suggest its universal application during recombinant protein production. The higher expression of soluble gamma-CGTase in a semi-synthetic medium showed the potential of the proposed process for the economical production of many enzymes on an industrial scale. PMID- 30419887 TI - Changes in renal papillary density after hydration therapy in calcium stone formers. AB - BACKGROUND: Previous studies have shown that, compared with non-stone formers, stone formers have a higher papillary density measured with computer tomography (CT) scan. The effect of increased hydration on such papillary density in idiopathic calcium stone formers is not known. METHODS: Patients with recurrent calcium oxalate stones undergoing endourological procedures for renal stones at our Institution from June 2013 to June 2014 were considered eligible for enrolment. Enrolled patients underwent a baseline unenhanced CT scan before the urological procedure; after endoscopic removal of their stones, the patients were instructed to drink at least 2 L/day of a hypotonic, oligomineral water low in sodium and minerals (fixed residue at 180 degrees C < 200 mg/L) for at least 12 months. Finally, the patients underwent a follow-up unenhanced CT scan during hydration regimen. RESULTS: Twenty-five patients were prospectively enrolled and underwent baseline and follow-up CT scans. At baseline, mean papillary density was 43.2 +/- 6.6 Hounsfield Units (HU) (43.2 +/- 6.7 for the left kidney and 42.8 +/- 7.1 HU for the right kidney). At follow-up and after at least 12 months of hydration regimen, mean papillary density was significantly reduced at 35.4 +/- 4.2 HU (35.8 +/- 5.0 for the left kidney and 35.1 +/- 4.2 HU for the right kidney); the mean difference between baseline and follow-up was - 7.8 HU (95% confidence interval - 10.6 to - 5.1 HU, p < 0.001). CONCLUSIONS: Increased fluid intake in patients with recurrent calcium oxalate stones was associated with a significant reduction in renal papillary density. TRIAL REGISTRATION: NCT03343743 , 15/11/2017 (Retrospectively registered). PMID- 30419888 TI - Design and implementation of RESCUR in Sweden for promoting resilience in children: a study protocol. AB - BACKGROUND: This research program aims to investigate the implementation and effects of a theoretically promising prevention method. It is being developed in a European research collaboration within a Comenius project (2012-2015) between 6 European universities (in Malta, Italy, Greece, Croatia, Portugal and Sweden) with the purpose of enhancing European children's resilience. METHODS/DESIGN: RESCUR in Sweden consists in a RCT study of the Resilience Curriculum (RESCUR) that is taking place in Sweden 2017-2019. The study is being performed by Junis, IOGT-NTO's Junior Association, part of IOGT International, in conjunction with researchers at Goteborg, Umea and Stockholm universities, and is being funded by the Public Health Agency of Sweden. Around 1000 children of the ages 7-12 will, through their schools and associations, or via groups in social services, be acquainted with the material. Children will learn and practice mindfulness, storytelling, group discussions and much more, all designed to strengthen protective factors and increase their resilience. The program also involves parents, who are taking part in the work to reinforce children's protective factors. Based on the work with groups of children, an effectiveness study including children aged 7-12 in school classes, with randomized and controlled pre- and post-measurements, self-rating questionnaires and group observations is being performed. The program will also be implemented in a non-governmental organization and in groups in social services. The study also investigates forms of implementation. DISCUSSION: The design of the study will enable the researchers to answer five research questions by using a mixed-methods approach. Implementation will be studied, which is a necessary prerequisite for an effect study. Moreover, the research procedure has been tailored to the target group, with age-appropriate measures as well as multiple informants, which will produce high-quality data for analysis. A special ethical challenge is the study of young children, and efforts to give children a voice have been included in the program. This project is regarded as having good potential to benefit children in general, and particularly children in vulnerable positions. TRIAL REGISTRATION: National Institute of Health, ClinicalTrials.gov identifier NCT03655418. Registered August 31, 2018. PMID- 30419889 TI - International phase IV validation study of an EORTC quality of life questionnaire for testicular cancer patients: the EORTC QLQ-TC26. AB - BACKGROUND: Given the high cure-rate for testicular cancer (TC) and the patients' young age, comprehensive evaluation of health-related quality of life (HRQOL) is an important consideration in this patient population. The EORTC QLQ-TC26 questionnaire module has been developed to supplement the EORTC QLQ-C30 in assessing TC-specific HRQOL in clinical trials and routine clinical practice. This international, multicentre phase IV validation study evaluated the psychometric properties of the new module. METHODS: This international, multicentre phase IV validation study enrolled testicular cancer patients from seven European countries. Patients completed the EORTC quality of life core questionnaire EORTC QLQ-C30 and the QLQ-TC26 at two consecutive time points and a debriefing questionnaire regarding the QLQ-TC26 after baseline assessment. Psychometric evaluation included examination of the hypothesized module scale structure, internal consistency and test-retest reliability, known-groups validity, responsiveness to change over time and cross-cultural acceptability. RESULTS: Data from 313 patients (mean age 38.6, SD 9.5) were analysed. All items exhibited a high completion rate with less than 2.4% missing values except for the sexuality items (up to 8.8%). The confirmatory factor analysis supported the hypothesised scale structure of the QLQ-TC26. Test-retest reliability was good for 8 of 12 scales (intraclass correlation: R t1|t2 ranged from 0.71-0.91) and four scales did not meet the acceptable criteria. Internal consistency was good for all twelve scales (Cronbach alpha = 0.79-0.90), except Communication (alpha = 0.67) and Sexual Functioning (alpha = 0.62). The module was able to distinguish clearly between patients with differing clinical status. Responsiveness to change over time was acceptable. CONCLUSION: The EORTC QLQ-TC26 is a valid, reliable and well-accepted condition-specific questionnaire, supplementing the EORTC QLQ-C30, for the assessment of testicular cancer patients' HRQOL in clinical trials. PMID- 30419890 TI - Factors influencing the use of the "not for generic substitution" mention for prescriptions in primary care: a survey with general practitioners. AB - BACKGROUND: Generic drug substitution is a public health policy challenge with high economic potential. Generic drugs are generally cheaper than brand-name drugs. Drugs are a significant part of the total health expenditure, especially in ambulatory care. We conducted a cross-sectional study with general practitioners in the Champagne-Ardenne region to determine physician-related factors and beliefs causing doctors to use the Not for Generic Substitution (NGS) mention. METHODS: Questionnaires were sent to General Practitioners (GPs) practicing in Champagne-Ardenne via 3 shipments, from January 2015 to May 2015. Prescriber characteristics and beliefs influencing the use of the NGS mention were assessed for frequent (>= 5%) and less frequent (< 5%) users of the NGS mention. RESULTS: Factors associated with above average NGS mention use in bivariate analysis included patient comorbidity, polypharmacy, a concern that generic and brand-name drugs are not bioequivalent and belief in higher efficacy of the brand name drug. The use of an e-prescribing system (EPS) and medical practice in rural areas appeared to be associated with lower use of NGS mention in bivariate analysis but not in multivariable analysis. In multivariable analysis, patient request was associated with a higher use of the NGS mention (NGS >= 5%, adjusted Odds Ratio (aOR) = 2.52; 95% CI = [1.46-4.35]; p = 0.001), which was also linked to patient age over 65 (NGS >= 5%, aOR = 2.33; 95% CI = [1.03-5.30]; p = 0.04). The NGS mention was often used for drugs where substitution is debated in the literature (thyroid hormones, antiepileptic drugs). CONCLUSION: This work highlights the involvement of the doctor-patient pair for the use of the NGS mention. Patient request was the major reason for using the NGS mention, even though it was not always endorsed by prescribers. Further studies are needed to assess patient views on generic drugs and drug substitution, accounting for their health status and socio-economic condition, to help improve the relevance of the information available to them. PMID- 30419891 TI - Designing mHealth for maternity services in primary health facilities in a low income setting - lessons from a partially successful implementation. AB - BACKGROUND: Increasing mobile phone ownership, functionality and access to mobile broad band internet services has triggered growing interest to harness the potential of mobile phone technology to improve health services in low-income settings. The present project aimed at designing an mHealth system that assists midlevel health workers to provide better maternal health care services by automating the data collection and decision-making process. This paper describes the development process and technical aspects of the system considered critical for possible replication. It also highlights key lessons learned and challenges during implementation. METHODS: The mHealth system had front-end and back-end components. The front-end component was implemented as a mobile based application while the back-end component was implemented as a web-based application that ran on a central server for data aggregation and report generation. The current mHealth system had four applications; namely, data collection/reporting, electronic health records, decision support, and provider education along the continuum of care including antenatal, delivery and postnatal care. The system was pilot-tested and deployed in selected health centers of North Shewa Zone, Amhara region, Ethiopia. RESULTS: The system was used in 5 health centers since Jan 2014 and later expanded to additional 10 health centers in June 2016 with a total of 5927 electronic forms submitted to the back-end system. The submissions through the mHealth system were slightly lower compared to the actual number of clients who visited those facilities as verified by record reviews. Regarding timeliness, only 11% of the electronic forms were submitted on the day of the client visit, while an additional 17% of the forms were submitted within 10 days of clients' visit. On average forms were submitted 39 days after the day of clients visit with a range of 0 to 150 days. CONCLUSIONS: In conclusion, the study illustrated that an effective mHealth intervention can be developed using an open source platform and local resources. The system impacted key health outcomes and contributed to timely and complete data submission. Lessons learned through the process including success factors and challenges are discussed. PMID- 30419892 TI - Meripilus giganteus ethanolic extract exhibits pro-apoptotic and anti proliferative effects in leukemic cell lines. AB - BACKGROUND: The interest towards botanicals and plant extracts has strongly risen due to their numerous biological effects and ability to counteract chronic diseases development. Among these effects, chemoprevention which represents the possibility to counteract the cancerogenetic process is one of the most studied. The extracts of mushroom Meripilus giganteus (MG) (Phylum of Basidiomycota) showed to exert antimicrobic, antioxidant and antiproliferative effects. Therefore, since its effect in leukemic cell lines has not been previously evaluated, we studied its potential chemopreventive effect in Jurkat and HL-60 cell lines. METHODS: MG ethanolic extract was characterized for its antioxidant activity and scavenging effect against different radical species. Moreover, its phenolic profile was evaluated by HPLC-MS-MS analyses. Flow cytometry (FCM) analyses of Jurkat and HL-60 cells treated with MG extract (0-750 MUg/mL) for 24 72 h- allowed to evaluate its cytotoxicity, pro-apoptotic and anti-proliferative effect. To better characterize MG pro-apoptotic mechanism ROS intracellular level and the gene expression level of FAS, BAX and BCL2 were also evaluated. Moreover, to assess MG extract selectivity towards cancer cells, its cytotoxicity was also evaluated in human peripheral blood lymphocytes (PBL). RESULTS: MG extract induced apoptosis in Jurkat and HL-60 cells in a dose- and time- dependent manner by increasing BAX/BCL2 ratio, reducing ROS intracellular level and inducing FAS gene expression level. In fact, reduced ROS level is known to be related to the activation of apoptosis in leukemic cells by the involvement of death receptors. MG extract also induced cell-cycle arrest in HL-60 cells. Moreover, IC50 at 24 h treatment resulted 2 times higher in PBL than in leukemic cell lines. CONCLUSIONS: Our data suggest that MG extract might be considered a promising and partially selective chemopreventive agent since it is able to modulate different mechanisms in transformed cells at concentrations lower than in non-transformed ones. PMID- 30419893 TI - Diabetes and TelecommunicationS (DATES) study to support self-management for people with type 2 diabetes: a randomized controlled trial. AB - BACKGROUND: The increasing prevalence of type 2 diabetes and suboptimal glycaemic control in Kuwait requires novel, wide-reaching, low-cost interventions to motivate and mobilise individuals towards more effective self-management. More than 2 million people in Kuwait own mobile phones. We will test whether automated personalised health text messages based on principles of motivational interviewing and are responsive to biodata delivered remotely is potentially effective in improving glycaemic control compared to usual care. METHODS: This is a two-arm parallel single-blind randomised controlled trial of 572 individuals with type 2 diabetes in Kuwait. We will develop a culturally appropriate database of text messages supporting positive lifestyle changes in type 2 diabetes. A computer programme will deliver over 400 text messages over a 12-month period using algorithms which provide participants with information on diet and physical activity as well as personalised messages regarding motivators to change behaviours. Individuals aged 18-75 years with established type 2 diabetes who are fluent in Arabic or English and officially resident in Kuwait will be identified via screening of hospital diabetes clinic and primary care practices and invited to participate. A sample of 572 participants will be randomised to usual care or usual care plus the DATES text message intervention. Randomisation will be conducted by an independent Clinical Trials Unit and researchers collecting baseline and outcome data will be blinded to treatment allocation. The primary outcome is change in HbA1c and weight at 12 months in both study arms. Secondary outcomes will include changes in physical activity, fasting lipids and quality of life in both study arms. DISCUSSION: The potential of mobile phones in improving diabetes self-care in settings with a high prevalence of diabetes and widespread mobile phone usage has face validity. Mobile phones and text messaging are an understudied virtual communication media which can deliver discrete focused psychological support to motivate and enable diabetes self-care changes. TRIAL REGISTRATION: ISRCTN10342151 . 11/03/2015. PMID- 30419894 TI - Health care utilization and cost after discharge from a mental health hospital; an RCT comparing community residential aftercare and treatment as usual. AB - BACKGROUND: Community residential aftercare (step-down) services can ease the transition after a mental health hospital stay for patients with severe mental illness (SMI). AIMS: To investigate use of community and specialised mental health care services and costs in patients with SMI the first 12 months after discharge from a mental health hospital (MHH), comparing community residential aftercare (CRA) and treatment as usual. METHODS: An open parallel group randomised controlled trial with 41 participants. Data on use of specialist services (hospital, ambulant treatment and outpatient treatment) and community services (residential stays, home help, home care nursing, mental health consultation) were collected from specialist and community registers and health records. RESULTS: For the primary outcome, utilisation of community mental health services, the intervention group used, on average, 29% fewer hours (mean differences - 21.6 h, 95% CI -93.1 to 44.9, p = .096) with a cost saving of 29% (mean differences - 1845 EUR, 95% CI -8267 to 4171, p = .102), but the estimates were imprecise. For the secondary outcome, the study groups had the same total number of inpatient days (66 days), but the intervention group had on average of 13.4 fewer inpatient days in the mental health hospital (95% CI -29.9 to 0.9. p = .008). The number of inpatient admissions (mean difference - 0.9 admissions, 95% CI -3.5 to 1.5, p = .224) and readmissions (- 0.8, 95% CI -2.5 to 0.9. p = .440) was lower in the intervention group. The intervention group had on average a total cost saving of 38.5% (mean differences - 23,071 EUR, 95% CI -45,450 to 3027. p = .057). A post hoc multivariable regression analysis controlling for baseline characteristics gave a reduction in total cost in favour of the intervention group of - 19,781 EUR (95% CI -44,072 to 4509, p=,107). CONCLUSION: In this study, it was not possible to draw a definite conclusion about the effect, due to the small sample and imprecision of the estimates. The direction of the results and size of the point estimate, in addition to findings in other studies, indicates that transferring patients ready for discharge from mental hospital to community residential aftercare can have the potential to reduce total consumption of health services and costs without increased hospital admissions. TRIAL REGISTRATION: Registered in clinicaltrials.gov ( NCT01719354 ). PMID- 30419895 TI - Comparative point prevalence survey of antimicrobial consumption between a hospital in Northern Ireland and a hospital in Jordan. AB - BACKGROUND: To assess antimicrobial prescribing in a Northern Ireland hospital (Antrim Area Hospital (AAH)) and compare them with those of a hospital in Jordan (Specialty Hospital). METHODS: Using the Global-PPS approach, the present study surveyed patients admitted to the hospital in 2015, the prescribed antibiotics, and a set of quality control indicators related to antibiotics. RESULTS: Ultimately, 444 and 112 inpatients in the AAH and the Specialty Hospital, respectively, were surveyed. For the medical group, 165 inpatients were prescribed 239 antibiotics in the AAH, while 44 patients in the Specialty Hospital were prescribed 65 antibiotics. In relation to the surgical group, 34 inpatients treated for infection were prescribed 66 antibiotics in the AAH, while 41 patients in the Specialty Hospital treated for infection were prescribed 56 antibiotics. For the medical patients, the most frequently prescribed antibiotics in the AAH were a combination of penicillins (18.8%) and penicillins with extended spectrum (18.8%). For the surgical patients, the most frequently prescribed antibiotics in the AAH were imidazole derivatives (24.2%). For the medical and surgical patients in the Specialty Hospital, the most frequently prescribed antibiotics were third-generation cephalosporins (26.2 and 37.5%, respectively). In medical patients, compliance to guidelines was 92.2% in the Specialty Hospital compared to 72.0% in the AAH (p < 0.001). In surgical patients, compliance to guidelines was 92.7% in the Specialty Hospital compared to 81.8% in the AAH (p = 0.012). CONCLUSIONS: The present study highlighted differences in the utilisation of antimicrobials between two hospitals in two distinct regions and benchmarked antibiotic prescriptions across two hospitals. PMID- 30419896 TI - Development and pilot evaluation of a pregnancy-specific mobile health tool: a qualitative investigation of SmartMoms Canada. AB - BACKGROUND: Mobile technology is ubiquitous. Women of childbearing age have embraced health information technology for pregnancy-related counsel as prenatal care provider communication is increasingly scarce and brief. Pregnant women and new mothers place high value in the use of online sources to support their pregnancy information needs. In Canada, over 300,000 women are pregnant annually, with approximately 60% exceeding evidence-based weight gain recommendations. Mobile health (mHealth) tools, such as mobile applications (app), have the potential to reduce excessive gestational weight gain, offering pregnant women trustworthy guidance, ultimately improving the health outcomes of mothers and infants. Therefore, the primary aim of this study was to implement a qualitative, descriptive research design to assess the receptiveness, functionality, and future prospective of the SmartMoms Canada mHealth app. METHODS: Two focus groups (n = 13) involving both currently pregnant and recently postpartum women were organized on the same day. Focus groups were transcribed verbatim and thematic analysis was undertaken using manual coding and NVivo software. Participants who took part in the focus groups (n = 13) and those who could not attend (n = 4) were asked to complete a Likert-scale survey. All survey responses (n = 17) were analyzed using simple tabulation and percentage analysis. RESULTS: Participants were technologically proficient and interacted with several mHealth tools prior to testing the SmartMoms Canada app. Six major themes emerged from thematic analysis: knowledge of pregnancy-specific mHealth services, knowledge and attitudes of weight gain guidelines, weight tracking, strengths of the app, critique and lastly, future suggestions for the app. CONCLUSIONS: Our thematic analysis found that women positively viewed the future potential of our app and offered constructive feedback to improve the next version. Participants sought more personalization and enhanced app interactivity, along with promotion of overall maternal health including nutrition and mental health, in addition to weight tracking. PMID- 30419897 TI - Metabolic modeling and response surface analysis of an Escherichia coli strain engineered for shikimic acid production. AB - BACKGROUND: Classic metabolic engineering strategies often induce significant flux imbalances to microbial metabolism, causing undesirable outcomes such as suboptimal conversion of substrates to products. Several mathematical frameworks have been developed to understand the physiological and metabolic state of production strains and to identify genetic modification targets for improved bioproduct formation. In this work, a modeling approach was applied to describe the physiological behavior and the metabolic fluxes of a shikimic acid overproducing Escherichia coli strain lacking the major glucose transport system, grown on complex media. RESULTS: The obtained flux distributions indicate the presence of high fluxes through the pentose phosphate and Entner-Doudoroff pathways, which could limit the availability of erythrose-4-phosphate for shikimic acid production even with high flux redirection through the pentose phosphate pathway. In addition, highly active glyoxylate shunt fluxes and a pyruvate/acetate cycle are indicators of overflow glycolytic metabolism in the tested conditions. The analysis of the combined physiological and flux response surfaces, enabled zone allocation for different physiological outputs within variant substrate conditions. This information was then used for an improved fed batch process designed to preserve the metabolic conditions that were found to enhance shikimic acid productivity. This resulted in a 40% increase in the shikimic acid titer (60 g/L) and 70% increase in volumetric productivity (2.45 gSA/L*h), while preserving yields, compared to the batch process. CONCLUSIONS: The combination of dynamic metabolic modeling and experimental parameter response surfaces was a successful approach to understand and predict the behavior of a shikimic acid producing strain under variable substrate concentrations. Response surfaces were useful for allocating different physiological behavior zones with different preferential product outcomes. Both model sets provided information that could be applied to enhance shikimic acid production on an engineered shikimic acid overproducing Escherichia coli strain. PMID- 30419898 TI - Protective immunity induced by Eimeria common antigen 14-3-3 against Eimeria tenella, Eimeria acervulina and Eimeria maxima. AB - BACKGROUND: Avian coccidiosis is often caused by co-infection with several species of Eimeria worldwide. Developing a multivalent vaccine with an antigen common to multiple Eimeria species is a promising strategy for controlling clinical common co-infection of Eimeria. In the previous study, 14-3-3 was identified as one of the immunogenic common antigen in E. tenella, E. acervulina and E. maxima. The aim of the present study was to evaluate the immunogenicity and protective efficacy of Ea14-3-3 in the form of DNA vaccine against infection with three species of Eimeria both individually and simultaneously. RESULTS: After vaccination with pVAX-Ea14-3-3, the Ea14-3-3 gene was transcribed and expressed in the injected muscles. Vaccination with pVAX-Ea14-3-3 significantly increased the proportion of CD4+ and CD8+ T lymphocytes and produced a strong IgY response in immunized chickens. Similarly, pVAX-Ea14-3-3 stimulated the chicken's splenocytes to produce high levels of Th1-type (IFN-gamma, IL-2) and Th2-type (IL 4) cytokines. The vaccine-induced immune response was responsible to increase weight gain, decreased the oocyst output, and alleviated enteric lesions significantly in immunized chickens as compared to control group, in addition to induce moderate anti-coccidial index (ACI). CONCLUSION: These results indicate that Ea14-3-3 is highly immunogenic and capable to induce significant immune responses. Furthermore, Ea14-3-3 antigen can provide effective protection against infection with Eimeria tenella, Eimeria acervulina, Eimeria maxima both individually and in combination with three Eimeria species. Significant outcomes of our study provide an effective candidate antigen for developing a multivalent Eimeria vaccine against mixed infection with various Eimeria species under natural conditions. PMID- 30419899 TI - Interrelationship between tetracycline resistance determinants, phylogenetic group affiliation and carriage of class 1 integrons in commensal Escherichia coli isolates from cattle farms. AB - BACKGROUND: Carriage of antibiotic-resistant foodborne pathogens by food production animals is one of many contributors to treatment failure in health care settings, and it necessitates an integrated approach to investigate the carriage of resistant pathogens harboring integrons in food-producing animals. METHODS: Escherichia coli isolates with reduced susceptibility to tetracycline antibiotics (n = 92) were tested for associations between carriage of class1 integrons, phylogenetic group affiliation and tetracycline resistance determinants using the MIC method, PFGE analysis, PCR and sequencing. RESULTS: Phylogroups B1 and A were the most common (58.7 and 19.6%, respectively), followed by groups D (20.7%) and B2 (1.1%). All isolates carried at least one of the tet genes examined. In addition, 88 (95.7%) of all tetracycline-resistant isolates carried tet(A) or tet(B), while 47 (51.1%) and 41 (44.6%) harbored only tet(A) or tet(B), respectively. Likewise, isolates harboring these genes had a higher chance (P < 0.05) of carrying class 1 integrons. Of the tested isolates, 38 (41.3%) carried the intI1 gene. Classical integrons with complete genes (sul1 and qacE?1) at the 3'-CS were recognized in 27 isolates. PCR screening and subsequent sequencing demonstrated that 84.2% (32/38) of the intI1-positive isolates harbored resistance gene cassettes. Overall, seven gene cassettes were identified, either solely or combined with another gene cassette. The most common gene was aadA1 (10 isolates), followed by a combination of aadA1-dfrA1 (seven isolates), aadA1-dfrA12 (six isolates) and aadA1-aadA2-dfrA12 (three isolates). Genetic typing using PFGE showed minimum clonal relatedness with 28 different clusters and 12-25 discernible DNA fragments. CONCLUSIONS: This study brings new insight into the relationships between the presence of integrons, phylogenetic group association and characteristics of tetracycline antibiotic resistance determinants in commensal E. coli strains. PMID- 30419900 TI - Maternal fruit and vegetable or vitamin C consumption during pregnancy is associated with fetal growth and infant growth up to 6 months: results from the Korean Mothers and Children's Environmental Health (MOCEH) cohort study. AB - BACKGROUND: Based on data obtained from pregnant women who participated in the Mothers and Children's Environmental Health (MOCEH) study in South Korea, we aimed to determine whether maternal intake of fruits and vegetables or vitamin C is associated with fetal and infant growth. METHODS: A total of 1138 Korean pregnant women at 12-28 weeks gestation with their infants were recruited as study participants for the MOCEH. Intake of fruits and vegetables or vitamin C during pregnancy was assessed by a 1-day 24-h recall method. Fetal biometry was determined by ultrasonography at late pregnancy. Infant weight and length were measured at birth and 6 months. RESULTS: A multiple regression analysis after adjusting for covariates showed that maternal intake of fruits and vegetables was positively associated with the biparietal diameter of the fetus and infant's weight from birth to 6 months. Also, maternal vitamin C intake was positively associated with the abdominal circumference of the fetus and infant birth length. In addition, there was a significant inverse relationship between consumption of fruits and vegetables (below the median compared to above the median of >=519 g/d) and the risk of low growth (<25th percentile) of biparietal diameter (odds ratio (OR): 2.220; 95% confidence interval (CI): 1.153-4.274) and birth weight (OR: 1.434; 95% CI: 1.001-2.056). A significant inverse relationship also existed between vitamin C consumption (below vs above the estimated average requirement (EAR) of >=85 mg/d) and the risk of low growth (<25th percentile) of birth weight (OR: 1.470; 95% CI: 1.011-2.139), weight from birth to 6 months (OR: 1.520; 95% CI: 1.066-2.165), and length at birth (OR: 1.579; 95% CI: 1.104-2.258). CONCLUSIONS: An increased intake of fruits and vegetables or vitamin C at mid pregnancy is associated with increased fetal growth and infant growth up to 6 months of age. PMID- 30419901 TI - Malaria epidemiology in Suriname from 2000 to 2016: trends, opportunities and challenges for elimination. AB - BACKGROUND: Suriname has experienced a significant change in malaria transmission risk and incidence over the past years. The country is now moving toward malaria elimination. The first objective of this study is to describe malaria epidemiological trends in Suriname between 2000 and 2016. The second objective is to identify spatiotemporal malaria trends in notification points between 2007 and 2016. METHODS: National malaria surveillance data resulting from active and passive screening between 2000 and 2016 were used for the temporal trend analysis. A space-time cluster analysis using SaTScanTM was conducted on Malaria Programme-data from 2007 to 2016 comparing cases (people tested positive) with controls (people tested negative). RESULTS: Suriname experienced a period of high malaria incidence during 2000-2005, followed by a steep decline in number of malaria cases from 2005 onwards. Imported malaria cases, mostly of Brazilian nationality and travelling from French Guiana, were major contributors to the reported number of cases, exceeding the national malaria burden (94.2% of the total). Most clusters in notification points are found in the border area between Suriname and French Guiana. Clustering was also found in the migrant clinic in Paramaribo. CONCLUSIONS: Suriname has successfully reduced malaria to near elimination level in the last 17 years. However, the high malaria import rate resulting from cross-border moving migrants is a major challenge for reaching elimination. This requires continued investment in the national health system, with a focus on border screening and migrant health. A regional approach to malaria elimination within the Guianas and Brazil is urgently needed. PMID- 30419902 TI - Evaluating the impact of a network of research partnerships: a longitudinal multiple case study protocol. AB - BACKGROUND: Conducting and/or disseminating research together with community stakeholders (e.g. policy-makers, practitioners, community organisations, patients) is a promising approach to generating relevant and impactful research. However, creating strong and successful partnerships between researchers and stakeholders is complex. Thus far, an in-depth understanding of how, when and why these research partnerships are successful is lacking. The aim of this study is to evaluate and explain the outcomes and impacts of a national network of researchers and community stakeholders over time in order to gain a better understanding of how, when and why research partnerships are successful (or not). METHODS: This longitudinal multiple case study will use data from the Canadian Disability Participation Project, a large national network of researchers and community stakeholders working together to enhance community participation among people with physical disabilities. To maximise the impact of research conducted within the Canadian Disability Participation Project network, researchers are supported in developing and implementing knowledge translation plans. The components of the RE-AIM framework (reach, effectiveness, adoption, implementation and maintenance) will guide this study. Data will be collected from different perspectives (researchers, stakeholders) using different methods (logs, surveys, timeline interviews) at different time points during the years 2018-2021. A combination of data analysis methods, including network analysis and cluster analysis, will be used to study the RE-AIM components. Qualitative data will be used to supplement the findings and further understand the variation in the RE-AIM components over time and across groups. DISCUSSION: The outcomes, impacts and processes of conducting and disseminating research together with community stakeholders will be extensively studied. The longitudinal design of this study will provide a unique opportunity to examine research partnerships over time and understand the underlying processes using a variety of innovative research methods (e.g. network analyses, timeline interviews). This study will contribute to opening the 'black box' of doing successful and impactful health research in partnership with community stakeholders. TRIAL REGISTRATION: Open Science Framework: https://osf.io/kj5xa/ . PMID- 30419904 TI - A social systems analysis of implementation of El Salvador's national HIV combination prevention: a research agenda for evaluating Global Health Initiatives. AB - BACKGROUND: Global Health Initiatives (GHIs) have been instrumental in the rapid acceleration of HIV prevention, treatment access, and availability of care and support services for people living with HIV (PLH) in low and middle income countries (LMIC). These efforts have increasingly used combination prevention approaches that include biomedical, behavioral, social and structural interventions to reduce HIV incidence. However, little research has evaluated their implementation. We report results of qualitative research to examine the implementation of a national HIV combination prevention strategy in El Salvador funded by the Global Fund to Fight AIDS, Tuberculosis and Malaria. METHODS: We conducted in-depth interviews with principal recipients of the funding, members of the Country Coordinating Mechanism (CCM) and front line peer outreach workers and their clients. We analyzed the data using a dynamic systems framework. RESULTS: El Salvador's national HIV combination prevention strategy had three main goals: 1) to decrease the sexual risk behaviors of men who have sex with men (MSM), commercial sex workers (CSW) and transgender women (TW); 2) to increase HIV testing rates among members of these populations and the proportion of PLH who know their status; and 3) to improve linkage to HIV treatment and adherence to antiretroviral therapy (ART). Intervention components to achieve these goals included peer outreach, community prevention centers and specialized STI/HIV clinics, and new adherence and retention protocols for PLH. In each intervention component, we identified several factors which reinforced or diminished intervention efforts. Factors that negatively affected all intervention activities were an increase in violence in El Salvador during implementation of the strategy, resistance to decentralization, and budget constraints. Factors that affected peer outreach and sexual risk reduction were the human resource capacity of grassroots organizations and conflicts of the national HIV strategy with other organizational missions. CONCLUSIONS: Overall, the national strategy improved access to HIV prevention and care through efforts to improve capacity building of grass roots organizations, reduced stigma, and improved coordination among organizations. However, failure to respond to environmental and organizational factors limited the intervention's potential impact. PMID- 30419905 TI - AXL phosphorylates and up-regulates TNS2 and its implications in IRS-1-associated metabolism in cancer cells. AB - BACKGROUND: TNS2 is a focal adhesions protein and a binding partner for many proteins, including the receptor tyrosine kinase Axl. Although TNS2 can bind with Axl, the details of their interactions have not been elucidated. TNS2 is involved in IRS-1 signaling pathway. In this study, we confirmed the relationship between TNS2 expression and the expression of Axl, IRS-1, PDK1 and Glut4 in pancreatic cancer patients. METHODS: The expression levels of TNS2, Axl, IRS-1, PDK1 and Glut4 in human cancer cells were measured by Western blot and/or IP-Western blot assays. Paired samples of pancreatic cancer and non-cancer tissues were obtained from 33 patients and were used to construct tissue microarrays. The expression levels of these markers in the tissue microarrays were measured by enzyme-linked Immunohistochemistry assay, and the relationships were analyzed by Pearson's chi square test and two-tailed t-test analysis. RESULTS: We demonstrated for the first time that TNS2 is a phosphorylation substrate of Axl. Moreover, we found a positive relationship between TNS2 expression and the expression of Axl, IRS-1, PDK1 and Glut4 in pancreatic cancer patients. Based on these results, we suggest that Axl modulates glucose metabolism potentially through TNS2 and IRS-1. We hypothesize that there exists a novel mechanism whereby Axl binds to and phosphorylates TNS2, releasing TNS2 from interaction with IRS-1 and resulting in increased stability of IRS-1. The two key enzymes of aerobic glycolysis (Glut4 and PDK1) were found to be up-regulated by Axl/TNS2/IRS-1 cross-talk and may play a critical role in glucose metabolism of cancer cells. CONCLUSIONS: Our results revealed for the first time that Axl binds to and phosphorylates TNS2 and that Axl/TNS2/IRS-1 cross-talk may potentially play a critical role in glucose metabolism of cancer cells. PMID- 30419906 TI - Paralytic rabies in a goat. AB - BACKGROUND: Paralytic form of rabies is frequent in cattle in Latin America, but it is uncommon in goats. There are few clinical reports on furious rabies affecting goats, and the sporadic cases of rabid goats from surveillance programs worldwide lack clinical data. Furthermore, few studies reported the cerebrospinal fluid findings in rabid livestock. CASE PRESENTATION: On a farm in Midwestern Brazil, six of 47 Saanen goats died within one week. No vaccination protocols were implemented on the farm and the owner stated bat bites history on the livestock. Although rabies is endemic in Brazil, livestock vaccination is not mandatory. One 1-year-old buck was evaluated and showed non-specific clinical signs evolving within 12-h to nervous signs. Cerebrospinal fluid analysis revealed mononuclear pleocytosis, hyperproteinemia and high glucose levels. At necropsy, no gross lesions were present. Microscopically, discrete to moderate perivascular lymphoplasmacytic cuffing in gray and white matter, neuronal necrosis, neuronophagia, and mononuclear ganglioneuritis was observed in the brainstem and cervical spinal cord. Immunohistochemistry revealed strong anti rabies virus immunostaining. Fresh central nervous system samples were positive for rabies in direct fluorescent antibody test (dFAT) and mouse intracerebral inoculation test (MIT). Exposed livestock recommendations included immediate vaccination, a strict isolation period of 90 days, and booster vaccinations during the third and eighth weeks. CONCLUSION: IHC revealed the widespread distribution of rabies virus antigen in the goat's CNS, contrasting the discrete pathological changes. In this goat, definitive diagnosis of paralytic rabies was obtained through the association of epidemiological, clinical, laboratorial, pathological findings (histology and IHC) and gold standard confirmatory tests (dFAT and MIT). PMID- 30419903 TI - Biomedical engineer's guide to the clinical aspects of intensive care mechanical ventilation. AB - BACKGROUND: Mechanical ventilation is an essential therapy to support critically ill respiratory failure patients. Current standards of care consist of generalised approaches, such as the use of positive end expiratory pressure to inspired oxygen fraction (PEEP-FiO2) tables, which fail to account for the inter- and intra-patient variability between and within patients. The benefits of higher or lower tidal volume, PEEP, and other settings are highly debated and no consensus has been reached. Moreover, clinicians implicitly account for patient specific factors such as disease condition and progression as they manually titrate ventilator settings. Hence, care is highly variable and potentially often non-optimal. These conditions create a situation that could benefit greatly from an engineered approach. The overall goal is a review of ventilation that is accessible to both clinicians and engineers, to bridge the divide between the two fields and enable collaboration to improve patient care and outcomes. This review does not take the form of a typical systematic review. Instead, it defines the standard terminology and introduces key clinical and biomedical measurements before introducing the key clinical studies and their influence in clinical practice which in turn flows into the needs and requirements around how biomedical engineering research can play a role in improving care. Given the significant clinical research to date and its impact on this complex area of care, this review thus provides a tutorial introduction around the review of the state of the art relevant to a biomedical engineering perspective. DISCUSSION: This review presents the significant clinical aspects and variables of ventilation management, the potential risks associated with suboptimal ventilation management, and a review of the major recent attempts to improve ventilation in the context of these variables. The unique aspect of this review is a focus on these key elements relevant to engineering new approaches. In particular, the need for ventilation strategies which consider, and directly account for, the significant differences in patient condition, disease etiology, and progression within patients is demonstrated with the subsequent requirement for optimal ventilation strategies to titrate for patient- and time-specific conditions. CONCLUSION: Engineered, protective lung strategies that can directly account for and manage inter- and intra-patient variability thus offer great potential to improve both individual care, as well as cohort clinical outcomes. PMID- 30419907 TI - Primary immunodeficiency diseases in lung disease: warning signs, diagnosis and management. AB - BACKGROUND: Pulmonary complications are common in primary immunodeficiency diseases (PID) and contribute to morbidity and mortality in these patients. However, their varied presentation and a general lack of awareness of PID in this setting make early diagnosis and treatment difficult. The aim of this study was to define the warning signs of PID in patients with respiratory manifestations, the necessary diagnostic tests, and the therapeutic management of both children and adults. METHODS: A review of the literature was performed, and 43 PID interdisciplinary specialists were consulted. RESULTS: This document identifies the pulmonary and extrapulmonary manifestations that should prompt a suspicion of PID, the immunological and respiratory tests that should be included in the diagnostic process according to the level of care, recommendations regarding the use of immunoglobulin replacement therapy according to the specific immunodeficiency, and the minimum recommended immunological and pulmonary monitoring in these patients. CONCLUSIONS: This document is the first to combine scientific evidence with the opinion of a broad panel of experts specializing in the treatment of patients with immunodeficiencies. It aims to provide a useful tool for all practitioners who are regularly involved in the management of these patients. PMID- 30419908 TI - Seroprevalence of border disease virus and other pestiviruses in sheep in Algeria and associated risk factors. AB - BACKGROUND: Border disease virus (BDV) is a pestivirus responsible for significant economic losses in sheep industry. The present study was conducted between 2015 and 2016 to determine the flock seroprevalence of the disease in Algeria and to identify associated risk factors. 56 flocks from nine departments were visited and 689 blood samples were collected from adult sheep between 6 and 24 months of age (n = 576) and from lambs younger than 6 months (n = 113). All samples were tested by RT-PCR as well as by Ag-ELISA, to detect Persistently Infected (PI) animals. Serum samples from adults were tested by Ab-ELISA (Enzyme Linked Immuno-Sorbent Assay), to detect specific antibodies against pestivirus and 197 of them were further characterized by VNT (virus neutralization test) for the detection of neutralizing antibodies specific for BDV and for Bovine virus diarrhea virus (BVDV-1 and BVDV-2). RESULTS: No PI animals were found among the 689 sheep tested. 144/197 sera were positive in VNT for BDV, and 2 sera were strongly positive BVDV-2. Fifty-five flocks (98%) had at least one seropositive animal and the apparent within-flock seroprevalence was estimated to be 60.17% (95% C.I.: 52.96-66.96). The true seroprevalence based on estimated sensitivity and specificity of the Ab-ELISA was 68.20% (95% C.I.; 60.2-76.3). Several risk factors were identified as linked to BDV such as climate, landscape, flock management and presence of other ruminant species in the farm. CONCLUSION: These high seroprevalence rates suggest that BDV is widespread and is probably endemic all over the country. Further studies are needed to detect and isolate the virus strains circulating in the country and understand the distribution and impact of pestiviruses in the Algerian livestock. PMID- 30419909 TI - Critically appraised topic on adverse food reactions of companion animals (6): prevalence of noncutaneous manifestations of adverse food reactions in dogs and cats. AB - BACKGROUND: Many reports describe the cutaneous signs of adverse food reactions (AFR) in the dog and cat. However, various non-cutaneous clinical signs are less well described. Our objective was to systematically evaluate these non-cutaneous signs of AFR in small animals. RESULTS: We searched two databases (MEDLINE and Web of Science) for pertinent references on non-cutaneous signs of adverse food reactions. Among 117 and 764 articles found in the MEDLINE and Web of Science databases, respectively, we selected 47 articles that reported data related to non-cutaneous clinical signs of AFR. Gastrointestinal signs, symmetrical lupoid onychitis, conjunctivitis, sneezing, and anaphylaxis were reported to be associated with AFR in dogs and gastrointestinal and respiratory signs, conjunctivitis, and hyperactive behaviour in cats. In Border terriers with paroxysmal gluten-sensitive dyskinesia, an underlying AFR should be considered. Of these clinical signs diarrhoea and frequent defecation were most frequently reported to be diet-responsive in dogs; in the cat, these were vomiting and diarrhoea. CONCLUSIONS: An elimination diet should be considered early in the work-up of dogs and cats with chronic vomiting and diarrhoea. Other non-cutaneous signs occur less commonly because of AFRs. PMID- 30419911 TI - Application of red light phototherapy in the treatment of radioactive dermatitis in patients with head and neck cancer. AB - BACKGROUND: To observe the effect of red light phototherapy (RLPT) on radioactive dermatitis (RD) caused by radiotherapy in patients with head and neck cancer (HNC). METHODS: Sixty patients with HNC admitted to our hospital were randomly divided into experimental group and control group, 30 patients in each group. The control group received routine daily care during radiotherapy treatment. In the experimental group, in addition to routine daily care during radiotherapy treatment, photon therapy apparatus RLPT was added, 10 min/time, 2 times/day, and lasted until the end of radiotherapy. The pain and conditions of the patients' skin were assessed daily, and the skin pain and dermatitis grades of the two groups were compared. RESULTS: In terms of the reaction degree of RD, experimental group was mainly grade 0-2, and control group was mainly grade 2-3, with a significant difference (P < 0.05). In terms of skin pain, according to the pain records at week 2, 3, and 4, the pain degree increased with time. However, the score of wound pain in experimental group was significantly lower than that in control group, and there was a significant difference between the two groups (P < 0.05). CONCLUSIONS: The application of RLPT in the treatment of RD can help accelerate wound healing and significantly shorten healing time. It can not only reduce wounds pain of patients, promote inflammation and ulcer healing, but also ensure the smooth progress of patients' radiotherapy and improve their quality of lives, which is worth popularization and application in the clinical practice. PMID- 30419910 TI - Sharing longitudinal, non-biological birth cohort data: a cross-sectional analysis of parent consent preferences. AB - BACKGROUND: Mandates abound to share publicly-funded research data for reuse, while data platforms continue to emerge to facilitate such reuse. Birth cohorts (BC) involve longitudinal designs, significant sample sizes and rich and deep datasets. Data sharing benefits include more analyses, greater research complexity, increased opportunities for collaboration, amplification of public contributions, and reduced respondent burdens. Sharing BC data involves significant challenges including consent, privacy, access policies, communication, and vulnerability of the child. Research on these issues is available for biological data, but these findings may not extend to BC data. We lack consensus on how best to approach these challenges in consent, privacy, communication and autonomy when sharing BC data. We require more stakeholder engagement to understand perspectives and generate consensus. METHODS: Parents participating in longitudinal birth cohorts completed a web-based survey investigating consent preferences for sharing their, and their child's, non biological research data. Results from a previous qualitative inquiry informed survey development, and cognitive interviewing methods (n = 9) were used to improve the question quality and comprehension. Recruitment was via personalized email, with email and phone reminders during the 14-day window for survey completion. RESULTS: Three hundred and forty-six of 569 parents completed the survey in September 2014 (60.8%). Participants preferred consent processes for data sharing in future independent research that were less-active (i.e. no consent or opt-out). Parents' consent preferences are associated with their communication preferences. Twenty percent (20.2%) of parents generally agreed that their child should provide consent to continue participating in research at age 12, while 25.6% felt decision-making on sharing non-biological research data should begin at age 18. CONCLUSIONS: These finding reflect the parenting population's preference for less project-specific permission when research data is non-biological and de-identified and when governance practices are highly detailed and rigourous. Parents recognize that children should become involved in consent for secondary data use, but there is variability regarding when and how involvement occurs. These findings emphasize governance processes and participant notification rather than project-specific consent for secondary use of de identified, non-biological data. Ultimately, parents prefer general consent processes for sharing de-identified, non-biological research data with ultimate involvement of the child. PMID- 30419912 TI - Extracorporeal shockwave treatment impedes tooth movement in rats. AB - BACKGROUND: Accelerated tooth movement has been a topic of interest for orthodontic research recently. Surgically facilitated orthodontic treatment has been shown to be an effective approach to accelerate tooth movement; however, it remains invasive, requires additional surgery, and may increase post-operative complications. In this study, we evaluate the effects of extracorporeal shockwave treatment (ESWT), a non-invasive approach to regenerate alveolar bone, on orthodontic tooth movement in rats. MATERIALS AND METHODS: Seventy-two male rats, aged 10 weeks old, were subjected to 10-cN closed-coil nickel-titanium springs for unilateral maxillary first molar tooth movement. One group of rats received a single treatment of extracorporeal shockwave treatment at 500 impulses at energy flux density 0.1 mJ/mm2, with a pulse rate of 5 pulses per second immediately after spring installation while the non-ESWT-treated group served as a control group. The rats were sacrificed at day 3, 7, 14, 21 and 28 for tooth movement evaluation and sample analyses. Faxitron radiography, histological, double bone labeling and gene expression analyses were performed. Serum biochemistry was evaluated at day 3, 7 and 28 of the study. Kruskal-Wallis analysis of variance was used to determine the mean difference among groups, and multiple comparisons were analyzed by Mann-Whitney-U tests with a significance level = 0.05. RESULTS: The results demonstrated that tooth movement in the ESWT-treated rats (0.11 +/- 0.07 mm) was impeded compared to the tooth movement in the non-ESWT-treated rats (0.44 +/- 0.09 mm). ESWT up-regulated several osteoblastic and osteoclastic gene markers and cytokines; however, the effects on osteoclasts were only transient. Double-fluorescence bone labeling demonstrated that osteoblastic activity increased after ESWT treatment. There was no difference in systemic RANKL/OPG ratio between groups. CONCLUSIONS: ESWT at 500 impulse at energy flux density 0.1 mJ/mm2 increased osteoblast and osteoclast activities and imbalanced bone remodeling resulting in impeded tooth movement in rats. PMID- 30419913 TI - Contraceptive utilization among new exotic dancers: a cross-sectional study. AB - BACKGROUND: Female exotic dancers are a population at high risk of unintended pregnancy. The objective of this study is to describe the reproductive health needs and contraceptive utilization of exotic dancers. METHODS: New exotic dancers (< 6 months dancing) from 26 clubs in Baltimore City/County completed a one-time survey. RESULTS: Of 117 participants, 96 (82%) had current contraceptive need. The mean age was 24 years, and 55% were black. Sex work (45%), alcohol use disorder (73%), illicit (44%; e.g., heroin, crack, cocaine), and injection drug use (8%) were common. The majority (66%) reported contraception use in the prior 6 months. Condoms were reported by 46% whereas 45% reported non-barrier methods, most commonly hormonal injection. Consistent condom use was rare (3%), and only 11% used a long-acting reversible method. CONCLUSIONS: Despite their unique reproductive health vulnerabilities, female exotic dancers have unmet contraceptive needs. Targeted harm reduction strategies are needed to fill this gap. PMID- 30419915 TI - Dedifferentiated liposarcoma of the gallbladder: first reported case. AB - BACKGROUND: Liposarcoma of the gallbladder is an extremely rare sarcoma, with only five cases reported in the literature according to our knowledge. CASE PRESENTATION: A 71-year-old woman was referred to the Surgical Oncology Division of Napoleao Laureano Hospital (Joao Pessoa, PB, Brazil) due to a solid mass at the right side of the abdomen and fever, with no signs of jaundice. Abdominal ultrasonography and computed tomography (CT) evidenced an extensive gallbladder lobular formation adhered to the inferior border of the right hepatic lobe and cholelithiasis. The CT report suggested gallbladder liposarcoma. A cholecystectomy associated with resection of segments IV-B and V of the liver were performed. Intraoperative frozen sections were compatible with gallbladder sarcoma. Anatomopathological examination and immunohistochemistry confirmed dedifferentiated liposarcoma with foci of heterologous leiomyosarcomatous differentiation and undifferentiated fusocellular areas of high histological grade. CONCLUSION: This is the first case of dedifferentiated liposarcoma of the gallbladder to be reported. PMID- 30419914 TI - Sunitinib-suppressed miR-452-5p facilitates renal cancer cell invasion and metastasis through modulating SMAD4/SMAD7 signals. AB - PURPOSE: Although microRNAs (miRNAs) were revealed as crucial modulators in tumor metastasis and target therapy, our understanding of their roles in metastatic renal cell carcinoma (mRCC) and Sunitinib treatment was limited. Here we sought to identify human miRNAs that acted as key regulators in renal cancer metastasis and Sunitinib treatment. EXPERIMENTAL DESIGN: We focused on 2 published microarray data to select out our anchored miRNA and then explored the roles of miR-452-5p both in vitro and in vivo, which was downregulated after Sunitinib treatment while upregulated in metastasis renal cell carcinoma (RCC) tissues. RESULTS: Here, we discovered that treating with Sunitinib, the targeted receptor tyrosine kinase inhibitor (TKI), inhibited renal cancer cell migration and invasion via attenuating the expression of miR-452-5p. The novel identified miR 452-5p was upregulated and associated with poor prognosis in RCC. Preclinical studies using multiple RCC cells and xenografts model illustrated that miR-452-5p could promote RCC cell migration and invasion in vitro and in vivo. Mechanistically, P65 could directly bind to the miR-452-5p promoter and thus transcriptionally induce miR-452-5p expression, which led to post transcriptionally abrogate SMAD4 expression, thus inhibition of its downstream gene SMAD7. CONCLUSION: Our study presented a road map for targeting this newly identified miR-452-5p and its SMAD4/SMAD7 signals pathway, which imparted a new potential therapeutic strategy for mRCC treatment. PMID- 30419916 TI - Objective and automatic classification of Parkinson disease with Leap Motion controller. AB - BACKGROUND: The main objective of this paper is to develop and test the ability of the Leap Motion controller (LMC) to assess the motor dysfunction in patients with Parkinson disease (PwPD) based on the MDS-UPDRSIII exercises. Four exercises (thumb forefinger tapping, hand opening/closing, pronation/supination, postural tremor) were used to evaluate the characteristics described in MDS-UPDRSIII. Clinical ratings according to the MDS/UPDRS-section III items were used as target. For that purpose, 16 participants with PD and 12 healthy people were recruited in Ospedale Cisanello, Pisa, Italy. The participants performed standardized hand movements with camera-based marker. Time and frequency domain features related to velocity, angle, amplitude, and frequency were derived from the LMC data. RESULTS: Different machine learning techniques were used to classify the PD and healthy subjects by comparing the subjective scale given by neurologists against the predicted diagnosis from the machine learning classifiers. Feature selection methods were used to choose the most significant features. Logistic regression (LR), naive Bayes (NB), and support vector machine (SVM) were trained with tenfold cross validation with selected features. The maximum obtained classification accuracy with LR was 70.37%; the average area under the ROC curve (AUC) was 0.831. The obtained classification accuracy with NB was 81.4%, with AUC of 0.811. The obtained classification accuracy with SVM was 74.07%, with AUC of 0.675. CONCLUSIONS: Results revealed that the system did not return clinically meaningful data for measuring postural tremor in PwPD. In addition, it showed limited potential to measure the forearm pronation/supination. In contrast, for finger tapping and hand opening/closing, the derived parameters showed statistical and clinical significance. Future studies should continue to validate the LMC as updated versions of the software are developed. The obtained results support the fact that most of the set of selected features contributed significantly to classify the PwPD and healthy subjects. PMID- 30419917 TI - Spatial-temporal distribution of Anopheles larval habitats in Uganda using GIS/remote sensing technologies. AB - BACKGROUND: Anopheles mosquitoes impose an immense burden on the African population in terms of both human health and comfort. Uganda, in particular, boasts one of the highest malaria transmission rates in the world and its entire population is at risk for infection. Despite the immense burden these mosquitoes pose on the country, very few programmes exist that directly combat the issue at the vector control level and even fewer programmes focus on the vector in its most vulnerable juvenile stages. This study utilizes remote sensing techniques and spatial autocorrelation models to identify and prioritize the most prolific Anopheline larval habitats for control purposes in a rural community in Uganda. METHODS: A community-based mosquito surveillance programme was developed and implemented in Papoli Parish in Eastern Uganda over a 4-month period. Each day, a trained field team sampled the larval habitats of Anopheles mosquitoes within the population-dense areas of the community. Habitats and their productivity were identified and plotted spatially on a daily basis. Daily output was combined and displayed as a weekly habitat time-series. Additional spatial analysis was conducted using the Global and Anselin's Local Moran's I statistic to assess habitat spatial autocorrelation. RESULTS: Spatial models were developed to identify highly significant habitats and dictated the priority of these habitats for larval control purposes. Weekly time-series models identified the locations and productivity of each habitat, while Local Moran's I cluster maps identified statistically significant clusters (Cluster: High) and outliers (High Outlier) that were then interpreted for control priority. Models were stitched together in a temporal format to visually demonstrate the spatial shift of statically significant, high priority habitats over the entire study period. DISCUSSION: The findings show that the spatial outcomes of productive habitats can be made starkly apparent through initial habitat modelling and resulting time-series output. However, mosquito control resources are often limited and it is at this point that the Local Moran's I statistics demonstrates its value. Focusing on habitats identified as Cluster: High and High Outlier outputs allow for the identification of the most influential larval habitats. Utilizing this method for malaria control allows for the optimization of control resources in a real time, community driven, fashion, as well as providing a framework for future control practices. PMID- 30419918 TI - Federating patients identities: the case of rare diseases. AB - BACKGROUND: Patient information in rare disease registries is generally collected from numerous data sources, necessitating the data to be federated. In addition, data for research purposes must be de-identified. Transforming nominative data into de-identified data is thus a key issue, while minimizing the number of identity duplicates. We propose a method enabling patient identity federation and rare disease data de-identification while preserving the pertinence of the provided data. RESULTS: We developed a rare disease patient identifier. The IdMR generation process is a three-phased algorithm involving a hash function to irreversibly de-identify nominative patient data, including those of foetuses. This process minimizes collision risks and reduces variability for the purpose of identity federation. The IdMR was generated for 360,000 patients of the CEMARA database. It allowed identity federation of 1771 duplicated files. No collisions were introduced. CONCLUSION: We examined and discussed the risks of collisions and the creation of duplicates as well as the risks of patient re-identification. We discussed our choice of nominative input information in light of that used by other patient identification solutions. The IdMR is a patient identifier that enables identity federation and file linkage. The simplicity of the algorithm and the universality and stability of the input data make it a good candidate for European cross-border rare disease projects. PMID- 30419919 TI - Inequalities in the geographic distribution of hospital beds and doctors in traditional Chinese medicine from 2004 to 2014. AB - OBJECTIVES: This study identifies inequities in the provincial-level geographical distribution of traditional Chinese Medicine (TCM) hospital beds and doctors in China from 2004 to 2014. This provides policy implications of the optimal allocation of TCM health care resources. METHODS: Our study used province level data on TCM hospital beds and doctors from 2004 to 2014. These data were obtained from the China TCM Yearbook 2004-2014 and the China Statistical Yearbook 2004 2014.Global and local spatial autocorrelation was performed by using Moran's index and the local Moran's index to describe the spatial distribution of TCM hospital beds (doctors) as well as their density. A Gini coefficient was used to estimate inequalities in the geographic distribution of TCM hospital beds (doctors) based on their density. Correlations of the Gini coefficients between TCM hospital beds and doctors were calculated by Pearson correlation analysis. RESULTS: All indicators of TCM hospital beds and doctor density have increased over the past 11 years. The number of TCM hospital beds per 10,000 populations increased the fastest. Geographical clustering was not obvious in the density distribution of TCM hospital beds or doctors, as no significant spatial autocorrelation was found. Gini coefficients showed that from 2004 to 2014 the distribution of TCM hospital beds per 10,000 population and doctors per 10,000 populations were equitable between different regions. A large gap existed in the distribution inequality of TCM hospital beds (doctors) per square kilometer among different regions. CONCLUSION: Targeted health policy with equitable distribution of TCM hospital beds (doctors) per square kilometer and the balance and coordination of related resources should be a priority in shaping China's healthcare system reform. PMID- 30419920 TI - Impact of biobanks on research outcomes in rare diseases: a systematic review. AB - BACKGROUND: Alleviating the burden of rare diseases requires research into new diagnostic and therapeutic strategies. We undertook a systematic review to identify and compare the impact of stand-alone registries, registries with biobanks, and rare disease biobanks on research outcomes in rare diseases. METHODS: A systematic review and meta-aggregation was conducted using the preferred reporting items for systematic reviews and meta-analyses (the PRISMA statement). English language publications were sourced from PubMed, Medline, Scopus, and Web of Science. Original research papers that reported clinical, epidemiological, basic or translational research findings derived from data contained in stand-alone registries, registries with biobanks, and rare disease biobanks were considered. Articles selected for inclusion were assessed using the critical appraisal instruments by JBI-QARI. Each article was read in its entirety and findings were extracted using the online data extraction software from JBI QARI. RESULTS: Thirty studies including 28 rare disease resources were included in the review. Of those, 14 registries were not associated to biobank infrastructure, 9 registries were associated with biobank infrastructure, and 6 were rare disease biobank resources. Stand-alone registries had the capacity to uncover the natural history of disease and contributed to evidence-based practice. When annexed to biobank infrastructure, registries could also identify and validate biomarkers, uncover novel genes, elucidate pathogenesis at the Omics level, and develop new therapeutic strategies. Rare disease biobanks in this review had similar capacity for biological investigations, but in addition, had far greater sample numbers and higher quality laboratory techniques for quality assurance processes. DISCUSSION: We examined the research outcomes of three specific populations: stand-alone registries, registries with biobanks, and stand alone rare disease biobanks and demonstrated that there are key differences among these resources. These differences are a function of the resources' design, aims, and objectives, with each resource having a distinctive and important role in contributing to the body of knowledge for rare disease research. Whilst stand alone registries had the capacity to uncover the natural history of disease, develop best practice, replace clinical trials, and improve patient outcomes, they were limited in their capacity to conduct basic research. The role of basic research in rare disease research is vital; scientists must first understand the pathways of disease before they can develop appropriate interventions. Rare disease biobanks, on the other hand (particularly larger biobanks), had the key infrastructure required to conduct basic research, making novel Omics discoveries, identify and validate biomarkers, uncover novel genes, and develop new therapeutic strategies. However, these stand-alone rare disease biobanks did not collect comprehensive data or impact on clinical observations like a rare disease registry. Rare disease research is important not only for rare diseases, but also for also common diseases. For example, research of low-density lipoprotein (LDL)-receptors in the rare disease known as familial hypercholesterolemia led to the discovery of statins, a drug therapy that is now used routinely to prevent heart disease. CONCLUSIONS: Rare diseases are still under-researched worldwide. This review made the important observation that registries with biobanks had the function of both stand-alone registries (the capacity to collect comprehensive clinical and epidemiological data) and stand alone rare disease biobanks (the ability to contribute to Omics research). We found registries with biobanks offer a unique, practical, cost-effective, and impactful solution for rare disease research. Linkage of stand-alone registries to rare disease biobanks will provide the appropriate resources required for the effective translation of basic research into clinical practice. Furthermore, facilitators such as collaboration, engagement, blended recruitment, pro-active marketing, broad consent, and "virtual biobank" online catalogues will, if utilised, add to the success of these resources. These important observations can serve to direct future rare diseases research efforts, ultimately improve patient outcomes and alleviate the significant burden associated with rare disease for clinicians, hospitals, society, and most importantly, the patients and their families. PMID- 30419921 TI - Correction to: Copper signalling: causes and consequences. AB - Following publication of the original article [1], the authors reported an error in Table 3. The correct version of Table 3 is shown below:The publishers apologise for this error. The original article [1] has been corrected. PMID- 30419922 TI - GAP43, a novel metastasis promoter in non-small cell lung cancer. AB - BACKGROUND: Brain metastasis is an extremely serious sequela with a dismal prognosis in non-small cell lung cancer (NSCLC). The present study aimed to identify novel biomarkers and potential therapeutic targets for brain metastases of NSCLC. METHODS: We performed high-throughput Luminex assays to profile the transcriptional levels of 36 genes in 70 operable NSCLC patients, among whom 37 developed brain metastases as the first relapse within 3 years after surgery. The Cox proportional hazards regression model was used to evaluate the association between genes and brain metastases. Wound healing assay and transwell assay was carried out to estimate the function of target gene in vitro. And left ventricular injection on nude mice was used to evaluate the effect of target gene in vivo. RESULTS: Growth-associated protein 43 (GAP43) was found to be related to brain metastasis. Multivariate Cox regression analysis showed that NSCLC patients with elevated GAP43 had a 3.29-fold increase in the risk for brain metastasis compared with those with low levels (95% confidence interval: 1.55-7.00; P = 0.002). Kaplan-Meier survival curves revealed that GAP43 was also associated with overall survival. Analysis of a cohort of 1926 NSCLC patients showed similar results: patients with high levels of GAP43 had worse progression-free and overall survival rates. Furthermore, in vitro experiments showed that GAP43 facilitated cell migration. Animal studies demonstrated that GAP43-silenced NSCLC cells were less likely to metastasize to the brain and bone than control cells. Immunofluorescence and F-actin/G-actin in vivo assays indicated that GAP43 knockdown triggered depolymerization of the F-actin cytoskeleton. Rho GTPase activation assays showed that Rac1 was deactivated after GAP43 was silenced. CONCLUSIONS: Our findings suggest that GAP43 is an independent predictor of NSCLC brain metastasis and that it may facilitate metastasis by regulating the Rac1/F actin pathway. PMID- 30419923 TI - Correlation of malaria parasitaemia with peripheral blood monocyte to lymphocyte ratio as indicator of susceptibility to severe malaria in Ghanaian children. AB - BACKGROUND: Even though malaria is generally on the decline due extensive control and elimination efforts, it still remains a public health problem for over 40% of the world's population. During the course of malaria infection, parasites and red blood cells come under oxidative stress and there is host immune response in an attempt to protect the red blood cells. The frequency of monocytes and lymphocytes in peripheral blood might, therefore, be expected to reflect the state of an individual's immune response to the infection. Circulating monocytes and lymphocytes could therefore serve as an index in relation to malaria parasitaemia. The purpose of this study was to determine whether the relative count of monocytes to lymphocytes in peripheral blood (M:L ratio) can predict parasitaemia and, therefore, the severity of malaria infection. METHODS: Two millilitre of venous blood sample were taken from participants by venisection into anticoagulant tubes. Thick and thin blood films were made and stained with Giemsa and examined for malaria parasites. Whole blood specimen were analysed for full blood count using ABX Pentra 60 C+ automated haematological analyzer. Data was entered into Microsoft Word and analysed using Statistical Package for Social Sciences (SPSS, Version 20.0) and Graphpad prism. Spearman's correlation was used to determine correlation between occurrences of clinical malaria and the monocytes and lymphocytes ratio. Statistical significance was taken as p <= 0.05 with 95% confidence interval. RESULTS: The study comprised of 1629 (m = 896; f = 733) children up to 5 years presenting with clinical malaria as cases and 445 (m = 257; f = 188) apparently healthy children as controls. The results indicated that there was a significant positive correlation between the monocytes to lymphocytes ratio and the presence of parasites (p = 0.04) and the level of parasitaemia within the age group of 0-3 years (p = 0.02) and 4-5 years (p = 0.03). CONCLUSIONS: The monocyte to lymphocyte ratio obtained correlated positively with the presence of malaria as well as the level of parasitaemia. The outcome of this work implies that monocyte to lymphocyte ratio can be used to predict the level of parasitaemia and together with other factors, the development of severe malaria. PMID- 30419924 TI - "We need good nutrition but we have no money to buy food": sociocultural context, care experiences, and newborn health in two UNHCR-supported camps in South Sudan. AB - BACKGROUND: Determinants of newborn health and survival exist across the reproductive life cycle, with many sociocultural and contextual factors influencing outcomes beyond the availability of, and access to, quality health services. In order to better understand key needs and opportunities to improve newborn health in refugee camp settings, we conducted a multi-methods qualitative study of the status of maternal and newborn health in refugee camps in Upper Nile state, South Sudan. METHODS: In 2016, we conducted 18 key informant interviews with health service managers and front-line providers and 13 focus group discussions in two Sudanese refugee camps in Maban County, South Sudan. Our focus group discussions comprised 147 refugee participants including groups of mothers, fathers, grandmothers, traditional birth attendants, community health workers, and midwives. We analysed our data for content and themes using inductive and deductive techniques. RESULTS: We found both positive practices and barriers to newborn health in the camps throughout the reproductive lifecycle. Environmental and contextual factors such as poor nutrition, lack of livelihood opportunities, and insecurity presented barriers to both general health and self-care during pregnancy. We found that the receipt of material incentives is one of the leading drivers of utilization of antenatal care and facility-based childbirth services. Barriers to facility-based childbirth included poor transportation specifically during the night; insecurity; being accustomed to home delivery; and fears of an unfamiliar birth environment, caesarean section, and encountering male health care providers during childbirth. Use of potentially harmful traditional practices with the newborn are commonplace including mixed feeding, use of herbal infusions to treat newborn illnesses, and the application of ash and oil to the newborn's umbilicus. CONCLUSIONS: Numerous sociocultural and contextual factors impact newborn health in this setting. Improving nutritional support during pregnancy, strengthening community-based transportation for women in labour, allowing a birth companion to be present during delivery, addressing harmful home based newborn care practices such as mixed feeding and application of foreign substances to the umbilicus, and optimizing the networks of community health workers and traditional birth attendants are potential ways to improve newborn health outcomes. PMID- 30419925 TI - Nano-silver-incorporated biomimetic polydopamine coating on a thermoplastic polyurethane porous nanocomposite as an efficient antibacterial wound dressing. AB - BACKGROUND: Developing an ideal wound dressing that meets the multiple demands of good biocompatibility, an appropriate porous structure, superior mechanical property and excellent antibacterial activity against drug-resistant bacteria is highly desirable for clinical wound care. Biocompatible thermoplastic polyurethane (TPU) membranes are promising candidates as a scaffold; however, their lack of a suitable porous structure and antibacterial activity has limited their application. Antibiotics are generally used for preventing bacterial infections, but the global emergence of drug-resistant bacteria continues to cause social concerns. RESULTS: Consequently, we prepared a flexible dressing based on a TPU membrane with a specific porous structure and then modified it with a biomimetic polydopamine coating to prepare in situ a nano-silver (NS) based composite via a facile and eco-friendly approach. SEM images showed that the TPU/NS membranes were characterized by an ideal porous structure (pore size: ~ 85 MUm, porosity: ~ 65%) that was decorated with nano-silver particles. ATR FITR and XRD spectroscopy further confirmed the stepwise deposition of polydopamine and nano-silver. Water contact angle measurement indicated improved surface hydrophilicity after coating with polydopamine. Tensile testing demonstrated that the TPU/NS membranes had an acceptable mechanical strength and excellent flexibility. Subsequently, bacterial suspension assay, plate counting methods and Live/Dead staining assays demonstrated that the optimized TPU/NS2.5 membranes possessed excellent antibacterial activity against P. aeruginosa, E. coli, S. aureus and MRSA bacteria, while CCK8 testing, SEM observations and cell apoptosis assays demonstrated that they had no measurable cytotoxicity toward mammalian cells. Moreover, a steady and safe silver-releasing profile recorded by ICP-MS confirmed these results. Finally, by using a bacteria-infected (MRSA or P. aeruginosa) murine wound model, we found that TPU/NS2.5 membranes could prevent in vivo bacterial infections and promote wound healing via accelerating the re epithelialization process, and these membranes had no obvious toxicity toward normal tissues. CONCLUSION: Based on these results, the TPU/NS2.5 nanocomposite has great potential for the management of wounds, particularly for wounds caused by drug-resistant bacteria. PMID- 30419926 TI - Perspectives on HIV pre-exposure prophylaxis (PrEP) utilization and related intervention needs among people who inject drugs. AB - BACKGROUND: Antiretroviral pre-exposure prophylaxis (PrEP) is clinically efficacious and recommended for HIV prevention among people who inject drugs (PWID), but uptake remains low and intervention needs are understudied. To inform the development of PrEP interventions for PWID, we conducted a qualitative study in the Northeastern USA, a region where recent clusters of new HIV infections have been attributed to injection drug use. METHODS: We conducted qualitative interviews with 33 HIV-uninfected PWID (hereafter, "participants") and 12 clinical and social service providers (professional "key informants") in Boston, MA, and Providence, RI, in 2017. Trained interviewers used semi-structured interviews to explore PrEP acceptability and perceived barriers to use. Thematic analysis of coded data identified multilevel barriers to PrEP use among PWID and related intervention strategies. RESULTS: Among PWID participants (n = 33, 55% male), interest in PrEP was high, but both participants and professional key informants (n = 12) described barriers to PrEP utilization that occurred at one or more socioecological levels. Individual-level barriers included low PrEP knowledge and limited HIV risk perception, concerns about PrEP side effects, and competing health priorities and needs due to drug use and dependence. Interpersonal-level barriers included negative experiences with healthcare providers and HIV-related stigma within social networks. Clinical barriers included poor infrastructure and capacity for PrEP delivery to PWID, and structural barriers related to homelessness, criminal justice system involvement, and lack of money or identification to get prescriptions. Participants and key informants provided some suggestions for strategies to address these multilevel barriers and better facilitate PrEP delivery to PWID. CONCLUSIONS: In addition to some of the facilitators of PrEP use identified by participants and key informants, we drew on our key findings and behavioral change theory to propose additional intervention targets. In particular, to help address the multilevel barriers to PrEP uptake and adherence, we discuss ways that interventions could target information, self-regulation and self-efficacy, social support, and environmental change. PrEP is clinically efficacious and has been recommended for PWID; thus, development and testing of strategies to improve PrEP delivery to this high-risk and socially marginalized population are needed. PMID- 30419927 TI - Influence of FTO rs9939609 and Mediterranean diet on body composition and weight loss: a randomized clinical trial. AB - BACKGROUND: The Mediterranean diet (MeD) plays a key role in the prevention of obesity. Among the genes involved in obesity, the Fat mass and obesity-associated gene (FTO) is one of the most known, but its interaction with MeD remained uncertain so far. METHODS: We carried out a study on a sample of 188 Italian subjects, analyzing their FTO rs9939609 alleles, and the difference in body composition between the baseline and a 4-weeks nutritional intervention. The sample was divided into two groups: the control group of 49 subjects, and the MeD group of 139 subjects. RESULTS: We found significant relations between MeD and both variation of total body fat (DeltaTBFat) (p = 0.00) and gynoid body fat (p = 0.04). ?TBFat (kg) demonstrated to have a significant relation with the interaction diet-gene (p = 0.04), whereas FTO was associated with the variation of total body water (p = 0.02). CONCLUSIONS: MeD demonstrated to be a good nutritional treatment to reduce the body fat mass, whereas data about FTO remain uncertain. Confirming or rejecting the hypothesis of FTO and its influence on body tissues during nutritional treatments is fundamental to decide whether its effect has to be taken into consideration during both development of dietetic plans and patients monitoring. Trial Registration ClinicalTrials.gov Id: NCT01890070. Registered 01 July 2013, https://clinicaltrials.gov/ct2/show/NCT01890070. PMID- 30419928 TI - Subjective health status of multimorbidity: verifying the mediating effects of medical and assistive devices. AB - BACKGROUND: This study aimed to verify the mediating effect of using assistive devices as a factor that alleviates the relationship between multimorbidity and subjective health status. METHODS: This study used three-year data (2011-2013) from the Korea Health Panel (KHP). The data were jointly collected by the consortium of the National Health Insurance Service and Korea Institute for Health and Social Affairs. RESULTS: The mediating effect of using assistive devices was verified, but the direction of the effect was deteriorated subjective health. In other words, in terms of the impact of multimorbidity on subjective health, using assistive devices had a negative impact (-) on subjective health. CONCLUSIONS: The current assessment system for medical devices, narrow scope for choice of assistive devices, and limited scope of health insurance benefits must change to ultimately lead to a positive mediating effect on using medical devices and on subjective health satisfaction of patients with chronic diseases. A system that embraces all ages and generations must be developed. To this end, it is necessary to expand the scope of medical devices and insurance payment in long term care insurance for elderly users, as well as the active meaning of medical devices in terms of health insurance. PMID- 30419929 TI - Delineation of lung cancer with FDG PET/CT during radiation therapy. AB - OBJECTIVES: To propose an easily applicable segmentation method (perPET-RT) for delineation of tumour volume during radiotherapy on interim fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in patients with non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: Sixty-seven patients (51 primary tumours, 60 lymph nodes), from 4 prospective studies, underwent an FDG PET/CT scan during the fifth week of radiation therapy, using different generations of PET/CT. Per-therapeutic PET/CT scans were delineated in consensus by two experienced physicians leading to the gold standard threshold to be applied. The mathematical expression of Thopt, the optimal threshold to be applied as a function of the maximum standard uptake value (SUVmax), was determined. The performance of this method (perPET-RT) was assessed by computing the DICE similarity coefficient (DSC) and was compared with 8 fixed threshold values and 3 adaptive thresholding methods. RESULTS: Thopt verified the following expression: Thopt = A.ln(1/SUVmax) + B where A and B were 2 constants. A and B were independent from the generation of PET/CT, but depended on the type of lesions (primary lung tumours vs. lymph nodes). PerPET-RT showed good to very good agreement in comparison to the gold standard. The mean and standard deviation of DSC value was 0.81 +/- 0.13 for lung lesions and 0.78 +/- 0.15 for lymph nodes. PerPET-RT showed a significant better agreement than the other segmentation methods (p < 0.001), except for one of the adaptive thresholding method ADT (p = 0.11). CONCLUSION: On the database used, perPET-RT has proven its reliability and accuracy for tumour delineation on per-therapeutic FDG PET/CT using only SUVmax measurement. This method may be used to delineate tumour volume for dose-escalation planning. TRIAL REGISTRATION: NCT01261598 , NCT01261585 , NCT01576796 . PMID- 30419930 TI - Herpes simplex virus type 2 infection triggers AP-1 transcription activity through TLR4 signaling in genital epithelial cells. AB - BACKGROUND: The pattern recognition receptors (PPRs) are the earliest phase of the host defense against pathogens in genital epithelium, and toll-like receptors (TLRs) are best characterized PPRs mediating innate immune responses. Herpes simplex virus type 2 (HSV-2), a member of herpesviridae family, causes one of the most prevalent sexually transmitted infection in the world. In this paper, we described that HSV-2 infection would induce activator protein 1 (AP-1) via TLR4 MyD88/TRIF pathway in human genital epithelial cell. METHODS: TLRs expression profiles and changes was investigated in HSV-2-infected cells. The effect of TLR4 MyD88/TRIF on HSV-2-induced AP-1 activation and viral replication was also evaluated. The TLR4 translocation change was examined after viral infection. Finally, viral ICP0 effect on TLR4 signaling and TLR4-promoter regulation were primarily studied. RESULTS: HSV-2-induced AP-1 activation was dependent on TLR4 and downstream adaptor molecules MyD88 and TRIF. And also, TLR4, MyD88 and TRIF was proved to affect HSV-2 replication. AP-1 activation would also be enhanced via overexpression of myeloid differentiation protein 2 (MD2), implicating that it might be a necessary accessory for TLR4 to sense HSV-2 infection. Protein quantification of cytoplasmic and membrane-associated TLR4 revealed that HSV-2 infection increased membrane-anchoring TLR4 level, but not cytoplasmic ones. Viral ICP0 could augment cellular AP-1, TLR4 promoter activation and TLR4 expression level. The specific inhibitor treatment and transcription factor binding site scanning in TLR4 promoter region showed that AP-1 activity was essential for TLR4-promoter activation. CONCLUSIONS: Taken together, HSV-2 infection could stimulate AP-1 activation via TLR4-MyD88/TRIF axis, and then feedback to up-regulate TLR4 expression in human genital epithelial cells. PMID- 30419931 TI - Functional brain activation changes associated with practice in delaying smoking among moderate to heavy smokers: study protocol and rationale of a randomized trial (COPE). AB - BACKGROUND: Most smokers struggle to overcome tobacco addiction. Neuroscientific models of addiction emphasize the importance of brain regions associated with cognitive control and reward to understand the cycle of addiction and relapse. During an attempt at abstinence, the cognitive control system appears to be underpowered to override the heightened reward system of the addicted brain. Thus, one neural target for treatment is to strengthen the cognitive control system. It may be possible to improve the functioning of the cognitive control system via deliberate practice. METHODS/DESIGN: This study will determine the effects of practicing delaying smoking on brain and behavioral measures of cognitive control. Smoking patterns will be monitored for 1 week and then smokers (N = 80) will be randomized to either practice cognitive control by delaying their first cigarette of the day for 2 weeks (practice group) or they will continue monitoring only (no practice group). Functional magnetic resonance imaging will be performed while smokers regulate their responses to smoking images (i) at baseline and (ii) after 2 weeks of practice (or no practice). DISCUSSION: The primary aim of this study will be to identify the impact of practicing cognitive control on functional brain activation changes in response to smoking cues. If successful, this project will establish a neurobiological biomarker for increasing cognitive control and demonstrate the feasibility of neuroimaging methods to predict the efficacy of an intervention without a large clinical trial. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03080844 . Registered March 15, 2017. PMID- 30419933 TI - Efficacy and safety of 3D print-assisted surgery for the treatment of pilon fractures: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: To compare the effects of 3D print-assisted surgery and conventional surgery in the treatment of pilon fractures. METHODS: PubMed, Embase, Web of Science, CNKI, CBM, and WanFang data were searched until July 2018. Two reviewers selected relevant studies, assessed the quality of studies, and extracted data. For continuous data, a weighted mean difference (WMD) and 95% confidence intervals (CI) were used. For dichotomous data, a relative risk (RR) and 95% CI were calculated as the summary statistics. RESULTS: There were seven randomized controlled trials (RCT) enrolling a total of 486 patients, 242 patients underwent 3D print-assisted surgery and 244 patients underwent conventional surgery. The pooled outcomes demonstrate 3D print-assisted surgery was superior to conventional surgery in terms of operation time [WMD = - 26.16, 95% CI (- 33.19, 19.14), P < 0.001], blood loss [WMD = - 63.91, 95% CI (- 79.55, - 48.27), P < 0.001], postoperative functional scores [WMD = 8.16, 95% CI (5.04, 11.29), P < 0.001], postoperative visual analogue score (VAS) [WMD = - 0.59, 95% CI (- 1.18, 0.01), P = 0.05], rate of excellent and good outcome [RR = 1.20, 95% CI (1.07, 1.34), P = 0.002], and rate of anatomic reduction [RR = 1.35, 95% CI (1.19, 1.53), P < 0.001]. However, there was no significant difference between the groups regarding the rate of infection [RR = 0.51, 95% CI (0.20, 1.31), P = 0.16], fracture union time [WMD = - 0.85, 95% CI (- 1.79, 0.08), P = 0.07], traumatic arthritis [RR = 0.34, 95% CI (0.06, 2.09), P = 0.24], and malunion [RR = 0.34, 95% CI (0.06, 2.05), P = 0.24]. CONCLUSIONS: Our meta-analysis demonstrates 3D print-assisted surgery was significantly better than conventional surgery in terms of operation time, blood loss, postoperative functional score, postoperative VAS, rate of excellent and good outcome, and rate of anatomic reduction. Concerning postoperative complications, there were no significant differences between the groups. PMID- 30419932 TI - Expanding the clinical phenotype of IARS2-related mitochondrial disease. AB - BACKGROUND: IARS2 encodes a mitochondrial isoleucyl-tRNA synthetase, a highly conserved nuclear-encoded enzyme required for the charging of tRNAs with their cognate amino acid for translation. Recently, pathogenic IARS2 variants have been identified in a number of patients presenting broad clinical phenotypes with autosomal recessive inheritance. These phenotypes range from Leigh and West syndrome to a new syndrome abbreviated CAGSSS that is characterised by cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, as well as cataract with no additional anomalies. METHODS: Genomic DNA from Iranian probands from two families with consanguineous parental background and overlapping CAGSSS features were subjected to exome sequencing and bioinformatics analysis. RESULTS: Exome sequencing and data analysis revealed a novel homozygous missense variant (c.2625C > T, p.Pro909Ser, NM_018060.3) within a 14.3 Mb run of homozygosity in proband 1 and a novel homozygous missense variant (c.2282A > G, p.His761Arg) residing in an ~ 8 Mb region of homozygosity in a proband of the second family. Patient-derived fibroblasts from proband 1 showed normal respiratory chain enzyme activity, as well as unchanged oxidative phosphorylation protein subunits and IARS2 levels. Homology modelling of the known and novel amino acid residue substitutions in IARS2 provided insight into the possible consequence of these variants on function and structure of the protein. CONCLUSIONS: This study further expands the phenotypic spectrum of IARS2 pathogenic variants to include two patients (patients 2 and 3) with cataract and skeletal dysplasia and no other features of CAGSSS to the possible presentation of the defects in IARS2. Additionally, this study suggests that adult patients with CAGSSS may manifest central adrenal insufficiency and type II esophageal achalasia and proposes that a variable sensorineural hearing loss onset, proportionate short stature, polyneuropathy, and mild dysmorphic features are possible, as seen in patient 1. Our findings support that even though biallelic IARS2 pathogenic variants can result in a distinctive, clinically recognisable phenotype in humans, it can also show a wide range of clinical presentation from severe pediatric neurological disorders of Leigh and West syndrome to both non syndromic cataract and cataract accompanied by skeletal dysplasia. PMID- 30419935 TI - Dam characteristics associated with pre-weaning diarrhea in mink (Neovison vison). AB - BACKGROUND: Pre-weaning diarrhea (PWD) in mink, also known as "sticky kits", is a frequently occurring syndrome in suckling mink kits on commercial mink farms. Outbreaks of PWD result in weakened kits, increased mortality and reduced growth and welfare as well as considerable economic losses for the farmers. The syndrome is regarded as multifactorial with a complex etiology, and studies have focused on associations with environment, management and dam characteristics. The present study was conducted from May to June 2015 and included 70 dams with mink litters with and without PWD. The aims were to examine associations between PWD and mastitis (bacterial infection and histological signs of inflammation or other lesions in the mammary gland), and to examine associations between PWD and other dam-related characteristics (age, litter size, body mass index, and weight and number of active mammary glands of the dam). RESULTS: Using multivariable mixed logistic regression analyses with farm id as a random intercept, we found that the odds for PWD in the litter were significantly higher in 1 year old dams versus > 1 year old (OR = 13.3, CI 2.0-90.2, P = 0.01), higher if litter size observed after birth was > 5 kits versus <= 5 kits (OR = 16.5, CI 2.2-123.7, P = 0.01), higher if the number of active mammary glands per kit was <= 1.5 versus > 1.5 glands per kit (OR = 6.5, CI 1.2-36.0), P = 0.03), and higher in farms with high prevalence of PWD versus low prevalence (OR = 16.8, CI 2.9-97.6, P = 0.002). There were no significant associations between PWD and bacterial infection, histological signs of inflammation or other lesions of the mammary gland, body mass index or weight of mammary gland per kit. CONCLUSION: Pre-weaning diarrhea had a statistically significant association with age of the dam, litter size and the number of active mammary glands per kit. However, PWD was not associated with mastitis, body mass index and weight of mammary gland tissue per kit. PMID- 30419934 TI - What drives adoption of a computerised, multifaceted quality improvement intervention for cardiovascular disease management in primary healthcare settings? A mixed methods analysis using normalisation process theory. AB - BACKGROUND: A computerised, multifaceted quality improvement (QI) intervention for cardiovascular disease (CVD) management in Australian primary healthcare was evaluated in a cluster randomised controlled trial. The intervention was associated with improved CVD risk factor screening but there was no improvement in prescribing rates of guideline-recommended medicines. The aim of this study was to conduct a process evaluation to identify and explain the underlying mechanisms by which the intervention did and did not have an impact. METHODS/DESIGN: Normalisation process theory (NPT) was used to understand factors that supported or constrained normalisation of the intervention into routine practice. A case study design was used in which six of the 30 participating intervention sites were purposively sampled to obtain a mix of size, governance, structure and performance. Multiple data sources were drawn on including trial outcome data, surveys of job satisfaction and team climate (68 staff) and in depth interviews (19 staff). Data were primarily analysed within cases and compared with quantitative findings in other trial intervention and usual care sites. RESULTS: We found a complex interaction between implementation processes and several contextual factors affecting uptake of the intervention. There was no clear association between team climate, job satisfaction and intervention outcomes. There were four spheres of influence that appeared to enhance or detract from normalisation of the intervention: organisational mission and history (e.g. strategic investment to promote a QI culture enhanced cognitive participation), leadership (e.g. ability to energise or demotivate others influenced coherence), team environment (e.g. synergistic activities of team members with different skill sets influenced collective action) and technical integrity of the intervention (e.g. tools that slowed computer systems limited reflective action). DISCUSSION: Use of NPT helped explain how certain contextual factors influence the work that is done by individuals and teams when implementing a novel intervention. Although these factors do not necessarily distil into a recipe for successful uptake, they may assist system planners, intervention developers, and health professionals to better understand the trajectory that primary health care services may take when developing and engaging with QI interventions. TRIAL REGISTRATION: ACTRN 12611000478910 . Registered 08 May 2011. PMID- 30419936 TI - High density lipoprotein cholesterol and proteome in SR-B1 KO mice: lost in precipitation. AB - Scavenger receptor class B type 1 (SR-B1) plays an essential role in high density lipoprotein (HDL) metabolism. SR-B1 deficient (SR-B1 KO) mice are prone to atherosclerosis and exhibit abnormally large, cholesterol-rich, dysfunctional HDL. In a recent issue of J Transl Med, Cao et al. described results of proteomics analyses of HDL isolated from wild-type (WT) and SR-B1 KO mice using precipitation of large lipoproteins with polyethylene glycol (PEG). They report abnormalities in SR-B1 KO HDL protein components that correlate with HDL function. In this commentary, we describe and discuss the differences in the results published by Cao et al. and those obtained in a recent study from our laboratory using shotgun proteomics of HDL of SR-B1 KO mice isolated by ultracentrifugation. We propose that different HDL purification procedures used may account for the discrepancies observed. We show that SR-B1 KO HDL purification using either PEG or dextran sulfate precipitation results in enrichment of small HDL subclasses, and may therefore underestimate alterations in lipoprotein composition or function. Compared to HDL obtained by ultracentrifugation, HDL isolated by PEG precipitation show a lower ApoE/ApoA-I proportion and reduced cholesterol content. HDL protein components described by Cao et al. or our laboratory are mostly inconsistent: only 33 HDL proteins were detected in both datasets, whereas a significant number of proteins were only identified by Cao et al. (n = 43) or Contreras-Duarte et al. (n = 26) datasets. The relative abundance of HDL-associated peptide and protein levels in WT vs SR B1 HDL were also highly different in both datasets. This study indicates that caution must be taken when interpreting results from HDL isolated by chemical precipitation. PMID- 30419938 TI - Magnetic resonance imaging of the Lisfranc ligament. AB - BACKGROUND: The Lisfranc joint has complex structures, and articular surfaces overlap on conventional X-ray radiographs. Hence, there is no available auxiliary examination for diagnosing related injuries. At present, few studies on the imaging of Lisfranc ligaments have been reported, and related imaging data are rare. Therefore, no imaging reference can be used for related diagnosis and repair operations. This study aims to observe and describe the morphology and structure of Lisfranc ligaments using magnetic resonance imaging (MRI), in order to provide imaging reference for the diagnosis and repair of Lisfranc joint injuries. METHODS: MRI scanning was performed on 60 sides of normal feet of 30 healthy adult volunteers. In the MRI scanning on the Lisfranc joint, sagittal scanning was focused on the area between the lateral margin and medial margin of the Lisfranc joint, while oblique coronal scanning was focused on the area parallel to the Lisfranc joint clearance. After acquisition of MRI images, data were burned into a CD, and the morphology and structure of the Lisfranc ligament on the MRI image were observed and described. Hence, the imaging parameters of the Lisfranc ligament were acquired, providing an imaging reference for the diagnosis and repair of Lisfranc joint injuries. RESULTS: By observing the obtained images of the Lisfranc ligament through appropriate MRI scanning, it was found that the Lisfranc ligament originates at the site 12.63 +/- 1.20 mm from the lateral side of the base of the medial cuneiform bone, with a length of 8.02 +/- 1.5 mm, a width of 2.53 +/- 0.61 mm, a height of 6.96 +/- 1.01 mm, forms an included angle of 46.79 +/- 3.47 degrees with the long axis of the first metatarsal bone, and finally ends at the base of the second phalanx. Detailed imaging parameters of the Lisfranc joint and ligament were obtained from the present imaging experiment, providing an imaging reference for the diagnosis and repair of Lisfranc joint injuries. CONCLUSIONS: On the MRI images, the sagittal section can clearly display the corresponding situation of the Lisfranc joint bone and longitudinal arch of the foot, tolerably display the Lisfranc joint dorsal ligaments and metatarsal ligaments, and poorly display the Lisfranc ligament. The oblique coronal section can clearly display the transverse arch of the foot and clearly display the cross-section of the Lisfranc ligament. The oblique crosssection can clearly display the horizontal arch of the Lisfranc joint and more clearly display its surrounding ligaments and tendons, especially the entire Lisfranc ligament and its attachment points. This is an important section for the diagnosis of Lisfranc ligament injuries. This study provides a certain imaging reference for the MRI scanning, diagnosis, and repair of Lisfranc joint injuries. Further research with large sample size is still needed to confirm the conclusions. PMID- 30419939 TI - Exploring factors associated with views on sharing of certain interim trial result measures by the data safety monitoring board (DSMB) with non-DSMB members. AB - BACKGROUND: Sharing interim result measures by the Data Safety Monitoring Board (DSMB) with non-DSMB members is an important issue that can affect trial integrity. Currently, it is unclear if there are demographic factors associated with sharing such information. This study's objective is to primarily explore the demographic factors associated with the DSMB sharing certain interim result measures and secondarily, explore demographic factors associated with the perceived usefulness in sharing certain interim result measures, with non-DSMB members. METHODS: We conducted an online survey of members of the Society of Clinical Trials (SCT) and International Society of Clinical Biostatistics (ISCB) in 2015 asking their professional views on the DSMB sharing interim trial results, specifically the interim control event rate (IControlER), interim combined even rate (ICombinedER), adaptive conditional power (ACP) and unconditional conditional power (UCP) with non-DSMB members. Binary logistic and multiple linear regressions were used to explore if demographic factors were associated with sharing a certain interim result measure and the perceived usefulness of sharing that interim result measure, respectively. Multiple imputation (MI) was used to evaluate the impact of missing data as a sensitivity analysis. RESULTS: Approximately 3136 (936 from SCT + ~ 2200 from ISCB) members were invited (response rate of 12%; [371/3136]. Two main findings: (1) involvement in more than 15 private industry-sponsored trials was associated with not endorsing the sharing of the IControlER (odds ratio [OR] = 2.92; 95% confidence interval [CI]: 1.31, 6.52]; p = 0.012), and (2) involvement in more than 15 private industry-sponsored trials was associated positively with an increase in the perceived usefulness in sharing the ACP by 2.35 points (beta coefficient estimate = 2.35 [95% CI: 0.45, 4.05], p = 0.017. The findings were similar after sensitivity analyses. CONCLUSIONS: An individual involved with more than 15 trials that had some form of private industry sponsorship is a demographic factor associated with NOT sharing the IControlER by the DSMB and an increased perceived usefulness in sharing the ACP at interim. Further studies are needed to evaluate for these demographic factors given the limitations of this study related to missing data. Due to some key limitations, regarding high non response and missing data, we caution interpreting the results as definitive, but rather look at them as a first exploratory step to find potential associations for further evaluation. PMID- 30419937 TI - Association of bovine major histocompatibility complex (BoLA) gene polymorphism with colostrum and milk microbiota of dairy cows during the first week of lactation. AB - BACKGROUND: The interplay between host genotype and commensal microbiota at different body sites can have important implications for health and disease. In dairy cows, polymorphism of bovine major histocompatibility complex (BoLA) gene has been associated with susceptibility to several infectious diseases, most importantly mastitis. However, mechanisms underlying this association are yet poorly understood. In the present study, we sought to explore the association of BoLA gene polymorphism with the dynamics of mammary microbiota during the first week of lactation. RESULTS: Colostrum and milk samples were collected from multiparous Holstein dairy cows at the day of calving and days 1 and 6 after calving. Microbiota profiling was performed using high-throughput sequencing of the V1-V2 regions of the bacterial 16S rRNA genes and ITS2 region of the fungal ribosomal DNA. Polymorphism of BoLA genes was determined using PCR-RFLP of exon 2 of the BoLA-DRB3. In general, transition from colostrum to milk resulted in increased species richness and diversity of both bacterial and fungal communities. The most dominant members of intramammary microbiota included Staphylococcus, Ruminococcaceae, and Clostridiales within the bacterial community and Alternaria, Aspergillus, Candida, and Cryptococcus within the fungal community. Comparing the composition of intramammary microbiota between identified BoLA-DRB3.2 variants (n = 2) revealed distinct clustering pattern on day 0, whereas this effect was not significant on the microbiota of milk samples collected on subsequent days. On day 0, proportions of several non-aureus Staphylococcus (NAS) OTUs, including those aligned to Staphylococcus equorum, Staphylococcus gallinarum, Staphylococcus sciuri, and Staphylococcus haemolyticus, were enriched within the microbiota of one of the BoLA-DRB3.2 variants, whereas lactic acid bacteria (LAB) including Lactobacillus and Enterococcus were enriched within the colostrum microbiota of the other variant. CONCLUSION: Our results suggest a potential role for BoLA-gene polymorphism in modulating the composition of colostrum microbiota in dairy cows. Determining whether BoLA-mediated shifts in the composition of colostrum microbiota are regulated directly by immune system or indirectly by microbiota-derived colonization resistant can have important implications for future development of preventive/therapeutic strategies for controlling mastitis. PMID- 30419940 TI - Premature ejaculation in primary care: communication strategies versus usual care for male patients consulting for a sexual, urogenital or psychological reason - GET UP: study protocol for a cluster randomised controlled trial. AB - BACKGROUND: Premature ejaculation (PE) is the most common sexual dysfunction among men. According to patients, the general practitioner (GP) is the appropriate professional with whom to discuss this issue. However, few patients receive the medical help needed because GPs find it difficult to talk to their patients about sex. A previous qualitative study provided six strategies described by GPs who had tackled the topic during consultation. A pilot study showed that using one of these strategies after a training course led to an increase in the rate of consultations where the topic was raised: an increase from 6.6 to 30.8%. The aim of this study is to compare whether training in communication skills with these six strategies is more effective than usual care on the incidence of patients bringing up the topic of PE with their GP. METHODS: A cluster randomised controlled trial, stratified over four areas comparing an intervention group, which will receive the six strategies training session, and a control group, which ensures routine medical care. The primary outcome is to investigate the efficacy of a training in communication skills directed towards this pathology, compared with usual care procedures, on the incidence of patients bringing up the topic of PE with their GP. The secondary objective relates to the variation in the quality of life of patients after having recently addressed the topic of PE. Quality of life will be evaluated using the SF-12 health scale, with scoring filled in by the patient immediately after the consultation and 4 weeks later. The patients suffering from PE will be identified if their score is higher than 9 on the Premature Ejaculation Diagnostic Tool filled in 4 weeks after the consultation. The number of patients necessary to highlight a significant difference between the two groups from 5 to 20% is 101. Therefore, a total of 600 patients is expected, 300 in each arm (40 GPs, 15 patients per GP; risk alpha = 5%; power = 90%; intra-cluster correlation coefficient rho = 0.2; Hawthorne effect = 15%; lost-to-follow-up rates for GPs = 10% and for patients = 20%). DISCUSSION: The implication for practice is the improvement in the quality of patient-centred care within a topic area which encompasses almost 30% of male sex related complaints. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02378779 . Registered on 3 February 2015. PMID- 30419941 TI - LncRNAs in polyploid cotton interspecific hybrids are derived from transposon neofunctionalization. AB - BACKGROUND: Interspecific hybridization and whole genome duplication are driving forces of genomic and organism diversification. But the effect of interspecific hybridization and whole genome duplication on the non-coding portion of the genome in particular remains largely unknown. In this study, we examine the profile of long non-coding RNAs (lncRNAs), comparing them with that of coding genes in allotetraploid cotton (Gossypium hirsutum), its putative diploid ancestors (G. arboreum; G. raimondii), and an F1 hybrid (G. arboreum * G. raimondii, AD). RESULTS: We find that most lncRNAs (80%) that were allelic expressed in the allotetraploid genome. Moreover, the genome shock of hybridization reprograms the non-coding transcriptome in the F1 hybrid. Interestingly, the activated lncRNAs are predominantly transcribed from demethylated TE regions, especially from long interspersed nuclear elements (LINEs). The DNA methylation dynamics in the interspecies hybridization are predominantly associated with the drastic expression variation of lncRNAs. Similar trends of lncRNA bursting are also observed in the progress of polyploidization. Additionally, we find that a representative novel lncRNA XLOC_409583 activated after polyploidization from a LINE in the A subgenome of allotetraploid cotton was involved in control of cotton seedling height. CONCLUSION: Our results reveal that the processes of hybridization and polyploidization enable the neofunctionalization of lncRNA transcripts, acting as important sources of increased plasticity for plants. PMID- 30419942 TI - Defining barriers and enablers for clinical pathway implementation in complex clinical settings. AB - BACKGROUND: While clinical pathways have the potential to improve patient outcomes and reduce healthcare costs, their true impact has been limited by variable implementation strategies and suboptimal research designs. This paper explores a comprehensive set of factors perceived by emergency department staff and administrative leads to influence clinical pathway implementation within the complex and dynamic environments of community emergency department settings. METHODS: This descriptive, qualitative study involved emergency health professionals and administrators of 15 community hospitals across Ontario, Canada. As part of our larger cluster randomized controlled trial, each site was in the preparation phase to implement one of two clinical pathways: pediatric asthma or pediatric vomiting and diarrhea. Data were collected from three sources: (i) a mediated group discussion with site champions during the project launch meeting; (ii) a semi-structured site visit of each emergency department; and (iii) key informant interviews with an administrative lead from each hospital. The Theoretical Domains Framework (TDF) was used to guide the interviews and thematically analyze the data. Domains within each major theme were then mapped onto the COM-B model-capability, opportunity, and motivation-of the Behaviour Change Wheel. RESULTS: Seven discrete themes and 58 subthemes were identified that comprised a set of barriers and enablers relevant to the planned clinical pathway implementation. Within two themes, three distinct levels of impact emerged, namely (i) the individual health professional, (ii) the emergency department team, and (iii) the broader hospital context. The TDF domains occurring most frequently were Memory, Attention and Decision Processes, Environmental Context and Resources, Behavioural Regulation, and Reinforcement. Mapping these barriers and enablers onto the COM-B model provided an organized perspective on how these issues may be interacting. Several factors were viewed as both negative and positive across different perspectives. Two of the seven themes were limited to one component, while four involved all three components of the COM-B model. CONCLUSIONS: Using a theory-based approach ensured systematic and comprehensive identification of relevant barriers and enablers to clinical pathway implementation in ED settings. The COM-B system of the Behaviour Change Wheel provided a useful perspective on how these factors might interact to effect change. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01815710 . PMID- 30419943 TI - The potential of an online educational platform to contribute to achieving sustainable development goals: a mixed-methods evaluation of the Peoples-uni online platform. AB - BACKGROUND: This paper reports on an online platform, People's Open Access Education Initiative (Peoples-uni), as a means of enhancing access to master's level public health education for health professionals. Peoples-uni seeks to improve population health in low- and middle-income countries by building public health capacity through e-learning at very low cost. We report here an evaluation of the Peoples-uni programme, conducted within the context of Sustainable Development Goal 4, which seeks to "ensure inclusive and quality education for all and promote lifelong learning" by 2030. The evaluation seeks to address the following three questions: (1) Did Peoples-uni meet its intended goals? (2) What were the different types of impacts that students experienced? (3) What suggestions for future changes in Peoples-uni did students recommend? METHODS: A mixed methods evaluation consisted of two parts, namely an online survey and a telephone interview. A total of 119 master's level graduates were invited to participate; responses were obtained from 71 of those invited, giving a response rate of 60%. Respondents were spread across 31 countries. Interviews were conducted with 18 respondents. RESULTS: There was strong evidence that Peoples uni had achieved its stated goals. Potential impacts on students included knowledge to enhance practice and appreciation of context, enhanced research capacity through knowledge of public health, critical thinking and evidence-based programming, and empowerment of students about the potential of education as a means of improving their lives. Accreditation through future partnerships with local universities was recommended by students. CONCLUSIONS: Peoples-uni has been able to deliver a credible public health master's level educational programme, with positive impacts on the students who graduated. Challenges are to find a way to accredit the programme to ensure its sustainability and to see how to take full advantage of the current, and future, graduates to turn this from an education programme into a capacity-building programme with real impact. PMID- 30419944 TI - Effectiveness of the Brazilian Visceral Leishmaniasis Surveillance and Control Programme in reducing the prevalence and incidence of Leishmania infantum infection. AB - BACKGROUND: Control strategies adopted by the Brazilian Visceral Leishmaniasis Surveillance and Control Programme (VLSCP) include identifying and culling seropositive infected dogs, early diagnosis and treatment of human cases, chemical control of the vector and population awareness. This study evaluated the effectiveness of the VLSCP on the prevalence and incidence rates of Leishmania infantum in children residing in areas under different VLSCP intervention times. METHODS: A quasi-experimental epidemiological study with a panel (two cross sectional) and a concurrent cohort was performed in three areas of Belo Horizonte, southeast Brazil. The first cross-sectional study (I) was carried out with 1875 children, 478 of which were enrolled in the cohort study. In the second cross-sectional study (II), 413 additional children were included, totalizing 891 children. Laboratory diagnosis was performed by ELISA-rK39. Analyses included multilevel logistic and Poisson regression models. RESULTS: The incidence rates of L. infantum infection were: 14.4% in the area where VLSCP intervention was initiated in 2006 (AI2006); 21.1% in the area where intervention was initiated in 2008 (AI2008); and 11.6% in the area where intervention was initiated in 2010 (AI2010 - control area). A follow-up period of 24 months showed that the persons time incidence rates in AI2006, AI2008, and AI2010 were: 6.2/100, 10/100, and 5.6/100 persons/24 months, respectively. The final prevalence rates of infection (cross-sectional II - in 2012), compared to the initial rates (cross-sectional I in 2010), increased 83.7% in AI2006, 74.1% in AI2008, and decreased 5% in AI2010. Analysis of the effectiveness revealed that children residing in AI2008 are more likely to be infected (OR = 1.84; 95% CI: 1.06-3.23) and present a higher risk of infection (IRR = 1.76; 95% CI: 1.05-2.95) compared to those in AI2010. No statistically significant differences were observed in asymptomatic infection (OR and IRR) in AI2006 compared to AI2010. CONCLUSIONS: The VLSCP was not effective at controlling L. infantum infection in areas where interventions had respectively been carried out for six and four years. However, it is unclear what the consequences in terms of human infection and diseases would be in the absence of the VLSCP. Efforts to improve the effectiveness of control measures remain a necessary priority. PMID- 30419946 TI - Upper tibial MRI vascular marks lost in early knee osteoarthritis. AB - BACKGROUND: We describe upper tibial radiating vascular marks on MRI scans. They are lost in early osteoarthritis (OA). METHODS: A literature search revealed no previous description of upper tibial MRI radial vascular marks. Fifty-six consecutive patients with anteroposterior knee X-rays and an axial PD_SPAIR MRI scan of the same knee within 1 year were studied. Their mean age was 53.1 years (range 22-85) with 27 males and 29 females. The medial and lateral compartments of each knee were scored for osteoarthritis using the Kellgren-Lawrence (K-L) classification. Marks on the MRI scans were counted by layer and quadrant position. RESULTS: Radial vascular marks were present in the first axial upper tibial subchondral slice, peaked between 6 and 10 mm depth and were absent by 16 mm depth. There was no association with age, left or right knee, BMI, or weight. There was more K-L graded OA medially and more vascular marks laterally. There was an inverse correlation between the number of marks and early grades of osteoarthritis medially (p < 0.001) and laterally (p < 0.002). CONCLUSION: We demonstrate previously undescribed subchondral vascular marks on axial MRI scans of the tibia and their inverse correlation with the presence and severity of early knee osteoarthritis. Our work offers a new insight into the possible vascular aetiology of osteoarthritis and potentially a means of earlier diagnosis and a therapeutic target. PMID- 30419945 TI - Overground walking patterns after chronic incomplete spinal cord injury show distinct response patterns to unloading. AB - BACKGROUND: Body weight support (BWS) is often provided to incomplete spinal cord injury (iSCI) patients during rehabilitation to enable gait training before full weight-bearing is recovered. Emerging robotic devices enable BWS during overground walking, increasing task-specificity of the locomotor training. However, in contrast to a treadmill setting, there is little information on how unloading is integrated into overground locomotion. We investigated the effect of a transparent multi-directional BWS system on overground walking patterns at different levels of unloading in individuals with chronic iSCI (CiSCI) compared to controls. METHODS: Kinematics of 12 CiSCI were analyzed at six different BWS levels from 0 to 50% body weight unloading during overground walking at 2kmh- 1 and compared to speed-matched controls. RESULTS: In controls, temporal parameters, single joint trajectories, and intralimb coordination responded proportionally to the level of unloading, while spatial parameters remained unaffected. In CiSCI, unloading induced similar changes in temporal parameters. CiSCI, however, did not adapt their intralimb coordination or single joint trajectories to the level of unloading. CONCLUSIONS: The findings revealed that continuous, dynamic unloading during overground walking results in subtle and proportional gait adjustments corresponding to changes in body load. CiSCI demonstrated diminished responses in specific domains of gait, indicating that their altered neural processing impeded the adjustment to environmental constraints. CiSCI retain their movement patterns under overground unloading, indicating that this is a viable locomotor therapy tool that may also offer a potential window on the diminished neural control of intralimb coordination. PMID- 30419947 TI - Expression quantitative trait loci in the developing human brain and their enrichment in neuropsychiatric disorders. AB - BACKGROUND: Genetic influences on gene expression in the human fetal brain plausibly impact upon a variety of postnatal brain-related traits, including susceptibility to neuropsychiatric disorders. However, to date, there have been no studies that have mapped genome-wide expression quantitative trait loci (eQTL) specifically in the human prenatal brain. RESULTS: We performed deep RNA sequencing and genome-wide genotyping on a unique collection of 120 human brains from the second trimester of gestation to provide the first eQTL dataset derived exclusively from the human fetal brain. We identify high confidence cis-acting eQTL at the individual transcript as well as whole gene level, including many mapping to a common inversion polymorphism on chromosome 17q21. Fetal brain eQTL are enriched among risk variants for postnatal conditions including attention deficit hyperactivity disorder, schizophrenia, and bipolar disorder. We further identify changes in gene expression within the prenatal brain that potentially mediate risk for neuropsychiatric traits, including increased expression of C4A in association with genetic risk for schizophrenia, increased expression of LRRC57 in association with genetic risk for bipolar disorder, and altered expression of multiple genes within the chromosome 17q21 inversion in association with variants influencing the personality trait of neuroticism. CONCLUSIONS: We have mapped eQTL operating in the human fetal brain, providing evidence that these confer risk to certain neuropsychiatric disorders, and identifying gene expression changes that potentially mediate susceptibility to these conditions. PMID- 30419948 TI - Long non-coding RNA DANCR promotes malignant phenotypes of bladder cancer cells by modulating the miR-149/MSI2 axis as a ceRNA. AB - BACKGROUND: Accumulating evidences have indicated that long non-coding RNAs (lncRNAs) are potential biomarkers that play key roles in tumor development and progression. Differentiation antagonizing non-protein noding RNA (DANCR) is a novel lncRNA that acts as a potential biomarker and is involved in the development of cancers. However, the clinical significance and molecular mechanism of DANCR in bladder cancer is still unknown. METHODS: The relative expression level of DANCR was determined by Real-Time qPCR in a total of 106 patients with urothelial bladder cancer and in different bladder cancer cell lines. Loss-of-function experiments were performed to investigate the biological roles of DANCR on bladder cancer cell proliferation, migration, invasion and tumorigenicity. Comprehensive transcriptional analysis, RNA-FISH, dual-luciferase reporter assay and western blot were performed to explore the molecular mechanisms underlying the functions of DANCR. RESULTS: In this study, we found that DANCR was significantly up-regulated in bladder cancer. Moreover, increased DANCR expression was positively correlated with higher histological grade and advanced TNM stage. Further experiments demonstrated that knockdown of DANCR inhibited malignant phenotypes and epithelial-mesenchymal transition (EMT) of bladder cancer cells. Mechanistically, we found that DANCR was distributed mostly in the cytoplasm and DANCR functioned as a miRNA sponge to positively regulate the expression of musashi RNA binding protein 2 (MSI2) through sponging miR-149 and subsequently promoted malignant phenotypes of bladder cancer cells, thus playing an oncogenic role in bladder cancer pathogenesis. CONCLUSION: This study is the first to demonstrate that DANCR plays a critical regulatory role in bladder cancer cell and DANCR may serve as a potential diagnostic biomarker and therapeutic target of bladder cancer. PMID- 30419949 TI - Dynamic linear models guide design and analysis of microbiota studies within artificial human guts. AB - BACKGROUND: Artificial gut models provide unique opportunities to study human associated microbiota. Outstanding questions for these models' fundamental biology include the timescales on which microbiota vary and the factors that drive such change. Answering these questions though requires overcoming analytical obstacles like estimating the effects of technical variation on observed microbiota dynamics, as well as the lack of appropriate benchmark datasets. RESULTS: To address these obstacles, we created a modeling framework based on multinomial logistic-normal dynamic linear models (MALLARDs) and performed dense longitudinal sampling of four replicate artificial human guts over the course of 1 month. The resulting analyses revealed how the ratio of biological variation to technical variation from sample processing depends on sampling frequency. In particular, we find that at hourly sampling frequencies, 76% of observed variation could be ascribed to technical sources, which could also skew the observed covariation between taxa. We also found that the artificial guts demonstrated replicable trajectories even after a recovery from a transient feed disruption. Additionally, we observed irregular sub-daily oscillatory dynamics associated with the bacterial family Enterobacteriaceae within all four replicate vessels. CONCLUSIONS: Our analyses suggest that, beyond variation due to sequence counting, technical variation from sample processing can obscure temporal variation from biological sources in artificial gut studies. Our analyses also supported hypotheses that human gut microbiota fluctuates on sub-daily timescales in the absence of a host and that microbiota can follow replicable trajectories in the presence of environmental driving forces. Finally, multiple aspects of our approach are generalizable and could ultimately be used to facilitate the design and analysis of longitudinal microbiota studies in vivo. PMID- 30419950 TI - LAT2 regulates glutamine-dependent mTOR activation to promote glycolysis and chemoresistance in pancreatic cancer. AB - BACKGROUND: Reprogrammed energy metabolism has become an emerging hallmark of cancer in recent years. Transporters have been reported to be amino acid sensors involved in controlling mTOR recruitment and activation, which is crucial for the growth of both normal and tumor cells. L-type amino acid transporter 2 (LAT2), encoded by the SLC7A8 gene, is a Na+-independent neutral amino acid transporter and is responsible for transporting neutral amino acids, including glutamine, which can activate mTOR. Previous studies have shown that LAT2 was overexpressed in gemcitabine-resistant pancreatic cancer cells. However, the role of LAT2 in chemoresistance in pancreatic cancer remains uncertain and elusive. METHODS: The effects of LAT2 on biological behaviors were analyzed. LAT2 and LDHB levels in tissues were detected, and the clinical value was evaluated. RESULTS: We demonstrated that LAT2 emerged as an oncogenic protein and could decrease the gemcitabine sensitivity of pancreatic cancer cells in vitro and in vivo. The results of a survival analysis indicated that high expression levels of both LAT2 and LDHB predicted a poor prognosis in patients with pancreatic cancer. Furthermore, we found that LAT2 could promote proliferation, inhibit apoptosis, activate glycolysis and alter glutamine metabolism to activate mTOR in vitro and in vivo. Next, we found that gemcitabine combined with an mTOR inhibitor (RAD001) could reverse the decrease in chemosensitivity caused by LAT2 overexpression in pancreatic cancer cells. Mechanistically, we demonstrated that LAT2 could regulate two glutamine-dependent positive feedback loops (the LAT2/p-mTORSer2448 loop and the glutamine/p-mTORSer2448/glutamine synthetase loop) to promote glycolysis and decrease gemcitabine (GEM) sensitivity in pancreatic cancer. CONCLUSION: Taken together, our data reveal that LAT2 functions as an oncogenic protein and could regulate glutamine-dependent mTOR activation to promote glycolysis and decrease GEM sensitivity in pancreatic cancer. The LAT2-mTOR-LDHB pathway might be a promising therapeutic target in pancreatic cancer. PMID- 30419951 TI - Seroprevalence and current infections of canine vector-borne diseases in Nicaragua. AB - BACKGROUND: Vector-borne diseases constitute a major problem for veterinary and public health, especially in tropical regions like Central America. Domestic dogs may be infected with several vector-borne pathogens of zoonotic relevance, which may also severely compromise canine health. METHODS: To assess the prevalence of canine vector-borne diseases in Nicaragua, 329 dogs from seven cities, which were presented to the veterinarian for various reasons, were included in this study. Dogs were examined clinically and diagnostic blood samples were taken for analysis of packed cell volume (PCV) and presence of microfilariae as well as antigen of Dirofilaria immitis and antibodies to Ehrlichia spp., Anaplasma spp. and Borrelia burgdorferi (sensu lato) by use of a commercially available rapid ELISA. To detect current infections, specific PCRs for the detection of E. canis, A. platys and A. phagocytophilum were carried out on blood samples of the respective seropositive dogs. Microfilaremic blood samples, as well as D. immitis antigen positive samples were further subjected to PCR and subsequent sequencing for filarial species identification. RESULTS: Antibodies against Ehrlichia spp. were present in 62.9% of dogs, while Anaplasma spp. seroprevalence was 28.6%. Antibodies against species of both genera were detected in 24.9% of dogs. Borrelia burgdorferi (s.l.) antibodies were not detected. Dirofilaria immitis antigen was present in six animals (1.8%), two of which also showed D. immitis microfilariae in buffy coat. In addition to D. immitis, Acanthocheilonema reconditum was identified by PCR and sequencing in two of four additional microfilaremic blood samples, which were tested negative for D. immitis antigen. Current E. canis infections as defined by DNA detection were present in 58.5% of Ehrlichia-seropositive dogs, while 5.3% of Anaplasma-seropositive dogs were PCR positive for A. platys, 2.2% for A. phagocytophilum and 16.0% for both Anaplasma species. Current E. canis infection had a statistically significant negative impact on PCV, whereas no relationship between infection status and clinical signs of disease could be observed. CONCLUSIONS: These results indicate that canine vector-borne diseases are widespread in Nicaragua and that dogs may constitute a reservoir for human infection with E. canis, A. phagocytophilum and D. immitis. Thus, the use of repellents or acaricides to protect dogs from vector borne diseases is strongly recommended. PMID- 30419952 TI - SETD2 mutations in primary central nervous system tumors. AB - Mutations in SETD2 are found in many tumors, including central nervous system (CNS) tumors. Previous work has shown these mutations occur specifically in high grade gliomas of the cerebral hemispheres in pediatric and young adult patients. We investigated SETD2 mutations in a cohort of approximately 640 CNS tumors via next generation sequencing; 23 mutations were detected across 19 primary CNS tumors. Mutations were found in a wide variety of tumors and locations at a broad range of allele frequencies. SETD2 mutations were seen in both low and high grade gliomas as well as non-glial tumors, and occurred in patients greater than 55 years of age, in addition to pediatric and young adult patients. High grade gliomas at first occurrence demonstrated either frameshift/truncating mutations or point mutations at high allele frequencies, whereas recurrent high grade gliomas frequently harbored subclones with point mutations in SETD2 at lower allele frequencies in the setting of higher mutational burdens. Comparison with the TCGA dataset demonstrated consistent findings. Finally, immunohistochemistry showed decreased staining for H3K36me3 in our cohort of SETD2 mutant tumors compared to wildtype controls. Our data further describe the spectrum of tumors in which SETD2 mutations are found and provide a context for interpretation of these mutations in the clinical setting. PMID- 30419953 TI - Trichinella britovi muscle larvae and adult worms: stage-specific and common antigens detected by two-dimensional gel electrophoresis-based immunoblotting. AB - BACKGROUND: Trichinella britovi is the second most common species of Trichinella that may affect human health. As an early diagnosis of trichinellosis is crucial for effective treatment, it is important to identify sensitive, specific and common antigens of adult T. britovi worms and muscle larvae. The present study was undertaken to uncover the stage-specific and common proteins of T. britovi that may be used in specific diagnostics. METHODS: Somatic extracts obtained from two developmental stages, muscle larvae (ML) and adult worms (Ad), were separated using two-dimensional gel electrophoresis (2-DE) coupled with immunoblot analysis. The positively-visualized protein spots specific for each stage were identified through liquid chromatography-tandem mass spectrometry (LC-LC/MS). RESULTS: A total of 272 spots were detected in the proteome of T. britovi adult worms (Ad) and 261 in the muscle larvae (ML). The somatic extracts from Ad and ML were specifically recognized by T. britovi-infected swine sera at 10 days post infection (dpi) and 60 dpi, with a total of 70 prominent protein spots. According to immunoblotting patterns and LC-MS/MS results, the immunogenic spots recognized by different pig T. britovi-infected sera were divided into three groups for the two developmental stages: adult stage-specific proteins, muscle larvae stage specific proteins, and proteins common to both stages. Forty-five Ad proteins (29 Ad-specific and 16 common) and thirteen ML proteins (nine ML-specific and four common) cross-reacted with sera at 10 dpi. Many of the proteins identified in Ad (myosin-4, myosin light chain kinase, paramyosin, intermediate filament protein B, actin-depolymerizing factor 1 and calreticulin) are involved in structural and motor activity. Among the most abundant proteins identified in ML were 14-3-3 protein zeta, actin-5C, ATP synthase subunit d, deoxyribonuclease-2-alpha, poly cysteine and histide-tailed protein, enolase, V-type proton ATPase catalytic and serine protease 30. Heat-shock protein, intermediate filament protein ifa-1 and intermediate filament protein B were identified in both proteomes. CONCLUSIONS: To our knowledge, this study represents the first immunoproteomic identification of the antigenic proteins of adult worms and muscle larvae of T. britovi. Our results provide a valuable basis for the development of diagnostic methods. The identification of common components for the two developmental stages of T. britovi may be useful in the preparation of parasitic antigens in recombinant forms for diagnostic use. PMID- 30419954 TI - Prevalence and genetic diversity of Enterocytozoon bieneusi in sheep in China. AB - BACKGROUND: Enterocytozoon bieneusi is a common species of microsporidia that not only influences human health but also threatens animal productive performance and value. However, there have been no systematic studies of the prevalence of E. bieneusi in sheep in China. RESULTS: A total of 953 fecal specimens were collected from sheep from 11 provinces across five regions of China and analyzed for E. bieneusi by nested PCR targeting the ribosomal internal transcribed spacer (ITS). Enterocytozoon bieneusi infections were detected in four regions, with an overall infection rate of 20.4% (194/953). The highest infection rate was detected in pre-weaned lambs (25.0%), followed by post-weaned lambs (22.2%) and adult sheep (14.6%). Enterocytozoon bieneusi was found in nine of the 11 tested provinces, with infection rates between 2.9-51.7%. Eleven genotypes were identified based on ITS analysis, including seven known genotypes (BEB6, CHG1, CHG3, CHS7, CHS8, COS-I and NESH5) and four novel genotypes (CHHLJS1, CHHLJS2, CHNXS1 and CHXJS1). All 11 genotypes were clustered into group 2, and the zoonotic genotype BEB6 was the dominant genotype (n = 129, 66.5%) in sheep. CONCLUSION: The prevalence of E. bieneusi was studied in five regions representing most areas where sheep are bred in China. This is the first report of E. bieneusi infection in sheep for seven Chinese provinces. Geographical differences were detected in the distribution of E. bieneusi genotypes, but no differences were found among sheep in different age groups. The zoonotic genotype BEB6 was the dominant genotype, indicating that sheep are a potential source of zoonotic microsporidiosis in China. These results improve our knowledge of the epidemiology of E. bieneusi in sheep in China. PMID- 30419956 TI - A dyadic planning intervention to quit smoking in single-smoking couples: design of a randomized controlled trial. AB - BACKGROUND: Tobacco use is the largest preventable cause of death. Smoking cessation interventions that use implementation intentions show promising results. Implementation intentions are if-then plans that specify a certain behaviour within a situational context. This study will examine whether involving a non-smoking partner could improve planning interventions, and whether and which partner interactions underlie this effectiveness. METHODS: This single-blind randomized controlled trial has a longitudinal design with a baseline questionnaire, end-of-day measurements for three weeks starting on the quit date, and a follow-up questionnaire after three months. PARTICIPANTS: single-smoking couples who live together and are in a relationship for more than one year. SETTING: couples are randomized to either a dyadic or individual planning condition. After the intervention the smoker attempts to quit smoking and the diary measurements start. MEASUREMENTS: The primary outcome variable is smoking abstinence. Secondary outcome measures are smoking behaviour and relationship satisfaction. Partner interactions are examined as a possible mediator. DISCUSSION: This RCT is the first to examine the effectiveness of dyadic planning to quit smoking in single-smoking couples. Partner interactions are thought to play an important role during the quit attempt, and therefore in the effectiveness of the intervention. This RCT will provide more insight into which daily partner interactions are beneficial for smoking abstinence and the couples' relationship satisfaction, and whether the type of intervention is related to different types or levels of partner interactions and smoking behaviour. When proven effective, this planning intervention in combination with coaching for the non-smoking partner will be a valuable and low-cost addition to existing smoking interventions. TRIAL REGISTRATION: The trial is retrospectively registered on 19/04/2017 on www.trialregister.nl ( TC: 6398 ). PMID- 30419955 TI - VIPER: variability-preserving imputation for accurate gene expression recovery in single-cell RNA sequencing studies. AB - We develop a method, VIPER, to impute the zero values in single-cell RNA sequencing studies to facilitate accurate transcriptome quantification at the single-cell level. VIPER is based on nonnegative sparse regression models and is capable of progressively inferring a sparse set of local neighborhood cells that are most predictive of the expression levels of the cell of interest for imputation. A key feature of our method is its ability to preserve gene expression variability across cells after imputation. We illustrate the advantages of our method through several well-designed real data-based analytical experiments. PMID- 30419958 TI - An unusual presentation of metastatic malignant melanoma causing jejuno-jejunal intussusception: a case report. AB - BACKGROUND: Small bowel intussusception in adults is rarely encountered. In most cases small bowel intussusception is caused by benign neoplastic lesions, but metastasis of cutaneous malignant melanoma causing small bowel intussusception is rare. We present such a case of jejuno-jejunal intussusception with an intraluminal metastatic lesion acting as a lead point. CASE PRESENTATION: We present a case of a 71-year-old Caucasian man who presented with small bowel obstruction. His medical history revealed that he had had a cutaneous malignant melanoma excised 7 years earlier and underwent total laryngectomy due to a metastasis 6 years later. The disease was classified as stage IV and he was receiving immunotherapy. An emergency abdominal computed tomography scan demonstrated small bowel obstruction, most probably caused by an intraluminal lesion. An emergency laparotomy revealed an intraluminal metastatic lesion causing jejuno-jejunal intussusception. Metastasectomy of the lesion was performed and 13 days later he was discharged. CONCLUSIONS: Jejuno-jejunal intussusception with a malignant melanoma metastasis acting as a lead point is very rare. With the gastrointestinal tract being a common location of distal metastases, a medical history of malignant melanoma treatment in cases of small bowel obstruction should raise a suspicion of possible metastatic disease. A computed tomography scan is the diagnostic modality of choice and surgery still remains the standard of care. PMID- 30419957 TI - Ectopic orbital meningioma: a retrospective case series. AB - BACKGROUND: To evaluate the ophthalmic manifestations and radiographic features of ectopic orbital meningioma to improve diagnostic accuracy. METHODS: Patient data from patients admitted to our institution during a 217-month period from August 1999 to September 2017 were included. Patient ophthalmic manifestations, radiographic features (CT and MRI), diagnosis, pathology, therapeutic regimens, and prognosis were retrospectively reviewed. RESULTS: Six patients with ectopic orbital meningioma were identified. The mean age at the first visit was 33.2 years (range, 7-56 years). All six patients displayed manifestations of exophthalmos, upper eyelid oedema, and motility impairment with a mean history of illness of 20.3 months (range 3-72 months). Optical lesions were located in the superonasal extraconal compartment (3/6, 50%), bitemporal extraconal compartment (1/6, 16.7%) and orbital intraconal compartment (2/6, 33%). Radiographic features were ill-defined, heterogeneous, enhancing soft tissue masses with extraocular muscular adhesion (6/6, 100%) and calcification (1/6, 16.7%), not adjacent to the optic nerve and not extending along the dura. Six cases were treated intraoperatively with complete surgical resection, indicating that all lesions were independent of the optic nerve and sphenoid ridge. The histopathologic classification was mostly of meningothelial cells (5/6, 83%). Immunohistochemistry revealed EMA and vimentin to have positive expression in all six cases, while two cases were calponin-positive and strongly expressed in the olfactory bulb. Postoperatively, lesions caused no visual impairment, and there were no cases of recurrence. CONCLUSIONS: Ectopic orbital meningiomas are rare tumours that are not easily diagnosed without postoperative histopathology. This report highlights some of the distinguishing features of isolated orbital lesions, especially around the location of frontoethmoidal suture. Accompanying upper eyelid oedema and eye mobility restriction were observed to be dissimilar to other orbital tumours. In these cases, a diagnosis of ectopic orbital meningioma should be considered. PMID- 30419959 TI - The physiological and molecular mechanism of brassinosteroid in response to stress: a review. AB - The negative effects of environmental stresses, such as low temperature, high temperature, salinity, drought, heavy metal stress, and biotic stress significantly decrease crop productivity. Plant hormones are currently being used to induce stress tolerance in a variety of plants. Brassinosteroids (commonly known as BR) are a group of phytohormones that regulate a wide range of biological processes that lead to tolerance of various stresses in plants. BR stimulate BRASSINAZOLE RESISTANCE 1 (BZR1)/BRI1-EMS SUPPRESSOR 1 (BES1), transcription factors that activate thousands of BR-targeted genes. BR regulate antioxidant enzyme activities, chlorophyll contents, photosynthetic capacity, and carbohydrate metabolism to increase plant growth under stress. Mutants with BR defects have shortened root and shoot developments. Exogenous BR application increases the biosynthesis of endogenous hormones such as indole-3-acetic acid, abscisic acid, jasmonic acid, zeatin riboside, brassinosteroids (BR), and isopentenyl adenosine, and gibberellin (GA) and regulates signal transduction pathways to stimulate stress tolerance. This review will describe advancements in knowledge of BR and their roles in response to different stress conditions in plants. PMID- 30419960 TI - Validity and reliability of the Maslach Burnout Inventory-Student Survey in Sri Lanka. AB - BACKGROUND: With ever increasing educational expectations and demands, burnout has emerged as a major problem negatively affecting the wellbeing of different student populations. Even though the validity of the Maslach Burnout Inventory Student Survey (MBI-SS) is widely assessed across the globe, there is a paucity of related literature in the South Asian settings. Hence, this study was aimed at assessing the factorial structure, validity, and reliability of the MBI-SS among collegiate cycle students in Sri Lanka. METHODS: The pre-tested Sinhala version of the MBI-SS was administered to a sample of 194 grade thirteen students in the Kurunegala district, Sri Lanka. The construct validity of the MBI-SS was assessed using multi-trait scaling analysis and confirmatory factor analysis (CFA), while reliability was assessed using internal consistency and test-retest reliability, which was assessed after an interval of two weeks. RESULTS: CFA revealed that the three-factor model of the MBI-SS fitted the data better than the one-factor and the two-factor model. Only one item (item 13) was identified as having poor psychometric properties. A modified version of the MBI-SS, with item 13 deleted, emerged as an acceptable fitting model with a combination of absolute, relative and parsimony fit indices reaching desired threshold values. All three subscales show high internal consistency with Cronbach's alpha coefficient values of 0.837, 0.869, and 0.881 and test-retest reliability was high (p < 0.001). CONCLUSIONS: The Sinhala version of the 15-item MBI-SS is a valid and a reliable instrument to assess the burnout status among collegiate cycle students in Sri Lanka. The Sinhala version of the 15-item MBI SS, due to its brevity, ease of administration, and sound psychometric properties, could be used as an effective screening tool to assess student burnout at the school level. PMID- 30419961 TI - Integrated traditional Chinese and conventional medicine in treatment of severe community-acquired pneumonia: study protocol for a randomized placebo-controlled trial. AB - BACKGROUND: Community-acquired pneumonia, especially severe community-acquired pneumonia (SCAP), remains the leading cause of death in the world. Despite advances in antimicrobial therapy, the mortality rates due to SCAP have not decreased significantly since antibiotics became routinely available. Traditional Chinese medicine (TCM) has been used for treating pneumonia for thousands of years. It is popular and widely practiced in Asia. In recent decades, evidence from both clinicians and patients suggests that TCM has some beneficial effect on SCAP. Thus, this study aims to compare the efficacy of a combination of a conventional drug and TCM to the conventional drug alone, to provide a scientific basis for clinical decisions. METHODS/DESIGN: A prospective, multi-center, single blinded, double-dummy, and randomized controlled clinical trial is being conducted to test the therapeutic effects of a combination of conventional medicine and TCM versus conventional medicine in the treatment of SCAP. A total of 198 patients will be enrolled in this study, with 99 in each treatment group (combination group or conventional medicine group). The TCM will be administered twice daily for 28 days. All patients will be followed for 3 months. The primary outcome measure is treatment failure, which is defined as clinical deterioration. Secondary outcome measures are time to clinical stability, length of hospital stay, in-hospital mortality, SOFA questionnaire, quality of life and cost of treatment. DISCUSSION: It is hypothesized that the combination of a conventional drug and TCM will reduce treatment failure, time to clinical stability, length hospital of stays, and in-hospital mortality, and improve the quality of life of SCAP patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03185923 . Registered on 20 June 2017. PMID- 30419962 TI - Investigation of antimicrobial susceptibility, class I and II integrons among Pseudomonas aeruginosa isolates from hospitalized patients in Isfahan, Iran. AB - OBJECTIVES: The role of integrons in the transfer of antibiotic resistance is one of the important issues, therefore, this study is aimed to investigate antibiotic resistance pattern and prevalence of class 1 and 2 integrons in P. aeruginosa isolated. RESULTS: Out of 72 confirmed P. aeruginosa isolates, 50% were from ICU patients. Antibacterial susceptibility pattern showed that isolates were most resistant to ceftazidime (76.4%) and colistin was the most effective antibiotic (100%) and molecular analysis of class I and II integrons showed 55.5% and 29.1% of isolates were positive, respectively and the proportions of MDR isolates were significantly higher among integron-positive isolates with 73.6% compared to negative isolates with 22.9%. Our results showed that there was a correlation among class 1 and 2 integrons with MDR P. aeruginosa isolates. According to the importance of integrons in acquisition and dissemination of antibiotics resistance genes, the performance of antibiotic surveillance programs and investigating the role of integrons is recommended to control the spreading of antibiotics resistance genes. PMID- 30419964 TI - Communicating health risks in science publications: time for everyone to take responsibility. AB - Research that is poorly communicated or presented is as potentially damaging as research that is poorly conducted or fraudulent. Recent examples illustrate how the problem often lies with researchers, not press officers or journalists. The quest for publication and 'impact' must not outweigh the importance of accurate representation of science; herein, we suggest steps that researchers, journalists and press officers can take to help ensure this. PMID- 30419963 TI - Polydatin effectively attenuates disease activity in lupus-prone mouse models by blocking ROS-mediated NET formation. AB - BACKGROUND: Neutrophil extracellular trap (NET) formation has been described to be closely involved in the pathogenesis of systemic lupus erythematosus (SLE). In this study, we aimed to investigate the effect of polydatin (PD) on NET formation and its effects on disease activity in lupus-prone mouse models. METHODS: In vitro, neutrophils from SLE patients and healthy people stimulated with phorbol 12-myristate 13-acetate (PMA) or phosphate-buffered saline (PBS) were treated with PD, and reactive oxygen species (ROS) production and NET formation examined. In vivo, pristane-induced lupus (PIL) mice were treated with vehicle, PD, mycophenolate mofetil (MMF) or cyclophosphamide (CYC) while MRL/lpr mice were treated with vehicle or PD. Proteinuria, serum autoantibodies, ROS production, NET formation and kidney histopathology were tested. RESULTS: Consistent with previous findings, blood neutrophils from SLE patients showed increased spontaneous NET formation. Both in vivo and in vitro, PD treatment significantly inhibited ROS production and NET release by neutrophils. In MRL/lpr mouse model, PD administration reduced the proteinuria, circulating autoantibody levels, and deposition of NETs and immune complex in the kidneys. In addition, PD treatment ameliorated lupus-like features in PIL mice as MMF or CYC did. CONCLUSIONS: PD treatment inhibited ROS-mediated NET formation and ameliorated lupus manifestations in both PIL mice and MRL/lpr mice. These results highlight the involvement of NETosis in SLE pathogenesis and reveal that PD might be a potential therapeutic agent for SLE or other autoimmune diseases. PMID- 30419966 TI - Effect of high-frequency alternating current transcutaneous stimulation over muscle strength: a controlled pilot study. AB - BACKGROUND: High-frequency alternating currents of greater than 1 kHz applied on peripheral nerves has been used in animal studies to produce a motor nerve block. It has been evidenced that frequencies higher than 5 kHz are necessary to produce a complete peripheral nerve block in primates, whose nerve thickness is more similar to humans. The aim of the study was to determine the effect on muscle strength after the application of a high-frequency stimulation at 5 and 10 kHz compared to sham stimulation in healthy volunteers. FINDINGS: Transcutaneous stimulation at 5 kHz, 10 kHz and sham stimulation were applied to eleven healthy volunteers over the ulnar and median nerves for 20 min. Maximal handgrip strength was measured before, during, immediately after the intervention, and 10 min after the end of intervention. The 10 kHz stimulation showed a lower handgrip strength during the intervention (28.1 N, SEM 3.9) when compared to 5 kHz (31.1 N, SEM 3.6; p < 0.001) and to sham stimulation (33.7 N, SEM 3.9; p < 0.001). Furthermore, only stimulation at 10 kHz decreased handgrip strength when compared to baseline. CONCLUSIONS: These findings suggest high-frequency stimulation has an inhibitory effect over muscle strength. Future studies are required in patients that are characterized by motor hyperactive such as spasticity or tremors. CLINICAL TRIAL REGISTRATION: NCT, NCT03169049 . Registered on 30 May 2017. PMID- 30419965 TI - Applicability and added value of novel methods to improve drug development in rare diseases. AB - BACKGROUND: The ASTERIX project developed a number of novel methods suited to study small populations. The objective of this exercise was to evaluate the applicability and added value of novel methods to improve drug development in small populations, using real world drug development programmes as reported in European Public Assessment Reports. METHODS: The applicability and added value of thirteen novel methods developed within ASTERIX were evaluated using data from 26 European Public Assessment Reports (EPARs) for orphan medicinal products, representative of rare medical conditions as predefined through six clusters. The novel methods included were 'innovative trial designs' (six methods), 'level of evidence' (one method), 'study endpoints and statistical analysis' (four methods), and 'meta-analysis' (two methods) and they were selected from the methods developed within ASTERIX based on their novelty; methods that discussed already available and applied strategies were not included for the purpose of this validation exercise. Pre-requisites for application in a study were systematized for each method, and for each main study in the selected EPARs it was assessed if all pre-requisites were met. This direct applicability using the actual study design was firstly assessed. Secondary, applicability and added value were explored allowing changes to study objectives and design, but without deviating from the context of the drug development plan. We evaluated whether differences in applicability and added value could be observed between the six predefined condition clusters. RESULTS AND DISCUSSION: Direct applicability of novel methods appeared to be limited to specific selected cases. The applicability and added value of novel methods increased substantially when changes to the study setting within the context of drug development were allowed. In this setting, novel methods for extrapolation, sample size re-assessment, multi-armed trials, optimal sequential design for small sample sizes, Bayesian sample size re-estimation, dynamic borrowing through power priors and fall-back tests for co-primary endpoints showed most promise - applicable in more than 40% of evaluated EPARs in all clusters. Most of the novel methods were applicable to conditions in the cluster of chronic and progressive conditions, involving multiple systems/organs. Relatively fewer methods were applicable to acute conditions with single episodes. For the chronic clusters, Goal Attainment Scaling was found to be particularly applicable as opposed to other (non-chronic) clusters. CONCLUSION: Novel methods as developed in ASTERIX can improve drug development programs. Achieving optimal added value of these novel methods often requires consideration of the entire drug development program, rather than reconsideration of methods for a specific trial. The novel methods tested were mostly applicable in chronic conditions, and acute conditions with recurrent episodes. PMID- 30419967 TI - Identification and internal validation of models for predicting survival and ICU admission following a traumatic injury. AB - BACKGROUND: Measures to improve the accuracy of determining survival and intensive care unit (ICU) admission using the International Classification of Injury Severity Score (ICISS) are not often conducted on a population-wide basis. The aim is to determine if the predictive ability of survival and ICU admission using ICISS can be improved depending on the method used to derive ICISS and incremental inclusion of covariates. METHOD: A retrospective analysis of linked injury hospitalisation and mortality data during 1 January 2010 to 30 June 2014 in New South Wales, Australia was conducted. Both multiplicative-injury and single-worst-injury ICISS were calculated. Logistic regression examined 90-day mortality and ICU admission with a range of predictor variables. The models were assessed in terms of their ability to discriminate survivors and non-survivors, model fit, and variation explained. RESULTS: There were 735,961 index injury admissions, 13,744 (1.9%) deaths within 90-days and 23,054 (3.1%) ICU admissions. The best predictive model for 90-day mortality was single-worst-injury ICISS including age group, gender, all comorbidities, trauma centre type, injury mechanism, and nature of injury as covariates. The multiplicative-injury ICISS with age group, gender, all comorbidities, injury mechanism, and nature of injury was the best predictive model for ICU admission. CONCLUSIONS: The inclusion of comorbid conditions, injury mechanism and nature of injury, improved discrimination for both 90-day mortality and ICU admission. Moves to routinely use ICD-based injury severity measures, such as ICISS, should be considered for hospitalisation data replacing more resource-intensive injury severity classification measures. PMID- 30419970 TI - Editorial: Everyone must see what is in Pandora's box. PMID- 30419968 TI - The burden of common variable immunodeficiency disorders: a retrospective analysis of the European Society for Immunodeficiency (ESID) registry data. AB - BACKGROUND: Common variable immunodeficiency disorders (CVID) are a group of rare innate disorders characterized by specific antibody deficiency and increased rates of infections, comorbidities and mortality. The burden of CVID in Europe has not been previously estimated. We performed a retrospective analysis of the European Society for Immunodeficiencies (ESID) registry data on the subset of patients classified by their immunologist as CVID and treated between 2004 and 2014. The registered deaths and comorbidities were used to calculate the annual average age-standardized rates of Years of Life Lost to premature death (YLL), Years Lost to Disability (YLD) and Disability Adjusted Life Years (DALY=YLL + YLD). These outcomes were expressed as a rate per 105 of the CVID cohort (the individual disease burden), and of the general population (the societal disease burden). RESULTS: Data of 2700 patients from 23 countries were analysed. Annual comorbidity rates: bronchiectasis, 21.9%; autoimmunity, 23.2%; digestive disorders, 15.6%; solid cancers, 5.5%; lymphoma, 3.8%, exceeded the prevalence in the general population by a factor of 34.0, 7.6, 8.1, 2.4 and 32.6, respectively. The comorbidities of CVID caused 8722 (6069; 12,363) YLD/105 in this cohort, whereas 44% of disability burden was attributable to infections and bronchiectasis. The total individual burden of CVID was 36,785 (33,078, 41,380) DALY/105. With estimated CVID prevalence of ~ 1/ 25,000, the societal burden of CVID ensued 1.5 (1.3, 1.7) DALY/105 of the general population. In exploratory analysis, increased mortality was associated with solid tumor, HR (95% CI): 2.69 (1.10; 6.57) p = 0.030, lymphoma: 5.48 (2.36; 12.71) p < .0001 and granulomatous lymphocytic interstitial lung disease: 4.85 (1.63; 14.39) p = 0.005. Diagnostic delay (median: 4 years) was associated with a higher risk of death: 1.04 (1.02; 1.06) p = .0003, bronchiectasis: 1.03 (1.01; 1.04) p = .0001, solid tumor: 1.08 (1.04; 1.11) p < .0001 and enteropathy: 1.02 (1.00; 1.05) p = .0447 and stayed unchanged over four decades (p = .228). CONCLUSIONS: While the societal burden of CVID may seem moderate, it is severe to the individual patient. Delay in CVID diagnosis may constitute a modifiable risk factor of serious comorbidities and death but showed no improvement. Tools supporting timely CVID diagnosis should be developed with high priority. PMID- 30419971 TI - Genetic and morphometric categorization of Taenia ovis from Sheep in Iran. AB - Little is known about the genetic and morphological characters of Taenia ovis. The purpose of the present study was to characterize sheep isolates of T. ovis using rostellar hook morphometry as well as mitochondrial genes sequence analysis. Ninety sheep specimens of Cysticercus ovis were collected from 18 slaughterhouses in Iran. The mean +/- s.d. for total length of large and small hooks were 174.1 +/- 6.4 and 116.7 +/- 5.4 um, respectively. CO1 and 12S rRNA sequence analysis showed 11 and nine haplotypes, respectively. The level of pairwise nucleotide variations between individual haplotypes of CO1 and 12S rRNA genes were 0.3-1.1 and 0.2-1.0%, respectively. Level of nucleotide variation in CO1 and 12S rRNA between T. ovis haplotypes from present study and eight other Taenia species was found to be 11.3-17.8 and 5.3-16.3%, respectively. Phylogenetic analysis clustered all T. ovis isolates into a single clade comprised of the all CO1 and 12S rRNA haplotypes. CO1 nucleotide difference between T. ovis ovis and T. asiatica was 13.6% that is lesser than the corresponding difference between T. ovis ovis and T. ovis krabbei, warranting the designation of two separate species as T. ovis and T. krabbei. Interclass correlation coefficients showed that there was no significant association between rostellar hook length variation and the variability of the mitochondrial genes. PMID- 30419972 TI - Public Health Emergency Preparedness System Evaluation Criteria and Performance Metrics: A Review of Contributions of the CDC-Funded Preparedness and Emergency Response Research Centers. AB - OBJECTIVES: The US Centers for Disease Control and Prevention (CDC)-funded Preparedness and Emergency Response Research Centers (PERRCs) conducted research from 2008 to 2015 aimed to improve the complex public health emergency preparedness and response (PHEPR) system. This paper summarizes PERRC studies that addressed the development and assessment of criteria for evaluating PHEPR and metrics for measuring their efficiency and effectiveness. METHODS: We reviewed 171 PERRC publications indexed in PubMed between 2009 and 2016. These publications derived from 34 PERRC research projects. We identified publications that addressed the development or assessment of criteria and metrics pertaining to PHEPR systems and describe the evaluation methods used and tools developed, the system domains evaluated, and the metrics developed or assessed. RESULTS: We identified 29 publications from 12 of the 34 PERRC projects that addressed PHEPR system evaluation criteria and metrics. We grouped each study into 1 of 3 system domains, based on the metrics developed or assessed: (1) organizational characteristics (n = 9), (2) emergency response performance (n = 12), and (3) workforce capacity or capability (n = 8). These studies addressed PHEPR system activities including responses to the 2009 H1N1 pandemic and the 2011 tsunami, as well as emergency exercise performance, situational awareness, and workforce willingness to respond. Both PHEPR system process and outcome metrics were developed or assessed by PERRC studies. CONCLUSIONS: PERRC researchers developed and evaluated a range of PHEPR system evaluation criteria and metrics that should be considered by system partners interested in assessing the efficiency and effectiveness of their activities. Nonetheless, the monitoring and measurement problem in PHEPR is far from solved. Lack of standard measures that are readily obtained or computed at local levels remains a challenge for the public health preparedness field. (Disaster Med Public Health Preparedness. 2018;page 1 of 13). PMID- 30419969 TI - A significant association between examination results and self-satisfaction with English language proficiency: preliminary findings among pre-clinical undergraduates. AB - OBJECTIVES: Learning methods and other related factors influence the success of medical undergraduates. This study aims at finding factors associated with the end of pre-clinical stream examination results among medical undergraduates of the Rajarata University of Sri Lanka. The results of this study will inform the tutors to plan and implement teaching methods as well as to guide the social welfare of the undergraduates. In general, we believe this study has the potential to improve the medical undergraduate's academic performance. RESULTS: Eighty-six per cent (112/130) of medical undergraduates have passed the examination and rest was referred. Logistic regression revealed a significant association between examination results and self-satisfaction for English language proficiency (P = 0.048). Passing the examination was more likely with high self-satisfaction for English language proficiency [odds ratio = 6.063 (95% CI 1.014 to 36.249)]. Also, a significant association between obtaining a class at the examination and using peer-revision notes (P = 0.019) was revealed. Obtaining a class at the examination was less likely with the frequent use of peer-revision notes [odds ratio = 0.228 (95% CI 0.066 to 0.790)]. PMID- 30419973 TI - The association between dietary protein intake, energy intake and physical frailty- results from the Rotterdam Study. PMID- 30419974 TI - A Paleolithic diet lowers resistant starch intake but does not affect serum trimethylamine-N-oxide concentrations in healthy women. PMID- 30419975 TI - Effects of feeding frequency of an elevated plane of milk replacer and calf age on behavior, and glucose and insulin kinetics in male Holstein calves. AB - Optimizing feeding regimens in early life to maximize lifelong growth and production are essential in the dairy industry. This study investigated the effects of milk replacer (MR) feeding frequency and calf age on behavior, and glucose and insulin kinetics of pre- and post-weaned calves fed an elevated plane of MR. Ten male Holstein calves (42.2+/-1.8 kg BW) were blocked by BW and randomly assigned to two treatments offering 8 l MR/day (150 g/l) in two (2*; meal size 4 l) or four (4*; meal size 2 l) feedings via an automated calf feeder. Milk replacer was gradually stepped down by 1 l/day during week 8, with calves being weaned by week 9. Water and pelleted calf starter were offered ad libitum. Individual intake of MR and starter were recorded daily, and BW was recorded weekly. The number of visits to the MR feeder (rewarded and unrewarded), and behaviors such as lying, cross-sucking, non-nutritive sucking and occupancy time in the feeder were recorded for individual calves from weeks 4 to 10. Jugular catheters were placed on weeks 4, 7 and 10 to facilitate postprandial blood sampling and glucose tolerance tests. Statistical analysis was conducted using the PROC GLIMMIX procedure (SAS) for behavioral observations, and the MIXED procedure (SAS) with repeated measures for BW, intake, plasma glucose and plasma insulin data. Final BW, starter and MR intake did not differ between treatments. There were no differences in observed calf behaviors; with the exception that 2* calves visited the MR feeder more often (P<0.01; total: unrewarded and rewarded). Baseline concentrations (mmol/l) and the maximum change in glucose (delta, mmol/l) were greater and lower (P=0.02) in 4*compared to 2*calves, respectively. Postprandial insulin AUC240 tended (P=0.09) to be greater in 2*calves, compared to 4*calves at week 7. Similarly, T max (min), AUC240 and delta values (uU/ml) were greater (P?0.05) in 2*calves, compared to 4*calves. No treatment *age interactions were observed for glucose or insulin during the glucose tolerance tests. Therefore, we conclude that feeding an elevated plane of MR (8 l/day) at a lower frequency (2* v. 4*) increased feeder visits, but not other hunger-related behaviors, and while postprandial glucose and insulin parameters varied, insulin sensitivity remained stable in Holstein dairy calves up to 10 weeks of age in calves consuming similar levels of calf starter. PMID- 30419976 TI - Does rescue in vitro maturation of germinal vesicle stage oocytes impair embryo morphokinetics development? AB - SummaryCurrently, rescue in vitro maturation (IVM) is not a routine method in assisted reproductive treatment (ART) programmes but is a promising procedure for ART to improve IVM. The aim of this study was to compare embryo morphokinetics of germinal vesicles (GV) with metaphase II (MII) oocytes from controlled ovarian hyperstimulation (COH) cycles by time-lapse photography monitoring (TLM). Morphokinetics of the same number of embryos derived from the in vivo (group I) and rescue of in vitro matured oocytes (group II) from 310 patients were analyzed and compared retrospectively. The time to form second PB extrusion (tPB2), time of pronuclei appearance (tPNa), time of pronuclei fading (tPNf) and time of two to eight discrete cells (t2-t8) were assessed. Abnormal cleavage patterns such as uneven blastomeres at the two-cell stage, cell fusion (Fu), trichotomous mitoses (TM), and the rates of embryo arrest were assessed. These data showed that tPB2, tPNa, tPNf, t2, t3 and t4 stages took place later in group II compared with group I (P<0.001, P=0.017, P<0.001, P<0.001, P<0.001, P<0.001, respectively). The rates of uneven blastomeres, Fu, TM, and embryo arrest were increased significantly in group II compared with group I (P=0.001, P<0.001, P=0.003, P<0.001, respectively). Based on the exact annotation of timing parameters and cleavage patterns, the present data agreed with the concept that rescue IVM of oocytes negatively influences embryo morphokinetics. Therefore, cautious use of embryos derived from rescue IVM of GV oocytes should be made. PMID- 30419977 TI - Evaluation of environmental cleaning of patient rooms: Impact of different fluorescent gel markers. AB - In this systematic evaluation of fluorescent gel markers (FGM) applied to high touch surfaces with a metered applicator (MA) made for the purpose versus a generic cotton swab (CS), removal rates were 60.5% (476 of 787) for the MA and 64.3% (506 of 787) for the CS. MA-FGM removal interpretation was more consistent, 83% versus 50% not removed, possibly due to less varied application and more adhesive gel. PMID- 30419978 TI - Glucose deprivation activates a cAMP-independent protein kinase from Trypanosoma equiperdum. AB - Kemptide (sequence: LRRASLG) is a synthetic peptide holding the consensus recognition site for the catalytic subunit of the cAMP-dependent protein kinase (PKA). cAMP-independent protein kinases that phosphorylate kemptide were stimulated in Trypanosoma equiperdum following glucose deprivation. An enriched kemptide kinase-containing fraction was isolated from glucose-starved parasites using sedimentation throughout a sucrose gradient, followed by sequential chromatography on diethylaminoethyl-Sepharose and Sephacryl S-300. The trypanosome protein possesses a molecular mass of 39.07-51.73 kDa, a Stokes radius of 27.4 A, a sedimentation coefficient of 4.06 S and a globular shape with a frictional ratio f/fo = 1.22-1.25. Optimal enzymatic activity was achieved at 37 degrees C and pH 8.0, and kinetic studies showed Km values for ATP and kemptide of 11.8 +/- 4.1 and 24.7 +/- 3.8 um, respectively. The parasite enzyme uses ATP and Mg2+ and was inhibited by other nucleotides and/or analogues of ATP, such as cAMP, AMP, ADP, GMP, GDP, GTP, CTP, beta,gamma-imidoadenosine 5' triphosphate and 5'-[p-(fluorosulfonyl)benzoyl] adenosine, and by other divalent cations, such as Zn2+, Mn2+, Co2+, Cu2+, Ca2+ and Fe2+. Additionally, the trypanosome kinase was inhibited by the PKA-specific heat-stable peptide inhibitor PKI-alpha. This study is the first biochemical and enzymatic characterization of a protein kinase from T. equiperdum. PMID- 30419979 TI - Prenatal stress and the developing brain: Risks for neurodevelopmental disorders ERRATUM. PMID- 30419980 TI - Review: New considerations to refine breeding objectives of dairy cows for increasing robustness and sustainability of grass-based milk production systems. AB - Although food from grazed animals is increasingly sought by consumers because of perceived animal welfare advantages, grazing systems provide the farmer and the animal with unique challenges. The system is dependent almost daily on the climate for feed supply, with the importation of large amounts of feed from off farm, and associated labour and mechanisation costs, sometimes reducing economic viability. Furthermore, the cow may have to walk long distances and be able to harvest feed efficiently in a highly competitive environment because of the need for high levels of pasture utilisation. She must, also, be: (1) highly fertile, with a requirement for pregnancy within ~80 days post-calving; (2) 'easy care', because of the need for the management of large herds with limited labour; (3) able to walk long distances; and (4) robust to changes in feed supply and quality, so that short-term nutritional insults do not unduly influence her production and reproduction cycles. These are very different and are in addition to demands placed on cows in housed systems offered pre-made mixed rations. Furthermore, additional demands in environmental sustainability and animal welfare, in conjunction with the need for greater system-level biological efficiency (i.e. 'sustainable intensification'), will add to the 'robustness' requirements of cows in the future. Increasingly, there is evidence that certain genotypes of cows perform better or worse in grazing systems, indicating a genotype*environment interaction. This has led to the development of tailored breeding objectives within countries for important heritable traits to maximise the profitability and sustainability of their production system. To date, these breeding objectives have focussed on the more easily measured traits and those of highest relative economic importance. In the future, there will be greater emphasis on more difficult to measure traits that are important to the quality of life of the animal in each production system and to reduce the system's environmental footprint. PMID- 30419981 TI - Ultrasound-Assisted Lumbar Puncture in a Neuromuscular Clinic has a High Success Rate and Less Pain. AB - BACKGROUND: Lumbar puncture (LP) performed with the assistance of ultrasound (US) may improve success rate, with fewer puncture attempts and less pain. OBJECTIVES: To explore the utility of US-assisted LP in a neuromuscular clinic. METHODS: We performed a prospective, randomized, open-label study between May 2016 and January 2017. The primary outcome measure was LP success rate, and the secondary outcome measures included procedure time, number of attempts, and the levels of pain, anxiety, and satisfaction. RESULTS: Lumbar puncture was performed in 40 consecutive patients. Ultrasound-assisted LP had a 100% success rate, compared with 85% (95% confidence interval: 58%-96%) without US assistance, although this difference failed to reach statistical significance. Ultrasound-assisted LP was associated with less pain and, also in patients >60 years of age, with fewer needle insertions. Both groups reported high satisfaction rates, regardless of the use of US. CONCLUSION: Ultrasound-assisted LP has a high success rate and less pain than unassisted LP, and can be accomplished easily in the outpatient neuromuscular clinic setting equipped with US. PMID- 30419982 TI - Development of Criteria for Epilepsy Genetic Testing in Ontario, Canada. AB - Multiple genes/variants have been implicated in various epileptic conditions. However, there is little general guidance available on the circumstances in which genetic testing is indicated and test selection in order to guide optimal test appropriateness and benefit. This is an account of the development of guidelines for genetic testing in epilepsy, which have been developed in Ontario, Canada. The Genetic Testing Advisory Committee was established in Ontario to review the clinical utility and validity of genetic tests and the provision of genetic testing in Ontario. As part of their mandate, the committee also developed recommendations and guidelines for genetic testing in epilepsy. The recommendations include mandatory prerequisites for an epileptology/geneticist/clinical biochemical geneticist consultation, prerequisite diagnostic procedures, circumstances in which genetic testing is indicated and not indicated and guidance for selection of genetic tests, including their general limitations and considerations. These guidelines represent a step toward the development of evidence-based gene panels for epilepsy in Ontario, the repatriation of genetic testing for epilepsy into Ontario molecular genetic laboratories and public funding of genetic tests for epilepsy in Ontario. PMID- 30419983 TI - The roles of early-life adversity and rumination in neural response to emotional faces amongst anxious and depressed adults. AB - BACKGROUND: Early-life adversity (ELA) is a risk factor for internalizing psychopathology (IP). ELA is also linked to alterations in neural phenotypes of emotion processing and maladaptive emotion regulatory strategies, such as ruminative brooding, in adulthood. We therefore expected that ELA would predict cortical brain activation to emotional faces in transdiagnostic IP and in turn, mediate the extent of rumination amongst patients with IPs and ELA (IP + ELA). METHOD: One hundred and thirty-two individuals, including 102 treatment-seeking adults with heterogeneous IPs and 30 healthy controls (HCs) performed an Emotional Face-Matching Task during functional magnetic resonance imaging. Whole brain analyses compared HC (n = 30), IP (n = 52), and IP + ELA (n = 50) neural responses to emotional (angry, fearful, happy, and sad) faces v. shapes, controlling for depression and anxiety symptoms. Parameter estimates of activation were extracted for significant between-group differences and tested as a mediator of ruminative brooding in IP + ELA. RESULTS: IP + ELA demonstrated increased activation in the superior frontal gyrus and anterior cingulate cortex (fear), superior parietal lobule, precuneus, posterior cingulate, and inferior temporal gyrus (fear only), and cuneus (fear and angry). These regions were preferentially correlated with ruminative brooding in IP + ELA, many of which mediated the link between IP + ELA and ruminative brooding. CONCLUSIONS: Results provide evidence that ELA history amongst IP patients augments engagement of brain regions involved in emotion processing, above and beyond what is accounted for by current symptoms. Though longitudinal designs are needed, alterations in the neural correlates of maladaptive processing of socio-emotional information may be a common pathway by which ELA poses risk for psychopathology. PMID- 30419984 TI - Duration of untreated illness in a cross-diagnostic sample of obsessive compulsive disorder, panic disorder, and social anxiety disorder. AB - OBJECTIVE: In this study, we compared duration of untreated illness (DUI) in obsessive-compulsive disorder (OCD), panic disorder (PD), and social anxiety disorder (SAD) patients and investigated its correlates, both within specific diagnoses and across the whole sample. METHODS: Eighty-eight patients (33 OCD, 24 SAD, and 31 PD) had their diagnosis confirmed by the Mini International Neuropsychiatric Interview, were assessed for treatment-seeking variables, and were evaluated with instruments aimed at quantifying transdiagnostic features (i.e., the Cause subscale of the Illness Perception Questionnaire-Mental Health and the Anxiety Sensitivity Index-Revised) and severity of illness (i.e., Beck Depression and Anxiety Inventories, the Dimensional Obsessive-Compulsive Scale, the Panic and Agoraphobia Scale, and the Social Phobia Inventory). RESULTS: The only differences between groups with short (<2 years) versus long (>2 years) DUI were greater fear of public display of anxiety in the first group and greater social avoidance in the second group. The DUI was significantly different between groups that sought treatment after the onset of illness, with OCD patients having longer DUI than PD patients and shorter DUI than SAD patients. Further, DUI correlated negatively with the perception of OCD being caused by stress and positively with severity of panic-related disability in SAD patients, but not in PD or OCD patients. CONCLUSION: There was substantial delay in treatment seeking among the anxiety and obsessive-compulsive disorder patients, particularly those with OCD or SAD. Perception of stress as a cause of OCD prompted treatment seeking, while severity of panic symptoms delayed treatment seeking. PMID- 30419985 TI - Childhood determinants of suicidality: comparing males in military and civilian employed populations. AB - BACKGROUND: To better understand the associations of childhood trauma and childhood disorder with past-year suicidality (thoughts, plans or attempts), we compared male military and civilian populations aged 18-60 years old. METHODS: Data derived from the 2010 Australian Defence Force (ADF) Mental Health Prevalence and Wellbeing Study and the 2007 Australian Bureau of Statistics Australian National Survey of Mental Health and Wellbeing were compared using logistic regression and Generalized Structural Equation Modelling (GSEM). RESULTS: A greater proportion of the ADF experienced suicidality than civilians. Those who experienced childhood trauma that was not interpersonal in nature were not at increased odds of suicidality, in either population. A higher proportion of the ADF experienced three or more types of trauma in childhood and first experienced three or more types of trauma in adulthood. Both were associated with suicidality in the ADF and civilians. Childhood anxiety had a strong and independent association with suicidality in the ADF (controlling for demographics and childhood trauma, adult trauma and adult onset disorder). Childhood anxiety fully mediated the relationship between childhood trauma and suicidality in the ADF, but not in civilians. CONCLUSIONS: These data highlight the need to take a whole life approach to understanding suicidality, and the importance of categorizing the nature of childhood trauma exposure. Importantly, childhood anxiety was not only associated with suicidality, it fully mediated the relationship between childhood trauma and suicidality in the more trauma exposed (military) population only. These findings have the potential to inform the development of strategies for suicide prevention. PMID- 30419986 TI - Diagnosing Unusual Presentations of Dopa-Responsive Conditions: Thinking on your Feet. PMID- 30419987 TI - Multidimensional understanding of religiosity/spirituality: relationship to major depression and familial risk. AB - BACKGROUND: Previous research has shown prospectively that religiosity/spirituality protects against depression, but these findings are commonly critiqued on two grounds, namely: (1) apparent religiosity/spirituality reflects merely an original absence of depression or elevated mood and (2) religiosity/spirituality too often is measured as a global construct. The current study investigates the relationship between depression and religiosity/spirituality by examining its multidimensional structural integrity. METHOD: Confirmatory factor analyses with a previously observed cross-cultural factor structure of religiosity/spirituality variables were conducted on an independent sample, diagnostic and familial risk subgroups from this sample, and a subsample of the original cross-cultural sample. Linear regressions onto a previous diagnosis of major depressive disorder (MDD) 5 years prior to assess the potential attenuating impact of a previous depression was explored. RESULTS: Across familial risk groups and clinical subgroups, each of the previously validated religiosity/spirituality domains was confirmed, namely: religious/spiritual commitment, contemplative practice, sense of interconnectedness, the experience of love, and altruistic engagement. Previous MDD diagnosis was associated with a lower religious/spiritual commitment among high-risk individuals, higher contemplation among low-risk individuals, and lower importance of religion or spirituality regardless of risk group. CONCLUSIONS: Structural integrity was found across familial risk groups and diagnostic history for a multidimensional structure of religiosity/spirituality. Differential associations between a previous diagnosis of MDD and level of religiosity/spirituality across domains suggest a complex and interactive relation between depression, familial risk, and religiosity/spirituality. Accounting for an empirically valid, multidimensional understanding of religiosity/spirituality may advance research on mechanisms underlying the relationship between religiosity/spirituality and mental health. PMID- 30419988 TI - Insulin-growth-factor-1 (IGF-1): just a few steps behind the evidence in treating schizophrenia and/or autism. PMID- 30419989 TI - Safety, Tolerability, and Efficacy of Desvenlafaxine in Children and Adolescents with Major Depressive Disorder: Results from Two Open-Label Extension Trials. AB - OBJECTIVE: Two similarly designed extension studies evaluated the long-term safety and tolerability of desvenlafaxine for the treatment of children and adolescents with major depressive disorder (MDD). Efficacy was evaluated as a secondary objective. METHODS: Both 6-month, open-label, flexible-dose extension studies enrolled children and adolescents who had completed one of two double blind, placebo-controlled, lead-in studies. One lead-in study included a 1-week transition period prior to the extension study. Patients received 26-week treatment with flexible-dose desvenlafaxine (20-50 mg/d). Safety assessments included comprehensive psychiatric evaluations, vital sign assessments, laboratory evaluations, 12-lead electrocardiogram, physical examination with Tanner assessment, and Columbia-Suicide Severity Rating Scale. Adverse events (AEs) were collected throughout the studies. Efficacy was assessed using the Children's Depression Rating Scale-Revised (CDRS-R). RESULTS: A total of 552 patients enrolled (completion rates: 66.4 and 69.1%). AEs were reported by 79.4 and 79.1% of patients in the two studies; 8.9 and 5.2% discontinued due to AEs. Treatment-emergent suicidal ideation or behavior was reported for 16.6 and 14.1% of patients in the two studies. Mean (SD) CDRS-R total score decreased from 33.83 (11.93) and 30.92 (10.20) at the extension study baseline to 24.31 (7.48) and 24.92 (8.45), respectively, at week 26. CONCLUSION: Desvenlafaxine 20 to 50 mg/d was generally safe and well tolerated with no new safety signals identified in children and adolescents with MDD who received up to 6 months of treatment in these studies. Patients maintained the reduction in severity of depressive symptoms observed in all treatment groups at the end of the lead-in study. PMID- 30419990 TI - The promotion dilemma for clinician teachers. PMID- 30419991 TI - Diet and physical activity in pregnancy and offspring's cardiovascular health: a systematic review. AB - There is increasing evidence linking maternal diet and physical activity before and during pregnancy with offspring's cardiovascular health. Although many studies examined this association, the evidence has not been reviewed systematically. We therefore undertook a systematic review to synthesize evidence examining the association of maternal diet and physical activity before and during pregnancy with offspring's blood pressure and vascular health. We systematically searched the databases MEDLINE and EMBASE from inception to June 30, 2017. Eligibility screening, data extraction and quality assessment were performed by two independent reviewers. A total of 19 articles were included comprising three randomized controlled trials and 16 observational studies. Of the studies that examined the association of interest, 60% (three out of five studies) showed that high maternal carbohydrate intake was associated with higher offspring's blood pressure. Maternal protein intake during pregnancy was negatively associated with offspring carotid intima-media thickness in two out of two studies. No consistent findings for maternal fatty acid intake were found. There were too few studies to draw conclusions on energy intake, fibre intake, protein/carbohydrate ratio, specific foods, dietary patterns and maternal physical activity. Heterogeneity in exposure and outcome assessment hampered pooling. Also, owing to the observational nature of most studies, causality cannot be established. Harmonization of valid exposure and outcome measurements, and the development of core outcome sets are needed to enable more robust conclusions. PMID- 30419992 TI - Relative abilities of young sheep and goats to self-medicate with tannin-rich sainfoin when infected with gastrointestinal nematodes. AB - Plant secondary metabolites (PSM) are one of the promising options to control gastrointestinal nematodes in sheep and goats. The objective of this study was to assess the abilities of sheep and goats to self-medicate with tannin-rich sainfoin (Onobrychis viciifolia) (SF) when infected with gastrointestinal nematodes, using a cafeteria and an operant conditioning trial. Hypotheses were that parasitized (P) lambs and goat kids would show greater intake and preference for SF than their non-parasitized (NP) counterparts, that kids would eat more SF than lambs (due to their lower resistance against parasites and their greater ability to consume PSM), and that SF intake would increase over time for P animals. We used 20 female kids and 20 ewe lambs aged 3 months. Half of the animals per species (n = 10) were experimentally infected with 170 L3 larvae of Haemonchus contortus/kg of BW (P). The other half were free from parasites throughout the study (NP). Five weeks after infection, animals were exposed to a 24-day cafeteria trial (three 8-day periods) offering a free choice between two legume pellets: SF (3.8% condensed tannins) and alfalfa (ALF, Medicago sativa; no tannin). Subsequently, animals were involved in an operant conditioning trial of two 4-day long sessions, to assess in short-term tests their motivation to walk for a SF reward when offered in choice with freely available ALF. In the cafeteria trial, SF preference was greater in kids than in lambs, particularly in the first two periods. We did not observe a greater preference for SF in P animals, which was even greater in NP animals for periods 1 and 2. Sainfoin intake increased through periods for P animals, which led to similar SF preferences for all groups during period 3. In the operant-conditioning trial, motivation to get the SF reward was similar between P and NP animals. These results support the hypotheses that goats are more willing to consume tanniferous feeds than sheep, and that P animals increased SF intake through time. However, the emergence of a curative self-medicative behaviour was not supported, as P individuals did not show greater SF intake, preference, nor a greater motivation to get SF than NP animals, regardless of animal species. These findings are discussed with previous results and some explanations are presented. PMID- 30419993 TI - Use of geographic information system tools to predict animal breed suitability for different agro-ecological zones. AB - Predicting breed-specific environmental suitability has been problematic in livestock production. Native breeds have low productivity but are thought to be more robust to perform under local conditions than exotic breeds. Attempts to introduce genetically improved exotic breeds are generally unsuccessful, mainly due to the antagonistic environmental conditions. Knowledge of the environmental conditions that are shaping the breed would be needed to determine its suitability to different locations. Here, we present a methodology to predict the suitability of breeds for different agro-ecological zones using Geographic Information Systems tools and predictive habitat distribution models. This methodology was tested on the current distribution of two introduced chicken breeds in Ethiopia: the Koekoek, originally from South Africa, and the Fayoumi, originally from Egypt. Cross-validation results show this methodology to be effective in predicting breed suitability for specific environmental conditions. Furthermore, the model predicts suitable areas of the country where the breeds could be introduced. The specific climatic parameters that explained the potential distribution of each of the breeds were similar to the environment from which the breeds originated. This novel methodology finds application in livestock programs, allowing for a more informed decision when designing breeding programs and introduction programs, and increases our understanding of the role of the environment in livestock productivity. PMID- 30419994 TI - Sugar-sweetened beverage taxation in the USA, state preemption of local efforts. PMID- 30419995 TI - Being born small-for-gestational-age is associated with an unfavourable dietary intake in Danish adolescent girls: findings from the Danish National Birth Cohort. AB - Individuals born small have an increased risk for developing type 2 diabetes. Altered food preferences in these subjects seem to play a role; however, limited evidence is available on the association between being born small-for-gestational age (SGA) at term and food intake in adolescence. Alterations in leptin, ghrelin and dopamine levels are suggested mechanisms linking SGA with later food intake. From a large prospective Danish National Birth Cohort, we compared dietary intake of adolescents being born SGA with normal-for-gestational-age (NGA) adolescents. Intake of foods and nutrients was assessed by a validated food frequency questionnaire in a subsample of 15,607 14-year-old individuals born at term. SGA was defined by birth weight (BW) <10th percentile (n=1470) and NGA as BW between 10 and 90th percentile (n=14,137) according to sex and gestational age-specific BW standard curves. Girls born SGA had a 7% (95% CI: 3-12%, P=0.002) higher intake of added sugar and a 2-8% lower intake of dietary fibre, vegetables, polyunsaturated fatty acids, and total n-6, compared with NGA girls (P<0.05). Adjusting for parental socio-occupational status, maternal smoking and diet in pregnancy did not substantially change the differences in dietary intake, except from dietary fibre, which were no longer statistically significant. No significant differences in dietary intake between SGA and NGA boys were found. In summary, girls born SGA had an unfavourable dietary intake compared with NGA girls. These differences persisted after controlling for potential confounders, thus supporting a fetal programming effect on dietary intake in girls born SGA at term. However, residual confounding by other factors operating early in childhood cannot be excluded. PMID- 30419996 TI - In vivo storage of oocytes leads to lower survival, increased abnormalities and may affect the ploidy status in the yellowtail tetra Astyanax altiparanae. AB - SummaryIn this study we analyzed whether the in vivo storage of oocytes (time after ovulation until fertilization) affects the survival and the ploidy status of the yellowtail tetra Astyanax altiparanae. Fish were induced to spawn and, after ovulation, a small aliquot was stripped and immediately fertilized (positive control group). Subsequently, aliquots (~150 oocytes) were stripped and fertilized at various time points of 60, 120, 180 or 240 min. Developmental stages, abnormalities, survival and the ploidy status of the hatched larvae were examined. As expected, in the control group, 100% of the larvae were diploid. Conversely, triploid individuals were observed just at the 60 min treatment time point (0.6%). In vivo storage of oocytes also influenced the survival rates (P < 0.05); the 180 and 240 min samples, respectively, presented lower survival rates at gastrula (50.10+/-6.26% and 40.92+/-5.32%), and somite (17.80+/-5.14% and 4.41+/-2.76%) stages and lower hatching rates (12.01+/-4.04% and 4.41+/-2.76%). A higher percentage (99.27+/-0.40%) of normal larvae and only a few abnormal larvae (0.73+/-0.40%) were observed in the control group (P = 0.0000). This observation did not differ from that observed at the 60 min treatment point (P = 0.9976). A significant increase in the percentage of abnormalities was observed in the other treatments, and, after 240 min, the highest percentage of abnormal larvae was seen (P=0.0024; 83.33+/-16.67%). In conclusion, we showed that oocyte ageing had a significant effect on survival and may affect the ploidy status in A. atiparanae. PMID- 30419997 TI - Impact of economic crises on mental health care: a systematic review. AB - : AimsUnmet needs for mental health treatment are large and widespread, and periods of economic crisis may increase the need for care and the treatment gap, with serious consequences for individuals and society. The aim of this systematic review was to summarise the empirical evidence on the association between periods of economic crisis and the use of mental health care. METHODS: Following the PRISMA statement, MEDLINE, Embase, Scopus, Open Grey and Cochrane Database were searched for relevant publications, published between 1990 and 2018, from inception to June 2018. Search terms included (1) economic crisis, (2) use of mental health services and (3) mental health problems. Study selection, data extraction and the assessment of study quality were performed in duplicate. RESULTS: Seventeen studies from different countries met the inclusion criteria. The results from the included articles suggest that periods of economic crisis might be linked to an increase of general help sought for mental health problems, with conflicting results regarding the changes in the use of specialised psychiatric care. The evidence on the use of mental health care specifically due to suicide behaviour is mixed. The results also suggest that economic crises might be associated with a higher use of prescription drugs and an increase in hospital admissions for mental disorders. CONCLUSIONS: Research on the impact of economic crises on the use of mental health care is scarce, and methodologies of the included papers are prone to substantial bias. More empirical and long-term studies on this topic are needed, in order to adapt mental health care systems to the specific needs of the population in times of economic crisis. PMID- 30419998 TI - Factors affecting Observers' Accuracy when Assessing Credibility: The Effect of the Interaction between Media, Senders' Competence and Veracity. AB - The present experiment examined how the interaction between senders' communicative competence, veracity and the medium through which judgments were made affected observers' accuracy. Stimuli were obtained from a previous study. Observers (N = 220) judged the truthfulness of statements provided by a good truth teller, a good liar, a bad truth teller, and a bad liar presented either via an audio-only, video-only, audio-video, or transcript format. Log-linear analyses showed that the data were best explained via the saturated model, therefore indicating that all the four variables interacted, G2(0) = 0, p = 1, Q2 = 1. Follow-up analyses showed that the good liar and bad liar were best evaluated via the transcript (z = 2.5) and the audio-only medium (z = 3.9), respectively. Both the good truth teller and the bad truth teller were best assessed through the audio-video medium (z = 2.1, good truth teller, z = 3.4, bad truth teller). Results indicated that all the factors interacted and played a joint role on observers' accuracy. Difficulties and suggestions for choosing the right medium are presented. PMID- 30419999 TI - Needs Assessment for Simulation Training for Prehospital Providers in Botswana. AB - BACKGROUND: In June 2012, the Botswana Ministry of Health and Wellness (MOHW; Gaborone, Botswana) initiated a national Emergency Medical Services (EMS) system in response to significant morbidity and mortality associated with prehospital emergencies. The MOHW requested external expertise to train its developing workforce. Simulation-based training was planned to equip these health care providers with clinical knowledge, procedural skills, and communication techniques. OBJECTIVE: The objective of this study was to assess the educational needs of the pioneer Botswana MOHW EMS providers based on retrospective EMS logbook review and EMS provider feedback to guide development of a novel educational curriculum. METHODS: Data were abstracted from a representative sample of the Gaborone, Botswana MOHW EMS response log from 2013-2014 and were quantified into the five most common call types for both adults and children. Informal focus groups with health professionals and EMS staff, as well as surveys, were used to rank common response call types and self-perceived educational needs. RESULTS: Based on 1,506 calls, the most common adult response calls were for obstetric emergencies, altered mental status, gastrointestinal/abdominal pain, trauma, gynecological emergencies, and cardiovascular and respiratory distress-related emergencies. The most common pediatric response calls were for respiratory distress, gastrointestinal complaints/dehydration, trauma and musculoskeletal injuries, newborn delivery, seizures, and toxic ingestion/exposure. The EMS providers identified these same chief complaints as priorities for training using the qualitative approach. A locally relevant, simulation-based curriculum for the Botswana MOHW EMS system was developed and implemented based on these data. CONCLUSIONS: Trauma, respiratory distress, gastrointestinal complaints, and puerperal/perinatal emergencies were common conditions for all age groups. Other age-specific conditions were also identified as educational needs based on epidemiologic data and provider feedback. This needs assessment may be useful when designing locally relevant EMS curricula in other low-income and middle-income countries.Glomb NW, Kosoko AA, Doughty CB, Rus MC, Shah MI, Cox M, Galapi C, Parkes PS, Kumar S, Laba B. Needs assessment for simulation training for prehospital providers in Botswana. PMID- 30420000 TI - Not all forms of dietary phosphorus are equal: an evaluation of postprandial phosphorus concentrations in the plasma of the cat. PMID- 30420001 TI - Optimizing patient expectancy in the pharmacologic treatment of major depressive disorder. AB - BACKGROUND: Patient expectancy is an important source of placebo effects in antidepressant clinical trials, but all prior studies measured expectancy prior to the initiation of medication treatment. Little is known about how expectancy changes during the course of treatment and how such changes influence clinical outcome. Consequently, we undertook the first analysis to date of in-treatment expectancy during antidepressant treatment to identify its clinical and demographic correlates, typical trajectories, and associations with treatment outcome. METHODS: Data were combined from two randomized controlled trials of antidepressant medication for major depressive disorder in which baseline and in treatment expectancy assessments were available. Machine learning methods were used to identify pre-treatment clinical and demographic predictors of expectancy. Multilevel models were implemented to test the effects of expectancy on subsequent treatment outcome, disentangling within- and between-patient effects. RESULTS: Random forest analyses demonstrated that whereas more severe depressive symptoms predicted lower pre-treatment expectancy, in-treatment expectancy was unrelated to symptom severity. At each measurement point, increased in-treatment patient expectancy significantly predicted decreased depressive symptoms at the following measurement (B = -0.45, t = -3.04, p = 0.003). The greater the gap between expected treatment outcomes and actual depressive severity, the greater the subsequent symptom reductions were (B = 0.49, t = 2.33, p = 0.02). CONCLUSIONS: Greater in-treatment patient expectancy is associated with greater subsequent depressive symptom reduction. These findings suggest that clinicians may benefit from monitoring and optimizing patient expectancy during antidepressant treatment. Expectancy may represent another treatment parameter, similar to medication compliance and side effects, to be regularly monitored during antidepressant clinical management. PMID- 30420002 TI - Use of single-step genome-wide association studies for prospecting genomic regions related to milk production and milk quality of buffalo. AB - The aim of this research communication was to identify chromosome regions and genes that could be related to milk yield (MY), milk fat (%F) and protein percentage (%P) in Brazilian buffalo cows using information from genotyped and non-genotyped animals. We used the 90 K Axiom(r) Buffalo Genotyping array. A repeatability model was used. An iterative process was performed to calculate the weights of markers as a function of the squared effects of Single Nucleotide Polymorphism (SNP) and allele frequencies. The 10 SNPs with the largest effects for MY, %F and %P were studied and they explained 7.48, 9.94 and 6.56% of the genetic variance, respectively. These regions harbor genes with biological functions that could be related to the traits analyzed. The identification of such regions and genes will contribute to a better understanding of their influence on milk production and milk quality traits of buffaloes. PMID- 30420003 TI - Functional Imaging of Neurotransmitters in Hymenolepis diminuta Treated with Senna Plant Through Light and Confocal Microscopy. AB - Previous studies have shown the anthelmintic efficacy of Senna alata, Senna alexandrina and Senna occidentalis on the zoonotic parasite Hymenolepis diminuta through microscopic studies on morphological structure. The present study is based on the light and confocal microscopic studies to understand if Senna extracts affect neurotransmitter activity of the parasites. A standard concentration (40 mg/mL) of the three leaf extracts and one set of 0.005 mg/mL concentration of the reference drug praziquantel were tested against the parasites, keeping another set of parasites in phosphate buffer saline as a control. Histochemical studies were carried out using acetylthiocholine iodide as the substrate and acetylcholinesterase as the marker enzyme for studying the expression of the neurotransmitter of the parasite and the staining intensity was observed under a light microscope. Immunohistochemical studies were carried out using anti serotonin primary antibody and fluorescence tagged secondary antibody and observed using confocal microscopy. Intensity of the stain decreases in treated parasites compared with the control which implies loss of activity of the neurotransmitters. These observations indicated that Senna have a strong anthelmintic effect on the parasite model and thus pose as a potential anthelmintic therapy. PMID- 30420004 TI - Evaluation of the Efficacy of a Dual Variable Speed Compressor over a Single Fixed Speed Compressor. AB - BACKGROUND: It has been suggested that hearing-impaired listeners with a good working memory (WM) should be fitted with a compression system using short time constants (i.e., fast-acting compression [FAC]), whereas those with a poorer WM should be fitted with a longer time constant (i.e., slow-acting compression [SAC]). However, commercial hearing aids (HAs) seldom use a fixed speed of compression. PURPOSE: The performance of a variable speed compression (VSC) system relative to a fixed speed compressor (FAC and SAC) on measures of speech intelligibility, recall, and subjective report of listening effort and tolerable time was evaluated. The potential interaction with the listeners' WM capacity (WMC) was also examined. RESEARCH DESIGN: A double-blinded, repeated measures design. STUDY SAMPLE: Seventeen HA wearers (16 with greater than one year HA experience) with a bilaterally symmetrical, mild to moderately severe sensorineural hearing loss participated in the study. DATA COLLECTION AND ANALYSIS: Participants wore the study HAs at three compression speeds (FAC, SAC, and VSC). Each listener was evaluated on the Office of Research in Clinical Amplification-nonsense syllable test (NST) at 50 dB SPL (signal-to-noise ratio [SNR] = +15 dB), 65 dB SPL (SNR = +5 dB), 80 dB SPL (SNR = 0 dB), and a split (80 dB SPL-50 dB SPL) condition. Listeners were also evaluated on a Repeat Recall Test (RRT), where they had to repeat six short sentences (both high- and low context sentences) after each was presented. Listeners recalled target words in all six sentences after they were presented. They also rated their listening effort and the amount of time they would tolerate listening under the specific condition. RRT sentences were presented at 75 dB SPL in quiet, as well as SNR = 0, 5, 10, and 15 dB. A Reading Span Test (RST) was also administered to assess listeners' WMC. Analysis of variance using RST scores as a covariate was used to examine differences in listener performance among compressor speeds. RESULTS: Listener performance on the NST was similar among all three compression speeds at 50, 65, and 80 dB SPL. Performance with FAC was significantly better than SAC for the split condition; however, performance did not differ between FAC and VSC or between SAC and VSC. Performance on the NST was not affected by listeners' RST scores. On the RRT, there was no effect of compressor speed on measures of repeat, recall, listening effort, and tolerable time. However, VSC resulted in significantly lower (better) speech reception threshold at the 85% correct recognition criterion (SRT85) than FAC and SAC. Listener RST scores significantly affected recall performance on the RRT but did not affect SRT85, repeat, listening effort, or tolerable time. CONCLUSION: These results suggest that the VSC, FAC, and SAC yield similar performance in most but not all test conditions. FAC outperforms SAC, where the stimulus levels change abruptly (i.e., split condition). The VSC yields a lower SRT85 than a fixed compression speed at a moderately high level with a favorable SNR. There is no interaction between compression speed and the participants' WMC. PMID- 30420006 TI - [Seventy years of the Spanish Society of Geriatrics and Gerontology]. PMID- 30420007 TI - Anti-aging effects of ingenol mebutate for patients with actinic keratosis. PMID- 30420005 TI - Meta-analysis challenges a textbook example of status signalling and demonstrates publication bias. AB - The status signalling hypothesis aims to explain within-species variation in ornamentation by suggesting that some ornaments signal dominance status. Here, we use multilevel meta-analytic models to challenge the textbook example of this hypothesis, the black bib of male house sparrows (Passer domesticus). We conducted a systematic review, and obtained primary data from published and unpublished studies to test whether dominance rank is positively associated with bib size across studies. Contrary to previous studies, the overall effect size (i.e. meta-analytic mean) was small and uncertain. Furthermore, we found several biases in the literature that further question the support available for the status signalling hypothesis. We discuss several explanations including pleiotropic, population- and context-dependent effects. Our findings call for reconsidering this established textbook example in evolutionary and behavioural ecology, and should stimulate renewed interest in understanding within-species variation in ornamental traits. PMID- 30420008 TI - Neuromodulatory treatment of recalcitrant plaque psoriasis with onabotulinumtoxinA. PMID- 30420009 TI - Comment on "Oral diabetes medications other than dipeptidyl peptidase-4 inhibitors are not associated with bullous pemphigoid: A Finnish nationwide case control study". PMID- 30420010 TI - Reply to: "Comment on 'Oral diabetes medications other than dipeptidyl peptidase 4 inhibitors are not associated with bullous pemphigoid: A Finnish nationwide case control study'". PMID- 30420011 TI - Editorial: Domoic acid 30 years on. PMID- 30420012 TI - The successional formation and release of domoic acid in a Pseudo-nitzschia bloom in the Juan de Fuca Eddy: A drifter study. AB - Blooms of Pseudo-nitzschia species are frequent, but presently unpredictable, in the Juan de Fuca Eddy region off the coasts of Washington (US) and British Columbia (Canada). This upwelling eddy region is proposed to be the bloom commencement site, before cells are entrained into the coastal surface currents. During a shipboard study, we characterized the different stages of the Pseudo nitzschia bloom development from its initiation and intensification, to its eventual sinking and dissipation. Specifically, we followed a water mass using lagrangian ARGOS-tracked drifters released at the eddy water mass and quantified production of dissolved and particulate domoic acid, and the physiological status of the Pseudo-nitzschia cells with regards to photosynthesis, nutrient needs and sinking rates, along with its relationship with competing species - in this case, the marine euglenoid, Eutreptiella spp. The drifter study allows for an interpretation of the presence or absence of Pseudo-nitzschia and domoic acid against active environmental factors - particularly copper and iron. PMID- 30420013 TI - Pseudo-nitzschia, Nitzschia, and domoic acid: New research since 2011. AB - Some diatoms of the genera Pseudo-nitzschia and Nitzschia produce the neurotoxin domoic acid (DA), a compound that caused amnesic shellfish poisoning (ASP) in humans just over 30 years ago (December 1987) in eastern Canada. This review covers new information since two previous reviews in 2012. Nitzschia bizertensis was subsequently discovered to be toxigenic in Tunisian waters. The known distribution of N. navis-varingica has expanded from Vietnam to Malaysia, Indonesia, the Philippines and Australia. Furthermore, 15 new species (and one new variety) of Pseudo-nitzschia have been discovered, bringing the total to 52. Seven new species were found to produce DA, bringing the total of toxigenic species to 26. We list all Pseudo-nitzschia species, their ability to produce DA, and show their global distribution. A consequence of the extended distribution and increased number of toxigenic species worldwide is that DA is now found more pervasively in the food web, contaminating new marine organisms (especially marine mammals), affecting their physiology and disrupting ecosystems. Recent findings highlight how zooplankton grazers can induce DA production in Pseudo nitzschia and how bacteria interact with Pseudo-nitzschia. Since 2012, new discoveries have been reported on physiological controls of Pseudo-nitzschia growth and DA production, its sexual reproduction, and infection by an oomycete parasitoid. Many advances are the result of applying molecular approaches to discovering new species, and to understanding the population genetic structure of Pseudo-nitzschia and mechanisms used to cope with iron limitation. The availability of genomes from three Pseudo-nitzschia species, coupled with a comparative transcriptomic approach, has allowed advances in our understanding of the sexual reproduction of Pseudo-nitzschia, its signaling pathways, its interactions with bacteria, and genes involved in iron and vitamin B12 and B7 metabolism. Although there have been no new confirmed cases of ASP since 1987 because of monitoring efforts, new blooms have occurred. A massive toxic Pseudo nitzschia bloom affected the entire west coast of North America during 2015-2016, and was linked to a 'warm blob' of ocean water. Other smaller toxic blooms occurred in the Gulf of Mexico and east coast of North America. Knowledge gaps remain, including how and why DA and its isomers are produced, the world distribution of potentially toxigenic Nitzschia species, the prevalence of DA isomers, and molecular markers to discriminate between toxigenic and non toxigenic species and to discover sexually reproducing populations in the field. PMID- 30420014 TI - The polychaete, Paraprionospio pinnata, is a likely vector of domoic acid to the benthic food web in the northern Gulf of Mexico. AB - A somewhat disparate, yet temporally cohesive, set of phytoplankton abundance, microphytobenthos, including the diatom Pseudo-nitzschia, benthic infauna, and sediment toxin data were used to develop a theory for the transfer of domoic acid (DA) from the toxic diatom to the benthos in the highly productive waters of the northern Gulf of Mexico near the Mississippi River plume. Archived samples and new data were used to test the theory that DA is likely to be incorporated into benthic consumers. High spring abundances of potentially toxic Pseudo-nitzschia diatoms were simultaneously present in the surface waters, bottom waters and on the seafloor. Examination of the gut contents of a typical deposit-feeding and suspension-feeding polychaete, Paraprionospio pinnata, during similar periods of high Pseudo-nitzschia abundance in surface water indicated consumption of the diatoms. Demersal fishes, particularly Atlantic croaker, are known to consume these polychaetes, with a potential for transfer of DA to even higher trophic levels. These findings warrant a theory to be tested with further studies about the trophic linkage of a phytoplankton toxin into the benthic food web. PMID- 30420015 TI - Can domoic acid affect escape response in copepods? AB - Copepods are important grazers on toxic phytoplankton and serve as vectors for algal toxins up the marine food web. Success of phytoplankton depends among other factors on protection against grazers like copepods, and same way copepod survival and population resilience relies on their ability to escape predators. Little is, however, known about the effect of toxins on the escape response of copepods. In this study we experimentally tested the hypothesis that the neurotoxin domoic acid (DA) produced by the diatom Pseudo-nitzschia affects escape responses of planktonic copepods. We found that the arctic copepods Calanus hyperboreus and C. glacialis reduced their escape response after feeding on a DA-producing diatom. The two species were not affected the same way; C. hyperboreus was affected after shorter exposure and less intake of DA. The negative effect on escape response was not related to the amount of DA accumulated in the copepods. Our results suggest that further research on the effects of DA on copepod behavior and DA toxicity mechanisms is required to evaluate the anti-grazing function of DA. PMID- 30420016 TI - Domoic acid in California sea lion fetal fluids indicates continuous exposure to a neuroteratogen poses risks to mammals. AB - Domoic acid (DA) is a neuroexcitotoxic amino acid that is naturally produced by some species of marine diatoms during harmful algal blooms (HABs). The toxin is transferred through the food web from plantivorous fish and shellfish to marine mammals resulting in significant morbidity and mortality. Due to the timing and location of DA producing HABs, it is well documented that pregnant female California sea lions (CSL) are regularly exposed to DA through their diet thereby posing exposure risks to a neuroteratogen in developing fetuses. In the present study, fluids from 36 fetuses sampled from naturally exposed pregnant CSLs were examined for DA. Domoic acid was detected in 79% of amniotic fluid (n = 24), 67% of allantoic fluid (n = 9), 75% of urine (n = 4), 41% of meconium (n = 17) and 29% of stomach content (n = 21) samples opportunistically collected from CSL fetuses. The distribution of DA in fetal samples indicates an increased prenatal exposure risk due to recirculation of DA in fetal fluids and continuous exposure to the developing brain. PMID- 30420017 TI - Production of domoic acid from large-scale cultures of Pseudo-nitzschia multiseries: A feasibility study. AB - The commercial demand for domoic acid (DA), the phycotoxin responsible for Amnesic Shellfish Poisoning, is currently met by extraction from a diminishing supply of stockpiled contaminated mussels (Mytilus edulis). As this supply becomes scarce, a more reliable source is needed. Purification of the toxin from an algal source would be easier and more economical than from shellfish tissue if algal growth and yield of toxin were maximized. This project was initiated to determine if DA could be produced using large-scale semi-continuous algal cultures, which should reduce labour and shorten the time required for biomass production. Pseudo-nitzschia multiseries was grown in 300-L fibreglass photobioreactors called a Brite-BoxTM. The effect of temperature and nutrient depletion on the yield of DA by P. multiseries was examined. A decline in maximum cell number without a substantial increase in cellular DA was associated with increased temperature. Maximum total cellular DA (8.8 pg cell-1) was achieved at 20 degrees C. Semi-continuous culture of P. multiseries is accompanied by increasing amounts of DA lost to the medium. The process was deemed to be feasible for growing P. multiseries but methods to recover this extracellular DA are necessary for this process to be economical. PMID- 30420018 TI - Induction of domoic acid production in diatoms-Types of grazers and diatoms are important. AB - Grazers can induce toxin (domoic acid, DA) production in diatoms. The toxic response has been observed in two species of Pseudo-nitzschia and was induced by Calanus copepods. In this study, interactions between diatoms and copepods were further explored using different species of diatoms and copepods. All herbivorous copepods induced toxin production, whereas exposure to carnivorous copepods did not. In line with this, increasing the number of herbivorous copepods resulted in even higher toxin production. The induced response is thus only elicited by copepods that pose a real threat to the responding cells, which supports that the induced toxin production in diatoms evolved as an inducible defense. The cellular toxin content in Pseudo-nitzschia was positively correlated to the concentration of a group of specific polar lipids called copepodamides that are excreted by the copepods. This suggests that copepodamides are the chemical cues responsible for triggering the toxin production. Carnivorous copepods were found to produce less or no copepodamides. Among the diatoms exposed to grazing herbivorous copepods, only two of six species of Pseudo-nitzschia and none of the Nitzschia or Fragilariopsis strains responded by producing DA, indicating that not all Pseudo nitzschia species/strains are able to produce DA, and that different diatom species might have different strategies for coping with grazing pressure. Growth rate was negatively correlated to cellular domoic acid content indicating an allocation cost associated with toxin production. Long-term grazing experiments showed higher mortality rates of grazers fed toxic diatoms, supporting the hypothesis that DA production is an induced defense mechanism. PMID- 30420020 TI - A decade and a half of Pseudo-nitzschia spp. and domoic acid along the coast of southern California. AB - Blooms of the marine diatom genus Pseudo-nitzschia that produce the neurotoxin domoic acid have been documented with regularity along the coast of southern California since 2003, with the occurrence of the toxin in shellfish tissue predating information on domoic acid in the particulate fraction in this region. Domoic acid concentrations in the phytoplankton inhabiting waters off southern California during 2003, 2006, 2007, 2011 and 2017 were comparable to some of the highest values that have been recorded in the literature. Blooms of Pseudo nitzschia have exhibited strong seasonality, with toxin appearing predominantly in the spring. Year-to-year variability of particulate toxin has been considerable, and observations during 2003, 2006, 2007, 2011 and again in 2017 linked domoic acid in the diets of marine mammals and seabirds to mass mortality events among these animals. This work reviews information collected during the past 15 years documenting the phenology and magnitude of Pseudo-nitzschia abundances and domoic acid within the Southern California Bight. The general oceanographic factors leading to blooms of Pseudo-nitzschia and outbreaks of domoic acid in this region are clear, but subtle factors controlling spatial and interannual variability in bloom magnitude and toxin production remain elusive. PMID- 30420021 TI - It's all in the name: Heart Failure. PMID- 30420022 TI - The disgraceful neglect of childhood pneumonia. PMID- 30420019 TI - Repeated low level domoic acid exposure increases CA1 VGluT1 levels, but not bouton density, VGluT2 or VGAT levels in the hippocampus of adult mice. AB - Domoic acid (DA) is a neurotoxin produced during harmful algal blooms that accumulates in marine organisms that serve as food resources for humans. While acute DA neurotoxicity can cause seizures and hippocampal lesions, less is known regarding how chronic, subacute DA exposure in adulthood impacts the hippocampus. With more frequent occurrences of harmful algal blooms, it is important to understand the potential impact of repeated, low-level DA exposure on human health. To model repeated, low-dose DA exposure, adult mice received a single low dose (0.75 +/- 0.05 MUg/g) of DA or vehicle weekly for 22 consecutive weeks. Quantitative immunohistochemistry was performed to assess the effects of repeated, low-level DA exposure on hippocampal cells and synapses. Vesicular glutamate transporter 1 (VGluT1) immunoreactivity within excitatory boutons in CA1 of DA-exposed mice was increased. Levels of other vesicular transporter proteins (i.e., VGluT2 and the vesicular GABA transporter (VGAT)) within boutons, and corresponding bouton densities, were not significantly altered in CA1, CA3, or dentate gyrus. There were no significant changes in neuron density or glial fibrillary acidic protein (GFAP) immunoreactivity following chronic, low-dose exposure. This suggests that repeated low doses of DA, unlike high doses of DA, do not cause neuronal loss or astrocyte activation in hippocampus in adult mice. Instead, these findings demonstrate that repeated exposure to low levels of DA leads to subtle changes in VGluT1 expression within CA1 excitatory boutons, which may alter glutamatergic transmission in CA1 and disrupt behaviors dependent on spatial memory. PMID- 30420023 TI - Progress towards reducing premature NCD mortality. PMID- 30420024 TI - Vaccine implementation reduces inequity. PMID- 30420025 TI - The role of bacterial vaccines in the prevention of influenza mortality. PMID- 30420026 TI - Global Alliance for Chronic Disease researchers' statement on multimorbidity. PMID- 30420027 TI - Breastfeeding and intelligence in adulthood: due to genetic confounding? PMID- 30420028 TI - Prevalence of smoking during pregnancy. PMID- 30420029 TI - Prevalence of smoking during pregnancy. PMID- 30420030 TI - Prevalence of smoking during pregnancy - Authors' reply. PMID- 30420031 TI - Achieving health equity in Ecuador. PMID- 30420032 TI - Effect on longevity of one-third reduction in premature mortality from non communicable diseases by 2030: a global analysis of the Sustainable Development Goal health target. AB - BACKGROUND: To curb the rising global burden of non-communicable diseases (NCDs), the UN Sustainable Development Goals (SDGs) include a target to reduce premature mortality from NCDs by a third by 2030. A quantitative assessment of the effect on longevity of meeting this target is one of the many important measures needed to advocate and inform national disease control policies. We did a global analysis to estimate improvements in average expected years lived between 30 and 70 years of age that would result from meeting the SDG target. METHODS: We estimated age-specific mortality in 183 countries in 2015, for the four major NCDs (cardiovascular diseases, cancers, chronic respiratory diseases, and diabetes) and all NCDs combined, using data from WHO Global Health Estimates. We then estimated the potential gains in average expected years lived between 30 and 70 years of age (LE[30-70)) by eliminating all or a third of premature mortality from specific causes of death in countries grouped by World Bank income groups. The feasibility of reducing mortality to the targeted level over 15 years was also assessed on the basis of historical mortality trends from 2000 to 2015. FINDINGS: Reducing a third of premature mortality from NCDs over 15 years is feasible in high-income and upper-middle-income countries, but remains challenging in countries with lower income levels. National longevity will improve if this target is met, corresponding to an average gain in LE[30-70) of 0.64 years worldwide from reduced premature mortality for the four major NCDs and 0.80 years for all NCDs. According to major NCD type, the largest gains attributable to cardiovascular diseases would be in lower-middle-income countries (a gain of 0.45 years), whereas gains attributable to cancer would be in low income countries (0.33 years). INTERPRETATION: A one-third reduction in premature mortality from the major NCDs in 2015-30 would have substantial effects on longevity. High-level political commitments to effective and equitable national surveillance and prioritised prevention, early detection, and treatment programmes tailored to the major NCD types are needed urgently in lower-resourced settings if this SDG target is to be met by 2030. FUNDING: None. PMID- 30420034 TI - Critically ill haematological cancer patients: How far the severity index score can determine the outcome and duration of aggressive support? PMID- 30420033 TI - Effect of ten-valent pneumococcal conjugate vaccine introduction on pneumococcal carriage in Fiji: results from four annual cross-sectional carriage surveys. AB - BACKGROUND: The indirect effects of pneumococcal conjugate vaccines (PCVs) are mediated through reductions in carriage of vaccine serotypes. Data on PCVs in Asia and the Pacific are scarce. Fiji introduced the ten-valent PCV (PCV10) in 2012, with a schedule consisting of three priming doses at 6, 10, and 14 weeks of age and no booster dose (3 + 0 schedule) without catch-up. We investigated the effects of PCV10 introduction using cross-sectional nasopharyngeal carriage surveys. METHODS: We did four annual carriage surveys (one pre-PCV10 and three post-PCV10) in the greater Suva area in Fiji, during 2012-15, of 5-8-week-old infants, 12-23-month-old children, 2-6-year-old children, and their caregivers (total of 8109 participants). Eligible participants were of appropriate age, had axillary temperature lower than 37 degrees C, and had lived in the community for at least 3 consecutive months. We used purposive quota sampling to ensure a proper representation of the Fiji population. Pneumococci were detected by real time quantitative PCR, and molecular serotyping was done with microarray. FINDINGS: 3 years after PCV10 introduction, vaccine-serotype carriage prevalence declined, with adjusted prevalences (2015 vs 2012) of 0.56 (95% CI 0.34-0.93) in 5-8-week-old infants, 0.34 (0.23-0.49) in 12-23-month-olds, 0.47 (0.34-0.66) in 2 6-year-olds, and 0.43 (0.13-1.42) in caregivers. Reductions in PCV10 serotype carriage were evident in both main ethnic groups in Fiji; however, carriage of non-PCV10 serotypes increased in Indigenous Fijian infants and children. Density of PCV10 serotypes and non-PCV10 serotypes was lower in PCV10-vaccinated children aged 12-23 months than in PCV10-unvaccinated children of the same age group (PCV10 serotypes -0.56 [95% CI -0.98 to -0.15], p=0.0077; non-PCV10 serotypes 0.29 [-0.57 to -0.02], p=0.0334). INTERPRETATION: Direct and indirect effects on pneumococcal carriage post-PCV10 are likely to result in reductions in pneumococcal disease, including in infants too young to be vaccinated. Serotype replacement in carriage in Fijian children, particularly Indigenous children, warrants further monitoring. Observed changes in pneumococcal density might be temporal rather than vaccine related. FUNDING: Department of Foreign Affairs and Trade of the Australian Government through the Fiji Health Sector Support Program; Victorian Government's Operational Infrastructure Support Program; Bill & Melinda Gates Foundation. PMID- 30420036 TI - [Anorexia nervosa: Figure of the Holy?] PMID- 30420035 TI - Rate of beta-amyloid accumulation varies with baseline amyloid burden: Implications for anti-amyloid drug trials. AB - INTRODUCTION: This study examined a longitudinal trajectory of beta-amyloid (Abeta) accumulation at the predementia stage of Alzheimer's disease in the context of clinical trials. METHODS: Analyzed were baseline (BL) and 2 years' follow-up 18F-florbetapir positron emission tomography data of 246 Abeta-positive subjects with normal cognition and mild cognitive impairment. We studied the relationship between annual accumulation rates of 18F-florbetapir and BL standard uptake value ratios in whole gray matter (SUVRGM). RESULTS: Subjects with BL SUVRGM of 0.56 to 0.92 (n = 134) appeared to accumulate Abeta approximately 1.5 times faster than remaining subjects. In subjects with SUVRGM above 0.95, most regions with the highest annual accumulation rate were outside the established set of Alzheimer's disease typical regions. CONCLUSION: There are global and regional variations in annual accumulation rate at the predementia stage of Alzheimer's disease. When taken into account, the sample size in anti-amyloid trials can be substantially reduced. Critically, treated and placebo groups should be matched for BL SUVRGM. PMID- 30420037 TI - Do grandparents influence parents' decision to vaccinate their children? A systematic review. AB - The global reduction in childhood infectious diseases since the 1960s is primarily due to the success of extensive worldwide immunisation campaigns. However, the universal vaccination coverage program appears to have lost momentum in the wake of negative, unfounded claims about the safety of vaccines. While parents of the 21st century have little first-hand knowledge of devastating childhood diseases, grandparents are more likely to remember family and community members who were afflicted. In the current age of vaccine hesitancy and science scepticism, where research-informed arguments are not always persuasive, grandparents, through their experience of the diseases, may positively influence paediatric vaccine uptake. This paper reviews the literature investigating potential direct or indirect influences of grandparents on parents' decisions to vaccinate their children. A database search using the keywords immunisation, vaccination, children and grandparents resulted in 1988 articles. Titles were screened for relevance and seventy-seven results were retained. After the abstracts were read, only five articles that either explored paediatric vaccines, factors promoting and/or inhibiting paediatric vaccine use and decision-making strategies were reviewed. One paper located through Google Scholar, which failed to show up on database searches, was also retained for a total of six papers. While none of the six papers set out to explore the impact of grandparents on vaccine uptake, they found that grandparents were involved to varying degrees in paediatric vaccine uptake within young families. The research clearly showing that grandparents, and older people more generally, promote vaccination uptake is not currently available. The dearth of literature shows the need for research exploring the perceived and real influences of grandparents on childhood vaccination. This will establish whether grandparents' memory and knowledge of preventable childhood infectious diseases could be harnessed as a public health measure to counteract the current, ill-informed, negative attention on paediatric vaccines. PMID- 30420038 TI - The Plasmodium yoelii microgamete surface antigen (PyMiGS) induces anti-malarial transmission blocking immunity that reduces microgamete motility/release from activated male gametocytes. AB - Malaria transmission-blocking vaccines aim to inhibit the development of malaria parasites in mosquitoes by inducing antibodies targeting surface proteins of sexual stage parasites. We have recently identified PyMiGS, a protein specifically expressed in the osmiophilic body of male gametocytes of Plasmodium yoelii (Py). PyMiGS is translocated to the surface of microgametes, and potent transmission-blocking activity was observed in mosquitoes fed on mice passively immunized with antibodies against PyMiGS. Here we demonstrate using a direct feeding assay that recombinant PyMiGS successfully induces anti-PyMiGS antibodies in mice and that the antibodies block parasite development in mosquitoes. We also show using the membrane-feeding assay that rabbit anti-PyMiGS antibody inhibits parasite development in mosquitoes in a dose-dependent manner without complement involvement. To investigate the mode of action of anti-PyMiGS antibodies against parasite development, we observed exflagellation after mixing Py gametocytes with activation medium containing anti-PyMiGS or anti-GST control antibodies. Whereas most microgametes were released from activated male gametocytes in the control group, a significantly reduced number of microgametes were released in the anti PyMiGS group, with most of the microgametes left attached to the activated male gametocytes. Moreover, anti-PyMiGS antibodies shortened the duration of the active movement of microgametes after the onset of exflagellation. Taken together, these findings suggest that anti-PyMiGS antibodies bind to the microgamete surface immediately after exflagellation, thereby reducing microgamete motility and inhibiting microgamete release from the activated male gametocytes. These results strongly suggest that PyMiGS orthologues in Plasmodium falciparum and Plasmodium vivax can be promising TBV candidates. PMID- 30420040 TI - Towards improved process efficiency in vaccine innovation: The Vaccine Innovation Cycle as a validated, conceptual stage-gate model. AB - Continuing investments in vaccine innovation are insufficiently translated into market entries of novel vaccines. This innovation paradox is in part caused by stakeholders lacking complete understanding of the complex array of steps necessary for vaccine development and collaboration difficulties between the wide variety of stakeholders involved. Models providing cross-domain understanding can improve collaboration but currently lack both comprehensibility and granularity to enable a prioritized view of activities and criteria. Key opinion leaders (KOLs) were asked to contribute to the definition of a vaccine innovation cycle (VIC). In a first step, 18 KOLs were interviewed on the stages (activities and results) and gates (evaluation criteria and outcomes) of vaccine innovation. This first description of the VIC was subsequently validated and refined through a survey among 46 additional KOLs. The VIC identifies 29 distinct stages and 28 corresponding gates, distributed in ten different but integrated workstreams, and comprehensibly depicted in a circular innovation model. Some stage-gates occur at defined moments, whereas the occurrence and timing of other stage-gates is contingent on a variety of contextual factors. Yet other stage-gates continuously monitor internal and external developments. A gap-overlap analysis of stage-gate criteria demonstrated that 5 out of 11 criteria employed by vaccine developers correspond with criteria employed by competent (regulatory) authorities. The VIC provides a comprehensive overview of stage-gates throughout the value chain of vaccine innovation. Its cyclical nature highlights the importance of synchronizing with unmet needs and market changes, and conceptualizes the difference between incremental and radical vaccine innovation. Knowledge on the gap between internal and external criteria will enhance the viability of newcomers to the field. The VIC can be used by stakeholders to improve understanding and communication in forming collaborative alliances and consortia. Such a boundary-spanning function may contribute to the reduction of process inefficiencies, especially in public-private partnerships. PMID- 30420039 TI - Re-evaluating the cost and cost-effectiveness of rotavirus vaccination in Bangladesh, Ghana, and Malawi: A comparison of three rotavirus vaccines. AB - INTRODUCTION: Diarrhea is a leading cause of mortality worldwide and rotavirus accounts for many of these deaths. As of August 2018, 96 countries have introduced rotavirus vaccines into their immunization programs. Two rotavirus vaccines, Rotarix(r) and RotaTeq(r), have been WHO-prequalified since 2009, with Rotarix(r) being the preferred product of most Gavi-supported countries. ROTAVAC(r) and ROTASIIL(r) have both been prequalified recently. MATERIALS AND METHODS: We reevaluated the costs and cost-effectiveness of rotavirus vaccination in Bangladesh, Ghana, and Malawi and compared Rotarix(r), ROTAVAC(r), and ROTASIIL(r) in each country. For consistency with previously published analyses in these countries, we used the same Excel-based cohort model and much of the same data as the original analyses. We varied the expected price (with and without Gavi subsidy), wastage, and incremental health system costs associated with each vaccine. We assumed the same efficacy and waning assumptions following administration of two or three doses for the respective product. RESULTS: The discounted cost per DALY averted compared to no vaccination ranged from 0.3 to 1.3 times GNI per capita for each vaccine. With the Gavi subsidy, the average cost-effectiveness ratios were below 0.3 times GNI per capita in all three countries. Though critical empirical cost data are not yet available, Rotarix(r) is the least costly and most cost-effective product in the countries examined in this modelling study. However, small decreases in the incremental health system cost for other products could result in cost and cost-effectiveness outcomes that match or surpass those of Rotarix(r). CONCLUSION: Countries may wish to consider new rotavirus vaccines entering the market. Countries should carefully examine multiple product attributes including price and the incremental health system costs associated with each vaccine. These costs will vary by country and may be a defining factor in determining the least costly and most cost-effective product for the population. PMID- 30420041 TI - Towards a subunit vaccine from a Shigella flexneri DeltatolR mutant. AB - Disruption of one or more components of the Tol-Pal system, involved in maintaining the integrity of the outer membrane of Gram-negative bacteria, has been proposed as a method to increase the yield obtained from natural production of outer membrane vesicles (OMV). We present a new OMV-based product, obtained from genetically modified Shigella flexneri 2a with a non-polar deletion in tolR and heat-inactivated (HT-DeltatolR). The S. flexneri DeltatolR strain lead to a higher release of vesicles, more than 8-times when compared to the yield obtained from chemically inactivated wild type strain. S. flexneri mutant strain appeared to be more sensitive to different chemical compounds, including antibiotics, bile salts or human complement and it was also less virulent in both in vitro and in vivo assays. The mutation produced some changes in the LPS O-chain and protein expression. S. flexneri DeltatolR was enriched in long and very long LPS O-chain and expressed a different pattern of surface proteins or lipoproteins. In vitro toxicity and activation properties were determined in Raw 267.4 macrophage cell line. HT-DeltatolR antigenic complex was non-cytotoxic and activation markers, such as MHC-II or CD40, were highly expressed during incubation with this product. Finally, preliminary studies on the antibody response elicited by HT DeltatolR demonstrated a robust and diverse response in mice. Considering these promising results, HT-DeltatolR antigenic extract appears as a new potential vaccine candidate to face shigellosis. PMID- 30420042 TI - Pneumococcal polysaccharide vaccine associated with reduced lengths of stay for cardiovascular events hospital admissions: Experience from the Hunter Community Study. AB - BACKGROUND: The pneumococcal polysaccharide vaccine (PPV) has been associated with reduced risk of cardiovascular events in human observational studies. Animal studies suggest that the phosphorylcholine epitope in the Streptococcus pneumoniae cell wall is structurally similar to oxidized low-density lipoprotein (oxLDL), hence PPV induces the production of antibodies that cross-react with anti-oxLDL and may cause regression of atherosclerotic plaque. We set out to determine the strength of association between PPV administration and reduction in cardiovascular events. METHODS: A longitudinal, population-based cohort study of older Australians, from the Hunter Community Study, with up to 11 years of follow up. We included participants aged >= 65 years at baseline (2004-2008), without a history of cardiovascular disease (CVD). History of PPV administration at baseline was the main exposure of interest. "Total number of hospital bed-days with CVD primary diagnosis" was one of the main outcomes measured. Models were adjusted for age, diabetes, alcohol intake, and smoking status. Influenza vaccine was the control exposure used and fracture bed-days was the control outcome used, to investigate the potential for residual confounding. RESULTS: 91 of the total 1074 participants (mean age = 72, male = 45%) experienced a CVD event during follow-up. PPV (regardless of influenza vaccine) was associated with a significant reduction in CVD bed-day, (n = 863, incident rate ratio, IRR = 0.65, 95%CI: 0.45-0.94, p = 0.02), but influenza vaccine (regardless of PPV) was not (n = 864, IRR = 0.86, 95%CI: 0.54-1.35, p = 0.51). Furthermore, PPV adjusted for influenza vaccine remained associated with CVD bed-days (IRR = 0.64, 95%CI: 0.43 0.96, p = 0.03) but was not associated with fracture bed-days (IRR = 0.75, 95%CI: 0.28-2.00, p = 0.56). CONCLUSION: PPV demonstrated a 35% reduction in CVD bed days. This finding was robust to residual confounding, using a control exposure and a control outcome, eliminating the concern for healthy-user bias. A large double-blinded placebo-controlled RCT is underway to confirm our finding and to explore the proposed mechanism of action (ACTRN12615000536561). PMID- 30420043 TI - Knowledge and attitudes toward HPV infection and vaccination among immigrants and refugees in Italy. AB - BACKGROUND: The objectives of the present cross-sectional study were to investigate the level of knowledge and attitudes regarding Human papillomavirus (HPV) infection and its vaccination and to understand the impact of different determinants among immigrants and refugees in Italy. METHODS: Between September 2016 and March 2018, a total of 519 potential participants were randomly recruited. The information was collected through a questionnaire administered by two researchers. RESULTS: Only 15.9% reported that they had heard of HPV infection before completing the survey and 83.8% of them were aware that the infection could be transmitted through sexual intercourses, 32.3% that it can lead to cervical cancer, 22% to warts, 16.2% to penile cancer, 13.2% to oral cancer, 39.7% that cervical cancer is a very severe disease, 47.1% that receiving the vaccine could protect against the infection, and 44.1% that a vaccine against HPV is available in Italy. Females, those who originated from Eastern Europe, Asia and South America, those who lived in a house compared to those who lived in a street, and those who had 1-10 years and 11 or more years of education compared to those illiterate were more likely to have heard about the HPV infection before completing the survey. Only 3 participants (0.7%) received the HPV vaccination. Out of the unvaccinated who had heard of HPV, 50.7% and 59% of those between the ages of 12 and 26 and of those who had at least one child aged 12-26 years, were willing to receive vaccination for themselves as well as their children. CONCLUSION: The results underscored the necessity to develop health education and promotion aimed at improving the knowledge and vaccination practice in immigrants and refugees. PMID- 30420044 TI - Factors associated with Human Papilloma Virus (HPV) vaccine recommendation by physicians in Lebanon, a cross-sectional study. AB - Persistent Human Papilloma Virus (HPV) infection is associated with the development of cervical cancer, a leading cause of female death worldwide. In Lebanon, cervical cancer is the 6th most common cancer amongst girls and women aged 14-44 years. Cervical cancer is preventable through HPV vaccination; however, Lebanon does not include HPV vaccination in its national routine vaccination schedule. Hence, physician recommendation is key for patient vaccine uptake. We conducted a cross-sectional study in Beirut, Lebanon to assess factors affecting physician recommendation regarding HPV vaccination. Physicians practicing in Obstetrics and Gynecology (OBGYN), Pediatrics, Family Medicine and Infectious Diseases were included in the study. In total, 228 physicians completed the survey (28.79% response rate). The survey consisted of a set of demographic and HPV knowledge questions along with clinical vignettes. The vignettes presented theoretical patients who differed in gender, age, sexual activity, social background and whether the patient presented with his mother or not. The results show that physicians tend to recommend the vaccine more commonly for vignettes presenting female patients, with an Adjusted Odds Ratio (AOR) of 6.8. Also, physicians were more likely to recommend the vaccine for vignettes with patients coming from a non-conservative background (AOR = 2.1), vignettes where patients claim to be sexually active (AOR = 2.7) and vignettes where patients presented with their mother (AOR = 1.4). Physicians tend to recommend the vaccine less in vignettes with married patients (AOR = 0.5). Physicians with higher knowledge scores recommended the vaccine more often (AOR = 3.4). Overall, OBGYN physicians recommended the vaccine less than pediatricians (AOR = 0.5). These results show that Lebanese physicians' recommendations rely on factors external to international guidelines. The results also highlight the importance of knowledge in adequate patient consultation. Thus, improved physician awareness towards international guidelines and physician education regarding HPV vaccination is essential in order to improve patient care in Lebanon. PMID- 30420045 TI - Should patients still be copied into their letters? A rapid review. AB - OBJECTIVE: To systematically identify, synthesise and evaluate the strength of the international evidence on copy letter practice. METHODS: A systematic search identified original research studies on copy letters. Searches were limited by date and language as permitted in rapid review methods guidance. Article screening, data extraction and strength of evidence assessment were completed independently by multiple authors. RESULTS: Thirty-seven studies were included. There was a lack of information about copy letter content. Many patients report being satisfied with copy letters, understand them and find them useful. However, there is a lack of objective, high quality evidence to suggest that copy letters increased patient understanding or improved physical or psychological health outcomes. Many letters were written at a level which would make them inaccessible to patients with low health literacy. The strength of evidence was either "emerging" or "acceptable" practice for most studies (n = 30). CONCLUSION: There is a lack of objective, high quality evidence to demonstrate the benefits of copy letters as described in health policy. PRACTICE IMPLICATIONS: Personalising letters and using lay rather than medical terms appears to be useful for improving copy letter readability. Further research is required to explore this, especially in people with low health literacy levels. PMID- 30420046 TI - Neuropilin-1 (NRP-1) upregulated by IL-6/STAT3 signaling contributes to invasion in pancreatic neuroendocrine neoplasms. AB - Although the upregulation of Neuropilin-1 (NRP-1) is associated with many solid tumors, its role in pancreatic neuroendocrine neoplasms (pNEN) has not been well elucidated. The aim of this study was to investigate the role of NRP-1 in improving treatment and determining the prognosis of pNEN. In this study, the expression of NRP-1 in pNEN tissue samples and pNEN cell line BON1 was analyzed by Western blot, polymerase chain reaction (PCR) and immunocytochemistry upon exposure to interleukin-6 (IL-6). Additionally, pNEN cell line BON1 was transfected with small interfering RNAs against NRP-1 or signal transducer and activator of transcription 3 (STAT3) and assessed by in vitro invasion assays. The expression of NRP-1 in pNEN tissues was markedly increased compared with adjacent normal pancreatic tissues. High NRP-1 expression was strongly correlated with tumor grades (P = .026), lymph node metastasis (P = .025), and tumor-node metastasis stages (P = .012). Furthermore, NRP-1 downregulation notably inhibited the metastatic capacity of pNEN cells, and STAT3 knockdown was found to downregulate the expression of NRP-1. BON1 cells upregulated NRP-1 expression upon stimulation with IL-6. This was accompanied by activation/phosphorylation of the AKT and STAT3 signaling pathways. Western blot of extracts of human pNENs confirmed increased NRP-1 expression, as well as AKT/STAT3 phosphorylation in tissue of pNENs with elevated expression levels of IL-6. In conclusion, our findings suggest that NRP-1 is upregulated in pNEN and is correlated with the metastatic capacity of pNEN cells, potentially via interaction with the IL 6/STAT3 signaling pathway. PMID- 30420047 TI - Targeted gene sequencing of Lynch syndrome-related and sporadic endometrial carcinomas. AB - About one-third of endometrial carcinomas (ECs), mainly of endometrioid histology, harbor the mismatch repair (MMR) defects and microsatellite instability (MSI). Among these, ECs arising in women with Lynch syndrome (LS) account for a large proportion. To date, no somatic genetic analyses have been published comparing LS-ECs with sporadic ECs. In this work, we examined the mutational profiles of a well-characterized series of sporadic and LS-related ECs, performing exonic targeted sequencing of 16 genes mainly involved in MSI ECs. Next-generation sequencing analysis was performed in 35 ECs on the MiSeq platform (Illumina, San Diego, CA), and the mutational profile was analyzed integrating molecular and immunohistochemical data. PTEN, ARID1A, and ARID2 were the most frequently mutated genes regardless of MSI status or family history. MSI ECs showed a higher mutational load than MMR-proficient cases, exhibiting an MMR deficient mutational signature. Among MSI tumors, LS-related and sporadic ECs exhibited similar mutational profiles, with MSH2 as the most commonly mutated gene. KRAS mutations seemed to be more common in sporadic MSI ECs than in LS related ECs even if further studies are needed to confirm this finding. MMR deficient ECs carried a higher mutational load and an excess of C>T transitions compared with MMR-proficient ECs, suggesting that the use of a small gene panel may be adequate to highlight significant differences between these 2 groups. An integrated analysis of genetic and epigenetic features of LS-related and sporadic ECs provides useful insights into disease biology and diagnostic classification of these tumors. PMID- 30420048 TI - Clonality assessment of multifocal lung adenocarcinoma by pathology evaluation and molecular analysis. AB - The aim of this study was to explore morphologic and molecular features distinguishing between multifocal lung adenocarcinoma (MLA) and intrapulmonary metastases (IMs). Sixteen patients with MLAs, a total of 34 tumors, were reviewed. Four approaches were used: (1) array-comparative genomic hybridization (CGH) as a standard clonality assessment; (2) EGFR and KRAS mutational profiles as a supplementary method; (3) comprehensive histologic assessment (CHA) was method I in pathology evaluation; and (4) CHA combined with lepidic component analysis was method II. The lepidic component was divided into low grade and high grade according to extent of atypia; tumors with low-grade lepidic component were defined as primary. Eight patients were found to have IMs and 8 to have multiple primaries (MPs) by array-CGH; 7 had MPs and 9 had IMs by method I; 5 had MPs and 11 had IMs by method II. Compared with array-CGH, method I had a lower coincidence rate (65%) than method II (85%). Univariate analysis revealed that patients with MP had a better clinical outcome than those with IM only if the MPs were diagnosed by array-CGH (P = .034) or method II (P = .027) but not EGFR/KRAS mutation (P = .843) or method I (P = .493). Our results suggest that a low-grade lepidic component is a sign of a primary tumor. CHA combined with a low-grade lepidic component (method II) is more accurate clinically and more cost-effective in distinguishing MLAs from IMs. Also, EGFR mutation is not an appropriate molecular marker for clonality assessment. PMID- 30420050 TI - Atypical mitoses are present in otherwise classical pleomorphic lipomas. PMID- 30420049 TI - IgA-dominant glomerulonephritis with a membranoproliferative pattern of injury. AB - Immunoglobulin A (IgA)-dominant membranoproliferative glomerulonephritis (MPGN) is a descriptive term for renal biopsies in which differential diagnoses of unusual IgA nephropathy (IgAN), infection-related GN, or other etiologies are considered. We sought to understand clinical and pathologic features of this finding. Native kidney biopsies with IgA-dominant immune deposits and diffuse MPGN features without significant exudative features or subepithelial deposits were retrospectively reviewed. Two groups (n = 27, 33 biopsies) were identified: patients with chronic liver disease and those without. Patients without chronic liver disease (n = 15) were men (73%, age 40) who presented with nephrotic-range proteinuria, hematuria, renal insufficiency, negative serologic studies, and no history of infection. At a median interval of 3 years, 11 had available follow-up information. Three (27%) progressed to end-stage renal disease. One had recurrent IgA-dominant GN in the renal allograft less than 1 year posttransplant. Four of 5 patients with repeat biopsies had persistent IgA-dominant MPGN. Patients with chronic liver disease (n = 12) had similar biopsy findings, but 42% had concurrent infections, some occult. At a median interval of 7 weeks, 8 patients (80% of those with follow-up) had died and 2 were dialysis dependent. In conclusion, IgA-dominant MPGN was seen in 2 clinical cohorts in this study. In patients without chronic liver disease, this appears to represent either a unique clinicopathologic entity with a poorer prognosis than IgAN or an aggressive variant of IgAN. Patients with chronic liver disease often have underlying infection, and regardless of treatment, die within 1 year because of complex medical conditions. PMID- 30420053 TI - Human Leukocyte Antigen Typing by Next-Generation Sequencing. AB - Human leukocyte antigen (HLA) allele ambiguities are the result of limitations of current HLA typing methodologies. Ambiguities maybe due to polymorphisms in unsequenced regions of HLA genes or cis/trans variants that cannot be distinguished by Sanger sequencing. Next generation sequencing (NGS) can resolve these two sources of ambiguity because the entire gene can be sequenced. Commercially available HLA NGS genotyping kits enable laboratories to deliver high-quality and unambiguous HLA typing results at an affordable cost. Third generation sequencing technologies are poised to further improve sequencing quality, shorten turn-around and library preparation times, as well as provide full-gene phasing. PMID- 30420052 TI - Melanin-concentrating hormone (MCH) neurons in the developing chick brain. AB - The present study was undertaken because no previous developmental studies exist on MCH neurons in any avian species. After validating a commercially-available antibody for use in chickens, immunohistochemical examinations first detected MCH neurons around embryonic day (E) 8 in the posterior hypothalamus. This population increased thereafter, reaching a numerical maximum by E20. MCH-positive cell bodies were found only in the posterior hypothalamus at all ages examined, restricted to a region showing very little overlap with the locations of hypocretin/orexin (H/O) neurons. Chickens had fewer MCH than H/O neurons, and MCH neurons also first appeared later in development than H/O neurons (the opposite of what has been found in rodents). MCH neurons appeared to originate from territories within the hypothalamic periventricular organ that partially overlap with the source of diencephalic serotonergic neurons. Chicken MCH fibers developed exuberantly during the second half of embryonic development, and they became abundant in the same brain areas as in rodents, including the hypothalamus (by E12), locus coeruleus (by E12), dorsal raphe nucleus (by E20) and septum (by E20). These observations suggest that MCH cells may play different roles during development in chickens and rodents; but once they have developed, MCH neurons exhibit similar phenotypes in birds and rodents. PMID- 30420054 TI - Technical Aspects of Crossmatching in Transplantation. AB - The presence of antibodies directed against HLA molecules expressed on the donor's cells is one the most important risk factor for serious clinical complications after transplantation. The lymphocyte crossmatch is one of the most important tests available to the laboratory as this assay detects the presence of donor-specific anti-HLA antibodies in potential allograft recipients. Early crossmatch methods used a complement-dependent cytotoxicity test, which was useful for detecting anti-HLA antibodies responsible for hyperacute graft rejection but lacked adequate sensitivity and specificity. Consequently, more sensitive and specific crossmatch methods were developed ultimately leading to the flow cytometry crossmatch as the preferred methodology. PMID- 30420055 TI - Human Leukocyte Antigen Epitope Matching in Solid Organ Transplantation. AB - HLA epitope matching provides a better approach to stratify patients at risk of developing antibody-mediated rejection compared with counting HLA mismatches. However, several immunologic parameters are not incorporated into these algorithms used to assess HLA epitopes, raising questions about the predictive value of these programs. Therefore, it is imperative to obtain more 3D structural data of antibody-antigen binding to "train" these computer algorithms. Also, mechanistic studies should be performed to prove these theoretic "epitopes." Most important, more information is needed to ensure these predictive computer algorithms are equitable and safe to use in clinical diagnostics before wide scale implementation. PMID- 30420056 TI - Maintaining the Health of the Renal Allograft: Laboratory and Histologic Monitoring After Kidney Transplantation. AB - Advances in posttransplant care, including new immunosuppressive medications have led to excellent short-term renal allograft survival. However, there is a small therapeutic window within which the patient and the clinician must balance the risk of rejection, with side effects such as infection, malignancy, and toxicity. Laboratory testing plays a key role in this ongoing monitoring, which includes relatively simple tests, such as serum creatinine, to complex tests, such as solid-phase assays, used to monitor for donor-specific antibody and surveillance allograft biopsies. This article reviews the role of the laboratory tests and surveillance biopsies in posttransplant monitoring. PMID- 30420057 TI - Recent Advancements in the Assessment of Renal Transplant Dysfunction with an Emphasis on Microarray Molecular Diagnostics. AB - Conventional assessment of renal transplant rejection and injury through use of histology, C4d staining, and HLA antibody testing, has been the standard approach to transplant management. By many measures, these methods of conventional assessment may be considered flawed, particularly with the subjective nature of histologic diagnoses. The Alberta Transplant Applied Genomics Center has developed the Molecular Microscope diagnostic system, which uses microarrays to measure gene expression. These data are analyzed using classifiers (weighted equations) that compare the tested biopsy to a proprietary reference set of biopsies to provide objective measures of the status of the renal transplant. PMID- 30420058 TI - Diversity of Killer Cell Immunoglobulin-Like Receptors and Disease. AB - Natural killer (NK) cells are bone marrow-derived large granular lymphocytes defined by CD3negCD56pos and represent 5% to 25% of peripheral blood mononuclear cell fraction of the healthy humans. NK cells have a highly specific and sophisticated target cell recognition receptor system arbitrated by the integration of signals triggered by a multitude of inhibitory and activating receptors. Human NK cells express distinct families of receptors, including (1) killer cell immunoglobulin-like receptors, (2) killer cell lectin-like receptors, (3) leukocyte immunoglobulin-like receptors, and (4) natural cytotoxicity receptors. PMID- 30420059 TI - The Role of Human Leukocyte Antigen in Celiac Disease Diagnostics. AB - Celiac disease is an autoimmune disease affecting the small intestine, triggered by gluten sensitization in genetically susceptible individuals worldwide. Celiac disease development is strongly linked to the presence of HLA-DQ2 and/or DQ8, which present the immunogenic gluten peptides and trigger the immune response leading to pathogenesis. Because of the variability of clinical symptoms, the disease is often underdiagnosed. Intestinal biopsy and the presence of antibodies to deamidated gliadin and tissue transglutaminase are recommended diagnostic tools. Genetic testing for HLA DQ2 and DQ8 can be used to rule out disease in at risk populations. PMID- 30420060 TI - Human Leukocyte Antigen Associations in Drug Hypersensitivity Reactions. AB - Severe adverse drug reactions are a common cause of morbidity and mortality. Some of the most severe reactions are immunologically mediated and have been linked to specific HLA alleles. The mechanisms underlying HLA-associated drug hypersensitivity are complex and not fully understood. Recent findings have provided insight into recognition mechanisms underlying drug-induced immunopathogenesis and criteria for increasing positive prediction of hypersensitivity. Refining pharmocogenetic testing strategies to better identify at-risk individuals can improve hypersensitivity prevention and mechanism characterization. PMID- 30420061 TI - Human Leukocyte Antigen and Disease Associations: A Broader Perspective. AB - HLA molecules play a significant role in immunity and disease susceptibility. GWAS studies underline the critical role of the MHC region in a wide range of diseases and remind us that the HLA genes, included within the MHC, interact extensively with other genomic regions which influence their functions. Recently, MHC/HLA genomic sequences encoding for miRNAs have been reported to interact with targets within and outside the MHC, influencing the expression of many transcripts. High throughput sequencing technologies provide unique opportunities for complete HLA/MHC sequence characterization, helping to elucidate their interactive relationships in a plethora of physiological and disease processes. PMID- 30420062 TI - HLA in Transplantation and Beyond. PMID- 30420063 TI - Nonmelanoma Skin Cancer. AB - This article reviews the most common nonmelanoma skin cancers affecting the head and neck region. Although the most common of these malignancies rarely result in mortality, local morbidity caused by the tumors and their extirpation cannot be underestimated. Complete tumor extirpation with pathologically confirmed negative margins is the gold standard. Regional and distant metastases are rare, but must be treated appropriately should they occur. Although reconstructive surgery can be life changing for the patients and rewarding for the clinicians, it behooves the treating surgeons to remain true to oncologic principles above all else. PMID- 30420064 TI - Periocular Reconstruction. AB - Options for periorbital reconstruction include primary wound closure, local flaps, regional/distant flaps, or full-thickness skin grafts. Optimal aesthetic and functional outcomes are achieved by assessing regional contours, skin type, and facial aesthetic units. Like tissue should replace like tissue; for example, skin with skin, tarsus with tarsus (or equivalent material, eg, hard palate, ear cartilage, or autologous substitute), and conjunctiva with mucous membrane or like substitute (buccal mucous membrane, amniotic membrane). Patient characteristics including wound care needs, transportation needs, smoking status, and history of radiation can influence the reconstruction plan. Techniques most commonly used in our practice are reviewed. PMID- 30420065 TI - The Role of Sentinel Lymph Node Biopsy in the Management of Cutaneous Malignancies. AB - Sentinel lymph node biopsy uses the concept of selective lymphatic drainage and the lymphatic microvasculature to identify first-echelon nodes draining a given malignancy. Although initially considered difficult and unreliable in the head and neck, experience with the technique has improved and evolved significantly over the last 3 decades. It is now recognized to be accurate and reliable for regional nodal staging and detection of occult nodal metastasis in the head and neck. Although initially described for nodal staging of melanoma, the usefulness of sentinel lymph node biopsy continues to expand and is now extended to other cutaneous malignancies. PMID- 30420066 TI - Radiotherapy for Skin Cancers of the Face, Head, and Neck. AB - Radiotherapy plays a role in the definitive or adjuvant management of early and late stage skin cancers including nonmelanoma basal cell carcinoma and cutaneous squamous cell carcinoma, melanoma, and Merkel cell carcinoma. The role of radiotherapy in skin cancers of the head and neck is reviewed including early and advanced-stage nonmelanoma skin cancers, melanoma, and Merkel cell carcinoma. In particular, the indications, oncologic outcomes, and technical aspects of radiotherapy for these diseases are discussed. PMID- 30420067 TI - Adjuvant and Neoadjuvant Treatment of Skin Cancer. AB - Skin cancer represents a broad classification of malignancies, which can be further refined by histology, including basal cell carcinoma, squamous cell carcinoma and melanoma. As these three cancers are distinct entities, we review each one separately, with a focus on their epidemiology, etiology including relevant genomic data, and the current evidence-based recommendations for adjuvant and neoadjuvant therapy. We also discuss future directions and opportunities for continued therapeutic advances. PMID- 30420068 TI - Mohs Micrographic Surgery. AB - Mohs micrographic surgery (MMS) is the gold standard for treating various cutaneous tumors. MMS has evolved into a single-day, outpatient procedure. The tumor is excised, mapped, and processed with frozen, horizontal sections for immediate histologic evaluation. The process is repeated as necessary until the tumor is completely removed, with maximal conservation of normal tissue. Evaluation of 100% of the surgical margin allows for exceptional cure rates. The Mohs surgeon is trained in tumor excision, histopathology interpretation, and surgical reconstruction. The use of MMS is often part of a multidisciplinary approach to treating cutaneous tumors. PMID- 30420069 TI - Tissue Engineering and 3-Dimensional Modeling for Facial Reconstruction. AB - Three-dimensional (3D) printing has transformed craniofacial reconstruction over the last 2 decades. For cutaneous oncologic surgeons, several 3D printed technologies are available to assist with craniofacial bony reconstruction and preliminary soft tissue reconstructive efforts. With improved accessibility and simplified design software, 3D printing has opened the door for new techniques in anaplastology. Tissue engineering has more recently emerged as a promising concept for complex auricular and nasal reconstruction. Combined with 3D printing, several groups have demonstrated promising preclinical results with cartilage growth. This article highlights the applications and current state of 3D printing and tissue engineering in craniofacial reconstruction. PMID- 30420070 TI - Health Outcome Studies in Skin Cancer Surgery. AB - As cutaneous cancers are the most common malignancies affecting US citizens, they represent a significant public health problem and health care cost burden. There are a variety of treatment options available to manage cutaneous malignancies, but limited data are available regarding outcomes, including quality of life, recurrence, and mortality. Here, we examine outcomes of skin cancer surgery as they relate to sociodemographic data and treatment factors. PMID- 30420071 TI - Management of Early-Stage Melanoma. AB - Melanoma is a potentially aggressive skin cancer with a steadily rising incidence. Most melanomas are diagnosed at an early stage and associated with an excellent prognosis when treated appropriately. Primary treatment for melanoma is surgical. Wider surgical margins and a variety of techniques for comprehensive histologic margin assessment may be considered for lentigo maligna type melanoma on the head and neck, due to characteristic broad subclinical extension. For invasive melanoma, sentinel lymph node biopsy may be indicated for staging, and to guide further management and follow-up. Appropriate treatment guidelines for early-stage melanoma are reviewed and discussed. PMID- 30420072 TI - Reconstruction of the Nose. AB - Nasal reconstructive techniques have advanced significantly over the past 50 years. Modern techniques in nasal reconstruction are based on the nasal aesthetic subunits. In order to achieve ideal outcomes, reconstructive surgeons must consider differences in tissue qualities across the nasal aesthetic subunits and formulate reconstructive plans based on these differences. Local flaps, skin grafts, and several types of interpolated flaps comprise the most commonly used techniques for nasal reconstruction. Defects that involve structural or internal lining defects require reconstruction of significantly higher complexity. PMID- 30420073 TI - Reconstruction of the Cheek. AB - The goal of cheek reconstruction is to restore an illusion of "normal." Attention must be directed toward the contralateral cheek skin color, texture, thickness, and contour, because this serves a template for reconstruction. The cheek is a peripheral facial subunit and largely frames the more central subunits (eyelids, nose, lips). As such, avoiding distortion or disfigurement of the central subunits is of paramount importance. The cheek possesses significant tissue laxity, elasticity, and mobility, thus allowing for the vast majority of cheek defects to be addressed with primary closure, local flaps, or locoregional flaps. PMID- 30420074 TI - Reconstruction of Defects Involving the Lip and Chin. AB - Successful perioral reconstruction is the result of consideration of both functional and esthetic goals. The lips are complex esthetic units with multiple tissue layers and distinct anatomic landmarks. Reconstruction can be difficult due to variables affecting the defect, such as size, depth, location, and involvement of adjacent subunits. There are many local flaps that can be used to match the complex tissue layers and anatomic landmarks. Use of the same reconstructive principles can be applied to secondary reconstruction to attain a successful outcome. This article focuses on local reconstructive options for defects of the lip and chin. PMID- 30420075 TI - Reconstruction of the Forehead and Scalp. AB - Tissue inelasticity and the hair-bearing nature of the scalp and forehead pose unique challenges during reconstruction. A thorough understanding of the surgical anatomy of the scalp and forehead is paramount for optimal reconstructive outcomes. Primary wound closure is usually preferred over secondary intention healing and skin grafting. Use of dermal alternatives and tissue expansion are adjunctive therapies to facilitate scalp wound closure. Local skin and soft tissue flaps are commonly used for most small to medium defects; however, microsurgical free tissue transfer can be considered for large full-thickness skin defects of the forehead and scalp. PMID- 30420076 TI - Reconstruction of the Ear. AB - Skin cancer is a common indication for reconstructive surgery of the ear. The unique anatomy of the external ear makes the restoration of form and function challenging for the reconstructive surgeon. This article reviews the relevant anatomy of the ear, defines the goals of reconstruction, outlines the assessment of defects based on location, and describes specific surgical techniques useful in auricular reconstruction. PMID- 30420077 TI - State-of-the-Art in Skin Cancer Surgery. PMID- 30420079 TI - Increasing knowledge of home based maternal and newborn care using self-help groups: Evidence from rural Uttar Pradesh, India. AB - BACKGROUND: In India, pregnant women and recently delivered mothers of marginalized communities in Uttar Pradesh (UP) remain un-reached by frontline health-workers. In these communities, self-help groups (SHGs) have the potential to reach these women with knowledge of home-based maternal and newborn care (HBMNC). OBJECTIVE: The study examines the feasibility of SHGs to improve knowledge of HBMNC. The study identifies the facilitating factors and barriers to knowledge change. METHODS: A panel study with a quasi-experimental design was conducted in Jhansi, UP. Peer educators, called Swasthya Sakhi, of the SHGs of the experimental area were trained on how to conduct discussions on HBMNC topics. Both at baseline and endline 233 women from the experimental area and 237 women from the comparison area were interviewed to measure their knowledge change in HBMNC topics. The net-effect of the intervention was examined using difference-in difference (DID) analysis with propensity-score-matching (PSM) controlling for the effect of background characteristics of the participants from two study areas. Generalized-estimating-equation (GEE) was used to identify the facilitating factors and barriers to the knowledge change. RESULTS: The findings show significant net-increases in women's knowledge for most of the HBMNC topics including danger signs for a pregnant mother and a newborn child, even after controlling for the background characteristics of the participants. The most significant determinant of the increase of knowledge was the women's education. CONCLUSION: Findings from the study showed SHGs can increase HBMNC knowledge among women. However, studies with longer duration are required to examine the scalability and sustainability of the intervention. PMID- 30420078 TI - "They were just waiting to die": Somali Bantu and Karen Experiences with Cancer Screening Pre- and Post-Resettlement in Buffalo, NY. AB - BACKGROUND: Little is known about how pre-resettlement experiences affect refugees' uptake of cancer screenings. The objective of this study was to characterize Somali Bantu and Karen experiences with cancer and cancer screenings prior to and subsequent to resettlement in Buffalo, NY in order to inform engagement by health providers. METHODS: The study was grounded in a community based participatory research approach, with data collection and analysis guided by the Health Belief Model and life course framework. Interviews were transcribed, independently coded by two researchers, and analyzed using an immersion-crystallization approach. We conducted 15 semi-structured interviews and six interview-focus group hybrids with Somali Bantu (n = 15) and Karen (n = 15) individuals who were predominantly female (87%). RESULTS: Cancer awareness was more prevalent among Karen compared to Somali Bantu participants. Prior to resettlement, preventative health care, including cancer screening, and treatment were unavailable or inaccessible to participants and a low priority compared with survival and acute health threats. There, Somali Bantu treated cancer-like diseases with traditional medicine (heated objects, poultices), and Karen reported traditional medicine and even late-stage biomedical treatments were ineffective due to extent of progressed, late-stage ulcerated tumors when care was sought. A fatalistic view of cancer was intertwined with faith (Somali Bantu) and associated with untreated, late-stage cancer (Karen). Karen but not Somali Bantu reported individuals living with cancer were stigmatized pre-resettlement due to the unpleasant manifestations of untreated, ulcerated tumors. Now resettled in the U.S., participants reported obtaining cancer screenings was challenged by transportation and communication barriers and facilitated by having insurance and interpretation services. While Somali Bantu women strongly preferred a female provider for screenings, Karen women felt cancer severity outweighed cultural modesty concerns in terms of provider gender. SIGNIFICANCE: Our findings suggest the need for culturally-relevant cancer education that incorporates the life course experiences and addresses logistical barriers in linking individuals with screening, to be complemented by trauma-informed care approaches by healthcare providers. PMID- 30420081 TI - Relation between mothers' types of labor, birth interventions, birth experiences and postpartum depression: A multicentre follow-up study. AB - AIM: This definitive and cross-sectional study was conducted to determine the relation between mothers' types of labor, birth interventions, birth experiences and postpartum depression. METHODS: A total of 1010 mothers who gave birth in four different provinces of Turkey were chosen to participate in the study via purposive sampling method Results: The Edinburgh Postpartum Depression Scale score was determined to be 13 and over in 36.4% of the women. In this study, it was determined that the Edinburgh Postpartum Depression Scale scores for women in the 18-24 age group who had a vaginal birth, did not have health insurance, experienced health problems during pregnancy and were not trained about type of labor during pregnancy were statistically higher. There was no significant correlation between the birth experiences and postpartum depression. The linear regression model showed that there was a statistically significant correlation between enema and amniotomy interventions practised during the birth and the Edinburgh Postpartum Depression Scale scores. CONCLUSION: In conclusion, it is thought that preparing the mothers for birth with birth preparation training in the antenatal period and imposing the necessary regulations in the delivery room for the mothers to have a positive birth experience are important in reducing postpartum depression risk. PMID- 30420080 TI - Women's mobile phone use in birth suite: A West Australian perspective. AB - Research investigating childbearing women's use of digital technology focuses on pregnancy and parenting, with none examining usage during labour. We explored the importance of having a mobile phone and how it was used in birth suite. This cohort study utilised women on a postnatal ward. Women (n = 300) who felt it was important to have a mobile phone were more likely than those who did not, to use their phone for social media and within an hour of birth. Few women used their phone whilst feeding their baby or felt phone usage would impact on quality time with their baby. PMID- 30420082 TI - Assessing the association between fatigue and functional status during postpartum. AB - OBJECTIVE: Fatigue and decreased functional status are common health concerns during postpartum. Although studied separately in the past, this study assessed levels and explored the relationship between these two variables. METHODS: A cross-sectional correlational study was conducted with a convenience sample of 315 women to measure levels and assess the association between fatigue and functional status during postpartum. RESULTS: Moderate levels of fatigue and functional status were found. Fatigue levels and functional status were significantly higher in multiparas compared to primiparas, and fatigue was significantly higher in women who had cesarean births compared to vaginal births. Additionally, no significant correlation was found between fatigue and functional status during postpartum in this study. CONCLUSION: The lack of a statistically significant association between fatigue and functional status warrants further research since limited studies have been conducted. Findings of this study may assist healthcare providers in planning and implementing holistic assessment and care for women in postpartum. PMID- 30420083 TI - Working with home birth - Swedish midwives' experiences. AB - OBJECTIVE: The aim was to describe Swedish midwives' experiences of working with home birth. METHODS: Two focus group interviews were conducted with eight home birth-attending midwives. Data were analysed with qualitative content analysis. RESULTS: Four main categories were identified: the birth as a meaningful moment; to fully focus on the birth; to practise the craft; and not to be part of the health care system. The midwives viewed childbirth as a significant moment that should be conducted on the woman's terms. Working with home birth enabled them to work at their own pace and focus fully on the woman. During home births, they learned more about normal birth, and developed their practical skills and professional knowledge with little reliance on technology. They did, however, not feel fully accepted in the maternity care system. CONCLUSION: This study contributes to the discussion about midwives' experiences of working with home birth in contexts where home birth is not covered by public health care. The study shows that the work environment influences how midwives perform their craft, how they follow and support normal birth, and how the birth setting influence valuing their work. PMID- 30420084 TI - Haemorrhoids - A neglected problem faced by women after birth. AB - OBJECTIVE: To investigate the prevalence and severity of haemorrhoids after birth among first-time mothers in relation to management during the second stage of labour and to describe the women's experiences with haemorrhoids. METHOD: A mixed method explanatory sequential design was used. Nulliparous women were allocated to an intervention group for whom the second-stage of labour practice followed the MIMA model (Midwives management during second stage of labour) or to a control group for whom standard-care practice was followed. Data were collected three weeks and 1.5 years after birth. RESULT: A total of 496 (82.1%) women responded to the questionnaire three weeks after birth, 120 (70%) responded to the questionnaire 1.5 years after the birth. The women in the intervention group had fewer symptoms from haemorrhoids three weeks after birth compared to the women in the control group (adj. OR 0.6 95% CI 0.4-0.9). Half of the women in the intervention and control group (50.8%) who reported problems with haemorrhoids three weeks after birth still experienced problems after 1.5 years. The majority of all women did not seek medical care due to their symptoms. The women who described that they experienced haemorrhoids as a problem after birth felt neglected by the healthcare system. CONCLUSION: A substantial percentage of women had symptoms from haemorrhoids after birth. Many of these women felt that their problems were neglected. Women who experienced a slow birth of the baby's head and spontaneous pushing suffered less from haemorrhoids 3 weeks after birth. PMID- 30420085 TI - Challenges to midwives' scope of practice in providing women's birthing care in an Australian hospital setting: A grounded theory study. AB - OBJECTIVE: To identify and explore processes midwives use to exercise their scope of practice whilst caring for women during normal birth. METHODS: Strauss and Corbin's (1998) grounded theory approach was used. Data were collected from 17 midwife participants using participant observation of women's labour and birth care followed by semi-structured interviews. RESULTS: The core category of promoting normal birthing: aspiring to develop a midwife-led scope of practice conceptualises midwives working to develop their scope of practice to promote and facilitate normal birthing for women. Two interrelated categories, promoting and maintaining healthy birthing and optimising scope of practice further explicate how midwives provide woman-centred care within their scope of practice. CONCLUSIONS: The theoretical framework generates conceptual knowledge of how midwives aspire to promote healthy, safe and responsive birthing care for women in their scope of practice in a hospital setting. Findings provide greater insights into the competing perspectives of birthing care challenging midwives' capacity to provide woman-centred care, influencing the degree to which midwives are able to exercise their scope of practice in promoting normal birth. PMID- 30420086 TI - An ecological perspective on risk factors for repeat induced abortion in China. AB - INTRODUCTION: Repeated induced abortion (RIA) is a challenging public health issue. Although many studies have investigated the characteristics of women who experience multiple abortions, most have focused only on limited intrapersonal variables. To frame the analysis, this study used an ecological model integrating intrapersonal, interpersonal and environmental variables to explore factors associated with RIA. METHODS: Single-site (Maternal and Child Health Hospital, Hubei, China) cross-sectional data were collected from 405 women between July 2015 and November 2015 using a self-administered questionnaire. Characteristics of women who experienced only one abortion were compared to those who had RIA (>=2 abortions). RESULTS: Among the 316 eligible women who completed the questionnaire, 110(34.8%) experienced one abortion, 206 (65.2%) experienced two or more. Multivariate binary logistic regression analysis showed a higher odds of RIA among women who were older, reported earlier age at sexual debut and reported higher abortion frequency among close female friends. Factors appearing to protect against RIA included higher frequency of partner agreement to women's contraceptive preference. CONCLUSIONS: Adapting an ecological perspective, this study examined social and environmental factors related to RIA. Our findings emphasize the importance of developing interventions that target both women and their male partner. Group norms relating to contraceptive use also need to be addressed to improve contraceptive use and reduce the risk of repeat abortions. PMID- 30420088 TI - Editorial. PMID- 30420087 TI - Access and utilisation of reproductive, maternal, neonatal and child health services among women who inject drugs in coastal Kenya: Findings from a qualitative study. AB - INTRODUCTION: The Kenyan government has committed to increasing access to comprehensive reproductive, maternal, neonatal and child health (RMNCH) services. However, inequalities still exist. Women who inject drugs are an important sub population for public health interventions, yet their RMNCH needs have largely been overlooked. Additionally, there is a lack of research to inform RMNCH interventions for this sub-population. METHODS: In 2015, we undertook interviews and focus group discussions with 45 women who inject drugs and five key stakeholders to understand these women's RMNCH experiences and needs. RESULTS: Women' access to essential services across the RMNCH continuum was low. Two thirds of the women were not using contraception. Many discovered they were pregnant late, due to amenorrhea of drug use, and thus were unable to enroll for antenatal care early. Facility-based deliveries were limited with many choosing to deliver at home. Following delivery, women's attendance to immunization services was sub-optimal. Stigma from healthcare workers was a major factor impeding women's use of existing RMNCH services. The prospect of experiencing withdrawals at health facilities where waiting times were long, deterred utilization of these services. Additionally, women faced competing priorities, having to choose between purchasing heroin or spending their money on health related costs. CONCLUSIONS: Several barriers disrupted women's access to services across the RMNCH continuum. Consequently, there is a need to develop equitable, comprehensive, and family-centered RMNCH interventions tailored to women who inject drugs, through a combination of supply- and demand-side interventions. For optimal impact, RMNCH services should be integrated into harm reduction programs. PMID- 30420089 TI - End-organ effects of primary hyperparathyroidism: A population-based study. AB - BACKGROUND: Patients with primary hyperparathyroidism are at risk for skeletal and renal end-organ damage. METHODS: We studied patients with biochemically confirmed primary hyperparathyroidism from 1995-2014 and quantified the frequency of osteoporosis, nephrolithiasis, hypercalciuria, and decrease in renal function. RESULTS: The cohort comprised 9,485 patients. In total, 3,303 (35%) had preexisting end-organ effects (osteoporosis, 24%; nephrolithiasis, 10%; hypercalciuria, 5%). Of 6,182 remaining patients, 1,769 (29%) exhibited progression to 1 or more end-organ effects over a median 3.7 years. Among patients with classic primary hyperparathyroidism (calcium and parathyroid hormone increased), progression was unrelated to the degree of hypercalcemia (calcium >11.5 mg/dL, hazard ratio 1.03, 95% confidence interval 0.85-1.25; 11.1 11.5 mg/dL, HR 1.07, 95% confidence interval 0.93-1.23; 10.5-11.0 mg/dL = reference). Patients with nonclassic primary hyperparathyroidism (calcium increased, parathyroid hormone 40-65 pg/mL) had a lesser risk of progression (calcium >11.5 mg/dL, hazard ratio 0.68, 95% confidence interval 0.50-0.94; 11.1 11.5 mg/dL, hazard ratio 0.68, 95% confidence interval 0.56-0.82; 10.5-11.0 mg/dL, hazard ratio 0.66, 95% confidence interval 0.59-0.74). End-organ damage developed before or within 5 years of diagnosis for 62% of patients. CONCLUSION: End-organ manifestations of primary hyperparathyroidism develop before biochemical diagnosis or within 5 years in most patients. End-organ damage occurred more frequently in patients with classic primary hyperparathyroidism versus nonclassic primary hyperparathyroidism, regardless of severity of hypercalcemia. PMID- 30420090 TI - NIFT-P: Are they indolent tumors? Results of a multi-institutional study. AB - BACKGROUND: Encapsulated follicular variant of papillary thyroid carcinoma has recently been reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features on the basis of its highly indolent behavior, as proposed by an international group of experienced thyroid pathologists. METHODS: All patients from 9 high-volume endocrine surgery departments who underwent surgery between 2005 and 2015 and whose final surgical pathology revealed noninvasive follicular thyroid neoplasm with papillary-like nuclear features (>10 mm) were included in this study. The primary outcome was to determine the potential for recurrent disease in these patients. RESULTS: Among the 363 patients with noninvasive follicular thyroid neoplasm with papillary-like nuclear features, 76% were female with a median age of 50 years (5-86 years); 345 patients (95%) underwent total thyroidectomy. A total of 65 patients had an associated micropapillary thyroid carcinoma. In the group of 133 patients who underwent prophylactic lymph node dissection (37%), 1 patient had a micrometastasis but with an associated micropapillary thyroid carcinoma. Over a median follow-up period of 5 years, 1 patient with an associated micropapillary thyroid carcinoma had recurrent disease at 6 years. All patients with noninvasive follicular thyroid neoplasm with papillary-like nuclear features without micropapillary thyroid carcinoma had no lymph node metastasis or recurrent disease. CONCLUSION: We found that noninvasive follicular thyroid neoplasm with papillary-like nuclear features presents with indolent behavior. However, the identification of an associated micropapillary thyroid carcinoma should be carefully evaluated because it could be a factor for lymph node metastasis and/or of recurrence. PMID- 30420091 TI - Risk of adhesive bowel obstruction after abdominal surgery. A national cohort study of 665,423 Danish women. AB - BACKGROUND: Adhesive bowel obstruction is associated with considerable morbidity and mortality, but the magnitude of the risk is debated. METHOD: In a national cohort of all Danish women with an abdominal operation (N = 665,423) between 1977 and 2013, the risk of adhesive bowel obstruction was assessed by Cox multiple regression. Covariates were the number of abdominal operations, the surgical methods, the anatomical site involved, and the calendar year. RESULTS: In the cohort, 1.4% experienced an episode of adhesive bowel obstruction. The risk increased 33-43% during the study period, was lower after gynecological and obstetrical procedures compared to gastrointestinal (HR 0.36 [0.34-0.38]), lower after laparoscopic compared to laparotomic surgery (HR 0.51 [0.48-0.54]) and increased proportionally after each additional operation. CONCLUSIONS: The risk of adhesive bowel obstruction after abdominal operations depends on the site of earlier operations, the method of access and the number of earlier operations. PMID- 30420092 TI - See one, do one, teach one: A randomized controlled study evaluating the benefit of autonomy in surgical education. AB - INTRODUCTION: "See one, do one, teach one" has represented the model for surgical education for over a century, however recent changes in education have reduced autonomy in training. The goal of this study was to assess the impact of autonomy on learning a procedural skill. METHODS: Senior medical students were randomized and trained to performance a vascular anastomosis utilizing progressive autonomy vs. constant supervision. Performance was tested using videotaped technical grading and anastomotic pressure testing. RESULTS: Mean baseline performance times and technical ratings were similar in both groups. Final completion times was faster in the autonomy group, 14:03min vs. 19:09min (p = 0.02). Final technical ratings were similar, 40.0 vs. 39.2points (max = 50), for each group and both demonstrated similar improvement in leak test against a standardized sample. CONCLUSION: Teaching a procedure, as a final step in graded autonomy, results in superior performance in timing while maintaining equal technical performance compared to trainees with less autonomy. PMID- 30420093 TI - The Role of OCT Guidance for Antiplatelet Therapy. PMID- 30420094 TI - Evolving Evidence for Cerebral Protection Devices in Transcatheter Aortic Valve Replacement. PMID- 30420095 TI - To screen and treat silent ischemia: A tough dilemma. PMID- 30420097 TI - Introduction to the Symposium In Print for Laura Kiessling. PMID- 30420096 TI - Long-term outcomes with Jetstream atherectomy with or without drug coated balloons in treating femoropopliteal arteries: A single center experience (JET SCE). AB - BACKGROUND: The long-term outcome of Jetstream atherectomy (JA) with or without adjunctive drug coated balloons (DCB) in a real-world setting remains unknown. We report 16-month target lesion revascularization (TLR) rates on patients treated for femoropopliteal (FP) artery disease with JA in a single center by one operator. METHODS: From 1/1/12 to 8/24/16 a total of 311 procedures were performed with atherectomy by a single operator at a single center. Of these procedures, 75 met inclusion and exclusion criteria. This report evaluates the outcomes of these 75 patients treated at index and who were followed up to 16 months. The primary endpoint of the study was clinically driven TLR. Patients were stratified by the use of DCB (vs angioplasty (PTA)) post-JA. TLR was calculated by excluding bailout stenting as TLR. Survival analysis for TLR over time was plotted. RESULTS: 75 patients (49.3% male, mean age 68.0 years, 54.7% diabetes) with de novo or restenotic FP lesions whose symptoms were classified as Rutherford category I-V were enrolled. Adjunctive PTA was performed on 50 patients (26 de novo, 13 in-stent restenosis, 3 non-stent restenosis, 8 mixed lesions) and adjunctive DCB (LUTONIX(r) 24, IN.PACT(r) 1) on 25 patients (21 de novo, 1 in-stent restenosis, 2 non-stent restenosis, 1 mixed lesion) (p = 0.0249). There was no difference in the median treated length between the adjunctive PTA (15 cm) and DCB (10 cm) groups (p = 0.0530). The estimated freedom from TLR (fTLR) was significantly higher with atherectomy and adjunctive DCB compared to atherectomy with adjunctive PTA at 12 months (94.7% vs 68.0%, p = 0.002) and 16 months (94.4% vs 54%; p = 0.002). CONCLUSIONS: In a single center cohort of JA reflecting real-world practice, JA with DCB had a superior TLR rate up to 16-month follow-up when compared to JA with PTA in treating all comers FP arterial disease. PMID- 30420098 TI - Optimizing testing for Clostridium difficile infection: A quality improvement project. AB - Overtesting for Clostridium difficile may result in increased health care facility-onset C difficile infection LabID events. Our quality improvement project optimized testing through standardization of laboratory processes, electronic health record clinical decision support, and real-time monitoring. Our intervention resulted in a 59% reduction in health care facility-onset C difficile infection LabID events. PMID- 30420099 TI - Authors' response to comments on "Flame retardants in UK furniture increase smoke toxicity more than they reduce fire growth rate". PMID- 30420100 TI - Large-scale temporo-parieto-frontal networks for motor and cognitive motor functions in the primate brain. AB - The extent to which neural circuits and mechanisms underlying sensory, motor, and cognitive cortical functions in the human brain are shared with those of other animals, especially non-human primates, is currently a key issue in the field of comparative neuroscience. Cortical functions result from the conjoint function of different, reciprocally connected areas working together as large-scale functionally specialized networks, which can be investigated in human subjects thanks to the development of non-invasive functional and connectional imaging techniques. In spite of their limitations in terms of spatial and temporal resolution, these techniques make it possible to address the issue of how and to what extent the neural mechanisms for different cortical functions differ from those of non-human primates. Indeed, 30 million years of independent evolution have resulted in significant differences between the brains of humans and macaques, which are the experimental model system phylogenetically closest to humans for obtaining highly detailed anatomical and functional information on the organization of cortical networks. In the macaque brain, architectonic, connectional, and functional data have provided evidence for functionally specialized large-scale cortical networks involving temporal, parietal, and frontal areas. These networks appear to play a primary role in controlling different aspects of motor and cognitive motor functions, such as hand action organization and recognition, or oculomotor behavior and gaze processing. In the present review, based on the comparison of these data with data from human studies, we will argue that there is clear evidence for human counterparts of these networks. These human and macaque putatively homolog networks appear to share phylogenetically older neural mechanisms, which, in the evolution of the human lineage, could have been exploited and differentiated, resulting in the emergence of human-specific higher-order cognitive functions. These considerations are fully in line with the notion of "neural reuse" in primate evolution. PMID- 30420101 TI - miR-218 inhibits gastric tumorigenesis through regulating Bmi-1/Akt signaling pathway. AB - BACKGROUND: Previous studies indicated that miR-218 was deregulated in gastric cancer patients and correlated with tumor invasion and prognosis. The aim of this study was to clarify the effect of miR-218 on the malignant behavior of gastric cancer and its role in regulating Bmi-1/Akt signaling pathway. MATERIALS AND METHODS: We used miR-218 mimic to transfect gastric cancer cell lines AGS and SGC 7901, and the overexpression efficiency was validated using qRT-PCR assay. MTT assay and Transwell chamber system were performed to detect the effect of miR-218 on cell proliferation, invasion and migration on gastric cancer. Western blot and qRT-PCR assay was used to test the role of miR-218 in regulating Bmi-1/Akt signaling pathway. RESULTS: As shown in our research, ectopic expression of miR 218 in gastric cancer cells inhibits the proliferation, invasion and migration of gastric cancer cells. In addition, miR-218 re-expression inhibits the expression of Bmi-1 and its downstream target p-Akt473, as well as MMPs and EMT process. CONCLUSIONS: miR-218 inhibits the proliferation, invasion and migration of gastric cancer cells through modulating EMT process and the expression of MMPs via Bmi-1/Akt signaling pathway. PMID- 30420102 TI - Impact of the 2018 ASCO/CAP HER2 guidelines update for HER2 testing by FISH in breast cancer. AB - Recently, the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) updated the guidelines on HER2 testing for invasive breast cancer. Little is known about the impact of the guidelines update. We aimed to study the impact of the 2018 ASCO/CAP HER2 testing guidelines update. We compared the HER2 FISH results interpreted by 2013 and 2018 ASCO/CAP guidelines in 331 cases of invasive breast cancers. We also analyzed the pathological features and clinical outcomes of these cases. In comparing to the 2013 ASCO/CAP guidelines, the HER2 negative rate was increased significantly from 62.5% to 75.8%(P < 0.05), and 13.3% changed from equivocal to negative by the 2018 guidelines. Our findings indicate that the guidelines update significantly increased the rate of negative results. The reclassification of the equivocal results by the 2018 guidelines is the main reason for this change. Patients with HER2 equivocal results were associated with larger tumor size and higher Ki67 index than those with negative results, while clinical outcomes were similar between them. PMID- 30420103 TI - Perceived health risks of electronic nicotine delivery systems (ENDS) users: The role of cigarette smoking status. AB - INTRODUCTION: Use of electronic nicotine delivery systems (ENDS) has increased markedly. We examined how current ENDS users differ in perceptions of tobacco and ENDS-related health risks as a function of cigarette smoking status. METHODS: We classified 1329 current ENDS users completing a national online survey based on cigarette smoking status, and employed linear and logistic regression to assess group differences in perceptions of tobacco-related health risks. RESULTS: The sample consisted of 38% Current Cigarette Smokers, 40% Former Cigarette Smokers, and 22% Non-Smokers. Our targeted recruitment strategy yielded a balance of key descriptive variables across participants. Significant differences were observed in race, employment and marital status across cigarette smoking status, but not in gender, education, income, or sexual orientation. Participants reported considerable perceived knowledge about health risks associated with tobacco use, but less regarding ENDS use. Current Smokers rated ENDS use as riskier than Non Smokers, and considered cigarette use less risky for both users and bystanders. Current Smokers were more likely to perceive cardiovascular diseases, diabetes and cancer as the health risks associated with ENDS use. Former Smokers were more likely to perceive such risks with traditional tobacco use. Further, regardless of smoking status, perceived knowledge about the health risks of tobacco or ENDS use was positively associated with perceived likelihood of high risks of cardiovascular diseases and cancer. CONCLUSIONS: Among current ENDS users, there were significant differences in perceived health risks based on cigarette smoking history. Improved health messaging can be achieved when cigarette smoking status is taken into account. PMID- 30420104 TI - Relation between prognostic impact of hyperuricemia and sympathetic overactivation in patients with heart failure. AB - BACKGROUND: Uric acid (UA), which could provide additional prognostic information in patients with heart failure (HF), can activate sympathetic nerve activity and vice versa, thus creating a vicious cycle in the cardiovascular system. However, it remains unclear whether hyperuricemia (UA>7.0mg/dl) can provide prognostic information independent of sympathetic nerve activity. METHODS: UA and potential prognostic variables including sympathetic nerve activity using microneurography (MSNA) were evaluated in 139 patients with HF (ejection fraction<45%). Primary composite cardiovascular endpoints included cardiovascular death and hospitalization due to HF. Predictors for outcomes were analyzed using univariate, multivariable, and Kaplan-Meier analyses. To determine whether the negative impact of hyperuricemia on outcomes is homogenous, prognostic impacts of hyperuricemia were compared in subgroups of HF. Ejection fraction was followed for 9 months after MSNA measurement in 102 patients. RESULTS: During a follow-up period of 1636 days, 54 patients fulfilled the primary composite endpoint of cardiovascular death or HF hospitalization. Patients with hyperuricemia had a higher cardiovascular event rate than those with normouricemia (p=0.006). On multivariable Cox proportional hazard analysis, hyperuricemia, higher MSNA, and beta-blocker dose were independent predictors of cardiovascular events. In subgroup analyses, impact of hyperuricemia on outcome was similar in all subgroups except sympathetic nerve activity (interaction, p=0.033). Hyperuricemia had negative impact on cardiovascular event rates (hazard ratio=3.44) in group with higher MSNA (p=0.0002), but not in those with lower MSNA. Additionally, the change in LVEF was also significantly lower in patients who had a higher MSNA burst incidence and hyperuricemia. CONCLUSION: Hyperuricemia might have detrimental effect on prognosis and cardiac function in HF patients with sympathetic overactivation. PMID- 30420105 TI - Update of acute and long-term tolvaptan therapy. AB - One of the vasopressin type 2 receptor antagonists, tolvaptan, has been used to treat congestive heart failure patients for over seven years in Japan. Beyond the initially suggested standard procedure, tolvaptan is currently used in patients with acute heart failure soon after their admission or it is used for long-term treatment in the ambulatory situation. Nevertheless, definitive evidence is lacking, particularly for the implication of long-term tolvaptan therapy. Now is the time to update the accumulating evidence and consider the optimal therapeutic strategy for short- and long-term tolvaptan therapy. PMID- 30420106 TI - Progress and Challenge of Cardiac Regeneration to Treat Heart Failure. AB - Cardiac muscle has limited proliferative capacity, and regenerative therapies are highly in demand as a new treatment strategy. Pharmacological and non pharmacological therapies have been developed, but these medical therapies have limited effects to cure patients with severe heart failure. Moreover, heart transplantation is limited due to the low number of donor organs. Thus, heart regeneration holds great potential to offer innovative therapy to treat heart failure patients. Currently, there are several strategies for heart regeneration. Transplantation of somatic stem cells was safe and modestly improved cardiac function after myocardial infarction mainly through paracrine mechanisms. Alternatively, new cardiomyocytes could be generated from induced pluripotent stem cells (iPSCs) to transplant into injured hearts. However, several issues remain to be resolved prior to using iPSC-derived cardiomyocytes, such as a potential risk of tumorigenesis and poor survival of transplanted cells in the injured heart. More recently, direct cardiac reprogramming has emerged as a novel technology to regenerate damaged myocardium by directly converting endogenous cardiac fibroblasts into induced cardiomyocyte-like cells to restore cardiac function. Following our first report of cardiac reprogramming, an improvement in cardiac reprogramming efficiency, in vivo direct cardiac reprogramming, and cardiac reprogramming in human cells were reported by many investigators. While these previous studies have advanced regenerative research, many challenges remain. Here, we review the current status of cardiac regenerative technology, a great hope to treat cardiovascular diseases. PMID- 30420107 TI - Pediatric Infective Endocarditis and Stroke:A 13-Year Single-Center Review. AB - OBJECTIVE: We explored the relationship between pediatric infective endocarditis and stroke. PATIENTS AND METHODS: All children encountered with infective endocarditis from January 2002 to December 2015 were included as our sample, and their medical records were comprehensively reviewed. RESULTS: Sixty children with infective endocarditis were identified, including 30 boys and 30 girls aged eight months to 18 years (mean +/- SD: 10.3 +/- 5.6), and om 43 (71.6%) of these individuals had congenital heart disease. Left-sided endocarditis occurred in 25 patients (41.7%), and vegetations were found in 58 individuals (96.6%). The most often encountered microorganisms were Streptococcus viridans and Staphylococcus aureus, which were identified in five and four patients, respectively. Postendocarditis stroke occurred in nine patients, including five with cerebral infarction, two with intracerebral hemorrhage, and one with subarachnoid hemorrhage. The remaining child experienced cerebral infarction, intracerebral hemorrhage and subarachnoid hemorrhage simultaneously. The incidence of stroke in children with left-sided endocarditis was significantly higher than that of which in those who had right-sided endocarditis (32% versus 2.8%, P < 0.01). The most common manifestation of stroke was hemiparesis (55.5%). Two girls died of stroke, and the mortality rate in the patients who had stroke was significantly higher than that in those without stroke (22.2 % versus 3.9 %, P < 0.05). CONCLUSIONS: Our data indicate that stroke is common among children with infective endocarditis, especially in those with left-sided endocarditis, and major stroke may increase their risk of death. Congenital heart disease is the main underlying disease in children with infective endocarditis in China. PMID- 30420108 TI - An Unusual Holohemispheric Abnormality. PMID- 30420109 TI - Serotonin Syndrome and Hippocampal Infarction. PMID- 30420110 TI - Language diversity, language disorder, and fetal alcohol spectrum disorder among youth sentenced to detention in Western Australia. AB - BACKGROUND: While studies confirm high prevalence of language disorder among justice-involved young people, little is known about the impact of Fetal Alcohol Spectrum Disorder (FASD) on language among this population. It is also not clear how language skills vary according to language diversity in Australian youth justice settings, where a disproportionate number of justice-involved youth are Aboriginal and may not speak Standard Australian English (SAE) as their first language. Language skills are important to understand, as language disorder and language difference can lead to a mismatch between the communication skills of a young person and the communication skills of the justice workforce with whom they are communicating. In the highly verbal environments that are common to justice systems, language disorder and language difference may result in a young person misunderstanding legal information and expectations placed on them and not being adequately understood by the justice workforce. METHODS: This study examined the language skills of 98 young people sentenced to detention in Western Australia (WA), who participated in a cross-sectional study examining the prevalence of FASD. Language skills assessed using standardised and non-standardised tasks were analysed by the three major language groups identified: speakers of SAE, Aboriginal English and English as an additional language. RESULTS: We identified rich diversity of languages, and multilingualism was common. Most young people for whom English was not their first language demonstrated difficulties in SAE competence. Further, nearly one in two young people were identified with language disorder - over half of whom had language disorder associated with FASD. CONCLUSIONS: This study has documented language diversity and the prevalence of language disorder associated with FASD among a representative sample of youth sentenced to detention in WA. Results underscore the need for the justice workforce to consider language difference when working with justice-involved youth, as well as language disorder and FASD. The findings also demonstrate the need for speech pathology to be embedded as core service in youth justice systems, working in collaboration with local cultural and language advisors and accredited interpreters. This can better enable appropriate identification of and response to communication and associated rehabilitation needs of young people navigating youth justice systems. PMID- 30420111 TI - Systemic and intraocular factors related to retinal thicknesses variations in patients with Parkinson's disease. AB - Parkinson's disease (PD) is characterized by a neurodegenerative process, which has been previously reported to involve some retinal layers, in particular the peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell complex (mGCC). When measuring pRNFL and mGCC by Optical Coherence Tomography in PD patients, it should not be neglected the role of possible both sistemic and intraocular factors, which have been proven to modify intraretinal thicknesses measurements. Nonetheless, also dopaminergic drugs administration could represent another important confounding factor, given their neuroprotective effect exerted on retina. PMID- 30420112 TI - Preoperative magnetic resonance imaging in predicting early continence recovery after robotic radical prostatectomy. AB - INTRODUCTION AND AIMS: Urinary incontinence is a common complication after radical prostatectomy. The aim of our study was to describe the preoperative anatomical features using magnetic resonance imaging in order to predict early continence recovery after robotic radical prostatectomy. MATERIAL AND METHODS: 72 patients who underwent robotic radical prostatectomy were prospectively analysed. EPIC questionnaire (1, 6 and 12 mo) and first self-reported continence were used to assess functional outcomes. Membranous urethral length (MUL) and MUL-prostate axis angle (aMULP) were assessed preoperatively on T2 weighted sagittal images. RESULTS: Continence rate was 67.2%, 92.6% and 95.2% at 1, 6 and 12 months, respectively. Early continence was achieved in patients with the lower aMULP. At 1 month, average aMULP in continent patients was 107.21 degrees (IC 95% 90.3 124.6) vs. 118.5 degrees (IC 95% 117.7-134) in incontinent ones (P=.014). At 6 month differences in aMULP among groups were found: 114.24 degrees (IC 95% 104.6 123.9) in continents vs. 142 degrees (IC 95% 126.5-157.6) in incontinents (P=0.015). At 12 month, continent group showed a significantly higher preoperative aMULP. aMULP was revealed as the only independent predictor of urinary continence at 6 mo in multivariate analysis, OR 0.007 (IC 95% 0.002 0.012), P=0.012. CONCLUSIONS: Preoperative anatomical parameters assessment prior surgery can help to identified those patients will achieve early continence recovery and it supports therapeutic decisions making. PMID- 30420113 TI - Repetitive transcranial magnetic stimulation: Re-wiring the alcoholic human brain. AB - Alcohol use disorders (AUDs) are one of the leading causes of mortality and morbidity worldwide. In spite of significant advances in understanding the neural underpinnings of AUDs, therapeutic options remain limited. Recent studies have highlighted the potential of repetitive transcranial magnetic stimulation (rTMS) as an innovative, safe, and cost-effective treatment for AUDs. Here, we summarize the fundamental principles of rTMS and its putative mechanisms of action via neurocircuitries related to alcohol addiction. We will also discuss advantages and limitations of rTMS, and argue that Hebbian plasticity and connectivity changes, as well as state-dependency, play a role in shaping some of the long term effects of rTMS. Visual imaging studies will be linked to recent clinical pilot studies describing the effect of rTMS on alcohol craving and intake, pinpointing new advances, and highlighting conceptual gaps to be filled by future controlled studies. PMID- 30420114 TI - Adult outcomes of being born late preterm or early term - What do we know? AB - The literature on adult outcomes of people born late preterm (LPT, 34-36 completed weeks) or early term (ET, 37-38 weeks) was reviewed. In PubMed, 9547 articles were identified; 53 were eligible. Of these, 12 were based on clinical cohorts, 32 on medical birth register linkages, and nine on historical birth cohorts; 48 out of 53 on Nordic countries; 50 out of 53 reported on LPT and eight out of 53 reported on ET. LPT plus ET have increased early (<45 years) adult all cause mortality. Despite increased cardiometabolic risk factors and slightly lower cardiorespiratory fitness in LPT, no studies showed increased risk for coronary heart disease, some showed increased risk for stroke, and all showed increased risk for type 2 diabetes. Most show increased risk for asthma and decreased allergic rhinitis. LPT have slightly lower cognitive abilities and higher rates of several mental disorders; ET have intermediate values. LPT and ET adults have slightly lower education, occupational status, and income. We recommend that authors report findings of LPT/ET separately from those born more preterm. PMID- 30420115 TI - Global characteristics of the rabies biologics market in 2017. AB - In 2017, the World Health Organization, the World Organisation for Animal Health, the Food and Agriculture Organization of the United Nations and the Global Alliance for Rabies control developed a strategic plan to end human rabies deaths by 2030. A survey for manufacturing capacity and product characteristics of rabies biologics was conducted to inform this process. Twenty-three of 42 manufacturers, responded, giving a market capacity for 2017 of 90 million vials for human vaccines, 2.5 million vials for rabies immunoglobulins, 2 million vials for monoclonal antibodies and 181 million vials for dog vaccines. Production capacity could be increased by many manufacturers but was limited by country demand, lack of long-term planning and restricted market expansion. Should countries implement national rabies elimination programmes where biologic needs are forecasted and production lead times respected, manufacturers can meet future supply needs towards global elimination of human dog-mediated rabies deaths. PMID- 30420117 TI - Development of a live attenuated vaccine against Muscovy duck reovirus infection. AB - The Muscovy duck reovirus (MDRV) is a highly pathogenic virus that causes substantial economic losses in the Muscovy duck industry. While MDRV poses a significant threat to Muscovy ducklings, no vaccine candidates are available to date to alleviate MDRV infection throughout the world. The present study presents efforts toward establishing an attenuated vaccine for MDRV. For this purpose, a live attenuated vaccine strain named CA was obtained via alternate propagation of the MDRV isolate MW9710 in both Muscovy duck embryo fibroblasts (MDEFs) and chicken embryo fibroblasts (CEFs) for 90 passages. The CA strain achieved an adaptive growth capacity in CEFs with a viral titer that ranged between 105.0 105.5 TCID50/100 MUL and lost its pathogenicity in 1-day-old Muscovy ducklings. Compared to the parent strain MW9710, the CA strain has 42 scattered amino acid substitutions, most of which are located in the lambdaB, lambdaC, MUB, sigmaB, and sigmaC protein. The CA strain maintained its attenuation and showed no gene mutation or virulence reversion after back propagation into 1-day-old ducklings for five rounds. The minimum protective dose was calculated to be 300 TCID50 of the CA strain. Furthermore, a single dose of CA vaccine protected immunized ducklings against lethal challenge by the virulent MDRV strain MW9710 and significantly decreased viral loads. In summary, the CA strain exhibited striking genetic stability, excellent safety, and effective immunogenicity. This CA strain of MDRV is a promising vaccine candidate for the prevention and control of MDRV infection. PMID- 30420116 TI - A Phase III open-label, randomized, active controlled clinical study to assess safety, immunogenicity and lot-to-lot consistency of a bovine-human reassortant pentavalent rotavirus vaccine in Indian infants. AB - BACKGROUND: A heat-stable bovine-human rotavirus reassortant pentavalent vaccine (BRV-PV, ROTASIIL(r)) was developed in India. In this study, the vaccine was tested for safety, immunogenicity and clinical lot-to-lot consistency. METHODS: This was a Phase III, open label, randomized, equivalence design study. The primary objective was to demonstrate lot-to-lot consistency of BRV-PV. Subjects were randomized into four arms, three arms received Lots A, B, and C of BRV-PV and the control arm, received Rotarix(r). Three doses of BRV-PV or two doses of Rotarix(r) and one dose of placebo were given at 6, 10, and 14 weeks of age. Blood samples were collected four weeks after the third dose to assess rotavirus IgA antibody levels. The three lots of BRV-PV were equivalent if the 95% Confidence Intervals (CIs) of the geometric mean concentration (GMC) ratios were between 0.5 and 2. Solicited reactions were collected by using diary cards. RESULTS: The study was conducted in 1500 randomized infants, of which 1341 infants completed the study. The IgA GMC ratios among the three lots were around 1 (Lot A versus Lot B: 1.07; Lot A versus Lot C: 1.06; and Lot B versus Lot C: 0.99). The 95% CIs for the GMC ratios were between 0.78 and 1.36. The IgA GMCs were: BRV-PV group 19.16 (95% CI 17.37-21.14) and Rotarix(r) group 10.92 (95% CI 9.36-12.74) (GMC ratio 1.75; 90% CI 1.51-2.04). Seropositivity rates were 46.98% (95% CI 43.86-50.11) and 31.12% (95% CI 26.17-36.41). The incidence of solicited reactions was comparable across the four arms. No serious adverse events were associated with the study vaccines, except two gastroenteritis events in the BRV PV groups. CONCLUSION: Lot-to-lot consistency of BRV-PV was demonstrated in terms of GMC ratios of IgA antibodies. The vaccine safety and immunogenicity profiles were similar to those of Rotarix(r). Clinical Trials.Gov [NCT02584816] and Clinical Trial Registry of India [CTRI/2015/07/006034]. PMID- 30420118 TI - A big pertussis outbreak in a primary school with high vaccination coverage in northern China: An evidence of the emerging of the disease in China. AB - BACKGROUND: A big pertussis outbreak occurred in a primary school with high vaccination coverage in northern China. An investigation was carried out in order to calculate the attack rate and identify the risk factors. METHODS: Between May 12 and July 29, an investigation was carried out in the primary school, which included 383 students and 27 teachers. Three definitions were used to distinguish the cases: confirmed, epidemiologically linked and suspected cases. A total of 232 blood samples were collected and examined by ELISA among healthy children in another primary school. RESULTS: A total of 138 suspected pertussis cases were counted, of which 116 students were confirmed. The attack rate among students was as high as 30.29%. The pertussis outbreak lasted 88 days, and had quaternary cases of transmission. Migrant children were almost four times as likely to catch the disease as local children (p = 0.005). In addition, students who had received the last dose of pertussis vaccine more than 4 years prior were three times more likely of becoming ill than those less than 4 years (p = 0.006). The average level of antibodies to pertussis was 30.99 IU/mL among healthy children. No statistically significant difference was observed between DTaP and DTwP (p = 0.843). CONCLUSIONS: This pertussis outbreak in a primary school with high vaccination coverage was an evidence of the pertussis resurgence in China. The major risk factor we identified was the waning of immunity in the years after pertussis vaccination. Booster vaccination for students should be given. PMID- 30420120 TI - Rising Proportion of Young Individuals With Rectal and Colon Cancer. AB - BACKGROUND: Recent trends have identified increasing number of young individuals with rectal and colon cancers. These individuals, who are younger than 50 years old, in most instances would not meet screening guidelines. We aimed to report the characteristics and trend of the rising proportion of young individuals being diagnosed with rectal and colon cancers at our institutions. PATIENTS AND METHODS: This study included 3381 rectal and colon cancer patients from the Mayo Clinic cancer registry from 1972 to 2017 who were diagnosed with rectal or colon cancer and who were < 50 years old. Patient and cancer characteristics are described. The Cochran-Armitage trend test was used to see if the change in percentage diagnosed at age < 50 years had a significant trend over the years. A linear regression model was fit to estimate the percentage change per year when the trend was approximately linear. RESULTS: The percentage of patients diagnosed with rectal or colon cancer in different age categories over the years showed a rising trend for individuals aged < 50. Most of these tumors were distal (rectum, left-sided colon, and right-sided colon were 49.8%, 28.8%, and 21.4%, respectively). This was more so for patients < 50 diagnosed with rectal cancer, which showed a linear increase at a rate of 0.26% per year (P < .001). CONCLUSION: Our study affirms the rising proportion of colorectal cancers found in young individuals, with a linear ongoing rise of rectal cancers in particular. This may have implications for the current screening recommendations for colorectal cancers, which are already being revised. PMID- 30420119 TI - Influenza vaccine effectiveness among patients with high-risk medical conditions in the United States, 2012-2016. AB - BACKGROUND: Annual influenza vaccination has been recommended for persons with high-risk conditions since the 1960s. However, few estimates of influenza vaccine effectiveness (VE) for persons with high-risk conditions are available. METHODS: Data from the U.S. Influenza Vaccine Effectiveness Network from 2012 to 2016 were analyzed to compare VE of standard-dose inactivated vaccines against medically attended influenza among patients aged >=6 months with and without high-risk medical conditions. Patients with acute respiratory illness were tested for influenza by RT-PCR. Presence of high-risk conditions and vaccination status were obtained from medical records. VE by influenza virus type/subtype and age group was calculated for patients with and without high-risk conditions using the test negative design. Interaction terms were used to test for differences in VE by high-risk conditions. RESULTS: Overall, 9643 (38%) of 25,369 patients enrolled during four influenza seasons had high-risk conditions; 2213 (23%) tested positive for influenza infection. For all ages, VE against any influenza was lower among patients with high-risk conditions (41%, 95% CI: 35-47%) than those without (48%, 95% CI: 43-52%; P-for-interaction = 0.02). For children aged <18 years, VE against any influenza was 51% (95% CI: 39-61%) and 52% (95% CI: 39-61%) among those with and without high-risk conditions, respectively (P-for interaction = 0.54). For adults aged >=18 years, VE against any influenza was 38% (95% CI: 30-45%) and 44% (95% CI: 38-50%) among those with and without high-risk conditions, respectively (P-for-interaction = 0.21). For both children aged <18 and adults aged >=18 years, VEs against illness related to influenza A(H3N2), A(H1N1)pdm09, and influenza B virus infection were similar among those with and without high-risk conditions. CONCLUSIONS: Influenza vaccination provided protection against medically-attended influenza among patients with high-risk conditions, at levels approaching those observed among patients without high-risk conditions. Results from our analysis support recommendations of annual vaccination for patients with high-risk conditions. PMID- 30420121 TI - Primary care physicians' experience with zoster vaccine live (ZVL) and awareness and attitudes regarding the new recombinant zoster vaccine (RZV). AB - BACKGROUND: The Advisory Committee on Immunization Practices (ACIP) has routinely recommended zoster vaccine live (ZVL) for adults >=60 since 2008; only 33% of eligible adults received it by 2016. A recombinant zoster vaccine (RZV) was licensed in 2017 and ACIP recommended in January 2018. Our objectives were to assess among primary care physicians (1) practices and attitudes regarding ZVL and (2) awareness of RZV. METHODS: We administered an Internet and mail survey from July to September 2016 to national networks of 953 primary care physicians. RESULTS: Response rate was 65% (603/923). Ninety-three % of physicians recommended ZVL to adults >=60, but fewer recommended it to adults >=60 with a prior history of zoster (88%), adults > 85 (62%) and adults >=60 on low-dose methotrexate (42%). Several physicians recommended ZVL in ways that are not recommended by ACIP including to adults 50-59 (50%), adults >=60 with HIV (33%), and adults >=60 on high dose prednisone (>=20 mg/day) (27%). Nineteen percent of physicians stocked and administered ZVL and did not refer patients elsewhere for vaccination, 37% did not stock and only referred patients to receive it, and 44% both stocked/administered and referred elsewhere. Twenty-three % (n = 115) of physicians who had ever administered ZVL in the office (n = 490) had stopped, citing primarily financial issues (90%). Only 5% were 'very aware' of RZV. CONCLUSIONS: Physicians report not recommending ZVL to certain ACIP-recommended groups, but report recommending it to some groups for which the vaccine should be avoided. Implementation of recommendations for RZV will need to consider financial barriers and the complex patchwork of office-based and pharmacy delivery ZVL has encountered. PMID- 30420122 TI - A two-drug regimen for antiretroviral therapy. PMID- 30420124 TI - After Astana: building the economic case for increased investment in primary health care. PMID- 30420125 TI - Department of Error. PMID- 30420126 TI - Association of hyperglycemia episodes on long-term mortality in type 2 diabetes mellitus with vascular dementia: A population-based cohort study. AB - AIM: This study investigated the effect of severe hyperglycemia episodes on survival and associated factors related to risk of mortality in type 2 diabetes mellitus (DM) patients with dementia. METHODS: We enrolled all type 2 DM patients newly diagnosed as having dementia in Taiwan from 1998 to 2005. These patients were categorized into those who had hyperglycemia episodes and those who did not based on whether or not they had been hospitalized for hyperglycemia after dementia diagnosis. Factors independently associated with mortality were evaluated. RESULTS: Of 5314 patients identified, 303 (5.7%) had at least one hyperglycemia hospitalization. Patients with at least one hyperglycemia hospitalization had a 30% greater risk of mortality than those who had no such admissions (adjusted hazard ratio: 1.30, 95% confidence interval: 1.09-1.55). Other variables, including age, sex, geographical region, insurance amount, patient with congestive heart failure, cerebrovascular disease, renal disease, use of anti-hypertensive drugs, use of anti-lipid drugs, and use of insulin were independently associated with risk of mortality. CONCLUSION: Severe hyperglycemia is common in type 2 DM patients with dementia and it substantially shortens their life. The findings of this study suggest a great need to improve care in DM patients with dementia. PMID- 30420127 TI - Determinants of prenatal exposure to perfluoroalkyl substances in the Slovak birth cohort. AB - BACKGROUND: Perfluoroalkyl substances (PFASs) are man-made fluorinated compounds with endocrine-disrupting properties, detected in 99% of serum samples worldwide and associated with adverse childhood health outcomes. The aim of this study was to describe determinants of prenatal exposure to PFASs in Slovakia. METHODS: This study was based on Slovak multicentric prospective mother-child cohort PRENATAL (N = 796). Cord blood samples were collected within 2010-2012 and PFASs were analyzed in a subpopulation of 322 newborns. Concentrations of perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA) were measured in the samples of cord blood using an ultrahigh-performance liquid chromatography- mass spectrometry (U-HPLC-MS) method. From questionnaires, we obtained information on medical history of mother, socio-demographic factors, nutrition and environmental factors. Association between maternal characteristics and PFASs exposure was analyzed using multivariable linear regression models. RESULTS: The highest cord blood concentration (geometric mean +/- SD) was observed for PFOA (0.79 +/- 2.21 ng/ml) followed by PFOS (0.36 +/- 2.56 ng/ml), PFNA (0.20 +/- 2.44 ng/ml) and PFHxS (0.07 +/- 2.36 ng/ml). Primiparity was associated with higher levels of all four PFAS: PFOS (exp. beta = 1.25; 95%CI[1.03; 1.53]), PFOA (exp. beta = 1.49; 95%CI[1.18; 1.89]), PFNA (exp. beta = 1.30; 95%CI[1.05; 1.60]) and PFHxS (exp. beta = 1.49; 95%CI [1.20; 1.86]). In addition, maternal age category 29 years and more was associated with higher PFNA and PFHxS levels (exp. beta = 1.27; 95%CI[1.04; 1.55] and exp. beta = 1.30; 95%CI[1.06; 1.60], respectively) and higher educational level of mother was associated with higher PFNA levels (exp. beta = 1.32; 95%CI[1.04; 1.68]). Higher fish consumption was associated with lower PFNA levels (exp. beta = 0.49; 95%CI[0.26; 0.92]). CONCLUSIONS: We observed that PFASs cord blood concentrations were comparable or lower than those measured in western or northern European countries. We identified parity as the main determinant of PFASs exposure in our population and maternal age and education as factors that might be associated with exposure to certain PFASs. PMID- 30420128 TI - Exposure to polycyclic aromatic hydrocarbons in women living in the Chinese cities of BaoDing and Dalian revealed by hair analysis. AB - Polycyclic aromatic hydrocarbons (PAH) are produced from incomplete combustion of organic matter and released as environmental contaminants from activities such as transports, wood combustion, coal-fired power plants. In numerous urban areas worldwide, the levels of PAH exposure are considered critical regarding public health issues. The possibility to detect PAH and PAH metabolites biologically incorporated in human hair was demonstrated and proposed as biomarkers of exposure. Nevertheless, the possibility to distinguish different levels of exposure between different populations is still needed to validate the relevance of hair analysis in epidemiological studies. In this work, hair samples were collected from 204 women from two cities in China based on one year Air Quality Index history from governmental data (Baoding as polluted city and Dalian less polluted city). 8 out of the 15 parent PAH and 7 out of the 56 metabolites analyzed in this study were detected in all the samples. The highest concentrations in hair were observed for phenanthrene (4.2 to 889 pg/mg) > fluoranthene (1.05 to 204 pg/mg) > pyrene (3.2 to 124 pg/mg) for parent PAH, and for 9-OH-fluorene (0.04 to 1.78 pg/mg) > 2-OH-naphthalene (0.68 to 811 pg/mg) > 1 OH-anthracene (0.24 to 10.9 pg/mg) for metabolites. 14 parent PAH and 15 metabolites presented a significantly higher concentration in the hair samples collected from Baoding, as compared to Dalian. The median concentration of parent PAH was from 1.5 to 2.8 times higher in the hair of the subjects from Baoding than in subjects from Dalian and that of PAH metabolites was from 1 to 2.3 times higher. The study of inter-chemical associations revealed similarities and differences between the two areas, suggesting common and different sources of exposure depending on PAH respectively. The results confirmed the relevance of hair analysis to identify qualitative and quantitative differences in PAH exposure between populations from different areas. This study is the first one to investigate both parent PAH and their metabolites in a biological matrix. PMID- 30420129 TI - Prevalence and transmission of antibiotic resistance and microbiota between humans and water environments. AB - The transmission routes for antibiotic resistance genes (ARGs) and microbiota between humans and water environments is poorly characterized. Here, we used high throughput qPCR analyses and 16S rRNA gene sequencing to examine the occurrence and abundance of antibiotic resistance genes and microbiota in both healthy humans and associated water environments from a Chinese village. Humans carried the most diverse assemblage of ARGs, with 234 different ARGs being detected. The total abundance of ARGs in feces, on skin, and in the effluent from domestic sewage treatment systems were approximately 23, 2, and 7 times higher than their abundance in river samples. In total, 53 ARGs and 28 bacteria genera that were present in human feces could also be found in the influent and effluent of rural sewage treatment systems, and also downstream of the effluent release point. We identified the bacterial taxa that showed a significant association with ARGs (P < 0.01, r > 0.8) by network analysis, supporting the idea that these bacteria could carry some ARGs and transfer between humans and the environment. Analysis of ARGs and microbiota in humans and in water environments helps to define the transmission routes and dynamics of antibiotic resistance within these environments. This study highlights human contribution to the load of ARGs into the environment and suggests means to prevent such dissemination. PMID- 30420123 TI - Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials. AB - BACKGROUND: Effective two-drug regimens could decrease long-term drug exposure and toxicity with HIV-1 antiretroviral therapy (ART). We therefore aimed to evaluate the efficacy and safety of a two-drug regimen compared with a three-drug regimen for the treatment of HIV-1 infection in ART-naive adults. METHODS: We conducted two identically designed, multicentre, double-blind, randomised, non inferiority, phase 3 trials: GEMINI-1 and GEMINI-2. Both studies were done at 192 centres in 21 countries. We included participants (>=18 years) with HIV-1 infection and a screening HIV-1 RNA of 500 000 copies per mL or less, and who were naive to ART. We randomly assigned participants (1:1) to receive a once daily two-drug regimen of dolutegravir (50 mg) plus lamivudine (300 mg) or a once daily three-drug regimen of dolutegravir (50 mg) plus tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg). Both drug regimens were administered orally. We masked participants and investigators to treatment assignment: dolutegravir was administered as single-entity tablets (similar to its commercial formulation, except with a different film colour), and lamivudine tablets and tenofovir disoproxil fumarate and emtricitabine tablets were over encapsulated to visually match each other. Primary endpoint was the proportion of participants with HIV-1 RNA of less than 50 copies per mL at week 48 in the intention-to-treat-exposed population, using the Snapshot algorithm and a non inferiority margin of -10%. Safety analyses were done on the safety population. GEMINI-1 and GEMINI-2 are registered with ClinicalTrials.gov, numbers NCT02831673 and NCT02831764, respectively. FINDINGS: Between July 18, 2016, and March 31, 2017, 1441 participants across both studies were randomly assigned to receive either the two-drug regimen (n=719) or three-drug regimen (n=722). At week 48 in the GEMINI-1 intention-to-treat-exposed population, 320 (90%) of 356 participants receiving the two-drug regimen and 332 (93%) of 358 receiving the three-drug regimen achieved plasma HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference -2.6%, 95% CI -6.7 to 1.5); in GEMINI-2, 335 (93%) of 360 in the two-drug regimen and 337 (94%) of 359 in the three-drug regimen achieved HIV 1 RNA of less than 50 copies per mL (adjusted treatment difference -0.7%, 95% CI 4.3 to 2.9), showing non-inferiority at a -10% margin in both studies (pooled analysis: 655 [91%] of 716 in the two-drug regimen vs 669 [93%] of 717 in the three-drug regimen; adjusted treatment difference -1.7%, 95% CI -4.4 to 1.1). Numerically, more drug-related adverse events occurred with the three-drug regimen than with the two-drug regimen (169 [24%] of 717 vs 126 [18%] of 716); few participants discontinued because of adverse events (16 [2%] in the three drug regimen and 15 [2%] in the two-drug regimen). Two deaths were reported in the two-drug regimen group of GEMINI-2, but neither was considered to be related to the study medication. INTERPRETATION: The non-inferior efficacy and similar tolerability profile of dolutegravir plus lamivudine to a guideline-recommended three-drug regimen at 48 weeks in ART-naive adults supports its use as initial therapy for patients with HIV-1 infection. FUNDING: ViiV Healthcare. PMID- 30420130 TI - Comment on: Dong et al. (2017) "Issues raised by the reference doses for perfluorooctonate sulfonate and perfluorooctanoic acid." PMID- 30420131 TI - Urinary metabolites of organophosphate flame retardants in China: Health risk from tris(2-chloroethyl) phosphate (TCEP) exposure. AB - Organophosphate esters (OPs) are substitutes for polybrominated diphenyl ether (PBDE) flame retardants. China is the largest producer of OPs globally, with the production rate increasing at 15% annually. Since some OPs are neurodevelopmental and/or carcinogenic toxicants, human exposure is a concern. In this study, concentrations of eight OP metabolites (mOPs) were measured in human urine samples collected from 13 cities located in Northern, Eastern, Southern, and Southwestern China. All target mOPs were frequently detected with detection rates of 50% to 100%, indicating widespread human exposure to OPs. Bis(2-chloroethyl) phosphate (BCEP; median: 0.68 ng/mL), bis(1-chloro-2-propyl) phosphate (BCIPP; 0.30 ng/mL), diphenyl phosphate (DPHP; 0.30 ng/mL), and dibutyl phosphate (DBP; 0.29 ng/mL) were the dominant mOPs across all participants. Regional differences in concentrations (SigmamOPs varied from 0.86 to 3.7 ng/mL) and composition profiles (contribution of chlorinated mOPs to SigmamOPs varied from 35% to 95%) of mOPs were observed within China. In comparison to the concentrations reported worldwide, urinary DPHP and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) levels in China were lower, whereas BCEP and DBP levels were comparable or higher. The total daily intake (TDI) of tris(2-chloroethyl) phosphate (TCEP), tris(1,3 dichloro-2-propyl) phosphate (TDCIPP) and triphenyl phosphate (TPHP) were estimated from daily urine excretion rate and the fraction of OP metabolized in human liver microsomes (TDIHLM) or S9 fraction (TDIS9). The intake estimates showed that Chinese residents were exposed to TCEP from 96.9 to 46,700 (or 52.2 to 25,200) ng/kg bw/day. Depending on the reference dose, we found that approximately 5% of the individuals exceeded the limit (i.e., 2200 ng/kg bw/day) for TCEP intake. To our knowledge, this is the first nationwide baseline survey to determine urinary levels of mOPs in Chinese residents. PMID- 30420132 TI - Metals and oxidative potential in urban particulate matter influence systemic inflammatory and neural biomarkers: A controlled exposure study. AB - BACKGROUND: Oxidative stress and inflammation are considered to be important pathways leading to particulate matter (PM)-associated disease. In this exploratory study, we examined the effects of metals and oxidative potential (OP) in urban PM on biomarkers of systemic inflammation, oxidative stress and neural function. METHODS: Fifty-three healthy non-smoking volunteers (mean age 28 years, twenty-eight females) were exposed to coarse (2.5-10 MUm, mean 213 MUg/m3), fine (0.15-2.5 MUm, 238 MUg/m3), and/or ultrafine concentrated ambient PM (<0.3 MUm, 136 MUg/m3). Exposures lasted 130 min, separated by >=2 weeks. Metal concentrations and OP (measured by ascorbate and glutathione depletion in synthetic airway fluid) in PM were analyzed. Blood and urine samples were collected pre-exposure, and 1-h and 21-h post exposure for assessment of biomarkers. We used mixed-regression models to analyze associations adjusting for PM size and mass concentration. RESULTS: Results for metals were expressed as change (%) from daily pre-exposure biomarker levels after exposure to a metal at a level equivalent to the mean concentration. Exposure to various metals (silver, aluminum, barium, copper, iron, potassium, lithium, nickel, tin, and/or vanadium) was significantly associated with increased levels of various blood or urinary biomarkers. For example, the blood inflammatory marker vascular endothelia growth factor (VEGF) increased 5.3% (95% confidence interval: 0.3%, 10.2%) 1-h post exposure to nickel; the traumatic brain injury marker ubiquitin C-terminal hydrolase L1 (UCHL1) increased 11% (1.2%, 21%) and 14% (0.3%, 29%) 1-h and 21-h post exposure to barium, respectively; and the systemic stress marker cortisol increased 1.5% (0%, 2.9%) and 1.5% (0.5%, 2.8%) 1-h and 21-h post exposure to silver, respectively. Urinary DNA oxidation marker 8-hydroxy-deoxy-guanosine increased 14% (6.4%, 21%) 1-h post exposure to copper; urinary neural marker vanillylmandelic acid increased 29% (3%, 54%) 1-h post exposure to aluminum; and urinary cortisol increased 88% (0.9%, 176%) 1-h post exposure to vanadium. Results for OP were expressed as change (%) from daily pre-exposure biomarker levels after exposure to ascorbate-related OP at a level equivalent to the mean concentration, or for exposure to glutathione-related OP at a level above the limit of detection. Exposure to ascorbate- or glutathione-related OP was significantly associated with increased inflammatory and neural biomarkers including interleukin-6, VEGF, UCHL1, and S100 calcium-binding protein B in blood, and malondialdehyde and 8-hydroxy-deoxy-guanosine in urine. For example, UCHL1 increased 9.4% (1.8%, 17%) in blood 21-h post exposure to ascorbate-related OP, while urinary malondialdehyde increased 19% (3.6%, 35%) and 8-hydroxy-deoxy guanosine increased 24% (2.9%, 48%) 21-h post exposure to ascorbate- and glutathione-related OP, respectively. CONCLUSION: Our results from this exploratory study suggest that metal constituents and OP in ambient PM may influence biomarker levels associated with systemic inflammation, oxidative stress, perturbations of neural function, and systemic physiological stress. PMID- 30420133 TI - Body image and condomless anal sex among Young Latino sexual minority men. AB - OBJECTIVE: To investigate body image and condomless anal sex (CAS) among young Latino sexual minority men (SMM)-a population with health disparities in HIV and body image concerns. METHODS: Participants were 151 young Latino SMM from the San Diego area who were HIV-negative or unknown. Participants completed a questionnaire online in either English or Spanish, which included body image and sexual behavior items. A binary CAS variable was created based on the number of CAS partners reported (0 vs 1 + over past 3 months). A logistic regression was conducted with body dissatisfaction, appearance investment, and their interaction term entered as predictor variables and CAS as the outcome. RESULTS: Of 151 participants, 54 (35.8%) reported no CAS in the past 3 months. Appearance investment, but not body dissatisfaction, was associated with higher odds of CAS. However, a significant interaction indicated that body dissatisfaction was associated with higher odds of CAS when appearance investment was high. CONCLUSIONS: Young Latino SMM who are highly invested in, and dissatisfied with, their appearance may be at significantly increased risk for acquiring HIV through elevated odds of CAS. Reducing appearance concerns in this population may lead to reductions in HIV risk behaviors. PMID- 30420134 TI - Toxicity evaluation of carboxylated carbon nanotubes to the reef-forming tubeworm Ficopomatus enigmaticus (Fauvel, 1923). AB - In recent years, oxidative stress has been recognized as one of the most common effects of nanoparticles in different organisms. Ficopomatus enigmaticus (Fauvel, 1923), a member of a large family of serpulidae polychates, is an important encrusting organism in a diverse set of marine habitats, from harbours to coral reefs. This species has been previously studied for ecotoxicological purposes, despite the lack of reported studies on this species biochemical response after exposure to different pollutants. For these reasons, and for the first time, a set of biomarkers related to oxidative status were assessed in polychaetes after 28 days of exposure. Furthermore, polychaetes metabolic performance and potential neurotoxicity were investigated. Results clearly demonstrated induced toxicity in the filter-feeder polychaetes after exposure to nanoparticles. Indeed, CNTs altered the biochemical and physiological status of F. enigmaticus, both in terms of energy reserves (reduction of protein and glycogen contents), oxidative status (expressed as damage in cell function such as protein carbonyl content and lipid peroxidation) and activation of antioxidant enzymes defences (Glutathione reductase, Catalase, Glutathione peroxidase and Glutathione S-transferases activities). The present study showed for the first time that this species can be used as a model organism for nanoparticle toxicology. PMID- 30420135 TI - Reduction of 24-h blood pressure variability in extreme obese patients 10 days and 6 months after bariatric surgery depending on pre-existing hypertension. AB - : Bariatric surgery is considered as a first line treatment in extreme obese patients to achieve a reduction in health risks. However, after surgical procedure obese patients with normal blood pressure (BP) levels still present residual risk, which may be partly related to lack of correction of BP profile and variability. AIM: To evaluate short (10 days) and mid-term (6 months) changes of mean values, profile and variability of BP after bariatric surgery in extremely obese patients with and without hypertension. MATERIALS & METHODS: A follow-up of cross-sectional study was conducted in 90 obese patients (aged 41.7 +/- 11.3, BMI = 46.7 +/- 5.7 kg/m2), who met the eligibility criteria and underwent bariatric surgery. Each patient underwent 24-h ambulatory BP monitoring with profile and variability estimation before, 10 days and 6 months after the intervention. RESULTS: Sixty-seven (74.4%) patients had hypertension. Significant decrease from baseline in mean values of systolic and diastolic BP in 10 days (p < .005) and 6 months (p < .005) follow-up were observed only in patients with hypertension. Moreover, only hypertensive subjects revealed significant reduction (p < 0,05) from baseline in 24-h systolic and diastolic BP weighted standard deviation and average real variability after surgical procedure. No changes were found in dipping status. CONCLUSIONS: Bariatric surgery not only decreased BP levels, but also contributed to reduction in BP variability in early period after intervention mainly in patients with pre-existing hypertension. PMID- 30420136 TI - Robust finite time cooperative control of second order agents:A Multi-input Multi output higher order super-twisting based approach. AB - This paper studies the formation of multiple mobile agents with double integrator dynamics and their target tracking. An algorithm consisting of an observer and a feedback control law of the nonsmooth type is proposed for the purpose of achieving finite-time formation and target tracking. The development is based on the Multi-input Multi-output (MIMO) super-twisting like approach aiming at finite time convergence without chattering. In addition to the formation; tracking, chattering prevention and robustness is also provided by the sliding mode mechanism which is demonstrated by simulations. PMID- 30420137 TI - Sensor placement optimization in the artificial lateral line using optimal weight analysis combining feature distance and variance evaluation. AB - Artificial lateral line is a multi-sensor system, mimicking the lateral line of fish to perceive the parameters of flow field. However, it can easily lead to information loss or redundancy with limited number of sensors due to unsuitable sensor placement. An optimal weight analysis algorithm is proposed to solve the problem on sensor placement of robotic fish. Firstly, signal features are extracted from the pressure data, which are collected from candidate sensor locations in different conditions. Then the improved distance evaluation is used to assess each feature, and the feature distance factor is regarded as the weight for distinguishing. Combined with the analysis of variance, the contribution vector of sensor locations is obtained. Three indexes selected by the algorithm are introduced to compare the sensor subsets. The results in both simulation and experiment show the effectiveness of the algorithm. The optimal number of sensors on the robotic fish is also studied. PMID- 30420138 TI - Stability and Performance Analysis of Networked Control Systems: A Lifted Sample Time Approach with L2 Induced Norm. AB - The lifted sample-time approach has been extensively applied to analyze the behavior of a Networked Control System (NCS) under instances of packet-drop and/or variable communication latency (jitter) of varying durations. This paper combines the simplicity of the lifted sample-time approach in modeling an NCS under arbitrary but bounded instances of packet-drop and/or jitter with the proven L2induced norm based approach of controller design to realize an NCS which is capable of preserving the designed value of the norm under assumed conditions of packet-drop and/or jitter and hence a satisfactory time response under these conditions. The design methodology presented in this paper assumes a state feedback controller and uses a simple criterion based on a Linear Matrix Inequality (LMI). The methodology is validated using credible offline and real time simulations. PMID- 30420139 TI - Robust fault-tolerant control for networked control systems subject to random delays via static-output feedback. AB - This paper focuses on the problem of fault-tolerant controller (FTC) design for uncertain networked control systems (NCSs) with random delays and actuator faults. A new fault model is proposed to represent more class of actuator faults. More precisely, the NCSs with random delays and the possible actuator faults are modeled as a Markovian jump system (MJS) with incomplete transition probabilities (TPs) and then LMI-based sufficient conditions are derived to ensure the stochastic stability of the closed-loop system. The sufficient conditions are constructed to synthesize the mode-dependent static-output feedback (SOF) control laws. Feasibility and reliability of the proposed FTC against actuator faults are indicated through simulation results. PMID- 30420140 TI - Novel fuzzy modeling and energy-saving predictive control of coordinated control system in 1000 MW ultra-supercritical unit. AB - In order to satisfy the growing demands of control performance and energy conservation in power generation process, a novel T-S fuzzy modeling method combined with the quantum artificial bee colony (QABC) algorithm is proposed and applied to the coordinated control system (CCS) of ultra-supercritical unit in 1000MW power plant. The T-S fuzzy modeling consists of the identifications of premise part and consequence part. In the premise part identification, the cluster number and initial cluster centers are obtained at first by using entropy based clustering method. Secondly, the initial cluster centers are modified through QABC algorithm to guarantee the integral of data and avoid possible marginalization. Then, the consequence part is identified through exponentially weighted least squares. Furthermore, on account of the obtained fuzzy model, an energy-saving predictive control (ESPC) algorithm based on the generalized predictive control is introduced. In the rolling optimization process of ESPC, the values of manipulated variables taken as energy consumption indicator are introduced into objective function to decrease the consumption of energy and improve the performance of control process. Meanwhile, the addition of manipulated variables constraints can obtain further improvements of energy saving efficiency and control performance. The simulation results demonstrate the high precision of identified model and ideal performance along with energy-saving ability of ESPC. PMID- 30420141 TI - Neural network adaptive sliding mode control for omnidirectional vehicle with uncertainties. AB - This paper presents a novel neural network adaptive sliding mode control (NNASMC) method to design the dynamic control system for an omnidirectional vehicle. The omnidirectional vehicle is equipped with four Mecanum wheels that are actuated by separate motors, and thus has the omnidirectional mobility and excellent athletic ability in a narrow space. Considering various uncertainties and unknown external disturbances, kinematic and dynamic models of the omnidirectional vehicle are established. The inner-loop controller is designed based the sliding mode control (SMC) method, while the out-loop controller uses the proportion integral derivative (PID) method. In order to achieve the stable and robust performance, the artificial neural network (ANN) based adaptive law is introduced to model and estimated the various uncertainties disturbances. Stability and robustness of the proposed control method are analyzed using the Lyapunov theory. The performance of the proposed NNASMC method is verified and compared with the classical PID controller and SMC controller through both the computer simulation and the platform experiment. Results validate the effectiveness and robustness of the NNASMC method in presence of uncertainties and unknown external disturbances. PMID- 30420142 TI - Dual-axis control of flexure-based motion system for optical fibre transceiver assembly using fixed-order controller. AB - High-frequency resonant modes appearing in the flexure-based motion systems are the key factors that limit the motion/positioning performance. This paper presents an approach to design the fixed-order (low-order) controller for the flexure-based motion system, which is used for industrial optical fibre transceiver alignment and assembly. The uniqueness of the proposed algorithm is that one single controller can simultaneously stabilize the uncertain high frequency resonant modes for both x and y-axis motion. Especially, the resulted controller can significantly enhance the tracking and disturbance rejection ability in low frequency. The novelty of the proposed method is mainly twofold. First, the finite-frequency specifications are introduced to robust control of the polytopic systems. As the entire-frequency specifications have the trend to place the dominant poles towards the central polynomial, the finite-frequency specifications largely relax the conservatism for the performance optimization. Second, a new and practical method is proposed to choose the central polynomial by designing a nominal controller, where two different central polynomials are utilized for x and y-axis separately for the practical applications, so that the stability and performance are guaranteed but the conservatism is reduced. Experiments are evaluated on the 2DOF flexure-based motion system, and the results show that the tracking error using designed fixed-order controller has a more than 50% reduction compared with the same-order notch filter based nominal controller, with respect to both the sinusoidal and triangular references. PMID- 30420143 TI - Perioperative myocardial infarction in elderly patients with hip fracture. Is there a role for early coronary angiography? AB - OBJECTIVES: To evaluate the effects of perioperative myocardial infarction in patients with hip fracture referred to multidisciplinary unit at a tertiary teaching hospital. METHODS: 1030 patients with hip fracture underwent troponin measurement, electrocardiogram and echocardiogram at admission, 24 and 48 h after surgery. Exclusion criteria were age < 70 years, severe aortic stenosis, myocardial infarction <30 days, stress cardiomyopathy, renal failure, sepsis, active neoplastic disease. End-points were 30-day and 1 year mortality. RESULTS: Troponin I levels >=0.5 MUg/l were found in 129/1030. 37 of them were excluded according to reported criteria. In the 92 patients included in the study in hospital and 1 year mortality were significantly higher than in controls (12.5% vs 3.5%, p .0012 and respectively 44% vs 16.1% at 12 months, p < .001). 18 patients underwent coronary angiography within 1 week from hip surgery. All had multivessel coronary artery disease. One patient died after angiography. At multivariate logistic analysis age (OR 1.09, 95% CI = 1.01 to 1.19, p = .044) and creatinine values (OR = 7. 55, 95% CI = 1.26 to 45.3, p = .02) were independent predictive factors of 1 year mortality whereas coronary revascularization (OR = 0.15, 95% CI = 0.03 to 0.78, p = .024) was an independent factor associated with improved survival. CONCLUSIONS: Perioperative TnI elevation is associated with a significantly increase in 30-day and 1-year mortality. Severe coronary disease may be suspected in patients with perioperative myocardial infarction after hip fracture surgery. Our study is one of the first providing data on the safety and feasibility of early (inhospital) coronary angiograpy and PCI after hip surgery. Further studies are needed to establish indication of coronary angiography in these patients. PMID- 30420144 TI - Positron emission tomography/computed tomography detection of increased 18F fluorodeoxyglucose uptake in the cardiac atria of patients with atrial fibrillation. AB - BACKGROUND: Direct evidence of inflammatory activity in the atria of patients with atrial fibrillation (AF) is scarce. We assessed the capability of positron emission tomography/computed tomography (PET/CT) to diagnose AF based on fluorodeoxyglucose (FDG) uptake in the atrial wall. METHODS AND RESULTS: Among 8233 patients who underwent FDG-PET/CT as work-up for malignancies, we identified 180 consecutive patients with AF (2.2%). Of those, we selected 137 patients who had fasted >12 h before FDG injection for inclusion in the experimental group (88 men and 49 women; age: 72.7 +/- 8.9 years). Controls were 62 age- and sex-matched patients without AF. For visual analysis, we used a 4-point grading system. For quantitative analysis, we used the maximum standard uptake value (SUVmax) in the left (LA) and right atrial (RA) myocardium and the target-to-background ratio (TBR) of SUVmax to blood pool activity. The sensitivity, specificity, and positive-predictive value for detecting AF visually were 54.0%, 95.2%, and 96.1%, respectively; for quantitative analysis, the respective values were 65.7%, 75.8%, and 85.7%. Multivariable analysis of 11 clinical and imaging variables showed significant associations with RA SUVmax (odds ratio [OR]: 14.353, P = 0.026) and LA volume (OR: 1.371, P = 0.0001). The RA TBR was greater in cases with persistent AF than in those with paroxysmal AF (P < 0.0001). Pathological investigation of 4 autopsy hearts confirmed infiltration of extravascular macrophages and lymphocytes in the regions with FDG uptake. CONCLUSIONS: Higher atrial FDG uptake was associated with AF. PET/CT could be a useful tool for detecting local inflammation in the atria with AF. PMID- 30420145 TI - Variations in cardiovascular risk factors in people with and without migration background in Germany - Results from the STAAB cohort study. AB - BACKGROUND: About 20% of the German population have a migration background which might influence prevalence of preventable cardiovascular risk factors (CVRF). METHODS: We report data of the prospective Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB) cohort study investigating a representative sample of inhabitants of the City of Wurzburg, Germany, aged 30 to 79 years. Individuals without migration background were defined as follows: German as native language, no other native language, and/or born in Germany. All other participants were defined as individuals with migration background. RESULTS: Of 2473 subjects (51% female, mean age 54 +/- 12 years), 291 (12%) reported a migration background: n = 107 (37%) from a country within the EU, n = 117 (40%) from Russia, and n = 67 (23%) from other countries. Prevalence of hypertension, atherosclerotic disease, and diabetes mellitus was similar in individuals with and without migration background. By contrast, prevalence of obesity and metabolic syndrome was significantly higher in individuals with migration background, with the least favourable profile apparent in individuals from Russia (individuals without vs. with migration background: obesity 19 vs. 24%, p < 0.05; odds ratio: EU: 1.6, Russia: 2.2*, other countries: 0.6; metabolic syndrome 18 vs. 21%, p < 0.05; odds ratio: EU: 1.2, Russia: 1.7*, other countries: 1.5; *p < 0.05). CONCLUSION: Individuals with migration background in Germany might exhibit a higher CVRF burden due to a higher prevalence of obesity and metabolic syndrome. Strategies for primary prevention of heart failure may benefit from deliberately considering the migration background. PMID- 30420146 TI - Sacubitril/valsartan therapeutic strategy in HFpEF: Clinical insights and perspectives. AB - Sacubitril/valsartan represents the first of a new class of drugs able to act as a neprilysin inhibitor and as an angiotensin receptor blocker. This double inhibition has the advantage of concomitantly blocking a pro-fibrotic/pro hypertrophic mechanism (angiotensin receptor blocker component) while stimulating an anti-fibrotic/anti-hypertrophic mechanism (neprilysin inhibitor component). Furthermore, the novel drug has natriuretic and diuretic properties, better preserves renal function, provides better blood pressure control as compared to renin angiotensin system inhibitors, and improves ventricular-arterial coupling. Consequently, sacubitril/valsartan provides greater target organ protection than angiotensin receptor blocker therapy alone, including cardiac, vascular, and renal protection. Up to now, this drug does not have an indication in patients with heart failure with preserved ejection fraction (HFpEF). However, its complex mechanism of action and previous experimental and clinical data seem to suggest its possible success in HFpEF. In this review we highlight and discuss the rationale, clinical insights, and perspectives behind the use of sacubitril/valsartan in HFpEF, specifically referring to its possible efficacy in pathophysiologic mechanisms, such as myocardial hypertrophy, fibrosis, and ischemia, renal dysfunction, impaired ventricular-arterial coupling, which are all tightly related to elevated left ventricular end diastolic pressure, a common hallmark for this multifaceted syndrome. PMID- 30420147 TI - Ambulatory Fontan pressure monitoring: Results from the implantable hemodynamic monitor Fontan feasibility cohort (IHM-FFC). AB - BACKGROUND: Implantable invasive hemodynamic monitoring (IHM) using the CardioMEMSTM HF system has been shown to reduce heart failure (HF) hospitalizations. IHMs have not yet been used in congenital heart disease (CHD). We aimed to evaluate feasibility and mid-term outcomes of IHM use in the single ventricle/Fontan population. METHODS: Six adult Fontan patients (>1 HF admission, NYHA FC >3) were enrolled (30 +/- 7 years old, mean pulmonary artery pressure (mPA) 16 +/- 4.7 mm Hg). Heart failure mediated events (HFME) were evaluated for 12 months: CV medication change, hospital admission, paracentesis, and change in orthotopic heart transplant (OHT) listing status. RESULTS: The IHM device was successfully placed in all participants. In total there were 671 IHM transmissions and 25(3.7%) HFME. The mean PA pressure across all episodes was 18.2 +/- 6.6 mm Hg (range 6-40 mm Hg). Higher mPA pressures were associated with greater odds of having a HFME (OR 1.17 [1.09, 1.25], p < 0.0001). Mean PA pressure had good ability to discriminate transmissions associated with HFME (AUC 0.76 [0.654, 0.866]), with mean PA pressures >24 mm Hg or individual mPA change >4 mm Hg, best discriminating transmissions associated with HFME. CONCLUSIONS: In the first feasibility series of adult Fontan patients undergoing CardioMEMSTM implantation we demonstrate early technical success and no device-related adverse events. We propose that ambulatory mean PA pressures >24 mm Hg or individual mPA change >4 mm Hg may be associated with more HFME. Further large-scale studies in this population are recommended. PMID- 30420148 TI - Relationship between occlusal force and condylar morphology in class II and III after bi-maxillary osteotomy. AB - PURPOSE: The purpose of this study was to examine the relationship between occlusal force and condylar morphology in class II and III after sagittal split ramus osteotomy (SSRO) with Le Fort I osteotomy. MATERIALS AND METHODS: The subjects were 42 female patients who underwent bi-maxillary surgery, and were divided into 2 groups (21 class II and 21 class III cases). They were selected randomly from among patients that underwent surgery from 2012 to 2017. Condylar height, ramus height, ramus inclination and condylar square were assessed by computed tomography (CT), preoperatively and 1 year postoperatively. Occlusal contact area and occlusal force were measured pre- and 1, 3, 6 and 12 months post operative. RESULTS: Condylar height and ramus height of the class II advancement cases decrease more significantly than those of class III. There were no significant differences in time-course changes of occlusal force and area between the class II and III. In the class II cases, occlusal force at 1 and 3 months was significantly lower than the preoperative value (P = 0.0009, P = 0.0002). On the other hand, in class III, occlusal force at 1, 3 and 6 months (P = 0.0038, P = 0.0031, P = 0.0283) was significantly lower than the preoperative value. CONCLUSION: This study suggested that occlusal force of the class II advancement cases reached the pre-operative level earlier than that of the class III setback cases, even though condylar height decreased after surgery in the class II cases. However, a correlation between occlusal force change and condylar height reduction after surgery could not be found. PMID- 30420149 TI - Improving the accuracy of automated cleft speech evaluation. AB - An automated cleft speech evaluator, available globally, has the potential to dramatically improve quality of life for children born with a cleft palate, as well as eliminating bias for outcome collaboration between cleft centers in the developed world. Our automated cleft speech evaluator interprets resonance and articulatory cleft speech errors to distinguish between normal speech, velopharyngeal dysfunction and articulatory speech errors. This article describes a significant update in the efficiency of our evaluator. Speech samples from our Craniofacial Team clinic were recorded and rated independently by two experienced speech pathologists: 60 patients were used to train the evaluator, and the evaluator was tested on the 13 subsequent patients. All sounds from 6 of the CAPS A-AM sentences were used to train the system. The inter-speech pathologist agreement rate was 79%. Our cleft speech evaluator achieved 85% agreement with the combined speech pathologist rating, compared with 65% agreement using the previous training model. This automated cleft speech evaluator demonstrates good accuracy despite low training numbers. We anticipate that as the training samples increase, the accuracy will match human listeners. PMID- 30420150 TI - Toward a higher accuracy in orthognathic surgery by using intraoperative computer navigation, 3D surgical guides, and/or customized osteosynthesis plates: A systematic review. AB - The aim of this study was to systematically review the accuracy of intraoperative computer navigation, three-dimensional surgical guides and customized osteosynthesis plates for the transfer of the virtual surgical plan to the patient in orthognathic surgery. A systematic review of the currently available publications was performed in databases MEDLINE, Embase, and Cochrane Library, using a PICOS search strategy, and reported according to PRISMA. The initial search yielded 3050 articles. In total, 16 studies were included for final quantitative analyses. The results of individual studies demonstrated a comparable accuracy in the transfer of planned surgical displacement of the jaws. A large variability was found with regard to the method of accuracy assessment and reported outcomes. The findings of this review show that these modern techniques have the potential to replace interocclusal splints in routine clinical practice in the future. We recommend that authors presenting new data on the accuracy of a technique should choose the method of accuracy assessment meticulously, acquiring postoperative imaging as soon as possible after surgery. They should report as much as possible, summarizing values or, ideally, even the raw data of the accuracy assessment in order to allow comparison with other techniques in a meta-analysis. PMID- 30420151 TI - Auricular reconstruction with polyethylene implants or silicone prosthesis: A single institution experience. AB - Auricular reconstruction is usually necessary in patients with congenital malformations, after traumatic ear amputations or in cases of neoplastic ear disease. Thirty-nine patients who underwent an auricular reconstruction with either silicon prosthesis (21 patients) or porous polyethylene (18 patients) between 2002 and 2013 were retrospectively analyzed at a tertiary academic institution. A total of 25 male und 14 female patients were included in the study. In all, 43 implants were installed in 39 patients. An implant failure was not observed in any of the examined groups. An operative revision was necessary in 5 patients in the silicon prosthesis group (N = 21) and in 4 patients in the porous polyethylene group (N = 18). The most common side effect in the porous polyethylene group was the formation of retroauricular adhesions in 11.1 % by postoperative scaring, while in the silicone prosthesis group 71.4 % of the patients presented with skin reactions around the titanium implants. Our study shows that both techniques are valuable and should be offered to patients in cases of auricular reconstruction due to the low rate of severe complications and the good functional results of both techniques. PMID- 30420152 TI - Mandibular subcondylar fracture accessibility with transparotid approach by rhytidectomy and modified Risdon approach: An anatomical comparative study. AB - PURPOSE: The purpose of our anatomical study was to compare the accessibility of the area at the level of the neck of the condyle and the condylar head by two different approaches: the modified Risdon approach and a transparotid approach by rhytidectomy (TPAR). METHODS: An anatomical study was performed on 12 heads of cadavers preserved with a solution rich in glycerin and ethanol, but very low in formalin. A modified Risdon approach and a TPAR were each performed on a hemiface of the same head. The bone surface was rendered digitally accessible on an anatomical diagram using Image J software. The software was used to determine a concordance score between the area of accessibility and the area of interest necessary for osteosynthesis of a high subcondylar fracture. This score was presented as a numerical scale from 0 to 100. We measured the total number of pixels in our area of interest and assigned it a score of 100. We then compared the area of accessibility with the area of interest necessary for osteosynthesis of a high subcondylar fracture. RESULTS: Using the modified Risdon approach, an average score of 55.88 (SD = 18.96) was found, or 55.88% of the accessible area of interest. Using TPAR, we found a score of 91.05 (SD = 7.95) or 91.05% of the accessible area of interest. This difference in score between the two techniques was significantly different (p < 0.001), taking into account intra-hemiface and intra-individual correlation. CONCLUSION: TPAR seems to be more effective in treating high condylar process fractures of the mandible. PMID- 30420154 TI - Evaluation of anatomical landmarks for transanal total mesorectal excision based on MRI. AB - BACKGROUND: Transanal total mesorectal excision (taTME) is a novel sphincter preserving procedure for low rectal cancer. This "bottom to up" approach is unfamiliar to colorectal surgeons and the crucial anatomical landmarks also remain unclear. METHODS: Two hundred and five cases of pelvic magnetic resonance imaging (MRI) from 2015 to 2016 were reviewed. Curvature of posterior mesorectal fascia, distal mesorectal angle, length of posterior mesorectal fascia, main structures around the mesorectum were measured and analyzed. The landmarks identified on MRI were verified in taTME procedures of five rectal cancer patients. RESULTS: The most of acute angles of posterior mesorectal fascia located at the joint of anococcygeal ligament-coccyx. Degree of distal mesorectal angle was independently correlated with gender and degree of angle of anococcygeal ligament-coccyx. Candidate landmarks evaluated by MRI with verification during taTME procedures included: anterior: seminal vesicle for male while cervix for female. And peritoneal reflection was a substitute landmark when cervix was hardly confirmed in operation; posterior: the joint of anococcygeal ligament-coccyx. The area between the joint of anococcygeal ligament-coccyx and S3S4 was a "transitional zone", the level of S3S4 could be the as the terminal landmark of transanal posterior dissection during taTME. CONCLUSIONS: Preoperative MRI geometrical measurement of mesorectum might play an important role in evaluating the difficulty of taTME procedure before operation, as well as standardizing landmarks during taTME procedure. PMID- 30420153 TI - The efficacy and safety of tazobactam/ceftolozane in Japanese patients with uncomplicated pyelonephritis and complicated urinary tract infection. AB - We report efficacy and safety results for a combination of a novel cephalosporin class antibiotic and a beta-Lactamase inhibitor, tazobactam/ceftolozane (1:2) at a dose of 1.5 g intravenously every 8 h in Japanese patients with uncomplicated pyelonephritis and complicated urinary tract infection. This study design was a nonrandomized, multicenter, open-label trial, and the treatment period was 7 days. Of 115 patients enrolled in this study, 114 received tazobactam/ceftolozane, and 90 were included in the efficacy analyses. Ninety nine isolates (bacterial count >=105 CFU/mL) were identified by urine culture. The main baseline uropathogens were Escherichia coli (80 isolates), Klebsiella pneumoniae (8 isolates), and Proteus mirabilis (3 isolates). Of these, 13 isolates were ESBL-producers. The favorable per-patient microbiological response rate at 7 days after the final administration of tazobactam/ceftolozane was 80.7% (71/88). The response rate in uncomplicated pyelonephritis was 90.0% (36/40), complicated pyelonephritis 63.6% (14/22), and complicated cystitis 80.8% (21/26). The favorable clinical response rate was 96.6% (86/89), and composite response rate (based on microbiological and clinical response) was 80.7% (71/88). The eradication rate by uropathogen was 83.5% (66/79) in E. coli, 42.9% (3/7) in K. pneumoniae, and 100% (3/3) in P. mirabilis. The incidence of drug-related adverse events was 17.5% (20/114 patients). The most common drug-related adverse events were diarrhea and alanine aminotransferase increased in 5.3% (6/114 patients each). Drug-related serious adverse events and deaths were not observed. These results support the safety and efficacy of tazobactam/ceftolozane and suggest it will be a useful treatment for uncomplicated pyelonephritis and complicated urinary tract infection. PMID- 30420155 TI - Anti-cholinergic burden and patient related clinical outcomes in an emergency general surgical setting. AB - BACKGROUND/OBJECTIVE: The impact of medications with anti-cholinergic properties on morbidity and mortality of unselected adult patients admitted to the emergency general surgical setting has not been investigated. METHODS: All cases were identified prospectively from unselected adult patients admitted to the emergency general surgical ward between May to July 2016 in a UK centre with a catchment population circa 500,000. Prescribed medication lists were ascertained from case notes and electronic medical records. Anti-Cholinergic Burden (ACB) was calculated from medication lists. Patients were categorised into three groups based on ACB; none (ACB score of 0); moderate (up to ACB score of two); high (ACB score more than two). The effect of increasing ACB on selected outcomes of 30- and 90-day mortality, hospital readmission within 30-days of discharge and increased length of hospital stay were examined using multivariable logistic regression models. RESULTS: The 452 patients had a mean age (SD) of 51.7 (+/ 20.6) years, 273 (60.4%) patients had no ACB burden, 106 (23.5%) had a ACB burden of up to two; and 73 (16.2%) had an ACB burden of > 2. Multivariable analyses showed no association between high ACB burden and 90-day (fully adjusted odds ratio [OR] 0.56 (95%CI 0.12-2.85); P = 0.48) and 30-day mortality (fully adjusted OR = 0.75 (95%CI 0.05-11.04); P = 0.84). A significant association was observed between moderate ACB burden and 30-day hospital readmission (fully adjusted OR = 2.01 (95%CI 1.09-3.71); P = 0.03). CONCLUSIONS: Anti-cholinergic burden may be linked to hospital readmission in adults admitted to an emergency general surgical ward. PMID- 30420156 TI - Full thickness chest wall defection and lung injury by electrical burn: A 5-years old child reconstruction case. PMID- 30420157 TI - Peritoneal metastasis after emergency hepatectomy and delayed hepatectomy for spontaneous rupture of hepatocellular carcinoma. AB - BACKGROUND AND OBJECTIVES: Delayed hepatectomy is the preferred approach for spontaneous rupture of resectable hepatocellular carcinoma (HCC). However, delayed surgery for ruptured HCC may increase the risk of peritoneal metastasis. METHODS: A retrospective analysis was conducted on the pooled data obtained from 44 HCC patients with spontaneously ruptured hemorrhage, These patients were divided into emergency group and delayed group. Perioperative events, overall survival (OS) and disease-free survival (DFS) rates, and the incidence of recurrent and metastatic disease were compared between these two groups. RESULTS: Median survival time was 17.0 months in the emergency group vs. 28.0 months in the delayed group. In the emergency group, the 6-month, 1-year and 3-year OS rates were 58.8%, 57.6% and 11.5%. In the delayed hepatectomy group, the 6-month, 1-year and 3-year OS rates of were 84.3%, 77.5% and 37.8%. The incidence of peritoneal metastasis was higher in delayed group than in the emergency group, but the difference was not statistically significant (40.7% vs. 35.3%, P > 0.05). CONCLUSION: Delayed hepatectomy warrants better short-term prognosis, compared with emergency hepatectomy, for HCC patients with spontaneously ruptured hemorrhage. Delayed hepatectomy does not increase the possibility of postoperative peritoneal metastasis. PMID- 30420159 TI - Clinical Practice Guidelines of the European Association for the study of the Liver - Advancing methodology but preserving practicability. PMID- 30420160 TI - TRPM2 activation: Paradigm shifted? AB - Transient receptor potential cation channel, subtype melastatin 2 (TRPM2), is important for several physiological functions, such as immune response or temperature regulation. Recently, the structure of full-length TRPM2 from zebrafish was published (Huang et al., 2018) proposing a new activation mechanism - is it really a paradigm shift or just reflects evolution of the channel?. PMID- 30420161 TI - Effects of Trypanocidal Treatment on Echocardiographic Parameters in Chagas Cardiomyopathy and Prognostic Value of Wall Motion Score Index: A BENEFIT Trial Echocardiographic Substudy. AB - BACKGROUND: Serial echocardiographic studies in chronic Chagas cardiomyopathy are scarce. The aims of this study were to evaluate whether therapy with benznidazole modifies the progression of cardiac impairment and to identify baseline echocardiographic parameters related to prognosis. METHODS: A prospective substudy was conducted in 1,508 patients with chronic Chagas cardiomyopathy randomized to benznidazole or placebo, who underwent two-dimensional echocardiography at enrollment, 2 years, and final follow-up (5.4 years). Left ventricular (LV) ejection fraction, LV wall motion score index (WMSI), indexed left atrial volume, and chamber dimensions were collected and correlated to all cause death and a composite hard outcome using univariate and multivariate analyses. RESULTS: At enrollment, most patients had normal chamber dimensions, and 70.5% had preserved LV ejection fractions. During follow-up, all chamber dimensions increased similarly in both treatment arms. LV ejection fraction was comparably reduced (55.7 +/- 12.7% to 52.1 +/- 14.6% vs 56.3 +/- 12.7% to 52.8 +/ 14.1%) and LV WMSI similarly increased (1.31 +/- 0.41 to 1.49 +/- 0.03 and 1.27 +/- 0.38 to 1.51 +/- 0.03) for the benznidazole and placebo groups, respectively (P > .05). A higher baseline LV WMSI was identified in subjects who died compared with those alive at final echocardiography (1.76 +/- 0.517 vs 1.271 +/- 0.393, P < .0001). There was a significant (P < .0001) graded increase in the risk for the composite outcome with worsening LV WMSI (hazard ratios, 2.27 [95% CI, 1.69-3.06] and 6.42 [95% CI, 4.94-8.33]) and also of death (hazard ratios, 2.45 [95% CI, 1.62-3.71] and 8.99 [95% CI, 6.3-12.82]) for 1 < LV WMSI < 1.5 and LV WMSI > 1.5, respectively. Both LV WMSI and indexed left atrial volume remained independent predictors in multivariate analysis. CONCLUSIONS: Trypanocidal treatment had no effect on echocardiographic progression of chronic Chagas cardiomyopathy over 5.4 years. Despite normal global LV systolic function, regional wall motion abnormalities and indexed left atrial volume identified patients at higher risk for hard adverse clinical outcomes. PMID- 30420162 TI - Natural history of ovarian function including assessment of ovarian reserve and premature ovarian failure. AB - This chapter describes ovarian anatomy and embryology in humans. The formation of the ovarian reserve is discussed, and events of folliculogenesis are described, including description of developmental events in primordial, primary, secondary, antral and periovulatory follicles. Paracrine and autocrine factors play critical roles in oocyte maturation and follicular development, and research related to the hypothesised roles of individual factors is discussed. Gonadotrophin dependent events relating to dominant follicle selection are discussed. The two cell, two-gonadotrophin hypothesis of ovarian steroidogenesis is explained. The clinical role of AMH is outlined. Premature ovarian failure and known associated aetiological factors are described. In the conclusion, with an understanding of the principle events of ovarian folliculogenesis, the follicular wave theory is described, and it is explained how adaptation of ovarian stimulation regimens may achieve time-efficient fertility preservation treatment options for patients with cancer. PMID- 30420163 TI - Human sperm acrosomal status, acrosomal responsiveness, and acrosin are predictive of the outcomes of in vitro fertilization: A prospective cohort study. AB - The sperm acrosome reaction (AR) is a physiological secretory course of membrane fusion and hydrolytic enzymes, as well as matrix protein release, enabling spermatozoa to penetrate the egg surroundings. An instable acrosomal status before a specific stimulus, insufficient acrosomal responsiveness, or inadequate enzymatic activity of acrosomal content can be detrimental to male fertility. This prospective cohort study was designed to determine whether three human sperm acrosome evaluation parameters-including spontaneous AR rate, AR after calcium ionophore A23187 challenge (ARIC) rate, and modified Kennedy acrosin activity-can predict fertilization outcomes in vitro and are correlated with male characteristics. A total of 485 eligible couples undergoing in vitro fertilization (IVF) therapy were included in two phases of this study. In a 'construction phase', three acrosome evaluation parameters were determined simultaneously in 132 cases, whereas in a 'validation phase', the spontaneous AR rate was determined in 353 cases. The results of the 'construction phase' revealed that the spontaneous AR rate was the only significant predictor of fertilization outcome (unadjusted odds ratio [OR] = 0.68, 95% confidence interval [CI]: 0.53-0.88, P = 0.003; adjusted OR = 0.64, 95% CI: 0.43-0.95, P = 0.03), and the cut-off value for total fertilization failure (TFF) prediction, determined by ROC curve analysis, was 9.91%; higher acrosin activity was shown to predict a higher fertilization rate only when patients were divided into groups (>=25 MUIU/106 spermatozoa, 14-25 MUIU/106 spermatozoa, <14 MUIU/106 spermatozoa). The spontaneous AR rate was negatively correlated with sperm motility, forward progression motility, and normal morphology; modified Kennedy acrosin activity was positively correlated with normal morphology; and the ARIC rate was not correlated with any of the male characteristics. A similar result was obtained for the spontaneous AR rate in the 'validation phase', and the cut off value in predicting TFF was calibrated for 9.52%. Clinically, patients can voluntarily choose spontaneous AR rate alone or in combination with modified Kennedy acrosin activity to predict TFF, and early rescue intracytoplasmic sperm injection (ICSI), half ICSI, or full ICSI should be considered in advance for men with spontaneous AR rates >=9.52% or spontaneous AR rates >=9.52% and AE activities <25 MUIU/106 spermatozoa. PMID- 30420164 TI - Robotic hip joint testing: Development and experimental protocols. AB - The use of robotic systems combined with force sensing is emerging as the gold standard for in vitro biomechanical joint testing, due to the advantage of controlling all six degrees of freedom independently of one another. This paper describes a novel robotic platform and the experimental protocol used for hip joint testing. An experimental protocol implemented optical tracking and registration techniques in order to define the position of the hip joint centre of rotation (COR) in the coordinate system of the robot's end effector. The COR coordinates defined the origin of the task-related coordinate system used to control the robot, with a hybrid force/position law to simulate standard clinical tests. The axes of this frame were defined using the International Society of Biomechanics (ISB) anatomical coordinate system. Experiments were carried out on two cadaveric hip joint specimens using the robotic testing platform and a mechanical testing rig previously developed and described by our group. Simulated internal-external and adduction/abduction laxity tests were carried out with both systems and the resulting peak range of motion (ROM) was measured. Similarities and differences were observed in these experiments, which were used to highlight some of the limitations of conventional systems and the corresponding advantages of robotics, further emphasising their added value in vitro testing. PMID- 30420158 TI - CureGN Study Rationale, Design, and Methods: Establishing a Large Prospective Observational Study of Glomerular Disease. AB - RATIONALE & OBJECTIVES: Glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and immunoglobulin A (IgA) nephropathy, share clinical presentations, yet result from multiple biological mechanisms. Challenges to identifying underlying mechanisms, biomarkers, and new therapies include the rarity of each diagnosis and slow progression, often requiring decades to measure the effectiveness of interventions to prevent end-stage kidney disease (ESKD) or death. STUDY DESIGN: Multicenter prospective cohort study. SETTING & PARTICIPANTS: Cure Glomerulonephropathy (CureGN) will enroll 2,400 children and adults with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (including IgA vasculitis) and a first diagnostic kidney biopsy within 5 years. Patients with ESKD and those with secondary causes of glomerular disease are excluded. EXPOSURES: Clinical data, including medical history, medications, family history, and patient-reported outcomes, are obtained, along with a digital archive of kidney biopsy images and blood and urine specimens at study visits aligned with clinical care 1 to 4 times per year. OUTCOMES: Patients are followed up for changes in estimated glomerular filtration rate, disease activity, ESKD, and death and for nonrenal complications of disease and treatment, including infection, malignancy, cardiovascular, and thromboembolic events. ANALYTICAL APPROACH: The study design supports multiple longitudinal analyses leveraging the diverse data domains of CureGN and its ancillary program. At 2,400 patients and an average of 2 years' initial follow-up, CureGN has 80% power to detect an HR of 1.4 to 1.9 for proteinuria remission and a mean difference of 2.1 to 3.0mL/min/1.73m2 in estimated glomerular filtration rate per year. LIMITATIONS: Current follow-up can only detect large differences in ESKD and death outcomes. CONCLUSIONS: Study infrastructure will support a broad range of scientific approaches to identify mechanistically distinct subgroups, identify accurate biomarkers of disease activity and progression, delineate disease specific treatment targets, and inform future therapeutic trials. CureGN is expected to be among the largest prospective studies of children and adults with glomerular disease, with a broad goal to lessen disease burden and improve outcomes. PMID- 30420166 TI - Acute myelitis associated with dengue infection. AB - OBJECTIVES: To present a rare neurological complication of dengue fever. PATIENTS AND METHODS: A 24-year-old female presented with acute myelitis seven days after dengue fever onset. RESULTS: The patient presented with intense fever. The day-7 examination revealed a paraparesis, T2 sensory level, and urinary retention. The patient complained of electric discharges in the four limbs. The sitting and standing positions were impossible. An MRI of the spinal cord performed on day 8 revealed diffuse medullar hyper intense lesions on T2-weighted sequences at the cervical and thoracic levels, with enhancement of the thoracic lesion after gadolinium injection. Laboratory tests revealed positive dengue antigen on day 5 and positive IgM/IgG on day 8. Treatment with intravenous pulse methylprednisolone was initiated. CONCLUSION: Dengue virus has not often been reported as a cause of myelitis. Physicians must be aware of this rare complication in patients living in or coming from endemic areas. PMID- 30420165 TI - Assessing the benefit of the 72-hour antibiotic therapy reassessment documentation. AB - OBJECTIVES: To assess the documentation of the 72-hour antibiotic therapy reassessment in medical records. METHODS: One-day prevalence evaluation of curative antibiotic therapies>=72hours. The documentation of the reassessment was defined according to three criteria: (1) "clear" documentation (clinical or microbiological comment associated with a comment on the need to adjust the antibiotic therapy or on the lack of need); (2) "tacit" documentation (only based on a clinical or microbiological comment); (3) no documentation. RESULTS: We assessed 114 antibiotic therapies in 26 hospital departments. A clear reassessment at 72hours was observed in only 45 (39%) records and 31 (27%) records had no reassessment. The planned duration of treatment was written in 63 (55%) records. At 72hours, among the 71 antibiotic therapies with a microbiological documentation, 69 (97%) were active and 44 (62%) had a narrow spectrum. Among the 48 antibiotic therapies with a broad spectrum on day 1, only 21 (44%) benefited from a de-escalation at 72hours. A clearly recorded reassessment at 72hours was associated with de-escalation (P=0.025) and the prescription of a planned duration of treatment was associated with antibiotic therapy compliance with local or national guidelines (P=0.018). CONCLUSION: Although reassessment was observed in 73% of records, it was correctly recorded at 72hours in only 39% of cases. The documentation of the reassessment and the prescription of a planned duration were associated with a better quality of antibiotic prescription (de-escalation, compliance with guidelines) and are relevant indicators for monitoring the proper use of antibiotics. PMID- 30420167 TI - End-of-life Decisions at Neonatal Intensive Care Units: Jordanian Nurses Attitudes and Viewpoints of Who, When, and How. AB - PURPOSE: To explore factors predicting neonatal nurses' attitude towards end-of life decisions in neonates, and to describe the nurses' viewpoints on end-of-life decisions; barriers to end-of-life decision making; parents', nurses', and ethical committees' involvement in the process of end-of-life decision making; and who should regulate end-of-life decisions regarding neonates. DESIGN AND METHODS: A cross-sectional descriptive correlational design was applied. Sample included 279 neonatal nurses working in 24 neonatal intensive care units across Jordan. Data were collected using internationally-accepted questionnaires. Descriptive and inferential statistics were applied in data analysis. RESULTS: Most nurses perceived that everything possible should be done to ensure a neonate's survival, even when they suffer severe prognosis (80%) and irrespective of the burden of the child's disability on the family (75%). Almost all nurses (96%) were against administering drugs with the purpose of ending the neonate's life and 63% were against continuing current treatment without adding others. The nurses' perceived effect of end-of-life decisions on their everyday life, and the importance of religious values to the nurses' personal lives, significantly predicted pro-life attitude scores. According to 80% of the nurses, legal constraints were the most significant barriers to end-of-life decision making. The majority of nurses (84%) indicated that non-religious bodies should establish end-of-life regulations for neonates. CONCLUSION: Generally, nurses' attitude was supportive of life saving decisions at end-of-life, regardless of the survival odds and the probable health outcomes of the neonates. PRACTICE IMPLICATIONS: Neonates' end-of-life care, and parents' bereavement care, should be standard practices in every NICU, worldwide. PMID- 30420168 TI - Sexual function in women with polycystic ovary syndrome: a systematic review and meta-analysis. AB - We present the first systematic review and meta-analysis of sexual function in women with polycystic ovary syndrome (PCOS) compared with women without PCOS. Data on this topic are limited and often contradicting. Sexual function is influenced by endocrine, mental and social factors, which are often compromised in women with PCOS. The main outcome measures were validated sexual function questionnaires and visual analogue scales (VAS). We identified and assessed 1925 original articles; 18 articles were included. Significant small effect sizes were found on sexual function subscales (total score: P = 0.006; arousal: P = 0.019; lubrication: P = 0.023; satisfaction: P = 0.015; orgasm: P = 0.028), indicating impaired sexual function in women with PCOS. Large effect sizes for the effect of body hair on sex were shown on VAS (P = 0.006); social effect of appearance (P = 0.007); sexual attractiveness (P < 0.001). Satisfaction with sex life was impaired (P < 0.001), but sexual satisfaction was rated equally important in women with PCOS and controls. We conclude that a satisfying sex life is important for women with PCOS; however, sexual function and feelings of sexual attractiveness are impaired. The findings imply that sexual function, sexual satisfaction and psychosocial functioning need to be part of every clinical assessment of women with PCOS. PMID- 30420169 TI - Gestational surrogacy: results of 10 years of experience in the Netherlands. AB - RESEARCH QUESTION: What are the reproductive and obstetric outcomes of the gestational surrogacy treatment in the Netherlands? DESIGN: This retrospective cohort study reports all data of gestational surrogacy treatment in the VU University Medical Centre over a period of 10 years. Data was collected from 60 intended parents and 63 gestational carriers, including reproductive and obstetric outcomes. RESULTS: All intended mothers had a medical indication for gestational surrogacy and used autologous oocytes, and semen of the intended father. Ninety-three IVF cycles were initiated in 60 intended mothers, with subsequent 184 single embryo transfers in 63 gestational carriers. This resulted in 35 ongoing singleton pregnancies. At least one live birth was achieved for 55.0% of intended couples. Pregnancy was complicated in 20.6% by a hypertensive disorder. Labour was induced in 52.9%, and the Caesarean section rate was 8.8%. None of the pregnancies was complicated by preterm birth. Postpartum haemorrhage (>500 ml) occurred in 23.5%. CONCLUSIONS: This study shows the effective results of the non-commercial gestational surrogacy programme in the Netherlands, in a multidisciplinary team setting. An increased risk for adverse obstetric outcomes in surrogate mothers is noted for hypertensive disorders and post-partum haemorrhage compared with the incidence in non-surrogacy pregnancies. PMID- 30420170 TI - Similar 24-Hour Dietary Recall Results from Low-Income Women When Collected by a Paraprofessional Nutrition Educator or Registered Dietitian Nutritionist. AB - BACKGROUND: The Expanded Food and Nutrition Education Program (EFNEP) is a federally funded, community nutrition education program that assists the low income population in acquiring knowledge and skills related to nutrition, food safety, food resource management, food security, and physical activity. Evaluation of EFNEP includes a 24-hour dietary recall (24HDR) administered by paraprofessional educators, yet protocols for most large-scale nutrition research studies employ registered dietitian nutritionists (RDNs) or individuals with educational backgrounds in nutrition or related fields to collect dietary recalls. OBJECTIVE: To compare 24HDRs collected by trained paraprofessional educators with recalls collected by an RDN. DESIGN: Exploratory cross-over study comparing same-day 24HDR in a one-on-one setting collected by paraprofessional educators and an RDN. Paired recalls were separated by at least 1 hour. PARTICIPANTS AND SETTING: The participants (n=41) were volunteer women who were eligible for participation in EFNEP in two states. MAIN OUTCOME MEASURES: The 24HDRs were compared for energy, macronutrients, micronutrients, and food groups. STATISTICAL ANALYSIS PERFORMED: Mixed-model analysis to account for repeated measures. Intraclass correlation and Spearman correlation coefficients to determine interrater agreement. RESULTS: No difference in 24HDR was seen when compared by interviewer (paraprofessional vs RDN) or by site (Colorado vs North Carolina). There were significant differences in four components (energy, total fat, saturated fat, and solid fats-added sugar) based on recall order, with a higher intake in the second recall compared with the first. CONCLUSION: The results of this preliminary study suggest that a well-trained paraprofessional educator using a valid methodology can collect a 24HDR that is similar to a recall collected by an RDN. The paraprofessional educator can be employed for dietary data collection, allowing the RDN to focus on more advanced aspects of scope of practice, such as data evaluation and program development. PMID- 30420171 TI - Fecal Akkermansia muciniphila Is Associated with Body Composition and Microbiota Diversity in Overweight and Obese Women with Breast Cancer Participating in a Presurgical Weight Loss Trial. AB - BACKGROUND: Akkermansia muciniphila (AM) is a gram-negative, mucin-degrading bacteria inhabiting the gastrointestinal tract associated with host phenotypes and disease states. OBJECTIVE: Explore characteristics of overweight and obese female early-stage (0 to II) breast cancer patients with low AM relative abundance (LAM) vs high (HAM) enrolled in a presurgical weight-loss trial. DESIGN: Secondary analysis of pooled participants in a randomized controlled trial (NCT02224807). PARTICIPANTS/SETTING: During the period from 2014 to 2017, 32 female patients with breast cancer were randomized to weight-loss or attention control arms from time of diagnosis-to-lumpectomy (mean=30+/-9 days). INTERVENTION: All were instructed to correct nutrient deficiencies via food sources and on upper-body exercises. The weight-loss group received additional guidance to promote 0.5 to 1 kg/wk weight-loss via energy restriction and aerobic exercise. MAIN OUTCOME MEASURES: At baseline and follow-up, sera, fecal samples, two-24 hour dietary recalls and dual x-ray absorptiometry were obtained. Bacterial DNA was isolated from feces and polymerase chain reaction (16S) amplified. Inflammatory cytokines were measured in sera. STATISTICAL ANALYSES PERFORMED: Differences between LAM and HAM participants were analyzed using t tests and nonparametric tests. Spearman correlations explored relationships between continuous variables. RESULTS: Participants were aged 61+/-9 years with body mass index 34.8+/-6. Mean AM relative abundance was 0.02% (0.007% to 0.06%) and 1.59% (0.59% to 13.57%) for LAM and HAM participants, respectively. At baseline, women with HAM vs LAM had lower fat mass (38.9+/-11.2 kg vs 46.4+/-9.0 kg; P=0.044). Alpha diversity (ie, species richness) was higher in women with HAM (360.8+/-84.8 vs 282.4+/-69.6; P=0.008) at baseline, but attenuated after weight loss (P=0.058). At baseline, interleukin-6 level was associated with species richness (rho=-0.471, P=0.008) and fat mass (rho=0.529, P=0.002), but not AM. Change in total dietary fiber was positively associated with AM in LAM (rho=0.626, P=0.002), but not HAM (rho=0.436, P=0.180) participants. CONCLUSIONS: Among women with early-stage breast cancer, body composition is associated with AM, microbiota diversity, and interleukin-6 level. AM may mediate the effects of dietary fiber in improving microbiota composition. PMID- 30420172 TI - Functional outcome and health-related quality of life in patients with sacrococcygeal teratoma - a Swedish multicenter study. AB - BACKGROUND/PURPOSE: The aims of this study were to evaluate bowel and urinary tract function, to identify predictors for dysfunctional outcome and to evaluate health-related quality-of life (QoL) in patients treated for sacrococcygeal teratomas (SCT). METHODS: Medical records of patients with SCT born between 1985 and 2015 treated at three Swedish pediatric surgical centers were reviewed. Questionnaires regarding urinary tract function, bowel function and QoL were sent to patients and parents. Different QoL instruments were used for the different age groups. RESULTS: Totally 85 patients were identified. Four patients died in the neonatal period. Forty-nine patients answered the questionnaires (60%). Median age at follow-up was 8.9 years (range 3.6-28.8). Bowel dysfunction was reported by 36% and urinary tract dysfunction by 46% of the patients. Univariate analysis revealed that urinary tract dysfunction correlated with gestational age (p = 0.018) and immature histology (p = 0.008), and bowel dysfunction correlated with gestational age (p = 0.016) and tumor size (p = 0.042). Low gestational age was an independent predictor for both urinary tract and bowel dysfunction. Good or very good QoL was reported by 56% of children aged 4-7 years, 90% of children aged 8-17 years and 67% of the adults. CONCLUSION: Although a considerable proportion of bowel and urinary tract dysfunction was found, the reported QoL was good in a majority of the patients with SCT. Low gestational age was found to be a predictor for bowel- and urinary tract dysfunction. LEVEL OF EVIDENCE: Level III. PMID- 30420173 TI - Can altered neuromuscular coordination restore soft tissue loading patterns in anterior cruciate ligament and menisci deficient knees during walking? AB - Injuries to the anterior cruciate ligament (ACL) and menisci commonly lead to early onset osteoarthritis. Treatments that can restore normative cartilage loading patterns may mitigate the risk of osteoarthritis, though it is unclear whether such a goal is achievable through conservative rehabilitation. We used musculoskeletal simulation to predict cartilage and ligament loading patterns during walking in intact, ACL deficient, menisci deficient, and ACL-menisci deficient knees. Stochastic simulations with varying coordination strategies were then used to test whether neuromuscular control could be modulated to restore normative knee mechanics in the pathologic conditions. During early stance, a 3 mm increase in anterior tibial translation was predicted in the ACL deficient knee. Mean cartilage contact pressure increased by 18% and 24% on the medial and lateral plateaus, respectively, in the menisci deficient knee. Variations in neuromuscular coordination were insufficient to restore normative cartilage contact patterns in either the ACL or menisci deficient knees. Elevated cartilage contact pressures in the pathologic knees were observed in regions where cartilage wear patterns have previously been reported. These results suggest that altered cartilage tissue loading during gait may contribute to region-specific degeneration patterns, and that varying neuromuscular coordination in isolation is unlikely to restore normative knee mechanics. PMID- 30420174 TI - An in vitro model of impaction during hip arthroplasty. AB - Impaction is required to properly seat press-fit implants and ensure initial implant stability and long term bone ingrowth, however excessive impaction or press-fit presents a high fracture risk in the acetabulum and femur. Current in vitro impaction testing methods do not replicate the compliance of the soft tissues surrounding the hip, a factor that may be important in fracture and force prediction. This study presents the measurement of compliance of the soft tissues supporting the hip during impaction in operative conditions, and replicates these in vitro. Hip replacements were carried out on 4 full body cadavers while impact force traces and acetabular/femoral displacement were measured. Compliance was then simulated computationally using a Voigt model. These data were subsequently used to inform the design of a representative in-vitro drop rig. Effective masses of 19.7 kg and 12.7 kg, spring stiffnesses of 8.0 kN/m and 4.1 kN/m and dashpot coefficients of 595 N s/m and 322 N s/m were calculated for the acetabular and femoral soft tissues respectively. A good agreement between cadaveric and in vitro peak displacement and rise time during impact is found. Such an in-vitro setup is of use during laboratory testing, simulation or even surgical training. PMID- 30420175 TI - Undress to redress internal thoracic artery could be the key! PMID- 30420176 TI - Combined surgery of mitral valve and atrial fibrillation. A demonstrated better alternative. PMID- 30420177 TI - Is rigid fixation of the greater trochanter necessary for arthroplasty of intertrochanteric fractures? AB - INTRODUCTION: Stable fixation of the greater trochanter fracture fragments is necessary in arthroplasty of intertrochanteric hip fractures, as nonunion of the greater trochanter fracture comminution may result in impaired function or dysfunction of the abductor lever arm. HYPOTHESIS: The ethibond suture technique is an efficient method for fixation of the greater trochanter fracture fragments. MATERIALS AND METHODS: A total of 47 cases were studied. The mean age of the patients was 80.6 years, and the minimum follow-up was 6 months. Radiologic evaluation was done by examination of greater trochanter healing and measurement of migration of the greater trochanter fragment. Functional evaluation was done by comparison of pre-injury and postoperative ambulation status. RESULTS: The mean migration of the greater trochanter fragment with ethibond sutures was 5.98mm. Union was achieved in 76.6%, and the nonunion rate was 23.4%. 86.9% of patients had no difference in ambulation or had a difference of only 1 level by the Koval score after treatment compared to their pre-injury status. DISCUSSION: The ethibond suture technique provides good fixation of the greater trochanter fragments in arthroplasty of intertrochanteric hip fractures. LEVEL OF EVIDENCE: IV, Case series. PMID- 30420178 TI - Sorption of benzene and naphthalene on (semi)-arid coastal soil as a function of salinity and temperature. AB - Considerable activities from the oil and natural gas sector have risen some concerns about the pollution of soil and groundwater by petroleum hydrocarbons (PHCs) in (semi)-arid coastal regions. The understanding of the fate and transport of PHCs in these regions is therefore necessary to develop strategies for remediation. To quantify the sorption rates of PHCs in (semi)-arid coastal soil environments, we conducted a series of controlled-laboratory batch experiments under variable temperature and salinity conditions. The soil samples were collected from the eastern coast of Qatar which is near the two largest off shore oil and natural gas fields of the country (North Gas and Al-Shaheen Oil Fields), and the volatile benzene and naphthalene were used as PHCs. The characterization of soil samples showed sand classification with the texture class of sabkha and saline beach sandy soils with calcite as potential dominant mineral. The concentrations of dissolved chloride and sodium were found to be high (> 400 mg L-1) with a chloride-to-sodium ratio of about 1.7. The results of sorption experiments showed that the rates of naphthalene sorption were more than for benzene, where the initial aqueous concentrations of benzene and naphthalene were reduced at equilibrium due to sorption by about 14-25% and 65-79%, respectively. This difference was attributed mainly to the organic carbon-water partitioning coefficient which is higher for naphthalene. The sorption rate experiments showed that sorption was stronger for benzene under higher salinity and lower temperature conditions. The sorption of naphthalene was not affected by the change in salinity but increased by 18% when the temperature decreased from 35 to 5 degrees C. A sorption kinetic model was also applied to define the sorption behavior of benzene and naphthalene for the coastal soil collected in Qatar and the best fits were achieved with the Langmuir sorption isotherm. PMID- 30420179 TI - Older patients' motives of whether or not to perform self-management during a hospital stay and influencing factors?. AB - Semi-structured in-depth interviews (n = 12) were held to explore older patients' motives of whether or not to perform self-management while hospitalized and to identify factors influencing self-management during hospitalization. These interviews were analyzed using the Quacol method. Self-management during hospitalization is operationalized as: collaboration with the nursing staff, having a proactive role, and having control over personal care. Three main themes, i.e., patients' abilities, expectations and opinions, as well as their perceived behavior of nurses were identified along with eight influencing factors. Results indicate that older inpatients perform self-management when they know that it impacts their recovery, when they perceive that a mistake is impending, when their own personal limits are exceeded, or when they are invited to self-manage by nurses. This study provides several suggestions for developing interventions to support patients' self-management during hospitalization. PMID- 30420180 TI - Ethical and epistemological challenges of using published evidence derived from social media: Six questions to ask your undergraduate students. PMID- 30420181 TI - Phase 1b Study of Trebananib Plus Paclitaxel and Trastuzumab in Patients With HER2-Positive Locally Recurrent or Metastatic Breast Cancer. AB - INTRODUCTION: Trebananib, a peptide-Fc fusion protein, blocks angiogenesis by inhibiting binding of angiopoietin-1/2 to the receptor tyrosine kinase Tie2. Trebananib plus trastuzumab and paclitaxel was evaluated in human epidermal growth factor receptor 2-positive breast cancer in an open-label phase 1b clinical study. PATIENTS AND METHODS: Women with human epidermal growth factor receptor 2-positive breast cancer received weekly paclitaxel (80 mg/m2), trastuzumab (8 mg/m2 then 6 mg/kg every 3 weeks), and intravenous trebananib (10 mg/kg or 30 mg/kg weekly) beginning week 2. The primary end point was the incidence of dose-limiting toxicities. Secondary end points included incidence of adverse events (AEs), pharmacokinetics, and tumor response (objective response and duration of response). RESULTS: Forty women were enrolled; 2 experienced dose limiting toxicities (grade 3 ocular transient ischemic attack [10 mg/kg cohort] and grade 3 elevation in gamma-glutamyl transferase [30 mg/kg cohort]). The most common treatment-emergent AEs were peripheral edema (n = 28), diarrhea (n = 27), alopecia (n = 26), fatigue (n = 24), and nausea (n = 24). Maximum observed concentration and area under the concentration-time curve increased proportionally with the trebananib dose. Objective response was confirmed in 31 patients. In the 10 mg/kg cohort, 16 patients (80%) experienced partial response, and none experienced complete response. In the 30 mg/kg cohort, 12 patients (71%) experienced partial response and 3 (18%) experienced complete response. Median (95% confidence interval) duration of response in the 10 and 30 mg/kg cohorts was 12.6 (4.3-20.2) and 16.6 (8.2-not estimable) months, respectively. CONCLUSION: This phase 1b study showed that trebananib was tolerated with manageable AEs at a dose up to 30 mg/kg weekly. Trebananib demonstrated anticancer activity, as indicated by objective response and duration of response. PMID- 30420182 TI - Questionable Study Inclusion in Meta-Analysis. PMID- 30420183 TI - Meta-analysis Comparing Culprit Vessel Only Versus Multivessel Percutaneous Coronary Intervention in Patients With Acute Myocardial Infarction and Cardiogenic Shock. AB - Cardiogenic shock (CS) after a myocardial infarction continues to be associated with high mortality. Whether percutaneous coronary intervention (PCI) of noninfarct coronary arteries (multivessel intervention [MVI]) improves outcomes in CS after acute myocardial infarction (AMI) remains controversial. MEDLINE, Cochrane CENTRAL, and Scopus databases were searched for original studies comparing MVI with culprit-vessel intervention (CVI) in AMI patients with multivessel disease and CS. Risk ratios (RRs) and 95% confidence intervals were calculated and pooled using a random effects model. Thirteen studies, consisting of 7,906 patients (nMVI = 1,937; nCVI = 5,969), were included in this meta analysis. Overall, the MVI and CVI groups did not differ significantly in the risk of short-term mortality (RR: 1.06 [0.91, 1.23]; p = 0.45; I2 = 75.82%), long term mortality (RR: 0.93 [0.78, 1.11]; p = 0.37; I2 = 67.92%), reinfarction (RR: 1.16 [0.75, 1.79]; p = 0.50; I2 = 0%), revascularization (RR: 0.84 [0.48, 1.47]; p = 0.54; I2 = 83.01%), bleeding (RR: 1.15 [0.96, 1.38]; p = 0.09, I2 = 0%), or stroke (RR: 1.29 [0.86, 1.94]; p = 0.80, I2 = 0%). However, significantly increased risk of renal failure was seen in the MVI group (RR: 1.35 [1.10, 1.66]; p = 0.004; I2 = 0%). On subgroup analysis, it was seen that results from retrospective studies showed higher short-term mortality in the MVI group in comparison with prospective studies (p = 0.003). The certainty in estimates is low due to the largely observational nature of the evidence. In conclusion, MVI provides no additional reduction in short- or long-term mortality in AMI patients with multivessel disease and CS. Additionally, the risk of renal failure may be higher with the use of MVI. PMID- 30420184 TI - Usefulness of Low-Dose Statin Plus Ezetimibe and/or Nutraceuticals in Patients With Coronary Artery Disease Intolerant to High-Dose Statin Treatment. AB - High-dose statin (HDS) therapy is recommended to reduce low-density lipoprotein cholesterol (LDL-C); however, some patients are unable to tolerate the associated side effects. Nutraceuticals have shown efficacy in lowering LDL-C. The aim of this study was to evaluate whether the combination of low-dose statin (LDS) plus ezetimibe (EZE) or LDS plus nutraceutical (Armolipid Plus [ALP] containing red yeast rice, policosanol, and berberine) can lead to a higher proportion of high risk patients achieving target LDL-C. A secondary objective was to assess the efficacy of triple combination LDS + EZE + ALP in resistant patients (LDL-C >70 mg/dl). A randomized, prospective, parallel-group, single-blind study was conducted in patients with coronary artery disease (n = 100) who had undergone percutaneous coronary intervention in the preceding 12 months, were HDS intolerant, and were not at LDL-C target (<70 mg/dl) with LDS alone. Patients received either LDS + EZE or LDS + ALP. Of the 100 patients, 33 patients (66%) treated with LDS + EZE and 31 patients (62%) treated with LDS + ALP achieved target LDL-C after 3 months, which was maintained at 6 months. Patients who did not achieve the therapeutic goal received a triple combination of LDS + EZE + ALP for a further 3 months. At 6 months, 28 of 36 patients (78%) achieved LDL-C target. Overall, 92% of patients enrolled in this study were at target LDL-C at 6 months. No patients in any group experienced major side effects. In conclusion, in HDS-intolerant coronary artery disease patients, the combination of LDS plus EZE and/or ALP represents a valuable therapeutic option allowing most patients to reach target LDL-C within 3 to 6 months. PMID- 30420185 TI - Effect of Obstructive Sleep Apnea on Cardiovascular Function in Obese Youth. AB - The increasing prevalence of overweight or obese children and adolescents is a significant global health concern. Although the effect of obesity on cardiovascular function has been investigated, little is known on the impact of associated obstructive sleep apnea (OSA) in obese youth. The aim of the present study was to investigate the influence of OSA on cardiovascular functional parameters in obese youth. This is a prospective single-center observational cross-sectional study. Forty-four obese patients and 44 age- and gender-matched control subjects were included. All patients underwent polysomnography and cardiovascular assessment including functional echocardiography and carotid femoral pulse wave velocity (PWV). Obese patients had higher left ventricular (LV) mass/height2.7, preserved LV systolic parameters, differences in LV diastolic parameters, and increased PWV and systolic blood pressure at rest compared with control group. In obese youth, 14 of 44 (32%) had OSA. There was no correlation between obesity and the apnea-hypopnea index (AHI). LV mass/height2.7 significantly correlated with body mass index z-score (r = 0.648, p <0.001) whereas PWV correlated with AHI (r = 0.352, p = 0.038). In obese patients, body mass index z-score was an independent predictor for LV mass/height2.7 (r = 0.61, p <0.001) and AHI was an independent predictor for higher PWV (r = 0.352, p = 0.038). In conclusion, both obesity and OSA influence cardiovascular performance in obese youth. Although obesity is associated with increased LV mass and reduced LV diastolic function, OSA is associated with changes in arterial stiffness. PMID- 30420186 TI - Letter re: Efficacy of isolated limb perfusion (ILP) in patients with Merkel cell carcinoma: A multicenter experience. PMID- 30420187 TI - HER2 as a potential biomarker guiding adjuvant chemotherapy in stage II colorectal cancer. AB - BACKGROUND: HER2 is a well-established therapeutic target in breast and gastric cancers, while the role of HER2 in colorectal cancer is unclear, and no studies have explored the impact of HER2 on the outcome of stage II colorectal cancer patients treated with 5-fluorouracial based adjuvant chemotherapy. METHODS: We analyzed HER2 mRNA expression of 206 patients in GSE39582 dataset and explored the impact of HER2 expression on benefit from adjuvant chemotherapy for stage II colon cancer patients. We further validated the finding by retrospectively analyzing HER2 detection of immunohistochemistry in a cohort of 282 patients in Fudan University Shanghai Cancer Center (FUSCC). RESULTS: In GSE39582 dataset, chemo-treated HER2-high patients had a better overall survival (OS) and relapse free survival (RFS) versus chemo-naive HER2-high patients (5-year OS: 100% vs 69.5%, 5-year RFS: 100% and vs 64%, P = 0.027 and 0.025, respectively). On the contrary, chemo-treated HER2-low patients had a worse RFS compared with chemo naive HER2-low patients (5-year RFS: 65.6% vs 82.1%, P = 0.022). In FUSCC cohort, chemo-treated HER2-positive patients exhibited better OS vs chemo-naive HER2 positive patients (5-year OS: 100% vs 73.8%, P < 0.001), and showed marginal evidence of a lower probability of recurrence (5-year RFS: 74.4% vs 58.7%, P = 0.072). After stratifying by mismatch repair (MMR) status, the results only kept consistency in patients with pMMR status. CONCLUSIONS: HER2-positve patients with stage II colorectal cancer can benefit from 5-fluorouracial based adjuvant chemotherapy, especially for patients with pMMR status. PMID- 30420188 TI - Meta-analysis of oncological outcomes of sigmoid cancers: A hidden epidemic of R1 "palliative" resections. AB - BACKGROUND: Colon cancer outcomes are now inferior to rectal cancer outcomes. The sigmoid colon is the most common site of colonic cancer. The aim of this review was to investigate the oncological outcomes for sigmoid cancer. METHODS: A systematic review and meta-analysis was performed. We included any study of the oncological outcomes for sigmoid cancer such as local recurrence, distant recurrence and disease free survival. A systematic search was conducted in Medline from inception to November 2016. Study quality was evaluated with the Newcastle-Ottawa Scale. The study was registered on PROSPERO (CRD42017069326). RESULTS: The search terms returned 1323 results. We identified a total of 17 eligible studies including 5953 patients. The pooled local recurrence rate was 10.5% in 15 studies with 5148 patients (95% CI 0.07-0.14) and heterogeneity measured by I2 was 94%. The pooled distant recurrence rate was 19.5% (7 studies, 2040 patients, 95% CI (0.14-0.25), I2 90%). The pooled disease free survival at 5 years was 80.4% (5 studies, 2336 patients, 95% CI 78.6%-82.1%, I2 11.5%.). The median Newcastle-Ottawa score was 4 out of 9. R1 and R2 resections were excluded or not described in 16/17 studies. Two studies described R1 and R2 rates of 15 20%. CONCLUSION: The pooled local recurrence rate of sigmoid cancer of 10.5% is higher than contemporary rates of local recurrence of rectal cancer. A large number of papers fail to describe or include R1 resections of sigmoid cancer, which are frequently described as palliative. PMID- 30420189 TI - Surgical excision versus observation as initial management of desmoid tumors: A population based study. AB - SYNOPSIS: Desmoid tumors can be safely managed with watchful waiting, including either observation alone or tamoxifen/NSAIDs. Surgery at first presentation can be associated with significant treatment burden. BACKGROUND: Immediate surgery was historically recommended for desmoid tumors. Recently, watchful waiting, (tamoxifen/NSAIDs or observation alone), has been advocated. METHODS: All diagnoses of desmoid tumor within the Alberta Cancer Registry from August 2004 to September 2015 were identified. Patients with FAP were excluded. Demographics, tumor characteristics and treatment and outcome data were collected. Outcomes were compared between immediate surgery and watchful waiting. The effect of abdominal wall site on progression and recurrence and the effect of microscopic margin on recurrence were assessed with Fisher's exact test. RESULTS: We identified 111 non-FAP patients. Median follow-up was 35 months from diagnosis. 74% were female. Mean age was 42. Fifty (45%) underwent watchful waiting, of whom 21(42%) progressed, with median PFS of 10 months. Fifty-three (48%) underwent resection at presentation, of whom 8 (15%) recurred, with median disease-free survival of 22 months. Abdominal wall lesions were equally represented in both groups, and equally likely to progress on watchful waiting (50% vs 39%, p = 0.53), but there was a trend toward decreased recurrence after surgery. (5% vs 23%, p = 0.08). Microscopic margin had no effect on recurrence (14% of margin negative vs 20% of margin positive, p = 1.0). CONCLUSIONS: Watchful waiting was successful in 58% of patients, and a further 28% only required one aggressive treatment thereafter, for a total of 86%. Surgery had a favorable recurrence rate (15%), but some recurrences were associated with significant treatment burden. Treatment should be tailored to individual patients in a multidisciplinary setting. A trial of observation appears warranted in most patients. Recurrence rate was not affected by positive margins. PMID- 30420190 TI - Behavioral addictions in bipolar disorders: A systematic review. AB - Clinical and epidemiological research suggests that behavioral addictions (BA) are associated with a wide range of psychiatric disorders. However, the relationship between BA and bipolar disorders (BD) has not been thoroughly explored. The aim of this systematic review was to critically summarize and evaluate the current available evidence regarding a possible association between BA and BD. A systematic review of major electronic databases according to PRISMA guidelines was conducted from inception to 31st December 2017. We sought quantitative studies data concerning prevalence of comorbidity, features and treatment related to BA-BD comorbidity. Data were narratively synthesized. Of the 1250 studies returned from the search, a total of 28 articles were included in this review. BA may be overrepresented in BD samples, and the other way around. Pathological gambling and kleptomania were the most prevalent conditions followed by compulsive buying, compulsive sexual behavior and internet addiction. BA was also associated with other mood disorders, anxiety disorders and substance use disorder. BD-BA comorbidity was related with more severe course of illness. Studies on treatment strategies for BD-BA comorbidity are rather limited; only one randomized controlled trial that fulfilled inclusion criteria was identified. Methodological heterogeneity in terms of design and results among studies was found. BD-BA commonly co-occurs although there is a need for rigorous studies. Routine screening and adequate assessment may be helpful in BD patients to identify individuals at risk for BA and to effectively manage the complex consequences associated with BA-BD comorbidity. PMID- 30420191 TI - Effect of Forearm Warming Compared to Hand Warming for Cold Intolerance Following Upper Extremity Trauma. AB - PURPOSE: This study evaluated the effect of forearm or hand warming versus bare hand conditions to improve cold-induced symptoms and skin temperatures in hand trauma patients. METHODS: Adults with symptoms of cold intolerance at least 3 months following hand trauma and age-/sex-matched controls were included. Testing sessions (bare hand, hand warming, forearm warming) were completed in a climate laboratory with continuous temperature monitoring. Outcomes included physical findings (skin temperature) and self-report symptoms (thermal comfort, pain). RESULTS: Eighteen participants (9 hand trauma patients, 9 control subjects) underwent testing. More severe cold intolerance was associated with higher Disabilities of the Arm, Shoulder, and Hand scores. With bare hands, skin temperatures changed significantly from baseline to cold exposure and to rewarming. Hand trauma patients had the lowest skin temperatures with cold exposure in the injured digits (14.3 degrees C +/- 3.5 degrees C) compared with the contralateral uninjured (16.9 degrees C +/- 4.1 degrees C) digits. Compared with bare hands, wearing gloves significantly increased the minimum temperature during cold exposure and the maximum temperature after rewarming. Patients reported higher pain with cold exposure. All participants reported significantly more comfort with less coldness with forearm and hand warming. CONCLUSIONS: There was cold response variability in hand trauma patients and control subjects. Hand trauma patients had greater changes in skin temperature during cold exposure that improved with glove warming. Continuous temperature monitoring identified subtle physiological changes associated with cold-induced pain and with warming interventions. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 30420192 TI - External Fixation Versus Volar Locking Plate for Unstable Dorsally Displaced Distal Radius Fractures-A 3-year Follow-Up of a Randomized Controlled Study. AB - PURPOSE: To determine if a volar locking plate (VLP) is superior to external fixation (EF) 3 years after surgery for unstable, dorsally displaced, distal radius fractures caused by low-energy injury in patients 50 to 74 years of age. METHODS: During 2009 to 2013, 140 patients with an unstable dorsally displaced distal radius fracture were randomized to either VLP or EF. One hundred eighteen patients (EF 56, VLP 62) were available for a 3-year follow-up. The primary outcome was the Disabilities of the Arm, Shoulder, and Hand score (DASH) at 3 years. Secondary outcomes were Patient-Related Wrist Evaluation score (PRWE), EuroQol-5 Dimensions (EQ-5D) score, range of motion (ROM), grip strength, and radiological signs of osteoarthritis (OA) at 3 years. Moreover, reoperations and minor complications during the first 3 years were recorded. RESULTS: There were no differences regarding DASH, PRWE, EQ-5D, ROM or grip strength. The reoperation rate was 21% (13 of 62) in the VLP group compared with 14% (8 of 56) in the EF group. The OA rate was 42% (25 of 59) in the VLP group compared with 28% (15 of 53) in the EF group. CONCLUSIONS: Three years after surgery for unstable dorsally displaced distal radius fractures, the clinical and radiological results for VLP and EF were comparable. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II. PMID- 30420193 TI - Visualization During Endoscopic Versus Open Cubital Tunnel Decompression: A Cadaveric Study. AB - PURPOSE: To determine the minimum incision size needed using an open cubital tunnel technique to obtain equivalent visualization comparable with an endoscopic technique. METHODS: Visualization was assessed in 10 fresh-frozen cadavers with a 2-cm incision, using percutaneous needle localization with the endoscopic system. The most proximal and distal extent of the field of view was marked. Next, an open cubital tunnel release was performed on each cadaver specimen. The incision size was increased incrementally, and the most proximal and distal extents of visualization were recorded for each incision size. The mean visualization distance and standard deviation for each incisional length were calculated. RESULTS: The mean proximal field of view with the endoscopic technique was 8.1 cm. The mean distal field of view was 8.3 cm. Using the open technique, a 2-cm incision allowed 5.9 cm visualization proximally and 5.2 cm distally, which was significantly less than the endoscopic view. A 4-cm open incision provided similar visualization as the endoscopic technique. A 6-cm open incision was required to obtain statistically significant improvements in visualization compared with an endoscopic technique. CONCLUSIONS: A 4-cm open incision allowed visualization of approximately 9 cm proximal and 9 cm distal to the medial epicondyle, which was equivalent to the 2-cm endoscopic technique for cubital tunnel release. CLINICAL RELEVANCE: Although the endoscopic release allows greater visualization of the ulnar nerve with a smaller incision, it is unclear whether this improvement in visualization improves the surgeon's ability to decompress the ulnar nerve. PMID- 30420194 TI - Current Concepts in Assessment of Upper Extremity Function. AB - Assessment of upper extremity function either before or after surgical treatment has been a rapidly evolving field. A reproducible, accurate, and valid assessment tool provides the ability to compare surgical interventions, evaluate physical therapy regimens, and assess novel assistive and restorative technologies. The purpose of this article is to detail the various upper extremity assessment tools and introduce the concept of real-world data acquisition of upper extremity function. PMID- 30420195 TI - The Relationship Between Hemihamate Graft Size and Proximal Interphalangeal Joint Flexion for Reconstruction of Fracture-Dislocations: A Biomechanical Study. AB - PURPOSE: The purpose of this study was to determine the relationship between hemihamate graft size and proximal interphalangeal (PIP) joint flexion in a biomechanical fracture-dislocation model. METHODS: We simulated middle finger PIP fracture-dislocations in 5 cadaver hands by resecting 50% of the palmar articular surface of the middle phalanx (P2) base. Fluoroscopy was used to confirm dorsal subluxation of the middle phalanx base after resection. A 10-mm osteochondral hamate graft was contoured to reconstruct the volar lip of the middle phalanx and was progressively downsized by 2-mm increments for each trial. A computer controlled articulator and jig simulated active flexion and extension of the fingers. Maximum PIP flexion was measured at each graft size using fluoroscopy and digital imaging software. Clinically significant flexion block was defined as PIP flexion less than 90 degrees . RESULTS: The actual mean size of the volar defect created was 52% (3.5 mm) of the middle phalanx articular surface, which created instability and dorsal subluxation in all tested fingers. After hemihamate reconstruction, all specimens were stable throughout flexion and extension for all graft sizes. A flexion block of 90 degrees occurred at a mean graft size of 191% of the defect (6.5 mm). With regard to the volar lip of the P2, grafts that projected an average 0.8 mm past the native volar lip position had 98 degrees (range, 84 degrees -107 degrees ) maximum PIP flexion. Grafts that projected an average of 3.1 mm past the native volar lip position had 90 degrees (range, 69 degrees -100 degrees ) maximum PIP flexion. Linear regression modeling incorporating all of the results predicted flexion block to occur at a graft size as small as 166% of the 50% volar P2 defect. In this model, for every 50% (1.7-mm) increase in graft size relative to the defect, PIP flexion decreased by approximately 6 degrees . CONCLUSIONS: Nonanatomical hemihamate grafts produce a PIP flexion block at extreme sizes, predicted to occur at greater than 166% of a 50% P2 base articular defect in our model. This suggests that relatively large grafts can be used for reconstruction of PIP fracture-dislocations without substantial biomechanical block to PIP flexion. We suggest sizing no larger than 3 mm past the native P2 volar lip position to avoid an important mechanical block to PIP flexion. CLINICAL RELEVANCE: The information from this study helps surgeons understand how large a hemihamate graft can be used for P2 volar base reconstruction before having a negative impact on PIP flexion. PMID- 30420196 TI - Durability of Collagenase Treatment for Dupuytren Disease of the Thumb and First Web After at Least 2 Years' Follow-Up. AB - PURPOSE: The aim of this study was to analyze the durability of the treatment results of the thumb and first web contractures in Dupuytren disease with collagenase Clostridium histolyticum. METHODS: Twelve patients (14 hands) were followed for an average of 35 months (range, 24-42 months). Two patients (3 hands) were excluded, yielding 11 hands available for assessment. Nondurability was defined as a worsening of at least 20 degrees of passive extension deficit at a treated joint or any decrease greater than 5 mm in intermetacarpal head distance, both relative to 30 days after injection or as intervention to correct new/worsening contracture. Durability was compared with that of a historic cohort of treated finger contractures. RESULTS: Five out of 11 patients with a metacarpophalangeal or interphalangeal joint contracture or first web contracture had a nondurable result at an average of 35 months. Results obtained at metacarpophalangeal joints of thumbs were more durable than those of interphalangeal joints. Most of the recurrences occurred in interphalangeal joints. CONCLUSIONS: Treatment of thumb and first web contractures was not durable in nearly half of the cases at an average follow-up of 35 months, and durability was clearly less than that of treated finger contractures. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 30420197 TI - The Fragility Index in Hand Surgery Randomized Controlled Trials. AB - PURPOSE: Randomized controlled trials (RCTs) are the gold standard for comparing clinical interventions. Statistical significance as reported via a P value has been used to determine if a difference between clinical interventions exists in an RCT. However, P values do not clearly convey information about the robustness of a study's conclusions. An emerging metric, called the fragility index (the number of subjects who would need to change outcome category to raise the P value above the .05 threshold), is an indirect measure of how likely a repeat of the trial would reach the same conclusions. This study addressed the fragility of RCTs using dichotomous outcomes in hand surgery. METHODS: Using systematic searching of the MEDLINE database, we identified hand surgery RCTs published in 11 high-impact journals published in the last decade (2007-2017). Studies were identified that involved 2 parallel arms, allocated patients to treatment and control in a 1:1 ratio, and reported statistical significance for a dichotomous variable. The fragility index was calculated using Fisher's exact test, using previously published methods. RESULTS: Five hand surgery RCTs were identified for inclusion reporting a range of fragility indices from 0 to 26. Two of the trials (40%) had a fragility index of 2 or less. Two of the trials (40%) reported that the number of patients lost to follow-up exceeded the fragility index, meaning that results of the patients lost to follow-up could theoretically completely reverse the study conclusions. CONCLUSIONS: The range of fragility indices reported in the recent hand surgery literature is consistent with previous reporting within orthopedic surgery. CLINICAL RELEVANCE: The fragility index is a useful metric to analyze the robustness of the study conclusions that should complement other methods of critical evaluation including the P value or effect sizes. Our results emphasize the need for future efforts to strengthen the robustness of RCT conclusions. PMID- 30420198 TI - Methods to monitor accurate and consistent electrode placements in conventional transcranial electrical stimulation. AB - BACKGROUND: Inaccurate electrode placement and electrode drift during a transcranial electrical stimulation (tES) session have been shown to alter predicted field distributions in the brain and thus may contribute to a large variation in tES study outcomes. Currently, there is no objective and independent measure to quantify electrode placement accuracy/drift in tES clinical studies. OBJECTIVE/HYPOTHESIS: We proposed and tested novel methods to quantify accurate and consistent electrode placements in tES using models generated from a 3D scanner. METHODS: Accurate electrode placements were quantified as Discrepancy in eight tES participants by comparing landmark distances of physical electrode locations F3/F4 to their model counterparts. Distances in models were computed using curve and linear based methods. Variability of landmark locations in a single subject was computed for multiple stimulation sessions to determine consistent electrode placements across four experimenters. MAIN RESULTS: We obtained an average of 0.4 cm in Discrepancy, which was within the placement accuracy/drift threshold (1 cm) for conventional tES electrodes (~35 cm2) to achieve reliable tES sessions suggested in the literature. Averaged Variability was 5.2%, with F4 electrode location as the least consistent placement. CONCLUSIONS: These methods provide objective feedback for experimenters on their performance in placing tES electrodes. Applications of these methods can be used to monitor electrode locations in tES studies of a larger cohort using F3/F4 montage and other conventional electrode arrangements. Future studies may include co-registering the landmark locations with imaging-derived head models to quantify the effects of electrode accuracy/drift on predicted field distributions in the brain. PMID- 30420199 TI - Delayed, distant skin lesions after transcranial direct current stimulation. PMID- 30420200 TI - Sexual function following hysterectomy for endometrial cancer: A five-year follow up investigation. AB - OBJECTIVES: We sought to determine a baseline and five-year follow up sexual function score in women undergoing hysterectomy for endometrial cancer. METHODS: A cross-section of endometrial cancer patients receiving care from 2006 to 2010 was identified. Patients were surveyed during academic year 2011 using the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ). Respondents were re-surveyed in 2016. The PISQ was also administered at a single time point to a control group of urogynecology patients. Statistical analyses were conducted using STATA software, version 13.1. RESULTS: 129 endometrial cancer and 63 matched urogynecology patients responded to an initial survey and sufficiently answered the PISQ. There was no statistical difference in BMI, race, diabetes, or smoking history between groups. In 2011, 62.5% of endometrial cancer patients versus 72.6% of urogynecology patients reported sexual activity (p = 0.166). Median PISQ score for these groups was 33 [IQR 29-38] and 32 [IQR 28-37] respectively (p = 0.472). Twenty-nine (22%) endometrial cancer patients sufficiently answered the initial and 5-year follow up PISQ to be included in follow up analysis. Median PISQ score at five years was not significantly different from baseline: 31 [IQR 27-39] versus 33 [IQR 31-38] (p = 0.299). With multivariable modeling, no demographic or clinical characteristics of endometrial cancer patients were independently associated with sexual function (p = NS). CONCLUSIONS: Sexual function for endometrial cancer patients was not significantly different from women treated for benign disease. Sexual function also remained stable for endometrial cancer patients regardless of time from initial treatment. Further prospective studies are needed to better characterize sexual function in endometrial cancer survivors. PMID- 30420201 TI - Hsp90 inhibitors suppress P53 phosphorylation in LPS - induced endothelial inflammation. AB - P53 has been recently involved in the defense against inflammation. The "guardian of the genome" appears to orchestrate cellular responses against bacterial toxins, by regulating crucial pathways that orchestrate the vascular barrier functions. Indeed, an emerging body of evidence suggests that this tumor suppressor is involved in the mediation of the beneficial effects of Hsp90 inhibition in the inflamed endothelium. Interestingly, those compounds augment the abundance of P53 in the intracellular niche, while LPS dramatically reduces it. The current study focuses on the outcome of LPS and Hsp90 inhibition on P53 phosphorylation, since this modification negatively affects P53 stability. In an in "vitro" model of LPS - induced vascular leak in bovine pulmonary arterial endothelial cells, LPS induced P53 phosphorylation in four distinct residues, namely Ser. 6, Ser. 15, Ser. 33 and Ser. 392. Furthermore, LPS triggered the activation of the myosin light chain 2, which produces endothelial barrier dysfunction by cellular retraction and intercellular gap formation. Indeed, mice exposed to the toxin demonstrated elevated levels of the pro - inflammatory cytokines IL-2 and IL-10 in the bronchoalveolar lavage fluid. In bold contrast, the HSP90 inhibitor 17-DMAG, counteracted the LPS - induced effects both in vivo and in vitro. Specifically, this hsp90 inhibitor reduced phosphorylated P53 levels and lessened the activation of myosin light chain 2 (phosphorylation) in the bovine endothelium. Moreover, 17 - DMAG suppressed inflammation in mouse lungs, as reflected in reduced IL-2 and IL-10 BALF levels. In summary, the present results support previous observations on the protective role of P53 against inflammation and clarify mechanisms that govern vascular barrier function. PMID- 30420202 TI - CCR5-Delta32 polymorphism is a genetic risk factor associated with dyslipidemia in patients with type 1 diabetes. AB - AIM: In the currently available literature there are no works investigating the correlation between CCR5-Delta32 polymorphism and dyslipidemia in children with type 1 diabetes mellitus (T1D). Therefore, we have decided to explore the potential role played by this polymorphic locus in the incidence of dyslipidemia as an important risk factor for cardiovascular disease (CVD) in patients with T1D. METHODS: A total of 380 patients with T1D were selected. Patients were divided into two groups: 180 patients with diabetic dyslipidemia and 200 controls without dyslipidemia. Characterization of CCR5-Delta32 genotypes was analyzed by polymerase chain reaction. Logistic regression model was used to examine the association between CCR5-Delta32 polymorphism and dyslipidemia. RESULTS: When participants were analyzed according to CCR5-Delta32 polymorphism, Delta32 carriers presented higher levels of: HbA1c (p < 0.001), fasting plasma glucose (p < 0.001), LDL (p = 0.02) as well as TG (p = 0.01) and lower levels of HDL (p = 0.01) than noncarriers. Moreover, the minor allele Delta32 was more frequent in dyslipidemic subjects than controls (p < 0.001) and conferred an increased individual risk for dyslipidemia (OR = 2.327; 95% CI = 11.241-4.365; p = 0.009). CONCLUSIONS: The findings of our study suggest that the CCR5-Delta32 polymorphism is associated with elevated plasma lipid levels and the Delta32 allele increases the risk of dyslipidemia in patients with T1D. Identification of the functional variant underlying these associations may potentially lead to the development of a novel and adjunctive approach for the treatment of dyslipidemia and CVD. PMID- 30420203 TI - Minimally invasive lumbar pedicle screw fixation using cortical bone trajectory - Screw accuracy, complications, and learning curve in 100 screw placements. AB - Cortical bone trajectory (CBT) is a novel pedicle insertion technique with comparable or superior mechanical properties and reduced invasiveness compared to traditional methods. We describe the screw accuracy, complications, and learning curve associated with CBT use. A prospective cohort study was performed involving 22 patients who underwent lumbar fusion with CBT screw placement. A total of 100 cortical screws were placed. Post-operative CT scans were reviewed to assess the adequacy of screw placement and calculate the incidence of vertebral body and pedicle breaches from cortical screw placement. Technique-related complications were examined. The entire surgical cohort was divided into two groups: early experience (first 11 patients) and late experience (last 11 patients), to study the effect of learning curve on CBT screw placement. Medial pedicle breach was observed in 6/100 cases and lateral vertebral body breach was observed in 1/100 cases. The incidence of durotomy related to the technique was 4.5% (N = 1/22). Post-surgical wound infection was seen in 9.1% of patients (N = 2/22). 66.7% (N = 4/6) of medial pedicle breaches, 100% (N = 1/1) of lateral breaches, 100% (N = 1/1) of CBT technique-related CSF leaks, and 100% (N = 2/2) of wound infections occurred in the early experience phase of our study (p = 0.0945). A shift in surgical technique and greater efficiency over time decreased the incidence of overall complications in the late cohort. The difference, however, did not reach statistical significance. A lateralized starting point for the cortical screw on the pars interarticularis and use of smaller diameter screws resulted in fewer medial pedicle out-fractures and breaches. PMID- 30420204 TI - Flattening the curvature of synthetic materials to relieve scalp skin tension in cranioplasty. AB - BACKGROUND: Scalp tissue shrinkage and volume contraction is a major problem in cranioplasty, and sometimes a tissue expander must be set before cranioplasty. The procedure for placing scalp expanders is cumbersome. In this study, we present a method for flattening the curvature of synthetic materials to relieve scalp skin tension and discuss the feasibility and limitations of the method. METHODS: A total of 25 cranioplasty patients were included in this study. The optimal degree of curvature flattening for each piece of bone substitute material was determined based on cosmetic considerations and the extent of encephalomalacia or atrophy due to primary disease. In this series, the correlation between the degree of curvature flattening and the size or location of the bone flap was considered, and the amount of scalp surface area that could be obtained through curvature flattening was estimated. RESULTS: The median degree of curvature flattening was 5.0 mm. The degree of curvature flattening showed moderate correlation with the rate of change in the area of synthetic material achieved through curvature flattening (p < 0.001). The 21 cases of fronto-temporal craniectomy were divided into two groups according to the distance from the midline. There was a statistically significant difference between these two groups in degree of flattening curvature. CONCLUSIONS: In the present cranioplasty series using synthetic materials, curvature flattening was a non-invasive and convenient method for skin closure. This method can be beneficial especially in patients requiring a larger craniotomy including convexity regions. PMID- 30420205 TI - Widening the phenotypic spectrum - Non epileptic presentation of folate transporter deficiency. AB - INTRODUCTION: Folate is essential for production of DNA, neurotransmitters and myelin and regulation of genetic activity. A specific transporter protein is required to transport folate from blood to CSF. Various inherited brain-specific folate transport defects have been recognized due to mutation in Folate Receptor alpha (FOLR1). FOLR1 mutation is one of the vitamin responsive encephalopathies and is inherited as an autosomal recessive condition. It has a wide spectrum of phenotype, commonly presenting as epileptic encephalopathy. Less frequently the condition may manifest with subtle hypotonia, movement disorder as tremors, ataxia or intellectual disability and autistic spectrum disorder. We present a case of folate transporter deficiency with non-epileptic manifestations, presenting with tremors, speech delay and stable white matter changes in MRI brain. OBJECTIVE: We present a case of Folate transporter defect with Non epileptic presentation. CONCLUSION: Folate transporter deficiency has a wide range of presenting symptoms. Presentation with slowly progressive atypical symptoms, stable white matter changes in brain MRI that does not fit a specific diagnosis, should raise a high suspicion of FOLR1 mutation, even in absence of seizures. Since folate transporter deficiency is a treatable neurodegenerative disorder, early diagnosis and supplementation with folinic acid is vital. PMID- 30420206 TI - The profile of blunt traumatic supratentorial cranial bleed types. AB - The characteristics of blunt traumatic supratentorial cranial bleed (STCB) types have not been directly compared. The National Trauma Data Bank (NTDB) 2014 was queried for adults with an isolated single STCB n = 57,278. Patients were grouped by STCB categories: subdural (SDH), subarachnoid (SAH), epidural (EDH), intraparenchymal (IPH), and intraventricular hemorrhage (IVH). Frequency, demographics, clinical characteristics, procedures, and outcomes were compared among groups. SDH was the most common STCB (53%) and occurred mostly in elderly patients after a fall (78%), 30% underwent craniotomy and their mortality was 7%. SAH occurred in 32% of patients and carried the lowest mortality (3%). SAH were least likely to have a severe brain injury (7%), and had the lowest Injury Severity Score (ISS, median 8) and complication rate (1%), as well as the shortest hospital length of stay (HLOS, 4.6 +/- 6.4 days). EDH was uncommon (2%), occurred in younger patients (median 35 years), and had the highest percentage of traffic related injuries (28%). While EDH patients presented with the poorest neurological status (16% Glasgow Coma Scale <= 8, ISS median 18) and were operated on more than any other STCB type (51%), their mortality was lower (4%) and they had the highest discharge to home rate (71%). IVH was the least common (2%), but most lethal (9%) STCB type. These patients had the highest HLOS and intensive care unit LOS, and the lowest craniotomy rate (21%). STCB types have different clinical course, and outcomes. Understanding these differences can be useful in managing patients with STB. PMID- 30420207 TI - Vascular factors and neuropathy in lower limb of diabetic patients. AB - Asymmetric clinical presentation in some patients with diabetic polyneuropathy may result from the different vascular environments in both lower limbs. The aim of the study is to determine the association of neuropathy with vascular factors in each lower limb of diabetic patients. A total of 102 patients (204 lower limbs) given a diagnosis of diabetic polyneuropathy were enrolled. The primary end points are sensory nerve action potential (SNAP) amplitude and conduction velocity (CV) of the sural nerve and independent variables are vascular and nonvascular factors. Vascular factors include mean arterial pressure and pulse pressure at the ankle, ankle-brachial index, and arterial stiffness assessed by pulse wave velocity. Nonvascular factors include age, gender, height, body weight, body mass index, total cholesterol, and hemoglobin A1C. Age, hemoglobin A1C, and ankle pulse pressure were inversely correlated with SNAP amplitude of the sural nerve, while no factors were correlated with CV of the sural nerve. Increased arterial stiffness was significant in the limbs group with abnormal SNAP amplitude of the sural nerve, while increased height was significant in the limbs group with abnormal CV of the sural nerve. Vascular factors were more significantly associated with decreased SNAP amplitude rather than decreased CV of the sural nerve in the nerve conduction study of diabetic patients. PMID- 30420208 TI - Periostin deletion suppresses late-phase response in mouse experimental allergic conjunctivitis. AB - BACKGROUND: To investigate the potential roles of periostin (POSTN), an extracellular matrix preferentially expressed in Th2-skewed conditions in the pathophysiology of allergic conjunctivitis. METHODS: The roles of POSTN in ragweed-induced experimental allergic conjunctivitis (RW-EAC) were evaluated using both POSTN-knockout (KO) and congenic BALB/c wild-type mice. Histological analysis was carried out to enumerate eosinophils/basophils in the conjunctival tissue. Th2 cytokine expression was evaluated by quantitative polymerase chain reaction (Q-PCR), and microarray analysis was performed to elucidate genes differentially expressed in POSTN-KO and wild-type mice in the RW-EAC model. RESULTS: Upregulation of POSTN expression and eosinophil infiltration was observed in subconjunctival tissue of RW-EAC in the wild-type mice. The number of infiltrating eosinophils in the conjunctivae of RW-EAC was diminished in POSTN-KO mice compared to wild-type mice. Q-PCR analysis of conjunctival tissue showed induction of Th2 cytokine (Ccl5, Il4, Il5, Il13) expression in the RW-EAC and attenuated Ccl5, Il4, Il13 mRNA expression in the conjunctivae of the RW-EAC using POSTN-KO mice. Microarray analysis and immunohistochemical analysis showed diminished basophil marker (Mcpt8) expression and reduced numbers of infiltrating basophils in the conjunctivae of RW-EAC in POSTN-KO mice. CONCLUSIONS: POSTN expression in conjunctival tissue plays an indispensable role in the late-phase reaction of the RW-EAC model by facilitating eosinophil/basophil infiltration and augmenting Th2 cytokine expression. PMID- 30420209 TI - The association between unexplained falls and cardiac arrhythmias: A scoping literature review. AB - BACKGROUND: Falls in older adults are common. Age is a risk factor for falls and with an ageing population, presentation to the emergency department (ED) resulting from falls is rising. Reasons for falls in older adults are numerous and include cardiac arrhythmias. However, older patients who present with falls do not appear to be routinely screened for cardiac arrhythmias. OBJECTIVES: To determine the association between cardiac arrhythmias and unexplained falls in older adults presenting to the ED and to identify the processes for cardiac screening in patients presenting to the ED after an unexplained fall. METHODS: A scoping literature review was conducted because of the scarce number of primary research articles using an investigational design to undertake a detailed systematic review. Several databases were searched using the search terms: emergency department; trauma centers; arrhythmias cardiac; fall; and accidental fall. DATA SOURCES: A structured and systematic search using MEDLINE, Embase, and PubMed was conducted from 2002 to December 2017. RESULTS: Five quantitative studies were included in this review that reported on adults who presented to the ED after an unexplained fall. Several factors associated with falls and cardiac arrhythmias were extracted from the data. These included age, past history of falls, current medications, comorbidities, electrocardiography, and other cardiac findings. CONCLUSION: Falls in the elderly population account for a significant number of presentations to the ED. A number of known factors are associated with falls in elderly patients, including cardiovascular causes, yet specific individualised factors are largely unknown. There is no routine screening process for the identification of cardiovascular risk factors in those who present to the ED with an unexplained fall. Further research is needed to identify specific cardiac factors associated with the risk of unexplained falls in this patient cohort and to transfer these findings into a routine screening process. PMID- 30420210 TI - Calprotectin and calgranulin C serum levels in bacterial sepsis. AB - The aim of this study was to evaluate the serum levels of calprotectin and calgranulin C and routine biomarkers in patients with bacterial sepsis (BS). The initial serum concentrations of calprotectin and calgranulin C were significantly higher in patients with BS (n = 66) than in those with viral infections (n = 24) and the healthy controls (n = 26); the level of calprotectin was found to be the best predictor of BS, followed by the neutrophil-lymphocyte count ratio (NLCR) and the level of procalcitonin (PCT). The white blood cell (WBC) count and the NLCR rapidly returned to normal levels, whereas PCT levels normalized later and the increased levels of calprotectin, calgranulin C, and C-reactive protein persisted until the end of follow-up. Our results suggest that the serum levels of calprotectin are a reliable biomarker of BS and that the WBC count and the NLCR are rapid predictors of the efficacy of antimicrobial therapy. PMID- 30420211 TI - Human fluids alter DNA-acquisition in Acinetobacter baumannii. AB - Transformation is one of the mechanisms of acquisition of foreign genetic material leading to the emergence of multidrug resistant (MDR) bacteria. Recently, human serum albumin (HSA) was shown to specifically increase transformation frequency in the nosocomial pathogen Acinetobacter baumannii. To further assess the relevance of HSA as a possible modulator of A. baumannii transformation in host-pathogen interactions, in this work we examined the effect of different human fluids. We observed a significant increase in transformation frequencies in the presence of pleural fluid, whole blood cells and liquid ascites, and to a lesser extent with urine. The observed effects correlate with both HSA and bacterial content found in the assayed patient fluids. Taken together, these results are in agreement with our previous findings that highlight HSA as a possible host signal with the ability to trigger natural transformation in A. baumannii. PMID- 30420213 TI - Skeletal Metastasis Evaluation: Value and Impact of PET/Computed Tomography on Diagnosis, Management and Prognosis. AB - A number of PET agents are useful for evaluation of skeletal metastatic disease, and have significant advantages over 99mTc-MDP scintigraphy, including superior diagnostic accuracy, higher spatial resolution, and shorter imaging times- often with the ability to depict soft tissue local recurrence and metastasis in the same examination. While these agents have excellent diagnostic utility, they are not 100% specific for skeletal metastasis, and so normal patterns of biodistribution, benign osseous lesions that may demonstrate radiotracer uptake, and the significance of morphologic changes on CT such as osteolysis or osteosclerosis must be kept in mind to ensure accurate interpretation. PMID- 30420214 TI - Hybrid Imaging (PET-Computed Tomography/PET-MR Imaging) of Bone Metastases. AB - Bone metastases are a common source of osseous malignancy in the skeleton and affect up to 70% of all cancer patients. Hybrid imaging modalities including positron emission tomography (PET)/computed tomography (CT) and PET/MRI play an increasing role for the detection and follow-up of metastatic disease, especially in monitoring treatment response upon local or systemic therapy. This review summarizes current applications of PET/CT and PET/MRI in the clinical setting for imaging of metastases. PMID- 30420215 TI - Metastatic Seeding Attacks Bone Marrow, Not Bone: Rectifying Ongoing Misconceptions. AB - Conventional modalities, such as bone scintigraphy, are commonly used to assess osseous abnormalities in skeletal metastasis. Fluorine-18 (18F)-sodium fluoride (NaF) PET similarly portrays osteoblastic activity but with improved spatial and contrast resolution and more accurate anatomic localization. However, these modalities rely on indirect evidence for tumor activity. PET imaging with 18F fluorodeoxyglucose (FDG) and tumor-specific tracers may have an increased role by directly portraying the metabolic activity of cancer cells, which are often seeded in bone marrow and cause osseous disease after initial latency. This article describes the utility and limitations of these modalities in assessing skeletal metastases. PMID- 30420212 TI - Applications of PET-Computed Tomography-Magnetic Resonance in the Management of Benign Musculoskeletal Disorders. AB - Although computed tomography (CT) and MR imaging alone have been used extensively to evaluate various musculoskeletal disorders, hybrid imaging modalities of PET CT and PET-MR imaging were recently developed, combining the advantages of each method: molecular information from PET and anatomical information from CT or MR imaging. Furthermore, different radiotracers can be used in PET to uncover different disease mechanisms. In this article, potential applications of PET-CT and PET-MR imaging for benign musculoskeletal disorders are organized by benign cell proliferation/dysplasia, diabetic foot complications, joint prostheses, degeneration, inflammation, and trauma, metabolic bone disorders, and pain (acute and chronic) and peripheral nerve imaging. PMID- 30420216 TI - Pediatric Musculoskeletal Imaging: The Indications for and Applications of PET/Computed Tomography. AB - The use of PET/computed tomography (CT) for the evaluation and management of children, adolescents, and young adults continues to expand. The principal tracer used is 18F-fluorodeoxyglucose and the principal indication is oncology, particularly musculoskeletal neoplasms. The purpose of this article is to review the common applications of PET/CT for imaging of musculoskeletal issues in pediatrics and to introduce the use of PET/CT for nononcologic issues, such as infectious/inflammatory disorders, and review the use of 18F-sodium fluoride in trauma and sports-related injuries. PMID- 30420217 TI - Imaging of Osteoarthritis by Conventional Radiography, MR Imaging, PET-Computed Tomography, and PET-MR Imaging. AB - Radiography remains the first-line imaging tool to characterize structural changes of osteoarthritis (OA) in both clinical and research settings, but MRI continues to play a large role in OA research. Compositional MRI enables evaluation of the biochemical properties of joint tissues, allowing assessment of early "premorphologic" changes that cannot be depicted on conventional MRI Hybrid PET-CT and PET-MRI allow integration of high-resolution structural information on CT and MRI with metabolic information obtained from PET related to OA disease process. We describe OA imaging by means of conventional radiography, MRI PET-CT, and PET-MRI. PMID- 30420218 TI - Hot Topics of Research in Musculoskeletal Imaging: PET/MR Imaging, MR Fingerprinting, Dual-energy CT Scan, Ultrashort Echo Time. AB - We aimed to review the latest cutting-edge trends in emerging techniques of musculoskeletal imaging. This study reviews the current status and the preliminary studies of Magnetic Resonance Fingerprinting (MRF), Ultrashort Echo Time (UTE) sequence, Positron Emission Tomography (PET)/MR and Dual-Energy CT scan (DECT) in various oncologic and non-oncologic conditions of the musculoskeletal system. The current application, current and future research trends and limitations of each imaging technique were discussed. There are substantial potentials in MRF, UTE, PET/MR and DECT for characterization of various musculoskeletal disorders. Further dedicated studies in various fields are necessary. PMID- 30420219 TI - Future Perspective of the Application of Positron Emission Tomography-Computed Tomography-MR Imaging in Musculoskeletal Disorders. AB - Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is the imaging method of choice in sarcoma patients. PET may help in diagnosis, grading, staging, biopsy guidance, monitoring response to therapy, restaging for recurrence, and prognosis. 18F-FDG-PET/MRI combines the higher tissue contrast of MRI in the study of soft-tissue lesions and the peculiarities of PET imaging that allow the characterization of tissues. The use of 18F-FDG PET/MRI in these patients has reduces the radiation dose, which is of great importance, particularly in children. Data support the routine use of 18F-FDG-PET either using CT or MRI in patients with sarcoma. PMID- 30420220 TI - Evolving Role of MR Imaging and PET in Assessing Osteoporosis. AB - An imbalance in bone remodeling results in many metabolic bone diseases, such as osteoporosis. fluorine-18 sodium fluoride PET imaging allows the assessment of bone remodeling process in a anatomy specific manner. On the other hand structural imaging modalities such as MRI can now generate high resolution images of bone including the trabecular and cortical microstructure. Molecular (functional) imaging with PET in conjunction with structural imaging has the potential to improve the way metabolic bone diseases are managed in the clinic. PMID- 30420221 TI - In Vivo Molecular Imaging of Musculoskeletal Inflammation and Infection. AB - In vivo molecular imaging detects biologic processes at molecular level and provides diagnostic information at an earlier time point during disease onset or repair. It offers definite advantage over anatomic imaging in terms of improved sensitivity and ability to quantify. Radionuclide molecular imaging has been widely used in clinical practice. This article discusses the role of radionuclide imaging in various infective and inflammatory diseases affecting musculoskeletal system with a focus on PET. It appears that, as more data become available, combined PET/MR imaging could emerge as a front runner in the imaging of musculoskeletal infection and inflammation. PMID- 30420222 TI - Clinical Applications of Positron Emission Tomography in the Evaluation of Spine and Joint Disorders. AB - Over the last decade, major advances have been made in PET imaging, including the introduction of hybrid PET/computed tomography and PET/MR imaging systems, facilitating a better understanding of the pathophysiology underlying a vast array of human diseases. PET has not only remained the clinical standard for most oncological disorders but also emerged as a potentially viable modality in nononcological disorders, including many musculoskeletal pathologies. PMID- 30420223 TI - Evolving Role of PET/CT-MRI in Assessing Muscle Disorders. AB - 2-Deoxy-2-[18F]fluoroglucose (FDG) uptake in muscle is influenced by many normal physiologic processes and can also indicate pathology. Variability in physiologic uptake can be reduced with proper patient preparation, allowing for a better determination of abnormal activity. Although malignant diseases, such as rhabdomyosarcoma and skeletal muscle metastasis, are clear applications of FDG PET/CT, there may be additional applications in infection and benign inflammatory disorders that warrant further research. PMID- 30420224 TI - PET Imaging of Peripheral Nerve Tumors. AB - PET has been founded as a useful technique in the staging, restaging, prognostication, and treatment planning for numerus cancers, with an incremental application in precision oncology. This paper summarized the current state-of-the art application of PET/CT in the management of patients with peripheral nerve tumors. Furthermore, the potential clinical uses of emerging themes and technological advances are reviewed, consisting hybrid PET/MR imaging and alternative radiotracers for the application in peripheral nerve oncology. PMID- 30420225 TI - Management of Primary Osseous Spinal Tumors with PET. AB - Knowledge of the PET imaging findings of osseous spinal neoplasms is essential, because they are common incidental findings on PET scans done for staging of unrelated primary malignancies. Additionally, PET can help differentiate lesions that are not clearly defined by anatomic modalities alone. PET can also be used for follow-up of aggressive tumors to assess response to treatment, often proving superior to CT or MR imaging alone for this purpose. This review discusses the role of PET/CT and PET/MR imaging in the diagnosis and management of primary benign and malignant osseous tumors of the spine. PMID- 30420226 TI - PET-Computed Tomography and PET-MR Imaging and Their Applications in the Twenty First Century. PMID- 30420227 TI - Interruptions in community pharmacies: Frequency, sources, and mitigation strategies. AB - BACKGROUND: Interruptions constitute a key part of the communication strategy for healthcare providers, including community pharmacy personnel. Previous research in other healthcare environments has shown that interruptions are very common and may present as patient safety hazards. One 1999 study, conducted in community pharmacy settings, found that interruptions were prevalent and associated with dispensing errors. In the last 20 years, pharmacies have expanded patient services and implemented new technology. Yet, it is unknown how these changes have affected interruption sources and frequency. OBJECTIVE: The objective was to characterize the frequency and sources of pharmacist task interruptions that occur in community pharmacies. METHODS: A cross-sectional qualitative study design was used to evaluate the frequency and sources of pharmacist task interruptions in Wisconsin community pharmacies. The participants included 9 pharmacists and 9 technicians working in 2 independently-owned, 2 mass merchandise, and 2 hospital/clinical-affiliated pharmacies. RESULTS: Interruption rates ranged from 3 to 7 per hour across the 6 pharmacies. Sources of interruptions included: patients, technicians, self-initiated interruptions, technology used in the pharmacy, and a second pharmacist. CONCLUSIONS: Interruptions are common in community pharmacies and the causes are multifactorial. Prudent management of interruptions in these work environments may involve improved technician training and better designs of pharmacy technology. PMID- 30420228 TI - Current value of intraoperative electrocorticography (iopECoG). AB - OBJECTIVE: Intraoperative electrocorticography (iopECoG) can contribute to delineate the resection borders of the anticipated epileptogenic zone in epilepsy surgery. However, it has several caveats that should be considered to avoid incorrect interpretation during intraoperative monitoring. METHODS: The literature on iopECoG application was reviewed, and pros and cons as well as obstacles to this technique were analyzed. RESULTS: The literature of the first half of the nineties was very enthusiastic in using iopECoG for tailoring the resection in temporal as well as extratemporal epilepsy surgery. Mostly, this resulted in a good correlation of postresection ECoG and excellent seizure outcome. In the second half of the nineties, many authors demonstrated lack of correlation between iopECoG and postoperative seizure outcome, especially in surgery for temporal lobe epilepsy with hippocampal sclerosis. In the noughties, investigators found that ECoG was significantly useful in neocortical lesional temporal lobe epilepsy as well as in extratemporal lesional epilepsies. Extratemporal epilepsy without lesions proved to be more a domain of chronic extraoperative ECoG, especially using depth electrode recordings. In recent years, iopECoG detecting high-frequency oscillations (ripples, 80-250 Hz, fast ripples, 250-500 Hz) for tailored resection was found to allow intraoperative prediction of postoperative seizure outcome. CONCLUSION: After a period of scepticism, iopECoG seems back in the focus of interest for intraoperative guidance of resecting epileptogenic tissue to raise postoperative favorable seizure outcome. In temporal and extratemporal lesional epilepsies, especially in cases of focal cortical dysplasia, tuberous sclerosis, or cavernous malformations, an excellent correlation between iopECoG-guided resection and postoperative seizure relief was found. PMID- 30420229 TI - The Global Antibiotic Research and Development Partnership (GARDP): a not-for profit antibiotic development organisation. PMID- 30420230 TI - Familiar barriers still unresolved-a perspective on the Zika virus outbreak research response. AB - Research is an important component of an effective response to the increasing frequency of widespread infectious disease outbreaks. In turn, the ability to do such studies relies on willingness of partners in different regions to collaborate and the capacity to mount a rapid research response. The EU-funded ZIKAlliance Consortium has initiated a multicountry epidemiological, clinical, and laboratory research agenda to determine the incidence, risk factors, and outcomes of Zika virus infection in pregnant women and their children. We reviewed the timeline of patient cohort initiation in relation to the Zika virus epidemic and mapped key events regarding funding, regulatory approvals, and site preparation during this timeline. We then assessed barriers and delays that the international research team experienced through a systematic telephone interview. We have identified three major bottlenecks in the implementation of a swift response: the absence of a timeline for the funding process, delays in regulatory and ethical approval, and the challenging logistics of laboratory support, including diagnostics. These bottlenecks illustrate the clear and urgent need for implementing a strong and permanent global emerging infectious diseases research capacity that has structured funding, enables long-term partnerships, and develops basic clinical and laboratorial research and a response infrastructure that is ready to deploy. PMID- 30420231 TI - Hypothermic Cardiac Arrest With Full Neurologic Recovery After Approximately Nine Hours of Cardiopulmonary Resuscitation: Management and Possible Complications. AB - We describe full neurologic recovery from accidental hypothermia with cardiac arrest despite the longest reported duration of mechanical cardiopulmonary resuscitation (CPR) and extracorporeal life support (8 hours, 42 minutes). Clinical data and blood samples were obtained from emergency medical services (EMS) and the intensive care department. A 31-year-old man experienced a witnessed hypothermic cardiac arrest with a core temperature of 26 degrees C (78.8 degrees F) during a summer thunderstorm; he received mechanical CPR for 3 hours and 42 minutes, followed by 5 hours of extracorporeal life support. The use of a standard operating procedure that integrates a technical mountain rescue performed by EMS, optimizes prolonged CPR to the hub hospital, and enables prompt placement of extracorporeal life support is described and discussed. Three months postaccident, the patient had recovered completely (Cerebral Performance Category score of 1) and resumed normal daily life. Neurologically intact survival from hypothermic cardiac arrest is common, suggesting that aggressive resuscitation measures are warranted. There is a need for the establishment of a clear standard operating procedure and multiteam education and training to further optimize the patient survival chain from on-site triage and treatment to inhospital extracorporeal life support and postresuscitation care. PMID- 30420232 TI - Identification of Clinical Characteristics Associated With High-Level Care Among Patients With Skin and Soft Tissue Infections. AB - STUDY OBJECTIVE: Serious adverse outcomes associated with skin and soft tissue infections are uncommon, and current hospitalization rates appear excessive. It would be advantageous to be able to differentiate between patients who require high-level inpatient services and those who receive little benefit from hospitalization. We sought to identify characteristics associated with the need for high-level inpatient care among emergency department patients presenting with skin and soft tissue infections. METHODS: We conducted a nonconcurrent review of existing records to identify emergency department (ED) patients treated for skin and soft tissue infections. For each case, we recorded the presence or absence of select criteria and whether the patient needed high-level care, defined as ICU admission, operating room surgical intervention, or death as the primary outcome. We applied recursive partitioning to identify the principal criteria associated with high-level care. RESULTS: We identified 2,923 patients, including 84 experiencing high-level events. Recursive partitioning identified 6 variables associated with high-level outcomes: abnormal computed tomography, magnetic resonance imaging, or ultrasonographic imaging result; systemic inflammatory response syndrome; history of diabetes; previous infection at the same location; older than 65 years; and an infection involving the hand. One or more of these variables were present in all 84 patients requiring high-level care. CONCLUSION: A limited number of simple clinical characteristics appear to be able to identify skin and soft tissue infection patients who require high-level inpatient services. Further research is needed to determine whether patients who do not exhibit these criteria can be safely discharged from the ED. PMID- 30420233 TI - Fast Protocol for Treating Acute Ischemic Stroke by Emergency Physicians: What Took So Long? PMID- 30420234 TI - Use of a novel atlas for muscles of mastication to reduce inter observer variability in head and neck radiotherapy contouring. AB - PURPOSE/OBJECTIVE(S): Trismus is caused by injury to the masticatory muscles resulting from cancer or its treatment. Contouring these muscles to reduce dose and radiation related trismus can be problematic due to interobserver variability. This study aimed to evaluate the reduction in interobserver variability achievable with a new contouring atlas. MATERIALS/METHODS: The atlas included: medial and lateral pterygoids (MP, LP), masseter (M) and temporalis (T) muscles, and the temporo-mandibular joint (TMJ). Seven clinicians delineated five paired structures on CT scans from 5 patients without the atlas. After >=5 weeks, contouring was repeated using the atlas. Using contours generated by the clinicians on the same 5 CT scans as reference, dice similarity coefficient (DSC), mean distance-to-agreement (DTA) and centre of mass (COM) difference were compared with and without the atlas. Comparison was also performed split by training grade. Mean and standard deviation (SD) values were measured. RESULTS: The atlas reduced interobserver variability for all structures. Mean DTA significantly improved for MP (p = 0.01), M (p < 0.01), T (p < 0.01) and TMJ (p < 0.01). Mean DTA improved using the atlas for the trainees across all muscles, with the largest reduction in variability observed for the T (4.3 +/- 7.1 v 1.2 +/- 0.4 mm, p = 0.06) and TMJ (2.1 +/- 0.7 v 0.8 +/- 0.3 mm, p < 0.01). Distance between the COM and interobserver variability reduced in all directions for MP and T. CONCLUSION: A new atlas for contouring masticatory muscles during radiotherapy planning for head and neck cancer reduces interobserver variability and could be used as an educational tool. PMID- 30420235 TI - Functional Swallowing Units (FSUs) as organs-at-risk for radiotherapy. PART 1: Physiology and anatomy. AB - BACKGROUND AND PURPOSE: When optimising radiotherapy treatments today, the pharyngeal constrictor muscles and the larynx are usually regarded as the swallowing organs at risk (SWOARs). The purpose of this study was to identify and describe additional, previously undefined groups of muscles (functional units) involved in crucial components of swallowing (hyolaryngeal elevation (HLE), tongue base retraction (TBR) and tongue motion), and to emphasise their relevance in radiation-induced dysphagia. MATERIAL AND METHODS: Based on available literature on human anatomy and swallowing physiology, the functional units of muscles involved in HLE, TBR and tongue motion have been identified and described. RESULTS AND CONCLUSION: Functional swallowing units (FSUs) were defined as groups of swallowing muscles sharing their function, that are in close proximity to each other. Seven FSUs involved in HLE, TBR and tongue motion were identified: floor of mouth, thyrohyoid muscles, posterior digastric/stylohyoid muscles complex, longitudinal pharyngeal muscles, hyoglossus/styloglossus muscles complex, genioglossus muscles, intrinsic tongue muscles. The swallowing physiology and anatomy of the FSUs described in this paper will lead to a greater understanding of radiation-induced dysphagia mechanisms and, consequently, to an improvement in the development of swallowing sparing strategies. This article (PART 1) serves as the theoretical foundation for a subsequent article (PART 2), which provides detailed delineation guidelines for FSUs. PMID- 30420236 TI - Comparison of lung clearance index determined by washout of N2 and SF6 in infants and preschool children with cystic fibrosis. AB - BACKGROUND: Multiple-breath washout (MBW) has been shown to detect early impairment of lung function in children with cystic fibrosis (CF). Nitrogen (N2) or sulfur hexafluoride (SF6) can be used as tracer gas for MBW. Recent data indicated higher lung clearance index (LCI) values measured with N2-MBW than concurrent SF6-MBW in older children and adults, however, a comparison in infants and younger children, as well as to other outcome measures of CF lung disease is pending. METHODS: N2- and SF6-MBW were performed consecutively in 31 sedated infants and preschool children with CF (mean age, 2.3 +/- 0.8 years) and 20 controls (mean age, 2.3 +/- 1.1 years) using the Exhalyzer D system. Children with CF also underwent chest magnetic resonance imaging (MRI). RESULTS: Mean difference (95% CI) in LCI between N2- and SF6-MBW was 1.1 +/- 0.4 (0.9 to 1.3) in controls and 2.1 +/- 1.9 (1.4 to 2.8) in CF. Agreement between N2- and SF6-LCI was poor in children with CF. N2-LCI and SF6-LCI correlated with MRI, however N2 LCI showed a higher concordance with MRI than SF6-LCI. The absolute difference between N2- and SF6-LCI values increased with the severity of CF lung disease as determined by MRI scores. CONCLUSION: N2-LCI values were higher than SF6-LCI values in infants and preschool children with CF and controls. Better concordance of N2-LCI than SF6-LCI with chest MRI scores point towards of a higher sensitivity of N2-LCI to detect early lung disease in children with CF. PMID- 30420237 TI - High-Deductible Health Plans and the Challenges They Pose to Radiologists. AB - Patients with high-deductible health plans will increasingly be motivated to contact their hospitals or various websites to try to obtain information about the costs of expensive services like advanced imaging. Unfortunately, they will not find price transparency but rather confusion and opaqueness. Hospital personnel and commercial websites often unwittingly provide erroneous pricing information. The reasons for this are explained. Detailed examples of the erroneous information are provided. State-mandated websites may be somewhat of an improvement, but their methodology seems to vary from state to state, and they too can be confusing. All this obviously creates problems for patients, who are left not knowing what their true costs will be. The situation also creates problems for radiologists and their hospitals. Because of misunderstandings that can occur during the information-gathering phase, the pricing information shown for many hospital facilities may be greatly inflated, placing them at a competitive disadvantage. Certain strategic solutions to the problems are available, and these are discussed. PMID- 30420238 TI - Eight Years' Experience With a Radiology-Sponsored Medical Student Research Fellowship Program. PMID- 30420239 TI - Hybrid Model for the Medical Physics Imaging Residency Training. PMID- 30420240 TI - To Tweet or Not to Tweet-Social Media in Radiological Practice. PMID- 30420241 TI - Accurate prediction of blood culture outcome in the intensive care unit using long short-term memory neural networks. AB - INTRODUCTION: Blood cultures are often performed in the intensive care unit (ICU) to detect bloodstream infections and identify pathogen type, further guiding treatment. Early detection is essential, as a bloodstream infection can give cause to sepsis, a severe immune response associated with an increased risk of organ failure and death. PROBLEM STATEMENT: The early clinical detection of a bloodstream infection is challenging but rapid targeted treatment, within the first place antimicrobials, substantially increases survival chances. As blood cultures require time to incubate, early clinical detection using physiological signals combined with indicative lab values is pivotal. OBJECTIVE: In this work, a novel method is constructed and explored for the potential prediction of the outcome of a blood culture test. The approach is based on a temporal computational model which uses nine clinical parameters measured over time. METHODOLOGY: We use a bidirectional long short-term memory neural network, a type of recurrent neural network well suited for tasks where the time lag between a predictive event and outcome is unknown. Evaluation is performed using a novel high-quality database consisting of 2177 ICU admissions at the Ghent University Hospital located in Belgium. RESULTS: The network achieves, on average, an area under the receiver operating characteristic curve of 0.99 and an area under the precision-recall curve of 0.82. In addition, our results show that predicting several hours upfront is possible with only a small decrease in predictive power. In this setting, it outperforms traditional non-temporal, machine learning models. CONCLUSION: Our proposed computational model accurately predicts the outcome of blood culture tests using nine clinical parameters. Moreover, it can be used in the ICU as an early warning system to detect patients at risk of blood stream infection. PMID- 30420242 TI - Computational normalization of H&E-stained histological images: Progress, challenges and future potential. AB - Different types of cancer can be diagnosed with the analysis of histological samples stained with hematoxylin-eosin (H&E). Through this stain, it is possible to identify the architecture of tissue components and analyze cellular morphological aspects that are essential for cancer diagnosis. However, preparation and digitization of histological samples can lead to color variations that influence the performance of segmentation and classification algorithms in histological image analysis systems. Among the determinant factors of these color variations are different staining time, concentration and pH of the solutions, and the use of different digitization systems. This has motivated the development of normalization algorithms of histological images for their color adjustments. These methods are designed to guarantee that biological samples are not altered and artifacts are not introduced in the images, thus compromising the lesions diagnosis. In this context, normalization techniques are proposed to minimize color variations in histological images, and they are topics covered by important studies in the literature. In this proposal, it is presented a detailed study of the state of art of computational normalization of H&E-stained histological images, highlighting the main contributions and limitations of correlated works. Besides, the evaluation of normalization methods published in the literature are depicted and possible directions for new methods are described. PMID- 30420243 TI - Segmentation of breast MR images using a generalised 2D mathematical model with inflation and deflation forces of active contours. AB - In medical computer aided diagnosis systems, image segmentation is one of the major pre-processing steps used to ensure only the region of interest, such as the breast region, will be processed in subsequent steps. Nevertheless, breast segmentation is a difficult task due to low contrast and inhomogeneity, especially when estimating the chest wall in magnetic resonance (MR) images. In fact, the chest wall comprises fat, skin, muscles, and the thoracic skeleton, which can misguide automatic methods when attempting to estimate its location. The objective of the study is to develop a fully automated method for breast and pectoral muscle boundary estimation in MR images. Firstly, we develop a 2D breast mathematical model based on 30 MRI slices (from a patient) and identify important landmarks to obtain a model for the general shape of the breast in an axial plane. Subsequently, we use Otsu's thresholding approach and Canny edge detection to estimate the breast boundary. The active contour method is then employed using both inflation and deflation forces to estimate the pectoral muscle boundary by taking account of information obtained from the proposed 2D model. Finally, the estimated boundary is smoothed using a median filter to remove outliers. Our two datasets contain 60 patients in total and the proposed method is evaluated based on 59 patients (one patient is used to develop the 2D breast model). On the first dataset (9 patients) the proposed method achieved Jaccard = 81.1% +/-6.1 % and dice coefficient= 89.4% +/-4.1 % and on the second dataset (50 patients) Jaccard = 84.9% +/-5.8 % and dice coefficient = 92.3% +/-3.6 %. These results are qualitatively comparable with the existing methods in the literature. PMID- 30420244 TI - Computational methods for Gene Regulatory Networks reconstruction and analysis: A review. AB - In the recent years, the vast amount of genetic information generated by new generation approaches, have led to the need of new data handling methods. The integrative analysis of diverse-nature gene information could provide a much sought overview to study complex biological systems and processes. In this sense, Gene Regulatory Networks (GRN) arise as an increasingly-promising tool for the modelling and analysis of biological processes. This review is an attempt to summarize the state of the art in the field of GRNs. Essential points in the field are addressed, thereof: (a) the type of data used for network generation, (b) machine learning methods and tools used for network generation, (c) model optimization and (d) computational approaches used for network validation. This survey is intended to provide an overview of the subject for readers to improve their knowledge in the field of GRN for future research. PMID- 30420246 TI - Baloxavir: game-changer or much ado about nothing? PMID- 30420245 TI - Incidence and risk factors for adalimumab and infliximab anti-drug antibodies in rheumatoid arthritis: A European retrospective multicohort analysis. AB - OBJECTIVES: To evaluate the incidence of anti-drug antibody (ADA) occurrences and ADA-related risk factors under adalimumab and infliximab treatment in rheumatoid arthritis (RA) patients. METHODS: The study combined retrospective cohorts from the ABIRISK project totaling 366 RA patients treated with adalimumab (n = 240) or infliximab (n = 126), 92.4% of them anti-TNF naive (n = 328/355) and 96.6% of them co-treated with methotrexate (n = 341/353) with up to 18 months follow-up. ADA positivity was measured by enzyme-linked immunosorbent assay. The cumulative incidence of ADA was estimated, and potential bio-clinical factors were investigated using a Cox regression model on interval-censored data. RESULTS: ADAs were detected within 18 months in 19.2% (n = 46) of the adalimumab-treated patients and 29.4% (n = 37) of the infliximab-treated patients. The cumulative incidence of ADA increased over time. In the adalimumab and infliximab groups, respectively, the incidence was 15.4% (5.2-20.2) and 0% (0-5.9) at 3 months, 17.6% (11.4-26.4) and 0% (0-25.9) at 6 months, 17.7% (12.6-37.5) and 34.1% (11.4 46.3) at 12 months, 50.0% (25.9-87.5) and 37.5% (25.9-77.4) at 15 months and 50.0% (25.9-87.5) and 66.7% (37.7-100) at 18 months. Factors associated with a higher risk of ADA development were: longer disease duration (1-3 vs. < 1 year; adalimumab: HR 3.0, 95% CI 1.0-8.7; infliximab: HR 2.7, 95% CI 1.1-6.8), moderate disease activity (DAS28 3.2-5.1 vs. < 3.2; adalimumab: HR 6.6, 95% CI 1.3-33.7) and lifetime smoking (infliximab: HR 2.7, 95% CI 1.2-6.3). CONCLUSIONS: The current study focusing on patients co-treated with methotrexate for more than 95% of them found a late occurrence of ADAs not previously observed, whereby the risk continued to increase over 18 months. Disease duration, DAS28 and lifetime smoking are clinical predictors of ADA development. PMID- 30420247 TI - Revising the definition of extensively drug-resistant tuberculosis. PMID- 30420248 TI - Do we really need a new classification of airway diseases? PMID- 30420249 TI - [Robotic systems for care at home: A scoping review]. AB - BACKGROUND: In the future, modern technologies could make a significant contribution to a self-determined life in one's own environment when in need of care. Robots might alleviate everyday domestic life and promote participation. In the nursing science debate concerns have been raised over alienation through technology and loss of direct social and emotional contact. Robots are also being tested in nursing care, for example as social robots in the nursing home setting. The current state of knowledge regarding the domestic application of robotic systems has so far not been examined in systematic reviews. AIM: To examine the possibilities of the usage and application of robotic systems in the home healthcare setting. In addition to the functions of the systems, methodological issues and further research in this subject area are considered. METHODS: In this scoping review, an overview of the subject area and current research activities is produced. Five databases and the reference lists of the publications identified were searched. All study designs and publications since 2005 were eligible. We included studies investigating robotic interventions in the home care setting and their impact on outcomes relevant to patients or family members. The relevance of the robotic systems for nursing care was assessed according to the six dimensions of the new definition of care dependency in the Eleventh Book of the German Social Code (SGB XI). RESULTS: The search revealed 7,755 hits; 19 studies were included. Two studies used a control group. Further studies were feasibility studies and acceptance surveys. The majority of studies were conducted in EU countries. Three out of 13 robotic systems were commercially available. Nine studies did not report ethical approval, and seven studies did not mention whether informed consent was obtained. DISCUSSION: Robotic systems in home care have mainly been investigated in exploratory or pilot studies. Apart from technical aspects, the studies focussed on ease of use and, to this purpose, predominantly employed prototype robots. No reference was made to users' living environment, and there was no proof of effectiveness. The devices are far from being in the stage of broad practical application. PMID- 30420250 TI - Pediatric reference values for arterial stiffness parameters cardio-ankle vascular index and CAVI0. AB - The process of arteriosclerosis begins early in life, and cardiovascular risk factors identified in childhood tend to persist into adulthood. Cardio-ankle vascular index (CAVI), a recent parameter of arterial stiffness, is considered an independent predictor of cardiovascular risk. However, there are no studies reporting sex- and age-specific physiological values of CAVI in childhood. We aimed to establish reference values for CAVI and its blood pressure-corrected variant (CAVI0) in 500 healthy children and adolescents aged 7 to 19 years and to study potential relationships with anthropometric indices. Sex- and age-specific distributions of CAVI and CAVI0 values in healthy children and adolescents are presented. Boys aged 15-19 years had lower CAVI than girls, which could result from CAVI's slight blood pressure dependence. CAVI0 did not show such sex difference. Body roundness index-a novel parameter to quantify abdominal fat-was a strong anthropometric predictor of both CAVI and CAVI0. This is the first study providing pediatric age- and sex-specific reference values for arterial stiffness parameters CAVI and CAVI0. The presented data can contribute to the understanding of the evolution of these indices during childhood and adolescence. Under specific conditions, CAVI0 may offer more robust information about arterial stiffness than standard CAVI. PMID- 30420251 TI - Epidemiology of Lyme disease in Pennsylvania 2006-2014 using electronic health records. AB - Lyme disease is the most common vector-borne disease in the United States. Electronic health record (EHR)-based research on Lyme disease is limited. We used Geisinger EHR data from 479,344 primary care patients in 38 Pennsylvania counties in 2006-2014 to compare EHR-based Lyme disease incidence rates to surveillance incidence rates, evaluate individual and community risk factors for incident Lyme disease, and to characterize the proportion of cases with diagnoses consistent with post-treatment Lyme disease syndrome in the EHR (PTLDSEHR). We primarily identified Lyme disease cases using diagnosis codes, serologic testing order codes, and medication orders but also completed subgroup analyses among those with positive serology and those with both diagnosis code and antibiotic treatment. We compared annual incidence rates from the EHR to surveillance by age, sex, and county. In case-control analyses, we compared cases to randomly selected controls (5:1) frequency-matched on year, age, and sex. We identified 9657 cases of Lyme disease, including 1791 cases with positive serology and 4992 cases with both diagnosis code and antibiotic treatment. Annual incidence rates in the EHR were 4.25-7.43 times higher than surveillance. In adjusted analyses, white non-Hispanic race/ethnicity (vs. black, Hispanic, or other) was associated with higher odds of Lyme disease (odds ratio [OR]: 2.06, 95% confidence interval [CI]: 1.73-2.44). Medical Assistance insurance use (always vs. never; OR: 0.77, 95% CI: 0.68-0.88), and higher community-level socioeconomic deprivation (quartile 4 vs. 1 OR: 0.50 (95% CI: 0.42-0.59) were associated with lower odds of Lyme disease. Within 4-52 weeks after Lyme disease diagnosis, 20.8% (n = 735) of cases with a diagnosis code and treatment had a diagnosis of malaise or fatigue, pain, or cognitive difficulties not present in the past 26 weeks. These results highlight the utility of EHR data for epidemiologic research on Lyme disease for case-finding, surveillance, risk factor evaluation, and characterization of PTLDS using EHR data. PMID- 30420252 TI - Patterns of Cortical Structures and Cognition in Antipsychotic-Naive Patients With First-Episode Schizophrenia: A Partial Least Squares Correlation Analysis. AB - BACKGROUND: Schizophrenia is associated with alterations in cortical structures and cognitive impairments, but antipsychotic medication may affect these measures. We investigated patterns of relationships between cortical structures and cognitive domains in antipsychotic-naive patients with first-episode schizophrenia. METHODS: T1-weighted 3T magnetic resonance imaging was performed in 105 patients and 136 healthy control subjects. Using FreeSurfer, we obtained measurements of cortical thickness, surface area, and mean curvature. Using an extensive neurocognitive battery including the Danish Adult Reading Test and subtests from the Cambridge Neuropsychological Test Automated Battery, we obtained estimates of premorbid intelligence, spatial working memory, spatial planning, intra-extradimensional set shifting, and reaction and movement times. With univariate analyses, we tested group differences between cortical structures and cognition. With partial least squares correlation analyses, we investigated patterns of associations between cortical structures and cognition. RESULTS: Patients had significantly higher mean curvature and were impaired on 7 of 11 cognitive parameters. The between-group partial least squares correlation analysis revealed two cortical thickness/cognition patterns that differentiated patients and healthy control subjects (omnibus test, p = .011). Most cortical regions contributed reliably to these patterns. In patients, spatial working memory, spatial planning, reaction and movement times, and premorbid intelligence contributed reliably to the pattern; in healthy control subjects, spatial planning and intra-extradimensional set shifting contributed reliably. CONCLUSIONS: Antipsychotic-naive patients with first-episode schizophrenia displayed a higher mean curvature, but no significant difference in other gray matter indices was found. Nevertheless, the pattern of associations between global cortical thickness and cognitive functions was markedly different between groups. These multivariate analyses reveal a novel linkage between regional cortical brain structure and cognitive deficits at the earliest, never-medicated illness stage. PMID- 30420253 TI - Letter to the Editor on "Indications for MARS-MRI in Patients Treated With Articular Surface Replacement XL Total Hip Arthroplasty". PMID- 30420254 TI - Results of Prostate Cancer Screening in a Unique Cohort at 19yr of Follow-up. AB - We assessed the effect of screening in the European Randomized study of Screening for Prostate Cancer (ERSPC) Rotterdam pilot 1 study cohort with men randomized in 1991-1992. A total of 1134 men were randomized on a 1:1 basis to a screening (S) and control (C) arm after prostate-specific antigen (PSA) testing (PSA >=10.0ng/ml was excluded from randomization). Further PSA testing was offered to all men in the S-arm with 4-yr intervals starting at age 55yr and screened up to the age of 74yr. Overall, a PSA level of >=3.0ng/ml triggered biopsy. At time of analysis, 63% of men had died. Overall relative risk of metastatic (M+) disease and prostate cancer (PCa) death was 0.46 (95% confidence interval [CI]: 0.19 1.11) and 0.48 (95% CI: 0.17-1.36), respectively, in favor of screening. This ERSPC Rotterdam pilot 1 study cohort, screened in a period without noteworthy contamination, shows that PSA-based screening could result in considerable reductions of M+ disease and mortality which if confirmed in larger datasets should trigger further discussion on pros/cons of PCa screening. PATIENT SUMMARY: In a cohort with 19yr of follow-up, we found indications for a more substantial reduction in metastatic disease and cancer-specific mortality in favor of prostate cancer screening than previously reported. If confirmed in larger cohorts, these findings should be considered in the ongoing discussion on harms and benefits of prostate cancer screening. PMID- 30420255 TI - Comparative Effectiveness of Radical Prostatectomy Versus External Beam Radiation Therapy Plus Brachytherapy in Patients with High-risk Localized Prostate Cancer. AB - A previous study comparing external beam radiation therapy with/without brachytherapy (EBRT+/-BT) and radical prostatectomy (RP) for high-risk localized prostate cancer (PCa) did not find a difference in overall survival (OS) between the treatments. However, this study was limited by short follow-up and assessment of OS in patients of divergent age and comorbidities. We therefore compared OS of EBRT+BT versus RP in comparatively young (<=65yr) and healthy men (Charlson Comorbidity Index=0) with high-risk localized PCa in the National Cancer Database. Inverse probability of treatment weighting (IPTW) adjustment was used to balance baseline characteristics. Median follow-up was 92mo (interquartile range 78-108). Using IPTW-adjusted Cox regression analysis, EBRT+BT was associated with a higher risk of all-cause mortality compared with RP (hazard ratio=1.22, 95% confidence interval 1.05-1.43). In young and healthy men presenting with high-risk localized PCa, RP showed statistically significant OS benefit compared with EBRT+BT. PATIENT SUMMARY: In an analysis restricted to young and healthy men presenting with high-risk localized prostate cancer, initial radical prostatectomy is associated with an overall survival benefit compared with external beam radiation therapy plus brachytherapy. PMID- 30420256 TI - Cytoreductive Nephrectomy: Assessing the Generalizability of the CARMENA Trial to Real-world National Cancer Data Base Cases. PMID- 30420257 TI - Dexmedetomidine low dose followed by constant rate infusion and antagonism by atipamezole in isoflurane-anesthetized cats: an echocardiographic study. AB - OBJECTIVE: To investigate the effects of a low dose of dexmedetomidine (DEX) followed by constant rate infusion (CRI) and reversal with atipamezole on systolic and diastolic functions in isoflurane-anesthetized healthy cats. STUDY DESIGN: Prospective cohort study. ANIMALS: A group of 11 client-owned adult cats. METHODS: Baseline transthoracic echocardiography (TTE) was performed, followed by intramuscular (IM) administration of DEX (5 MUg kg-1). After 10 minutes, sedation was scored, adverse effects were recorded and another TTE performed. Approximately 40 minutes after DEX administration, anesthesia was induced by isoflurane mask and maintained with 1.2% end-tidal isoflurane and DEX CRI (1 MUg kg-1 hour-1) for 80 minutes. Physiological variables were recorded every 10 minutes, and TTE was repeated 10, 30 and 60 minutes after the start of anesthesia. CRI was stopped, atipamezole (30 MUg kg-1) was administered IM and a final TTE was performed after 10 minutes. Repeated measures over time were submitted to one-way analysis of variance or Kruskal-Wallis test according to data distribution; significance was assumed at p < 0.05. RESULTS: After DEX premedication, mild sedation and a slight but significant increase in systolic arterial pressure occurred, and vomiting was a common adverse effect. The cardiac output (CO) and heart rate decreased during anesthesia, with no changes after administration of atipamezole. Trivial valvular insufficiencies were commonly seen after DEX premedication and during CRI. Myocardial radial and longitudinal systolic functions were not affected by sedation or by anesthesia. The late phase of diastole on both right and left ventricles was affected by isoflurane-DEX CRI. Global left ventricular myocardial performance was not impaired. CONCLUSIONS: and clinical relevance Decreased CO and late diastolic impairment were observed in healthy cats administered a low dose of DEX for premedication followed by anesthesia with isoflurane and DEX CRI. PMID- 30420258 TI - Elevated urinary lipocalin-2, interleukin-6 and monocyte chemoattractant protein 1 levels in children with congenital ureteropelvic junction obstruction. AB - INTRODUCTION: In children with congenital ureteropelvic junction obstruction (UPJO), urinary biomarkers could assist in the diagnosis of renal damage or kidneys at risk for damage. Urinary levels of interleukin-6 (IL6), neutrophil gelatinase-associated lipocalin (LCN2), monocyte chemoattractant protein-1 (MCP1), and transforming growth factor-beta1 (TGFB1) proteins have been correlated with renal damage in several contexts. Whether they might be useful non-invasive biomarkers of obstructive nephropathy due to unilateral and bilateral congenital UPJO was tested. PATIENTS AND METHODS: A cohort study was performed at People's Hospital of Xinjiang Uygur Autonomous Region in China. Bladder urine samples from 17 patients with UPJO were obtained before surgical intervention and from 17 healthy age-matched controls. Levels of IL6, LCN2, MCP1, and TGFB1 were determined by enzyme-linked immunosorbent assay and normalized to urinary creatinine levels. RESULTS: Levels of urinary LCN2, MCP1, and IL6 were significantly elevated in the urine from individuals with UPJO compared with controls (P = 0.0003, P = 0.0003, and P = 0.0073, respectively). Children with bilateral UPJO (n = 5) showed significantly higher levels of IL6, LCN2, and MCP1 protein in their urine compared with controls or those with unilateral UPJO (n = 12; P = 0.007, P < 0.0001, and P = 0.0002, respectively). Combining LCN2 and MCP1 slightly improved biomarker performance. DISCUSSION: Urinary biomarkers could be used in obstructed patients to monitor for renal damage and might find particular utility on patients with bilateral UPJO. Monitoring urinary biomarkers and imaging features in untreated patients could provide insights into the natural history of renal damage due to obstruction and will be necessary to test their performance characteristics as biomarkers. CONCLUSIONS: Urinary levels of LCN2 and MCP1 protein are promising biomarkers monitoring children with UPJO, particularly in those with bilateral disease. PMID- 30420259 TI - Distinct cortical responses evoked by electrical stimulation of the thalamic ventral intermediate nucleus and of the subthalamic nucleus. AB - OBJECTIVE: To investigate the spatial and temporal pattern of cortical responses evoked by deep brain stimulation (DBS) of the subthalamic nucleus (STN) and ventral intermediate nucleus of the thalamus (VIM). METHODS: We investigated 7 patients suffering from Essential tremor (ET) and 7 patients with Parkinson's Disease (PD) following the implantation of DBS electrodes (VIM for ET patients, STN for PD patients). Magnetoencephalography (MEG) was used to record cortical responses evoked by electric stimuli that were applied via the DBS electrode in trains of 5 Hz. Dipole fitting was applied to reconstruct the origin of evoked responses. RESULTS: Both VIM and STN DBS led to short latency cortical responses at about 1 ms. The pattern of medium and long latency cortical responses following VIM DBS consisted of peaks at 13, 40, 77, and 116 ms. The associated equivalent dipoles were localized within the central sulcus, 3 patients showed an additional response in the cerebellum at 56 ms. STN DBS evoked cortical responses peaking at 4 ms, 11 ms, and 27 ms, respectively. While most dipoles were localized in the pre- or postcentral gyrus, the distribution was less homogenous compared to VIM stimulation and partially included prefrontal brain areas. CONCLUSION: MEG enables localization of cortical responses evoked by DBS of the VIM and the STN, especially in the sensorimotor cortex. Short latency responses of 1 ms suggest cortical modulation which bypasses synaptic transmission, i.e. antidromic activation of corticofugal fiber pathways. PMID- 30420260 TI - Non-synonymous genetic variants of flavin-containing monooxygenase 3 (FMO3) in cynomolgus macaques. AB - Polymorphic human flavin-containing monooxygenase (FMO) 3 is an important drug metabolizing enzyme for nitrogen- or sulfur-containing compounds. Cynomolgus macaques, a non-human primate species widely used in drug metabolism studies, have corresponding FMO3 molecular and enzymatic similarities to humans; however, genetic polymorphisms have not been investigated in macaques. In this study, re sequencing of FMO3 in 64 cynomolgus and 32 rhesus macaques found a total of 18 non-synonymous variants. Nine variants were unique to cynomolgus macaques, of which 4 (including Q506K) were found only in Indochinese, 4 (including V299I, E348H, and G530A) only in Indonesian lineages, and one was common. Other five variants (including S504T at >10% allele frequencies) were unique to rhesus macaques. By functional characterization using cynomolgus FMO3 proteins heterologously expressed in Escherichia coli, FMO3 R509H variant appeared to suppress methimazole and benzydamine S- or N-oxygenations. Seven variants showed substantially lower benzydamine N-oxygenation as compared with wild-type FMO3 protein. Further analysis indicated that two of these variants, FMO3 G530A and R417H, showed significantly lower benzydamine N-oxygenation in liver microsomes of the homozygotes as compared with wild-type animals. Therefore, inter-animal variability of FMO3-dependent drug metabolism is at least partly accounted for by genetic polymorphisms in cynomolgus and rhesus macaques, similar to humans. PMID- 30420261 TI - Outcomes After One Stage Versus Two Stage Open Repair of Type II Thoraco abdominal Aortic Aneurysms. AB - OBJECTIVE/BACKGROUND: This study compared the outcomes of open one stage with open two stage repair of type II thoraco-abdominal aortic aneurysms (TAAA). METHODS: This retrospective study included 94 patients (68 men) with a mean +/- SD age of 54.5 +/- 14 years who underwent open type II TAAA repair from March 2006 to January 2016. The mean aneurysm diameter was 65 +/- 14.4 mm. The median follow up was 42 months (range 12-96). Seventy-six patients received one stage open repair and 18 patients were treated in two steps: 12 received two open procedures (thoracic and abdominal) and six received hybrid repair (one open and one endovascular procedure). This study focused on the comparison of open one stage and open two stage TAAA repair. The median time between the two steps was 31.5 days (range 1-169). RESULTS: In hospital mortality after open one stage repair versus open two stage type II repair was 22.4% versus 0% (odds ratio 7.352, 95% confidence interval [CI] 0.884-959.1]; p = .19). The one year survival rate after one stage repair versus open two stage repair was 74.7% (95% CI 62.7 83.3) versus 90.9% (95% CI 50.8-98.7 [p = .225]). The five year survival rate after one stage repair versus open two stage repair was 53.0% (95% CI 37.2-66.5) versus 90.9% (95% CI 50.8-98.7 [p = .141]). The hazard ratio for survival after one stage repair and after open two stage repair was 4.563 (95% CI 96.9-81.4 [p = .137]). Paraplegia was observed after open one stage repair versus open two stage in 10.5% vs. 8% (p = 1). Acute kidney injury requiring permanent dialysis and myocardial infarction were assessed for after open one stage repair and open two stage and were seen in 3.9% vs. 0% (p = 1) and in 5.3% vs. 0% (p = 1), respectively. CONCLUSION: Open two stage repair may be recommended as a treatment option for type II TAAAs if anatomically feasible, as it has a lower mortality and similar complication rates to one stage repair. PMID- 30420262 TI - Transthoracic cholecystectomy following biliary pancreatitis arising from a thoracic herniated gallbladder. AB - Asymptomatic right diaphragmatic rupture with liver and gallbladder herniation and secondary Budd-Chiari syndrome is a rare complication of abdominal trauma. In this setting, the management of gallbladder stones remains poorly described and may require a thoracic approach. PMID- 30420263 TI - Changes in the composition of the upper respiratory tract microbial community in granulomatosis with polyangiitis. AB - Dysbiosis i.e. changes in microbial composition at a mucosal interface, is implicated in the pathogenesis of many chronic inflammatory and autoimmune diseases. To assess the composition of the microbial upper respiratory tract (URT) community in patients with granulomatosis with polyangiitis (GPA), we used culture-independent high-throughput methods. In this prospective clinical study, nasal swabs were collected from patients with GPA, patients with rheumatoid arthritis (RA, disease control), and healthy controls. Nasal bacterial taxa were assessed using V3-V4 region 16S rRNA amplicon sequencing. Staphylococcus aureus, Haemophilus influenza, and entero- and rhinoviruses were detected using qPCR. Unbiased metagenomic RNA sequencing (UMERS) was performed in a subset of samples to determine the relative abundance of bacterial, fungal, and viral species. A trend toward reduced microbiome diversity was detected in GPA samples compared with healthy controls. The abundance of bacterial taxa and microbial richness were significantly decreased in GPA samples compared with RA samples. The relative abundance of bacterial families shifted, with increased Planococcaceae and decreased Moraxellaceae, Tissierellaceae, Staphylococcaceae, and Propionibacteriaceae in GPA and RA. Further, decreased abundance of Corynebacteriaceae, and Aerococcaceae was observed in GPA samples. Significantly more colonization of S. aureus was seen in the nasal microbiome of GPA compared with RA and healthy control samples. H. influenzae colonization was also observed in GPA samples. UMERS detected the presence of rhinoviral sequences in some GPA samples. Thus, our study uncovered changes in the URT microbial composition in patients with GPA and RA, suggesting that both immunosuppression and disease background affect the URT microbiome. Complex alterations of host-microbiome interactions in the URT could influence chronic endonasal inflammation in GPA. PMID- 30420264 TI - Prognostic models in primary biliary cholangitis. AB - Risk prediction modelling is important to better understand the determinants of the course and outcome of PBC and to inform the risk across the disease continuum in PBC enabling risk-stratified follow-up care and personalised therapy. Current prognostic models in PBC are based on treatment response to ursodeoxycholic acid because of the well-established relationship between alkaline phosphatase on treatment and long-term outcome. In addition, serum alkaline phosphatase correlates with ductular reaction and biliary metaplasia, which are hallmark of biliary injury. Considering the waiting time for treatment failure in high-risk patients is not inconsequential, efforts are focused on bringing forward risk stratification at diagnosis by predicting treatment response at onset. There is a need for better prognostic variables that are central to the disease process. We should take an integrative approach that incorporates multiple layers of information including genetic and environmental influences, host characteristics, clinical data, and molecular alterations for risk assessments. Biomarker discovery has an accelerated pace taking advantage of the emergence of large scale omics platforms (genomics, epigenomics, transcriptomics, proteomics, metabolomics, and others) and whole-genome sequencing. In the digital era, applications of artificial intelligence, such as machine learning, can support the computing power required to analyse the vast amount of data produced by omics. The information is then used for the development of personalised risk prediction models that through clinical trials and hopefully industry partnerships can guide risk management strategies. We are facing an unprecedented opportunity for the integration of molecular diagnostics into the clinic, which promotes progress toward the personalised management of patients with PBC. PMID- 30420266 TI - Safety and efficacy of mechanical thrombectomy with stent-retrievers in anticoagulated patients with anterior circulation stroke. AB - AIM: To assess the safety and efficacy of mechanical thrombectomy (MT) with stent retrievers in anterior circulation stroke (ACS) patients due to the occlusion of major cerebral arteries, and to compare the results achieved in patients on oral anticoagulation (OAC) and those not on OAC. MATERIALS AND METHODS: The present retrospective study comprised 285 consecutive patients (115 males; mean age 74+/ 13 years). The following data were collected: baseline characteristics, occurrence of risk factors, pre-event treatment with OAC, neurological deficit at the time of treatment, time to therapy, recanalisation rate (successful recanalisation defined as Thrombolysis in Cerebral Infarction score >=2b), post treatment imaging findings. The 90-day clinical outcome was assessed using modified Rankin scale (good outcome defined as 0-2). RESULTS: The following statistically insignificant differences were found in 26 patients on OAC versus 259 patients without OAC: occurrence of symptomatic intracerebral haemorrhage 7.7% versus 8.1%, achievement of successful recanalisation 69.2% versus 82.6%, good 90-day clinical outcome 34.6% versus 56.8%, 90-day mortality 26.9% versus 20.8% (p>0.05 in all cases). Age and neurological deficit at the time of treatment were identified as independent negative predictors of good 90-day clinical outcome (odds ratio [OR]=0.90, 95% confidence interval [CI]: 0.88-0.94 and OR=0.83, 95% CI: 0.77-0.90, respectively) and as independent positive predictors of mortality (OR=1.12, 95% CI: 1.06-1.18 and, OR=1.17, 95% CI: 1.07 1.27, respectively; p<0.05 in all cases). CONCLUSIONS: MT with stent-retrievers is safe and effective in ACS patients on OAC. PMID- 30420265 TI - Managing diabetes and liver disease association. AB - There is strong association between liver diseases and diabetes (DM) which is higher than expected by a chance association of two very common disorders. It can be classified into three categories: Liver disease related to diabetes, hepatogenous diabetes (HD), and liver disease occurring coincidentally with DM. The criteria for the diagnosis of diabetes associating liver disease are the same for primary diabetes. Two hours post glucose load is a better screening test for HD. HbA1c may not be suitable for diagnosis or monitoring of diabetes associating advanced liver disease. Apart from the increased cardiovascular risk in patients with type 2 DM (T2 DM) and NAFLD, the cardiovascular and retinopathy risk is low in HD. Patients with metabolic derangement should be screened for NAFLD which in turn may predict T2 DM development. Similarly, patients with established T2 DM should also be screened for NAFLD which further contributes to diabetes worsening. Diabetes is a significant risk factor for progression of the chronic liver disease. It is associated with poor patient survival. Treatment of diabetes associating liver disease appears beneficial. Metformin, if tolerated and not contraindicated, is recommended as a first-line therapy for patients with diabetes and chronic liver disease (CLD). If the hepatic disease is severe, insulin secretagogues should be avoided because of the increased risk of hypoglycaemia. Pioglitazone may be useful in patients with fatty liver disease. DPP-4 inhibitors showed effectiveness and safety for the treatment of T2 DM in CLD patients up to those with child B stage. GLP-1 receptor agonists and SGLT-2 inhibitors exhibit positive effects on weight and are associated with minimal risk of hypoglycaemia. Insulin must be used with caution, as hypoglycaemia may be a problem. Insulin analogues are preferred in the context of hypoglycaemia Statins can be used to treat dyslipidaemia in NAFLD, also the use of angiotensin II receptor antagonist for hypertension is safe and beneficial Given the clear association between diabetes mellitus and hepatocellular carcinoma, the strict control of glycaemia with insulin sensitizers can be essential in its prevention. The addition of DM to the currently used scores (Child-Pugh and MELD scores) may enhance the sensitivity and the specificity for prediction of morbidity and mortality rates in cirrhotic patients. In the new era of directly acting antiviral agents (DAAs) for HCV treatment, it is recommended to follow up lipid profile and blood sugar levels following SVR in order to adjust doses of medications used in diabetic (SVR is associated with reduction in insulin requirements) and dyslipidaemic patients (rebound increase in the lipid profile after clearing the virus may increase risk of cardiovascular disease (CVD)). The issues of post liver transplant diabetes and relation between DM and chronic HBV are highlighted. This narrative review and Consensus-based practice guidance (under revision and criticism) are based on a formal review and analysis of the recently published world literature on the topic (Medline search up to September 2017); and the experience of the authors and independent reviewers. PMID- 30420267 TI - Targeted Sequencing of 10,198 Samples Confirms Abnormalities in Neuronal Activity and Implicates Voltage-Gated Sodium Channels in Schizophrenia Pathogenesis. AB - BACKGROUND: Sequencing studies have pointed to the involvement in schizophrenia of rare coding variants in neuronally expressed genes, including activity regulated cytoskeleton-associated protein (ARC) and N-methyl-D-aspartate receptor (NMDAR) complexes; however, larger samples are required to reveal novel genes and specific biological mechanisms. METHODS: We sequenced 187 genes, selected for prior evidence of association with schizophrenia, in a new dataset of 5207 cases and 4991 controls. Included among these genes were members of ARC and NMDAR postsynaptic protein complexes, as well as voltage-gated sodium and calcium channels. We performed a rare variant meta-analysis with published sequencing data for a total of 11,319 cases, 15,854 controls, and 1136 trios. RESULTS: While no individual gene was significantly associated with schizophrenia after genome wide correction for multiple testing, we strengthen the evidence that rare exonic variants in the ARC (p = 4.0 * 10-4) and NMDAR (p = 1.7 * 10-5) synaptic complexes are risk factors for schizophrenia. In addition, we found that loss-of function variants and missense variants at paralog-conserved sites were enriched in voltage-gated sodium channels, particularly the alpha subunits (p = 8.6 * 10 4). CONCLUSIONS: In one of the largest sequencing studies of schizophrenia to date, we provide novel evidence that multiple voltage-gated sodium channels are involved in schizophrenia pathogenesis and confirm the involvement of ARC and NMDAR postsynaptic complexes. PMID- 30420268 TI - The effect of adipose-derived mesenchymal stem cells and chondrocytes with platelet-rich fibrin releasates augmentation by intra-articular injection on acute osteochondral defects in a rabbit model. AB - BACKGROUND: This study aimed to investigate the efficacy of adipose-derived mesenchymal stem cells (ADSCs), platelet-rich fibrin releasates (PRFr), and chondrocyte transplantation in rabbit acute osteochondral defects. METHODS: Thirty rabbits were randomly assigned to five groups: untreated controls; ADSCs alone; PRFr alone; PRFr + ADSCs; and PRFr + chondrocytes. The critical size osteochondral defects in right knee femoral condyles were injected intra articularly according to the groups, as listed. The experimental rabbits received treatments once a week for two weeks postoperatively. All evaluations were conducted for 14 weeks following surgery, and the regenerated cartilages were assessed by gross inspection and histological examination. RESULTS: There were no complications encountered in any of the rabbits. The size of the defect decreased and the volume of repaired cartilage increased in the medial femoral condyles of the PRFr + ADSCs group. Relative to the ADSCs or PRFr group, histological examination demonstrated that the PRFr + ADSCs group had thicker hyaline cartilage-specific extracellular matrix. Grading scores revealed that PRFr + ADSCs injection had better matrix, cell distribution, and surface indices than other groups (P < 0.05). However, the histological scores reported for PRFr + chondrocytes on cartilage repair were similar to those of PRFr, and there were no significant between-group differences. CONCLUSIONS: These findings showed that intra-articular injections of PRFr + ADSCs into the knee can reduce cartilage defects by regenerating hyaline-like cartilage without complications. This approach may provide an alternative method for functional reconstruction of acute osteochondral defects with an unlimited source of cells and releasates. PMID- 30420269 TI - Identification of MPhi specific POTEE expression: Its role in mTORC2 activation via protein-protein interaction in TAMs. AB - POTE is known as cancer antigen, expressed in many cancers, along with very few normal tissues like prostate, ovary, testes and embryo. Till date, POTEE identified as majorly expressed POTE paralog. Functionally, POTEF regulates TLR signaling which play important role in innate immunity provided clue about expression of POTE in immune cells. We have chosen three Thp1monocytes, Jurkat T1 and MPhi cells as a model. Here, first time we report expression of POTEE in immune cells specifically only in MPhi but not in monocytes or T-cells. In addition, expression level remains unaltered in MPhi subtypes M1 and M2 and MPhi subjected to various stresses, except MPhis treated with Hyp-CM where MPhis acquires properties of TAMs. In TAMs, POTEE was involved differential protein protein interaction with mTOR, RICTOR, and Rad51 indicating its biological role in cell invasion through mTORC2 activation. siRNA mediated knockdown of POTEE suggests its importance in cell survival of MPhis as well as TAMs. PMID- 30420270 TI - Let's make pediatric physical therapy a true evidence-based field! Can we count on you? PMID- 30420272 TI - Bone regeneration after traumatic skull injury in Xenopus tropicalis. AB - The main purpose of regenerative biology is to improve human health by exploiting cellular and molecular mechanisms favoring tissue repair. In recent years, non mammalian vertebrates have emerged as powerful model organisms to tackle the problem of tissue regeneration. Here, we analyze the process of bone repair in metamorphosing Xenopus tropicalis tadpoles subjected to traumatic skull injury. Five days after skull perforation, a dense and highly vascularized mesenchymal is apparent over the injury site. Using an in vivo bone staining procedure based on independent pulses of Alizarin red and Calcein green, we show that the deposition of new bone matrix completely closes the wound in 15 days. The absence of cartilage implies that bone repair follows an intramembranous ossification route. Collagen second harmonic imaging reveals that while a well-organized lamellar type of bone is deposited during development, a woven type of bone is produced during the early-phase of the regeneration process. Osteoblasts lying against the regenerating bone robustly express fibrillar collagen 1a1, SPARC and Dlx5. These analyses establish Xenopus tropicalis as a new model system to improve traumatic skull injury recovery. PMID- 30420271 TI - PRaVDA: The first solid-state system for proton computed tomography. AB - PURPOSE: Proton CT is widely recognised as a beneficial alternative to conventional X-ray CT for treatment planning in proton beam radiotherapy. A novel proton CT imaging system, based entirely on solid-state detector technology, is presented. Compared to conventional scintillator-based calorimeters, positional sensitive detectors allow for multiple protons to be tracked per read out cycle, leading to a potential reduction in proton CT scan time. Design and characterisation of its components are discussed. An early proton CT image obtained with a fully solid-state imaging system is shown and accuracy (as defined in Section IV) in Relative Stopping Power to water (RSP) quantified. METHOD: A solid-state imaging system for proton CT, based on silicon strip detectors, has been developed by the PRaVDA collaboration. The system comprises a tracking system that infers individual proton trajectories through an imaging phantom, and a Range Telescope (RT) which records the corresponding residual energy (range) for each proton. A back-projection-then-filtering algorithm is used for CT reconstruction of an experimentally acquired proton CT scan. RESULTS: An initial experimental result for proton CT imaging with a fully solid-state system is shown for an imaging phantom, namely a 75 mm diameter PMMA sphere containing tissue substitute inserts, imaged with a passively-scattered 125 MeV beam. Accuracy in RSP is measured to be ?1.6% for all the inserts shown. CONCLUSIONS: A fully solid-state imaging system for proton CT has been shown capable of imaging a phantom with protons and successfully improving RSP accuracy. These promising results, together with system the capability to cope with high proton fluences (2*108 protons/s), suggests that this research platform could improve current standards in treatment planning for proton beam radiotherapy. PMID- 30420273 TI - Symbiotic bacteria associated with ascidian vanadium accumulation identified by 16S rRNA amplicon sequencing. AB - Ascidians belonging to Phlebobranchia accumulate vanadium to an extraordinary degree (<= 350 mM). Vanadium levels are strictly regulated and vary among ascidian species; thus, they represent well-suited models for studies on vanadium accumulation. No comprehensive study on metal accumulation and reduction in marine organisms in relation to their symbiotic bacterial communities has been published. Therefore, we performed comparative 16S rRNA amplicon sequence analyses on samples from three tissues (branchial sac, intestine, and intestinal lumen) involved in vanadium absorption, isolated from two vanadium-rich (Ascidia ahodori and Ascidia sydneiensis samea) and one vanadium-poor species (Styela plicata). For each sample, the abundance of every bacteria and an abundance value normalized to their abundance in seawater were calculated and compared. Two bacterial genera, Pseudomonas and Ralstonia, were extremely abundant in the branchial sacs of vanadium-rich ascidians. Two bacterial genera, Treponema and Borrelia, were abundant and enriched in the intestinal content of vanadium-rich ascidians. The results suggest that specific selective forces maintain the bacterial population in the three ascidian tissues examined, which contribute to successful vanadium accumulation. This study furthers the understanding of the relationship between bacterial communities and metal accumulation in marine life. PMID- 30420274 TI - Phospholipase C-beta1 interacts with cyclin E in adipose- derived stem cells osteogenic differentiation. AB - Adipose-derived stem cells (ADSCs) are multipotent mesenchymal stem cells that have the ability to differentiate into several cell types, including chondrocytes, osteoblasts, adipocytes, and neural cells. Given their easy accessibility and abundance, they became an attractive source of mesenchymal stem cells, as well as candidates for developing new treatments for reconstructive medicine and tissue engineering. Our study identifies a new signaling pathway that promotes ADSCs osteogenic differentiation and links the lipid signaling enzyme phospholipase C (PLC)-beta1 to the expression of the cell cycle protein cyclin E. During osteogenic differentiation, PLC-beta1 expression varies concomitantly with cyclin E expression and the two proteins interact. These findings contribute to clarify the pathways involved in osteogenic differentiation and provide evidence to develop therapeutic strategies for bone regeneration. PMID- 30420275 TI - Motives and merits of counterfactual histories of science. AB - I consider the motives of historians devising counterfactual histories, analyze the narrative structure of these histories, and assess their merits. Richard Evans attacked counterfactual histories as motivated by wishful thinking. And he claimed that they could not contribute anything to the understanding of the past because they are concerned "with pointing out supposedly preferable alternatives." Both claims can be refuted with two particular counterfactual histories of biology. An analysis of the narrative structure of counterfactual histories suggests objective criteria that can distinguish those that have been designed, in order to reach a certain narrative ending, from those that were open ended at the beginning. These criteria are then applied to two examples from the history of biology: Bowler's Darwin Deleted and Radick's 'Other Histories, Other Biologies.' Radick did not determine his counterfactual in advance, to meet a certain narrative ending. This refutes the first claim (wishful thinking). Bowler self-avowedly did design his counterfactual in advance, but its narrative ending still contributes to understanding. In particular, it shows that the idea of natural selection is not necessarily associated with its social discontents. This refutes the second claim (cannot contribute to understanding). PMID- 30420276 TI - [The role of genetics, pathology and immunology laboratories in the management of rare dermatological diseases]. PMID- 30420277 TI - [Specificities of occupational asthma in women and its interactions with hormonal status]. AB - BACKGROUND: Occupational asthma (OA) is described as the most common respiratory disease in industrialized countries. A female predominance characterizes many populations of asthmatic workers. Differences in occupational exposures by gender as well as hormonal variations could affect OA in women. PURPOSE: To identify the socio-occupational and medical characteristics of OA in women compared to men and to investigate a possible hormonal influence on OA in women. MATERIAL AND METHODS: This is a retrospective study, based on medical records of out patients of the Department of Occupational Medicine during the period between 1st January 2009 and 30 June 2016 for OA completed by a phone call to collect missing data. RESULTS: Over 222 cases of OA, a female predominance was noted (60.81%), which was predominantly in the textile sector (61.5%). Clinically, men had more exercise dyspnea and wheezing, whereas the association with rhinitis was significantly greater in women. The majority of women with asthma had irregular menstrual cycles (46.2%), they were multiparous in 54%, menopaused in 13% of cases with a mean age of menarche of 12+/-1.65 years. A worsening of OA was noted in 58% of women during their perimenstrual period, 75% during pregnancy and 14% of women when taking hormonal contraceptives. In asthmatic women, only the presence of non-specific bronchial hyperreactivity was significantly associated with menarche age (P=0.007). CONCLUSION: Differences between men and women in OA with variability of symptoms during female genital life have been identified. Further studies to personalized care strategies for women need to be undertaken. PMID- 30420278 TI - [Spontaneous pneumothorax and lung emphysema in cannabis users]. AB - INTRODUCTION: If pulmonary complications of tobacco smoking are well documented, those associated with cannabis use are less known. OBJECTIVES: Systematic literature review of data on pneumothorax and lung emphysema in cannabis users. DOCUMENTARY SOURCES: Medline, on the period 1980-2018 with the following keywords cannabis or marijuana and pneumothorax or emphysema, limits "title/abstract". Among 97 articles, 42 abstracts have given use to a dual reading to select 20 studies. RESULTS: Eighteen case reports (8 with SP) showed bullae in the upper lobes in combined cannabis and tobacco smokers (CS) and in the 2 cannabis only smokers (COS). The risk of SP was increased in CS, but not in COS. In patients less than 35-years old presenting with SP, the incidence of bullae on thoracic computed tomography (CT) was higher in CS than in tobacco only smokers (TOS). CT in patients with SP showed no significant difference as regards of the prevalence, location and type of emphysema between CS and TOS. Proportion of low lung density areas was higher in CS than in non-smokers (NS), but was similar in TOS and NS. CONCLUSION: These results suggest a cumulative toxic effect of tobacco and cannabis on the risk of SP and lung emphysema. PMID- 30420279 TI - Validation of a novel system for co-registration of coronary angiographic and intravascular ultrasound imaging. AB - INTRODUCTION: Intravascular ultrasound (IVUS) is a useful adjunct to guide percutaneous coronary intervention (PCI). Correlating IVUS images with angiographic findings can be challenging. We evaluated the utility of a novel co registration system for IVUS and coronary angiography. METHODS AND RESULTS: A 3-D virtual catheter trajectory was constructed from separate angiographic imaging runs using bespoke software. Intravascular ultrasound images were obtained using a commercially available mechanical rotational transducer with motorized pullback. Co-registration of ultrasound and angiographic images was then performed retrospectively based on the length of pullback, the 3-D trajectory and the start position of the catheter. Validation was performed in a spherical phantom model and in vivo in the coronary circulation of patients undergoing coronary angiography and intravascular imaging for clinical purposes. 111 paired angiographic and IVUS runs were performed in 3 phantom models. The differences between the reference length and the length measured on the 3D reconstructed path was -0.01 +/- 0.40 mm. Intra-observer variability was 0.4%. We enrolled 25 patients in 3 European hospitals and performed 35 co-registration attempts with an 86% success rate. 71 landmarks were selected by the first operator, 68 by the second. Differences between angiographic and IVUS landmarks were -0.22 +/- 0.72 mm and 0.05 +/- 1.01 mm, respectively. Inter-observer variability was 0.23 +/- 0.63 mm. CONCLUSION: We present a novel method for the co-registration of IVUS and coronary angiographic images. This system performed well in a phantom model and using images obtained from the human coronary circulation. CLASSIFICATIONS: Innovation, intravascular ultrasound, other technique. PMID- 30420280 TI - Analysis of genetic polymorphisms and mutations at 23 autosomal STR loci in Guangdong Han population. PMID- 30420281 TI - Haplotype data of 27 Y-STR loci in Hong Kong Chinese. PMID- 30420282 TI - Does Dual-Task Gait Differ in those with Late-Life Depression versus Mild Cognitive Impairment? AB - OBJECTIVES: To compare the dual-task gait performance of older adults with Late Life Depression (LLD) versus Mild Cognitive Impairment (MCI). DESIGN: Cross sectional study with three matched groups: LLD, MCI and non-depressed and cognitively intact (NDCI). SETTING: LLD group participants were recruited from geriatric psychiatry clinics in London, Ontario. Matched participants meeting criteria for the MCI or NDCI groups were previously recruited for other research studies from geriatric clinics and the community. PARTICIPANTS: Individuals aged 60-85 who met criteria for mild-moderate LLD (N=23) without a diagnosis of a neurocognitive disorder. MEASUREMENTS: Participants completed questionnaires regarding mood, cognition and physical activity. Gait speed was recorded using an electronic walkway during simple and dual-task gait (walking while naming animals aloud). Dual-task cost (DTC) is the percentage change in gait speed between simple and dual-task gait. It is a clinically relevant indicator of fall risk and is strongly associated with cognitive decline. For comparison, 23 MCI and 23 NDCI participants, matched with respect to age, sex and comorbidities, were randomly selected from existing research databases. RESULTS: Each group had 8 males and 15 females, with mean age of 69.0-69.6 years. The mean (+/-SD) DTC of the NDCI, LLD and MCI groups were statistically different at 2.4+/-11.4%, 11.8+/-9.9% and 22.2+/-16.7%, respectively. CONCLUSION: Older adults with LLD perform worse on dual-task gait than NDCI; however, they are less impaired than those with MCI. The elevated DTC seen in LLD is likely because of underlying executive dysfunction that is less significant than in those with MCI. PMID- 30420283 TI - Corrigendum to "Uncovering the underlying physical mechanism for cancer-immunity of MHC class I diversity". [Biochem. Biophys. Res. Commun. 504 (2018) 532-537. PMID- 30420284 TI - IL-10 gene-modified dendritic cells-induced type 1 T regulatory cells inhibit graft-versus-host disease while preserving graft-versus-leukemia effect. AB - To explore the role of type 1 regulatory T (Tr1) cells in allogeneic bone marrow transplantation (allo-BMT), we generated Tr1 cells from naive CD4+ T cells in donor mice that were subjected to stimulation of recipient interleukin (IL)-10 gene-modified dendritic cells (DCs). In animal models, the severity of graft versus-host disease (GVHD) in the group co-infused with DC-induced Tr1 cells was markedly milder than that in the groups without infusion of Tr1 cells. Moreover, the co-infusion Tr1 cells significantly prolonged the leukemia-free survival in tumor-bearing mice. Besides, Tr1-induced cells mediated the shift from T helper (Th)1 to Th2 cytokines in allo-BMT recipients. In Conclusions, our findings suggest that IL-10 gene-modified DC-induced Tr1 cells could inhibit GVHD while maintaining Graft-versus-leukemia (GVL) through mediating the shift of Th1/Th2 cytokines in an allo-BMT mice model. PMID- 30420286 TI - Feasibility of using colloidal gold immunochromatography for point-of-care identification of parathyroid glands during thyroidectomy. AB - AIM: To determine the feasibility of using colloidal gold immunochromatography for rapid identification of parathyroid glands during thyroidectomy. MATERIAL AND METHODS: 127 patients undergoing thyroidectomy were randomly divided into PTH ICGT group (64 cases) and conventional naked eye group (63 cases). The rate of identification of parathyroid glands and the incidence of hypoparathyroidism were compared between the two groups. RESULTS: PTH-CGI assay results showed that PTH concentration in the parathyroid tissue was (955.3 +/- 16.1) ng/L; skeletal muscle tissue [(14.5 +/- 1.5) ng/L], thyroid tissue [(15.0 +/- 1.3) ng/L], adipose tissue [(15.3 +/- 1.2) ng/L], lymph node tissue [(14.0 +/- 1.2) ng/L];PTH levels in parathyroid tissues were compared with PTH levels in skeletal muscle, thyroid, fat, and lymph node tissues, respectively. The differences were statistically significant(t values were 23.62, 33.42, 39.34, 30.77, P < 0.0001, respectively); Among the 127 patients undergoing total thyroidectomy, the rate of detection of parathyroid glands was 92.7% in the conventional naked eye group and 96.4% in the PTH-ICGT group. There was no significant difference in the detection rate of parathyroid gland between the two groups (chi2 = 0.7067, P = 0.40). The incidence of temporary hypoparathyroidism after surgery in both groups was 11.3% and 5.7%, respectively (chi2 = 1.093, P > 0.05). The incidence of postoperative permanent hypoparathyroidism in both groups was 3.8% and 0, respectively (Fisher's exact test, P = 0.495). CONCLUSION: PTH-CGI has a high efficiency in identifying parathyroid glands, which may increase the rate of clinical parathyroid detection and reduce the incidence of postoperative hypoparathyroidism. PMID- 30420285 TI - MUC1/KL-6 expression confers an aggressive phenotype upon myeloma cells. AB - The sialic glycoprotein, MUC1, is known to be involved in the pathogenesis of various types of cancers. KL-6 is one of the surface antigens of MUC1 and also a marker of interstitial pneumonitis. A fraction of patients with myeloma (3.9%) have elevated serum KL-6 levels without any evidence of interstitial pneumonitis and their myeloma cells have high MUC1 expression. We established a myeloma cell line designated EMM1 from a patient with multiple myeloma accompanied with elevated serum KL-6. EMM1 cells expressed high levels of MUC1 compared with other myeloma cell lines. Knockdown of MUC1 in EMM1 cells induced cell cycle arrest during S phase and apoptosis, suggesting that the MUC1 expression is involved in accelerated growth of EMM1 cells. RNA-seq analysis suggests that MUC1 expression activates k-ras and TNFalpha-induced NFkappaB pathways in EMM1 cells. We injected EMM1 cells subcutaneously into Rag2-/-Jak3-/- Balb/c mice to establish a mouse xenograft model. These mice had aggressive tumor growth that was accompanied by high serum KL-6 levels. In addition, MUC1 knockdown in EMM1 cells led to inhibited tumor growth. These findings demonstrate that MUC1 serves as a potential target for developing drugs for treatment of patients with KL-6+ myeloma, and EMM1 cells and EMM1-engrafted mice are useful tools for the development of such novel agents. PMID- 30420287 TI - Long noncoding RNA LSINCT5 acts as an oncogene via increasing EZH2-induced inhibition of APC expression in osteosarcoma. AB - Long noncoding RNAs (lncRNAs) are recognized as a class of critical regulators in various tumors. Recently, lncRNA LSINCT5 has been reported to promote the progression of bladder cancer, ovarian cancer, gastric cancer, and breast cancer. However, the biological function of LSINCT5 remains elusive in osteosarcoma (OS). In our study, we found that LSINCT5 was significantly upregulated in OS tissues than in adjacent normal tissues. Additionally, the expression of LSINCT5 was inversely associated with the prognosis of patients with OS. LSINCT5 knockdown dramatically inhibited OS cell proliferation in vitro and tumor growth in vivo. Mechanistic exploration revealed that LSINCT5 interacted with EZH2 to suppress the expression of APC, a negative regulator of the Wnt/beta-catenin pathway. Moreover, rescue assays suggested that LSINCT5 exerted oncogenic roles by partially inhibiting APC expression in OS. In summary, our study demonstrated that LSINCT5 was a promising candidate for OS prognosis and therapy. PMID- 30420288 TI - Intensive Versus Moderate Statin Therapy Discontinuation in Patients With Acute Ischemic Stroke or Transient Ischemic Attack. AB - PURPOSE: The differences of discontinuation risk between intensive and mild-to moderate statin therapy in patients with acute ischemic stroke is not clear. This study aimed to clarify whether intensive statin therapy resulted in a significant increase in discontinuation early after discharge. METHODS: This multicenter registry study enrolled consecutive hospitalized patients with ischemic stroke or transient ischemic attack. All the patients were prescribed statin therapy at discharge. Intensity of statin therapy was defined according to the 2013 American College of Cardiology/American Heart Association guideline on the treatment of blood cholesterol. A logistic regression model was used to analyze the association between statin therapy intensity and discontinuation. FINDINGS: This study included 505 patients, of whom 64 and 441 received intensive and moderate statin therapy, respectively (mean follow-up, approximately 6 months). The rates of discontinuation of intensive and moderate statin therapy were 31.3% and 10.7% (P < 0.001), respectively. Variables with significant differences between the intensive and moderate statin therapy groups were included in the adjusted logistic regression model. Intensive statin therapy significantly increased discontinuation risk by 273.0% (odds ratio = 3.730; 95% CI, 2.013-6.911; P < .001) compared with moderate statin therapy. The result was consistent in most subgroups, except for patients with National Institutes of Health Stroke Scale scores >=4. IMPLICATIONS: In stroke secondary prevention, intensive statin therapy may significantly increase the risk of early discontinuation compared with moderate statin therapy. Future clinical trials that involve a comparison between intensive and moderate statin therapy for stroke secondary prevention should address the differences in discontinuation between these 2 groups. PMID- 30420289 TI - Multiple-dose Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Oral LCB01-0371 in Healthy Male Volunteers. AB - PURPOSE: LCB01-0371 is a novel oxazolidinone broad-spectrum antibacterial that is more potent than linezolid against systemic infections in animals. The goal of this investigation was to evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of multiple-dose LCB01-0371 as well as the pharmacokinetic characteristics of a new 400-mg tablet formulation. METHODS: Thirty-two healthy male subjects received BID 400-1600 mg multiple oral dosing of LCB01-0371 (200-mg tablet or 400-mg tablet) for 7 days, and 6 subjects received an 800-mg single oral dose of LCB01-0371 (400-mg tablet). Safety assessments were undertaken at regular intervals. Blood and urine were sampled, and drug concentration and inhibitory and bactericidal titers were measured. FINDINGS: LCB01-0371 was generally safe and well tolerated up to 1200 mg BID for 7 days. Adverse events were mild, except for headache, nausea, and dizziness at the dose of 1600 mg, and resolved spontaneously. LCB01-0371 was absorbed rapidly within 2 h after administration, and its accumulation observed on day 7 ranged between 1.10- and 1.46-fold. The elimination t1/2 was 1.64-1.94 h, which remained unchanged across all doses. AUC0-12 and Cmax were not dose proportional across the dose range from 400 to 1200 mg after both single and multiple dosing, indicating a nonlinear pharmacokinetic profile. The percentage of the dose excreted via the urine ranged from 7.84% to 8.95%. The new (400-mg tablet) formulation exhibited less interindividual variability with pharmacokinetic characteristics similar to the original formulation (200-mg tablet). LCB01-0371 exhibited both early serum inhibitory and bactericidal activities against the 4 strains tested in the ex vivo pharmacodynamics study. IMPLICATIONS: BID doses of LCB01-0371 up to 1200 mg for 7 days were well tolerated and exhibited rapid serum inhibitory and bactericidal activities against common gram-positive pathogens. The results warrant further clinical investigation of the antibacterial effect of BID LCB01-0371 administration. ClinicalTrial.gov identifier: NCT01842516. PMID- 30420290 TI - Why Are We Still Creating Individual Case Safety Reports? AB - The history of drug safety monitoring, or pharmacovigilance, has been an interesting one. Despite many and ongoing changes, it has typically been characterized by a rather slow-moving and reactive progression. Pharmacovigilance has always lagged behind other fields and industries and has been slow to adapt to new approaches. The main aspect holding it back has been a focus on the administrative and adherence side of creating individual case safety reports (ICSRs) and distributing these reports to the various stakeholders per strict regulatory requirements. Now, in 2018, we are more behind the curve than ever, and the field seems to be at a breaking point, calling for urgent and drastic changes. The question at hand is whether in this era of an abundance of electronically available data and technological advancements, which allow the application of automation, this process still makes sense. Is there still a place for creating and redistributing ICSRs from marketed use in a current, state-of the-art safety system? Artificial intelligence, deep machine learning, and related technologies are already in place in many other industries. Swift and rigorous change is necessary for the discipline of pharmacovigilance to keep up with what is happening in the world at large. PMID- 30420291 TI - Evidence of muscle loss delay and improvement of hyperinsulinemia and insulin resistance in Duchenne muscular dystrophy supplemented with omega-3 fatty acids: A randomized study. AB - BACKGROUND & AIMS: Duchenne Muscular Dystrophy (DMD) is the most prevalent dystrophy of childhood and is characterized by generalized motor delays due to progressive muscular weakness, leading to loss of muscle mass. Additionally, patients with DMD develop obesity, hyperinsulinemia, and Insulin Resistance (IR). Omega-3 Long-Chain PolyUnsaturated Fatty Acids (Omega-3LCPUFA) increase fat mass, decrease lean mass, and decrease hyperinsulinemia and IR. The aim of this study was to analyze the impact of Omega-3LCPUFA consumption on lean mass, fat mass, hyperinsulinemia, and IR in children with DMD. METHODS: This placebo-controlled, double-blind, randomized study was carried out in 28 patients with DMD supplemented with 2.9 g/d of Omega-3LCPUFA (n = 14) or sunflower oil (placebo, n = 14) during 6 months. Serum glucose and insulin were measured at baseline and thereafter at months 3 and 6 of the intervention to estimate IR by HOmeostasis Model Assessment. Body composition was assessed by Dual Energy X-ray Absorptiometry. RESULTS: The percentage of change in EicosaPentaenoic Acid (EPA) and DocosaHexaenoic Acid (DHA) in erythrocytes was significantly (p < 0.05) higher in boys who consumed Omega-3LCPUFA than in the placebo group. Lean mass and fat mass (both in g/kg of Body Weight [BW]) had a trend toward being higher (p = 0.07 at month 3 and p = 0.085 at month 6) and lower (p = 0.05 at month 3 and p = 0.085 at month 6) respectively, in boys with DMD supplemented with Omega 3LCPUFA compared with the placebo group. The loss of lean mass was delayed in the Omega-3LCPUFA group; it started at month 6 but, in placebo, it started at month 3 of supplementation in comparison with the baseline of each group. Fasting insulin, percentage of boys with hyperinsulinemia, and IR were similar between the placebo and Omega-3LCPUFA groups during the 6 months of supplementation. The percentage of boys with IR was significantly (p = 0.045) lower at month 6 of supplementation in the Omega-3LCPUFA group than in the placebo group. CONCLUSION: This study suggests that Omega-3LCPUFA (2.9 g/day) intake during 6 months likely slows the progression of muscle loss, decreases the fat mass, and reduces IR in boys with DMD. The findings of this study provide scientific background for conducting a randomized trial focused of confirming the possible beneficial role of Omega-3LCPUFA on the previously mentioned alterations mentioned in boys with early muscle damage (without fibrosis) DMD. This research was registered at clinicaltrials.gov (NCT018264229). PMID- 30420292 TI - Transcriptomics and proteomics analyses of anti-cancer mechanisms of TR35-An active fraction from Xinjiang Bactrian camel milk in esophageal carcinoma cell. AB - BACKGROUND & AIMS: The aim of the paper is to investigate the effect of the active fraction extracted from the Xinjiang Bactrian camel whey on the human cancer cells using an in vitro and in vivo model of human carcinoma of the esophagus. METHODS AND RESULTS: Our results demonstrated that an antitumor active fraction, TR35, isolated from Xinjiang Bactrian camel milk could significantly inhibit Eca109 cell proliferation and induce its apoptosis (indicated by MTT assay, Annexin V-FITC Apoptosis Detection, and caspase-3 activity). Moreover, we found that TR35 could inhibit the growth of xenografted tumor in nude mice without loss in body weight. Furthermore, we used RNA-Seq and 2-DE combined Mass Spectrometry analysis to identify differentially expressed RNA and protein markers of apoptosis and necrosis. Compared with untreated Eca109 cells, a total of 405 differentially expressed genes and 55 differentially expressed proteins were identified in TR35 treated Eca109 cells. KEGG analysis uncovered signaling pathways closely associated with cancer inhibition that were enriched in the TR35 treated cells. CONCLUSIONS: These results might implicate that downregulation of specific proteins identified in this study may be the cause of this tumor growth inhibition. This study sheds light on the potential therapeutic advantages based on the historical anti-cancer activities of camel milk. PMID- 30420293 TI - "Strap up:" Sexual socialization and safer sex practices among African American youth in foster care. AB - Adolescent sexual health is often reflected through a problem-oriented lens. This serves to reinforce prevailing sexual scripts and cultural images of disenfranchised youth. Very little is known about the support young people in foster care, particularly youth of color, need to stay sexually healthy and safe. This article presents data on the sources and types of sexual socialization experiences that supported African American transitional age youth in foster care to protect against sexually transmitted infections (STIs) and human immunodeficiency virus (HIV). Eighteen African American participants (18 to 21 years old) who reported condom use in two quantitative interviews were selected to participate in a qualitative interview. A mapping exercise and thematic analyses were used to identify the participants' sources of support and sexual socialization experiences. The study's findings indicated the youth had a combination of informal and formal sources that conveyed four types of STI/HIV prevention messages: Effective, Affective, Affinity, & Tangible. The majority of the participants (83%) received all four types of STI/HIV prevention messages from adult, partner and/or peer sources. Sources who motivated the participants the most to protect against STIs/HIV had a strong relationship with the youth and communicated openly about safer sex practices. Results of this study provide implications for future research as well as indications for practice that may be incorporated into training for child welfare practitioners, foster parents, kinship caregivers, and others who encounter youth in foster care. PMID- 30420294 TI - Clinical outcomes after posterior cervical decompression and fusion surgery for destructive spondyloarthropathy in patients undergoing long-term hemodialysis: A matched case-control study. AB - BACKGROUND: Cervical destructive spondyloarthropathy (DSA) often leads to cervical myelopathy in long-term hemodialysis patients. However, the surgical outcomes after instrumented fusion surgery for cervical DSA are still unclear. The objective of this study was to investigate the clinical outcomes of cervical DSA in comparison with a control group. MATERIALS AND METHODS: A consecutive series of 20 undergoing long-term hemodialysis patients who underwent instrumented fusion surgery for cervical DSA between 2010 and 2016 were included in this study (DSA group). The mean age at surgery was 65 years, and there were 11 men and 9 women. The average length of hemodialysis was 23 years. The age- and sex-matched control group consisted of 20 patients (degenerative conditions). The Japanese Orthopedic Association (JOA) score, recovery rate, complications, and loss of correction of fused level were compared between the groups. RESULTS: Two of the 20 patients died due to perioperative complications. More than 1 year of follow-up data after surgery was available for 18 patients. The mean JOA score significantly increased from 5.4 before surgery to 9.7 at 1 year after surgery and 8.3 at the final follow-up (mean: 33.2 +/- 21.3 months, P = 0.019). There were no significant differences in the mean recovery rate (41% vs. 37%, P = 0.44) between the DSA group and control group. Loss of correction of more than 5 degrees was significantly higher in the DSA group (44% vs. 10%, P = 0.027). The rate of pseudarthrosis (17% vs. 5%, P = 0.328) and adjacent segment disease (22% vs. 10%, P = 0.17) tended to be higher in the DSA group. DISCUSSION: The clinical outcomes showed significant recovery in both groups. Therefore, posterior cervical decompression and fusion surgery was effective for treating cervical DSA. PMID- 30420295 TI - Introduction. PMID- 30420296 TI - Treatment of heritable diseases using CRISPR: Hopes, fears, and reality. AB - CRISPR gene editing is poised to transform the therapeutic landscape for diseases of genetic origin. The ease and agility by which CRISPR can make specific changes to DNA holds great promise not only for the treatment of heritable diseases, but also their prevention through germline editing. CRISPR-based therapeutic strategies are currently under development for numerous monogenic diseases. These strategies range from proof of concept studies demonstrating pre-fertilization gamete editing to recently initiated clinical trials for postnatal ex vivo therapies. The promise of CRISPR's human genome editing potential has captivated the public's attention. It is of paramount importance that medical professionals who work with patients who may have or carry a monogenic heritable disease understand CRISPR technology in order to have informed and compassionate discussions with their patients. Understanding CRISPR means understanding its evolving therapeutic applications' nuances, limitations, and barriers to access as well as the regulatory landscape they inhabit. In this piece we provide a review of the promises and pitfalls of CRISPR germline gene editing and their implications for patient decision-making throughout various stages of the reproductive process. PMID- 30420297 TI - Natural Variations in BRLF1 Promoter Contribute to the Elevated Reactivation Level of Epstein-Barr Virus in Endemic Areas of Nasopharyngeal Carcinoma. AB - BACKGROUND: Epstein-Barr virus (EBV) infection is a crucial risk factor for nasopharyngeal carcinoma (NPC), but the mechanism for its elevated activation level in NPC endemic areas remains unclear. This study aims to identify the EBV natural variations contributed to the different reactivation potential between NPC endemic and non-endemic areas. METHODS: 1030 subjects were recruited in China, including 303 healthy individuals from two NPC non-endemic areas, 483 healthy people from three endemic areas and 244 NPC patients. Among which, saliva DNA samples from 244 participants were sequenced for the EBV immediate early (IE) genes of BRLF1 and BZLF1, their promoters were included; the rest 786 subjects were used for the validation of significant variations among three different populations. Haplotype and population structure analysis were conducted. Dual luciferase assay was used to detect the promoter activity. RESULTS: A total of 246 distinct variations were detected, 29 showed significant difference in the frequencies between healthy people from NPC endemic area and non-endemic area. Population structure analysis clustered EBV strains into 9 subgroups mostly in accordance with the geographical origin of samples. Interestingly, two EBV genotypes, Rp-V1 and Rp-V2, were identified according to the linkage relationship of the variations in BRLF1 promoter (Rp). Rp-V1 has higher frequency in NPC endemic areas than in non-endemic areas (52.38% vs 18.15%, P = 2.07 * 10-14), and was associated with higher oral EBV DNA levels (adjusted OR = 1.64, 95% CI = 1.21 2.24, P = .002), suggesting a more powerful activation ability of Rp-V1 than that of the prototype Rp-of the EBV strain; On the contrary, Rp-V2 has higher frequency in NPC non-endemic areas than in endemic areas (18.48% vs 0.38%, P = 1.17 * 10-7), might represent a reduced activation potential of EBV. Further dual luciferase assay showed Rp-V1 has higher promoter activity while compared with Rp V2 (P < .0001). Notably, Rp-V1 impaired the transcription repression effect of YY1 while Rp-V2 strengthened the transcription repression effect of EBF1 on Rp. In addition, significant differences of Rta 393-407 CTL epitope which may influence the recognition of Rta by CD8+ T cells were detected between healthy people from NPC endemic area and non-endemic area. CONCLUSIONS: This study identified natural variations in cis-acting elements (YY1 and EBF1) of EBV Rp altering Rp transcription activities, which may contribute to the elevated EBV activation level in NPC endemic areas than non-endemic areas. PMID- 30420299 TI - Intensive genetic analysis for Chinese patients with very high triglyceride levels: Relations of mutations to triglyceride levels and acute pancreatitis. AB - BACKGROUND: Severe hypertriglyceridemia (SHTG, TG >=5.65 mmol/L), a disease, usually resulting from a combination of genetic and environmental factors, may increase the risk of acute pancreatitis (AP). However, previous genetic analysis has been limited by lacking of related observation of gene to AP. METHODS: The expanding genetic sequencing including 15 TG-related genes (LPL, LMF1, APOC2, GPIHBP1, GCKR, ANGPTL3, APOB, APOA1-A4-C3-A5, TRIB1, CETP, APOE, and LIPI) was performed within 103 patients who were diagnosed with primary SHTG and 46 age- and sex-matched normal controls. FINDINGS: Rare variants were found in 46 patients and 12 controls. The detection rate of rare variants in SHTG group increased by 19.5% via intensive genetic analysis. Presence of rare variants in LPL, APOA5, five LPL molecular regulating genes and all the sequenced genes were found to be associated with SHTG (p < 0.05). Of noted, patients with history of AP presented higher frequency of rare variants in LPL gene and all the LPL molecular regulating genes (27.8% vs.4.7% and 50.0% vs. 20.0%). The risk scores for SHTG determined by common TG-associated variants were increased in subgroups according to the extent of SHTG when they were compared with that of controls. Finally, patients without rare variants within SHTG group also presented higher risk scores than control group (p < 0.05). INTERPRETATION: Expanding genetic analysis had a higher detection rate of rare variants in patients with SHTG. Rare variants in LPL and its molecular regulating genes could increase the risk of AP among Chinese patients with SHTG. FUND: This work was partially supported by the Capital Health Development Fund (201614035) and CAMS. Major Collaborative Innovation Project (2016-I2M-1-011) awarded to Dr. Jian-Jun Li, MD, PhD. PMID- 30420298 TI - PPARgamma maintains the metabolic heterogeneity and homeostasis of renal tubules. AB - BACKGROUND: The renal tubules, which have distant metabolic features and functions in different segments, reabsorb >99% of approximately 180 l of water and 25,000 mmol of Na + daily. Defective metabolism in renal tubules is involved in the pathobiology of kidney diseases. However, the mechanisms underlying the metabolic regulation in renal tubules remain to be defined. METHODS: We quantitatively compared the proteomes of the isolated proximal tubules (PT) and distal tubules (DT) from C57BL/6 mouse using tandem mass tag (TMT) labeling-based quantitative mass spectrometry. Bioinformatics analysis of the differentially expressed proteins revealed the significant differences between PT and DT in metabolism pathway. We also performed in vitro and in vivo assays to investigate the molecular mechanism underlying the distant metabolic features in PT and DT. FINDINGS: We demonstrate that the renal proximal tubule (PT) has high expression of lipid metabolism enzymes, which is transcriptionally upregulated by abundantly expressed PPARalpha/gamma. In contrast, the renal distal tubule (DT) has elevated glycolytic enzyme expression, which is mediated by highly expressed c-Myc. Importantly, PPARgamma transcriptionally enhances the protease iRhom2 expression in PT, which suppresses EGF expression and secretion and subsequent EGFR dependent glycolytic gene expression and glycolysis. PPARgamma inhibition reduces iRhom2 expression and increases EGF and GLUT1 expression in PT in mice, resulting in renal tubule hypertrophy, tubulointerstitial fibrosis and damaged kidney functions, which are rescued by 2-deoxy-d-glucose treatment. INTERPRETATION: These findings delineate instrumental mechanisms underlying the active lipid metabolism and suppressed glycolysis in PT and active glycolysis in DT and reveal critical roles for PPARs and c-Myc in maintaining renal metabolic homeostasis. FUND: This work was supported by the National Natural Science Foundation of China (grants 81572076 and 81873932; to Q.Z.), the Applied Development Program of the Science and Technology Committee of Chongqing (cstc2014yykfB10003; Q.Z.), the Program of Populace Creativities Workshops of the Science and Technology Committee of Chongqing (Q.Z.), the special demonstration programs for innovation and application of techniques (cstc2018jscx-mszdX0022) from the Science and Technology Committee of Chongqing (Q.Z.). PMID- 30420300 TI - Elevated microRNA-141-3p in placenta of non-diabetic macrosomia regulate trophoblast proliferation. AB - BACKGROUND: Several studies have reported microRNAs (miRNAs) could regulate the placental development, though the role and mechanism of miRNAs in the development of non-diabetic macrosomia (NDFMS) remains unclear. METHODS: To identify the aberrantly expressed key miRNAs in placenta of NDFMS, we employed a strategy consisting of initial screening with miRNA microarray and further validation with quantitative RT-PCR assay (qRT-PCR). In vitro cellular model and a mouse pregnancy model were used to delineate the functional effects of key miRNA on proliferation, invasion, and migration. FINDINGS: miR-141-3p was identified as the key miRNA with expression level significantly higher in placentas of NDFMS compared with those from normal controls. Overexpressed miR-141-3p in HTR-8/SVneo cells contributed to increased cell proliferation, invasion, and migration. miR 141-3p inhibition in HTR-8/SVneo cells resulted in decreased cell proliferation and invasion. Significantly increased infant birth weight was observed in late pregnancy of C57BL/6J mice treated with miR-141-3p agomir. However, no significant difference was found in early pregnancy of C57BL/6J mice treated with miR-141-3p agomir. INTERPRETATION: miR-141-3p could stimulate placental cell proliferation to participate in the occurrence and development of NDFMS. PMID- 30420301 TI - Corrigendum to "TRPA1 inhibition ameliorates pressure overload-induced cardiac hypertrophy and fibrosis in mice" [EBioMedicine (2018) 54-62]. PMID- 30420302 TI - Cavitation inception of water with solid nanoparticles: A molecular dynamics study. AB - Cavitation in liquid with impurities is important in heterogeneous nucleation applications. One of the most widely existing kinds of impurities is solid particles, which can be found in natural water from rivers and specially prepared water such as nanofluids. Understanding the effects caused by the existence of nanoparticles on cavitation in water is vital to the rapidly developed nanotechnologies and medical researches. In this study, cavitation in water with nanoparticles is investigated through molecular dynamics simulations. The effects by nanoparticle materials and sizes on cavitation are discussed by using SiO2 and polyethylene spherical nanoparticles with different diameters. The nucleation rate and the formation of critical bubbles in cavitation are studied via the Voronoi tessellation and the mean first passage time methods. The hydrogen bond network in water is also analyzed. Results reveal that SiO?2 and polyethylene nanoparticles may destabilize the hydrogen bond network in water. With the same particle size, cavitation in water with polyethylene nanoparticles is promoted to a greater extent than that with SiO2 nanoparticles. With the same nanoparticle material, cavitation is promoted with the increase in particle size in a range spanning half to ten times the critical bubble radius. Beyond this range, particle size has little influence on cavitation. Reasons for those effects on cavitation due to the presence of solid nanoparticles are discussed by analysing the changes of hydrogen bonds network in water. PMID- 30420303 TI - Lung transplantation in a patient with Niemann-Pick disease. PMID- 30420304 TI - Delivering Midwifery: A Scoping Review of Employment Models in Canada. AB - The majority of Canadian Provinces have regulated and publicly funded midwifery. No comprehensive review has summarized and compared the various types of employment models, practice organizations, and compensation for midwives across Canada. The aim of this scoping review was to gain an understanding of evidence related to funding models, organization of practice models, and compensation for midwives. The Arksey and O'Malley five-stage framework for conducting scoping reviews guided our methodology. The constructs of interest for inquiry related to Canadian midwifery were the following: (1) employment models, (2) organization of practice, and (3) compensation. The study selection was an iterative search process. After duplicates were removed from both database and grey literature sources, a total of 1540 records were initially screened. After final screening was complete, a total of 111 records were included that contained content related to constructs of interest. Currently, midwifery services are publicly funded in Alberta, British Columbia, Manitoba, Ontario, Quebec, Nunavut, Nova Scotia, Northwest Territories, and Saskatchewan. The four types of employment models in which midwives work are private practice, private fee for service (deemed as course of care), course of care, and salaried. Compensation varies by province depending on the model of employment. This review of publicly available literature illustrates the range of employment, practice models, and compensation of regulated midwifery across Canada, as well as the evolution of the profession in the past 27 years. This type of information is relevant to inform health workforce planning for midwifery services across the country (Canadian Task Force Classification III). PMID- 30420305 TI - Postmenopausal Patient with Suprapubic Pain. PMID- 30420306 TI - Anisocoria from Cocaine Exposure: A Case Report. PMID- 30420307 TI - Hypothenar Hammer Syndrome. PMID- 30420308 TI - Acute Presentation and Management of the Encephalopathic Child With an Undiagnosed Inborn Error of Metabolism. AB - BACKGROUND: Inborn errors of metabolism (IEM) commonly present in infancy and, less commonly, later in life. CASE REPORT: This case describes an IEM, specifically, ornithine transcarbamylase deficiency, in a previously healthy 7 year-old boy who presented to an emergency department with vomiting for approximately 24 h prior to admission. The child became progressively encephalopathic while in the emergency department, but an ammonia level was not obtained until several hours after admission. Irreversible brain damage with cerebral edema was already present at time of diagnosis, leading to death. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case emphasizes that acute hyperammonemia can rapidly cause irreversible neurological damage and, in the case of a newly encephalopathic pediatric patient, ammonia levels should be evaluated early to facilitate proper diagnostic tests and treatment. PMID- 30420309 TI - A Cryptic Cause of Cardiac Arrest. AB - BACKGROUND: RIPPLY2-associated spondylocostal dysostosis is a rare disorder that leads to segmentation defects of the vertebrae. These vertebral defects can result in severe instability of the cervical spine, leading to cardiac arrest after only minor whiplash injury. CASE REPORT: We present the case of a healthy 7 year-old child who experienced an out-of-hospital cardiac arrest. He was reported to have profound respiratory distress and collapsed after going down a slide, without trauma. He was resuscitated in the field, and presented to the emergency department, where return of spontaneous circulation was achieved. Imaging of his cervical spine revealed multiple abnormalities. It was determined that a whiplash injury led to hypoxia and bradycardia due to the anatomic abnormalities of his cervical spine, resulting in cardiovascular collapse. He recovered fully and was later diagnosed with SCDO6, an autosomal recessive inherited disorder caused by a mutation in the RIPPLY2 gene. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Unfamiliarity of providers with this mechanism of cardiac arrest, and the rarity of the syndrome itself, make early recognition very difficult. Late diagnosis and lack of preventative measures, including immediate cervical spine stabilization, can lead to catastrophic outcomes. In patients with cardiac arrest of unclear etiology, early consideration of cervical spine immobilization and evaluation can be lifesaving. PMID- 30420310 TI - Silent Aortic Dissection after the Heimlich Maneuver: A Case Report. AB - BACKGROUND: The Heimlich maneuver is a simple and universal resuscitative procedure that is performed to relieve foreign-body airway obstruction. We present a case of silent Stanford type A aortic dissection, a rarely reported complication of the Heimlich maneuver. CASE REPORT: A 67-year-old male presented to the emergency department with left-sided hemiplegia shortly after receiving a Heimlich maneuver. Acute ischemic stroke was suspected, and the thrombolytic protocol was initiated. Fortunately, Stanford type A aortic dissection was diagnosed before the thrombolytic therapy was initiated. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Aortic dissection can develop after the Heimlich maneuver. For patients who develop a neurologic deficit after the Heimlich maneuver, vascular dissection should be considered as a possible cause. PMID- 30420311 TI - Chromatin condensation, fragmentation of DNA and differences in the epigenetic signature of infertile men. AB - Epidemiological studies report an increase of pathologies of male reproductive tracts and suggest a link between this trend and the increased exposure of men to endocrine disruptors (EDs). The mechanisms by which EDs impact male fertility are far to be elucidated although DNA, chromatin and epigenome of spermatozoa appear to be relevant targets for these molecules. Indeed, many studies report associations between increased levels of sperm DNA fragmentation (sDF) or aberrant chromatin condensation or epigenetic modifications and poor semen quality and/or infertile phenotype. In this scenario, therapies able to reduce sperm damage to DNA, chromatin and epigenome are sought. Currently, antioxidants and FSH administration is proposed for treating high levels of sDF, but whether or not such therapies are really effective is still debated. Further studies are necessary to understand the link between endocrine disruptor exposure and damage to sperm function and/or structure and thus to define effective therapeutic strategies. PMID- 30420312 TI - Nasally Inhaled Nitric Oxide for Sudden Right-Sided Heart Failure in the Intensive Care Unit: NO Time Like the Present. PMID- 30420313 TI - Intratracheal Milrinone for Acute Right Heart Dysfunction: Another Tool in the Pocket. PMID- 30420314 TI - Anesthetic and Procedural Considerations for Patients Undergoing Tricuspid Valve Replacement with NaviGate Valved Stent. PMID- 30420315 TI - Effect of Stride Management Assist Gait Training for Poststroke Hemiplegia: A Single Center, Open-Label, Randomized Controlled Trial. AB - BACKGROUND: Poststroke gait disorders negatively impact activities of daily living. Rehabilitation for stroke patients is aimed at improving their walking ability, balance, and quality of life. Robot-assisted gait training (RAGT) is associated with an increased number of task-specific exercises, which may benefit poststroke motor learning. We investigated the effects of RAGT using Stride Management Assist (SMA, which increases walk ratio by inducing hip-joint flexion and extension) in subacute stroke patients with hemiplegia. METHODS: We conducted a single center, open-label randomized controlled trial in hemiplegia patients who experienced a first ever stroke and were admitted to the convalescent rehabilitation ward. A total of 41 were divided into the control (20 patients) and experimental group (21 patients). A 10-day, conventional gait training program was carried out for the control group; and RAGT with SMA was used for the experimental group. The maximum walking speed and other gait parameters were compared preintervention and postintervention. The intergroup differences in the improvement ratio were compared using an intention-to-treat analysis. RESULTS: Ten-day intervention was completed by 36 patients. There was no difference between the 2 groups regarding gait parameters at intervention initiation. The improvement ratio of the maximum walking speed was significantly higher for the experimental group. Significant improvements were observed postintervention for maximum walking speed, paralysis-side step length, symmetry, and cadence in the experimental group. No adverse events attributable to the SMA were observed. CONCLUSIONS: Ten days of RAGT with the SMA was effective for improving gait disorders of subacute stroke patients. PMID- 30420316 TI - Aerobic Training Efficacy in Inflammation, Neurotrophins, and Function in Chronic Stroke Persons: A Randomized Controlled Trial Protocol. AB - BACKGROUND: Neuroinflammation is an important part of stroke pathophysiology and has both detrimental and beneficial effects after stroke. Besides that the enhancement of neurotrophins seems to be related to improvements in stroke recovery. Evidences suggest that exercise plays a role in modulating anti inflammatory and neurotrophic effects. However, little is known about its impact in stroke survivors, mainly in chronic stroke. The purpose of this study is to investigate the efficacy of moderate-intensity treadmill exercise in changing inflammatory mediators, interleukin-6 (IL-6), soluble tumor necrosis factor receptors I and II (sTNFRI, sTNFRII), interleukin-10 (IL-10), and brain-derived neurotrophic factor (BDNF) levels in chronic stroke patients. The secondary objective is to investigate the effects of training in improve mobility and exercise capacity. METHODS: This is a randomized controlled trial. Chronic stroke patients will be randomized to an experimental or control group, and will receive group interventions three times per week, over 12 weeks. The experimental group will receive moderate-intensity (60%-80% of maximum heart rate reserve) treadmill exercise. Control group will perform walking training on the ground (<40% of maximum heart rate reserve). Primary outcomes include IL-6, sTNFRI, sTNFRII, IL 10, and BDNF levels. Secondary outcomes include mobility and exercise capacity. Outcomes will be measured at baseline, postintervention, and at the 4-week follow up. DISCUSSION: The findings of this trial have the potential to provide important insights regarding the effects of an aerobic physical program in the inflammatory process and in the neuronal plasticity in stroke persons and its impact on mobility and exercise capacity. PMID- 30420317 TI - The Hippocratic Doctrine of "the Acute Brain Suffering" as the Brain Stroke. AB - BACKGROUND: The ancient Greek term "apoplexy" as is repeatedly mentioned by the Hippocratic School of Medicine, included a cluster of diseases, mainly those concerning the central nervous system. The term was wrongfully infiltrated in Western European medicine as synonymous to what is called today a "stroke" of the brain. OBJECTIVE: While in "Corpus Hippocraticum" the definition of the stroke was rather ambiguous; our study aims to unveil those fragments referring to it, in order to compose the Hippocratic theory of what it stood for "Acute Brain Suffering" (Greek: Omicronxiepsiloniotaepsilonsigma Omicrondeltaupsilonnuepsilonsigma tauomicronupsilon Epsilongammakappaepsilonphialphalambdaomicronupsilon) during the Classical era of ancient Greece. METHOD: A bibliographic research of the "Hippocratic Collection" was conducted during our study in order to connect all fragments from the original ancient Greek text, and reconstruct the "Hippocratic Stroke Theory". Three editions have been used as reference. French edition by Littre, and two Greek ones by Kaktos and Pournaropoulos. RESULTS: The "Acute Brain Suffering" seems to be the entity we call "Stroke" in modern clinical practice. Edema (collection of fluids-humours theory) was considered to be the most significant element which though could have been addressed by a cranial decompression for the symptoms to improve. The symptoms in question were, acute brain pain, diplopia, vertigo, ataxia, saliva, and urine loss as well as feces incontinence. CONCLUSION: Both therapeutic approach and symptomatology exhibited significant similarities with the modern concept of the stroke. The Hippocratic School was a scientifically advanced sect of medicophilosophers who promoted global medicine. PMID- 30420318 TI - Spanish Implantable Cardioverter-defibrillator Registry. 14th Official Report of the Spanish Society of Cardiology Electrophysiology and Arrhythmias Section (2017). AB - INTRODUCTION AND OBJECTIVES: The Spanish Automatic Defibrillator Registry has provided activity data since 2002. METHODS: The data in this registry are submitted by implantation centers that voluntarily complete a data collection sheet. RESULTS: During 2017, a total of 6273 implant sheets were received, compared with 6429 reported by Eucomed (European Confederation of Medical Suppliers Associations). Therefore, the registry contains data on 97.6% of the devices implanted in Spain. Compliance ranged from 99.7% for the field "name of the implanting hospital" to 46.1% for the variable "New York Heart Association functional class". A total of 181 hospitals reported data to the registry, representing an increase compared with the number of participating hospitals in 2016 (177) and in previous years (169 in 2015, 162 in 2014, 154 in 2013, and 153 in 2012). CONCLUSIONS: The number of implants per million inhabitants in Spain increased for several years but decreased in 2017. As in previous years, the total number of implants in Spain is still much lower than the European Union average, and the gap continues to widen. There are still substantial differences between autonomous communities. PMID- 30420319 TI - Alpha-fetoprotein screening in patients with hepatitis C-induced cirrhosis who achieved a sustained virologic response in the direct-acting antiviral agents era. PMID- 30420320 TI - Use of laparoscopic videos amongst surgical trainees in the United Kingdom. AB - BACKGROUND: Surgical trainers consider laparoscopic videos as a useful teaching aid to maximize trainees' learning and skill development given the backdrop of time constraints and productivity demands. Aim of this study is to assess the current use of laparoscopic videos amongst surgical trainees in the United Kingdom. METHODS: A steering committee of 15 experienced laparoscopic trainers from 8 countries developed a survey on the use of laparoscopic videos by surgical trainees. The survey items were finalized by discussion through e-mails, teleconferences, and face-to-face meetings and a finalised questionnaire was distributed amongst surgical trainees in the United Kingdom. RESULTS: 92 trainees were invited and 75 returned the questionnaire (81.5%). 86.7% of the trainees routinely watched online surgical videos and the more frequently used websites were Youtube.com and Websurg.com. Trainees require laparoscopic videos to have supplementary educational content such as English commentary (90.7%) and use of snapshots (93.3%) and diagrams (86.7%). Position of the patient and trocars, indication for surgery, preoperative data and postoperative outcomes are required characteristics of laparoscopic videos. 29 trainees (38.7%) do not record the laparoscopic procedures they perform, despite the majority of them recognising the usefulness of routine video-recording for training purposes (78.7%). CONCLUSIONS: Surgical trainees consider videos a useful adjunct in laparoscopic surgery training, with preference for open access sources. Trainees value highly informative videos with supplementary educational content. PMID- 30420321 TI - Endoscopic lateralization of the vocal fold. AB - Vocal fold paralysis in adduction can result in significant breathing difficulties. Techniques such as vocal fold lateralization and/or arytenoidopexy help to improve respiratory function in this setting. These techniques require open approach or specific instruments. The authors describe an original vocal fold lateralization technique performed exclusively via an endoscopic approach. This technique helps to enlarge the glottic aperture, while preserving laryngeal architecture, and permanently improves respiratory function in patients with vocal fold paralysis in adduction. PMID- 30420322 TI - Treatment completion, treatment compliance and outcomes of old and very old patients treated by dose adapted stereotactic ablative radiotherapy (SABR) for T1 T3N0M0 non-small cell lung cancer. AB - AIM: This is a retrospective single-institution review of the treatment completion and clinical outcomes of patients aged 75 and older, treated with stereotactic ablative body radiotherapy (SABR) for T1-T3 N0 M0 non-small cell lung cancer (NSCLC). MATERIAL: METHODS: From April 2008 to September 2015, 200 patients, aged 75-93, received respiratory-managed, intensity-modulated-based SABR. Dose fractionation was risk-adapted and delivered in 2-3 weekly treatments. Treatment completion, local control, overall survival and treatment-related toxicities were evaluated. RESULTS: All patients completed the prescribed SABR course. However, 29 patients required interruption of at least one fraction of SABR and optimization of pain control before continuation of the fraction. Median follow-up was 20.9 months. The median OS was 31.6 months with 1-,3-year survival rates of 80.7%, and 44.4% respectively. Local control at 1- and 3- years were 97.6%, 83.5% respectively. Treatment was well-tolerated. However, there were two (1%) G5 (fatal) toxicities: one acute sudden dyspnoea of unknown cause and one late SABR-related haemoptysis. No statistically significant differences in outcomes/toxicities were observed between old (75-84 years old) and very old patients (>85 years old). CONCLUSIONS: Old and very old patients can successfully complete SABR for NSCLC, with good local control, survival and acceptable toxicity. Old patients might require increased supportive care for successful treatment delivery. PMID- 30420323 TI - Performance of the Vulnerable Elders Survey 13 screening tool in identifying cancer treatment modification after geriatric assessment in pre-treatment patients: A retrospective analysis. AB - PURPOSE: Geriatric assessment (GA) is recommended for older adults >= 70 years with cancer to guide treatment selection. Screening tools such as the Vulnerable Elders Survey (VES-13) and G6 have been used to identify patients at highest need of GA. Whether either tool predicts a change in oncologic treatment following GA is unclear. METHODS: Patients attending a geriatric oncology clinic between July 2015 and June 2017 who completed a VES-13 and underwent subsequent GA were included. Clinical information was extracted from a prospectively maintained database. G6 scores were assigned retrospectively. Patients were stratified into those who were "VES-13 positive" (score >= 3) and "VES-13 negative" (score < 3). Logistic regression was used to explore the relationship between VES-13 score, G6 score, and treatment modification. RESULTS: Ninety-nine patients were seen prior to initiating cancer treatment. The median VES-13 score was 7; with 81.8% of patients scoring >=3. The treatment plan was modified in 47.5% of patients after GA. VES-13 score was predictive of treatment plan modification (63.0% among VES 13 positive versus 16.7% among VES-13 negative patients; p = 0.001). G6 performed similarly to the VES-13. The only statistically significant predictor of treatment change in multivariable analysis was performance status. CONCLUSION: VES-13 positive patients are more likely to undergo treatment modification to reduce treatment intensity or supportive care only. The VES-13 may provide oncologists with a rapid, reliable way of identifying vulnerability in older adults with cancer who may need further GA prior to commencing cancer treatment. PMID- 30420325 TI - Synthesis, DNA and protein interactions and human topoisomerase inhibition of novel Spiroacridine derivatives. AB - Nine new spiroacridine derivatives were synthetized by introducing cyano-N acylhydrazone group between the acridine and phenyl-substituted rings followed by spontaneous cyclization. The new compounds were assayed for their DNA binding properties, human topoisomerase IIalpha inhibition and bovine serum albumin (BSA) interaction. Besides, docking analysis were performed in order to better understanding the biomolecule-compounds interactions. All compounds interacted with BSA which was demonstrated by the fluorescence suppression constant of 104 M 1. Compounds with chloro and NO2 substituents at that para-position on phenyl ring demonstrated the best results for BSA interaction. DNA binding constant determined by UV-vis data demonstrated high values for AMTAC-11 and AMTAC-14, 1.1 * 108 M-1 and 4.8 * 106 M-1, respectively, and all others presented constant values of 105 M-1. AMTAC-06 with chloro at para-position on phenyl ring presented a topoisomerase II inhibition of 84.34% in comparison to the positive controls used. Docking studies indicated that AMTAC-06 is able to intercalate the DNA base pairs at topoisomerase IIalpha active site, preventing DNA connection after break, in a process known as poisoning. Topoisomerase enzyme inhibition result was correlated to BSA interaction profile, since AMTAC-06 showed the best results in both analysis. The findings obtained here proved that methoxy or chloro substitution on phenyl ring at para-position is fundamental for in vitro activity of new spiroacridine derivatives, and indicates that AMTAC-06 is a promising entity and should serve as a lead compound in the development of new DNA and protein binders, as well as human topoisomerase II inhibitors. PMID- 30420326 TI - Syntheses of prodrug-type 2'-O-methyldithiomethyl oligonucleotides modified at natural four nucleoside residues and their conversions into natural 2'-hydroxy oligonucleotides under reducing condition. AB - We previously reported that reducing-environment-responsive prodrug-type small interfering RNA (siRNA) bearing 2'-O-methyldithiomethyl (2'-O-MDTM) uridine exhibits efficient knockdown activity and nuclease resistance. In this report, we describe the preparation of 2'-O-MDTM oligonucleotides modified not only at uridine but also at adenosine, guanosine and cytidine residues by post-synthetic modification. Precursor oligonucleotides bearing 2'-O-(2,4,6 trimethoxybenzylthiomethyl) (2'-O-TMBTM) adenosine, guanosine, and cytidine were reacted with dimethyl(methylthio)sulfonium tetrafluoroborate to form 2'-O-MDTM oligonucleotides in the same manner as the oligonucleotide bearing 2'-O-TMBTM uridine. Furthermore, the oligonucleotides bearing 2'-O-MDTM adenosine, guanosine, and cytidine were efficiently converted into corresponding natural 2' hydroxy oligonucleotides under the cytosol-mimetic reducing condition. PMID- 30420327 TI - Synthetic construction of sugar-amino acid hybrid polymers involving globotriaose or lactose and evaluation of their biological activities against Shiga toxins produced by Escherichia coli O157:H7. AB - Synthetic assembly of sugar moieties and amino acids in order to create "sugar amino acid hybrid polymers" was accomplished by means of simple radical polymerization of carbohydrate monomers having an amino acid-modified polymerizable aglycon. Amines derived from globotriaoside and lactoside as glycoepitopes were condensed with known carbobenzyloxy derivatives, including Z Gly, Z-l-Ala and Z-beta-Ala, which had appropriate spacer ability and a chiral center to afford fully protected sugar-amino acid hybrid compounds in good yields. After deprotection followed by acryloylation, the water-soluble glycomonomers were polymerized with or without acrylamide in the presence of a radical initiator in water to give corresponding copolymers and homopolymers, which were shown by SEC analysis to have high molecular weights. Evaluation of the biological activities of the glycopolymers against Shiga toxins (Stxs) was carried out, and the results suggested that glycopolymers having highly clustered globotriaosyl residues had high affinity against Stx2 (KD = 2.7~4.0 uM) even though other glycopolymers did not show any affinity or showed very weak binding affinity. When Stx1 was used for the same assay, all of the glycopolymers having globotriaosyl residues showed high affinity (KD = 0.30~1.74 uM). Interestingly, couple of glycopolymers having lactosyl moieties had weaker binding affinity against Stx1. In addition, when cytotoxicity assays were carried out for both Stxs, glycopolymers having highly clustered globotriaosyl residues showed higher affinity than that of the copolymers, and only highly clustered-type glycopolymers displayed neutralization potency against Stx2. PMID- 30420328 TI - Lobaric acid and pseudodepsidones inhibit NF-kappaB signaling pathway by activation of PPAR-gamma. AB - Herein we report the anti-inflammatory activity of lobaric acid and pseudodepsidones isolated from the nordic lichen Stereocaulon paschale. Lobaric acid (1) and three compounds (2, 7 and 9) were found to inhibit the NF-kappaB activation and the secretion of pro-inflammatory cytokines (IL-1beta and TNF alpha) in LPS-stimulated macrophages. Inhibition and docking simulation experiments provided evidence that lobaric acid and pseudodepsidones bind to PPAR gamma between helix H3 and the beta sheet, similarly to partial PPAR-gamma agonists. These findings suggest that lobaric acid and pseudodepsidones reduce the expression of pro-inflammatory cytokines by blocking the NF-kappaB pathway via the activation of PPAR-gamma. PMID- 30420329 TI - Design and synthesis of boron containing monosaccharides by the hydroboration of d-glucal for use in boron neutron capture therapy (BNCT). AB - Boron neutron capture therapy (BNCT) is one of the radiotherapies that involves the use of boron-containing compounds for the treatment of cancer. Boron-10 (10B) containing compounds that can accumulate in tumor tissue are expected to be suitable agents for BNCT. We report herein on the design and synthesis of some new BNCT agents based on a d-glucose scaffold, since glycoconjugation has been recognized as a useful strategy for the specific targeting of tumors. To introduce a boryl group into a d-glucose scaffold, we focused on the hydroboration of d-glucal derivatives, which have a double bond between the C1 and C2 positions. It was hypothesized that a C-B bond could be introduced at the C2 position of d-glucose by the hydroboration of d-glucal derivatives and that the products could be stabilized by conversion to the corresponding boronic acid ester. To test this hypothesis, we prepared some 2-boryl-1,2-dideoxy-d-glucose derivatives as boron carriers and evaluated their cytotoxicity and cellular uptake activity to cancer cells, especially under hypoxic conditions. PMID- 30420330 TI - High copy number mutants derived from Corynebacterium glutamicum cryptic plasmid pAM330 and copy number control. AB - A high copy number mutant plasmid, designated pVC7H1, was isolated from an Escherichia coli-Corynebacterium glutamicum shuttle vector pVC7N derived from cryptic plasmid pAM330 that was originally found in Brevibacterium lactofermentum 2256 (formally C. glutamicum ATCC 13869). The copy number of pVC7N was estimated to be about 11 per chromosome, whereas pVC7H1 displayed a copy number of 112 per chromosome in C. glutamicum. The mutation (designated copA1) was in a region between long inverted repeats (designated the copA1 region) and was identified as a single base conversion of cytosine to adenine. By introduction of a cytosine to guanine mutation (designated copA2) at the same site as copA1, a further high copy number mutant (>300 copies of the plasmid per chromosome) was generated. Through genetic and RNA-Seq analyses of the copA1 region, it was determined that a small RNA (designated sRNA1) is produced from the upstream region of repA, a gene encoding a possible replication initiator protein, and sRNA1 is a possible regulator of the copy number of pAM330-replicon-contaning plasmids. Determination of the precise transcription start sites of sRNA1 and repA-mRNA suggested that sRNA1 could sequester a presumed ribosome binding site of repA-mRNA from ribosomes by an antisense RNA-mediated mechanism. Our data also indicate that the secondary-structure of sRNA1 is crucial for its function in plasmid copy number control. PMID- 30420324 TI - A randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis. AB - Calcineurin inhibitors added to standard-of-care induction therapy for lupus nephritis (LN) may increase complete renal remission (CRR) rates. The AURA-LV study tested the novel calcineurin inhibitor voclosporin for efficacy and safety in active LN. AURA-LV was a Phase 2, multicenter, randomized, double-blind, placebo-controlled trial of two doses of voclosporin (23.7 mg or 39.5 mg, each twice daily) versus placebo in combination with mycophenolate mofetil (2 g/d) and rapidly tapered low-dose oral corticosteroids for induction of remission in LN. The primary endpoint was CRR at 24 weeks; the secondary endpoint was CRR at 48 weeks. Two hundred sixty-five subjects from 79 centers in 20 countries were recruited and randomized to treatment for 48 weeks. CRR at week 24 was achieved by 29 (32.6%) subjects in the low-dose voclosporin group, 24 (27.3%) subjects in the high-dose voclosporin group, and 17 (19.3%) subjects in the placebo group (OR=2.03 for low-dose voclosporin versus placebo). The significantly greater CRR rate in the low-dose voclosporin group persisted at 48 weeks, and CRRs were also significantly more common in the high-dose voclosporin group compared to placebo at 48 weeks. There were more serious adverse events in both voclosporin groups, and more deaths in the low-dose group compared to placebo and high-dose voclosporin groups (11.2%, 1.1%, and 2.3%, respectively). These results suggest that the addition of low-dose voclosporin to mycophenolate mofetil and corticosteroids for induction therapy of active LN results in a superior renal response compared to mycophenolate mofetil and corticosteroids alone, but higher rates of adverse events including death were observed. PMID- 30420331 TI - Enriched microbial consortia for dark fermentation of sugarcane vinasse towards value-added short-chain organic acids and alcohol production. AB - The role of sugarcane vinasse as a nutrient source and the impacts of different inoculum pretreatment methods (acid-thermal and thermal treatment) were assessed in acidogenic systems aiming to produce value-added short-chain organic acids (SCOA) and alcohols. In-depth microbiome characterization was also conducted by high-throughput sequencing of the 16S rRNA gene using the Miseq Illumina platform. SCOA production was 47.3 % higher in vinasse-fed reactors, with isobutyric (up to 10.3 g L-1) and butyric (up to 10.6 g L-1) acids as the primary metabolites most likely resulting from lactate conversion. Ethanol comprised the main product from solventogenic pathways in all conditions, with values ranging between 2.7 and 5.2 g L-1, whereas no butanol was detected. Microbial analyses revealed high relative abundance values for the Clostridium, Lactobacillus, Bacillus and Ruminococcus genera, with the predominance of the Clostridium genus (17%) in acid-thermal treatment reactors and the Lactobacillus genus (37%) in thermal treatment reactors. Overall, vinasse proved to be a suitable substrate for value-added SCOA production, which characterizes a potential management approach to this wastewater stream. In this sense, the biochemical production of butyrate from vinasse could diversify the product portfolio of sugarcane biorefineries, also minimizing bioenergy losses by converting residual carbon fractions. PMID- 30420332 TI - Inhibition of nuclear thioredoxin aggregation attenuates PM2.5-induced NF-kappaB activation and pro-inflammatory responses. AB - Exposure to fine particulate matter (PM2.5) can induce oxidative stress and proinflammatory cytokine production, which are central for the induction of PM2.5 mediated adverse effects on public health. Nuclear factor kappa B (NF-kappaB) signaling is essential for inflammation. The subcellular distribution of thioredoxin (Trx) is related to the activation of NF-kappaB, but the mechanism involved is unclear. In the current study, we focused on the relationship between the antioxidant Trx and NF-kappaB in human bronchial epithelial cells (BEAS-2B) after PM2.5 exposure. We inhibited the nuclear translocation of Trx by cHCEU (4 cyclohexyl-[3-(2-chloroethyl)ureido]benzene) and subsequently increased the transcriptional activity of Nrf2 to upregulate the expression of Trx by t-BHQ. Our data suggest that PM2.5 exposure induces the activation of NF-kappaB and the expression of the downstream proinflammatory cytokines IL-1, IL-6, IL-8 and TNF alpha in BEAS-2B cells. CHCEU alleviates inflammatory cytokines by blocking Trx nuclear translocation and inhibits the DNA binding activity of NF-kappaB. T-BHQ could promote the transcriptional activity of Nrf2 but failed to alleviate the production of inflammatory cytokines. Furthermore, the synergistic effect of t BHQ and cHCEU on alleviating PM2.5-induced inflammation is more effective than the use of cHCEU alone. Our findings characterize the underlying molecular mechanisms of proinflammatory responses induced by PM2.5 and show that the nuclear translocation and accumulation of Trx in nuclei play important roles in PM2.5-induced NF-kappaB activation and proinflammatory responses. PMID- 30420333 TI - Microvscular networks with uniform flow. AB - Within animals, oxygen exchange occurs within vascular transport networks containing potentially billions of microvessels that are distributed throughout the body. By comparison, large blood vessels are theorized to minimize transport costs, leading to tree-like networks that satisfy Murray's law. We know very little about the principles underlying the organization of healthy micro-vascular networks. Indeed capillary networks must also perfuse tissues with oxygen, and efficient perfusion may be incompatible with minimization of transport costs. While networks that minimize transport costs have been well-studied, other optimization principles have received much less scrutiny. In this work we derive the morphology of networks that uniformize blood flow distribution, inspired by the zebrafish trunk micro-vascular network. To find uniform flow networks, we devise a gradient descent algorithm able to optimize arbitrary differentiable objective functions on transport networks, while exactly respecting arbitrary differentiable constraint functions. We prove that in a class of networks that we call stackable, which includes a model capillary bed, the uniform flow network will have the same flow as a uniform conductance network, i.e., in which all edges have the same conductance. This result agrees with uniform flow capillary bed network found by the algorithm. We also show that the uniform flow completely explains the observed radii within the zebrafish trunk vasculature. In addition to deriving new results on optimization of uniform flow in micro-vascular networks, our algorithm provides a general method for testing hypotheses about possible optimization principles underlying real microvascular networks, including exposing tradeoffs between flow uniformity and transport cost. PMID- 30420334 TI - Therapeutic potential of luteolin in transgenic Drosophila model of Alzheimer's disease. AB - A transgenic fly line expressing wild type human Abeta42 were exposed to luteolin mixed in diet at final concentration of 5, 10, 15 and 20MUM. The climbing assay, activity pattern, life span, aversive phototaxis suppression assay (APS) along with the estimation of protein carbonyl content (PCC), glutathione-S-transferase (GSTs) activity, glutathione (GSH) content, lipid peroxidation (LPO), acetylcholinesterase activity (AChE), superoxide dismutase (SOD) activity, catalase (CAT) activity, caspase 3 and 9 activities in the brain of treated as well as untreated AD flies (Positive control) were studied. Histopathology of Drosophila brain sections was done by performing thioflavin-S, Bielschowsky's silver staining and toluidine blue staining. A dose-dependent increase in the life span, delay in the loss of climbing ability as well as activity was observed in AD flies exposed to luteolin compared to unexposed AD flies. A dose-dependent reduction in LPO, PCC, GST, AChE, SOD, CAT, caspase 9 and caspase 3 activity and an increase in the GSH content was also observed. Histopathological examination of fly brains using thioflavin-S and silver staining has revealed a significant dose-dependent reduction in the expression of Abeta42 peptides in AD fly groups exposed to 10, 15 and 20MUM of luteolin. No gross morphological changes were observed in the brain sections of AD and control flies stained with toluidine blue. Molecular docking results have revealed that luteolin binds to AChE and Abeta42 at specific sites that might result in the inhibition of AChE and disaggregation/prevention of Abeta42 plaque formation. PMID- 30420336 TI - Methacycline displays a strong efficacy in reducing toxicity in a SCA3 Caenorhabditis elegans model. AB - BACKGROUND: We have previously demonstrated the neuroprotective activity of tetracycline on a Spinocerebellar Ataxia 3 nematode model. Here, we present the screening of a small library of tetracycline congeners in order to identify the most effective compound in preventing ataxin-3 aggregation. METHODS: We performed the assays on the Josephin Domain as it is directly involved in the onset of fibrillation. We used thioflavin T and solubility assays to spot out the most effective tetracycline congeners; Fourier transform infrared and NMR spectroscopies to characterize their mode of action. We employed an ataxic Caenorhabditis elegans model to evaluate the pharmacological efficacy of tetracycline congeners. RESULTS: Methacycline was identified as the most effective compound. Like tetracycline, methacycline neither significantly affected the aggregation kinetics nor did it change the secondary structures of the final aggregates but increased the solubility of the aggregated species. Saturation transfer NMR experiments demonstrated methacycline capability to only bind the oligomeric species of Josephin Domain. Competition assays also showed that methacycline binds to the Josephin Domain more tightly than tetracycline. The treatment with methacycline induced a significant improvement in motility and locomotion of the transgenic C. elegans without changing its lifespan. The efficacy was distinctly stronger than that of tetracycline. Noteworthy, unlike tetracycline, methacycline was able to retard aging-related decline in motility of even the healthy worms used. CONCLUSIONS: The apparent absence of toxic effects displayed by methacycline, along with its stronger efficacy in contrasting expanded ataxin-3 toxicity, makes it a possible candidate for a chronic treatment of the disease. PMID- 30420335 TI - A20-mediated deubiquitination of ERalpha in the microenvironment of CD163+ macrophages sensitizes endometrial cancer cells to estrogen. AB - Continuous estrogen signaling is thought to be the main mechanism causing endometrial cancer (EC). Studies have demonstrated that CD163+ macrophages could promote the development of estrogen-dependent EC, but the mechanisms involved remain unclear. We found that CD163+ macrophages were the dominant macrophages in atypical endometrial hyperplasia and cancer, and their infiltration was positively associated with ERalpha expression. CD163+ macrophages mainly increased ERalpha protein levels but with little upregulatory effect on ESR1 (ERalpha coding gene) transcripts. The ubiquitin-editing enzyme A20, screened from the endometrial microarray obtained from mice receiving a high-fat diet and sustained estrogen-intervened, was highly expressed in endometrial lesions rich with CD163+ macrophages, and positively correlated with ERalpha expression. Similarly, A20 and ERalpha were both upregulated by CD163+ macrophages via cytokines such as IL1alpha, IL17A and TNFalpha. Mechanistically, A20 overexpression in EC cells prolonged ERalpha protein half-life without affecting ESR1 transcripts. A20 increased functional ERalpha protein levels and enhanced estrogen-driven EC cell proliferation through preventing ERalpha protein degradation by its deubiquitinase activity. Our study revealed that A20-mediated deubiquitination of ERalpha might be an important mechanism by which CD163+ macrophages sensitize EC cells to estrogen. PMID- 30420337 TI - Improved heat resistance properties of poly(l-lactide)/basalt fiber biocomposites with high crystallinity under forming hybrid-crystalline morphology. AB - In this work, the heat resistance and thermomechanical properties of biodegradable poly(l-lactide) (PLLA) was improved greatly by using short basalt fibers (SBF). The heat deformation temperature (HDT) of PLLA/SBF composites was markedly improved from 62.5 to158.8 degrees C when its crystallinity was increased from 44.3% to 67.7% after appropriate thermal treatment. Fibers reinforcement and interface crystalline morphology were the two important reasons for the change of in heat deformation and storage modulus of PLLA before and after crystallization. Polarized optical microscopy (POM) demonstrated that the transcrystalline and shish-kebab were successfully induced by SBF, and the "crystalline-network" structure was formed in the composites after isothermal treatment. The PLLA/SBF composites with the formation of interface crystalline had a significantly higher overall heat resistance compared with the common PLLA. As the scanning electron microscope (SEM) analysis, the low values of impact strength might be due to the presence of large spherulites cracks and weak interfacial adhesion. PMID- 30420338 TI - Utilization of Pap testing among women living with HIV enrolled in primary care in Baltimore, Maryland: A 10-year longitudinal study, 2005-2014. AB - Frequent Pap testing is recommended among women living with HIV (WLWH) due to their elevated risk for cervical cancer. However, there are few recent longitudinal evaluations of utilization and determinants of Pap testing among WLWH. Medical and pathology records of WLWH seen at Johns Hopkins Hospital between 2005 and 2014 were assessed using Prentice, Williams, Peterson models. Of 554 WLWH in care for >= 18 months, 79% received Pap testing, however only 11% consistently received Pap testing at the recommended interval. Some women (5%) were consistently under-screened (tested at longer intervals) and 21% did not receive any Pap testing at during follow-up. WLWH with decreased likelihood of screening included older women, injection drug users, whites and those who had lived for longer with HIV. In contrast, only women with a prior abnormal Pap result were more likely to receive Pap testing. CD4 cell count and health insurance were not significant determinants. Although many WLWH in care received Pap testing, some WLWH were unscreened or underscreened. Determinants of Pap testing for WLWH include socio-demographic factors and a prior abnormal result; these present potential targets in an urban HIV care setting for closer monitoring and directed interventions to improve utilization among WLWH. PMID- 30420339 TI - Different kinetics of viral replication and DNA integration in the main HIV-1 cellular reservoirs in the presence and absence of integrase inhibitors. AB - To compare the kinetics of integration, p24 production and equilibrium of the different HIV-DNA forms in human primary cells in the presence/absence of integrase-inhibitors (INIs) in vitro. Monocyte-derived-macrophages (MDMs), CD4+ T cells and peripheral blood mononuclear cells (PBMCs) were infected with HIV-1 in the presence/absence of raltegravir and dolutegravir. HIV-DNA levels and p24 production were measured by qPCR and ELISA assays, respectively. In the absence of INIs, levels of HIV-DNA forms were initially very low, with an increase in the integration process starting at 3 dpi. HIV-DNA increased more slowly in MDMs than it did in CD4+ T-cells and PMBCs peaking at 21 dpi with a mean of 1580 (+/-890) and 615 (+/-37) copies/103 cells for proviral and unintegrated HIV-DNA, and 455,972 (+/-213,255) pg/mL of p24 at the same time point. In CD4+ T-cells the proviral HIV-DNA increased together with unintegrated HIV-DNA peaking at 7 dpi (583 +/- 261 and 338 +/- 254 copies/103 cells) when the p24 was 218,000 (+/ 75,600) pg/mL. A similar trend was observed in PBMCs (494 +/- 361 and 350 +/- 123 copies/103 cells for proviral and unintegrated HIV-DNA, and p24 production of 149,400 +/- 131,800 pg/mL). Both INIs inhibited viral replication and integration in all the cell types that were tested, especially starting at 3 dpi. However, a small but measurable amount of HIV-DNA (<5 copies/103 cells) was still observed in treated-MDMs up to 30 dpi. In conclusion, our study showed differences in HIV DNA kinetic integration between CD4+ T-cells and MDMs, which could explain the divergent kinetics of viral-replication. Both INIs inhibited HIV-1 integration and replication with no difference found between CD4+ T-cells and MDMs. However, residual HIV-DNA remained detectable up to 30 dpi in INI-treated MDMs although complete inhibition of HIV replication was achieved. The clinical significance of this minor DNA persistence deserves further investigation considering the role of macrophages as reservoirs. PMID- 30420340 TI - Next-Generation Sequencing in Autism Spectrum Disorder. AB - Autism spectrum disorder (ASD) is a common disorder that causes substantial distress. Heritability studies consistently show a strong genetic contribution, raising the hope that identifying ASD-associated genetic variants will offer insights into neurobiology and ultimately therapeutics. Next-generation sequencing (NGS) enabled the identification of disruptive variants throughout protein-coding regions of the genome. Alongside large cohorts and novel statistical methods, these NGS methods revolutionized ASD gene discovery. NGS methods have also contributed substantially to functional genetic data, such as gene expression, used to understand the neurobiological consequences of disrupting these ASD-associated genes. These functional data are also critical for annotating the noncoding genome as whole-genome sequencing (WGS) begins to provide initial insights outside of protein-coding regions. NGS methods still have a major role to play, as do similarly transformative advances in stem cell and gene-editing methods, in translating genetic discoveries into a first generation of ASD therapeutics. PMID- 30420341 TI - Comparing responses to differently framed and formatted persuasive messages to encourage help-seeking for depression in Japanese adults: a cross-sectional study with 2-month follow-up. AB - OBJECTIVE: To examine audience's responses to differently framed and formatted persuasive messages in the context of developing depression help-seeking messages. DESIGN: Cross-sectional followed by 2-month follow-up study. SETTING AND PARTICIPANTS: A web-based survey was conducted in July 2017 among Japanese adults aged 35-45 years. There were 1957 eligible respondents without psychiatric history. Of these, 1805 people (92.2%) completed the 2-month follow-up questionnaire. MAIN OUTCOME MEASURES: Six depression help-seeking messages were prepared with three frames (neutral, loss and gain framed)*2 formats (formatted and unformatted). Participants were asked to rate one of the messages in terms of comprehensibility, persuasiveness, emotional responses, design quality and intended future use. Help-seeking intention for depression was measured using vignette methodology before and after exposure to the messages. Subsequent 2 month help-seeking action for their own mental health (medical service use) was monitored by the follow-up survey. RESULTS: The loss-framed messages more strongly induced negative emotions (surprise, fear, sadness and anxiety), while the gain-framed messages more strongly induced a positive emotion (happiness). The message formatting applied the Centres for Disease Control and Prevention Clear Communication Index, enhanced the emotional responses and increased the likelihood that the message will be read. The loss-framed formatted message alone had a significantly greater OR of having help-seeking intention for depression compared with the neutral-framed unformatted message as a reference group. All messages had little impact on maintaining help-seeking intention or increasing help-seeking action. CONCLUSION: Message framing and formatting may influence emotional responses to the depression help-seeking message, willingness to read the message and intention to seek help for depression. It would be recommendable to apply loss framing and formatting to depression help-seeking messages, to say the least, but further studies are needed to find a way to sustain the effect of messaging for a long time. PMID- 30420342 TI - Living with disabling chronic pain: results from a face-to-face cross-sectional population-based study. AB - OBJECTIVES: To estimate the prevalence of disabling chronic pain (DCP) in Spanish adults, to analyse its characteristics, to determine its multimorbidity and to identify its associated factors. SETTINGS: 2011 Andalusian Health Survey, a cross sectional population survey based on face-to-face home interviews. PARTICIPANTS: 6507 people aged 16 years or older and living in Andalusia, Spain. OUTCOMES: The response variable was disabling chronic pain. Multivariate multinomial logistic regression models were used to analyse the association of factors with disabling chronic pain. The sample design was considered throughout the statistical analysis. RESULTS: The prevalence of disabling chronic pain in the Spanish adult population was 11.36% (95% CI 11.23 to 11.49), while that of non-disabling chronic pain was 5.67% (95% CI 5.57 to 5.77). Disabling chronic pain was associated with high multimorbidity (especially in women (51%) and in the elderly (70%) with three or more additional chronic diseases), as well as with disadvantaged social status (such as female gender (OR=2.12), advanced age (OR10 year increase=1.28), unemployment (OR=1.33), manual work (OR=1.26), low income (OR=1.14) and reduced emotional social support (OR=1.04)). Other influential factors were tobacco consumption (OR=1.42), sleeping <=7 hours (OR=1.2)], environmental or work conditions (OR=1.16) and quality of life (ORmental=1.21, ORphysical=2.37). CONCLUSIONS: The population with disabling chronic pain was associated with multimorbidity, vulnerable social status and an impaired quality of life. In contrast, the population with non-disabling chronic pain showed almost no differences when compared with the population without chronic pain. The association between DCP and mental disorders highlights the need for psychosocial services in the management of chronic pain. PMID- 30420343 TI - Sarcopenia as a predictor of all-cause mortality among older nursing home residents: a systematic review and meta-analysis. AB - OBJECTIVES: This study aims to review the evidence of sarcopenia as a predictor of all-cause mortality among nursing home residents. DESIGN: Systematic review and meta-analysis of observational cohort studies. DATA SOURCES: PubMed, EMBASE and the Cochrane Library databases were searched for relevant articles. PARTICIPANTS: Nursing home residents. PRIMARY AND SECONDARY OUTCOME MEASURES: All cause mortality. DATA ANALYSIS: Summary-adjusted HRs or risk ratios (RRs) were calculated by fixed-effects model. The risk of bias was assessed by Newcastle Ottawa Scale. RESULTS: Of 2292 studies identified through the systematic review, six studies (1494 participants) were included in the meta-analysis. Sarcopenia was significantly associated with a higher risk for all-cause mortality among nursing home residents (pooled HR 1.86, 95% CI 1.42 to 2.45, p<0.001, I2=0). In addition, the subgroup analysis demonstrated that sarcopenia was associated with all-cause mortality (pooled HR 1.87,95% CI 1.38 to 2.52, p<0.001) when studies with a follow-up period of 1 year or more were analysed; however, this was not found for studies with the follow-up period less than 1 year. Furthermore, sarcopenia was significantly associated with the risk of mortality among older nursing home residents when using bioelectrical impedance analysis to diagnosis muscle mass (pooled HR 1.88, 95% CI 1.39 to 2.53, p<0.001); whereas, it was not found when anthropometric measures were used to diagnosis muscle mass. CONCLUSION: Sarcopenia is a significant predictor of all-cause mortality among older nursing home residents. Therefore, it is important to diagnose and treat sarcopenia to reduce mortality rates among nursing home residents. PROSPERO REGISTRATION NUMBER: CRD42018081668. PMID- 30420344 TI - Effect of family practice contract services on the quality of primary care in Guangzhou, China: a cross-sectional study using PCAT-AE. AB - OBJECTIVE: Current healthcare reform in China has an overall goal of strengthening primary care and establishing a family practice system based on contract services. The objective of this study was to determine whether contracting a general practitioner (GP) could improve quality of primary care. DESIGN: A cross-sectional study using two-stage sampling conducted from June to September 2014. Propensity score matching (PSM) was employed to control for confounding between patients with and without contracted GP. SETTING: Three community health centres in Guangzhou, China. PARTICIPANTS: 698 patients aged 18 89 years. MAIN OUTCOME MEASURES: The quality of primary care was measured using a validated Chinese version of primary care assessment tool (PCAT). Eight domains are included (first contact utilisation, accessibility, continuity, comprehensiveness, coordination, family-centredness, community orientation and cultural competence from patient's perceptions). RESULTS: A total of 692 effective samples were included for data analysis. After PSM, 94 pairs of patients were matched between the patients with and without contracted GPs. The total PCAT score, continuity (3.12 vs 2.68, p<0.01), comprehensiveness (2.31 vs 2.04, p<0.01) and family-centredness (2.11 vs 1.79, p<0.01) were higher in patients who contracted GPs than those did not. However, the domains of first contact utilisation (2.74 vs 2.87, p=0.14) and coordination (1.76 vs 1.93, p<0.05) were lower among patients contracted with GPs than in those who did not. CONCLUSION: Our findings demonstrated that patients who had a contracted GP tend to experience higher quality of primary care. Our study provided evidence for health policies aiming to promote the implementation of family practice contract services. Our results also highlight further emphases on the features of primary care, first contact services and coordination services in particular. PMID- 30420345 TI - How well do national and local policies in England relevant to maternal and child health meet the international standard for non-communicable disease prevention? A policy analysis. AB - OBJECTIVES: (1) To identify national policies for England and local policies for Southampton City that are relevant to maternal and child health. (2) To quantify the extent to which these policies meet the international standards for nutrition and physical activity initiatives set out in the WHO Global Action Plan for the Prevention and Control of Non-Communicable Diseases (WHO Action Plan). DESIGN: The policy appraisal process involved three steps: (1) identifying policy documents relevant to maternal and infant health, (2) developing a policy appraisal framework from the WHO Action Plan, and (3) analysing the policies using the framework. SETTING: England and Southampton City. PARTICIPANTS: 57 national and 10 local policies. RESULTS: Across both national and local policies, priority areas supporting public health processes, such as evidence-based practice, were adopted more frequently than the action-oriented areas targeting maternal and child dietary and physical activity behaviours. However, the policy option managing conflicts of interest was rarely considered in the national policies (12%), particularly in white papers or evidence-based guidelines. For the action-oriented priority areas, maternal health policy options were more frequently considered than those related to child health or strengthening health systems. Complementary feeding guidance (9%) and workforce training in empowerment skills (14%) were the least frequent action-oriented policy options adopted among the national policies. The maternal nutrition-focused and workforce development policy options were least frequent among local policies adopted in 10% or fewer. Macroenvironmental policy options tended to have a lower priority than organisational or individual options among national policies (p=0.1) but had higher priority among local policies (p=0.02). CONCLUSIONS: Further action is needed to manage conflicts of interest and adopt policy options that promote a system-wide approach to address non-communicable diseases caused by poor diet and physical inactivity. PMID- 30420346 TI - Decision-making for people with dementia and advanced kidney disease: a secondary qualitative analysis of interviews from the Conservative Kidney Management Assessment of Practice Patterns Study. AB - OBJECTIVE: To explore dialysis decision-making for adults who lack capacity due to cognitive impairment, a common and under-recognised condition in those with advanced chronic kidney disease (CKD). DESIGN: Secondary analysis of qualitative data collected during the Conservative Kidney Management Assessment of Practice Patterns Study programme of research was performed. Sixty semistructured interviews were conducted with multiprofessional team members from UK renal centres. Staff were asked about local facilities, the value of conservative kidney management (CKM), when and with whom CKM was discussed and how CKM could be improved. Thematic analysis was employed to identify, characterise and report on themes that emerged from the data, focused on the specific issues experienced by people with dementia. SETTING: A purposive sample of nine UK renal centres differing in the scale of their CKM programmes. PARTICIPANTS: Clinical directors of renal centres identified staff involved in CKM. Staff were asked to participate if they had experience of low clearance clinics or of caring for patients with advanced CKD (estimated glomerular filtration rate <20mL/min/1.732 or >65 years with end-stage kidney disease). RESULTS: Two overarching themes were identified: factors taken into consideration during decision-making, and the process of decision-making itself. Comorbidity, social support, quality of life and the feasibility of dialysis were reported as factors pertinent to clinicians' decisions regarding suitability. The majority of renal centres practised multidisciplinary 'best interests' decision-making for those without capacity. Attitudes to advance care planning were divided. CONCLUSIONS: In view of the prevalence of cognitive impairment among those with advanced CKD, we suggest consideration of routine assessment of cognition and capacity. In the UK, dialysis is initiated and continued for individuals with dementia and services should be adapted to meet the needs of this population. PMID- 30420347 TI - Effects of a mindfulness-based intervention (MYmind) for children with ADHD and their parents: protocol for a randomised controlled trial. AB - INTRODUCTION: Mindfulness is one of the potential alternative interventions for children with attention-deficit hyperactivity disorder (ADHD). Some evidence suggests that mindfulness is related to changes in brain regions associated with ADHD. The potential benefits of mindfulness on children with ADHD, as well as the feasibility of this intervention approach, are warranted through prior local and foreign studies. This study aims to evaluate the effect of mindfulness-based group intervention for children with ADHD and their respective parents through a robust research design. METHODS AND ANALYSIS: This study will adopt a randomised controlled trial design including 140 children aged 8-12 years with ADHD together with one of their parents (n=140). These families will be randomised into intervention group (n=70) who will be offered the MYmind programme delivered by trained healthcare professionals, and an active control group (n=70) who will be offered the CBT programme. The intervention includes 8 weekly 90 min group sessions for children with ADHD (aged 8-12 years) and their respective parents. The primary and secondary outcomes will include children's attention, ADHD related symptoms, behaviours, executive function and mindfulness levels measured by validated objective measures and parent's reported instruments. Parents' parental stress, parenting styles, ADHD related symptoms, well-being, rumination level and mindfulness levels will also be measured. Analysis is by intention to treat. The effects of intervention will be evaluated by comparing outcomes between the two arms, as well as comparing outcomes within subject through comparing measurements at baseline (T0), immediately after the 8 week intervention (T1) and at 3 (T2) and 6 (T3) months postintervention. ETHICS AND DISSEMINATION: Ethics approval has been granted by the Joint Chinese University of Hong Kong - New Territories East Cluster Clinical Research Ethics Committee (The Joint CUHK-NTEC CREC). Participants will be required to sign informed consent form from both parents and children. Findings will be reported in conferences and peer-reviewed publications in accordance with recommendations of Consolidated Standards of Reporting Trials. TRIAL REGISTRATION NUMBER: ChiCTR1800014741; Pre-results. PMID- 30420348 TI - Is length of time in a stroke unit associated with better outcomes for patients with stroke in Australia? An observational study. AB - OBJECTIVE: Spending at least 90% of hospital admission in a stroke unit (SU) is a recommended indicator of receiving high-quality stroke care. However, whether this makes a difference to patient outcomes is unknown. We aimed to investigate outcomes and factors associated with patients with acute stroke spending at least 90% of their admission in an SU, compared with those having less time in the SU. DESIGN: Observational study using cross-sectional data. SETTING: Data from hospitals which participated in the 2015 Stroke Foundation National Audit: Acute Services (Australia) and had an SU. This audit includes an organisational survey and retrospective medical record audit of approximately 40 admissions from each hospital. PARTICIPANTS: Patients admitted to an SU during their acute admission were included. OUTCOME MEASURES: Hospital-based patient outcomes included length of stay, independence on discharge, severe complications and discharge destination. Patient, organisational and process indicators were included in multilevel logistic modelling to determine factors associated with spending at least 90% of their admission in an SU. RESULTS: Eighty-eight hospitals with an SU audited 2655 cases (median age 76 years, 55% male). Patients who spent at least 90% of their admission in an SU experienced: a length of stay that was 2 days shorter (coefficient -2.77, 95% CI -3.45 to -2.10), fewer severe complications (adjusted OR (aOR) 0.60, 95% CI 0.43 to 0.84) and were less often discharged to residential aged care (aOR 0.59, 95% CI 0.38 to 0.94) than those who had less time in the SU. Patients admitted to an SU within 3 hours of hospital arrival were three times more likely to spend at least 90% of their admission in an SU. CONCLUSION: Spending at least 90% of time in an SU is a valid measure of stroke care quality as it results in improved patient outcomes. Direct admission to SUs is warranted. PMID- 30420349 TI - Quality improvement collaborative aiming for Proactive HEAlthcare of Older People in Care Homes (PEACH): a realist evaluation protocol. AB - INTRODUCTION: This protocol describes a study of a quality improvement collaborative (QIC) to support implementation and delivery of comprehensive geriatric assessment (CGA) in UK care homes. The QIC will be formed of health and social care professionals working in and with care homes and will be supported by clinical, quality improvement and research specialists. QIC participants will receive quality improvement training using the Model for Improvement. An appreciative approach to working with care homes will be encouraged through facilitated shared learning events, quality improvement coaching and assistance with project evaluation. METHODS AND ANALYSIS: The QIC will be delivered across a range of partnering organisations which plan, deliver and evaluate health services for care home residents in four local areas of one geographical region. A realist evaluation framework will be used to develop a programme theory informing how QICs are thought to work, for whom and in what ways when used to implement and deliver CGA in care homes. Data collection will involve participant observations of the QIC over 18 months, and interviews/focus groups with QIC participants to iteratively define, refine, test or refute the programme theory. Two researchers will analyse field notes, and interview/focus group transcripts, coding data using inductive and deductive analysis. The key findings and linked programme theory will be summarised as context-mechanism-outcome configurations describing what needs to be in place to use QICs to implement service improvements in care homes. ETHICS AND DISSEMINATION: The study protocol was reviewed by the National Health Service Health Research Authority (London Bromley research ethics committee reference: 205840) and the University of Nottingham (reference: LT07092016) ethics committees. Both determined that the Proactive HEAlthcare of Older People in Care Homes study was a service and quality improvement initiative. Findings will be shared nationally and internationally through conference presentations, publication in peer-reviewed journals, a graphical illustration and a dissemination video. PMID- 30420350 TI - Is there a correlation between an eGFR slope measured over a 5-year period and incident cardiovascular events in the following 5 years among a Flemish general practice population: a retrospective cohort study. AB - OBJECTIVES: To examine if the estimated glomerular filtration rate (eGFR) slope over a 5-year period is related to incident cardiovascular (CV) events in the following 5 years. DESIGN: Retrospective cohort study. SETTING: Primary care. PARTICIPANTS: All patients aged >=50 years with at least four eGFR measurements between 01 January 2006 and 31 December 2010 were included in the study. OUTCOME MEASURES: During the follow-up period (01 January 2011 until 31 December 2015), CV events (acute myocardial infarction, stroke (cerebrovascular accident (CVA)/transient ischemic attack (TIA)), peripheral arterial disease and acute heart failure) were identified. METHODS: The slope was calculated by the least square method (in mL/min/year). The following slope categories were considered: ( 1 to 1), (-3 to -1) (-5 to -3), <=-5, (1 to 3), (3 to 5) and >=5.00 mL/min/year. Cox proportional hazards model was used to assess the association between eGFR slope and incidence of CV events. Survival probability from CV events was estimated per slope category. RESULTS: 19 567 patients had at least four eGFR measurements, of whom 52% was female. 12% of the <=-5 slope category developed a new CV event in comparison to 7.8% of the reference group and 5.4% of the >=5 slope category. Survival rates were worst in those with a slope <=-5. Patients with a slope of (-5 to -3) and <=-5 had an adjusted HR of 1.37 and 1.55, respectively. Most patients with a slope <-3 mL/min had an eGFR still >60 mL/min. CONCLUSIONS: Negative eGFR slopes of at least 3 mL/min/year give irrespectively of the eGFR itself a higher risk of CV events compared with patient groups with stable or improved kidney function. So the eGFR slope identifies an easy to define group of patients with a high risk for developing CV events. PMID- 30420351 TI - Qualitative cross-country comparison of whether, when and how people diagnosed with lung cancer talk about cigarette smoking in narrative interviews. AB - OBJECTIVES: To compare and examine whether, when and how patients with lung cancer in three countries, with different survival rates, talk about cigarette smoking and its relationship with help-seeking. DESIGN: A qualitative cross country comparison with analysis of narrative interviews. SETTING: Participants in Sweden, Denmark and England were interviewed during 2015-2016. Interviews, using a narrative approach, were conducted in participants' home by trained and experienced qualitative researchers. PARTICIPANTS: Seventy-two men and women diagnosed with lung cancer were interviewed within 6 months of their diagnosis. RESULTS: The English participants, regardless of their own smoking status, typically raised the topic of smoking early in their interviews. Smoking was mentioned in relation to symptom appraisal and interactions with others, including health professionals. Participants in all three countries interpreted their symptoms in relation to their smoking status, but in Sweden (unlike England) there was no suggestion that this deterred them from seeking care. English participants, but not Swedish or Danish, recounted reluctance to consult healthcare professionals with their symptoms while they were still smoking, some gave up shortly before consulting. Some English patients described defensive strategies to challenge stigma or pre-empt other people's assumptions about their culpability for the disease. A quarter of the Danish and 40% of the Swedish participants did not raise the topic of smoking at any point in their interview. CONCLUSION: The causal relationship between smoking and lung cancer is well known in all three countries, yet this comparative analysis suggests that the links between a sense of responsibility, stigma and reluctance to consult are not inevitable. These findings help illuminate why English patients with lung cancer tend to be diagnosed at a later stage than their Swedish counterparts. PMID- 30420352 TI - Quality of outpatient parenteral antimicrobial therapy (OPAT) care from the patient's perspective: a qualitative study. AB - OBJECTIVES: Current outpatient parenteral antimicrobial therapy (OPAT) guidelines recommend delivering patient-centred care. However, little is known about what patients define as good quality of OPAT care and what their needs and preferences are.The aim of this qualitative study is to explore the patients' perspective on high-quality care, and to explore what patient-centred care means to adult OPAT patients. DESIGN AND SETTING: This is an explorative, descriptive study using qualitative methods. We conducted focus group interviews with 16 adult patients (5 female, 11 male) from 3 different hospitals, who received OPAT and 2 individual semistructured interviews with their informal caregivers in the Netherlands. We used purposive sampling to ensure diversity of participants. We used the eight Picker principles of patient-centredness to guide data collection and analysis. RESULTS: Participants reported several elements considered as important for patient-centred OPAT care, like patient involvement in the decision making process, a responsible OPAT lead, intensive collaboration between all disciplines involved, information provision and adherence to hygiene guidelines. Two central dimensions emerged as essential constituents of patient-centred OPAT care: freedom and safety. Both are heavily influenced by the behaviours of healthcare professionals and by organisational aspects beyond the direct influence of these professionals. CONCLUSION: This study provides insights into the needs and preferences of adult patients who receive OPAT care. Future interventions directed at the improvement of patient-centredness of OPAT care should focus on elements that enhance patients' feelings of freedom and safety. PMID- 30420354 TI - US doctors react to criticism from National Rifle Association. PMID- 30420353 TI - Cost-effectiveness of a care manager collaborative care programme for patients with depression in primary care: economic evaluation of a pragmatic randomised controlled study. AB - OBJECTIVE: To evaluate the cost-effectiveness of a care manager (CM) programme compared with care as usual (CAU) for treatment of depression at primary care centres (PCCs) from a healthcare as well as societal perspective. DESIGN: Cost effectiveness analysis. SETTING: 23 PCCs in two Swedish regions. PARTICIPANTS: Patients with depression (n=342). MAIN OUTCOME MEASURES: A cost-effectiveness analysis was applied on a cluster randomised trial at PCC level where patients with depression had 3 months of contact with a CM (11 intervention PCCs, n=163) or CAU (12 control PCCs, n=179), with follow-up 3 and 6 months. Effectiveness measures were based on the number of depression-free days (DFDs) calculated from the Montgomery-Asberg Depression Rating Scale-Self and quality-adjusted life years (QALYs). Results were expressed as the incremental cost-effectiveness ratio: ?Cost/?QALY and ?Cost/?DFD. Sampling uncertainty was assessed based on non parametric bootstrapping. RESULTS: Health benefits were higher in intervention group compared with CAU group: QALYs (0.357 vs 0.333, p<0.001) and DFD reduction of depressive symptom score (79.43 vs 60.14, p<0.001). The mean costs per patient for the 6-month period were ?368 (healthcare perspective) and ?6217 (societal perspective) for the intervention patients and ?246 (healthcare perspective) and ?7371 (societal perspective) for the control patients (n.s.). The cost per QALY gained was ?6773 (healthcare perspective) and from a societal perspective the CM programme was dominant. DISCUSSION: The CM programme was associated with a gain in QALYs as well as in DFD, while also being cost saving compared with CAU from a societal perspective. This result is of high relevance for decision-makers on a national level, but it must be observed that a CM programme for depression implies increased costs at the primary care level. TRIAL REGISTRATION NUMBER: NCT02378272; Results. PMID- 30420355 TI - LC3 and STRAP regulate actin filament assembly by JMY during autophagosome formation. AB - During autophagy, actin filament networks move and remodel cellular membranes to form autophagosomes that enclose and metabolize cytoplasmic contents. Two actin regulators, WHAMM and JMY, participate in autophagosome formation, but the signals linking autophagy to actin assembly are poorly understood. We show that, in nonstarved cells, cytoplasmic JMY colocalizes with STRAP, a regulator of JMY's nuclear functions, on nonmotile vesicles with no associated actin networks. Upon starvation, JMY shifts to motile, LC3-containing membranes that move on actin comet tails. LC3 enhances JMY's de novo actin nucleation activity via a cryptic actin-binding sequence near JMY's N terminus, and STRAP inhibits JMY's ability to nucleate actin and activate the Arp2/3 complex. Cytoplasmic STRAP negatively regulates autophagy. Finally, we use purified proteins to reconstitute LC3- and JMY-dependent actin network formation on membranes and inhibition of network formation by STRAP. We conclude that LC3 and STRAP regulate JMY's actin assembly activities in trans during autophagy. PMID- 30420356 TI - Nuclear phosphatidylinositol 5-phosphatase is essential for allelic exclusion of variant surface glycoprotein genes in trypanosomes. AB - Allelic exclusion of variant surface glycoprotein (VSG) genes is essential for African trypanosomes to evade the host antibody response by antigenic variation. The mechanisms by which this parasite expresses only one of its ~2,000 VSG genes at a time are unknown. We show that nuclear phosphatidylinositol 5-phosphatase (PIP5Pase) interacts with repressor activator protein 1 (RAP1) in a multiprotein complex and function in the control of VSG allelic exclusion. RAP1 binds PIP5Pase substrate, PI(3,4,5)P3, and catalytic mutation of PIP5Pase that inhibits PI(3,4,5)P3 dephosphorylation results in simultaneous transcription of VSGs from all telomeric expression sites (ES) and from silent subtelomeric VSG arrays. PIP5Pase and RAP1 bind to telomeric ESs, especially at 70bp repeats and telomeres, and their binding is altered by PIP5Pase inactivation or knockdown implying changes in ES chromatin organization. Our data suggest a model whereby PIP5Pase controls PI(3,4,5)P3 binding by RAP1, and thus RAP1 silencing of telomeric and subtelomeric VSG genes. Allelic exclusion of VSG genes may hence entail control of nuclear phosphoinositides. PMID- 30420357 TI - Cancer associated eIF1A mutants impair Rps3 and Rps10 binding and enhance scanning of cell cycle genes. AB - Protein synthesis is linked to cell proliferation and its deregulation contributes to cancer. eIF1A plays a key role in scanning and AUG selection and differentially affects translation of distinct mRNAs. Its unstructured N-terminal tail (NTT) is frequently mutated in several malignancies. Here we report that eIF1A is essential for cell proliferation and cell-cycle progression. Ribosome profiling of eIF1A knockdown cells revealed a substantial enrichment of cell cycle mRNAs among the downregulated genes, which are predominantly characterized by lengthy 5'UTR. Conversely, eIF1A depletion caused a broad stimulation of 5'UTRs initiation at near-cognate AUG, unveiling a prominent role of eIF1A in suppressing 5'UTR translation. In addition, the AUG-context dependent auto regulation of eIF1 is disrupted by eIF1A depletion suggesting for their cooperation in AUG-context discrimination and scanning. Importantly, cancer associated eIF1A-NTT mutants augment eIF1A positive effect on long 5'UTR while hardly affecting AUG selection. Mechanistically, these mutations diminish eIF1A interaction with Rps3 and Rps10 implicated in scanning-arrest. Our findings suggest that reduced binding of eIF1A NTT mutants to the ribosome retains its open state and facilitate scanning of long 5'UTR-containing cell cycle genes. PMID- 30420358 TI - Research waste is still a scandal-an essay by Paul Glasziou and Iain Chalmers. PMID- 30420359 TI - Experimental evidence for re-secretion of PGE2 across rat alveolar epithelium by OATP2A1/SLCO2A1-mediated transcellular transport. AB - Prostaglandin transporter Oatp2a1/Slco2a1 is expressed at the apical (AP) membranes of type-1 alveolar epithelial (AT1) cells. To investigate the role of OATP2A1 in PGE2 handling by alveolar epithelium, we studied PGE2 transport across and secretion from monolayers of rat AT1-like (AT1-L) cells obtained by trans differentiation of type-2 alveolar epithelial cells (AT2) isolated from male Wistar rats. Rat AT1-L cells expressed Oatp2a1/Slco2a1, together with smaller amounts of Mrp4/Abcc4 and Oct1/Slc22a1 PGE2 uptake was saturable with Km 43.9 +/- 21.9 nM. Transcellular transport of PGE2 across AT1-L cells grown on permeable filters in the AP-to-basolateral (BL) direction was 5-fold greater than that in the reverse direction, and was saturable with Km 118 +/- 26.8 nM; it was significantly inhibited by OATP inhibitors, bromosulfophthalein (BSP) and suramin, and an MRP4 inhibitor, ceefourin-1. The effects of BSP on the distribution of PGE2 produced by bradykinin-treated AT1-L cells and PGE2-d4 externally added on the AP side of the cells were simultaneously monitored. In the presence of BSP, PGE2 increased more rapidly on the AP side, while PGE2-d4 decreased more slowly on the AP side. The decrease in PGE2-d4 from the AP side corresponded well to the increase on the BL side, indicating that intracellular metabolism did not occur. These results suggest that Oatp2a1 and Mrp4 mediate transepithelial transport of PGE2 in the AP-to-BL direction. Therefore, OATP2A1 may be an important regulator of PGE2 in alveolar epithelium by reducing secretion of PGE2 and facilitating "re-secreting" PGE2 present in the alveolar lumen to the interstitial space or blood. PMID- 30420360 TI - Convulsant effects of abused synthetic cannabinoids JWH-018 and 5F-AB-PINACA are mediated by agonist actions at CB1 receptors in mice. AB - Convulsant effects of abused synthetic cannabinoid (SCB) drugs have been reported in humans and laboratory animals, but the mechanism of these effects is not known. We compared convulsant effects of partial CB1R agonist ?9 tetrahydrocannabinol (THC), full CB1R agonist SCBs JWH-018 and 5F-AB-PINACA, and classical chemical convulsant pentylenetetrazol (PTZ) using an observational rating scale in mice. THC did not elicit convulsions, but both SCBs did so as effectively and more potently than PTZ. SCB-elicited convulsions were attenuated by the CB1R antagonist rimonabant or by THC, or by dose regimens of THC and JWH 018 which downregulate and desensitize CB1Rs. None of these treatments altered the convulsant effects of PTZ, although diazepam attenuated PTZ-elicited convulsions without altering SCB-induced convulsant effects. Repeated administration of a sub-threshold dose of PTZ kindled convulsant effects, but this was not observed with the SCBs, and no cross-kindling was observed. Repeated administration of the SCBs resulted in tolerance to convulsant effects, but no cross-tolerance to PTZ was observed. Inhibition on Phase I metabolism via non selective inhibition of CYP450s with 1-aminobenzotriazole (1-ABT) potentiated the hypothermic effects of the SCBs and protected against the convulsant effects of JWH-018, but not those of 5F-AB-PINACA or PTZ. Incubation of human liver microsomes with the SCBs showed that JWH-018 is eliminated via oxidation, while 5F-AB-PINACA is not. These studies suggest that SCB-elicited convulsions are mediated by high intrinsic efficacy at CB1Rs, and that benzodiazepines may not be effective treatments. Finally, drug metabolism may dramatically modulate the convulsant effects of some, but not all, SCBs. PMID- 30420361 TI - Colluding With the Decline of Continuity. PMID- 30420362 TI - Perspectives in Primary Care: Disseminating Scientific Findings in an Era of Fake News and Science Denial. PMID- 30420363 TI - Higher Primary Care Physician Continuity is Associated With Lower Costs and Hospitalizations. AB - PURPOSE: Continuity of care is a defining characteristic of primary care associated with lower costs and improved health equity and care quality. However, we lack provider-level measures of primary care continuity amenable to value based payment, including the Medicare Quality Payment Program (QPP). We created 4 physician-level, claims-based continuity measures and tested their associations with health care expenditures and hospitalizations. METHODS: We used Medicare claims data for 1,448,952 beneficiaries obtaining care from a nationally representative sample of 6,551 primary care physicians to calculate continuity scores by 4 established methods. Patient-level continuity scores attributed to a single physician were averaged to create physician-level scores. We used beneficiary multilevel models, including beneficiary controls, physician characteristics, and practice rurality to estimate associations with total Medicare Part A & B expenditures (allowed charges, logged), and any hospitalization. RESULTS: Our continuity measures were highly correlated (correlation coefficients ranged from 0.86 to 0.99), with greater continuity associated with similar outcomes for each. Adjusted expenditures for beneficiaries cared for by physicians in the highest Bice-Boxerman continuity score quintile were 14.1% lower than for those in the lowest quintile ($8,092 vs $6,958; beta = -0.151; 95% CI, -0.186 to -0.116), and the odds of hospitalization were 16.1% lower between the highest and lowest continuity quintiles (OR = 0.839; 95% CI, 0.787 to 0.893). CONCLUSIONS: All 4 continuity scores tested were significantly associated with lower total expenditures and hospitalization rates. Such indices are potentially useful as QPP measures, and may also serve as proxy resource-use measures, given the strength of association with lower costs and utilization. PMID- 30420364 TI - From Good to Great: The Role of Performance Coaching in Enhancing Tobacco Dependence Treatment Rates. AB - PURPOSE: The purpose of this study was to examine the incremental effect of performance coaching, delivered as part of a multicomponent intervention (Ottawa Model for Smoking Cessation [OMSC]), in increasing rates of tobacco-dependence treatment by primary care clinicians. METHODS: In a cluster-randomized controlled trial, 15 primary care practices were randomly assigned to 1 of the following active-treatment conditions: OMSC or OMSC plus performance coaching (OMSC+). All practices received support to implement the OMSC. In addition, clinicians in the OMSC+ group participated in a 1.5-hour skills-based coaching session and received an individualized performance report. All clinicians and a cross-sectional sample of their patients were surveyed before and 4 months after introduction of the interventions. The primary outcome measure was rates of tobacco-dependence treatment strategy (Ask, Advise, Assist, Arrange) delivery. Secondary outcomes were patient quit attempts and smoking abstinence measured at 6 months' follow up. RESULTS: Primary care clinicians (166) and patients (1,990) were enrolled in the trial. Clinicians in the OMSC+ group had statistically greater rates of delivery for Ask (adjusted odds ratio [AOR] = 1.69; 95% CI, 1.05-2.72), Assist (AOR = 1.64; 95% CI, 1.08-2.49), and Arrange (AOR = 2.01; 95% CI, 1.22-3.31). Sensitivity analysis found that the rate of delivery for Advise was greater only among those clinicians who attended the coaching session (AOR = 1.65; 95% CI, 1.10-2.49; P = .02). No differences were documented between groups for cessation outcomes. CONCLUSIONS: Performance coaching significantly increased rates of tobacco-dependence treatment by primary care clinicians when delivered as part of a multicomponent intervention. PMID- 30420365 TI - Prenatal Point-of-Care Tobacco Screening and Clinical Relationships. AB - PURPOSE: Up to one-third of female smokers with Medicaid deny tobacco use during pregnancy. Point-of-care urine tests for cotinine, a tobacco metabolite, can help to identify women who may benefit from cessation counseling. We sought to evaluate patient and clinician perspectives about using such tests during prenatal care to identify smokers, with particular focus on the impact of testing on clinical relationships and the potential for tobacco cessation. METHODS: We conducted 19 individual interviews and 4 focus groups with 40 pregnant or postpartum women covered by Medicaid who smoked before or during pregnancy. Patients also took the urine cotinine test and received sample results. Interviews were conducted with 20 health care practitioners. We analyzed the transcripts using an inductive approach and developed a model of how prenatal testing for cotinine could affect the patient-clinician relationship. RESULTS: Patients were more likely than clinicians to believe that testing could encourage discussions on tobacco cessation but emphasized that the clinician's approach to testing was critical. Clinicians feared that testing would negatively affect relationships. CONCLUSIONS: Despite having reservations, low-income patients had a surprisingly favorable view of using point-of-care urine testing to promote smoking cessation during pregnancy, which could increase the availability of cessation resources to women who do not disclose their tobacco use to clinicians. PMID- 30420366 TI - Legacy Drug-Prescribing Patterns in Primary Care. AB - PURPOSE: Polypharmacy is a key clinical challenge for primary care. Drugs that should be prescribed for an intermediate term (longer than 3 months, but not indefinitely) that are not appropriately discontinued could contribute to polypharmacy. We named this type of prescribing legacy prescribing. Commonly prescribed drugs with legacy prescribing potential include antidepressants, bisphosphonates, and proton pump inhibitors (PPIs). We evaluated the proportion of legacy prescribing within these drug classes. METHODS: We conducted a population-based retrospective cohort study using prospectively collected data from the McMaster University Sentinel and Information Collaboration (MUSIC) Primary Care Practice Based Research Network, located in Hamilton, Ontario. All adult patients (aged 18 or older) in the MUSIC data set during 2010-2016 were included (N = 50,813). We calculated rates of legacy prescribing of antidepressants (prescription longer than 15 months), bisphosphonates (longer than 5.5 years), and PPIs (longer than 15 months). RESULTS: The proportion of patients having a legacy prescription at some time during the study period was 46% (3,766 of 8,119) for antidepressants, 14% (228 of 1,592) for bisphosphonates, and 45% (2,885 of 6,414) for PPIs. Many of these patients held current prescriptions. The mean duration of prescribing for all legacy prescriptions was significantly longer than that for non-legacy prescriptions (P <.001). Concurrent legacy prescriptions for both antidepressants and PPIs was common, signaling a potential prescribing cascade. CONCLUSIONS: The phenomenon of legacy prescribing appears prevalent. These data demonstrate the potential of legacy prescribing to contribute to unnecessary polypharmacy, providing an opportunity for system-level intervention in primary care with enormous potential benefit for patients. PMID- 30420367 TI - Clinic-Based Patellar Mobilization Therapy for Knee Osteoarthritis: A Randomized Clinical Trial. AB - PURPOSE: We performed a phase 2 randomized clinical trial to evaluate the preliminary effectiveness of a clinic-based patellar mobilization therapy (PMT) in patients with knee osteoarthritis. METHODS: We recruited 208 patients with knee osteoarthritis at primary care clinics in Hong Kong. Patients were randomly assigned (1:1) to the intervention group or the control group. The intervention group received 3 PMT treatment sessions from primary care physicians at 2-month intervals, with concomitant prescription of a home-based vastus medialis oblique muscle exercise. The control group received PMT after the study period. The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score. Secondary outcomes included the WOMAC composite, function, and stiffness scores; the visual analog scale score for pain; objective physical function tests (30-s chair stand, 40-m walk test, timed up and go test, and EuroQol-5D). All outcomes were evaluated at baseline and at 24 weeks through intention-to-treat analysis. RESULTS: We observed no baseline between-group differences. The WOMAC pain score showed greater improvement in the intervention group than in the control group at 24 weeks (between-group difference - 15.6, 95% CI, - 20.5 to - 10.7, P <.001). All secondary outcomes also demonstrated significant between-group differences. CONCLUSIONS: Patellar mobilization therapy has the potential to reduce pain and improve function and quality of life for patients with knee osteoarthritis. Future clinical trials with comparison to other active comparator controls will help determine the overall efficacy and facilitate the deployment of PMT in real-world practice. PMID- 30420368 TI - Older Adults' Preferences for Discussing Long-Term Life Expectancy: Results From a National Survey. AB - PURPOSE: Clinical practice guidelines recommend incorporating long-term life expectancy to inform a number of decisions in primary care. We aimed to examine older adults' preferences for discussing life expectancy in a national sample. METHODS: We invited 1,272 older adults (aged 65 or older) from a national, probability-based online panel to participate in 2016. We presented a hypothetical patient with limited life expectancy who was not imminently dying. We asked participants if they were that patient, whether they would like to talk with the doctor about how long they may live, whether it was acceptable for the doctor to offer this discussion, whether they want the doctor to discuss life expectancy with family or friends, and when it should be discussed. RESULTS: The 878 participants (69.0% participation rate) had a mean age of 73.4 years. The majority, 59.4%, did not want to discuss how long they might live in the presented scenario. Within this group, 59.9% also did not think that the doctor should offer the discussion, and 87.7% also did not want the doctor to discuss life expectancy with family or friends. Fully 55.8% wanted to discuss life expectancy only if it were less than 2 years. Factors positively associated with wanting to have the discussion included higher educational level, believing that doctors can accurately predict life expectancy, and past experience with either a life-threatening illness or having discussed life expectancy of a loved one. Reporting that religion is important was negatively associated. CONCLUSIONS: The majority of older adults did not wish to discuss life expectancy when we depicted a hypothetical patient with limited life expectancy. Many also did not want to be offered discussion, raising a dilemma for how clinicians may identify patients' preferences regarding this sensitive topic. PMID- 30420369 TI - Factors Associated With Loss of Usual Source of Care Among Older Adults. AB - PURPOSE: Access to a usual source of care (USC) is associated with better preventive health and chronic disease treatment. Although most older adults have a USC, loss of USC, and factors associated with loss of USC, have not previously been examined. METHODS: We followed 7,609 participants of the National Health and Aging Trends Study annually for up to 6 years (2011-2016). Discrete time-to-event techniques and pooled logistic regression were used to identify demographic, clinical, and social factors associated with loss of USC. RESULTS: Ninety-five percent of older adults reported having a USC in 2011, of whom 5% subsequently did not. Odds of losing a USC were higher among older adults with unmet transportation needs (adjusted odds ratio [aOR] 1.67), who moved to a new residence (aOR 2.08), and who reported depressive symptoms (aOR 1.40). Odds of losing a USC were lower for those who had >=4 chronic conditions (vs 0-1; aOR 0.42) and with supplemental (aOR 0.52) or Medicaid (aOR 0.67) insurance coverage. CONCLUSIONS: We identified factors associated with older adults' loss of a USC. Potentially modifiable factors, such as access to transportation and supplemental insurance, deserve further investigation to potentially assist older adults with continuous access to care. PMID- 30420370 TI - Panel Size, Clinician Time in Clinic, and Access to Appointments. AB - Large panel sizes are often held responsible for worse access to appointments in primary care. We evaluated the relationship between appointment backlog, panel size, and primary care clinician time in clinic, using Spearman correlation and multiple regression in a retrospective analysis. We found no independent association between panel size and days until third next available appointment, but larger panel size adjusted for clinician time in clinic was associated with worse access. Less clinician time in clinic was independently associated with longer backlogs for appointments. Our findings suggest that patients of part-time clinicians may be less likely to obtain timely appointments than patients of fulltime clinicians, regardless of panel size. PMID- 30420371 TI - Access to Primary Care for Persons Recently Released From Prison. AB - We aimed to determine if a history of recent imprisonment affects access to primary care. Using patient roles, we telephoned to request an initial appointment with all family physicians (n = 339) who were accepting new patients in British Columbia, Canada. We sequentially assigned patient scenarios: male or female recently released from prison; male or female control. Controls were 1.98 (95% CI, 1.59-2.46) times as likely to be offered an appointment compared with persons recently released from prison, with an absolute risk difference of 41.8% (95% CI, 31.0-52.5). Our study suggests discrimination is a barrier to primary care for people released from prison, even with universal health insurance. We need to improve access to primary care during the high-risk period following prison release. PMID- 30420372 TI - Clinical Interpretation of Peripheral Pulse Oximeters Labeled "Not for Medical Use". AB - The purpose of our study was to clarify limitations of off-label use for low cost nonmedical use (NMU) pulse oximeters by primary care providers. These devices are widely marketed over the Internet and in drugstores but are not intended for medical use or reviewed by the Food and Drug Administration (FDA). Our study compared oxygen saturation (SpO2) in patients from 1 medical use (MU) pulse oximeter to 8 NMU pulse oximeters. Measured arterial oxygenation (SaO2) was compared with SpO2 when available. In patients who were normoxic (SpO2 >=90%), all oximeters exhibited similar readings. This finding suggests that NMU pulse oximeters may be able to rule out hypoxemia in clinical settings. PMID- 30420373 TI - Primary Care Clinicians' Willingness to Care for Transgender Patients. AB - Transgender patients report negative experiences in health care settings, but little is known about clinicians' willingness to see transgender patients. We surveyed 308 primary care clinicians in an integrated Midwest health system and 53% responded. Most respondents were willing to provide routine care to transgender patients (85.7%) and Papanicolaou (Pap) tests (78.6%) to transgender men. Willingness to provide routine care decreased with age; willingness to provide Pap tests was higher among family physicians, those who had met a transgender person, and those with lower transphobia. Medical education should address professional and personal factors related to caring for the transgender population to increase access. PMID- 30420374 TI - Communicating With Patients Who Have Nonbinary Gender Identities. AB - The increasing visibility of transgender people and others who do not conform to traditional gender norms challenges us to think about gender in new ways, and to use new terminology when communicating with patients. People who describe themselves as nonbinary have a gender identity that is not exclusively girl/woman or boy/man. A small but growing body of research indicates they experience high levels of societal victimization and discrimination, and are misunderstood by health care clinicians. Using language that is inclusive of all gender identities can reduce these burdens and barriers. In this essay, we use a case scenario that illustrates ways to interact respectfully and affirmatively with nonbinary people throughout the patient care experience. PMID- 30420375 TI - The Gift of Empanelment in a "Clinic First" Residency. AB - Empanelment in a "clinic first" residency has helped me develop competency in medicine and understand the value of primary care. Taking care of a panel of patients longitudinally aligns with education research on how we best learn; we learn best when learning sessions are longitudinal, spaced in time and interleaved with diverse topics. By caring for patients longitudinally, I have developed competency and proficiency in providing comprehensive care to my patients. Empanelment has also allowed me, as a resident, to build relationships with my patients and realize the value of primary care. To build the primary care workforce of the future, I have no doubt every resident needs to have this type of rewarding experience in their clinics. PMID- 30420376 TI - A Health Systems Genogram for Improving Hospital Transitions to Primary Care. PMID- 30420377 TI - STFM BEGINS UPDATE OF ITS STRATEGIC PLAN. PMID- 30420378 TI - ALTERNATIVE PAYMENT MODELS IN DEPARTMENTS OF FAMILY MEDICINE: OUR JOURNEY TOWARD THE QUADRUPLE AIM. PMID- 30420380 TI - NAPCRG ANNUAL MEETING DISTINGUISHED PAPERS. PMID- 30420379 TI - ADVOCACY IN FAMILY MEDICINE: FAMILY MEDICINE ADVOCACY SUMMIT. PMID- 30420381 TI - AAFP ADDS 5 NEW "CHOOSING WISELY" RECOMMENDATIONS. PMID- 30420382 TI - PISACANO LEADERSHIP FOUNDATION NAMES 2018 PISACANO SCHOLARS. PMID- 30420383 TI - Legacy Drug Prescribing Patterns in Primary Care: A Cohort Study. PMID- 30420385 TI - Robot assisted surgery is blamed for heart patient's death. PMID- 30420384 TI - Retinoic acid-induced CYP51 nuclear translocation promotes meiosis prophase I process and is correlated to the expression of REC8 and STAG3 in mice. AB - Lanosterol 14 alpha-demethylase (CYP51) plays a crucial role in cholesterol biosynthesis. In gamete development, CYP51 is involved in initiating meiosis resumption in oocytes through its product, meiosis activating sterol (MAS). In this study, CYP51 was observed to localize within the nucleus of germ cells undergoing meiotic prophase I. Following the addition of retinoic acid (RA) to induce meiosis or the RA receptor pan-antagonist AGN193109 to block meiosis in fetal ovaries, the translocation of CYP51 into the nucleus of oocytes was advanced or delayed, respectively. In addition, treatment with Cyp51-siRNA or RS21745, a specific CYP51 inhibitor, significantly delayed the meiotic progression of oocytes in the ovary, with most oocytes arresting at the zygotene stage, and likewise, significantly reduced perinatal primordial follicle formation. Furthermore, inhibition of CYP51 is correlated to significantly decreased expression of REC8 and STAG3, both of which are meiosis-specific cohesin subunits. To sum up, RA-induced CYP51 nuclear translocation is critical for oocytes meiotic progression, and consequently folliculogenesis, which might act through impacting the expression of meiosis-specific cohesins REC8 and STAG3. PMID- 30420386 TI - Nonfasting lipid testing: the new standard for cardiovascular risk assessment. PMID- 30420387 TI - Mental health outcomes after major trauma in Ontario: a population-based analysis. AB - BACKGROUND: Major injury continues to be a common source of morbidity and mortality; improving the functional recovery of survivors of major trauma requires a better understanding of the mental health outcomes that may occur in this population. We assessed the association between major trauma and the development of a new mental health diagnosis or death by suicide. METHODS: We completed a population-based, self-controlled, longitudinal cohort analysis using linked administrative data on patients treated for major trauma in Ontario between 2005 and 2010. All survivors were included and composite rates of mental health diagnoses during inpatient admissions were compared between the 5 years after injury and the 5 years before injury, using Poisson regression with generalized estimating equations. The incidence of suicide was calculated for the 5 years after injury. Risk factors for suicide were calculated using Cox proportional hazard regression analyses. RESULTS: The analysis included 19 338 patients, predominantly men (70.7%) from urban areas (82.6%), with unintentional (89%), blunt injuries (93.4%). Overall, trauma was associated with a 40% increase in the postinjury rate of mental health diagnoses (incidence rate ratio [IRR] 1.4, 95% [confidence interval] CI 1.1 to 1.8). The suicide rate was 70 per 100 000 patients per year, substantially higher than the population average. Risk factors for completing suicide were prior inpatient diagnosis of mood disorder (hazard ratio [HR] 4.3, 95% CI 2.1 to 8.8) and self-inflicted injury (HR 7.8, 95% CI 3.9 to 15.4). INTERPRETATION: Survivors of major trauma are at a heightened risk of developing mental health conditions or death by suicide in the years after their injury. Patients with pre-existing mental health disorders or who are recovering from a self-inflicted injury are at particularly high risk. PMID- 30420388 TI - Canadian and international winners of major health research prizes, 1959-2018. PMID- 30420389 TI - Severe pet-transmitted zoonosis in a patient with a compromised immune system. PMID- 30420390 TI - Avulsion fracture of the calcaneus. PMID- 30420391 TI - Doctor, physician, professor, teacher. PMID- 30420392 TI - Treatment options for obstructive sleep apnea. PMID- 30420394 TI - Many doctors pessimistic about direction of medical profession. PMID- 30420393 TI - Postnatal exposure to household disinfectants, infant gut microbiota and subsequent risk of overweight in children. PMID- 30420395 TI - Ethnicity-based fetal growth charts could reduce inductions and elective cesarean sections. PMID- 30420396 TI - Ontario doctors angry over government's proposal for primary care. PMID- 30420397 TI - "Same questions". PMID- 30420398 TI - Stopping 5-aminosalicylates in patients with ulcerative colitis starting biologic therapy does not increase the risk of adverse clinical outcomes: analysis of two nationwide population-based cohorts. AB - OBJECTIVE: The benefit of continuing 5-aminosalicylate (5-ASA) in patients with ulcerative colitis (UC) who initiate anti-tumour necrosis factor-alpha (anti-TNF) biologics is unknown. We aimed to compare clinical outcomes in patients with UC already on 5-ASA who started anti-TNF and then either stopped or continued 5-ASA. DESIGN: Our primary outcome was any adverse clinical event defined as a composite of new corticosteroid use, UC-related hospitalisation or surgery. We used two national databases: the United States (US) Truven MarketScan health claims database and the Danish health registers. Patients with UC who started anti-TNF after having been on oral 5-ASA for at least 90 days were included. Patients were classified as stopping 5-ASA if therapy was discontinued within 90 days of starting anti-TNF. We performed multivariable Cox regression models controlling for demographics, clinical factors and healthcare utilisation. Adjusted HRs (aHR) with 95% CI are reported comparing stopping 5-ASA with continuing 5-ASA. RESULTS: A total of 3589 patients with UC were included (2890 US and 699 Denmark). Stopping 5-ASA after initiating anti-TNF was not associated with an increased risk of adverse clinical events in the U.S. cohort (aHR 1.04; 95% CI 0.90 to 1.21, p=0.57) nor in the Danish cohort (aHR 1.09; 95% CI 0.80 to 1.49, p=0.60). Results were similar in sensitivity analyses investigating concomitant immunomodulator use and duration of 5-ASA treatment before initiating anti-TNF. CONCLUSION: In two national databases, stopping 5-ASA in patients with UC starting anti-TNF therapy did not increase the risk of adverse clinical events. These results should be validated in a prospective clinical trial. PMID- 30420399 TI - Resilience of human gut microbial communities for the long stay with multiple dietary shifts. PMID- 30420400 TI - An Asian consensus on standards of diagnostic upper endoscopy for neoplasia. AB - BACKGROUND: This is a consensus developed by a group of expert endoscopists aiming to standardise the preparation, process and endoscopic procedural steps for diagnosis of early upper gastrointestinal (GI) cancers. METHOD: The Delphi method was used to develop consensus statements through identification of clinical questions on diagnostic endoscopy. Three consensus meetings were conducted to consolidate the statements and voting. We conducted a systematic literature search on evidence for each statement. The statements were presented in the second consensus meeting and revised according to comments. The final voting was conducted at the third consensus meeting on the level of evidence and agreement. RESULTS: Risk stratification should be conducted before endoscopy and high risk endoscopic findings should raise an index of suspicion. The presence of premalignant mucosal changes should be documented and use of sedation is recommended to enhance detection of superficial upper GI neoplasms. The use of antispasmodics and mucolytics enhanced visualisation of the upper GI tract, and systematic endoscopic mapping should be conducted to improve detection. Sufficient examination time and structured training on diagnosis improves detection. Image enhanced endoscopy in addition to white light imaging improves detection of superficial upper GI cancer. Magnifying endoscopy with narrow-band imaging is recommended for characterisation of upper GI superficial neoplasms. Endoscopic characterisation can avoid unnecessary biopsy. CONCLUSION: This consensus provides guidance for the performance of endoscopic diagnosis and characterisation for early gastric and oesophageal neoplasia based on the evidence. This will enhance the quality of endoscopic diagnosis and improve detection of early upper GI cancers. PMID- 30420401 TI - Advances in optimizing the prescription of antibiotics in outpatient settings. AB - The inappropriate use of antibiotics can increase the likelihood of antibiotic resistance and adverse events. In the United States, nearly a third of antibiotic prescriptions in outpatient settings are unnecessary, and the selection of antibiotics and duration of treatment are also often inappropriate. Evidence shows that antibiotic prescribing is influenced by psychosocial factors, including lack of accountability, perceived patient expectations, clinician workload, and habit. A varied and growing body of evidence, including meta analyses and randomized controlled trials, has evaluated interventions to optimize the use of antibiotics. Interventions informed by behavioral science such as communication skills training, audit and feedback with peer comparison, public commitment posters, and accountable justification-have been associated with improved antibiotic prescribing. In addition, delayed prescribing, active monitoring, and the use of diagnostics are guideline recommended practices that improve antibiotic use for some conditions. In 2016, the Centers for Disease Control and Prevention released the Core Elements of Outpatient Antibiotic Stewardship, which provides a framework for implementing these interventions in outpatient settings. This review summarizes the varied evidence on drivers of inappropriate prescription of antibiotics in outpatient settings and potential interventions to improve their use in such settings. PMID- 30420402 TI - Cholesterol intake and statin use regulate neuronal G protein-gated inwardly rectifying potassium channels. AB - Cholesterol, a critical component of the cellular plasma membrane, is essential for normal neuronal function. Cholesterol content is highest in the brain, where most cholesterol is synthesized de novo; HMG-CoA reductase controls the synthesis rate. Despite strict control, elevated blood cholesterol levels are common and are associated with various neurological disorders. G protein-gated inwardly rectifying potassium (GIRK) channels mediate the actions of inhibitory brain neurotransmitters. Loss of GIRK function enhances neuron excitability; gain of function reduces neuronal activity. However, the effect of dietary cholesterol or HMG-CoA reductase inhibition (i.e., statin therapy) on GIRK function remains unknown. Using a rat model, we compared the effects of a high-cholesterol versus normal diet both with and without atorvastatin, a widely prescribed HMG-CoA reductase inhibitor, on neuronal GIRK currents. The high-cholesterol diet increased hippocampal CA1 region cholesterol levels and correspondingly increased neuronal GIRK currents. Both phenomena were reversed by cholesterol depletion in vitro. Atorvastatin countered the high-cholesterol diet effects on neuronal cholesterol content and GIRK currents; these effects were reversed by cholesterol enrichment in vitro. Our findings suggest that high-cholesterol diet and atorvastatin therapy affect ion channel function in the brain by modulating neuronal cholesterol levels. PMID- 30420403 TI - Beyond fat accumulation, NAFLD genetics converges on lipid droplet biology. PMID- 30420404 TI - Prediction of human distribution volumes of compounds in various elimination phases using physiologically based pharmacokinetic modeling and experimental pharmacokinetics in animals. AB - Predicting the pharmacokinetics of compounds in humans is an important part of the drug development process. In this study, the plasma concentration profiles of 10 marketed compounds exhibiting two-phase elimination after intravenous administration in humans were evaluated in terms of distribution volumes just after intravenous administration (V1), at steady state (Vss), and in the elimination phase (Vbeta) using physiologically based pharmacokinetic (PBPK) modeling implemented in a commercially available simulator (Simcyp). When developing human PBPK models, the insight gained from prior animal PBPK models based on nonclinical data informed the optimization of compounds' lipophilicity input and the selection of the appropriate mechanistic tissue partition methods. The accuracy of V1, Vss, and Vbeta values predicted using human PBPK models developed in accordance with prior animal PBPK models was superior to those predicted using conventional approaches, such as allometric scaling, especially for V1 and Vbeta. By conventional approaches, V1 and Vbeta values of 4 - 5 out of 10 compounds were predicted within 3-fold error of observed values whereas Vss values for their majority were predicted as such. PBPK models predicted V1, Vss, and Vbeta values for almost all compounds within 3-fold errors, resulting in better predictions of plasma concentration profiles than allometric scaling. The distribution volumes predicted using human PBPK models based on prior animal PBPK modeling were more accurate than those predicted without reference to animal models. This study demonstrated that human PBPK models developed with consideration of animal PBPK models could accurately predict distribution volumes in various elimination phases. PMID- 30420405 TI - Identification of 19-(S/R)Hydroxyeicosatetraenoic Acid as the First Endogenous Non-Competitive Inhibitor of Cytochrome P450 CYP1B1 with Enantioselective Activity. AB - The overexpression of cytochrome P450 1B1 (CYP1B1) is a common characteristic of several diseases and conditions, such as inflammation, cancer and cardiac hypertrophy. CYP1B1 is believed to contribute to pathogenesis of these diseases by mediating the formation of toxic compounds, either from exogenous or endogenous origin. We recently reported that an arachidonic acid metabolite, 19(S/R-)hydroxyeicosatetraenoic (HETE) acid, protects from cardiac hypertrophy by inhibiting the formation of toxic compounds, midchain HETEs, known to be formed by CYP1B1. This raised the question whether 19(S/R)-HETE can directly inhibit CYP1B1. In the current study, we are reporting that 19(S/R)-HETE enantioselectively inhibits human recombinant CYP1B1 activity measured by 7 ethoxyresorufin O deethylation assay. 19(S)-HETE is more potent than the R enantiomer (Ki = 37.3 and 89.1 nM, respectively). Non-competitive inhibition was identified as the mechanism of CYP1B1 inhibition, which underlines the potentially important physiological role of 19(S/R)-HETE as an endogenous CYP1B1 inhibitor; to our knowledge, 19(S/R)-HETE is the first inhibitor of its kind to be reported. PMID- 30420407 TI - Predicting tuberculosis relapse in patients treated with the standard 6-month regimen: an individual patient data meta-analysis. AB - BACKGROUND: Relapse continues to place significant burden on patients and tuberculosis (TB) programmes worldwide. We aimed to determine clinical and microbiological factors associated with relapse in patients treated with the WHO standard 6-month regimen and then evaluate the accuracy of each factor at predicting an outcome of relapse. METHODS: A systematic review was performed to identify randomised controlled trials reporting treatment outcomes on patients receiving the standard regimen. Authors were contacted and invited to share patient-level data (IPD). A one-step IPD meta-analysis, using random intercept logistic regression models and receiver operating characteristic curves, was performed to evaluate the predictive performance of variables of interest. RESULTS: Individual patient data were obtained from 3 of the 12 identified studies. Of the 1189 patients with confirmed pulmonary TB who completed therapy, 67 (5.6%) relapsed. In multipredictor analysis, the presence of baseline cavitary disease with positive smear at 2 months was associated with an increased odds of relapse (OR 2.3(95% CI 1.3 to 4.2)) and a relapse risk of 10%. When area under the curve for each multipredictor model was compared, discrimination between low risk and higher-risk patients was modest and similar to that of the reference model which accounted for age, sex and HIV status. CONCLUSION: Despite its poor predictive value, our results indicate that the combined presence of cavitary disease and 2-month positive smear status may be the best currently available marker for identifying individuals at an increased risk of relapse, particularly in resource-limited setting. Further investigation is required to assess whether this combined factor can be used to indicate different treatment requirements in clinical practice. PMID- 30420408 TI - Where next for cell-based therapy in ARDS. PMID- 30420406 TI - Second round results from the Manchester 'Lung Health Check' community-based targeted lung cancer screening pilot. AB - We report results from the second annual screening round (T1) of Manchester's 'Lung Health Check' pilot of community-based lung cancer screening in deprived areas (undertaken June to August 2017). Screening adherence was 90% (n=1194/1323): 92% of CT scans were classified negative, 6% indeterminate and 2.5% positive; there were no interval cancers. Lung cancer incidence was 1.6% (n=19), 79% stage I, treatments included surgery (42%, n=9), stereotactic ablative radiotherapy (26%, n=5) and radical radiotherapy (5%, n=1). False positive rate was 34.5% (n=10/29), representing 0.8% of T1 participants (n=10/1194). Targeted community-based lung cancer screening promotes high screening adherence and detects high rates of early stage lung cancer. PMID- 30420409 TI - Why didn't the budget include tax rises to pay for the NHS funding boost? PMID- 30420410 TI - Baby care: RCOG finds average of seven factors behind each stillbirth, neonatal death, and brain injury. PMID- 30420411 TI - Structural studies of the spliceosome: past, present and future perspectives. AB - The spliceosome is a multi-subunit RNA-protein complex involved in the removal of non-coding segments (introns) from between the coding regions (exons) in precursors of messenger RNAs (pre-mRNAs). Intron removal proceeds via two transesterification reactions, occurring between conserved sequences at intron exon junctions. A tightly regulated, hierarchical assembly with a multitude of structural and compositional rearrangements posed a great challenge for structural studies of the spliceosome. Over the years, X-ray crystallography dominated the field, providing valuable high-resolution structural information that was mostly limited to individual proteins and smaller sub-complexes. Recent developments in the field of cryo-electron microscopy allowed the visualisation of fully assembled yeast and human spliceosomes, providing unprecedented insights into substrate recognition, catalysis, and active site formation. This has advanced our mechanistic understanding of pre-mRNA splicing enormously. PMID- 30420412 TI - Platelets in cancer development and diagnosis. AB - Platelets are involved in the development and progression of cancer through several mechanisms. Platelet activation at the site of tissue damage contributes to the initiation of a cascade of events which promote tumorigenesis. In fact, platelets release a wide array of proteins, including growth and angiogenic factors, lipids and extracellular vesicles rich in genetic material, which can mediate the induction of phenotypic changes in target cells, such as immune, stromal and tumor cells, and promote carcinogenesis and metastasis formation. Importantly, the role of platelets in tumor immune escape has been described. These lines of evidence open the way to novel strategies to fight cancer based on the use of antiplatelet agents. In addition to their ability to release factors, platelets are able of up-taking proteins and genetic material present in the bloodstream. Platelets are like 'sentinels' of the disease state. The evaluation of proteomics and transcriptomics signature of platelets and platelet-derived microparticles could represent a new strategy for the development of biomarkers for early cancer detection and/or therapeutic drug monitoring in cancer chemotherapy. Owing to the ability of platelets to interact with cancer cells and to deliver their cargo, platelets have been proposed as a 'biomimetic drug delivery system' for anti-tumor drugs to prevent the occurrence of off-target adverse events associated with the use of traditional chemotherapy. PMID- 30420413 TI - Ribosomal flavours: an acquired taste for specific mRNAs? AB - The regulation of translation is critical in almost every aspect of gene expression. Nonetheless, the ribosome is historically viewed as a passive player in this process. However, evidence is accumulating to suggest that variations in the ribosome can have an important influence on which mRNAs are translated. Scope for variation is provided via multiple avenues, including heterogeneity at the level of both ribosomal proteins and ribosomal RNAs and their covalent modifications. Together, these variations provide the potential for hundreds, if not thousands, of flavours of ribosome, each of which could have idiosyncratic preferences for the translation of certain messenger RNAs. Indeed, perturbations to this heterogeneity appear to affect specific subsets of transcripts and manifest as cell-type-specific diseases. This review provides a historical perspective of the ribosomal code hypothesis, before outlining the various sources of heterogeneity, their regulation and functional consequences for the cell. PMID- 30420414 TI - 'Stop' in protein synthesis is modulated with exquisite subtlety by an extended RNA translation signal. AB - Translational stop codons, UAA, UAG, and UGA, form an integral part of the universal genetic code. They are of significant interest today for their underlying fundamental role in terminating protein synthesis, but also for their potential utilisation for programmed alternative translation events. In diverse organisms, UAA has wide usage, but it is puzzling that the high fidelity UAG is selected against and yet UGA, vulnerable to suppression, is widely used, particularly in those archaeal and bacterial genomes with a high GC content. In canonical protein synthesis, stop codons are interpreted by protein release factors that structurally and functionally mimic decoding tRNAs and occupy the decoding site on the ribosome. The release factors make close contact with the decoding complex through multiple interactions. Correct interactions cause conformational changes resulting in new and enhanced contacts with the ribosome, particularly between specific bases in the mRNA and rRNA. The base following the stop codon (fourth or +4 base) may strongly influence decoding efficiency, facilitating alternative non-canonical events like frameshifting or selenocysteine incorporation. The fourth base is drawn into the decoding site with a compacted stop codon in the eukaryotic termination complex. Surprisingly, mRNA sequences upstream and downstream of this core tetranucleotide signal have a significant influence on the strength of the signal. Since nine bases downstream of the stop codon are within the mRNA channel, their interactions with rRNA, and r-proteins may affect efficiency. With this understanding, it is now possible to design stop signals of desired strength for specific applied purposes. PMID- 30420415 TI - PARPs in genome stability and signal transduction: implications for cancer therapy. AB - The poly(ADP-ribose) polymerase (PARP) superfamily of enzymes catalyses the ADP ribosylation (ADPr) of target proteins by using nicotinamide adenine dinucleotide (NAD+) as a donor. ADPr reactions occur either in the form of attachment of a single ADP-ribose nucleotide unit on target proteins or in the form of ADP-ribose chains, with the latter called poly(ADP-ribosyl)ation. PARPs regulate many cellular processes, including the maintenance of genome stability and signal transduction. In this review, we focus on the PARP family members that possess the ability to modify proteins by poly(ADP-ribosyl)ation, namely PARP1, PARP2, Tankyrase-1, and Tankyrase-2. Here, we detail the cellular functions of PARP1 and PARP2 in the regulation of DNA damage response and describe the function of Tankyrases in Wnt-mediated signal transduction. Furthermore, we discuss how the understanding of these pathways has provided some major breakthroughs in the treatment of human cancer. PMID- 30420416 TI - The regulatory role of the kinase-homology domain in receptor guanylyl cyclases: nothing 'pseudo' about it! AB - The availability of genome sequence information and a large number of protein structures has allowed the cataloging of genes into various families, based on their function and predicted biochemical activity. Intriguingly, a number of proteins harbor changes in the amino acid sequence at residues, that from structural elucidation, are critical for catalytic activity. Such proteins have been categorized as 'pseudoenzymes'. Here, we review the role of the pseudokinase (or kinase-homology) domain in receptor guanylyl cyclases. These are multidomain single-pass, transmembrane proteins harboring an extracellular ligand-binding domain, and an intracellular domain composed of a kinase-homology domain that regulates the activity of the associated guanylyl cyclase domain. Mutations that lie in the kinase-homology domain of these receptors are associated with human disease, and either abolish or enhance cGMP production by these receptors to alter downstream signaling events. This raises the interesting possibility that one could identify molecules that bind to the pseudokinase domain and regulate the activities of these receptors, in order to alleviate symptoms in patients harboring these mutations. PMID- 30420417 TI - Calcium and Ca2+/Calmodulin-dependent kinase II as targets for helminth parasite control. AB - In eukaryotes, effective calcium homeostasis is critical for many key biological processes. There is an added level of complexity in parasites, particularly multicellular helminth worms, which modulate calcium levels while inhabiting the host microenvironment. Parasites ensure efficient calcium homeostasis through gene products, such as the calmodulin-dependent kinases (CaMK), the main focus of this review. The importance of CaMK is becoming increasingly apparent from recent functional studies of helminth and protozoan parasites. Investigations on the molecular regulation of calcium and the role of CaMK are important for both supplementing current drug regimens and finding new antiparasitic compounds. Whereas calcium regulators, including CaMK, are well characterised in mammalian systems, knowledge of their functional properties in parasites is increasing but is still in its infancy. PMID- 30420418 TI - Correction for Salinas et al., "Zika Virus Efficiently Replicates in Human Retinal Epithelium and Disturbs Its Permeability". PMID- 30420419 TI - The Terrible Toll of the Kidney Shortage. PMID- 30420420 TI - Anticoagulant-Related Nephropathy. AB - Anticoagulant-related nephropathy (ARN) is a newly recognized form of AKI in which overanticoagulation causes profuse glomerular hemorrhage, which manifests on renal biopsy as numerous renal tubules filled with red cells and red cell casts. The glomeruli show changes, but they are not sufficient to account for the glomerular hemorrhage. We were the first to study ARN, and since then, our work has been confirmed by numerous other investigators. Oral anticoagulants have been in widespread use since the 1950s; today, >2 million patients with atrial fibrillation take an oral anticoagulant. Despite this history of widespread and prolonged exposure to oral anticoagulants, ARN was discovered only recently, suggesting that the condition may be a rare occurrence. This review chronicles the discovery of ARN, its confirmation by others, and our animal model of ARN. We also provide new data on analysis of "renal events" described in the post hoc analyses of three pivotal anticoagulation trials and three retrospective analyses of large clinical databases. Taken together, these analyses suggest that ARN is not a rare occurrence in the anticoagulated patient with atrial fibrillation. However, much work needs to be done to understand the condition, particularly prospective studies, to avoid the biases inherent in post hoc and retrospective analyses. Finally, we provide recommendations regarding the diagnosis and management of ARN on the basis of the best information available. PMID- 30420421 TI - The Long-Term Impact of Renin-Angiotensin System (RAS) Inhibition on Cardiorenal Outcomes (LIRICO): A Randomized, Controlled Trial. AB - BACKGROUND: The comparative effectiveness of treatment with angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or their combination in people with albuminuria and cardiovascular risk factors is unclear. METHODS: In a multicenter, randomized, open label, blinded end point trial, we evaluated the effectiveness on cardiovascular events of ACE or ARB monotherapy or combination therapy, targeting BP<130/80 in patients with moderate or severe albuminuria and diabetes or other cardiovascular risk factors. End points included a primary composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for cardiovascular causes and a revised end point of all-cause mortality. Additional end points included ESRD, doubling of serum creatinine, albuminuria, eGFR, BP, and adverse events. RESULTS: Because of slow enrollment, the trial was modified and stopped 41% short of targeted enrollment of 2100 participants, corresponding to 35% power to detect a 25% reduced risk in the primary outcome. Our analysis included 1243 adults, with median follow-up of 2.7 years. Efficacy outcomes were similar between groups (ACE inhibitor versus ARB, ACE inhibitor versus combination, ARB versus combination) as were rates of serious adverse events. The rate of permanent discontinuation for ARB monotherapy (6.3%) was significantly lower than for ACE inhibitor monotherapy (15.7%) or combined therapy (18.3%). CONCLUSIONS: Patients may tolerate ARB monotherapy better than ACE inhibitor monotherapy. However, data from this trial and similar trials, although as yet inconclusive, show no trend suggesting differences in mortality and renal outcomes with ACE inhibitors or ARBs as dual or monotherapy in patients with albuminuria and diabetes or other cardiovascular risk factors. PMID- 30420423 TI - Investigating sudden hearing loss in adults. PMID- 30420422 TI - Association of Blood Pressure Trajectories in Early Life with Subclinical Renal Damage in Middle Age. AB - BACKGROUND: Although high BP is one of the most important factors affecting renal function, whether longitudinal BP trajectories in early life course are associated with renal function damage in later life is unclear. METHODS: To investigate the correlation between BP trajectories from childhood to adulthood and renal function in middle age, we used group-based trajectory models to identify BP trajectories in 2430 individuals (aged 6-15 years old at baseline) participating in the ongoing Hanzhong Adolescent Hypertension Cohort. We tested the association between these trajectories and subclinical renal damage in middle age, adjusting for several covariates. RESULTS: We identified four distinct systolic BP trajectories among 2430 subjects: low stable, moderate stable, high stable, and moderate increasing on the basis of systolic BP levels at baseline and during the 30-year follow-up period. The urinary albumin-to-creatinine ratio (uACR) was higher in moderate stable, high stable, and moderate increasing groups compared with the low stable group. A total of 228 individuals had subclinical renal disease by 2017. Compared with the low stable trajectory group, the other groups had increasingly greater odds of experiencing subclinical renal disease in middle age. These associations were not altered after adjustment for other covariates, except for in the moderate stable group. Analyzed results were similar for the mean arterial pressure and diastolic BP trajectory groups. CONCLUSIONS: Higher BP trajectories were correlated with higher of uACR levels and risk of subclinical renal disease in middle age. Identifying long-term BP trajectories from early age may assist in predicting individuals' renal function in later life. PMID- 30420424 TI - Dynamic interactions of the Homologous Pairing 2 (Hop2)- Meiotic Nuclear Divisions 1 (Mnd1) protein complex with meiotic presynaptic filaments in budding yeast. AB - Homologous recombination (HR) is a universally conserved DNA repair pathway that can result in the exchange of genetic material. In eukaryotes, HR has evolved into an essential step in meiosis. During meiosis many eukaryotes utilize a two recombinase pathway. This system consists of Rad51 and the meiosis-specific recombinase Dmc1. Both recombinases have distinct activities during meiotic HR despite being highly similar in sequence and having closely related biochemical activities, raising the question how these two proteins can perform separate functions. A likely explanation for their differential regulation are meiosis specific recombination proteins, such as Hop2 and Mnd1, which are part of a highly conserved eukaryotic protein complex that participates in HR, albeit through poorly understood mechanisms. To better understand how Hop2-Mnd1 functions during HR, here we have used DNA curtains in conjunction with single molecule imaging to measure and quantify the binding of the Hop2-Mnd1 complex from Saccharomyces cerevisiae to recombination intermediates comprised of Rad51 and Dmc1 ssDNA in real time. We find that yeast Hop2-Mnd1 binds rapidly to Dmc1 ssDNA filaments with high affinity and remains bound for ~1.3 minutes before dissociating. We also observed that this binding interaction is highly specific for Dmc1, and found no evidence for an association of Hop2-Mnd1 with Rad51-ssDNA or RPA-ssDNA. Our findings provide new quantitative insights into the binding dynamics of Hop2-Mnd1 with the meiotic presynaptic complex. On the basis of these findings we propose a model in which recombinase specificities for meiotic accessory proteins enhances separation of the recombinases' functions during meiotic HR. PMID- 30420425 TI - Tri-arginine exosite patch of caspase-6 recruits substrates for hydrolysis. AB - Caspases are cysteine-aspartic proteases involved in the regulation of programmed cell death (apoptosis) and a number of other biological processes. Despite overall similarities in structure and active-site composition, caspases show striking selectivity for particular protein substrates. Exosites are emerging as one of the mechanisms by which caspases can recruit, engage, and orient these substrates for proper hydrolysis. Following computational analyses and database searches for candidate exosites, we utilized site-directed mutagenesis to identify a new exosite within the N-terminal domain (NTD) of caspase-6 at the hinge between the disordered NTD, residues 23-45, and core of the caspase-6 structure. We observed that substitutions of the tri-arginine patch Arg-42-Arg-44 or the R44K cancer-associated mutation in caspase-6 markedly alter its rates of protein substrate hydrolysis. Notably, turnover of protein substrates but not of short peptide substrates was affected by these exosite alterations, underscoring the importance of this region to protein substrate recruitment. Hydrogen deuterium exchange MS-mediated interrogation of the intrinsic dynamics of these enzymes suggested the presence of a substrate-binding platform encompassed by the NTD and the 240's region (containing residues 236-246), which serves as a general exosite for caspase-6-specific substrate recruitment. In summary, we have identified an exosite on caspase-6 that is critical for protein substrate recognition and turnover and therefore highly relevant for diseases such as cancer in which caspase-6-mediated apoptosis is often disrupted and neurodegeneration in which caspase-6 lays a central role. PMID- 30420426 TI - Structure and reactivity of a siderophore-interacting protein from the marine bacterium Shewanella reveals unanticipated functional versatility. AB - Siderophores make iron accessible under iron-limited conditions and play a crucial role in the survival of microorganisms. Because of their remarkable metal scavenging properties and ease in crossing cellular envelopes, siderophores hold great potential in biotechnological applications, raising the need for a deeper knowledge of the molecular mechanisms underpinning the siderophore pathway. Here, we report the structural and functional characterization of a siderophore interacting protein from the marine bacterium Shewanella frigidimarina NCIBM400 (SfSIP). SfSIP is a flavin-containing ferric-siderophore reductase with an FAD- and NAD(P)H-binding domain that has high homology with other characterized SIPs. However, we found here that it mechanistically departs from what has been described for this family of proteins. Unlike other FAD-containing SIPs, SfSIP did not discriminate between NADH and NADPH. Furthermore, SfSIP required the presence of the Fe2+-scavenger ferrozine to use NAD(P)H to drive the reduction of Shewanella-produced hydroxamate ferric-siderophores. Additionally, this is the first SIP reported that also uses a ferredoxin as electron donor, and in contrast to NAD(P)H, its utilization did not require the mediation of ferrozine, and electron transfer occurred at fast rates. Finally, FAD oxidation was thermodynamically coupled to deprotonation at physiological pH values, enhancing the solubility of ferrous iron. On the basis of these results and the location of the SfSIP gene downstream of a sequence for putative binding of aerobic respiration control protein A (ArcA), we propose that SfSIP contributes an additional layer of regulation that maintains cellular iron homeostasis according to environmental cues of oxygen availability and cellular iron demand. PMID- 30420427 TI - Reaction mechanism of the bioluminescent protein mnemiopsin1 revealed by X-ray crystallography and QM/MM simulations. AB - Bioluminescence of a variety of marine organisms, mostly cnidarians and ctenophores, is carried out by Ca2+-dependent photoproteins. The mechanism of light emission operates via the same reaction in both animal families. Despite numerous studies on the ctenophore photoprotein family, the detailed catalytic mechanism and arrangement of amino acid residues surrounding the chromophore in this family are a mystery. Here, we report the crystal structure of Cd2+-loaded apo-mnemiopsin1, a member of the ctenophore family, at 2.15 A resolution and used quantum mechanics/molecular mechanics (QM/MM) to investigate its reaction mechanism. The simulations suggested that an Asp-156-Arg-39-Tyr-202 triad creates a hydrogen-bonded network to facilitate the transfer of a proton from the 2 hydroperoxy group of the chromophore coelenterazine to bulk solvent. We identified a water molecule in the coelenteramide-binding cavity that forms a hydrogen bond with the amide nitrogen atom of coelenteramide, which, in turn, is hydrogen bonded via another water molecule to Tyr-131. This observation supports the hypothesis that the function of the coelenteramide-bound water molecule is to catalyze the 2-hydroperoxycoelenterazine decarboxylation reaction by protonation of a dioxetanone anion, thereby triggering the bioluminescence reaction in the ctenophore photoprotein family. PMID- 30420428 TI - Endoplasmic reticulum stress alters ryanodine receptor function in the murine pancreatic beta cell. AB - Alterations in endoplasmic reticulum (ER) calcium (Ca2+) levels diminish insulin secretion and reduce beta-cell survival in both major forms of diabetes. The mechanisms responsible for ER Ca2+loss in beta cells remain incompletely understood. Moreover, a specific role for either ryanodine receptor (RyR) or inositol 1,4,5-triphosphate receptor (IP3R) dysfunction in the pathophysiology of diabetes remains largely untested. To this end, here we applied intracellular and ER Ca2+imaging techniques in INS-1 beta cells and isolated islets to determine whether diabetogenic stressors alter RyR or IP3R function. Our results revealed that the RyR is sensitive mainly to ER stress-induced dysfunction, whereas cytokine stress specifically alters IP3R activity. Consistent with this observation, pharmacological inhibition of the RyR with ryanodine and inhibition of the IP3R with xestospongin C prevented ER Ca2+loss under ER and cytokine stress conditions, respectively. However, RyR blockade distinctly prevented beta cell death, propagation of the unfolded protein response (UPR), and dysfunctional glucose-induced Ca2+oscillations in tunicamycin-treated INS-1 beta cells and mouse islets and Akita islets. Monitoring at the single-cell level revealed that ER stress acutely increases the frequency of intracellular Ca2+transients that depend on both ER Ca2+leakage from the RyR and plasma membrane depolarization. Collectively, these findings indicate that RyR dysfunction shapes ER Ca2+dynamics in beta cells and regulates both UPR activation and cell death, suggesting that RyR-mediated loss of ER Ca2+may be an early pathogenic event in diabetes. PMID- 30420429 TI - Phage single-gene lysis: Finding the weak spot in the bacterial cell wall. AB - In general, the last step in the vegetative cycle of bacterial viruses, or bacteriophages, is lysis of the host. Double-stranded DNA phages require multiple lysis proteins, including at least one enzyme that degrades the cell wall (peptidoglycan). In contrast, the lytic ssDNA and ssRNA phages have a single lysis protein that achieves cell lysis without enzymatically degrading the peptidoglycan (PG). Here, we review four "Single-gene lysis" or Sgl proteins. Three of the Sgls block bacterial cell wall synthesis by binding to and inhibiting several enzymes in the PG precursor pathway. The target of the fourth Sgl, L from bacteriophage MS2, is still unknown, but we review evidence indicating that it is likely a protein involved in maintaining cell wall integrity. Even though only a few phage genomes are available to date, the ssRNA Leviviridae are a rich source of novel Sgls, which may facilitate further unraveling of bacterial cell wall biosynthesis and discovering new antibacterial agents. PMID- 30420430 TI - Receptor-interacting Ser/Thr kinase 1 (RIPK1) and myosin IIA-dependent ceramidosomes form membrane pores that mediate blebbing and necroptosis. AB - Formation of membrane pores/channels regulates various cellular processes, such as necroptosis or stem cell niche signaling. However, the roles of membrane lipids in the formation of pores and their biological functions are largely unknown. Here, using the cellular stress model evoked by the sphingolipid analogue drug FTY720, we show that formation of ceramide-enriched membrane pores, referred to here as ceramidosomes, is initiated by a receptor-interacting Ser/Thr kinase 1 (RIPK1)-ceramide complex, transported to the plasma membrane by non muscle myosin IIA-dependent trafficking in human lung cancer cells. Molecular modeling/simulation coupled with site-directed mutagenesis revealed that Asp-147 or Asn-169 of RIPK1 are key for ceramide binding, and that Arg-258 or Leu-293 residues are involved in the myosin IIA interaction, leading to ceramidosome formation and necroptosis. Moreover, generation of ceramidosomes independently of any external drug/stress stimuli was also detected in the plasma membrane of germline stem cells (GSC) in ovaries during the early stages of oogenesis in Drosophila melanogaster. Inhibition of ceramidosome formation via myosin IIA silencing limited GSC signaling and abrogated oogenesis. In conclusion, our findings indicate that the RIPK1-ceramide complex forms large membrane pores, we name here ceramidosomes. They further suggest that, in addition to their roles in stress-mediated necroptosis, these ceramide-enriched pores also regulate membrane integrity and signaling, and might also play a role in D. melanogaster ovary development. PMID- 30420432 TI - Vitamin D does not reduce cancer or cardiovascular events in healthy adults, trial finds. PMID- 30420431 TI - In vitro reconstitution of Wnt acylation reveals structural determinants of substrate recognition by the acyltransferase human Porcupine. AB - Wnt proteins regulate a large number of processes including cellular growth, differentiation and tissue homeostasis through the highly conserved Wnt signaling pathway in metazoans. Porcupine (PORCN) is an endoplasmic reticulum (ER)-resident integral membrane enzyme that catalyzes posttranslational modification of Wnts with palmitoleic acid, an unsaturated lipid. This unique form of lipidation with palmitoleic acid is a vital step in the biogenesis and secretion of Wnt and PORCN inhibitors are currently in clinical trials for cancer treatment. However, PORCN mediated Wnt lipidation has not been reconstituted in vitro with purified enzyme. Here, we report the first successful purification of human PORCN and confirm, through in vitro reconstitution with the purified enzyme, that PORCN is necessary and sufficient for Wntacylation. By systematically examining a series of substrate variants, we show that PORCN intimately recognizes the local structure of Wnt around the site of acylation. Our in vitro assay enabled us to examine the activity of PORCN with a range of fatty acyl-CoA's with varying length and unsaturation. The selectivity of human PORCN across a spectrum of fatty acyl CoA's suggested that the kink in the unsaturated acyl chain is a key determinant PORCN-mediated catalysis. Finally, we show that two putative PORCN inhibitors that were discovered with cell-based assays indeed target human PORCN. Together, these results provide discrete, high-resolution biochemical insights into the mechanism of PORCN-mediated Wnt acylation and pave the way for further detailed biochemical and structural studies. PMID- 30420433 TI - Adverse drug reactions. PMID- 30420434 TI - Sixty seconds on . . . meat tax. PMID- 30420436 TI - Cutting Edge: B Cells Expressing Cyclic Citrullinated Peptide-Specific Antigen Receptor Are Tolerized in Normal Conditions. AB - Generation of neoantigens by citrullination is implicated in the production of anti-citrullinated protein Abs in rheumatoid arthritis, but citrullination is also a physiological process. To verify whether citrullin-specific B cells are immunologically ignorant or tolerant in normal conditions, transgenic (Tg) mice expressing IgM with the V region of an anti-cyclic citrullinated peptide (CCP) mAb cloned from a rheumatoid arthritis patient were generated. CCP-specific B cells developed in the anti-CCP IgM Tg mice with an alteration of bone marrow B cell fractions, and the number of mature B cells decreased compared with wild type or the control anti-influenza nucleoprotein-specific IgM Tg mice. In addition, B cells in anti-CCP IgM Tg mice are functionally anergic. Thus, tolerance is induced in CCP-specific B cells in vivo, suggesting that the immune systems are naturally exposed to citrullinated Ags, and anti-CCP Ab production requires additional steps beyond the generation of neoantigens by citrullination. PMID- 30420435 TI - Brief Exposure of Skin to Near-Infrared Laser Modulates Mast Cell Function and Augments the Immune Response. AB - The treatment of skin with a low-power continuous-wave (CW) near-infrared (NIR) laser prior to vaccination is an emerging strategy to augment the immune response to intradermal vaccine, potentially substituting for chemical adjuvant, which has been linked to adverse effects of vaccines. This approach proved to be low cost, simple, small, and readily translatable compared with the previously explored pulsed-wave medical lasers. However, little is known on the mode of laser-tissue interaction eliciting the adjuvant effect. In this study, we sought to identify the pathways leading to the immunological events by examining the alteration of responses resulting from genetic ablation of innate subsets including mast cells and specific dendritic cell populations in an established model of intradermal vaccination and analyzing functional changes of skin microcirculation upon the CW NIR laser treatment in mice. We found that a CW NIR laser transiently stimulates mast cells via generation of reactive oxygen species, establishes an immunostimulatory milieu in the exposed tissue, and provides migration cues for dermal CD103+ dendritic cells without inducing prolonged inflammation, ultimately augmenting the adaptive immune response. These results indicate that use of an NIR laser with distinct wavelength and power is a safe and effective tool to reproducibly modulate innate programs in skin. These mechanistic findings would accelerate the clinical translation of this technology and warrant further explorations into the broader application of NIR lasers to the treatment of immune-related skin diseases. PMID- 30420437 TI - CD8alpha+ Dendritic Cells Dictate Leukemia-Specific CD8+ T Cell Fates. AB - APCs are essential for the orchestration of antitumor T cell responses. Batf3 lineage CD8alpha+ and CD103+ dendritic cells (DCs), in particular, are required for the spontaneous initiation of CD8+ T cell priming against solid tumors. In contrast, little is known about the APCs that regulate CD8+ T cell responses against hematological malignancies. Using an unbiased approach, we aimed to characterize the APCs responsible for regulating CD8+ T cell responses in a syngeneic murine leukemia model. We show with single-cell resolution that CD8alpha+ DCs alone acquire and cross-present leukemia Ags in vivo, culminating in the induction of leukemia-specific CD8+ T cell tolerance. Furthermore, we demonstrate that the mere acquisition of leukemia cell cargo is associated with a unique transcriptional program that may be important in regulating tolerogenic CD8alpha+ DC functions in mice with leukemia. Finally, we show that systemic CD8alpha+ DC activation with a TLR3 agonist completely prevents their ability to generate leukemia-specific CD8+ T cell tolerance in vivo, resulting instead in the induction of potent antileukemia T cell immunity and prolonged survival of leukemia-bearing mice. Together, our data reveal that Batf3-lineage DCs imprint disparate CD8+ T cell fates in hosts with solid tumors versus systemic leukemia. PMID- 30420438 TI - Talin1 Methylation Is Required for Neutrophil Infiltration and Lipopolysaccharide Induced Lethality. AB - Talin1, a well-established integrin coactivator, is critical for the transmigration of neutrophils across the vascular endothelium into various organs and the peritoneal cavity during inflammation. Several posttranslational modifications of talin1 have been proposed to play a role in this process. In this study, we show that trimethylation of talin1 at Lys2454 by cytosolic Ezh2 is substantially increased in murine peritoneal neutrophils upon induction of peritonitis. By reconstituting talin1-deficient mouse myeloid cells with wild type, methyl-mimicking, or unmethylatable talin1 variants, we demonstrate that methylation of talin1 at Lys2454 is important for integrin-dependent neutrophil infiltration into the peritoneal cavity. Furthermore, we show that treatment with an Ezh2 inhibitor or reconstitution of talin1-deficient myeloid cells with unmethylatable talin1 significantly reduces the number of organ-infiltrating neutrophils and protects mice from LPS-induced mortality. PMID- 30420439 TI - Dietary acrylamide is not associated with renal cell cancer risk in the CPS-II Nutrition Cohort. AB - BACKGROUND: Acrylamide, an industrial chemical and probable human carcinogen, can be formed in primarily carbohydrate-containing foods during high heat cooking or processing. Most epidemiological studies show no associations of dietary acrylamide intake with most cancer outcomes, but limited prospective evidence suggests a positive association with renal cell carcinoma (RCC). METHODS: In 1999, 102,154 men and women from the Cancer Prevention Study-II Nutrition Cohort completed a questionnaire on diet, lifestyle and cancer risk factors and were followed through June 30, 2013. Cox proportional hazards regression was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the association between estimated dietary acrylamide intake and risk of RCC. RESULTS: After 1,137,441 person-years of follow-up, 412 cases of invasive RCC occurred. In multivariable adjusted models, there was no association between acrylamide intake and risk of RCC (HR=1.09, 95% CI 0.82-1.43) for the highest vs. lowest quartile of intake. Associations were not modified by sex or smoking history. CONCLUSIONS: We found no associations between dietary acrylamide exposure and risk of invasive RCC. IMPACT: Findings from this large, prospective analysis do not support a positive association between higher dietary acrylamide intake and RCC risk. PMID- 30420440 TI - Cancer risk from exposure to particulate matter and ozone according to obesity and health-related behaviors: A nationwide population-based cross-sectional study. AB - BACKGROUND: There is little evidence of an association between cancer risk and long-term exposure to ambient particulate matter <10 MUm (PM10) and ozone (O3) according to obesity and health-related behaviors. METHODS: In the 2012 Korean Community Health Survey, survey data on socioeconomic characteristics, health related behaviors, and previous cancer history were collected from 100,867 participants. Daily average concentrations of PM10 and O3 (2003-2012) were obtained from the Korean Air Pollutants Emission Service. The cancer risks for interquartile increases in PM10 and O3 were evaluated using multiple logistic regression and were stratified by age, sex, obesity, and health-related behaviors. RESULTS: Increased cancer risk was found among obese subjects aged >=50 years after adjusting for confounding factors (PM10: >=60 years: odds ratio [OR]: 1.34, 95% confidence interval [CI]: 1.03-1.74; 50-60 years: 1.40, 1.00 1.96; O3: >=60 years: 1.12, 1.04-1.20; 50-60 years: 1.20, 1.08-1.33). However, we did not observe similar trends in the non-obese subjects. Among obese subjects aged >=50 who had been exposed to PM10, men, ever smokers, and inactive subjects were at increased cancer risk. Regarding O3, the cancer risk was significantly higher among obese adults >50 years old, regardless of sex or health-related behaviors. CONCLUSIONS: Long-term exposure to PM10 and O3 was found to increase cancer risk. In particular, the risk differed according to obesity status, age, sex, and health-related behaviors. IMPACT: The effect of air pollution on cancer risk was compounded by obesity, smoking, and physical inactivity among subjects over 50 years old. PMID- 30420441 TI - Low Tristetraprolin Expression is Associated with Lethal Prostate Cancer. AB - PURPOSE: Inflammation is linked to prostate cancer (PrCa) progression and is mediated by Nuclear Factor Kappa B (NFkappaB). Tristetraprolin is a key node of NFkappaB activation and we investigated its biological and prognostic role in lethal PrCa. METHODS: In vitro assays assessed the function of tristetraprolin and the association between low mRNA tristetraprolin levels and lethal PrCa (metastatic disease or death) was assessed across independent prostatectomy cohorts: (i) nested case-control studies from Health Professionals Follow-up Study and Physicians' Health Study, and (ii) prostatectomy samples from Cleveland Clinic, Mayo Clinic, Johns Hopkins and MSKCC. Tristetraprolin expression levels in prostatectomy samples from patients with localized disease and biopsies of metastatic castration resistant PrCa (mCRPC) were assessed in a Cornell University cohort. RESULTS: In vitro tristetraprolin expression was inversely associated with NFkappaB-controlled genes, proliferation and enzalutamide sensitivity. Men with localized PrCa and lower quartile of tumor tristetraprolin expression had a significant, nearly 2-fold higher risk of lethal PrCa after adjusting for known clinical and histological prognostic features (age, RP Gleason score, T-stage). Tristetraprolin expression was also significantly lower in mCRPC compared with localized PrCa. CONCLUSIONS: Lower levels of tristetraprolin in human PrCa prostatectomy tissue are associated with more aggressive PrCa and may serve as an actionable prognostic and predictive biomarker. IMPACT: There is a clear need for improved biomarkers to identify patients with localized prostate cancer in need of treatment intensification, such as adjuvant testosterone suppression, or treatment de-intensification, such as active surveillance. Tristetraprolin levels may serve as informative biomarkers in localized PrCa. PMID- 30420442 TI - Cluster endophthalmitis due to Stenotrophomonas maltophilia following intravitreal bevacizumab: outcomes of patients from North India. AB - PURPOSE: To study features, management and outcomes of cluster endophthalmitis following intravitreal bevacizumab (BCZ) injection in North India. METHODS: In this retrospective study, 28 patients (23 men) (mean age of 59.07+/-13 years) who received intravitreal injection of BCZ were included. Demographic details, best corrected visual acuity (BCVA), clinical features, microbiological findings and management of patients who developed endophthalmitis after injection of contaminated BCZ injections were reviewed. The organism isolated was Stenotrophomonas maltophilia. RESULTS: All patients suffered from painful diminution of vision within 24-48 hours. Of the 28 eyes, 12 had lid and corneal oedema, raised intraocular pressure (IOP) (difference between mean preinjection and postinjection IOP: 4.42 mm Hg; p=0.005) and toxic anterior segment syndrome like picture. 16 eyes presented with clear cornea, severe vitritis and poor media clarity. Among these, three eyes showed posterior hypopyon. Seventeen eyes underwent primary pars plana vitrectomy (PPV) and intravitreal vancomycin+ceftazidime based on severity of inflammation. Eleven eyes underwent primary tap and inject. Among these, four eyes required PPV due to persistent inflammation. Eleven eyes showed positive staining for Gram-negative bacilli. Seven eyes were culture positive for S. maltophilia. Mean preinjection BCVA was 0.77+/-0.48. The first recorded postinjection BCVA was 2.52+/-0.82. BCVA (at 1 month) improved to 0.88+/-0.66. CONCLUSIONS: S. maltophilia can be found contaminating hospital surfaces and water supply. Early PPV, prompt intravitreal antibiotics and close communication with microbiologists greatly aided in salvaging all eyes from our cohort. Majority of the patients recovered their preinjection BCVA and IOP and achieved quiescence of inflammation. PMID- 30420443 TI - The rhomboid protease GlpG has weak interaction energies in its active site hydrogen bond network. AB - Intramembrane rhomboid proteases are of particular interest because of their function to hydrolyze a peptide bond of a substrate buried in the membrane. Crystal structures of the bacterial rhomboid protease GlpG have revealed a catalytic dyad (Ser201-His254) and oxyanion hole (His150/Asn154/the backbone amide of Ser201) surrounded by the protein matrix and contacting a narrow water channel. Although multiple crystal structures have been solved, the catalytic mechanism of GlpG is not completely understood. Because it is a serine protease, hydrogen bonding interactions between the active site residues are thought to play a critical role in the catalytic cycle. Here, we dissect the interaction energies among the active site residues His254, Ser201, and Asn154 of Escherichia coli GlpG, which form a hydrogen bonding network. We combine double mutant cycle analysis with stability measurements using steric trapping. In mild detergent, the active site residues are weakly coupled with interaction energies (DeltaDeltaG Inter) of -1.4 kcal/mol between His254 and Ser201 and -0.2 kcal/mol between Ser201 and Asn154. Further, by analyzing the propagation of single mutations of the active site residues, we find that these residues are important not only for function but also for the folding cooperativity of GlpG. The weak interaction between Ser and His in the catalytic dyad may partly explain the unusually slow proteolysis by GlpG compared with other canonical serine proteases. Our result suggests that the weak hydrogen bonds in the active site are sufficient to carry out the proteolytic function of rhomboid proteases. PMID- 30420444 TI - Inhibition of mTOR Signaling and Clinical Activity of Rapamycin in Head and Neck Cancer in a Window of Opportunity Trial. AB - PURPOSE: We studied the impact of mTOR signaling inhibition with rapamycin in head and neck squamous cell carcinoma (HNSCC) in the neoadjuvant setting. The goals were to evaluate the mTOR pathway as a therapeutic target for advanced HNSCC patients, and the clinical safety, anti-tumor, and molecular activity of rapamycin administration on HNSCC. EXPERIMENTAL DESIGN: Patients with untreated stage II-IVA HNSCC received rapamycin for 21 days (day 1, 15mg; days 2-12, 5mg) prior to definitive treatment with surgery or chemoradiation. Treatment responses were assessed clinically and radiographically with CT and FDG-PET. Pre- and post treatment biopsies and blood were obtained for toxicity, immune monitoring and immunohistochemical assessment of mTOR signaling, as well as exome sequencing. RESULTS: Sixteen patients (8 oral cavity, 8 oropharyngeal) completed rapamycin and definitive treatment. Half of patients were p16 positive. One patient had a pathological complete response and 4 (25%) patients met RECIST criteria for response (1 CR, 3 PR, 12 SD). Treatment was well tolerated with no grade 4 or unexpected toxicities. No significant immune suppression was observed. Downstream mTOR signaling was downregulated in tumor tissues as measured by phosphorylation of S6 (p<0.0001), AKT (p<0.0001), and 4EBP (p=0.0361), with a significant compensatory increase in phosphorylated ERK in most patients (p<0.001). Ki67 was reduced in tumor biopsies in all patients (p=0.013). CONCLUSIONS: Rapamycin treatment was well tolerated, reduced mTOR signaling and tumor growth, and resulted in significant clinical responses despite the brief treatment duration, thus supporting the potential role of mTOR inhibitors in treatment regimens for HNSCC. PMID- 30420445 TI - Whole-body imaging of cell death provides a systemic, minimally invasive, dynamic and near-real time indicator for chemotherapeutic drug toxicity. AB - PURPOSE: Response to toxicity in chemotherapies vary considerably from tissue to tissue and from patient to patient. An ability to monitor the tissue damage done by chemotherapy may have a profound impact on treatment and prognosis allowing for a proactive management in understanding and mitigating such events. For the first time, we investigated the feasibility of using whole-body imaging to map chemotherapeutic drug-induced toxicity on an individual-basis. EXPERIMENTAL DESIGN: In a preclinical proof-of-concept, rats were treated with a single clinical dose of cyclophosphamide, methotrexate or cisplatin. In vivo whole-body imaging data were acquired using 99mTc-duramycin which identifies dead and dying cells as an unambiguous marker for tissue injury in susceptible organs. Imaging results were cross-validated using quantitative ex vivo measurements and histopathology and compared to standard blood and serum panels for toxicology. RESULTS: The in vivo whole-body imaging data detected widespread changes, where spatially-heterogeneous toxic effects were identified across different tissues, within substructures of organs, as well as among different individuals. The signal changes were consistent with established toxicity profiles of these chemotherapeutic drugs. Apart from generating a map of susceptible tissues, this in vivo imaging approach was more sensitive compared to conventional blood and serum markers used in toxicology. Also, repeated imaging during the acute period after drug treatment captured different kinetics of tissue injury among susceptible organs in males and females. CONCLUSIONS: This novel and highly translational imaging approach shows promise in optimizing therapeutic decisions by detecting and managing drug toxicity on a personalized basis. PMID- 30420446 TI - Targeting Purinergic Receptor P2Y2 prevents the growth of pancreatic ductal adenocarcinoma by inhibiting cancer cell glycolysis. AB - PURPOSE: Extensive research has reported that the tumor microenvironment components play crucial roles in tumor progression. Thus, blocking the supports of tumor microenvironment is a promising approach to prevent cancer progression. We aimed to determine whether blocking extracellular ATP-P2RY2 axis could be a potential therapeutic approach for PDAC treatment. EXPERIMENTAL DESIGN: Expression of P2RY2 was determined in 264 human PDAC samples, and correlated to patient survival. P2RY2 was inhibited in human PDAC cell lines by antagonist and shRNA, respectively, and cell viability, clonogenicity and glycolysis were determined. RNA sequencing of PDAC cell line was applied to reveal underlying molecular mechanisms. Multiple PDAC mouse models were used to assess the effects of the P2RY2 inhibition on PDAC progression. RESULTS: P2RY2 was upregulated and associated with poor prognosis in PDAC. Activated P2RY2 by increased extracellular ATP in tumor microenvironment promoted PDAC growth and glycolysis. Further studies showed that the agonist-activated P2RY2 triggered PI3K/AKT-mTOR signaling by crosstalk with PDGFR mediated by Yes1, resulting in elevating expression of c-Myc and HIF1a, which subsequently enhanced cancer cell glycolysis. Genetic and pharmacological inhibition of P2RY2 impaired tumor cell growth in subcutaneous and orthotopic xenograft model, as well as delayed tumor progression in inflammation-driven PDAC model. Additionally, synergy was observed when AR-C118925XX, the selective antagonist of P2RY2 receptor, and gemcitabine were combined, resulting in prolonged survival of xenografted PDAC mice. CONCLUSIONS: These findings revealed the roles of the P2RY2 in PDAC metabolic reprogramming, suggesting that P2RY2 might be a potential metabolic therapeutic target for PDAC. PMID- 30420447 TI - Preclinical efficacy of endoglin-targeting antibody-drug conjugates for the treatment of Ewing sarcoma. AB - PURPOSE: Endoglin (ENG; CD105) is a co-receptor of the transforming growth factor beta (TGF-beta) family that is highly expressed in proliferating endothelial cells. Often coopted by cancer cells, ENG can lead to neo-angiogenesis and vasculogenic mimicry in aggressive malignancies. It exists both as a transmembrane cell surface protein, where it primarily interacts with TGF-beta, and as a soluble matricellular protein (sENG) when cleaved by matrix metalloproteinase 14 (MMP14). High ENG expression has been associated with poor prognosis in Ewing sarcoma (ES), an aggressive bone cancer that primarily occurs in adolescents and young adults. However, the therapeutic value of ENG-targeting has not been fully explored in this disease. EXPERIMENTAL DESIGN: We characterized the expression pattern of transmembrane ENG, sENG and MMP14 in preclinical and clinical samples. Subsequently, the antineoplastic potential of two novel ENG-targeting monoclonal antibody-drug conjugates (ADCs), OMTX503 and OMTX703, which differed only by their drug payload (nigrin-b A chain and cytolysin, respectively), was assessed in cell lines and preclinical animal models of ES. RESULTS: Both ADCs suppressed cell proliferation in proportion to the endogenous levels of ENG observed in vitro Moreover, the ADCs significantly delayed tumor growth in ES cell line-derived xenografts and patient-derived xenografts (PDXs) in a dose-dependent manner. CONCLUSIONS: Taken together, these studies demonstrate potent preclinical activity of first-in-class anti-ENG ADCs as a nascent strategy to eradicate ES. PMID- 30420448 TI - E3611- A Randomized Phase II Study of Ipilimumab at 3 or 10 mg/kg Alone or in Combination with High Dose Interferon-alpha2b in Advanced Melanoma. AB - PURPOSE: Interferon-alpha favors a Th1 shift in immunity and combining with ipilimumab (ipi) at 3 or 10 mg/kg may downregulate CTLA4-mediated suppressive effects leading to more durable antitumor immune responses. A study of tremelimumab and high-dose interferon-alpha (HDI) showed promising efficacy supporting this hypothesis. EXPERIMENTAL DESIGN: E3611 followed a 2 by 2 factorial design (A: ipi10+HDI; B: ipi10; C: ipi3+HDI; D: ipi3) to evaluate (i) no HDI versus HDI (across ipi doses) and (ii) ipi3 versus ipi10 (across HDI status). We hypothesized that median progression free survival (PFS) would improve from 3 to 6 months with HDI versus no HDI and with ipi10 versus ipi3. RESULTS: For eligible and treated patients (N=81) at a median follow-up time of 29.8 months, median PFS was 4.4 months (95%CI: 2.7-8.2) when ipilimumab was used alone and 7.5 months (95%CI: 5.1-11.0) when HDI was added. Median PFS was 3.8 months (95%CI: 2.6-7.5) with 3mg/kg ipilimumab and 6.5 months (95%CI: 5.1-13.5) with 10mg/kg. By study arm, median PFS was 8.0 months (95%CI: 2.8-20.2) in arm A, 6.2 months (95%CI: 2.7-25.7) in B, 5.7 months (95%CI: 1.5-11.1) in C and 2.8 months (95%CI: 2.6-5.7) in D. The differences in PFS and overall survival (OS) did not reach statistical significance. Adverse events were consistent with the known profiles of ipilimumab and HDI and significantly higher with HDI and ipi10. CONCLUSIONS: While PFS was increased, the differences resulting from adding interferon-alpha or higher dose of ipilimumab did not reach statistical significance and do not outweigh the added toxicity risks. PMID- 30420449 TI - Distinct biological types of ocular adnexal sebaceous carcinoma: HPV-driven and virus-negative tumors arise through non-overlapping molecular-genetic alterations. AB - PURPOSE: Ocular adnexal (OA) sebaceous carcinoma is an aggressive malignancy of the eyelid and ocular adnexa that frequently recurs and metastasizes, and effective therapies beyond surgical excision are lacking. There remains a critical need to define the molecular-genetic drivers of the disease to understand carcinomagenesis and progression and to devise novel treatment strategies. EXPERIMENTAL DESIGN: We present next generation sequencing of a targeted panel of cancer-associated genes in 42 and whole transcriptome RNA sequencing from 8 OA sebaceous carcinomas from 29 patients. RESULTS: We delineate two potentially distinct molecular-genetic subtypes of OA sebaceous carcinoma. The first is defined by somatic mutations impacting TP53 and/or RB1 (20/29 [70%] patients, including 10 patients whose primary tumors contained co-existing TP53 and RB1 mutations) with frequent concomitant mutations affecting NOTCH genes. These tumors arise in older patients and show frequent local recurrence. The second subtype (9/29 [31%] patients) lacks mutations affecting TP53, RB1, or NOTCH family members, but in 44% (4/9) of these tumors, RNA sequencing and in situ hybridization studies confirm transcriptionally active high-risk human papillomavirus (HPV). These tumors arise in younger patients and have not shown local recurrence. CONCLUSIONS: Together, our findings establish a potential molecular-genetic framework by which to understand the development and progression of OA sebaceous carcinoma and provide key molecular-genetic insights to direct the design of novel therapeutic interventions. PMID- 30420450 TI - Interplay of nitric oxide synthase (NOS) and SrrAB in modulation of Staphylococcus aureus metabolism and virulence. AB - Staphylococcus aureus nitric oxide synthase (saNOS) is a major contributor to virulence, stress resistance, and physiology, yet the specific mechanism(s) by which saNOS intersects with other known regulatory circuits are largely unknown. The SrrAB two-component system, which modulates gene expression in response to the reduced state of respiratory menaquinones, is a positive regulator of nos expression. Several SrrAB-regulated genes were also previously-shown to be induced in an aerobically-respiring nos mutant, suggesting potential interplay between saNOS and SrrAB. Therefore, a combination of genetic, molecular and physiological approaches was employed to characterize a nos srrAB mutant, which had significant reductions in maximum specific growth rate and oxygen consumption when cultured in conditions promoting aerobic respiration. The nos srrAB mutant secreted elevated lactate levels, correlating with increased transcription of lactate dehydrogenases. Expression of nitrate and nitrite reductase genes were also significantly enhanced in the nos srrAB double mutant, and its aerobic growth defect could be partially rescued with supplementation with nitrate, nitrite, or ammonia. Furthermore, elevated ornithine and citrulline levels and highly upregulated expression of arginine deiminase genes were observed in the double mutant. These data suggest that dual deficiency in saNOS and SrrAB limits S. aureus to fermentative metabolism, with a reliance on nitrate assimilation and the urea cycle to help fuel energy production. The nos, srrAB, and nos srrAB mutants showed comparable defects in endothelial intracellular survival, whereas srrAB and nos srrAB mutants were highly attenuated during murine sepsis, suggesting that SrrAB-mediated metabolic versatility is dominant in vivo. PMID- 30420451 TI - Nitrogen starvation induces persister cell formation in Escherichia coli. AB - To cope with fluctuations in their environment bacteria have evolved multiple adaptive stress responses. One such response is the nitrogen regulation stress response, which allows bacteria such as Escherichia coli to cope with and overcome conditions of nitrogen limitation. This response is directed by the two component system NtrBC, where NtrC acts as the major transcriptional regulator to activate the expression of genes to mount the response. Recently we showed that NtrC directly regulates the expression of the relA gene, the major (p)ppGpp synthetase in E. coli, coupling the nitrogen regulation stress and stringent responses. As elevated levels of (p)ppGpp have been implicated in the formation of persister cells, here I investigated whether nitrogen starvation promotes their formation and whether the NtrC-RelA regulatory cascade plays a role in this. The results reveal that both nitrogen starved E. coli synthesise (p)ppGpp and form a higher percentage of persister cells than non-starved cells, and that both NtrC and RelA are important for these processes. This provides novel insights into how the formation of persisters can be promoted in response to a nutritional stress.IMPORTANCE Bacteria often reside in environments where nutrient availability is scarce and therefore they have evolved adaptive responses to rapidly cope with conditions of feast and famine. Understanding the mechanisms that underpin the regulation of how bacteria cope with this stress is a fundamentally important question in the wider context of understanding the biology of the bacterial cell and bacterial pathogenesis. Two major adaptive mechanisms to cope with starvation are the nitrogen regulation (ntr) stress and stringent responses. Here I describe how these bacterial stress responses are coordinated under conditions of nitrogen starvation to promote the formation of antibiotic tolerant persister cells by elevating levels of the secondary messenger (p)ppGpp. PMID- 30420452 TI - Importance of Pyruvate Sensing and Transport for the Resuscitation of Viable but Nonculturable Escherichia coli K-12. AB - Escherichia coli and many other bacterial species can enter into a viable but nonculturable (VBNC) state, which is a survival strategy adopted by cells exposed to adverse environmental conditions. Pyruvate is known to be one factor that promotes resuscitation of VBNC cells. Here we studied the role of a pyruvate sensing network, composed of the two histidine kinase/response regulator systems BtsS/BtsR and YpdA/YpdB and one of the target genes btsT encoding the high affinity pyruvate/H+ symporter BtsT, in the resuscitation of VBNC E. coli K-12 cells after exposure to cold for 120 days. Analysis of the proteome of VBNC cells revealed upregulation, relative to exponentially growing cells, of BtsT and other proteins involved in pyruvate metabolism. Provision of pyruvate stimulated protein and DNA biosynthesis, and thus resuscitation, in wild-type but not btsSRypdAB mutant VBNC cells. This result was corroborated by time-dependent tracking of the resuscitation of individual VBNC E. coli cells observed in a microfluidics system. Finally, transport assays revealed that 14C-labeled pyruvate is rapidly taken up into VBNC cells by BtsT. These results provide the first evidence that pyruvate is taken up as a carbon source for the resuscitation of VBNC E. coli cells.IMPORTANCEViable but nonculturable (VBNC) bacteria do not form colonies in standard medium but otherwise retain their metabolic activity and can express toxic proteins. Many bacterial genera have been shown to enter the VBNC state, including Escherichia, Vibrio, and Listeria upon exposure to adverse conditions, such as low temperature, radiation and starvation. Ultimately, these organisms pose a public health risk with potential implications for the pharmaceutical and food industries, as dormant organisms are especially difficult to selectively eliminate, and VBNC bacteria can be resuscitated if placed in an environment with appropriate nutrition and temperature. Here we used a microfluidics system to monitor the resuscitation of single VBNC cells over time. We provide new molecular insights into the initiation of resuscitation by demonstrating that VBNC E. coli rapidly takes up pyruvate by an inducible high affinity transporter, whose expression is triggered by the BtsSR/YpdAB sensing network. PMID- 30420453 TI - Cyanophage A-1(L) adsorbs to lipopolysaccharides of Anabaena sp. PCC 7120 via the tail protein LIP (ORF36). AB - Ecological functions of cyanophages in aquatic environments depend on their interactions with cyanobacterial hosts. The first step of phage-host interaction involves adsorption to cell surface. We report that adsorption of a cyanophage, A 1(L), to the outer membrane of Anabaena sp. PCC 7120 is based on the binding of a tail protein, ORF36, to the O-antigen of lipopolysaccharides (LPS). Removal of O antigen by gene inactivation abolished the infection by A-1(L); consistently, preincubation of the cyanophage with extracted Anabaena LPS partially blocked the infection. In contrast, inactivation of major outer membrane protein genes in Anabaena or addition of Synechocystis LPS showed no effect on the infection. ORF35 and ORF36 are two predicted tail proteins of A-1(L). Antibodies against either ORF35 or ORF36 strongly inhibited the infection. Enzyme-linked immunosorbent assay showed a specific interaction between ORF36 and the LPS of Anabaena 7120. These findings indicate that ORF35 and ORF36 are probably both required for adsorption of A-1(L) to cell surface, but ORF36 specifically binds to the O-antigen of LPS.IMPORTANCECyanophages play an important role in regulating the dynamics of cyanobacterial communities in aquatic environments. Hitherto, the mechanisms for cyanophage infection have been barely investigated. In this study, the first cyanophage tail protein that binds to the receptor (LPS) on cell surface was identified and shown to be essential for the A-1(L) infection of Anabaena 7120. The Protein-LPS interaction may represent an important route for adsorption of cyanophages to their hosts. PMID- 30420454 TI - Escherichia coli Lrp regulates one-third of the genome via direct, cooperative, and indirect routes. AB - The global regulator Lrp plays a crucial role in regulating metabolism, virulence and motility in response to environmental conditions. Lrp has previously been shown to activate or repress approximately 10% of genes in Escherichia coli However, the full spectrum of targets, and how Lrp acts to regulate them, has stymied earlier study. We have combined matched ChIP-seq and RNA-seq under nine physiological conditions to comprehensively map the binding and regulatory activity of Lrp as it directs responses to nutrient abundance. In addition to identifying hundreds of novel Lrp targets, we observe two new global trends: first, that Lrp will often bind to promoters in a poised position under conditions when it has no regulatory activity to enable combinatorial interactions with other regulators, and second, that nutrient levels induce a global shift in the equilibrium between less sequence-specific and more sequence specific DNA binding. The overall regulatory behavior of Lrp, which as we now show extends to 38% of E. coli genes directly or indirectly under at least one condition, thus arises from the interaction between changes in Lrp binding specificity and cooperative action with other regulators.ImportanceTo survive, bacteria such as E. coli must rapidly respond to changing environmental conditions, including nutrient levels. A decrease in nutrient availability causes bacteria to stop rapid replication and enter stationary phase, where they perform limited to no cell division. The E. coli global regulatory protein Lrp has been previously implicated in modulating the expression of genes particularly important at this transition from rapid to slowed growth. Here we monitor Lrp's DNA-binding locations and effect on gene expression in three different nutrient conditions across three growth stages. We find that Lrp's role is even broader than previously suspected, and that it appears to interact with many other bacterial regulators to perform its function in a condition-specific manner. PMID- 30420455 TI - What's happening in Neurology(r) Clinical Practice. PMID- 30420456 TI - What's happening in Without Borders. PMID- 30420457 TI - Imaging microglial activation in tacrolimus-associated CNS vasculitis with translocator protein PET. PMID- 30420459 TI - Editors' note: Atrial fibrillation detected after stroke is related to a low risk of ischemic stroke recurrence. PMID- 30420458 TI - Child Neurology: Brown-Vialetto-Van Laere syndrome: Dramatic visual recovery after delayed riboflavin therapy. PMID- 30420460 TI - Reader response: Atrial fibrillation detected after stroke is related to a low risk of ischemic stroke recurrence. PMID- 30420461 TI - Author response: Atrial fibrillation detected after stroke is related to a low risk of ischemic stroke recurrence. PMID- 30420463 TI - Reader response: Education research: The current state of neurophysiology education in selected neurology residency programs. PMID- 30420462 TI - Editors' note: Education research: The current state of neurophysiology education in selected neurology residency programs. PMID- 30420464 TI - Clinical Reasoning: A 35-year-old woman with diplopia, ataxia, and altered mental status. PMID- 30420465 TI - Teaching NeuroImages: Complex bilateral corpus callosum infarction after paradoxical embolism: Lightning strikes twice. PMID- 30420466 TI - Teaching NeuroImages: Adolescent Wallenberg syndrome with overlooked signs: Ipsipulsion and ipsilateral facial palsy. PMID- 30420467 TI - Concern about NHS is key factor in shift in views on Brexit. PMID- 30420468 TI - CRISPR/Cas9 Methodology for the Generation of Knockout Deletions in Caenorhabditis elegans. AB - The Caenorhabditis elegans Gene Knockout Consortium is tasked with obtaining null mutations in each of the more than 20,000 open reading frames (ORFs) of this organism. To date, approximately 15,000 ORFs have associated putative null alleles. As there has been substantial success in using CRISPR/Cas9 in C. elegans, this appears to be the most promising technique to complete the task. To enhance the efficiency of using CRISPR/Cas9 to generate gene deletions in C. elegans we provide a web-based interface to access our database of guide RNAs (http://genome.sfu.ca/crispr). When coupled with previously developed selection vectors, optimization for homology arm length, and the use of purified Cas9 protein, we demonstrate a robust and effective protocol for generating deletions for this large-scale project. Debate and speculation in the larger scientific community concerning off-target effects due to non-specific Cas9 cutting has prompted us to investigate through whole genome sequencing the occurrence of single nucleotide variants and indels accompanying targeted deletions. We did not detect any off-site variants above the natural spontaneous mutation rate and therefore conclude that this modified protocol does not generate off-target events to any significant degree in C. elegans We did, however, observe a number of non-specific alterations at the target site itself following the Cas9-induced double-strand break and offer a protocol for best practice quality control for such events. PMID- 30420469 TI - Genotype Imputation in Winter Wheat Using First-Generation Haplotype Map SNPs Improves Genome-Wide Association Mapping and Genomic Prediction of Traits. AB - Genome-wide single nucleotide polymorphism (SNP) variation allows for the capture of haplotype structure in populations and prediction of unobserved genotypes based on inferred regions of identity-by-descent (IBD). Here we have used a first generation wheat haplotype map created by targeted re-sequencing of low-copy genomic regions in the reference panel of 62 lines to impute marker genotypes in a diverse panel of winter wheat cultivars from the U.S. Great Plains. The IBD segments between the reference population and winter wheat cultivars were identified based on SNP genotyped using the 90K iSelect wheat array and genotyping by sequencing (GBS). A genome-wide association study and genomic prediction of resistance to stripe rust in winter wheat cultivars showed that an increase in marker density achieved by imputation improved both the power and precision of trait mapping and prediction. The majority of the most significant marker-trait associations belonged to imputed genotypes. With the vast amount of SNP variation data accumulated for wheat in recent years, the presented imputation framework will greatly improve prediction accuracy in breeding populations and increase resolution of trait mapping hence, facilitate cross referencing of genotype datasets available across different wheat populations. PMID- 30420470 TI - Uninterrupted Infant Sleep, Development, and Maternal Mood. AB - OBJECTIVES: Contrary to the importance of total sleep duration, the association between sleeping through the night and development in early infancy remains unclear. Our aims were to investigate the proportion of infants who sleep through the night (6- or 8-hour sleep blocks) at ages 6 and 12 months in a longitudinal cohort and to explore associations between sleeping through the night, mental and psychomotor development, maternal mood, and breastfeeding. METHODS: At 6 and 12 months of age, maternal reports were used to assess the longest period of uninterrupted infant sleep and feeding method (n = 388). Two different criteria were used to determine if infants slept through the night: 6 and 8 hours of uninterrupted sleep. Mental and psychomotor developmental indices (Bayley Scales of Infant Development II) and maternal mood (Center for Epidemiologic Studies Depression Scale) were measured at 6, 12, and 36 months of age. RESULTS: Using a definition of either 6 or 8 hours of uninterrupted sleep, we found that 27.9% to 57.0% of 6- and 12-month-old infants did not sleep through the night. Linear regressions revealed no significant associations between sleeping through the night and concurrent or later mental development, psychomotor development, or maternal mood (P > .05). However, sleeping through the night was associated with a much lower rate of breastfeeding (P < .0001). CONCLUSIONS: Considering that high proportions of infants did not sleep through the night and that no associations were found between uninterrupted sleep, mental or psychomotor development, and maternal mood, expectations for early sleep consolidation could be moderated. PMID- 30420471 TI - Does Sleep Matter? Impact on Development and Functioning in Infants. PMID- 30420472 TI - Sport-Related Concussion in Children and Adolescents. AB - Sport-related concussion is an important topic in nearly all sports and at all levels of sport for children and adolescents. Concussion knowledge and approaches to management have progressed since the American Academy of Pediatrics published its first clinical report on the subject in 2010. Concussion's definition, signs, and symptoms must be understood to diagnose it and rule out more severe intracranial injury. Pediatric health care providers should have a good understanding of diagnostic evaluation and initial management strategies. Effective management can aid recovery and potentially reduce the risk of long term symptoms and complications. Because concussion symptoms often interfere with school, social life, family relationships, and athletics, a concussion may affect the emotional well-being of the injured athlete. Because every concussion has its own unique spectrum and severity of symptoms, individualized management is appropriate. The reduction, not necessarily elimination, of physical and cognitive activity is the mainstay of treatment. A full return to activity and/or sport is accomplished by using a stepwise program while evaluating for a return of symptoms. An understanding of prolonged symptoms and complications will help the pediatric health care provider know when to refer to a specialist. Additional research is needed in nearly all aspects of concussion in the young athlete. This report provides education on the current state of sport-related concussion knowledge, diagnosis, and management in children and adolescents. PMID- 30420473 TI - Tolerance of Chromosomal Instability in Cancer: Mechanisms and Therapeutic Opportunities. AB - Chromosomal instability (CIN) is the result of ongoing changes in the number (aneuploidy) and structure of chromosomes. CIN is induced by chromosome missegregation in mitosis and leads to karyotypic diversity within the cancer cell population, thereby adding to intratumor heterogeneity. Regardless of the overall pro-oncogenic function of CIN, its onset is typically detrimental for cell fitness and thus tumors must develop CIN-tolerance mechanisms in order to propagate. There is overwhelming genetic and functional evidence linking mutations in the tumor suppressor TP53 with CIN-tolerance. However, the pathways leading to p53 activation following chromosome missegregation remain controversial. Recently, additional mechanisms have been identified in CIN surveillance, resulting in a more complex network of pathways acting independently or in cooperation with p53. Tolerance might also be achieved by modifying aspects of the cancer cell physiology in order to attenuate CIN or by adaptation to the consequences of aneuploid karyotypes. In this review, we summarize the current knowledge about p53-dependent and -independent mechanisms of CIN-tolerance in cancer, the adaptations observed in CIN cells buffering CIN levels, its consequences for cellular homeostasis, and the potential of exploiting these adaptations in order to design new cancer therapies. PMID- 30420474 TI - Mas receptor activation slows tumor growth and attenuates muscle wasting in cancer. AB - Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of skeletal muscle mass associated with significant functional impairment. Cachexia robs patients of their strength and capacity to perform daily tasks and live independently. Effective treatments are needed urgently. Here we investigated the therapeutic potential of activating the 'alternative' axis of the Renin-Angiotensin System (RAS), involving ACE2, angiotensin-(1-7), and the mitochondrial assembly receptor (MasR), for treating cancer cachexia. Plasmid overexpression of the MasR or pharmacological angiotensin-(1-7)/MasR activation did not affect healthy muscle fiber size in vitro or in vivo but attenuated atrophy induced by co-culture with cancer cells in vitro. In mice with cancer cachexia, the MasR agonist AVE 0991 slowed tumor development, reduced weight loss, improved locomotor activity, and attenuated muscle wasting, with the majority of these effects dependent on the orexigenic and not anti-tumor properties of AVE 0991. Proteomic profiling and immunohistochemistry revealed that mechanisms underlying AVE 0991 effects on skeletal muscle involved miR-23a regulated preservation of the fast, glycolytic fibers. MasR activation is a novel regulator of muscle phenotype and AVE 0991 has orexigenic, anti-cachectic and anti-tumorigenic effects, identifying it as a promising adjunct therapy for cancer and other serious muscle wasting conditions. PMID- 30420476 TI - The inhibition of protein secretion in Escherichia coli and sub-MIC effects of arylomycin antibiotics. AB - At sufficient concentrations, antibiotics effectively eradicate many bacterial infections. However, during therapy bacteria are unavoidably exposed to lower antibiotic concentrations, and sub-minimum inhibitory concentration (MIC) exposure can result in a wide variety of other effects, including the induction of virulence, which can complicate therapy, or horizontal gene transfer (HGT), which can accelerate the spread of resistance genes. Bacterial type I signal peptidase (SPase) is an essential protein that acts at the final step of the general secretory pathway. This pathway is required for the secretion of many proteins, including many required for virulence, and the arylomycins are a class of natural product antibiotics that target SPase. Here, we investigated the consequences of exposing Escherichia coli to sub-MIC levels of an arylomycin. Using multidimensional protein identification technology mass spectrometry, we find that arylomycin treatment inhibits the proper extracytoplasmic localization of many proteins, both those that appear to be SPase substrates as well as several that do not. The identified proteins are involved in a broad range of extracytoplasmic processes and include a number of virulence factors. The effects of arylomycin on several processes required for virulence were then individually examined, and we found that even at sub-MIC levels, the arylomycins potently inhibit flagellation, motility, biofilm formation, and the dissemination of antibiotic resistance via HGT. Thus, we conclude that the arylomycins represent promising novel therapeutics with the potential to eradicate infections while simultaneously reducing virulence and the dissemination of resistance. PMID- 30420475 TI - Metabolically Healthy Obesity and High Carotid Intima-Media Thickness in Children and Adolescents: International Childhood Vascular Structure Evaluation Consortium. AB - OBJECTIVE: It has been argued that metabolically healthy obesity (MHO) does not increase cardiovascular disease (CVD) risk. This study examines the association of MHO with carotid intima-media thickness (cIMT), a proxy of CVD risk, in children and adolescents. RESEARCH DESIGN AND METHODS: Data were available for 3,497 children and adolescents aged 6-17 years from five population-based cross sectional studies in Brazil, China, Greece, Italy, and Spain. Weight status categories (normal, overweight, and obese) were defined using BMI cutoffs from the International Obesity Task Force. Metabolic status (defined as "healthy" [no risk factors] or "unhealthy" [one or more risk factors]) was based on four CVD risk factors: elevated blood pressure, elevated triglyceride levels, reduced HDL cholesterol, and elevated fasting glucose. High cIMT was defined as cIMT >=90th percentile for sex, age, and study population. Logistic regression model was used to examine the association of weight and metabolic status with high cIMT, with adjustment for sex, age, race/ethnicity, and study center. RESULTS: In comparison with metabolically healthy normal weight, odds ratios (ORs) for high cIMT were 2.29 (95% CI 1.58-3.32) for metabolically healthy overweight and 3.91 (2.46-6.21) for MHO. ORs for high cIMT were 1.44 (1.03-2.02) for unhealthy normal weight, 3.49 (2.51-4.85) for unhealthy overweight, and 6.96 (5.05-9.61) for unhealthy obesity. CONCLUSIONS: Among children and adolescents, cIMT was higher for both MHO and metabolically healthy overweight compared with metabolically healthy normal weight. Our findings reinforce the need for weight control in children and adolescents irrespective of their metabolic status. PMID- 30420477 TI - Efficacy of Humanized Cefiderocol Exposures Over 72 hours Against a Diverse Group of Gram-Negative Isolates in the Neutropenic Murine Thigh Infection Model. AB - Herein, we evaluated sustainability of humanized exposures of cefiderocol in vivo over 72h against pathogens with cefiderocol MICs of 0.5-16 MUg/mL in the neutropenic murine thigh model. In Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae displaying MICs 0.5-8 (n=11), sustained kill was observed at 72h among 9 isolates. Post-exposure MICs revealed a single 2 dilution increase compared with control in one animal (1/54 samples, 1.8%) at 72h. Adaptive resistance during therapy was not observed. PMID- 30420478 TI - Population Pharmacodynamics of Amphotericin B Deoxycholate for Disseminated Infection Caused by Talaromyces marneffei. AB - Amphotericin B deoxycholate (DAmB) is a first-line agent for the initial treatment of talaromycosis. However, little is known about the population pharmacokinetics and pharmacodynamics of DAmB for talaromycosis. Pharmacokinetic data were obtained from 78 patients; among them 55 patients had serial fungal colony forming units counts in blood also available for analysis. A population pharmacokinetics-pharmacodynamics model was fitted to the data. The relationships between area under the concentration time curve (AUC):MIC, and the time to blood culture sterilization and the time to death were investigated. There was only modest pharmacokinetic variability in the average AUC with a mean (standard deviation) of 11.51 (3.39) mg*h/L. The maximal rate of drug induced kill was 0.133 log10CFU/mL/h, and the plasma concentration of the DAmB that induced half maximal rate of kill was 0.02 mg/L. Fifty percent of patients sterilized their bloodstream by 83.16 hours (range 13-264 hours). A higher initial fungal burden was associated with longer time to sterilization (hazard ratio (HR): 0.51, 95% confidence interval (CI): 0.36-0.70, p<0.001). There was no relationship between AUC:MIC and the time to sterilization (HR: 1.03, 95% CI: 1.00-1.06, p=0.091). Furthermore, there was no relationship between the AUC:MIC and time to death (HR: 0.97, 95% CI: 0.88-1.08, p=0.607); or early fungicidal activity (slope= log(0.501 0.003*AUC:MIC), p=0.319) adjusted for the initial fungal burden. The population pharmacokinetics of DAmB are surprisingly consistent. The time to sterilization of the bloodstream is a useful pharmacodynamic endpoint for future studies. PMID- 30420479 TI - DRUG INTERACTIONS BETWEEN DOLUTEGRAVIR AND ARTEMETHER-LUMEFANTRINE OR ARTESUNATE AMODIAQUINE. AB - Across sub-Saharan Africa, patients with HIV on antiretrovirals often get malaria and need co-treatment with artemisinin-containing therapies. We undertook two pharmacokinetic studies in healthy volunteers, using standard adult doses of artmether-lumefantrine or artesunate-amodiaquine given with 50mg once daily dolutegravir (DTG) to investigate the drug-drug interaction between artmether lumefantrine or artesunate-amodiaquine and dolutegravir. The dolutegravir/artmether-lumefantrine interaction was evaluated in a two-way cross over study and measured artemether, dihydroartemisinin, lumefantrine, desbutyl lumefantrine over 264 hours. The dolutegravir/artesunate-amodiaquine interaction was investigated using a parallel study design due to long half-life of the amodiaquine metabolite, desethylamodiaquine and measured artesunate, amodiaquine, desethylamodiaquine over 624 hours. Non-compartmental analysis was performed, and geometric mean ratios and 90% confidence intervals generated for evaluation of both interactions. Dolutegravir did not significantly change the maximum concentration in plasma, time to maximum concentration and area under the concentration-time curve (AUC) for artemether, dihydroartemisinin, lumefantrine and desbutyl-lumefantrine nor significantly alter AUC for artesunate, dihydroartemisinin, amodiaquine and desethylamodiaquine. Co-administration of dolutegravir with artmether-lumefantrine resulted in a 37% decrease in DTG trough concentrations. Co-administration of dolutegravir with artesunate-amodiaquine resulted in a decrease of approximately 42% and 24% in DTG trough concentrations and AUC respectively. The significant decreases in DTG trough concentrations with artemether-lumefantrine and artesunate-amodiaquine and dolutegravir exposure with artesunate-amodiaquine are unlikely to be of clinical significance as DTG trough concentrations were above dolutegravir target concentrations of 300ng/mL. Study drugs were well-tolerated with no serious adverse events. Standard doses of artemether-lumefantrine and artesunate-amodiaquine should be used in patients receiving dolutegravir. PMID- 30420480 TI - A protein complex from human milk enhances the activity of antibiotics and drugs against Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis (TB), has surpassed HIV/AIDS as the leading cause of death from a single infectious agent. The increasing occurrence of drug resistant strains has become a major challenge for health care systems and, in some cases, rendered TB untreatable. However, developing new TB drugs has been plagued with high failure rates and costs. Alternative strategies to increase the efficacy of current TB treatment regimens include host-directed therapies or agents that make Mtb more susceptible to existing TB drugs. In this study, we show that HAMLET, an alpha-lactalbumin - oleic acid complex derived from human milk, has bactericidal activity against Mtb. HAMLET consists of a micellar oleic acid core surrounded by a shell of partially denatured alpha-lactalbumin molecules and unloads oleic acid into cells upon contact with lipid membranes. At sub-lethal concentrations, HAMLET potentiated a remarkably broad array of TB drugs and antibiotics against Mtb. For example, the minimal inhibitory concentrations of rifampicin, bedaquiline, delamanid and clarithromycin were decreased by 8- to 16-fold. HAMLET also killed Mtb and enhanced the efficacy of TB drugs inside macrophages, a natural habitat of Mtb. Previous studies showed that HAMLET is stable after oral delivery in mice and non-toxic in humans and that it is possible to package hydrophobic compounds in the oleic acid core of HAMLET to increase their solubility and metabolic stability. The potential of HAMLET and other liprotides as drug delivery and sensitization agents in TB chemotherapy is discussed. PMID- 30420481 TI - High-dosage cefazolin achieves sufficient cerebrospinal diffusion to treat an external ventricular drainage-related Staphylococcus aureus ventriculitis. AB - A patient received continuous infusion of cefazolin 10 g then 8 g daily for an external ventricular drainage-related methicillin susceptible Staphylococcus aureus (MSSA) ventriculitis.Median free concentrations in the cerebrospinal fluid were 11.9 mg/L and 6.1 mg/L after a 10-g and an 8-g dosage respectively. Free concentrations in the cerebrospinal fluid were always above MIC usually displayed by MSSA.These results support the use of high dose cefazolin to achieve sufficient meningeal concentrations. PMID- 30420482 TI - Antibiotic Resistance of Campylobacter spp. in a Pediatric Cohort Study. AB - ObjectivesTo determine phenotypic patterns of antibiotic resistance and epidemiology of drug-resistant Campylobacter spp. from a low-resource setting.MethodsA birth cohort of 303 was followed until 5 years of age. Stool from asymptomatic (n= 10,008) and diarrhea samples (n=3175) were cultured for Campylobacter Disk diffusion to CIP, NAL, ERY, AZM, TET, GM, AMP, AMC, CRO, C and TMS were determined. Antibiotic resistance between C. jejuni and non-C. jejuni isolates, and surveillance and diarrhea samples were compared and the association between personal macrolide exposure and subsequent occurrence of a macrolide resistant Campylobacter spp. was assessed.ResultsOf 917 Campylobacter isolates, 77.4% of C. jejuni isolates and 79.8% non-C. jejuni isolates were resistant to ciprofloxacin while 4.9% of C. jejuni isolates and 24.8% of non-C. jejuni isolates were not susceptible to azithromycin. Of the 303 children, 33.1% were ever diagnosed with a Campylobacter strain non-susceptible to both azithromycin and ciprofloxacin. Personal macrolide exposure did not affect the risk of macrolide resistant Campylobacter Amoxicillin and clavulanic acid (94.0%) was one of the antibiotics with the highest rates of susceptibility.ConclusionThere is a high incidence of quinolone and macrolide resistant Campylobacter infections in infants under 24 months of age. Given the lack of association between personal exposure to macrolides and a subsequent Campylobacter infection resistant to macrolides, there is a need to evaluate the source of MDR Campylobacter This study provides compelling evidence to propose amoxicillin/clavulanic acid as a treatment for Campylobacteriosis. PMID- 30420483 TI - Target (MexB) and efflux based mechanisms decreasing the effectiveness of the efflux pump inhibitor D13-9001 in P. aeruginosa PAO1: uncovering a new role for MexMN-OprM in efflux of beta-lactams and a novel regulatory circuit (MmnRS) controlling MexMN expression. AB - Efflux pumps contribute to antibiotic resistance in Gram-negative pathogens. Correspondingly, efflux pump inhibitors (EPIs) may reverse this resistance. D13 9001 specifically inhibits MexAB-OprM in P. aeruginosa Mutants with decreased susceptibility to MexAB-OprM inhibition by D13-9001 were identified and these fell into two categories; those having alterations in the target MexB (F628L and DeltaV177) and those with mutations in PA1438 (L172P substitution) which encoded a putative sensor kinase of unknown function. The alterations in MexB were consistent with reported structural studies of D13-9001 interaction with MexB. The PA1438L172P alteration mediated a >150-fold upregulation of MexMN pump gene expression and >50-fold upregulation of PA1438 and the neighboring response regulator gene PA1437. We propose that these be renamed as mmnR/mmnS for MexMN Regulator and Sensor. MexMN was shown to partner with the outer membrane channel protein OprM and to pump several beta-lactams, monobactams and tazobactam. Upregulated MexMN functionally replaced MexAB-OprM to efflux these compounds but was insusceptible to inhibition by D13-9001. MmnSL172P also mediated a decrease in susceptibility to imipenem / biapenem that was independent of MexMN-OprM. Expression of oprD, encoding the uptake channel for these compounds was downregulated, suggesting that this channel is also part of the MmnSR regulon. RNA-seq of cells encoding MmnSL172P revealed among other things an interrelationships between regulation of mexMN and genes involved in heavy metal resistance. PMID- 30420484 TI - Development of a broad-spectrum antimicrobial combination for the treatment of Staphylococcus aureus and Pseudomonas aeruginosa corneal infections. AB - Staphylococcus aureus and Pseudomonas aeruginosa are two of the most common causes of bacterial keratitis and corresponding corneal blindness. Accordingly, such infections are predominantly treated with broad spectrum fourth generation fluoroquinolones, such as moxifloxacin. Yet rising fluoroquinolone resistance has necessitated the development of alternative therapeutic options. Herein we describe development of a polymyxin B/trimethoprim (PT) ophthalmic formulation containing the antibiotic rifampicin, which exhibits synergistic antimicrobial activity toward a panel of contemporary ocular clinical S. aureus and P. aeruginosa isolates, low spontaneous resistance frequency, and displays in vitro bactericidal kinetics and antibiofilm activities equaling or exceeding the antimicrobial properties of moxifloxacin. The PT + rifampicin combination also demonstrated increased efficacy in comparison to either commercial PT or moxifloxacin in a murine keratitis model of infection, resulting in bacterial clearance of 70% in animals treated. These results suggest that the combination PT and rifampicin may represent a novel antimicrobial agent in the treatment of bacterial keratitis. PMID- 30420485 TI - Monitoring of fluconazole and caspofungin activity against in vivo Candida glabrata biofilms by bioluminescence imaging. AB - Candida glabrata can attach to various medical implants and forms thick biofilms despite its inability to switch from-yeast-to hyphae. Current in vivo C. glabrata biofilm models only provide limited information about colonization and infection and usually require animal sacrifice. To gain real-time information from individual BALB/c mice we developed a non-invasive imaging technique to visualize C. glabrata biofilms in catheter fragments that were subcutaneously implanted on the back of mice. Bioluminescent C. glabrata reporter strains (luc OPT 7/2/4 and luc OPT 8/1/4), free of auxotrophic markers, expressing a codon-optimized firefly luciferase were generated. A murine subcutaneous model was used to follow real time in vivo biofilm formation in the presence and absence of fluconazole and caspofungin. Fungal load in biofilms was quantified by colony forming unit counts and by bioluminescence imaging (BLI). C. glabrata biofilms formed within the first 24 h, as documented by the increased number of device-associated cells and elevated bioluminescent signal compared to adhesion at the time of implant. The in vivo model allowed monitoring of the anti-biofilm activity of caspofungin against C. glabrata biofilms through bioluminescent imaging from day four after initiation of treatment. Contrarily, signals emitted from biofilms implanted in fluconazole-treated mice was similar to the light emitted from control-treated mice.This study gives insights into real-time development of C. glabrata biofilms under in vivo conditions. BLI proved to be a dynamic, non-invasive and sensitive tool to monitor continuous biofilm formation and activity of antifungal agents against C. glabrata biofilms formed on abiotic surfaces in vivo. PMID- 30420486 TI - PTMiner: localization and quality control of protein modifications detected in an open search and its application to comprehensive PTM characterization in human proteome. AB - The open (mass tolerant) search of tandem mass spectra of peptides shows great potential in the comprehensive detection of post-translational modifications (PTMs) in shotgun proteomics. However, this search strategy has not been widely used by the community, and one bottleneck of it is the lack of appropriate algorithms for automated and reliable post-processing of the coarse and error prone search results. Here we present PTMiner, a software tool for confident filtering and localization of modifications (mass shifts) detected in an open search. After mass-shift-grouped false discovery rate (FDR) control of peptide spectrum matches (PSMs), PTMiner uses an empirical Bayesian method to localize modifications through iterative learning of the prior probabilities of each type of modification occurring on different amino acids. The performance of PTMiner was evaluated on three data sets, including simulated data, chemically synthesized peptide library data and modified-peptide spiked-in proteome data. The results showed that PTMiner can effectively control the PSM FDR and accurately localize the modification sites. At 1% real false localization rate (FLR), PTMiner localized 93%, 84% and 83% of the modification sites in the three data sets, respectively, far higher than two open search engines we used and an extended version of the Ascore localization algorithm. We then used PTMiner to analyze a draft map of human proteome containing 25 million spectra from 30 tissues, and confidently identified over 1.7 million modified PSMs at 1% FDR and 1% FLR, which provided a system-wide view of both known and unknown PTMs in the human proteome. PMID- 30420488 TI - Combining facilitated tucking and non-nutritive sucking appears to promote greater regulation for preterm neonates following heel lance, but does not provide effective pain relief. PMID- 30420487 TI - Heterochromatin-Enriched Assemblies Reveal the Sequence and Organization of the Drosophila melanogaster Y Chromosome. AB - Heterochromatic regions of the genome are repeat-rich and poor in protein coding genes, and are therefore underrepresented in even the best genome assemblies. One of the most difficult regions of the genome to assemble are sex-limited chromosomes. The Drosophila melanogaster Y chromosome is entirely heterochromatic, yet has wide-ranging effects on male fertility, fitness, and genome-wide gene expression. The genetic basis of this phenotypic variation is difficult to study, in part because we do not know the detailed organization of the Y chromosome. To study Y chromosome organization in D. melanogaster, we develop an assembly strategy involving the in silico enrichment of heterochromatic long single-molecule reads and use these reads to create targeted de novo assemblies of heterochromatic sequences. We assigned contigs to the Y chromosome using Illumina reads to identify male-specific sequences. Our pipeline extends the D. melanogaster reference genome by 11.9 Mb, closes 43.8% of the gaps, and improves overall contiguity. The addition of 10.6 MB of Y-linked sequence permitted us to study the organization of repeats and genes along the Y chromosome. We detected a high rate of duplication to the pericentric regions of the Y chromosome from other regions in the genome. Most of these duplicated genes exist in multiple copies. We detail the evolutionary history of one sex-linked gene family-crystal-Stellate While the Y chromosome does not undergo crossing over, we observed high gene conversion rates within and between members of the crystal-Stellate gene family, Su(Ste), and PCKR, compared to genome-wide estimates. Our results suggest that gene conversion and gene duplication play an important role in the evolution of Y-linked genes. PMID- 30420489 TI - Evaluating falls prevention strategies in community settings: marginal reduction on rate of falls with individual risk-based multifactorial interventions compared to 'usual care'. PMID- 30420490 TI - Anti-tumor activity of Shikonin against afatinib resistant non-small cell lung cancer via negative regulation of PI3K/Akt signaling pathway. AB - Acquired resistance of afatinib is a significant challenge for NSCLC therapy and the mechanisms remain unclear. Aberrant activation of EGFR-dependent downstream pathways, especially PI3K/AKT signaling pathway has been reported to be involved in the occurrence of afatinib resistance. Developing effective anti-cancer agents to overcome afatinib resistance by targeting PI3K/Akt signaling pathway will be a potential strategy for NSCLC treatment. Shikonin is a naphthoquinone compound isolated from the roots of Lithospermum erythrorhizon. In this study, the anti cancer activity of Shikonin was evaluated on afatinib resistant NSCLC in vitro and in vivo. The data showed that Shikonin inhibited the proliferation and induced apoptosis of afatinib-resistant NSCLC cell line by activating apoptosis signaling pathway and negatively regulating PI3K/Akt signaling pathway. These results revealed that Shikonin was a potential apoptosis inducer in afatinib resistant NSCLC and a promising candidate for treating patients clinically. PMID- 30420491 TI - Carbohydrate response element binding protein (ChREBP) modulates the inflammatory response of mesangial cells in response to glucose. AB - Diabetic nephropathy (DN) is one of the most devastating complications of diabetes mellitus. Carbohydrate response element binding protein (ChREBP) is a basic helix-loop-helix leucine zipper transcription factor that primarily mediates glucose homeostasis in the body. The present study investigated the role of ChREBP in the pathogenesis of DN. The expression of ChREBP was detected in patients with type 2 diabetes mellitus (T2DM), diabetic mice and mesangial cells. ELISA was used to measure cytokine production in mesangial cells. Flow cytometry analysis was performed to detect the apoptosis of mesangial cells in the presence of high glucose. The expression levels of ChREBP and several cytokines (TNFalpha, IL-1beta, and IL-6) were up-regulated in T2DM patients. The mRNA and protein levels of ChREBP were also significantly elevated in the kidneys of diabetic mice. Moreover, glucose treatment promoted mRNA levels of TNF-alpha, IL-1beta and IL-6 in mesangial cells. Glucose stimulation induced significant apoptosis of SV40 MES 13 cells. In addition, transfection with ChREBP siRNA significantly inhibited ChREBP expression. Consequently, the inflammatory responses and apoptosis were inhibited in SV40 MES 13 cells. These results demonstrated that ChREBP could mediate the inflammatory response and apoptosis of mesangial cells, suggesting that ChREBP may be involved in the pathogenesis of DN. PMID- 30420492 TI - TP73 G4C14-A4T14 Polymorphism and Cancer Susceptibility: Evidence from 36 case control studies. AB - G4C14-A4T14 polymorphism of TP73 gene has been reported with a potential association in cancer risks through affect cell homeostasis, however the results were not consistent. We performed a comprehensive meta-analysis to explore the associations between G4C14-A4T14 polymorphism and cancer susceptibility. Extensive retrieve was performed in PubMed, EMBASE, Google Scholar, Web of Science, Wanfang database and CNKI database up to May 20, 2018. Odds ratios (ORs) and 95% confidence intervals (CIs) were conducted to evaluate the overall strength of the associations in five genetic models, as well as in subgroup analyses. Q-test, false-positive report probability analysis and trial sequential analysis, Egger's test and Begg's funnel plot were applied to evaluate the robustness of the results. In-silico analysis was managed to demonstrate the relationship of TP73 expression correlated with cancer tissues. Finally, 36 case control studies with a total of 9,493 cancer cases and 13,157 healthy controls were enrolled into the meta-analysis. The pooled results present a significantly higher risk of G4C14-A4T14 polymorphism in all the five genetic models, as well as in the subgroups of Caucasian, cervical cancer, colorectal cancer, H-B subgroup and comfort to HWE subgroup. In-silico analysis revealed that the expression of TP73 in cervical cancer tissue is higher than it in corresponding normal tissue, as well as in cervical cancer. All in all, TP73 G4C14-A4T14 polymorphism causes an upgrade cancer risk, especially in Caucasian population. G4C14-A4T14 polymorphism might be a potential biomarker for judging the tumorigenesis of cervical cancer and colorectal cancer. PMID- 30420493 TI - Jumping mechanics of desert kangaroo rats. AB - Kangaroo rats are small bipedal desert rodents that use erratic vertical jumps to escape predator strikes. In this study we examined how individual hind limb joints of desert kangaroo rats (Dipodomys deserti) power vertical jumps across a range of heights. We hypothesized that increases in net work would be equally divided across hind limb joints with increases in jump height. To test this hypothesis, we used an inverse dynamics analysis to quantify the mechanical output from the hind limb joints of kangaroo rats jumping vertically over a wide range of heights. The kangaroo rats in this study reached maximal jump heights up to ~9-times hip height. Net joint work increased significantly with jump height at the hip, knee and ankle, and decreased significantly at the metatarsal phalangeal joint. The increase in net work generated by each joint was not proportional across joints but was dominated by the ankle, which ranged from contributing 56% of the work done on the center of mass at low jumps to 70% during the highest jumps. Therefore, the results of this study did not support our hypothesis. However, using an anatomical model, we estimated that a substantial proportion of the work delivered at the ankle (48%) was transferred from proximal muscles via the biarticular ankle extensors. PMID- 30420494 TI - The fallacy of the P crit - are there more useful alternatives? AB - P crit - generally defined as the P O2 below which the animal can no longer maintain a stable rate of O2 consumption (M O2 ), such that M O2 becomes dependent upon P O2 - provides a single number into which a vast amount of experimental effort has been invested. Here, with specific reference to water breathers, I argue that this focus on the P crit is not useful for six reasons: (1) calculation of P crit usually involves selective data editing; (2) the value of P crit depends greatly on the way it is determined; (3) there is no good theoretical justification for the concept; (4) P crit is not the transition point from aerobic to anaerobic metabolism, and it disguises what is really going on; (5) P crit is not a reliable index of hypoxia tolerance; and (6) P crit carries minimal information content. Preferable alternatives are loss of equilibrium (LOE) tests for hypoxia tolerance, and experimental description of full M O2 versus P O2 profiles accompanied by measurements of ventilation, lactate appearance and metabolic rate by calorimetry. If the goal is to assess the ability of the animal to regulate M O2 from this profile in a mathematical fashion, promising, more informative alternatives to P crit are the regulation index and Michaelis-Menten or sigmoidal allosteric analyses. PMID- 30420495 TI - Evolution of bacterial trade in a two-species community. PMID- 30420497 TI - Ancient DNA of the extinct Jamaican monkey Xenothrix reveals extreme insular change within a morphologically conservative radiation. AB - The insular Caribbean until recently contained a diverse mammal fauna including four endemic platyrrhine primate species, all of which died out during the Holocene. Previous morphological studies have attempted to establish how these primates are related to fossil and extant platyrrhines, whether they represent ancient or recent colonists, and whether they constitute a monophyletic group. These efforts have generated multiple conflicting hypotheses, from close sister taxon relationships with several different extant platyrrhines to derivation from a stem platyrrhine lineage outside the extant Neotropical radiation. This diversity of opinion reflects the fact that Caribbean primates were morphologically extremely unusual, displaying numerous autapomorphies and apparently derived conditions present across different platyrrhine clades. Here we report ancient DNA data for an extinct Caribbean primate: a limited-coverage entire mitochondrial genome and seven regions of nuclear genome for the most morphologically derived taxon, the Jamaican monkey Xenothrix mcgregori We demonstrate that Xenothrix is part of the existing platyrrhine radiation rather than a late-surviving stem platyrrhine, despite its unusual adaptations, and falls within the species-rich but morphologically conservative titi monkey clade (Callicebinae) as sister to the newly recognized genus Cheracebus These results are not congruent with previous morphology-based hypotheses and suggest that even morphologically conservative lineages can exhibit phenetic plasticity in novel environments like those found on islands. Xenothrix and Cheracebus diverged ca. 11 Ma, but primates have been present in the Caribbean since 17.5-18.5 Ma, indicating that Caribbean primate diversity was generated by multiple over-water colonizations. PMID- 30420496 TI - Training in cognitive strategies reduces eating and improves food choice. AB - Obesity rates continue to rise alarmingly, with dire health implications. One contributing factor is that individuals frequently forgo healthy foods in favor of inexpensive, high-calorie, unhealthy foods. One important mechanism underlying these choices is food craving: Craving increases with exposure to unhealthy foods (and food cues, such as advertisements) and prospectively predicts eating and weight. Prior work has shown that cognitive regulation strategies that emphasize the negative consequences of unhealthy foods reduce craving. In Studies 1 and 2, we show that cognitive strategies also increase craving for healthy foods by emphasizing their positive benefits, and change food valuation (willingness to pay) for both healthy and unhealthy foods. In Studies 3 and 4, we demonstrate that brief training in cognitive strategies ("Regulation of Craving Training"; ROC-T) increases subsequent healthy (vs. unhealthy) food choices. This was striking because this change in food choices generalized to nontrained items. Importantly, in Study 5, we show that brief training in cognitive strategies also reduces food consumption by 93-121 calories. Consumed calories correlated with changes in food choice. Finally, in Study 6, we show that the training component of ROC-T is necessary, above and beyond any effect of framing. Across all studies (NTOTAL = 1,528), we find that cognitive strategies substantially change craving and food valuation, and that training in cognitive strategies improves food choices by 5.4-11.2% and reduces unhealthy eating, including in obese individuals. Thus, these findings have important theoretical, public health, and clinical implications for obesity prevention and treatment. PMID- 30420498 TI - Mutations in Plasmodium falciparum actin-binding protein coronin confer reduced artemisinin susceptibility. AB - Drug resistance is an obstacle to global malaria control, as evidenced by the recent emergence and rapid spread of delayed artemisinin (ART) clearance by mutant forms of the PfKelch13 protein in Southeast Asia. Identifying genetic determinants of ART resistance in African-derived parasites is important for surveillance and for understanding the mechanism of resistance. In this study, we carried out long-term in vitro selection of two recently isolated West African parasites (from Pikine and Thies, Senegal) with increasing concentrations of dihydroartemisinin (DHA), the biologically active form of ART, over a 4-y period. We isolated two parasite clones, one from each original isolate, that exhibited enhanced survival to DHA in the ring-stage survival assay. Whole-genome sequence analysis identified 10 mutations in seven different genes. We chose to focus on the gene encoding PfCoronin, a member of the WD40-propeller domain protein family, because mutations in this gene occurred in both independent selections, and the protein shares the beta-propeller motif with PfKelch13 protein. For functional validation, when pfcoronin mutations were introduced into the parental parasites by CRISPR/Cas9-mediated gene editing, these mutations were sufficient to reduce ART susceptibility in the parental lines. The discovery of a second gene for ART resistance may yield insights into the molecular mechanisms of resistance. It also suggests that pfcoronin mutants could emerge as a nonkelch13 type of resistance to ART in natural settings. PMID- 30420499 TI - Biomechanics of a moth scale at ultrasonic frequencies. AB - The wings of moths and butterflies are densely covered in scales that exhibit intricate shapes and sculptured nanostructures. While certain butterfly scales create nanoscale photonic effects, moth scales show different nanostructures suggesting different functionality. Here we investigate moth-scale vibrodynamics to understand their role in creating acoustic camouflage against bat echolocation, where scales on wings provide ultrasound absorber functionality. For this, individual scales can be considered as building blocks with adapted biomechanical properties at ultrasonic frequencies. The 3D nanostructure of a full Bunaea alcinoe moth forewing scale was characterized using confocal microscopy. Structurally, this scale is double layered and endowed with different perforation rates on the upper and lower laminae, which are interconnected by trabeculae pillars. From these observations a parameterized model of the scale's nanostructure was formed and its effective elastic stiffness matrix extracted. Macroscale numerical modeling of scale vibrodynamics showed close qualitative and quantitative agreement with scanning laser Doppler vibrometry measurement of this scale's oscillations, suggesting that the governing biomechanics have been captured accurately. Importantly, this scale of B. alcinoe exhibits its first three resonances in the typical echolocation frequency range of bats, suggesting it has evolved as a resonant absorber. Damping coefficients of the moth-scale resonator and ultrasonic absorption of a scaled wing were estimated using numerical modeling. The calculated absorption coefficient of 0.50 agrees with the published maximum acoustic effect of wing scaling. Understanding scale vibroacoustic behavior helps create macroscopic structures with the capacity for broadband acoustic camouflage. PMID- 30420500 TI - Alpine ice evidence of a three-fold increase in atmospheric iodine deposition since 1950 in Europe due to increasing oceanic emissions. AB - Iodine is an important nutrient and a significant sink of tropospheric ozone, a climate-forcing gas and air pollutant. Ozone interacts with seawater iodide, leading to volatile inorganic iodine release that likely represents the largest source of atmospheric iodine. Increasing ozone concentrations since the preindustrial period imply that iodine chemistry and its associated ozone destruction is now substantially more active. However, the lack of historical observations of ozone and iodine means that such estimates rely primarily on model calculations. Here we use seasonally resolved records from an Alpine ice core to investigate 20th century changes in atmospheric iodine. After carefully considering possible postdepositional changes in the ice core record, we conclude that iodine deposition over the Alps increased by at least a factor of 3 from 1950 to the 1990s in the summer months, with smaller increases during the winter months. We reproduce these general trends using a chemical transport model and show that they are due to increased oceanic iodine emissions, coupled to a change in iodine speciation over Europe from enhanced nitrogen oxide emissions. The model underestimates the increase in iodine deposition by a factor of 2, however, which may be due to an underestimate in the 20th century ozone increase. Our results suggest that iodine's impact on the Northern Hemisphere atmosphere accelerated over the 20th century and show a coupling between anthropogenic pollution and the availability of iodine as an essential nutrient to the terrestrial biosphere. PMID- 30420501 TI - Subspecialization within default mode nodes characterized in 10,000 UK Biobank participants. AB - The human default mode network (DMN) is implicated in several unique mental capacities. In this study, we tested whether brain-wide interregional communication in the DMN can be derived from population variability in intrinsic activity fluctuations, gray-matter morphology, and fiber tract anatomy. In a sample of 10,000 UK Biobank participants, pattern-learning algorithms revealed functional coupling states in the DMN that are linked to connectivity profiles between other macroscopical brain networks. In addition, DMN gray matter volume was covaried with white matter microstructure of the fornix. Collectively, functional and structural patterns unmasked a possible division of labor within major DMN nodes: Subregions most critical for cortical network interplay were adjacent to subregions most predictive of fornix fibers from the hippocampus that processes memories and places. PMID- 30420503 TI - Testing the Empathizing-Systemizing theory of sex differences and the Extreme Male Brain theory of autism in half a million people. AB - The Empathizing-Systemizing (E-S) theory of typical sex differences suggests that individuals may be classified based on empathy and systemizing. An extension of the E-S theory, the Extreme Male Brain (EMB) theory suggests that autistic people on average have a shift towards a more masculinized brain along the E-S dimensions. Both theories have been investigated in small sample sizes, limiting their generalizability. Here we leverage two large datasets (discovery n = 671,606, including 36,648 autistic individuals primarily; and validation n = 14,354, including 226 autistic individuals) to investigate 10 predictions of the E-S and the EMB theories. In the discovery dataset, typical females on average showed higher scores on short forms of the Empathy Quotient (EQ) and Sensory Perception Quotient (SPQ), and typical males on average showed higher scores on short forms of the Autism Spectrum Quotient (AQ) and Systemizing Quotient (SQ). Typical sex differences in these measures were attenuated in autistic individuals. Analysis of "brain types" revealed that typical females on average were more likely to be Type E (EQ > SQ) or Extreme Type E and that typical males on average were more likely to be Type S (SQ > EQ) or Extreme Type S. In both datasets, autistic individuals, regardless of their reported sex, on average were "masculinized." Finally, we demonstrate that D-scores (difference between EQ and SQ) account for 19 times more of the variance in autistic traits (43%) than do other demographic variables including sex. Our results provide robust evidence in support of both the E-S and EMB theories. PMID- 30420504 TI - Autism in the broader context of cognitive sex differences. PMID- 30420502 TI - Long-range regulation of p53 DNA binding by its intrinsically disordered N terminal transactivation domain. AB - Atomic resolution characterization of the full-length p53 tetramer has been hampered by its size and the presence of extensive intrinsically disordered regions at both the N and C termini. As a consequence, the structural characteristics and dynamics of the disordered regions are poorly understood within the context of the intact p53 tetramer. Here we apply trans-intein splicing to generate segmentally 15N-labeled full-length p53 constructs in which only the resonances of the N-terminal transactivation domain (NTAD) are visible in NMR spectra, allowing us to observe this region of p53 with unprecedented detail within the tetramer. The N-terminal region is dynamically disordered in the full-length p53 tetramer, fluctuating between states in which it is free and fully exposed to solvent and states in which it makes transient contacts with the DNA-binding domain (DBD). Chemical-shift changes and paramagnetic spin-labeling experiments reveal that the amphipathic AD1 and AD2 motifs of the NTAD interact with the DNA-binding surface of the DBD through primarily electrostatic interactions. Importantly, this interaction inhibits binding of nonspecific DNA to the DBD while having no effect on binding to a specific p53 recognition element. We conclude that the NTAD:DBD interaction functions to enhance selectivity toward target genes by inhibiting binding to nonspecific sites in genomic DNA. This work provides some of the highest-resolution data on the disordered N terminus of the nearly 180-kDa full-length p53 tetramer and demonstrates a regulatory mechanism by which the N terminus of p53 transiently interacts with the DBD to enhance target site discrimination. PMID- 30420506 TI - Roles of mucus adhesion and cohesion in cough clearance. AB - Clearance of intrapulmonary mucus by the high-velocity airflow generated by cough is the major rescue clearance mechanism in subjects with mucoobstructive diseases and failed cilial-dependent mucus clearance, e.g., subjects with cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD). Previous studies have investigated the mechanical forces generated at airway surfaces by cough but have not considered the effects of mucus biophysical properties on cough efficacy. Theoretically, mucus can be cleared by cough from the lung by an adhesive failure, i.e., breaking mucus-cell surface adhesive bonds and/or by cohesive failure, i.e., directly fracturing mucus. Utilizing peel-testing technologies, mucus-epithelial surface adhesive and mucus cohesive strengths were measured. Because both mucus concentration and pH have been reported to alter mucus biophysical properties in disease, the effects of mucus concentration and pH on adhesion and cohesion were compared. Both adhesive and cohesive strengths depended on mucus concentration, but neither on physiologically relevant changes in pH nor bicarbonate concentration. Mucus from bronchial epithelial cultures and patient sputum samples exhibited similar adhesive and cohesive properties. Notably, the magnitudes of both adhesive and cohesive strength exhibited similar velocity and concentration dependencies, suggesting that viscous dissipation of energy within mucus during cough determines the efficiency of cough clearance of diseased, hyperconcentrated, mucus. Calculations of airflow-induced shear forces on airway mucus related to mucus concentration predicted substantially reduced cough clearance in small versus large airways. Studies designed to improve cough clearance in subjects with mucoobstructive diseases identified reductions of mucus concentration and viscous dissipation as key therapeutic strategies. PMID- 30420505 TI - Structure-based design of a quadrivalent fusion glycoprotein vaccine for human parainfluenza virus types 1-4. AB - Parainfluenza virus types 1-4 (PIV1-4) are highly infectious human pathogens, of which PIV3 is most commonly responsible for severe respiratory illness in newborns, elderly, and immunocompromised individuals. To obtain a vaccine effective against all four PIV types, we engineered mutations in each of the four PIV fusion (F) glycoproteins to stabilize their metastable prefusion states, as such stabilization had previously enabled the elicitation of high-titer neutralizing antibodies against the related respiratory syncytial virus. A cryoelectron microscopy structure of an engineered PIV3 F prefusion-stabilized trimer, bound to the prefusion-specific antibody PIA174, revealed atomic-level details for how introduced mutations improved stability as well as how a single PIA174 antibody recognized the trimeric apex of prefusion PIV3 F. Nine combinations of six newly identified disulfides and two cavity-filling mutations stabilized the prefusion PIV3 F immunogens and induced 200- to 500-fold higher neutralizing titers in mice than were elicited by PIV3 F in the postfusion conformation. For PIV1, PIV2, and PIV4, we also obtained stabilized prefusion Fs, for which prefusion versus postfusion titers were 2- to 20-fold higher. Elicited murine responses were PIV type-specific, with little cross-neutralization of other PIVs. In nonhuman primates (NHPs), quadrivalent immunization with prefusion stabilized Fs from PIV1-4 consistently induced potent neutralizing responses against all four PIVs. For PIV3, the average elicited NHP titer from the quadrivalent immunization was more than fivefold higher than any titer observed in a cohort of over 100 human adults, highlighting the ability of a prefusion stabilized immunogen to elicit especially potent neutralization. PMID- 30420508 TI - Correction to Supporting Information for Kim et al., Yin-and-yang bifurcation of opioidergic circuits for descending analgesia at the midbrain of the mouse. PMID- 30420507 TI - Genetic and plastic variation in opsin gene expression, light sensitivity, and female response to visual signals in the guppy. AB - According to the sensory drive model, variation in visual properties can lead to diverse female preferences, which in turn results in a range of male nuptial colors by way of sexual selection. However, the cause of variation in visual properties and the mechanism by which variation drives female response to visual signals remain unclear. Here, we demonstrate that both differences in the long wavelength-sensitive 1 (LWS-1) opsin genotype and the light environment during rearing lead to variation in opsin gene expression. Opsin expression variation affects the visual sensitivity threshold to long wavelengths of light. Moreover, a behavioral assay using digitally modified video images showed that the expression of multiple opsin genes is positively correlated with the female responsiveness to images of males with luminous orange spots. The findings suggest that genetic polymorphisms and light environment in habitats induce variations in opsin gene expression levels. The variations may facilitate variations in visual sensitivity and female responsiveness to male body colors within and among populations. PMID- 30420509 TI - Correction for Sormaz et al., Default mode network can support the level of detail in experience during active task states. PMID- 30420510 TI - Conserved behavioral circuits govern high-speed decision-making in wild fish shoals. AB - To evade their predators, animals must quickly detect potential threats, gauge risk, and mount a response. Putative neural circuits responsible for these tasks have been isolated in laboratory studies. However, it is unclear whether and how these circuits combine to generate the flexible, dynamic sequences of evasion behavior exhibited by wild, freely moving animals. Here, we report that evasion behavior of wild fish on a coral reef is generated through a sequence of well defined decision rules that convert visual sensory input into behavioral actions. Using an automated system to present visual threat stimuli to fish in situ, we show that individuals initiate escape maneuvers in response to the perceived size and expansion rate of an oncoming threat using a decision rule that matches dynamics of known loom-sensitive neural circuits. After initiating an evasion maneuver, fish adjust their trajectories using a control rule based on visual feedback to steer away from the threat and toward shelter. These decision rules accurately describe evasion behavior of fish from phylogenetically distant families, illustrating the conserved nature of escape decision-making. Our results reveal how the flexible behavioral responses required for survival can emerge from relatively simple, conserved decision-making mechanisms. PMID- 30420512 TI - QnAs with Steven A. Kliewer. PMID- 30420511 TI - A long-term survey unveils strong seasonal patterns in the airborne microbiome coupled to general and regional atmospheric circulations. AB - Airborne microbes (bacteria, archaea, protists, and fungi) were surveyed over a 7 y period via high-throughput massive sequencing of 16S and 18S rRNA genes in rain and snow samples collected fortnightly at a high-elevation mountain Long-Term Ecological Research (LTER) Network site (LTER-Aiguestortes, Central Pyrenees, Spain). This survey constitutes the most comprehensive mountain-top aerobiology study reported to date. The air mass origins were tracked through modeled back trajectories and analysis of rain water chemical composition. Consistent microbial seasonal patterns were observed with highly divergent summer and winter communities recurrent in time. Indicative microbial taxa were unveiled as a forensic signature, and ubiquitous taxa were observed as common atmosphere inhabitants, highlighting aerosols as a potentially successful mechanism for global microbial dispersal. Source-tracking analyses identified freshwater, cropland, and urban biomes as the most important sources for airborne bacteria in summer, while marine and forest biomes prevailed in winter, in agreement with air mass retrotrajectories and the prevailing general and regional atmospheric circulation. PMID- 30420513 TI - Ant-plant interactions evolved through increasing interdependence. AB - Ant-plant interactions are diverse and abundant and include classic models in the study of mutualism and other biotic interactions. By estimating a time-scaled phylogeny of more than 1,700 ant species and a time-scaled phylogeny of more than 10,000 plant genera, we infer when and how interactions between ants and plants evolved and assess their macroevolutionary consequences. We estimate that ant plant interactions originated in the Mesozoic, when predatory, ground-inhabiting ants first began foraging arboreally. This served as an evolutionary precursor to the use of plant-derived food sources, a dietary transition that likely preceded the evolution of extrafloral nectaries and elaiosomes. Transitions to a strict, plant-derived diet occurred in the Cenozoic, and optimal models of shifts between strict predation and herbivory include omnivory as an intermediate step. Arboreal nesting largely evolved from arboreally foraging lineages relying on a partially or entirely plant-based diet, and was initiated in the Mesozoic, preceding the evolution of domatia. Previous work has suggested enhanced diversification in plants with specialized ant-associated traits, but it appears that for ants, living and feeding on plants does not affect ant diversification. Together, the evidence suggests that ants and plants increasingly relied on one another and incrementally evolved more intricate associations with different macroevolutionary consequences as angiosperms increased their ecological dominance. PMID- 30420514 TI - Late Bronze Age cultural origins of dairy pastoralism in Mongolia. PMID- 30420515 TI - PPARgamma-K107 SUMOylation regulates insulin sensitivity but not adiposity in mice. AB - The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is a master regulator of adipocyte differentiation and is the target for the insulin-sensitizing thiazolidinedione (TZD) drugs used to treat type 2 diabetes. In cell-based in vitro studies, the transcriptional activity of PPARgamma is inhibited by covalent attachment of small ubiquitin-related modifier (SUMOylation) at K107 in its N terminus. However, whether this posttranslational modification is relevant in vivo remains unclear. Here, using mice homozygous for a mutation (K107R) that prevents SUMOylation at this position, we demonstrate that PPARgamma is SUMOylated at K107 in white adipose tissue. We further show that in the context of diet-induced obesity PPARgamma-K107R-mutant mice have enhanced insulin sensitivity without the corresponding increase in adiposity that typically accompanies PPARgamma activation by TZDs. Accordingly, the PPARgamma K107R mutation was weaker than TZD treatment in stimulating adipocyte differentiation in vitro. Moreover, we found that both the basal and TZD dependent transcriptomes of inguinal and epididymal white adipose tissue depots were markedly altered in the K107R-mutant mice. We conclude that PPARgamma SUMOylation at K107 is physiologically relevant and may serve as a pharmacologic target for uncoupling PPARgamma's beneficial insulin-sensitizing effect from its adverse effect of weight gain. PMID- 30420517 TI - Relationship between intact HIV-1 proviruses in circulating CD4+ T cells and rebound viruses emerging during treatment interruption. AB - Combination antiretroviral therapy controls but does not cure HIV-1 infection because a small fraction of cells harbor latent viruses that can produce rebound viremia when therapy is interrupted. The circulating latent virus reservoir has been documented by a variety of methods, most prominently by viral outgrowth assays (VOAs) in which CD4+ T cells are activated to produce virus in vitro, or more recently by amplifying proviral near full-length (NFL) sequences from DNA. Analysis of samples obtained in clinical studies in which individuals underwent analytical treatment interruption (ATI), showed little if any overlap between circulating latent viruses obtained from outgrowth cultures and rebound viruses from plasma. To determine whether intact proviruses amplified from DNA are more closely related to rebound viruses than those obtained from VOAs, we assayed 12 individuals who underwent ATI after infusion of a combination of two monoclonal anti-HIV-1 antibodies. A total of 435 intact proviruses obtained by NFL sequencing were compared with 650 latent viruses from VOAs and 246 plasma rebound viruses. Although, intact NFL and outgrowth culture sequences showed similar levels of stability and diversity with 39% overlap, the size of the reservoir estimated from NFL sequencing was larger than and did not correlate with VOAs. Finally, intact proviruses documented by NFL sequencing showed no sequence overlap with rebound viruses; however, they appear to contribute to recombinant viruses found in plasma during rebound. PMID- 30420519 TI - GMC should apologise for its handling of Bawa-Garba case, says RCP president. PMID- 30420516 TI - Role of humoral immunity against hepatitis B virus core antigen in the pathogenesis of acute liver failure. AB - Hepatitis B virus (HBV)-associated acute liver failure (ALF) is a dramatic clinical syndrome leading to death or liver transplantation in 80% of cases. Due to the extremely rapid clinical course, the difficulties in obtaining liver specimens, and the lack of an animal model, the pathogenesis of ALF remains largely unknown. Here, we performed a comprehensive genetic and functional characterization of the virus and the host in liver tissue from HBV-associated ALF and compared the results with those of classic acute hepatitis B in chimpanzees. In contrast with acute hepatitis B, HBV strains detected in ALF livers displayed highly mutated HBV core antigen (HBcAg), associated with increased HBcAg expression ex vivo, which was independent of viral replication levels. Combined gene and miRNA expression profiling revealed a dominant B cell disease signature, with extensive intrahepatic production of IgM and IgG in germline configuration exclusively targeting HBcAg with subnanomolar affinities, and complement deposition. Thus, HBV ALF appears to be an anomalous T cell independent, HBV core-driven B cell disease, which results from the rare and unfortunate encounter between a host with an unusual B cell response and an infecting virus with a highly mutated core antigen. PMID- 30420520 TI - Arginine methylation of SIRT7 couples glucose sensing with mitochondria biogenesis. AB - Sirtuins (SIRTs) are a class of lysine deacylases that regulate cellular metabolism and energy homeostasis. Although sirtuins have been proposed to function in nutrient sensing and signaling, the underlying mechanism remains elusive. SIRT7, a histone H3K18-specific deacetylase, epigenetically controls mitochondria biogenesis, ribosomal biosynthesis, and DNA repair. Here, we report that SIRT7 is methylated at arginine 388 (R388), which inhibits its H3K18 deacetylase activity. Protein arginine methyltransferase 6 (PRMT6) directly interacts with and methylates SIRT7 at R388 in vitro and in vivo R388 methylation suppresses the H3K18 deacetylase activity of SIRT7 without modulating its subcellular localization. PRMT6-induced H3K18 hyperacetylation at SIRT7-target gene promoter epigenetically promotes mitochondria biogenesis and maintains mitochondria respiration. Moreover, high glucose enhances R388 methylation in mouse fibroblasts and liver tissue. PRMT6 signals glucose availability to SIRT7 in an AMPK-dependent manner. AMPK induces R388 hypomethylation by disrupting the association between PRMT6 and SIRT7. Together, PRMT6-induced arginine methylation of SIRT7 coordinates glucose availability with mitochondria biogenesis to maintain energy homeostasis. Our study uncovers the regulatory role of SIRT7 arginine methylation in glucose sensing and mitochondria biogenesis. PMID- 30420518 TI - Histone H3 lysine 4 methylation signature associated with human undernutrition. AB - Chronically undernourished children become stunted during their first 2 years and thereafter bear burdens of ill health for the rest of their lives. Contributors to stunting include poor nutrition and exposure to pathogens, and parental history may also play a role. However, the epigenetic impact of a poor environment on young children is largely unknown. Here we show the unfolding pattern of histone H3 lysine 4 trimethylation (H3K4me3) in children and mothers living in an urban slum in Dhaka, Bangladesh. A pattern of chromatin modification in blood cells of stunted children emerges over time and involves a global decrease in methylation at canonical locations near gene start sites and increased methylation at ectopic sites throughout the genome. This redistribution occurs at metabolic and immune genes and was specific for H3K4me3, as it was not observed for histone H3 lysine 27 acetylation in the same samples. Methylation changes in stunting globally resemble changes that occur in vitro in response to altered methylation capacity, suggesting that reduced levels of one-carbon nutrients in the diet play a key role in stunting in this population. A network of differentially expressed genes in stunted children reveals effects on chromatin modification machinery, including turnover of H3K4me3, as well as posttranscriptional gene regulation affecting immune response pathways and lipid metabolism. Consistent with these changes, reduced expression of the endocytic receptor gene LDL receptor 1 (LRP1) is a driver of stunting in a mouse model, suggesting a target for intervention. PMID- 30420521 TI - Shelterin and subtelomeric DNA sequences control nucleosome maintenance and genome stability. AB - Telomeres and the shelterin complex cap and protect the ends of chromosomes. Telomeres are flanked by the subtelomeric sequences that have also been implicated in telomere regulation, although their role is not well defined. Here, we show that, in Schizosaccharomyces pombe, the telomere-associated sequences (TAS) present on most subtelomeres are hyper-recombinogenic, have metastable nucleosomes, and unusual low levels of H3K9 methylation. Ccq1, a subunit of shelterin, protects TAS from nucleosome loss by recruiting the heterochromatic repressor complexes CLRC and SHREC, thereby linking nucleosome stability to gene silencing. Nucleosome instability at TAS is independent of telomeric repeats and can be transmitted to an intrachromosomal locus containing an ectopic TAS fragment, indicating that this is an intrinsic property of the underlying DNA sequence. When telomerase recruitment is compromised in cells lacking Ccq1, DNA sequences present in the TAS promote recombination between chromosomal ends, independent of nucleosome abundance, implying an active function of these sequences in telomere maintenance. We propose that Ccq1 and fragile subtelomeres co-evolved to regulate telomere plasticity by controlling nucleosome occupancy and genome stability. PMID- 30420522 TI - Barnaba: Software for Analysis of Nucleic Acids Structures and Trajectories. AB - RNA molecules are highly dynamic systems characterized by a complex interplay between sequence, structure, dynamics, and function. Molecular simulations can potentially provide powerful insights into the nature of these relationships. The analysis of structures and molecular trajectories of nucleic acids can be non trivial because it requires processing very high-dimensional data that are not easy to visualize and interpret. Here we introduce Barnaba, a Python library aimed at facilitating the analysis of nucleic acids structures and molecular simulations. The software consists of a variety of analysis tools that allow the user to i) calculate distances between three-dimensional structures using different metrics, ii) back-calculate experimental data from three-dimensional structures, iii) perform cluster analysis and dimensionality reductions, iv) search three-dimensional motifs in PDB structures and trajectories and v) construct elastic network models (ENM) for nucleic acids and nucleic acids protein complexes. In addition, Barnaba makes it possible to calculate torsion angles, pucker conformations and to detect base-pairing/base-stacking interactions. Barnaba produces graphics that conveniently visualize both secondary structure and dynamics for a set of molecular conformations. The software is available both as a command-line tool as well as a library, and supports a variety of file formats such as PDB, dcd and xtc files. Source code, documentation and examples are freely available at https://github.com/srnas/barnaba under GNU GPLv3 license. PMID- 30420523 TI - The Fading of a Shining Star. PMID- 30420525 TI - Retroperitoneal Schwannoma: An Incidental Finding. AB - BACKGROUND: This case study details an ancient retroperitoneal schwannoma found incidentally on sonography and examines the rarity and characteristics of these tumors, as well as the role of sonography in diagnosis. DISCUSSION: Schwannomas tumors that arise from a nerve sheath-predominantly are found on the flexor surfaces of the extremities, as well as the trunk, head, and neck. Retroperitoneal schwannomas are larger than other schwannomas and characterized by degenerative features. Schwannomas with degenerative changes are called ancient schwannomas; they are slow growing and benign with little malignant transformation. CONCLUSION: Assessing, diagnosing, and treating retroperitoneal schwannomas requires a blend of diagnostic imaging techniques. In this case study, sonography was a valuable adjunct modality used to locate the mass, and computed tomography was used to guide fine-needle aspiration and core biopsy. The mass was excised surgically, which is the preferred treatment. PMID- 30420524 TI - Radiologic Technologists' Job Satisfaction: A Look at Work Environment, Communication, and Leadership. AB - PURPOSE: To explore radiologic technologist job satisfaction pertaining to work environment, communication, and leadership. METHODS: Investigators designed and distributed a 12-item survey to 117 registered technologists (R.T.s). Data were statistically analyzed using descriptive statistics, independent t tests, and a univariate analysis of variance. RESULTS: Fifty-nine R.T.s responded to the survey. No significant differences in total satisfaction scores were found between technologists who have an associate degree and those who have a bachelor's degree. A univariate analysis of variance yielded a significant difference in satisfaction scores between technologists with different levels of experience. R.T.s with fewer than 20 years of experience were less satisfied than technologists with 20 or more years of experience. DISCUSSION: Results suggest R.T.s want effective leadership and appreciate continuing education opportunities and supportive peers. R.T.s valued being recognized for good work and were less satisfied with changes in administration because of moving to a system-wide approach. R.T. satisfaction influenced by length of time in the profession demonstrated a pattern of overall greater satisfaction among those in the field 20 or more years. An exception to this group's overall greater satisfaction is their low scoring of satisfaction with recent changes involved in becoming a hospital system. CONCLUSION: R.T.s value competent leadership, teamwork, peer support, and effective communication. PMID- 30420526 TI - Imaging and Treatment of Strokes. AB - Patients who go to the emergency department with stroke symptoms almost always undergo a medical imaging examination. Technologists should be familiar with the modalities used to diagnose strokes, as well as their contraindications, so that they can help appropriately when caring for a patient who has had or might be having a stroke. This article discusses the types of strokes, risk factors, signs and symptoms, and how strokes are diagnosed and treated. PMID- 30420527 TI - Imaging the Vermiform Appendix. AB - Near the ileocecal valve, at the junction of the small intestine and large intestine, lies a blind-ended tube and possible homeostatic regulator called the vermiform appendix. The organ can cause several abdominal maladies that, if left untreated, can result in a complicated recovery or death. Imaging professionals should understand the structure and function of the entire gastrointestinal tract to provide optimal care for patients undergoing diagnostic imaging. This article provides a brief overview of gastrointestinal anatomy, appendix physiology and function, clinical evaluation, appendix imaging, and treatment of appendicitis. PMID- 30420528 TI - Reducing Incorrect Examination Orders. PMID- 30420530 TI - Good Reads. PMID- 30420529 TI - Good Reads. PMID- 30420532 TI - Adverse Reactions to Contrast: A Review. PMID- 30420531 TI - Prevalence of Frontal Sinus Agenesis in Chachapoyan Mummies. PMID- 30420533 TI - Accidental Arterial Sticks: Signs and Actions. PMID- 30420534 TI - Monitoring Patients in Interventional and Acute Care Settings. PMID- 30420535 TI - Increasing the Cultural Competence of Student Radiographers. PMID- 30420536 TI - Write That Manuscript, Get It Published. PMID- 30420537 TI - SPECT Is Not Computed Tomography. PMID- 30420538 TI - Mobile Medical Screening Clinic in India. PMID- 30420539 TI - What's Inside? PMID- 30420540 TI - Computed Tomography of Adult Rhinosinusitis. AB - Rhinosinusitis involves symptomatic inflammation of the paranasal sinuses. This common condition affects approximately 1 in 7 adults in the United States and is associated with significant morbidity and financial costs. Although rhinosinusitis primarily is a clinical diagnosis, medical imaging plays a unique role in sinusitis diagnosis and treatment, particularly in presurgical planning. This article reviews sinus anatomy, the characteristics of rhinosinusitis, and the modalities used to image the paranasal sinuses. PMID- 30420542 TI - On the possibility of spontaneous chemomechanical oscillations in adsorptive porous media. AB - We derive general conditions for the emergence of sustained chemomechanical oscillations from a non-oscillatory adsorption/desorption reaction in a gas/solid porous medium. The oscillations arise from the nonlinear response of the solid matrix to the loading of the adsorbed species. More particularly, we prove that, in order for oscillations to occur, adsorption of the gas must in general cause a swelling of the solid matrix. We also investigate the prototypical case of Langmuir kinetics both numerically and analytically.This article is part of the theme issue 'Dissipative structures in matter out of equilibrium: from chemistry, photonics and biology (part 2)'. PMID- 30420541 TI - Inverse Bayesian inference in swarming behaviour of soldier crabs. AB - Animals making a group sometimes approach and sometimes avoid a dense area of group mates, and that reveals the ambiguity of density preference. Although the ambiguity is not expressed by a simple deterministic local rule, it seems to be implemented by probabilistic inference that is based on Bayesian and inverse Bayesian inference. In particular, the inverse Bayesian process refers to perpetual changing of hypotheses. We here analyse a time series of swarming soldier crabs and show that they are employed to Bayesian and inverse Bayesian inference. Comparing simulation results with data of the real swarm, we show that the interpretation of the movement of soldier crabs which can be based on the inference can lead to the identification of a drastic phase shift-like transition of gathering and dispersing.This article is part of the theme issue 'Dissipative structures in matter out of equilibrium: from chemistry, photonics and biology (part 2)'. PMID- 30420543 TI - Spatially localized structures in the Gray-Scott model. AB - Spatially localized structures in the one-dimensional Gray-Scott reaction diffusion model are studied using a combination of numerical continuation techniques and weakly nonlinear theory, focusing on the regime in which the activator and substrate diffusivities are different but comparable. Localized states arise in three different ways: in a subcritical Turing instability present in this regime, and from folds in the branch of spatially periodic Turing states. They also arise from the fold of spatially uniform states. These three solution branches interconnect in complex ways. We use numerical continuation techniques to explore their global behaviour within a formulation of the model that has been used to describe dryland vegetation patterns on a flat terrain.This article is part of the theme issue 'Dissipative structures in matter out of equilibrium: from chemistry, photonics and biology (part 2)'. PMID- 30420544 TI - Spiral wave initiation in excitable media. AB - Spiral waves represent an important example of dissipative structures observed in many distributed systems in chemistry, biology and physics. By definition, excitable media occupy a stationary resting state in the absence of external perturbations. However, a perturbation exceeding a threshold results in the initiation of an excitation wave propagating through the medium. These waves, in contrast to acoustic and optical ones, disappear at the medium's boundary or after a mutual collision, and the medium returns to the resting state. Nevertheless, an initiation of a rotating spiral wave results in a self-sustained activity. Such activity unexpectedly appearing in cardiac or neuronal tissues usually destroys their dynamics which results in life-threatening diseases. In this context, an understanding of possible scenarios of spiral wave initiation is of great theoretical importance with many practical applications.This article is part of the theme issue 'Dissipative structures in matter out of equilibrium: from chemistry, photonics and biology (part 2)'. PMID- 30420545 TI - Dissipative structures induced by photoisomerization in a dye-doped nematic liquid crystal layer. AB - Order-disorder phase transitions driven by temperature or light in soft matter materials exhibit complex dissipative structures. Here, we investigate the spatio temporal phenomena induced by light in a dye-doped nematic liquid crystal layer. Experimentally, for planar anchoring of the nematic layer and high enough input power, photoisomerization processes induce a nematic-isotropic phase transition mediated by interface propagation between the two phases. In the case of a twisted nematic layer and for intermediate input power, the light induces a spatially modulated phase, which exhibits stripe patterns. The pattern originates as an instability mediated by interface propagation between the modulated and the homogeneous nematic states. Theoretically, the phase transition, emergence of stripe patterns and front dynamics are described on the basis of a proposed model for the dopant concentration coupled with the nematic order parameter. Numerical simulations show quite a fair agreement with the experimental observations.This article is part of the theme issue 'Dissipative structures in matter out of equilibrium: from chemistry, photonics and biology (part 2)'. PMID- 30420546 TI - Fluctuations out of equilibrium. AB - A generalized fluctuation-dissipation theorem involving slowly varying parameters is presented. Application of the Langevin method, the method of moments and of a multiscale technique reveal that not only dissipation but also dispersive contributions determine the spectral functions of fluctuations in arbitrary statistical systems. The non-Joule dispersive contribution is characterized by a novel non-local effect due to the additional phase shift between the force and the response of the system. This phase shift occurs as a result of parametric control to the system. The general formalism is illustrated by concrete examples and applications.This article is part of the theme issue 'Dissipative structures in matter out of equilibrium: from chemistry, photonics and biology (part 2)'. PMID- 30420547 TI - Stationary localized structures and the effect of the delayed feedback in the Brusselator model. AB - The Brusselator reaction-diffusion model is a paradigm for the understanding of dissipative structures in systems out of equilibrium. In the first part of this paper, we investigate the formation of stationary localized structures in the Brusselator model. By using numerical continuation methods in two spatial dimensions, we establish a bifurcation diagram showing the emergence of localized spots. We characterize the transition from a single spot to an extended pattern in the form of squares. In the second part, we incorporate delayed feedback control and show that delayed feedback can induce a spontaneous motion of both localized and periodic dissipative structures. We characterize this motion by estimating the threshold and the velocity of the moving dissipative structures.This article is part of the theme issue 'Dissipative structures in matter out of equilibrium: from chemistry, photonics and biology (part 2)'. PMID- 30420548 TI - Observation and modelling of vegetation spirals and arcs in isotropic environmental conditions: dissipative structures in arid landscapes. AB - We report for the first time on the formation of spirals like vegetation patterns in isotropic and uniform environmental conditions. The vegetation spirals are not waves and they do not rotate. They belong to the class of dissipative structures found out of equilibrium. Isolated or interacting spirals and arcs observed in South America (Bolivia) and North Africa (Morocco) are interpreted as a result of curvature instability that affects the circular shape of localized patches. The biomass exhibits a dynamical behaviour with arcs that transform into spirals. Interpretation of observations and of the predictions provided by the theory is illustrated by recent measurements of peculiar plant morphology (the alfa plant, or Stipa tenacissima L.) originated from northwestern Africa and the southern part of the Iberian Peninsula.This article is part of the theme issue 'Dissipative structures in matter out of equilibrium: from chemistry, photonics and biology (part 2)'. PMID- 30420549 TI - Numerical path integral calculation of the probability function and exit time: an application to non-gradient drift forces. AB - We provide numerical solutions based on the path integral representation of stochastic processes for non-gradient drift Langevin forces in the presence of noise, to follow the temporal evolution of the probability density function and to compute exit times even for arbitrary noise. We compare the results with theoretical calculations, obtaining excellent agreement in the weak noise limit.This article is part of the theme issue 'Dissipative structures in matter out of equilibrium: from chemistry, photonics and biology (part 2)'. PMID- 30420550 TI - Stabilizing a homoclinic stripe. AB - For a large class of reaction-diffusion systems with large diffusivity ratio, it is well known that a two-dimensional stripe (whose cross-section is a one dimensional homoclinic spike) is unstable and breaks up into spots. Here, we study two effects that can stabilize such a homoclinic stripe. First, we consider the addition of anisotropy to the model. For the Schnakenberg model, we show that (an infinite) stripe can be stabilized if the fast-diffusing variable (substrate) is sufficiently anisotropic. Two types of instability thresholds are derived: zigzag (or bending) and break-up instabilities. The instability boundaries subdivide parameter space into three distinct zones: stable stripe, unstable stripe due to bending and unstable due to break-up instability. Numerical experiments indicate that the break-up instability is supercritical leading to a 'spotted-stripe' solution. Finally, we perform a similar analysis for the Klausmeier model of vegetation patterns on a steep hill, and examine transition from spots to stripes.This article is part of the theme issue 'Dissipative structures in matter out of equilibrium: from chemistry, photonics and biology (part 2)'. PMID- 30420551 TI - From the Lugiato-Lefever equation to microresonator-based soliton Kerr frequency combs. AB - The model, that is usually called the Lugiato-Lefever equation (LLE), was introduced in 1987 with the aim of providing a paradigm for dissipative structure and pattern formation in nonlinear optics. This model, describing a driven, detuned and damped nonlinear Schroedinger equation, gives rise to dissipative spatial and temporal solitons. Recently, the rather idealized conditions, assumed in the LLE, have materialized in the form of continuous wave driven optical microresonators, with the discovery of temporal dissipative Kerr solitons (DKS). These experiments have revealed that the LLE is a perfect and exact description of Kerr frequency combs-first observed in 2007, i.e. 20 years after the original formulation of the LLE-and in particular describe soliton states. Observed to spontaneously form in Kerr frequency combs in crystalline microresonators in 2013, such DKS are preferred state of operation, offering coherent and broadband optical frequency combs, whose bandwidth can be extended exploiting soliton induced broadening phenomena. Combined with the ability to miniaturize and integrate on-chip, microresonator-based soliton Kerr frequency combs have already found applications in self-referenced frequency combs, dual-comb spectroscopy, frequency synthesis, low noise microwave generation, laser frequency ranging, and astrophysical spectrometer calibration, and have the potential to make comb technology ubiquitous. As such, pattern formation in driven, dissipative nonlinear optical systems is becoming the central Physics of soliton micro-comb technology.This article is part of the theme issue 'Dissipative structures in matter out of equilibrium: from chemistry, photonics and biology (part 2)'. PMID- 30420552 TI - Dissipative structures in matter out of equilibrium: from chemistry, photonics and biology, the legacy of Ilya Prigogine (part 2). PMID- 30420553 TI - Correction to: 'Causality re-established'. PMID- 30420554 TI - Nebulised recombinant activated factor VII (rFVIIa) does not attenuate the haemorrhagic effects of blast lung injury. AB - INTRODUCTION: Primary blast lung injury causes intrapulmonary haemorrhage. A number of case reports have suggested the efficacy of recombinant activated factor VII (rFVIIa) in the treatment of diffuse alveolar haemorrhage from a range of medical causes, but its efficacy in blast lung is unknown. The aim of this study was to investigate whether nebulised rFVIIa attenuates the haemorrhagic effects of blast lung injury in an animal model. METHODS: Terminally anaesthetised rabbits subjected to blast lung injury were randomised to receive either rFVIIa or placebo via a nebuliser. The primary outcome was the level of blood iron-transferrin complex, a marker of the extent of blast lung injury, analysed using low temperature electron paramagnetic resonance spectroscopy. RESULTS: Blast exposure led to a significant fall in iron-bound transferrin in both groups of animals (p<0.001), which remained depressed during the study. There were no significant differences in iron-transferrin between the rFVIIa and placebo treatment groups over the duration of the study (p=0.081), and there was no trend towards elevated iron-transferrin in the rFVIIa-treated group once drug treatment had started. There was suggestive evidence of systemic absorption of rFVIIa given via the inhaled route. CONCLUSION: A single dose of nebulised rFVIIa did not attenuate pulmonary haemorrhage in a rabbit model of blast lung injury. As there was some evidence of systemic absorption, the inhaled route does not avoid the concern about potential thromboembolic complications from administration of rFVIIa. PMID- 30420555 TI - Tailoring of Proteostasis Networks with Heat Shock Factors. AB - Heat shock factors (HSFs) are the main transcriptional regulators of the heat shock response and indispensable for maintaining cellular proteostasis. HSFs mediate their protective functions through diverse genetic programs, which are composed of genes encoding molecular chaperones and other genes crucial for cell survival. The mechanisms that are used to tailor HSF-driven proteostasis networks are not yet completely understood, but they likely comprise from distinct combinations of both genetic and proteomic determinants. In this review, we highlight the versatile HSF-mediated cellular functions that extend from cellular stress responses to various physiological and pathological processes, and we underline the key advancements that have been achieved in the field of HSF research during the last decade. PMID- 30420556 TI - Excessive tubulin polyglutamylation causes neurodegeneration and perturbs neuronal transport. AB - Posttranslational modifications of tubulin are emerging regulators of microtubule functions. We have shown earlier that upregulated polyglutamylation is linked to rapid degeneration of Purkinje cells in mice with a mutation in the deglutamylating enzyme CCP1. How polyglutamylation leads to degeneration, whether it affects multiple neuron types, or which physiological processes it regulates in healthy neurons has remained unknown. Here, we demonstrate that excessive polyglutamylation induces neurodegeneration in a cell-autonomous manner and can occur in many parts of the central nervous system. Degeneration of selected neurons in CCP1-deficient mice can be fully rescued by simultaneous knockout of the counteracting polyglutamylase TTLL1. Excessive polyglutamylation reduces the efficiency of neuronal transport in cultured hippocampal neurons, suggesting that impaired cargo transport plays an important role in the observed degenerative phenotypes. We thus establish polyglutamylation as a cell-autonomous mechanism for neurodegeneration that might be therapeutically accessible through manipulation of the enzymes that control this posttranslational modification. PMID- 30420558 TI - Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone-responsive myopathy. AB - As a consequence of impaired glucose or fatty acid metabolism, bioenergetic stress in skeletal muscles may trigger myopathy and rhabdomyolysis. Genetic mutations causing loss of function of the LPIN1 gene frequently lead to severe rhabdomyolysis bouts in children, though the metabolic alterations and possible therapeutic interventions remain elusive. Here, we show that lipin1 deficiency in mouse skeletal muscles is sufficient to trigger myopathy. Strikingly, muscle fibers display strong accumulation of both neutral and phospholipids. The metabolic lipid imbalance can be traced to an altered fatty acid synthesis and fatty acid oxidation, accompanied by a defect in acyl chain elongation and desaturation. As an underlying cause, we reveal a severe sarcoplasmic reticulum (SR) stress, leading to the activation of the lipogenic SREBP1c/SREBP2 factors, the accumulation of the Fgf21 cytokine, and alterations of SR-mitochondria morphology. Importantly, pharmacological treatments with the chaperone TUDCA and the fatty acid oxidation activator bezafibrate improve muscle histology and strength of lipin1 mutants. Our data reveal that SR stress and alterations in SR mitochondria contacts are contributing factors and potential intervention targets of the myopathy associated with lipin1 deficiency. PMID- 30420559 TI - Secretory cervical schwannoma: first of its kind. AB - Schwannomas arising from cervical sympathetic chain are rare benign neoplasms which are slow growing, usually asymptomatic, biochemically non-secretory and functionally inactive tumours. We present a case of secretory schwannoma arising from the cervical sympathetic chain, causing hypertension and associated with raised urinary catecholamine degradation by-products. Transcervical excision of the tumour was followed by normalisation of blood pressure and urinary vanillylmandelic acid levels and pathologically the tumour was proved to be a schwannoma. PMID- 30420560 TI - Anti-HMGCR antibody-associated necrotising myopathy and its association with statin use. AB - A 66-year-old man presented with chest pain and a 1-year history of generalised weakness, accompanied with generalised aches and pains. Symptoms worsened when he was initiated on statins. Investigations yielded high creatine kinase, high HMG coenzymeA reductase (HMGCR) antibody titre, myopathic features on electromyography and muscle biopsy, and muscle atrophy on MRI. These results were in keeping with anti-HMGCR antibody myopathy. The patient responded well to immunosuppressive therapy. PMID- 30420561 TI - Bilateral central retinal artery occlusion from catastrophic antiphospholipid syndrome. AB - A 23-year-old woman with history of systemic lupus erythematous presented with dizziness and headache and was admitted for the stroke workup. During her stay, she had sudden painless loss of vision in her right eye consistent with central retinal artery occlusion (CRAO). Ocular massage and paracentesis were attempted without success to resume the flow. She was started on oral high-dose steroids (1 mg/kg) for lupus flare and therapeutic anticoagulation for antiphospholipid syndrome (positive for anticardiolipin and beta-2 microglobulin antibodies). On day 4, she started having painful bluish discoloration of her left index finger and right fifth toe, and on day 5 she had acute onset of left blurry vision with findings consistent with CRAO. She fulfilled the criteria of catastrophic antiphospholipid syndrome and was started on intravenous pulse steroids, plasmapheresis and higher international normalised ratio goal of 3-3.5 with improvement in her left eye vision from 20/200 to 20/20 on near card test by the end of treatment. PMID- 30420563 TI - Renal pseudomass: be aware of splenorenal fusion. AB - Splenosis is the heterotopic implantation of splenic tissue that usually occurs in a previous major abdominal trauma or splenectomy setting. However, splenorenal fusion is an uncommon entity, categorised as a developmental anomaly. There have been several confirmed cases in the literature. Despite some helpful imaging features, it can be easily misdiagnosed as a neoplastic renal mass, resulting in unnecessary nephrectomy. Here we presented a case of splenorenal fusion in an elderly female patient, which was initially misdiagnosed as renal cell carcinoma in sonography. More specific imaging modalities and biopsy are helpful in suggesting the correct diagnosis. PMID- 30420562 TI - Cerebral tuberculomas in a 6-year-old girl causing central diabetes insipidus. AB - A 6-year-old girl presented acutely with worsening frontal headaches. She had a 3 month history of lethargy, reduced appetite, weight loss, cough and intermittent fevers. A chest X-ray showed a left upper lobe consolidation, and a CT head showed multiple enhancing lesions with significant surrounding oedema in both cerebral hemispheres. Due to the strong suspicion of tuberculosis (TB), she was admitted and treated with anti-TB therapy and steroids. Following this, pulmonary infection with Mycobacterium tuberculosis was confirmed by a positive PCR from induced sputum. Cerebral spinal fluid (CSF) analysis was normal and tested negative for M. tuberculosis on PCR. During her first week of treatment, she developed polyuria, nocturia and polydipsia and was diagnosed with central diabetes insipidus. She was started on desmopressin which rapidly improved her symptoms, and she was continued on desmopressin for 3 months. Currently, she remains well and has shown a good response to TB treatment. PMID- 30420557 TI - Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration. AB - A set of glutamylases and deglutamylases controls levels of tubulin polyglutamylation, a prominent post-translational modification of neuronal microtubules. Defective tubulin polyglutamylation was first linked to neurodegeneration in the Purkinje cell degeneration (pcd) mouse, which lacks deglutamylase CCP1, displays massive cerebellar atrophy, and accumulates abnormally glutamylated tubulin in degenerating neurons. We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile onset neurodegeneration and confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation. The human disease mainly affected the cerebellum, spinal motor neurons, and peripheral nerves. We also demonstrate previously unrecognized peripheral nerve and spinal motor neuron degeneration in pcd mice, which thus recapitulated key features of the human disease. Our findings link human neurodegeneration to tubulin polyglutamylation, entailing this post-translational modification as a potential target for drug development for neurodegenerative disorders. PMID- 30420564 TI - Clinical and radiological findings in a severe case of cleidocranial dysplasia. AB - Cleidocranial dysplasia (CCD) is a rare congenital autosomal dominant condition, causing hypoplasia of the clavicle, abnormal formation of teeth, skeletal and craniofacial bones. CCD is caused by the mutation of RUNX2/CBFA1 present in the short arm of chromosome 6 at position 21.1, a transcription factor essential for the formation of teeth, cartilage and bone. Patients with CCD show the classical features of excessive mobility of the shoulder bone, lack of resorption of the deciduous teeth, failure to erupt permanent teeth, multiple impacted and supernumerary teeth, and open fontanelle and sutures of the skull. In this article we report a case of CCD in a 16-year-old male patient, with an aim to highlight the clinical, radiological and recommended treatment guidelines. PMID- 30420566 TI - Auxin function in the brown alga Dictyota dichotoma. AB - Auxin controls body plan patterning in land plants and has been proposed to play a similar role in the development of brown algae (Phaeophyta) despite their distant evolutionary relationship with land plants. The mechanism of auxin action in brown algae remains controversial because of contradicting conclusions derived from pharmacological studies on Fucus. In this study, we used Dictyota dichotoma as a model system to show that auxin plays a role during the apical-basal patterning of the embryo of brown algae. Indole-3-acetic acid (IAA) was detectable in D. dichotoma germlings and mature tissue. Although two-celled D. dichotoma zygotes normally develop a rhizoid from one pole and a thallus meristem from the other, addition of exogenous auxins to one-celled embryos affected polarization, and both poles of the spheroidal embryo developed into rhizoids instead. The effect was strongest at lower pH and when variable extrinsic informational cues were applied. 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid (BUM), an inhibitor of ABC-B/multi-drug resistance/P-glycoprotein (ABCB) subfamily of transporters in land plants, affected rhizoid formation by increasing rhizoid branching and inducing ectopic rhizoids. An in silico survey of auxin genes suggested a diverse range of biosynthesis genes and transport genes, such as PIN-LIKES (PILS) and ATP-binding cassete subfamily (ABCB) transporters, from land plants have homologues in D. dichotoma and Ectocarpus siliculosus. Together with reports on auxin function in basal lineages of green algae, these results suggest that auxin function predates the divergence between the green and brown lineage and the transition towards land plants. PMID- 30420565 TI - Predicting novel therapies and targets: Regulation of Notch3 by the bromodomain protein BRD4. AB - BACKGROUND: Systematic approaches for accurate re-purposing of targeted therapies are needed. We developed and aimed to biologically validate our Therapy Predicting Tool (TPT) for the re-purposing of targeted therapies for specific tumor types by testing the role of Bromodomain and Extra-Terminal motif inhibitors (BETis) in inhibiting BRD4 function and downregulating Notch3 signaling in ovarian cancer. METHODS: Utilizing established ovarian cancer pre clinical models, we carried out in vitro and in vivo studies using clinically relevant BETis to determine their therapeutic effect and impact on Notch3 signaling. RESULTS: Treatment with BETis or siRNA mediated BRD4 knockdown resulted in decreased cell viability, reduced cell proliferation and increased cell apoptosis in vitro. In vivo with orthotopic mouse models demonstrated that treatment with BETi decreased tumor growth. Additionally, knockdown of BRD4 with doxycycline inducible shRNA increased survival up to 50% (p < 0.001). Treatment with either BETis or BRD4 siRNA decreased Notch3 expression both in vitro and in vivo. BRD4 inhibition also decreased the expression of NOTCH3 targets, including HES1. Chromatin immunoprecipitation revealed that BRD4 was present at the NOTCH3 promoter. CONCLUSION: Our findings provide biological validation for the TPT by demonstrating that BETis can be an effective therapeutic for ovarian cancer by downregulating Notch3 expression. IMPACT: The TPT could rapidly identify candidate drugs for ovarian or other cancers along with novel companion biomarkers. PMID- 30420567 TI - Genetic dissection of Fe-dependent signaling in root developmental responses to phosphate deficiency. AB - The inhibition of primary root (PR) growth is a major developmental response of Arabidopsis (Arabidopsis thaliana) to phosphate (Pi) deficiency. Previous studies have independently uncovered key roles of the LOW PHOSPHATE RESPONSE 1 (LPR1) ferroxidase, the tonoplast-localized ALUMINIUM SENSITIVE 3 (ALS3)/ SENSITIVE TO ALUMINUM RHIZOTOXICITY 1 (STAR1) transporter complex, and the SENSITIVE TO PROTON RHIZOTOXICITY 1 (STOP1, a transcription factor)- ALUMINUM-ACTIVATED MALATE TRANSPORTER 1 (ALMT1, a malate transporter) regulatory module in mediating this response by controlling iron (Fe) homeostasis in roots, but how these three components interact to regulate PR growth under Pi deficiency remains unknown. Here, we dissected genetic relationships among these three key components and found that: 1) STOP1, ALMT1, and LPR1 act downstream of ALS3/STAR1 in controlling PR growth under Pi deficiency; 2) ALS3/STAR1 inhibits the STOP1-ALMT1 pathway by repressing STOP1 protein accumulation in the nucleus; 3) STOP1-ALMT1 and LPR1 control PR growth under Pi deficiency in an interdependent manner involving the promotion of malate-dependent Fe accumulation in roots. Further, this malate mediated Fe accumulation depends on external Pi availability. We also performed a detailed analysis of the dynamic changes in the tissue-specific Fe accumulation patterns in the root tips of plants exposed to Pi deficiency. The results indicate that the degree of inhibition of PR growth induced by Pi deficiency is not linked to the level of Fe accumulated in the root apical meristem or elongation zone. Our work provides insights into the molecular mechanism that regulates the root developmental response to Pi deficiency. PMID- 30420568 TI - Powerful Together. PMID- 30420569 TI - Effects of Continuing Education Incentives on Clinical Instructors. AB - PURPOSE: To research whether the ability to earn continuing education (CE) credit for time spent teaching motivates radiologic science professionals to teach students in clinic and to assess whether sonographers, who earn CE credit for time teaching, have more positive attitudes toward teaching than those in modalities who do not earn CE credit for time spent teaching. METHODS: Researchers developed a 2-track digital survey and delivered it electronically and on paper to clinical instructors working at hospitals affiliated with Department of Medical Imaging and Radiation Sciences programs at the University of Oklahoma Health Sciences Center. Responses were collected for 2 weeks and then compared quantitatively using chi-square tests and logistic regression models. Qualitative results were examined for themes, and proportions among themes were reported. RESULTS: A total of 239 people responded, with 166 responses coming from individuals working in radiography, radiation therapy, nuclear medicine, and medical dosimetry, and 73 responses from sonography. Receiving CE credit did not result in a difference in teaching attitudes (x2 5 0.0004, DF 5 1, P 5 .985). However, the non-CE credit-earning population showed a 12% increase in positive attitudes if allowed to earn CE credit in the future (95% CI; 0.08, 0.17). DISCUSSION: Student learning and performance in clinic directly are related to experiencing a positive learning environment. Factors other than CE credit appear to motivate instructors to teach students. Although the results of this study did not support the hypotheses, this study furthers the need to discuss whether offering CE credit for clinic instruction is something the profession should consider. CONCLUSION: Clinical instructors who are willing to teach are the most desirable to students. Further evaluation of CE credit as an extrinsic motivating factor for clinical instructorship is important for providing the best positive learning environment for students. PMID- 30420570 TI - Collaborative Concept Mapping in an Image Evaluation Course: A Pilot Study. AB - PURPOSE: To evaluate student perceptions of collaborative concept mapping exercises in an image acquisition and technical evaluation course. METHODS: First year radiologic technology students worked collaboratively throughout the semester to create concept maps for receptor exposure, contrast, spatial resolution, and distortion. They completed a survey at the end of the course that detailed whether the maps were helpful for learning and understanding the content. RESULTS: The majority (90%) of the student participants responded favorably to the concept mapping activity, saying the maps were helpful for learning how certain technical factors affect image quality. In addition, 85% of the participants thought concept maps should be used in future radiologic technology courses. DISCUSSION: Although this pilot study was limited by its small sample size, students' favorable results suggest that concept mapping is a valuable instructional tool in helping students learn image evaluation principles and therefore warrants a larger-scale investigation. CONCLUSION: Additional research is warranted to address the use of concept maps in other radiologic science content areas. PMID- 30420571 TI - Myocardial Perfusion Study to Detect Coronary Artery Disease. AB - Nuclear medicine uses radiopharmaceuticals to diagnose and treat disease. The myocardial perfusion study shows how well blood flows through the coronary arteries to the muscle tissue of the heart. The procedure most often is used to diagnose coronary artery disease (CAD), a condition where plaque and inflammation has damaged the coronary arteries. This article discusses CAD and its risk factors, functions of the heart, the role of radiopharmaceuticals in myocardial perfusion studies, and diagnosis and treatment of common coronary artery blockages. PMID- 30420572 TI - Fluoroscopic Evaluation of Adult Male Urethral Abnormalities. AB - Retrograde urethrograms and voiding cystourethrograms provide clinicians with important information to determine treatment options and surgical interventions for patients with urethral abnormalities. This article discusses the elements with which radiologic technologists should be familiar, including urethra anatomy, the pathology of urethral abnormalities, imaging techniques, and special considerations for preoperative and postoperative patients. PMID- 30420573 TI - Virtual Simulation in Radiologic Science Education. PMID- 30420574 TI - Learning Theories: Behaviorism. PMID- 30420575 TI - Learning Theories: Cognitivism. PMID- 30420577 TI - Digital Portfolios: A Method to Assess Student Understanding. PMID- 30420576 TI - Learning Theories: Constructivism. PMID- 30420578 TI - Getting Started: Putting Courses Online. PMID- 30420579 TI - Engaging Students Online. PMID- 30420580 TI - Integrating Informatics in the Patient Care Classroom. PMID- 30420581 TI - Interprofessional Education: Learning With, From, and About One Another. PMID- 30420582 TI - Student Supervision in the Clinical Setting. PMID- 30420583 TI - PET-CT Cancer Imaging. AB - Positron emission tomography-computed tomography (PET-CT) imaging combines the anatomic precision of CT with the molecular-metabolic detail of PET. This creates information-enriched images that can inform diagnostic oncology, tumor staging, treatment planning, and treatment monitoring. PMID- 30420584 TI - Color Spectrographic Respiratory Monitoring from the External Ear Canal. AB - The need for simple and reliable means of respiratory monitoring has existed since the beginnings of medicine. In this study we describe the use of color spectrographic analysis of breathing sounds recorded from the external ear canal as a candidate technology to meet this need. A miniature electret microphone was modified with the addition of an adapter to allow it to be placed comfortably in the external ear canal. The amplified signal was then connected to a real-time color spectrogram program running on a laptop personal computer utilizing the Windows operating system. Based on the results obtained, we hypothesize that the real-time display of color spectrogram breathing patterns locally or at a central monitoring station may turn out to be a useful means of respiratory monitoring in patients at increased risk of respiratory depression or other respiratory problems. Finally, we conducted a statistical analysis that suggests that significant spectrogram differences may exist among some groups investigated in the study. PMID- 30420585 TI - THC for age-related cognitive decline? PMID- 30420586 TI - Drain amylase monitoring for early diagnosis of anastomotic leakage in sleeve gastrectomy An animal study. AB - BACKGROUND: Sleeve gastrectomy(SG) is a popular bariatric surgery procedure with rare but dreaded complications. Although drain amylase levels are a reliable early predictor of anastomosis leakage in oesophagectomy and pancreaticoduodenectomy, for SG have not yet been studied. We aimed to monitor drain amylase levels to ascertain their applicability for early diagnosis of gastric leakage in SG. METHODS: Twenty-four rats were randomly divided into three groups: Group A: only laparotomy and abdominal drain; Group B: laparotomy, SG, and drain; Group C: laparotomy, SG with fistula,and drain. On postoperative days 0,1,2,3, and 4, drain lavage samples were collected to measure amylase. RESULTS: Groups were compared in pairs. Preoperative weights were not significantly different in any comparison. On postoperative days 0,1,2,3, and 4, drain amylase levels were found to be significantly lower in Group A than in Group B as well as in Group A than in Group C but were significantly higher in Group C than in Group B. For postoperative day 1, a receiver operating characteristic curve was done. Drain amylase levels over 1514 IU were statistically significant for leakage. CONCLUSIONS: Drain amylase levels were significantly high in sleeve gastrectomy with fistula. This indicates that drain amylase level monitoring might be an easy and cheap alternative for determining staple-line leakage for high risk patients with Body Mass Index(BMI)>50kg/m2 in whom we cannot use radiological imaging. KEY WORDS: Animal Experimental Study, Bariatric Surgery, Drain amylase, Sleeve gastrectomy, Staple-line leakage. PMID- 30420588 TI - Expression and Molecular Regulation of the Cox2 Gene in Gastroenteropancreatic Neuroendocrine Tumors and Antiproliferation of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). AB - BACKGROUND Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has had a significant increase over the past 4 decades. The pathophysiological role of the cyclooxygenase-2 (cox-2) gene and factors responsible for the expression in GEP NETs is of clinical value. Current study determined the expression of cox-2 gene in human GEP-NET tissues and corresponding cell lines, investigated the molecular mechanisms underlying the regulation of cox-2 gene expression and assessed the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on both anchorage dependent and independent growth of GEP-NET cells. MATERIAL AND METHODS GEP-NET tissues and QGP-1, BON, and LCC-18 GEP-NET cell lines were used. The expression of cox-2 gene was analyzed by immunohistochemistry, western blot, RT-PCR, and enzyme immunoassay. Transient transfection and luciferase assays along with electrophoretic mobility shift assays were conducted to explore the regulation of cox-2 gene expression. The effect of COX-inhibitors on GEP-NET cell growth was determined by proliferation assays and colony growth assessment. RESULTS We found 87.8% of GEP-NET tissues stained positive for COX-2. QGP-1 and LCC-18 cells expressed cox-2 gene. PGE2 (prostaglandin E2) amounts quantified in the supernatants of NET cells matched to cox-2 expression level. The CRE-E-box element (-56 to -48 bp) and binding of USF1, USF2, and CREB transcription factors to this proximal promoter element were essential for cox-2 promoter activity in GEP-NET cells. COX-2-specific inhibitor NS-398 potently and dose-dependently inhibited PGE2 release from QGP-1 cells. Interestingly, both NS-398 and acetylic salicylic acid effectively suppressed proliferation of QGP-1 and BON cells in a dose-dependent manner. CONCLUSIONS The majority of GEP-NETs over express cox-2 gene. The binding of CREB and USF-1/-2 transcription factors to a proximal, overlapping CRE-Ebox element is the underlying mechanism for cox-2 gene expression. NSAIDs potently suppressed the proliferations and may offer a novel approach for chemoprevention and therapy of GEP-NETs. PMID- 30420587 TI - Worldwide Variation in Human Milk Metabolome: Indicators of Breast Physiology and Maternal Lifestyle? AB - Human milk provides essential substrates for the optimal growth and development of a breastfed infant. Besides providing nutrients to the infant, human milk also contains metabolites which form an intricate system between maternal lifestyle, such as the mother's diet and the gut microbiome, and infant outcomes. This study investigates the variation of these human milk metabolites from five different countries. Human milk samples (n = 109) were collected one month postpartum from Australia, Japan, the USA, Norway, and South Africa and were analyzed by nuclear magnetic resonance. The partial least squares discriminant analysis (PLS-DA) showed separation between either maternal countries of origin or ethnicities. Variation between countries in concentration of metabolites, such as 2 oxoglutarate, creatine, and glutamine, in human milk, between countries, could provide insights into problems, such as mastitis and/or impaired functions of the mammary glands. Several important markers of milk production, such as lactose, betaine, creatine, glutamate, and glutamine, showed good correlation between each metabolite. This work highlights the importance of milk metabolites with respect to maternal lifestyle and the environment, and also provides the framework for future breastfeeding and microbiome studies in a global context. PMID- 30420589 TI - Preterm Labor Caused by Hemolysis, Elevated Liver Enzymes, Low Platelet Count (HELLP) Syndrome and Postpartum Infection Complicated with Actinomyces Species: A Case Report. AB - BACKGROUND Actinomyces species are normal flora of the upper respiratory, female genital, and gastrointestinal tract. Actinomyces species are generally considered to have a low virulence potential. Here we report one case of Actinomyces viscosus isolated from a neonatal blood culture as a consequence of extreme prematurity in the presence of HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome. CASE REPORT A 23-week gestational age female infant was born to a 32-year-old mother. The pregnancy was complicated by severe HELLP syndrome leading to cesarean section at 23-week gestation. The initial blood culture grew anaerobic gram-positive branching rods consistent with Actinomyces species. Due to patient instability, antibiotic was started and continued for a total of 13 days. On day of life 26, the reference laboratory identified the organism as A. viscosus by 16S ribosomal RNA. CONCLUSIONS In this case, Actinomyces species was a consequence of HELLP syndrome and consecutive extreme prematurity. Further research to look more closely at Actinomyces species isolated from neonatal blood culture will help to elucidate the true significance of these isolates. PMID- 30420591 TI - [Zika virus epidemic. The Public Health response in Spain]. AB - By mid-2015, an increase in the number of cases of microcephaly among newborns and neurologic disorders was detected in the Northwest of Brazil, which was possibly associated with Zika virus infection. Later on, this phenomenon was also observed in several Latin-American countries. In February 2016, the World Health Organization (WHO) on this basis, declared a Public Health Emergency of International Concern. From that moment on, several measures were adopted to achieve the epidemic control at both international and national levels. The WHO launched a strategic response plan based on case detection, infection control and treatment, as well as, the research and development of new vector control tools, diagnostic tests and vaccines. In Europe both surveillance and vector control systems were reinforced. The countries reporting most cases were France, Spain and the United Kingdom. In Spain, due to the high probability of case importation based on the close relationships with Latin-America, numerous measures were adopted to achieve a rapid response and an optimal control. Those included: the implementation of an active surveillance in collaboration with several experts, institutions and scientific societies; entomologic surveillance enhancement; the development of communication activities and recommendations for both healthcare workers and general population. PMID- 30420590 TI - Recurrence of Hepatitis B Infection in Liver Transplant Patients Receiving Long Term Hepatitis B Immunoglobulin Prophylaxis. AB - BACKGROUND Long-term real-world data are relatively sparse regarding recurrence of chronic hepatitis B virus (HBV) infection after liver transplantation using hepatitis B immunoglobulin (HBIg) and nucleos(t)ide analogue (NUC) prophylaxis. MATERIAL AND METHODS Data from 371 adults transplanted for HBV-related disease at 20 European centers and given HBIg for 312 months +/- NUC therapy were analyzed retrospectively. RESULTS HBIg comprised Hepatect(r) (iv HBIgB; n=299), subcutaneous Zutectra(r) (sc HBIg, n=236), and other HBIg preparations (n=130); 93.5% received NUC therapy. Mean follow-up was 6.8+/-3.5 years. The primary efficacy variable, freedom from HBV recurrence, occurred in 95.7% of patients (95% CI [93.1%, 97.5%]). The observed incidence of recurrence was 16/371 (4.3%) (annual rate 0.65%); 5/16 patients with recurrence had discontinued HBIg and 7/16 had anti-HBs <100 IU/l. Excluding these 7 patients, the HBV recurrence rate was 2.4%. The recurrence rate while on HBIg therapy was 1 per 2069 months. In patients who discontinued HBIg, risk of HBV recurrence versus sc HBIg users was increased by 5.2-fold (1 per 1 603 versus 1 per 8379 treatment months). The annual rate of HBV-related hepatocellular carcinoma (HCC) recurrence was 1.7%. CONCLUSIONS These results support the long-term use of HBIg with NUC therapy as an effective management strategy to minimize risk of HBV recurrence and virus related complications after liver transplantation. PMID- 30420593 TI - Prognostic and therapeutic significance of phosphorylated STAT3 and protein tyrosine phosphatase-6 in peripheral-T cell lymphoma. AB - Peripheral T cell lymphomas (PTCL) is a heterogenous group of non-Hodgkin lymphoma and many patients remain refractory to the frontline therapy. Identifying new prognostic markers and treatment is an unmet need in PTCL. We analyzed phospho-STAT3 (pSTAT3) expression in a cohort of 169 PTCL tumors and show overall 38% positivity with varied distribution among PTCL subtypes with 27% (16/59) in PTCL-NOS; 29% (11/38) in AITL, 57% (13/28) in ALK-negative ALCL, and 93% in ALK-pos ALCL (14/15), respectively. Correlative analysis indicated an adverse correlation between pSTAT3 and overall survival (OS). PTPN6, a tyrosine phosphatase and potential negative regulator of STAT3 activity, was suppressed in 62% of PTCL-NOS, 42% of AITL, 60% ALK-neg ALCL, and 86% of ALK-pos ALCL. Loss of PTPN6 combined with pSTAT3 positivity predicted an infwere considered significantferior OS in PTCL cases. In vitro treatment of TCL lines with azacytidine (aza), a DNA methyltransferase inhibitor (DNMTi), restored PTPN6 expression and decreased pSTAT3. Combining DNMTi with JAK3 inhibitor resulted in synergistic antitumor activity in SUDHL1 cell line. Overall, our results suggest that PTPN6 and activated STAT3 can be developed as prognostic markers, and the combination of DNMTi and JAK3 inhibitors as a novel treatment for patients with PTCL subtypes. PMID- 30420592 TI - Prognostic Value of MicroRNAs in Esophageal Carcinoma: A Meta-Analysis. AB - BACKGROUND: Numerous articles have reported that abnormal expression levels of microRNAs (miRNAs) are related to the survival times of esophageal carcinoma (EC) patients, which contains esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). Nevertheless, there has not been a comprehensive meta analysis to assess the accurate prognostic value of miRNAs in EC. METHODS: Studies published in English up to April 12, 2018 that evaluated the correlation of the expression levels of miRNAs with overall survival (OS) in EC were identified by online searches in PubMed, EMBASE, Web of Science, and the Cochrane Database of Systematic Reviews performed by two independent authors. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were used to estimate the correlation between OS and miRNA expression. HR >= 2 was considered cutoff for considering the miRNA as prognostic candidate. RESULTS: Forty-four pertinent articles with 22 miRNAs and 4310 EC patients were ultimately included. EC patients with tissue expression levels of high miR-21 or low miR-133a (HR = 2.48, 95% CI = 1.50-4.12), miR-133b (HR = 2.15, 95% CI = 1.27-3.62), miR-138 (HR = 2.27, 95% CI = 1.68-3.08), miR-203 (HR = 2.83, 95% CI = 1.35-5.95), miR-375 and miR-655 (HR = 2.66, 95% CI = 1.16-6.12) had significantly poorer OS (P < 0.05). In addition, EC patients with blood expression levels of high miR-21 (HR = 2.19, 95% CI = 1.31-3.68) and miR-223 had significantly shorter OS (P < 0.05). CONCLUSIONS: In conclusion, tissue expression levels of miR-21, miR-133a, miR 133b, miR-138, miR-203, miR-375, and miR-655 and blood expression levels of miR 21 and miR-223 demonstrate significant prognostic value. Among them, the expression levels of miR-133a, miR-133b, miR-138, miR-203, and miR-655 in tissue and the expression level of miR-21 in blood are potential prognostic candidates for predicting OS in EC. PMID- 30420596 TI - Dynamic Greenland ice sheet driven by pCO2 variations across the Pliocene Pleistocene transition. AB - It is generally considered that the perennial glaciation of Greenland lasting several orbital cycles began around 2.7 Ma along with the intensification of Northern Hemisphere glaciation (NHG). Both data and model studies have demonstrated that a decline in atmospheric pCO2 was instrumental in establishing a perennial Greenland ice sheet (GrIS), yet models have generally used simplistic pCO2 constraints rather than data-inferred pCO2 evolution. Here, using a method designed for the long-term coupling of climate and cryosphere models and pCO2 scenarios from different studies, we highlight the pivotal role of pCO2 on the GrIS expansion across the Plio-Pleistocene Transition (PPT, 3.0-2.5 Ma), in particular in the range between 280 and 320 ppm. Good qualitative agreement is obtained between various IRD reconstructions and some of the possible evolutions of the GrIS simulated by our model. Our results underline the dynamism of the GrIS waxing and waning under pCO2 levels similar to or lower than today, which supports recent evidence of a dynamic GrIS during the Plio-Pleistocene. PMID- 30420595 TI - Pressure shock fronts formed by ultra-fast shear cracks in viscoelastic materials. AB - Spontaneously propagating cracks in solids emit both pressure and shear waves. When a shear crack propagates faster than the shear wave speed of the material, the coalescence of the shear wavelets emitted by the near-crack-tip region forms a shock front that significantly concentrates particle motion. Such a shock front should not be possible for pressure waves, because cracks should not be able to exceed the pressure wave speed in isotropic linear-elastic solids. In this study, we present full-field experimental measurements of dynamic shear cracks in viscoelastic polymers that result in the formation of a pressure shock front, in addition to the shear one. The apparent violation of classic theories is explained by the strain-rate-dependent material behavior of polymers, where the crack speed remains below the highest pressure wave speed prevailing locally around the crack tip. These findings have important implications for the physics and dynamics of shear cracks such as earthquakes. PMID- 30420594 TI - Increased virulence of the oral microbiome in oral squamous cell carcinoma revealed by metatranscriptome analyses. AB - Oral squamous cell carcinoma (OSCC) is the most prevalent and most commonly studied oral cancer. However, there is a void regarding the role that the oral microbiome may play in OSCC. Although the relationship between microbial community composition and OSCC has been thoroughly investigated, microbial profiles of the human microbiome in cancer are understudied. Here we performed a small pilot study of community-wide metatranscriptome analysis to profile mRNA expression in the entire oral microbiome in OSCC to reveal molecular functions associated with this disease. Fusobacteria showed a statistically significantly higher number of transcripts at tumour sites and tumour-adjacent sites of cancer patients compared to the healthy controls analysed. Regardless of the community composition, specific metabolic signatures were consistently found in disease. Activities such as iron ion transport, tryptophanase activity, peptidase activities and superoxide dismutase were over-represented in tumour and tumour adjacent samples when compared to the healthy controls. The expression of putative virulence factors in the oral communities associated with OSCC showed that activities related to capsule biosynthesis, flagellum synthesis and assembly, chemotaxis, iron transport, haemolysins and adhesins were upregulated at tumour sites. Moreover, activities associated with protection against reactive nitrogen intermediates, chemotaxis, flagellar and capsule biosynthesis were also upregulated in non-tumour sites of cancer patients. Although they are preliminary, our results further suggest that Fusobacteria may be the leading phylogenetic group responsible for the increase in expression of virulence factors in the oral microbiome of OSCC patients. PMID- 30420598 TI - Light-controlled switching of the spin state of iron(III). AB - Controlled switching of the spin state of transition metal ions, particularly of FeII and FeIII, is a prerequisite to achieve selectivity, efficiency, and catalysis in a number of metalloenzymes. Here we report on an iron(III) porphyrin with a photochromic axial ligand which, upon irradiation with two different wavelengths reversibly switches its spin state between low-spin (S = 1/2) and high-spin (S = 5/2) in solution (DMSO-acetone, 2:598). The switching efficiency is 76% at room temperature. The system is neither oxygen nor water sensitive, and no fatigue was observed after more than 1000 switching cycles. Concomitant with the spin-flip is a change in redox potential by ~60 mV. Besides serving as a simple model for the first step of the cytochrome P450 catalytic cycle, the spin switch can be used to switch the spin-lattice relaxation time T1 of the water protons by a factor of 15. PMID- 30420597 TI - Vibrio cholerae motility exerts drag force to impede attack by the bacterial predator Bdellovibrio bacteriovorus. AB - The bacterial predator Bdellovibrio bacteriovorus is evolved to attack and kill other bacteria, including the human intestinal pathogen Vibrio cholerae. Although B. bacteriovorus exhibit a broad prey range, little is known about the genetic determinants of prey resistance and sensitivity. Here we perform a genetic screen on V. cholerae and identify five pathways contributing to predation susceptibility. We find that the essential virulence regulators ToxR/S increase susceptibility to predation, as mutants of these genes are more resistant to predation. We observe by flow cytometry that lipopolysaccharide is a critical defense, as mutants lacking O-antigen are rapidly attacked by predatory B. bacteriovorus. Using polymer solutions to alter media viscosity, we find that when B. bacteriovorus attacks motile V. cholerae, increased drag forces slow its ability to prey. These results provide insights into key prey resistance mechanisms, and may be useful in the application of B. bacteriovorus in treating infections. PMID- 30420599 TI - Trends in Q fever serologic testing by immunofluorescence from four large reference laboratories in the United States, 2012-2016. AB - Laboratory testing for Q fever (Coxiella burnetii) is essential for a differential diagnosis, yet little is known about Q fever diagnostic testing practices in the United States. We retrospectively analyzed Q fever immunoglobulin G (IgG) indirect immunofluorescence assay (IFA) testing data between 1/1/2012-10/31/2016 from ARUP, LabCorp, Mayo Medical Laboratories, and Quest Diagnostics. Data included IgG phase I and phase II titers, patient age and sex, and state and date of specimen collection. On average, 12,821 specimens were tested for Q fever annually by the participating laboratories. Of 64,106 total specimens, 84.1% tested negative for C. burnetii-specific antibodies. Positive titers ranged from 16 to 262,144 against both phase I and phase II antigens. Submission of specimens peaked during the summer months, and more specimens were submitted from the West North Central division. Testing occurred more frequently in males (53%) and increased with age. In conclusion, few U.S. Q fever cases are reported, despite large volumes of diagnostic specimens tested. Review of commercial laboratory data revealed a lack of paired serology samples and patterns of serology titers that differ from case reporting diagnostic criteria. PMID- 30420600 TI - Amelioration of diabetic nephropathy in db/db mice treated with tibetan medicine formula Siwei Jianghuang Decoction Powder extract. AB - Siwei Jianghuang Decoction Powder (SWJH) documented originally in the Four Medical Tantras-Blue Glaze exhibited beneficial effects on diabetic nephropathy (DN) via combined synergistically action of multiple formula components including Curcumae longae Rhizoma, Berberidis dictyophyllae Cortex, Phyllanthi Fructus and Tribuli Fructus. This study investigated the effects of SWJH on DN in db/db mice and possible underlying mechanisms. The ten weeks old db/db mice treated with SWJH by intra-gastric administration once a day for 8 weeks. After 8 weeks, body weight, water and food intake of mice were recorded. The level of fasting blood glucose (FBG) was measured. Serum creatinine (Scr), blood urea nitrogen (BUN), urine microalbumin (UMAlb), serum uric acid (UA) and urinary albumin excretion (UAE) were detected. An enzyme-linked immunosorbent assay was performed to test serum vascular endothelial growth factor (VEGF) and transforming growth factor beta1 (TGF-beta1). Real-time PCR and Western blot analysis were used to test mRNA and protein expression of hypoxia inducible factor-1alpha (HIF-1alpha), VEGF and TGF-beta1 in kidney tissue. SWJH treatment significantly reduced the levels of FBG, Scr, BUN, UMAlb, UA and UAE and retarded renal fibrosis. SWJH treatment further significantly reduced serum TGF-beta1 level and downregulated the expression of HIF-1alpha, VEGF and TGF-beta1 at both mRNA and protein levels. Principal component analysis and partial least squares regression and hierarchical cluster analysis demonstrated that SWJH treatment significantly ameliorated renal damage in DN mice. These consequences suggested that SWJH formulations were effective in the treatment of DN through regulating the HIF 1alpha, VEGF and TGF-beta1 overexpression. PMID- 30420601 TI - Driving the expression of the Salmonella enterica sv Typhimurium flagellum using flhDC from Escherichia coli results in key regulatory and cellular differences. AB - The flagellar systems of Escherichia coli and Salmonella enterica exhibit a significant level of genetic and functional synteny. Both systems are controlled by the flagellar specific master regulator FlhD4C2. Since the early days of genetic analyses of flagellar systems it has been known that E. coli flhDC can complement a ?flhDC mutant in S. enterica. The genomic revolution has identified how genetic changes to transcription factors and/or DNA binding sites can impact the phenotypic outcome across related species. We were therefore interested in asking: using modern tools to interrogate flagellar gene expression and assembly, what would the impact be of replacing the flhDC coding sequences in S. enterica for the E. coli genes at the flhDC S. entercia chromosomal locus? We show that even though all strains created are motile, flagellar gene expression is measurably lower when flhDCEC are present. These changes can be attributed to the impact of FlhD4C2 DNA recognition and the protein-protein interactions required to generate a stable FlhD4C2 complex. Furthermore, our data suggests that in E. coli the internal flagellar FliT regulatory feedback loop has a marked difference with respect to output of the flagellar systems. We argue due diligence is required in making assumptions based on heterologous expression of regulators and that even systems showing significant synteny may not behave in exactly the same manner. PMID- 30420602 TI - Coherent Tabletop EUV Ptychography of Nanopatterns. AB - Coherent diffraction imaging (CDI) or lensless X-ray microscopy has become of great interest for high spatial resolution imaging of, e.g., nanostructures and biological specimens. There is no optics required in between an object and a detector, because the object can be fully recovered from its far-field diffraction pattern with an iterative phase retrieval algorithm. Hence, in principle, a sub-wavelength spatial resolution could be achieved in a high numerical aperture configuration. With the advances of ultrafast laser technology, high photon flux tabletop Extreme Ultraviolet (EUV) sources based on the high-order harmonic generation (HHG) have become available to small-scale laboratories. In this study, we report on a newly established high photon flux and highly monochromatic 30 nm HHG beamline. Furthermore, we applied ptychography, a scanning CDI version, to probe a nearly periodic nanopattern with the tabletop EUV source. A wide-field view of about 15 * 15 MUm was probed with a 2.5 MUm-diameter illumination beam at 30 nm. From a set of hundreds of far-field diffraction patterns recorded for different adjacent positions of the object, both the object and the illumination beams were successfully reconstructed with the extended ptychographical iterative engine. By investigating the phase retrieval transfer function, a diffraction-limited resolution of reconstruction of about 32 nm is obtained. PMID- 30420603 TI - Dorsal raphe serotonin neurons inhibit operant responding for reward via inputs to the ventral tegmental area but not the nucleus accumbens: evidence from studies combining optogenetic stimulation and serotonin reuptake inhibition. AB - The monoamine neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) exerts an inhibitory influence over motivation, but the circuits mediating this are unknown. Here, we used an optogenetic approach to isolate the contribution of dorsal raphe nucleus (DRN) 5-HT neurons and 5-HT innervation of the mesolimbic dopamine (DA) system to motivated behavior in mice. We found that optogenetic stimulation of DRN 5-HT neurons enhanced downstream 5-HT release, but this was not sufficient to inhibit operant responding for saccharin, a measure of motivated behavior. However, combining optogenetic stimulation of DRN 5-HT neurons with a low dose of the selective serotonin reuptake inhibitor (SSRI) citalopram synergistically reduced operant responding. We then examined whether these effects could be recapitulated if optogenetic stimulation specifically targeted 5-HT terminals in the ventral tegmental area (VTA) or nucleus accumbens (NAc) of the mesolimbic DA system. Optogenetic stimulation of 5-HT input to the VTA combined with citalopram treatment produced a synergistic decrease in responding for saccharin, resembling the changes produced by targeting 5-HT neurons in the DRN. However, this effect was not observed when optogenetic stimulation targeted 5-HT terminals in the NAc. Taken together, these results suggest that DRN 5-HT neurons exert an inhibitory influence over operant responding for reward through a direct interaction with the mesolimbic DA system at the level of the VTA. These studies support an oppositional interaction between 5-HT and DA systems in controlling motivation and goal-directed behavior, and have important implications for the development and refinement of treatment strategies for psychiatric disorders such as depression and addiction. PMID- 30420604 TI - Unprecedented rains decimate surface microbial communities in the hyperarid core of the Atacama Desert. AB - The hyperarid core of the Atacama Desert, the driest and oldest desert on Earth, has experienced a number of highly unusual rain events over the past three years, resulting in the formation of previously unrecorded hypersaline lagoons, which have lasted several months. We have systematically analyzed the evolution of the lagoons to provide quantitative field constraints of large-scale impacts of the rains on the local microbial communities. Here we show that the sudden and massive input of water in regions that have remained hyperarid for millions of years is harmful for most of the surface soil microbial species, which are exquisitely adapted to survive with meager amounts of liquid water, and quickly perish from osmotic shock when water becomes suddenly abundant. We found that only a handful of bacteria, remarkably a newly identified species of Halomonas, remain metabolically active and are still able to reproduce in the lagoons, while no archaea or eukaryotes were identified. Our results show that the already low microbial biodiversity of extreme arid regions greatly diminishes when water is supplied quickly and in great volumes. We conclude placing our findings in the context of the astrobiological exploration of Mars, a hyperarid planet that experienced catastrophic floodings in ancient times. PMID- 30420605 TI - A Lateral Flow Immunochromato-graphic Strip Test for Rapid Detection of Oseltamivir Phosphate in Egg and Chicken Meat. AB - A lateral flow immunochromatographic strip test (LFIST) based on a competitive format was developed for rapid and sensitive on-site detection of oseltamivir phosphate (OP) residues in poultry product. The sensitivity (half inhibitory concentration, IC50) of the LFIST in the detection of egg and chicken meat samples was confirmed to be 2.56 and 2.63 ug/kg, and the limit detection (LOD) value were 0.43 and 0.42 ug/kg, respectively. For intra-assay and inter-assay reproducibility, recoveries of OP spiked samples ranged between 82.8% and 91.2% with coefficients of variations (CV) less than 5.67% (intra-assay) and 6.52% (inter-assay). The performance of LFIST was comparable to high-performance liquid chromatography (HPLC) in a parallel testing of egg samples and chicken samples. LFIST takes less than 5 minutes, eliminates the dependency on professional personnel, and thus can be used as a surveillance tool for on-site detection of OP residues. PMID- 30420607 TI - Author Correction: Self-organization of a human organizer by combined Wnt and Nodal signalling. AB - Ref. 7 from Benvenisty and colleagues was inadvertently omitted; this has now been cited in the text and added to the reference list, and subsequent references have been renumbered. The Letter has been corrected online. PMID- 30420606 TI - The entropic force generated by intrinsically disordered segments tunes protein function. AB - Protein structures are dynamic and can explore a large conformational landscape1,2. Only some of these structural substates are important for protein function (such as ligand binding, catalysis and regulation)3-5. How evolution shapes the structural ensemble to optimize a specific function is poorly understood3,4. One of the constraints on the evolution of proteins is the stability of the folded 'native' state. Despite this, 44% of the human proteome contains intrinsically disordered peptide segments greater than 30 residues in length6, the majority of which have no known function7-9. Here we show that the entropic force produced by an intrinsically disordered carboxy terminus (ID-tail) shifts the conformational ensemble of human UDP-alpha-D-glucose-6-dehydrogenase (UGDH) towards a substate with a high affinity for an allosteric inhibitor. The function of the ID-tail does not depend on its sequence or chemical composition. Instead, the affinity enhancement can be accurately predicted based on the length of the intrinsically disordered segment, and is consistent with the entropic force generated by an unstructured peptide attached to the protein surface10-13. Our data show that the unfolded state of the ID-tail rectifies the dynamics and structure of UGDH to favour inhibitor binding. Because this entropic rectifier does not have any sequence or structural constraints, it is an easily acquired adaptation. This model implies that evolution selects for disordered segments to tune the energy landscape of proteins, which may explain the persistence of intrinsic disorder in the proteome. PMID- 30420608 TI - Hepatitis A virus infections, immunisations and demographic determinants in children and adolescents, Germany. AB - Hepatitis A is a vaccine-preventable disease with a global distribution. It predominantly occurs in regions with inadequate living conditions, but also affects populations in industrialised countries. Children are frequently involved in the transmission of hepatitis A virus (HAV) and thus play a central role in the epidemiology of hepatitis A. Here, we investigated HAV infections, immunisations, and associated demographic determinants in a nationwide, population-based, cross-sectional survey conducted in Germany from 2003-2006. Out of 17,640 children and adolescents, complete data sets (HAV serology, demographic information and vaccination card) were available for 12,249 (69%), all aged 3-17 years. We found protective antibody levels (>=20 IU/L) in 1,755 (14%) individuals, 1,395 (11%) were vaccinated against hepatitis A, 360 (3%) individuals were HAV seropositive without prior hepatitis A vaccination, thus indicating a previous HAV infection. Antibody prevalence (attributable to vaccination or infection) increased significantly with age. Multivariate logistic regression revealed that predominantly children and adolescents with migration background-even if they were born in Germany-are affected by HAV infections. Our results provide a rationale to emphasise existing vaccination recommendations and, moreover, to consider additional groups with a higher risk of infection for targeted vaccination, especially children with a migration background. PMID- 30420609 TI - High-throughput three-dimensional chemotactic assays reveal steepness-dependent complexity in neuronal sensation to molecular gradients. AB - Many cellular programs of neural development are under combinatorial regulation by different chemoattractive or chemorepulsive factors. Here, we describe a microfluidic platform that utilizes well-controlled three-dimensional (3D) diffusion to generate molecular gradients of varied steepness in a large array of hydrogel cylinders, allowing high-throughput 3D chemotactic assays for mechanistic dissection of steepness-dependent neuronal chemotaxis. Using this platform, we examine neuronal sensitivity to the steepness of gradient composed of netrin-1, nerve growth factor, or semaphorin3A (Sema3A) proteins, and reveal dramatic diversity and complexity in the associated chemotactic regulation of neuronal development. Particularly for Sema3A, we find that serine/threonine kinase-11 and glycogen synthase kinase-3 signaling pathways are differentially involved in steepness-dependent chemotactic regulation of coordinated neurite repellence and neuronal migration. These results provide insights to the critical role of gradient steepness in neuronal chemotaxis, and also prove the technique as an expandable platform for studying other chemoresponsive cellular systems. PMID- 30420610 TI - 5D operando tomographic diffraction imaging of a catalyst bed. AB - We report the results from the first 5D tomographic diffraction imaging experiment of a complex Ni-Pd/CeO2-ZrO2/Al2O3 catalyst used for methane reforming. This five-dimensional (three spatial, one scattering and one dimension to denote time/imposed state) approach enabled us to track the chemical evolution of many particles across the catalyst bed and relate these changes to the gas environment that the particles experience. Rietveld analysis of some 2 * 106 diffraction patterns allowed us to extract heterogeneities in the catalyst from the A to the nm and to the MUm scale (3D maps corresponding to unit cell lattice parameters, crystallite sizes and phase distribution maps respectively) under different chemical environments. We are able to capture the evolution of the Ni containing species and gain a more complete insight into the multiple roles of the CeO2-ZrO2 promoters and the reasons behind the partial deactivation of the catalyst during partial oxidation of methane. PMID- 30420611 TI - Denosumab and breast cancer risk in postmenopausal women: a population-based cohort study. AB - BACKGROUND: Denosumab inhibits the receptor activator of nuclear factor kappaB (RANK) pathway and is used to treat osteoporosis. Emerging evidence suggests RANK blockade may play a role in mammary tumourigenesis. Thus, we undertook a population-based study of denosumab use and breast cancer risk in a large cohort of postmenopausal women. METHODS: We included women 67+ years with prior bisphosphonate use who filled a first prescription for denosumab. They were matched on age, date, cumulative prior use of and time since last use of a bisphosphonate to women with no history of denosumab. Cox proportional hazards was used to estimate the hazard ratio (HR) of breast cancer with denosumab use. RESULTS: A total of 100,368 women were included in the analysis with 1271 incident breast cancer events. Denosumab use was associated with a 13% decreased breast cancer risk (HR = 0.87; 95% CI 0.76-1.00). There was no relationship between increasing number of denosumab doses and breast cancer risk (P-trend = 0.15). CONCLUSION: These findings suggest a potential protective effect of ever denosumab use on breast cancer risk in a cohort of older women previously treated with bisphosphonates. PMID- 30420612 TI - Bcl-2-dependent synthetic lethal interaction of the IDF-11774 with the V0 subunit C of vacuolar ATPase (ATP6V0C) in colorectal cancer. AB - BACKGROUND: The IDF-11774, a novel clinical candidate for cancer therapy, targets HSP70 and inhibits mitochondrial respiration, resulting in the activation of AMPK and reduction in HIF-1alpha accumulation. METHODS: To identify genes that have synthetic lethality to IDF-11774, RNA interference screening was conducted, using pooled lentiviruses expressing a short hairpin RNA library. RESULTS: We identified ATP6V0C, encoding the V0 subunit C of lysosomal V-ATPase, knockdown of which induced a synergistic growth-inhibitory effect in HCT116 cells in the presence of IDF-11774. The synthetic lethality of IDF-11774 with ATP6V0C possibly correlates with IDF-11774-mediated autolysosome formation. Notably, the synergistic effect of IDF-11774 and the ATP6V0C inhibitor, bafilomycin A1, depended on the PIK3CA genetic status and Bcl-2 expression, which regulates autolysosome formation and apoptosis. Similarly, in an experiment using conditionally reprogramed cells derived from colorectal cancer patients, synergistic growth inhibition was observed in cells with low Bcl-2 expression. CONCLUSIONS: Bcl-2 is a biomarker for the synthetic lethal interaction of IDF 11774 with ATP6V0C, which is clinically applicable for the treatment of cancer patients with IDF-11774 or autophagy-inducing anti-cancer drugs. PMID- 30420613 TI - SOX9 expression decreases survival of patients with intrahepatic cholangiocarcinoma by conferring chemoresistance. AB - BACKGROUND: Sex-determining region Y-box (SRY-box) containing gene 9 (SOX9) expression confers cancer stem cell features. However, SOX9 function in intrahepatic cholangiocarcinoma (iCCA) is unknown. This study investigated the effects and underlying mechanisms of SOX9 in iCCA. METHODS: SOX9 expression in 59 iCCA patients was examined by immunohistochemistry. The association between SOX9 expression and clinical outcome was evaluated. Gene signature and biological functions of SOX9 in iCCA were examined in vitro. RESULTS: iCCA patients with high SOX9 expression had shorter survival time than those with low SOX9. In patients receiving chemotherapy, median survival time in patients with low and high levels of SOX9 were 62 and 22 months, respectively. In vitro, gemcitabine increased SOX9 expression in iCCA cells. When SOX9 was knocked down, gemcitabine induced apoptosis was markedly increased. Silencing SOX9 significantly inhibited gemcitabine-induced phosphorylation of checkpoint kinase 1, a key cell cycle checkpoint protein that coordinates the DNA damage response and inhibited the expression of multidrug resistance genes. Microarray analyses showed that SOX9 knockdown in CCA cells altered gene signatures associated with multidrug resistance and p53 signalling. CONCLUSIONS: SOX9 governs the response of CCA cells to chemotherapy. SOX9 is a biomarker to select iCCA patients eligible for efficient chemotherapy. PMID- 30420614 TI - Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma. AB - BACKGROUND: Next-generation sequencing has identified actionable genetic aberrations in intrahepatic cholangiocarcinomas (iCCA), including the fibroblast growth factor receptor 2 (FGFR2) fusions. Derazantinib (ARQ 087), an orally bioavailable, multi-kinase inhibitor with potent pan-FGFR activity, has shown preliminary therapeutic activity against FGFR2 fusion-positive iCCA. METHODS: This multicentre, phase 1/2, open-label study enrolled adult patients with unresectable iCCA with FGFR2 fusion, who progressed, were intolerant or not eligible to first-line chemotherapy (NCT01752920). Subjects received derazantinib in continuous daily doses. Tumour response was assessed according to RECIST 1.1 every 8 weeks. RESULTS: Twenty-nine patients (18 women/11 men; median age, 58.7 years), 2 treatment-naive and 27 who progressed after at least one prior systemic therapy, were enrolled. Overall response rate was 20.7%, disease control rate was 82.8%. Estimated median progression-free survival was 5.7 months (95% CI: 4.04 9.2 months). Treatment-related adverse events (AE) were observed in 27 patients (93.1%, all grades), including asthenia/fatigue (69.0%), eye toxicity (41.4%), and hyperphosphatemia (75.9%). Grade >= 3 AEs occurred in 8 patients (27.6%). CONCLUSION: Derazantinib demonstrated encouraging anti-tumour activity and a manageable safety profile in patients with advanced, unresectable iCCA with FGFR2 fusion who progressed after chemotherapy. A pivotal trial of derazantinib in iCCA is ongoing (NCT03230318). PMID- 30420615 TI - Binding of eEF1A2 to the RNA-dependent protein kinase PKR modulates its activity and promotes tumour cell survival. AB - BACKGROUND: Through several not-fully-characterised moonlighting functions, translation elongation factor eEF1A2 is known to provide a fitness boost to cancer cells. Furthermore, eEF1A2 has been demonstrated to confer neoplastic characteristics on preneoplastic, nontumourigenic precursor cells. We have previously shown that eEF1A2 is the target of plitidepsin, a marine drug currently in development for cancer treatment. Herein, we characterised a new signalling pathway through which eEF1A2 promotes tumour cell survival. METHODS: Previously unknown binding partners of eEF1A2 were identified through co immunoprecipitation, high-performance liquid chromatography-mass spectrometry and proximity ligation assay. Using plitidepsin to release eEF1A2 from those protein complexes, their effects on cancer cell survival were analysed in vitro. RESULTS: We uncovered that double-stranded RNA-activated protein kinase (PKR) is a novel eEF1A2-interacting partner whose pro-apoptotic effect is hindered by the translation factor, most likely through sequestration and inhibition of its kinase activity. Targeting eEF1A2 with plitidepsin releases PKR from the complex, facilitating its activation and triggering a mitogen-activated protein kinase signalling cascade together with a nuclear factor-kappaB-dependent activation of the extrinsic apoptotic pathway, which lead to tumour cell death. CONCLUSIONS: Through its binding to PKR, eEF1A2 provides a survival boost to cancer cells, constituting an Achilles heel that can be exploited in anticancer therapy. PMID- 30420617 TI - Smoking cessation sharply reduced lung cancer mortality in a historical cohort of 3185 Chinese silicotic workers from 1981 to 2014. AB - BACKGROUND: Population-based studies showed an over 50% decrease in lung cancer risk after quitting smoking for 5-6 years, but the beneficial effect in silicotics remains unknown. We aimed to rectify this knowledge gap using a large historical cohort of 3185 Chinese silicotics since 1981 and followed-up till 2014. METHODS: Baseline information on workers' socio-demographics, smoking habits, occupational history, and medical history was collected. Smoking status was reassessed during follow-up. Multiple Cox proportional hazards model was performed to evaluate the impact of smoking cessation on lung cancer mortality. RESULTS: Overall, 1942 deaths occurred and 188 lung cancer deaths were identified. Compared with never quitters, silicotics who were new quitters had almost halved their lung cancer risk [hazard ratio (HR) = 0.51, 95%CI: 0.34 0.76], while persistent quitters had a 53% risk reduction (HR = 0.47, 95%CI: 0.33 0.66). Lung cancer mortality approximately halved after quitting smoking for 10 years. While the risk kept decreasing with years since cessation, it did not reverse back to that of never smokers. Persistent quitters with small opacities tended to have higher beneficial effects than those with large opacities. CONCLUSIONS: Smoking cessation for 10 years halved lung cancer mortality among silicotics, while the beneficial effect was prominent for patients with small opacities. PMID- 30420616 TI - SCOT: a comparison of cost-effectiveness from a large randomised phase III trial of two durations of adjuvant Oxaliplatin combination chemotherapy for colorectal cancer. AB - BACKGROUND: The Short Course Oncology Therapy (SCOT) study is an international, multicentre, non-inferiority randomised controlled trial assessing the efficacy, toxicity, and cost-effectiveness of 3 months (3 M) versus the usually given 6 months (6 M) of adjuvant chemotherapy in colorectal cancer. METHODS: In total, 6088 patients with fully resected high-risk stage II or stage III colorectal cancer were randomised and followed up for 3-8 years. The within-trial cost effectiveness analysis from a UK health-care perspective is presented using the resource use data, quality of life (EQ-5D-3L), time on treatment (ToT), disease free survival after treatment (DFS) and overall survival (OS) data. Quality adjusted partitioned survival analysis and Kaplan-Meier Sample Average Estimator estimated QALYs and costs. Probabilistic sensitivity and subgroup analysis was undertaken. RESULTS: The 3 M arm is less costly (-L4881; 95% CI: -L6269; -L3492) and entails (non-significant) QALY gains (0.08; 95% CI: -0.086; 0.230) due to a better significant quality of life. The net monetary benefit was significantly higher in 3 M under a wide range of monetary values of a QALY. The subgroup analysis found similar results for patients in the CAPOX regimen. However, for the FOLFOX regimen, 3 M had lower QALYs than 6 M (not statistically significant). CONCLUSIONS: Overall, 3 M dominates 6 M with no significant detrimental impact on QALYs. The results provide the economic case that a 3 M treatment strategy should be considered a new standard of care. PMID- 30420618 TI - Assessment of proportional hazard assumption in aggregate data: a systematic review on statistical methodology in clinical trials using time-to-event endpoint. AB - BACKGROUND: The evaluation of the proportional hazards (PH) assumption in survival analysis is an important issue when Hazard Ratio (HR) is chosen as summary measure. The aim is to assess the appropriateness of statistical methods based on the PH assumption in oncological trials. METHODS: We selected 58 randomised controlled trials comparing at least two pharmacological treatments with a time-to-event as primary endpoint in advanced non-small-cell lung cancer. Data from Kaplan-Meier curves were used to calculate the relative hazard at each time point and the Restricted Mean Survival Time (RMST). The PH assumption was assessed with a fixed-effect meta-regression. RESULTS: In 19% of the trials, there was evidence of non-PH. Comparison of treatments with different mechanisms of action was associated (P = 0.006) with violation of the PH assumption. In all the superiority trials where non-PH was detected, the conclusions using the RMST corresponded to that based on the Cox model, although the magnitude of the effect given by the HR was systematically greater than the one from the RMST ratio. CONCLUSION: As drugs with new mechanisms of action are being increasingly employed, particular attention should be paid on the statistical methods used to compare different types of agents. PMID- 30420619 TI - Small molecule natural compound agonist of SIRT3 as a therapeutic target for the treatment of intervertebral disc degeneration. AB - Oxidative stress-induced mitochondrial dysfunction is implicated in the pathogenesis of intervertebral disc degeneration (IVDD). Sirtuin 3 (SIRT3), a sirtuin family protein located in mitochondria, is essential for mitochondrial homeostasis; however, the role of SIRT3 in the process of IVDD has remained elusive. Here, we explored the expression of SIRT3 in IVDD in vivo and in vitro; we also explored the role of SIRT3 in senescence, apoptosis, and mitochondrial homeostasis under oxidative stress. We subsequently activated SIRT3 using honokiol to evaluate its therapeutic potential for IVDD. We assessed SIRT3 expression in degenerative nucleus pulposus (NP) tissues and oxidative stress induced nucleus pulposus cells (NPCs). SIRT3 was knocked down by lentivirus and activated by honokiol to determine its role in oxidative stress-induced NPCs. The mechanism by which honokiol affected SIRT3 regulation was investigated in vitro, and the therapeutic potential of honokiol was assessed in vitro and in vivo. We found that the expression of SIRT3 decreased with IVDD, and SIRT3 knockdown reduced the tolerance of NPCs to oxidative stress. Honokiol (10 MUM) improved the viability of NPCs under oxidative stress and promoted their properties of anti oxidation, mitochondrial dynamics and mitophagy in a SIRT3-dependent manner. Furthermore, honokiol activated SIRT3 through the AMPK-PGC-1alpha signaling pathway. Moreover, honokiol treatment ameliorated IVDD in rats. Our study indicated that SIRT3 is involved in IVDD and showed the potential of the SIRT3 agonist honokiol for the treatment of IVDD. PMID- 30420622 TI - PCSK9 inhibitors: clinical evidence and implementation. AB - The gene encoding PCSK9 was first identified and linked to the phenotype of familial hypercholesterolaemia approximately 15 years ago. Soon after, studies uncovered the role of PCSK9 in the regulation of LDL-receptor recycling and identified loss-of-function variants of PCSK9 that were associated with low circulating levels of LDL cholesterol (LDL-C) and a reduced risk of coronary artery disease. With amazing rapidity, monoclonal antibodies against PCSK9 were developed and studied in large clinical programmes. These PCSK9 inhibitors lowered plasma LDL-C levels by approximately 60%, even in patients already receiving maximum-dose statin therapy. In the past year, three cardiovascular outcome trials were completed and showed that PCSK9 inhibitors significantly reduce the risk of major vascular events. Reassuringly, this benefit comes with no major offsetting adverse events, such as an excess of myalgias, elevation of hepatic aminotransferases levels in the plasma, incident diabetes mellitus or neurocognitive adverse events. The clinical benefit of PCSK9 inhibitors seen in these trials occurred in the setting of reducing LDL-C levels to unprecedentedly low levels, suggesting that more aggressive LDL-C targets should be adopted. New technologies to inhibit PCSK9 are now being harnessed and might further revolutionize our treatment of dyslipidaemia. PMID- 30420620 TI - Elevated allostatic load early in the course of schizophrenia. AB - Stress plays a significant role in schizophrenia from disease onset to exacerbation of psychotic symptoms. Allostatic load (AL) is a measure of cumulative stress to the organism. This study is an extension of our previous work on AL and its relationship to brain structures. Here, we further determined whether elevated AL is a function of illness chronicity, or if it is already present early in the course of schizophrenia. AL was compared in schizophrenia patients early in the illness (within 5 years of disease onset), patients with chronic schizophrenia (more than 5 years of illness), and two groups of healthy controls that were age-and sex-matched to the two patient groups. This work is presented with an expanded sample and includes about two-thirds of the participants who were previously reported. We found that patients with early psychosis had significantly elevated AL score compared with their age-matched controls (p = 0.005). Chronic course patients also had elevated AL compared with age-matched controls (p = 0.003). Immune and stress hormone AL subcomponents were nominally higher in early-stage patients compared with controls (p = 0.005 and 0.04, respectively). Greater AL was also associated with more severe positive psychotic symptoms in early-stage patients (r = 0.54, p = 0.01). Elevated levels of allostatic load are already present in the early years of the schizophrenia illness, particularly in patients with more severe psychotic symptoms. AL may be a useful evaluation for the need of early intervention on psychosomatic comorbidity. PMID- 30420621 TI - Author Correction: Promoter interactome of human embryonic stem cell-derived cardiomyocytes connects GWAS regions to cardiac gene networks. AB - In the original version of the Article, the gene symbol for tissue factor pathway inhibitor was inadvertently given as 'TFP1' instead of 'TFPI'. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 30420623 TI - TCF-1 takes HEB up a Notch. PMID- 30420625 TI - CD8 helps TCR catch slippery self pMHC. PMID- 30420624 TI - Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. AB - Up to 49% of certain types of cancer are attributed to obesity, and potential mechanisms include overproduction of hormones, adipokines, and insulin. Cytotoxic immune cells, including natural killer (NK) cells and CD8+ T cells, are important in tumor surveillance, but little is known about the impact of obesity on immunosurveillance. Here, we show that obesity induces robust peroxisome proliferator-activated receptor (PPAR)-driven lipid accumulation in NK cells, causing complete 'paralysis' of their cellular metabolism and trafficking. Fatty acid administration, and PPARalpha and PPARdelta (PPARalpha/delta) agonists, mimicked obesity and inhibited mechanistic target of rapamycin (mTOR)-mediated glycolysis. This prevented trafficking of the cytotoxic machinery to the NK cell tumor synapse. Inhibiting PPARalpha/delta or blocking the transport of lipids into mitochondria reversed NK cell metabolic paralysis and restored cytotoxicity. In vivo, NK cells had blunted antitumor responses and failed to reduce tumor growth in obesity. Our results demonstrate that the lipotoxic obese environment impairs immunosurveillance and suggest that metabolic reprogramming of NK cells may improve cancer outcomes in obesity. PMID- 30420626 TI - The gammadeltaTCR combines innate immunity with adaptive immunity by utilizing spatially distinct regions for agonist selection and antigen responsiveness. AB - T lymphocytes expressing gammadelta T cell antigen receptors (TCRs) comprise evolutionarily conserved cells with paradoxical features. On the one hand, clonally expanded gammadelta T cells with unique specificities typify adaptive immunity. Conversely, large compartments of gammadeltaTCR+ intraepithelial lymphocytes (gammadelta IELs) exhibit limited TCR diversity and effect rapid, innate-like tissue surveillance. The development of several gammadelta IEL compartments depends on epithelial expression of genes encoding butyrophilin-like (Btnl (mouse) or BTNL (human)) members of the B7 superfamily of T cell co stimulators. Here we found that responsiveness to Btnl or BTNL proteins was mediated by germline-encoded motifs within the cognate TCR variable gamma-chains (Vgamma chains) of mouse and human gammadelta IELs. This was in contrast to diverse antigen recognition by clonally restricted complementarity-determining regions CDR1-CDR3 of the same gammadeltaTCRs. Hence, the gammadeltaTCR intrinsically combines innate immunity and adaptive immunity by using spatially distinct regions to discriminate non-clonal agonist-selecting elements from clone specific ligands. The broader implications for antigen-receptor biology are considered. PMID- 30420627 TI - TCF-1 and HEB cooperate to establish the epigenetic and transcription profiles of CD4+CD8+ thymocytes. AB - Thymocyte development requires a complex orchestration of multiple transcription factors. Ablating either TCF-1 or HEB in CD4+CD8+ thymocytes elicits similar developmental outcomes including increased proliferation, decreased survival, and fewer late Tcra rearrangements. Here, we provide a mechanistic explanation for these similarities by showing that TCF-1 and HEB share ~7,000 DNA-binding sites genome wide and promote chromatin accessibility. The binding of both TCF-1 and HEB was required at these shared sites for epigenetic and transcriptional gene regulation. Binding of TCF-1 and HEB to their conserved motifs in the enhancer regions of genes associated with T cell differentiation promoted their expression. Binding to sites lacking conserved motifs in the promoter regions of cell-cycle-associated genes limited proliferation. TCF-1 displaced nucleosomes, allowing for chromatin accessibility. Importantly, TCF-1 inhibited Notch signaling and consequently protected HEB from Notch-mediated proteasomal degradation. Thus, TCF-1 shifts nucleosomes and safeguards HEB, thereby enabling their cooperation in establishing the epigenetic and transcription profiles of CD4+CD8+ thymocytes. PMID- 30420628 TI - A TCR mechanotransduction signaling loop induces negative selection in the thymus. AB - The T cell antigen receptor (TCR) expressed on thymocytes interacts with self peptide major histocompatibility complex (pMHC) ligands to signal apoptosis or survival. Here, we found that negative-selection ligands induced thymocytes to exert forces on the TCR and the co-receptor CD8 and formed cooperative TCR-pMHC CD8 trimolecular 'catch bonds', whereas positive-selection ligands induced less sustained thymocyte forces on TCR and CD8 and formed shorter-lived, independent TCR-pMHC and pMHC-CD8 bimolecular 'slip bonds'. Catch bonds were not intrinsic to either the TCR-pMHC or the pMHC-CD8 arm of the trans (cross-junctional) heterodimer but resulted from coupling of the extracellular pMHC-CD8 interaction to the intracellular interaction of CD8 with TCR-CD3 via associated kinases to form a cis (lateral) heterodimer capable of inside-out signaling. We suggest that the coupled trans-cis heterodimeric interactions form a mechanotransduction loop that reinforces negative-selection signaling that is distinct from positive selection signaling in the thymus. PMID- 30420629 TI - Genotype specific pathogenicity of hepatitis E virus at the human maternal-fetal interface. AB - Hepatitis E virus (HEV) infection, particularly HEV genotype 1 (HEV-1), can result in fulminant hepatic failure and severe placental diseases, but mechanisms underlying genotype-specific pathogenicity are unclear and appropriate models are lacking. Here, we model HEV-1 infection ex vivo at the maternal-fetal interface using the decidua basalis and fetal placenta, and compare its effects to the less pathogenic genotype 3 (HEV-3). We demonstrate that HEV-1 replicates more efficiently than HEV-3 both in tissue explants and stromal cells, produces more infectious progeny virions and causes severe tissue alterations. HEV-1 infection dysregulates the secretion of several soluble factors. These alterations to the cytokine microenvironment correlate with viral load and contribute to the tissue damage. Collectively, this study characterizes an ex vivo model for HEV infection and provides insights into HEV-1 pathogenesis during pregnancy that are linked to high viral replication, alteration of the local secretome and induction of tissue injuries. PMID- 30420630 TI - Performance of Deep Learning Architectures and Transfer Learning for Detecting Glaucomatous Optic Neuropathy in Fundus Photographs. AB - The ability of deep learning architectures to identify glaucomatous optic neuropathy (GON) in fundus photographs was evaluated. A large database of fundus photographs (n = 14,822) from a racially and ethnically diverse group of individuals (over 33% of African descent) was evaluated by expert reviewers and classified as GON or healthy. Several deep learning architectures and the impact of transfer learning were evaluated. The best performing model achieved an overall area under receiver operating characteristic (AUC) of 0.91 in distinguishing GON eyes from healthy eyes. It also achieved an AUC of 0.97 for identifying GON eyes with moderate-to-severe functional loss and 0.89 for GON eyes with mild functional loss. A sensitivity of 88% at a set 95% specificity was achieved in detecting moderate-to-severe GON. In all cases, transfer improved performance and reduced training time. Model visualizations indicate that these deep learning models relied on, in part, anatomical features in the inferior and superior regions of the optic disc, areas commonly used by clinicians to diagnose GON. The results suggest that deep learning-based assessment of fundus images could be useful in clinical decision support systems and in the automation of large-scale glaucoma detection and screening programs. PMID- 30420631 TI - Microevolution of Neisseria lactamica during nasopharyngeal colonisation induced by controlled human infection. AB - Neisseria lactamica is a harmless coloniser of the infant respiratory tract, and has a mutually-excluding relationship with the pathogen Neisseria meningitidis. Here we report controlled human infection with genomically-defined N. lactamica and subsequent bacterial microevolution during 26 weeks of colonisation. We find that most mutations that occur during nasopharyngeal carriage are transient indels within repetitive tracts of putative phase-variable loci associated with host-microbe interactions (pgl and lgt) and iron acquisition (fetA promotor and hpuA). Recurrent polymorphisms occurred in genes associated with energy metabolism (nuoN, rssA) and the CRISPR-associated cas1. A gene encoding a large hypothetical protein was often mutated in 27% of the subjects. In volunteers who were naturally co-colonised with meningococci, recombination altered allelic identity in N. lactamica to resemble meningococcal alleles, including loci associated with metabolism, outer membrane proteins and immune response activators. Our results suggest that phase variable genes are often mutated during carriage-associated microevolution. PMID- 30420633 TI - Migrated Surgical Mesh Masquerading as a Luminal Stent. PMID- 30420632 TI - In silico identification and characterization of a diverse subset of conserved microRNAs in bioenergy crop Arundo donax L. AB - MicroRNAs (miRNAs) are small non-coding RNA molecules involved in the post transcriptional regulation of gene expression in plants. Arundo donax L. is a perennial C3 grass considered one of the most promising bioenergy crops. Despite its relevance, many fundamental aspects of its biology still remain to be elucidated. In the present study we carried out the first in silico mining and tissue-specific characterization of microRNAs and their putative targets in A. donax. We identified a total of 141 miRNAs belonging to 14 families along with the corresponding primary miRNAs, precursor miRNAs and a total of 462 high confidence predicted targets and novel target sites were validated by 5'-race. Gene Ontology functional annotation showed that miRNA targets are constituted mainly by transcription factors, but three of the newly validated targets are enzymes involved in novel functions like RNA editing, acyl lipid metabolism and post-Golgi trafficking. Folding variability of pre-miRNA loops and phylogenetic analyses indicate variable selective pressure acting on the different miRNA families. The set of miRNAs identified in this study will pave the road to further miRNA research in Arundo donax and contribute towards a better understanding of miRNA-mediated gene regulatory processes in other bioenergy crops. PMID- 30420634 TI - Fragmented Care is Prevalent among Inflammatory Bowel Disease Readmissions and is Associated with Worse Outcomes. AB - BACKGROUND: Inflammatory bowel disease (IBD) is a complex chronic disease that often requires a multispeciality approach; thus, IBD patients are prone to care fragmentation. We aim to determine the prevalence of fragmentation among hospitalized IBD patients and identify associated predictors and visit-level outcomes. METHODS: The State Inpatient Databases for New York and Florida were used to identify 90-day readmissions among IBD inpatients from 2009 to 2013. The prevalence of fragmentation, defined as a readmission to a non-index hospital, was reported. Characteristics associated with fragmented care were identified using multivariable logistic regression. Multivariable models were utilized to determine the association between fragmentation and outcomes (in-hospital mortality, readmission length of stay, and inpatient colonoscopy). RESULTS: Among IBD inpatients, 25,241 and 29,033 90-day readmission visits were identified, in New York and Florida, respectively. The prevalence of fragmentation was 26.4% in New York and 32.5% in Florida. Younger age, a non-emergent admission type, public payer or uninsured status, mood disorder, and substance abuse were associated with fragmented care, while female gender and a primary diagnosis of an IBD related complication had an inverse association. Fragmented inpatient care is associated with a higher likelihood of in-hospital death, higher rates of inpatient colonoscopy, and a longer readmission length of stay. CONCLUSION: Over one in four IBD inpatient readmissions are fragmented. Disparities and differences in fragmentation exist and contribute to poor patient outcomes. Additional efforts targeting fragmentation should be made to better coordinate IBD management, reduce healthcare gaps, and promote high-value care. PMID- 30420635 TI - How I Approach It: Using Ergonomics to Prevent Injuries for the Endoscopist. PMID- 30420636 TI - An Algorithm for Enhancing the Image Contrast of Electron Tomography. AB - Three-dimensional (3D) reconstruction of a single protein molecule is essential for understanding the relationship between the structural dynamics and functions of the protein. Electron tomography (ET) provides a tool for imaging an individual particle of protein from a series of tilted angles. Individual particle electron tomography (IPET) provides an approach for reconstructing a 3D density map from a single targeted protein particle (without averaging from different particles of this type of protein), in which the target particle was imaged from a series of tilting angles. However, owing to radiation damage limitations, low-dose images (high noise, and low image contrast) are often challenging to be aligned for 3D reconstruction at intermediate resolution (1-3 nm). Here, we propose a computational method to enhance the image contrast, without increasing any experimental dose, for IPET 3D reconstruction. Using an edge-preserving smoothing-based multi-scale image decomposition algorithm, this method can detect the object against a high-noise background and enhance the object image contrast without increasing the noise level or significantly decreasing the image resolution. The method was validated by using both negative staining (NS) ET and cryo-ET images. The successful 3D reconstruction of a small molecule (<100 kDa) indicated that this method can be used as a supporting tool to current ET 3D reconstruction methods for studying protein dynamics via structure determination from each individual particle of the same type of protein. PMID- 30420638 TI - Publisher Correction: EMT cells increase breast cancer metastasis via paracrine GLI activation in neighbouring tumour cells. AB - This Article contains an error in Figure 2. In panel a, the second lane of the western blot should have been labelled 'siNT'. A correct version of Figure 2a appears in the Author Correction associated with this Article; the error has not been fixed in the original Article. PMID- 30420637 TI - Promotion of tumor progression and cancer stemness by MUC15 in thyroid cancer via the GPCR/ERK and integrin-FAK signaling pathways. AB - Thyroid cancer is the fifth most common cancer diagnosed in women worldwide. Notwithstanding advancements in the prognosis and treatment of thyroid cancer, 10 20% of thyroid cancer patients develops chemotherapeutic resistance and experience relapse. According to previous reports and TCGA database, MUC15 (MUCIN 15) upregulation is highly correlated with thyroid cancer progression. However, the role of MUC15 in tumor progression and metastasis is unclear. This study aimed to investigate factors mediating cancer stemness in thyroid cancer. MUC15 plays an important role in sphere formation, as an evident from the expression of stemness markers including SOX2, KLF4, ALDH1A3, and IL6. Furthermore, ectopic expression of MUC15 activated extracellular signal-regulated kinase (ERK) signaling via G-protein-coupled receptor (GPCR)/cyclic AMP (cAMP) and integrin/focal adhesion kinase pathways. Interestingly, ectopic expression of MUC15 did not affect RAF/mitogen-activated protein kinase kinase (MEK)-mediated ERK activation. The present findings may provide novel insights into the development of diagnostic, prognostic, and therapeutic applications of MUC15 in thyroid cancer. PMID- 30420640 TI - A two-miRNA signature (miR-33a-5p and miR-128-3p) in whole blood as potential biomarker for early diagnosis of lung cancer. AB - MicroRNAs (MiRNAs) have been found to be dysregulated in lung cancer tissues compared to their matched paracancerous tissues. However, the roles of miRNAs in peripheral blood as potential biomarkers for early diagnosis of lung cancer remain poorly understood. Here we found that miR-33a-5p and miR-128-3p were down regulated in lung cancer tissues and cell lines. The expression levels of miR-33a 5p and miR-128-3p in lung cancer tissues were significantly correlated to TNM stages. MiR-128-3p in lung cancer tissues was also remarkably related to smoking and tumor size. The relative expression levels of miR-33a-5p and miR-128-3p were positively correlated in lung cancer tissues. Notably, miR-33a-5p and miR-128-3p in whole blood of lung cancer patients or early-stage lung cancer patients (TNM stage I-II) were lowly expressed as compared with that in healthy controls. The receiver operating characteristic curve (ROC) analyses revealed higher area under the ROC curve (AUC) values and higher sensitivity/specificity of miR-33a-5p and miR-128-3p alone and in combination were superior to that of traditional tumor markers (CYFR21-1, NSE and CA72-4). Importantly, both miR-33a-5p and miR-128-3p in whole blood were highly stable even under different harsh conditions. The results demonstrate that tumor suppressor miR-33a-5p/miR-128-3p in whole blood can serve as novel biomarkers for the early detection of lung cancer. PMID- 30420641 TI - Downregulation of VEGFR3 signaling alters cardiac lymphatic vessel organization and leads to a higher mortality after acute myocardial infarction. AB - Heart has a wide lymphatic network but the importance of cardiac lymphatic system in heart diseases has remained unclear. Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) is a key molecule in the development and maintenance of cardiac lymphatic vessels. Here we characterized the role of VEGFR3 in healthy hearts and after myocardial infarction (MI) by using sVEGFR3 transgenic mice expressing a soluble decoy VEGFR3 under K14 promoter and Chy mice which have an inactivating mutation in the VEGFR3 gene. Cardiac lymphatic vessels were significantly dilated in the healthy hearts of sVEGFR3 mice when compared to controls. Lymphatic vessels formed large sheet-like structures in Chy mice. Attenuated VEGFR3 signaling led to a more severe MI predisposing to a significantly higher mortality in sVEGFR3 mice than in control mice. sVEGFR3 mice displayed intramyocardial hemorrhages in the infarcted area indicating hyperpermeability of the vasculature. Furthermore, novel MRI methods TRAFF2 and TRAFF4 and histological analysis revealed a modified structure of the fibrotic infarcted area in sVEGFR3 mice. In conclusion, the downregulation of VEGFR3 signaling modifies the structure of cardiac lymphatic network and causes vascular leakiness and increased mortality after MI. PMID- 30420639 TI - Human adipose glycerol flux is regulated by a pH gate in AQP10. AB - Obesity is a major threat to global health and metabolically associated with glycerol homeostasis. Here we demonstrate that in human adipocytes, the decreased pH observed during lipolysis (fat burning) correlates with increased glycerol release and stimulation of aquaglyceroporin AQP10. The crystal structure of human AQP10 determined at 2.3 A resolution unveils the molecular basis for pH modulation-an exceptionally wide selectivity (ar/R) filter and a unique cytoplasmic gate. Structural and functional (in vitro and in vivo) analyses disclose a glycerol-specific pH-dependence and pinpoint pore-lining His80 as the pH-sensor. Molecular dynamics simulations indicate how gate opening is achieved. These findings unravel a unique type of aquaporin regulation important for controlling body fat mass. Thus, targeting the cytoplasmic gate to induce constitutive glycerol secretion may offer an attractive option for treating obesity and related complications. PMID- 30420642 TI - Hydroxyurea prevents arterial and late venous thrombotic recurrences in patients with myeloproliferative neoplasms but fails in the splanchnic venous district. Pooled analysis of 1500 cases. AB - We collected 1500 patients with myeloproliferative neoplasms (MPN) and arterial or venous thrombosis (935/565), pooling three independent cohorts previously reported. Long-term treatment with antiplatelet drugs or vitamin K-antagonists (VKA) was given to 1391 (92.7%) patients; 975 (65%) patients received hydroxyurea (HU). We recorded 348 recurrences (venous in 142 cases) over 6075 patient-years, with an incidence rate of 5.7 per 100 pt-years (95% CI 5.1-6.4). The site of the first thrombosis predicted the site of recurrence. Independent factors influencing the rate of novel arterial thrombosis were HU (HR 0.67, 95% CI 0.46 0.98), antiplatelet treatment (HR 0.54, 95% CI 0.35-0.82), and VKA (HR 0.58, 95% CI 0.35-0.96). On the contrary, the recurrence of venous thromboses was significantly diminished only by VKA (HR 0.60, 95% CI 0.37-0.95), while HU prevented late but not early recurrences after venous thrombosis at common sites. Of note, we failed to demonstrate a positive effect of HU in the prevention of recurrent splanchnic vein thrombosis. In conclusion, in MPN patients, HU plays a role in the prevention of arterial thrombosis, together with aspirin and VKA, whereas its action in the prevention of recurrent venous thrombosis is uncertain. Such findings call for future studies to optimize and personalize secondary prophylaxis after MPN-related thrombosis. PMID- 30420643 TI - Factors associated with intra-individual visit-to-visit variability of blood pressure in four countries: the INTERMAP study. AB - Several studies demonstrated that visit-to-visit variability of blood pressure (BP) predicted future events of total death, stroke and cardiovascular disease. Little is known about factors associated with visit-to-visit BP variability in different countries. We recruited participants aged 40-59 years from four countries (Japan, the People's Republic of China [PRC], the United Kingdom [UK] and the United States [US]). At each study visit, BP was measured twice by trained observers using random zero sphygmomanometers after five minutes resting. We defined visit-to-visit BP variability as variation independent of mean (VIM) by using average systolic BP of 1st and 2nd measurement across four study visits. Data on 4680 men and women were analyzed. Mean +/- standard deviation of VIM values among participants in Japan, the PRC, the UK and the US were 5.44 +/- 2.88, 6.85 +/- 3.49, 5.65 +/- 2.81 and 5.84 +/- 3.01, respectively; VIM value in the PRC participants was significantly higher. Sensitivity analyses among participants without antihypertensive treatment or past history of cardiovascular disease yielded similar results. Higher VIM value was associated with older age, female gender, lower pulse rate and urinary sodium excretion and use of antihypertensive agents such as angiotensin converting enzyme inhibitors, beta blockers and calcium channel blockers. The difference of visit-to-visit BP variability between PRC and other countries remained significant after adjustment for possible confounding factors. In this large international study across four countries, visit-to-visit BP variability in the PRC was higher than in the other three countries. Reproducibility and mechanisms of these findings remain to be elucidated. PMID- 30420644 TI - 24-Hour ambulatory blood pressure levels and control in a large cohort of adult outpatients with different classes of obesity. AB - Effective and sustained blood pressure (BP) control in hypertensive patients with moderate-to-severe obesity is often difficult to achieve. We evaluated clinic, 24h, day-time and night-time systolic/diastolic BP levels and control in a large cohort of adult outpatients with different classes of obesity. A single center, prospective, cohort study was conducted at Hypertension Unit, Division of Cardiology, Sant'Andrea Hospital, Rome Italy. All BP measurements were performed and BP thresholds were set according to guidelines. Study population was stratified according to BMI. We included 4,766 individuals (women 48.6%, age 60.3 +/- 11.6 years, clinic BP 143.8 +/- 18.2/90.9 +/- 12.3 mmHg, 24h BP 130.2 +/- 13.3/79.1 +/- 9.5 mmHg), among whom 36.0% had normal weight, 43.5% were overweight, 15.7% had class I, and 4.8% class II/III obesity. Obese outpatients had higher prevalence of risk factors, and were treated more frequently and with more antihypertensive drugs than those with normal body weight. Obese outpatients showed higher systolic BP levels at all BP measurements, mostly 24h and night time periods, than those observed in normal weight outpatients. BMI resulted significantly related with clinic (r = 0.053; P < 0.001), 24h (r = 0.098; P < 0.001) and night-time systolic BP (r = 0.126; P < 0.001), and left ventricular mass indexed by height^2.7 (r = 0.311; P < 0.001). BMI was also negatively and independently associated with predefined BP goals at all types of BP measurements. Obesity was associated with higher systolic BP levels during the entire 24h period and increased left ventricular mass. These effects were independently observed, even after correction for major cardiovascular risk factors and comorbidities, as well as the number and type of antihypertensive drug classes. PMID- 30420645 TI - Buddhist Activities related to Sedentary behavior and Hypertension in Tibetan monks. AB - Previous studies suggest sedentary behavior (SB) is a risk factor for hypertension. However, buddhist activities related to SB in Tibetan monks is quite different from common SB. Meditation, chanting, and buddhist teaching are the main features during sitting. There is no study to examine the association between buddhist activities related to sitting and hypertension. There were 594 Tibetan monks included for analysis. Buddhist activities related to SB involve hours of meditation, chanting, and buddhist teaching for a typical weekday and weekend day. After controlling potential risk factors, compared with Tibetan monks who has the sedentary time < 8 h/d, those with 10 h/d <= sedentary time < 11 h/d was associated with about 80% decrease in the risk of hypertension (OR = 0.22;95% CI = 0.07-0.71), and about 90% decrease (OR = 0.11; 95% CI = 0.03-0.40) in those with sedentary time >= 11 h/d. In hypertension subgroup, buddhist activities related to SB is associated with a decrease in BP during linear regression analysis (standard beta = -0.355; P = 0.004 for SBP; standard beta = 0.345; P = 0.013 for DBP). We conclude that sitting might not simply represent the extremely low energy expenditure of the physical activity continuum. Psychosocial activities may play an important role in SB. PMID- 30420646 TI - Glutathione S-Transferase M1 and T1 polymorphisms and hypertension risk: an updated meta-analysis. AB - Recently, Glutathione S-transferase M1 (GSTM1), glutathione S-transferase T1 (GSTT1), and their interaction with hypertension risk have been focused on. However, the results of previous studies have been inconsistent. Hence, the present meta-analysis was performed to explore the association. Twenty-two case control studies met the inclusion criteria for GSTM1 (including 3577 hypertension cases and 3784 controls), twenty-two for GSTT1 (including 3741 cases and 4444 controls), and nine for their combined effects (including 1073 cases and 781 controls). Pooled analyses on the association between GSTM1 present/null polymorphism and hypertension risk were observed to be insignificant in overall and subgroup analyses. The individual who carries the GSTT1 null-genotype had a statistically significant overall population (OR = 1.28, 95% CI: 1.03, 1.60), Indians (OR = 2.45, 95% CI: 1.08, 5.59), and hospital-based controls (OR = 1.53, 95% CI: 1.21, 1.94). For the GSTM1-GSTT1 interaction, we found that the GSTM1/GSTT1 double-null-genotype was significantly associated with hypertension risks (double-null vs. double-present: OR = 2.68, 95% CI: 1.06, 6.81). To summarize, this meta-analysis indicates that Indians with the GSTT1 null-genotype has a raised hypertension risks; the GSTM1 null/GSTT1 null-genotype is association with raised hypertension risks, while the GSTM1 null-genotype is not associated with hypertension risks. In addition, I2 > 75% cannot be eliminated for GSTM1 in Indians or Asians, hence, it will be very important to explore the GSTM1 null-genotype and hypertension susceptibility in Indians and Asians for a large new sample, on population-based control study. PMID- 30420648 TI - Cilia-driven cerebrospinal fluid flow directs expression of urotensin neuropeptides to straighten the vertebrate body axis. AB - Straightening of the body axis is a major morphogenetic event that produces the typical head-to-tail shape of the vertebrate embryo. Defects in axial straightening can lead to debilitating disorders such as idiopathic scoliosis, characterized by three-dimensional curvatures of the spine1. Although abnormal cerebrospinal fluid (CSF) flow has been implicated in the development of idiopathic scoliosis2, the molecular mechanisms operating downstream of CSF flow remain obscure. Here we show that, in zebrafish embryos, cilia-driven CSF flow transports adrenergic signals that induce urotensin neuropeptides in CSF contacting neurons along the spinal cord. Urotensins activate their receptor on slow-twitch muscle fibers of the dorsal somite; the contraction of these fibers likely results in straightening of the body axis. Consistent with this, mutation of the urotensin receptor resulted in severe scoliosis in adult zebrafish, closely mimicking the human disorder. These findings suggest that disruption of urotensin signaling by impaired CSF flow could be a critical etiological factor underlying the pathology of idiopathic scoliosis. PMID- 30420647 TI - Genebank genomics highlights the diversity of a global barley collection. AB - Genebanks hold comprehensive collections of cultivars, landraces and crop wild relatives of all major food crops, but their detailed characterization has so far been limited to sparse core sets. The analysis of genome-wide genotyping-by sequencing data for almost all barley accessions of the German ex situ genebank provides insights into the global population structure of domesticated barley and points out redundancies and coverage gaps in one of the world's major genebanks. Our large sample size and dense marker data afford great power for genome-wide association scans. We detect known and novel loci underlying morphological traits differentiating barley genepools, find evidence for convergent selection for barbless awns in barley and rice and show that a major-effect resistance locus conferring resistance to bymovirus infection has been favored by traditional farmers. This study outlines future directions for genomics-assisted genebank management and the utilization of germplasm collections for linking natural variation to human selection during crop evolution. PMID- 30420649 TI - Subtype-specific regulatory network rewiring in acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a heterogeneous disease caused by a variety of alterations in transcription factors, epigenetic regulators and signaling molecules. To determine how different mutant regulators establish AML subtype specific transcriptional networks, we performed a comprehensive global analysis of cis-regulatory element activity and interaction, transcription factor occupancy and gene expression patterns in purified leukemic blast cells. Here, we focused on specific subgroups of subjects carrying mutations in genes encoding transcription factors (RUNX1, CEBPalpha), signaling molecules (FTL3-ITD, RAS) and the nuclear protein NPM1). Integrated analysis of these data demonstrates that each mutant regulator establishes a specific transcriptional and signaling network unrelated to that seen in normal cells, sustaining the expression of unique sets of genes required for AML growth and maintenance. PMID- 30420650 TI - Author Correction: Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors. AB - In the version of the article published, the author list is not accurate. Igor Cima and Min-Han Tan should have been authors, appearing after Mark Wong in the author list, while Paul Jongjoon Choi should not have been listed as an author. Igor Cima and Min-Han Tan both have the affiliation Institute of Bioengineering and Nanotechnology, Singapore, Singapore, and their contributions should have been noted in the Author Contributions section as "I.C. preprocessed Primary Cell Atlas data with inputs from M.-H.T." The following description of the contribution of Paul Jongjoon Choi should not have appeared: "P.J.C. supported the smFISH experiments." In the 'RCA: global panel' section of the Online Methods, the following sentence should have appeared as the second sentence, "An expression atlas of human primary cells (the Primary Cell Atlas) was preprocessed similarly to in ref. 55," with new reference 55 (Cima, I. et al. Tumor-derived circulating endothelial cell clusters in colorectal cancer. Science Transl. Med. 8, 345ra89, 2016). PMID- 30420651 TI - The role of submesoscale currents in structuring marine ecosystems. AB - From microbes to large predators, there is increasing evidence that marine life is shaped by short-lived submesoscales currents that are difficult to observe, model, and explain theoretically. Whether and how these intense three-dimensional currents structure the productivity and diversity of marine ecosystems is a subject of active debate. Our synthesis of observations and models suggests that the shallow penetration of submesoscale vertical currents might limit their impact on productivity, though ecological interactions at the submesoscale may be important in structuring oceanic biodiversity. PMID- 30420652 TI - Large-area and adaptable electrospun silicon-based thermoelectric nanomaterials with high energy conversion efficiencies. AB - Large amounts of waste heat generated in our fossil-fuel based economy can be converted into useful electric power by using thermoelectric generators. However, the low-efficiency, scarcity, high-cost and poor production scalability of conventional thermoelectric materials are hindering their mass deployment. Nanoengineering has proven to be an excellent approach for enhancing thermoelectric properties of abundant and cheap materials such as silicon. Nevertheless, the implementation of these nanostructures is still a major challenge especially for covering the large areas required for massive waste heat recovery. Here we present a family of nano-enabled materials in the form of large area paper-like fabrics made of nanotubes as a cost-effective and scalable solution for thermoelectric generation. A case study of a fabric of p-type silicon nanotubes was developed showing a five-fold improvement of the thermoelectric figure of merit. Outstanding power densities above 100 W/m2 at 700 degrees C are therefore demonstrated opening a market for waste heat recovery. PMID- 30420653 TI - Dewetting of monolayer water and isopropanol between MoS2 nanosheets. AB - Understanding dewetting of solvent molecules confined to layered material (LM) interfaces is crucial to the synthesis of two-dimensional materials by liquid phase exfoliation. Here, we examine dewetting behavior of water and isopropanol/water (IPA/H2O) mixtures between molybdenum disulfide (MoS2) membranes using molecular dynamics (MD) simulations. We find that a monolayer of water spontaneously ruptures into nanodroplets surrounded by dry regions. The average speed of receding dry patches is close to the speed of sound in air. In contrast, monolayer mixtures of IPA/H2O between MoS2 membranes slowly transform into percolating networks of nanoislands and nanochannels in which water molecules diffuse inside and IPA molecules stay at the periphery of islands and channels. These contrasting behaviors may explain why IPA/H2O mixtures are much more effective than H2O alone in weakening interlayer coupling and exfoliating MoS2 into atomically thin sheets. PMID- 30420655 TI - REX1 is the critical target of RNF12 in imprinted X chromosome inactivation in mice. AB - In mice, imprinted X chromosome inactivation (iXCI) of the paternal X in the pre implantation embryo and extraembryonic tissues is followed by X reactivation in the inner cell mass (ICM) of the blastocyst to facilitate initiation of random XCI (rXCI) in all embryonic tissues. RNF12 is an E3 ubiquitin ligase that plays a key role in XCI. RNF12 targets pluripotency protein REX1 for degradation to initiate rXCI in embryonic stem cells (ESCs) and loss of the maternal copy of Rnf12 leads to embryonic lethality due to iXCI failure. Here, we show that loss of Rex1 rescues the rXCI phenotype observed in Rnf12-/- ESCs, and that REX1 is the prime target of RNF12 in ESCs. Genetic ablation of Rex1 in Rnf12-/- mice rescues the Rnf12-/- iXCI phenotype, and results in viable and fertile Rnf12-/ :Rex1-/- female mice displaying normal iXCI and rXCI. Our results show that REX1 is the critical target of RNF12 in XCI. PMID- 30420654 TI - Brain injury induces HIF-1alpha-dependent transcriptional activation of LRRK2 that exacerbates brain damage. AB - Leucine-rich repeat kinase 2 (LRRK2), originally identified as a causative genetic factor in Parkinson's disease, is now associated with a number of pathologies. Here, we show that brain injury induces a robust expression of endogenous LRRK2 and suggest a role of LRRK2 after injury. We found that various in vitro and in vivo models of traumatic brain injury (TBI) markedly enhanced LRRK2 expression in neurons and also increased the level of hypoxia-inducible factor (HIF)-1alpha. Luciferase reporter assay and chromatin immunoprecipitation revealed direct binding of HIF-1alpha in LRRK2 proximal promoter. We also found that HIF-1alpha-dependent transcriptional induction of LRRK2 exacerbated neuronal cell death following injury. Furthermore, application of G1023, a specific, brain permeable inhibitor of LRRK2, substantially prevented brain tissue damage, cell death, and inflammatory response and alleviated motor and cognitive defects induced by controlled cortical impact injury. Together, these results suggest HIF 1alpha-LRRK2 axis as a potential therapeutic target for brain injury. PMID- 30420656 TI - Increasing compound events of extreme hot and dry days during growing seasons of wheat and maize in China. AB - Compound events of climate extremes such as extremely high temperature and low precipitation during crop growing seasons can greatly affect agricultural production and food security. No study has investigated how Compound Extreme Hot and Dry days (CEHD days) during crop-growing seasons have changed or will change in response to climate warming. Based on observations, we find upward trends in CEHD days during wheat and maize growing seasons in China in the historical period 1980-2015. These trends are remarkably different during wheat and maize growing seasons, pointing to the need for targeted analysis focusing on crop specific growing seasons. Projections of future temperature and precipitation from the Coordinated Regional Climate Downscaling Experiment show that upward trends will continue into future. On average over China, the frequencies of CEHD days during wheat and maize growing seasons are projected to increase respectively by 168% and 162% in 2036-2050 relatively to 1980-2015 under the RCP8.5 emissions scenario. The projected increases may have serious implications for China's food production, adding to the need for resilience planning to limit the impacts of growing-season CEHD days. PMID- 30420657 TI - Clinical implications of changes in the diversity of c-MYC copy number variation after neoadjuvant chemotherapy in breast cancer. AB - Chemotherapy can alter the makeup of a tumor cell population by exerting selection pressure. We examined the change in Shannon index, a mathematical diversity measure used in ecology, for c-MYC copy number variation (CNV) after neoadjuvant chemotherapy and evaluated its clinical significance in breast cancer. Associations between Shannon indices for c-MYC CNV in pre- and post neoadjuvant chemotherapy breast cancer samples and clinicopathologic features of tumors as well as patient survival were analyzed in 144 patients. A change in c MYC amplification and copy number gain status was found in 14.3% and 33.6% with most cases showing positive to negative conversion. The chemo-sensitive group showed a significant decrease in Shannon index after neoadjuvant chemotherapy. However, there was no difference in diversity indices between pre- and post neoadjuvant chemotherapy specimens in the chemo-resistant group. In survival analyses, high Shannon indices for c-MYC CNV in post-neoadjuvant chemotherapy samples as well as those in pre-neoadjuvant chemotherapy samples were revealed as independent prognostic factors for poor disease-free survival not only in the whole group but also in the chemo-resistant subgroup. These findings suggest that a change in Shannon index for c-MYC CNV after neoadjuvant chemotherapy reflects chemo-responsiveness and that Shannon indices after neoadjuvant chemotherapy have a prognostic value in breast cancer patients who receive neoadjuvant chemotherapy. PMID- 30420659 TI - Designer liquid-liquid interfaces made from transient double emulsions. AB - Current methods for generating liquid-liquid interfaces with either controlled composition or coverage often rely on adsorption equilibria which limits the freedom to design such multiphase materials, in particular when different components are used. Moreover, when interfaces become densely populated, slowing down of adsorption may impose additional constraints. Up to now, it is not possible to control surface coverage and composition of droplet interfaces at will. Here, we report a generic and versatile method to create designer liquid liquid interfaces, using transient double emulsions. We demonstrate how the surface coverage in Pickering emulsions can be controlled at will, even for dense particulate layers going up to multilayers. Moreover, composite droplet interfaces with compositional control can be generated, even with particles which would have intrinsically different or even opposite adsorption characteristics. Given its simplicity, this method offers a general approach for control of composition of liquid-liquid interfaces in a variety of multiphase systems. PMID- 30420658 TI - Increased sporulation underpins adaptation of Clostridium difficile strain 630 to a biologically-relevant faecal environment, with implications for pathogenicity. AB - Clostridium difficile virulence is driven primarily by the processes of toxinogenesis and sporulation, however many in vitro experimental systems for studying C. difficile physiology have arguably limited relevance to the human colonic environment. We therefore created a more physiologically-relevant model of the colonic milieu to study gut pathogen biology, incorporating human faecal water (FW) into growth media and assessing the physiological effects of this on C. difficile strain 630. We identified a novel set of C. difficile-derived metabolites in culture supernatants, including hexanoyl- and pentanoyl-amino acid derivatives by LC-MSn. Growth of C. difficile strain 630 in FW media resulted in increased cell length without altering growth rate and RNA sequencing identified 889 transcripts as differentially expressed (p < 0.001). Significantly, up to 300 fold increases in the expression of sporulation-associated genes were observed in FW media-grown cells, along with reductions in motility and toxin genes' expression. Moreover, the expression of classical stress-response genes did not change, showing that C. difficile is well-adapted to this faecal milieu. Using our novel approach we have shown that interaction with FW causes fundamental changes in C. difficile biology that will lead to increased disease transmissibility. PMID- 30420660 TI - Dehydrative pi-extension to nanographenes with zig-zag edges. AB - Zig-zag nanographenes are promising candidates for the applications in organic electronics due to the electronic properties induced by their periphery. However, the synthetic access to these compounds remains virtually unexplored. There is a lack in efficient and mild strategies origins in the reduced stability, increased reactivity, and low solubility of these compounds. Herein we report a facile access to pristine zig-zag nanographenes, utilizing an acid-promoted intramolecular reductive cyclization of arylaldehydes, and demonstrate a three step route to nanographenes constituted of angularly fused tetracenes or pentacenes. The mild conditions are scalable to gram quantities and give insoluble nanostructures in close to quantitative yields. The strategy allows the synthesis of elusive low bandgap nanographenes, with values as low as 1.62 eV. Compared to their linear homologues, the structures have an increased stability in the solid-state, even though computational analyses show distinct diradical character. The structures were confirmed by X-ray diffraction or scanning tunneling microscopy. PMID- 30420661 TI - Flexible fate determination ensures robust differentiation in the hair follicle. AB - Tissue homeostasis is sustained by stem cell self-renewal and differentiation. How stem cells coordinately differentiate into multiple cell types is largely unclear. Recent studies underline the heterogeneity among stem cells or common progenitors, suggesting that coordination occurs at the stem cell/progenitor level1-4. Here, by tracking and manipulating the same stem cells and their progeny at the single-cell level in live mice, we uncover an unanticipated flexibility of homeostatic stem cell differentiation in hair follicles. Although stem cells have been shown to be flexible upon injury, we demonstrate that hair germ stem cells at the single-cell level can flexibly establish all of the differentiation lineages even in uninjured conditions. Furthermore, stem cell derived hair progenitors in the structure called matrix, previously thought to be unipotent, flexibly change differentiation outcomes as a consequence of unexpected dynamic relocation. Finally, the flexible cell fate determination mechanism maintains normal differentiation and tissue architecture against an ectopic differentiation stimulus induced by Wnt activation. This work provides a model of continual fate channelling and late commitment of stem cells to achieve coordinated differentiation and robust tissue architecture. PMID- 30420662 TI - Multiple phosphorylations control recruitment of the KMN network onto kinetochores. AB - To establish a functional kinetochore, the constitutive centromere-associated network (CCAN) forms a foundation on the centromere and recruits the KMN network, which directly binds to spindle microtubules. The CENP-C and CENP-T pathways in the CCAN recruit the KMN network to kinetochores, independently. The CENP-C pathway has been considered the major scaffold for the KMN network in vertebrate CCAN. However, we demonstrate that it is mainly the CENP-T pathway that recruits the KMN network onto the kinetochores and that CENP-T-KMN interactions are essential in chicken DT40 cells. By contrast, less Ndc80 binds to the CENP-C pathway in mitosis and the Mis12-CENP-C association is decreased during mitotic progression, which is consistent with the finding that the Mis12 complex-CENP-C binding is dispensable for cell viability. Furthermore, we find that multiple phosphoregulations of CENP-T and the Mis12 complex make the CENP-T pathway dominant. These results provide key insights into kinetochore dynamics during mitotic progression. PMID- 30420663 TI - CENP-T bears the load in mitosis. PMID- 30420665 TI - The 44th Annual Meeting of the European Society for Blood and Marrow Transplantation: Physicians Poster Sessions. PMID- 30420664 TI - TBK1 and IKKepsilon prevent TNF-induced cell death by RIPK1 phosphorylation. AB - The linear-ubiquitin chain assembly complex (LUBAC) modulates signalling via various immune receptors. In tumour necrosis factor (TNF) signalling, linear (also known as M1) ubiquitin enables full gene activation and prevents cell death. However, the mechanisms underlying cell death prevention remain ill defined. Here, we show that LUBAC activity enables TBK1 and IKKepsilon recruitment to and activation at the TNF receptor 1 signalling complex (TNFR1 SC). While exerting only limited effects on TNF-induced gene activation, TBK1 and IKKepsilon are essential to prevent TNF-induced cell death. Mechanistically, TBK1 and IKKepsilon phosphorylate the kinase RIPK1 in the TNFR1-SC, thereby preventing RIPK1-dependent cell death. This activity is essential in vivo, as it prevents TNF-induced lethal shock. Strikingly, NEMO (also known as IKKgamma), which mostly, but not exclusively, binds the TNFR1-SC via M1 ubiquitin, mediates the recruitment of the adaptors TANK and NAP1 (also known as AZI2). TANK is constitutively associated with both TBK1 and IKKepsilon, while NAP1 is associated with TBK1. We discovered a previously unrecognized cell death checkpoint that is mediated by TBK1 and IKKepsilon, and uncovered an essential survival function for NEMO, whereby it enables the recruitment and activation of these non-canonical IKKs to prevent TNF-induced cell death. PMID- 30420666 TI - Author Correction: Pathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding. AB - The original version of this Article contained an error in the spelling of the author Jonah B Sacha, which was incorrectly given as Jonah Sacha. These errors have now been corrected in both the PDF and HTML versions of the Article. PMID- 30420668 TI - Excess solvent in precipitates. PMID- 30420669 TI - Magneto-ionic control of magnetism using a solid-state proton pump. AB - Voltage-gated ion transport as a means of manipulating magnetism electrically could enable ultralow-power memory, logic and sensor technologies. Earlier work made use of electric-field-driven O2- displacement to modulate magnetism in thin films by controlling interfacial or bulk oxidation states. However, elevated temperatures are required and chemical and structural changes lead to irreversibility and device degradation. Here we show reversible and non destructive toggling of magnetic anisotropy at room temperature using a small gate voltage through H+ pumping in all-solid-state heterostructures. We achieve 90 degrees magnetization switching by H+ insertion at a Co/GdOx interface, with no degradation in magnetic properties after >2,000 cycles. We then demonstrate reversible anisotropy gating by hydrogen loading in Pd/Co/Pd heterostructures, making metal-metal interfaces susceptible to voltage control. The hydrogen storage metals Pd and Pt are high spin-orbit coupling materials commonly used to generate perpendicular magnetic anisotropy, Dzyaloshinskii-Moriya interaction, and spin-orbit torques in ferromagnet/heavy-metal heterostructures. Thus, our work provides a platform for voltage-controlled spin-orbitronics. PMID- 30420667 TI - Challenges in the introduction of next-generation sequencing (NGS) for diagnostics of myeloid malignancies into clinical routine use. AB - Given the vast phenotypic and genetic heterogeneity of acute and chronic myeloid malignancies, hematologists have eagerly awaited the introduction of next generation sequencing (NGS) into the routine diagnostic armamentarium to enable a more differentiated disease classification, risk stratification, and improved therapeutic decisions. At present, an increasing number of hematologic laboratories are in the process of integrating NGS procedures into the diagnostic algorithms of patients with acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPNs). Inevitably accompanying such developments, physicians and molecular biologists are facing unexpected challenges regarding the interpretation and implementation of molecular genetic results derived from NGS in myeloid malignancies. This article summarizes typical challenges (Table 1) that may arise in the context of NGS-based analyses at diagnosis and during follow-up of myeloid malignancies. Table 1 Challenges accompanying the introduction of massive parallel sequencing in clinical routine diagnostics in hemato-oncology Challenge Background Current and future approach Discrimination of leukemia-related mutations from polymorphisms or passenger mutations Driver mutations expected to occur at higher allele frequency in patient samples than passenger mutations; driver mutations more likely to have an impact on protein function than polymorphisms or passenger mutations Optimization of cancer-specific databases including reporting of rare physiological gene variants Implementation of novel bioinformatic algorithms based on prediction of functional impact Quantitative and dynamic VAF monitoring (separately and together with other mutations) at follow-up Discrimination of somatic leukemia related mutations from CHIP CHIP is presented in ~10% of individuals aged 70 to 80 and in up to 20% in the age group > 80 years Quantitative and dynamic VAF monitoring (separately and together with other mutations) at follow-up Clarifying the significance of CHIP in the context of myeloid malignancies Discrimination of leukemia-related somatic mutations from pathogenic germline alterations Challenge to differentiate acquired somatic mutations from germline pathogenic variants at diagnosis Mutation detection in germline control samples (e.g., skin fibroblasts, saliva) in mutations such as in RUNX1, CEBPA Thorough medical family history followed by molecular genetic tests in relatives if necessary High and stable VAF (e.g., 40-50%) at follow-up despite clinical response to treatment may be indicative for germline alteration Discrimination of true genetic alterations from PCR, sequencing and post-sequencing artifacts Many artefacts are known to arise during NGS library preparation, sequencing and data analysis Error correction using molecular identifiers that individually label original input DNA molecules Refinement of error-correction computational methods in post-sequencing NGS data analysis Confirmation using Sanger sequencing Limited sensitivity of NGS for minimal residual disease (MRD) assessment Mutations detected at diagnosis may be re-identified at best to a VAF of 1-2% Error-corrected sequencing using molecular identifiers Complementation of NGS by established MRD tools like real time PCR and flow cytometry High financial burden; demand on interdisciplinary approaches Expensive technical and staff equipment, sophisticated data interpretation Complex translation of NGS results into therapeutic decisions Development of continuously updated NGS interpretation sets and algorithms for well-established mutational profiles within distinct hematological malignancies Interdisciplinary leukemia boards VAF variant allele frequency, CHIP clonal hematopoiesis of indeterminate significance, bp base pairs, G guanine, C cytosine, ITDs internal tandem duplication. PMID- 30420670 TI - Diffusion-defining atomic-scale spinodal decomposition within nanoprecipitates. AB - Stoichiometric precipitates owe their fixed composition to an ordered crystal structure. Deviations from that nominal value, however, are encountered at times. Here we investigate composition, structure and diffusion phenomena of ordered precipitates that form during heat treatment in an industrially cast Al-Mg-Sc-Zr alloy system. Experimental investigations based on aberration-corrected scanning transmission electron microscopy and analytical tomography reveal the temporal evolution of precipitate ordering and formation of non-equilibrium structures with unprecedented spatial resolution, supported by thermodynamic calculations and diffusion simulations. This detailed view reveals atomic-scale spinodal decomposition to majorly define the ongoing diffusion process. It is illustrated that even small deviations in composition and ordering can have a considerable impact on a system's evolution, due to the interplay of Gibbs energies, atomic jump activation energies and phase ordering, which may play an important role for multicomponent alloys. PMID- 30420671 TI - Large Pockels effect in micro- and nanostructured barium titanate integrated on silicon. AB - The electro-optical Pockels effect is an essential nonlinear effect used in many applications. The ultrafast modulation of the refractive index is, for example, crucial to optical modulators in photonic circuits. Silicon has emerged as a platform for integrating such compact circuits, but a strong Pockels effect is not available on silicon platforms. Here, we demonstrate a large electro-optical response in silicon photonic devices using barium titanate. We verify the Pockels effect to be the physical origin of the response, with r42 = 923 pm V-1, by confirming key signatures of the Pockels effect in ferroelectrics: the electro optic response exhibits a crystalline anisotropy, remains strong at high frequencies, and shows hysteresis on changing the electric field. We prove that the Pockels effect remains strong even in nanoscale devices, and show as a practical example data modulation up to 50 Gbit s-1. We foresee that our work will enable novel device concepts with an application area largely extending beyond communication technologies. PMID- 30420672 TI - Deformation twinning and grain partitioning in a hexagonal close-packed magnesium alloy. AB - Pervasive deformation twinning in magnesium greatly affects its strength and formability. The local stress fields associated with twinning play a key role on deformation behavior and fracture but are extremely difficult to characterize experimentally. In this study, we perform synchrotron experiments with differential-aperture X-ray microscopy to measure the 3D stress fields in the vicinity of a twin with a spatial resolution of 0.5 micrometer. The measured local stress field aids to identify the sequence of events involved with twinning. We find that the selected grain deforms elastically before twinning, and the twin formation splits the grain into two non-interacting domains. Under further straining one domain of the grain continued to deform elastically, whereas the other domain deforms plastically by prismatic slip. This heterogeneous deformation behavior may be mediated by the surrounding medium and it is likely to lead to asymmetric twin growth. PMID- 30420673 TI - Audit of stored strain energy and extent of future earthquake rupture in central Himalaya. AB - The deadly 25 April 2015 Gorkha earthquake (Mw = 7.8) and aftershocks have partially released the accumulated interseismic strain along the Main Himalayan Thrust (MHT). Postseismic deformation associated with this earthquake is mainly confined to the north of the rupture. This suggests possible occurrence of future large events towards west or south, where MHT is locked. Asperities arising due to heterogeneity in the stress-strain patterns are believed to play a major role in controlling the coseismic rupture propagation. We determine interseismic coupling along the MHT and spatial variations in total strain rate using two decades of GPS, InSAR and sprit leveling data. Further, b-values derived from the seismicity data are used to identify zones of stress accumulation. We demonstrate that the 2015 earthquake ruptured an asperity which hosted high strain and stress accumulation prior to the event. A similar asperity towards west of the epicenter with unreleased strain energy is identified. This could spawn a future large earthquake akin in magnitude to the 2015 Gorkha event. These findings compel a revisit of the seismic hazard assessment of the central Himalaya. PMID- 30420674 TI - Clustering and climate associations of Kawasaki Disease in San Diego County suggest environmental triggers. AB - Kawasaki Disease (KD) is the most common cause of pediatric acquired heart disease, but its etiology remains unknown. We examined 1164 cases of KD treated at a regional children's hospital in San Diego over a period of 15 years and uncovered novel structure to disease incidence. KD cases showed a well-defined seasonal variability, but also clustered temporally at much shorter time scales (days to weeks), and spatiotemporally on time scales of up to 10 days and spatial scales of 10-100 km. Temporal clusters of KD cases were associated with strongly significant regional-scale air temperature anomalies and consistent larger-scale atmospheric circulation patterns. Gene expression analysis further revealed a natural partitioning of KD patients into distinct groups based on their gene expression pattern, and that the different groups were associated with certain clinical characteristics that also exhibit temporal autocorrelation. Our data suggest that one or more environmental triggers exist, and that episodic exposures are modulated at least in part by regional weather conditions. We propose that characterization of the environmental factors that trigger KD in genetically susceptible children should focus on aerosols inhaled by patients who share common disease characteristics. PMID- 30420675 TI - Observation of a topologically protected state in a magnetic domain wall stabilized by a ferromagnetic chemical barrier. AB - The precise control and stabilization of magnetic domain walls is key for the development of the next generation magnetic nano-devices. Among the multitude of magnetic configurations of a magnetic domain wall, topologically protected states are of particular interest due to their intrinsic stability. In this work, using XMCD-PEEM, we have observed a topologically protected magnetic domain wall in a ferromagnetic cylindrical nanowire. Its structure is stabilized by periodic sharp alterations of the chemical composition in the nanowire. The large stability of this topologically protected domain wall contrasts with the mobility of other non protected and non-chiral states also present in the same nanowire. The micromagnetic simulations show the structure and the conditions required to find the topologically protected state. These results are relevant for the design of future spintronic devices such as domain wall based RF oscillators or magnetic memories. PMID- 30420676 TI - Near-infrared STED nanoscopy with an engineered bacterial phytochrome. AB - The near infrared (NIR) optical window between the cutoff for hemoglobin absorption at 650 nm and the onset of increased water absorption at 900 nm is an attractive, yet largely unexplored, spectral regime for diffraction-unlimited super-resolution fluorescence microscopy (nanoscopy). We developed the NIR fluorescent protein SNIFP, a bright and photostable bacteriophytochrome, and demonstrate its use as a fusion tag in live-cell microscopy and STED nanoscopy. We further demonstrate dual color red-confocal/NIR-STED imaging by co-expressing SNIFP with a conventional red fluorescent protein. PMID- 30420677 TI - Assessment of fibroblast nuclear morphology aids interpretation of LMNA variants. AB - The phenotypic heterogeneity of Lamin A/C (LMNA) variants renders it difficult to classify them. As a consequence, many LMNA variants are classified as variant of unknown significance (VUS). A number of studies reported different types of visible nuclear abnormalities in LMNA-variant carriers, such as herniations, honeycomb-like structures and irregular Lamin staining. In this study, we used lamin A/C immunostaining and nuclear DAPI staining to assess the number and type of nuclear abnormalities in primary dermal fibroblast cultures of laminopathy patients and healthy controls. The total number of abnormal nuclei, which includes herniations, honeycomb-structures, and donut-like nuclei, was found to be the most discriminating parameter between laminopathy and control cell cultures. The percentage abnormal nuclei was subsequently scored in fibroblasts of 28 LMNA variant carriers, ranging from (likely) benign to (likely) pathogenic variant. Using this method, 27 out of 28 fibroblast cell cultures could be classified as either normal (n = 14) or laminopathy (n = 13) and no false positive results were obtained. The obtained specificity was 100% (CI 40-100%) and sensitivity 77% (46-95%). We conclude that assessing the percentage of abnormal nuclei is a quick and reliable method, which aids classification or confirms pathogenicity of identified LMNA variants causing formation of aberrant lamin A/C protein. PMID- 30420678 TI - Genetic variation in the Estonian population: pharmacogenomics study of adverse drug effects using electronic health records. AB - Pharmacogenomics aims to tailor pharmacological treatment to each individual by considering associations between genetic polymorphisms and adverse drug effects (ADEs). With technological advances, pharmacogenomic research has evolved from candidate gene analyses to genome-wide association studies. Here, we integrate deep whole-genome sequencing (WGS) information with drug prescription and ADE data from Estonian electronic health record (EHR) databases to evaluate genome- and pharmacome-wide associations on an unprecedented scale. We leveraged WGS data of 2240 Estonian Biobank participants and imputed all single-nucleotide variants (SNVs) with allele counts over 2 for 13,986 genotyped participants. Overall, we identified 41 (10 novel) loss-of-function and 567 (134 novel) missense variants in 64 very important pharmacogenes. The majority of the detected variants were very rare with frequencies below 0.05%, and 6 of the novel loss-of-function and 99 of the missense variants were only detected as single alleles (allele count = 1). We also validated documented pharmacogenetic associations and detected new independent variants in known gene-drug pairs. Specifically, we found that CTNNA3 was associated with myositis and myopathies among individuals taking nonsteroidal anti-inflammatory oxicams and replicated this finding in an extended cohort of 706 individuals. These findings illustrate that population-based WGS-coupled EHRs are a useful tool for biomarker discovery. PMID- 30420679 TI - Mendelian randomization reveals unexpected effects of CETP on the lipoprotein profile. AB - According to the current dogma, cholesteryl ester transfer protein (CETP) decreases high-density lipoprotein (HDL)-cholesterol (C) and increases low density lipoprotein (LDL)-C. However, detailed insight into the effects of CETP on lipoprotein subclasses is lacking. Therefore, we used a Mendelian randomization approach based on a genetic score for serum CETP concentration (rs247616, rs12720922 and rs1968905) to estimate causal effects per unit (ug/mL) increase in CETP on 159 standardized metabolic biomarkers, primarily lipoprotein subclasses. Metabolic biomarkers were measured by nuclear magnetic resonance (NMR) in 5672 participants of the Netherlands Epidemiology of Obesity (NEO) study. Higher CETP concentrations were associated with less large HDL (largest effect XL-HDL-C, P = 6 * 10-22) and more small VLDL components (largest effect S VLDL cholesteryl esters, P = 6 * 10-6). No causal effects were observed with LDL subclasses. All these effects were replicated in an independent cohort from European ancestry (MAGNETIC NMR GWAS; n ~20,000). Additionally, we assessed observational associations between ELISA-measured CETP concentration and metabolic measures. In contrast to results from Mendelian randomization, observationally, CETP concentration predominantly associated with more VLDL, IDL and LDL components. Our results show that CETP is an important causal determinant of HDL and VLDL concentration and composition, which may imply that the CETP inhibitor anacetrapib decreased cardiovascular disease risk through specific reduction of small VLDL rather than LDL. The contrast between genetic and observational associations might be explained by a high capacity of VLDL, IDL and LDL subclasses to carry CETP, thereby concealing causal effects on HDL. PMID- 30420681 TI - Higher-Order Interactions in Quantum Optomechanics: Analysis of Quadratic Terms. AB - This article presents a full operator analytical method for studying the quadratic nonlinear interactions in quantum optomechanics. The method is based on the application of higher-order operators, using a six-dimensional basis of second order operators which constitute an exactly closed commutators. We consider both types of standard position-field and the recently predicted non standard momentum-field quadratic interactions, which is significant when the ratio of mechanical frequency to optical frequency is not negligible. This unexplored regime of large mechanical frequency can be investigated in few platforms including the superconducting electromechanics and simulating quantum cavity electrodynamic circuits. It has been shown that the existence of non standard quadratic interaction could be observable under appropriate conditions. PMID- 30420680 TI - Calcium stabilizes the strongest protein fold. AB - Staphylococcal pathogens adhere to their human targets with exceptional resilience to mechanical stress, some propagating force to the bacterium via small, Ig-like folds called B domains. We examine the mechanical stability of these folds using atomic force microscopy-based single-molecule force spectroscopy. The force required to unfold a single B domain is larger than 2 nN the highest mechanostability of a protein to date by a large margin. B domains coordinate three calcium ions, which we identify as crucial for their extreme mechanical strength. When calcium is removed through chelation, unfolding forces drop by a factor of four. Through systematic mutations in the calcium coordination sites we can tune the unfolding forces from over 2 nN to 0.15 nN, and dissect the contribution of each ion to B domain mechanostability. Their extraordinary strength, rapid refolding and calcium-tunable force response make B domains interesting protein design targets. PMID- 30420684 TI - Magnetic field driven complex phase diagram of antiferromagnetic heavy-fermion superconductor Ce3PtIn11. AB - We present the results of our comprehensive investigation on the antiferromagnetic heavy-fermion superconductor Ce3PtIn11 carried out by means of electrical transport, heat capacity and ac magnetic susceptibility measurements, performed on single-crystalline specimens down to 50 mK in external magnetic fields up to 9 T. Our experimental results elucidate a complex magnetic field - temperature phase diagram which contains both first- and second-order field induced magnetic transitions and highlights the emergence of field stabilized phases. Remarkably, a prominent metamagnetic transition was found to occur at low temperatures and strong magnetic fields. In turn, the results obtained in the superconducting phase of Ce3PtIn11 corroborate an unconventional nature of Cooper pairs formed by heavy quasiparticles. The compound is an almost unique example of a heavy fermion system in which superconductivity may coexist microscopically with magnetically ordered state. PMID- 30420683 TI - Two novel, putative mechanisms of action for citalopram-induced platelet inhibition. AB - Citalopram, a selective serotonin reuptake inhibitor (SSRI), inhibits platelet function in vitro. We have previously shown that this action is independent of citalopram's ability to block serotonin uptake by the serotonin transporter and must therefore be mediated via distinct pharmacological mechanisms. We now report evidence for two novel and putative mechanisms of citalopram-induced platelet inhibition. Firstly, in platelets, citalopram blocked U46619-induced Rap1 activation and subsequent platelet aggregation, but failed to inhibit U46619 induced increases in cytosolic Ca2+. Similarly, in neutrophils, citalopram inhibited Rap1 activation and downstream functions but failed to block PAF induced Ca2+ mobilisation. In a cell-free system, citalopram also reduced CalDAG GEFI-mediated nucleotide exchange on Rap1B. Secondly, the binding of anti-GPVI antibodies to resting platelets was inhibited by citalopram. Furthermore, citalopram-induced inhibition of GPVI-mediated platelet aggregation was instantaneous, reversible and displayed competitive characteristics, suggesting that these effects were not caused by a reduction in GPVI surface expression, but by simple competitive binding. In conclusion, we propose two novel, putative and distinct inhibitory mechanisms of action for citalopram: (1) inhibition of CalDAG GEFI/Rap1 signalling, and (2) competitive antagonism of GPVI in platelets. These findings may aid in the development of novel inhibitors of CalDAG-GEFI/Rap1 dependent nucleotide exchange and novel GPVI antagonists. PMID- 30420685 TI - Fast, in vivo voltage imaging using a red fluorescent indicator. AB - Genetically encoded voltage indicators (GEVIs) are emerging optical tools for acquiring brain-wide cell-type-specific functional data at unparalleled temporal resolution. To broaden the application of GEVIs in high-speed multispectral imaging, we used a high-throughput strategy to develop voltage-activated red neuronal activity monitor (VARNAM), a fusion of the fast Acetabularia opsin and the bright red fluorophore mRuby3. Imageable under the modest illumination intensities required by bright green probes (<50 mW mm-2), VARNAM is readily usable in vivo. VARNAM can be combined with blue-shifted optical tools to enable cell-type-specific all-optical electrophysiology and dual-color spike imaging in acute brain slices and live Drosophila. With enhanced sensitivity to subthreshold voltages, VARNAM resolves postsynaptic potentials in slices and cortical and hippocampal rhythms in freely behaving mice. Together, VARNAM lends a new hue to the optical toolbox, opening the door to high-speed in vivo multispectral functional imaging. PMID- 30420682 TI - Acute alcohol administration dampens central extended amygdala reactivity. AB - Alcohol use is common, imposes a staggering burden on public health, and often resists treatment. The central extended amygdala (EAc)-including the bed nucleus of the stria terminalis (BST) and the central nucleus of the amygdala (Ce)-plays a key role in prominent neuroscientific models of alcohol drinking, but the relevance of these regions to acute alcohol consumption in humans remains poorly understood. Using a single-blind, randomized-groups design, multiband fMRI data were acquired from 49 social drinkers while they performed a well-established emotional faces paradigm after consuming either alcohol or placebo. Relative to placebo, alcohol significantly dampened reactivity to emotional faces in the BST. To rigorously assess potential regional differences in activation, data were extracted from unbiased, anatomically predefined regions of interest. Analyses revealed similar levels of dampening in the BST and Ce. In short, alcohol transiently reduces reactivity to emotional faces and it does so similarly across the two major divisions of the human EAc. These observations reinforce the translational relevance of addiction models derived from preclinical work in rodents and provide new insights into the neural systems most relevant to the consumption of alcohol and to the initial development of alcohol abuse in humans. PMID- 30420686 TI - Closed-loop all-optical interrogation of neural circuits in vivo. AB - Understanding the causal relationship between neural activity and behavior requires the ability to perform rapid and targeted interventions in ongoing activity. Here we describe a closed-loop all-optical strategy for dynamically controlling neuronal activity patterns in awake mice. We rapidly tailored and delivered two-photon optogenetic stimulation based on online readout of activity using simultaneous two-photon imaging, thus enabling the manipulation of neural circuit activity 'on the fly' during behavior. PMID- 30420687 TI - Quantifying and comparing bacterial growth dynamics in multiple metagenomic samples. AB - The accurate quantification of microbial growth dynamics for species without complete genome sequences is biologically important, but computationally challenging in metagenomics. Here we present dynamic estimator of microbial communities (DEMIC; https://sourceforge.net/projects/demic/ ), a multi-sample algorithm based on contigs and coverage values, to infer the relative distances of contigs from the replication origin and to accurately compare bacterial growth rates between samples. We demonstrate robust performances of DEMIC for various sample sizes and assembly qualities using multiple synthetic and real datasets. PMID- 30420688 TI - Nutritional status in chronic spinal cord injury: a systematic review and meta analysis. AB - STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVES: The objective was to investigate nutritional status in chronic spinal cord injury (SCI), and compare macronutrient and micronutrient intake to the recommended values by the United States Department of Agriculture (USDA) 2015-2020 Dietary Guidelines for Americans. SETTING: United States of America. METHODS: A MEDLINE/PubMed, Google Scholar, Scopus, and Web of Science search was performed, identifying 268 papers. All papers included were English-language papers examining adults with chronic SCI. A meta-analysis was performed to produce weighted averages and 95% confidence intervals (CI) when summary statistics were provided. RESULTS: The systematic review included 15 articles, while the meta-analysis included 12. Resting metabolic rate (1492 kcal/day; CI: 1414-1569) fell below the able-bodied average, and total energy (1876 kcal/day; CI: 1694-2059) and fiber (17 g/day; CI: 14-20) intake were below USDA guidelines. Protein (319 kcal/day; CI: 294-345) and carbohydrate (969 kcal/day; CI: 851-1087) intake were above guidelines. Fat intake (663 kcal/day; CI: 590-736) was within USDA guidelines. Vitamins A, B5, B7, B9, D, E, potassium, and calcium were deficient, while vitamins B1, B2, B3, B12, C, K, sodium, phosphorus, copper, and zinc were in excess according to USDA guidelines. Vitamin B6, iron, and magnesium were within USDA guidelines. CONCLUSION: Findings indicate greater energy intake relative to energy needs in those with chronic SCI, and an imbalance in fiber intake and micronutrients compared to the USDA guidelines. Future research examining nutritional health status is needed in order to establish evidence-based, SCI-specific dietary guidelines. PMID- 30420690 TI - O-GlcNAcylation of GLI transcription factors in hyperglycemic conditions augments Hedgehog activity. AB - Modification of proteins by O-linked beta-N-acetylglucosamine (O-GlcNAc) promotes tumor cell survival, proliferation, epigenetic changes, angiogenesis, invasion, and metastasis. Here we demonstrate that in conditions of elevated glucose, there is increased expression of key drug resistance proteins (ABCB1, ABCG2, ERCC1, and XRCC1), all of which are regulated by the Hedgehog pathway. In elevated glucose conditions, we determined that the Hedgehog pathway transcription factors, GLI1 and GLI2, are modified by O-GlcNAcylation. This modification functionally enhanced their transcriptional activity. The activity of GLI was enhanced when O GlcNAcase was inhibited, while inhibiting O-GlcNAc transferase caused a decrease in GLI activity. The metabolic impact of hyperglycemic conditions impinges on maintaining PKM2 in the less active state that facilitates the availability of glycolytic intermediates for biosynthetic pathways. Interestingly, under elevated glucose conditions, PKM2 directly influenced GLI activity. Specifically, abrogating PKM2 expression caused a significant decline in GLI activity and expression of drug resistance proteins. Cumulatively, our results suggest that elevated glucose conditions upregulate chemoresistance through elevated transcriptional activity of the Hedgehog/GLI pathway. Interfering in O GlcNAcylation of the GLI transcription factors may be a novel target in controlling cancer progression and drug resistance of breast cancer. PMID- 30420689 TI - Aberrant ARID5B expression and its association with Ikaros dysfunction in acute lymphoblastic leukemia. AB - Mutations and single nucleotide polymorphisms of AT-rich interactive domain containing protein 5B (ARID5B) are involved in the oncogenesis of acute lymphoblastic leukemia (ALL) and treatment outcomes. However, ARID5B expression and clinical significance in ALL remain unclear. We found ARID5B is significantly down-regulated in ALL compared to healthy bone marrow controls. ARID5B also interacts with PHD finger protein 2 (PHF2). Low expression of ARID5B (ARID5Blow) or ARID5B and PHF2 (ARID5BlowPHF2low) is correlated with the markers of cell proliferation and poor prognosis in ALL patients. Ikaros directly regulates ARID5B expression in ALL. Restoring Ikaros function by Casein Kinase II inhibition also promotes ARID5B expression through recruitment of trimethylation of lysine 4 on histone H3 (H3K4me3) at its promoter region. In summary, our data show that aberrant expression of ARID5B and PHF2 is related to leukemic cell proliferation and several poor prognostic markers. Our data indicate ARID5Blow expression, particularly ARID5BlowPHF2low expression, is linked to Ikaros dysfunction and involved in the oncogenic effect of high-risk ALL, which may represent a high-risk subgroup of ALL. PMID- 30420691 TI - Divining sugar substrates. PMID- 30420692 TI - Structural insights into the subtype-selective antagonist binding to the M2 muscarinic receptor. AB - Human muscarinic receptor M2 is one of the five subtypes of muscarinic receptors belonging to the family of G-protein-coupled receptors. Muscarinic receptors are targets for multiple neurodegenerative diseases. The challenge has been designing subtype-selective ligands against one of the five muscarinic receptors. We report high-resolution structures of a thermostabilized mutant M2 receptor bound to a subtype-selective antagonist AF-DX 384 and a nonselective antagonist NMS. The thermostabilizing mutation S110R in M2 was predicted using a theoretical strategy previously developed in our group. Comparison of the crystal structures and pharmacological properties of the M2 receptor shows that the Arg in the S110R mutant mimics the stabilizing role of the sodium cation, which is known to allosterically stabilize inactive state(s) of class A GPCRs. Molecular dynamics simulations reveal that tightening of the ligand-residue contacts in M2 receptors compared to M3 receptors leads to subtype selectivity of AF-DX 384. PMID- 30420693 TI - Functional and informatics analysis enables glycosyltransferase activity prediction. AB - The elucidation and prediction of how changes in a protein result in altered activities and selectivities remain a major challenge in chemistry. Two hurdles have prevented accurate family-wide models: obtaining (i) diverse datasets and (ii) suitable parameter frameworks that encapsulate activities in large sets. Here, we show that a relatively small but broad activity dataset is sufficient to train algorithms for functional prediction over the entire glycosyltransferase superfamily 1 (GT1) of the plant Arabidopsis thaliana. Whereas sequence analysis alone failed for GT1 substrate utilization patterns, our chemical-bioinformatic model, GT-Predict, succeeded by coupling physicochemical features with isozyme recognition patterns over the family. GT-Predict identified GT1 biocatalysts for novel substrates and enabled functional annotation of uncharacterized GT1s. Finally, analyses of GT-Predict decision pathways revealed structural modulators of substrate recognition, thus providing information on mechanisms. This multifaceted approach to enzyme prediction may guide the streamlined utilization (and design) of biocatalysts and the discovery of other family-wide protein functions. PMID- 30420695 TI - Lake Lazarus: the strange rebirth of a Californian ecosystem. PMID- 30420694 TI - Selective blockade of the lyso-PS lipase ABHD12 stimulates immune responses in vivo. AB - ABHD12 metabolizes bioactive lysophospholipids, including lysophosphatidylserine (lyso-PS). Deleterious mutations in human ABHD12 cause the neurological disease PHARC, and ABHD12-/- mice display PHARC-like phenotypes, including hearing loss, along with elevated brain lyso-PS and features of stimulated innate immune cell function. Here, we develop a selective and in vivo-active inhibitor of ABHD12 termed DO264 and show that this compound elevates lyso-PS in mouse brain and primary human macrophages. Unlike ABHD12-/- mice, adult mice treated with DO264 exhibited minimal perturbations in auditory function. On the other hand, both DO264-treated and ABHD12-/- mice displayed heightened immunological responses to lymphocytic choriomeningitis virus (LCMV) clone 13 infection that manifested as severe lung pathology with elevated proinflammatory chemokines. These results reveal similarities and differences in the phenotypic impact of pharmacological versus genetic blockade of ABHD12 and point to a key role for this enzyme in regulating immunostimulatory lipid pathways in vivo. PMID- 30420696 TI - Why I became a mental-health first-aider at my research institute. PMID- 30420697 TI - Practically simple reactions convert hydrocarbons to precious chemicals. PMID- 30420698 TI - Collective antiskyrmion-mediated phase transition and defect-induced melting in chiral magnetic films. AB - Magnetic phase transitions are a manifestation of competing interactions whose behavior is critically modified by defects and becomes even more complex when topological constraints are involved. In particular, the investigation of skyrmions and skyrmion lattices offers insight into fundamental processes of topological-charge creation and annihilation upon changing the magnetic state. Nonetheless, the exact physical mechanisms behind these phase transitions remain unresolved. Here, we show numerically that it is possible to collectively reverse the polarity of a skyrmion lattice in a field-induced first-order phase transition via a transient antiskyrmion-lattice state. We thus propose a new type of phase transformation where a skyrmion lattice inverts to another one due to topological constraints. In the presence of even a single defect, the process becomes a second-order phase transition with gradual topological-charge melting. This radical change in the system's behavior from a first-order to a second-order phase transition demonstrates that defects in real materials could prevent us from observing collective topological phenomena. We have systematically compared ultra-thin films with isotropic and anisotropic Dzyaloshinskii-Moriya interactions (DMIs), and demonstrated a nearly identical behavior for such technologically relevant interfacial systems. PMID- 30420699 TI - Pathway-based subnetworks enable cross-disease biomarker discovery. AB - Biomarkers lie at the heart of precision medicine. Surprisingly, while rapid genomic profiling is becoming ubiquitous, the development of biomarkers usually involves the application of bespoke techniques that cannot be directly applied to other datasets. There is an urgent need for a systematic methodology to create biologically-interpretable molecular models that robustly predict key phenotypes. Here we present SIMMS (Subnetwork Integration for Multi-Modal Signatures): an algorithm that fragments pathways into functional modules and uses these to predict phenotypes. We apply SIMMS to multiple data types across five diseases, and in each it reproducibly identifies known and novel subtypes, and makes superior predictions to the best bespoke approaches. To demonstrate its ability on a new dataset, we profile 33 genes/nodes of the PI3K pathway in 1734 FFPE breast tumors and create a four-subnetwork prediction model. This model out performs a clinically-validated molecular test in an independent cohort of 1742 patients. SIMMS is generic and enables systematic data integration for robust biomarker discovery. PMID- 30420701 TI - Spin-torque devices with hard axis initialization as Stochastic Binary Neurons. AB - Employing the probabilistic nature of unstable nano-magnet switching has recently emerged as a path towards unconventional computational systems such as neuromorphic or Bayesian networks. In this letter, we demonstrate proof-of concept stochastic binary operation using hard axis initialization of nano magnets and control of their output state probability (activation function) by means of input currents. Our method provides a natural path towards addition of weighted inputs from various sources, mimicking the integration function of neurons. In our experiment, spin orbit torque (SOT) is employed to "drive" nano magnets with perpendicular magnetic anisotropy (PMA) -to their metastable state, i.e. in-plane hard axis. Next, the probability of relaxing into one magnetization state (+mi) or the other (-mi) is controlled using an Oersted field generated by an electrically isolated current loop, which acts as a "charge" input to the device. The final state of the magnet is read out by the anomalous Hall effect (AHE), demonstrating that the magnetization can be probabilistically manipulated and output through charge currents, closing the loop from charge-to-spin and spin to-charge conversion. Based on these building blocks, a two-node directed network is successfully demonstrated where the status of the second node is determined by the probabilistic output of the previous node and a weighted connection between them. We have also studied the effects of various magnetic properties, such as magnet size and anisotropic field on the stochastic operation of individual devices through Monte Carlo simulations of Landau Lifshitz Gilbert (LLG) equation. The three-terminal stochastic devices demonstrated here are a critical step towards building energy efficient spin based neural networks and show the potential for a new application space. PMID- 30420700 TI - Semiconductor Hyperbolic Metamaterials at the Quantum Limit. AB - We study semiconductor hyperbolic metamaterials (SHMs) at the quantum limit experimentally using spectroscopic ellipsometry as well as theoretically using a new microscopic theory. The theory is a combination of microscopic density matrix approach for the material response and Green's function approach for the propagating electric field. Our approach predicts absorptivity of the full multilayer system and for the first time allows the prediction of in-plane and out-of-plane dielectric functions for every individual layer constructing the SHM as well as effective dielectric functions that can be used to describe a homogenized SHM. PMID- 30420703 TI - T cell help to stem cells. PMID- 30420704 TI - Immune response by touch. PMID- 30420705 TI - Central CD4+ T cell tolerance: deletion versus regulatory T cell differentiation. AB - The diversion of MHC class II-restricted thymocytes into the regulatory T (Treg) cell lineage is driven by intrathymic encounter of agonist self-antigens in a similar manner to the clonal deletion of thymocytes. Somewhat paradoxically, it thus seems that the expression of an autoreactive T cell receptor is a shared characteristic of T cells that are subject to clonal deletion and T cells that are diverted into the Treg cell lineage. Here, we discuss how thymocyte-intrinsic and thymocyte-extrinsic determinants may specify the choice between these two fundamentally different T cell fates. PMID- 30420706 TI - Maternal obesity and offspring cognition: the role of inflammation. AB - BACKGROUND: High pre-pregnancy body mass index (ppBMI) has been linked to neurodevelopmental impairments in childhood. However, very few studies have investigated mechanisms in human cohorts. METHODS: Among 1361 mother-child pairs in Project Viva, we examined associations of ppBMI categories with the Peabody Picture Vocabulary Test III [PPVT] and Wide Range Assessment of Visual Motor Abilities [WRAVMA] in early childhood (median 3.2y); and with the Kaufman Brief Intelligence test (KBIT) and WRAVMA in mid-childhood (7.7y). We further examined the role of maternal inflammation in these associations using the following measures from the 2nd trimester of pregnancy: plasma C-reactive protein (CRP), dietary inflammatory index (DII), and plasma omega-6 (n-6): n-3 fatty acid ratio. RESULTS: Children of mothers with prenatal obesity (ppBMI >=30 kg/m2) had WRAVMA scores that were 2.1 points lower (95% CI: -3.9, -0.2) in early childhood than children of normal weight mothers (ppBMI 18.5-<25 kg/m2), in a covariate adjusted model. This association was attenuated when we additionally adjusted for maternal CRP (beta -1.8 points; 95% CI: -3.8, 0.2) but not for other inflammatory markers. PpBMI was not associated with other cognitive outcomes. CONCLUSION: Maternal inflammation may modestly mediate the association between maternal obesity and offspring visual motor abilities. PMID- 30420702 TI - Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors. AB - Chromothripsis and chromoanasynthesis are catastrophic events leading to clustered genomic rearrangements. Whole-genome sequencing revealed frequent complex genomic rearrangements (n = 16/26) in brain tumors developing in mice deficient for factors involved in homologous-recombination-repair or non homologous-end-joining. Catastrophic events were tightly linked to Myc/Mycn amplification, with increased DNA damage and inefficient apoptotic response already observable at early postnatal stages. Inhibition of repair processes and comparison of the mouse tumors with human medulloblastomas (n = 68) and glioblastomas (n = 32) identified chromothripsis as associated with MYC/MYCN gains and with DNA repair deficiencies, pointing towards therapeutic opportunities to target DNA repair defects in tumors with complex genomic rearrangements. PMID- 30420707 TI - Wide clinical spectrum in ALG8-CDG: clues from molecular findings suggest an explanation for a milder phenotype in the first-described patient. AB - BACKGROUND: Congenital disorders of glycosylation (CDG) includes ALG8 deficiency, a protein N-glycosylation defect with a broad clinical spectrum. If most of the 15 previously reported patients present an early-onset multisystem severe disease and early death, three patients including the cas princeps, present long-term survival and less severe symptoms. METHODS: In order to further characterize ALG8 CDG, two new ALG8 patients are described and mRNA analyses of the ALG8-CDG cas princeps were effected. RESULTS: One new patient exhibited a hepato-intestinal and neurological phenotype with two novel variants (c.91A > C p.Thr31Pro; c.139dup p.Thr47Asnfs*12). The other new patient, homozygous for a known variant (c.845C > T p.Ala282Val), presented a neurological phenotype with epilepsy, intellectual disability and retinis pigmentosa. The cas princeps ALG8-CDG patient was reported to have two heterozygous frameshift variants predicted to be without activity. We now described a novel ALG8 transcript variant in this patient and the 3D model of the putative encoded protein reveals no major difference with that of the normal ALG8 protein. CONCLUSION: The description of the two new ALG8 patients affirms that ALG8-CDG is a severe disease. In the cas princeps, as the originally described frameshift variants are degraded, the novel variant is promoted and could explain a milder phenotype. PMID- 30420708 TI - Abnormalities in autonomic function in obese boys at-risk for insulin resistance and obstructive sleep apnea. AB - STUDY OBJECTIVES: Current evidence in adults suggests that, independent of obesity, obstructive sleep apnea (OSA) can lead to autonomic dysfunction and impaired glucose metabolism, but these relationships are less clear in children. The purpose of this study was to investigate the associations among OSA, glucose metabolism, and daytime autonomic function in obese pediatric subjects. METHODS: Twenty-three obese boys participated in: overnight polysomnography; a frequently sampled intravenous glucose tolerance test; and recordings of spontaneous cardiorespiratory data in both the supine (baseline) and standing (sympathetic stimulus) postures. RESULTS: Baseline systolic blood pressure and reactivity of low-frequency heart rate variability to postural stress correlated with insulin resistance, increased fasting glucose, and reduced beta-cell function, but not OSA severity. Baroreflex sensitivity reactivity was reduced with sleep fragmentation, but only for subjects with low insulin sensitivity and/or low first-phase insulin response to glucose. CONCLUSIONS: These findings suggest that vascular sympathetic activity impairment is more strongly affected by metabolic dysfunction than by OSA severity, while blunted vagal autonomic function associated with sleep fragmentation in OSA is enhanced when metabolic dysfunction is also present. PMID- 30420709 TI - Maternal nutrient restriction in guinea pigs leads to fetal growth restriction with increased brain apoptosis. AB - BACKGROUND: We determined whether maternal nutrient restriction (MNR) in guinea pigs leading to fetal growth restriction (FGR) impacts cell death in the brain with implications for neurodevelopmental adversity. METHODS: Guinea pigs were fed ad libitum (Control) or 70% of the control diet before pregnancy, switching to 90% at mid-pregnancy (MNR). Fetuses were necropsied near term and brain tissues processed for necrosis (H&E), apoptosis (TUNEL), and pro- (Bax) and anti- (Bcl-2 and Grp78) apoptotic protein immunoreactivity. RESULTS: FGR-MNR fetal and brain weights were decreased 38% and 12%, respectively, indicating brain sparing but with brains still smaller. While necrosis remained unchanged, apoptosis was increased in the white matter and hippocampus in the FGR brains, and control and FGR-related apoptosis were increased in males for most brain areas. Bax was increased in the CA4 and Bcl-2 was decreased in the dentate gyrus in the FGR brains supporting a role in the increased apoptosis, while Grp78 was increased in the FGR females, possibly contributing to the sex-related differences. CONCLUSIONS: MNR-induced FGR results in increased brain apoptosis with regional and sex-related differences that may contribute to the reduction in brain area size reported clinically and increased risk in FGR males for later neurodevelopmental adversity. PMID- 30420711 TI - Organelle DNA degradation contributes to the efficient use of phosphate in seed plants. AB - Mitochondria and chloroplasts (plastids) both harbour extranuclear DNA that originates from the ancestral endosymbiotic bacteria. These organelle DNAs (orgDNAs) encode limited genetic information but are highly abundant, with multiple copies in vegetative tissues, such as mature leaves. Abundant orgDNA constitutes a substantial pool of organic phosphate along with RNA in chloroplasts, which could potentially contribute to phosphate recycling when it is degraded and relocated. However, whether orgDNA is degraded nucleolytically in leaves remains unclear. In this study, we revealed the prevailing mechanism in which organelle exonuclease DPD1 degrades abundant orgDNA during leaf senescence. The DPD1 degradation system is conserved in seed plants and, more remarkably, we found that it was correlated with the efficient use of phosphate when plants were exposed to nutrient-deficient conditions. The loss of DPD1 compromised both the relocation of phosphorus to upper tissues and the response to phosphate starvation, resulting in reduced plant fitness. Our findings highlighted that DNA is also an internal phosphate-rich reservoir retained in organelles since their endosymbiotic origin. PMID- 30420712 TI - Cytokinin modulates context-dependent chromatin accessibility through the type-B response regulators. AB - The phytohormone cytokinin regulates diverse aspects of plant growth and development, probably through context-dependent transcriptional regulation that relies on a dynamic interplay between regulatory proteins and chromatin. We employed the assay for transposase accessible chromatin with sequencing to profile changes in the chromatin landscape of Arabidopsis roots and shoots in response to cytokinin. Our results reveal differentially accessible chromatin regions indicative of dynamic regulation in response to cytokinin. These changes in chromatin occur preferentially upstream of cytokinin-regulated genes. The changes also largely overlap with binding sites for the type-B ARABIDOPSIS RESPONSE REGULATORS (ARRs), transcription factors that mediate the primary response to cytokinin. Furthermore, the type-B ARRs were found to be necessary for the changes in chromatin state in response to cytokinin. Last, we identified context-dependent responses by comparing root and shoot profiles. This study provides new insight into the dynamics between cytokinin and chromatin with regard to directing transcriptional programmes and how cytokinin mediates its pleiotropic effects. PMID- 30420710 TI - Identification of DKK-1 as a novel mediator of statin effects in human endothelial cells. AB - This study shows that DKK-1, a member of the Dickkopf family and a regulator of the Wnt pathways, represents a novel target of statins which, through the inhibition of HMG-CoA reductase and of non-steroidal isoprenoid intermediates, exert extra-beneficial effect in preventing atherosclerosis beyond their effect on the lipid profile. We found that atorvastatin downregulates DKK-1 protein ( 88.3 +/- 4.1%) and mRNA expression (-90 +/- 4.2%) through the inhibition of Cdc42, Rho and Rac geranylgeranylated proteins. Further, a combined approach based on the integration of label-free quantitative mass spectrometry based proteomics and gene silencing allowed us to demonstrate that DKK-1 itself mediates, at least in part, statin effects on human endothelial cells. Indeed, DKK-1 is responsible for the regulation of the 21% of the statin-modulated proteins, which include, among others, clusterin/apoJ, plasminogen activator inhibitor type 1 (PAI-1), myristoylated alanine-rich C-kinase substrate (MARCKS), and pentraxin 3 (PTX3). The Gene Ontology enrichment annotation revealed that DKK 1 is also a potential mediator of the extracellular matrix organization, platelet activation and response to wounding processes induced by statin. Finally, we found that plasma level of DKK-1 from cholesterol-fed rabbits treated with atorvastatin (2.5 mg/kg/day for 8 weeks) was lower (-42 +/- 23%) than that of control animals. Thus, DKK-1 is not only a target of statin but it directly regulates the expression of molecules involved in a plethora of biological functions, thus expanding its role, which has been so far restricted mainly to cancer. PMID- 30420713 TI - A204E mutation in Nav1.4 DIS3 exerts gain- and loss-of-function effects that lead to periodic paralysis combining hyper- with hypo-kalaemic signs. AB - Periodic paralyses (PP) are characterized by episodic muscle weakness and are classified into the distinct hyperkalaemic (hyperPP) and hypokalaemic (hypoPP) forms. The dominantly-inherited form of hyperPP is caused by overactivity of Nav1.4 - the skeletal muscle voltage-gated sodium channel. Familial hypoPP results from a leaking gating pore current induced by dominant mutations in Nav1.4 or Cav1.1, the skeletal muscle voltage-gated calcium channel. Here, we report an individual with clinical signs of hyperPP and hypokalaemic episodes of muscle paralysis who was heterozygous for the novel p.Ala204Glu (A204E) substitution located in one region of Nav1.4 poor in disease-related variations. A204E induced a significant decrease of sodium current density, increased the window current, enhanced fast and slow inactivation of Nav1.4, and did not cause gating pore current in functional analyses. Interestingly, the negative impact of A204E on Nav1.4 activation was strengthened in low concentration of extracellular K+. Our data prove the existence of a phenotype combining signs of hyperPP and hypoPP due to dominant Nav1.4 mutations. The hyperPP component would result from gain-of-function effects on Nav1.4 and the hypokalemic episodes of paralysis from loss-of-function effects strengthened by low K+. Our data argue for a non negligible role of Nav1.4 loss-of-function in familial hypoPP. PMID- 30420714 TI - Neural mechanisms for learning self and other ownership. AB - Sense of ownership is a ubiquitous and fundamental aspect of human cognition. Here we used model-based functional magnetic resonance imaging and a novel minimal ownership paradigm to probe the behavioural and neural mechanisms underpinning ownership acquisition for ourselves, friends and strangers. We find a self-ownership bias at multiple levels of behaviour from initial preferences to reaction times and computational learning rates. Ventromedial prefrontal cortex (vmPFC) and anterior cingulate sulcus (ACCs) responded more to self vs. stranger associations, but despite a pervasive neural bias to track self-ownership, no brain area tracked self-ownership exclusively. However, ACC gyrus (ACCg) specifically coded ownership prediction errors for strangers and ownership associative strength for friends and strangers but not for self. Core neural mechanisms for associative learning are biased to learn in reference to self but also engaged when learning in reference to others. In contrast, ACC gyrus exhibits specialization for learning about others. PMID- 30420716 TI - Insights into the Role of Plasma in Atmospheric Pressure Chemical Vapor Deposition of Titanium Dioxide Thin Films. AB - In this work, the effect of plasma on the chemistry and morphology of coatings deposited by Atmospheric Pressure Plasma Enhanced Chemical Vapor Deposition (AP PECVD) is investigated. To do so, plasma deposited amorphous titanium dioxide (TiO2) thin films are compared to thin films deposited using Atmospheric Pressure Chemical Vapor Deposition (AP-CVD) not involving the use of plasma. We focus here on the effect and the interest of plasma in the AP-PECVD process over AP-CVD for low substrate temperature deposition. The advantages of AP-PECVD over AP-CVD are often suggested in many articles however no direct evidence of the role of the plasma for TiO2 deposition at atmospheric pressure was reported. Hence, herein, the deposition via both methods is directly compared by depositing coatings with and without plasma using the same CVD reactor. Through the control of the plasma parameters, we are able to form low carbon coatings at low temperature with a deposition rate twice faster than AP-CVD, clearly showing the interest of plasma. Plasma enhanced methods are promising for the deposition of coatings at industrial scale over large surface and at high rate. PMID- 30420715 TI - Imaging the distribution of skin lipids and topically applied compounds in human skin using mass spectrometry. AB - The barrier functions of skin against water loss, microbial invasion and penetration of xenobiotics rely, in part, on the spatial distribution of the biomolecular constituents in the skin structure, particularly its horny layer (stratum corneum). However, all skin layers are important to describe normal and dysfunctional skin conditions, and to develop adapted therapies or skin care products. In this work, time-of-flight secondary ion mass spectrometry (ToF-SIMS) combined with scanning electron microscopy (SEM) was used to image the spatial distribution of a variety of molecular species, from stratum corneum down to dermis, in cross-section samples of human abdominal skin. The results demonstrate the expected localization of ceramide and saturated long-chain fatty acids in stratum corneum (SC) and cholesterol sulfate in the upper part of the viable epidermis. The localization of exogenous compounds is demonstrated by the detection and imaging of carvacrol (a constituent of oregano or thyme essential oil) and ceramide, after topical application onto ex vivo human skin. Carvacrol showed pronounced accumulation to triglyceride-containing structures in the deeper parts of dermis. In contrast, the exogenous ceramide was found to be localized in SC. Furthermore, the complementary character of this approach with classical ex vivo skin absorption analysis methods is demonstrated. PMID- 30420717 TI - A model of breast cancer meningeal metastases: characterization with in vivo molecular imaging. AB - Meningeal metastasis is a fatal complication of breast cancer which affects 8-15% of patients who experience severe neurological complications of cranial nerves, cerebrum, and spinal cord. Survival once diagnosed is less than 4 months. Currently there is no cure. Aggressive multimodal radiation, intra-CSF, or systemic chemotherapy is palliative. Investigation of urgently needed new treatment modalities is hindered by the lack of suitable animal models to effectively study tumor growth kinetics. We present a model of meningeal metastases where tumor growth and associated neurological symptoms have been characterized over 3 weeks by sequential molecular imaging, tumor growth kinetics, and histopathology. Meningeal metastases were induced by stereotaxic injection of human breast cancer cells (MDA-MB-231-Rluc) into the lateral ventricle. Tumor identified by Gd-MRI and Rluc-bioluminescence depict growth in 3 phases, namely lag, exponential, and plateau phase. Invasive tumor growth was highlighted by changes in contrast distribution in the meninges, ventricle and brain compartments over time where moderate contrast uptake in the early growth phase gave rise to a heavy tumor burden in the base of the brain in the latter phases. Tumor growth was accompanied with debilitating neurological symptoms and change in body mass. Tumor was confirmed by ex vivo histology. The reliability of the model to study novel therapeutics was confirmed by oncolytic virus delivered into the lateral ventricle showed potential for treatment. This effective and reliable model resembles human disease progression and is ideally suited to investigate novel treatments. PMID- 30420718 TI - Intratumoral IFN-alpha gene delivery reduces tumor-infiltrating regulatory T cells through the downregulation of tumor CCL17 expression. AB - The effect of IFN-alpha on the immunosuppressive tumor microenvironment is not fully understood. We previously reported that intratumoral IFN-alpha gene transduction decreased the frequency of regulatory T cells (Tregs) in the tumor by inducing the secretion of IL-6 from dendritic cells. In this study, we examined whether IFN-alpha affects the trafficking of Tregs to the tumor. Since CT26 cells expressed CCL17 among Treg-attracting chemokines, we focused on its role in IFN-alpha-mediated Treg suppression. IFN-alpha directly suppressed CCL17 production from CT26 cells in vitro, and IFN-alpha transduction reduced CCL17 expression in tumors in vivo. Next, to investigate whether CCL17 downregulation is related to the suppression of Treg trafficking, CCL17-downregulated CT26 cells produced using short hairpin RNA (CT26-shCCL17) were inoculated into mice. The frequency of Tregs in CT26-shCCL17 tumors was reduced and tumor growth was suppressed. Finally, to examine the combinatorial effect of IFN-alpha expression with CCL17 downregulation, IFN-alpha was transduced into CT26-shCCL17 tumors. This resulted in an elevation of CT26-specific CD8+ T cells and the complete eradication of tumors. This study shows a novel mechanism of IFN-alpha-mediated Treg suppression, and combining IFN-alpha gene therapy with strong CCL17 downregulation could offer a promising strategy for the treatment of cancer. PMID- 30420719 TI - Inhibition of oncogenic cap-dependent translation by 4EGI-1 reduces growth, enhances chemosensitivity and alters genome-wide translation in non-small cell lung cancer. AB - Hyperactivation of eIF4F-mediated translation occurs in many if not all cancers. As a consequence, cancer cells aberrantly enhance expression of malignancy related proteins that are involved in cell cycle progression, angiogenesis, growth, and proliferation. With this in mind eIF4F is a promising molecular target for therapeutics that counteract pathological eIF4F activity. Here we used 4EGI-1, a small-molecule inhibitor of cap-mediated translation that disrupts formation of the eukaryotic initiation factor 4F (eIF4F) complex to treat non small cell lung cancer (NSCLC). Treatment of cells with 4EGI-1 reduced cell proliferation, decreased cap-dependent complex formation, induced apoptosis, enhanced sensitivity to gemcitabine, and altered global cellular translation. Suppression of cap-dependent translation by 4EGI-1 resulted in diminished expression of oncogenic proteins c-Myc, Bcl-2, cyclin D1, and survivin, whereas beta-actin expression was left unchanged. In light of these results, small molecule inhibitors like 4EGI-1 alone or with chemotherapy should be further evaluated in the treatment of NSCLC. PMID- 30420720 TI - Influence of dietary supplementation with Bacillus licheniformis and Saccharomyces cerevisiae as alternatives to monensin on growth performance, antioxidant, immunity, ruminal fermentation and microbial diversity of fattening lambs. AB - Alternatives to antibiotics for improving productivity and maintaining the health of livestock health are urgently needed. The scope of this research was conducted to investigate the effects of two alternatives (Bacillus licheniformis and Saccharomyces cerevisiae) to monensin on growth performance, antioxidant capacity, immunity, ruminal fermentation and microbial diversity of fattening lambs. One hundred and sixty Dorper * Thin-tailed Han sheep (32 +/- 3.45 kg BW) were randomly assigned into 5 treatments of n = 32 lambs/group. Lambs in the control group were fed a basal diet (NC) while the other four treatments were fed basal diets supplemented with monensin (PC), Bacillus licheniformis (BL), Saccharomyces cerevisiae (SC), and the combination of Bacillus licheniformis and Saccharomyces cerevisiae with protease (BS), respectively. The experiment lasted for 66 d. Feed intake was recorded every 2 d and lambs were weighed every 20 d. Ten lambs from each group were slaughtered at the end of the trial, and samples of serum and rumen fluid were collected. The results indicated that the dietary regimen did not affect the dry matter intake (DMI). The average daily gain (ADG) of BS treatment was significantly higher than NC group (P < 0.05). Compared with the NC treatment, the other four supplementation treatments increased the concentration of growth hormone (GH), insulin-like growth factor I (IGF-I) and insulin (INS) (P < 0.05). The malondialdehyde (MDA) and total antioxidant capacity (TAOC) showed no significant difference among the 5 treatments while the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) of BS group was significantly increased (P < 0.05). The supplementation regimen decreased the concentration of ammonia Nitrogen (NH3-N) and increased the content of microbial crude proteins (MCP) (P < 0.05). The supplementation of antibiotics and probiotics reduced the concentrations of acetate and increased the concentrations of propionate (P < 0.05). The supplementation treatments increased the relative abundance of Lentisphaerae, Fibrobacteres and Tenericutes at the phylum level, whereas at the genus level, they increased the relative abundance of Fibrobacter (P < 0.05). Overall, this study confirmed the facilitating effect of B. licheniformis, S. cerevisiae and their compounds on growth performance, improve the antioxidant capacity and immune function, and beneficially manipulate ruminal fermentation and microbial diversity of fatting lambs. PMID- 30420721 TI - Crystallographic and kinetic analyses of human IPMK reveal disordered domains modulate ATP binding and kinase activity. AB - Inositol polyphosphate multikinase (IPMK) is a member of the IPK-superfamily of kinases, catalyzing phosphorylation of several soluble inositols and the signaling phospholipid PI(4,5)P2 (PIP2). IPMK also has critical non-catalytic roles in p53, mTOR/Raptor, TRAF6 and AMPK signaling mediated partly by two disordered domains. Although IPMK non-catalytic functions are well established, it is less clear if the disordered domains are important for IPMK kinase activity or ATP binding. Here, kinetic and structural analyses of an engineered human IPMK lacking all disordered domains (DeltaIPMK) are presented. Although the KM for PIP2 is identical between DeltaIPMK and wild type, DeltaIPMK has a 1.8-fold increase in kcat for PIP2, indicating the native IPMK disordered domains decrease IPMK activity in vitro. The 2.5 A crystal structure of DeltaIPMK is reported, confirming the conserved ATP-grasp fold. A comparison with other IPK-superfamily structures revealed a putative "ATP-clamp" in the disordered N-terminus, we predicted would stabilize ATP binding. Consistent with this observation, removal of the ATP clamp sequence increases the KM for ATP 4.9-fold, indicating the N terminus enhances ATP binding to IPMK. Together, these structural and kinetic studies suggest in addition to mediating protein-protein interactions, the disordered domains of IPMK impart modulatory capacity to IPMK kinase activity through multiple kinetic mechanisms. PMID- 30420723 TI - Is leptin protective against heart failure with preserved ejection fraction? A complex interrelationship among leptin, obesity, and left ventricular hypertrophy. PMID- 30420722 TI - Deciphering the immune microenvironment of a tissue by digital imaging and cognition network. AB - Evidence has highlighted the importance of immune cells in various gut disorders. Both the quantification and localization of these cells are essential to the understanding of the complex mechanisms implicated in these pathologies. Even if quantification can be assessed (e.g., by flow cytometry), simultaneous cell localization and quantification of whole tissues remains technically challenging. Here, we describe the use of a computer learning-based algorithm created in the Tissue Studio interface that allows for a semi-automated, robust and rapid quantitative analysis of immunofluorescence staining on whole colon sections according to their distribution in different tissue areas. Indeed, this algorithm was validated to characterize gut immune microenvironment. Its application to the preclinical colon cancer APCMin/+ mouse model is illustrated by the simultaneous counting of total leucocytes and T cell subpopulations, in the colonic mucosa, lymphoid follicles and tumors. Moreover, we quantify T cells in lymphoid follicles for which quantification is not possible with classical methods. Thus, this algorithm is a new and robust preclinical research tool, for investigating immune contexture exemplified by T cells but it is also applicable to other immune cells such as other myeloid and lymphoid populations or other cellular phenomenon along mouse gut. PMID- 30420725 TI - Reduction of personal PM2.5 exposure via indoor air filtration systems in Detroit: an intervention study. AB - The adverse health effects of fine particulate matter (PM < 2.5 MUm in diameter [PM2.5]) air pollution are well-documented. There is a growing body of evidence that high-efficiency particulate arrestance (HEPA) filtration can reduce indoor PM2.5 concentrations and deliver some health benefits via the reduction of exposure to PM. However, few studies have tested the ability of portable air filtration systems to lower overall personal-level PM2.5 exposures. The Reducing Air Pollution in Detroit Intervention Study (RAPIDS) was designed to evaluate cardiovascular health benefits and personal PM2.5 exposure reductions via indoor portable air filtration systems among senior citizens in Detroit, Michigan. We evaluated the utility of two commercially available high-efficiency (HE: true HEPA) and low-efficiency (LE: HEPA-type) indoor air filtration to reduce indoor PM2.5 concentrations and personal PM2.5 exposures for 40 participants in a double blinded randomized crossover intervention. Each participant was subjected to three intervention scenarios: HE, LE, or no filter (control) of three consecutive days each, during which personal, indoor, and outdoor PM2.5 concentrations were measured daily. For mean indoor PM2.5 concentrations, we observed 60 and 52% reductions using HE and LE filters, respectively, relative to no filtration. Personal PM2.5 exposures were reduced by 53 and 31% using HE and LE filters, respectively, when compared with the control scenario. To our knowledge, this is the first indoor air filtration intervention study to examine the effectiveness of both HE and LE filters in reducing personal PM2.5 exposures. PMID- 30420724 TI - Exploring representations of human grasping in neural, muscle and kinematic signals. AB - Movement covariates, such as electromyographic or kinematic activity, have been proposed as candidates for the neural representation of hand control. However, it remains unclear how these movement covariates are reflected in electroencephalographic (EEG) activity during different stages of grasping movements. In this exploratory study, we simultaneously acquired EEG, kinematic and electromyographic recordings of human subjects performing 33 types of grasps, yielding the largest such dataset to date. We observed that EEG activity reflected different movement covariates in different stages of grasping. During the pre-shaping stage, centro-parietal EEG in the lower beta frequency band reflected the object's shape and size, whereas during the finalization and holding stages, contralateral parietal EEG in the mu frequency band reflected muscle activity. These findings contribute to the understanding of the temporal organization of neural grasping patterns, and could inform the design of noninvasive neuroprosthetics and brain-computer interfaces with more natural control. PMID- 30420726 TI - Long-term exposure to ambient air pollution and renal function in African Americans: the Jackson Heart Study. AB - Renal dysfunction is prevalent in the US among African Americans. Air pollution is associated with renal dysfunction in mostly white American populations, but has not been studied among African Americans. We evaluated cross-sectional associations between 1-year and 3-year fine particulate matter (PM2.5) and ozone (O3) concentrations, and renal function among 5090 African American participants in the Jackson Heart Study. We used mixed-effect linear regression to estimate associations between 1-year and 3-year PM2.5 and O3 and estimated glomerular filtration rate (eGFR), urine albumin/creatinine ratio (UACR), serum creatinine, and serum cystatin C, adjusting for: sociodemographic factors, health behaviors, and medical history and accounting for clustering by census tract. At baseline, JHS participants had mean age 55.4 years, and 63.8% were female; mean 1-year and 3-year PM2.5 concentrations were 12.2 and 12.4 ug/m3, and mean 1-year and 3-year O3 concentrations were 40.2 and 40.7 ppb, respectively. Approximately 6.5% of participants had reduced eGFR (< 60 mL/min/1.73m2) and 12.7% had elevated UACR (> 30 mg/g), both indicating impaired renal function. Annual and 3-year O3 concentrations were inversely associated with eGFR and positively associated with serum creatinine; annual and 3-year PM2.5 concentrations were inversely associated with UACR. We observed impaired renal function associated with increased O3 but not PM2.5 exposure among African Americans. PMID- 30420727 TI - Amplification of DNA damage-inducible transcript 3 (DDIT3) is associated with myxoid liposarcoma-like morphology and homologous lipoblastic differentiation in dedifferentiated liposarcoma. AB - Dedifferentiated liposarcoma is defined as progression of atypical lipomatous tumor/well-differentiated liposarcoma to a higher grade usually non-lipogenic sarcoma, with amplification of 12q13-15. This region contains several genes involved in liposarcoma pathogenesis, including MDM2, CDK4, and DDIT3. While the former two are thought of as the main drivers in dedifferentiated liposarcoma, DDIT3 is typically rearranged in myxoid liposarcoma. Overexpression of DDIT3, along with MDM2 and CDK4, may contribute to the pathogenesis of dedifferentiated liposarcoma by interfering with adipocytic differentiation. Dedifferentiated liposarcoma with DDIT3 amplification has not been well characterized. In this study we evaluate the presence of DDIT3 amplification in 48 cases of dedifferentiated liposarcoma by cytogenomic microarray analysis and its correlation with demographic, clinical, and morphologic characteristics. Data from The Cancer Genome Atlas were also evaluated to determine a relationship between DDIT3 amplification and prognostic outcomes. Of the 48 cases, 16 (33%) had amplification of DDIT3; these patients were on average 11 years younger than patients without DDIT3 amplification (P < 0.05). Myxoid liposarcoma-like morphologic features were identified in 12/16 (75%) cases with DDIT3 amplification and in 7/32 (22%) cases without amplification (P < 0.05). Homologous lipoblastic differentiation was seen in 6/16 (38%) cases with DDIT3 amplification and 2/32 (6%) cases without it (P < 0.05). There was no significant correlation between DDIT3 amplification and tumor location, disease-specific or recurrence-free survival, and distant metastasis. DDIT3 amplification appears to interfere with the adipogenic molecular program and plays a role in inducing or maintaining a lipogenic phenotype in dedifferentiated liposarcoma. From a diagnostic standpoint, it is important to consider DDIT3-amplified dedifferentiated liposarcoma in the differential diagnosis of myxoid liposarcoma, particularly in small biopsies. Further studies evaluating the significance of DDIT3 amplification in the pathogenesis of dedifferentiated liposarcoma, as well as a potential predictor of tumor behavior in well-differentiated liposarcoma, are needed. PMID- 30420728 TI - Gene prioritization, communality analysis, networking and metabolic integrated pathway to better understand breast cancer pathogenesis. AB - Consensus strategy was proved to be highly efficient in the recognition of gene disease association. Therefore, the main objective of this study was to apply theoretical approaches to explore genes and communities directly involved in breast cancer (BC) pathogenesis. We evaluated the consensus between 8 prioritization strategies for the early recognition of pathogenic genes. A communality analysis in the protein-protein interaction (PPi) network of previously selected genes was enriched with gene ontology, metabolic pathways, as well as oncogenomics validation with the OncoPPi and DRIVE projects. The consensus genes were rationally filtered to 1842 genes. The communality analysis showed an enrichment of 14 communities specially connected with ERBB, PI3K-AKT, mTOR, FOXO, p53, HIF-1, VEGF, MAPK and prolactin signaling pathways. Genes with highest ranking were TP53, ESR1, BRCA2, BRCA1 and ERBB2. Genes with highest connectivity degree were TP53, AKT1, SRC, CREBBP and EP300. The connectivity degree allowed to establish a significant correlation between the OncoPPi network and our BC integrated network conformed by 51 genes and 62 PPi. In addition, CCND1, RAD51, CDC42, YAP1 and RPA1 were functional genes with significant sensitivity score in BC cell lines. In conclusion, the consensus strategy identifies both well-known pathogenic genes and prioritized genes that need to be further explored. PMID- 30420729 TI - Whole exome sequencing identifies recessive germline mutations in FAM160A1 in familial NK/T cell lymphoma. PMID- 30420731 TI - The thickness-induced magneto-transport and optic properties enhancement in Sb2Te3 flakes. AB - The electric and optical properties were studied in Sb2Te3 with different thickness. It reveals the same resistivity at measured temperatures, but shows a larger magnetoresistance ratio at thicker flakes. All measured data conformed to a linear correlation between magnetoresistance ratio which is one-order enhanced, and mobility over a wide mobility range. A higher photocurrent response is observed in thicker flakes. These results support that the thickness enhances the effective carrier mobility which leads to magneto-transport and optic properties enhancement. PMID- 30420732 TI - Neuronal stability in medial frontal cortex sets individual variability in decision-making. AB - In the brain, decision making is instantiated in dedicated neural circuits. However, there is considerable individual variability in decision-making behavior, particularly under uncertainty. The origins of decision variability within these conserved neural circuits are not known. Here we demonstrate in the rat medial frontal cortex (MFC) that individual variability is a consequence of altered stability in neuronal populations. In a sensory-guided choice task, rats trained on familiar stimuli were exposed to unfamiliar stimuli, resulting in variable choice responses across individuals. We created a recurrent network model to examine the source of variability in MFC neurons, and found that the landscape of neural population trajectories explained choice variability across different unfamiliar stimuli. We experimentally confirmed model predictions showing that trial-by-trial variability in neuronal activity indexes the landscape and predicts individual variation. These results show that neural stability is a critical component of the MFC neural dynamics that underpins individual variation in decision-making. PMID- 30420730 TI - SPINK1, PRSS1, CTRC, and CFTR Genotypes Influence Disease Onset and Clinical Outcomes in Chronic Pancreatitis. AB - OBJECTIVES: Rare pathogenic variants in the SPINK1, PRSS1, CTRC, and CFTR genes have been strongly associated with a risk of developing chronic pancreatitis (CP). However, their potential impact on the age of disease onset and clinical outcomes, as well as their potential interactions with environmental risk factors, remain unclear. These issues are addressed here in a large Chinese CP cohort. METHODS: We performed targeted next-generation sequencing of the four CP associated genes in 1061 Han Chinese CP patients and 1196 controls. To evaluate gene-environment interactions, the patients were divided into three subgroups, idiopathic CP (ICP; n = 715), alcoholic CP (ACP; n = 206), and smoking-associated CP (SCP; n = 140). The potential impact of rare pathogenic variants on the age of onset of CP and clinical outcomes was evaluated using the Kaplan-Meier model. RESULTS: We identified rare pathogenic genotypes involving the SPINK1, PRSS1, CTRC, and/or CFTR genes in 535 (50.42%) CP patients but in only 71 (5.94%) controls (odds ratio = 16.12; P < 0.001). Mutation-positive patients had significantly earlier median ages at disease onset and at diagnosis of pancreatic stones, diabetes mellitus and steatorrhea than mutation-negative ICP patients. Pathogenic genotypes were present in 57.1, 39.8, and 32.1% of the ICP, ACP, and SCP patients, respectively, and influenced age at disease onset and clinical outcomes in all subgroups. CONCLUSIONS: We provide evidence that rare pathogenic variants in the SPINK1, PRSS1, CTRC, and CFTR genes significantly influence the age of onset and clinical outcomes of CP. Extensive gene-environment interactions were also identified. PMID- 30420733 TI - Same lesson, varied choices by frontal cortex. PMID- 30420734 TI - Addendum: Low-value approvals and high prices might incentivize ineffective drug development. AB - In hindsight, we realize that we could have been more precise when using the terms 'profit' and 'revenue' in our article 'Low-value approvals and high prices might incentivize ineffective drug development'. Total revenue is defined as the receipts from sales1. Profit is defined as the excess of the receipts from sales over the spending of a business during any period1. Hence, profit is the total revenue minus the costs of a business, over a given period. Profit calculations include credit transactions and asset revaluations as well as cash transactions and changes in the value of real assets1. PMID- 30420735 TI - Enhanced EPR directed and Imaging guided Photothermal Therapy using Vitamin E Modified Toco-Photoxil. AB - Herein we report synthesis, characterization and preclinical applications of a novel hybrid nanomaterial Toco-Photoxil developed using vitamin E modified gold coated poly (lactic-co-glycolic acid) nanoshells incorporating Pgp inhibitor d alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) as a highly inert and disintegrable photothermal therapy (PTT) agent. Toco-Photoxil is highly biocompatible, physiologically stable PTT material with an average diameter of 130 nm that shows good passive accumulation (2.3% ID) in solid tumors when delivered systemically. In comparison to its surface modified counterparts such as IR780-Toco-Photoxil, FA-Toco-Photoxil or FA-IR780-Toco-Photoxil accumulation are merely ~0.3% ID, ~0.025% ID and ~0.005% ID in folate receptor (FR) negative and positive tumor model. Further, Toco-Photoxil variants are prepared by tuning the material absorbance either at 750 nm (narrow) or 915 nm (broad) to study optimal therapeutic efficacy in terms of peak broadness and nanomaterial's concentration. Our findings suggest that Toco-Photoxil tuned at 750 nm absorbance is more efficient (P = 0.0097) in preclinical setting. Toco-Photoxil shows complete passiveness in critical biocompatibility test and reasonable body clearance. High tumor specific accumulation from systemic circulation, strong photothermal conversion and a very safe material property in body physiology makes Toco-Photoxil a superior and powerful PTT agent, which may pave its way for fast track clinical trial in future. PMID- 30420736 TI - A changing paradigm of transcriptional memory propagation through mitosis. AB - The highly reproducible inheritance of chromosomes during mitosis in mammalian cells involves nuclear envelope breakdown, increased chromatin compaction, loss of long-range intrachromosomal interactions, loss of enhancer-promoter proximity, displacement of many transcription regulators from the chromatin and a marked decrease in RNA synthesis. Despite these dramatic changes in the mother cell, daughter cells are able to faithfully re-establish the parental chromatin and gene expression features characteristic of the cell type. Pioneering studies of mitotic chromatin signatures showed that despite global repression of transcription, the Hsp70 gene promoter retains an open chromatin conformation, which was proposed to allow the reactivation of the Hsp70 gene upon completion of mitosis - a phenomenon termed mitotic bookmarking. It was later shown that various cell-type-specific transcription factors, such as GATA-binding factor 1 (GATA1) in erythroblasts and forkhead box protein A1 (FOXA1) in hepatocytes, remain bound at a subset of their interphase binding sites in mitosis. Such bookmarking transcription factors remain on chromosomes in mitosis and have been shown to enable a subset of genes to be reactivated in a timely fashion upon mitotic exit. In addition, sensitive new methods to measure transcription revealed that mitotic cells retain residual transcription at a large number of genes. Furthermore, genes recover their interphase level of transcription in distinct waves. Thus, gene expression is precisely regulated as cells pass through mitosis to ensure faithful propagation of cell identity and function through cellular generations. PMID- 30420738 TI - Characterization of CNTNAP2 nanostructures on interneuronal dendrites. PMID- 30420737 TI - Correction: Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa. AB - The fortieth author's name was listed incorrectly. The correct presentation is A Keski-Rahkonen. PMID- 30420740 TI - Minimal memory for details in real life events. AB - The extent to which the details of past experiences are retained or forgotten remains controversial. Some studies suggest massive storage while others describe memories as fallible summary recreations of original events. The discrepancy can be ascribed to the content of memories and how memories are evaluated. Many studies have focused on recalling lists of words/pictures, which lack the critical ingredients of real world memories. Here we quantified the ability to remember details about one hour of real life. We recorded video and eye movements while subjects walked along specified routes and evaluated whether they could distinguish video clips from their own experience from foils. Subjects were minimally above chance in remembering the minutiae of their experiences. Recognition of specific events could be partly explained by a machine-learning model of video contents. These results quantify recognition memory for events in real life and show that the details of everyday experience are largely not retained in memory. PMID- 30420739 TI - Comparison of linear frequency and amplitude modulation for intraneural sensory feedback in bidirectional hand prostheses. AB - Recent studies have shown that direct nerve stimulation can be used to provide sensory feedback to hand amputees. The intensity of the elicited sensations can be modulated using the amplitude or frequency of the injected stimuli. However, a comprehensive comparison of the effects of these two encoding strategies on the amputees' ability to control a prosthesis has not been performed. In this paper, we assessed the performance of two trans-radial amputees controlling a myoelectric hand prosthesis while receiving grip force sensory feedback encoded using either linear modulation of amplitude (LAM) or linear modulation of frequency (LFM) of direct nerve stimulation (namely, bidirectional prostheses). Both subjects achieved similar and significantly above-chance performance when they were asked to exploit LAM or LFM in different tasks. The feedbacks allowed them to discriminate, during manipulation through the robotic hand, objects of different compliances and shapes or different placements on the prosthesis. Similar high performances were obtained when they were asked to apply different levels of force in a random order on a dynamometer using LAM or LFM. In contrast, only the LAM strategy allowed the subjects to continuously modulate the grip pressure on the dynamometer. Furthermore, when long-lasting trains of stimulation were delivered, LFM strategy generated a very fast adaptation phenomenon in the subjects, which caused them to stop perceiving the restored sensations. Both encoding approaches were perceived as very different from the touch feelings of the healthy limb (natural). These results suggest that the choice of specific sensory feedback encodings can have an effect on user performance while grasping. In addition, our results invite the development of new approaches to provide more natural sensory feelings to the users, which could be addressed by a more biomimetic strategy in the future. PMID- 30420741 TI - No evidence for kin protection in the expression of sickness behaviors in house mice. AB - When infected, animals change their behaviors in several ways, including by decreasing their activity, their food and water intake, and their interest in social interactions. These behavioral alterations are collectively called sickness behaviors and, for several decades, the main hypotheses put forward to explain this phenomenon were that engaging in sickness behaviors facilitated the fever response and improved the likelihood of host survival. However, a new hypothesis was recently proposed suggesting that engaging in sickness behaviors may serve to protect kin. We tested this kin protection hypothesis by combining a field and a laboratory experiment in house mice. In both experiments, we induced sickness behaviors by administration of a pro-inflammatory agent. In the field experiment, we then collected genetic data and assessed whether relatedness affected the intensity of sickness behaviors. In the lab experiment, we manipulated relatedness in small social groups and assessed whether having a closely related individual (a sibling) in the group altered social interactions or visits to common resources (such as food and water containers) once immune challenged. Our results do not support the kinship protection hypothesis and therefore advance our understanding of why such an apparently costly set of behavioral changes would be evolutionarily maintained. PMID- 30420742 TI - Author Correction: Deep Learning and Radiomics predict complete response after neo-adjuvant chemoradiation for locally advanced rectal cancer. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30420744 TI - Global vegetation's CO2 uptake. PMID- 30420743 TI - Productive instability of coral reef fisheries after climate-driven regime shifts. AB - Tropical coastal communities are highly reliant on coral reefs, which provide nutrition and employment for millions of people. Climate-driven coral bleaching events are fundamentally changing coral reef ecosystems and are predicted to reduce productivity of coral reef fish and fisheries, with significant implications for food security and livelihoods. Yet evidence of long-term bleaching impacts on coral reef fishery productivity is lacking. Here, we analyse over 20 years of fish abundance, catch and habitat data to assess long-term impacts of climate-driven coral mass mortality and regime shifts on nearshore artisanal coral reef fisheries in the Seychelles. Contrary to expectations, total catch and mean catch rates were maintained or increased after coral bleaching, consistent with increasing abundance of herbivorous target species in underwater surveys, particularly on macroalgal-dominated reefs. Catch instability increased as habitats followed divergent post-disturbance trajectories and the distribution of target species became more spatially variable, potentially impacting fisher incomes and local market supply chains. Although coral bleaching increased fishery dependence on herbivore species, our results show that climate-impacted reefs can still provide livelihoods and fish protein for coastal communities. PMID- 30420745 TI - Enhanced peak growth of global vegetation and its key mechanisms. AB - The annual peak growth of vegetation is critical in characterizing the capacity of terrestrial ecosystem productivity and shaping the seasonality of atmospheric CO2 concentrations. The recent greening of global lands suggests an increasing trend of terrestrial vegetation growth, but whether or not the peak growth has been globally enhanced still remains unclear. Here, we use two global datasets of gross primary productivity (GPP) and a satellite-derived Normalized Difference Vegetation Index (NDVI) to characterize recent changes in annual peak vegetation growth (that is, GPPmax and NDVImax). We demonstrate that the peak in the growth of global vegetation has been linearly increasing during the past three decades. About 65% of the NDVImax variation is evenly explained by expanding croplands (21%), rising CO2 (22%) and intensifying nitrogen deposition (22%). The contribution of expanding croplands to the peak growth trend is substantiated by measurements from eddy-flux towers, sun-induced chlorophyll fluorescence and a global database of plant traits, all of which demonstrate that croplands have a higher photosynthetic capacity than other vegetation types. The large contribution of CO2 is also supported by a meta-analysis of 466 manipulative experiments and 15 terrestrial biosphere models. Furthermore, we show that the contribution of GPPmax to the change in annual GPP is less in the tropics than in other regions. These multiple lines of evidence reveal an increasing trend in the peak growth of global vegetation. The findings highlight the important roles of agricultural intensification and atmospheric changes in reshaping the seasonality of global vegetation growth. PMID- 30420747 TI - Towards a greener Common Agricultural Policy. PMID- 30420748 TI - Targeting autoimmune-specific metabolic processes. PMID- 30420746 TI - Pezizomycetes genomes reveal the molecular basis of ectomycorrhizal truffle lifestyle. AB - Tuberaceae is one of the most diverse lineages of symbiotic truffle-forming fungi. To understand the molecular underpinning of the ectomycorrhizal truffle lifestyle, we compared the genomes of Piedmont white truffle (Tuber magnatum), Perigord black truffle (Tuber melanosporum), Burgundy truffle (Tuber aestivum), pig truffle (Choiromyces venosus) and desert truffle (Terfezia boudieri) to saprotrophic Pezizomycetes. Reconstructed gene duplication/loss histories along a time-calibrated phylogeny of Ascomycetes revealed that Tuberaceae-specific traits may be related to a higher gene diversification rate. Genomic features in Tuber species appear to be very similar, with high transposon content, few genes coding lignocellulose-degrading enzymes, a substantial set of lineage-specific fruiting body-upregulated genes and high expression of genes involved in volatile organic compound metabolism. Developmental and metabolic pathways expressed in ectomycorrhizae and fruiting bodies of T. magnatum and T. melanosporum are unexpectedly very similar, owing to the fact that they diverged ~100 Ma. Volatile organic compounds from pungent truffle odours are not the products of Tuber specific gene innovations, but rely on the differential expression of an existing gene repertoire. These genomic resources will help to address fundamental questions in the evolution of the truffle lifestyle and the ecology of fungi that have been praised as food delicacies for centuries. PMID- 30420749 TI - Selective JAK inhibition for AS. PMID- 30420750 TI - Pathogenic stromal cells as therapeutic targets in joint inflammation. AB - Knowledge of how the joint functions as an integrated unit in health and disease requires an understanding of the stromal cells populating the joint mesenchyme, including fibroblasts, tissue-resident macrophages and endothelial cells. Knowledge of the physiological and pathological mechanisms that involve joint mesenchymal stromal cells has begun to cast new light on why joint inflammation persists. The shared embryological origins of fibroblasts and endothelial cells might shape the behaviour of these cell types in diseased adult tissues. Cells of mesenchymal origin sustain inflammation in the synovial membrane and tendons by various mechanisms, and the important contribution of newly discovered fibroblast subtypes and their associated crosstalk with endothelial cells, tissue-resident macrophages and leukocytes is beginning to emerge. Knowledge of these mechanisms should help to shape the future therapeutic landscape and emphasizes the requirement for new strategies to address the pathogenic stroma and associated crosstalk between leukocytes and cells of mesenchymal origin. PMID- 30420751 TI - Author Correction: Limitation of Fermi level shifts by polaron defect states in hematite photoelectrodes. AB - The original version of this Article contained an error in Fig. 2b in which the bottom of the pink-shaded conduction band region was incorrectly positioned at a value of 1.75 eV. The correct conduction band minimum has a value of 2.2 eV. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 30420752 TI - Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Leukemia stem cells (LSCs) drive the initiation and perpetuation of AML, are quantifiably associated with worse clinical outcomes, and often persist after conventional chemotherapy resulting in relapse1-5. In this report, we show that treatment of older patients with AML with the B cell lymphoma 2 (BCL-2) inhibitor venetoclax in combination with azacitidine results in deep and durable remissions and is superior to conventional treatments. We hypothesized that these promising clinical results were due to targeting LSCs. Analysis of LSCs from patients undergoing treatment with venetoclax + azacitidine showed disruption of the tricarboxylic acid (TCA) cycle manifested by decreased alpha-ketoglutarate and increased succinate levels, suggesting inhibition of electron transport chain complex II. In vitro modeling confirmed inhibition of complex II via reduced glutathionylation of succinate dehydrogenase. These metabolic perturbations suppress oxidative phosphorylation (OXPHOS), which efficiently and selectively targets LSCs. Our findings show for the first time that a therapeutic intervention can eradicate LSCs in patients with AML by disrupting the metabolic machinery driving energy metabolism, resulting in promising clinical activity in a patient population with historically poor outcomes. PMID- 30420753 TI - Paradoxical effects of obesity on T cell function during tumor progression and PD 1 checkpoint blockade. AB - The recent successes of immunotherapy have shifted the paradigm in cancer treatment, but because only a percentage of patients are responsive to immunotherapy, it is imperative to identify factors impacting outcome. Obesity is reaching pandemic proportions and is a major risk factor for certain malignancies, but the impact of obesity on immune responses, in general and in cancer immunotherapy, is poorly understood. Here, we demonstrate, across multiple species and tumor models, that obesity results in increased immune aging, tumor progression and PD-1-mediated T cell dysfunction which is driven, at least in part, by leptin. However, obesity is also associated with increased efficacy of PD-1/PD-L1 blockade in both tumor-bearing mice and clinical cancer patients. These findings advance our understanding of obesity-induced immune dysfunction and its consequences in cancer and highlight obesity as a biomarker for some cancer immunotherapies. These data indicate a paradoxical impact of obesity on cancer. There is heightened immune dysfunction and tumor progression but also greater anti-tumor efficacy and survival after checkpoint blockade which directly targets some of the pathways activated in obesity. PMID- 30420754 TI - Fecal microbiota transplantation for refractory immune checkpoint inhibitor associated colitis. AB - We report the first case series of immune checkpoint inhibitors (ICI)-associated colitis successfully treated with fecal microbiota transplantation, with reconstitution of the gut microbiome and a relative increase in the proportion of regulatory T-cells within the colonic mucosa. These preliminary data provide evidence that modulation of the gut microbiome may abrogate ICI-associated colitis. PMID- 30420755 TI - Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis. AB - Multiple sclerosis (MS) is characterized by an immune system attack targeting myelin, which is produced by oligodendrocytes (OLs). We performed single-cell transcriptomic analysis of OL lineage cells from the spinal cord of mice induced with experimental autoimmune encephalomyelitis (EAE), which mimics several aspects of MS. We found unique OLs and OL precursor cells (OPCs) in EAE and uncovered several genes specifically alternatively spliced in these cells. Surprisingly, EAE-specific OL lineage populations expressed genes involved in antigen processing and presentation via major histocompatibility complex class I and II (MHC-I and -II), and in immunoprotection, suggesting alternative functions of these cells in a disease context. Importantly, we found that disease-specific oligodendroglia are also present in human MS brains and that a substantial number of genes known to be susceptibility genes for MS, so far mainly associated with immune cells, are expressed in the OL lineage cells. Finally, we demonstrate that OPCs can phagocytose and that MHC-II-expressing OPCs can activate memory and effector CD4-positive T cells. Our results suggest that OLs and OPCs are not passive targets but instead active immunomodulators in MS. The disease-specific OL lineage cells, for which we identify several biomarkers, may represent novel direct targets for immunomodulatory therapeutic approaches in MS. PMID- 30420756 TI - Correlation between genomic index lesions and mpMRI and 68Ga-PSMA-PET/CT imaging features in primary prostate cancer. AB - Magnetic resonance imaging (MRI) and prostate specific membrane antigen (PSMA)- positron emission tomography (PET)/computed tomography (CT)-imaging of prostate cancer (PCa) are emerging techniques to assess the presence of significant disease and tumor progression. It is not known, however, whether and to what extent lesions detected by these imaging techniques correlate with genomic features of PCa. The aim of this study was therefore to define a genomic index lesion based on chromosomal copy number alterations (CNAs) as marker for tumor aggressiveness in prostate biopsies in direct correlation to multiparametric (mp) MRI and 68Ga-PSMA-PET/CT imaging features. CNA profiles of 46 biopsies from five consecutive patients with clinically high-risk PCa were obtained from radiologically suspicious and unsuspicious areas. All patients underwent mpMRI, MRI/TRUS-fusion biopsy, 68Ga-PSMA-PET/CT and a radical prostatectomy. CNAs were directly correlated to imaging features and radiogenomic analyses were performed. Highly significant CNAs (>=10 Mbp) were found in 22 of 46 biopsies. Chromosome 8p, 13q and 5q losses were the most common findings. There was an strong correspondence between the radiologic and the genomic index lesions. The radiogenomic analyses suggest the feasibility of developing radiologic signatures that can distinguish between genomically more or less aggressive lesions. In conclusion, imaging features of mpMRI and 68Ga-PSMA-PET/CT can guide to the genomically most aggressive lesion of a PCa. Radiogenomics may help to better differentiate between indolent and aggressive PCa in the future. PMID- 30420758 TI - Recipient BCL2 inhibition and NK cell ablation form part of a reduced intensity conditioning regime that improves allo-bone marrow transplantation outcomes. AB - Allogeneic hematopoietic stem cell transplantation (alloSCT) is used to treat over 15,000 patients with acute myeloid leukemia (AML) per year. Donor graft versus-leukemia (GVL) effect can prevent AML relapse; however, alloSCT is limited by significant toxicity related to conditioning intensity, immunosuppression, opportunistic infections, and graft-versus-host disease (GVHD). Reducing the intensity of conditioning regimens prior to alloSCT has improved their tolerability, but does not alter the pattern of GVHD and has been associated with increased rates of graft rejection and relapse. Here, using a murine pre-clinical model, we describe a novel recipient conditioning approach combining reduced intensity conditioning with either genetic or pharmacological inhibition of NK cell numbers that permits efficient donor engraftment and promotes GVL without inducing GVHD. We show that NK cell-specific deletion of Bcl2 or Mcl1 in mice, or pharmacological inhibition of BCL2 impairs radio-resistant NK cell-mediated rejection of allogeneic engraftment and allows reduction of conditioning intensity below that associated with GVHD priming. The combination of reduced intensity conditioning and NK cell targeting in mice allowed successful donor T cell engraftment and protective immunity against AML while avoiding GVHD. These findings suggest that reduced conditioning in combination with targeted therapies against recipient NK cells may allow the delivery of effective alloSCT against AML while reducing the toxicities associated with more intensive conditioning including GVHD. PMID- 30420759 TI - Memristor crossbar arrays with 6-nm half-pitch and 2-nm critical dimension. AB - The memristor1,2 is a promising building block for next-generation non-volatile memory3, artificial neural networks4-7 and bio-inspired computing systems8,9. Organizing small memristors into high-density crossbar arrays is critical to meet the ever-growing demands in high-capacity and low-energy consumption, but this is challenging because of difficulties in making highly ordered conductive nanoelectrodes. Carbon nanotubes, graphene nanoribbons and dopant nanowires have potential as electrodes for discrete nanodevices10-14, but unfortunately these are difficult to pack into ordered arrays. Transfer printing, on the other hand, is effective in generating dense electrode arrays15 but has yet to prove suitable for making fully random accessible crossbars. All the aforementioned electrodes have dramatically increased resistance at the nanoscale16-18, imposing a significant barrier to their adoption in operational circuits. Here we demonstrate memristor crossbar arrays with a 2-nm feature size and a single-layer density up to 4.5 terabits per square inch, comparable to the information density achieved using three-dimensional stacking in state-of-the-art 64-layer and multilevel 3D-NAND flash memory19. Memristors in the arrays switch with tens of nanoamperes electric current with nonlinear behaviour. The densely packed crossbar arrays of individually accessible, extremely small functional memristors provide a power-efficient solution for information storage and processing. PMID- 30420757 TI - Structural insights into the function of type VI secretion system TssA subunits. AB - The type VI secretion system (T6SS) is a multi-protein complex that injects bacterial effector proteins into target cells. It is composed of a cell membrane complex anchored to a contractile bacteriophage tail-like apparatus consisting of a sharpened tube that is ejected by the contraction of a sheath against a baseplate. We present structural and biochemical studies on TssA subunits from two different T6SSs that reveal radically different quaternary structures in comparison to the dodecameric E. coli TssA that arise from differences in their C terminal sequences. Despite this, the different TssAs retain equivalent interactions with other components of the complex and position their highly conserved N-terminal ImpA_N domain at the same radius from the centre of the sheath as a result of their distinct domain architectures, which includes additional spacer domains and highly mobile interdomain linkers. Together, these variations allow these distinct TssAs to perform a similar function in the complex. PMID- 30420760 TI - Robust topologically protected transport in photonic crystals at telecommunication wavelengths. AB - Photonic topological insulators offer the possibility to eliminate backscattering losses and improve the efficiency of optical communication systems. Despite considerable efforts, a direct experimental demonstration of theoretically predicted robust, lossless energy transport in topological insulators operating at near-infrared frequencies is still missing. Here, we combine the properties of a planar silicon photonic crystal and the concept of topological protection to design, fabricate and characterize an optical topological insulator that exhibits the valley Hall effect. We show that the transmittances are the same for light propagation along a straight topological interface and one with four sharp turns. This result quantitatively demonstrates the suppression of backscattering due to the non-trivial topology of the structure. The photonic-crystal-based approach offers significant advantages compared with other realizations of photonic topological insulators, such as lower propagation losses, the presence of a band gap for light propagating in the crystal-slab plane, a larger operating bandwidth, a much smaller footprint, compatibility with complementary metal-oxide semiconductor fabrication technology, and the fact that it allows for operation at telecommunications wavelengths. PMID- 30420761 TI - In situ quantification of interphasial chemistry in Li-ion battery. AB - The solid-electrolyte interphase (SEI) is probably the least understood component in Li-ion batteries. Considerable effort has been put into understanding its formation and electrochemistry under realistic battery conditions, but mechanistic insights have mostly been inferred indirectly. Here we show the formation of the SEI between a graphite anode and a carbonate electrolyte through combined atomic-scale microscopy and in situ and operando techniques. In particular, we weigh the graphitic anode during its initial lithiation process with an electrochemical quartz crystal microbalance, which unequivocally identifies lithium fluoride and lithium alkylcarbonates as the main chemical components at different potentials. In situ gas analysis confirms the preferential reduction of cyclic over acyclic carbonate molecules, making its reduction product the major component in the SEI. We find that SEI formation starts at graphite edge sites with dimerization of solvated Li+ intercalation between graphite layers. We also show that this lithium salt, at least in its nascent form, can be re-oxidized, despite the general belief that an SEI is electrochemically inert and its formation irreversible. PMID- 30420762 TI - Robust and compact waveguides. PMID- 30420763 TI - NSAIDs-hypersensitivity often induces a blended reaction pattern involving multiple organs. AB - Non-steroidal anti-inflammatory drugs (NSAIDs)-induced hypersensitivity reactions are classified by the European Network on Drug Allergy (ENDA) as either cross reactive or selective. The former is the most frequent type and includes patients with exclusively respiratory symptoms (NSAIDs-exacerbated respiratory disease, NERD) or exclusively cutaneous symptoms: NSAIDs-induced urticaria/angioedema (NIUA); and NSAIDs-exacerbated cutaneous disease (NECD). However, although not reflected in the current classification scheme (ENDA), in clinical practice a combination of both skin and respiratory symptoms or even other organs such as gastrointestinal tract symptoms (mixed or blended reactions) is frequently observed. This entity has not been sufficiently characterised. Our aim was to clinically characterize blended reactions to NSAIDs, comparing their clinical features with NERD and NIUA. We evaluated patients with symptoms suggestive of hypersensitivity to NSAIDs who attended the Allergy Unit of the Regional University Hospital of Malaga (Malaga, Spain) between 2008 and 2015. We included 880 patients confirmed as cross-reactive based on clinical history, positive nasal provocation test with lysine acetylsalicylate (NPT-LASA), and/or positive drug provocation test (DPT) with acetylsalicylic acid (ASA), who were classified as blended (261; 29.6%), NERD (108; 12.3%) or NIUA (511; 58.1%). We compared symptoms, drugs, underlying diseases and diagnostic methods within and between groups. Among blended patients the most common sub-group comprised those developing urticaria/angioedema plus rhinitis/asthma (n = 138), who had a higher percentage of underlying rhinitis (p < 0.0001) and asthma (p < 0.0001) than NIUA patients, showing similarities to NERD. These differences were not found in the sub-group of blended patients who developed such respiratory symptoms as glottis oedema; these were more similar to NIUA. The percentage of positive NPT-LASA was similar for blended (77%) and NERD groups (78.7%). We conclude that blended reactions are hypersensitivity reactions to NSAIDs affecting at least two organs. In addition to classical skin and respiratory involvement, in our population a number of patients also develop gastrointestinal symptoms. Given the high rate of positive responses to NPT-LASA in NERD as well as blended reactions, we suggest that all patients reporting respiratory symptoms, regardless of whether they have other associated symptoms, should be initially evaluated using NPT-LASA, which poses less risk than DPT. PMID- 30420766 TI - Colony takeover. PMID- 30420764 TI - Intrinsic disorder in the regulatory N-terminal domain of diacylglycerol acyltransferase 1 from Brassica napus. AB - Proteins with multifunctional regulatory domains often demonstrate structural plasticity or protein disorder, allowing the binding of multiple regulatory factors and post-translational modifications. While the importance of protein disorder is clear, it also poses a challenge for in vitro characterization. Here, we report protein intrinsic disorder in a plant molecular system, which despite its prevalence is less studied. We present a detailed biophysical characterization of the entire cytoplasmic N-terminal domain of Brassica napus diacylglycerol acyltransferase, (DGAT1), which includes an inhibitory module and allosteric binding sites. Our results demonstrate that the monomeric N-terminal domain can be stabilized for biophysical characterization and is largely intrinsically disordered in solution. This domain interacts with allosteric modulators of DGAT1, CoA and oleoyl-CoA, at micromolar concentrations. While solution scattering studies indicate conformational heterogeneity in the N terminal domain of DGAT1, there is a small gain of secondary structure induced by ligand binding. PMID- 30420765 TI - A model for RAS mutation patterns in cancers: finding the sweet spot. AB - The three RAS genes - HRAS, NRAS and KRAS - are collectively mutated in one-third of human cancers, where they act as prototypic oncogenes. Interestingly, there are rather distinct patterns to RAS mutations; the isoform mutated as well as the position and type of substitution vary between different cancers. As RAS genes are among the earliest, if not the first, genes mutated in a variety of cancers, understanding how these mutation patterns arise could inform on not only how cancer begins but also the factors influencing this event, which has implications for cancer prevention. To this end, we suggest that there is a narrow window or 'sweet spot' by which oncogenic RAS signalling can promote tumour initiation in normal cells. As a consequence, RAS mutation patterns in each normal cell are a product of the specific RAS isoform mutated, as well as the position of the mutation and type of substitution to achieve an ideal level of signalling. PMID- 30420767 TI - Cell-in-cell phenomena in cancer. AB - Cell-in-cell structures are reported in numerous cancers, and their presence is an indicator for poor prognosis. Mechanistic studies have identified how cancer cells manage to ingest whole neighbouring cells to form such structures, and the consequences of cell-in-cell formation on cancer progression have been elucidated. In this Opinion article, we discuss how two related cell-in-cell processes, cell cannibalism and entosis, are regulated and how these mechanisms promote cancer progression. We propose that cannibalistic activity is a hallmark of cancer that results in part from selection by metabolic stress and serves to feed aggressive cancer cells. PMID- 30420768 TI - Comparison of Prognostic Accuracy of the quick Sepsis-Related Organ Failure Assessment between Short- & Long-term Mortality in Patients Presenting Outside of the Intensive Care Unit - A Systematic Review & Meta-analysis. AB - The purpose of this meta-analysis was to compare the ability of the qSOFA in predicting short- (<=30 days or in-hospital mortality) and long-term (>30 days) mortality among patients outside the intensive care unit setting. Studies reporting on the qSOFA and mortality were searched using MEDLINE and SCOPUS. Studies were included if they involved patients presenting to the ED with suspected infection and usage of qSOFA score for mortality prognostication. Data on qSOFA scores and mortality rates were extracted from 36 studies. The overall pooled sensitivity and specificity for the qSOFA were 48% and 86% for short-term mortality and 32% and 92% for long-term mortality, respectively. Studies reporting on short-term mortality were heterogeneous (Odd ratio, OR = 5.6; 95% CI = 4.6-6.8; Higgins's I2 = 94%), while long-term mortality studies were homogenous (OR = 4.7; 95% CI = 3.5-6.1; Higgins's I2 = 0%). There was no publication bias for short-term mortality analysis. The qSOFA score showed poor sensitivity but moderate specificity for both short and long-term mortality, with similar performance in predicting both short- and long- term mortality. Geographical region was shown to have nominal significant (p = 0.05) influence on qSOFA short term mortality prediction. PMID- 30420769 TI - Cyclosporine A binding to COX-2 reveals a novel signaling pathway that activates the IRE1alpha unfolded protein response sensor. AB - Cyclosporine, a widely used immunosuppressant in organ transplantation and in treatment of various autoimmune diseases, activates the unfolded protein response (UPR), an ER stress coping response. In this study we discovered a new and unanticipated cyclosporine-dependent signaling pathway, with cyclosporine triggering direct activation of the UPR. COX-2 binds to and activates IRE1alpha, leading to IRE1alpha splicing of XBP1 mRNA. Molecular interaction and modeling analyses identified a novel interaction site for cyclosporine with COX-2 which caused enhancement of COX-2 enzymatic activity required for activation of the IRE1alpha branch of the UPR. Cyclosporine-dependent activation of COX-2 and IRE1alpha in mice indicated that cyclosporine-COX-2-IRE1alpha signaling pathway was functional in vivo. These findings identify COX-2 as a new IRE1alpha binding partner and regulator of the IRE1alpha branch of the UPR pathway, and establishes the mechanism underlying cytotoxicity associated with chronic cyclosporine exposure. PMID- 30420770 TI - Modulation of salivary cytokines in response to alcohol, tobacco and caffeine consumption: a pilot study. AB - It has been shown that long-term stimulant consumption alters the biological and microbiological status of the oral cavity. We present a pilot study describing stimulant-specific oral immunomodulation in the oral cavity. Changes in salivary cytokine levels in response to long-term alcohol, tobacco and caffeine were identified. Volunteers were recruited from amongst the patients visiting University Dental Clinic of CEU Cardenal Herrera University (Alfara del Patriarca, Spain). Participants were grouped according to their self-reported levels of consumption of either caffeine, alcohol or tobacco (control group volunteers were non-consumers of all three). Informed consent was provided and stimulated saliva samples were obtained and assayed for interleukin-1alpha IL 1alpha), Tumor Necrosis Factor alpha (TNF-alpha) and Interferon gamma IFN-gamma). Long-term, high-level consumers of alcohol or tobacco exhibited elevated salivary concentrations of the three inflammatory cytokines with respect to control values. Specifically, IL-1alpha was found to be elevated in alcohol users whilst IFN-gamma concentration higher in tobacco users versus controls. Long-term caffeine consumers displayed elevated levels of IFN-gamma and TNF-alpha, whereas IL-1alpha levels were reduced with respect to control volunteers. This pilot study demonstrates that salivary cytokines can be modulated in response to quantity and duration of alcohol, caffeine or tobacco consumption. PMID- 30420771 TI - Risk Of Human Dietary Exposure To Organochlorine Pesticide Residues In Fruits From Ghana. AB - The objectives of this present study were to assess the level of organochlorine pesticide (OCP) residues in fruits and to determine the potential health risks associated with the exposure to these pesticides. A total of 120 fruits (watermelon, pineapple, and banana) were collected from five communities and a local market within the Mampong Municipality and analyzed for organochlorine pesticide residues. The results showed that the concentrations ranged from not detectable (ND)-48.22 ng/g for DDTs, ND-19.03 ng/g for HCHs, ND-4.10 ng/g for CHLs, ND-22.84 ng/g for Aldrin, and ND-11.53 ng/g for other OCPs. Levels of methoxychlor, Aldrin and gamma-hexachlorocyclohexane (HCH) exceeded the maximum residue limits in watermelon. Estimated health risk revealed that Aldrin in watermelon could pose potential toxicity to the consumer. Estimated average daily intake for Aldrin was above the acceptable average daily intake. PMID- 30420772 TI - Low-intensity shock wave therapy ameliorates erectile dysfunction in men with pelvic fractures associated with urethral injury. AB - Erectile dysfunction (ED) is common in patients with pelvic fractures associated with urethral injury (PFUI). We aim to assess the efficacy and safety of low intensity shock wave therapy (LiSWT) in ED treatment related to PFUI. Forty-three consecutive patients with PFUI who underwent surgical repair between January 2014 and March 2017 were sampled in Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. ED onset following surgical repair was initially treated with oral phosphodiesterase type 5 inhibitors (PDE5i) for six months. PDE5i non-responders were referred for LiSWT of six weekly sessions. Erectile function was evaluated by the International Index of Erectile Function-5 (IIEF-5) and Erection Hardness Score (EHS). Forty-three consecutive patients were enrolled in our study. ED was observed in 79.1% (34/43) patients following surgical repair. These 34 patients were given oral PDE5i (Tadalafil(r) 5 mg) daily treatment, 64.7% (22/34) patients restored erectile function to normal range (EHS: 3.4 +/- 1.3, IIEF-5: 21.7 +/- 1.0). The other twelve PDE5i non-responders were referred for LiSWT. Seven patients (58.3%, 7/12) remained unable to maintain the rigidity for full sexual intercourse. The other five patients reported allowing full sexual intercourse. Based on our results, LiSWT may ameliorate the ED in men with PFUI and shift PDE5i non-responders to responders. PMID- 30420773 TI - RNA motifs and combinatorial prediction of interactions, stability and localization of noncoding RNAs. AB - Although the number of documented noncoding RNAs (ncRNAs) is rapidly increasing, knowledge of their molecular function is lagging behind. The identification of specific RNA motifs that mediate transcript stability, interactions and localization may aid in the prediction of these features in new transcripts and may have potential implications for ncRNA function. Here, we review RNA motifs, focusing on four recent studies identifying nuclear-retention motifs, and discuss the limited specificity of short-RNA motifs and the resulting challenge for effective functional prediction. Future approaches may succeed by integrating combinatorial and cooperative effects of additional partially sequence-based properties. PMID- 30420774 TI - The role of bridging ligands in dinitrogen reduction and functionalization by uranium multimetallic complexes. AB - Cooperativity between metal centres is identified as a crucial step in dinitrogen reduction both for the industrial Haber-Bosch process and for the natural fixation of nitrogen by nitrogenase enzymes, but the mechanism of N2 reduction remains poorly understood. This is in large part because multimetallic complexes that reduce and functionalize dinitrogen in the absence of strong alkali reducing agents are crucial to establish a structure-activity relationship, but remain extremely rare. Recently, we reported a multimetallic nitride-bridged diuranium(III) complex capable of reducing and functionalizing dinitrogen. Here we show that an analogous complex assembled with an oxo instead of a nitride linker also effects the four-electron reduction of dinitrogen, but the reactivity of the resulting oxo-(N2) complex differs significantly from that of the nitride (N2). Computational studies show a different bonding scheme for the dinitrogen where the bridging nitride does participate in the binding and consequent activation of N2, while the oxide does not. PMID- 30420775 TI - Prevention of dendrite growth and volume expansion to give high-performance aprotic bimetallic Li-Na alloy-O2 batteries. AB - Rechargeable aprotic alkali metal (Li or Na)-O2 batteries are the subject of great interest because of their high theoretical specific energy. However, the growth of dendrites and cracks at the Li or Na anode, as well as their corrosive oxidation lead to poor cycling stability and safety issues. Understanding the mechanism and improving Li/Na-ion plating and stripping electrochemistry are therefore essential to realizing their technological potential. Here, we report how the use of a Li-Na alloy anode and an electrolyte additive realizes an aprotic bimetal Li-Na alloy-O2 battery with improved cycling stability. Electrochemical investigations show that stripping and plating of Li and Na and the robust and flexible passivation film formed in situ (by 1,3-dioxolane additive reacting with the Li-Na alloy) suppress dendrite and buffer alloy anode volume expansion and thus prevent cracking, avoiding electrolyte consumption and ensuring high electron transport efficiency and continued electrochemical reactions. PMID- 30420776 TI - A biomimetic receptor for glucose. AB - Specific molecular recognition is routine for biology, but has proved difficult to achieve in synthetic systems. Carbohydrate substrates are especially challenging, because of their diversity and similarity to water, the biological solvent. Here we report a synthetic receptor for glucose, which is biomimetic in both design and capabilities. The core structure is simple and symmetrical, yet provides a cavity which almost perfectly complements the all-equatorial beta pyranoside substrate. The receptor's affinity for glucose, at Ka ~ 18,000 M-1, compares well with natural receptor systems. Selectivities also reach biological levels. Most other saccharides are bound approximately 100 times more weakly, while non-carbohydrate substrates are ignored. Glucose-binding molecules are required for initiatives in diabetes treatment, such as continuous glucose monitoring and glucose-responsive insulin. The performance and tunability of this system augur well for such applications. PMID- 30420777 TI - Robust gold nanorods stabilized by bidentate N-heterocyclic-carbene-thiolate ligands. AB - Although N-heterocyclic carbenes (NHCs) have demonstrated outstanding potential for use as surface anchors, synthetic challenges have limited their application to either large planar substrates or very small spherical nanoparticles. The development of a strategy to graft NHCs onto non-spherical nanomaterials, such as gold nanorods, would greatly expand their utility as surface ligands. Here, we use a bidentate thiolate-NHC-gold(I) complex that is easily grafted onto commercial cetyl trimethylammonium bromide-stabilized gold nanorods through ligand exchange. On mild reduction of the resulting surface-tethered NHC-gold(I) complexes, the gold atom attached to the NHC complex is added to the surface as an adatom, thereby precluding the need for reorganization of the underlying surface lattice upon NHC binding. The resulting thiolate-NHC-stabilized gold nanorods are stable towards excess glutathione for up to six days, and under conditions with large variations in pH, high and low temperatures, high salt concentrations, or in biological media and cell culture. We also demonstrate the utility of these nanorods for in vitro photothermal therapy. PMID- 30420778 TI - Author Correction: Inhibiting amyloid-beta cytotoxicity through its interaction with the cell surface receptor LilrB2 by structure-based design. AB - In the version of this Article originally published online, the upper right panel of Fig. 5a was mistakenly a repeat of the lower right panel. This has now been corrected in all versions of the Article. PMID- 30420779 TI - Design and effectiveness evaluation of mirror myoelectric interfaces: a novel method to restore movement in hemiplegic patients. AB - The motor impairment occurring after a stroke is characterized by pathological muscle activation patterns or synergies. However, while robot-aided myoelectric interfaces have been proposed for stroke rehabilitation, they do not address this issue, which might result in inefficient interventions. Here, we present a novel paradigm that relies on the correction of the pathological muscle activity as a way to elicit rehabilitation, even in patients with complete paralysis. Previous studies demonstrated that there are no substantial inter-limb differences in the muscle synergy organization of healthy individuals. We propose building a subject specific model of muscle activity from the healthy limb and mirroring it to use it as a learning tool for the patient to reproduce the same healthy myoelectric patterns on the paretic limb during functional task training. Here, we aim at understanding how this myoelectric model, which translates muscle activity into continuous movements of a 7-degree of freedom upper limb exoskeleton, could transfer between sessions, arms and tasks. The experiments with 8 healthy individuals and 2 chronic stroke patients proved the feasibility and effectiveness of such myoelectric interface. We anticipate the proposed method to become an efficient strategy for the correction of maladaptive muscle activity and the rehabilitation of stroke patients. PMID- 30420781 TI - Legionella pneumophila inhibits immune signalling via MavC-mediated transglutaminase-induced ubiquitination of UBE2N. AB - The bacterial pathogen Legionella pneumophila modulates host immunity using effectors translocated by its Dot/Icm transporter to facilitate its intracellular replication. A number of these effectors employ diverse mechanisms to interfere with protein ubiquitination, a post-translational modification essential for immunity. Here, we have found that L. pneumophila induces monoubiquitination of the E2 enzyme UBE2N by its Dot/Icm substrate MavC(Lpg2147). We demonstrate that MavC is a transglutaminase that catalyses covalent linkage of ubiquitin to Lys92 and Lys94 of UBE2N via Gln40. Similar to canonical transglutaminases, MavC possess deamidase activity that targets ubiquitin at Gln40. We identified Cys74 as the catalytic residue for both ubiquitination and deamidation activities. Furthermore, ubiquitination of UBE2N by MavC abolishes its activity in the formation of K63-type polyubiquitin chains, which dampens NF-kappaB signalling in the initial phase of bacterial infection. Our results reveal an unprecedented mechanism of modulating host immunity by modifying a key ubiquitination enzyme by ubiquitin transglutamination. PMID- 30420780 TI - Investigation of the Roles of Plasma Species Generated by Surface Dielectric Barrier Discharge. AB - As an emerging sterilization technology, cold atmospheric plasma offers a dry, non-thermal, rapid process that is minimally damaging to a majority of substrates. However, the mechanisms by which plasma interacts with living cells are poorly understood and the plasma generation apparatuses are complex and resource-intensive. In this study, the roles of reactive oxygen species (ROS), nitric oxide (NO), and charged particles (ions) produced by surface dielectric barrier discharge (SDBD) plasma on prokaryotic (Listeria monocytogenes (Gram positive)) and eukaryotic (human umbilical vein endothelial cells (HUVEC)) cellular function were evaluated. HUVEC and bacterial oxidative stress responses, the accumulation of nitrite in aqueous media, air ion density, and bacterial inactivation at various distances from SDBD actuators were measured. SDBD actuator designs were also varied in terms of electrode number and length to evaluate the cellular effects of plasma volume and power distribution. NO and ions were found to contribute minimally to the observed cellular effects, whereas ROS were found to cause rapid bacterial inactivation, induce eukaryotic and prokaryotic oxidative stress, and result in rapid oxidation of bovine muscle tissue. The results of this study underscore the dominance of ROS as the major plasma generated species responsible for cellular effects, with ions and RNS having a secondary, complimentary role. PMID- 30420782 TI - Pneumolysin binds to the mannose receptor C type 1 (MRC-1) leading to anti inflammatory responses and enhanced pneumococcal survival. AB - Streptococcus pneumoniae (the pneumococcus) is a major cause of mortality and morbidity globally, and the leading cause of death in children under 5 years old. The pneumococcal cytolysin pneumolysin (PLY) is a major virulence determinant known to induce pore-dependent pro-inflammatory responses. These inflammatory responses are driven by PLY-host cell membrane cholesterol interactions, but binding to a host cell receptor has not been previously demonstrated. Here, we discovered a receptor for PLY, whereby pro-inflammatory cytokine responses and Toll-like receptor signalling are inhibited following PLY binding to the mannose receptor C type 1 (MRC-1) in human dendritic cells and mouse alveolar macrophages. The cytokine suppressor SOCS1 is also upregulated. Moreover, PLY-MRC 1 interactions mediate pneumococcal internalization into non-lysosomal compartments and polarize naive T cells into an interferon-gammalow, interleukin 4high and FoxP3+ immunoregulatory phenotype. In mice, PLY-expressing pneumococci colocalize with MRC-1 in alveolar macrophages, induce lower pro-inflammatory cytokine responses and reduce neutrophil infiltration compared with a PLY mutant. In vivo, reduced bacterial loads occur in the airways of MRC-1-deficient mice and in mice in which MRC-1 is inhibited using blocking antibodies. In conclusion, we show that pneumococci use PLY-MRC-1 interactions to downregulate inflammation and enhance bacterial survival in the airways. These findings have important implications for future vaccine design. PMID- 30420783 TI - Epstein-Barr virus BORF2 inhibits cellular APOBEC3B to preserve viral genome integrity. AB - The apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like (APOBEC) family of single-stranded DNA (ssDNA) cytosine deaminases provides innate immunity against virus and transposon replication1-4. A well-studied mechanism is APOBEC3G restriction of human immunodeficiency virus type 1, which is counteracted by a virus-encoded degradation mechanism1-4. Accordingly, most work has focused on retroviruses with obligate ssDNA replication intermediates and it is unclear whether large double-stranded DNA (dsDNA) viruses may be similarly susceptible to restriction. Here, we show that the large dsDNA herpesvirus Epstein-Barr virus (EBV), which is the causative agent of infectious mononucleosis and multiple cancers5, utilizes a two-pronged approach to counteract restriction by APOBEC3B. Proteomics studies and immunoprecipitation experiments showed that the ribonucleotide reductase large subunit of EBV, BORF26,7, binds APOBEC3B. Mutagenesis mapped the interaction to the APOBEC3B catalytic domain, and biochemical studies demonstrated that BORF2 stoichiometrically inhibits APOBEC3B DNA cytosine deaminase activity. BORF2 also caused a dramatic relocalization of nuclear APOBEC3B to perinuclear bodies. On lytic reactivation, BORF2-null viruses were susceptible to APOBEC3B-mediated deamination as evidenced by lower viral titres, lower infectivity and hypermutation. The Kaposi's sarcoma-associated herpesvirus homologue, ORF61, also bound APOBEC3B and mediated relocalization. These data support a model where the genomic integrity of human gamma-herpesviruses is maintained by active neutralization of the antiviral enzyme APOBEC3B. PMID- 30420784 TI - Centrosomal protein TRIM43 restricts herpesvirus infection by regulating nuclear lamina integrity. AB - Tripartite motif (TRIM) proteins mediate antiviral host defences by either directly targeting viral components or modulating innate immune responses. Here we identify a mechanism of antiviral restriction in which a TRIM E3 ligase controls viral replication by regulating the structure of host cell centrosomes and thereby nuclear lamina integrity. Through RNAi screening we identified several TRIM proteins, including TRIM43, that control the reactivation of Kaposi's sarcoma-associated herpesvirus. TRIM43 was distinguished by its ability to restrict a broad range of herpesviruses and its profound upregulation during herpesvirus infection as part of a germline-specific transcriptional program mediated by the transcription factor DUX4. TRIM43 ubiquitinates the centrosomal protein pericentrin, thereby targeting it for proteasomal degradation, which subsequently leads to alterations of the nuclear lamina that repress active viral chromatin states. Our study identifies a role of the TRIM43-pericentrin-lamin axis in intrinsic immunity, which may be targeted for therapeutic intervention against herpesviral infections. PMID- 30420785 TI - Vaccinia virus hijacks EGFR signalling to enhance virus spread through rapid and directed infected cell motility. AB - Cell motility is essential for viral dissemination1. Vaccinia virus (VACV), a close relative of smallpox virus, is thought to exploit cell motility as a means to enhance the spread of infection1. A single viral protein, F11L, contributes to this by blocking RhoA signalling to facilitate cell retraction2. However, F11L alone is not sufficient for VACV-induced cell motility, indicating that additional viral factors must be involved. Here, we show that the VACV epidermal growth factor homologue, VGF, promotes infected cell motility and the spread of viral infection. We found that VGF secreted from early infected cells is cleaved by ADAM10, after which it acts largely in a paracrine manner to direct cell motility at the leading edge of infection. Real-time tracking of cells infected in the presence of EGFR, MAPK, FAK and ADAM10 inhibitors or with VGF-deleted and F11-deleted viruses revealed defects in radial velocity and directional migration efficiency, leading to impaired cell-to-cell spread of infection. Furthermore, intravital imaging showed that virus spread and lesion formation are attenuated in the absence of VGF. Our results demonstrate how poxviruses hijack epidermal growth factor receptor-induced cell motility to promote rapid and efficient spread of infection in vitro and in vivo. PMID- 30420786 TI - Measuring molecular abundances in comet C/2014 Q2 (Lovejoy) using the APEX telescope. AB - Comet composition provides critical information on the chemical and physical processes that took place during the formation of the Solar System. We report here on millimeter spectroscopic observations of the long-period bright comet C/2014 Q2 (Lovejoy) using the Atacama Pathfinder Experiment (APEX) band 1 receiver between UT 16.948 to 18.120 January 2015, when the comet was at heliocentric distance of 1.30 au and geocentric distance of 0.53 au. Bright comets allow for sensitive observations of gaseous volatiles that sublimate in their coma. These observations allowed us to detect HCN, CH3OH (multiple transitions), H2CO and CO, and to measure precise molecular production rates. Additionally, sensitive upper limits were derived on the complex molecules acetaldehyde (CH3CHO) and formamide (NH2CHO) based on the average of the strongest lines in the targeted spectral range to improve the signal-to-noise ratio. Gas production rates are derived using a non-LTE molecular excitation calculation involving collisions with H2O and radiative pumping that becomes important in the outer coma due to solar radiation. We find a depletion of CO in C/2014 Q2 (Lovejoy) with a production rate relative to water of 2.0 %, and relatively low abundances of Q(HCN)/Q (H2O),0.1%, and Q (H2CO)/Q (H2O), 0.2 %. In contrast the CH3OH relative abundance Q (CH3OH)/Q (H2O),2.2 %, is close to the mean value observed in other comets. The measured production rates are consistent with values derived for this object from other facilities at similar wavelengths taking into account the difference in the fields of view. Based on the observed mixing ratios of organic molecules in four bright comets including C/2014 Q2, we find some support for atom addition reactions on cold dust being the origin of some of the molecules. PMID- 30420787 TI - Radiologic image-based statistical shape analysis of brain tumours. AB - We propose a curve-based Riemannian geometric approach for general shape-based statistical analyses of tumours obtained from radiologic images. A key component of the framework is a suitable metric that enables comparisons of tumour shapes, provides tools for computing descriptive statistics and implementing principal component analysis on the space of tumour shapes and allows for a rich class of continuous deformations of a tumour shape. The utility of the framework is illustrated through specific statistical tasks on a data set of radiologic images of patients diagnosed with glioblastoma multiforme, a malignant brain tumour with poor prognosis. In particular, our analysis discovers two patient clusters with very different survival, subtype and genomic characteristics. Furthermore, it is demonstrated that adding tumour shape information to survival models containing clinical and genomic variables results in a significant increase in predictive power. PMID- 30420788 TI - Cigarette tax rates, behavioral disengagement, and quit ratios among daily smokers. AB - Cigarette taxation is an economics-based policy associated with increased population-level quit ratios. However, the estimated effects of tax increase on smoking behavior vary substantially, underscoring the need to identify moderating variables. We examined whether behavioral disengagement - the tendency to abandon goals when experiencing stress - modified the association between cigarette taxes and daily smoking behavior. We connected state-level cigarette tax rate data with individual-level behavioral data, including a national sample of 725 US adults who smoked daily at baseline and reported follow-up data approximately 10 years later, and 376 who were resampled a third time after another 10 years. Analyses involved multilevel logistic regression (with time as a nested variable and anonymized state codes as a grouping variable), where current smoking status (dichotomous) was regressed on behavioral disengagement, state-level cigarette tax at baseline and current time, and the interaction between disengagement and current tax. Consistent with hypotheses, tax rate interacted with disengagement (OR=0.95, 95% CI=0.90,0.99, p=.0255): Among those one SD above the mean for disengagement, tax rate was unassociated with quit ratio (OR=0.99, 95% CI=0.85,1.16, p=.6975). However, among those one SD below the mean, tax rate was significantly associated with higher quit ratio (OR=1.22, 95% CI=1.04,1.43, p=.0163). Our data suggest the possibility that cigarette taxes may be more effective in facilitating cessation among smokers low in behavioral disengagement or when accompanied by interventions that reduce stress or maintain goal pursuit. Identifying psychological moderators of policy effectiveness holds promise for improving policy design and targeting. PMID- 30420789 TI - Firearm Ownership in High-Conflict Families: Differences According to State Laws Restricting Firearms to Misdemeanor Crimes of Domestic Violence Offenders. AB - This study examines the association between state laws that prohibit firearm ownership for offenders convicted of misdemeanour crimes of domestic violence (MCDV) and firearm ownership in two-parent families with high-conflict male partners with arrest histories. Mixed effects logistic regression models applied to data from the Early Childhood Longitudinal Study-Birth cohort (n = 5,350) determined that living in a state with laws that prohibited firearm ownership for convicted MCDV offenders decreased the likelihood of firearm ownership among families with high-conflict males by 62%. The length of the time limit length on firearm prohibition was correlated with incremental decreases in firearm ownership in such families, with the probability of firearm ownership among families with high-conflict males decreasing from 30% in states with no MCDV laws restricting access from firearms to 12% in states with permanent prohibition on firearm ownership. These findings have significance for public health policy aimed at decreasing intimate-partner homicide. PMID- 30420791 TI - Novel Approaches in Diagnosing the Role of Inflammation in the Onset Cardiovascular Disorders. PMID- 30420790 TI - Shock Wave Therapy Enhances Mitochondrial Delivery into Target Cells and Protects against Acute Respiratory Distress Syndrome. AB - This study tested the hypothesis that shock wave therapy (SW) enhances mitochondrial uptake into the lung epithelial and parenchymal cells to attenuate lung injury from acute respiratory distress syndrome (ARDS). ARDS was induced in rats through continuous inhalation of 100% oxygen for 48 h, while SW entailed application 0.15 mJ/mm2 for 200 impulses at 6 Hz per left/right lung field. In vitro and ex vivo studies showed that SW enhances mitochondrial uptake into lung epithelial and parenchyma cells (all p < 0.001). Flow cytometry demonstrated that albumin levels and numbers of inflammatory cells (Ly6G+/CD14+/CD68+/CD11b/c+) in bronchoalveolar lavage fluid were the highest in untreated ARDS, were progressively reduced across SW, Mito, and SW + Mito (all p < 0.0001), and were the lowest in sham controls. The same profile was also seen for fibrosis/collagen deposition, levels of biomarkers of oxidative stress (NOX-1/NOX-2/oxidized protein), inflammation (MMP-9/TNF-alpha/NF-kappaB/IL-1beta/ICAM-1), apoptosis (cleaved caspase 3/PARP), fibrosis (Smad3/TGF-beta), mitochondrial damage (cytosolic cytochrome c) (all p < 0.0001), and DNA damage (gamma-H2AX+), and numbers of parenchymal inflammatory cells (CD11+/CD14+/CD40L+/F4/80+) (p < 0.0001). These results suggest that SW-assisted Mito therapy effectively protects the lung parenchyma from ARDS-induced injury. PMID- 30420792 TI - Corrigendum to "Role of Interleukin-18 in Modulation of Oral Carcinoma Cell Proliferation". AB - [This corrects the article DOI: 10.1155/MI/2006/67120.]. PMID- 30420793 TI - General Semiparametric Shared Frailty Model: Estimation and Simulation with frailtySurv. AB - The R package frailtySurv for simulating and fitting semi-parametric shared frailty models is introduced. Package frailtySurv implements semi-parametric consistent estimators for a variety of frailty distributions, including gamma, log-normal, inverse Gaussian and power variance function, and provides consistent estimators of the standard errors of the parameters' estimators. The parameters' estimators are asymptotically normally distributed, and therefore statistical inference based on the results of this package, such as hypothesis testing and confidence intervals, can be performed using the normal distribution. Extensive simulations demonstrate the flexibility and correct implementation of the estimator. Two case studies performed with publicly available datasets demonstrate applicability of the package. In the Diabetic Retinopathy Study, the onset of blindness is clustered by patient, and in a large hard drive failure dataset, failure times are thought to be clustered by the hard drive manufacturer and model. PMID- 30420795 TI - Proposal of Two Prognostic Models for the Prediction of 10-Year Survival after Liver Resection for Colorectal Metastases. AB - Background: One-third of 5-year survivors after liver resection for colorectal liver metastases (CLM) develop recurrence or tumor-related death. Therefore 10 year survival appears more adequate in defining permanent cure. The aim of this study was to develop prognostic models for the prediction of 10-year survival after liver resection for colorectal liver metastases. Methods: N=965 cases of liver resection for CLM were retrospectively analyzed using univariable and multivariable regression analyses. Receiver operating curve analyses were used to assess the sensitivity and specificity of developed prognostic models and their potential clinical usefulness. Results: The 10-year survival rate was 15.2%. Age at liver resection, application of chemotherapies of the primary tumor, preoperative Quick's value, hemoglobin level, and grading of the primary colorectal tumor were independent significant predictors for 10-year patient survival. The generated formula to predict 10-year survival based on these preoperative factors displayed an area under the receiver operating curve (AUROC) of 0.716. In regard to perioperative variables, the distance of resection margins and performance of right segmental liver resection were additional independent predictors for 10-year survival. The logit link formula generated with pre- and perioperative variables showed an AUROC of 0.761. Conclusion: Both prognostic models are potentially clinically useful (AUROCs >0.700) for the prediction of 10 year survival. External validation is required prior to the introduction of these models in clinical patient counselling. PMID- 30420797 TI - Fully-Automatic Synapse Prediction and Validation on a Large Data Set. AB - Extracting a connectome from an electron microscopy (EM) data set requires identification of neurons and determination of connections (synapses) between neurons. As manual extraction of this information is very time-consuming, there has been extensive research efforts to automatically segment the neurons to help guide and eventually replace manual tracing. Until recently, there has been comparatively little research on automatic detection of the actual synapses between neurons. This discrepancy can, in part, be attributed to several factors: obtaining neuronal shapes is a prerequisite for the first step in extracting a connectome, manual tracing is much more time-consuming than annotating synapses, and neuronal contact area can be used as a proxy for synapses in determining connections. However, recent research has demonstrated that contact area alone is not a sufficient predictor of a synaptic connection. Moreover, as segmentation improved, we observed that synapse annotation consumes a more significant fraction of overall reconstruction time (upwards of 50% of total effort). This ratio will only get worse as segmentation improves, gating the overall possible speed-up. Therefore, we address this problem by developing algorithms that automatically detect presynaptic neurons and their postsynaptic partners. In particular, presynaptic structures are detected using a U-Net convolutional neural network (CNN), and postsynaptic partners are detected using a multilayer perceptron (MLP) with features conditioned on the local segmentation. This work is novel because it requires minimal amount of training, leverages advances in image segmentation directly, and provides a complete solution for polyadic synapse detection. We further introduce novel metrics to evaluate our algorithm on connectomes of meaningful size. When applied to the output of our method on EM data from Drosphila, these metrics demonstrate that a completely automatic prediction can be used to effectively characterize most of the connectivity correctly. PMID- 30420796 TI - Very Delayed Remote Ischemic Post-conditioning Induces Sustained Neurological Recovery by Mechanisms Involving Enhanced Angioneurogenesis and Peripheral Immunosuppression Reversal. AB - Ischemic conditioning is defined as a transient and subcritical period of ischemia integrated in an experimental paradigm that involves a stimulus of injurious ischemia, activating endogenous tissue repair mechanisms that lead to cellular protection under pathological conditions like stroke. Whereas ischemic pre-conditioning is irrelevant for stroke treatment, ischemic post-conditioning, and especially non-invasive remote ischemic post-conditioning (rPostC) is an innovative and potential strategy for stroke treatment. Although rPostC has been shown to induce neuroprotection in stroke models before, resulting in some clinical trials on the way, fundamental questions with regard to its therapeutic time frame and its underlying mechanisms remain elusive. Hence, we herein used a model of non-invasive rPostC of hind limbs after cerebral ischemia in male C57BL6 mice, studying the optimal timing for the application of rPostC and its underlying mechanisms for up to 3 months. Mice undergoing rPostC underwent three different paradigms, starting with the first cycle of rPostC 12 h, 24 h, or 5 days after stroke induction, which is a very delayed time point of rPostC that has not been studied elsewhere. rPostC as applied within 24 h post-stroke induces reduction of infarct volume on day three. On the contrary, very delayed rPostC does not yield reduction of infarct volume on day seven when first applied on day five, albeit long-term brain injury is significantly reduced. Likewise, very delayed rPostC yields sustained neurological recovery, whereas early rPostC (i.e., <24 h) results in transient neuroprotection only. The latter is mediated via heat shock protein 70 that is a well-known signaling protein involved in the pathophysiological cellular cascade of cerebral ischemia, leading to decreased proteasomal activity and decreased post-stroke inflammation. Very delayed rPostC on day five, however, induces a pleiotropic effect, among which a stimulation of angioneurogenesis, a modulation of the ischemic extracellular milieu, and a reversal of the stroke-induced immunosuppression occur. As such, very delayed rPostC appears to be an attractive tool for future adjuvant stroke treatment that deserves further preclinical attention before large clinical trials are in order, which so far have predominantly focused on early rPostC only. PMID- 30420794 TI - How to Modulate Tumor Hypoxia for Preclinical In Vivo Imaging Research. AB - Tumor hypoxia is related with tumor aggressiveness, chemo- and radiotherapy resistance, and thus a poor clinical outcome. Therefore, over the past decades, every effort has been made to develop strategies to battle the negative prognostic influence of tumor hypoxia. For appropriate patient selection and follow-up, noninvasive imaging biomarkers such as positron emission tomography (PET) radiolabeled ligands are unprecedentedly needed. Importantly, before being able to implement these new therapies and potential biomarkers into the clinical setting, preclinical in vivo validation in adequate animal models is indispensable. In this review, we provide an overview of the different attempts that have been made to create differential hypoxic in vivo cancer models with a particular focus on their applicability in PET imaging studies. PMID- 30420798 TI - Temporal Relationship of Ocular and Tail Segmental Movements Underlying Locomotor Induced Gaze Stabilization During Undulatory Swimming in Larval Xenopus. AB - In larval xenopus, locomotor-induced oculomotor behavior produces gaze stabilizing eye movements to counteract the disruptive effects of tail undulation during swimming. While neuronal circuitries responsible for feed-forward intrinsic spino-extraocular signaling have recently been described, the resulting oculomotor behavior remains poorly understood. Conveying locomotor CPG efference copy, the spino-extraocular motor command coordinates the multi-segmental rostrocaudal spinal rhythmic activity with the extraocular motor activity. By recording sequences of xenopus tadpole free swimming, we quantified the temporal calibration of conjugate eye movements originating from spino-extraocular motor coupled activity during pre-metamorphic tail-based undulatory swimming. Our results show that eye movements are produced only during robust propulsive forward swimming activity and increase with the amplitude of tail movements. The use of larval isolated in vitro and semi-intact fixed head preparations revealed that spinal locomotor networks driving the rostral portion of the tail set the precise timing of the spino-extraocular motor coupling by adjusting the phase relationship between spinal segment and extraocular rhythmic activity with the swimming frequency. The resulting spinal-evoked oculomotor behavior produced conjugated eye movements that were in phase opposition with the mid-caudal part of the tail. This time adjustment is independent of locomotor activity in the more caudal spinal parts of the tail. Altogether our findings demonstrate that locomotor feed-forward spino-extraocular signaling produce conjugate eye movements that compensate specifically the undulation of the mid-caudal tail during active swimming. Finally, this study constitutes the first extensive behavioral quantification of spino-extraocular motor coupling, which sets the basis for understanding the mechanisms of locomotor-induced oculomotor behavior in larval frog. PMID- 30420799 TI - Behavioral and Neurophysiological Effects of Transcranial Direct Current Stimulation (tDCS) in Fronto-Temporal Dementia. AB - Fronto-temporal dementia (FTD) is the clinical-diagnostic term that is now preferred to describe patients with a range of progressive dementia syndromes associated with focal atrophy of the frontal and anterior temporal cerebral regions. Currently available FTD medications have been used to control behavioral symptoms, even though they are ineffective in some patients, expensive and may induce adverse effects. Alternative therapeutic approaches are worth pursuing, such as non-invasive brain stimulation with transcranial direct current (tDCS). tDCS has been demonstrated to influence neuronal excitability and reported to enhance cognitive performance in dementia. The aim of this study was to investigate whether applying Anodal tDCS (2 mA intensity, 20 min) over the fronto temporal cortex bilaterally in five consecutive daily sessions would improve cognitive performance and behavior symptoms in FTD patients, also considering the neuromodulatory effect of stimulation on cortical electrical activity measured through EEG. We recruited 13 patients with FTD and we tested the effect of Anodal and Sham (i.e., placebo) tDCS in two separate experimental sessions. In each session, at baseline (T0), after 5 consecutive days (T1), after 1 week (T2), and after 4 weeks (T3) from the end of the treatment, cognitive and behavioral functions were tested. EEG (21 electrodes, 10-20 international system) was recorded for 5 min with eyes closed at the same time points in nine patients. The present findings showed that Anodal tDCS applied bilaterally over the fronto temporal cortex significantly improves (1) neuropsychiatric symptoms (as measured by the neuropsychiatric inventory, NPI) in FTD patients immediately after tDCS treatment, and (2) simple visual reaction times (sVRTs) up to 1 month after tDCS treatment. These cognitive improvements significantly correlate with the time course of the slow EEG oscillations (delta and theta bands) measured at the same time points. Even though further studies on larger samples are needed, these findings support the effectiveness of Anodal tDCS over the fronto-temporal regions in FTD on attentional processes that might be correlated to a normalized EEG low-frequency pattern. PMID- 30420800 TI - Born to Cry: A Genetic Dissection of Infant Vocalization. AB - Infant vocalizations are one of the most fundamental and innate forms of behavior throughout avian and mammalian orders. They have a critical role in motivating parental care and contribute significantly to fitness and reproductive success. Dysregulation of these vocalizations has been reported to predict risk of central nervous system pathologies such as hypoxia, meningitis, or autism spectrum disorder. Here, we have used the expanded BXD family of mice, and a diallel cross between DBA/2J and C57BL/6J parental strains, to begin the process of genetically dissecting the numerous facets of infant vocalizations. We calculate heritability, estimate the role of parent-of-origin effects, and identify novel quantitative trait loci (QTLs) that control ultrasonic vocalizations (USVs) on postnatal days 7, 8, and 9; a stage that closely matches human infants at birth. Heritability estimates for the number and frequency of calls are low, suggesting that these traits are under high selective pressure. In contrast, duration and amplitude of calls have higher heritabilities, indicating lower selection, or their importance for kin recognition. We find suggestive evidence that amplitude of infant calls is dependent on the maternal genotype, independent of shared genetic variants. Finally, we identify two loci on Chrs 2 and 14 influencing call frequency, and a third locus on Chr 8 influencing the amplitude of vocalizations. All three loci contain strong candidate genes that merit further analysis. Understanding the genetic control of infant vocalizations is not just important for understanding the evolution of parent-offspring interactions, but also in understanding the earliest innate behaviors, the development of parent-offspring relations, and the early identification of behavioral abnormalities. PMID- 30420801 TI - Disrupted Functional Connectivity of Cornu Ammonis Subregions in Amnestic Mild Cognitive Impairment: A Longitudinal Resting-State fMRI Study. AB - Background: The cornu ammonis (CA), as part of the hippocampal formation, represents a primary target region of neural degeneration in amnestic mild cognitive impairment (aMCI). Previous studies have revealed subtle structural deficits of the CA subregions (CA1-CA3, bilateral) in aMCI; however, it is not clear how the network function is impacted by aMCI. The present study examined longitudinal changes in resting state functional connectivity (FC) of each CA subregion and how these changes relate to neuropsychological profiles in aMCI. Methods: Twenty aMCI and 20 healthy control (HC) participants underwent longitudinal cognitive assessment and resting state functional MRI scans at baseline and 15 months afterward. Imaging data were processed with published routines in SPM8 and CONN software. Two-way analysis of covariance was performed with covariates of age, gender, education level, follow up interval, gray matter volume, mean FD, as well as global correlation (GCOR). Pearson's correlation was conducted to evaluate the relationship between the longitudinal changes in CA subregional FC and neuropsychological performance in aMCI subjects. Results: Resting state FC between the right CA1 and right middle temporal gyrus (MTG) as well as between the left CA2 and bilateral cuneal cortex (CC) were decreased in aMCI subjects as compared to HC. Longitudinal decrease in FC between the right CA1 and right MTG was correlated with reduced capacity of episodic memory in aMCI subjects. Conclusion: The current findings suggest functional alterations in the CA subregions. CA1 connectivity with the middle temporal cortex may represent an important neural marker of memory dysfunction in aMCI. PMID- 30420802 TI - The Luxembourg Parkinson's Study: A Comprehensive Approach for Stratification and Early Diagnosis. AB - While genetic advances have successfully defined part of the complexity in Parkinson's disease (PD), the clinical characterization of phenotypes remains challenging. Therapeutic trials and cohort studies typically include patients with earlier disease stages and exclude comorbidities, thus ignoring a substantial part of the real-world PD population. To account for these limitations, we implemented the Luxembourg PD study as a comprehensive clinical, molecular and device-based approach including patients with typical PD and atypical parkinsonism, irrespective of their disease stage, age, comorbidities, or linguistic background. To provide a large, longitudinally followed, and deeply phenotyped set of patients and controls for clinical and fundamental research on PD, we implemented an open-source digital platform that can be harmonized with international PD cohort studies. Our interests also reflect Luxembourg-specific areas of PD research, including vision, gait, and cognition. This effort is flanked by comprehensive biosampling efforts assuring high quality and sustained availability of body liquids and tissue biopsies. We provide evidence for the feasibility of such a cohort program with deep phenotyping and high quality biosampling on parkinsonism in an environment with structural specificities and alert the international research community to our willingness to collaborate with other centers. The combination of advanced clinical phenotyping approaches including device-based assessment will create a comprehensive assessment of the disease and its variants, its interaction with comorbidities and its progression. We envision the Luxembourg Parkinson's study as an important research platform for defining early diagnosis and progression markers that translate into stratified treatment approaches. PMID- 30420803 TI - Smarter Than Thou, Holier Than Thou: The Dynamic Interplay Between Cognitive and Moral Enhancement. AB - The debate about the desirability of using drugs to enhance human skills encompasses cognitive abilities such as memory and attention, and moral capacities such as emotional empathy and a sense of fairness. These two strands of literature in bioethics have grown relatively independent from each other, and an implicit framing assumption has emerged suggesting that apparently morally neutral cognitive capacities and paradigmatically moral capacities are distinct and vary independently of each other. Here, we identify key distinctions between competing accounts of cognitive enhancement and moral enhancement and argue that, despite the polarized nature of the bioethical debate, cognitive and moral capacities are intertwined. For example, moral behavior can be improved by enhancing "morally neutral" abilities such as attention span; and cognitive skills can be honed by means of socio-moral interaction. Further, cognitive skill is frequently assigned the abstract status of virtue and treated in the same way as more paradigmatically "moral" traits. We argue that the distinction between moral and cognitive enhancement is more apparent than real, since despite being nominally treated as distinct, cognitive and moral skills are frequently interdependent. As such we present evidence to support the claim that the enhancement of these two kinds of capacities cannot be clearly disaggregated from each other in the way that the theoretical poles of the debate in the literature suggest. We synthesize relevant scientific and bioethical literature and combine it with a line of analysis derived from Peter Hacker to show more clearly the terms of what can be said intelligibly about cognitive and moral skills and their enhancement. As a result of this analysis, we conclude that ethical questions in human bioenhancement are only fully intelligible at the level of persons imbued with feelings, thoughts, intentions, desires, values, and abilities, embedded within a particular social context, rather than at the level of pharmacological modulation of particular cognitive or affective capacities which, though conceptually distinguishable, in the embodied context of moral agency are profoundly intertwined. PMID- 30420805 TI - Losartan Alleviates Renal Fibrosis and Inhibits Endothelial-to-Mesenchymal Transition (EMT) Under High-Fat Diet-Induced Hyperglycemia. AB - The endothelial-to-mesenchymal transition (EMT) of glomerular vascular endothelial cells is considered to be pivotal in diabetic nephropathy (DN). The risk of DN can be decreased by losartan, but the potential molecular mechanism(s) are not fully understood. Extensive data show that the EMT occurs in proximal tubular endothelial cells resulting in an endothelial phenotype switch (fibrotic matrix accumulation), consequently enhancing the development of renal interstitial fibrosis. Here, we found that losartan significantly ameliorated DN induced renal fibrosis progression via inhibition of the EMT in mice. In vivo experiments suggested that losartan significantly alleviated microalbuminuria and pathologic changes under high-fat diet-induced hyperglycemia. Immunohistochemistry indicated that losartan suppressed the EMT in glomeruli. In addition, losartan decreased oxidative stress damage and inhibited the transforming growth factor (TGF)-beta1/Smad pathway. Furthermore, consistent changes were detected in vitro where losartan markedly inhibited the EMT and TGF beta1/Smad pathway induced by high glucose in glomerular endothelial cells. Together, these results suggested that losartan could alleviate the EMT in glomeruli via inhibition of oxidative stress damage and the TGF-beta1/Smad signaling pathway under hyperglycemia. PMID- 30420806 TI - Sexually Dimorphic Regulation of EET Synthesis and Metabolism: Roles of Estrogen. AB - Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid via cytochrome P450 (CYP)/epoxygenase and are hydrolyzed by soluble epoxide hydrolase (sEH). Circulating and tissue levels of EETs are controlled by CYP (EET synthesis) and sEH (EET degradation). Therefore, both increases in CYP activity and decreases in sEH expression potentiate EET bioavailability, responses that prevail in the female sex as a function of estrogen. This mini review, based on subtitles listed, briefly summarizes studies focusing specifically on (1) female specific potentiation of CYP/epoxygenase activity to compensate for the endothelial dysfunction; and (2) estrogen-dependent downregulation of sEH expression, which yields divergent actions in both systemic and pulmonary circulation, respectively. Estrogen-Potentiating EET Synthesis in Response to Endothelial Dysfunction: This section summarizes the current understanding regarding the roles of estrogen in facilitating EET synthesis in response to endothelial dysfunction. In this regard, estrogen recruitment of EET-driven signaling serves as a back-up mechanism, which compensates for NO deficiency to preserve endothelium-dependent vasodilator responses and maintain normal blood pressure. Estrogen-Dependent Downregulation of Ephx2/sEH Expression: This section focuses on molecular mechanisms responsible for the female-specific downregulation of sEH expression. Roles of EETs in Systemic Circulation, as a Function of Estrogen-Dependent Downregulation of sEH: This section summarizes studies conducted on animals that are either deficient in the Ephx2 gene (sEH-KO) or have been treated with sEH inhibitors (sEHIs), and exhibit EET-mediated cardiovascular protections in the cerebral, coronary, skeletal, and splanchnic circulations. In particular, the estrogen-inherent silencing of the Ephx2 gene duplicates the action of sEH deficiency, yielding comparable adaptations in attenuated myogenic vasoconstriction, enhanced shear stress-induced vasodilation, and improved cardiac contractility among female WT mice, male sEH-KO and sEHI treated mice. Roles of Estrogen-Driven EET Production in Pulmonary Circulation: This section reviews epidemiological and clinical studies that provide the correlation between the polymorphism, or mutation of gene(s) involving estrogen metabolism and female predisposition to pulmonary hypertension, and specifically addresses an intrinsic causation between the estrogen-dependent downregulation of Ephx2 gene/sEH expression and female-susceptibility of being pulmonary hypertensive, a topic that has never been explored before. Additionally, the issue of the "estrogen paradox" in the incidence and prognosis of pulmonary hypertension is discussed. PMID- 30420807 TI - A Selective Histamine H4 Receptor Antagonist, JNJ7777120, Is Protective in a Rat Model of Transient Cerebral Ischemia. AB - Cerebral ischemia is a multifactorial pathology characterized by different events evolving in time. The acute injury, characterized by excitoxicity, is followed by a secondary brain injury that develops from hours to days after ischemia. Extracellular levels of histamine increase in the ischemic area after focal cerebral ischemia induced by occlusion of the middle cerebral artery (MCAo). The histamine H4 receptor (H4R) is predominantly expressed in cell types of immune system where is involved in the regulation of immunological and inflammatory responses, and in numerous area of the Central Nervous System (CNS) including cortex and striatum. Our aim was to assess the putative neuroprotective effects of the potent and selective H4R antagonist, JNJ7777120 (JNJ), chronically administered (1 mg/kg, i.p., twice/day for 7 days) on damage parameters in a rat model of focal ischemia induced by transient MCAo (tMCAo). Chronic treatment with the H4R antagonist JNJ, significantly protected from the neurological deficit and from body weight loss after tMCAo. Seven days after the ischemic insult, JNJ reduced the volume of the ischemic cortical and striatal damage, the number of activated microglia and astrocytes in the ischemic cortex and striatum and decreased the plasma levels of IL-1beta and TNF-alpha, while increased the levels of IL-10. Two days after ischemia, JNJ has reduced granulocyte infiltration in the ischemic area. Results demonstrate that the selective antagonist of H4R, JNJ, systemically and chronically administered after ischemia, reduces the ischemic brain damage, improves the neurological deficit and decreases blood pro inflammatory cytokines, suggesting that H4R is a valuable pharmacological target after focal brain ischemia. PMID- 30420804 TI - To Protect and to Preserve: Novel Preservation Strategies for Extracellular Vesicles. AB - Extracellular vesicles (EVs)-based therapeutics are based on the premise that EVs shed by stem cells exert similar therapeutic effects and these have been proposed as an alternative to cell therapies. EV-mediated delivery is an effective and efficient system of cell-to-cell communication which can confer therapeutic benefits to their target cells. EVs have been shown to promote tissue repair and regeneration in various animal models such as, wound healing, cardiac ischemia, diabetes, lung fibrosis, kidney injury, and many others. Given the unique attributes of EVs, considerable thought must be given to the preservation, formulation and cold chain strategies in order to effectively translate exciting preclinical observations to clinical and commercial success. This review summarizes current understanding around EV preservation, challenges in maintaining EV quality, and also bioengineering advances aimed at enhancing the long-term stability of EVs. PMID- 30420808 TI - Decision Tree for Early Detection of Cognitive Impairment by Community Pharmacists. AB - Purpose: The early detection of Mild Cognitive Impairment (MCI) is essential in aging societies where dementia is becoming a common manifestation among the elderly. Thus our aim is to develop a decision tree to discriminate individuals at risk of MCI among non-institutionalized elderly users of community pharmacy. A more clinically and patient-oriented role of the community pharmacist in primary care makes the dispensation of medication an adequate situation for an effective, rapid, easy, and reproducible screening of MCI. Methods: A cross-sectional study was conducted with 728 non-institutionalized participants older than 65. A total of 167 variables were collected such as age, gender, educational attainment, daily sleep duration, reading frequency, subjective memory complaint, and medication. Two screening tests were used to detect possible MCI: Short Portable Mental State Questionnaire (SPMSQ) and the Mini-Mental State Examination (MMSE). Participants classified as positive were referred to clinical diagnosis. A decision tree and predictive models are presented as a result of applying techniques of machine learning for a more efficient enrollment. Results: One hundred and twenty-eight participants (17.4%) scored positive on MCI tests. A recursive partitioning algorithm with the most significant variables determined that the most relevant for the decision tree are: female sex, sleeping more than 9 h daily, age higher than 79 years as risk factors, and reading frequency. Moreover, psychoanaleptics, nootropics, and antidepressants, and anti inflammatory drugs achieve a high score of importance according to the predictive algorithms. Furthermore, results obtained from these algorithms agree with the current research on MCI. Conclusion: Lifestyle-related factors such as sleep duration and the lack of reading habits are associated with the presence of positive in MCI test. Moreover, we have depicted how machine learning provides a sound methodology to produce tools for early detection of MCI in community pharmacy. Impact of findings on practice: The community of pharmacists provided with adequate tools could develop a crucial task in the early detection of MCI to redirect them immediately to the specialists in neurology or psychiatry. Pharmacists are one of the most accessible and regularly visited health care professionals and they can play a vital role in early detection of MCI. PMID- 30420809 TI - Muscle Thickness and Curvature Influence Atrial Conduction Velocities. AB - Electroanatomical mapping is currently used to provide clinicians with information about the electrophysiological state of the heart and to guide interventions like ablation. These maps can be used to identify ectopic triggers of an arrhythmia such as atrial fibrillation (AF) or changes in the conduction velocity (CV) that have been associated with poor cell to cell coupling or fibrosis. Unfortunately, many factors are known to affect CV, including membrane excitability, pacing rate, wavefront curvature, and bath loading, making interpretation challenging. In this work, we show how endocardial conduction velocities are also affected by the geometrical factors of muscle thickness and wall curvature. Using an idealized three-dimensional strand, we show that transverse conductivities and boundary conditions can slow down or speed up signal propagation, depending on the curvature of the muscle tissue. In fact, a planar wavefront that is parallel to a straight line normal to the mid-surface does not remain normal to the mid-surface in a curved domain. We further demonstrate that the conclusions drawn from the idealized test case can be used to explain spatial changes in conduction velocities in a patient-specific reconstruction of the left atrial posterior wall. The simulations suggest that the widespread assumption of treating atrial muscle as a two-dimensional manifold for electrophysiological simulations will not accurately represent the endocardial conduction velocities in regions of the heart thicker than 0.5 mm with significant wall curvature. PMID- 30420810 TI - Altered Ca2+ and Na+ Homeostasis in Human Hypertrophic Cardiomyopathy: Implications for Arrhythmogenesis. AB - Hypertrophic cardiomyopathy (HCM) is the most common mendelian heart disease, with a prevalence of 1/500. HCM is a primary cause of sudden death, due to an heightened risk of ventricular tachyarrhythmias that often occur in young asymptomatic patients. HCM can slowly progress toward heart failure, either with preserved or reduced ejection fraction, due to worsening of diastolic function. Accumulation of intra-myocardial fibrosis and replacement scars underlies heart failure progression and represents a substrate for sustained arrhythmias in end stage patients. However, arrhythmias and mechanical abnormalities may occur in hearts with little or no fibrosis, prompting toward functional pathomechanisms. By studying viable cardiomyocytes and trabeculae isolated from inter-ventricular septum samples of non-failing HCM patients with symptomatic obstruction who underwent myectomy operations, we identified that specific abnormalities of intracellular Ca2+ handling are associated with increased cellular arrhytmogenesis and diastolic dysfunction. In HCM cardiomyocytes, diastolic Ca2+ concentration is increased both in the cytosol and in the sarcoplasmic reticulum and the rate of Ca2+ transient decay is slower, while the amplitude of Ca2+ release is preserved. Ca2+ overload is the consequence of an increased Ca2+ entry via L-type Ca2+-current [due to prolongation the action potential (AP) plateau], combined with a reduced rate of Ca2+-extrusion through the Na+/Ca2+ exchanger [due to increased cytosolic (Na+)] and a lower expression of SERCA. Increased late Na+ current (INaL) plays a major role, as it causes both AP prolongation and Na+ overload. Intracellular Ca2+ overload determines an higher frequency of Ca2+ waves leading to delayed-afterdepolarizations (DADs) and premature contractions, but is also linked with the increased diastolic tension and slower relaxation of HCM myocardium. Sustained increase of intracellular [Ca2+] goes hand-in-hand with the increased activation of Ca2+/calmodulin-dependent protein-kinase-II (CaMKII) and augmented phosphorylation of its targets, including Ca2+ handling proteins. In transgenic HCM mouse models, we found that Ca2+ overload, CaMKII and increased INaL drive myocardial remodeling since the earliest stages of disease and underlie the development of hypertrophy, diastolic dysfunction and the arrhythmogenic substrate. In conclusion, diastolic dysfunction and arrhythmogenesis in human HCM myocardium are driven by functional alterations at cellular and molecular level that may be targets of innovative therapies. PMID- 30420811 TI - Combined Aerobic and Resistance Exercise Training Improve Hypertension Associated With Menopause. AB - The prevalence of hypertension sharply increases in menopausal women. Recent studies have demonstrated that aerobic or resistance training may help control hypertension. In this study, we report that combining aerobic and resistance training may provide an effective therapeutic approach for hypertension control, attenuating inflammation and oxidative stress in ovariectomized rats. Female Wistar and spontaneous hypertensive rats (SHR) were distributed into four groups: sedentary control (C), sedentary hypertensive (HR), sedentary hypertensive ovariectomized (HR-O), and combined trained hypertensive ovariectomized (T-HR-O). Combined exercise training was performed on a motor treadmill (aerobic training) and on a ladder adapted to rats (resistance training), in alternate days for 8 weeks. Direct arterial pressure was recorded and oxidative stress and inflammation were evaluated in cardiac and renal tissue. Ovariectomy increases increased mean arterial blood pressure, sympathetic modulation, and oxidative stress in SHR. Combining aerobic and resistance training reduced mean arterial blood pressure (12% vs. HR-O), heart rate (8% vs. HR-O), vascular sympathetic modulation (40% vs. HR-O), and improved baroreflex sensitivity. Combined training reduced cardiac inflammation (TNF and IL-6) and cardiac and renal lipoperoxidation (59% and 57%, respectively vs. HR-O). It also enhanced cardiac (71%) and renal (76%) total antioxidant capacity when compared to HR-O group. In conclusion, combining aerobic and resistance training improves mean arterial blood pressure, cardiovascular autonomic control, preventing cardiac and renal oxidative stress and inflammation in an experimental hypertension model with surgical menopause induced with ovariectomy. PMID- 30420812 TI - Modular Control of Human Movement During Running: An Open Access Data Set. AB - The human body is an outstandingly complex machine including around 1000 muscles and joints acting synergistically. Yet, the coordination of the enormous amount of degrees of freedom needed for movement is mastered by our one brain and spinal cord. The idea that some synergistic neural components of movement exist was already suggested at the beginning of the 20th century. Since then, it has been widely accepted that the central nervous system might simplify the production of movement by avoiding the control of each muscle individually. Instead, it might be controlling muscles in common patterns that have been called muscle synergies. Only with the advent of modern computational methods and hardware it has been possible to numerically extract synergies from electromyography (EMG) signals. However, typical experimental setups do not include a big number of individuals, with common sample sizes of 5 to 20 participants. With this study, we make publicly available a set of EMG activities recorded during treadmill running from the right lower limb of 135 healthy and young adults (78 males and 57 females). Moreover, we include in this open access data set the code used to extract synergies from EMG data using non-negative matrix factorization (NMF) and the relative outcomes. Muscle synergies, containing the time-invariant muscle weightings (motor modules) and the time-dependent activation coefficients (motor primitives), were extracted from 13 ipsilateral EMG activities using NMF. Four synergies were enough to describe as many gait cycle phases during running: weight acceptance, propulsion, early swing, and late swing. We foresee many possible applications of our data that we can summarize in three key points. First, it can be a prime source for broadening the representation of human motor control due to the big sample size. Second, it could serve as a benchmark for scientists from multiple disciplines such as musculoskeletal modeling, robotics, clinical neuroscience, sport science, etc. Third, the data set could be used both to train students or to support established scientists in the perfection of current muscle synergies extraction methods. All the data is available at Zenodo (doi: 10.5281/zenodo.1254380). PMID- 30420813 TI - Long-Range Temporal Correlations of Patients in Minimally Conscious State Modulated by Spinal Cord Stimulation. AB - Spinal cord stimulation (SCS) has been shown to improve the consciousness levels of patients with disorder of consciousness (DOC). However, the underlying mechanisms of SCS remain poorly understood. This study recorded resting-state electroencephalograms (EEG) from 16 patients with minimally conscious state (MCS), before and after SCS, and investigated the mechanisms of SCS on the neuronal dynamics in MCS patients. Detrended fluctuation analysis (DFA), combined with surrogate data method, was employed to measure the long-range temporal correlations (LRTCs) of the EEG signals. A surrogate data method was utilized to acquire the genuine DFA exponents (GDFAE) reflecting the genuine LRTCs of brain activity. We analyzed the GDFAE in four brain regions (frontal, central, posterior, and occipital) at five EEG frequency bands [delta (1-4 Hz), theta (4-8 Hz), alpha (8-13 Hz), beta (13-30 Hz), and gamma (30-45 Hz)]. The GDFAE values ranged from 0.5 to 1, and showed temporal and spatial variation between the pre SCS and the post-SCS states. We found that the channels with GDFAE spread wider after SCS. This phenomenon may indicate that more cortical areas were engaged in the information integration after SCS. In addition, the GDFAE values increased significantly in the frontal area at delta, theta, and alpha bands after SCS. At the theta band, a significant increase in GDFAE was observed in the occipital area. No significant change was found at beta or gamma bands in any brain region. These findings show that the enhanced LRTCs after SCS occurred primarily at low frequency bands in the frontal and occipital regions. As the LRTCs reflect the long-range temporal integration of EEG signals, our results indicate that information integration became more "complex" after SCS. We concluded that the brain activities at low-frequency oscillations, particularly in the frontal and occipital regions, were improved by SCS. PMID- 30420814 TI - Metabolites Alterations in the Medial Prefrontal Cortex of Methamphetamine Users in Abstinence: A 1H MRS Study. AB - Background: The medial prefrontal cortex (mPFC) contains various neurotransmitter systems and plays an important role in drug use. Broad body of literature on how methamphetamine (MA) affects the structure and metabolism in the animal's mPFC is emerging, while the effects on metabolites of mPFC among human is still unclear. In this study, proton magnetic resonance spectroscopy (1H MRS) was used to measure metabolites of mPFC in methamphetamine dependent subjects. Methods: Sixty one subjects with a history of MA dependence (fulfiled the Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria) and 65 drug naive control subjects (age19-45) completed 1H MRS scans using 3.0T Siemens MRI scanner. Single voxel spectra were acquired from the mPFC bilaterally using a point resolved spectroscopy sequence (PRESS). The 1H MRS data were automatically fit with linear combination model for quantification of metabolite levels of n acetyl-aspartate (NAA), myo-inositol (mI), glycerophosphocholine plus phosphocholine(GPC+PC), phosphocreatine plus creatine (PCr+Cr), and glutamate (Glu). Metabolite levels were reported as ratios to PCr+Cr. Results: The MA group showed a significant reduction in NAA/PCr+Cr ratio and elevation in Glu/PCr+Cr ratio and mI/PCr+Cr ratio, compared with healthy control. No significant correlation was found between metabolite ratios and MA use variables. Conclusions: MA use is associated with a significant increased Glu/PCr+Cr ratio, mI/PCr+Cr ratio and reduced NAA/PCr+Cr ratio in the mPFC of MA dependence subjects. These findings suggest that Glu may play a key role in MA induced neurotoxicity. PMID- 30420815 TI - Psychotherapeutic Group Intervention for Traumatized Male Refugees Using Imaginative Stabilization Techniques-A Pilot Study in a German Reception Center. AB - Background: Due to persecution, human rights violations and armed conflicts, the prevalence of post-traumatic stress disorder (PTSD) is high in refugee populations. Previous studies indicate that trauma-focused treatments are highly effective in treating PTSD in refugees. However, these approaches rely on the stability of the therapeutic setting, treatment continuity, and safe housing. Although early treatment of PTSD is recommended, these requirements are not met in reception centers. Therefore, we conducted a pilot study to examine the effect of imaginative stabilization techniques derived from psychodynamic psychotraumatology therapy for the early stabilization of traumatized refugees in a reception center. Methods: From May 2017 to April 2018, 86 imaginative stabilization group therapy sessions have taken place. A sample of 43 out of 46 traumatized refugees completed self-report questionnaires assessing PTSD, depression, and anxiety symptoms prior to attending open imaginative stabilization group therapy sessions. Furthermore, participants filled in self report questionnaires on distress and emotional state (valence/arousal/dominance) before and after each session. After having participated in four consecutive sessions, a sub-group of 17 participants completed a follow-up assessment of PTSD, depression, and anxiety symptoms. Follow-up interviews were conducted with 25 participants 2 weeks after their last session attendance to explore self practice habits post intervention. Results: The pre-post-intervention comparison of scores indicated a significant reduction of distress (z = -3.35, p < 0.001, r = -0.51) and an improvement of affective reports for valence (z = -4.79, p < 0.001, r = -0.82) and dominance (z = -3.89, p < 0.001, r = -0.59), whereas arousal scores were not affected. We found a significant reduction of anxiety symptoms (z = -2.04, p < 0.05, r = -0.49), whereas PTSD and depression scores remained unchanged. Follow-up interviews revealed that 80% of the participants continued to practice the imaginative stabilization techniques after redistribution to other accommodation. Conclusion: The results indicate that imaginative stabilization techniques are a promising and feasible approach to treat refugees in unstable reception center settings. In regular imaginative stabilization group therapy sessions, we were able to reduce the participants' distress and anxiety symptoms while strengthening their internal resources and increasing their emotional stability. PMID- 30420816 TI - Widespread Genotype-Phenotype Correlations in Intellectual Disability. AB - Background: Linking genotype to phenotype is a major aim of genetics research, yet the underlying biochemical mechanisms of many complex conditions continue to remain elusive. Recent research provides evidence that relevant gene-phenotype associations are discoverable in the study of intellectual disability (ID). Here we expand on that work, identifying distinctive gene interaction modules with unique enrichment patterns reflective of associated clinical features in ID. Methods: Two hundred twelve forms of monogenic ID were curated according to comorbidities with autism and epilepsy. These groups were further subdivided according to secondary clinical manifestations of complex vs. simple facial dysmorphia and neurodegenerative-like features due to their clinical prominence, modest symptom overlap, and probable etiological divergence. An aggregate gene interaction ID network for these phenotype subgroups was discovered via a public database of known gene interactions: protein-protein, genetic, and mRNA coexpression. Additional annotation resources (Gene Ontology, Human Phenotype Ontology, TRANSFAC/JASPAR, and KEGG/WikiPathways) were utilized to assess functional and phenotypic enrichment patterns within subgroups. Results: Phenotypic analysis revealed high rates of complex facial dysmorphia in ID with comorbid autism. In contrast, neurodegenerative-like features were overrepresented in ID with epilepsy. Network analysis subsequently showed that gene groups divided according to clinical features of interest resulted in distinctive interaction clusters, with unique functional enrichments according to gene set. Conclusions: These data suggest that specific comorbid and secondary clinical features in ID are predictive of underlying genotype. In summary, ID form unique clusters, which are comprised of individual conditions with remarkable genotypic and phenotypic overlap. PMID- 30420817 TI - Executive Function and Spatial Cognition Mediate Psychosocial Dysfunction in Major Depressive Disorder. AB - Background: Cognitive and psychosocial dysfunction are prevalent and disabling features of Major Depressive Disorder (MDD). Emerging evidence suggests that poor cognitive functioning mediates the negative effect of MDD on psychosocial function. However, there is a lack of research examining the domain-specific nature of this relationship. The current study evaluated whether the relationship between MDD and specific psychosocial subdomains (e.g., autonomy, occupational functioning) was mediated by domain-specific cognitive deficits. Methods: Data from 155 participants was obtained from the Cognitive Function and Mood Study (CoFaMS), a cross-sectional analysis of mood, cognition, social cognition, and functioning in individuals with MDD. Cognitive functioning was assessed (Current MDD n = 45, Healthy n = 110), with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Colorado Assessment Tests (CATs), and the Psychology Experiment Building Language (PEBL). Psychosocial functioning was clinically evaluated with the Functioning Assessment Short Test (FAST). Results: The results indicated that spatial cognition and executive functioning partially mediated the negative effect of MDD on overall psychosocial functioning, autonomy, and subjective cognition. In contrast, spatial and executive domains showed divergent mediation patterns on interpersonal relationships and leisure time. Conclusions: The findings suggest that executive and spatial cognition play an important role in the pathology of overall psychosocial functioning, and specific functional issues in MDD. Treatments targeting psychosocial recovery in MDD may be improved by emphasizing executive and spatial cognitive remediation. PMID- 30420819 TI - Contingent National Belonging: The Perceived Fit and Acceptance of Culturally Different Peers Predicts Minority Adolescents' Own Belonging. AB - Prevailing definitions of national identities in Europe equate belonging to the nation with "fitting in" culturally and leave immigrant minorities who are culturally different from the majority group struggling to belong. The present study focuses on an under-researched minority perspective on the intersubjective cultural contents of the national identity. We propose that minorities' national belonging is contingent on their perception that minority peers who deviate from the majority culture are accepted as real nationals. Our study aims to establish (a) minority perceptions of the national fit and acceptance of culturally different peers, and to test (b) the consequences of perceived fit and acceptance for minority adolescents' own national belonging, and (c) its affordances by the local peer context. Drawing on a large random sample of 1,489 Moroccan and Turkish minority youth (aged 12-18) and their peers across 312 classes in 63 Belgian schools, we varied cultural difference from the majority in three vignettes describing imaginary acculturating peers. Minority participants rated to what extent they saw each peer as a real national (perceived fit) and whether other nationals would accept this peer (perceived acceptance). As a measure of their own national belonging, they indicated their national self-identification. Additionally, the multi-level design included classroom contextual measures of majority peer presence and peer acculturation norms (peer norm of heritage culture maintenance). As expected, minority youth who perceived better national fit of culturally different peers, self-identified more strongly as nationals than those who perceived worse fit. This association was not explained by their own acculturation attitudes. In line with the contextual affordance of national fit, only in classes with majority peers, minority youth perceived higher national fit and acceptance of culturally different peers when peer norms supported the maintenance of a distinct heritage culture. We conclude that the national belonging of minority youth is contingent on the peer context through the perceived fit and acceptance of culturally different peers. PMID- 30420818 TI - Relationship Between Shyness and Generalized Pathological Internet Use Among Chinese School Students: The Serial Mediating Roles of Loneliness, Depression, and Self-Esteem. AB - The present study aimed to explore the mediating effects of loneliness, depression, and self-esteem on the association between shyness and generalized pathological Internet use (GPIU). A total of 5215 school students completed questionnaires regarding shyness, loneliness, depression, self-esteem, and GPIU (aged 11-23 years old, M = 16.19, SD = 3.10). The self-reported scores for GPIU, shyness, loneliness, depression, and self-esteem were tested in students from elementary schools to universities. The results of a variance analysis indicated that senior high school students had the greatest prevalence of GPIU of all the study stages. With the study stages resolved, the results of a structural equation model revealed that: (a) shyness positively predicted GPIU; (b) shyness/loneliness/depression predicted GPIU through self-esteem; (c) shyness predicted GPIU through loneliness/depression -> self-esteem; and (d) shyness predicted GPIU through loneliness -> depression -> self-esteem. In conclusion, these results provided significant implications for preventing or reducing GPIU in Chinese school students. PMID- 30420820 TI - Effect of Volume in Resistance Training on Inhibitory Control in Young Adults: A Randomized and Crossover Investigation. AB - Purpose: The aim of the study is to compare the effect of resistance training volume on inhibitory control in young adults with previous experience in resistance training. Method: All the 27 participants underwent 40-week experiment, divided in three training phases of 8-week duration. A washout period of 8 weeks between each of the training phases was carried out. The participants performed 1, 3, or 5 sets of the same exercises with equalized intensity (loading zones) and rest. Inhibitory control was assessed by the Stroop Test. Results: Interaction effect was found for inhibitory control accuracy [F (5,22) = 56.88, p < 0.01] and mean response time [F (5,22) = 83.02, p < 0.01] for 3 sets (p = 0.01; ES = 0.6) and 5 sets (p = 0.01; ES = 0.8) when compared to 1 set. Conclusion: In conclusion, 1 set of resistance training may provide insufficient volume stimulus for positive adaptation in inhibitory control when compared to 3 or 5 sets. PMID- 30420821 TI - Stepovers and Signal Detection: Response Sensitivity and Bias in the Differentiation of Genuine and Deceptive Football Actions. AB - The ability to differentiate genuine and deceptive actions was examined using a combination of spatial and temporal occlusion to examine sensitivity to lower body, upper body, and full body sources of visual information. High-skilled and low-skilled association football players judged whether a player genuinely intended to take the ball to the participant's left or right or intended to step over the ball then take it in the other direction. Signal detection analysis was used to calculate measures of sensitivity (d') in differentiating genuine and deceptive actions and bias (c) toward judging an action to be genuine or deceptive. Analysis revealed that high-skilled players had higher sensitivity than low-skilled players and this was consistent across all spatial occlusion conditions. Low-skilled players were more biased toward judging actions to be genuine. Receiver Operating Characteristic (ROC) curves revealed that accuracy on deceptive trials in the lower body and full body conditions most accurately classified participants as high-skilled or low-skilled. The results highlight the value of using signal detection analysis in studies of deceptive actions. They suggest that information from the lower body or upper body was sufficient for differentiating genuine and deceptive actions and that global information concurrently derived from these sources was not necessary to support the expert advantage. PMID- 30420822 TI - Suppressing the Chills: Effects of Musical Manipulation on the Chills Response. AB - Research on musical chills has linked the response to multiple musical features; however, there exists no study that has attempted to manipulate musical stimuli to enable causal inferences, meaning current understanding is based mainly on correlational evidence. In the current study, participants who regularly experience chills (N = 24) listened to an original and manipulated version of three pieces reported to elicit chills in a previous survey. Predefined chills sections were removed to create manipulated conditions. The effects of these manipulations on the chills response were assessed through continuous self reports, and skin conductance measurements. Results show that chills were significantly less frequent following stimulus manipulation across all three pieces. Continuous measurements of chills intensity were significantly higher in the chills sections compared with control sections in the pieces; similar patterns were found for phasic skin conductance, although some differences emerged. Continuous measurements also correlated with psychoacoustic features such as loudness, brightness and roughness in two of the three pieces. Findings are discussed in terms of understanding structural and acoustic features and chills experiences within their local music contexts, the necessity of experimental approaches to musical chills, and the possibility of different features activating different underlying mechanisms. PMID- 30420824 TI - Are California Elementary School Test Scores More Strongly Associated With Urban Trees Than Poverty? AB - Unprecedented rates of urbanization are changing our understanding of the ways in which children build connections to the natural world, including the importance of educational settings in affecting this relationship. In addition to influencing human-nature connection, greenspace around school grounds has been associated with benefits to students' cognitive function. Questions remain regarding the size of this benefit relative to other factors, and which features of greenspace are responsible for these effects. We conducted a large-scale correlative study subsampling elementary schools (n = 495) in ecologically, socially and economically diverse California. After controlling for common educational determinants (e.g., socio-economic status, race/ethnicity, student teacher ratio, and gender ratio) we found a significant, positive association between test scores and tree and shrub cover within 750 and 1000 m of urban schools. Tree and shrub cover was not associated with test scores in rural schools or five buffers closer to urban schools (10, 50, 100, 300, and 500 m). Two other greenspace variables (NDVI and agricultural area) were not associated with test performance at any of the analyzed buffer distances for rural or urban schools. Minority representation had the largest effect size on standardized test scores (8.1% difference in scores with 2SD difference in variable), followed by tree and shrub cover around urban schools, which had a large effect size (2.9 3.0% at 750 and 1000 m) with variance from minority representation and socioeconomic status (effect size 2.4%) included. Within our urban sample, average tree-cover schools performed 4.2% (3.9-4.4, and 95% CI) better in terms of standardized test scores than low tree-cover urban schools. Our findings support the conclusion that neighborhood-scale (750-1000 m) urban tree and shrub cover is associated with school performance, and indicate that this element of greenspace may be an important factor to consider when studying the cognitive impacts of the learning environment. These results support the design of experimental tests of tree planting interventions for educational benefits. PMID- 30420823 TI - Predictors of Executive Functions in Preschoolers: Findings From the SPLASHY Study. AB - Executive functions (EFs) have been reported to play a crucial role in children's development, affecting their academic achievement, health, and quality of life. This study examined individual and interpersonal predictors for EFs in 555 typically developing preschool children aged 2-6 years. Children were recruited from 84 child care centers in the German- and French-speaking parts of Switzerland within the Swiss Preschoolers' Health Study (SPLASHY). A total of 20 potential predictors were assessed at the first measurement (T1). These included eight demographic/biological predictors, such as socioeconomic status, preterm birth, physical activity, and motor skills; six psychological predictors, such as hyperactivity, visual perception, and emotionality; and six interpersonal predictors, such as parenting style and stress, presence of siblings, and days spent in the child care center. The predictive value of these variables on EFs 1 year later (T2) was assessed using both standard multiple regression analysis and penalized regression to avoid overfitting due to the number of potential predictors. Female sex (beta = 0.14), socio-economic status (beta = 0.15), fine motor skills (beta = 0.17), visual perception at T1 (beta = 0.16), and EFs at T1 (beta = 0.30) were all associated with EFs at T2, exhibiting small to medium effect sizes. All predictors together accounted for 31% of the variability in EFs. However, none of the interpersonal predictors were significant. Thus, we conclude that most of the factors that can predict EFs in preschool age are individual variables, and these tend to be more difficult to influence than interpersonal factors. In fact, children from families with low socio-economic status may be particularly vulnerable to poor EFs. Furthermore, encouraging fine motor skills early in life may support the development of EFs. PMID- 30420825 TI - Expertise Moderates Incidentally Learned Associations Between Words and Images. AB - Individuals with expertise in a domain of knowledge demonstrate superior learning for information in their area of expertise, relative to non-experts. In this study, we investigated whether expertise benefits extend to learning associations between words and images that are encountered incidentally. Sport-knowledge experts and non-sports-experts encountered previously unknown faces through a basic perceptual task. The faces were incidentally presented as candidates for a position in a sports team (a focus of knowledge for only the sports-experts) or for a job in a business (a focus of knowledge for both the sports-experts and non sports-experts). Participants later received a series of surprise memory tests that tested: ability to recognize each face as being old, the amount of information recalled about each face, and ability to select a correct face from equally familiar alternatives. Relative to non-sports-experts, participants with superior sports expertise were able to better recall the information associated with each face and could better select associated faces from similarly familiar options for the hypothetical prospective athletes. Hypothetical job candidates were recalled and selected at similar levels of performance in both groups. The groups were similarly familiar with the images (in a yes/no recognition memory test) when the faces were prospective athletes or job candidates. These findings suggest a specific effect of expertise on associative memory between words and images, but not for individual items, supporting a dissociation in how expertise modulates the human memory system for word-image pairings. PMID- 30420826 TI - Current Treatment of Comorbid Insomnia and Obstructive Sleep Apnea With CBTI and PAP-Therapy: A Systematic Review. AB - Insomnia and obstructive sleep apnea (OSA) are often both present in patients with sleep-disordered-breathing (SDB). The coexistence of the two disorders shows an increase in cumulative morbidity and an overall greater illness severity. There is still considerable controversy regarding management decisions in this group of patients. This systematic review focused on more recent evidence regarding treatment of patients presenting with both clinical entities of comorbid insomnia and OSA (COMISA) in terms of their management, especially using combinations of positive airway pressure [PAP, namely aPAP, cPAP, adaptive servo ventilation (ASV)] and CBTi as well as each one of these two modalities alone. As a conclusion it is necessary to specifically target distinct combinations of both insomnia (initial, middle, late) and OSA (mild, moderate, severe) phenotypes. The present review gives reason to assume that both CBTi and PAP-therapy are necessary. However, it appears that distinct treatment patterns may suit different COMISA phenotypes. PMID- 30420827 TI - Motor Unit-Driven Identification of Pathological Tremor in Electroencephalograms. AB - Background: Traditional studies on the neural mechanisms of tremor use coherence analysis to investigate the relationship between cortical and muscle activity, measured by electroencephalograms (EEG) and electromyograms (EMG). This methodology is limited by the need of relatively long signal recordings, and it is sensitive to EEG artifacts. Here, we analytically derive and experimentally validate a new method for automatic extraction of the tremor-related EEG component in pathological tremor patients that aims to overcome these limitations. Methods: We exploit the coupling between the tremor-related cortical activity and motor unit population firings to build a linear minimum mean square error estimator of the tremor component in EEG. We estimated the motor unit population activity by decomposing surface EMG signals into constituent motor unit spike trains, which we summed up into a cumulative spike train (CST). We used this CST to initialize our tremor-related EEG component estimate, which we optimized using a novel approach proposed here. Results: Tests on simulated signals demonstrate that our new method is robust to both noise and motor unit firing variability, and that it performs well across a wide range of spectral characteristics of the tremor. Results on 9 essential (ET) and 9 Parkinson's disease (PD) patients show a ~2-fold increase in amplitude of the coherence between the estimated EEG component and the CST, compared to the classical EEG EMG coherence analysis. Conclusions: We have developed a novel method that allows for more precise and robust estimation of the tremor-related EEG component. This method does not require artifact removal, provides reliable results in relatively short datasets, and tracks changes in the tremor-related cortical activity over time. PMID- 30420828 TI - Comorbid Symptoms Occurring During Acute Low-Tone Hearing Loss (AHLH) as Potential Predictors of Meniere's Disease. AB - Acute low-tone sensorineural hearing loss (ALHL) is a type of idiopathic sudden sensorineural hearing loss. ALHL is rarely a solitary condition but rather co occurs with vertigo and tinnitus, being an element of contemporary diagnostic criteria for Meniere's disease (MD). The goal of our present study was to determine the value of ALHL for the early diagnosis of MD in patients presenting in the emergency room with ALHL as a main complaint. The files of 106 patients with ALHL who were admitted to the emergency room over the period of 7 years and 104 patients with acute high- tone sensorineural hearing loss (AHHL) from the same period were included in this retrospective study. Forty ALHL patients presented with recurrent episode of hearing loss and 66 remaining patients presented with ALHL for the first time. Of the latter group, 25 patients gave consent for the follow-up. First, we analyzed the difference in the occurrence of tinnitus and vertigo between the ALHL and AHHL groups. In patients with ALHL, the incidence of vertigo with tinnitus and the number of recurrent episodes were statistically higher than in patients with AHHL. Next, we focused on the ALHL follow-up group (25 patients). In that group, two patients had all MD symptoms at presentation, 18 had ALHL and tinnitus and five ALHL only. Of 18 patients with ALHL and tinnitus at admission, five developed vertigo and thus the triad of Meniere's disease. None of the five patients with AHLH as a sole symptom developed MD during the follow-up time but four of them have developed tinnitus. Patients with recurrent ALHL had significantly higher incidence of MD than the patients with first episode. We conclude that some patients who present with ALHL and concomitant tinnitus or have recurrent episodes of ALHL are more likely to develop Meniere's disease than these patients, who present with ALHL as a sole symptom. Nonetheless, we recommend otological follow-up for all patients presenting with ALHL. PMID- 30420829 TI - Sensitivity of Speech Output to Delayed Auditory Feedback in Primary Progressive Aphasias. AB - Delayed auditory feedback (DAF) is a classical paradigm for probing sensori-motor interactions in speech output and has been studied in various disorders associated with speech dysfluency and aphasia. However, little information is available concerning the effects of DAF on degenerating language networks in primary progressive aphasia: the paradigmatic "language-led dementias." Here we studied two forms of speech output (reading aloud and propositional speech) under natural listening conditions (no feedback delay) and under DAF at 200 ms, in a cohort of 19 patients representing all major primary progressive aphasia syndromes vs. healthy older individuals and patients with other canonical dementia syndromes (typical Alzheimer's disease and behavioral variant frontotemporal dementia). Healthy controls and most syndromic groups showed a quantitatively or qualitatively similar profile of reduced speech output rate and increased speech error rate under DAF relative to natural auditory feedback. However, there was no group effect on propositional speech output rate under DAF in patients with nonfluent primary progressive aphasia and logopenic aphasia. Importantly, there was considerable individual variation in DAF sensitivity within syndromic groups and some patients in each group (though no healthy controls) apparently benefited from DAF, showing paradoxically increased speech output rate and/or reduced speech error rate under DAF. This work suggests that DAF may be an informative probe of pathophysiological mechanisms underpinning primary progressive aphasia: identification of "DAF responders" may open up an avenue to novel therapeutic applications. PMID- 30420830 TI - Manual Dexterity and Aging: A Pilot Study Disentangling Sensorimotor From Cognitive Decline. AB - Manual dexterity measures can be useful for early detection of age-related functional decline and for prediction of cognitive decline. However, what aspects of sensorimotor function to assess remains unclear. Manual dexterity markers should be able to separate impairments related to cognitive decline from those related to healthy aging. In this pilot study, we aimed to compare manual dexterity components in patients diagnosed with cognitive decline (mean age: 84 years, N = 11) and in age comparable cognitively intact elderly subjects (mean age: 78 years, N = 11). In order to separate impairments due to healthy aging from deficits due to cognitive decline we also included two groups of healthy young adults (mean age: 26 years, N = 10) and middle-aged adults (mean age: 41 years, N = 8). A comprehensive quantitative evaluation of manual dexterity was performed using three tasks: (i) visuomotor force tracking, (ii) isochronous single finger tapping with auditory cues, and (iii) visuomotor multi-finger tapping. Results showed a highly significant increase in force tracking error with increasing age. Subjects with cognitive decline had increased finger tapping variability and reduced ability to select the correct tapping fingers in the multi-finger tapping task compared to cognitively intact elderly subjects. Cognitively intact elderly subjects and those with cognitive decline had prolonged force release and reduced independence of finger movements compared to young adults and middle-aged adults. The findings suggest two different patterns of impaired manual dexterity: one related to cognitive decline and another related to healthy aging. Manual dexterity tasks requiring updating of performance, in accordance with (temporal or spatial) task rules maintained in short-term memory, are particularly affected in cognitive decline. Conversely, tasks requiring online matching of motor output to sensory cues were affected by age, not by cognitive status. Remarkably, no motor impairments were detected in patients with cognitive decline using clinical scales of hand function. The findings may have consequences for the development of manual dexterity markers of cognitive decline. PMID- 30420831 TI - Vestibular Evoked Myogenic Potentials Are Abnormal in Idiopathic REM Sleep Behavior Disorder. AB - Objectives: To investigate brainstem function in idiopathic REM sleep Behavior Disorder (iRBD), a condition occurring as a result of a derangement of connections within brainstem structures, with a battery of Vestibular Evoked Myogenic Potentials (VEMPs), neurophysiological tools suited for the functional investigation of the brainstem. Neurophysiological data were correlated with clinical characteristics of patients. Methods: Twenty patients with iRBD and 22 healthy controls underwent cervical (cVEMP), masseter (mVEMP) and ocular (oVEMP) VEMP recording. Patients were assessed clinically according to presence of motor as well as non-motor symptoms such as constipation, depression, and hyposmia. Also, they were screened for postural instability through the Berg Balance Scale (BBS). VEMPs were categorized as for increasing degrees of abnormalities, namely latency delay, amplitude reduction and absence; a VEMP score was built accordingly. Results: Compared with controls, iRBD had higher rates of abnormalities both in the VEMP battery (iRBD 75%, Controls 23%; p < 0.01) as well as in each single VEMP (cVEMP: 45 vs. 5%; mVEMP: 65 vs. 13.6%; oVEMP: 50 vs. 5%; p < 0.01), which exhibited significantly lower amplitudes (cVEMP and oVEMP: p < 0.0001; mVEMP: p = 0.001) in iRBD. Within altered reflexes, absence was predominant in oVEMP (81%), amplitude reduction in mVEMP (50%) and cVEMP (70%). Severity of VEMP alterations was significantly higher in iRBD compared with controls (p < 0.05 for all VEMPs), as indicated by the larger VEMP scores in the former. The oVEMP score correlated inversely with poor performances on the BBS. Conclusion: VEMPs unveil consistent and extensive brainstem abnormalities in iRBD patients. Further studies are warranted for testing the potential of VEMPs in the monitoring of the evolution of iRBD over time. PMID- 30420832 TI - Oropharyngeal Muscle Exercise Therapy Improves Signs and Symptoms of Post-stroke Moderate Obstructive Sleep Apnea Syndrome. AB - The primary aim of the current study was to assess the effects of oropharingeal muscle exercises in obstruction severity on stroke patients with OSAS. The secondary aims were to evaluate the effects of the exercises on rehabilitation of neurological function, sleeping, and morphology change of upper airway. An open label, single-blind, parallel-group, randomized, controlled trial was designed. Fifty post-stroke patients with moderate OSAS were randomly assigned into 2 groups (25 in each group). For the therapy group, oropharyngeal muscle exercise was performed during the daytime for 20 min, twice a day, for 6 weeks. The control group was subjected to sham therapy of deep breathing. Primary outcomes were the obstruction severity by polysomnography. Secondary outcomes included recovery of motor and neurocognitive function, personal activities of daily living assessment (ADL), sleep quality and sleepiness scale. It also included upper airway magnetic resonance imaging (MRI) measurements. Assessments were made at baseline and after 6-week exercise. Finally, 49 patients completed the study. The apnea-hypopnea index, snore index, arousal index, and minimum oxygen saturation improved after exercise (P < 0.05). Oropharyngeal muscle exercises improved subjective measurements of sleep quality (P = 0.017), daily sleepiness (P = 0.005), and performance (both P < 0.05) except for neurocognition (P = 0.741). The changes in obstruction improvement, sleep characteristics and performance scale were also associated with training time, as detected by Pearson's correlation analysis. The anatomic structural remodeling of the pharyngeal airway was measured using MRI, including the lager retropalatal distance (P = 0.018) and shorter length of soft palate (P = 0.044) compared with the baseline. Hence, oropharyngeal muscle exercise is a promising alternative treatment strategy for stroke patients with moderate OSAS. Clinical Trial Registration: http://www.chictr.org.cn. Unique identifier: ChiCTR-IPR-16009970. PMID- 30420833 TI - Influence of Strategic Cortical Infarctions on Pupillary Function. AB - Objective: Cortical activity, including cognitive and emotional processes, may influence pupillary function. The exact pathways and the site of cortical pupillary innervation remain elusive, however. We investigated the effects of select cortical strokes, i.e. ischemic infarcts affecting the insular cortex and prefrontal eye field, on pupillary function. Methods: Seventy-four patients with acute ischemic stroke, consecutively admitted to our institution from March to July 2018, were assessed 24 h after endovascular recanalization therapy (i.e., day 2 after the stroke), using automated pupillometry. Stroke location and volume and clinical severity (estimated by the Alberta Stroke Program Early CT Score and National Institute of Health Stroke Scale) were recorded. We excluded patients with posterior circulation stroke, intracranial pathology other than ischemic stroke, midline shift on computed tomography exceeding 5 millimeters or a history of eye disease. Pupillometry data from 25 neurologically normal patients with acute myocardial infarction were acquired for control. Results: Fifty stroke patients after thrombectomy were included for analysis. Twenty-five patients (50%) had insular cortex or prefrontal eye field involvement (group 1, strategic infarcts); 25 patients had infarcts located in other cerebral areas (group 2, other infarcts). The pupillary light reflex, as measured by constriction velocity and maximal/minimal pupillary diameters, was within physiological limits in all patients, including controls. However, while pupillary size and constriction velocities were correlated in all subjects, the correlation of size and dilatation velocity was absent in right-hemispheric infarcts (left hemisphere infarcts, group 1 (r 2 = 0.15, p = 0.04), group 2 (r 2 = 0.41, p = 0.0007); right hemisphere infarcts, group 1 (r 2 = 0.008, p = 0.69); group 2 (r 2 = 0.12, p = 0.08); controls (r 2 = 0.29, p <= 0.0001). Conclusions: Cortical infarcts of the prefrontal eye field or insula do not impair the pupillary light reflex in humans. However, subtle changes may occur when the pupils dilate back to baseline, probably due to autonomic dysfunction. Replication is needed to explore the possible influence of hemispheric lateralization. We suggest that endovascular therapy for acute ischemic stroke may serve as a clinical research model for the study of acquired cortical lesions in humans. PMID- 30420834 TI - Identification of Cortical and Subcortical Correlates of Cognitive Performance in Multiple Sclerosis Using Voxel-Based Morphometry. AB - Objective: Cognitive impairment is an important feature in multiple sclerosis (MS) and has been associated to several Magnetic Resonance Imaging (MRI) markers, but especially brain atrophy. However, the relationship between specific neuropsychological tests examining several cognitive functions and brain volumes has been little explored. Furthermore, because MS frequently damage subcortical regions, it may be an interesting model to examine the role of subcortical areas in cognitive functioning. Our aim was to identify correlations between specific brain regions and performance in neuropsychological tests evaluating different cognitive functions in a large series of patients with MS. Methods: A total of 375 patients were evaluated with a comprehensive neuropsychological battery and with MRI. Voxel-based morphometry was conducted to analyse the correlation between cognitive performance and gray matter damage, using Statistical Parametric Mapping with the toolboxes VBM8 and Lesion Segmentation Tool. Results: The following correlations were found: Corsi block-tapping test with right insula; Trail Making Test with caudate nucleus, thalamus, and several cortical regions including the posterior cingulate and inferior frontal gyrus; Symbol Digit Modalities Test with caudate nucleus, thalamus, posterior cingulate, several frontal regions, insula, and cerebellum; Stroop Color and Word Test with caudate nucleus and putamen; Free and Cued Selective Reminding Test and Rey Osterrieth Complex Figure with thalamus, precuneus, and parahippocampal gyrus; Boston Naming Test with thalamus, caudate nucleus, and hippocampus; semantic verbal fluency with thalamus and phonological verbal fluency with caudate nucleus; and Tower of London test with frontal lobe, caudate nucleus, and posterior cingulate. Conclusion: Our study provides valuable data on the cortical and subcortical basis of cognitive function in MS. Neuropsychological tests mainly assessing attention and executive function showed a stronger association with caudate volume, while tests primarily evaluating memory were more strongly correlated with the thalamus. Other relevant regions were the posterior cingulate/precuneus, which were associated with attentional tasks, and several frontal regions, which were found to be correlated with planning and higher order executive functioning. Furthermore, our study supports the brain vertical organization of cognitive functioning, with the participation of the cortex, thalamus, basal ganglia, and cerebellum. PMID- 30420835 TI - Comparison of the Effect of Glycemic Control in Type 2 Diabetes Outpatients Treated With Premixed and Basal Insulin Monotherapy in China. AB - Background: Basal and premixed insulin have been widely used for insulin therapy of type 2 diabetes mellitus (T2DM) in China. The aim of this study is to compare the sustained efficacy of basal and premixed insulin therapies in T2DM outpatients with insulin monotherapy. Materials and Methods: The survey was conducted in 602 hospitals across China from April to June in 2013. The participants included outpatients who were receiving basal or premixed insulin monotherapy for more than 3 months, and the outcome was attaining a glycated hemoglobin A1C (HbA1c) of <7.0% as a measure of sustained glycemic control. Results: A total of 49,119 T2DM outpatients on basal (n = 11,967) or premixed insulin (n = 37,152) monotherapy were included in the final analyses. Using multivariable model analysis, patients using premixed insulin exhibited a better glycemic control, with more outpatients achieving the target HbA1c level than those using basal insulin (model 1, OR 0.695, 95%CI 0.664-0.728; model 2, OR 0.708, 95%CI 0.676-0.742; model 3, OR 0.717, 95%CI 0.684-0.752; model 4, OR 0.750, 95%CI 0.715-0.787). Using subgroup analysis stratified by age, sex, duration of diabetes, duration of insulin treatment, and complications, still more outpatients in every subgroup treated with premixed insulin achieved the target HbA1c (HbA1c < 7%) than those receiving basal insulin. Conclusions: Premixed insulin monotherapy had a better glycemic control (HbA1c < 7.0%) than basal insulin monotherapy for Chinese T2DM outpatients in daily. PMID- 30420837 TI - Vitamin A Promotes Leydig Cell Differentiation via Alcohol Dehydrogenase 1. AB - Vitamin A (retinol) is important for multiple functions in mammals. In testis, the role of vitamin A in the regulation of testicular functions is clearly involved in rodents. It is essential for sperm production. Vitamin A deficiency adversely affects testosterone secretion. Adult Leydig cells are responsible for testosterone production in male. The role of vitamin A in regulating the differentiation of Leydig cells is still unknown. In this study, we explored the roles and underlying mechanisms of vitamin A in Leydig cell differentiation. We found that vitamin A could regulate the Leydig cells differentiation. Leydig cell differentiation is adversely affected in mice maintained on a vitamin A-free diet. This effect is mediated by alcohol dehydrogenase 1 (ADH1). ADH1 could increase retinoic acid (RA) synthesis, then RA facilitates Leydig cell differentiation by activating the steroidogenic factor 1 gene (Nr5a1) promoter activity, which consequently promotes Leydig cell specific gene expression, resulting in progenitor Leydig cells differentiation into functional Leydig cells. This is the first study connecting a metabolic enzyme of retinol (ADH1) to the the regulation of Leydig cell differentiation, which will provide experimental evidence for the development of therapeutics to promote Leydig regeneration through the administration of a RA signaling regulator or a vitamin A supplement. PMID- 30420836 TI - Chronic O-GlcNAcylation and Diabetic Cardiomyopathy: The Bitterness of Glucose. AB - Type 2 diabetes (T2D) is a major risk factor for heart failure. Diabetic cardiomyopathy (DC) is characterized by diastolic dysfunction and left ventricular hypertrophy. Epidemiological data suggest that hyperglycaemia contributes to the development of DC. Several cellular pathways have been implicated in the deleterious effects of high glucose concentrations in the heart: oxidative stress, accumulation of advanced glycation end products (AGE), and chronic hexosamine biosynthetic pathway (HBP) activation. In the present review, we focus on the effect of chronic activation of the HBP on diabetic heart function. The HBP supplies N-acetylglucosamine moiety (O-GlcNAc) that is O-linked by O-GlcNAc transferase (OGT) to proteins on serine or threonine residues. This post-translational protein modification modulates the activity of the targeted proteins. In the heart, acute activation of the HBP in response to ischaemia reperfusion injury appears to be protective. Conversely, chronic activation of the HBP in the diabetic heart affects Ca2+ handling, contractile properties, and mitochondrial function and promotes stress signaling, such as left ventricular hypertrophy and endoplasmic reticulum stress. Many studies have shown that O GlcNAc impairs the function of key protein targets involved in these pathways, such as phospholamban, calmodulin kinase II, troponin I, and FOXO1. The data show that excessive O-GlcNAcylation is a major trigger of the glucotoxic events that affect heart function under chronic hyperglycaemia. Supporting this finding, pharmacological or genetic inhibition of the HBP in the diabetic heart improves heart function. In addition, the SGLT2 inhibitor dapagliflozin, a glucose lowering agent, has recently been shown to lower cardiac HBP in a lipodystophic T2D mice model and to concomitantly improve the diastolic dysfunction of these mice. Therefore, targeting cardiac-excessive O-GlcNAcylation or specific target proteins represents a potential therapeutic option to treat glucotoxicity in the diabetic heart. PMID- 30420838 TI - A Cross-Scale Neutral Theory Approach to the Influence of Obesity on Community Assembly of Human Gut Microbiome. AB - Background: The implications of gut microbiome to obesity have been extensively investigated in recent years although the exact mechanism is still unclear. The question whether or not obesity influences gut microbiome assembly has not been addressed. The question is significant because it is fundamental for investigating the diversity maintenance and stability of gut microbiome, and the latter should hold a key for understanding the etiological implications of gut microbiome to obesity. Methods: In this study, we adopt a dual neutral theory modeling strategy to address this question from both species and community perspectives, with both discrete and continuous neutral theory models. The first neutral theory model we apply is Hubbell's neutral theory of biodiversity that has been extensively tested in macro-ecology of plants and animals, and the second we apply is Sloan's neutral theory model that was developed particularly for microbial communities based on metagenomic sequencing data. Both the neutral models are complementary to each other and integrated together offering a comprehensive approach to more accurately revealing the possible influence of obesity on gut microbiome assembly. This is not only because the focus of both neutral theory models is different (community vs. species), but also because they adopted two different modeling strategies (discrete vs. continuous). Results: We test both the neutral theory models with datasets from Turnbaugh et al. (2009). Our tests showed that the species abundance distributions of more than 1/2 species (59-69%) in gut microbiome satisfied the prediction of Sloan's neutral theory, although at the community level, the number of communities satisfied the Hubbell's neutral theory was negligible (2 out of 278). Conclusion: The apparently contradictory findings above suggest that both stochastic neutral effects and deterministic environmental (host) factors play important roles in shaping the assembly and diversity of gut microbiome. Furthermore, obesity may just be one of the host factors, but its influence may not be strong enough to tip the balance between stochastic and deterministic forces that shape the community assembly. Finally, the apparent contradiction from both the neutral theories should not be surprising given that there are still near 30-40% species that do not obey the neutral law. PMID- 30420839 TI - Negative Control of RpoS Synthesis by the sRNA ReaL in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa (Pae) is an opportunistic human pathogen, able to resist host defense mechanisms and antibiotic treatment. In Pae, the master regulator of stress responses RpoS (sigmaS) is involved in the regulation of quorum sensing and several virulence genes. Here, we report that the sRNA ReaL translationally silences rpoS mRNA, which results in a decrease of the RpoS levels. Our studies indicated that ReaL base-pairs with the Shine-Dalgarno region of rpoS mRNA. These studies are underlined by a highly similar transcription profile of a rpoS deletion mutant and a reaL over-expressing strain. PMID- 30420841 TI - Exploring the Prokaryotic Community Associated With the Rumen Ciliate Protozoa Population. AB - Ciliate protozoa are an integral part of the rumen microbiome and were found to exert a large effect on the rumen ecosystem itself as well as their host animal physiology. Part of these effects have been attributed to their ability to harbor a diverse ecto- and endo-symbiotic community of prokaryotic cells. Studies on the relationship between the protozoa population and their associated prokaryotic community in the rumen mainly focused on the methanogens, revealing that protozoa play a major role in enhancing methanogenesis potential. In contrast, little is known about the composition and function of the bacteria associated with rumen protozoa and the extent of this association. In this study, we characterize the prokaryotic communities associated with different protozoa populations and compare their structure to the free-living prokaryotic population residing in the cow rumen. We show that the overall protozoa associated prokaryotic community structure differs significantly compared to the free-living community in terms of richness and composition. The methanogens proportion was significantly higher in all protozoa populations compared to the free-living fraction, while the Lachnospiraceae was the most prevalent bacterial family in the protozoa associated bacterial communities. Several taxa not detected or detected in extremely low abundance in the free-living community were enriched in the protozoa associated bacterial community. These include members of the Endomicrobia class, previously identified as protozoa symbionts in the termite gut. Our results show that rumen protozoa harbor prokaryotic communities that are compositionally different from their surroundings, which may be the result of specific tropism between the prokaryotic community and protozoa. PMID- 30420840 TI - Evolutionary History of Copper Membrane Monooxygenases. AB - Copper membrane monooxygenases (CuMMOs) oxidize ammonia, methane and some short chain alkanes and alkenes. They are encoded by three genes, usually in an operon of xmoCAB. We aligned xmo operons from 66 microbial genomes, including members of the Alpha-, Beta-, and Gamma-proteobacteria, Verrucomicrobia, Actinobacteria, Thaumarchaeota and the candidate phylum NC10. Phylogenetic and compositional analyses were used to reconstruct the evolutionary history of the enzyme and detect potential lateral gene transfer (LGT) events. The phylogenetic analyses showed at least 10 clusters corresponding to a combination of substrate specificity and bacterial taxonomy, but with no overriding structure based on either function or taxonomy alone. Adaptation of the enzyme to preferentially oxidize either ammonia or methane has occurred more than once. Individual phylogenies of all three genes, xmoA, xmoB and xmoC, closely matched, indicating that this operon evolved or was consistently transferred as a unit, with the possible exception of the methane monooxygenase operons in Verrucomicrobia, where the pmoB gene has a distinct phylogeny from pmoA and pmoC. Compositional analyses indicated that some clusters of xmoCAB operons (for example, the pmoCAB in gammaproteobacterial methanotrophs and the amoCAB in betaproteobacterial nitrifiers) were compositionally very different from their genomes, possibly indicating recent lateral transfer of these operons. The combined phylogenetic and compositional analyses support the hypothesis that an ancestor of the nitrifying bacterium Nitrosococcus was the donor of methane monooxygenase (pMMO) to both the alphaproteobacterial and gammaproteobacterial methanotrophs, but that before this event the gammaproteobacterial methanotrophs originally possessed another CuMMO (Pxm), which has since been lost in many species. PMID- 30420842 TI - Growth Enhancement of Probiotic Pediococcus acidilactici by Extractive Fermentation of Lactic Acid Exploiting Anion-Exchange Resin. AB - Fermentation employing lactic acid bacteria (LAB) often suffers end-product inhibition which reduces the cell growth rate and the production of metabolite. The utility of adsorbent resins for in situ lactic acid removal to enhance the cultivation performance of probiotic, Pediococcus acidilactici was studied. Weak base anion-exchange resin, Amberlite IRA 67 gave the highest maximum uptake capacity of lactic acid based on Langmuir adsorption isotherm (0.996 g lactic acid/g wet resin) compared to the other tested anion-exchange resins (Amberlite IRA 410, Amberlite IRA 400, Duolite A7 and Bowex MSA). The application of Amberlite IRA 67 improved the growth of P. acidilactici about 67 times compared to the control fermentation without resin addition. Nevertheless, the in situ addition of dispersed resin in the culture created shear stress by resins collision and caused direct shear force to the cells. The growth of P. acidilactici in the integrated bioreactor-internal column system containing anion exchange resin was further improved by 1.4 times over that obtained in the bioreactor containing dispersed resin. The improvement of the P. acidilactici growth indicated that extractive fermentation using solid phase is an effective approach for reducing by-product inhibition and increasing product titer. PMID- 30420844 TI - The Effect of Captivity on the Dynamics of Active Bacterial Communities Differs Between Two Deep-Sea Coral Species. AB - Microbes play a crucial role in sustaining the coral holobiont's functions and in particular under the pressure of environmental stressors. The effect of a changing environment on coral health is now a major branch of research that relies heavily on aquarium experiments. However, the effect of captivity on the coral microbiome remains poorly known. Here we show that different cold-water corals species have different microbiome responses to captivity. For both the DNA and the RNA fraction, Madrepora oculata bacterial communities were maintained for at least 6 months of aquarium rearing, while Lophelia pertusa bacteria changed within a day. Interestingly, bacteria from the genus Endozoicomonas, a ubiquitous symbiont of numerous marine hosts, were resilient and remained active in M. oculata for several months. Our results demonstrate that a good knowledge of the coral microbiome and an understanding of the ecological strategy of the holobiont is needed before designing aquarium experiments. PMID- 30420845 TI - Combining Different Potato-Associated Pseudomonas Strains for Improved Biocontrol of Phytophthora infestans. AB - Late blight caused by Phytophthora infestans is considered as the most devastating disease of potato and is a re-emerging problem worldwide. Current late blight control practices rely mostly on synthetic fungicides or copper-based products, but growing awareness of the negative impact of these compounds on the environment has led to the search for alternative control measures. A collection of Pseudomonas strains isolated from both the rhizosphere and the phyllosphere of potato was recently characterized for in vitro protective effects against P. infestans. In the present study, we used a leaf disk assay with three different potato cultivars to compare the disease inhibition capacity of nine selected Pseudomonas strains when applied alone or in all possible dual and triple combinations. Results showed a strong cultivar effect and identified strains previously thought to be inactive based on in vitro assays as the best biocontrol candidates. One strain was much more active alone than in combination with other strains, while two other strains provided significantly better protection in dual combination than when applied alone. A subset of five strains was then further selected to determine their mutual influence on each other's survival and growth, as well as to characterize their activity against P. infestans in more details. This revealed that the two strains whose dual combination was particularly efficient were only weakly interfering with each other's growth and had complementary modes of action. Our results highlight the potential to harness the crop's native rhizosphere and phyllosphere microbiome through re-assembling strains with differing modes of action into small communities, thereby providing more consistent protection than with the application of single strains. We consider this as a first step toward more elaborate microbiome management efforts, which shall be integrated into global strategies for sustainable control of potato late blight. PMID- 30420843 TI - Novel Ethanol- and 5-Hydroxymethyl Furfural-Stimulated beta-Glucosidase Retrieved From a Brazilian Secondary Atlantic Forest Soil Metagenome. AB - Beta-glucosidases are key enzymes involved in lignocellulosic biomass degradation for bioethanol production, which complete the final step during cellulose hydrolysis by converting cellobiose into glucose. Currently, industry requires enzymes with improved catalytic performance or tolerance to process-specific parameters. In this sense, metagenomics has become a powerful tool for accessing and exploring the biochemical biodiversity present in different natural environments. Here, we report the identification of a novel beta-glucosidase from metagenomic DNA isolated from soil samples enriched with decaying plant matter from a Secondary Atlantic Forest region. For this, we employed a functional screening approach using an optimized and synthetic broad host-range vector for library production. The novel beta-glucosidase - named Lfa2 - displays three GH3 family conserved domains and conserved catalytic amino acids D283 and E487. The purified enzyme was most active in pH 5.5 and at 50 degrees C, and showed hydrolytic activity toward several pNP synthetic substrates containing beta glucose, beta-galactose, beta-xylose, beta-fucose, and alpha-arabinopyranose, as well as toward cellobiose. Lfa2 showed considerable glucose tolerance, exhibiting an IC50 of 300 mM glucose and 30% of remaining activity in 600 mM glucose. In addition, Lfa2 retained full or slightly enhanced activity in the presence of several metal ions. Further, beta-glucosidase activity was increased by 1.7-fold in the presence of 10% (v/v) ethanol, a concentration that can be reached in conventional fermentation processes. Similarly, Lfa2 showed 1.7-fold enhanced activity at high concentrations of 5-hydroxymethyl furfural, one of the most important cellulase inhibitors in pretreated sugarcane bagasse hydrolysates. Moreover, the synergistic effect of Lfa2 on Bacillus subtilis GH5-CBM3 endoglucanase activity was demonstrated by the increased production of glucose (1.6-fold). Together, these results indicate that beta-glucosidase Lfa2 is a promissory enzyme candidate for utilization in diverse industrial applications, such as cellulosic biomass degradation or flavor enhancement in winemaking and grape processing. PMID- 30420846 TI - Nicotine Enhances Staphylococcus epidermidis Biofilm Formation by Altering the Bacterial Autolysis, Extracellular DNA Releasing, and Polysaccharide Intercellular Adhesin Production. AB - Staphylococcus epidermidis is a common bacterial colonizer of human skin and mucous membranes, yet it has emerged as an important nosocomial pathogen largely due to its ability to form biofilms. Tobacco smoke has been demonstrated as a contributor to various infection diseases by improving the biofilm formation of multiple bacterial species; however, the association between tobacco smoke and S. epidermidis biofilm is still unclear. In this study, we tested the effect of nicotine, one of the most active components of tobacco, on S. epidermidis biofilm formation, and we studied the underlying mechanisms. Our results showed that nicotine promoted the biofilm formation of S. epidermidis 1457 strain (SE1457) and enhanced its initial attachment to a polyethylene surface as well as polysaccharide intercellular adhesin (PIA) production. In addition, an increased extracellular DNA release and a higher autolysis rate of SE1457 was detected after nicotine treatment, which was consistent with the increased ratio of dead cells in nicotine-treated SE1457 biofilm observed with confocal laser-scanning microscopy. Furthermore, the effect of nicotine on several autolysis-related and biofilm-related gene knockout mutants of SE1457 was tested. It showed that in DeltasaeRS, DeltalytSR, and DeltasceD, nicotine induced increase in biofilm formation was similar to that in SE1457; but in DeltaarlRS, DeltaatlE, and DeltaicaC, the effect was obviously impaired. Consistently, the increase of the bacterial autolysis rate in DeltaarlRS and DeltaatlE induced by nicotine was not as significant as that in SE1457. Meanwhile, the growth inhibition of nicotine on SE1457 was observed, and it was much less on DeltaarlRS and restored by the arlRS complementation. The arlRS transcription in SE1457 was inhibited by nicotine during cultivation as indicated by a promoter reporter assay using green fluoresent protein. Taken together, our study indicates that nicotine improves S. epidermidis biofilm formation by promoting its initial attachment and intercellular accumulation; the arlRS, atlE, and ica genes mediating bacterial autolysis and PIA production play an important role in this process. PMID- 30420847 TI - Higher Prevalence of PldA, a Pseudomonas aeruginosa Trans-Kingdom H2-Type VI Secretion System Effector, in Clinical Isolates Responsible for Acute Infections and in Multidrug Resistant Strains. AB - Pseudomonas aeruginosa can manipulate eukaryotic host cells using secreted effectors delivered by the type III or the type VI Secretion Systems (T3SS and T6SS). The T3SS allows the injection of bacterial effectors (Exo toxins) into eukaryotic cell. P. aeruginosa, encodes three T6SSs, H1-, H2- and H3-T6SS. The H1 T6SS is mainly involved in delivering toxins to kill bacterial competitors. Recently, two T6SS-secreted phospholipases D, PldA (H2-T6SS) and PldB (H3-T6SS), were identified as trans-kingdom virulence effectors, triggering both killing of bacterial competitors and internalization into non-phagocytic cells. We deciphered the prevalence of T3SS and T6SS effectors encoding genes in 185 clinical isolates responsible for infections (septicaemia, pulmonary infections, urinary tract infections, and chronic infections in CF patients), 47 environmental strains, and on 33 carbapenemase-producers. We included 107 complete genomes of P. aeruginosa available in public databases. The prevalence of pldA is increased in clinical isolates responsible for severe acute infection and particularly in multi-drug resistant strains. In contrast, the pldB prevalence was high (96.8%) in all isolates. Regarding T3SS effectors, exoT and exoY are present in nearly all isolates while exoS and exoU were found to be exclusive with a higher prevalence of exoU + strains in severe acute infections. The hypervirulent exoU + isolates are more prone to be pldA +, suggesting a role of PldA in virulence. Finally, we observed that extremely drug resistant isolates producing an IMP-type carbapenemase were all pldA +. Our results suggest that PldA might have a role during pulmonary infections and have been co-selected in multidrug resistant strains particularly IMP-producers. PMID- 30420848 TI - The Cheese Matrix Modulates the Immunomodulatory Properties of Propionibacterium freudenreichii CIRM-BIA 129 in Healthy Piglets. AB - Propionibacterium freudenreichii is a beneficial bacterium, used as a cheese starter, which presents versatile probiotic properties. These properties are strain-dependent. We hypothesized they may also be delivery vehicle-dependent. In this study, we thus explored in healthy piglets how the cheese matrix affects the immunomodulatory properties of P. freudenreichii. During 2 weeks, three groups of weaned piglets consumed, respectively, P. freudenreichii as a liquid culture (PF culture), P. freudenreichii under the form of a cheese (PF-cheese), or a control sterile cheese matrix (Cheese-matrix). The in vivo metabolic activity of P. freudenreichii was assessed by determining short chain fatty acids (SCFA) concentration and bifidobacteria population in feces. Whatever the delivery vehicle, P. freudenreichii was metabolically active in piglets' colon and enhanced both bifidobacteria and SCFA in feces. P. freudenreichii consumption decreased the secretion of TNFalpha and of IL-10 by peripheral blood mononuclear cells (PBMC). It did not alter IL-10, IFNgamma, IL-17, and TNFalpha secretion in mesenteric lymph node immune cells (MLNC). PF-cheese enhanced significantly Treg phenotype, while PF-culture decreased significantly Th17 phenotype in PBMC and MLNC. Remarkably, only PF-cheese induced an increase of Th2 phenotype in PBMC and MLNC. Ex vivo stimulation of PBMC and MLNC by Lipopolysaccharides and Concanavalin A emphasized the difference in the immunomodulatory responses between PF-culture and PF-cheese group, as well as between PBMC and MLNC. This study shows the importance to consider the delivery vehicle for probiotic administration. It confirms the anti-inflammatory potential of P. freudenreichii. It opens new perspectives for the use propionibacteria-fermented products as preventive agents for inflammatory bowel diseases and intestinal infectious diseases. PMID- 30420849 TI - Drug Resistance in Toxoplasma gondii. AB - Toxoplasma gondii (T. gondii) is a global protozoan parasite infecting up to one third of the world population. Pyrimethamine (PYR) and sulfadiazine (SDZ) are the most widely used drugs for treatment of toxoplasmosis; however, several failure cases have been recorded as well; suggesting the existence of drug resistant strains. This review aims to give a systematic and comprehensive understanding of drug resistance in T. gondii including mechanisms of resistance and sites of drug action in parasite. Analogous amino acid substitutions in the Toxoplasma enzyme were identified to confer PYR resistance. Moreover, resistance to clindamycin, spiramycin, and azithromycin is encoded in the rRNA genes of T. gondii. However, T. gondii SDZ resistance mechanism has not been proved yet. Recently there has been a slight increase in SDZ resistance. That is why the majority of studies were carried out using SDZ. Six strains resistant to SDZ were found in clinical cases between 2013 and 2017 which among Brazilian T. gondii isolates, TgCTBr11, Ck3, and Pg1 were identified in human toxoplasmosis, as well as in livestock intended for human consumption. In conclusion, recent experimental studies in clinical cases have clearly shown that drug resistance in Toxoplasma is ongoing. Thus, establishing a more effective therapeutic scheme in the treatment of toxoplasmosis is critically needed. The emergence of T. gondii strains resistant to current drugs, reviewed here, represents a concern not only for treatment failure but also for increased clinical severity in immunocompromised patients. To improve the therapeutic outcome in patients, a greater understanding of the exact mechanisms of drug resistance in T. gondii should be developed. Thus, monitoring the presence of resistant parasites, in food products, would seem a prudent public health program. PMID- 30420850 TI - Exposure to Antibiotics Affects Saponin Immersion-Induced Immune Stimulation and Shift in Microbial Composition in Zebrafish Larvae. AB - In the last decades, pollution of the environment by large scale use of antibiotics in agriculture and human medicine have led to increased antimicrobial resistance in both the environment and the host animal microbiome. Disturbances in the host microbiome can result in impaired immunity and reduced resilience of aquaculture species. Here, we investigated whether environmentally measured levels of the commonly used antibiotics ciprofloxacin and oxytetracycline influences the host microbiome and susceptibility toward saponin-induced immune stimulation in larval zebrafish. Firstly, neutrophil and macrophage reporter zebrafish larvae were exposed to different concentrations of soy saponin by immersion. A dose-dependent increase in neutrophil presence in the intestinal area was observed together with increased expression of immune genes il1b, tnfa, il22 and mmp9. To investigate the effect of antibiotics, larval zebrafish were immersed in ciprofloxacin or oxytetracycline in the presence or absence of a low dose of saponin. In vivo imaging revealed that antibiotic treatment did not reduce the number of neutrophils that were recruited to the intestinal area upon saponin exposure, although it did tend to lower pro-inflammatory cytokine levels. Microbial sequencing of whole larvae revealed that exposure to a low dose of saponin already shifted the microbial composition. The combination of oxytetracycline and saponin significantly increased alpha-diversity compared to the controls. In conclusion, the current study provides evidence that the combination of low levels of antibiotics with low levels of anti-nutritional factors (saponin) can induce inflammatory phenotypes and can modify the microbiota, which might lead to altered disease susceptibility. PMID- 30420851 TI - Characterization of Bacterial Communities in Mexican Artisanal Raw Milk "Bola de Ocosingo" Cheese by High-Throughput Sequencing. AB - The dynamics of bacteria community of "Bola de Ocosingo" cheese, a Mexican artisanal raw milk cheese was investigated by high-throughput sequencing (454 pyrosequencing). Dairy samples (raw milk, curd, cheese at 50 and 110 days of ripening) were collected at dry (March-June) and rainy season (August-November) from three producers located in Chiapas, Mexico. In general, raw milk contained high bacterial diversity which was reduced throughout cheese manufacture. However, in two productions an important increase during cheese ripening was observed probably due to cross-contamination. Species such as Streptococcus thermophilus, Lactococcus lactis, Lactobacillus helveticus, L. delbrueckii and L. plantarum from which potential probiotic strains may be obtained, predominated during processing, varying its prevalence from one producer to another. Furthermore, low proportions of Escherichia coli/Shigella flexnerii were detected in almost all processes, however, could not be recovered by traditional methodology, indicating presence of non-cultivable cells. This work provides insights into bacteria communities of Bola de Ocosingo cheese for starter culture development, many of which are reported to provide health related benefits, and the usefulness of high-throughput sequencing to evidence cross-contamination during processing. PMID- 30420852 TI - Coinfection With Influenza A Virus and Klebsiella oxytoca: An Underrecognized Impact on Host Resistance and Tolerance to Pulmonary Infections. AB - Pneumonia is a world health problem and a leading cause of death, particularly affecting children and the elderly (1, 2). Bacterial pneumonia following infection with influenza A virus (IAV) is associated with increased morbidity and mortality but the mechanisms behind this phenomenon are not yet well-defined (3). Host resistance and tolerance are two processes essential for host survival during infection. Resistance is the host's ability to clear a pathogen while tolerance is the host's ability to overcome the impact of the pathogen as well as the host response to infection (4-8). Some studies have shown that IAV infection suppresses the immune response, leading to overwhelming bacterial loads (9-13). Other studies have shown that some IAV/bacterial coinfections cause alterations in tolerance mechanisms such as tissue resilience (14-16). In a recent analysis of nasopharyngeal swabs from patients hospitalized during the 2013-2014 influenza season, we have found that a significant proportion of IAV-infected patients were also colonized with Klebsiella oxytoca, a gram-negative bacteria known to be an opportunistic pathogen in a variety of diseases (17). Mice that were infected with K. oxytoca following IAV infection demonstrated decreased survival and significant weight loss when compared to mice infected with either single pathogen. Using this model, we found that IAV/K. oxytoca coinfection of the lung is characterized by an exaggerated inflammatory immune response. We observed early inflammatory cytokine and chemokine production, which in turn resulted in massive infiltration of neutrophils and inflammatory monocytes. Despite this swift response, the pulmonary pathogen burden in coinfected mice was similar to singly-infected animals, albeit with a slight delay in bacterial clearance. In addition, during coinfection we observed a shift in pulmonary macrophages toward an inflammatory and away from a tissue reparative phenotype. Interestingly, there was only a small increase in tissue damage in coinfected lungs as compared to either single infection. Our results indicate that during pulmonary coinfection a combination of seemingly modest defects in both host resistance and tolerance may act synergistically to cause worsened outcomes for the host. Given the prevalence of K. oxytoca detected in human IAV patients, these dysfunctional tolerance and resistance mechanisms may play an important role in the response of patients to IAV. PMID- 30420853 TI - Rheumatoid Arthritis Patients With Circulating Extracellular Vesicles Positive for IgM Rheumatoid Factor Have Higher Disease Activity. AB - Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that mainly affects synovial joints. Validated laboratory parameters for RA diagnosis are higher blood levels of rheumatoid factor IgM (IgM-RF), anti-citrullinated protein autoantibodies (ACPA), C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR). Clinical parameters used are the number of tender (TJC) and swollen joints (SJC) and the global patient visual analog score (VAS). To determine disease remission in patients a disease activity score (DAS28) can be calculated based on SJC, TJC, VAS, and ESR (or alternatively CRP). However, subtle and better predictive changes to follow treatment responses in individual patients cannot be measured by the above mentioned parameters nor by measuring cytokine levels in blood. As extracellular vesicles (EVs) play a role in intercellular communication and carry a multitude of signals we set out to determine their value as a biomarker for disease activity. EVs were isolated from platelet-free plasma of 41 RA patients and 24 healthy controls (HC) by size exclusion chromatography (SEC). We quantified the particle and protein concentration, using NanoSight particle tracking analysis and micro-BCA, respectively, and observed no differences between RA patients and HC. In plasma of 28 out of 41 RA patients IgM-RF was detectable by ELISA, and in 13 out of these 28 seropositive RA patients (RF+RA) IgM-RF was also detected on their isolated pEVs (IgM-RF+). In seronegative RA patients (RF-RA) we did not find any RF present on pEVs. When comparing disease parameters we found no differences between RF+RA and RF-RA patients, except for increased ESR levels in RF+RA patients. However, RF+RA patients with IgM-RF+ pEVs showed significantly higher levels of CRP and ESR and also VAS and DAS28 were significantly increased compared to RA+ patients without IgM-RF+ pEVs. This study shows for the first time the presence of IgM-RF on pEVs in a proportion of RF+RA patients with a higher disease activity. PMID- 30420854 TI - Hormonal Regulation of Physiology, Innate Immunity and Antibody Response to H1N1 Influenza Virus Infection During Pregnancy. AB - In 2009, the H1N1 swine flu pandemic highlighted the vulnerability of pregnant women to influenza viral infection. Pregnant women infected with influenza A virus were at increased risk of hospitalization and severe acute respiratory distress syndrome (ARDS), which is associated with high mortality, while their newborns had an increased risk of pre-term birth or low birth weight. Pregnant women have a unique immunological profile modulated by the sex hormones required to maintain pregnancy, namely progesterone and estrogens. The role of these hormones in coordinating maternal immunotolerance in uterine tissue and cellular subsets has been well researched; however, these hormones have wide-ranging effects outside the uterus in modulating the immune response to disease. In this review, we compile research findings in the clinic and in animal models that elaborate on the unique features of H1N1 influenza A viral pathogenesis during pregnancy, the crosstalk between innate immune signaling and hormonal regulation during pregnancy, and the role of pregnancy hormones in modulating cellular responses to influenza A viral infection at mid-gestation. We highlight the ways in which lung architecture and function is stressed by pregnancy, increasing baseline inflammation prior to infection. We demonstrate that infection disrupts progesterone production and upregulates inflammatory mediators, such as cyclooxygenase-2 (COX-2) and prostaglandins, resulting in pre-term labor and spontaneous abortions. Lastly, we profile the ways in which pregnancy alters innate and adaptive cellular immune responses to H1N1 influenza viral infection, and the ways in which these protect fetal development at the expense of effective long-term immune memory. Thus, we highlight advancements in the field of reproductive immunology in response to viral infection and illustrate how that knowledge might be used to develop more effective post-infection therapies and vaccination strategies. PMID- 30420857 TI - Pre-emptive Allogeneic Hematopoietic Stem Cell Transplantation in Ataxia Telangiectasia. AB - Ataxia telangiectasia (A-T) is a primary immunodeficiency with mutations in the gene encoding the A-T mutated (ATM) protein that interacts with immune, hematopoietic, and endocrine targets resulting in broad multi-systemic clinical manifestations with a devastating outcome. Apart from a progressive neurodegenerative disorder, A-T leads to significantly increased susceptibility to malignancies. It is a matter of discussion whether pre-emptive allogeneic hematopoietic stem cell transplantation (alloHSCT) using a reduced intensity conditioning regimen would be an option to restore immune-competence and prevent malignancy, as shown in animal models, because conventional treatment protocols of malignant diseases using radio- and/or chemotherapy have a high rate of therapy-related morbidity and mortality in these patients. We present the course of the disease, including immune reconstitution and neurological outcome following pre-emptive alloHSCT in a 4-year-old boy with A-T on a 6 year follow up. Our manuscript provides a proof-of-concept of alloHSCT as an individual pre emptive treatment strategy from which some A-T patients might benefit. PMID- 30420856 TI - Engineering CAR-T Cells for Improved Function Against Solid Tumors. AB - Genetic engineering T cells to create clinically applied chimeric antigen receptor (CAR) T cells has led to improved patient outcomes for some forms of hematopoietic malignancies. While this has inspired the biomedical community to develop similar strategies to treat solid tumor patients, challenges such as the immunosuppressive character of the tumor microenvironment, CAR-T cell persistence and trafficking to the tumor seem to limit CAR-T cell efficacy in solid cancers. This review provides an overview of mechanisms that tumors exploit to evade eradication by CAR-T cells as well as emerging approaches that incorporate genetic engineering technologies to improve CAR-T cell activity against solid tumors. PMID- 30420858 TI - Baseline Circulating Activated TFH and Tissue-Like Exhausted B Cells Negatively Correlate With Meningococcal C Conjugate Vaccine Induced Antibodies in HIV Infected Individuals. AB - Since 2006, meningococcal serogroup C (MenC) conjugate (MCC) vaccines have been supplied by the Brazilian government for HIV-infected children under 13 years old. For measuring protection against MenC, the serum bactericidal antibody (SBA) assay is the method of choice. The characterization of T follicular helper cells (TFH) cells has been an area of intensive study because of their significance in multiple human diseases and in vaccinology. The objective of this study was to characterize the phenotype of peripheral TFH cells and B cells and how they associated with each other and with SBA levels induced by vaccination as well as with serum cytokine levels of HIV-infected and non-infected children and adolescents. We found that CD27-IgD-CD21-CD38+ (exhausted B cells) as well as short-lived plasmablasts (CD27+IgD-CD21-CD38+) are increased in cART treated HIV patients and negatively associated with MCC vaccine induced SBA levels. Baseline frequency of activated peripheral TFH cells was a negative correlate for SBA response to MCC vaccine but positively correlated with circulating plasmablast frequency. Baseline IL4-levels positively associated with SBA response but showed a negative correlation with activated peripheral TFH cells frequency. The increased frequency of activated peripheral TFH cells found in non-responders to the vaccine implies that higher activation/differentiation of CD4 T cells within the lymph node is not necessarily associated with induction of vaccine responses. PMID- 30420855 TI - Targeting Chemokines and Chemokine Receptors in Melanoma and Other Cancers. AB - The tumor microenvironment is highly heterogeneous. It is composed of a diverse array of immune cells that are recruited continuously into lesions. They are guided into the tumor through interactions between chemokines and their receptors. A variety of chemokine receptors are expressed on the surface of both tumor and immune cells rendering them sensitive to multiple stimuli that can subsequently influence their migration and function. These features significantly impact tumor fate and are critical in melanoma control and progression. Indeed, particular chemokine receptors expressed on tumor and immune cells are strongly associated with patient prognosis. Thus, potential targeting of chemokine receptors is highly attractive as a means to quench or eliminate unconstrained tumor cell growth. PMID- 30420859 TI - A Low Frequency of IL-17-Producing CD8+ T-Cells Is Associated With Persistent Immune Activation in People Living With HIV Despite HAART-Induced Viral Suppression. AB - Immune activation is the hallmark of HIV infection, even in patients with highly active anti-retroviral therapy (HAART)-induced viral suppression. A major cause of immune activation during HIV infection is the intestinal microbial translocation as a consequence, among other factors, of the decrease and/or dysfunction of interleukin (IL)-17-producing T-cells, due to their role promoting the integrity of the intestinal barrier. A population of IL-17-producing CD8+ T cells (Tc17 cells), characterized by the expression of CD161, has been described, but its relation with the persistent immune activation in non-viremic people living with HIV (PLWH) on HAART is unclear. By flow cytometry, we characterized the activation phenotype (evaluated by the expression of HLA-DR and CD38) of circulating CD161-expressing CD8+ T-cells; in addition, we explored the functionality of polyclonally-stimulated Tc17 cells in PLWH under HAART-induced viral suppression, and in healthy individuals. Finally, we determined the association of Tc17 cells with the expression of cellular and soluble activation markers. Circulating CD161-expressing CD8+ T-cells were decreased in PLWH compared with healthy individuals, despite their similar basal activation state. After polyclonal stimulation, IL-17 production was higher in CD8+ T-cells co expressing HLA-DR and CD38 in healthy individuals. In contrast, although PLWH had a higher frequency of HLA-DR+ CD38+ CD8+ T-cells after stimulation, they had a lower production of IL-17. Interferon (IFN)-gamma-producing CD8+ T-cells (Tc1 cells) were increased in PLWH. The low Tc17 cells response was associated with a high expression of CD38 and programmed death 1 protein, high levels of soluble CD14 and the treatment duration. Finally, to explore potential immunomodulatory strategies, the in vitro effect of the anti-inflammatory agent sulfasalazine was assessed on Tc17 cells. Interestingly, a decreased inflammatory environment, death of activated CD8+ T-cells, and an increased frequency of Tc17 cells were observed with sulfasalazine treatment. Thus, our findings suggest that activated CD8+ T-cells have a marked capacity to produce IL-17 in healthy individuals, but not in PLWH, despite HAART. This dysfunction of Tc17 cells is associated with the persistent immune activation observed in these patients, and can be partially restored by anti-inflammatory agents. PMID- 30420860 TI - Divergent lncRNA GATA3-AS1 Regulates GATA3 Transcription in T-Helper 2 Cells. AB - Long non-coding RNAs (lncRNAs) possess a diverse array of regulatory functions including activation and silencing of gene transcription, regulation of splicing, and coordinating epigenetic modifications. GATA3-AS1 is a divergent lncRNA gene neighboring GATA3. GATA3 is considered the master regulator of TH2 lineage commitment enabling TH2 effector cells to efficiently transcribe genes encoding cytokines IL-4, IL-5, and IL-13. Here, we show that the GATA3-AS1 lncRNA is selectively expressed under TH2 polarizing conditions and is necessary for efficient transcription of GATA3, IL5, and IL13 genes, while being sufficient for GATA3 transcription. GATA3-AS1 is required for formation of permissive chromatin marks, H3K27 acetylation and H3K4 di/tri-methylation, at the GATA3-AS1-GATA3 locus. Further, GATA3-AS1 binds components of the MLL methyltransferase and forms a DNA-RNA hybrid (R-loop) thus tethering the MLL methyltransferase to the gene locus. Our results indicate a novel regulatory function for a divergent lncRNA and provide new insight into the function of lncRNAs in T helper cell differentiation. PMID- 30420861 TI - Nitrogen Distribution in Annual Growth of 'Italia' Table Grape Vines. AB - Little information is available about nitrogen (N) content and its concentration in table grape vines. Knowledge of the quantity of N accumulated by the vine organs during the season could support sustainable fertilization programs for table grape vineyards. The aim of the present study was to determine the N content and its concentration in different annual organs, including summer and winter pruning materials, clusters at harvest, and fallen leaves at post-harvest. Specifically, biomass and N were analyzed at six phenological growth stages (flowering, berry-set, berry growth, veraison, ripening, and harvest) from 2012 to 2015. Nitrogen concentration was highest (>40 g/kg d.w.) in the leaves of the secondary shoots at flowering, whereas values >30 g/kg were measured in the leaves of the primary shoots. Nitrogen concentration in the clusters at harvest was 5.3-7.6 g/kg with an accumulation of 18.6-25.4 g/vine in the seasons. The decrease of N content in the primary leaves after flowering indicated a remobilization toward the clusters, which acted as a stronger sink. Later in the season (veraison-ripening), leaves translocated N to permanent organs and primary stems. Pruned wood and fallen leaves accounted for the largest N removal from the vine after clusters, 6.0-7.9 and 9.2-10.2 g/vine, respectively. With regard of the vine annual biomass, the growth followed a sigmoidal model reaching 7300-7500 g of d.w./vine at harvest. Vine leaf area, including both primary and secondary leaves, peaked at veraison (17-21 m2). Vines accumulated ?35 g/vine of N at harvest, not considering the N removed with the intense summer pruning practices (?7 g/vine) and the fraction mobilized toward the storage organs (10-15 g/vine). The overall N required by the vine was around 50-55 g/vine, which corresponded to ?80 kg of N/ha in a vineyard with 1500 vines and a yield of 40 t/ha. Summer and winter pruning practices removed 29-31 g/vine of N which will be partly available (to be considered in the fertilization schedule) for the vine in the successive years if pruned residues were incorporated and mineralized in the soil. PMID- 30420862 TI - AlNAC4 Transcription Factor From Halophyte Aeluropus lagopoides Mitigates Oxidative Stress by Maintaining ROS Homeostasis in Transgenic Tobacco. AB - NAC proteins are a large family of plant-specific transcription factors which regulate both ABA-dependent and -independent gene expression. These transcription factors participate in biotic and abiotic stress-response through intricate regulation at transcriptional, post-transcriptional and post-translational levels. In the present study, AlNAC4 transcription factor was isolated from a salt excreting halophyte Aeluropus lagopoides. The AlNAC4 has an open reading frame of 936 bp, encoding a protein of 312 amino acid, with an estimated molecular mass of 34.9 kDa. The AlNAC4 showed close homology to monocot NACs in the phylogenetic tree. In silico analysis revealed that AlNAC4 possess the characteristic A-E subdomains within the NAC domain. The AlNAC4 showed sixteen post-translational phosphorylation sites. The AlNAC4 transcript was significantly upregulated with dehydration and H2O2 treatments, showing its role in osmotic and oxidative stress, respectively. The recombinant protein showed binding to mono as well as tandem repeats of NAC recognition sequence (NACRS) of the erd1 promoter. This is the first report mentioning that overexpression of AlNAC4 improved oxidative stress tolerance in tobacco transgenics. The transgenics maintained ROS homeostasis during H2O2 treatment. The transgenics showed regulation of stress responsive genes including CAT, SOD, LEA5, PLC3, ERD10B, THT1 and transcription factors like AP2, ZFP during oxidative stress. Key Message: The AlNAC4 transcription factor from recretohalophyte Aeluropus showed regulation with abiotic stresses and binding to NACRS elements of erd1 promoter. The AlNAC4 tobacco transgenics showed improved growth with oxidative stress. PMID- 30420863 TI - Novel Avenues for Plant Protection: Plant Propagation by Somatic Embryogenesis Enhances Resistance to Insect Feeding. AB - Somatic embryogenesis (SE), a clonal propagation method utilizing somatic cells, occurs under conditions that activate plant stress adaptation mechanisms such as production of protective secondary metabolites. Surprisingly, possible differences in susceptibility to insect pests between SE-generated and conventionally cultivated plants have not been previously explored. Here, we recorded frequencies and levels of bark-feeding damage by pine weevils (Hylobius abietis) in two large field trials, consisting of emblings (SE-propagated plants) and seedlings from 50 half-sib Norway spruce (Picea abies) families. We found that emblings were less frequently attacked by pine weevils, and when attacked, they were damaged to a lesser extent than seedlings. Moreover, we detected significant additive genetic variation in damage levels received by plants, indicating a heritable component to differences in resistance to insect herbivory among half-sib families. We present first-time evidence that emblings can be more resistant than seedlings to herbivorous insect damage, thus, SE appears to confer a previously unknown plant protection advantage. This finding indicates novel avenues to explore mechanisms underlying plant resistance and new approaches to develop non-toxic measures against insect pests. PMID- 30420865 TI - Detection of T. urartu Introgressions in Wheat and Development of a Panel of Interspecific Introgression Lines. AB - Tritcum urartu (2n = 2x = 14, AuAu), the A genome donor of wheat, is an important source for new genetic variation for wheat improvement due to its high photosynthetic rate and disease resistance. By facilitating the generation of genome-wide introgressions leading to a variety of different wheat-T. urartu translocation lines, T. urartu can be practically utilized in wheat improvement. Previous studies that have generated such introgression lines have been unable to successfully use cytological methods to detect the presence of T. urartu in these lines. Many have, thus, used a variety of molecular markers with limited success due to the low-density coverage of these markers and time-consuming nature of the techniques rendering them unsuitable for large-scale breeding programs. In this study, we report the generation of a resource of single nucleotide polymorphic (SNP) markers, present on a high-throughput SNP genotyping array, that can detect the presence of T. urartu in a hexaploid wheat background making it a potentially valuable tool in wheat pre-breeding programs. A whole genome introgression approach has resulted in the transfer of different chromosome segments from T. urartu into wheat which have then been detected and characterized using these SNP markers. The molecular analysis of these wheat-T. urartu recombinant lines has resulted in the generation of a genetic map of T. urartu containing 368 SNP markers, spread across all seven chromosomes of T. urartu. Comparative analysis of the genetic map of T. urartu and the physical map of the hexaploid wheat genome showed that synteny between the two species is highly conserved at the macro-level and confirmed the presence of the 4/5 translocation in T. urartu also present in the A genome of wheat. A panel of 17 wheat-T. urartu recombinant lines, which consisted of introgressed segments that covered the whole genome of T. urartu, were also selected for self-fertilization to provide a germplasm resource for future trait analysis. This valuable resource of high-density molecular markers specifically designed for detecting wild relative chromosomes and a panel of stable interspecific introgression lines will greatly enhance the efficiency of wheat improvement through wild relative introgressions. PMID- 30420864 TI - A Critical Assessment of 60 Years of Maize Intragenic Recombination. AB - Until the mid-1950s, it was believed that genetic crossovers did not occur within genes. Crossovers occurred between genes, the "beads on a string" model. Then in 1956, Seymour Benzer published his classic paper describing crossing over within a gene, intragenic recombination. This result from a bacteriophage gene prompted Oliver Nelson to study intragenic recombination in the maize Waxy locus. His studies along with subsequent work by others working with maize and other organisms described the outcomes of intragenic recombination and provided some of the earliest evidence that genes, not intergenic regions, were recombination hotspots. High-throughput genotyping approaches have since replaced single gene intragenic studies for characterizing the outcomes of recombination. These large scale studies confirm that genes, or more generally genic regions, are the most active recombinogenic regions, and suggested a pattern of crossovers similar to the budding yeast Saccharomyces cerevisiae. In S. cerevisiae recombination is initiated by double-strand breaks (DSBs) near transcription start sites (TSSs) of genes producing a polarity gradient where crossovers preferentially resolve at the 5' end of genes. Intragenic studies in maize yielded less evidence for either polarity or for DSBs near TSSs initiating recombination and in certain respects resembled Schizosaccharomyces pombe or mouse. These different perspectives highlight the need to draw upon the strengths of different approaches and caution against relying on a single model system or approach for understanding recombination. PMID- 30420866 TI - Transpiration Response of Cotton to Vapor Pressure Deficit and Its Relationship With Stomatal Traits. AB - Many studies have demonstrated that the cotton in warm environments is vulnerable to water-limitations thus reducing the yield. A number of plant traits have been recommended to ameliorate the effects of water deficits on plant growth and yield. Limitation on maximum transpiration rate (TR) under high vapor pressure deficit (VPD), usually occurs during midday, is often considered as a water conservation trait. The genotypes with this trait are desirable in high VPD environments where water deficits commonly develop in the later part of the growing season. Our objective of the study was to find the genotypic variation for the trait limited TR under high VPD and also to study leaf temperature, water potential, photosynthesis, and stomatal conductance responses. Also, our objective was also to study the structural changes in the stomatal traits when exposed to long term high VPD conditions and involvement in such responses. In the present study, 17 cotton genotypes were studied for their (TR) response to various VPD environments under well irrigated conditions. Out of 17, eight genotypes limited TR after approximately 2 kPa VPD and rest of them increased their TR with increased VPD. Five selected genotypes with different TR response to increasing VPD were further studied for gas exchange and stomatal properties. All genotypes, irrespective of exhibiting limited TR at high VPD, reduced stomatal conductance, photosynthesis and water potential at high VPD of 3.3 kPa. The genotypes with limited TR modified their stomatal traits mostly on the adaxial surface with frequent and small stomata under high VPD. The genotypes with limited TR also exhibited an increase in epidermal cell expansion and stomatal index at contrasting VPD gradients to effectively balance the liquid and vapor phase conductance to limit TR at high VPD. PMID- 30420867 TI - How to Evolve a Perianth: A Review of Cadastral Mechanisms for Perianth Identity. AB - The flower of angiosperms is considered to be a major evolutionary innovation that impacted the whole biome. In particular, two properties of the flower are classically linked to its ecological success: bisexuality and a differentiated perianth with sepals and petals. Although the molecular basis for floral organ identity is well understood in extant species and summarized in the famous ABC model, how perianth identity appeared during evolution is still unknown. Here we propose that cadastral mechanisms that maintain reproductive organ identities to the center of the flower could have supported perianth evolution. In particular, repressing B- and C-class genes expression toward the inner whorls of the flower, is a key process to isolate domains with sepal and petal identity in the outer whorls. We review from the literature in model species the diverse regulators that repress B- and C-class genes expression to the center of the flower. This review highlights the existence of both unique and conserved repressors between species, and possible candidates to investigate further in order to shed light on perianth evolution. PMID- 30420868 TI - Understanding Synergistic Toxicity of Terpenes as Insecticides: Contribution of Metabolic Detoxification in Musca domestica. AB - Essential oils, which are mixtures of terpenes, frequently show stronger insecticide activity, i.e., lower lethal dose 50 (LC50), than their most abundant terpenes. Synergy between terpenes provides a plausible explanation, but its demonstration has been elusive. In the present work, we look for an alternative explanation, by considering the influence of insect metabolic detoxification. Basically, we propose a model (metabolic model, MM) in which the LC50 of the major terpene in a mixture is expected to include a fraction that is detoxified by the insect, whereas a minor terpene would act unimpeded, showing a lower LC50 than when acting alone. In order to test this idea, we analyzed the effects of inhibiting the cytochrome P450 detoxification system with piperonyl butoxide (PBO), on the lethal concentration of terpenes as fumigants against Musca domestica. We found that, within a group of 10 terpenes [linalool, citronellal, (R)-alpha-pinene, 1,8-cineole, gamma-terpinene, limonene, alpha-terpinene, (S) beta-pinene, thymol and (R)-pulegone], seven showed the LC50PBO (the lethal concentration for PBO-treated flies) between 1.7 and 12.4 times lower than the corresponding LC50 when P450 was not inhibited. Only in one case, that of (R) pulegone, was the LC50PBO greater than the LC50, while two terpenes [(S)-beta pinene and thymol] showed no changes in toxicity. The increased activity of most terpenes (particularly linalool and citronellal) in PBO-treated flies supports our hypothesis that normally the LC50 includes a fraction of inactive compound, due to detoxification. Having previously determined that M. domestica preferentially oxidizes the most abundant terpene in a mixture, while terpenes in smaller proportions are poorly or not detoxified by the P450 system, we assessed whether the toxicity of minority terpenes in a mixture is similar to their activity under P450 inhibition. We chose suitable binary combinations in such a way that one terpene (in greater proportion) should be the target of P450 while the other (in smaller proportion) should intoxicate the fly with LC50PBO or similar. Combinations of 1,8-cineole-citronellal, 1,8-cineole-linalool, linalool citronellal, (R)-pulegone-linalool, (R)-pulegone-1,8-cineole and (R)-pulegone citronellal were assayed against M. domestica, and the LC50 of each mixture was determined and compared to values predicted by MM (considering the LC50PBO for minor component) or by the classical approach (LC50 for both components). The MM showed the best fit to the data, suggesting additive rather than synergistic effects, except for the combination of (R)-pulegone-citronellal that was clearly synergistic. Thus, the experimental data indicate that the insect preferentially oxidizes the major component in a mixture, while the terpene in lesser proportion acts as a toxicant, with higher toxicity than when it was assayed alone. These findings contribute to a deeper understanding of the higher toxicity of essential oils compared to their component terpenes and provide important information for the design of effective insecticides based on essential oils or terpenes. PMID- 30420869 TI - Methadone Dosage and Plasma Levels, SNPs of OPRM1 Gene and Age of First Drug Use Were Associated With Outcomes of Methadone Maintenance Treatment. AB - Objective: To explore the association between methadone dosage, plasma drug concentration, SNPs of MU-opioid receptor gene (OPRM1), ATP-binding cassette subfamily B member 1 gene (ABCB1), and methadone maintenance treatment (MMT) response. Method: A total of 240 Chinese Han participants receiving MMT were recruited from Shanghai. Nine single nucleotide polymorphisms (SNPs) of the OPRM1 gene and three SNPs of the ABCB1 gene were genotyped, plasma methadone concentration was detected, and a morphine urine test was taken from all subjects. Results: Methadone dosage, plasma methadone concentration, and negative rate of morphine urine test of retention participants were significantly higher, although the addiction severity index (ASI) was not significantly different between the two groups. A allele and AA genotype carriers of rs562859 (OPRM1 gene) had better compliance of MMT, and AA genotype carriers had a higher negative rate of morphine urine test. However, the difference was not significant after adjusting influence factors (age, sex, and methadone dosage). GG genotype carriers of rs3192723 (OPRM1 gene) had a significantly lower negative rate of morphine urine test, and the difference was still significant after adjusting influence factors. Logistic regression analysis showed that methadone-free trough concentration (OR = 0.910, p = 0.023) and AA genotype of rs526859 (OR = 0.580, p = 0.037) were associated with better compliance of MMT. After Bonferroni correction, only free trough concentration of methadone was negatively correlated with MMT compliance. The SNPs rs6912029 (OR = 0.021, p = 0.066) and rs6902403 (OR = 0.910, p = 0.007) of the OPRM1 gene, age at first use (OR = 1.118, p = 0.005), and average methadone dosage (OR = 1.033, p = 0.045) were associated with MMT effect. After Bonferroni correction, average methadone dosage was no longer correlated with MMT effect. Conclusion: Dosage of methadone, plasma methadone concentration, several SNPs (rs3192723, rs6912029, rs6902403) of the OPRM1 gene, and age of first drug use were associated with better MMT outcomes. PMID- 30420870 TI - A Comparison of the TempO-Seq S1500+ Platform to RNA-Seq and Microarray Using Rat Liver Mode of Action Samples. AB - The TempO-SeqTM platform allows for targeted transcriptomic analysis and is currently used by many groups to perform high-throughput gene expression analysis. Herein we performed a comparison of gene expression characteristics measured using 45 purified RNA samples from the livers of rats exposed to chemicals that fall into one of five modes of action (MOAs). These samples have been previously evaluated using AffymetrixTM rat genome 230 2.0 microarrays and Illumina(r) whole transcriptome RNA-Seq. Comparison of these data with TempO-Seq analysis using the rat S1500+ beta gene set identified clear differences in the platforms related to signal to noise, root mean squared error, and/or sources of variability. Microarray and TempO-Seq captured the most variability in terms of MOA and chemical treatment whereas RNA-Seq had higher noise and larger differences between samples within a MOA. However, analysis of the data by hierarchical clustering, gene subnetwork connectivity and biological process representation of MOA-varying genes revealed that the samples clearly grouped by treatment as opposed to gene expression platform. Overall these findings demonstrate that the results from the TempO-Seq platform are consistent with findings on other more established approaches for measuring the genome-wide transcriptome. PMID- 30420871 TI - Newborn Screening and Molecular Profile of Congenital Hypothyroidism in a Chinese Population. AB - To review the characteristics of newborn screening of congenital hypothyroidism (CH), we reviewed the newborn screening data, including the levels of blood spot thyroid-stimulating hormone (TSH), and serum TSH and free thyroxine (FT4), of all newborn infants who accepted the newborn screening program during the last 14 years. In total, 437,342 newborn infants underwent CH screening and 192 infants were diagnosed with CH and the incidence of CH was 1:2278. The positive rate of the initial screening was 0.96%, and the positive predictive value was 4.8%. We also designed a target sequencing panel including 13 causative genes: DUOX2, TG, TPO, TSHR, TTF1, TTF2, PAX8, NKX2-5, GNAS, THRA, TSHB, IYD and SLC5A5, to identify the spectrum and prevalence of disease-causing gene mutations in Chinese CH patients. CH-causing genes were detected by targeted next-generation sequencing in 106 CH infants. A total of 132 mutations were identified in 69 cases (65.1%). Of these 132 mutations, 92 (69.70%), 28 (21.21%), and 12 (9.09%) were related to thyroid dyshormonogenesis, thyroid dysgenesis, and thyrotropin resistance, respectively. Mutations in CH-causing genes were found mainly in DUOX2, TG and TSHR, and DUOX2 is the most gene mutation in Chinese CH patients. PMID- 30420873 TI - Biogenic Synthesis of Copper and Silver Nanoparticles Using Green Alga Botryococcus braunii and Its Antimicrobial Activity. AB - The spread of infectious diseases and the increase in the drug resistance among microbes has forced the researchers to synthesize biologically active nanoparticles. Improvement of the ecofriendly procedure for the synthesis of nanoparticles is growing day-by-day in the field of nanobiotechnology. In the present study, we use the extract of green alga Botryococcus braunii for the synthesis of copper and silver nanoparticles. The characterization of copper and silver nanoparticles was carried out by using UV-Vis spectroscopy, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and scanning electron spectroscopy (SEM). FTIR measurements showed all functional groups having control over reduction and stabilization of the nanoparticles. The X-ray diffraction pattern revealed that the particles were crystalline in nature with a face-centred cubic (FCC) geometry. SEM micrographs have shown the morphology of biogenically synthesized metal nanoparticles. Furthermore, these biosynthesized nanoparticles were found to be highly toxic against two Gram-negative bacterial strains Pseudomonas aeruginosa (MTCC 441) and Escherichia coli (MTCC 442), two Gram-positive bacterial strains Klebsiella pneumoniae (MTCC 109) and Staphylococcus aureus (MTCC 96), and a fungal strain Fusarium oxysporum (MTCC 2087). The zone of inhibition was measured by the agar well plate method, and furthermore, minimum inhibitory concentration was determined by the broth dilution assay. PMID- 30420875 TI - A Two-Step Neural Dialog State Tracker for Task-Oriented Dialog Processing. AB - Dialog state tracking in a spoken dialog system is the task that tracks the flow of a dialog and identifies accurately what a user wants from the utterance. Since the success of a dialog is influenced by the ability of the system to catch the requirements of the user, accurate state tracking is important for spoken dialog systems. This paper proposes a two-step neural dialog state tracker which is composed of an informativeness classifier and a neural tracker. The informativeness classifier which is implemented by a CNN first filters out noninformative utterances in a dialog. Then, the neural tracker estimates dialog states from the remaining informative utterances. The tracker adopts the attention mechanism and the hierarchical softmax for its performance and fast training. To prove the effectiveness of the proposed model, we do experiments on dialog state tracking in the human-human task-oriented dialogs with the standard DSTC4 data set. Our experimental results prove the effectiveness of the proposed model by showing that the proposed model outperforms the neural trackers without the informativeness classifier, the attention mechanism, or the hierarchical softmax. PMID- 30420874 TI - Control of a Robot Arm Using Decoded Joint Angles from Electrocorticograms in Primate. AB - Electrocorticogram (ECoG) is a well-known recording method for the less invasive brain machine interface (BMI). Our previous studies have succeeded in predicting muscle activities and arm trajectories from ECoG signals. Despite such successful studies, there still remain solving works for the purpose of realizing an ECoG based prosthesis. We suggest a neuromuscular interface to control robot using decoded muscle activities and joint angles. We used sparse linear regression to find the best fit between band-passed ECoGs and electromyograms (EMG) or joint angles. The best coefficient of determination for 100 s continuous prediction was 0.6333 +/- 0.0033 (muscle activations) and 0.6359 +/- 0.0929 (joint angles), respectively. We also controlled a 4 degree of freedom (DOF) robot arm using only decoded 4 DOF angles from the ECoGs in this study. Consequently, this study shows the possibility of contributing to future advancements in neuroprosthesis and neurorehabilitation technology. PMID- 30420876 TI - Aberrances of Cortex Excitability and Connectivity Underlying Motor Deficit in Acute Stroke. AB - Purpose: This study was aimed at evaluating the motor cortical excitability and connectivity underlying the neural mechanism of motor deficit in acute stroke by the combination of functional magnetic resonance imaging (fMRI) and electrophysiological measures. Methods: Twenty-five patients with motor deficit after acute ischemic stroke were involved. General linear model and dynamic causal model analyses were applied to fMRI data for detecting motor-related activation and effective connectivity of the motor cortices. Motor cortical excitability was determined as a resting motor threshold (RMT) of motor evoked potential detected by transcranial magnetic stimulation (TMS). fMRI results were correlated with cortical excitability and upper extremity Fugl-Meyer assessment scores, respectively. Results: Greater fMRI activation likelihood and motor cortical excitability in the ipsilesional primary motor area (M1) region were associated with better motor performance. During hand movements, the inhibitory connectivity from the contralesional to the ipsilesional M1 was correlated with the degree of motor impairment. Furthermore, ipsilesional motor cortex excitability was correlated with an enhancement of promoting connectivity in ipsilesional M1 or a reduction of interhemispheric inhibition in contralesional M1. Conclusions: The study suggested that a dysfunction of the ipsilesional M1 and abnormal interhemispheric interactions might underlie the motor disability in acute ischemic stroke. Modifying the excitability of the motor cortex and correcting the abnormal motor network connectivity associated with the motor deficit might be the therapeutic target in early neurorehabilitation for stroke patients. PMID- 30420872 TI - Signaling Mechanisms of Selective PPARgamma Modulators in Alzheimer's Disease. AB - Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by abnormal protein accumulation, synaptic dysfunction, and cognitive impairment. The continuous increase in the incidence of AD with the aged population and mortality rate indicates the urgent need for establishing novel molecular targets for therapeutic potential. Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists such as rosiglitazone and pioglitazone reduce amyloid and tau pathologies, inhibit neuroinflammation, and improve memory impairments in several rodent models and in humans with mild-to-moderate AD. However, these agonists display poor blood brain barrier permeability resulting in inadequate bioavailability in the brain and thus requiring high dosing with chronic time frames. Furthermore, these dosing levels are associated with several adverse effects including increased incidence of weight gain, liver abnormalities, and heart failure. Therefore, there is a need for identifying novel compounds which target PPARgamma more selectively in the brain and could provide therapeutic benefits without a high incidence of adverse effects. This review focuses on how PPARgamma agonists influence various pathologies in AD with emphasis on development of novel selective PPARgamma modulators. PMID- 30420877 TI - A Retrospective Analysis of Colorectal Serrated Lesions from 2005 to 2014 in a Single Center: Importance of the Establishment of Diagnostic Patterns. AB - Background: Serrated colorectal lesions are increasingly recognized as an important process in the development of colorectal cancer. Endoscopic and histological diagnosis may be difficult, and knowledge of the serrated lesions is important for the establishment of strategies for treating colorectal lesions. We aimed to analyze serrated lesions diagnosed at a single center and evaluate if there was an increase in their identification over the years. Design and Setting: A retrospective analysis of colonoscopy reports was performed at a specialized center from 2005 to 2014. Methods: Colonoscopy reports about any resected endoscopic lesions were reviewed and subjected to histological diagnosis from 2005 to 2014. Then, serrated lesions were evaluated based on morphological characterization, location, size, occurrence of synchronous lesions, and the patient's history of colorectal cancer and polyps. Results: A total of 2126 colonoscopy examination reports were reviewed, and 3494 lesions were analyzed. On histopathological examination, 1089 (31.2%) were classified as hyperplastic polyps, 22 (0.6%) as sessile serrated adenomas, and 21 (0.6%) as traditional serrated adenomas. There was an increase in the number of cases of sessile and traditional serrated adenomas diagnosed after 2010. Before 2010, two cases of sessile serrated adenomas and seven cases of traditional serrated adenomas were diagnosed; after 2010, 20 cases of sessile serrated adenoma and 14 cases of traditional serrated adenomas were diagnosed. Conclusion: There was an increase in the diagnosis of sessile serrated adenomas over the years, which can be attributed to better accuracy in colonoscopy and histological classification. PMID- 30420879 TI - Simultaneous Determination of Phenolic Compounds in Leptadenia pyrotechnica (Forssk.) Decne. by Using High-Performance Liquid Chromatography (HPLC-DAD-UV). AB - During the present study, an endeavor has been made to produce a simple, rapid, and simultaneous method for determination of phenolic compounds by using high performance liquid chromatography in aerial parts of Leptadenia pyrotechnica (Forssk.) Decne. collected from the Indian Thar Desert. The optimized process was used for the quantification of ten phenolic compounds. The chromatographic separation was accomplished on an Atlantis T3 column at 25 degrees C with isocratic elution. A mixture of acetonitrile and water was used as the mobile phase at a flow rate of 0.8 mL/min. The linear regression examination data for the calibration plots displayed a good linear relationship with r 2 > 0.999 in the concentration range of 2-20 uL. In the methanolic extracts of the whole plant of L. pyrotechnica, the content of caffeic acid (3.3%) was reported to be the highest concentration. PMID- 30420878 TI - Diminished DEFA6 Expression in Paneth Cells Is Associated with Necrotizing Enterocolitis. AB - Background: Necrotizing enterocolitis (NEC) is the most common gastrointestinal disorder in premature infants with a high morbidity and mortality. Paneth cell dysfunction has been suggested to be involved in the pathogenesis of NEC. Defensin alpha-6 (DEFA6) is a specific marker for Paneth cells acting as part of the innate immunity in the human intestines. The aim of this study was to investigate the expression of DEFA6 in infants with NEC. Materials and Methods: Infants who underwent bowel resection for NEC at level III NICU in Sweden between August 2004 and September 2013 were eligible for the study. Macroscopically vital tissues were selected for histopathological evaluation. All infants in the control group underwent laparotomy and had ileostomy due to dysmotility, and samples were taken from the site of the stoma. DEFA6 expression was studied by immunohistochemistry. Digital image analysis was used for an objective and precise description of the samples. Results: A total of 12 infants were included in the study, eight with NEC and four controls. The tissue samples were taken from the colon (n = 1), jejunum (n = 1), and ileum (n = 10). Both the NEC and control groups consisted of extremely premature and term infants (control group: 25-40 gestational weeks, NEC group: 23-39 gestational weeks). The postnatal age at the time of surgery varied in both groups (control group: 4-47 days, NEC group: 4-50 days). DEFA6 expression in the NEC group was significantly lower than that in the control group and did not correlate with gestational age. Conclusion: The diminished DEFA6 expression in Paneth cells associated with NEC in this study supports the hypothesis that alpha-defensins are involved in the pathophysiology of NEC. Future studies are needed to elucidate the role of alpha-defensins in NEC aiming at finding preventive and therapeutic strategies against NEC. PMID- 30420880 TI - The Modified Gil-Vernet Antireflux Surgery: A Successful Technique for High-Grade Vesicoureteral Reflux Correction in Children-Long-Term Follow-Up. AB - Introduction: Vesicoureteral reflux (VUR) is a common urologic anomaly in children. Many techniques have been offered to manage this condition, in which one of them is modified Gil-Vernet antireflux surgery. The study fullfiled to evaluate the efficacy and safety of modified Gil-Vernet antireflux surgery in correction of high-grade VUR. Materials and Methods: A retrospective study in which we evaluated efficacy, safety, and complications of modified Gil-Vernet antireflux surgery as a choice procedure for high-grade reflux in all patients who underwent it since 2000 to 2016 at 2 hospitals of Kermanshah University of medical sciences that all of them were done by one surgeon. Results: 183 patients with 290 high-grade refluxing units (grade IV or V) were reviewed. 182 refluxing units were grade IV, and 108 units were grade V. There were 76 (41.54%) patients with unilateral and 107 (58.46%) patients with bilateral VUR. Reflux in high grade group corrected completely in 278 (95.86%) refluxing units and 175 patients (95.62%). Conclusions: Our results are remarkable and compatible with other techniques' results. This simple and safe technique can correct bilateral VURs simultaneously; thus, it is rational to be considered for high-grade VUR correction. According to our results, we suggest the modified Gil-Vernet antireflux procedure for high-grade VUR correction as a simple, safe, and successful technique. This trial is registered with 67145/86/1233. PMID- 30420881 TI - Introducing Videoconferencing on Tablet Computers in Nurse-Patient Communication: Technical and Training Challenges. AB - Background: This article examines personnel and patient experiences of videoconferencing (VC) trials on tablet computers between oncology certified nurses (OCNs) and patients with cancer who live at home. The study points to organizational pitfalls during the introduction process. In many different arenas, the use of VC has increased recently owing to improved Internet access and capacity. This creates new opportunities for contact between patients living at home and their nurses. Video conferencing presupposes knowledge about Internet access, training, and usability of technological equipment. The aim of this pilot study was to illuminate patients' and nurses' experiences of the technical functionality, usability, and training of tablet use in VC in primary cancer care. The results point to the drawbacks concerning the introduction of VC. Method: A pilot study with an explorative design was used to describe patients' and OCNs' experiences of technical functionality and usability of VC on tablet computers. After a three-month trial, data were gathered, focusing on both patients' and nurses' perspectives. Individual interviews with four female OCNs, aged 32-65 (mean 46), and six patients with cancer, two men and four women aged 49-78 (mean 69), were content-analyzed. Results: The analysis revealed two main categories: network connectivity and tablet usability and training and educational pitfalls. Conclusion: When planning VC implementation, the organizational leadership should consider network access and stability, as well as individualized VC training on tablets. Ensuring patient safety should also be a priority. Further research should provide knowledge of technological and educational pitfalls, and possible implications of VC on the care quality of nursing. PMID- 30420882 TI - Using Accelerometers to Measure Physical Activity in Older Patients Admitted to Hospital. AB - Background: Low levels of physical activity in older patients during hospitalization have been linked to loss of functional ability. Practical methods of measuring physical activity are needed to better understand this association and to measure the efficacy of interventions. The aims of this study were to evaluate the feasibility of using accelerometers to discriminate between lying, sitting, standing, and standing and moving and to determine the acceptability of the method from the patients' perspective. Methods: A convenience sample of 24 inpatients was recruited. Participants wore accelerometers on their thigh and on their lower leg (just above the ankle) for 48 hours during their hospitalization. Postural changes and movement during the 48 hours were differentiated using derived pitch angles of the lower leg and thigh, and nongravity vector magnitude of the lower leg, respectively. Results: On average, patients were lying for 61.2% of the recording time, sitting for 35.6%, standing but not moving 2.1%, and standing and moving 1.1%. All participants found the accelerometers acceptable to wear. Conclusions: The methodology described in this study can be used to differentiate between lying, sitting, standing, and moving and is acceptable from a hospitalized older person's perspective. PMID- 30420883 TI - Influence of Methylprednisolone Pulse Therapy on Liver Function in Patients with Graves' Orbitopathy. AB - Purpose: Intravenous methylprednisolone (IVMP) pulse therapy is the first-line treatment in active moderate-to-severe Graves' orbitopathy (GO) and dysthyroid optic neuropathy (DON). One of the adverse effects of this therapy is liver dysfunction that can be mild (ALT < 100 U/L), moderate (ALT: 100-300 U/L), and severe defined as acute liver injury (ALI) (ALT > 300 U/L). ALI can be irreversible and fatal. The aim of the study was to evaluate the influence of two different schemes of therapy with IVMP in moderate-to-severe GO and DON on biochemical liver parameters. Materials and Methods: 49 patients with moderate-to severe GO were treated with IVMP in every week schedule (cumulative dose 4.5 g), and 19 patients with DON received 3.0 g IVMP (1.0 g/day for 3 consecutive days). AST, ALT, and total bilirubin were measured before treatment and after IVMP in the following selected pulses: after 0.5 g (A1), 3.0 g (A2), and 4.5 g (A3) in the group with moderate-to-severe GO and after 3.0 g IVMP in the group with DON (B1). Results: We observed a statistically higher level of AST and ALT after therapy with 3.0 g of IVMP (B1) than after 0.5 g (A1), 3.0 g (A2), and 4.5 g of IVMP (A3). Mild elevation of ALT was found in 4% and 11% of patients with moderate-to-severe GO and DON, respectively. Moderate elevation of ALT was found in 0% and 21% of patients with moderate-to-severe GO and DON, respectively. There were no cases of ALI. Conclusion: Therapy of GO with higher doses (1.0 g) of IVMP in consecutive days is associated with higher risk of liver damage than treatment with moderate doses (<=0.5 g) in every week schedule. This trial is registered with NCT03667157. PMID- 30420885 TI - Prevalence of Temporomandibular Disorder Symptoms among Orthognathic Patients in Southern Germany: Retrospective Study. AB - This study investigated the prevalence of temporomandibular disorder (TMD) among patients before and after orthognathic surgery and assessed the effect of orthognathic surgery on each of the TMD symptoms (clicking, pain, crepitus, and MRI findings). A sample of 100 consecutive patients undergoing bimaxillary surgery for correction of craniofacial deformities (31 male and 69 female), with ages ranging between 17 and 58 years (mean age: 27.7 +/- 9.3 years), were interviewed and examined regarding signs and symptoms of TMD. Clinical examination and X-ray and magnetic resonance imaging of the temporomandibular junction were performed at the time of surgery and 1 year thereafter. The prevalence of TMD preoperatively and postoperatively was 35% and 27%, respectively. A high frequency of relief was found in the patients with TMD symptoms (74.3%; 19 (70.3%) of patients had reduced clicking, 7 (87.5%) patients had reduced pain, 4 (100%) patients had reduced crepitus, and 4 (57.1%) patients showed changes in MRI findings), 12 patients who were asymptomatic before surgery developed clicking in TMJ after surgery, 3 developed pain, and 3 developed crepitus. TMD problems can occur in a variety of patients, including those who have facial deformities, and require orthognathic surgery. However, orthognathic surgery may not predictably treat or reduce the symptoms of TMD. PMID- 30420886 TI - Development of a Robust UPLC Method for Simultaneous Determination of a Novel Combination of Sofosbuvir and Daclatasvir in Human Plasma: Clinical Application to Therapeutic Drug Monitoring. AB - A rapid and selective UPLC-DAD method was developed and validated for simultaneous analysis of the novel two-drug combination Darvoni(r) for the treatment of HCV: Sofosbuvir (SF)/Daclatasvir (DC) in human plasma using Ledipasvir as internal standard (IS) where the extraction process was conducted using automated SPE. Although the analysis of the combination after concomitant oral intake of two tablets of SF and DC individually was reported in literature, yet simultaneous analysis of this new combination in human plasma after a single oral dose was not previously reported. The adopted chromatographic separation was achieved on Waters(r) Acquity UPLC BEH C18 column (2.1 * 50 mm, 1.7 um) as a stationary phase using isocratic elution using a mobile phase system of ammonium formate (pH 3.5; 5 mM) and acetonitrile (60:40 v/v) pumped at a flow rate of 0.2 mL.min-1. The UV detection was carried out at 261 nm for SF and 318 nm for DC and IS. SF was eluted at 1.123 min while DC was eluted at 3.179 min. The proposed chromatographic method was validated in accordance with guidelines of FDA for bioanalytical method validation. A linear range was achieved in the range of 25 6400 and 50-12800 ng.mL-1 for SF and DC, respectively. The proposed UPLC-DAD method was found to be accurate with % bias ranging between -10.0-7.2 for SF and 6.9-8.0 for DC. Also it was proved to be precise with % CV for intraday precision ranging between 3.8-9.6 for SF and 2.8-9.2 for DC whereas interday precision ranged between 5.1-9.3 for SF and 3.7-9.1 for DC. Moreover, % extraction recovery ranged between 90.0-107.2 for SF and 93.1-108.0 for DC using the suggested method. The adopted chromatographic method was successfully applied to the therapeutic drug monitoring of SF and DC in healthy volunteers after the oral intake of one Darvoni(r) tablet. PMID- 30420887 TI - Grammatophyllum speciosum Ethanolic Extract Promotes Wound Healing in Human Primary Fibroblast Cells. AB - Grammatophyllum speciosum is a plant in Orchidaceae family which contains a variety of phytochemical compounds that might be beneficial for medicinal use. This study aimed to evaluate the activity of pseudobulb of G. speciosum extract (GSE) in wound healing processes in human primary fibroblast cells along with in vitro antioxidant activity and total phenolic content of GSE. Scratch wound healing assay indicated that GSE was capable of increasing migration rate after 6 and 9 hours of treatment. Besides, the extract was able to scavenge DPPH, ABTS, and superoxide anion radicals indicating the antioxidative property of GSE. This study suggested a novel role of the of pseudobulb extract of G. speciosum as a wound healing enhancer. The results from this study might be beneficial for the development of further novel active compounds for skin wound healing. PMID- 30420884 TI - Gender in Endocrine Diseases: Role of Sex Gonadal Hormones. AB - Gender- and sex- related differences represent a new frontier towards patient tailored medicine, taking into account that theoretically every medical specialty can be influenced by both of them. Sex hormones define the differences between males and females, and the different endocrine environment promoted by estrogens, progesterone, testosterone, and their precursors might influence both human physiology and pathophysiology. With the term Gender we refer, instead, to behaviors, roles, expectations, and activities carried out by the individual in society. In other words, "gender" refers to a sociocultural sphere of the individual, whereas "sex" only defines the biological sex. In the last decade, increasing attention has been paid to understand the influence that gender can have on both the human physiology and pathogenesis of diseases. Even the clinical response to therapy may be influenced by sex hormones and gender, but further research is needed to investigate and clarify how they can affect the human pathophysiology. The path to a tailored medicine in which every patient is able to receive early diagnosis, risk assessments, and optimal treatments cannot exclude the importance of gender. In this review, we have focused our attention on the involvement of sex hormones and gender on different endocrine diseases. PMID- 30420888 TI - The Effect of Prednisone on Tuberculin Skin Test Reaction in Patients with Rheumatoid Arthritis. AB - Objectives: To assess the correlation between prednisone and methotrexate (MTX) treatment duration and dosage with the TST induration diameter of the TST reaction among rheumatoid arthritis (RA) patients. Method: We retrospectively analyzed consecutive cases of RA patients who were TNF-i therapy candidates. TST measurements, prednisone and methotrexate dosages, and treatment durations were recorded. A control group was randomly selected from healthy subjects. We compared TST reaction size between the following three groups: RA patients with current prednisone treatment, RA prednisone naive patients, and healthy individuals. Results: Our study sample comprised 43 RA patients with prednisone treatment, 22 prednisone naive patients, and 195 healthy subjects. There was no significant difference in mean TST between the groups (5.3+/-6.6, 7.8+/-6.2, and 7.6+/-7.0, respectively, p=0.149). No correlation was noted between TST size and prednisone u-y (r=0.229, p=0.140) or methotrexate u-y in patients with and without prednisone therapy (r=0.219, p=0.158; and r=-0.293, p=0.186, respectively). Conclusions: Our results show that the TST reaction size among RA patients may not be affected by prednisone therapy. In addition, the TST reaction of RA patients may present similarly to that of healthy individuals. Therefore, we suggest that the criterion of a TST reaction of 5 mm to define latent TB infection in our population should be reevaluated. PMID- 30420889 TI - The Myc/Max/Mxd Network Is a Target of Mutated Flt3 Signaling in Hematopoietic Stem Cells in Flt3-ITD-Induced Myeloproliferative Disease. AB - Acute myeloid leukemia (AML) has poor prognosis due to various mutations, e.g., in the FLT3 gene. Therefore, it is important to identify pathways regulated by the activated Flt3 receptor for the discovery of new therapeutic targets. The Myc network of oncogenes and tumor suppressor genes is involved in mechanisms regulating proliferation and survival of cells, including that of the hematopoietic system. In this study, we evaluated the expression of the Myc oncogenes and Mxd antagonists in hematopoietic stem cell and myeloid progenitor populations in the Flt3-ITD-knockin myeloproliferative mouse model. Our data shows that the expression of Myc network genes is changed in Flt3-ITD mice compared with the wild type. Mycn is increased in multipotent progenitors and in the pre-GM compartment of myeloid progenitors in the ITD mice while the expression of several genes in the tumor suppressor Mxd family, including Mxd1, Mxd2, and Mxd4, is concomitantly downregulated, as well as the expression of the Mxd-related gene Mnt and the transcriptional activator Miz-1. LSKCD150+CD48- hematopoietic long-term stem cells are decreased in the Flt3-ITD cells while multipotent progenitors are increased. Of note, PKC412-mediated inhibition of Flt3-ITD signaling results in downregulation of cMyc and upregulation of the Myc antagonists Mxd1, Mxd2, and Mxd4. Our data provides new mechanistic insights into downstream alterations upon aberrant Flt3 signaling and rationale for combination therapies for tyrosine kinase inhibitors with Myc antagonists in treating AML. PMID- 30420890 TI - Neurotrophic Activity of the Carrageenophyte Kappaphycus alvarezii Cultivated at Different Depths and for Different Growth Periods in Various Areas of Indonesia. AB - The carrageenophyte Kappaphycus alvarezii (Rhodophyta) has neurotrophic activity in primary hippocampal neurons. This seaweed is abundant and easily cultivated in tropical coastal areas. To determine the best growth conditions for neurotrophic activity, thalli were grown at different depths and for different periods in various areas of Indonesia. Neurotrophic activity was measured based on the number of primary neurites, the total length of the primary neurites, and the length of the longest neurite. K. alvarezii had higher neurotrophic activity than carrageenophytes K. striatum and Eucheuma denticulatum cultured under the same conditions. K. alvarezii grown at the surface for 45 days had higher (1.4- to 1.8 fold) neurotrophic activity than thalli grown at depth (2 m) or harvested sooner (15 days) (P < 0.05). Relatively high activities were detected in thalli cultured at Ternate and Garut, Indonesia. Therefore, from a commercial perspective, the culture conditions at the surface for 45 days were optimal for the production of both neurotrophic compounds and carrageenan. K. alvarezii produced neurotrophic compounds under various environmental conditions, although some conditions were optimal. PMID- 30420891 TI - Chemical Profiling of Xueshuan Xinmaining Tablet by HPLC and UPLC-ESI-Q-TOF/MS. AB - Xueshuan Xinmaining Tablet (XXT) is a widely used traditional Chinese medicine for the treatment of stroke, chest pain, coronary heart disease, and angina pectoris caused by blood stasis. Having a multiple-component preparation, it is still far from meeting the requirements of modernization and standardization because its detailed chemical basis and action mechanism have not been clarified. In this work, the different batches of XXT samples were analyzed by HPLC and the typical sample was analyzed by UPLC-ESI-Q-TOF/MS to understand its chemical profiling. As a result, 77 chromatographic peaks were detected, among which 63 constituents were identified or tentatively characterized based on the comparison of retention time and UV spectra with authentic compounds as well as by summarized MS fragmentation rules and matching of empirical molecular formula with those of published components. This is the first systematic report on the chemical profiling of the commercial XXT products, which provides the sufficiently chemical evidence for the global quality evaluation of XXT products. PMID- 30420892 TI - A Randomized Double-Blind Placebo-Controlled Trial to Evaluate Prophylactic Effect of Traditional Chinese Medicine Supplementing Qi and Hemostasis Formula on Gastrointestinal Bleeding after Percutaneous Coronary Intervention in Patients at High Risks. AB - Objective: To evaluate the clinical efficacy of traditional Chinese medicine (TCM) supplementing Qi and hemostasis formula on gastrointestinal (GI) bleeding after percutaneous coronary intervention (PCI) and thus find out the optimal therapeutic regimen to reduce incidence of GI bleeding without increase of major adverse cardiovascular events (MACEs). Methods: In the randomized, double blinded, controlled trial, 117 participants who underwent PCI were enrolled and evenly distributed into treatment arm (59) and control arm (58). Numerous end points were assessed including the primary endpoint of GI bleeding and MACEs and secondary endpoint of thromboelastogram (TEG) (mainly MAadp, inhibition of ADP, and inhibition of AA) and TCM syndrome score during the follow-up phase of 90 days. Results: Incidence of bleeding including GI bleeding and MACE did not differ significantly between two arms (28.82% in treatment arm versus 24.44% in control). However, on both days 30 and 90, TCM treatment remarkably reduced the TCM syndrome total score with notable alteration (P<0.05) except for some parameters such as pulse manifestation. When it came to TEG, however, MAADP increased significantly on day 30 in control arm, accompanied by a notable descending in inhibition rate of ADP pathway (both P<0.01). Conclusion: (1) Supplementing Qi and hemostasis formula is equal to Pantoprazole Sodium Enteric Coated Capsule in hemostasis and gastric mucosal protection; (2) supplementing Qi and hemostasis formula is superior to Pantoprazole Sodium Enteric-Coated Capsule in improving TCM syndrome manifestation possibly through the multitarget mechanism; (3) interference on clopidogrel of supplementing Qi and hemostasis formula might be much less than Pantoprazole Sodium Enteric-Coated Capsule due to the potential CYP450-independent mechanism. This trial is registered with ChiCTR1800014485. PMID- 30420893 TI - Grain Amaranth Is Associated with Improved Hepatic and Renal Calcium Metabolism in Type 2 Diabetes Mellitus of Male Wistar Rats. AB - Background: Dysregulation of calcium signaling is a hallmark of diabetes mellitus (DM) and grain amaranth (AG) has antidiabetic properties. Information on the mechanism of action of AG on blood, renal, and hepatic tissues is sparse, although it continues to be an important alternative medicinal plant in several developing countries. The objective of the study was to determine key changes in calcium levels and s100a1 protein levels and antioxidant and histopathologic changes in blood, renal, and hepatic tissues of male diabetic Wistar rats. Materials and Methods: This was an experimental study in which 30 male Wistar rats were kept for 5 weeks (6 groups, N =5). Groups 1-IV had T2DM induced using Nicotinamide and Streptozotocin: Group I, Mixtard(r); group II, positive control; group III, 25% AG; group IV, 50% AG. Furthermore, group V consisted of normal rats given 50% GA and group VI was negative control. Blood, renal, and hepatic tissues were collected and analyzed for calcium, s100a1 protein levels, and antioxidant and histopathological changes. Results and Discussion: In blood, renal, and hepatic tissue, calcium and s100a1 levels were low during T2DM and these increased following AG supplementation. This was important for improved metabolic processes, thus leading to the low malondialdehyde (MDA) and glutathione peroxidase (GPx) activity in the tissues. Efficient antioxidant status was important for improved calcium signaling mechanisms, thus leading to improved tissue function and protection demonstrating the importance of AG as an alternative medicinal source through the calcium signaling pathway. Conclusion: Grain amaranth exerts its antidiabetic properties through improved calcium homeostasis in blood, kidney, and liver. PMID- 30420894 TI - Hydroethanolic Extracts of Erigeron floribundus and Azadirachta indica Reduced Plasmodium berghei Parasitemia in Balb/c Mice. AB - Malaria is one of the most important infectious diseases in Africa especially in Cameroon. The nonaccessibility to current treatments for poor people and the appearance of drug-resistant Plasmodium falciparum parasites stimulate the search for alternative treatments. The aim of this study was to evaluate the antimalarial activity and the safety of hydroethanolic extracts from Erigeron floribundus and Azadirachta indica. The crude hydroethanolic extracts of E. floribundus (HEEF) and A. indica (HEAI) were prepared via maceration of the whole plant powder of E. floribundus and the leaves of A. indica in 70% ethanol. The antimalarial activity was determined according to Peter's 4-day suppressive test using the murine model Plasmodium berghei/Balb C mice, while the acute and subacute toxicity tests were assessed according to the OECD 425 and 407 guidelines, respectively. The results indicate a reduction of parasitemia ranging from 49.75 +/- 3.64 to 69.28 +/- 1.36% for HEAI and from 30.46 +/- 4.30 to 62.36 +/- 2.32% for HEEI. Overall, HEEF and HEAI at doses of 60, 120, and 240 mg/kg b.w. and 75, 150, and 300 mg/kg b.w., respectively, showed a significant (p<=0.001) parasitemia reduction on P. berghei infecting BALB/c mice. HEEF and HEAI caused a significant (p<0.001) attenuation of body temperature drop in mice compared to negative control, except for the 150 mg/kg b.w. dose in the female group. Moreover, there was no mice mortality observed with these extracts even at 5000 mg/kg, while the aspartate amino transferase (ASAT) level of mice treated with 300 mg/kg b.w. of HEAI extract increased when compared with the control. The results of this study support the traditional use of these plants species extracts against malaria infection in rural zones of Northern Cameroon, therefore confirming their potential as sources for the development of efficient phytomedicines for malaria-poverty disease alleviation. PMID- 30420895 TI - Acupuncture for the Treatment of Taxane-Induced Peripheral Neuropathy in Breast Cancer Patients: A Pilot Trial. AB - Objectives: Some chemotherapy drugs can damage the nerves and cause peripheral neuropathy which is accompanied by severe neuropathic pain or gait impairment. The purpose of this study was to assess the feasibility and the safety of acupuncture for the treatment of peripheral neuropathy following chemotherapy in Korean breast cancer patients. Design: This study was a prospective single-arm observational study using before and after measurements in breast cancer patients presenting with taxane-induced peripheral neuropathy. Settings/Location: This study was performed at East-West Medical Center at Daegu Catholic University Hospital, Daegu, South Korea. Interventions: Acupuncture was administered 3 times a week for 4 consecutive weeks, for 25 +/- 5 minutes at each session. Outcome Measures: The primary outcome measure was severity of CIPN using the Neuropathic Pain Symptom Inventory (NPSI) assessed by a self-administered questionnaire and Nerve Conduction Study (NCS) of extremities. The secondary outcome measure was quality of life (QoL) assessed by a self-administered questionnaire using the 36 Item Short From Health Survey (SF-36). Results: Acupuncture significantly reduced the severity of CIPN assessed by NPSI score. Four weeks after the last treatment, the symptoms were not aggravated. According to NCS, 42.9% of participants showed improvement of sensory neuropathy. At the end of the treatment, SF-36 scores were significantly increased for variables including physical functioning, role limitations due to physical health problems, social functioning, and general health perceptions compared to those of baseline measurement. Conclusions: Acupuncture improved symptoms of CIPN and QoL in Korean women suffering from peripheral neuropathy after chemotherapy using taxane for breast cancer. The effects of acupuncture lasted for at least 1 month after the treatment. PMID- 30420896 TI - Electroacupuncture Relieves Visceral Hypersensitivity by Inactivating Protease Activated Receptor 2 in a Rat Model of Postinfectious Irritable Bowel Syndrome. AB - Background: The role of protease-activated receptor 2 (PAR2) in the analgesic effect of electroacupuncture (EA) on visceral hypersensitivity (VH) in postinfectious irritable bowel syndrome (PI-IBS) has yet to be elucidated. Aim: In this study, we investigated the molecular mechanisms underlying the analgesic effect of EA in a rat model of PI-IBS. Methods: Visceral hypersensitivity was evaluated by the abdominal withdrawal reflex test before and after administration of the PAR2 agonist, PAR2-AP, and/or EA. The protein expression and mRNA levels of PAR2, CGRP, SP, and TPSP in colon tissues were measured by immunofluorescence, western blot, and RT-PCR. Results: We found that EA could alleviate VH and significantly decrease protein and mRNA levels of PAR2, TPSP, CGRP, and SP in PI IBS rats. The analgesic effect of EA on VH was slightly reduced in the presence of PAR2-AP. Conclusions: These results suggest that EA alleviates VH symptoms through downregulation of the levels of the TPSP/PAR2/SP/CGRP signaling axis in colon tissues in PI-IBS rats. Together, our data suggests that PAR2 plays a critical role in the analgesic effect of EA on VH in PI-IBS. PMID- 30420897 TI - Galangin and Pinocembrin from Propolis Ameliorate Insulin Resistance in HepG2 Cells via Regulating Akt/mTOR Signaling. AB - Insulin resistance has a critical role in type 2 diabetes. The aim of this study was to investigate the effect of pinobanksin, galangin, chrysin, and pinocembrin from propolis on insulin resistance. Our study shows that galangin and pinocembrin can ameliorate insulin resistance; on the contrary, pinobanksin and chrysin are ineffective. Galangin and pinocembrin treatments substantially increase glucose consumption and glycogen content by enhancing the activities of hexokinase and pyruvate kinase. Galangin treatment with 80 MUM increased hexokinase and pyruvate kinase activities by 21.94% and 29.12%, respectively. Moreover, we hypothesize that galangin and pinocembrin may have a synergistic effect on the improvement of insulin resistance via Akt/mTOR signaling pathway, through distinctly upregulating the phosphorylation of IR, Akt, and GSK3beta and remarkably downregulating the phosphorylation of IRS. Most notably, this is the first study to our knowledge to investigate pinocembrin about the alleviation of insulin resistance. Our results provide compelling evidence for the depth development of propolis products to ameliorate insulin resistance. PMID- 30420898 TI - Preparation of Magnetic Nanoliposomes of Sesquiterpene-Rich Fraction from Cichorium glandulosum and Its Tissue Distribution in Mice. AB - Objective: To prepare and study the distribution of magnetic nanoliposomes of Sesquiterpene-Rich Fraction from Cichorium glandulosum (SRF-MLN) (under magnetic field) in the main organs of mice. Methods: The SRF-MLN was prepared by ethanol injection-sonication precipitation method. The quality of its pharmaceutical properties was investigated by the active ingredient lactucin. The drug concentration and distribution of lactucin in different tissues and organs including whole blood, liver, heart, spleen, lung, and kidney were evaluated with Sesquiterpene-Rich Fraction from Cichorium glandulosum (SRF-LP) as a control. Results: The prepared SRF-MLN was spherical and monodispersed with an average particle diameter of 65 +/- 1 nm, encapsulation efficiency of 91.3% +/- 1.5% (RSD% = 1.5), and drug loading rate of 4.7% +/- 0.3% (RSD% = 0.7). Dispersion coefficient PDI was 0.157 and Zeta potential was -17.5 mV. The lactucin concentration of SRF-MLN after 10 min of intravenous injection in heart, liver, spleen, lung, and kidney was significantly higher than that of SRF-LP group. The AUC0-12h values of liver tissue were obviously higher than other tissues and MRT was significantly prolonged under the action of the magnetic field (p<0.01). Conclusion: The prepared SRF-MLN can change the distribution of drugs in different tissues and organs, prolonging the action time of the drugs in the body, and it has certain specificity under the action of applied magnetic field. PMID- 30420899 TI - Active Impedance Control of Bioinspired Motion Robotic Manipulators: An Overview. AB - There are two main categories of force control schemes: hybrid position-force control and impedance control. However, the former does not take into account the dynamic interaction between the robot's end effector and the environment. In contrast, impedance control includes regulation and stabilization of robot motion by creating a mathematical relationship between the interaction forces and the reference trajectories. It involves an energetic pair of a flow and an effort, instead of controlling a single position or a force. A mass-spring-damper impedance filter is generally used for safe interaction purposes. Tuning the parameters of the impedance filter is important and, if an unsuitable strategy is used, this can lead to unstable contact. Humans, however, have exceptionally effective control systems with advanced biological actuators. An individual can manipulate muscle stiffness to comply with the interaction forces. Accordingly, the parameters of the impedance filter should be time varying rather than value constant in order to match human behavior during interaction tasks. Therefore, this paper presents an overview of impedance control strategies including standard and extended control schemes. Standard controllers cover impedance and admittance architectures. Extended control schemes include admittance control with force tracking, variable impedance control, and impedance control of flexible joints. The categories of impedance control and their features and limitations are well introduced. Attention is paid to variable impedance control while considering the possible control schemes, the performance, stability, and the integration of constant compliant elements with the host robot. PMID- 30420900 TI - Patients' perception of community pharmacists as healthcare providers and willingness to participate in pharmacist services: a pilot study. AB - OBJECTIVES: To explore the extent to which patients identify community pharmacists as healthcare providers and the relationship of this perception to a willingness to engage in pharmacist-provided services. METHODS: A cross-sectional survey was conducted at a retail pharmacy and a patient centered medical home (PCMH) in the New Orleans, Louisiana metropolitan area. The survey assessed patients' perception of community pharmacists and their roles in the provision of healthcare, as well as willingness to participate in commonly offered pharmacist provided services. RESULTS: This study included 49 participants who interacted with pharmacy personnel to receive prescriptions regularly. Of the 49 patients surveyed, 91.8% perceived community pharmacists to be healthcare providers and this perception significantly impacted patient willingness to participate in medication therapy management, medication optimization, and travel vaccination services. Other services were not significantly impacted by perception. CONCLUSION: A greater percentage of patients perceived community pharmacists as healthcare providers. This affirmative perception positively impacted patient willingness to participate in several pharmacist-provided services. Since no comparative studies are available, further study is needed to assess consistency of observations and assess innovative ways to highlight pharmacists' cognitive attributes and increase participation in pharmacist-provided services. PMID- 30420901 TI - A Powerful Test for SNP Effects on Multivariate Binary Outcomes using Kernel Machine Regression. AB - Evaluating multiple binary outcomes is common in genetic studies of complex diseases. These outcomes are often correlated because they are collected from the same individual and they may share common marker effects. In this paper, we propose a procedure to test for effect of a SNP-set on multiple, possibly correlated, binary responses. We develop a score-based test using a nonparametric modeling framework that jointly models the global effect of the marker set. We account for the nonlinear effects and potentially complicated interaction between markers using reproducing kernels. Our testing procedure only requires estimation under the null hypothesis and we use multivariate generalized estimating equations (GEEs) to estimate the model components to account for the correlation among the outcomes. We evaluate finite sample performance of our test via simulation study and demonstrated our methods using the CATIE antibody study data and the CoLaus Study data. PMID- 30420902 TI - The Evaluation of the Relationship between sTREM-1, VEGF-B, and VEGF Gene Expression Levels with Disease Activity of Behcet's Patients. AB - Background: There is no specific marker that shows the disease activity in Behcet's disease. Aim: In this study, we aimed to investigate VEGF-B and VEGF gene expressions and sTREM-1 levels in association with the activation of Behcet's disease. Study Design: Case-control study. Methods: Clinical features of patients who applied in the rheumatology clinic and were diagnosed with BD according to the international working group's criteria were investigated. 30 healthy volunteers and 30 patients in the active period according to the EBDCAF scoring were studied. VEGF-B and VEGF gene expressions and sTREM-1 levels were studied in the serum samples of the patients and the control subjects. Results: The VEGF-B expressions and sTREM-1 levels were higher in the BD than those in the healthy group, but this difference did not reach statistical significance. VEGF gene expression was statistically significant (p = 0.008). Behcet's disease patients with oral aphthae, genital ulcer, eye, joint, vascular, skin, and neurological involvement were analyzed separately as subgroups. We find that VEGF gene expression level of Behcet's disease patients with joint involvement (arthritis/arthralgia) and also VEGF-B and VEGF gene expression of Behcet's disease with vascular involvement (DVT/thrombophlebitis) were significantly higher (p = 0.035, p = 0.021). Each subgroup was analyzed with the control group. We determined that VEGF gene expression in all subgroups was significantly higher than that in the control group. At the same time, VEGF-B levels of patients with genital ulcer and vascular involvement (DVT/thrombophlebitis) were significantly higher than those in the control group. Conclusion: VEGF-B and VEGF gene expressions can be activity indicators for BD. In addition, this study shows that new treatment options should be explored for Behcet's disease patients with joint and vascular involvement. In the following years, new treatment methods are needed to investigate for revealing the role of the etiopathogenesis of BD and the activation and prognosis of VEGF by examining this study and providing much more participation. In our study group, the sTREM-1 levels were high but the results did not reach statistical significance. More studies are needed with larger groups in order the highlight the exact role of STREM-1 in Behcet's disease. PMID- 30420903 TI - UBE2D1 RNA Expression Was an Independent Unfavorable Prognostic Indicator in Lung Adenocarcinoma, but Not in Lung Squamous Cell Carcinoma. AB - In this study, we investigated the potential prognostic value of ubiquitin conjugating enzyme E2D1 (UBE2D1) RNA expression in different histological subtypes of non-small-cell lung cancer (NSCLC). A retrospective study was performed by using molecular, clinicopathological, and survival data in the Cancer Genome Atlas (TCGA)-Lung Cancer. Results showed that both lung adenocarcinoma (LUAD) (N = 514) and lung squamous cell carcinoma (LUSC) (N = 502) tissues had significantly elevated UBE2D1 RNA expression compared to the normal tissues (p < 0.001 and p = 0.036, respectively). UBE2D1 RNA expression was significantly higher in LUAD than in LUSC tissues. Increased UBE2D1 RNA expression was independently associated with shorter OS (HR: 1.359, 95% CI: 1.031 1.791, p = 0.029) and RFS (HR: 1.842, 95% CI: 1.353-2.508, p < 0.001) in LUAD patients, but not in LUSC patients. DNA amplification was common in LUAD patients (88/551, 16.0%) and was associated with significantly upregulated UBE2D1 RNA expression. Based on these findings, we infer that UBE2D1 RNA expression might only serve as an independent prognostic indicator of unfavorable OS and RFS in LUAD, but not in LUSC. PMID- 30420904 TI - Herpes Zoster Burden in Canadian Provinces: A Narrative Review and Comparison with Quebec Provincial Data. AB - Background: The main aim of this review was to assess incidence rates and trends of medically attended and death cases of herpes zoster in Canada. Methods: The search was conducted in five databases (PubMed, Cochrane, Embase, PsycNET, and Web of Science). Data on herpes zoster-related consultations and hospitalisations and deaths were also extracted from three Quebec provincial administrative databases (RAMQ, MED-ECHO, and ISQ). Results: The electronic search yielded 587 publications. Seventeen publications satisfied inclusion criteria. These publications reported data from eleven studies. Ten studies used provincial databases, and one study used the Canadian Primary Care Sentinel Surveillance Network electronic database. Seven studies evaluated overall rates of medically attended cases (consultations and hospitalisations). Four of these studies reported an increase in rates of medically attended cases during the study period; one study reported stable rates, and two studies reported only an average rate. The rates varied from 316 to 450/100,000 p.y. The Quebec analysis shows similar rates with a slight decreasing trend (from 369 to 350/100,000 p.y.). Incidence rates of consultations were reported separately in three studies. Two studies reported an increase in rates (from 258 to 348/100,000 p.y. and from 324 to 366/100,000 p.y.), and the third study reported a decrease (from 525 to 479/100,000 p.y.). Hospitalization rates were reported separately in two studies, both reporting a decrease (from 12 to 8 cases/100,000 p.y. and from 9 to 4 cases/100,000 p.y.). Quebec data also showed a decrease, from 9 to 6 cases/100,000 p.y. One study reported herpes zoster-related deaths. In this study, the reported death rate was 0.7/1,000,000 p.y. in the overall population and 5.5/1,000,000 p.y. in those aged >=65 years. Quebec analysis showed a death rate of 1.2/1,000,000 p.y. in the overall population and 8.6/1,000,000 p.y. in those aged >=65 years. Conclusions: The results of the reviewed studies and our analysis of Quebec provincial data indicate important variations in the reported overall incidence rates of medically attended herpes zoster cases in Canada. The trends in time are heterogeneous in studies in which hospitalisations and medical consultations were pooled together. We observed a decrease in hospitalization rates and a slight increase in consultation rates in studies reporting hospitalisations and consultations separately. These results consolidate the understanding of the herpes zoster burden in Canada and might be used as a tool in decision-making regarding future preventive interventions. PMID- 30420905 TI - Helicobacter pylori Infection and Its Risk Factors: A Prospective Cross-Sectional Study in Resource-Limited Settings of Northwest Ethiopia. AB - Background: Helicobacter pylori (H. pylori) is implicated for the causation of gastrointestinal tract infections including gastric cancer. Although the infection is prevalent globally, the impact is immense in countries with poor environmental and socioeconomic status including Ethiopia. Epidemiological study on the magnitude of H. pylori and possible risk factors has priceless implication. Therefore, in this study, we determined the prevalence and risk factors of H. pylori infection in the resource-limited area of northwest Ethiopia. Methods: A prospective cross-sectional study was conducted on northwest Ethiopia among 201 systematically selected dyspeptic patients. Data were collected using a structured and pretested questionnaire, and stool and serum samples were collected and analyzed by SD BIOLINE H. pylori Ag and dBest H. pylori Disk tests, respectively. Chi-square test was performed to see association between variables, and binary and multinomial regression tests were performed to identify potential risk factors. P values <0.05 were taken statistically significant. Result: Prevalence of H. pylori was found to be 71.1% (143/201) and 37.3% (75/201) using the dBest H. pylori Test Disk and SD BIOLINE H. pylori Ag test, respectively. H. pylori seropositivity, using dBest H. pylori Disk tests, is significantly associated in age groups <10 years (P=0.044) and married patients (P=0.016). In those patients with H. pylori (a positive result with either the Ab or Ag test), drinking water from well sources had 2.23 times risk of getting H. pylori infection (P=0.017), and drinking coffee (1.51 (0.79-2.96, P=0.025)) and chat chewing (1.78 (1.02-3.46, P=0.008) are the common risk factors. Conclusion: The present study discovered considerable magnitude of H. pylori among the dyspeptic patients in the study area. H. pylori infection is frequent in individuals drinking water from well sources, and thus, poor sanitation and unhygienic water supply are contributing factors. Policies aiming at improving the socioeconomic status will reduce potential sources of infection, transmission, and ultimately the prevalence and incidence of H. pylori. PMID- 30420906 TI - Antioxidant Activity Mediates Pirfenidone Antifibrotic Effects in Human Pulmonary Vascular Smooth Muscle Cells Exposed to Sera of Idiopathic Pulmonary Fibrosis Patients. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by an exacerbated fibrotic response. Although molecular and cellular determinants involved in the onset and progression of this devastating disease are largely unknown, an aberrant remodeling of the pulmonary vasculature appears to have implications in IPF pathogenesis. Here, we demonstrated for the first time that an increase of reactive oxygen species (ROS) generation induced by sera from IPF patients drives both collagen type I deposition and proliferation of primary human pulmonary artery smooth muscle cells (HPASMCs). IPF sera-induced cellular effects were significantly blunted in cells exposed to the NADPH oxidase inhibitor diphenyleneiodonium (DPI) proving the causative role of ROS and suggesting their potential cellular source. Contrary to IPF naive patients, sera from Pirfenidone-treated IPF patients failed to significantly induce both ROS generation and collagen synthesis in HPASMCs, mechanistically implicating antioxidant properties as the basis for the in vivo effect of this drug. PMID- 30420908 TI - Falcarinol Is a Potent Inducer of Heme Oxygenase-1 and Was More Effective than Sulforaphane in Attenuating Intestinal Inflammation at Diet-Achievable Doses. AB - Nuclear factor- (erythroid-derived 2) like 2 (Nrf2) is a transcription factor that regulates the expression of a battery of antioxidant, anti-inflammatory, and cytoprotective enzymes including heme oxygenase-1 (Hmox1, Ho-1) and NADPH:quinone oxidoreductase-1 (Nqo1). The isothiocyanate sulforaphane (SF) is widely understood to be the most effective natural activator of the Nrf2 pathway. Falcarinol (FA) is a lesser studied natural compound abundant in medicinal plants as well as dietary plants from the Apiaceae family such as carrot. We evaluated the protective effects of FA and SF (5 mg/kg twice per day in CB57BL/6 mice) pretreatment for one week against acute intestinal and systemic inflammation. The phytochemical pretreatment effectively reduced the magnitude of intestinal proinflammatory gene expression (IL-6, Tnfalpha/Tnfalphar, Infgamma, STAT3, and IL-10/IL-10r) with FA showing more potency than SF. FA was also more effective in upregulating Ho-1 at mRNA and protein levels in both the mouse liver and the intestine. FA but not SF attenuated plasma chemokine eotaxin and white blood cell growth factor GM-CSF, which are involved in the recruitment and stabilization of first-responder immune cells. Phytochemicals generally did not attenuate plasma proinflammatory cytokines. Plasma and intestinal lipid peroxidation was also not significantly changed 4 h after LPS injection; however, FA did reduce basal lipid peroxidation in the mesentery. Both phytochemical pretreatments protected against LPS-induced reduction in intestinal barrier integrity, but FA additionally reduced inflammatory cell infiltration even below negative control. PMID- 30420909 TI - Gankyrin Drives Malignant Transformation of Gastric Cancer and Alleviates Oxidative Stress via mTORC1 Activation. AB - Gastric cancer, as a malignant epithelial tumor, is a major health threat leading to poor overall survival and death. It is usually diagnosed at an advanced stage due to asymptomatic or only nonspecific early symptoms. The present study demonstrated that gankyrin contributes to the early malignant transformation of gastric cancer and can be selected to predict the risk of gastric cancer in those patients harboring the precancerous lesions (dysplasia and intestinal metaplasia). In addition, a new insight into gastric cancer was provided, which stated that gankyrin alleviates oxidative stress via mTORC1 pathway activation. It can potentiate the mTORC1 by PGK1-AKT signaling that promotes the tumor process, and this phenomenon is not completely consistent with the previous report describing colorectal cancer. PMID- 30420910 TI - Neuroprotective Effect of Caryocar brasiliense Camb. Leaves Is Associated with Anticholinesterase and Antioxidant Properties. AB - Pequi (Caryocar brasiliense) is an endemic species from Brazilian Cerrado, and their fruits are widely used in regional cuisine. In this work, a crude hydroalcoholic extract (CHE) of C. brasiliense leaves and its resulting fractions in hexane (HF), chloroform (CF), ethyl acetate (EAF), and butanol (BF) were investigated for their antioxidant properties and anticholinesterase activities. The antioxidant properties were evaluated by free radical scavenging and electroanalytical assays, which were further correlated with the total phenolic content and LC-MS results. The acetylcholinesterase and butyrylcholinesterase inhibitory activities were examined using Ellman's colorimetric method. The LC-MS analysis of EAF revealed the presence of gallic acid and quercetin. CHE and its fractions, EAF and BF, showed anticholinesterase and antioxidant activities, suggesting the association of both effects with the phenolic content. In addition, behavioral tests performed with CHE (10, 100, and 300 mg/kg) showed that it prevented mice memory impairment which resulted from aluminium intake. Moreover, CHE inhibited brain lipid peroxidation and acetyl and butyryl cholinesterase activities and the extract's neuroprotective effect was reflected at the microscopic level. Therefore, the leaves of pequi are a potential source of phenolic antioxidants and can be potentially used in treatments of memory dysfunctions, such as those associated with neurodegenerative disorders. PMID- 30420907 TI - Possible Clues for Brain Energy Translation via Endolysosomal Trafficking of APP CTFs in Alzheimer's Disease. AB - Vascular dysfunctions, hypometabolism, and insulin resistance are high and early risk factors for Alzheimer's disease (AD), a leading neurological disease associated with memory decline and cognitive dysfunctions. Early defects in glucose transporters and glycolysis occur during the course of AD progression. Hypometabolism begins well before the onset of early AD symptoms; this timing implicates the vulnerability of hypometabolic brain regions to beta-secretase 1 (BACE-1) upregulation, oxidative stress, inflammation, synaptic failure, and cell death. Despite the fact that ketone bodies, astrocyte-neuron lactate shuttle, pentose phosphate pathway (PPP), and glycogenolysis compensate to provide energy to the starving AD brain, a considerable energy crisis still persists and increases during disease progression. Studies that track brain energy metabolism in humans, animal models of AD, and in vitro studies reveal striking upregulation of beta-amyloid precursor protein (beta-APP) and carboxy-terminal fragments (CTFs). Currently, the precise role of CTFs is unclear, but evidence supports increased endosomal-lysosomal trafficking of beta-APP and CTFs through autophagy through a vague mechanism. While intracellular accumulation of Abeta is attributed as both the cause and consequence of a defective endolysosomal autophagic system, much remains to be explored about the other beta-APP cleavage products. Many recent works report altered amino acid catabolism and expression of several urea cycle enzymes in AD brains, but the precise cause for this dysregulation is not fully explained. In this paper, we try to connect the role of CTFs in the energy translation process in AD brain based on recent findings. PMID- 30420911 TI - Errors and improvements in the use of archived meteorological data for chemical transport modeling: an analysis using GEOS-Chem v11-01 driven by GEOS-5 meteorology. AB - Global simulations of atmospheric chemistry are commonly conducted with off-line chemical transport models (CTMs) driven by archived meteorological data from general circulation models (GCMs). The off-line approach has advantages of simplicity and expediency, but incurs errors due to temporal averaging in the meteorological archive and the inability to reproduce the GCM transport algorithms exactly. The CTM simulation is also often conducted at coarser grid resolution than the parent GCM. Here we investigate this cascade of CTM errors by using 222Rn-210Pb-7Be chemical tracer simulations offline in the GEOS-Chem CTM at rectilinear 0.25 degrees *0.3125 degrees (~25 km) and 2 degrees *2.5 degrees (~200 km) resolutions, and on-line in the parent GEOS-5 GCM at cubed-sphere c360 (~25 km) and c48 (~200 km) horizontal resolutions. The c360 GEOS-5 GCM meteorological archive, updated every 3 hours and remapped to 0.25 degrees *0.3125 degrees , is the standard operational product generated by the NASA Global Modeling and Assimilation Office (GMAO) and used as input by GEOS-Chem. We find that the GEOS-Chem 222Rn simulation at native 0.25 degrees *0.3125 degrees resolution is affected by vertical transport errors of up to 20% relative to the GEOS-5 c360 on-line simulation, in part due to loss of transient organized vertical motions in the GCM (resolved convection) that are temporally averaged out in the 3-hour meteorological archive. There is also significant error caused by operational remapping of the meteorological archive from cubed-sphere to rectilinear grid. Decreasing the GEOS-Chem resolution from 0.25 degrees *0.3125 degrees to 2 degrees *2.5 degrees induces further weakening of vertical transport as transient vertical motions are averaged out spatially as well as temporally. The resulting 222Rn concentrations simulated by the coarse-resolution GEOS-Chem are overestimated by up to 40% in surface air relative to the on-line c360 simulations, and underestimated by up to 40% in the upper troposphere, while the tropospheric lifetimes of 210Pb and 7Be against aerosol deposition are affected by 5-10%. The lost vertical transport in the coarse-resolution GEOS-Chem simulation can be partly restored by re-computing the convective mass fluxes at the appropriate resolution to replace the archived convective mass fluxes, and by correcting for bias 20 in spatial averaging of boundary layer mixing depths. PMID- 30420912 TI - The Effect of Optical Crosstalk on Accuracy of Reflectance-Type Pulse Oximeter for Mobile Healthcare. AB - According to the theoretical equation of the pulse oximeter expressed by the ratio of amplitude (AC) and baseline (DC) obtained from the photoplethysmographic signal of two wavelengths, the difference of the amount of light absorbed depending on the melanin indicating the skin color is canceled by normalizing the AC value to the DC value of each wavelength. Therefore, theoretically, skin color does not affect the accuracy of oxygen saturation measurement. However, if there is a direct path for the light emitting unit to the light receiving unit instead of passing through the human body, the amount of light reflected by the surface of the skin changes depending on the color of the skin. As a result, the amount of crosstalk that varies depending on the skin color affects the ratio of AC to DC, resulting in errors in the calculation of the oxygen saturation value. We made crosstalk sensors and crosstalk-free sensors and performed desaturation experiments with respiratory gas control on subjects with various skin colors to perform oxygen saturation measurements ranging from 60 to 100%. Experimental results showed that there was no difference in the measurement error of oxygen saturation according to skin color in the case of the sensor which prevented crosstalk (-0.8824 +/- 2.2859 for Asian subjects, 0.6741 +/- 3.2822 for Caucasian subjects, and 0.9669 +/- 2.2268 for African American subjects). However, a sensor that did not prevent crosstalk showed a large error in dark skin subjects (0.8258 +/- 2.1603 for Asian subjects, 0.8733 +/- 1.9716 for Caucasian subjects, and 3.0591 +/- 3.9925 for African Americans). Based on these results, we reiterate the importance of sensor design in the development of pulse oximeters using reflectance-type sensors. PMID- 30420913 TI - Smart Gold Nanoparticle-Stabilized Ultrasound Microbubbles as Cancer Theranostics. AB - Smart gold nanoparticle-stabilized microbubbles (SAuMBs) composed of a gas-filled core and shell including smart gold nanoparticles (SAuNPs) which can be aggregated in tumors were applied as ultrasound-mediated cancer theranostics. The gas core in the microstructure enabled the detection of tumors using ultrasound and facilitated the delivery of SAuNPs by sonoporation. The SAuNPs spontaneously aggregated in tumors, which allowed photoacoustic (PA) monitoring and photothermal treatment (PTT) of tumors. PMID- 30420914 TI - Comparison of Individual Retinal Layer Thicknesses after Epiretinal Membrane Surgery with or without Internal Limiting Membrane Peeling. AB - Purpose: To compare changes in the retinal layer thickness and visual outcomes in patients undergoing epiretinal membrane (ERM) surgery with or without internal limiting membrane (ILM) peeling. Methods: Seventy-six eyes of 76 patients who underwent ERM surgery from January 2013 to March 2015 at the Department of Ophthalmology, Yonsei University College of Medicine, Seoul, South Korea, were analyzed. While ERM removal with ILM peeling was performed in ILM peeling (P) group (n=39), ILM peeling was not performed in non-ILM peeling (NP) group (n=37). Retinal layer segmentation was performed using optical coherence tomography images. Individual retinal layer thicknesses before and at 6 months after ERM surgery were compared. The postoperative best-corrected visual acuity (BCVA) was also compared. Results: In the P group, the thicknesses of retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), and inner plexiform layer (IPL) were significantly reduced. In the NP group, significant decreases in the RNFL, GCL, IPL, inner nuclear layer, and outer plexiform layer were observed. The P group manifested a greater mean postoperative GCL (35.56 +/- 1.53 um vs 29.86 +/- 2.16 um; p=0.033) and less loss of GCL (-10.26 +/- 1.91 um vs -19.86 +/- 2.74 um; p=0.004) compared to the NP group. No statistically significant differences were observed when comparing the changes in BCVA. Conclusions: This study demonstrates that ILM peeling for ERM surgery may result in better preservation of GCL compared to no ILM peeling. PMID- 30420916 TI - Visual and Refractive Outcomes of Small-Incision Lenticule Extraction in High Myopia: 5-Year Results. AB - Purpose: To report long-term visual and refractive results of small-incision lenticule extraction (SMILE) in treatment of high myopia. Materials and Methods: Medical records of patients who underwent SMILE for surgical correction of myopia or myopic astigmatism were retrospectively reviewed. Only patients with a preoperative spherical equivalent of subjective manifest refraction (SE) >= 6 D and a postoperative follow-up of 5 years were included in the study. Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), and SE were analyzed preoperatively and at 1-, 3-, and 5-year postoperative periods. Results: Thirty-seven eyes of 37 patients were included in the study. The mean attempted SE was -7.47 +/- 1.10 D (range -6.00 to -10.00 D). At the 5-year visit, the mean difference between achieved and attempted SE was -0.43 +/- 0.47 (0.50 to -1.25 D). Mean postoperative UDVA and CDVA were 0.20 +/- 0.18 and 0.06 +/- 0.08 logMAR, respectively. At the 1-year visit, 70% and 97% of the eyes were within +/ 0.50 D and +/-1.00 D of the intended correction. At the 5-year follow-up, 59% and 92% percent of the eyes were within +/-0.50 D and +/-1.00 D of the intended SE, respectively. At the 5-year visit, the efficacy index was 0.89 +/- 0.26 and the safety index was 1.16 +/- 0.20. Fifty-four percent of the eyes gained one or more lines of CDVA. Conclusion: SMILE with an intended correction of up to a spherical equivalent of 10 D is safe and effective. However, there is regression of the refractive effect over extended follow-up. PMID- 30420915 TI - A Comparative Study of Characteristics and Outcomes of Patients with Proved and Suggested Sarcoid Uveitis Occurring after Ophthalmic Procedure. AB - Purpose: To describe patients with new onset sarcoid uveitis occurring after an ophthalmic procedure and compare them with patients with sarcoid uveitis without ocular procedure. Methods: Retrospective analysis of case records from patients with postophthalmic procedure sarcoid uveitis seen at our institution between April 2004 and October 2016. Patients with a previous history of uveitis were not included. Each patient was randomly matched with four controls from our incident cohort of new onset sarcoid uveitis without ophthalmic procedure. Results: We identified 11 patients (8.5%) from our incident cohort of sarcoid uveitis (n=130), who were all women, with a postophthalmic procedure uveitis (mostly after cataract surgery (36%)). These patients were older (69.7 vs 52.7 years) and presented more synechiae than controls. After a mean follow-up of 30 (3-60) months, there was no significant difference between the postprocedure and the control group with regard to demography, clinical presentation, disease course, treatment, and outcome. Conclusions: Sarcoid uveitis has similar characteristics in patients with new onset sarcoid uveitis after or without ophthalmic procedure. As a consequence, ophthalmic intervention should be seen as a potential trigger of latent sarcoidosis. PMID- 30420917 TI - The Efficacy of Lidocaine Spray in Pain Relief during Outpatient-Based Endometrial Sampling: A Randomized Placebo-Controlled Trial. AB - Abnormal vaginal bleeding is one of the most frequent problems found in gynecology. Endometrial histopathology is needed for definite diagnosis. It was obtained either from endometrial tissue sampling or from standard uterine curettage. Office endometrial tissue sampling is an easy and low morbid procedure. It is usually associated with pain and discomfort. Topical anesthetic agent is needed for pain relieving. This study was conducted in outpatient gynecology clinic, Thammasat University Hospital, Thailand. It was a double blind randomized controlled trial. A total of 140 participants were enrolled in study and control group. Each group consisted of 70 cases. Study group received topical spray of 10% lidocaine (40 mg) before endometrial aspiration. Topical spray of 0.9% normal saline was performed in control group. Novak curettage was an application for endometrial tissue obtaining in this study. Visual analog scale (10cm-VAS) was used for pain evaluation. Demographic character of both groups showed no statistical difference. The percentage of participants who had severe pain (VAS>=7) during tenaculum application and Novak curettage insertion and during procedure were 28.5% (20/70) versus 12.9% (9/70), 55.7% (39/70) versus 38.5% (27/70), and 78.5% (55/70) versus 60% (42/70) in control and study group, respectively. Both groups had no significant differences of postoperative pain at 15 minutes and 2 hours. This study indicates that topical lidocaine spray can relieve pain during endometrial tissue sampling. PMID- 30420918 TI - Effectiveness of Integrated Neurocognitive Therapy on Cognitive Impairment and Functional Outcome for Schizophrenia Outpatients. AB - Cognitive impairment is highly prevalent in patients with schizophrenia and schizoaffective disorder. Many interventions have been developed to treat cognitive deficit, since it has a strong impact on functional outcome; however, there are no integrated interventions targeting multiple neuro- and social cognitive domains with a particular focus on the generalization of the effects of therapy on the functional outcome. Recently, a group of experts has developed a cognitive remediation group therapy approach called Integrated Neurocognitive Therapy (INT), which includes exercises to improve the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) neuro- and social cognitive domains. This systematic review and meta-analysis aimed to assess the efficacy of this approach. We conducted a search of PubMed, Scopus, Web of Science, and PsycINFO to select primary studies evaluating INT in schizophrenic and schizoaffective patients. The primary outcomes of the meta-analysis included negative and positive symptoms and global functioning. Two randomized controlled trials met inclusion criteria. A total of 217 participants were included. Based on the results from the Positive and Negative Syndrome Scale (PANSS), a significant pooled effect size was observed for negative symptoms, which demonstrated not only an improvement in the patients treated immediately after therapy but also a permanence of positive results at a 9-12-month follow-up. On the other hand, no significant effect size was observed for positive symptoms. In addition, a significant pooled effect size was found for Global Assessment of Functioning (GAF), which shows how INT's integrated approach has lasting positive implications on patients' functional outcome. We concluded that INT might be an effective treatment for negative symptoms and global functioning in patients with schizophrenia, compared to treatment as usual (TAU). PMID- 30420919 TI - What Are the Participants' Perspectives of Taking Melatonin for the Treatment of Nocturia in Multiple Sclerosis? A Qualitative Study Embedded within a Double Blind RCT. AB - Background: Multiple Sclerosis (MS) is a chronic neurological disorder caused by neurodegeneration within the central nervous system. It results in impaired physical, cognitive, and psychological functioning and can also lead to lower urinary tract symptoms including nocturia. While clinical trials have suggested an association between nocturia and melatonin secretion, to our knowledge, no qualitative research has been conducted on the experience of taking melatonin to treat nocturia in progressive MS within a clinical trial. Methods: 17 semistructured qualitative interviews were conducted as part of a double-blind, randomised, placebo controlled, crossover, clinical trial with consenting adults with MS. Interviews explored participants' experiences of nocturia associated with MS and their experience of taking melatonin as a trial treatment for nocturia versus a placebo. Data was analysed using a thematic analysis. Results: Themes on the experience of nocturia revealed participants' understandings of nocturia, the impact it had on their night, and increased daily fatigue. Themes on the intervention showed perceived improvements to nocturia, sleep, and energy and negative effects including lethargy, a lack of significant change, and physical side effects including vivid dreams. Conclusion: This qualitative exploration revealed an association between nocturia and increased levels of fatigue during the day by those with MS. However, perspectives towards the effectiveness of melatonin as a potential treatment varied as both placebo and melatonin were perceived as having very similar effects. PMID- 30420920 TI - Prevalence and Factors Influencing Alcohol Use in Pregnancy among Women Attending Antenatal Care in Dodoma Region, Tanzania: A Cross-Sectional Study. AB - Background: Alcohol use during pregnancy is high despite the well-established evidence on its adverse pregnancy outcomes and poor child development. Early identification and behavioural modification are of great significance. This study aimed to determine the prevalence and associated factors of alcohol use during pregnancy among women in Dodoma region. Methods: 365 randomly selected pregnant women attending antenatal care services in Dodoma region were included. Structured questionnaires were used to assess sociodemographic characteristic and alcohol use. Both descriptive and inferential analyses were used to estimate the prevalence and independent relationships of factors associated with alcohol use in pregnancy, respectively. Results: Results showed a prevalence of 15.1% out of the 365 women attending antenatal services in Dodoma region. Prepregnancy alcohol use and having relatives who use alcohol were associated with alcohol use (AOR= 5.19; 95% CI: 4.791-34.867 and AOR=1.57; 95% CI: 1.393-6.248), respectively. Moreover, other associated factors included low education status (AOR=10.636; 95% CI: 1.89-19.844), making local brews as a source of income (AOR=11.44; 95% CI: 1.008-19.86), and not having had complications in previous pregnancies (AOR=4.93; 95% CI: 1.031-23.59). Conclusion: There is a significantly high prevalence of alcohol use during pregnancy in Dodoma. Social networks and low social, economic status were associated with alcohol use in pregnancy. There is a need for public health interventions to address alcohol use particularly targeting women of reproductive age with low socioeconomic status. PMID- 30420921 TI - The Relationship between Gestational Weight Gain and Postpartum Depression in Normal and Overweight Pregnant Women. AB - Objective: To investigate the relationship between weight gain in pregnancy and postpartum depression (PPD) in normal and overweight pregnant women. Methods: The participants of this prospective cohort study were 223 healthy pregnant women with the first trimester body mass index (BMI) between 18.5 and 30 and the gestational age of 10-14 weeks and depressed women were excluded with Beck questionnaire in the first trimester. The evaluation included weight gain at the end of the second and third trimesters and the screening of PPD in 6-8 weeks after delivery by Edinburgh scale. Results: 49 participants were excluded from the study and data from 174 people were analyzed. 32.2% of mothers were scored above 12 in the Edinburgh scale. The only variable associated with depression was the third trimester weight gain (OR 1.17, 95%CI 1.04-1.32). Conclusion: In addition to considering other risk factors for postpartum depression, health care providers should consider the higher probability of PPD in prepregnancy normal and overweight women who have excessive weight gain especially in the third trimester of pregnancy. PMID- 30420922 TI - Standardised Warfarin Reversal Expedites Time to Theatre for Fractured Neck of Femur Surgery and Improves Mortality Rates: A Matched Cohort Study. AB - Background: This study aims to evaluate outcomes for warfarinised hip fracture patients and compare them with a matched nonwarfarinised group, before and after the introduction of national hip fracture guidelines in the United Kingdom. Methods: A retrospective cohort study of 1743 hip fracture patients was undertaken. All patients admitted taking warfarin were identified. These patients were then matched to nonwarfarinised patients using nearest neighbour propensity score matching, accounting for age, sex, hip fracture type, and Nottingham Hip Fracture Score. A pre-guideline group (no standardised warfarin reversal regimen) and a post-guideline group (standardised regimen) were identified. Outcomes assessed included time to INR less than 1.7, time to theatre, length of stay, and 30-day and 1-year mortality. Results: Forty-six warfarinised hip fracture patients were admitted in the pre-guideline group (mean age 80.5, F:M 3:1) and 48 in the post-guideline group (mean age 81.2 years, F:M 3:1). Post-guideline patients were reversed to a safe operative INR level within 18 hours of admission, decreasing the time to first dose vitamin K (p<0.001). 70% of warfarinised patients were operated upon within 36 hours, compared to 19.6% with no regimen (p<0.05). After anticoagulation reversal protocol, thirty-day mortality decreased from 15.2% to 8.3% and 1-year mortality from 43.5% to 33% for warfarinised patients, which is comparable to nonwarfarinised matched patients. There was no significant change in the length of stay pre- and post-guideline for both groups of patients. Conclusions: Proactive anticoagulant management and expedient surgery reduces morbidity and mortality when managing this surgically challenging subset of hip fracture patients. PMID- 30420923 TI - Use of Awake Flexible Fiberoptic Bronchoscopic Nasal Intubation in Secure Airway Management for Reconstructive Surgery in a Pediatric Patient with Burn Contracture of the Neck. AB - Although the use of awake flexible fiberoptic bronchoscopic (FFB) intubation is a well-recognized airway management technique in patients with difficult airway, its use in smaller children with burn contractures or in an uncooperative older child may be challenging. Herein, we report successful management of difficult airway in a 7-year-old boy with burn contracture of the neck, by application of FFB nasal intubation in a stepwise approach, first during an initial preoperative trial phase to increase patient cooperation and then during anesthesia induction for the reconstructive surgery planned for burn scars and contractures. Our findings emphasize the importance of a preplanned algorithm for airway control in secure airway management and feasibility of awake FFB intubation in a pediatric patient with burn contracture of the neck during anesthesia induction for reconstructive surgery. Application of FFB intubation based on a stepwise approach including a trial phase prior to operation day seemed to increase the chance of a successful intubation in our patient in terms of technical expertise and increased patient cooperation and tolerance by enabling familiarity with the procedure. PMID- 30420924 TI - A Fulminant Case of Acute Respiratory Distress Syndrome Associated with Mycoplasma Pneumonia Treated with Nasal High-Flow Oxygen Therapy. AB - Introduction: The prognosis of mycoplasma pneumonia in adults is generally favorable, but a few patients show progression to acute respiratory distress syndrome (ARDS). We have described the management of a patient who showed progression of mycoplasma pneumonia to ARDS. Presentation of Case: A 26-year-old male patient with no significant past medical or social history presented with a 5-day history of fever. Following this, he was diagnosed with bacterial pneumonia and treated with tazobactam/piperacillin; however, he showed little clinical improvement with this treatment approach. We diagnosed the patient with mycoplasma pneumonia with an antigen test and treated him with azithromycin and prednisolone. Despite the appropriate antimicrobial therapy, his symptoms worsened and therefore we changed his oxygen therapy from a reservoir mask to nasal high-flow oxygen in addition to minocycline. Consequently, with this treatment, he recovered from severe mycoplasma pneumonia. Discussion: In patients with severe pneumonia who experience respiratory failure, it has been reported that nasal high-flow oxygen therapy is not inferior to noninvasive positive pressure ventilation therapy regarding intubation rate. In this case, induction of nasal high-flow oxygen therapy led to avoidance of ventilator management. This is a valuable case report highlighting the optimal outcome of nasal high-flow oxygen therapy in a fulminant case of acute respiratory distress syndrome. Conclusion: In patients who present with severe mycoplasma pneumonia with respiratory failure, nasal high-flow oxygen therapy can help reduce the needs for ventilator management including intubation. PMID- 30420925 TI - Papillary Thyroid Carcinoma as a Lateral Neck Cyst: A Cystic Metastatic Node versus an Ectopic Thyroid Tissue. AB - Papillary thyroid carcinoma is the most common thyroid malignancy and frequently metastasizes to regional lymph nodes. Occasionally, metastatic lymph nodes are palpable without the evidence of primary tumour. Papillary thyroid carcinoma of lateral neck cyst is a rare condition. It may arise from thyroid primary which underwent cystic degeneration or true malignant transformation of ectopic thyroid tissue. Herein, we reported two cases with preoperative diagnosis of benign lateral neck cyst but postoperative histopathological results showed primary papillary thyroid carcinoma. Ultrasonography and computed tomography of the neck in both cases showed no significant thyroid lesion. However, the patient in Case 2 was subjected for total thyroidectomy and histopathological results showed the origin of primary tumour. In conclusion, thorough investigations including total thyroidectomy are indicated in cases of papillary thyroid carcinoma of lateral neck cyst. This practice is to ensure that this type of thyroid cancer can be detected earlier because it has a very good prognosis if treated earlier. PMID- 30420926 TI - V144D Mutation of SPTLC1 Can Present with Both Painful and Painless Phenotypes in Hereditary Sensory and Autonomic Neuropathies Type I. AB - Hereditary sensory and autonomic neuropathy type I (HSAN I) is an autosomal dominant disease characterized by distal sensory loss, pain insensitivity, and autonomic disturbances. The major underlying causes of HSAN I are point mutations in the SPTLC1 gene. Patients with mutations in the SPTLC1 genes typically exhibit dense sensory loss and incidence of lancinating pain. Although most of these mutations produce sensory loss, it is unclear which mutations would lead to the painful phenotype. In this case series, we report that the V144D mutation in SPTLC1 gene may relate to both painful and painless peripheral neuropathies. The unique clinical phenotype of this mutation may guide clinical workup and treatment for patients with painful and painless neuropathies. PMID- 30420927 TI - Congenital Glaucoma: a Novel Ocular Manifestation of Hajdu-Cheney Syndrome. AB - Hajdu-Cheney Syndrome (HSC) is a rare multisystem disease in which the phenotype involves acro-osteolysis, severe osteoporosis, short stature, wormian bones, facial dysmorphism, central neurological abnormalities, cardiovascular defects, and polycystic kidneys. We describe an infant with severe manifestations of HCS in whom congenital glaucoma was a significant early feature, which has not been reported to date. HCS cases reported to date have involved truncating mutations in exon 34 of NOTCH2 upstream the PEST domain that lead to the development of a truncated and stable NOTCH2 protein which upregluates notch signaling. We describe a hitherto undescribed missense mutation that is predicted to be pathogenic, with functional characterization remaining to be performed. Serpentine fibula-polycystic kidney syndrome (SFPKS) is allelic to HCS and commonly associated with missense NOTCH2 mutations. Our patient provides new ophthalmological manifestations of HCS and provides insight into the potential role of notch signaling in the anterior chamber development. PMID- 30420928 TI - Drug-Induced Hypersensitivity Syndrome: A Clinical, Radiologic, and Histologic Mimic of Lymphoma. AB - Drug-induced hypersensitivity syndrome (DIHS; also known as drug reaction with eosinophilia and systemic symptoms, or DRESS) is a rare, potentially life threatening condition that typically presents 2-8 weeks after drug exposure with fever, rash, organ dysfunction, and lymphadenopathy. Here, we describe the case of an 18-year-old African American female who presented with cervical lymphadenopathy, fevers, and a macular rash. A PET scan showed diffuse hypermetabolic lymphadenopathy suggestive of lymphoma, with involvement of the spleen and kidneys. The clinical history, imaging, and biopsy findings initially raised concern for a malignant process, with a differential diagnosis including classic Hodgkin's lymphoma and T-cell lymphoma. However, the morphologic and immunophenotypic features were not entirely typical for those diagnoses. The patient was ultimately diagnosed with DIHS after it was learned that she recently had been treated with minocycline, a medication previously implicated in causing DIHS. PMID- 30420929 TI - Selective Reduction of a Heterotopic Cesarean Scar Pregnancy Complicated by Septic Abortion. AB - Background: Heterotopic pregnancy involving the implantation of an ectopic pregnancy into a prior cesarean scar with a concurrent intrauterine pregnancy is a rare and potentially life-threatening condition with minimal information in the literature to guide treatment and management options. Case: A 40-year-old G5P3103 at 12 weeks and 3 days with a history of two cesarean deliveries was diagnosed with a live heterotopic pregnancy containing a cesarean scar ectopic and an intrauterine pregnancy. After selective reduction of the cesarean scar gestation with potassium chloride (KCl), the patient presented ten days later to the emergency department with septic abortion and sepsis. The patient underwent bilateral uterine artery embolization followed by ultrasound guided uterine evacuation with dilation and curettage, which was complicated by intraoperative hemorrhage and persistent bacteremia. The patient had resolution of her bacteremia after total abdominal hysterectomy. Conclusion: Conservative management of uterine infection resulting from selective reduction of a heterotopic pregnancy cesarean scar pregnancy may be considered; however, severe septicemia and persistent bacteremia may necessitate definitive surgical management. PMID- 30420930 TI - Metastatic Cecal Adenocarcinoma to the Gallbladder Presenting with Acute Cholecystitis. AB - Colorectal cancer (CRC) is one of the most common cancers and the second highest cause of cancer-related deaths (Jemal et al., 2011). Common presentations of CRC include alterations in bowel habit, weight loss, and lower gastrointestinal bleeding. We report a case of a 74-year-old male who presented with fever and right upper quadrant pain, with positive Murphy's sign on examination. The case was initially managed with a routine cholecystectomy. Histological examination revealed a moderately differentiated adenocarcinoma with a superimposed histologically proven acute acalculous cholecystitis. CT scan done postsurgery showed a cecal mass with retroperitoneal lymphadenopathy. Biopsy result of cecal mass was remarkable for colon adenocarcinoma. We are not aware of any similar prior cases reported in English literature. PMID- 30420931 TI - Radiological-Pathological Correlation in Plasmablastic Lymphoma in an Immunocompromised Patient. AB - Plasmablastic lymphoma (PBL) is a malignant, rare, and aggressive form of non Hodgkin's lymphoma with poor response to treatment that most commonly involves the oral mucosa of immunodeficient patients. The orbit might be primarily or secondarily involved; on the other hand other pathological conditions, i.e., fungal infections, may localize in the orbit in both immunocompromised patients and drug user, which might have similar radiological features. We describe the clinical, radiological, and pathological features of an orbital plasmablastic lymphoma (PBL) in an immunocompromised HIV positive drug user patient. PMID- 30420932 TI - Acanthomatous Ameloblastoma of Mandible in a Paediatric Patient. AB - Ameloblastoma is a slow-growing, benign odontogenic tumor derived from odontogenic epithelial components with a mature fibrous stroma. It is the second most common odontogenic neoplasm following odontome. Acanthomatous ameloblastoma histologically presents with squamous epithelial metaplastic transformation of odontogenic tissue. The present case report of a 12-year-old male exclusively elaborates the issues concerned with the aggressive nature of acanthomatous ameloblastoma (AA) which is a distinctive variant of ameloblastoma. PMID- 30420933 TI - Corrigendum to "Amiodarone Induced Hyponatremia Masquerading as Syndrome of Inappropriate Antidiuretic Hormone Secretion by Anaplastic Carcinoma of Prostate". AB - [This corrects the article DOI: 10.1155/2014/136984.]. PMID- 30420934 TI - A Rare Case of Multiorgan Calciphylaxis in a Patient with Stage 5 Chronic Kidney Disease. AB - Calciphylaxis or calcific uremic arteriolopathy (CUA) is a potentially life threatening vasculopathy involving the skin and subcutaneous tissues. It is usually associated with chronic kidney disease (CKD) and rarely with acute renal failure or predialysis patients. The clinical diagnosis of calcific uremic arteriolopathy relies on high index of suspicion. CUA is commonly associated with secondary hyperparathyroidism and high serum calcium and phosphate products. Moreover, using biopsy as a diagnostic tool is controversial, due to the high risk of poor wound healing and sepsis. Radiological studies usually reveal extensive calcification of branching vessels such as penile arteries, eventually leading to gangrene formation in extremities and penis. Histopathological analysis confirms the diagnosis of calcific uremic arteriolopathy and rules out the presence of malignancy. CUA is a systematic disease that involves multiple organs, and to the best of our knowledge this is the first reported case involving the penis, bladder, and eyes. PMID- 30420935 TI - DNA Nanotweezers with Hydrolytic Activity for Enzyme-Free and Sensitive Detection of Fusion Gene via Logic Operation. AB - Gene fusion is a molecular event occurring in cellular proliferation and differentiation, and the occurrence of irregular fusion gene results in various malignant diseases. So, sensing fusion gene with high performance is an important task for integrating individual disease information. Here, we proposed a nonenzymatic and high-throughput fluorescent assay system for the detection of fusion gene by employing DNA nanotweezers with hydrolytic activity. This tweezer was assembled by three single-stranded DNAs and engineered with sensing elements and reporting subunits. In the absence of the fusion gene, the engineered tweezer remained opened and inactive which led to no signal output. However, the addition of fusion genes would cause structure alterations of the tweezer from open to close and further DNAzyme activation with the assembly of two reporting subunits. Then, the activated DNAzyme catalyzed fluorescence substrates for signal conversion. Taking BCR/ABL fusion gene as an example, the tweezer-based assay system showed not only excellent distinguishing capability towards different input targets but also high sensitivity with a detection limit of 5.29 pM. In addition to good detection performance, this system was simple and enzyme-free, offering a powerful nanometer tool as a smart nanodevice for sensing fusion detection. PMID- 30420936 TI - Quantitative Analysis and Band Gap Determination for CIGS Absorber Layers Using Surface Techniques. AB - Recently, Cu(In X Ga(1-X))Se2 (CIGS) absorber layers have been extensively studied by many research groups for thin-film solar cell technology. CIGS material is particularly promising due to its exceptionally high absorption coefficient and large band gap range, which is adjustable as a function of alloy stoichiometry. To enhance the conversion performance of CIGS solar cells, understanding the CIGS structure and composition is a crucial challenge. We conducted a quantitative study to determine the bulk composition of the major elements such as Cu, In, Ga, and Se of four different CIGS photovoltaic cells. The compositional information was obtained by X-ray fluorescence (XRF), inductively coupled plasma atomic emission spectroscopy (ICP-AES), and femtosecond laser ablation inductively coupled plasma mass spectrometry (fs-LA ICP-MS). Then, the XRF concentration ratio was compared with the intensity ratio of fs-LA-ICP-MS to investigate the potential of accurate and rapid analysis using the fs-LA-ICP-MS technique. In contrast to the bulk information, the surface techniques can supply detailed information about the chemical composition across the depth profile. Here, elemental depth distributions of CIGS thin films were investigated using magnetic sector secondary ion mass spectrometry (SIMS) and Auger electron spectroscopy (AES). The atomic distributions of four different CIGS absorber layers exhibited a good agreement although they were obtained using two different surface instruments, AES and SIMS. Comparative analysis results of different CIGS absorber layers using SIMS, AES, and fs-LA-ICP-MS provide us with the appropriate technique for the information of accurate composition in a rapid analysis time. Thanks to a simple approach using the Ga/(In + Ga) ratio, the optical band gap energy of the Cu(In X Ga(1-X))Se2 quaternary layer was monitored in the entire CIGS layer. The elemental distribution and the band gap determination were then used to elucidate their relationship to the corresponding CIGS cell efficiency result. PMID- 30420937 TI - Combination of Microwave-Assisted Girard Derivatization with Ionic Liquid Matrix for Sensitive MALDI-TOF MS Analysis of Human Serum N-Glycans. AB - We developed a new method for MALDI-TOF MS detection of N-glycans derived from human serum. The synergistic combination of microwave-assisted Girard T derivatization, solid-phase extraction desalting, and an ionic liquid matrix (2, 5-dihydroxybenzoic acid/aniline) (GT-SPE-DHB/An) allowed of more sensitive N glycans detection than a conventional ionic liquid matrix in MALDI-TOF MS. The superior sensitivity of our method was confirmed by the number of assigned N glycans in 900-2,000 m/z range. Using our GT-SPE-DHB/An method, we were successfully able to assign 31 glycans. However, with the established method, i.e., DHB/An method, only 15 glycans were assigned. To the best of our knowledge, this GT-SPE-DHB/An method is the first to combine cationic derivatization of N glycan and ionic liquid matrix for N-glycan analysis in MALDI-TOF MS. PMID- 30420938 TI - Predicting Imminent Aggression Onset in Minimally-Verbal Youth with Autism Spectrum Disorder Using Preceding Physiological Signals. AB - We test the hypothesis that changes in preceding physiological arousal can be used to predict imminent aggression proximally before it occurs in youth with autism spectrum disorder (ASD) who are minimally verbal (MV-ASD). We evaluate this hypothesis through statistical analyses performed on physiological biosensor data wirelessly recorded from 20 MV-ASD youth over 69 independent naturalistic observations in a hospital inpatient unit. Using ridge-regularized logistic regression, results demonstrate that, on average, our models are able to predict the onset of aggression 1 minute before it occurs using 3 minutes of prior data with a 0.71 AUC for global, and a 0.84 AUC for person-dependent models. PMID- 30420939 TI - Standardized Assessment Accommodations for Individuals with Intellectual Disability. PMID- 30420940 TI - Preliminary Feasibility and Acceptability of the Remote Food Photography Method for Assessing Nutrition in Young Children with Type 1 Diabetes. AB - Background: Nutrition is a critical component of diabetes and other chronic diseases for young children. However, nutritional intake is burdensome to measure accurately and easily, making it difficult to evaluate in research or clinical contexts. Objective: This pilot study examined the feasibility and acceptability of having parents of young children with T1D use the Remote Food Photography Method (RFPM) to measure breakfast nutrition. Methods: Participants were 9 mothers of children ages 2-5 years (Mage=4.2), with a T1D duration of at least 1 year (Mage=2.4 years at diagnosis), representing diverse backgrounds (55.6% Caucasian; 44.4% African American; 55.6% married). During baseline and follow-up of a healthy eating and physical activity intervention for children with T1D, parents used the RFPM to capture before and after images of their children's breakfast. Feasibility and acceptability were assessed by adherence to taking photos, percent of usable photos, and participant satisfaction. Results: The RFPM was feasible across participants with high adherence rates (100% at baseline and 87% at follow-up) for sending usable photographs. Most participants reported satisfaction with the method. Conclusions: Using the RFPM to assess nutrition in a small sample of young children with T1D was feasible and acceptable. Given the importance of assessing nutrition in young children with T1D as well as other chronic illnesses (e.g., cystic fibrosis, obesity), the RFPM may be a useful tool for both research and clinical data collection in lieu of other methods. More research is needed to evaluate reliability and validity of RFPM in pediatric populations. PMID- 30420941 TI - Endophytic Fungus Isolated From Achyrocline satureioides Exhibits Selective Antiglioma Activity-The Role of Sch-642305. AB - Glioblastoma is the most devastating primary brain tumor. Current treatment is palliative, making necessary the development of new therapeutic strategies to offer alternatives to patients. Therefore, endophytes represent an interesting source of natural metabolites with anticancer potential. These microorganisms reside in tissues of living plants and act to improve their growth. Evidence revealed that several medicinal plants are colonized by endophytic fungi producer of antitumor metabolites. Achyrocline satureioides is a Brazilian medicinal plant characterized by its properties against gastrointestinal disturbances, anticancer and antioxidant effects. However, there are no reports describing the endophytic composition of A. satureioides. The present study proposes the isolation of endophytic fungus from A. satureioides, extract preparation, phytochemical characterization and evaluation of its antiglioma potential. Our data showed that crude extracts of endophyte decreased glioma viability with IC50 values of 1.60 1.63 MUg/mL to eDCM (dichloromethane extract) and 37.30-55.12 MUg/mL to eEtAc (ethyl acetate extract), respectively. Crude extracts induced cell death by apoptosis with modulation of redox status. In order to bioprospect anticancer metabolites, endophytic fungus extracts were subjected to guided fractionation and purification yielded five fractions of each extract. Six of ten fractions showed selective antiproliferative activity against glioma cells, with IC50 values ranged from 0.95 to 131.3 MUg/mL. F3DCM (from eDCM) and F3EtAc (from eEtAc) fractions promoted C6 glioma toxicity with IC50 of 1.0 and 27.05 MUg/mL, respectively. F3EtAc fraction induced late apoptosis and arrest in G2/M stage, while F3DCM promoted apoptosis with arrest in Sub-G1 phase. Moreover, F3DCM increased antioxidant defense and decreased ROS production. Additionally, F3DCM showed no cytotoxic activity against astrocytes, revealing selective effect. Based on promising potential of F3DCM, we identified the production of Sch 642305, a lactone, which showed antiproliferative properties with IC50 values of 1.1 and 7.6 MUg/mL to C6 and U138MG gliomas, respectively. Sch-642305 promoted arrest on cell cycle in G2/M inducing apoptosis. Furthermore, this lactone decreased glioma cell migration and modulated redox status, increasing superoxide dismutase and catalase activities and enhancing sulfhydryl content, consequently suppressing reactive species of oxygen generation. Taken together, these results indicate that metabolites produced by endophytic fungus isolated from A. satureioides have therapeutic potential as antiglioma agent. PMID- 30420942 TI - Prognostic Effect of Bisphosphonate Exposure for Patients With Diagnosed Solid Cancer: A Systematic Review With Meta-Analysis of Observational Studies. AB - Background: Bisphosphonates are widely prescribed for the prevention and treatment of osteoporosis. Recent epidemiological studies indicate that people with bisphosphonate use may have lower cancer risk and have improved survival. The aim of this study is to determine the association between bisphosphonate use and survival outcomes in solid cancer patients using systematic review and meta analysis. Methods: A systematic literature search was performed using the PubMed, Embase, and Cochrane databases. Original articles published until April, 2018 were selected. The survival outcome measures assessed included overall survival (OS), cancer-specific survival (CSS) and recurrence-free survival (RFS). Pooled hazard ratio (HR) and their 95% confidence interval (95% CI) were derived using a random-effects model. Results: Out of 9,742 retrieved citations, six cohort studies and two nested case-control studies satisfying the inclusion criteria were included for analyses. Bisphosphonate use was significantly associated with improved OS (HR 0.84, 95% CI 0.76-0.93), CSS (HR 0.73, 95% CI 0.58-0.90) and RFS (HR 0.72, 95% CI 0.53-0.96). The results of subgroup analyses stratified by major study characteristics were generally consistent with the main findings. For individual cancer type, we found that bisphosphonate use was significantly associated with longer OS for patients with gastroesophageal cancer (HR 0.62, 95% CI 0.40-0.98), as well as longer CSS for patients with breast cancer (HR 0.73, 95% CI 0.55-0.95). Conclusions: Current evidence indicates that bisphosphonate use is significantly associated with improved survival for patients with solid cancer. However, the prognostic effects in specific solid tumors remains to be confirmed by further large prospective cohort studies. PMID- 30420943 TI - Reassessing the Role of Entamoeba gingivalis in Periodontitis. AB - The protozoan Entamoeba gingivalis resides in the oral cavity and is frequently observed in the periodontal pockets of humans and pets. This species of Entamoeba is closely related to the human pathogen Entamoeba histolytica, the agent of amoebiasis. Although E. gingivalis is highly enriched in people with periodontitis (a disease in which inflammation and bone loss correlate with changes in the microbial flora), the potential role of this protozoan in oral infectious diseases is not known. Periodontitis affects half the adult population in the world, eventually leads to edentulism, and has been linked to other pathologies, like diabetes and cardiovascular diseases. As aging is a risk factor for the disorder, it is considered an inevitable physiological process, even though it can be prevented and cured. However, the impact of periodontitis on the patient's health and quality of life, as well as its economic burden, are underestimated. Commonly accepted models explain the progression from health to gingivitis and then periodontitis by a gradual change in the identity and proportion of bacterial microorganisms in the gingival crevices. Though not pathognomonic, inflammation is always present in periodontitis. The recruitment of leukocytes to inflamed gums and their passage to the periodontal pocket lumen are speculated to fuel both tissue destruction and the development of the flora. The individual contribution to the disease of each bacterial species is difficult to establish and the eventual role of protozoa in the fate of this disease has been ignored. Following recent scientific findings, we discuss the relevance of these data and propose that the status of E. gingivalis be reconsidered as a potential pathogen contributing to periodontitis. PMID- 30420944 TI - Overshadow Effect of Psl on Bacterial Response to Physiochemically Distinct Surfaces Through Motility-Based Characterization. AB - Biofilms of Pseudomonas aeruginosa are ubiquitously found on surfaces of many medical devices, which are the major cause of hospital-acquired infections. A large amount of work has been focused on bacterial attachment on surfaces. However, how bacterial cells evolve on surfaces after their attachment is the key to get better understanding and further control of biofilm formation. In this work, by employing both single-cell- and collective-motility of cells, we characterized the bacterial surface movement on physiochemically distinct surfaces. The measurement of cell surface motility showed consistent results that gold and especially platinum surfaces displayed a stronger capability in microcolony formation than polyvinyl chloride and polycarbonate surfaces. More interestingly, we found that overproduction of Psl led to a narrower variance in cell surface motility among tested surfaces, indicating an overshadow effect of Psl for bacteria by screening the influence of physicochemical properties of solid surfaces. Our results provide insights into how Pseudomonas aeruginosa cells adapt their motion to physiochemically distinct surfaces, and thus would be beneficial for developing new anti-biofouling techniques in biomedical engineering. PMID- 30420945 TI - Challenges in Pediatric Cardiac Anesthesia in Developing Countries. AB - Introduction: Approximately 90% of a million children worldwide born with congenital heart defect do not have an access to adequate pediatric cardiac care. The World Society for Pediatric and Congenital Heart Surgery, established in 2006 shifted the focus from providing individual pediatric cardiac care to developing global standards for the practice of pediatric cardiac surgery and professional education of the local teams. Materials and Methods: After recognizing the challenges of the local team regarding providing safe anesthesia and functioning as a broader team, we have focused our education on simplifying anesthetic procedures and advancing structured team approach. The appropriate selection of patients and simplifying anesthetic technique should be the standard of care. We introduced structured approach to daily education using just in time teaching, case based discussions and simple skill training simulation sessions. Furthermore, we enhanced team-training approach applying tools such as WHO surgical safety checklist and implementation manual, SAFE communication, introducing KDD with SMART aim, SCAMPs, advanced protocols of care and culture change tools. Results: Following a significant number of short missions to developing centers we have, within NGO, succeeded to support building and maintaining several local pediatric cardiac centers with structured approach to anesthesia and team building. Conclusion: The appropriate selection of patients is one of the most important contributing factors for decreasing morbidity and mortality rate in pediatric cardiac surgery patients. The anesthesia technique for pediatric cardiac procedures should be aimed at fast-track surgery, with early extubation as a goal. Regional blocks such as paravertebral and caudal should be considered for perioperative pain control. By introducing structured approach to daily education and by enhancing team-training approach we have contributed evolving sustainable pediatric cardiac centers in developing countries. PMID- 30420947 TI - Key Components for Antibiotic Dose Optimization of Sepsis in Neonates and Infants. AB - Sepsis in neonates and infants remains a major cause of death despite a decline in child mortality and morbidity over the last decades. A key factor in further reducing poor clinical outcomes is the optimal use of antibiotics in sepsis management. Developmental changes such as maturation of organ function and capacity of drug metabolizing enzymes can affect the pharmacokinetic profile and therefore the antibiotic exposure and response in neonates and infants. Optimal antibiotic treatment of sepsis in neonates and young infants is dependent on several key components such as the determination of treatment phase, the administered dose and the resulted drug exposure and microbiological response. During the initial phase of suspected sepsis, the primary focus of empirical treatment is to assure efficacy. Once bacterial infection as the cause of sepsis is confirmed the focus shifts toward a targeted treatment, ensuring an optimal balance between efficacy and safety. Interpretation of antibiotic exposure and microbiological response in neonates and infants is multifaceted. The response or treatment effect can be determined by the microbiological parameters (MIC) together with the characteristics of the pathogen (time- or concentration dependent). The antibiotic response is influenced by the properties of the causative pathogen and the unique characteristics of the vulnerable patient population such as reduced humoral response or reduced skin barrier function. Therapeutic drug monitoring (TDM) of antibiotics may be used to increase effectiveness while maximizing safety and minimizing the toxicity, but requires expertise in different fields and requires collaborations between physicians, lab technicians, and quantitative clinical pharmacologists. Understanding these clinical, pharmacological, and microbiological components and their underlying relationship can provide a scientific basic for proper antibiotic use and reduction of antibiotic resistance in neonates and infants. This highlights the necessity of a close multidisciplinary collaboration between physicians, pharmacists, clinical pharmacologists and microbiologist to assure the optimal utilization of antibiotics in neonates and young infants. PMID- 30420948 TI - Plane Double-Layer Structure of AC@S Cathode Improves Electrochemical Performance for Lithium-Sulfur Battery. AB - Due to the high theoretical specific capacity of lithium-sulfur batteries, it is considered the most promising electrochemical energy storage device for the next generation. However, the development of lithium-sulfur battery has been restricted by its low cycle efficiency and low capacity. We present a Plane double-layer structure of AC@S cathode to improve the electrochemical performance of lithium-sulfur batteries. The battery with this cathode showed good electrochemical performance. The initial discharge capacity of the battery with the structure of AC@S cathode could reach 1,166 mAhg-1 at 0.1 C. After 200 cycles, it still remains a reversible capacity of 793 mAh g-1 with a low fading rate of 0.16% per cycle. Furthermore, the batteries could hold a discharge capacity of 620 mAh g-1 after 200 cycles at a typical 0.5 C rate. The improvement of electrochemical performance is attributed to that the polysulfide produced during charge/discharge can be better concentrated in the cathode by the planar double-layer structure, thus reducing the loss of sulfur. PMID- 30420946 TI - Fluid Overload in Critically Ill Children. AB - Background: A common practice in the management of critically ill patients is fluid resuscitation. An excessive administration of fluids can lead to an imbalance in fluid homeostasis and cause fluid overload (FO). In pediatric critical care patients, FO can lead to a multitude of adverse effects and increased risk of morbidity. Objectives: To review the literature highlighting impact of FO on a multitude of outcomes in critically-ill children, causative vs. associative relationship of FO with critical illness and current pediatric fluid management guidelines. Data Sources: A literature search was conducted using PubMed/Medline and Embase databases from the earliest available date until June 2017. Data Extraction: Two authors independently reviewed the titles and abstracts of all articles which were assessed for inclusion. The manuscripts of studies deemed relevant to the objectives of this review were then retrieved and associated reference lists hand-searched. Data Synthesis: Articles were segregated into various categories namely pathophysiology and sequelae of fluid overload, assessment techniques, epidemiology and fluid management. Each author reviewed the selected articles in categories assigned to them. All authors participated in the final review process. Conclusions: Recent evidence has purported a relationship between mortality and FO, which can be validated by prospective RCTs (randomized controlled trials). The current literature demonstrates that "clinically significant" degree of FO could be below 10%. The lack of a standardized method to assess FB (fluid balance) and a universal definition of FO are issues that need to be addressed. To date, the impact of early goal directed therapy and utility of hemodynamic parameters in predicting fluid responsiveness remains underexplored in pediatric resuscitation. PMID- 30420949 TI - Nutritional Value of the Duckweed Species of the Genus Wolffia (Lemnaceae) as Human Food. AB - Species of the genus Wolffia are traditionally used as human food in some of the Asian countries. Therefore, all 11 species of this genus, identified by molecular barcoding, were investigated for ingredients relevant to human nutrition. The total protein content varied between 20 and 30% of the freeze-dry weight, the starch content between 10 and 20%, the fat content between 1 and 5%, and the fiber content was ~25%. The essential amino acid content was higher or close to the requirements of preschool-aged children according to standards of the World Health Organization. The fat content was low, but the fraction of polyunsaturated fatty acids was above 60% of total fat and the content of n-3 polyunsaturated fatty acids was higher than that of n-6 polyunsaturated fatty acids in most species. The content of macro- and microelements (minerals) not only depended on the cultivation conditions but also on the genetic background of the species. This holds true also for the content of tocopherols, several carotenoids and phytosterols in different species and even intraspecific, clonal differences were detected in Wolffia globosa and Wolffia arrhiza. Thus, the selection of suitable clones for further applications is important. Due to the very fast growth and the highest yield in most of the nutrients, Wolffia microscopica has a high potential for practical applications in human nutrition. PMID- 30420951 TI - Controlled Human Infections As a Tool to Reduce Uncertainty in Clinical Vaccine Development. AB - Vaccines can be extremely cost-effective public health measures. Unfortunately the research and development (R&D) of novel vaccines is suffering from rising costs and declining success rates. Because many vaccines target low- and middle income markets (LMIC), output needs to be maintained at a constrained budget. In addition, scientific neglect and political uncertainty around reimbursement decisions make it an unattractive arena for private investors. The vaccine development pipeline for LMIC thus is in need for a different, sustainable, and cost-effective development model. In conventional vaccine development, objectives for every clinical development phase have been predefined. However, given the scarcity of resources, the most efficient clinical development path should identify vaccine candidates with the highest potential impact as soon as possible. We argue for a custom-made question-based development path based on the scientific questions, success probabilities and investments required. One question can be addressed by several studies and one study can provide partial answers to multiple questions. An example of a question-based approach is the implementation of a controlled human malaria infection model (CHMI). Malaria vaccine R&D faces major scientific challenges and has limited resources. Therefore, early preliminary efficacy data needs to be obtained in order to reallocate resources as efficiently as possible and reduce clinical development costs. To meet this demand, novel malaria vaccines are tested for efficacy in so called CHMI trials in which small groups of healthy volunteers are vaccinated and subsequently infected with malaria. Early evaluation studies of critical questions, such as CHMI, are highly rewarding, since they prevent expenditures on projects that are unlikely to succeed. Each set of estimated probabilities and costs (combined with market value) will have its own optimal priority sequence of questions to address. Algorithms can be designed to determine the optimal order in which questions should be addressed. Experimental infections of healthy volunteers is an example of how a question-based approach to vaccine development can be implemented and has the potential to change the arena of clinical vaccine development. PMID- 30420950 TI - Heavy Metal Removal by Bioaccumulation Using Genetically Engineered Microorganisms. AB - Wastewater effluents from mines and metal refineries are often contaminated with heavy metal ions, so they pose hazards to human and environmental health. Conventional technologies to remove heavy metal ions are well-established, but the most popular methods have drawbacks: chemical precipitation generates sludge waste, and activated carbon and ion exchange resins are made from unsustainable non-renewable resources. Using microbial biomass as the platform for heavy metal ion removal is an alternative method. Specifically, bioaccumulation is a natural biological phenomenon where microorganisms use proteins to uptake and sequester metal ions in the intracellular space to utilize in cellular processes (e.g., enzyme catalysis, signaling, stabilizing charges on biomolecules). Recombinant expression of these import-storage systems in genetically engineered microorganisms allows for enhanced uptake and sequestration of heavy metal ions. This has been studied for over two decades for bioremediative applications, but successful translation to industrial-scale processes is virtually non-existent. Meanwhile, demands for metal resources are increasing while discovery rates to supply primary grade ores are not. This review re-thinks how bioaccumulation can be used and proposes that it can be developed for bioextractive applications-the removal and recovery of heavy metal ions for downstream purification and refining, rather than disposal. This review consolidates previously tested import storage systems into a biochemical framework and highlights efforts to overcome obstacles that limit industrial feasibility, thereby identifying gaps in knowledge and potential avenues of research in bioaccumulation. PMID- 30420952 TI - MicroRNA-141 and MicroRNA-200c Are Overexpressed in Granulosa Cells of Polycystic Ovary Syndrome Patients. AB - Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in reproductive-aged women, affecting 6-8% of women and characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. Accumulating evidence demonstrates that different microRNAs (miRNAs) expressions may contribute to the pathogenesis of PCOS. Therefore, the goal of this study is to compare the expression levels of miR-141 and miR-200c in granulosa cells isolated from PCOS patients and also evaluate their predictive values for pregnancy complications. First, RNA extraction, reverse transcription, and reverse transcription-polymerase chain reaction (RT-PCR) were performed to assess the expression levels of miR-141 and miR-200c in granulosa cells isolated from 62 PCOS patients and 61 controls. Second, according to each mean of miR-141 and miR 200c measured values in all patients, PCOS, and controls were divided into low expression group and high-expression group to better evaluate their predictive values for pregnancy complications. Significantly elevated expressions of miR-141 and miR-200c were observed in PCOS patients compared with the controls (p < 0.001 and p = 0.002, respectively). Furthermore, PCOS patients had a significantly increased incidence of pregnancy complications in low-expression groups of miR 141 and miR-200c (p = 0.007 and p = 0.002, respectively). Our findings demonstrated that the expressions of both miR-141 and miR-200c were significantly increased in PCOS patients, which might contribute to the pathogenesis of PCOS. PCOS patients had an increased risk of pregnancy complications in low-expression groups of both miR-141 and miR-200c. PMID- 30420954 TI - Recent Advances in Short QT Syndrome. AB - Short QT syndrome is a highly malignant inherited cardiac disease characterized by ventricular tachyarrhythmias leading to syncope and sudden cardiac death. It is responsible of lethal episodes in young people, mainly infants. International guidelines establish diagnostic criteria with the presence of a QTc <= 340 ms in the electrocardiogram despite clinical diagnostic values remain controversial. In last years, clinical diagnosis, risk stratification as well as preventive therapies have been improved due to identification of pathophysiological mechanisms. The only effective option is implantation of a defibrillator despite Quinidine may be at times an effective option. Currently, a limited number of rare variants have been identified in seven genes, which account for nearly 20 30% of families. However, some of these variants are associated with phenotypes showing a shorter QT interval but no conclusive diagnosis of Short QT syndrome. Therefore, an exhaustive interpretation of each variant and a close genotype phenotype correlation is necessary before clinical translation. Here, we review the main clinical and genetic hallmarks of this rare entity. PMID- 30420955 TI - Molecular Investigation of the Transmission Pattern of Brucella suis 3 From Inner Mongolia, China. AB - Brucellosis is an endemic disease in China affecting both humans and livestock. The aim of the present study was to analyze two Brucella strains isolated from sheep spleens from Ulanqab in Inner Mongolia, China using classical and molecular typing techniques. The two strains were identified as Brucella suis biovar 3 and were closely related to isolates previously obtained from two different hosts (human and swine) in Guangxi Province. Our results suggest that B. suis can be directly or indirectly transferred from swine to sheep, which act as reservoirs for B. suis infection and later transmitted to humans. Multiple locus variable number tandem repeat analysis (MLVA) is a useful tool for tracing the geographical origin of brucellosis infections and elucidating its transmission patterns. PMID- 30420953 TI - Inherited Disorders of Iron Overload. AB - Dietary iron absorption and systemic iron traffic are tightly controlled by hepcidin, a liver-derived peptide hormone. Hepcidin inhibits iron entry into plasma by binding to and inactivating the iron exporter ferroportin in target cells, such as duodenal enterocytes and tissue macrophages. Hepcidin is induced in response to increased body iron stores to inhibit further iron absorption and prevent iron overload. The mechanism involves the BMP/SMAD signaling pathway, which triggers transcriptional hepcidin induction. Inactivating mutations in components of this pathway cause hepcidin deficiency, which allows inappropriately increased iron absorption and efflux into the bloodstream. This leads to hereditary hemochromatosis (HH), a genetically heterogenous autosomal recessive disorder of iron metabolism characterized by gradual buildup of unshielded non-transferrin bound iron (NTBI) in plasma and excessive iron deposition in tissue parenchymal cells. The predominant HH form is linked to mutations in the HFE gene and constitutes the most frequent genetic disorder in Caucasians. Other, more severe and rare variants are caused by inactivating mutations in HJV (hemojuvelin), HAMP (hepcidin) or TFR2 (transferrin receptor 2). Mutations in SLC40A1 (ferroportin) that cause hepcidin resistance recapitulate the biochemical phenotype of HH. However, ferroportin-related hemochromatosis is transmitted in an autosomal dominant manner. Loss-of-function ferroportin mutations lead to ferroportin disease, characterized by iron overload in macrophages and low transferrin saturation. Aceruloplasminemia and atransferrinemia are further inherited disorders of iron overload caused by deficiency in ceruloplasmin or transferrin, the plasma ferroxidase and iron carrier, respectively. PMID- 30420956 TI - Action and Non-Action Oriented Body Representations: Insight from Behavioural and Grey Matter Modifications in Individuals with Lower Limb Amputation. AB - Objective: Following current model of body representations, we aimed to systematically investigate the association between brain modifications, in terms of grey matter loss, and body representation deficits, in terms of alterations of the body schema (BS) and of non-action oriented body representations (NA), in individuals with lower limb amputation (LLA). Method: BS and NA (both semantic and visuospatial NA) were evaluated in 11 healthy controls and in 14 LLA, considering the impact of clinical variables such as prosthesis use. The association between BS and NA deficits and grey matter loss was also explored in LLA by using Voxel Based Morphometry analysis. Results: LLA's performance was fine in terms of semantic NA, while it showed behavioural impairments both in BS and visuospatial NA as compared to healthy controls. Interestingly the visuospatial NA performance was related to the amount of prosthesis use. NA deficits in terms of visuospatial body map processing were associated with grey matter reduction in left (lobule VIII) and right (crus II) cerebellum, while BS deficits were associated with grey matter reduction in right anterior cingulate cortex and the bilateral cuneus. No significant association was detected for semantic NA. Conclusion: The study of BS and NA representations after limb loss has informed our understanding of the different dynamics (i.e., adjustments to body change) of such representations, supporting current cognitive models of body representation. The clinical relevance of present findings is also discussed. PMID- 30420957 TI - Cosmetic Reconstruction of Frontotemporal Depression Using Polyethylene Implant after Pterional Craniotomy. AB - Purpose: Pterional craniotomy is a useful approach for the treatment of a variety of intracranial pathologies. However, it can result in temporal hollowing, which causes significant craniomaxillofacial asymmetry and esthetic deformity. The present study was performed to determine the postoperative outcomes of patients following frontotemporal depression reconstruction using a high-density porous polyethylene (HDPE) implant (Medpor(r); Stryker, Kalamazoo, MI) after pterional craniotomy. Materials and Methods: The patients had undergone reconstruction of frontotemporal depression using Medpor(r) implants after pterional craniotomy at our medical institution during the period from February 2010 to March 2014. We evaluated the thickness and volume of both the temporalis muscle and Medpor(r) implant through a retrospective review of the medical records and computed tomography (CT) scans of 92 patients. Results: The mean temporalis muscle thickness ratio (muscle thickness of the affected side/nonaffected side) was 0.61 +/- 0.16. The mean reconstructed temporalis muscle thickness ratio (muscle and Medpor(r) implant thickness of affected side/muscle thickness of nonaffected side) was 1.15 +/- 0.02. The mean temporalis muscle volume ratio (muscle volume of affected side/nonaffected side) was 0.67 +/- 0.02. The mean reconstructed temporalis muscle volume ratio (muscle and Medpor(r) implant volume of affected side/muscle volume of nonaffected side) was 1.18 +/- 0.02. Conclusions: Temporalis muscle thickness and volume were significantly decreased on the affected side after pterional craniotomy. Reconstruction of frontotemporal lesions using Medpor(r) implants after the pterional approach improved temporal hollowing without additional complications. PMID- 30420958 TI - Predicting Advanced Prostate Cancer from Modeling Early Indications in Biopsy and Prostatectomy Samples via Transductive Semi-Supervised Survival Analysis. AB - Prostate cancer is the most prevalent form of cancer and the second most common cause of cancer deaths among men in the United States. Accurate prognosis is important as it is the principal factor in determining the treatment plan. Prostate cancer is a complex disease which advances in stages. While clinical failure (including metastasis) is a significant endpoint following a radical prostatectomy, it can often take years to manifest, usually too late to be optimistically treated. In practice, the earlier endpoint of PSA Recurrence is frequently used as a surrogate in prognostic modeling. The central issue in these models is managing censored observations which challenge traditional regression techniques. The true target times of a majority of instances are unknown; what is known is a censored target representing some earlier indeterminate time. In this work we apply a novel transduction approach for semi-supervised survival analysis which has previously been shown to be powerful in medical prognosis. The approach considers censored samples as semi-supervised regression targets leveraging the partial nature of unsupervised information. We explore the use of this approach in building prostate cancer progression models from multimodal characteristics extracted from both biopsy and prostatectomy tissues samples. In this work, the approach leads to a significant increase in performance for predicting advanced prostate cancer from earlier endpoints and may also be useful in other diseases for predicting advanced endpoints from earlier stages of the disease. PMID- 30420959 TI - Brief Report: Exercise and Anxiety in Adults with Arthritis and Other Rheumatic Diseases: Support for Evidential Value. AB - Objective: Given the high prevalence of anxiety in adults with arthritis and other rheumatic diseases (AORD) and the subsequent need for interventions to reduce anxiety, this brief report sought to determine if evidential value exists to support the role of exercise for reducing anxiety in adults with AORD. Methods: Utilizing data from a prior meta-analysis, a recently developed approach, P-curve, was used to determine evidential value by assessing for publication bias and p-hacking. Binomial tests as well as the more robust Stouffer's test were used to examine for evidential value. To examine the influence of selected studies on p-curve results, findings were also examined by dropping the highest and lowest p values from the analysis. Results: The binomial test for evidential value was not statistically significant (p = 0.11) while the more robust Stouffer's test satisfied both conditions for evidential value (p = 0.002). Power analyses suggested a good fit for the observed p-curve. Results were generally robust when the least and most extreme values were excluded. Conclusions: The results of this study provide evidential support for the benefits of exercise on anxiety in adults with AORD. PMID- 30420961 TI - Impact in Participatory Health Research. PMID- 30420960 TI - Efficacy of Second-Look Ultrasound with MR Coregistration for Evaluating Additional Enhancing Lesions of the Breast: Review of the Literature. AB - Contrast enhanced magnetic resonance imaging (CE-MRI) has acquired a central role in the field of diagnosis and evaluation of breast cancer due to its high sensitivity; on the other hand, MRI has shown a variable specificity because of the wide overlap between the imaging features of benign and malignant lesions. Therefore, when an additional breast lesion is identified at CE-MRI, a second look with targeted US is generally performed because it provides additional information to further characterise the target lesion and makes it possible to perform US-guided biopsies which are costless and more comfortable for patients compared with MRI-guided ones. Nevertheless, there is not always a correspondence between CE-MR findings and targeted US due to several factors including different operator's experience and position of patients. A new technique has recently been developed in order to overcome these limitations: US with MR coregistration, which can synchronise a sonography image and the MR image with multiplanar reconstruction (MPR) of the same section in real time. The aim of our study is to review the literature concerning the second look performed with this emerging and promising technique, showing both advantages and limitations in comparison with conventional targeted US. PMID- 30420962 TI - Biomechanical Analysis Using FEA and Experiments of Metal Plate and Bone Strut Repair of a Femur Midshaft Segmental Defect. AB - This investigation assessed the biomechanical performance of the metal plate and bone strut technique for fixing recalcitrant nonunions of femur midshaft segmental defects, which has not been systematically done before. A finite element (FE) model was developed and then validated by experiments with the femur in 15 deg of adduction at a subclinical hip force of 1 kN. Then, FE analysis was done with the femur in 15 deg of adduction at a hip force of 3 kN representing about 4 x body weight for a 75 kg person to examine clinically relevant cases, such as an intact femur plus 8 different combinations of a lateral metal plate of fixed length, a medial bone strut of varying length, and varying numbers and locations of screws to secure the plate and strut around a midshaft defect. Using the traditional "high stiffness" femur-implant construct criterion, the repair technique using both a lateral plate and a medial strut fixed with the maximum possible number of screws would be the most desirable since it had the highest stiffness (1948 N/mm); moreover, this produced a peak femur cortical Von Mises stress (92 MPa) which was below the ultimate tensile strength of cortical bone. Conversely, using the more modern "low stiffness" femur-implant construct criterion, the repair technique using only a lateral plate but no medial strut provided the lowest stiffness (606 N/mm), which could potentially permit more in line interfragmentary motion (i.e., perpendicular to the fracture gap, but in the direction of the femur shaft long axis) to enhance callus formation for secondary type fracture healing; however, this also generated a peak femur cortical Von Mises stress (171 MPa) which was above the ultimate tensile strength of cortical bone. PMID- 30420963 TI - Time Course Changes of the Mechanical Properties of the Iris Pigment Epithelium in a Rat Chronic Ocular Hypertension Model. AB - Background: The flow field of aqueous humor correlates to the stiffness of iris pigment epithelium (IPE) which acts as a wall of posterior chamber. We focus on the variations of IPE stiffness in a rat ocular hypertension (OHT) model, so as to prepare for exploring the mechanism of duration of OHT. Methods: Episcleral venous cauterization (EVC) was applied on one eye of male adult Sprague-Dawley rats to induce chronic high intraocular pressure. According to the duration of OHT (0, 1, 2, 4, and 8 weeks), rats were randomly divided into Gw0, Gw1, Gw2, Gw4, and Gw8. Atomic force microscope (AFM) analysis was applied to test IPE stiffness in three regions: iris root, mid-periphery, and pupillary-margin in each group. Histological changes of IPE were also examined in Gw4 and Gw8. Results: There was an overall growing tendency of IPE stiffness in EVC eye. IPE in EVC eye was significantly stiffer than fellow eye in Gw2, Gw4, and Gw8 (in iris root, mid-periphery, and pupillary-margin, p<0.05). IPE in EVC eye in pupillary-margin was significantly stiffer than iris root in Gw4 and Gw8 (p<0.05). In EVC eye, IPE becomes thinner and IPE cell density decreases. Conclusion: IPE stiffness increases gradually with the duration of chronic high intraocular pressure. PMID- 30420964 TI - The Influence of Position of the Displaced Lesser Trochanter on Clinical Outcome of Unstable Trochanteric Femur Fractures in the Elderly. AB - Purpose: This study aimed to evaluate whether position of the displaced lesser trochanter affected clinical outcome in the treatment of unstable trochanteric fractures with intramedullary fixation. Patients and Methods: Patients with unstable trochanteric fractures and displaced lesser trochanter who received intramedullary fixation were retrospectively reviewed in this study. Based on displacement distance of the lesser trochanter and whether the lesser trochanter was reduced operatively, patients were divided into three groups: patients with the displaced lesser trochanter less than 1cm (Group A), those with the displaced lesser trochanter more than 1 cm without operative reduction (Group B), or those with operative reduction (Group C). The surgical time, reduction quality, Harris Hip Score (HHS), Visual Analog Score (VAS), and complication rate were reviewed. Results: There were 42 patients in Group A, 33 in Group B, and 36 in Group C with comparable demographic characteristics. The surgical time was significantly longer in Group C (P=0.009), compared with Groups A and B. Fracture reduction quality was comparable with over 85% good reduction among the three groups. The VAS score was significantly higher in Group B (P=0.023) without significant difference between Groups A and B. The HHS score was slightly lower in Group B, but it did not reach significant difference. The complication rate was statistically higher in Group B (p=0.043) than Groups A and C. Conclusion: The severe displaced lesser trochanter may increase postoperative complications and postoperative pain in the treatment of unstable trochanteric femur fractures. However, the displaced lesser trochanter may not affect hip function. PMID- 30420965 TI - Effects of Two Types of 9-Month Adapted Physical Activity Program on Muscle Mass, Muscle Strength, and Balance in Moderate Sarcopenic Older Women. AB - The present study aimed to evaluate the effects of two types of 9-month adapted physical activity (APA) program, based on a muscle reinforcement training and a postural training, respectively, on muscle mass, muscle strength, and static balance in moderate sarcopenic older women. The diagnosis of sarcopenia was done in accordance with measurable variables and cut-off points suggested by the European Working Group on Sarcopenia in Older People (EWGSOP). Seventy-two participants were randomly assigned to two groups: the muscle reinforcement training group (RESISTANCE) (n=35; 69.9 +/- 2.7 years) and the postural training group (POSTURAL) (n=37; 70.0+/-2.8 years). Body composition, muscle mass, skeletal muscle mass index (SMI), and handgrip strength (HGS) were evaluated for sarcopenia assessment, whereas Sway Path, Sway Area, Stay Time, and Spatial Distance were evaluated for static balance assessment. Sixty-six participants completed the study (RESISTANCE group: n=33; POSTURAL group: n=33). Significant increases of muscle mass, SMI, and handgrip strength values were found in the RESISTANCE group, after muscle reinforcement program. No significant differences appeared in the POSTURAL group, after postural training. Furthermore, RESISTANCE group showed significant improvements in static balance parameters, whereas no significant differences appeared in the POSTURAL group. On the whole, the results of this study suggest that the APA program based on muscle reinforcement applied on moderate sarcopenic older women was able to significantly improve muscle mass and muscle strength, and it was also more effective than the applied postural protocol in determining positive effects on static balance. PMID- 30420966 TI - Cyclin G2 Suppresses Glomerulosclerosis by Regulating Canonical Wnt Signalling. AB - Recent data has shown that cyclin G2 (CCNG2) is an atypical cyclin that inhibits cell cycle progression and is often dysregulated in human cancers. The involvement of cyclin G2 in the occurrence and development of diabetic nephropathy (DN) has not been determined. In the present study, we conducted cyclin G2 knockout studies to determine whether this protein regulates glomerulosclerosis in DN mice. We found that cyclin G2 regulated the expression of renal glomerulosclerosis-related proteins via the canonical Wnt signalling pathway in glomerular mesangial cells. A cyclin G2 deficiency resulted in more severe renal injury in DN mice. These findings provided new insight into the pathogenesis of DN, revealing that cyclin G2 has a protective role in glomerulosclerosis and is a potential new target for the prevention and treatment of DN. PMID- 30420967 TI - Knockdown of BCL6 Inhibited Malignant Phenotype and Enhanced Sensitivity of Glioblastoma Cells to TMZ through AKT Pathway. AB - Background: BCL6 was a critical prooncogene of human B-cell lymphomas which promoted tumor progress and contributed to malignant behavior in several kinds of cancers. This study was to detect the expression of BCL6 and its biological effect on glioma. Methods: RT-PCR and Western blot were used to detect the expression of BCL6 mRNA and protein in tissues and glioblastoma cell lines. The expression of BCL6 was knockdown in two glioblastoma cell lines (U87 and U251) using BCL6 shRNA. The CCK8, colony-formation, flow cytometry, Transwell, and wound-healing assays were used to evaluate the malignant phenotypic change of glioblastoma cells. Results: The expression of BCL6 was higher in glioma tissues and glioblastoma cell lines than normal tissues. Knockdown of BCL6 expression reduced the proliferation, migration, and invasion of glioblastoma cells. Moreover, knockdown of BCL6 changed expression of proteins related to malignant behaviors of glioblastoma cells. The suppression of BCL6 could increase chemosensitivity of U87 and U251 to temozolomide. Downregulation of BCL6 levels suppressed the expression of BCL2, cyclin D1, MMP2, and MMP9 proteins as well as two classic signaling pathway proteins p-AKT and p-ERK. Simultaneously, BAX and p21 protein levels were upregulated along with knockdown of BCL6. Conclusions: Our results indicated that BCL6 may be a tumor oncogene involved in the progression of glioma via affecting AKT and MAPK signaling pathways. PMID- 30420968 TI - Percutaneous Total Endoscopic Resection of Partial Articular Processes for Treatment of Lateral Crypt Stenosis and Lumbar Spinal Stenosis: Technical Report and Efficacy Analysis. AB - Objective: To observe the clinical curative effect of posterior total endoscopic precision decompression for the treatment of single-segment lateral crypt lumbar spinal stenosis (LSS). Method: A total of 27 patients with single-segment LSS satisfying the inclusion criteria were recruited from July 2013 to September 2015. There were 18 cases of unilateral stenosis of the L4-5 segments and 9 cases of unilateral stenosis of the L5-S1 segment. All patients were treated via the posterior approach with the precise lateral crypt decompression technique. Precise decompression was performed on the narrow areas causing clinical symptoms. Clinical efficacy was assessed at 3 days, 3 months, 6 months, and 2 years after surgery. Low-back pain and sciatic nerve pain assessed by visual analog scale (VAS) score and the functional Oswestry Disability Index (ODI) were used to evaluate lumbar function, and modified MacNab score criteria were used to investigate long-term efficacy. Result: All patients completed the operation successfully, and the follow-up time was 2 years. The VAS score of lumbago was lower after than before surgery (preoperative: 6.96+/-0.90; postoperative: 2.04+/ 1.02, P<0.05). The VAS score of sciatica was also lower after than before surgery (preoperative: 7.19+/-0.88, postoperative: 1.93+/-0.92, P<0.05), and the ODI was improved at the last follow-up (29.62+/-4.26) % compared with before surgery (80.07+/-3.98) %. The MacNab efficacy evaluation showed improvement at the end of the follow-up period: 20 cases were excellent, 6 cases were good, and 1 case was satisfactory, with a good/excellent rate of 96%. No surgical site infections, iatrogenic nerve root injuries, epidural hematomas, or other complications occurred. Conclusion: Total endoscopic decompression of posterior facet arthrodesis for the treatment of single-segment lateral crypt LSS has the advantages of safety, reduced recurrence and trauma, and a satisfactory curative effect. This trial is registered with ChiCTR1800015628. PMID- 30420969 TI - A Randomized Trial of Insulin Glargine plus Oral Hypoglycemic Agents versus Continuous Subcutaneous Insulin Infusion to Treat Newly Diagnosed Type 2 Diabetes. AB - Aims: Basal insulin plus oral hypoglycemic agents (OHAs) has not been investigated for early intensive antihyperglycemic treatment in people with newly diagnosed type 2 diabetes. This study is aimed at comparing the short-term (over a period of 12 days) effects of basal insulin glargine plus OHAs and continuous subcutaneous insulin infusion (CSII) on glycemic control and beta-cell function in this setting. Methods: An open-label parallel-group study. Newly diagnosed hospitalized patients with type 2 diabetes and fasting plasma glucose (FPG) >=11.1 mmol/L or glycated hemoglobin (HbA1c) >=9% (75 mmol/mol) were randomized to CSII or insulin glargine in combination with metformin and gliclazide. The primary outcome measure was the mean amplitude of glycemic excursions (MAGE), and secondary endpoints included time to reach glycemic control target (FPG < 7 mmol/L and 2-hour postprandial plasma glucose < 10 mmol/L), markers of beta-cell function, and hypoglycemia. Results: Subjects in the CSII (n = 35) and basal insulin plus OHA (n = 33) groups had a similar significant reduction from baseline to end of treatment in glycated albumin (-6.44 +/- 3.23% and- 6.42 +/- 3.56%, P = 0.970). Groups A and B have comparable time to glycemic control (3.6 +/- 1.2 days and 4.0 +/- 1.4 days), MAGE (3.40 +/- 1.40 mmol/L vs. 3.16 +/- 1.38 mmol/L; p = 0.484), and 24-hour mean blood glucose (7.49 +/- 0.96 mmol/L vs. 7.02 +/- 1.03 mmol/L). Changes in the C-peptide reactivity index, the secretory unit of islet in transplantation index, and insulin secretion-sensitivity index-2 indicated a greater beta-cell function improvement with basal insulin plus OHAs versus CSII. Conclusions: Short-term insulin glargine plus OHAs may be an alternative to CSII for initial intensive therapy in people with newly diagnosed type 2 diabetes. PMID- 30420970 TI - Role of the Specialized Proresolving Mediator Resolvin D1 in Systemic Lupus Erythematosus: Preliminary Results. AB - Objective: Systemic lupus erythematosus (SLE) is an autoimmune systemic disease and its pathogenesis has not yet been completely clarified. Patients with SLE show a deranged lipid metabolism, which can contribute to the immunopathogenesis of the disease and to the accelerated atherosclerosis. Resolvin D1 (RvD1), a product of the metabolism of the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA), acts as a specialized proresolving mediator which can contribute in restoring the homeostasis in inflamed tissues. The aim of the present pilot study is to evaluate plasma levels of RvD1 in patients with SLE and healthy subjects, investigating its potential role as a biomarker of SLE and assessing its relationship with disease activity and laboratory parameters. Methods: Thirty patients with SLE and thirty age- and sex-matched healthy subjects (HSs) have been consecutively recruited at Campus Bio-Medico University Hospital. RvD1 plasma levels were measured by ELISA according to the manufacturer's protocol (Cayman Chemical Co.). RvD1 levels were compared using Mann-Whitney test. Discriminatory ability for SLE has been evaluated by the area under the ROC curve. Results: Lower levels of RvD1, 45.6 (35.5-57.4) pg/ml, in patients with SLE have been found compared to HSs, 65.1 (39.43-87.95) pg/ml (p = 0.0043). The area under the ROC curve (AUC) for RvD1 was 0.71 (95% CI: 0.578 0.82) and the threshold value of RvD1 for the classification of SLE was <58.4 pg/ml, sensitivity 80% (95% CI: 61.4-92.3), and specificity 63.3% (95% CI: 43.9 80.1), likelihood ratio 2.2 (95% CI: 1.3-3.6). Conclusions: The present preliminary study allows hypothesizing a dysregulation of RvD1 in patients with SLE, confirming the emerging role of bioactive lipids in this disease. PMID- 30420971 TI - Trajectory Modelling to Assess Trends in Long-Term Readmission Rate among Abdominal Aortic Aneurysm Patients. AB - Introduction: The aim of the study was to use trajectory analysis to categorise high-impact users based on their long-term readmission rate and identify their predictors following AAA (abdominal aortic aneurysm) repair. Methods. In this retrospective cohort study, group-based trajectory modelling (GBTM) was performed on the patient cohort (2006-2009) identified through national administrative data from all NHS English hospitals. Proc Traj software was used in SAS program to conduct GBTM, which classified patient population into groups based on their annual readmission rates during a 5-year period following primary AAA repair. Based on the trends of readmission rates, patients were classified into low- and high-impact users. The high-impact group had a higher annual readmission rate throughout 5-year follow-up. Short-term high-impact users had initial high readmission rate followed by rapid decline, whereas chronic high-impact users continued to have high readmission rate. Results: Based on the trends in readmission rates, GBTM classified elective AAA repair (n=16,973) patients into 2 groups: low impact (82.0%) and high impact (18.0%). High-impact users were significantly associated with female sex (P=0.001) undergoing other vascular procedures (P=0.003), poor socioeconomic status index (P < 0.001), older age (P < 0.001), and higher comorbidity score (P < 0.001). The AUC for c-statistics was 0.84. Patients with ruptured AAA repair (n=4144) had 3 groups: low impact (82.7%), short-term high impact (7.2%), and chronic high impact (10.1%). Chronic high impact users were significantly associated with renal failure (P < 0.001), heart failure (P = 0.01), peripheral vascular disease (P < 0.001), female sex (P = 0.02), open repair (P < 0.001), and undergoing other related procedures (P=0.05). The AUC for c-statistics was 0.71. Conclusion: Patients with persistent high readmission rates exist among AAA population; however, their readmissions and mortality are not related to AAA repair. They may benefit from optimization of their medical management of comorbidities perioperatively and during their follow-up. PMID- 30420972 TI - Deep advantage learning for optimal dynamic treatment regime. AB - Recently deep learning has successfully achieved state-of-the-art performance on many difficult tasks. Deep neural network outperforms many existing popular methods in the field of reinforcement learning. It can also identify important covariates automatically. Parameter sharing of convolutional neural network (CNN) greatly reduces the amount of parameters in the neural network, which allows for high scalability. However few research has been done on deep advantage learning (A-learning). In this paper, we present a deep A-learning approach to estimate optimal dynamic treatment regime. A-learning models the advantage function, which is of direct relevance to the goal. We use an inverse probability weighting (IPW) method to estimate the difference between potential outcomes, which does not require to make any model assumption on the baseline mean function. We implemented different architectures of deep CNN and convexified convolutional neural networks (CCNN). The proposed deep A-learning methods are applied to a data from the STAR*D trial and are shown to have better performance compared with the penalized least square estimator using a linear decision rule. PMID- 30420975 TI - Dielectrophoresis-actuated liquid lenses with dual air/liquid interfaces tuned from biconcave to biconvex. AB - This paper reports an electrically reconfigurable optofluidic lens with two air liquid (silicone oil) interfaces actuated by dielectrophoretic (DEP) force. Initially, a symmetric biconcave air-liquid lens is formed by the surface tension in a microfluidic chip. Then, the DEP force deforms the air-liquid interfaces from biconcave to biconvex, tuning the focal length from -0.5 mm to infinite to +0.5 mm. The wide tunability of the focal length results from the large refractive index difference (~0.4 at the air-liquid interface), which is only 0.1 in previous liquid-liquid lenses. In the experiment, the lens achieves an f number of 0.91 while consuming only 6.7 nJ per circle. Some asymmetric working states, such as concave-convex and plano-convex lenses, have also been demonstrated. Compared with continuous liquid flow-sustained lenses, this stationary liquid lens holds promise of better compatibility and higher scalability. Its wide tunability, low power consumption and easy operation make it suitable for light manipulation in microfluidic networks. PMID- 30420976 TI - Oxygen-rich chemotherapy via modified Abraxane to inhibit the growth and metastasis of triple-negative breast cancer. AB - Abraxane(r) (Abx), an FDA approved albumin-bound paclitaxel nano-formulation, is one of the most common chemical drugs for the treatment of metastatic triple negative breast cancer (mTNBC). However, acquired resistance and metastasis are critical factors that limit the treatment of mTNBC by Abx. In particular, both the tumor hypoxic microenvironment and the increase in hydrogen peroxide (H2O2) levels via paclitaxel stimulation primarily mediate the resistance to chemotherapy, where multiple drug resistance proteins such as P-gp and tumor invasion-related cytokines such as VEGF are continuously activated to pump out chemical drugs and aggravate tumor metastasis, respectively. Therefore, it is of great importance to combine tumor oxygenation with commercial chemical drugs for overcoming the acquired resistance and metastasis. In this study, a facile method was developed to deposit manganese dioxide (MnO2) onto the surface of Abraxane(r) (Abx) to form MnO2-modified Abx (M-Abx). The modification process did not change the critical characteristics of the parent Abx, which might have great potential for application in clinics for the treatment of mTNBC. Tumor oxygenation mediated by M-Abx specifically occurs within the H2O2-overexpressed tumor microenvironment, and significantly downregulates the content of tumor progression-related proteins, such as HIF-1alpha, P-gp, and VEGF. Ultimately, M Abx treatment results in about a 2-fold increase in inhibition efficiency of tumor growth in both primary and metastatic tumors compared with traditional Abx therapy. Therefore, oxygen-rich chemotherapy was realized to efficiently sensitize paclitaxel, relieve acquired resistance and inhibit tumor metastasis. PMID- 30420973 TI - CAR T cells targeting alphavbeta3 integrin are effective against advanced cancer in preclinical models. AB - Objective: Integrins are heterodimeric receptors that convey cell-to-cell and cell-to-matrix interactions. Integrin alphavbeta3 is expressed in several tumour entities including melanoma, glioblastoma, breast, pancreatic and prostate cancer, where it promotes tumour cell survival and metastasis. Here, we generated alphavbeta3-specific chimeric antigen receptor (CAR) T-cells and analysed their antitumour function in pre-clinical models in vitro and in vivo. Methods: alphavbeta3-CARs comprising a super-humanised hLM609 targeting domain with either high or low affinity (hLM609v7, K d = 3 nM vs. hLM609v11, K d = 160 nM) and equipped with either a long or a short IgG4-Fc extracellular spacer (229 vs. 12 amino acids) were expressed in CD8+ and CD4+ T-cells through lentiviral transduction. Results: alphavbeta3-CAR T-cells eliminated alphavbeta3-positive tumour cells rapidly and specifically, produced IFN-gamma and IL-2 (CD4+ > CD8+) and exhibited productive proliferation. In vitro, we observed the strongest reactivity with the higher-affinity hLM609v7 alphavbeta3-CAR in the short spacer configuration, consistent with the tumour membrane-distal localization of the hLM609 epitope. In a murine xenograft model of metastatic A-375 melanoma, the strongest antitumour effect was mediated by the lower-affinity hLM609v11 alphavbeta3-CAR. Notably, a single administration of hLM609v11 alphavbeta3-CAR T cells was able to induce complete elimination of melanoma lesions, leading to long-term tumour-free survival. Conclusions: These data establish alphavbeta3 integrin as a novel target for CAR T-cell immunotherapy, and affirm our previous notion that binding domain affinity and spacer length can be calibrated to augment CAR reactivity. Clinical implications: alphavbeta3-CAR T-cells have therapeutic potential in several prevalent solid tumours, including melanoma and triple-negative breast cancer. PMID- 30420974 TI - Neoadjuvant Dose-dense Gemcitabine and Cisplatin in Muscle-invasive Bladder Cancer: Results of a Phase 2 Trial. AB - Background: Accelerated (also termed dose-dense, DD) chemotherapy regimens such as accelerated methotrexate, vinblastine, doxorubicin, and cisplatin have shown better efficacy and tolerability in the metastatic setting, and shortened the time to surgery in the neoadjuvant setting compared to standard-schedule regimens. We hypothesized that a DD schedule of gemcitabine and cisplatin (GC) would shorten the time to surgery and yield similar pathologic complete response rates (pT0) in patients with muscle-invasive bladder cancer (MIBC) compared with historical controls with standard GC. Objective: To determine the safety and efficacy of neoadjuvant DDGC in MIBC. Design setting and participants: Patients with cT2-4a, N0-1, M0 MIBC were eligible and received three 14-d cycles of DDGC with pegfilgrastim support followed by radical cystectomy with lymph node dissection. The primary end point was the pT0 rate. Molecular subtypes were assigned and correlated with survival. Results and limitations: Thirty-one patients were evaluable for toxicity and response, of whom 58% had baseline clinical stage >T2N0M0; the median age was 69 yr. Ten patients (32%, 95% confidence interval [CI] 16-49%) achieved ypT0N0 status at cystectomy. Another four patients (13%, 95% CI 1-25%) were downstaged to non-muscle-invasive (400 mV nm-1). To achieve a 1 base per MUs translocation speed (1 GHz bandwidth), we suggest that three methods could be applied, including a decrease in the applied voltage, a decrease in the diameter of the MoS2 nanopore or modification of the MoS2 nanopore. In addition, the size of the nanopore can severely affect the possibility of DNA entering the nanopore, and the translocation time of DNA could be significantly increased with a smaller MoS2 nanopore. These findings may help to design MoS2 nanopores with higher resolution for use in DNA sequencing. PMID- 30420981 TI - Mild dynamic kinetic resolution of amines by coupled visible-light photoredox and enzyme catalysis. AB - Herein, we described photoenzymatic dynamic kinetic resolution (DKR) of amines under mild conditions. The racemization of amines via a photoredox-mediated hydrogen atom transfer (HAT) protocol in conjunction with an enzyme catalyst to achieve the DKR of amines allows a variety of primary amines to be converted into a single enantiomer in high yield and with excellent enantioselectivity. Notably, this protocol can also be extended to 1,4-diamine derivatives with high levels of diastereo- and enantioselectivity. PMID- 30420982 TI - Distinct relaxation timescales of neurites revealed by rate-dependent indentation, relaxation and micro-rheology tests. AB - Although the dynamic response of neurites is believed to play crucial roles in processes like axon outgrowth and formation of the neural network, the dynamic mechanical properties of such protrusions remain poorly understood. In this study, by using AFM (atomic force microscopy) indentation, we systematically examined the dynamic behavior of well-developed neurites on primary neurons under different loading modes (step loading, oscillating loading and ramp loading). Interestingly, the response was found to be strongly rate-dependent, with an apparent initial and long-term elastic modulus around 800 and 80 Pa, respectively. To better analyze the measurement data and extract information of key interest, the finite element simulation method (FEM) was also conducted where the neurite was treated as a viscoelastic solid consisting of multiple characteristic relaxation times. It was found that a minimum of three relaxation timescales, i.e. ~0.01, 0.1 and 1 seconds, are needed to explain the observed relaxation curve as well as fit simulation results to the indentation and rheology data under different loading rates and driving frequencies. We further demonstrated that these three characteristic relaxation times likely originate from the thermal fluctuations of the microtubule, membrane relaxation and cytosol viscosity, respectively. By identifying key parameters describing the time dependent behavior of neurites, as well as revealing possible physical mechanisms behind, this study could greatly help us understand how neural cells perform their biological duties over a wide spectrum of timescales. PMID- 30420983 TI - Electron transport behavior of quinoidal heteroacene-based junctions: effective electron-transport pathways and quantum interference. AB - The electron transport behavior through a series of molecular junctions composed of tetracene (TC) and S/O substituted-TC (S/O-TC) has been studied using density functional theory (DFT) combined with the non-equilibrium Green's function (NEGF) method. The unique transport behavior has been interpreted using correlated quantum interference and electron transport pathway models. In the TC system, two dominant electron transfer channels exist as demonstrated by a detailed transmission pathway analysis. In the substituted S/O-TC systems, the electron transport behavior is regulated through either constructive or destructive quantum interference due to the existence of additional p-electrons, leading to a significant diversity of current-voltage curves. Compared to the TC molecule in the bias region from 0 to 1.0 V, an alpha-connected molecular junction exhibits a greater current, whereas a beta-connected molecular junction shows a smaller current. The substitution with O and S atoms shows a minor effect on the conductance of the molecular junctions. In order to clarify the role of heteroatoms, a series of artificial models designed by removing specific sulfur and carbon atoms in alpha-S-TC have been investigated in detail. The results have demonstrated that only the S heteroatom on one side of the molecule contributes to the junction conductivity through constructive quantum interference. It has also been observed that current exchange occurs between the two electron transfer channels. PMID- 30420984 TI - Catalyst and additive-free regioselective oxidative C-H thio/selenocyanation of arenes and heteroarenes with elemental sulfur/selenium and TMSCN. AB - A regioselective oxidative C-H thio/selenocyanation of arenes and heteroarenes with TMSCN and elemental sulfur/selenium was demonstrated under catalyst-free and additive-free conditions. Dimethyl sulfoxide (DMSO) was employed as the mild oxidant as well as the solvent. The reaction is operationally simple and scalable with a broad substrate scope. PMID- 30420985 TI - Different binding sites of serum albumins in the protein corona of gold nanoparticles. AB - The interaction of bovine serum albumin (BSA) and human serum albumin (HSA), sharing a sequence similarity of 77.5%, with gold nanoparticles of a size of ~30 nm was investigated by surface-enhanced Raman scattering (SERS). The spectra provide information on those residues of the proteins in proximity of the nanoparticles. The SERS signals indicate an electrostatic interaction of both proteins with the citrate ligands at the nanoparticle surface via lysine residues. HSA, different from BSA also binds directly to the gold surface by particularly flexible protein segments that were identified by comparison of the vibrational bands with the known amino acid sequence of the molecule. The data suggest that both the direct binding as well as interaction with the citrate ligands determine the interaction, yet to varying extent in the two very similar serum proteins. This has implications for their use in bio-functionalization, and for the application of gold nanostructures in bioanalytics and medicine. PMID- 30420986 TI - Non-coordinative metal selectivity bias in human metallothioneins metal-thiolate clusters. AB - Mammalian metallothioneins (MT-1 through MT-4) are a class of metal binding proteins containing two metal-thiolate clusters formed through the preferential coordination of d10 metals, Cu(i) and Zn(ii), by 20 conserved cysteine residues located in two protein domains. MT metalation (homometallic or heterometallic Zn(ii)/Cu(i) species) appears to be isoform specific and controlling zinc and copper concentrations to perform specific and distinct biological functions. Structural and functional relationships, and in vivo metalation studies, identified evolutionary features defining the metal-selectivity nature for MTs. Metallothionein-3 (MT-3) has been shown to possess the most pronounced Cu thionein character forming Cu(i)-containing species more favorably than metallothionein-2 (MT-2), which possesses the strongest Zn-thionein character. In this work, we identify isoform-specific determinants which control metal binding selectivity bias in different MTs isoforms. By studying the reactivity of Zn7MT 2, Zn7MT-3 and Zn7MT-3 mutants towards Cu(ii) to form Cu(i)4Zn4MTs, we have identified isoform-specific key non-coordinating residues governing folding/outer sphere control of metal selectivity bias in MTs metal clusters. By mutating selected residues and motifs in MT-3 to the corresponding MT-2 amino acids, we dissected key roles in modulating cluster dynamic and metal exchange rates, in increasing the Cu(i)-affinity in MT-3 N-terminal beta-domain and/or modulating the higher stability of the Zn(ii)-thiolate cluster in MT-2 beta-domain. We thus engineered MT-3 variants in which the copper-thionein character is converted into a zinc-thionein. These results provide new insights into the molecular determinants governing metal selectivity in metal-thiolate clusters. PMID- 30420987 TI - Morphology-based prediction of cancer cell migration using an artificial neural network and a random decision forest. AB - Metastasis is the cause of death in most patients of breast cancer and other solid malignancies. Identification of cancer cells with highly migratory capability to metastasize relies on markers for epithelial-to-mesenchymal transition (EMT), a process increasing cell migration and metastasis. Marker based approaches are limited by inconsistences among patients, types of cancer, and partial EMT states. Alternatively, we analyzed cancer cell migration behavior using computer vision. Using a microfluidic single-cell migration chip and high content imaging, we extracted morphological features and recorded migratory direction and speed of breast cancer cells. By applying a Random Decision Forest (RDF) and an Artificial Neural Network (ANN), we achieved over 99% accuracy for cell movement direction prediction and 91% for speed prediction. Unprecedentedly, we identified highly motile cells and non-motile cells based on microscope images and a machine learning model, and pinpointed and validated morphological features determining cell migration, including not only known features related to cell polarization but also novel ones that can drive future mechanistic studies. Predicting cell movement by computer vision and machine learning establishes a ground-breaking approach to analyze cell migration and metastasis. PMID- 30420988 TI - Correction: Unsupervised capture and profiling of rare immune cells using multi directional magnetic ratcheting. AB - Correction for 'Unsupervised capture and profiling of rare immune cells using multi-directional magnetic ratcheting' by Coleman Murray et al., Lab Chip, 2018, 18, 2396-2409. PMID- 30420989 TI - Shape-control of super-branched Pd-Cu alloys with enhanced electrocatalytic performance for ethylene glycol oxidation. AB - Pd-Cu alloys with adjustable morphologies were synthesized and examined as nanocatalysts for electro-oxidation of ethylene glycol. The Cu2+ can effectively adjust the morphology of the Pd-Cu alloys. The as-prepared super-branched Pd-Cu alloys exhibit a greatly enhanced catalytic activity toward ethylene glycol electro-oxidation, because the super-branched structure creates abundant surface active sites and a suitable electronic landscape benefiting from alloying Pd with Cu. PMID- 30420990 TI - Deciphering the helicity switching mechanism: a case study of the rigid three tiered stacked architecture. AB - Understanding the switching mechanism of helical molecular cages is critical in regulating their functions of asymmetric catalysis and enantioseparation. The helical inversion of a three-tiered stacked architecture was investigated by employing molecular dynamics simulations combined with free-energy calculations. A two-dimensional free-energy landscape characterizing the spinning processes of the top and bottom tiers around the z axis was determined using the extended adaptive biasing force method. The free-energy barrier in the least free-energy pathway was estimated to be 17.6 kcal mol-1, in excellent agreement with experimental measurements. Further analysis revealed that the barrier was caused by geometric deformation, weakening of pi-pi stacking between aromatic rings, and the re-orientation of polarized amine moieties. The present contribution takes a step toward understanding the dynamic helicity-based functions related to asymmetric reactions and optical resolution. PMID- 30420991 TI - Photoabsorption spectra of small mercury clusters: a computational study. AB - Photoabsorption spectra of small HgN clusters (N = 2-5) have been calculated using a diatomics-in-molecules interaction model and an atoms-in-molecules approach for transition probability calculations. Absorption cross-sections are provided over a broad range of photon energies, Ephot = 4.0-7.5 eV, as calculated for various cluster temperatures ranging between T = 0 K and T = 40 K. Quantum as well as temperature-induced delocalization of nuclear positions has been taken into account at various levels using classical and quantum (path-integral) Monte Carlo methods as well as sampling from the square of cluster vibrational ground state wavefunctions. A thorough comparison of the calculated data with available experimental records is also provided. PMID- 30420992 TI - The non-covalently bound SOH2O system, including an interpretation of the differences between SOH2O and O2H2O. AB - Despite the interest in sulfur monoxide (SO) among astrochemists, spectroscopists, inorganic chemists, and organic chemists, its interaction with water remains largely unexplored. We report the first high level theoretical geometries for the two minimum energy complexes formed by sulfur monoxide and water, and we report energies using basis sets as large as aug-cc-pV(Q+d)Z and correlation effects through perturbative quadruple excitations. One structure of SOH2O is hydrogen bonded and the other chalcogen bonded. The hydrogen bonded complex has an electronic energy of -2.71 kcal mol-1 and a zero kelvin enthalpy of -1.67 kcal mol-1, while the chalcogen bonded complex has an electronic energy of -2.64 kcal mol-1 and a zero kelvin enthalpy of -2.00 kcal mol-1. We also report the transition state between the two structures, which lies below the SOH2O dissociation limit, with an electronic energy of -1.26 kcal mol-1 and an enthalpy of -0.81 kcal mol-1. These features are much sharper than for the isovalent complex of O2 and H2O, which only possesses one weakly bound minimum, so we further analyze the structures with open-shell SAPT0. We find that the interactions between O2 and H2O are uniformly weak, but the SOH2O complex surface is governed by the superior polarity and polarizability of SO, as well as the diffuse electron density provided by sulfur's extra valence shell. PMID- 30420993 TI - Dual excitation wavelength system for combined fingerprint and high wavenumber Raman spectroscopy. AB - A fiber optic probe-based Raman spectroscopy system using a single laser module with two excitation wavelengths, at 680 and 785 nm, has been developed for measuring the fingerprint and high wavenumber regions using a single detector. This system is simpler and less expensive than previously reported configurations of combined fingerprint and high wavenumber Raman systems, and its probe-based implementation facilitates numerous in vivo applications. The high wavenumber region of the Raman spectrum ranges from 2800-3800 cm-1 and contains valuable information corresponding to the molecular vibrations of proteins, lipids, and water, which is complimentary to the biochemical signatures found in the fingerprint region (800-1800 cm-1), which probes DNA, lipids, and proteins. The efficacy of the system is demonstrated by tracking changes in water content in tissue-mimicking phantoms, where Voigtian decomposition of the high wavenumber water peak revealed a correlation between the water content and type of water tissue interactions in the samples. This dual wavelength system was then used for in vivo assessment of cervical remodeling during mouse pregnancy, a physiologic process with known changes in tissue hydration. The system shows that Raman spectroscopy is sensitive to changes in collagen content in the fingerprint region and hydration state in the high wavenumber region, which was verified using an ex vivo comparison of wet and dry weight. Simultaneous fingerprint and high wavenumber Raman spectroscopy will allow precise in vivo quantification of tissue water content in the high wavenumber region, paired with the high biochemical specificity of the fingerprint region. PMID- 30420994 TI - First-principle atomistic thermodynamic study on the early-stage corrosion of NiCr alloy under fluoride salt environment. AB - The atomic morphology change in the NiCr alloy surface induced by fluorine chemisorption was investigated by the ab initio atomistic thermodynamic method to elucidate early-stage corrosion processes of nickel-based alloys in strong oxidizing environment. The surface phase diagrams of Cr-doped Ni(111) surface as a function of fluorine chemical potential were obtained to track the surface structures that are most likely to be fostered in various temperature and pressure conditions. The adsorption of fluorine on the top site of Cr in the alloy surface was the most energetically favorable one. With increasing fluorine chemical potential, more fluorine atoms started to agglomerate in the trapping sink of Cr. Fluorine-fluorine repulsion interaction coupled with strong F-Cr bonding could facilitate a decided morphology modification of the metal substrate. Moreover, an insight into the desorption pathways for potential species revealed that in the presence of fluorine, the dissociation of Cr predominantly stems from the relatively easy desorption in the form of CrF2/CrF3 molecules from the non-passivated Ni-based alloy surface. PMID- 30420995 TI - Correction: CuAAC click chemistry for the enhanced detection of novel alkyne based natural product toxins. AB - Correction for 'CuAAC click chemistry for the enhanced detection of novel alkyne based natural product toxins' by Edward S. Hems et al., Chem. Commun., 2018, 54, 12234-12237. PMID- 30420996 TI - Authors' response to "Multiple-job holding is not a type of precarious employment". AB - We would like to thank the authors of the letter entitled "Multiple job holding is not a type of precarious employment" (1) and extend our thanks to the Editor in-Chief for giving us the opportunity to respond. The authors of the letter point out that precarious employment is a multidimensional construct, with which we completely agree. There is however no consensus on which dimensions should be included in this construct, and therefore we chose a broad approach including three of the most wide-spread definitions: Guy Standing's (2), the Employment Precarious Scale (3) and the ILO's (4). A one-on-one comparison of these can be found in table 1 of our review (5). We found very few studies using a multidimensional definition of precarious employment and so our review ended up investigating studies on single dimensions, such as holding multiple jobs. The main argument of Bouwhuis et al is that multiple job holding should not be included as a dimension of precarious employment as it "does not relate to the quality of the terms of employment" and "not all multiple job holders are vulnerable or precarious". This argument could be made about any single dimension and is the rational behind creating a multidimensional construct, ie, no single variable is enough to capture the complexity of the issue. In the case of employment instability, some temporary workers are precarious and some are not (6). Some part-time workers are precarious although many are not. And as the authors of the letter has shown in their own study; some multiple job holders are precarious while some are not (7). Thus, we can all agree that holding multiple jobs is not the same as being precariously employed. However, we believe that multiple job holding should continue to be considered as an important dimension of precarious employment. There are several ongoing initiatives to try to reach consensus on what comprises precarious employment. We are glad that the debate on precarious employment is alive and well in this journal and elsewhere. Any reader interested in contributing to this effort are welcome to contact us. References 1. Bouwhuis S, Geuskens GA, van der Beek AJ, Boot CRL. Multiple-job holding is not a type of precarious employment. Scand J Work Environ Health - online first. https://doi.org/10.5271/sjweh.3782 2. Standing G. The precariat: The new dangerous class. London: Bloomsbury Publishing; 2011. 3. Vives A, Amable M, Ferrer M, , Moncada S, Llorens C, Muntaner C, et al. The Employment Precariousness Scale (EPRES): psychometric properties of a new tool for epidemiological studies among waged and salaried workers. Occup Environ Med. 2010;67(8):548-55. https://doi.org/10.1136/oem.2009.048967. 4. ILO. Non-standard forms of employment. Geneva: International Labour Office; 2015. 5. Koranyi I, Jonsson J, Ronnblad T, Stockfelt L, Bodin T.. Precarious employment and occupational accidents and injuries - a systematic review. Scand J Work Environ Health. 2018;44(4):341-50. https://doi.org/10.5271/sjweh.3720. 6. Julia M, Vives A, Tarafa G, Benach J. S09-4 The precarization of the spanish labour market and its impact on mental health. Occup Environ Med. 2016;73:A109-A110 https://doi.org/10.1136/oemed-2016-103951.296. 7. Bouwhuis S, Hoekstra T, Bongers PM, Boot CRL, Geuskens GA, van der Beek AJ. Distinguishing groups and exploring health differences among multiple job holders aged 45 years and older. Int Arch Occup Environ Health. 2018:1-13. https://doi.org/10.1007/s00420-018-1351-2. PMID- 30420997 TI - Percutaneous Orthotopic IVC Construction in a Pediatric Patient with Symptomatic IVC Agenesis. AB - Inferior vena cava agenesis is an uncommon condition usually attributed to embryologic dysgenesis. When symptomatic, unprovoked deep venous thrombosis and/or lower extremity venous congestion are the most frequent manifestations. Its rarity has precluded consensus regarding appropriate management. Symptomatic chronic venous congestion requires surgical construction of auxiliary venous pathways, which may involve substantial morbidity, prolonged recovery and extensive scarring. We report successful minimally invasive management via percutaneous endovascular orthotopic inferior vena cava construction in a pediatric patient, thereby obviating the need for surgery and its associated morbidity. LEVEL OF EVIDENCE: Level IV, case study. PMID- 30420998 TI - Percutaneous Patency Recovery and Biodegradable Stent Placement in a Totally Occluded Hepaticojejunostomy After Paediatric Living Donor Liver Transplantation. AB - Biliary complications after living donor liver transplantation (LDLT) cause severe morbidity and mortality, with biliary anastomotic stricture being the most common form of presentation. Surgical revision is risky, and it is avoided whenever possible. When a Roux-en-Y hepaticojejunostomy (RYHJ) is used for bilioenteric reconstruction, endoscopic approach is more difficult, if not impracticable. Therefore, percutaneous approach remains as a first-line treatment in these patients. In this case presentation, a percutaneous approach was used to recover patency in an intractable, totally occluded RYHJ stricture in an LDLT paediatric recipient, using a Rosch-Uchida needle to access to the collapsed jejunal loop from the bile duct. Once recanalization of the RYHJ was achieved, a biodegradable stent was placed with middle-term patency at follow-up. PMID- 30420999 TI - Transition of inner cell mass to embryonic stem cells: mechanisms, facts, and hypotheses. AB - Embryonic stem cells (ESCs) are immortal stem cells that own multi-lineage differentiation potential. ESCs are commonly derived from the inner cell mass (ICM) of pre-implantation embryos. Due to their tremendous developmental capacity and unlimited self-renewal, ESCs have diverse biomedical applications. Different culture media have been developed to procure and maintain ESCs in a state of naive pluripotency, and to preserve a stable genome and epigenome during serial passaging. Chromatin modifications such as DNA methylation and histone modifications along with microRNA activity and different signaling pathways dynamically contribute to the regulation of the ESC gene regulatory network (GRN). Such modifications undergo remarkable changes in different ESC media and determine the quality and developmental potential of ESCs. In this review, we discuss the current approaches for derivation and maintenance of ESCs, and examine how differences in culture media impact on the characteristics of pluripotency via modulation of GRN during the course of ICM outgrowth into ESCs. We also summarize the current hypotheses concerning the origin of ESCs and provide a perspective about the relationship of these cells to their in vivo counterparts (early embryonic cells around the time of implantation). Finally, we discuss generation of ESCs from human embryos and domesticated animals, and offer suggestions to further advance this fascinating field. PMID- 30421000 TI - Diagnosis of osteoporotic vertebral fractures in children. AB - Osteoporosis is a generalised disorder of the skeleton with reduced bone density and abnormal bone architecture. It increases bone fragility and renders the individual susceptible to fractures. Fractures of the vertebrae are common osteoporotic fractures. Vertebral fractures may result in scoliosis or kyphosis and, because they may be clinically silent, it is imperative that vertebral fractures are diagnosed in children accurately and at an early stage, so the necessary medical care can be implemented. Traditionally, diagnosis of osteoporotic vertebral fractures has been from lateral spine radiographs; however, a small number of studies have shown that dual energy x-ray absorptiometry is comparable to radiographs for identifying vertebral fractures in children, while allowing reduced radiation exposure. The diagnosis of vertebral fractures from dual energy x-ray absorptiometry is termed vertebral fracture assessment. Existing scoring systems for vertebral fracture assessment in adults have been assessed for use in children, but there is no standardisation and observer reliability is variable. This literature review suggests the need for a semiautomated tool that (compared to the subjective and semiquantitative methods available) will allow more reliable and precise detection of vertebral fractures in children. PMID- 30421001 TI - [Radiotherapeutic studies of head and neck cancer-highlights of the 2018 ASCO Annual Meeting]. AB - BACKGROUND: Radiotherapy is an important treatment option in patients with advanced head and neck cancer. At the 2018 Annual Meeting of the American Society of Clinical Oncology (ASCO), study results were presented that could further develop and modify existing therapy concepts in the future. MATERIALS AND METHODS: All ASCO abstracts and presentations concerning radiotherapy of head and neck cancer were screened and the most interesting abstracts were selected for further review. RESULTS: One major topic was the combination of radiation with immunotherapy. Presented trials included combination treatment of epidermal growth factor receptor (EGFR) antibodies and platin-based chemoradiotherapy, as well as programmed cell death protein 1 (PD-1) antibodies in combination with platin-based chemoradiotherapy or cetuximab radiotherapy. In one study, the impact of adjuvant (chemo)radiotherapy for overall survival of human papillomavirus (HPV)-associated head and neck cancer with low to intermediate risk was analyzed. Additionally, studies focusing on the prophylaxis or reduction of radiation-mediated oral mucositis were presented. CONCLUSION: The data presented do not justify a change of current treatment paradigms just yet. However, interesting developments can be expected in the coming years, particularly in the field of immunotherapy. PMID- 30421003 TI - ? PMID- 30421002 TI - [Interdisciplinary rheumatology]. PMID- 30421004 TI - Commentary on: Quality of life in oropharyngeal cancer: a structured review of the literature. PMID- 30421005 TI - Multifunctional behaviour in a sandy shore crab enhances performance in extreme intertidal environments. AB - Soft sediment shores in the tropics are highly dynamic environments, where behavioural patterns of organisms are constrained by tidal conditions, and environmental temperatures during an organisms' activity periods can exceed their thermal tolerance levels. In such extreme habitats, behavioural responses to environmental changes are key to survival, driving differential performance. We investigated sponging behaviour (water uptake from sediments) of the deposit feeding crab, Scopimera intermedia, on tropical sandy shores to determine its thermoregulatory function. The thermal physiology of the crabs and their habitat conditions were quantified by measuring thermal performance curves and recording environmental temperatures during the crabs' activity periods. Environmental temperatures were combined with experimental data to investigate the role of sponging on the thermal performances of the crabs by simulating field body temperatures. Sponging rate was strongly and positively correlated with feeding rate, as sponging replenishes water for flotation feeding. Sponging, however, also reduced body temperatures on average by 1.3 degrees C. Simulated populations of crabs which were unable to sponge had more variable body temperatures, which exceeded the critical thermal maximum of the crabs (~ 39 degrees C) nearly 2000 times more often than crabs able to sponge. Sponging is, therefore, a multifunctional behavioural trait important for both feeding and thermoregulation. The evolution of such multifunctional traits is likely to be a widespread, but overlooked phenomenon in intertidal species, as maintaining a functional body temperature is energetically costly in habitats where environmental conditions fluctuate strongly such as on tropical shores. PMID- 30421006 TI - Patterns of selective predation change with ontogeny but not density in a marine fish. AB - Phenotypic variation is prevalent in the early life-history stages of many organisms and provides the basis for selective mortality on size and growth related traits of older life stages. Densities of organisms can vary widely at important life-history transitions, raising additional questions about the interplay between selection and density-dependent processes. We evaluate density dependence in patterns of selective mortality for a temperate reef fish. Specifically, we exposed pre-settlement and post-settlement stages of the common triplefin (Forsterygion lapillum) to a natural predator and evaluated patterns of selective mortality on early life-history traits as a function of ontogenetic stage and density. We used otoliths to reconstruct the traits of fish that survived versus fish that were consumed (i.e., we recovered otoliths from the guts of predators), and we estimated selection by analysing the relationship between absolute fitness and standardised traits. Absolute fitness was negatively correlated with size and larval growth rate for pre-settlement fish (i.e., larger and faster growing individuals were more likely to be consumed by predators), and this was consistent across the range of densities evaluated. Post-settlement fish experienced no selective mortality. Additionally, absolute fitness was equal across density treatments, suggesting mortality was density-independent. Collectively, these results suggest that patterns of selection change with ontogeny, but may be stable across densities when mortality is density independent. Shifts in selective mortality for species with distinct life-stages can mask and complicate relationships between traits and fitness, and the importance of such traits may be underappreciated for earlier life stages. PMID- 30421007 TI - Limb blood flow and tissue perfusion during exercise with blood flow restriction. AB - INTRODUCTION: Exercise with blood flow restriction (BFR) is emerging as an effective modality for improving muscular function in clinical and athletic populations. Selection of cuff pressure is critical because it should maximize metabolic stress without completely occluding blood flow or compromising user safety. It is unknown how cuff pressures determined at rest influence blood flow hemodynamics during exercise. PURPOSE: We evaluated changes in blood flow and tissue perfusion before, during, and after exercise with BFR. METHODS: Ten males performed rhythmic handgrip exercise (30 contractions, 30% MVC) at 0%, 60%, 80%, 100%, and 120% of limb occlusion pressure (LOP). Brachial artery blood flow and tissue saturation were assessed using Doppler ultrasound and near-infrared spectroscopy, respectively. RESULTS: At rest blood flow generally decreased with increased pressure (0% > 60% ~ 80% > 100% ~ 120% LOP). During 60% and 80% LOP conditions, blood flow increased during exercise from rest and decreased after exercise (all P < 0.05). Compared to 0% LOP, relative blood flow at 60% and 80% LOP decreased by 22-47% at rest, 22-48% during exercise, and 52-71% after exercise (all P < 0.05). Increased LOP decreased tissue saturation during exercise with BFR (P < 0.05). Heart rate, mean arterial pressure, and cardiac output did not differ across LOP. CONCLUSION: At pressures below LOP the cardiovascular system overcame the external pressure and increased blood flow to exercising muscles. Relative reductions in blood flow at rest were similar to those during exercise. Thus, the relative occlusion measured at rest approximated the degree of occlusion during exercise. Moderate cuff pressures increased metabolic stress without completely occluding blood flow. PMID- 30421008 TI - Anodal transcranial direct current stimulation does not influence the neural adjustments associated with fatiguing contractions in a hand muscle. AB - PURPOSE: The objective of the current study was to investigate the mechanisms responsible for the briefer time to failure of a submaximal contraction (C2) when performed 60 min after a similar contraction (C1), and the influence of anodal transcranial direct current stimulation (a-tDCS) applied over the motor cortex on these mechanisms. METHODS: In two sessions, ten adults sustained two isometric contractions (35% of maximum) to failure with the abductor pollicis brevis (APB). Before C2, either a-tDCS or sham stimulation was applied over the motor cortex. Fatigue-related changes in Hoffmann (H) and long-latency (LLR) reflexes, motor evoked potential (MEP) induced by transcranial magnetic stimulation and associated silent period (SP), maximal motor wave (Mmax), voluntary activation (VA), electromyographic (EMG) activity and peak force (PT3) evoked by a 3 pulse train (100 Hz) were investigated. RESULTS: The results indicate that regardless of session, the time to failure was briefer (- 13%, p < 0.05) for C2 than C1, with no a-tDCS effect. During C1, MEP amplitude, SP duration and LLR amplitude increased, H-reflex amplitude did not change, and Mmax, VA and PT3 decreased (p < 0.05). Except for EMG activity that was greater during C2 than C1 (p < 0.001), all variables were similar in C1 and C2 (p > 0.05), and recovered their initial values after the 60-min rest, except PT3. CONCLUSIONS: The results of the current study indicate that a-tDCS did not influence corticospinal excitability and time to failure of C2 when performed with the APB. These observations may reflect a peripheral origin of the briefer C2 time to failure in the APB. PMID- 30421009 TI - Combination Immune Checkpoint Blockade Strategies to Maximize Immune Response in Gynecological Cancers. AB - PURPOSE OF REVIEW: Immune checkpoint blockade targeting PD-1 and PD-L1 improves immune recognition of tumor cells but had only modest success in gynecological cancers as monotherapy. Growing focus has been placed on combination immunotherapy strategies to overcome this resistance, and this review serves to discuss some of the most promising studies in gynecological cancers. RECENT FINDINGS: PD-1- and PD-L1-targeting antibodies are being combined with many novel agents including anti-CTLA-4 antibodies, PARP inhibitors, targeted agents, and traditional chemotherapy in promising studies with the hopes of increasing the immune response and overcoming resistance by targeting other pathways. Novel immune techniques including vaccines and adoptive cell therapies are also being implemented in gynecological cancers. Immune checkpoint combinations and novel immunotherapy strategies have demonstrated potential to overcome resistance to PD 1/PD-L1 blockade in gynecological cancers. Identification of biomarkers of response and resistance is a priority to tailor specific combination therapies to the appropriate patients. PMID- 30421010 TI - Social Media and Ophthalmology: Perspectives of Patients and Ophthalmologists. AB - Recent research has analyzed how patients use social media, but little information exists evaluating how patients utilize social media in the perioperative period or how ophthalmologists and eye institutions integrate social media into their practices. This observational study aimed to examine (1) how patients interact on social media when undergoing LASIK and (2) how ophthalmologists and (3) eye institutions utilize social media accounts. We analyzed 2592 Instagram posts between August 2016 and April 2017 on a related hashtag (#lasiksurgery). Content was coded based on time frame of the post in relation to the procedure, references to return to work/activity, post-surgical photographs, mention of the surgical institution, tone, and complaints regarding the procedure. Twitter and Instagram accounts for 30 ophthalmologists and eye institutes were also located. The 20 most recent posts were categorized by message type and topic (physicians, patients, education, conference, etc.). Patients using the hashtag posted photographs (92%), had a positive tone (88%), referenced the clinic where they were treated (62%), and posted during the day of the procedure (44%). Ophthalmologists' personal tweets focused on research conferences (35%), personal topics (25%), and the accomplishments of other physicians (21%). Eye institutions generally posted content relating to institutional promotion (22%), physician accomplishments (20%), and research publications (19%). Similar to other medical specialties, ophthalmology has a meaningful presence on both Twitter and Instagram. While LASIK patients tend to comment on their renewed vision and return to activity, ophthalmologists post to promote their research and accomplishments. PMID- 30421011 TI - Clinical feasibility of catheter-directed selective intracoronary computed tomography angiography using an extremely low dose of iodine in patients with coronary artery disease. AB - OBJECTIVE: This study aimed to evaluate the clinical feasibility of catheter directed selective computed tomography angiography (S-CTA) in patients with coronary artery disease (CAD). METHODS: We prospectively enrolled 65 patients diagnosed with CAD who underwent conventional computed tomography angiography (C CTA). C-CTA was performed with 60-90 mL of contrast medium (370 mg iodine/mL), whereas S-CTA was performed with 15 mL of contrast medium and 17.19 mg iodine/mL. Luminal enhancement range, homogeneity of luminal enhancement, image quality, plaque volume (PV), and percent aggregate plaque volume (%APV) were measured. Paired Student's t test, Wilcoxon rank-sum test, and Pearson's correlation coefficient were used to compare two methods. RESULTS: Luminal enhancement was significantly higher on S-CTA than on C-CTA (324.4 +/- 8.0 Hounsfield unit (HU) vs. 312.0 +/- 8.0 HU, p < 0.0001 in the per-vessel analysis). Transluminal attenuation gradient showed a significantly slower reduction pattern on S-CTA than on C-CTA (-0.65 HU/10 mm vs. -0.89 HU/10 mm, p < 0.0001 in the per-vessel analysis). Image noise was significantly lower on S-CTA than on C-CTA (39.6 +/- 10.0 HU vs. 43.9 +/- 9.4 HU, p < 0.0001). There was excellent correlation between S-CTA and C-CTA with respect to PV and %APV (r = 0.99, r = 0.98, respectively). CONCLUSIONS: S-CTA might be useful in facilitating atherosclerotic plaque analysis and providing guidance for complex lesions such as chronic total occlusion, particularly in cases in which on-site procedure planning is required. KEY POINTS: * Selective computed tomography angiography (S-CTA) can serve as an intraprocedural computed tomography angiography protocol. * S-CTA was performed with low dose of iodine compared with conventional computed tomography angiography. * S-CTA enables on-site atherosclerotic plaque analysis. PMID- 30421012 TI - Swallowing MRI-a reliable method for the evaluation of the postoperative gastroesophageal situs after Nissen fundoplication. AB - PURPOSE: To evaluate the diagnostic performance of swallowing MRI of the gastroesophageal junction (GEJ) in the postoperative care of patients after laparoscopic antireflux surgery (LARS) MATERIAL AND METHODS: In this institutional review board-approved prospective study, 79 symptomatic patients (mean age, 52.3 years; range, 26-80 years) were evaluated after laparoscopic Nissen fundoplication. MRI findings were correlated with revision surgery, endoscopy, and high-resolution manometry (HRM) as standard of reference. MRI was performed on a 3.0-T unit using T2-weighted half-Fourier acquisition single-shot turbo spin echo (HASTE) sequences for anatomical assessment of the GEJ followed by dynamic MR swallowing (fast low-angle shot sequences). Four independent readers (two radiologists, two surgeons) rated 83 MR scans according to defined criteria, such as wrap disruption, slipping, recurrent hiatal hernia, and esophageal motility disorder. RESULTS: Wrap disruption was correctly diagnosed concordantly with the standard of reference in 87.8%, slipping in 81.5%, and recurrent hiatal hernia in 84.9% of the cases. For esophageal motility disorder, MRI interpretation was consistent with manometry in 66.2% of the subjects. Interobserver analysis showed substantial agreement for recurrent hiatal hernia (k = 0.703), moderate agreement for wrap disruption (k = 0.585), and fair agreement for motility disorder and slipping (k = 0.234 and k = 0.200, respectively). CONCLUSION: MR swallowing readily depicts the major failure mechanisms of LARS and has good reliability even in non-experienced readers. KEY POINTS: * MR swallowing accurately readily depicts the major failure mechanisms of laparoscopic antireflux surgery and has good reliability even in non experienced readers. * It should be included in the preoperative workup for revision surgery after fundoplication. * It will be of great benefit to surgeons in considering and planning a reoperation. PMID- 30421013 TI - Reliability of fast magnetic resonance imaging for acute ischemic stroke patients using a 1.5-T scanner. AB - OBJECTIVES: To determine whether fast scanned MRI using a 1.5-T scanner is a reliable method for the detection and characterization of acute ischemic stroke in comparison with conventional MRI. METHODS: From May 2015 to June 2016, 862 patients (FLAIR, n = 482; GRE, n = 380; MRA, n = 190) were prospectively enrolled in the study, with informed consent and under institutional review board approval. The patients underwent both fast (EPI-FLAIR, ETL-FLAIR, TR-FLAIR, EPI GRE, parallel-GRE, fast CE-MRA) and conventional MRI (FLAIR, GRE, time-of-flight MRA, fast CE-MRA). Two neuroradiologists independently assessed agreements in acute and chronic ischemic hyperintensity, hyperintense vessels (FLAIR), microbleeds, susceptibility vessel signs, hemorrhagic transformation (GRE), stenosis (MRA), and image quality (all MRI), between fast and conventional MRI. Agreements between fast and conventional MRI were evaluated by generalized estimating equations. Z-scores were used for comparisons of the percentage agreement among fast FLAIR sequences and fast GRE sequences and between conventional and fast MRA. RESULTS: Agreements of more than 80% were achieved between fast and conventional MRI (ETL-FLAIR, 96%; TR-FLAIR, 97%; EPI-GRE, 96%; parallel-GRE, 98%; fast CE-MRA, 86%). ETL- and TR-FLAIR were significantly superior to EPI-FLAIR in the detection of acute ischemic hyperintensity and hyperintense vessels, while parallel-GRE was significantly superior to EPI-GRE in the detection of susceptibility vessel sign (p value < 0.05 for all). There were no significant differences in the other scores and image qualities (p value > 0.05). CONCLUSIONS: Fast MRI at 1.5 T is a reliable method for the detection and characterization of acute ischemic stroke in comparison with conventional MRI. KEY POINTS: * Fast MRI at 1.5 T may achieve a high intermethod reliability in the detection and characterization of acute ischemic stroke with a reduction in scan time in comparison with conventional MRI. PMID- 30421014 TI - Automatic quantification of tenosynovitis on MRI of the wrist in patients with early arthritis: a feasibility study. AB - OBJECTIVES: Tenosynovitis (inflammation of the synovial lining of the sheath surrounding tendons) is frequently observed on MRI of early arthritis patients. Since visual assessment of tenosynovitis is a laborious task, we investigated the feasibility of automatic quantification of tenosynovitis on MRI of the wrist in a large cohort of early arthritis patients. METHODS: For 563 consecutive early arthritis patients (clinically confirmed arthritis >= 1 joint, symptoms < 2 years), MR scans of the wrist were processed in three automatic stages. First, super-resolution reconstruction was applied to fuse coronal and axial scans into a single high-resolution three-dimensional image. Next, 10 extensor/flexor tendon regions were segmented using atlas-based segmentation and marker-based watershed. A measurement region of interest (ROI) was defined around the tendons. Finally, tenosynovitis was quantified by identifying image intensity values associated with tenosynovial inflammation using fuzzy clustering and measuring the fraction of voxels with these characteristic intensities within the measurement ROI. A subset of 60 patients was used for training and the remaining 503 patients for validation. Correlation between quantitative measurements and visual scores was assessed through Pearson correlation coefficient. RESULTS: Pearson correlation between quantitative measurements and visual scores across 503 patients was r = 0.90, p < 0.001. False detections due to blood vessels and synovitis present within the measurement ROI contributed to a median offset from zero equivalent to 13.8% of the largest measurement value. CONCLUSION: Quantitative measurement of tenosynovitis on MRI of the wrist is feasible and largely consistent with visual scores. Further improvements in segmentation and exclusion of false detections are warranted. KEY POINTS: * Automatic measurement of tenosynovitis on MRI of the wrist is feasible and largely consistent with visual scores. * Blood vessels and synovitis in the vicinity of evaluated tendons can contribute to false detections in automatic measurements. * Further improvements in segmentation and exclusion of false detections are important directions of future work on the path to a robust quantification framework. PMID- 30421015 TI - Ultrasound-based radiomics score: a potential biomarker for the prediction of microvascular invasion in hepatocellular carcinoma. AB - PURPOSE: To develop an ultrasound (US)-based radiomics score for preoperative prediction of microvascular invasion (MVI) in hepatocellular carcinoma (HCC). METHODS: Between January 1, 2012, and October 31, 2017, a total of 482 HCC patients who underwent contrast-enhanced ultrasound (CEUS) were retrospectively reviewed. The study population was divided into a training cohort (n = 341) and a validation cohort (n = 141) based on a cutoff time of January 1, 2016. Radiomics features were extracted from the grayscale US images of HCC. After features selection, a radiomics score was developed from the training cohort. The incremental value of the radiomics score to the clinic-pathological factors for MVI prediction was assessed in the validation cohort with respect to discrimination, calibration, and clinical usefulness. RESULTS: The US-based radiomics score consisted of six selected features. Multivariate logistic regression analysis showed that the radiomics score, alpha-fetoprotein (AFP), and tumor size were independent predictors of MVI. The radiomics nomogram (based on the three factors) showed better performance for MVI detection (area under the curve [AUC] 0.731[0.647, 0.815] than the clinical nomogram (based on AFP and tumor size) (0.634 [0.543, 0.724]) (p = 0.015). Both nomograms showed good calibration. Decision curve analysis demonstrated that in terms of clinical usefulness, the radiomics nomogram outperformed the clinical nomogram. CONCLUSION: The US-based radiomics score was an independent predictor of MVI in HCC. Combining the radiomics score with clinical factors improved the prediction efficacy. KEY POINTS: * Radiomics can be applied in US images. * US-based radiomics score was an independent predictor of MVI. * Radiomics nomogram incorporated with the radiomics score showed good performance for MVI prediction. PMID- 30421017 TI - Sarcopenia: ultrasound today, smartphones tomorrow? PMID- 30421016 TI - Quantitative 3-T multi-parametric MRI and step-section pathology of recurrent prostate cancer patients after radiation therapy. AB - OBJECTIVES: Diagnosis of radio-recurrent prostate cancer using multi-parametric MRI (mp-MRI) can be challenging due to the presence of radiation effects. We aim to characterize imaging of prostate tissue after radiation therapy (RT), using histopathology as ground truth, and to investigate the visibility of tumor lesions on mp-MRI. METHODS: Tumor delineated histopathology slides from salvage radical prostatectomy patients, primarily treated with RT, were registered to MRI. Median T2-weighted, ADC, Ktrans, and kep values in tumor and other regions were calculated. Two radiologists independently performed mp-MRI-based tumor delineations which were compared with the true pathological extent. General linear mixed-effect modeling was used to establish the contribution of each imaging modality and combinations thereof in distinguishing tumor and benign voxels. RESULTS: Nineteen of the 21 included patients had tumor in the available histopathology slides. Recurrence was predominantly multifocal with large tumor foci seen after external beam radiotherapy, whereas these were small and sparse after low-dose-rate brachytherapy. MRI-based delineations missed small foci and slightly underestimated tumor extent. The combination of T2-weighted, ADC, Ktrans, and kep had the best performance in distinguishing tumor and benign voxels. CONCLUSIONS: Using high-resolution histopathology delineations, the real tumor extent and size were found to be underestimated on MRI. mp-MRI obtained the best performance in identifying tumor voxels. Appropriate margins around the visible tumor-suspected region should be included when designing focal salvage strategies. Recurrent tumor delineation guidelines are warranted. KEY POINTS: * Compared to the use of individual sequences, multi-parametric MRI obtained the best performance in distinguishing recurrent tumor from benign voxels. * Delineations based on mp-MRI miss smaller foci and slightly underestimate tumor volume of local recurrent prostate cancer. * Focal salvage strategies should include appropriate margins around the visible tumor. PMID- 30421018 TI - Validation of overestimation ratio and TL-SVS as imaging biomarker of cardioembolic stroke and time from onset to MRI. AB - OBJECTIVE: We aimed to determine in the "THRACE" trial, the clinical and MRI technical parameters associated with the two-layered susceptibility vessel sign (TL-SVS) and the overestimation ratio (overR). MATERIALS AND METHODS: Patients with pre-treatment brain gradient echo (GRE) sequence and an etiological work-up were identified. Two readers reviewed TL-SVS, i.e., a SVS with a linear low intense signal core surrounded by a higher intensity and measured the overR as the width of SVS divided by the width of the artery. Binomial and ordinal logistic regression respectively tested the association between TL-SVS and quartiles of overR with patient characteristics, cardioembolic stroke (CES), time from onset to imaging, and GRE sequence parameters (inter slice gap, slice thickness, echo time, flip angle, voxel size, and field strength). RESULTS: Among 258 included patients, 102 patients were examined by 3 Tesla MRI and 156 by 1.5 Tesla MRI. Intra- and inter-reader agreements for quartiles of overR and TL-SVS were good to excellent. The median overR was 1.59 (IQR, 1.30 to 1.86). TL-SVS was present in 101 patients (39.2%, 95%CI, 33.1 to 45.1%). In multivariate analysis, only CES was associated with overR quartiles (OR, 1.83; 95%CI, 1.11 to 2.99), and every 60 min increase from onset to MRI time was associated with TL-SVS (OR, 1.72; 95%CI, 1.10 to 2.67). MRI technical parameters were statistically associated with neither overR nor TL-SVS. CONCLUSION: Independent of GRE sequence parameters, an increased overR was associated to CES, while the TL-SVS is independently related to a longer time from onset to MRI. KEY POINTS: * An imaging biomarker would be useful to predict the etiology of stroke in order to adapt secondary prevention of stroke. * The two-layered susceptibility vessel sign and the overestimation ratio are paramagnetic effect derived markers that vary according to the MRI machines and sequence parameters. * Independent of sequence parameters, an increased overestimation ratio was associated to cardioembolic stroke, while the two-layered susceptibility vessel sign is independently related to a longer time from onset to MRI. PMID- 30421019 TI - Differentiation between pilocytic astrocytoma and glioblastoma: a decision tree model using contrast-enhanced magnetic resonance imaging-derived quantitative radiomic features. AB - OBJECTIVE: To differentiate brain pilocytic astrocytoma (PA) from glioblastoma (GBM) using contrast-enhanced magnetic resonance imaging (MRI) quantitative radiomic features by a decision tree model. METHODS: Sixty-six patients from two centres (PA, n = 31; GBM, n = 35) were randomly divided into training and validation data sets (about 2:1). Quantitative radiomic features of the tumours were extracted from contrast-enhanced MR images. A subset of features was selected by feature stability and Boruta algorithm. The selected features were used to build a decision tree model. Predictive accuracy, sensitivity and specificity were used to assess model performance. The classification outcome of the model was combined with tumour location, age and gender features, and multivariable logistic regression analysis and permutation test using the entire data set were performed to further evaluate the decision tree model. RESULTS: A total of 271 radiomic features were successfully extracted for each tumour. Twelve features were selected as input variables to build the decision tree model. Two features S(1, -1) Entropy and S(2, -2) SumAverg were finally included in the model. The model showed an accuracy, sensitivity and specificity of 0.87, 0.90 and 0.83 for the training data set and 0.86, 0.80 and 0.91 for the validation data set. The classification outcome of the model related to the actual tumour types and did not rely on the other three features (p < 0.001). CONCLUSIONS: A decision tree model with two features derived from the contrast enhanced MR images performed well in differentiating PA from GBM. KEY POINTS: * MRI findings of PA and GBM are sometimes very similar. * Radiomics provides much more quantitative information about tumours. * Radiomic features can help to distinguish PA from GBM. PMID- 30421020 TI - Deep learning analysis of left ventricular myocardium in CT angiographic intermediate-degree coronary stenosis improves the diagnostic accuracy for identification of functionally significant stenosis. AB - OBJECTIVES: To evaluate the added value of deep learning (DL) analysis of the left ventricular myocardium (LVM) in resting coronary CT angiography (CCTA) over determination of coronary degree of stenosis (DS), for identification of patients with functionally significant coronary artery stenosis. METHODS: Patients who underwent CCTA prior to an invasive fractional flow reserve (FFR) measurement were retrospectively selected. Highest DS from CCTA was used to classify patients as having non-significant (<= 24% DS), intermediate (25-69% DS), or significant stenosis (>= 70% DS). Patients with intermediate stenosis were referred for fully automatic DL analysis of the LVM. The DL algorithm characterized the LVM, and likely encoded information regarding shape, texture, contrast enhancement, and more. Based on these encodings, features were extracted and patients classified as having a non-significant or significant stenosis. Diagnostic performance of the combined method was evaluated and compared to DS evaluation only. Functionally significant stenosis was defined as FFR <= 0.8 or presence of angiographic high-grade stenosis (>= 90% DS). RESULTS: The final study population consisted of 126 patients (77% male, 59 +/- 9 years). Eighty-one patients (64%) had a functionally significant stenosis. The proposed method resulted in improved discrimination (AUC = 0.76) compared to classification based on DS only (AUC = 0.68). Sensitivity and specificity were 92.6% and 31.1% for DS only (>= 50% indicating functionally significant stenosis), and 84.6% and 48.4% for the proposed method. CONCLUSION: The combination of DS with DL analysis of the LVM in intermediate-degree coronary stenosis may result in improved diagnostic performance for identification of patients with functionally significant coronary artery stenosis. KEY POINTS: * Assessment of degree of coronary stenosis on CCTA has consistently high sensitivity and negative predictive value, but has limited specificity for identifying the functional significance of a stenosis. * Deep learning algorithms are able to learn complex patterns and relationships directly from the images without prior specification of which image features represent presence of disease, and thereby may be more sensitive to subtle changes in the LVM caused by functionally significant stenosis. * Addition of deep learning analysis of the left ventricular myocardium to the evaluation of degree of coronary artery stenosis improves diagnostic performance and increases specificity of resting CCTA. This could potentially decrease the number of patients undergoing invasive coronary angiography. PMID- 30421021 TI - Minimizing individual variations in arterial enhancement on coronary CT angiographs using "contrast enhancement optimizer": a prospective randomized single-center study. AB - OBJECTIVES: To investigate the clinical utility of our newly developed contrast enhancement optimizer (CEO) software for coronary CT angiography (CCTA). METHODS: We randomly assigned 295 patients (168 males, 127 females, median age 71 years) undergoing CCTA to one of two contrast media injection protocols. Group A (n = 150) was injected with a CEO-selected iodine dose based on patient factors. In group B (n = 145), we used our standard protocol (245 mg I/kg). We recorded the CT number in the ascending aorta and determined whether the CT number was equivalent in groups A and B. For the equivalence test, we adopted 75 Hounsfield units (HU) as the equivalence margin. The standard deviation in the CT number and the rate of patients with an acceptable CT number were compared using the F test and the chi-square test, respectively. RESULTS: The iodine dose in group A was significantly smaller than that in group B (235.7 vs. 253.6 mg I/kg, p < 0.001). The CT number of the ascending aorta was 428.6 +/- 55.5 HU in group A and 436.1 +/- 68.7 HU in group B; the 95% confidence interval for the difference between the groups was -4.3 HU to 16.9 HU and within the range of the predetermined equivalence margins. In group A, the variance was significantly smaller than that in group B (p = 0.009). The number of patients with an acceptable CT number was significantly higher in group A than in group B (84.7% vs. 71.7%, p = 0.007). CONCLUSIONS: The use of our CEO for CCTA studies yielded optimal aortic contrast enhancement in significantly more patients than the standard protocol based on the body weight. KEY POINTS: * With our contrast enhancement optimizer (CEO) software, optimal and stable aortic enhancement can be obtained on coronary CT angiography scans irrespective of patient factors. * Management of contrast media becomes more appropriate by the CEO software. * The CEO software can control contrast enhancement at different tube voltage levels. PMID- 30421022 TI - Fluid sparing and norepinephrine use in a rat model of resuscitated haemorrhagic shock: end-organ impact. AB - BACKGROUND: Haemostasis and correction of hypovolemia are the pillars of early haemorrhage shock (HS) management. Vasopressors, which are not recommended as first-line therapy, are an alternative to aggressive fluid resuscitation, but data informing the risks and benefits of vasopressor therapy as fluid-sparing strategy is lacking. We aimed to study its impact on end organs, in the setting of a haemodynamic response to the initial volume resuscitation. METHODS: Following controlled HS (60 min) induced by blood withdrawal, under anaesthesia and ventilation, male Wistar rats (N = 10 per group) were randomly assigned to (1) sham, (2) HS with fluid resuscitation only [FR] and (3) HS with fluid resuscitation to restore haemodynamic (MAP: mean arterial pressure) then norepinephrine [FR+NE]. After a reperfusion time (60 min) during which MAP was maintained with fluid or norepinephrine, equipment was removed and animals were observed for 24 h (N = 5) or 72 h (N = 5) before euthanasia. Besides haemodynamic parameters, physiological markers (creatinine, lactate, pH, PaO2) and one potential contributor to vasoplegia (xanthine oxidase activity) were measured. Apoptosis induction (caspase 3), tissue neutrophil infiltration (MPO: myeloperoxidase) and illustrative protein markers were measured in the lung (Claudin-4), kidney (KIM-1) and brain amygdala (Iba1). RESULTS: No difference was present in MAP levels during HS or reperfusion between the two resuscitation strategies. FR required significantly more fluid than FR+NE (183% vs 106% of bleed-out volume; p = 0.003), when plasma lactate increased similarly. Xanthine oxidase was equally activated in both HS groups. After FR+NE, creatinine peaked higher but was similar in all groups at later time points. FR+NE enhanced MPO in the lung, when Claudin-4 increased significantly after FR. In the brain amygdala, FR provoked more caspase 3 activity, MPO and microglial activation (Iba1 expression). CONCLUSION: Organ resuscitation after controlled HS can be assured with lesser fluid administration followed by vasopressors administration, without signs of dysoxia or worse evolution. Limiting fluid administration could benefit the brain and seems not to have a negative impact on the lung or kidney. PMID- 30421024 TI - ? PMID- 30421025 TI - ? PMID- 30421023 TI - Feasibility of the imatinib stop study in the Japanese clinical setting: delightedly overcome CML expert stop TKI trial (DOMEST Trial). AB - BACKGROUND: Treatment-free remission (TFR), the ability to maintain a molecular response (MR), occurs in approximately 50% of patients with chronic myelogenous leukemia (CML) treated with tyrosine kinase inhibitors (TKIs). METHODS: A multicenter phase 2 trial (Delightedly Overcome CML Expert Stop TKI Trial: DOMEST Trial) was conducted to test the safety and efficacy of discontinuing imatinib. Patients with CML with a sustained MR of 4.0 or MR4.0-equivalent for at least 2 years and confirmed MR4.0 at the beginning of the study were enrolled. In the TFR phase, the international scale (IS) was regularly monitored by IS-PCR testing. Molecular recurrence was defined as the loss of MR4.0. Recurrent patients were immediately treated with dasatinib or other TKIs including imatinib. RESULTS: Of 110 enrolled patients, 99 were evaluable. The median time from diagnosis to discontinuation of imatinib was 103 months, and the median duration of imatinib therapy was 100 months. Molecular recurrence-free survival rates were 69.6%, 68.6% and 64.3% at 6, 12, and 24 months, respectively. After discontinuation of imatinib therapy, 26 patients showed molecular recurrence, and 25 re-achieved deep MR after dasatinib treatment. Molecular response MR4.0 was achieved in 23 patients within 6 months and 25 patients within 12 months. Multivariate analysis revealed that a longer time from diagnosis to discontinuation of imatinib therapy (p = 0.0002) and long duration of imatinib therapy (p = 0.0029) predicted a favorable prognosis. CONCLUSIONS: This DOMEST Trial showed the feasibility of TKI discontinuation in a Japanese clinical setting. PMID- 30421026 TI - Flavobacterium edaphi sp. nov., isolated from soil from Jeju Island, Korea. AB - An aerobic, Gram-stain-negative, bright yellow-pigmented, oxidase and catalase positive, non-motile, non-spore forming, rod-shaped strain designated DMN11T was isolated from the soil of crossroads of Jeju Island in South Korea. Colonies were circular, bright yellow-pigmented and smooth with regular edges and measured approximately 1-2 mm in diameter. Flexirubin-type pigments were absent. Phylogenetic tree analysis based on the 16SrRNA gene sequence revealed that the strain DMN11T formed a lineage within the family Flavobacteriaceae of the phylum Bacteroidetes, and it was the most closely related to Flavobacterium suzhouense XIN-1T and Flavobacterium hauense BX12T (98.6% and 98.2% similarity, respectively). The major isoprenoid quinone was MK-6. The major fatty acids were summed feature 3 (comprising C16:1 omega7c and/or C16:1 omega6c), iso-C15:0 and iso-C15:0 3OH. The polar lipid profile of the strain DMN11T showed the presence of phosphatidylethanolamine (PE) as major lipid. The DNA G+C content was 35.3 mol%, as determined by the thermal denaturation method. The mean levels of DNA DNA relatedness of the strain DMN11T with F. suzhouense XIN-1T and F. hauense BX12T were 20.5% and 29.2%, respectively. Thus, the data accumulated in this study support the suggestion that the strain DMN11T is considered to represent a novel species of the genus Flavobacterieum, for which the name Flavobacterium edaphi sp. nov. is proposed. The type strain is DMN11T (= KCTC 62114T = JCM 32372T). PMID- 30421028 TI - "Bucket" cerebrospinal fluid bulk flow-is it a fact or a fiction? PMID- 30421027 TI - Endozoicomonas coralli sp. nov., isolated from the coral Acropora sp. AB - A novel bacterium, designated strain Acr-12T, was isolated from the coral Acropora sp. off coast of Southern Taiwan. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain Acr-12T belonged to the genus Endozoicomonas and had closest phylogenetic identity to Endozoicomonas acroporae Acr-14T (98.7%) and Endozoicomonas atrinae WP70T (97.8%). Cells of strain Acr-12T were Gram-negative, aerobic, non-motile, poly-beta-hydroxybutyrate-accumulating, rod-shaped and formed creamy white colonies. Optimal growth occurred at 30 degrees C, pH 7, and in the presence of 3% NaCl. Strain Acr-12T contained summed feature 3 (C16:1omega7c and/or C16:1omega6c), summed feature 8 (C18:1omega7c and/or C18:1omega6c) and C16:0 as the predominant fatty acids. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. The predominant isoprenoid quinone was Q-9. The genomic DNA G + C content was 49.6 mol%. The DNA-DNA relatedness of strain Acr-12T with respect to the closest species of the genus Endozoicomonas was less than 30%. Phenotypic characteristics of the novel strain also differed from those of the closest related species of the genus Endozoicomonas. On the basis of the genotypic, chemotaxonomic, and phenotypic data, strain Acr-12T represents a novel species in the genus Endozoicomonas, for which the name Endozoicomonas coralli sp. nov. is proposed. The type strain is Acr-12T (= BCRC 80921T = KCTC 42900T). PMID- 30421029 TI - Hereditary clear cell meningiomas in a single family: three-cases report. AB - Clear cell meningiomas (CCMs) are rare subtypes of meningiomas and usually treated by maximum safely achievable tumor resection. We here present three hereditary cases with CCMs which were confirmed by Sanger sequencing of lymphocyte DNA. Gross total resection was achieved in a 5-year-old son with a spinal CCM and a 34-year-old father with a CCM in the cerebellopontine angle (CPA). For a 14-year-old daughter with CCM in the CPA, total resection was not achieved due to its large size. Early detection by screening high-risk family with CCM is strongly recommended. PMID- 30421030 TI - Class II MHC antigen processing in immune tolerance and inflammation. AB - Presentation of peptide antigens by MHC-II proteins is prerequisite to effective CD4 T cell tolerance to self and to recognition of foreign antigens. Antigen uptake and processing pathways as well as expression of the peptide exchange factors HLA-DM and HLA-DO differ among the various professional and non professional antigen-presenting cells and are modulated by cell developmental state and activation. Recent studies have highlighted the importance of these cell-specific factors in controlling the source and breadth of peptides presented by MHC-II under different conditions. During inflammation, increased presentation of selected self-peptides has implications for maintenance of peripheral tolerance and autoimmunity. PMID- 30421031 TI - Forever young: Neoteny, neurogenesis and a critique of critical periods in olfaction. AB - The critical period concept has been one of the most transcendent in science, education, and society forming the basis of our fixation on 'quality' of childhood experiences. The neural basis of this process has been revealed in developmental studies of visual, auditory and somatosensory maps and their enduring modification through manipulations of experience early in life. Olfaction, too, possesses a number of phenomena that share key characteristics with classical critical periods like sensitive temporal windows and experience dependence. In this review, we analyze the candidate critical period-like phenomena in olfaction and find them disanalogous to classical critical periods in other sensory systems in several important ways. This leads us to speculate as to why olfaction may be alone among exteroceptive systems in lacking classical critical periods and how life-long neurogenesis of olfactory sensory neurons and bulbar interneurons-a neotenic vestige-- relates to the structure and function of the mammalian olfactory system. PMID- 30421032 TI - [Cervical spine involvement in rheumatoid arthritis : Diagnostics and treatment of instability due to rheumatism]. AB - In addition to involvement of small peripheral joints, the cervical spine is the second most affected body region in rheumatoid arthritis (RA). Due to improvement of pharmaceutical treatment in recent years, new data show that there is a decreasing prevalence of cervical involvement; however, depending on the severity of cervical lesions surgical treatment still plays an important role. The sequelae of involvement of the cervical spine are craniocervical and atlantoaxial instability, which can cause severe pain, neural deficits and even death. Multimodal conservative treatment can lead to an alleviation of pain but in cases of therapy-resistant pain or neural deficits surgical treatment alone is essential to improve patient outcome. For isolated atlantoaxial instability (AAS), atlantoaxial fusion by posterior C1-2 fixation according to Harms and Goel is the method of choice. Posterior stabilization including C0 should be avoided whenever possible due to substantial limitations in range of movement. PMID- 30421033 TI - [Response of dermatomyositis with lung involvement to Janus kinase inhibitor treatment]. AB - We report on a 32-year-old male patient presenting with anti-MDA-5 and anti-Ro52 antibody positive hypomyopathic dermatomyositis (CADM) with clinically leading interstitial pulmonary involvement. Under several immunosuppressive treatment regimens including high-dose steroids, cyclophosphamide, rituximab, immunoglobulins, plasmapheresis, ciclosporin and mycophenolate mofetil, pulmonary involvement was refractory to progressive. Based on the detection of a clear-cut interferon signature by flow cytometric determination of SIGLEC-1 as an interferon-dependent marker, treatment with the Janus kinase inhibitor tofacitinib was initiated. This resulted in a response to treatment with a significant increase in physical performance, an ameliorated skin condition and computed tomographic (CT) morphologically improved interstitial lung disease with overall good tolerability. PMID- 30421034 TI - Evaluation of restless legs syndrome and sleep disorders in patients with psoriatic arthritis. AB - OBJECTIVES: Restless legs syndrome (RLS) is a neurological disease with a chronic course that is characterised by sleep disorders and sensorimotor impairment. The aim of this study was to evaluate the prevalence and severity of RLS in psoriatic arthritis (PSA) patients and those with psoriasis (P). PATIENTS AND METHODS: The study included 50 patients with psoriasis (28 females, 22 males), 50 PSA patients (33 females, 17 males) and 50 healthy control subjects (34 females, 16 males), and all 3 groups were matched with respect to age, gender and body mass index (BMI). Evaluations were made using the International RLS Rating Scale, Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale, Insomnia Severity Index, Fatigue Severity Scale (FSS), Beck Depression Index (BDI) and the SF-36 quality of life scores. RESULTS: RLS was determined at a higher rate in the PSA patients (64.0%), compared to the P group (20.0%, p < 0.001) and the control group (14.0%, p < 0.001). The number of moderate and severe RLS cases was significantly higher in the PSA group (68.7%) compared to the P group (30%, p < 0.001) and the control group (0%, p < 0.001). In regression analysis, an independent correlation was found between the RLS score and PSQI (beta [beta] = 0.269, p = 0.002), FSS (beta = 0.243, p = 0.003), SF-36 physical score (beta = 0.242, p = 0.004) and BDI (beta = 0.177, p = 0.036). CONCLUSION: RLS was determined in PSA patients at a higher rate than in psoriasis patients. The presence of RLS in PSA and psoriasis patients is related to impairments in sleep and quality of life, fatigue and depression. PMID- 30421035 TI - Where Are We Going with Sentinel Lymph Node Mapping in Gynecologic Cancers? AB - PURPOSE OF REVIEW: Sentinel lymph node (SLN) mapping is a standard of care for lymphatic assessment of many early-stage gynecologic malignancies. We review the current data, emphasizing the utility of SLN mapping in the management of gynecologic cancers. RECENT FINDINGS: Endometrial cancer: recent studies have focused on confirming the safety and efficacy of SLN mapping for high-risk patients. Cervical cancer: the LACC Trial demonstrated reduced survival with minimally invasive surgery, calling into question the validity of prior studies evaluating SLN mapping with a minimally invasive approach. Vulvar cancer: the ongoing GROINS-V-II trial is investigating whether patients with SLN metastasis < 2 mm in diameter can safely undergo adjuvant radiation +/- chemotherapy without completion inguinal lymphadenectomy. NCCN guidelines have incorporated SLN mapping as a lymphatic assessment strategy for endometrial, cervical, and vulvar malignancies. SLN mapping appears to reduce morbidity while still maintaining an appropriate detection rate of lymphatic metastasis. Additional clinical trials will further our knowledge of these procedures. PMID- 30421036 TI - Reconfiguration patterns of large-scale brain networks in motor imagery. AB - Motor imagery (MI) is a multidimensional cognitive ability which recruited multiple brain networks. However, how connections and interactions are adjusted among distributed networks during MI remains unknown. To investigate these issues, we analyze the reconfiguration patterns of large-scale networks for different MI states. In our work, we explored the specific patterns of large scale functional network organization from rest to different MI tasks using group independent component analysis (ICA), and evaluated the potential relationships between MI and the patterns of large-scale networks. The results indicate that task-related large-scale networks show the balanced relation between the within- and between-network connectivities during MI, and reveal the somatomotor network and dorsal attention network play critical roles in switching context-specific MI, and also demonstrate the change of large-scale networks organization toward effective topology could facilitate MI performance. Moreover, based on the large scale network connectivities, we could differentiate an individual's three states (i.e., left-hand MI, right-hand MI and rest) with an 72.73% accuracy using a multi-variant pattern analysis, suggesting that the specific patterns of large scale network can also provide potential biomarkers to predict an individual's behavior. Our findings contribute to the further understanding of the neural mechanisms underlying MI from large-scale network patterns and provide new biomarkers to predict the individual's behaviors. PMID- 30421037 TI - Functional hierarchy of oculomotor and visual motion subnetworks within the human cortical optokinetic system. AB - Optokinetic look nystagmus (look OKN) is known to engage cortical visual motion and oculomotor hubs. Their functional network hierarchy, however, and the role of the cingulate eye field (CEF) and the dorsolateral prefrontal cortex (DLPFC) in particular have not been investigated. We used look OKN in fMRI to identify all cortical visual motion and oculomotor hubs involved. Using these activations as seed regions, we employed hierarchical clustering in two differing resting state conditions from a separate public data set. Robust activations in the CEF highlight its functional role in OKN and involvement in higher order oculomotor control. Deactivation patterns indicate a decreased modulatory involvement of the DLPFC. The hierarchical clustering revealed a changeable organization of the eye fields, hMT, V3A, and V6 depending on the resting state condition, segregating executive from higher order visual subnetworks. Overall, hierarchical clustering seems to allow for a robust delineation of physiological cortical networks. PMID- 30421039 TI - Impact of the economic crises on suicide in Italy: the moderating role of active labor market programs. AB - PURPOSE: To analyze the association between unemployment and suicide in Italy during the years 1990-2014, with a peculiar focus on the great recession (GR) and the role played by social protection as buffering mechanism against the negative effect on health outcomes. METHODS: Fixed effects panel regressions were used to assess the association between changes in unemployment rate and suicide rates. Additional models investigated the role of active labor market programs (ALMPs) as possible moderators of the association. Analyses were carried out for both males and females, stratified by age and region. RESULTS: The negative time-trend displayed by suicide rate in Italy until 2007 was slowed down by changes in unemployment at the beginning of the GR, when this trend reversed and the rate of suicide started increasing. Male workers aged 25-64 and women aged 55-64 years were affected by both "normal" unemployment rate fluctuations as well as severe economic crises. Women aged 35-44 were only influenced by the latter. Men benefit from ALMPs mainly in Central Italy, while women did not benefit significantly from ALMPs. CONCLUSIONS: In Italy, economic downturns were associated with increased suicides mainly among men, while severe economic crises were associated with increased suicides among both men and women. ALMPs showed to be effective in moderating the association between unemployment and suicide among men aged 45-54 only in Central Italy. The overall small effectiveness of such programs may be due to lack of sufficient funding. PMID- 30421038 TI - Dual-aptamer-based voltammetric biosensor for the Mycobacterium tuberculosis antigen MPT64 by using a gold electrode modified with a peroxidase loaded composite consisting of gold nanoparticles and a Zr(IV)/terephthalate metal organic framework. AB - An ultrasensitive aptasensor is described for the voltammetric determination of the Mycobacterium tuberculosis antigen MPT64 in human serum. Firstly, an amino modified Zr(IV) based metal-organic framework (MOF; type UiO-66-NH2; made up from Zr6O32 units and 2-amino-terephthalate linkers) with a high specific surface was synthesized and used as the carrier of the gold nanoparticles and the aptamers. Then the signalling nanoprobe was fabricated after the horseradish peroxidase was cast on the nanomaterials. The two aptamers with synergistic effect on binding MPT64 were anchored on the gold electrode. Differential pulse voltammetry indicated that the peak current is highest if the ratio of the two aptamers is 1:1. The assay has a wide linear response range (0.02 to 1000 pg.mL-1 of MPT64) and a 10 fg.mL-1 detection limit at a working potential of around -96 mV (vs Ag/AgCl). The results show this biosensor to be a viable tool for detection of tuberculosis at an early stage. Graphical abstract Schematic presentation of the construction of the nanoprobe and biosensor. Firstly, the surface of UiO-66-NH2 was anchored to gold nanoparticles (AuNPs). A dual-aptamer and HRP were added to form the signalling nanoprobe (Aptamer/HRP/AuNPs/UiO-66-NH2). Then, the aptamers I and II were attached on the surface of gold electrode and 6-mercapto-1-hexanol was used to block the uncovered active site of the gold electrode. Finally, after incubation with MPT64, the signalling nanoprobe was dropped on the modified electrode and the DPV measurements was used for the analysis of Mycobacterium tuberculosis antigen MPT64. (PVP: poly(vinyl pyrrolidone); HRP: horseradish peroxidase; MCH: 6-Mercapto-1-hexanol; HQ: hydroquinone; BQ: benzoquinone). PMID- 30421040 TI - Suicide risk among native- and foreign-origin persons in Sweden: a longitudinal examination of the role of unemployment status. AB - PURPOSE: Prior research has documented an association between unemployment and elevated suicide risk. Yet, few Swedish studies have explicitly considered how such risk may vary by different migration background characteristics among persons of foreign-origin, who often experience diverse forms of labor market marginalization. This study examines the extent to which unemployment status may differentially influence suicide risk among the foreign-origin by generational status, region of origin, age at arrival, and duration of residence. METHODS: Population-based registers were used to conduct a longitudinal, open cohort study of native-origin and foreign-origin Swedish residents of working age (25-64 years) from 1993 to 2008. Hazard ratios and 95% confidence intervals for suicide mortality were estimated using gender-stratified Cox proportional hazards models. RESULTS: Elevated suicide risk observed among foreign-origin unemployed groups was generally of a similar or lower magnitude than that found in unemployed native-origin, although unemployed second-generation Swedish men demonstrated significantly greater (p < 0.05) excess risk of suicide than that observed among their native-origin counterparts. Unemployed foreign-born men with a younger age at arrival and longer duration of residence demonstrated an increased risk of suicide, while those who arrived as adults, and a shorter duration of residence did not show any increased risk. Among foreign-born women, excess suicide risk persisted regardless of age at arrival and duration of residence in the long-term unemployed. CONCLUSIONS: Multiple migration background characteristics should be considered when examining relationships between employment status and suicide among the foreign-origin. PMID- 30421041 TI - ASO Author Reflections: Outcomes of Gastroesophageal Neuroendocrine Tumors. PMID- 30421042 TI - ASO Author Reflections: Circulating Tumor DNA in Peritoneal Carcinomatosis. PMID- 30421043 TI - ASO Author Reflections: Diagnosis and Features of Ruptured GISTs in Clinical Practice. PMID- 30421044 TI - Outcomes of Low-Grade Appendiceal Mucinous Neoplasms with Remote Acellular Mucinous Peritoneal Deposits. AB - BACKGROUND: Occasionally, low-grade appendiceal mucinous neoplasms (LAMN) present with mucinous peritoneal deposits (MPD) localized to periappendiceal tissue or diffused throughout the peritoneum. OBJECTIVE: This study was aimed at evaluating the relevance of mucin cellularity for predicting outcomes of LAMN with remote MPD. METHODS: The records of patients with LAMN and remote MPD who underwent initial assessment at a comprehensive cancer center from 1990 to 2015 were reviewed, and diagnostic procedures, treatments, and outcomes were analyzed. RESULTS: Of 48 patients included in the analysis, 19 had cellular MPD (CMPD) and 29 had acellular MPD. Of 33 patients who underwent cytoreductive surgery, 30 had a complete cytoreduction; the 3 patients with an incomplete cytoreduction had CMPD. In the follow-up period (median, 4 years), 6 patients died of the disease, all of whom had CMPD. Of 11 patients who had progression of disease, 10 had CMPD. CONCLUSION: Cellularity of remote MPD is an important determinant of disease outcome in LAMN. Approaches such as active surveillance may have a role in selected patients with LAMN and AMPD. PMID- 30421045 TI - Microsatellitosis in Patients with Melanoma. AB - BACKGROUND: Microsatellitosis (mS) in melanoma has been considered a marker of unfavorable tumor biology, leading to the current American Joint Committee on Cancer staging of IIIB/C/D disease, despite few investigative studies of this entity limited by the small sample sizes and incomplete nodal microstaging. We sought to better characterize outcomes and prognostic factors in a multi institutional cohort of patients with mS and nodal microstaging. METHODS: The Sentinel Lymph Node Working Group cohort included 414 mS patients who underwent sentinel lymph node (SLN) biopsy. Cox regression analysis was used to evaluate the prognostic significance of established clinicopathologic characteristics. Melanoma-specific survival (MSS) of patients with mS was compared with 3002 similarly staged patients from the Surveillance, Epidemiology, and End Results (SEER) Program registry. RESULTS: The median age of the mS cohort was 64.9 years; 39.6% were female. Median thickness was 3 mm, 40.6% of cases were ulcerated, and the SLN positivity rate was 46.7%. Increasing thickness, male sex, and SLN positivity were significantly associated with poorer MSS. Stage IIIB/C/D 5-year MSS rates were 86.3% (95% confidence interval [CI] 79.4-93.3%), 54.1% (95% CI 45.4-59.7%), and 44.2% (95% CI 25.4-63.0%), respectively. MSS survival for the stage IIIB mS cohort was significantly better than a similarly staged SEER cohort (5-year MSS of 70.1%, 95% CI 66.0-74.2%), while no significant difference was observed for the stage IIIC or D cohorts. CONCLUSIONS: SLN metastases are common and are a significant prognostic factor in patients with mS. Survival in stage IIIB patients with mS was considerably more favorable than their stage would otherwise suggest, which has important implications for decisions regarding adjuvant therapy for patients with mS. PMID- 30421046 TI - Is Robotic-Assisted Surgery Safe in the Elderly Population? An Analysis of Gynecologic Procedures in Patients >= 65 Years Old. AB - BACKGROUND: The elderly population is expanding worldwide but is underrepresented in clinical trials. We sought to assess the safety of robotic gynecologic surgery in an elderly cohort and to identify factors associated with unfavorable outcomes. METHODS: All patients >= 65 years who underwent a robotically assisted procedure at a single institution between May 2007 to December 2016 were divided into three age groups: 65-74 (Group 1); 75-84 (Group 2); >= 85 (Group 3). Perioperative outcomes were recorded in patients who did not require conversion to laparotomy. We compared clinical variables among groups and performed multivariate logistic regression to detect variables associated with major complications (>= Grade 3) or 90-day mortality. RESULTS: We retrospectively identified 982 cases: 685 in Group 1; 249 in Group 2; 48 in Group 3. Median age = 71 years. Median BMI = 28.9. Malignancy was documented in 72.8% of cases; the majority were endometrial cancer (61.8%). Thirty-four patients (3.5%) were readmitted within 30 days. Seventy-seven (7.8%) had a postoperative complication, and 23 (2.3%) had a major complication. Ninety-day mortality was 0.5%. There was significant difference between groups with respect to body mass index (P = 0.026), ECOG PS (P <= 0.001), > 5 comorbidities (P = 0.005), hospital stay (P < 0.001), major complications (P = 0.001), and 90-day mortality (P < 0.001). On multivariable logistic regression, age >= 85 years was associated with major complications. Body mass index, age >= 85 years, and major complications were significantly associated with 90-day mortality. CONCLUSIONS: Robotic-assisted surgery appears to be safe in an elderly cohort. The incidence of overall and major complications is consistent with those reported in the literature. Patients >= 85 years old appear to be at higher risk of unfavorable outcomes. PMID- 30421047 TI - ASO Author Reflections: Prognostic Impact of Body Composition Change After Gastrectomy for Advanced Gastric Cancer. PMID- 30421048 TI - ASO Author Reflections: PCI is Not Predictive of Survival After Complete CRS/HIPEC for High-Grade Appendiceal Primaries. PMID- 30421049 TI - ASO Author Reflections: Implementing a Program of Talimogene laherparepvec. PMID- 30421050 TI - ASO Author Reflections: Rate of Axillary Lymph Node Dissection has Decreased in Patients Treated with Neoadjuvant Systemic Therapy. PMID- 30421051 TI - ASO Author Reflections: To Med or Not to Med? That is the Question. PMID- 30421052 TI - Narrow-Band Imaging Improves Detection of Colorectal Peritoneal Metastases: A Clinical Study Comparing Advanced Imaging Techniques. AB - BACKGROUND: Colorectal peritoneal metastases (PM) are often diagnosed in an advanced disease stage. Cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) improve survival of patients with colorectal PM, although most benefit is seen in patients with limited peritoneal disease. Advanced imaging techniques might improve the detection of PM, potentially leading to earlier diagnosis and improved cytoreduction. This prospective clinical trial compared three advanced techniques with conventional white-light imaging for the detection of colorectal PM: narrow-band imaging (NBI), near-infrared indocyanine green fluorescent imaging (NIR-ICG), and spray-dye chromoendoscopy (SDCE). METHODS: Patients with colorectal PM were prospectively included. Prior to cytoreduction and HIPEC, all abdominal regions were inspected with white-light imaging, NBI, NIR-ICG, and SDCE during exploratory laparoscopy. Primary endpoints were sensitivity and specificity for the detection of PM, using pathological examination of biopsied lesions as the reference standard. The safety of all techniques was assessed. RESULTS: Between May 2016 and March 2018, four different techniques were analyzed in 28 patients, resulting in 169 biopsies. Sensitivity for the detection of PM significantly increased from 80.0% with white light to 96.0% with NBI (p = 0.008), without loss of specificity (74.8% vs. 73.1%, respectively, p = 0.804). The use of NIR-ICG and SDCE was discontinued after 10 patients had undergone treatment because the lesions were not fluorescent using NIR-ICG, and because SDCE did not visualize the whole peritoneum. No adverse events relating to the imaging techniques occurred. CONCLUSION: NBI substantially increased the detection of PM. This method is safe and could improve the detection of metastatic lesions and help optimize cytoreduction in patients with colorectal PM. PMID- 30421053 TI - ASO Author Reflections: Size of Tumor Volume in Glioblastoma Patients. PMID- 30421054 TI - ASO Author Reflections: Evolving Concepts for Radiation Therapy in Extremity and Trunk Soft Tissue Sarcoma. PMID- 30421055 TI - ASO Author Reflections: Use of Retrospective Administrative Datasets in Rare Cancer Subtypes to Determine the Efficacy of Adjuvant Therapy. PMID- 30421056 TI - ASO Author Reflections: Systematic Lymph Node Dissection in Ovarian Cancer Under Attack. PMID- 30421057 TI - ASO Author Reflections: Preoperative Risk Stratification in Differentiated Thyroid Cancer. PMID- 30421058 TI - Adjuvant Therapy is Associated with Improved Survival in pT1N1 Gastric Cancer in a Heterogeneous Western Patient Population. AB - BACKGROUND: Two recent South Korean studies showed adjuvant therapy (AT) was not associated with improved survival in pT1N1 gastric adenocarcinoma (GAC). We established the prognostic utility of lymph node status, determined the pattern of use of AT, and compared survival stratified by type of AT in pT1N1 GAC in a Western patient population. METHODS: We identified patients with pT1N0 and pT1N1 GAC using the National Cancer Database from 2004 to 2012. Clinicopathologic variables, treatment regimens, and overall survival (OS) were compared. RESULTS: We compared 4516 (86.6%) pT1N0 to 696 (13.4%) pT1N1 patients. pT1N1 tumors were larger (median size 2.5 vs. 1.8 cm, p < 0.001), more often poorly differentiated (56.2% vs. 39.6%, p < 0.001), and had higher median retrieved lymph nodes (RLN) (14 vs. 12, p < 0.001) compared with pT1N0. pT1N1 was associated with worse median overall survival (OS) (6.9 vs. 9.9 years for pT1N0, p < 0.001). pN1 was independently associated with worse OS (hazard ratio [HR] 2.17, 95% confidence interval [CI] 1.84-2.56). Increased RLN was associated with improved OS (HR 0.73, 95% CI 0.65-0.83). Among pT1N1 patients, 330 (47.4%) had observation (OBS), 77 (11.1%) received adjuvant chemotherapy (ACT), 68 (9.8%) received adjuvant radiation therapy (ART), and 221 (31.8%) received adjuvant chemoradiation therapy (ACRT). ACT and ACRT were independently associated with improved OS (HR 0.37, 95% CI 0.22-0.65 and HR 0.40, 95% CI 0.28-0.57). CONCLUSIONS: pN1 was associated with worse survival and RLN >= 15 was associated with improved survival in pT1 GAC. ACT and ACRT were independently associated with improved survival in pT1N1 gastric cancer suggesting a valuable role in Western patients. PMID- 30421059 TI - ASO Author Reflections: RAS Mutations in Metastatic Colorectal Cancer. PMID- 30421060 TI - Selecting the Right Tumors for Genomic Testing. PMID- 30421061 TI - ASO Author Reflections: Decision Timing for Organ Preservation in Rectal Cancer After Chemoradiation. PMID- 30421062 TI - ASO Author Reflections: Borrmann Type as a Characteristic Phenotype of Advanced Gastric Cancer. PMID- 30421063 TI - Robotic Nipple-Sparing Mastectomy: The Next Step in the Evolution of Minimally Invasive Breast Surgery. PMID- 30421064 TI - ASO Author Reflections: Long-Term Survival Is Feasible After Complete CRS/HIPEC for Biphasic Peritoneal Mesothelioma. PMID- 30421065 TI - ASO Author Reflections: Management of Malignant Peritoneal Mesothelioma. PMID- 30421066 TI - Patient Survival after Surgical Management in Intrathoracic Pseudomyxoma peritonei. AB - BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare disease, characterized by mucinous ascites and deposits diffusely present on the peritoneal surfaces. However, extension of PMP to the thoracic cavity is extremely rare. Although there are a few case reports on the long-term postoperative prognosis of intrathoracic lesions, whether surgical resection of these lesions can improve patient prognosis remains unclear. METHODS: We reviewed 17 patients with PMP who underwent resection of intrathoracic lesions after abdominal cytoreductive surgery and examined their clinical outcome after surgery. RESULTS: Direct extension into the pleural cavity was identified in 11 patients. Extrapleural pneumonectomy of the lesions followed by hyperthermic intrathoracic chemotherapy (HITOC) was performed in four patients, parietal pleurectomy and visceral tumor resection followed by HITOC in four patients, resection of all disseminated pleural and visceral lesions followed by HITOC in one patient, resection of a single disseminated lesion in one patient, and composite resection of basal segment with the diaphragm in one patient. Pulmonary metastases were found in six patients. Partial resection was performed in four patients, segmentectomy in one patient, and lobectomy in one patient. We could perform macroscopic resection of the tumor in all the cases. The 5-year overall survival rate after thoracic surgery for the 17 patients was 46.1% and relapse-free survival was 34.9%. CONCLUSIONS: Resection of intrathoracic lesions of PMP after abdominal cytoreductive surgery achieved 5 years survival in at least 46.1% of the patients. Aggressive tumor resection should be considered for patients with PMP extending to thoracic cavity. PMID- 30421067 TI - [Appendectomy: open versus laparoscopic versus single port : Evidence for choice of surgical procedure]. AB - The treatment of choice in acute appendicitis is still the surgical removal of an inflamed vermiform appendix. There is still some disagreement regarding the optimal access route, i.e. conventional open or minimally invasive. The best available evidence is used to answer the question of the current optimal choice of procedure. For laparoscopic appendectomy there are evidence-based benefits in terms of access trauma, postoperative pain, wound infection rates and convalescence. For the alternative minimally invasive procedure single port appendectomy, mini-laparoscopic appendectomy or NOTES appendectomy, there is still a lack of scientific evidence to advocate the broad clinical use of these procedures. It is recommended that whenever the infrastructure permits, laparoscopic appendectomy should be the treatment of choice. PMID- 30421068 TI - Simulation of radionuclide atmospheric dispersion and dose assessment for inhabitants of Tehran province after a hypothetical accident of the Tehran Research Reactor. AB - Radiological dose assessment is one of the main categories of safety assessment for nuclear reactors and facilities. The radiation risks to the public and to the environment that may arise from these facilities have to be assessed and, if necessary, controlled. The main objective of this paper is the assessment of radiation doses to residents of Tehran province after a hypothetical accident of the Tehran Research Reactor (TRR) including the determination of any protective actions that might be needed for the benefit of people's health. The concentration of radionuclides in air and deposited on the ground surface as a result of a hypothetical radionuclide release from the TRR, following a hypothetical accident scenario, have been calculated by the HYSPLIT computer code. Simulations were performed using selected source terms taken from the TRR Final Safety Analysis Report (FSAR). Meteorological data of the Air Resources Laboratory of the National Oceanic and Atmospheric Administration (NOAA) have been used in these calculations. The simulation results indicate that maximum annual total effective dose equivalent values for the residents of the Tehran province are less than the protective action dose limits. Thus, it is concluded that during this hypothetical accident in the TRR, required safety due to public radiation is achieved and the residents of Tehran province are safe under a TRR accident condition. PMID- 30421069 TI - Subcutaneous tocilizumab alone or with a csDMARD in rheumatoid arthritis patients: subanalysis of Italian data from a multicenter phase IIIb/IV trial. AB - To assess, in a setting close to real life, the efficacy and safety of weekly subcutaneous tocilizumab (TCZ-SC) 162 mg, alone or with a conventional synthetic DMARD (csDMARD), in moderate-to-severe RA patients with inadequate response to DMARDs or anti-TNFalpha drugs. This national, multicenter, open-label, phase IIIb trial is part of an umbrella study (TOZURA). Patients were treated for 52 weeks followed by 8 weeks drug-free to evaluate immunogenicity. The primary end point was the Clinical Disease Activity Index (CDAI) change from baseline at weeks 2 and 24. Other efficacy parameters, including sleep quality, and the safety and immunogenicity were also assessed up to week 52. Of 288 patients enrolled in 43 Italian centers, 78.8% received TCZ-SC (86.8% females; mean age 54.7 +/- 12.1 years; mean disease duration 7.8 +/- 7.5 years; DMARD-IRs 94.7%). Of these, 78.0% completed the 52-week period and 52.0% received concomitant methotrexate. TCZ-SC yielded a significant reduction in median CDAI from baseline already at week 2, which progressed up to week 24 and remained stable thereafter (P < 0.0001 at each time point). A significant, rapid, and sustained improvement of the other efficacy variables was also observed. Patients were deemed as ready for home administration after a median of 2.0 (range 1-8) administrations, with a rate (since the last visit) of 80.6% and 95.5% at weeks 2 and 52, respectively. TCZ-SC displayed low immunogenicity and no unexpected toxicities. TCZ-SC, alone or with a csDMARD, yielded rapid and sustained efficacy in DMARD/anti-TNFalpha-IR RA patients, with acceptable toxicity. Home administration seems feasible. PMID- 30421070 TI - Predictive value of lymphoscintigraphy in patients with breast cancer-related lymphedema undergoing complex decongestive therapy. AB - PURPOSE: We evaluated the prognostic value of lymphoscintigraphy after complex decongestive therapy (CDT) in breast cancer-related secondary lymphedema. METHODS: Prior to CDT, 80 patients with breast cancer-related lymphedema underwent a 99mTc tin-colloid lymphoscintigram. We investigated the uptake patterns of axillary lymph nodes (LNs), main lymphatic vessels, collateral lymphatic vessels, and dermal back flow in the lymphoscintigraphy of the upper extremities. We also compared the above findings with other clinical variables between patients who respond well to CDT (responders) and those who do not (poor responders). We used Pearson's chi2 test and Fisher's exact test to compare the lymphoscintigram findings with the studied variables. RESULTS: There were 50 poor responders and 30 responders 1 year after CDT. There were significant differences between the two groups with regard to compliance (P < 0.05) and visualization of axillary LNs (P < 0.05). In combined results, the odds ratio was 21.33 (2.37 192.03) in the compliance and visible axillary LNs group compared to the poor compliance and invisible axillary LNs group. CONCLUSION: Lymphoscintigraphy of the upper extremities can be a useful tool to predict the prognosis of CDT in breast cancer-related lymphedema patients. PMID- 30421071 TI - Colorimetric DNA assay by exploiting the DNA-controlled peroxidase mimicking activity of mesoporous silica loaded with platinum nanoparticles. AB - A nanozyme composed of mesoporous silica and platinum nanoparticles (MS-PtNPs) was synthesized and is shown to display peroxidase-like activity. Its activity can be controlled by loading with single-stranded DNA. The PtNPs on the MS are homogeneously distributed and act as enzyme mimics. The adsorption of DNA probe on the MS blocks the nucleation sites of PtNPs. This leads to a decrease in the peroxidase-mimicking activity. After introduction of target DNA that is complementary to the DNA probe, the activity of the nanozyme is recovered. By using the 3,3,5,5-tetramethylbenzidine/H2O2 chromogenic system, a rapid method was developed for colorimetric determination of DNA. The assay, best performed at 450 nm, has a linear response in the 5 nM to 100 nM DNA concentration range and a 2.6 nM detection limit. It possesses high selectivity and can distinguish even a single-base mismatch. Graphical abstract The peroxidase-like activity of mesoporous silica and platinum nanoparticles (MS-PtNPs) was depressed when noncovalent ssDNA-MS was in-situ deposited on the PtNPs. After introduction of target DNA, the complementary dsDNA releases from the MS, and then its activity is recovered. PMID- 30421072 TI - Genomic classification and risk stratification of bladder cancer. AB - Bladder cancer is the fourth most common cancer in men and fifth most common overall. The use of next-generation sequencing (NGS) approaches is crucial to precisely characterize the molecular defects of tumors, and this information could be combined with other clinical data, such as tumor histology and TNM staging, with the goal of precise tumor classification. In many settings, targeted NGS is evaluated in patients with first- and second-line metastatic cancer. Yet, in the decade to come we anticipate increased application of precision oncology at all stages of bladder cancer with the aim of customizing cancer treatment. Here, we review the genomic and transcriptomic features associated with risk stratification in bladder cancer and summarize the current efforts for precision oncology in localized urothelial carcinomas. PMID- 30421073 TI - Trends in utilization and perioperative outcomes in live donor nephrectomies: a multi-surgical discipline analysis. AB - OBJECTIVE: We aim to analyze the trends in donor nephrectomy (DN) across three surgical disciplines-urology, general surgery, and transplant surgery, specifically to analyze the surgical techniques and perioperative outcomes. MATERIALS AND METHODS: We reviewed all live DN reported in the Statewide Planning and Research Cooperative System database of New York State (NYS) from 1995 to 2015. Surgeons were grouped in their respective disciplines using their state license number and the American Medical Association masterfile. We analyzed the volume of DN performed by each group along with how the surgical approach is, such as open, laparoscopic or robotic. Perioperative outcomes assessed were length of stay (LOS), 30-day and 90-day readmission rates, and complication rates RESULTS: A total of 6803 DN were performed with urologists, transplant surgeons and general surgeons accounting for 42%, 29%, and 29% of them, respectively. Urologists performed a higher case volume with a mean surgical volume of 17.4 +/- 6.5 per year (p < 0.0001). During the study period, case volumes for urologists and transplant surgeons trended upward, while those for general surgeons trended downward. Urologists also utilized a minimally invasive surgery (MIS) such as laparoscopy or robotic approach in a higher percentage of their cases (p < 0.0001). Regarding perioperative outcomes, general surgeons had a higher mean LOS (p < 0.0001), while transplant surgeons had higher rates of 30-day and 90-day readmission rates (p < 0.0001). There were no statistically significant differences in complication rates following DN among the groups. CONCLUSION: Urologists remain vital members of the renal transplantation team as they perform a majority of DN in NYS and are increasingly achieving them via an MIS approach when compared to their general and transplant surgery counterparts. Perioperative outcomes are similar amongst all disciplines; however, general surgeons have higher mean LOS, while transplant surgeons have higher readmission rates. PMID- 30421074 TI - Cell-based therapies for the treatment of myocardial infarction: lessons from cardiac regeneration and repair mechanisms in non-human vertebrates. AB - Ischemic cardiomyopathy is the cardiovascular condition with the highest impact on the Western population. In mammals (humans included), prolonged ischemia in the ventricular walls causes the death of cardiomyocytes (myocardial infarction, MI). The loss of myocardial mass is soon compensated by the formation of a reparative, non-contractile fibrotic scar that ultimately affects heart performance. Despite the enormous clinical relevance of MI, no effective therapy is available for the long-term treatment of this condition. Moreover, since the human heart is not able to undergo spontaneous regeneration, many researchers aim at designing cell-based therapies that allow for the substitution of dead cardiomyocytes by new, functional ones. So far, the majority of such strategies rely on the injection of different progenitor/stem cells to the infarcted heart. These cardiovascular progenitors, which are expected to differentiate into cardiomyocytes de novo, seldom give rise to new cardiac muscle. In this context, the most important challenge in the field is to fully disclose the molecular and cellular mechanisms that could promote active myocardial regeneration after cardiac damage. Accordingly, we suggest that such strategy should be inspired by the unique regenerative and reparative responses displayed by non-human animal models, from the restricted postnatal myocardial regeneration abilities of the murine heart to the full ventricular regeneration of some bony fishes (e.g., zebrafish). In this review article, we will discuss about current scientific approaches to study cardiac reparative and regenerative phenomena using animal models. PMID- 30421075 TI - On a Generalization of Local Independence in Item Response Theory Based on Knowledge Space Theory. AB - Knowledge space theory (KST) structures are introduced within item response theory (IRT) as a possible way to model local dependence between items. The aim of this paper is threefold: firstly, to generalize the usual characterization of local independence without introducing new parameters; secondly, to merge the information provided by the IRT and KST perspectives; and thirdly, to contribute to the literature that bridges continuous and discrete theories of assessment. In detail, connections are established between the KST simple learning model (SLM) and the IRT General Graded Response Model, and between the KST Basic Local Independence Model and IRT models in general. As a consequence, local independence is generalized to account for the existence of prerequisite relations between the items, IRT models become a subset of KST models, IRT likelihood functions can be generalized to broader families, and the issues of local dependence and dimensionality are partially disentangled. Models are discussed for both dichotomous and polytomous items and conclusions are drawn on their interpretation. Considerations on possible consequences in terms of model identifiability and estimation procedures are also provided. PMID- 30421076 TI - Robotic-assisted versus laparoscopic left pancreatectomy at a high-volume, minimally invasive center. AB - INTRODUCTION: While minimally invasive left pancreatectomy has become more widespread and generally accepted over the last decade, opinions on modality of minimally invasive approach (robotic or laparoscopic) remain mixed with few institutions performing a significant portion of both operative approaches simultaneously. METHODS: 247 minimally invasive left pancreatectomies were retrospectively identified in a prospectively maintained institutional REDCapTM database, 135 laparoscopic left pancreatectomy (LLP) and 108 robotic-assisted left pancreatectomy (RLP). Demographics, intraoperative variables, postoperative outcomes, and OR costs were compared between LLP and RLP with an additional subgroup analysis for procedures performed specifically for pancreatic adenocarcinoma (35 LLP and 23 RLP) focusing on pathologic outcomes and 2-year actuarial survival. RESULTS: There were no significant differences in preoperative demographics or indications between LLP and RLP with 34% performed for chronic pancreatitis and 23% performed for pancreatic adenocarcinoma. While laparoscopic cases were faster (p < 0.001) robotic cases had a higher rate of splenic preservation (p < 0.001). Median length of stay was 5 days for RLP and LLP, and rate of clinically significant grade B/C pancreatic fistula was approximately 20% for both groups. Conversion rates to laparotomy were 4.3% and 1.8% for LLP and RLP approaches respectively. RLP had a higher rate of readmission (p = 0.035). Pathologic outcomes and 2-year actuarial survival were similar between LLP and RLP. LLP on average saved $206.67 in OR costs over RLP. CONCLUSIONS: This study demonstrates that at a high-volume center with significant minimally invasive experience, both LLP and RLP can be equally effective when used at the discretion of the operating surgeon. We view the laparoscopic and robotic platforms as tools for the modern surgeon, and at our institution, given the technical success of both operative approaches, we will continue to encourage our surgeons to approach a difficult operation with their tool of choice. PMID- 30421077 TI - A Society of Gastrointestinal and Endoscopic Surgeons (SAGES) statement on closed social media (Facebook(r)) groups for clinical education and consultation: issues of informed consent, patient privacy, and surgeon protection. AB - INTRODUCTION: Closed social media groups (CSMG), including closed Facebook(r) groups, are online communities providing physicians with platforms to collaborate privately via text, images, videos, and live streaming in real time and optimize patient care. CSMG platforms represent a novel paradigm in online learning and education, so it is imperative to ensure that the public and patients trust the physicians using these platforms. Informed consent is an essential aspect of establishing this trust. With the launch of several of its own CSMG, Society of Gastrointestinal and Endoscopic Surgeons (SAGES) sought to define its position on CSMG platforms and provide an informed consent template for educating and protecting patients, surgeons, and institutions. METHODS: A review of the literature (2012-2018) discussing the informed consent process for posting clinical scenarios, photography, and/or videography on social media was performed. Pertinent articles and exemplary legal counsel-approved CSMG policies and informed consent forms were reviewed by members of the SAGES Facebook(r) Task Force. RESULTS: Eleven articles and two institutional CSMG policies discussing key components of the informed consent process, including patient transparency and confidentiality, provider-patient partnerships, ethics, and education were included. Using this information and expert opinion, a SAGES-approved statement and informed consent template were formulated. CONCLUSIONS: SAGES endorses the professional use of medical and surgical CSMG platforms for education, patient care optimization, and dissemination of clinical information. Despite the growing use of social media as an integral tool for surgical practice and education, issues of informed consent still exist and remain the responsibility of the physician contributor. Responsible, ethical, and compliant use of CSMG platforms is essential. Surgeons and patients embracing CSMG for quality improvement and optimized outcomes should be legally protected. SAGES foresees the use of this type of platform continuing to grow. PMID- 30421078 TI - Emergency laparoscopic and open repair of incarcerated ventral hernias: a multi institutional comparative analysis with coarsened exact matching. AB - BACKGROUND: The safety of emergent laparoscopic repair of incarcerated ventral hernias is not well established. The objective of this study was to determine if emergent laparoscopic repair of incarcerated ventral hernias is comparable to open repair with respect to short-term clinical outcomes. METHODS: Patients undergoing emergency repair of an incarcerated ventral hernia with associated obstruction and/or gangrene were identified using the ACS-NSQIP 2012-2016 dataset. One-to-one coarsened exact matching (CEM) was conducted between patients undergoing laparoscopic and open repair. Matched cohorts were compared with respect to morbidity, mortality, readmission, reoperation, missed enterotomies, and length of stay. Missed enterotomy was defined as any re-operative procedure within 30 days that required resection of large or small bowel segments, based on CPT codes. Multivariate analysis was conducted to determine adjusted predictors of morbidity. RESULTS: A total of 1642 patients were identified after CEM. Laparoscopic compared to open repair was associated with a lower rate of 30-day wound-morbidity (OR 0.35, 95% CI 0.22-0.57, p < 0.001). Laparoscopic repair was not associated with lower 30-day non-wound morbidity (OR 0.73, 95% CI 0.51-1.06, p = 0.094). Laparoscopic repair was associated with shorter LOS (3.6 days vs. 4.3 days, p = 0.014). A higher rate of missed enterotomies was observed in the laparoscopic cohort (0.7% vs. 0.0%, p = 0.031). There were no group differences with respect to 30-day readmission, reoperation, or mortality. CONCLUSIONS: Emergency laparoscopic repair of incarcerated ventral hernias is associated with lower rates of wound-morbidity and shorter hospital stays compared to open repair. However, laparoscopic repair is associated with a higher rate of missed enterotomies; a rate which is low and comparable to elective non-incarcerated ventral hernia repairs. PMID- 30421079 TI - Robotic enucleations of pancreatic benign or low-grade malignant tumors: preliminary results and comparison with robotic demolitive resections. AB - BACKGROUND: The incidental detection of benign to low-grade malignant small pancreatic neoplasms increased in the last decades. The surgical management of these patients is still under debate. The aim of this paper is to evaluate the safety and feasibility of robotic enucleations and to compare the outcomes with non-parenchymal sparing robotic resections. METHODS: The study included a total of 25 patients. Nine of them underwent a robotic enucleation (EN Group) and 16 patients received a robotic demolitive resection (DR Group). Perioperative and medium-term outcomes were compared between the two groups. RESULTS: Patients' baseline characteristics were similar in the two groups except for presence of symptoms and tumor size, due to the inclusion criteria. Operative time was significantly shorter and postoperative results were better for EN group, including a significant shorter hospitalization (5 vs. 8 days, p = 0.027), reduced pancreatic leaks (22% vs. 50%, p = 0.287) and a better preservation of glandular function (100% vs. 62.5%, p = 0.066). Mortality rate was zero in both groups, with all patients free from disease at a median follow-up of 18 months. CONCLUSIONS: The risks of under/overtreatment remain still unavoidable for benign to low-grade malignant small pancreatic neoplasms. Simple enucleation should be performed whenever oncological appropriate, to achieve the best postoperative outcomes. The adoption of robotic technique might widen the indications for parenchymal sparing, minimally invasive surgery. PMID- 30421080 TI - Novel real-time optical imaging modalities for the detection of neoplastic lesions in urology: a systematic review. AB - BACKGROUND: Current optical diagnostic techniques for malignancies are limited in their diagnostic accuracy and lack the ability to further characterise disease, leading to the rapidly increasing development of novel imaging methods within urology. This systematic review critically appraises the literature for novel imagining modalities, in the detection and staging of urological cancer and assesses their effectiveness via their utility and accuracy. METHODS: A systematic literature search utilising MEDLINE, EMBASE and Cochrane Library Database was conducted from 1970 to September 2018 by two independent reviewers. Studies were included if they assessed real-time imaging modalities not already approved in guidelines, in vivo and in humans. Outcome measures included diagnostic accuracy and utility parameters, including feasibility and cost. RESULTS: Of 5475 articles identified from screening, a final 46 were included. Imaging modalities for bladder cancer included optical coherence tomography (OCT), confocal laser endomicroscopy, autofluorescence and spectroscopic techniques. OCT was the most widely investigated, with 12 studies demonstrating improvements in overall diagnostic accuracy (sensitivity 74.5-100% and specificity 60-98.5%). Upper urinary tract malignancy diagnosis was assessed using photodynamic diagnosis (PDD), narrow band imaging, optical coherence tomography and confocal laser endomicroscopy. Only PDD demonstrated consistent improvements in overall diagnostic accuracy in five trials (sensitivity 94-96% and specificity 96.6-100%). Limited evidence for optical coherence tomography in percutaneous renal biopsy was identified, with anecdotal evidence for any modality in penile cancer. CONCLUSIONS: Evidence supporting the efficacy for identified novel imaging modalities remains limited at present. However, OCT for bladder cancer and PDD in upper tract malignancy demonstrate the best potential for improvement in overall diagnostic accuracy. OCT may additionally aid intraoperative decision making via real-time staging of disease. Both modalities require ongoing investigation through larger, well-conducted clinical trials to assess their diagnostic accuracy, use as an intraoperative staging aid and how to best utilise them within clinical practice. PMID- 30421081 TI - Quality of life in patients with loco-regional rectal cancer after ELRR by TEM versus VLS TME after nChRT: long-term results. AB - BACKGROUND: Endoluminal loco-regional resection (ELRR) by transanal endoscopic microsurgery (TEM) may be an alternative treatment option to Laparoscopic total mesorectal excision (LTME), in selected patients with N0 rectal cancer. Post operative quality of life (QoL) evaluation is an important parameter of outcomes related to high percentage of functional sequelae. We reported, in a previous paper, the short and medium term results of QoL in patients who underwent ELRR or LTME. The aim is to evaluate the 3 year QoL in patients with iT2-T3 N0/+ rectal cancer who underwent ELRR by TEM or LTME after neoadjuvant radio-chemotherapy (nChRT) in a retrospective analysis of prospectively collected data. METHODS: We enrolled in this study, 39 patients with iT2-T3 rectal cancer who underwent ELRR (n = 19) or LTME (n = 20), according to predefined criteria. QoL was evaluated by EORTC QLQ-C30 and QLQ-CR38 questionnaires at admission, after n-RCT and 1, 6, 12, and 36 months after surgery. RESULTS: No statistically significant differences in QoL evaluation were observed between the two groups, both at admission and after n-RCT. In short term (1-6 months) period, significantly better results were observed in ELRR group by QLQ-C30 in global health status (p = 0.03), physical functioning (p = 0.026), role functioning (p = 0.04), emotional functioning (p = 0.04), cognitive functioning, fatigue (p < 0.05), dyspnoea (p < 0.001), insomnia (p < 0.05), appetite loss (p < 0.05), constipation (<= 0.05), and by QLQ-CR38 in: body image (p = 0.03) and defecation (p = 0.025). At 1 year, the two groups were homogenous as assessed by QLQ-C30, whereas the QLQCR38 still showed better results of ELRR versus LTME in body image (p = 0.006), defecation problems (p = 0.01), and weight loss (p = 0.005). At 3 years, no statistically significant differences were observed between the two groups. CONCLUSIONS: In selected patients with rectal cancer, who underwent ELRR by TEM or LTME, QoL tests at 3 years do not show any statistical differences on examined items. PMID- 30421082 TI - Clinical characteristics and surgical outcomes of internal hernia after gastrectomy in gastric cancer patients: retrospective case control study. AB - BACKGROUND: Although the internal hernia is rare after gastric cancer surgery, it is a serious complication, and prompt surgical treatment is essential. However, internal hernia has not been studied because of low incidence and difficulty of diagnosis. This study investigated the clinical characteristics and proper management of internal hernia after gastrectomy. METHODS: From June 2001 to June 2016, patients who underwent gastrectomy, either open or laparoscopic (robotic) surgery, with potential internal hernia defect were enrolled. The hernia defect was not closed in any of the enrolled patients. The clinicopathological data of internal hernia patients were compared to patients without internal hernia to identify risk factors. Surgical outcomes of internal hernia were compared between patients who underwent early and late intervention group according to time interval from symptom onset to operation. RESULTS: Of 5777 patients who underwent gastrectomy with possible internal hernia, 24 (0.4%) underwent emergency or scheduled surgery for internal hernia. Internal hernia through the Petersen space was observed in 15 cases, and through the jejunojejunostomy mesenteric defect in 9 cases. Low body mass index (odds ratio [OR] 4.403, p = 0.003) and laparoscopic approach (OR 6.930 p < 0.001) were statistically significant factors in multivariate analysis. Postoperative complication rate (16.7% vs. 50% p = 0.083) and mortality rate (8.3% vs. 25.0% p = 0.273) were slightly higher in the late intervention group. CONCLUSIONS: Although internal hernia is a rare complication, it is difficult to diagnose and cause serious complications. To prevent internal hernia, the necessity of hernia defect closure should be investigated in the further studies. Early surgical treatment is necessary when it is suspected. PMID- 30421084 TI - Cheminformatics-based enumeration and analysis of large libraries of macrolide scaffolds. AB - We report on the development of a cheminformatics enumeration technology and the analysis of a resulting large dataset of virtual macrolide scaffolds. Although macrolides have been shown to have valuable biological properties, there is no ready-to-screen virtual library of diverse macrolides in the public domain. Conducting molecular modeling (especially virtual screening) of these complex molecules is highly relevant as the organic synthesis of these compounds, when feasible, typically requires many synthetic steps, and thus dramatically slows the discovery of new bioactive macrolides. Herein, we introduce a cheminformatics approach and associated software that allows for designing and generating libraries of virtual macrocycle/macrolide scaffolds with user-defined constitutional and structural constraints (e.g., types and numbers of structural motifs to be included in the macrocycle, ring size, maximum number of compounds generated). To study the chemical diversity of such generated molecules, we enumerated V1M (Virtual 1 million Macrolide scaffolds) library, each containing twelve common structural motifs. For each macrolide scaffold, we calculated several key properties, such as molecular weight, hydrogen bond donors/acceptors, topological polar surface area. In this study, we discuss (1) the initial concept and current features of our PKS (polyketides) Enumerator software, (2) the chemical diversity and distribution of structural motifs in V1M library, and (3) the unique opportunities for future virtual screening of such enumerated ensembles of macrolides. Importantly, V1M is provided in the Supplementary Material of this paper allowing other researchers to conduct any type of molecular modeling and virtual screening studies. Therefore, this technology for enumerating extremely large libraries of macrolide scaffolds could hold a unique potential in the field of computational chemistry and drug discovery for rational designing of new antibiotics and anti-cancer agents. PMID- 30421083 TI - New experience of endoscopic papillectomy for ampullary neoplasms. AB - AIM: To establish the clinical value of endoscopic papillectomy for duodenal papillary tumor based on endoscopic and clinical characteristics. PATIENTS AND METHODS: This single-center, retrospective study included 110 patients with duodenal papillary tumor who underwent endoscopic papillectomy between January 2006 and April 2017 at the gastrointestinal endoscopic center of the Chinese PLA General Hospital. Clinical data, postoperative pathology, procedure-related complications, and therapeutic outcomes were analyzed. RESULTS: Endoscopic papillectomy was technically feasible in all patients, and was mainly performed by four experienced endoscopists. The primary success rate of endoscopic papillectomy for ampullary neoplasms was 78.2%. A total of 13 patients experienced recurrence during a mean follow-up period of 16.28 months (range 6 132 months), the predictive factors that were related to recurrence were complete resection (53.8% vs. 94.2%; P = 0.001), and final pathology findings (P = 0.001). Delayed hemorrhage, the most common procedure-related complication, occurred in 20% (22/110) of patients and was significantly related to intraoperative bleeding (P = 0.042). Pancreatitis was the second most common complication, which was closely related to intraoperative bleeding requiring intervention (P = 0.040) and larger tumor size (P = 0.044). Histology, type of resection, stent placement, sphincterotomy, and duration of procedure were not related to post-procedure hemorrhage or pancreatitis. Older age (63.7 +/- 13.5 vs. 57.4 +/- 12.2; P = 0.033), jaundice (47.8% vs. 13.8%; P = 0.001), endoscopic forceps biopsy diagnosis of high-grade intraepithelial neoplasia (82.6% vs. 14.9%; P = 0.001), tumor size >= 2 cm (60.9% vs. 34.5%; P = 0.022), and dilation of the bile duct (34.8% vs. 9.2%; P = 0.006) were clinical features for ampullary carcinoma. The rate of complete resection (52.2% vs. 92.0%; P = 0.001) and recurrence (34.8% vs. 6.8%; P = 0.001) were also related to the diagnosis of ampullary carcinoma at final pathology. CONCLUSIONS: Endoscopic papillectomy is a feasible and reasonable option for both diagnosis and treatment of tumors of the duodenal papilla in properly selected patients. PMID- 30421085 TI - Development and application of high-resolution melting analysis for the classification of infectious laryngotracheitis virus strains and detection of recombinant progeny. AB - Live attenuated vaccines against infectious laryngotracheitis virus (ILTV) are widely used in the poultry industry to control disease and help prevent economic losses. Molecular epidemiological studies of currently circulating strains of ILTV within poultry flocks in Australia have demonstrated the presence of highly virulent viruses generated by genomic recombination events between vaccine strains. In this study, high-resolution melting (HRM) analysis was used to develop a tool to classify ILTV isolates and to investigate ILTV recombination. The assay was applied to plaque-purified progeny viruses generated after co infection of chicken embryo kidney (CEK) monolayers with the A20 and Serva ILT vaccine strains and also to viruses isolated from field samples. The results showed that the HRM analysis is a suitable tool for the classification of ILTV isolates and can be used to detect recombination between ILTV vaccine strains in vitro. This method can be used to classify a broad range of ILTV strains to facilitate the classification and genotyping of ILTV and help to further understand recombination in these viruses. PMID- 30421086 TI - Resting state functional connectivity abnormalities and delayed recall performance in patients with amnestic mild cognitive impairment. AB - Amnestic Mild Cognitive Impairment (aMCI) represents the transition between healthy aging and Alzheimer's dementia (AD) wherein gradual impairment of cognitive abilities, especially memory sets in. Impairment in episodic memory, especially delayed recall, is a hallmark of AD and therefore, patients with aMCI with more severe impairment in episodic memory are considered to be at greater risk of imminent conversion to AD. Brain structural and functional abnormalities were examined by comparing gray matter volumes, white matter micro-structural integrity and resting state functional connectivity (rsFC), between patients with aMCI (n = 46) having lower vs. higher episodic memory delayed recall (EM-DR) performance scores, correcting the influences of age, sex, number of years of formal education and total brain volumes using voxel-based morphometry, whole brain tract based spatial statistics and dual regression analysis respectively. 'Low' performers (n = 27) when compared to 'high' performers (n = 19) showed significantly increased rsFC in the dorsal attention network (DAN) and central executive network (CEN) in the absence of demonstrable gray matter volumetric or white matter micro-structural integrity differences at family-wise error (FWE) corrected (p < 0.05) significance threshold. Follow-up data available for 38 (low performers = 22; high performers = 16) of the above 46 subjects (82.60% follow-up rate) over a median follow-up period of 24.5 months revealed that 7 subjects (18.42%) had converted to dementia. These converted subjects included 5 of the 22 low performers (22.72%) and 2 of the 16 high performers (12.5%) within the follow up sample (n = 38). The results of the study indicate that imminent conversion of aMCI to dementia is higher in low performers in comparison to high performers, which may be characterized by increased rsFC in task positive networks, viz., DAN and CEN, as opposed to gray or white matter structural changes. This finding, therefore, might be considered as a prognostic indicator of progression from aMCI to dementia. PMID- 30421088 TI - The Effectiveness of Sorafenib over Other Targeted Agents in the Second-Line Treatment of Metastatic Renal Cell Carcinoma: a Meta-Analysis. AB - The aim of the study was to perform a meta-analysis to compare the therapeutic effects and adverse events (AEs) of sorafenib in second-line treatments of metastatic renal cell carcinoma (mRCC). We searched online electronic databases: Pubmed, Embase, Cochrane library updated on November 2017.Trials of the effectiveness of sorafenib in second-line treatments of advanced RCC were included, of which the main outcomes were objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and grade 3/4 AE. Other TAs significantly reduced the risk of PFS compared to sorafenib with respect to second-line treatment (HR = 0.74; 95% CI, 0.65-0.83; p < 0.00001). No significant differences were, however, found in patients in terms of the ORR (HR = 1.82; 95% CI, 0.98-3.35; p = 0.06). Frequencies of the most common toxicities were overall similar and adverse events differed only in sensitivity analysis in rash with exclusion of other TAs (HR = 0.16; 95% CI, 0.05-0.52; p = 0.002). Overall survival was not debated between groups. In patients with mRCC, second-line sorafenib is associated with similar ORR as other target agents. While, sorafenib did not demonstrate a PFS advantage compared with other target agents, suggests sorafenib may not benefit patients with mRCC. Tolerability due to toxicities is similar compared sorafenib with other target agents. Further characterization of the RCC oncogenic pathway, and the ongoing clinical trials should help optimize the treatment option for second-line therapy of advanced renal cell carcinoma. PMID- 30421087 TI - Use of Dynamic MRI of the Pelvic Floor in the Assessment of Anterior Compartment Disorders. AB - PURPOSE OF REVIEW: Approximately 25% of women in the USA suffer from pelvic floor disorders. Disorders of the anterior compartment of the pelvic floor, in particular, can cause symptoms such as incomplete urinary voiding, urinary incontinence, pelvic organ prolapse, dyspareunia, and pelvic pain, potentially negatively impacting a woman's quality of life. In some clinical situations, clinical exam alone may be insufficient, especially when patient's symptoms are in excess of their pelvic exam findings. In many of these patients, dynamic magnetic resonance imaging (dMRI) of the pelvic floor can be a valuable imaging tool allowing for comprehensive assessment of the entire pelvic anatomy and its function. RECENT FINDINGS: Traditionally, evaluation of the anterior compartment has been primarily through clinical examination with occasional use of urodynamic testing and ultrasound. In recent years, dMRI has continued to gain popularity due to its improved imaging quality, reproducibility, and ability to display the entire pelvic floor. Emerging evidence has also shown utility of dMRI in the postoperative setting. In spite of advances, there remains an ongoing discussion in contemporary literature regarding the accuracy of dMRI and its correlation with clinical examination and with patient symptoms. Dynamic pelvic MRI is a helpful adjunct to physical examination and urodynamic testing, particularly when a patient's symptoms are in excess of the physical examination findings. Evaluation with dMRI can guide preoperative and postoperative surgical management in many patients, especially in the setting of multicompartmental disorders. This review will summarize relevant pelvic floor anatomy and discuss the clinical application, imaging technique, imaging interpretation, and limitations of dMRI. PMID- 30421089 TI - Co-expression of XIAP and CIAP1 Play Synergistic Effect on Patient's Prognosis in Head and Neck Cancer. AB - To explore the influence of chemotherapy on prognosis of Head and Neck Squamous Cell Carcinoma (HNSCC) and the relationship between XIAP and CIAP1 co-expression and the prognosis in HNSCC. 129 patients were recruited in our study, they were divided into two groups, neoadjuvant group (n = 60) and non-neoadjuvant group (n = 69). Expression level of XIAP and CIAP1 were examed in neoadjuvant group, and was correlated with clinical outcomes of the patients. The unselected patients were not benefit from neoadjuvant chemotherapy. Moreover, the patients whose tumors co-express high level of XIAP and CIAP1 presented poorer overall and disease-free survival rates than those whose tumors co-express low level of XIAP and CIAP1 (overall survival P < 0.001, disease-free survival P < 0.001). Our results validate that individual chemotherapy is important for HNSCC, and co expression of XIAP and CIAP1 prompted a worse prognosis. PMID- 30421090 TI - Downregulation of NOP53 Ribosome Biogenesis Factor Leads to Abnormal Nuclear Division and Chromosomal Instability in Human Cervical Cancer Cells. AB - NOP53 ribosome biogenesis factor (NOP53) is a nucleolar protein involved in oncogenesis/tumor suppression, cell cycle regulation, and cell death. Here, we investigated the role of NOP53 in the maintenance of normal nuclear shape and chromosomal stability. Depletion of NOP53 by shRNA caused abnormal nuclear morphology, including large nucleus, irregular nucleus, and multinucleated cells, and chromosomal instability resulting in micronucleus or nuclear bud formation. The abnormal nuclear shape and chromosomal instability were restored by re expression of NOP53. We further showed that NOP53 was involved in chromosome congression in metaphase. Downregulation of NOP53 induced aberrant chromosome congression and spindle checkpoint activation, resulting in delayed mitosis and mitotic arrest. Thus, our findings demonstrated that the nucleolar protein NOP53 participated in mitotic progression and that dysregulated NOP53 expression caused chromosomal instability in cancer cells. PMID- 30421092 TI - Ac34 protein of AcMNPV promoted progeny virus production and induced the apoptosis in host Sf9 cells. AB - OBJECTIVES: To analyze the function of Ac34 in Autographa californica multiple nuclear polyhedrosis virus (AcMNPV) and elucidate the JNK apoptotic signaling pathway activation in host Spodoptera frugiperda 9 (Sf9) cells induced by the recombinant virus AcMNPV-Ac34-EGFP. RESULTS: AcMNPV is an important species of baculoviruses. First, viral propagation assay indicated that overexpression of Ac34 protein promoted replication of AcMNPV. Quantitative RT-PCR analysis showed that Ac34 increased the transcriptional level of late genes 38k and vp39, which suggested that Ac34 promoted the production of progeny virus by upregulating transcription of late genes. Second, AcMNPV-Ac34-EGFP inhibited the proliferation of Sf9 cells. Moreover, Sf9 cells infected with AcMNPV-Ac34-EGFP resulted in abundant expression of SfP53 and its accumulation in the nucleus. c-Jun N terminal kinase (JNK) activation requires MKK4 and MKK7 mediated phosphorylation at Thr183 and Tyr185. We found increased levels of p-JNK1/2 in Sf9 cells infected by AcMNPV-Ac34-EGFP, with concomitant induction of Sf9 cell death. Furthermore, treatment of infected Sf9 cells with SP600125 (an inhibitor of JNK pathway) downregulated p-JNK1/2 and influenced the expression of virus-induced apoptosis protein SfP53, as well as Cytochrome C and Bax. CONCLUSION: AcMNPV-Ac34-EGFP virus upregulated the progeny virus production and triggered apoptosis via activation of the JNK pathway in Sf9 cells. In this work, we unveiled an effective virus replication factor-Ac34 and more importantly, developed a recombinant virus that can be used as an improved version of biopesticide. PMID- 30421091 TI - An Expandable Mechanopharmaceutical Device (1): Measuring the Cargo Capacity of Macrophages in a Living Organism. AB - PURPOSE: Clofazimine (CFZ) is an FDA-approved, poorly soluble small molecule drug that precipitates as crystal-like drug inclusions (CLDIs) which accumulate in acidic cytoplasmic organelles of macrophages. In this study, we considered CLDIs as an expandable mechanopharmaceutical device, to study how macrophages respond to an increasingly massive load of endophagolysosomal cargo. METHODS: First, we experimentally tested how the accumulation of CFZ in CLDIs impacted different immune cell subpopulations of different organs. Second, to further investigate the mechanism of CLDI formation, we asked whether specific accumulation of CFZ hydrochloride crystals in lysosomes could be explained as a passive, thermodynamic equilibrium phenomenon. A cellular pharmacokinetic model was constructed, simulating CFZ accumulation driven by pH-dependent ion trapping of the protonated drug in the acidic lysosomes, followed by the precipitation of CFZ hydrochloride salt via a common ion effect caused by high chloride concentrations. RESULTS: While lower loads of CFZ were mostly accommodated in lung macrophages, increased CFZ loading was accompanied by organ-specific changes in macrophage numbers, size and intracellular membrane architecture, maximizing the cargo storage capabilities. With increasing loads, the total cargo mass and concentrations of CFZ in different organs diverged, while that of individual macrophages converged. The simulation results support the notion that the proton and chloride ion concentrations of macrophage lysosomes are sufficient to drive the massive, cell type-selective accumulation and growth of CFZ hydrochloride biocrystals. CONCLUSION: CLDIs effectively function as an expandable mechanopharmaceutical device, revealing the coordinated response of the macrophage population to an increasingly massive, whole-organism endophagolysosomal cargo load. PMID- 30421094 TI - Clinical practice, deliberate practice, and "big data". PMID- 30421093 TI - Brain metastases as first manifestation of advanced cancer: exploratory analysis of 459 patients at a tertiary care center. AB - Symptomatic brain metastases (BM) are a frequent and late complication in cancer patients. However, a subgroup of cancer patients presents with BM as the first symptom of metastatic cancer. Here we aimed to analyze the clinical course and prognostic factors of this particular BM patient population. Patients presenting with newly diagnosed BM without a history of metastatic cancer were identified from the Vienna Brain Metastasis Registry. Clinical characteristics and overall survival were retrieved by chart review. 459/2419 (19.0%) BM patients presented with BM as first symptom of advanced cancer. In 374/459 (81.5%) patients, an extracranial primary tumor, most commonly lung cancer, could be identified within 3 months after BM diagnosis. In 85/459 (18.5%) patients no extracranial primary tumor could be identified despite comprehensive diagnostic workup within the first 3 months after diagnosis of BM. Survival of patients with identified extracranial tumor differed only numerically from patients with cancer of unknown primary (CUP), however patients receiving targeted therapy after molecular workup showed significantly enhanced survival (20 months vs. 7 months; p = 0.003; log rank test). The GPA score showed a statistically significant association with median overall survival times in the CUP BM patients (class I: 46 months; class II: 7 months; class III: 4 months; class IV: 2 months; p < 0.001; log rank test). The GPA score has a strong prognostic value in patients with CUP BM and may be useful for patient stratification in the clinical setting. Comprehensive diagnostic workup including advanced imaging techniques and molecular tissue analyses appears to benefit patients by directing specific molecular targeted therapies. PMID- 30421095 TI - Gout: Update on Dual-Energy Computed Tomography with Emphasis on Artifact Identification. AB - PURPOSE OF REVIEW: Gout is the most common inflammatory arthritis and is increasing in prevalence and incidence in many countries worldwide. Accurate diagnosis is important to direct treatment that may include chronic medication. Burden quantification and treatment monitoring are key in the effective care of patients with gout. This review highlights the positive impact of dual-energy computed tomography (DECT) on the evaluation of gout patients and discusses common imaging artifacts that limit this imaging modality. RECENT FINDINGS: DECT has become the most accurate imaging method for confirming or excluding gout. Of note, however, it has reduced sensitivity in early disease, including initial attacks. Burden quantification is another important role of DECT, which can now be performed using automated software methods, allowing for a more reliable assessment of treatment effect. However, the analysis of gout DECT images can be impeded by artifacts related to the DECT reconstruction technique. DECT is the most sensitive and specific imaging modality for diagnosis, burden quantification, and treatment monitoring in patients with gout. A working knowledge of common DECT artifacts is essential for mitigating their occurance and misinterpretation. PMID- 30421096 TI - Addiction in the light of African values: Undermining vitality and community. AB - I address the question of what makes addiction morally problematic, and seek to answer it by drawing on values salient in the sub-Saharan African philosophical tradition. Specifically, I appeal to life-force and communal relationship, each of which African philosophers have at times advanced as a foundational value, and spell out how addiction, or at least salient instances of it, could be viewed as unethical for flouting them. I do not seek to defend either vitality or community as the best explanation of when and why addiction is immoral, instead arguing that each of these characteristically African values grounds an independent and plausible account of that. I conclude that both vitalism and communalism merit consideration as rivals to accounts that western ethicists would typically make, according to which addiction is immoral insofar as it degrades rationality or autonomy, as per Kantianism, or causes pain or dissatisfaction, a la utilitarianism. PMID- 30421097 TI - Editorial: Special Issue on Verification, Validation, and Uncertainty Quantification of Cardiovascular Models: Towards Effective VVUQ for Translating Cardiovascular Modelling to Clinical Utility. PMID- 30421098 TI - Influence of symptomatic pseudoaneurysms on postoperative renal function after partial nephrectomy: results of a matched pair analysis. AB - PURPOSE: A symptomatic pseudoaneurysm (SPA) is a rare but severe complication after partial nephrectomy (PN). Selective trans-arterial embolization (TAE) is the treatment of choice with high success rates. However, the influence of this intervention on postsurgical renal function has not been studied. METHODS: Between 2005 and 2016 we performed 1047 PNs at our institution. Postsurgical SPA occurred in 40 patients (3.8%). Patients with and without SPA were matched in a 1:2 ratio concerning tumor complexity (RENAL) and pre-operative renal function (CKD stage). Any CKD upstage and a relevant CKD progression (CKD >= III) were defined as endpoints. Furthermore, the influence of the amount of contrast agent applied during TAE was assessed. RESULTS: All patients with SPA were treated successfully with TAE. No significant difference could be detected concerning clinical, functional and surgical aspects. Median follow-up time accounted for 12.5 (6.75-27.5) months. Kaplan-Meier analyses detected an increased rate of any CKD upstage (p = 0.066) and relevant CKD progression (p = 0.01) in patients with SPA. Multivariate analysis identified post-operative SPA to be an independent predictor for a relevant CKD progression (HR 4.15, p = 0.01). The amount of contrast agents used did not have an impact on the development of a relevant CKD progression (p = 0.72). CONCLUSION: Patients treated with TAE after PN show an additional risk for an impairment of renal function over time. Hence, those patients should explicitly be informed about possible consequences and closely monitored by nephrologists. PMID- 30421099 TI - Detoxification and reduction of selenite to elemental red selenium by Frankia. AB - Four Frankia strains (EuI1c, CN3, ACN14a and CcI3) were tested for selenite tolerance. Frankia inefficax strain EuI1c was resistant to selenite with a MIC value of 518.8 ug ml-1. After 48 h incubation with selenite, a reddish precipitate began to appear in these cultures. The red color suggests the reduction of the toxic, soluble, and colorless sodium selenite (Na2SeO32-) to the nontoxic, insoluble, and red colored elemental selenium (Seo). Analysis showed F. inefficax strain EuI1c cultures exposed to 17.3 and 86.5 ug ml-1selenite completely reduced all of the selenite after 5 and 8 days, respectively. When observed under Scanning Electron Microscopy, selenite-resistant F. inefficax strain EuI1c grown with selenite formed nanosphere particles on the hyphal surface as free deposits or in aggregates and inside the hyphae. EDAX analysis of the nanosphere particles determined that they are composed of selenium with up to 27.3-fold increase in intensity as compared to control cells. FTIR Spectroscopy of selenite-stressed cells showed cell surface changes in fatty acids, polysaccharides, carbohydrates and phosphate groups. This result suggests a mechanism for selenite reduction and nanosphere transport through cell membrane in this strain. Native gel electrophoresis of extracted cell-free protein revealed one band showing activity after staining with selenite and NADH. SDS PAGE analysis revealed the presence of several bands with one dominant band of 37.8 kDa. Mass spectrometry analysis of the bands determined that the main proteins were a periplasmic-binding protein, sulfate ABC transporter and extracellular ligand-binding receptor. PMID- 30421100 TI - Phyllobacterium phragmitis sp. nov., an endophytic bacterium isolated from Phragmites australis rhizome in Kumtag Desert. AB - A Gram-negative rod, designated strain 1N-3T, was isolated from a rhizome of Phragmites australis grown in Kumtag Desert, China. Phylogenetic analysis showed that the strain is closely related to Phyllobacterium salinisoli LMG 30173T with 99.0% sequence similarity in the 16S rRNA gene and 92.9% in the atpD gene. Growth was observed at salinities of 0-4% (w/v), over a pH range of 5.0-10.0 (optimum 8.0) and at temperatures of 15-40 degrees C (optimum 30 degrees C). The predominant cellular fatty acids were identified as summed feature 8 (C18:1omega7c/C18:1omega6c). The G+C content of strain 1N-3T was determined to be 60.1%. Based on phenotypic, chemotaxonomic, phylogenetic properties and genomic comparison, it is concluded that strain 1N-3T represents a novel species of the genus Phyllobacterium, for which the name Phyllobacterium phragmitis sp. nov. is proposed. The type strain is 1N-3T (=KCTC 62183T =ACCC 60071T). PMID- 30421101 TI - ALMS1 and Alstrom syndrome: a recessive form of metabolic, neurosensory and cardiac deficits. AB - Alstrom syndrome (AS) is characterised by metabolic deficits, retinal dystrophy, sensorineural hearing loss, dilated cardiomyopathy and multi-organ fibrosis. Elucidating the function of the mutated gene, ALMS1, is critical for the development of specific treatments and may uncover pathways relevant to a range of other disorders including common forms of obesity and type 2 diabetes. Interest in ALMS1 is heightened by the recent discovery of its involvement in neonatal cardiomyocyte cell cycle arrest, a process with potential relevance to regenerative medicine. ALMS1 encodes a ~ 0.5 megadalton protein that localises to the base of centrioles. Some studies have suggested a role for this protein in maintaining centriole-nucleated sensory organelles termed primary cilia, and AS is now considered to belong to the growing class of human genetic disorders linked to ciliary dysfunction (ciliopathies). However, mechanistic details are lacking, and recent studies have implicated ALMS1 in several processes including endosomal trafficking, actin organisation, maintenance of centrosome cohesion and transcription. In line with a more complex picture, multiple isoforms of the protein likely exist and non-centrosomal sites of localisation have been reported. This review outlines the evidence for both ciliary and extra-ciliary functions of ALMS1. PMID- 30421102 TI - Mexican rheumatology: where do we stand? AB - The aim of this review was to provide an overall overview of the past, present, and future situations and main challenges that are facing Mexican Rheumatology as a medical subspecialty in the context of their national healthcare system, where a deficit of workforce at the national level coexists with a shortage of specialists in the less-developed southern states of the country and a great surplus of professionals within large metropolitan areas. We also analyzed the prevalence and burden of Rheumatic and Musculoskeletal Diseases (RMDs), the structural composition and distribution of Mexican Rheumatology, and the clinical profile of the Mexican Rheumatologist. Last, we examined comorbidities, education and training programs and one scenario for Mexican Rheumatology wherein the principal main threats and opportunities are determined. PMID- 30421103 TI - Comparison of non-invasive assessment of arrhythmias, conduction disturbances and cardiac autonomic tone in systemic sclerosis and systemic lupus erythematosus. AB - Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are connective tissue diseases presenting cardiac complications including different arrhythmias, then direct electrocardiographic comparison may be useful in everyday clinical decision making. We examined 86 adult SSc patients, 76 with SLE and 45 healthy controls. Among other examinations all subjects underwent 24-h Holter monitoring with time-domain heart rate variability and heart rate turbulence evaluation. Patients with various co-existing conditions which might markedly influence arrhythmias and autonomic modulation were excluded from further analysis (SSc n = 12, SLE n = 6). Finally, 76 SSc and 70 SLE subjects were eligible for this study, mean age 51.9 +/- 13.1 and 46.5 +/- 12.7 years (p = 0.11), with median disease duration 6.0 and 8.5 years (p = 0.15), respectively. As compared to SLE, patients with SSc were characterised by more frequent incidence of various supraventricular and ventricular arrhythmias. As compared to SSc, patients with SLE presented prolonged corrected QT intervals and also significant correlations between corrected QT length and heart rate variability indices. Both SSc and SLE subjects presented impaired sympathetic cardiac autonomic modulation, while indices associated with parasympathetic activity in SLE were not diminished. Disease duration was not associated with arrhythmias' occurrence (except for ventricular tachycardia in SSc, p = 0.02) and also with autonomic function in both groups of patients. Patients with SSc and SLE differ in terms of arrhythmias, conduction disturbances and cardiac autonomic tone. Regular Holter monitoring should be considered as a part of routine evaluation in connective tissue diseases patients, especially in systemic sclerosis. PMID- 30421104 TI - Comparison of the effects of exercise and anti-TNF treatment on cardiovascular health in rheumatoid arthritis: results from two controlled trials. AB - People with rheumatoid arthritis (RA) are at increased risk for cardiovascular disease (CVD). Both pharmacological treatment and exercise are suggested in the management of CVD risk in RA. This study explored the effects of exercise and anti-TNF treatment on CVD risk in RA. Twenty RA patients (70% female, 50 (10) years) completed a 3-month exercise intervention and 23 RA patients (65% female, 54 (15) years) started anti-TNF treatment. Markers of disease activity, CVD risk, and vascular function were assessed before and after 3-months of intervention/treatment. Both exercise and anti-TNF treatment improved functional ability and fatigue, anti-TNF treatment was more successful in improving inflammation, disease activity, functional ability and pain. Exercise induced a reduction in overall CVD risk and improvement in vascular function, which was significantly different from anti-TNF treatment where no such changes were found. These findings showed that exercise and anti-TNF had differential effects on CVD risk in RA, and should be combined for optimal CVD risk reduction. Whereas anti TNF treatment is likely to impact on CVD risk through reducing the systemic inflammatory load, exercise should be recommended to people with RA as an effective self-management strategy to reduce CVD risk further. Once RA patients have responded successfully to anti-TNF treatment, increasing exercise should be encouraged to reduce the risk for CVD. Thus, supporting exercise programmes when the disease is controlled, is likely to enhance the uptake and the maintenance of exercise, which will result in additional benefits to cardiovascular health and wellbeing in people with RA. PMID- 30421105 TI - Efficacy and safety of biological therapy compared to synthetic immunomodulatory drugs or placebo in the treatment of Behcet's disease associated uveitis: a systematic review. AB - The aim of this study is to compare the efficacy and safety of biological therapy with cyclosporin A (CsA), azathioprine (AZA), or placebo in uveitis flares and other ocular outcomes in patients with Behcet disease. A comprehensive and sensitive search in MEDLINE, EMBASE, and the Cochrane Library was performed. We selected articles including: (1) adult patients with Behcet's and uveitis; (2) on biological therapies; (3) placebo or active control with CsA or AZA; (4) analyzing efficacy (number of uveitis flares, macular edema, etc.) and/or safety outcomes. Meta-analyses, systematic reviews, clinical trials, and observational studies with > 10 patients were included. The selection, data collection and quality assessment (Oxford scale) was carried out by 2 reviewers independently. Nine articles of moderate quality were included (6 randomized clinical trials and 3 retrospective studies) involving 378 patients. Most of them, apart from the study drugs received systemic corticosteroids and other immunosuppressant drugs. Infliximab was more effective than CsA in reducing short-term uveitis flares and severe complications of retinal vasculitis in the long term. Rituximab was similar to a combination of cytotoxic drugs in improving inflammatory activity. In patients with active uveitis adalimumab was associated with a lower risk of uveitic flare or visual impairment, and in patients with inactive uveitis to a significantly lowered the risk of flare upon corticosteroid withdrawal. Secukinumab and daclizumab were not superior to placebo in reducing uveitis flares, like interferonalpha compared to other drugs. Our results highlight the need for better designed comparative studies on Behcet's uveitis. PMID- 30421106 TI - Bile salt hydrolase activity is present in nonintestinal lactic acid bacteria at an intermediate level. AB - It is generally considered that bile salt hydrolase (BSH) activity is hardly detected in nonintestinal lactic acid bacteria (LAB). The aim of this study was to investigate the distribution and intensity of BSH activity in LAB isolated from naturally fermented vegetables and milk. A total of 624 lactic acid bacterial strains classified into 6 genera and 50 species were isolated from 144 naturally fermented vegetable samples and 103 naturally fermented milk samples, and their BSH activity was screened by gas chromatography with electron capture detection. The BSH-positive strains were further analyzed quantitatively for their deconjugation ability against six human-conjugated bile salts by HPLC based on the disappearance of the conjugated bile salts from the reaction mixture. The results showed that 39% of the strains possessed BSH activity distributed in 24 lactic acid bacterial species. The strains of the fermented vegetable origin showed a 0.5-fold higher incidence of BSH-positive strains than those of the fermented milk origin, and the lactic acid bacilli exhibited 2.5-fold higher incidence of BSH-positive strains than the lactic acid cocci in general. The strains of the fermented vegetable origin generally had greater bile salt deconjugation ability than those of the fermented milk origin. More than 97% and 93% of the BSH-positive strains exhibited a greater substrate preference for glycoconjugated bile salts than tauroconjugated bile salts and for dihydroxy bile salts than trihydroxy bile salts, respectively. This study demonstrated that BSH activity was also present in nonintestinal LAB. PMID- 30421107 TI - Current strategies and future prospects for enhancing microbial production of citric acid. AB - Aspergillus niger and Yarrowia lipolytica are highly important in citric acid (CA) production. To further minimize the cost of CA bio-production using A. niger and Y. lipolytica, some strategies (e.g., metabolic engineering, efficient mutagenesis, and optimal fermentation strategies) were developed to enhance CA production and low-cost carbon sources were also utilized to decrease CA bio production cost. In this review, we summarize the recent significant progresses in CA bio-production, including metabolic engineering, efficient mutagenesis and screening methods, optimal fermentation strategies, and use of low-cost carbon sources, and future prospects in this field are also discussed, which could help in the development of CA production industry. PMID- 30421108 TI - Chlorogenic acid attenuates virulence factors and pathogenicity of Pseudomonas aeruginosa by regulating quorum sensing. AB - Quorum sensing (QS) is a cell-to-cell communication that is used by bacteria to regulate collective behaviors. Quorum sensing controls virulence factor production in many bacterial species and it is regarded as an attractive target to combat bacterial pathogenicity, especially against antibiotic-resistant bacteria. Chlorogenic acid (CA), abundant in fruits, vegetables, and Chinese herbs, processes multiple activities. In this research, we explored its quorum sensing quenching activity. In Pseudomonas aeruginosa, CA significantly inhibited the formation of biofilm, the ability of swarming, and virulence factors including protease and elastase activities and rhamnolipid and pyocyanin production. CA showed similar inhibitory effects in Chromobacterium violaceum on its biofilm formation, swarming motility, chitinolytic activity and violacein production. We examined the expression of QS-related genes in P.aeruginosa and found these genes were all downregulated by CA treatment. Computational modeling revealed that CA can form hydrogen bonds with all three QS receptors. Caenorhabditis elegans and mouse infection models were employed to explore the anti-virulence ability of CA and its effect on pathogenesis process in vivo. CA extended the survival period and reduced the quantity of P. aeruginosa in nematode gut, showing a moderate protective effect on C. elegans. In mice wound model, CA-treated groups showed an accelerating healing rate and the bacteria number in wound area was also decreased by CA treatment. It is suggested by our research that CA has potential to be used as an anti-virulence factor in P. aeruginosa infection. PMID- 30421109 TI - Process for symbiotic culture of Saccharomyces cerevisiae and Chlorella vulgaris for in situ CO2 mitigation. AB - Industrial biotechnology relies heavily on fermentation processes that release considerable amounts of CO2. Apart from the fact that this CO2 represents a considerable part of the organic substrate, it has a negative impact on the environment. Microalgae cultures have been suggested as potential means of capturing the CO2 with further applications in high-value compounds production or directly for feed applications. We developed a sustainable process based on a mixed co-dominant culture of Saccharomyces cerevisiae and Chlorella vulgaris where the CO2 production and utilization controlled the microbial ecology of the culture. By mixing yeast and microalga in the same culture, the CO2 is produced in dissolved form and is available to the microalga avoiding degassing and dissolution phenomena. With this process, the CO2 production and utilization rates were balanced and a mutual symbiosis between the yeast and the microalga was set up in the culture. In this study, the reutilization of CO2 and growth of C. vulgaris was demonstrated. The two organism populations were balanced at approximately 20 * 106 cells ml-1 and almost all the CO2 produced by yeast was reutilized by microalga within 168 h of culture. The C. vulgaris inoculum preparation played a key role in establishing co-dominance of the two organisms. Other key factors in establishing symbiosis were the inoculum ratio of the two organisms and the growth medium design. A new method allowed the independent enumeration of each organism in a mixed culture. This study could provide a basis for the development of green processes of low environmental impact. PMID- 30421110 TI - In vitro antioxidant activities of Rhodobacter sphaeroides and protective effect on Caco-2 cell line model. AB - The present study aimed to evaluate the in vitro antioxidant activities and the protective effect of Rhodobacter sphaeroides on H2O2-induced oxidative stress in Caco-2 cells. The results showed that the antioxidant action of R. sphaeroides varied with different cell concentrations and treatments. Also, the intact cells and intracellular cell-free extracts showed better antioxidant activities. Caco-2 cell-based oxidative stress model was developed by optimizing H2O2 concentration and culture time with the half lethal dose and methyl thiazolyl tetrazolium. By increasing the activity of endogenous antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase, upregulating the antioxidant ability of the anti-superoxide anion and anti-hydroxyl radical, R. sphaeroides, especially the mutant strain R. sphaeroides (CGMCC No. 8513), exhibited significant protective activity against H2O2-induced oxidative stress in Caco-2 cells. Taken together, R. sphaeroides (CGMCC No. 8513) exhibits strong antioxidant activities and is a candidate to be investigated as a potential probiotic in the future. PMID- 30421111 TI - Efficient production of porcine circovirus virus-like particles using the nonconventional yeast Kluyveromyces marxianus. AB - Porcine circovirus type 2 (PCV2) is a ubiquitous virus with high pathogenicity closely associated with the postweaning multisystemic wasting syndrome (PMWS) and porcine circovirus diseases (PCVDs), which caused significant economic losses in the swine industry worldwide every year. The PCV2 virus-like particles (VLPs) are a powerful subunit vaccine that can elicit high immune response due to its native PCV2 virus morphology. The baculovirus expression system is the widely used platform for producing commercial PCV2 VLP vaccines, but its yield and cost limited the development of low-cost vaccines for veterinary applications. Here, we applied a nonconventional yeast Kluyveromyces marxianus to enhance the production of PCV2 VLPs. After codon optimization, the PCV2 Cap protein was expressed in K. marxianus and assemble spontaneously into VLPs. Using a chemically defined medium, we achieved approximately 1.91 g/L of PCV2 VLP antigen in a 5-L bioreactor after high cell density fermentation for 72 h. That yield greatly exceeded to recently reported PCV2 VLPs obtained by baculovirus-insect cell, Escherichia coli and Pichia pastoris. By the means of two-step chromatography, 652.8 mg of PCV2 VLP antigen was obtained from 1 L of the recombinant K. marxianus cell culture. The PCV2 VLPs induced high level of anti PCV2 IgG antibody in mice serums and decreased the virus titers in both livers and spleens of the challenged mice. These results illustrated that K. marxianus is a powerful yeast for cost-effective production of PCV2 VLP vaccines. PMID- 30421112 TI - In Vitro Anti-hepatitis B Virus Activity of 2',3'-Dideoxyguanosine. AB - 2',3'-dideoxyguanosine (DoG) has been demonstrated to inhibit duck hepatitis B virus (DHBV) replication in vivo in a duck model of HBV infection. In the current study, the in vitro antiviral effects of DoG on human and animal hepadnaviruses were investigated. Our results showed that DoG effectively inhibited HBV, DHBV, and woodchuck hepatitis virus (WHV) replication in hepatocyte-derived cells in a dose-dependent manner, with 50% effective concentrations (EC50) of 0.3 +/- 0.05, 6.82 +/- 0.25, and 23.0 +/- 1.5 MUmol/L, respectively. Similar to other hepadnaviral DNA polymerase inhibitors, DoG did not alter the levels of intracellular viral RNA but induced the accumulation of a less-than-full-length viral RNA species, which was recently demonstrated to be generated by RNase H cleavage of pgRNA. Furthermore, using a transient transfection assay, DoG showed similar antiviral activity against HBV wild-type, 3TC-resistant rtA181V, and adefovir-resistant rtN236T mutants. Our results suggest that DoG has potential as a nucleoside analogue drug with anti-HBV activity. PMID- 30421113 TI - Long-term follow-up after MIPO Philos plating for proximal humerus fractures. AB - INTRODUCTION: Minimally invasive plate osteosynthesis (MIPO) has been described as a suitable technique for the treatment of proximal humerus fractures, but long term functional results have never been reported. The aim of this study was to describe the long-term functional outcome and implant-related irritation after MIPO for proximal humerus fractures. METHODS: A long-term prospective cohort analysis was performed on all patients treated for a proximal humerus fracture using MIPO with a Philos plate (Synthes, Switzerland) between December 2007 and October 2010. The primary outcome was the QuickDASH score. Secondary outcome measures were the subjective shoulder value (SSV), implant related irritation and implant removal. RESULTS: Seventy-nine out of 97 patients (81%) with a mean age of 59 years were available for follow-up. The mean follow-up was 8.3 years (SD 0.8). The mean QuickDASH score was 5.6 (SD 14). The mean SSV was 92 (SD 11). Forty out of 79 patients (50.6%) had implant removal, and of those, 27/40 (67.5%) were due to implant-related irritation. On average, the implant was removed after 1.2 years (SD 0.5). In bivariate analysis, there was an association between the AO classification and the QuickDASH (p = 0.008). CONCLUSION: Treatment of proximal humerus fractures using MIPO with Philos through a deltoid split approach showed promising results. A good function can be assumed due to the excellent scores of patient oriented questionnaires. However, about one-third of the patients will have a second operation for implant removal due to implant related irritation. PMID- 30421114 TI - Divergence in Diversity and Composition of Root-Associated Fungi Between Greenhouse and Field Studies in a Semiarid Grassland. AB - Investigations of plant-soil feedbacks (PSF) and plant-microbe interactions often rely exclusively on greenhouse experiments, yet we have little understanding of how, and when, results can be extrapolated to explain phenomena in nature. A systematic comparison of microbial communities using the same host species across study environments can inform the generalizability of such experiments. We used Illumina MiSeq sequencing to characterize the root-associated fungi of two foundation grasses from a greenhouse PSF experiment, a field PSF experiment, field monoculture stands, and naturally occurring resident plants in the field. A core community consisting < 10% of total fungal OTU richness but > 50% of total sequence abundance occurred in plants from all study types, demonstrating the ability of field and greenhouse experiments to capture the dominant component of natural communities. Fungal communities were plant species-specific across the study types, with the core community showing stronger host specificity than peripheral taxa. Roots from the greenhouse and field PSF experiments had lower among sample variability in community composition and higher diversity than those from naturally occurring, or planted monoculture plants from the field. Core and total fungal composition differed substantially across study types, and dissimilarity between fungal communities did not predict plant-soil feedbacks measured in experiments. These results suggest that rhizobiome assembly mechanisms in nature differ from the dynamics of short-term, inoculation studies. Our results validate the efficacy of common PSF experiment designs to test soil inoculum effects, and highlight the challenges of scaling the underlying microbial mechanisms of plant responses from whole-community inoculation experiments to natural ecosystems. PMID- 30421116 TI - The effects of monthly air temperature and rainfall variations on the reproductive performance and lambing distribution of the Jezersko-Solcava sheep. AB - The aim of this study was to investigate the effects of monthly air temperature and rainfall variations on the reproductive performance and lambing distribution of the Jezersko-Solcava breed in northwestern Croatia during 7 years period from 2010 until 2016. At 11 medium-scale sheep farms, the sheep were kept on a pasture in a semi-intensive environment with access to the stables. The anomalies of rainfall observed on a monthly basis during monitoring were statistically significant. Non-parametric test showed that the percentages of lambing differ among the months during the year (P = 0.0001). By using regression analysis, it was found that the percentages of pregnant sheep were linearly associated with the sequential number of the month. The seasonal distribution of lambings were 53.85% of ewes delivered in winter (n = 1296), 21.13% in spring (n = 509), 8.91% in summer (n = 215) and 16.11% in autumn (n = 387). Sexual activity was lowest during spring and early summer (from March to May) with a peak from the end of July to October. The conception rate during year 2011 was significantly lower (89.74%), and the litter size was the lowest (1.05) than in other years of the observation. Average conception rate was 92.85% and average litter size 1.21. Despite being a seasonally polyoestrous, the distribution of matings and lambings of this breed of sheep was not uniform throughout the seasons. There were established a positive or negative correlations between the air temperature and rainfall precipitation variations with tested reproductive performances of Jezersko-Solcava breed sheep in the Northwestern part of Croatia. PMID- 30421117 TI - Laparoscopic Transcystic Common Bile Duct Exploration in the Emergency Is as Effective and Safe as in Elective Setting. AB - BACKGROUND: Emergent laparoscopic transcystic common bile duct exploration (LTCBDE) has been reported to be on the increase in some institutions, reflecting the growing confidence with the technique. However, no study has focused on the outcomes of LTCBDE in the non-elective setting. The aim of this study is to investigate whether LTCBDE can be performed effectively and safely in the emergency. METHODS: This is a retrospective study of 500 consecutive patients with choledocholithiasis subjected for LTCBDE at the Hospital Italiano de Buenos Aires from January 2009 to January 2018. Procedures were classified according to the setting as emergent or elective. Demographic data and perioperative parameters were compared between groups. RESULTS: Throughout the period comprised, 500 patients were admitted for choledocholithiasis and gallstones. A single-step treatment combining LTCBDE and laparoscopic cholecystectomy was attempted: 211 (42.2%) were performed electively and the 289 (57.8%) as an emergency. There was no significant difference in the success rate of LTCBDE (93.9% versus 93.8%, p = 0.975) for the two groups. The operative time was slightly longer in the emergency group (122 +/- 63 versus 106 +/- 53 min, p = 0.002). Postoperative recovery was slower in the emergency group, as reflected by a higher rate of prolonged postoperative stay (21.1% vs 5.7%, p < .001). The rates of postoperative complications were similar between groups (2.8% vs 5.9%, p = 0.109). CONCLUSION: Emergent LTCBDE can be performed with equivalent efficacy and morbidity when compared to an elective procedure. Patients undergoing emergent procedures have longer procedures and hospital stays. PMID- 30421118 TI - Laparoscopic Liver Resection: Experience of 436 Cases in One Center. AB - BACKGROUND: To report experience of laparoscopic liver resection (LLR) in one center. METHODS: We retrospectively reviewed 436 consecutive LLRs in 411 patients between December 2010 and December 2016. On the basis of the 2008 Louisville Statement, we divided the 436 cases into two groups: Simple Group (n = 203) and Difficult Group (n = 233). RESULTS: The indications were HCC (n = 194), colorectal cancer liver metastasis (n = 156), benign tumors (n = 62), hepatolithiasis (n = 2), and other malignant lesions (n = 22). The median tumor size was 24 mm (range 3 to 130). Procedures of LLR included wedge resection (n = 230), one segmentectomy (n = 8), two segmentectomies (n = 12), left lateral sectionectomy (n = 75), right hepatectomy (n = 52), left hepatectomy (n = 31), extended right hepatectomy (n = 2), extended left hepatectomy (n = 5), central bisectionectomy (n = 3), right posterior sectionectomy (n = 12), and right anterior sectionectomy (n = 6). The median operative time was 228 min (range 9 843) and median blood loss was 150 ml (range 2-3500). Twenty-five cases required blood transfusion (5.7%). Conversion to open surgery was required in six cases (1.4%). The mean length of stay was 6.4 +/- 2.9 days. Overall complication rate was 9.4% and major complication rate was 5%. One patient died of liver failure on the thirtieth postoperative day after a right hepatectomy. We had higher median blood loss (200 vs. 100 ml; p < 0.001), higher transfusion rate (8.2 vs. 2.9%; p = 0.020), longer median operative time (297 vs. 164 min; p < 0.001), higher conversion rate (2.6 vs. 0%; p = 0.021), higher complication rate (14.2 vs. 3.9%; p < 0.001), and longer mean postoperative hospital stay (6.8 +/- 2.9 vs. 5.9 +/- 3.0 days; p < 0.001) in the Difficult Group. CONCLUSIONS: Laparoscopic liver resection is safe for selected patients in the Difficult Group. On the basis of the 2008 Louisville Statement, selection criteria of LLR are helpful to predict the difficulty of the operation and the postoperative outcomes of LLR. PMID- 30421119 TI - Laparoscopic Liver Resection Difficulty Score-a Validation Study. AB - OBJECTIVE(S): The technical complexity of laparoscopic liver resection (LLR) poses unique challenges distinct from open surgery. An objective scoring system was developed that preoperatively quantifies the difficulty of LRR to help guide surgeon decision-making regarding the feasibility and safety of minimally invasive approaches. The aim of this multiinstitutional study was to externally validate this scoring system. METHODS: Patients who underwent LLR at two institutions were reviewed. LLR difficulty score (LDS) was calculated based on patient, tumor, and anatomic characteristics by two independent, blinded hepatobiliary surgeons. Surrogates of case complexity (e.g., conversion rate, operative time) were used for validation of this index. RESULTS: From 2006 to 2016, 444 LLR were scored as low (n = 94), intermediate (n = 98), and high difficulty (n = 152) with respective conversion rates of 5.3%, 15.7%, and 25%. Cases of higher LDS correlated with larger mean blood loss (203 ml vs. 331 ml vs. 635 ml). Mean operative and Pringle maneuver used were associated with increasing LDS (155 min vs. 202 min vs. 315 min and 14.4% vs. 29.7% vs. 45.1% respectively). These operative surrogates of difficulty correlated significantly with the LDS (all p < 0.0001). CONCLUSIONS: This comprehensive external validation of the LDS is robust and applicable in diverse patient populations. This LDS serves as a useful objective predictor of technical difficulty for LLR to help surgeons in selecting patients according to their individual operative experience and is valuable for preoperative risk estimation and stratification in randomized trials. PMID- 30421120 TI - Facility Variation in Local Staging of Rectal Adenocarcinoma and its Contribution to Underutilization of Neoadjuvant Therapy. AB - BACKGROUND: Guidelines recommend neoadjuvant therapy (NT) for clinical stage II III (locally advanced) rectal adenocarcinoma, but utilization remains suboptimal. The causes of NT omission remain poorly understood. METHODS: The main outcomes in this study of patients with resected clinically non-metastatic rectal adenocarcinoma in the 2010-2015 National Cancer Database were local staging utilization in patients with non-metastatic tumors (i.e., undocumented clinical stage/pathologic stage I-III) and NT utilization for locally advanced tumors. Multivariable regression was used to examine predictors of these outcomes. Facility-specific risk- and reliability-adjusted local staging and NT rates were calculated. Positive margins and overall survival (OS) were examined as secondary outcomes. RESULTS: Local staging was omitted in 7737/43,819 (17.7%) patients with clinically non-metastatic tumors and NT was omitted in 5199/31,632 (16.4%) patients with locally advanced tumors. NT was utilized in 24,826 (91.1%) locally advanced patients who had local staging vs. 1607 (36.6%) patients who did not; 2785 (53.6%) locally advanced patients with NT omitted also had local staging omitted. Treatment at facilities with lowest quintile local staging rates was associated with NT omission (relative risk 2.41, 95% confidence interval 2.11, 2.75). Adjusted facility local staging rates varied sixfold (16.1-98.0%), facility NT rates varied twofold (43.9-95.9%), and they were correlated (r = 0.58; P < 0.001). Local staging omission and NT omission were independently associated with positive margins and decreased OS. CONCLUSIONS: Local staging omission is a common care process in over half of cases of omitted NT. These data emphasize the need for quality improvement efforts directed at providing facilities feedback about their local staging rates. PMID- 30421121 TI - Facilitation and retardation of flavor preference conditioning following prior exposure to the flavor conditioned stimulus. AB - In two experiments, rats received pairings of an almond flavor (Experiments 1 and 2B) or a vanilla flavor (Experiment 2A) with sucrose. In each experiment, half of the rats received prior exposure to the flavor and half were exposed to water. Conditioned preference was then assessed through two-bottle, flavor versus water, choice tests. Latent inhibition (indicated by a weaker preference in pre-exposed subjects) was observed in the experiment using the vanilla flavor. However, facilitation (a stronger preference in pre-exposed subjects) instead of latent inhibition was evident with the almond flavor, both across acquisition trials and in the final choice test. These results indicate that, unlike most other paradigms of Pavlovian conditioning, conditioned stimulus pre-exposure in flavor preference learning may either facilitate or retard the acquisition (or the expression) of a conditioned flavor preference. We explore the proposal that the critical difference between the flavors lies in their hedonic values, with facilitation being more likely in a flavor that is initially disliked. PMID- 30421122 TI - Metacognition in dogs: Do dogs know they could be wrong? AB - In the current study, we investigated the question of whether dogs were sensitive to the information that they themselves had or had not acquired. For this purpose, we conducted three consecutive experiments in which dogs had to find a reward that was hidden behind one of two V-shaped fences with a gap at the point of the V. This setup allowed us to distinguish between selecting one of the fences by walking around it and seeking additional information by checking through the gap in the fence. We varied whether dogs had visual access to the baiting procedure or not. In addition, we manipulated the type and quality of reward as well as the time delay between baiting and choosing to analyze if the dogs' searching behavior was affected. Our results were partly consistent with the findings of Call (Animal Cognition, 13 (5), 689-700, 2010) with great apes, on whose findings we based our experiments. We found that dogs checked more often through the corner of the V-shaped fence when they had not seen where the reward was hidden. Interestingly, dogs rewarded with toys selected the correct fence more often than dogs rewarded with food. Even though dogs' performance was not affected by the food quality condition, dogs were significantly faster in fetching a high-quality food reward as opposed to a low-quality food reward. When testing whether forgetting and checking would increase as a function of delay, we found that although dogs slightly decreased in their success in finding the food when time delays were longer, they were not more likely to check before choosing. We show that - similar to apes - dogs seek additional information in uncertain situations, but their behavior in uncertain situations is less flexible compared to great apes. PMID- 30421123 TI - Associative structure of conditioned inhibition produced by inhibitory perceptual learning treatment. AB - Exposure to a set of complex stimuli yields an enhanced ability to discriminate between these stimuli. In previous experimental studies, two distinguishable stimuli, X and A, were each repeatedly paired with a common Stimulus B to create compound Stimuli XB and AB. Prior evidence suggests that unique Features X and A form mutually inhibitory associations. This was evidenced by pairing Feature A with a biologically relevant stimulus (i.e., an unconditioned stimulus [US]) and observing that Stimulus X alone later serves to inhibit anticipatory behaviors for that US. These observations may reflect the mutually inhibitory nature of the two Features X and A. However, by assessing the influence of X on behavior that anticipates the US rather than Feature A, these experiments tested inhibition only indirectly. In the present experiments, a more direct measure of inhibition is proposed and tested with rats. We found evidence of retardation and negative summation of associations between unique Features X and A in their capacity to serve as competing cues during overshadowing treatments. Stimulus X was less susceptible to overshadowing by A (which is indicative of retardation of the establishment of an X-A within-compound association) and was able to suppress overshadowing by A of another stimulus (Y) when X was presented with Y at test (which is indicative of negative summation of the representation of A by X). Thus, XB/AB trials were seen to establish an inhibitory relationship between X and A. PMID- 30421124 TI - To peck or not peck: Which do pigeons prefer? AB - Animals are expected to minimize time and effort to reinforcement. Thus, not pecking should be preferred over pecking. However, even if time is held constant, pigeons often peck when it is allowed but not required (e.g., fixed time schedules), but with such schedules pecking may be adventitiously reinforced. In the present experiment, to better compare a schedule of reinforcement that requires pecking with one that requires the absence of pecking, we compared a modified fixed-interval (FI) schedule in which reinforcement follows the first peck after the interval has elapsed and a differential-reinforcement-of-other behavior (DRO) schedule, which requires pigeons to abstain from pecking for a similar interval. The delay to reinforcement was matched on a trial-by-trial basis by yoking the duration of the FI to match the DRO schedule that preceded it. Of 12 pigeons, six preferred the DRO schedule over the FI schedule and six did not show a schedule preference. Those that were indifferent between the schedules apparently had a stronger spatial preference than their schedule preference. Individual differences in the preference of the pigeons may have been related to their behavior during the DRO schedule. PMID- 30421126 TI - The early detection of asthma based on blood gene expression. AB - Asthma is a complex heterogeneous disorder with hereditary tendency and the most widely used therapy is inhalation of anti-inflammatory corticosteroids. But it has systemic side effects. If the chronic inflammation can be detected in early stage, the dosage of corticosteroids will be low and the side effects can be avoided. Therefore, to discover the early stage blood biomarkers for asthma, we analyzed the gene expression profiles in the blood of 77 moderate asthma patients and 87 healthy controls. With advanced feature selection methods, minimal Redundancy Maximal Relevance and Incremental Feature Selection, we identified 31 genes, such as MYD88, ZFP36, CCR3 and CYP3A5, as the optimal asthma biomarker. The sensitivity, specificity and accuracy of the 31-gene Support Vector Machine predictor evaluated with Leave-One-Out Cross Validation were 0.870, 0.816 and 0.841, respectively. Through literature survey, many biomarker genes have asthma associated functions. Our results not only provided the easy-to-apply blood gene expression biomarkers for early detection of asthma, but also an explainable qualitative model with biological significance. PMID- 30421125 TI - Expression of the miR-190 family is increased under DDT exposure in vivo and in vitro. AB - A non-genotoxic insecticide dichlorodiphenyltrichloroethane (DDT), can affect mRNA and microRNA levels, however, its precise mechanism of action remains poorly understood. Using in silico methods we found that the rat miR-190 family is potentially regulated by CAR and ER receptors activated by DDT. We showed that exposure to DDT results in a dose- and organ-dependent increase in the expression of miR-190a, -190b in the liver, uterus, ovaries and mammary gland of female Wistar rats. Additionally, we demonstrate a decrease in protein product level of Tp53inp1, the target gene of these microRNAs, in the rat uterus. It is known that miR-190 is probably regulated by ER in humans, thus we measured the level of miR 190a, -190b in primary cultures of malignant and normal human endometrial cells treated with different doses of DDT. We detected an increase in miR-190b level in normal endometrial cells under DDT exposure. Thus, our results indicate that DDT exposure lead to change in the expression of oncogenic miR-190 family and its target gene Tp53inp1 which may be due to activation of CAR and ER. PMID- 30421127 TI - Development of drug-loaded protein nanoparticles displaying enzymatically conjugated DNA aptamers for cancer cell targeting. AB - Modification of protein-based drug carriers with tumor-targeting properties is an important area of research in the field of anticancer drug delivery. To this end, we developed nanoparticles comprised of elastin-like polypeptides (ELPs) with fused poly-aspartic acid chains (ELP-D) displaying DNA aptamers. DNA aptamers were enzymatically conjugated to the surface of the nanoparticles via genetic incorporation of Gene A* protein into the sequence of the ELP-D fusion protein. Gene A* protein, derived from bacteriophage phiX174, can form covalent complexes with single-stranded DNA via the latter's recognition sequence. Gene A* protein displaying nanoparticles exhibited the ability to deliver the anticancer drug paclitaxel (PTX), whilst retaining activity of the conjugated Gene A* protein. PTX-loaded protein nanoparticles displaying DNA aptamers known to bind to the MUC1 tumor marker resulted in increased cytotoxicity with MCF-7 breast cancer cells compared to PTX-loaded protein nanoparticles without the DNA aptamer modification. PMID- 30421128 TI - Superparamagnetic iron oxide nanoparticles as a tool to track mouse neural stem cells in vivo. AB - Cell transplantation offers a promising approach in many neurological disorders. Neural stem (NS) cells are potential candidates for cell therapy. The ability to track the grafted cells in the host tissue will refine this therapy. Superparamagnetic iron oxide nanoparticles (SPION) have been suggested as a feasible method, but there is no consensus about its safety. Here we investigated the feasibility of label NS cells with SPION and track by MRI after transplantation into mouse striatum with SPION cells and its therapeutic effects by grafting the cells into mouse striatum. We demonstrated that SPION-labeled NS cells display normal patterns of cellular processes including proliferation, migration, differentiation and neurosphere formation. Transmission electron microscopy reveals SPION in the cytoplasm of the cells, which was confirmed by microanalysis. Neurons and astrocytes generated from SPION-labeled NS cells were able to carry nanoparticles after 7 days under differentiation. SPION-labeled NS cells transplanted into striatum of mice were detected by magnetic resonance imaging (MRI) and microscopy 51 days later. In agreement with others reports, we demonstrated that NS cells are able to incorporate SPION in vitro without altering the stemness, and can survive and be tracked by MRI after they have been grafted into mice striatum. PMID- 30421129 TI - Expression of TLR4-PTGE2 signaling genes in atherosclerotic carotid plaques and peripheral blood. AB - Toll-like receptor 4 (TLR4)/prostaglandine synthetase 2 (PTGS2) signaling plays a relevant role in atherosclerotic plaque vulnerability. The purpose of this study was to check the gene expression of 6 genes participating to TLR4/PTGS2 signaling (TLR4, PTGS2, ACSL4, PTGER3, PTGER4, and EPRAP) in carotid plaques and blood samples from the same individual and to evaluate these genes as biomarker of plaque progression. We investigated differential gene expression by qRT-PCR in 62 atherosclerotic patients' carotid plaques and corresponding blood sample. A very weak or no correlation was observed in the overall population or analyzing asymptomatic patients. These analyzed genes are most likely not suitable for inclusion in the clinical routine as biomarkers of plaque instability. PMID- 30421130 TI - Correction to: Preparation, optimization and pharmacological evaluation of 99mTc 4-hydroxy-3-(2-hydroxy-3-methoxybenzylideneamino) benzoic acid complex: as a novel potential radiopharmaceutical agent with hepatobiliary excretion. AB - In the published original version, the complete list of authors was omitted. The complete list of contributing authors is updated with this Correction. PMID- 30421131 TI - Life-history consequences of bidirectional selection for male morph in a male dimorphic bulb mite. AB - Intralocus sexual conflict (IASC) arises when males and females have different trait optima. Some males pursue different alternative reproductive tactics (ARTs) with different trait optima, resulting in different strengths of IASC. Consequently, for instance daughter fitness is differentially affected by her sire's morph. We tested if-and which-other life-history traits correlatively change in bidirectional, artificial selection experiments for ARTs. We used the male-dimorphic bulb mite Rhizoglyphus robini, the males of which are high-fitness 'fighters' or low-fitness 'scramblers'. Twice in each of the five generations of selection, we assessed clutch composition (number of mites of the various life stages present) and size (total number of offspring). Furthermore, we tracked offspring from egg to adulthood in the first and final generation to detect differences between selection lines in the size and duration of stages, and in maturation time. We found that selection for male morph increased the frequency of that morph. Furthermore, compared to fighter lines, scrambler lines produced more females, which laid larger eggs (in the final generations), and maintained a higher egg-laying rate for longer. Otherwise, our results showed no consistent differences between the selection lines in clutch size and composition, life stage size or duration, or maturation time. Though we found few correlated life history trait changes in response to selection on male morph, the differences in egg laying rate and egg size suggest that IASC between fighters is costlier to females than IASC with scramblers. We hypothesize that these differences in reproductive traits allow fighter-offspring to perform better in small, declining populations but scrambler-offspring to perform better in large, growing populations. PMID- 30421132 TI - In vitro efficacy of Metarhizium anisopliae sensu lato against unfed Amblyomma parvum (Acari: Ixodidae). AB - Amblyomma parvum Aragao (Acari: Ixodidae) is a tick species found with wide distribution in the Neotropical region. Even though it is a wildlife-related tick, it is also a frequent parasite of domestic animals, is aggressive to human beings and may harbor pathogenic microorganisms. Therefore, it is a target species for control on domestic animals, particularly those at the rural-wildlife interface. Herein, the efficacy of two isolates (E9 and IBCB 425) of an entomopathogenic fungus, Metarhizium anisopliae sensu lato, already evaluated for ticks that parasitize domestic animals, was tested against unfed A. parvum adults. Both isolates displayed high acaricidal efficacy after immersion in fungal conidial suspensions for 5 min. Isolate E9 killed all ticks by the 7th day post-treatment, and isolate IBCB 425 did so by the 11th day. Tick mortality of 80 and 90% was achieved as early as the 3rd and 4th days, respectively, with both treatments. Thus, if a commercial M. anisopliae s.l. acaricide against domestic animal ticks is developed, it would also be effective against A. parvum. PMID- 30421133 TI - A prescription for drug-free rivers: uptake of pharmaceuticals by a widespread streamside willow. AB - Following human excretion and limited removal with wastewater treatment, pharmaceuticals are accumulating in rivers worldwide. These chemicals can challenge the health of fish and aquatic organisms and since rivers provide drinking water sources, there is concern for cumulative exposure to humans. In this study, we discovered that sandbar willow (Salix exigua), a predominant riparian shrub along streams throughout North America, has the capacity to quickly remove pharmaceuticals from aqueous solutions. Our study tracked [3H]- or [14C]-labeled substances including 17alpha-ethynylestradiol (EE2), a synthetic estrogen in oral contraceptives; the antihypertensive, diltiazem (DTZ); and the anti-anxiety drug, diazepam (DZP); and for comparison, atrazine (ATZ), a root absorbed herbicide. In growth chambers, willow saplings removed 40-80% of the substances from solutions in 24 h. Following uptake, the EE2 and DTZ were retained within the roots, while DZP and ATZ were partly passed on to the shoots. The absorbed EE2 was unextractable and apparently bound to the root tissue, while DTZ, DZP, and ATZ remained largely soluble (extractable). The uptake and translocation of the pharmaceuticals, reflected in the transpiration stream and root concentration factors, were reasonably predicted from their physicochemical properties, including octanol-water partitioning coefficients. These findings suggest the removal of pharmaceuticals as an unrecognized ecosystem service provided by riparian vegetation and especially the inundation tolerant sandbar willow. This encourages the conservation of riparian willows that line riverbanks, to remove pharmaceuticals and other contaminants. This phytoremediation also encourages the preservation of complex, braided channels and islands, which increase the extent of stream shorelines and riparian willows. PMID- 30421134 TI - [HPV-associated oropharyngeal cancer-incidence, trends, diagnosis, and treatment]. AB - A rising incidence of oropharyngeal squamous cell carcinoma (OPSCC) is reported by many countries worldwide and OPSCC associated with human papillomavirus (HPV) has been recently defined as a new class of head and neck cancers. Besides tobacco and alcohol consumption, HPV is an accepted risk and prognostic factor for OPSCC. Although the incidence increase of HPV-associated OPSCC is convincing, cancer registry studies and studies based on cohorts often have drawbacks regarding data linkage to comparable experimental data, comparable anatomical definitions or HPV diagnostics. Patients with HPV-associated OPSCC have remarkably better prognosis and the tumors differ from HPV-negative OPSCC with respect to molecular and genetic aspects. Nevertheless, choice of therapy is independent of HPV, and rather is subject to the individual patient's condition, local preference and anatomic characteristics. New concepts emerge in immune checkpoint oncology, which might be a valuable add-on to established concepts. Also, treatment de-escalation (e.g., by reduction of radiation dosage) might be suitable for patients with certain risk profiles. Prophylactic vaccination can contribute to reducing HPV-induced disease, likewise OPSCC. Prerequisite is a high rate of vaccination, which is currently not sufficient in Germany. Because of currently low vaccination rates and the rather long time between initial infection and HPV-induced carcinogenesis, reduction of incidence increase or prevalence of HPV-associated OPSCC is not expected in the near future. PMID- 30421135 TI - Microbiome and its relation to gestational diabetes. AB - PURPOSE: Gestational diabetes mellitus (GDM), the major endocrine pathology in pregnancy, has been associated with the development of an intense inflammatory process and increased insulin resistance. The maternal microbiota is involved in several metabolic functions; however, its role in GDM physiopathology remains unclear. The aim of this study was to assess the composition of the microbiota at different sites and evaluate its relationship with the occurrence of GDM. METHODS: This cross-sectional study recruited women in the third trimester of gestation with and without GDM. Oral, vaginal, and stool samples were evaluated using next-generation sequencing. We included 68 participants: 26 with and 42 without GDM. RESULTS: The analysis of the oral microbiome did not show significant differences in phyla and genus among the studied groups. In contrast, GDM patients presented a specific vaginal and intestinal microbiome composition, which was less diverse than those found in the control group, showing genera related to dysbiosis. CONCLUSIONS: Our findings suggest that changes in the composition of the vaginal and intestinal microbiome might be involved in the development of GDM. The follow-up of these patients in order to evaluate vaginal and intestinal samples after delivery may contribute to understanding the development of metabolic disease in women with previous GDM. PMID- 30421136 TI - Letter to the Editor: SNAS and thyroid autoimmunity risk. PMID- 30421138 TI - Association between maternal diabetes, being large for gestational age and breast feeding on being overweight or obese in childhood. AB - AIMS/HYPOTHESIS: This study aimed to examine the association of maternal diabetes, being large for gestational age (LGA) and breast-feeding with being overweight or obese in pre-school-aged children. METHODS: Data on height and weight at the time of their pre-school (age 4-6 years) immunisation visit between January 2009 and August 2017, as well as breast-feeding status in the first 5 months of life, for 81,226 children born between January 2005 and August 2013 were linked with maternal hospitalisation and outpatient records and birth registry data. Children were grouped into six categories based on maternal diabetes status during pregnancy (no diabetes, gestational diabetes or pre existing diabetes) and birthweight (appropriate for gestational age [AGA] or LGA). WHO criteria were used to identify children who were overweight or obese. RESULTS: There were 69,506 children in the no diabetes/AGA group (control), 5926 in the no diabetes/LGA group, 4563 in the gestational diabetes/AGA group, 573 in the gestational diabetes/LGA group, 480 in the pre-existing diabetes/AGA group and 178 in the pre-existing diabetes/LGA group. The rate of being overweight/obese at pre-school age ranged from 20.5% in the control group to 42.9% in the gestational diabetes/LGA group. The adjusted attributable risk per cent for LGA alone (39.4%) was significantly higher than that for maternal gestational diabetes (16.0%) or pre-existing diabetes alone (15.1%); the risk for the combinations of gestational diabetes/LGA and pre-existing diabetes/LGA were 50.1% and 39.1%, respectively. Further stratification of the pre-existing diabetes groups found the prevalence of being overweight/obese was 21.2% in the type 1/AGA group, 31.4% in the type 1/LGA group (similar to those in the no diabetes groups), 26.7% in the type 2/AGA group and 42.5% in the type 2/LGA group. Breast-feeding was associated with a lower likelihood of being overweight/obese in childhood in all groups except gestational diabetes/LGA and pre-existing diabetes/LGA (both type 1 and type 2). CONCLUSION/INTERPRETATION: LGA is a stronger marker for risk of being overweight/obese in early childhood, compared with maternal diabetes during pregnancy. Rates of being overweight/obese in childhood were highest in LGA children born to mothers with gestational diabetes or pre-existing type 2 diabetes. Breast-feeding was associated with a lower risk of being overweight/obese in childhood in the majority of children; however, this association was not maintained in LGA children of mothers with diabetes. PMID- 30421137 TI - Quality of life assessment in patients with HNF1A-MODY and GCK-MODY. AB - AIM: The impact of maturity onset diabetes of the young (MODY) on quality of life (QoL) has never been examined. We assessed disease impact on QoL among patients with HNF1A-MODY and GCK mutation carrier status. METHODS: The study included 80 patients with HNF1A-MODY and 89 GCK gene mutation carriers. We also examined 128 type 1 diabetes (T1DM) patients for comparison. Diabetes-specific QoL was assessed using the Audit of Diabetes Dependent Quality of Life questionnaire. RESULTS: HNF1A-MODY and GCK-MODY groups had similar mean age (41.7 vs. 38.0 years, respectively) and BMI (24.1 vs. 24.3 kg/m2), whereas T1DM patients were on average younger (34.2 years) with similar BMI (25.0 kg/m2). Less than a third of GCK mutation carriers were on pharmacotherapy (n = 20, 31%), while the majority of HNF1A mutation carriers used oral drugs or insulin (n = 66, 82.5%). While current QoL was similar across the three groups (p = 0.66), two other major indices-the impact of diabetes on QoL and the average weighted impact (AWI) differed among them (p < 0.001 for both comparisons). The impact of diabetes on patient QoL and AWI observed in both MODY groups was smaller than in T1DM. Etiological diagnosis of diabetes and a diagnosis of retinopathy were the only independent factors influencing the impact of diabetes on QoL and AWI in regression analysis. In HNF1A-MODY, all three major indices of QoL were more heavily influenced for patients on insulin in comparison to other treatment sub groups. CONCLUSION: MODY has a smaller negative impact on QoL compared to T1DM. Mode of treatment further stratifies QoL decline for HNF1A-MODY subjects. PMID- 30421139 TI - [EOLIA trial : Does ECMO confer a survival advantage in ARDS?] PMID- 30421141 TI - Changes in bone mineral density (BMD): a longitudinal study of osteoporosis patients in the real-world setting. AB - : In clinical practice, the frequency of patients achieving improved T-scores and the expected change in bone mineral density (BMD) according to osteoporosis drugs is unknown. We found that osteoporosis medications infrequently achieve improved femoral neck T-scores over 1.2 years. BMD increases were more often seen with IV bisphosphonates and denosumab. PURPOSE: To determine the frequency of osteoporosis patients achieving improvement in T-scores and quantify the change in bone mineral density (BMD) over time according to osteoporosis medication use. METHODS: The study included all patients receiving clinical care at United Osteoporosis Centers, Gainesville, GA, 1995-2015, who had at least two measures of femoral neck BMD (N = 1232). We evaluated successive pairs of BMD tests to describe the distribution of transitions between T-score categories. Generalized estimating equations were used to estimate %BMD change between successive pairs of BMD tests according to osteoporosis medication, adjusted for age, sex, height, weight, baseline BMD, previous fracture, and follow-up time. RESULTS: Mean (+/ SD) age was 68 (+/-10) years, and 90% of patients were women. Mean baseline T score was - 2.04 (+/- 0.85). In total, 1232 patients had 4918 pairs of successive BMD tests, with a mean 1.2 years (+/- 0.9) between assessments. Frequency of transition to an improved T-score category was 41% when prior T-score <= - 3.5, and 15% when prior T-score - 1.99 to - 1.50. Most individuals (69%) remained in the same T-score category. BMD increased 0.54% (95% CI 0.23-0.85%) with IV bisphosphonates and 1.23% (95% CI 0.56-1.90%) with denosumab, whereas no significant change was seen with oral bisphosphonates, teriparatide, or raloxifene. CONCLUSIONS: Osteoporosis patients are unlikely to improve femoral neck T-scores over 1.2 years. Additional studies are needed to determine the optimal time to repeat BMD testing while receiving osteoporosis treatment and to determine whether fracture risk is reduced in patients who achieve target T scores. PMID- 30421140 TI - Potentially toxic elements in urban soils: source apportionment and contamination assessment. AB - Soils play a vital role in the quality of the urban environment and the health of its residents. City soils and street dusts accumulate various contaminants and particularly potentially toxic elements (PTEs) from a variety of human activities. This study investigates the current condition of elemental concentration in the urban soils of Hamedan, the largest and the fastest-growing city in western Iran. Thirty-four composite soil samples were collected from 0 to 10 cm topsoil of various land uses in Hamedan city and were analyzed for total concentration of 63 elements by ICP-MS. The possible sources of elemental loadings were verified using multivariate statistical methods (principal component analysis and cluster analysis) and geochemical indices. The spatial variability of the main PTEs was mapped using geographic information system (GIS) technique. The results revealed a concentration for As, Co, Cr, Mn, Mo, Ni, and V in the soil samples comparable to the background values as well as a range of associations among these elements in a single component suggesting geogenic sources related to geological and pedogenic processes, while the soils mostly presented a moderate to considerable enrichment/contamination of Cd, Zn, Pb, and Sb and moderate enrichment/contamination of Cu, Zn, and Mo. It was found that anthropogenic factors, vehicular traffic in particular, control the concentration of a spectrum of elements that are typical of human activities, i.e., Cd, Cu, Hg, Pb, Sb, and Zn. Lead and Sb were both the most enriched elements in soils with no correlation with land use highlighting general urban emissions over time and the impact of transport networks directly on soil quality. The highest concentrations of As were recorded in the southern part of the city reflecting the influence of metamorphic rocks. The effect of the geological substrate on the Co and Ni contents was confirmed by their maximum concentrations in the city's marginal areas. However, high spatial variability of urban elements' contents displayed the contribution of various human activities. In particular, the increased concentration of Cd, Sb, and Pb was found to be consistent with the areas where vehicular traffic is heaviest. PMID- 30421142 TI - Prognostic Value of Patient Knowledge of Cancer on Quality of Life in Advanced Lung Cancer During Chemotherapy. AB - The purpose of the study was to assess the impact of cancer knowledge and patient's lifestyle on QOL and the relationship between QOL and various environmental factors in patients with non-small-cell lung cancer treated with chemotherapy. The study group consisted of 129 patients with metastatic lung cancer patients treated between May 2010 and December 2015 in two centres. The knowledge of cancer and their lifestyle was rated by method of diagnostic survey, using the Behavioral Health Inventory IZZ by Prof. Juczynski. We sought factors affecting to response to treatment, overall survival and quality of life. The general level of knowledge of cancer and the level of health behaviours was low. Ninety percent of lung cancer patients were smokers. The average age of the study group was 64 years. Eighty-nine patients received chemotherapy with cisplatin, 28 schemes containing carboplatin, 6 inhibitors of EGFR tyrosine kinase, and 6 vinorelbine or gemcitabine monotherapy. Complete regression was observed in 2 patients, partial response in 33 patients (26%), stable disease in 51 (40%) and 54 (42%) patients had progression. In multivariate analysis, significant effects on survival were performance status, schemes of treatment and response to treatment. Quality of life before and after treatment did not differ from each other. We found impact on quality of life: performance status, response to treatment and knowledge of cancer and lifestyle. The level of knowledge of oncological patients and their lifestyle observed in clinical practice are associated with QOL. PMID- 30421144 TI - In Vitro Antimicrobial Activities of Commercially Available Tea Tree (Melaleuca alternifolia) Essential Oils. AB - Melaleuca alternifolia tea tree oil (TTO) is largely used in cutaneous infections. Clinical observations reported antibacterial, antifungal, and antiviral activities, whereas in vitro experiments ascribed most of biological properties to terpinen-4-ol. Since different plant chemotypes and storage conditions result in variations of chemical composition of commercially available TTO, in this study we investigated the antimicrobial activity and the chemical profile of ten commercially available TTO products. The antimicrobial activity was assessed against Candida glabrata, Herpes simplex virus type 1 (HSV-1), methicillin-resistant Staphylococcus aureus (MRSA), and Pseudomonas aeruginosa grown in planktonic mode or biofilms. Only five out of ten TTO batches reported significant antimicrobial activity. The identified TTO products reduced bacterial survival in biofilms, generated oxidative damage in C. glabrata, and diminished HSV-1 infectivity. GC-MS analysis revealed that all the analyzed TTO batches fitted into the terpinen-4-ol chemotype even if we reported great variability in composition of nine major ISO-specified TTO components. Overall, we were not able to ascribe the antimicrobial activity to the content in terpinen-4-ol. We therefore conclude that the antimicrobial activity of TTO results from complex interaction among different components. PMID- 30421143 TI - Transcriptome-Based Identification of a Strong Promoter for Hyper-production of Natamycin in Streptomyces. AB - Streptomyces are famed producers of secondary metabolites with diverse bioactivities and structures. However, biosynthesis of natural products will consume vast precursors from primary metabolism, and some secondary metabolites are toxic to the hosts. To overcome this circumstance and over-produce secondary metabolites, one of the strategies is to over-express biosynthetic genes under strong promoters specifically expressed during secondary metabolism. For this purpose, here based on Microarray and eGFP reporter assays, we obtained a promoter thlM4p, whose activity was undetectable in the first 2 days of fermentation, but sevenfold higher than the strong promoter ermE*p in the following days. Moreover, when the positive regulator gene scnRII was driven from thlM4p, natamycin yield increased 30% compared to ermE*p. Therefore, we provide a new way to identify promoters, which is silenced during primary metabolism while strongly expressed under secondary metabolism of Streptomyces. PMID- 30421145 TI - Comparative transcriptome analysis highlights the hormone effects on somatic embryogenesis in Catalpa bungei. AB - KEY MESSAGE: The major pathways and key events related to somatic embryo development in Catalpa bungei were illustrated by deep analysis of DEGs and quantification of hormone contents. Catalpa bungei C.A. Meyer is a valuable timber species, known as "The king of wood" in China. Due to the low propagation rate, somatic embryogenesis-based rapid propagation can regenerate a large number of new plants in a very short period of time and thus has great commercial value for this timber species. However, the mechanisms of somatic embryogenesis in C. bungei remain largely unclear so far. In our previous study, we established the vegetative propagation system in C. bungei using immature zygotic embryo as explants. Here, we further compared the transcriptional profiles and hormones contents between the embryogenic callus (EC) and non-embryogenic callus (NEC). RNA-seq analysis showed a total assembly of 73038 unigenes, and identified 12310 differentially expressed genes (DEGs) between EC and NEC. Also, six DEGs were chosen to verify the authenticity of the transcriptome sequencing results by qRT PCR. Moreover, by using LC-MS approaches, we quantified various plant hormone contents and found that auxin and ABA were dramatically higher in EC than those in NEC. Accordingly, DEGs were enriched in plant hormone signaling pathways. Taken together, we highlight the hormone effects on somatic embryogenesis in a tree species, C. bungei. The use of certain genes as markers of embryogenesis induction in C. bungei regeneration process will provide new tools to pre-screen genotypes or tissue culture hormone combinations suitable for somatic embryo production. Our results provide theoretical references for the somatic embryogenesis mechanism and experimental bases for breeding and rapid propagation of C. bungei. PMID- 30421146 TI - Association between known or strongly suspected malignant hyperthermia susceptibility and postoperative outcomes: an observational population-based study. AB - PURPOSE: Whether current standards of care management for malignant hyperthermia (MH)-susceptible patients result in acceptable postoperative clinical outcomes at a population level is not known. Our objective was to determine if patients with susceptibility to MH experienced similar outcomes as patients without MH susceptibility after surgery under general anesthesia. METHODS: This was a retrospective, population-based cohort study from 1 April 2009 until 31 March 2016 in the Canadian province of Ontario. Participants were adults who underwent common in- or outpatient surgeries under general anesthesia. The exposure studied was either known or strongly suspected MH susceptibility as determined by usage of a specific physician billing code. The primary outcome was a composite of all cause death, hospital readmission, or major postoperative complications, all within 30 postoperative days. Separate analyses were employed, based on whether a patient had in- or outpatient surgery. Inverse probability of exposure weighting based on the propensity score was used to estimate adjusted exposure effects. RESULTS: The cohort included 957,876 patients (583,254 in- and 374,622 outpatients). There were 2,900 (0.3%) patients with a known or strong suspicion of MH susceptibility. For inpatients, the primary outcome occurred in 146,192 (25.1%) of the non-MH-susceptible group and in 337 (20.1%) of the MH-susceptible group (unadjusted risk difference [RD], -5.0%; 95% confidence interval [CI], -6.9 to -3.1%; P < 0.001). In outpatients, the primary outcome occurred in 9,146 (2.4%) of the non-MH-susceptible group and in 32 (2.6%) of the MH-susceptible group (RD, 0.2%; 95% CI, -0.7 to 1.1%; P = 0.72). After adjustment, MH susceptibility was not associated with the primary outcome in either the inpatients (adjusted risk difference [aRD], 1.2%; 95% CI, -1.3 to 3.6%; P = 0.35) or outpatients (aRD, -0.1%; 95% CI -1.0 to 0.9%; P = 0.90). CONCLUSIONS: Among adults in Ontario who underwent common surgeries under general anesthesia from 2009 to 2016, known or strongly suspected MH was not associated with a higher risk of adverse postoperative outcomes. These findings support the current standard of care management for MH-susceptible patients. PMID- 30421147 TI - [Vitrectomy for endophthalmitis : Incubation time and prognosis following intravitreal injection vs. cataract surgery]. AB - BACKGROUND: Bacterial endophthalmitis is a rare but devastating complication following intraocular surgery. Guidelines on the diagnostics and treatment are based mainly on experience of endophthalmitis treatment following cataract surgery. OBJECTIVE: In this study we analyzed infectious endophthalmitis cases following either intravitreal operative drug injection (IVOM) or cataract surgery for possible differences in the clinical course and prognosis. MATERIAL AND METHODS: All cases of endophthalmitis from January 2013 through December 2017 retrieved from our electronic database were examined and analyzed according to the type of intervention, time elapsed until diagnosis, pathogen detection, postinterventional visual acuity and the presence of comorbidities. RESULTS: A total of 29 cases were included, 11 secondary to IVOM and 18 secondary to cataract surgery. Symptoms for all cases presented at a mean of 6.8 days, with a significant difference between patients following IVOM (5.5 days) and patients following cataract surgery (4.1 days, p < 0.05). Patients with endophthalmitis following cataract surgery had a significantly better visual outcome 1 year after treatment compared to patients with endophthalmitis following IVOM (p < 0.05). The most commonly isolated pathogen was Staphylococcus epidermidis. CONCLUSION: Knowledge of the typical clinical course in the development of endophthalmitis following IVOM or cataract surgery is a critical prerequisite for the timely diagnosis and initiation of adequate treatment measures. Our results point towards a significantly delayed clinical manifestation of endophthalmitis following IVOM, possibly also caused by the anatomical origin of the infection. In an era of increasing numbers of IVOM this clinical observation could be helpful for a careful follow-up control beyond the previous traditional timepoints. PMID- 30421148 TI - Vestibular Evoked Myographic Correlation. AB - This work started from the hypothesis that the physiological processes giving rise to the vestibular evoked myogenic potential (VEMP) can be induced not only by transient sounds but also by a continuous stimulation with a stochastic signal. The hypothesis is based on the idea that the number of motor unit action potentials (MUAPs) decreases after a momentary amplitude increase of the effective stimulus, whereas a momentary amplitude decrease has the opposite effect. This concept was theoretically analyzed by assuming that the effective stimulus is closely related to the envelope of the stimulus actually presented. The analysis led to the prediction that the cross-correlation function of the effective stimulus and the measured electromyogram (EMG) has VEMP-like properties. Experiments confirmed this prediction, thus providing evidence of a novel electrophysiological response: the vestibular evoked myographic correlation (VEMCorr). The methodological approach corresponded to a conventional VEMP study, except that the stimulus (delivered with a hand-held minishaker) comprised not only a series of 500-Hz tone pulses (classical VEMP measurement, for comparison) but also sequences of narrow-band noise with a center frequency of 500 Hz (VEMCorr measurement). Each of the 12 test persons showed a clear VEMCorr. Moreover, VEMP and VEMCorr largely resembled each other, as predicted. Apparently they are two different expressions of a more general mechanism that leads to a roughly linear relationship between stimulus envelope and expectation of the EMG. Future applications of the VEMCorr could exploit that a continuous-stimulation paradigm allows for varying the center frequency of the stimulus without changing the relative bandwidth. PMID- 30421149 TI - Evaluation of the methoxy-X04 derivative BSC4090 for diagnosis of prodromal and early Alzheimer's disease from bioptic olfactory mucosa. AB - Alzheimer's disease (AD) pathology precedes the onset of clinical symptoms by several decades. Thus, biomarkers are required to identify prodromal disease stages to allow for the early and effective treatment. The methoxy-X04-derivative BSC4090 is a fluorescent ligand which was designed to target neurofibrillary tangles in AD. BSC4090 staining was previously detected in post-mortem brains and olfactory mucosa derived from AD patients. We tested BSC4090 as a potential diagnostic marker of prodromal and early AD using olfactory mucosa biopsies from 12 individuals with AD, 13 with mild cognitive impairment (MCI), and 10 cognitively normal (CN) controls. Receiver-operating curve analysis revealed areas under the curve of 0.78 for AD versus CN and of 0.86 for MCI due to AD versus MCI of other causes. BSC4090 labeling correlated significantly with cerebrospinal fluid levels of tau protein phosphorylated at T181. Using NMR spectroscopy, we find that BSC4090 binds to fibrillar and pre-fibrillar but not to monomeric tau. Thus, BSC4090 may be an interesting candidate to detect AD at the early disease stages. PMID- 30421150 TI - Cerebral blood flow responses during prosaccade and antisaccade preparation in major depression. AB - While impairments in executive functions have been well established in major depressive disorder (MDD), specific deficits in proactive control have scarcely been studied so far. Proactive control refers to cognitive processes during anticipation of a behaviorally relevant event that facilitate readiness to react. In this study, cerebral blood flow responses were investigated in MDD patients during a precued antisaccade task requiring preparatory attention and proactive inhibition. Using functional transcranial Doppler sonography, blood flow velocities in the middle cerebral arteries of both hemispheres were recorded in 40 MDD patients and 40 healthy controls. In the task, a target appeared left or right of the fixation point 5 s after a cuing stimulus; subjects had to move their gaze to the target (prosaccade) or its mirror image position (antisaccade). Video-based eye-tracking was applied for ocular recording. A right dominant blood flow increase arose during prosaccade and antisaccade preparation, which was smaller in MDD patients than controls. Patients exhibited a higher error rate than controls for antisaccades but not prosaccades. The smaller blood flow response may reflect blunted anticipatory activation of the dorsolateral prefrontal and inferior parietal cortices in MDD. The patients' increased antisaccade error rate suggests deficient inhibitory control. The findings support the notion of impairments in proactive control in MDD, which are clinically relevant as they may contribute to the deficits in cognition and behavioral regulation that characterize the disorder. PMID- 30421151 TI - Artifactual increase in bispectral index caused by connector contaminated with povidone-iodine. PMID- 30421152 TI - Head-to-head comparison of two continuous glucose monitoring systems on a cardio surgical ICU. AB - In critical illness hypo-and hyperglycemia have a negative influence on patient outcome. Continuous glucose monitoring (CGM) could help in early detection of hypo-and hyperglycemia. A requirement for these new methods is an acceptable accuracy and precision in clinical practice. In this pilot study we prospectively evaluated the accuracy and precision of two CGM sensors (subcutaneous sensor: Sentrino(r), Medtronic and intravasal sensor: Glucoclear(r), Edwards) in 20 patients on a cardio-surgical ICU in a head to head comparison. CGM data were recorded for up to 48 h and values were compared with blood-gas-analysis (BGA) values, analysed with Bland-Altman-plots and color-coded surveillance error grids. Shown are means +/- standard deviations. In total 270/255 intravasal/subcutaneous pairs with BGA-values were analysed. The average runtime of the sensors was 28.4 +/- 6.4 h. Correlation with BGA values yielded a correlation coefficient of 0.76 (subcutaneous sensor) and 0.92 (intravasal sensor). The Bland Altman Plots revealed an accuracy of 2.5 mg/dl, and a precision of + 43.0 mg/dl to - 38.0 mg/dl (subcutaneous sensor) and an accuracy of - 6.0 mg/dl, and a precision of + 12.4 mg/dl to - 24.4 mg/dl (intravasal sensor). No severe hypoglycemic event, defined as BG level below 40 mg/dl, occurred during treatment. Both sensors showed good accuracy in comparison to the BGA values, however they differ regarding precision, which in case of the subcutaneous sensor is considerable high. PMID- 30421153 TI - Common mycorrhizal networks influence the distribution of mineral nutrients between an invasive plant, Solidago canadensis, and a native plant, Kummerowa striata. AB - Invasive species often reduce ecosystem services and lead to a serious threat to native biodiversity. Roots of invasive plants are often linked to roots of native plants by common mycorrhizal networks (CMNs) of arbuscular mycorrhizal (AM) fungi, but whether and how CMNs mediate interactions between invasive and native plant species remains largely uninvestigated. We conducted two microcosm experiments, one in which we amended the soil with mineral N and another in which we amended the soil with mineral P. In each experiment, we grew a pair of test plants consisting of Kummerowia striata (native to our research site) and Solidago canadensis (an invasive species). CMNs were established between the plants, and these were either left intact or severed. Intact CMNs increased growth and nutrient acquisition by S. canadensis while they decreased nutrient acquisition by K. striata in comparison with severed CMNs. 15N and P analyses indicated that compared to severed CMNs, intact CMNs preferentially transferred mineral nutrients to S. canadensis. CMNs produced by different species of AM fungi had slightly different effects on the interaction between these two plant species. These results highlight the role of CMNs in the understanding of interactions between the invasive species S. canadensis and its native neighbor. PMID- 30421154 TI - Correspondence between bone mineral density and intervertebral disc degeneration across age and sex. AB - : The distribution of bone tissue within the vertebra can modulate vertebral strength independently of average density and may change with age and disc degeneration. Our results show that the age-associated decrease in bone density is spatially non-uniform and associated with disc health, suggesting a mechanistic interplay between disc and vertebra. PURPOSE: While the decline of bone mineral density (BMD) in the aging spine is well established, the extent to which age influences BMD distribution within the vertebra is less clear. Measures of regional BMD (rBMD) may improve predictions of vertebral strength and suggest how vertebrae might adapt with intervertebral disc degeneration. Thus, we aimed to assess how rBMD values were associated with age, sex, and disc height loss (DHL). METHODS: We measured rBMD in the L3 vertebra of 377 participants from the Framingham Heart Study (41-83 years, 181 M/196 F). Integral (Int.BMD) and trabecular BMD (Tb.BMD) were measured from QCT images. rBMD ratios (anterior/posterior, superior/mid-transverse, inferior/mid-transverse, and central/outer) were calculated from the centrum. A radiologist assigned a DHL severity score to adjacent intervertebral discs (L2-L3 and L3-L4). RESULTS: Int.BMD and Tb.BMD were both associated with age, though the decrease across age was greater in women (Int.BMD, - 2.6 mg/cm3 per year; Tb.BMD, - 2.6 mg/cm3 per year) than men (Int.BMD, - 0.5 mg/cm3 per year; Tb.BMD, - 1.2 mg/cm3 per year). The central/outer (- 0.027/decade) and superior/mid-transverse (- 0.018/decade) rBMD ratios were negatively associated with age, with similar trends in men and women. Higher Int.BMD or Tb.BMD was associated with increased odds of DHL after adjusting for age and sex. Low central/outer ratio and high anterior/poster and superior/mid-transverse ratios were also associated with increased odds of DHL. CONCLUSIONS: Our results indicate that the distribution of bone within the L3 vertebra is different across age, but not between sexes, and is associated with disc degeneration. PMID- 30421155 TI - A decade in female reproduction: an endocrine view of the past and into the future. AB - Over the last decade, huge achievements have been made in the fields of neurophysiology, molecular endocrinology, and biochemistry, as well as in the successful translation of clinical research into diseases into clinical practice. As regards female reproduction, most of the advances made in this area were achieved in gonadal axis regulation, regulation of behavior through sex steroids, reproductive genetics, preservation of ovarian reproductive function, steroid profiling, and metabolic and overall reproductive outcomes. The coming years are expected to bring further understanding of the relationships between nutrition, energy metabolism, and reproductive function and to succeed in identifying new genetic markers linked to adverse metabolic and unfavorable cardiovascular outcomes in women. From our perspective, future research in the field of female reproduction should be directed toward doing research into genetic reproductive abnormalities and neuroendocrine diseases, pathophysiology, long-term health outcomes for oligo/amenorrhea, hyperandrogenism, and ovulatory dysfunction. It is additionally expected that a better understanding will be gained of the endocrinology of the placenta and of pregnancy, the role of the microbiome in female reproduction, the role of insulin sensitizers, anti-obesity and anti diabetic drugs, and various advances in the prevention of ovarian damage caused by various oncology therapies, while new therapeutic options for the treatment of infertility, including kisspeptin, will be developed. PMID- 30421156 TI - Serum glucose, triglycerides, and cholesterol in relation to prostate cancer death in the Swedish AMORIS study. AB - PURPOSE: Lifestyle-related conditions such as obesity are associated with prostate cancer progression, but the associations with hyperglycemia and dyslipidemia are unclear. This study, therefore, aims to examine the association of glucose, triglycerides, and total cholesterol with prostate cancer death. METHODS: From the Swedish AMORIS cohort, we selected 14,150 men diagnosed with prostate cancer between 1996 and 2011 who had prediagnostic measurements of serum glucose, triglycerides, and total cholesterol. Multivariable Cox proportional hazards regression models were used to determine the hazard ratios for death in relation to the aforementioned metabolic markers. RESULTS: Using clinical cut-off points, a non-significant positive association was observed between glucose and prostate cancer death. When compared to those with glucose in the lowest quartile, those in the highest quartile had greater risk of prostate cancer death (HR 1.19; 95% CI 1.02-1.39). However, neither total cholesterol nor triglycerides were associated with prostate cancer death. Glucose and triglycerides were positively associated with overall, cardiovascular, and other deaths. Hypercholesterolemia was only associated with risk of CVD death. CONCLUSION: Our results suggest that glucose levels may influence prostate cancer survival, but further studies using repeated measurements are needed to further elucidate how glucose levels may influence prostate cancer progression. PMID- 30421157 TI - The Role of Pediatric Psychologists in the Transition of Youth to Adult Health Care: A Descriptive Qualitative Study of Their Practice and Recommendations. AB - Transition from pediatric to adult health care setting is a challenge for young patients because of the psychosocial issues they may present that could hinder their commitment to treatment and medical care. Psychologists play a key role in supporting these patients. They intervene with the most vulnerable ones for whom the current transitional practice does not necessarily meet their specific needs and help them to develop an appropriate level of autonomy despite medical condition. To date, few studies have described their clinical practice in this field. This study aimed to gather in-depth information about the elements that characterize their different roles in transition care. Following a semi structured interviews with ten pediatric psychologists, we conducted a thematic content analysis to identify common themes among participants. The results indicate that the psychologists' practice focuses on four main aspects: assessment, intervention, education, and liaison. Their recommendations point towards a better organization of health care services and a reflection on the best practices in psychology. These results highlight the specific roles that pediatric psychologists play in the transition process within the health care environment. PMID- 30421158 TI - Possible effects of radiofrequency electromagnetic fields on in vivo C6 brain tumors in Wistar rats. AB - PURPOSE: Glioblastoma is a malignant brain tumor which has one of the poorest prognosis. It is not clear if toxic environmental factors can influence its aggressiveness. Recently, it was suggested that brain cancer patients with heavy cell phone use showed reduced survival. Here we aimed to assess the effect of controlled brain averaged specific absorption rate (BASAR) from heavy use of cell phone radiofrequency electromagnetic fields (RF-EMF) on in vivo C6 brain tumors in Wistar rats. METHODS: C6 cells grafted male rats were exposed to GSM 900 MHz signal at environmental BASAR, 0 (sham), 0.25 or 0.5 W/kg (5 days a week, 45 min a day in restraint), or were cage controls (no restraint). At death, tumor volume and immunohistochemistry for CD31, cleaved caspase (CC) 3 and Ki67 were assessed to examine vascularization, apoptosis and cellular divisions, respectively. Moreover, immune cell invasion, necrosis and mitotic index were determined. RESULTS: Results showed no BASAR effect on survival (31 days post-graft median), tumor volume, mitotic index, vascularization, infiltration, necrosis or cell division. However, results suggested a BASAR-dependent reduction of immune cell invasion and apoptosis. CONCLUSIONS: Our data suggested an action of RF-EMF by reducing immune cell invasion and glioblastoma cell apoptosis, at probably too low amplitude to impact survival. Further replication studies are needed to confirm these observations. PMID- 30421160 TI - Survival of glioma patients in relation to mobile phone use in Denmark, Finland and Sweden. AB - PURPOSE: Gliomas are the most common cancer of the brain, with a poor prognosis in particular for glioblastoma. In 2014, a study suggested reduced survival in relation to latency of mobile phone use among glioblastoma patients. A joint epidemiological/experimental project to study effects of RF-EMF on tumor development and progression was established. The current analysis relates to the epidemiological part and addresses whether pre-diagnostic mobile phone use was associated with survival among glioma patients. METHODS: Glioma cases (n = 806) previously enrolled in a collaborative population-based case-control study in Denmark, Finland and Sweden were followed up for survival. Vital status, date of death, date of emigration, or date last known to be alive was obtained based on registry linkages with a unique personal ID in each country. Cox regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) stratified by country. Covariates investigated were sex, age, education, histology, treatment, anatomic location and marital status. RESULTS: No indication of reduced survival among glioblastoma patients was observed for various measures of mobile phone use (ever regular use, time since start of regular use, cumulative call time overall or in the last 12 months) relative to no or non-regular use. All significant associations suggested better survival for mobile phone users. Results were similar for high-grade and low-grade gliomas. CONCLUSIONS: We found no evidence of reduced survival among glioma patients in relation to previous mobile phone use. PMID- 30421161 TI - Practical Strategies for Optimizing and Integrating Palliative Care in Cancer. AB - PURPOSE OF REVIEW: Recent reforms in medical payment coupled with a rapidly evolving pharmacotherapeutic armamentarium is creating a transition in the field of oncology. This transition represents a key period for conceptual reevaluation, providing an opportunity for furthered strategic integration of palliative care within the realm of oncology. RECENT FINDINGS: Historically, oncologists have relied upon prognostic assessments to gauge appropriateness for referrals to specialty palliative care. Recent literature has elucidated on the early palliative burdens of cancer, demonstrated the importance of complexity-based palliative referrals, and begun the conversation to define provider-specific roles. Herein, we describe a model that overlaps complexity with oncology capacity, to target specialty services to those who could benefit most. This article will review the role of palliative care as a care philosophy, the enduring and important role of the oncologist in providing palliative care, and the important areas for integration of specialty services when needed. PMID- 30421162 TI - Orthosilicic Acid Accelerates Bone Formation in Human Osteoblast-Like Cells Through the PI3K-Akt-mTOR Pathway. AB - Silicon is one of the essential trace elements in the human body; the deficiency of which may lead to bone diseases. Numerous animal experiments have shown that an appropriate increase in the intake of silicon is beneficial to enhancing bone density and toughness to prevent osteoporosis. However, the molecular mechanisms of the silicon-mediated osteogenesis process have not been sufficiently clarified. In this study, we determined the possible osteogenesis-related mechanisms of orthosilicic acid at a molecular level. We detected the relevant pathway and osteogenic indicators by immunofluorescence (IF), Western blot, alkaline phosphatase (ALP) staining (using 5-bromo-4-chloro-3-indolyl phosphate/nitro blue tetrazolium [BCIP/NBT]), ALP enzyme labeling method, osteocalcin (OCN), and N-terminal propeptide of type 1 procollagen (P1NP) enzyme linked immunosorbent assay (ELISA). We found that orthosilicic acid is capable of enhancing the expression of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), phospho-protein kinase B (P-Akt), phospho-mammalian target of rapamycin (P-mTOR), and related osteogenic markers (runt-related transcription factor 2 [RUNX2], type I collagen [COL1], ALP, OCN, and P1NP). However, with the addition of PI3K-Akt-mTOR pathway-specific inhibitor LY294002, the expression of PI3K, P Akt, P-mTOR, RUNX2, COL1, ALP, OCN, and P1NP decreased. The results indicated that the PI3K-Akt-mTOR pathway played a positive regulatory role in the process of orthosilicic acid-mediated osteogenesis in vitro. PMID- 30421163 TI - Robert Dickson, Juergen Harms (eds): Modern management of spinal deformities: a theoretical, practical, and evidence-based text : Thieme Verlag, New York, Stuttgart, Delhi, Rio de Janeiro, 2017, 330 pp, 935 figs., 280,00 mm, Hardcover (GEB), EUR (D) 199,99, EUR (A) 205,60, CHF 230,00, ISBN: 978-3-13-201631-6. PMID- 30421164 TI - Reconstruction of the medial patellofemoral ligament and reinforcement of the medial patellotibial ligament is an effective treatment for patellofemoral instability with patella alta. AB - PURPOSE: To evaluate the clinical outcome of the combined reconstruction of the medial patellofemoral ligament (MPFL) and medial patellotibial ligament (MPTL) for patellar instability with patella alta. METHODS: A total of 108 patients underwent a combined reconstruction of the MPFL and MPTL, and 58 patients were included in this study. The clinical results were evaluated and compared using the International Knee Documentation Committee (IKDC) scores, Kujala scores, and visual analogue scale (VAS) scores. The tibial tuberosity-trochlear groove (TT TG) distance, three indices of patellar height (Insall-Salvati ratio, modified Insall-Salvati ratio, and Caton-Deschamps index), and patellar shift and tilt were defined preoperatively and at the 12- and 24-month follow-up visits. RESULTS: At the 12- and 24-month follow-up visits, 86.2% (50/58) and 87.9% (51/58) of the subjective outcomes were excellent, 5/58 (8.6%) and 4/58 (6.9%) were good, 1/58 (1.7%) and 2/58 (3.4%) were fair, and 2/58 (3.4%) and 1/58 (1.7%) were poor. There were significant improvements in the IKDC scores, from 51.9 +/- 13.8 preoperatively to 80 +/- 19.2 (P < 0.05) at 12 months and 85 +/- 13.9 (P < 0.05) at 24 months; Kujala scores, from 55.1 +/- 15.2 preoperatively to 82.6 +/- 14.9 (P < 0.05) at 12 months and 89.5 +/- 10.2 (P < 0.05) at 24 months; and VAS scores, from 58 +/- 11 preoperatively to 12 +/- 5 (P < 0.05) at 12 months and 11 +/- 4 (P < 0.05) at 24 months. The patellar tilt, patellar shift, Insall-Salvati ratio, modified Insall-Salvati ratio, Caton-Deschamps index, and TT-TG distance all decreased significantly compared with the preoperative values, and there were no significant differences between the values at the 12- and 24-month follow-ups. CONCLUSION: The results of this study show that a combined reconstruction of the MPFL and MPTL is an effective treatment for patellar instability with patella alta. This article emphasizes the combined effect of MPFL and MPTL instead of MPFL alone and provides an effective option for the treatment of recurrent patellar dislocation with patella alta. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 30421165 TI - Kinematic alignment in total knee arthroplasty leads to a better restoration of patellar kinematics compared to mechanic alignment. AB - PURPOSE: The influence of different implantation techniques in TKA on tibiofemoral kinematics was analysed in few investigations so far. However, the influence on patellar kinematics remain unclear. The aim of the present investigation was to compare patellar kinematics of the natural knee with those of knees after both kinematically and mechanically aligned TKAs. METHODS: Patellar kinematics of ten cadaveric knees before and after TKAs implanted using both a kinematic and mechanic alignment technique were investigated and compared using a commercial optical computer navigation system. RESULTS: There was a statistically significant difference between natural patellar kinematics and both implantation techniques analysing mediolateral shift. Patellar lateral tilt showed significant better results in the kinematically compared to the mechanically aligned TKAs. In terms of patella rotation, the patella of both mechanically and kinematically aligned TKAs showed significant higher values for external rotation compared to the natural knee. Regarding epicondylar distance again a significant better restoration of natural kinematics could be found in the kinematically aligned TKAs. CONCLUSION: Kinematically aligned TKAs showed a better overall restoration of patellar kinematics compared to a conventional mechanical alignment technique. In terms of clinical usefulness, the present study highlights the potential benefit for clinical outcome using a kinematically aligned implantation technique in TKA to achieve a better restoration of natural patellofemoral kinematics. PMID- 30421166 TI - The significant effect of the medial hamstrings on dynamic knee stability. AB - PURPOSE: While hamstring autograft is a popular option for the general population, BTB autograft is still significantly more popular among professional athletes due to concerns of altering knee kinematics with hamstring harvest. This study seeks to quantify the contribution of the medial hamstrings to knee stability. METHODS: Valgus knee laxity, anterior tibial translation, and rotational motion were measured in eight fresh-frozen cadaveric knees after forces were applied on the tibia in each plane (coronal, sagittal, and axial). Four muscle loading conditions were tested: (1) physiologic fully loaded pes anserinus, (2) semitendinosus only loaded, (3) gracilis only loaded, and (4) unloaded pes anserinus. The protocol was then repeated with the ACL transected. RESULTS: In the ACL intact knee, the neutral position of the tibia with an unloaded pes anserinus was significantly more externally rotated (p < 0.01) and anteriorly translated (p < 0.05) at all knee flexion angles than a tibia with a physiologic loaded pes anserinus. Applying an external rotation torque significantly increased external rotation for the fully unloaded (p < 0.001), gracilis only loaded (p < 0.001), and semitendinosus only loaded (p < 0.01) conditions at all flexion angles. Applying a valgus torque resulted in a significant increase in laxity for the fully unloaded condition only at 30 degrees of flexion (p < 0.05). Applying an anterior tibial force resulted in significant increase in anterior translation for the fully unloaded condition at all flexion angles (p < 0.01), and for the gracilis only loaded condition in 30 degrees and 60 degrees of flexion (p < 0.05). Similar results were seen in the ACL deficient model. CONCLUSION: The medial hamstrings are involved in rotational, translational, and varus/valgus control of the knee. Applying anterior, external rotation, and valgus forces on the hamstring deficient knee significantly increases motion in those planes. Harvesting the gracilis and semitendinosus tendons alters native knee kinematics and stability. This is clinically relevant and should be a consideration when choosing graft source for ACL reconstruction, especially in the elite athlete population. PMID- 30421168 TI - Development of Cortical Pyramidal Cell and Interneuronal Dendrites: a Role for Kainate Receptor Subunits and NETO1. AB - During neuronal development, AMPA receptors (AMPARs) and NMDA receptors (NMDARs) are important for neuronal differentiation. Kainate receptors (KARs) are closely related to AMPARs and involved in the regulation of cortical network activity. However, their role for neurite growth and differentiation of cortical neurons is unclear. Here, we used KAR agonists and overexpression of selected KAR subunits and their auxiliary neuropilin and tolloid-like proteins, NETOs, to investigate their influence on dendritic growth and network activity in organotypic cultures of rat visual cortex. Kainate at 500 nM enhanced network activity and promoted development of dendrites in layer II/III pyramidal cells, but not interneurons. GluK2 overexpression promoted dendritic growth in pyramidal cells and interneurons. GluK2 transfectants were highly active and acted as drivers for network activity. GluK1 and NETO1 specifically promoted dendritic growth of interneurons. Our study provides new insights for the roles of KARs and NETOs in the morphological and physiological development of the visual cortex. PMID- 30421167 TI - Involvement of the Cholinergic Parameters and Glial Cells in Learning Delay Induced by Glutaric Acid: Protection by N-Acetylcysteine. AB - Dysfunction of basal ganglia neurons is a characteristic of glutaric acidemia type I (GA-I), an autosomal recessive inherited neurometabolic disease characterized by deficiency of glutaryl-CoA dehydrogenase (GCDH) and accumulation of glutaric acid (GA). The affected patients present clinical manifestations such as motor dysfunction and memory impairment followed by extensive striatal neurodegeneration. Knowing that there is relevant striatal dysfunction in GA-I, the purpose of the present study was to verify the performance of young rats chronically injected with GA in working and procedural memory test, and whether N acetylcysteine (NAC) would protect against impairment induced by GA. Rat pups were injected with GA (5 MUmol g body weight-1, subcutaneously; twice per day; from the 5th to the 28th day of life) and were supplemented with NAC (150 mg/kg/day; intragastric gavage; for the same period). We found that GA injection caused delay procedural learning; increase of cytokine concentration, oxidative markers, and caspase levels; decrease of antioxidant defenses; and alteration of acetylcholinesterase (AChE) activity. Interestingly, we found an increase in glial cell immunoreactivity and decrease in the immunoreactivity of nuclear factor-erythroid 2-related factor 2 (Nrf2), nicotinic acetylcholine receptor subunit alpha 7 (alpha7nAChR), and neuronal nuclei (NeuN) in the striatum. Indeed, NAC administration improved the cognitive performance, ROS production, neuroinflammation, and caspase activation induced by GA. NAC did not prevent neuronal death, however protected against alterations induced by GA on Iba-1 and GFAP immunoreactivities and AChE activity. Then, this study suggests possible therapeutic strategies that could help in GA-I treatment and the importance of the striatum in the learning tasks. PMID- 30421169 TI - Progressive multifocal leukoencephalopathy developing after obinutuzumab treatment for chronic lymphocytic leukemia. PMID- 30421170 TI - Biomimetic oxidase sensor based on functionalized surface of carbon nanotubes and iron prophyrins for catechol detection. AB - A novel and highly stable biomimetic oxidase sensor system was designed for catehol detection. FePP used as biomimetic horseradish peroxidase (HRP) was immobilized onto modified multi-walled carbon nanotubes (MWCNTs). Functional groups such as -OH, -NH2 and -COOH were introduced onto the surface of MWCNTs to provide biomimetic microenvironment for iron porphyrins (FePP). Stable biomimetic enzyme electrode has been developed to detect catechol as a simple, economical and efficient method. At optimal condition, the detection limit of OH MWCNTs/FePP/Nafion was 3.754 * 10- 6 M. After stored at - 4 degrees C for 35 days, the oxidation current value still maintained 98.3% of initial activity. In repetitive nature test, relative standard deviation (RSD) of oxidation current remained within 1.0% after ten consecutive measurements in the same concentration of catechol solution, while most of reported oxidase sensor was within 2.0% under the same condition. PMID- 30421171 TI - Anticancer, antimicrobial, antioxidant, and catalytic activities of green synthesized silver and gold nanoparticles using Bauhinia purpurea leaf extract. AB - The synthesis of metal nanoparticles by green methods attained enormous attention in recent years due to its easiness, non-toxicity, and eco-friendly nature. In the present study, noble metal nanoparticles such as silver and gold were prepared using an aqueous leaf extract of a medicinal plant, Bauhinia purpurea. The leaf extract performed as both reducing and stabilizing agents for the development of nanoparticles. The formations of silver and gold nanoparticles were confirmed by observing the surface plasmon resonance peaks at 430 nm and 560 nm, respectively, in UV-Vis absorption spectrum. Various properties of nanoparticles were demonstrated using the characterization techniques such as FTIR, XRD, TEM, and EDX. The synthesized silver and gold nanoparticles had a momentous anticancer effect against lung carcinoma cell line A549 in a dose dependent manner with IC50 values of 27.97 ug/mL and 36.39 ug/mL, respectively. The antimicrobial studies of synthesized nanoparticles were carried out by agar well diffusion method against six microbial strains. Silver and gold nanoparticles were also showed high antioxidant potentials with IC50 values of 42.37 ug/mL and 27.21 ug/mL, respectively; it was measured using DPPH assay. Additionally, the nanoparticles were observed to be good catalysts for the reduction of organic dyes. PMID- 30421172 TI - Immobilized Talaromyces thermophilus lipase as an efficient catalyst for the production of LML-type structured lipids. AB - LML-type structured lipids are one type of medium- and long-chain triacylglycerols. LML was synthesized using immobilized Talaromyces thermophilus lipase (TTL)-catalyzed interesterification of tricaprylin and ethyl linoleate. The resin AB-8 was chosen, and the lipase/support ratio was determined to be 60 mg/g. Subsequently, the immobilized TTL with strict sn-1,3 regiospecificity was applied to synthesize LML. Under the optimized conditions (60 degrees C, reaction time 6 h, enzyme loading of 6% of the total weight of substrates, substrate of molar ratio of ethyl linoleate to tricaprylin of 6:1), Triacylglycerols with two long- and one medium-chain FAs (DL-TAG) content as high as 52.86 mol% was obtained. Scale-up reaction further verified the industrial potential of the established process. The final product contained 85.24 mol% DL TAG of which 97 mol% was LML after purification. The final product obtained with the high LML content would have substantial potential to be used as functional oils. PMID- 30421173 TI - Planting and seasonal and circadian evaluation of a thymol-type oil from Lippia thymoides Mart. & Schauer. AB - BACKGROUND: The oil and extracts of Lippia thymoides have been used for various medicinal and food applications. Entrepreneurs in the Amazon have been considering the economic exploitation of this plant. The present study evaluated the influence of the seasonal and circadian rhythm on the yield and composition of the essential oil of leaves and thin branches of a Lippia thymoides specimen cultivated in Abaetetuba, State of Para, Brazil. The constituents of the oils were identified by GC and GC-MS and with the application of multivariate analysis: Principal Component Analysis (PCA) and Hierarchical Cluster Analysis (HCA). RESULTS: The predominance of oxygenated monoterpenes (70.6-91.8%) was observed in oils, followed by monoterpene hydrocarbons (1.2 to 21.6%) and sesquiterpene hydrocarbons (3.9 to 9.1%). Thymol, thymol acetate, gamma terpinene, p-cymene, and (E)-caryophyllene were the first compounds. The mean thymol content was higher in the rainy season (seasonal: 77.0%; circadian: 74.25%) than in the dry period (seasonal: 69.9%; circadian: 64.5%), and it was influenced by climatic variables: rainfall precipitation, solar radiation, temperature, and relative humidity. For the circadian study, PCA and HCA analysis were applied to the constituents of oils from rainy and dry periods. Two groups were formed. A higher thymol content characterized the group 1, followed by (Z) hexen-3-ol, alpha-thujene, alpha-pinene, alpha-phellandrene and humulene epoxide II, in minor percent. A higher content of p-cymene formed the group 2, gamma terpinene, thymol acetate and (E)-caryophyllene, followed by myrcene, alpha terpinene, 1,8-cineole, terpinen-4-ol, methylthymol, and germacrene D, in a low percentage. CONCLUSIONS: The different chemical profiles found in the oils of L. thymoides must be associated with the environmental conditions existing at its collection site. The knowledge of this variation in the oil composition is essential from the ecological and taxonomic point of view, regarding the management and economic use of the species. PMID- 30421174 TI - An international comparison of diagnostic and management strategies for vestibular schwannoma. AB - OBJECTIVE: To compare international diagnostic and management strategies for vestibular schwannoma (VS). METHODS: A web-based questionnaire was sent to 130 otolaryngologists, mainly identified through the European Skull Base Society. It contained questions on general information including guideline usage as well as questions on diagnosis (focussing on selection of patients for MRI) and management of VS, including case scenarios. Descriptive statistics were reported. RESULTS: Thirty-six otolaryngologists working in 11 different countries completed the questionnaire (response rate: 28%). Guidelines for diagnosis and management of VS are used by 44% and 42% of respondents, respectively. In the diagnostic strategy for VS, different types and combinations of audiovestibular function tests are used when deciding whether a patient should undergo an MRI. Respondents apply 18 different definitions of asymmetrical hearing loss. Variation was also apparent from reported considerations on management of VS. Most respondents (84%) prefer a wait-and-scan strategy in case of a small intrameatal VS (Koos 1). Variety in management strategies increases for patients with a medium to large sized VS (Koos 2, 3 and 4). The details of each management strategy (wait-and scan, microsurgery, stereotactic radiosurgery and fractionated radiotherapy) also differ among respondents. CONCLUSIONS: A large variation in diagnostic and management strategies for VS was identified between respondents. More evidence and/or consensus seem warranted to reduce uncertainties for patients, and differences in outcome and costs that might result from the variety of strategies currently being applied. PMID- 30421176 TI - Fluid signal in the mastoid is a common incidental finding on MRI of the brain. AB - Incidental findings are common on patients undergoing magnetic resonance imaging (MRI) of the brain. Fluid signal in the mastoid can be such an incidental finding on MRI of the brain. In only a small number of patients, this relates to inflammatory disease of the middle ear or mastoid. In a small retrospective study, the prevalence of this finding has been studied. Fluid signal in the mastoid was found in 21 out of 84 patients (25%). Only in two patients MRI revealed a cause for the mastoid fluid (mastoid osteolysis in a patient with metastatic breast cancer and presumed recurrent cholesteatoma in another patient). Two patients reported about longstanding presbyacusis. At the initial examination, none of the patients reported symptoms of an inflammatory otological disease, and clinical examination was unremarkable in all patients. In conclusion, fluid signal in the mastoid seems to be a frequent incidental finding in asymptomatic patients. A diagnosis of mastoiditis should only be made if there are distinct clinical findings. PMID- 30421175 TI - Facial canal dehiscence rate: a retrospective analysis of 372 chronic otitis media cases. AB - PURPOSE: This study aimed to investigate the rate and location of facial canal dehiscence (FCD) observed during surgery for chronic otitis media (COM) with or without cholesteatoma. MATERIAL AND METHOD: Operative details of 1296 patients who underwent chronic otitis media surgery from January 2000 to January 2017 by the same surgeon were included in this retrospective study focusing on intraoperative observations of FCD. RESULTS: Because of the type of the surgery, the Fallopian canal could not be seen completely, so 924 of the cases which only involved performing a tympanoplasty were not included in the study. A total of 372 patients (196 males and 176 females) who had a canal wall down (CWD) or canal wall up (CWU) mastoidectomy were included in the study. A CWD mastoidectomy was performed on 250 patients, while 122 patients underwent a CWU mastoidectomy. The prevalence of FCD was 11.29% (42/372 patients). The dehiscence was more common in patients with cholesteatoma (n = 37; 88.1%) than those with non-cholesteatoma (n = 5; 11.9%). The tympanic segment (n = 32; 76.19%) was the most common location for FCD. When we compared the ossicular erosion results of the cases that had FCD, erosion in three ossicles together was more statistically significantly frequent than the other possibilities. CONCLUSION: It is possible to see FCD because of COM, especially with cholesteatoma. FCD is most commonly seen around the oval window. If stapes or all three ossicles are eroded, the surgeons must be more careful regarding FCD to be more effective in preventing facial nerve damage. PMID- 30421177 TI - Linking Physiological Biomarkers of Ventilator-Induced Lung Injury to a Rich-Get Richer Mechanism of Injury Progression. AB - Mechanical ventilation is a crucial tool in the management of acute respiratory distress syndrome, yet it may itself also further damage the lung in a phenomenon known as ventilator-induced lung injury (VILI). We have previously shown in mice that volutrauma and atelectrauma act synergistically to cause VILI. We have also postulated that this synergy arises because of a rich-get-richer mechanism in which repetitive lung recruitment generates initial small holes in the blood-gas barrier which are then expanded by over-distension in a manner that favors large holes over small ones. In order to understand the causal link between this process and the derangements in lung mechanics associated with VILI, we developed a mathematical model that incorporates both atelectrauma and volutrauma to predict how the propensity of the lung to derecruit depends on the accumulation of plasma-derived fluid and proteins in the airspaces. We found that the model accurately predicts derecruitment in mice with experimentally induced VILI. PMID- 30421178 TI - The protective effects of melatonin on blood cell counts of rectal cancer patients following radio-chemotherapy: a randomized controlled trial. AB - PURPOSE: We aimed to examine the radioprotective effects of melatonin on the blood cell counts of patients with rectum cancer undergoing radiotherapy. MATERIALS AND METHODS: This double-blind placebo-controlled study was conducted on 60 rectal cancer patients who were referred to Rajaii Hospital of Babolsar, Iran. An equal number of patients were randomly assigned to the control group which received placebo and study group which received 20 mg melatonin a day as an intervention. The melatonin was administered 5 days a week for 28 days. Blood samples were taken before melatonin received on day 1 and also day 28; then, to measure the changes in blood cell counts representing our primary outcomes, the samples were analyzed by Sysmex K810i auto-analyzer. RESULTS: Our results showed that the platelet, white blood cells, lymphocyte, and neutrophil population reduction induced by radiotherapy were slighter or even insignificant in melatonin recipients compared to control. However, the difference between red blood cells in both groups was not significant. CONCLUSION: Our results are indicating that melatonin could prevent or minimize the unfavorable effects of radiotherapy on blood cell count reductions by attenuating the adverse influence of radiation, probably through stimulation of cellular antioxidant potential as previously reported in animal models. IRANIAN REGISTRY OF CLINICAL TRIALS (IRCT): Registry No. IRCT2016021626586N1. PMID- 30421179 TI - Effects of Ambient Atmospheric PM2.5, 1-Nitropyrene and 9-Nitroanthracene on DNA Damage and Oxidative Stress in Hearts of Rats. AB - Exposure to fine particulate matter (PM2.5) increased the risks of cardiovascular diseases. PM2.5-bound 1-nitropyrene (1-NP) and 9-nitroanthracene (9-NA) are released from the incomplete combustion of fossil fuels and derived from polycyclic aromatic hydrocarbons (PAHs). The toxicities of 1-NP and 9-NA are mainly reflected in their carcinogenicity and mutagenicity. However, studies of PM2.5-bound 1-NP and 9-NA on the cardiac genotoxicity are limited so far. In this study, histopathology, DNA damage, DNA repair-related gene expression, and oxidative stress were investigated in the hearts of male Wistar rats exposed to PM2.5 [1.5 mg/kg body weight (b.w.)] or three different dosages of 1-NP (1.0 * 10 5, 4.0 * 10- 5, and 1.6 * 10- 4 mg/kg b.w.) or 9-NA (1.3 * 10- 5, 4.0 * 10- 5, and 1.2 * 10- 4 mg/kg b.w.). The results revealed that (1) PM2.5, higher dosages of 1-NP (4.0 * 10- 5 and 1.6 * 10- 4 mg/kg b.w.) and 9-NA (4.0 * 10- 5 and 1.2 * 10- 4 mg/kg b.w.) caused obvious pathological responses and DNA damage (DNA strand breaks, 8-OHdG formation and DNA-protein cross-link), accompanied by increasing OGG1 and GADD153 expression while inhibiting MTH1 and XRCC1 expression in rat hearts. Also, they elevated the hemeoxygenase-1 (HO-1), glutathione S transferase (GST), and malondialdehyde (MDA) levels and decreased superoxide dismutase (SOD) activity compared with the control. (2) The lowest dosages 1-NP or 9-NA could not cause DNA damage and oxidative stress. (3) At the approximately equivalent dose level, PM2.5-induced DNA damage effects were more obvious than 1 NP or 9-NA along with positive correlation. Taken together, heart DNA damage caused by PM2.5, 1-NP and 9-NA may be mediated partially through influencing the DNA repair capacity and causing oxidative stress, and such negative effects might be related to the genotoxicity PM2.5, 1-NP, and 9-NA. PMID- 30421180 TI - Validating team communication data using a transmission-duration threshold and voice activity detection algorithm. AB - The processes underlying team effectiveness can be understood by analyzing the temporal dynamics of team communication sequences. The results of such analyses have shown that the complexity of team communication is associated with team performance on task-related variables, and hence communication complexity statistics have been proposed for use as measures for real-time feedback on team performance. In two analyses of historical team communication sequences, we found that filtering via use of a transmission-duration threshold and voice activity detection algorithm resulted in significant changes in complexity relative to not filtering the data or using a transmission-duration filter alone. The use of these filtering techniques showed significant effects on the complexity of communication sequences in both a laboratory-based experiment, with participants with little experience with voice communication protocols, and in a mission simulation with trained military operators. There was also a significant non linear relationship between the complexity of communication sequences and task performance. However, an analysis of the impact of the changes in communication dynamics gained through filtering did not demonstrate that the changed temporal dynamics of filtered data better explained team performance. It is concluded that pre-filtering of invalid communication data should be included during the data cleaning stage of statistical analysis as a matter of good scientific practice. Furthermore, such use of filtering will ensure that inferences made about the relationship between the complexity of communication between team members and their performance are not confounded by the presence of invalid communication events. PMID- 30421181 TI - How well do word recognition measures correlate? Effects of language context and repeated presentations. AB - In the present study we assessed the extent to which different word recognition time measures converge, using large databases of lexical decision times and eyetracking measures. We observed a low proportion of shared variance between these measures, which limits the validity of lexical decision times to real-life reading. We further investigated and compared the role of word frequency and length, two important predictors of word-processing latencies in these paradigms, and found that they influenced the measures to different extents. A second analysis of two different eyetracking corpora compared the eyetracking reading times for short paragraphs with those from reading of an entire book. Our results revealed that the correlations between eyetracking reading times of identical words in two different corpora are also low, suggesting that the higher-order language context in which words are presented plays a crucial role. Finally, our findings indicate that lexical decision times better resemble the average processing time of multiple presentations of the same word, across different language contexts. PMID- 30421182 TI - [Pain - The most interesting new findings in the last ten years]. PMID- 30421183 TI - [Recent progress in otorhinolaryngology]. PMID- 30421184 TI - [Hallmarks in obstetrics and gynecology]. PMID- 30421185 TI - [Urology - what are the most important trends over the last decade?] PMID- 30421186 TI - [The most important innovations in forensic medicine in the past 10 years]. PMID- 30421187 TI - [Palliative medicine: a pivotal task for primary care physicians]. PMID- 30421188 TI - [Geriatrics on the move - what happened during the last 10 years?] PMID- 30421189 TI - [Vaccination - what's new during the past 10 years?] PMID- 30421190 TI - [HIV - Innovation of diagnosis and treatment during the last decade]. PMID- 30421191 TI - [Pneumology: what are the most important innovations of the decade?] PMID- 30421192 TI - [Hepatitis C: Innovations in the last 10 years]. PMID- 30421193 TI - ? PMID- 30421194 TI - [Gastrointestinal innovations]. PMID- 30421195 TI - [Endocrinology: What are the most important practically relevant advances over the last ten years?] PMID- 30421196 TI - [Rheumatology (rheumatoid arthritis, psoriatic arthritis, Spondyloarthritis): What are the most important innovations in the last 10 years?] PMID- 30421197 TI - [Anticoagulation in patients with venous thromboembolism: What have been the most important changes within the last 10 years?] PMID- 30421198 TI - [Lipidology - important changes of the last 10 years]. PMID- 30421199 TI - [Diabetology: The most important innovations of the past 10 years]. PMID- 30421200 TI - [Anticoagulation for stroke prevention in atrial fibrillation - new concepts, new challenges]. PMID- 30421201 TI - [New directions in cardiology over the past 10 years]. PMID- 30421203 TI - ? PMID- 30421202 TI - [Choosing wisely to protect our patients]. PMID- 30421204 TI - ? PMID- 30421205 TI - ? PMID- 30421206 TI - ? PMID- 30421207 TI - ? PMID- 30421208 TI - ? PMID- 30421209 TI - ? PMID- 30421210 TI - ? PMID- 30421211 TI - ? PMID- 30421212 TI - ? PMID- 30421214 TI - ? PMID- 30421213 TI - ? PMID- 30421216 TI - ? PMID- 30421217 TI - Palliative Care in Patients with Leukemia: When and How? AB - PURPOSE OF REVIEW: Patients with hematologic malignancies get more aggressive treatment and the end-of-life, more ICU deaths, and prolonged hospital stays. In comparison to solid tumors, their access to palliative care and hospice is less. RECENT FINDINGS: Multiple factors seem to play a role including curative goals, different treatment options, stronger relationship between patients and oncologist, symptom burden, and limitations of hospice care. Improving the perception of palliative care in these patients, characterizing their needs, and more education can help to increase referrals and access to palliative care. Innovative ways to improve integration between hematology-oncology and palliative care are needed. PMID- 30421218 TI - Short-term upper-limb immobilization alters peripersonal space representation. AB - Peripersonal space is a multisensory interface between the environment and the body subserving motor interactions with the physical and social world. Although changing body properties has been shown to alter the functional processing of space, little is known about the effect of short-term limb immobilization specifically on the motor representation of peripersonal space. In the present study, we investigated the effect of a right upper-limb immobilization for a duration of 24 h on a reachability judgment task and a brightness judgment task. Analyses of perceptual thresholds revealed a reduction of peripersonal space representation after the immobilization period, which was not observed when there was no immobilization (control group). In contrast, no variation appeared in the brightness judgment task, suggesting no presence of specific visual perception or decisional deficits in the limb immobilization group. Considered together, the results confirm the crucial role of the motor system in the representation of peripersonal space. They also highlight the plasticity of the motor system resulting in a rapid change of its activity following limb immobilization, with a concomitant effect on motor-related perceptual and cognitive processes. PMID- 30421220 TI - Deprescribing in multi-morbid older people with polypharmacy: agreement between STOPPFrail explicit criteria and gold standard deprescribing using 100 standardized clinical cases. AB - PURPOSE: Older people with advanced frailty are among the highest consumers of medications. When life expectancy is limited, some of these medications are likely to be inappropriate. The aim of this study was to compare STOPPFrail, a concise, easy-to-use, deprescribing tool based on explicit criteria, with gold standard, systematic geriatrician-led deprescribing. METHODS: One hundred standardized clinical cases involving 1024 medications were prepared. Clinical cases were based on anonymized hospitalized patients aged >= 65 years, with advanced frailty (Clinical Frailty Scale >= 6), receiving >= 5 regular medications, who were selected from a recent observational study. Level of agreement between deprescribing methods was measured by Cohen's kappa coefficient. Sensitivity and positive predictive value of STOPPFrail-guided deprescribing relative to gold standard deprescribing was also measured. RESULTS: Overall, 524 medications (51.2%) of medications prescribed to this frail, elderly cohort were potentially inappropriate by gold standard criteria. STOPPFrail guided deprescribing led to the identification of 70.2% of the potentially inappropriate medications. Cohen's kappa was 0.60 (95% confidence interval 0.55 0.65; p < 0.001) indicating moderate agreement between STOPPFrail-guided and gold standard deprescribing. The positive predictive value of STOPPFrail was 89.3% indicating that the great majority of deprescribing decisions aligned with gold standard care. CONCLUSIONS: STOPPFrail removes an important barrier to deprescribing by explicitly highlighting circumstances where commonly used medications can be safely deprescribed in older people with advanced frailty. Our results suggest that in multi-morbid older patients with advanced frailty, the use of STOPPFrail criteria to address inappropriate polypharmacy may be reasonable alternative to specialist medication review. PMID- 30421221 TI - Microbial Metabolomics: A General Overview. AB - In the biosciences, there has been growing interest in the elucidation of gene function. Consequently, metabolomics has garnered a lot of attention of late due to its provision of metabolic information pertaining to both function and phenotype. Furthermore, when metabolomics data is integrated with other "omics" data, precise characterization of metabolic activity can be achieved. This chapter briefly introduces a few important aspects of the metabolome, the challenges faced when acquiring metabolomic information and the steps that are necessary to overcoming them. This chapter also briefly covers current analytical technologies and some microbial metabolomic applications. PMID- 30421222 TI - Mass Spectrometry-Based Microbial Metabolomics: Techniques, Analysis, and Applications. AB - The demand for understanding the roles genes play in biological systems has steered the biosciences into the direction the metabolome, as it closely reflects the metabolic activities within a cell. The importance of the metabolome is further highlighted by its ability to influence the genome, transcriptome, and proteome. Consequently, metabolomic information is being used to understand microbial metabolic networks. At the forefront of this work is mass spectrometry, the most popular metabolomics measurement technique. Mass spectrometry-based metabolomic analyses have made significant contributions to microbiological research in the environment and human disease. In this chapter, we break down the technical aspects of mass spectrometry-based metabolomics and discuss its application to microbiological research. PMID- 30421223 TI - Metabolomics: A Microbial Physiology and Metabolism Perspective. AB - Metabolomics is valuable for studying microbial metabolism, which is often used to elucidate biological functions. Effective application of metabolomics is enhanced by fundamental understanding of microbial physiology and metabolism. This review briefly highlights important aspects of metabolism that are essential for designing and executing effective metabolic and metabolomics studies. The influence of microbial physiology and metabolism on growth, energy metabolism and regulation is briefly reviewed. The chapter also evaluates factors affecting metabolic prediction. PMID- 30421224 TI - Untargeted Soil Metabolomics Using Liquid Chromatography-Mass Spectrometry and Gas Chromatography-Mass Spectrometry. AB - The molecular composition of soil organic matter (SOM) sets the foundation for terrestrial microbial community structures and carbon cycling dynamics. However, the specific chemical constituents of SOM are underexplored. In this chapter we present a protocol for the extraction of small molecule metabolites from soil followed by compound detection and identification using liquid chromatography mass spectrometry and gas chromatography-mass spectrometry. There are options within the protocol to assess either the extracellular pool of metabolites or the total pool (including intracellular) and either polar or nonpolar metabolites, depending on the reader's research interests. These methods can be followed individually for a more targeted analysis or all methods can be combined to obtain a more comprehensive understanding of SOM metabolite composition (such as amino acids, nucleobases, organic acids, fatty acids, carbohydrates, secondary metabolites, and antibiotics). PMID- 30421225 TI - Fatty Acid Metabolome Extraction from Mycobacterial Cells for GC-MS Metabolomics Analysis. AB - Metabolomics is becoming an increasingly popular research tool for identifying new biomarkers, which can, among other applications, be applied to elucidate various microbial growth and virulence mechanisms. Since the lipid composition of numerous microorganisms are unique and characteristic of the particular species, and in many instances also associated with several of their growth and virulence features, we developed a method for extracting the total free fatty acid metabolome from mycobacterial cells, in order to better characterize these using a gas chromatography-mass spectrometry (GC-MS) metabolomics approach. The described method can be considered an optimized Bligh-Dyer approach, since it uses the traditional solvents; chloroform, methanol and water, in a ratio of 1:2:1. However, due to the robust cell walls associated with mycobacteria, and many other microorganisms, the method was adapted to include a step which allows for the physical disruption of the cells using a vibration mill, which dramatically increases the efficiency of this approach. Hereafter, the organic phase is collected, dried, and methylated (as a derivatization step), prior to GC MS analyses. PMID- 30421226 TI - Total Metabolome Extraction from Mycobacterial Cells for GC-MS Metabolomics Analysis. AB - Over the past 10 years, the number of metabolomics based publications in the available scientific literature has exponentially grown, a large portion of which describing new biomarkers better elucidating microbial disease mechanisms and improved diagnostics and treatment thereof. Here, we describe a metabolomics method for extracting the total metabolome (all compounds present in the microbial cell irrespective of the compound class), for analysis in a single analytical run using only one analytical instrument. This method includes disruption of robust microbial cell walls, and the precipitation of proteins and cell debris using a combination of mechanical methods and solvents. These extracts are subsequently derivatized, in order to improve the volatility of polar compounds for efficient gas chromatography-mass spectrometry (GC-MS) analysis. This methodology can be applied to all microbes, including those with robust cell walls, such as M. tuberculosis. To date, the biomarkers identified using this approach have led to improved tuberculosis (TB) diagnostics, improved TB treatment approaches, and better understanding of host-microbe interactions and associated mycobacterial genomics. PMID- 30421227 TI - High-Throughput Solid-Phase Microextraction-Liquid Chromatography-Mass Spectrometry for Microbial Untargeted Metabolomics. AB - Nowadays, metabolomics data, when combined with other "omics" data, can provide important information regarding systems biology. Acquiring a comprehensive untargeted metabolome snapshot of complex sample matrices requires proper sample preparation, and access to sophisticated analytical instrumentation such as mass spectrometry. In metabolomics, sample preparation has substantial influence on the quality of the obtained metabolome profile. To achieve a real snapshot of the metabolome, the analysis method must be capable of inhibiting metabolite interconversion by immediately quenching all metabolome activity. Application of solid-phase microextraction (SPME), particularly in its in vivo set up, when undertaken in conjunction with a conscious selection of coating type based on the chosen sample matrix and the physicochemical properties of the analytes under study, is capable of providing extraction of representative metabolomes for many biological matrices. Metabolomes identified by SPME include low-abundance species and short-lived or unstable metabolites hardly captured by traditional extraction techniques. SPME coupled to liquid chromatography-high-resolution mass spectrometry has recently been introduced as an innovative alternative technique that integrates sampling, sample preparation, and extraction for metabolic profiling and isolation of candidate biomarkers. This chapter presents a detailed protocol for microbial metabolome analysis of Escherichia coli as a model organism, applying the high-throughput SPME-LC-MS workflow. PMID- 30421228 TI - Targeted Metabolomics of Xylose-Fermenting Yeasts Based on Mass Spectrometry. AB - Mass spectrometry is a sensitive and selective analytical technique that enables detection and quantitation of low abundance compounds in a complex sample matrix. Targeted metabolomics allows for quantitative analysis of metabolites, providing kinetic information of production and consumption rates, an essential step to investigate microbial metabolism. Here, we describe a targeted metabolomics protocol for yeast samples, from sample preparation to mass spectrometry analysis, which enables the identification of metabolic fluxes after xylose consumption. Sample preparation methods were optimized for quenching of yeast metabolism followed by intracellular metabolite extraction, using cold methanol and boiling ethanol protocols. Ultrahigh performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) methods using ion pair chromatography (IPC) and hydrophilic interaction liquid chromatography (HILIC) allowed for the quantitation of 18 metabolites involved in central carbon metabolism (glycolysis, pentose phosphate pathway, and tricarboxylic acid cycle). The protocol here described was successfully applied to quantify metabolites in Scheffersomyces stipitis, Spathaspora passalidarum, Spathaspora arborariae, and Candida tenuis samples after xylose consumption. PMID- 30421229 TI - Exploiting High-Resolution Mass Spectrometry for Targeted Metabolite Quantification and 13C-Labeling Metabolism Analysis. AB - Quantification of targeted metabolites, especially trace metabolites and structural isomers, in complex biological materials is an ongoing challenge for metabolomics. In this chapter, we summarize high-resolution mass spectrometry based approaches mainly used for targeted metabolite and metabolomics analysis, and then introduce an MS1/MS2-combined PRM workflow for quantification of central carbon metabolism intermediates, amino acids, and shikimate pathway-related metabolites. Major steps in the workflow, including cell culture, metabolite extraction, LC-MS analysis and data processing, are described. Furthermore, we adapt this new approach to a dynamic 13C-labeling experiment and demonstrate its unique advantage in capturing and correcting isotopomer labeling curves to facilitate nonstationary 13C-labeling metabolism analysis. PMID- 30421230 TI - Quantitative Profiling of Endogenous Metabolites Using Hydrophilic Interaction Liquid Chromatography-Tandem Mass Spectrometry (HILIC-MS/MS). AB - Dynamic modeling of metabolic reaction networks requires absolute quantification of intracellular and extracellular metabolite concentrations with high precision and accuracy. This chapter presents a robust HILIC-ESI-MS/MS procedure for targeted quantitative profiling of more than 50 polar key metabolites in multicomponent endogenous extracts. Without using ion-pairing-agents or prior derivatization protocols, organic acids, amino acids, sugar phosphates, coenzymes, and nucleotides are measured on a triple quadrupole platform in positive and negative electrospray ionization modes with preoptimized MRM transitions. Robust polymer-based zwitterionic stationary phases (ZIC(r)-pHILIC) support alkaline mobile phase conditions (pH 9.2) for enhancing retention and chromatographic performance of polar analytes in bicratic elution mode without unfavourable column bleed. The quality of the method was extensively validated and demonstrated by absolute metabolite quantification in endogenous Escherichia coli extracts by comparative use of standard-based external calibration, isotope dilution, and standard addition as quantification strategies. In sum, alkaline ZIC(r)-pHILIC chromatography emerged as an efficient approach providing high selectivity and sensitivity for comprehensive metabolic studies. PMID- 30421231 TI - Liquid Chromatography and Mass Spectrometry Analysis of Isoprenoid Intermediates in Escherichia coli. AB - Isoprenoids are a highly diverse group of natural products with broad application as high value chemicals and advanced biofuels. They are synthesized using two primary building blocks, namely, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) that are generated via the mevalonate (MVA) or deoxy-D xylulose-5-phosphate (DXP) pathways. Isoprenoid biosynthetic pathways are prevalent in eukaryotes, archaea, and bacteria. Measurement of isoprenoid intermediates via standard liquid chromatography-mass spectrometry (LC-MS) protocols is generally challenging because of the hydrophilicity and complex physicochemical properties of the molecules. In addition, there is currently no reliable analytical method that can simultaneously measure metabolic intermediates from MVA and DXP pathways, including the prenyl diphosphates. Therefore, we describe a robust hydrophilic interaction liquid chromatography time-of-flight mass spectrometry (HILIC-TOF-MS) method for analyzing isoprenoid intermediates from metabolically engineered Escherichia coli strains. PMID- 30421232 TI - Determining the Mode of Action of Antimalarial Drugs Using Time-Resolved LC-MS Based Metabolite Profiling. AB - Methods for assessing the mode of action of new antimalarial compounds identified in high throughput phenotypic screens are needed to triage and facilitate lead compound development and to anticipate potential resistance mechanisms that might emerge. Here we describe a mass spectrometry-based approach for detecting metabolic changes in asexual erythrocytic stages of Plasmodium falciparum induced by antimalarial compounds. Time-resolved or concentration-resolved measurements are used to discriminate between putative targets of the compound and nonspecific and/or downstream secondary metabolic effects. These protocols can also be coupled with 13C-stable-isotope tracing experiments under nonequilibrative (or nonstationary) conditions to measure metabolic dynamics following drug exposure. Time-resolved 13C-labeling studies greatly increase confidence in target assignment and provide a more comprehensive understanding of the metabolic perturbations induced by small molecule inhibitors. The protocol provides details on the experimental design, Plasmodium falciparum culture, sample preparation, analytical approaches, and data analysis used in either targeted (pathway focused) or untargeted (all detected metabolites) analysis of drug-induced metabolic perturbations. PMID- 30421233 TI - Use of Liquid Chromatography-Mass Spectrometry-Based Metabolomics to Identify Biomarkers of Tuberculosis. AB - Liquid chromatography-mass spectrometry (LC-MS) based metabolomics has proven to be a powerful analytical tool for biomarker screening. Here we describe two workflows which employ untargeted metabolomics to study serum biomarkers in tuberculosis patients. Expression profiles for samples of hydrophilic metabolites and hydrophobic metabolites (lipids) may be obtained by this method. PMID- 30421234 TI - Metabolomics Analysis of Leishmania by Capillary Electrophoresis and Mass Spectrometry. AB - Capillary electrophoresis coupled to mass spectrometry is an analytical platform ideal for the analysis of ionic or polar metabolites. It constitutes a perfect complement to reversed-phase liquid chromatography, offering a good alternative to polar stationary phases where reproducibility is not guaranteed. Herein, we describe a robust standardized methodology for the fingerprinting analysis of Leishmania, a taxonomic genus which comprises more than 20 protozoa species. PMID- 30421235 TI - A High-Throughput Targeted Metabolomics Workflow for the Detection of 200 Polar Metabolites in Central Carbon Metabolism. AB - Targeted metabolomics aims to analyze a set of pre-selected metabolites from biologically relevant metabolic pathways. The triple quadrupole mass spectrometry (QqQ-MS) based multiple reaction monitoring (MRM) technique is the most widely approach used for targeted metabolomics, and features high selectivity and sensitivity, good reproducibility and wide dynamic range in quantitative analysis. Here, we describe an MRM based targeted metabolomics workflow for the quantitative analysis of 200 polar metabolites in central carbon metabolic pathways, including the data acquisition method and the automated data processing procedures using our in-house R package MRMAnalyzer. The workflow described in this chapter combines a hydrophilic interaction liquid chromatography (HILIC) separation and positive/negative ion polarity switching based MS detection, and is able to acquire data from multiple types of biological samples such as bacteria, cultured mammalian cells, animal tissues and biofluids (e.g., serum and urine). Finally, the MRMAnalyzer software can automatically process the generated large-scale data set with high efficiency. We hope it is a valuable and efficient workflow for researchers to facilitate the respective biological studies using targeted metabolomics. PMID- 30421236 TI - Cluster Analysis of Untargeted Metabolomic Experiments. AB - Untargeted metabolite profiling based upon LC-MS methodology can be used to identify unique metabolic phenotypes associated with stress, disease or environmental exposure of cells using mathematical clustering. Here, we show how unsupervised data analysis is a powerful tool for both quality control and answering simple biological questions. We will demonstrate how to format untargeted mass spectrometry data for import into R, a programming language and software environment for statistical computing (R Development Core Team. R: A language and environment for statistical computing, reference index version 2.15. R Foundation for Statistical Computing, Vienna, 2012). Using R, we transform untargeted metabolite data using hierarchical clustering and principal component analysis (PCA) to create visual representations of change between biological samples and explore how these can be used predictively, in determining environmental stress, health and metabolic insight. PMID- 30421237 TI - Machine Learning in Untargeted Metabolomics Experiments. AB - Machine learning is a form of artificial intelligence (AI) that provides computers with the ability to learn generally without being explicitly programmed. Machine learning refers to the ability of computer programs to adapt when exposed to new data. Here we examine the use of machine learning for use with untargeted metabolomics data, when it is appropriate to use, and questions it can answer. We provide an example workflow for training and testing a simple binary classifier, a multiclass classifier and a support vector machine using the Waikato Environment for Knowledge Analysis (Weka), a toolkit for machine learning. This workflow should provide a framework for greater integration of machine learning with metabolomics study. PMID- 30421238 TI - Dynamic 13C Labeling of Fast Turnover Metabolites for Analysis of Metabolic Fluxes and Metabolite Channeling. AB - Dynamic or isotopically nonstationary 13C labeling experiments are a powerful tool not only for precise carbon flux quantification (e.g., metabolic flux analysis of photoautotrophic organisms) but also for the investigation of pathway bottlenecks, a cell's phenotype, and metabolite channeling. In general, isotopically nonstationary metabolic flux analysis requires three main components: (1) transient isotopic labeling experiments; (2) metabolite quenching and isotopomer analysis using LC-MS; (3) metabolic network construction and flux quantification. Labeling dynamics of key metabolites from 13C-pulse experiments allow flux estimation of key central pathways by solving ordinary differential equations to fit time-dependent isotopomer distribution data. Additionally, it is important to provide biomass requirements, carbon uptake rates, specific growth rates, and carbon excretion rates to properly and precisely balance the metabolic network. Labeling dynamics through cascade metabolites may also identify channeling phenomena in which metabolites are passed between enzymes without mixing with the bulk phase. In this chapter, we outline experimental protocols to probe metabolic pathways through dynamic labeling. We describe protocols for labeling experiments, metabolite quenching and extraction, LC-MS analysis, computational flux quantification, and metabolite channeling observations. PMID- 30421239 TI - Genome-Scale 13C Fluxomics Modeling for Metabolic Engineering of Saccharomyces cerevisiae. AB - Synthetic biology is a rapidly developing field that pursues the application of engineering principles and development approaches to biological engineering. Synthetic biology is poised to change the way biology is practiced, and has important practical applications: for example, building genetically engineered organisms to produce biofuels, medicines, and other chemicals. Traditionally, synthetic biology has focused on manipulating a few genes (e.g., in a single pathway or genetic circuit), but its combination with systems biology holds the promise of creating new cellular architectures and constructing complex biological systems from the ground up. Enabling this merge of synthetic and systems biology will require greater predictive capability for modeling the behavior of cellular systems, and more comprehensive data sets for building and calibrating these models. The so-called "-omics" data sets can now be generated via high throughput techniques in the form of genomic, proteomic, transcriptomic, and metabolomic information on the engineered biological system. Of particular interest with respect to the engineering of microbes capable of producing biofuels and other chemicals economically and at scale are metabolomic datasets, and their insights into intracellular metabolic fluxes. Metabolic fluxes provide a rapid and easy to understand picture of how carbon and energy flow throughout the cell. Here, we present a detailed guide to performing metabolic flux analysis and modeling using the open source JBEI Quantitative Metabolic Modeling (jQMM) library. This library allows the user to transform metabolomics data in the form of isotope labeling data from a 13C labeling experiment into a determination of cellular fluxes that can be used to develop genetic engineering strategies for metabolic engineering.The jQMM library presents a complete toolbox for performing a range of different tasks of interest in metabolic engineering. Various different types of flux analysis and modeling can be performed such as flux balance analysis, 13C metabolic flux analysis, and two-scale 13C metabolic flux analysis (2S-13C MFA). 2S-13C MFA is a novel method that determines genome-scale fluxes without the need of every single carbon transition in the metabolic network. In addition to several other capabilities, the jQMM library can make model based predictions for how various genetic engineering strategies can be incorporated toward bioengineering goals: it can predict the effects of reaction knockouts on metabolism using both the MoMA and ROOM methodologies. In this chapter, we will illustrate the use of the jQMM library through a step-by-step demonstration of flux determination and knockout prediction in a complex eukaryotic model organism: Saccharomyces cerevisiae (S. cerevisiae). Included with this chapter is a digital Jupyter Notebook file that provides a computable appendix showing a self-contained example of jQMM usage, which can be changed to fit the user's specific needs. As an open source software project, users can modify and extend the code base to make improvements at will, allowing them to share their development work and contribute back to the jQMM modeling community. PMID- 30421240 TI - Peak airway pressure is lower during pressure-controlled than during manual facemask ventilation for induction of anesthesia in pediatric patients-a randomized, clinical crossover trial. AB - PURPOSE: Facemask ventilation during the induction of general anesthesia in paediatric patients remains a challenge as it may result in hypoxic conditions and gastric insufflation with subsequent regurgitation and aspiration. So far, it is unclear if pressure-controlled or manual facemask ventilation is preferable in children. We hypothesized that pressure-controlled ventilation in apnoeic children results in lower peak airway pressure and flow rates compared to manual ventilation at comparable respiratory rates and tidal volumes. METHODS: Sixty-two lung-healthy children undergoing scheduled ear-nose-throat surgery were included in the study. After the induction of anesthesia, the patient's lungs were consecutively ventilated via a facemask in either manual or pressure-controlled mode, in randomized order. The primary outcome measure was peak airway pressure. Secondary outcome measures included positive end-expiratory pressure, airway compliance, tidal volume and airway flow. RESULTS: Data of 52 patients could be analyzed. Pressure-controlled ventilation resulted in a lower mean and peak inspiratory pressure (both p < 0.001), airway pressure amplitude (p = 0.01) and inspiratory peak flow rate (p = 0.005) compared to manual ventilation. The ratio of inspiration to expiration time was lower in pressure-controlled ventilation compared to manual ventilation (p < 0.001). CONCLUSION: Pressure-controlled facemask ventilation during induction of anesthesia in pediatric patients results in lower airway pressure, and lower flow rates compared to manual ventilation, at comparable tidal and minute volumes. PMID- 30421241 TI - Influence of Annual Meetings of the American Society of Anesthesiologists and of Large National Surgical Societies on Caseloads of Major Therapeutic Procedures. AB - Statistical methods to calculate the hours into which cases are scheduled, based on minimizing the inefficiency of use of anesthesia and/or operating room (OR) time, assure that anesthesiologists and OR nurses are available on each day to care for patients while infrequently working late. The method assumes that anesthesia staffing is planned based on the workload and not vice-versa. We used the American Society of Anesthesiologists (ASA) meeting to test the assumption across a large population. The observational study cohort was all 3,191,282 major therapeutic procedures performed during 2,517,842 cases at all 121 non-federal hospitals in the State of Iowa, 2007-16. The Fridays to Wednesdays of the annual ASA meetings were compared pairwise by year with those days of the other (mean = 43.0 [SE =0.3]) weeks without a federal holiday. Differences in counts of procedures (P = 0.45, 0.5% [0.7%]) and cases performed (P = 0.93, 0.1% [1.0%]) were not significant. In contrast, compared to non-meeting weeks, during the American College of Surgeons meeting, there were fewer general surgery procedures performed (P = 0.0009, -9.1% [1.9%]), fewer procedures performed of any type (P = 0.022, -2.1% [0.8]), and fewer cases of any type (P = 0.003, -2.5% [0.6%]). Similarly, during the American Academy of Orthopaedic Surgeons meeting, there were fewer joint arthroplasties performed (P < 0.0001, -27.1% [3.1%]), fewer procedures (P = 0.011, -6.3% [2.0%]), and fewer cases (P = 0.018, -5.9% [2.0%]). The results show that, in routine practice, anesthesia staffing and staff scheduling are being chosen to prevent the meeting from affecting patients' and surgeons' access to OR time. PMID- 30421242 TI - Inhibition of VDAC1 Protects Against Glutamate-Induced Oxytosis and Mitochondrial Fragmentation in Hippocampal HT22 Cells. AB - The involvement of glutamate in neuronal cell death in neurodegenerative diseases and neurotrauma is mediated through excitotoxicity or oxytosis. The latter process induces oxidative stress via glutamate-mediated inhibition of cysteine transporter xCT, leading to depletion of the cellular glutathione pool. Mitochondrial damage, loss of mitochondrial membrane potential (MMP), and depletion of energy metabolites have been shown in this process. The Voltage Dependent Anion Channel-1 (VDAC1) is one of the main components of the mitochondrial outer membrane and plays a gatekeeping role in mitochondria cytoplasm transport of metabolites. In this study, we explored the possible participation of VDAC-1 in the pathophysiology of oxytosis. Administration of glutamate in HT22 cells that lack the glutamate ionotropic receptors induced an upregulation and oligomerization of VDAC1. This was associated with an increase in ROS and loss of cell survival. Glutamate-mediated oxytosis in this model also decreased MMP and promoted ATP depletion, resulting in translocation of cytochrome c (cyt C) and apoptosis inducing factor (AIF) from mitochondria into the cytosol. This was also accompanied by cleavage of AIF to form truncated AIF. Inhibition of VDAC1 oligomerization using 4,4'-Diisothiocyanatostilbene-2,2' disulfonate (DIDS), significantly improved the cell survival, decreased the ROS levels, improved mitochondrial functions, and decreased the mitochondrial damage. Notably, DIDS also inhibited the mitochondrial fragmentation caused by glutamate, indicating the active role of VDAC1 oligomerization in the process of mitochondrial fragmentation in oxytosis. These results suggest a critical role for VDAC1 in mitochondrial fragmentation and its potential therapeutic value against glutamate-mediated oxidative neurotoxicity. PMID- 30421243 TI - Bioremediation of tannery effluent by Cr- and salt-tolerant bacterial strains. AB - Microorganisms have great potential to control environmental pollution, particularly industrial sources of water pollution. Currently, leather industry is regarded as the most polluting and suffering from negative impacts due to the pollution it adds to the environment. Chromium, one of the hazardous pollutants discharged from tanneries, is highly toxic and carcinogenic in nature. Effective treatment of tannery effluent is a dire need of the era as a part of environmental management. Among all the wastewater treatment technologies, bioremediation is the most effective and environment-friendly tool to manage the water pollution. The present study evaluated the potential of 11 previously isolated bacterial strains, tolerant to high concentrations of salts and Cr for the bioremediation of tannery effluent. Among all the tested strains, Enterobacter sp. HU38, Microbacterium arborescens HU33, and Pantoea stewartii ASI11 were found most effective in reducing biological oxygen demand (BOD), chemical oxygen demand (COD), total dissolved solids (TDS), total suspended solids (TSS), and chromium (Cr) 70, 63, 57, 87, and 54%, respectively, of tannery effluent and proliferated well under highly toxic conditions, at 9 days of incubation. The pollutant removal efficacy of these bacterial strains can be improved by extending the incubation period or by increasing the amount of inoculum. PMID- 30421244 TI - Differential effects of vestibular processing on orienting exogenous and endogenous covert visual attention. AB - Recent research highlights the overwhelming role of vestibular information for higher order cognition. Central to body perception, vestibular cues provide information about self-location in space, self-motion versus object motion, and modulate the perception of space. Surprisingly, however, little research has dealt with how vestibular information combines with other senses to orient one's attention in space. Here we used passive whole body rotations as exogenous (Experiment 1) or endogenous (Experiment 2) attentional cues and studied their effects on orienting visual attention in a classical Posner paradigm. We show that-when employed as an exogenous stimulus-rotation impacts attention orienting only immediately after vestibular stimulation onset. However, when acting as an endogenous stimulus, vestibular stimulation provides a robust benefit to target detection throughout the rotation profile. Our data also demonstrate that vestibular stimulation boosts attentional processing more generally, independent of rotation direction, associated with a general improvement in performance. These data provide evidence for distinct effects of vestibular processing on endogenous and exogenous attention as well as alertness that differ with respect to the temporal dynamics of the motion profile. These data reveal that attentional spatial processing and spatial body perception as manipulated through vestibular stimulation share important brain mechanisms. PMID- 30421245 TI - Correction to: Discovery and Identification of an Endogenous Metabolite of Tramiprosate and Its Prodrug ALZ-801 that Inhibits Beta Amyloid Oligomer Formation in the Human Brain. AB - Page 856: Fig. 6 was an incorrect duplication of Fig. 5. The correct figure is given below. PMID- 30421246 TI - Trigonelline protects hippocampus against intracerebral Abeta(1-40) as a model of Alzheimer's disease in the rat: insights into underlying mechanisms. AB - Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most common phenotype of dementia. Trigonelline is an alkaloid found in medicinal plants such as fenugreek seeds and coffee beans with neuroprotective potential and according to existing evidences, a favorable agent for treatment of neurodegenerative disorders. In this study, the possible protective effect of trigonelline against intracerebral Abeta(1-40) as a model of AD in the rat was investigated. For induction of AD, aggregated A(1-40) (10 MUg/2 ?l for each side) was bilaterally microinjected into the hippocampal CA1 area. Trigonelline was administered p.o. at a dose of 100 mg/kg. The results showed that trigonelline pretreatment of Abeta-microinjected rats significantly improves spatial recognition memory in Y maze and performance in novel object recognition (NOR) task, mitigates hippocampal malondialdehyde (MDA), protein carbonyl, lactate dehydrogenase (LDH), and improves mitochondrial membrane potential (MMP), glutathione (GSH), and superoxide dismutase (SOD) with no significant change of catalase activity, nitrite level, caspase 3 activity, and DNA fragmentation. Additionally, trigonelline ameliorated hippocampal levels of glial fibrillary acidic protein (GFAP), S100b, cyclooxygenase 2 (Cox2), tumor necrosis factor alpha (TNFalpha), and interleukin 6 (IL-6) with no significant alteration of inducible nitric oxide synthase (iNOS). In addition, trigonelline pretreatment prevented loss of hippocampal CA1 neurons in Abeta-microinjected group. Therefore, our results suggest that trigonelline pretreatment in Abeta model of AD could improve cognition and is capable to alleviate neuronal loss through suppressing oxidative stress, astrocyte activity, and inflammation and also through preservation of mitochondrial integrity. PMID- 30421247 TI - Preclinical 19F MRI cell tracking at 3 Tesla. AB - PURPOSE: To develop methods for fluorine-19 (19F) MRI cell tracking in mice on a 3 Tesla clinical scanner. Compared to iron-based cell tracking, 19F MRI has lower sensitivity and, consequently, preclinical 19F cell tracking has only been performed at relatively high magnetic field strengths (> 3 T). Here, we focus on using 19F MRI to detect macrophages in tumors; macrophage density is an indication of tumor aggressiveness and, therefore, 19F MRI could be used as an imaging biomarker. METHODS: Perfluorocarbon (PFC)-labeled macrophages were imaged at 3 T and NMR spectroscopy was performed to validate 19F spin quantification. In vivo 19F MRI was performed on tumor-bearing mice, post-PFC at both 9.4 T and 3 T. 3 T MRI utilized varying NEX and 19F images were analyzed two different ways for 19F quantification. RESULTS: As few as 25,000 cells could be detected as cell pellets at 3 T. 19F quantification in cell pellets by 3 T MRI agreed with NMR spectroscopy. 19F signal was observed in the liver, spleen and tumor in all mice at 9.4 T and 3 T and there was no significant difference in 19F spin quantification. CONCLUSION: This study demonstrates the ability to detect and quantify 19F signal in murine tumors using 19F MRI at 3 T. PMID- 30421248 TI - In vivo 19F MR inflammation imaging after myocardial infarction in a large animal model at 3 T. AB - OBJECTIVES: Fluorine-19 (19F) MRI with intravenously applied perfluorocarbons allows the in vivo monitoring of infiltrating immune cells as demonstrated in small animal models at high field. Here, we aimed to transfer this approach to a clinical scanner for detection of inflammatory processes in the heart after acute myocardial infarction (AMI) in a large animal model. MATERIALS AND METHODS: Optimization of coil and sequence performance was carried out on phantoms and in vivo at a 3 T Philips Achieva. AMI was induced in Munich mini pigs by 90-min occlusion of the left anterior descending artery. At day 3 after AMI, pigs received a body weight-adjusted intravenous dose of a perfluorooctyl bromide nanoemulsion followed by 1H/19F MRI at day 6 after AMI. RESULTS: A balanced steady-state free precession turbo gradient echo sequence using an ellipsoidal 19F/1H surface coil provided the best signal-to-noise ratio and a superior localization of 19F patterns in vivo. This approach allowed the reliable detection of 19F signals in the injured myocardium within less than 20 min. The 19F signal magnitude correlated significantly with the functional impairment after AMI. CONCLUSION: This study demonstrates the feasibility of in vivo 19F MR inflammation imaging after AMI at 3 T within a clinically acceptable acquisition time. PMID- 30421249 TI - Longitudinal 19F magnetic resonance imaging of brain oxygenation in a mouse model of vascular cognitive impairment using a cryogenic radiofrequency coil. AB - INTRODUCTION: We explored the use of a perfluoro-15-crown-5 ether nanoemulsion (PFC) for measuring tissue oxygenation using a mouse model of vascular cognitive impairment. METHODS: Seventeen C57BL/6 mice underwent stereotactic injection of PFC coupled to a fluorophore into the striatum and corpus callosum. Combined 1H/19F magnetic resonance imaging (MRI) to localize the PFC and R1 mapping to assess pO2 were performed. The effect of gas challenges on measured R1 was investigated. All mice then underwent bilateral implantation of microcoils around the common carotid arteries to induce global cerebral hypoperfusion. 19F-MRI and R1 mapping were performed 1 day, 1 week, and 4 weeks after microcoil implantation. In vivo R1 values were converted to pO2 through in vitro calibration. Tissue reaction to the PFC was assessed through ex vivo immunohistochemistry of microglial infiltration. RESULTS: R1 increased with increasing oxygen concentrations both in vitro and in vivo and the strength of the 19F signal remained largely stable over 4 weeks. In the two mice that received all four scans, tissue pO2 decreased after microcoil implantation and recovered 4 weeks later. We observed infiltration of the PFC deposits by microglia. DISCUSSION: Despite remaining technical challenges, intracerebrally injected PFC is suitable for monitoring brain oxygenation in vivo. PMID- 30421250 TI - Fluorine-19 MRI at 21.1 T: enhanced spin-lattice relaxation of perfluoro-15-crown 5-ether and sensitivity as demonstrated in ex vivo murine neuroinflammation. AB - OBJECTIVE: Fluorine MR would benefit greatly from enhancements in signal-to-noise ratio (SNR). This study examines the sensitivity gain of 19F MR that can be practically achieved when moving from 9.4 to 21.1 T. MATERIALS AND METHODS: We studied perfluoro-15-crown-5-ether (PFCE) at both field strengths (B0), as a pure compound, in the form of nanoparticles (NP) as employed to study inflammation in vivo, as well as in inflamed tissue. Brains, lymph nodes (LNs) and spleens were obtained from mice with experimental autoimmune encephalomyelitis (EAE) that had been administered PFCE NPs. All samples were measured at both B0 with 2D-RARE and 2D-FLASH using 19F volume radiofrequency resonators together. T1 and T2 of PFCE were measured at both B0 strengths. RESULTS: Compared to 9.4 T, an SNR gain of > 3 was observed for pure PFCE and > 2 for PFCE NPs at 21.1 T using 2D-FLASH. A dependency of 19F T1 and T2 relaxation on B0 was demonstrated. High spatially resolved 19F MRI of EAE brains and LNs at 21.1 T revealed signals not seen at 9.4 T. DISCUSSION: Enhanced SNR and T1 shortening indicate the potential benefit of in vivo 19F MR at higher B0 to study inflammatory processes with greater detail. PMID- 30421251 TI - Early identification of first-year students at risk of dropping out of high school entry medical school: the usefulness of teachers' ratings of class participation. AB - Dropping out from undergraduate medical education is costly for students, medical schools, and society in general. Therefore, the early identification of potential dropout students is important. The contribution of personal features to dropout rates has merited exploration. However, there is a paucity of research on aspects of student experience that may lead to dropping out. In this study, underpinned by theoretical models of student commitment, involvement, and engagement, we explored the hypothesis of using inferior participation as an indicator of a higher probability of dropping out in year 1. Class participation was calculated as an aggregate score based on teachers' daily observations in class. The study used a longitudinal dataset of six cohorts of high-school entry students (N = 709, 67% females) in one medical school with an annual intake of 120 students. The findings confirmed the initial hypothesis and showed that lower scores of class participation in year 1 added predictive ability to pre-entry characteristics (Pseudo-R2 raised from 0.22 to 0.28). Even though the inclusion of course failure in year 1 resulted in higher explanatory power than participation in class (Pseudo-R2 raised from 0.28 to 0.63), ratings of class participation may be advantageous to anticipate dropout identification, as those can be collected prior to course failure. The implications for practice are that teachers' ratings of class participation can play a role in indicating medical students who may eventually drop out. We conclude that the scores of class participation can contribute to flagging systems for the early detection of student dropouts. PMID- 30421252 TI - The 10 signs telling me that my cancer patient in the emergency department is at high risk of becoming critically ill. PMID- 30421253 TI - Obstructive renal failure as a complication of anticoagulant therapy. PMID- 30421255 TI - Future of the ICU: finding treatable needles in the data haystack. PMID- 30421254 TI - Post-intubation tracheal laceration. PMID- 30421256 TI - Timing of onset of persistent critical illness: a multi-centre retrospective cohort study. AB - PURPOSE: Persistent critical illness has been described as a subtype of chronic critical illness, characterized as a transition after ICU admission where primary diagnosis and illness acuity are no better at predicting outcome than pre hospital characteristics. Herein we describe the occurrence and outcomes associated with persistent critical illness in a large Canadian health region. METHODS: In this multi-center observational cohort study, all patients aged older than 14 years admitted to 12 ICUs in Alberta, Canada, between June 2012 and December 2014 were included. Primary outcome was in-hospital mortality. Predictors at ICU admission were separated into: (1) antecedent characteristics component (e.g., demographics, chronic health component of the APACHE II score, comorbid conditions); and (2) acute illness component (e.g., APACHE II score at admission, SOFA score, primary diagnostic category, surgical status, acute organ support). Using multiple statistical methods and randomly splitting the cohort into development and validation samples for risk scoring using logistic regression, we examined mortality prediction of each of these components to characterize the timing of transition to persistent critical illness. RESULTS: We included 17,783 patients with a median (IQR) age 61 years (49-71), 62% were male, and mean APACHE II score was 19.0 (7.9). In-hospital mortality was 16.8%. Among patients alive and in ICU, the acute illness component, which accurately predicted outcome at the time of admission [area under the receiver operating characteristics curve (AUC) 0.861; 95% CI 0.860-0.862], progressively lost predictive ability and was no longer more predictive than antecedent characteristics after 9 days. This transition defined the onset of persistent critical illness and comprised 16.1% (n = 2856) of the cohort. Transition ranged between 5 and 21 days across subgroups. In-hospital mortality was greater for those with persistent critical illness [23.9% vs. 15.5%, odds ratio (OR) 1.54; 95% CI 1.43-1.67, p < 0.001]. Persistently critically ill patients accounted for 54.5% of 97844 ICU bed-days and 36.3% of 420119 hospital bed-days, respectively. CONCLUSIONS: Persistent critical illness occurred in one in six patients admitted to Alberta ICUs and portended greater risk of death, prolonged ICU and hospital stay, and disproportionate use of health resources compared to patients without persistent critical illness. PMID- 30421257 TI - Relationship between height and outcomes among critically ill adults: a cohort study. AB - PURPOSE: Many diagnostic and therapeutic interventions for critically ill adult patients are not performed according to patient size, but are standardized for an idealized 174-cm man (ideal body weight 70 kg). This study aims to determine whether critically ill patients with heights significantly different from a standardized patient have higher hospital mortality or greater resource utilization. METHODS: Retrospective cohort study of consecutive patients admitted to 210 intensive care units (ICUs) in the United Kingdom participating in the Intensive Care National Audit and Research Centre's Case Mix Programme Database from April 1, 2009, to March 31, 2015. Primary outcome was hospital mortality, adjusted for age, comorbid disease, severity of illness, socioeconomic status and body mass index, using hierarchical modeling to account for clustering by ICU. Data were stratified by sex, and the effect of height was modeled continuously using restricted cubic splines. RESULTS: The cohort included 233,308 men and 184,070 women, with overall hospital mortality of 22.5% and 20.6%, respectively. After adjustment for potential confounders, hospital mortality decreased with increasing height; predicted mortality (holding all other covariates at their mean value) decreased from 24.1 to 17.1% for women and from 29.2 to 21.0% for men across the range of heights. Similar patterns were observed for ICU mortality and several additional secondary outcomes. CONCLUSIONS: Short stature may be a risk factor for mortality in critically ill patients. Further work is needed to determine which unmeasured patient characteristics and processes of care may contribute to the increased risk observed. PMID- 30421258 TI - Oxygen and carbon dioxide targets during and after resuscitation of cardiac arrest patients. PMID- 30421260 TI - Surgical Management of Lung Cancer: History, Evolution, and Modern Advances. AB - PURPOSE OF REVIEW: Although surgery for lung cancer was not common before the early twentieth century, it has enjoyed remarkable progress since then both in type of resection and technical approach. This has been coupled with significant technological advances. Here, we will review the history and evolution of this relatively new field of surgery. RECENT FINDINGS: The gold standard of the extent of resection for lung cancer evolved from pneumonectomy to lobectomy to even sublobar resection for select situations. In addition, major advances have occurred in the technical aspect of the surgical procedure. The incisional approach has evolved from rib spreading thoracotomy to thoracoscopic surgery with the latter showing significant improvement in short-term outcomes over open thoracotomy. However, standard video-assisted thoracoscopic surgery or VATS is associated with visual and mechanical limitations, including lack of depth perception and rigid straight instruments. This makes it appropriate only for early-stage peripheral and small tumors. Most of the limitations of VATS can be overcome with the more recently introduced robotic-assisted thoracic surgery (RATS). RATS utilizes wristed instruments that are introduced in the chest through 8-mm ports and can mimic the movements of the human hand. In addition, magnified, three-dimensional and high definition imaging gives the surgeon an image of the lung unlike any other modality. This has allowed surgeons to perform advanced resections such as pneumonectomy or sleeve resection in a minimally invasive fashion. In addition, RATS has become a platform for the addition of other technical enhancements such as incorporating a near infra-red light source into the camera allowing identification of autoflourescent agents, such as indocyanin green. This has allowed localization of small nodules for resection and identification of tissue planes for sublobar resection. However, new technologies also require investments in time and money. Thoracic surgery for lung cancer has evolved to include advanced minimally invasive techniques including video-assisted and robotic-assisted thoracoscopy. RATS in particular may enable surgeons to perform more advanced procedures in a minimally invasive fashion. It is hoped that the higher costs of new surgical technology may be offset by the potential for improved patient outcomes and resultant socioeconomic benefits. PMID- 30421261 TI - Peritoneal dialysis patient having fish bone-induced colon perforation. PMID- 30421262 TI - Fluid dynamic assessment of tracheal flow in infants with congenital tracheal stenosis before and after surgery. AB - Tracheal flow in infants with congenital tracheal stenosis (CTS) was numerically investigated using subject-specific airway models before and after reconstructive surgery. We quantified tracheal flow based on airway resistance during inhalation, and compared it between controls and patients before and after surgery. The airway resistance in each subject was assessed using geometrical parameters of the trachea: the minimum cross-sectional area Amin, the minimum cross-sectional area normalized by the standard deviation of the cross-sectional area Amin/sigmaA, the area ratio of the minimum and maximum cross-sectional area Amin/Amax, and ratio of the normalized standard deviation of cross-sectional area to the mean cross-sectional area sigmaA/Amean. Our numerical results demonstrated that such geometrical parameters could be used to assess the severity of CTS. Since subjects can be more clearly categorized as controls and most preoperative patients in terms of the airway resistance, a simulation using subject-specific airway models can lead us to a precise understanding of tracheal flow, and also provide knowledge about therapeutic decision. Our numerical results also demonstrated that significant surgical expansion of cross-sectional area did not help recover tracheal flow because of expansion loss. These results will be helpful not only when making therapeutic decisions about surgery but also when assessing quality of life in postoperative patients. Graphical abstract ?. PMID- 30421264 TI - Clinical and economic impact of surgery for treating infantile hemangiomas in the era of propranolol: overview of single-center experience from La Paz Hospital, Madrid. AB - Propranolol has changed the management of infantile hemangiomas (IHs). We summarize the evolution of surgical treatment for IH at La Paz Children's Hospital (Madrid) in the era of propranolol, with a focus on hepatic IHs.Retrospectively, we compared surgical treatment of IHs in children referred during the periods 2004-2009 and 2009-2014. Hepatic IH mortality rates before and after the introduction of propranolol therapy were evaluated specifically.The majority of hemangiomas needing surgical excision were located on the head/face/scalp of female patients. Since the introduction of propranolol therapy, surgery for IH has decreased from about 60 to 6 procedures/year at our institution and no transplants for hepatic IH have been registered.Conclusions: Surgical procedures for IH have decreased by about 90% at our institution since the introduction of propranolol treatment and hepatic IH have not needed liver transplantation. Referrals for surgery for IH are generally the consequence of absent or delayed propranolol treatment. Given the significant reduction in the number of surgical procedures, propranolol can be considered as having a strong economic and social impact. What is Known: * The use of oral propranolol solution is currently considered as the treatment of choice in the management of infantile hemangiomas. * Propranolol treatment achieves better outcomes and less side effects than systemic corticosteroids. What is New: * Social and financial impact of the significant reduction in the number of reconstructive surgical procedures and liver transplants due to the use of propranolol in tertiary health institutions remains to be analyzed. PMID- 30421263 TI - Fluorescent Neoglycoprotein Gold Nanoclusters: Synthesis and Applications in Plant Lectin Sensing and Cell Imaging. AB - Carbohydrate-protein interactions mediate fundamental biological processes, such as fertilization, cell signaling, or host-pathogen communication. However, because of the enormous complexity of glycan recognition events, new tools enabling their analysis or applications emerge in recent years. Here, we describe the first preparation of neoglycoprotein functionalized fluorescent gold nanoclusters, containing a biantennary N-glycan G0 as targeting molecule, ovalbumin as carrier/model antigen, and a fluorescent gold core as imaging probe (G0-OVA-AuNCs). Subsequently, we demonstrate the utility of generated G0-OVA AuNCs for specific sensing of plant lectins and in vitro imaging of dendritic cells. PMID- 30421265 TI - Clinical recovery in children with uncomplicated appendicitis undergoing non operative treatment: secondary analysis of a prospective cohort study. AB - Non-operative treatment of uncomplicated appendicitis in children is gaining ground. Pending definitive evidence regarding its effectiveness, there is a call to evaluate clinical recovery after non-operative treatment. In this study, we analyzed data collected during initial admission of a multicenter prospective cohort in which children, 7-17 year, were treated non-operatively for uncomplicated appendicitis. During admission clinical parameters (pain and gastro intestinal symptoms), inflammation parameters and sequential abdominal ultrasound were recorded. In total, 45 children were included, 42(93%) were discharged without the need for appendectomy; median [IQR] pain scores on admission were 5 [4-7], decreasing to 2 [0-3] after 1 day of treatment. Initially, 28/42 (67%) reported nausea and 19/42 (45%) vomiting; after 1 day, this was 3/42 (7%) and 1/42 (2%), respectively. White blood cell count declined from a median [IQR] of 12.9 [10.7-16.7] 10E9/L on admission to 7.0 [5.8-9.9] 10E9/L on day 1. Median [IQR] C-reactive protein levels increased from 27.5 [9-69] mg/L on admission to 48 [22-80] mg/L on day 1, declining to 21.5 [11-42] mg/L on day 2. Follow-up ultrasound showed no signs of complicated appendicitis in any of the patients.Conclusion: Clinical symptoms resolved in most children after 1 day of non-operative treatment. This suggests that non-operative treatment is a viable alternative to appendectomy regarding clinical recovery.Trail registration: NCT01356641 What is Known: * Non-operative treatment of uncomplicated appendicitis in children is safe and its use around the world is gaining ground, however high quality evidence from adequately designed randomized trials is still lacking. * Concerns have been raised regarding the potentially prolonged clinical recovery associated with non-operative treatment. What is New: * Most clinical symptoms resolve after 1 day of non-operative treatment in the majority of children. PMID- 30421266 TI - Preventing Chronic Emotional Distress in Stroke Survivors and Their Informal Caregivers. AB - BACKGROUND/OBJECTIVE: Chronic emotional distress (e.g., depression, anxiety, post traumatic stress) is common after stroke and interdependent between patients and their informal caregivers. We measured stroke survivors', caregivers', and neurocritical care nurses' views of primary drivers of distress during the stroke experience, and needs and preferences for the structure, topics, mode of delivery, and timing of an intervention to promote emotional recovery. METHODS: We conducted semi-structured interviews with 24 patient-caregiver dyads within the Neuroscience Intensive Care Unit (Neuro-ICU). Additionally, we conducted two focus groups with 15 nurses. Interviews and focus groups were audio-recorded, transcribed, and coded using NVivo 11 (QSR International) software. RESULTS AND CONCLUSIONS: The challenges and impacts of stroke most commonly reported by dyads were: uncertainty about future health, fear of recurrent strokes, negative emotions, and role changes post-stroke. Dyads and nurses agreed that resiliency skills such as mindfulness/focusing on the present, problem solving, gratitude/optimism, self-care, interpersonal communication and developing a supportive team of family, friends, and medical staff are beneficial to optimize recovery. The potential barrier to intervention delivery was accessibility, due to challenges of time and travel to appointments. Participants agreed that starting the intervention at hospitalization and continuing via live video after discharge is an ideal delivery modality. Stroke survivors, caregivers, and Neuro ICU nurses believe that a resiliency skills-based intervention to prevent chronic emotional distress is necessary and urgent. This qualitative study provides valuable information on the challenges faced by dyads, intervention topics to prioritize, and strategies to maximize feasibility, acceptability, and effect. PMID- 30421268 TI - The Effect of Religion Intervention on Life Satisfaction and Depression in Elderly with Heart Failure. AB - The elderly suffering from heart failure is facing with some problems such as lowering of life satisfaction and depression. Regarding a lack of information in this issue, the current study was conducted to determine the effect of religion intervention on life satisfaction and depression in the elderly with heart failure, in Ilam-Iran. In a clinical trial study conducted on the elderly with heart failure disease in Ilam-Iran, the patients were randomly allocated into two experimental (46) and control (47) groups. The used instruments were a demographic checklist, life satisfaction questionnaire of LSI-Z and Beck depression inventory. The intervention done for test group was a religion spiritual program designed based on the Richards and Bergin model, and according to Islam and Shia regulations and conducted during six sessions, each 30-45 min. The tools were completed before and after intervention. Gathered data were entered into SPSS software and analyzed by descriptive (mean and standard deviation) and inferential (independent t test and ANOVA) statistics. The results showed that there was no significant difference between the mean (SD) of life satisfaction in the experimental group [5.47 (3.37)] and control [5.85 (3.92)] before the intervention (P = 0.62) but after the intervention. The mean (SD) of life satisfaction of the test group [8.08 (4.36)] was higher than that of the control group [5.55 (3.96)] (P = 0.006). Also, no significant difference between the mean (SD) of depression in the experimental group [47.80 (10.48)] and control [49.87 (11.40)] before the intervention (P = 0.62) but after the intervention. The mean (SD) of depression of the test group [28.28 (14.78)] was lower than that of the control group [50.44 (14.02)] (P = 0.006). Regarding the positive effect of religion-spiritual program in depression and life satisfaction of the elderly with heart failure, it is suggested this program will be educated to these patients by health-care workers. PMID- 30421267 TI - Vascular Genetics: Presentations, Testing, and Prognostics. AB - PURPOSE OF REVIEW: Numerous studies have begun to unravel the genetic basis of not only aortic disease but also other forms of commonly encountered vascular diseases. The goal of this review is to provide clinicians a reference to help identify and diagnose different types of vascular disease with a genetic underpinning. RECENT FINDINGS: Ongoing studies have identified numerous genes involved in the TGF-beta signaling pathway that are also associated with thoracic aortic aneurysm and dissection, and it is possible to test for pathogenic variants in these genes in the clinical setting using commercially available genetic testing panels. Additional studies have begun to identify genetic variants associated with an increased risk of bicuspid aortic valve, abdominal aortic aneurysm, and fibromuscular dysplasia. With increased availability of low cost genetic testing, clinicians are now able to not only definitively diagnose some vascular syndromes but also provide information on the risk of disease in other family members, as well as provide guidance in terms of family planning. As the cost of genetic testing continues to drop with the benefit of increasing insurance coverage, genetic data will increasingly become part of clinical care for many patients with vascular disease. PMID- 30421269 TI - BET bromodomain inhibitors: fragment-based in silico design using multi-target QSAR models. AB - Epigenetics has become a focus of interest in drug discovery. In this sense, bromodomain-containing proteins have emerged as potential epigenetic targets in cancer research and other therapeutic areas. Several computational approaches have been applied to the prediction of bromodomain inhibitors. Nevertheless, such approaches have several drawbacks such as the fact that they predict activity against only one bromodomain-containing protein, using structurally related compounds. Also, there are no reports focused on meaningfully analyzing the physicochemical/structural features that are necessary for the design of a bromodomain inhibitor. This work describes the development of two different multi target models based on quantitative structure-activity relationships (mt-QSAR) for the prediction and in silico design of multi-target bromodomain inhibitors against the proteins BRD2, BRD3, and BRD4. The first model relied on linear discriminant analysis (LDA) while the second focused on artificial neural networks. Both models exhibited accuracies higher than 85% in the dataset. Several molecular fragments were extracted, and their contributions to the inhibitory activity against the three BET proteins were calculated by the LDA model. Six molecules were designed by assembling the fragments with positive contributions, and they were predicted as multi-target BET bromodomain inhibitors by the two mt-QSAR models. Molecular docking calculations converged with the predictions performed by the mt-QSAR models, suggesting that the designed molecules can exhibit potent activity against the three BET proteins. These molecules complied with the Lipinski's rule of five. PMID- 30421270 TI - Invited commentary: advantages and cautions for developing valid prognostic models of simultaneous pancreas and kidney transplantation outcomes. PMID- 30421272 TI - Reliability of cartilage digestion and FDA-EB fluorescence staining for the detection of chondrocyte viability in osteochondral grafts; statistical issue to avoid misdiagnosis and misinterpretation. PMID- 30421271 TI - Independent Component Analysis and Graph Theoretical Analysis in Patients with Narcolepsy. AB - The present study was aimed to evaluate resting-state functional connectivity and topological properties of brain networks in narcolepsy patients compared with healthy controls. Resting-state fMRI was performed in 26 adult narcolepsy patients and 30 matched healthy controls. MRI data were first analyzed by group independent component analysis, then a graph theoretical method was applied to evaluate the topological properties in the whole brain. Small-world network parameters and nodal topological properties were measured. Altered topological properties in brain areas between groups were selected as region-of-interest seeds, then the functional connectivity among these seeds was compared between groups. Partial correlation analysis was performed to evaluate the relationship between the severity of sleepiness and functional connectivity or topological properties in the narcolepsy patients. Twenty-one independent components out of 48 were obtained. Compared with healthy controls, the narcolepsy patients exhibited significantly decreased functional connectivity within the executive and salience networks, along with increased functional connectivity in the bilateral frontal lobes within the executive network. There were no differences in small-world network properties between patients and controls. The altered brain areas in nodal topological properties between groups were mainly in the inferior frontal cortex, basal ganglia, anterior cingulate, sensory cortex, supplementary motor cortex, and visual cortex. In the partial correlation analysis, nodal topological properties in the putamen, anterior cingulate, and sensory cortex as well as functional connectivity between these regions were correlated with the severity of sleepiness (sleep latency, REM sleep latency, and Epworth sleepiness score) among narcolepsy patients. Altered connectivity within the executive and salience networks was found in narcolepsy patients. Functional connection changes between the left frontal cortex and left caudate nucleus may be one of the parameters describing the severity of narcolepsy. Changes in the nodal topological properties in the left putamen and left posterior cingulate, changes in functional connectivity between the left supplementary motor area and right occipital as well as in functional connectivity between the left anterior cingulate gyrus and bilateral postcentral gyrus can be considered as a specific indicator for evaluating the severity of narcolepsy. PMID- 30421273 TI - Stem cell banking: Are South Indian mothers aware? AB - Umbilical cord blood (UCB) is an important source of stem cells, the heart of regenerative medicine. As the globalization and population of the world continues to increase, we are faced with an inundation of new diseases, affecting millions of people. Research work considering stem cells is essential for developing therapy for various conditions. Reduced availability of UCB serves as a hindrance to promote further research. Hence, India being one of the most densely populated countries in the world, can be considered a potential UCB repository. In this study 428 mothers of children born in the period from 2012 to 2017 were asked to fill questionnaires that evaluated their awareness regarding stem cell banking. This investigation deliberates if expectant mothers in this region are aware of stem cell banking and if there is a significant pattern regarding awareness based on parameters like age, educational qualification, locality, annual income and consulted hospitals. Although, majority of the women were unaware of this facility, knowledge was heightened in wealthy, educated, women from urban areas who consulted private hospitals. Hence, great efforts need to be made to further the awareness of expectant mothers in South India regarding UCB storage and donation. PMID- 30421274 TI - Home-Based Treatment with Immunoglobulins: an Evaluation from the Perspective of Patients and Healthcare Professionals. AB - PURPOSE: This study aims to evaluate home-based treatment with immunoglobulin (IgG) by assessing and comparing the experiences and perceived value of patients and healthcare professionals, and potential differences in experiences between subcutaneous (SCIg) and intravenous (IVIg) modes of administration. As choices on the location and type of treatment are determined in a shared decision-making process, we evaluated the home-based treatment from the perspectives of both patients and professionals. METHODS: A questionnaire study was conducted among 205 patients, 44 informal caregivers, 43 hospital professionals, and 21 nurses of the Sanquin Home Service (SHS) that provides home treatment with immunoglobulins in the Netherlands. Experiences, perceived benefits, and effects on the patients' quality of life and overall ratings were assessed. RESULTS: Both patients and professionals were predominantly positive about the home treatment, irrespective of the administration mode. The home-based treatment with Ig contributed to the patients' autonomy, participation, and perceived health. Patients and informal caregivers valued the treatment with a global rating of 8.84, and professionals with 8.32 (on a scale from 0 "worst" to 10 "best possible care"). SCIg and IVIg patient groups differed in their experiences regarding the accessibility and communication of the home treatment service. Furthermore, hospital professionals reported lower effects on quality of life than patients themselves. CONCLUSIONS: Home-based treatment with immunoglobulins is highly valued because of its personalized and effective character, meeting the needs and preferences of patients. Nonetheless, patients and professionals do have different perspectives on the value of this type of care. PMID- 30421275 TI - The Pollard lab at Salk: moving the leading edge forward. AB - This essay will review the years that the Pollard lab was at the Salk Institute in the last half of the 1990s. It was a highly productive time both in research and in training. For me personally, it shaped my career for the better in ways I am still discovering. PMID- 30421276 TI - "Essentially, all models are wrong, but some are useful"-a cross-disciplinary agenda for building useful models in cell biology and biophysics. AB - Intuition alone often fails to decipher the mechanisms underlying the experimental data in Cell Biology and Biophysics, and mathematical modeling has become a critical tool in these fields. However, mathematical modeling is not as widespread as it could be, because experimentalists and modelers often have difficulties communicating with each other, and are not always on the same page about what a model can or should achieve. Here, we present a framework to develop models that increase the understanding of the mechanisms underlying one's favorite biological system. Development of the most insightful models starts with identifying a good biological question in light of what is known and unknown in the field, and determining the proper level of details that are sufficient to address this question. The model should aim not only to explain already available data, but also to make predictions that can be experimentally tested. We hope that both experimentalists and modelers who are driven by mechanistic questions will find these guidelines useful to develop models with maximum impact in their field. PMID- 30421277 TI - Building a dendritic actin filament network branch by branch: models of filament orientation pattern and force generation in lamellipodia. AB - We review mathematical and computational models of the structure, dynamics, and force generation properties of dendritic actin networks. These models have been motivated by the dendritic nucleation model, which provided a mechanistic picture of how the actin cytoskeleton system powers cell motility. We describe how they aimed to explain the self-organization of the branched network into a bimodal distribution of filament orientations peaked at 35 degrees and - 35 degrees with respect to the direction of membrane protrusion, as well as other patterns. Concave and convex force-velocity relationships were derived, depending on network organization, filament, and membrane elasticity and accounting for actin polymerization at the barbed end as a Brownian ratchet. This review also describes models that considered the kinetics and transport of actin and diffuse regulators and mechanical coupling to a substrate, together with explicit modeling of dendritic networks. PMID- 30421278 TI - Lessons from one year experience of pooled procurement of pharmaceuticals: exploration of indicators and assessing pharmacies' performance. AB - BACKGROUND: Joint procurement of medicines is a way to improve access and justice in developing countries. The aim of this study is to determine local indicators for assessing the performance of joint procurement agencies and compare the indicators in those pharmacies which use centralized purchasing before and after this change. METHODS: This was a mixed method study. In the first qualitative phase, 3 expert panels were held including 20 national experts who were selected through purposeful sampling. Data was analyzed applying a five-stage framework analysis using MAXQDA. In the second quantitative phase, financial, supply and procurement, physical and functional indicators of two hospitals affiliated with joint procurement were assessed and the satisfactions of patients from the pharmacy performance were compared applying a valid questionnaire. Data was analyzed using SPSS through independent test, Paired t-test and ANOVA. RESULTS: Results show that after settlement of joint procurement, the cost of transportation has increased by 54%, a part of the cost of overhead has increased by 30%, the cost of manpower has increased by 88.9% and cost of insurance of warehouses has increased by 71.85% in 2016 compared to 2015. In addition, the total costs of holding were 89.8% of selling revenue. In other words, the profit was about 10% of revenue in total. Moreover the average score of pharmacies under the Holding has been higher than similar ones in all aspects of satisfaction from the patients' points of view. CONCLUSION: The one-year experience of deploying centralized purchasing to supply medicine has led to increased income and patient satisfaction. However, increase in staffing costs, longevity, overhead and warehouse costs have been significant that need appropriate monitoring and interventions. Graphical abstract Graphical abstract of lessons from one year experience of pooled procurement of pharmaceuticals in south of Iran. PMID- 30421279 TI - Correction to: Ready player one? Autophagy shapes resistance to photodynamic therapy in cancers. AB - The below funding information was not submitted and hence not included in the original publication. The funding information is given below. PMID- 30421281 TI - Generation of Isogenic Controls for In Vitro Disease Modelling of X-Chromosomal Disorders. AB - Generation of proper controls is crucial in induced pluripotent stem cell (iPSC) studies. X-chromosomal disorders offer the potential to develop isogenic controls due to random X-chromosomal inactivation (XCI). However, the generation of such lines is currently hampered by skewed X-inactivation in fibroblast lines and X chromosomal reactivation (XCR) after reprogramming. Here we describe a method to generate a pure iPSC population with respect to the specific inactivated X chromosome (Xi). We used fibroblasts from Rett patients, who all have a causal mutation in the X-linked MeCP2 gene. Pre-sorting these fibroblasts followed by episomal reprogramming, allowed us to overcome skewness in fibroblast lines and to retain the X-chromosomal state, which was unpredictable with lentiviral reprogramming. This means that fibroblast pre-sorting followed by episomal reprogramming can be used to reliably generate iPSC lines with specified X chromosomal phenotype such as Rett syndrome. PMID- 30421280 TI - Ischemic Conditions Affect Rerouting of Tau Protein Levels: Evidences for Alteration in Tau Processing and Secretion in Hippocampal Neurons. AB - The spreading of misfolded protein species contributes to the propagation of harmful mediators in proteinopathies, including Alzheimer's disease (AD). Cellular stress circumstances, such as abnormal protein accumulation or nutrient deprivation, elicit the secretion of soluble misprocessed proteins and insoluble aggregates via multiple mechanisms of unconventional secretion. One of them consists in the rerouting of autophagic vacuoles towards exocytosis, an unconventional type of autophagy mediated by caspase-3 activation under starvation. Ischemic injury is a starvation condition characterized by oxygen/nutrient deprivation, whose contribution in AD onset has definitely been endorsed. Thus, we investigated the effect of oxygen-glucose deprivation (OGD), an experimental condition mimicking cerebral ischemia, in search of alteration in Tau processing and secretion in hippocampal neurons primary cultures. Our results showed that OGD caused alterations in Tau phosphorylation and processing, paralleled by an induction of its secretion. Interestingly, together with caspase 3 activation, full-length (FL) and fragmented Tau forms were secreted by their own or through a heterogeneous population of microvesicles (MVs), including autophagosome marker LC3-positive vesicles. Accordingly, confocal microscopy revealed a partial colocalization of intracellular Tau and LC3. Summarizing, our findings indicate that OGD alters Tau intracellular levels and protein processing. Consequently, Tau clearance was stimulated through multiple mechanisms related to unconventional Tau secretion, including exophagy. However, the activation of this response represent a double edge sword, because it could contribute to the spreading of misfolded Tau, a neurodegeneration pathway in AD and other tauopathies. PMID- 30421282 TI - Assessment of children with pectus excavatum without surgical correction. AB - OBJECTIVE: To assess respiratory function and functional capacity in children with pectus excavatum who followed a physical therapy program, to compare these parameters to healthy controls and to evaluate adherence of this category of patients (pectus excavatum without surgical indications) to a supervised exercise program. METHODS: This study included 14 children with pectus excavatum and 14 gender and age-matched healthy controls. The study patients performed a 12-week exercise program. They were assessed at the beginning and at the end of rehabilitation by spirometry and functional capacity testing (6-min walk test). Parents of children with pectus excavatum completed a 10-item adherence questionnaire. RESULTS: In the study patients all respiratory parameters increased after rehabilitation. After 12 weeks there were no differences between study patients and controls, except for functional capacity that still had lower values in children with pectus excavatum. The parents of all patients agreed about fitting of the training program with their child's daily routine, low difficulty of the exercises, the child following the physiotherapist's instructions and confidence in the results of rehabilitation. CONCLUSIONS: In children with pectus excavatum without surgical indications, forced vital capacity, forced expiratory volume in 1 s and functional capacity assessed by the 6-min walk test improved significantly after a 12-week supervised exercise program. The study showed that adherence to the exercise-based program was good for all patients. PMID- 30421283 TI - Fulfillment of physical activity guidelines in the general population and frailty status in the elderly population : A correlation study of data from 11 European countries. AB - BACKGROUND: We report on the correlation between the proportion of people who fulfil the recommended amount of aerobic physical activity in the general population and the prevalence of frailty or prefrailty in the population >=65 years in 11 European countries (Austria, Czech Republic, Denmark, Estonia, France, Germany, Italy, Luxembourg, Slovenia, Spain and Sweden). In a subgroup analysis, it was assessed if people who do aerobic physical activity also do strength training. METHODS: Aggregated physical activity data were taken from the European Health Interview Survey with the minimum effective sample size of 90,036 participants. Data on frailty status were taken from the Survey of Health Ageing and Retirement in Europe (SHARE) study (N = 24,590). For the subgroup analysis, data of the Austrian Health Interview Survey (ATHIS) (N = 15,770) were included. RESULTS: The results indicate a significant negative correlation between the proportion of people fulfilling the minimal aerobic physical activity recommendations (>=150 min/week) and the proportion of prefrail or frail people (R = -0.745; p = 0.008). The correlation between the optimal aerobic physical activity recommendations (>=300 min/week) and the proportion of prefrail or frail individuals was R = -0.691 (p = 0.019). In both data sets a north-south gradient was seen. Austrian data showed that 52.0% of the participants fulfilled the minimal aerobic physical activity recommendations and conducted strength training, whereas 18.4% did not fulfil the aerobic recommendations but performed strength training (p < 0.001). CONCLUSIONS: By taking into account that the number of people >=65 years will increase in the future these results may be relevant in planning public health interventions for the whole population with the goal of reducing frailty in the elderly. PMID- 30421284 TI - Coronary artery fistula between the left circumflex artery and right atrium : Multimodal imaging. PMID- 30421285 TI - Tenotomy of the middle ear muscles : An unknown surgical approach in Meniere's disease. AB - Tenotomy of the tendon of the stapedius and tensor tympani muscles is a relatively unknown therapeutic procedure in Meniere's disease. Widespread approaches include medicinal treatment with betahistine or diuretics as well as interventional procedures, such as intratympanic gentamicin or glucocorticoid injection, vestibular neurectomy, labyrinthectomy or endolymphatic sac surgery. The exact pathomechanism of this approach is not fully known. It is assumed that by cutting the tendons of both middle ear muscles in cases of endolymphatic hydrops the stapes is not additionally actively pushed against the oval window but can deviate laterally and thereby does not augment the inner ear pressure even further. Studies have shown that this method does not only improve vestibular symptoms but also, in contrast to most other strategies, increases the hearing level. The formation of scar tissue and the resulting reduction of ossicular chain mobility, especially due to postoperative infections, may limit the success of tenotomy and should be considered as a possible factor in cases of limited postoperative vertigo control. PMID- 30421286 TI - Alprostadil treatment of critical limb ischemia in hemodialysis patients : A retrospective single-center analysis. AB - BACKGROUND: Peripheral artery disease and critical limb ischemia are common in patients undergoing chronic hemodialysis treatment and are associated with a high rate of amputation and mortality. The effect of treatment with prostanoids in this specific group of patients is unknown. METHODS: A retrospective single center analysis of hemodialysis patients with critical limb ischemia was performed who were treated with the prostanoid analogue alprostadil as an infusion during hemodialysis in the period from 2000 to 2013. The primary study outcome was a combined end-point including amputation and death 1 year after start of alprostadil. Kaplan-Meier curves were used to describe amputation-free survival and overall survival. A multivariable adjusted Cox proportional hazards model was calculated for the primary outcome. RESULTS: A total of 86 patients (60 males, 69.7%) were studied. The median alprostadil treatment period was 1.8 months. The 1-year amputation-free survival was 41%. In 36% of patients an amputation was necessary and 35% died. Despite alprostadil treatment, 36% of the study patients additionally underwent an endovascular procedure and 16% had bypass surgery. Men had a significantly higher amputation rate (45%) than women (15%) (P = 0.009). Male sex and dialysis vintage were significantly associated with an increased risk for primary outcome CONCLUSIONS: Despite treatment with alprostadil the mortality, amputation rate and the need for revascularization procedures in hemodialysis patients with critical limb ischemia remained high. The outcome, however, was comparable with that of other treatment, such as endovascular procedures and bypass surgery. The effect of any current treatment strategy on amputation rate or mortality in that patient group remains uncertain. PMID- 30421287 TI - [Time trend in programme sensitivity within the German mammography screening programme in North Rhine-Westphalia and Lower Saxony]. AB - BACKGROUND: The programme sensitivity is a performance indicator for evaluating the quality of the mammography screening programme (MSP). OBJECTIVES: We analysed the development of the programme sensitivity over time in two federal states of Germany, North Rhine-Westphalia (NRW) and Lower Saxony (NDS). MATERIALS AND METHODS: Data from 2,717,801 (NRW) and 1,197,660 (NDS) screening examinations between 2006 and 2011 were linked with data of the State Cancer Registry NRW and the Epidemiological Cancer Registry NDS, respectively. Breast cancers (invasive and in situ) were either detected at screening or diagnosed within the 24-month interval after an inconspicuous screening result outside the programme. The crude and age-standardized programme sensitivity was calculated per calendar year. The German mammography screening office provided aggregated recall rates. RESULTS: The age-standardized programme sensitivity increased markedly for initial screening examinations from 2006 to 2011 from 75.0% (95% CI: 72.1-77.9) to 80.5% (95% CI: 78.5-82.5) in NRW, and from 74.9% (95% CI: 71.4-78.5) to 84.7% (95% CI: 81.1-88.3) in NDS. Concurrently, recall rates increased as well. For subsequent screening examinations, the programme sensitivity increased from 2008 to 2011 from 68.1% (95% CI: 63.1-73.1) to 71.9% (95% CI: 70.2-73.6) in NRW, and from 69.8% (95% CI: 64.2-75.4) to 74.9% (95% CI: 72.3-77.5) in NDS, whereas the recall rates remained relatively constant. CONCLUSIONS: In both federal states, the programme sensitivity increased over time. This increase, possibly indicating an improved quality of diagnosis within the MSP as a learning system, is discussed under consideration of the age distribution of screening participants and the recall rates. PMID- 30421288 TI - [Interviewing children in cases of suspected child endangerment: pitfalls and quality assurance]. AB - Doctors and especially paediatricians in clinics and private practices are often the first professionals to be confronted with the suspicion of a child endangerment (sexual abuse, physical abuse, neglect, Munchausen-by-proxy syndrome). They thus play a key role in the early assessment and clarification of suspicion and setting the course for the further interdisciplinary procedure.The clinical investigation of a suspicion is a diagnostic and communicative challenge. The procedure includes biomedical diagnostics, structured medical history based on standardized questionnaires and a forensic (investigative) interview of caregivers and especially of the affected child.The child's statements are subject to various risks of bias. The mental processing of events can modulate and distort the scope and quality of the report in many ways. Expectations on how the professionals will use this information and the consequences that may arise for the family as well as the resulting conflicts of loyalty are superimposed on the child's willingness to talk and to provide valid statements. On the part of the interviewer too, motivational, affective and cognitive processes pose risks for a suggestive influence on the child as well as for the objectivity in carrying out the interview and the interpretation of the findings. Complex pitfalls endanger the validity and forensic usability of the interview results. In order to assure the quality of their findings, interviewers are therefore required to carefully register and reflect on their own motivational tendencies and implicit hypotheses, to know and avoid suggestive question formulations and to make use of standardized interview protocols whenever possible. PMID- 30421289 TI - [Structured interviewing of children in suspected child endangerment cases: The German version of the revised NICHD Investigative Interview Protocol]. AB - Interviewing a child of a suspected abuse (physical abuse, sexual abuse, neglect, Munchausen-by-proxy syndrome) is subject to complex risks of suggestion and distortion. The use of a standardized interview protocol as part of the investigation can significantly increase the scope and validity of the child's report in different settings (for example, pediatrics, child welfare services, court).In this paper, the interview protocol provided by the National Institute of Child Health and Human Development (NICHD) in its revised and complete version is presented in German and made available for free clinical use in the Appendix. The NICHD interview protocol is the most prominent and most carefully evaluated tool. It is currently considered as a reference for the assessment of child abuse. The protocol follows certain guiding principles. At the beginning of the interview, basic rules are explained to the child (e. g. telling the truth, correct the interviewer if necessary). The focus is placed on detailed exploration of critical abusive episodes. Open questions are asked instead of closed questions. A good rapport has to be established before moving to the actual interview topic.In addition to a technically correct application of the protocol, further competencies of the interviewer are essential to ensure the validity of the findings, such as: sensitive contact with the child; knowledge of the typical sources of bias and suggestion; awareness and control of personal impulses, motives and implicit assumptions; a hypothesis-led approach; and developmentally appropriate interpretation and evaluation of the child's report. PMID- 30421290 TI - ? PMID- 30421291 TI - A Lesson in Mental Health Stigma. PMID- 30421292 TI - Profile of Dr. Tao Xu. PMID- 30421293 TI - Profile of Dr. Zhigang Tian. PMID- 30421294 TI - Profile of Dr. Zhao-Shen Li. PMID- 30421295 TI - The Arabidopsis AGAMOUS 5'-UTR represses downstream gene translation. PMID- 30421296 TI - NK cells in liver homeostasis and viral hepatitis. AB - As an important member of the innate immune system, natural killer (NK) cells are well known for their rapid and efficient immune responses against infectious agents and tumors. NK cells are widely distributed throughout the body and are particularly enriched within the liver, where they display unique phenotypic and functional properties, playing important roles in various liver diseases. Herein, we present an overview of liver NK cell properties with regard to phenotype, function, and subset composition at steady state, and we also summarize the complex reciprocal interactions between liver NK cells and other cell types within the local environment of the liver. We also provide an overview of recent advances demonstrating the roles of NK cells in viral hepatitis, including a discussion of NK cell altered states and their beneficial versus harmful effects during hepatitis B virus and hepatitis C virus infection. PMID- 30421298 TI - Recurrent groin hernia surgery after primary open inguinal procedures: a reappraisal of the open preperitoneal (Ugahary) technique. AB - PURPOSE: There are several methods for repairing recurrent inguinal hernia, depending on the type of initial repair. Our aim was to analyze our long follow up results on the open preperitoneal repair for patients with recurrent inguinal hernia. METHODS: Our retrospective survey included 135 consecutive recurrent inguinal hernia patients, operated on during 1999-2010, with a mean follow-up time of 8.7 years. RESULTS: During the mean follow-up time of 8.7 years, only four (3%) patients developed a re-recurrence. Two of these patients were asymptomatic, and the two other were operated on. Early postoperative complications occurred in four (3%) patients. The complications comprised one hematoma, one seroma, and two infections. Chronic pain was diagnosed in five (3.7%) patients, but their symptoms disappeared spontaneously within a few years. CONCLUSIONS: We conclude that in competent hands, the open preperitoneal repair (Ugahary) is a good surgical option in operating recurrent inguinal hernias. PMID- 30421299 TI - Risk factors of postoperative complications after emergency repair of incarcerated groin hernia for adult patients: a retrospective cohort study. AB - PURPOSE: This study aimed to explore risk factors of postoperative complications for adult patients with incarcerated groin hernia (IGH). METHODS: From January 2010 to December 2017, consecutive patients undergoing emergency hernia repair for IGH in our center were retrospectively reviewed. Postoperative complications, such as surgical site infection, seroma, hernia recurrence and mortality, were investigated, with risk factors for such complications analyzed using univariate and multivariate regressions. RESULTS: Sixty-four patients were included, with 51 males and 13 females (mean age 65.1, range 25-98 years). Ten patients (15.6%) underwent resection of necrotic bowel and anastomosis. 43 patients (67.2%) received open tension-free herniorrhaphy with polypropylene mesh, whereas the rest (32.8%) received herniorrhaphy without mesh. The overall postoperative complication rate was 40.6% (26/64), with an incisional complication rate of 31.2% (20/64) and an infection rate of 6.2% (4/64). At a median follow-up of 32 months, hernia recurrence and mortality were recorded in five cases each (7.8%). Mesh repair was associated with decreased recurrence rate compared with non-mesh repair (2.3% vs. 19.0%, p = 0.019). Diabetes mellitus (OR 8.611, 95%CI 1.292 57.405; p = 0.026) was an independent risk factor of postoperative complications, together with chronic obstructive pulmonary disease (COPD; OR 14.365, 95%CI 1.652 127.767, p = 0.016), intestinal necrosis (OR 14.260, 95%CI 1.079-188.460, p = 0.044), and general anesthesia (OR 14.543, 95%CI 1.682-125.711, p = 0.015) as risk for incisional complications after surgery. CONCLUSIONS: Diabetes mellitus was an independent risk factor of postoperative complications for IGH, along with COPD, intestinal necrosis and general anesthesia associated with incisional complications. The use of polypropylene mesh did not increase infection or recurrence rate in this cohort. PMID- 30421297 TI - Gastroduodenal "Dysbiosis": a New Clinical Entity. AB - PURPOSE OF REVIEW: Like the rest of the gastrointestinal tract, the small intestine is colonised by microbes, but how this "microbiome" affects the immune system and digestive functions has largely been overlooked, especially in the "omics" era. Here, we present recent findings that show that the diversity, density and interactions of these microbes in the small intestine can play an important role in the pathogenesis of a number of gastrointestinal and extraintestinal disorders. RECENT FINDINGS: Changes in the small intestinal mucosa-associated microbiota (SI-MAM) have been shown to occur with inflammatory bowel diseases, functional gastrointestinal disorders, metabolic disorders such as obesity and type 2 diabetes. More recently, there is emerging evidence that small intestinal dysbiosis can be a driver for the progression of chronic liver disease. Initially believed that small intestinal dysbiosis (e.g. SIBO) is mainly due to alterations of luminal conditions (e.g. after surgical resections of the ileocecal valve), there is now enough evidence to conclude that small intestinal dysbiosis can occur without underlying structural abnormalities. Alterations of the SI-MAM appear to play a key role for the manifestation and progression of inflammatory and metabolic disorders. PMID- 30421301 TI - Haemaphysalis longicornis: a tick of considerable importance, now established in North America. PMID- 30421300 TI - Feasibility of pedicled anterolateral thigh flap with tensor fascia lata and vastus lateralis for difficult abdominal wall closure. AB - PURPOSE: Long-term follow-up for pedicled anterolateral thigh (ALT) flap with vastus lateralis and tensor fascia lata for complex abdominal wall reconstruction is rarely reported. This study aimed to evaluate the feasibility of extended pedicled ALT flap. METHODS: This retrospective review was conducted at a single medical center between 2011 and 2018. A total of 35 patients with complex abdominal wall defects reconstructed with partition (n = 20) or pedicled ALT flap (n = 15) were enrolled. Data on gender, age, fascial defect size, operation time, hospital days, follow-up duration, and complications were obtained. Mann-Whitney test evaluated the differences in continuous data, and Chi-square test analyzed categorical data. RESULTS: The partition technique was associated with 10.15 cm (range 8-14 cm) mean defect size, 146 min average operation time, 13.5 hospital days, and 95.42 months of mean follow-up duration. Short- and long-term complications were observed in seven (35%) and six (30%) cases, respectively. The pedicled ALT flap technique was associated with 13.4 cm (range 10.6-16 cm), 342.86 min average operation time, 22.33 hospital days, and 69.4 months of mean follow-up duration. Short- and long-term complications were observed in six (40%) and five (33%) cases, respectively. Significant differences in defect size, operative time, hospital days, and donor-site skin graft loss (p < 0.05) were observed between the groups. CONCLUSIONS: Extended pedicled ALT flap is a reliable option for complex abdominal wall reconstruction. Compared with the partition technique group, the extended pedicled ALT group had closure of larger fascia defects. However, it was associated with a higher risk of donor-site skin graft loss and longer operative time and hospital days. PMID- 30421302 TI - Pathogenic significance of hemorrhagic pneumonia in hematologic malignancy patients with Stenotrophomonas maltophilia bacteremia: clinical and microbiological analysis. AB - Hemorrhagic pneumonia (HP) is known as the clinical manifestation of Stenotrophomonas maltophilia infection, while catheter-related blood stream infection (CRBSI) is the common clinical presentation of S. maltophilia bacteremia (SMB). The purpose of this study is to evaluate the risk factors for mortality in hematologic malignancy patients with SMB and to analyze clinical and microbiological characteristics of HP associated with SMB and CRBSI. SMB cases of patients with a hematologic malignancy were collected from 2006 through 2016. The overall 30-day mortality rate and mortality risk factors were assessed. The expression of major virulence-associated genes from S. maltophilia isolates, which included genes encoding type-1 fimbriae (smf-1), proteases (StmPr1 and StmPr2), and esterase (Smlt3773), from the blood of patients with HP and CRBSI was investigated. The phenotypic and genotypic traits were also compared. A total of 118 cases of SMB were included. The overall 30-day mortality rate was 61.0%. A multivariable analysis showed that HP was the most important risk factor for mortality (adjusted OR = 106.41; 95% CI = 5.18-2184.55). Although no statistical significance was observed in microbiological analysis, isolates from HP have a trend toward a higher protease activity (93.8% vs. 73.3%, P = 0.172). Clinical analysis showed that thrombocytopenia (P = 0.037) and prolonged neutropenia (P = 0.043) were significant factors associated with HP. Our data, which includes hematologic malignancy patients with SMB, suggest that HP is the significant risk factor for mortality and that the unique characteristics of patients and microbes contribute to the pathogenesis. PMID- 30421303 TI - [Extensive emphysema after intramedullary nailing of a pertrochanteric fracture : Life-threatening infection or benign complication]. AB - The development of emphysema after intramedullary nailing can represent an easily manageable complication but in the differential diagnostics it could, however, be a life-threatening infection with Clostridium perfringens. This is a report about the case of an extensive subcutaneous and retroperitoneal emphysema, which developed after intramedullary nailing of a pertrochanteric femoral fracture and where such an infection was suspected. PMID- 30421304 TI - [Ankle dislocation without osseous lesions]. AB - Approximately 7-10% of all emergency department patients are diagnosed with distortion of the upper ankle joint. A dislocation of the upper ankle joint without fracture is described in the literature as being very rare. In 33-50% the ankle dislocations are at least first-degree open and associated with a fracture of the tibia, the fibula or the talus. We report the course, treatment and results 12 months after trauma of a posteromedial first-degree open dislocation of the upper ankle joint without fracture. To our knowledge, there is no record of this pathology mentioned in the German language literature. PMID- 30421305 TI - Calcific olecranon bursitis in end-stage renal disease. PMID- 30421306 TI - Rituximab and Omalizumab for the Treatment of Bullous Pemphigoid: A Systematic Review of the Literature. AB - BACKGROUND: Bullous pemphigoid (BP) is the most common autoimmune blistering skin disease worldwide. Systemic corticosteroids are considered the mainstay of therapy; however, they may cause significant adverse effects and treatment failures, so additional therapeutic modalities with better safety profiles are required. Rituximab and omalizumab are novel biologic agents administered in recent years for the treatment of BP, yet data regarding their use in the disease are limited. OBJECTIVE: Our objective was to systematically review the current literature regarding the use of rituximab and omalizumab for the treatment of BP to evaluate their safety and efficacy. METHODS: A systematic review of all publications evaluating patients with BP treated with rituximab or omalizumab was performed. The primary outcome was clinical response; secondary outcomes were adverse events and recurrence rate. RESULTS: The systematic review included 35 publications (84 patients: 62 receiving rituximab and 22 receiving omalizumab). In total, 61 of 63 patients had not experienced disease control with systemic corticosteroids before receiving the biologic treatment. Complete response rates were 85% and 84% for rituximab and omalizumab, respectively. The recurrence rate was considerably lower with rituximab (29%) than with omalizumab (80%). Mean time to recurrence was 10.2 and 3.4 months, and adverse effects occurred in 24% and 20% of the patients, respectively. CONCLUSIONS: Available data, although potentially limited because of publication bias, suggest that rituximab and omalizumab have similar safety profiles and provide clinical benefit for patients with BP. The reviewed data indicated that rituximab resulted in lower recurrence rates and a longer time until recurrence than omalizumab. PMID- 30421308 TI - Transanal hemorrhoidal dearterialization (THD) versus stapled hemorrhoidopexy (SH) in treatment of internal hemorrhoids: a systematic review and meta-analysis of randomized clinical trials. AB - BACKGROUND: Although conventional hemorrhoidectomy proved effective in treatment of hemorrhoidal disease, postoperative pain remains a vexing problem. Alternatives to conventional hemorrhoidectomy as transanal hemorrhoidal dearterialization (THD) and stapled hemorrhoidopexy (SH) were described. The present meta-analysis aimed to review the randomized trials that compared THD and SH to determine which technique is superior in terms of recurrence of hemorrhoids, complications, and postoperative pain. METHODS: Electronic databases were searched for randomized trials that compared THD and SH for internal hemorrhoids. The PRISMA guidelines were followed when reporting this meta analysis. The primary endpoint of the analysis was persistence or recurrence of hemorrhoidal disease. Secondary endpoints were postoperative pain, complications, readmission, return to work, and patients' satisfaction. RESULTS: Six randomized trials including 554 patients (THD = 280; SH = 274) were included. The mean postoperative pain score of THD was significantly lower than SH (2.9 +/- 1.5 versus 3.3 +/- 1.6). 13.2% of patients experienced persistent or recurrent hemorrhoids after THD versus 6.9% after SH (OR = 1.93, 95%CI = 1.07-3.51, p = 0.029). Complications were recorded in 17.1% of patients who underwent THD and 23.3% of patients who underwent SH (OR = 0.68, 95%CI 0.43-1.05, p = 0.08). The average duration to return to work after THD was 7.3 +/- 5.2 versus 7.7 +/- 4.8 days after SH (p = 0.34). Grade IV hemorrhoids was significantly associated with persistence or recurrence of hemorrhoidal disease after both procedures. CONCLUSION: THD had significantly higher persistence/recurrence rate compared to SH whereas complication and readmission rates, hospital stay, return to work, and patients' satisfaction were similar in both groups. PMID- 30421309 TI - Sex- and site-specific differences in colorectal cancer risk among people with type 2 diabetes. AB - PURPOSE: The prevalence of colorectal cancer is higher among patients with type 2 diabetes mellitus (T2D) than among patients without diabetes. Furthermore, men are at higher risk for developing colorectal cancer than women in the general population and also subsite-specific risks differ per sex. The aim was to evaluate the impact of T2D on these associations. METHODS: A population-based matched cohort study was performed using data from the PHARMO Database Network. Patients with T2D were selected and matched (1:4) to diabetes free controls. Cox proportional hazards models were used to estimate hazard ratios (HRs) for CRC and its subsites. HRs were determined per sex and adjusted for age and socioeconomic status. The ratio of distal versus proximal colon cancer was calculated for people with T2D and controls per sex and stratified by age. RESULTS: Over 55,000 people with T2D were matched to > 215,000 diabetes free controls. Men and women with T2D were 1.3 times more likely to develop colorectal cancer compared to controls. Men with T2D were at higher risk to develop distal colon cancer (hazard ratio (95% confidence interval), 1.42 (1.08-1.88)), and women with T2D were at higher risk for developing proximal colon cancer (hazard ratio (95% confidence interval), 1.58 (1.13-2.19)). For rectal cancer, no statistically significant risk was observed for both men and women. CONCLUSIONS: Sex-specific screening strategies and prevention protocols should be considered for people with T2D. More tailored screening strategies may optimize the effectiveness of colorectal cancer screening in terms of reducing incidence and mortality. PMID- 30421307 TI - The Role of Hypnosis in Cancer Care. AB - PURPOSE OF REVIEW: This paper reviews the current evidence-base for the use of hypnosis as an adjunct treatment for common cancer-related symptoms and side effects, including those experienced during treatment, as well as long-term and late effects. First, a general description and history of medical hypnosis in cancer care is provided, followed by a review of the latest evidence across a range of common symptoms. RECENT FINDINGS: The evidence suggests that hypnosis may help treat symptoms of nausea and vomiting in breast cancer patients, manage pain in a variety of contexts, and also reduce levels of anxiety and overall distress around surgical and medical procedures, both in children and adults. Emerging research shows promise for treating hot flashes in women with breast cancer. The research in this area would benefit from assessing populations beyond women with breast cancer, including late-stage disease, using more rigorous study designs, following published reporting guidelines and better describing and standardizing interventions. PMID- 30421310 TI - [Health and wellbeing of older migrants in the Netherlands: A narrative literature review]. AB - In the past few years there has been a growing attention for older migrants, but the question of what we actually know about this group of people remains open. This article strives to fill this knowledge lacuna by presenting an overview of current research findings on health and wellbeing. In total 104 publications were taken into account in this literature review, including 69 articles published in (inter)national journals and 35 reports. The results show that a great deal of research is dedicated to the three largest groups of non-western migrants - Surinamese, Turkish and Moroccan older adults - and health-related themes such as health status and healthcare utilization and quality. Interest in the field of wellbeing is, on the other hand, still rather small. Furthermore, there seems to be little attention to diversity on the current research agenda, although prior research has shown relatively large differences between migrant groups. Based on this literature review, we conclude with a plea for more explanatory research, which goes beyond country of origin and socio-economic status. PMID- 30421311 TI - [Stronger feelings of loneliness among Moroccan and Turkish older adults in the Netherlands: A search for an explanation]. AB - The prevalence of loneliness among Turkish- and Moroccan-Dutch older adults is higher than among Dutch older adults of non-migrant origin. Two explanations may account for this difference. (1) The meaning of the concept may differ, or there is differential item functioning. This might result in scores that not only differ in intensity but also in meaning across groups. (2) The position of older migrants is much more vulnerable than of non-migrant older people. Data from the Longitudinal Aging Study Amsterdam were used to examine support for both explanations. Feelings of loneliness are explored among 176 people born in Morocco and 235 people born in Turkey, aged 55-66 years, and living in urban areas. They migrated on average 35 years ago to the Netherlands. They are compared with a matched sample of 292 older people of Dutch origin. The psychometric properties of the loneliness scale are satisfying, although there is some differential item functioning. Older migrants have more frequent social contacts, but are at a disadvantage in other domains. Taking into account differences in social participation, satisfaction with their income, mastery and depressive symptoms, the difference between older migrants' and non-migrants' loneliness is reduced to more than half. Being an older migrant and belonging to a minority might further contribute to feelings of loneliness. Interventions should not be directed at stimulating social contact, but rather, for example, at enhancing the appreciation of their social status and at avoiding negative interpretations of the situation. PMID- 30421312 TI - Purification of carbamoyl phosphate synthetase 1 (CPS1) from wood frog (Rana sylvatica) liver and its regulation in response to ice-nucleation and subsequent whole-body freezing. AB - Carbamoyl phosphate synthetase I (CPS1) represents an important regulatory enzyme of the urea cycle that mediates the ATP-driven reaction ligating ammonium, carbonate, and phosphate to form carbamoyl phosphate. The freeze-tolerant wood frog (Rana sylvatica or Lithobates sylvaticus) accumulates high concentrations of urea during bouts of freezing to detoxify any ammonia generated and to contribute as a cryoprotectant thereby helping to avoid freeze damage to cells. Purification of CPS1 to homogeneity from wood frog liver was performed in control and frozen wood frogs by a three-step chromatographic process. The affinity of CPS1 for its three substrates was tested in the purified control and freeze-exposed enzyme under a variety of conditions including the presence and absence of the natural cryoprotectants urea and glucose. The results demonstrated that affinity for ammonium was higher in the freeze-exposed CPS1 (1.26-fold) and that with the addition of 400 mM glucose it displayed higher affinity for ATP (1.30-fold) and the obligate activator N-acetylglutamate (1.24-fold). Denaturation studies demonstrated the freeze-exposed enzyme was less thermally stable than the control with an unfolding temperature approximately 1.5 degrees C lower (52.9 degrees C for frozen and 54.4 degrees C for control). The control form of CPS1 had a significantly higher degree of glutarylated lysine residues (1.42-fold increase) relative to the frozen. The results suggest that CPS1 activation and maintenance of urea cycle activity despite the hypometabolic conditions associated with freezing are important aspects in the metabolic survival strategies of the wood frog. PMID- 30421313 TI - Recent Versus Old Previous Injury and Its Association with Running-Related Injuries During Competition by SeRUN(r) Running Profiles: a Cross-sectional Study. AB - BACKGROUND: Previous injury in the last 12 months is the main risk factor for future running-related injuries (RRI) during training and competition environments. However, the relationship between a recent versus old previous injury and a new RRI has not been established yet, nor a separate analysis by different types of runners. METHODS: An online questionnaire was sent to 6000 participants of a running event (10 km, 21 km and 42 km), 10 days following the event. The questionnaire included the following information: the presence and topography of new RRIs during the race, old previous injury (from 12-4 months before the race), recent previous injury (from 3-0 months before the race), running experience, training factors and socio-demographic characteristics. Univariate binomial regression analysis was applied to assess different associated factors, and multivariable binomial backward regression (p < 0.05) was used to analyse the relationship between the new and previous injury. RESULTS: A total of 868 surveys were analysed (10 km, 32.6%; 21 km, 52%; 42 km, 15.4%). The median age was 38 years (IQR 31-46), and 63.5% were males. Previous injury was reported by 30.3% and 27.6% for old and recent, respectively. The majority of runners were categorised into the advanced group (42.9%), having more than 5 years of running experience. During the race, 7.0% reported a RRI, with 36.1% located at the knee. The multivariable analysis showed an association only between new injury and recent injury. CONCLUSION: The delineation of recent and old previous injuries should be considered in running epidemiological research. PMID- 30421314 TI - Learning concepts when instances never repeat. AB - Three experiments explored the learning of categories where the training instances either repeated in each training block or appeared only once during the entire learning phase, followed by a classification transfer (Experiment 1) or a recognition transfer test (Experiments 2 and 3). Subjects received training instances from either two (Experiment 2) or three categories (Experiments 1-3) for either 15 or 20 training blocks. The results showed substantial learning in each experiment, with the notable result that learning was not slowed in the non repeating condition in any of the three experiments. Furthermore, subsequent transfer was marginally better in the non-repeating condition. The recognition results showed that subjects in the repeat condition had substantial memory for the training instances, whereas subjects in the non-repeat condition had no measurable memory for the training instances, as measured either by hit and false alarm rates or by signal detectability measures. These outcomes are consistent with prototype models of category learning, at least when patterns never repeat in learning, and place severe constraints on exemplar views that posit transfer mechanisms to stored individual traces. A formal model, which incorporates changing similarity relationships during learning, was shown to explain the major results. PMID- 30421315 TI - Skeletal muscle fibrosis: an overview. AB - Extracellular matrix (ECM) is an essential component of skeletal muscle. It provides a framework structure that holds myofibers and blood capillaries and nerves supplying the muscle. In addition, it has a principal role in force transmission, maintenance and repair of muscle fibers. Excessive accumulation of ECM components, especially collagens, either due to excessive ECM production, alteration in ECM-degrading activities, or a combination of both is defined as fibrosis. Skeletal muscle fibrosis impairs muscle function, negatively affects muscle regeneration after injury and increases muscle susceptibility to re injury, therefore, it is considered a major cause of muscle weakness. Fibrosis of skeletal muscle is a hallmark of muscular dystrophies, aging and severe muscle injuries. Thus, a better understanding of the mechanisms of muscle fibrosis will help to advance our knowledge of the events that occur in dystrophic muscle diseases and develop innovative anti-fibrotic therapies to reverse fibrosis in such pathologic conditions. This paper explores an overview of the process of muscle fibrosis, as well as different murine models for studying fibrosis in skeletal muscles. In addition, factors regulating fibrosis and strategies to inhibit muscle fibrosis are discussed. PMID- 30421316 TI - Correlation of central and peripheral keratometric parameters after corneal collagen cross-linking in keratoconus patients. AB - PURPOSE: To evaluate the difference in the central and peripheral keratometric parameters in patients with keratoconus after corneal collagen cross-linking (CXL). METHODS: Forty-eight eyes of 32 patients (18 males, 16-28 years) affected by progressive keratoconus in different stages of evolution underwent CXL using the standard epithelium-off protocol. Corneal thickness and corneal curvature before CXL and after 6 and 12 months using the Sirius tomographer were analyzed. The values of the mean corneal thickness at the corneal apex (CAT), center of the pupil (PCT), thinnest point (CTTL) and along concentric circles of 2, 4, 6, 8, 8.5, 9, 9.5 and 10 mm diameter were evaluated; the values of the mean curvature at the corneal apex and at the points in which the inferior, superior, nasal and temporal meridians crossed the above-mentioned concentric circles were also evaluated. RESULTS: The mean preoperative values for CAT, PCT and CTTL were 461.4 +/- 30.3, 475.3 +/- 30.5 and 441 +/- 32.0, respectively. The values after 12 months of CXL were 444.6 +/- 36.2, 451.6 +/- 36.7 and 418.2 +/- 41.4. The peripheral corneal thickness at the eight points ranged from 479 to 733 preoperatively. At 12-month post-CXL, the values ranged from 444.6 to 734.1. The mean posterior curvature from apex to periphery ranged from - 4.5 to - 9.1 days preoperatively and from - 4.5 to - 9.2 days at 12 months. These were not statistically significant (ANOVA and unpaired T test). CONCLUSIONS: Our data suggest that CXL over an 8-mm zone can stabilize the peripheral cornea. Longer term follow-up studies on the peripheral cornea after CXL will provide useful information. PMID- 30421317 TI - Automated macular segmentation with spectral domain optical coherence tomography in the fellow eyes of patients with unilateral retinal vein occlusion. AB - PURPOSE: To assess the change in the macular layers in the fellow eyes of unilateral retinal vein occlusion (RVO) patients and to evaluate whether certain layers are more affected based on RVO type. METHODS: This retrospective study included 87 fellow eyes of patients with unilateral RVO (26 central, 61 branch) and 105 eyes of 105 subjects without RVO. Spectral domain optical coherence tomography was used for automatized retinal segmentation. The thicknesses of retinal nerve fiber layer (RNFL), ganglion cells, inner plexiform, inner nuclear, outer plexiform, outer nuclear, photoreceptor layers, overall inner retinal layers and retinal pigment epithelium (RPE) were documented. RESULTS: Inner plexiform layer was thinner in inferior sector in RVO group compared with the control group (p = 0.047). The subgroup analysis showed that the retina was thinner in RVO group compared with the controls without systemic diseases in some sectors of the following layers: inferior retina, RNFL, ganglion cell layer, inner plexiform layer, inner retinal layers and RPE (p < 0.05). Retinal thickness was decreased in the fellow eyes of branch RVO group compared to that in the central RVO group in the some sectors (p < 0.05). CONCLUSIONS: The fellow eyes of unilateral RVO patients did not show major structural differences compared with the controls; however, they revealed significant sectoral thinning in many retinal layers when compared with the eyes of healthy subjects without systemic diseases. Central macula was thinner in the fellow eyes of patients with branch RVO compared to that in central RVO. PMID- 30421318 TI - Prognosis after lamellar keratoplasty for limbal dermoids using preserved corneas. AB - PURPOSE: To evaluate the safety and efficacy of lamellar keratoplasty using preserved donor corneas to treat limbal dermoids. STUDY DESIGN: Retrospective study. METHODS: The clinical records of 19 patients with limbal dermoids, who underwent lamellar keratoplasty using preserved corneas that were observed for more than 6 months at the Keio University School of Medicine between January, 2000 and December, 2017, were retrospectively reviewed. We retrospectively analyzed demographics, surgical outcomes, the occurrence of any surgically induced changes in refraction, and intra and postoperative complications. RESULTS: Patient age at surgery showed 2 peaks, the first ranged from 0 to 6 years, and the second from 13 to 20 years. All patients except one had good cosmetic results. Preoperative astigmatism was more than 2 diopters in 12 of 16 eyes for which refractive data were recorded. The refractive cylinder in 8 of the 16 eyes differed after surgery by less than 2 diopters. Treatment of amblyopia by occlusion of the fellow eye and spectacle prescription was done either prior to or following surgery, and resulted in improved visual acuity in 7 patients. Intraoperative complications did not occur in any of the patients. Postoperatively, all patients except one showed corneal re-epithelialization within a week. CONCLUSION: Lamellar keratoplasty using preserved corneas for limbal dermoid yields good cosmetic results. However, improvements in astigmatism and visual acuity are not guaranteed. Preoperative treatment of amblyopia gives a better prognosis for improved visual acuity postoperatively. Long-term observation including amblyopia treatment is required before and after surgery. PMID- 30421319 TI - The Role of Immunohistochemistry and Molecular Analysis of Succinate Dehydrogenase in the Diagnosis of Endocrine and Non-Endocrine Tumors and Related Syndromes. AB - Succinate dehydrogenase (SDH) is an enzyme complex, composed of four protein subunits, that plays a role in both the citric acid cycle and the electron transport chain. The genes for SDHA, SDHB, SDHC, and SDHD are located in the nuclear DNA, and mutations in these genes have initially been described in paragangliomas (PGL) and pheochromocytomas (PCC), which are relatively rare tumors derived from the autonomic nervous system and the adrenal medulla, respectively. Patients with SDH mutations, that are almost exclusively in the germline, are frequently affected by multiple PGL and/or PCC. In addition, other tumors have been associated with SDH mutations as well, including gastrointestinal stromal tumors, SDH-deficient renal cell carcinoma, and pituitary adenomas. Immunohistochemistry for SDHB and SDHA has been shown to be a valuable additional tool in the histopathological analysis of these tumors, and can be considered as a surrogate marker for molecular analysis. In addition, SDHB immunohistochemistry is relevant in the decision-making whether a genetic sequence variant represents a pathogenic mutation or not. In this review, we highlight the current knowledge of the physiologic and pathologic role of the SDH enzyme complex and its involvement in endocrine and non-endocrine tumors, with an emphasis on the applicability of immunohistochemistry. PMID- 30421320 TI - Recurrent venous thromboembolism in primary membranous nephropathy despite direct Xa inhibitor therapy. AB - Clinically apparent venous thromboembolism (VTE) occurs in approximately 7% of patients with membranous nephropathy. Hypoalbuminemia at diagnosis is an independent risk factor for VTE, and risk increases significantly as albumin falls. Optimal prophylactic and treatment anticoagulation regimens in the nephrotic syndrome remain unproven but novel oral anti-coagulants have become attractive therapeutic options. We describe a patient diagnosed with anti phospholipase A2 receptor antibody positive membranous nephropathy and recurrent VTE while on therapeutic dosing of apixaban. A direct factor Xa inhibitor, apixaban has been shown to be non-inferior to warfarin for the treatment of VTE in the general population. However, because it is highly protein-bound, apixaban may have altered pharmacokinetics and pharmacodynamics in patients with nephrotic syndrome and hypoalbuminemia. This case report highlights the need for further studies of direct oral anticoagulants to fully assess their effectiveness in this high-risk population. PMID- 30421321 TI - Acute toxic and genotoxic effects of formalin in Danio rerio (zebrafish). AB - Formalin is a readily soluble chemical used as a sanitizing agent in the home and hospital. Formaldehyde solutions are routinely used in aquaculture for the prophylaxis and treatment of parasites and fungi, but the adverse effects of their application need to be further investigated. Danio rerio or zebrafish has characteristics favorable to its handling and breeding, and it is highly sensitive to various chemicals, being an ideal experimental model for this type of investigation. Thus, the objective of this study was to verify the toxic and genotoxic effects of formalin and to determine the lethal concentrations of this chemical to support its safe use in disinfection processes. Acute and chronic tests were performed using methods in accordance with international protocols. The genotoxic effect of formalin was evaluated with the micronucleus test using blood samples, which were collected at 96 and 192 h of exposure. The LC50-96h of formalin in D. rerio was 45.73 mg L-1, demonstrating its high resistance compared to other species. Regarding the genotoxic effect, the sublethal concentrations of formalin showed a positive correlation with micronuclei according to the increase in its concentration independent of the time of exposure. The incidence of micronuclei increased with concentration, and the addition of 1 mg L-1 formalin corresponded to an increase of 2.9% in the average number of micronuclei. In other words, formalin at even sublethal concentrations caused genotoxic effects in peripheral blood erythrocytes of D. rerio. Therefore, we recommend further studies and other tests involving this chemical for its use at environmentally safe concentrations. PMID- 30421322 TI - The Gothenburg H70 Birth cohort study 2014-16: design, methods and study population. AB - To improve health care for older persons, we need to learn more about ageing, e.g. identify protective factors and early markers for diseases. The Gothenburg H70 Birth Cohort Studies (the H70 studies) are multidisciplinary epidemiological studies examining representative birth cohorts of older populations in Gothenburg, Sweden. So far, six birth cohorts of 70-year-olds have been examined over time, and examinations have been virtually identical between studies. This paper describes the study procedures for the baseline examination of the Birth cohort 1944, conducted in 2014-16. In this study, all men and women born 1944 on specific dates, and registered as residents in Gothenburg, were eligible for participation (n = 1839). A total of 1203 (response rate 72.2%; 559 men and 644 women; mean age 70.5 years) agreed to participate in the study. The study comprised sampling of blood and cerebrospinal fluid, psychiatric, cognitive, and physical health examinations, examinations of genetics and family history, use of medications, social factors, functional ability and disability, physical fitness and activity, body composition, lung function, audiological and ophthalmological examinations, diet, brain imaging, as well as a close informant interview, and qualitative studies. As in previous examinations, data collection serves as a basis for future longitudinal follow-up examinations. The research gained from the H70 studies has clinical relevance in relation to prevention, early diagnosis, clinical course, experience of illness, understanding pathogenesis and prognosis. Results will increase our understanding of ageing and inform service development, which may lead to enhanced quality of care for older persons. PMID- 30421324 TI - Trabecular Bone Score (TBS) and Bone Metabolism in Patients Affected with Type 1 Neurofibromatosis (NF1). AB - In patients with neurofibromatosis type 1 (NF1), decreased bone mineral density (BMD) and low levels of 25-hydroxy vitamin D3 (25OHD) have been reported. Recently, the trabecular bone score (TBS) measurement has been proposed as index of bone microarchitecture and fracture risk. In 74 NF1 patients (48 females, 26 males, age 41 +/- 12), we measured TBS and investigated clinical stage, lifestyle, vitamin D, serum bone turnover markers, vertebral and femoral BMD. A homogenous cohort of 61 healthy subjects was used as control group. TBS was lower in NF1 patients (1.266 +/- 0.113 vs. 1.346 +/- 0.105) without differences between sexes. No correlations with 25OHD, low exercise, low calcium intake, reduced sun exposure, and number of skin neurofibromas were observed. As expected, hypovitaminosis D was common (98.6%), as well as BMD reduction in hip and spine sites: In NF1 patients, bone texture evaluated by TBS was low in both sexes without any correlation with clinical or metabolic parameters, suggesting a direct role of the fibromin mutation. PMID- 30421325 TI - MiR-4465 directly targets PTEN to inhibit AKT/mTOR pathway-mediated autophagy. AB - Autophagy plays an important role in maintaining cell function. Abnormal autophagy leads to cell dysfunction and is associated with many diseases such as tumors, immunodeficiency diseases, lysosomal storage disorders, and neurodegenerative diseases. Autophagy is precisely regulated, and PTEN plays an important role in regulating autophagy. As noncoding small RNAs, miRNAs play an important role in the fine regulation of cellular processes. However, the mechanism of the miRNA regulation of PTEN-related autophagy has not been fully elucidated. In this study, our results showed that miR-4465 significantly inhibited the expression of PTEN, upregulated phosphorylated AKT, and thereby inhibited autophagy by activating mTOR in HEK293, HeLa, and SH-SY5Y cells. Further studies indicated that miR-4465 reduced PTEN mRNA levels through posttranscriptional regulation via directly targeting the 3'-UTR. Our novel findings provide useful hints for the comprehensive elucidation of the molecular mechanism of miRNA-regulated PTEN-related autophagy and may also provide some new insights for the exploration of miRNAs in the treatment of PTEN-related diseases. PMID- 30421323 TI - Analysis of treatment pathways for three chronic diseases using OMOP CDM. AB - The present study examined treatment pathways (the ordered sequence of medications that a patient is prescribed) for three chronic diseases (hypertension, type 2 diabetes, and depression), compared the pathways with recommendations from guidelines, discussed differences and standardization of medications in different medical institutions, explored population diversification and changes of clinical treatment, and provided clinical big data analysis-based data support for the development and study of drugs in China. In order to run the "Treatment Pathways in Chronic Disease" protocol in Chinese data sources,we have built a large data research and analysis platform for Chinese clinical medical data. Data sourced from the Clinical Data Repository (CDR) of the First Affiliated Hospital of Nanjing Medical University was extracted, transformed, and loaded into an observational medical outcomes partnership common data model (OMOP CDM) Ver. 5.0. Diagnosis and medication information for patients with hypertension, type 2 diabetes, and depression from 2005 to 2015 were extracted for observational research to obtain treatment pathways for the three diseases. The most common medications used to treat diabetes and hypertension were metformin and acarbose, respectively, at 28.5 and 20.9% as first-line medication. New drugs were emerging for depression; therefore, the favorite medication changed accordingly. Most patients with these three diseases had different treatment pathways from other patients with the same diseases. The proportions of monotherapy increased for the three diseases, especially in recent years. The recommendations presented in guidelines show some predominance. High quality, effective guidelines incorporating domestic facts should be established to further guide medication and improve therapy at local hospitals. Medical institutions at all levels could improve the quality of medical services, and further standardize medications in the future. This research is the first application of the CDM model and OHDSI software in China, which were used to study, treatment pathways for three chronic diseases (hypertension, type 2 diabetes and depression), compare the pathways with recommendations from guidelines, discuss differences and standardization of medications in different medical institutions, demonstrate the urgent need for quality national guidelines, explores population diversification and changes of clinical treatment, and provide clinical big data analysis-based data support for the development and study of drugs in China. PMID- 30421326 TI - Bariatric Surgery Worldwide: Baseline Demographic Description and One-Year Outcomes from the Fourth IFSO Global Registry Report 2018. AB - BACKGROUND: Since 2014, the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) has produced an annual report of all bariatric surgery submitted to the Global Registry. We describe baseline demographics of international practice from the 4th report. METHODS: The IFSO Global Registry amalgamated data from 51 different countries, 14 of which provided data from their national registries. Data were available from 394,431 individual records, of which 190,177 were primary operations performed since 2014. RESULTS: Data were submitted on 72,645 Roux en Y gastric bypass operations (38.2%), 87,467 sleeve gastrectomy operations (46.0%), 14,516 one anastomosis gastric bypass procedures (7.6%) and 9534 gastric banding operations (5.0%) as the primary operation since 2014. The median patient body mass index (BMI) pre-surgery was 41.7 kg m2 (inter quartile range: 38.3-46.1 kg m2). Following gastric bypass, 84.1% of patients were discharged within 2 days of surgery; and 84.5% of sleeve gastrectomy patients were discharged within 3 days. Assessing operations performed between 2012 and 2016, at one year after surgery, the mean recorded percentage weight loss was 28.9% and 66.1% of those taking medication for type 2 diabetes were recorded as not using them. The proportion of patients no longer receiving treatment for diabetes was highly dependent on weight loss achieved. There was marked variation in access and practice. CONCLUSIONS: A global description of patients undergoing bariatric surgery is emerging. Future iterations of the registry have the potential to describe the operated patients comprehensively. PMID- 30421327 TI - Student Self-Efficacy, Classroom Engagement, and Academic Achievement: Comparing Three Theoretical Frameworks. AB - Student self-efficacy, behavioral engagement, and emotional engagement are key factors for academic achievement. Research has yet to identify the developmental cascades linking these four constructs. Three theoretical frameworks, i.e., Self Efficacy Theory, the Self-System Model of Motivational Development, and Expectancy-Value Theory, suggest different nexus. Following 671 students (51.8% girls) from their 4th to 6th grade, this study aims to assess competing hypotheses from these three frameworks in math. Three cross-lag models were tested to test each theoretical framework. A fourth and final model was tested to include the significant paths from the previous models. Mediation paths were also tested. Results mainly support assumptions from Self-Efficacy Theory, that is student self-efficacy and academic achievement are mutually associated from 4th to 6th grades. Some of the propositions of Expectancy-Value Theory were also supported. Self-efficacy was associated with later emotional engagement and academic achievement. However, emotional engagement in 5th grade was negatively associated with achievement in 6th grade and was not associated with behavioral engagement. Assumptions from the Self-System Model were not supported by the data. Testing the fourth model revealed an unexpected developmental cascade: 5th grade self-efficacy mediated the association between 4th-grade achievement and 6th-grade emotional engagement. This last finding may have great implications for young adolescents as emotional engagement is an indicator of student well-being and intrinsic value of learning. Implications for theory validation and intervention targets for adolescents are discussed. PMID- 30421329 TI - Contact Dermatitis to Cosmetics. AB - Allergic contact dermatitis (ACD) to cosmetics is extremely common-probably the most common reason patients present for patch testing. The diagnosis should initially be suspected based on the patient history and the distribution of the dermatitis. Once the diagnosis is suspected, empiric recommendations for low allergenicity products should be implemented until patch testing is performed. The face is exposed to greatest number of cosmetics, and as a result, facial dermatitis is the prototypical presentation of cosmetic contact dermatitis. In particular, the eyelids are frequently involved, with common sources including shampoo, conditioner, facial cleansers, makeup remover, mascara, nail polish, acrylic nails, makeup sponges, eyelash curlers, and allergens transferred from the hands. Other typical facial distributions include lateral facial dermatitis, central facial dermatitis, and generalized facial dermatitis, each with its own unique set of most likely causes. Lateral facial and/or neck dermatitis is often a "rinse-off" pattern, with shampoo and/or conditioner rinsing down over these areas. Central facial dermatitis, when due to ACD, can be due to gold being released from gold rings and contaminating makeup foundation or to ingredients in moisturizers, wrinkle creams, topical medications, or makeup. Sparing of the lateral face is largely due to the fact that patients are more assiduous about applying the aforementioned substances to the central face than to the lateral face. Generalized facial dermatitis should trigger consideration of airborne contactants, facial cleansers, makeup foundation, and moisturizers and medications that are being applied confluently. Once adequate patch testing has been performed, there are a number of extremely helpful resources to help patients find products that are safe for use, such as the American Contact Dermatitis Society's "Contact Allergen Management Program" app. PMID- 30421328 TI - Aerial and terrestrial-based monitoring of channel erosion, headcutting, and sinuosity. AB - Headcuts are points of accelerated channel erosion that frequently have ecological consequences. A particularly large and dynamic headcut in southwest Wyoming has affected natural and anthropogenic resources for decades. To better understand and address this issue, we undertook a review of the headcut's upstream retreat, followed by photogrammetric monitoring of the present condition for erosion monitoring. Aerial photography shows the Bitter Creek headcut retreated > 200 m upstream in 68 years (1948-2016) at ~ 1.4 m year-1. Following installation of a concrete slab structure in the mid-1970s, headcut retreat slowed to ~ 0.5 m year-1. Channel sinuosity downstream of the headcut is greater than upstream, which we attribute to the presence of the headcut, given that there are no major changes in valley geometry, geology, or soils through this reach. Both aerial and terrestrial-based image platforms were used to collect stereo imagery and create 3D photogrammetric models of the headcut in 2016. From these two models, we measured soil loss downstream of the headcut at ~ 126 m3 m-1 valley length. Since 1954, soil loss within the channel has been ~ 98 m3 year-1 or ~871 t ha-1 year-1since then. Models created from aerial- and terrestrial based images differed in volumetric estimates by 2%, indicating that either method could be used for this type of monitoring. The ground-based imagery model showed more detail, especially on vertical and overhanging surfaces, while the aerial imagery model produced a more realistic orthomosaic and efficiently covered a larger area. Ground-based image acquisition took longer and was more costly per unit area, but is an efficient method for small project areas, or areas where aerial imagery cannot be safely or practically acquired. Historical imagery and photogrammetric modeling proved very useful in elucidating stream dynamics associated with this large, dynamic headcut. PMID- 30421330 TI - Comprehensive MS-based screening and identification of pharmaceutical transformation products formed during enzymatic conversion. AB - In this study, transformation products (TPs) of diclofenac, mefenamic acid, and sotalol derived from peroxidase- and laccase-catalyzed transformations were studied with different mass spectrometry (MS)-based workflows. A straightforward pre-screening of enzymatic degradation rate was performed using a robotic nano ESI source coupled to single quadrupole MS. Accurate mass data and information on molecular hydrophobicity were obtained from a serial coupling of reversed phase liquid chromatography (RPLC) with hydrophilic interaction liquid chromatography (HILIC) to a time-of-flight-mass spectrometer (ToF-MS). These parameters were combined with fragmentation information from product ion scan operated in enhanced mode (EPI) with precursor selection in Q3 and data from multiple reaction monitoring (MRM) modes using a hybrid triple quadrupole-linear ion trap mass spectrometer (QqQ/LIT-MS). "Suspect" MRM modes did not provide a significant sensitivity improvement compared to EPI experiments. The complementarity of the data from different MS-based workflows allowed for an increase of identification confidence. Overall, this study demonstrated that dimerization, hydroxylation, and dehydration reactions were the predominant mechanisms found for diclofenac and mefenamic acid during enzyme-catalyzed transformation, whereas a degradation product was observed for the peroxidase-catalyzed conversion of sotalol. Results can contribute to understand enzymatic mechanisms and provide a basis for assessing risks and benefits of enzyme-based remediation. Graphical abstract ?. PMID- 30421331 TI - Re-using questions in classroom-based assessment: An exploratory study at the undergraduate medical education level. AB - INTRODUCTION: To alleviate some of the burden associated with the development of novel quality questions on a regular basis, medical education programs may favour the use of item banks. This practice answers the real pragmatic need of having to create exams de novo at each administration while benefiting from using psychometrically sound questions to assess students. Unfortunately, programs cannot prevent trainees from engaging in cheating behaviours such as content sharing, and little is known about the impact of re-using items. METHODS: We conducted an exploratory descriptive study to assess the effect of repeated use of banked items within an in-house assessment context. The difficulty and discrimination coefficients for the 16-unit exams of the past 5 years (1,629 questions) were analyzed using repeated measure ANOVAs. RESULTS: Difficulty coefficients increased significantly (M = 79.8% for the first use of an item, to a mean difficulty coefficient of 85.2% for the fourth use) and discrimination coefficients decreased significantly with repeated uses (M = 0.17, 0.16, 0.14, 0.14 for the first, second, third and fourth uses respectively). DISCUSSION: The results from our study suggest that using an item three times or more within a short time span may cause a significant risk to its psychometric properties and consequently to the quality of the examination. Pooling items from different institutions or the recourse to automatic generated items could offer a greater pool of questions to administrators and faculty members while limiting the re-use of questions within a short time span. PMID- 30421332 TI - Reflecting on what? The difficulty of noticing formative experiences in the moment. AB - INTRODUCTION: In the spirit of enacting an educational model of guided, collective reflection to support positive professional identity construction in healthcare learners, we implemented a reflection-based course for medical students transitioning to clerkship with three goals: to sensitize learners to the hidden curriculum; to provide a safe and confidential forum to discuss their experiences; and to co-construct strategies to deal with the pressures in the clinical environment METHODS: We used a design-based research protocol. Twelve students participated in ten sessions starting during their transition to clerkship. Faculty debriefed after each session, adjusting the format of the subsequent sessions. Data included student logs, transcripts of the course sessions, faculty debriefings, and the course evaluation. Data were analyzed via an iterative process of independent coding and discussion. RESULTS: The main adjustments to the course were to eliminate didactic content in favour of using prompts prior to course sessions and de-emphasizing written reflection. Participants felt the course achieved its three goals and students reported enhanced resiliency during transition to clerkship, although, despite prompting, students offered no examples of their joining in with the negative behaviours around them. CONCLUSIONS: The course was successful in its key objectives. However, a key aspect of reflection, students noticing their own behaviour in the moment as something that needs to be reflected on, was challenging. Future research exploring the value of reflection as an intervention to redress the unwanted aspects of the hidden curriculum might focus on efforts to move the students to explicitly explore the enculturation process in themselves. PMID- 30421334 TI - Addressing Lifestyle Management During Visits Involving Patients with Prediabetes: NAMCS 2013-2015. AB - BACKGROUND: The gap between treatment guidelines and clinical practice in prediabetes management has been identified in previous studies. The knowledge related to addressing lifestyle change during office visits in clinical practice to manage prediabetes is limited. OBJECTIVE: To describe patterns of lifestyle management addressed during office-based visits involving patients with prediabetes and identify factors associated with addressing lifestyle management during physician office visits in the USA. DESIGN: Cross-sectional study PARTICIPANTS: US National Ambulatory Medical Care Survey (NAMCS) data from 2013 to 2015 were combined to identify office-based visits involving patients with prediabetes. MAIN MEASURES: The major outcome is lifestyle management including diet/nutrition, exercise, and/or weight reduction. Patient and physician characteristics were collected for analysis. The prevalence and patterns of addressing lifestyle management during visits were estimated and described. Multivariate logistic regression model identified significant factors associated with lifestyle management. The patient visit weight was applied to all analyses to achieve nationally representative estimates. KEY RESULTS: Among 4039 office based visits involving patients with prediabetes between 2013 and 2015, 22.8% indicated lifestyle management was addressed during the visits. Diet/nutrition, exercise, and weight reduction accounted for 86.1%, 62.6%, and 34.1% of the visits with lifestyle management addressed, respectively. Lifestyle management was more likely to be addressed during the visits involving patients with hyperlipidemia (OR = 1.74, 95% CI 1.24-2.46) and obesity (OR = 4.03, 95% CI 2.91 5.56), seeing primary physicians (vs. other specialties, OR = 1.46, 95% CI 1.03 2.08), and living in the southern region (vs. northeast, OR = 1.96, 95% CI 1.20 3.19). CONCLUSIONS: The prevalence of addressing lifestyle management during office visits involving patients with prediabetes remained low in the USA. Patients' clinical characteristics, geographic region, and physician's specialty were associated with addressing lifestyle management during the visits. PMID- 30421333 TI - Students as stakeholders in assessment: how students perceive the value of an assessment. AB - INTRODUCTION: For assessment to fill an educational role, students must see the results generated by assessment as valuable, and actively engage with this feedback in order to support learning. Few studies include examinees as stakeholders in validation beyond general notions of acceptability. Here, we explore students as stakeholders in the validation of a newly implemented assessment. METHODS: A student-relevant validity framework based on the unified theory of validity was created and adapted to a survey format. Likert-style items were used to examine first- and second-year medical students' perceptions of a new cumulative assessment, with several open-ended items. Analysis included: mean ratings per subscale of validity evidence, thematic analysis of comments, and a correlation between questionnaire subscores and exam performance. RESULTS: Seventy-seven students participated (20.5%). Student perceptions of the assessment were favourable, with significantly different ratings across validity evidence (Response Process (4.8 (SD = 0.7); scored/6), Content (4.6(0.9)), Consequential (4.4(0.8)), Internal Structure (4.2(0.9)), and Relationship to Other Variables (4.0(1.0))). Exam performance correlated with subscores for Relationship to Other Variables (r = 0.34, p < 0.005) and Response Process (r = 0.24, p < 0.05). DISCUSSION: Students perceived the assessment as facilitating learning, providing 'checkpoints', and were disappointed when it did not meet their expectations regarding the purpose of assessment. If students perceive that results do not reflect their future performance in clinical environments, or do not align with their perceived purpose of assessment, the educational value of assessment may be limited. It is critical to understand when, and how students engage in interpreting and integrating assessment-generated feedback to ensure that assessment contributes positively to learning. PMID- 30421335 TI - Medically Tailored Meal Delivery for Diabetes Patients with Food Insecurity: a Randomized Cross-over Trial. AB - BACKGROUND: Food insecurity, defined as inconsistent food access owing to cost, leads to poor health. OBJECTIVE: To test whether a medically tailored meal delivery program improved dietary quality in individuals with type 2 diabetes and food insecurity. DESIGN: Randomized cross-over clinical trial. PARTICIPANTS: Forty-four adults with diabetes, hemoglobin A1c > 8.0%, and food insecurity (defined as at least one positive item on the two-item "Hunger Vital Sign"). INTERVENTION: In the Community Servings: Food as Medicine for Diabetes cross-over clinical trial (NCT02426138), conducted from June 2015 to July 2017, we randomly assigned the order of "on-meals" (home delivery of 10 meals/week for 12 weeks delivered by Community Servings, a non-profit organization) and "off-meals" (12 weeks usual care and a Choose MyPlate healthy eating brochure) periods. MAIN MEASURES: The primary outcome was Healthy Eating Index 2010 score (HEI), assessed by three 24-h food recalls in both periods. Higher HEI score (range 0-100; clinically significant difference 5) represents better dietary quality. Secondary outcomes included food insecurity and self-reported hypoglycemia. KEY RESULTS: Mean "on-meal" HEI score was 71.3 (SD 7.5) while mean "off-meal" HEI score was 39.9 (SD 7.8) (difference 31.4 points, p < 0.0001). Participants experienced improvements in almost all sub-categories of HEI score, with increased consumption of vegetables, fruits, and whole grains and decreased solid fats, alcohol, and added sugar consumption. Participants also reported lower food insecurity (42% "on-meal" vs. 62% "off-meal," p = 0.047), less hypoglycemia (47% "on-meal" vs. 64% "off-meal," p = 0.03), and fewer days where mental health interfered with quality of life (5.65 vs. 9.59 days out of 30, p = 0.03). CONCLUSIONS: For food-insecure individuals with diabetes, medically tailored meals improved dietary quality and food insecurity and reduced hypoglycemia. Longer-term studies should evaluate effects on diabetes control (e.g., hemoglobin A1c) and patient-reported outcomes (e.g., well-being). PMID- 30421336 TI - Equal Rights for General Internists. PMID- 30421337 TI - Apple Watch Steps. PMID- 30421338 TI - A case-control study of the determinants for cervicocerebral artery dissection. AB - BACKGROUND: Cervicocerebral artery dissection (CAD) is a major cause of ischemic stroke in young adults. There are many existing studies on determinants for CAD; however, they are still not totally defined. We conduct the study to further investigate the determinants for CAD based on ischemic stroke patients. METHODS: 81 ischemic stroke patients with CAD were enrolled in the CAD stroke group and 84 ischemic stroke patients without CAD were enrolled in the non-CAD stroke group. Their clinical data, such as age, gender, vascular risk factors, headache and neck pain and clinical laboratory data, were collected to analyze the differences between the two groups. RESULTS: A total of 165 ischemic stroke patients were included. The mean age of CAD stroke group was (51.6 +/- 12.4) years, and (55.5 +/- 8.1) years in non-CAD stroke group, with a statistically significant difference (P = 0.017). The average level of triglycerides in CAD stroke group was (1.3 +/- 0.7) mmol/L, and (1.7 +/- 1.1) mmol/L in non-CAD stroke group, with a statistically significant difference (P = 0.012). There were 42.0% (34/81) of headache and neck pain in CAD stroke group and 22.6% (19/84) in non-CAD stroke group, with a statistically significant difference (P = 0.008). The key findings with significant difference were stratified and multivariate logistic regression analysis showed that age < 50 years old (OR 2.98, 95% CI 1.43-6.21, P = 0.004), triglycerides < 1.6 mmol/L (OR 3.51, 95% CI 1.69-7.27, P = 0.001) and headache and neck pain (OR 2.94, 95% CI 1.39-6.20, P = 0.005) showed a positive correlation with CAD. CONCLUSION: In the process of diagnosis and treatment of ischemic stroke, for patients with age < 50 years old, headache and neck pain and triglycerides < 1.6 mmol/L, the cervicocerebral artery dissection should be considered, and vascular imaging examination needs to be performed in time. PMID- 30421339 TI - Anti-ganglioside antibody-associated acute unilateral peripheral vestibulopathy. PMID- 30421340 TI - Admission diagnoses of patients later diagnosed with autoimmune encephalitis. AB - BACKGROUND: Since the detection of autoantibodies against neuronal surface antigens, autoimmune encephalitis (AE) has been more frequently diagnosed, especially in patients with symptoms typical of limbic encephalitis, such as seizures, short-term memory deficits, or psychosis. However, the clinical spectrum of AE may be much wider, making correct clinical diagnosis difficult. METHODS: We retrospectively analysed symptoms and admission diagnoses at first clinical presentation in 50 AE patients. We included patients with a clinical diagnosis of AE for whom a FDG-PET imaging was available. Final diagnoses were re evaluated by a blinded investigator according to the most recent consensus suggestions published in 2016 for AE diagnostic criteria. We additionally describe two patients with Morvan syndrome who showed CASPR2 antibodies. RESULTS: In 40 patients (80.0%), the clinical presentation at first admission was typical for AE. Ten patients (20.0%) initially suffered from atypical symptoms; among these patients, isolated headache and cerebellar dysfunction were most frequent (three patients each). However, an initial diagnosis of suspected encephalitis was only reached in 16 patients (32.0%), nine (18.0) of which were suspected to have infectious encephalitis, and seven (14.0%) patients were suspected to have AE. In 34 patients (68.0%), a diagnosis other than encephalitis was considered, (e.g., epilepsy, psychiatric diseases, transient ischemic attack, dementia, meningitis, and cerebellitis). CONCLUSIONS: These data show the broad spectrum of initial symptoms of AE; the correct initial diagnosis of AE is often missed or delayed. Hence, clinicians in neurological and psychiatric hospitals should consider AE in the differential diagnosis of cases with atypical clinical presentations. PMID- 30421341 TI - Business models and provider satisfaction in in vitro fertilization centers in the USA. AB - PURPOSE: The number of in vitro fertilization (IVF) cycles is increasing and the majority of patients undergoing IVF pay out of pocket. Reproductive endocrinology and infertility practitioners employ different business models to help create financial pathways for patients needing IVF but details regarding the different types of business models being used and physician satisfaction with those models have not been described previously. METHODS: A cross-sectional survey was sent to members of the Society of Reproductive Endocrinology and Infertility. The survey included 30 questions designed to assess demographics, practice patterns, and business models utilized. RESULTS: A total of 222/736 (30%) physicians responded to the survey. The majority of physicians offer a-la-carte (67%), bundled services (69%), grants (57%), and cost/risk-sharing (50%). The majority answered that the single ideal business model is bundled services (53%). There was no significant association between financial package offered and region of practice or state-mandated insurance. The largest barrier to care reported was cost with or without state-mandated coverage (94% and 99%, respectively). The majority of practices are satisfied with their business model (75%). Higher physician satisfaction was associated with private practice [69% vs 27%; OR (95%CI) = 3.8 (1.7, 8.6)], male gender [59% vs 30%; OR = 2.4 (1.1, 5.4)], and offering bundled services [83% vs 59%; OR = 2.8 (1.2, 6.7)]. CONCLUSIONS: Physicians utilize a variety of business models and most are satisfied with their current model. Cost is the major barrier to care in states with and without mandated coverage. PMID- 30421342 TI - The model of "genetic compartments": a new insight into reproductive genetics. AB - Currently, we are witnessing revolutionary advances in the analytical power of genetic tools. An enormous quantity of data can now be obtained from samples; however, the translation of genetic findings to the general status of individuals, or their offspring, should be done with caution. This is especially relevant in the reproductive context, where the concepts of "transmission" and "inheritability" of a trait are crucial. Against this background, we offer new insight based on a systemic view of genetic constitution in the compartmentalized organism, that is, the human body. This model considers the coexistence of "different" genomes in the same individual and the repercussion of this on reproductive efficacy and offspring. Herein, we review the major differences between somatic, germinal, embryonic, and fetal/placental genomes and their contribution to the next generation and its reproductive efficacy. The major novelty of our approach is the holistic interaction between microsystems within a macrosystem (i.e., the reproductive system). This panoramic model allows us to sketch the future implications of genetic results in function of the origin (compartment) of the sample: peripheral blood or other somatic tissues, gametes, zygotes, preimplantation embryos, fetus, or placenta. We believe this perspective can be of great use in the context of reproductive genetic counseling. PMID- 30421343 TI - Time-lapse imaging reveals delayed development of embryos carrying unbalanced chromosomal translocations. AB - PURPOSE: The purpose of the study was to compare the morphokinetic parameters of embryos carrying balanced chromosomal translocations with those carrying unbalanced chromosomal translocations using time-lapse microscopy. METHODS: The study group included 270 embryos that underwent biopsies on day 3 for preimplantation genetic diagnosis (PGD) for chromosomal translocations in our unit between 2013 and 2015. All embryos were incubated under time-lapse microscopy and evaluated for timing of developmental events up to day 5. The timing of these events was compared between balanced and unbalanced embryos, potentially viable and nonviable variants, and maternal versus paternal inheritance of the translocation. RESULTS: The PGD analysis found that 209 (77%) of the 270 biopsied embryos carried an unbalanced translocation. Embryos carrying unbalanced translocations, which are expected to lead to implantation failure or miscarriage, cleaved less synchronously and were delayed in time of cleavage to the 4-cell stage (t4) and in time of start of blastulation (tSB) compared with balanced embryos (P < 0.05). Furthermore, embryos carrying nonviable translocations demonstrated a significant delay at the time of pronuclei fading (tPNf) compared with those carrying potentially viable translocations (P < 0.05). Embryos whose unbalanced translocations were of maternal origin were significantly delayed in most of the morphokinetic parameters (including tPNf, t2, t3, t4, t6, t7, t8, cc2, s2, and tSB) compared with embryos carrying balanced translocations (P < 0.05). CONCLUSIONS: Embryos carrying unbalanced chromosomal translocations mainly of maternal origin undergo delayed development and asynchronous cleavage that may lead to implantation failure or miscarriage. PMID- 30421345 TI - Correcting QT for Heart Rate When Both are Affected by a Drug. PMID- 30421344 TI - Covalently Modified Graphene Oxide and Polymer of Intrinsic Microporosity (PIM-1) in Mixed Matrix Thin-Film Composite Membranes. AB - In this study, mixed matrix membranes (MMMs) consisting of graphene oxide (GO) and functionalized graphene oxide (FGO) incorporated in a polymer of intrinsic microporosity (PIM-1) serving as a polymer matrix have been fabricated by dip coating method, and their single gas transport properties were investigated. Successfully surface-modified GOs were characterized by Fourier transform infrared spectroscopy (FTIR), UV-Vis spectroscopy, Raman spectroscopy, scanning electron microscopy (SEM), and thermogravimetric analysis (TGA). The effect of FGO loading on MMM morphology and performance was investigated by varying the FGO content in polymer matrix from 9 to 84 wt.%. Use of high FGO content in the polymer matrix helped to reveal difference in interaction of functionalized fillers with PIM-1 and even to discuss the change of FGO stiffness and filler alignment to the membrane surface depending on functional group nature. PMID- 30421346 TI - Advances in Epidemiological Methods and Utilisation of Large Databases: A Methodological Review of Observational Studies on Central Nervous System Drug Use in Pregnancy and Central Nervous System Outcomes in Children. AB - INTRODUCTION: Studies have used various epidemiological approaches to study associations between central nervous system (CNS) drug use in pregnancy and CNS outcomes in children. Studies have generally focused on clinical adverse effects, whereas variations in methodologies have not received sufficient attention. OBJECTIVE: Our objective was to review the methodological characteristics of existing studies to identify any limitations and recommend further research. METHODS: A systematic literature search was conducted on observational studies listed in PubMed from 1 January 1946 to 21 September 2017. Following independent screening and data extraction, we conducted a review addressing the trends of relevant studies, differences between various data sources, and methods used to address bias and confounders; we also conducted statistical analyses. RESULTS: In total, 111 observational studies, 25 case-control studies, and 86 cohort studies were included in the review. Publications dating from 1978 to 2006 mainly focused on antiepileptic drugs, but research on antidepressants increased from 2007 onwards. Only one study focused on antipsychotic use during pregnancy. A total of 46 studies obtained data from an administrative database/registry, 20 from ad hoc disease registries, and 41 from ad hoc clinical samples. Most studies (58%) adjusted the confounding factors using general adjustment, whereas only a few studies used advanced methods such as sibling-matched models and propensity score methods; 42 articles used univariate analyses and 69 conducted multivariable regression analyses. CONCLUSION: Multiple factors, including different study designs and data sources, have led to inconsistent findings in associations between CNS drug use in pregnancy and CNS outcomes in children. Researchers should allow for study designs with clearly defined exposure periods, at the very least in trimesters, and use advanced confounding adjustment methodology to increase the accuracy of the findings. PMID- 30421347 TI - Filling gaps in the microsporidian tree: rDNA phylogeny of Chytridiopsis typographi (Microsporidia: Chytridiopsida). AB - Microsporidia are intracellular eukaryotic parasites of animals, characterized by unusual morphological and genetic features. They can be divided in three main groups, the classical microsporidians presenting all the features of the phylum and two putative primitive groups, the chytridiopsids and metchnikovellids. Microsporidia originated from microsporidia-like organisms belonging to a lineage of chytrid-like endoparasites basal or sister to the Fungi. Genetic and genomic data are available for all members, except chytridiopsids. Herein, we filled this gap by obtaining the rDNA sequence (SSU-ITS-partial LSU) of Chytridiopsis typographi (Chytridiopsida), a parasite of bark beetles. Our rDNA molecular phylogenies indicate that Chytridiopsis branches earlier than metchnikovellids, commonly thought ancestral, forming the more basal lineage of the Microsporidia. Furthermore, our structural analyses showed that only classical microsporidians present 16S-like SSU rRNA and 5.8S/LSU rRNA gene fusion, whereas the standard eukaryote rRNA gene structure, although slightly reduced, is still preserved in the primitive microsporidians, including 18S-like SSU rRNA with conserved core helices, and ITS2-like separating 5.8S from LSU. Overall, our results are consistent with the scenario of an evolution from microsporidia-like rozellids to microsporidians, however suggesting for metchnikovellids a derived position, probably related to marine transition and adaptation to hyperparasitism. The genetic and genomic data of additional members of Chytridiopsida and Rozellomycota will be of great value, not only to resolve phylogenetic relationships but also to improve our understanding of the evolution of these fascinating organisms. PMID- 30421348 TI - Niosomes for enhanced activity of praziquantel against Schistosoma mansoni: in vivo and in vitro evaluation. AB - Praziquantel (PZQ) is recommended by the WHO as the first line in treatment of schistosomiasis. Unfortunately, it exhibits low oral bioavailability which can compromise its efficacy. Nanostructures showed promising potential to overcome this problem. Accordingly, the aim of this study was to investigate the effect of niosomal encapsulation of PZQ on its activity on Schistosoma mansoni in vitro and in vivo. PZQ was encapsulated in niosomal formulation comprising span 60, cholesterol with peceol being included as absorption enhancer. The in vitro work determined the schistosomicidal activity and morphological changes after incubation with drug solution or PZQ-niosomes. The in vivo study utilized infected mice which received PZQ orally as solution or as niosomes. The activity was assessed by monitoring egg and worm count in addition to histopathological and immunohistochemical studies. The in vitro studies revealed that niosomes alone caused a 30% death of adult parasites and caused completely coiled body, destruction, and peeling of tubercles and spines, with flattening and effacement of gynecophoric canal, blebbing with niosomes vesicles attached to it. Niosomes containing PZQ at a concentration of 0.001 MUg/ml increased the death from 30 to 50% with the corresponding PZQ solution causing only 10% death. The in vivo study reflected of niosome-PZQ over PZQ solution as indicated from significant reduction of adult worm count, hepatic and intestinal egg depositions, hepatic granuloma size, and numbers, with marked reduction of vascular endothelial growth factor expression. The study introduced niosomes as promising carriers for enhanced activity of PZQ. PMID- 30421349 TI - Ticks and associated pathogens from dogs in northern Vietnam. AB - The medical and veterinary significance of ticks and tick-borne pathogens (TBPs) in tropical and subtropical zones is well recognized. Although ticks and TBPs are known to occur in Southeast Asia, limited data is available in the international literature for some countries, such as Vietnam. The aim of this study was to investigate the species of ticks and TBPs associated with dogs in northern Vietnam. Out of 359 dogs enrolled in this study, 26.2% (n = 94) were infested by 466 ticks (i.e., 287 males, 139 females, 30 nymphs, and 10 larvae). All ticks were morphologically identified as Rhipicephalus sanguineus sensu lato, and some of them genetically characterized as belonging to the tropical lineage. A total of 302 ticks were molecularly screened for the detection of selected TBPs. Three ticks were positive for Hepatozoon canis, one for Ehrlichia canis, and one for Babesia vogeli, representing the first molecular characterization of these pathogens in Vietnam. In conclusion, the tropical lineage of R. sanguineus s.l. is the dominant tick taxon infesting dogs from northern Vietnam, where different TBPs are circulating. PMID- 30421350 TI - Monte Carlo on the manifold and MD refinement for binding pose prediction of protein-ligand complexes: 2017 D3R Grand Challenge. AB - Manifold representations of rotational/translational motion and conformational space of a ligand were previously shown to be effective for local energy optimization. In this paper we report the development of the Monte-Carlo energy minimization approach (MCM), which uses the same manifold representation. The approach was integrated into the docking pipeline developed for the current round of D3R experiment, and according to D3R assessment produced high accuracy poses for Cathepsin S ligands. Additionally, we have shown that (MD) refinement further improves docking quality. The code of the Monte-Carlo minimization is freely available at https://bitbucket.org/abc-group/mcm-demo . PMID- 30421351 TI - Perception and attitude of the general population towards Alzheimer's disease in Jeddah, Saudi Arabia. AB - There are many conflicting beliefs about Alzheimer's disease in the general population. Conducting a study on public awareness, attitude, and knowledge towards Alzheimer's disease is useful in decreasing discrimination and stigmatization. This study aims to determine the public perception and attitude towards Alzheimer's disease in Jeddah, Saudi Arabia. In addition, we aim to identify the religious and cultural beliefs about the causes and treatment of Alzheimer's disease in Saudi Arabia. This is a cross-sectional study that was conducted in malls and public places in Jeddah, Saudi Arabia. The instrument used in this study was a self-administered questionnaire that consists of 40 items. A total of 32 questions were included into the survey, which was subdivided into four sources of information that include general information about Alzheimer's disease, information about Alzheimer's disease in the society, general information about persons with Alzheimer's disease, and information about the care of persons with Alzheimer's disease. In addition, eight questions were used to collect information about the demographic profile of the participants. A total of 1698 individuals participated in the study. 1511 participants (89%) had heard about Alzheimer's disease before. Around 46% of the participants think that the cause of Alzheimer's disease is a brain disease and 44.9% think that is a normal part of aging. Approximately, 30% of the participants believe that Alzheimer's disease is treated with medications and 24.6% believe that there is no treatment. Around 30% of the participant think that the society treats persons with Alzheimer's disease with stigmatization. More than half of the participants (56.2%) think that persons with Alzheimer's disease should not be admitted to the nursing home. The results of the present study suggest that the perception of the general public of Alzheimer's disease is lagging behind. Many wrong beliefs were identified in the general public regarding the causes and management. The findings of our study suggest that more information about Alzheimer's disease would be valuable and beneficial for everyone. Awareness campaigns and public education are needed to increase the knowledge of the general public regarding several aspects of the disease including prevention, causes, and management. Dissemination of information about Alzheimer's disease should be of high priority. Increased awareness will lead to earlier detection of Alzheimer's disease and other dementia cases and appropriate care and management of those persons. PMID- 30421352 TI - Unusual case of complex fracture dislocation of the elbow. PMID- 30421353 TI - The added value of right ventricular longitudinal strain in patients with chronic thromboembolic pulmonary hypertension. PMID- 30421354 TI - Assessment of peri-device leaks after interventional left atrial appendage closure using standardized imaging by cardiac computed tomography angiography. AB - Cardiac computed tomography angiography (cCTA) has recently been proposed for evaluation of successful interventional left atrial appendage closure (LAA/LAAC). This prospective longitudinal observational study aims to assess this proposal by applying a standardized imaging protocol to detect and quantify peri-device leaks (PDL) after LAAC. cCTA datasets of consecutive patients 6 months after successful LAAC were acquired on a third generation dual-source computed tomography system and reconstructed with a slice thickness of 0.5 mm. The standardized multi-planar reconstruction LAA occluder view for post-implantation evaluation (LOVE) algorithm was used to assess PDL in relation to LAA morphology and implanted LAAC devices. A total of 49 patients (median age 80 years, 24% female) were included consecutively. Overall PDL rate was 31%. Leak rates among different left atrial appendage morphologies varied largely. Windsock type had the highest incidence of PDL (47%). AMPLATZERTM AMULETTM device type revealed slightly higher PDL rates than WATCHMANTM type and showed larger leaks. However, no statistical differences were found. PDL can be sized best in LOVE sagittal views, whereas a synopsis of LOVE sagittal, axial and coronal views allows further examination and detection of small leaks. PDL are common after successful interventional LAAC, which can be accurately detected and sized by standardized cCTA imaging protocols. PMID- 30421356 TI - Optic tectal superficial interneurons detect motion in larval zebrafish. AB - Detection of moving objects is an essential skill for animals to hunt prey, recognize conspecifics and avoid predators. The zebrafish, as a vertebrate model, primarily uses its elaborate visual system to distinguish moving objects against background scenes. The optic tectum (OT) receives and integrates inputs from various types of retinal ganglion cells (RGCs), including direction-selective (DS) RGCs and size-selective RGCs, and is required for both prey capture and predator avoidance. However, it remains largely unknown how motion information is processed within the OT. Here we performed in vivo whole-cell recording and calcium imaging to investigate the role of superficial interneurons (SINs), a specific type of optic tectal neurons, in motion detection of larval zebrafish. SINs mainly receive excitatory synaptic inputs, exhibit transient ON- or OFF-type of responses evoked by light flashes, and possess a large receptive field (RF). One fifth of SINs are DS and classified into two subsets with separate preferred directions. Furthermore, SINs show size-dependent responses to moving dots. They are efficiently activated by moving objects but not static ones, capable of showing sustained responses to moving objects and having less visual adaptation than periventricular neurons (PVNs), the principal tectal cells. Behaviorally, ablation of SINs impairs prey capture, which requires local motion detection, but not global looming-evoked escape. Finally, starvation enhances the gain of SINs' motion responses while maintaining their size tuning and DS. These results indicate that SINs serve as a motion detector for sensing and localizing sized moving objects in the visual field. PMID- 30421355 TI - Hyperkalaemia in Heart Failure-Pathophysiology, Implications and Therapeutic Perspectives. AB - PURPOSE OF REVIEW: Hyperkalaemia is a frequent and sometimes life-threatening condition that may be associated with arrhythmia and cardiac dysfunction. Evaluating the prevalence of hyperkalaemia in patients with heart failure (HF) and potential treatments of this condition is essential for patients using renin angiotensin-aldosterone system inhibitors or angiotensin receptor-neprilysin inhibitor and mineralocorticoid receptor antagonists, which represent the cornerstone and highly proven life-saving therapy. RECENT FINDINGS: Novel findings from the past few years include data regarding the epidemiology, pathomechanisms, implications and novel therapeutic approaches to counteract hyperkalaemia in patients with HF. Whilst older potassium-binding agents are associated with serious adverse events, novel potassium-binding drugs are effective in lowering potassium levels and are generally well tolerated. Hyperkalaemia represents both a direct risk of cardiovascular complication and an indirect biomarker of the severity of the underlying disease such as neurohormonal activation and renal dysfunction. Novel potassium-binding drugs such as patiromer and sodium zirconium cyclosilicate may help to optimize therapy in HF and achieve guideline-recommended doses. PMID- 30421357 TI - Screening for mutations in human cardiomyopathy- is RBM24 a new but rare disease gene? PMID- 30421358 TI - Structural basis of AimP signaling molecule recognition by AimR in Spbeta group of bacteriophages. PMID- 30421359 TI - Single senescent cell sequencing reveals heterogeneity in senescent cells induced by telomere erosion. PMID- 30421360 TI - Internal Energy Distribution of Secondary Ions Under Argon and Bismuth Cluster Bombardments: "Soft" Versus "Hard" Desorption-Ionization Process. AB - The emission/ionization process under massive argon cluster bombardment was investigated by measuring the internal energy distributions of a series of benzylpyridinium ions. Argon clusters with kinetic energies between 10 and 20 keV and cluster sizes ranging from 500 to 10,000 were used to establish the influence of their size, energy, and velocity on the internal energy distribution of the secondary ions. It is shown that the internal energy distribution of secondary ions principally depends on the energy per atom or the velocity of the cluster ion beam (E/n ? v2). Under low energy per atom (E/n ? 10 eV), the mean internal energy and fragmentation yield increase rapidly with the incident energy of individual constituents. Beyond 10 eV/atom impact (up to 40 eV/atom), the internal energy reaches a plateau and remains constant. Results were compared with those generated from bismuth cluster impacts for which the mean internal energies correspond well to the plateau values for argon clusters. However, a significant difference was found between argon and bismuth clusters concerning the damage or disappearance cross section. A 20 times smaller disappearance cross section was measured under 20 keV Ar2000+ impact compared to 25 keV Bi5+ bombardment, thus quantitatively showing the low damage effect of large argon clusters for almost the same molecular ion yield. Graphical Abstract ?. PMID- 30421361 TI - LC-MS/MS-Based Separation and Quantification of Marfey's Reagent Derivatized Proteinogenic Amino Acid DL-Stereoisomers. AB - D-Amino acids are important biological molecules. Improved analytical methods for their resolution and quantification remain of keen interest. In this study, we investigated the use of Marfey's reagent (chiral) derivatization coupled with LC MS/MS-based separation and detection of the resulting diastereomers for quantification of the 19 common L- and D-amino acids and glycine. Standard formic acid (pH 2)-based separations on reverse phase media were unable to separate all 19 amino acid DL pairs. In contrast, a water/acetonitrile/ammonium acetate (pH 6.5) solvent system allowed all 19 amino acid DL pairs to be chromatographically resolved on a 30 min gradient, with negative mode detection at pH 6.5 giving good sensitivity. Derivatization reaction rates between amino acids varied substantially, with overnight derivatization required for some amino acids. Chromatography at pH 6.5 combined with MS/MS quantification in negative mode demonstrated good linearity over a wide concentration range for all 20 amino acids. Matrix effects, assessed with an MRSA extract, were negligible. Marfey's derivatized analytes were stable for 24 h at room temperature. This method was demonstrated by determining the levels of these analytes in mid-log phase MRSA extracts. This approach provides for the chromatographic resolution and MS/MS based quantification of all 20 common L- and D-amino acids in complex matrices. Graphical Abstract ?. PMID- 30421363 TI - Effect of lights with various wavelengths on bleaching by 30% hydrogen peroxide. AB - The objective of this study was to evaluate the bleaching effect of light sources with various wavelengths using 30% hydrogen peroxide (HP) in vitro. The hematoporphyrin-stained paper was bleached with HP and irradiated for 10 min using LED light sources with 265, 310, 365, 405, or 450 nm respectively. In control group, HP was applied for 10 min without light irradiation. The bleaching procedure was repeated two times. The L*a*b* values of the samples before bleaching and after each bleaching step were measured using a colorimeter. Color changes of specimens were then calculated and statistically analyzed. There was an interaction between light sources and time of irradiation in the color change (p < 0.05). Time and light sources significantly affected DeltaE and DeltaL (p < 0.05). The light source of 256 nm showed the highest bleaching effect over time followed by that of 310 nm, which were statistically different from other groups (p < 0.001). The 365 nm, 450 nm groups, and control group showed low bleaching effect visually with no significant differences in DeltaE and DeltaL (p > 0.05). It was concluded that the wavelengths of the light sources affected the bleaching by HP. The 310-nm light can be a potential source for bleaching. PMID- 30421362 TI - Expression optimization of recombinant cholesterol oxidase in Escherichia coli and its purification and characterization. AB - Cholesterol oxidase is a bacterial flavoenzyme which catalyzes oxidation and isomerization of cholesterol. This enzyme has a great commercial value because of its wide applications in cholesterol analysis of clinical samples, synthesis of steroid-derived drugs, food industries, and potentially insecticidal activity. Accordingly, development of an efficient protocol for overexpression of cholesterol oxidase can be very valuable and beneficial. In this study, expression optimization of cholesterol oxidase from Streptomyces sp. SA-COO was investigated in Escherichia coli host strains. Various parameters that may influence the yield of a recombinant enzyme were evaluated individually. The optimal host strain, culture media, induction time, Isopropyl beta-D-1 thiogalactopyranoside concentration, as well as post-induction incubation time and temperature were determined in a shaking flask mode. Applying the optimized protocol, the production of recombinant cholesterol oxidase was significantly enhanced from 3.2 to 158 U/L. Under the optimized condition, the enzyme was produced on a large-scale, and highly expressed cholesterol oxidase was purified from cell lysate by column nickel affinity chromatography. Km and Vmax values of the purified enzyme for cholesterol were estimated using Lineweaver-Burk plot. Further, the optimum pH and optimum temperature for the enzyme activity were also determined. We report a straightforward and easy protocol for cholesterol oxidase production which can be performed in any laboratory. PMID- 30421365 TI - Pushing people to their tipping point: Phenomenal tipping point is predicted by phenomenal vertical and intuitive beliefs. AB - Previous work has shown that people overestimate their own body tilt by a factor of about 1.5, the same factor by which people overestimate geographical and man made slopes. In Experiment 1 we investigated whether people can accurately identify their own and others' tipping points (TPs) - the point at which they are tilted backward and would no longer be able to return to upright - as well as their own and others' center of mass (COM) - the relative position of which is used to determine actual TP. We found that people overestimate their own and others' TP when tilted backward, estimate their own and others' COM higher than actual, and that COM estimation is unrelated to TP. In Experiment 2, we investigated people's intuitive beliefs about the TP. We also investigated the relationship between phenomenal TP and perceived vertical. Whether verbally (conceptually) estimating the TP, drawing the TP, or demonstrating the position of the TP, people believe that the TP is close to 45 degrees . In Experiment 3, we found that anchoring influences phenomenal TP and vertical. When accounting for starting position, the TP seems to be best predicted by an intuitive belief that it is close to 45 degrees . In Experiment 4, we show that there is no difference in phenomenal TP and vertical when being tilted about the feet or waist/hips. We discuss the findings in terms of action-perception differences found in other domains and practical implications. PMID- 30421364 TI - Outcome differences between recanalized malignant central airway obstruction from endoluminal disease versus extrinsic compression. AB - We compared the outcome of Nd:YAG laser therapy with stent placement for malignant central airway obstruction (CAO) at our center over a 10-year period. This is a retrospective review of patients undergoing Nd:YAG laser therapy or self-expanding metal stent (SEMS) placement for malignant CAO between November 2007 and October 2017. Seventy-two patients were recanalized for malignant CAO. The median (range) age was 63 (23-86) years, with 49 (68%) males. Patients underwent either laser therapy alone (N = 36), stent placement alone (N = 30), or both (N = 6). The wavelength of Nd:YAG laser used was 1064 nm, and median (range) laser energy used was 25 (15-35) W, in 377 (115-1107) pulses. Fifty-one (71%) patients died with median survival of 7.2 months. In subgroup analysis, 21 (58.3%) vs. 25 (83.3%), p = 0.03 patients died in the "laser resection" vs. "stent placement" group with longer median survival of 12.4 months in the former vs. 4.5 months, p = 0.0004 in the later. Esophageal cancer and left main bronchus involvement were significantly more common (10 (33.3%) vs. 0, p = 0.0001, and 16 (53.3%) vs. 8 (22.2%), p = 0.01), in the stent placement vs. laser resection group, respectively. Trachea or main bronchi involvement and respiratory failure on presentation requiring mechanical ventilation correlated with poorer survival. The immediate restoration of luminal patency, complication rate, and 30-day mortality was similar among the two groups. The median (range) energy used for laser therapy was 25 (15-35) W. Median of 377 pulses was used for the duration of 287.5 s. The results were compared using a Wilcoxon two-sample test, and Fischer exact test with p values considered indicative of a significant difference if less than 0.05. In patients requiring recanalization of malignant CAO, the extrinsic compression from esophageal cancer, trachea or main bronchi involvement, respiratory failure on presentation requiring mechanical ventilation, and stent placement correlated with poorer survival. Interventional pulmonology training program should emphasize on dedicated training in laser therapy as it is associated with improved survival. PMID- 30421366 TI - Learned and cued distractor rejection for multiple features in visual search. AB - Ignoring distracting information is critical for effective visual search. When individuals are cued to ignore a stimulus, they first attend the to-be-ignored stimulus before learning to reject it. Individuals can learn to overcome the initial distraction produced by the explicit cues, although this cued distractor rejection appears for only one distractor feature. Multiple distractor colors cannot be rejected effectively, even with extensive experience. We asked if this apparent limit on distractor rejection was caused by a restriction on the number of different features (i.e., colors) that could be learned and rejected as distractors. To explore this potential capacity limitation, we asked if attention can learn to reject the smallest possible number of multiple distractors, namely, two. In four experiments examining cued distractor rejection, individuals searched through heterogeneously colored arrays containing reliable, non-target color information. In Experiments 1 and 2, we explicitly cued individuals with which of two colors (both colors in Experiment 1 or one color in Experiment 2) could be safely ignored. Cued distractors were not reliably rejected, replicating previous findings. Additionally, in Experiment 2, we presented a to-be-ignored color without explicit cues and we found that these "uncued" distractors were reliably rejected. In Experiments 3 and 4, we presented the to-be-ignored color information without explicit cues; individuals learned to reliably ignore multiple distractor colors without explicit cueing. These results suggest that learned distractor rejection is better suited to experience-driven learning than explicitly cued distractor learning: Explicit cueing reliably interferes with learned distractor rejection. PMID- 30421367 TI - Determination of biochemical oxygen demand and dissolved oxygen for semi-arid river environment: application of soft computing models. AB - Surface and ground water resources are highly sensitive aquatic systems to contaminants due to their accessibility to multiple-point and non-point sources of pollutions. Determination of water quality variables using mathematical models instead of laboratory experiments can have venerable significance in term of the environmental prospective. In this research, application of a new developed hybrid response surface method (HRSM) which is a modified model of the existing response surface model (RSM) is proposed for the first time to predict biochemical oxygen demand (BOD) and dissolved oxygen (DO) in Euphrates River, Iraq. The model was constructed using various physical and chemical variables including water temperature (T), turbidity, power of hydrogen (pH), electrical conductivity (EC), alkalinity, calcium (Ca), chemical oxygen demand (COD), sulfate (SO4), total dissolved solids (TDS), and total suspended solids (TSS) as input attributes. The monthly water quality sampling data for the period 2004 2013 was considered for structuring the input-output pattern required for the development of the models. An advance analysis was conducted to comprehend the correlation between the predictors and predictand. The prediction performances of HRSM were compared with that of support vector regression (SVR) model which is one of the most predominate applied machine learning approaches of the state-of the-art for water quality prediction. The results indicated a very optimistic modeling accuracy of the proposed HRSM model to predict BOD and DO. Furthermore, the results showed a robust alternative mathematical model for determining water quality particularly in a data scarce region like Iraq. PMID- 30421368 TI - Response of the antioxidant enzymes of rats following oral administration of metal-oxide nanoparticles (Al2O3, CuO, TiO2). AB - Metal-oxide nanoparticles (NPs), as a new emerging technological compound, promise a wide range of usage areas and consequently have the potential to cause environmental toxicology. In the present work, aluminum (Al2O3), copper (CuO), and titanium (TiO2) nanoparticles (NPs) were administered via oral gavage to mature female rats (Rattus norvegicus var. albinos) for 14 days with a dose series of 0 (control), 0.5, 5, and 50 (mg/kg b.w./day). Enzyme activities of the antioxidant system such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione S-transferase (GST), and glutathione reductase (GR) in the liver were measured. Transmission electron microscope (TEM) images of the liver were taken to demonstrate NP accumulation and distribution in liver tissue. Data showed that all NPs caused some significant (P > 0.05) alterations in the activities of antioxidant enzymes. CAT activity increased after CuO and TiO2 administrations, while SOD activity decreased after Al2O3 administration. The activities of enzymes associated with glutathione (GR, GPx, GST) metabolisms were also significantly altered by NPs. GPx activity increased in rats received Al2O3, CuO NPs, while GR activity increased only by Al2O3. However, there were increases (TiO2) and decreases (CuO) in GST activity in the liver of rats. TEM images of the liver demonstrated that all NPs accumulated in the liver, even at the lowest dose. This study indicated that the antioxidant enzymes in the liver of rats were affected by all NPs, suggesting the antioxidant system of rats suffered after NP administration. PMID- 30421369 TI - Synthesis and characterization of magnetic bio-adsorbent developed from Aegle marmelos leaves for removal of As(V) from aqueous solutions. AB - A novel magnetic bio-adsorbent was prepared from the leaves of Aegle marmelos tree (Indian bael) and Fe2O3 nanoparticles. The AMP@Fe2O3 nanocomposite (Aegle marmelos leaf powder) was synthesized by pyrolysis process and applied for As(V) removal through batch adsorption process. The synthesized AMP@Fe2O3 nanocomposite was analyzed by several instrumental techniques like XRD, FESEM, TEM, HRTEM, FTIR, BET, and VSM studies. Maximum amount of As(V) was removed at pH 3, contact time of 250 min, adsorbent dose of 0.1 g/L, and initial concentration of 0.5 mg/L at room temperature. The model study revealed that the pseudo-second-order kinetics and Langmuir isotherm models were best fitted with the experimental data. The nanocomposite showed a maximum adsorption capacity of 69.65 mg/g. The endothermic nature of the adsorption process was ascertained from the thermodynamics studies. The zeta potential and FTIR analysis before and after adsorption demonstrated two types of adsorption mechanism. The first one was the electrostatic attraction between negatively charged As(V) ions (H2AsO4-) and protonated -OH group present on the Fe2O3 surface and the second one was ligand exchange between the surface hydroxyl groups and As(V) ions. The AMP@Fe2O3 nanocomposite was desorbed with 0.5 M NaOH solutions and also used up to four cycles without any major decrease in removal efficiency. Thus, AMP@Fe2O3 nanocomposite can be applied as a potential adsorbent for As(V) removal from wastewater. PMID- 30421370 TI - Using Shannon entropy to model turbulence-induced flocculation of cohesive sediment in water. AB - Turbulence-induced flocculation of cohesive fine-grained sediment plays an important role in the transport characteristics of pollutants and nutrients absorbed on the surface of sediment in estuarine and coastal waters via the complex processes of sediment transport, deposition, resuspension and consolidation. In this study, the concept of Shannon entropy based on probability is applied to modelling turbulence-induced flocculation of cohesive sediment in water. Using the hypothesis regarding the cumulative distribution function, the function of floc size with flocculation time is derived by assuming a characteristic floc size as a random variable and maximizing the Shannon entropy, subject to certain constraints. The Shannon entropy-based model is capable of modelling the variation in floc size as the flocculation time progresses from zero to infinity. The model is tested against some existing experimental data from the literature and against a few deterministic mathematical models. The model yields good agreement with the observed data and yields better prediction accuracy than the other models. The parameter that has been incorporated into the model exhibits an empirical power-law relationship with the flow shear rate. An empirical model formulation is proposed, and it exhibits high prediction accuracy when applied to existing experimental data. PMID- 30421371 TI - A study on the evaluation of water-bloom using image processing. AB - This study utilized remote sensing techniques using an unmanned aerial vehicle (UAV) with an attached multispectral sensor to monitor the Nakdong River. In this study, chlorophyll-a, an indicator of water quality and the normalization difference vegetation index (NDVI), which indicates the vitality of plant growth was employed. NDVI images were generated using georeferenced and Orthomosaic images. The data (field samples) used to conduct the study was collected in September 2017. The relationship between the chlorophyll-a concentrations and NDVI was then examined. The results of the relationship can be used in monitoring of green algae for water quality management. PMID- 30421372 TI - Performance and emission characteristics of CNG-fueled compression ignition engine with Ricinus communis methyl ester as pilot fuel. AB - Surge in petroleum prices, its drying sources and degradation in air quality focused interest on renewable energy sources as substitute for existing fuels for internal combustion engines. This study highlights the combustion, performance, and emission characteristics of diesel engines fueled with compressed natural gas (CNG) as primary fuel and castor (Ricinus communis) oil methyl ester (COME) as pilot fuel. COME was produced from non-edible grade Ricinus communis oil. The biodiesel fuel properties and characterization was done as per ASTM D6751 specifications. The CNG was inducted through inlet manifold fumigation at a consistent flow rate of 15 l/min under dual-fuel mode. It is evident from the test results that B20-CNG yields brake thermal efficiency of 23.6% when compared to 25 and 27% for D-CNG and diesel fuel, respectively. The peak cylinder gas pressure was lower in dual-fuel mode when compared to conventional diesel. The emission results show increase in NOx emission by 24.5 and 28.4% for D-CNG and B20-CNG, respectively when compared to baseline diesel fuel at full engine load. There was increase in HC emission by 6.7 and 11% whereas CO emissions decreased by 31.6 and 37.4% for B20-CNG and D-CNG, respectively at similar operating conditions. Reduction in smoke opacity by 49.4 and 59.6% was achieved respectively for D-CNG and B20-CNG under dual-fuel mode. On the whole, COME exhibits a better pilot fuel choice for dual-fuel combustion mode in comparison to conventional fossil petroleum diesel in terms of combustion, performance, and emissions characteristics. PMID- 30421373 TI - Increase of global DNA methylation patterns in beauty salon workers exposed to low levels of formaldehyde. AB - Formaldehyde (FA) is a carcinogenic aldehyde illegally added to creams as a hair straightening agent for the Brazilian blowout (BB). This study aimed to investigate the possible effects of occupational exposure to FA on global DNA methylation in salon workers with different exposure levels. FA exposure was monitored using environmental and biological measurements. The study included 49 salon workers divided by FA levels in the workplace into group A (FA < 0.01 ppm; n = 8), group B (0.03 ppm < FA < 0.06 ppm; n = 15), and group C (0.08 ppm < FA < 0.24 ppm; n = 26). The global DNA methylation levels were 3.12%, 4.55%, and 4.29% for groups A, B, and C, respectively, with statistically higher values for groups B and C compared to group A (p = 0.002). A correlation was found between FA in passive samplers and global DNA methylation (rs = 0.307, p = 0.032). Additionally, when only taking into account the hairdressers that performed the BB on clients instead of the whole group, a stronger correlation was observed between FA in personal passive samplers and global DNA methylation (rs = 0.764, p = 0.006). For the first time, an increase in DNA methylation was observed in subjects occupationally exposed to FA. In conclusion, our results indicated that even low levels of FA exposure could cause a disturbance in DNA methylation, leading to epigenetic changes, which is associated with cancer development. These data suggest a possible contribution of FA to cancer development through occupational exposure. PMID- 30421374 TI - Seroepidemiological characterization and risk factors associated with seroconversion to Corynebacterium pseudotuberculosis in goats from Northeastern Brazil. AB - Goat breeding in the Northeast region of Brazil plays an important socioeconomic role. However, there are significant losses caused by sanitary deficits and infectious diseases, particularly caseous lymphadenitis (CL). Although CL is considered endemic in Northeastern Brazil, a comprehensive and up-to-date study of this disease in goat herds in this region is necessary. The objective of this study was to determine the farm-level and animal-level seroprevalences for the disease and to identify the possible risk factors that characterize CL in the caprine species of five Northeastern's states (Ceara, Piaui, Rio Grande do Norte, Paraiba, and Sergipe). A total of 2744 goat serum samples from 230 farms were collected between 2010 and 2012. The diagnosis of Corynebacterium pseudotuberculosis infection was performed using the indirect ELISA technique. Farm-level and animal-level seroprevalences were 87.8% and 30.3%, respectively, suggesting that C. pseudotuberculosis is widespread in goat herds of the Northeast region. The risk factors were as follows: absence of forage silage (odds ratio = 5.39), not separating animals by sex (odds ratio = 4.16) or by age (odds ratio = 6.30), not replacing old goat breeders (odds ratio = 7.80), and non treatment of CL lumps prior to spontaneous rupture (odds ratio = 10.34). This study supports the idea that caseous lymphadenitis is widely disseminated in goats from Northeastern Brazil and based on the risk factor analysis attention should be given to the need to establish adequate control measures, such as incision and early drainage of superficial abscesses, quarantine and elimination of affected animals, periodic inspection of the herd, non-introduction of infected animals, and early disposal of animals with recurrent CL. PMID- 30421375 TI - Effect of Stem Cell Treatment on Acute Liver Failure Model Using Scaffold. AB - BACKGROUND: Injecting MSCs via blood vessel is most commonly used method, which has a major drawback of safety. The aim of our study was to evaluate efficacy using scaffold-loaded MSCs in acute liver failure model. METHOD: Acute liver failure was induced in mice using thioacetamide (TAA) (200 mg/kg, i.p) once a day for two consecutive days. The animals were divided in four acute liver failure groups: (1) TAA; (2) empty scaffold; (3) MSCs injected through tail vein; (4) MSC + Scaffold, scaffold loaded with MSCs, to evaluate the mortality and changes in liver function. Polylactic-co-glycolic acid scaffold alone and loaded with human MSCs was implanted on mice dorsum. RESULTS: TAA dose was titrated until one-third mortality rate was achieved. TAA (200 mg/kg) once daily for two consecutive days was injected to establish the acute liver failure model. The mortality of TAA and scaffold groups was 55.9% and 63.2%, respectively. Although, mortality of MSC-TV group decreased 14.7% as compared to TAA group (p = 0.200), MSC + Scaffold group had the lowest mortality (31.4%) (p = 0.013). Cells implanted in PLGA biomaterial were survived until 3 weeks, and their function was increased. Area of hepatic inflammation and necrosis was significantly reduced in MSC-TV and MSC + Scaffold groups; but there was no difference between the two groups. Gene expressions related to inflammation were significantly decreased in MSC-TV and MSC + Scaffold groups compared to TAA group. In MSC + Scaffold group, no migration of stem cells to liver tissue was observed. Although, not all cells in scaffold were stained, some of them were differentiated into hepatocyte-like cells which stained positive for PAS and CYP2E1 antibody. CONCLUSION: Scaffold loaded with MSCs showed protective effects via paracrine signaling on acute liver failure model. PMID- 30421376 TI - Childhood Executive Function Predicts Later Autistic Features and Adaptive Behavior in Young Autistic People: a 12-Year Prospective Study. AB - Longitudinal studies of autistic people show that the behavioral features of autism generally endure into adulthood. Yet the prognostic indicators remain far from certain, especially for cognitively able individuals. Here, we test the predictive power of specific cognitive skills, namely theory of mind and executive function, measured in childhood, on young people's autistic features and adaptive behavior 12 years later. Twenty-eight young autistic people (2 female) were seen twice within the space of 12 years. At Time 1 (M = 5 years; 7 months, SD = 11 months), participants were assessed on components of executive function (planning, inhibition and cognitive flexibility) and theory of mind (false-belief understanding). At Time 2, 12 years later (M = 17 years 10 months, SD = 1 year; 2 months), we measured participants' autistic features and adaptive behavior. Only Time 1 executive function skills predicted significant variance in autistic adolescents' autistic features, over and above variance attributable to early age, intellectual ability and theory of mind skills. Furthermore, early EF skills, in addition to early verbal ability and nonverbal ability, predicted significant variance in young people's adaptive behavior at the 12-year follow up. These long-term longitudinal findings clearly demonstrate that executive function measured in early childhood has prognostic significance in a sample of young autistic people approaching emerging adulthood and underscore their importance as a key target for early intervention and support. PMID- 30421377 TI - Training improves inhibitory control in water rescue dogs. AB - Inhibitory control is a collection of several processes that are aimed to refrain from any impulsive response in the subject during inappropriate situations. Evidence suggests that in dogs, the inhibitory control is affected by domestication process, but also experiences during ontogeny could be an important driver in acquiring inhibitory control. The aim of the study was to compare the performance of highly trained dogs (i.e., water rescue dogs) and pet dogs in the A-not-B task. In this procedure, the animals have to inhibit their urge of going to a previous reinforced place. The results showed that the trained dogs committed fewer errors in the task than the pet dogs suggesting a better inhibitory control. This result could indicate that inhibitory control is a flexible ability affected by ontogenetic processes such as the training experience. PMID- 30421378 TI - Should positron emission tomography be the standard of care for non-invasive surveillance following cardiac transplantation? PMID- 30421379 TI - The prognostic value of quantitating and localizing F-18 FDG uptake in cardiac sarcoidosis. AB - BACKGROUND: There is no identified level of FDG uptake in cardiac sarcoidosis (CS) associated with increased risk of arrhythmias, conduction disease, heart failure, or death. We aim to utilize standardized uptake value (SUV) quantitation and localization to identify patients at increased risk of cardiac events. METHODS AND RESULTS: F18-FDG PET/CT with MPI was used in CS diagnosis (N = 67). Mean and max SUV were measured and grouped as basal, mid, and apical disease. Post-scan ventricular tachycardia, AICD placement, complete heart block, pacemaker placement, atrial fibrillation, heart failure, and cardiac-related hospital admissions were recorded (mean follow up 2.98 +/- 2 years). Poisson regression analysis revealed that max SUV, mean SUV, as well as mean basal SUV, and LVEF were significantly associated with total cardiac events. Max SUV odds ratio (OR) = 1.068 (95% CI 1.024-1.114, P = 0.002), mean SUV OR = 1.059 (95% CI 1.008-1.113, P = 0.023), mean SUV OR = 1.061 (95% CI 1.012-1.112, P = 0.014), scan LVEF OR = 0.731 (95% CI 0.664-0.805, P < 0.001). CONCLUSIONS: SUV at time of CS diagnosis has significant associations with future cardiac events. Patients with higher SUV, particularly in basal segments, are at increased risk of events. Further studies are needed to identify treatment methods utilizing risk stratification of CS. PMID- 30421380 TI - Patient motion correction for dynamic cardiac PET: Current status and challenges. PMID- 30421381 TI - Myocardial blood flow quantification conventional single photon tracers: Yet another critical appraisal : Atsutaka Okizaki et al: Noninvasive estimation of quantitative myocardial blood flow with Tc-99m MIBI by a compartment model analysis in rat. PMID- 30421382 TI - Multimodal imaging of cardiac-calcified amorphous tumor. AB - Cardiac-calcified amorphous tumor (CAT) is a rare non-neoplastic tumor and its origin and pathogenesis are still unclear. In addition, it is difficult to clinically diagnose as cardiac CAT without pathological findings. We present a case of a 78-year-male diagnosed with cardiac CAT after surgical resection. We could evaluate tumor aspects by multimodal imaging including echocardiography, contrast-enhanced computed tomography (CT), magnetic resonance image, and 18F fluorodeoxyglucose-positron emission tomography/CT before surgery. PMID- 30421383 TI - Skin Penetration and Permeation Properties of Transcutol(r)-Neat or Diluted Mixtures. AB - A heightened interest in (trans)dermal delivery is in part driven by the need to improve the existing skin therapies and also the demand for alternative routes of administration, notably for pharmaceutical actives with undesirable oral absorption characteristics. The premise of delivering difficult actives to the skin or via the skin however is weighed down by the barrier function properties of the stratum corneum. Short of disrupting the skin by physical means, scientists have resorted to formulation with excipients known to enhance the skin penetration and permeation of drugs. A vehicle that has emerged over the years as a safe solubilizer and enhancer for a broad range of drug actives is the highly purified NF/EP grade of diethylene glycol monoethyl ether (DEGEE) commercially known as Transcutol(r). Whereas numerous studies affirm its enhancing effect on drug solubilization, percutaneous absorption rate, and/or drug retention in the skin, there are few publications that unite the body of the published literature in describing the precise role and mechanisms of action for Transcutol(r). In view of the current mechanistic understanding of skin barrier properties, this paper takes on a retrospective review of the published works and critically evaluates the data for potential misses due to experimental variables such as formulation design, skin model, skin hydration levels, and drug properties. The goal of this review is to mitigate the incongruence of the published works and to construct a unified, comprehensive understanding of how Transcutol(r) influences skin penetration and permeation. Graphical Abstract Transcutol has affinity for the hydrophilic head groups of the stratum corneum structures. PMID- 30421384 TI - Risk factors for postoperative complications and long-term survival in elderly lung cancer patients: a single institutional experience in Turkey. AB - BACKGROUND: Lung cancer is a typical disease of elderly patients. While there are many publications in the literature on factors affecting survival, there is still no consensus on the survival impact of lymph node dissection. Our objective in this study was to evaluate prognostic factors influencing rates of complications, mortality, and survival in geriatric patients who underwent surgery for non-small cell lung cancer. MATERIALS AND METHODS: Data obtained from the medical records of patients aged 70 years or older with early-stage non-small cell lung cancer who underwent surgery between January 01, 2008 and December 31, 2015 were evaluated retrospectively. RESULTS: Of the 72 patients included, 57 (79.2%) were male and 15 (20.8%) were female. Complications were observed in 42 patients (58.3%). Nineteen patients (26.4%) developed major complications. Percent predicted forced expiratory volume in 1 s (ppFEV1) and age was found to be risk factors for complications. Thirty days days mortality rate was 8.3%. Mortality was not significantly associated with low CCI, physical status, and ppFEV1 values. The 5-year survival rate was 40.5%. ppFEV1 were risk factors affecting survival, whereas radical lymph node dissection was not associated with survival. CONCLUSION: The main prognostic factors affecting long-term postoperative survival in the present study was a low postoperative ppFEV1 value. Radical lymph node dissection did not increase the risk of postoperative complications and it did not affect long-term survival in patients aged 70 years or older. A key finding was that comorbidities were not associated with postoperative complications or long-term survival. PMID- 30421385 TI - Long-term outcomes of Ross and Ross-Konno operations in patients under 15 years of age. AB - OBJECTIVE: The Ross operation is an excellent surgical option for young children, regardless of aortic pathology type. However, failure rates are concerning during the second postoperative decade. We sought to determine the predictors of long term outcomes after Ross and Ross-Konno operation performed in childhood. METHODS: We performed 34 Ross and 9 Ross-Konno operations in pediatric patients (age < 15 years) from 1996 to 2016, and retrospectively evaluated the long-term results. RESULTS: The postoperative follow-up period was 13.5 +/- 3.9 years. In the Ross group, there were one inpatient death and one death after discharge. There were no inpatient deaths in the Ross-Konno group. There were 6 reoperations in the Ross group and 1 in the Ross-Konno group for left ventricular outflow tract (LVOT). Cumulative survival rates were 96.8% and 100% in the Ross and Ross Konno groups, respectively. The reoperation free rate for LVOT /RVOT (right ventricular outflow tract) were 98.6/85.5% and 91.9/63.4% in the 5th and 10th years of follow-up, respectively. Patients who underwent the operations at age > 8.6 years had higher risks of reoperation for LVOT. Aortic annulus measurements > 24 mm or aorta/pulmonary artery diameter (Ao/PA) ratios > 1.2 conferred higher risks of reoperation for LVOT. CONCLUSIONS: Long-term outcomes after Ross and Ross-Konno operations in children were satisfactory. However, new-onset aortic regurgitation was progressive and reoperation was needed in some children. Age, aortic annulus diameter, and Ao/PA ratio may be able to predict of long-term outcomes after Ross and Ross-Konno operations. PMID- 30421386 TI - CT and MR imaging findings of infection-free and benign second branchial cleft cysts. AB - PURPOSE: The present study aimed to assess CT and MR imaging findings of infection-free and benign second branchial cleft cysts (SBCCs). METHODS: Eleven patients with histopathologically confirmed infection-free and benign SBCCs underwent preoperative contrast-enhanced CT (CECT) and/or MR imaging. We assessed qualitative (presence and extent of wall thickening, degree of contrast enhancement of the thickened wall on CECT images, and signal intensity of the thickened wall on T2-weighted images) and quantitative (maximum thickness of the thickened wall) imaging findings. RESULTS: Eccentric and smooth wall thickening was observed in 11/11 (100%) patients. The wall thickening extent (percentage of the thickened wall to the circumference of the wall) was small (1%-25%) in 4/11 (36%), moderate (26%-50%) in 6/11 (54%), extensive (51%-75%) in 1/11 (9%), and diffuse (76%-100%) in 0/11 (0%) patients. Mild homogeneous enhancement of the thickened wall on CECT images was observed in 7/7 (100%) patients. The signal intensity of the thickened wall on T2-weighted images was isointense relative to that of normal lymph nodes in 7/8 (88%) and mildly hyperintense in 1/8 (12%) patient. The maximum thickness of the thickened walls ranged from 2 to 4 (mean 3.4) mm. CONCLUSIONS: Infection-free and benign SBCCs are identifiable as cysts with eccentric and smooth wall thickening on CECT and MR images. The wall thickness was almost always less than half of the wall circumference, isointense relative to normal lymph nodes, and showed mild homogeneous enhancement. PMID- 30421387 TI - Influence of age and subtype in outcome of operable liposarcoma. AB - AIM: Liposarcoma (LPS) is rare tumor deriving from adipocytes. LPS is classified into histological subtypes: well-differentiated (WDLPS), dedifferentiated (DDLPS), myxoid (MLPS) and pleomorphic (PLPS). A tailored approach taking into account the specificity of disease subtype and age at presentation could be helpful in delineating therapeutic management of liposarcoma. In this paper, we report a retrospective series of a single-institution cohort of patients with LPS, undergoing surgery and radiotherapy and/or chemotherapy. The aim of this study is to evaluate whether clinical characteristics, tumor- and treatment related features affect clinical outcome in patients treated with curative intent for non-metastatic liposarcoma. METHODS: Data of patients with locally advanced, non-metastatic liposarcoma treated between 1990 and 2015 were retrospectively reviewed. Data about patient, tumor and treatment features were collected. Two patients subgroups were identified according to age (cutoff: age < 65 years or > 65 years). Statistical analysis was performed to assess correlation between the above-cited variables and local recurrence-free survival (DFS-LR), distant metastasis-free survival, overall survival (OS) and disease-specific survival (DSS); moreover, differences in clinical outcome between the two age groups were identified. RESULTS: Data of 186 patients were collected. At diagnosis, 27.4% of patients were 65 years or older. At a median follow-up of 8.6 years (range 0.1 27.3 years), Kaplan-Meier (KM) survival analysis showed that LR, DM, OS and DSS were 75.5%, 76.6%, 48.1% and 72.1%, respectively. KM analysis showed that age > 65, DDLPS and lower limb localization were related to LR (p = 0.001, p = 0.0001 and p = 0.0001, respectively). Association between LR, age and DDLPS persisted both at univariate (p = 0.003 and p = 0.0001, respectively) and multivariate Cox regression (CR) analysis (p = 0.024 and p = 0.002). Age, tumor depth and grading influenced distant recurrence, both at KM (p = 0.023, p = 0.026 and p = 0.016) and univariate CR (p = 0.026, p = 0.042 and p = 0.012). Age and grading were confirmed at multivariate analysis (p = 0.009 and p = 0.017). Patients with WDLPS and wide excision had significantly better OS (p = 0.001 and p = 0.03, respectively), while histological G3 and age > 65 were related with worse OS (p = 0.008 and p = 0.0001, respectively). Age, DDLPS and grade were related to OS at univariate (p = 0.0001, p = 0.0001 and p = 0.03, respectively) and multivariate CR analysis (p = 0.031, p = 0.0001 and p = 0.001, respectively). However, analyzing the specific causes of death, female died less often for tumor-related causes, with a DSS of 91.0% compared to 57.4% of male counterpart (p = 0.005). At Kaplan-Meier analysis, postoperative radiotherapy resulted in a statistically significant better disease-specific survival than postoperative radiotherapy (82.9% vs. 46.2%, p = 0.045). High grade correlated with poorer disease-specific survival (59.3%) than intermediate and low grade (73.4% and 91.6%, respectively) (p = 0.008). Association between DSS, sex and grade persisted both at univariate (p = 0.008 and p = 0.022, respectively) and multivariate Cox regression (CR) analysis (p = 0.014 and p = 0.038). Histotype-driven schedules of treatment should be developed to take into account biological heterogeneity of this disease. Further studies are needed to stratify patients subgroup and develop tailored treatment strategies (i.e., altered fractionations and different chemotherapy regimens in aggressive subtypes), in particular more prospective trials are needed to develop treatment guidelines in elderly STS, taking into account the frailty and the peculiarity of this subgroup. PMID- 30421388 TI - Genetic variation in health insurance coverage. AB - We provide the first investigation into whether and how much genes explain having health insurance coverage or not and possible mechanisms for genetic variation. Using a twin-design that compares identical and non-identical twins from a national sample of US twins from the National Survey of Midlife Development in the United States, we find that genetic effects explain over 40% of the variation in whether a person has any health coverage versus not, and nearly 50% of the variation in whether individuals younger than 65 have private coverage versus whether they have no coverage at all. Nearly one third of the genetic variation in being uninsured versus having private coverage is explained by employment industry, self-employment status, and income, and together with education, they explain over 40% of the genetic influence. Marital status, number of children, and available measures of health status, risk preferences, and prevention effort do not appear to be important channels for genetic effects. That genes have meaningful effects on the insurance status suggests an important source of heterogeneity in insurance take up. PMID- 30421389 TI - Comment on: A Systematic Review and Meta-Analyses of the Association Between Anti hypertensive Classes and the Risk of Falls Among Older Adults. PMID- 30421390 TI - Authors' Reply to Kahlaee et al: "A Systematic Review and Meta-Analyses of the Association Between Anti-hypertensive Classes and the Risk of Falls Among Older Adults". PMID- 30421392 TI - Co-delivery of curcumin and doxorubicin in PEGylated liposomes favored the antineoplastic C26 murine colon carcinoma microenvironment. AB - Our recent studies have demonstrated that the antitumor efficacy of doxorubicin (DOX), administered in long-circulating liposomes (LCL), could be considerably improved after its co-encapsulation with curcumin (CURC). Thus, the question addressed within this article is whether LCL-CURC-DOX can be exploited more efficiently than liposomal DOX for future colorectal cancer therapy. Therefore, we investigated the physicochemical and biological properties of LCL-CURC-DOX and the mechanisms of its antitumor activity in C26 murine colon carcinoma in vivo. Our results proved that the developed nanoformulation based on the co encapsulation of CURC and DOX met the requirements of a modern drug delivery system for future cancer therapy, demonstrating enhanced antitumor activity on C26 colon carcinoma in vivo. The antitumor efficacy of LCL-CURC-DOX relied on suppressive effects on main protumor processes such as angiogenesis, inflammation, oxidative stress, invasion and resistance to apoptosis, and on the dysregulation of Th1/Th2 cell axis which favored the antineoplastic phenotype of cells in tumor microenvironment (TME). The development of multitargeted strategies aiming at stimulating antitumor effects within the tumor milieu and counteracting the escape mechanisms of cancer cells would be beneficial in the management of colon cancer in the future. PMID- 30421391 TI - Dabigatran Versus Rivaroxaban for Secondary Stroke Prevention in Patients with Atrial Fibrillation Rehabilitated in Skilled Nursing Facilities. AB - BACKGROUND: Thromboembolic and bleeding risk are elevated in older patients with atrial fibrillation and prior stroke. We compared dabigatran with rivaroxaban for secondary prevention in a national population after skilled nursing facility (SNF) discharge. METHODS: Medicare fee-for-service beneficiaries aged >= 65 years with atrial fibrillation hospitalized for ischemic stroke (November 2011-October 2013) and subsequently admitted to an SNF were studied. Dabigatran (n = 332) and rivaroxaban users (n = 378) were compared in a retrospective, active comparator, new-user cohort. The index medication claim occurred within 120 days after hospital discharge and exposure continued until a 14-day treatment gap ('as treated'). The primary net clinical benefit outcome was the time to recurrent stroke, transient ischemic attack, intracranial hemorrhage, extracranial bleed, myocardial infarction, venous thromboembolism, or death. All-cause mortality was evaluated separately as a secondary outcome. Multivariable adjusted Cox models stratified by dosage estimated hazard ratios (aHR). RESULTS: Among those receiving low dosages, the crude composite event rate was 40.4/100 person-years among dabigatran users and 33.7/100 person-years among rivaroxaban users. The composite outcome [aHR 1.48; 95% confidence interval (CI) 0.87-2.51] and all cause mortality (aHR 1.67; 95% CI 0.84-3.31) rates were higher among low-dose dabigatran users. For those receiving standard doses, the crude composite event rates were 19.5/100 person-years for dabigatran users and 37.1/100 person-years for rivaroxaban users. Although no difference in mortality was observed, the composite outcome rate was lower among standard-dose dabigatran users (aHR 0.65; 95% CI 0.36-1.15). CONCLUSIONS: In older adults treated with direct-acting oral anticoagulants after ischemic stroke, outcome rates varied considerably by drug and dosage. PMID- 30421393 TI - Study of glutathione S-transferase levels in patients receiving intravenous paracetamol perioperatively: A randomized controlled trial. AB - BACKGROUND AND AIMS: Many studies have analyzed the effect of paracetamol on liver functions. The aim of this study was to measure glutathione S-transferase (GST) concentrations in patients receiving intravenous (IV) paracetamol infusions as part of their perioperative pain relief regimen to assess its effect on hepatocellular integrity. METHODS: Patients between the ages of 18 and 60 years of both sexes, of American Society of Anesthesiologists (ASA) grades 1 and 2, undergoing laparoscopic gastrointestinal (GI) surgeries were included in the study. Patients in the saline group received three doses of normal saline as placebo 8 h apart, with the first dose administered following the induction of anesthesia. Patients in the paracetamol group received IV paracetamol at identical time points. Blood samples were collected preoperatively, after 1, 6, and at 24 h after induction. GST levels were measured at baseline and after 1, 6, and 24 h in both the groups. RESULTS: There was no statistical difference in the demographic variables between the groups. The duration and type of surgery were identical between both the groups. GST values were found to be significantly elevated both within groups, as compared to baseline, and also in the group receiving IV paracetamol as compared to the saline group. Significant elevations of liver enzymes and decrease in serum albumin levels were also noted both within and between the groups at 24 h postoperatively, as compared to the baseline values. CONCLUSION: Intravenous paracetamol infusion during laparoscopic GI surgeries can lead to demonstrable, although subclinical impairment of hepatic function as evident by the rise in levels of GST and hepatic enzymes. Most of such subclinical injury did not progress to clinical hepatic impairment in otherwise healthy patients, as demonstrated by the fact that none of our patients manifested drug-induced hepatitis clinically. ? ?. PMID- 30421394 TI - Xiao Ke Qing improves glycometabolism and ameliorates insulin resistance by regulating the PI3K/Akt pathway in KKAy mice. AB - Xiao Ke Qing (XKQ) granule has been clinically used to treat type 2 diabetes mellitus (T2DM) for 10 years in Chinese traditional medication. However, its mechanisms against hyperglycemia remain poorly understood. This study aims to investigate XKQ mechanisms on diabetes and diabetic liver disease by using the KKAy mice model. Our results indicate that XKQ can significantly reduce food and water intake. XKQ treatment also remarkably decreases both the fasting blood glucose and blood glucose in the oral glucose tolerance test. Additionally, XKQ can significantly decrease the serum alanine aminotransferase level and liver index and can alleviate the fat degeneration in liver tissues. Moreover, XKQ can ameliorate insulin resistance and upregulate the expression of IRS-1, PI3K (p85), p-Akt, and GLUT4 in the skeletal muscle of KKAy mice. XKQ is an effective drug for T2DM by ameliorating insulin resistance and regulating the PI3K/Akt signaling pathway in the skeletal muscle. PMID- 30421395 TI - Resveratrol reduces intracellular reactive oxygen species levels by inducing autophagy through the AMPK-mTOR pathway. AB - Oxidative stress induced by free fatty acid aggravates endothelial injury, which leads to diabetic cardiovascular complications. Reduction of intracellular oxidative stress may attenuate these pathogenic processes. The dietary polyphenol resveratrol reportedly exerts potential protective effects against endothelial injury. This study determined whether resveratrol can reduce the palmitic acid (PA)-induced generation of reactive oxygen species (ROS) and further explored the underlying molecular mechanisms. We found that resveratrol significantly reduced the PA-induced endothelial ROS levels in human aortic endothelial cells. Resveratrol also induced endothelial cell autophagy, which mediated the effect of resveratrol on ROS reduction. Resveratrol stimulated autophagy via the AMP activated protein kinase (AMPK)-mTOR pathway. Taken together, these data suggest that resveratrol prevents PA-induced intracellular ROS by autophagy regulation via the AMPK-mTOR pathway. Thus, the induction of autophagy by resveratrol may provide a novel therapeutic candidate for cardioprotection in metabolic syndrome. PMID- 30421396 TI - Radiomics: a critical step towards integrated healthcare. AB - Medical imaging is a vital part of the clinical decision-making process, especially in an oncological setting. Radiology has experienced a great wave of change, and the advent of quantitative imaging has provided a unique opportunity to analyse patient images objectively. Leveraging radiomics and deep learning, there is increased potential for synergy between physicians and computer networks via computer-aided diagnosis (CAD), computer-aided prediction of response (CARP), and computer-aided biological profiling (CABP). The ongoing digitalization of other specialties further opens the door for even greater multidisciplinary integration. We envision the development of an integrated system composed of an aggregation of sub-systems interoperating with the aim of achieving an overarching functionality (in this case' better CAD, CARP, and CABP). This will require close multidisciplinary cooperation among the clinicians, biomedical scientists, and (bio)engineers as well as an administrative framework where the departments will operate not in isolation but in successful harmony. KEY POINTS: * The advent of quantitative imaging provides a unique opportunity to analyse patient images objectively. * Radiomics and deep learning allow for a more detailed overview of the tumour (i.e., CAD, CARP, and CABP) from many different perspectives. * As it currently stands, different medical disciplines have developed different stratification methods, primarily based on their own field often to the exclusion of other departments. * The digitalization of other specialties further opens the door for multidisciplinary integration. * The long term vision for precision medicine should focus on the development of integration strategies, wherein data derived from the patients themselves (via multiple disciplines) can be used to guide clinical decisions. PMID- 30421397 TI - Rule-Based Models and Applications in Biology. AB - Complex systems are governed by dynamic processes whose underlying causal rules are difficult to unravel. However, chemical reactions, molecular interactions, and many other complex systems can be usually represented as concentrations or quantities that vary over time, which provides a framework to study these dynamic relationships. An increasing number of tools use these quantifications to simulate dynamically complex systems to better understand their underlying processes. The application of such methods covers several research areas from biology and chemistry to ecology and even social sciences.In the following chapter, we introduce the concept of rule-based simulations based on the Stochastic Simulation Algorithm (SSA) as well as other mathematical methods such as Ordinary Differential Equations (ODE) models to describe agent-based systems. Besides, we describe the mathematical framework behind Kappa (kappa), a rule based language for the modeling of complex systems, and some extensions for spabetatial models implemented in PISKaS (Parallel Implementation of a Spatial Kappa Simulator). To facilitate the understanding of these methods, we include examples of how these models can be used to describe population dynamics in a simple predator-prey ecosystem or to simulate circadian rhythm changes. PMID- 30421398 TI - Optimized Protein-Protein Interaction Network Usage with Context Filtering. AB - Protein-protein interaction networks (PPIs) collect information on physical-and in some cases-functional interactions between proteins. Most PPIs are annotated with confidence scores, which reflect the probability that a reported interaction is a true interaction. These scores, however, do not allow users to isolate interactions relevant in a particular biological context. Here, we describe solutions for performing context filtering on PPIs to allow biological data interpretation and functional inference in two publicly available PPIs resources (HIPPIE and STRING) and in the proprietary pathway analysis tool and knowledge base Ingenuity Pathway Analysis. PMID- 30421399 TI - SignaLink: Multilayered Regulatory Networks. AB - Biological networks are graphs used to represent the inner workings of a biological system. Networks describe the relationships of the elements of biological systems using edges and nodes. However, the resulting representation of the system can sometimes be too simplistic to usefully model reality. By combining several different interaction types within one larger multilayered biological network, tools such as SignaLink provide a more nuanced view than those relying on single-layer networks (where edges only describe one kind of interaction). Multilayered networks display connections between multiple networks (i.e., protein-protein interactions and their transcriptional and posttranscriptional regulators), each one of them describing a specific set of connections. Multilayered networks also allow us to depict cross talk between cellular systems, which is a more realistic way of describing molecular interactions. They can be used to collate networks from different sources into one multilayered structure, which makes them useful as an analytic tool as well. PMID- 30421400 TI - Interplay Between Long Noncoding RNAs and MicroRNAs in Cancer. AB - In the last decade noncoding RNAs (ncRNAs) have been extensively studied in several biological processes and human diseases including cancer. microRNAs (miRNAs) are the best-known class of ncRNAs. miRNAs are small ncRNAs of around 20 22 nucleotides (nt) and are crucial posttranscriptional regulators of protein coding genes. Recently, new classes of ncRNAs, longer than miRNAs have been discovered. Those include intergenic noncoding RNAs (lincRNAs) and circular RNAs (circRNAs). These novel types of ncRNAs opened a very exciting field in biology, leading researchers to discover new relationships between miRNAs and long noncoding RNAs (lncRNAs), which act together to control protein coding gene expression. One of these new discoveries led to the formulation of the "competing endogenous RNA (ceRNA) hypothesis." This hypothesis suggests that an lncRNA acts as a sponge for miRNAs reducing their expression and causing the upregulation of miRNA targets. In this chapter we first discuss some recent discoveries in this field showing the mutual regulation of miRNAs, lncRNAs, and protein-coding genes in cancer. We then discuss the general approaches for the study of ceRNAs and present in more detail a recent computational approach to explore the ability of lncRNAs to act as ceRNAs in human breast cancer that has been shown to be, among the others, the most precise and promising. PMID- 30421401 TI - Methods and Tools in Genome-wide Association Studies. AB - Many traits, such as height, the response to a given drug, or the susceptibility to certain diseases are presumably co-determined by genetics. Especially in the field of medicine, it is of major interest to identify genetic aberrations that alter an individual's risk to develop a certain phenotypic trait. Addressing this question requires the availability of comprehensive, high-quality genetic datasets. The technological advancements and the decreasing cost of genotyping in the last decade led to an increase in such datasets. Parallel to and in line with this technological progress, an analysis framework under the name of genome-wide association studies was developed to properly collect and analyze these data. Genome-wide association studies aim at finding statistical dependencies-or associations-between a trait of interest and point-mutations in the DNA. The statistical models used to detect such associations are diverse, spanning the whole range from the frequentist to the Bayesian setting.Since genetic datasets are inherently high-dimensional, the search for associations poses not only a statistical but also a computational challenge. As a result, a variety of toolboxes and software packages have been developed, each implementing different statistical methods while using various optimizations and mathematical techniques to enhance the computations.This chapter is devoted to the discussion of widely used methods and tools in genome-wide association studies. We present the different statistical models and the assumptions on which they are based, explain peculiarities of the data that have to be accounted for and, most importantly, introduce commonly used tools and software packages for the different tasks in a genome-wide association study, complemented with examples for their application. PMID- 30421402 TI - Identifying Differentially Expressed Genes Using Fluorescence-Activated Cell Sorting (FACS) and RNA Sequencing from Low Input Samples. AB - Cell type-specific gene expression profiles are useful for understanding genes that are important for the development of different tissues and organs. Here, we describe how to perform fluorescence-activated cell sorting (FACS) on Arabidopsis root protoplasts to isolate specific cell types in the root. We then detail how to extract and process RNA from a very low number of cells (>=40 cells) for RNA sequencing (RNA seq). Finally, we describe how to process RNA seq data using TopHat and how to identify differentially expressed genes using PoissonSeq. PMID- 30421403 TI - Computational and Experimental Approaches to Predict Host-Parasite Protein Protein Interactions. AB - In host-parasite systems, protein-protein interactions are key to allow the pathogen to enter the host and persist within the host. The study of host parasite molecular communication improves the understanding the mechanisms of infection, evasion of the host immune system and tropism across different tissues. Current trends in parasitology focus on unraveling host-parasite protein protein interactions to aid the development of new strategies to combat pathogenic parasites with better treatments and prevention mechanisms. Due to the complexity of capturing experimentally these interactions, computational approaches integrating data from different sources (mainly "omics" data) become key to complement or support experimental approaches. Here, we focus on the application of experimental and computational methods in the prediction of host parasite interactions and highlight the potential of each of these methods in specific contexts. PMID- 30421404 TI - An Integrative Approach to Virus-Host Protein-Protein Interactions. AB - Since cell regulation and protein expression can be dramatically altered upon infection by viruses, studying the mechanisms by which viruses infect cells and the regulatory networks they disrupt is essential to understanding viral pathogenicity. This line of study can also lead to discoveries about the workings of host cells themselves. Computational methods are rapidly being developed to investigate viral-host interactions, and here we highlight recent methods and the insights that they have revealed so far, with a particular focus on methods that integrate different types of data. We also review the challenges of working with viruses compared with traditional cellular biology, and the limitations of current experimental and informatics methods. PMID- 30421405 TI - The SQUAD Method for the Qualitative Modeling of Regulatory Networks. AB - The wealth of molecular information provided by high-throughput technologies has enhanced the efforts dedicated to the reconstruction of regulatory networks in diverse biological systems. This information, however, has proven to be insufficient for the construction of quantitative models due to the absence of sufficiently accurate measurements of kinetic constants. As a result, there have been efforts to develop methodologies that permit the use of qualitative information about patterns of expression to infer the regulatory networks that generate such patterns. One of these approaches is the SQUAD method, which approximates a Boolean network with the use of a set of ordinary differential equations. The main benefit of the SQUAD method over purely Boolean approaches is the possibility of evaluating the effect of continuous external signals, which are pervasive in biological phenomena. A brief description and code on how to implement this method can be found at the following link: https://github.com/caramirezal/SQUADBookChapter . PMID- 30421406 TI - miRNet-Functional Analysis and Visual Exploration of miRNA-Target Interactions in a Network Context. AB - To gain functional insights into microRNAs (miRNAs), researchers usually look for pathways or biological processes that are overrepresented in their target genes. The interpretation is often complicated by the fact that a single miRNA can target many genes and multiple miRNAs can regulate a single gene. Here we introduce miRNet ( www.mirnet.ca ), an easy-to-use web-based tool designed for creation, customization, visual exploration and functional interpretation of miRNA-target interaction networks. By integrating multiple high-quality miRNA target data sources and advanced statistical methods into a powerful network visualization system, miRNet allows researchers to easily navigate the complex landscape of miRNA-target interactions to obtain deep biological insights. This tutorial provides a step-by-step protocol on how to use miRNet to create miRNA target networks for visual exploration and functional analysis from different types of data inputs. PMID- 30421407 TI - Systems Biology Analysis to Understand Regulatory miRNA Networks in Lung Cancer. AB - Lung cancer has currently the highest cancer-related mortality rate worldwide. MicroRNAs (miRNAs) are small noncoding RNAs that play a fundamental role in gene expression and are linked to disease progression of different cancer types such as lung cancer. However, functional characterization is made difficult by the fact that miRNAs generally regulate several mRNA interaction partners, resulting in complex regulatory networks. Thus, analysis of the network biology of miRNAs is essential for comprehensive understanding of their regulatory effects in lung cancer. A deeper understanding of miRNA networks in cancer could finally serve as a basis for the development of new therapeutic interventions. Here, we present a systems biology approach to analyze regulatory miRNA interaction networks to get better insight into their function. PMID- 30421408 TI - Spatial Analysis of Functional Enrichment (SAFE) in Large Biological Networks. AB - Spatial analysis of functional enrichment (SAFE) is a systematic quantitative approach for annotating large biological networks. SAFE detects network regions that are statistically overrepresented for functional groups or quantitative phenotypes of interest, and provides an intuitive visual representation of their relative positioning within the network. In doing so, SAFE determines which functions cocluster in a network, which parts of the network they are associated with and how they are potentially related to one another.Here, I provide a detailed stepwise description of how to perform a SAFE analysis. As an example, I use SAFE to annotate the genome-scale genetic interaction similarity network from Saccharomyces cerevisiae with Gene Ontology (GO) biological process terms. In addition, I show how integrating GO with chemical genomic data in SAFE can recapitulate known modes of action of chemical compounds and potentially identify novel drug mechanisms. PMID- 30421409 TI - Toward Large-Scale Computational Prediction of Protein Complexes. AB - Cellular functions are often performed by multiprotein structures called protein complexes. These complexes are dynamic structures that evolve during the cell cycle or in response to external and internal stimuli, and are tightly regulated by protein expression in different tissues resulting in quantitative and qualitative variation of protein complexes. Advances in high-throughput techniques, such as mass-spectrometry and yeast two-hybrid provided a large amount of data on protein-protein interactions. This sparked the development of computational methods able to predict protein complex formation under a variety of biological and clinical conditions. However, the challenges that need to be addressed for successful computational protein complex prediction are highly complex.The post-genomic era saw an emerging number of algorithms and software, which are able to predict protein complexes from protein-protein interaction networks and a variety of other sources. Despite the high capacity of these methods to qualitatively predict protein complexes, they could provide only limited or no quantitative information of the predicted complexes. Recently, a new large-scale simulation of protein complexes was able to achieve this task by simulating protein complex formation on the proteome scale.In this chapter, we review representative methods that can predict multiple protein complexes at different scales and discuss how these can be combined with emerging sources of data in order to improve protein complex characterization. PMID- 30421410 TI - Computational Models of Cell Cycle Transitions. AB - The cell cycle is one of the best understood cellular processes in biology. Many of the key interactions occurring throughout the cell cycle have already been identified. This feature makes the system ideally suited for modelers who can use all the available interaction knowledge to build a systems level model of the underlying molecular regulatory network. This model can serve to identify gaps in our knowledge and to test theoretical assumptions or constrain the space of possible solutions. The cell cycle is a repetitive chain of events that goes through several checkpoints. Thus, the cell cycle can be studied under the perspective of an oscillator with checkpoints built into it, or as a series of switch-like transitions that goes from one state to another, converging on a closed loop. We shall discuss that latter position and present a framework for building and analyzing differential equation models of switch-like behavior. We shall then apply and review diverse models for each of the cell cycle transitions and discuss how multiple switches are combined in the cell cycle to create fast and robust transitions. PMID- 30421411 TI - Simultaneous Profiling of DNA Accessibility and Gene Expression Dynamics with ATAC-Seq and RNA-Seq. AB - This chapter describes sequencing-based methods for profiling dynamic changes in DNA accessibility and gene expression in Saccharomyces cerevisiae. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq) is a powerful technique for identifying nucleosome-free regions of the genome. Combining ATAC-Seq with RNA Sequencing (RNA-Seq) is a rapid approach for studying the relationship between genome structure and changes in global patterns of gene expression from a single experiment. A laboratory protocol is presented for these methods as well as examples of typical results and visualizations. PMID- 30421412 TI - Computational Network Analysis for Drug Toxicity Prediction. AB - The computational prediction of compound effects from molecular data is an important task in hazard and risk assessment and pivotal for judging the safety of any drug, chemical or cosmetic compound. In particular, the identification of such compound effects at the level of molecular interaction networks can be helpful for the construction of adverse outcome pathways (AOPs). AOPs emerged as a guiding concept for toxicity prediction, because of the inherent mechanistic information of such networks. In fact, integrating molecular interactions in transcriptome analysis and observing expression changes in closely interacting genes might allow identifying the key molecular initiating events of compound toxicity.In this work we describe a computational approach that is suitable for the identification of such network modules from transcriptomics data, which is the major molecular readout of toxicogenomics studies. The approach is composed of different tools (1) for primary data analysis, i.e., the biostatistical quantification of the gene expression changes, (2) for functional annotation and prioritization of genes using literature mining, as well as (3) for the construction of an interaction network that consists of interactions with high confidence and the identification of predictive modules from these networks. We describe the different steps of the approach and demonstrate its performance with public data on drugs that induce hepatic and cardiac toxicity. PMID- 30421413 TI - Modeling the Epigenetic Landscape in Plant Development. AB - Computational mechanistic models enable a systems-level understanding of plant development by integrating available molecular experimental data and simulating their collective dynamical behavior. Boolean gene regulatory network dynamical models have been extensively used as a qualitative modeling framework for such purpose. More recently, network modeling protocols have been extended to model the epigenetic landscape associated with gene regulatory networks. In addition to understanding the concerted action of interconnected genes, epigenetic landscape models aim to uncover the patterns of cell state transition events that emerge under diverse genetic and environmental background conditions. In this chapter we present simple protocols that naturally extend gene regulatory network modeling and demonstrate their use in modeling plant developmental processes under the epigenetic landscape framework. We focus on conceptual clarity and practical implementation, providing directions to the corresponding technical literature. The protocols presented here can be applied to any well-characterized gene regulatory network in plants, animals, or human disease. PMID- 30421414 TI - Developing Network Models of Multiscale Host Responses Involved in Infections and Diseases. AB - Complex interactions involved in host response to infections and diseases require advanced analytical tools to infer drivers of the response in order to develop strategies for intervention. This chapter discusses approaches to assemble interactions ranging from molecular to cellular levels and their analysis to investigate the cross talk between immune pathways. Particularly, construction of immune networks by either data-driven or literature-driven methods is explained. Next, graph theoretic approaches for probing static network properties as well as visualization of networks are discussed. Finally, development of Boolean models for simulation of network dynamics to investigate cross talk and emergent properties are considered along with Boolean-like models that may compensate for some of the limitations encountered in Boolean simulations. In conclusion, the chapter will allow readers to construct and analyze multiscale networks involved in immune responses. PMID- 30421415 TI - Exploring Dynamics and Noise in Gonadotropin-Releasing Hormone (GnRH) Signaling. AB - Gonadotropin-releasing hormone (GnRH) acts via G-protein coupled receptors on pituitary gonadotropes. These are Gq-coupled receptors that mediate acute effects of GnRH on the exocytotic secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH), as well as the chronic regulation of their synthesis. FSH and LH control steroidogenesis and gametogenesis in the gonads so GnRH mediates control of reproduction by the central nervous system. GnRH is secreted in short pulses and the effects of GnRH on its target cells are dependent on the dynamics of these pulses. Here we provide a brief overview of the signaling network activated by GnRH with emphasis on the use of high content imaging for their examination. We also describe computational approaches that we have used to simulate GnRH signaling in order to explore dynamics, noise, and information transfer in this system. PMID- 30421416 TI - Recurrence in Uterine Tumors with Ovarian Sex-Cord Tumor Resemblance: A Case Report and Systematic Review. AB - OBJECTIVE: The aim of this study was to evaluate the prognostic factors of recurrence in uterine tumors resembling ovarian sex-cord tumors (UTROSCT) and to determine clinical-pathological characteristics, treatment options and outcome. MATERIAL AND METHOD: An electronic literature search was conducted from 1976 to 2018. After the comprehensive evaluation and conjunction with our case, the study included 79 cases. RESULTS: The median age at initial diagnosis was 49 years (range; 16-86 years). The age was under 40 years in 21 (26.6%) patients. Whereas 68 patients underwent at least hysterectomy, 9 patients had organ sparing surgery. There was necrosis in 4 (5.1%) patients, atypia in 16 (20.3%) patients, and infiltrative tumor border in 34 (43%) patients. At least one mitosis per 10 high power fields was determined in 36 (45.5%) patients. The tumor involved at least part of the myometrium in 54 (68.3%) patients. Median follow-up time was 30 months (range; 3-296 months). Recurrence was determined in 5 (6.3%) patients. The disease free survival (DFS) was significantly related only to surgery type. None of the pathologic features were associated with DFS. The 5-year DFS was 86% and 96% in patients who underwent organ sparing surgery or not, respectively (p=0.038). CONCLUSION: The accurate pathologic diagnosis of UTROSCT has great value in shaping surgical management and management during the follow-up period. Organ sparing surgery was related to poor DFS. Although recurrence is rare, it should be kept in mind for patients with UTROSCT. PMID- 30421417 TI - Are all bony fishes oxygen regulators? Evidence for oxygen regulation in a putative oxygen conformer, the swamp eel Synbranchus marmoratus. AB - This study investigated the oxygen consumption of the putative oxygen conformer marbled swamp eel Synbranchus marmoratus during progressive hypoxia. Earlier studies have not reached agreement on whether S. marmoratus is a conformer or regulator. Our results support the view that S. marmoratus is an oxygen regulator, like most bony fishes. This article is protected by copyright. All rights reserved. PMID- 30421418 TI - Choice of high-quality mates versus avoidance of low-quality mates. AB - Research in sexual selection assumes that individuals attempt to choose high quality mates, and that sexual signals evolve to indicate high quality. But it may often be more important to instead discriminate and avoid low-quality mates, thus reducing the likelihood of large penalties in fitness. We show, using simulations, that avoidance of low-quality mates (i.e., rejecting low-quality and accepting either high- or medium-quality mates) evolves in socio-ecological circumstances such as monogamy with moderate opportunities for choice, costly choice, or abundant low-quality mates. We also show that this strategy is qualitatively different from choosing high-quality mates (i.e., preferring high quality over medium- and low-quality mates). Rather than selecting signals that distinguish high- from low- and medium-quality mates, avoiding low-quality mates selects for signals or cues attuned at discriminating low-quality mates from the remaining (e.g., low-cost signals, absence of signaling mistakes). This may help explain the high diversity of sexual signals in nature, and their high evolutionary turnover with frequent losses and replacements (rather than reductions/increases of the same signal) over evolutionary time. PMID- 30421419 TI - The PI 3-kinase PI3KC2alpha regulates mouse platelet membrane structure and function independently of membrane lipid composition. AB - PI3KC2alpha is a phosphoinositide 3-kinase with a recently reported function in platelets; PI3KC2alpha-deficient mouse platelets have altered membrane structure and impaired function. Yet, how these membrane changes cause platelet dysfunction remains unknown. Here, focused ion beam-scanning electron microscopy of PI3KC2alpha-deficient platelet ultrastructure reveals a specific effect on the internal membrane structure, while liquid chromatography-tandem mass spectrometry profiling of 294 lipid species shows unaltered lipid composition. Functionally, PI3KC2alpha-deficient platelets exhibit impaired thrombosis specifically under conditions involving membrane tethering. These studies indicate that the structural changes in PI3KC2alpha-deficient platelets are limited to the membrane, occur without major changes in lipid composition, and selectively impair cell function during thrombus formation. These findings illustrate a unique mechanism that may be targetable for anti-thrombotic benefit. PMID- 30421420 TI - The effect of Peruvian small-scale fisheries on sunfishes (Molidae). AB - Reports were compiled of sunfish (family Molidae) by-catch in Peruvian small scale fisheries and sunfish by-catch rates were estimated using data from shore based and onboard monitoring programmes. A total of 114 sunfishes were reported in the longline and gillnet fisheries along the Peru coast from 2005 to 2017. Systematic monitoring effort of small-scale gillnets leads to an estimate of between 23 and 352 individuals captured annually by the fleet fishing from the northern port of Salaverry and central ports of Ancon and Chorrillos and suggests that the actual number captured by the Peruvian gillnet fleet is in the thousands of individuals. Thus, Peruvian small-scale fisheries have the potential to greatly affect populations of these still poorly studied species. Moreover, new occurrence locations are reported for the newly described Mola tecta, which was only observed south of 11 degrees S. Because of physical similarities among Mola species it was difficult to identify sunfishes to the species level and thus further studies (e.g.,, genetics) will be required to provide more detailed information on individual species vulnerability to by-catch in Peruvian waters. This article is protected by copyright. All rights reserved. PMID- 30421421 TI - The X chromosome favors males under sexually antagonistic selection. AB - The X chromosome is found twice as often in females as males. This has led to an intuition that X-linked genes for traits experiencing sexually antagonistic selection should tend to evolve toward the female optimum. However, this intuition has never been formally examined. In this paper, I present a simple mathematical model and ask whether the X chromosome is indeed biased toward effecting female-optimal phenotypes. Counter to the intuition, I find that the exact opposite bias exists; the X chromosome is revealed to be a welcome spot for mutations that benefit males at the expense of females. Not only do male beneficial alleles have an easier time of invading and spreading through a population, but they also achieve higher equilibrium frequencies than comparable female-beneficial alleles. The X chromosome is therefore expected over evolutionary time to nudge phenotypes closer to the male optimum. Consequently, the X chromosome should find itself engaged in perpetual intragenomic conflicts with the autosomes and the mitochondria over developmental outcomes. The X chromosome's male bias and the intragenomic conflicts that ensue bear on the evolution of gene regulation, speciation, and our concept of organismality. PMID- 30421422 TI - Driving Better Health Policy: "It's the Evidence, Stupid": Uwe Reinhardt Memorial Lecture. AB - Health policy can be substantially improved by the use of high-quality evidence, but this requires dedication and discipline. First, it is important to define policies with enough specificity to allow serious assessment. Second, articulating goals as distinct from policies is crucial to evaluating the most effective policies for achieving those goals. Third, researchers must assess an often nuanced body of evidence without allowing their own policy preferences to bias their interpretation. Last, researchers need to dedicate effort to timely, accessible, reliable translation in order for evidence to have a real impact on policy. PMID- 30421423 TI - Regarding "Committee Representation and Medicare Reimbursements: An Examination of the Resource-Based Relative Value Scale". PMID- 30421424 TI - Bifactor model of effortful control and impulsivity and their prospective prediction of ego resiliency. AB - OBJECTIVE: Children's effortful control and impulsivity are important predictors of the personality trait, ego resiliency (i.e., resiliency). Most researchers have not considered the fact that effortful control and impulsivity share substantial conceptual and empirical overlap, yet they also have been shown to be distinct. We tested a bifactor model of effortful control and impulsivity to characterize their shared and unique variance, the prospective prediction of resiliency by the factors of the bifactor model, and moderation by sex and age. METHOD: In a longitudinal study of children (N = 214; 76.5% non-Hispanic Caucasian, 12.2% Hispanic, 11.3% other race/ethnicity), parent- and teacher reported effortful control and impulsivity, as well as behavioral measures of effortful control, were assessed on two occasions (T1: 4.5-8 years; T2: 6-10 years). Parent-reported resiliency was used as a covariate (T1) and the outcome (T3: 8-12 years). RESULTS: The bifactor model yielded a common effortful inhibitory control factor, pure attentional control factor, and pure impulsivity factor. Pure impulsivity and pure attentional control positively predicted resiliency, but only for girls. Effortful inhibitory control did not uniquely predict resiliency. CONCLUSION: Disentangling the shared and unique aspects of effortful control and impulsivity could clarify the roles they play in important outcomes, such as resiliency. PMID- 30421426 TI - Cold deacclimation mechanisms and reacclimation potential in flower buds of blackcurrant (Ribes nigrum). AB - As a consequence of global climate change, cold acclimation and deacclimation cycles are becoming increasingly frequent during winter in temperate regions. However, little is known about plant deacclimation and in particular reacclimation mechanisms, although deacclimation resistance and the ability to reacclimate may have wide-ranging consequences regarding plant productivity in a changing climate. Here we report time-dependent responses of freezing tolerance, respiration rates, metabolite contents (HR-MAS NMR) and fatty acid levels (gas chromatography) in flower buds of two ecodormant Ribes nigrum cultivars exposed to three different deacclimation temperatures followed by a reacclimation treatment at 4 degrees C. The data reveal that despite differences in the progression of deacclimation, the capacity of blackcurrant flower buds to reharden in late winter is virtually non-existing, implying that increasingly irregular temperature patterns is critical for blackcurrant fruit yield. The early phase of deacclimation is associated with a transient increase in respiration and decreasing contents of amino acids, tricarboxylic acid (TCA) cycle intermediates and sugars, indicating an increased need for carbon sources and respiratory energy production for the activation of growth. Decreasing sugar levels may additionally cause loss of freezing tolerance. Deacclimation also involves desaturation of membrane lipids, which likely also contributes to decreased freezing tolerance but may also reflect biosynthesis of signaling molecules stimulating growth and floral organ differentiation. These data provide new insights into the under-researched deacclimation mechanisms and the ability of blackcurrant to reacclimate following different advancements of deacclimation and contribute to our understanding of plant responses to increasingly irregular temperature patterns. This article is protected by copyright. All rights reserved. PMID- 30421425 TI - International Society of Blood Transfusion Working Party on Red Cell Immunogenetics and Blood Group Terminology: Report of the Dubai, Copenhagen and Toronto meetings. AB - BACKGROUND AND OBJECTIVES: The International Society of Blood Transfusion (ISBT) Working Party for Red Cell Immunogenetics and Blood Group Terminology meets in association with the ISBT congress and has met three times since the last report: at the international meetings held in Dubai, United Arab Emirates, September 2016 and Toronto, Canada, June 2018; and at a regional congress in Copenhagen, Denmark, June 2017 for an interim session. METHODS: As in previous meetings, matters pertaining to blood group antigen nomenclature and classification were discussed. New blood group antigens were approved and named according to the serologic and molecular evidence presented. RESULTS AND CONCLUSIONS: Fifteen new blood group antigens were added to eight blood group systems. One antigen was made obsolete based on additional data. Consequently, the current total of blood group antigens recognized by the ISBT is 360, of which 322 are clustered within 36 blood groups systems. The remaining 38 antigens are currently unassigned to a known system. Clinically significant blood group antigens continue to be discovered, through serology/sequencing and/or recombinant or genomic technologies. PMID- 30421427 TI - T-Helper 2 Lymphocyte Immunophenotype Is Associated With Iatrogenic Laryngotracheal Stenosis. AB - OBJECTIVE/HYPOTHESIS: This prospective controlled human and murine study assessed the presence of inflammatory cells and cytokines to test the hypothesis that immune cells are associated with fibroproliferation in iatrogenic laryngotracheal stenosis (iLTS). METHODS: Inflammation was assessed by histology and immunofluorescence (IF), quantitative real-time polymerase chain reaction (qRT PCR), and flow cytometry of cricotracheal resections of iLTS patients compared to normal controls. An iLTS murine model assessed the temporal relationship between inflammation and fibrosis. RESULTS: iLTS specimens showed increased inflammation versus normal controls (159/high power field [hpf] vs. 119/hpf, P = 0.038), and increased CD3 + T-cells, CD4 + cells, and CD3+/CD4 + T-helper (TH ) cells (all P < 0.05). The inflammatory infiltrate was located immediately adjacent to the epithelial surface in the superficial aspect of the thickened lamina propria. Human flow cytometry and qRT-PCR showed a significant increase in interleukin (IL)-4 gene expression, indicating a TH 2 phenotype. Murine IF revealed a dense CD4 + T-cell inflammatory infiltrate on day 4 to 7 postinjury, which preceded the development of fibrosis. Murine flow cytometry and qRT-PCR studies mirrored the human ones, with increased T-helper cells and IL-4 in iLTS versus normal controls. CONCLUSION: CD3/CD4 + T-helper lymphocytes and the proinflammatory cytokine IL-4 are associated with iLTS. The association of a TH 2 immunophenotype with iLTS is consistent with findings in other fibroinflammatory disorders. The murine results reveal that the inflammatory infiltrate precedes the development of fibrosis. However, human iLTS specimens with well-developed fibrosis also contain a marked chronic inflammatory infiltrate, suggesting that the continued release of IL-4 by T-helper lymphocytes may continue to propagate iLTS. LEVEL OF EVIDENCE: NA. Laryngoscope, 2018. PMID- 30421428 TI - Quantification of injection force mechanics during injection laryngoplasty. AB - OBJECTIVES: In-office or operative injection laryngoplasty requires needle stability for accurate material placement. To date, no reports compare injection forces based on needle gauge, bends, length, or material type or temperature. We hypothesize these factors alter injection forces and could impact clinical use. METHODS: Swine larynges were placed in a compression testing machine. Syringes were affixed to a stabilizing crossbeam. Straight needles (25G 1.5-inch; 27G 1.25 inch; or 9.8-inch malleable shaft 16G per oral with 24G tapered needle tip) were inserted into the swine vocal folds to simulate realistic tissue resistance pressure. Compressive loading was conducted at 40 mm/minute until steady-state force was achieved. Tests were completed with calcium hydroxylapatite (CaHa), carboxymethylcellulose, and hyaluronic acid at various temperatures and CaHa with various bends in the needles (n = 3 per group, comparisons performed by two-way analysis of variance (ANOVA), Tukey's post-hoc). RESULTS: Needle size, shape, and temperature altered injection force. Steady-state force was highest with the per oral needle at a mean of 44.55N compared to 26.44N and 29.77N in the 25G and 27G percutaneous needles, respectively (P < 0.001). Stiffness rate (initial increasing force vs. distance to initiate injection) ranged from 19.75N/mm (per oral) to 22.06N/mm (25G) to 24.56N/mm (27G), (P = 0.875). Adding multiple bends to the per-oral needle increased stiffness rate to 24.99N/mm (P = 0.035), whereas the 25G needle stiffness rate remained unchanged (P = 0.941), with the stiffness rate decreasing in the 27G needle with increasing bends (P = 0.033). Increased temperature decreased injection forces across all materials. CONCLUSION: Needle caliber, length, and bends impact steady-state forces and stiffness rates during vocal fold injection. LEVEL OF EVIDENCE: NA. Laryngoscope, 2018. PMID- 30421429 TI - People with motor neurone disease require regular assessment and review to ensure appropriate wheelchair prescription. PMID- 30421430 TI - Introducing Functional and Dysfunctional Self-Licensing: Associations with Indices of (Un)Successful Dietary Regulation. AB - OBJECTIVE: Giving in to food temptations is typically labeled as self-regulation failure. However, when indulgence stems from self-licensing processes, i.e., relying on reasons to justify diet deviations, these instances might actually promote successful goal striving. This research aimed to theoretically define and test under what conditions self-licensing would be considered functional (e.g., when it ultimately serves the long-term goal of weight control) and dysfunctional (e.g., when it threatens successful goal striving) METHOD: First, a pool of items reflecting functional and dysfunctional ways of self-licensing was tested and representative items were selected (Study 1; N = 194). Next, their classification was corroborated by examining the associations with indices of (un)successful dietary regulation (Study 2; N = 147). Finally, it was tested whether (dys)functional self-licensing predicted unhealthy snack intake, by means of participants keeping an unhealthy snack diary (Study 3; N = 54) RESULTS: The theorized distinction was confirmed, and the obtained correlational patterns supported the proposed (dys)functionality of the two types of self-licensing. Importantly, results showed that dysfunctional self-licensing predicted higher snack intake, whereas functional self-licensing predicted lower snack intake CONCLUSION: The present studies provide evidence for the existence of two types of self-licensing, and thereby contributes to theoretical development. This article is protected by copyright. All rights reserved. PMID- 30421431 TI - Gamification as a tool for resident education in otolaryngology: A pilot study. PMID- 30421432 TI - The European baseline series and recommended additions: 2019. PMID- 30421434 TI - Extranodal extension in resected oral cavity squamous cell carcinoma: more to it than meets the eye. AB - OBJECTIVE/HYPOTHESIS: Extranodal extension (ENE) is an independent prognosticator in head-neck Squamous cell carcinoma (SCC). All patients with ENE, however, do not behave the same, and there is a need for further risk stratification. This study evaluates the prognostic significance of various grades of ENE and the number of nodes with ENE on overall survival (OS) in oral cavity SCC (OCSCC). STUDY DESIGN: Retrospective cohort study. METHODS: Ninety-four patients with node positive OCSCC treated with primary surgery and appropriate adjuvant therapy during the year 2011 were evaluated. Surgical histopathology slides of all patients were reviewed, and ENE was graded according to the grading system proposed by Lewis Jr et al. RESULTS: On univariate analysis, lymph node density (LND) greater than or equal to 0.12 (P = 0.013), the presence of ENE in more than two nodes (P = 0.006), and ENE grade 3 through 4 (P = 0.035) were associated with worse (OS). Conventional prognostic factors such as tumor (T) stage, nodal (N) stage, stage grouping, depth of invasion, and pattern of invasion did not have a significant impact on OS. On multivariate analysis, the presence of ENE in more than two nodes (P = 0.018) independently predicted a worse OS. Extranodal extension grade 3 through 4 showed a trend toward significance (P = 0.08). A combination of LND greater than or equal to 0.12, ENE grade 3 through 4, and ENE in more than two lymph nodes conferred the poorest prognosis (3-year OS: 18%; P = 0.000). CONCLUSION: In patients with ENE and advanced nodal disease, T stage, N stage, stage group, depth, and pattern of invasion lose their impact on OS. In patients with ENE, nodal characteristics such as LND, the number of nodes with ENE, and grade of ENE serve as important prognosticators and aid in further risk stratification. LEVEL OF EVIDENCE: 4. Laryngoscope, 2018. PMID- 30421433 TI - Localized synovial sarcoma of the foot or ankle: A series of 32 Cooperative Weichteilsarkom Study Group patients. AB - BACKGROUND: Synovial sarcoma of the foot/ankle is rare. Mutilating surgery is often discussed. METHODS: Patients registered from 1981 to 2013 were analyzed. Cooperative Weichteilsarkom Studiengruppe (CWS) protocols recommend chemotherapy for all synovial sarcoma patients. RESULTS: Thirty-two of 330 patients with localized synovial sarcoma had their tumor at the foot/ankle. Eleven of thirty two tumors were >5 cm. Twenty were T1, 11 T2, and one TX, respectively. Eight (25%) patients underwent primary complete resection with free margins (Intergroup Rhabdomyosarcoma Study [IRS] I), 12 of 32 (38%) primary complete resection with positive margins (IRS II), and 12 of 32 (38%) had macroscopic residuals (IRS III). The best surgical result at any time was R0 in 19, R1 in 10 and R2 in one patient, and missing in two. Mutilation was documented in 14 of 32 (44%). Radiotherapy was conducted in 20 patients. All patients achieved a first complete remission. Five-year-event-free survival and overall survival rates were 80% and 86%, respectively. Four patients suffered local and four other metastatic recurrences. IRS and the best surgical result at any time did not correlate with survival. There was no prognostic difference between R0- and R1-resection. CONCLUSION: Survival expectancies for patients with localized synovial sarcomas of the foot/ankle compare favorably to that of those with other affected sites. DISCUSSION: Further studies are needed to set the limits of minimally required aggressiveness of local therapies. PMID- 30421435 TI - Population genetic analyses of seven Chinese indigenous chicken breeds in a context of global breeds. AB - Jiangxi province in China is rich in indigenous chicken breeds, which have diverse phenotypes and represent a valuable genetic resource for further genetic improvement of modern breeds. Here, we conducted a series of analyses to reveal genetic diversity, phylogenetic relationships and population structure of seven chicken breeds in Jiangxi province in the context of nine non-local chicken breeds, using 600K SNP data. We show that Jiangxi indigenous breeds have more abundant nucleotide diversity than do European local and commercial breeds. Among Jiangxi breeds, Dongxiang Blue-eggshell (DX) and Chongren Partride (CR) display remarkably reduced genetic diversity, as the two breeds exhibit increased inbreeding coefficients, runs of homozygosity, extent of linkage disequilibrium and reduced expected heterozygosity. DX, CR and Taihe Silkie (TH) represent three ancestral lineages of the Jiangxi chicken and display genetic differentiation from the other four Jiangxi breeds, which show a signature of admixture with European commercial breeds. These findings provide insight for the establishment of an efficient conservation program for Jiangxi chicken breeds. Considering the current status of genetic diversity and ancestral representativeness, particular attention should be paid to DX, CR and TH chickens. PMID- 30421436 TI - Mediation analysis in a case-control study when the mediator is a censored variable. AB - Mediation analysis is an approach for assessing the direct and indirect effects of an initial variable on an outcome through a mediator. In practice, mediation models can involve a censored mediator (eg, a woman's age at menopause). The current research for mediation analysis with a censored mediator focuses on scenarios where outcomes are continuous. However, the outcomes can be binary (eg, type 2 diabetes). Another challenge when analyzing such a mediation model is to use data from a case-control study, which results in biased estimations for the initial variable-mediator association if a standard approach is directly applied. In this study, we propose an approach (denoted as MAC-CC) to analyze the mediation model with a censored mediator given data from a case-control study, based on the semiparametric accelerated failure time model along with a pseudo likelihood function. We adapted the measures for assessing the indirect and direct effects using counterfactual definitions. We conducted simulation studies to investigate the performance of MAC-CC and compared it to those of the naive approach and the complete-case approach. MAC-CC accurately estimates the coefficients of different paths, the indirect effects, and the proportions of the total effects mediated. We applied the proposed and existing approaches to the mediation study of genetic variants, a woman's age at menopause, and type 2 diabetes based on a case-control study of type 2 diabetes. Our results indicate that there is no mediating effect from the age at menopause on the association between the genetic variants and type 2 diabetes. PMID- 30421437 TI - Alcohol septal ablation vs myectomy for symptomatic hypertrophic obstructive cardiomyopathy: Systematic review and meta-analysis. AB - BACKGROUND: Surgical myectomy (SM) and Alcohol septal ablation (ASA) are effective therapies for patients with hypertrophic cardiomyopathy who remain symptomatic despite medical therapy. A plethora of data has recently emerged on the long-term outcomes of these procedures. We hence sought to perform an updated meta-analysis comparing both procedures. METHODS: Studies reporting long-term (>3 years) outcomes of SM and/or ASA were included. The primary endpoint was all cause mortality. Secondary endpoints included cardiovascular mortality, sudden cardiac death (SCD), reintervention, and complications including death, pacemaker implantation, and stroke. RESULTS: Twenty-two ASA cohorts (n = 4213; follow-up = 6.6-years) and 23 SM cohorts (n = 4240; follow-up = 6.8-years) were included. Septal myectomy was associated with higher periprocedural mortality and stroke (2% vs 1.2%, P = 0.009 and 1.5% vs 0.8% P = 0.013, respectively), but ASA was associated with more need of pacemaker (10% vs 5%, P < 0.001). During long-term follow-up, all-cause mortality, cardiovascular mortality, and sudden cardiac death rates were 1.5%, 0.4%, and 0.3% per person-year in the ASA group and 1.1%, 0.5%, and 0.3% per person-year in the SM group (P = 0.21, P = 0.53, P = 0.43), respectively. Repeat septal reduction intervention(s) were more common after ASA (11% vs 1.5%, P < 0.001). CONCLUSION: Compared with SM, ASA is associated with lower periprocedural mortality and stroke but higher rates of pacemaker implantations and reintervention. However, there was no difference between ASA and SM with regards to long-term all-cause mortality, cardiovascular mortality, or SCD. PMID- 30421438 TI - Organizational model and reactions to alerts in remote monitoring of cardiac implantable electronic devices: a survey from the Home Monitoring Expert Alliance (HMEA) project. AB - BACKGROUND: This survey aimed to describe the organizational workflow of cardiac implantable electronic devices (CIEDs) remote monitoring (RM) service in ordinary practice. METHODS: A questionnaire was designed for our purpose and completed by 49 sites participating to the Italian Home Monitoring Expert Alliance. RESULTS: A dedicated organizational model for RM was set up for 86% of centers. The median RM team consisted of 2 [Interquartile range (IQR):1-3] physicians and 1 [IQR:0-2] nurse. RM service was available in working hours and the median percentage of patients included was 100% [IQR:10%-100%] for implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy (CRT) recipients and 5% [IQR:0%-30%] for pacemakers. In-office follow-up was performed every 12 and 6 months for pacemaker and ICD/CRT recipients, respectively. More than 90% of sites used to activate all technical alerts, with a prompt reaction in case of an out of-range parameter. The threshold for atrial fibrillation (AF) daily burden notification in most cases ranged from 2.4 to 7.2 hours. All ventricular arrhythmias alerts were usually switched on: an inappropriate therapy or more than one appropriate episode triggered an urgent in-hospital visit. Concerning heart failure, low CRT percentage pacing alert was always used, while the other available notifications were less frequently switched on. CONCLUSIONS: This survey showed that RM service was usually set up with a primary nursing model including on average 2 responsible physicians and 1 nurse and mainly offered to ICD/CRT patients. Technical, AF and ventricular arrhythmia alerts triggered prompt reactions, while heart failure related indexes were generally less applied. This article is protected by copyright. All rights reserved. PMID- 30421439 TI - Sex-specific Effects of DHEA on Bone Mineral Density and Body Composition: A Pooled Analysis of Four Clinical Trials. AB - OBJECTIVE: Studies of dehydroepiandrosterone (DHEA) therapy in older adults suggest sex-specific effects on bone mineral density (BMD) and body composition, but the ability of a single study to reach this conclusion was limited. We evaluated the effects of DHEA on sex hormones, BMD, fat mass, and fat-free mass in older women and men enrolled in four similar clinical trials. DESIGN: Pooled analyses of data from four double-blinded, randomized controlled trials. PARTICIPANTS: Women (n=295) and men (n=290) aged 55 years or older who took DHEA or placebo tablet daily for 12 months. MEASUREMENTS: 12-month changes in BMD, fat mass, fat-free mass, and serum DHEA sulfate (DHEAS), (17)estradiol, testosterone, and insulin-like growth factor-1 (IGF-1). RESULTS: Women on DHEA had increases (mean+/-SD; all p<0.001 vs placebo) in DHEAS (231+/-164 MUg/dL), testosterone (18.6+/-20.9 MUg/dL), (17)estradiol (8.7 +/-11.0 pg/mL), and IGF-1 (25.1+/-52.3 ng/mL), and men had increases in DHEAS (269.0+/-177 MUg/dL; p<0.01), (17)estradiol (4.8+/-12.2 pg/m; p<0.01), and IGF-1 (6.3+/-41.4 ng/mL; p<0.05). Women on DHEA had increases in lumbar spine (1.0%+/-3.4%) and trochanter (0.5%+/ 3.8%) BMD and maintained total hip BMD (0.0%+/-2.8%); men had no BMD benefit and a decrease in fat mass (-0.4+/-2.6 kg; all p<0.01 vs placebo). CONCLUSIONS: DHEA therapy may be an effective approach for preserving bone and muscle mass in women. Key questions are 1) the extent to which longer duration DHEA can attenuate the loss of bone and muscle in women, and 2) whether DHEA has a more favorable benefit-to-risk profile for women than estrogen therapy. This article is protected by copyright. All rights reserved. PMID- 30421440 TI - Therapeutic strategies involving survivin inhibition in cancer. AB - Survivin is a small protein that belongs to the inhibitor of apoptosis protein family. It is abundantly expressed in tumors compared with adult differentiated tissues, being associated with poor prognosis in many human neoplasms. This apoptotic inhibitor has a relevant role in both the promotion of cancer cell survival and in the inhibition of cell death. Consequently, aberrant survivin expression stimulates tumor progression and confers resistance to several therapeutic strategies in a variety of tumors. In fact, efficient survivin downregulation or inhibition results in spontaneous apoptosis or sensitization to chemotherapy and radiotherapy. Therefore, all these features make survivin an attractive therapeutic target to treat cancer. Currently, there are several survivin inhibitors under clinical evaluation, although more specific and efficient survivin inhibitors are being developed. Moreover, novel combination regimens targeting survivin together with other therapeutic approaches are currently being designed and assessed. In this review, recent progress in the therapeutic options targeting survivin for cancer treatment is analyzed. Direct survivin inhibitors and their current development status are explored. Besides, the major signaling pathways implicated in survivin regulation are described and different therapeutic approaches involving survivin indirect inhibition are evaluated. Finally, promising novel inhibitors under preclinical or clinical evaluation as well as challenges of developing survivin inhibitors as a new therapy for cancer treatment are discussed. PMID- 30421442 TI - Genetic diversity of Chinese cattle revealed by Y-SNP and Y-STR markers. AB - With its vast territory and complex natural environment, China boasts rich cattle genetic resources. To gain the further insight into the genetic diversity and paternal origins of Chinese cattle, we analyzed the polymorphism of Y-SNPs (UTY19 and ZFY10) and Y-STRs (INRA189 and BM861) in 34 Chinese cattle breeds/populations, including 606 males representative of 24 cattle breeds/populations collected in this study as well as previously published data for 302 bulls. Combined genotypic data identified 14 Y-chromosome haplotypes that represented three haplogroups. Y2-104-158 and Y2-102-158 were the most common taurine haplotypes detected mainly in northern and central China, whereas the indicine haplotype Y3-88-156 predominates in southern China. Haplotypes Y2-108 158, Y2-110-158, Y2-112-158 and Y3-92-156 were private to Chinese cattle. The population structure revealed by multidimensional scaling analysis differentiated Tibetan cattle from the other three groups of cattle. Analysis of molecular variance showed that the majority of the genetic variation was explained by the genetic differences among groups. Overall, our study indicates that Chinese cattle retain high paternal diversity (H = 0.607 +/- 0.016) and probably much of the original lineages that derived from the domestication center in the Near East without strong admixture from commercial cattle carrying Y1 haplotypes. PMID- 30421441 TI - Platelet Inhibition to Target Reperfusion Injury (The PITRI trial): Rationale and Study Design. AB - STRUCTURED ABSTRACT: BACKGROUND: In ST-segment elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PPCI), current oral P2Y12 platelet inhibitors do not provide maximal platelet inhibition at the time of reperfusion. Furthermore, administration of cangrelor prior to reperfusion has been shown in pre-clinical studies to reduce myocardial infarct (MI) size. Therefore, we hypothesize that cangrelor administered prior to reperfusion in STEMI patients will reduce the incidence of microvascular obstruction (MVO) and limit MI size in STEMI patients treated with PPCI. METHODS: The Platelet Inhibition to Target Reperfusion Injury (PITRI) trial, is a phase 2A, multi-center, double-blinded, randomized controlled trial, in which 210 STEMI patients will be randomized to receive either an intravenous (IV) bolus of cangrelor (30MUg/kg) followed by a 120 minutes infusion (4 MUg/kg/min) or matching saline placebo, initiated prior to reperfusion (NCT03102723). RESULTS: The study started in October 2017 and the anticipated end date would be July 2020. The primary end-point will be MI size quantified by cardiovascular magnetic resonance (CMR) on day 3 post-PPCI. Secondary endpoints will include markers of reperfusion, incidence of MVO, MI size and adverse left ventricular remodelling at 6 months, and major adverse cardiac and cerebrovascular events. SUMMARY: The aim of the PITRI trial is to assess whether cangrelor administered prior to reperfusion would reduce acute MI size and MVO, as assessed by CMR. This article is protected by copyright. All rights reserved. PMID- 30421443 TI - Detergent-compatible bacterial cellulases. AB - Cellulases, lipases, proteases, and amylases are employed in the detergent preparation to speed up the detergency process. Microbial cellulases are now commercially manufactured and are being used by various industries like detergent industry. Currently, the supplementation of detergent-compatible enzymes is a new trend followed by most of the detergent industries. The cellulases are supplemented to the detergents to improve the fabric smoothness and soil removal without damaging them. They act by passing through the textile interfibril spaces and thus the fabric quality is preserved. The process is environment friendly, and the use of cellulases and other detergent-compatible enzymes diminishes the utilization of toxic detergent constituents that are hazardous to humans. Alkaline cellulases active at ambient and low temperature are now preferred to maintain the fabric quality and use of low energy. The review reports on the production, purification, and properties studies of detergent-compatible proteases, amylases, and lipases are available. However, there is no report on detergent-compatible bacterial cellulases. In the present review, an overview on the production, purification, and characterization of detergent bacterial cellulases is presented. The stability and compatibility of the alkaline bacterial cellulases in the presence of the detergents and the detergent constituents are also discussed. PMID- 30421444 TI - Identification of cancer omics commonality and difference via community fusion. AB - The analysis of cancer omics data is a "classic" problem; however, it still remains challenging. Advancing from early studies that are mostly focused on a single type of cancer, some recent studies have analyzed data on multiple "related" cancer types/subtypes, examined their commonality and difference, and led to insightful findings. In this article, we consider the analysis of multiple omics datasets, with each dataset on one type/subtype of "related" cancers. A Community Fusion (CoFu) approach is developed, which conducts marker selection and model building using a novel penalization technique, informatively accommodates the network community structure of omics measurements, and automatically identifies the commonality and difference of cancer omics markers. Simulation demonstrates its superiority over direct competitors. The analysis of TCGA lung cancer and melanoma data leads to interesting findings. PMID- 30421445 TI - Sex-Differences in Post-Discharge Outcomes Among Patients Hospitalized for Atrial Fibrillation. AB - BACKGROUND: Patients with atrial fibrillation (AF) are at risk for both thromboembolic and bleeding complications. While the risk for thromboembolism is higher among women with AF than men, the sex-related differences in post discharge outcomes after hospitalization is not clearly understood. METHODS: We conducted a retrospective cohort study using data from the 2013-2014 Nationwide Readmission Database (NRD), to compare outcomes among men and women, >=50 years of age after hospitalization for AF. The primary patient outcome was all-cause re hospitalization at 90-days after initial hospitalization. Survey weighted Cox proportional hazard regression models were used to estimate the hazard ratios (HR) and their 95% confidence intervals (CI) for bleeding events at 30, 60, 90 and 270 days after hospitalization. RESULTS: From the 28 million patients in the NRD, we identified 522,521 individuals with an index hospitalization for AF. Compared to men, women hospitalized for AF accounted for 53.3% of the cohort and had higher rates of thrombotic (1.7%, 1.4%) and bleeding complications (1.4%, 1.1%). After adjustment, the 90-day risk among women versus men was significantly greater; all-cause re-hospitalization (24.2%, 17.0%; HR=1.07, 95% CI=1.05-1.09), re-hospitalization related to ischemic stroke (0.6%, 0.3%; HR 1.31, 95% CI=1.14 1.51)], pulmonary embolism (0.4%, 0.2%; HR 1.21, 95% CI=1.01-1.45), and any thrombotic event (1.3%, 0.7%; HR 1.20, 95% CI=1.09-1.32). CONCLUSIONS: Hospitalization for AF is common and frequently associated with both in-hospital complications and re-admission, which were more commonly observed among women with AF. Further research into epidemiological factors and treatment differences between men and women with AF is warranted. PMID- 30421446 TI - Robust remapping of equine SNP array coordinates to EquCab3. PMID- 30421449 TI - Resolving the role of the paramedian thalamus in forebrain arousal mechanisms. PMID- 30421447 TI - Once-daily darunavir/ritonavir 400/100 mg in triple therapy: efficacy and penetration in seminal compartment in ANRS-165 DARULIGHT study. PMID- 30421448 TI - Cartesian MR fingerprinting in the eye at 7T using compressed sensing and matrix completion-based reconstructions. AB - PURPOSE: To explore the feasibility of MR Fingerprinting (MRF) to rapidly quantify relaxation times in the human eye at 7T, and to provide a data acquisition and processing framework for future tissue characterization in eye tumor patients. METHODS: In this single-element receive coil MRF approach with Cartesian sampling, undersampling is used to shorten scan time and, therefore, to reduce the degree of motion artifacts. For reconstruction, approaches based on compressed sensing (CS) and matrix completion (MC) were used, while their effects on the quality of the MRF parameter maps were studied in simulations and experiments. Average relaxation times in the eye were measured in 6 healthy volunteers. One uveal melanoma patient was included to show the feasibility of MRF in a clinical context. RESULTS: Simulation results showed that an MC-based reconstruction enables large undersampling factors and also results in more accurate parameter maps compared with using CS. Experiments in 6 healthy volunteers used a reduction in scan time from 7:02 to 1:16 min, producing images without visible loss of detail in the parameter maps when using the MC-based reconstruction. Relaxation times from 6 healthy volunteers are in agreement with values obtained from fully sampled scans and values in literature, and parameter maps in a uveal melanoma patient show clear difference in relaxation times between tumor and healthy tissue. CONCLUSION: Cartesian-based MRF is feasible in the eye at 7T. High undersampling factors can be achieved by means of MC, significantly shortening scan time and increasing patient comfort, while also mitigating the risk of motion artifacts. PMID- 30421450 TI - Left ventricular septal lipoma. PMID- 30421451 TI - Correcting image blur in spiral, retraced in/out (RIO) acquisitions using a maximized energy objective. AB - PURPOSE: Images acquired with spiral k-space trajectories can suffer from off resonance image blur. Previous work showed that averaging 2 images acquired with a retraced, in/out (RIO) trajectory self-corrects image blur so long as off resonant spins accrue less than 1 half-cycle of relative phase over the readout. Practical scenarios frequently exceed this threshold. Here, we derive and characterize a more-robust off-resonance image blur correction method for RIO acquisitions. METHODS: Phantom and human volunteer data were acquired using a RIO trajectory with readout durations ranging from 4 to 60 ms. The resulting images were deblurred using 3 candidate methods: conventional linear correction of the component images; semiautomatic deblurring of the component images using an established minimized phase objective function; and semiautomatic deblurring of the average of the component images using a maximized energy objective function, derived below. Deblurring errors were estimated relative to images acquired with 4 ms readouts. RESULTS: All 3 methods converged to similar solutions in cases where less than 2 and 4 cycles of phase accrued over the readout in in vivo and phantom images, respectively (<13 ms readout at 3T). Above this threshold, the linear and minimized phase methods introduced several errors. The maximized energy function provided accurate deblurring so long as less than 6 and 10 cycles of phase accrued over the readout in in vivo and phantom images, respectively (<34 ms readout at 3T). CONCLUSION: The maximized energy objective function can accurately deblur RIO acquisitions over a wide spectrum of off resonance frequencies. PMID- 30421452 TI - A paediatric puzzle: pulsating, pruritic papules and plaques. PMID- 30421453 TI - Protective effects of the ROCK inhibitor fasudil against cognitive dysfunction following status epilepticus in male rats. AB - Despite remarkable advances in epilepsy research, prevention and reversal of cognitive deficits following epilepsy remain a challenge. It was reported that the Rho kinase (ROCK) inhibitor fasudil hydrochloride (FH) could improve cognitive deficits in animal models of Alzheimer's disease (AD). Thus, the aim of the present study was to determine whether FH-mediated inhibition of the effects of ROCK signaling could improve cognitive deficits in male rats (postnatal 21-day old) following status epilepticus (SE) induced by lithium-pilocarpin, the therapeutic window of opportunity and to elucidate the underlying mechanisms. Western blotting analysis showed upregulation of phosphorylated RhoA (p-RhoA) expression, and indicated activation of Rho/ROCK signaling after SE. The Morris water maze (MWM) test was used to analyze learning-memory ability. HE staining, immunofluorescence staining with antineuronal nuclei (NeuN) and anti neurofilament proteins 200 kD (NF200), transmission electron microscopy, and quantitative analysis of NeuN and synaptophysin by western blotting were performed to observe alterations in neurons, axons, and synapses in the hippocampi. Electroencephalogram (EEG) monitoring was used to record electrophysiological activities after SE. Our results indicated that treatment with FH at the first day following SE or 5 days later both could ameliorate cognitive dysfunction by reducing neuron, axon, and synapse damage, and mitigating EEG discharges, suggesting various roles for the Rho/ROCK signaling pathway in the pathological processes of brain damages following SE induced by lithium-pilocarpine. The Rho/ROCK signaling pathway is, therefore, a potential therapeutic target for the prevention or reversal of epilepsy induced brain damages. PMID- 30421454 TI - Attributable Risk of Alzheimer's Dementia Due to Age-Related Neuropathologies. AB - OBJECTIVE: The degree to which Alzheimer's versus other neuropathologies contribute to the risk of Alzheimer's dementia is unknown. We examined the risk of Alzheimer's dementia attributable to pathologic AD and eight other neuropathologies. METHODS: Participants (n=1,161) came from two clinical pathologic studies of aging. Multivariable logistic regression models examined associations of eight neuropathologic indices with Alzheimer's dementia and quantified the percentage of cases attributable to each. Further, because some dementia cases are not driven by common neuropathologies, we re-estimated the attributable risks after empirically adjusting for such cases. RESULTS: Of 1,161 persons, 512 (44.1%) had Alzheimer's dementia at the time of death. With the exception of microinfarcts, all neuropathologic indices were independently associated with greater odds of Alzheimer's dementia. 210 (41.0%) Alzheimer's dementia cases were attributable to pathologic AD. Separately, 8.9% were attributable to macroscopic infarcts, 10.8% to Lewy bodies, 5.2% to hippocampal sclerosis, 11.7% to TDP-43, 8.1% to CAA, 6.0% to atherosclerosis and 5.2% to arteriolosclerosis. A total of 83.3% of cases were attributable to all eight indices combined. However, after further adjustment for cases driven by other factors, a total of 67.5% of cases were attributable to all eight neuropathologic indices combined. INTERPRETATION: Pathologic AD accounts for a considerable percentage of Alzheimer's dementia cases, but multiple other neuropathologies also contribute. In total, just over two thirds of Alzheimer's dementia cases are attributable to common age-related neuropathologies, suggesting that other disease and resilience factors are important. This article is protected by copyright. All rights reserved. PMID- 30421455 TI - Clinical outcomes depending on acute blood pressure after cerebral hemorrhage. AB - OBJECTIVE: To determine the association between clinical outcomes and acute systolic blood pressure (SBP) levels achieved after intracerebral hemorrhage (ICH). METHODS: Eligible patients who were randomized to the Antihypertensive Treatment in Intracerebral Hemorrhage 2 (ATACH-2) trial (ClinicalTrials.gov NCT01176565) were divided into 5 groups by 10-mmHg strata of average hourly minimum SBP (<120 mmHg, 120-130, 130-140, 140-150 and >=150) during 2 to 24 hours after randomization. Outcomes included: 90-day modified Rankin Scale (mRS) 4-6; hematoma expansion, defined as an increase >=6 mL from baseline to 24-hour computed tomography; and cardio-renal adverse events within 7 days. RESULTS: Of the 1,000 subjects in ATACH-2, 995 with available SBP data were included in the analyses. The proportion of mRS 4-6 was 37.5%, 36.0%, 42.8%, 38.6%, and 38.0%, respectively. For the '140-150' group relative to the '120-130', the odds ratio, adjusting for sex, race, age, onset-to-randomization time, baseline National Institutes of Health Stroke Scale score, hematoma volume, and hematoma location, was 1.62 (95% confidence interval 1.02-2.58). Hematoma expansion was identified in 16.9%, 13.7%, 21.4%, 18.5%, and 26.4%, respectively. The '140-150' (odds ratio 1.80, 95% confidence interval 1.05-3.09) and '>=150' (1.98, 1.12-3.51) showed a higher frequency of expansion than '120-130' group. Cardio-renal events occurred in 13.6%, 16.6%, 11.5%, 8.1%, and 8.2%, respectively. The '140-150' (0.43, 0.19 0.88) and '>=150' (0.44, 0.18-0.96) showed a lower frequency of the events than the '120-130'. INTERPRETATION: Beneficial effects of lowering and maintaining SBP at 120-130 mmHg during the first 24 hours on clinical outcomes by suppressing hematoma expansion was somewhat offset by cardio-renal complications. This article is protected by copyright. All rights reserved. PMID- 30421456 TI - Restricting maintenance allopurinol dose according to kidney function in patients with gout is inappropriate! PMID- 30421457 TI - Thalamic Strokes that Severely Impair Arousal Extend into the Brainstem. AB - In this study we evaluate the role of the thalamus in the neural circuitry of arousal. Level of consciousness within the first 12 hours of a thalamic stroke is assessed with lesion symptom mapping. Impaired arousal correlates with lesions in the paramedian posterior thalamus near the centromedian and parafascicular nuclei, posterior hypothalamus, and midbrain tegmentum. All patients with severely impaired arousal (coma, stupor) had lesion extension into the midbrain and/or pontine tegmentum, whereas purely thalamic lesions did not severely impair arousal. These results are consistent with growing evidence that pathways most critical for human arousal lay outside the thalamus. This article is protected by copyright. All rights reserved. PMID- 30421458 TI - Analysis of Nutrition Support in Very Low-Birth-Weight Infants With Extrauterine Growth Restriction. AB - OBJECTIVE: To assess the incidence of extrauterine growth restriction (EUGR) in very low-birth-weight infants (VLBWIs) and evaluate the nutrition factors in VLBWIs associated with inadequate nutrient intakes during hospitalization. METHODS: A total of 128 VLBWIs were divided into an EUGR group (n = 87) and a non EUGR group (n = 41). Growth and parenteral nutrition (PN) and enteral nutrition (EN) practices were analyzed. Actual energy and protein intakes were subtracted from recommended energy (120 kcal/kg/d) and protein (3.75 g/kg/d) intakes, and nutrition deficits were calculated. RESULTS: Growth restriction was 21.9% at birth and 68.0% at discharge. Compared with established guidelines, PN was started late, and the maximum amino acid intake was low in both groups. EN interruption rate was higher in the EUGR group. The average energy intake in the first day after PN termination was lower in the EUGR group. There were significant differences in actual energy and protein intakes in the 2 groups for several weeks during hospitalization. The cumulative energy and protein deficits were significantly higher in the first 8 weeks and during the third to seventh weeks in the EUGR group, respectively. Step regression analysis showed that there was a significant negative correlation between the cumulative deficit of energy and changes of weight z-scores (r = -0.001, P < .05): as the energy deficit loss increased by 100 kcal, the weight z-scores dropped by 0.1 SD. CONCLUSION: Inadequate nutrition intake aggravated the occurrence of EUGR in VLBWIs, especially the energy intake. PMID- 30421459 TI - Brd4 inhibition suppresses HPV16 E6 expression and enhances chemoresponse: A potential new target in cervical cancer therapy. AB - Although a vast amount of research underlines the roles of the HR HPV E6 and E7 oncogenes in HPV-induced carcinogenesis of cervical cancer, it remains unclear whether these oncogenes are also involved in the resistance of the cancer against chemotherapy. We examined the role of the HPV16 E6 oncogene in cisplatin resistance by analysing its expression in newly established cisplatin-sensitive versus -resistant cervical cancer cell lines (CC7, CC10). Resistant variants were obtained by interval exposure treatment with 1-2 MUM cisplatin for 8-9 months. Our results demonstrate that the expression level of HPV16 E6 directly correlates with the extent of cisplatin resistance in novel as well as established (SiHa) drug resistant cervical cancer cell lines. Overexpression of HPV16 E6 in cisplatin-naive cells rendered these cells more resistant to cisplatin. Reducing E6 expression by JQ1 treatment reversed the drug resistant phenotype and strongly enhanced chemoresponse only in HPV-positive cisplatin-resistant variants and not in HPV-negative C33A cervical cancer cells. The level of E6 directly correlated with the extent of cisplatin sensitivity and was shown to be increased in newly established drug-resistant cell line variants, while reducing E6 expresssion using Brd4-inhibitors enhanced chemoresponse when co-delivered with cisplatin. Inhibition of Brd4 could represent a new therapeutic option by increasing treatment response in cervical cancer cells and might allow lower cisplatin dosages, thus reducing negative side effects. This article is protected by copyright. All rights reserved. PMID- 30421460 TI - Calycosin attenuates MPTP-induced Parkinson's disease by suppressing the activation of TLR/NF-kappaB and MAPK pathways. AB - Parkinson is the second common neurodegenerative disease. The characteristics of Parkinson's disease (PD) are the dopamin neurons loss caused by neuroinflammation responses. C alycosin, an isoflavone phytoestrogen isolated from Astragalus membranaceus, has multiple pharmacological activities, such as anti-inflammation, anti-tumor, and neuroprotective effects. However, it is unknown whether calycosin can mitigate PD symptoms. This study aims to explore whether calycosin can alleviate PD symptoms and the underlying mechanisms. PD was induced in mice by 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injection, and calycosin was given intracerebroventricularly to these mice. A cell model of nerve inflammation was established by BV2 microglia cells injected with lipopolysaccharide (LPS). The motor states were evaluated by stepping, whisker, and cylinder experiments. The states of dopaminergic neurons and microglia were detected by immunostainning of tyrosine hydroxylase and cluster of differentiation molecule 11b (CD11b). The expression levels of inflammatory factors were detected by qPCR. Toll-like receptor (TLR)/nuclear factor kappa B (NF-kappaB) and mitogen-activated protein kinase (MAPK) pathways were investigated by western blot. We found that calycosin treatment mitigated the behavioral dysfunctions and inflammatory responses in MPTP-induced PD mice. The TLR/NF-kappaB and MAPK pathways in MPTP-induced PD mice were inhibited by calycosin treatment, which was coincident with experiments in LPS-induced BV2 cells. Above all, calycosin mitigates PD symptoms through TLR/NF kappaB and MAPK pathways in mice and cell lines. PMID- 30421463 TI - Effect of puerarin on melanogenesis in human melanocytes and vitiligo mouse models and the underlying mechanism. AB - Puerarin is the major bioactive ingredient derived from the root of the Pueraria lobata (Willd.), and its antioxidative stress effects have been demonstrated in several previous studies. Moreover, Puerarin can upregulate melanin synthesis and microphthalmia-associated transcription factor (MITF) transcription by increasing cAMP level of intracellular cyclic adenosine monophosphate. Vitiligo is an acquired cutaneous disorder of pigmentation, and the pathogenesis has remained elusive. Current treatment modalities are directed towards achieving repigmentation. In this study, we found that after treating with puerarin at various concentrations of 40 MUmol/L, the melanin content of human melanocytes increased significantly and the apparent level of protein and the RNA levels of MITF, tyrosinase (TYR), and tyrosinase-related protein 1 (TRP-1) were also increased. Further, puerarin was shown to inhibit phosphorylation and activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) without significantly affecting p38 and c-Jun N-terminal kinase phosphorylation. These results demonstrated that puerarin stimulated melanogenesis in human melanocytes via inhibition of ERK1/2 signaling pathways, which leads to upregulation of MITF and TYR as well as TRP-1 subsequently. Additionally, mice vitiligo models with puerarin treatment showed lighter pathological changes. Therefore, we suggested that puerarin might be a potential medicine for vitiligo. PMID- 30421462 TI - Home-based early intervention in infants and young children with visual impairment using the Developmental Journal: longitudinal cohort study. AB - AIM: To investigate the effects of home-based early intervention in children with severe visual impairment using the Developmental Journal for babies and young children with visual impairment (DJVI). METHOD: A longitudinal observational study was undertaken with a national cohort (OPTIMUM) of infants with congenital disorders of the peripheral visual system (CDPVS) and profound-severe visual impairment; and followed up after 12 months and 24 months. Intervention was categorized according to the practitioner diary records of their usual practice over 12 months from baseline comparing those receiving the DJVI and those receiving 'Other Support'. Outcome measures of cognition and language, behaviour difficulties, parenting stress, and satisfaction with parent-practitioner partnership were collected. RESULTS: In the 54 children (26 males, 28 females, baseline mean age 13.5mo, SD 2.3mo, range 8-17mo) with 'total' CDPVS (including 16 'complex' and 38 'simple' with or without known brain disorder respectively), linear mixed effects pointed towards acceleration in sensorimotor understanding and expressive language especially in the 'simple' subsample (11.72 developmental quotient, 95% confidence interval -1.17 to 24.61, p>0.05) in those receiving the DJVI. Vision level also predicted outcomes (p<0.05). The DJVI group showed improvements in behavioural withdrawal (eta2 =0.20, p=0.02, 'simple') and parenting stress (d=0.78, d=0.92, p=0.02 total and 'simple' respectively) and perceived practitioner-parent relationship (eta2 =0.16, p=0.01). INTERPRETATION: Infants and young children with visual impairment receiving home-based early intervention using the DJVI with a structured developmental approach had better outcomes than those receiving 'other' home-based early interventions. Moderate to large effect improvements were found in child cognition and language, behaviour and parenting stress and the perceived practitioner-parent relationship, although cognition did not reach 5% significance level. WHAT THIS PAPER ADDS: Early intervention using the Developmental Journal for babies and young children with visual impairment was associated with enhanced developmental outcomes compared to other approaches. Improvements were also found in child behaviour, parenting stress, and perceived parent practitioner outcomes. Type and complexity of visual impairment also influenced outcomes. PMID- 30421464 TI - Abnormal Immunolabeling of SMAD4 in Cell Block Specimens Distinguish Malignant and Benign Pancreatic Cells. AB - BACKGROUND: Accurate diagnosis of malignant and benign pancreatic lesions can be challenging, especially in case of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) samples that are small and/or degraded. In the present study, we determined how to best evaluate abnormal SMAD4 expression by immunohistochemical staining on cell-block specimens from EUS-FNA samples. RESULTS: In surgically resected pancreas, when abnormal SMAD4 immunolabeling was evaluated as negative SMAD4 expression, the sensitivity was low (33%), but when it was evaluated as decreased SMAD4 expression, the sensitivity improved (53%). Specificity and positive predictive value were high for both evaluations. There were no false positive cases. In cell-block specimens, decreased SMAD4 expression showed 47% sensitivity and 72% specificity, while negative SMAD4 expression showed lower sensitivity (20%) and higher specificity (100%). Both evaluations in cell-block specimens showed lower sensitivity and specificity compared to the case for resected specimens. False positive and negative rates were higher for cell blocks than for resected specimens. CONCLUSIONS: Decreased SMAD4 immunolabeling provided improved sensitivity as compared to negative SMAD4 immunolabeling; therefore, it is important to compare SMAD4 expression in a sample to its expression in normal cells. Abnormal SMAD4 labeling showed low sensitivity and high specificity; therefore, SMAD4 staining using EUS-FNA samples might be helpful to detect malignancies that possess SMAD4 gene abnormalities. This article is protected by copyright. All rights reserved. PMID- 30421465 TI - Early luteal development in Santa Ines ewes superovulated with reduced doses of porcine follicle-stimulating hormone. AB - The aim was to compare the early luteal development in ewes superovulated with different doses of pFSH. Twenty-nine Santa Ines ewes received a progesterone device (CIDR(r)) for 8 days. Gonadotrophic treatment started on Day 6: G200 (control, n = 9, 200 mg); G133 (n = 10, 133 mg); and G100 (n = 10, 100 mg of pFSH). On Day 6, all females received eCG (300 IU). B-mode and spectral Doppler ultrasonography were performed daily during the early luteal phase (Days 11-15) to monitor the development of corpora lutea (CLs; dimensions) and ovarian arteries indices. CLs were also classified as normal or prematurely regressed (PRCL) on Day 15 by videolaparoscopy. Ewes from G100 and G133 showed gradual increase in luteal diameter during the early luteal phase (p < 0.001), whereas G200 animals presented increase from Day 11 to Day 13, and then decrease on Days 14 and 15 (p < 0.001). The G200 females showed greater percentage of PRCL (45.20%) than those of the other groups (p < 0.001). The normal CLs number was greater in G100 than in G133 (p = 0.04), while the PRCL number was greater in G200 than in the other groups (p = 0.03). Resistive index (RI) was greater in G200 than in G100 (p = 0.02). RI was lower in Day 12 than Day 15 (p = 0.02). Pulsatility index (PI) was greater on Days 14 and 15 (p < 0.01). In conclusion, the lowest dose of pFSH (100 mg) can be considered sufficient for an efficient superovulatory response in sheep, producing better CLs development dynamic in early luteal phase and ovarian blood perfusion and smaller number of PRCL than the traditional (200 mg) pFSH dose. PMID- 30421466 TI - Isobavachalcone attenuates myotube atrophy induced by TNF-alpha through muscle atrophy F-box signaling and the nuclear factor erythroid 2-related factor 2 cascade. AB - Skeletal muscle atrophy is a condition characterized by damaged muscle fibers and reduced numbers of muscle cells due to various causes. Muscle atrophy is associated with chronic diseases, such as heart failure, diabetes, and aging related diseases. Isobavachalcone (IBC) is a flavonoid found in various foods and natural products, and studies have investigated its diverse effects, including its neuroprotective and anticancer effects. However, no studies have evaluated the effects of IBC on muscle atrophy. Thus, in this study, we assessed the effects of IBC on prevention of muscle atrophy. To evaluate the preventive effects of IBC on muscle atrophy, we used C2C12 myoblasts and induced muscle atrophy by tumor necrosis factor (TNF)-alpha. IBC regulated the expression levels of muscle atrophy F-box and muscle RING finger-1 in response to damaged muscle cells, thereby restoring the expression of myosin heavy chain and myogenin. Moreover, IBC regulated the phosphorylation of the nuclear factor-kappaB and p38 and upregulated the expression of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1, which are involved in regulating oxidative stress. Our results indicated that IBC acted to relieve TNF-alpha-induced skeletal muscle atrophy by regulating the factors related to inflammation and oxidative stress. PMID- 30421467 TI - Curcumin gum formulation for prevention of oral cavity head and neck squamous cell carcinoma. AB - OBJECTIVES/HYPOTHESIS: Head and neck squamous cell carcinoma represents the sixth most common cancer. As a result of field cancerization, second primaries and recurrences are high. Hence, research has focused on chemoprevention. Curcumin, a polyphenol compound with anticarcinogenic properties, is one such promising nutraceutical. As poor bioavailability limits curcumin's use, a novel gum formulation was tested allowing for direct mucosal absorption into the bloodstream. This preliminary study validates curcumin gum efficacy by assessing release and transmucosal absorption, along with measuring its effects on serum cytokine levels. STUDY DESIGN: Clinical trial. METHODS: Protocols consisting of initial chew (chewing gum for 30 minutes) and revised chew (alternating chewing and parking gum against buccal mucosa for 30 minutes) were tested in healthy volunteers. High-performance liquid chromatography measured remnant curcumin in chewed gum, serum, and saliva. Serum levels were assayed for 15 proinflammatory cytokines via multiplex analysis. RESULTS: Revised chew samples demonstrated significantly higher curcumin release and absorption (P = .0078). Curcumin serum levels were significantly higher at 4 hours in samples > 2.0 g of curcumin release (P = .01). As saliva levels decreased, a concurrent increase in serum levels was observed, with no significance in the inverse relationship (P = .1423). When evaluating differences between gender, race, and age, the Asian population showed significantly lower curcumin release and serum levels (P = .009). CXCL1 (GRO-alpha) and TNF-alpha were significantly decreased in serum after chewing the gum (P = .036, P < .001, respectively). CONCLUSIONS: Enhanced mucosal contact appears critical in improving curcumin release and absorption. CXCL1 and TNF-alpha both represent potential biomarkers for the future study of curcumin chemoprevention. LEVEL OF EVIDENCE: 2b Laryngoscope, 2018. PMID- 30421468 TI - Distribution of cervical and breast cancer risk factors in women and their screening behaviours. AB - Breast cancer and cervical cancer are important causes of cancer-related mortality in women all over the world. The present study was conducted in order to investigate the distribution of cervical and breast cancer risk factors in women and their knowledge and behaviours about cancer screening methods. The study is cross-sectional in nature. It was conducted with the participation of 1,886 women in Turkey. Data were collected through a questionnaire. The knowledge and behaviours of women aged 40 and over about breast cancer or cervical cancer screening methods were investigated according to the education level; results showed that the rates of those who knew and did breast self-examination were significantly lower in illiterate women. Besides, the rates of women who did breast self-examination were significantly lower in those who were aged 40 and over, and the rates of those who had clinical breast examination and Pap smear test were significantly lower in women aged 39 and below (p < 0.01). This study identified the most notable breast and cervical cancer risk factors as low education levels, high number of deliveries, short breastfeeding period, obesity and low socio-economic level. For this reason, public health policies should be developed to minimise these risk factors. PMID- 30421470 TI - Flexible longitudinal linear mixed models for multiple censored responses data. AB - In biomedical studies and clinical trials, repeated measures are often subject to some upper and/or lower limits of detection. Hence, the responses are either left or right censored. A complication arises when more than one series of responses is repeatedly collected on each subject at irregular intervals over a period of time and the data exhibit tails heavier than the normal distribution. The multivariate censored linear mixed effect (MLMEC) model is a frequently used tool for a joint analysis of more than one series of longitudinal data. In this context, we develop a robust generalization of the MLMEC based on the scale mixtures of normal distributions. To take into account the autocorrelation existing among irregularly observed measures, a damped exponential correlation structure is considered. For this complex longitudinal structure, we propose an exact estimation procedure to obtain the maximum-likelihood estimates of the fixed effects and variance components using a stochastic approximation of the EM algorithm. This approach allows us to estimate the parameters of interest easily and quickly as well as to obtain the standard errors of the fixed effects, the predictions of unobservable values of the responses, and the log-likelihood function as a byproduct. The proposed method is applied to analyze a set of AIDS data and is examined via a simulation study. PMID- 30421469 TI - Machine-learning-derived sleep-wake staging from around-the-ear electroencephalogram outperforms manual scoring and actigraphy. AB - Quantification of sleep is important for the diagnosis of sleep disorders and sleep research. However, the only widely accepted method to obtain sleep staging is by visual analysis of polysomnography (PSG), which is expensive and time consuming. Here, we investigate automated sleep scoring based on a low-cost, mobile electroencephalogram (EEG) platform consisting of a lightweight EEG amplifier combined with flex-printed cEEGrid electrodes placed around the ear, which can be implemented as a fully self-applicable sleep system. However, cEEGrid signals have different amplitude characteristics to normal scalp PSG signals, which might be challenging for visual scoring. Therefore, this study evaluates the potential of automatic scoring of cEEGrid signals using a machine learning classifier ("random forests") and compares its performance with manual scoring of standard PSG. In addition, the automatic scoring of cEEGrid signals is compared with manual annotation of the cEEGrid recording and with simultaneous actigraphy. Acceptable recordings were obtained in 15 healthy volunteers (aged 35 +/- 14.3 years) during an extended nocturnal sleep opportunity, which induced disrupted sleep with a large inter-individual variation in sleep parameters. The results demonstrate that machine-learning-based scoring of around-the-ear EEG outperforms actigraphy with respect to sleep onset and total sleep time assessments. The automated scoring outperforms human scoring of cEEGrid by standard criteria. The accuracy of machine-learning-based automated scoring of cEEGrid sleep recordings compared with manual scoring of standard PSG was satisfactory. The findings show that cEEGrid recordings combined with machine learning-based scoring holds promise for large-scale sleep studies. PMID- 30421471 TI - Increased incidence of axonal Guillain-Barre syndrome in La Spezia area of Italy: a thirteen-years follow-up study. AB - BACKGROUND: Guillain-Barre syndrome (GBS) is an acute immune-mediated polyradiculoneuropathy with a worldwide incidence of 0,81- 1,89 per 100,000 person-years. In Europe and North America only 5% of patients with GBS have axonal subtypes, which in South America and Asia account for 30-47% of cases. OBJECTIVE: To assess the annual incidence and clinical features of GBS in La Spezia area in Italy. MATERIAL AND METHODS: A retrospective (from January 1st 2003 to December 31st 2011) followed by a prospective (from January 1st 2012 to December 31st 2015) analysis was carried out on patients admitted to La Spezia hospital who fulfilled the GBS diagnostic criteria. RESULTS: A total of 86 patients (58 men), mean age of 62.7 years (range 21-90), were included. The mean annual incidence rate was 3/100000 (range: 0.9/100000 - 5.37/100000) significantly higher than the European incidence (p<0.001). Forty-seven percent were classified as acute inflammatory demyelinating polyradiculoneuropathy (AIDP), 35% as acute motor and motor-sensory axonal neuropathy (AMAN-AMSAN), 13% as variant forms, and 5% were not defined. AIDP was most common in "Golfo dei Poeti" (50%) and "Val di Magra" (63.2%), whereas AMAN/AMSAN prevailed in "Val di Vara" (63.6%) and "Riviera Spezzina" (62.5%) (p=0.024). CONCLUSIONS: In La Spezia area GBS incidence (especially the AMAN subtype) is significantly higher than the incidence reported in Europe. AIDP predominates in the Eastern area whereas AMAN/AMSAN in the Western, with a significantly different incidence rate (p=0.003). Prospective studies to assess possible predisposing environmental factors are needed. This article is protected by copyright. All rights reserved. PMID- 30421472 TI - Spontaneous oscillatory markers of cognitive status in two forms of dementia. AB - Abnormal oscillatory brain activity in dementia may indicate incipient neuronal/synaptic dysfunction, rather than frank structural atrophy. Leveraging a potential link between the degree of abnormal oscillatory activity and cognitive symptom severity, one could localize brain regions in a diseased but pre-atrophic state, which may be more amenable to interventions. In the current study, we evaluated the relationships among cognitive deficits, regional volumetric changes, and resting-state magnetoencephalography abnormalities in patients with mild cognitive impairment (MCI; N = 10; age: 75.9 +/- 7.3) or primary progressive aphasia (PPA; N = 12; 69.7 +/- 8.0), and compared them to normal aging [young (N = 18; 24.6 +/- 3.5), older controls (N = 24; 67.2 +/- 9.7]. Whole-brain source level resting-state estimates of relative oscillatory power in the delta (1-4 Hz), theta (4-7 Hz), alpha (8-12 Hz), and beta (15-30 Hz) bands were combined with gray matter volumes and cognitive scores to examine between-group differences and brain-behavior correlations. Language and executive function (EF) abilities were impaired in patients with PPA, while episodic memory was impaired in MCI. Widespread oscillatory speeding and volumetric shrinkage was associated with normal aging, whereas the trajectory in PPA indicated widespread oscillatory slowing with additional volumetric reductions. Increases in delta and decreases in alpha power uniquely predicted group membership to PPA. Beyond volumetric reductions, more delta predicted poorer memory. In patients with MCI, no consistent group difference among oscillatory measures was found. The contributions of delta/alpha power on memory abilities were larger than volumetric differences. Spontaneous oscillatory abnormalities in association with cognitive symptom severity can serve as a marker of neuronal dysfunction in dementia, providing targets for promising treatments. PMID- 30421473 TI - A neural microcircuit model for a scalable scale-invariant representation of time. AB - Scale-invariant timing has been observed in a wide range of behavioral experiments. The firing properties of recently described time cells provide a possible neural substrate for scale-invariant behavior. Earlier neural circuit models do not produce scale-invariant neural sequences. In this article, we present a biologically detailed network model based on an earlier mathematical algorithm. The simulations incorporate exponentially decaying persistent firing maintained by the calcium-activated nonspecific (CAN) cationic current and a network structure given by the inverse Laplace transform to generate time cells with scale-invariant firing rates. This model provides the first biologically detailed neural circuit for generating scale-invariant time cells. The circuit that implements the inverse Laplace transform merely consists of off-center/on surround receptive fields. Critically, rescaling temporal sequences can be accomplished simply via cortical gain control (changing the slope of the f-I curve). PMID- 30421474 TI - Factors influencing the use of opioids for breakthrough cancer pain: a secondary analysis of the IOPS-MS study. AB - Controversies exist about the choice and the doses of opioid medication in breakthrough cancer pain (BTcP). The aim was to assess factors influencing the use and the doses of opioids prescribed for BTcP. It was performed a secondary analysis of a national, multicenter study that involving 32 centers performed in patients having BTcP. Diagnosis of BTcP was based on a definite algorithm. Patients using opioids for background pain and for BTcP, were selected. Average pain intensity and opioids used for background pain and BTcP, and adverse effects were assessed, as well as patient's satisfaction and the grade of mucositis. The analysis was performed in 2771 patients. Opioid doses given for BTcP were significantly associated with those given for background pain. No relationship between adverse effects and the use and the doses of opioids used for BTcP was found. Drugs and doses were not correlated to the grade of oral mucositis. Nasal fentanyl preparations provided the fastest meaningful pain relief in comparison with other fentanyl transmucosal preparations or morphine preparations (p=.000). The majority of patients were satisfied with opioid medications given for BTcP. Only 2.8% of patients reported adverse effects related to opioid medication used for BTcP. Age and gender were independently associated with dosages of some fentanyl products. Opioids for BTcP were effective and safe in a large sample of cancer patients with different stages of disease. Doses of opioids proportional to doses used for background pain, seem to guarantee both efficacy and safety. This article is protected by copyright. All rights reserved. PMID- 30421475 TI - Identification and monitoring of atypical PML/RARA fusion transcripts in acute promyelocytic leukemia. AB - Once the diagnostic suspicion of acute promyelocytic leukemia (APL) has been raised, international guidelines recommend prompt initiation of tailored therapy and supportive care, while awaiting for genetic confirmation of the diagnosis, and the identification of the specific PML/RARA isoform by reverse transcriptase polymerase chain reaction (RT-PCR). Depending on the PML break point, usually located within intron 6, exon 6, or intron 3, different PML/RARA transcript isoforms may be generated, that is, long (bcr1), variant (bcr2), and short (bcr3), respectively. We report here the characterization of three APL cases harboring atypical PML/RARA transcripts, which were not clearly detectable after standard RT-PCR amplification. In all three cases, clinical, morphological, and immunophenotypic features were consistent with APL. Direct sequencing allowed the identification of atypical break points within the PML and RARA genes. Then, we designed a patient-specific quantitative real-time PCR for the atypical transcripts, which allowed for specific quantitative evaluation of minimal residual disease (MRD) during follow-up. Despite the rarity of APL cases with an atypical PML/RARA fusion, our study indicates that an integrated laboratory approach, employing several diagnostic techniques is crucial to timely diagnose APL. This approach allows prompt initiation of specific targeted treatment and reliable MRD monitoring in atypical APL cases. PMID- 30421476 TI - Absence of an early hippocampal encoding signal after medial temporal lesions: no consequence for the spacing effect. AB - Immediately repeated meaningful pictures in a continuous recognition task induce a positive frontal potential at about 200-300 ms, which appears to emanate from the medial temporal lobe (MTL) centered on the hippocampus, as concluded from inverse solutions, coherence measurements and depth electrode recordings in humans. In this study, we tested patients with unilateral MTL lesions due to stroke to verify the provenance of this signal and its association with the spacing effect (SE) - the improved learning of material encountered in spaced rather than massed presentation. We found that unilateral left or right MTL lesions abolished the early frontal MTL-mediated signal but not the spacing effect. We conclude that the early frontal signal at 200-300 ms after immediate picture repetition may serve as a direct biomarker of MTL integrity that may be useful in the early stages of diseases like Alzheimer's. A second conclusion is that the SE does not depend on MTL integrity. This article is protected by copyright. All rights reserved. PMID- 30421477 TI - Corticosteroids for Preventing Post Herpetic Neuralgia after Herpes Zoster Infection. AB - Post-herpetic neuralgia is a painful condition of persistent chronic pain following acute reactivation of varicella zoster virus. The review defines PHN as persisting or recurring pain at the site of shingles at least one month after the onset of the acute rash. The incidence of shingles increases with age, almost doubling in each decade after 50 years of age. Of these cases, roughly 20% go on to develop PHN, with age again being the strongest risk factor.1 The pain of PHN is frequently debilitating and can significantly affect quality of life. It is thought that the anti-inflammatory effects of corticosteroids might decrease nerve damage and prevent PHN. This Cochrane review is an update of a previous Cochrane review first published in 2008 and updated in 2010. This update concludes based on moderate quality evidence that steroids do not provide benefit in the prevention of PHN, whereas prior reviews indicated insufficient evidence to draw a conclusion. More up to date data analysis methods were used in this review to provide conclusions It included all RCTs in which corticosteroids were given by oral, intramuscular, or intravenous routes within 7 days after onset of rash and in which steroids were compared to either no treatment or to placebo. Five trials with a total of 787 patients were included. The meta-analysis provides moderate-quality evidence that corticosteroids are not effective in preventing PHN six months after onset of acute herpetic rash (Relative risk (RR) 0.95, 95% confidence interval (CI) 0.45 to 1.99). The review found no statistically significant difference in the secondary outcome of pain severity at 3, 6, or 12 months. Non-serious adverse events were recorded in all of the trials, and there were no statistically significant differences between steroid and placebo. Serious events, including pneumonia, myocardial infarction, cardiac insufficiency, and death for example were reported in three of the trials, but there were no statistically significant differences between steroid and placebo (6/376, 1.6% and 3/379, 0.8% respectively)Two of the trials made note of the absence of serious adverse events in the steroid groups. The Cochrane authors suggest that future trials should include measurements of function and quality of life, and furthermore, that there should be longer-term follow-up in order to determine an effect of steroids on the likelihood of transition from acute pain to PHN. This article is protected by copyright. All rights reserved. PMID- 30421478 TI - Cognitive impairment and homelessness: A scoping review. AB - This paper reports the findings of a scoping review designed to identify research which has explored the relationship between cognitive impairment and homelessness. A systematic search of databases for articles published between 2007 and 2017 was conducted using keywords relating to cognitive impairments and homelessness. Sources were expanded using manual searches of citations and grey literature. Forty studies represented in 45 papers were selected for review using predefined inclusion criteria. Sources were subject to quality appraisal and data were extracted in line with review questions. Prevalence studies were over represented in the review, while qualitative data were lacking. Aetiology of impairments was delineated by acquired and developmental causes. A variety of measures were employed by studies which were not validated in homeless populations. Studies did not give sufficient consideration to co-occurring disorders and overlapping symptoms between aetiologies. Because of these factors, it was difficult to conclude that all studies had accurately measured what they set out to; however, the evidence suggested that cognitive impairment was disproportionately over-represented in homeless populations. Cognitive impairment was found to be both a risk factor to and perpetuator of homelessness. Risk factors for homelessness were similar to those of the general population, though exaggerated by sequelae of certain cognitive impairments. The results of this review suggest that more attention needs to be paid to the underlying socioeconomic disadvantages, persons with cognitive impairments face which may lead to homelessness. Further research should prioritise the voice of homeless persons with cognitive impairments, to better understand both causes of homelessness and effective methods of rehabilitation. PMID- 30421479 TI - Comprehensive analysis of the mitochondrial DNA diversity in Chinese cattle. AB - Complete mitochondrial DNA D-loop sequences of 1105 individuals were used to assess the diversity of maternal lineages of cattle populations in China. In total, 250 taurine and 88 zebu haplotypes were identified. Five main haplogroups T1a, T2, T3, T4 and T5-were identified in Bos taurus, whereas Bos indicus harbored two haplogroups-I1 and I2. Our results suggest that the distribution of T1a in Asia was concentrated mainly in the northeast region (northeast China, Korea and Japan); haplogroups T2, T3 and T4 were predominant in Chinese cattle; and T5 was sporadically detected in Mongolian and Pingwu cattle. In contrast to the widespread presence of I1, I2 was distributed only in southwestern China (Yunnan-Guizhou Plateau and the Tibet Autonomous Region) and Xinjiang Uygur Autonomous Region. This is the first time that all five taurine haplogroups and two zebu haplogroups have been found in Mongolian cattle. In addition, eight individuals in Tibetan cattle carried the Bos grunniens mtDNA type. The high mtDNA diversity (H = 0.904 +/- 0.008) and the weak genetic structure among the 57 Chinese cattle breeds/populations are consistent with their complex historical background, migration route and ecological environment. PMID- 30421480 TI - Parallel plumage colour evolution and introgressive hybridization in wheatears. AB - Genetic and phenotypic mosaics, in which various phenotypes and different genomic regions show discordant patterns of species or population divergence, offer unique opportunities to study the role of ancestral and introgressed genetic variation in phenotypic evolution. Here, we investigated the evolution of discordant phenotypic and genetic divergence in a monophyletic clade of four songbird taxa - pied wheatear (O. pleschanka), Cyprus wheatear (O. cypriaca), and western and eastern subspecies of black-eared wheatear (O. h. hispanica and O. h. melanoleuca). Phenotypically, black back and neck sides distinguish pied and Cyprus wheatears from the white-backed/necked black-eared wheatears. Meanwhile, mitochondrial variation only distinguishes western black-eared wheatear. In the absence of nuclear genetic data, and given frequent hybridization among eastern black-eared and pied wheatear, it remains unclear whether introgression is responsible for discordance between mitochondrial divergence patterns and phenotypic similarities, or whether plumage coloration evolved in parallel. Multispecies coalescent analyses of about 20 000 SNPs obtained from RAD data mapped to a draft genome assembly resolve the species tree, provide evidence for the parallel evolution of colour phenotypes and establish western and eastern black-eared wheatears as independent taxa that should be recognized as full species. The presence of the entire admixture spectrum in the Iranian hybrid zone and the detection of footprints of introgression from pied into eastern black eared wheatear beyond the hybrid zone despite strong geographic structure of ancestry proportions furthermore suggest a potential role for introgression in parallel plumage colour evolution. Our results support the importance of standing heterospecific and/or ancestral variation in phenotypic evolution. PMID- 30421481 TI - Design of the randomized, placebo-controlled evolocumab for early reduction of LDL-cholesterol levels in patients with acute coronary syndromes (EVOPACS) trial. AB - Statins lower low-density lipoprotein cholesterol (LDL-C) and improve clinical outcomes in patients with atherosclerotic cardiovascular disease (CVD). Patients with acute coronary syndromes (ACS) often do not achieve LDL-C targets despite potent statin treatment, and have a particularly high risk of early recurrent events. Evolocumab, a proprotein convertase subtilisin/kexin type (PCSK9) inhibitor resulting in rapid, marked LDL-C reduction, has been studied in hypercholesterolemic subjects without CVD and stabilized patients with CVD; the feasibility, safety, and efficacy of this treatment initiated in the acute phase of ACS remain unknown. We report the design of evolocumab for early reduction of LDL-cholesterol levels in patients with ACS (EVOPACS), a phase-3, multicenter, randomized, double-blind, placebo-controlled trial to assess the feasibility, safety, and LDL-C-lowering efficacy of evolocumab on top of atorvastatin 40 mg in patients with ACS. The primary endpoint is percent change in LDL-C from baseline to 8 weeks. Secondary endpoints are adverse events and serious adverse events. Against a background of beneficial cardiovascular effects of statins beyond LDL-C lowering and in view of preclinical evidence of similar effects of PCSK9 inhibition, the study will also address a variety of exploratory endpoints including the change in C-reactive protein and other inflammatory biomarkers; platelet reactivity; and occurrence of contrast-induced acute kidney injury and myocardial injury in patients undergoing cardiac catheterization. An intracoronary imaging sub-study will investigate the change from baseline in the lipid core burden index in non-culprit lesions, as assessed by serial near infrared spectroscopy. Recruitment began in January 2018 and enrollment of 308 patients is planned. PMID- 30421482 TI - On the Use of Thermodynamic Cycles for the Calculation of Standard Potentials for the Oxidation of Solid Metals in Solution. AB - The performance of a thermodynamic cycle for the calculation of the standard reduction potential (SRP) of a series of metals is examined. It is found that the introduction of simple entropic corrections substantially improves the agreement with experimental data. The accuracy of the estimations is in the range of 0.04 V, which opens the possibility to calculate the SRP for metals in non-aqueous solvents or other unusual situations. PMID- 30421483 TI - Ethanol-induced alterations in endocannabinoids and relevant neurotransmitters in the nucleus accumbens of fatty acid amide hydrolase knockout mice. AB - Deletion of fatty acid amide hydrolase (FAAH), enzyme responsible for degrading endocannabinoids, increases alcohol consumption and preference. However, there is a lack of data on neurochemical events in mice exposed to alcohol in the absence of FAAH. Extracellular levels of endocannabinoids and relevant neurotransmitters were measured by in vivo microdialysis in the nucleus accumbens (NAc) of FAAH knockout (KO) and wild-type (WT) mice during an ethanol (EtOH; 2 g/kg, ip) challenge in EtOH-naive and repeated (r) EtOH-treated mice. In both genotypes, EtOH treatment caused no changes in baseline endocannabinoid levels, although FAAH KO mice displayed higher baseline N-arachidonoylethanolamine levels than WT mice. EtOH challenge caused a sustained increase in 2-arachidonoylglycerol (2-AG) levels in EtOH-naive WT mice but not in FAAH KO mice. In contrast, 2-AG levels were decreased following EtOH challenge in (r)EtOH-treated mice in both genotypes. Whereas (r)EtOH-treated mice showed higher baseline dopamine and serotonin levels than EtOH-naive mice in WT mice, these differences were attenuated in FAAH KO mice. Significant differences in baseline gamma aminobutyric acid (GABA) and glutamate levels by EtOH history were observed in WT mice but not in FAAH KO mice. Moreover, opposed effects on glutamate response were observed after EtOH challenge in EtOH-naive and (r)EtOH-treated FAAH KO mice. Finally, FAAH deletion failed to show EtOH-induced locomotion sensitivity. These data provide evidence of a potential influence of 2-AG in the neurochemical response to EtOH exposure in the NAc. PMID- 30421484 TI - CO2 -Cross-Linked Frustrated Lewis Networks as Gas-Regulated Dynamic Covalent Materials. AB - The design of structurally dynamic molecular networks can offer strategies for fabricating stimuli-responsive adaptive materials. Herein we first report a gas responsive dynamic gel system based on frustrated Lewis pair (FLP) chemistry. Two trefoil-like molecules with bulky triphenylborane and triphenylphosphine groups are synthesized as complementary Lewis acid and base with trivalent sites. They can together bind CO2 gas molecules and further form a cross-linked network via the bonding interactions between FLPs and CO2 . Such CO2 -bridged dative linkages are shown to be dynamic covalent bonds, which endow the frustrated Lewis network with adaptable behaviors and unprecedented gas-regulated viscoelastic, mechanical, and self-healing performance. This study is an initial attempt to apply the FLP concept in materials chemistry, but we believe that this strategy will open a promising future for gas-sensitive smart materials. PMID- 30421485 TI - Concurrent Asymmetric Reactions Combining Photocatalysis and Enzyme Catalysis: Direct Enantioselective Synthesis of 2,2-Disubstituted Indol-3-ones from 2 Arylindoles. AB - The combination of photoredox and enzymatic catalysis for the direct asymmetric one-pot synthesis of 2,2-disubstituted indol-3-ones from 2-arylindoles through concurrent oxidization and alkylation reactions is described. 2-Arylindoles can be photocatalytically oxidized to 2-arylindol-3-one with subsequent enantioselective alkylation with ketones catalyzed by wheat germ lipase (WGL). The chiral quaternary carbon center at C2 of the indoles was directly constructed. This mode of concurrent photobiocatalysis provides a mild and powerful strategy for one-pot enantioselective synthesis of complex compounds. The experiments proved that other lipases containing structurally analogous catalytic triad in the active site also can catalyze the reaction in the same way. This reaction is the first example of combining the non-natural catalytic activity of hydrolases with visible-light catalysis for enantioselective organic synthesis and it does not require any cofactors. PMID- 30421486 TI - A new regulator RsdA mediating fungal secondary metabolism has a detrimental impact on asexual development in Pestalotiopsis fici. AB - Secondary metabolite (SM) production and development are correlated processes in fungi that are often coordinated by pleiotropic regulators. The eukaryotic regulators are critical players in mediating SM production related to fungal development, yet little data are available to support this hypothesis. In this study, a global regulator, RsdA (regulation of secondary metabolism and development), was identified through genome-wide analysis and deletion of the regulator gene in the endophytic fungus Pestalotiopsis fici. Here, we established that RsdA regulation of SMs is accompanied by the repression of asexual development. Deletion of rsdA significantly reduces not only asexual development, resulting in low sporulation and abnormal conidia, but also the major SM production, while remarkably increasing the melanin production. Overproduction of melanin leads to the formation of unusual, heavily pigmented hyphae. Transcriptome analysis data provide the evidence that RsdA globally regulates genes involved in secondary metabolism and asexual development. Double deletion of rsdA and the melanin polyketide synthase gene PfmaE confirm that RsdA regulation of asexual development is independent of the melanin biosynthetic pathway. Finally, our results demonstrate that RsdA can be used for the discovery of secondary metabolites in filamentous fungi. This article is protected by copyright. All rights reserved. PMID- 30421487 TI - Ingestible Contrast Agents for Gastrointestinal Imaging. AB - Gastrointestinal (GI) ailments cover a wide variety of diseases involving the esophagus, stomach, small intestine, large intestine or rectum. They bring about many inconveniences in daily life in chronic diseases and can even be life threatening in acute cases. Rapid and safe detection approaches are essential for early diagnosis and timely managements. Contrast agent of GI imaging could enhance the contrast to distinguish the abnormal lesions from normal structures. CT and MRI are two important diagnostic tools for the evaluation of GI conditions. This review mainly involves several common GI diseases including inflammatory diseases, intestinal tumors, diarrhea, constipation and gastroesophageal reflux diseases. Selected contrast agents are summarized such as barium sulfate, iodine-based agents, gadolinium-based agents and others. Going forward, continued endeavors are being made to develop more emerging contrast agents for other imaging modalities. PMID- 30421488 TI - Zinc(II)-Dipicolylamine Coordination Nanotheranostics: Toward Synergistic Nanomedicine by Combined Photo/Gene Therapy. AB - We report the rational design of coordination-driven self-assembly metal-organic nanostructures for multifunctional nanotheranostics. Zinc(II) coordination-based nano-formulations capable of loading indocyanine green (ICG) and therapeutic genes were prepared to achieve a fluorescence/photoacoustic imaging-guided combination photo/gene therapy strategy. We showed the enhanced theranostic capability of zinc(II)-dipicolylamine-assisted assembly of ICG, as well as simultaneous targeted gene delivery in an experimental mouse model of cancer. Such a co-assembly strategy provides a facile way to achieve combined therapeutic functions for personalized nanomedicine. PMID- 30421489 TI - Multicomponent Reactions of Pyridines To Give Ring-Fused Pyridiniums: In Situ Activation Strategy Using 1,2-Dichloroethane as a Vinyl Equivalent. AB - Reported herein is a rhodium(III)-catalyzed three-component annulation reaction of simple pyridines, alkynes, and 1,2-dichloroethane (DCE), affording a streamlined pathway to diverse ring-fused pyridiniums. DCE not only serves as a vinyl equivalent but also as an in situ activating agent for pyridine C2-H activation. A cationic five-membered rhodacycle complex has been isolated and proposed as a possible intermediate. This strategy can be extended to other N containing heteroarenes for the synthesis of multiring-fused pyridiniums. These multicomponent reactions exhibit excellent regioselectivity for 1,3-diynes, paving a path to the cascade cyclization of 3-fluoropyridine or N-methylpyridin-3 amine with 1,3-diynes for the construction of brand-new tricyclic-fused pyrano- or hydropyridoquinolizinium salts. These ionic fluorophores have been investigated as potential biomarkers. PMID- 30421490 TI - Diversity of phytobeneficial traits revealed by whole-genome analysis of worldwide-isolated phenazine-producing Pseudomonas spp. AB - Plant-beneficial Pseudomonas spp. competitively colonize the rhizosphere and display plant-growth promotion and/or disease-suppression activities. Some strains within the P. fluorescens species complex produce phenazine derivatives, such as phenazine-1-carboxylic acid. These antimicrobial compounds are broadly inhibitory to numerous soil-dwelling plant pathogens and play a role in the ecological competence of phenazine-producing Pseudomonas spp. We assembled a collection encompassing 63 strains representative of the worldwide diversity of plant-beneficial phenazine-producing Pseudomonas spp. In this study, we report the sequencing of 58 complete genomes using PacBio RS II sequencing technology. Distributed among four subgroups within the P. fluorescens species complex, the diversity of our collection is reflected by the large pangenome which accounts for 25,413 protein-coding genes. We identified genes and clusters encoding for numerous phytobeneficial traits, including antibiotics, siderophores and cyclic lipopeptides biosynthesis, some of which were previously unknown in these microorganisms. Finally, we gained insight into the evolutionary history of the phenazine biosynthetic operon. Given its diverse genomic context, it is likely that this operon was relocated several times during Pseudomonas evolution. Our findings acknowledge the tremendous diversity of plant-beneficial phenazine producing Pseudomonas spp., paving the way for comparative analyses to identify new genetic determinants involved in biocontrol, plant-growth promotion and rhizosphere competence. This article is protected by copyright. All rights reserved. PMID- 30421491 TI - Lithium Monotherapy Associated Longitudinal Effects on Resting State Brain Networks in Clinical Treatment of Bipolar Disorder. AB - OBJECTIVES: Lithium is one of the most effective and specific treatments for bipolar disorder (BP), but the neural mechanisms by which lithium impacts symptoms remain unclear. Past research has been limited by a reliance on cross sectional designs, which does not allow for identification of within-person changes due to lithium and has not examined communication between brain regions (i.e., networks). In the present study, we prospectively investigated the lithium monotherapy associated effects in vivo on the brain connectome in medication-free BP patients. In particular, we examined the within-person impact of lithium treatment on connectome indices previously linked to mania and depression in bipolar disorder. METHODS: Thirty-nine medication-free subjects - 26 BP (13 (hypo)manic and 13 depressed) and 13 closely matched health controls (HC) - were included. fMRI data was obtained at 3 timepoints: baseline, after 2 weeks, and after 8 weeks (total of 117 scans: 78 BP and 39 HC scans). BP subjects were clinically treated with lithium for 8 weeks while HC were scanned at the same time points but not treated. Graph theory metrics and repeated measures GLM were used to analyze lithium treatment associated effects. RESULTS: Consistent with hypotheses, lithium treatment was associated with a normalizing effect on mania related connectome indices. Furthermore, shifts in both mania- and depression related connectome indices were proportional to symptom change. Finally, lithium treatment-associated impact on amygdala function differed depending on baseline mood. CONCLUSIONS: Present findings provide deeper insight into the therapeutic neural mechanisms associated with lithium treatment. This article is protected by copyright. All rights reserved. PMID- 30421492 TI - Auditive training effects from a dichotic listening app in children with dyslexia. AB - Dichotic listening (DL) taps information on the brain's language laterality, processing, and attention. Research has shown that DL responses in dyslexia deviate from the typical pattern. Here, effects of DL training and its correspondence to rapid naming (RAN) and digit span (DS) in typical children and children with dyslexia were assessed. Three groups of third graders participated: two training groups, control training (CT) and dyslexia training (DT), and a control group that received no training (control no training, CnT). All took part in testing pretraining and posttraining. DL measures were on laterality, response scores, and attention. The three groups showed different response patterns: minor changes in CnT, change in all measures in CT, and some changes in DT. RAN and DS scores correlated significantly with some of the DL measures, especially with the attention scores. Our findings support arguments that brain architecture for language in dyslexia is lateralised in the same way as in children without dyslexia. However, the ability to modulate attention during DL is weaker in dyslexia than in typically developing children. A training-induced normalisation of lateralisation was observed in free recall in the dyslexia group, which suggests that DL training may be a promising intervention approach. PMID- 30421494 TI - Reply to 'Overuse or underuse of methylphenidate in adults in France: commentary on Pauly et al. 2018' by Weibel et al. PMID- 30421493 TI - CD147 promotes progression of head and neck squamous cell carcinoma via NF-kappa B signaling. AB - CD147/basigin (BSG) is highly upregulated in many types of cancer, our previous study has found that CD147/BSG is highly expressed in head and neck squamous cell carcinoma (HNSCC) stem cells, but its role in HNSCC and the underlying mechanism is still unknown. In this study, we investigated the role of CD147 in the progression of HNSCC. Real-time PCR, western blot and immunohistochemistry were used to detect the expression of CD147 in total 189 HNSCC tissues in compared with normal tissues. In addition, we used proliferation, colony formation, cell cycle and apoptosis, migration and invasion as well as wound-healing assay to determine the biological roles of CD147 in HNSCC. Then, a xenograft model was performed to evaluate tumor-promoting and metastasis-promoting role of CD147 in HNSCC. The results showed that upregulated CD147 expression was associated with aggressive clinicopathologic features in HNSCC. In addition, CD147 promoted proliferation, migration and reduced the apoptosis phenotype of HNSCC cells in vitro as well as tumor initiation and progression in vivo. Furthermore, we demonstrated that CD147 promoted HNSCC progression through nuclear factor kappa B signaling. Therefore, we concluded that CD147 promoted tumor progression in HNSCC and might be a potential prognostic and treatment biomarker for HNSCC. PMID- 30421495 TI - Periodontal reconstructive surgery of deep intraosseous defects using an apical approach. Non-incised papillae surgical approach (NIPSA): A retrospective cohort study. AB - BACKGROUND: The objective of this study was to compare a minimally-invasive surgical technique (MIST) and a non-incised papilla surgical approach (NIPSA) in periodontal reconstructive surgery of deep intraosseous defects. METHODS: Data on 30 patients with a deep intraosseous defect treated with MIST (n = 15) or NIPSA (n = 15) were analyzed retrospectively. All patients met the same inclusion criteria and were treated following the same protocol, except for the surgical management of soft tissue (MIST versus NIPSA). Clinical parameters at baseline and at 1-year post-surgery, early healing at 1 week, and postoperative pain were assessed. RESULTS: NIPSA and MIST resulted in significant clinical attachment gain (CAG) (P < 0.001) and probing depth reduction (PDr) (P < 0.001) at 1-year post-surgery. However, NIPSA resulted in significantly lower recession of the tip of the interdental papilla compared with MIST (P < 0.001). Smoking negatively influenced early healing in both techniques (P < 0.05). CONCLUSIONS: NIPSA and MIST both resulted in significant improvements in clinical parameters. NIPSA showed significant soft tissue preservation. NIPSA may represent a promising papillae preservation technique in the treatment of intraosseous periodontal defects. PMID- 30421496 TI - Diffusion-weighted MRI of the lung at 3T evaluated using echo-planar-based and single-shot turbo spin-echo-based acquisition techniques for radiotherapy applications. AB - PURPOSE: To compare single-shot echo-planar (SS-EPI)-based and turbo spin-echo (SS-TSE)-based diffusion-weighted imaging (DWI) in Non-Small Cell Lung Cancer (NSCLC) patients and to characterize the distributions of apparent diffusion coefficient (ADC) values generated by the two techniques. METHODS: Ten NSCLC patients were enrolled in a prospective IRB-approved study to compare and optimize DWI using EPI and TSE-based techniques for radiotherapy planning. The imaging protocol included axial T2w, EPI-based DWI and TSE-based DWI on a 3 T Philips scanner. Both EPI-based and TSE-based DWI sequences used three b values (0, 400, and 800 s/mm2 ). The acquisition times for EPI-based and TSE-based DWI were 5 and 8 min, respectively. DW-MR images were manually coregistered with axial T2w images, and tumor volume contoured on T2w images were mapped onto the DWI scans. A pixel-by-pixel fit of tumor ADC was calculated based on monoexponential signal behavior. Tumor ADC mean, standard deviation, kurtosis, and skewness were calculated and compared between EPI and TSE-based DWI. Image distortion and ADC values between the two techniques were also quantified using fieldmap analysis and a NIST traceable ice-water diffusion phantom, respectively. RESULTS: The mean ADC for EPI and TSE-based DWI were 1.282 +/- 0.42 * 10-3 and 1.211 +/- 0.31 * 10-3 mm2 /s. The average skewness and kurtosis were 0.14 +/- 0.4 and 2.43 +/- 0.40 for DWI-EPI and -0.06 +/- 0.69 and 2.89 +/- 0.62 for DWI TSE. Fieldmap analysis showed a mean distortion of 13.72 +/- 8.12 mm for GTV for DWI-EPI and 0.61 +/- 0.4 mm for DWI-TSE. ADC values obtained using the diffusion phantom for the two techniques were within 0.03 * 10-3 mm2 /s with respect to each other as well as the established values. CONCLUSIONS: Diffusion-weighted turbo spin-echo shows better geometrical accuracy compared to DWI-EPI. Mean ADC values were similar with both acquisitions but the shape of the histograms was different based on the skewness and kurtosis values. The impact of differences in respiratory technique on ADC values requires further investigation. PMID- 30421497 TI - alpha-galactosylceramide generates lung regulatory T cells through the activated natural killer T cells in mice. AB - Our previous study showed that intraperitoneal injection of alpha galactosylceramide (alpha-GalCer) has the ability to activate lung iNKT cells, but alpha-GalCer-activated iNKT cells do not result in airway inflammation in wild-type (WT) mice. Many studies showed that iNKT cells had the capacity to induce Treg cells, which gave rise to peripheral tolerance. Therefore, we examined the influence of intraperitoneal administration of alpha-GalCer on the expansion and suppressive activity of lung Treg cells using iNKT cell-knockout mice and co-culture experiments in vitro. We also compared airway inflammation and airway hyperresponsiveness (AHR) after alpha-GalCer administration in specific anti-CD25 mAb-treated mice. Our data showed that intraperitoneal injection of alpha-GalCer could promote the expansion of lung Treg cells in WT mice, but not in iNKT cell-knockout mice. However, alpha-GalCer administration could not boost suppressive activity of Treg cells in WT mice and iNKT cell knockout mice. Interestingly, functional inactivation of Treg cells could induce airway inflammation and AHR in WT mice treated with alpha-GalCer. Furthermore, alpha-GalCer administration could enhance iNKT cells to secrete IL-2, and neutralization of IL-2 reduced the expansion of Treg cells in vivo and in vitro. Thus, intraperitoneal administration of alpha-GalCer can induce the generation of lung Treg cells in mice through the release of IL-2 by the activated iNKT cells. PMID- 30421498 TI - Resilience and health (care): A dynamic adaptive perspective. AB - This special forum on resilience explores particular worldviews of resilience clinical, psychosocial, sociological, complexity science, organizational, and political economy through eight papers. This forum aims to open up the wealth of understandings and implications in health care by taking a transdisciplinary overview. PMID- 30421499 TI - Developing a surgeon-patient communication checklist for total knee arthroplasty. AB - BACKGROUND: Total knee arthroplasty (TKA) is a well-established surgical procedure with high rates of clinical success, yet up to 20% of patients are dissatisfied with their outcomes. Surgeon-patient communication is an important contributor to patient satisfaction, particularly in the area of setting or resetting postoperative expectations that are reasonable and achievable for individual patients. OBJECTIVE: The goal of the present research was to develop a communication checklist for surgeons to use with their patients, to enhance communication in order better to manage postoperative expectations and increase patient satisfaction with TKA. METHODS: Content analysis was used to identify a preliminary list of checklist items from audio-recorded interviews of eight patients who were between 6 weeks and 6 months of their recovery from TKA. Patients identified eight issues for which more information was desired. The proportion of mentions for each topic was calculated, and chi-square tests assessed the distribution and pattern of the categories mentioned across groups of patients. RESULTS: Certain topics were used significantly more often than others. Age and employment status, but not gender, affected which topics were mentioned more often. The final categories for the checklist included pain management, physiotherapy, medication and general outcome information. CONCLUSION: An in-depth analysis of patient experiences of recovering from TKA was the foundation of this research. The result was a checklist that creates a potential new avenue for increasing patient satisfaction by improving surgeon patient communication. The research described here could extend to any other type of intervention in which understanding patient expectations and increasing patient satisfaction is the goal. PMID- 30421500 TI - In response to the published article: "Cultural Capital: A Concept Analysis". PMID- 30421501 TI - Development of novel three-dimensional scaffolds based on bacterial nanocellulose for tissue engineering and regenerative medicine: Effect of processing methods, pore size, and surface area. AB - Despite the efforts focused on manufacturing biological engineering scaffolds for tissue engineering and regenerative medicine, a biomaterial that meets the necessary characteristics for these applications has not been developed to date. Bacterial nanocellulose (BNC) is an outstanding biomaterial for tissue engineering and regenerative medicine; however, BNC's applications have been focused on two-dimensional (2D) medical devices, such as wound dressings. Given the need for three-dimensional (3D) porous biomaterials, this work evaluates two methods to generate (3D) BNC scaffolds. The structural characteristics and physicochemical, mechanical, and cell behaviour properties were evaluated. Likewise, the effects of the pore size and surface area in the mechanical performance of BNC biomaterials and their cell response in a fibroblast cell line are discussed for the first time. In this study, a new method is proposed for the development of 3D BNC scaffolds using paraffin wax. This new method is less time consuming, more robust in removing the paraffin and less aggressive toward the BNC microstructure. Moreover, the biomaterial had regular porosity with good mechanical behaviour; the cells can adhere and increase in number without overcrowding. Regarding the pore size and surface area, highly interconnected porosities (measuring approximately 60 MUm) and high surface area are advantageous for the biomaterial's mechanical properties and cell behaviour. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2018. PMID- 30421502 TI - Corrigendum. PMID- 30421503 TI - Exposure to cigarette smoke via respiratory system may induce abnormal alterations of reproductive organs in female diabetic rats. AB - Cigarette smoke (CS) has harmful effects on human fertility, reproduction, and development as well as on patients suffering from metabolic diseases such as diabetes than on healthy individuals. This study was conducted to investigate the relationship between CS exposure and histological alterations of reproductive organs in female diabetic rats. We evaluated the histology of uteruses and ovaries obtained from female rats exposed to smoke from standard cigarettes for 4 weeks (28 hours a week). After CS exposure, tissue slides were made from uterine and ovarian samples and examined after hematoxylin and eosin staining. Immunohistochemistry was used for detection of matrix metallopeptidase 9 (MMP9), C-X-C chemokine receptor type 4 (CXCR4), and estrogen receptor (ER)alpha in the uterus and ovary. MMP9 is an inflammatory biomarker that increases during progression to endometriosis. As a chemokine receptor, CXCR4 is involved in development of the inner wall of the uterus and cell adhesion. In the uterus, the occurrence of MMP9, CXCR4, and ERalpha and the number of endometrial glands were increased by CS exposure, while in the ovary, occurrence of MMP9, CXCR4, ERalpha, proliferating cell nuclear antigen and the number of corpus lutea or cyst follicles were increased by CS exposure. Collectively, this study indicates that CS induced abnormal development of the uterus and ovary under induced diabetes, leading to adverse effects on normal function of reproductive organs in female rats. HIGHLIGHTS: Cigarette smoke (CS) exposure adversely affected reproductive organs of diabetic female rats. In the uterus, expression of matrix metallopeptidase 9 (MMP9), C-X-C chemokine receptor type 4 (CXCR4), estrogen receptor (ER)alpha, and the number of endometrial glands were increased by CS exposure, In the ovary, the expression of MMP9, CXCR4, ERalpha, and proliferating cell nuclear antigen and the number of corpus lutea or cyst follicles were increased by CS exposure. Exposure to CS via the respiratory system exerted a harmful impact on the uterus and ovary in female rats with diabetes. PMID- 30421504 TI - Integrative analysis of differential genes and identification of a "2-gene score" associated with survival in esophageal squamous cell carcinoma. AB - BACKGROUND: Developments in high-throughput genomic technologies have led to improved understanding of the molecular underpinnings of esophageal squamous cell carcinoma (ESCC). However, there is currently no model that combines the clinical features and gene expression signatures to predict outcomes. METHODS: We obtained data from the GSE53625 database of Chinese ESCC patients who had undergone surgical treatment. The R packages, Limma and WGCNA, were used to identify and construct a co-expression network of differentially expressed genes, respectively. The Cox regression model was used, and a nomogram prediction model was constructed. RESULTS: A total of 3654 differentially expressed genes were identified. Bioinformatics enrichment analysis was conducted. Multivariate analysis of the clinical cohort revealed that age and adjuvant therapy were independent factors for survival, and these were entered into the clinical nomogram. After integrating the gene expression profiles, we identified a "2-gene score" associated with overall survival. The combinational model is composed of clinical data and gene expression profiles. The C-index of the combined nomogram for predicting survival was statistically higher than the clinical nomogram. The calibration curve revealed that the combined nomogram and actual observation showed better prediction accuracy than the clinical nomogram alone. CONCLUSIONS: The integration of gene expression signatures and clinical variables produced a predictive model for ESCC that performed better than those based exclusively on clinical variables. This approach may provide a novel prediction model for ESCC patients after surgery. PMID- 30421505 TI - Integration of Diffraction Phase Microscopy and Raman Imaging for Label-free Morpho-molecular Assessment of Live Cells. AB - Label-free quantitative imaging is highly desirable for studying live cells by extracting pathophysiological information without perturbing cell functions. Here we demonstrate a novel label-free multimodal optical imaging system with the capability of providing comprehensive morphological and molecular attributes of live cells. Our morpho-molecular microscopy (3M) system draws on the combined strength of quantitative phase microscopy (QPM) and Raman microscopy to probe the morphological features and molecular fingerprinting characteristics of each cell under observation. While the common-path geometry of our QPM system allows for highly sensitive phase measurement, the Raman microscopy is equipped with dual excitation wavelengths and utilizes the same detection and dispersion system, making it a distinctive multi-wavelength system with a small footprint. We demonstrate the applicability the 3M system by investigating nucleated and non nucleated cells. This integrated, label-free platform has a promising potential in preclinical research, as well as in clinical diagnosis in the near future. This article is protected by copyright. All rights reserved. PMID- 30421506 TI - Potentiation of paclitaxel effect by resveratrol in human breast cancer cells by counteracting the 17beta-estradiol/estrogen receptor alpha/neuroglobin pathway. AB - Neuroglobin (NGB), an antiapoptotic protein upregulated by 17beta-estradiol (E2), is part of E2/estrogen receptor alpha (ERalpha) pathway pointed to preserve cancer cell survival in presence of microenvironmental stressors including chemotherapeutic drugs. Here, the possibility that resveratrol (Res), an anticancer plant polyphenol, could increase the susceptibility of breast cancer cells to paclitaxel (Pacl) by affecting E2/ERalpha/NGB pathway has been evaluated. In MCF-7 and T47D (ERalpha-positive), but not in MDA-MB 231 (ERalpha negative) nor in SK-N-BE (ERalpha and ERbeta positive), Res decreases NGB levels interfering with E2/ERalpha-induced NGB upregulation and with E2-induced ERalpha and protein kinase B phosphorylation. Although Res treatment does not reduce cell viability by itself, this compound potentiates Pacl proapoptotic effects. Notably, the increase of NGB levels by NGB expression vector transfection prevents Pacl or Res/Pacl effects. Taken together, these findings indicate a new Res-based mechanism that acts on tumor cells impairing the E2/ERalpha/NGB signaling pathways and increasing cancer cell susceptibility to chemotherapeutic agent. PMID- 30421508 TI - Effect of hemodialysis on the red blood cell life span in patients with end-stage kidney disease. AB - The aim of this study was to use a CO breath test to investigate hemodialysis effects on red blood cell lifespan in patients with chronic kidney disease. A cohort of 17 non-smoking men with end-stage kidney disease undergoing hemodialysis via a polysolfone dialysis membrane (as opposed to a traditional cellulose acetate membrane) were subjected to a repeated Levitt's CO breath test to compare red blood cell lifespan before versus after dialysis. None of the patients showed significant fluctuations in endogenous CO concentration during the dialysis procedure. The mean red blood cell lifespan was 66.0 +/- 31.0 d before dialysis and 72.0 +/- 26.0 d after dialysis, with no significant difference between the assessment time points (p > .05). In conclusion, dialysis using a polysulfone membrane did not appear to disrupt red blood cells or reduce their lifespan in patients with end-stage kidney disease. PMID- 30421509 TI - Intramural schwannoma involving a vein. AB - Schwannoma involving the blood vessels is a rare phenomenon. So far, only three cases of intravascular schwannoma have been described (all of which were intraluminal), and the origin of the schwannoma in such cases is not yet completely understood. Here we describe a very rare intramural venous schwannoma in the subcutaneous right prepatellar area of a 31-year-old man. The schwannoma grew by enlarging and thickening the blood vessel wall, between two preserved layers of the vein. In some areas, there was erosion of the luminal layer, with fibrin apposed to the tumor. The tumor expressed S100 and was negative for CD31, CD34, desmin and smooth muscle actin. The expression of p16 was preserved. Endothelial markers such as CD31 and Factor VIII demonstrated the endothelial lining (which was D2-40-negative) above the tumor. Although degenerative atypia was present, there were no mitoses or necrosis identified. This article is protected by copyright. All rights reserved. PMID- 30421510 TI - Visualizing the "Sandwich" Structure of Osteocytes in Their Native Environment Deep in Bone in Vivo. AB - Osteocytes are the most abundant cells in bone and always the focus of bone research. They are embedded in the highly scattering mineralized bone matrix. Consequently, visualizing osteocytes deep in bone with subcellular resolution poses a major challenge for in vivo bone research. Here we overcome this challenge by demonstrating 3-photon imaging of osteocytes through the intact mouse skull in vivo. Through broadband transmittance characterization, we establish that the excitation at the 1700-nm window enables the highest optical transmittance through the skull. Using label-free third-harmonic generation (THG) imaging excited at this window, we visualize osteocytes through the whole 140-MUm mouse skull and 155 MUm into the brain in vivo. By developing selective labeling technique for the interstitial space, we visualize the "sandwich" structure of osteocytes in their native environment. Our work provides novel imaging methodology for bone research in vivo. This article is protected by copyright. All rights reserved. PMID- 30421511 TI - Evaluation of the effect of foot disease activity on Boolean remission in Japanese patients with rheumatoid arthritis: A cross-sectional study. PMID- 30421512 TI - Students shooting videos to learn pharmacology. AB - BACKGROUND: Patient education videos are an effective medium of communication to improve patient knowledge. Developing patient-centered communication requires a reflection on the social dynamics and economic realities of patients, aspects that are essential for the professional development of students, but often not overtly present in the curriculum. We tasked medical students to develop patient education videos and were interested in their experience of the process, including how this medium facilitated reflection on health care in the country. METHODS: Groups of students conceptualised and then made a 2-minute video educating patients on pharmacotherapy, aimed at the layperson. We adapted an existing tool for developing and assessing public communication material to design a marking rubric, and collected student feedback. RESULTS: Students conveyed universal factual therapeutic information in a uniquely South African context, using depictions that patients could relate to, and framed the information within the social circumstances of patients. The videos addressed various therapeutic topics, including some not covered in the module, and demonstrated that students were able to apply classroom knowledge in the health care environment. Students relayed complex concepts through visually innovative and easy-to-understand ways. Students conveyed universal factual therapeutic information in a uniquely South African context DISCUSSION: Health care practitioners should be responsive to the needs of their patients, which demands a sensitivity to local imperatives, social dynamics and economic realities. Although the principles of patient-centredness are taught in the curriculum, the depth of understanding evident in the videos demonstrated emergent learning from the hidden curriculum. Students can be architects of their own learning in creative and meaningful ways. PMID- 30421513 TI - Breast cancer diagnosis in a specialised breast clinic: Are cancers detected by ultrasound alone less aggressive? AB - INTRODUCTION: The aim of this study was to determine the relationship between the way breast cancer is diagnosed and its prognostic features. METHODS: We studied new primary invasive and non-invasive breast cancers (670) diagnosed between 2013 and 2015 where detection included at least clinical examination, mammography and breast ultrasound (BUS). The cancers were classified into six Diagnostic Groups according to the results of each modality. RESULTS: Overall, 79% of cancers were positive on mammography, but another 20% were diagnosed on BUS after a negative mammogram. The largest group (37.6% of cases), had all three modalities positive (Group 1). BUS was the only modality positive in 14.6% (Group 4). Mammography alone was positive in 21.2%, of which 73.9% were ductal carcinoma in situ (DCIS). Invasive lobular carcinoma comprised 9.6% of the groups where mammography was positive, but 16.5% of the groups where mammography was negative and BUS positive. Dense breast tissue was more common in the groups where mammography was negative and BUS positive. Invasive cancers comprised 82.7% of Group 4 and 95.2% of Group 1. For those in Group 4, the average size (10.2 mm) and the percentages with lymphovascular invasion (11.1%), lymph node involvement (17.3%) and poor differentiation (12.3%) were less than half the corresponding figures for Group 1 (27.3 mm, 35%, 44%, 44%). CONCLUSION: This study illustrates the complementary benefits of mammography and BUS, especially where breast density is high. Tumours diagnosed by BUS alone had better prognostic features in terms of size, lymphovascular invasion, lymph node status, differentiation and hormone receptors, compared with cancers where all three modalities were positive. PMID- 30421514 TI - Heat-treatment assisted molten-salt strategy to enhance electrochemical performances of Li-rich assembled microspheres by tailoring their surface features. AB - Constructing Li-rich Mn-based layered oxides (LMROs) assembled microsphere with fast kinetics and stable surface will significantly improve discharge capacity and cyclic stability. In this work, a heat-treatment assisted (HA) molten-salt (MS) strategy is designed to prepare LMRO assembled microsphere (HA-MS-LMRO). Electrochemical measurements demonstrate that HA-MS-LMRO possesses superior performance as a cathode for lithium-ion batteries. It delivers an initial discharge capacity of 181 mA h g-1 at 200mA g-1, much higher than that of the LMRO (145 mA h g-1). After 100 cycles, the capacity retention ratio for HA-MS LMRO is 74.69%, which is far larger than that of LMRO (23.06%). More detail analysis of structure, valence state, and electrochemical impedance spectra show that heat-treatment assisted molten-salt process play an important role for the excellent performance of HA-MS-LMRO, i.e. HA process enables the transition metal ions in the synthesized samples have the stable surface valence states, which is conducive to maintaining structural stability and improving cycling performance, and the following MS process prohibits the formation of lithium-containing amorphous compounds on the surface during lithiation process, thus enhancing the Li ions kinetics and increasing the initial discharge capacity. Current work would provide guidance to promote the electrochemical performances of assembled microspheres cathode materials. PMID- 30421515 TI - In vivo Visualization of the Process of Hg2+ Bioaccumulation in Water Flea Daphnia carinata by a Novel Aggregation-Induced Emission Fluorogen. AB - This paper employs a specially designed aggregation-induced emission fluorogen (AIEgen) to in vivo visualize the process of Hg2+ bioaccumulation in a common species of freshwater zooplankton Daphnia carinata (D. carinata) by two methods, direct Hg2+ absorption and ingestion of Hg2+ contaminated food. We analysed the relevance between photoluminescence (PL, I595 /I480 ) ratios and Hg2+ (CHg2+ ) and developed the master curve for Hg2+ determination based on measuring the PL intensity of the solution. Meanwhile, fluorescent image analysis showed that the major recipient organs of Hg2+ in D. carinata were the compound eyes and carapace, followed by the intestine and shell gland, but not the brain or heart. The response of D. carinata to Hg2+ via uptake from surrounding water differed distinctly from that through food intake of the algae (Euglena gracilis) contaminated by mercury. When Hg2+ was encapsulated by algae membrane, no fluorescence was detected, and the carapace morphology remained intact after ingesting algae for 80 min, in contrast to the rapid carapace deformation by direct Hg2+ absorption. The D. carinata showed higher mortality by direct Hg2+ immersion than via food ingestion. The reason for the high mortality after Hg2+ immersion was possibly due to carapace deformity after chemical reaction between chitin and mercury, but the biochemical pathway leading to morality needs further study. PMID- 30421516 TI - Teicoplanin hypersensitivity during anaesthesia and surgery. PMID- 30421517 TI - Topical Antibiotics for Clinical and Microbiological Cure of Bacterial Conjunctivitis. AB - Acute bacterial conjunctivitis is an infective condition frequently resulting in mucopurulent ocular discharge, bulbar and palpebral injection, and discomfort.. It may be difficult to differentiate between viral and bacterial conjunctivitis on clinical grounds, and swabbing eyes for cultures is not considered clinically practical. Therefore, although most cases are self-limited, antibiotics are typically given based on the belief that they decrease time to recovery, reduce sight-threatening complications, and reduce the rate of relapse. This review, an update of a previous Cochrane review from 2006, included 11 randomized control trials totaling 3673 patients with bacterial conjunctivitis, whereas the prior review included five randomized control trials and 1034 patients. The review included trials that made the diagnosis of bacterial conjunctivitis based on either clinical or microbiological grounds.1 Clinical criteria required varied but generally included ocular discharge and conjunctival injection. Two of the trials required microbiologically proven bacterial conjunctivitis with the remainder making the diagnosis on clinical grounds. The primary outcomes of this review included both clinical and microbiological cure rates.1 How cure was assessed varied between trials but in general, it was defined by absence of symptoms or microbiological eradication. Data analysis from the trials indicated improved early (2-5 day) clinical cure rate of 40% (risk ratio (RR) 1.36, 95% confidence interval (CI), 1.15 to 1.61) and microbiological cure (RR 1.55, 95% CI, 1.37 to 1.76). At 6 to 10 days (considered the 'late' time point) antibiotics continued to show clinical benefit in clinical and microbiological cure (RR 1.21, 95% CI, 1.10 to 1.33 and RR 1.37, 95% CI, 1.24 to 1.52 respectively). The absolute risk difference for early and late clinical cure were 11% and 9%, respectively, corresponding to an NNT of 9 and 11.1 Among subjects in the placebo groups, 30% achieved clinical cure by day 5, and 41% of cases had resolved by day 6-10. No serious outcomes were reported in either placebo groups or treatment groups. This article is protected by copyright. All rights reserved. PMID- 30421518 TI - A reductionist approach to dissecting grain weight and yield in wheat. AB - Grain yield is a highly polygenic trait that is influenced by the environment and integrates events throughout the life cycle of a plant. In wheat, the major grain yield components often present compensatory effects among then, which alongside the polyploid nature of wheat, makes their genetic and physiological study challenging. We propose a reductionist and systematic approach as an initial step to understand the gene networks regulating each individual yield component. Here we focus on grain weight and discuss the importance of examining individual sub components, not only to help in their genetic dissection, but also to inform our mechanistic understanding of how they interrelate. This knowledge should allow the development of novel combinations, across homoeologs and between complementary modes of action, thereby advancing towards a more integrated strategy for yield improvement. We argue that this will break barriers in terms of phenotypic variation, enhance our understanding of the physiology of yield, and potentially deliver improved on-farm yield. PMID- 30421519 TI - Parents' perceptions of bedside teaching. AB - BACKGROUND: Bedside teaching (BST) in a hospital setting can play an important role during medical students' clinical placements in paediatrics. Parents often feel obliged to allow their child to participate, even if they are reluctant. The aim of this study was to examine the perceptions of parents who, with their children, were involved in medical students' BST. METHODS: Consenting parents participated in a semi-structured interview assessing their experience of having their child involved in BST. The qualitative data were analysed using thematic analysis. Parents were assured that their children's treatment would not be negatively affected in the case of withdrawal from the study. RESULTS: A total of 54 parents responded and discussed their experience of their children's participation in clinical teaching. The majority of parents were keen to support medical students' learning, and felt that they could develop better insight into their child's health in association with the teaching session. Some parents found the sessions tiring; their interest increased when they were more actively involved in planning the BST sessions. DISCUSSION: This study emphasises children's and adolescents' autonomy as a main principle in making decisions about involving them in BST. Clinical teachers often face problems attempting to properly plan and conduct BST sessions. Parents appreciate having an active role in planning the sessions and are supportive of medical student education. Clinical teachers must ensure that they protect the best interests of paediatric patients and their parents. At the same time, they should advocate for the obvious benefits of BST. PMID- 30421520 TI - Young girl with bruising: Finding the X factor. PMID- 30421521 TI - Characterization of the novel HLA-DRB1*03:147 allele by sequencing-based typing. AB - HLA-DRB1*03:147 differs from HLA-DRB1*03:01:01:01 by one nucleotide substitution at codon 233 in exon 5. PMID- 30421522 TI - Early invasive Squamous Cell Carcinoma recurrence rates: a study examining surgical margins, tumor surface diameter, invasion depth and grade of differentiation in 1,296 cases over 9 years. AB - BACKGROUND: Invasive squamous cell carcinoma (SCC) is typically treated by surgical excision. METHOD: Consecutive SCC excisions were reviewed prospectively in a single Australian center from 2009-2017. Cases were examined for recurrence by histopathologic margins, microscopic tumor surface diameter, invasion depth, grade of differentiation and anatomic site. RESULTS: Over 9 years 1,296 cases were collected. By grade of differentiation maximum average microscopic surface diameters ranged from 8.0 to 9.6mm and maximum average depths from 1.3 to 2.5mm. Minimum average histopathologic margins for well, moderate and poorly differentiated SCC respectively were 1.4, 1.1 and 1.3mm. Recurrence occurred in 1.7 % of well (n=18/1084), 1.8 % moderate (n=3/165) and 6.4% in poorly differentiated (n=3/47) SCC. No recurrence occurred beyond a histopathologic margin of 3.5 mm for well and 2.5 mm for moderately differentiated SCC. Highest recurrence for well differentiated SCC by anatomic site were the lip (7.0%) then ear (4.6%). CONCLUSION: We found a recurrence rate of 1.0% for histopathologic margins of 1.5 mm with early well differentiated SCC. The grade of differentiation and anatomic site had a larger influence on recurrence rates compared to the histopathologic margins. Poorly differentiated SCC and ear or lip sites require wider surgical margins. This article is protected by copyright. All rights reserved. PMID- 30421523 TI - Combined treatment of sodium ferulate, n-butylidenephthalide, and ADSCs rehabilitates neurovascular unit in rats after photothrombotic stroke. AB - The remodelling of structural and functional neurovascular unit (NVU) becomes a central therapeutic strategy after cerebral ischaemic stroke. In the present study, we investigated the effect of combined therapy of sodium ferulate (SF), n butylidenephthalide (BP) and adipose-derived stromal cells (ADSCs) to ameliorate the injured NVU in the photochemically induced thrombotic stroke in rats. After solely or combined treatment, the neovascularization, activation of astrocytes, neurogenesis, expressions of vascular endothelial growth factor (VEGF) and claudin-5 were assessed by immunohistochemical or immunofluorescence staining. In order to uncover the underlying mechanism of therapeutic effect, signalling of protein kinase B/mammalian target of rapamycin (AKT/mTOR), extracellular signal regulated kinase 1/2 (ERK1/2), and Notch1 in infarct zone were analysed by western blot. 18 F-2-deoxy-glucose/positron emission tomography, magnetic resonance imaging, Evans blue staining were employed to evaluate the glucose metabolism, cerebral blood flow (CBF), and brain-blood barrier (BBB) permeability, respectively. The results showed that combined treatment increased the neovascularization, neurogenesis, and VEGF secretion, modulated the astrocyte activation, enhanced the regional CBF, and glucose metabolism, as well as reduced BBB permeability and promoted claudin-5 expression, indicating the restoration of structure and function of NVU. The activation of ERK1/2 and Notch1 pathways and inhibition of AKT/mTOR pathway might be involved in the therapeutic mechanism. In summary, we have demonstrated that combined ADSCs with SF and BP, targeting the NVU remodelling, is a potential treatment for ischaemic stroke. These results may provide valuable information for developing future combined cellular and pharmacological therapeutic strategy for ischaemic stroke. PMID- 30421524 TI - Characterization of the novel HLA-DPA1*02:12 allele by sequencing-based typing. AB - HLA-DPA1*02:12 differs from HLA-DPA1*02:07:01:01 by one nucleotide substitution at codon 224 in exon 4. PMID- 30421525 TI - Effective bioreactor pH control using only sparging gases. AB - pH control is critical in bioreactor operations, typically realized through a two sided control loop, where CO2 sparging and base addition are used in bicarbonate buffered media. Though a common approach, base addition could compromise culture performance due to the potential impact from pH excursions and osmolality increase in large-scale bioreactors. In this study, the feasibility of utilizing control of sparge gas composition as part of the pH control loop was assessed in Chinese hamster ovary (CHO) fed-batch cultures. Fine pH control was evaluated in multiple processes at different setpoints in small-scale ambr(r)250 bioreactors. Desired culture pH setpoints were successfully maintained via air sparge feedback control. As part of the pH control loop, air sparging was increased to improve CO2 removal automatically, hence increase culture pH, and vice versa. The effectiveness of this pH control strategy was seamlessly transferred from ambr(r)250 to 200 L scale, demonstrating scalability of the proposed methodology. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 2018. PMID- 30421526 TI - Biomechanical efficacy of contact lens-assisted collagen cross-linking in porcine eyes. AB - PURPOSE: Contact lens-assisted corneal cross-linking (CACXL) has been proposed for the cross-linking treatment in thin corneas. The aim of this study was to assess the biomechanical efficacy of this treatment. METHODS: Post-mortem porcine eyes were treated with standard cross-linking and with cross-linking placing a contact lens soaked with isoosmolar riboflavin solution on the debrided cornea with or without an adherent precorneal riboflavin film of up to 100 MUm thickness. Three soft contact lenses (Air Optix Aqua, SofLens and Galifa) with different degrees of hydrophilic properties were tested. After cross-linking with a surface UVA irradiance of 3 mW/cm2 for 30 min (fluence 5.4 J/cm2), a 400 MUm deep anterior corneal flap was created using a lamellar rotating microkeratome. Biomechanical stress-strain measurements and thermal shrinkage tests were performed. RESULTS: In the Air Optix Aqua group (30% hydration) without riboflavin film, Young's modulus and stress at 8% strain were increased significantly versus untreated controls and the effect was 92.4% respectively 86.35% of the standard CXL value. In the SofLens group (59% hydration) without riboflavin film, Young's modulus and stress at 8% strain were increased significantly versus untreated controls and the effect was 67.04% respectively 65.28% of the standard CXL value. In the Galifa group (72% hydration) without riboflavin film, Young's modulus and stress at 8% strain were increased significantly versus untreated controls and the effect was about 68.48% respectively 75.52% of the standard CXL value. In all samples with a precorneal riboflavin film under the contact lens, there was no significant biomechanical effect compared to the untreated controls. Similarly, in the hydrothermal experiments at 70 degrees C, there was a typical mushroom pattern with increased resistance to thermal shrinkage in the anterior stroma after standard CXL, a markedly reduced mushroom effect using a riboflavin-soaked contact lens only and no effect with the use of a riboflavin-soaked contact lens plus a precorneal riboflavin film. CONCLUSIONS: The biomechanical effect of CACXL in porcine corneas is about one-third less than after standard CXL. The efficacy of CACXL might be improved by reducing or omitting the riboflavin film on the contact lens. Further risk assessment studies are necessary. PMID- 30421527 TI - Board exam stress effect on diastolic function. AB - BACKGROUND: To this date, effects of mental stress on cardiac function have not been clearly investigated. Although hemodynamic and neuroendocrine adverse effects of daily mental stress on cardiovascular morbidity and mortality have been reported, its direct impact on diastolic function of the heart has not been previously studied. In this study, we aimed to assess the role of Board Exam anxiety on right and left ventricular diastolic function in medical residents. METHODS: Forty medical residents prior to participation in the medical board exam were enrolled in our study. Right prior to as well as 2 month after the exam, all residents underwent trans-thoracic Doppler echocardiography. Right ventricular systolic and diastolic functions and echocardiography indices were measured. Levels of anxiety were measured using Beck Anxiety Inventory Questionnaire before and after the exam. Pre exam and post exam results of study population as well as low and high anxiety groups were evaluated. RESULTS: Early to late mitral inflow velocity (E/A ratio) in LV inflow increased after board exam (P-value <.001). E/A ratio in RV inflow increased after board exam (P-value: .002). Early mitral inflow to its annular velocity (E/E' ratio) in septal wall decreased after board exam (P-value<.001). The change in E/E' RV free wall did not reach statistical significance (P = .57). Mitral annuls velocities measured by TDI in septal and lateral wall and also tricuspid annulus velocity increased after board exam (P value<.05). The comparison of these changes between the high-stress and low stress groups of residents revealed significant differences. Comparison of changes of E/A ratio in the mitral and tricuspid inflow as well as the E/E' in the septum and free wall of the right ventricle before and after the Board Exam between high-stress and low-stress groups was not statistically significant, although there was a trend of more changes in high- stress group residents. CONCLUSION: This is the first report of comprehensive sequential assessment of left and right ventricular diastolic functions during and after a real subacute stress occasion. The finding of a decreased E/A and E' in response to mental stress suggests that repetitive mental stress may induce diastolic dysfunction which is a mechanism of diastolic heart failure in individuals at risk. PMID- 30421528 TI - Self-poisoning with 60 tablets of Apixaban, a pharmacokinetics case report. AB - A 67-year-old man was admitted to the emergency department about 5 h after deliberate self-poisoning with 300 mg of Apixaban. The clinical examination did not show any organ dysfunctions or haemorrhagic signs, and the patient's life was not in danger. The first analysis, upon admission, showed a concentration of 2655 MUg l-1 of Apixaban. The Cmax was observed 17 h after the intake (3654 MUg l-1 ), about four times the classical Tmax value (median [range]: 4 h [2-4]). The Apixaban was then eliminated following a first order elimination with a calculated half-life of 10.8 h. The anti-Xa activity seems to be linearly related to concentration up to 4000 MUg l-1 . This report suggests that the use of activated charcoal should be effective up to 17 h after a massive intake. PMID- 30421529 TI - Cyp2b-Knockdown Mice Poorly Metabolize Corn Oil and Are Age-Dependent Obese. AB - We previously made a RNAi-based cytochrome P450 2b (Cyp2b)-knockdown (Cyp2b-KD) mouse to determine the in vivo role of the Cyp2b subfamily in xenobiotic detoxification. Further studies reported here indicate a role for Cyp2b in unsaturated fatty-acid (UFA) metabolism and in turn obesity. Mice were treated intraperitoneally (i.p.) with 100 MUL corn oil as a carrier or the potent Cyp2b inducer 3,3',5,5'-Tetrachloro-1,4-bis(pyridyloxy)benzene (TCPOBOP (TC)) dissolved in corn oil. Surprisingly, female Cyp2b-KD mice but not male mice showed increased liver lipid accumulation. Male Cyp2b-KD mice had higher serum triacylglycerols, cholesterol, very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) than wildtype (WT) mice; females had higher cholesterol, LDL, and HDL. Thus, Cyp2b-KD mice are unable to clear a high bolus dose of corn oil, potentially because the Cyp2b-KD mice were unable to metabolize the UFA in the corn oil. Therefore, WT and Cyp2b-KD mice were housed for 35 weeks and necropsies performed to test whether Cyp2b-KD mice develop age onset obesity. Cyp2b-KD mice exhibited a significant increase in body weight caused by an increase in white adipose tissue deposition relative to WT mice. Serum cholesterol, triacylglycerol, LDL, and VLDL were significantly greater in 35-week-old Cyp2b-KD males compared to WT males; only serum triacylglycerol and LDL were higher in females. In conclusion, changes in Cyp2b expression led to perturbation in lipid metabolism and depuration in Cyp2b-KD mice. This suggests that Cyp2b is more than a detoxification enzyme, but also involved in the metabolism of UFA, as Cyp2b-KD mice have increased the body weight, fat deposition, and serum lipids. PMID- 30421531 TI - Pnictogen-Based Enzymatic Phenol Biosensors: Phosphorene, Arsenene, Antimonene, and Bismuthene. AB - Two-dimensional materials have allowed for great advances in the biosensors field and to obtain sophisticated, smart, and miniaturized devices. In this work, we optimized a highly sensitive and selective phenol biosensor using 2D pnictogens (phosphorene, arsenene, antimonene, and bismuthene) as sensing platforms. Exfoliated pnictogen were obtained by the shear-force method, undergoing delamination and downsizing to thin nanosheets. Interestingly, compared with the other tested elements, antimonene exhibited the highest degree of exfoliation and the lowest oxidation-to-bulk ratio, to which we attribute its enhanced performance in the phenol biosensor system reported here. The proposed design represents the first biosensor approach developed using exfoliated pnictogens beyond phosphorene. PMID- 30421530 TI - Differences in synaptic integration between direct and indirect striatal projection neurons: Role of CaV 3 channels. AB - Different corticostriatal suprathreshold responses in direct and indirect striatal projection neurons (SPNs) of rodents have been reported. Responses consist in prolonged synaptic potentials of polysynaptic and intrinsic origin, in which voltage-gated Ca2 + currents play a role. Recording simultaneous Ca2 + imaging and voltage responses at the soma, while activating the corticostriatal pathway, we show that encoding of synaptic responses into trains of action potentials (APs) is different in SPNs: firing of APs in D1-SPNs increase gradually, in parallel with Ca2 + entry, as a function of stimulus intensity. In contrast, D2-SPNs attain a maximum number of evoked spikes at low stimulus intensities, Ca2 + entry is limited, and both remain the same in spite of increasing stimulus strength. Stimulus needs to reach certain intensity, to have propagated Ca2 + potentials to the soma plus a sudden step in Ca2 + entry, without changing the number of fired APs, phenomena never seen in D1-SPNs. Constant firing in spite of changing stimulus, suggested the involvement of underlying inactivating potentials. We found that Ca?3 currents contribute to Ca2+ entry in both classes of SPNs, but have a more notable effect in D2-SPNs, where a low-threshold spike was disclosed. Blockade of CaV 3 channels retarded the steep rise in firing in D2-SPNs. Inhibition block increased the number of spikes fired by D2-SPNs, without changing firing in D1-SPNs. These differences in synaptic integration enable a biophysical dissimilarity: dendritic inhibition appears to be more relevant for D2-SPNs. This may imply distinctions in the set of interneurons affecting each SPN class. PMID- 30421532 TI - Characterization of the novel HLA-A*03:315 allele by sequencing-based typing. AB - HLA-A*03:315 differs from HLA-A*03:01:01:01 by one nucleotide substitution at codon 285 in exon 5. PMID- 30421533 TI - Review: The regenerating tail blastema of lizards as a model to study organ regeneration and tumor growth regulation in amniotes. AB - Tail regeneration in lizards is a unique case of organ regeneration among amniotes. The Review summarizes past and recent studies indicating that tail regeneration utilizes numerous signaling pathways typical for tumor growth. The regenerative blastema-cone contains sparse proliferating cells that utilize coding and non-coding RNAs in an environment rich in water and hyaluronate, as typical for tumor outgrowth. Differently from tumors, the blastema appears as a polarized outgrowth where the distal region contains proliferating cells mainly driven by the up-regulation of Wnt, snoRNAs and associated onco-genes. The down regulation of immune-genes coupled with the high production of hyaluronate coating blastema cells likely protect them from attach by immune cells. Immunoevasion of blastema cells allows the proliferation and migration necessary for the morphogenesis of a new tail. Transcriptome and immunolabeling data suggest that gradients for wnts, shh, msx, and signaling receptors are present in the tail blastema. It is hypothesized that cells along these gradients activate different genes, including tumor suppressors that are expressed in more proximal regions where cells stop proliferating and differentiate into tissues of the new tail. The continuous proliferation at the apex of the blastema is turned into a regulated growth in more proximal regions near the original tail. In contrast, it is hypothesized that no or non-responding gradients of signaling proteins are present in tumor outgrowths so that cell proliferation but no differentiation occurs in expanding tumors. Considering signaling gradients, the lizard model of regeneration can help in understanding the lack of regulation of tumor growth. This article is protected by copyright. All rights reserved. PMID- 30421534 TI - From Anomalous Arteries to Selective Brain Cooling: Parallel Evolution of the Artiodactyl Carotid Rete. AB - Terrestrial artiodactyls (even-toed ungulates) inhabit some of the world's most extreme environments, including arid deserts and high elevations. As medium-to large-bodied mammals, artiodactyls have a suite of specialized physiologies to facilitate occupation of regions unavailable to other large mammals. One such physiology is selective brain cooling, wherein reduction of brain temperature below core body temperature has been demonstrated to reduce evaporative water loss. This physiology is enabled by an arterial heat-exchanger called the carotid rete. The ubiquity of the carotid rete throughout the clade, as well as its evolutionary history, is currently uninvestigated. Here, I use osteological correlates to survey clade-wide presence and morphology of the carotid rete, prior to conducting a preliminary evolutionary analysis. Nearly all living artiodactyls possess a carotid rete and are capable of selective brain cooling; however, major arteries supplying the rete are derived from different embryonic aortic arches on a suborder-specific basis. Ancestral character estimation infers this pattern of variation to be the result of independent evolutionary processes, suggesting carotid rete homoplasy arising via parallelism. This is a surprising finding given the role this structure plays in driving a physiology that has been implicated in mitigating artiodactylan responses to extreme environmental conditions. Future studies should incorporate extinct species represented in the fossil record to better parse between parallel and convergent mechanisms, as well as to better understand the relationship between the carotid rete, selective brain cooling, and survivorship of climate perturbation. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30421535 TI - Widefield multi-frequency fluorescence lifetime imaging using a two-tap CMOS camera with lateral electric field charge modulators. AB - Widefield frequency-domain fluorescence lifetime imaging microscopy (FD-FLIM) measures the fluorescence lifetime of entire images in a fast and efficient manner. We report a widefield FD-FLIM system based on a complementary Metal-Oxide Semiconductor (CMOS) camera equipped with two-tap true correlated double sampling (CDS) lock-in pixels and lateral electric field charge modulators. Due to the fast intrinsic response and modulation of the camera, our system allows parallel multi-frequency Fluorescence Lifetime Imaging Microscopy (FLIM) in one measurement via Fast Fourier Transform. We demonstrate that at a fundamental frequency of 20MHz, 31-harmonics can be measured with 64 phase images per laser repetition period. As a proof of principle, we analyzed cells transfected with Cerulean and with a construct of Cerulean-Venus that shows Forster Resonance Energy Transfer (FRET) at different modulation frequencies. We also tracked the temperature change of living cells via the fluorescence lifetime of Rhodamine B at different frequencies. These results indicate that our widefield multi frequency FD-FLIM system is a valuable tool in the biomedical field. This article is protected by copyright. All rights reserved. PMID- 30421536 TI - Incidence and risk factors for clinical neurodegenerative Langerhans cell histiocytosis: a longitudinal cohort study. AB - Neurodegenerative (ND) complications in Langerhans cell histiocytosis (LCH) are a late-onset but dramatic sequelae for which incidence and risk factors are not well defined. Based on a national prospective registry of paediatric LCH patients, we determined the incidence rate of clinical ND LCH (cND-LCH) and analysed risk factors, taking into account disease extent and molecular characteristics. Among 1897 LCH patients, 36 (1.9%) were diagnosed with a cND LCH. The 10-year cumulative incidence of cND-LCH was 4.1%. cND-LCH typically affected patients previously treated for a multisystem, risk organ-negative LCH, represented in 69.4% of cND-LCH cases. Pituitary gland, skin and base skull/orbit bone lesions were more frequent (P < 0.001) in cND-LCH patients compared to those without cND-LCH (respectively 86.1% vs. 12.2%, 75.0% vs. 34.2%, and 63.9% vs. 28.4%). The 'cND susceptible patients' (n = 671) i.e., children who had experienced LCH disease with pituitary or skull base or orbit bone involvement, had a 10-year cND risk of 7.8% vs. 0% for patients who did not meet these criteria. Finally, BRAFV 600E status added important information among these cND susceptible patients, with the 10-year cND risk of 33.1% if a BRAFV 600E mutation was present compared to 2.9% if it was absent (P = 0.002). PMID- 30421537 TI - Glecaprevir/Pibrentasvir in Patients with Chronic HCV Genotype 3 Infection: An Integrated Phase 2/3 Analysis. AB - Glecaprevir coformulated with pibrentasvir (G/P) is approved to treat hepatitis C virus (HCV) infection and was highly efficacious in phase 2 and 3 studies. Treating HCV genotype (GT) 3 infection remains a priority, as these patients are harder to cure and at a greater risk for liver steatosis, fibrosis progression, and hepatocellular carcinoma. Data were pooled from five phase 2 or 3 trials that evaluated 8-, 12-, and 16-week G/P in patients with chronic HCV GT3 infection. Patients without cirrhosis or with compensated cirrhosis were either treatment naive or experienced with interferon- or sofosbuvir-based regimens. Safety and sustained virologic response 12 weeks post-treatment (SVR12) were assessed. The analysis included 693 patients with GT3 infection. SVR12 was achieved by 95% of treatment-naive patients without cirrhosis receiving 8-week (198/208) and 12-week (280/294) G/P. Treatment-naive patients with cirrhosis had a 97% (67/69) SVR12 rate with 12-week G/P. Treatment-experienced, non-cirrhotic patients had SVR12 rates of 90% (44/49) and 95% (21/22) with 12- and 16-week G/P, respectively; 94% (48/51) of treatment-experienced patients with cirrhosis treated for 16 weeks achieved SVR12. No serious adverse events (AEs) were attributed to G/P; AEs leading to study drug discontinuation were rare (<1%). G/P was well-tolerated and efficacious for patients with chronic HCV GT3 infection, regardless of cirrhosis status or prior treatment experience. Eight- and 12-week durations were efficacious for treatment-naive patients without cirrhosis and with compensated cirrhosis, respectively; 16-week G/P was efficacious in patients with prior treatment experience irrespective of cirrhosis status. This article is protected by copyright. All rights reserved. PMID- 30421538 TI - Red- and green-emitting nano-clay materials doped with Eu3+ and/or Tb3. AB - Trivalent europium (Eu3+ ) and terbium (Tb3+ ) ions are important activator centers used in different host lattices to produce red and green emitting materials. The current work shows the design of new clay minerals to act as host lattices for rare earth (RE) ions. Based on the hectorite structure, nano chlorohectorites and nano-fluorohectorites were developed by replacing the OH- present in the hectorite structure with Cl- or F- , thus avoiding the luminescence quenching expected due to the OH- groups. The produced matrices were characterized through X-ray powder diffraction (XPD), transmission electron microscopy (TEM), FT-IR, 29 Si MAS (magic angle spinning) NMR, nitrogen sorption, thermogravimetry-differential scanning calorimetry (TGA-DSC) and luminescence measurements, indicating all good features expected from a host lattice for RE ions. The nano-clay materials were successfully doped with Eu3+ and/or Tb3+ to yield materials preserving the hectorite crystal structure and showing the related luminescence emissions. Thus, the present work shows that efficient RE3+ luminescence can be obtained from clays without the use of organic 'antenna' molecules. PMID- 30421539 TI - Diverse Synthesis of Natural Trehalosamines and Synthetic 1,1'-Disaccharide Aminoglycosides. AB - We report a general strategy for diverse synthesis of ten disaccharide aminoglycosides including natural 2-trehalosamine (1), 3-trehalosamine (2), 4 trehalosamine (3), 6-trehalosamine (4), and neotrehalosyl 3,3'-diamine (8), and synthetic aminoglycosides (4-7, 9, and 10). The aminoglycoside compounds feature different anomeric configurations and numbers of the amino groups. The key step for the synthesis is the 1,1'-glycosylation coupling of a stereo-directing donor and a configuration stable TMS glycoside acceptor with or without azido group substitution in high stereoselectivity. The compounds obtained in present study are fully characterized with the 1D and 2D NMR spectroscopy. PMID- 30421540 TI - Sewing up the wounds : The epithelial morphogenesis as a central mechanism of calcaronean sponge regeneration. AB - Sponges (Porifera) demonstrate prominent regeneration abilities and possess a wide variety of mechanisms, used during this process. In the current study, we combined in vivo observations with histological, immunohistochemical, and ultrastructural technics to elucidate the fine cellular mechanisms of the regeneration in the calcareous sponge Leucosolenia cf. variabilis. The regeneration of Leucosolenia cf. variabilis ends within 4-6 days. The crucial step of the process is the formation of the transient regenerative membrane, formed by the epithelial morphogenesis-spreading of the intact exopinacoderm and choanoderm. The spreading of the choanoderm is accompanied by the transdifferentiation of the choanocytes. The regenerative membrane develops without any contribution of the mesohyl cells. Subsequently, the membrane gradually transforms into the body wall. The cell proliferation is neither affected nor contributes to the regeneration at any stage. Thus, Leucosolenia cf. variabilis regeneration relies on the remodeling of the intact tissues through the epithelial morphogenesis, accompanied by the transdifferentiation of some differentiated cell types, which makes it similar to the regeneration in homoscleromorphs and eumetazoans. PMID- 30421541 TI - Mechanisms of reduced sleepiness symptoms in heart failure and obstructive sleep apnea. AB - Patients with both heart failure and obstructive sleep apnea often have poor, repeatedly disrupted sleep, and yet they frequently do not complain of excessive daytime sleepiness. Understanding this lack of perceived sleepiness is crucial for the case identification and treatment of obstructive sleep apnea in the heart failure population at high risk of this disease, especially given the association between untreated obstructive sleep apnea and mortality among patients with heart failure. In this review, we present epidemiologic evidence concerning the lack of sleepiness symptoms in heart failure and obstructive sleep apnea, explore possible mechanistic explanations for this relationship, assess the benefits of treatment in this population, discuss implications for clinical practice and explore directions for future research. PMID- 30421542 TI - Melatonin reduces lung cancer stemness through inhibiting of PLC, ERK, p38, beta catenin, and Twist pathways. AB - Lung cancer is one of the most common cancer in cancer-related deaths worldwide, which is characterized by its strong metastatic potential. The melatonin hormone secreted by the pineal grand has an antioxidant effect and protects cells against carcinogenic substances. However, the effects of melatonin in lung cancer stemness are largely unknown. We found that melatonin reduces CD133 expression by ~50% in lung cancer cell lines, while results of a sphere formation assay showed that melatonin inhibits lung cancer stemness. These effects of melatonin were reversed when the cell lines were incubated with phospholipase C (PLC), ERK/p38, and a beta-catenin activator. Transfection with Twist siRNA augmented the inhibitory effects of melatonin, indicating that melatonin suppresses lung cancer stemness by inhibiting the PLC, ERK/p38, beta-catenin, and Twist signaling pathways. We also found CD133 expression is positively correlated with Twist expression in lung cancer specimens. Melatonin shows promise in the treatment of lung cancer stemness and deserves further study. PMID- 30421543 TI - Overview on neural tube defects: From development to physical characteristics. AB - Neural tube defects (NTDs) are the second most common congenital malformations in humans affecting the development of the central nervous system. Although NTD pathogenesis has not yet been fully elucidated, many risk factors, both genetic and environmental, have been extensively reported. Classically divided in two main sub-groups (open and closed defects) NTDs present extremely variable prognosis mainly depending on the site of the lesion. Herein, we review the literature on the histological and pathological features, epidemiology, prenatal diagnosis, and prognosis, based on the type of defect, with the aim of providing important information based on NTDs classification for clinicians and scientists. PMID- 30421544 TI - Hepatobiliary and Pancreatic: Sclerosing extramedullary hematopoietic tumor involving hepatic hilum. PMID- 30421545 TI - Insulin glargine/lixisenatide fixed-ratio combination improves glycaemic variability and control without increasing hypoglycaemia. AB - Maintaining optimal glycaemic control reduces the risk of micro-/macrovascular complications in patients with type 2 diabetes. Typically, glycaemic control is based on HbA1c as a measure of mean glucose concentration. However, this parameter does not accurately reflect glycaemic variability (GV), which is characterized by the amplitude, frequency, and duration of hypo-/hyperglycaemic fluctuations. In this study, we analysed data from the LixiLan-O trial, which compared iGlarLixi, a titratable fixed-ratio combination of the glucagon-like peptide 1 receptor agonist lixisenatide (Lixi) and long-acting basal insulin glargine 100 units/mL (iGlar), with its individual components, and the LixiLan-L trial, which compared iGlarLixi with iGlar. GV parameters measured were mean and standard deviation (SD) of self-measured plasma glucose (SMPG), high (HBGI) and low blood-glucose indices, area under the SMPG curve for each patient (AUCn), mean absolute glucose (MAG) and mean amplitude of glycaemic excursions (MAGE). By Week 30, iGlarLixi improved all GV parameters from baseline with no increased hypoglycaemia risk. Significant improvements were observed in SMPG, SD of SMPG, HBGI, AUCn, MAG, and MAGE compared with iGlar, and in SMPG, HBGI, and AUCn, compared with Lixi. This article is protected by copyright. All rights reserved. PMID- 30421546 TI - Anterior hippocampus volume loss in narcolepsy with cataplexy. AB - Narcolepsy with cataplexy is a lifelong disease resulting from the loss of hypocretin neurons in the hypothalamus; structural changes are not, however, limited only to the hypothalamus. We previously revealed an overall hippocampal volume loss in narcolepsy with cataplexy. The aim of this study is to describe the volume reduction of the anterior and posterior parts of the hippocampus in patients with narcolepsy with cataplexy in comparison with a control group. The anterior hippocampus is more involved in episodic memory and imagination, and the posterior hippocampus in spatial memory. Manual magnetic resonance imaging hippocampal volumetry was performed in 48 patients with narcolepsy with cataplexy and in 37 controls using the manual delineation technique in the ScanView program. All participants were examined on the same 1.5 T MR scanner; measurement was carried out as T1W 3D image with a slice thickness of 1.0/0 mm. There was a significant absolute loss of the total volume of the anterior hippocampus (sum of left and right) in patients with narcolepsy with cataplexy as compared with the controls (10.5%, p = .03 ANCOVA after correcting for total brain volume and multiple testing). We found a negative correlation between the total anterior hippocampus volume and the duration of the disease (R = -0.4036, p = .016 corrected for multiple testing). PMID- 30421547 TI - The relative efficacy of mindfulness versus distraction: The moderating role of attentional bias. AB - BACKGROUND: This study investigated whether the ability to disengage quickly from pain-related stimuli moderated the relative efficacy of a mindfulness-based intervention versus distraction in response to an experimental pain task. METHODS: Participants (n = 100) completed a dot probe task with eye tracking and were then randomized (2:2:1) to receive a mindfulness-based interoceptive exposure task (MIET), distraction instructions or no instructions (control group) before engaging in the cold pressor test. RESULTS: Participants who were allocated to the MIET condition reported a significantly higher pain threshold and distress than the distraction group, although not significantly higher than the control group. Those in the MIET group had improved tolerance compared to both the distraction and control groups. Difficulty disengaging from pain-related stimuli, as measured by the duration of the first fixation on sensory words, was found to moderate the relative efficacy of mindfulness versus distraction in terms of pain threshold and distress, but not tolerance. Those with difficulty disengaging from sensory pain words benefited less from the MIET. Duration of first fixation on sensory and affective pain words were highly correlated, and duration of first fixation on affective pain words also moderated the relative efficacy of MIET and distraction on threshold, but not distress. CONCLUSIONS: These results show that a single brief session of a mindfulness task was sufficient to change an acute pain experience in comparison with a distraction task, and that those who disengaged quickly from pain words benefited most. SIGNIFICANCE: This study demonstrated the efficacy of a novel, exposure-based mindfulness technique for pain tolerance and showed that those who disengaged easily from pain stimuli benefited most. This brief task could be clinically useful, particularly for those who are not overly focused on their pain symptoms. PMID- 30421548 TI - Heart Valve Disease Predict Mortality in Hemodiaylsis Patients: A Single Center Experience. AB - INTRODUCTION: Our aim is to investigate the clinical and laboratory findings affecting the mortality of the patients in 3 years follow up who underwent hemodialysis at our center. METHODS: In this retrospective, observational cohort study, 432 patients who underwent hemodialysis at our center for at least 5 months were included. The first recorded data and subsequent clinical findings of patients who died and survived were compared. FINDING: 290 patients survived, 142 patients died. The mean age of the patients who died was higher (63,4+/-12,3 years, vs 52+/-16,1 years, p=0,0001), 60.5% of them had coronary artery disease (p:0,0001), 93.7% of them had a heart valve disease. Duration of hemodialysis [survived 57 (21-260) months; died 44 (5-183) months, p:0,000] were lower in patients who died. Serum potassium level before dialysis (5,1+/-0,6; 4,9+/-0,7 mEq/L, p:0,030), parathyroid hormone [435 (4-3054); 304 (1-3145) pq/ml, p:0,0001], albumin [ 3,9+/-0,4; 3,8+/-0,4 mg/dl, p:0,0001] and Kt/V [1,48+/-0,3; 1,40+/-0,3, p:0,019]; levels were lower, C-reactive protein [ 5(1-208); 8,7(2 256) mg/L, p:0,000] levels was higher in patients who died. Logistic regression analysis showed age ( OR:1,1), coronary artery disease (OR:1,7) more than one heart valve disease (OR: 2,4) are independent risk factors for mortality. Potassium level before dialysis (OR:0,60), parathyroid hormone ( OR:0,99), higher Kt/V (OR: 0,28) were found to be an advantage for survival. DISCUSSION: Age, coronary artery disease and especially pathology in more than one heart valve are risk factors for mortality. Heart valve problems might developed due to malnutrition and inflammation caused by the chronic renal failure. PMID- 30421549 TI - Management of oral mucositis in pediatric patients receiving cancer therapy: A systematic review and meta-analysis. AB - BACKGROUND: One of the most common complications of cancer chemotherapy is oral mucositis (OM). OM affects more than 75% of patients undergoing chemotherapy and represents a significant burden to patients and caregivers. We performed a systematic review and meta-analysis of published studies to investigate the effects of agents and techniques in reducing OM. PROCEDURE: This systematic review investigated, critically appraised, and rated the evidence on agents used to manage OM in children undergoing cancer therapy. A comprehensive search of the relevant literature was performed from January 2006 to December 2017. MEDLINE, Scopus, the Cochrane Database of Systematic Reviews, EMBASE, and the Web of Science were searched. Nine eligible studies were identified. Using random effects models, standardized mean difference was estimated between treated and control groups across all studies. The Cochran test and the I2 index were performed for heterogeneity between studies. The significance level was set at P = 0.05. RESULTS: Palifermin reduced the incidence (OR = 4.131, P = 0.000), duration (St diff mean = 0.803, P = 0.000), and severity (St diff mean = 0.637, P = 0.000) of OM in pediatric cancer patients significantly. However, the laser did not show significant efficacy in decreasing the incidence rate of OM (OR = 2.870, P = 0.364). CONCLUSION: This review provided a comprehensive examination of available options for children who have OM. The results support the possibility of a positive effect of palifermin on reducing OM in children receiving cancer therapy. PMID- 30421550 TI - Prolonged central apnoea after intravenous morphine administration in a 12-year old male with a UGT1A1 loss-of-function polymorphism. AB - ADVERSE EVENT: Repeated and prolonged episodes of central apnoea and hypoxia after receiving intravenous morphine for analgesia and ketamine for sedation. DRUG IMPLICATED: Intravenous morphine sulfate. THE PATIENT: Previously healthy 12 year-old male with no history of sleep apnoea who presented with distal tibia and fibula fracture. EVIDENCE THAT LINKS DRUG TO EVENT: Pharmacogenomic testing revealed that the patient was homozygous for the T allele at the rs887829 SNP in UGT1A1, an enzyme involved in the metabolism of morphine. This polymorphism is a loss-of-function variant, leading to impaired metabolism of morphine. MECHANISM: Morphine is metabolized by UDP-glucuronosyltransferase (UGT)-2B7 and UGT1A1 to form its major metabolites morphine-3-glucuronide (M3G) and morphine-6 glucuronide (M6G). Our patient was a poor metabolizer through UGT1A1, likely leading to increased respiratory depression as morphine has greater respiratory depressant effects compared to its metabolites. IMPLICATIONS: When appropriate, physicians should enquire about prior receipt of opioids, in both the patient and family, to be better prepared for potential adverse reactions. In the patient with excessive sedation or respiratory depression to standard doses of morphine, genetic testing may be warranted, especially if there is a family or past history that supports a metabolic defect in morphine metabolism and/or excretion. PMID- 30421551 TI - In vitro and in vivo phasor analysis of stoichiometry and pharmacokinetics using short lifetime near-infrared dyes and time-gated imaging. AB - We introduce a simple new approach for time-resolved multiplexed analysis of complex systems using near-infrared (NIR) dyes, applicable to in vitro and in vivo studies. We show that fast and precise in vitro quantification of NIR fluorophores' short (sub-nanosecond) lifetime and stoichiometry can be done using phasor analysis, a computationally efficient and user-friendly representation of complex fluorescence intensity decays obtained with pulsed laser excitation and time-gated camera imaging. We apply this approach to the study of binding equilibria by Forster resonant energy transfer using two different model systems: primary/secondary antibody binding in vitro and ligand/receptor binding in cell cultures. We then extend it to dynamic imaging of the pharmacokinetics of transferrin engagement with the transferrin receptor in live mice, elucidating the kinetics of differential transferrin accumulation in specific organs, straightforwardly differentiating specific from non-specific binding. Our method, implemented in a freely-available software, has the advantage of time-resolved NIR imaging, including better tissue penetration and background-free imaging, but simplifies and considerably speeds up data processing and interpretation, while remaining quantitative. These advances make this method attractive and of broad applicability for in vitro and in vivo molecular imaging, and could be extended to applications as diverse as image guided-surgery or optical tomography. This article is protected by copyright. All rights reserved. PMID- 30421552 TI - ARC and BDNF expression after cocaine self-administration or cue-induced reinstatement of cocaine seeking in adolescent and adult male rats. AB - Recreational drug use peaks during adolescence. Our research with adolescent vs adult male rats, however, shows that rats taking cocaine as adolescents have lower levels of cue-induced reinstatement of drug-seeking than adults, despite similar levels of intravenous (i.v.) cocaine self-administration. Lower rates of reinstatement in younger rats could be explained by higher levels of brain plasticity. Two neuroplasticity-related genes, activity-regulated cytoskeletal associated gene (Arc) and brain-derived neurotrophic factor (Bdnf), influence cocaine self-administration and cue-induced reinstatement. We tested whether reinstatement of cocaine seeking correlates with expression of these genes in reinforcement-related brain regions. Adolescent and adult male rats (postnatal day 35 or 83-95 at start) were allowed to acquire lever-pressing maintained by i.v. infusions of cocaine in daily 2-h sessions over 13 days. At one of three experimental time points, rats were sacrificed and tissue collected to analyze Arc and Bdnf mRNA by in situ hybridization in the entire medial prefrontal cortex and entire nucleus accumbens, as well as relevant subregions: prelimbic cortex, infralimbic cortex, and nucleus accumbens core and shell. Despite taking similar amounts of cocaine, adolescents reinstated less than adults. Gene expression was most notable in the prelimbic cortex, was generally higher in adolescent-onset groups, and was higher with longer abstinence. These data partially support the hypothesis that higher levels of Arc and/or Bdnf gene expression in reinforcement related brain regions of younger animals contribute to lower rates of extinction responding and/or reinstatement. Future studies should include mechanistic analysis of Arc, Bdnf, and their signaling pathways in age-dependent effects of cocaine. PMID- 30421553 TI - Little information about fertility preservation is provided for cancer patients: A survey of oncologists' knowledge, attitude and current practice. AB - The objective of this survey was to explore the knowledge, attitude and current practice of Iranian oncologists about fertility preservation (FP) services provided to cancer patients. Oncologists who completed this survey were a convenience sample of 103 specialists in radiation oncology and haematology who attended large national and international congresses and symposia across Iran. A 23-item self-administered questionnaire included questions on knowledge, attitudes and practice. The most well known of the FP methods among Iranian oncologists were gonadotropin-releasing hormone therapy and sperm cryopreservation, with scores of 2.77 (1.10) and 2.64 (1.00) respectively. These scores were above the median value of 2.5 on a 4-point Likert scale, in contrast to a mean knowledge score across all the FP options of 2.25 (0.71). With regard to attitudes, age was the most important reason for discussing FP with patients, mean score 3.75 (0.54), while heredity was the least important, mean score 2.98 (0.87). In terms of practice, most oncologists did not provide their patients with written information about FP. However, 74 (72.5%) said they referred cancer patients on to reproductive specialists. This sample of Iranian oncologists would benefit from more information on FP methods and prevent loss of fertility among cancer patients. PMID- 30421554 TI - Prognostic significance of BRAF mutation alone and in combination with microsatellite instability in stage III colon cancer. AB - PURPOSE: The prognostic significance of biomarkers in colorectal cancer is still being defined. This study aimed to determine the prognostic significance of BRAF mutation alone and in combination with microsatellite instability (MSI), in stage III colon cancer. METHODS: Curatively resected stage III colon cancers were studied from a 33-year period. Clinicopathological data were collated (adjuvant chemotherapy, age, gender, obstruction, perforation, tumour location, grade, presence of mucin, nodal stage, extramural vascular, and perineural invasion). MSI status was established and molecular testing for BRAF (V600E) was performed. Four mutation categories were examined: "traditional" (microsatellite stable [MSS]/BRAF -ve), "presumed Lynch" (MSI/BRAF -ve), "sporadic MSI" (MSI/BRAF +ve), and "other BRAF" (MSS/BRAF +ve). These factors were correlated with cancer specific survival. RESULTS: In total, 686 unselected cases met our inclusion criteria, of which 15.7% had a BRAF mutation and 13.8% showed MSI. In the adjusted analysis, neither BRAF mutation nor MSI mutation were independently prognostic. On univariate analysis, survival in presumed Lynch cancers was similar to traditional cancers (5-year survival: 62% and 61%, respectively). While there was no difference in cancer-specific survival between sporadic MSI and other BRAF, both these tumour group had poorer outcome when compared to traditional or presumed Lynch cancers. Adjusted analysis of the four groups, however, showed that none of the subgroups were independently prognostic. CONCLUSION: BRAF-mutated cancers demonstrated a trend toward poorer outcomes, however, when adjusted for clinicopathological factors and chemotherapy, BRAF mutation was not found to be an independent prognostic biomarker in stage III colon cancer, even when combined with MSI. PMID- 30421555 TI - Herbal medicine in oral lichen planus. AB - Oral lichen planus (OLP) is a common chronic inflammatory and T cell-mediated autoimmune disease in which the oral mucosa, tongue, and gingiva are involved. Different treatments have been suggested to reduce the symptoms of this disease. Currently, a common treatment for OLP is the use of corticosteroids as the gold standard, although they have considerable side effects. The chronicity of the disease needs the long-term use of these drugs with ensuing side effects. Therefore, various studies have been done to find an alternative and effective treatment. The use of herbal medicine as an alternative therapy with antioxidant and anti-inflammatory properties seems promising. Hence, this review study was done to summarize the efficiency of different herbal medicine in the treatment of OLP. PMID- 30421556 TI - A correlated Bayesian rank likelihood approach to multiple ROC curves for endometriosis. AB - In analysis of diagnostic data with multiple tests, it is often the case that these tests are correlated. Modeling the correlation explicitly not only produces valid inference results but also enables borrowing of information. Motivated by the Physician Reliability Study (PRS) that investigated the diagnostic performance of physicians in diagnosing endometriosis, we construct a correlated modeling framework to estimate ROC curves and the associated area under the curves. This correlated approach is quite appealing for the PRS data set that suffers from the problem of small sample sizes, as it enables information borrowing between physician groups and sessions. Given that the test scores appear to be non-normal even after logarithm transformation, we use the ranks of the data to conduct likelihood estimation and inference. We use the deviance information criterion to select competing models and conduct simulation studies to assess model performances. In application to the PRS data set, we found that the physicians are not significantly different in their diagnostic performance between groups; however, they are different between the sessions. This suggests that clinical information may play a more important role in physicians' diagnostic performance than their experiences. Our empirical evidence also demonstrates that when using both woman- and physician-specific random effects, the model parameter estimates are much smoother. PMID- 30421557 TI - Denitrifying haloarchaea within the genus Haloferax display divergent respiratory phenotypes, with implications for their release of nitrogenous gases. AB - Haloarchaea are extremophiles, generally thriving at high temperatures and salt concentrations, thus with limited access to oxygen. As a strategy to maintain a respiratory metabolism, many halophilic archaea are capable of denitrification. Among them are members of the genus Haloferax, which are abundant in saline/hypersaline environments. Three reported haloarchaeal denitrifiers, Haloferax mediterranei, Haloferax denitrificans and Haloferax volcanii, were characterized with respect to their denitrification phenotype. A semi-automatic incubation system was used to monitor the depletion of electron acceptors and accumulation of gaseous intermediates in batch cultures under a range of conditions. Out of the species tested, only H. mediterranei was able to consistently reduce all available N-oxyanions to N2 , whilst the other two released significant amounts of NO and N2 O, which affect tropospheric and stratospheric chemistries, respectively. The prevalence and magnitude of hypersaline ecosystems are on the rise due to climate change and anthropogenic activity. Thus, the biology of halophilic denitrifiers is inherently interesting, due to their contribution to the global nitrogen cycle, and potential application in bioremediation. This work is the first detailed physiological study of denitrification in haloarchaea, and as such a seed for our understanding of the drivers of nitrogen turnover in hypersaline systems. This article is protected by copyright. All rights reserved. PMID- 30421558 TI - The shape of the simplest non-proteinogenic amino acid alpha-aminoisobutyric (Aib). AB - The simplest non-proteinogenic amino acid alpha-aminoisobutyric acid (Aib), an analog of glycine and alanine, has been vaporized by laser ablation and probed by high-resolution Fourier transform microwave spectroscopic techniques. Comparison of the experimental rotational and 14N nuclear quadrupole constants with that predicted ab initio has allowed the identification of three conformers of Aib exhibiting the three types of hydrogen bond interactions I (NH...O=C, cis-COOH), II (OH...N, trans-COOH) and III (N-H...O-H, cis-COOH) within the amino acid backbone. The observation of conformer III, not detected previously for related proteinogenic amino acids with non-polar side chain in a supersonic expansion, indicates that the presence of the methyl groups should restrict the conformational relaxation from conformer Aib-III to Aib-I. For conformer Aib-II, the rotational spectra of the 13C isotopomers reveal a tunneling motion arising from the two equivalent methyl groups in the molecule. The observation of a single transition at the mid-point of the two 13C of the methyl groups have been explained regarding a double minimum potential function with a low energy interconversion barrier for a large amplitude internal motion. This singular fact has been corroborated by the anomalous centrifugal distortion effects determined in conformer Aib-II. PMID- 30421559 TI - Cannabinoid dependence induces sustained changes in GABA release in the globus pallidus without affecting dopamine release in the dorsal striatum: A dual microdialysis probe study. AB - A dual probe microdialysis study was designed to characterize GABA and dopamine (DA) release in the basal ganglia of cannabinoid-dependent Wistar rats. Whereas chronic administration of the cannabinoid receptor agonist WIN55,212 (WIN) resulted in increased basal GABA release, the D2 agonist receptor-mediated control of GABA and DA release elicited by quinpirole was similar in both cannabinoid-dependent and non dependent animals. However, quinpirole did induce a greater number of more stereotypies in cannabinoid-dependent animals, indicating a dysregulated behavioral response. PMID- 30421560 TI - Good clinical practice can and must include comparative effectiveness research. PMID- 30421561 TI - HLA-B*45:22: a novel allele that differs from HLA-B*45:01:01 at several locations. AB - Discovery of a novel HLA-B*45:22 allele in a Middle Eastern heart and lung transplant candidate. PMID- 30421562 TI - IgG4-related disease in patients with idiopathic orbital inflammation syndrome: data from the French SIOI prospective cohort. AB - PURPOSE: To better characterize IgG4-related disease (RD) in the setting of idiopathic orbital inflammation syndrome (IOIS). METHODS: National, multicentre, prospective, observational cohort study. Among the patients consecutively included in the French multicentre SIOI cohort, we selected those who underwent orbital and/or adnexal biopsy. Clinical, morphological and pathological findings at diagnosis were blindly analysed. Serum IgG4 levels at inclusion were measured and all available biopsy specimens were immunostained for IgG4 and IgG. Biopsy samples with more than 10 IgG4-positive plasma cells per high-power field and a IgG4+/IgG+ plasma cell ratio above 40% were scored as positive. IgG4-positive patients were then screened for comprehensive diagnostic criteria for IgG4-RD. RESULTS: Of the 87 patients included, 35 had histologically documented IOIS. Thirteen patients (37%) with a mean age at onset of 27 years (range 21-78) had IgG4-positive biopsies, among which 10 patients (77%) and 3 (23%, with IgG4 serum levels >1.35 g/L) were considered as having probable and definite IgG4-RD, respectively. The latter 13 patients more frequently fulfilled histological criteria for IgG4-RD (including plasmacytic infiltrate (p = 0.006), fibrosis (p = 0.0025) and periphlebitis (p = 0.075)) than IgG4-negative patients. Storiform fibrosis was exclusively found in orbital tissues from IgG4-positive patients (n = 3, 23%). Eosinophilia associated with recurrent sinusitis or asthma was a prominent feature in patients with definite IgG4-RD. CONCLUSIONS: More than one third of patients with biopsy-proven IOIS satisfied criteria for IgG4-RD, but only a few had a definite type. PMID- 30421563 TI - Proepicardium: Current Understanding of its Structure, Induction, and Fate. AB - The proepicardium (PE) is a transitory extracardiac embryonic structure which plays a crucial role in cardiac morphogenesis and delivers various cell lineages to the developing heart. The PE arises from the lateral plate mesoderm (LPM) and is present in all vertebrate species. During development, mesothelial cells of the PE reach the naked myocardium either as free-floating aggregates in the form of vesicles or via a tissue bridge; subsequently, they attach to the myocardium and, finally, form the third layer of a mature heart-the epicardium. After undergoing epithelial-to-mesenchymal transition (EMT) some of the epicardial cells migrate into the myocardial wall and differentiate into fibroblasts, smooth muscle cells, and possibly other cell types. Despite many recent findings, the molecular pathways that control not only proepicardial induction and differentiation but also epicardial formation and epicardial cell fate are poorly understood. Knowledge about these events is essential because molecular mechanisms that occur during embryonic development have been shown to be reactivated in pathological conditions, for example, after myocardial infarction, during hypertensive heart disease or other cardiovascular diseases. Therefore, in this review we intended to summarize the current knowledge about PE formation and structure, as well as proepicardial cell fate in animals commonly used as models for studies on heart development. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30421564 TI - Anti-hypersensitive effect of angiotensin (1-7) on streptozotocin-induced diabetic neuropathic pain in mice. AB - BACKGROUND: We have recently reported that the spinal angiotensin (Ang) converting enzyme (ACE)/Ang II/AT1 receptor axis and downstream p38 MAPK phosphorylation are activated in streptozotocin (STZ)-induced diabetic mice and lead to tactile hypersensitivity. Moreover, our previous results suggested that the intrathecal (i.t.) administration of Ang (1-7), an N-terminal fragment of Ang II, may attenuate the Ang II-induced nociceptive behaviour through the inhibition of p38 MAPK phosphorylation via Mas receptors. Here, we investigated whether the i.t. administration of Ang (1-7) can attenuate STZ-induced diabetic neuropathic pain. METHODS: Tactile and thermal hypersensitivities were determined using the von Frey filament and Hargreaves tests, respectively. The protein expression of ACE2, Mas receptors and phospho-p38 MAPK was measured by western blotting. Spinal ACE2 activity was determined using ACE2 activity assay kit. RESULTS: The i.t. administration of Ang (1-7) significantly reduced the tactile and thermal hypersensitivities on day 14 after STZ injection, and these effects were significantly prevented by the Mas receptor antagonist A779. The expression of ACE2 and Mas receptors in the plasma membrane fraction of the lumbar dorsal spinal cord was both significantly decreased in STZ mice. Spinal ACE2 activity was also decreased while p38 MAPK phosphorylation was increased in the lumbar dorsal region of these mice. This phosphorylation was attenuated by the injection of Ang (1-7), whose effect was reversed by A779. CONCLUSIONS: Our data demonstrate that Ang (1-7) attenuates STZ-induced diabetic neuropathic pain and that this occurs through a mechanism involving spinal Mas receptors and he inhibition of p38 MAPK phosphorylation. SIGNIFICANCE: The ACE2/Ang (1-7)/Mas receptor axis was down-regulated in the spinal cord of STZ mice and the i.t. administration of Ang (1-7) attenuated the STZ-induced diabetic neuropathic pain via Mas receptors. Therefore, the activation of this axis could be an effective therapeutic target to alleviate the neuropathic pain in diabetic patients. PMID- 30421566 TI - Mitral valve aneurysm associated with aortic valve endocarditis. PMID- 30421565 TI - Antiviral Medications for the Prevention of Post Herpetic Neuralgia after Herpes Zoster Infection. AB - Post herpetic neuralgia (PHN) is a condition of persistent, refractory pain in an area previously affected by an acute herpes zoster infection. Age remains an important risk factor for the development of PHN, with 40% of patients older than 50 years and 75% of patients 75 years and older developing PHN after an initial episode of shingles.1 Persistent pain can lead to significant long-term problems such as depression, altered activities of daily living, and anorexia.1 Prior systematic reviews have suggested that treatment with antivirals within 72 hours of the onset of rash may reduce the incidence or duration of PHN. The Cochrane systematic review discussed here is an update of a previous Cochrane review from 2009, and draws no new conclusions compared to the earlier review. The current review included 6 double-blinded randomized placebo-controlled trials and a total of 1211 patients. Five of these trials evaluated oral acyclovir, and the sixth trial evaluated famciclovir. Fifteen other studies were excluded for reasons such as a short follow-up interval, lack of placebo control, or initiation of treatment beyond 72 hours from the onset of rash. This review found no significant difference between acyclovir and placebo in the incidence of PHN at 4 months (risk ratio (RR): 0.75, 95% confidence interval (CI) 0.51 to 1.11) or at 6 months (RR: 1.05, 95% CI 0.87 to 1.27). The single study that evaluated famciclovir also failed to show reduced incidence compared to placebo. One trial comparing placebo and acyclovir with 46 participants reported statistically significant lower mean pain scores between two and six months using the VAS validated pain scale. The most common adverse drug events included nausea, vomiting, and headache, but these were not significantly different than in patients who received placebo. The Cochrane review concludes that there is high quality evidence that acyclovir does not reduce the incidence of PHN and suggests that further trials should focus on famciclovir and other antiviral agents since there is currently insufficient evidence to determine their efficacy. This article is protected by copyright. All rights reserved. PMID- 30421567 TI - Jean-Pierre Flatt, PhD (1933-2018). PMID- 30421568 TI - Anticancer activity of paroxetine in human colon cancer cells: Involvement of MET and ERBB3. AB - The concept of drug repositioning has recently received considerable attention in the field of oncology. In the present study, we propose that paroxetine can be used as a potent anticancer drug. Paroxetine, one of the selective serotonin reuptake inhibitors (SSRIs), has been widely prescribed for the treatment of depression and anxiety disorders. Recently, SSRIs have been reported to have anticancer activity in various types of cancer cells; however, the underlying mechanisms of their action are not yet known. In this study, we investigated the potential anticancer effect of paroxetine in human colorectal cancer cells, HCT116 and HT-29. Treatment with paroxetine reduced cell viability, which was associated with marked increase in apoptosis, in both the cell lines. Also, paroxetine effectively inhibited colony formation and 3D spheroid formation. We speculated that the mode of action of paroxetine might be through the inhibition of two major receptor tyrosine kinases - MET and ERBB3 - leading to the suppression of AKT, ERK and p38 activation and induction of JNK and caspase-3 pathways. Moreover, in vivo experiments revealed that treatment of athymic nude mice bearing HT-29 cells with paroxetine remarkably suppressed tumour growth. In conclusion, paroxetine is a potential therapeutic option for patients with colorectal cancer. PMID- 30421569 TI - A leaf shape mutant provides insight into PINOID Serine/Threonine Kinase function in cucumber (Cucumis sativus L.). AB - Optimizing leaf shape is a major challenge in efforts to develop an ideal plant type. Cucumber leaf shapes are diverse; however, the molecular regulatory mechanisms underlying leaf shape formation are unknown. In this study, we obtained a round leaf mutant (rl) from an ethyl methanesulfonate-induced mutagenesis population. Genetic analysis revealed that a single recessive gene, rl, is responsible for this mutation. A modified MutMap analysis combined linkage mapping identified a single nucleotide polymorphism within a candidate gene, Csa1M537400, as the mutation underlying the trait. Csa1M537400 encodes a PINOID kinase protein involved in auxin transport. Expression of Csa1M537400 was significantly lower in the rl mutant than in wild type, and it displayed higher levels of IAA (indole-3-acetic acid) in several tissues. Treatment of wild-type plants with an auxin transport inhibitor induced the formation of round leaves, similar to those in the rl mutant. Altered expression patterns of several auxin related genes in the rl mutant suggest that rl plays a key role in auxin biosynthesis, transport, and response in cucumber. These findings provide insight into the molecular mechanism underlying the regulation of auxin signaling pathways in cucumber, and will be valuable in the development of an ideal plant type. PMID- 30421570 TI - The inferior occipital gyrus is a major cortical source of the face-evoked N170: Evidence from simultaneous scalp and intracerebral human recordings. AB - The sudden onset of a face image leads to a prominent face-selective response in human scalp electroencephalographic (EEG) recordings, peaking 170 ms after stimulus onset at occipito-temporal (OT) scalp sites: the N170 (or M170 in magnetoencephalography). According to a widely held view, the main cortical source of the N170 lies in the fusiform gyrus (FG), whereas the posteriorly located inferior occipital gyrus (IOG) would rather generate earlier face selective responses. Here, we report neural responses to upright and inverted faces recorded in a unique patient using multicontact intracerebral electrodes implanted in the right IOG and in the OT sulcus above the right lateral FG (LFG). Simultaneous EEG recordings on the scalp identified the N170 over the right OT scalp region. The latency and amplitude of this scalp N170 were correlated at the single-trial level with the N170 recorded in the lateral IOG, close to the scalp lateral occipital surface. In addition, a positive component maximal around the latency of the N170 (a P170) was prominent above the internal LFG, whereas this region typically generates an N170 (or "N200") over its external/ventral surface. This suggests that electrophysiological responses in the LFG manifest as an equivalent dipole oriented mostly along the vertical axis with likely minimal projection to the lateral OT scalp region. Altogether, these observations provide evidence that the IOG is a major cortical generator of the face-selective scalp N170, qualifying the potential contribution of the FG and questioning a strict serial spatiotemporal organization of the human cortical face network. PMID- 30421571 TI - Effect of technetium-99 conjugated with methylene diphosphonate (99 Tc-MDP) on OPG/RANKL/RANK system in vitro. AB - BACKGROUND: RANKL and RANK play an important role in jaw resorption during the development of the ameloblastomas. Therefore, the aim of this study was to explore the effect of 99 Tc-MDP on OPG/RANKL/RANK system on RAW264.7 and MC3T3-E1 cell lines in vitro, and provide the theoretical basis for the clinical treatment of the jaw ameloblastoma. METHODS: Different concentrations of 99 Tc-MDP were used to treat RAW264.7 and MC3T3-E1 cell lines. The cell proliferative inhibition rate was analyzed by CCK-8. Cell apoptosis and cell cycle were detected by flow cytometry. Western blot were used to detect the expression of OPG, RANKL and RANK. RESULTS: Treatment of RAW264.7 cell lines with different concentrations of 99 Tc-MDP had inhibitory effects and decreased the expression of RANK protein. The cell proliferation of 99 Tc-MDP on MC3T3-E1cell lines was stronger at 48h than at 24h except for 100MUg/ml concentration group. Compared with the concentration of 0.01MUg/ml, the treatment of MC3T3-E1 cells with 100MUg/ml 99 Tc MDP showed that the cell proliferative effect decreased at 24h and 48h (P<0.05). After treatment with 0.01MUg/ml 99 Tc-MDP, the expression of OPG in MC3T3-E1 cells was significantly increased (P<0.05). Compared with 0.01MUg/ml, the expression of RANKL was decreased after treatment with 100MUg/ml 99 Tc-MDP (P<0.05). CONCLUSION: 99 Tc-MDP can induce apoptosis of RAW264.7 cells and inhibit the expression of RANK protein. The effect of 0.01MUg/ml of low concentration of 99 Tc-MDP can promote the proliferation of MC3T3-E1 cells and increase the expression of OPG and RANKL protein. 99 Tc-MDP may have adjuvant therapeutic effects on the treatment of jaw ameloblastoma. This article is protected by copyright. All rights reserved. PMID- 30421572 TI - Gene cluster conservation identifies melanin and perylenequinone biosynthesis pathways in multiple plant pathogenic fungi. AB - Perylenequinones are a family of structurally related polyketide fungal toxins with nearly universal toxicity. These photosensitizing compounds absorb light energy which enables them to generate reactive oxygen species that damage host cells. This potent mechanism serves as an effective weapon for plant pathogens in disease or niche establishment. The sugar beet pathogen Cercospora beticola secretes the perylenequinone cercosporin during infection. We have shown recently that the cercosporin toxin biosynthesis (CTB) gene cluster is present in several other phytopathogenic fungi, prompting the search for biosynthetic gene clusters (BGCs) of structurally similar perylenequinones in other fungi. Here, we report the identification of the elsinochrome and phleichrome BGCs of Elsinoe fawcettii and Cladosporium phlei, respectively, based on gene cluster conservation with the CTB and hypocrellin BGCs. Furthermore, we show that previously reported BGCs for elsinochrome and phleichrome are involved in melanin production. Phylogenetic analysis of the corresponding melanin polyketide synthases (PKSs) and alignment of melanin BGCs revealed high conservation between the established and newly identified C. beticola, E. fawcettii, and C. phlei melanin BGCs. Mutagenesis of the identified perylenequinone and melanin PKSs in C. beticola and E. fawcettii coupled with mass spectrometric metabolite analyses confirmed their roles in toxin and melanin production. This article is protected by copyright. All rights reserved. PMID- 30421573 TI - Implementation of HPV-based cervical cancer screening in an organised regional screening programme: 3 years of experience. AB - OBJECTIVE: The aim of this study was to evaluate the performance of human papillomavirus (HPV)-based screening in the framework of an organised cervical cancer screening programme. METHODS: A total of 46 708 women aged 35-60 years invited to the regional cervical cancer screening programme from 1 January 2012, to 31 December 2014, were enrolled. Overall, 17 770 women were screened by the Abbot RealTime hrHPV test with cytology triage and 15 605 were screened by conventional (Papanicolaou, Pap) cytology. In both groups, women with at least low-grade squamous intraepithelial lesions were referred directly for colposcopy, whereas HPV-positive women with borderline or normal cytology were invited to intensified screening in the following year. In the Pap group, the indication for intensified follow-up was borderline cytology. RESULTS: The attendance rate was similar in the HPV and Pap groups (72% and 71%, respectively). Overall, 6.0% of women in the HPV group vs 6.4% in the Pap group were referred to intensified follow-up (relative risk 0.94, 95% confidence interval [CI]: 0.87-1.03). At the index screening years, the relative sensitivity of the HPV test with cytology triage vs conventional screening was 1.64 (95% CI: 1.05-2.55) for CIN2+ and 2.06 (95% CI: 1.17-3.41) for CIN3+. The specificity of the hrHPV test with cytology triage for CIN2+ and CIN3+ was equal to that of the Pap screening (99.2% vs 99.2% for CIN2+ and 99.1% vs 99.1% for CIN3+). CONCLUSIONS: Due to its high sensitivity and specificity, primary hrHPV testing with cytology triage seems to be acceptable for cervical cancer screening in an organised setting. PMID- 30421574 TI - Fe, N-codoped Graphdiyne Displaying Efficient Oxygen Reduction Reaction Activity. AB - On account of the high-cost of platinum, researchers are working to develop a new catalyst which is cheaper and has a catalytic effect that is equivalent to platinum. Herein, owing to the unique acetylenic bonds in the graphdiyne, the iron-nitrogen-doped graphdiyne (Fe-N-GDY) as a new promising nonprecious metal catalyst is developed with just a small amount of iron precursor to substitute for Pt-based catalysts. The as-synthesized Fe-N-GDY composited catalyst shows excellent catalytic performance with the onset potential of 0.94V versus RHE and limited current density of 5.4 mA cm-2. And it shows good resistance to methanol poisoning and stability in both acidic and alkaline electrolytes, which makes it the potential application in oxygen reduction reaction field. PMID- 30421575 TI - Stress responding and stress-related changes in cue reactivity in heavy smokers, problem gamblers, and healthy controls. AB - Addictions, both substance and behavioral, have been conceptualized as involving similar biopsychosocial processes with different opportunistic expressions. A maladaptive stress response in combination with craving or urges to engage in the addictive behavior may be among the underlying factors common to behavioral and substance addictions. The current study compared the neuroendocrine (cortisol) and subjective responses to stress of gamblers and smokers to healthy controls. We assessed if participants responded differently to smoking or gambling cues before and after a psychosocial stressor. To this end, the subjective urges/cravings of all participants were measured in response to smoking or gambling cues versus neutral cues, once under normal conditions and again after exposure to a stressor. Salivary cortisol was measured prior to, immediately following, and 10 minutes after conclusion of the stressor. Smokers and gamblers showed a similar blunted cortisol response to the acute stressor that differed from the control group's response. Following a stressor, subjective craving in smokers increased whereas gamblers' urges decreased. In smokers, a blunted cortisol and subjective stress response were related to increased urges. In contrast, for gamblers, changes in cortisol levels were unrelated to urges, and higher subjective stress was associated with decreased urges. In conclusion, individuals with a substance and a behavioral addiction share common patterns of reactivity to stress. However, while the stressor enhanced cue-related craving in smokers, it generally had the opposite effect on gamblers. Further research is necessary to elucidate the complicated patterns of similarities and differences that underlie substance and behavioral addictions. PMID- 30421576 TI - Analysis of the chromatin binding affinity of retrotransposases reveals novel roles in diploid and tetraploid cotton. AB - LTR-retrotransposable elements are major components of diploid (Gossypium arboreum) and tetraploid (Gossypium hirsutum) cotton genomes that have undergone dramatic increases in copy number during the course of evolution. However, little is known about the biological functions of LTR-retrotransposable elements in cotton. Here, we show that a copia-like LTR-retrotransposable element has maintained considerable activity in both G. arboreum and G. hirsutum. We identified two functional domains of the retrotransposon and analyzed their expression levels in various cotton tissues, including leaves, ovules, and germinating seeds. ChIP-qPCR (chromatin immunoprecipitation followed by quantitative PCR), using a copia-specific antibody, established that copia-like proteins primarily bind to the first exons of several protein-coding genes in cotton cells. This finding suggests that retrotransposons play a novel, important role in regulating the transcriptional activities of protein-coding genes with various biological activities. PMID- 30421577 TI - Questionnaire study of the dietary habits of breast cancer survivors and their relationship to quality of life (KROG 14-09). AB - We evaluated the dietary habits of breast cancer survivors and investigated the relationship with quality of life (QoL), with 1,156 survivors recruited from 17 institutions. We used the Questionnaire Survey of Dietary Habits of Korean Adults (Q-DH-KOR) comprising 25 questions. The following indices were derived as follows: (1) quality of healthy dietary habits (Q-HD)-eight questions on number of meals, regularity, quantity, duration, skipping breakfast, dinner with companion(s), overeating and late-night snacks; (2) habits of nutritional balance (H-NB)-questions on consuming five food categories (grains, fruits, proteins, vegetables and dairy products); and (3) habits of unhealthy foods (H-UF) questions on consuming three food categories (fatty, instant and fast foods). The times and regularity of meals, frequency of skipping breakfast, dinner with companion(s) and overeating were better in groups with high symptomatic and functional QoL. Symptomatic QoL positively affected Q-HD and H-NB (p < 0.001 and p = 0.024 respectively) and negatively affected H-UF (p = 0.02). Breast cancer survivors more frequently ate from the fruit, protein and vegetable categories than did the control group, with lower H-UF and higher Q-HD values (p < 0.001 and p < 0.001 respectively). Our findings supported the relationship between QoL and dietary habit and showed healthier dietary habits of breast cancer survivors than controls. PMID- 30421578 TI - Treatment and outcome of patients with thoracic tumors of the Ewing sarcoma family: A report from the Cooperative Weichteilsarkom Studiengruppe CWS-81, -86, 91, -96, and -2002P trials. AB - BACKGROUND: Ewing tumors are the most frequent malignant tumors of the chest wall in children and young adults. Surgical management of these tumors can be challenging. Optimal local control remains controversial. The aim of this study was to analyze treatment, outcome, and surgical procedures in patients with thoracic tumors of the Ewing sarcoma family (TES) treated within four Cooperative Soft-Tissue Sarcoma (CWS) trials and one registry. PATIENTS AND METHODS: Sixty two patients from 0 to 21 years treated between 1981 and 2014 were selected for this analysis. A retrospective chart analysis was carried out. Institutional review board approval was obtained for all trials. RESULTS: The median age of the patients was 7 years. The 5-year overall (OS) and event-free survival (EFS) rates were 58.7% (52.7-64.7) and 52.8% (46.8-58.8). Patients with intrathoracic tumor localization (n = 24) had a worse outcome (EFS: 37.5%; 27.5-37.5) compared with those with chest wall tumors (n = 38; EFS: 62.3%; 54.3-70.3, P = 0.008). Patients <=10 years (n = 38) had a better survival compared with those > 10 years (EFS: 65.7%; 57.7-73.7 vs 31.3%; 21.3-41.3, P = 0.01). Tumor size <=5 cm (n = 15) was associated with significantly better survival compared with a size > 5 cm (n = 47, EFS: 93.3%; 87.3-99.3 vs 40%; 33-47, P = 0.002). Primary resections were carried out in 36 patients, of which 75% were incomplete resulting in inferior EFS (P = 0.006). Complete secondary resections were performed in 22 of 40. CONCLUSIONS: Positive predictive factors for outcome are age <=10 years, size <=5 cm, and localization at the chest wall. Diverse IRS groups require individual treatment. PMID- 30421580 TI - Impact of local endometrial injury on in vitro fertilization/intracytoplasmic sperm injection outcomes: A systematic review and meta-analysis. AB - AIM: Recent studies have revealed positive effects of endometrial injury on clinical pregnancy rates, but with inconsistent results. The aim of this meta analysis was to assess the efficacy of endometrial injury (biopsy and/or hysteroscopy) as a potential treatment measure for implantation failure in the in vitro fertilization population. METHODS: We searched in PubMed for studies comparing the efficacy of endometrial injury versus no intervention in women with at least one implantation failure. A random-effects model was used to evaluate the clinical pregnancy rate (CPR) and the live birth rate (LBR). RESULTS: Seventeen studies (11 randomized and 6 non-randomized studies) were included in this meta-analysis, including 1864 women in the intervention group and 2193 women in the control group. Overall, the CPR and LBR were significantly higher in the intervention group than in the control group (for CPR, n = 3997, 16 studies, P < 0.00001, risk ratio (RR) = 1.47, 95% confidence interval [CI] [1.24, 1.74]; for LBR, n = 2361, 11 studies, P = 0.003, RR = 1.41, 95% CI [1.12, 1.78]). However, after excluding the non-randomized studies, there was no significant difference in CPR (P = 0.29 for endometrial biopsy, P = 0.05 for hysteroscopy) and LBR (P = 0.23 for endometrial biopsy, P = 0.39 for hysteroscopy) between the intervention group and the control group. CONCLUSION: There is still insufficient evidence to support the use of endometrial injury in women with implantation failure. Robust randomized controlled studies should be designed and performed before clinical implementation of endometrial injury. PMID- 30421579 TI - PSMD12 haploinsufficiency in a neurodevelopmental disorder with autistic features. AB - Protein homeostasis is tightly regulated by the ubiquitin proteasome pathway. Disruption of this pathway gives rise to a host of neurological disorders. Through whole exome sequencing (WES) in families with neurodevelopmental disorders, we identified mutations in PSMD12, a core component of the proteasome, underlying a neurodevelopmental disorder with intellectual disability (ID) and features of autism spectrum disorder (ASD). We performed WES on six affected siblings from a multiplex family with ID and autistic features, the affected father, and two unaffected mothers, and a trio from a simplex family with one affected child with ID and periventricular nodular heterotopia. We identified an inherited heterozygous nonsense mutation in PSMD12 (NM_002816: c.367C>T: p.R123X) in the multiplex family and a de novo nonsense mutation in the same gene (NM_002816: c.601C>T: p.R201X) in the simplex family. PSMD12 encodes a non-ATPase regulatory subunit of the 26S proteasome. We confirm the association of PSMD12 with ID, present the first cases of inherited PSMD12 mutation, and demonstrate the heterogeneity of phenotypes associated with PSMD12 mutations. PMID- 30421581 TI - A rapid scoping review of Middle East respiratory syndrome coronavirus in animal hosts. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging zoonotic pathogen discovered in 2012. The purpose of this scoping review was to summarize the empirical evidence for MERS-CoV in animals in order to map knowledge gaps and to extract data for modelling disease transmission in dromedary camels. A review protocol was developed a priori, and a systematic search, data extraction and summary were conducted using the Arksey and O'Malley framework. Ninety-nine publications were identified for full review out of 1,368 unique records. Of these publications, 71 were articles in scientific journals. Ninety of the studies were observational and the remaining nine were experimental. We summarize characteristics of animal studies including study design, study population and outcomes of interest for future transmission modelling in the reservoir population. The majority of field studies reported measures of prevalence, while experimental studies provided estimates of transmission parameters that pertain to the natural course of disease. PMID- 30421582 TI - Recognition of dominant attractants by key chemoreceptors mediates recruitment of plant growth-promoting rhizobacteria. AB - Chemotaxis to plant root exudates is supposed to be a prerequisite for efficient root colonization by rhizobacteria. This is a highly multifactorial process since root exudates are complex compound mixtures of which components are recognized by different chemoreceptors. Little information is available as to the key components in root exudates and their receptors that drive colonization related chemotaxis. We present here the first global assessment of this issue using the plant growth-promoting rhizobacterium (PGPR) Bacillus velezensis SQR9 (formerly B. amyloliquefaciens). This strain efficiently colonizes cucumber roots and here we show that chemotaxis to cucumber root exudates was essential in this process. We conducted chemotaxis assays using cucumber root exudates at different concentrations, individual exudate components as well as recomposed exudates, taking into account their concentrations detected in root exudates. Results indicated that two key chemoreceptors, McpA and McpC, were essential for root exudate chemotaxis and root colonization. Both receptors possess a broad ligand range and recognize most of the exudate key components identified (malic, fumaric, gluconic, and glyceric acids, Lys, Ser, Ala, and mannose). The remaining 6 chemoreceptors did not contribute to exudate chemotaxis. This study provides novel insight into the evolution of the chemotaxis system in rhizobacteria. This article is protected by copyright. All rights reserved. PMID- 30421583 TI - Characterization of the novel HLA-DRB5*02:21 allele by sequencing-based typing. AB - HLA-DRB5*02:21 differs from HLA-DRB5*02:02:01 by one nucleotide substitution at codon 203 in exon 4. PMID- 30421584 TI - Characterization of the novel HLA-A*30:135 allele by sequencing-based typing. AB - HLA-A*30:135 differs from HLA-A*30:01:01 by one nucleotide substitution at codon 304 in exon 5. PMID- 30421586 TI - Assessing Hemorrhagic Shock: Feasibility of Using an Ultracompact Photoacoustic Microscope. AB - Hemorrhagic shock, as an important clinical issue, is regarding as a critical disease with a high mortality rate. Unfortunately, existing clinical technologies are inaccessible to assess the hemorrhagic shock via hemodynamics in microcirculation. Here, we propose an ultracompact photoacoustic microscope to assess hemorrhagic shock using a rat model and demonstrate its clinical feasibility by visualizing buccal microcirculation of healthy volunteers. Both functional and morphological features of the microvascular network including concentration of total hemoglobin (CHbT ), number of blood vessels (VN), small vascular density (SVD) and vascular diameter (VD) were derived to assess the microvascular hemodynamics of different organs. Animal studies show the feasibility of the proposed tool to assess and stage the hemorrhagic shock via microcirculation. In vivo oral imaging of healthy volunteers indicates the translational possibility of this technique for clinical evaluation of hemorrhagic shock. This article is protected by copyright. All rights reserved. PMID- 30421585 TI - ce-Subpathway: Identification of ceRNA-mediated subpathways via joint power of ceRNAs and pathway topologies. AB - Competing endogenous RNAs (ceRNAs) represent a novel mechanism of gene regulation that may mediate key subpathway regions and contribute to the altered activities of pathways. However, the classical methods used to identify pathways fail to specifically consider ceRNAs within the pathways and key regions impacted by them. We proposed a powerful strategy named ce-Subpathway for the identification of ceRNA-mediated functional subpathways. It provided an effective level of pathway analysis via integrating ceRNAs, differentially expressed (DE) genes and their key regions within the given pathways. We respectively analysed one pulmonary arterial hypertension (PAH) and one myocardial infarction (MI) data sets and demonstrated that ce-Subpathway could identify many subpathways whose corresponding entire pathways were ignored by those non-ceRNA-mediated pathway identification methods. And these pathways have been well reported to be associated with PAH/MI-related cardiovascular diseases. Further evidence showed reliability of ceRNA interactions and robustness/reproducibility of the ce Subpathway strategy by several data sets of different cancers, including breast cancer, oesophageal cancer and colon cancer. Survival analysis was finally applied to illustrate the clinical application value of the ceRNA-mediated functional subpathways using another data sets of pancreatic cancer. Comprehensive analyses have shown the power of a joint ceRNAs/DE genes and subpathway strategy based on their topologies. PMID- 30421587 TI - Catalytic characteristics of a sn-1(3) regioselective lipase from Cordyceps militaris. AB - A total of 39 agricultural products were screened for natural sources of lipases with distinctive positional specificity. Based on this, Cordyceps militaris lipase (CML) was selected and subsequently purified by sequential chromatography involving anion-exchange, hydrophobic-interaction, and gel-permeation columns. As a result of the overall purification procedure, a remarkable increase in the specific activity of the CML (4.733 U/mg protein) was achieved, with a yield of 2.47% (purification fold of 94.54). The purified CML has a monomeric structure with a molecular mass of approximately 62 kDa. It was further identified as a putative extracellular lipase from C. militaris by the partial sequence analysis using ESI-Q-TOF MS. In a kinetic study of the CML-catalyzed hydrolysis, the values of Vmax , Km , and kcat were determined to be 4.86 MUmol.min-1 .mg-1 , 0.07 mM, and 0.29 min-1 , respectively. In particular, the relatively low Km value indicated that CML has a high affinity for its substrate. With regard to positional specificity, CML selectively cleaved triolein at the sn-1 or 3 positions of glycerol backbone, releasing 1,2(2,3)-diolein as the major products. Therefore, CML can be considered a distinctive biocatalyst with sn-1(3) regioselectivity. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 2018. PMID- 30421588 TI - Clinical Course and Treatment Response of Neuromyelitis Optica Spectrum Disease: An 8-Year Experience. AB - PURPOSE: To report the clinical course and treatment response in a cohort of neuromyelitis optica spectrum disorder (NMOSD) patients from a single referral center. DESIGN: Case series. METHODS: Ninety-six NMOSD patients who received treatment and follow-up checks at National Taiwan University Hospital for at least 2 years between 2008 and 2016 were recruited. Detailed characteristics of clinical course including acute episodes, maintenance therapies, and visual outcome were collected. Patients were examined every 6 months and during each episode of relapse. The study was approved by the institutional review board and informed consent was obtained. RESULTS: Among all patients, 68 (70.8%) had optic neuritis. Optic neuritis was the initial presentation of NMOSD in 44 patients. Among patients with optic neuritis, 32.4% had recurrent optic neuritis within 1 year from the first episode. Compared with the group without optic neuritis, the group with optic neuritis had a younger age of presentation (34.4 +/- 15.9 versus 42.4 +/- 14.7 years, P = 0.02) and a higher 1-year recurrence rate (64.7% versus 17.9%, P < 0.001). Among the patients with optic neuritis, 51.5% of patients had a final visual acuity of worse than 20/200. Multiple regression analysis showed that the presence of aquaporin-4-IgG antibodies and poor initial visual acuity were risk factors of worse visual outcome. CONCLUSIONS: In this study, patients with optic neuritis were younger and had a higher 1-year recurrence rate. Despite using steroid therapy during the acute phase and immunosuppressive agents as long term treatment, visual prognosis was poor. Aquaporin-4-IgG antibodies and initial visual acuity were associated with final visual outcome. PMID- 30421589 TI - The History of Exfoliation Syndrome. AB - The first description of exfoliation syndrome (XFS) was presented by John Gustaf Lindberg in his doctoral thesis 100 years ago. The syndrome is an age-related disorder in which abnormal fibrillar extracellular material is produced and accumulates in several ocular tissues. Once thought to be peculiar to Scandinavia, XFS is found in almost every race and ethnic group. Subsequent studies provided evidence for the systemic nature of XFS, which involves an aberrant connective tissue metabolism throughout the body. There is a prominent association with zonular instability. This study presents the developments in the understanding of the pathomechanism and clinical significance of XFS and explains the problem of terminology in the description of XFS and pseudoexfoliation. PMID- 30421590 TI - Role of apparent diffusion coefficient values in prostate diseases characterization on diffusion-weighted magnetic resonance imaging. AB - BACKGROUND: To evaluate if normal and pathological prostate tissue can be distinguished by using apparent diffusion coefficient (ADC) values on magnetic resonance imaging (MRI) and to understand if it is possible to differentiate among pathological prostate tissues using ADC values. METHODS: Our population consisted in 81 patients (mean age 65.4) in which 84 suspicious areas were identified. Regions of interest were placed over suspicious areas, detected on MRI, and over areas with normal appearance, and ADC values were recorded. Statistical differences between ADC values of suspicious and normal areas were evaluated. Histopathological diagnosis, obtained from targeted biopsy using MRI US fusion biopsies in 39 patients and from prostatectomy in 42 patients, were correlated to ADC values. RESULTS: Histopathological diagnosis revealed 58 cases of prostate cancer (PCa), 19 patients with indolent PCa (Gleason score <= 6) and 39 patients with clinically significant PCa (Gleason score >=7), 16 of high-grade prostatic intraepithelial neoplasia (HG-PIN) and 10 of atypical small acinar proliferation (ASAP). Significant statistical differences between mean ADC values of normal prostate tissue versus PCa (p-value: < .00001), HG-PIN (p-value: < .00001.) and ASAP (p-value < .00001) were found. Significant differences were observed between mean ADC values of PCa versus HG-PIN (p-value: < .00001) and ASAP (p-value : < .00001.) with many overlapping values. Differences between mean ADC values of HG-PIN versus ASAP (p-value: .015) were not significant. Significant differences of ADC values were also observed between patients with indolent and clinically significant PCa (p-value: < .00001). CONCLUSIONS: ADC values allow differentiation between normal and pathological prostate tissue and between indolent and clinically significant PCa but do not allow a definite differentiation between PCa, HG-PIN and ASAP. PMID- 30421591 TI - Small cell carcinoma of the upper urinary tract and factors associated with progress survival: a systematic review and pooled analysis. AB - INTRODUCTION: Little is known about the small cell carcinoma of the upper urinary tract (UUT-SCC), the aim of this study is to identify the risk factors in relation to survival of patients with UUT-SCC. EVIDENCE ANALYSIS: Literature search on UUT-SCC was performed in databases including MEDLINE, EMBASE, Wangfang, and CNKI. Studies were eligible for inclusion if outcomes of patients with histopathologically confirmed UUT-SCC were reported. The relevant data on clinic, pathology, and therapy were collected. Progress survival was evaluated using the Cox regression model with the robust sandwich estimates of the covariance matrix. EVIDENCE SYNTHESIS: There were 55 eligible publications identified, contributing 76 patients in total. The median of overall survival (OS) was 14 months. In univariable analyses, pathological stage and platinum-based chemotherapy regimen were associated with OS (pT3-pT4 versus pT1-pT2, HRs=3.228, P=0.005; other chemotherapies versus platinum-based, HRs=6.249, p=0.035). The median of cancer specific survival (CSS) was 15 months. In univariable analyses, pathological stage and platinum-based chemotherapy regimen were associated with CCS (pT3-pT4 versus pT1-pT2, HRs=3.332, P=0.004; non-platinum based versus platinum-based, HRs=7.784, p=0.025). CONCLUSIONS: In multivariable analyses, no variables were associated with OS and CSS. UUT-SCC is a rare tumor characterized by an aggressive clinical course. Pathological stage and platinum-based chemotherapy regimen are the most important factors related to OS and CSS. PMID- 30421592 TI - Surgical management of a rare case of giant penile cancer. AB - Primary penile cancer is a rare malignant disease. In most cases, it presents as a clinically obvious lesion leading to early diagnosis in most patients. However, even in developed Countries, it carries a significant social stigma leading to diagnosis at locally advanced stages in a non-negligible proportion of patients. Yet, bulky penile lesions are becoming extremely rare in current clinical practice. We present a case of a patient with a giant primary penile cancer managed with radical penectomy, bilateral inguinal lymphadenectomy and perineal urethrostomy, who experienced disease recurrence 6 months after surgery and died with metastatic disease after denial of further treatment. The management of our case was challenging due to the extremely late diagnosis, the huge dimensions and the infiltrative nature of the tumour; however, from a histopathological perspective, the cancer itself did not display any microscopic peculiarity. Our case highlights that such bulky penile tumors can still occur in current urologic practise and require complex salvage surgical interventions in the context of a multidisciplinary setting. PMID- 30421593 TI - Phase I study of a new tablet based image guided surgical system in robotic assisted radical prostatectomy. AB - Robotic assisted radical prostatectomy is, currently, the most commonly utilized procedure for the treatment of localized prostate cancer. Image-guided surgical systems have been proposed in the literature as a valuable tool for the better utilization of the preoperative data in theatre. In this Phase 1 trial, we tested the feasibility and safety of a new, cutting - edge tablet based surgical imaging system designed for Robotic assisted radical prostatectomy (RARP). It utilizes the preoperative MRI images of the prostate, mapping them intra-operatively, real time to the patient by magnetic tracking to fixed points of the pelvis. The system is comprised of a tablet computer with a touch screen display; a tracking system housed in a portable cart, a magnetic field generator and position sensors. It updates image data over 20 times per second to compensate with anatomical alterations during the operation. 4 patients diagnosed with prostate adenocarcinoma were enrolled in this study. All 4 patients had negative surgical margins along with satisfactory functional recovery regarding continence and potency. The navigational accuracy and the real time information provided by the imaging system was mainly utilized in the more challenging parts of the operation including the apical dissection, the nerve sparing procedure and the bladder neck dissection. The system proved to be safe and its clinical efficacy is due to be assessed with a Phase II clinical study. PMID- 30421594 TI - R.U.G. technique: replacement of the ureter with gonadal vein. A cadaveric study. AB - BACKGROUND: Ureteral defect lesions may result from retroperitoneal fibrosis, radiation damage, tumors, or surgical procedures; the management of long-segment ureteral defects is a challenge for urologists. Total or partial replacement of the ureter is sometimes required, with consequent ileal interposition, but this technique may lead to several complications, such as severe urinary infections. In a few cases, nephrectomy may be required. Starting from the above considerations, we can postulate the RUG technique (Replacement of the Ureter with Gonadal vein), using the Gonadal Vein (GoV) as an autologous graft to substitute the ureter. For this reason, we decided to test this novel idea on an experimental model. METHODS: We tested the above technique on a cadaveric model, performing complete procedure (RUG #1), segmental replacement of the ureter (RUG #2), and ureteroplasty with a GoV patch (RUG #3). All the procedures involved an open approach. After RUG #3, the treated segment of the ureter was sampled for histologic analysis. RESULTS: Four RUGs were performed (two RUG #1, one RUG #2, one RUG #3). All anatomic structures were easily identified, and all procedures were completed successfully. The dimensions of the ureters were comparable to those of the GoV in all cases, as usual. Histologic analysis demonstrated perfect adherence of the two anastomosed structures. CONCLUSIONS: The RUG technique resulted in an adequate, safe and easy-to-perform surgical alternative. PMID- 30421595 TI - Cold ischemia technique during robotic partial nephrectomy: a propensity score matched comparison with open approach. AB - BACKGROUND: Open ice slush for renal cooling during partial nephrectomy (PN) has been reproduced during robotic PN (RPN). The aim of this study is to compare the perioperative and functional outcomes between RPN and open PN (OPN) using a cold ischemia technique. METHODS: Consecutive patients undergoing PN using cold ischemia technique were extracted from our prospectively-maintained database (2007-2016). RPN and OPN patients were 1:2 propensity-score (PS) matched via a greedy algorithm. The balance of the baseline variables was checked for the matched cohorts. Perioperative and functional outcomes were compared. RESULTS: 51 RPN and 334 OPN using cold ischemia were extracted. After PS adjustments, 51 RPN vs 102 OPN with no significant differences in baseline features were compared. Regarding preoperative outcomes, blood loss (100 mL [IQR 50; 200] vs 260 mL [IQR 200; 350], < 0.001), postoperative complications rate (10 patients (19.6%) vs 38 patients (37.3%), p = 0.027) and hospital stay (3 days [IQR 2; 4] vs 5 days [IQR 4; 6], p < 0.001) favored RPN. Renal functional outcomes were comparable at repeated measures analysis. CONCLUSIONS: In our experience, cold ischemia technique can be effectively reproduced during RPN, with a potential advantage in terms of blood loss, complications rate and hospital stay over the traditional OPN procedure. PMID- 30421596 TI - Intraoperative assessment of ureteral and graft reperfusion during robotic kidney transplantation with indocyanine green fluorescence videography: a pilot study and systematic review of the literature. AB - BACKGROUND: To report the first preliminary experience with intraoperative indocyanine green (ICG) fluorescence videography (IFV) to assess graft and ureteral reperfusion during robot-assisted kidney transplantation (RAKT). METHODS: We prospectively collected data from consecutive patients undergoing RAKT and IFV from living-donors at our Institution between January 2017 and April 2018. RAKT was performed following the principles of the Vattikuti-Medanta technique. ICG was injected intravenously after vascular anastomoses to quantitate graft and ureteral fluorescence signal. The signal intensity within selected intraoperative snapshots was evaluated for renal parenchyma, ureter and vascular anastomoses. A systematic review of the English-language literature about the topic was performed according to the PRISMA statement recommendations. RESULTS: Six patients were included. Neither conversions to open surgery nor major intra- or postoperative complications were recorded. At a median follow-up of 12 months (IQR 8-13), median estimated glomerular filtration rate was 64.2 ml/min/1,73m2 (IQR 45.3 - 98.4). Intraoperative quantitative assessment of ICG fluorescence was successful in all patients. Of the 5 studies selected by our review, most were prospective and all included open KT series. Yet, most studies were limited by lack of quantitative measures of IFV fluorescence. CONCLUSIONS: IFV during RAKT is feasible and safe and provides a reliable assessment of graft reperfusion. Larger studies are needed to standardize the technique and to evaluate the association between fluorescence signal, ultrasound parameters and postoperative kidney function. PMID- 30421597 TI - The role of side-specific biopsy and dominant tumor location at radical prostatectomy in predicting the side of nodal metastases in organ confined prostate cancer: is lymphatic spread really unpredictable? AB - BACKGROUND: The aim of this study was to evaluate the correlation between the location of prostate cancer (PCa) either at biopsy or at radical prostatectomy (RP) specimens and the side of positive lymph nodes (LNs). Furthermore, we assessed the risk of contralateral LN metastasis (LNMs) in patients with unilateral positive biopsy and/or dominant lesion at RP. METHODS: We reviewed retrospectively our prospectively maintained database of patients with LNM treated with robot assisted RP and bilateral robot-assisted extended pelvic lymph node dissection (EPLND) for PCa from January 2014 to May 2018 at a surgical high volume center. All men with a suspicion for PCa underwent a 12-cores prostate biopsy. In case of a first negative biopsy but the persistence of suspicion, all the patients underwent prostate multiparametric magnetic resonance imaging (mpMRI) and subsequently either fusion targeted biopsy (TBx) or systematic standard biopsy (SBx), in case of positive or negative mpMRI, respectively. All patients underwent a robot-assisted RP. Whole-mount histological sections resected from the RP specimens were used as reference standards. RESULTS: Eighty seven patients were enrolled for the study. Median number of LNs retrieved per patient was 26, specifically 13 and 12, on the left and right side, respectively. Seven of 24 (29.1%) right lobe positive biopsy showed positive LNs on the left side (one exclusively left, 6 bilateral LNMs). Again, 12 of 26 (46.1%) left lobe positive biopsy showed positive LNs on the right side (one exclusively right, 11 bilateral LNMs). No significant differences of performance to predict the side of LNMs were recorded in the SBx and TBx groups. Concerning RP specimens, only five of 22 (22.7%) right lobe dominant cases showed positive LNs on the left side (two exclusively left, 3 bilateral LN metastases). Again, none of 16 left lobe dominant cases showed positive LNs on the contralateral side (15 exclusively right, 1 bilateral LNMs). CONCLUSIONS: Our results suggest confirmed that a unilateral LN dissection limited to the tumor-bearing side of the gland evaluated by biopsy specimens should not be recommended due to the substantial risk of missing contralateral LNMs. PMID- 30421598 TI - BCG unresponsive in patients with NMIBC: what the urologists must know. A review of the current literature. AB - Transurethral resection of bladder (TURB) with adjuvant intravesical bacillus Calmette-Guerin (BCG) remains the gold standard therapy for intermediate and high risk non-muscle invasive bladder cancer (NMIBC). However, this disease is burdened with a high risk of recurrence or progression. For this reason, we sought to review and summarize the current evidence with a non-systematic Medline/Pubmed literature search, regarding optimal treatment in BCG-failure patients. Radical cystectomy (RC) should be considered as the preferred option in patients who experience a BCG-failure, especially in case of Ta or T1 high grade recurrence which occurred within 3 months of start-date of induction or in early intermediate BCG relapsing tumors or in case of recurrence after >= 1 maintenance course with a maintenance exposure >= 6 months. However, in BCG intolerant patients and in patients unfit or who refuse RC, alternative treatments can be proposed. In particular in BCG intolerant patients a reduction of dwell-time, an increase of length of intervals between the doses, use of anti-inflammatory drugs and antibiotics can be practiced for reducing symptoms. In patients with a low intermediate grade recurrence for primary intermediate-risk tumor or for CIS disease after a single course of induction, a second induction course of BCG (but not further) can be performed. Intravesical chemotherapeutic agents are considered suboptimal but can be proposed in patients unfit or who refuse RC. On the contrary, combination chemotherapy is not indicated in BCG-failure patients. Several ongoing trials are testing with promising prospects the efficacy of cytotoxic agents, immunotherapeutic agents, target therapies, devices and other molecules in BCGfailure patients. PMID- 30421599 TI - Laser Annealing of TiO2 Electron-Transporting Layer in Perovskite Solar Cells. AB - Solution-processed TiO2 and other metal-oxide electron-transporting layers (ETLs) for perovskite solar cells commonly require high-temperature annealing (>450 degrees C), causing the underlying indium-tin oxide (ITO) to degrade and inhibiting the use of flexible plastic substrates, such as poly(ethylene naphthalate). Laser-based solar cell manufacturing is attracting increased interest and can enable rapid and low-temperature fabrication of perovskite solar cells. By using novel pulsed ultraviolet laser processing on the solution processed TiO2, we demonstrate a champion 17.1% efficient flexible perovskite solar cell. We can independently control the annealing of the ETL without affecting the underlying ITO or substrate due to the shallow absorption depth and short pulse duration of the laser. Ellipsometry and X-ray photoelectron spectroscopy verify that the laser-annealed TiO2 thin film is stoichiometric and relatively denser than the thermally annealed control sample. The efficiencies of the laser-processed devices exceeded those fabricated via hot plate, but with the added benefit of a high-throughput, low-temperature, and flexible-substrate friendly process. PMID- 30421600 TI - Trion-Inhibited Strong Excitonic Emission and Broadband Giant Photoresponsivity from Chemical Vapor-Deposited Monolayer MoS2 Grown in Situ on TiO2 Nanostructure. AB - 2D material-based heterostructures often prepared by wet transfer technique suffers from poor interface and contamination issues and it results in inferior device performance. Herein, we report an in situ chemical vapor deposition (CVD) growth of MoS2@TiO2 core-shell heterojunction with single-layer MoS2 (1L-MoS2) as the shell and 3D TiO2 nanoflower (NF) as the core for multifunctional optoelectronic applications. We explore a powerful approach to switch the trions in 1L-MoS2 into neutral excitons by developing a core-shell heterostructure with TiO2 and demonstrate a giant photoluminescence (PL) enhancement in the 1L-MoS2 shell. 3D TiO2 NFs with average diameter ~1 MUm are uniformly coated with 1L-MoS2 shell by in situ CVD technique, resulting in ~83- and ~30-fold enhancement in PL intensity at room temperature from the 1L-MoS2 shell on TiO2 NFs as compared to that of 1L-MoS2 grown on Ti and sapphire substrate, respectively. This high PL enhancement is attributed to the migration of excess electrons from MoS2 to TiO2, leading to a heavy p-doping in the MoS2 lattice, as evidenced by the Raman and X ray photoelectron spectroscopy analyses. Additionally, the formation of the core shell heterojunction facilitates the suppression of nonradiative recombination of the excitons even at the room temperature, as revealed from the low-temperature PL study. The charge transfer-induced p-doping effect in 1L-MoS2 is verified from the oxygen plasma treatment of the 1L-MoS2@Ti and it shows similar PL enhancement. Further, the 1L-MoS2@TiO2 p-n heterojunction is demonstrated as a high-performance broadband photodetector owing to its favorable band alignment and high absorption in the spectral range of 300-900 nm. The heterojunction photodetector exhibits a record high responsivity and detectivity of ~35.9 A W-1 and 1.98 * 1013 jones, respectively, in the UV region, and ~18.5 A W-1 and 1.09 * 1013 jones, respectively, in the visible region. As compared to the 1L-MoS2@Ti and 1L-MoS2@SiO2 with slow photoresponse, 1L-MoS2@TiO2 heterojunction exhibits more than 1 order of magnitude faster photoresponse (rise/fall time ~33.7/28.2 ms), which is attributed to the fast photogenerated carrier transport at the p-n heterojunction due to the large built-in electric field. This high-performance 1L MoS2@TiO2 core-shell heterojunction grown by a novel in situ CVD technique is promising for the cutting-edge optoelectronic applications. PMID- 30421601 TI - Higher Strength and Ductility than Diamond: Nanotwinned Diamond/Cubic Boron Nitride Multilayer. AB - Recently, the nanotwinned structure has attracted considerable attention because of unprecedented improvement in its mechanical properties, thermal stability, and other properties. Here, we introduce the nanotwinned structure between two superhard materials [diamond and cubic boron nitride (cBN)] and obtain a nanotwinned diamond/cBN multilayered material with ultrahigh strength and unprecedented ductility. Under continuous shear deformation, the stress and total energy in the material develop in a zigzag way because of atomic reconfiguration. Further research shows that atomic reconfiguration occurs preferentially in the cBN region, followed by that in the diamond region by partial slip, and finally occurs at the interface through alternate "exchange" of the positions of C and B atoms. This multilevel stress release model can account for the significant increase in the strain range and peak stress of nanotwinned materials. These results could provide available information for the design of superhard materials with multilevel resistance to plastic deformation. PMID- 30421602 TI - All-Metal Broadband Optical Absorbers Based on Block Copolymer Nanolithography. AB - The growing interest in solar energy during recent years has spurred on the development of high-efficiency optical absorbers using emerging concepts in plasmonics and metamaterials. Most absorber designs require patterning on a subwavelength scale, making large-scale fabrication expensive or impractical. This study presents an all-metal metasurface with tightly packed, sub-80 nm nanodomes fabricated by template-stripping thin gold films from reusable silicon templates. Subwavelength patterning was achieved via molecular self-assembly of block copolymers, which enables large-area, periodic patterning with nanometer precision. The proposed nanodome surface acts as an optical absorber capable of absorbing 97% of incident light in the visible range 320-650 nm, and still more than 90% at high incidence angles. We demonstrate both experimentally and theoretically that the absorption behavior of the thin film can be controlled by changing the size of the nanodomes, namely, the gap between the structures. The enhanced absorption of light is attributed to localized particle plasmon and gap plasmon resonances. This research provides a straightforward and cost-effective strategy to design and fabricate thin, large-area, light-absorbing coatings that can be transferred onto nearly any rigid or flexible substrate. The all-metal metasurfaces are a promising candidate for plasmon-induced hot electron generation for efficient solar energy conversion in photovoltaic and photocatalytic devices. PMID- 30421603 TI - Chitosan-Lysozyme Conjugates for Enzyme-Triggered Hydrogel Degradation in Tissue Engineering Applications. AB - Tuning hydrogel degradation enables effective and successful tissue regeneration by modulating cellular behaviors and matrix formation. In this work, we develop a novel degradable hydrogel scaffold on the basis of a unique enzyme-substrate complex by photocrosslinking. Chitosan and lysozyme are chemically modified with methacrylate moieties to be tethered in hydrogels, and in the presence of riboflavin initiator, these hydrogels are cured by blue light irradiation. The incorporation of lysozyme to chitosan hydrogels accelerates the degradation rate of the crosslinked hydrogels in a dose-dependent manner, as evidenced by an increase in pore size and interconnectivity through cryogenic scanning electron microscopy over time. Those noncytotoxic materials significantly enhance cellular proliferation and migration, which contribute to osteogenic differentiation of encapsulated mesenchymal stem cells in vitro and bone formation in mouse calvarial defects. These findings suggest a promising strategy to modulate the degradation behavior of hydrogels for use in tissue engineering. PMID- 30421604 TI - Chirality-Enabled Liquid Crystalline Physical Gels with High Modulus but Low Driving Voltage. AB - Self-supporting liquid crystalline physical gels with facile electro-optic response are highly desirable, but their development is challenging because both the storage modulus and driving voltage increase simultaneously with gelator loading. Herein, we report liquid crystalline physical gels with high modulus but low driving voltage. This behavior is enabled by chirality transfer from the molecular level to three-dimensional fibrous networks during the self-assembly of 1,4-benzenedicarboxamide phenylalanine derivatives. Interestingly, the critical gel concentration is as low as 0.1 wt %. Our findings open doors to understanding and exploiting the role of chirality in organic gels. PMID- 30421605 TI - IL-27 Production and Regulation in Human Dendritic Cells Treated with the Chemical Sensitizer NiSO4. AB - Allergic contact dermatitis (ACD) is a major cause of occupational skin disease, and nickel is among the most prevalent contact allergens. Dendritic cells (DC) play an important role in ACD and in the type of the ensuing immune response through differential phenotypes and cytokine production. The interleukin (IL)-12 cytokine family is composed of heterodimeric cytokines sharing homology at the subunit, receptors and signaling levels. We previously showed that nickel can upregulate the production of IL-12p40 and IL-23, both known to be pro inflammatory. In this work, we aimed to extend our knowledge on nickel regulation of the IL-12 cytokine family by focusing on IL-27, a recently identified immunomodulatory cytokine from this family. We showed that nickel induced the production of IL-27 in human monocyte-derived DC (MoDC), regulating IL-22 production by human CD4+ T cells. We also showed that nickel was able to induce the expression of the two subunits of IL-27: il-27p28 and ebi3. Furthermore, we demonstrated that the production of IL-27 was dependent on the TLR4, p38 MAPK, NF kappaB, and Jak-STAT signaling. However, IL-27 subunits were differentially regulated by these pathways. Indeed, both subunits were positively regulated by the TLR4 and NF-kappaB pathways, but only il-27p28 was also dependent on p38 MAPK and Jak-STAT pathways. Our results contribute to a better understanding of nickel induced ACD by focusing on the IL-12 cytokine family and elucidating the mechanism of IL-27 regulation in human dendritic cells. PMID- 30421606 TI - Modulating the Chemical Transport Properties of a Transmembrane Antiporter via Alternative Anion Flux. AB - ClC-ec1 is a prototype of the ClC antiporters, proteins that stoichiometrically exchange Cl- and H+ ions in opposite directions across a membrane. It has been shown that other polyatomic anions, such as NO3- and SCN-, can also be transported by ClC-ec1, but with partially or completely uncoupled proton flux. Herein, with the help of multiscale computer simulations in which the Grotthuss mechanism of proton transport (PT) is treated explicitly, we demonstrate how the chemical nature of these anions alters the coupling mechanism and qualitatively explain the shifts in the ion stoichiometry. Multidimensional free energy profiles for PT and the coupled changes in hydration are presented for NO3- and SCN-. The calculated proton conductances agree with experiment, showing reduced or abolished proton flux. Surprisingly, the proton affinity of the anion is less influential on the PT, while its size and interactions with the protein significantly alter hydration and shift its influence on PT from facilitating to inhibiting. We find that the hydration of the cavity below the anion is relatively fast, but connecting the water network past the steric hindrance of these polyatomic anions is quite slow. Hence, the most relevant coordinate to the PT free energy barrier is the water connectivity along the PT pathway, but importantly only in the presence of the excess proton, and this coordinate is significantly affected by the nature of the bound anion. This work again demonstrates how PT is intrinsically coupled with protein cavity hydration changes as well as influenced by the protein environment. It additionally suggests ways in which ion exchange can be modulated and exchange stoichiometries altered. PMID- 30421607 TI - Microchip Cytometry for Multiplexed Single-Cell Protein Detection in a Low Resource Setting toward Point of Care Diagnosis. AB - Multiplex measurement of protein expression with the single-cell resolution has been challenging. Although a few conventional approaches including flow cytometry and immunofluorescence-based methods have been developed to detect proteins in individual cells, they are either dependent on bulky instrument or not multiplexed and high-throughput enough. Here we present a portable single-cell analysis system that is operable in a resource-limited environment. A stand-sit microchip housed in a clamp enables simple and instrument-free operation of all necessary steps, and the detection based on immunogold enhancement exonerates the reliance on fluorescence optics and electronics. The quantified sensitivity was found comparable to the conventional fluorescence approaches. We used this system to analyze five immune effector proteins and found the system is equally effective to detect those proteins in hundreds of single cells. Significant increase of cytokine protein production by THP1 monocytes was observed upon stimulation by lipopolysaccharide. Further study showed that a low-end imaging setup with low resolution can also detect signals without much loss of sensitivity. Taken together, this portable multiplex single-cell system may find broad biomedical applications in a field setting. PMID- 30421608 TI - "Waltz" of Cell Membrane-Coated Nanoparticles on Lipid Bilayers: Tracking Single Particle Rotation in Ligand-Receptor Binding. AB - Understanding the binding of nanoparticles to receptors on biomembranes is critical to the development and screening of therapeutic materials. A prevailing understanding is that multivalent ligand-receptor binding leads to slower and confined translational motion of nanoparticles. In contrast, we report in this study distinct types of rotational dynamics of nanoparticles during their seemingly similar translational confinements in ligand-receptor binding. Our nanoparticles are fluorescently anisotropic and camouflaged with T cell membranes. As they bind to ligands on planar lipid bilayers, the particles transition from back-and-forth rocking motion to circling and eventually confined circling motion, while "hopping" between translational confinements. Both rotational and translational motions of the nanoparticles become more confined at higher ligand density. The time-dependent changes in particle rotation reveal different stages in the progression of multivalent binding between the cell membrane coated nanoparticles and their ligands. Our work also demonstrates the promise of using combined rotational and translational single particle tracking to resolve biological interactions that could be "hidden" in translational measurements alone. PMID- 30421609 TI - Uranyl-Organic Coordination Compounds Incorporating Photoactive Vinylpyridine Moieties: Synthesis, Structural Characterization, and Light-Induced Fluorescence Attenuation. AB - The fluorescence of uranyl originated from electronic transitions (S11-S00 and S10-S0v, v = 0-4) of the ligand-to-metal charge transfer (LMCT) process is an intrinsic property of many uranyl coordination compounds. However, light-induced regulation on fluorescence features of uranyl hybrid materials through photoactive functional groups is less investigated. In this work, the photoactive vinyl group-containing ligands, ( E)-methyl 3-(pyridin-4-yl)acrylate and ( E) methyl 3-(pyridin-3-yl)acrylate, have been used in the construction of uranyl coordination polymers in the presence of 1,10-phenanthroline (phen). Five compounds (UO2)3(MU3-O)(MU2-OH)2(L1)2( phen)2(1), (UO2)3(MU3-O)(MU2-OH)3(L1)( phen)2 (2), (UO2)3(MU3-O)(MU2-OH)3(L2)( phen)2 (3), [(UO2)2(MU2-OH)2(L2)2( phen)2].2H2O (4), and (UO2)Zn(SO4)(phen)(H2O)(OH)2(5) were obtained under hydrothermal conditions. Compounds 1-4 are polynuclear uranyl structures with abundant pi-pi interactions and hydrogen bonds contributed to the 3D crystal packing of them. As model compounds, 1 and 3 are selected for exploring photoresponsive behaviors. The emission intensities of these two compounds are found to decrease gradually over the exposure time of UV irradiation. X-ray single crystal structural analysis suggests that the fluorescence attenuation can be explained by the slight rotation of pyridinyl groups around the carbon-carbon double bond during UV irradiation, which is accompanied by the change of weak interactions, i.e., pi-pi interactions and hydrogen bonds in strength and density. This feature of light-induced fluorescence attenuation may enable these two compounds to act as potential photoresponsive sensor materials. PMID- 30421610 TI - Effect of Ancillary Ligand in Cyclometalated Ru(II)-NHC-Catalyzed Transfer Hydrogenation of Unsaturated Compounds. AB - In an effort to develop efficient Ru(II)-NHC-based catalyst considering their stereoelectronic effect for hydride-transfer reaction, we found that the ancillary NHC ligand can play a significant role in its catalytic performance. This effect is demonstrated by comparing the activity of two different types of orthometalated precatalysts of general formula [( p-cymene)(NHC)RuII(X)] (NHC = an imidazolylidene-based ImNHC, compound 2a-c, or a mesoionic triazolylidene based tzNHC, compound 4) in transfer hydrogenation of carbonyl substrates. The electron-rich precatalyst, 2c, containing p-OMe-substituted NHC ligand performed significantly better than both unsubstituted complex 2a and p-CF3 substituted electron-poor complex 2b in ketone reduction. Whereas bulky mesoionic triazolylidene ligand containing complex 4 was found to be superior catalyst for aldehyde reduction and the precatalyst 2a is more suitable for the selective transfer hydrogenation of a wide range of aromatic aldimines to amines. To the best of our knowledge, this is the first systematic study on the effect of stereoelectronic tuning of ancillary orthometalated NHC ligand in Ru(II) catalyzed transfer hydrogenations of various types of unsaturated compounds with broad substrate scope. PMID- 30421611 TI - meso-Triaryl-Substituted Smaragdyrins: Facile Aromaticity Switching. AB - All-aza smaragdyrin, a historic but elusive pentapyrrolic macrocycle, was successfully synthesized and characterized for the first time. [22]Smaragdyrin BF2-complex 3 was smoothly synthesized by 2-fold SNAr reaction of 1,9-dibromo-5 mesityldipyrrin with 5,10-dimesityltripyrrane. Treatment of 3 with methanesulfonic acid gave [20]smaragdyrin 5 as a stable antiaromatic compound. Reduction of 5 with NaBH4 under inert conditions gave [22]smaragdyrin 6 as an aromatic congener, which was easily oxidized back to 5 in the air. Complex 3 was interconvertible with its 20pi-congener 4 via oxidation with MnO2 and reduction with NaBH4. Treatment of 3 or 4 with CuCl2 in the presence of NaOAc gave hetero bimetal complex 8. PMID- 30421612 TI - An Advanced Hand-Held Microfiber-Based Sensor for Ultrasensitive Lead Ion Detection. AB - This study demonstrated a l-glutathione-modified nonadiabatic microfiber sensor to detect a trace level of heavy metal ions in aqueous solution. The sensor showed an exclusively selective response to Pb2+ among other metal ions and a measured detection limit of 5 MUg/L, lower than the maximum allowable limit of Pb2+ in drinking water by the World Health Organization. Moreover, a novel compact all-fiber-based interrogation scheme was proposed to promote the development of a portable hand-held system for on-site measurement. The presented scheme does not require costly and bulky laboratory equipment but operates based on the reflected optical power of two fiber Bragg gratings (FBG), measured using photodetectors independently. PMID- 30421614 TI - dCas9-mediated Nanoelectrokinetic Direct Detection of Target Gene for Liquid Biopsy. AB - The-state-of-the-art bio- and nanotechnology have opened up an avenue to noninvasive liquid biopsy for identifying diseases from biomolecules in bloodstream, especially DNA. In this work, we combined sequence-specific-labeling scheme using mutated clustered regularly interspaced short palindromic repeats associated protein 9 without endonuclease activity (CRISPR/dCas9) and ion concentration polarization (ICP) phenomenon as a mechanism to selectively preconcentrate targeted DNA molecules for rapid and direct detection. Theoretical analysis on ICP phenomenon figured out a critical mobility, elucidating two distinguishable concentrating behaviors near a nanojunction, a stacking and a propagating behavior. Through the modulation of the critical mobility to shift those behaviors, the C-C chemokine receptor type 5 ( CCR5) sequences were optically detected without PCR amplification. Conclusively, the proposed dCas9 mediated genetic detection methodology based on ICP would provide rapid and accurate micro/nanofluidic platform of liquid biopsies for disease diagnostics. PMID- 30421613 TI - Cobalt(I) Complexes of 5-Aryl-2-iminopyrrolyl Ligands: Synthesis, Spin Isomerism, and Application in Catalytic Hydroboration. AB - This work reports the first successful isolation and full characterization of cobalt(I) complexes of 5-aryl-2-iminopyrrolyl ligands. In one approach, when [Co{kappa2 N,N'-5-(2,4,6-R3-C6H2)-NC4H2-2-C(H)?N(2,6-iPr2-C6H3)}(Py)Cl] (R = iPr, 1a; R = Ph, 1b) were reacted with K(HBEt3) or Na(Hg) in toluene, the Co(I) arene complexes [Co{kappa2 N,N'-5-(2,4,6-iPr3-C6H2)-NC4H2-2-C(H)?N(2,6-iPr2-C6H3)}(eta6 C6H5CH3)] (2a) and [ Co{kappa2 N,N'-5-[2'-(kappa:eta6- C6H5)-C6H2-4',6'-Ph2] NC4H2-2-C(H)?N(2,6-iPr2-C6H3)}] (2b) were formed. The reaction of complex 1a with KC8 in Et2O yielded the [Co{kappa2 N,N'-5-(2,4,6-iPr3-C6H2)-NC4H2-2-C(H)?N(2,6 iPr2-C6H3)}]2 (3). On another approach, the metathesis of potassium 5-(2,4,6 triisopropylphenyl)-2-( N-2,6-diisopropylphenylformimino)pyrrolyl (KLa) with CoCl(PMe3)3 yielded the bis(trimethylphosphine) complex [Co{kappa2 N,N'-5-(2,4,6 iPr3-C6H2)-NC4H2-2-C(H)?N(2,6-iPr2-C6H3)}(PMe3)2] (4) in a good yield. Complexes 2a, 3, and 4 are paramagnetic, high-spin species, while 2b is a diamagnetic complex. Compound 2b exhibited a spin isomerism behavior ( S = 0 <-> S = 1) as determined by variable-temperature 1H NMR experiments (Delta H degrees = 7.7 kcal mol-1), being also supported by computational studies (Delta E = 4.2 kcal mol-1). All complexes were tested in the hydroboration of styrene with pinacolborane (HBPin), with complex 4 exclusively yielding the respective anti Markovnikov addition product. Additionally, all complexes catalyzed the fast and quantitative hydroboration of benzaldehyde with HBPin. PMID- 30421615 TI - Incurred sample reproducibility. PMID- 30421616 TI - Outcomes of medically managed patients with myocardial infarction. AB - AIMS:: The purpose of this study was to compare outcomes associated with medical management of ST-elevation myocardial infarction and non-ST-elevation myocardial infarction patients presenting to hospitals with and without onsite catheterization facilities. METHODS: All patients ( n=25,921) with ST-elevation myocardial infarction ( n=10,563) or non-ST-elevation myocardial infarction ( n=15,358) in Alberta, Canada between April 2010-March 2016 were categorized according to availability of catheterization facilities at the hospital they presented to and their management strategy (medically managed without coronary angiography or medically managed after coronary angiography). RESULTS:: Overall, 51% presented to hospitals without catheterization facilities; and 34% were managed medically (18% without coronary angiography, and 16% after coronary angiography). Rates of medical management were higher at hospitals without versus those with catheterization facilities (43% vs. 24%, p<0.01). However, both the rate of presentation to hospitals without catheterization facilities (70% non-ST elevation myocardial infarction, 24% ST-elevation myocardial infarction, p<0.01) and medical management (45% non-ST-elevation myocardial infarction, 18% ST elevation myocardial infarction, p<0.01) differed by myocardial infarction type. The lack of catheterization facilities at the presenting hospital had no association with in-hospital mortality in patients medically managed without coronary angiography, but was associated with a lower risk of mortality among patients medically managed after coronary angiography. However, the latter benefit was restricted to non-ST-elevation myocardial infarction patients only (adjusted hazard ratio 0.43, 95% confidence interval: 0.25-0.76). CONCLUSION:: The availability of catheterization facilities at the hospital at which non-ST elevation myocardial infarction and ST-elevation myocardial infarction patients presented influenced their likelihood of being medically managed, but was not associated with adverse short- or long-term mortality outcomes. PMID- 30421617 TI - An alternative method of localised topical antibiotic delivery in deep musculoskeletal infection. PMID- 30421618 TI - Evaluation of Pro-re-Nata (PRN) and Treat and Extend Bevacizumab treatment protocols in Sorsby Fundus Dystrophy. AB - PURPOSE:: To describe long-term outcomes with intravitreal Bevacizumab for choroidal neovascularization secondary to Sorsby fundus dystrophy. MATERIALS/METHODS:: Observational case series. RESULTS:: Two sisters of the same family formally diagnosed with Sorsby fundus dystrophy were followed-up for 12 years. The elder sister (S1) presented with significant decline in vision due to choroidal neovascularization in her right eye (OD). She developed choroidal neovascularization 3 years later in her left eye (OS). She was treated with Bevacizumab intravitreal injections on a on a pro-re-nata (PRN) until April 2015, when a treat-and-extend (T&E) approach was adopted. Best corrected visual acuities at the time of switch to T&E were 1.09 OD and 0.85 LogMar OS. Best corrected visual acuities at the last follow-up were LogMar 1.1 OD and 0.82 OS. Her younger sister (S2) presented with best corrected visual acuities of LogMar 0.1 OD and 0.0 OS. She developed choroidal neovascularization 5 years later in both eyes. OS developed choroidal neovascularization 18 months after her right eye. She received Bevacizumab on a pro re nata basis until April 2015 when a switch to a T&E was performed. Best corrected visual acuity in the left eye at the switch to T&E was 0.34 LogMar. At the last follow-up, best corrected visual acuities were LogMar 1.2 OD and 0.29 OS. CONCLUSION:: Bevacizumab is an effective therapy for choroidal neovascularization secondary to Sorsby fundus dystrophy. A T&E protocol appears more effective compared to pro re nata protocol in minimizing recurrence of choroidal neovascularization with potential secondary scar formation or atrophy. PMID- 30421619 TI - Reperfusion cardiac arrhythmias and their relation to reperfusion-induced cell death. AB - Reperfusion does not only salvage ischaemic myocardium but can also cause additional cell death which is called lethal reperfusion injury. The time of reperfusion is often accompanied by ventricular arrhythmias, i.e. reperfusion arrhythmias. While both conditions are seen as separate processes, recent research has shown that reperfusion arrhythmias are related to larger infarct size. The pathophysiology of fatal reperfusion injury revolves around intracellular calcium overload and reactive oxidative species inducing apoptosis by opening of the mitochondrial protein transition pore. The pathophysiological basis for reperfusion arrhythmias is the same intracellular calcium overload as that causing fatal reperfusion injury. Therefore both conditions should not be seen as separate entities but as one and the same process resulting in two different visible effects. Reperfusion arrhythmias could therefore be seen as a potential marker for fatal reperfusion injury. PMID- 30421620 TI - A rare case of successful endoscopic management of a fibroepithelial polyp with intussusception of the ureter and periodic prolapse into bladder. AB - Fibroepithelial polyps of the ureter are rare non-epithelial benign tumours with a slight female predominance. They are primarily located in the upper left ureter, incidentally diagnosed in patients who are evaluated for gross haematuria or renal colic. Fibroepithelial polyps are traditionally managed by open surgery with resection of the polyp and its stalk or partial resection of the ureter. We describe the case of a fibroepithelial polyp located in the distal right ureter, which occurred in a 42-year-old man with lower urinary tract symptoms, haematuria and flank pain. To our knowledge, this is the first reported case of ureteral fibroepithelial polyp acting as a lead point for ureteral intussusception and to protruding periodically into the bladder cavity, which was successfully resected by ureteroscopic electrocauterisation with good outcome. PMID- 30421621 TI - Mahaim fibers coexisting with coarctation of aorta and bicuspid aortic valve. AB - We found a coexistence of Mahaim fibers, coarctation of aorta and bicuspid valve in a young patient presenting with palpitations and subraventricular tachycardia. This rare combination of these three congenital cardiac abnormalities occurring in the same patient has not been reported previously. Detailed cardiac studies unmasked the patient's cardiac abnormalities. Furthermore, successful percutaneous intervention in treating coarctation and catheter-based ablation of Mahaim fibers were performed with resolution of symptoms. This case is discussed here in detail, alongside a review of the literature. PMID- 30421622 TI - Incurred sample reproducibility: what have we learned and how can we build on our learnings? PMID- 30421623 TI - Phakic intraocular lens as a temporary barrier in aphakic Descemet's membrane endothelial keratoplasty. AB - BACKGROUND:: Descemet's membrane endothelial keratoplasty has a lower risk of endothelial rejection than Descemet's stripping automated endothelial keratoplasty. In aphakic eyes requiring endothelial transplantation, approaches aimed at reducing the risk of posterior graft dislocation in Descemet's stripping automated endothelial keratoplasty are not transferable to Descemet's membrane endothelial keratoplasty. TECHNIQUE:: Here we describe the use of an implantable collamer lens placed over the iris to provide a temporary intraoperative platform, to facilitate graft unfolding and to avoid posterior graft dislocation in an aphakic, vitrectomised eye with a fixed, dilated pupil in a young patient with chronic uveitis and previous failed Descemet's stripping automated endothelial keratoplasty. PMID- 30421624 TI - Treatment patterns, duration and outcomes of pemetrexed maintenance therapy in patients with advanced NSCLC in a real-world setting. AB - OBJECTIVES: In patients with non-squamous non-small cell lung cancer (NSCLC), maintenance therapy regimens, including pemetrexed, have been shown to prolong overall survival (OS) and progression-free survival (PFS). The purpose of this study was to describe real-world maintenance use of pemetrexed and associated outcomes in patients with advanced NSCLC. METHODS: This was a retrospective, observational study that used longitudinal, demographically and geographically diverse electronic health record data in the United States. Eligible patients were adults with advanced non-squamous NSCLC who had received maintenance treatment with pemetrexed monotherapy or pemetrexed plus bevacizumab. Descriptive statistics were used to describe the patient population and multivariable logistic regression was used to identify the factors associated with duration of maintenance therapy. Kaplan-Meier curves and Cox regression models were used for time-to-event analysis. RESULTS: Patients receiving pemetrexed maintenance therapy were treated with either pemetrexed monotherapy (66.0%) or pemetrexed plus bevacizumab (34.0%). Carboplatin and pemetrexed (37.9%) or carboplatin, pemetrexed and bevacizumab (36.1%) were the most commonly used first-line therapies observed. The majority (84.9%) of these maintenance patients responded to first-line therapy. The median duration of maintenance therapy was 6.0 months for pemetrexed and bevacizumab and 4.1 months for pemetrexed monotherapy. The median OS from the start of first-line therapy of the total study cohort was 21.5 months (95% CI 20.0, 22.9). CONCLUSION: Real-world effectiveness of pemetrexed maintenance therapy is similar to that observed in published randomized controlled trials, confirming a role for pemetrexed maintenance in eligible patients in clinical practice. PMID- 30421625 TI - The fluid mechanics of ureteroscope irrigation. AB - Purpose To develop a physical understanding of uretero-renoscopy irrigation, we derive mathematical models from basic physical principals, and compare these predictions with the results of bench-top experiments. Mathematical modelling can be used to understand the role of inlet pressure, tip deflection, the presence of working tools, geometric properties of the instruments used, and material properties of the irrigation fluid on resulting flow rate. Materials and Methods We develop theoretical models to describe irrigation flow in an idealised setup and compare with bench-top experiments for flow through a straight scope, a scope with a deflected tip, and a scope with a working tool inserted. The bench-top experiments were performed using Boston Scientific's LithoVue ureteroscope and a variety of Boston Scientific working tools. Standard ureteroscope working channels have circular cross-sections, but using theoretical models we investigate whether modifications to the cross-sectional geometry can enhance flow rates. Results The theoretical flow predictions are confirmed by experimental results. Tip deflection is shown to have a negligible effect on flow rate, but the presence of working tools decreases flow significantly (for a fixed driving pressure). Flow rate is predicted to improve when tools are placed at the edge of the channel, rather than the center, and modifying the cross-sectional shape from a circle to an ellipse can further increase flow rate. Conclusions A mathematical framework is formulated and shown to accurately predict the properties of ureteroscope irrigation flow. The theoretical approach has significant potential in quantifying irrigation flow and improving ureteroscope design. PMID- 30421626 TI - Measuring perceived outcomes from participating at a clubhouse for persons with mental illness: Psychometric properties and associated factors. AB - BACKGROUND: The clubhouses are part of a growing international movement concerned with providing work-oriented psychosocial rehabilitation for people with a history of mental illness. Instruments used for measuring outcomes from clubhouse participation is in a developing phase. AIMS: This study aimed to assess psychometric properties of an outcome survey tool used at a Norwegian clubhouse, and to explore factors associated with members' perceived outcomes from participation at the clubhouse. METHODS: A cross-sectional design was used. The instrument's factor structure was examined with Principal Components Analysis (PCA), and internal consistency was assessed with Cronbach's alpha. Associations with the derived outcome scale score were examined with linear regression analysis. RESULTS: All scale items belonged to the same latent factor, and internal consistency of the items was alpha = 0.81. Members, who used the clubhouse more frequently perceived the outcomes from participating to be better, compared to their counterparts. CONCLUSION: The outcome scale was unidimensional and the items fit well together. Active members were likely to evaluate outcomes of clubhouse participation as more positive, compared to less active members. SIGNIFICANCE: The scale can be useful for exploring clubhouse members' perceptions of the outcomes they relate to their participation at the clubhouse. PMID- 30421627 TI - Metformin can inhibit Helicobacter pylori growth. AB - AIM: Helicobacter pylori infection is a worldwide infection, its eradication rates with conventional therapies have fallen to unacceptable levels. In this context we were interested in metformin, to determine its effect on H. pylori growth. MATERIALS & METHODS: Antimicrobial susceptibility tests and survival curves were performed in vitro and a H. pylori-infected mice model was used to determine metformin effect in vivo. RESULTS: Helicobacter pylori survival and growth were decreased in presence of metformin. Furthermore, metformin-treated mice had significantly less bacteria in their stomach than the untreated mice. CONCLUSION: Our work is the first to demonstrate a direct antimicrobial effect of metformin on H. pylori, indicating that this molecule has not yet revealed its full potential. PMID- 30421628 TI - Is it always necessary to perform an axillary lymph node dissection after neoadjuvant chemotherapy for breast cancer? AB - INTRODUCTION: Recent prospective studies support the feasibility of performing sentinel lymph node biopsy following neoadjuvant chemotherapy in initially fine needle aspiration cytology or ultrasound-guided biopsy-proven node-positive breast cancer. The main aid is to identify preoperative features that help us predict a complete axillary response to neoadjuvant chemotherapy in these patients and thus select the candidates for sentinel lymph node biopsy post neoadjuvant chemotherapy to avoid unnecessary axillary lymphadenectomy. MATERIALS AND METHODS: A retrospective observational study with a total of 150 patients, biopsy-proven node-positive breast cancer who underwent neoadjuvant chemotherapy followed by breast surgery and axillary lymphadenectomy were included and retrospectively analysed. A predictive model was generated by a multivariate logistic regression analysis for pathological complete response-dependent variable. RESULTS: The response of the primary lesion to neoadjuvant chemotherapy according to post-treatment magnetic resonance imaging, Her2/neu overexpression and a low estrogen receptor expression are associated with a higher rate of nodal pathologically complete response. The multivariant model generated a receiver operating characteristic curve with an area under the curve of 0.79 and a confidence interval of 0.72-0.87 at a 95% level of significance. CONCLUSIONS: This model could be a helpful tool for the surgeon to help in predicting which cases have a higher likelihood of achieving a pathologically complete response and therefore selecting those who may benefit from a post-neoadjuvant chemotherapy sentinel lymph node biopsy and avoid unnecessary axillary lymphadenectomy. PMID- 30421629 TI - Feasibility of 3D-printed models of the proximal femur to real bone: a cadaveric study. AB - INTRODUCTION:: 3D technology has increased popularity during the past decade due to recent advancements and has been described as a useful tool in several fields of medicine including orthopaedic surgery. Applications include preoperative planning, custom-made implants, patient-specific guides, etc. The aim of this study was to evaluate the similarity between 3D-printed models and cadaveric femoral heads, based on CT scans. METHODS:: Cadaveric study of 12 male hips. Computed tomography (CT) was performed and through a semi-automatic segmentation process created the 3D model. Using a 3D printer, the model was printed in ABS plastic. 1 observer performed several measurements in the cadaver, and a 2nd observer performed the same measurements in the 3D-printed model. A 3rd observer compared both measurements and performed the statistical analysis. RESULTS:: There were no significant differences in the measurements of bony structures between the cadaveric specimens and the 3D-printed model ( p > 0.05 in all cases). We found significant differences when comparing measurements containing a soft tissue element, for example the dimensions of the cartilage covered femoral head ( p < 0.0001). CONCLUSIONS:: 3D-printed models of the hip are accurate and feasible to the real bone and can thus be reliable for preoperative planning or other uses that may arise in orthopaedic surgery. Presence of cartilage must be considered when creating the 3D model from CT that considers bone but not cartilage. PMID- 30421630 TI - Evaluation of MALDI-TOF VITEK(r)MS and VITEK(r) 2 system for the identification of Staphylococcus saprophyticus. AB - AIM: To compare two identification methods for coagulase-negative staphylococci (CoNS) isolated from patients with urinary tract infections, VITEK(r) 2 and MALDI TOF VITEK(r)MS, with genotypic identification by internal transcribed spacer PCR (ITS-PCR). RESULTS: A total of 217 CoNS isolates were studied. Agreement of the VITEK(r) 2 system with ITS-PCR was 84.8%, with 98% sensitivity and 100% specificity. Thirty-one of the 33 strains incorrectly identified by VITEK(r) 2 belonged to the species Staphylococcus saprophyticus. MALDI-TOF VITEK(r)MS showed an excellent correlation with ITS-PCR since it correctly identified all CoNS isolates. CONCLUSION: MALDI-TOF VITEK(r)MS is more accurate than the automated VITEK(r) 2 system in identifying CoNS isolated from urinary tract infections to species level, particularly urinary isolates of S. saprophyticus. PMID- 30421631 TI - Kinematic Correlates of Kinetic Outcomes Associated With Running-Related Injury. AB - High magnitudes and rates of loading have been implicated in the etiology of running-related injuries (RRI). Knowledge of kinematic variables that are predictive of kinetic outcomes could inform clinic-based gait retraining programs. Healthy novice female runners ran on a treadmill while 3D biomechanical data were collected. Kinetic outcomes consisted of vertical impact transient (VIT), average vertical loading rate (AVLR), instantaneous vertical loading rate (IVLR), and peak braking force (PBF). Kinematic outcomes included step length (SL); hip flexion angle at initial contact (HFA); horizontal distance from heel to centre of mass at initial contact (HCOM); shank angle at initial contact (SA); and foot strike angle (FSA). Stepwise multiple linear regression was used to evaluate the amount of variance in kinetic outcomes explained by kinematic outcomes. A moderate amount of variance in kinetic outcomes (VIT=46%; AVLR=37%; IVLR=49%; PBF=54%) was explained by several discrete kinematic variables predominantly speed, HCOM, FSA, and SL. HFA and SA did not contribute to any models. Decreasing SL and transitioning from a rearfoot strike may reduce kinetic risk factors for RRI. In contrast, clinical strategies such as modifying SA and HFA would not appear to contribute significantly to the variance of kinetic outcomes after accounting for other variables. PMID- 30421632 TI - Editorial Comment on END-2018-0614-OR.R1. PMID- 30421634 TI - A PCA Approach to Quantifying Foot Clearance and Foot Clearance Variability. AB - Low foot clearance and high variability may be related to falls risk. Foot clearance is often defined as the local minimum in toe height during swing; however, not all strides have this local minimum. The primary purpose of this study was to identify a non-discrete measure of foot clearance during all strides, and compare discrete and non-discrete measures in ability to rank individuals on foot clearance and variability. Thirty-five participants (young adults (n=10), older fallers (n=10), older non-fallers (n=10), and stroke survivors (n=5)) walked overground while lower-extremity 3D kinematics were recorded. Principal Components Analysis (PCA) of the toe height waveform yielded representation of toe height when it was closest to the ground. Spearman rank order correlation assessed the association of foot clearance and variability between PCA and discrete variables, including the local minimum. PCA had significant (P<0.05) moderate or strong associations with discrete measures of foot clearance and variability. An approximation of the discrete local minimum had a weak association with PCA and other discrete measures of foot clearance. A PCA approach to quantifying foot clearance can be used to identify the behavioral components of toe height when it is closest to the ground, even for strides without a local minimum. PMID- 30421633 TI - Muscular strength and function after total hip arthroplasty performed with three different surgical approaches: one-year follow-up study. AB - BACKGROUND:: Surgical approach influences short-term muscular strength, and leg strength asymmetry has been demonstrated after total hip arthroplasty (THA). We evaluated muscular strength, physical function and patient-reported outcome measures (PROMs) up to 12 months postoperatively, in patients operated on using 3 different surgical approaches. METHODS:: 60 patients scheduled for primary THA were allocated to the direct lateral (DLA), posterior (PA) or anterior (AA) approach. The following parameters were evaluated: leg press and abduction strength, pain, 6-minute walking test, Harris Hip Score and Hip disability and Osteoarthritis Outcome Score - Physical Function Shortform (HOOS-PS). RESULTS:: Abduction strength in the DLA group was significantly more reduced than the PA and AA groups 12 months postoperatively ( p < 0.001). A significant interleg difference in abduction ( p < 0.01) and leg press ( p < 0.03) persisted in all groups up to 6 months, and up to 12 months in the DLA ( p < 0.05). In the AA group, interleg difference in leg press was present up to 12 months ( p = 0.01). Pain scores were higher in the DLA than the AA group at 6 months ( p = 0.01). Patients in the PA group had better HOOS-PS score than those in the DLA group 3 months postoperatively ( p = 0.02). No intergroup differences in pain or PROMs were found 12 months postoperatively. CONCLUSION:: Patients operated via the DLA had reduced muscular strength, HOOS-PS scores and higher pain scores than those who underwent PA and AA type surgery. The non-operated leg was significantly stronger than the operated leg in all groups 6 months postoperatively and this persisted up to 12 months postoperatively for the DLA and AA groups. Clinical Trial Protocol number: ClinicalTrials.gov (NCT01506024). PMID- 30421635 TI - Influence of Sacroiliac Bracing on Muscle Activation Strategies During Two Functional Tasks in Standing-Tolerant and Standing-Intolerant Individuals. AB - People who develop low back pain (LBP) during standing (standing-intolerant) are a sub-clinical group at risk for clinical LBP. Standing-intolerant individuals respond favorably to stabilization exercise, and may be similar to people with sacroiliac joint dysfunction (SIJD) that respond to stabilization approaches including sacroiliac joint (SIJ) bracing. The purpose was to characterize muscle activation and response to SIJ bracing in standing-tolerant and standing intolerant individuals during forward flexion and unilateral stance. Trunk and hip EMG data were collected from 31 participants, 17 standing-tolerant and 14 standing-intolerant, while performing these tasks with and without SIJ bracing. Kinematics were captured concurrently and used for movement phase identification. Cross-correlation quantified trunk coactivation and extensor timing during return to-stand from forward flexion; rms amplitude quantified gluteal activity during unilateral stance. The standing-intolerant group had elevated erector spinae external oblique coactivation without bracing, and erector spinae-internal oblique coactivation with bracing during return-to-stand compared with standing tolerant individuals. Both groups reversed extensor sequencing during return-to stand with bracing. Standing-tolerant individuals had higher hip abductor activity in non-dominant unilateral stance, and increased hip extensor activity with bracing. SIJ bracing could be a useful adjunct to other interventions targeted towards facilitating appropriate muscle activation in standing intolerant individuals. PMID- 30421636 TI - Intrapelvic component retrieval via anterior inferior iliac spine osteotomy in revision total hip arthroplasty. AB - INTRODUCTION:: In the revision setting, intrapelvic acetabular components provide a unique set of challenges for the treating surgeon. Retrieval is complicated by complex anatomical relationships within the pelvis and historically, surgeons have used multiple approaches to safely retrieve the cup. CASE PRESENTATION:: We present the case of a 53-year-old female with intrapelvic migration of the acetabular components of her total hip arthroplasty. Patient was treated through a novel, single incision approach with utilisation of an anterior inferior iliac spine (AIIS) osteotomy. RESULTS:: An AIIS osteotomy allows for improved visualisation within the pelvis and safe retrieval through a single exposure without compromising the ability to perform definitive, revision reconstruction. At 1-year follow-up, the patient has had no complications related to infection or failure of the implants. Ambulation is performed with the aid of a cane in the community with mild, occasional pain. PMID- 30421637 TI - Clinical relevance of bone remodelling around conventional and conservative (short-stem) total hip arthroplasty implants. AB - Based on data from the existing literature, we can safely suggest that bone mineral changes around cementless and cemented conventional femoral stems, and conservative femoral stems, are not predictive of either satisfactory or unsatisfactory total hip arthroplasty long term clinical outcomes. Additionally, studies with a follow up shorter than 5-10 years are perhaps clinically irrelevant. These observations may be helpful in interpreting the existing literature. PMID- 30421638 TI - An analysis of potential predictors of tunneled hemodialysis catheter infection or dysfunction. AB - PURPOSE:: To assess the ability of various clinical factors to predict infection or dysfunction of tunneled hemodialysis catheters. METHODS:: A retrospective review of all adult patients who had a tunneled hemodialysis catheter placed between 2012 and 2016 was performed. Tunneled hemodialysis catheters were considered infected based on clinical suspicion or culture-positive bacteremia. Dysfunction was defined as all other non-infectious causes for line failure. Time to-removal or exchange was recorded. Clinical parameters analyzed as potential predictors of tunneled hemodialysis catheter infection or dysfunction, included the following: age, sex, site of placement, inpatient versus outpatient status at time of placement, body mass index, Charlson Comorbidity Index, neutrophil-to lymphocyte ratio, platelet-to-lymphocyte ratio, platelet count, white blood cell count, international normalized ratio, and partial thromboplastin time. RESULTS:: A total of 177 patients (95: female, 82: male; 71.7%: African American; mean age: 54.9 years) qualified for inclusion. The internal jugular vein was the site of placement in 97.1% of patients with 79.7% of lines being placed on the right side. One patient (0.5%) had minor bleeding after catheter insertion but no other complications were recorded. A total of 17 patients (9.6%) had lines removed or exchanged due to infection at a median of 86 (range: 13-626) days, while 68 patients (38.4%) had lines removed or exchanged due to dysfunction at a median of 42 (range: 1-531) days. A total of 92 patients (51.9%) had lines removed due to completion of therapy at a median of 68 (range: 7-433) days. Dysfunctional lines had a shorter time-to-removal than successful lines ( p = 0.007). No difference was seen in time-to-removal between infected lines and successful lines ( p = 0.16). Multivariate analysis showed that female sex ( p = 0.003) and left-sided line placement ( p = 0.007) were independent predictors of line dysfunction. No evaluated factors were predictive of tunneled hemodialysis catheter infection. CONCLUSION:: Female sex and left-sided line placement were independent predictors of tunneled hemodialysis catheter dysfunction, but none of the evaluated parameters predicted tunneled hemodialysis catheter infection. PMID- 30421639 TI - Children Born With Congenital Zika Syndrome Display Atypical Gross Motor Development and a Higher Risk for Cerebral Palsy. AB - IMPORTANCE:: Congenital Zika syndrome virus infection is said to interfere in children's development. OBJECTIVE:: evaluate gross motor trajectories and the frequency of cerebral palsy in children with congenital Zika syndrome. DESIGN:: Cohort study applying the Alberta Infant Motor Scale (AIMS) and the Bayley III Scales in infants from 6 to 18 months of age. SETTING:: The SARAH network, Rio de Janeiro. PARTICIPANTS:: Thirty-nine infants whose diagnoses were established through clinical history, serology tests, and neuroimaging findings. Main outcomes and measures: Congenital Zika syndrome is associated with severe motor delays and is a risk factor to the diagnosis of cerebral palsy. RESULTS:: The Alberta Infant Motor Scale mean raw score at 6 months was 9.74 (SD 4.80) or equivalent to 2 to 3 months of motor developmental age. At the age of 12 months, 14.13 (SD 11.90), corresponding to 3 to 4 months of motor development age; the Bayley III Scales results correlated to the Alberta Infant Motor Scale ( P < .001) at this age. At 18 months, 15.77 (SD 13.80) or a motor development equivalent to 4 to 5 months of age. Thirty-five of 39 children (89.7%) met criteria for the diagnosis of cerebral palsy. Conclusions and relevance: Gross motor development marginally progresses from 6 to 18 months of age. These individuals also displayed a high frequency of cerebral palsy. PMID- 30421640 TI - Accurate delineation of cell cycle phase transitions in living cells with PIP FUCCI. AB - Cell cycle phase transitions are tightly orchestrated to ensure efficient cell cycle progression and genome stability. Interrogating these transitions is important for understanding both normal and pathological cell proliferation. By quantifying the dynamics of the popular FUCCI reporters relative to the transitions into and out of S phase, we found that their dynamics are substantially and variably offset from true S phase boundaries. To enhance detection of phase transitions, we generated a new reporter whose oscillations are directly coupled to DNA replication and combined it with the FUCCI APC/C reporter to create "PIP-FUCCI". The PIP degron fusion protein precisely marks the G1/S and S/G2 transitions; shows a rapid decrease in signal in response to large doses of DNA damage only during G1; and distinguishes cell type-specific and DNA damage source-dependent arrest phenotypes. We provide guidance to investigators in selecting appropriate fluorescent cell cycle reporters and new analysis strategies for delineating cell cycle transitions. PMID- 30421641 TI - Enhancing natural killer cells is beneficial in multiple sclerosis - Yes. PMID- 30421642 TI - Enhancing natural killer cells is beneficial in multiple sclerosis - No. PMID- 30421643 TI - TLR3 and TLR4 SNP variants in the liver disease resulting from hepatitis B virus and hepatitis C virus infection. AB - BACKGROUND: Chronic infection with hepatitis B (HBV) and C virus (HCV) is linked with a pro-inflammatory state, predisposing to cirrhosis and liver cancer, particularly hepatocellular carcinoma (HCC). A role for toll-like receptor (TLR) signalling in hepatocarcinogenesis was recently documented. We hypothesised a link TLR3 and TLR4 polymorphisms and HCC, as surrogates for the significance of TLR signalling in the promotion and initiation of HCC. MATERIALS & METHODS: We recruited 174 HCV-infected patients, 100 HBV-infected patients, and 360 healthy control subjects. TLR3 (rs3775290) and TLR4 (rs4986790) genotyping was done by PCR-restriction fragment length polymorphisms (PCR-RFLP), LFTs and AFP by standard routine techniques. Liver fibrosis was assessed clinical by the Fibrotest and Actitest. RESULT: The TLR3 rs3775290 minor T genotype was linked with increased risk of chronic HBV (P = 0.05) and HCV (P = 0.031) infection. The TLR4 rs4986790 minor G genotype was linked with significantly increased risk for HBV/HCV chronic infection (P<0.001). Subgroups analyses indicated decreased risk of HBV-related HCC in relation to TLR3 rs3775290 CC/CT genotype (P = 0.022), with increased risk ascribed to the minor (T) allele (P = 0.04). Likewise, TLR4 rs4985790 minor (GG) genotype was positively associated with HBV-linked HCC (P<0.001). Furthermore, a link between TLR3 TT (P<0.001) andTLR4 GG (P=0.04) minor genotypes was noted in relation to increased risk of HCV-related disease. CONCLUSION: TLR3 and TLR4 polymorphisms are promising biomarkers of liver cirrhosis and cancer associated with HBV and HCV infection. PMID- 30421644 TI - How nanomedicine can be used in the treatment of tumors: an interview with Dr Gang Zheng. AB - Dr Zheng received his PhD in 1999 from SUNY Buffalo in Medicinal Chemistry. Following 2 years of postdoctoral training in photodynamic therapy at the Roswell Park Cancer Institute, he joined the University of Pennsylvania in 2001 as an Assistant Professor of Radiology, where he established the molecular imaging chemistry program and introduced photodynamic molecular beacons and lipoprotein like nanoparticles. Since moving to Canada in 2006, his research has been focused on developing clinically translatable technology platforms to combat cancer. His lab discovered porphysome nanotechnology that opened a new frontier in cancer imaging and therapy (Nature Materials 2011), which was named one of the 'top 10 cancer breakthroughs of 2011' by the Canadian Cancer Society. Dr Zheng is an Associate Editor for Bioconjugate Chemistry and a Fellow of the American Institute for Medical and Biological Engineering. PMID- 30421646 TI - ASPHER's European List of Core Competences for the Public Health Professional. PMID- 30421645 TI - EXPRESS: Pulmonary artery denervation improves hemodynamics and cardiac function in pulmonary hypertension secondary to heart failure. PMID- 30421647 TI - The use of extracorporeal membrane oxygenation in HIV-positive patients with severe respiratory failure: a retrospective observational case series. AB - The objective is to describe the outcomes of patients with human immunodeficiency virus (HIV) infection who received extracorporeal membrane oxygenation (ECMO) for severe respiratory failure (SRF). The design and setting was a single centre retrospective observational case series, from January 2012 to June 2017, at a tertiary university hospital and regional referral centre for ECMO in the United Kingdom. The participants were all patients referred with SRF and HIV infection. The main outcome measure was patient 90-day survival. Twenty-four patients were referred, of whom nine received ECMO. Six out of nine (67%) of patients were alive at 90 days. Median duration of ECMO was 18 days. There were no identified differences between survivors and non-survivors. ECMO can be used successfully in selected patients with HIV and SRF, including those with poor HIV control and high illness severity. HIV status alone should not exclude patients from treatment with extracorporeal therapy. PMID- 30421648 TI - Multimaterial segmented fiber printing for gradient tissue engineering. AB - In this work, we present a printing method to fabricate scaffolds consisting of multimaterial segmented fibers. Particularly, we developed a reproducible printing process to create single fibers with multiple discrete compositions and control over the distribution of particulate ceramics-namely hydroxyapatite (HA) and beta-tricalcium phosphate (TCP)-within poly(epsilon-caprolactone)-based composite scaffolds. Tensile testing revealed the mechanical integrity of individual segmented fibers was preserved compared to non-segmented fibers, and microcomputed tomography and thermal analysis confirmed the homogeneous distribution of ceramics incorporated in the fiber compositions. Moreover, we printed and characterized composite scaffolds containing model inverse radial gradients of HA and TCP that could serve as a tunable platform to control the degradation rate of the scaffolds and match bone tissue ingrowth. The morphology of the gradient scaffolds was assessed, and their bulk compressive mechanical properties were found to be in the same range as human trabecular bone. Finally, scaffold degradation was monitored for up to 10 weeks in phosphate buffered saline pH 7.4 and 0.1 M HCl solution, and scaffolds containing TCP in their composition showed increased degradation compared to those containing HA. This work provides a new methodology for the fabrication and characterization of porous scaffolds containing designer composition gradients that could serve as a platform for the preparation of complex scaffolds for tissue engineering applications. PMID- 30421649 TI - Quantifying the Effect of Repeated Impacts and Lateral Tip Movements on Brain Responses During Controlled Cortical Impact. AB - Controlled cortical impact (CCI) is a widely used laboratory neurotrauma model to study traumatic brain injury. During CCI, the brain is damaged by an impactor tip, which travels along its axial direction to a predefined depth at a preset speed. However, a recent study using high-speed imaging analysis demonstrated that impactor tip of electromagnetically driven CCI device experienced repeated impacts and lateral movements, rather than a single axial impact. How these repeated impacts and lateral movements affect internal brain stresses/strains -- which are the direct cause of neuronal damage and affect the accuracy and reproducibility of CCI -- remains unknown. We aim to use a previously validated, highly detailed three-dimensional finite element (FE) mouse brain model to investigate the effect of repeated impacts and lateral movements on brain responses during CCI. We also measured tip movements of an in-house pneumatically driven CCI and conducted FE simulations. We found that the repeated impacts had minimal effect on peak strains. However, the lateral movement of tip greatly increased brain strains and affected large brain regions. Hence, it is necessary to monitor and control lateral movement to ensure the accuracy and reproducibility of CCI. PMID- 30421650 TI - Enhancing natural killer cells is beneficial in multiple sclerosis - Commentary. PMID- 30421652 TI - EXPRESS: Treatment patterns, healthcare resource utilization, and healthcare costs among patients with pulmonary arterial hypertension in a real-world US database. PMID- 30421653 TI - Decelluarized Cortical Bone Scaffold Promotes Organized Neovascularization In Vivo. AB - Significant bone loss due to disease or traumatic injury requires surgical intervention to modulate the natural healing process of bone. The current bone grafting options, autografts and allografts, can potentially lead to donor site morbidity or mechanical failure over time. The use of tissue engineering is a promising alternative, but the mechanical stability and integrated vasculature in vivo still remains a major challenge. In this work, we introduce a scaffold that mimics the cylindrical structure of native cortical bone and provides biological cues without the addition of growth factors to promote the differentiation of stem cells along the angiogenic lineage. Biocompatibilty of the scaffold was tested with two human endothelial cell types, human microvascular endothelial cells and human umbilical vein endothelial cells, and the angiogenic decellularized scaffold matrix led to a 78% increase in angiogenic protein secretion from human bone marrow derived stem cells. Histological analysis of the scaffolds implanted subcutaneously in the dorsum of BALB/c mice confirmed vessel development and integration at 4 weeks with a decrease in fibrous capsule thickness up to 8 weeks. Future work will need to be performed to evaluate this novel scaffold as a vascularized tissue engineered graft in a large animal model. PMID- 30421654 TI - Tumor growth rate does not predict malignancy in surgically resected thyroid nodules classified as Bethesda category III with architectural atypia. AB - BACKGROUND: It is unknown whether the growth of thyroid nodules with a Bethesda category III cytology (atypia of undetermined significance, AUS) is predictive of malignancy, especially in cases with architectural atypia (AUS-A). We evaluated whether tumor growth rates can help distinguish malignant from benign nodules in the AUS-A subcategory. METHODS: This retrospective, single center cohort study included 172 patients who underwent diagnostic thyroid surgery because of a nodule with a cytological diagnosis of AUS-A. The growth kinetics of nodules was assessed by serial preoperative neck ultrasonography (US) over a median follow-up of 52.6 months (range, 12.7-198.3 months). RESULTS: Pathological examinations showed that 112 (65%) and 60 (35%) patients had benign and malignant nodules, respectively. The largest diameter and volume of both benign and malignant nodules increased gradually (p<0.001 each, and p<0.001 each). However, there was no significant difference in the growth rates of benign and malignant nodules based on the largest diameter (p=0.132) and volume (p=0.200). The time to tumor growth curves and estimated median time to significant tumor growth from baseline were not significantly different in malignant nodules compared to benign nodules (p=0.458 and p=0.568, respectively). The relative risk (RR) of malignancy of growing and stable nodules did not differ significantly based on the largest diameter (RR=0.5, p=0.064) and volume (RR=0.9, p=0.748). CONCLUSIONS: The size of thyroid nodules classified as AUS-A increased linearly, regardless whether these nodules were benign or malignant. These results suggest that growth kinetics on serial preoperative neck US cannot predict malignancy in the AUS-A subcategory. PMID- 30421655 TI - Addressing transport safety and accessibility for people with a disability in developing countries: a formative evaluation of the Journey Access Tool in Cambodia. AB - BACKGROUND: The intersection between health, disability and transport has significant practical challenges for people with a disability living in low- and middle-income countries (LMICs), where road infrastructure is poor and travel unsafe. Lack of transport access to health, education, employment and other services impedes achievement of the Sustainable Development Goals and affects quality of life. The Journey Access Tool (JAT) combines access audit and road safety audit approaches to identify barriers to transport on journeys taken by people with a disability. To be useful and effective, it must fit the expectations of people with a disability (be acceptable) and be feasible for use in different settings (adoptable). Accordingly, a formative evaluation process was undertaken in Phnom Penh, Cambodia. OBJECTIVES: To undertake a formative evaluation of the JAT using an iterative process to tailor the tool, pilot its use by people with a disability, and develop a template for its implementation in other LMICs. METHODS: An iterative process of consultation and three pilots was undertaken. Participants were people with a disability who undertook journeys with a public transport component accompanied by assistants. Focus groups were held after each pilot, and results were integrated into JAT revisions. RESULTS: Issues of terminology were resolved early, as were process issues related to the length of time taken to complete the JAT. Interpersonal issues were more difficult to address, with assistants tending to exceed their role and record their own comments. Use of the tool provided rich information on barriers. CONCLUSIONS: The JAT was both acceptable and adoptable for people with a disability and other stakeholders, and the experience gained will facilitate adaptation of the tool to new settings. The tool has significant potential to shape and support advocacy for change and engagement with transport services and also health, education, employment and other services. PMID- 30421656 TI - Potential mechanisms for the effects of far-infrared on the cardiovascular system - a review. AB - Far-infrared (FIR) is a form of thermal radiation, which may have beneficial effects on cardiovascular health. Clinical studies suggest that FIR irradiation may have therapeutic effects in heart failure, myocardial ischaemia and may improve flow and survival of arteriovenous fistula. Animal studies have suggested a wide range of potential mechanisms involving endothelial nitric oxide synthase and nitric oxide bioavailability, oxidative stress, heat shock proteins and endothelial precursor cells. However, the exact cellular and molecular mechanism of FIR on the cardiovascular system remains elusive. The purpose of this review is to discuss the current literature, focusing on mechanistic studies involving the cardiovascular system, and with a view to highlighting areas for future investigation. PMID- 30421661 TI - Effect of metformin treatment in patients with type 2 diabetes with respect to glyoxalase 1 activity in atherosclerotic lesions. AB - BACKGROUND: The enzyme glyoxalase1 (GLO1) is the main opponent in the degradation of the reactive metabolite methylglyoxal (MG), which by glycation of macromolecules is involved in atherogenesis. Reduced GLO1-activity in atherosclerotic tissue is known to be associated with diabetes. It has been shown that treatment of patients with type 2 diabetes with metformin leads to increased GLO1-activity in peripheral-blood-cells. The aim of this study was to evaluate whether metformin treatment increases GLO1-activity in atherosclerotic lesions of patients with type 2 diabetes. PATIENTS AND METHODS: Patients with type 2 diabetes and carotid artery disease were included into the study prospectively. Type of diabetes-medication was documented upon admission along with demographic and clinical history. Using shock frozen endarterectomy-derived carotid artery plaques, GLO1-activity as well as protein expression was measured by a spectophotometric assay and western-blotting respectively. RESULTS: 33 patients (76 % male, mean age 71 years) were included into the study and were divided according to treatment with metformin or not (15 vs. 18 patients). GLO1-activity was increased by the factor 1.36 when treated with metformin - however, not significantly (0.86 vs. 0.63 U/mg, p = 0.056). Normalisation of GLO1-activity onto GLO1-expression level lead to a significant increase by more than twofold (8.48 vs. 3.85, p = 0.044) while GLO1-protein levels did not differ significantly. GLO1-activity correlated positively with increasing HbA1c, especially under metformin treatment. CONCLUSIONS: Treatment with metformin in patients with type 2 diabetes is associated with enhanced GLO1-activity in atherosclerotic lesions. Regarding the macro- and microvascular complications in these patients further studies are needed to gain more insight into the effect of metformin on the GLO/MG system. PMID- 30421662 TI - Posttraumatic Symptomatology and Alcohol Misuse Among Black College Students: Examining the Influence of Anxiety Sensitivity. AB - OBJECTIVE: Posttraumatic stress symptoms (PTSS) have been found to be associated with alcohol (mis)use among college students. Anxiety sensitivity has been theoretically and empirically linked to both PTSS and alcohol (mis)use. The goal of the present study was to extend research by examining the relations among PTSS, anxiety sensitivity, and alcohol misuse within a sample of trauma-exposed Black college students. METHODS: Participants were 121 Black undergraduate college students who endorsed exposure to a traumatic event (M age = 22.98, 77.7% female). RESULTS: Correlational findings provide support for significant positive relations between PTSS and both anxiety sensitivity and alcohol misuse. Further, analyses revealed a significant indirect effect of anxiety sensitivity on alcohol misuse through PTSS. Specifically, greater anxiety sensitivity was associated with higher levels of PTSS, which, in turn, were associated with higher levels of alcohol misuse. CONCLUSIONS: These findings suggest that the assessment of anxiety sensitivity may be useful in identifying trauma-exposed Black individuals who are likely to experience alcohol misuse and the clinical utility of addressing PTSS in this population reporting anxiety sensitivity to possibly prevent alcohol misuse and related negative consequences. PMID- 30421663 TI - Sexual Assault Information Posted on College and University Websites: Size and Setting Matter. AB - To better understand what and how institutions of higher education (IHEs) communicate information about sexual assault (SA) on their websites, the current cross-sectional descriptive exploratory study analyzed a stratified sample representing 15% of the IHE websites in the United States. Findings show the availability, location, and type of SA information posted on IHE websites differ based on student population and residential character. Large and primarily residential schools are more likely to include SA information, across multiple pages, with a wider informational span than other categories. However, informational gaps are apparent across all websites. Implications for policy and practice are highlighted. PMID- 30421664 TI - Cerebral microbleeds temporarily become less visible or invisible in acute susceptibility weighted magnetic resonance imaging: a rat study. AB - Previously we reported human traumatic brain injury cases demonstrating acute to subacute microbleed appearance changes in susceptibility weighted magnetic resonance imaging (SWI). This study aims to confirm and characterize such temporal microbleed appearance alterations in an experimental model. To elicit microbleed formation brains of male Sprague Dawley rats were pierced in a depth of 4 mm, in a parasagittal position bilaterally using 159 MUm and 474 MUm needles, without the injection of autologous blood or any agent. Rats underwent 4.7 T MRI immediately, then at multiple time points until 125 h. Volumes of hypointensities consistent with microbleeds in SWI were measured using intensity threshold-based approach. Microbleed volumes across time points were compared using repeated measures ANOVA. Microbleeds were assessed by Prussian blue histology at different time points. Hypointensity volumes referring to microbleeds were significantly decreased (corrected p < 0.05) at 24 h compared to the immediate or the 125 h time points. By visual inspection, microbleeds were similarly detectable at the immediate and 125 h imaging but were decreased in extent or completely absent at 24 h or 48 h. Histology confirmed the presence of microbleeds at all time points and all animals. This study confirmed a general temporary reduction in visibility of microbleeds in the acute phase in SWI. Such short-term appearance dynamics of microbleeds should be considered when using SWI as a diagnostic tool for microbleeds in traumatic brain injury and various diseases. PMID- 30421665 TI - Synergetic disintegration of waste activated sludge: improvement of the anaerobic digestion and hygienization of sludge. AB - The main aim of this study was to investigate the impact of a hybrid disintegration process with the use of alkalization and freezing by dry ice on waste activated sludge (WAS) and on the course of the process of mesophilic methane fermentation. In order to achieve the mentioned goal, various analytical techniques were used for assessment of the sludge disintegration and its influence on the further biogas production. As a result of the investigation, it was found that the chemical-thermal process of destruction of WAS results in an increased concentration of organic compounds in the supernatant (expressed as a change in the value of the soluble chemical oxygen demand - SCOD). The use of disintegrated WAS and feeding of the material into the fermentation digester influences, depending on its proportion by volume, the production of biogas and the biogas yield (higher biogas production by ca. 39% in comparison to blank sample was achieved with the appropriately disintegrated sludge). The hybrid process is simple and easy to implement in the full technical scale and does not influence or change the pH value of the sludge feed into the fermentation chambers (the dry ice neutralizes the high pH of the sludge). Additionally, it was determined that the herein developed process, can improve hygienization of the digested sludge. PMID- 30421666 TI - Cornered at a Bar: How Victim Clothing, Alcohol Intake, and Relationship With Bystander Impact Intention to Help. AB - While a negative relationship between rape myth acceptance (RMA) and bystander behavior is established, the specific myths associated with bystander behavior are not well understood. In Study 1, we presented 260 participants with vignettes manipulating clothing and alcohol intake of a woman victim to see how it affected intention to help. In Study 2, we presented 247 participants with similar vignettes, manipulating alcohol intake and relationship with the bystander. Contrary to previous research on RMA, participants were significantly more willing to intervene if the woman was intoxicated. Intervention also depended upon the participants' relationship to the woman: stranger or acquaintance. PMID- 30421667 TI - Moving family interventions into the real world: What matters to oncology stakeholders? AB - BACKGROUND: Family interventions targeting patients and/or informal caregivers are beneficial, but few have been integrated in oncology clinical care. Understanding diverse stakeholder perspectives may inform implementation and dissemination efforts. METHODS: We are currently conducting a randomized controlled trial of CareSTEPS, a telephone-based intervention for caregivers of advanced lung cancer patients. CareSTEPS seeks to improve caregiver and patient self-care behaviors, quality of life, and satisfaction with care. With an eye toward integrating CareSTEPS into clinical care, semi-structured interviews were conducted with 7 experts in integrated care [practice thought leaders] and 26 individuals representing different oncology stakeholder groups (i.e., potential end users of CareSTEPS including counselors, social workers, nurse specialists, and psychologists) [N = 13], decision-makers, including physicians and administrators [N = 6], and key dissemination partners, including representatives from cancer and caregiving advocacy groups [N = 7]). Questions focused on existing caregiver support services, barriers to integrating care for caregivers in routine patient care, and possible models for clinical uptake and dissemination. Interviews were transcribed and analyzed using directed content analysis. RESULTS: Stakeholders noted a mismatch between caregiver needs and services offered, and expressed interest in broader service offerings. Barriers for integrating caregiver support into clinical care included inadequate funding, lack of interdisciplinary training among providers, and concern that research based interventions are often not flexible enough to roll out into clinical practice. To secure buy-in, stakeholders noted the importance of evaluating intervention cost, cost savings, and revenue generation. Possible avenues for dissemination, through bottom-up and top-down (e.g., policy change) approaches, were also discussed. CONCLUSIONS: Findings highlight the importance of evaluating outcomes important to diverse oncology stakeholder groups to speed translation of research into practice. They also suggest that pragmatic trials are needed that allow for flexibility in the delivery of family interventions and that consider the resource limitations of clinical care. PMID- 30421668 TI - From recognition to reaction mechanism: an overview on the interactions between HIV-1 protease and its natural targets. AB - Current investigations of the human immunodeficiency virus protease (HIV-1 PR) as a druggable target towards the treatment of AIDS require an update to facilitate further development of promising inhibitors with improved inhibitory activities. For the past two decades, up to 100 scholarly reports appeared annually on the inhibition and catalytic mechanism of HIV-1 PR. A fundamental literature review on the prerequisite of HIV-1 PR action leading to the release of infectious virion is absent. Herein, recent advances (both computationally and experimentally) on the recognition mode and reaction mechanism of HIV-1 PR involving its natural targets is provided. This overview features more than 80 peer review articles from reputable journals. Recognition of the natural Gag and Gag-Pol cleavage junctions by this enzyme and its mutant analogues was first addressed. Thereafter, a comprehensive dissect of the enzymatic mechanism of HIV 1 PR on its natural polypeptide sequences from literature was put together. In addition, we highlighted ongoing research topics in which in silico methods could be harnessed to provide better insights on the catalytic mechanism of the HIV-1 protease in the presence of its natural substrates. Understanding the recognition and catalytic mechanism of HIV-1 PR leading to the release of an infective virion, which advertently affects the immune system, will assist in designing mechanism-based inhibitors with better bioactivity. PMID- 30421669 TI - Use of hemoglobin for delivering exogenous carbon monoxide in medicinal applications. AB - Carbon monoxide (CO), at low concentrations, can have a variety of positive effects on the body including anti-apoptosis, anti-inflammatory, anti-oxidative and anti-proliferative effects. Although CO has great potential for use as a potent medical bioactive gas, for it to exist in the body in stable form, it must be associated with a carrier. Hemoglobin (Hb) represents a promising material for use as a CO carrier because most of the total CO in the body is stored associated with Hb in red blood cells (RBC). Attempts have been made to develop an Hb-based CO carrying system using RBC and Hb-based artificial oxygen carriers. Some of these have been reported to be safe and to have therapeutic value as a CO donor in preclinical and clinical studies. In the present review, we overview the potential of RBC and Hb-based artificial oxygen carriers as CO carriers based on the currently available literature evidence for their use in pharmaceutical therapy against intractable disorders. PMID- 30421670 TI - Machine Learning Methods in Precision Medicine Targeting Epigenetics Diseases. AB - BACKGROUND: On a tide of big data machine learning is coming to its day. Referring to huge amounts of epigenetic data coming from biological experiments and clinic, machine learning can help in detecting epigenetic features in genome, finding correlations between phenotypes and modifications in histone or genes, accelerating the screen of lead compounds targeting epigenetics diseases and many other aspects around the study on epigenetics, which consequently realizes the hope of precision medicine. METHODS: In this minireview, we will focus on reviewing the fundamentals and applications of machine learning methods which are regularly used in epigenetics filed and explain their features. Their advantages and disadvantages will also be discussed. RESULTS: Machine learning algorithms have accelerated studies in precision medicine targeting epigenetics diseases. CONCLUSION: In order to make full use of machine learning algorithms, one should get familiar with the pros and cons of them, which will benefit from big data by choosing the most suitable method(s). PMID- 30421672 TI - Thymoquinone shows the diverse therapeutic actions by modulating multiple cell signaling pathways: single drug for multiple targets. AB - Thymoquinone (TQ), derived from Nigella sativa, has lately been shown as a miracle drug because of it's a wide range of therapeutic effects against various diseases, including cancer, asthma, diabetes, colitis, infectious diseases etc. In the present review, we aimed to decipher the molecular mechanisms of therapeutic action of TQ. Many in vivo and in vitro studies have demonstrated the therapeutic efficacy of TQ against a wide range of diseases. We extensively searched the literature of the therapeutic properties of TQ and its formulations from various online sources, including PubMed, Google Scholar, Scopus and Science Direct. TQ possesses potent anti-inflammatory and immunomodulatory effects by specifically targeting the NF-kB, IL-1beta and TNF-alpha signaling pathways. The anticancer activity of TQ has been primarily shown by altering the expression of signal transducers and activator transcription (STAT3), PTEN and p53 genes. TQ alleviates the hyperglycemia-associated complications, the hepatic or renal ailments through its potential antioxidant and anti-inflammatory properties. Interestingly, the liposome- or nanoparticle-based TQ formulations have shown greater effectiveness against various diseases in animal models. Thus, the understanding of the molecular mechanisms of TQ action may lead to the development of its therapeutic formulations to cure of a wide variety of diseases. PMID- 30421671 TI - Simulated protein thermal detection (SPTD) for enzyme thermostability study and an application example for pullulanase from Bacillus deramificans. AB - BACKGROUND: The relationship between protein structure and its bioactivity is one of the fundamental problems for protein engineering and pharmaceutical design. METHOD: A new method, called SPTD (Simulated Protein Thermal Detection), was proposed for studying and improving the thermal stability of enzymes. The method was based on the evidences observed by conducting the MD (Molecular Dynamics) simulation for all the atoms of an enzyme vibrating from the velocity at a room temperature (e.g., 25 degrees C) to a desired working temperature (e.g., 65 degrees C). According to the recorded MD trajectories and the coordinate deviations of the constituent residues under the two different temperatures, some new strategies have been found that are useful for both drug delivery and starch industry. CONCLUSION: The SPTD technique presented in this paper may become a very useful tool for pharmaceutical design and protein engineering. PMID- 30421673 TI - Halogenated Compounds from Corals: Chemical Diversity and Biological Activities. AB - As important marine biological resources, corals produce a large amount of active organic compounds in their secondary metabolic processes, including numerous brominated, chlorinated, and iodinated compounds. These compounds, with novel structures and unique activities, guide the discovery and research of important lead compounds and novel biological mechanisms. Through large numbers of literature survey, this paper summarized a total of 145 halogenated secondary metabolites which were roughly divided into four major classes of terpenes, prostaglandins, steroids and alkaloids. And they were mainly isolated from ten coral families, Ellisellidae, Gorgoniidae, Briareidae, Plexauridae, Anthothelidae, Alcyoniidae, Clavularidae, Tubiporidae, Nephtheidae and Dendrophyllidae at the best of our knowledge. In addition, their organism species, structure composition and biological activity were also discussed in the form of chart in this essay. PMID- 30421674 TI - Design of artificial immunogens containing melanoma-associated T-cell epitopes. AB - OBJECTIVE: Immunotherapy based on induction of T-cell response is a promising approach to treatment of oncological diseases that currently attracts particular attention of researchers. The study aims to design artificial epitope-based immunogens, DNA vaccine candidates against melanoma and evaluate their antitumor response within the system of T-cell response induction ex vivo. METHODS: The study used computer methods for predicting T-cell epitopes and designing polyepitope antigens, DNA vaccine candidates against melanoma. Evaluating target gene expression was carried out using two methods: (1) detection of synthesis of specific mRNA in HEK-293T cells transfected with DNA-vaccine constructs; and (2) immunochemical staining of transfected cell preparations using MAb. Analysis of cytotoxic activity of autologous effector lymphocytes generated in the system of T-cell response induction ex vivo involved detecting the content of lactate dehydrogenase released from the damaged target cells. RESULTS: Using original software we have predicted T-cell epitopes and designed two DNA vaccine constructs - pMEL-TCI and pMEL-A0201 - encoding T-cell epitopes of six immunodominant melanoma antigens (NY-ESO-1, MART1, MAGE-A1, MAGE-A11, MAGE-A3, and MAGE-C1). We have demonstrated that the designed genetic constructs provide synthesis of respective mRNAs and proteins in a culture of transfected eukaryotic HEK-293T cells. Dendritic cells from HLA-A*02:01+ donors transfected with DNA vaccine constructs induce autologous T-lymphocytes to develop a specific cytotoxic activity to Mel Is melanoma cells in the model of T-cell response induction ex vivo. CONCLUSION: The described approach may become a common platform for designing not only vaccines against oncological diseases but also immunoprophylactic vaccines against infectious diseases. PMID- 30421675 TI - Enhanced resistance of triploid crucian carp to cadmium-induced oxidative and endoplasmic reticulum stresses. AB - Cadmium (Cd) is highly toxic to aquatic organisms. In this study, we found a new variety of triploid crucian carp with strong Cd resistance. Under Cd stress, the mortality and abnormality rates in triploid crucian carp were lower than those of diploid strains. To explore the molecular mechanisms underlying Cd stress, the liver transcriptomes of triploid crucian carp were obtained. The expression of 5,797 unigenes in Cd-treated triploid crucian carp differed significantly from those of control group. These differential expression genes mainly involved in endoplasmic reticulum (ER) associated ubiquitin-dependent proteins, membrane proteins of ER and mitochondria. Quantitative real-time PCR and enzyme activity analysis all confirmed triploid crucian carp resistance to Cd stress was regulated by both oxidative stress and ER stress responses. Underlying Cd stress, the enhanced expression of sestrin-1 gene may increase triploid crucian carp survival compared to diploid fish. This study also provides important clue that IRE-1 and PERK, but not ATF-6, were involved in enhancement of Cd resistance in triploid crucian carp. Moreover, our results showed that egg envelopes of crucian carp had strong ability to block Cd and could protect embryos from Cd stress damage. PMID- 30421676 TI - Establishment of retinal degeneration model in rat and monkey by intravitreal injection of sodium iodate. AB - BACKGROUND: Animal models play critical roles in studying etiology and therapy of retinal degeneration (RD). OBJECTIVE: To establish a RD model in monkey without severe systemic side-effects. METHODS: Cynomolgus monkeys and Sprague-Dawley rats were treated with intravenous and intravitreal sodium iodate (SI). The ERG, FFA, OCT and retinal morphology were examined to evaluate the retinal function and structure. ARPE19 cells were treated with SI for cell viability and morphology examinations. GSH was used to the SI-treated culture cells and rats for mechanistic study. RESULTS: Intravenous SI failed to induce retinal degeneration in monkeys due to its lethal toxicity and spontaneous recovery of the visual function. Intravitreal injection of SI induced very faster and violent retina damages in monkeys and rats. Different dosages of SI were tested in both rats and monkeys and a proper SI dosage for the model was calculated. Glutathione partially rescued the oxidation-damage in SI-treated retinas, but not through neutralizing SI. Combination of a proper dosage of intravitreal SI and intravenous GSH could generate a moderate sub-acute degeneration in retina. CONCLUSIONS: Retinal degeneration model could be established in cynomolgus monkey by intravitreal injection of SI. Its key advantages are that the lethal SI side effects can be avoid, and the structural and functional changes are closer to those in the patients with retinal degeneration, except it develops too fast and more severe. A proper dosage of SI plus systemic GSH generates a delayed and moderate degeneration in retina. Such a prolonged therapeutic window provides a tool for development of new therapies like gene or stem cell-based therapy for retinal degeneration. PMID- 30421677 TI - The inhibition of digitoxin on Store Operated Calcium Entry is dependent on the phosphorylation sites and pore region of Orai1. AB - BACKGROUND: Mostly mediated by STIM1 and Orai1, Store-operated Ca2+ entry (SOCE) is a major Ca2+ influx pathway that has been linked with many types of diseases like myopathy, epilepsy, immune deficient diseases, and cancer. Currently many details about SOCE process have been revealed. However, the dissection of the molecular mechanisms underlying SOCE activation and the development possible treatments of SOCE related diseases are hindered, partly due to the lack of more specific pharmacological tools and poor understandings of currently available SOCE modifiers, including the a newly identified SOCE inhibitor, digitoxin. OBJECTIVE AND METHODS: Using a combination of Ca2+ and forster resonance energy transfer (FRET) imaging, we aimed to systemically delineate the sites or domains needed for the inhibition of digitoxin on SOCE. RESULTS: We revealed that the inhibitory effects of digitoxin are exerted on Orai1. If digitoxin were applied to resting Orai1, then its inhibition was dependent on S27-S30 residues of Orai1. While 8h-incubation of digitoxin with STIM1-prebound Orai1 or its constitutively active mutant Orai1-ANSGA, its inhibition was no longer dependent on S27/S30 residues. Instead, the inhibition may involve the pore region of Orai1 channels, as V102C mutant at the pore region would greatly diminish or abolish the inhibition on pre-activated Orai1. CONCLUSIONS: Our study identified two sites critical for the inhibition on Orai1 channels, providing valuable targets for future design of SOCE inhibitors. PMID- 30421678 TI - Alpha1-Antitrypsin Deficiency: Transition of Care for the Child With AAT Deficiency into Adulthood. AB - IMPORTANCE Alpha1-antitrypsin (AAT) deficiency is a common, but underdiagnosed genetic condition, affecting 1 in 1500 individuals, which can present insidiously with liver disease in children. Although clinical practice guidelines exist for the management of AAT deficiency, especially with regards to pulmonary involvement, there are no published recommendations that specifically relate to the management of the liver disease and monitoring for lung disease associated with this condition, particularly in children. OBJECTIVE To review the literature on the management of AAT deficiency-associated liver disease in adults and children. EVIDENCE REVIEW A systematic search for articles indexed in PubMed and published was undertaken. Some earlier selected landmark references were included in the review. Search terms included: "alpha1-antitrypsin deficiency"; "liver disease"; "end-stage liver disease"; "liver transplantation" and "preventative management". Recommendations for the management of children with suspected or confirmed AAT deficiency were made according to the Strength of Recommendation Taxonomy scale. FINDINGS Liver complications arising from AAT deficiency result from the accumulation of mutated AAT protein within hepatocytes. Liver disease occurs in 10% of children, manifested by cholestasis, pruritus, poor feeding, hepatomegaly, and splenomegaly, but the presentation is highly variable. A diagnostic test for AAT deficiency is recommended for these children. Baseline liver function tests should be obtained to assess for liver involvement; however, the only curative treatment for AAT deficiency-associated liver disease is organ transplantation. CONCLUSIONS AND RELEVANCE There should be a greater vigilance for AAT deficiency testing among pediatricians. Diagnosis should prompt assessment of liver involvement. Children with AAT-deficiency-associated liver disease should be referred to a liver specialist and monitored throughout their lifetimes for the symptoms of AAT-deficiency-related pulmonary involvement. PMID- 30421679 TI - Breath-Holding Spells in Pediatrics: A Narrative Review of the Current Evidence. AB - BACKGROUND: Breath-holding spells are common, frightening, but fortunately benign events. Familiarity with this condition is important so that an accurate diagnosis can be made. OBJECTIVE: To familiarize physicians with the clinical manifestations, diagnosis, evaluation, and management of children with breath holding spells. METHODS: A PubMed search was completed in Clinical Queries using the key term "breath-holding spells". The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies, and reviews. Only papers published in the English literature were included in this review. The information retrieved from the above search was used in the compilation of the present article. RESULTS: Breath-holding spells affect 0.1 to 4.6% of otherwise healthy young children. The onset is usually between 6 and 18 months of age. The etiopathogenesis is likely multifactorial and includes autonomic nervous system dysregulation, vagally-mediated cardiac inhibition, delayed myelination of the brain stem, and iron deficiency anemia. Breath-holding spells may be cyanotic or pallid. The former are usually precipitated by anger or frustration while the latter are more often precipitated by pain or fear. In the cyanotic type, the child usually emits a short, loud cry, which leads to a sudden involuntary holding of the breath in forced expiration. The child becomes cyanosed, rigid or limp, followed by a transient loss of consciousness, and a long-awaited inspiration and resolution of the spell. In the pallid type, crying may be minimal or "silent". The apneic period in the pallid type is briefer than that in the cyanotic type prior to the loss of consciousness and posture. The episode in the pallid type then proceeds in the same manner as a cyanotic spell except that the child in the pallid type develops pallor rather than cyanosis. In both types, the entire episode lasts approximately 10 to 60 seconds. The spells usually disappear spontaneously by 5 years of age. CONCLUSION: Although breath holding spells are benign, they can be quite distressing to the parents. Confident reassurance and frank explanation are the cornerstones of treatment. Underlying cause, if present, should be treated. Interventions beyond iron supplementation may be considered for children with severe and frequent breath holding spells which have a strong impact on the lifestyle of both the child and family. PMID- 30421680 TI - The Unlicensed and Off-label Prescription of Medications in General Paediatric Ward: an Observational Study. AB - BACKGROUND: The unlicensed (UL) and off-label (OL) prescription of medications is common in paediatrics and does not constitute negligent practice, since there is often no approved alternative. AIM: to determine the current frequency of UL and OL prescriptions in children from one month to 12 years of age in a paediatric inpatient unit (PIU). METHODS: Observational, prospective study, reviewing the prescriptions of all patients admitted to the PIU in a university hospital in a single week in August 2014 and a single week in January 2015. RESULTS: We included 157 patients, median age 18 months and median length of stay 24 days. There were 1,328 prescription items (average of 8.4 items/patient) and only two patients without UL/OL use. During the winter season (August), 27% of prescriptions were classified as UL and 44.6% as OL, and during summer (January), 29.6% UL and 45.1% OL. We identified 188 medications, of which the most prescribed were paracetamol (11%) and dipyrone (9.5%). The most frequent OL classification was drug formulation (15.8%). In the winter week, the most frequent reasons for admission were respiratory (44%), followed by other clinical causes (CC) (17.3%), while in the summer week, they were CC (26.3%), followed by surgical and gastro-hepatic (23.7%). CONCLUSION: The OL prescription of medicines for children in Brazil is in accordance with the international literature. The higher prevalence of OL due to formulation found in this study is related to the use of formulations other than those used by the FDA. PMID- 30421681 TI - Helicobacter pylori infection in Sjogren's syndrome:Co-incidence or causality? AB - BACKGROUND AND AIM: Lymphoid cell infiltration and destruction of exocrine glands, specifically lacrimal and salivary glands are characteristics of Sjogren's syndrome (SS). An etiological role has been proposed for Helicobacter pylori (H.Pylori), interacting in the clinical course and complications of SS (including gastric cancer and lymphoma). The aim of this study was to identify the probable correlation between H. pylori infection and Sjogren's syndrome (SS). METHOD: In this case-control study, ELISA method was used to determine serum level of IgA and IgM anti H. pylori antibody in 43 subjects with SS according to the international criteria and 95 healthy subjects as control. SPSS-17 was used to analysis data with t-test. P value <0.05 were considered significant. RESULTS: Serum level of IgM (34.9% vs 10.5%, p-value= 0.001) and IgA (67.4% vs 46.3% p value= 0.021) anti H.Pylori antibody were significantly higher in SS patients compared to the control group. There was a positive correlation between age and H.Pylori infection (r=0.2, P-value=0.05). CONCLUSIONS: Patients with SS had a higher prevalence of H. pylori infection compared to the normal population. Eradication of H.Pylori is recommended particularly in older patients with SS. PMID- 30421682 TI - A Narrative Review of Diabetes Group Visits in Low-Income and Underserved Settings. AB - BACKGROUND: Prior studies have supported the efficacy of diabetes group visits. However, the benefit of diabetes group visits for low-income and underserved individuals is not clear. The purpose of this study was to conduct a narrative review in order to clarify the efficacy of diabetes group visits in low-income and underserved settings. METHODS: The authors performed a narrative review, categorizing studies into nonrandomized and randomized. RESULTS: A total of 14 studies were identified. Hemoglobin A1c was the most commonly measured outcome, which improved for the majority of group visit participants. Preventive care showed consistent improvement for intervention arms. There were several other study outcomes including metabolic (i.e., blood pressure), behavioral (i.e., exercise), functional (i.e., quality of life), and system-based (i.e., cost). CONCLUSIONS: Diabetes group visits for low-income and underserved individuals resulted in superior preventive care but the impact on glycemic control remains unclear. PMID- 30421683 TI - Acute kidney injury post cardiac catheterization: Does vascular access route matter? AB - BACKGROUND: Acute Kidney Injury as a complication of cardiac catheterization is associated with increased length of hospital stay and mortality. In recent years, the use of the radial artery for cardiac catheterization is increasing in frequency. OBJECTIVE: The objective of this concise review was to evaluate method of cardiac access site and its impact on Acute Kidney Injury following cardiac catheterization. METHODS: After a thorough search on Medline, Google Scholar and PubMed, we included all literature relevant to Acute kidney injury following transradial and transfemoral cardiac catheterization. RESULTS: While acute kidney injury was caused due to a variety of reasons, it is important to consider each case on an individual basis. We found a trend towards increased use of transradial approach in patients at high risk of developing kidney injury. However, limitations such as operator experience, anatomical challenges and so on do exist with this approach. CONCLUSION: Transradial access offers several advantages to a patient at high risk of acute kidney injury undergoing cardiac catheterization. Further large studies are needed to establish this trend in the years ahead. PMID- 30421684 TI - Application of Cell Therapy for Anti-Aging Facial Skin. AB - The human skin undergoes the complex process of aging which is prompted by the interplay of intrinsic mechanisms and extrinsic influences. Aging is unavoidable but can be somewhat delayed. Numerous approaches have been developed to slow down or improve on facial skin aging process as it is of interest to stake holders in the beauty and fashion world as well as to plastic surgeons. Adipose-derived stem cell [ADSC] and mesenchymal stem cell [MSC] as potential anti-ageing agents to some extent has provided a promising and effective alternative in managing skin and facial skin ageing. Furthermore, bone marrow-derived mesenchymal stem cell [BMMSC] have exhibited similar ability to rejuvenate aged skin. This review is aimed at giving a comprehensive account of the application of stem cells especially ADSCs and MSCs to reduce or slow down the rate of facial skin aging process. PMID- 30421685 TI - Molecular analysis of uropathogenic E.coli isolates from Urinary tract infections in Ilam. AB - The aim of the current study was to investigate the prevalence virulence genes profile in UPEC isolates in Ilam. For this purpose, a total of 8o UPEC isolates for patients with UTIs were collected during 6 months period. The multiplex polymerase chain reaction (Multiplex PCR) was used for detection of the papEF, fimH, iucD, hlyA, fyuA, and ompT genes. The prevalence of genes the fimH, papEF, iucD, fyuA, hlyA, hlyA and ompT were 87.5, 47.5, 60, 67.5, 27.5, 47.5 and 71.2, respectively. Among all of isolates, 27 gene profiles were obtained. The number isolates related to 4 virulence factor simultaneous that were 25 isolates. Considering the different antibiotic patterns, will be proposed develop and an appropriate program for antibiotics in each region and even in each hospital. Also, investigation about the profile of different virulence genes which capable of inducing various pathogens is will be done in the future. PMID- 30421686 TI - Evaluation the effect of Cinnarizine on promastigote and amastigote forms of Leishmania major AB - As an important global disease, cutaneous leishmaniasis is associated with complications such as secondary infections and atrophic scars. The first line treatment with antimonials is expensive and has serious side effects including development of drug resistance. The main objective of this study was to evaluate the effect of Cinnarizine on standard strains of Leishmania major because of paucity of information on this subject. In this experimental study, four concentrations of the drug (5, 10, 15 and 20 ug/ml) were added to Leishmania major cultures at 24, 48 and 72 hours intervals. MTT assays were performed to determine parasite viability and drug toxicity. Leishmania major promastigotes were augmented to the in vitro cultured macrophages (J774 cells) and then incubated for 72 hours. Half maximal inhibitory concentration (IC50) was ascertained by counting parasites. The inhibitory effect of the drug was compared with that of Glucantime. Flow-cytometry was performed to investigate apoptosis. Each test was repeated trice. The IC50 values of Cinnarizine at 20 ug/ml concentrations after 72 hours were calculated to be 34.76 ug/ml and 23.73 ug/ml for promastigotes and amastigotes respectively. The results of MTT assays showed 48 % decrease in promastigote viability after 72 hour-exposure to Cinnarizine at 20 ug/ml concentration. Programmed cell death in promastigote- and amastigote infected macrophages was quantified to be 13.66 % and 98.7 % respectively. Flow- cytometry analysis indicated that Cinnarizine induces early and late apoptosis in parasites . All treatments produced results which differed significantly from control group (P<0.05). Cinnarizine showed low toxicity with anti-leishmanial and apoptosis effects on both promastigote and intracellular amastigote forms. Therefore, we may suggest further assessment in animal models of this drug as candidates for cutaneous leishmaniasis therapy. PMID- 30421687 TI - Evaluation of glucose and lipid lowering activity of Arganimide A in normal and streptozotocin-induced diabetic rats. AB - AIMS: Arganimide A (4,4-dihydroxy-3,3-imino-di-benzoic acid) is a compound belonging to a family of aminophenolics found in fruit of Argania spinosa. The purpose of this study was to investigate the glucose and lipid lowering activity of Arganimide A (ARG A). METHODS: The effect of a single dose and daily oral administration of Arganimide A (ARG A) on blood glucose levels and plasma lipid profile was tested in normal and streptozotocin (STZ) diabetic rats at a dose of 2 mg/kg body weight. RESULTS: Single oral administration of ARG A reduced blood glucose levels from 26.50+/-0.61 mmol/L to 14.27+/-0.73 mmol/L (p<0.0001) six hours after administration in STZ diabetic rats. Furthermore, blood glucose levels were decreased from 5.35+/-0.30 mmol/L to 3.57+/-0.17 mmol/L (p<0.0001) and from 26.50+/-0.61 mmol/L to 3.67+/-0.29 mmol/L (p<0.0001) in normal and STZ diabetic rats, respectively, after seven days of treatment. Moreover, no significant changes in body weight in normal and STZ rats were shown. According to the lipid profile, the plasma triglycerides levels were decreased significantly in diabetic rats after seven days of ARG treatment (p<0.05). Moreover, seven days of ARG A treatment decreased significantly the plasma cholesterol concentrations (p<0.001). CONCLUSION: ARG A possesses glucose and lipid lowering activity in diabetic rats and this natural compound may be beneficial in the treatment of diabetes. PMID- 30421688 TI - How differing methods of ascribing ethnicity and socio-economic status affect risk estimates for hospitalisation with infectious disease. AB - Significant ethnic and socio-economic disparities exist in infectious diseases (IDs) rates in New Zealand, so accurate measures of these characteristics are required. This study compared methods of ascribing ethnicity and socio-economic status. Children in the Growing Up in New Zealand longitudinal cohort were ascribed to self-prioritised, total response and single-combined ethnic groups. Socio-economic status was measured using household income, and both census derived and survey-derived deprivation indices. Rates of ID hospitalisation were compared using linked administrative data. Self-prioritised ethnicity was simplest to use. Total response accounted for mixed ethnicity and allowed overlap between groups. Single-combined ethnicity required aggregation of small groups to maintain power but offered greater detail. Regardless of the method used, Maori and Pacific children, and children in the most socio-economically deprived households had a greater risk of ID hospitalisation. Risk differences between self-prioritised and total response methods were not significant for Maori and Pacific children but single-combined ethnicity revealed a diversity of risk within these groups. Household income was affected by non-random missing data. The census-derived deprivation index offered a high level of completeness with some risk of multicollinearity and concerns regarding the ecological fallacy. The survey-derived index required extra questions but was acceptable to participants and provided individualised data. Based on these results, the use of single combined ethnicity and an individualised survey-derived index of deprivation are recommended where sample size and data structure allow it. PMID- 30421689 TI - Association between rs12252 and influenza susceptibility and severity: an updated meta-analysis. AB - In several lately published studies, the association between single-nucleotide polymorphism (SNP, rs12252) of IFITM3 and the risk of influenza is inconsistent. To further understand the association between the SNP of IFITM3 and the risk of influenza, we searched related studies in five databases including PubMed published earlier than 9 November 2017. Ten sets of data from nine studies were included and data were analysed by Revman 5.0 and Stata 12.0 in our updated meta analysis, which represented 1365 patients and 5425 no-influenza controls from four different ethnicities. Here strong association between rs12252 and influenza was found in all four genetic models. The significant differences in the allelic model (C vs. T: odds ratio (OR) = 1.35, 95% confidence interval (CI) (1.03-1.79), P = 0.03) and homozygote model (CC vs. TT: OR = 10.63, 95% CI (3.39-33.33), P < 0.00001) in the Caucasian subgroup were discovered, which is very novel and striking. Also novel discoveries were found in the allelic model (C vs. T: OR = 1.37, 95% CI (1.08-1.73), P = 0.009), dominant model (CC + CT vs. TT: OR = 1.48, 95% CI (1.08-2.02), P = 0.01) and homozygote model (CC vs. TT: OR = 2.84, 95% CI (1.36-5.92), P = 0.005) when we compared patients with mild influenza with healthy individuals. Our meta-analysis suggests that single-nucleotide T to C polymorphism of IFITM3 associated with increasingly risk of severe and mild influenza in both Asian and Caucasian populations. PMID- 30421690 TI - Transmission of Staphylococcus aureus from dry surface biofilm (DSB) via different types of gloves. AB - BACKGROUND: Pathogens can survive for extended periods when incorporated into biofilm on dry hospital surfaces (ie, dry-surface biofilm, DSB). Bacteria within biofilm are protected from desiccation and have increased tolerance to cleaning agents and disinfectants. OBJECTIVE: We hypothesized that gloved hands of healthcare personnel (HCP) become contaminated with DSB bacteria and hence may transmit bacteria associated with healthcare-associated infections (HAIs). METHOD: Staphylococcus aureus DSB was grown in vitro on coupons in a bioreactor over 12 days with periodic nutrition interspersed with long periods of dehydration. Each coupon had ~107 DSB bacterial cells. Transmission was tested with nitrile, latex, and surgical gloves by gripping DSB-covered coupons then pressing finger tips onto a sterile horse blood agar surface for up to 19 consecutive touches and counting the number of colony-forming units (CFU) transferred. Coupons were immersed in 5% neutral detergent to simulate cleaning, and the experiment was repeated. RESULTS: Bacterial cells were readily transmitted by all 3 types of gloves commonly used by HCP. Surprisingly, sufficient S. aureus to cause infection were transferred from 1 DSB touch up to 19 consecutive touches. Also, 6 times more bacteria were transferred by nitrile and surgical gloves than to latex gloves (P <.001). Treating the DSB with 5% neutral detergent increased the transmission rate of DSB bacteria 10-fold. CONCLUSION: Staphylococcus aureus incorporated into environmental DSB and covered by extracellular polymeric substances readily contaminates gloved hands and can be transferred to another surface. These results confirm the possibility that DSB contributes to HAI acquisition. PMID- 30421691 TI - A systematic review and meta-analysis of the prevalence and associations of stress and burnout among staff in long-term care facilities for people with dementia. AB - : ABSTRACTBackground:Care home staff stress and burnout may be related to high turnover and associated with poorer quality care. We systematically reviewed and meta-analyzed studies reporting stress and burnout and associated factors in staff for people living with dementia in long-term care. METHODS: We searched MEDLINE, PsycINFO, Web of Science databases, and CINAHL database from January 2009 to August 2017. Two raters independently rated study validity using standardized criteria. We meta-analyzed burnout scores across comparable studies using a random effects model. RESULTS: 17/2854 identified studies met inclusion criteria. Eight of the nine studies reporting mean Maslach Burnout Inventory (MBI) scores found low or moderate burnout levels. Meta-analysis of four studies using the 22-item MBI (n = 598) found moderate emotional exhaustion levels (mean 18.34, 95% Confidence Intervals 14.59-22.10), low depersonalization (6.29, 2.39 10.19), and moderate personal accomplishment (33.29, 20.13-46.46). All three studies examining mental health-related quality of life reported lower levels in carer age and sex matched populations. Staff factors associated with higher burnout and stress included: lower job satisfaction, lower perceived adequacy of staffing levels, poor care home environment, feeling unsupported, rating home leadership as poor and caring for residents exhibiting agitated behavior. There was preliminary evidence that speaking English as a first language and working shifts were associated with lower burnout levels. CONCLUSIONS: Most care staff for long-term care residents with dementia experience low or moderate burnout levels. Prospective studies of care staff burnout and stress are required to clarify its relationship to staff turnover and potentially modifiable risk factors. PMID- 30421692 TI - The impact of frailty and cognitive impairment on quality of life: employment and social context matter. AB - : ABSTRACTBackground:How cognitive impairment and frailty combine to impact on older adults' Quality of Life (QoL) is little studied, but their inter relationships are important given how often they co-occur. We sought to examine how frailty and cognitive impairment, as well as changes in frailty and cognition, are associated with QoL and how these relationships differ based on employment status and social circumstances. METHODS: Using the Survey of Health, Ageing, and Retirement in Europe data, we employed moderated regression, followed by simple slopes analysis, to examine how the relationships between levels of health (i.e., of frailty and cognition) and QoL varied as a function of sex, age, education, social vulnerability, and employment status. We used the same analysis to test whether the relationships between changes in health (over two years) and QoL varied based on these same moderators. RESULTS: Worse frailty (b = -1.61, p < .001) and cognitive impairment (b = -0.08, p < .05) were each associated with lower QoL. Increase in frailty (b = -2.17, p < .001) and cognitive impairment (b = -0.25, p < .001) were associated with lower QoL. The strength of these relationships varied depending on interactions with age, sex, education, social vulnerability, and employment status. Higher social vulnerability was consistently associated with lower QoL in analyses examining both static health (b = -3.16, p < .001) and change in health (b = -0.66, p < .001). CONCLUSIONS: Many predictors of QoL are modifiable, providing potential targets to improve older adults' QoL. Even so, the relationships between health, cognition, and social circumstances that shape QoL in older adults are complex, highlighting the importance for individualized interventions. PMID- 30421693 TI - Trichostatin A induces Trypanosoma cruzi histone and tubulin acetylation: effects on cell division and microtubule cytoskeleton remodelling. AB - Trypanosoma cruzi, the causative agent of Chagas disease, is a public health concern in Latin America. Epigenetic events, such as histone acetylation, affect DNA topology, replication and gene expression. Histone deacetylases (HDACs) are involved in chromatin compaction and post-translational modifications of cytoplasmic proteins, such as tubulin. HDAC inhibitors, like trichostatin A (TSA), inhibit tumour cell proliferation and promotes ultrastructural modifications. In the present study, TSA effects on cell proliferation, viability, cell cycle and ultrastructure were evaluated, as well as on histone acetylation and tubulin expression of the T. cruzi epimastigote form. Protozoa proliferation and viability were reduced after treatment with TSA. Quantitative proteomic analyses revealed an increase in histone acetylation after 72 h of TSA treatment. Surprisingly, results obtained by different microscopy methodologies indicate that TSA does not affect chromatin compaction, but alters microtubule cytoskeleton dynamics and impair kDNA segregation, generating polynucleated cells with atypical morphology. Confocal fluorescence microscopy and flow cytometry assays indicated that treated cell microtubules were more intensely acetylated. Increases in tubulin acetylation may be directly related to the higher number of parasites in the G2/M phase after TSA treatment. Taken together, these results suggest that deacetylase inhibitors represent excellent tools for understanding trypanosomatid cell biology. PMID- 30421694 TI - Human papillomaviruses 16 and 58 are distributed widely among women living in Shanghai, China, with high-grade, squamous intraepithelial lesions. AB - The distribution of human papillomaviruses (HPVs) must be understood for the control and prevention of cervical cancer. Community-based Papanicolaou and HPV DNA tests were performed on 41 578 women. The prevalences of HPV genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 were assessed. In total, 10% women were infected/co-infected by these HPVs. The infection rate increased from 7.1% in women aged ?30 years to 10.4% in those aged 50-60 years, and then decreased slightly to 9.9% in those aged >60 years. The HPV 16 and 58 positivity rates were significantly higher among women with high-grade squamous intraepithelial lesions (HSILs) than among those with cervicitis/negativity for intraepithelial lesion or malignancy (NILM) or low-grade SILs (LSILs). The HPV 18, 52 and 68 infection rates were significantly lower in women with HSILs than in those with NILM or LSILs. The proportion of women infected by multiple HPV strains was higher among those with HSILs. The proportions of the five most common genotypes, HPV 16, 18, 33, 52 and 58, increased with the number of co infecting strains. HPV 16 and 58 were the high-risk HPVs in the Shanghai community and should be the focus in HPV screening and vaccination. PMID- 30421695 TI - Cyberbullying victimisation and internalising and externalising problems among adolescents: the moderating role of parent-child relationship and child's sex. AB - : AimsPrevious research has found links between cyberbullying victimisation and internalising and externalising problems among adolescents. However, little is known about the factors that might moderate these relationships. Thus, the present study examined the relationships between cyberbullying victimisation and psychological distress, suicidality, self-rated poor mental health and substance use among adolescents, and tested whether parent-child relationship and child's sex would moderate these relationships. METHODS: Self-report data on experiences of cyberbullying victimisation, self-rated poor mental health, psychological distress, suicidality and substance use were derived from the 2013 Ontario Student Drug Use and Health Survey, a province-wide school-based survey of students in grades 7 through 12 aged 11-20 years (N = 5478). Logistic regression models adjusted for age, sex, ethnicity, subjective socioeconomic status and involvement in physical fighting, bullying victimisation and perpetration at school. RESULTS: Cyberbullying victimisation was associated with self-rated poor mental health (adjusted odds ratio (OR) 2.15; 95% confidence interval (CI) 1.64 2.81), psychological distress (OR 2.41; 95% CI 1.90-3.06), suicidal ideation (OR 2.38; 95% CI 1.83-3.08) and attempts (OR 2.07; 95% CI 1.27-3.38), smoking tobacco cigarette (OR 1.96; 95% CI 1.45-2.65), cannabis use (OR 1.82; 95% CI 1.32-2.51), and binge drinking (OR 1.44; 95% CI 1.03-2.02). The association between cyberbullying victimisation and psychological distress was modified by parent child relationship and child's sex (three-way interaction term p < 0.05). The association between cyberbullying victimisation and psychological distress was much stronger among boys who have a negative relationship with their parents. CONCLUSIONS: Findings suggest that cyberbullying victimisation is strongly associated with psychological distress in most adolescents with the exception of males who get along well with their parents. Further research using a longitudinal design is necessary to disentangle the interrelationship among child's sex, parent-child relationship, cyberbullying victimisation and mental health outcomes among adolescents in order to improve ongoing mental health prevention efforts. PMID- 30421696 TI - Perceived barriers of tobacco dependence treatment: a mixed-methods study among primary healthcare physicians in Armenia. AB - BACKGROUND: Despite compelling evidence that physicians play a prominent role in smoking cessation, most smokers do not receive the recommended smoking cessation counseling.AimTo identify perceived barriers that hinder primary healthcare physicians (PHPs) from providing smoking cessation treatment to patients in Armenia. METHODS: A sequential exploratory mixed-methods study was conducted among PHPs from two Armenian cities (Yerevan and Gyumri). We implemented qualitative phase through focus group discussions (FGDs) using a semi-structured guide. For the subsequent quantitative phase, the data were collected through cross-sectional survey. A directed deductive content analysis technique was used to analyze the FGDs and questionnaires were analyzed descriptively. Following the data collection (March 2015-May 2016) and descriptive analysis, the qualitative and quantitative data sets were merged by drawing quantitative data onto qualitative categories.FindingsOverall, 23 PHPs participated in five FGDs and 108 participants completed the survey. Three main categories of barriers were identified: physician-based, patient-based, and system-based barriers. The main physicians-based barriers were insufficient knowledge and inadequate training on tobacco-dependence treatment. Lack of patients' motivation to quit, poor compliance with the treatment, patients' withdrawal symptoms were identified as patient-based disincentives. System-based barriers included lack of reimbursement for providing smoking cessation counseling, high price and low availability of smoking cessation medications. Most of the qualitative descriptions were confirmed by quantitative findings. CONCLUSIONS: Targeted interventions are needed to address barriers that limited PHPs' involvement in providing smoking cessation services in Armenia. There is an urgent need to enhance PHPs' knowledge and skills in delivering smoking cessation counseling, to increase patients' demand for smoking cessation services, and to ensure availability and affordability of smoking cessation services in Armenia. PMID- 30421697 TI - Patterns of depressive symptoms among younger elderly (60-74 years old) and older elderly (>=75 years old) in Jamaica. AB - : ABSTRACTObjectives:We sought to explore factors associated with depressive symptom severity among older persons (>=60 years of age) and to compare the depressive symptoms commonly experienced by older elderly (>=75 years) with those commonly experienced by younger elderly (<75 years). DESIGN: Secondary analysis was conducted on data from a nationally representative survey. SETTING: Four parishes in Jamaica. PARTICIPANTS: A total of 2,943 older community dwellers participated. MEASUREMENTS: The survey included the Zung Self-rating Depression Scale (ZSDS), the Mini Mental State Examination (MMSE), and items on age, sex, and educational level. Linear regression analysis was used to determine the association between ZSDS score and: age, sex, MMSE score, and educational level. Logistic regression analysis was used to determine, for each ZSDS item, whether particular responses were more associated with older or younger elderly. RESULTS: Higher ZSDS scores were associated with increasing age (B = 0.13, p < 0.001), lower MMSE score (B = -0.42, p < 0.001), the female sex (B = 3.52, p < 0.001), and lower educational level (B = -1.27, p < 0.001). The ZSDS items that were endorsed significantly more (p < 0.05) by older elderly related to negative evaluations about their functionality and value. Hopelessness was also more prominent among the older elderly. The items that were endorsed significantly more (p < 0.05) by the younger elderly had less of a focus. CONCLUSION: Among older persons, increasing age was associated with marginally higher levels of depressive symptoms. Female gender, cognitive deficits, preoccupations about value and functionality, and feelings of hopelessness may serve as useful screening parameters. PMID- 30421698 TI - Evolution of incidence and geographical distribution of Chagas disease in Mexico during a decade (2007-2016). AB - Chagas disease, whose aetiological agent is the protozoan Trypanosoma cruzi, mainly occurs in Latin America. In order to know the epidemiology and the geographical distribution of this disease in Mexico, the present work analyses the national surveillance data (10 years) for Chagas disease issued by the General Directorate of Epidemiology (GDE). An ecological analysis of Chagas disease (2007-2016) was performed in the annual reports issued by the GDE in Mexico. The cases and incidence were classified by year, state, age group, gender and seasons. A national distribution map showing Chagas disease incidence was generated. An increase of new cases was identified throughout the country (rates from 0.37 to 0.81 per 100 000 inhabitants). Of the total cases accumulated (7388), the major cases were attributed to the states of Veracruz, Chiapas, Quintana Roo, Oaxaca, Morelos and Yucatan. The analysis per age groups and gender revealed that, in most age groups, the incidence was higher in the male population. The most number of cases was identified in spring and summer; a direct relationship between the environmental temperature increase and the number of new cases was identified. The analysis showed that the rate of Chagas disease increased presumably due to state programmes; the search for new cases has expanded and we speculate that the disease is associated with occupational activities. These results summarise and recall how important it is to implement the monitoring of Chagas disease mainly in south states of the Mexican Republic in order to implement strategies to control this disease. PMID- 30421700 TI - The prevalence of child sexual abuse in South Africa: The Optimus Study South Africa. PMID- 30421699 TI - South African dyslipidaemia guideline consensus statement: 2018 update A joint statement from the South African Heart Association (SA Heart) and the Lipid and Atherosclerosis Society of Southern Africa (LASSA). AB - South Africa (SA) is home to a heterogeneous population with a wide range of cardiovascular risk factors. Cholesterol reduction in combination with aggressive management of modifiable risk factors, including nutrition, physical activity, blood pressure and smoking, can help to reduce and prevent morbidity and mortality in individuals who are at increased risk of cardiovascular events. This updated consensus guide to management of dyslipidaemia in SA is based on the updated European Society of Cardiology and European Atherosclerosis Society dyslipidaemia guidelines published in 2016. For individuals who are not considered to be at high or very high cardiovascular risk, the decision whether to treat and which interventional strategy to use is based on a cardiovascular risk score calculated using total cholesterol, high-density lipoprotein cholesterol (HDL-C), gender, age and smoking status. The cardiovascular risk score refers to the 10-year risk of any cardiovascular event and includes 4 categories of risk (low, moderate, high and very high). People with established cardiovascular disease, diabetes mellitus, chronic kidney disease and genetic or severe dyslipidaemias are considered to already be at high or very high risk and do not require risk scoring. Therapeutic lifestyle change is the mainstay of management for all patients. The need for and intensity of drug therapy is determined according to baseline low-density lipoprotein (LDL-C) levels and the target LDL-C concentration appropriate to the individual. LDL-C treatment targets are based on pre-treatment risk and are as follows: <3 mmol/L in low- and moderate risk cases; <2.5 mmol/L and a reduction of at least 50% if the baseline concentration is 2.5 - 5.2 mmol/L in high-risk cases; and <1.8 mmol/L and a reduction of at least 50% if the baseline concentration is 1.8 - 3.5 mmol/L in very high-risk cases. A statin is usually recommended first-line; the specific agent is based on the required degree of cholesterol reduction, comorbidities and co-prescribed medication. Special attention should be paid to children with a family history of genetic or severe dyslipidaemia, who should be screened for dyslipidaemia from 8 years of age. In SA, HIV infection is not considered to be a significant cardiovascular risk factor and treatment recommendations for HIV positive individuals are the same as for the general population, with careful choice of pharmacotherapy to avoid potential adverse drug-drug interactions. The benefit of statins in individuals older than 70 years is uncertain and clinical judgement should be used to guide treatment decisions and to avoid side-effects and overmedication in this group. PMID- 30421701 TI - Role of procalcitonin in paediatric burn wound sepsis. PMID- 30421702 TI - Child mortality in South Africa: Is the Sustainable Development Goal (3.2) target achievable with current efforts? PMID- 30421703 TI - Extended-spectrum beta-lactamase-producing Escherichia coli harbouring mcr-1 gene isolated from pigs in South Africa. PMID- 30421704 TI - Developing an advocacy agenda for increasing access to opioid substitution therapy as part of comprehensive services for people who use drugs in South Africa. PMID- 30421705 TI - Towards timely diagnosis of symptomatic breast and cervical cancer in South Africa. PMID- 30421706 TI - Use of the consent provisions of the Choice on Termination of Pregnancy Act for live births by caesarean section when unable to follow the procedures in the Children's Act. PMID- 30421707 TI - Mortality analysis of people with severe mental illness transferred from long stay hospital to alternative care in the Life Esidimeni tragedy. AB - A mortality analysis of the Life Esidimeni tragedy was precluded during the investigation by the Health Ombud by the lack of data integrity. Information on the mental healthcare users (MHCUs) transferred out of Life Esidimeni hospitals between October 2015 and June 2016 was subsequently collected by the Gauteng Department of Health, permitting statistical analysis. Survival rates were calculated according to gender and transfer destination and adjusted for patient age. Mortality was compared with that of the general population for the calendar year of 2016. Of the 1 442 MHCUs, 15% were transferred to specialised psychiatric hospitals and 85% to a rehabilitation centre or non-governmental residential facility. By the end of August 2017, 9% (n=131) of the cohort had died. Significant predictors of survival were younger age (p<0.0001) and transfer to a psychiatric institution (p=0.004). The age-adjusted death rate was 63/1 000 and the overall standardised mortality ratio (SMR) was 4.9 (95% confidence interval (CI) 3.92 - 5.80), with an SMR of 3.9 (95% CI 2.95 - 4.86) for men and 6.3 (95% CI 4.22 - 8.38) for women. The excess deaths are therefore quantified, and the high-risk environment of the rehabilitation centre and residential facilities confirmed. High mortality among MHCUs is unlikely to be confined to the Life Esidimeni tragedy; monitoring of preventable deaths in this vulnerable population is recommended. PMID- 30421708 TI - Neonatal listeriosis during a countrywide epidemic in South Africa: A tertiary hospital's experience. AB - BACKGROUND: A countrywide epidemic of Listeria monocytogenes (LM) in South Africa began in the first quarter of 2017, rapidly becoming the world's largest LM outbreak to date. METHODS: We describe the clinical course of neonates with culture-confirmed LM infection admitted to a tertiary neonatal unit at Tygerberg Hospital, Cape Town (1 January 2017 - 31 January 2018). Current epidemic LM cases were compared with a historical cohort of sporadic neonatal LM cases at our institution (2006 - 2016). The global literature on epidemic neonatal LM outbreaks (1 January 1978 - 31 December 2017) was reviewed. RESULTS: Twelve neonates (median gestational age 35 weeks, median birth weight 2 020 g) were treated for confirmed LM bacteraemia in 2017/18, presenting at a median age of 0.5 days. In 5 cases, neurolisteriosis was suspected. Three neonates died (25.0%) v. 8/13 neonatal deaths (61.6%) in the sporadic listeriosis cohort (2006 - 2016) (p=0.075). The institution's neonatal LM infection incidence increased significantly in 2017 from a historical rate of 0.17/1 000 live births to 1.4/1 000 (p<0.001). During the current LM epidemic, the crude neonatal fatality rate exceeded the average calculated global epidemic neonatal LM mortality (3/12 (25.0%) v. 50/290 (17.2%); p=0.448). Possible factors contributing to the high mortality rate in this epidemic LM neonatal cohort may include more virulent disease associated with sequence type 6 and the predominance of early-onset disease. CONCLUSIONS: Epidemic neonatal listeriosis at Tygerberg Hospital was associated with a predominance of bacteraemic, early-onset disease. Listeriosis associated mortality rates were higher than previously published, but lower than the rate in a historical institutional cohort. PMID- 30421709 TI - Research ethics committees in a tight spot: Approving consent strategies for child research that are prima facie illegal but are ethical in terms of national guidelines. AB - It is an internationally accepted principle that ethics norms should be applied and enforced in research with humans through ethics review by research ethics committees (RECs). This places RECs at the very heart of the system for protecting participants and enforcing their rights. In the South African ethical legal framework for child research, there are divergent approaches to consent. That is, section 71 of the National Health Act (No. 61 of 2003) (NHA) requires mandatory parental consent for child research, and limits the authority for proxy consent to parents and legal guardians. However, national ethics guidelines authorised by section 72 of the NHA and issued by the National Health Research Ethics Council (NHREC) acting in terms of its mandate (National Department of Health, 2015) allow a more nuanced approach - i.e. self-consent by older adolescents, provided certain conditions are met, and consent by a range of parental substitutes where there are no available parents or legal guardians. We have argued elsewhere that the consent approach in section 71 is inappropriately restrictive and are of the view that the consent approach endorsed in national ethics guidelines is more defensible. An REC that elects to approve a consent strategy allowable in ethics guidelines is effectively electing to not follow section 71, which raises the question of what the consequences might be for that REC. This article examines the legal liability of RECs through three 'threads' of accountability: the NHREC, the institutions hosting RECs, and the courts. We conclude that: (i) if an REC approves a child protocol with consent strategies allowable in terms of national ethics guidelinesbut not in terms of section 71, it is unlikely that the NHREC would discipline the REC in the face of a complaint - provided the REC acted within national ethics guidelines issued by the NHREC in terms of the latter's section 72 mandate to set national norms and standards; (ii) if an REC approves a consent approach allowed for in ethics guidance, it is also unlikely that the host institution would discipline the REC in the face of a complaint - especially if the institution is aware of the REC's explicit decision to follow national ethics guidelines that are authorised by section 72 of the NHA; and (iii) an REC could only be sued by a participant in terms of the law of delict (and be liable for damages) if several demanding components are proven, such as that the harm suffered by the participant resulted directly from the REC's actions in approving a particular consent strategy for that research. Furthermore, the court may well look to national ethics guidelines in making determinations about whether an REC's conduct was wrongful for the purposes of liability in civil law. RECs are protected from being collectively liable by insurance taken out by their host institutions. We make a series of recommendations to address this issue. PMID- 30421710 TI - Juvenile idiopathic arthritis flare due to rice bodies in the knee of a 10-year old girl. AB - A 10-year-old girl with juvenile idiopathic arthritis in remission presented with a flare of her arthritis. All her joints responded to treatment except the right knee, despite the use of disease-modifying antirheumatic drugs, non-steroidal anti-inflammatory medication and high-dose cortisone. A magnetic resonance imaging scan showed a knee densely packed with rice bodies. After surgical removal of the rice bodies the inflammation settled once again, and the patient remains well on her usual medication. PMID- 30421711 TI - Appendicectomy in private practice in KwaZulu-Natal Province, South Africa. AB - BACKGROUND: The treatment of appendicitis is regarded as a bellwether procedure that can be used to describe the delivery of essential surgical care. Little has been published on clinical outcomes in the private sector in South Africa (SA), and this study attempts to address this deficiency. OBJECTIVES: To extend our understanding of the outcomes of acute appendicitis in the public and private sectors in SA. METHODS: Data on patients covered by a leading medical aid who underwent appendicectomy in 26 private hospitals in Durban and Pietermaritzburg, KwaZulu-Natal Province, during the period 2010 - 2015 were obtained and compared with existing data from a recent study of patients with appendicitis treated in the Pietermaritzburg academic complex. RESULTS: Between January 2010 and December 2015, 397 patients covered by the medical aid underwent appendicectomy in private hospitals. Their mean age was 29.7 years (range 3.7 - 87.6), the mean length of stay 4.6 days (range 1 - 41) and the mean operation time 70.6 minutes (range 24.0 - 335.0). Of the procedures 66.5% were laparoscopic. A total of 33 patients (8.3%) required intensive care unit (ICU) admission, and 38 (9.6%) were readmitted. While there was no information on the reasons for readmission, this is a proxy marker for possible complications. The mean total event cost per patient was ZAR38 934. A total of 134 open operations were performed (33.8%). In the state sector, a total of 1 004 patients were documented. The mean patient age was 20.2 years (difference not statistically significant), mean length of stay was significantly longer at 7.3 days (p=0.02, one-tailed t-test), and 10% of patients required ICU admission. In the state hospitals only 3% of the operations were laparoscopic. None of the private sector patients but 40% of the state patients required further surgery. CONCLUSIONS: Medical aid data provide useful information on disease profiles and outcomes in private practice. The outcome of acute appendicitis in the private sector appears to be significantly better than in the state sector. Further work is required to fully elucidate the reasons for this, although late presentation in the state patients almost certainly contributes to their poor outcome. In terms of cost, SA private practice appears to be highly efficient and is relatively inexpensive in comparison with international equivalents. PMID- 30421713 TI - Preoperative serum sodium measurements and postoperative inpatient mortality: A case-control analysis of data from the South African Surgical Outcomes Study. AB - BACKGROUND: Abnormal preoperative serum sodium measurements have been shown to be associated with increased postoperative mortality in US and European surgical populations. It is possible that such measurements are also associated with increased postoperative mortality in a South African (SA) setting, but this is yet to be confirmed. Establishing whether preoperative serum sodium measurements are associated with postoperative mortality could have implications for perioperative risk stratification in SA settings. OBJECTIVES: To determine whether preoperative serum sodium measurements are associated with postoperative mortality in SA surgical patients. METHODS: This was an unmatched case-control study of patient data (demographics, comorbidities, procedure-related variables, and preoperative serum sodium measurements) collected during the South African Surgical Outcomes Study. Data were analysed using recommended statistical methods for unmatched case-control studies. RESULTS: The study population comprised 103 patients and 410 controls. Cases were defined as patients who suffered postoperative inpatient mortality, while controls were defined as patients who did not suffer postoperative inpatient mortality. Preoperative hypernatraemia (i.e. a preoperative serum sodium measurement >144 mEq/L) was independently associated with a four-fold higher risk of postoperative inpatient mortality compared with a normal preoperative serum sodium measurement of 135 - 144 mEq/L (odds ratio (OR) 4.21, 95% confidence interval (CI) 1.19 - 14.83, p=0.025). Preoperative hyponatraemia (i.e. a preoperative serum sodium measurement <135 mEq/L) was not independently associated with a higher or lower risk of postoperative inpatient mortality compared with a normal preoperative serum sodium measurement (OR 1.39, 95% CI 0.70 - 2.76, p=0.346). CONCLUSIONS: Preoperative hypernatraemia, but not preoperative hyponatraemia, is a risk factor for postoperative inpatient mortality in SA surgical patients. PMID- 30421712 TI - Preoperative anaemia and clinical outcomes in the South African Surgical Outcomes Study. AB - BACKGROUND: In high-income countries, preoperative anaemia has been associated with poor postoperative outcomes. To date, no large study has investigated this association in South Africa (SA). The demographics of SA surgical patients differ from those of surgical patients in the European and Northern American settings from which the preoperative anaemia data were derived. These associations between preoperative anaemia and postoperative outcomes are therefore not necessarily transferable to SA surgical patients. OBJECTIVES: The primary objective was to determine the association between preoperative anaemia and in-hospital mortality in SA adult non-cardiac, non-obstetric patients. The secondary objectives were to describe the association between preoperative anaemia and (i) critical care admission and (ii) length of hospital stay, and the prevalence of preoperative anaemia in adult SA surgical patients. METHODS: We performed a secondary analysis of the South African Surgical Outcomes Study (SASOS), a large prospective observational study of patients undergoing inpatient non-cardiac, non-obstetric surgery at 50 hospitals across SA over a 1-week period. To determine whether preoperative anaemia is independently associated with mortality or admission to critical care following surgery, we conducted a multivariate logistic regression analysis that included all the independent predictors of mortality and admission to critical care identified in the original SASOS model. RESULTS: The prevalence of preoperative anaemia was 1 727/3 610 (47.8%). Preoperative anaemia was independently associated with in-hospital mortality (odds ratio (OR) 1.657, 95% confidence interval (CI) 1.055 - 2.602; p=0.028) and admission to critical care (OR 1.487, 95% CI 1.081 - 2.046; p=0.015). CONCLUSIONS: Almost 50% of patients undergoing surgery at government-funded hospitals in SA had preoperative anaemia, which was independently associated with postoperative mortality and critical care admission. These numbers indicate a significant perioperative risk, with a clear need for quality improvement programmes that may improve surgical outcomes. Long waiting lists for elective surgery allow time for assessment and correction of anaemia preoperatively. With a high proportion of patients presenting for urgent or emergency surgery, perioperative clinicians in all specialties should educate themselves in the principles of patient blood management. PMID- 30421714 TI - 'Going the extra mile': Supervisors' perspectives on what makes a 'good' intern. AB - BACKGROUND: Much has been published on whether newly graduated doctors are ready for practice, seeking to understand how to better prepare graduates for the workplace. Most studies focus on undergraduate education as preparation for internship by investigating knowledge and skills in relation to clinical proficiencies. The conversion from medical student to internship, however, is influenced not only by medical competencies, but also by personal characteristics and organisational skills. Most research focuses largely on the interns' own perceptions of their preparation. Supervisors who work closely with interns could therefore present alternative perspectives. OBJECTIVES: To explore the views of medical intern supervisors on the internship training context, as well as their perspectives on attributes that would help an intern to function optimally in the public health sector in South Africa (SA). This article intends to extend our current understanding of what contributes to a successful internship by including the views of internship supervisors. METHODS: Twenty-seven semi-structured interviews were held with medical intern supervisors in 7 of the 9 provinces of SA. The data were thematically analysed and reported using an existing framework, the Work Readiness Scale. RESULTS: The intern supervisors indicated that interns were challenged by the transition from student to doctor, having to adapt to a new environment, work long hours and deal with a large workload. Clinical competencies, as well as attributes related to organisational acumen, social intelligence and personal characteristics, were identified as being important to prepare interns for the workplace. Diligence, reliability, self-discipline and a willingness to work ('go the extra mile') emerged as key for a 'good' intern. The importance of organisational skills such as triage, prioritisation and participation was foregrounded, as were social skills such as teamwork and adaptability. CONCLUSIONS: This article contributes to our understanding of what makes a successful medical internship by exploring the previously uncanvassed views of intern supervisors who are working at the coalface in the public health sector. It is envisaged that this work will stimulate debate among the medical fraternity on how best to prepare interns for the realities of the workplace. Educational institutions, health services and interns themselves need to take ownership of how to instil, develop and support these important attributes. PMID- 30421715 TI - Retrospective case-series analysis of haematological malignancies in goldmining areas of South Africa. AB - BACKGROUND: South Africa (SA)'s high levels of environmental contamination of mine tailings from uranium and its decay products, coupled with remarkably short distances between mine tailings and residential areas, raise concern about whether there is an association between environmental uranium exposure and risk of cancer, including haematological malignancies. OBJECTIVES: We reviewed information on cases from the central hospital offering cancer diagnostics and treatment in a major mining area of SA to describe their basic clinical and demographic characteristics, as part of assessing whether a cancer epidemiological study in this area would be feasible. METHODS: Basic clinical, demographic and residential information on patients with haematological malignancy diagnosed between 2004 and 2013 was collected retrospectively from the patient files at Chris Hani Baragwanath Academic Hospital in Soweto, Johannesburg. RESULTS: In total, 1 880 patients aged 18 - 94 years were identified. Referral from distant provinces was not uncommon, but >80% lived within 50 km of the hospital. Non-Hodgkin's lymphoma accounted for 44% of the haematological malignancies, followed by leukaemia with 26%. HIV status was known for 93% of the patients, of whom 47% were HIV-positive. CONCLUSIONS: Caution is required when interpreting spatial distributions of patients, given inaccuracies in residential addresses and referral patterns to the hospital, and with HIV and other infections probable important confounders. Our study therefore shows that active case recruitment is required for accurate assessment of residential information. However, some findings on spatial distributions in the study warrant the continuation of efforts to develop a study protocol to investigate the possible link between uranium exposure in mining areas and haematological malignancies in residents. Disproportionately high incidence rates of haematological malignancies observed in specific districts would be relevant for further investigation. PMID- 30421716 TI - Is the intravenous giving set a reliable alternative to the spinal manometer in measuring cerebrospinal fluid opening pressure? AB - BACKGROUND: Measurement of the cerebrospinal fluid (CSF) opening pressure (OP) during lumbar puncture (LP) should be routine practice. In resource-limited centres, spinal manometers are seldom available and alternative procedures to measure CSF OP are undertaken. OBJECTIVES: To investigate whether the intravenous giving set (IVGS) with a measuring tape is a reliable alternative to the spinal manometer. METHODS: One hundred patients requiring CSF examination by LP were consecutively recruited in the Department of Medicine at Edendale Hospital, Pietermaritzburg, South Africa. A three-way stopcock was attached to the end of a 22G spinal needle and the IVGS and spinal manometer were attached to the other two openings of the stopcock. CSF OP was consecutively recorded between the two techniques with 50 patients in each group. RESULTS: The mean (standard deviation (SD)) CSF OP of the 100 patients was 22.7 (10.0) cm CSF measured with the manometer v. 16.2 (9.3) cm CSF measured with the IVGS (p<0.001). Subgroup analysis showed similarly significant findings of consistently lower CSF OP with the IVGS, regardless of whether the IVGS reading was done first or second. The manometer detected 34 cases of elevated CSF OP of >25 cm CSF, but the IVGS detected 11 cases only (p<0.001, McNemar's chi2 test). Similar differences were noted for the subgroups of manometer first and IVGS first. Despite this, linear correlation showed very good correlation (r=0.78) and a 75% agreement between the two techniques. The relationship between the manometer reading and the IVGS reading was M = 0.85V + 8.9 in cm CSF, where M was the manometer reading and V the IVGS reading. CONCLUSIONS: The IVGS consistently underestimated the CSF OP against the tried-and-tested spinal manometer, which should be the preferred method of measuring CSF OP. Based on the equation that describes the relationship between the spinal manometer and IVGS reading, the upper limit of normal CSF OP of 25 cm CSF on the manometer is equivalent to 19 cm CSF on the IVGS. PMID- 30421717 TI - Can routine inpatient mortality data improve HIV mortality estimates? Inpatient mortality at an urban hospital in South Africa. AB - BACKGROUND: South Africa (SA) has one of the world's largest HIV treatment programmes, to which a dramatic increase in life expectancy has been attributed. However, there continue to be concerns regarding the reporting of HIV-related mortality in SA, which varies by source. As accurate HIV mortality estimates are key to measuring the success of the national programme as well as identifying areas for improvement, we propose a complementary approach to monitoring changes in HIV-related mortality using routine inpatient records to examine trends in causes of death and HIV status over time. OBJECTIVES: To investigate the feasibility of this approach by calculating mortality due to natural causes in the medical ward of a hospital during 2010 by HIV status. METHODS: We conducted a cross-sectional study of inpatient mortality at a regional hospital in Johannesburg, SA, analysing all deaths due to natural causes among adult medical ward inpatients. Cause of death was recorded from the mortuary register. HIV status was ascertained directly from the mortuary register or from laboratory tests specific for HIV diagnosis or monitoring. RESULTS: Of 1 167 inpatients who died, the majority were HIV-positive (58%). HIV positivity among males (55%) was slightly lower than that among females (61%), and HIV-positive patients were younger (median 40 years) than those who were HIV-negative (56 years) and of unknown HIV status (68 years). 'Infections and parasites' was the most common cause of natural death (29%). On average, HIV-positive patients were admitted for slightly longer (mean 10.5 days) than HIV-negative patients (9.6 days) and those of unknown HIV status (8.9 days), yet HIV-positive inpatient deaths accounted for the majority (62%) of the total bed days. CONCLUSIONS: Even with widespread access to antiretroviral therapy, the majority of inpatient natural deaths at a large public sector hospital in 2010 were of HIV-positive patients and were probably related to HIV. In view of the importance of accurate data on causes of death, both for the HIV programme and to track other diseases, large-scale expansion of this approach over a longer period should be considered. PMID- 30421718 TI - The demographic and clinical profiles of women presenting with vaginal discharge syndrome at primary care facilities in South Africa: Associations with age and implications for management. AB - BACKGROUND: Current South African guidelines for the management of vaginal discharge syndrome (VDS) do not recommend treatment for sexually transmitted infection (STI) pathogens for women aged >=35 years whose partners do not have male urethritis syndrome. The guideline assumes that older women are unlikely to have an STI and that their partners do not have asymptomatic infections. OBJECTIVES: To describe the demographic, behavioural and clinical characteristics of women with VDS, comparing older women (>=35 years) with younger women, and to determine the performance of age alone as a criterion for predicting the presence of STI. METHODS: This was a cross-sectional study at seven primary healthcare centres taking part in the aetiological surveillance of STIs between January 2015 and December 2016. Eligible women presenting with VDS were enrolled and completed a nurse-administered questionnaire. Genital swabs and blood specimens were collected for laboratory testing. Data were entered into surveillance-specific databases and exported into Stata 14 for analysis. Descriptive statistics were used to compare demographic and clinical profiles of older with younger women. A receiver operator curve (ROC) was used to determine the age cut-off that would best differentiate between women who had infection with STI pathogens and those without. RESULTS: Of 757 women enrolled, 157 (20.7%) were aged >=35 years. HIV positivity was 46.6%, and higher in older than younger women (54.9% v. 44.5%; p=0.02). Of those enrolled, 283 (37.4%) had bacterial vaginosis (BV) and/or Candida infection only, 232 (30.7%) had BV or Candida with STI pathogens detected, 98 (13%) were infected with STI pathogens only, and 144 (19.0%) did not have any detectable STI or non-STI causes. Although older women were less likely than younger women to have Neisseria gonorrhoeae, Chlamydia trachomatis or Mycoplasma genitalium infection (23.6% v. 38.2%; p<0.01), the burden in older women was not negligible. The area under the ROC for age was 57.5% (95% confidence interval 53.2 - 61.8%), which implies suboptimal performance. CONCLUSIONS: Although older women with VDS were less likely than younger women to have STIs, a significant proportion of them did have an infection with STI pathogens. Age alone was not a good criterion for discriminating between women with and without infection with STI pathogens. Other ways of improving the VDS algorithm performance are needed, as is better integration of HIV and STI prevention and treatment. PMID- 30421719 TI - Dopamine neurons drive fear extinction learning by signaling the omission of expected aversive outcomes. AB - Extinction of fear responses is critical for adaptive behavior and deficits in this form of safety learning are hallmark of anxiety disorders. However, the neuronal mechanisms that initiate extinction learning are largely unknown. Here we show, using single-unit electrophysiology and cell-type specific fiber photometry, that dopamine neurons in the ventral tegmental area (VTA) are activated by the omission of the aversive unconditioned stimulus (US) during fear extinction. This dopamine signal occurred specifically during the beginning of extinction when the US omission is unexpected, and correlated strongly with extinction learning. Furthermore, temporally-specific optogenetic inhibition or excitation of dopamine neurons at the time of the US omission revealed that this dopamine signal is both necessary for, and sufficient to accelerate, normal fear extinction learning. These results identify a prediction error-like neuronal signal that is necessary to initiate fear extinction and reveal a crucial role of DA neurons in this form of safety learning. PMID- 30421720 TI - Rescue of cognitive function following fractionated brain irradiation in a novel preclinical glioma model. AB - More than half of long-term brain tumor survivors develop irreversible cognitive decline that severely affect their quality of life. However, there is no pre clinical model that allows long-term assessment of cognition, and there is no treatment which ameliorates cognitive deficits in patients. Here, we report a novel glioma mouse model that offers manageable tumor growth and reliable assessment of cognitive functions in a post-treatment manner. Using this model, we found that fractionated whole-brain irradiation (fWBI), but not tumor growth, results in memory deficits. Transient inhibition of CSF-1R during fWBI prolongs survival of glioma-bearing mice and fully prevents fWBI-induced memory deficits. This result suggests that CSF-1R inhibition during radiotherapy can be explored as an approach to improve both survival and cognitive outcomes in patients who will receive fWBI. Taken together, the current study provides a proof of concept of a powerful tool to study radiation-induced cognitive deficits in glioma bearing animals. PMID- 30421721 TI - Neurotheranostics as personalized medicines. AB - The discipline of neurotheranostics was forged to improve diagnostic and therapeutic clinical outcomes for neurological disorders. Research was facilitated, in largest measure, by the creation of pharmacologically effective multimodal pharmaceutical formulations. Deployment of neurotheranostic agents could revolutionize staging and improve nervous system disease therapeutic outcomes. However, obstacles in formulation design, drug loading and payload delivery still remain. These will certainly be aided by multidisciplinary basic research and clinical teams with pharmacology, nanotechnology, neuroscience and pharmaceutic expertise. When successful the end results will provide "optimal" therapeutic delivery platforms. The current report reviews an extensive body of knowledge of the natural history, epidemiology, pathogenesis and therapeutics of neurologic disease with an eye on how, when and under what circumstances neurotheranostics will soon be used as personalized medicines for a broad range of neurodegenerative, neuroinflammatory and neuroinfectious diseases. PMID- 30421722 TI - Enhanced osteogenic activity by MC3T3-E1 pre-osteoblasts on chemically surface modified poly(epsilon-caprolactone) 3D-printed scaffolds compared to RGD immobilized scaffolds. AB - In bone tissue engineering, the intrinsic hydrophobicity and surface smoothness of three-dimensional (3D)-printed poly(epsilon-caprolactone) scaffolds hamper cell attachment, proliferation and differentiation. This intrinsic hydrophobicity of poly(epsilon-caprolactone) can be overcome by surface modifications, such as surface chemical modification or immobilization of biologically active molecules on the surface. Moreover, surface chemical modification may alter surface smoothness. Whether surface chemical modification or immobilization of a biologically active molecule on the surface is more effective to enhance pre osteoblast proliferation and differentiation is currently unknown. Therefore, we aimed to investigate the osteogenic response of MC3T3-E1 pre-osteoblasts to chemically surface-modified and RGD-immobilized 3D-printed poly(epsilon caprolactone) scaffolds. Poly(epsilon-caprolactone) scaffolds were 3D-printed consisting of strands deposited layer by layer with alternating 0 degrees /90 degrees lay-down pattern. 3D-printed poly(epsilon-caprolactone) scaffolds were surface-modified by either chemical modification using 3 M sodium hydroxide (NaOH) for 24 or 72 h, or by RGD-immobilization. Strands were visualized by scanning electron microscopy. MC3T3-E1 pre-osteoblasts were seeded onto the scaffolds and cultured up to 14 d. The strands of the unmodified poly(epsilon caprolactone) scaffold had a smooth surface. NaOH treatment changed the scaffold surface topography from smooth to a honeycomb-like surface pattern, while RGD immobilization did not alter the surface topography. MC3T3-E1 pre-osteoblast seeding efficiency was similar (44%-54%) on all scaffolds after 12 h. Cell proliferation increased from day 1 to day 14 in unmodified controls (1.9-fold), 24 h NaOH-treated scaffolds (3-fold), 72 h NaOH-treated scaffolds (2.2-fold), and RGD-immobilized scaffolds (4.5-fold). At day 14, increased collagenous matrix deposition was achieved only on 24 h NaOH-treated (1.8-fold) and RGD-immobilized (2.2-fold) scaffolds compared to unmodified controls. Moreover, 24 h, but not 72 h, NaOH-treated scaffolds, increased alkaline phosphatase activity by 5-fold, while the increase by RGD immobilization was only 2.5-fold. Only 24 h NaOH treated scaffolds enhanced mineralization (2.0-fold) compared to unmodified controls. In conclusion, RGD immobilization (0.011 MUg mg-1 scaffold) on the surface and 24 h NaOH treatment of the surface of 3D-printed PCL scaffold both enhance pre-osteoblast proliferation and matrix deposition while only 24 h NaOH treatment results in increased osteogenic activity, making it the treatment of choice to promote bone formation by osteogenic cells. PMID- 30421723 TI - Wet spinning and riboflavin crosslinking of collagen type I/III filaments. AB - Reconstituted fibrillary collagen is one of the most advantageous biomaterials for biomedical applications. The objective of the research project described in this paper was to evaluate whether riboflavin-induced photo-crosslinking could be used as a non-toxic alternative to glutaraldehyde (GA)-crosslinking for the preparation of wet spun collagen filaments. Collagen filaments were produced on a laboratory wet spinning line and crosslinked with GA or riboflavin with and without UV exposure. Based on mechanical and thermal analyses, it was concluded that the combination of riboflavin and UV light leads to crosslinked collagen filaments having improved mechanical and thermal properties. Furthermore, riboflavin-crosslinked filaments exhibited a higher cytocompatibility for human mesenchymal stem cells compared to GA-crosslinked filaments. PMID- 30421724 TI - Mechanics of wet adhesion in soft interaction with patterned morphology. AB - Locking surfaces with a wet interface can enhance interactions between a grasped object and a soft pad. This paper presents a mechanical approach to understanding the role of morphological design in achieving wet adhesion for secure grasping by a soft pad. Two conditions were compared in modeling wet interfaces between an object and a soft pad: a pad with a flat surface, and a pad with a micropatterned surface. The latter was designed and analyzed based on the wet attachment between the surface of a tree-frog's toes and its substrate. In this model, we proposed a method to estimate the contact force in both normal and tangential directions between a soft pad with a micropattern surface and a rigid flat surface substrate. A square mold containing 3600 85 MUm * 85 MUm cells interspaced by grooves 15 MUm wide and 15 MUm deep was fabricated, using e-beam technology, as the micropattern pad. The generated normal and tangential contact forces of the pad with a micropattern surface, and a pad with a flat surface were measured in both normal and tangential directions under wet conditions. Experimental results showed good agreement with theoretical results, indicating that the micropattern significantly enhanced the contact force of the pad by approximately two-fold for the normal and 1.2- to 1.4-fold for the tangential force. This theoretical approach can be potentially utilized to investigate the association of soft pad morphology with wet adhesion, and enhance efficient grasping by soft robotic hands in wet and high-moisture environments. PMID- 30421725 TI - Photonic quantum information processing: a review. AB - Photonic quantum technologies represent a promising platform for several applications, ranging from long-distance communications to the simulation of complex phenomena. Indeed, the advantages offered by single photons do make them the candidate of choice for carrying quantum information in a broad variety of areas with a versatile approach. Furthermore, recent technological advances are now enabling first concrete applications of photonic quantum information processing. The goal of this manuscript is to provide the reader with a comprehensive review of the state of the art in this active field, with a due balance between theoretical, experimental and technological results. When more convenient, we will present significant achievements in tables or in schematic figures, in order to convey a global perspective of the several horizons that fall under the name of photonic quantum information. PMID- 30421726 TI - Investigation on acoustic reception pathways in finless porpoise (Neophocaena asiaorientalis sunameri) with insight into an alternative pathway. AB - Sound transmission and reception are both vital components to odontocete echolocation and daily life. Here, we combine computed tomography (CT) scanning and finite element modeling to investigate the acoustic propagation of finless porpoise (Neophocaena asiaorientalis sunameri) echolocation pulses. The CT scanning and finite element method wave propagation model results support the well-accepted jaw-hearing pathway hypothesis and suggest an additional alternative auditory pathway composed of structures, mandible (lower jaw) and internal mandibular fat, with different acoustic impedances, which may also conduct sounds to the ear complexes. The internal mandibular fat is attached to the ear complex and encased by the mandibles laterally and anteriorly. The simulations show signals in this pathway initially propagate along the solid mandibles and are transmitted to the acoustically coupled soft tissue of the internal mandibular fat which conducts the stimuli posteriorly as it eventually arrives at ear complexes. While supporting traditional theories, this new bone tissue conduction pathway might be meaningful to understand the hearing and sound reception processes in a wide variety of odontocetes species. PMID- 30421727 TI - Reliable autapse formation using the single-cell patterning method. AB - Auto neuronal synapses, or autapses, are aberrant structures where the synaptic contact of a neuron forms onto its own branch. The functions of autapses, however, remain unknown. Here, we introduce a simple patterning method for capturing a single-cell, in which we maintained the isolated cell until it reached maturity, and developed arrays of autapses for electrophysiological analysis using multi-electrode arrays (MEA). The pattern arrays were formed by selective patterning of poly-L-lysine and various cell repellent materials. We tested the efficiency of single neuron pattern formed according to materials and pattern dimensions. Autapse formation was verified by immunostaining synaptic markers and physiological measurements via recordings from MEA. The results demonstrated that our multiscale patterning method increased the number of autapses consisting of a single neuron, which matured to connect onto themselves. The proposed patterning method (4.06 +/- 0.33 isolated single-cells mm-2) is at least twelve times more efficient and productive than the spray method (0.31 +/- 0.10 isolated single-cells mm-2). The spontaneous activity of a single neuron on the patterned MEA occured after 11 d in vitro. The single neuron activity consisted of bursts followed by spike trains (the burst rate was 2.56 min-1). This indicates that our method could be used for electrophysiological analysis, including MEA. PMID- 30421728 TI - Clinical Inertia in Type 2 Diabetes Patients in Primary Health Care Clinics in Central Bosnia. AB - BACKGROUND The goal of this research was to determine the frequency of clinical inertia of general practice physicians in the region of Central Bosnia in healthcare for type 2 diabetes patients, to analyze characteristics of patients and physicians, as well as glucose regulation during clinical inertia, and, on the basis of these indicators, give recommendations for reducing clinical inertia. MATERIAL AND METHODS This study included 29 doctors, family physicians, or general practitioners, who collected data in a total sample of 541 type 2 diabetes mellitus patients from July to November 2017. The research was conducted using 2 questionnaires. The glucose concentration in plasma and the percentage of glycosylated hemoglobin (HbA1c) were determined. Concertation of cholesterol, triglycerides, AST, and ALT were also measured. After the collection, new data were processed and the degree of clinical inertia was determined. RESULTS Levels of HbA1c ranged from 4.3% to 13.0%, and 38.4% of all patients had HbA1c level higher than 7.5%, while 8.3% of them had HbA1c level 9.0% or higher. Clinical inertia in our research was 12.6% out of all patients and 48.2% were referred to a specialist by their doctor. CONCLUSIONS For better regulation of glycemia and reduction of clinical inertia with type 2 diabetes patients, more specialized training is needed for selected physicians. Strengthening of primary healthcare and encouraging doctors to perform procedures can contribute to better outcomes of treatment, lower clinical inertia, and better education of patients. PMID- 30421729 TI - ? PMID- 30421730 TI - What will you die from? PMID- 30421731 TI - ? PMID- 30421732 TI - Antiangiogenic treatment of ocular diseases. PMID- 30421733 TI - ? PMID- 30421734 TI - Nuclear weapons ban, the Nobel Prize and the contribution made by doctors. PMID- 30421735 TI - A woman in her twenties with urinary incontinence. PMID- 30421736 TI - ? AB - Facial paralysis can be a stigmatising condition, and in many cases it may affect the closing function of the eye, facial expression, the nasal airway passage, language and nutritional intake to varying degrees. For the majority of patients, treatment methods exist that may improve function and quality of life. This article aims to provide a review of relevant surgical reconstruction methods and treatment options for patients with facial paralysis. PMID- 30421738 TI - ? PMID- 30421737 TI - ? AB - BACKGROUND: We wished to assess our experiences with laparoscopy used in curative resection for gastric cancer. MATERIAL AND METHOD: All patients with gastric cancer who underwent curative-intent surgery, irrespective of access, in the period 1 May 2015-28 February 2018 at Oslo University Hospital Ulleval were included. The patient care pathway and oncological results were registered continuously and analysed retrospectively. RESULTS: A total of 93 patients underwent surgery, 48 of whom were women. Median age was 73 (32-89) years, and 16 patients were 80 years of age or above. The duration of the procedure was 265 (125-644) minutes. Altogether seven patients underwent laparotomy, one was planned and six were converted to open surgery. Standardised lymph node dissection was performed in 88 patients. Complications were recorded in 48 patients, of which 11 were serious. A total of six patients had anastomotic leakage. Three died within 30 days/during hospitalisation. Postoperative hospitalisation was 12 (5-78) days. A total of 86 patients underwent radical surgery, five had tumour infiltration in the resection margins, and two had indeterminate resection status. The median number of lymph nodes identified was 18 (0-53). Tumours were locally advanced in 56 patients. INTERPRETATION: Laparoscopic gastric resection with standardised lymph node dissection can be performed in most patients with gastric cancer who undergo curative-intent surgery. The method has become standard in our department. PMID- 30421739 TI - Immediate telephonic alerting of deviating pharmacological test results. PMID- 30421740 TI - ? PMID- 30421741 TI - ? PMID- 30421742 TI - ? PMID- 30421743 TI - ? AB - BACKGROUND: Alcohol use disorder can lead to serious illness and early death. The lifetime prevalence rate among the Norwegian population is estimated at 7-10 %. Many patients are never admitted to any kind of treatment programme, and it is assumed that few of those who are treated receive medicinal treatment. There are a variety of drugs on the market that can help reduce alcohol consumption and maintain abstinence. We wanted to gain an insight into the prescription prevalence rate and practice for these drugs. MATERIAL AND METHOD: We obtained encrypted data from the Norwegian Prescription Database of everyone who received drugs for alcohol use disorder in the period 2004-2016. The drugs included were disulfiram, acamprosate, naltrexone 50 mg and nalmefene. RESULTS: The annual prescription prevalence rate increased from 0.85 to 1.13 per 1000 during the observation period. Half of all patients only received prescribed drugs once, and Disulfiram was the most commonly prescribed drug. There was a slight increase in the prevalence rate in age groups up to and including 55 years, and a significant increase for the over-55s. CONCLUSION: There was a slight increase in the prescription prevalence rate during the observation period. Disulfiram was the most commonly prescribed drug. The prescription increase was greatest among women and in the group of over-55s. PMID- 30421744 TI - Psychedelic drugs in the treatment of anxiety, depression and addiction. AB - BAKGRUNN: Det er okt interesse for psykedeliske stoffer til bruk i behandling av psykiske lidelser. Stoffene regnes som trygge nar de gis innenfor en klinisk ramme. Eldre studier fra for 1970 har metodologiske svakheter, men i de senere ar har det kommet lovende resultater fra bruk ved unipolar depresjon, depresjon ved livstruende sykdom, angst og avhengighet. Formalet med denne litteraturgjennomgangen er a gi en oversikt over nyere resultater og disse studienes begrensninger. KUNNSKAPSGRUNNLAG: Vi sokte i databasen PubMed etter kliniske studier fra perioden 1990-2017 med sokeordene angst, depresjon, avhengighet og psykedeliske stoffer. Kvaliteten pa studiene ble sa vurdert ut ifra metode og styrkeberegning. RESULTATER: Soket ga 424 artikler, hvorav ni ble inkludert (fire om angst og depresjon ved livstruende sykdom, to om depresjon, to om avhengighetslidelse og en om tvangslidelse). To dobbeltblinde, randomiserte, kontrollerte fase II-studier med et moderat antall pasienter fant umiddelbar, markert og vedvarende effekt av en enkeltdose psilocybin mot angst og depresjon ved livstruende sykdom. De andre studiene hadde mer usikre resultater. Det var ingen alvorlige bivirkninger eller rapportering om avhengighet. FORTOLKNING: Psykedeliske stoffer i behandling av flere psykiske lidelser har vist lovende resultater, men studiene er sma og har metodologiske utfordringer. Det er behov for systematiske kliniske studier for a skaffe solid dokumentasjon for effekt og etablere rutiner for overvakning av mulige bivirkninger. PMID- 30421746 TI - Authors' response (March 14, 2018) to the letter to the Editor concerning the paper "Histological findings and lung dust analysis as the basis for occupational disease compensation in asbestos-related lung cancer in Germany". PMID- 30421745 TI - Letter to the Editor (February 14, 2018) concerning the paper "Histological findings and lung dust analysis as the basis for occupational disease compensation in asbestos-related lung cancer in Germany". PMID- 30421747 TI - Red blood cell-derived nanovesicles for safe and efficient macrophage-targeted drug delivery in vivo. AB - Macrophage-targeted drug delivery has great therapeutic potential for the treatment of cancers and inflammatory diseases. There is also an unmet need for efficient and nontoxic means of in vivo macrophage depletion to determine the role of macrophages under normal and disease settings. Herein, we explored the potential of red blood cell (RBC)-derived nanovesicles (RDNVs) as drug nanocarriers to specifically deplete macrophages. We show that RDNVs are effective hydrophilic drug carriers and can effectively deliver drugs into macrophages both in vitro and in vivo. Nanovesicles derived from both wild-type mouse RBCs (WT-RDNVs) and CD47 KO mouse RBCs (KO-RDNVs) can encapsulate clodronate with good stability in PBS for long-term storage. However, KO-RDNVs were more efficiently engulfed by macrophages in vitro and more rapidly cleared in vivo than WT-RDNVs, indicating that CD47 also serves as a "don't eat me" molecule for RDNVs as it does for RBCs. Accordingly, clodronate-encapsulated KO RDNVs (KO-RDNV/CLD) were significantly more toxic to mouse macrophages in vitro than drug-loaded WT-RDNVs (WT-RDNV/CLD). Furthermore, WT-RDNV/CLD showed prolonged accumulation in tissues (e.g., liver and lung) and macrophage depletion versus KO-RDNV/CLD. Importantly, RBC-derived nanovesicles are more biocompatible and less toxic in vivo than clodronate-encapsulated liposomes-the current gold standard macrophage-depleting reagent. This study offers a useful strategy for macrophage-targeted drug delivery. PMID- 30421748 TI - 21st century developments in the understanding and control of molecular solids. AB - The first decades of the 21st Century have seen very significant advances in the understanding, prediction and control of molecular solids. Advances in crystallization techniques, polymorphism, co-crystals, co-amorphous materials, crystal engineering and instrumentation have all contributed to what is now an extremely active field. There are huge fundamental implications as well as applications particularly in the pharmaceutical, agrochemicals and energetic materials sectors. This highlight article surveys some of the key recent developments. PMID- 30421749 TI - The Ouzo effect to selectively assemble molybdenum clusters into nanomarbles or nanocapsules with increased HER activity. AB - Metal cluster nanoparticles are obtained by simple solvent shifting called the Ouzo effect. Remarkably, the assembly of [{Mo6Br8}L6]2- (L = Br- or NCS-) cluster units can be directed into nanomarbles or nanocapsules depending on the cluster chemistry. When deposited on electrodes, these nanoparticles show good activities in electrochemical water splitting under mild conditions. PMID- 30421750 TI - Difunctionalization of ketones via gem-bis(boronates) to synthesize quaternary carbon with high selectivity. AB - All-carbon quaternary centres are significant and prevalent structural frameworks but their preparation routes are rare and challenging, especially methods with common substrates. Herein, we report a convenient process to construct all-carbon quaternary centres from ketones via the diborylation process and Suzuki-Miyaura cross-coupling reaction. This methodology, which simultaneously introduces two different kinds of electrophilic structures, exhibits a large substrate scope and high functional group tolerance. The reaction products with aldehyde and allylic groups have proved to be versatile synthons to prepare complex molecules crucial for natural product synthesis. PMID- 30421751 TI - Binding for endohedral-metallofullerene superatoms induced by magnetic coupling. AB - To design new materials based on artificial superatoms, clarifying their involved interaction is particularly important. In this study, we discuss first-principle calculations to show that the interaction between endohedral metallofullerenes (EMFs) of U@C28 can lead to different chemical and physical adsorption structures. Especially, these structures are derived from different magnetic coupling resonances, and they can transform by changing the distance between U@C28 superatoms. These findings will promote the future development for bottom up assembling of new functional materials and even devices. PMID- 30421752 TI - Photohealable ion gels based on the reversible dimerisation of anthracene. AB - We report a photohealable ion gel based on the photodimerisation of anthracene as a dynamic covalent bond. A tetra-arm poly(ethylene glycol) terminally functionalised with anthracene was synthesised and combined with an ionic liquid to form an ion gel. The photodimerisation reaction was utilised to realise photohealing of the ion gels. PMID- 30421753 TI - A homochiral Zn-Dy heterometallic left-handed helical chain complex without chiral ligands: anion-induced assembly and multifunctional integration. AB - Both second-order nonlinear optical and single-molecule magnet properties are observed in a novel 1D homochiral Zn-Dy heterometallic left-handed helical chain complex (1) without chiral ligands, which evolves from a Zn3Dy2 pentanuclear cluster complex (2), thanks to the structural guiding role of perchlorate anions. PMID- 30421754 TI - A supramolecular porous material comprising Fe(ii) mesocates. AB - The dinuclear mesocate [Fe2L3](BF4)4, 1, is a supramolecular building block for a microporous material. Structural analysis reveals that extensive noncovalent interactions in the solid state generate a 3D framework with microporous channels. These channels are permanently accessible to incoming guest molecules and adsorption isotherms demonstrate that the material has a high selectivity for CO2 over N2. PMID- 30421757 TI - The hitchhiker's guide to quantitative diffusion measurements. AB - Quantifying diffusional motion of submicron tracer particles with high spatiotemporal resolution is often key to assess the dynamics of physico-chemical systems, e.g. in complex fluids, colloidal suspensions, or living cells. A variety of methods has been developed over the past decades, but often their quantitative comparability has remained poorly explored on an experimental basis. Yet, knowing their experimental benefits and limitations can be a crucial piece of information when designing experiments on new and unexplored specimen. Therefore, we have implemented three very widespread techniques for quantifying diffusional motion (single-particle tracking, fluorescence correlation spectroscopy, and differential dynamic microscopy) in a light sheet microscope and performed a quantitative comparison on standardized samples of varying concentrations. Light sheet microscopy is particularly suited for imaging-based diffusion measurements because of its high spatiotemporal resolution in combination with an improved contrast and signal-to-noise-ratio at low excitation powers. As a result, all three methods are found to yield good quantitative estimates with respect to the theoretically predicted diffusion constant, yet their accuracy and bias varies markedly, raising specific caveats for the individual methods' range of applicability. PMID- 30421758 TI - Structures and properties of large supramolecular coordination complexes predicted with the generalized energy-based fragmentation method. AB - The generalized energy-based fragmentation (GEBF) method has been extended to facilitate ab initio calculations of large supramolecular coordination complexes. For metal-containing coordination complexes, a special fragmentation scheme is proposed for GEBF calculations, in which coordinate bonds between metal ions and ligands are kept intact, and only single covalent bonds in organic ligands are cut into fragments. A simple strategy is exploited for the determination of the ground-state spin multiplicity of each metal ion so that the total spin of all metal-containing subsystems is assigned automatically. With this fragmentation scheme, the GEBF method is demonstrated to provide reliable energies, optimized geometry, nuclear magnetic resonance (NMR) properties and the infrared spectrum for a medium-sized supramolecular coordination complex, which are very consistent with those from the full-system quantum chemistry calculations. The GEBF method is then applied to two large supramolecular coordination complexes to illustrate its capability. For the trimetallic coordination complex Fe2Zn2(RuL2)2 (with 618 atoms), the calculated 1H chemical shifts from GEBF calculations with the B97-2 functional can account well for the experimental NMR spectrum. For the cage-guest complex Pd4L8(BF4-)3, the computed infrared spectrum obtained with the GEBF-M06 2X method can help assign the experimental peaks to the corresponding vibrational motions. The GEBF method combining with advanced electronic structure methods is expected to be a useful tool to understand and interpret structural and spectroscopic information of various supramolecular coordination complexes. PMID- 30421759 TI - Optical properties of magnesium nanorods using time dependent density functional theory calculations. AB - Plasmonic nanostructures made of Earth-abundant and low-cost metals such as aluminum and magnesium have recently emerged as a potential alternative candidate to conventional plasmonic metals such as gold and silver. Here using computationally efficient time-dependent density-functional theory calculations, we explore optical response modulations of magnesium nanorods via aspect ratio and absolute size variations. We reveal that both the aspect ratio and absolute size of the nanorods are critical for elucidating their optical characteristics. We show that both tuning factors cause significant optical response modulations in the case of thin nanorods (emergence of localized surface plasmon resonances, significant spectral shifting and spectral intensity re-distributions), whereas, very marginal changes in the case of thick nanorods. We believe that our theoretical results would help in the design of magnesium based nano-plasmonic devices. PMID- 30421760 TI - Self-adaptive multiscaling algorithm for efficient simulations of many-protein systems in crowded conditions. AB - A method is described for the efficient simulation of multiprotein systems in crowded environments. It is based on an adaptive, reversible structural coarsening algorithm that preserves relevant physical features of the proteins across scales. Water is treated implicitly whereas all the other components of the aqueous solution, such as ions, cosolutes, or osmolytes, are treated in atomic detail. The focus is on the analytical adaptation of the solvent model to different levels of molecular resolutions, which allows continuous, on-the-fly transitions between scales. This permits the analytical calculation of forces during dynamics and preserves detailed balance in Monte Carlo simulations. A major computational speedup can be achieved in systems containing hundreds of proteins without cutting off the long-range interactions. The method can be combined with a self-adaptive configurational-bias sampling technique described previously, designed to detect strong, weak, or ultra-weak protein associations and shown to improve sampling efficiency and convergence. The implementation aims to simulate early stages of multimeric complexation, aggregation, or self assembly. The method can be adopted as the basis for a more general algorithm to identify vertices, edges, and hubs in protein interaction networks or to predict critical steps in signal transduction pathways. PMID- 30421764 TI - Temperature effects on the nanoindentation characterization of stiffness gradients in confined polymers. AB - The stiffening of polymers near inorganic fillers plays an important role in strengthening polymer nanocomposites, and recent advances in metrology have allowed us to sample such effects using local mechanical measurement techniques such as nanoindentation and atomic force microscopy. A general understanding of temperature and confinement effects on the measured stiffness gradient length scale xiint is lacking however, which convolutes molecular interpretation of local property measurements. Using coarse-grained molecular dynamics and finite element nanoindentation simulations, we show that the measured xiint increases with temperature in highly confined polymer systems, a dependence which acts in the opposite direction in systems with low confinement. These disparate trends are closely related to the polymer's viscoelastic state and the resulting changes in incompressibility and dissipative ability as the polymer transitions from glassy to rubbery. At high temperatures above the glass transition temperature, a geometrically confined system restricts the viscous dissipation of the applied load by the increasingly incompressible polymer. The indentation causes a dramatic build-up of hydrostatic pressure near the confining surface, which contributes to an enlarged measurement of xiint. By contrast, a less-confined system allows the pressure to dissipate via intermolecular motion, thus lowering the measured xiint with increased temperature above the glass transition temperature. These findings suggest that the well-established thin film nancomposite analogy for polymer mobility near interfaces can be convoluted when measuring local mechanical properties, as the viscoelastic state and geometric confinement of the polymer can affect the nanomechanical response during indentation purely from continuum effects. PMID- 30421765 TI - Electron-poor hemilabile dicationic palladium NHC complexes - synthesis, structure and catalytic activity. AB - We present a new class of dicationic palladium NHC complexes with two carbene ligands bearing different aryl substituents and a hemilabile pyrimidyl group. They can either be synthesized from the imidazolium salts via the silver transmetalation route to a halide-free palladium(ii) precursor or by direct deprotonation by palladium acetate. For four complexes we could determine their solid-state structures by X-ray diffraction experiments. Insight gained by NMR spectroscopy and DFT calculations revealed that in solution the two potentially bidentate ligands interchange between chelating and non-chelating coordination modes. The preference of these coordination modes is governed by the steric influence of the different ligands. The complexes were shown to be active catalysts for the hydroarylation of alkynes, and their performance was rationalized by DFT calculations. PMID- 30421766 TI - Synthesis of tetraarylborates via tetralithio intermediates and the effect of polar functional groups and cations on their crystal structures. AB - A novel general protocol for the preparation of functionalized (COOH, CHO, C(O)NHtBu, B(OH)2) tetraphenyl- and tetrakis(4'-biphenylyl)borates is reported. It involves four-fold halogen-lithium exchange in potassium tetrakis(iodophenyl)borates and tetrakis(4'-bromobiphenylyl)borate) using t-BuLi in THF at -78 degrees C followed by treatment of the resulting tetralithio intermediates with electrophiles (CO2, DMF, t-BuNCO, B(OMe)3). X-ray crystal structures of ammonium tetrakis[4-(dihydroxyboryl)phenyl]borate, lithium tetrakis(3-carboxyphenyl)borate, and lithium tetrakis[4-(tert butylcarbamoyl)phenyl]borate were determined showing a strong effect of the cation and polar functional group on supramolecular architecture. PMID- 30421767 TI - Optical manipulation of animal behavior using a ruthenium-based phototrigger. AB - A visible-light activatable caged compound based on a ruthenium-polypyridine complex was used to elicit the feeding response of the freshwater cnidarian Hydra vulgaris. The phototrigger delivers l-arginine in a clean reaction under irradiation with blue or green light. The synthesis, characterization and application mode of this caged arginine are described. A combination of fiber optics setup and a high absorbance medium allows the precise control of uncaging in the submillimetric range, needed to address the zone where activation takes place. PMID- 30421769 TI - Glassy relaxation slows down by increasing mobility. AB - We find a striking trend reversal in the relaxation dynamics of mixtures with strong dynamical asymmetry. Simulations by both Brownian and Newtonian dynamics reveal that in mixtures of fast and slow hard spheres, above a critical density, the dynamics becomes slower upon increasing the mobility of the fast particles. Below that density, the same increase in mobility speeds up the dynamics. The critical density itself can be identified with the glass transition of the mode coupling theory that does not depend on the dynamical asymmetry. The asymptotic dynamics close to the critical density is universal, but strong pre-asymptotic effects prevail in particular when the dynamical asymmetry also involves size asymmetry. Our observations reconcile earlier findings, where a strong dependence on kinetic parameters was found for the glassy dynamics, with the paradigm that the glass transition is determined by the properties of configuration space alone. PMID- 30421770 TI - An ultra-thin highly flexible microfluidic device for blood oxygenation. AB - Many neonates who are born premature suffer from respiratory distress syndrome (RDS) for which mechanical ventilation and an extracorporeal membrane oxygenation (ECMO) device are used in treatment. However, the use of these invasive techniques results in higher risk of complications like bronchopulmonary dysplasia or requires surgery to gain vascular access. An alternative biomimetic approach is to use the umbilical cord as a vascular access and to connect a passive device to the baby that functions like a placenta. This concept, known as the artificial placenta, provides enough oxygenation and causes minimal distress or complications. Herein, we have developed a new artificial placenta-type microfluidic blood oxygenator (APMBO) with high gas exchange, low priming volume and low hydraulic resistance such that it can be operated only by pressure differential provided by the baby's heart. Mimicking the placenta, we have made our new device ultra-thin and flexible so that it can be folded into a desired shape without losing its capability for gas exchange and achieve a compact form factor. The ability to fold allowed optimization of connectors and reduced the overall priming volume to the sub-milliliter range while achieving a high oxygen uptake which would be sufficient for preterm neonates with a birth-weight of around 0.5 kg. PMID- 30421772 TI - Glutathione as a photo-stabilizer of avobenzone: an evaluation under glass filtered sunlight using UV-spectroscopy. AB - Avobenzone is the most widely used UVA filter in sunscreen lotion and it is prone to degradation in the presence of sunlight/UV radiation. To overcome the photo instability of avobenzone, various photostabilizers have been used as additives, including antioxidants such as vitamin C, vitamin E, and ubiquinone. In the present study, the well known antioxidant, glutathione, was evaluated for protecting avobenzone from photodegradation in the presence of glass-filtered sunlight. The features of glutathione as a skin whitener and a radical scavenger in cells have prompted the assessment of the photostabilzing activity of glutathione on avobenzone. Glutathione significantly attenuated the glass filtered sunlight-induced degradation of avobenzone at equimolar or higher ratios of glutathione and avobenzone. Mutational studies have been undertaken to investigate the role of the thiol group and the isopeptide bond of glutathione on its photoprotection activity towards avobenzone. The thiol group of glutathione plays a vital role in exhibiting the photoprotection activity, which was further supported by the studies on photodegradation of avobonzone in the presence of beta-mercaptoethanol. The dual role of glutathione as a skin whitening agent and a photostabilizer of avobenzone may be useful for the development of multipurpose cosmetic lotions. PMID- 30421774 TI - Incorporation of Cu-Nx cofactors into graphene encapsulated Co as biomimetic electrocatalysts for efficient oxygen reduction. AB - Unlike metals with incomplete d-shells such as Pt and Fe, copper (Cu) with a filled d-electron shell is generally regarded as a sluggish oxygen reduction reaction (ORR) electrocatalyst. However, laccase and other copper enzymes could catalyze the ORR efficiently in nature. Inspired by this, we incorporated Cu-Nx cofactors (Cu-N2 and Cu-N4) into graphene encapsulated Co frameworks by direct annealing of MOFs with a post etching process. The bioinspired electrocatalyst exhibits excellent performance and stability for ORR which is comparable to or even better than Pt/C. Meanwhile, it also illustrates a fantabulous performance in a zinc-air battery device. The excellent performance can be ascribed to the abundant atomically dispersed Cu-Nx cofactors in the graphene frameworks confirmed by aberration corrected HAADF-STEM and XAFS analyses. Density functional theory calculations suggest that when Cu atoms are coordinated with the surrounding N atoms, the valence electrons of Cu atoms will transfer to nitrogen atoms, simultaneously tuning the d electronic states near the Fermi level to realize fast ORR kinetics. PMID- 30421775 TI - Long-distance transmission of broadband near-infrared light guided by a semi disordered 2D array of metal nanoparticles. AB - Near-infrared (NIR) waveguides are a key component of planar photonic devices such as optical communication couplers, image sensors, and spectroscopes for chemical or biological molecules. Conventional NIR waveguides used for signal transmission include silicon-on-insulator (SOI) waveguides and channel/ridge-type metal micro-strips. However, these waveguides usually have limitations of either signal delay or signal loss in optically integrated devices. In this study, a novel NIR waveguide composed of a semi-disordered array of metal nanoparticles (sDAMNPs) on Si substrate was proposed, fabricated, and tested. The disordered metallic nanoparticles array is geometrically localized in the form of 1D metal strips, thus replacing sDAMNPs with less lossy micro strip channel waveguides. From the measurements supported by various computational models, the fabricated waveguides operate effectively in the broadband NIR region (1100 to 1700 nm). The waveguide does not support signal transmission in the ultra violet-visible spectrum due to strong signal absorption, scattering, and localization effects inside the metal nanoparticles. Instead, it is capable of transmitting NIR over a distance longer than 100 MUm (signal loss ~3.85 dB per 100 MUm for NIR from 1200 to 1600 nm), which is also sufficiently longer than the conventional surface plasmon polariton propagation distance at the metal-Si interface. Compared to a waveguide-free reference, the waveguide exhibited greatly improved signal transmission efficiency up to a factor of 7.42 * 104 at 1367 nm. It also exhibits a high deflection angle sensitivity of 1.89 dB per 0.01 rad, thus efficiently and straightly guiding the broadband NIR signal over a long distance. PMID- 30421777 TI - Crossover from three- to six-fold symmetry of colloidal aggregates in circular traps. AB - At sufficiently low temperatures and high densities, repulsive spherical particles in two-dimensions (2d) form close-packed structures with six-fold symmetry. By contrast, when the interparticle interaction has an attractive anisotropic component, the structure may exhibit the symmetry of the interaction. We consider a suspension of spherical particles interacting through an isotropic repulsive potential and a three-fold symmetric attractive interaction, confined in circular potential traps in 2d. We find that, due to the competition between the interparticle and the external potentials, the particles self-organize into structures with three- or six-fold symmetry, depending on the width of the traps. For intermediate trap widths, a core-shell structure is formed, where the core has six-fold symmetry and the shell is three-fold symmetric. When the width of the trap changes periodically in time, the symmetry of the colloidal structure also changes, but it does not necessarily follow that of the corresponding static trap. PMID- 30421778 TI - Food matrix and processing modulate in vitro protein digestibility in soybeans. AB - Soybeans represent the largest source of plant proteins on the planet but their proteins are associated with low digestibility. Although several studies addressed the limiting factors affecting the rate and extent of soy protein digestion, the net effect of the food matrix, especially of an intact cell wall, has been poorly investigated so far. The purpose of the present study was to examine the relationship between the cell matrix and protein hydrolysis during simulated in vitro digestion of soybean particles of different sizes prepared from unheated and boiled cotyledons. In addition, intact cells were isolated from unheated and autoclaved cotyledons and then digested with and without lipase inhibitors to understand the impact of an intact cell wall and the presence of oil bodies on soybean protein digestibility. Protein digestibility was the highest in the particles prepared after boiling of previously milled cotyledons compared to particles of the same size obtained by milling previously cooked cotyledons as well as of uncooked cotyledons. Protein digestibility in isolated intact cells was lower than that of extracted proteins regardless of the thermal load applied whereas inhibition of pancreatic lipase reduces protein digestibility only slightly. The data indicated that the cell wall could contribute to limit protein digestion in soybean tissues; however, it is not an absolute barrier to pancreatic proteases. An accurate design of the milling and cooking process could be instrumental to modulate the digestion kinetics of soybean proteins. PMID- 30421779 TI - Capillary force induced air film for self-aligned short channel: pushing the limits of inkjet printing. AB - Ultrashort channels of electrodes are essential for the construction of advanced functional devices with high-level integration and high operation speed. However, the channel length of fabricated electrodes is limited to 20 MUm in inkjet printing. Although several methods have been previously proposed to obtain short channels, they require extra processing steps. In this paper, channel self aligning phenomenon was observed in directly patterned electrodes on unmodified substrate by inkjet printing, when using an interspace defects growing method. Further exploring the underlying mechanism reveals that the capillary force induced air film prevents droplets coalescence, even on a substrate with no temperature differences. The wetting region, which is generated by the receding droplets impingement, will draw droplets closer together at a larger drop space, thus demanding smaller air pressure for coalescence inhibition and contributing to the self-aligning phenomenon of micro-sized droplets released by inkjet printing. Accordingly, an ultrashort channel of 2.38 MUm is obtained with relatively smooth boundaries, when electrodes are printed on a slightly heated substrate, which reduces the air pressure between two neighboring droplets. This work will provide a significant reference for future high resolution applications of inkjet printing technology. PMID- 30421780 TI - Intradialytic resistance training: an effective and easy-to-execute strategy. AB - : Chronic kidney disease (CKD) alters the morphology and function of skeletal muscles, thereby decreasing patient physical capacity (PC) and quality of life (QoL). Intradialytic resistance training (IRT) is a pragmatic tool used to attenuate these complications. However, IRT has not been strongly adopted in nephrology care centers. This study aimed to assess the efficacy and safety of a low-cost, easy-to-use IRT protocol. METHODS: The study enrolled 43 patients (52.8 +/- 13.85 years) on HD for five to 300 months followed from April 2014 to July 2017. The efficacy of IRT was assessed based on PC - derived from muscle strength (MS) and preferred walking speed (PWS) - and QoL. The occurrence of adverse events was used as a measure of safety. The IRT protocol consisted of exercises of moderate to high intensity for the main muscle groups performed three times a week. RESULTS: The mean follow-up time was 9.3 +/- 3.24 months, for a total of 4,374 sessions of IRT. Compliance to the protocol was 96.5 +/- 2.90%, and patients presented significant improvements in MS (from 27.3 +/- 11.58 Kgf to 34.8 +/- 10.77 Kgf) and PWS (from 0.99 +/- 0.29 m/s to 1.26 +/- 0.22 m/s). Physical and emotional components of QoL also increased significantly. CONCLUSION: IRT led to significant increases in PC and higher scores in all domains of QoL. Important adverse events were not observed during intradialytic resistance training. PMID- 30421781 TI - Pathogenesis, histopathologic findings and treatment modalities of lipoprotein glomerulopathy: A review. AB - Lipoprotein glomerulopathy (LPG) is an uncommon cause of nephrotic syndrome and/or kidney failure. At microscopy, LPG is characterized by the presence of lipoprotein thrombi in dilated glomerular capillaries due to different ApoE mutations. ApoE gene is located on chromosome 19q13.2, and can be identified in almost all serum lipoproteins. ApoE works as a protective factor in atherosclerosis due its interaction with receptor-mediated lipoprotein clearance and cholesterol receptor. Most common polymorphisms include ApoE2/2, ApoE3/2, ApoE3/3, ApoE4/2, ApoE4/3, and ApoE4/4. All age-groups can be affected by LPG, with a discrete male predominance. Compromised patients typically reveal dyslipidemia, type III hyperlipoproteinemia, and proteinuria. LPG treatment includes fenofibrate, antilipidemic drugs, steroids, LDL aphaeresis, plasma exchange, antiplatelet drugs, anticoagulants, urokinase, and renal transplantation. Recurrence in kidney graft suggests a pathogenic component(s) of extraglomerular humoral complex resulting from abnormal lipoprotein metabolism and presumably associated to ApoE. PMID- 30421782 TI - Association between religiosity and happiness in patients with chronic kidney disease on hemodialysis. AB - OBJECTIVES: Religiosity/spirituality (R/S) seems to be a relevant factor in chronic diseases adaptation, but there is a lack of studies involving chronic kidney disease (CKD). This study aimed to investigate the association between R/S and happiness among CKD patients on hemodialysis and whether Sense of Coherence (SC) mediates this possible association. METHODS: This was a cross-sectional study in two renal replacement therapy centers in Brazil, involving 161 adults on hemodialysis. Linear regressions were performed to evaluate the association between R/S (predicting variable measured with Duke Religious Index - DUREL) and happiness (outcome variable), adjusted for sociodemographic, clinical, and some laboratory variables. Later, SC was added to the model to test the possible mediating effect. RESULTS: Most patients (91.20%) reported some religious affiliation. Private Religiosity (PR) (beta = 0.53; 95% CI = 0.01 a 1.06), Intrinsic Religiosity (IR) (beta = 0.48; 95% CI = 0.18 a 0.79), and SC (beta = 0.11; 95% CI = -0.09 a 0.15) correlated with higher levels of happiness, controlling for clinical and sociodemographic variables. When SC was included in the model, IR (beta = 0.34; 95% CI = 0.07 to 0.60) and SC (beta = 0.11; 95% CI = 0.08 to 0.14) remained significantly. No clinical or sociodemographic variable correlated with happiness. CONCLUSIONS: Patients on hemodialysis showed high levels of R/S, which correlated with higher happiness levels. Clinical and sociodemographic variables were not correlated with patients' happiness. Psychosocial variables such as R/S and SC are potential key targets for interventions to promote better survival quality among CKD patients. PMID- 30421783 TI - Micro RNA 146a-5p expression in Kidney transplant recipients with delayed graft function. AB - INTRODUCTION: The development of novel non-invasive biomarkers of kidney graft dysfunction, especially in the course of the delayed graft function period would be an important step forward in the clinical practice of kidney transplantation. METHODS: We evaluated by RT-PCR the expression of miRNA-146 to -5p ribonucleic micro-acids (miRNAs) in the peripheral blood and renal tissue obtained from kidney transplant recipients who underwent a surveillance graft biopsy during the period of delayed graft function. RESULTS: In biopsy samples, the expression of miR-146a-5p was significantly increased in the group of patients with delayed graft function (DGF) (n = 33) versus stables patients (STA) (n = 13) and patients with acute rejection (AR) (n = 9) (p = 0.008). In peripheral blood samples, a non significant increase of miR-146a-5p expression was found in the DGF group versus STA and AR groups (p = 0.083). No significant correlation was found between levels of expression in biopsy and plasma. ROC curve analysis revealed an AUC of 0.75 (95% CI: 0.62-0.88) for the renal tissue expression and 0.67 (95% CI 0.52 0.81) for the peripheral blood expression. CONCLUSION: We conclude that miR-146a 5p expression has a distinct pattern in the renal tissue and perhaps in the peripheral blood in the setting of DGF. Further refinements and strategies for studies should be developed in the field of non-invasive molecular diagnosis of kidney graft dysfunction. PMID- 30421784 TI - Hypertension in patients on dialysis: diagnosis, mechanisms, and management. AB - Hypertension (blood pressure > 140/90 mm Hg) is very common in patients undergoing regular dialysis, with a prevalence of 70-80%, and only the minority has adequate blood pressure (BP) control. In contrast to the unclear association of predialytic BP recordings with cardiovascular mortality, prospective studies showed that interdialytic BP, recorded as home BP or by ambulatory blood pressure monitoring in hemodialysis patients, associates more closely with mortality and cardiovascular events. Although BP is measured frequently in the dialysis treatment environment, aspects related to the measurement technique traditionally employed may be unsatisfactory. Several other tools are now available and being used in clinical trials and in clinical practice to evaluate and treat elevated BP in chronic kidney disease (CKD) patients. While we wait for the ongoing review of the CKD Blood Pressure KIDGO guidelines, there is no guideline for the dialysis population addressing this important issue. Thus, the objective of this review is to provide a critical analysis of the information available on the epidemiology, pathogenic mechanisms, and the main pillars involved in the management of blood pressure in stage 5-D CKD, based on current knowledge. PMID- 30421785 TI - A UFLC-MS/MS method for the simultaneous determination of eight bioactive constituents from red wine and dealcoholized red wine in rat plasma: Application to a comparative pharmacokinetic study. AB - To explore whether alcohol has an effect on the pharmacokinetic behavior of phenolic acids, the main bioactive constituents in red wine, a highly sensitive and simple ultra-fast liquid chromatography coupled with triple quadrupole mass spectrometry (UFLC-MS/MS) method was developed for simultaneous quantitation of eight phenolic acids in plasma samples. Plasma samples were extracted by liquid liquid extraction and the chromatographic separation was achieved on a Zorbax SB C18 column within 7.0 min. Results of the validated method revealed that all of the calibration curves displayed good linear regression (r > 0.99). The intra- and inter-day precisions of the analytes were <14.0% and accuracies ranged from 8.5 to 7.3%. The extraction recoveries of the analytes were from 71.2 to 110.2% and the matrix effects ranged from 86.2 to 105.5%. The stability of these compounds under various conditions satisfied the requirements of biological sample measurement. The method was successfully applied to a comparative pharmacokinetic study of phenolic acids in rat plasma. For gallic acid and gentisic acid, the parameters AUC0-t and AUC0-infinity increased remarkably (p < 0.05) after oral administration of red wine, which suggested that alcohol might enhance their absorption. This is the first report to compare the pharmacokinetic behavior of phenolic acids in red wine and dealcoholized red wine. PMID- 30421786 TI - Glucosylation of (Z)-3-hexenol informs interspecies interactions in plants: A case study in Camellia sinensis. AB - Plants emit a variety of volatiles in response to herbivore attack and (Z)-3 hexenol and its glycosides have been shown to function as defense compounds. Although the ability to incorporate and convert (Z)-3-hexenol to glycosides is widely conserved in plants, the enzymes responsible for the glycosylation of (Z) 3-hexenol remained unknown until today. In this study, uridine-diphosphate dependent glycosyltransferase (UGT) candidate genes were selected by correlation analysis and their response to airborne (Z)-3-hexenol, which has been shown to be taken up by the tea plant. The allelic proteins UGT85A53-1 and -2 showed the highest activity towards (Z)-3-hexenol and are distinct from UGT85A53-3 which displayed a similar catalytic efficiency for (Z)-3-hexenol and nerol. A single amino acid exchange E59D enhanced the activity towards (Z)-3-hexenol, whereas a L445M mutation reduced the catalytic activity toward all substrates tested. Transient over-expression of CsUGT85A53-1 in tobacco significantly increased the level of (Z)-3-hexenyl glucoside. The functional characterization of CsUGT85A53 as a (Z)-3-hexenol UGT not only provides the foundation for the biotechnological production of (Z)-3-hexenyl glucoside, but also delivers insights for the development of novel insect pest control strategies in tea plant and might be generally applicable to other plants. PMID- 30421787 TI - The role of genetics in the current diagnostic workup of idiopathic non histaminergic angioedema. PMID- 30421788 TI - Increased evolutionary rates and conserved transcriptional response following allopolyploidization in brown algae. AB - Genome mergers between independently evolving lineages, via allopolyploidy, can potentially lead to instantaneous sympatric speciation. However, little is known about the consequences of allopolyploidy and the resultant "genome shock" on genome evolution and expression beyond the plant and fungal branches of the Tree of Life. The aim of this study was to compare substitution rates and gene expression patterns in two allopolyploid brown algae (Phaeophyceae and Heterokonta) and their progenitors in the genus Pelvetiopsis N. L. Gardner in the north-east Pacific, and to date their relationships. We used RNA-seq data, all potential orthologues, and putative single-copy loci for phylogenomic, divergence, and gene expression analyses. The multispecies coalescent placed the origin of allopolyploids in the late Pleistocene (0.35-0.05 Ma). Homoeologues displayed increased nonsynonymous divergence compared with parental orthologues, consistent with relaxed selective constraint following allopolyploidization, including for genes with no evidence of pseudogenization or neofunctionalization. Patterns of homoeologue-orthologue expression conservation and expression level dominance were largely shared with both natural plant and fungal allopolyploids. Our results provide further support for common cross-Kingdom patterns of allopolyploid genome evolution and transcriptional responses, here in the evolutionarily distinct marine heterokont brown algae. PMID- 30421789 TI - A colorful killer: Daphnia infected with the bacterium Spirobacillus cienkowskii exhibit unexpected color variation. PMID- 30421790 TI - Experimental implementation of a joint statistical image reconstruction method for proton stopping power mapping from dual-energy CT data. AB - PURPOSE: To experimentally commission a dual-energy CT (DECT) joint statistical image reconstruction (JSIR) method, which is built on a linear basis vector model (BVM) of material characterization, for proton stopping power ratio (SPR) estimation. METHODS: The JSIR-BVM method builds on the relationship between the energy-dependent photon attenuation coefficients and the proton stopping power via a pair of BVM component weights. The two BVM component images are simultaneously reconstructed from the acquired DECT sinograms and then used to predict the electron density and mean excitation energy (I-value), which are required by the Bethe equation for SPR computation. A post-reconstruction image based DECT method, which utilizes the two separate CT images reconstructed via the scanner's software, was implemented for comparison. The DECT measurement data were acquired on a Philips Brilliance scanner at 90 and 140 kVp for two phantoms of different sizes. Each phantom contains 12 different soft and bony tissue surrogates with known compositions. The SPR estimation results were compared to the reference values computed from the known compositions. The difference of the computed water equivalent path lengths (WEPL) across the phantoms between the two methods was also compared. RESULTS: The overall root-mean-square (RMS) of SPR estimation error of the JSIR-BVM method are 0.33% and 0.37% for the head- and body-sized phantoms, respectively, and all SPR estimates of the test samples are within 0.7% of the reference ground truth. The image-based method achieves overall RMS errors of 2.35% and 2.50% for the head- and body-sized phantoms, respectively. The JSIR-BVM method also reduces the pixel-wise random variation by 4-fold to 6-fold within homogeneous regions compared to the image-based method. The average differences between the JSIR-BVM method and the image-based method are 0.54% and 1.02% for the head- and body-sized phantoms, respectively. CONCLUSION: By taking advantage of an accurate polychromatic CT data model and a model-based DECT statistical reconstruction algorithm, the JSIR-BVM method accounts for both systematic bias and random noise in the acquired DECT measurement data. Therefore, the JSIR-BVM method achieves good accuracy and precision on proton SPR estimation for various tissue surrogates and object sizes. In contrast, the experimentally achievable accuracy of the image-based method may be limited by the uncertainties in the image formation process. The result suggests that the JSIR-BVM method has the potential for more accurate SPR prediction compared to post-reconstruction image-based methods in clinical settings. PMID- 30421791 TI - Biomodification of compromised extraction sockets using hyaluronic acid and rhBMP 2: An experimental study in dogs. AB - BACKGROUND: This experimental study aims to evaluate the effect of hyaluronic acid on healing of infected extraction sockets compared with recombinant human bone morphogenetic protein-2 (rhBMP-2). METHODS: Both third and fourth mandibular premolars of six beagle dogs were hemisected, and the distal roots were extracted at baseline. Subsequently, combined endodontic-periodontic lesions were induced at the remaining mesial roots. After 4 months, the mesial roots on both sides of the mandible were removed. Four sockets per dog were randomly allocated to four groups: Group 1, Control; Group 2, only absorbable collagen sponge (ACS: carrier); Group 3, 1% hyaluronic acid (HA) gel + ACS; and Group 4, rhBMP-2 + ACS. After 3 months of healing, the dogs were euthanized for microcomputed tomography and histologic analysis. RESULTS: After the lesion induction period (4 months), communication between the periodontal lesion and endodontic periapical lesion was observed at all remaining mesial roots. Alveolar bone overgrowth was observed in groups 3 and 4, but bone volume density was not significantly different among all groups. At the crestal portion, mineralization, and osteocalcin expression were higher in groups 3 and 4 than in groups 1 and 2. CONCLUSION: Treatment with HA can promote bone formation and improve the wound healing rate comparable to rhBMP 2 in infected extraction sockets. PMID- 30421792 TI - Pharmacokinetics, bioavailability and metabolism of scopoletin in dog by ultra high-performance liquid chromatography combined with linear ion trap-Orbitrap tandem mass spectrometry. AB - A highly sensitive and selective method based on ultra-high-performance liquid chromatography combined with linear ion trap-Orbitrap tandem mass spectrometry (UHPLC-LTQ-Orbitrap-MS) has been developed and validated for the determination of scopoletin in dog plasma. The analyte was extracted from plasma samples using acetonitrile and separated on an Acquity UPLC BEH C18 column (50 * 2.1 mm, 1.7 MUm) with 0.05% ammonium hydroxide and acetonitrile as mobile phase. The developed method was linear over the concentration range of 1-500 ng/mL, with a correlation coefficient >0.9988. The intra- and inter-day precisions (RSD) were <8.93% while the accuracy (RE) ranged from -6.50 to 8.12%. Extraction recovery, matrix effect and stability for dog plasma samples were within the required limits. The validated method has been successfully applied to investigate the pharmacokinetics and metabolism of scopoletin in dog plasma after intravenous (1 mg/kg) and oral (10, 25, 50 mg/kg) administration. The results revealed that (a) scopoletin showed short elimination half-life in dog; (b) its oral bioavailability was low (within the range of 5.69-7.08%); (c) scopoletin showed dose-independent pharmacokinetic profiles in dog plasma over the dose range of 10 50 mg/kg; and (d) glucuronidation was the predominant metabolic pathway in dog. PMID- 30421793 TI - Autoantibodies to Killer Cell Immunoglobulin-Like Receptor 3DL1 in Patients with Systemic Lupus Erythematosus. AB - A genetic variant of the killer immunoglobulin-like receptor 3DL1 (KIR3DL1) has been found in patients with systemic lupus erythematosus (SLE). Herein, we investigated the presence of autoantibodies to KIR3DL1 in a cohort of patients with SLE. We tested sera from 28 patients with SLE, 11 patients with rheumatoid arthritis (RA), and 17 healthy control subjects for anti-KIR3DL1 activity by an enzyme-linked immunosorbent assay (ELISA) using recombinant KIR3DL1-EGFP and EGFP proteins. Anti-KIR3DL1 antibodies were detected in 22 (79%) out of the 28 patients with SLE, whereas they were present only in three (27%) out of the 11 patients with RA examined. Notably, 10 (91%) out of the 11 samples from patients with SLE prior to therapy had anti-KIR3DL1 antibodies. None of the samples from healthy donors were positive for the antibodies. Here, we report the presence of anti-KIR3DL1 antibodies in the sera of patients with SLE for the first time. Anti KIR3DL1 autoantibodies may be involved in the pathogenesis of autoimmune diseases. This article is protected by copyright. All rights reserved. PMID- 30421794 TI - Prenatal Diagnosis And Clinical Implications Of An Apparently Isolated Right Aortic Arch. AB - OBJECTIVE: To define the associations of prenatally diagnosed, apparently isolated right aortic arch (RAA) with chromosomal or genetic abnormalities and tracheal compression. METHODS: This was a retrospective study of apparently isolated RAA assessed by fetal cardiologists and fetal medicine specialists at Kings College Hospital, London between 2000 and 2017. RESULTS: The search identified 138 cases of apparently isolated RAA. Invasive testing was performed in 75 and chromosomal or genetic anomalies were identified in 16 (22%) and the most common was 22q11 microdeletion. An aberrant left subclavian artery was seen in 51% of cases. Symptoms of a vascular ring were present in 24 of 97 (25%) children who were reviewed after birth. Bronchoscopy was performed in 33 children and significant tracheal compression was diagnosed in 28, including 18 of 19 symptomatic and 10 of 14 asymptomatic children. CONCLUSIONS: An apparently isolated RAA is associated with a high incidence of chromosomal or genetic abnormalities and a high incidence of tracheal compression in symptomatic and asymptomatic patients. Prenatal counselling for genetic associations and postnatal airway assessment in the context of the vascular anatomy is recommended. PMID- 30421795 TI - Novel cytokine and chemokine markers of hidradenitis suppurativa reflect chronic inflammation and itch. PMID- 30421796 TI - Prevalence of Falls and Fall-Related Outcomes in Older Adults with Self-Reported Vision Impairment. AB - OBJECTIVES: To determine the prevalence of falls, fear of falling (FoF), and activity limitation due to FoF in a nationally representative study of older adults with self-reported vision impairment (VI). DESIGN: Cross-sectional analysis of panel survey data. SETTING: National Health and Aging Trends Study, a nationally representative survey administered annually from 2011 to 2016 to U.S. Medicare beneficiaries aged 65 and older. PARTICIPANTS: Respondents (N=11,558) who contributed 36,229 participant observations. MEASUREMENTS: We performed logistic regression to calculate the unadjusted and adjusted prevalence of self reported history of more than 1 fall in the past year, any fall in the past month, FoF, and activity limitation due to FoF in participants with and without self-reported VI. RESULTS: The weighted proportion of participants reporting VI was 8.6% (95% confidence interval (CI)=8.0-9.2%). The unadjusted prevalence of more than 1 fall in the past year was 27.6% (95% CI=25.5-29.7%) in participants with self-reported VI and 13.2% (95% CI=12.7-13.7%) in those without self reported VI. In respondents with self-reported VI, the prevalence of FoF was 48.3% (95% CI=46.1-50.6%) and of FoF limiting activity was 50.8% (95%CI 47.3 54.2%), and in those without self-reported VI, the prevalence of FoF was 26.7% (95% CI=25.9-27.5%) and of FoF limiting activity was 33.9% (95% CI=32.4-35.4%). The prevalence of all fall and fall-related outcomes remained significantly higher among those with self-reported VI after adjusting for sociodemographics and potential confounders. CONCLUSION: The prevalence of falls, FoF, and activity limitation due to FoF is high in older adults with self-reported VI. This is the first study to provide nationally representative data on the prevalence of fall related outcomes in older Americans with self-reported VI. These findings demonstrate the need to treat avoidable VI and to develop interventions to prevent falls and fall-related outcomes in this population. PMID- 30421797 TI - Testing models of post-traumatic intrusions, trauma-related beliefs, hallucinations, and delusions in a first episode psychosis sample. AB - OBJECTIVE: There is increasing evidence that childhood trauma may play a role in the aetiology of psychosis. Cognitive models implicate trauma-related symptoms, specifically post-traumatic intrusions and trauma-related beliefs as primary mechanisms, but these models have not been extensively tested. This study investigated relationships between childhood trauma, psychotic symptoms (hallucinations and delusions), post-traumatic intrusions, and trauma-related beliefs while accounting for comorbid symptoms. METHODS: Sixty-six people with first episode psychosis aged between 15 and 24 years were assessed for hallucinations, delusions, childhood trauma, post-traumatic intrusions, post traumatic avoidance, and trauma-related beliefs. RESULTS: Fifty-three per cent of the sample had experienced childhood trauma, and 27% met diagnostic criteria for post-traumatic stress disorder. Both post-traumatic intrusions and trauma-related beliefs mediated the relationships between childhood trauma and hallucinations, and childhood trauma and delusions. Multiple regression analyses revealed that post-traumatic intrusions (but not childhood trauma, post-traumatic avoidance, or trauma-related beliefs) were independently associated with hallucination severity (beta = .53, p = .01). Post-traumatic intrusions and trauma-related beliefs (but not childhood trauma or post-traumatic avoidance) were independently associated with delusion severity (beta = .67, p < .01 and beta = .34, p < .01, respectively). CONCLUSIONS: These findings support cognitive models that implicate post-traumatic intrusions in hallucination aetiology, and post traumatic intrusions and trauma-related beliefs in delusion aetiology. The results suggest that trauma and post-traumatic stress disorder, including trauma related beliefs, should be addressed in the assessment and treatment of people with early psychosis. PRACTITIONER POINTS: Trauma and post-traumatic stress disorder, including trauma-related beliefs, should be addressed in the assessment and treatment of people with early psychosis. Routine assessment of childhood trauma and PTSD in clinical services dealing with young people with first episode psychosis is needed. These findings support cognitive models of trauma and hallucinations and delusions. PMID- 30421798 TI - Inflammation in osteoarthritis: is it time to dampen the alarm(in) in this debilitating disease? AB - Osteoarthritis (OA) is the most common joint disease that strongly reduces the quality of life in patients; However, no disease-modifying therapy is available. For a long time, OA was considered a non-inflammatory disease that was the result of 'wear-and-tear' and abnormal mechanics, and therefore many considered the term 'osteoarthritis' a misnomer. However, during the last decades the notion arose that inflammation is not only present in the majority of OA patients but, rather, actively involved in the progression of the disease. Influx of immune cells is observed in the synovium and a plethora of inflammatory mediators is present in tissues and fluids from OA patients. These mediators cause the production of degrading enzymes that break down the cartilage matrix, which is the main hallmark of OA. Alarmins, which belong to the group of danger signals, have been implicated in many inflammatory diseases. They are among the first factors to be released upon cell stress due to, for example, infection, damage and inflammation. They attract and activate cells of the immune system and therefore lie at the base of the inflammatory reaction. In this narrative review, an overview of the history of OA, the evolving concept of inflammation as important factor in the OA pathogenesis, and particularly the central role that alarmins play in the initiation and maintenance of the low-grade inflammatory response in OA, is provided. Moreover, the targeting of alarmins as a promising approach to dampen the inflammation in OA is highlighted. PMID- 30421799 TI - Editorial. PMID- 30421800 TI - From San Luis, A Few Words of Gratitude. AB - The Photochemical Research Group from San Luis (Argentina) highlights the contributions of Dr. Norman Andino Garcia to the development of the group as a way to show him our gratitude for all his support. PMID- 30421801 TI - Should I trust you? Autistic traits predict reduced appearance-based trust decisions. AB - Facial impressions of trustworthiness guide social decisions in the general population, as shown by financial lending in economic Trust Games. As an exception, autistic boys fail to use facial impressions to guide trust decisions, despite forming typical facial trustworthiness impressions (Autism, 19, 2015a, 1002). Here, we tested whether this dissociation between forming and using facial impressions of trustworthiness extends to neurotypical men with high levels of autistic traits. Forty-six Caucasian men completed a multi-turn Trust Game, a facial trustworthiness impressions task, the Autism-Spectrum Quotient, and two Theory of Mind tasks. As hypothesized, participants' levels of autistic traits had no observed effect on the impressions formed, but negatively predicted the use of those impressions in trust decisions. Thus, the dissociation between forming and using facial impressions of trustworthiness extends to the broader autism phenotype. More broadly, our results identify autistic traits as an important source of individual variation in the use of facial impressions to guide behaviour. Interestingly, failure to use these impressions could potentially represent rational behaviour, given their limited validity. PMID- 30421802 TI - Simple determination of plasma ibrutinib concentration using high-performance liquid chromatography. AB - Ibrutinib is an oral inhibitor of Bruton tyrosine kinase, which is one of the key drugs used for the treatment of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). In this study, we aimed to develop a simple method for determining plasma ibrutinib concentration. The analysis required extraction of a 200 MUL plasma sample and precipitation of proteins using solid-phase extraction. Ibrutinib and nilotinib, which was used as an internal standard, were separated using high-performance liquid chromatography (HPLC) using a mobile phase of acetonitrile:0.5% monopotassium phosphate (KH2 PO4 , pH 3.0; 52:48, v/v) on a Capcell Pack C18 MG II (250 mm * 4.6 mm) monitored at 260 nm, at a flow rate of 1.0 mL/min. The calibration curve was linear at the plasma concentration range of 10-500 ng/mL with a coefficient of determination (r2 ) of 0.9999. The coefficients of intra-day and inter-day validation were 4.0-6.6 % and 2.6-7.7%, respectively. The assay accuracy was -4.4-8.6 %, and the recovery was > 84%. This HPLC method coupled with ultraviolet (UV) detection for determining ibrutinib plasma concentration has several advantages such as simplicity and applicability to routine therapeutic drug monitoring (TDM) at hospital laboratories. PMID- 30421804 TI - New horizons in particle therapy systems. AB - Particle therapy is rapidly expanding and claiming its position as the treatment modality of choice in teletherapy. However, the rate of expansion continues to be restricted by the size and cost of the associated particle therapy systems and their operation. Additional technical limitations such as dose delivery rate, treatment process efficiency, and achievement of superior dose conformity potentially hinder the complete fulfillment of the promise of particle therapy. These topics are explored in this review considering the current state of particle therapy systems and what improvements are required to overcome the current challenges. Beam production systems (accelerators), beam transport systems including gantries and beam delivery systems are addressed explicitly in these regards. PMID- 30421805 TI - Current state and future applications of radiological image guidance for particle therapy. AB - In this review paper, we first give a short overview of radiological image guidance in photon radiotherapy, placing emphasis on the fact that linac based radiotherapy has outpaced particle therapy in the adoption of volumetric image guidance. While cone beam computed tomography (CBCT) has been an established technique in linac treatment rooms for almost two decades, the widespread adoption of volumetric image guidance in particle therapy, whether by means of CBCT or in-room CT imaging, is recent. This lag may be attributable to the bespoke nature and lower number of particle therapy installations, as well as the differences in geometry between those installations and linac treatment rooms. In addition, for particle therapy the so called shift invariance of the dose distribution rarely applies. An overview of the different volumetric image guidance solutions found at modern particle therapy facilities is provided, covering gantry, nozzle, C-arm, and couch-mounted CBCT as well different in-room CT configurations. A summary of the use of in-room volumetric imaging data beyond anatomy-based positioning is also presented as well as the necessary corrections to CBCT images for accurate water equivalent thickness calculation. Finally, the use of non-ionizing imaging modalities is discussed. PMID- 30421806 TI - Radiobiological issues in prospective carbon ion therapy trials. AB - Carbon ion radiotherapy (CIRT) is developing toward a versatile tool in radiotherapy; however, the increased relative biological effectiveness (RBE) of carbon ions in tumors and normal tissues with respect to photon irradiation has to be considered by mathematical models in treatment planning. As a consequence, dose prescription and definition of dose constraints are performed in terms of RBE weighted rather than absorbed dose. The RBE is a complex quantity, which depends on physical variables, such as dose and beam quality as well as on normal tissue- or tumor-specific factors. At present, three RBE models are employed in CIRT: (a) the mixed-beam model, (b) the Microdosimetric Kinetic Model (MKM), and (c) the local effect model. While the LEM is used in Europe, the other two models are employed in Japan, and unfortunately, the concepts of how the nominal RBE weighted dose is determined and prescribed differ significantly between the European and Japanese centers complicating the comparison, transfer, and reproduction of clinical results. This has severe impact on the way treatments should be prescribed, recorded, and reported. This contribution reviews the concept of the clinical application of the different RBE models and the ongoing clinical CIRT trials in Japan and Europe. Limitations of the RBE models and the resulting radiobiological issues in clinical CIRT trials are discussed in the context of current clinical evidence and future challenges. PMID- 30421803 TI - In vivo range verification in particle therapy. AB - Exploitation of the full potential offered by ion beams in clinical practice is still hampered by several sources of treatment uncertainties, particularly related to the limitations of our ability to locate the position of the Bragg peak in the tumor. To this end, several efforts are ongoing to improve the characterization of patient position, anatomy, and tissue stopping power properties prior to treatment as well as to enable in vivo verification of the actual dose delivery, or at least beam range, during or shortly after treatment. This contribution critically reviews methods under development or clinical testing for verification of ion therapy, based on pretreatment range and tissue probing as well as the detection of secondary emissions or physiological changes during and after treatment, trying to disentangle approaches of general applicability from those more specific to certain anatomical locations. Moreover, it discusses future directions, which could benefit from an integration of multiple modalities or address novel exploitation of the measurable signals for biologically adapted therapy. PMID- 30421807 TI - Radiogenomics. AB - PURPOSE: Radiogenomics is the study of genomic changes that underlie the radioresponse of normal and tumor tissues. And while this is generally regarded as a whole genome approach, one must keep in mind the impact of single gene biology on radioresponse, (ataxia telangiectasia, Nijmegen breakage syndrome). METHODS: This review begins with the association of single nucleotide polymorphisms in the DNA with adverse normal tissue events to the prediction of therapeutic outcome after radiotherapy. From there it covers transcriptome (protein coding RNA transcripts) analysis, which is where the greatest understanding of the molecular signaling responsible for the radioresponse of tumors and normal tissues is known. Non-protein coding RNA transcripts (miRNA, lncRNA), transcribed from what was once thought of as junk DNA, are now known to be negative regulators of the transcription of mRNA by multiple mechanisms. miRNA can act as tumor suppressors or oncogenes regulating a diverse range of cellular processes that drive radioresponse and biosignatures that predict outcome after radiotherapy are described. RESULTS: Biological signatures that explain differences in radioresponse based upon cell type, biological signatures that predict surviving fraction at 2 Gy and signatures that identify hypoxia have been described. The omics analysis of the response of mammalian cells to charged particle, predominantly proton and carbon ions, is less mature than that seen with low LET radiation exposures. However, there appear to be responses after charged particle exposure that parallel the responses seem with low LET exposures. This commonality of response is centered around the downstream signaling of p53. There are also novel omics responses to charged particles that help explain the response of tumors to charged particle exposures. For instance, signaling pathways associated with angiogenesis, vasculogenesis, migration and invasion appear to be downregulated in a number of cell types when exposed to charged particles. This response supports both in vitro and in vivo data suggesting that tumors exposed to charged particles are less invasive, unlike the response of tumors to low LET exposures. Profoundly lacking for low LET and charged particle exposures are predictive or prognostic signatures of radioresponse or tumor physiology affecting radioresponse that have been validated in prospective clinical trials. For example, the identification of low LET tumor radioresistance could be used as a marker of patient eligibility for carbon therapy. Tissue specific signatures, or accurate imaging of hypoxic regions, could be used for charged particle selection to overcome hypoxia per se, or could be used to prescribe a high LET therapeutic boost to a hypoxic region of a tumor. CONCLUSIONS: Integrating radiogenomics into radiation oncology has the potential to personalize an already precise form of cancer therapy. PMID- 30421808 TI - A comparison of mechanism-inspired models for particle relative biological effectiveness (RBE). AB - BACKGROUND AND SIGNIFICANCE: The application of heavy ion beams in cancer therapy must account for the increasing relative biological effectiveness (RBE) with increasing penetration depth when determining dose prescriptions and organ at risk (OAR) constraints in treatment planning. Because RBE depends in a complex manner on factors such as the ion type, energy, cell and tissue radiosensitivity, physical dose, biological endpoint, and position within and outside treatment fields, biophysical models reflecting these dependencies are required for the personalization and optimization of treatment plans. AIM: To review and compare three mechanism-inspired models which predict the complexities of particle RBE for various ion types, energies, linear energy transfer (LET) values and tissue radiation sensitivities. METHODS: The review of models and mechanisms focuses on the Local Effect Model (LEM), the Microdosimetric-Kinetic (MK) model, and the Repair-Misrepair-Fixation (RMF) model in combination with the Monte Carlo Damage Simulation (MCDS). These models relate the induction of potentially lethal double strand breaks (DSBs) to the subsequent interactions and biological processing of DSB into more lethal forms of damage. A key element to explain the increased biological effectiveness of high LET ions compared to MV x rays is the characterization of the number and local complexity (clustering) of the initial DSB produced within a cell. For high LET ions, the spatial density of DSB induction along an ion's trajectory is much greater than along the path of a low LET electron, such as the secondary electrons produced by the megavoltage (MV) x rays used in conventional radiation therapy. The main aspects of the three models are introduced and the conceptual similarities and differences are critiqued and highlighted. Model predictions are compared in terms of the RBE for DSB induction and for reproductive cell survival. RESULTS AND CONCLUSIONS: Comparisons of the RBE for DSB induction and for cell survival are presented for proton (1 H), helium (4 He), and carbon (12 C) ions for the therapeutically most relevant range of ion beam energies. The reviewed models embody mechanisms of action acting over the spatial scales underlying the biological processing of potentially lethal DSB into more lethal forms of damage. Differences among the number and types of input parameters, relevant biological targets, and the computational approaches among the LEM, MK and RMF models are summarized and critiqued. Potential experiments to test some of the seemingly contradictory aspects of the models are discussed. PMID- 30421809 TI - Dose detectors, sensors, and their applications. AB - This article is intended to present the different types of particle and radiation detectors available for applications in particle therapy. Several types of detectors and sensors exist for measurements of absorbed dose in reference and nonreference conditions and the ones in use for beam monitoring. Therefore, this manuscript focuses on the following applications: (a) primary methods for dosimetry in ion beams, (b) measurements of absorbed dose in realistic patient specific scenarios with different dose delivery configurations, and (c) beam monitoring. Water and graphite calorimeters, Faraday cups, ionization based gas detectors are described first, followed by the description of the protocols for proton and ion dosimetry. Then films, scintillator and solid-state detectors are reviewed. Finally, several types of ionization chambers (large, pinpoint, arrays of chambers arranged in regular 1D or 2D pattern, parallel-plate configuration with large integral electrodes or with anode segmented in strips or pixels, multi wire, and the multi-gap prototype) have been considered. New beam monitors to deal with a wide range of intensity and pulsed beams expected from new accelerators, different dose fractionation and advanced delivery techniques are presented. The existing detectors available for particle therapy have been described taking into account the different requirements for devices used in reference and nonreference conditions and the ones designed for beam monitoring. PMID- 30421810 TI - Noninvasive cardiac arrhythmia ablation with particle beams. AB - Cardiac arrhythmias are a major health burden, associated with reduced quality of life and substantial morbidity and mortality. Current therapy includes moderately effective medication and catheter-based ablation of arrhythmogenic substrates in the heart. Catheter interventions frequently have to be repeated due to recurrent arrhythmia, can have rare but severe side-effects and are less suited especially for potentially lethal left ventricular tachycardia. Noninvasive alternatives are therefore warranted. Photon and ion beam radiotherapy has been studied in animal models and first patient cases have been reported using photons. Ion beams might offer the possibility to greatly reduce dose to surrounding healthy tissue, including critical cardiac substructures. Based on a recently conducted animal study, we report advantages and disadvantages of 4D-ion beam therapy, and strategies necessary for a clinical transition. Motion management of both respiration and heartbeat are discussed, as well as range uncertainty resulting from both regular motion and interfractional anatomic changes. Image guidance both in 3D and 4D has to be employed for a safe irradiation, but also population based data on motion variability and time behavior of interfractional changes are necessary. Range verification could play a crucial role at least during development of clinical protocols. For clinical realization, it appears necessary to suppress or conformally mitigate the large respiratory motion to avoid normal tissue complications. Cardiac motion has to be incorporated into treatment planning, either through adequate range-considering internal margins or through more conformal strategies such as ECG-based gating or even 4D-optimization. The latter strategies would necessitate online 4D image guidance. PMID- 30421811 TI - Advanced Treatment Planning. AB - Treatment planning for protons and heavier ions is adapting technologies originally developed for photon dose optimization, but also has to meet its particular challenges. Since the quality of the applied dose is more sensitive to geometric uncertainties, treatment plan robust optimization has a much more prominent role in particle therapy. This has led to specific planning tools, approaches, and research into new formulations of the robust optimization problems. Tools for solution space navigation and automatic planning are also being adapted to particle therapy. These challenges become even greater when detailed models of relative biological effectiveness (RBE) are included into dose optimization, as is required for heavier ions. PMID- 30421812 TI - What will the medical physics of proton therapy look like 10 yr from now? A personal view. AB - Despite growing rapidly, proton therapy is still a relatively immature treatment modality, at least in comparison to conventional radiotherapy using photons. As such, in this article, the author gives a very personal view of some of the potential areas for development in medical physics for proton therapy in the next 10 yr by identifying six topics for detailed discussion. The first of these are all related to reducing various "parameters" of proton therapy treatments (size and cost, treatment times, penumbras, and margins), while the second group are related to providing more quantitative "knowledge" about the quality of the treatments we are delivering. In conclusion, there is much interesting and important work still to be done in many areas of medical physics related to proton therapy, of which, the topics selected here are just the tip of the iceberg. PMID- 30421813 TI - Current challenges and prospects in particle therapy. PMID- 30421814 TI - Computational models and tools. AB - In this chapter, we describe two different methods, analytical (pencil beam) algorithms and Monte Carlo simulations, used to obtain the intended dose distributions in patients and evaluate their strengths and shortcomings. We discuss the difference between the prescribed physical dose and the biologically effective dose, the relative biological effectiveness (RBE) between ions and photons and the dependence of RBE on the linear energy transfer (LET). Lastly, we show how LET- or RBE-based optimization can be used to improve treatment plans and explore how the availability of multimodality ion beam facilities can be used to design a tumor-specific optimal treatment. PMID- 30421815 TI - Motion management in particle therapy. AB - In this review article, we introduced the importance of "motion management" in advanced particle therapy. Several publications have reported that organ motion causes dose distribution disturbances due to interplay and blurring effects. Furthermore, motion can result in target dose miss and unwanted dose to healthy structures around the target. To avoid these problems, motion should be assessed and monitored prior and during treatment. In this review article, we give an overview about clinically available motion monitoring systems. Based on the acquired motion information an adequate motion mitigation technique should be chosen. This article reviews the clinical status of motion mitigation techniques like rescanning, gating and tracking. A limited number of centers have now started the treatment of targets in the thorax and abdomen using scanned particle beams. Therefore, the establishment of guidelines for motion monitoring and motion mitigation will be essential in the coming years. PMID- 30421816 TI - Upregulation of Helicoverpa armigera core RNAi genes by bacterial infections and its effect on the insect-bacteria interaction. AB - RNA interference (RNAi) is an extremely conserved defense mechanism. The antiviral role of the RNAi pathway in insects is well documented; however, the relevance of this pathway in other aspects of insect immunity is largely unknown. In this study, we questioned whether RNAi has any function during insect-bacteria interactions. For this, we assessed induction of the RNAi pathway in response to bacterial infections by monitoring the expression of dicer1/argonaute1 and dicer2/argonaute2 that are important genes in the microRNA and short interfering RNA sub-pathways, respectively. Bacterial cells of Bacillus thuringiensis and Serratia marcescens were injected into the hemocoel of fifth-instar larvae of Helicoverpa armigera while double-distilled water was injected into control insects. Expression levels of the RNAi-related genes increased in the bacteria injected larvae compared to controls. Transcript knockdown of dicer1 reduced the replication of B. thuringiensis and as a consequence larval mortality decreased compared with the control. However, replication of S. marcescens increased following dicer1 silencing which led to higher rates of larval mortality when compared with the control. RNAi of dicer2 promoted replication of both bacteria in the larvae and also enhanced larval mortality. Therefore, dicer1 and dicer2 affected larval survival and the replication rates of the pathogenic bacteria suggesting their roles in the interactions. This article is protected by copyright. All rights reserved. PMID- 30421817 TI - Distribution of Internal Thoracic Artery Perforators: A Clinical Anatomical Study. AB - INTRODUCTION: There are various modifications of the transverse rectus abdominis musculocutaneous (TRAM) flap and deep inferior epigastric perforator (DIEP) flap to reduce the morbidity of the donor site or to augment the vascularity of the flap. For microanastomosis of multiple pedicles, multiple recipient vessels or an intervening vein graft should be provided. In addition, alternative perforator based flaps used in breast reconstruction have small caliber pedicles. Therefore, small recipient vessels such as internal thoracic artery perforators are more suitable for appropriate microanastomosis. Therefore, it is important to acquaint the distribution and anatomical characteristics of internal thoracic artery perforators. MATERIALS AND METHODS: We researched the perforators running in the intercostal spaces under the pectoralis major muscle to provide an overview of the anatomical distribution and characteristics of the perforators in patients who underwent immediate subpectoral implant-based breast reconstructions. RESULTS: In our study, the major perforators (diameter > 1.5 mm) were easily found 2-7 cm medially between the third and fourth intercostal space (ICS) and were sparse in the lateral area from the midline of the breast (usually 8-9 cm lateral to the midsternal line) and above the third rib. In each side of the breast, the average number of perforators greater than 1.5 mm was 1.6, and the average number of perforators between 1 mm and 1.5 mm in diameter was 3.2. CONCLUSION: Our results provide information about perforators in the anterior chest wall related to the breast area. This article is protected by copyright. All rights reserved. PMID- 30421818 TI - Pattern of planned systemic therapy usage in newly diagnosed, nonmetastatic squamous cell carcinoma of the head and neck in a commercially insured population in the United States. AB - BACKGROUND: We analyzed systemic therapy plans submitted for commercially insured patients with untreated, newly diagnosed squamous cell carcinoma of the head and neck (SCCHN) to investigate patterns of practice. METHODS: Consecutive chemotherapy treatment plans were submitted using Eviti Connect (https://www.marylandphysicianscare.com/content/dam/centene/maryland/pdfs/evitiCo nectFactSheet.pdf) portal for preauthorization between June 1, 2011, and June 30, 2015, were analyzed. RESULTS: A total of 387 treatment plans were submitted for 340 patients; 68 and 272 patients were from academic centers and community practices, respectively. Single agent cisplatin (57%), cetuximab (18%), and carboplatin (9%) were the most commonly proposed regimens concurrent with definitive radiotherapy (RT). The frequency of cetuximab use was not significantly different between academic centers and community practices. A clinical trial was proposed in only 15% of patients. CONCLUSION: Among commercially insured patients with newly diagnosed, nonmetastatic SCCHN, the choice of systemic therapy in initial treatment plans was not significantly different between academic centers and community practices. Clinical trials are underutilized and should be encouraged. PMID- 30421819 TI - The Anatomy of Concussion and Chronic Traumatic Encephalopathy-A Comprehensive Review. AB - Concussion is defined as a complex pathophysiological process that affects the brain as a result of traumatic biomechanical forces. Repeated unrecovered concussions can result in chronic brain injury syndrome which is referred to in the literature today as chronic traumatic encephalopathy." There is an exponential increase in public and political interest in this condition in the recent times resulting in a significant investment in research to improve the current understanding of the disease, ways to decrease its incidence and determine its prognosis. Broadly the research involves three main disciplines of medicine including neuropathology, neuroradiology and biological markers. Although progress has been made, to date there is no definite pathological, radiological or neurobiological marker which has shown consistent promise to make the diagnosis and prognosticate the disease. Possible reasons are multiple such as inconsistencies in the methods studies have used, different time periods in which the tests were conducted, the small numbers of subjects included in the studies, and inconsistencies in the definitions of concussion or mild TBI. Herein, we present a comprehensive review of the current literature on this topic. PET scans with radioactive ligands such as T807 as an imaging biomarker, and neurofilament light (NfL) and Ubiquitin C-terminal Hydrolase (UCH-L1) as serum biomarkers have shown some promise lately in diagnosing concussion and CTE and also determining their prognosis. This article is protected by copyright. All rights reserved. PMID- 30421820 TI - Low back pain and associated disability in Swedish adolescents. AB - INTRODUCTION: Low back pain (LBP) defined as ache or pain in the lowest part of the back is a common experience among people all over the world. The lifetime prevalence is reported to be as high as 84%, and the prevalence of LBP seems to be almost the same among adolescents as among adults. The risk for having LBP later in life if you experienced LBP in adolescence is high. MATERIAL AND METHODS: In this cross-sectional study of 2550 students aged 16-20 years, we used the Standardized Nordic Questionnaire for the analysis of musculo-skeletal symptoms. We studied gender difference, prevalence, and disability of Low back pain. We also studied differences in LBP in adolescent athletes depending on hours spent on sports or physical activity. RESULTS: Significantly, more girls than boys had had problems sometimes during their life. Those who participated in sports reported LBP to a significantly higher extent than those who were physically inactive in their spare time. Gender and spare time sports were important risk factors for getting LBP some time in life. There was a higher risk for girls to have low back pain problems more than 30 days or daily the last year if they had had low back pain some time earlier in life. CONCLUSION: This study shows that low back pain (LBP) is common among Swedish adolescents, more common among girls than boys. High sport activity was associated with the risk of having LBP, length of time with LBP, and disability due to LBP. PMID- 30421821 TI - Patterns of failure after postoperative intensity-modulated radiotherapy for locally advanced buccal cancer: Initial masticator space involvement is the key factor of recurrence. AB - BACKGROUND: The purpose of this study was to determine failure patterns and clinicopathologic prognostic factors in patients with locally advanced buccal cancer after postoperative intensity-modulated radiotherapy (IMRT). METHODS: Eighty-two patients with locally advanced (American Joint Committee on Cancer [AJCC] stage III/IV) buccal cancer who underwent surgery followed by postoperative IMRT between January 2007 and October 2012 were retrospectively analyzed. RESULTS: Eighteen patients had local recurrences as the first recurrent site and 11 had supramandibular notch recurrences; the majority of recurrences were classified as marginal failures. The median time from the first local or regional recurrence to death was 5.9 months. In multivariate analyses of survivals, the initial masticator space involvement was the most important prognostic factor. Masticator space involvement, N classification, and maxillectomy were the significant prognostic predictors for supramandibular notch recurrences. CONCLUSION: Postoperative IMRT for buccal cancer should not include the surgical beds alone, rather, it should be based on the potential patterns of spread. PMID- 30421822 TI - Intra- and inter-individual variability of stable strontium isotope ratios in hard and soft body tissues of pigs. AB - RATIONALE: Stable isotope analysis has become an indispensable tool for the identification of the flow of matter in ecological sciences. Stable strontium isotope ratios are used in several different scientific fields as markers for provenance, mobility, and migration. A crucial prerequisite for such studies is a reliable definition of local ranges and an estimation of expected isotopic variability. METHODS: To study the local variability of stable strontium isotope ratios at a specific place, a farrow of ecologically and locally grown pigs was investigated and strontium was extracted from their hard tissues (tooth enamel, bones and bristles) as well as soft tissues (meat, organs and blood) via dry and wet ashing procedures and subsequent column separation. 87 Sr/86 Sr was then measured via TIMS (Thermal ionization mass spectrometry). RESULTS: Reliable 87 Sr/86 Sr data was generated from all tissue types. Both intra- and inter individual variability was high and tissue specific patterns could be identified. High ranges occurred in sample types which were analyzed for animals of different age (pigs as well as piglets): teeth, parietal, mandible, femur, and leg muscle as well as in jaw muscle samples, which were only analyzed in adult pigs. Tooth enamel data showed a tooth-type dependent pattern. CONCLUSIONS: We conclude that a time factor played a role for the observed variability, e.g. a shift in food supply. Furthermore we presume that local range estimates from literature only work for tissues which integrate all consumed components over a sufficient amount of time and average fluctuations which can be found in tissues with higher turnover rates. PMID- 30421823 TI - Effects of soil bound water exchange on the recovery of spike water by cryogenic water extraction. AB - RATIONALE: The effects that alter the isotopic composition of water added to soil samples that have been oven-dried previously are not fully understood. METHODS: Oven-dried clay-rich soil was repeatedly rewetted with two waters of strongly differing isotopic composition. This approach allowed to determine the amount and the isotopic composition of soil-bound water that exchanges with spike water after rewetting. RESULTS: After oven drying, 1.8 % and 1.4 % water (gravimetric content) exchanged with the added spike water, for delta2 H and delta18 O values, respectively. The isotopic composition of this soil residual water was depleted by 89.7 mUr and 5.42 mUr relative to the water extracted from field fresh soil for H and O, respectively. The cryogenic extraction method was more efficient than oven drying in terms of water removal from soil. CONCLUSIONS: Our results show that the isotopic difference between extractable (mobile) water and non extractable (soil bound) water explains the isotopic effects observed in spike water experiments. This difference, however, can also lead to a considerable isotopic offset between extractable and total soil water. PMID- 30421824 TI - Salivary duct carcinoma: A prospective multicenter study of 61 cases of the Reseau d'Expertise Francais des Cancers ORL Rares. AB - BACKGROUND: The purposes of this study were to describe the characteristics of a prospective multicenter series of patients with salivary duct carcinoma and to investigate prognostic factors. METHODS: Patients included for salivary duct carcinoma between 2009 and 2016 in the Reseau d'Expertise Francais des Cancers ORL Rares (REFCOR) database were selected. Immunohistochemical analyses were performed. RESULTS: Sixty-one patients were included in this study. The primary site was the parotid gland in 90% of the cases. Fifty-seven percent of the tumors were stage IV, 65% of patients had lymph node involvement, and 10% had metastases. Tumors showed androgen receptor (89%) and human epidermal growth factor receptor 2 (HER2)/neu (36%). Ninety-four percent of patients underwent surgery and 86% had postoperative radiotherapy. Six patients were treated with targeted therapies. The 3-year overall survival (OS) was 74% and the 3-year disease-free survival (DFS) was 44%. Tumor stages III to IV reduced DFS (hazard ratio [HR] 4.3; P = .04). The N2/3 class reduced distant metastasis-free survival (HR 7.3; P = .007). CONCLUSION: Salivary duct carcinoma prognosis is poor and is correlated with tumor stage and lymph node classification. Androgen receptor and HER2/neu should be tested as they offer the possibility of targeted therapies. PMID- 30421825 TI - Functional integrity of honeybee (Apis mellifera L.) RDL GABA receptor channels conjugated with three fluorescent proteins. AB - To generate an efficient tool used in Xenopus oocyte expression for in situ investigation of channel receptor expression, distribution, and function, the C terminus of the honeybee (Apis mellifera L.) resistant to dieldrin (RDL) subunit was fused with monomeric red, enhanced yellow, or enhanced green fluorescent protein (referred to as mRFP, EYFP, and EGFP, respectively). In the present study, all fused *FP-AmRDL could be visualized using fluorescence and laser confocal microscopy in cRNA-injected oocytes. Fluorescence was distributed isotropically in the cellular membrane. The potencies of the agonist GABA, but not beta-alanine, and the antagonists (fipronil, flufiprole, dieldrin, alpha endosulfan, bifenazate, and avermectin B1a) in the tagged AmRDL receptor did not significantly differ from that of the untagged receptor with two-electrode voltage clamp detection. The EC50 s of GABA in untagged AmRDL, EGFP-AmRDL, EYFP AmRDL, and mRFP-AmRDL receptors were 11.98, 12.61, 18.92, and 22.11MUM, respectively, and those of beta-alanine were 651.6, 629.6, 1643.0, and 2146.0 MUM, respectively. Inhibition percentages of fipronil, flufiprole, dieldrin, alpha-endosulfan, bifenazate, and avermectin B1a against *FP-AmRDL and AmRDL were without significant difference. Overall, the consistency in the functional properties between *FP-AmRDL and untagged AmRDL receptors makes it a promising tool for further in situ investigation of GABA receptors. This article is protected by copyright. All rights reserved. PMID- 30421826 TI - Chemical shift assignment of mono- and di-bromo triimidazo[1,2-a:1',2'-c:1",2" e][1,3,5] triazine derivatives by DFT/NMR integrated approach. AB - Solid state organic compounds, endowed with enhanced emission, have been gaining great attention in the scientific community for their potential application in different areas, such as lighting technologies or bioimaging. In this field, mono and di-bromo derivatives of triimidazo[1,2-a:1',2'-c:1",2"-e][1,3,5] triazine have been proposed as new organic molecules presenting a very rich and complex photophysical behavior. Their structures were investigated by standard 1D and 2D NMR experiments, but the correct structural assignment of all proton and carbon resonances was made difficult since the lack of crucial and diagnostic long-range correlations between quaternary carbon and proton signals. Thus, we afforded the correct chemical shift assignment by integrating the experimental data with DFT calculation of NMR parameters. Our findings lay foundation for a structural reference in the organic synthesis and characterization of new congeners of this intriguing class of molecules. PMID- 30421827 TI - Excess mortality among Indiana firefighters, 1985-2013. AB - BACKGROUND: Firefighters are exposed to toxic agents increasing their risk for cancer and cardiovascular disease. We examined the odds of cancer and cardiovascular mortality of firefighters relative to a matched group of non firefighters from the general population. METHODS: Firefighter death records were matched to four non-firefighter death records on age at time of death, sex, race, ethnicity, and year of death. Exact odds ratios, 95% confidence intervals, and P values were calculated using conditional logistic regression to compare groups. RESULTS: The odds of death due to malignant cancers was significantly higher for firefighters than non-firefighters (OR: 1.19; 95%CI 1.08, 1.30). There was no difference in the odds of death for cardiovascular diseases, including ischemic heart disease, between the two groups. CONCLUSIONS: The study suggests the importance of early and effective cancer prevention strategies among firefighters including worksite health promotion programs and incumbent physical activity evaluation. PMID- 30421828 TI - "Methotrexate and NSAIDs in rheumatoid arthritis-Confirmation of a known NSAIDs adverse effect rather than a dangerous combination". PMID- 30421829 TI - MAI-FTMS for the Analysis of Lipids. AB - RATIONALE: Assessing the utility of vacuum MAI-ionization for the direct and rapid analysis of lipids in complex samples with emphasis on bacterial taxonomy. METHODS: Matrix assisted ionization Fourier transform mass spectrometry (MAI FTMS) was used to characterize polar and non-polar lipids in mixtures. RESULTS: For non-polar lipid triacylglycerol's (TAGs), MAI-FTMS produced lipid-specific ions for eight different edible oils and allowed these oils to be identified based on their MAI-FTMS profiles. For polar lipids from bacteria, MAI-FTMS of crude lipid extracts allowed taxonomic identification of 8 blind-coded samples based on taxonomy-specific phospholipid profiles. MAI ionization produced results comparable and complementary to benchmark MALDI and ESI methods currently used for characterization of polar and non-polar lipids in the same mixtures. CONCLUSION: The newly developed MAI-ionization technique is a rapid, simple and complementary method for the characterization of polar and non-polar lipids in complex mixtures. PMID- 30421830 TI - Reference materials selection for the stable carbon isotope analysis of dissolved carbon using a wet oxidation system. AB - RATIONALE: Wet chemical oxidation combined with isotope ratio mass spectrometry has become a routine technique for analyzing the stable carbon isotope composition of dissolved organic (DOC) and inorganic (DIC) carbon. Methodological inconsistencies between laboratories in using different reference materials lead to a discrepancy in results. We experimentally tested the precision and accuracy of the analysis of commonly available international reference materials and other chemicals potentially suitable for laboratory standards. METHODS: The solid international reference materials and other simple chemicals were used to prepare water solutions. A range of carbon concentrations was chosen to optimize tests for 1) precision and accuracy, 2) linearity, 3) detection limits, 4) memory effects, and 5) efficiency of DIC removal from a DOC/DIC mixtures. Samples were analyzed using an LC-IsoLink coupled with a Delta V Plus Isotope Ratio Mass Spectrometer (Thermo Fisher Scientific). RESULTS: The analytical setup had a negligible memory effect, good reproducibility (<0.21 0/00) and accuracy (maximum difference from the true values <0.35 0/00) for the analyzed organic compounds if approximately >=9 * 10-09 mole of dissolved carbon was injected into the system (~11 mg C L-1 if a 10-MUL loop was used). Analyses of sodium bicarbonate or calcium carbonate solutions had a two-fold lower accuracy despite maintaining a high precision. CONCLUSIONS: Water solutions of international reference materials such as L-glutamic acids (USGS40, USGS41), benzoic acid (IAEA-601) and sucrose (IAEA-CH-6), can be successfully used for direct normalization of results to the VPDB scale. By contrast, analyses of caffeine and urea returned very reproducible but highly inaccurate results and these materials are not recommended for standards. PMID- 30421831 TI - Metabolomics for the mountains; bring on the biomarkers! PMID- 30421832 TI - The impact of childhood bullying on the daily lives of Nordic children and young adolescents. AB - AIM: Childhood bullying may negatively affect the mental health in children and adolescents, but few studies have explored this potential link. We aimed to investigate the association between childhood bullying and the impact of poor mental health on the daily life in a population of Nordic children and adolescents aged 5-16 years. METHODS: This cross-sectional study was based on data from the Nordic survey on Children's Health and Wellbeing (NordChild) from 2011. The study population included 4966 children from Denmark, Finland, Iceland, Norway and Sweden. Mental health was measured by a parent-reported version of the Strength and Difficulties Questionnaire. We conducted multiple logistic regression analyses to estimate the odds ratios of poor mental health in bullied compared to non-bullied children and adolescents while adjusting for sex, age, body mass index and parental socioeconomic status. RESULTS: Bullied children and adolescents were four times more likely than their non-bullied peers to have mental health problems with negative impact on their daily life at home, in their relations to friends, learning in school or leisure activities (adjusted odds ratio: 4.32; 95% CI: 3.54-5.26). CONCLUSION: This study found negative impact on the mental health in bullied children and adolescents, which affected several arenas of daily life. PMID- 30421833 TI - Hygienic conditions influence sensitization to Blomia tropicalis allergenic components: Results from the FRAAT birth cohort. AB - BACKGROUND: In tropical zones, perennial exposure to house dust mite (HDM) allergens and helminth infections is present. Studying the impact of these conditions on the inception and evolution of allergic diseases is necessary to have an accurate view of their natural history. We aimed to evaluate the dynamics of genuine sensitization to Blomia tropicalis and Ascaris in children from the FRAAT birth cohort and the effects of helminth infection, environmental HDM allergen levels, and sociodemographic factors. METHODS: Children were followed up to 6 years old. Specific IgE to recombinant allergens from B. tropicalis (Blo t 5 and Blo t 12) and Ascaris spp (Asc l 3, Asc l 13 and Asc s 1) was measured by ELISA at different time points. Allergen levels were measured in dust when children were 6 months old. RESULTS: IgE sensitization increased over time up to 3 years old. Correlation among the specific IgE levels to B. tropicalis and Ascaris components is poor at year 1, but coefficients are high and significant (Spearman's rho coefficients >0.70) at year 6. Unhygienic conditions increased the odds of sensitization to B. tropicalis allergenic components. Blo t 5 levels were lower in the poorest. IgE response to Blo t 5 and Blo t 12 was less intense in children with high exposure to Blo t 5 (levels >80th percentile). CONCLUSION: In this tropical community, the pattern of childhood IgE sensitization is different from that in developing countries and is influenced by the hygienic conditions. PMID- 30421834 TI - Mechanisms and Beyond: Elucidation of Fluxional Dynamics by Exchange NMR. AB - Detailed mechanistic information is crucial to our understanding of reaction pathways and selectivity. Dynamic exchange NMR techniques, in particular 2D EXSY and its modifications, provide indispensable intricate information on the mechanisms of organic and inorganic reactions, and other phenomena e.g. dynamics of interfacial processes. In this review we systematise and discuss key results of exchange NMR studies of small molecules over the last few decades. After a brief theory introduction, we will identify key types of dynamic processes and give fundamental examples of intra- and intermolecular reactions which, in turn, could involve, or not, bond making and bond breaking events. Following that logic, internal molecular rotation, intramolecular stereomutation, and molecular recognition will first be considered as they do not typically involve bond breaking. Then we will discuss rearrangements, substitution-type reactions, cyclisations, additions, and other processes affecting chemical bonds. Finally we will touch upon interfacial molecular dynamics and unexpected combinations of different types of fluxional processes. We will show how exchange NMR helps to identify conformational changes, coordination, and molecular recognition processes as well as quantify reaction energy barriers and extract detailed mechanistic information by using reaction rates theory in conjunction with computational techniques. PMID- 30421835 TI - Long-term quality of life in older patients with HPV-related oropharyngeal cancer. AB - BACKGROUND: We explored if age affects quality of life (QOL) in survivors of locally advanced human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (SCC). METHODS: In a cross-sectional survey of 185 patients, at least 12 months from radiation, we evaluated generic (EuroQOL-5D questionnaire [EQ-5D]) and head and neck specific (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Head and Neck 35-questions [EORTC-QLQ H&N35]) QOL questionnaires and compared differences between younger (<65) and older (>=65) patients. RESULTS: The median age was 57.0 years (range 25-77 years), and 31 patients (16.8%) were >=65 years old. There was no significant difference in EQ-5D global QOL scores by age (P = .53). Patients >=65 years reported more immobility (P < .01), problems with social eating (P < .0001), and coughing (P < .01). Patients >=65 years were not more likely to ever require a gastrostomy (P = .24) but were more likely to remain gastrostomy-dependent at the time of the survey (P = .02). CONCLUSION: Despite similar generic QOL, older survivors may have more mobility problems and issues with social eating compared with younger survivors deserving of further evaluation. PMID- 30421836 TI - Home care service utilisation by people with dementia-A retrospective cohort study of community nursing data in Australia. AB - Progressive aged care reforms are shifting dementia care into the community. These efforts have been shown to prevent transition to residential aged care facilities and hospitals. There is a paucity of studies examining the utilisation of home care services for people living with dementia. This study aims to address the current knowledge gap by providing a comprehensive summary of older adults receiving home care and comparing service use for people with and without dementia. A retrospective secondary data analysis was conducted using routine data prospectively collected from a cohort (n = 2,703 with dementia matched to 9,224 without dementia; total 11,927) using a community home nursing service in metropolitan Melbourne, Australia, in 2014. Descriptive statistics compared individuals with and without dementia on client-level demographics and their episode of home care service use. A comparative analysis on select variables was also performed using a conditional Poisson regression to estimate relative risk (RR). Compared to older adults without dementia, people with dementia were more likely to be born overseas (RR 1.10, 95% CI [1.03-1.19]), require an interpreter (RR 1.41, 95% CI [1.26-1.59]), and live with family (RR 1.09 [1.01-1.16]). When examining an individual's episode of care, people with dementia were more likely to require acute care (RR 1.07, 95% CI [1.01-1.14]) and be discharged from home care with personal care services (RR 1.46, 95% CI [1.24-1.72]). People with dementia were less likely to be referred from a hospital (RR 0.73, 95% CI [0.69 0.77]), achieve their home care goals (RR 0.91, 95% CI [0.87-0.94]), or die while in receipt of home care services (RR 0.82, 95% CI [0.72-0.94]). Our findings suggest that people with dementia have different socio-demographic characteristics and interactions with home care services compared to people without dementia. PMID- 30421837 TI - Grafting of Polymer Brushes from Silica Particles Functionalized with Xanthates. AB - Monodisperse silica particles (SiPs) were surface-modified with a newly designed silane coupling agent comprising a triethoxy silane and an alkyl halide, 6 (triethoxysilyl)hexyl 2-bromopropionate which was further reacted with potassium O-ethyl dithiocarbonate (PEX) to immobilize xanthate molecules on the particle surfaces. Surface-initiated macromolecular design via interchange of xanthates (MADIX) polymerization of vinyl acetate (VAc) was conducted with the xanthate functionalized SiPs. The polymerization was well-controlled and produced SiPs coated with poly(vinyl acetate) (PVAc) with a well-defined target molar mass and a graft density of around 0.2 chains/nm2. Dynamic light scattering and transmission electron microscopy measurements reveal that the hybrid particles were highly dispersible in good solvents without any aggregation. The PVAc brushes were hydrolyzed with hydrochloric acid to produce poly(vinyl alcohol) brushes on the SiP surfaces. In addition, the number of xanthate molecules introduced on the SiP surfaces could be successfully controlled by adjusting the concentration of PEX. Thus, the SiPs possessed two functionalities: xanthates able to act as MADIX chain transfer agent and alkyl bromide atom transfer radical polymerization (ATRP) initiation sites. Using these unique bifunctional particles, mixed polymer brushes were constructed on the SiPs by MADIX of VAc followed by ATRP of styrene or methyl methacrylate. PMID- 30421838 TI - Increases in controlled-release oxycodone utilisation following the subsidy of oxycodone with naloxone formulations: An Australian population-based study. AB - PURPOSE: Despite increasing use of oxycodone/naloxone controlled-release (CR) in Australia, little is known about how it has affected the overall oxycodone CR market since its subsidy in 2011. METHODS: We used Pharmaceutical Benefits Scheme dispensing claims (2006-2016) and interrupted time series analysis to examine changes in the quarterly rates of dispensing of oral oxycodone CR formulations (oxycodone/naloxone CR and single-ingredient oxycodone CR) and new oxycodone CR treatment episodes. We also performed a retrospective cohort study in a sample of people initiating a new oxycodone CR treatment episode in 2009, 2012/2013, and 2016 to compare opioid utilisation patterns over time. RESULTS: The subsidy of oxycodone/naloxone CR was associated with a 1.6-fold increase in the growth rate of oxycodone CR dispensing, resulting from rapid uptake of low strength (<=5 mg) oxycodone/naloxone CR. In our cohort of initiators, the number of new oxycodone CR treatment episodes increased 2.1-fold between 2009 and 2016; in 2016, 91.4% of new treatment episodes involved oxycodone/naloxone CR. Comparing 2016 with 2009, we observed an increase in people initiating with a tablet strength less than or equal to 5-mg (risk difference [RD] = 21.1%, 95% CI, 19.9%-22.4%) in people initiating with no other opioid dispensing 90 days prior to initiation (RD = 5.2%, 3.8%-6.6%) and with no further opioid dispensing 90 days after initiation (RD = 8.8%, 7.4%-10.2%). CONCLUSIONS: After its subsidy, the uptake of low-dose oxycodone/naloxone CR was greater than expected if it were substituting the single-ingredient oxycodone CR, resulting in an expansion of the oxycodone CR market. PMID- 30421839 TI - Overall and cause-specific mortality in the Sentinel system: A power analysis. AB - PURPOSE: Mortality data within the Sentinel Death Tables remain generally uncharacterized. Assessment of mortality data within Sentinel will help inform its utility for medical product safety studies. METHODS: To determine if Sentinel contains sufficient all-cause and cause-specific mortality events to power postmarketing safety studies. We calculated crude rates of all-cause mortality and suicide and proportional mortality from suicide from 2004 to 2012 in seven Sentinel data partners. Results were stratified by data partner, sex, age group, and calendar year and compared with national estimates from Centers for Disease Control and Prevention Wide-ranging ONline Data for Epidemiologic Research. We performed sample size estimations for all-cause mortality and 10 leading causes of death. RESULTS: We observed 479 694 deaths, including 5811 suicides, during 68 million person-years of follow-up. Pooled mean death and suicide rates in the data partners were 710 and 8.6 per 100 000 person-years, respectively (vs 810 and 11.8 nationally). The mean proportional mortality from suicide among the data partners was 1.2%, compared with 1.5% nationally. National trends of decreasing overall mortality and increasing proportional mortality for suicide were reflected within Sentinel. We estimated that detecting hazard ratios of 1.25 and 3 would require 16 442 and 460 exposed patients, respectively, for overall mortality, and 1.3 million and 37 411, respectively, for suicide. CONCLUSIONS: This was the first study to investigate mortality data in the Sentinel death tables. We found that all-cause mortality appeared well powered for use as a safety outcome and cause-specific mortality outcomes may be adequately powered in certain circumstances. Further investigation into the quality of the Sentinel death data is needed. PMID- 30421840 TI - The effects of solution additives and gas-phase modifiers on the molecular environment and conformational space of common heme proteins. AB - RATIONALE: The molecular environment is known to impact the secondary and tertiary structure of biomolecules both in solution and in the gas-phase, shifting the equilibrium between different conformational and oligomerization states. However, there is a lack of studies monitoring the impacts of solution additives and gas-phase modifiers on biomolecules characterized using ion mobility techniques. METHODS: The effect of solution additives and gas-phase modifiers on the molecular environment of two common heme proteins, bovine cytochrome c and equine myoglobin, is investigated as a function of the time after desolvation (e.g., 100-500 ms) using nanoelectrospray ionization coupled to trapped ion mobility spectrometry with detection by time-of-flight mass spectrometry. Organic compounds used as additives/modifiers (methanol, acetonitrile, acetone) were either added to the aqueous protein solution before ionization or added to the ion mobility bath gas by nebulization. RESULTS: Changes in the mobility profiles are observed depending on the starting solution composition (i.e., in aqueous solution at neutral pH or in the presence of organic content: methanol, acetone, or acetonitrile) and the protein. In the presence of gas-phase modifiers (i.e., N2 containing methanol, acetone, or acetonitrile), a shift in the mobility profiles driven by the gas-modifier mass and size and changes in the relative abundances and number of IMS bands are observed. CONCLUSIONS: We attribute the observed changes in the mobility profiles in the presence of gas-phase modifiers to a clustering/declustering mechanism by which organic molecules adsorb to the protein ion surface and lower energetic barriers for interconversion between conformational states, thus redefining the free energy landscape and equilibria between conformers. These structural biology experiments open new avenues for manipulation and interrogation of biomolecules in the gas-phase with the potential to emulate a large suite of solution conditions, ultimately including conditions that more accurately reflect a variety of intracellular environments. PMID- 30421841 TI - Use of Twitter in Communicating Living Solid Organ Donation Information to the Public: An Exploratory Study of Living Donors and Transplant Professionals. AB - BACKGROUND: As transplant centers start leveraging Twitter for information dissemination and public engagement, it is important to understand current living solid organ donation-related Twitter use. METHODS: We identified public Twitter profiles available in 01/2017 that referenced living organ donation and analyzed use of donation-related Twitter handles, names, or profile information. Tweets were manually abstracted and qualitatively analyzed for common themes. Social media influence of those tweeting about living donation was evaluated using Klout score. RESULTS: We identified 93 donors, 61 professionals, 12 hospitals, and 19 organizations that met eligibility criteria. Social media influence was similar across these groups (p=0.4). Donors (16%) and organizations (23%) were more likely than professionals (7%) or hospitals (0%) to include transplant-related educational information in their profiles (p=0.007). Living donation-related tweets were most commonly donation stories (33%), news reports (20%), reports about new transplant research (15%), and sharing transplant candidates' searches for donors (14%). CONCLUSIONS: This exploratory study of living donors and transplant professionals, hospitals, and organizations on Twitter provides insight into how the social media platform may be used to communicate about and disseminate information about living donation. This article is protected by copyright. All rights reserved. PMID- 30421842 TI - Conductance Photoswitching of Metal-Organic Frameworks with Embedded Spiropyran. AB - Conductive metal-organic frameworks (MOFs) as well as smart, stimuli-responsive MOF materials attract considerable attention with respect to advanced applications in energy harvesting and storing as well as in signal processing. Here, the conductance of MOF films of type UiO-67 with embedded photoswitchable nitro-substituted spiropyran is investigated. Under UV-irradiation, spiropyran (SP) reversibly isomerizes to the merocyanine (MC) form, a zwitterionic molecule with an extended size and extended conjugated pi-system. We show the light induced SP-MC isomerization results in remote control over the conductance of the SP@UiO-67 MOF film and the conductance can be increased by one order of magnitude. This research has the potential to lead to the development of a new generation of photoelectronic devices based on smart hybrid materials. PMID- 30421843 TI - Prospective Evaluation of Internalized Weight Bias and Weight Change Among Successful Weight-Loss Maintainers. AB - OBJECTIVE: Internalized weight bias (IWB) has been associated with weight regain after intentional weight loss, but reliance on cross-sectional data limits the understanding of this relationship. This study prospectively evaluated IWB as a predictor of weight change in a longitudinal observational study of successful weight-loss maintainers. METHODS: National Weight Control Registry participants (maintained 13.6-kg weight loss for >= 1 y) were asked to complete an online questionnaire including current weight and Weight Bias Internalization Scale Modified (WBIS-M) at baseline and 12 months. RESULTS: At baseline, 1,250 of 1,643 eligible individuals completed the baseline assessment (71% female; 94% white; mean age +/- SD: 52 y +/- 13.1; BMI: 27 +/- 5.5). The average WBIS-M score was 3.0 (+/- 1.3). Study completers (n = 862) reported 2.2% (+/- 7.8%) weight gain. Higher baseline IWB predicted weight gain among men (n = 254; t = -2.28; P = 0.02) but not women (n = 608; t = 1.22; P = 0.22). A one-point reduction in WBIS M score at follow-up was associated with a 3.0% weight loss. CONCLUSIONS: Among weight-loss maintainers, IWB may be a risk factor for weight gain among men. Weight loss at follow-up was associated with reduced IWB in both men and women. Reliance on female-only samples may limit our understanding of IWB and its implications for weight control. PMID- 30421845 TI - Hydrogen Bonding Regulated Supramolecular Nanostructures and Impact on Multivalent Binding. AB - This communication reveals H-bonding regulated nanostructure, thermodynamics and multivalent binding of two unsymmetric bola-amphiphiles (NDI-1, NDI-2) consisting of a hydrophobic naphthalene-diimide (NDI), connected to a hydrophilic wedge by a H-bonding group in one arm and a glucose moiety on the other arm. They merely differ by the single H-bonding group, namely hydrazide and amide, which triggers distinct self-assembly producing vesicle and cylindrical micelle, respectively. H bonding among the rigid hydrazide groups in NDI-1 contributes to a major enthalpy gain and relatively less entropy gain. For NDI-2, a relatively less enthalpy gain is compensated by the additional entropy originated from the conformational freedom of the open chain structure. Although the extended H-bonding among the single H-bonding group ensures stacking with head-to-head orientation and multiple array of the appended glucose moieties in both systems, adaptive cylindrical structure exhibits much superior multivalent binding with Concanavalin (ConA) than that of the rigid vesicle. Control amphiphile (NDI-3), lacking any H-bonding group, assembles with random lateral orientation, producing spherical micelle without any notable multivalent binding. PMID- 30421844 TI - A Randomized, Double-Blind, Placebo-Controlled Study of Gelesis100: A Novel Nonsystemic Oral Hydrogel for Weight Loss. AB - OBJECTIVE: This study aims to assess the efficacy and safety of Gelesis100, a novel, nonsystemic, superabsorbent hydrogel to treat overweight or obesity. METHODS: The Gelesis Loss Of Weight (GLOW) study was a 24-week, multicenter, randomized, double-blind, placebo-controlled study in patients with BMI >= 27 and <= 40 kg/m2 and fasting plasma glucose >= 90 and <= 145 mg/dL. The co-primary end points were placebo-adjusted weight loss (superiority and 3% margin super superiority) and at least 35% of patients in the Gelesis100 group achieving >= 5% weight loss. RESULTS: Gelesis100 treatment caused greater weight loss over placebo (6.4% vs. 4.4%, P = 0.0007), achieving 2.1% superiority but not 3% super superiority. Importantly, 59% of Gelesis100-treated patients achieved weight loss of >= 5%, and 27% achieved >= 10% versus 42% and 15% in the placebo group, respectively. Gelesis100-treated patients had twice the odds of achieving >= 5% and >= 10% weight loss versus placebo (adjusted OR: 2.0, P = 0.0008; OR: 2.1, P = 0.0107, respectively), with 5% responders having a mean weight loss of 10.2%. Patients with prediabetes or drug-naive type 2 diabetes had six times the odds of achieving >= 10% weight loss. Gelesis100 treatment had no apparent increased safety risks. CONCLUSIONS: Gelesis100 is a promising new nonsystemic therapy for overweight and obesity with a highly desirable safety and tolerability profile. PMID- 30421847 TI - Organocatalytic Asymmetric One-Step Desymmetrizing Dearomatization Reaction of Indoles: Development and Bioactivity Evaluation. AB - An organocatalytic one-step desymmetrizing dearomatization reaction of indoles with in situ formed vinylidene ortho-quinone methides is reported. A set of [6-6 5] and/or [5-6-5] fused indoline heterocycles were obtained in excellent yields with excellent diastereoselectivities (>20:1 d.r.) and enantioselectivities (up to 99 % ee). Moreover, some of the obtained products were screened against a panel of cancer cell lines, and one was identified to inhibit the proliferation of all the tested cancer cells, but showed marginal effects against non-cancerous cells. The methodology provides a platform for the synthesis of new leading compounds with antitumor activity. PMID- 30421846 TI - Intraoperative computer-assisted prediction of intraarticular contact pressures in the knee during high tibial osteotomy. AB - OBJECTIVES: To develop an accurate intraoperative method to estimate changes in intraarticular contact pressures during high tibial osteotomy (HTO). METHODS: Changes in knee alignment and pressure were monitored in real time in seven cadaver specimens that received HTO. Intraarticular contact pressure (N/mm2 ) in each knee compartment was estimated based on extraarticularly acquired data (leg alignment, correction, and ankle tilt) and based on the application of an axial force of half bodyweight (400-450 N). RESULTS: Contact pressure estimation was more accurate in the lateral compartment (R2 = 0.940) than in the medial compartment of the knee (R2 = 0.835). The optimism-corrected R2 was 0.936 for the lateral compartment and 0.821 for the medial compartment. CONCLUSIONS: We have established a framework for estimating the change in intraarticular contact pressures based on extraarticular data. This research could be helpful in generating appropriate algorithms to estimate joint alignment changes based on applied loads. PMID- 30421848 TI - A new insight into lead (II) tolerance of environmental fungi based on a study of Aspergillus niger and Penicillium oxalicum. AB - Environmental microorganisms have been widely applied in heavy metal remediation. This study explored the mechanisms of lead tolerance between two typical filamentous fungi, A. niger and P. oxalicum. It is shown that the mechanisms of reducing Pb toxicity by these two fungi have three major pathways. The secreted oxalic acid can react with Pb (II) to form insoluble Pb minerals, primarily lead oxalate. Then, the enhanced biosorption via forming new border of cell wall prevents the transportation of Pb (II) into hypha. In addition, the fungal activity could be maintained even at high Pb concentration due to the intracellular accumulation. It was confirmed that A. niger has the higher Pb tolerance (up to 1500 mg/L Pb level) compared with P. oxalicum (up to 1000 mg/L). Meanwhile, Pb levels below 1000 mg/L partially stimulate the bioactivity of A. niger, which is confirmed by its elevated respiration (from 53 to 63 mg C L-1 medium h-1 ). This subsequently enhanced microbial functions of A. niger to resist Pb toxicity. A better understanding of Pb tolerance of these two fungi sheds a bright future of applying them to remediate lead-contaminated environments. This article is protected by copyright. All rights reserved. PMID- 30421850 TI - Ultrastructural analysis of spores from diverse Bacillales species isolated from Brazilian soil. AB - Many species in the order Bacillales form a specialized cell type called a spore that is resistant to a range of environmental stresses. Transmission electron microscopy (TEM) reveals that the spore is comprised of a series of concentric shells, surrounding an interior compartment harbouring the spore DNA. The outermost of these shells varies considerably in morphology among species, likely reflecting adaptations to the highly diverse niches in which spores are found. To better characterize the variation in spore ultrastructure among diverse species, we used TEM to analyse spores from a collection of 23 aerobic spore-forming bacteria from the Solo do Distrito Federal (SDF strains), spanning the genera Bacillus, Lysinibacillus, Paenibacillus and Brevibacillus, isolated from soil from central Brazil. We found that the structures of these spores varied widely, as expected. Interestingly, even though these isolates are novel strains of each species, they were structurally very similar to the known examples of each species in the literature. Because in most cases, the species we analysed are poorly characterized, our data provide important evidence regarding which structural features are likely to be constant within a taxon and which are likely to vary. PMID- 30421849 TI - Geographic Variation in Obesity, Behavioral Treatment, and Bariatric Surgery for Veterans. AB - OBJECTIVE: This study aims to describe geographic variation in veterans' prevalence of obesity, participation in Veterans Health Administration's behavioral weight management program (MOVE!), and receipt of bariatric surgery in fiscal year (FY) 2016. METHODS: In this retrospective cohort study of veterans with obesity who received Veterans Health Administration care in FY2016, electronic health record data were obtained on weight, height, outpatient visits to the MOVE! program, and bariatric surgeries. For each Veterans Integrated Service Network (VISN) region, the prevalence rate of veterans with obesity (BMI >= 30 kg/m2 ), MOVE! participation rates, and bariatric surgery rates are presented. RESULTS: The prevalence of obesity in veterans ranged from 30.5% to 40.5% across VISNs in FY2016. MOVE! participation among veterans with obesity was low (2.8%-6.9%) across all VISNs, but veterans with class II and III obesity (BMI >= 35) had higher MOVE! participation rates (4.3%-10.8%) than veterans with class I obesity. There was 20-fold variation across VISNs in receipt of bariatric surgery among veterans with BMI >= 35, ranging from 0.01% to 0.2%. Among veterans with BMI >= 35 participating in MOVE!, there was 46-fold variation in bariatric surgery provision, ranging from 0.07% to 3.27%. CONCLUSIONS: Despite veterans' high prevalence of obesity, behavioral and surgical weight management participation is low and varies across regions. PMID- 30421851 TI - Alcohol Intake and Weight Loss During Intensive Lifestyle Intervention for Adults with Overweight or Obesity and Diabetes. AB - OBJECTIVE: This study aimed to assess whether alcohol consumption decreases during an intensive lifestyle intervention (ILI) and whether alcohol consumption is associated with weight loss among participants with overweight or obesity and type 2 diabetes. METHODS: Participants (n = 4,901) were from the Action for Health in Diabetes (Look AHEAD) study, a randomized controlled trial that compared an ILI with a diabetes support and education (DSE) control. Mixed effects models were used to estimate the effect of the ILI on alcohol consumption and the influence of alcohol consumption on weight loss at year 4. RESULTS: ILI and DSE participants did not differ in changes in alcohol consumption. Alcohol intake was not associated with weight loss at year 1 of the ILI. ILI participants who abstained from alcohol lost 5.1% +/- 0.3% of initial weight at year 4 compared with a significantly (P = 0.04) smaller 2.4% +/- 1.3% for consistent heavy drinkers. ILI participants who abstained from alcohol consumption over the 4 years lost 1.6% +/- 0.5% more weight relative to individuals who drank alcohol at any time during the intervention (P = 0.003). DSE participants did not differ in weight loss by alcohol consumption. CONCLUSIONS: Heavy alcohol drinkers are at risk for suboptimal long-term weight loss. Decreasing alcohol consumption may improve weight management among individuals with diabetes. PMID- 30421852 TI - Relationships among tongue volume, hyoid position, airway volume and maxillofacial form in paediatric patients with Class-I, Class-II and Class-III malocclusions. AB - OBJECTIVES: To clarify the associations among tongue volume, hyoid position, airway volume and maxillofacial form using cone beam computed tomography (CBCT) data for children with Class-I, Class-II and Class-III malocclusion. SETTING AND SAMPLE POPULATION: Sixty children (mean age, 9.2 years) divided into Class-I, Class-II and Class-III malocclusion groups according to the A-nasion-B angle. MATERIAL AND METHODS: Cone beam computed tomography was used for three dimensional reconstruction of the maxillofacial region and airway. The hyoid position and the tongue, airway and oral cavity volumes were evaluated. Upper airway ventilation status was calculated using computational fluid dynamics. The groups were compared using analysis of variance and Kruskal-Wallis tests; relationships among the parameters were assessed using Pearson's and Spearman's rank correlation tests. RESULTS: The tongue volume was larger in Class-III patients (50.63 cm3 ) than in Class-I patients (44.24 cm3 ; P < 0.05). The hyoid position was lower (49.44 cm), and anatomical balance (AB; tongue volume/oral cavity volume; 85.06%) was greater in Class-II patients than in Class-I patients (46.06 cm, 80.57%, respectively; P < 0.05 for both). The hyoid height showed a positive correlation with AB (r = 0.614; P < 0.001). CONCLUSIONS: Children with Class-III malocclusion have large tongue volumes and small AB; the reverse is true for children with Class-II malocclusion. The hyoid position is closely associated with AB in children with malocclusion. PMID- 30421854 TI - Genetic risk factors for the development of pulmonary disease identified by genome-wide association. AB - Chronic respiratory diseases are a major cause of morbidity and mortality. Asthma and chronic obstructive pulmonary disease (COPD) combined affect over 500 million people worldwide. While environmental factors are important in disease progression, asthma and COPD have long been known to be heritable with genetic components playing an important role in the risk of developing disease. Identification of genetic variation contributing to disease progression is important for a number of reasons including identification of risk alleles, understanding underlying disease mechanisms and development of novel therapies. Genome-wide association studies (GWAS) have been successful in identifying many loci associated with lung function, COPD and asthma. In recent years, meta analyses and improved imputation have facilitated the growth of GWAS in terms of numbers of subjects and the number of single nucleotide polymorphisms (SNP) that can be interrogated. As a consequence, there has been a significant increase in the number of signals associated with asthma, COPD and lung function. SNP that have shown association with lung function reassuringly show a significant overlap with SNP associated with COPD giving a glimpse at pathways that may be involved in COPD mechanisms including genes in, for example, developmental pathways. In asthma, association signals are often in or near genes involved in both adaptive and innate immune response pathways, epithelial cell homeostasis and airway structural changes. The challenges now are translating these genetic signals into a new understanding of lung biology, understanding how variants impact health and disease and how they may provide opportunities for therapeutic intervention. PMID- 30421853 TI - Association of Obesity Subtypes in the Longitudinal Assessment of Bariatric Surgery Study and 3-Year Postoperative Weight Change. AB - OBJECTIVE: The study objective was to empirically identify subgroups of patients with obesity and investigate their association with postoperative weight change. METHODS: A longitudinal analysis of 2,458 adults in the Longitudinal Assessment of Bariatric Surgery (LABS) study was used. Baseline data were used to identify subgroups. The outcome was 3-year weight change after bariatric surgery. RESULTS: We identified four classes (subtypes) of obesity, which could be characterized as diabetes with low rates of high-density lipoprotein (Class 1), disordered eating (Class 2), mixed (Class 3), and extreme obesity with early onset (Class 4). Approximately 98% of participants in Class 1 had diabetes compared with < 40% in the other classes. There were high rates of binge eating in Class 2, and more than 92% of those in this class reported eating when not hungry. Class 4 was characterized by a higher BMI at baseline. Adults in Class 4 lost an average of 25.0% (males) and 30.3% (females) of their baseline weight over 3 years. In contrast with participants in Class 1, those in Classes 2 and 3 had significantly larger 3-year weight losses than their peers in Class 4. CONCLUSIONS: Obesity is a heterogeneous disease. Bariatric surgery may be most beneficial for adults with disordered eating. PMID- 30421855 TI - Relationship status and quality of the partner relationship in parents of long term childhood cancer survivors: The Swiss Childhood Cancer Survivor Study Parents. AB - OBJECTIVE: The intensive and long-lasting experience of childhood cancer is a tremendous stressor for the parental relationship. We aimed to (1) compare civil status and partner relationship of parents of long-term childhood cancer survivors with population-based comparisons, (2) identify cancer-related characteristics associated with not being married, and (3) evaluate the quality of the partner relationship. METHODS: We sent questionnaires to parents of survivors aged <=16 years at diagnosis and >=20 years at study. Population-based comparisons were derived from a random sample of the general population (>=1 child aged >=20 years) and standardized by sociodemographic characteristics of survivor parents. We used logistic regression to identify cancer-related characteristics associated with not being married. The quality of the partner relationship was evaluated using the relationship-specific attachment scale for adults assessing the dimensions security (secure-fearful) and dependency (dependent-independent). RESULTS: A total of 784 parents (58.9% mothers) of 512 survivors (response rate: 44.0%) and 471 comparison parents completed the questionnaire. Parents of survivors were less often divorced/separated (9.0% vs 17.5%, P < 0.001) and more often in a partner relationship (89.9% vs 85.0%, P = 0.010) than comparisons. Not being married was not associated with cancer-related characteristics. Parents of survivors reported similar security (P = 0.444) but higher dependency (P = 0.032) within the partner relationship than comparisons. In both populations, fathers indicated higher security and dependency than mothers. CONCLUSIONS: Long after the diagnosis of cancer in their child, parents' relationship appears similar as in parents of the general population. The increased dependency reported by parents of survivors suggests that they managed their child's disease as a team. PMID- 30421856 TI - Intensive Behavioral Therapy for Obesity Combined with Liraglutide 3.0 mg: A Randomized Controlled Trial. AB - OBJECTIVE: The Centers for Medicare and Medicaid Services (CMS) covers intensive behavioral therapy (IBT) for obesity. The efficacy, however, of the specific approach has never been evaluated in a randomized trial, as described here. The 1 year trial also assessed whether the addition to IBT of liraglutide 3.0 mg would significantly increase weight loss and whether the provision of meal replacements would add further benefit. METHODS: A total of 150 adults with obesity were randomly assigned to: IBT (IBT-alone), providing 21 counseling visits; IBT combined with liraglutide (IBT-liraglutide); or IBT-liraglutide combined for 12 weeks with a 1,000- to 1,200-kcal/d meal-replacement diet (Multicomponent). All participants received weekly IBT visits in month 1, every-other-week visits in months 2 to 6, and monthly sessions thereafter. RESULTS: Ninety-one percent of participants completed 1 year, at which time mean (+/- SEM) losses for IBT-alone, IBT-liraglutide, and Muticomponent participants were 6.1 +/- 1.3%, 11.5 +/- 1.3%, and 11.8 +/- 1.3% of baseline weight, respectively. Fully 44.0%, 70.0%, and 74.0% of these participants lost >= 5% of weight, respectively. The liraglutide-treated groups were superior to IBT-alone on both outcomes. Weight loss in all three groups was associated with clinically meaningful improvements in cardiometabolic risk factors. CONCLUSIONS: The findings demonstrate the efficacy of IBT for obesity and the potential benefit of adding pharmacotherapy to this approach. PMID- 30421857 TI - Effect of prior stroke on long-term outcomes of percutaneous coronary interventions in Chinese patients: A large single-center study. AB - OBJECTIVES: To evaluate the effect of prior stroke on long-term outcomes in patients undergoing percutaneous coronary interventions (PCI). BACKGROUND: Patients with coronary heart disease (CHD) and prior stroke history have more serious clinical and angiographic conditions, which make the choice of treatment strategy complex. METHODS: A total of 10,724 consecutive patients who underwent PCI from January 2013 to December 2013 were enrolled. 2-Year clinical outcomes between patients with prior stroke (n = 1150) and those with no prior stroke (n =9574) were compared. RESULTS: The proportion of patients with prior stroke was 10.72%. These patients had higher clinical risks (age, sex, and cardiovascular risk factors) and more extensive coronary disease (higher pre-PCI and residual SYNTAX scores). During the 2-year follow-up, patients with prior stroke had a higher incidence of major adverse cardiac and cerebrovascular events (MACCE), all cause death, stent thrombosis and stroke than those without prior stroke (14.3% vs. 11.8%, p = 0.02; 2.3% vs. 1.1%, p < 0.01; 1.6% vs. 0.8%, p < 0.01; 3.3% vs. 1.1%, p < 0.01, respectively). Multivariable regression analyses identified a positive association between prior stroke and risk of stroke (HR = 2.07, 95%CI: 1.35-3.19, p < 0.01). Propensity score matched analyses (962 pairs) indicated that the only primary end point that differed in incidence between the groups was stroke and prior stroke was the only independent predictor of stroke (HR = 2.31, 95%CI: 1.20-4.45, p = 0.01). CONCLUSIONS: Prior stroke history was the only predictor of risk of post-PCI stroke. The noncerebrovascular adverse events were not increased after adjusted analyses of baseline characteristics and propensity analyses. PMID- 30421858 TI - Bariatric Surgery Does Not Affect Food Preferences, but Individual Changes in Food Preferences May Predict Weight Loss. AB - OBJECTIVE: Using an ad libitum buffet meal targeting direct behavior, the authors of the current study previously reported no effect of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) surgery on food preferences 6 months after surgery. The current study investigated changes in food preferences at 18 months after surgery and whether changes in food preferences at 6 months predicted weight loss. METHODS: Twenty food items separated into the following food categories were served at the buffet meal: high-fat, low-fat, sweet, savory, high fat savory, high-fat sweet, low-fat savory, and low-fat sweet. Energy intake and intake from each of the food items were registered. Energy intake prior to the meal was standardized. RESULTS: Thirty-nine subjects completed visits before surgery and 18 months following RYGB (n = 29) and SG (n = 10) surgery. Energy intake decreased 41% (4,470 +/- 209 kJ vs. 2,618 +/- 209 kJ, P < 0.001), but no change occurred in relative energy intake from any of the food categories (all P >= 0.23), energy density (P = 0.20), or macronutrient intake (all P >= 0.28). However, changes in high-fat food intake, protein intake, energy intake, and energy density at 6 months predicted weight loss at 18 months (P <= 0.02). CONCLUSIONS: RYGB surgery and SG surgery do not affect food preferences. However, changes in food preferences seem to be predictive of weight loss. PMID- 30421859 TI - Carbon dots-involved chemiluminescence: Recent advances and developments. AB - In recent years, more and more nanomaterials-based chemiluminescence (CL) systems have appeared to improve the sensitivity and expand the scope of the analytical applications with the explosive growth and development of nanomaterials and technology. As a fascinating class of luminescent carbon nanomaterials, carbon dots (CDs) are now substantially studied in fabricating CL based assays due to their unique optical and mechanical properties. Herein, we summarize and highlight the current developments of CDs-involved weak or ultraweak CL systems, as well as the corresponding mechanisms and proper applications in some fields. CDs can take part in the CL reactions as oxidants, emitting species directly involved in redox oxidation, energy acceptors of CL energy transfer, or even catalysts involving other luminophores. In fact, they always have more than one role in many cases, owing to the formation of various excited species with short life in CL systems. Therefore, in this review article, the most recent progress of the different CDs-assisted CL systems including the mechanisms and applications are presented. Finally, the conclusions and future prospects of this field are also discussed. The significant features of the CDs-based CL systems may open up new prospects and challenges in a wider range of fields. PMID- 30421860 TI - GABAB receptor positive allosteric modulators with different efficacies affect neuroadaptation to and self-administration of alcohol and cocaine. AB - Drugs of abuse induce widespread synaptic adaptations in the mesolimbic dopamine (DA) neurons. Such drug-induced neuroadaptations may constitute an initial cellular mechanism eventually leading to compulsive drug-seeking behavior. To evaluate the impact of GABAB receptors on addiction-related persistent neuroplasticity, we tested the ability of orthosteric agonist baclofen and two positive allosteric modulators (PAMs) of GABAB receptors to suppress neuroadaptations in the ventral tegmental area (VTA) and reward-related behaviors induced by ethanol and cocaine. A novel compound (S)-1-(5-fluoro-2,3-dihydro-1H inden-2-yl)-4-methyl-6,7,8,9-tetrahydro-[1,2,4]triazolo[4,3-a]quinazolin-5(4H) one (ORM-27669) was found to be a GABAB PAM of low efficacy as agonist, whereas the reference compound (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H benzofuran-2-one (rac-BHFF) had a different allosteric profile being a more potent PAM in the calcium-based assay and an agonist, coupled with potent PAM activity, in the [35 S] GTPgammaS binding assay in rat and human recombinant receptors. Using autoradiography, the high-efficacy rac-BHFF and the low-efficacy ORM-27669 potentiated the effects of baclofen on [35 S] GTPgammaS binding with identical brain regional distribution. Treatment of mice with baclofen, rac-BHFF, or ORM-27669 failed to induce glutamate receptor neuroplasticity in the VTA DA neurons. Pretreatment with rac-BHFF at non-sedative doses effectively reversed both ethanol- and cocaine-induced plasticity and attenuated cocaine i.v. self administration and ethanol drinking. Pretreatment with ORM-27669 only reversed ethanol-induced neuroplasticity and attenuated ethanol drinking but had no effects on cocaine-induced neuroplasticity or self-administration. These findings encourage further investigation of GABAB receptor PAMs with different efficacies in addiction models to develop novel treatment strategies for drug addiction. PMID- 30421861 TI - Youth Subjective Social Status (SSS) is Associated with Parent SSS, Income, and Food Insecurity but not Weight Loss Among Low-Income Hispanic Youth. AB - OBJECTIVE: Subjective social status (SSS), perceived rank in the social ladder, is associated with weight, but determinants of SSS in youth remain unknown. Relationships between youth SSS and income, food insecurity, parent SSS, and BMI change were investigated during an obesity intervention. METHODS: Data came from a family-centered, community-based obesity intervention for low-income families. Parent and youth SSS were assessed using a validated, age-appropriate SSS scale. Food insecurity and socioeconomic factors were assessed in parents; child and parent weight-related data were measured at baseline and post intervention. RESULTS: Participants included 110 primarily Hispanic (97%) low-income youth and their parents. Food insecurity was reported in 66.4% of families. Youth SSS was positively associated with parent SSS (P = 0.0014). In both parents and children, the association between income and SSS was moderated by food insecurity such that lower income was more strongly associated with lower SSS among food-insecure households (P = 0.0286 and P = 0.0327, respectively). Youth SSS was not associated with youth BMI reduction. CONCLUSIONS: Youth SSS was not predictive of weight loss in this intervention. Intriguingly, the association between income and SSS was modified by food insecurity, suggesting that food insecurity shapes the contribution of socioeconomic factors to one's perceived social status. PMID- 30421862 TI - Weight Recidivism After Roux-en-Y Gastric Bypass Surgery: An 11-Year Experience in a Multiethnic Medical Center. AB - OBJECTIVE: Weight recidivism following Roux-en-Y gastric bypass (RYGB) is common and is associated with recurrence of comorbidities. Studies with long-term follow up of recidivism quantified by weight regain (WR) are lacking. A retrospective review of all RYGB at our center from 2004 to 2015 was performed to examine the effects of race and type 2 diabetes on WR following RYGB. METHODS: Multivariable linear mixed models were used for the effects of time and race on weight, WR relative to nadir weight (WR/nadir), and WR relative to maximal weight loss, and Cox regressions were used for low, moderate, and high WR/nadir. RESULTS: A total of 1,395 participants were identified. The sample was limited to African American (AA), Caucasian American (CA), and Hispanic American (HA) participants. The effects of time (P < 0.0001), race (P < 0.0001), and race * time interaction (P = 0.0008) on weight trajectory were significant. AA had significantly more WR than CA (P < 0.01). AA and HA had a higher hazard ratio for having low, moderate, and rapid WR/nadir. CONCLUSIONS: Racial disparities after RYGB include WR and particularly affect AA. Understanding the etiologic factors that contribute to these disparities is important to optimize the long-term clinical outcomes of bariatric surgery. PMID- 30421863 TI - Effectiveness of Total Meal Replacement Program (OPTIFAST Program) on Weight Loss: Results from the OPTIWIN Study. AB - OBJECTIVE: The aim of this study was to test the effectiveness of the OPTIFAST program (OP), a total meal replacement dietary intervention, compared with a food based (FB) dietary plan for weight loss. METHODS: Participants with BMI 30 to 55 kg/m2 , age 18 to 70 years old, were randomized to OP or FB dietary and lifestyle interventions for 26 weeks, followed by a weight-maintenance phase. Outcomes were percent change in body weight (%WL) from baseline to weeks 26 and 52, associated changes in body composition (using dual energy x-ray absorptiometry), and adverse events. Primary analysis used repeated-measures multivariable linear mixed models to compare outcomes between groups in a modified intention-to-treat fashion (mITT). RESULTS: A total of 273 participants (83% of randomized; 135 OP, 138 FB) made up the mITT population. Mean age was 47.1 +/- 11.2 years; 82% were female and 71% non-Hispanic white. Baseline BMI was 38.8 +/- 5.9 kg/m2 . At 26 weeks, OP %WL was 12.4% +/- 0.6% versus 6.0% +/- 0.6% in FB (P < 0.001). At 52 weeks, OP %WL was 10.5% +/- 0.6% versus 5.5% +/- 0.6% in FB (P < 0.001). Fat mass loss was greater for OP; lean mass loss was proportional to total weight loss. There was no difference in serious adverse event rates between groups. CONCLUSIONS: Compared with an FB approach, OP was more effective with greater sustained weight loss. PMID- 30421864 TI - Does Partial Meal Replacement During Pregnancy Reduce 12-Month Postpartum Weight Retention? AB - OBJECTIVE: This randomized trial tested whether a behavioral intervention with meal replacements in pregnancy could increase the proportion of women who returned to prepregnancy weight and reduce postpartum weight retention by 12 months after delivery. METHODS: Women (N = 264; 13.7 weeks' gestation) with overweight or obesity were randomly assigned to usual care or intervention. The intervention reduced excess gestational weight gain and was discontinued at delivery. At follow-up, 83.7% completed the 12-month assessment. RESULTS: Compared with usual care, prenatal intervention had no significant effect on odds of achieving prepregnancy weight (38/128 [29.7%] vs. 41/129 [31.8%]; P = 0.98) or in reducing the magnitude of weight retained (3.3 vs. 3.1 kg; P = 0.82) at 12 months. After delivery, significant (P < 0.0001) declines in meal replacements, practice of weight control behaviors, and dietary restraint were observed in the intervention group. Independent of group, lower gestational weight gain was the strongest predictor of achieving prepregnancy weight at 12 months (P = 0.0008). CONCLUSIONS: A prenatal behavioral intervention with meal replacements that reduced pregnancy weight gain had no significant effect on 12-month postpartum weight retention. PMID- 30421865 TI - Analyzing the suitability of a baffled orbitally shaken bioreactor for cells cultivation using the computational fluid dynamics approach. AB - Orbitally shaken bioreactors (OSRs) is one of important bioreactors for mammalian cells cultivation in suspension, especially for the screening of valuable microorganisms and in basic bioprocess development experiments. However, the suitability of OSRs for cells culture in large scale is still under development. In this article, a new kind of OSRs with baffle structure was proposed and a three-dimensional CFD model was established to analyze the influence of baffle structure on the flow field. Lower installation height of baffles was found suitable for improving the mixing efficiency. Compared to the unbaffled OSR, the baffled OSR could enhance the level of oxygen transfer largely but the oxygen transfer rate was independent on the baffle installation height. Moreover, as the baffle installation height increased, the energy transferred for liquid motion was decreased. Finally, the shear stress of the baffled OSRs proposed was gentle for mammalian cells growth. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 2018. PMID- 30421866 TI - Identification of a new Cordyceps javanica fungus isolate and its toxicity evaluation against Asian citrus psyllid. AB - The Asian citrus psyllid, Diaphorina citri Kuwayama, is the most serious pest of citrus worldwide. It acts as a vector for a group of phloem-limited bacteria (Candidatus Liberibacter spp.) that causes Huanglongbing (HLB) disease. Thus, D. citri management is an important strategy against HLB, and biological control is currently considered as the most effective method because of the unsustainable and negative side effects of chemical control. Here, we isolated a new strain of entomopathogenic fungus, Cordyceps javanica (GZQ-1), from one cadaver of D. citri adult based on its morphological and phylogenetic data. Five conidial concentrations of the C. javanica pathogen (1 * 103 , 1 * 104 , 1 * 105 , 1 * 106 , and 1 * 107 conidia/ml) were assessed against six life stages of D. citri (1st 5th instar nymphs and adults). Results showed that C. javanica GZQ-1 was highly pathogenic to D. citri nymphs (69.49%-90.87% mortality) and adults (69.98% mortality). The LC50 and LT50 values of C. javanica against 1st-2nd instar (younger), 3rd-4th instar (middle aged), 5th instar (older), and adults were 1.20 * 105 , 1.10 * 106 , 4.47 * 106 , 8.12 * 106 conidia/ml and 4.25, 4.51, 5.17, 5.49 days, respectively. Moreover, glasshouse experiments indicated that this C. javanica GZQ-1 caused higher infection rates of D. citri adults compared to two other fungal strains we previously isolated in the laboratory, Cordyceps fumosorosea (IF010) and Metarhizium anisopliae (CNGD7). PMID- 30421867 TI - Method for isolation of pancreatic blood vessels, their culture and coculture with islets of langerhans. AB - The only cure available for Type 1 diabetes involves the transplantation of islets of Langerhans isolated from donor organs. However, success rates are relatively low. Disconnection from vasculature upon isolation and insufficient rate of revascularization upon transplantation are thought to be a major cause, as islet survival and function depend on extensive vascularization. Research has thus turned toward the development of pretransplantation culture techniques to enhance revascularization of islets, so far with limited success. With the aim to develop a technique to enhance islet revascularization, this work proposes a method to isolate and culture pancreas-derived blood vessels. Using a mild multistep digestion method, pancreatic blood vessels were retrieved from whole murine pancreata and cultured in collagen Type 1. After 8 days, 50% of tissue explants had formed anastomosed microvessels which extended up to 300 MUm from the explant tissue and expressed endothelial cell marker CD31 but not ductal marker CK19. Cocultures with islets of Langerhans revealed survival of both tissues and insulin expression by islets up to 8 days post-embedding. Microvessels were frequently found to encapsulate islets, however no islet penetration could be detected. This study reports for the first time the isolation and culture of pancreatic blood vessels. The methods and results presented in this work provide a novel explant culture model for angiogenesis and tissue engineering research with relevance to islet biology. It opens the door for in vivo validation of the potential of these pancreatic blood vessel explants to improve islet transplantation therapies. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 2018. PMID- 30421868 TI - High incidence of hip and knee arthroplasty in former professional, male football players. AB - AIM: The purpose of this study was to estimate the incidence of hip and knee arthroplasty in Italian male professional football (soccer) players who have played for a minimum 10 years in the Italian major football leagues. METHODS: The study group was formed by 104 male professional football players who were interviewed to evaluate the incidence of hip and knee arthroplasty. The data were collected through a questionnaire and the results collected were compared with a control group of 100 volunteers matched for age, weight and height, who did not present orthopaedic diseases but had never practiced sport. RESULTS: In the study group, 26 subjects (25 %) underwent hip and knee arthroplasty at an average mean age of 62.1 + 6 years. The frequency of arthroplasty was: 13.5% for the hip, 5.8% for the knee and 5.8% for both hip and knee. In the control group, the incidence of arthroplasty was 1% for the knee and no subjects presented hip arthroplasty. CONCLUSIONS: Italian male, former professional football players present a higher than normal incidence of hip and knee arthroplasty. Further studies are necessary to understand the pathological pathways underlying the ethiology of hip and knee osteoarthritis in male populations of former professional football players in order to develop effective preventive programmes to reduce the percentage of arthroplasties. PMID- 30421870 TI - Effects of sport on static balance in athletes with visual impairments. AB - BACKGROUND: Proper balance is crucial for postural control and physical activity performance. Issues related to balance as well as effects of various factors on balance are in the centre of attention of specialists in a number of fields including sport. Research results show that every sports discipline demands different motor preparation (including balance) and persons with visual impairments exhibit worse balance compared to their sighted counterparts. Therefore, this study sought to assess static balance in athletes with visual impairments with reference to the type of sport they did, the length of their training experience, training loadsand dysfunction level. METHODS: The study involved 57 men (shooters, tandem cyclists, football and goalball players) with visual impairments. AMTI stabilographic platform was used to assess static balance. The study participants performed the following tests: standing on both feet with eyes open and closed and single-leg stance with eyes open and closed. RESULTS: Balance in tests performed while standing on both feet did not differentiate athletes in terms of the sport they did. Static balance of athletes with visual impairments significantly differs in the single leg stance. Better balance was observed in tests with eyes open. Taking into consideration sports disciplines practised by the athletes, significant differences in balance in single left leg tests with eyes open and closed were observed. Athletes training more than 5 hours per week manifested better balance compared to those who practiced less than 5 hours per week. CONCLUSIONS: The findings indicate that athletes performing particular sports may use strategies of maintaining balance that result from the structure of these sports. The lack of differences in balance among athletes with different degrees of dysfunction may indicate their high fitness levels and show how balance is affected by physical activity performance. Results of the analysis of balance with regard to the length of training experience may suggest that it is not this factor but rather the quality of training that may exert an influence on this ability. PMID- 30421869 TI - Combined aerobic and resistance training improves microcirculation in metabolic syndrome. AB - BACKGROUND: Exercise intervention improves macrovascular function in Metabolic Syndrome (MeS) patients, but few studies have evaluated the effect of exercise on microcirculatory dysfunction, which plays a key role in the development of MeS and its correlated organ damage. We carried out this intervention study to evaluate the influence of an aerobic and resistance training on skin microvascular reactivity in MeS patients. METHODS: Post-Occlusive Reactive Hyperemia (PORH) of the forearm skin was evaluated, by laser- Doppler flowmetry, before and after a 12-week program of aerobic and resistance training in 15 MeS patients referring to our Lipid Metabolism Outpatients Clinic, together with anthropometric, fitness and metabolic parameters; 15 matched MeS patients who did not exercise, served as a control group. The exercise training consisted of 2 sessions/week of aerobic and resistant exercise. RESULTS: Following exercise program, we observed a significant reduction in body weight, fat mass, fasting blood glucose, serum HbA1c and triglycerides, while HDL-cholesterol significantly increased. The exercise-treated group experienced a significant improvement in the Area of Hyperaemia (AH) after PORH, and in all fitness parameters: VO2max, strength on the pulldown lat machine, chest press, leg press and leg extension. A significant correlation emerged between the increase in AH and the reduction in HbA1c and between increase in AH and strength at the chest press, and at the leg extension. CONCLUSIONS: Our study showed that a short-term combined aerobic resistance training positively affects microvascular reactivity in MeS patients. This improvement is correlated with the reduction of HbA1c and fitness parameters, and particularly with increased muscle strength at the upper and lower limbs. PMID- 30421871 TI - Air pollution and football players' performance: an empirical test with regression discontinuity designs. PMID- 30421872 TI - Laboratory-based ergometry for swimmers: a narrative review. AB - INTRODUCTION: The first widely-available dry-land training machines for swimmers were introduced about 40 years ago. They were designed so that swimmers could perform resistance exercise whilst more-closely replicating the movements of swimming, than when using other gymnasium-based resistance training machines. These machines were subsequently adapted and used as measurement tools (ergometers) in an array swimming research studies. This narrative review categorises and summarises what has been shown by the research studies that have utilised this laboratory-based ergometry. EVIDENCE ACQUISITION: A search was conducted in PubMed, Web of Science, ScienceDirect and Scopus (1970-2018) and relevant publications were included. Publications were grouped into 4 main areas of research: (i) physiological responses to exercise, (ii) functional evaluation of swimmers, (iii) monitoring of training, and (iv) muscular work output of swimmers. EVIDENCE SYNTHESIS: Significant differences were showed between swim bench exercise and real swimming, especially in regard to the muscles involved. The difficulties of accurate reproduction of the movements and coordinated dynamic actions of swimming have not been overcome. Nevertheless, the literature shows that the use of these devices has provided a valuable contribution to swimming physiology, while overcoming difficulties presented by attempting to make physiological measurements in the water. CONCLUSIONS: In spite of its limitations, laboratory-based ergometry has allowed a valuable contribution to the understanding of the physiology, effects of training and efficiency of swimming. PMID- 30421873 TI - The effect of running barefoot and in barefoot-style footwear on running economy at two self-determined speeds. AB - BACKGROUND: The impact of barefoot running and footwear choice on running economy (RE; steady state oxygen consumption) is heavily debated. Therefore, this study measured RE when running barefoot versus two shod conditions. METHODS: Recreational male runners (N = 8) with experience running in both five- toed minimal (FTMS) and standard cushioned running shoes (SCRS), participated in RE trials while barefoot, FTMS, and SCRS for 5 minutes each trial at both 50% and 70% of speed at VO2max (sVO2max), while RE and step frequency (Sf) were measured. Separate one-way repeated measures ANOVA's were conducted for each footwear condition and each speed, on RE and Sf. RESULTS: No significant differences in RE were found at 50% or 70% sVO2max. Step frequency was significantly different at 70% sVO2max F (2, 14) = 6.74, p = 0.009, partial omega2 = 0.06, as running barefoot (M = 173.00, SD = 10.50) exhibited a higher step frequency than running in FTMS (M = 168.81, SD = 10.94), p = 0.008 or SCRS (M = 166.62, SD = 8.42), p = 0.044 conditions. CONCLUSIONS: No statistical RE benefit was found when running barefoot over FTMS or SCRS, possibly explained by a SF adaptation at higher speeds. However, practically speaking, when shoe mass is controlled for, footwear choice has a moderate but worthwhile effect on RE. Consequently, formal familiarization and/or training in the FTMS may improve RE when compared to running in SCRS or barefoot in certain individuals. PMID- 30421874 TI - A systematic review examining the physiological, perceptual, and performance effects of active and passive recovery modes applied between repeated-sprints. AB - INTRODUCTION: Repeated-sprinting involves performing frequent short sprints (<= 10 s) interspersed with brief recovery periods (<= 60 s). Studies involving repeated-sprint protocols have typically employed active or passive recovery modes applied between running and cycling sprints. This review synthesized the literature to determine the acute physiological, perceptual, and performance effects of recovery mode applied between repeated-sprints during running and cycling protocols. EVIDENCE ACQUISITION: A systematic search was conducted according to PRISMA guidelines. Articles were retrieved from PubMed, Scopus, SPORTDiscus, and MEDLINE databases. Studies were eligible if they: (1) compared active and passive recovery applied between repeated-sprints; (2) examined sprints lasting <= 10 s, and; (3) included <= 60 s recovery between sprints. Nine studies were included in this review. Five of the included studies examined running and four studies examined cycling. EVIDENCE SYNTHESIS: Passive recovery induced less physiological stress (heart rate, oxygen consumption, and changes in oxyhemoglobin), lower perceptual stress (rating of perceived exertion), and reduced performance decrement (sprint time, speed, and sprint decrement) compared to active recovery in all running studies. Findings were equivocal in cycling. CONCLUSIONS: Application of passive recovery between running repeated-sprints is recommended to reduce performance decrement than passive recovery. Alternatively, active recovery applied between running repeated-sprints provides greater physiological stress than passive recovery and may be a useful training overload strategy to promote physiological adaptation. The mixed findings for physiological and performance measures in cycling studies suggest further research is required to reach definitive conclusions regarding application of recovery modes between cycling repeated-sprints. PMID- 30421875 TI - Novel insights into the molecular mechanisms underlying the beneficial effects of exercise training on pulmonary arterial hypertension. AB - BACKGROUND: Recent animal and clinical studies report that exercise training exert positive influences in pulmonary arterial hypertension (PAH), however, the underlying mechanisms are largely unknown. To give insight into the molecular mechanisms of the improvement effects, we performed gene expression analysis. METHODS: Three GEO datasets were analyzed, including peripheral blood mononuclear (PBMC) gene expression profiles of exercise training in men and patients with PAH. Differentially expressed genes (DEGs) in each dataset were identified, and then, the common DEGs positively regulated by PAH and negatively regulated by exercise training, or the opposite, were further identified. Subsequently, biological processes and pathways were analyzed. RESULTS: A total of 7229 DEGs with logFC>0.3 and P<0.05 were identified in exercise, whereas 749 and 2207 DEGs were identified in PAH from the two datasets. After overlapping the whole DEGs from all three datasets, total 16 common DEGs were identified, including BCLAF1, SATB1 and ZFP36L2. Seven of them were up-regulated in exercise training and down regulated in PAH, and the others were opposite. In addition, these common DEGs were mainly enriched in negative regulation of cellular process, negative regulation of biological process and negative regulation of cellular macromolecule biosynthetic process. CONCLUSIONS: Some genes have been implicated in the improvement of pulmonary vascular remodeling and PAH. These findings could not only improve the knowledge about the molecular mechanisms underlying the beneficial effects of exercise training on PAH, but also provide clues for further clinical and animal studies. PMID- 30421876 TI - The risk of injuries among CrossFit athletes: an Italian observational retrospective survey. AB - BACKGROUND: CrossFit is a strength and conditioning training program, that begin very popular in the last ten years. One of the most concerned characteristics of model is the high intensity activity performed under fatigue conditions that was proposed as potential risk of injuries; current literature on this topic was not conclusive. The purpose of this research was to examine injury epidemiology and risk factors for injury in CrossFit. METHODS: This is a retrospective observational study carried out by an anonymous, self administered questionnaire in a convenience sample of CrossFit athletes. RESULTS: 454 subjects completed and returned the questionnaire, of which 325 (71.6%) were male with an average age of 28.8+/-7.9. 39.9% reported skeletal or muscles injury after to start training Cross Fit. Lifetime Prevalence is 0.23 events per year of training/person. The average number of muscles and skeletal injuries reported was of 1.96+/-1.36. 16.7% reported tendinitis. Time of CrossFit training is a determinant of tendinitis (aOR = 1.02; p = 0.021). Attending the On-Ramp program seemed to protect against the occurrence of injuries. CONCLUSIONS: According our results the risk of injury in the Cross Fit practice is acceptable and, as discussed in a recent published review, CrossFit is comparable to other exercise programs with similar injury rates and health outcomes. PMID- 30421878 TI - Stand Up and Be Counted. PMID- 30421877 TI - Legislative Update - Short Session Drawing to a close. PMID- 30421879 TI - [CD64 index as a marker of infection in patients with postoperative fever]. AB - OBJECTIVE: To evaluate the utility of the granulocyte CD64 index as a marker of infection in patients with postoperative fever. METHODS: Prospective observational study of a cohort of patients with postoperative fever (2nd-21st day after the intervention) collected during 14 months. Obtaining blood samples during the first 24 hours after the febrile peak to determine the CD64 index (ratio of fluorescence intensity, measured, in the granulocytes of the patient with respect to healthy controls), procalcitonin and C-reactive protein (CRP). RESULTS: During the study period, 50 patients were included, 28 patients (56%) with infection and 22 patients (44%) without evidence of infection. The PCR, procalcitonin and the CD64 index showed significantly higher values in the group of patients who suffered infection. The CD64 index showed a sensitivity of 88.9%, with a specificity of 65.2%. The positive predictive value (PPV) was 75% and the negative predictive value (NPV) was 83.3%, with an area under the curve (AUC) of 0.805 (95% CI 0.68-0.93). Procalcitonin presented a sensitivity of 53.9% and specificity of 86.4%, with NPV and PPV of 82.4% and 61.3% respectively, with AUC of 0.752 (95% CI 0.61-0.89). Regarding the PCR, it showed a sensitivity of 100%, with specificity of 4.4% with an area under the curve of 0.676 (95% CI 0.52 0.83). CONCLUSIONS: The quantification of the CD64 index in patients who develop fever in the early postoperative period is useful to distinguish post-surgical inflammatory phenomena from episodes of established infection. PMID- 30421880 TI - Infectious postoperative endophthalmitis after cataract surgery performed over 7 years. The role of azithromycin versus ciprofloxacin eye drops. AB - OBJECTIVE: Although topical antibiotics have been used as antimicrobial prophylaxis after ocular surgery, recent studies have determined that intracameral cefuroxime at the end of surgery significantly reduce the risk to suffer an infection and suggest that the use of topical antibiotics in the prophylaxis of infectious postoperative endophthalmitis (IPOE) is controversial. Moreover, there is no evidence to confirm the higher effectiveness of topical ciprofloxacin, considered the standard of care, or topical azithromycin in preventing IPOE of cataract surgeries. METHODS: IPOE topical prophylaxis was performed with two different strategies: with azithromycin from January 1st, 2010 to December 31st, 2014 (group I) and with ciprofloxacin from January 1st, 2015 to January 31st, 2017 (group II). Patient characteristics and clinical signs and symptoms of IPOE from all consecutive cataract surgeries performed over a 7-year period were collected. RESULTS: A total of 15,146 cataract surgeries were conducted; 10,756 in group I and 4,390 in group II. Two cases of IPOE in each group were diagnosed, showing a 0.019% and 0.046% rate respectively, with no statistically significance. IPOE cases were related with aging, systemic and ocular comorbidities or with a complicated cataract surgery. CONCLUSIONS: The benefit of the application of topical antibiotics after cataract surgery is questionable when intracameral cefuroxime prophylaxis is performed and no better effectiveness with ciprofloxacin or azithromycin was observed. PMID- 30421881 TI - [Description of Influenza B in seasonal epidemics in Spain]. AB - OBJECTIVE: Seasonal influenza epidemics are a major public health concern. They are caused by the influenza A and B viruses; although the A virus is more prominent, influenza B virus infection causes a disease with similar characteristics. There are two phylogenetically distinct influenza B lineages (B/Victoria and B/Yamagata), only one of which is present in the trivalent vaccine formulated each season. METHODS: Epidemiological data from the Spanish Influenza Surveillance System for 2007 to 2017 were reviewed to establish the relative proportion of each type of virus and the characterization of the B lineages in relation to the composition of the trivalent vaccine. RESULTS: The median proportion of B (2007-2017) was 27.2% (0.7%-74.8%) vs. 16.3% (0.4%-98.6%) for A-H3 and 44.2% (0.1%-98.0%) for pandemic A-H1N1 (20092017). The B lineages co circulated in 8/10 seasons and there was mismatch with the B vaccine strain in 4/10 seasons. The B virus was dominant in 2007/08 and 2012/13 throughout Spain. There was a combination of dominance/codominance of influenza B and mismatch with the vaccine lineage in at least one third of epidemic seasons reviewed. CONCLUSIONS: Epidemiological information on influenza B has been less compiled in comparison with data on the A virus. Influenza virus type B is responsible for a significant number of cases in almost all seasons. The predominant B lineage in each season is unpredictable, affecting the protection conferred by the seasonal vaccine. Spanish epidemiological data support the rationale for a quadrivalent vaccine with both B virus lineages similarly to data from other settings. PMID- 30421882 TI - [Utilisation of first-line antibiotics six years after a multifaceted intervention]. AB - OBJECTIVE: No study has evaluated the impact of a multifaceted intervention on the quality of the antibiotics prescribed more than 5 years later. METHODS: A total of 210 general practitioners (GP) from eight different regions of Spain were asked to participate in two registrations of respiratory tract infections (RTI) in 2008, before, and in 2009, just after a multifaceted intervention including prescriber feedback, clinical guidelines, training sessions focused on appropriate antibiotic prescribing, workshop on rapid tests and provision of these tests in the GP consultation. They were all again invited to participate in a similar registration in 2015. A new group of clinicians from the same areas who had never participated in antimicrobial stewardship courses were also invited to participate and acted as controls. RESULTS: The 121 GPs who continued the study (57.6%) and the 117 control GPs registered 22,407 RTIs. The antibiotic most commonly prescribed was amoxicillin and clavulanic acid, prescribed in 1,801 cases (8.1% of the total), followed by amoxicillin (1,372 prescriptions, 6.2%), being lower among GPs just after the intervention. The third leading antibiotic among GPs just after the intervention was penicillin V (127 cases, 3.3%) whereas macrolides ranked third in the other three groups of GPs. CONCLUSIONS: The use of first-line antibiotic for RTIs wanes over time after an intervention, but their utilisation is still significantly greater among intervened clinicians six years later compared to GPs who have never been exposed to any antimicrobial stewardship programmes. PMID- 30421883 TI - Interleukin (IL) -1 beta, IL-6 and tumor necrosis factor in patients with seasonal flu. AB - OBJECTIVE: The role of tumor necrosis factor (TNF), interleukin (IL)-1beta and IL 6 in the pathogenicity of seasonal flu is unknown. METHODS: We analyzed the profiles of these cytokines in 77 flu patients and 17 controls with non-flu respiratory infection, using molecular biology techniques (real-time polymerase chain reaction). RESULTS: Flu patients had lower monocyte counts (p=0.029) and a slightly lower median level of IL-6 (P=0.05) than the control group. Twenty-four flu patients (31.2%) had pneumonia; this group had higher C-reactive proteins (p=0.01) and monocyte levels (p=0.009). Pro-inflammatory cytokines levels did not rise in patients with pneumonia complicating seasonal influenza. CONCLUSIONS: IL 6 levels were lower in adults with influenza. PMID- 30421884 TI - Severe bacterial non-AIDS infections in HIV women. PMID- 30421886 TI - Advocate for the people. PMID- 30421885 TI - [Review of infections by Actinotignum schaalii diagnosed in the University General Hospital of Castellon]. PMID- 30421888 TI - In Your Corner: Transitioning from School. PMID- 30421887 TI - The Doctor of Nursing Practice Explained. PMID- 30421889 TI - The North Carolina-Republic of Moldova Nursing Collaborative. PMID- 30421890 TI - Chipping Away at Resistance. PMID- 30421891 TI - Wearable Technology for Nurses. PMID- 30421892 TI - A Look Back at the NC Association of Colored Graduate Nurses. PMID- 30421893 TI - In Your Corner: Combating Burnout or Compassion Fatigue. PMID- 30421894 TI - Intracranial pressure monitor insertion in traumatic brain injury: a single center, retrospective decision process analysis. AB - BACKGROUND: Evidence-based indications for intracranial pressure (ICP) monitoring in patients with traumatic brain injury (TBI) are lacking. The aim of this study was to analyze the main factors that guided the decision-making of invasive ICP monitoring in a large cohort of TBI patients from our institution. METHODS: This is a retrospective, single centre, observational study including adult TBI patients consecutively admitted to our NeuroIntensive Care Unit over 20 years. Logistic regression analyses were performed to identify potential factors associated with the decision for ICP monitor insertion. A decision tree was developed to identify the combination of factors with the highest statistical power to predict the decision for ICP monitor insertion. RESULTS: A total of 857 adult patients were included in the analysis. The decision to monitor ICP was strongly related to different factors, including Glasgow Coma Scale (GCS), Computed Tomography (CT) scan classification, pupils' reactivity, and patients' prognosis at the admission calculated by the International Mission on Prognosis in Traumatic Brain Injury (IMPACT) score (p<0.01). Results from the decision tree showed an overall ability of the 72% in the prediction of ICP monitoring and that, among the factors analysed, CT findings had the primarily and strongest discrimination power. CONCLUSIONS: The decision to insert an invasive ICP monitoring in patients with TBI is multifactorial. Among the different factors analysed in our cohort of TBI patients, prognostication factors as for IMPACT score and in particular CT findings could potentially explain the decision making for ICP monitoring. PMID- 30421895 TI - The algorithms of adjuvant therapy in gliomas and their effect on survival. AB - The treatment of gliomas became more sophisticated during the last decades. As by now, adjuvant treatment after maximum safe resection is considered an important and effective treatment strategy in most gliomas, yet the decision is based on several factors. This review summarizes the available evidence for the current adjuvant treatment algorithms with a focus on the impact on the survival of glioma patients. The review is based on the current guidelines, but it also includes new insights which have not yet been included into the official guidelines. PMID- 30421896 TI - Surgical management of tuberculum sellae meningiomas in the endoscopy era. PMID- 30421897 TI - Competence in endosonographic techniques. AB - Endobronchial ultrasound (EBUS) has revolutionized the field of bronchoscopy because it allows to observe peribronchial structures and distal peripheral lung lesions. The use of EBUS was first described by Hurte and Hanrath in 1992. EBUS technology exists in two forms: radial and convex transducer probes. The radial EBUS probe has a 20-MHZ (12-30 MHz available) rotating transducer that can be inserted together with or without a guide sheath through the working channel (2.0 2.8mm) of a standard flexible bronchoscope. The transducer rotates and produces a 360-degree circular image around the central position of the probe. There are two types of radial EBUS probes: "peripheral" probes, used to identify parenchymal lung lesions, and "central" probes, with balloon sheaths, used for the assessment of airway walls and peribronchial lymph nodes. PMID- 30421898 TI - The Empowering Opportunities of NCNA's Leadership Academy. PMID- 30421899 TI - Legislative Update: Long Session Preview & Election Fallout. PMID- 30421900 TI - NC Nurses PAC: Keep Up the Pressure. PMID- 30421901 TI - In the Eye of the Storm. PMID- 30421902 TI - Beyond the Bedside: Nurses as Social Justice Advocates. PMID- 30421903 TI - Margaret Dolan -- National Nursing Leader. PMID- 30421904 TI - Dedicated Education Unit for Clinical Learning. PMID- 30421905 TI - Enhancing the Selectivity of H2O2 Electrogeneration by Steric Hindrance Effect. AB - Selective hydrogen peroxide (H2O2) electrogeneration by oxygen reduction reaction (ORR) is an efficient and promising synthetic method for H2O2 production. Herein, we build a particular inorganic-organic interface to enhance the electrocatalytic selectivity of reduced graphene oxide (rGO) aerogels for H2O2 electrogeneration by modifying rGO aerogels with polyethyleneimine (PEI). The three-dimensional porous structure of aerogels and the steric hindrance effect of PEI on rGO endow PEI-functionalized rGO (rGO/PEI) aerogels with enhanced selectivity (90.7%), production rate (106.4 mmol gcat-1 h-1), and durability for H2O2 electrogeneration by the two-electron pathway of ORR. PMID- 30421906 TI - Edge-Functionalized Graphene Nanoribbon Chemical Sensor: Comparison with Carbon Nanotube and Graphene. AB - With growing focus on the use of carbon nanomaterials in chemical sensors, one dimensional graphene nanoribbon (GNR) has become one of the most attractive channel materials, owing to its enhanced conductance fluctuation by quantum confinement effects and dense, abundant edge sites. Due to the narrow width of a basal plane with one-dimensional morphology, chemical modification of edge sites would greatly affect the electrical channel properties of a GNR. Here, we demonstrate for the first time that chemically functionalizing the edge sites with aminopropylsilane (APS) molecules can significantly enhance the sensing performance of the GNR sensor. The resulting APS-functionalized GNR has a sensitivity ((Delta R/ Rb)max) of ~30% at 0.125 ppm nitrogen dioxide (NO2) and an ultrafast response time (~6 s), which are, respectively, 7- and 15-fold enhancements compared to a pristine GNR sensor. This is the fastest and most sensitive gas-sensing performance of all GNR sensors reported. To demonstrate the superiority of the GNR-APS sensor, we compare its sensing performance with that of APS-functionalized carbon nanotube (CNT) and reduced graphene oxide (rGO) sensors prepared in identical synthesis conditions. Very interestingly, the GNR APS sensor exhibited 30- and 93-fold enhanced sensitivity compared to the CNT-APS and rGO-APS sensors. This might be attributed to highly active edge sites with superior chemical reactivity, which are not present in CNT and rGO materials. Density functional theory clearly shows that the greatly enhanced gas response of GNR with edge functionalization can be attributed to the higher electron densities in the highest occupied molecular orbital levels of GNR-APS and incorporation of additional adsorption sites. This finding is the first demonstration of the importance of edge functionalization of GNR for chemical sensors. PMID- 30421907 TI - Paper-Based Origami Photoelectrochemical Sensing Platform with TiO2/Bi4NbO8Cl/Co Pi Cascade Structure Enabling of Bidirectional Modulation of Charge Carrier Separation. AB - A bidirectional modulation of photoinduced charge carrier separation strategy based on TiO2/Bi4NbO8Cl/Co-Pi was proposed in microfluidic paper based photoelectrochemical analytical device (MU-POAD). Perovskite Bi4NbO8Cl with high charge carrier mobility was employed as visible light absorber, sandwiching between electron transporting material (ETM) and hole transporting material (HTM). Paper based TiO2 nanosheet arrays (PTNAs) serve as the ETM to provide a direct pathway for electron transport and Co-Pi works as the HTM to extract holes. Driven by a built-in electric field, the generated electrons of Bi4NbO8Cl are extracted by PTNAs, while holes are drawn toward Co-Pi, achieving efficient carrier separation. Remarkably, it is the first time that the HTM was introduced into MU-POAD to efficiently output holes and enhance the sensitivity. With the aid of ETM and HTM, 2.59 and 14.6 times higher photocurrent density was obtained compared with PTNAs/Bi4NbO8Cl and Bi4NbO8Cl photoelectrode, respectively. Benefiting from this dramatic photocurrent signal, ultrasensitive detection of beta human chorionic gonadotrophin is realized with the linear range of 0.01-3000 IU L-1 and detection limitation of 0.005 IU L-1. This work demonstrates the importance of efficient carrier separation to the sensitivity of MU-POAD and paves the way for developing a high-performance analytical device. PMID- 30421908 TI - Phase-Dependent Fluorescence Quenching Efficiency of MoS2 Nanosheets and Their Applications in Multiplex Target Biosensing. AB - Two-dimensional layered transition-metal dichalcogenide nanosheets have shown great potential in biosensors owing to their unique properties. Here, we exfoliated ultrathin metallic and semiconductive MoS2 nanosheets based on a chemical exfoliation method. We compared the difference of fluorescence quenching efficiency between metallic and semiconductive MoS2 nanosheets. We found that the fluorescence quenching efficiency of MoS2 nanosheets is phase-dependent. The ultrathin metallic MoS2 nanosheets with larger contents of a 1T-phase structure show higher fluorescence quenching efficiency than semiconductive MoS2 nanosheets, which can be ascribed to the higher conductivity of metallic MoS2 nanosheets. On the basis of the excellent fluorescence quenching efficiency of metallic MoS2 nanosheets and their discriminative adsorption toward single-strand DNA and double-strand DNA, a fluorescent biosensor for multiplex detection of DNA was developed. This fluorescent biosensing platform allows simultaneous fluorescence quenching of two single-strand DNA probes labeled with different fluorophores, resulting in multiplex detection of different DNA sequences in one homogeneous solution with high sensitivity. PMID- 30421909 TI - Neuroprotective Efficacy of a Novel Sigma 2 Receptor/TMEM97 Modulator (DKR-1677) after Traumatic Brain Injury. AB - Compounds targeting the sigma 2 receptor, which we recently cloned and showed to be identical with transmembrane protein 97 (?2R/TMEM97), are broadly applicable therapeutic agents currently in clinical trials for imaging in breast cancer and for treatment of Alzheimer's disease and schizophrenia. These promising applications coupled with our previous observation that the ?2R/TMEM97 modulator SAS-0132 has neuroprotective attributes and improves cognition in wild type mice, suggests that modulating ?2R/TMEM97 may also have therapeutic benefits in other neurodegenerative conditions, such as traumatic brain injury (TBI). Herein, we report that DKR-1677, a novel derivative of SAS-0132 with increased affinity and selectivity for ?2R/Tmem97 (Ki = 5.1 nM), is neuroprotective after blast-induced and controlled cortical impact (CCI) TBI in mice. Specifically, we have discovered that treatment with DKR-1677 decreases axonal degeneration after blast induced TBI, and it enhances survival of cortical neurons and oligodendrocytes after CCI injury. Furthermore, treatment with DKR-1677 preserves cognition in the Morris water maze after blast-TBI. Our results support an increasingly broad role for ?2R/Tmem97 modulation in neuroprotection and suggest a new approach for treating patients suffering from TBI. PMID- 30421910 TI - Ten Years with New Delhi Metallo-beta-lactamase-1 (NDM-1): From Structural Insights to Inhibitor Design. AB - The worldwide emergence of New Delhi metallo-beta-lactamase-1 (NDM-1) as a carbapenemase able to hydrolyze nearly all available beta-lactam antibiotics has characterized the past decade, endangering efficacious antibacterial treatments. No inhibitors for NDM-1 are available in therapy, nor are promising compounds in the pipeline for future NDM-1 inhibitors. We report the studies dedicated to the design and development of effective NDM-1 inhibitors. The discussion for each agent moves from the employed design strategy to the ability of the identified inhibitor to synergize beta-lactam antibiotics. A structural analysis of NDM-1 mechanism of action based on selected X-ray complexes is also reported: the intrinsic flexibility of the binding site and the comparison between penicillin/cephalosporin and carbapenem mechanisms of hydrolysis are evaluated. Despite the valuable progress in terms of structural and mechanistic information, the design of a potent NDM-1 inhibitor to be introduced in therapy remains challenging. Certainly, only the deep knowledge of NDM-1 architecture and of the variable mechanism of action that NDM-1 employs against different classes of substrates could orient a successful drug discovery campaign. PMID- 30421911 TI - Self-Assembled Sandwich-like MXene-Derived Nanocomposites for Enhanced Electromagnetic Wave Absorption. AB - Sandwich-like MXene/Fe3O4 and C/TiO2/alpha-Fe two-dimensional (2D) nanocomposites were fabricated via in situ hydrothermal assembly of Fe3O4 nanoparticles on MXene nanosheets and postannealing. The as-prepared sandwich-like MXene/Fe3O4 nanocomposites contain uniformly distributed Fe3O4 nanoparticles between the interlayers of the 2D MXene Ti3C2T x nanoflakes. The redox reaction, Ti3C2T x + Fe3O4 -> 3TiO2 + 2C + 3Fe, has also been reported for the first time to transform the binary MXene/Fe3O4 nanocomposites into ternary C/TiO2/alpha-Fe nanocomposites with the 2D structure maintained intact. Such a transition during postannealing gives rise to further enhanced electromagnetic wave absorption compared with that of the MXene/Fe3O4 nanocomposites on top of the already improved performance of the MXene/Fe3O4 compared with that of pristine MXene. The 2D C/TiO2/alpha-Fe nanocomposites exhibit effective absorption bandwidths of 3.3 and 3.5 GHz at thicknesses of 1 and 1.5 mm, respectively. This work offers a new route for fabricating novel electromagnetic wave absorbers, and the fine balance among lightweight, broad band, and small thickness of the C/TiO2/alpha-Fe nanocomposites makes them promising in the field of electromagnetic wave absorption. PMID- 30421912 TI - Metallothermic Reduction of Molten Adduct [PCl4+][AlCl4-] at 50 degrees C to Amorphous Phosphorus or Crystallized Phosphides. AB - A molten salt metallothermic reduction strategy is developed for preparing phosphorus (P) or phosphides controllably at low temperature, which is simple, energy-saving, and easy to scale up. Typically, synthesis of spongelike porous amorphous P (a-P) is realized through reduction of PCl5 with Zn (or Al) at 50 degrees C assisted by AlCl3. It is demonstrated that an adduct salt PCl5.AlCl3 composed of PCl4+ and AlCl4- ions with a low melting point below 50 degrees C is formed from covalent salts PCl5 and AlCl3. This system is also suitable for producing nanostructured phosphides by adding corresponding transition-metal (Co, Fe, and Cu) chlorides even at 50 degrees C. As a Li storage anode, the as prepared a-P exhibits a capacity of 1605 mA h g-1 at 0.2 C, a good rate capability of 1283 mA h g-1 at 10 C, and a long-term cycling stability of 1082 mA h g-1 after 200 cycles. Additionally, the Na-/K-ion storage performance is investigated systematically. PMID- 30421913 TI - Off-the-Shelf Biomimetic Graphene Oxide-Collagen Hybrid Scaffolds Wrapped with Osteoinductive Extracellular Matrix for the Repair of Cranial Defects in Rats. AB - Hydrogels such as type I collagen (COL) have been widely studied in bone tissue repair, whereas their weak mechanical strength has limited their clinical application. By adding graphene oxide (GO) nanosheets, researchers have successfully improved the mechanical properties and biocompatibility of the hydrogels. However, for large bone defects, the osteoinductive and cell adhesion ability of the GO hybrid hydrogels need to be improved. Mesenchymal stem cell (MSC) secreted extracellular matrix (ECM), which is an intricate network, could provide a biomimetic microenvironment and functional molecules that enhance the cell proliferation and survival rate. To synergize the advantages of MSC-ECM with GO-COL hybrid implants, we developed a novel ECM scaffold construction method. First, an osteoinductive extracellular matrix (OiECM) was created by culturing osteodifferentiated bone marrow mesenchymal stem cells (BMSCs) for 21 days. Then, the GO-COL scaffold was fully wrapped with the OiECM to construct the OiECM-GO COL composite for implantation. The morphology, physical properties, biocompatibility, and osteogenic performance of the OiECM-GO-COL implants were assessed in vitro and in vivo (5 mm rat cranial defect model). Both gene expression and cell level assessments suggested that the BMSCs cultured on OiECM GO-COL implants had a higher proliferation rate and osteogenic ability compared to the COL or GO-COL groups. In vivo results showed that the OiECM-GO-COL implants achieved better repair effects in a rat critical cranial defect model, whereas bone formation in other groups was limited. This study provides a promising strategy, which greatly improves the osteogenic ability and biocompatibility of the GO hydrogels without the procedure of seeding and culturing MSCs on scaffolds in vitro, demonstrating its potential as an off-the shelf method for bone tissue engineering. PMID- 30421914 TI - HDAC1 Substrate Profiling using Proteomics-Based Substrate Trapping. AB - Histone Deacetylase (HDAC) proteins are overexpressed in multiple diseases, including cancer, and have emerged as anticancer drug targets. HDAC proteins regulate cellular processes, such as cell cycle, apoptosis, and cell proliferation, by deacetylating histone and non-histone substrates. Although a plethora of acetylated proteins have been identified using large-scale proteomic approaches, the HDAC proteins responsible for their dynamic deacetylation are poorly studied. For example, few substrates of HDAC1 have been identified, which is mainly due to the scarcity of the substrate identification tools. We recently developed a mutant trapping strategy to identify novel substrates of HDAC1. Herein, we introduce an improved version of the trapping method that uses mass spectrometry-based proteomics to identify multiple substrates simultaneously. Among the substrate hits, CDK1, AIFM1, MSH6 and RuvB-Like1 were identified as likely HDAC1 substrates. These newly discovered HDAC1 substrates are involved in various biological processes, suggesting novel functions of HDAC1 apart from epigenetics. Substrate trapping combined with MS-based proteomics provides an efficient approach to HDAC1 substrate identification and contributes to the full characterization of HDAC function in normal and disease states. PMID- 30421915 TI - Mechanisms of the Ethynyl Radical Reaction with Molecular Oxygen. AB - The ethynyl radical, *C2H, is a key intermediate in the combustion of various alkynes. Once produced, the ethynyl radical will rapidly react with molecular oxygen to produce a variety of products. This research presents the first comprehensive high level theoretical study of the reaction of the *C2H (2Sigma+) radical with molecular oxygen (3Sigmag-). Correlation methods as complete as CCSDT(Q) were used; basis sets as large as cc-pV6Z were adopted. Focal point analysis was employed to approach relative energies within the bounds of chemical accuracy (<=1 kcal mol-1). Two dominate reaction pathways from the ethynyl peroxy radical include oxygen-oxygen cleavage from the ethynyl peroxy radical that is initially formed to produce HCCO (2A") and O (3P) and an isomerization of the ethynyl peroxy radical to eventually yield HCO (2A') and CO (1Sigma+). The branching ratio between these two competitive reaction pathways was determined to be 1:1 at 298 K. Minor reaction pathways leading to the production of CO2 (1Sigmag+) and CH (2Pi, 4Sigma-, 2Delta) were also characterized. The absence of CCO (3Sigma-) and OH (2Pi) was explained in terms competition with more accessible reaction pathways. PMID- 30421916 TI - Lewis Acid Catalyzed Dynamic Kinetic Asymmetric Transformation of Racemic N Sulfonylaziridines. AB - The first Lewis acid catalyzed stereoconvergent transformation of racemic 2 (hetero)aryl- N-sulfonylaziridines via C-N bond cleavage with nucleophiles is presented. This includes the [3 + 2] annulations with (hetero)aromatic aldehydes and 1,3-disubstituted indoles, asymmetric Friedel-Crafts type reaction with electron-rich (hetero)arenes, and asymmetric aminolysis with amines, providing facile access to chiral 1,3-isoxazolidines, pyrroloindolines, 2 (hetero)arylphenethylamines, and vicinal diamines. This method features a simple and cheaply available complex of Cu(I)-chiral BINAP catalyst, excellent yield and high diastereo- and enantioselectivities, and mild reaction conditions. A mechanism involving type I dynamic kinetic asymmetric transformations (DyKATs) of the racemic aziridines is proposed based on the results of control experiments. PMID- 30421917 TI - Late-Stage Aromatic C-H Oxygenation. AB - Synthetic methods for oxidative aromatic C-O bond formation are sparse, despite their demand in metabolite synthesis for drug discovery and development. We report a novel methodology for late-stage C-O bond formation of arenes. The reaction proceeds with excellent functional group tolerance even for highly functionalized substrates. The resulting aryl mesylates provide access to potential human metabolites of pharmaceuticals, and may be used directly to install a C-F bond to block metabolic hotspots. A charge-transfer interaction between the reagent bis(methanesulfonyl) peroxide and the substrate arenes may be relevant for the chemoselective functionalization of arenes over other functional groups. PMID- 30421918 TI - Planar Benzo[1,2-b:4,5-b']dithiophene Derivatives Decorated with Nitronyl- and Imino-Nitroxides. AB - Four weakly antiferromagnetic interacting biradicals of benzo[1,2-b:4,5 b']dithiophene (BDT), and BDT extended with two thiophenes (BDTTh2) linked with nitronyl- and imino-nitroxides (NN and IN) as BDT-NN, BDT-IN, BDTTh2-NN and BDTTh2-IN were designed synthesized and characterized. Short inter-molecular pi pi distances were found (3.42 A) for BDT-NN whereas larger ones for BDT-IN (3.54 A) and BDTTh2-NN (3.67 A), respectively. Intra-molecular magnetic interaction (Jintra,exp/kB) of BDT-NN (-26 K) is much larger than for BDT-IN (-5.3 K), while it is reduced for the dithiophene extended molecule BDTTh2-NN (-2.3 K). Inter molecular interactions (zJinter,exp/kB) of BDT-NN (-6.5 K) and BDT-IN (-6.0 K) are stronger than for BDTTh2-NN (-4.6 K). Such large intermolecular couplings resulting from good ?-stacking mark BDT-IN and BDTTh2-NN highlight for well promising crystalline materials with similar sized Jintra and Jinter. In addition, we also extracted a coupling within the chain of Jchain/kB = -2.2 K and a coupling between the chains of zJinter-chain = -1.5 K for BDTTh2-NN by a Heisenberg chain model. Intra- and inter-molecular interactions and spin densities were examined by DFT studies. PMID- 30421919 TI - Functionalized-ZnO-Nanoparticle Seed Treatments to Enhance Growth and Zn Content of Wheat ( Triticum aestivum) Seedlings. AB - This study investigated the potential of ZnO-nanoparticle (NP) seed treatments for enhancing Zn nutrition in wheat ( Triticum aestivum). We tested bare, ZnO core Zn3(PO4)2 shell, dextran (DEX)-coated, and dextran sulfate (DEX(SO4))-coated ZnO NPs and ZnSO4 solution as an ionic control. We measured root and shoot Zn concentrations, lengths, biomasses, and seed germination upon termination of the assay. All ZnO NPs were more effective than ZnSO4 in increasing tissue Zn concentrations and seedling growth. Exposure to higher concentrations of ZnSO4 significantly decreased growth and germination rates relative to those of the controls and the ZnO-NP groups, whereas none of the ZnO NPs significantly affected seed germination. Bare and DEX-ZnO NPs increased Zn concentrations in wheat without decreasing growth. The results of this study demonstrated that ZnO NPs can be used as an effective seed treatment to enhance both Zn nutrition and plant growth. PMID- 30421920 TI - Metabolic Mechanism of Aryl Phosphorus Flame Retardants by Cytochromes P450: A Combined Experimental and Computational Study on Triphenyl Phosphate. AB - Understanding metabolic mechanisms is critical and remains a difficult task in the risk assessment of emerging pollutants. Triphenyl phosphate (TPHP), a widely used aryl phosphorus flame retardant (aryl-PFR), has been frequently detected in the environment, and its major metabolite was considered as diphenyl phosphate (DPHP). However, knowledge of the mechanism for TPHP leading to DPHP and other metabolites is lacking. Our in vitro study shows that TPHP is metabolized into its diester metabolite DPHP and mono- and dihydroxylated metabolites by cytochromes P450 (CYP) in human liver microsomes, while CYP1A2 and CYP2E1 isoforms are mainly involved in such processes. Molecular docking gives the conformation for TPHP binding with the active species Compound I (an iron IV-oxo heme cation radical) in specific CYP isoforms, showing that the aromatic ring of TPHP is likely to undergo metabolism. Quantum chemical calculations have shown that the dominant reaction channel is the O-addition of Compound I onto the aromatic ring of TPHP, followed by a hydrogen-shuttle mechanism leading to ortho hydroxy-TPHP as the main monohydroxylated metabolite; the subsequent H abstraction-OH-rebound reaction acting on ortho-hydroxy-TPHP yields the meta- and ipso-position quinol intermediates, while the former of which can be metabolized into dihydroxy-TPHP by fast protonation, and the latter species needs to go through type-I ipso-substitution and fast protonation to be evolved into DPHP. We envision that the identified mechanisms may give inspiration for studying the metabolism of several other aryl-PFRs by CYP. PMID- 30421921 TI - Directed Copper-Catalyzed Intermolecular Heck-Type Reaction of Unactivated Olefins and Alkyl Halides. AB - A new type of intermolecular alkylative olefination of unactivated olefins and alkyl halides has been realized for the first time. This copper-promoted Heck type reaction employs a directing-group strategy to efficiently produce the coupled alkyl olefin products with excellent regio- and stereoselectivity. A broad substrate scope including 1 degrees , 2 degrees , and 3 degrees alkyl bromides and various nonactivated alkenes could be well tolerated. DFT calculations disclosed a dimethyl sulfoxide assisted concerted H-Br elimination process of a conformationally strained Cu(III) cyclic transition state. PMID- 30421922 TI - Correction to "Biocompatibility of Magnetic Resonance Imaging Nanoprobes Improved by Transformable Gadolinium Oxide Nanocoils". PMID- 30421924 TI - Exploration of Reaction Pathways and Chemical Transformation Networks. AB - For the investigation of chemical reaction networks, the identification of all relevant intermediates and elementary reactions is mandatory. Many algorithmic approaches exist that perform explorations efficiently and automatedly. These approaches differ in their application range, the level of completeness of the exploration, as well as the amount of heuristics and human intervention required. Here, we describe and compare the different approaches based on these criteria. Future directions leveraging the strengths of chemical heuristics, human interaction, and physical rigor are discussed. PMID- 30421923 TI - Particle Capture in Solid-State Multipores. AB - Utilization of multiple-channel structure is a promising way of accomplishing high-throughput detections of analytes in solid-state pore sensors. Here we report on systematic investigation of particle capture efficiency in Si3N4 multipore systems of various array configurations. We demonstrated enhanced detection throughput with increasing numbers of pore channels in a membrane. Meanwhile, we also observed significant contributions of the interchannel crosstalk in closely integrated multipores that tended to deteriorate throughput performance by causing shrinkage of the absorption zone via the interference derived weakening of the electric field around the pore orifice. At the same time, the interference-derived electric field distributions were also found to diminish the electroosmotic contributions to the particle capture efficiency. The present findings can be useful in designing pore arrays with optimal throughput performance. PMID- 30421925 TI - Participation of beta-Ketothioamides in N-Heterocyclic Carbene-Catalyzed [3 + 3] Spiroannulation: Asymmetric Synthesis of Functionalized Spiro-piperidinone Derivatives. AB - An N-heterocyclic carbene-catalyzed asymmetric [3 + 3] spiroannulation of beta ketothioamide was successfully developed. beta-Ketothioamides exhibit an unusual reactivity to undergo a previously challenging lactamization reaction, and the desired spiro-piperidinone derivatives containing two vicinal stereogenic centers were synthesized in good to high yields with high stereoselectivities, whose structure can be converted to the corresponding imide and delta-lactam derivatives smoothly. PMID- 30421926 TI - Correction to "Inhibitor Complexes of the Pseudomonas Serine-Carboxyl Proteinase". PMID- 30421927 TI - Minimizing the Abnormal High-Potential Discharge Process Related to Redox Mediators in Lithium-Oxygen Batteries. AB - Nonaqueous lithium-oxygen batteries can achieve a reduced charge potential when an available redox mediator is introduced. However, there are accompanying problems, such as the shuttle effect and the abnormal high-potential discharge process (>2.96 V) after the first cycle. The shuttle effect can be addressed by developing a blocking separator or resistant solid electrolyte interphase on the anode. No attention has been paid to the abnormal discharge process. Here, we unravel the underlying mechanism causing the undesired abnormal phenomenon. Our results show that the slow reaction rate between the discharged lithium peroxide and redox mediator and the low yield of lithium peroxide should take primary responsibility for the abnormal discharge issue. The sluggish reaction kinetics results from the formed byproducts covering lithium peroxide. We propose developing redox mediator-containing hydrate-melt lithium-oxygen batteries. The lithium hydroperoxide intermediator shows high reaction activity with the redox mediator and improves battery charge ability, thus solving the abnormal discharge problem. This work sheds light on the further design of lithium-oxygen batteries using a redox mediator. PMID- 30421928 TI - SERS and Cryo-EM Directly Reveal Different Liposome Structures during Interaction with Gold Nanoparticles. AB - The combination of gold nanoparticles with liposomes is important for nano- and biotechnology. Here, we present direct, label-free characterization of liposome structure and composition at the site of its interaction with citrate-stabilized gold nanoparticles by surface-enhanced Raman scattering (SERS) and cryogenic electron microscopy (cryo-EM). Evidenced by the vibrational spectra and cryo-EM, the gold nanoparticles destroy the bilayer structure of interacting liposomes in the presence of a high amount of citrate, while at lower citrate concentration the nanoparticles interact with the surface of the intact liposomes. The spectra of phosphatidylcholine and phosphatidylcholine/sphingomyelin liposomes show that at the site of interaction the lipid chains are in the gel phase. The SERS spectra indicate that cholesterol has strong effects on the contacts of the vesicles with the nanoparticles. By combining cryo-EM and SERS, the structure and properties of lipid-nanoparticle composites could be tailored for the development of drug delivery systems. PMID- 30421929 TI - Vlasoulamine A, a Neuroprotective [3.2.2]Cyclazine Sesquiterpene Lactone Dimer from the Roots of Vladimiria souliei. AB - Vlasoulamine A (1), an unprecedented sesquiterpene lactone dimer featuring a fully hydrogenated pyrrolo[2,1,5- cd]indolizine core, and vlasoulones A and B (2 and 3), a pair of epimeric dimers formed from a proposed Diels-Alder [4 + 2] cycloaddition between a germacrane sesquiterpene lactone and a eudesmane sesquiterpene, were isolated from the roots of Vladimiria souliei. Their structures and absolute configurations were established by NMR, MS, and single crystal X-ray spectroscopic analysis. Moreover, 1 exhibited neuroprotective activity when evaluated for glutamate-induced cytotoxicity, nuclear Hoechst 33258 staining, and measuring intracellular reactive oxygen species levels, using a rat pheochromocytoma PC12 cell-based model system. PMID- 30421930 TI - Effect of Fluoride Treatment on the Acid Resistance of Hydroxyapatite. AB - The etching behavior of polycrystalline synthetic hydroxyapatite samples has been evaluated to explore the protective impact of fluoride on a tooth-like model system. Etching rates before and after fluoridation with a NaF solution at pH 6 were determined by atomic force microscopy. Despite a very low F concentration of ca. 0.2 atom % in the hydroxyapatite surface, a very strong effect on the acid resistance can be observed. Depending on the crystal orientation, etching in a NaAc buffer at pH 4.5 was completely inhibited for at least 5 min. The major part of the surface withstood etching even for more than 23 min. These results give new insights into how the amount of incorporated fluoride in hydroxyapatite correlates with its protective impact. PMID- 30421931 TI - Native Chemical Ligation at Serine Revisited. AB - Standard conditions for the formation of seryl-cysteinyl junctions by Native Chemical Ligation (NCL) can result in significant epimerization of the serine residue. Epimerization can be minimized to background level by adjusting peptide concentration and working at 4 degrees C. PMID- 30421932 TI - Controllable Self-Assembly of Pills and Cages via Imine Condensation for Silver Cation Detection. AB - By condensing a trisamino linker with one of the two analogous bisaldehyde ligands, pills and tetrahedrons could be self-assembled. The self-assembled preference could be controlled by tuning the reaction conditions, including the size of side chain, concentration, and temperature. Coordination of silver cation quenches the fluorescence of the fluorene moieties on the pill, opening up opportunities for Ag+ cation detection. PMID- 30421933 TI - Silk Molecular Weight Influences the Kinetics of Enzymatically Cross-linked Silk Hydrogel Formation. AB - We transform reconstituted silk solutions into robust hydrogels through covalent dityrosine cross-linking resulting from an enzymatic reaction. The bulk rheological properties and the covalent dityrosine bond formation of these gels are measured during polymerization. We compare the time-resolved bond formation to the mechanical properties, where we find that the gelation process is consistent with a model of percolation. The molecular weight of the protein determines whether a secondary mode of growth postpercolation exists, indicating that molecular weight changes affect the mechanisms by which these gels polymerize. PMID- 30421934 TI - Magnetic Field-Driven Convection for Directed Surface Patterning of Colloids. AB - Drying sessile droplets is a promising route to transform colloidal dispersions into surface coatings, which are widely used in material design and biochemical detection. However, directing the assembly of the particles within drying droplets and achieving surface patterns beyond the well-known coffee-ring formation remain a challenge. Here, we present a new principle of directing the assembly of nonmagnetic colloidal particles dispersed in a magnetic fluid and generating unusual surface patterns. We use the ability of ferrofluids to change phases with the application of magnetic fields to program the assembly of nonmagnetic microparticles present in drying sessile droplets. We show that in the absence of external magnetic field, the superparamagnetic nanoparticles in the magnetic fluid are spontaneously transported to the droplet edge because of solvent evaporation. This nanoparticle transport leads to the formation of nanoparticle-rich edge and nanoparticle-depleted center of the drying droplet. Upon the application of a uniform external magnetic field, the asymmetry in the magnetic nanoparticle distribution drives a magnetostatic convection and finger like instability from the droplet edge to the center. This magnetic microconvection from droplet edge-to-center reverses the particle transport from center-to-edge, well-known for drying droplets in the absence of external field. We use this magnetostatic microconvection to assemble secondary nonmagnetic microspheres in droplets, overwriting ring formation and direct their assembly into four distinct kinetically stable states. The method presented here offers an active control over the colloidal assembly achieved by drying sessile droplets and thus enables a new route for fabricating complex patterns and functional surface coating. PMID- 30421935 TI - Copper-Catalyzed Three-Components Intermolecular Alkylesterification of Styrenes with Toluenes and Peroxyesters or Acids. AB - A simple protocol for the three-component intermolecular alkylesterification of styrenes with toluenes and peroxyesters using a copper catalyst is described. A variety of ester-containing complex compounds were synthesized with excellent functional group tolerance and step efficiency. Employing the combination of carboxylic acids and di- tert-butyl peroxide (DTBP) oxidant instead of peroxyesters also gave similar results. In this transformation, aromatic acids, aliphatic acids, and amino acids were suitable substrates. PMID- 30421936 TI - Determination of Internal Density Profiles of Smart Acrylamide-Based Microgels by Small-Angle Neutron Scattering: A Multishell Reverse Monte Carlo Approach. AB - The internal structure of nanometric microgels in water has been studied as a function of temperature, cross-linker content, and level of deuteration. Small angle neutron scattering from poly( N-isopropylmethacrylamide) (volume phase transition ~ 44 degrees C) microgel particles of radius well below 100 nm in D2O has been measured. The intensities have been analyzed with a combination of polymer chain scattering and form-free radial monomer volume fraction profiles defined over spherical shells, taking polydispersity in size of the particles determined by atomic force microscopy into account. A reverse Monte Carlo optimization using a limited number of parameters was developed to obtain smoothly decaying profiles in agreement with the experimentally scattered intensities. The results are compared to the swelling curve of microgel particles in the temperature range from 15 to 55 degrees C obtained from photon correlation spectroscopy (PCS). In addition to hydrodynamic radii measured by PCS, our analysis provides direct information about the internal water content and gradients, the strongly varying steepness of the density profile at the particle-water interface, the total spatial extension of the particles, and the visibility of chains. The model has also been applied to a variation of the cross linker content, N, N'-methylenebisacrylamide, from 5 to 15 mol %, providing insight on the impact of chain architecture and cross-linking on water uptake and on the definition of the polymer-water interface. The model can easily be generalized to arbitrary monomer contents and types, in particular mixtures of hydrogenated and deuterated species, paving the way to detailed studies of monomer distributions inside more complex microgels, in particular core-shell particles. PMID- 30421937 TI - Collaborating With the Perinatal Team for Optimal Oral Health Before, During, and After a Healthy Pregnancy. AB - Collaboration with other health professionals can be challenging when attempting to coordinate healthcare before, during, and after pregnancy. However, advantages of interdisciplinary and interprofessional collaborative approaches include facilitation of accurate and timely diagnosis and optimally sequenced treatment for improved health outcomes. This article reviews the current guidelines fostering collaboration between dental professionals and members of the perinatal team and identifies the roles of healthcare providers to support the care of women around the time of pregnancy. Recognizing the maternal oral changes that occur during pregnancy will enable providers to effectively offer diagnosis and referral and organize and deliver comprehensive care. The article discusses how complementing medical care with early professional dental care can help reduce unplanned, expensive "emergency" treatment and describes the concepts of medical and dental homes. PMID- 30421938 TI - The Need to Replace a Missing Second Molar With a Dental Implant Restoration: Analysis of a Controversial Issue. AB - Whether or not a second molar should be replaced after its removal is debatable. To assess the evidence and discuss the pros and cons of replacing a missing second molar with a dental implant restoration, the authors searched the literature for articles that evaluated the following factors: chewing efficiency, tooth loss, super-eruption, extrusion, over-eruption, and occlusal interferences. The data indicated that replacing a second molar provides some increased masticatory performance, but first-molar occlusion facilitates 90% chewing efficiency. Super-eruption of unopposed posterior teeth occurs frequently, and approximately 20% of these teeth extrude 2 mm, but the degree of over-eruption is not strongly related to the incidence of occlusal interferences. It was concluded that after a patient/dentist discussion regarding second-molar replacement, it is the patient's preference that usually dictates the decision. In this regard, if a patient perceives a chewing deficiency or dislikes having a gap in his or her dentition after the loss of a second molar, the tooth could be replaced with an implant-supported restoration. However, if the patient does not recognize any reduced masticatory efficiency, replacement of a second molar typically is unnecessary. This is due to the findings that most extrusion over time is minor and usually does not affect occlusal function; also, concerns about over-eruption can be managed in a preventive manner, and/or unopposed second molars can be monitored. Nevertheless, super-eruption of teeth can complicate restorative cases. PMID- 30421939 TI - Utilizing Digital Technology to Facilitate Dentofacial Integration. AB - As digital technology evolves, an increasing number of tools are becoming available to improve team communication during the treatment planning and provision of restorative dentistry. The esthetic relationships among the face, teeth, and tissue can be analyzed using high-quality photographs, presentation software, and video capture, all critical elements for cases requiring digital dentofacial integration. Video capture communicates maximum lip movement and tooth reveal during speech with precision and ease. This article demonstrates predictable and successful use of these digital tools to enhance dentist-to laboratory communication in an esthetically challenging case. In the age of digital dentistry, many protocols that clinicians have traditionally performed manually are being facilitated by newer, technologically advanced resources, making restorative procedures faster, simpler, and more dimensionally comprehensive. Use of video and presentation software is an effective method to communicate desired outcomes to the laboratory and allows the clinician to preoperatively plan the smile design and visualize treatment outcomes prior to treatment initiation. PMID- 30421940 TI - Measurement of the "Bungee Dip" in Implant Stability Using Resonance Frequency Analysis: Two Case Reports. AB - Implant stability is a key consideration when determining the point in time a dental implant should be loaded. Often a change in implant stability is observed as healing progresses from initial mechanical stability to biologic stability, ie, osseointegration, during the bone modeling/remodeling process. This change in stability can be objectively measured using resonance frequency analysis (RFA). Because bone healing varies from patient to patient, the timing of this sequence may be unpredictable; in a small subset of patients the drop in implant stability can be quite precipitous and profound. Such a drop is referred to as a "bungee dip." If the implant is loaded too prematurely, it may fail due to inadequate healing. This article presents two case reports that demonstrate the use of RFA and its values, known as implant stability quotients, to monitor implant stability during healing. RFA is a form of personalized care that provides objective evidence that can guide the clinician in establishing safe and successful loading protocols. PMID- 30421941 TI - No-Preparation Veneers: A Minimally Invasive Approach for a Naturally Esthetic Smile. AB - Typically, dentists spend many years training to learn how to prepare teeth for restorations. Whether the restoration comprises a filling, veneer, crown, inlay, onlay, or bridge, teeth often require preparation to allow adequate space to accommodate the thickness of the restorative material. However, dentists may face a dilemma if a patient inquires about receiving an enhanced smile without tooth preparation. In such cases, the dentist needs to determine the optimal course of action for the patient. This also raises the issue of removing enamel, which is perhaps the most prized commodity in the dentition. This article discusses the question of whether to prepare or not to prepare a tooth for restoration and presents a case demonstrating the meticulous use of eight no-preparation porcelain veneers. PMID- 30421942 TI - Ceramic Restorations Flourishing With State-of-the-Art Materials, Methods. PMID- 30421943 TI - Electrical stimulation of alpha oscillations stabilizes performance on visual attention tasks. AB - Neural oscillations in the alpha band (7-13 Hz) have long been associated with reductions in attention. However, recent studies have suggested a more nuanced perspective in which alpha oscillations also facilitate processes of cognitive control and perceptual stability. Transcranial alternating current stimulation (tACS) over occipitoparietal cortex at 10 Hz (alpha-tACS) can selectively enhance EEG alpha power. To assess the contribution of alpha oscillations to attention, we delivered alpha-tACS across 4 experiments while 178 participants performed sustained attention tasks. Poor performance on all visual tasks was previously associated with increased EEG alpha power. We therefore predicted initially that alpha-tACS would consistently impair visual task performance. However, alpha-tACS was instead found to prevent deteriorations in visual performance that otherwise occurred during sham- and 50 Hz-tACS. This finding was observed in 2 experiments, using different sustained attention tasks. In a separate experiment, we also found that alpha-tACS limited improvements on a visual task where learning was otherwise observed. Consequently, alpha-tACS appeared to exert a consistently stabilizing effect on visual attention. Such effects were not seen in an auditory control task, indicating specificity to the visual domain. We suggest that these results are most consistent with the view that alpha oscillations facilitate processes of top-down control and attentional stability. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30421944 TI - Monitoring prediction errors facilitates cognition in action. AB - Cognition in action requires strategic allocation of attention between internal processes and the sensory environment. We hypothesized that this resource allocation could be facilitated by mechanisms that predict sensory results of self-generated actions. Sensory signals conforming to predictions would be safely ignored to facilitate focus on internally generated content, whereas those violating predictions would draw attention for additional scrutiny. During a visual-verbal serial digit-recall task, we varied the temporal relationship between task-irrelevant keypresses and auditory distractors so that the distractors were either temporally coupled or decoupled with keypresses. Consistent with our hypothesis, distractors were more likely to interfere with target maintenance and intrude into working memory when they were decoupled from keypresses, thereby violating action-based sensory predictions. Interference was maximal when sounds preceded keypresses, suggesting that stimuli were most distracting when their timing was inconsistent with expected action-sensation contingencies. In a follow-up experiment, neither auditory nor visual cues to distractor timing produced similar effects, suggesting a unique action-based mechanism. These results suggest that action-based sensory predictions are used to dynamically optimize attentional allocation during cognition in action. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30421945 TI - Exploring the use of Sidekicks! For children with autism spectrum disorder (ASD). AB - Clinicians and educators are increasingly using technology within the context of existing therapies and teaching methodologies. The growing use of mobile clinical tools is particularly exciting for individuals with autism spectrum disorder (ASD), as technologically based interventions have been shown to be both efficacious (to target academics, adaptive behavior, disruptive behavior, etc.) and accepted in this population (Odom et al., 2015). In addition, these tools have the potential to address two significant impediments in ASD intervention, the anxiety and/or skill deficits often associated with face-to-face interactions and skill generalization outside of the therapy office (Wieckowski & White, 2017). In other words, the use of technology may serve as an important preliminary or prerequisite step for face-to-face therapeutic progress. The purpose of this paper is to present a new, interactive clinical app that explicitly utilizes an individual's restricted interests to teach skills and improve communication. The paper will briefly review the ways in which individuals with ASD may be good candidates for technological-based interventions, explore the current role of technology in existing evidence-based therapies, and discuss the use of a new technology, Sidekicks!, that has been developed for this population. A case example will then illustrate the use of Sidekicks! and its anticipated functionality across several public service settings, including hospitals, outpatient clinics, and school systems, thereby coordinating the intervention efforts of various professionals involved in the treatment of children with ASD. Finally, limitations of the app (and of technology more generally) and the need for future research will be discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30421946 TI - Digital methods can help you . . . If you're careful, critical, and not historiographically naive. AB - This special section on the digital history of psychology includes target articles by Ivan Flis and Nees Jan van Eck and Jeremy Trevelyan Burman, with comments by Melinda Baldwin, Ted Porter, and Chris Green. In his introduction to the section, Burman explains his original motivation in turning to tools borrowed from the digital humanities: helping graduate students to identify dissertation topics more easily, and thereby reduce completion times for the doctorate, while at the same time doing "good history." Since then, a new field-digital history of psychology-has blossomed. John Burnham, especially, is recognized here as an important interlocutor. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30421947 TI - A perspective from the history of scientific journals. AB - In their articles for this special issue on digital humanities, Jeremy Burman (2018) and Ivan Flis and Nees Jan van Eck (Flis & van Eck, 2018) examine how psychology journals can be used as sources for large-scale data sets that might illuminate the development of psychology as a research discipline. In my commentary, I seek to situate these two articles in a broader history of scientific publishing and offer further thoughts on the possibilities and pitfalls of data-based methods for the history of scientific publishing. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30421948 TI - Digital humanism. AB - Much history of psychology presumes a discordance between its humanistic methods and the focus on rigorous statistical reasoning that is typical of the field it studies. However, the conditions of abundant data typical of digital humanities tend to relax the constraints of tests of significance and to allow greater freedom to try out alternative interpretations within the frame of a single study. At the same time, the elusiveness of rigorous standardization within a very large database, especially if it stretches over wide spaces or many decades, may be seen to demand meticulous source criticism of a sort that has more often been associated with the humanities than with quantitative science. There is even a tendency for the data itself to drift away from its usual function as a means of research and to become itself an object of study, inspiring reflection on how the tools and concepts of a field like psychology may be evolving in response to new constraints or ambitions. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30421949 TI - Digital history of psychology takes flight. AB - The articles authored by Flis and van Eck (2018) and by Burman (2018) serve as fine examples of the ways in which digital historical methods can illuminate aspects of psychology's past that would probably not be possible otherwise. This success, however, presents no reason to think that digital history is some kind of threat to conventional historiography or that former aims to replace the latter. The two can work complementarily-so closely, in fact, that it sometimes becomes difficult to know which of the two one is practicing at any given moment. Multiple skill sets need not define the historian as being a particular "kind": They just enable any historian to do his or her work more completely than before. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30421950 TI - Digital humanities as the historian's Trojan horse: Response to commentary in the special section on digital history. AB - The commentaries by Baldwin (2018), Green (2018), and Porter (2018) on the 2 articles (Burman, 2018; Flis & Van Eck, 2018) in this special section provide a unique perspective on digital humanities approaches to history of psychology. Each of the commentators approached the topic through their own lens-Melinda Baldwin as a historian of scientific journals, Christopher Green as a pioneer in digital history of psychology, and Ted Porter as a historian of quantification. In my response, I tried to reply to the 3 comments by critically discussing 4 themes the special section has raised: the relationship between digital history and conventional history, the perspective that takes databases as both sources for historians and objects in history, the relationship between "thick descriptions" and "thin" digital ones, and finally, the role of digital history as a type of a "trading creole" between scientists working in quantified disciplines like scientific psychology and less quantified ones like history. I think the commentators have rightly observed some pitfalls in the uncritical application of digital history. On the other hand, in my response, I argue that the careful use of digital methods, where the user stays in communication with nondigital historians, opens new perspectives for historians of science, historians of psychology, and psychologists themselves. Digital methods are not there to supplant historicist work but to add to it and translate it to new audiences. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30421952 TI - Development of the Self-Forgiveness Dual-Process Scale. AB - Progress in the scientific study of self-forgiveness reveals a need for (a) integration of the extant self-forgiveness literature with general psychological theory, (b) development of measures that reflect nuanced conceptualizations of self-forgiveness, (c) better understanding of the impact of self-forgiveness on personal and interpersonal functioning, and (d) development of evidence-based clinical applications of self-forgiveness. Accordingly, we conceptualized self forgiveness within the framework of Social Cognitive Theory and developed the Self-Forgiveness Dual-Process Scale to assess value reorientation (VRO) and esteem restoration (ERS) following perceived interpersonal offense. In Study 1, we identified the hypothesized 2-factor structure in a sample of university students (N = 191). For Study 2, we used an independent sample (N = 100) to replicate the factor structure and provide initial evidence of construct validity by exploring associations of value reorientation and esteem restoration with established measures of self-forgiveness, self-punishment, and self-exoneration. In Study 3, we recruited a third sample (N = 66) to assess contributions of value reorientation and esteem restoration to explain variance in offense-related rumination beyond that explained by an existing measure of state self forgiveness. Overall, findings supported conceptualization of self-forgiveness according to processes of value reorientation and esteem restoration, distinguished self-forgiveness from other responses to wrongdoing, and revealed the unique impacts of value reorientation and esteem restoration on functioning. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30421953 TI - No evidence for strategic nature of age-related slowing in sentence processing. AB - Older adults demonstrate a slower speed of linguistic processing, including sentence processing. In nonlinguistic cognitive domains such as memory, research suggests that age-related slowing of processing speed may be a strategy adopted in order to avoid potential error and/or to spare "cognitive resources." So far, very few studies have tested whether older adults' slower processing speed in the linguistic domain has a strategic nature as well. To fill this gap, we tested whether older adults can maintain language processing accuracy when a faster processing speed is enforced externally. Specifically, we compared sentence comprehension accuracy in younger and older adults when sentences were presented at the participant's median self-paced reading speed versus twice as fast. We hypothesized that an external speed increase will cause a smaller accuracy decline in older than younger adults because older adults tend to adopt self paced processing speeds "further away" from their performance limits. The hypothesis was not confirmed: The decline in accuracy due to faster presentation did not differ by age group. Thus, we found no evidence for strategic nature of age-related slowing of sentence processing. On the basis of our experimental design, we suggest that the age-related slowing of sentence processing is caused not only by motor slowdown, but also by a slowdown in cognitive processing. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30421954 TI - Age-related decline in item but not spatiotemporal associative memory for a real world event. AB - Normal aging is typically associated with reduced ability to reconstruct the spatiotemporal context of past events, a core component of episodic memory. However, little is known about our ability to remember the order of events comprising extended real-world experiences and how this ability changes with age. We leveraged the richness and structure of a museum exhibit to address this question. Three months after visiting the exhibit, 141 adults aged 18-84 completed a test of spatiotemporal order memory and old/new recognition using pictures from the exhibit and similar lures, from which measures of associative and item memory were derived. Order discrimination accuracy was modulated by interitem order and distance in younger and older adults, extending findings from recognition of laboratory stimuli at short delays to remote real-world experiences. In contrast to established findings from laboratory-based assessments, we observed a significant effect of aging on item memory driven by increased lure susceptibility, but no age-related reduction in spatiotemporal associative memory. These findings present novel insights into different components of memory for real-world experiences at naturalistic timescales and across the lifespan. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30421955 TI - Hepatitis B virus in patients with chronic hepatitis C treated with direct antiviral agents. AB - INTRODUCTION: cases of hepatitis B virus (HBV) reactivation have been reported in patients with hepatitis C virus (HCV) treated with direct antiviral agents (DAA). OBJECTIVES AND METHODS: the main objectives of the present study are: a) to determine the prevalence of HBV/HCV coinfection in HCV patients treated with DAAs in the Autonomous Community of Madrid (CM) and also to determine the incidence and clinical relevance of HBV reactivation; and b) to determine the HBV screening rates in HCV patients in our region. For that purpose, 1,337 HCV patients were consecutively treated with DAAs in two hospitals located in South CM between January 2015 and June 2017. RESULTS: nine of the 1,337 (0.67%) participants were HBsAg positive and 356 (26.6%) had previous HBV infection markers. Two of the four (50%) HBsAg positive patients with untreated HBV developed a virological reactivation, but not a biochemical reaction. Of the 356 patients with previous HBV infection markers, all had normal transaminases at the end of treatment and during follow-up. The HBV screening rate amounted to 92.9% of the cohort. CONCLUSIONS: the prevalence of HBV (HBsAg positive) infection in patients with chronic hepatitis C in the southern area of the CM is low. HBV reactivation in HBsAg positive patients treated with DAAs is common, although without clinical relevance. In our region, there is a high rate of HBV screening in patients with HCV that are likely treated with DAAs. PMID- 30421956 TI - Consensus document on exclusion diets in irritable bowel syndrome (IBS). AB - This paper summarizes the contents of a consensus document on exclusion diets in irritable bowel disease that was developed by a task force from SEPD, FEAD, SENPE, FESNAD, SEN, SEEN, SEGHNP, SEDCA and ADENYD. The complete document is available at the SEPD website. Irritable bowel syndrome is a highly prevalent functional digestive disorder where, in addition to drugs, therapy includes diet and acquisition of healthy habits as basic elements for its control. In order to facilitate dietary counseling for these patients in daily practice, the present consensus document on the role of exclusion diets was developed. To this end, consensus opinions were collected from various experts in the national scientific societies aiming at establishing recommendations applicable to the health care of patients with irritable bowel syndrome. PMID- 30421957 TI - Klatskin tumors and "Klatskin-mimicking lesions": our 22-year experience. AB - Background and study purpose: Hilar cholangiocarcinoma, also known as Altemeier Klatskin tumor, is a rare malignancy that arises in the confluence of the hepatic ducts of the porta hepatis. The prognosis is rather poor. Several lesions mimic these tumors and lead to a misdiagnosis, resulting in radical hepatic resections. These lesions are known as Klatskin-mimicking lesions. We present our experience with the diagnosis and treatment of pathological lesions that can mimic a perihilar cholangiocarcinoma and establish an algorithm of treatment Methods: For the current retrospective study, a prospectively established bile-duct tumor database was analyzed by selecting patients with a preoperative diagnosis of perihilar cholangiocarcinoma. Results: In the last 22 years (from January 1, 1996, to December 31, 2017), 73 patients who were referred to our tertiary center with a primary diagnosis of a Klatskin tumor were treated. All patients underwent a thorough evaluation before deciding upon the treatment. However, only 58 cases had a confirmed preoperative diagnosis of hilar cholangiocarcinoma in the final histopathological examination. The final diagnosis in 15 patients differed from the primary cause for referral and the lesions were regarded as Klatskin mimicking lesions. Conclusions: Clinicians should always highly suspect Klatskin mimicking lesions when they evaluate a patient for a possible hilar cholangiocarcinoma in order to avoid a misdiagnosis and propose a proper treatment. PMID- 30421958 TI - Perforated emphysematous cholecystitis and Streptococcus bovis. AB - Streptococcus bovis is an uncommon cause of biliary tract infection, being acute cholecystitis including this microorganism extremely rare. This entity is more frequent in older patients with cardiovascular disease, diabetes, hepatitis, or neoplasms as colon cancer. PMID- 30421959 TI - Endoscopic sump syndrome secondary to EUS-guided choledocho-duodenostomy with a lumen-apposing metal stent. AB - Sump syndrome (SS) is associated with choledocho-duodenostomy (CDD) dysfunction, which occurs due to accumulation of detritus, biliary mud and food remains in the suprapapillary distal common bile duct. The prevalence is low after CDD. Currently, biliary drainage endoscopic ultrasound (EUS)-guided with a lumen apposing metal stent (LAMS) is a new minimally invasive alternative for biliary stenosis for patients in whom endoscopy retrograde cholangial-pancreatography (ERCP) is not feasible. CDD via EUS-guided LAMS is increasing. Thus, SS has become a potential associated complication that was previously unreported in the literature. PMID- 30421960 TI - The effects of resveratrol intake on weight loss: a systematic review and meta analysis of randomized controlled trials. AB - This systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to summarize the effect of resveratrol intake on weight loss. We searched the following databases until July 2018: MEDLINE, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials. Data were pooled using the inverse variance method and expressed as standardized mean difference (SMD) with 95% confidence intervals (95% CI). Out of 831 reports, 36 RCTs were eligible for including to our meta-analysis. The pooled results, using random-effects model showed that resveratrol supplementation significantly decreased body weight (SMD = -0.17; 95% CI, -0.33, -0.01; P = 0.03; I2: 62.6), body mass index (BMI) (SMD = 0.20; 95% CI, -0.35, -0.05; P = 0.01; I2: 60.6), fat mass (SMD = -0.32; 95% CI, 0.62, -0.03; P = 0.03; I2: 77.9) and waist circumference (WC) (SMD = -0.42; 95% CI, -0.68, -0.16; P = 0.001; I2: 75.2), and significantly increased lean mass (SMD = 1.21; 95% CI, 0.75, 1.67; P < 0.001; I2: 87.6). We found no significant effect of resveratrol administration on leptin (SMD = -0.20; 95% CI, -0.68, 0.27; P = 0.40; I2: 85.3) and adiponectin levels (SMD = 0.08; 95% CI, -0.39, 0.55; P = 0.74; I2: 91.0). Resveratrol supplementation significantly decreased body weight in obese patients (SMD -0.43; 95% CI, -0.60, -0.26) compared with other diseases (SMD 0.02; 95% CI, -0.29, 0.33), and type 2 diabetes mellitus (SMD -0.17; 95% CI, -0.37, 0.02). Overall, the current meta-analysis demonstrated that resveratrol intake significantly reduced weight, BMI, WC and fat mass, and significantly increased lean mass, but did not affect leptin and adiponectin levels. PMID- 30421961 TI - Implementation of a supervised exercise therapy programme. AB - INTRODUCTION: Guidelines for peripheral vascular disease state that supervised exercise therapy (SET) programmes improve walking distance and quality of life in patients with intermittent claudication. This paper outlines the steps needed to implement a successful SET programme and discusses some of the challenges. METHODS: Edinburgh Leisure was approached to coordinate an exercise programme aimed at rehabilitation, run by level 4 members of the Register of Exercise Professionals. It is estimated to be cost effective at 500 referrals compared with physiotherapy referral. Success is measured by walking distance, reduction of symptoms and weight loss. Edinburgh Leisure also measures success with feedback and membership numbers at its health centres. RESULTS: Between 4 March 2014 and 25 January 2016, 155 patients were referred to the SET programme with a median age of 68 years (range: 39-95 years) and a male-to-female ratio of 1.2:1. Of these, 117 patients attended and 29 have completed the programme. The mean walking distance increased from 298.5m (range: 150-385m) to 360m (range: 195 482m), an improvement of 20%. Increasing class numbers and venues, and introducing evening classes to make the programme accessible to more patients has addressed initial patient engagement issues. CONCLUSIONS: Collaboration with motivated local authorities can help implement a successful healthcare intervention. Early analysis is necessary to improve the system and engage as many patients as possible. The SET programme discussed has shown similar results to those of previous studies but is available at no personal cost to regional patients with intermittent claudication. PMID- 30421962 TI - Physiological responses to central and peripheral injection of polyinosinic polycytidylic acid in chicks. AB - 1. The purpose of the present study was to determine if intracerebroventricular (ICV) and intraperitoneal (IP) injection of polyinosinic-polycytidylic acid (poly I:C), a viral mimetic that binds to toll-like receptor-3 (TLR3), affects food intake, voluntary activity, cloacal temperature, plasma corticosterone (CORT) and glucose concentrations, and crop emptying rate in chicks (Gallus gallus). 2. Both ICV and IP injection of poly I:C significantly decreased food intake. 3. IP but not ICV injection of poly I:C significantly suppressed voluntary activity, whereas ICV injection decreased time spent sitting. Both ICV and IP injection of poly I:C significantly increased plasma CORT and glucose concentration. Neither ICV nor IP injection of poly I:C significantly affected cloacal temperature. 4. In addition, ICV injection of poly I:C significantly reduced crop emptying rate, whereas IP injection had no effect. 5. These results suggested that central TLR3 is related to anorexia, stress response and retardation of crop emptying while peripheral TLR3 is related to anorexia, change in behaviour and stress responses during viral infection in chicks. PMID- 30421963 TI - EXPRESS: Measurement of Laser-Induced Plasma: Stark Broadening Parameters of Pb(II) 2203.5 and 4386.5 A Spectral Lines. PMID- 30421964 TI - Chemically characterised Pimenta dioica (L.) Merr. essential oil as a novel plant based antimicrobial against fungal and aflatoxin B1 contamination of stored maize and its possible mode of action. AB - The chemical characterisation of Pimenta dioica essential oil (PDEO) revealed the presence of 50 components, amongst which alpha-Terpineol (30.31%) was the major component followed by beta-Linalool (6.75%) and gamma-Terpinene (4.64%). The oil completely inhibited the growth of aflatoxin B1 secreting strain Aspergillus flavus LHP-VS-8 and aflatoxin B1 production at 2.5 uL/mL and 1.5 uL/mL, respectively. The oil caused dose dependent reduction of methylglyoxal (an AFB1 inducer), enhanced leakage of Ca2+, Mg2+ and K+ ions and significantly reduced ergosterol content of fungal plasma membrane. During in situ experiments, PDEO exhibited complete protection of fumigated maize cob slices from fungal infestation without affecting seed germination. The chemically characterised PDEO is recommended as a plant based preservative and shelf life enhancer of food commodities by preventing fungal growth, AFB1 production and lipid peroxidation. This is the first report on PDEO as inhibitor of AFB1 secretion and methylglyoxal biosynthesis.[Formula: see text]. PMID- 30421965 TI - Psychometric Properties of the Pediatric Acute-Onset Neuropsychiatric Syndrome Global Impairment Score in Children and Adolescents with Pediatric Acute-Onset Neuropsychiatric Syndrome. AB - OBJECTIVES: This study validates the caregiver-rated Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) Global Impairment Score (GIS), a single-item, 0 100 scale, for use in PANS. METHODS: We collected longitudinal data from community patients meeting PANS criteria. We included 128 patients with 1926 GISs, each from a unique clinic visit. To assess discriminant validity, we compared GISs from patients with PANS with scores from a population of healthy controls. To evaluate external validity, we compared global impairment with a clinician-reported global measure-the Child Global Assessment Scale (CGAS)-using the Bland-Altman plots and correlation coefficients. Then, we evaluated associations between the PANS GIS and symptom-specific disease severity variables by fitting mixed models with repeated measures. RESULTS: The GIS shows excellent discriminant validity, distinguishing patients with PANS from healthy controls. The scores on the GIS show an acceptable level of agreement with the clinician reported CGAS. The regression line in the Bland-Altman plot had a positive slope, indicating that parents tend to report higher disease severity than clinicians at higher levels of disease severity. Correlation was higher during disease remissions than during disease flares (r = -0.69 vs. r = -0.48). All disease severity scales predicted GIS in the expected direction. CONCLUSION: The GIS has excellent discriminant validity and acceptable construct validity. PMID- 30421966 TI - Letter to the editor: economic analysis lacks external validity to support universal syndromic testing for suspected meningitis/encephalitis. AB - In Response to: Duff S, et al. "Economic analysis of rapid multiplex polymerase chain reaction testing for meningitis/encephalitis in pediatric patients" Future Microbiology (2018) (Epub ahead of print). PMID- 30421967 TI - Using a Functional Analysis Followed by Differential Reinforcement and Extinction to Reduce Challenging Behaviors in Children With Smith-Magenis Syndrome. AB - Smith-Magenis syndrome (SMS) is a genetic disorder, commonly caused by a 17p11.2 deletion, affecting the Retinoic Acid Induced 1 gene. It affects approximately 1 in 25,000 individuals, with over 90% engaging in challenging behaviors. Function based treatments, using the principles of applied behavior analysis, have consistently been shown to decrease challenging behaviors exhibited by individuals with developmental delays. However, additional research is needed to determine the effects of these interventions with specific diagnostic subsets, including SMS. The current study identified the function of challenging behavior for 2 children with SMS and found a function-based treatment, consisting of differential reinforcement and extinction, reduced challenging behavior for both. PMID- 30421968 TI - Associations Between Medical History, Cognition, and Behavior in Youth With Down Syndrome: A Report From the Down Syndrome Cognition Project. AB - The cause of the high degree of variability in cognition and behavior among individuals with Down syndrome (DS) is unknown. We hypothesized that birth defects requiring surgery in the first years of life (congenital heart defects and gastrointestinal defects) might affect an individual's level of function. We used data from the first 234 individuals, age 6-25 years, enrolled in the Down Syndrome Cognition Project (DSCP) to test this hypothesis. Data were drawn from medical records, parent interviews, and a cognitive and behavior assessment battery. Results did not support our hypothesis. That is, we found no evidence that either birth defect was associated with poorer outcomes, adjusting for gender, race/ethnicity, and socioeconomic status. Implications for study design and measurement are discussed. PMID- 30421969 TI - Psychometric Properties of the Spanish Version of the Self-Determination Inventory Student Self-Report: A Structural Equation Modeling Approach. AB - Instruments to measure self-determination have only been available in the Spanish language to date, for adolescents with intellectual disability (ID). However, given the development of a new measure of self-determination for youth with and without disabilities, the Self-Determination Inventory, there is a need to adapt and validate this tool in the Spanish language so as to provide practitioners with a psychometrically strong measure of self-determination. This study provides evidence of reliability and validity of the Spanish version of the scale, empirically tested with a sample of 620 youth with and without disabilities in Spain. Specifically, validity was evidenced through structural equation modeling approaches, confirming the instrument adequacy to measure self-determination in Spanish speaking youth. Future lines of research are suggested. PMID- 30421970 TI - The Association Between Continuity of Primary Care and Preventive Cancer Screening in Women With Intellectual Disability. AB - Women with intellectual disability have low screening rates for breast and cervical cancer. This population-based cohort study examined the association between the level of primary care continuity and breast and cervical cancer screening rates in women with intellectual disability. Data were obtained from the Institute for Clinical Evaluative Sciences and the Ontario Ministry of Community and Social Services. Neither high (adjusted OR [aOR] = 1.06; 95% CI: 0.88-1.29) nor moderate (aOR = 1.11; 95% CI: 0.91-1.36) continuity of care were associated with mammography screening. Women were less likely to receive a Pap test with high (aOR = 0.70; 95% CI: 0.64-0.77) and moderate (aOR = 0.81, 95% CI 0.74-0.89) versus low continuity of care. Improving continuity of care may not be sufficient for increasing preventive screening rates. PMID- 30421971 TI - Resumenes al Espanol. PMID- 30421973 TI - Resumes en Francais. PMID- 30421972 TI - The PRETEND Program: Evaluating the Feasibility of a Remote Parent-Training Intervention for Children With Prader-Willi Syndrome. AB - Research has shown that children with Prader-Willi syndrome (PWS) have social cognitive challenges and decreased quality parent-child interactions. However, given the low prevalence rate, developing interventions for children with PWS is faced with the significant challenge of enrolling enough participants for local studies. To better understand the feasibility and acceptability of telehealth, the current study delivered a 6-week remote parent training intervention to 15 primary caregivers of a child with PWS (ages 3-6). Behavioral Intervention Rating Scale results indicate good acceptability (5.64/6.00) and satisfaction (4.75/5.00) with the intervention. These results are one of the first to support the use of telehealth in conducting parent training in rare disorders, such as PWS. PMID- 30421974 TI - The Relationship Between Children's Exposure to Intimate Partner Violence and Intellectual and Developmental Disabilities: A Systematic Review of the Literature. AB - Children exposed to intimate partner violence (IPV) can experience negative social, emotional, behavioral, and academic outcomes. A growing body of research has examined the relationship between intellectual and developmental disabilities (IDD) and IPV exposure. We systematically reviewed the literature for research exploring this relationship and found a limited number of studies meeting inclusion criteria ( N = 11). Over half (64%) identified a significant relationship between IPV and IDD, although the cross-sectional methodologies of the majority of studies (82%) prevented the ability to ascertain directionality. Further, the studies defined and measured IPV and IDD in various ways. Some studies were limited by poor external validity and small sample sizes. More research is needed to understand the intersection between IPV exposure and IDD. PMID- 30421975 TI - Procedures to Promote Ethical Open Access Publishing: A Comment to Shaw and Elger. PMID- 30421976 TI - Loss Aversion of Time: Serving School Lunches Faster without Impacting Meal Experience. AB - Loss aversion has been extensively studied in economics, but there is less discussion of it in the context of time. Results from a field experiment conducted in a U.S. public school lunch cafeteria suggest that students could be loss averse to time and that interventions, such as a pre-plated service lane could increase the speed of service and guide students to make better food choices. Faster, pre-plated service lanes may leverage loss aversion bias, be beneficial for larger schools, reduce wait time for students, and thereby increase their satisfaction with the service process. PMID- 30421977 TI - Swabbing the surface: critical factors in environmental monitoring and a path towards standardization and improvement. AB - Cross-contamination can be broadly defined as the transfer, direct or indirect, of microorganisms from a contaminated product to a non-contaminated product. Events that may result in cross-contamination include inadequate hygiene practices, contaminated equipment surfaces, contamination via food handling personnel, further product processing, or storage abuse All of these niches require consistent environmental surveillance systems to monitor microbial harborage sites to prevent foodborne illnesses via cross-contamination. Environmental surveillance is achieved through routine surface sampling of the food contact surfaces and surrounding areas. To better understand cross contamination, the role of environmental surface transmission during outbreaks due to the presence and persistence of pathogenic microorganisms on various food contact surfaces must be investigated. However, studies on environmental sampling techniques are rarely performed in an actual food processing environment but rather under controlled variables within a laboratory-setting. Moreover, results and conclusions of studies differ because of the considerable variability across surface sampling tools due to individual operator dependency, low recovery rates, and low reproducibility. Information is also often lacking on environmental sampling tools used within a processing facility, the characterization of these tools, and the optimization of recovery of microorganisms for surface sampling. Thus, this review aims to: (1) discuss and compare factors impacting the recovery of microorganisms and the standardization of surface sampling methods for optimal recovery of microorganisms and (2) examine how research strategies could focus more towards the development of standard methodologies for surface sampling. PMID- 30421978 TI - Hormonal Risk Factors for Osteoporosis: Different Profile Among Antipsychotics. AB - OBJECTIVES: Osteoporosis is a major risk factor for fracture and treatment is mainly preventive. Patients with severe psychiatric condition and treated with antipsychotics are at risk for vitamin D deficiency and iatrogenic hyperprolactinemia, two serious risk factors of osteoporosis. We aim to determine whether all antipsychotics are similar regarding the risk of osteoporosis in young patients. METHODS: From January 2009 to March 2015, we determined the vitamin D blood level (VDBL) among 484 inpatients and from January 2012 to March 2015, we determined the prolactin blood level (PBL) among 205 inpatients. We systematically recorded well-documented risk factors (e.g., age, gender, ethnic origin, body mass index, or season) and suspected risk factors (e.g., disease type or antipsychotic treatment). RESULTS: Up to 89% of the inpatients had a VDBL under the recommended threshold. Up to 60% of the inpatients had hyperprolactinemia. The multivariate model found a significant effect on VDBL for seasonality (higher VDBL in summer), ethnicity (lower VDBL in Black individuals), and treatment exposure. The multivariate model found a significant effect on PBL for gender and treatment exposure. In both models, aripiprazole had a safer profile compared with other antipsychotics. CONCLUSION: Because adolescence is a period of bone construction and a critical window of opportunity for maximizing bone mass, we recommend vitamin D supplementation in young patients with severe mental condition. It could be interesting to reconsider to regularly monitor PBL among youth patients treated with antipsychotic, with the exception of aripiprazole. PMID- 30421979 TI - Why are children more resistant to mortality from severe infections? PMID- 30421980 TI - World Naturopathic Federation: The Central Role of Research in the Growth of the Global Naturopathic Profession. PMID- 30421981 TI - Current regulatory guidelines and resources to support research of dietary supplements in the United States. AB - The U.S. Dietary Supplement Health and Education Act (DSHEA) established the regulatory framework for dietary supplements as foods through the Food and Drug Administration (FDA). DSHEA outlined the legal definition, labeling requirements, and process for adverse event reporting for dietary supplements. FDA also issued formal guidance on current Good Manufacturing Practice to ensure that processes for preparation, packaging, labeling, and storage of supplements and ingredients are documented and meet specifications to ensure purity, composition, and strength. However, efficacy of dietary supplements is not required under U.S. law. Despite regulations to improve the marketplace, many challenges remain; as a result, the quality and safety of products available can be highly variable, especially for botanical and herbal products. The ability of regulators to successfully carry out their mission is hampered by the sheer number of products and manufacturing facilities and a lack of analytical methods for all ingredients and products in the marketplace, this is especially difficult for herbal and botanical dietary supplements. Safety issues continue to exist such as adulteration and contamination, especially with specific product types (i.e. body building, sexual enhancement). Thus, a need remains for continued efforts and improved techniques to assess the quality of dietary supplements, especially with regard to purity, bioavailability, and safety. This review will highlight the existing American regulatory framework for dietary supplements and will describe the remaining regulatory barriers to ensuring that safe and high-quality dietary supplements are offered in the marketplace. PMID- 30421982 TI - EXPRESS: Surface-Enhanced Raman Spectroscopy (SERS) of Mancozeb and Thiamethoxam Assisted Using Gold and Silver Nanostructures Produced by Laser Techniques on Paper. PMID- 30421983 TI - Relevance of functional foods in the Mediterranean diet: the role of olive oil, berries and honey in the prevention of cancer and cardiovascular diseases. AB - The traditional Mediterranean diet (MedDiet) is a well-known dietary pattern associated with longevity and improvement of life quality as it reduces the risk of the most common chronic pathologies, such as cancer and cardiovascular diseases (CVDs), that represent the principal cause of death worldwide. One of the most characteristic foods of MedDiet is olive oil, a very complex matrix, which constitutes the main source of fats and is used in the preparation of foods, both raw as an ingredient in recipes, and in cooking. Similarly, strawberries and raspberries are tasty and powerful foods which are commonly consumed in the Mediterranean area in fresh and processed forms and have attracted the scientific and consumer attention worldwide for their beneficial properties for human health. Besides olive oil and berries, honey has lately been introduced in the MedDiet thanks to its relevant nutritional, phytochemical and antioxidant profile. It is a sweet substance that has recently been classified as a functional food. The aim of this review is to present and discuss the recent evidence, obtained from in vitro, in vivo and epidemiological studies, on the potential roles exerted by these foods in the prevention and progression of different types of cancer and CVDs. PMID- 30421984 TI - Evaluation of Nutrition Knowledge of Pregnant Women before and after Nutrition Education according to Sociodemographic Characteristics. AB - The aim of this cross-sectional study is to evaluate the effect of nutrition education on nutritional knowledge levels of pregnant women. The study was undertaken on a sample of pregnant women (i = 743) attending health centers in Istanbul for prenatal care. Nutrition knowledge scores were significantly higher in posttest (23.0) than pretest (16.0) after receiving nutrition education (p < .001). Significant differences in pretest (p < .05) but not posttest (p > .05) scores were found for factors, such as education level, work status, and the number of pregnancies; significant differences in both test scores were found for age and nutrition information (p < .05). In conclusion, pregnant women need to be given adequate and appropriate nutrition education for maternal and child health according to sociodemographic characteristics. PMID- 30421985 TI - New Frontiers for Cognitive Assessment: An Exploratory Study of the Potentiality of 360 degrees Technologies for Memory Evaluation. AB - One of the most recent trends in technology field is the 360 degrees technology. In order to investigate its potentiality for the evaluation of memory function, we compared participants' performance in two memory tasks between an encoding delivered through an immersive 360 degrees environment and a non-immersive 360 degrees one. Specifically, we investigated if the immersive 360 degrees environment would facilitate memory encoding in comparison to the non-immersive 360 degrees one. Forty-two participants visualized two 360 degrees pictures of a bedroom containing specific items and items shared by the two rooms, either in the "non-immersive -> immersive" order or in the "immersive -> non-immersive" one. Results showed that the immersive set-up was able to strengthen the mnestic trace only when participants performed the tasks in the "non-immersive -> immersive" order. A possible explanation is a potential familiarity with the technologies used to explore the 360 degrees environments. Overall, these results only partially supported the effectiveness of immersive 360 degrees technology in facilitating episodic memory encoding; future studies should further explore the potentiality of this innovative technology. PMID- 30421986 TI - Comparative transcriptome profiles of Lindian chicken eyelids identify melanin genes controlling eyelid pigmentation. AB - 1. During the long history of chicken domestication, eyelid colour, like skin colour and shank colour, has been one of the physical traits of Chinese indigenous chickens that influence consumer buying behaviour. In China, the Lindian chicken, which has coloured feathers, is renowned for the appetizing flavour of its meat and eggs, and its eyelid colours vary from deep (black) to light shades (light yellow). 2. To investigate genes involved in eyelid colour, the expression profiles of black and light-yellow eyelids of Lindian chickens were analysed with transcriptome sequencing. 3. A total of 13 466 genes were detected in the eyelids, among which 14 were differentially expressed. Among these differentially expressed genes (DEGs), three key genes, premelanosome protein (PMEL), dopachrome tautomerase (DCT), and tyrosinase (TYR), encoded proteins that positively regulate melanogenesis and melanin deposition. PMEL, DCT and TYR were expressed much more strongly in the black eyelids than in the light yellow eyelids. A Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that tyrosine metabolism and melanogenesis genes were significantly enriched among these DEGs (corrected P < 0.05). 4. In conclusion, melanin may be one of the main factors involved in Lindian chicken eyelid colour. Furthermore, these results provide a valuable resource for the future study of the physical traits of Lindian chicken. PMID- 30421987 TI - Effects of Heat-Treated Hempseed Supplementation on Performance, Egg Quality, Sensory Evaluation and Antioxidant Activity of Laying Hens. AB - This study was conducted to determine the effects of raw and heat-treated hempseed (HS, Cannabis sativa L.) on performance, egg quality and antioxidant activity in laying hens. A total of 108 laying hens, aged 36 weeks, were divided into three treatment groups with 12 replicates and each replicate contained three laying hens. The treatments were as follows: 1) Control (no hempseed), 2) 15% raw hempseed (RHS) in diet and 3) 15% heat-treated hempseed in the diet (HHS). Experiments lasted for 12 weeks. Feed intake of the RHS group was lower than those of the control and HHS groups. Egg weight, egg mass, shell weight, shell surface area and shell thickness of the HHS group were significantly (P<0.05) higher than that of the RHS group. Roche (DSM) colour fan values of the RHS group were higher than that of the HHS group (P<0.01). Palmitic, palmitoleic and oleic acids of egg yolk were significantly (P<0.05) decreased in the RHS and HHS groups; however, linoleic, alpha-linolenic and docosahexaenoic acids (DHA) of egg yolk increased (P<0.05) for both treatment diets compared to the control group. Both RHS and HHS supplementation to layer diets did not influence malondialdehyde (MDA) and superoxide dismutase (SOD) activity and blood lipid profile. It was concluded that heat-treated HS was superior in improving the egg quality of laying hens as compared to the raw HS. PMID- 30421988 TI - Recent developments in Hericium erinaceus polysaccharides: extraction, purification, structural characteristics and biological activities. AB - Hericium erinaceus (H. erinaceus), an edible mushroom with medicinal value, has a long history of usage in China and other oriental countries. Polysaccharide is supposed to be one of the major bioactive compounds in H. erinaceus, which possesses immunomodulating, anti-cancer, antioxidant, gastroprotection and intestinal health promotion, neuroprotective, hepatoprotective, antihpyerglycemic and hypolipidemic activities. In this review, the current advancements on extraction, purification, structural characteristics and biological activities of polysaccharide from different sources (fruiting body, mycelium and culture broth) of H. erinaceus were summarized. Among these aspects, summaries of the structural characteristics focused on the purified polysaccharides. Meanwhile, comparisons on the structural characteristics among the purified polysaccharides obtained from above three sources were made. Moreover, their biological activities were introduced on the basis of in vivo and in vitro experiments, and some possible action mechanisms were listed. Furthermore, the structure-activity relationship of the polysaccharide was discussed. New perspectives for the future work of Hericium erinaceus polysaccharide were also proposed. HIGHLIGHTS Extraction, purification, structural characteristics and biological activities of Hericium erinaceus polysaccharide (HEP) were summarized. Structural characteristics of the purified polysaccharides from different sources (fruiting body, mycelium and culture broth) of Hericium erinaceus were summarized and compared. Structure activity relationship of HEP was discussed, and new perspectives for the future work of this polysaccharide were proposed. PMID- 30421990 TI - Effects of Pacing Properties on Performance in Long-Distance Running. AB - This article focuses on the performance of runners in official races. Based on extensive public data from participants of races organized by the Boston Athletic Association, we demonstrate how different pacing profiles can affect the performance in a race. An athlete's pacing profile refers to the running speed at various stages of the race. We aim to provide practical, data-driven advice for professional as well as recreational runners. Our data collection covers 3 years of data made public by the race organizers, and primarily concerns the times at various intermediate points, giving an indication of the speed profile of the individual runner. We consider the 10 km, half marathon, and full marathon, leading to a data set of 120,472 race results. Although these data were not primarily recorded for scientific analysis, we demonstrate that valuable information can be gleaned from these substantial data about the right way to approach a running challenge. In this article, we focus on the role of race distance, gender, age, and the pacing profile. Since age is a crucial but complex determinant of performance, we first model the age effect in a gender- and distance-specific manner. We consider polynomials of high degree and use cross validation to select models that are both accurate and of sufficient generalizability. After that, we perform clustering of the race profiles to identify the dominant pacing profiles that runners select. Finally, after having compensated for age influences, we apply a descriptive pattern mining approach to select reliable and informative aspects of pacing that most determine an optimal performance. The mining paradigm produces relatively simple and readable patterns, such that both professionals and amateurs can use the results to their benefit. PMID- 30421989 TI - The relationship between cognitive change and physical health and behavioural outcomes in a Ugandan cohort of adults living with HIV - a longitudinal study. AB - We investigated changes in cognitive function and physical health and behavioural outcomes (HIV disease progression, health-seeking behaviour, adherence to HIV medications and risky sexual behaviour) at baseline and 12 months later among 1126 Ugandan adults living with HIV. Overall, cognitive function improved from baseline to follow-up, except for gait speed, which was slower at follow-up compared to baseline. There were improvements in physical health and behavioural outcomes by follow-up, with greater improvements among individuals on ART compared to those not on ART. Change in gait speed over time significantly predicted risky sexual behaviours at follow-up. This is the first study to investigate the longitudinal relationships between cognitive function and health outcomes among Ugandan adults living with HIV and provide insights into the possible links between cognitive function and negative clinical and behavioural health outcomes in people living with HIV. PMID- 30421991 TI - The Potential of Electroencephalography as a Tool for Empowering Cognition. PMID- 30421992 TI - Self-Persuasion on Facebook Increases Alcohol Risk Perception. AB - In this experiment, we examined if participating in a Facebook group by generating antialcohol arguments (self-persuasion) is more effective than reading antialcohol posts of others (direct persuasion) in changing alcohol consumption, risk perception, and attitudes. In addition, it was examined if submitting posts moderated these effects. Participants logged into their Facebook account and joined a group that contained posts with antialcohol arguments. They either generated their own arguments with or without posting them, or read those present in the group with or without posting that they had read them. Next, participants rated movie clips in a 30-minute ad libitum drinking session in dyads, and their alcohol consumption was measured. Finally, measures of alcohol risk perception and attitudes were completed. Results show that generating antialcohol arguments regardless of whether they are posted online-is effective in increasing alcohol risk perception but does not affect immediate alcohol consumption. PMID- 30421993 TI - HoloMedical3D: Connecting the Dots for Medical Holography. PMID- 30421994 TI - The Next Level of Virtual Reality Isn't Technology-It's Storytelling. PMID- 30421995 TI - Assessing the Relationship Between Attitudinal and Perceptual Component of Body Image Disturbance Using Virtual Reality. AB - Body image disturbance (BID) affects quality of life even in the absence of clinically diagnosable eating pathology, and numerous studies have shown its crucial role in the emergence and maintenance of eating disorders. This study aimed at exploring attitudinal and perceptual components of BID using a novel virtual reality (VR)-based paradigm. A community sample of women (N = 27) recreated in VR their perceived body in both an allocentric (third-person view) and egocentric (first-person view) perspective. Specifically, women were able to choose between a wide range of three-dimensional bodies spanning body mass index 12.5-42.5 kg/m2. Attitudinal indexes of BID (body dissatisfaction, body uneasiness, and body image avoidance) were assessed through questionnaires. Attitudinal components predicted the perceptual BID only in the allocentric perspective. Specifically, overestimation was predicted by body image avoidance, while underestimation was predicted by body uneasiness. Furthermore, a common predictor of underestimation and overestimation was body dissatisfaction. In line with the allocentric lock hypothesis, the current results seem to confirm the presence of two different mechanisms underlying BID: one related to real-time perception-driven inputs (egocentric frame) and one related to abstract knowledge, beliefs, and attitudes related to a person's body (allocentric frame). These findings contribute to a better understanding of the nature and mechanisms underlying BID and provide additional evidence about the suitability of using VR for exploring and assessing body image-related components and disturbances. PMID- 30421996 TI - Game Perspective-Taking Effects on Players' Behavioral Intention, Attitudes, Subjective Norms, and Self-Efficacy to Help Immigrants: The Case of "Papers, Please". AB - This study expands on game character perspective-taking effects on political opinions while controlling for players' social dominance orientation or inclination for inequality among social groups. Random assignment to play a game as an immigration inspector decreased intention, subjective norms, and self efficacy to help immigrants relative to baseline scores. The scores of participants randomly assigned to play a game similar in style but instead featuring the role of a newspaper editor remained unchanged. Within-subjects effects implied that baseline reductions in intention, subjective norms, and self efficacy to help immigrants were solely attributed to playing games as game immigration inspectors. The study provides initial evidence that taking on the perspective of game characters can influence players' opinions about political issues, such as immigration. PMID- 30421997 TI - The Protective Role of Dispositional Mindfulness Against the Perpetuation of Cyberbullying Victimization and Perpetration Among Adolescents. AB - Few studies have examined the protective factors that contribute to reducing long term involvement in cyberbullying (CB). This study examined whether dispositional mindfulness is associated with the reduced stability over time (i.e., long-term involvement) of CB victimization and perpetration and with the lower reciprocity of both. This was a three-wave longitudinal study spaced 6 months apart. The sample consisted of 985 high school students from the Basque Country (Spain). The participants completed a mindfulness measure at time one and measures of CB victimization and perpetration at three time points. Dispositional mindfulness was negatively associated with both CB victimization and CB perpetration over time. The predictive association between CB victimization and perpetration was reciprocal from time two to time three. Moreover, the interaction between dispositional mindfulness and CB victimization indicated that victimization was less stable over time when mindfulness was higher. The model was invariant across gender or age. The results indicate that CB is a long-term problem and that dispositional mindfulness can be beneficial because it predicts a lower frequency of CB victimization and perpetration over time. PMID- 30421998 TI - A Quasi-Experimental Study of a Fitbit-Based Self-Regulation Intervention to Improve Physical Activity, Well-Being, and Mental Health. AB - Self-regulation strategies are helpful for increasing goal commitment and maintaining behavior change. Evidence suggests that the self-regulation strategy of mental contrasting with implementation intentions (MCII) shows promise in helping people increase their physical activity. The purpose of this research was to investigate whether these self-regulation strategies would increase physical activity, which would, in turn, improve well-being and mental health. In a quasi experimental study, participants were randomized by school to an experimental group (n = 40) and control group (n = 45). The experimental group received self regulation strategies, whereas the control group did not. Both groups were given a Fitbit and the goal of 10,000 steps per day. Participants' well-being and depressive, anxiety, and stress symptoms were measured at baseline and after the 3-week intervention. The experimental group's physical activity increased from 7,938 to 9,288 steps per day (p = 0.001), whereas that of the control group did not increase. In the experimental group, the findings suggested a significant increase for men, and a nonsignificant increasing trend for women. The study demonstrated the benefits of self-regulation strategies such as MCII on achieving physical activity goals. Findings also suggested that self-regulation strategies provided improvement beyond physical activity by decreasing the depressive symptoms of female participants in the experimental group. Given the small sample size, effects by gender have to be interpreted with caution. Limitations and suggestions for future research are discussed. PMID- 30421999 TI - Epidemiology and diagnostic process of amyotrophic lateral sclerosis as distinct from myelopathy: 5-year cohort study of whole-population in South Korea. AB - OBJECTIVE: To investigate the incidence, prevalence, and demographic factors of all amyotrophic lateral sclerosis (ALS) patients diagnosed in South Korea from 2011 to 2015, and to analyze cases misdiagnosed as myelopathy. METHODS: The whole population registered under the Korean National Health Insurance Service (KNHIS) was applied. All 4551 patients who were registered as having ALS code from 2011 to 2015 were included. For all ALS patients, the incidence, prevalence, and demographic factors were assessed. Trends of diagnosis for myelopathy, and surgery prior to confirmation of ALS diagnosis were identified. RESULTS: When the whole 48,135,715 KNHIS population enrolled in 2015, the incidence of ALS in 2015 was estimated to be 1.68 per 100,000 person-years, and the prevalence was 6.49 per 100,000 persons. Life expectancy of ALS can be calculated as 3.9 years after the diagnosis, and the mean age of diagnosis was 59.5 +/- 13.1. A total of 1902 patients diagnosed with myelopathy before a diagnosis of ALS accounted for 0.13% of all myelopathy patients, and 41.8% of all ALS patients. It took an average of 471.7 d to confirm a diagnosis of ALS after the myelopathy diagnosis. Among the patients finally diagnosed with ALS, more patients underwent surgery for myelopathy (n = 263, 13.8%) than among patients who were diagnosed with myelopathy alone, and underwent surgery (n = 141,148, 9.8%). CONCLUSIONS: This whole-population nationwide demographic study confirmed the data from previous studies. Clinicians should consider the possibility of ALS when making a myelopathy diagnosis, especially if the symptoms are sufficiently severe to require surgery. PMID- 30422000 TI - TREX1 D18N mice fail to process erythroblast DNA resulting in inflammation and dysfunctional erythropoiesis. AB - Anaemia is commonly observed in chronic inflammatory conditions, including systemic lupus erythematosus (SLE), where ~50% of patients display clinical signs of anaemia. Mutation at the aspartate residue 18 of the three prime repair exonuclease 1 (TREX1) gene causes a monogenic form of cutaneous lupus in humans and the genetically precise TREX1 D18N mice recapitulate a lupus-like disease. TREX1 degrades single- and double-stranded DNA (dsDNA), and the link between failed DNA degradation by nucleases, including nucleoside-diphosphate kinases (NM23H1/H2) and Deoxyribonuclease II (DNase II), and anaemia prompted our studies to investigate whether TREX1 dysfunction contributes to anaemia. Utilizing the TREX1 D18N mice we demonstrate that (1) TREX1 mutant mice develop normocytic normochromic anaemia and (2) TREX1 exonuclease participates in the degradation of DNA originating from erythroblast nuclei during definitive erythropoiesis. Gene expression, hematocrit, hemoglobin, immunohistochemistry (IHC) and flow cytometry were used to quantify dysfunctional erythropoiesis. An altered response to induced anaemia in the TREX1 D18N mice was determined through IHC, flow cytometry, and interferon-stimulated gene (ISG) expression analysis of the liver, spleen and erythroblastic islands (EBIs). IHC, flow cytometry, and ISG expression studies were performed in vitro to determine the role of TREX1 in the degradation of erythroblast DNA within EBIs. The TREX1 D18N mice exhibit altered erythropoiesis including a 20% reduction in hematocrit, 10-20 fold increased erythropoietic gene expression levels in the spleen and phenotypic signs of normocytic normochromic anaemia. Anaemia in TREX1 D18N mice is accompanied by increased erythropoietin (Epo), normal hepcidin levels and the TREX1 D18N mice display an inappropriate response to anaemic challenge. Enhanced ISG expression results from failed processing and subsequent sensing of undegraded erythroblast DNA in EBIs. TREX1 participates in the degradation of erythroblast DNA in the EBI and TREX1 D18N mice exhibit a normocytic normochromic anaemia. PMID- 30422001 TI - Vibralactone Z4, the first chain-like vibralactone derivative from cultures of the basidiomycete Boreostereum vibrans. AB - The first chain-Like vibralactone derivative, vibralactone Z4 (1), together with three known ones (2-4), were isolated from cultures of the basidiomycete Boreostereum vibrans. Vibralactone Z4 (1) is likely to be a key intermediate from 3 to 4 in their biosynthetic pathway. It showed a weak cytotoxicity to human cancer cell line SW480 (IC50 29.2 +/- 1.38 MUM). PMID- 30422002 TI - Antioxidant activity and Neurite outgrowth-enhancing activity of scorbamic acid and a red pigment derived from ascorbic acid. AB - L-Ascorbic acid (AA), known as vitamin C, can form browning products by a non enzymatic process during storage and the browning products cause deterioration of agricultural products. In the browning reaction, a red pigment, 2,2'-nitrilodi 2(2')-deoxy-L-ascorbic acid ammonium salt (NDA), is generated from AA via L scorbamic acid (SCA) as an intermediate. However, the biological activities of SCA and NDA have not yet been clarified. In this study, we assayed the antioxidant activities of SCA and NDA using ABTS radical cation and their neurite outgrowth-enhancing activities in PC12 cells. SCA showed stronger radical scavenging activity than that of AA, while NDA hardly showed any activity. SCA and NDA enhanced the neurite outgrowth induced by dibutyryl cyclic AMP after their incorporation into cells in the same manner as that of AA. The results indicated that SCA has antioxidant activity and that SCA and NDA have neurite outgrowth-enhancing activity. PMID- 30422003 TI - Justified indulgence: self-licensing effects on caloric consumption. AB - OBJECTIVE: Research on self-licensing, i.e. employing justifications to give into temptation, largely consists of studies examining dichotomous food choices (healthy vs. unhealthy), while evidence for its effects on how much (unhealthy) food is consumed remains scarce. The present studies aimed to demonstrate self licensing effects on caloric consumption in both lab (Study 1 & 2) and field setting (Study 3). DESIGN: In all studies, female student samples were recruited. They either received a justification cue (license condition) or not (control condition), after which they could eat freely from unhealthy snacks (Study 1, N = 85 and Study 2, N = 95) or choose a snack for direct consumption at a take-out lunch place (Study 3, N = 110). MAIN OUTCOME MEASURES: Caloric value of consumed snacks (Study 1 and 2) and chosen snack (Study 3). RESULTS: In all studies, caloric consumption was higher in the license condition compared to the control condition: Participants ate more of the provided unhealthy snacks (Study 1 and 2) and chose a snack of higher caloric value (Study 3). CONCLUSIONS: The present research corroborates self-licensing as an important factor in the consumption of unhealthy foods by employing more ecologically valid outcomes. PMID- 30422004 TI - Flavone glucosides from Artemisia juncea. AB - A new flavone glucoside, 4',5-dihydroxy-3',5',6-trimethoxyflavone-7-O-beta-D glucoside was obtained from aerial parts of Artemisia juncea, together with the known flavone eupatilin (5,7-dihydroxy-3',4',6-trimethoxyflavone). The compounds were comprehensively analytically characterized by IR, UV, NMR and HR-MS, and their chemical structures ascertained. The EtOAc fraction of A. juncea showed the strongest DPPH radical scavenging ability as well as reducing power (in CUPRAC and FRAP assays) and phosphomolybdenum activity. This fraction also exhibited the strongest inhibitory effects on tyrosinase. Additionally, the best antidiabetic effects were observed for eupatilin and the CHCl3 fraction. PMID- 30422005 TI - Emerging cell cycle inhibitors for treating metastatic castration-resistant prostate cancer. AB - INTRODUCTION: Disease progression despite androgen suppression defines lethal castration-resistant prostate cancer (CRPC). Most of these cancers remain androgen receptor (AR)-signaling dependent. Therapy for metastatic CRPC includes abiraterone acetate, enzalutamide, docetaxel, cabazitaxel, sipuleucel-T, and radium-223. However, survival remains modest for men with progressive disease despite AR-targeted therapy and docetaxel, and therefore novel treatments are needed. Areas covered: Recent evidence of genomic heterogeneity and sensitivity to PARP inhibitors supports investigation of targeted agents in CRPC. Cell cycle inhibitors are therefore logical molecules to investigate. Review of the current literature identified cell cycle inhibitors under study in early phase clinical trials targeting the G1 (palbociclib, ribociclib, AZD-5363, ipatasertib), S (M 6620, prexasertib), G2 (adavosertib), and M (alisertib) phases of the cell cycle. Expert opinion: Strategies combining cell cycle inhibitors with active agents in CRPC are most likely to have clinical impact with CDK4/6 and Wee1 inhibitors appearing most promising. Identification of predictive biomarkers may be essential and currently trials are testing circulating cell-free DNA as an approach. Incremental toxicities such as neutropenia are important in this population. Results from most current clinical trials of cell cycle inhibitors in CRPC are still pending but it is anticipated they will provide important insights into the heterogeneous biology of CRPC. PMID- 30422006 TI - Neurological complications associated with left ventricular assist device therapy. AB - INTRODUCTION: Associated with significant morbidity and mortality, neurological complications in adult patients with left ventricular assist devices (LVAD) approaches a prevalence as high as 25%. As the number of individuals using LVAD support grows, it is increasingly important for providers to understand the hematologic and hemodynamic changes associated with LVAD implantation, the risk factors for neurological complications and their mitigation strategies. Areas covered: PubMed searches were completed using the terms 'Left ventricular assist device and stroke' (994 results) then 'Left ventricular assist device and stroke risk factors' (199 results). Results were filtered by 'humans' (178 results). The manuscript focuses on the risk factors and mitigation strategies for stroke identified in the literature following LVAD implantation and managing this complication. Expert commentary: There is little consensus on how to accurately predict stroke risk in the LVAD population. While some recent large-scale clinical trials identified a limited number of risk factors, further research is warranted to generate reliable predictive models and treatment protocols for these patients. This should include developing novel agents and monitoring techniques to individualize anticoagulation therapy while safely balancing the risk of bleeding, thrombosis and stroke. A multi-specialty commitment is necessary to further standardize the management of these patients. PMID- 30422007 TI - Positive fluid balance is associated with increased in-hospital mortality in patients with intracerebral hemorrhage. AB - OBJECTIVE: This study aimed to investigate the association between fluid balance (FB) and in-hospital mortality in patients with intracerebral hemorrhage (ICH). METHODS: Data were extracted from the online database Multi-parameter Intelligent Monitoring in Intensive Care III. Patients were divided into two groups according to the FB status at 48 hours after intensive care unit (ICU) admission: negative and positive 48-hour FB groups. The primary outcome was in-hospital mortality. RESULTS: Data of 1407 patients were analyzed. Linear spline function in logistic models showed significant association between the volume of positive FB and in hospital mortality (odds ratio (OR) 1.006; 95% CI: 1.002-1.010), while the association between the volume of negative FB and in-hospital mortality was non significant. For interpretation, FB was further divided into four quartiles. Referred to Q1, the OR of in-hospital mortality stepwise increased from Q2 (OR, 1.11; 95% CI: 0.72-1.68) to Q4 (OR, 1.68; 95% CI: 1.13-2.48). A similar association was also found between FB and Glasgow coma scale at ICU discharge. CONCLUSIONS: In patients with ICH, increased volume of positive FB was associated with higher in-hospital mortality while the volume of negative FB was not. Whether maintaining a zero FB status is a beneficial strategy needs further investigation. PMID- 30422008 TI - Ixazomib for the treatment of multiple myeloma. AB - INTRODUCTION: Proteasome inhibitors (PIs) are among the backbones of multiple myeloma (MM) treatment; however, their long-term use can be limited by parenteral administration and treatment-related toxicities. Ixazomib, the first oral PI to enter the clinic, is approved around the world, in combination with lenalidomide and dexamethasone, for the treatment of patients with MM who have received at least one prior therapy. Areas covered: This review summarizes the clinical data leading to approval of ixazomib; its pharmacology, efficacy, and safety. Building on the data in relapsed/refractory MM (RRMM), it also reviews the available clinical trial data for ixazomib across the MM treatment algorithm in newly diagnosed MM, RRMM, and as maintenance therapy, and looks ahead to ongoing clinical trials and the expanding role of ixazomib in these indications. Expert opinion: Ixazomib is an efficacious and well-tolerated addition to the treatment armamentarium for RRMM, with benefit as a long-term, continuous therapy for all patients, including 'poor prognosis' patients, such as those with advanced stage disease, high-risk cytogenetic abnormalities, and elderly and frail patients. Data from ongoing clinical studies are expected to expand the role of ixazomib across the MM treatment algorithm and in a broader range of combination regimens. PMID- 30422009 TI - Consensus on interprofessional facilitator capabilities. AB - Interprofessional education is one of many strategies aimed at addressing the healthcare workforce crisis. Few educators in healthcare professions have been exposed to interprofessional education (IPE) or have experienced collaborative practice (CP), because health professionals have traditionally been trained in silos. Interprofessional facilitators must acquire a new skillset as expert facilitation of learning is essential for successful interprofessional education. Seven experts participated in a Delphi survey to reach consensus on the capabilities required of interprofessional facilitators. All capabilities discussed should be included in the faculty development programme based on 80% agreement, standard deviation <1.5 and content validity index >=.8. However, facilitation of learning, teamwork, role clarification as well as development of reflexivity is less essential than the other capabilities based on the low content validity ratio of .43. Surprisingly, and contrary to literature, the use of standardised tools that incorporate social determinants of health seems not to be essential with a content validity ratio (CVR) of -.14. Interprofessional facilitator capabilities that may promote transformative learning in health profession students have been identified and prioritised. These interprofessional facilitator capabilities are deemed to be essential for the development of an effective and collaborative healthcare workforce. PMID- 30422010 TI - Synthesis of novel 6,7-dimethoxy-4-anilinoquinolines as potent c-Met inhibitors. AB - HGF/c-Met signalling pathway plays an important role in the development of cancers. A series of 6,7-dimethoxy-4-anilinoquinolines possessing benzimidazole moiety were synthesised and identified as potent inhibitors of the tyrosine kinase c-Met. Their in vitro biological activities against three cancer cell lines (A549, MCF-7, and MKN-45) were also evaluated. Most of these compounds exhibited moderate to remarkable potency. Among them, compound 12n showed the most potent inhibitory activity against c-Met with IC50 value of 0.030 +/- 0.008 uM and it also showed excellent anticancer activity against the tested cancer cell lines at low micromolar concentration. Molecular docking verified the results and revealed the possible binding mode of the most promising compound 12n into the ATP-binding site of c-Met kinase. PMID- 30422011 TI - Phytochemical, antimicrobial and antiquorum-sensing studies of pulicaria undulata L.: a revision on the structure of 1beta,2alpha,3beta,19alpha,23-pentahydroxy-urs 12-en-28-oic acid. AB - Phytochemical study of the aerial part of Pulicaria undulata L. led to the isolation of nine compounds. The structure of 1beta,2alpha,3beta,19alpha,23 pentahydroxy-urs-12-en-28-oic acid (4) was revised and confirmation of the stereochemical configuration of the hydroxyl groups was established using NOESY and selective decoupling experiments. The other compounds were identified as 1,2 dehydro-1,10alpha-dihydropseudoivalin (1), axillarin (2), grandifloric acid-15 beta-glucoside (3), myrianthic acid (5), caffeic acid (6), quercetin (7), paniculoside IV (8) and caffeic anhydride (9). The structures were characterized by 1 D, 2 D NMR spectroscopy and confirmed with HRMS. Antimicrobial and antiquorum-sensing activities of the different extracts and isolated compounds of the plant were investigated. Generally, the phenolic rather than the terpenoidal compounds exhibited remarkable antimicrobial and antiquorum-sensing activity. [Formula: see text]. PMID- 30422012 TI - Shyness, social anxiety, social anxiety disorder, and substance use among normative adolescent populations: A systematic review. AB - : Researchers have increasingly studied shyness, social anxiety, and social anxiety disorder (SAD) as potential precursors of substance use. OBJECTIVES: The objective of this study was to review the relationships between these variables and tobacco use, alcohol use, and cannabis/drug use in normative adolescent populations and the extent to which these associations differ by gender. METHODS: A systematic search in PsycINFO and PubMed was conducted, reference screening was performed, and five experts were consulted. RESULTS: Fifty articles published between 1980 and 2016 were included for review. Shyness was frequently associated with lower use of tobacco, alcohol, and cannabis/drug. Similar findings emerged for social anxiety. In contrast, SAD tended to be associated with higher use of tobacco and cannabis/drug, although the association between SAD and the use of alcohol appeared inconclusive. Furthermore, limited evidence suggests that shy females use less tobacco than shy males and that males with social anxiety use less drugs than socially anxious females. CONCLUSIONS: In conclusion, these results highlight that shyness, social anxiety, and SAD may exert different effects on substance use. Higher use of substances among adolescents suffering from a SAD may be explained, among other possibilities, by a self-medication mechanism. While all adolescents should benefit from prevention efforts targeted at substance use, a systematic screening for substance use disorders during the clinical evaluation that precedes SAD treatments is advised. PMID- 30422013 TI - A new abietane diterpenoid glycoside from ajuga ovalifolia var. calantha. AB - A new abietane diterpenoid glycoside, ajugaside B (1), along with three known compounds (2-4), were isolated from the whole plants of Ajuga ovalifolia var. calantha. The structure of the new compound (1) was elucidated by means of spectroscopic analyses (HRESIMS, IR, NMR and ECD). All of the isolated compounds were evaluated for their antitumor activities against MGC803, MCF-7, A549, HT29 and HepG2 cell lines. Compounds 3-4 showed moderate cytotoxicity against all tested cell lines with IC50 values of 1.8-7.3 MUM. PMID- 30422014 TI - Cell secretome based approaches in Parkinson's disease regenerative medicine. AB - INTRODUCTION: The available therapeutic strategies for Parkinson's disease (PD) rely only on the amelioration of the symptomatology of the disease, lacking neuroprotection or neuroregeneration capacities. Therefore, the development of disease modifying strategies is extremely important for the management of PD in the long term. Areas covered: In this review, the authors provide an overview of the current therapeutic approaches for PD and the emerging use of stem cell transplantation as an alternative. Particularly, the use of the secretome from mesenchymal stem cells (MSCs), as well as some methodologies used for the modulation of their paracrine signaling, will be discussed. Indeed, there is a growing body of literature highlighting the use of paracrine factors and vesicles secreted from different cell populations, for this purpose. Expert opinion: Secretome from MSCs has shown its potential as a therapy for PD. Nevertheless, in the coming years, research should focus in several key aspects to enable the translation of this strategy from the bench to the bedside. PMID- 30422015 TI - Pre-filled syringes for immunoglobulin G (IgG) replacement therapy: clinical experience from other disease settings. AB - INTRODUCTION: Ready-to-use pre-filled syringes for drug delivery are increasingly used across a broad spectrum of clinical specialties. For patients with primary immunodeficiencies manifesting as antibody deficiencies, immunoglobulin G (IgG) replacement therapy (IgRT) by subcutaneous administration is an established treatment modality. Expanding IgRT administration options through the introduction of pre-filled syringes may further improve its utility. Areas covered: Here, we collate experience with pre-filled syringes from other clinical settings to inform on their practicality and suitability for IgRT. In addition to discussing drug characteristics such as stability, pharmacokinetics, and efficacy, we focus on treatment delivery, physician/patient experience, costs, and the importance of education for the use of pre-filled syringes. Expert opinion: Perceived benefits of pre-filled syringes include accurate dosing, sterility, and reduced treatment time, while offering patients greater choice, convenience, and ease-of-use. Our review of clinical experience with pre-filled syringes supports this consensus. Relatively few studies directly compare pre filled syringes with conventional administration, and robust studies of cost effectiveness and health-related quality of life are needed on a drug-by-drug basis. Growth in the availability of pre-filled syringes will continue, encouraged by the importance of patient choice and treatment convenience, toward the goal of individualized treatment regimens and improved quality of life. PMID- 30422016 TI - Links between HPA axis and adipokines: clinical implications in paradigms of stress-related disorders. AB - INTRODUCTION: In the human organism, a constant interplay exists between the stress system [which includes the activity of the hypothalamic-pituitary-adrenal (HPA) axis] and the adipose tissue. This interplay is mediated by hormones of the HPA axis such as corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and glucocorticoids (GCs) and adipokines secreted by the adipose tissue. Areas covered: In this critical review, the bi-directional interactions between HPA axis and the most studied adipokines such as leptin and adiponectin, as well as the pro-inflammatory adipocytokines tumor necrosis factor (TNF) and interleukin (IL) 6 are presented. Furthermore, these interactions are described in normalcy as well as in specific clinical paradigms of stress-related disorders such as eating disorders, hypothalamic amenorrhea, and stress-related endogenous hypercortisolism states. Wherever new therapeutic strategies emerge, they are presented accordingly. Expert commentary: Additional research is needed to clarify the mechanisms involved in the interplay between the HPA axis and the adipose tissue. Research should be focused, in particular, on the development of new therapeutic means targeting dysfunctional adipose tissue in stress-related situations. PMID- 30422017 TI - Lung cancer: active therapeutic targeting and inhalational nanoproduct design. AB - INTRODUCTION: Pulmonary drug delivery is organ-specific and benefits local drug action for lung cancer. The use of nanotechnology and targeting ligand enables cellular-specific drug action. Combination approaches increase therapeutic efficacy and reduce adverse effects of cancer chemotherapeutics that have narrow therapeutic index window and high cytotoxicity levels. The current progress of inhaled cancer chemotherapeutics has not been examined with respect to targeting strategy and clinical application potential. Areas covered: This review examines the state of the art in passive (processing and formulation) and active (targeting ligand and receptor binding) technologies in association with the use of nanocarrier to combat lung cancer. It highlights routes to equip nanocarrier with targeting ligands as a function of the chemistry of participating biomolecules and challenges in inhalational nanoproduct development and clinical applications. Both research and review articles were examined using the Scopus, Elsevier, Web of Science, Chemical Abstracts, Medline, CASREACT, CHEMCATS, and CHEMLIST database with the majority of information retrieved between those of 2000-2018. Expert commentary: The therapeutic efficacy of targeting ligand decorated nanocarriers needs to be demonstrated in vivo in the form of finished inhalational products. Their inhalation efficiency and medical responses require further examination. Clinical application of inhaled nanocancer chemotherapeutics is premature. PMID- 30422018 TI - Identification of discrepancy between CTLA4 expression and CTLA4 activation in gastric cancer. AB - OBJECTIVE: Recently, immune checkpoints blockers showed higher anti-tumor activity for advanced gastric cancer (GC). The purpose of the study is to find out predictive biomarkers related to anti-cytotoxic lymphocyte antigen 4 (CTLA4) therapy. MATERIALS AND METHODS: Datasets of gene expression omnibus (GEO), the cancer genome atlas (TCGA), and gene set enrichment analysis (GESA) were extracted. Differential expression of CTLA4 between cancer tissues and normal mucosa, enrichment of WT (wild type) vs. CTLA4_KO (knockout) upregulated gene set and clinical significance were analyzed. The expression of CTLA4, CD3, and granzyme A (GZMA) were validated on 30 cases of Chinese GC. Microsatellite instability (MSI) marker MLH1 and Epstein-Barr virus (EBV) marker EBER were examined on 30 cases of Chinese GC by immunohistochemistry and in situ hybridization. RESULTS: CTLA4 was upregulated in GC tissue relative to normal mucosa in datasets of GSE27342 (fold change = 1.586, p < .001) and GSE63089 (fold change = 1.365, p < .001). Increased CTLA4 expression was positively related to CTLA4 activation. EBV-associated GC (EBVaGC) and microsatellite instability GC (MSIGC) disclosed higher CTLA4 levels than other GCs. Genomic stability GC (GSGC) also showed higher enrichment score of CTLA4 activation. CTLA4 activation resulted in shorter overall survival in GC. The expression level of CTLA4 was well correlated to expression levels of GZMA (R = 0.701, p < .001) and CD3 (R = 0.750, p < .001). CONCLUSIONS: Based on bioinformatics analysis, GSGC should be worth noticed as a potential GC subtypes responsive to anti-CTLA4 treatment. PMID- 30422019 TI - A novel synthetic small molecule DMFO targets Nrf2 in modulating proinflammatory/antioxidant mediators to ameliorate inflammation. AB - Inflammation is a protective immune response against invading pathogens, however, dysregulated inflammation is detrimental. As the complex inflammatory response involves multiple mediators, including the involvement of reactive oxygen species, concomitantly targeting proinflammatory and antioxidant check-points may be a more rational strategy. We report the synthesis and anti inflammatory/antioxidant activity of a novel indanedione derivative DMFO. DMFO scavenged reactive oxygen species (ROS) in in-vitro radical scavenging assays and in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. In acute models of inflammation (carrageenan-induced inflammation in rat paw and air pouch), DMFO effectively reduced paw oedema and leucocyte infiltration with an activity comparable to diclofenac. DMFO stabilised mast cells (MCs) in in-vitro A23187 and compound 48/80-induced assays. Additionally, DMFO stabilised MCs in an antigen (ovalbumin)-induced MC degranulation model in-vivo, without affecting serum IgE levels. In a model of chronic immune-mediated inflammation, Freund's adjuvant induced arthritis, DMFO reduced arthritic score and contralateral paw oedema, and increased the pain threshold with an efficacy comparable to diclofenac but without being ulcerogenic. Additionally, DMFO significantly reduced serum TNFalpha levels. Mechanistic studies revealed that DMFO reduced proinflammatory genes (IL1beta, TNFalpha, IL6) and protein levels (COX2, MCP1), with a concurrent increase in antioxidant genes (NQO1, haem oxygenase 1 (HO-1), Glo1, Nrf2) and protein (HO-1) in LPS-stimulated macrophages. Importantly, the anti inflammatory/antioxidant effect on gene expression was absent in primary macrophages isolated from Nrf2 KO mice suggesting an Nrf2-targeted activity, which was subsequently confirmed using siRNA transfection studies in RAW macrophages. Therefore, DMFO is a novel, orally-active, safe (even at 2 g/kg p.o.), a small molecule which targets Nrf2 in ameliorating inflammation. PMID- 30422020 TI - Necrotizing Fasciitis: An Overview and 2 Illustrative Cases. AB - Necrotizing fasciitis is the generic term for a series of progressive gangrenous infections of the skin and subcutaneous tissues. Typically, necrotizing fasciitis start with an, often small, infected lesion with atypical symptoms, which then quickly develops into a rapidly spreading, massive infection. The primary therapy is excision of all necrotic tissue in combination with treatment of systemic symptoms such as shock. The defects resulting from rigorous excision are often very large. Once they are clean, they require closure with an autograft. This article reviews the symptoms and treatment of necrotizing fasciitis. In addition, it illustrates, with 2 cases, how a hyaluronic-based extracellular matrix can be used to "fill in" with neodermis for the lost dermis and can create a wound bed most suitable for grafting. PMID- 30422021 TI - Polydatin protects against ovalbumin-induced bronchial asthma in rats; involvement of urocortin and surfactant-D expression. AB - CONTEXT: Prevalence of bronchial asthma massively increases worldwide, while the frequent therapies are still not sufficient. Polydatin, a naturally occurring glycoside, was known as to have anti-inflammatory and anti-oxidant effects. OBJECTIVE: The current study aimed to investigate the possible protective effect of polydatin against experimental bronchial asthma in rats. MATERIAL AND METHODS: Bronchial asthma was induced by ovalbumin (OVA) sensitization and challenge. Rats were randomly allocated into five groups; Group I (normal control group); Group II (asthma control group) received OVA; Group III (reference standard treatment group) received dexamethasone (1 mg/kg/day); Group IV (treatment group) received polydatin (200/mg/kg); and Group V (polydatin control group). The inflammatory biomarkers interleukin-4 (IL-4), IL-5, IL-13, tumor necrosis factor-alpha, interferon-gamma and absolute eosinophil count in bronchoalveolar lavage fluid (BALF), as well as serum immunoglobulin E were assessed, coupled with the oxido nitrative stress biomarkers malondialdehyde and glutathione reduced levels and superoxide dismutase activity in the lung tissue, besides inducible nitric oxide synthase level in BALF. Western blot analysis of surfactant-D and immunohistochemical assay of urocortin (UCN) expression in the lung was performed. RESULTS: Polydatin significantly reduced the inflammatory mediators and restored the normal values of oxidative and nitrosative stress biomarkers. It also significantly reduced the expression of surfactant-D and UCN as compared to asthma control. The histopathological study strongly augmented the biochemical results. DISCUSSION AND CONCLUSIONS: Polydatin may be a promising protective agent against experimentally induced bronchial asthma. Modulation of SP-D and UCN expressions seems to mediate such protective effects. PMID- 30422022 TI - Characterization of Natural Killer Cells in HIV Patients Beginning Therapy with a High Burden of Cytomegalovirus. AB - BACKGROUND: Active infections with cytomegalovirus (CMV) increase NK cell expression of the inhibitory receptor LIR-1 and the activating receptor NKG2C in transplant recipients. However, the effects of CMV on NK cells are different in HIV patients stable on antiretroviral therapy (ART) and have not been analyzed in young HIV patients beginning ART. METHODOLOGY: We followed a cohort of 78 Indonesian HIV patients beginning ART. CMV antibodies were measured in plasma before ART (baseline), and after 1, 3, 6, and 12 months. CMV DNA was sought in blood granulocytes at baseline by quantitative PCR assay and a deletion in the NKG2C gene was identified by PCR. NK cell profiles were monitored by flow cytometry in 19 patients stratified by the presence of CMV DNA. Healthy controls (n = 17) were assessed once. RESULTS: All 78 patients were CMV seropositive and 41 had detectable CMV DNA. CMV DNA+ patients had higher proportions of total NK cells and CD16+ NK cells at baseline, but similar expression of LIR-1 and NKp30 on NK cells on ART. However, levels of CMV antibody were inversely related to median LIR-1 expression on NK cells. A dramatic elevation in cells expressing NKG2C was restricted to CMV DNA+ patients heterozygous for the NKG2C deletion. Patients with High NKG2C expression had lower levels of CMV antibodies. CONCLUSION: A subpopulation of NK cells expressing NKG2C was induced by CMV replication in HIV patients heterozygous for a deletion in this gene. Individuals with an abundant NKG2C+ and LIR-1+ NK cells displayed lower levels of CMV reactive antibody. PMID- 30422023 TI - Oxidative DNA and RNA damage and their prognostic values during Salmonella enteritidis-induced intestinal infection in rats. AB - Emerging evidence suggests that microbial pathogens may induce oxidative stress in infected hosts. The aim of the present study was to investigate the relationship between changes in oxidative stress and intestinal infection with and without antibiotic treatment in animal models. Sprague-Dawley (SD) rats were divided into three groups: rats infected with Salmonella enterica serovar Enteritidis (S. enteritidis), rats infected with S. enteritidis followed by norfloxacin treatment, and the control group. To evaluate oxidative stress changes, levels of 8-oxo-7,8-dihydroguanosine (8-oxo-Gsn) and 8-oxo-7,8-dihydro-2 deoxyguanosine (8-oxo-dGsn), which represented oxidative damage to RNA and DNA, respectively, were analysed in urine and tissue samples. In urine, the level of 8 oxo-Gsn increased significantly after oral exposure to S. enteritidis (p <= 0.001) and returned to baseline after recovery. Notably, norfloxacin treatment decreased the level of 8-oxo-Gsn in urine significantly (p = 0.001). Changes of 8 oxo-Gsn measured in tissues from the small intestine, colon, liver and spleen were consistent with 8-oxo-Gsn measured in urine. Our study suggested that 8-oxo Gsn in urine may serve as a highly sensitive biomarker for evaluating the severity of S. enteritidis infection and the effectiveness of antibiotic treatment against infection. PMID- 30422024 TI - Response to: Is there such a thing as a fair OSCE? PMID- 30422025 TI - Dentists' use of digital radiographic techniques: Part II - extraoral radiography: a questionnaire study of Swedish dentists. AB - OBJECTIVE: The present study aims to gain knowledge about the dentist's use and choice of digital extraoral imaging methods, panoramic radiography and cone beam computed tomography (CBCT). MATERIALS AND METHODS: A questionnaire sent to 2481 dentists within the Swedish Dental Society contained questions about the panoramic technique and CBCT technique used, education, clinic size and type of service. The response rate was 53%. RESULTS: The study showed that 61% of the Swedish dentists had access to panoramic techniques and that 84% used a direct digital sensor, while 6% used storage phosphor plate techniques. Around 8% of the Swedish dentists had access to CBCT. It was also observed that group practices had two times higher odds of having panoramic equipment compared with solo practices. Approximately 40% of the dentists had undergone postgraduate education in oral radiology during the last 5 years. Dental nurses and dental hygienists exposed 92% of the panoramic radiographs and 75% of the CBCTs. Thirty per cent of those clinics with access to a panoramic unit exposed >30 panoramic radiographs per month and 56% of the clinics having access to CBCT did more than 75 examinations per year. CONCLUSIONS: Today 61% of Swedish dentists have access to panoramic radiography and 8% have access to CBCT. There is a greater likelihood of having access if the dentist works in the public dental health service or in a group practice and if the dentist has undergone any postgraduate course in oral radiology. PMID- 30422026 TI - Monocyte/HDL Ratio and Lymphocyte/Monocyte Ratio in Patients with Pseudoexfoliation Syndrome. AB - PURPOSE: To evaluate the association between monocyte count/high-density lipoprotein (HDL) ratio (MHR) and lymphocyte count/monocyte count ratio (LMR) with pseudoexfoliation syndrome (PEXS) and pseudoexfoliation glaucoma (PEXG). MATERIALS AND METHODS: A total of 63 participants included in the study. Participants were divided into three groups. Twenty-one patients with PEXS regarded as group 1, 21 patients with PEXG regarded as group 2 and 21 participants without PEXS or PEXG regarded as the control group. Blood parameters were accessed from file records and database retrospectively. RESULTS: The mean MHRs were significantly higher in group 1 and group 2 (p = 0.003, p = 0.036) than the control group, whereas there was no difference between group 1 and group 2 (p = 0.686). The mean LMRs were lower in group 1 and group 2 than the control group but the difference was insignificant (p = 0.232). CONCLUSION: We found that there is an association between higher MHR and lower LMR with PEXS. PMID- 30422027 TI - The Norwegian Occupational Balance Questionnaire (OBQ11-N) - development and pilot study. AB - BACKGROUND: The concept occupational balance has been linked with health and well being, and it is therefore viewed as an important concept for occupational therapy practice, theory and research. To operationalize and measure occupational balance, the Occupational Balance Questionnaire (OBQ) was developed in Sweden. To date, no Norwegian translations of the OBQ exists. AIM: To describe the process of developing a Norwegian version of the 11-items Occupational Balance Questionnaire (OBQ11-N) and to evaluate its feasibility and face validity. METHODS: The development process followed a predetermined series of steps, including forward and back translation and cognitive interviews with a pilot sample. RESULTS: The pilot study sample (n = 8) varied with respect to age, gender and education level. There was high level of agreement between the participants with regard to their understanding of the content of the items. Three of the items were slightly modified in terms of words and phrasing. CONCLUSION: The OBQ11-N was developed according to established translation guidelines and appears to be feasible and have good face validity. SIGNIFICANCE: The OBQ11-N may prove useful for assessing occupational balance and associated factors in Norwegian population groups. However, more research is needed to establish the Norwegian version of the questionnaire as psychometrically valid. PMID- 30422028 TI - Endoplasmic reticulum stress mediates inflammatory response triggered by ultra small superparamagnetic iron oxide nanoparticles in hepatocytes. AB - Ultra-small superparamagnetic iron oxide nanoparticles (USPIO-NPs) are widely used as clinical magnetic resonance imaging contrast agents for hepatic diseases diagnosis. USPIO-NPs often damage the hepatocytes and affect the function of liver but its mechanism of action remains unclear. In the present study, USPIO NPs caused higher cytotoxicity and lactate dehydrogenase (LDH) leakage in hepatic L02 cells than SPIO-NPs. Subsequently, USPIO-NPs affected more genes' expression than SPIO-NPs analyzed through microarray and bioinformatics analysis. The affected genes were involved in several biological processes, including calcium ion homeostasis, inflammatory response-related leukocyte chemotaxis, and migration. In addition, the level of endoplasmic reticulum (ER) calcium ion was increased by USPIO-NPs. USPIO-NPs also upregulated the genes related to acute phase inflammation, including IL1B, IL6, IL18, TNFSF12, TNFRSF12, SAA1, SAA2, JAK1, STAT5B, and CXCL14. Furthermore, interleukin-6 (IL-6) secretion was elevated by USPIO-NPs as detected using ELISA. On the other hand, USPIO-NPs changed the morphology of ER and triggered the ER stress and unfolded protein response PERK/ATF4 pathway. Furthermore, blocking ER stress with inhibitor or ATF4 small interfering RNA counteracted IL-6-related acute-phase inflammation and cytotoxicity caused by USPIO-NPs. Taken together, we found that the USPIO-NPs could trigger stronger IL-6-related acute-phase inflammation than SPIO-NPs in hepatocytes. We demonstrated, for the first time, that IL-6-related acute-phase inflammation caused by NPs was regulated by PERK/ATF4 signaling. The PERK/ATF4 pathway explored in this study could be a candidate for diagnostic and therapeutic target against NPs-induced liver injury and cytotoxicity, which would be helpful for USPIO-NPs medical application. PMID- 30422029 TI - Vacuolar hydrolysis and efflux: current knowledge and unanswered questions. AB - Hydrolysis within the vacuole in yeast and the lysosome in mammals is required for the degradation and recycling of a multitude of substrates, many of which are delivered to the vacuole/lysosome by autophagy. In humans, defects in lysosomal hydrolysis and efflux can have devastating consequences, and contribute to a class of diseases referred to as lysosomal storage disorders. Despite the importance of these processes, many of the proteins and regulatory mechanisms involved in hydrolysis and efflux are poorly understood. In this review, we describe our current knowledge of the vacuolar/lysosomal degradation and efflux of a vast array of substrates, focusing primarily on what is known in the yeast Saccharomyces cerevisiae. We also highlight many unanswered questions, the answers to which may lead to new advances in the treatment of lysosomal storage disorders. Abbreviations: Ams1: alpha-mannosidase; Ape1: aminopeptidase I; Ape3: aminopeptidase Y; Ape4: aspartyl aminopeptidase; Atg: autophagy related; Cps1: carboxypeptidase S; CTNS: cystinosin, lysosomal cystine transporter; CTSA: cathepsin A; CTSD: cathepsin D; Cvt: cytoplasm-to-vacuole targeting; Dap2: dipeptidyl aminopeptidase B; GS-bimane: glutathione-S-bimane; GSH: glutathione; LDs: lipid droplets; MVB: multivesicular body; PAS: phagophore assembly site; Pep4: proteinase A; PolyP: polyphosphate; Prb1: proteinase B; Prc1: carboxypeptidase Y; V-ATPase: vacuolar-type proton-translocating ATPase; VTC: vacuolar transporter chaperone. PMID- 30422030 TI - Alpha- and gamma-mangostins exhibit anti-acne activities via multiple mechanisms. AB - OBJECTIVE: Acne is a chronic skin disease that involves four key pathogenic factors: excess sebum production, ductal epidermal hyperproliferation, Propionibacterium acnes (P. acnes) colonization, and skin inflammation. Mangostins are well-known for their anti-bacterial and anti-inflammatory effects, suggesting that mangostins may have therapeutic potential for acne. The present study aimed to explore the anti-acne effects of mangostins from the perspective of multiple pathogenic mechanisms of acne. METHODS: The effects of alpha- and gamma-mangostins on the growth of P. acnes and lipase activity were analyzed. Their effects on P. acnes-induced keratinocyte proliferation were examined by CCK 8. The expression of inflammatory genes and activation of NF-kappaB and MAPK signaling pathways were detected by quantitative real-time PCR and western blotting, respectively. RESULTS: Alpha- and gamma-mangostins not only inhibited the growth of P. acnes, but also reduced the proliferation of keratinocytes induced by heat-killed P. acnes. Furthermore, alpha- and gamma-mangostins were able to suppress P. acnes-induced expression of pro-inflammatory cytokines, including TNF-alpha, IL-1beta, and IL-6 in keratinocytes by inhibiting the activation of NF-kappaB and MAPK signaling pathways. DISCUSSION AND CONCLUSIONS: Mangostins appeared to possess multiple anti-acne activities, including the inhibition of P. acnes growth, regulation of keratinocytes proliferation, and attenuation of skin inflammatory reaction. Hence, mangostins might be developed into a potential therapeutic agent for the treatment of acne. PMID- 30422031 TI - Durability of single-dose rVSV-ZEBOV vaccine responses: what do we know? AB - INTRODUCTION: The live-attenuated recombinant vesicular stomatitis virus vaccine expressing the glycoprotein (GP) of Zaire Ebola virus (rVSV-ZEBOV) has proven immunogenic in humans and effective in field studies. Yet long-term durability of vaccine responses is unknown. Areas covered: We survey the evidence available in the literature for the durability of human responses to rVSV-ZEBOV. We also review determinants of initial responses and of their persistence. Expert commentary: Persistence of EBOV-GP-specific antibody responses is strong at 2 years - currently the longest post-vaccination interval studied - after a single injection. Vaccine dose predicts persistence of seropositivity, though the magnitude of antibody responses at later time points becomes less dose-dependent. Vaccine-related arthritis is a significant predictor of both persistence and magnitude of the antibody response. PMID- 30422032 TI - Body Mass Index and Mortality in Elderly Subjects from the Moli-Sani Study: A Possible Mediation by Low-Grade Inflammation? AB - The association between obesity and mortality in the elderly remains controversial. To test the association between BMI and mortality, with the hypothesis of a mediation by low-grade inflammation (LGI), a prospective study design (median follow-up 7.8 years) was used on a sample of 4,970 elderly subjects (age >= 65 years) from the Moli-sani Study cohort. The association between BMI categories and overall or cause-specific mortality (hazard ratio, HR) was calculated by multivariable Cox regression. Dose-response relationship was tested using restricted cubic splines. Interaction between BMI and LGI, assessed through high-sensitivity C-reactive protein (hs-CRP) and INFLA-score, was also tested. In comparison with normal-weight, overweight was significantly associated with a 20% (adjusted HR = 0.80; 95%CI 0.67-0.95) reduced risk of total mortality, while severe obesity (BMI > 40) with an increased risk (HR = 1.81; 95%CI 1.13 2.93). Cubic spline curves showed a U-shaped relationship between BMI and total mortality (p value for nonlinear relationship = 0.001). Similar results were found for cardio-cerebrovascular and other causes mortality. Hs-CRP and INFLA score were associated with an increased risk of total mortality in adjusted analyses. Mediation analysis did not show any effect of LGI on the association between BMI and mortality. However, after stratification for LGI under or below the population median, greater LGI increased the risk of mortality in obese elderly more than expected (p for interaction = 0.04). A U-shaped association between BMI and mortality was observed in Italian elderly subjects. While the association was independent of LGI levels, there was a significant interaction between BMI and LGI in increasing mortality risk in obese elderly individuals. PMID- 30422033 TI - Establishing a new medical school: A contemporary approach to personalizing medical education. AB - OBJECTIVE: To borrow a public health concept, there has been a global outbreak, perhaps a pandemic, of new medical schools during the last 20 years, resulting in a diverse range of programs in many different contexts. The question posed was: how should the task of establishing a new medical program be approached in 2018? METHODS: Based on involvement with several new medical programs, this paper presents a highly idealistic commentary on what a new medical program might look like. The paper adopts the organizational structure of the World Federation of Medical Education Basic Medical Education standards as a scaffold, because accreditation both locally and globally is intended. RESULTS: The program design reflects both progress in learning technology and the challenges faced in a changing world, where disruption appears inevitable, and innovation may be necessary to produce the medical graduates needed to improve the health status of an expanding, ageing and ailing global population. CONCLUSION: The program model described represents a combination of educational design, emerging technology and a focus on future health care needs. PMID- 30422035 TI - Key features to assess clinical decisions. PMID- 30422034 TI - Enamel matrix derivative (Emdogain) in treatment of replanted teeth - a systematic review. AB - OBJECTIVE: The main purpose of the present systematic review was to evaluate the efficacy of enamel matrix derivative Emdogain in healing of replanted teeth in humans. MATERIALS AND METHODS: This review conducted in adherence to PRISMA standards and was registered in PROSPERO with registration number CRD42017062736. We graded the methodological quality of the studies by means of Cochrane's tool of risk of bias in non-randomized studies - of interventions (ROBINS-I). RESULTS: In total, 65 studies were identified for screening, and five studies were eligible. The uneventful healing of replanted teeth was varied from 20% to 75%. Two controlled trials found Emdogain treatment significantly reduced resorption of replanted teeth and improved the healing of periodontal ligament compared with controls. Two studies showed high recurrent resorption in Emdogain treated teeth. CONCLUSIONS: To conclude, the number of publications that met all inclusion criteria were limited and did not allow for drawing evidence for Emdogain being effective in supporting healing of replanted teeth. PMID- 30422036 TI - Medical Teacher reviewers in 2018. PMID- 30422037 TI - Increased platelet reactivity and platelet-leukocyte aggregation after elective coronary bypass surgery. AB - Inflammatory mechanisms are activated, and thrombotic complications occur during the initial months after coronary artery bypass grafting (CABG). Therefore, changes over time of platelet activation and platelet-leukocyte interactions after CABG are of interest. Whole-blood flow cytometry was performed before, and 4-6 days, one month, and three months after elective CABG in 54 men with stable coronary artery disease treated with acetylsalicylic acid (ASA). Single platelets and platelet-leukocyte aggregates (PLAs) among monocytes (P-Mon), neutrophils (P Neu), and lymphocytes (P-Lym) were studied without and with stimulation by submaximal concentrations of ADP, thrombin, and the thromboxane analog U46619. White blood cell counts were increased during the initial postoperative course, and platelet counts were increased after one month. Platelet P-selectin expression was significantly enhanced at one month when stimulated by thrombin and U46619 and at three months with ADP and thrombin. All PLAs subtypes were increased at one month without stimulation in vitro. P-Mon and P-Neu stimulated by ADP, thrombin, or U46619 were significantly increased one month after the operation but decreased compared to baseline at three months. Agonist stimulated P-Lyms were increased at one month and remained increased at three months after ADP stimulation. There was significant platelet activation and formation of PLAs unstimulated and after agonist stimulation by ADP, thrombin, and a thromboxane analog after CABG in patients with stable coronary artery disease irrespective of ASA treatment. Changes observed up to three months after CABG support further studies of the clinical implications of protracted increases in platelet activation and platelet-leukocyte interactions. PMID- 30422038 TI - Reproducibility of Task-Oriented Bimanual and Unimanual Strength Measurement in Children with Unilateral Cerebral Palsy. AB - AIM: To examine reproducibility of the arm-hand strength measured while performing the bimanual crate task and the unimanual pitcher task. METHODS: 105 children diagnosed with unilateral Cerebral Palsy, aged between 6 and 18 years, participated in this study. The test-retest reliability of the force generated during bimanual crate task and unimanual pitcher task of the Task-oriented Arm hAnd Capacity instrument was investigated using intraclass correlation two-way random model with absolute agreement. The intraclass correlations were calculated for two age groups (6-12 and 13-18 years old). RESULTS: The results showed good test-retest reliability for the crate and pitcher task with the non-affected hand for both age groups. The results of the pitcher task for the affected hand showed moderate test-retest reliability for both age groups. CONCLUSION: The Task oriented Arm-hAnd Capacity instrument has moderate to good test-retest reliability. It is a simple and objective instrument to assess task-oriented strength in children with unilateral cerebral palsy. PMID- 30422039 TI - Chronic liver disease, thrombocytopenia and procedural bleeding risk; are novel thrombopoietin mimetics the solution? AB - Chronic liver disease (CLD) alters normal hemostatic and thrombotic systems via multiple mechanisms including reduced platelet function and number, leading to challenging peri-operative planning. Hepatic thrombopoietin (TPO) synthesis is reduced in CLD, leading to several recent randomized, placebo-controlled trials examining the utility of TPO-mimetics to increase platelet counts prior to surgery. While these trials do suggest that TPO-mimetics are efficacious at increasing platelet counts in patients with CLD and have led to several recent drug approvals in this space by the U.S. Food & Drug Administration, it remains unclear whether these results translate to the relevant clinical endpoint of reduced perioperative bleeding rate and severity. In this article, we review several recently-published, phase 3 trials on the TPO-mimetics eltrombopag, avatrombopag and lusutrombopag, and discuss the clinical significance of their results. PMID- 30422040 TI - Relationship Between Two-Dimensional Frontal Plane Measures and the Knee Abduction Angle During the Drop Vertical Jump. AB - CONTEXT:: Knee abduction angle (KAA), as measured by three-dimensional marker based motion capture systems during jump landing tasks, has been correlated with an elevated risk of anterior cruciate ligament (ACL) injury in females. Due to the high cost and inefficiency of KAA measurement with marker-based motion capture, surrogate two-dimensional frontal plane measures have gained attention for injury risk screening. The knee-to-ankle separation ratio (KASR) and medial knee position (MKP) have been suggested as potential frontal plane surrogate measures to the KAA, but investigations into their relationship to the KAA during a bilateral drop vertical jump task are limited. OBJECTIVE:: To investigate the relationship between knee-to-ankle separation ratio (KASR) and medial knee position (MKP) to the knee abduction angle (KAA) during initial contact of the bilateral drop vertical jump. DESIGN:: Descriptive. SETTING:: Biomechanics laboratory. PARTICIPANTS:: Eighteen healthy female participants (mean age: 24.1 +/- 3.88 years, mass: 65.18 +/- 10.34 kg, and height: 1.63 +/- 0.06 m). INTERVENTION:: Participants completed 5 successful drop vertical jump trials measured by a Vicon marker-based motion capture system and two AMTI force plates. MAIN OUTCOME MEASURES:: For each jump, KAA of the tibia relative to the femur was measured at initial contact along with the KASR and MKP calculated from planar joint center data. The coefficient of determination (r2) was used to examine the relationship between the KASR and MKP to KAA. RESULTS:: A strong linear relationship was observed between MKP and KAA (r2=0.71), as well as between KASR and KAA (r2=0.72). CONCLUSIONS:: Two-dimensional frontal planes measures show strong relationships to the KAA during the bilateral drop vertical jump. PMID- 30422041 TI - "A Fine Line That We Walk Every Day": Self-care Approaches Used by Family Caregivers of Persons With Dementia. AB - Individuals living with Alzheimer's disease and related dementias (ADRD) often exhibit behavioral and psychological symptoms of distress that can contribute to the strain experienced by their family caregivers. This strain can increase levels of stress for family caregivers and reduce quality of life, which can have a negative impact on physical health and wellbeing for both the caregiver and the person with ADRD. This study used blogs written by family caregivers of persons with ADRD to explore self-care strategies practiced by these caregivers. Using a qualitative thematic analysis, seven themes related to self-care approaches used by caregivers of persons with ADRD were identified: (1) health and wellness; (2) altruism and activism; (3) reminiscing and legacy building; (4) social support; (5) information exchange; (6) organization and planning; and (7) spirituality. By understanding the ways in which caregivers for someone with ADRD practice self care, interventions and services can be developed in an effort to improve caregiver quality of life. PMID- 30422042 TI - Differences between Men and Women Regarding Early Maladaptive Schemas in an Australian Adult Alcohol Dependent Clinical Sample. AB - BACKGROUND: Recent research indicates that there are widespread differences between men and women's Early Maladaptive Schemas (EMSs) in alcohol dependent populations. This study examined this claim. OBJECTIVE: The purpose of this study was to examine differences between men and women's EMSs in an Australian clinical sample who had sought treatment specifically for alcohol dependence. METHODS: A total of 111 men and 114 women completed the Young Schema Questionnaire-Long Form (YSQ-L3) between 2012 and 2015 in order to assess them on 18 EMSs. RESULTS: Despite previous findings suggesting that women report higher levels across a number of EMSs, the strongest evidence pointed to women scoring significantly higher than men on the EMS of self-sacrifice (the tendency to excessively help others whilst continually sacrificing one's own needs). Smaller differences between men and women were noted for the subjugation and failure EMSs. Conclusions/Importance: With the exception regarding the finding that woman scored higher on the self-sacrifice EMS than men, the homogeneity of the remaining EMS scores across men and women found in this study support the use of inter-gender group Schema Therapy (ST) with alcohol-dependent adults in Australia. PMID- 30422043 TI - Impact of immature platelet fraction on platelet reactivity during prasugrel maintenance treatment. AB - Residual high on-treatment platelet reactivity (HTPR) despite dual antiplatelet therapy (DAPT) has emerged as a predictor of major ischemic events in patients undergoing percutaneous coronary interventions (PCIs), especially after an acute cardiovascular event. However, its determinants are still poorly defined. Therefore, the aim of the present study was to evaluate the role of the percentage of reticulated platelets on HTPR in patients on DAPT with ASA (100-160 mg) and prasugrel (10 mg). Platelet reactivity and the reticulated platelets fraction (immature platelets fraction [IPF]) were assessed at 30-90 days after an acute coronary syndrome. Aggregation was assessed by multiple-electrode aggregometry. HTPR was defined as ADP test > 417 AU * min. Our population is represented by 180 ACS patients undergoing stent implantation, divided according to median values of IPF (< or >= 2.8%). Higher IPF values were associated to lower platelet count (p < 0.001) and a higher rate of active smokers (p = 0.02). No difference was observed in terms of mean platelet reactivity, with different activating stimuli. The prevalence of HTPR on prasugrel did not significantly differ in patients with IPF < or >= 2.8% (8%vs. 11.8%, p = 0.46; adjusted OR [95% CI] = 1.89 [0.66-5.4], p = 0.24). Our study showed that in patients treated with prasugrel after PCI for ACS, the immature platelet fraction influences neither platelet reactivity nor the rate of HTPR. PMID- 30422044 TI - LEAARC News Brief. PMID- 30422045 TI - Neuropsychological tests of the future: how do we get there from here? AB - OBJECTIVE: This article reviews current approaches to neuropsychological assessment, identifies opportunities for development of new methods using modern psychometric theory and advances in technology, and suggests a transition path that promotes application of novel methods without sacrificing validity. METHODS: Theoretical/state-of-the-art review. CONCLUSIONS: Clinical neuropsychological assessment today does not reflect advances in neuroscience, modern psychometrics, or technology. Major opportunities for improving practice include both psychometric and technological strategies. Modern psychometric approaches including item response theory (IRT) enable linking procedures that can place different measures on common scales; adaptive testing algorithms that can dramatically increase efficiency of assessment; examination of differential item functioning (DIF) to detect measures that behave differently in different groups; and person fit statistics to detect aberrant patterns of responding of high value for performance validity testing. Opportunities to introduce novel technologies include computerized adaptive testing, Web-based assessment, healthcare- and bio informatics strategies, mobile platforms, wearables, and the 'internet-of things'. To overcome inertia in current practices, new methods must satisfy requirements for back-compatibility with legacy instrumentation, enabling us to leverage the wealth of validity data already accrued for classic procedures. A path to achieve these goals involves creation of a global network to aggregate item-level data into a shared repository that will enable modern psychometric analyses to refine existing methods, and serve as a platform to evolve novel assessment strategies, which over time can revolutionize neuropsychological assessment practices world-wide. PMID- 30422046 TI - JHL News. PMID- 30422047 TI - [Polypharmacy of psychotropic drugs in child and adolescent psychiatry in Germany - rather the rule than the exception]. AB - : Polypharmacy of psychotropic drugs in child and adolescent psychiatry in Germany - rather the rule than the exception Abstract. BACKGROUND: Polypharmacy increases the risk of interactions and enhances the chance of adverse drug reactions (ADRs). Hence, child and adolescent psychiatrists generally try to avoid polypharmacy with psychotropic drugs. However, only little data regarding the frequency of polypharmacy in child and adolescent psychiatry are available. This study analyzes clinical data on polypharmacy and the possible association with a higher risk of ADRs in Germany, with a focus on antidepressants and antipsychotics. METHODS: We investigated a total of 940 datasets from descriptive studies on therapeutic drug monitoring (TDM) of pediatric patients treated with different psychotropic drugs. RESULTS: The frequency of polypharmacy ranged up to 45.6 % (escitalopram) and 72.1 % (olanzapine). In 17.4 % of the cases, polypharmacy consisted of four or more psycho-/neuropharmacological substances. No increased incidence of ADRs was reported with polypharmacy of antipsychotics compared to monotherapy. Polypharmacy with sertraline was associated with a higher number of ADRs. DISCUSSION AND CONCLUSION: There is a high prevalence of polypharmacy with psychotropic drugs in child and adolescent psychiatry in Germany. Conclusions concerning individual drugs should be drawn with care since the subsample sizes were relatively small. However, our results do provide an indication of the prevalence of polypharmacy, although the validity of the data is limited. There is an urgent need to analyze data from larger and more homogeneous groups under more controlled conditions. PMID- 30422048 TI - Transformation of nad7 into the nuclear genome rescues the slow growth3 mutant in Arabidopsis. AB - Plant pentatricopeptide repeat (PPR) proteins are mostly involved in chloroplast or mitochondrial RNA metabolism. However, direct evidence that correction of the molecular defects in the organelles can restore the plant phenotypes has yet to be demonstrated in a ppr mutant. Arabidopsis slow growth3 (slo3), a ppr mutant, is impaired in the splicing of mitochondrial nad7 intron 2. Here, we have used slo3 as an example to demonstrate that transformation of correctly spliced nad7 into the nuclear genome and targeting the Nad7 subunit into mitochondria can restore complex I activity and plant phenotypes in the mutant. These results provide direct evidence that the strong growth and developmental phenotypes of the slo3 mutant are caused by defects in mitochondrial nad7. PMID- 30422050 TI - We Need Grassroots Activism Now - More than Ever! PMID- 30422049 TI - Development of Secondary Choroidal Neovascularization in Focal Choroidal Excavation of Punctate Inner Choroidopathy. AB - PURPOSE: To elaborate a case of focal choroidal excavation (FCE) in punctate inner choroidopathy (PIC) complicated by secondary choroidal neovascularization (CNV) based on multimodal imaging findings. METHODS: In this retrospective case report, multimodal imaging including near-infrared reflectance, blue peak autofluorescence, spectral domain-optical coherence tomography (OCT), fluorescein and indocyanine green angiography (Heidelberg Engineering GmbH, Germany), and swept source-OCT angiography (SS-OCTA; Topcon Corporation, Japan) was performed. PATIENTS: A 27-year-old moderate myopic woman presented with inactive CNV of unknown origin in her left eye, which had been previously treated with intravitreal anti-vascular endothelial growth factor. RESULTS: Multimodal imaging revealed PIC as the causative disease and systemic corticosteroids were administered. Similar complaints 13 months later showed new CNV formation at the already documented FCE. No sign of PIC could be detected at follow-up. CONCLUSION: This well-documented case highlighted FCE as the preferential location for CNV development in PIC with multimodal imaging emphasizing a chorioretinal entity. SUMMARY: This case report demonstrated the clinical course of focal choroidal excavation in a patient initially diagnosed with punctate inner choroidopathy complicated by choroidal neovascularization and its treatment response, well documented by multimodal imaging including optical coherence tomography angiography. PMID- 30422051 TI - A Republication of TIME WAS... 1894: The Household Guide or Domestic Cyclopedia, Home Remedies for Man and Beast. PMID- 30422052 TI - First-generation versus second-generation drug-eluting stents in patients with chronic kidney disease: a systematic review and meta-analysis. AB - Background:Chronic kidney disease (CKD) patients are associated with very high rate of adverse cardiovascular outcomes after drug-eluting stents (DES) implantation. The clinical outcomes of second-generation DES versus first generation DES in CKD patients remain controversial. Objective: The aim of the current study was to perform a systematic review and meta-analysis to assess the safety and efficacy of second-generation DES versus first-generation DES in CKD patients. Methods:A systematical search of databases of PubMed, EMBASE, and Cochrane Library was conducted for eligible studies comparing the clinical outcomes of first-generation DES versus second-generation DES. Sirolimus-eluting and paclitaxel-eluting stents were classified as first-generation DES, and everolimus-eluting, zotarolimus-eluting and biolimus-eluting stent (BES) were classified as second-generation DES. A pooled odds ratio (OR) and 95% confidence interval (CI) were used to summary the estimates. Heterogeneity, subgroup analysis, sensitivity analysis and publication bias were also performed. Results:We identified 14 trials involving 9,542 patients with CKD undergoing percutaneous coronary intervention. First-generation DES implantation was associated with higher risk of long-term all-cause mortality (OR, 1.31; 95% CI, 1.02-1.69; P = 0.04; I2 = 0%), in stent restenosis (OR, 1.69; 95% CI, 1.14-2.49; P = 0.008; I2 = 49%) and stent thrombosis (OR, 1.64; 95% CI, 1.00-2.69; P = 0.05; I2 = 49%) compared with second-generation DES implantation. First-generation DES and second-generation DES showed similar efficacy in decreasing risk of repeat revascularization, myocardial infarction (MI), or major adverse cardiac events (MACE) between first-generation and second-generation DES implantation. Conclusions: In CKD patients, the use of second-generation DES was associated with lower risk of long-term all-cause mortality, in stent restenosis and stent thrombosis as compared with first-generation DES. No differences were found regarding repeat revascularization, MI, and MACE. PMID- 30422053 TI - ILCA News Brief: Realizing our Strategic Map through Courageous Conversations. PMID- 30422054 TI - The Usefulness of Aqueous Fluid Analysis for Epstein-Barr Virus in Patients with Uveitis. AB - PURPOSE: To determine characteristics of patients with laboratory findings indicative of intraocular Epstein-Barr-virus (EBV) infection and to establish the usefulness of the laboratory analysis in patients with uveitis. METHODS: Retrospective study of patients who underwent diagnostic aqueous fluid analysis. Diverse demographic data of patients were registered. RESULTS: EBV-PCR tested positive in 3/201 (1%) and EBV-GWC in 22/245 (9%). The prevalence of immunosuppression was similar in EBV positive (by PCR/GWC) and EBV negative patients (7/25; 28% vs. 50/272;18%, P = 0.29). Out of all 22 EBV-GWC positive patients, GWC was between 3 and 10 in 91%. In total, 14 patients had laboratory results indicating only EBV infection. Patients without an alternative explanation for uveitis (6/14; 43%) had a chronic recurrent course and good visual prognosis. CONCLUSION: Low EBV-GWC values combined with multiple positive GWC and/or PCR for other infectious agents. Intraocular assessment for EBV in the initial examination of uveitis patients has limited value. PMID- 30422055 TI - Occupants' seatbelt use are related to vehicle type and usage on a Ghanaian university campus. AB - Seat belt use does not only save lives but prevents the severity of injuries in road traffic crashes (RTCs). Vehicle type and usage have been found to influence the use of seat belt in cities like Kumasi, the host of Kwame Nkrumah University of Science and Technology (KNUST) campus. This paper presents a study on an un obstructive survey of seat belt use by vehicle occupants entering and leaving KNUST campus through the four entrances from 7 to 9 am and 3 to 5 pm on five weekdays. A total of 5489 vehicles with 9542 occupants comprising 5489 drivers, front-right and first back seat and second back seat passengers were observed. The majority of the private and SUV drivers used seat belts. Meanwhile, almost all the commercial drivers did not use seat belts. There is a statistically significant relationship between vehicle type and use and the use of seat belt in KNUST. PMID- 30422056 TI - In vitro generation of tau aggregates conformationally distinct from parent tau seeds of Alzheimer's brain. AB - Normal monomeric tau can be converted into pathogenic aggregates and acquire protease resistance in a prion-like manner. This acquisition of partial protease resistance in tau aggregates has to date only been partially investigated in various studies exploring the prion-like properties of tau. In this study, we induced the aggregation of tau repeat domain (RD) in cultured cells using detergent insoluble fractions of Alzheimer's brain tissue as seeds. The seeded aggregation of tau RD in cultured cells formed a ~7 kDa protease-resistant fragment in contrast to the ~12 kDa tau fragment characteristic of the AD seeds, suggesting that the in vitro generated tau aggregates were conformationally distinct from parent seeds. PMID- 30422058 TI - Correction. PMID- 30422057 TI - Lateral kinetic proficiency and asymmetry in backstroke start performed with horizontal and vertical handgrips. AB - We aimed to compare preferred, non-preferred, hand, foot kinetics and their asymmetry in two backstroke start variants. Complementarily, asymmetries were correlated to the resultant take-off velocity. Nine swimmers completed four 15 m backstroke starts with horizontal handgrips and four with vertical handgrips on an instrumented block (right, left hand, foot forces and impulse, normalised to swimmers' weight and time). We applied handedness and footedness questionnaires. Preferred hand and foot depicted a very and most likely moderate to large increase on horizontal force before hands-off (-0.51 +/- 0.10; -0.47 +/- 0.10; 0.87 +/- 0.15; 0.90 +/- 0.18 (N/N)) and a very and most likely large to very large increase on horizontal impulse (-0.28 +/- 0.05; -0.26 +/- 0.04; 0.50 +/- 0.03; 0.51 +/- 0.04 (N/N)*(s/s)) in both variants. Non-preferred hand and foot showed a very likely large to moderate increase (95% to 99%) on vertical and lateral impulse (0.30 +/- 0.03; 0.31 +/- 0.03; 0.07 +/- 0.04; 0.05 +/- 0.03 (N/N)*(s/s)) in both variants. The horizontal handgrip demonstrated likely moderate greater horizontal forces asymmetry on hands in the starting signal ( 20.39 +/- 7.16 (N/N), 92%), before hands-off (-71.46 +/- 24.48 (N/N), 90%) and impulse asymmetry (-21.13 +/- 5.80 (N/N), 94%). Asymmetry and resultant take-off velocity in both variants were strongly associated (r = -0.733 and -0.833 for feet horizontal impulse). Kinetics lateralisation was noticed in backstroke start and asymmetry hampers desirable performance. PMID- 30422059 TI - Internet- and Mobile-Based Interventions for Mental and Somatic Conditions in Children and Adolescents. AB - This meta-review integrates the current meta-analysis literature on the efficacy of internet- and mobile-based interventions (IMIs) for mental disorders and somatic diseases in children and adolescents. Further, it summarizes the moderators of treatment effects in this age group. Using a systematic literature search of PsycINFO and MEDLINE/PubMed, we identified eight meta-analyses (N = 8,417) that met all inclusion criteria. Current meta-analytical evidence of IMIs exists for depression (range of standardized mean differences, SMDs = .16 to .76; 95 % CI: -.12 to 1.12; k = 3 meta-analyses), anxiety (SMDs = .30 to 1.4; 95 % CI: -.53 to 2.44; k = 5) and chronic pain (SMD = .41; 95 % CI: .07 to .74; k = 1) with predominantly nonactive control conditions (waiting-list; placebo). The effect size for IMIs across mental disorders reported in one meta-analysis is SMD = 1.27 (95 % CI: .96 to 1.59; k = 1), the effect size of IMIs for different somatic conditions is SMD = .49 (95 % CI: .33 to .64; k = 1). Moderators of treatment effects are age (k = 3), symptom severity (k = 1), and source of outcome assessment (k = 1). Quality ratings with the AMSTAR-2-checklist indicate acceptable methodological rigor of meta-analyses included. Taken together, this meta-review suggests that IMIs are efficacious in some health conditions in youths, with evidence existing primarily for depression and anxiety so far. The findings point to the potential of IMIs to augment evidence based mental healthcare for children and adolescents. PMID- 30422060 TI - Preparation allergenic pollen extracts; the points should be considered to make high-quality products. AB - Atopic diseases have an increasing trend worldwide during the last two decades. Determining the main cause of allergic diseases, allergens, is the first step in managing and improving the issue, usually is done by Skin Prick tests (SPTs). Having allergenic extract in high quality is desired to perform a reliable SPT. Several parameters of extracts are considered including composition, stability, potency, preservation conditions, and unit definition. In this review, these factors have been explained pointing to factors might have profitable points or harmful drawback in the quality of allergen extracts. PMID- 30422061 TI - Does fundamental movement skill proficiency vary by sex, class group or weight status? Evidence from an Irish primary school setting. AB - This study examined fundamental movement skill (FMS) proficiency among male (N = 216) and female (N = 198) Irish primary school pupils from Year 2 to Year 7 (9.0 +/- 1.7 years). Following anthropometric measurements, participants were video recorded performing 15 FMS and scored using the TGMD-3, Victorian Fundamental Movement skills Manual and the Get skilled: Get active guidelines. Percentage mastery ranged between 1.4% (gallop) and 35.7% (slide). A two-way ANOVA evaluated the effect of sex (male/female) and class group (Year 2/3/4/5/6/7) on individual skills, locomotor subtest, object-control subtest and total TGMD-3 (GMQ) scores. No significant sex *class interaction effects were found. Large effect sizes were reported for male superiority in object-control subtest (etap2 = 0.26) and GMQ (etap2 = 0.16) scores (both p < 0.001). Older classes had higher object-control subtest scores than younger classes, but scores plateaued after Year 5. Furthermore, overweight participants had significantly lower locomotor subtest (p < 0.001, d = 0.7), object-control subtest (p = 0.03, d = 0.3) and GMQ scores (p < 0.001, d = 0.5) than non-overweight participants. This study highlights very poor levels of FMS mastery among Irish schoolchildren and stresses the need for developmentally appropriate, FMS intervention programmes that are inclusive regardless of age, sex or weight status. PMID- 30422062 TI - Passivos, ativos and versateis: men who have sex with men, sexual positions and vulnerability to HIV infection in the northeast of Brazil. AB - In Brazil, men who practise receptive anal sex (passivos) and both insertive and receptive anal sex (versateis) are at greater risk of HIV infection than men who practise only insertive anal sex (ativos). In this study, which combined participant observation, 25 biographical interviews and a behavioural survey of 380 self-identified men who had sex with men in the metropolitan region of Recife (Brazil), we investigated how the sex-gender system, through body stylisation (masculine and effeminate) engenders desire and sexual positioning in men's sexual scenes. The analysis indicated that the sex-gender system tends to reinforce images that portray masculine men as ativos and effeminate men as passivos. However, regarding sexual positioning, sexual versatility is most common (83.3%), which can increase the likelihood of HIV infection and transmission. Stylisations also engender differences in violence related to sexual orientation (e.g. effeminate men were 1.9 times more likely to have experienced violence than masculine men) and desirability (e.g. effeminate men are 6.1 times more likely to be rejected erotically than masculine men). Sexual positioning and stylisation jointly enable community sexual scripts and pathways for HIV to circulate, producing individual and social vulnerability to the epidemic. PMID- 30422063 TI - Involvement of MAPK/ERK1/2 pathway in microcystin-induced microfilament reorganization in HL7702 hepatocytes. AB - Several studies previously demonstrated that microcystin (MC)-LR produced cytoskeletal damage, especially to actin filaments. However, the underlying mechanisms of MC-induced cytoskeletal reorganization remain to be determined. The aim of this study was to examine the effects of 5 or 10 uM MC-LR on microfilament depolarization and expression of microRNA-451a (miR-451a) which plays a crucial role in cellular processes including cell proliferation, apoptosis and tumorigenesis in HL7702 liver cells after 24 hr treatment. Data demonstrated that MC-LR increased microfilament depolarization, elevated phosphorylation levels of mitogen-activated protein kinase (MAPK/ERK1/2) and vasodilator-stimulated phosphoprotein (VASP) but lowered miR-451a RNA expression levels. These molecular processes were associated with no marked changes in total protein ERK1/2. Data demonstrate that transfection with miR-451a may not be effective in the presence of MC-LR as evidenced by the inability of excess microRNA to prevent toxin induced inhibition of threonine protein phosphatases1 (PP1) and 2A (PP2A) and microfilament reorganization in HL7702 cells. PMID- 30422064 TI - Art therapy for anxiety, depression, and fatigue in females with breast cancer: A systematic review. AB - This systematic review employed a meta-analysis to examine the effectiveness of art therapy for treating anxiety, depression, and fatigue in female patients with breast cancer, the most prevalent cancer and the most common cause of cancer related mortality among women worldwide. The review included nine original studies and analyzed data from a total of 754 patients. Data extraction and quality assessment were conducted by two independent reviewers. In total, 1,466 articles were retrieved. We excluded studies in which the participant, interventions, and study design did not satisfy the inclusion criteria, leaving nine articles for analysis, The Cochrane risk of bias assessment tools were used for quality evaluation. The analysis revealed a significant difference in treatment outcomes between patients who received art therapy and those who did not (SMD = -0.48, 95%CI [-0.75, -0.21, p = 0.0005]). The review provides initial evidence to suggest that art therapy benefits female breast cancer patients with respect to the treatment of anxiety, depression, and fatigue. However, additional and better-quality studies must be conducted, particularly with larger sample sizes, greater specificity of the design of trials and interventions, and a longer follow-up duration. PMID- 30422065 TI - Pharmacogenetic guidelines and decision support tools for depression treatment: application to late-life. AB - Late-life depression (LLD) is a major depressive disorder that affects someone after the age of 60 years. LLD is frequently associated with inadequate response and remission from antidepressants, in addition to polypharmacy. Pharmacogenetics offers a promising approach to improve clinical outcomes in LLD via new discoveries determining the genetic basis of response rates and side effects, as well as the development of tailored pharmacogenetic-based decision support tools. This invited review evaluates the LLD pharmacogenetic evidence base and the extent to which this was incorporated into existing commercial decision support tools and clinical pharmacogenetic guidelines. PMID- 30422066 TI - [Operationalized Psychodynamic Diagnosis - Structure Questionnaire (OPD-SQ) in Youth: First Results on Reliability and Validity]. AB - Operationalized Psychodynamic Diagnosis - Structure Questionnaire (OPD-SQ) in Youth: First Results on Reliability and Validity The OPD structure axis questionnaire (OPD-SQ) demonstrated good empirical findings and usability in therapeutic work. Therefore, the aim of this study was to verify the OPD-SQ for an adolescent sample in order to further implement the questionnaire as an economic instrument in clinical childhood and adolescence psychiatry routine. The overall sample consisted of 180 adolescent inpatients (72.8 % female) and 152 pupils (57.9 % female). In order to test reliability, Cronbach's alpha and discriminatory power were assessed. To test validity, YSR11-18 data was collected for the overall sample, and further data (AIDA, LoPF Q12-18, SKID-II, WISC-IV) was collected for the inpatient-sample. Cronbach's alpha was satisfactory for overall OPD-SQ, and all dimensions and sub-dimensions. The differences in mean values between inpatients and pupils were as expected. When controlled for overall symptom severity, gender differences lost significance. Adolescents with one or more SCID-II diagnoses had significantly lower psychic structure. Both construct-related questionnaires (AIDA, LoPF Q12-18) correlated high with OPD-SQ, no correlations were found for psychic structure and intelligence. OPD-SQ proved to be well applicable for the use on adolescents and can be implemented as an economic instrument for the measure of psychic structure in clinical adolescent psychiatry routine. PMID- 30422067 TI - [Editorial]. PMID- 30422068 TI - [Congress Dates]. PMID- 30422069 TI - [Identity - An Illusion? Self Development in Adolescence]. AB - Identity - An Illusion? Self Development in Adolescence With support from their social environment, five out of six young people progress through adolescent development relatively well, while approximately 15 % are at risk of developing psychological problems (Kaess, Ghinea, Fischer-Waldschmidt, Resch, 2017). Those who cannot cope with the challenges of society and who do not have a safe space in the family or among friends to deal with worries and adjustment issues may attempt to stabilize their identity and self-esteem through risk-taking behavior (Kaess et al., 2017). Addictive behavior, e. g. substance abuse or extreme media consumption, may be an expression of adolescents' desire to assert and define their own identity - and not only to anesthetize themselves and forget their troubles. The "Who am I?" question in addictive behavior appears to be closely connected with consumption. The issue of identity will play a very important role for future generations of youth. The following overview, based on scientific findings, examines identity development in adolescence, the connection between identity and risk-taking behavior, and the connection between identity and zeitgeist. PMID- 30422070 TI - [Identity Diffusion Among Adolescents - Validation of the Inventory of Personality Organization in a Clinical Adolescent Sample (IPO-A)]. AB - Identity Diffusion Among Adolescents - Validation of the Inventory of Personality Organization in a Clinical Adolescent Sample (IPO-A) The main objective of the current study was to analyze the psychometric properties of the German version of the Inventory of Personality Organization for Adolescents (IPO-A). The instrument consisting of 91 items is based on the theoretical structural model by Kernberg and investigates the severity of identity diffusion, reality testing and defense mechanisms in order to determine the level of personality organization. The factor structure, the internal consistency and the convergent validity was measured among 144 inpatients aged between 13 and 18 years drawn from the Child and Adolescent Psychiatry of the University Clinic of Cologne. The investigation revealed a five factor structure: identity diffusion, reality testing, defense mechanisms, aggression and instability of goals. Moreover, testing the psychometric properties of the instrument showed a high internal consistency and meaningful significant correlations with well-validated youth self-report instruments assessing personality pathology and psychopathology. Thus, the results indicate that the IPO-A can be considered to be a reliable instrument that measures personality organization and identity diffusion in adolescents with personality disorders. PMID- 30422071 TI - [Assessment and Therapy of Adolescent Identity Diffusion]. AB - Assessment and Therapy of Adolescent Identity Diffusion Identity diffusion, one of the main diagnosis criteria for borderline personality disorder (BPD), is characterized by a lack of coherent sense of self and of significant others, paired with a painful sense of incoherence. The revision of the age limit for the diagnosis of personality disorders in DSM-5 has opened the doors to research on diagnosis and treatment of BPD in adolescence. This paper offers a summary of past and present work on the diagnosis and therapy of identity disturbance in adolescent patients. PMID- 30422072 TI - [Identity Development, Family Relations, and Symptomatology in Adolescents from Seven Countries]. AB - Identity Development, Family Relations, and Symptomatology in Adolescents from Seven Countries This study analyzed identity development and parental rearing in adolescents from seven countries. In a sample of 2,259 adolescents (M = 15 years; 54 % female) from France, Germany, Turkey, Greece, Peru, Pakistan, and Poland, maternal parenting (support, psychological control, anxious rearing), identity development (exploration, commitment and ruminative exploration) and psychopathology was assessed. Adolescents from central Europe (France and Germany) were characterized by quite low scores in most identity dimensions, compared to adolescents from all other countries. Particular high were scores in exploration and commitment among adolescents from Turkey, Greece, Peru and Pakistan. In some countries, adolescents described the family relations as characterized by high levels of anxious rearing and psychological control, which was, however, not associated with elevated levels of total symptomatology. The findings show that what is adaptive in one cultural context is depending on cultural norms and family traditions. This information is helpful in designing interventions. PMID- 30422073 TI - [Authors]. PMID- 30422074 TI - [Contents]. PMID- 30422075 TI - The use of a dual-task paradigm to identify superior sensory organisation ability in rhythmic gymnasts. AB - Previous study has showed superior sensory organisation ability in rhythmic gymnasts, but mostly in longitudinal data. With a cross-sectional design, this study used a dual-task paradigm to examine the above phenomenon. Fifteen female rhythmic gymnasts (15.0 +/- 1.8 yr.) and matched peers (15.1 +/- 2.1 yr.) were recruited. The Sensory Organization Test (SOT) was administered with a concurrent lower-demand (serial subtraction of three, serving as the baseline) or higher demand (serial subtraction of seven, serving as the dual-task) arithmetic task. The results showed no main effect of group, but a group by level of arithmetic task (P = 0.001) interaction effect on SOT equilibrium score. The higher-demand task facilitated balance performance in the gymnasts, but it impeded performance in the controls, with the differences more pronounced in challenging SOT conditions. With the higher-demand task, the gymnasts adopted a sensory strategy with a higher visual ratio but a smaller somatosensory ratio compared to the controls. Better visual utilisation of sensory organisation ability was apparent in gymnasts, but only when the SOT test was performed with a higher-demand secondary task. We have demonstrated the efficacy of using the dual-task paradigm to identify the superior sensory organisation ability of adolescent rhythmic gymnasts. PMID- 30422076 TI - Discriminative capacity and construct validity of the Clock Drawing Test in Mild Cognitive Impairment and Alzheimer's disease. AB - OBJECTIVES: The aim of this study was to analyze the psychometric and diagnostic properties of the Clock Drawing Test (CDT), scored according to the Babins, Rouleau, and Cahn scoring systems, for Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD) screening, and develop corresponding cutoff scores. Additionally, we assessed the construct validity of the CDT through exploratory and confirmatory factor analysis. METHODS: We developed a cross-sectional study of ambulatory MCI and AD patients, divided in two clinical groups (450 MCI and 250 mild AD patients) and a normal control group (N = 400). All participants were assessed with the CDT, Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) for convergent validity. RESULTS: The selected scoring systems presented adequate validity and reliability values. The proposed cutoff scores showed 60 to 65% sensitivity and 58 to 62% specificity to identify MCI patients. The corresponding values for AD were 84 to 90% sensitivity and 76 to 78% specificity. Exploratory and confirmatory factor analysis revealed that the Babins scoring system had good construct validity and allowed us to propose a three-factor model for this system. CONCLUSIONS: Our results confirmed the complexity of the CDT and support it as a cognitive screening instrument particularly sensitive to AD. The use of the CDT with MCI patients should be interpreted with more caution due to the lower sensitivity and specificity for milder forms of cognitive impairment. PMID- 30422077 TI - Enabling biomarker discovery in Parkinson's disease using multiomics: challenges, promise and the future. PMID- 30422078 TI - Masculinity and engagement in HIV care among male fisherfolk on HIV treatment in Uganda. AB - This study explored the intersection of masculinity and HIV care engagement among fishermen and other male fisherfolk on antiretroviral therapy (ART) in Wakiso District, Uganda. We conducted 30 in-depth interviews with men on ART recruited from HIV treatment sites and used a thematic analysis approach. Since HIV diagnosis and ART initiation, men had adopted masculine identities more conducive to HIV care engagement. The masculine roles of worker and provider, husband and sexual partner and the appearance of physical strength were compromised by HIV, but restored by ART's positive effects on health. Peers also emerged as facilitators to HIV care, with men supporting each other to seek testing and treatment. However, structural and occupational barriers to HIV care associated with the masculine role of worker remained a barrier to care engagement. Findings suggest that emphasising the benefits of ART in bolstering men's ability to fulfil the roles important to them may improve the effectiveness of HIV testing and treatment messaging for men. Differentiated care models that address structural-level barriers to care, and community-level gender-transformative programming to help fishermen engage in HIV care, may be beneficial. PMID- 30422079 TI - Current perspectives on psychedelic therapy: use of serotonergic hallucinogens in clinical interventions. AB - Humans have used serotonergic hallucinogens (i.e. psychedelics) for spiritual, ceremonial, and recreational purposes for thousands of years, but their administration as part of a structured therapeutic intervention is still a relatively novel practice within Western medical and psychological frameworks. In the mid-20th century, considerable advances were made in developing therapeutic approaches integrating administration of low (psycholytic) and high (psychedelic) doses of serotonergic hallucinogens for treatment of a variety of conditions, often incorporating psychoanalytic concepts prevalent at that time. This work contributed seminal insights regarding how these substances may be employed with efficacy and safety in targeted therapeutic interventions, including the importance of optimizing set (frame of mind) and setting (therapeutic environment). More recently, clinical and pharmacological research has revisited the effects and therapeutic potential of psychedelics utilizing a variety of approaches. The current article provides an overview of past and present models of psychedelic therapy, and discusses important considerations for future interventions incorporating the use of psychedelics in research and clinical practice. PMID- 30422080 TI - A review and validation of overall survival extrapolation in health technology assessments of cancer immunotherapy by the National Institute for Health and Care Excellence: how did the initial best estimate compare to trial data subsequently made available? AB - BACKGROUND: Validation of overall survival (OS) extrapolations of immune checkpoint inhibitors (ICIs) during the National Institute for Health and Care Excellence (NICE) Single Technology Assessment (STA) process is limited due to data still maturing at the time of submission. Inaccurate extrapolation may lead to inappropriate decision-making. The availability of more mature trial data facilitates a retrospective analysis of the plausibility and validity of initial extrapolations. This study compares these extrapolations to subsequently available longer-term data. METHODS: A systematic search of completed NICE appraisals of ICIs from March 2000 to December 2017 was performed. A targeted search was also undertaken to procure published OS data from the pivotal clinical trials for each identified STA made available post-submission to NICE. Initial Kaplan-Meier curves and associated extrapolations from NICE documentation were extracted to compare the accuracy of OS projections versus the most mature data. RESULTS: The review identified 11 STAs, of which 10 provided OS data upon submission to NICE. The extrapolations undertaken considered parametric or piecewise survival models. Additional data cut-offs provided a mean of 18 months of OS beyond the end of the original data. Initial extrapolations typically under estimated OS from the most mature data cut-off by 0.4-2.7%, depending on the choice of assessment method and use of the manufacturer- or ERG-preferred extrapolation. CONCLUSION: Long-term extrapolation of OS is required for NICE STAs based on initial immature OS data. The results of this study demonstrate that the initial OS extrapolations employed by manufacturers and ERGs generally predicted OS reasonably well when compared to more mature data (when available), although on average they appeared to underestimate OS. This review and validation shows that, while the choice of OS extrapolation is uncertain, the methods adopted are generally aligned with later-published follow-up data and appear appropriate for informing HTA decisions. PMID- 30422081 TI - Management of Sleep Disturbances in Parkinson's Disease Patients, Carers and the Patient and Carer Dyadic Relationship: A Scoping Review. AB - OBJECTIVES: Sleep disturbances are a debilitating non-motor symptom in Parkinson's disease (PD) and negatively impact patients, their carers and the patient-carer dyadic relationship. This review outlines the phenomenology, as well as factors associated with and treatment of sleep disturbances, in PD patients and their informal carers. METHODS: The following terms were used in four databases: Parkinson*, sleep* disturbance*, carer*, dyad*, intervention* and treatment*. RESULTS: Across the articles reviewed, the frequency of reported sleep disturbances in PD ranged between 60% and 98%. Common sleep problems in PD included insomnia, excessive day time sleepiness, REM sleep behavior disorder (RBD), sleep apnoea, periodic limb movements and sleep attacks. Within dyads, significant correlations were found with depression, anxiety and carer burden relating to night time care in particular. Despite the negative impact of sleep disturbance in PD, the evidence-base for treatment remains limited. CONCLUSIONS: While addressing individual factors associated with sleep disturbances, it is also important to emphasize the needs arising from the patient-carer dyadic relationship. While a number of non-pharmacological interventions were suggested in the literature, further well-controlled trials are still required. CLINICAL IMPLICATIONS: Multiple approaches are required to reduce sleep disturbances and associated burden in PD. PMID- 30422082 TI - "When I get married...": Contributing factors to intimate partner violence among married Jordanian women: A qualitative study. AB - The authors in this study have explored and sought to gain an understanding of the contributing factors related to intimate partner violence among married Jordanian women. A qualitative research design using ten semi-structured interviews was used. Our analysis revealed two main themes: "when I get married" and "the role of family". Financial, cultural and sexual factors were found to be vital in shaping the overall path of IPV. Therefore, if IPV is to be addressed carefully, then a multi-approach strategy within the social, legal and political levels of society is urgently needed. PMID- 30422083 TI - The perceived risk, safety climate and safety behaviour in Moroccan construction sites. AB - In Morocco, the construction sector is very dynamic economically, but suffers from weak safety performances. The few available statistics about the rates of occupational injuries and fatalities point to an alarming situation. However, root causes are yet to be identified. To fill this gap in knowledge, we conducted this study using an exploratory approach. Literature review, onsite observations and a survey were conducted to gather information about safety and risk aspects in construction sites. We conducted a series of correlation tests and a regression analysis using IBM SPSS version 20. The results showed that: (1) there is a relatively strong risk perception bias among workers, with an underestimation of risk severity, and occurrence probability. (2) Risk perception was not found to predict safety behavior. (3) Furthermore, a positive safety climate seems to neutralize the negative impact that a high risk tolerance had on safety behavior. PMID- 30422085 TI - Quantification of Normal Parametric Values: A Prerequisite for Routine Cardiac MRI. PMID- 30422084 TI - The development of national multisectoral action plans for the prevention and control of noncommunicable diseases: experiences of national-level stakeholders in four countries. AB - BACKGROUND: In October 2012, the WHO Eastern Mediterranean Region (EMR) developed a Regional Framework for Action to implement multisectoral action plans (MAPs) for the prevention and control of noncommunicable diseases (NCDs). OBJECTIVES: The aim of this project was to draw on the experiences of four EMR countries that had made good progress in developing these MAPs, to identify best practice and barriers in the development of them. METHODS: Structured interviews were held with key stakeholders in the development of the MAPs from the four focal EMR countries: Lebanon, Morocco, Sudan, and Yemen. These interviews comprised two stages: first we conducted face-to-face interviews in September 2014; we then carried out follow-up teleconference interviews during October 2014. Thematic analysis of transcripts was used to identify several themes, including examples of best practices and challenges that were common to all four focal countries and are likely to be also relevant to many other countries in the development of MAPs. RESULTS: Best practice in the development of MAPs includes methods to identify and recruit key sectors, ways to foster collaboration between sectors in the development and implementation of the action plan and means through which to encourage public support. Challenges identified included measuring outcomes in evaluating MAP success, current pressures and competing priorities for sectors and the perception of health issues as the responsibility of the health sector. Cultural and bureaucratic challenges were also discussed along with multisectoral fatigue, through the promotion of multisectoral approaches for a number of national issues. CONCLUSIONS: Although the development of multisectoral action plans to tackle NCDs is recommended, the process is a challenging one. Reflections from those countries which have experience in developing such action plans is important in identifying common challenges as well as recommending best practice, such that other countries may learn from their experiences. PMID- 30422086 TI - Radiomic versus Convolutional Neural Networks Analysis for Classification of Contrast-enhancing Lesions at Multiparametric Breast MRI. AB - Purpose To compare the diagnostic performance of radiomic analysis (RA) and a convolutional neural network (CNN) to radiologists for classification of contrast agent-enhancing lesions as benign or malignant at multiparametric breast MRI. Materials and Methods Between August 2011 and August 2015, 447 patients with 1294 enhancing lesions (787 malignant, 507 benign; median size, 15 mm +/- 20) were evaluated. Lesions were manually segmented by one breast radiologist. RA was performed by using L1 regularization and principal component analysis. CNN used a deep residual neural network with 34 layers. All algorithms were also retrained on half the number of lesions (n = 647). Machine interpretations were compared with prospective interpretations by three breast radiologists. Standard of reference was histologic analysis or follow-up. Areas under the receiver operating curve (AUCs) were used to compare diagnostic performance. Results CNN trained on the full cohort was superior to training on the half-size cohort (AUC, 0.88 vs 0.83, respectively; P = .01), but there was no difference for RA and L1 regularization (AUC, 0.81 vs 0.80, respectively; P = .76) or RA and principal component analysis (AUC, 0.78 vs 0.78, respectively; P = .93). By using the full cohort, CNN performance (AUC, 0.88; 95% confidence interval: 0.86, 0.89) was better than RA and L1 regularization (AUC, 0.81; 95% confidence interval: 0.79, 0.83; P < .001) and RA and principal component analysis (AUC, 0.78; 95% confidence interval: 0.76, 0.80; P < .001). However, CNN was inferior to breast radiologist interpretation (AUC, 0.98; 95% confidence interval: 0.96, 0.99; P < .001). Conclusion A convolutional neural network was superior to radiomic analysis for classification of enhancing lesions as benign or malignant at multiparametric breast MRI. Both approaches were inferior to radiologists' performance; however, more training data will further improve performance of convolutional neural network, but not that of radiomics algorithms. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 30422087 TI - Can MRI Features of Combined Hepatocellular Carcinoma-Intrahepatic Cholangiogarcinoma Help Predict Tumor Behavior Better than Histologic Findings? PMID- 30422088 TI - LI-RADS Classification and Prognosis of Primary Liver Cancers at Gadoxetic Acid enhanced MRI. AB - Purpose To (a) evaluate the postsurgical prognostic implication of the Liver Imaging Reporting and Data System (LI-RADS) categories of primary liver cancers and (b) determine the performance of LI-RADS version 2017 in differentiating hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma (IHCC) and combined hepatocellular-cholangiocarcinoma (cHCC-CC) at gadoxetic acid-enhanced MRI. Materials and Methods In this retrospective study, 194 patients with cirrhosis and surgically proven single primary liver cancer (53 with cHCC-CC, 44 with IHCC, and 97 with HCC) were evaluated with gadoxetic acid-enhanced MRI between 2009 and 2014. The mean patient age was 57 years (age range, 30-83 years). There were 155 men with a mean age of 56 years (range, 30-81 years) and 39 women with a mean age of 58 years (range, 38-83 years). Two independent readers assigned an LI-RADS category for each nodule. Overall survival (OS), recurrence-free survival (RFS), and their associated factors were evaluated by using the Kaplan-Meier method, log-rank test, and Cox proportional hazard model. Results In the multivariable analysis, the LI-RADS category was an independent factor for OS (hazard ratio, 4.2; P < .001) and RFS (hazard ratio, 2.6; P = .01). The LR-M category showed more correlation with poorer OS and RFS than did the LR 4 or LR-5 category for all primary liver cancers (P < .001 for both), HCCs (P = .01 and P < .001, respectively), and cHCC-CCs (P = .01 and P = .03, respectively). The LR-5 category had a sensitivity of 69% (67 of 97) and a specificity of 87% (84 of 97) in the diagnosis of HCC; most false-positive diagnoses (85%, 11 of 13) were the result of misclassification of cHCC-CCs. Conclusion The Liver Imaging Reporting and Data System (LI-RADS) category was associated with postsurgical prognosis of primary liver cancers, independent of pathologic diagnosis. The LI-RADS enabled the correct classification of most hepatocellular carcinomas (HCCs) and intrahepatic cholangiocarcinomas, whereas differentiation of combined hepatocellular-cholangiocarcinoma from HCC was unreliable. (c) RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Bashir and Chernyak in this issue. PMID- 30422089 TI - Deep Learning for Triage of Chest Radiographs: Should Every Institution Train Its Own System? PMID- 30422090 TI - Fluoroscopy and Cone-Beam CT-guided Fixation by Internal Cemented Screw for Pathologic Pelvic Fractures. AB - Purpose To evaluate the safety and efficacy of palliative treatment of patients with pathologic pelvic by using fluoroscopy and cone-beam CT needle guidance software to perform percutaneous fixation by internal cemented screw (FICS). Materials and Methods This single-center study involved retrospective analysis of 100 consecutive patients with cancer with pathologic pelvic fractures managed with percutaneous FICS. Image guidance was performed with fluoroscopy and cone beam CT needle guidance software. Pain palliative outcomes and opioid use after FICS were compared by means of paired-sample t test. Results A total of 107 percutaneous FICS procedures were performed from 2010 to 2017 to palliate 141 pathologic fractures in 100 patients (mean age, 65.0 years +/- 17.6 [standard deviation; female age, 66.3 years +/- 18.0; mean, 63.7 years +/- 17.2]). Of 107 procedures, 104 (97.2%) were technically successful, with mean postprocedure hospitalization of 2 days +/- 3. Complications occurred in 14 patients: focal pain at procedure site for longer than 48 hours (n = 5), hematoma (n = 3), progressive fracture despite fixation (n = 2), infection (n = 1), tumor track seeding (n = 1), and screw displacement (n = 2). In the 88 patients who completed early follow-up, mean numeric rating scale pain score was significantly improved at 6 weeks from 6.1 +/- 2.5 to 2.1 +/- 3.0 (P < .001). Opioid use was reduced at 6 weeks (preprocedure vs postprocedure, 91.3 g +/- 121 vs 64.6 g +/- 124, respectively; P = .04). Conclusion Fluoroscopy and cone-beam CT-guided percutaneous fixation of pathologic pelvis fractures by internal cemented screw is a safe and effective approach that can reduce pain and opioid use. (c) RSNA, 2018. PMID- 30422091 TI - Long-term Excretion of Gadolinium-based Contrast Agents: Linear versus Macrocyclic Agents in an Experimental Rat Model. AB - Purpose To investigate the long-term course of MRI signal intensity (SI) changes and the presence of gadolinium in the rat brain during a 1-year period after multiple administrations of gadolinium-based contrast agents (GBCAs). Materials and Methods Rats received a linear GBCA (gadodiamide, gadopentetate dimeglumine, gadobenate dimeglumine), a macrocyclic GBCA (gadobutrol, gadoterate meglumine, gadoteridol), or saline. Animals received eight injections over 2 weeks (1.8 mmol/kg per injection). Brain MRI and gadolinium measurements were performed with inductively coupled plasma mass spectrometry (ICP-MS) and laser ablation ICP-MS 5, 26, and 52 weeks after administration. Results Animals that received linear GBCAs showed higher deep cerebellar nuclei (DCN)-to-brainstem SI ratios compared with the saline group (P < .001 at all time points). After 1 year, mean gadolinium concentrations in the cerebellum were 3.38 nmol/g (gadodiamide), 2.13 nmol/g (gadopentetate dimeglumine), and 1.91 nmol/g (gadobenate dimeglumine). For linear agents, laser ablation ICP-MS revealed gadolinium depositions in the cerebellar nuclei. For macrocyclic GBCAs, the DCN-to-brainstem SI ratios did not significantly differ from those in the saline group (P > .42) and the cerebellar gadolinium concentrations decreased between weeks 5 and 52, reaching 0.08 nmol/g (gadobutrol), 0.04 nmol/g (gadoterate meglumine), and 0.07 nmol/g (gadoteridol). The respective laser ablation ICP-MS analysis showed no gadolinium depositions. Conclusion Increased signal intensity in the deep cerebellar nuclei of rats persists for at least 1 year after administration of linear gadolinium-based contrast agents (GBCAs), in line with persistent brain gadolinium concentrations with no elimination after the initial 5-week period. The animals that received macrocyclic GBCAs showed an ongoing elimination of gadolinium from the brain during the entire observation period. (c) RSNA, 2018. PMID- 30422092 TI - Native T1 and Extracellular Volume Measurements by Cardiac MRI in Healthy Adults: A Meta-Analysis. AB - Purpose To summarize the literature by performing a systematic review and pooled analysis of the data, to understand the extent of variability among studies of native T1 and extracellular volume (ECV) measurements, and to identify covariates that account for heterogeneity between studies. Materials and Methods PubMed, Web of Science, and Cochrane Central were searched for native T1 and ECV measurements of the left ventricle in health adult study participants. The search terms used were "T1 mapping heart," "Native T1 heart," and "ECV heart." Summary means were generated with random-effects modeling. Heterogeneity was assessed by using the inconsistency factor (I 2). Subgroup analyses and meta-regression analyses were conducted to identify etiologic causes of heterogeneity. Results This systematic review of native T1 included 120 articles, with 5541 participants (mean age, 50 years; 51.0% men [2826 of 5541]). The pooled mean of native T1 was 976 msec (95% confidence interval [CI]: 969 msec, 983 msec) at 1.5 T and 1159 msec (95% CI: 1143 msec, 1175 msec) at 3.0 T. I 2 was 99% at both field strengths. Eighty-one articles were included in the systematic review of ECV, with 3872 participants (mean age, 52 years; 50.0% men [1936 of 3872]). The pooled mean of ECV was 25.9% at field strength of 1.5 T (95% CI: 25.5%, 26.3%) and 3.0 T (95% CI: 25.4%, 26.5%). I 2 was 94% and 90% at 1.5 and 3.0 T, respectively. Conclusion The pooled means of extracellular volume and native T1 measurements in healthy adult participants are summarized in this analysis. There was significant heterogeneity found among studies, highlighting the importance of standardized cardiac MRI protocols and the derivation of institution specific reference ranges. (c) RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Dodd and Dewey in this issue. PMID- 30422093 TI - Assessment of Convolutional Neural Networks for Automated Classification of Chest Radiographs. AB - Purpose To assess the ability of convolutional neural networks (CNNs) to enable high-performance automated binary classification of chest radiographs. Materials and Methods In a retrospective study, 216 431 frontal chest radiographs obtained between 1998 and 2012 were procured, along with associated text reports and a prospective label from the attending radiologist. This data set was used to train CNNs to classify chest radiographs as normal or abnormal before evaluation on a held-out set of 533 images hand-labeled by expert radiologists. The effects of development set size, training set size, initialization strategy, and network architecture on end performance were assessed by using standard binary classification metrics; detailed error analysis, including visualization of CNN activations, was also performed. Results Average area under the receiver operating characteristic curve (AUC) was 0.96 for a CNN trained with 200 000 images. This AUC value was greater than that observed when the same model was trained with 2000 images (AUC = 0.84, P < .005) but was not significantly different from that observed when the model was trained with 20 000 images (AUC = 0.95, P > .05). Averaging the CNN output score with the binary prospective label yielded the best-performing classifier, with an AUC of 0.98 (P < .005). Analysis of specific radiographs revealed that the model was heavily influenced by clinically relevant spatial regions but did not reliably generalize beyond thoracic disease. Conclusion CNNs trained with a modestly sized collection of prospectively labeled chest radiographs achieved high diagnostic performance in the classification of chest radiographs as normal or abnormal; this function may be useful for automated prioritization of abnormal chest radiographs. (c) RSNA, 2018 Online supplemental material is available for this article. See also the editorial by van Ginneken in this issue. PMID- 30422094 TI - The effect of a care program and social support on anxiety level in mothers of late preterm infants in Sistan and Baluchestan, Iran. AB - Late and moderate preterm (LAMP) neonates are at risk of developing severe complications that can lead to anxiety in mothers. The aim of this study was to determine the effectiveness of a care program on the anxiety level of mothers with LAMP babies and to determine the effectiveness of the care program on the level of anxiety of new mothers in the presence of social support. This quasi experimental study was conducted on 80 mothers whose late preterm infants were admitted to neonatal intensive care unit at Ali-ibn Abi Talib Hospital, Zahedan. Data were gathered between July 10 and October 13, 2016. The intervention group received the care program. Anxiety and social support were evaluated using the State-Trait Anxiety Inventory and Multidimensional Scale of Perceived Social Support (MSPSS), respectively. After receiving the intervention, the mean MSPSS was higher for the mothers in the intervention group (p = .0025). Additionally, they experienced less state anxiety 72 hours after discharge and 1 month after delivery (p < .0025). Regression analysis showed that mothers with higher social support were 39 percent more likely to be in the "no to moderate STAI" (<51) group. Perceived social support can mediate the effect of care programs on diminishing anxiety. PMID- 30422095 TI - Inflammatory effects of atazanavir/ritonavir versus darunavir/ritonavir in treatment naive, HIV-1-infected patients. AB - BACKGROUND: Limited studies have compared the impact of different antiretroviral regimens on soluble markers of inflammation with discordant results. METHODS: In this prospective study, treatment naive HIV-1-infected patients were included if they started their current regimen with atazanavir/ritonavir (ATV/r) (N = 73, Group 1) or darunavir/ritonavir (DRV/r) (N = 85, Group 2) plus tenofovir/emtricitabine. The analysis of IL-6, MCP-1, sCD163, VCAM-1, ox-LDL, and adiponectine was performed on two stored plasma samples, the first prior to antiretroviral therapy initiation and the second one year after initiation. RESULTS: The results of our analysis show a difference in ox-LDL between the two groups with higher mean (SD) values in ATV/r based group 608.5 +/- 137.4 versus 519.1 +/- 119.6 in DRV/r group, after controlling for baseline levels of ox-LDL as well as other potential confounding factors controlled by means of matching design or linear regression modelling. CONCLUSIONS: Our analysis provides further data examining the association between the modulation of vascular inflammatory and of activation markers with specific protease inhibitors-based treatments over one year of exposure to these drugs. The data show little evidence for an association, supporting the notion that antiretroviral regimens has generally poor efficiency in downregulating these soluble markers. PMID- 30422096 TI - Factors affecting rehabilitation and use of upper limb after stroke: views from healthcare professionals and stroke survivors. AB - BACKGROUND: Training of the upper limb (UL) is limited in stroke rehabilitation, and about 50% of stroke survivors do not regain useful function in their upper limb. OBJECTIVES: This study explored what factors affect rehabilitation and use of upper limb after stroke from a stroke survivor and healthcare professional perspective to better understand low engagement in UL rehabilitation in the chronic stages of stroke. METHOD: Eight chronic stroke survivors and 21 healthcare professionals took part in semi-structured interviews or in one of three focus groups, respectively. RESULTS: Thematic analysis revealed three main themes: Availability of resources, Healthcare professional-patient relationship, and Psychosocial factors. Availability of resources and Healthcare professional patient relationship indicated that due to resource pressures and a lack of communication and education, positive upper limb rehabilitation behaviors (e.g. engaging and integrating the upper limb in daily activity) were not always established in the early stages post-stroke. Psychosocial factors illustrated the cognitive and psychological barriers to sustained engagement with upper limb rehabilitation. CONCLUSION: The findings indicate that stroke survivors and healthcare professionals have very similar understandings of barriers to UL activity, and positive upper limb rehabilitation behaviors are not always established early in recovery post-stroke. Increased resources and healthcare professional-patient relationships seem key factors to establishing positive perceptions of UL rehabilitation. Addressing psychosocial issues and resource limitations may help sustain engagement with UL rehabilitation. PMID- 30422097 TI - Predictors of caregiver burden in mothers of children with leukemia and cerebral palsy. AB - OBJECTIVE: Caring for a sick child can lead to considerable burden in the caregiver. Comparative studies of burden in mothers of children with different types of disorders are rare. METHODS: We assessed levels of and risk factors for burden in mothers of children with leukemia (n: 70) or with cerebral palsy (CP) (n: 69). Subjects were recruited from two hospitals in Ankara. RESULTS: Levels of burden or depression were not different between groups. Burden was predicted by the presence of depression in the mother and severity of illness in both groups. In the leukemia group, mothers reported higher burden if the child was male or younger; no such relationship was observed in the CP group. CONCLUSION: Our results show that type of illness has an effect on levels of burden. Mothers of children with leukemia should receive more attention, especially if their child is male or younger, to take preventive measures against burden. PMID- 30422098 TI - Landing Stiffness Between Individuals With and Without a History of Low Back Pain. AB - CONTEXT:: Reduced spinal stabilization, delayed onset of muscle activation, and increased knee joint stiffness have been reported in individuals with a history of low back pain (LBP). Biomechanical adaptations resulting from LBP may increase the risk for future injury due to suboptimal loading of the lower extremity or lumbar spine. Assessing landing mechanics in these individuals could help identify which structures might be susceptible to future injury. OBJECTIVE:: To compare vertical and joint stiffness of the lower extremity and lumbar spine between individuals with and without a previous history of LBP. DESIGN:: Cross sectional study. SETTING:: Research laboratory. PARTICIPANTS:: Forty-five participants (24 without a previous history of LBP (age: 23(8) years; height: 169.0(8.5) cm; mass: 69.8(13.8) kg), 21 with a previous history of LBP (age: 25(9) years; height: 170.0(8.0) cm; mass: 70.2(11.8) kg). INTERVENTIONS:: Single limb landing trials on the dominant and non-dominant limb from a 30-centimeter box. MAIN OUTCOME MEASURES:: Vertical stiffness and joint stiffness of the ankle, knee, hip and lumbar spine. RESULTS:: Individuals with a previous history of LBP had lower vertical stiffness (P=.04), but not joint stiffness measures compared to those without a previous history of LBP (P>.05). Overall females had lower vertical (P=.01), ankle (P=.02) and hip stiffness (P=.04) compared to males among all participants. Males with a previous history of LBP had lower vertical stiffness compared to males without a previous history LBP (P=.01). Among all individuals without a previous history of LBP females had lower vertical (P<.01) and ankle stiffness measures (P=.04) compared to males. CONCLUSIONS:: Landing stiffness may differ among males and females and a previous history of LBP. Comparisons between individuals with and without previous LBP should be considered when assessing landing strategies and future research should focus on how LBP impacts landing mechanics. PMID- 30422100 TI - Correction. PMID- 30422099 TI - Red blood cell distribution width as an easily measurable biomarker of persistent inflammation and T cell dysregulation in antiretrovirally treated HIV-infected adults. AB - BACKGROUND: Chronic inflammation and immune dysfunction occur in human immunodeficiency virus (HIV)-infection despite stable antiretroviral therapy (ART). Red blood cell distribution width (RDW) has been shown to correlate with markers of inflammation in non-HIV conditions. The study objective was to determine associations between RDW with cellular markers of immune activation and immune dysfunction including soluble inflammatory mediators in ART treated HIV infection. METHODS: We performed a cross-sectional analysis of the Hawaii Aging with HIV-Cardiovascular study. RDW was defined as one standard deviation of RBC size divided by mean corpuscular volume multiplied by 100%. Correlations were analyzed between RDW, soluble inflammatory biomarkers and T cell activation (CD38 + HLA-DR+), senescence (CD28-CD57+), and immune exhaustion (PD-1, TIGIT, TIM-3 expression). RESULTS: Of 158 participants analyzed, median age was 50 years, duration of ART 12.6 years, virally suppressed 84.4%, and CD4 count 503 cells/mm3. Significant positive correlations were identified between RDW and soluble biomarkers including sICAM, IL-8, IL-6, SAA, TNF-alpha, sE-selection, fibrinogen, D-dimer, CRP, CD4/CD8 ratio, and frequency of multiple CD8 T-cell populations such as CD38 + HLA-DR + T-cells, single TIGIT+, and dual expressing of TIGIT + PD1+, TIGIT + TIM3+, and TIM3 + PD1+ CD8+ T-cell subsets (p < .05). Frequencies of CD38 + HLA-DR + CD8+ T-cells and TIGIT + CD8+ T-cells remained significant adjusting for baseline variables (p < .01). CONCLUSION: Our study revealed correlations between RDW with systemic inflammatory biomarkers and CD8+ T-cell populations related to immune activation and exhaustion in HIV-infected individuals on ART. Further studies are warranted to determine the utility of RDW as a marker of immune dysregulation in HIV. PMID- 30422102 TI - A Modular Millifluidic Homeostatic Imaging Plate for Imaging of Larval Zebrafish. AB - Zebrafish larvae are suitable in vivo models for toxicological and pharmacological screens due to their transparency, small size, ex utero development, and genetic and physiological similarity to humans. Using modern imaging techniques, cells and tissues can be dynamically visualized over several days in multiple zebrafish larvae. However, precise specimen immobilization and maintenance of homeostatic conditions remain a challenge for longitudinal studies. A highly customizable mounting configuration with inbuilt means of controlling temperature and media flow would therefore be a valuable tool to facilitate long-term imaging of a large number of specimens. Using three dimensional printing, we have developed a millifluidic, modular homeostatic imaging plate (HIP), which consists of a customizable sample insert and a temperature-controlled incubation chamber that is continuously perfused, providing an ideal environment for long-term experiments where homeostatic conditions are desired. The HIP is cheap to produce, has a standard microtiter well plate format, and can be fitted to most microscopes. We used the device to image dynamic regeneration of spinal cord neurons. The flexibility and adaptability of the HIP facilitate long-term in vivo imaging of many samples, and can be easily adapted to suit a broad range of specimens. PMID- 30422101 TI - Heterogeneities in utilization of antenatal care in Uttar Pradesh, India: the need to contextualize interventions to individual contexts. AB - BACKGROUND: This paper explores the heterogeneities in antenatal care (ANC) utilization in India's most populated state, Uttar Pradesh. Taking an intersectionality lens, multiple individual- and district-level factors are used to identify segments of any antenatal care usage in Uttar Pradesh Objective: This paper seeks to understand the multilevel contexts of ANC utilization. The planning and programming challenge is that such knowledge of contextual specificity is rarely known upfront at the initial stages of planning or implementing an intervention. Exploratory data analysis might be needed to identify such contextual specificity. METHODS: Tree-structured regression methods are used to identify segments and interactions between factors. The results from the tree-structured regression were complemented with multilevel models that controlled for the clustering of individuals within districts. RESULTS: Heterogeneities in utilization of any ANC were observed. The multiple segments of ANC utilization that were developed went from a low utilization of 23.7% for respondents who were not literate and did not have home ownership to a high of 82.4% for respondents who were literate and at the highest level of wealth. Key variables that helped define the segments of ANC utilization include: woman's literacy, ownership of home, wealth index, and district-level sex ratio. Based on the multilevel model of any ANC utilization, cross-level interactions also were obtained between sex ratio and ownership of home as well as between sex ratio and literacy. Increases in sex ratio increased the influence of ownership of home on any ANC, while increases in sex ratio reduced the impact of woman's literacy on receiving any ANC. CONCLUSION: We argue that a focus on heterogeneous segments of utilization can help build knowledge of the mechanisms that underlie inequities in maternal health utilization. Such knowledge of heterogeneity needs to be incorporated in contextualizing interventions to meet a variety of recipients' needs. PMID- 30422103 TI - Changes in depressed patients' self-statements. AB - OBJECTIVE: Individuals' use of self-statements reflecting self-criticism, a sense of inadequacy, and low self-worth has been linked to the incidence, severity, and recurrence of major depressive disorder [de Graaf, L. E., Huibers, M. J. H., Cuijpers, P., & Arntz, A. (2010). Minor and major depression in the general population: Does dysfunctional thinking play a role? Comprehensive Psychiatry, 51(3), 266-274. doi: 10.1016/j.comppsych.2009.08.006 ; Riso, L. P., du Toit, P. L., Blandino, J. A., Penna, S., Dacey, S., Duin, J. S., ... Ulmer, C. S. (2003). Cognitive aspects of chronic depression. Journal of Abnormal Psychology, 112(1), 72-80. doi: 10.1037/0021-843X.112.1.72 ]. The present study used an observer rated measure, the Structural Analysis of Social Behavior [Benjamin, L. S. (1974). Structural Analysis of Social Behavior. Psychological Review, 81(5), 392 425. doi: 10.1037/h0037024 ], to examine patients' self-directed communication over the course of psychotherapy. METHOD: Self-talk in early and late therapy sessions was examined using cases (N = 44) from the cognitive therapy arm of Jacobson and colleagues' component study of cognitive therapy for depression [Jacobson, N. S., Dobson, K. S., Truax, P. A., Addis, M. E., Koerner, K., Gollan, J. K., ... Prince, S. E. (1996). A component analysis of cognitive-behavioral treatment for depression. Journal of Consulting and Clinical Psychology, 64(2), 295-304. doi: 10.1037/0022-006x.64.2.295 , Jacobson, N. S., Dobson, K. S., Truax, P. A., Addis, M. E., Koerner, K., Gollan, J. K., ... Prince, S. E. (2000). A component analysis of cognitive-behavioral treatment for depression. Prevention & Treatment, 3(1). doi: 10.1037/1522-3736.3.1.323a ]. We identified changes at treatment termination, and used hierarchical multiple regression to examine whether improvements in patient self-talk influenced treatment outcome up to 24 months post-termination. RESULTS: Trends indicate that patients used friendlier and less critical self-statements at the end of treatment. Decreased self critical behaviour was associated with fewer symptoms at the end of treatment and up to one year later; increased self-acceptance was linked to symptom improvement a year and a half after termination. CONCLUSION: Consistent with cognitive theory, reduced self-criticism was associated with better treatment outcomes. Longer-term improvement was linked to the development of friendlier and more accepting self-referential behaviour. PMID- 30422104 TI - Dongshaea marina gen. nov., sp. nov., a facultatively anaerobic marine bacterium that ferments glucose with gas production. AB - Two isolates of heterotrophic, facultatively anaerobic, marine bacteria, designated DM1 and DM2T, were recovered from a lagoon sediment sample of Dongsha Island, Taiwan. Cells were Gram-reaction-negative rods. Nearly all of the cells were non-motile and non-flagellated during the late exponential to early stationary phase of growth, while a few of the cells exhibited motility with monotrichous flagellation. The two isolates required NaCl for growth and grew optimally at about 30 degrees C, 2-3 % NaCl and pH 7-8. They grew aerobically and could achieve anaerobic growth by fermenting d-glucose or other carbohydrates with production of acids and the gases, including CO2 and H2. Ubiquinone Q-8 was the only respiratory quinone. Cellular fatty acids were predominated by C16 : 0, C18 : 1omega7c and C16 : 1omega7c. The major polar lipid was phosphatidylethanolamine. Strains DM1 and DM2T had DNA G+C contents of 52.0 and 51.8 mol%, respectively, as determined by HPLC analysis. Phylogenetic analyses based on 16S rRNA gene sequences clearly indicated that the two isolates formed a distinct genus-level lineage in the family Aeromonadaceae of the class Gammaproteobacteria and was an outgroup with respect to a stable supragenic clade comprising species of the genera Oceanimonas, Oceanisphaera and Zobellella. The phylogenetic data and those from chemotaxonomic, physiological and morphological characterizations support the establishment of a novel species and genus inside the family Aeromonadaceae, for which the name Dongshaea marina gen. nov., sp. nov. is proposed. The type strain is DM2T (=BCRC 81069T=JCM 32096T). PMID- 30422105 TI - Lysobacter silvisoli sp. nov., isolated from forest soil. AB - A yellow-pigmented, Gram-stain-negative, gliding and rod-shaped bacterial strain, designated zong2l5T, was isolated from a forest soil sample at Dinghu Mountain, Guangdong Province, PR China. Phylogenetic analysis based on the 16S rRNA gene sequence showed that strain zong2l5T belongs to the genus Lysobacter, and was most closely related to Lysobacter enzymogenes KCTC 12131T (97.7 %) and Lysobacter soli KCTC 22011T (97.6 %). The novel strain showed an average nucleotide identity (ANI) value of 81.5 % and a digital DNA-DNA hybridization (dDDH) value of 25.3 % with L. enzymogenes KCTC 12131T based on draft genome sequences, followed by L. soli KCTC 22011T with ANI and dDDH values of 79.4 % and 22.7 %, respectively. The DNA G+C content of strain zong2l5T based on the whole genome sequence was 69.2 mol%. The major fatty acids were iso-C15 : 0, iso-C17 : 0 and summed feature 9 (iso-C17 : 1omega9c and/or 10-methyl C16 : 0). Strain zong2l5T contained Q-8 as the major isoprenoid quinone and the major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidyl-N methylethanolamine, phosphatidylethanolamine, three unidentified phospholipids and an unidentified aminolipid. The phenotypic, genotypic and chemotaxonomic anlyses clearly showed that strain zong2l5T represents a novel species of the genus Lysobacter, for which the name Lysobactersilvisoli sp. nov. is proposed. The type strain is zong2l5T (=GDMCC 1.1489T=KCTC 52923T). PMID- 30422106 TI - Comparison of susceptibility testing methods for determining the activity of colistin against Gram-negative bacilli of clinical origin. AB - PURPOSE: Despite being in clinical use for decades, colistin susceptibility testing remains challenging because of its inherent cationic properties. We aimed to compare the performance characteristics of different methods for testing susceptibility to colistin in a series of clinical isolates of Gram-negative bacilli. METHODOLOGY: One hundred and nine clinical isolates of Klebsiella pneumoniae (n=34), Escherichia coli (n=20), Acinetobacter baumannii (n=17) and Pseudomonas aeruginosa (n=38) were studied for colistin susceptibility using broth microdilution (BMID), broth macrodilution (BMAD), agar dilution (AD) as well as disc-diffusion (DD) utilizing two different commercial disc sources. RESULTS: By using BMID as reference method, 88 and 21 isolates were found to be colistin susceptible and resistant, respectively. Overall, acceptable essential agreement (EA) and categorical agreement (CA) were observed between BMAD and reference method (100 %). Whereas the AD method revealed the lowest rate of EA (61.7, 11.7, 5.0 and 5.2 % for K. pneumoniae, A. baumannii, E. coli and P. aeruginosa, respectively), it showed acceptable or near acceptable CA for K. pneumoniae (100 %), E. coli (100 %) and A. baumannii (88.2 %) isolates but not for P. aeruginosa (13.1 %). DD was unable to detect resistance in colistin resistant (colR) P. aeruginosa (n=5, very major errors of 100 %) but successfully categorized all ColR K. pneumoniae and A. baumannii isolates as non-susceptible. CONCLUSION: We found BMAD to be very reliable for colistin MIC determination. Methods AD and DD should not be used for colistin susceptibility testing in P. aeruginosa isolates as these are associated with false-resistant and -susceptible results, respectively. PMID- 30422107 TI - Sialidase and N-acetylneuraminate catabolism in nutrition of Mycoplasma alligatoris. AB - The contribution of N-acetylneuraminate scavenging to the nutrition of Mycoplasma alligatoris was examined. The wild-type grew substantially faster (P<0.01) than the mutant strains that were unable either to liberate (extracellular NanI- mutants) or to catabolize (NanA- mutants) N-acetylneuraminate from glycoconjugates in minimal SP-4 medium supplemented only with serum, but the growth of sialidase-negative mutants could not be restored to wild-type rate simply by adding unconjugated sialic acid to the culture medium. In 1 : 1 growth competition assays the wild-type was recovered in >99-fold excess of a sialidase negative mutant after co-culture on pulmonary fibroblasts in serum-free RPMI 1640 medium, even with supplemental glucose. The advantage of nutrient scavenging via this mechanism in a complex glycan-rich environment may help to balance the expected selective disadvantage conferred by the pathogenic effects of mycoplasmal sialidase in an infected host. PMID- 30422108 TI - Coxiella burnetii: A Pathogenic Intracellular Acidophile. AB - of Coxiella burnetii infection. Bacteria are typically spread to humans by aerosol from infected ruminants. Following inhalation of contaminated aerosols, C. burnetii establishes the depicted intracellular lifestyle by means of a type 4 secretion system. Replicating bacteria fill a large parasitophorous vacuole within alveolar macrophages. Formation of this vacuole is critical for progression of Q fever. CM-cytoplasmic membrane. PV-parasitophorous vacuole. NM nuclear membrane. (All images created by E.I. Shaw, T.S. Hughes and D.E. Voth.)Coxiella burnetii is an obligate intracellular pathogen that causes acute and chronic Q fever. C. burnetii grows within a eukaryotic host cell in a vacuole highly similar to a phagolysosome. Found worldwide, this environmentally stable pathogen is maintained in nature via chronic infection of ruminants. Aerosol mediated infection of humans results in infection and usurpation of alveolar macrophages through mechanisms using a bacterial Type 4B Secretion System and secreted effector proteins. Advances in axenic culture and genetic systems are changing our understanding of the pathogen's physiology and intimate molecular manipulations of host cells during infection. PMID- 30422109 TI - In vivo activity of co-trimoxazole combined with colistin against Acinetobacter baumannii producing OXA-23 in a Galleria mellonella model. AB - OBJECTIVES: Acinetobacter baumannii is a critical nosocomial pathogen. A. baumannii infections have become a grave challenge due to their ability to develop resistance to different antimicrobial agents. The current study aimed to evaluate the potential synergism and bactericidal activity of a combination of colistin and cotrimoxazole against carbapenem-resistant A. baumannii (CRAB) in a Galleria mellonella model. METHODS: Four clinical A. baumannii isolates were biochemically and molecularly identified. Their antimicrobial susceptibility levels were established and the molecular characterization of the carbapenemase encoding genes was performed. The synergism and bactericidal effect of the colistin/cotrimoxazole combination was assessed using the checkerboard assay and time-kill experiments. An in vivo evaluation of the activity of the combination was performed using the Galleria mellonella model. RESULTS: A fractional inhibitory concentration index (FICI) of <=0.5 was found for all strains, indicating that the colistin/cotrimoxazole combination exhibited powerful synergistic activity. The combination displayed both synergistic and bactericidal activity at sub-breakpoint concentrations for all strains. Cotrimoxazole monotherapy showed the least protective activity in the G. mellonella model. The survival rate ranged from 66.7-79.2 % at 24 h and was 29.2-60.4 % at 96 h for the tested isolates. Colistin monotherapy performed better than cotrimoxazole monotherapy; the G. mellonella survival rate ranged from 77.1-97.9 %, at 24 h and from 64.5-72. % at 96 h. The colistin/cotrimoxazole combination improved G. mellonella's survival rate at 96 h remarkably in comparison to colistin or cotrimoxazole monotherapy. CONCLUSIONS: Finally, the combination of colistin and cotrimoxazole appears to be a promising therapeutic option for the management of CRAB-associated infections. It is essential to assess the clinical application and the dose-response relationships of combinations such as colistin plus cotrimoxazole. PMID- 30422110 TI - Structural basis of tubulin recruitment and assembly by microtubule polymerases with tumor overexpressed gene (TOG) domain arrays. AB - XMAP215/Stu2/Alp14 proteins accelerate microtubule plus-end polymerization by recruiting tubulins via arrays of tumor overexpressed gene (TOG) domains, yet their mechanism remains unknown. Here, we describe the biochemical and structural basis for TOG arrays in recruiting and polymerizing tubulins. Alp14 binds four tubulins via dimeric TOG1-TOG2 subunits, in which each domain exhibits a distinct exchange rate for tubulin. X-ray structures revealed square-shaped assemblies composed of pseudo-dimeric TOG1-TOG2 subunits assembled head-to-tail, positioning four unpolymerized tubulins in a polarized wheel-like configuration. Crosslinking and electron microscopy show Alp14-tubulin forms square assemblies in solution, and inactivating their interfaces destabilize this organization without influencing tubulin binding. An X-ray structure determined using approach to modulate tubulin polymerization revealed an unfurled assembly, in which TOG1-TOG2 uniquely bind to two polymerized tubulins. Our findings suggest a new microtubule polymerase model in which TOG arrays recruit tubulins by forming square assemblies that then unfurl, facilitating their concerted polymerization into protofilaments. PMID- 30422112 TI - Comment on 'Orthogonal lipid sensors identify transbilayer asymmetry of plasma membrane cholesterol'. AB - The plasma membrane in mammalian cells is rich in cholesterol, but how the cholesterol is partitioned between the two leaflets of the plasma membrane remains a matter of debate. Recently, Liu et al. used domain 4 (D4) of perfringolysin O as a cholesterol sensor to argue that cholesterol is mostly in the exofacial leaflet (Liu et al., 2017). This conclusion was made by interpreting D4 binding in live cells using in vitro calibrations with liposomes. However, liposomes may be unfaithful in mimicking the plasma membrane, as we demonstrate here. Also, D4 binding is highly sensitive to the presence of cytosolic proteins. In addition, we find that a D4 variant, which requires >35 mol% cholesterol to bind to liposomes in vitro, does in fact bind to the cytoplasmic leaflet of the plasma membrane in a cholesterol-dependent manner. Thus, we believe, based on the current evidence, that it is unlikely that there is a significantly higher proportion of cholesterol in the exofacial leaflet of the plasma membrane compared to the cytosolic leaflet. PMID- 30422111 TI - Oxytocin-mediated social enrichment promotes longer telomeres and novelty seeking. AB - The quality of social relationships is a powerful determinant of lifetime health. Here, we explored the impact of social experiences on circulating oxytocin (OT) concentration, telomere length (TL), and novelty-seeking behaviour in male and female rats. Prolonged social housing raised circulating OT levels in both sexes while elongating TL only in females. Novelty-seeking behaviour in females was more responsive to social housing and increased OT levels than males. The OT antagonist (OT ANT) L-366,509 blocked the benefits of social housing in all conditions along with female-specific TL erosion and novelty-seeking deficit. Thus, females seem more susceptible than males to genetic and behavioural changes when the secretion of endogenous OT in response to social life is interrupted. Social enrichment may, therefore, provide a therapeutic avenue to promote stress resiliency and chances of healthy aging across generations. PMID- 30422113 TI - Molecular mechanisms that stabilize short term synaptic plasticity during presynaptic homeostatic plasticity. AB - Presynaptic homeostatic plasticity (PHP) compensates for impaired postsynaptic neurotransmitter receptor function through a rapid, persistent adjustment of neurotransmitter release, an effect that can exceed 200%. An unexplained property of PHP is the preservation of short-term plasticity (STP), thereby stabilizing activity-dependent synaptic information transfer. We demonstrate that the dramatic potentiation of presynaptic release during PHP is achieved while simultaneously maintaining a constant ratio of primed to super-primed synaptic vesicles, thereby preserving STP. Mechanistically, genetic, biochemical and electrophysiological evidence argue that a constant ratio of primed to super primed synaptic vesicles is achieved by the concerted action of three proteins: Unc18, Syntaxin1A and RIM. Our data support a model based on the regulated availability of Unc18 at the presynaptic active zone, a process that is restrained by Syntaxin1A and facilitated by RIM. As such, regulated vesicle priming/super-priming enables PHP to stabilize both synaptic gain and the activity-dependent transfer of information at a synapse. PMID- 30422116 TI - Action Plan to Reach the Global Availability of Adrenaline Auto-Injectors. AB - Adrenaline is the first-line treatment for anaphylaxis and, therefore, listed as an essential medication for the treatment of anaphylaxis by the World Health Organization (WHO). However, the availability of auto-injector (AAI) forms for use in the first-aid treatment is limited to only 32% of all 195-world countries, mostly high-income countries. The key issues leading to the lack of availability of AAIs include cost but also national regulations, lack of regional evidence about the value of epinephrine and the limited accurate data about the epidemiology of anaphylaxis. For these reasons, regional and international allergy academies support the initiatives to narrow these gaps. Our WHO Collaborating Centre is deeply involved in this process and the purpose of this document is serving as baseline to reach: (I) an adequate access to AAI in affordable cost for all patients/societies and (II) the development of disease/patient-specific approaches. Therefore, we propose a 5 steps action plan (gather accurate anaphylaxis epidemiological data and AAI consumption indicators, confirm partnerships, strengthen awareness and include AAI into the WHO Model List of Essential Medicine), which should be considered in combination. A prioritized research agenda should encapsulate all these steps in the frame a global initiative against anaphylaxis. More than calling for the global availability of AAIs for best management of anaphylaxis, we propose an action plan as baseline of a global initiative against anaphylaxis. We strongly believe the combined efforts are a strong public health and societal move, leading to optimal care of allergic patients and best practice of allergology. PMID- 30422114 TI - Translesion polymerase kappa-dependent DNA synthesis underlies replication fork recovery. AB - DNA replication stress is often defined by the slowing or stalling of replication fork progression leading to local or global DNA synthesis inhibition. Failure to resolve replication stress in a timely manner contribute toward cell cycle defects, genome instability and human disease; however, the mechanism for fork recovery remains poorly defined. Here, we show that the translesion DNA polymerase (Pol) kappa, a DinB orthologue, has a unique role in both protecting and restarting stalled replication forks under conditions of nucleotide deprivation. Importantly, Pol kappa-mediated DNA synthesis during hydroxyurea (HU)-dependent fork restart is regulated by both the Fanconi Anemia (FA) pathway and PCNA polyubiquitination. Loss of Pol kappa prevents timely rescue of stalled replication forks, leading to replication-associated genomic instability, and a p53-dependent cell cycle defect. Taken together, our results identify a previously unanticipated role for Pol kappa in promoting DNA synthesis and replication stress recovery at sites of stalled forks. PMID- 30422117 TI - Cardiac CaV1.2 channels require beta subunits for beta-adrenergic-mediated modulation but not trafficking. AB - Ca2+ channel beta-subunit interactions with pore-forming alpha-subunits are long thought to be obligatory for channel trafficking to the cell surface and for tuning of basal biophysical properties in many tissues. Unexpectedly, we demonstrate that transgenic expression of mutant cardiac alpha1C subunits lacking capacity to bind CaVbeta because of alanine-substitutions of three conserved residues - Y467, W470, and I471 in the alpha-interaction domain of rabbit alpha1C - can traffic to the sarcolemma in adult cardiomyocytes in vivo and sustain normal excitation-contraction coupling. However, these beta-less Ca2+ channels cannot be stimulated by beta-adrenergic pathway agonists, and thus adrenergic augmentation of contractility is markedly impaired in isolated cardiomyocytes and in hearts. Similarly, viral-mediated expression of a beta-subunit-sequestering peptide sharply curtailed beta-adrenergic stimulation of wild-type Ca2+ channels, identifying an approach to specifically modulate beta-adrenergic regulation of cardiac contractility. Our data demonstrate that beta subunits are required for beta-adrenergic regulation of CaV1.2 channels and positive inotropy in the heart, but are dispensable for CaV1.2 trafficking to the adult cardiomyocyte cell surface, and for basal function and excitation-contraction coupling. PMID- 30422115 TI - Targeting MYC dependency in ovarian cancer through inhibition of CDK7 and CDK12/13. AB - High-grade serous ovarian cancer is characterized by extensive copy number alterations, among which the amplification of MYC oncogene occurs in nearly half of tumors. We demonstrate that ovarian cancer cells highly depend on MYC for maintaining their oncogenic growth, indicating MYC as a therapeutic target for this difficult-to-treat malignancy. However, targeting MYC directly has proven difficult. We screen small molecules targeting transcriptional and epigenetic regulation, and find that THZ1 - a chemical inhibiting CDK7, CDK12, and CDK13 - markedly downregulates MYC. Notably, abolishing MYC expression cannot be achieved by targeting CDK7 alone, but requires the combined inhibition of CDK7, CDK12, and CDK13. In 11 patient-derived xenografts models derived from heavily pre-treated ovarian cancer patients, administration of THZ1 induces significant tumor growth inhibition with concurrent abrogation of MYC expression. Our study indicates that targeting these transcriptional CDKs with agents such as THZ1 may be an effective approach for MYC-dependent ovarian malignancies. PMID- 30422118 TI - Do Sepsis-3 criteria facilitate earlier recognition of sepsis and septic shock? A retrospective cohort study. AB - BACKGROUND: New Sepsis-3 criteria are supposed to "facilitate earlier recognition...of patients with sepsis". To test this, we performed novel and direct comparisons of Sepsis-1 vs. Sepsis-3 criteria with respect to time differences of sepsis onset. METHODS: In a cohort of intensive care unit (ICU) patients prospectively diagnosed with severe sepsis or septic shock according to Sepsis-1 criteria between 01/2010-12/2015 the time differences between meeting Sepsis-1 vs. Sepsis-3 criteria as time of sepsis onset and the corresponding differences in illness severity were tested. Similar comparisons were performed for septic shock subset meeting different Sepsis-1 vs. Sepsis-3 criteria. Patients with non-ICU acquired sepsis and patients with sepsis onset > 48 h post admission (ICU acquired sepsis) were analyzed separately to account for differences in availability of routinely collected organ dysfunction data. RESULTS: 10905 ICU patients were screened. 862 patients met Sepsis-1 criteria, of whom 834 (97%) also met Sepsis-3 criteria. In patients, admitted to the ICU with sepsis, Sepsis-3 criteria compared to Sepsis-1 criteria were more frequently fulfilled within the first 3 hours (84% vs. 75%, P < 0.001).In patients with ICU acquired sepsis, sepsis onset was in 50% at least one day earlier after application of Sepsis-3(P = 0.011). These patients were SIRS negative at the earlier sepsis onset, but suffered already from organ dysfunction. Sepsis-3 criteria were timely in 86% and one day delayed in 7%. Only 7% (8 patients) did not meet Sepsis-3 criteria in this group. These patients had already an increased SOFA score and did develop neither a further increase nor the new septic shock criteria. Classification according to Sepsis-3 reduced the proportion of septic shock (51% vs. 75%, P < 0.001).28-day mortality was 38% for new septic shock compared to 33% of Sepsis-1 septic shock (P > 0.05). Patients not detected by Sepsis-3 had a 28-day mortality of 11%. CONCLUSIONS: Sepsis-3 criteria facilitate an earlier and more predictive recognition of sepsis and septic shock in patients with non-ICU and ICU acquired sepsis primarily diagnosed by Sepsis-1 criteria. These results require further validation with prospectively collected data. PMID- 30422119 TI - RNA-seq transcriptomic profiling of crassulacean acid metabolism pathway in Dendrobium catenatum. AB - The regulation of crassulacean acid metabolism (CAM) pathway has recently become a topic of intensive research and has been explored in terms of several aspects, including phylogenetics, genomics, and transcriptomics. Orchidaceae, which contains approximately 9,000 CAM species, is one of the largest lineages using this special photosynthetic pathway. However, no comprehensive transcriptomic profiling focused on CAM regulation in orchid species had previously been performed. In this report, we present two Illumina RNA-seq datasets, including a total of 24 mature leaf samples with 844.4 million reads, from Dendrobium catenatum (Orchidaceae), a facultative CAM species. The first dataset was generated from a time-course experiment based on the typical CAM phases in a diel. The second was derived from an experiment on drought stress and stress removal. A series of quality assessments were conducted to verify the reliability of the datasets. These transcriptomic profiling datasets will be useful to explore and understand the essence of CAM regulation. PMID- 30422120 TI - Phase contrast time-lapse microscopy datasets with automated and manual cell tracking annotations. AB - Phase contrast time-lapse microscopy is a non-destructive technique that generates large volumes of image-based information to quantify the behaviour of individual cells or cell populations. To guide the development of algorithms for computer-aided cell tracking and analysis, 48 time-lapse image sequences, each spanning approximately 3.5 days, were generated with accompanying ground truths for C2C12 myoblast cells cultured under 4 different media conditions, including with fibroblast growth factor 2 (FGF2), bone morphogenetic protein 2 (BMP2), FGF2 + BMP2, and control (no growth factor). The ground truths generated contain information for tracking at least 3 parent cells and their descendants within these datasets and were validated using a two-tier system of manual curation. This comprehensive, validated dataset will be useful in advancing the development of computer-aided cell tracking algorithms and function as a benchmark, providing an invaluable opportunity to deepen our understanding of individual and population-based cell dynamics for biomedical research. PMID- 30422121 TI - High content organelle trafficking enables disease state profiling as powerful tool for disease modelling. AB - Neurodegenerative diseases pose a complex field with various neuronal subtypes and distinct differentially affected intra-neuronal compartments. Modelling of neurodegeneration requires faithful in vitro separation of axons and dendrites, their distal and proximal compartments as well as organelle tracking with defined retrograde versus anterograde directionality. We use microfluidic chambers to achieve compartmentalization and established high throughput live organelle imaging at standardized distal and proximal axonal readout sites in iPSC-derived spinal motor neuron cultures from human amyotrophic lateral sclerosis patients to study trafficking phenotypes of potential disease relevance. Our semi-automated pipeline of organelle tracking with FIJI and KNIME yields quantitative, multiparametric high content phenotypic signatures of organelle morphology and their trafficking in axons. We provide here the resultant large datasets to enable systemic signature interrogations for comprehensive and predictive disease modelling, mechanistic dissection and secondary hit validation (e.g. drug screens, genetic screens). Due to the nearly complete coverage of analysed motility events, our quantitative method yields a bias-free statistical power superior over common analyses of a handful of manual kymographs. PMID- 30422122 TI - Transcriptome profiling in the spathe of Anthurium andraeanum 'Albama' and its anthocyanin-loss mutant 'Xueyu'. AB - Anthurium andraeanum is a popular tropical ornamental plant. Its spathes are brilliantly coloured due to variable anthocyanin contents. To examine the mechanisms that control anthocyanin biosynthesis, we sequenced the spathe transcriptomes of 'Albama', a red-spathed cultivar of A. andraeanum, and 'Xueyu', its anthocyanin-loss mutant. Both long reads and short reads were sequenced. Long read sequencing produced 805,869 raw reads, resulting in 83,073 high-quality transcripts. Short read sequencing produced 347.79 M reads, and the subsequent assembly resulted in 111,674 unigenes. High-quality transcripts and unigenes were quantified using the short reads, and differential expression analysis was performed between 'Albama' and 'Xueyu'. Obtaining high-quality, full-length transcripts enabled the detection of long transcript structures and transcript variants. These data provide a foundation to elucidate the mechanisms regulating the biosynthesis of anthocyanin in A. andraeanum. PMID- 30422123 TI - Fluctuations in anthropogenic nighttime lights from satellite imagery for five cities in Niger and Nigeria. AB - Dynamic measures of human populations are critical for global health management but are often overlooked, largely because they are difficult to quantify. Measuring human population dynamics can be prohibitively expensive in under resourced communities. Satellite imagery can provide measurements of human populations, past and present, to complement public health analyses and interventions. We used anthropogenic illumination from publicly accessible, serial satellite nighttime images as a quantifiable proxy for seasonal population variation in five urban areas in Niger and Nigeria. We identified population fluxes as the mechanistic driver of regional seasonal measles outbreaks. Our data showed 1) urban illumination fluctuated seasonally, 2) corresponding population fluctuations were sufficient to drive seasonal measles outbreaks, and 3) overlooking these fluctuations during vaccination activities resulted in below target coverage levels, incapable of halting transmission of the virus. We designed immunization solutions capable of achieving above-target coverage of both resident and mobile populations. Here, we provide detailed data on brightness from 2000-2005 for 5 cities in Niger and Nigeria and detailed methodology for application to other populations. PMID- 30422124 TI - Small non-coding RNA expression in mouse nephrogenic mesenchymal progenitors. AB - MicroRNAs (miRNAs) are small non-coding RNAs that are essential for the regulation of gene expression and play critical roles in human health and disease. Here we present comprehensive miRNA profiling data for mouse nephrogenic mesenchymal progenitors, a population of cells enriched for nephron progenitors that give rise to most cell-types of the nephron, the functional unit of the kidney. We describe a miRNA expression in nephrogenic mesenchymal progenitors, with 162 miRNAs differentially expressed in progenitors when compared to whole kidney. We also annotated 49 novel miRNAs in the developing kidney and experimentally validated 4 of them. Our data are available as a public resource, so that it can be integrated into future studies and analyzed in the context of other functional and epigenomic data in kidney development. Specifically, it will be useful in the effort to shed light on molecular mechanisms underlying processes essential for normal kidney development, like nephron progenitor specification, self-renewal and differentiation. PMID- 30422125 TI - PaleoClim, high spatial resolution paleoclimate surfaces for global land areas. AB - High-resolution, easily accessible paleoclimate data are essential for environmental, evolutionary, and ecological studies. The availability of bioclimatic layers derived from climatic simulations representing conditions of the Late Pleistocene and Holocene has revolutionized the study of species responses to Late Quaternary climate change. Yet, integrative studies of the impacts of climate change in the Early Pleistocene and Pliocene - periods in which recent speciation events are known to concentrate - have been hindered by the limited availability of downloadable, user-friendly climatic descriptors. Here we present PaleoClim, a free database of downscaled paleoclimate outputs at 2.5-minute resolution (~5 km at equator) that includes surface temperature and precipitation estimates from snapshot-style climate model simulations using HadCM3, a version of the UK Met Office Hadley Centre General Circulation Model. As of now, the database contains climatic data for three key time periods spanning from 3.3 to 0.787 million years ago: the Marine Isotope Stage 19 (MIS19) in the Pleistocene (~787 ka), the mid-Pliocene Warm Period (~3.264-3.025 Ma), and MIS M2 in the Late Pliocene (~3.3 Ma). PMID- 30422126 TI - A longitudinal plasma lipidomics dataset from children who developed islet autoimmunity and type 1 diabetes. AB - Early prediction and prevention of type 1 diabetes (T1D) are currently unmet medical needs. Previous metabolomics studies suggest that children who develop T1D are characterised by a distinct metabolic profile already detectable during infancy, prior to the onset of islet autoimmunity. However, the specificity of persistent metabolic disturbances in relation T1D development has not yet been established. Here, we report a longitudinal plasma lipidomics dataset from (1) 40 children who progressed to T1D during follow-up, (2) 40 children who developed single islet autoantibody but did not develop T1D and (3) 40 matched controls (6 time points: 3, 6, 12, 18, 24 and 36 months of age). This dataset may help other researchers in studying age-dependent progression of islet autoimmunity and T1D as well as of the age-dependence of lipidomic profiles in general. Alternatively, this dataset could more broadly used for the development of methods for the analysis of longitudinal multivariate data. PMID- 30422127 TI - Top soil physical and chemical properties in Kazakhstan across a north-south gradient. AB - Kazakhstan's soil properties have yet to be comprehensively characterized. We sampled 40 sites consisting of ten major soil types at spring (wet) and late summer (dry) seasons. The sample locations range from semi-arid to arid with an annual mean air temperature from 1.2 to 10.7 degrees C and annual precipitation from less than 200 to around 400 mm. Overall topsoil total (STC), organic (SOC), and inorganic (SIC) carbon did not change significantly between spring and late summer. STC and SOC show a wave like pattern from north to south with two maxima in northern and southern Kazakhstan and one minimum in central Kazakhstan. With a few exceptions SIC content at northern sites is generally low, whereas at Lake Balkhash SIC can exceed 75% of STC. Independent of the seasons, SOC significantly differed among soil types. Total nitrogen content distribution among our sampling sites followed a similar pattern as SOC with significant differences between soil types occurring in northern, central and southern Kazakhstan. PMID- 30422128 TI - EEG, behavioural and physiological recordings following a painful procedure in human neonates. AB - We present a dataset of cortical, behavioural, and physiological responses following a single, clinically required noxious stimulus in a neonatal sample. Cortical activity was recorded from 112 neonates (29-47 weeks gestational age at study) using a 20-channel electroencephalogram (EEG), which was time-locked to a heel lance. This data is linked to pain-related behaviour (facial expression), physiology (heart rate, oxygenation) and a composite clinical score (Premature Infant Pain Profile, PIPP). The dataset includes responses to non-noxious sham and auditory controls. The infants' relevant medical and pain history was collected up to the day of the study and recorded in an extensive database of variables including clinical condition at birth, diagnoses, medications, previous painful procedures, injuries, and selected maternal information. This dataset can be used to investigate the cortical, physiological, and behavioural pain-related processing in human infants and to evaluate the impact of medical conditions and experiences upon the infant response to noxious stimuli. Furthermore, it provides information on the formation of individual pain phenotypes. PMID- 30422129 TI - ASPiH standards for simulation-based education: process of consultation, design and implementation. PMID- 30422130 TI - RING-CLOSING METATHESIS STRATEGY TO UNSATURATED gamma- AND delta-LACTONES: SYNTHESIS OF HYDROXYETHYLENE ISOSTERE FOR PROTEASE INHIBITORS. AB - Ring-closing olefin metathesis of acrylates derived from allylic and homo allylic alcohols in the presence of the Grubbs' catalyst (10-15 mol%) and titanium isopropoxide (0.3-3 equiv) provided ready access to alpha, beta-unsaturated gamma and delta-lactones and an important dipeptide isostere intermediate. PMID- 30422131 TI - Stereoselective Synthesis of Dihydroisocoumarin Moiety of Microbial Agent AI-77 B: a Diels-Alder Based Strategy. AB - The dihydroisocoumarin fragment of the gastroprotective natural product AI-77-B has been synthesized in optically active form by using a regiospecific Diels Alder reaction of 1-methoxy-1,3-cyclohexadiene and an acetylenic ester derivative, prepared stereoselectively from leucinal. PMID- 30422132 TI - TiCl4 Promoted Three Component Coupling Reaction : A New Method for the Synthesis of Functionalized Tetrahydrofurans and Tetrahydropyrans. AB - TiC14 promoted coupling of ethyl glyoxylate and dihydrofuran or dihydropyran provided oxonium ion intermediates which upon reaction with a nucleophilic trapping agent such as allyltrimethylsilane provided 2,3-disubstituted tetrahydrofurans and pyrans in good yields. The overall protocol constitutes an efficient three component coupling reaction in one pot. PMID- 30422134 TI - An artificial intelligence atomic force microscope enabled by machine learning. AB - Artificial intelligence (AI) and machine learning have promised to revolutionize the way we live and work, and one of the particularly promising areas for AI is image analysis. Nevertheless, many current AI applications focus on the post processing of data, while in both materials sciences and medicine, it is often critical to respond to the data acquired on the fly. Here we demonstrate an artificial intelligence atomic force microscope (AI-AFM) that is capable of not only pattern recognition and feature identification in ferroelectric materials and electrochemical systems, but can also respond to classification via adaptive experimentation with additional probing at critical domain walls and grain boundaries, all in real time on the fly without human interference. Key to our success is a highly efficient machine learning strategy based on a support vector machine (SVM) algorithm capable of high fidelity pixel-by-pixel recognition instead of relying on the data from full mapping, making real time classification and control possible during scanning, with which complex electromechanical couplings at the nanoscale in different material systems can be resolved by AI. For AFM experiments that are often tedious, elusive, and heavily rely on human insight for execution and analysis, this is a major disruption in methodology, and we believe that such a strategy empowered by machine learning is applicable to a wide range of instrumentations and broader physical machineries. PMID- 30422135 TI - Facile synthesis of Ni11(HPO3)8(OH)6/rGO nanorods with enhanced electrochemical performance for aluminum-ion batteries. AB - The electrochemical behaviors of the ultrashort nickel phosphite nanorods supported on reduced graphene oxide (Ni11(HPO3)8(OH)6/rGO nanorods), as a candidate for cathodic applications in aluminum-ion batteries, are firstly investigated. Ni11(HPO3)8(OH)6/rGO nanorods are synthesized by a facile solvothermal process. Ni11(HPO3)8(OH)6 and Ni11(HPO3)8(OH)6/rGO cathodes both possess very high initial discharge capacities of 132.4 and 182.0 mA h g-1 at a current density of 200 mA g-1, respectively. In addition, the long-term cycling stability of the Ni11(HPO3)8(OH)6/rGO cathode is further evaluated, exhibiting a discharge capacity of 49.2 mA h g-1 even over 1500 cycles. More importantly, the redox reaction mechanism of the Ni11(HPO3)8(OH)6 cathode for aluminum-ion batteries revealed that Ni11(HPO3)8(OH)6 is partially substituted with Al3+ to form AlmNin(HPO3)8(OH)6 and metallic Ni in the nanorod-like Ni11(HPO3)8(OH)6 cathodes during the discharge process. These findings are of great significance for the further development of novel materials for aluminum-ion batteries. PMID- 30422137 TI - Photodeamination to quinone methides in cucurbit[n]urils: potential application in drug delivery. AB - We demonstrate a proof of principle for a new approach in the development of a drug delivery system. A positively charged prodrug (phenol) can form a stable inclusion complex with CB[7], which enables more efficient delivery of the prodrug. After photochemical transformation (photoactivation) inside the complex, an active drug quinone methide (QM) is formed and released from the complex, since it is a neutral molecule and forms a less stable complex with CB[7]. PMID- 30422136 TI - Iron phosphide encapsulated in P-doped graphitic carbon as efficient and stable electrocatalyst for hydrogen and oxygen evolution reactions. AB - The development of durable and efficient non-noble electrocatalysts for the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) is highly desirable but challenging for the commercialization of renewable energy systems. Herein, a facile strategy is developed for the synthesis of iron phosphide (FeP) nanoparticles protected with an overcoat of "multifunctional" P-doped graphitic carbon as a cost-effective electrocatalyst. The key point is the utilization of MOF-derived iron nanoparticles embedded in graphitic carbon (Fe@GC), which are synthesized via the pyrolysis of the Fe-MIL-88 template and subsequent phosphorization of Fe and simultaneous doping of P in carbon. Compared to the direct phosphorization of Fe-MIL-88, resulting in Fe2P on amorphous carbon (Fe2P@APC), this strategy gives easier access to phosphorization and P doping through pyrolysis temperature regulation. High-temperature pyrolysis can also yield the graphitic carbon encapsulated nanoparticle structure (FeP@GPC), which increases conductivity and prevents agglomeration as well as dissolution under harsh operating conditions, and thus contributes to enhanced activity and long time stability. The optimized FeP@GPC exhibits superior activity compared to Fe2P/FeP@GPC and Fe2P@APC, which is attributed to the modified electronic structure of FeP due to its greater P proportion than Fe2P together with the strong synergy between the nanoparticles and graphitic carbon. In detail, FeP@GPC exhibits an ultralow overpotential of 72 mV and 278 mV to achieve the current density of 10 mA cm-2 for the HER in acid and OER in alkaline media, respectively, together with negligible degradation after 20 h, which ranks among the best Fe-based electrocatalysts. PMID- 30422138 TI - Remarkable similarity of force induced dsRNA conformational changes to stretched dsDNA and their detection using electrical measurements. AB - In spite of the striking difference between twist-stretch coupling of dsRNA and dsDNA under external force, dsRNA shows similar structural polymorphism to dsDNA under different pulling protocols. Our atomistic MD simulations show that overstretching dsRNA along the 3' direction of the opposite strands (OS3) leads to the emergence of S-RNA whereas overstretching along the 5' directions of the opposite strands (OS5) leads to melting of dsRNA at lower forces. Using the dsRNA morphology from pulling MD simulations, we use a multiscale method involving ab initio calculations and Kinetic Monte Carlo (KMC) simulations to estimate the conductance of dsRNA and find that the conformational changes drastically affect its conductance. The current through dsRNA chains drastically drops after a critical stretching length and critically depends on the pulling protocol. The critical stretching length for the OS3 pulling case is around 65% higher than that of the OS5 case. PMID- 30422139 TI - Low intensity focused ultrasound (LIFU) triggered drug release from cetuximab conjugated phase-changeable nanoparticles for precision theranostics against anaplastic thyroid carcinoma. AB - Currently, multifunctional nanotechnology is strongly expected to improve the prospect of treatment and diagnosis. In this study, we synthesized epidermal growth factor (EGFR)-targeted phase-changeable polymer nanoparticles (C-HPNs) loaded with two drugs (C225 and 10-HCPT) for specific tumor targeting, synergistic chemotherapy, and ultrasound imaging under low-intensity focused ultrasound (LIFU). Cetuximab (C225), an EGFR-targeted monoclonal antibody, was conjugated on the surface of the nanoparticles, leading to a significantly high binding affinity to EGFR-overexpressing anaplastic thyroid C643 cells both in vitro and in vivo. As expected, an increase of more than 3- to 4-fold in the release rates of 10-HCPT was observed after LIFU irradiation in vitro, demonstrating that LIFU could enhance the release of drugs from the nanoparticles. Combined treatment with C-HPNs and LIFU showed excellent inhibition of cell proliferation in vitro, as well as a remarkable therapeutic effect in vivo. Moreover, the combined treatment simultaneously enhanced ultrasound imaging by LIFU-induced acoustic droplet vaporization (ADV). In conclusion, C225-modified and phase-changeable nanoparticles combined with LIFU exhibited great promise for concurrent targeted ultrasound molecular imaging and effective synergistic antitumor therapy. PMID- 30422140 TI - Morphology-controlled synthesis of 3D, mesoporous, rosette-like CeCoOx catalysts by pyrolysis of Ce[Co(CN)6] and application for the catalytic combustion of toluene. AB - We synthesized one-dimensional (1D) nanoparticles, 2D hexagonal nanosheets and 3D rosettes of Ce[Co(CN)6] by a hydrothermal process at different temperatures, and CeCoOx catalysts with similar shapes were obtained by the pyrolysis of Ce[Co(CN)6]. T90 of 1D nanoparticles, 2D hexagonal nanosheets and 3D rosette-like CeCoOx catalysts was 306, 275 and 168 degrees C, respectively. The 3D ordered mesoporous rosettes of CeCoOx had superior catalytic activity for toluene combustion, superior thermal stability and moisture resistance, and curves for three consecutive catalytic runs showed overlapping due to more oxygen vacancies, larger pore sizes, more surface Ce3+ species, more surface Co3+ species, and chemically adsorbed oxygen on the surface. PMID- 30422141 TI - Water-soluble MoS2 quantum dots for facile and sensitive fluorescence sensing of alkaline phosphatase activity in serum and live cells based on the inner filter effect. AB - We report a facile and sensitive method for the detection of alkaline phosphatase (ALP) activity in serum and live cells using molybdenum disulfide quantum dots (MoS2 QDs) based on the Inner Filter Effect (IFE). In the present work, water soluble MoS2 QDs with bright green fluorescence were synthesized through direct ultrasonic exfoliation of MoS2 powder in 85 vol% aqueous ethanol solution. p Nitrophenylphosphate (PNPP) was employed to act as an ALP substrate, and its enzyme catalytic product (p-nitrophenol (PNP)) functioned as a powerful absorber in the IFE to influence the excitation of MoS2 QDs. PNPP was transformed into PNP in the presence of ALP, leading to the transition of the absorption peak from 310 nm to 405 nm and therefore resulted in a complementary overlap between the absorption of PNP and the excitation of MoS2 QDs. The fluorescence of MoS2 QDs was quenched due to the significant weakening of the excitation of MoS2 QDs by competitive absorption between QDs and PNP. A good linear relationship was obtained from 0 to 5 U L-1 (R2 = 0.9919) using the present IFE based sensing strategy with the lowest detection activity of 0.1 U L-1. The proposed sensing approach was successfully applied to ALP sensing in serum samples and ALP inhibitor investigation, as well as in ALP cell imaging. PMID- 30422142 TI - Mechanisms induced by transition metal contaminants and their effect on the hydrothermal stability of zirconia-containing bioceramics: an XPS study. AB - Zirconia containing bioceramics suffer from low temperature degradation in biological and hydrothermal environments, and the presence of transition metal contamination has been shown to greatly affect the zirconia stability in different materials. In this paper, X-ray photoelectron spectroscopy was used to investigate the compositional and structural variations of different zirconia containing hip-joint bioceramics with and without transition metal stains in hydrothermal environments. Non-stained and stainless-steel-stained femoral head samples of 3 mol% Y2O3 doped tetragonal zirconia polycrystals (3Y-TZP) and zirconia-toughened alumina (ZTA) subjected to isothermal treatments in water vapor were investigated with quantifying their respective compositional XP lines. The outputs of these spectroscopic experiments revealed a significant difference in the off-stoichiometric reactions taking place at the surface of zirconia containing ceramics in the presence and absence of transition metal contamination. The complex off-stoichiometric chemistry that occurred in the presence of metal contaminants could be interpreted in terms of defect-related chemical reactions among metal, water vapor, and oxide lattice, with a crucial contribution of the alumina phase in the transformation kinetics of ZTA. PMID- 30422143 TI - Oxygen vacancy enriched hollow cobaltosic oxide frames with ultrathin walls for efficient energy storage and biosensing. AB - Transition metal oxides (TMOs) with desired morphologies and atomic structures have promising applications in energy storage, catalysis, and biosensing because of their large specific surface area, high theoretical capacitance, abundant active sites, etc. In this study, hierarchical Co3O4 with enriched oxygen vacancies and finely tuned nanostructures, e.g. high porosity, thin wall thickness, hollow or yolk-shell structure, is prepared by dynamically balancing the decomposition and oxidation of the zeolitic imidazolate framework-67 (ZIF-67) precursor directly calcined in air at 300 degrees C. The optimized Co3O4 hollow frame inherits the original shape of the parent ZIF-67 with a high volume retention of 83% and features an ultrathin wall thickness of 10 nm, a large accessible surface area of 63.7 m2 g-1 and a high content of surface oxygen vacancies. It thus delivers an excellent specific capacitance of 770 F g-1 at 1 A g-1, a rate capability of 570.9 F g-1 at 20 A g-1 and excellent cycling stability for energy storage, and a high sensitivity of 0.7 mA mM-1 cm-2, a low detection limit of 0.2 MUM (S/N = 3), and a wide linear detectable range of 0.005-1.175 mM for electrochemical non-enzymatic detection of glucose. PMID- 30422144 TI - Inverse-electron-demand Diels-Alder reactions of alpha,beta-unsaturated hydrazones with 3-methoxycarbonyl alpha-pyrones. AB - Inverse-electron-demand Diels-Alder reactions of 3-electron-withdrawing group substituted alpha-pyrones with alpha,beta-unsaturated hydrazones as electron-rich counterparts are catalyzed by Eu(hfc)3 to afford bicyclic lactone cycloadducts. This is an example of umpolung cycloaddition based on functional transformation of carbonyls to hydrazones. A subsequent dehydrazonation reaction enables indirect synthesis of carbonyl group-containing bicyclic lactones, which cannot be easily obtained by the cycloaddition of alpha-pyrones and enals. PMID- 30422145 TI - Facile synthesis of fused polycyclic compounds via intramolecular oxidative cyclization/aromatization of beta-tetralone or beta-tetralone oximes. AB - A mild and efficient NBS promoted intramolecular oxidative cyclization/aromatization of beta-tetralone oximes has been explored. Under the optimized conditions, fused alpha-carbolines containing pentacyclic rings were obtained in moderate to good yields. Furthermore, various benzo[5,6]chromeno[2,3 b]indoles were successfully synthesized in moderate yields from beta-tetralones using slightly modified conditions. We proposed a possible reaction pathway based on the experimental results. PMID- 30422146 TI - Single and polycrystalline CeO2 nanorods as oxygen-electrode materials for lithium-oxygen batteries. AB - Single and polycrystalline CeO2 nanorods (NRs) were prepared for application as oxygen-electrode electrocatalysts for lithium-oxygen batteries. The CeO2 NRs were prepared via a time-controlled hydrothermal process. At a high current rate of 1000 mA g-1, the single crystalline CeO2 NRs exhibited a higher reversibility and a lower voltage gap than polycrystalline CeO2 NRs. We compared the oxygen reduction and evolution kinetics of single and polycrystalline CeO2 NRs using electrochemical impedance spectroscopy. PMID- 30422147 TI - A time of change: dietary reconstruction of the Merovingian cemetery of Norroy-le Veneur, France. AB - The aim of this work was to analyse the diet of a Merovingian population sample of 80 individuals buried at Norroy-le-Veneur, France, with regard to their social status and chronology. A carbon and nitrogen stable isotope analysis of human adult bone collagen and related fauna from the same cemetery showed a diet based primarily on C3 plants, supplemented with animal protein in a range comparable to other contemporary sites. No significant contribution of C4 plants (e.g. millet) or marine-derived protein was detected. In terms of socio-economic stratification, individuals buried with rich grave good assemblages formed a narrow group with a significantly higher mean of delta13C than low-ranking individuals. We argue that this may represent a step in the gradual formation of the dietary exclusivity of Frankish elites, following a progressive rise in power of the Merovingian nobility. Also, during the timespan of the cemetery there was a population-wide decrease of 0.3 0/00 in the mean value of delta13C. The role of the Christian conversion of the population is questioned, but another factor influencing diet might have played a role. PMID- 30422148 TI - The association of psychosomatic health with physical status and lifestyle factors in adolescence. AB - The main purposes were to analyse the age pattern of experiencing psycho-somatic complaints in children; to study the influence of physical status and lifestyle factors on psycho-somatic status. The sample (n: 13,331, aged 7-18) represented a subsample of the 2nd Hungarian National Representative Growth Study. Subjects were divided into underweight, normal, preobese and obese subgroups. A standard symptom list was used to assess the experience of psycho-somatic complaints. Children rated their current health status in terms of excellent, good, fair and poor. Subjects were divided into physical activity subgroups. The prevalence of the psycho-somatic complaints increased with age, girls reported more symptoms than boys. Irritability and waking up tired were the most frequent symptoms. Subjective health status, nutritional status, body image, academic achievement, stature, body mass and socioeconomic status influenced the pattern of psycho somatic complaints in girls, while physical activity, self-esteem, socioeconomic status and subjective health status in boys. PMID- 30422149 TI - Post-factum autopsy to confirm cardiac structures visible on computed tomography images of Korean mummies: the radiological basis of paleo-cardiology. AB - Accurate interpretation of radiological data is important for reliable paleopathological study of mummies. This is especially true for the mummified heart, an anatomically complicated organ that is distorted and displaced due to long-term dehydration and the action of gravity. In the present study, we compared post-factum autopsy results for mummified hearts of differing preservation statuses with corresponding radiological (computed tomography [CT] image) findings in order to obtain information necessary for accurate radiological diagnosis. We found that the valvular apparatus (especially the aortic valve and chordae tendinae) was easily distinguishable on the CT images of mummies in which more cardiac structures were preserved. We also identified several situations that are known to incur misdiagnosis of cardiac CT images: the presence of pseudo-cavities in the cardiac wall, confusion of the valvular apparatus with cardiac-wall debris, and invisibility of cardiac structures on CT images due to collapse or adhesion. While acknowledging the merits of top priority CT scanning in non-invasive research, post-factum autopsy also has value as a complementary and confirmatory analysis for enhanced accuracy of diagnoses in paleo-radiological studies. PMID- 30422150 TI - Aggressive-Appearing Intratracheal Mass in an Older Woman. PMID- 30422133 TI - Genetically elevated high-density lipoprotein cholesterol through the cholesteryl ester transfer protein gene does not associate with risk of Alzheimer's disease. AB - Introduction: There is conflicting evidence whether high-density lipoprotein cholesterol (HDL-C) is a risk factor for Alzheimer's disease (AD) and dementia. Genetic variation in the cholesteryl ester transfer protein (CETP) locus is associated with altered HDL-C. We aimed to assess AD risk by genetically predicted HDL-C. Methods: Ten single nucleotide polymorphisms within the CETP locus predicting HDL-C were applied to the International Genomics of Alzheimer's Project (IGAP) exome chip stage 1 results in up 16,097 late onset AD cases and 18,077 cognitively normal elderly controls. We performed instrumental variables analysis using inverse variance weighting, weighted median, and MR-Egger. Results: Based on 10 single nucleotide polymorphisms distinctly predicting HDL-C in the CETP locus, we found that HDL-C was not associated with risk of AD (P > .7). Discussion: Our study does not support the role of HDL-C on risk of AD through HDL-C altered by CETP. This study does not rule out other mechanisms by which HDL-C affects risk of AD. PMID- 30422151 TI - Can Better Cardiovascular Care Close the Mortality Gap for People With Schizophrenia? PMID- 30422152 TI - Comparison of Insurance Status and Diagnosis Stage Among Patients With Newly Diagnosed Cancer Before vs After Implementation of the Patient Protection and Affordable Care Act. AB - Importance: Having health insurance is a strong determinant of cancer outcomes in the United States, and Medicaid expansion under the Patient Protection and Affordable Care Act (ACA) may have reduced the prevalence of uninsured patients. Prior research has only assessed the aggregate effects of expansions, and little is known about changes in uninsured patients by state and key sociodemographic groups, including sex, race/ethnicity, census tract-level poverty, and rurality. Objective: To examine changes in the percentage of uninsured patients and stage at diagnosis among nonelderly patients with cancer by state and key sociodemographic groups after implementation of the ACA. Design, Setting, and Participants: This study used difference-in-differences analysis to determine the percentage of uninsured patients and early-stage cancer diagnoses among patients aged 18 to 64 years from the population-based cancer registries of 40 states before (January 1, 2010, to December 31, 2013) and after (January 1, 2014, to December 31, 2014) the ACA Medicaid expansion. Data analysis was performed from November 2017 to April 2018. Main Outcomes and Measures: Changes in the percentage of uninsured patients and early-stage diagnoses. Results: A total of 2 471 154 patients (mean age, 52.7 years; age range, 18-64 years; 51.4% female; 70.9% non-Hispanic white) were included from Medicaid expansion (n = 1 234 156) and nonexpansion (n = 1 236 998) states. In 2014, the percentage of uninsured patients decreased in almost all states. However, decreases were greater in expansion than nonexpansion states and were greatest in expansion states with high baseline uninsured rates. For example, the percentage of uninsured patients decreased from 8.3% before implementation of the ACA to 2.1% (-6.2 difference) after implementation of the ACA in the expansion state of Kentucky compared with 9.1% to 7.5% (-1.5 difference) in the nonexpansion state of Tennessee. In expansion states, the decreases in the percentage of uninsured patients were higher among minorities and patients in high-poverty or rural areas, diminishing or eliminating disparities. In contrast, sociodemographic disparities in the percentage of uninsured patients remained high in nonexpansion states. Stage at diagnosis shifted slightly to earlier stage for most cancer types in Medicaid expansion states. Conclusions and Relevance: This study found state variation in reductions in the percentage of uninsured patients among nonelderly patients with cancer after implementation of the ACA, with larger decreases in expansion than nonexpansion states. Disparities in the percentage of uninsured patients by race/ethnicity, census tract-level poverty, and rurality were diminished or eliminated in Medicaid expansion states but remained high in nonexpansion states, highlighting the promising role of Medicaid expansion in reducing disparities among sociodemographic subpopulations. Future studies should monitor changes in cancer presentation, treatment, and outcomes after implementation of the ACA. PMID- 30422154 TI - Error in Table 2. PMID- 30422153 TI - Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With Outcomes After Acute Kidney Injury. AB - Importance: Patients with acute kidney injury (AKI) are at an increased long-term risk of death. Effective strategies that improve long-term outcomes in patients with AKI are unknown. Objective: To evaluate whether the use of angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) after hospital discharge is associated with better outcomes in patients with AKI. Design, Setting, and Participants: This retrospective cohort study used data from the Alberta Kidney Disease Network population database to evaluate 46 253 adults 18 years or older with an episode of AKI during a hospitalization between July 1, 2008, and March 31, 2015, in Alberta, Canada. All patients who survived to hospital discharge were followed up for a minimum of 2 years. Exposures: Use of an ACEI or ARB within 6 months after hospital discharge. Main Outcomes and Measures: The primary outcome was mortality; secondary outcomes included hospitalization for a renal cause, end-stage renal disease (ESRD), and a composite outcome of ESRD or sustained doubling of serum creatinine concentration. An AKI was defined as a 50% increase between prehospital and peak in-hospital serum creatinine concentrations. Propensity scores were used to construct a matched-pairs cohort of patients who did and did not have a prescription for an ACEI or ARB within 6 months after hospital discharge. Results: The study evaluated 46 253 adults (mean [SD] age, 68.6 [16.4] years; 24 436 [52.8%] male). Within 6 months of discharge, 22 193 (48.0%) of the participants were prescribed an ACEI or ARB. After adjustment for comorbidities, ACEI or ARB use before admission, demographics, baseline kidney function, other factors related to index hospitalization, and prior health care services, ACEI or ARB use was associated with lower mortality in patients with AKI after 2 years (adjusted hazard ratio, 0.85; 95% CI, 0.81-0.89). However, patients who received an ACEI or ARB had a higher risk of hospitalization for a renal cause (adjusted hazard ratio, 1.28; 95% CI, 1.12-1.46). No association was found between ACEI or ARB use and progression to ESRD. Conclusions and Relevance: Among patients with AKI, ACEI or ARB therapy appeared to be associated with lower mortality but a higher risk of hospitalization for a renal cause. These results suggest a potential benefit of ACEI or ARB use after AKI, but cautious monitoring for renal specific complications may be warranted. PMID- 30422155 TI - The Development of Kraepelin's Mature Diagnostic Concepts of Paranoia (Die Verrucktheit) and Paranoid Dementia Praecox (Dementia Paranoides): A Close Reading of His Textbooks From 1887 to 1899. AB - Over 12 years (1887-1899), in his second through sixth editions of his textbook Psychiatrie: Ein Lehrbuch fur Studierende und Arzte, Emil Kraepelin created, through an iterative, self-examining process, his mature concepts of Verrucktheit (paranoia) and Paranoide Formen Dementia Praecox. I seek in this essay to show this skilled nosologist at work. Four themes were prominent. First, Kraepelin used symptoms throughout, but he transitioned from superficial phenomenon (delusional themes) to those he considered more pathognomonic: disorganized fantastical delusions vs organized, nonbizarre delusions. Second, he increasingly emphasized the distinction between delusions arising from misinterpretations of real events vs delusions arising from hallucinations. Third, the putative causes of the disorder became more important as he came to understand Verrucktheit from a psychological and developmental perspective, whereas dementia paranoides (the precursor to paranoide formen dementia praecox) resulted from pathological brain changes. Fourth, Kraepelin appreciated the importance of disease course, but he initially lacked adequate data to elucidate it. As his research program developed, he used the well-recognized disease of general paralysis of the insane as a paradigm and correlated symptoms, modes of delusion formation, and presumed mechanisms of disease with course and outcome. Patients with slowly developing, referential, nonbizarre delusions without hallucinations were typically stable for years with minimal deterioration. Patients with rapidly developing, poorly organized, fantastical delusions emerging from prominent hallucinations tended to deteriorate quickly. Using conceptual tools first proposed by Kahlbaum and Hecker, Kraepelin developed his concepts of Verrucktheit and paranoide formen dementia praecox using an exploratory, conceptual, and data-gathering process in which each syndrome was defined in contrast to the other and, in addition to a core focus on disease course, multiple additional levels of clinical inquiry were included. PMID- 30422156 TI - Continuation of Bevacizumab vs Cetuximab Plus Chemotherapy After First Progression in KRAS Wild-Type Metastatic Colorectal Cancer: The UNICANCER PRODIGE18 Randomized Clinical Trial. AB - Importance: Second-line treatment with chemotherapy plus bevacizumab or cetuximab is a valid option for metastatic colorectal cancer. Objective: To evaluate the progression-free survival (PFS) rate at 4 months with chemotherapy plus bevacizumab vs cetuximab for patients with progression of metastatic colorectal cancer after bevacizumab plus chemotherapy. Design, Setting, and Participants: A prospective, open-label, multicenter, randomized phase 2 trial was conducted from December 14, 2010, to May 5, 2015. The main eligibility criterion was disease progression after bevacizumab plus fluorouracil with irinotecan or oxaliplatin in patients with wild-type KRAS exon 2 metastatic colorectal cancer. All analyses were performed on the modified intent-to-treat population. Interventions: Patients were randomized to arm A (FOLFIRI [fluorouracil and folinic acid combined with irinotecan] or modified FOLFOX6 [fluorouracil and folinic acid combined with oxaliplatin] plus bevacizumab) or arm B (FOLFIRI or modified FOLFOX6 plus cetuximab); the second-line chemotherapy regimen was chosen according to first-line treatment (crossover). Main Outcomes and Measures: The primary end point was the 4-month PFS rate. Secondary end points included safety, objective response rate, overall survival, and PFS. Results: A total of 132 patients (47 women and 85 men; median age, 63.0 years [range, 33.0-84.0 years]; 74 patients with an Eastern Cooperative Oncology Group performance status of 0, 54 patients with a performance status of 1, and 4 patients with unknown performance status) were included at 25 sites. The 4-month PFS rate was 80.3% (95 CI%, 68.0%-88.3%) in arm A and 66.7% (95% CI, 53.6%-76.8%) in arm B. The median PFS was 7.1 months (95% CI, 5.7-8.2 months) in arm A and 5.6 months (95% CI, 4.2 6.5 months) in arm B (hazard ratio, 0.71; 95% CI, 0.50-1.02; P = .06), and the median overall survival was 15.8 months (95% CI, 9.5-22.3 months) in arm A and 10.4 months (95% CI, 7.0-16.2 months) in arm B (hazard ratio, 0.69; 95% CI, 0.46 1.04; P = .08). A central analysis of KRAS (exons 2, 3, and 4), NRAS (exons 2, 3, and 4), and BRAF (V600) was performed for 95 tumor samples. Eighty-one patients had wild-type KRAS and wild-type NRAS tumors. Conclusions and Relevance: The results of the PRODIGE18 (Partenariat de Recherche en Oncologie DIGEstive) study showed a nonsignificant difference but favored continuation of bevacizumab with chemotherapy crossover for patients with wild-type RAS metastatic colorectal cancer that progressed with first-line bevacizumab plus chemotherapy. Trial Registration: ClinicalTrials.gov identifier: NCT01442649 and clinicaltrialsregister.eu identifier: EUDRACT 2009-012942-22. PMID- 30422158 TI - Association of Secondary Preventive Cardiovascular Treatment After Myocardial Infarction With Mortality Among Patients With Schizophrenia. AB - Importance: Cardioprotective medication use is an important secondary preventive treatment after cardiovascular events. Patients with schizophrenia have excess cardiovascular morbidity and mortality, but no studies have investigated whether taking recommended cardioprotective medication can reduce this excess mortality. Objective: To assess the association of exposure to secondary cardiovascular treatment with all-cause mortality after myocardial infarction among patients with schizophrenia compared with the general population. Design, Setting, and Participants: This nationwide cohort study included individuals admitted with first-time myocardial infarction in Denmark from January 1, 1995, to December 31, 2015. The cohort was dichotomously divided by a diagnosis of schizophrenia. Data on the prescription of guideline-recommended cardioprotective medication, including antithrombotics, beta-blockers, vitamin K antagonist, angiotensin converting enzyme inhibitors, and statins, were obtained from the nationwide registries. Exposures: Time exposed to cardioprotective medication. Main Outcomes and Measure: Cox proportional hazards regression was used to calculate hazard ratios (HRs) with 95% CIs for the association between treatment exposure and all cause mortality after myocardial infarction between patients with and without schizophrenia. Results: The cohort included 105 018 patients with myocardial infarction, including 684 patients with schizophrenia (0.7%; 483 male [70.6%]; mean [SD] age at diagnosis, 57.3 [10.6] years) and 104 334 general population patients (99.3%; 73 454 male [70.4%]; mean [SD] age at diagnosis, 61.0 [10.6] years), with a total follow-up of 796 435 person-years and 28 059 deaths. Patients diagnosed with schizophrenia who did not receive cardioprotective treatment had the highest mortality rate (HR, 8.78; 95% CI, 4.37-17.64) compared with the general population treated, with treated patients diagnosed with schizophrenia having an increased HR of 1.97 (95% CI, 1.25-3.10). The analyses of the associations of different cardiac therapy strategies with mortality rates revealed that patients with schizophrenia who were treated with any combination of triple therapy had mortality rates similar to those observed in the general population (HR, 1.05; 95% CI, 0.43-2.52) in the multivariable analysis. Conclusions and Relevance: Cardioprotective medication after myocardial infarction should be carefully managed to improve prognosis. The study results suggest that some of the increased cardiac mortality among patients with schizophrenia can be reduced if these patients are efficiently administered combinations of secondary preventive treatments after cardiac events. PMID- 30422159 TI - Danish-like Regulations May Improve Postabortion Mental Health Risk. PMID- 30422157 TI - Donor, Recipient, and Operative Factors Associated With Increased Endothelial Cell Loss in the Cornea Preservation Time Study. AB - Importance: Determining factors associated with endothelial cell loss after Descemet stripping automated endothelial keratoplasty (DSAEK) could improve long term graft survival. Objective: To evaluate the associations of donor, recipient, and operative factors with endothelial cell density (ECD) 3 years after DSAEK in the Cornea Preservation Time Study. Design, Setting, and Participants: This cohort study was a secondary analysis of data collected in a multicenter, double masked, randomized clinical trial. Forty US clinical sites with 70 surgeons participated, with donor corneas provided by 23 US eye banks. Individuals undergoing DSAEK for Fuchs dystrophy or pseudophakic/aphakic corneal edema were included. Interventions: The DSAEK procedure, with random assignment of a donor cornea with a preservation time of 0 to 7 days or 8 to 14 days. Main Outcomes and Measures: Endothelial cell density at 3 years as determined by a reading center from eye bank and clinical specular or confocal central endothelial images. Results: The study included 1090 participants (median age, 70 years) with 1330 affected eyes (240 bilateral cases [22.0%]), who underwent DSAEK for Fuchs dystrophy (1255 eyes [94.4%]) or pseudophakic/aphakic corneal edema (PACE) (75 eyes [5.6%]). Of these, 801 eyes (60.2%) belonged to women and 1207 (90.8%) to white individuals. A total of 749 participants (913 eyes; 164 [21.9%] bilateral cases) had functioning grafts with acceptable endothelial images preoperatively and at 3 years postoperatively and were included in this analysis. Factors associated with a lower ECD at 3 years (estimated effect with 99% CI) in the final multivariable model included donors with diabetes (-103 [-196 to -9] cells/mm2), lower screening ECD (-234 [-331 to -137] per 500 cells/mm2), recipient diagnosis of PACE (-257 [-483 to -31] in cells/mm2), and operative complications (-324 [-516 to -133] in cells/mm2). Endothelial cell loss (ECL) from a preoperative measurement to a 3-year postoperative measurement was 47% (99% CI, 42%-52%) for participants receiving tissue from donors with diabetes vs 43% (99% CI, 39%-48%) without diabetes; it was 53% (99% CI, 44%-62%) for participants diagnosed with PACE vs 44% (99% CI, 39%-49%) for those diagnosed with Fuchs dystrophy, and 55% (99% CI, 48%-63%) in participants who experienced operative complications vs 44% (99% CI, 39%-48%) in those who did not. No other donor, recipient, or operative factors were significantly associated with 3-year ECD. Conclusions and Relevance: Donor diabetes, lower screening ECD, a PACE diagnosis in the recipient, and operative complications were associated with lower ECD at 3 years after DSAEK surgery and may be associated with long-term graft success. While causation cannot be inferred, further studies on the association of donor diabetes and PACE in recipients with lower 3-year ECD warrant further study. PMID- 30422161 TI - Missing Conflict of Interest Disclosure. PMID- 30422162 TI - Failure to Accurately Disclose Conflicts of Interest in Articles Published in JAMA Oncology. PMID- 30422160 TI - Herpetic Whitlow-A Case of Inadvertent Inoculation With Melanoma Viral Therapy. PMID- 30422163 TI - Danish-like Regulations May Improve Postabortion Mental Health Risk-Reply. PMID- 30422164 TI - Missing Conflict of Interest Disclosure. PMID- 30422165 TI - Failure to Disclose Conflict of Interest in Article Published in JAMA on Detection of Cancer-Related Genes. PMID- 30422166 TI - The Illness We Carry. PMID- 30422167 TI - Have Tent, Will Do Pop-up HIV Screening. PMID- 30422168 TI - Reduction of Opiates for Ambulatory Surgery-Endocrine Surgeons at the Cutting Edge. PMID- 30422169 TI - Pacritinib in Patients With Myelofibrosis. PMID- 30422170 TI - Opioid Prescribing Practice and Needs in Thyroid and Parathyroid Surgery. AB - Importance: In recent years, the medical community's inadvertent contribution to opioid addiction has been recognized. Objective: To determine the opioid prescribing practices and opioid needs for patients undergoing thyroid and parathyroid surgery to help reduce postoperative opioid administration. Design, Setting, and Participants: This retrospective cohort study included 1788 opioid naive patients who underwent thyroid and parathyroid surgery from January 1, 2012, through December 31, 2017, at the high-volume academic endocrine surgery center at Oregon Health and Sciences University. Patients with long-term opioid treatment and those who underwent other head and neck procedures or robotic thyroidectomy were excluded. For analysis, 1765 procedures were available (723 parathyroidectomy, 400 hemithyroidectomy, and 642 total thyroidectomy). Main Outcomes and Measures: The quantity of prescribed opioids was determined in morphine milligram equivalents (MME). Opioid refill data after discharge were also analyzed. Patients were then divided into past (1336 in group 1 [January 1, 2012, to September 30, 2016]) and current (429 in group 2 [October 31, 2016, to December 31, 2017]) prescribing practices. For each procedure, the mean quantity prescribed for each group, difference between the means, 95% CI for the difference, and effect size were calculated. Results: A total of 1702 patients (80.0% female [n = 1361]; mean age, 51.2 years [range, 7-97 years]) undergoing 1765 procedures were included in the analysis. For parathyroidectomy, the mean (SD) opioid quantity prescribed was 176.20 (86.66) MME in group 1 vs 80.08 (74.43) MME in group 2 (effect size, 1.139); for hemithyroidectomy, 204.65 (112.24) MME in group 1 vs 112.24 (102.31) MME in group 2 (effect size, 0.842); and for total thyroidectomy, 214.87 (161.09) MME for group 1 vs 102.29 (87.72) MME for group 2 (effect size, 0.754). In the last quarter of 2017, the numbers of patients discharged without any opioid prescription were 15 of 26 (57.5%) for parathyroidectomy, 12 of 32 (37.5%) for hemithyroidectomy, and 9 of 27 (33.3%) for total thyroidectomy. Patient calls requesting pain medications for group 2 were similar or fewer, depending on the procedure. Those who were prescribed less than 75.0 MME postoperatively did not call for additional opioid prescriptions. Conclusions and Relevance: Our study suggests that patients undergoing thyroid and parathyroid surgery need little, if any, postoperative opioids. PMID- 30422171 TI - Characterizing the Normative Voice Tremor Frequency in Essential Vocal Tremor. AB - Importance: Essential vocal tremor (EVT) is a neurologic voice disorder characterized by periodic fluctuations in pitch and loudness that can hinder intelligibility. Defining the normative range of vocal tremor frequency may assist in diagnosis and provide insight into disease mechanisms. Objective: To characterize the normative voice tremor frequency in EVT (in hertz). Design, Setting, and Participants: Cross-sectional observational study of 160 patients with EVT. The setting was a tertiary voice center. Participants were identified from a database of consecutive patients diagnosed as having laryngeal movement disorders between January 1, 1990, and April 1, 2017. Main Outcomes and Measures: The following 3 methods measured the frequency of tremor experienced by patients with EVT: perceptual method, computerized peak detection method, and laryngeal electromyography method. Within-person and population-level tremor frequencies were compared across modalities to assess measurement reliability and consistency and to characterize the normal distribution of tremor frequencies in this population. Results: Among 160 participants (median age, 70 years; interquartile range [IQR], 64-77 years; 90.6% female [n = 145]), the median frequency of EVT was consistently between 4 and 5 Hz across all 3 methods (perceptual, 4.8 Hz [IQR, 4.4-5.5 Hz]; computerized peak detection, 4.6 Hz [IQR, 4.2-5.0 Hz]; and laryngeal electromyography, 4.3 Hz [IQR, 3.8-5.0 Hz]). The mean in-person differences between each measurement method were not clinically meaningful (range, 0.1-0.5 Hz). Including all interquartile ranges across measurement modalities, the normative tremor frequency range for EVT was 3.8 to 5.5 Hz. Conclusions and Relevance: To our knowledge, this is the largest study to date to characterize the normal frequency of tremor in patients with EVT. The normative frequency of EVT (range, 3.8-5.5 Hz) falls within a much narrower range than previously reported. Those whose frequency is outside this range may still have EVT but should be carefully evaluated for potential other causes of vocal tremor. Defining characteristics of EVT may aid appropriate diagnosis and improve understanding of this disease. PMID- 30422172 TI - A Long-term Benefit Approach vs Standard Risk-Based Approaches for Statin Eligibility in Primary Prevention. AB - Importance: A 10-year benefit-based approach to statin therapy in primary prevention includes younger individuals with higher low-density lipoprotein cholesterol (LDL-C) and prevents more cardiovascular events than a risk-based approach. However, a 10-year treatment duration likely underestimates the expected benefits of statins. Objective: To model the impact of a 30-year benefit approach to select individuals for statin therapy. Design, Setting, and Participants: This cross-sectional analysis of the National Health and Nutrition Survey (NHANES) data set included samples of the US population from the 2009 2010, 2011-2012, and 2013-2014 data collection cycles. Individuals between 40 to 60 years old who did not have atherosclerotic cardiovascular disease, diabetes, or LDL-C levels greater than 190 mg/dL and who were not taking statins were included. Data analysis took place from November 2017 to August 2018. Exposures: We calculated 10-year risk of atherosclerotic cardiovascular disease and 10-year and 30-year absolute risk reduction (10-year ARR and 30-year ARR) of atherosclerotic cardiovascular disease for each individual. Main Outcomes and Measures: Number of individuals meeting eligibility for statins based on 10-year (atherosclerotic) cardiovascular disease risk, 10-year ARR, or 30-year ARR. Results: A total of 1688 individuals were included, representing 56.6 million US individuals. Statin eligibility based on 7.5% CVR10 was 9.5%; based on 2.3% 10 year ARR, 13.0%, and based on 15% 30-year ARR, 17.5%. The 10-year risk, 10-year benefit, and 30-year benefit approaches all led to similar acceptable mean absolute risk reductions at 30 years, with the benefit-based approaches better able to avoid treatment of individuals with low expected benefit. Individuals who met statin eligibility based solely on the 30-year ARR threshold of 15% or greater were younger (mean age, 50 [95% CI, 48-52] years) and more likely to be women (43% [95% CI, 26%-59%]) than those recommended with a 10-year ARR threshold of 2.3% or greater (mean age, 56 [95% CI, 54-57] years; 22% [95% CI, 10%-34%] women). This group also had lower 10-year risk (mean risk, 4.7% [95% CI, 4.4% 5.1%]) and higher LDL-C levels (mean level, 149 mg/dL [95% CI, 142-155 mg/dL]) than those recommended with a 10-year ARR threshold of 2.3% or greater (mean risk, 9.3% [95% CI, 8.3%-10.2%]; mean LDL-C levels, 110 [103-118] mg/dL). Preventable atherosclerotic cardiovascular disease events in 10 and 30 years were highest using the 30-year benefit approach (296 000 at 10 years and 2.03 million at 30 years) and lowest based on 10-year risk (204 000 at 10 years and 1.18 million at 30 years). Conclusions and Relevance: A long-term benefit approach to statin eligibility identifies nearly 1 in 6 individuals as having a high degree of expected long-term benefit of statins, with a number needed to treat of less than 7. This approach identifies younger individuals with higher LDL-C levels who would not be currently recommended for treatment and may provide a more optimal approach for determining statin eligibility in primary prevention. PMID- 30422173 TI - Association of Apolipoprotein E epsilon4 With Transactive Response DNA-Binding Protein 43. AB - Importance: Transactive response DNA-binding protein 43 (TDP-43) is associated with Alzheimer disease (AD), progressive hippocampal atrophy, and cognitive decline. The apolipoprotein E (APOE) epsilon4 allele is strongly associated with beta-amyloid (Abeta) aggregation and risk of AD, but its association with TDP-43 is unknown. Objective: To determine whether the APOE epsilon4 allele is a risk factor for TDP-43. Design, Setting, Participants: This cross-sectional, genetic histologic study analyzed APOE genotype, TDP-43 status (positive vs negative), Abeta status (positive vs negative), and tau neurofibrillary tangle stage (B0, Braak stage 0; B1, Braak stages I-II; B2, Braak stages III-IV; B3, Braak stage >= V). We fit structural equation models to map the association between APOE and TDP 43, Abeta, and tau, accounting for age and hippocampal sclerosis. We identified 751 participants with an AD pathological spectrum diagnosis and completed Abeta, tau, and TDP-43 data who were enrolled in the Mayo Clinic Alzheimer Disease Research Center, Mayo Clinic Alzheimer Disease Patient Registry, or the population based Mayo Clinic Study of Aging and died between May 12, 1999, and December 31, 2015. However, 13 were excluded from the analyses because of missing APOE data, leaving a total of 738 participants. Main Outcomes and Measures: Transactive response DNA-binding protein 43 was the main outcome of interest. We hypothesized that the APOE epsilon4 allele would be significantly directly and indirectly associated with TDP-43. Results: The 751 study participants were older (median age [interquartile range], 87 years [51-105 years]), 395 (54%) were women, and 324 (44%) were APOE epsilon4 carriers. The patients died between May 12, 1999, and December 31, 2015. Accounting for age, Abeta, and tau, APOE epsilon4 had a direct association with TDP-43 (estimate [SE], 0.31 (0.11); P = .01). The association was present among individuals with an intermediate to high likelihood of having AD (neurofibrillary tangle stage B2/B3; n = 604 [81.8%]; estimate [SE], 0.51 [0.11]; P < .001), with a similar trend for those with a low likelihood of having AD (B1; n = 134 [18.2%]; estimate [SE], 0.54 [0.32]; P = .10). We also found an indirect association of APOE epsilon4 with TDP-43 via Abeta and tau (estimate [SE], 0.34 [0.06]; P < .001), which was similar in magnitude to the direct association and an indirect association of APOE epsilon4 with hippocampal sclerosis via TDP-43 (estimate [SE], 0.65 [0.26]; P = .01). Conclusions and Relevance: The study's findings, which mapped a system of risk factors and outcomes, showed that the APOE epsilon4 allele appears to be a risk factor for TDP-43 independently of Abeta in patients with AD. PMID- 30422174 TI - Conflicts of Interests, Authors, and Journals: New Challenges for a Persistent Problem. PMID- 30422175 TI - Pacritinib in Patients with Myelofibrosis-Reply. PMID- 30422176 TI - Association of Search Engine Queries for Chest Pain With Coronary Heart Disease Epidemiology. AB - Importance: Online search for symptoms is common and may be useful in early identification of patients experiencing coronary heart disease (CHD) and in epidemiologically studying the disease. Objective: To investigate the correlation of online symptom search for chest pain with disease prevalence of CHD. Design, Setting, and Participants: This retrospective study used Google Trends, a publicly available tool that provides relative search frequency for queried terms, to find searches for chest pain from January 2010 to June 2017 in the United States, the United Kingdom, and Australia. For the United States, results were obtained by state. These data were compared with publicly available prevalence data from the US Centers for Disease Control and Prevention of CHD hospitalizations by state for the same period. The same terms were used to evaluate seasonal and diurnal variation. Data were analyzed from July 2017 to October 2017. Main Outcomes and Measures: Correlation of search engine query for chest pain symptoms with temporal and geographic epidemiology. Results: State-by state comparisons with reported CHD hospitalization were correlated (R = 0.81; P < .001). Significant monthly variation was appreciated in all countries studied, with the United States, United Kingdom, and Australia showing an 11% to 39% increase in search frequency in winter months compared with summer months. Diurnal variation showed a morning peak for search between local time 6 am and 8 am, with a greater than 100% increase seen in peak searching hours, which was consistent among the 3 countries studied. Conclusions and Relevance: Relative search frequency closely correlated with CHD epidemiology. This may have important implications for search engines as a resource for patients and a potential early-detection mechanism for physicians moving forward. PMID- 30422177 TI - Device Reduces Heart Failure Hospitalizations and Deaths. PMID- 30422178 TI - Recovery of Voluntary Movement After Paralysis. PMID- 30422180 TI - Minor Errors to Power Calculation Information. PMID- 30422179 TI - Relapses After CAR-T Therapy. PMID- 30422181 TI - Screening for Unhealthy Alcohol Use. PMID- 30422182 TI - Overcoming Inertia to Improve Medication Use and Deprescribing. PMID- 30422184 TI - No Intimations as Yet. PMID- 30422185 TI - Provision of Naloxone Without a Prescription by California Pharmacists 2 Years After Legislation Implementation. PMID- 30422186 TI - Naloxone Accessibility Without a Prescriber Encounter Under Standing Orders at Community Pharmacy Chains in Texas. PMID- 30422187 TI - Guidelines on Glycemic Targets for Persons With Type 2 Diabetes. PMID- 30422188 TI - Methods of Screening for Cervical Cancer. PMID- 30422189 TI - Injection Drug Use-Associated Infective Endocarditis. PMID- 30422190 TI - Guidelines on Glycemic Targets for Persons With Type 2 Diabetes-Reply. PMID- 30422191 TI - Methods of Screening for Cervical Cancer-Reply. PMID- 30422192 TI - Injection Drug Use-Associated Infective Endocarditis-Reply. PMID- 30422194 TI - Screening and Counseling to Reduce Unhealthy Alcohol Use. PMID- 30422193 TI - Effect of a Pharmacist-Led Educational Intervention on Inappropriate Medication Prescriptions in Older Adults: The D-PRESCRIBE Randomized Clinical Trial. AB - Importance: High rates of inappropriate prescribing persist among older adults in many outpatient settings, increasing the risk of adverse drug events and drug related hospitalizations. Objective: To compare the effectiveness of a consumer targeted, pharmacist-led educational intervention vs usual care on discontinuation of inappropriate medication among community-dwelling older adults. Design, Setting, and Participants: A cluster randomized trial (D PRESCRIBE [Developing Pharmacist-Led Research to Educate and Sensitize Community Residents to the Inappropriate Prescriptions Burden in the Elderly]) that recruited community pharmacies in Quebec, Canada, from February 2014 to September 2017, with follow-up until February 2018, and randomly allocated them to intervention or control groups. Patients included were adults aged 65 years and older who were prescribed 1 of 4 Beers Criteria medications (sedative-hypnotics, first-generation antihistamines, glyburide, or nonsteroidal anti-inflammatory drugs), recruited from 69 community pharmacies. Patients were screened and enrolled before randomization. Interventions: Pharmacists in the intervention group were encouraged to send patients an educational deprescribing brochure in parallel to sending their physicians an evidence-based pharmaceutical opinion to recommend deprescribing. The pharmacists in the control group provided usual care. Randomization occurred at the pharmacy level, with 34 pharmacies randomized to the intervention group (248 patients) and 35 to the control group (241 patients). Patients, physicians, pharmacists, and evaluators were blinded to outcome assessment. Main Outcomes and Measures: Discontinuation of prescriptions for inappropriate medication at 6 months, ascertained by pharmacy medication renewal profiles. Results: Among 489 patients (mean age, 75 years; 66% women), 437 (89%) completed the trial (219 [88%] in the intervention group vs 218 [91%] in the control group). At 6 months, 106 of 248 patients (43%) in the intervention group no longer filled prescriptions for inappropriate medication compared with 29 of 241 (12%) in the control group (risk difference, 31% [95% CI, 23% to 38%]). In the intervention vs control group, discontinuation of inappropriate medication occurred among 63 of 146 sedative-hypnotic drug users (43.2%) vs 14 of 155 (9.0%), respectively (risk difference, 34% [95% CI, 25% to 43%]); 19 of 62 glyburide users (30.6%) vs 8 of 58 (13.8%), respectively (risk difference, 17% [95% CI, 2% to 31%]); and 19 of 33 nonsteroidal anti-inflammatory drug users (57.6%) vs 5 of 23 (21.7%), respectively (risk difference, 35% [95% CI, 10% to 55%]) (P for interaction = .09). Analysis of the antihistamine drug class was not possible because of the small sample size (n = 12). No adverse events requiring hospitalization were reported, although 29 of 77 patients (38%) who attempted to taper sedative-hypnotics reported withdrawal symptoms. Conclusions and Relevance: Among older adults in Quebec, a pharmacist-led educational intervention compared with usual care resulted in greater discontinuation of prescriptions for inappropriate medication after 6 months. The generalizability of these findings to other settings requires further research. Trial Registration: ClinicalTrials.gov Identifier: NCT02053194. PMID- 30422196 TI - Grief After Suicide. PMID- 30422198 TI - Screening and Behavioral Counseling Interventions to Reduce Unhealthy Alcohol Use in Adolescents and Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. AB - Importance: Unhealthy alcohol use is common, increasing, and a leading cause of premature mortality. Objective: To review literature on the effectiveness and harms of screening and counseling for unhealthy alcohol use to inform the US Preventive Services Task Force. Data Sources: MEDLINE, PubMed, PsycINFO, and the Cochrane Central Register of Controlled Trials through October 12, 2017; literature surveillance through August 1, 2018. Study Selection: Test accuracy studies and randomized clinical trials of screening and counseling to reduce unhealthy alcohol use. Data Extraction and Synthesis: Independent critical appraisal and data abstraction by 2 reviewers. Counseling trials were pooled using random-effects meta-analyses. Main Outcomes and Measures: Sensitivity, specificity, drinks per week, exceeding recommended limits, heavy use episodes, abstinence (for pregnant women), and other health, family, social, and legal outcomes. Results: One hundred thirteen studies (N = 314 466) were included. No studies examined benefits or harms of screening programs to reduce unhealthy alcohol use. For adolescents (10 studies [n = 171 363]), 1 study (n = 225) reported a sensitivity of 0.73 (95% CI, 0.60 to 0.83) and specificity of 0.81 (95% CI, 0.74 to 0.86) using the AUDIT-C (Alcohol Use Disorders Identification Test-Consumption) to detect the full spectrum of unhealthy alcohol use. For adults (35 studies [n = 114 182]), brief screening instruments commonly reported sensitivity and specificity between 0.70 and 0.85. Two trials of the effects of interventions to reduce unhealthy alcohol use in adolescents (n = 588) found mixed results: one reported a benefit in high-risk but not moderate-risk drinkers, and the other reported a statistically significant reduction in drinking frequency for boys but not girls; neither reported health or related outcomes. Across all populations (68 studies [n = 36 528]), counseling interventions were associated with a decrease in drinks per week (weighted mean difference, -1.6 [95% CI, -2.2 to -1.0]; 32 studies [37 effects; n = 15 974]), the proportion exceeding recommended drinking limits (odds ratio [OR], 0.60 [95% CI, 0.53 to 0.67]; 15 studies [16 effects; n = 9760]), and the proportion reporting a heavy use episode (OR, 0.67 [95% CI, 0.58 to 0.77]; 12 studies [14 effects; n = 8108]), and an increase in the proportion of pregnant women reporting abstinence (OR, 2.26 [95% CI, 1.43 to 3.56]; 5 studies [n = 796]) after 6 to 12 months. Health outcomes were sparsely reported and generally did not demonstrate group differences in effect. There was no evidence that these interventions could be harmful. Conclusions and Relevance: Among adults, screening instruments feasible for use in primary care are available that can effectively identify people with unhealthy alcohol use, and counseling interventions in those who screen positive are associated with reductions in unhealthy alcohol use. There was no evidence that these interventions have unintended harmful effects. PMID- 30422200 TI - Antibiotic Resistance Challenge. PMID- 30422201 TI - Alzheimer Burden. PMID- 30422199 TI - Screening and Behavioral Counseling Interventions to Reduce Unhealthy Alcohol Use in Adolescents and Adults: US Preventive Services Task Force Recommendation Statement. AB - Importance: Excessive alcohol use is one of the most common causes of premature mortality in the United States. From 2006 to 2010, an estimated 88 000 alcohol attributable deaths occurred annually in the United States, caused by both acute conditions (eg, injuries from motor vehicle collisions) and chronic conditions (eg, alcoholic liver disease). Alcohol use during pregnancy is also one of the major preventable causes of birth defects and developmental disabilities. Objective: To update the US Preventive Services Task Force (USPSTF) 2013 recommendation on screening for unhealthy alcohol use in primary care settings. Evidence Review: The USPSTF commissioned a review of the evidence on the effectiveness of screening to reduce unhealthy alcohol use (defined as a spectrum of behaviors, from risky drinking to alcohol use disorder, that result in increased risk for health consequences) morbidity, mortality, or risky behaviors and to improve health, social, or legal outcomes; the accuracy of various screening approaches; the effectiveness of counseling interventions to reduce unhealthy alcohol use, morbidity, mortality, or risky behaviors and to improve health, social, or legal outcomes; and the harms of screening and behavioral counseling interventions. Findings: The net benefit of screening and brief behavioral counseling interventions for unhealthy alcohol use in adults, including pregnant women, is moderate. The evidence is insufficient to assess the balance of benefits and harms of screening and brief behavioral counseling interventions for unhealthy alcohol use in adolescents. Conclusions and Recommendation: The USPSTF recommends screening for unhealthy alcohol use in primary care settings in adults 18 years or older, including pregnant women, and providing persons engaged in risky or hazardous drinking with brief behavioral counseling interventions to reduce unhealthy alcohol use. (B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening and brief behavioral counseling interventions for alcohol use in primary care settings in adolescents aged 12 to 17 years. (I statement). PMID- 30422202 TI - Association of Weather With Day-to-Day Incidence of Myocardial Infarction: A SWEDEHEART Nationwide Observational Study. AB - Importance: Whether certain weather conditions modulate the onset of myocardial infarction (MI) is of great interest to clinicians because it could be used to prevent MIs as well as guide allocation of health care resources. Objective: To determine if weather is associated with day-to-day incidence of MI. Design, Setting, and Participants: In this prospective, population-based and nationwide setting, daily weather data from the Swedish Meteorological and Hydrological Institute were extracted for all MIs reported to the Swedish nationwide coronary care unit registry, Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART), during 1998 to 2013 and then merged with each MI on date of symptom onset and coronary care unit. All patients admitted to any coronary care unit in Sweden owing to MI were included. A total of 280 873 patients were included, of whom 92 044 were diagnosed as having ST-elevation MI. Weather data were available for 274 029 patients (97.6%), which composed the final study population. Data were analyzed between February 2017 and April 2018. Exposures: The nationwide daily mean air temperature, minimum air temperature, maximum air temperature, wind velocity, sunshine duration, atmospheric air pressure, air humidity, snow precipitation, rain precipitation, and change in air temperature. Main Outcomes and Measures: The nationwide daily counts of MI as outcome. Results: In 274 029 patients, mean (SD) age was 71.7 (12) years. Incidence of MI increased with lower air temperature, lower atmospheric air pressure, higher wind velocity, and shorter sunshine duration. The most pronounced association was observed for air temperature, where a 1-SD increase in air temperature (7.4 degrees C) was associated with a 2.8% reduction in risk of MI (unadjusted incidence ratio, 0.972; 95% CI, 0.967-0.977; P <.001). Results were consistent for non-ST elevation MI as well as ST-elevation MI and across a large range of subgroups and health care regions. Conclusions and Relevance: In this large, nationwide study, low air temperature, low atmospheric air pressure, high wind velocity, and shorter sunshine duration were associated with risk of MI with the most evident association observed for air temperature. PMID- 30422203 TI - Errors in Figure Label and Caption. PMID- 30422204 TI - Making It Easier for Hospitals to Participate in, and Succeed Under, Bundled Payments. PMID- 30422205 TI - Organic Foods for Cancer Prevention-Worth the Investment? PMID- 30422206 TI - Characteristics of Hospitals Exiting the Newly Voluntary Comprehensive Care for Joint Replacement Program. PMID- 30422207 TI - Assessment of Challenges Encountered by Dutch Oncologists When Patients Ask for Second Opinions. PMID- 30422208 TI - Use of Renin Angiotensin System Blockers After Acute Kidney Injury: Balancing Tradeoffs. PMID- 30422209 TI - Clinical Significance of Magnetic Resonance Imaging Markers of Vascular Brain Injury: A Systematic Review and Meta-analysis. AB - Importance: Covert vascular brain injury (VBI) is highly prevalent in community dwelling older persons, but its clinical and therapeutic implications are debated. Objective: To better understand the clinical significance of VBI to optimize prevention strategies for the most common age-related neurological diseases, stroke and dementia. Data Source: We searched for articles in PubMed between 1966 and December 22, 2017, studying the association of 4 magnetic resonance imaging (MRI) markers of covert VBI (white matter hyperintensities [WMHs] of presumed vascular origin, MRI-defined covert brain infarcts [BIs], cerebral microbleeds [CMBs], and perivascular spaces [PVSs]) with incident stroke, dementia, or death. Study Selection: Data were taken from prospective, longitudinal cohort studies including 50 or more adults. Data Extraction and Synthesis: We performed inverse variance-weighted meta-analyses with random effects and z score-based meta-analyses for WMH burden. The significance threshold was P < .003 (17 independent tests). We complied with the Meta-analyses of Observational Studies in Epidemiology guidelines. Main Outcomes and Measures: Stroke (hemorrhagic and ischemic), dementia (all and Alzheimer disease), and death. Results: Of 2846 articles identified, 94 studies were eligible, with up to 14 529 participants for WMH, 16 012 participants for BI, 15 693 participants for CMB, and 4587 participants for PVS. Extensive WMH burden was associated with higher risk of incident stroke (hazard ratio [HR], 2.45; 95% CI, 1.93-3.12; P < .001), ischemic stroke (HR, 2.39; 95% CI, 1.65-3.47; P < .001), intracerebral hemorrhage (HR, 3.17; 95% CI, 1.54-6.52; P = .002), dementia (HR, 1.84; 95% CI, 1.40-2.43; P < .001), Alzheimer disease (HR, 1.50; 95% CI, 1.22-1.84; P < .001), and death (HR, 2.00; 95% CI, 1.69-2.36; P < .001). Presence of MRI-defined BIs was associated with higher risk of incident stroke (HR, 2.38; 95% CI, 1.87-3.04; P < .001), ischemic stroke (HR, 2.18; 95% CI, 1.67-2.85; P < .001), intracerebral hemorrhage (HR, 3.81; 95% CI, 1.75-8.27; P < .001), and death (HR, 1.64; 95% CI, 1.40-1.91; P < .001). Presence of CMBs was associated with increased risk of stroke (HR, 1.98; 95% CI, 1.55-2.53; P < .001), ischemic stroke (HR, 1.92; 95% CI, 1.40-2.63; P < .001), intracerebral hemorrhage (HR, 3.82; 95% CI, 2.15-6.80; P < .001), and death (HR, 1.53; 95% CI, 1.31-1.80; P < .001). Data on PVS were limited and insufficient to conduct meta-analyses but suggested an association of high PVS burden with increased risk of stroke, dementia, and death; this requires confirmation. Conclusions and Relevance: We report evidence that MRI markers of VBI have major clinical significance. This research prompts careful evaluation of the benefit-risk ratio for available prevention strategies in individuals with covert VBI. PMID- 30422210 TI - Redefining the Role of Prophylactic Cranial Irradiation in the Modern Era of Active Surveillance in Small Cell Lung Cancer. PMID- 30422211 TI - Comparison of Outcomes of Early vs Delayed Graft Reconstruction of Mohs Micrographic Surgery Defects. AB - Importance: Reconstructing Mohs defects often requires grafting in the form of full-thickness skin grafts (FTSGs) and composite grafts. These grafts can be complicated by a variable and often indeterminable survival rate. Other researchers have found that delaying FTSG reconstruction improves graft outcomes, but the optimal interval between excision and reconstruction remains unclear, and no study has examined the association between delaying composite graft reconstruction and graft survival. Objective: To review the outcomes of Mohs micrographic surgery defect reconstruction using FTSG and composite grafts with respect to patient- and surgery-specific variables, particularly early vs delayed reconstruction. Design, Setting, and Participants: This retrospective, single institution cohort study assessed patients who underwent Mohs reconstructive surgery from January 1, 2012, to January 1, 2018. No patients had to be excluded for inadequate follow-up or incomplete medical records. Delayed reconstruction was defined as greater than 6 days after Mohs excision, the third quartile of the interval to reconstruction among our cohort. Main Outcomes and Measures: Primary outcome was postoperative complications, including hematoma, infection, dehiscence, epidermolysis, and partial or full graft loss. Results: A total of 320 defects were reconstructed with FTSG or composite grafts in 310 patients (median [range] age, 68 [21-96] years; 167 female [53.9%]) during the 6-year study period. The mean interval between the ablative and reconstructive operations was 4.73 days (range, 0-35 days). Univariate logistic regression was used to determine the significant indicators among patient and defect characteristics analyzed. A multivariate logistic regression model found delayed reconstruction to have a protective association (odds ratio, 0.52; 95% CI, 0.27 0.97; P = .046) and male sex to have a harmful association (odds ratio, 2.51; 95% CI, 1.52-4.20; P < .001) with postoperative complications. Conclusions and Relevance: This study found that delaying reconstruction in FTSGs and composite grafts was associated with decreased rates of postoperative complications, and male sex was associated with an increased risk of postoperative complications. The findings suggest that this strategy can be considered in patients at increased risk for developing postoperative complications, such as current smokers, patients with large defects, and patients who require use of composite grafts. Level of Evidence: 3. PMID- 30422213 TI - Surviving Cancer in the Midst of a Treatment Revolution: Hope and Delusion. PMID- 30422212 TI - Association of Frequency of Organic Food Consumption With Cancer Risk: Findings From the NutriNet-Sante Prospective Cohort Study. AB - Importance: Although organic foods are less likely to contain pesticide residues than conventional foods, few studies have examined the association of organic food consumption with cancer risk. Objective: To prospectively investigate the association between organic food consumption and the risk of cancer in a large cohort of French adults. Design, Setting, and Participants: In this population based prospective cohort study among French adult volunteers, data were included from participants with available information on organic food consumption frequency and dietary intake. For 16 products, participants reported their consumption frequency of labeled organic foods (never, occasionally, or most of the time). An organic food score was then computed (range, 0-32 points). The follow-up dates were May 10, 2009, to November 30, 2016. Main Outcomes and Measures: This study estimated the risk of cancer in association with the organic food score (modeled as quartiles) using Cox proportional hazards regression models adjusted for potential cancer risk factors. Results: Among 68 946 participants (78.0% female; mean [SD] age at baseline, 44.2 [14.5] years), 1340 first incident cancer cases were identified during follow-up, with the most prevalent being 459 breast cancers, 180 prostate cancers, 135 skin cancers, 99 colorectal cancers, 47 non-Hodgkin lymphomas, and 15 other lymphomas. High organic food scores were inversely associated with the overall risk of cancer (hazard ratio for quartile 4 vs quartile 1, 0.75; 95% CI, 0.63-0.88; P for trend = .001; absolute risk reduction, 0.6%; hazard ratio for a 5-point increase, 0.92; 95% CI, 0.88-0.96). Conclusions and Relevance: A higher frequency of organic food consumption was associated with a reduced risk of cancer. If these findings are confirmed, further research is necessary to determine the underlying factors involved in this association. PMID- 30422214 TI - Optimal Timing of Reconstruction When Using Tissue Grafts After Mohs Micrographic Surgery. PMID- 30422215 TI - Association of Somatic GNAQ Mutation With Capillary Malformations in a Case of Choroidal Hemangioma. AB - Importance: Choroidal hemangiomas are defined by a thickened choroid owing to vessel overgrowth, which may increase the intraocular pressure and lead to glaucoma. Choroidal hemangioma and glaucoma often co-occur in patients with Sturge-Weber syndrome, a rare neurocutaneous disorder characterized by capillary malformations. Objective: To determine whether the mutation found in most capillary malformations, GNAQ R183Q (c.548G>A), was present in the choroidal hemangioma of a patient with Sturge-Weber syndrome. Design, Setting, and Participant: Using laser-capture microdissection, choroidal blood vessels were isolated from paraffin-embedded tissue sections, and genomic DNA was extracted for mutational analysis. Choroidal sections were analyzed in parallel. A patient with choroidal hemangioma and Sturge-Weber syndrome who had undergone enucleation was analyzed in this study at Boston Children's Hospital. Negative controls were choroidal tissue from an eye with retinoblastoma and unaffected lung tissue; brain tissue from a different patient with Sturge-Weber syndrome served as a positive control. Infantile hemangioma was analyzed as well. Data were analyzed in 2018. Main Outcomes and Measures: The mutant allelic frequency of GNAQ R183 and GNAQ Q209L/H/P was determined by droplet digital polymerase chain reaction on isolated genomic DNA. The infantile hemangioma marker glucose transporter-1 was visualized by immunofluorescent staining of tissue sections. Results: The GNAQ R183Q mutation was present in the patient's choroidal vessels (21.1%) at a frequency similar to that found in brain tissue from a different patient with Sturge-Weber syndrome (25.1%). In contrast, choroidal vessels from a case of retinoblastoma were negative for the mutation (0.5%), as was lung tissue (0.2%). The patient's choroidal tissue was negative for the 3 GNAQ mutations associated with congenital hemangioma and for the infantile hemangioma marker glucose transporter-1. Conclusions and Relevance: The results suggest that a more accurate description for choroidal hemangioma in patients with Sturge-Weber syndrome is choroidal capillary malformation. This finding may explain why propranolol, used to treat infantile hemangiomas, has been largely ineffective in patients with choroidal hemangioma. Further studies are needed to corroborate this finding. PMID- 30422216 TI - Precision Medicine in Neurocritical Care. PMID- 30422217 TI - Prohibited Stimulants in Dietary Supplements After Enforcement Action by the US Food and Drug Administration. PMID- 30422218 TI - Bilateral Optic Atrophy in an Adolescent Male Patient. PMID- 30422219 TI - Does the Term Intensive Care Unit Promote Aggressive Treatment? PMID- 30422220 TI - Pervasive Errors in the Key Points, Abstract, Results, Discussion, Table 3, and eTable in the Supplement. PMID- 30422221 TI - Volumizing Hyaluronic Acid Filler for Treatment of Infraorbital Hollows. PMID- 30422222 TI - Myelin Oligodendrocyte Glycoprotein Antibody-Associated Demyelination Comorbid With Leber Hereditary Optic Neuropathy. PMID- 30422223 TI - How Community Health Workers Can Affect Health Care. PMID- 30422224 TI - Effect of Community Health Worker Support on Clinical Outcomes of Low-Income Patients Across Primary Care Facilities: A Randomized Clinical Trial. AB - Importance: Addressing the social determinants of health has been difficult for health systems to operationalize. Objective: To assess a standardized intervention, Individualized Management for Patient-Centered Targets (IMPaCT), delivered by community health workers (CHWs) across 3 health systems. Design, Setting, and Participants: This 2-armed, single-blind, multicenter randomized clinical trial recruited patients from 3 primary care facilities in Philadelphia, Pennsylvania, between January 28, 2015, and March 28, 2016. Patients who resided in a high-poverty zip code, were uninsured or publicly insured, and who had a diagnosis for 2 or more chronic diseases were recruited, and patients were randomized to either the CHW intervention or the control arm (goal setting only). Follow-up assessments were conducted at 6 and 9 months after enrollment. Data were analyzed using an intention-to-treat approach from June 2017 to March 2018. Intervention: Participants set a chronic disease management goal with their primary care physician; those randomized to the CHW intervention received 6 months of tailored support. Main Outcomes and Measures: The primary outcome was change in self-rated physical health. The secondary outcomes were self-rated mental health, chronic disease control, patient activation, patient-reported quality of primary care, and all-cause hospitalization. Results: Of the 592 participants, 370 (62.5%) were female, with a mean (SD) age of 52.6 (11.1) years. Participants in both arms had similar improvements in self-rated physical health (mean [SD], 1.8 [11.2] vs 1.6 [9.9]; P = .89). Patients in the intervention group were more likely to report the highest quality of care (odds ratio [OR], 1.8; 95% CI, 1.4-2.4; risk difference [RD], 0.12; P < .001) and spent fewer total days in the hospital at 6 months (155 days vs 345 days; absolute event rate reduction, 69%) and 9 months (300 days vs 471 days; absolute event rate reduction, 65%). This reduction was driven by a shorter average length of stay (difference, -3.1 days; 95% CI, -6.33 to 0.22; P = .06) and a lower mean number of hospitalizations (difference, -0.3; 95% CI, -0.6 to 0.0; P = .07) among patients who were hospitalized. Patients in the intervention group had a lower odds of repeat hospitalizations (OR, 0.4; 95% CI, 0.2-0.9; RD, -0.24; P = .02), including 30-day readmissions (OR, 0.3; 95% CI, 0.1-0.9; RD, -0.17; P = .04). Conclusions and Relevance: A standardized intervention did not improve self-rated health but did improve the patient-perceived quality of care while reducing hospitalizations, suggesting that health systems may use a standardized intervention to address the social determinants of health. Trial Registration: ClinicalTrials.gov identifier: NCT02347787. PMID- 30422225 TI - Association of Cognitive Impairment and Dementia With Receipt of Cataract Surgery Among Community-Dwelling Medicare Beneficiaries. PMID- 30422227 TI - Missing Conflict of Interest Disclosure. PMID- 30422226 TI - Prevalence of False-Negative Results of Intraoperative Consultation on Surgical Margins During Resection of Gastric and Gastroesophageal Adenocarcinoma. AB - Importance: Intraoperative consultation (IOC) on surgical margins during curative intent resection of gastric and gastroesophageal adenocarcinoma presents sampling and interpretive challenges. A false-negative (FN) IOC result can affect clinical care. Many factors may be associated with higher risk for an FN result of IOC on surgical margins. Objective: To assess the prevalence and clinical implications of FN results of IOC on surgical margins during resection of gastric and gastroesophageal adenocarcinoma. Design, Setting, and Participants: This retrospective study assessed the results of IOC on surgical margins to determine the prevalence of FN results and the accuracy and clinical implications of the results for patients undergoing curative intent resection for gastric or gastroesophageal adenocarcinoma. The study examined patients with gastric or gastroesophageal adenocarcinoma who underwent resection with curative intent at a single-institution referral center from January 1, 1992, to December 31, 2015. Interventions: Curative intent gastric and/or esophageal resection. Main Outcomes and Measures: False-negative results of IOC on surgical margins, accuracy of the results, factors associated with decreased accuracy of the results, and clinical implications of FN results. Results: This study included 2002 patients (median age, 65 years; 1343 [67.1%] male; 1638 [81.8%] white) who received 3171 IOCs on surgical margins. Of the 3171 IOCs, the prevalence of FN results was 1.7%, with an accuracy of 98.1%. The prevalence of an FN IOC result was 1.2% for esophageal margins, 2.0% for gastric margins, and 2.5% for duodenal margins (P = .04). The prevalence of an FN IOC result was higher for patients with diffuse or signet ring disease compared with those without (2.6% vs 1.2%, P = .002) and for those not receiving neoadjuvant radiotherapy compared with those receiving neoadjuvant radiotherapy (1.4% vs 0.7%, P < .001). The prevalence of FN results of IOCs performed by nongastrointestinal pathologists was similar to that of IOCs performed by gastrointestinal pathologists (2.3% vs 1.9%, P = .60). The disease specific survival was 34 months (95% CI, 20.7-47.2 months) for those with an FN result and 26.9 months (95% CI, 18.3-35.4; P = .72) for those with a true positive result. Half of the patients with FN IOC results received further margin directed therapy, including subsequent resection or radiotherapy. Conclusions and Relevance: This study found that IOC on surgical margins was accurate at a specialty center. Signet ring or diffuse disease, duodenal margins, and not receiving neoadjuvant radiotherapy were challenging scenarios for IOC on surgical margins. The use of IOC on surgical margins may be optimal when it will affect intraoperative decision making framed by the stage of disease, tumor location, and surgical fitness of the patient. PMID- 30422228 TI - Association of Quality of Life With Surgical Excision of Early-Stage Melanoma of the Head and Neck. AB - Importance: Surgical excision is the standard-of-care treatment for Tis and T1a melanomas of the head and neck. Currently, however, the association of diagnosis and surgical treatment of these typically slowly progressive and nonfatal melanomas with a patient's health-related quality of life (HRQoL) is unknown. Objective: To characterize and assess HRQoL in patients with Tis and T1a head and neck melanoma, evaluate changes in HRQoL over the surgical treatment course, and identify patient characteristics associated with lower HRQoL. Design, Setting, and Participants: This longitudinal, prospective cohort study involved patients with Tis or T1a melanoma of the head and neck who underwent staged excision at a single tertiary care center (Memorial Sloan Kettering Cancer Center, New York, New York) and were recruited from June 1, 2016, to February 28, 2017. Patients were followed up for 1 year after their surgical procedure. Participants were asked to complete 2 patient-reported outcome measure questionnaires, Skindex-16 and Skin Cancer Index (SCI), at 4 time points: baseline, perioperative (1 to 2 weeks after surgery), and 6-month and 1-year follow-up. Main Outcomes and Measures: Scores on the Skindex-16 and SCI questionnaires. Results: In total, 56 patients were included in the study, among whom 24 (43%) were female and 32 (57%) were male, with a mean (range) age of 67.2 (32-88) years; all patients self identified as white. Forty-one (73%) questionnaires at perioperative, 49 (88%) at 6-month postoperative, and 41 (73%) at 1-year postoperative time points were completed. At baseline, female patients and those younger than 65 years had statistically significantly worse HRQoL on the Skindex-16 questionnaire (mean score, 14.2 [95% CI, 9.1-21.9] and 16.1 [95% CI, 9.8-26.4]) and on the SCI questionnaire (mean score, 57.2 [95% CI, 48.3-67.6] and 53.2 [95% CI, 44.1-64.3]) compared with males (mean Skindex-16 score, 7.0 [95% CI, 4.8-10.3]; mean SCI score, 73.5 [95% CI, 66.0-81.7]) and those aged 65 years or older (mean Skindex 16 score 7.1 [95% CI, 5.0-10.0]; mean SCI score, 74.3 [95% CI, 67.7-81.6]). Questions that demonstrated the worst scores at baseline were worry about skin condition (Skindex-16) and worry about future skin cancers (SCI). The emotions subscale scores on the Skindex-16 questionnaire showed the greatest improvement from baseline to 1-year follow-up levels (26.6 vs 15.3; P < .001) and so did the appearance subscale scores on the SCI questionnaire (64.0 vs 84.6; P < .001). The score difference in HRQoL by sex diminished over time, whereas the score difference by age persisted through the first year. Conclusions and Relevance: Improvement in HRQoL at the 6-month and 1-year follow-up was associated with surgical excision in patients with early-stage head and neck melanoma, and younger and female patients experienced worse HRQoL. These results may be used in tailoring counseling for this patient population. PMID- 30422229 TI - Failure to Accurately Disclose Conflicts of Interest in Article Published in JAMA Otolaryngology-Head & Neck Surgery. PMID- 30422230 TI - Clinical Features, Metastasis, and Survival in Patients Younger Than 21 Years With Posterior Uveal Melanoma. AB - Importance: Given the rarity of posterior uveal melanoma in patients younger than 21 years, reporting clinical experience in this area has relevance. Objective: To describe the baseline clinical features, treatment, and clinical course of a group of patients younger than 21 years who have primary posterior uveal melanoma. Design, Setting, and Participants: This retrospective descriptive case series of patients younger than 21 years who have a primary choroidal or ciliochoroidal melanoma was conducted at a single-center subspecialty referral practice. Patients in the relevant age group who were treated in a single practice between July 1980 and December 2013 were included; clinical data collected through December 2017 were captured to permit adequate follow-up time in all cases. Main Outcomes and Measures: Conventional descriptive statistics of relevant clinical variables (eg, demographic, tumor, treatment, and outcome variables) of each patient were recorded. Actuarial metastasis-free and overall survival curves were computed and plotted, as was a postdetection survival curve of patients who developed metastasis during available follow-up. Results: Of 2265 patients with posterior uveal melanoma encountered by the authors during the study interval, 18 (0.8%) were younger than 21 years when diagnosed and treated. Ten were female and 8 male, and the mean (SD) age was 16.6 (4.2) years. Through available follow-up, 8 of these patients had developed metastatic uveal melanoma (44%). All 8 died of metastasis. Actuarial survival analysis showed that the cumulative probability of metastatic death in this group exceeded 50%. The median overall survival time after treatment of the primary intraocular tumor was 11.9 (95% CI, 7.3-16.5) years. The median survival time after detection of metastasis in the 8 patients who developed metastasis was 2.3 months (95% CI, 0.0-5.2) months. Conclusions and Relevance: Posterior uveal melanoma in patients younger than 21 years appears to have a similar if not worse prognosis than patients with PUM in the population overall. Owing to the later onset of metastasis observed, patients younger than 21 years should continue to have surveillance tests for more than 10 years after treatment. PMID- 30422231 TI - Programming Error Led to Underestimate of Effect Sizes in Study of Association of Maternal Preeclampsia and Risk of Infant Retinopathy of Prematurity. PMID- 30422232 TI - Is There a Seasonal Influence on Cognition and Dementia? PMID- 30422233 TI - Frozen Sections in Gastric Cancer: How Negative Is the False-Negative? PMID- 30422234 TI - Should Failure to Disclose Significant Financial Conflicts of Interest Be Considered Research Misconduct? PMID- 30422237 TI - Smartphone Photographs-Proceed, but With Caution. PMID- 30422236 TI - Evaluation of Wound Photography for Remote Postoperative Assessment of Surgical Site Infections. AB - Importance: Surgeons are increasingly interested in using mobile and online applications with wound photography to monitor patients after surgery. Early work using remote care to diagnose surgical site infections (SSIs) demonstrated improved diagnostic accuracy using wound photographs to augment patients' electronic reports of symptoms, but it is unclear whether these findings are reproducible in real-world practice. Objective: To determine how wound photography affects surgeons' abilities to diagnose SSIs in a pragmatic setting. Design, Setting, and Participants: This prospective study compared surgeons' paired assessments of postabdominal surgery case vignettes with vs without wound photography for detection of SSIs. Data for case vignettes were collected prospectively from May 1, 2007, to January 31, 2009, at Erasmus University Medical Center, Rotterdam, the Netherlands, and from July 1, 2015, to February 29, 2016, at Vanderbilt University Medical Center, Nashville, Tennessee. The surgeons were members of the American Medical Association whose self-designated specialty is general, abdominal, colorectal, oncologic, or vascular surgery and who completed internet-based assessments from May 21 to June 10, 2016. Intervention: Surgeons reviewed online clinical vignettes with or without wound photography. Main Outcomes and Measures: Surgeons' diagnostic accuracy, sensitivity, specificity, confidence, and proposed management with respect to SSIs. Results: A total of 523 surgeons (113 women and 410 men; mean [SD] age, 53 [10] years) completed a mean of 2.9 clinical vignettes. For the diagnosis of SSIs, the addition of wound photography did not change accuracy (863 of 1512 [57.1%] without and 878 of 1512 [58.1%] with photographs). Photographs decreased sensitivity (from 0.58 to 0.50) but increased specificity (from 0.56 to 0.63). In 415 of 1512 cases (27.4%), the addition of wound photography changed the surgeons' assessment (215 of 1512 [14.2%] changed from incorrect to correct and 200 of 1512 [13.2%] changed from correct to incorrect). Surgeons reported greater confidence when vignettes included a wound photograph compared with vignettes without a wound photograph, regardless of whether they correctly identified an SSI (median, 8 [interquartile range, 6-9] vs median, 8 [interquartile range, 7 9]; P < .001) but they were more likely to undertriage patients when vignettes included a wound photograph, regardless of whether they correctly identified an SSI. Conclusions and Relevance: In a practical simulation, wound photography increased specificity and surgeon confidence, but worsened sensitivity for detection of SSIs. Remote evaluation of patient-generated wound photographs may not accurately reflect the clinical state of surgical incisions. Effective widespread implementation of remote postoperative assessment with photography may require additional development of tools, participant training, and mechanisms to verify image quality. PMID- 30422235 TI - Effect of Lanreotide on Kidney Function in Patients With Autosomal Dominant Polycystic Kidney Disease: The DIPAK 1 Randomized Clinical Trial. AB - Importance: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation in both kidneys and loss of renal function, eventually leading to a need for kidney replacement therapy. There are limited therapeutic management options. Objective: To examine the effect of the somatostatin analogue lanreotide on the rate of kidney function loss in patients with later-stage ADPKD. Design, Setting, and Participants: An open-label randomized clinical trial with blinded end point assessment that included 309 patients with ADPKD from July 2012 to March 2015 at 4 nephrology outpatient clinics in the Netherlands. Eligible patients were 18 to 60 years of age and had an estimated glomerular filtration rate (eGFR) of 30 to 60 mL/min/1.73 m2. Follow up of the 2.5-year trial ended in August 2017. Interventions: Patients were randomized to receive either lanreotide (120 mg subcutaneously once every 4 weeks) in addition to standard care (n = 153) or standard care only (target blood pressure <140/90 mm Hg; n = 152). Main Outcomes and Measures: Primary outcome was annual change in eGFR assessed as slope through eGFR values during the 2.5-year treatment phase. Secondary outcomes included change in eGFR before vs after treatment, incidence of worsening kidney function (start of dialysis or 30% decrease in eGFR), change in total kidney volume and change in quality of life (range: 1 [not bothered] to 5 [extremely bothered]). Results: Among the 309 patients who were randomized (mean [SD] age, 48.4 [7.3] years; 53.4% women), 261 (85.6%) completed the trial. Annual rate of eGFR decline for the lanreotide vs the control group was -3.53 vs -3.46 mL/min/1.73 m2 per year (difference, -0.08 [95% CI, -0.71 to 0.56]; P = .81). There were no significant differences for incidence of worsening kidney function (hazard ratio, 0.87 [95% CI, 0.49 to 1.52]; P = .87), change in eGFR (-3.58 vs -3.45; difference, -0.13 mL/min/1.73 m2 per year [95% CI, -1.76 to 1.50]; P = .88), and change in quality of life (0.05 vs 0.07; difference, -0.03 units per year [95% CI, -0.13 to 0.08]; P = .67). The rate of growth in total kidney volume was lower in the lanreotide group than the control group (4.15% vs 5.56%; difference, -1.33% per year [95% CI, -2.41% to 0.24%]; P = .02). Adverse events in the lanreotide vs control group included injection site discomfort (32% vs 0.7%), injection site papule (5.9% vs 0%), loose stools (91% vs 6.6%), abdominal discomfort (79% vs 20%), and hepatic cyst infections (5.2% vs 0%). Conclusions and Relevance: Among patients with later stage autosomal dominant polycystic kidney disease, treatment with lanreotide compared with standard care did not slow the decline in kidney function over 2.5 years of follow-up. These findings do not support the use of lanreotide for treatment of later-stage autosomal dominant polycystic kidney disease. Trial Registration: ClinicalTrials.gov Identifier: NCT01616927. PMID- 30422238 TI - Association of APOA5 and APOC3 Genetic Polymorphisms With Severity of Hypertriglyceridemia in Patients With Cutaneous T-Cell Lymphoma Treated With Bexarotene. AB - Importance: Hypertriglyceridemia is the most frequent and limiting adverse effect of bexarotene therapy in cutaneous T-cell lymphoma (CTCL). Despite standard prophylactic measures, there is a wide variability in the severity of this complication, which could be associated with both genetic and environmental factors. Objectives: To analyze the association between genetic polymorphisms of apolipoprotein genes APOA5, APOC3, and APOE and the severity of hypertriglyceridemia during bexarotene therapy and to optimize patient selection for bexarotene therapy based on adverse effect profile. Design, Setting, and Participants: This case series study was conducted in 12 university referral hospitals in Spain from September 17, 2014, to February 6, 2015. One hundred twenty-five patients with a confirmed diagnosis of CTCL who had received bexarotene therapy for at least 3 months were enrolled. Nine patients were excluded owing to missing analytic triglyceride level data, leaving a study group of 116 patients. Data on demographic and cardiovascular risk factor were collected, and a complete blood analysis, including lipid profile and genetic analysis from a saliva sample, was performed. Main Outcomes and Measures: Primary outcomes were the maximal triglyceride levels reported in association with the minor alleles of the polymorphisms studied. Results: Among 116 patients, the mean (SD) age was 61.2 (14.7) years, 69 (59.5%) were men, and 85 (73.2%) had mycosis fungoides, the most prevalent form of CTCL. During bexarotene therapy, 96 patients (82.7%) experienced hypertriglyceridemia, which was severe or extreme in 8 of these patients (8.3%). Patients who carried minor alleles of the polymorphisms did not show significant differences in baseline triglyceride concentrations. After bexarotene treatment, carriers of at least 1 of the 2 minor alleles of APOA5 c.-1131T>C and APOC3 c.*40C>G showed lower levels of triglycerides than noncarriers (mean [SD], 241.59 [169.91] vs 330.97 [169.03] mg/dL, respectively; P = .02). Conclusions and Relevance: These results indicate that the screening of APOA5 and APOC3 genotypes may be useful to estimate changes in triglyceride concentrations during bexarotene treatment in patients with CTCL and also to identify the best candidates for bexarotene therapy based on the expected adverse effect profile. PMID- 30422239 TI - Association of Opioid Prescribing With Opioid Consumption After Surgery in Michigan. AB - Importance: There is growing evidence that opioids are overprescribed following surgery. Improving prescribing requires understanding factors associated with opioid consumption. Objective: To describe opioid prescribing and consumption for a variety of surgical procedures and determine factors associated with opioid consumption after surgery. Design, Setting, and Participants: A retrospective, population-based analysis of the quantity of opioids prescribed and patient reported opioid consumption across 33 health systems in Michigan, using a sample of adults 18 years and older undergoing surgery. Patients were included if they were prescribed an opioid after surgery. Surgical procedures took place between January 1, 2017, and September 30, 2017, and were included if they were performed in at least 25 patients. Exposures: Opioid prescription size in the initial postoperative prescription. Main Outcomes and Measures: Patient-reported opioid consumption in oral morphine equivalents. Linear regression analysis was used to calculate risk-adjusted opioid consumption with robust standard errors. Results: In this study, 2392 patients (mean age, 55 years; 1353 women [57%]) underwent 1 of 12 surgical procedures. Overall, the quantity of opioid prescribed was significantly higher than patient-reported opioid consumption (median, 30 pills; IQR, 27-45 pills of hydrocodone/acetaminophen, 5/325 mg, vs 9 pills; IQR, 1-25 pills; P < .001). The quantity of opioid prescribed had the strongest association with patient-reported opioid consumption, with patients using 0.53 more pills (95% CI, 0.40-0.65; P < .001) for every additional pill prescribed. Patient reported pain in the week after surgery was also significantly associated with consumption but not as strongly as prescription size. Compared with patients reporting no pain, patients used a mean (SD) 9 (1) more pills if they reported moderate pain and 16 (2) more pills if they reported severe pain (P < .001). Other significant risk factors included history of tobacco use, American Society of Anesthesiologists class, age, procedure type, and inpatient surgery status. After adjusting for these risk factors, patients in the lowest quintile of opioid prescribing had significantly lower mean (SD) opioid consumption compared with those in the highest quintile (5 [2] pills vs 37 [3] pills; P < .001). Conclusions and Relevance: The quantity of opioid prescribed is associated with higher patient-reported opioid consumption. Using patient-reported opioid consumption to develop better prescribing practices is an important step in combating the opioid epidemic. PMID- 30422240 TI - Did Medicaid Expansion Reduce Mortality Among Patients Initiating Dialysis for Irreversible Kidney Failure? PMID- 30422241 TI - Risk Factors, Patterns, and Outcomes of Late Recurrence After Liver Resection for Hepatocellular Carcinoma: A Multicenter Study From China. AB - Importance: Late recurrence (more than 2 years) after liver resection for hepatocellular carcinoma (HCC) is generally considered as a multicentric tumor or a de novo cancer. Objective: To investigate the risk factors, patterns, and outcomes of late recurrence after curative liver resection for HCC. Design, Setting, and Participants: This study was a multicenter retrospective analysis of patients who underwent curative liver resection for HCC at 6 hospitals in China from January 2001 to December 2015. Among 734 patients who were alive and free of recurrence at 2 years after resection, 303 patients developed late recurrence. Data were analyzed from June 2017 to February 2018. Interventions: Liver resection for HCC. Main Outcomes and Measures: Risk factors of late recurrence as well as patterns, treatments, and long-term outcomes of patients with late recurrence. Univariate and multivariate Cox regression analyses were performed to identify independent risk factors of late recurrence. Results: Of the included 734 patients, 652 (88.8%) were male, and the mean (SD) age was 51.0 (10.3) years. At a median (interquartile range) follow-up of 78.0 (52.8-112.5) months, 303 patients (41.3%) developed late recurrence. Multivariate analysis revealed that male sex, cirrhosis, multiple tumors, satellite nodules, tumor size greater than 5 cm, and macroscopic and microscopic vascular invasion were independent risk factors of late recurrence. Of the 303 patients with late recurrence, 273 (90.1%) had only intrahepatic recurrence, 30 (9.9%) had both intrahepatic and extrahepatic recurrence, and none had only extrahepatic recurrence. Potentially curative treatments were given to 165 of 303 patients (54.5%) with late recurrence, which included reresection, transplant, and local ablation. Multivariate Cox regression analysis showed that regular surveillance for postoperative recurrence (hazard ratio [HR], 0.470; 95% CI, 0.310-0.713; P = .001), cirrhosis (HR, 1.381; 95% CI, 1.049-1.854; P = .02), portal hypertension (HR, 2.424; 95% CI, 1.644-3.574; P < .001), Child-Pugh grade of B or C (HR, 1.376; 95% CI, 1.153-1.674; P < .001), Barcelona Clinic Liver Cancer stage B (HR, 1.304; 95% CI, 1.007-1.708; P = .04) and stage C (HR, 2.037; 95% CI, 1.583-2.842; P < .001), and potentially curative treatment (HR, 0.443; 95% CI, 0.297-0.661; P < .001) were independent predictors of overall survival for patients with late recurrence. Conclusions and Relevance: Late recurrence after HCC resection was associated with sex, cirrhosis, and several aggressive tumor characteristics of the initial HCC. The patterns of late recurrence suggested surveillance for recurrence after 2 years of surgery should be targeted to the liver. Postoperative surveillance improved the chance of potentially curative treatments, with improved survival outcomes in patients with late recurrence. PMID- 30422242 TI - Overdiagnosis of Penicillin Allergy Leads to Costly, Inappropriate Treatment. PMID- 30422244 TI - Successes and Challenges in Precision Medicine in Psychiatry. PMID- 30422243 TI - Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial. AB - Importance: This analysis provides long-term follow-up in patients with BRAF wild type advanced melanoma receiving first-line therapy based on anti-programmed cell death 1 receptor inhibitors. Objective: To compare the 3-year survival with nivolumab vs that with dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma. Design, Setting, and Participants: This follow-up of a randomized phase 3 trial analyzed 3-year overall survival data from the randomized, controlled, double-blind CheckMate 066 phase 3 clinical trial. For this ongoing, multicenter academic institution trial, patients were enrolled from January 2013 through February 2014. Eligible patients were 18 years or older with confirmed unresectable previously untreated stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 but without a BRAF mutation. Interventions: Patients were treated until progression or unacceptable toxic events with nivolumab (3 mg/kg every 2 weeks plus dacarbazine matched placebo every 3 weeks) or dacarbazine (1000 mg/m2 every 3 weeks plus nivolumab-matched placebo every 2 weeks). Main Outcome and Measure: Overall survival. Results: At minimum follow-ups of 38.4 months among 210 participants in the nivolumab group (median age, 64 years [range, 18-86 years]; 57.6% male) and 38.5 months among 208 participants in the dacarbazine group (median age, 66 years [range, 25-87 years]; 60.1% male), 3-year overall survival rates were 51.2% (95% CI, 44.1%-57.9%) and 21.6% (95% CI, 16.1%-27.6%), respectively. The median overall survival was 37.5 months (95% CI, 25.5 months-not reached) in the nivolumab group and 11.2 months (95% CI, 9.6-13.0 months) in the dacarbazine group (hazard ratio, 0.46; 95% CI, 0.36-0.59; P < .001). Complete and partial responses, respectively, were reported for 19.0% (40 of 210) and 23.8% (50 of 210) of patients in the nivolumab group compared with 1.4% (3 of 208) and 13.0% (27 of 208) of patients in the dacarbazine group. Additional analyses were performed on outcomes with subsequent therapies. Treatment-related grade 3/4 adverse events occurred in 15.0% (31 of 206) of nivolumab-treated patients and in 17.6% (36 of 205) of dacarbazine-treated patients. There were no deaths due to study drug toxic effects. Conclusions and Relevance: Nivolumab led to improved 3 year overall survival vs dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma. Trial Registration: ClinicalTrials.gov identifier: NCT01721772. PMID- 30422245 TI - Comparing Adjuvant vs Early-Salvage Radiotherapy After Radical Prostatectomy. PMID- 30422246 TI - Comparing Adjuvant vs Early-Salvage Radiotherapy After Radical Prostatectomy. PMID- 30422247 TI - Comparing Adjuvant vs Early-Salvage Radiotherapy After Radical Prostatectomy. PMID- 30422248 TI - Comparing Adjuvant vs Early-Salvage Radiotherapy After Radical Prostatectomy Reply. PMID- 30422250 TI - Orphan Cancer Drugs in the Era of Precision Medicine. PMID- 30422249 TI - Risk of Esophageal Adenocarcinoma After Antireflux Surgery in Patients With Gastroesophageal Reflux Disease in the Nordic Countries. AB - Importance: Gastroesophageal reflux disease (GERD) is associated with a strong and severity-dependent increased risk of esophageal adenocarcinoma. Whether antireflux surgery prevents esophageal adenocarcinoma is a matter of uncertainty. Objectives: To examine whether antireflux surgery is associated with reduced risk of esophageal adenocarcinoma and whether the risk is different between surgically and medically treated patients. Design, Setting, and Participants: In this multinational, population-based retrospective cohort study from Denmark, Finland, Iceland, Norway, and Sweden, patients undergoing surgery were followed up for a median of 12.7 years, and a comparison group of patients receiving medication only were followed up for a median of 4.8 years. All patients with a registered diagnosis of GERD (or an associated disorder), including 48 414 individuals undergoing surgery and 894 492 receiving medication only, were included in the study. The study periods varied in the different countries depending on the year of initiation of registration and the date of data retrieval, from January 1, 1964, to December 21, 2014. Exposures: Antireflux surgery for GERD. Main Outcomes and Measures: The risk of esophageal adenocarcinoma over time after surgery was compared with that in a corresponding background population using standardized incidence ratios (SIRs) with 95% CIs and with patients with GERD who received medication using multivariable Cox proportional hazards regression, providing hazard ratios (HRs) with 95% CIs adjusted for confounders. Results: In this study of 942 906 patients with GERD, 48 414 underwent antireflux surgery (median [interquartile range] age, 66.0 [58.0-73.0] years; 27 161 male [56.1%]) and 894 492 received medication only (median [interquartile range] age, 71.0 [62.0-78.0] years; 434 035 male [48.6%]). Among patients undergoing surgery, 177 developed esophageal adenocarcinoma. Esophageal adenocarcinoma risk decreased in a time dependent manner after surgery compared with the background population (5 to <10 years after surgery: SIR, 7.63; 95% CI, 5.42-10.43; >=15 years after surgery: SIR, 1.34; 95% CI, 0.98-1.80). Among patients with more severe and objectively determined GERD, the SIRs were 10.08 (95% CI, 6.98-14.09) at 5 to less than 10 years after surgery and 1.67 (95% CI, 1.15-2.35) at 15 years or more after surgery. The risk of esophageal adenocarcinoma did not change over time in surgical patients compared with patients who received medication only (5 to <10 years after surgery: HR, 2.02; 95% CI, 1.44-2.84; >=15 years: HR, 1.80; 95% CI, 1.28-2.54). The risk remained stable over time in analyses restricted to severe reflux disease (5 to <10 years after surgery: HR, 1.81; 95% CI, 1.24-2.63; >=15 years after surgery: HR, 1.69; 95% CI, 1.14-2.51). Conclusions and Relevance: Medical and surgical treatment of GERD were associated with a similar reduced esophageal adenocarcinoma risk, with the risk decreasing to the same level as that in the background population over time, supporting the hypothesis that effective treatment of GERD might prevent esophageal adenocarcinoma. PMID- 30422251 TI - Association of Medicaid Expansion With 1-Year Mortality Among Patients With End Stage Renal Disease. AB - Importance: The Affordable Care Act Medicaid expansion may be associated with reduced mortality, but evidence to date is limited. Patients with end-stage renal disease (ESRD) are a high-risk group that may be particularly affected by Medicaid expansion. Objective: To examine the association of Medicaid expansion with 1-year mortality among nonelderly patients with ESRD initiating dialysis. Design, Setting, and Participants: Difference-in-differences analysis of nonelderly patients initiating dialysis in Medicaid expansion and nonexpansion states from January 2011 to March 2017. Exposure: Living in a Medicaid expansion state. Main Outcomes and Measures: The primary outcome was 1-year mortality. Secondary outcomes were insurance, predialysis nephrology care, and type of vascular access for hemodialysis. Results: A total of 142 724 patients in expansion states (mean age, 50.2 years; 40.2% women) and 93 522 patients in nonexpansion states (mean age, 49.7; 42.4% women) were included. In Medicaid expansion states, 1-year mortality following dialysis initiation declined from 6.9% in the preexpansion period to 6.1% after expansion (change, -0.8 percentage points; 95% CI, -1.1 to -0.5). In nonexpansion states, mortality rates were 7.0% before expansion and 6.8% after expansion (change, -0.2 percentage points; 95% CI, -0.5 to 0.2), yielding an adjusted absolute reduction in mortality in expansion states of -0.6 percentage points (95% CI, -1.0 to -0.2). Mortality reductions were largest for black patients (-1.4 percentage points; 95% CI, -2.2, -0.7; P=.04 for interaction) and patients aged 19 to 44 years (-1.1 percentage points; 95% CI, -2.1 to -0.3; P=.01 for interaction). Expansion was associated with a 10.5-percentage-point (95% CI, 7.7-13.2) increase in Medicaid coverage at dialysis initiation, a -4.2-percentage-point (95% CI, -6.0 to -2.3) decrease in being uninsured, and a 2.3-percentage-point (95% CI, 0.6-4.1) increase in the presence of an arteriovenous fistula or graft. Changes in predialysis nephrology care were not significant. Conclusions and Relevance: Among patients with ESRD initiating dialysis, living in a state that expanded Medicaid under the Affordable Care Act was associated with lower 1-year mortality. If this association is causal, further research is needed to understand what factors may have contributed to this finding. PMID- 30422252 TI - Prehospital Advanced Life Support for Out-of-Hospital Cardiac Arrest in Blunt Trauma Patients. PMID- 30422254 TI - Sham Treatment Is as Effective for Treatment-Resistant Depression as Repetitive Transcranial Magnetic Stimulation. PMID- 30422253 TI - Patient-Reported Outcomes and Factors Associated With Patient Satisfaction After Surgical Treatment of Facial Nonmelanoma Skin Cancer. PMID- 30422255 TI - Translating Research Findings Into Practice-The Unfulfilled and Unclear Mission of Observational Data. PMID- 30422256 TI - The Fragility Index in Randomized Clinical Trials as a Means of Optimizing Patient Care. AB - Importance: The Fragility Index (FI) is the minimum number of participants in a randomized clinical trial (RCT) whose status would have to change from a nonevent (not experiencing the primary end point) to an event (experiencing the primary end point) required to turn a statistically significant result to a nonsignificant result. The FI measures the robustness (or fragility) of the results of an RCT and is an important aid to the clinician's interpretation of RCT results. It has now been recognized that RCTs, which provide the foundation for treatment guideline recommendations, may not be robust. Observations: Most RCTs in surgery and general medicine are fragile (with a low FI score), in contrast to those in cardiac disease and heart failure, where most RCTs are robust (with high FI scores). For clinical trials of trauma, we identified that the median (interquartile range) FI score was 3 (1-8), which means that adding 3 events to the opposite treatment arm in a given RCT eliminated statistical significance. The median Fragility Quotient (the FI score divided by the total study sample size) was 0.016 (0.0043-0.0408). Conclusions and Relevance: The provision of high-quality, evidence-based clinical care in surgery for optimal patient outcomes requires a foundation of robust clinical research evidence, and knowledge of the FI will assist in future surgical RCT design. We strongly recommend the routine reporting of FI scores for all future trauma and surgical RCTs to assist in appropriate and optimal decision making in the care of patients who have experienced trauma and/or need surgery. We also recommend the routine inclusion of the FI score in the development of clinical guidelines to assist the clinician in ascertaining whether guideline recommendations are robust. Surgeons should be aware to particularly exercise caution when considering a potential change in clinical practice based on RCTs with a low FI score. PMID- 30422258 TI - African Clinicians' Prioritization of Needs in International Breast Cancer Partnerships. PMID- 30422257 TI - Effect of Damaging Rare Mutations in Synapse-Related Gene Sets on Response to Short-term Antipsychotic Medication in Chinese Patients With Schizophrenia: A Randomized Clinical Trial. AB - Importance: The underlying mechanism for individual differences in patient response to antipsychotic medication remains unknown. Objective: To discover genes and gene sets harboring rare variants associated with short-term antipsychotic medication efficacy. Design, Setting, and Participants: In this multicenter, open-label, randomized clinical trial conducted between July 6, 2010, and December 31, 2011, 3023 patients recruited in China of Chinese Han descent with schizophrenia with total Positive and Negative Syndrome Scale (PANSS) score >= 60 received a 6-week treatment of antipsychotic medications randomly chosen from 5 atypical and 2 typical antipsychotic medications. Whole exome sequencing (WES) was performed in 316 participants (grouped into those with the best response [n=156] and those who had no response [n=160] to the antipsychotic medication prescribed), according to the total PANSS score reduction rate after 6 weeks of treatment. Validation was performed using targeted sequencing in an independent sample of 1920 patients. Data analyses was performed between March 15, 2016, and March 1, 2017. Main Outcomes and Measures: Drug efficacy at week 6 was assessed according to the change in PANSS scores from baseline. Extremely good and extremely poor responders were selected for an initial WES association study, from which a subset of genes showing putative association was selected for independent replication with a targeted sequencing approach. Results: Of the 3023 patients (1549 [51.24%] female and 1474 [48.8%] male; mean [SD] age, 31.2 [7.9] years), 2336 (77.3%) were eligible for genetic analysis. After quality-control exclusions, 316 patients (10.5%) were included for WES and 1920 (63.5%) were included for replication. In the WES discovery stage, 2 gene sets (reduced NMDA [N-methyl-D-aspartate]-mediated synaptic currents and reduced AMPA [alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid]-mediated synaptic currents) were found to be enriched with rare damaging variants in the nonresponder group, suggesting the involvement of these gene sets in antipsychotic medication efficacy. Reduced NMDA-mediated synaptic currents gene set was further replicated in an independent sample using targeting sequencing. No statistically significant differences in antipsychotic drug response were found among the patients who received different antipsychotic drugs. Conclusions and Relevance: Genetic variation in glutamatergic or NMDA neurotransmission is implicated in short-term antipsychotic medication efficacy; WES may have utility in the study of rare genetic variation in pharmacogenetics. Trial Registration: Chinese Clinical Trials Registry Identifier: ChiCTR-TRC 10000934. PMID- 30422260 TI - Screening and Brief Behavioral Counseling Interventions to Reduce Unhealthy Alcohol Use in Adults 18 Years and Older, Including Pregnant Women. PMID- 30422261 TI - Treating Obesity-Moving From Recommendation to Implementation. PMID- 30422259 TI - Effect of a Lay Counselor Intervention on Prevention of Major Depression in Older Adults Living in Low- and Middle-Income Countries: A Randomized Clinical Trial. AB - Importance: Preventing depression in older adults living in low- and middle income countries is important because of the scarcity of treatment resources and the risk of disability, suicide, and dementia. Objective: To assess whether an intervention for depression prevention provided by lay counselors is effective in older adults from low- and middle-income countries. Design, Setting, and Participants: This parallel-group randomized clinical trial with masked outcome assessment was performed in 181 older adults (>=60 years) with subsyndromal depressive symptoms at rural and urban primary care clinics in Goa, India. The first participant entered the trial on March 31, 2015, and the last exited on June 2, 2017. Data analysis used the intention-to-treat approach. Interventions: Lay counselors provided problem-solving therapy, brief behavioral treatment for insomnia, education in self-care of common medical disorders such as diabetes, and assistance in accessing medical and social programs. Main Outcomes and Measures: The main outcome was incidence of major depressive episodes. The study also assessed symptom change during 12 months (12-item General Health Questionnaire [GHQ-12]; score range of 0 to 12, with higher scores indicating greater symptoms of depression and anxiety), functional status (World Health Organization Disability Assessment Schedule 2.0; score range of 12 to 60, with higher scores indicating greater disability), cognition (Hindi Mini-Mental State Examination; score range of 0 to 30, with higher scores indicating better cognitive functioning), blood pressure, and body mass index to provide further clinical context. Results: The study enrolled 181 participants (mean [SD] age, 69.6 [7.2] years; 114 [63.0%] female): 91 to the intervention arm (depression in later life [DIL] intervention) and 90 to care as usual (CAU). Incident episodes of major depression were lower in the DIL intervention than in the CAU group (4.40% vs 14.44%; log-rank P = .04; number needed to treat, 9.95; 95% CI, 5.12 182.43). The 12-month Kaplan-Meier estimates of percentage of depression-free participants were 95.1% (95% CI, 90.5%-99.9%) in the DIL group vs 87.4% (95% CI, 80.4%-95.1%) in the CAU group. The incidence of depressive symptoms (GHQ-12) was also less (12-month mean difference, -1.18; 95% CI, -2.03 to -0.31; group * time interaction P < .001). There were no changes in measures of disability or cognition. The DIL intervention was associated with a significantly greater lowering of systolic blood pressure (12-month mean difference, -6.98; 95% CI, 11.96 to -2.01; group * time interaction P < .001) and change in body mass index (12-month mean difference, 0.23; 95% CI, -0.97 to 1.43; P = .04). Conclusions and Relevance: The DIL intervention is effective for preventing episodes of major depression in older persons with subsyndromal symptoms. If replicated, the DIL intervention may be effective in older adults living in low- and middle-income countries. Trial Registration: ClinicalTrials.gov Identifier: NCT02145429. PMID- 30422262 TI - The Shift From Heart Disease to Cancer as the Leading Cause of Death in High Income Countries: A Social Epidemiology Perspective. PMID- 30422264 TI - Disturbing Lack of Early Intervention Studies in Bipolar Disorder. PMID- 30422265 TI - Disturbing Lack of Early Intervention Studies in Bipolar Disorder-Reply. PMID- 30422263 TI - Increasing Safe Outpatient Management of Emergency Department Patients With Pulmonary Embolism: A Controlled Pragmatic Trial. AB - Background: Many low-risk patients with acute pulmonary embolism (PE) in the emergency department (ED) are eligible for outpatient care but are hospitalized nonetheless. One impediment to home discharge is the difficulty of identifying which patients can safely forgo hospitalization. Objective: To evaluate the effect of an integrated electronic clinical decision support system (CDSS) to facilitate risk stratification and decision making at the site of care for patients with acute PE. Design: Controlled pragmatic trial. (ClinicalTrials.gov: NCT03601676). Setting: All 21 community EDs of an integrated health care delivery system (Kaiser Permanente Northern California). Patients: Adult ED patients with acute PE. Intervention: Ten intervention sites selected by convenience received a multidimensional technology and education intervention at month 9 of a 16-month study period (January 2014 to April 2015); the remaining 11 sites served as concurrent controls. Measurements: The primary outcome was discharge to home from either the ED or a short-term (<24-hour) outpatient observation unit based in the ED. Adverse outcomes included return visits for PE-related symptoms within 5 days and recurrent venous thromboembolism, major hemorrhage, and all-cause mortality within 30 days. A difference-in-differences approach was used to compare pre-post changes at intervention versus control sites, with adjustment for demographic and clinical characteristics. Results: Among 881 eligible patients diagnosed with PE at intervention sites and 822 at control sites, adjusted home discharge increased at intervention sites (17.4% pre- to 28.0% postintervention) without a concurrent increase at control sites (15.1% pre- and 14.5% postintervention). The difference in-differences comparison was 11.3 percentage points (95% CI, 3.0 to 19.5 percentage points; P = 0.007). No increases were seen in 5-day return visits related to PE or in 30-day major adverse outcomes associated with CDSS implementation. Limitation: Lack of random allocation. Conclusion: Implementation and structured promotion of a CDSS to aid physicians in site-of-care decision making for ED patients with acute PE safely increased outpatient management. Primary Funding Source: Garfield Memorial National Research Fund and The Permanente Medical Group Delivery Science and Physician Researcher Programs. PMID- 30422266 TI - Association of Cannabinoid Administration With Experimental Pain in Healthy Adults: A Systematic Review and Meta-analysis. AB - Importance: Cannabinoid drugs are widely used as analgesics, but experimental pain studies have produced mixed findings. The analgesic properties of cannabinoids remain unclear. Objective: To conduct a systematic review and meta analysis of the association between cannabinoid drug administration and experimental pain outcomes in studies of healthy adults. Design, Setting, and Participants: A systematic search of PubMed, EMBASE, MEDLINE, PsycINFO, and CINAHL was conducted from the inception of each database to September 30, 2017. Studies were eligible for inclusion if they met criteria, including healthy participants and an experimentally controlled administration of any cannabinoid preparation in a quantified dose. Studies that used participants with chronic pain were excluded. Data extracted included study characteristics, cannabinoid types and doses, sex composition, and outcomes. Study quality was assessed using a validity measure previously established in published reviews. Random-effects meta-analyses were used to pool data and generate summary estimates. Main Outcomes and Measures: Experimental pain threshold, pain tolerance, pain intensity, pain unpleasantness, and mechanical hyperalgesia. Results: Eighteen placebo-controlled studies (with 442 participants) were identified. Of the 442 participants, 233 (52.7%) were male and 209 (47.3%) were female. For sample ages, 13 (72%) of the 18 studies reported a mean sample age (26.65 years), 4 (22%) reported a range, and 1 (6%) reported a median value. The search yielded sufficient data to analyze 18 pain threshold comparisons, 22 pain intensity comparisons, 9 pain unpleasantness comparisons, 13 pain tolerance comparisons, and 9 mechanical hyperalgesia comparisons. Cannabinoid administration was associated with small increases in pain threshold (Hedges g = 0.186; 95% CI, 0.054-0.318; P = .006), small to medium increases in pain tolerance (Hedges g = 0.225; 95% CI, 0.015-0.436; P = .04), and a small to medium reduction in the unpleasantness of ongoing experimental pain (Hedges g = 0.288; 95% CI, 0.104 0.472; P = .002). Cannabinoid administration was not reliably associated with a decrease in experimental pain intensity (Hedges g = 0.017; 95% CI, -0.120 to 0.154; P = .81) or mechanical hyperalgesia (Hedges g = 0.093; 95% CI, -0.059 to 0.244; P = .23). The mean quality rating across studies was good. Conclusions and Relevance: Cannabinoid drugs may prevent the onset of pain by producing small increases in pain thresholds but may not reduce the intensity of experimental pain already being experienced; instead, cannabinoids may make experimental pain feel less unpleasant and more tolerable, suggesting an influence on affective processes. Cannabis-induced improvements in pain-related negative affect may underlie the widely held belief that cannabis relieves pain. PMID- 30422269 TI - Alcohol Use Screening and Behavioral Counseling With Adolescents in Primary Care: A Call to Action. PMID- 30422270 TI - Case-Control Studies: Using "Real-world" Evidence to Assess Association. PMID- 30422271 TI - The Challenge of Reforming Nutritional Epidemiologic Research. PMID- 30422272 TI - Is US Medical Care Inefficient? PMID- 30422273 TI - What Can Medicine Learn From Social Science Studies of Sexual Harassment? PMID- 30422274 TI - Premature Mortality From Drug Overdoses: A Comparative Analysis of 13 Organisation for Economic Co-operation and Development Member Countries With High Quality Death Certificate Data, 2001 to 2015. PMID- 30422275 TI - Socioeconomic Differences in the Epidemiologic Transition From Heart Disease to Cancer as the Leading Cause of Death in the United States, 2003 to 2015: An Observational Study. AB - Background: Recent data suggest that the United States is in the midst of an epidemiologic transition in the leading cause of death. Objective: To examine county-level sociodemographic differences in the transition from heart disease to cancer as the leading cause of death in the United States. Design: Observational study. Setting: U.S. death records, 2003 to 2015. Participants: Decedents aged 25 years or older, classified by racial/ethnic group. Measurements: All-cause, heart disease, and cancer mortality stratified by quintiles of county median household income. Age- and sex-adjusted mortality rates and average annual percentage of change were calculated. Results: Heart disease was the leading cause of death in 79% of counties in 2003 and 59% in 2015. Cancer was the leading cause of death in 21% of counties in 2003 and 41% in 2015. The shift to cancer as the leading cause of death was greatest in the highest-income counties. Overall, heart disease mortality rates decreased by 28% (30% in high-income counties vs. 22% in low income counties) from 2003 to 2015, and cancer mortality rates decreased by 16% (18% in high-income counties vs. 11% in low-income counties). In the lowest income counties, heart disease remained the leading cause of death among all racial/ethnic groups, and improvements were smaller for both heart disease and cancer. Limitation: Use of county median household income as a proxy for socioeconomic status. Conclusion: Data show that heart disease is more likely to be the leading cause of death in low-income counties. Low-income counties have not experienced the same decrease in mortality rates as high-income counties, which suggests a later transition to cancer as the leading cause of death in low income counties. Primary Funding Source: National Institute on Minority Health and Health Disparities. PMID- 30422276 TI - Unhealthy Alcohol Use in Primary Care-The Elephant in the Examination Room. PMID- 30422277 TI - Association of Psoriasis With Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. AB - Importance: Patients with psoriasis may experience comorbidities involving cardiovascular diseases, chronic kidney disease, uveitis, psychiatric disturbances, and metabolic syndrome. However, the association between psoriasis and inflammatory bowel disease (IBD) has been largely unclear. Objective: To investigate the association of psoriasis with IBD. Data Sources: For this systematic review and meta-analysis, MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched for relevant studies from inception to January 17, 2018. Study Selection: Case-control, cross-sectional, or cohort studies that examined either the odds or risk of IBD in patients with psoriasis were included. No geographic or language limitations were used in the search. Data Extraction and Synthesis: The PRISMA and MOOSE guidelines were followed for data extraction. The Newcastle-Ottawa Scale was used to evaluate the risk of bias of included studies. Crohn disease and ulcerative colitis were analyzed separately and random-effects model meta-analysis was conducted. A subgroup analysis was performed on psoriatic arthritis. Main Outcomes and Measures: The risk and odds of IBD, Crohn disease, and ulcerative colitis in patients with psoriasis. Results: A total of 5 case-control or cross-sectional studies and 4 cohort studies with 7 794 087 study participants were included. Significant associations were found between psoriasis and Crohn disease (odds ratio, 1.70; 95% CI, 1.20-2.40) and between psoriasis and ulcerative colitis (odds ratio, 1.75; 95% CI, 1.49-2.05). Patients with psoriasis had an increased risk of Crohn disease (risk ratio, 2.53; 95% CI, 1.65-3.89) and ulcerative colitis (risk ratio, 1.71; 95% CI, 1.55-1.89). Conclusions and Relevance: These findings suggest that psoriasis is significantly associated with IBD. Gastroenterology consultation may be indicated when patients with psoriasis present with bowel symptoms. PMID- 30422278 TI - Aligning Patient and Physician Incentives. PMID- 30422279 TI - Matching for Fellowship Interviews. PMID- 30422280 TI - Mounting Evidence for Safe Home Treatment of Selected Patients With Acute Pulmonary Embolism. PMID- 30422281 TI - Incorrect Expansion of a Term and Other Clarifications. PMID- 30422282 TI - Weight Management in Adults With Obesity: What Is a Primary Care Clinician to Do? PMID- 30422284 TI - Generic Form of EpiPen Approved. PMID- 30422283 TI - Physician Burnout-A Serious Symptom, But of What? PMID- 30422285 TI - Vaginal Ring Contraceptive Remains Effective for 1 Year. PMID- 30422286 TI - Brain Stimulation Approved for Obsessive-Compulsive Disorder. PMID- 30422287 TI - On Deep Learning for Medical Image Analysis. PMID- 30422289 TI - Enabling School Success to Improve Community Health. PMID- 30422290 TI - Proprietaries, Pianos and Probity. PMID- 30422291 TI - Association Between Maintaining Certification in General Surgery and Loss-of License Actions. PMID- 30422292 TI - Scholarship Support for Veterans Enrolling in MD, JD, and MBA Programs. PMID- 30422293 TI - Safety of Topical Calcineurin Inhibitors for Hailey-Hailey Disease. PMID- 30422294 TI - Treatment of Chronic Hepatitis B Infection. PMID- 30422295 TI - Premedication for Neonates Requiring Nonemergency Intubation. PMID- 30422296 TI - Safety of Topical Calcineurin Inhibitors for Hailey-Hailey Disease-Reply. PMID- 30422297 TI - Treatment of Chronic Hepatitis B Infection-Reply. PMID- 30422298 TI - Premedication for Neonates Requiring Nonemergency Intubation-Reply. PMID- 30422300 TI - Increasing the Participation of Pregnant Women in Clinical Trials. PMID- 30422299 TI - Association of Clinical Specialty With Symptoms of Burnout and Career Choice Regret Among US Resident Physicians. AB - Importance: Burnout among physicians is common and has been associated with medical errors and lapses in professionalism. It is unknown whether rates for symptoms of burnout among resident physicians vary by clinical specialty and if individual factors measured during medical school relate to the risk of burnout and career choice regret during residency. Objective: To explore factors associated with symptoms of burnout and career choice regret during residency. Design, Setting, and Participants: Prospective cohort study of 4732 US resident physicians. First-year medical students were enrolled between October 2010 and January 2011 and completed the baseline questionnaire. Participants were invited to respond to 2 questionnaires; one during year 4 of medical school (January March 2014) and the other during the second year of residency (spring of 2016). The last follow-up was on July 31, 2016. Exposures: Clinical specialty, demographic characteristics, educational debt, US Medical Licensing Examination Step 1 score, and reported levels of anxiety, empathy, and social support during medical school. Main Outcomes and Measures: Prevalence during second year of residency of reported symptoms of burnout measured by 2 single-item measures (adapted from the Maslach Burnout Inventory) and an additional item that evaluated career choice regret (defined as whether, if able to revisit career choice, the resident would choose to become a physician again). Results: Among 4696 resident physicians, 3588 (76.4%) completed the questionnaire during the second year of residency (median age, 29 [interquartile range, 28.0-31.0] years in 2016; 1822 [50.9%] were women). Symptoms of burnout were reported by 1615 of 3574 resident physicians (45.2%; 95% CI, 43.6% to 46.8%). Career choice regret was reported by 502 of 3571 resident physicians (14.1%; 95% CI, 12.9% to 15.2%). In a multivariable analysis, training in urology, neurology, emergency medicine, and general surgery were associated with higher relative risks (RRs) of reported symptoms of burnout (range of RRs, 1.24 to 1.48) relative to training in internal medicine. Characteristics associated with higher risk of reported symptoms of burnout included female sex (RR, 1.17 [95% CI, 1.07 to 1.28]; risk difference [RD], 7.2% [95% CI, 3.1% to 11.3%]) and higher reported levels of anxiety during medical school (RR, 1.08 per 1-point increase [95% CI, 1.06 to 1.11]; RD, 1.8% per 1-point increase [95% CI, 1.6% to 2.0%]). A higher reported level of empathy during medical school was associated with a lower risk of reported symptoms of burnout during residency (RR, 0.99 per 1-point increase [95% CI, 0.99 to 0.99]; RD, -0.5% per 1-point increase [95% CI, -0.6% to -0.3%]). Reported symptoms of burnout (RR, 3.20 [95% CI, 2.58 to 3.82]; RD, 15.0% [95% CI, 12.8% to 17.3%]) and clinical specialty (range of RRs, 1.66 to 2.60) were both significantly associated with career choice regret. Conclusions and Relevance: Among US resident physicians, symptoms of burnout and career choice regret were prevalent, but varied substantially by clinical specialty. Further research is needed to better understand these differences and to address these issues. PMID- 30422302 TI - ? PMID- 30422301 TI - [Recommendations for sepsis risk stratification in adults out of hospital]. AB - A national Swedish expert group has presented recommendations for sepsis risk stratification, aimed to be used on patients with suspected infections out of hospital. Based on general condition, physiological parameters, and risk factors, the patients are stratified, according to risk of ongoing or subsequent sepsis, to green light (low risk), yellow light (moderate to high risk), or red light (high risk). Initial patient management should be guided by risk group, i.e. patients with green light can in most cases return to their homes, whereas patients with red light should immediately be transferred to hospital. PMID- 30422303 TI - Wnt signaling in physiological and pathological bone formation. AB - Wnt signaling, canonical or non-canonical, plays conserved roles in numerous physiological and pathological processes. However, it is well beyond the scope of this review to cover all functional aspects of Wnt signaling in different contexts at reasonable depth; therefore this review intends to cover only the roles of Wnt signaling in bone biology; more specifically, we intend to first update the roles of Wnt signaling in physiological bone process, including in osteogenesis and chondrogenesis, since recent years have witnessed tremendous progressions in this area, and then we seek to extend our understanding to the pathological bone process, especially to the heterotopic ossification (HO), even though the understanding of Wnt signaling in HO has been limited. We then further clarify the potential crosstalking between Wnt and other conserved signaling pathways, including FGF, GPCR and Hif1alpha pathways. Overall, our goal is to update the progressions, identify the general theme and the knowledge gaps and discuss the potential promising avenue for future applications in HO prevention and treatment. PMID- 30422304 TI - Immature survival, fertility, and density dependence drive global population dynamics in a long-lived species. AB - Disentangling the influence of demographic parameters and the role of density dependence on species' population dynamics is a challenge, especially when fractions of the population are unobservable. Additionally, due to the difficulty of gathering data at large spatial scales, most studies ignore the global dynamic of a species, which would integrate local heterogeneity dynamics and remove the noise of dispersal. We developed an integrated population model (IPM) at a global scale to disentangle the main demographic drivers of population dynamics in a long-lived species. We used 28 yr of Audouin's Gull demographic data encompassing 69 local patches (comprising 90% of the world population). Importantly, we took into account the unobservable fraction of non-breeders and also assessed the strength of density dependence for this fraction of the population. As predicted by life histories of long-lived organisms, temporal random variation in survival was highest for immature individuals (1.326, 95% credible interval [CRI] 1.290 1.940) and lowest for adults (0.499, 95% CRI 0.487-0.720). Large temporal fluctuations in the probability of taking a reproductive sabbatical would partly explain the consistency in adult survival, with individuals most likely refraining from breeding when environmental conditions were harsh. Immature survival and fertility were the main drivers of population dynamics during the study period (r2 = 0.83, 0.77-0.87 and 0.73, 0.63-0.79, respectively). We found strong evidence of density dependence, not only due to the number of breeders (r2 = -0.34, -0.43 to -0.24) but also due to individuals on sabbatical (r2 = -0.18, -0.33 to -0.01). From a conservation point of view, the species shows a 5% annual global decrease during the last 10 years, and we propose an update of its conservation status. Even though population dynamics of long-lived organisms are very sensitive to changes in adult survival, we show here that, in the absence of strong environmental perturbations affecting this vital rate, fluctuations in population density are mainly driven by variations in survival of immature individuals and fertility. Integrated models based on long-term monitoring at a global scale may enhance our ecological and evolutionary understanding of how demographic drivers influence population dynamics. PMID- 30422305 TI - Increased Alcohol Consumption Among Swedish 70-Year-Olds 1976 to 2016: Analysis of Data from The Gothenburg H70 Birth Cohort Studies, Sweden. AB - BACKGROUND: The older adult population is increasing worldwide, as is the number of older adults who consume alcohol. Although there is a growing body of research on alcohol consumption among older people, few studies focus on changes in at risk consumption over time across well-defined birth cohorts of older adults. METHODS: This study used a serial cross-sectional design in order to compare alcohol consumption patterns among birth cohorts of Swedish 70-year-olds (total n = 2,268) examined in 1976 to 1977 (n = 393), 1992 to 1993 (n = 248), 2000 to 2002 (n = 458), and 2014 to 2016 (n = 1,169). Participants took part in a multidisciplinary study on health and aging. Face-to-face interviews were conducted by healthcare professionals. Protocols regarding alcohol consumption were similar for all cohorts. The volume of weekly alcohol consumption was estimated during the past month. At-risk consumption was defined as >=100 g alcohol/wk corresponding roughly to the National Institute on Alcohol Abuse and Alcoholism definition of heavy consumption. RESULTS: The proportion of at-risk consumers among men increased from 16.1% in 1976 to 1977 to 29.9% in 2000 to 2002 (p = 0.001) and 45.3% in 2014 to 2016 (p < 0.001). In women, proportions were low in 1976 to 1977 (0.5%) and 1992 to 1993 (2.0%; p = 0.134), but increased to 9.5% in 2000 to 2002 (p < 0.001) and 24.3% in 2014 to 2016 (p < 0.001). The male:female ratio regarding consumption of >=100 g/wk decreased from 32.2:1 in 1976 to 1977 to 3.1:1 in 2000 to 2002 to 1.9:1 in 2014 to 2016. Spirit consumption decreased dramatically among men during the study period, while women reported very low spirit consumption at all examinations. Wine consumption increased in both sexes between 2000 to 2002 and 2014 to 2016. Beer consumption increased among men between 2000 to 2002 and 2014 to 2016. CONCLUSIONS: Recent cohorts of 70-year-olds in Sweden report significantly higher levels of alcohol consumption than previous cohorts. There was a dramatic increase in at-risk consumption among 70-year-olds from the 1970s to the mid-2010s, and this was particularly pronounced among women. PMID- 30422306 TI - Lifetime alcohol use patterns and risk of diabetes onset in the National Alcohol Survey. AB - BACKGROUND: Studies of the role of alcohol use in diabetes risk have rarely included lifetime alcohol use measures, including the frequency of heavy occasions, or evaluated risks among Black or Hispanic respondents in US samples. METHODS: Data from the 2014-15 National Alcohol Survey of the U.S. population were used to estimate diabetes risk from drinking patterns at the time of onset in Cox proportional hazards models in a retrospective cohort design. Models for the population, males and females and for White, Black and Hispanic respondents of both genders were estimated using two versions of drinking pattern groupings at each age. RESULTS: While a number of significant results were found with the first version of the drinking measures, we focus on those confirmed with measures from responses strictly prior to the age of risk estimation. Compared to the lifetime abstainer group, the 'drinking at least weekly with less than monthly 5+' group had a significantly lower hazard ratio (HR) for the total sample (HR=0.64) and among Whites (HR=0.42). Significantly reduced risks were found in the same models for those who drank 5+ at least monthly but not weekly. No significantly elevated risks were found for either current or prior heavy occasion drinking. CONCLUSIONS: These results are consistent with some prior studies in finding reduced risks for regular light to moderate drinkers, but not consistent with findings from other studies showing increased risk from heavy occasion drinking, particularly among women. New and larger studies with well defined drinking pattern measures are needed, particularly for US Blacks and Hispanics, to address varying results in this literature. This article is protected by copyright. All rights reserved. PMID- 30422307 TI - The impact of timing of maternal influenza immunization on infant antibody levels at birth. AB - Pregnant women and infants are at an increased risk of severe disease after influenza infection. Maternal immunization is a potent tool to protect both these at-risk groups. While the primary aim of maternal influenza vaccination is to protect the mother, a secondary benefit is the transfer of protective antibodies to the infant. A recent study using the tetanus, diphtheria and acellular pertussis (Tdap) vaccine indicated that children born to mothers immunized in the second trimester of pregnancy had the highest antibody titres compared to children immunized in the third trimester. The aim of the current study was to investigate how the timing of maternal influenza immunization impacts infant antibody levels at birth. Antibody titres were assessed in maternal and cord blood samples by both immunoglobulin (Ig)G-binding enzyme-linked immunosorbent assay (ELISA) and haemagglutination inhibition assay (HAI). Antibody titres to the H1N1 component were significantly higher in infants born to mothers vaccinated in either the second or third trimesters than infants born to unvaccinated mothers. HAI levels in the infant were significantly lower when maternal immunization was performed less than 4 weeks before birth. These studies confirm that immunization during pregnancy increases the antibody titre in infants. Importantly, antibody levels in cord blood were significantly higher when the mother was vaccinated in either trimesters 2 or 3, although titres were significantly lower if the mother was immunized less than 4 weeks before birth. Based on these data, seasonal influenza vaccination should continue to be given in pregnancy as soon as it becomes available. PMID- 30422309 TI - Colonization of preterm gnotobiotic piglets with probiotic Lactobacillus rhamnosus GG and its interference with Salmonella Typhimurium. AB - A balanced microbiota of the gastrointestinal tract (GIT) is a prerequisite for a healthy host. The GIT microbiota in preterm infants is determined by the method of delivery and nutrition. Probiotics can improve the GIT microbiota balance and suitable animal models are required to verify their harmlessness. Preterm gnotobiotic piglets were colonized with Lactobacillus rhamnosus GG (LGG) to evaluate its safety and possible protective action against infection with an enteric pathogen, Salmonella Typhimurium (ST). Clinical signs (anorexia, somnolence, fever and diarrhea), bacterial interference and translocation, intestinal histopathology, transcriptions of claudin-1, occludin and interferon (IFN)-gamma, intestinal and systemic protein levels of interleukin (IL)-8, IL 12/23 p40 and IFN-gamma were compared among (i) germ-free, (ii) LGG-colonized, (iii) ST-infected and (iv) LGG-colonized and subsequently ST-infected piglets for 24 h. Both LGG and ST-colonized the GIT; LGG translocated in some cases into mesenteric lymph nodes and the spleen but did not cause bacteremia and clinical changes. ST caused clinical signs of gastroenteritis, translocated into mesenteric lymph nodes, the spleen, liver and blood, increased claudin-1 and IFN gamma transcriptions, but decreased occludin transcription and increased local and systemic levels of IL-8 and IL-12/23 p40. Previous colonization with LGG reduced ST colonization in the jejunum and translocation into the liver, spleen and blood. It partially ameliorated histopathological changes in the intestine, reduced IL-8 levels in the jejunum and plasma and IL-12/23 p40 in the jejunum. The preterm gnotobiotic piglet model of the vulnerable preterm immunocompromised infant is useful to verify the safety of probiotics and evaluate their protective effect. PMID- 30422308 TI - Isocitrate dehydrogenase 1 and 2 mutations, 2-hydroxyglutarate levels, and response to standard chemotherapy for patients with newly diagnosed acute myeloid leukemia. AB - BACKGROUND: Acute myeloid leukemia (AML) cells harboring mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) produce the oncometabolite 2-hydroxyglutarate (2HG). This study prospectively evaluated the 2HG levels, IDH1/2 mutational status, and outcomes of patients receiving standard chemotherapy for newly diagnosed AML. METHODS: Serial samples of serum, urine, and bone marrow aspirates were collected from patients newly diagnosed with AML, and 2HG levels were measured with mass spectrometry. Patients with baseline serum 2HG levels greater than 1000 ng/mL or marrow pellet 2HG levels greater than 1000 ng/2 * 106 cells, which suggested the presence of an IDH1/2 mutation, underwent serial testing. IDH1/2 mutations and estimated variant allele frequencies were identified. AML characteristics were compared with the Wilcoxon test and Fisher's exact test. Disease-free survival and overall survival (OS) were evaluated with log-rank tests and Cox regression. RESULTS: Two hundred and two patients were treated for AML; 51 harbored IDH1/2 mutations. IDH1/2-mutated patients had significantly higher 2HG levels in serum, urine, bone marrow aspirates, and aspirate cell pellets than wild-type patients. A serum 2HG level greater than 534.5 ng/mL was 98.8% specific for the presence of an IDH1/2 mutation. Patients with IDH1/2-mutated AML treated with 7+3-based induction had a 2-year event-free survival (EFS) rate of 44% and a 2-year OS rate of 57%. There was no difference in complete remission rates, EFS, or OS between IDH1/2-mutated and wild-type patients. Decreased serum 2HG levels on day 14 as a proportion of the baseline were significantly associated with improvements in EFS (P = .047) and OS (P = .019) in a multivariate analysis. CONCLUSIONS: Among patients with IDH1/2-mutated AML, 2HG levels are highly specific for the mutational status at diagnosis, and they have prognostic relevance in patients receiving standard chemotherapy. PMID- 30422310 TI - Identification and characterization of circular RNAs involved in mechanical force induced periodontal ligament stem cells. AB - Circular RNAs (circRNAs) play critical roles in signal transduction during cell proliferation, differentiation, and apoptosis in a posttranscriptional manner. Recently, circRNAs have been proved to be a large class of animal RNAs with regulatory potency. However, whether circRNAs can respond to mechanical force (MF) and impact on human periodontal ligament stem cells (PDLSCs) and the orthodontic tooth movement (OTM) process remain unknown. Here, we investigated the circRNAs expression patterns in PDLSCs induced by MF and found that circRNAs were responsive to the MF in PDLSCs. Through the valid reads' distribution analysis, we found that the majority of reads in both the control PDLSCs and the MF-induced PDLSCs were distributed in exons. Then we analyzed Gene Ontology terms of genes that overlap with or are neighbors of the stress-responsive circRNAs and found unique enrichment patterns in biological processes, molecular function, and cellular component of PDLSCs. Next, we predicted the possible functions of circRNAs through circRNAs-miRNAs networks. We found that one circRNA may regulate one or several miRNA/miRNAs and one miRNA may interact with one or multiple circRNA/circRNAs. Importantly, a number of circRNAs were predicted to directly or indirectly regulate miRNAs-mediated osteogenic differentiation in mesenchymal stem cells. For instance, circRNA3140 was highly and widely associated with microRNA-21, which plays a critical role in MF-induced osteogenic differentiation of PDLSCs. Taken together, these findings reveal a previously unrecognized mechanism that MF can induce the expression changes of circRNAs in PDLSCs, which may modulate the OTM process and the alveolar bone remodeling. PMID- 30422311 TI - The relationships and interactions between age, exercise and physiological function. AB - This brief review focuses on the relationships and interactions between human ageing, exercise and physiological function. It explores the importance of the selection of participants for ageing research, the strengths and deficiencies of both cross-sectional and longitudinal studies and the complexities involved in understanding time-dependent, lifelong physiological processes. As being physically active is crucial to fostering healthy ageing, it is essential that participants in health and ageing research are defined in terms of their physical activity / exercise status as well as other lifestyle factors. Comparisons of exercisers with non-exercisers has suggested that there is a mosaic of regulation of ageing both within and across physiological systems. We suggest that four broad categories exist which encompass this regulation. These are i) systems and indices that are age-dependent, but activity independent; ii) systems that are age-dependent, but also malleable by exercise; iii) systems that are not age affected but are altered by exercise and iv) systems that are neither age nor activity dependent. We briefly explore the concept of a mosaic of regulation in a selection of physiological systems that include skeletal muscle, the immune and endocrine systems and cognitive function and how these categories fit within the broad framework of understanding the physiology of human ageing. Schematic to depict how healthy or diseased ageing phenotypes are the product of the interaction and regulation of physiological systems that can broadly be grouped into 4 categories on the basis of their malleability or otherwise to exercise and to the ageing process. This article is protected by copyright. All rights reserved. PMID- 30422312 TI - HSPB8 overexpression prevents disruption of blood-brain barrier by promoting autophagic flux after cerebral ischemia/reperfusion injury. AB - Heat shock protein B8(HSPB8) has been recently reported to confer neuroprotection against ischemia-reperfusion(I/R)-induced cerebral injury in vivo and in vitro. However, the molecular mechanism is still elusive. The present study focused on the effect of intracerebroventricular (i.c.v) delivery of lenti-HSPB8 virus against neurological injury in a rat model of cerebral I/R and explored the underlying mechanism. We found that lentivirus i.c.v injection-induced HSPB8 overexpression strongly alleviated infarct volume, improved neurobehavioral outcomes and reduced brain edema in rat middle cerebral artery occlusion/reperfusion (MCAO/R) model. Concomitantly, HSPB8 overexpression noticeably prevented BBB disruption after cerebral I/R injury as indicated by the reduction of Evan's blue (EB) leakage and IgG detection in the ipsilateral hemisphere compared with the vehicle group. Moreover, immunoblotting and immunofluorescence staining of tight junction proteins (TJPs) claudin-5 and occludin showed that HSPB8 overexpression prevented the degradation of these proteins induced by MCAO/R, which indicated the protective effect of HSPB8 on BBB. Western blotting and immunostaining techniques were also utilized to analyze the expression of the markers of autophagy. We found that HSPB8 overexpression promoted autophagic flux, evidenced by increased ratio of LC3 I/II, accumulation of Beclin-1 expression and enhanced p62 degradation. i.c.v injection of 15 MUg autophagy inhibitor 3-methyladenine (3-MA) was applied at the onset of reperfusion. The results showed that 3-MA elicited a significant loss of the protective effect of HSPB8 against MCAO/R-induced neurological defect, EB extravasation and the loss TJPs, suggesting that the BBB protective role of HSPB8 was, at least in part, mediated through autophagy. Collectively, HSPB8 may represent a potential therapeutic agent for preserving BBB integrity following cerebral I/R injury. This article is protected by copyright. All rights reserved. PMID- 30422313 TI - miR-150 might inhibit cell proliferation and promote cell apoptosis by targeting LMO4 in Burkitt lymphoma. AB - This study aimed at investigating the effect of microRNA-150 (miR-150) on cell proliferation of Burkitt lymphoma and its molecular mechanism. Gene expression analysis was applied to identify target genes of miR-150 in Burkitt lymphoma cell line ST486 based on the dataset from the Gene Expression Omnibus (GEO) datasets GSE86432. miRNA mimics, inhibitor and small interfering RNA (siRNA) were fluorescently labeled by Cy3, whereas plasmid vector was labeled by EGFP. Cells were viewed by fluorescence microscope and transfection efficiency was evaluated through fluorescent cell percentage. Quantitative real-time polymerase chain reaction analysis (qRT-PCR) and western blot were applied to detect the expression level of miR-150 and LMO4. Cell proliferation, cell cycle, and apoptosis were explored by CCK-8, flow cytometry. Targeting relationship was validated by the Luciferase reporter assay. Tumor xenograft and immunohistochemical analysis were conducted in nude mice model. In Burkitt lymphoma cells, miR-150 expression was significantly lower than normal ones, whereas the expression of LMO4 was upregulated. miR-150 might inhibit cell proliferation and promoted apoptosis in Burkitt lymphoma deterioration by downregulating LMO4. The results of tumor xenograft further confirmed the role of miR-150 in Burkitt lymphoma. Targeting LMO4 is a significant mechanism by which miR-150 suppresses cell growth and promotes apoptosis in Burkitt lymphoma cells, thus may provide a novel target for Burkitt lymphoma therapy in the future. PMID- 30422314 TI - Association between hidradenitis suppurativa and hospitalization for psychiatric disorders: A cross-sectional analysis of the National Inpatient Sample. AB - BACKGROUND: Hidradenitis suppurativa (HS) is associated with pain, disfigurement, psychosocial distress and poor quality of life, all of which may lead to higher likelihood of mental health (MH) disorders. However, little is known about the MH comorbidities of HS. OBJECTIVES: to determine the MH disorders and cost-burden associated with HS. METHODS: Data were examined from the 2002-2012 National Inpatient Sample, comprising a ~20% sample of all US pediatric and adult hospitalizations (n=87,053,155 admissions). RESULTS: MH disorders were much more common in inpatients with vs. without HS (34.27% vs. 20.05%). In multivariable logistic regression models controlling for gender, age, race/ethnicity, and insurance status, HS was associated with significantly higher odds of a MH disorder (adjusted odds ratio [95% confidence interval]: 2.53 [2.42-2.63]), including 10 of 15 MH disorders examined. In contrast, HS was not associated with primary hospitalization for a MH disorder overall (0.95 [0.84-1.07]), but was associated with primary hospitalization for 8 of 15 MH disorders examined. Among inpatients with HS, primary admission for a MH disorder was associated with female sex, public or no insurance, more chronic diseases, but inversely associated with older age, female sex, and non-white race/ethnicity. HS was associated with >$38 million of excess mean annual costs of hospitalization for MH disorders. CONCLUSIONS: Inpatients with HS had increased odds of comorbid mental health disorders, overall, and multiple primary mental health admissions, in particular, which were associated with considerable excess costs. This article is protected by copyright. All rights reserved. PMID- 30422315 TI - The red leg dilemma: a scoping review of the challenges of diagnosing lower limb cellulitis. AB - BACKGROUND: Suspected lower limb cellulitis presentations are commonly misdiagnoses, resulting in avoidable antibiotic prescribing or hospital admissions. Understanding the challenges posed in diagnosing cellulitis may help enhance future care. OBJECTIVES: To examine and map out the challenges and facilitators identified by patients and health professionals in diagnosing lower limb cellulitis. METHODS: A scoping systematic review was performed in MEDLINE and Embase in October 2017. Thematic analysis was used to identify key themes. Quantitative data was summarised by narrative synthesis. RESULTS: Three themes were explored: (i) clinical case reports of misdiagnosis, (ii) service development and (iii) diagnostic aids. Forty-seven different pathologies were misdiagnosed, including seven malignancies. Two different services have been piloted to reduce the misdiagnosis rates of lower limb cellulitis and save costs. Four studies have looked at biochemical markers, imaging and a scoring tool to aid diagnosis. CONCLUSIONS: This review highlights the range of alternative pathologies that can be misdiagnosed as cellulitis, and emerging services and diagnostic aids developed to minimise misdiagnosis. Future work should focus on gaining a greater qualitative understanding of the diagnostic challenges from the perspective of patients and clinicians. This article is protected by copyright. All rights reserved. PMID- 30422316 TI - Increasing Therapy Related Myeloid Neoplasms in Multiple Myeloma. AB - BACKGROUNG: Despite the longer survival achieved in multiple myeloma (MM) patients due to new therapy strategies, a concern is emerging regarding an increased risk of secondary primary malignancies (SPMs) and how to characterize those patients at risk. We performed a retrospective study covering a 28-year follow-up period (1991-2018) in a tertiary single institution. MATERIAL AND METHODS: Data of 403 MM patients was recorded and compared with the epidemiologic register of the population area covered by our center, calculating the standarize incidence ratio (SIR) for the different types of SPMs diagnosed in the MM cohort. Fine and Gray regression models were used to identify risk factors for SPMs. RESULTS: Out of the 403 MM patients, 23 (5.7%) developed SPMs: 13 therapy related myeloid (TRM) malignancies (10 of them (77%) myelodysplastic syndrome (MDS), 1 acute lymphoid leukemia and 9 solid neoplasms. In the MM cohort, the relative risk of MDS was significantly higher than in the general population. Survival of patients with TRM malignancies was poor with a median of 4 months from the diagnosis, and most of them showed complex karyotype. Within the MM subset, multivariable analysis showed a higher risk of TRM malignancies in patients that previously received prolonged treatment with lenalidomide (> 18 months). CONCLUSIONS: Though the improvement in MM outcome during the last decades is an unprecedented achievement, it has been accompanied by the rise in TRM malignancies with complex cytogenetic profile and poor prognosis that are in the need of an improved biologic and therapeutic approach. This article is protected by copyright. All rights reserved. PMID- 30422318 TI - Let-7g-5p regulates mouse mammary cells differentiation and function by targeting PRKCA. AB - MicroRNAs (miRNAs) are closely related with the posttranscriptional regulation of gene expression. Our past study showed that let-7g-5p decreased during pregnancy and lactation in mouse mammary gland, what suggested the prospective regulating role of let-7g-5p in mammary epithelial cells. In this study, to unravel the role of let-7g-5p, we found PRKCA (PKC-alpha, PKC-alpha) might serve as potential targets of let-7g-5p by bioinformatics. Then let-7g-5p was knocked down by an antisense oligonucleotide in mouse primary mammary epithelial cells. As predicted, PRKCA gene expression and mammary epithelial cells growth were increased by anti-let-7g-5p regulation in vitro. By using reporter constructs, it showed that the let-7g-5p could direct binding with 3'-the untranslated regions (3'-UTR) of PRKCA mRNA. Furthermore, ectopic overexpression of let-7g-5p in vivo reduced PRKCA and beta-casein protein expression as well as inhibited mammary gland growth. These results suggested that let-7g-5p could inhibit the mammary epithelial cells differentiation and beta-casein protein synthesis and expression through suppression of PRKCA on the cycle of mammary cell differentiation and development and that let-7g-5p may be a novel important regulated target in mammary cells function. PMID- 30422317 TI - Pulse wave velocity to global longitudinal strain ratio in hypertension. AB - BACKGROUND: Arterial elastance to left ventricular elastance ratio assessed by echocardiography is widely used as a marker of ventricular-arterial coupling. MATERIALS AND METHODS: We investigated whether the ratio of carotid-femoral pulse wave velocity, as a marker of arterial stiffness, to global longitudinal strain, as a marker of left ventricular performance, could be better associated with vascular and cardiac damage than the established arterial elastance/left ventricular elastance index. In 299 newly-diagnosed untreated hypertensives we measured, carotid-femoral pulse wave velocity, and carotid intima-media thickness, coronary-flow reserve, arterial elastance/left ventricular elastance, global longitudinal strain, and markers of left ventricular diastolic function (E/A and E') by echocardiography. RESULTS: Pulse wave velocity-to-global longitudinal strain ratio (PWV/GLS) was lower in hypertensives than controls ( 0.61+/-0.21 vs -0.45+/-0.11m/sec%, p<0.001). Low PWV/GLS values were associated with carotid-intima media thickness>0.9mm (p=0.003), E/A<=0.8 (p=0.019) and E'<=9 cm/sec (p=0.002) and coronary-flow reserve<2.5 (p=0.017), after adjustment for age, sex and mean arterial pressure. Low PWV/GLS was also associated with increased left ventricular mass and left atrial volume in the univariate (p=0.003 and p=0.038) but not in the multivariate model. In hypertensives, there was no significant association of arterial elastance-to-left ventricular elastance index with carotid intima media thickness, coronary flow reserve, E/A, E', or left atrial volume with the exception of an inverse association with left ventricular mass (p=0.027). CONCLUSIONS: Pulse wave velocity-to-global longitudinal strain ratio but not the echocardiography-derived arterial elastance-to left ventricular elastance index is related to impaired carotid-intima media thickness, coronary flow reserve and diastolic function in hypertensives. This article is protected by copyright. All rights reserved. PMID- 30422319 TI - Pharmacokinetic Interactions of Rolapitant With Cytochrome P450 3A Substrates in Healthy Subjects. AB - Rolapitant (Varubi) is a neurokinin-1 receptor antagonist approved for the prevention of chemotherapy-induced nausea and vomiting. Rolapitant is primarily metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme. Unlike other neurokinin-1 receptor antagonists, rolapitant is neither an inhibitor nor an inducer of CYP3A4 in vitro. The objective of this analysis was to examine the pharmacokinetics of rolapitant in healthy subjects and assess drug-drug interactions between rolapitant and midazolam (a CYP3A substrate), ketoconazole (a CYP3A inhibitor), or rifampin (a CYP3A4 inducer). Three phase 1, open-label, drug-drug interaction studies were conducted to examine the pharmacokinetic interactions of orally administered rolapitant with midazolam, rolapitant with ketoconazole, and rolapitant with rifampin. The pharmacokinetic profiles of midazolam and 1-hydroxy midazolam metabolites were essentially unchanged when coadministered with rolapitant, indicating the lack of a clinically relevant inhibition or induction of CYP3A by rolapitant. Coadministration of ketoconazole with rolapitant had no effects on rolapitant maximum concentration and resulted in an approximately 20% increase in the area under the concentration-time curve of rolapitant, suggesting that strong CYP3A inhibitors have minimal inhibitory effects on rolapitant exposure. Repeated administrations of rifampin appeared to reduce rolapitant exposure, resulting in a 33% decrease in maximum concentration and 87% decrease in area under the concentration-time curve from time zero to infinity. Coadministration of rolapitant did not affect the exposure of midazolam. Rifampin coadministration resulted in lower concentrations of rolapitant, and ketoconazole coadministration had no or minimal effects on rolapitant exposure. Rolapitant was safe and well tolerated when coadministered with ketoconazole, rifampin, or midazolam. No new safety signals were reported compared with previous studies of rolapitant. PMID- 30422320 TI - Pulsed electromagnetic fields regulate osteocyte apoptosis, RANKL/OPG expression, and its control of osteoclastogenesis depending on the presence of primary cilia. AB - Growing evidence has shown that pulsed electromagnetic fields (PEMF) can modulate bone metabolism in vivo and regulate the activities of osteoblasts and osteoclasts in vitro. Osteocytes, accounting for 95% of bone cells, act as the major mechanosensors in bone for transducing external mechanical signals and producing cytokines to regulate osteoblastic and osteoclastic activities. Targeting osteocytic signaling pathways is becoming an emerging therapeutic strategy for bone diseases. We herein systematically investigated the changes of osteocyte behaviors, functions, and its regulation on osteoclastogenesis in response to PEMF. The osteocyte-like MLO-Y4 cells were exposed to 15 Hz PEMF stimulation with different intensities (0, 5, and 30 Gauss [G]) for 2 hr. We found that the cell apoptosis and cytoskeleton organization of osteocytes were regulated by PEMF with an intensity-dependent manner. Moreover, PEMF exposure with 5 G significantly inhibited apoptosis-related gene expression and also suppressed the gene and protein expression of the receptor activator of nuclear factor kappaB ligand/osteoprotegerin (RANKL/OPG) ratio in MLO-Y4 cells. The formation, maturation, and osteoclastic bone-resorption capability of in vitro osteoclasts were significantly suppressed after treated with the conditioned medium from PEMF-exposed (5 G) osteocytes. Our results also revealed that the inhibition of osteoclastic formation, maturation, and bone-resorption capability induced by the conditioned medium from 5 G PEMF-exposed osteocytes was significantly attenuated after abrogating primary cilia in osteocytes using the polaris siRNA transfection. Together, our findings highlight that PEMF with 5 G can inhibit cellular apoptosis, modulate cytoskeletal distribution, and decrease RANKL/OPG expression in osteocytes, and also inhibit osteocyte-mediated osteoclastogenesis, which requires the existence of primary cilia in osteocytes. This study enriches our basic knowledge for further understanding the biological behaviors of osteocytes and is also helpful for providing a more comprehensive mechanistic understanding of the effect of electromagnetic stimulation on bone and relevant skeletal diseases (e.g., bone fracture and osteoporosis). PMID- 30422321 TI - Population Pharmacokinetic Modeling to Evaluate Standard Magnesium Sulfate Treatments and Alternative Dosing Regimens for Women With Preeclampsia. AB - Magnesium sulfate is the standard therapy for prevention and treatment of eclampsia. Two standard dosing regimens require either continuous intravenous infusion or frequent, large-volume intramuscular injections, which may preclude patients from receiving optimal care. This project sought to identify alternative, potentially more convenient, but similarly effective dosing regimens that could be used in restrictive clinical settings. A 2-compartment population pharmacokinetic (PK) model was developed to characterize serial PK data from 92 pregnant women with preeclampsia who received magnesium sulfate. Body weight and serum creatinine concentration had a significant impact on magnesium PK. The final PK model was used to simulate magnesium concentration profiles for the 2 standard regimens and several simplified alternative dosing regimens. The simulations suggest that intravenous regimens with loading doses of 8 g over 60 minutes followed by 2 g/h for 10 hours and 12 g over 120 minutes followed by 2 g/h for 8 hours (same total dose as the standard intravenous regimen but shorter treatment duration) would result in magnesium concentrations below the toxic range. For the intramuscular regimens, higher maintenance doses given less frequently (4 g intravenously + 10-g intramuscular loading doses with maintenance doses of 8 g every 6 hours or 10 g every 8 hours for 24 hours) or removal of the intravenous loading dose (eg, 10 g intramusculary every 8 hours for 24 hours) may be reasonable alternatives. In addition, individualized dose adjustments based on body weight and serum creatinine were proposed for the standard regimens. PMID- 30422322 TI - miR-483 inhibits bovine myoblast cell proliferation and differentiation via IGF1/PI3K/AKT signal pathway. AB - MicroRNAs (miRNAs) have been established to regulate skeletal muscle development in mammals. However, few studies have been conducted on the regulation of proliferation and differentiation of bovine myoblast cells by miRNAs. The aim of our study was to explore the function of miR-483 in cell proliferation and differentiation of bovine myoblast. Here, we found that miR-483 declined in both proliferation and differentiation stages of bovine myoblast cells. During the proliferation phase, the overexpression of miR-483 downregulated the cell cycle associated genes cyclin-dependent kinase 2 (CDK2), proliferating cell nuclear antigen (PCNA) messenger RNA (mRNA), and the protein levels. At the cellular level, cell cycle, cell counting kit-8, and 5-ethynyl-2'-deoxyuridine results indicated that the overexpression of miR-483 block cell proliferation. During differentiation, the overexpression of miR-483 led to a decrease in the levels of the myogenic marker genes MyoD1 and MyoG mRNA and protein. Furthermore, the immunofluorescence analysis results showed that the number of MyHC-positive myotubes was reduced. In contrast, the opposite experimental results were obtained concerning both proliferation and differentiation after the inhibition of miR-483. Mechanistically, we demonstrated that miR-483 target insulin-like growth factor 1 (IGF1) and downregulated the expression of key proteins in the PI3K/AKT signaling pathway. Altogether, our findings indicate that miR-483 acts as a negative regulator of bovine myoblast cell proliferation and differentiation. PMID- 30422323 TI - Arthrocentesis in the management of internal derangement of the temporomandibular joint. AB - BACKGROUND: Temporomandibular disorders (TMD) cover a wide spectrum of disorder; myalgic, arthralgic and psychogenic. The procedure of TMJ arthrocentesis has a role in managing patients with arthralgic pain and limitation if they fail to respond to non-surgical therapy. METHOD: The patient records of a single private specialist OMS were searched over the nine year period of 2006-2014 to identify patients who had arthrocentesis as part of their multidisciplinary management. The detailed demographic, diagnosis, pre and post arthrocentesis procedure were identified and put on a database. Appropriate statistics were performed. RESULTS: Seventy six patients had 115 arthrocentesis procedures performed in the study period. Fifty of 76 had improvement in their pain and 16 of 41 had an increased jaw opening of more than 10mm. There was no complications or morbidity. Analysis of patient variables generally showed no correlations. CONCLUSIONS: Temporomandibular joint arthrocentesis has a role in the multidisciplinary, multimodality treatment of arthralgic TMD. This article is protected by copyright. All rights reserved. PMID- 30422325 TI - Moonlight enhances growth in larval fish. AB - Moonlight mediates trophic interactions and shapes the evolution of life-history strategies for nocturnal organisms. Reproductive cycles and important life history transitions for many marine organisms coincide with moon phases, but few studies consider the effects of moonlight on pelagic larvae at sea. We evaluated effects of moonlight on growth of pelagic larvae of a temperate reef fish using 'master chronologies' of larval growth constructed from age-independent daily increment widths recorded in otoliths of 321 individuals. We found that daily growth rates of fish larvae were enhanced by lunar illumination after controlling for the positive influence of temperature and the negative influence of cloud cover. Collectively, these results indicate that moonlight enhances growth rates of larval fish. This pattern is likely the result of moonlight's combined effects on foraging efficiency and suppression of diel migrations of mesopelagic predators, and has the potential to drive evolution of marine life histories. This article is protected by copyright. All rights reserved. PMID- 30422324 TI - Key microRNAs in the biology of breast cancer; emerging evidence in the last decade. AB - microRNAs (miRNAs) are a family of small noncoding RNAs that play a pivotal role in the regulation of main biological and physiological processes, including cell cycle regulation, proliferation, differentiation, apoptosis, stem cell maintenance, and organ development. Dysregulation of these tiny molecules has been related to different human diseases, such as cancer. It has been estimated that more than 50% of these noncoding RNA sequences are placed on fragile sites or cancer-associated genomic regions. After the discovery of the first specific miRNA signatures in breast cancer, many studies focused on the involvement of these small RNAs in the pathophysiology of breast tumors and their possible clinical implications as reliable prognostic biomarkers or as a new therapeutic approach. Therefore, the present review will focus on the recent findings on the involvement of miRNAs in the biology of breast cancer associated with their clinical implications. PMID- 30422326 TI - Older melanoma patients may respond better to anti-PD1 immunotherapy. PMID- 30422327 TI - Lifestyle-related cancers increase, highlight need for prevention. PMID- 30422328 TI - US Food and Drug Administration considers comments on proposed nicotine product regulations: Some criticize the agency for not moving fast enough to stop youth e cigarette use. PMID- 30422329 TI - Fluid biomarkers for frontotemporal dementias. AB - Frontotemporal dementias (FTDs) are clinically, genetically and pathologically heterogeneous neurodegenerative disorders that affect the frontal and anterior temporal lobes of the brain. They are relatively common causes of young-onset dementia and usually present with behavioural disturbance (behavioural variant FTD) or language impairment (primary progressive aphasia), but there is also overlap with motor neurone disease and the atypical parkinsonian disorders, corticobasal syndrome and progressive supranuclear palsy. At post mortem, neuronal inclusions containing tau, TDP-43 or infrequently FUS protein are seen in most cases. However, a poor correlation between clinical syndrome and underlying pathology means that it is difficult to diagnose the underlying molecular basis using clinical criteria. At this point, biomarkers for the underlying pathology come into play. This paper provides a brief update on fluid biomarkers for FTDs that may be useful to dissect the underlying molecular changes in patients presenting with signs of frontal and/or temporal lobe dysfunction. The hope is that such biomarkers, together with genetics and imaging, would be useful in clinical trials of novel drug candidates directed against specific pathologies and, in the long run, helpful in clinical practice to select the most appropriate treatment at the right dose for individual patients. PMID- 30422330 TI - Protease-deficient SOS constitutive cells have RecN-dependent cell division phenotypes. AB - In Escherichia coli, after DNA damage, the SOS response increases the transcription (and protein levels) of approximately 50 genes. As DNA repair ensues, the level of transcription returns to homeostatic levels. ClpXP and other proteases return the high levels of several SOS proteins to homeostasis. When all SOS genes are constitutively expressed and many SOS proteins are stabilized by the removal of ClpXP, microscopic analysis shows that cells filament, produce mini-cells and have branching protrusions along their length. The only SOS gene required (of 19 tested) for the cell length phenotype is recN. RecN is a member of the Structural Maintenance of Chromosome (SMC) class of proteins. It can hold pieces of DNA together and is important for double-strand break repair (DSBR). RecN is degraded by ClpXP. Overexpression of recN+ in the absence of ClpXP or recN4174 (A552S, A553V), a mutant not recognized by ClpXP, produce filamentous cells with nucleoid partitioning defects. It is hypothesized that when produced at high levels during the SOS response, RecN interferes with nucleoid partitioning and Z-Ring function by holding together sections of the nucleoid, or sister nucleoids, providing another way to inhibit cell division. PMID- 30422331 TI - Genomic dissection of pod shattering in common bean: mutations at nonorthologous loci at the basis of convergent phenotypic evolution under domestication of leguminous species. AB - The complete or partial loss of shattering ability occurred independently during the domestication of several crops. Thus, the study of this trait can provide an understanding of the link between phenotypic and molecular convergent evolution. The genetic dissection of 'pod shattering' in Phaseolus vulgaris is achieved here using a population of introgression lines and next-generation sequencing techniques. The 'occurrence' of the indehiscent phenotype (indehiscent vs. dehiscent) depends on a major locus on chromosome 5. Furthermore, at least two additional genes are associated with the 'level' of shattering (number of shattering pods per plant: low vs. high) and the 'mode' of shattering (nontwisting vs. twisting pods), with all of these loci contributing to the phenotype by epistatic interactions. Comparative mapping indicates that the major gene identified on common bean chromosome 5 corresponds to one of the four quantitative trait loci for pod shattering in Vigna unguiculata. None of the loci identified comprised genes that are homologs of the known shattering genes in Glycine max. Thus, although convergent domestication can be determined by mutations at orthologous loci, this was only partially true for P. vulgaris and V. unguiculata, which are two phylogenetically closely related crop species, and it was not the case for the more distant P. vulgaris and G. max. Conversely, comparative mapping suggests that the convergent evolution of the indehiscent phenotype arose through mutations in different genes of the same underlying gene networks that are involved in secondary cell-wall biosynthesis and lignin deposition patterning at the pod level. This article is protected by copyright. All rights reserved. PMID- 30422332 TI - Ultrafast Sodium/Potassium-Ion Intercalation into Hierarchically Porous Thin Carbon Shells. AB - The large-scale application of sodium/potassium-ion batteries is severely limited by the low and slow charge storage dynamics of electrode materials. The crystalline carbons exhibit poor insertion capability of large Na+ /K+ ions, which limits the storage capability of Na/K batteries. Herein, porous S and N co doped thin carbon (S/N@C) with shell-like (shell size ~20-30 nm, shell wall ~8-10 nm) morphology for enhanced Na+ /K+ storage is presented. Thanks to the hollow structure and thin shell-wall, S/N@C exhibits an excellent Na+ /K+ storage capability with fast mass transport at higher current densities, leading to limited compromise over charge storage at high charge/discharge rates. The S/N@C delivers a high reversible capacity of 448 mAh g-1 for Na battery, at the current density of 100 mA g-1 and maintains a discharge capacity up to 337 mAh g-1 at 1000 mA g-1 . Owing to shortened diffusion pathways, S/N@C delivers an unprecedented discharge capacity of 204 and 169 mAh g-1 at extremely high current densities of 16 000 and 32 000 mA g-1 , respectively, with excellent reversible capacity for 4500 cycles. Moreover, S/N@C exhibits high K+ storage capability (320 mAh g-1 at current density of 50 mA g-1 ) and excellent cyclic life. PMID- 30422333 TI - Sex- and sub region-dependent modulation of arcuate kisspeptin neurons by vasopressin and vasoactive intestinal peptide. AB - A population of kisspeptin neurons located in the hypothalamic arcuate nucleus (ARN) very likely represent the gonadotrophin-releasing hormone pulse generator responsible for driving pulsatile luteinizing hormone secretion in mammals. As such, it has become important to understand the neural inputs that modulate the activity of ARN kisspeptin (ARNKISS ) neurons. Using a transgenic GCaMP6 mouse model allowing the intracellular calcium levels (i[Ca2+ ]) of individual ARNKISS neurons to be assessed simultaneously, we examined whether the circadian neuropeptides vasoactive intestinal peptide (VIP) and arginine vasopressin (AVP) modulated the activity of ARNKISS neurons directly. To validate this methodology, we initially evaluated the effects of neurokinin B (NKB) on i[Ca2+ ] in kisspeptin neurons residing within the rostral, middle and caudal ARN subregions of adult male and female mice. All experiments were undertaken in the presence of tetrodotoxin and ionotropic amino acid antagonists. NKB was found to evoke an abrupt increase in i[Ca2+ ] in 95-100% of kisspeptin neurons throughout the ARN of both sexes. In marked contrast, both VIP and AVP were found to primarily activate kisspeptin neurons located in the caudal ARN of female mice. Whereas 58 and 59% of caudal ARN kisspeptin neurons responded to AVP and VIP, respectively, in female mice, only 0-8% of kisspeptin neurons located in other ARN subregions responded in females and 0-12% of cells in any subregion in males (p<0.05). These observations demonstrate unexpected sex differences and marked heterogeneity in functional neuropeptide receptor expression amongst ARNKISS neurons organized on a rostro-caudal basis. The functional significance of this unexpected influence of VIP and AVP on ARNKISS neurons remains to be established. This article is protected by copyright. All rights reserved. PMID- 30422334 TI - Effect of racing on blood variables in Standardbred horses. AB - BACKGROUND: Blood is collected for hematologic and biochemical analyses when racehorses perform poorly. However, racing affects most analyte levels; therefore, the timing of blood sampling can affect analyte levels and interpretations. OBJECTIVE: This study aimed to determine if the blood variable levels returned to pre-racing levels 2 and 3 days post-racing. METHODS: Blood was sampled from 17 healthy racehorses pre- and post-racing. The variables measured from plasma were albumin, cholesterol, creatinine, calcium (Ca), phosphorus (P), magnesium (Mg), sodium (Na), potassium (K), creatine phosphokinase (CK), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), gamma-glutamyl transferase (GGT), and cortisol. Hematocrit (HCT), hemoglobin (HGB), white blood cell (WBC), red blood cell (RBC), granulocyte, and lymphocyte counts were analyzed from blood collected in EDTA-coated vials. RESULTS: Calcium was lower 3 days post-racing compared with 2 days pre-racing (P < 0.01), P and GGT were higher 2 and 3 days post-racing compared with those at the pre-racing timepoints (P <= 0.01), and RBC, HCT, and HGB were higher 2 days post-racing compared with those at the pre-racing and 3-day post-racing time points (P < 0.01, all). CONCLUSIONS: A few blood biochemical and hematologic variables were significantly altered 2 and 3 days post-racing. The level of these changes did not affect the clinicopathologic interpretation of the values. PMID- 30422335 TI - Drug sales confirm clinical advantage of multi-target inhibition of drug escapes by anticancer kinase inhibitors. AB - Hit, Lead & Candidate Discovery The clinical advantage of co-targeting cancer drug escape has been indicated by the percentage of these co-targeting drugs among all multi-target drugs in clinics and clinical trials. This clinical advantage needs to be further interrogated from such perspectives as the clinical impact of multi-target inhibition of drug-escape mediators. This impact may be reflected by drug sales data, that is, multi-target inhibition of higher number of drug-escape mediators favors the expanded coverage of drug-resistant patients leading to higher sales. We investigated whether this expectation is followed by the 25 FDA-approved anticancer kinase inhibitors, which were divided into 11 groups of comparable therapeutic mechanisms and approval years. We found 19 (76%) drugs to follow and 3 (12%) drugs not to follow this expectation. The remaining two (8%) and one (4%) drugs cannot be assessed due to insufficient data and incomparability. Therefore, drug sales strongly indicate the clinical advantage of multi-target inhibition of cancer drug escapes. PMID- 30422336 TI - Biomechanical properties of plate constructs for feline ilial fracture gap stabilization. AB - OBJECTIVE: To determine the biomechanical properties of plating techniques for comminuted feline ilial fractures. STUDY DESIGN: Ex vivo study on 40 paired feline hemipelves. SAMPLE POPULATION: Forty paired fresh-frozen hemipelves that had been collected from 20 cats aged 2-6 years and weighing 4.0-5.5 kg. METHODS: A transverse 3-mm gap was created in each ilium. Hemipelves were fixed with one of the following methods (n = 10 per group): (1) a dorsal plate and nonlocking screws, (2) a lateral plate and nonlocking screws, (3) a lateral plate and locking screws, or (4) a lateral and dorsal locking compression plate using nonlocking screws. Each specimen was subjected to incremental, sinusoidal cyclic loading until failure, defined as 10-mm displacement. The initial stiffness and number of cycles required to reach 1-, 2-, 5-, and 10-mm axial displacement were statistically analyzed. RESULTS: The initial stiffness and number of cycles to failure were higher in specimens fixed with double nonlocking plates than in all other fixations (P < .05) except specimens fixed with lateral locking plate at 10 mm displacement (P = .44). Locking implants withstood more cycles to 5- (P < .05) and 10-mm (P < .05) displacement compared with other single-plate nonlocking groups. Screw loosening occurred only in the 3 nonlocking fixations. CONCLUSION: Double plating improved stiffness and resistance to failure of comminuted feline ilial fracture constructs compared with all other fixations. Single locking plates produced superior constructs compared with single nonlocking constructs. CLINICAL SIGNIFICANCE: Locking implants are recommended to repair comminuted feline ilial fractures for their extended fatigue life and resistance to screw loosening. Orthogonal plating offers a strong nonlocking alternative. PMID- 30422337 TI - Non-invasive imaging in dermatology and the unique potential of Raster-Scan Optoacoustic Mesoscopy (RSOM). AB - In recent years, several non-invasive imaging methods have been introduced to facilitate diagnostics and therapy monitoring in dermatology. The microscopic imaging methods are restricted in their penetration depth, while the mesoscopic methods probe deeper but provide only morphological, not functional, information. "Raster-scan optoacoustic mesoscopy" (RSOM), an emerging new imaging technique, combines deep penetration with contrast based on light absorption, which provides morphological, molecular, and functional information. Here we compare the capabilities and limitations of currently available dermatological imaging methods and highlight the principles and unique abilities of RSOM. We illustrate the clinical potential of RSOM, in particular for non-invasive, high-resolution diagnosis and monitoring of inflammatory and oncological skin diseases. This article is protected by copyright. All rights reserved. PMID- 30422338 TI - Melasma: Updates and Perspectives. AB - Management of melasma is highly challenging due to inconsistent treatment results and frequent relapses. However, recent studies revealed that melasma may not only be a disease of melanocytes, but also a photoaging skin disorder. Herein, we attempt to validate that melasma is indeed a photoaging disorder by presenting the histopathologic findings of melasma: solar elastosis, altered basement membrane, increased vascularization, and increased mast cell count. We also provide some therapeutic implications based on these findings and a discussion on the latest updates and perspectives regarding treatment. This article is protected by copyright. All rights reserved. PMID- 30422339 TI - Serrated Protein Acidic And Rich In Cysteine (SPARC) Gene Variants: Impact On Susceptibility & Survival Of HCC Patients. AB - BACKGROUND: Secreted protein acidic and rich in cysteine (SPARC) is a glycoprotein involved in extracellular matrix (ECM) remodeling which regulates cell growth. It could be involved in hepatic fibrogenesis related to chronic inflammations, hepatocellular carcinoma (HCC) angiogenesis, and tumor progression. AIM: We aimed to study the expressions of single nucleotide polymorphisms (SNPs) in the SPARC gene and their impact on susceptibility and survival of HCC patients. PATIENTS AND METHODS: We conducted a case-control study on 200 HCC patients and 50-matched healthy controls. All patients were subjected to laboratory investigations, ultrasound and Real-time Polymerase chain reaction (RT-PCR) to detect the genetic polymorphisms (rs3210714, rs11950384, and rs7719521) in the SPARC gene in blood. RESULTS: 160(80%) of patients were men with a mean age of 43 years. The SPARC gene showed a significant higher prevalence of rs3210714 mutation (i.e., AA or AG) and a significant lower prevalence of rs11950384 mutation (i.e., AA or AC) among HCC patients in comparison to controls (83% vs. 22%, p=<0.001) and (65.5 vs. 86%, p 0.005) respectively, while rs7719521 mutation did not reach significance. On univariate and multivariate analysis, elder age and having at least one copy of the mutant rs3210714 were associated with a significantly increased risk of HCC (p<0.001 for both). Whereas the presence of at least one copy of the mutant rs11950384 carried a significantly reduced risk of having HCC (p<0.01). Overall survival did not differ significantly between any of the SPARC gene mutation groups. CONCLUSIONS: The SPARC gene polymorphisms had a diverse impact on the susceptibility of HCC due to its ability to inhibit or promote tumor progression. SPARC gene polymorphisms were not related to survival of our HCC patients, probably this needs further analysis of other SPARC gene nucleotides. PMID- 30422340 TI - Tattoos among elite football players during the 2018 FIFA World Cup Russia. AB - Currently 10 to 30% of the general population has tattoos. Professional athletes harbor visible tattoos during sports events and advertisement. Motivations for tattoos may include body embellishment, expression of personal values or group affiliation. Tattoos may bolster ego, be the expression of physical strength and of traits of aggression and rebelliousness. We wondered whether being tattooed reflects players' performance and discipline. We investigated this hypothesis among elite football players during the 2018 FIFA World Cup. This article is protected by copyright. All rights reserved. PMID- 30422341 TI - Sunflower resistance to multiple downy mildew pathotypes revealed by recognition of conserved effectors of the oomycete Plasmopara halstedii. AB - Over the last forty years, new sunflower downy mildew isolates (Plasmopara halstedii) have overcome major gene resistances in sunflower, requiring the identification of additional and possibly more durable broad-spectrum resistances. 354 RXLR effectors defined in silico from our new genomic data were classified in a network of 40 connected components sharing conserved protein domains. Among 205 RXLR effector genes encoding conserved proteins in 17 P. halstedii pathotypes of varying virulence, we selected 30 effectors that were expressed during plant infection, as potentially essential genes to target broad spectrum resistance in sunflower. The transient expression of the 30 core effectors in sunflower and in Nicotiana benthamiana leaves revealed a wide diversity of targeted subcellular compartments, including organelles not so far shown to be targeted by oomycete effectors such as chloroplasts and processing bodies. More than half of the 30 core effectors were able to suppress Pattern Triggered Immunity in N. benthamiana, and five of them induced hypersensitive responses (HR) in sunflower broad-spectrum resistant lines. HR triggered by PhRXLRC01 co-segregated with Pl22 resistance in F3 populations and both traits localized in 1.7 Mb on chromosome 13 of the sunflower genome. Pl22 resistance was physically mapped on the sunflower genome recently sequenced, unlike all the other downy mildew resistances published so far. PhRXLRC01 and Pl22 are proposed as an Avirulence/Resistance gene couple not previously described in sunflower. Core effector recognition is a successful strategy to accelerate broad-spectrum resistance gene identification in complex crop genomes such as sunflower. This article is protected by copyright. All rights reserved. PMID- 30422342 TI - Comparison of Endoscopic Ultrasound Tissue Acquisition Methods for Genomic Analysis of Pancreatic Cancer. AB - BACKGROUND AND AIM: Tumor genotyping may allow for improved prognostication and targeted therapy for pancreatic adenocarcinoma (PDAC). We aimed to compare endoscopic ultrasonography (EUS) with fine needle aspiration (FNA) to fine needle biopsy (FNB) for obtaining sufficient tissue for genomic analysis and theranostic potential. METHODS: A retrospective cohort study of patients undergoing EUS-FNA and EUS-FNB with either positive or suspicious cytology for PDAC between March 2016 and December 2017. Demographic, procedural, and cytology data were recorded. Genetic alterations were recorded and Kaplan-Meier survival curves were calculated. RESULTS: The study included 167 patients, 145 patients had FNA and 22 patients underwent FNB. Overall, 117 samples (70.1%) were sufficient for targeted next-generation sequencing. FNB resulted in a higher proportion of patients with sufficient samples compared to FNA (90.9% vs 66.9%, P = 0.02). In multivariable modeling, only FNB (OR 4.95, 95% CI 1.11 - 22.05, P = 0.04) was associated with sufficient sampling for genomic testing. FNB was more likely to obtain sufficient tissue from tumors < 3cm (100% vs. 68.4%, P = 0.017) and tumors located in the head/neck of the pancreas (100% vs. 63.1%, P = 0.03) compared to FNA. The most commonly identified alterations were in KRAS (88%), TP53 (68%), and SMAD4 (16%). CONCLUSIONS: EUS can reliably obtain sufficient tissue from PDAC for targeted genomic sequencing for prognostication and theranostics. FNB should be considered when tumor genotyping is requested, especially for tumors <3 cm or tumors located in the head/neck of the pancreas. PMID- 30422343 TI - Blood pressure target for the dialysis patient. AB - The appropriate blood pressure (BP) target for dialysis patients remains controversial. Although there have been remarkable advances in this area in the general population, extrapolation of these data to dialysis patients is not possible. Observational studies in dialysis patients suggest that low BP is associated with worse outcomes. However, this is likely a result of confounding, considering that among dialysis patients with fewer cardiovascular comorbidities and longer survival, a more linear relationship exists between BP and mortality. Use of home BP measurements and ambulatory blood pressure monitoring (ABPM) measurements are more useful from a prognostic standpoint than in-center predialysis BP measurements. Large clinical trial data are, however, lacking and firm recommendations on BP targets for dialysis patients are not possible. PMID- 30422344 TI - Oral Hygiene of Children with Cleft Lip and Palate: Efficacy of the Cleft Toothbrush - a Designed Add-on to Regular Toothbrushes. AB - BACKGROUND: The anatomical and morphological alterations associated with cleft lip and palate (CLP) favor the buildup of dental plaque. AIM: To assess the efficacy of a new add-on to regular toothbrush - the Cleft toothbrush, in removing the dental plaque of CLP patients, compared to a regular Toothbrush. DESIGN: Forty-five children with CLP were randomly organized into two groups: A (n=26, 2-6 years old) and B (n=19, 7-12 years old). They were evaluated at days 0, 15, 30 and 60. After brushing their teeth with a regular toothbrush or with the Cleft Toothbrush, the dental plaque was recorded using an adapted Plaque Index (aPI). Data analyses were performed in IBM SPSS(c) and all statistic inference comparisons were made using non-parametric tests. RESULTS: In the first 15 days, children used a new regular toothbrush and aPI-C (teeth adjacent to the cleft) was recorded. The Cleft Toothbrush, used by all children from day 15 to day 30, showed high efficacy in removing dental plaque in the cleft area, evidenced by significantly lower aPI-C values, compared to those observed with the regular toothbrush (p<0.001). When given free option of brushing technique, from day 30 to day 60, most of the children (38 out of 45) chose the Cleft Toothbrush. CONCLUSIONS: The Cleft Toothbrush showed high efficacy in removing dental plaque in the cleft area, and presented high level of acceptance by parents and children, compared to a regular toothbrush. This is expected to improve the health status of the local adjacent tissues, a requirement for their rehabilitation. This article is protected by copyright. All rights reserved. PMID- 30422345 TI - A systematic review on risk factors in developing a first time Venous Leg Ulcer. AB - Venous Leg Ulcers (VLU) occur in about 1% of the Western population. A VLU takes three to twelve months to heal, it recurs often, and it has a negative impact on the quality of life. The risk factors for the development of a first VLU are not well-understood and prevention of a first VLU therefore remains underappreciated. The aim of this study is to identify risk factors for developing a first VLU in adults (aged >18 years) by searching the literature. We searched the Cochrane Library, Pubmed, Cinalh, and Narcis to identify studies that investigated risk factors in developing a VLU. The last search was performed in January 2018. Two reviewers independently reviewed the abstracts and full-text articles, and assessed the methodological quality of the included studies. Results of studies using duplex scanning, and comparing participants with and without VLUs were included in the qualitative analysis. Where possible a quantitative meta-analysis was conducted. We found five studies that investigated the relation of several risk factors with VLU development. The methodological differences of the studies made it impossible to perform a quantitative analysis. The risk factors: higher age (four studies), higher Body Mass Index (four studies), low physical activity (four studies), arterial hypertension (four studies), deep vein reflux (three studies), deep venous thrombosis (three studies) and family history of VLU (three studies) were significantly associated with a VLU in the majority of the studies. To what extent they influence the development of a VLU remains unclear because of the limited number of studies that investigated the association of these risk factors with VLU development, and the heterogeneity of these studies. Further studies are needed to confirm the association of these risk factors with the development of a VLU and to explore overweight and low physical activity in more detail. This article is protected by copyright. All rights reserved. PMID- 30422346 TI - Nanoscale Behavior and Manipulation of the Phase Transition in Single-Crystal Cu2 Se. AB - Phase transition is a fundamental physical phenomenon that has been widely studied both theoretically and experimentally. According to the Landau theory, the coexistence of high- and low-temperature phases is thermodynamically impossible during a second-order phase transition in a bulk single crystal. Here, the coexistence of two (alpha and beta) phases in wedge-shaped nanosized single crystal Cu2 Se over a large temperature range are demonstrated. By considering the surface free-energy difference between the two phases and the shape effect, a thermodynamic model is established, which explicitly explains their coexistence. Intriguingly, it is found that with a precise control of the heating temperature, the phase boundary can be manipulated at atomic level. These discoveries extend the understanding of phase transitions to the nanoscale and shed light on rational manipulation of phase transitions in nanomaterials. PMID- 30422347 TI - The ABCs of CRISPR in Tephritidae: Developing methods for inducing heritable mutations in the genera Anastrepha, Bactrocera, and Ceratitis. AB - Tephritid fruit flies are destructive agricultural pests that are the targets of expensive population eradication and suppression efforts. Genetic pest management is one of the strategies for reducing or eliminating tephritid populations, relying upon the genetic manipulation of insects to render them sterile or capable of transmitting deleterious traits through gene drive. Currently, radiation, chemical mutagenesis, and transgenic techniques are employed to generate agents for genetic pest management, but new methods must be explored and developed for all tephritid pest species. Targeted mutagenesis induced by non homologous end join repair of CRISPR/Cas9 nuclease has been demonstrated to be an efficient method for creating knock-out mutants and can be utilized to create germline mutations in Tephritidae. In this manuscript, we describe detailed methods to knockout the white gene in three tephritid species in the genera Anastrepha, Bactrocera, and Ceratitis, including the first demonstration of CRISPR/Cas9 induced mutations in the genus Anastrepha. Lastly, we discuss the variables in tephritid systems that directed method development as well as recommendations for performing injections in remote containment facilities with little molecular biology capabilities. These methods and recommendations combined can serve as a guide for others to use in pursuit of developing CRISPR/Cas9 methods in tephritid systems. This article is protected by copyright. All rights reserved. PMID- 30422348 TI - Urinary proteomics: fancy gadgetry or a clinically useful diagnostic instrument? The end-user's perspective. AB - Late deterioration of kidney function is a major challenge in transplantation medicine, thus early detection of subclinical kidney damage is of outstanding importance. Conventional laboratory parameters such as declining kidney function assessed by serum creatinine or creatinine clearance and proteinuria are late indicators of an already established damage. While urine properties have long been the subject of medical investigations, classical parameters based on physico chemical properties and microscopic analysis remain far from helpful for establishing a refined etiological diagnosis and generally do not indicate the stage of kidney disease. This article is protected by copyright. All rights reserved. PMID- 30422349 TI - Dermoscopic features of psoriasis of the skin, scalp and nails - A systematic review. AB - Dermoscopy is a non-invasive in-office method, which enables the diagnosis of many dermatoses and reduces the need for performing biopsies. To date, no systematic review about the diagnostic usability of dermoscopy in psoriasis has been available. The objective of this article is to summarize and critically analyze literature data on the dermoscopy of skin, scalp and nail changes in psoriasis. A systematic search of three medical databases was performed. A total of 45 articles were included into the analysis. Cutaneous psoriatic lesions assessed in all studies at a low magnification showed regularly distributed red dots. At a 50-fold or higher magnification capillary bushes (glomerular vessels) with a diameter range of 50-146 MUm were observed. The background color was described as reddish or pinkish with white or yellowish scales. The most frequent dermoscopic (trichoscopic) feature of scalp psoriasis was the presence of red dots/globules and twisted red loops. Typical dermoscopic (onychoscopic) signs of nail psoriasis were onycholysis, salmon patches and splinter hemorrhages. There is an accumulating body of evidence that dermoscopy (both handheld and videodermoscopy) is a useful tool in differential diagnosis in doubtful cases of psoriasis of the skin, scalp, nails, palms, soles, and genital regions. This article is protected by copyright. All rights reserved. PMID- 30422350 TI - Epidermolysis bullosa-specific module of the Infants and Toddlers Dermatology Quality of Life (InToDermQoL) questionnaire. AB - BACKGROUND: Epidermolysis bullosa (EB) may have severe impact on different aspects of patients' life. Until now there was no EB-specific quality of life (QoL) instrument for young children. OBJECTIVE: To create EB-specific proxy module of the Infants and Toddlers Dermatology Quality of Life (InToDermQoL) questionnaire. METHODS: Focus groups with parents of children with EB were organized. Parents of EB children were interviewed by the project staff with regard to their perception of QoL issues of the skin disease of their children. RESULTS: Focus groups with parents of EB children in Ukraine and Romania were organized. Parents represented eight boys and 12 girls from 3 months to 4 years old with different EB types and disease severity. Based on the analysis of focus groups' results, two EB specific items that were not mentioned by parents of children with other skin diseases and therefore were not included to the dermatology-specific InToDermQoL questionnaire were developed: 'problems with defecation' and 'problems with shoes'. These problems were mentioned by 55% of all parents and 11.76% of parents that represented EB children older than 1 year, respectively. CONCLUSION: We want to invite other centres and EB related organizations to join our project starting from the pilot test. There are many different reasons why QoL measurement is important in dermatology clinical practice and our goal is practical use of the instrument in children with EB. PMID- 30422351 TI - Defining the in vivo characteristics of acute myeloid leukemia cells behavior by intravital imaging. AB - The majority of acute myeloid leukemia (AML) patients have a poor response to conventional chemotherapy. The survival of chemoresistant cells is thought to depend on leukemia-bone marrow (BM) microenvironment interactions, which are not well understood. The CXCL12/CXCR4 axis has been proposed to support AML growth but was not studied at the single AML cell level. We recently showed that T-cell lymphoblastic leukemia (T-ALL) cells are highly motile in the BM; however, the characteristics of AML cell migration within the BM remain undefined. Here, we characterize the in vivo migratory behavior of AML cells and their response to chemotherapy and CXCR4 antagonism, using high-resolution 2-photon and confocal intravital microscopy of mouse calvarium BM and the well-established MLL-AF9 driven AML mouse model. We used the Notch1-driven T-ALL model as a benchmark comparison and AMD3100 for CXCR4 antagonism experiments. We show that AML cells are migratory, however, and in contrast with T-ALL, chemoresistant AML cells become less motile. Moreover, and in contrast with T-ALL, the in vivo exploratory behavior of expanding and chemoresistant AML cells is unaffected by AMD3100. These results expand our understanding of AML cells-BM microenvironment interactions, highlighting unique traits of leukemia of different lineages. This article is protected by copyright. All rights reserved. PMID- 30422352 TI - Early-onset and persistent traumatic granuloma of the tongue (Riga-Fede disease) associated with neonatal teeth and Down syndrome. AB - Riga-Fede disease (RFD) is a rare disorder characterized by an ulcerated lesion on the ventral surface of the tongue. It can be seen at any age and has also been referred to as traumatic granuloma of the tongue, eosinophilic granuloma of the tongue, and traumatic ulcerative granuloma with stromal eosinophilia. The sucking reflex, uncontrolled movements of the tongue, and macro-glossy are risk factors facilitating repetitive trauma produced by the teeth. This article is protected by copyright. All rights reserved. PMID- 30422354 TI - Low Valent Magnesium Chemistry with a Super Bulky beta-Diketiminate Ligand. AB - The steric bulk of the well-known DIPP BDI ligand (CH[C(CH3 )N-DIPP]2 , DIPP=2,6 diisopropylphenyl) was increased by replacing isopropyl for isopentyl groups. This very bulky DIPeP BDI ligand could not stabilize the radical species (DIPeP BDI)Mg. : reduction of (DIPeP BDI)MgI with Na gave (DIPeP BDI)2 Mg2 with a rather long Mg-Mg bond of 3.0513(8) A. Addition of TMEDA prior to reduction gave complex (DIPeP BDI)2 Mg2 (C6 H6 ), which could also be obtained as its THF adduct. It is speculated that combination of a bulky spectator ligand and TMEDA prevents dimerization of the intermediate MgI radical, which then reacts with the benzene solvent. Complex (DIPeP BDI)2 Mg2 (C6 H6 ), which formally contains the anti aromatic anion C6 H6 2- , reacted with tBuOH as a Bronsted base to 1,3- and 1,4 cyclohexadiene and with H2 as a two electron donor to (DIPeP BDI)2 Mg2 H2 and C6 H6 . It also reductively cleaved the C-F bond in fluorobenzene and gave (DIPeP BDI)MgPh, (DIPeP BDI)MgF, and C6 H6 . PMID- 30422353 TI - Heterogeneity in alpha-synuclein subtypes and their expression in cortical brain tissue lysates from Lewy body diseases and Alzheimer's disease. AB - AIMS: Lewy body diseases are neuropathologically characterized by the abnormal accumulation of alpha-synuclein (alpha-syn) protein within vulnerable neurons. Although studies have evaluated alpha-syn in post mortem brain tissue, previous findings have been limited by typically employing pan-alpha-syn antibodies that may not recognize disease-relevant forms of protein. We investigated the presence of alpha-syn species present in post mortem brain tissues from Lewy body disease and Alzheimer's disease. METHODS: Soluble and insoluble/aggregated alpha-syn from frontal cortex of post mortem brain tissues form Parkinson's disease (PD), dementia with Lewy bodies (DLB), Alzheimer's disease (AD) and aged control cases were sequentially extracted using buffers with increasing detergent concentrations. Enzyme-linked immunosorbent assay (ELISA) was used to quantify the levels of total-, oligomeric- and phosphorylated-Ser129-alpha-syn (t-, o- and pS129-alpha-syn). ELISA data were validated by western blot and compared to histological data from the same region of the contralateral hemisphere. RESULTS: There was no difference in t-alpha-syn levels between groups in the aqueous soluble, detergent-soluble or urea-soluble tissue fractions. However, aqueous soluble non-phosphorylated o-alpha-syn was increased not only in PD and DLB but also in AD without neocortical Lewy bodies. In PD and AD, pS129-alpha-syn was increased in the detergent-soluble tissue fragment and, in AD, this was positively correlated with the burden of tau pathology. Increased levels of urea soluble pS129-alpha-syn were demonstrated only in DLB tissue lysates but this did not correlate with Lewy body pathological burden. CONCLUSIONS: Taken together, these findings suggest that DLB have elevated levels of insoluble pS129-alpha syn, but that increased levels of aqueous-soluble o-alpha-syn and detergent soluble pS129-alpha-syn are also observed in PD and AD, suggesting different changes to alpha-syn across the spectrum of neurodegenerative proteopathies. PMID- 30422355 TI - Effect of osteoarthritis on the repeatability of patella tendon angle measurement in dogs. AB - OBJECTIVE: To evaluate the influence of osteoarthritis on the measurement of patella tendon angle (PTA) and determine intraobserver and interobserver variability. STUDY DESIGN: Retrospective clinical study. SAMPLE POPULATION: Eighty-seven mediolateral radiographs that were obtained prior to tibial tuberosity advancement. METHODS: Radiographic osteoarthritis was scored by 2 observers using guidelines derived from the International Elbow Working Group Protocol. Patella tendon angle was measured by 3 observers on 3 occasions, with at least 7 days between measurements. The data were statistically analyzed via weighted kappa and Kruskal-Wallis testing. RESULTS: A fair strength of agreement was found among observers scoring osteoarthritis, with the same grades in 48% of radiographs. The intraobserver average bias between PTA measurements 1 and 3 ranged from -0.38 degrees to -0.94 degrees . Interobserver bias in angle measurement ranged from -0.92 degrees to -2.00 degrees . Observer 1 had the narrowest range of PTA differences (12.1 degrees ), and observer 3 had the highest range of PTA differences (23.5 degrees ). Observer 2 had the lowest mean bias (-0.38 degrees ). The mean bias was lowest between observers 1 and 2 (-0.92 degrees ) and highest between observers 1 and 3 (-2.0 degrees ). The mean intraobserver standard deviation of the PTA measurement differences was 2.90 degrees , and interobserver standard deviation of the PTA measurement differences was 2.26 degrees . The degree of osteoarthritis did not influence PTA measurements or their variability. CONCLUSION: The current study did not find evidence of an influence of osteoarthritis on PTA or on the repeatability of measurements. CLINICAL SIGNIFICANCE: Our findings suggest that osteoarthritis should not affect the radiographic planning for tibial tuberosity advancement surgery. The high variances in PTA measurement in less experienced observers may influence the clinical outcome of surgery. PMID- 30422356 TI - Two venom allergen-like proteins, HaVAP1 and HaVAP2, are involved in the parasitism of Heterodera avenae. AB - Despite venom allergen-like proteins (VAPs) having been identified in many animal and plant parasitic nematodes, studies on VAPs in Heterodera avenae, which is an important phytonematode, are still in their infancy. Here we isolated, cloned and characterized two VAPs, named HaVAP1 and HaVAP2, from H. avenae. The two encoded proteins, HaVAP1 and HaVAP2, harbour a SCP-like domain each but share only 38% identity with each other. HaVAP1 and HaVAP2 are expressed in subventral esophageal glands and dorsal esophageal gland, respectively. HaVAP1 is expressed mainly at the early stages, whereas HaVAP2 accumulate principally at the late stages. Both HaVAP1 and HaVAP2 are secreted when expressed in Nicotiana benthamiana leaves, but HaVAP1 is delivered into chloroplasts while HaVAP2 is translocated to the nucleus without signal peptides. Knocking down HaVAP1 increased the virulence of H. avenae. In contrast, silencing HaVAP2 hampered the parasitism of H. avenae. Both HaVAP1 and HaVAP2 suppressed the cell death induced by BAX in N. benthamiana leaves. Moreover, HaVAP2 physically interacted with a CYPRO4-like protein (HvCLP) of Hordeum vulgare in the nucleus of plant. It is reasonable to speculate that the changes in the transcript of HvCLP are associated with HaVAP2 during the parasitism of H. avenae. All results obtained in this study show that both HaVAP1 and HaVAP2 are involved in the parasitism of H. avenae, but they possess different functions, broadening our understanding about the parasitic mechanism of H. avenae. This article is protected by copyright. All rights reserved. PMID- 30422357 TI - Urinary albumin excretion in rheumatoid arthritis is not associated with markers of vasculopathy in distal microvascular beds. AB - OBJECTIVE: Increased UAE is a marker of generalized vascular damage in high cardiovascular risk patients. However, it remains unknown whether it corresponds to a state of diffuse vasculopathy in high-risk patients with RA. METHODS: UAE was estimated in 24-hour urine samples in RA and non-RA individuals. Retinal arteriolar and venular diameters were calculated from retinal images with computerized software. SEVR was estimated as an index of microvascular coronary perfusion with applanation tonometry. Dermal capillary density was measured from images obtained with nailfold capillaroscopy, using specifically designed software. RESULTS: In a total of 111 individuals, neither UAE (5.1 [2.8-10.8] vs 6.5 [3.0-11.7] mg/24 h) nor prevalence of microalbuminuria (11.0% vs 8.1%) significantly differed between patients (n = 74) and controls (n = 37). In the RA group, UAE was not significantly associated with inflammation, nor with any of the studied microvascular indices of the retinal microvasculature, the coronary microcirculation, and the dermal capillary network. CONCLUSION: Among RA patients, UAE was not associated with markers of vasculopathy in distal microvascular beds. Increased UAE in RA might be primarily considered as a manifestation of localized, compromised function of the renal microvasculature, rather than a marker of generalized microvascular impairment. PMID- 30422358 TI - Pyranopterin Related Dithiolene Molybdenum Complexes as Homogeneous Catalysts for CO2 Photoreduction. AB - Two original dithiolenes, with a pyrazine ring fused with a pyran ring carrying the dithiolene chelate, mimicking molybdopterin (MPT) present in the active site of formate dehydrogenases (FDHs), have been synthesized. The first one mimicks MPT in the dihydropyrazine form while the second mimicks MPT in the more biologically relevant tetrahydropyrazine form. Both have been structurally characterized as a ligand within a cobalt(cyclopentadienyl)(dithiolene) complex. The corresponding MoO(dithiolene)2 complexes have been also prepared and are reported as the first functional and stable catalysts inspired by the Mo center of FDHs so far: they indeed catalyze the photoreduction of CO2 into formic acid, as the major product, and carbon monoxide, achieving more than 100 turnover numbers in about 8 h. PMID- 30422359 TI - Impaired microvascular reactivity in gestational diabetes is associated with altered glycemic parameters. AB - OBJECTIVES: To assess microvascular reactivity and glycemic parameters in gestational diabetes mellitus (GDM) compared to age and gestational age (GA) matched controls. METHODS: This study involved 21 GDM patients and 31 controls. Microvascular reactivity was assessed using laser Doppler fluximetry and post occlusive skin reactive hyperemia (PORH). Microvascular parameters; PORHmax , PORHpeak , and time to peak perfusion (Tp) were recorded after release of three minutes' upper arm occlusion. Homeostasis model assessment for insulin resistance (HOMA-IR) was performed to evaluate insulin resistance. RESULTS: Average age and GA for subjects were 32.9 years and 29.2 weeks. Mean fasting blood glucose (FBG) and a two-hour postprandial for GDM and controls were 4.87 +/- 0.71 vs 3.99 +/- 0.59 mmol/L; p <0.001 and 9.50 +/- 1.8 vs 5.67 +/- 1.0 mmol/L; p <0.001. Fasting insulin (13.88 +/- 18.9 vs 8.37 +/- 11.0 MUlU/ml; p = 0.031) and HOMA-IR (3.14 +/ 4.6 vs 1.52 +/- 2.2; p = 0.004) were higher in GDM. Tp was prolonged in GDM (16.27 +/- 4.3 vs 13.86 +/- 2.1 sec.; p = 0.011). Positive correlations were seen between Tp and FBG and two-hour postprandial levels. CONCLUSION: Tp was prolonged in GDM compared to age matched controls, indicating impaired microvascular reactivity. This article is protected by copyright. All rights reserved. PMID- 30422360 TI - Measurement of very fast exchange rates of individual amide protons in proteins by NMR spectroscopy. AB - NMR spectroscopy is a pivotal technique to measure hydrogen exchange rates in proteins. However, currently available NMR methods to measure backbone exchange are limited to rates of up to a few per second. To raise this limit, we have developed an approach that is capable of measuring proton exchange rates up to approximately 10^4 s-1. Our method relies on the detection of signal loss due to the decorrelation of antiphase operators 2NxHz by exchange events that occur during a series of pi pulses on the 15N channel. In practice, signal attenuation was monitored in a series of 2D H(CACO)N spectra, recorded with varying pi-pulse spacing, and the exchange rate was obtained by numerical fitting to the evolution of the density matrix. The method was applied to the small calcium-binding protein Calbindin D9k, where exchange rates up to 600 s-1 were measured for amides, where no signal was detectable in 15N-1H HSQC spectra. A temperature variation study allowed us to determine apparent activation energies in the range 47-69 kJ/mol for these fast exchanging amide protons, consistent with hydroxide catalyzed exchange. PMID- 30422361 TI - Nursing resources and major immobility complications among bedridden patients: a multicenter descriptive study in China. AB - BACKGROUND: Being bedridden, which is a common clinical phenomenon, causes a series of complications related to immobilization. Effective management of immobility complications requires a reasonable allocation of nursing resources. Unit-level evidence about the relationship between nursing resources and immobility complications is lacking. OBJECTIVES: To gain insight into nursing resources in China and explore the relationship between nursing resources and the incidence of major immobility complications among bedridden patients. The major immobility complications included in our study were pressure ulcers, deep vein thrombosis, pneumonia, and urinary tract infection. DESIGN: A nationwide, multicenter, cross-sectional survey. SETTING: From November 2015 to June 2016, 18 hospitals (6 tertiary and 12 secondary) from six provinces and cities in different geographic regions (eastern, southern, western, northern, and central) in China participated in our study. PARTICIPANT: Intensive care units, internal medicine and surgery wards with high proportions of bedridden patients were chosen as investigation sites. Of the total of 23,637 patients in the selected wards, 19,530 were recruited. METHODS: Data on nursing resources and ward characteristics were collected mainly by questionnaire. The incidence of major immobility complications among bedridden patients was measured by trained investigators. Data on patient characteristics were collected from the patient record system of each hospital. Multilevel regression analysis was used to estimate the impact of nursing resources on the incidence of major immobility complications, adjusting for patient and ward characteristics. RESULTS: The study included 23,637 patients in 213 wards, and 19,530 were recruited. The incidence of the four complications was 0.77% (pressure ulcers), 0.82% (deep vein thrombosis), 3.39% (pneumonia), and 0.86% (urinary tract infection), and the overall incidence of major immobility complications was 5.41%. The incidence of major immobility complications was higher in wards not attaining the target bed to-nurse ratios than in those that met these criteria (beta=0.44, 95% confidence interval [CI]: 0.02-0.87; OR=1.553, 95% CI: 1.002-2.387). The incidence of major immobility complications was negatively associated with the proportion of nurses with intermediate or senior job titles (beta=-2.12, 95% CI: -3.78--0.45; OR=0.120, 95% CI: 0.023-0.638). However, the incidence of major immobility complications was unexpectedly positively associated with the proportion of nurses with a bachelor's degree or higher (beta=1.06, 95% CI: 0.31-1.81; OR=2.886, 95% CI:1.363-6.110). CONCLUSIONS: Sufficient nurse staffing and higher professional titles of nurses might contribute to reducing the incidence of major immobility complications. Nurse experience was not related to the incidence of major immobility complications. However, the association between nurse education level and the incidence of major immobility complications requires further investigation. This article is protected by copyright. All rights reserved. PMID- 30422362 TI - Inhibition of calcium/calmodulin-dependent protein kinase kinase (CaMKK) exacerbates impairment of endothelial cell and blood-brain barrier after stroke. AB - Brain microvascular endothelial cells play an essential role in maintaining blood brain barrier (BBB) integrity, and disruption of the BBB aggravates the ischemic injury. CaMKK (alpha and beta) is a major kinase activated by elevated intracellular calcium. Previously, we demonstrated that inhibition of CaMKK exacerbated outcomes, conversely, overexpression reduced brain injury after stroke in mice. Interestingly, CaMKK has been shown to activate a key endothelial protector, sirtuin 1 (SIRT1). We hypothesized that CaMKK protects brain endothelial cells via SIRT1 activation after stroke. In this study, Oxygen Glucose Deprivation (OGD) was performed in human brain microvascular endothelial cells. Stroke was induced by middle cerebral artery occlusion (MCAO) in male mice. Knockdown of CaMKK beta using siRNA increased cell death following OGD. Inhibition of CaMKK beta by STO-609 significantly and selectively down-regulated levels of phosphorylated SIRT1 after OGD. Changes in the downstream targets of SIRT1 were observed following STO-609 treatment. The effect of STO-609 on cell viability after OGD was absent, when SIRT1 was concurrently inhibited. We also demonstrated that STO-609 increased endothelial expression of the pro inflammatory proteins ICAM-1 and VCAM-1 and inhibition of CaMKK exacerbated OGD induced leukocyte-endothelial adhesion. Finally, intracerebroventricular injection of STO-609 exacerbated endothelial apoptosis and reduced BBB integrity after 24-hr reperfusion following MCAO in vivo. Collectively, these results demonstrated that CaMKK inhibition reduced endothelial cell viability, exacerbated inflammatory responses and aggravated BBB impairment after ischemia. CaMKK activation may attenuate ischemic brain injury via protection of the microvascular system and a reduction in the infiltration of pro-inflammatory factors. PMID- 30422363 TI - Gas phase hydration of polyethylene glycol-metal cation complexes. PMID- 30422364 TI - Identifying the Constructs of Empowering Nurse Leader Communication Through an Instrument Development Process. AB - AIM: The purpose of this article is to describe the constructs of empowering front-line Nurse Leader communication behaviors. BACKGROUND: Leaders' communication behaviors are instrumental in establishing a positive work environment. Nurse empowerment, a characteristic of a positive work environment, is influenced by communication behaviors. However, characteristics of empowering Nurse Leader communication behaviors have not been well-defined. METHODS: The constructs of empowering Nurse Leader communication behaviors were identified and refined during the instrument development process. A priori constructs were identified through a literature search, presented to focus groups of military nurses (N=16), and refined during the procedures of item development. RESULTS: Eight final constructs emerged as a result of the iterative methods of item development: Comprehensibility, Listening, Openness, Feedback, Empathy, Nonverbal, Paralanguage, and Manner. CONCLUSION: The constructs that describe empowering Nurse Leader communication behaviors are based on theoretical tenets of empowering communication and leadership, as well as the perspectives of military nurses. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse Managers can use the findings to implement innovative leadership assessments and training that focuses on Nurse Leader communication to enhance the nursing workplace environment. This article is protected by copyright. All rights reserved. PMID- 30422365 TI - Could prenatal food insecurity influence neonatal abstinence syndrome severity? AB - BACKGROUND AND AIMS: In general populations, prenatal food insecurity negatively affects maternal and infant health. Our aim was to estimate and test the association between prenatal food insecurity and neonatal abstinence syndrome (NAS) severity. DESIGN/SETTING: Single-site prospective cohort design. Women receiving opioid agonist treatment with methadone or buprenorphine were interviewed (including demographics and food insecurity) during the third trimester at the combined obstetric/opioid use disorder treatment clinic at Boston Medical Center (BMC) in Boston, MA, USA, a large urban safety-net hospital. During postnatal hospitalization, infants were assessed and treated per hospital NAS protocol. Maternal clinic and infant hospitalization data were abstracted from medical records. PARTICIPANTS: Women (n = 75; aged >= 18 years; fluent English; singleton pregnancy; intending to deliver at BMC and maintain parental custody) receiving care in the specialized clinic were study eligible (2013-15). Women who delivered infants < 36 weeks gestational age or required prolonged newborn intensive care unit stay were excluded from analyses. PRIMARY MEASUREMENTS: Predictors: validated two-question Hunger Vital SignTM food insecurity screener; outcomes: extent of NAS pharmacological treatment and length of hospital stay (LOS) for NAS. FINDINGS: Of the mother-infant dyads, 61 (81%) infants were treated pharmacologically for NAS. Mean hospital LOS was 19.9 (standard deviation = 9.4) days. Maternal food insecurity (n = 43, 57.3%) was associated with infant NAS pharmacological treatment in logistic regression analyses individually adjusted for prenatal: maternal depression [adjusted odds ratios (aOR) = 3.69 (95% confidence intervals (CI) = 1.02-13.43, P = 0.05)] and methadone agonist treatment [aOR = 4.17 (95% CI = 1.05-16.50, P = 0.04)]. Associations of food insecurity and LOS were inconclusive regardless of covariate control (P > 0.05). CONCLUSION: Among women receiving opioid agonist treatment, prenatal food insecurity appears to be associated with increased risk for neonatal abstinence syndrome pharmacological treatment. PMID- 30422366 TI - FACE facts hold for multiple generations; Evidence from natural CO2 springs. AB - Rising atmospheric CO2 concentration is a key driver of enhanced global greening, thought to account for up to 70% of increased global vegetation in recent decades. CO2 fertilization effects have further profound implications for ecosystems, food security and biosphere-atmosphere feedbacks. However, it is also possible that current trends will not continue, due to ecosystem level constraints and as plants acclimate to future CO2 concentrations. Future predictions of plant response to rising [CO2 ] are often validated using single generation short-term FACE (Free Air CO2 Enrichment) experiments but whether this accurately represents vegetation response over decades is unclear. The role of transgenerational plasticity and adaptation in the multigenerational response has yet to be elucidated. Here, we propose that naturally occurring high CO2 springs provide a proxy to quantify the multigenerational and long-term impacts of rising [CO2 ] in herbaceous and woody species respectively, such that plasticity, transgenerational effects and genetic adaptation can be quantified together in these systems. In this first meta-analysis of responses to elevated [CO2 ] at natural CO2 springs, we show that the magnitude and direction of change in eight of nine functional plant traits are consistent between spring and FACE experiments. We found increased photosynthesis (49.8% in spring experiments, comparable to 32.1% in FACE experiments) and leaf starch (58.6% spring, 84.3% FACE), decreased stomatal conductance (gs , 27.2% spring, 21.1% FACE), leaf nitrogen content (6.3% spring, 13.3% FACE) and Specific Leaf Area (SLA, 9.7% spring, 6.0% FACE). These findings not only validate the use of these sites for studying multigenerational plant response to elevated [CO2 ], but additionally suggest that long-term positive photosynthetic response to rising [CO2 ] are likely to continue as predicted by single-generation exposure FACE experiments. PMID- 30422367 TI - Intralesional triamcinolone alone or in combination with botulinium toxin A is ineffective for the treatment of formed keloid scar: A double blind controlled pilot study. AB - Cutaneous injury can ignite excessive fibroproliferative growth that results in keloid formation. Keloids are associated with significant morbidity related to disfigurement and/or symptoms (e.g. pain, pruritus). First-line treatment of formed keloids involves topical or intralesional steroids. Recurrent or resistant keloids are managed by surgical excision or cryotherapy, followed by steroidal application or adjuvant irradiation. While adjuvant irradiation appears to be most efficacious, alternative therapeutic options are needed for patients without access to radiation centers. Botulinum Toxin A (BTA) appears to have similar inhibitory effects to irradiation on the cell cycle via downregulation of pathogenic cytokines. Herein, we conducted a study to compare the efficacy of intralesional triamcinolone used alone, or in combination with BTA, in the treatment of formed keloid scars. 20 patients with a cumulative of 40 keloids completed the study. There was no significant difference between treatment arms with respect to height vascularization, pliability and pigmentation scores. The addition of BTA resulted in significant symptomatic improvement of pain and pruritus as compared to intralesional triamcinolone alone (P<0.001). Irradiation is only effective when administered in the adjuvant setting where inhibitory effects on cell cycle and migration are optimized. Future studies with intralesional triamcinolone and BTA should be performed adjuvantly. This article is protected by copyright. All rights reserved. PMID- 30422369 TI - Abstracts from the 34th Annual Meeting of the Histiocyte Society Lisbon, Portugal October 22-23, 2018. PMID- 30422368 TI - Oral esomeprazole in Japanese pediatric patients with gastric acid-related diseases: Safety, Efficacy, and Pharmacokinetics. AB - BACKGROUND: Proton pump inhibitors (PPIs) are widely used for the treatment of gastric acid-related diseases, but they are not approved for use in children in Japan. To assess the safety, pharmacokinetics, pharmacodynamics, and efficacy (gastrointestinal symptom improvement) of PPIs in Japanese pediatric patients with gastric acid-related diseases, we conducted an 8-week, open-label, parallel group, multicenter, phase I/III study of once-daily oral esomeprazole use. METHODS: Japanese children, aged 1-14 years with gastric acid-related diseases, were stratified by weight and age into five groups (10 patients/group) to receive esomeprazole as granules for suspension (10 mg) or capsules (10 mg or 20 mg) once daily. RESULTS: Esomeprazole was absorbed and eliminated rapidly in all groups, with a median tmax of 1.47-1.75 h, an arithmetic mean t1/2 of 0.80-1.37 h, and a weight-correlated CL/F of 0.216-0.343 L/h/kg. AUCtau and Cmax were generally higher in study groups given a higher dose (20 mg) or with a lower age/weight, but also in patients identified as poor metabolizers by cytochrome P450 2C19 genotype. Most patients who had any upper gastrointestinal symptoms at baseline were asymptomatic at the end of the study. Thirty-three patients (66%) reported >=1 adverse events, including three patients that reported serious adverse events not judged to be causally related to esomeprazole. CONCLUSIONS: Oral esomeprazole, at 10 mg or 20 mg once daily, demonstrated a similar safety, efficacy, and pharmacokinetic profile in Japanese pediatric patients to that previously seen in adults and Caucasian children. This article is protected by copyright. All rights reserved. PMID- 30422370 TI - High response and re-infection rates among people who inject drugs treated for hepatitis C in a community needle and syringe programme. AB - To achieve WHO Hepatitis C virus (HCV) elimination targets by 2030, mathematical models suggest there needs to be significant scale-up of treatment among people who inject drugs (PWID). We tested whether people who actively inject drugs can be recruited and treated successfully through a community needle and syringe programme (NSP), and assessed rates of re-infection. 105 HCV RNA positive participants were enrolled prospectively. Participants were recruited from the largest NSP in Dundee over 42 months. 94/105 individuals commenced treatment. Genotype 1 (G1) individuals (n=37) were treated with peg interferon+ribavirin+Simepravir/Telaprevir. Genotype 2/3 (G2/3) (n=57) received peg-interferon+ribavirin. Weekly study visits took place within the NSP. Mean age of participants was 34.0 years (SD 6.9), 71.3% (61/94) were male. 1 in 5 (20/94) participants were homeless. 68.1% (64/94) were on OST (opiate substitution therapy) at enrolment; participants injected median 6.5 times/week. In terms of clinical outcomes, >80% treatment adherence was 71.3% (67/94). There was no difference in SVR-12 rates by Genotype: 81.0% 30/37 for G1 and 82.5% 47/55 for G2/3. At 18-months post-treatment 15/77 participants were reinfected, followed up over 69.8 person-years, yielding a re-infection rate of 21.5/100 person-years (95% CI 13.00-35.65). This trial demonstrates that HCV treatment can be delivered successfully to the target population of treatment as prevention strategies. We report higher rates of re-infection than existing estimates among PWID. Scale-up of HCV treatment should be pursued alongside a comprehensive programme of harm reduction interventions to help minimize re-infection and reduce HCV transmission. This article is protected by copyright. All rights reserved. PMID- 30422371 TI - Fixed dose combinations of anti-tubercular, antimalarial and antiretroviral medicines on the Indian market: critical analysis of ubiquity, sales and regulatory status. AB - OBJECTIVE: To assess the proportion and sales of unapproved Fixed Dose Combinations (FDCs) of anti-tubercular, antimalarial and antiretroviral medicines available on the Indian market. METHODS: Available FDCs of anti-tubercular, antimalarial and antiretrovirals were screened against the Central Drugs Standard Control Organization (CDSCO) database of approved FDCs. The FDC sales information in the given categories was obtained from AIOCD AWACS PharmaTrac, a market database. FDCs available in India were also screened against the National List of Essential Medicines India 2015 and the Orange Book Database of products approved by USFDA. RESULTS: Of 110 available first- to fourth-line anti-tubercular FDCs, only 32 were approved. Of 20 antimalarial FDCs available, eight were approved. However, almost 95% of available antiretroviral FDCs and branded products were approved. The sales volume of all anti-tubercular drugs was 730 million units of which 71% were unapproved, amounting to 14.30 billion rupees in sales value (58%). Almost half of the sales value and volume of antimalarials was generated by unapproved products. About 1% of sales volume of antiretroviral FDCs came from unapproved formulations, accounting for 5% of sales value. CONCLUSION: A large proportion of FDC formulations available in India has never been approved by CDSCO, hence raising the doubts about their safety and efficacy. An opaque regulatory framework and ambiguity over licensing powers have contributed to the problem. The rationality of unapproved FDCs should be reviewed and irrational formulations should be banned. PMID- 30422372 TI - Reduced Cerebrovascular Reactivity among Adolescents with Bipolar Disorder. AB - OBJECTIVES: Cardiovascular disease (CVD) is excessive and premature among individuals with bipolar disorder (BD). Cerebrovascular reactivity (CVR), reflecting vasodilatory capacity of cerebral blood vessels in response to vasoactive substances, is a marker of cerebrovascular health. Despite informative findings in other diseases, CVR has not previously been examined in BD. METHODS: Twenty-five adolescents with BD and 25 age and sex-matched psychiatrically healthy controls (HCs) completed six 15-second breath-holds (BHs) during functional magnetic resonance imaging (fMRI) at 3-Tesla. CVR was determined by comparing blood-oxygenation-level dependent (BOLD) signal changes. Voxel-wise contrasts were analyzed. Body mass index (BMI) was examined as a potential confound. RESULTS: CVR in the posterior cingulate gyrus and periventricular white matter was lower in BD vs. HC. After controlling for differences in BMI, additional between-group CVR differences were observed in the temporal poles, supramarginal gyrus, and lingual gyrus. There were no regions in which CVR was significantly greater in BD vs. HC. CVR was not associated with mood symptoms. CONCLUSIONS: This preliminary study provides evidence of cerebrovascular dysfunction in BD, including regions known to be susceptible to cerebrovascular dysfunction and/or disease. These findings warrant additional research on the causes and consequences of cerebrovascular dysfunction in early-onset BD. This article is protected by copyright. All rights reserved. PMID- 30422373 TI - Elevated Mirror Neuron System Activity in Bipolar Mania: Evidence from a Transcranial Magnetic Stimulation Study. AB - OBJECTIVES: The role of the 'mirror neuron system' (MNS) in the pathophysiology of mood disorders is not well studied. Given its posited role in the often impaired socio-emotional processes like intention detection, empathy, and imitation, we compared putative MNS-activity in patients with bipolar mania and healthy comparison subjects. We also examined the association between putative MNS-activity and hyper-imitative behaviors in patients. METHODS: We studied 39 medication-free individuals diagnosed with mania and 45 healthy comparison subjects. TMS-evoked motor cortical reactivity was measured via single and paired pulse stimuli (assessing SICI - short and LICI - long interval intracortical inhibition) while subjects viewed a static image and goal-directed actions. Manic symptom severity and imitative behaviors were quantified using the Young's Mania Rating Scale and a modification of the Echolalia Questionnaire. RESULTS: Two-way repeated measures analysis of variance demonstrated a significant group * time interaction effect indicating greater facilitation of cortical reactivity during action observation (putative MNS-activity) in the patient group as compared to the healthy group. While LICI-mediated MNS-activity had a significant association with manic symptom severity (r = 0.35, p = 0.038), SICI-mediated MNS-activity was significantly associated with incidental echolalia scores in a sub-group of 17 patients with incidental echolalia (r = 0.75, p <0.001). CONCLUSIONS: Our findings demonstrate that putative MNS-activity is heightened in mania, possibly because of disinhibition, and associated with behavioral consequences (incidental echolalia). This article is protected by copyright. All rights reserved. PMID- 30422374 TI - Oxidized graphene nanoparticles as a delivery system for the pro-apoptotic sphingolipid C6 ceramide. AB - Sphingolipids such as ceramide have attracted much attention as possible anticancer agents due to their potent pro-apoptotic effects. However, due to their extreme hydrophobicity, there is currently no clinically approved delivery method for in vivo use as a therapeutic agent. To this end, we have developed a novel method for loading the short-chain C6 ceramide onto oxidized graphene nanoribbons (O-GNRs) and graphene nanoplatelets (GNPs). Mass spectrometry revealed loading efficiencies of 57% and 51.5% for C6 ceramide onto O-GNRs and GNPs, respectively. The PrestoBlue viability assay revealed that 100 ug/mL of C6 ceramide-loaded O-GNRs and C6 ceramide-loaded GNPs reduced HeLa cell viability by approximately 93% and approximately 76%, respectively, compared to untreated HeLa cells, while equal concentrations of these nanoparticles without C6 ceramide did not significantly reduce HeLa cell viability. We confirmed that this cytotoxicity was apoptotic in nature via capase-3 activity and Hoechst staining. Using live cell confocal imaging with the fluorescent NBD-ceramide loaded on O-GNRs, we observed robust uptake into HeLa cells within 30 min while NBD-ceramide on its own was uptaken much more rapidly. Transmission electron microscopy confirmed that C6 ceramide-loaded O-GNRs were actually entering cells. Taken together, these data show that O-GNRs are a promising delivery agent for ceramide. To our knowledge, this study is the first to use such a loading method. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 25-37, 2019. PMID- 30422375 TI - Weight gain as a predictor of frontal and temporal lobe volume loss in bipolar disorder: A prospective MRI study. AB - OBJECTIVES: A sizable fraction of people with bipolar I disorder (BDI) experience a deteriorating clinical course with increasingly frequent mood episodes and chronic disability. This is believed to result from neurobiological illness progression, or neuroprogression. Excessive weight gain predicts neuroprogression across multiple brain illnesses, but no prospective studies have investigated this in BDI. The objective of this study was to determine whether BDI patients who experienced clinically significant weight gain (CSWG; gaining >=7% of baseline weight) over 12 months had greater 12-month brain volume loss in frontal and temporal regions important to BDI. METHODS: In 55 early-stage BDI patients we measured (i) rates of CSWG, (ii) the number of days with mood symptoms, using NIMH LifeCharts, and (iii) baseline and 12-month brain volumes, using 3T MRI. We quantified brain volumes using the longitudinal processing stream in FreeSurfer v6.0. We used general linear models for repeated measures to investigate whether CSWG predicted volume loss, adjusting for potentially confounding clinical and treatment variables. RESULTS: After correction for multiple comparisons, CSWG in patients predicted greater volume loss in the left orbitofrontal cortex (effect size [ES; Cohen's d] = -1.01, P = 0.002), left cingulate gyrus (ES = -1.31, P < 0.001), and left middle temporal gyrus (ES = -0.96, P = 0.004). Middle temporal volume loss predicted more days with depression (beta = -0.406, P = 0.010). CONCLUSIONS: These are the first prospective data on weight gain and neuroprogression in BDI. CSWG predicted neuroprogression, and neuroprogression predicted a worse clinical illness course. Trials of weight loss interventions are needed to confirm the causal direction of the weight gain-neuroprogression relationship, and to determine whether weight loss is a disease-modifying treatment. PMID- 30422376 TI - Daily and weekly mood ratings using a remote capture method in high-risk offspring of bipolar parents: Compliance and symptom monitoring. AB - OBJECTIVES: To determine the compliance and clinical utility of weekly and daily mood symptom monitoring in adolescents and young adults at risk for mood disorder. METHODS: Fifty emerging adult offspring of bipolar parents were recruited from the Flourish Canadian high-risk cohort study along with 108 university student controls. Participants were assessed by KSADS/SADS-L semi structured interviews and used a remote capture method to complete weekly and daily mood symptom ratings using validated scales for 90 consecutive days. Hazard models and generalized estimating equations were used to determine differences in summary scores and regularity of ratings. RESULTS: 78% and 77% of high-risk offspring and 97% and 93% of controls completed the first 30 days of weekly and daily ratings, respectively. There were no differences in drop-out rates between groups over 90 days (high-risk p=0.2149; controls p=0.9792). There were no differences in mean summary scores or regularity of weekly anxiety, depressive or hypomanic symptom ratings between high-risk and control groups. However, high risk offspring compared to controls had daily ratings indicating lower positive affect and higher negative affect (p=0.0317). High-risk offspring with remitted mood disorder compared to those without had more irregularity in weekly anxiety and depressive symptom ratings and daily ratings of lower positive affect, higher negative affect, and higher shame and self-doubt (p=0.0365). CONCLUSIONS: Findings support that high-resolution symptom tracking may be a feasible and clinically useful approach to monitoring emerging psychopathology in young people at high-risk of mood disorder onset or recurrence. This article is protected by copyright. All rights reserved. PMID- 30422378 TI - Undegraded peptides in organelles convey toxic signals. PMID- 30422377 TI - Comprehensive and cell-type-based characterization of the dorsal midbrain during development. AB - The layer structure has been intensively characterized in the developing neocortex and cerebellum based on the various molecular markers. However, as to the developing dorsal midbrain, comprehensive analyses have not been intensely carried out, and thus, the name as well as the definition of each layer is not commonly shared. Here, we redefined the three layers, such as the ventricular zone, intermediate zone and marginal zone, based on various markers for proliferation and differentiation in embryonic dorsal midbrain. Biphasic Ki67 expression defines the classical VZ, in which there is clear separation of the mitotic and interphase zones. Next, we mapped the distribution of immature neurons to the defined layers, based on markers for glutamatergic and GABAergic lineage. Interestingly, Tbr2 and Neurog2 were expressed in the postmitotic neurons. We also report that active (phosphorylated) JNK is a useful marker to demarcate layers during the embryonic stage. Finally, we validated the final arrival layers of the migratory glutamatergic and GABAergic neurons. These results form a foundation for analyses of brain development, especially in the proliferation and migration of excitatory and inhibitory neurons in the dorsal midbrain. PMID- 30422379 TI - Upregulation of proteins of the NLRP3 inflammasome in patients with periodontitis and uncontrolled type 2 diabetes. AB - OBJECTIVES: To evaluate the expression of proteins related to activation of the NLRP3 inflammasome in patients with chronic periodontitis (CP) and type 2 diabetes mellitus (T2D), and to determine whether the exacerbated periodontal pathological process observed in diabetic patients is related to its upregulation. MATERIALS AND METHODS: We performed an observational, analytical, cross-sectional study in three study groups: individuals systemically and orally healthy, and patients with CP with and without T2D. Gingival biopsies were taken from the three study groups. The expression of mRNAs for CASP1, NLRP3, and ASC was detected using real-time PCR, the expression of NLRP3 and ASC proteins was determined by immunohistochemistry. The quantification of IL-18 and IL-1beta was determined in the gingival crevicular fluid using ELISA. The results were analyzed by ANOVA followed by Tukey's test to compare differences between individual groups. RESULTS: Patients with CP and uncontrolled T2D presented severe periodontal disease and inflammation (PPD, p= 0.0072; CAL, p = 0.0480; bone loss, p = 0.0088), higher levels of CASP1 mRNA expression (p = 0.0026), a stronger pattern of staining for NLRP3 and ASC proteins in the epithelium and connective tissues, and significantly higher production of IL-18 (p = 0.0063) and IL-1beta (p = 0.0018) in comparison with healthy or CP subjects. CONCLUSION: The upregulation of genes and proteins involved in the activation of the NLRP3 inflammasome components in patients with periodontitis and uncontrolled T2D suggests a possible role in the more severe pathological processes leading to destruction of periodontal tissues observed in these patients. This article is protected by copyright. All rights reserved. PMID- 30422380 TI - Electrostatic-Field Induced Tip-Electrospray Ionization Mass Spectrometry for Direct Analysis of Raw Food Materials. AB - Rapid characterization of metabolites and risk compounds such as chemical residues and natural toxins in raw food materials such as vegetables, meats and edible living plants and animals plays an important part in ensuing food quality and safety. To rapidly characterize the analytes in raw food materials, it is essential to develop in situ method for directly analyzing raw food materials. In this work, raw food materials including biological tissues and living samples were placed between an electrode and mass spectrometric (MS) inlet under a strong electrostatic field, analytes were rapidly induced to generate electrospray ionization (ESI) from the sample tip by adding a drop of solvent onto the sample. Therefore, the electrostatic-field induced tip-ESI-MS allows raw samples to avoid contacting high voltage, and thus this method has the advantage for in vivo analysis of food living plants and animals. Metabolite profiling, residues of pesticides and veterinary drugs, natural toxins from raw food materials have been successfully detected. The analytical performances, including the linear ranges, sensitivity, and reproducibility were investigated for direct sample analysis. The ionization mechanism of electrostatic-field induced tip-ESI was also discussed in this work. PMID- 30422381 TI - Nursing schools: dumbing down or reaching up? AB - Universities and their nursing faculties are changing dramatically. Rather than serving as bastions of knowledge generation, professional innovation, curation and dissemination of knowledge, many have become corporatised monoliths intent on a perverse form of utilitarianism on steroids. Their sole function it seems is to produce commoditised 'outputs' that can contribute to the 'knowledge economy'. This article is protected by copyright. All rights reserved. PMID- 30422382 TI - Simultaneous determination of selected estrogenic endocrine disrupting chemicals and bisphenol A residues in whole milk using fabric phase sorptive extraction coupled to HPLC-UV detection and LC-MS/MS. AB - A simple and sensitive analytical methodology is developed for rapid screening and quantification of selected estrogenic endocrine disrupting chemicals and bisphenol A from intact milk using fabric phase sorptive extraction in combination with high-performance liquid chromatography coupled to ultraviolet detection/tandem mass spectrometry. The new approach eliminates protein precipitation and defatting step from the sample preparation workflow. In addition, the error prone and time-consuming solvent evaporation and sample reconstitution step used as the sample post-treatment has been eliminated. Parameters with most significant impact on the extraction efficiency of fabric phase sorptive extraction including sorbent chemistry, sample volume, extraction time have been thoroughly studied and optimized. Separation of the selected estrogenic endocrine disrupting chemicals including alpha-estradiol, hexestrol, estrone, 17alpha-ethinyl estradiol, diethylstilboestrol, and bisphenol A were achieved using a Zorbax Extend-C18 high-performance liquid chromatography column (15 cm * 4.6 mm, 5 MUm particle size). The limit of detection values obtained in fabric phase sorptive extraction with high-performance liquid chromatography with ultraviolet detection ranged from 25.0 to 50.0 ng/mL. The method repeatability values were 3.6-13.9 (relative standard deviation, %) and intermediate precision values were 4.6-12.7 (relative standard deviation, %). The fabric phase sorptive extraction method was also coupled to liquid chromatography with tandem mass spectrometry for identifying each endocrine disrupting chemical at 10 ng/mL. PMID- 30422383 TI - Gene-targeted deletion in mice of the Ets-1 transcription factor, a candidate gene in the Jacobsen syndrome kidney "critical region," causes abnormal kidney development. AB - Ets-1 is a member of the Ets family of transcription factors and has critical roles in multiple biological functions. Structural kidney defects occur at an increased frequency in Jacobsen syndrome (OMIM #147791), a rare chromosomal disorder caused by deletions in distal 11q, implicating at least one causal gene in distal 11q. In this study, we define an 8.1 Mb "critical region" for kidney defects in Jacobsen syndrome, which spans ~50 genes. We demonstrate that gene targeted deletion of Ets-1 in mice results in some of the most common congenital kidney defects occurring in Jacobsen syndrome, including: duplicated kidney, hypoplastic kidney, and dilated renal pelvis and calyces. Taken together, our results implicate Ets-1 in normal mammalian kidney development and, potentially, in the pathogenesis of some of the most common types of human structural kidney defects. PMID- 30422384 TI - Propeptide glycosylation and galectin-3 binding decrease proteolytic activation of human proMMP-9/progelatinase B. AB - Matrix metalloproteinases (MMPs) are secreted as proenzymes, containing propeptides that interact with the catalytic zinc, thereby controlling MMP activation. The MMP-9 propeptide is unique in the MMP family because of its post translational modification with an N-linked oligosaccharide. ProMMP-9 activation by MMP-3 occurs stepwise by cleavage of the propeptide in an aminoterminal (pro AT) and carboxyterminal (pro-CT) peptide. We chemically synthesized aglycosyl pro AT and pro-CT and purified recombinant glycosylated pro-ATS f-9 . First, we report new cleavage sites in the MMP-9 propeptide by MMP-3 and neutrophil elastase. Additionally, we demonstrated with the use of western blot analysis a higher resistance of glycosylated versus aglycosyl pro-AT against proteolysis by MMP-3, MMP-9, meprin alpha, neutrophil elastase and by protease-rich synovial fluids from rheumatoid arthritis patients. Moreover, we investigated the effect of glycosylation on proteolytic activation of human proMMP-9 with the use of zymography and dye-quenched gelatin cleavage analysis. Compared to recombinant Sf 9 proMMP-9 glycoforms, larger oligosaccharides of human neutrophil proMMP-9 increased resistance against proteolytic activation. Additionally, proMMP-9 from Congenital Disorder of Glycosylation patients, compared to healthy controls, showed a higher activation rate by MMP-3. Finally, we demonstrated that glycan galectin-3 interactions reduced proMMP-9 activation. In conclusion, modification of MMP-9 propeptide glycosylation is a fine-tuning mechanism and co-determines the specific activity of MMP-9 in physiology and pathology. ENZYMES: MMP-9 EC 3.4.24.35, MMP-3 EC 3.4.24.17, meprin alpha EC 3.4.24.18, neutrophil elastase EC 3.4.21.37, trypsin EC 3.4.21.4 and PNGase F EC 3.5.1.52. PMID- 30422385 TI - Spin in a closed-shell organic molecule on a metal substrate generated by a sigmatropic reaction. AB - Depositing intact organic radicals on various substrates can be challenging. Generally, inert metal surfaces present more chances of hosting the intact radicals, but the large amounts of delocalized electronic states favor charge transfer and ultimately spin quenching. Reducing the molecule-substrate interaction is a usual strategy to stabilize radicals on surfaces. To this end, thin insulating layers have been introduced to provide a controllable degree of electronic decoupling. Recently, retinoid molecules adsorbed on gold have been manipulated with a scanning tunneling microscope (STM) to exhibit a localized spin. Previous calculations have failed to find a radical derivative of the molecule on the surface. Here, we propose the formation of a neutral radical that is spatially localized in a tilted and lifted cyclic end of the molecule. The spin is created in a two-step process: a [1,3] sigmatropic hydrogen shift yielding an allene motif and the abstraction of the shifted hydrogen atom. The allene function provokes a perpendicular tilt of the cyclic end with respect to the rest of the conjugated chain and thus localizes the spin of the dehydrogenated allene in its lifted subpart. The results of density functional theory (DFT) calculations and additional STM manipulations lend support to the proposed mechanism. This work indicates that the controlled generation of molecular spins directly on a metallic surface may be achieved with a range of closed-shell molecules. PMID- 30422386 TI - The interaction of p130Cas with PKN3 promotes malignant growth. AB - Protein p130Cas constitutes an adaptor protein mainly involved in integrin signaling downstream of Src kinase. Owing to its modular structure, p130Cas acts as a general regulator of cancer cell growth and invasiveness induced by different oncogenes. However, other mechanisms of p130Cas signaling leading to malignant progression are poorly understood. Here, we show a novel interaction of p130Cas with Ser/Thr kinase PKN3, which is implicated in prostate and breast cancer growth downstream of phosphoinositide 3-kinase. This direct interaction is mediated by the p130Cas SH3 domain and the centrally located PKN3 polyproline sequence. PKN3 is the first identified Ser/Thr kinase to bind and phosphorylate p130Cas and to colocalize with p130Cas in cell structures that have a pro invasive function. Moreover, the PKN3-p130Cas interaction is important for mouse embryonic fibroblast growth and invasiveness independent of Src transformation, indicating a mechanism distinct from that previously characterized for p130Cas. Together, our results suggest that the PKN3-p130Cas complex represents an attractive therapeutic target in late-stage malignancies. PMID- 30422387 TI - Strontium-substituted hydroxyapatite stimulates osteogenesis on poly(propylene fumarate) nanocomposite scaffolds. AB - Incorporation of hydroxyapatite (HA) into polymer networks is a promising strategy to enhance the mechanical properties and osteoinductivity of the composite scaffolds for bone tissue engineering. In this study, we designed a group of nanocomposite scaffolds based on cross-linkable poly(propylene fumarate) (PPF) and 30 wt % strontium-hydroxyapatite (Sr-HA) nanoparticles. Four different Sr contents [Sr:(Sr + Ca), molar ratio] in the Sr-HA particles were studied: 0% (HA), 5% (Sr5-HA), 10% (Sr10-HA), and 20% (Sr20-HA). Two-dimensional (2D) disks were prepared using a thermal crosslinking method. The structure and surface morphology of different Sr-HA and PPF/Sr-HA composites were characterized using scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), transmission electron microscopy (TEM), and atomic force microscopy (AFM). To detect cellular responses in vitro, MC3T3-E1 cells were seeded and cultured on the different PPF/Sr-HA composite disks. Cell morphology after 24 h and 5 days were imaged using Live/Dead live cell staining and SEM, respectively. Cell proliferation was quantified using an MTS assay at 1, 4, and 7 days. Osteogenic differentiation of the cells was examined by alkaline phosphatase (ALP) staining at 10 days and quantified using ALP activity and osteocalcin assays at 7, 14, and 21 days. The sizes of the HA, Sr5-HA, Sr10-HA, and Sr20-HA particles were mainly between 10 * 20 nm and 10 * 250 nm, and these nanoparticles were dispersed or clustered in the composite scaffolds. in vitro cell studies showed that the PPF/Sr10-HA scaffold was significantly better than the other three groups (PPF/HA, PPF/Sr5-HA, and PPF/Sr20-HA) in supporting MC3T3-E1 cell adhesion, proliferation, and differentiation. PPF/Sr10-HA may, therefore, serve as a promising scaffold material for bone tissue engineering. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 00A: 000-000, 2018. PMID- 30422388 TI - The Nasal Complex of a Semiaquatic Artiodactyl, the Moose (Alces alces): Is it a Good Evolutionary Model for the Ancestors of Cetaceans? AB - Among Cetartiodactyla, cetaceans are the only obligate aquatic dwellers. Given morphological similarities between cetacean relatives such as Indohyus (the best represented Eocene raoellid artiodactyl) with other, later artiodactyls, any crown artiodactyl that engages in aquatic behaviors is of interest as an evolutionary model for the adaptations that accompanied the origins of cetaceans. The American moose (Alces alces) is the only non-cetacean artiodactyl to engage in aquatic foraging and, other than Hippopotamus, is distinctive in its diving behaviors. This study surveyed the soft and hard tissue nasal morphology of Alces alces to assess phylogenetic polarity and the presence of adaptations for diving and feeding in fresh water habitats. A fresh dissection of the facial musculature and nasal cavity was performed on one subadult male individual and osteological analyses were also performed on dry crania. This species was analyzed alongside fossil crania of Cervalces (its presumed ancestor), other cervids (e.g., Odocoileus virginianus, the white tail deer; Dama dama, the fallow deer), a bovid (Bos taurus, domestic cattle), and a carnivoran (Ursus americanus, the American black bear). A fresh dissection of the facial musculature and nasal anatomy of one fallow deer specimen was also performed for comparison with the moose. Results indicate that Alces alces exhibited a primitive configuration of maxillolabial muscles and, like Dama, exhibited a series of subcutaneous fibrous tissues connecting these muscles to skin. This article is protected by copyright. All rights reserved. PMID- 30422389 TI - Assembly of fully substituted 2H-indazoles catalyzed by Cu2O rhombic dodecahedra and evaluation of anti-cancer activity. AB - Simultaneous C-N, and N-N bond forming methods for the one-pot transformation are highly demanding in synthetic organic chemistry. In this report, we demonstrated the Cu2O rhombic dodecahedra catalyzed synthesis of 2H-indazoles with very good to excellent yields from readily available chemicals. This one-pot procedure involves the Cu2O nanoparticle catalyzed consecutive C-N, and N-N bond formation followed by the cyclization to obtain 2H-indazoles with broad substrate scope and high functional group tolerance. Various cell based bio-assay studies demonstrated that 2H-indazoles inhibits the growth of cancer cells typically through induction of apoptosis in a dose dependent manner. Moreover 2H-indazoles are capable of inhibiting cancer cell migration and invasion when tested in MDA MB-468 cell line. Thus we show here that 2H-indazoles have potent in-vitro anticancer activity which can be explored further. PMID- 30422390 TI - A Randomized, Placebo-Controlled, Multiple-Ascending-Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Soluble Guanylate Cyclase Stimulator Praliciguat in Healthy Subjects. AB - Nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling is central to the regulation of several physiological processes, including blood flow and inflammation. Deficient NO signaling is implicated in multiple diseases. sGC stimulators are small molecules that enhance sGC activity, particularly in combination with NO. In a randomized, placebo-controlled phase 1 study, the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending doses of the sGC stimulator praliciguat were assessed in 44 healthy adults. Four cohorts of 11 subjects (8 praliciguat, 3 placebo) received once-daily praliciguat for 14 days before up-titrating for 7 days (treatment sequences: 15/30 mg, 20/40 mg, 30/40 mg, and weight-based). All doses were tolerated. No serious or severe adverse events (AEs) were reported. The most common AEs in praliciguat recipients were headache and symptoms consistent with blood pressure (BP) lowering/vasodilation. There were no laboratory, vital sign, electrocardiographic, or platelet function findings indicative of a safety concern. Pharmacokinetics were dose proportional, with an effective half-life of 24-37 hours, supporting once-daily dosing. Praliciguat produced dose-related increases in plasma cGMP consistent with stimulation of sGC. Repeated once-daily dosing showed sustained decreases in BP. Results support evaluation of praliciguat for the treatment of conditions associated with deficient NO signaling. PMID- 30422391 TI - Retracted: Bisindole-oxadiazole hybrids, T3P mediated(r) -synthesis and appraisal of their apoptotic, antimetastatic and computational Bcl-2 binding potential. AB - Retraction: Kamath PR, Joseph MM, Ajees AA, et al. Bisindole-oxadiazole hybrids, T3P mediated synthesis and appraisal of their apoptotic, antimetastatic and computational Bcl-2 binding potential. J Biochem Mol Toxicol. 2017;31:e21962. https://doi.org/10.1002/jbt.21962 The above article from the Journal of Biochemical and Molecular Toxicology, published online on 19 July 2017 in Wiley Online Library (https://onlinelibrary.wiley.com/doi/abs/10.1002/jbt.21962) and in Volume 31, Issue 11, has been retracted by agreement of the Journal Editor-in Chief, Dr Hari Bhat, and Wiley Periodicals, Inc. The retraction has been agreed due to the absence of access to the original data needed to answer questions about the reliability of some of the findings presented in the paper. PMID- 30422392 TI - Costs of weaponry: unarmed males sire more offspring than armed males in a male dimorphic mite. AB - Morphological structures used as weapons in male-male competition are not only costly to develop but are also probably costly to maintain during adulthood. Therefore, having weapons could reduce the energy available for other fitness enhancing actions, such as post-copulatory investment. We tested the hypothesis that armed males make lower post-copulatory investments than unarmed males, and that this difference will be most pronounced under food-limited conditions. We performed two experiments using the male-dimorphic bulb mite Rhizoglyphus robini, in which males are either armed 'fighters' or unarmed 'scramblers'. Firstly, we tested whether fighters and scramblers differed in their reproductive output after being starved or fed for one or 2 weeks. Secondly, we measured the reproductive output of scramblers and fighters (starved or fed) after one, two or three consecutive matings. Scramblers sired more offspring than fighters after 1 week, but scramblers and fighters only sired a few offspring after 2 weeks. Scramblers also sired more offspring than fighters at the first mating, and males rarely sired offspring after consecutive matings. Contrary to our hypothesis, the fecundity of starved and fed males did not differ. The higher reproductive output of scramblers suggests that, regardless of nutritional state, scramblers make larger post-copulatory investments than fighters. Alternatively, (cryptic) female choice generally favours scramblers. Why the morphs differed in their reproductive output is unclear. Neither morph performed well relatively late in life or after multiple matings. It remains to be investigated to what extent the apparent scrambler advantage contributes to the maintenance and evolution of male morph expression. PMID- 30422393 TI - The 1918 Influenza pandemic in Montevideo: the southernmost capital city in the Americas. AB - BACKGROUND: Few studies have addressed the impact and dynamics of the 1918-1919 influenza pandemic in temperate regions of South America. OBJECTIVE: To identify key factors for influenza onset, spread and mortality in Montevideo and Uruguay in 1918-1919. METHODS: An analysis of official national records of the public health system of Uruguay was performed. RESULTS: From November to December of 1918 (spring), a total of 131 deaths due to influenza occurred in Montevideo and a total of 296 deaths accounted from July to September of 1919 (winter) in the same city. The total deaths attributed to influenza in Uruguay in 1918 and 1919 were 926 and 1,089, respectively. In contrast, the mean annual mortality attributed to influenza in Uruguay from 1908 to 1917 was 50.9. A pattern of age shift in mortality in the two pandemic waves studied was observed. CONCLUSIONS: The results of studies revealed that Montevideo was first hit by the devastating second wave of the pandemic of 1918, arriving Montevideo at the end of the spring of that year. The third wave arrived by July 1919, in the winter season, and in the Capital city was as severe as the second one. This article is protected by copyright. All rights reserved. PMID- 30422394 TI - Good Citizenship Made Easy: A Step-by-Step Guide to Submitting RNA-Seq Data to NCBI. AB - The analysis of transcriptome data from non-model organisms contributes to our understanding of diverse aspects of evolutionary biology, including developmental processes, speciation, adaptation, and extinction. Underlying this diversity is one shared feature, the generation of enormous amounts of sequence data. Data availability requirements in most journals oblige researchers to make their raw transcriptome data publicly available, and the databases housed at the National Center for Biotechnology Information (NCBI) are a popular choice for data deposition. Unfortunately, the successful submission of raw sequences to the Sequence Read Archive (SRA) and transcriptome assemblies to the Transcriptome Shotgun Assembly (TSA) can be challenging for novice users, significantly delaying data availability and publication. Here we present two comprehensive protocols for submitting RNA-Seq data to NCBI databases, accompanied by an easy to-use website that facilitates the timely submission of data by researchers of any experience level. (c) 2018 by John Wiley & Sons, Inc. PMID- 30422395 TI - Melatonin in the seasonal response of the aphid Acyrthosiphon pisum. AB - Aphids display life cycles largely determined by the photoperiod. During the warm long-day seasons, most aphid species reproduce by viviparous parthenogenesis. The shortening of the photoperiod in autumn induces a switch to sexual reproduction. Males and sexual females mate to produce overwintering resistant eggs. In addition to this full life cycle (holocycle), there are anholocyclic lineages that do not respond to changes in photoperiod and reproduce continuously by parthenogenesis. The molecular or hormonal events that trigger the seasonal response (i.e. induction of the sexual phenotypes) are still unknown. Although circadian synthesis of melatonin is known to play a key role in vertebrate photoperiodism, the involvement of the circadian clock and/or of the hormone melatonin in insect seasonal responses is not so well established. Here we show that melatonin levels in the aphid Acyrthosiphon pisum are significantly higher in holocyclic aphids reared under short days than under long days, while no differences were found between anholocyclic aphids under the same conditions. We also found that melatonin is localised in the aphid suboesophageal ganglion (SOG) and in the thoracic ganglionic mass (TGM). In analogy to vertebrates, insect-type arylalkylamine N-Acetyltransferases (i-AANATs) are thought to play a key role in melatonin synthesis. We measured the expression of four i-AANAT genes identified in A. pisum and localised two of them in situ in the insect central nervous systems (CNS). Levels of expression of these genes were compatible with the quantities of melatonin observed. Moreover, like melatonin, expression of these genes was found in the SOG and the TGM. This article is protected by copyright. All rights reserved. PMID- 30422396 TI - Pre-Processing MALDI/TOF Mass Spectra by Using Geena 2. AB - Geena 2 is a tool for filtering, averaging, and aligning MALDI/TOF mass spectra, designed to assist scientists in the analysis of high volumes of data and support them for comparative studies. Three web interfaces are available with different levels of complexity. In this manuscript, we explain how to use Geena 2 with these three interfaces to perform analyses of one's own data. Two support protocols showing how to check the example input file and how to create an input file with own data are also presented. (c) 2018 by John Wiley & Sons, Inc. PMID- 30422398 TI - Structural basis for protein phosphatase 1 recruitment by glycogen-targeting subunits. AB - The rate-limiting enzymes in glycogen metabolism are subject to regulation by reversible phosphorylation. The glycogen-targeted protein phosphatase 1 (PP1) holoenzyme catalyzes their dephosphorylation. It is composed of a catalytic subunit (PP1C) and a glycogen-targeting subunit (G subunit). To date, seven G subunits have been identified. They all contain an RVxF PP1C-binding motif. The interactions between this motif in the skeletal muscle-specific GM and PP1C have been revealed by structural studies. However, whether elements outside of this motif contribute to the interaction with PP1C is not clear. In this study, we found that residues next to the RVxF motif in GM also mediate interactions to PP1C and revealed the mechanism of the interaction by structural studies. Sequence analysis revealed that the PP1C-binding region in GM is highly conserved among G subunits. Consistently, we found that the equivalent region in the liver enriched GL adopts a similar structure upon binding PP1C. Dephosphorylation experiments indicated that this region and the glycogen-binding region in GM cooperate to stimulate PP1C's activity toward glycogen-associated substrates. DATABASES: The structure factors and coordinates for the PP1Calpha-GM (1-99) and PP1Calpha-GL (31-105) complexes have been deposited into the Protein Data Bank (http://www.pdb.org), with the accession codes 5ZQV and 5ZT0, respectively. PMID- 30422397 TI - Concurrent detection of lysosome and tissue transglutaminase activation in relation to cell cycle position during apoptosis induced by different anticancer drugs. AB - Described is the new cytometric approach do detect either stimulation or a collapse of lysosomal proton pump (lysosomes rupture) combined with activation of transglutaminase 2 (TG2) during induction of apoptosis. Apoptosis of human lymphoblastoid TK6 cells was induced by combination of 2-deoxyglucose with the isoquinoline alkaloid berberine, by DNA topoisomerase I inhibitor camptothecin, its analog topotecan, topoisomerase II inhibitors etoposide or mitoxantrone, as well as by the cytotoxic anticancer ribonuclease ranpirnase (onconase). Activity of the proton pump of lysosomes was assessed by measuring entrapment and accumulation of the basic fluorochrome acridine orange (AO) resulting in its metachromatic red luminescence (F>640 ) within these organelles. Activation of TG2 was detected in the same cell subpopulation by the evidence of crosslinking of cytoplasmic proteins revealed by the increased intensity of the side light scatter (SSC) as well as following cell lysis by detergent, by its red fluorescence after staining by sulforhodamine 101. Because at low AO concentration nuclear DNA of the lysed cells was stoichiometrically stained green (F530 ) its quantity provided information on effects of the drug treatments on cell cycle in relation to activation of TG2. The data reveal that activation of lysosomal proton pump was evident in subpopulations of cells treated with 2 deoxyglucose plus berberine, topotecan, etoposide and mitoxantrone but not with ranpirnase. The collapse of lysosomal proton pump possibly reporting rupture of these organelles was observed in definite cell subpopulations after treatment with each of the studied drugs. Because regardless of the inducer of apoptosis TG2 activation invariably was correlated with lysosomes rupture it is likely that it was triggered by calcium ions or protons released from the ruptured lysosomes. This new methodological approach offers the means to investigate mechanisms and factors affecting autophagic lysosomes proton pump activity vis-a-vis TG2 activation that are common in several pathological states. (c) 2018 International Society for Advancement of Cytometry. PMID- 30422399 TI - Fibroblast Growth Factor 2 lethally sensitizes cancer cells to stress-targeted therapeutic inhibitors. AB - In malignant transformation, cellular stress-response pathways are dynamically mobilized to counterbalance oncogenic activity, keeping cancer cells viable. Therapeutic disruption of this vulnerable homeostasis might change the outcome of many human cancers, particularly those for which no effective therapy is available. Here, we report the use of fibroblast growth factor 2 (FGF2) to demonstrate that further mitogenic activation disrupts cellular homeostasis and strongly sensitizes cancer cells to stress-targeted therapeutic inhibitors. We show that FGF2 enhanced replication and proteotoxic stresses in a K-Ras-driven murine cancer cell model, and combinations of FGF2 and proteasome or DNA damage response-checkpoint inhibitors triggered cell death. CRISPR/Cas9-mediated K-Ras depletion suppressed the malignant phenotype and prevented these synergic toxicities in these murine cells. Moreover, in a panel of human Ewing's sarcoma family tumor cells, sublethal concentrations of bortezomib (proteasome inhibitor) or VE-821 (ATR inhibitor) induced cell death when combined with FGF2. Sustained MAPK-ERK1/2 overactivation induced by FGF2 appears to underlie these synthetic lethalities, as late pharmacological inhibition of this pathway restored cell homeostasis and prevented these described synergies. Our results highlight how mitotic signaling pathways which are frequently overridden in malignant transformation might be exploited to disrupt the robustness of cancer cells, ultimately sensitizing them to stress-targeted therapies. This approach provides a new therapeutic rationale for human cancers, with important implications for tumors still lacking effective treatment, and for those that frequently relapse after treatment with available therapies. PMID- 30422401 TI - CMS will pay hospitals to push cardiac rehab. Is that enough? AB - Cardiologists hope financial incentives for hospitals will boost participation in cardiac rehab. But they also wonder if other strategies, such as paying for home based rehab, would do more to address what stops patients from showing up. PMID- 30422400 TI - Characteristics of metabolic stability and the cell permeability of 2-pyrimidinyl piperazinyl-alkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione with antidepressant- and anxiolytic-like activities. AB - A series of 2-pyrimidinyl-piperazinyl-alkyl derivatives of 1H-imidazo[2,1 f]purine-2,4(3H,8H)-dione has been synthesized in an attempt to discover a new class of psychotropic agents. Compounds were evaluated for their in vitro affinity for serotonin 5-HT1A , 5-HT7 , and phosphodiesterases PDE4 and PDE10. The most potent compound 2-pyrimidinyl-1-piperazinyl-butyl-imidazo[2,1-f]purine 2,4-dione (4b) behaved as strong and selective antagonist of 5-HT1A . Molecular modeling studies revealed differences in binding mode between compound 4b and buspirone, which might reflect variation of the ligands' affinity and potency in the 5-HT1A receptor. Compound 4b in silico models demonstrated drug-likeness properties and, contrary to buspirone, showed a metabolic stability in mouse liver microsomes system. Experimentally obtained value of apparent permeability coefficient Papp for 4b in parallel artificial permeability assay indicates the possibility of binding weakly to plasma proteins and high intestinal absorption fraction. Evaluation of the antidepressant- and anxiolytic-like activities of 4b revealed both activities at the same dose of 1.25 mg/kg and seemed to be specific. The antidepressant and/or anxiolytic properties of 4b may be related to its first-pass effect. PMID- 30422403 TI - Medicare Advantage is still the 'only safe game in town' for insurers. PMID- 30422402 TI - Self-employed fear repealing ACA will bring back'job lock'. AB - Would-be entrepreneurs may hesitate to cut ties with employer-based health coverage with the ACA's insurance protections up in the air. PMID- 30422404 TI - Growing number of doctors allowing, patients to read their notes. AB - The tools and precedent exist for doctors to share their notes with patients, and a growing number of providers are getting over their fears about what will happen if they do. PMID- 30422406 TI - Republicans target Medicaid, Medicare for big changes. PMID- 30422405 TI - 2017 Outlook: Healthcare re-reform. AB - Healthcare stakeholders risk seeing bargains made during ACA negotiations unraveled. But they'll also have significant leverage as Trump and congressional Republicans try to deliver on their healthcare promises. PMID- 30422407 TI - Rise of high-deductible plans has providers boosting collection efforts. PMID- 30422408 TI - Insurers seek to shape GOP repeal-and-replace plans. PMID- 30422409 TI - Value-based payment will continue, but who will lead the way? PMID- 30422410 TI - Manufacturers count on faster product approvals under Cures Act. PMID- 30422411 TI - Redefining the right to healthcare down. AB - With Republican leaders promising to quickly repeal the Affordable Care Act and only promising to enact a replacement, it's worth revisiting the question of whether healthcare is a right. PMID- 30422412 TI - Strategic provider partnerships deliver best value in pursuit of population health. PMID- 30422413 TI - New pay models mean hospitals need stellar post-acute networks to thrive. PMID- 30422414 TI - 'The challenge in American medicine is one of economics and mathematics and less about politics'. AB - Dr. Robert Pearl leads the 9,000 physicians employed by the Permanente Medical Group, which serves over 4 million Kaiser Permanente members in California and around Washington, D.C. A plastic surgeon by training, Pearl has emerged as a leading champion of using electronic health records.and new technologies to improve quality while lowering the cost of care. He was recently named chair of the Council of Accountable Physician Practices, or CAPP, which includes medical groups from the Mayo Clinic, Geisinger Health System, Intermountain Healthcare and other integrated delivery networks. Modern Healthcare Managing Editor Gregg Blesch recently spoke with Pearl about the advantages and challenges facing physicians working in large integrated delivery systems. The following is an edited excerpt. PMID- 30422415 TI - Highest and lowest performing safety net hospitals': Ranked by outcomes in four clinical areas. PMID- 30422416 TI - ? PMID- 30422417 TI - [Staying at home : which dimensions to assess in older persons ?] AB - Defining the limits of home long term care is not an easy task. For the health care professionals, deciding whether to support older patients in their plan to stay at home requires a structured approach, based on objective information. It is critical to systematically collect information on a patient's needs resulting from medical problems and their management, from his or her functional, cognitive, affective and nutritional status, as well as on mobility, social, spiritual, and financial resources that can be mobilized by the patient, his or her relatives, and the health care professionals. This information allows to first determine the potential gap between the patient's needs and available resources, and then to define possible scenarios to discuss with the patient and his or her relatives to reach a sustainable decision. PMID- 30422418 TI - [Prevention in older age : key factors]. AB - The extended life expectancy questions the quality of life of these additional years: with or without disability ? A review of the literature gives us some tips on preventive measures to maintain good health at an advanced age. Engaging in regular and moderate physical activity (such as walking) offers a range of health benefits, including reduced risk of all-cause mortality, lower risk for various diseases (ischemic stroke, ischemic heart disease, diabetes, breast and colon cancer), prevention of falls and functional decline in seniors living at home. Maintaining a healthy lifestyle (non-smoking, low alcohol consumption, adequate nutrition) as well as up-to-date immunization status and vitamin D supplementation in the deficient or vulnerable population, are factors that contribute to a better health in the last years of life. PMID- 30422419 TI - [Video games and smartphones : what impacts on cognitive capacities ?] AB - Age-related changes in mental health are an important concern in today's world. Researchers have investigated the effects of video games on mental health for the past 30 years but research on the cognitive impact of smartphones is just beginning. Studies have shown contradictory results and need to be interpreted with caution. Users should be made aware of current knowledge on their potential risks and benefits, without demonizing these relatively new technologies. They should learn how to take advantage of the great potential of these modern devices (they can for example enhance curiosity, sense of purpose and creativity) without becoming enslaved by them. PMID- 30422420 TI - [Pneumonia of the elderly and its link to oral health]. AB - Pneumonia is a frequent and serious disease among the elderly, often associated with functional and cognitive impairments, dysphagia, malnutrition and immunosenescence. Although the link between the oral hygiene and the risk of pneumonia has been established, the oral status and swallowing function are not routinely screened in the context of a geriatric assessment. Bacteria from oral plaque are regularly aspirated into the lungs and periodontitis induces a chronic inflammation favoring the oral and respiratory epithelial colonization with respiratory pathogens, hence facilitating infections. The poor oral health status and related masticatory impairment are often associated with malnutrition and dehydration. Patients are stranded in a vicious circle of respiratory infections and relapses. Prevention in form of oral health care and daily oral hygiene has proven to be effective. PMID- 30422421 TI - [Osteoporosis in patients with chronic renal failure : evaluation and management ? Role of bone biopsy]. AB - The management of osteoporosis in patients with mild to moderate chronic kidney disease (CKD) can be established as in general population. In severe or terminal CKD, bone densitometry is indicated. Bone-specific alkaline phosphatase is considered a useful marker for distinguishing among the histologic types of renal osteodystrophy. In ambiguous cases, bone biopsy together with quantitative histomorphometry will be necessary. As far as the treatment is concerned, the bisphosphonates, which had been avoided due to their renal excretion as well as the official warnings against using them in case of renal clearance lower than 30 ml/min, seem to be effective even in advanced stages of renal disease. There are limited data, though, regarding the management of osteoporosis in terminal stages of CKD. PMID- 30422422 TI - [Which alternative to benzodiazepines, Z-pills and other hypnotics for aged people ? Melatonin, valerian, or clomethiazole]. AB - Sleep disorders are a recurrent complaint in geriatrics. Of multifactorial origin, they have a significant impact on health and quality of life. However, the answer is (too) often the prescription of benzodiazepines or related-drugs (Z pills), sedative antidepressant, or another psychotropic medication. More recently, melatonin, valerian and, in Switzerland, clomethiazol are widely considered as effective and more suitable alternatives for aged people. We present a systematic review of the literature on the efficacy and tolerance of these molecules, of which the main objective is to demonstrate that non pharmacological approach must remain the first-line therapy of insomnia in geriatrics. PMID- 30422423 TI - [Metabolic acidosis in critical care : theoretical and practical aspects]. AB - Acid-base disorders, and metabolic acidosis in particular, are frequently encountered in critical care typically in shock states, metabolic diseases decompensations or intoxications. Their systematic and careful evaluation frequently helps identifying underlying disease and guide clinical management. In most instances, therapy should focus on the underlying disease. Symptomatic treatment of metabolic acidosis is controversial and rarely indicated. This review focuses on the main causes of metabolic acidosis and their diagnostic approach. PMID- 30422424 TI - ? PMID- 30422425 TI - ? PMID- 30422426 TI - ? PMID- 30422427 TI - ? PMID- 30422428 TI - ? PMID- 30422429 TI - ? PMID- 30422430 TI - ? PMID- 30422431 TI - Direct trans-cervical endolymphatic thoracic duct stent-graft for plastic bronchitis. AB - Plastic bronchitis is a poorly understood and uncommon diagnosis, arising from multiple etiologies. Traditional treatment consists of steroids and vasodilators, with thoracic duct embolization emerging as a new procedural therapy. Herein, abnormal lymphatic vessels were noted on lymphangiography in an adult patient with debilitating plastic bronchitis, but anterograde lymphatic access was not feasible due to the patient's morbid obesity and non-visualization of retroperitoneal lymphatics. After trans-venous thoracic duct access could not be established, direct trans-cervical thoracic duct access was performed. A thoracic duct stent-graft was placed, excluding the abnormal bronchial lymphatics and maintaining physiologic anterograde flow through the central lymphatics. At three month follow-up, the patient's condition had resolved. PMID- 30422432 TI - Left ventricular rotational mechanics differ between lipedema and lymphedema: Insights from the three-dimensional speckle tracking echocardiographic MAGYAR path study. AB - The present study aimed to assess LV rotational mechanics by three-dimensional speckle-tracking echocardiography (3DSTE) in lipedema (n=25), lymphedema (n=26) patient groups with age- and gender-matched healthy controls (n=54). 3 lipedema and 4 lymphedema patients were excluded due to insufficient image quality for 3DSTE analysis. LV apical rotation (9.61 +/- 4.25 degree vs. 6.40 +/- 2.63 degree, p <0.05) and LV twist (13.83 +/- 4.89 degree vs. 10.04 +/- 3.56 degree, p <0.05) are impaired in lipedema patients as compared to matched controls; similar alterations in lymphedema were not found. Moreover, in some lipedema and lymphedema patients severe LV rotational abnormalities could be detected. Our results suggest that lipedema-associated impaired LV apical rotation and twist assessed by 3DSTE could be a novel differential diagnostic point between lipedema and lymphedema. PMID- 30422433 TI - Secondary lymphedema after head and neck cancer therapy: A review. AB - Secondary head and neck lymphedema (SHNL) is a chronic condition affecting patients who have undergone treatment for head and neck cancers. It results from the disruption of normal lymphatic flow by surgery and/or radiation. The incidence of secondary head and neck lymphedema varies anywhere between 12 and 54% of all patients treated for head and neck cancer, but it is still commonly under-diagnosed in routine clinical practice. In spite of awareness of this condition, treatment has been difficult as definitive staging, diagnostic, and assessment tools are still under development. This review article is aimed at looking at the evidence, standards of management, and deficiencies in current literature related to SHNL to optimize management of these patients and improve their quality of life. PMID- 30422434 TI - Plantar lymphatic network. AB - Anatomical descriptions of the lymphatic system of the foot remain imprecise. In the present report, we aim to elucidate the anatomical lymphatic plantar network in order to improve current clinical practice on the foot. Lower limbs from a total of 25 human cadavers, 4 amputated limbs, and 8 term fetuses were studied. All cadavers were subjected to injection procedures, formalized, immersed in a solution of hydrogen peroxide, and finally dissected. On 6 of the fetal samples, the diaphanization Spatelholz technique was followed. The superficial lymphatic network of the sole is morphologically divided into three plexuses: anterior, medium, and posterior, with the medium differing from the rest. The anterior plexus presents lymphatic vessels forming scarce polygonal figures of considerable size that converge towards the medial edge to constitute ascending trunks. The middle plexus is characterized by the presence of transverse interconnected trunks that extend from one edge to the other of the sole. The posterior plexus presents polygonal figures of smaller size and greater number than the anterior plexus and forms ascending trunks that are directed to the dorsal surface of the foot. These observations demonstrate that the plantar lymphatic network display important differences among the caliber of the lymphatic vessels as well as in the communication and morphological shape of their plexus. Finally, a comparative distribution and organization between the lymphatic and the venous networks was also examined. PMID- 30422435 TI - Tissue dielectric constant ratios as a method to characterize truncal lymphedema. AB - Truncal lymphedema is one possible complication of breast cancer treatment. It affects many women and is diagnosed based on symptoms and clinical assessment. Because changes occur late in the process, it is useful to have a quantitative assessment that is applied earlier to detect more subtle changes and quantitively assess treatment progress. Our goal was to describe a possible method to accomplish this via measurements of tissue dielectric constant (TDC). TDC was measured at lateral thorax, anterior forearm, and biceps in 120 women awaiting surgery for breast cancer. Inter-side TDC ratios were defined as values measured on the at-risk (cancer-side) lateral thorax divided by TDC values measured on contralateral thorax, forearm, and biceps. These ratios, designated as thorax thorax, thorax-forearm, and thorax- biceps were (mean +/- SD) 1.017 +/- 0.121, 1.138 +/- 0.223, and 1.263 +/- 0.255 respectively. Corresponding truncal lymphedema thresholds were determined by adding 2.5SD to each mean yielding thresholds of 1.32, 1.70 and 1.90. For these thresholds, 99.4% of patients would have inter-side ratios less than the threshold value. Thus, from assessments in a non-lymphedematous patient-group a set of reference threshold-ratios are now available against which patients surgically treated for breast cancer may be prospectively compared. PMID- 30422436 TI - Is lymphatic reconstitution possible after meshed skin grafting? AB - Restorative potential of lymph transport after skin graft has rarely been discussed. We report a case of lymphatic reconstitution across meshed, split thickness skin graft performed for a patient with necrotizing fasciitis. The patient underwent extensive circumferential soft tissue debridement of the lower leg and resurfacing of the skin defect with meshed split-thickness skin graft. Indocyanine green fluorescence lymphography was performed 3 years after surgery and demonstrated that injected dye in the foot traveled across the skin graft and reached to the adjacent native skin in the proximal region. Our observation revealed that transferred split-thickness skin graft possessed some potential to allow for transport of lymph fluid possibly owing to the retention of lymphatic capillaries. PMID- 30422437 TI - Legislative Update. PMID- 30422438 TI - School Nurses: Daily Impact. PMID- 30422440 TI - History of Legislation Affecting NPs in North Carolina. PMID- 30422439 TI - Recognizing the Fire of Activation. PMID- 30422441 TI - BYPASS SURGERY IN PATIENTSWITH COMBINED ATHEROSCLEROTICLESIONS OF COMMON AND INTERNALCAROTID ARTERY. AB - An analysis of data of carotid angiographies was made in146 patients with chronic cerebrovascular disease. Combinedlesions of the common and internal carotid artery with clinicalsigns were revealed in 2 (1,4%) patients. A crossed extraanatomicbypass from the left common carotid artery to the right internalcarotid artery was performed in one patient. The orthotopiccommon internal autovenous bypass on the right side was carriedout for another patient. According to obtained results, the authorssuggested that the orthotopic or extraanatomic common-internalcarotid artery bypasses could be applied in case of impossibilityof endovascular intervention, when patients had the combinedatherosclerotic lesions of common carotid and internal carotidartery. PMID- 30422442 TI - URGENT DIAGNOSTICS OF CEREBRAL VENOUSTROMBOSIS. AB - Investigations were carried out in 24 patients in order toevaluate information value of the data of clinical, laboratory,neuroradiological methods of research and develop the diagnosticalgorithm in case of cerebral venous thrombosis (CVT). Themain group consisted of 11 patients (7 male, 4 female, averageage 49,1+/-4,3) with CVT. The comparison group included 13patients (6 male, 7 female; average age 68,1+/-9,5) with ischemicstroke (IS) of moderate severity. There were revealed changes inblood and cerebrospinal fluid (CSF) as form of leukocytosis ofblood and moderately increased cell count with elevated proteinin CSF and blood in case of CTV. The authors noted an elevatedprotein in CSF and blood and leukocytosis with predominantlymphopenia in blood and neurophilic predominance in CSFwithin the reference range of CSF in patient with ischemic stroke.The epileptic attacks, meningeal syndromes, headaches weremore often among clinical syndromes at CTV than in case ofischemic stroke. The algorithm of neuroimaging research methodsand modes of MRI were determined and allowed an effectivediagnostics of damages of venous sinuses, superficial and deepcerebral veins in case of urgent hospitalization of patients. Itwas possible to suggest the venous pathology in 7 (63,6%) casesdue to SKT (without contrast) and in case of application of MRvenography (2D TOFmode), there were revealed 100% of cases. PMID- 30422443 TI - ENDOBRONCHIAL PHOTODYNAMICTHERAPY UNDER FLUORESCENCE CONTROL:PHOTODYNAMIC THERANOSTICS. AB - One of the disadvantages of photodynamic therapy is impossibilityto specify the method according to biological features ofmalignant tumor such as a degree of blood supply, accumulationof photosensibilizator in tumorous tissue, proliferative activityand etc. The authors aimed to develop a mode of individualizationof endobronchial photodynamic therapy of central non-smallcell carcinoma of lung and assessment of method efficacy. Thesuggested method is based on fluorescent diagnostics of degreeof accumulation of photosensibilizator in timorous tissue and therate of its expenditure in process of performing of photodynamictherapy. There was made a comparison of parameters of methodsand results of photodynamic therapy in 2 randomized groups.Each group consisted of 45 patients. The research method wasapplied in the main group and the standard method was usedin the comparison group. It was found that the research methodallowed significant reduction of duration of irradiation comparedwith conventional method (at the average from 690+/-65sec to470+/-45sec, p=0,02), though the treatment results were the same.The suggested method allowed separation of group of patientswith absence of fluorescence of timorous tissue. Performance ofphotodynamic therapy is unreasonable for these patients. PMID- 30422444 TI - TRA.NSTHORACIC PUNCTURE BIOPSYIN DIAGNOSTICS OF FOCAL LESIONSOF THE LUNG. AB - The transthoracic puncture biopsy was performed undersurveillance of X-ray computed tomography in order to verifydiagnoses in 80 patients with lung tumors. This procedureallowed verification of diagnosis and choice of treatment strategyin 95% of cases. The complications obtained as result ofintervention didn't bring severe character and were arrested interm of two days. PMID- 30422445 TI - ARTERIAL CHEMOINFUSION IN PATIENTSWITH LOCALLY ADVANCED AND METASTATICPANCREAS CANCER. AB - The chemoinfusions (310) were carried out in celiac trunkin 167 patients with non removed pancreas cancer at the periodfrom 2000 to 2015. Locally advanced timorous process (stage III,n=79) was revealed in 79 patients and liver metastases (stage IV,n=88) were noted in 88 cases. The celiac axis infusion by Gemcitabine(1000 mg/m2) was applied for patients and GEMOX(Gemcitabine+Oxaliplatin 75 mg/m2) has been using since 2012.Symptomatic improvement such as decrease of pain, growthof body weight was noted in majority of patients. An averagelifetime, median and one year survival consisted of 7,6 months,5,8 months and 10%. The patients (133) were treated by 1-2cycles and after that by course of total body chemotherapeutics.There weren't any serious complications. Toxic manifestationsof chemotherapy weren't higher than I-II degree and they werearrested by corrective therapy in 92 patients (55%). The celiacaxis infusion is safe in patients with locally advanced and inoperablepancreas cancer. Symptomatic improvement showed themost patients. The objective response to the treatment had 20%patients and performance of repeated cycles led to increase oftheir survival. PMID- 30422446 TI - APPLICATION OF MINI-PLATESAND MINI-SCREWS IN TREATMENTOF PATIENTS WITH RADIAL HEAD FRACTURES. AB - An article presents an experience of application of compressionheadless mini screws (Gerbert's screws) and mini-platesin treatment of radial head fractures. The authors showedadvantages and disadvantages of given methods of treatment in41 patients. Gerbert's screws were used in 32 cases and miniplateswere applied in 9 patients. Mini-plates in combinationwith Gerbert's screws were used in 4 patients. There weren'tnoted complications in early postoperative period. Patients(27-84%) with Gerbert's screws were followed up in termsmore than 6 months. Mean score was 91 according to the scaleof Mayo Elbow Performance Score. Results of application ofmini-plates were followed up in terms more than 6 months in 7(77%) patients. Mean score of Mayo Elbow Performance Scoreconsisted of 72. Based on the analysis of results, the authorsconcluded that the application of mini-screws in radial head fracturesallowed doctors to obtain a good anatomical and functionalresult. Osteosynthesis by mini-plates didn't always support thesecure fixation of all fractures due to strictly given positioningon the head of radial bone. In case of osteosynthesis of splinteredfractures of Mason type III, it should be reasonable to combinemini-plates and Gerbert's screws. PMID- 30422447 TI - NEW TECHNOLOGIES IN TREATMENTOF FRACTURES OF THE UPPER EXTREMITIESIN PATIENTS WITH SEVERE MULTIPLEAND POLYTRAUMA. AB - A comparative analysis of treatment results of fractures of long bones of the upper extremities was made in 172 victimswith severe polytrauma. The traditional strategy of treatment wasused in the first group. The new technologies such as prognostictactics, method of Damage control orthopedics and low invasiveosteosynthesis developed by the authors were applied in the secondgroup. The application of new technologies allowed doctorsto improve the immediate and long-term results of surgery. Therate of lethality decreased in 1,6 times, incidence of complicationsreduced in 1,4 times. Hospital stay shortened in 2 times:for victims with favorable prognosis - on 7 days; for patientswith unfavorable prognosis - on 13 days. The long-term resultswere studied in 154 (89,5%) patients. The common duration oftreatment reduced on 30 days and the quantity of good resultsincreased on 18,6%. The number of patients with vocationalrehabilitation increased from 82,3 to 90,7%. PMID- 30422448 TI - MEDIASTINOSCOPY IN SURGERY OF BENIGNDISEASES OF ESOPHAGUS AND CARDIACORIFICE. AB - An article presents the results of application of mediatinoscopyin extirpation of the esophagus and cardiac orifice. Thecomparative assessment was made in group of patients whounderwent the standard surgery. An application of mediastinoscopyfor excretion and extirpation of the esophagus allowed doctors to cut down the duration of intervention on 40,15%. Thevolume of intraoperative loss of blood was reduced on 45,52%and the rate of intraoperative complications decreased on morethan 45% compared with standard surgery. There was noted thereduction of the rate of postoperative complications more than30% and the course of postoperative period was smooth. Thesefactors shortened hospital stay and time the patients should be inresuscitation department. PMID- 30422449 TI - APPENDICEAL MASS: DIAGNOSTICSAND TREATMENT STRATEGY. AB - One of the frequent complications of acute appendicitisis appendiceal mass (AM). This research aimed to specify thecriteria of AM diagnostics and determine the rational treatmentstrategy. It was stated that the duration of disease morethan 3 days in combination with palpable infiltrate in the rightiliac region and absence of positive appendiceal signs allowedformation of the clinical diagnosis of dense AM and definitionof the following diagnostics program. An application of ultrasoundstudy gave the possibility to differentiate AM accordingto maturity into loose and dense cases. Somputer tomographyand irrigoscopy were used routinely in controversial sases ofdifferential diagnostics of dense AM and oncological diseasesof the right areas of the large intestine. Diagnostic laparoscopyshould be rational in patients with uncertain clinical findings duringdynamic monitoring of imaging of inflammatory infiltrate inthe right iliac region and it could facilitate to assess of the possibilityof its safe separation. The application of given method ofdia gnostics algorithm determined the treatment strategy: laparoscopicappendectomy in case of loose AM and conservativetherapy in case of dense AM. PMID- 30422596 TI - Case 19-2018: A 15-Year-Old Girl with Acute Kidney Injury. PMID- 30422597 TI - Case 23-2018: A Man with Episodes of Confusion and Hypoglycemia. PMID- 30422607 TI - Acute milk-alkali syndrome AB - Summary: A 74-year-old woman presented with progressive lethargy, confusion, poor appetite and abdominal pain. She was found to have non-PTH-mediated severe hypercalcemia with renal failure and metabolic alkalosis. Extensive workup for hypercalcemia to rule out alternate etiology was unrevealing. Upon further questioning, she was taking excess calcium carbonate (Tums) for her worsening heartburn. She was diagnosed with milk-alkali syndrome (MAS). Her hypercalcemia and alkalosis recovered completely with aggressive hydration along with improvement in her renal function. High index of suspicion should be maintained and history of drug and supplements, especially calcium ingestion, should be routinely asked in patients presenting with hypercalcemia to timely diagnose MAS and prevent unnecessary tests and treatments. Learning Points: Suspect milk alkali syndrome in patients with hypercalcemia, metabolic alkalosis and renal failure, especially in context of ingestion of excess calcium-containing supplements.Careful history of over-the-counter medications, supplements and diet is crucial to diagnose milk-alkali syndrome.Milk-alkali syndrome may cause severe hypercalcemia in up to 25-30% of cases. PMID- 30422609 TI - Communicating Risks: Let's Talk Numeracy. PMID- 30422608 TI - How to Prepare for and Survive a Violent Patient Encounter. PMID- 30422610 TI - Preparations for Treating Opioid Use Disorder in the Office. PMID- 30422611 TI - What Makes a Doctor Truly Great. PMID- 30422612 TI - Six Mobile Apps to Make Prescribing Easier. PMID- 30422613 TI - Five Ways to Communicate Risks So That Patients Understand. PMID- 30422614 TI - Water and Oil Insoluble PEGDA-Based Microcapsule: Biocompatible and Multicomponent Encapsulation. AB - Despite the recent development in various materials capable of encapsulating biomolecules, there exist limited reports on multicomponent encapsulation in biocompatible microcapsules. In this letter, we utilize the molecular weight dependent solubility of poly(ethylene glycol) diacrylate (PEGDA) and droplet microfluidics to achieve direct encapsulation of both hydrophilic and hydrophobic cargoes in PEG microcapsules. By using PEGDA 250 as the middle phase, we demonstrate that these PEGDA-based microcapsules allow simultaneous encapsulation of both hydrophilic and hydrophobic cargoes. We further confirm the validity of this approach by demonstrating that complex biomolecule such as protein can be effectively encapsulated within these PEGDA-based microcapsules. PMID- 30422615 TI - Mechanistic Understanding of the Growth Kinetics and Dynamics of Nanoparticle Superlattices by Coupling Interparticle Forces from Real-Time Measurements. AB - Superlattice structures formed by nanoparticle (NP) self-assembly have attracted increasing attention due to their potential as a class of nanomaterials with enhanced physicochemical properties tailored by the assembly structure. However, many key questions remain regarding the correlation between the dynamics of individual NPs and emerging superlattice patterns. Here we investigated the self assembly of gold NPs by employing in situ transmission electron microscopy equipped with direct detection camera capabilities, which enabled us to track the rapid motion of individual nanoparticles in real time. By calculating the contributions of Brownian, van der Waals, hydrodynamic, and steric hindrance forces, we obtained a quantitative evaluation of the competitive interactions that drive the assembly process. Such competition between forces over various separations is critical for the kinetics of cluster growth, leading to the superlattice formation. Brownian motion resulted in the formation of small-sized clusters, whose growth dynamics was characterized as reaction-limited aggregation. Subsequently, at relative short-range particle separations, van der Waals force overrode the Brownian force and dominantly drove the assembly process. When the particles were in close proximity, a delicate balance between van der Waals and steric hindrance forces led to an unexpected dynamic nature of the assembled superlattice. Our study provides a fundamental understanding of coupling energetics and dynamics of NPs involved in the assembly process, enabling the control and design of the structure of nanoparticle superlattices. PMID- 30422616 TI - Cobalt Phosphate Nanostructures for Non-Enzymatic Glucose Sensing at Physiological pH. AB - Nanostructured materials have potential as platforms for analytical assays and catalytic reactions. Herein, we report the synthesis of electrocatalytically active cobalt phosphate nanostructures (CPNs) using a simple, low-cost, and scalable preparation method. The electrocatalytic properties of CPNs toward the electrooxidation of glucose (Glu) were studied by cyclic voltammetry and chronoamperometry in relevant biological electrolytes, such as phosphate-buffered saline (PBS), at physiological pH (7.4). Using CPNs, Glu detection could be achieved over a wide range of biologically relevant concentrations, from 1 to 30 mM Glu in PBS, with a sensitivity of 7.90 nA/mM cm2 and a limit of detection of 0.3 mM, thus fulfilling the necessary requirements for human blood Glu detection. In addition, CPNs showed a high structural and functional stability over time at physiological pH. The CPN-coated electrodes could also be used for Glu detection in the presence of interfering agents (e.g., ascorbic acid and dopamine) and in human serum. Density functional theory calculations were performed to evaluate the interaction of Glu with different faceted cobalt phosphate surfaces; the results revealed that specific surface presentations of under-coordinated cobalt led to the strongest interaction with Glu, suggesting that enhanced detection of Glu by CPNs can be achieved by lowering the surface coordination of cobalt. Our results highlight the potential use of phosphate-based nanostructures as catalysts for electrochemical sensing of biochemical analytes. PMID- 30422617 TI - Understanding Electric Double-Layer Gating Based on Ionic Liquids: from Nanoscale to Macroscale. AB - In electric double-layer transistors (EDLTs), it is well known that the EDL formed by ionic liquids (ILs) can induce an ultrahigh carrier density at the semiconductor surface, compared to solid dielectric. However, the mechanism of device performance is still not fully understood, especially at a molecular level. Here, we evaluate the gating performance of amorphous indium gallium zinc oxide (a-IGZO) transistor coupled with a series of imidazolium-based ILs, using an approach combining of molecular dynamics simulation and finite element modeling. Results reveal that the EDL with different ion structures could produce inhomogeneous electric fields at the solid-electrolyte interface, and the heterogeneity of electric field-induced charge distributions at semiconductor surface could reduce the electrical conductance of a-IGZO during gating process. Meanwhile, a resistance network analysis was adopted to bridge the nanoscopic data with the macroscopic transfer characteristics of IL-gated transistor, and showed that our theoretical results could well estimate the gating performance of practical devices. Thereby, our findings could provide both new concepts and modeling techniques for IL-gated transistors. PMID- 30422618 TI - Metallophthalocyanine-Based Molecular Dipole Layer as a Universal and Versatile Approach to Realize Efficient and Stable Perovskite Solar Cells. AB - It is well known that tailoring the interfacial structure is very important for perovskite solar cells, especially for its performance and stability. Here, we report a universal and versatile method of modulating the energetic alignment between the perovskite and hole-transporting layer by introducing a multifunctional dipole layer based on metallophthalocyanine derivatives copperphthalocyanine (CuPc) or highly fluorinated copper hexadecafluorophthalocyanine (F16CuPc). Both molecules were introduced through an "antisolution" process to treat the surface of organic-inorganic CH3NH3PbI3 perovskite. The dipole layer can well align the interfacial energy levels, passivate the CH3NH3PbI3 surface, and fill the grain boundaries, resulting in greatly suppressed charge recombination. As a result, our planar CH3NH3PbI3 perovskite devices exhibit the best power conversion efficiency of 20.2%, with significantly enhanced open-circuit voltages ( Voc) of 1.112 V (CuPc) and 1.145 V (F16CuPc), which is a record high Voc value for CH3NH3PbI3 thin-film solar cells. More importantly, the use of highly fluorinated F16CuPc produces a significantly more hydrophobic surface, leading to drastically improved long-term stability under ambient conditions. We believe that our study offers a general approach to making multifunctional dipole layers, which are necessary for achieving both stable and efficient perovskite solar cells. PMID- 30422619 TI - Atomic- and Molecular-Resolution Mapping of Solid-Liquid Interfaces by 3D Atomic Force Microscopy. AB - Hydration layers are ubiquitous in life and technology. Hence, interfacial aqueous layers have a central role in a wide range of phenomena from materials science to molecular and cell biology. A complete understanding of those processes requires, among other things, the development of very-sensitive and high-resolution instruments. Three-dimensional atomic force microscopy (3D-AFM) represents the latest and most successful attempt to generate atomically resolved three-dimensional images of solid-liquid interfaces. This review provides an overview of the 3D-AFM operating principles and its underlying physics. We illustrate and explain the capability of the instrument to resolve atomic defects on crystalline surfaces immersed in liquid. We also illustrate some of its applications to imaging the hydration structures on DNA or proteins. In the last section, we discuss some perspectives on emerging applications in materials science and molecular biology. PMID- 30422620 TI - High-Resolution Surface Analysis on Aluminum Oxide-Coated Li1.2Mn0.55Ni0.15Co0.1O2 with Improved Capacity Retention. AB - Thin alumina coatings on Li-rich nickel cobalt manganese oxide (Li-rich NCM) particles used as cathode material in Li-ion batteries can improve the capacity retention during cycling. However, the underlying mechanisms are still not fully understood. It is crucial to determine the degree of coverage of the particle's coating on various length scales from micrometer to nanometer and to link it to the electrochemical properties. Alumina coatings applied on Li-rich NCM by atomic layer deposition or by chemical solution deposition were examined. The degree of coverage and the morphology of the particle coatings were investigated by time-of flight secondary-ion mass spectrometry (ToF-SIMS), scanning electron microscopy, elemental analysis using inductively coupled plasma optical emission spectrometry, and scanning/transmission electron microscopy. ToF-SIMS allows investigating the coverage of a coating on large length scales with high lateral resolution and a surface sensitivity of a few nanometers. Regardless of the chosen coating route, analytical investigations revealed that the powder particles were not covered by a fully closed and homogenous alumina film. This study shows that a fully dense coating layer is not necessary to achieve an improvement in capacity retention. The results indicate that rather the coating process itself likely causes the improvement of the capacity retention and increases the initial capacity. PMID- 30422621 TI - Enhanced Photoelectrochemical Water Oxidation Performance on BiVO4 by Coupling of CoMoO4 as a Hole-Transfer and Conversion Cocatalyst. AB - Manipulation of interfacial charge separation and transfer is one of the primary breakthroughs to improve the water oxidation activity and stability of BiVO4 photoanode. In the present work, a CoMoO4-coupled BiVO4 (BiVO4/CoMoO4) film was designed and prepared as the photoanode for photoelectrochemical (PEC) water oxidation. Compared with the bare BiVO4 film, obviously improved PEC water oxidation performance was observed on the BiVO4/CoMoO4 film. Specifically, a higher water oxidation photocurrent density of 3.04 mA/cm2 at 1.23 V versus RHE was achieved on the BiVO4/CoMoO4 photoanode, which is of about 220% improvement over bare BiVO4 photoanode (1.34 mA/cm2 at 1.23 V vs RHE). In addition, the BiVO4/CoMoO4 film photoanode was of better stability and faster hole-to-oxygen kinetics for water oxidation, without significant activity attenuation for 6 h of reaction at 0.65 V versus RHE. The enhanced water oxidation performance on the BiVO4/CoMoO4 film photoanode can be ascribed to the synergistic effect of the following factors: (i) thermodynamically, the photogenerated holes of BiVO4 are directionally transferred to CoMoO4 through their physical coupling interface and valance band potential matching; and (ii) kinetically, the transferred holes induce the formation of Co3+-active sites on CoMoO4 that could synergistically oxidize H2O to molecular O2 with stable activity. PMID- 30422622 TI - Enhanced Metabolic Activity of Cytochrome P450 via Carbon Nanocage-Based Photochemical Bionanoreactor. AB - Recently, the early screening of the genotoxicity of new chemicals and drugs calls for the envelope of micro-/nanoreactors for metabolic study. Herein, a novel light-driven enzymatic bionanoreactor is designed with the gold nanoparticle (NP)-modified carbon nanocage (Au@CNC) as a nanoreactor and meso tetrakis(4-carboxyphenyl)porphyrin (TCPP) as a photosensitizer for cytochrome P450-mediated drug metabolism. By confining the cytochrome P450 3A4 (CYP3A4) enzyme and TCPP inside the pores of Au@CNC, a high metabolic activity is achieved by using 7-ethoxytrifluoromethyl coumarin as the substrate because of the three dimensional hierarchical porous structure, large surface area, and fast electron transfer capacity of Au@CNC. It is noted that owing to the presence of AuNPs inside CNC, the surface hydrophilicity of CNC is much improved, which further promotes the catalytic activity of the CYP3A4 enzyme. To our knowledge, this is the first attempt to apply CNC as a bionanoreactor for NADPH-free and light driven in vitro drug metabolism. In addition, the presented bionanoreactor exhibits a variety of advantages in terms of fast response, short assay time (10 min), high sensitivity, and good selectivity, which are expected to expedite drug screening and render potential advances in drug discovery and development. PMID- 30422623 TI - Lattice Incorporation of Cu2+ into the BaCe0.7Zr0.1Y0.1Yb0.1O3-delta Electrolyte on Boosting Its Sintering and Proton-Conducting Abilities for Reversible Solid Oxide Cells. AB - Lattice modification by incorporating heteroatoms could effectively and precisely tune their intrinsic properties to get improved sinterability and electrochemical performance. Here, by introducing Cu2+ into the interstitial position of a ABO3 type perovskite, a 2 times higher protonic conductivity (1.9 * 10-2 S cm-1 at 700 degrees C) and low-temperature (1200 degrees C) sinterability were achieved for the BaCe0.68Zr0.1Y0.1Yb0.1Cu0.02O3-delta (BCZYYC2) electrolyte, compared to the precursor electrolyte. Meanwhile, the modified BCZYYC2 also exhibits excellent chemical stability in high-temperature and high-humidity conditions, as well as good compatibility with the components of cell. When used as the electrolyte in reversible fuel cell (FC)/electrolysis cell (EC) operational modes, the reversible solid oxide cell with the BCZYYC2 electrolyte illustrates prominent FC (0.85 W cm-2 at 700 degrees C) and EC (-1.96 A cm-2 at 700 degrees C and 1.3 V) performances with high film-electrolyte conductivity (8.7 * 10-3 S cm-1 at 700 degrees C). Additionally, an obvious increase in current density is observed during the short-term stability test, which has shown great promise for their practical application. PMID- 30422624 TI - Gold Nanoprisms as Optical Coherence Tomography Contrast Agents in the Second Near-Infrared Window for Enhanced Angiography in Live Animals. AB - Optical coherence tomography angiography (OCTA) is an important tool for investigating vascular networks and microcirculation in living tissue. Traditional OCTA detects blood vessels via intravascular dynamic scattering signals derived from the movements of red blood cells (RBCs). However, the low hematocrit and long latency between RBCs in capillaries make these OCTA signals discontinuous, leading to incomplete mapping of the vascular networks. OCTA imaging of microvascular circulation is particularly challenging in tumors due to the abnormally slow blood flow in angiogenic tumor vessels and strong attenuation of light by tumor tissue. Here, we demonstrate in vivo that gold nanoprisms (GNPRs) can be used as OCT contrast agents working in the second near-infrared window, significantly enhancing the dynamic scattering signals in microvessels and improving the sensitivity of OCTA in skin tissue and melanoma tumors in live mice. With GNPRs as contrast agents, the postinjection OCT angiograms showed 41 and 59% more microvasculature than preinjection angiograms in healthy mouse skin and melanoma tumors, respectively. By enabling better characterization of microvascular circulation in vivo, GNPR-enhanced OCTA could lead to better understanding of vascular functions during pathological conditions, more accurate measurements of therapeutic response, and improved patient prognoses. PMID- 30422625 TI - Directional Flow-Aided Sonochemistry Yields Graphene with Tunable Defects to Provide Fundamental Insight on Sodium Metal Plating Behavior. AB - We report a directional flow-aided sonochemistry exfoliation technique that allows for unparalleled control of graphene structural order and chemical uniformity. Depending on the orientation of the shockwave relative to the flow aligned graphite flakes, the resultant bilayer and trilayer graphene is nearly defect free (at-edge sonication graphene "AES-G") or is highly defective (in plane sonication graphene "IPS-G"). AES-G has a Raman G/D band intensity ratio of 14.3 and an XPS-derived O content of 1.3 at. %, while IPS-G has an IG/D of 1.6 and 6.2 at. % O. AES-G and IPS-G are then employed to understand the role of carbon support structure and chemistry in Na metal plating/stripping for sodium metal battery anodes. The presence of graphene defects and oxygen groups is highly deleterious: In a standard carbonate solution (1 M NaClO4, 1:1 EC-DEC, 5 vol % FEC), AES-G gives stable cycling at 2 mA/cm2 with 100% Coulombic efficiency (CE) (within instrument accuracy) and an area capacity of 1 mAh/cm2. Meanwhile IPS-G performs on-par with the baseline Cu support in terms of poor CE, severe mossy metal dendrites, and periodic electrical shorts. We argue that solid electrolyte interface (SEI) stability is the key for stable cycling, with defects of IPS-G being catalytic toward SEI formation. For IPS-G, the SEI layer also shows F-rich "hot spots" due to accelerated decomposition of FEC additive in localized regions. PMID- 30422626 TI - Design of Fe-Based Bulk Metallic Glasses with Improved Wear Resistance. AB - The application of bulk metallic glasses (BMGs) as advanced wear-resistant materials has remained limited despite optimistic expectations. In this work, we develop a series of novel Fe-based BMGs with improved wear resistance by altering the Cr and Mo contents in an Fe-Cr-Mo-C-B-Y glass-forming system. Experimental results demonstrate that increasing Cr and Mo contents enhance the thermal stability and hardness ( Hv) of the resulting BMGs without reducing their fracture toughness ( Kc). The enhanced hardness is mainly attributed to the increased fraction of the stiff (Cr,Mo)-C covalent bonds in the resultant BMGs, as revealed by X-ray photoelectron spectrograph measurement. Worn surface/subsurface observations and stress field modeling reveal the activity of two kinds of wear mechanisms, i.e., hardness-controlled abrasion wear and toughness-controlled fatigue wear. We further clarify the enhanced wear performance of the Fe-based BMGs according to an effective indicator Kc3/4 Hv1/2 that correlates positively with the wear resistance of the samples. The optimal Fe-based BMG sample possessed versatile properties, including a strong glass forming ability (i.e., a critical diameter of 8 mm), a high hardness of 1335 Hv, and a very low specific wear rate of ~1.3 * 10-6 mm3 N-1 m-1, which represents one of the most outstanding Fe-based BMGs reported thus far. PMID- 30422627 TI - Correlated Materials Characterization via Multimodal Chemical and Functional Imaging. AB - Multimodal chemical imaging simultaneously offers high resolution chemical and physical information with nanoscale, and in select cases atomic resolution. By coupling modalities that collect physical and chemical information, we can address scientific problems in biological systems, battery and fuel cell research, catalysis, pharmaceuticals, photovoltaics, medicine and many others. The combined systems enable local correlation of material properties with chemical makeup, making fundamental questions in how chemistry and structure drive functionality approachable. In this review we present recent progress and offer a perspective for chemical imaging used to characterize a variety of samples by a number of platforms. Specifically, we present cases in infrared and Raman spectroscopies combined with scanning probe microscopy; optical microscopy and mass spectrometry; nonlinear optical microscopy; and finally, ion, electron and probe microscopies with mass spectrometry. We also discuss the challenges associated with the use of data originated by the combinatorial hardware, analysis, and machine learning as well as processing tools necessary for interpretation of multidimensional data acquired from multimodal studies. PMID- 30422628 TI - Pulse Dynamics of Electric Double Layer Formation on All-Solid-State Graphene Field-Effect Transistors. AB - Electric double layer (EDL) dynamics in graphene field-effect transistors (FETs) gated with polyethylene oxide (PEO)-based electrolytes are studied by molecular dynamics (MD) simulations from picoseconds to nanoseconds and experimentally from microseconds to milliseconds. Under an applied field of approximately mV/nm, EDL formation on graphene FETs gated with PEO:CsClO4 occurs on the timescale of microseconds at room temperature and strengthens within 1 ms to a sheet carrier density of nS ~ 1013 cm-2. Stronger EDLs (i.e., larger nS) are induced experimentally by pulsing with applied voltages exceeding the electrochemical window of the electrolyte; electrochemistry is avoided using short pulses of a few milliseconds. Dynamics on picosecond to nanosecond timescales are accessed using MD simulations of PEO:LiClO4 between graphene electrodes with field strengths of hundreds of mV/nm which is 100* larger than experiment. At 100 mV/nm, EDL formation initiates in sub-nanoseconds achieving charge densities up to 6 * 1013 cm-2 within 3 nanoseconds. The modeling shows that under sufficiently high electric fields, EDLs with densities ~1013 cm-2 can form within a nanosecond, which is a timescale relevant for high-performance electronics such as EDL transistors (EDLTs). Moreover, the combination of experiment and modeling shows that the timescale for EDL formation ( nS = 1013 to 1014 cm-2) can be tuned by 9 orders of magnitude by adjusting the field strength by only 3 orders of magnitude. PMID- 30422629 TI - Mechanistic Characterization of Long Residence Time Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2). AB - Diacylglycerol acyltransferase2 (DGAT2) catalyzes the final step in triacylglycerol (TAG) synthesis. Genetic knockdown or pharmacological inhibition of DGAT2 leads to reduction in very-low-density lipoprotein (VLDL) TAG secretion and hepatic lipid levels in rodents, indicating DGAT2 may represent an attractive therapeutic target for treatment of hyperlipidemia and hepatic steatosis. We have previously described potent and selective imidazopyridine DGAT2 inhibitors with high oral bioavailability. However, the detailed mechanism of DGAT2 inhibition has not been reported. Herein, we describe imidazopyridines represented by (PF 06424439, 1) and (2) as long residence time inhibitors of DGAT2. We demonstrate that 1 and 2 are slowly reversible, time-dependent inhibitors, which inhibit DGAT2 in a noncompetitive mode with respect to the acyl-CoA substrate. Detailed kinetic analysis demonstrated that 1 and 2 inhibit DGAT2 in a two-step binding mechanism, in which the initial enzyme-inhibitor complex (EI) undergoes an isomerization step resulting in a much higher affinity complex (EI*) with overall inhibition constants (Ki* values) of 16.7 and 16.0 nM for 1 and 2, respectively. The EI* complex dissociates with dissociation half-lives of 1.2 and 1.0 hr for 1 and 2, respectively. A binding assay utilizing [125I]-labeled imidazopyridine demonstrated that imidazopyridine binding to DGAT2 mutant enzymes, H161A and H163A, dramatically decreased to 11-17% of that of the WT enzyme, indicating that these residues are critical for imidazopyridines to bind to DGAT2. Taken together, imidazopyridines may thus represent a promising lead series for the development of DGAT2 inhibitors that display an unprecedented combination of potency, selectivity, and in vivo efficacy. PMID- 30422630 TI - A "Soft" and "Hard" Ionization Method for Comprehensive Studies of Molecules. AB - Ambient mass spectrometry can be rapidly and directly effective for molecular studies, while there still seems to be a gap between two major groups of electrospray ionization (ESI)- and atmospheric pressure chemical ionization (APCI)-related techniques, for detection of moderately polar to polar and low polar to nonpolar molecules in a relatively low mass range, respectively. Here, an extensively applicable "soft" and "hard" ionization method, spray-dependent plasma mass spectrometry (SDP MS), was established for detecting various molecules with diverse polarities or molecular weights. By SDP MS, both fragment ions and intact molecular ions can be obtained. Significantly, cluster ions of aggregates in high mass range formed by weak molecular interactions can also be well recorded, much softer than traditional ESI MS. By filling the gap between ESI-based and APCI-based ionization techniques, SDP MS would enhance MS performance for comprehensive molecular studies and be extensively applicable in fields of organic synthesis, biological chemistry, medical chemistry, and clinical diagnosis. PMID- 30422631 TI - Microwave-Assisted Solvothermal Synthesis of Upconverting and Downshifting Rare Earth-Doped LiYF4 Microparticles. AB - Growing attention toward optically active materials has prompted the development of novel synthesis methods for a more reliable and efficient access to these systems. In this regard, microwave-assisted approaches provide unique advantages over traditional solvothermal methods reliant on convectional heating: namely, significantly shorter reaction durations, more rigid reaction conditions, and thus a higher degree of reproducibility. Reported herein for the first time is a rapid synthesis of rare-earth (RE3+)-doped LiYF4 upconverting and downshifting microparticles with well-defined bipyramidal morphology and good size dispersion via a microwave-assisted solvothermal process. The suggested material growth mechanism identifies a suitable Li+ to RE3+ ion ratio, an abundance of pH sensitive acetate surface-capping ligands, and an appropriate reaction temperature/time profile as crucial for enabling a phase transformation of an intermediary yttrium ammonium fluoride phase into LiYF4 and subsequent particle ripening. The versatility of the reported method is highlighted by its extension toward the synthesis of other state of the art M(RE)F4 (M = alkali metal) optical materials: RE3+-doped LiYbF4 microparticles and beta-NaGdF4 and alpha-NaYF4 nanoparticles. All of the obtained Yb3+/Er3+- and Yb3+/Tm3+-codoped M(RE)F4 materials exhibited characteristic upconversion emission, while downshifting capabilities were induced through Ce3+/Tb3+ codoping of LiYF4. Further attention was devoted to single-particle optical characterization via hyperspectral imaging of Yb3+/Er3+- and Yb3+/Tm3+-codoped LiYF4 microparticles to explore the spatial variability of upconversion emission within individual particles. PMID- 30422632 TI - Delayed Puberty by Ziram Is Associated with Down Regulation of Testicular Phosphorylated AKT1 and SIRT1/PGC-1alpha Signaling. AB - Ziram is a dimethyldithiocarbamate fungicide, which may influence the male reproductive system as a potential endocrine disruptor. We interrogated the disruption of ziram on rat progenitor Leydig cell development. Prepubertal male Sprague-Dawley rats were orally treated with 0, 2, 4, or 8 mg/kg ziram for 2 weeks. We investigated the effects of ziram on serum testosterone levels, Leydig cell number, and Leydig and Sertoli cell gene and protein expression, SIRT1/PGC 1alpha levels, and phosphorylation of AKT1, ERK1/2, and AMPK in vivo. We also interrogated the effects of ziram on reactive oxidative species (ROS) level, apoptosis rate, and mitochondrial membrane potential of progenitor Leydig cells in vitro. Ziram decreased serum testosterone and follicle-stimulating hormone levels, the down-regulated Leydig cell-specific gene ( Lhcgr, Scarb1, Star, Cyp17a1, and Hsd17b3), and their protein expression. However, ziram stimulated anti-Mullerian hormone production. Ziram lowered SIRT1/PGC-1alpha and phosphorylated protein levels of AKT1. Ziram induced ROS and apoptosis and lowered the mitochondrial membrane potential of progenitor Leydig cells in vitro. In conclusion, ziram disrupts Leydig cell development during the prepubertal period potentially through the SIRT1/PGC-1alpha and phosphorylated AKT1 signaling. PMID- 30422633 TI - Proxy Measures for Simplified Environmental Assessment of Manufactured Nanomaterials. AB - Proxy measures have been proposed as a low-data option for simplified assessment of environmental threat given the high complexity of the natural environment. We here review studies of environmental release, fate, toxicity, and risk to identify relevant proxy measures for manufactured nanomaterials (MNMs). In total, 18 potential proxy measures were identified and evaluated regarding their link to environmental risk, an aspect of relevance, and data availability, an aspect of practice. They include socio-technical measures (e.g., MNM release), particle specific measures (e.g., particle size), partitioning coefficients (e.g., the octanol-water coefficient), and other fate-related measures (e.g., half-life) as well as various ecotoxicological measures (e.g., 50% effect concentration). For most identified proxy measures, the link to environmental risk was weak and data availability low. Two exceptions were global production volume and ecotoxicity, for which the links to environmental risk are strong and data availability relatively decent. As proof of concept, these were employed to assess seven MNMs: titanium dioxide, cerium dioxide, zinc oxide, silver, silicon dioxide, carbon nanotubes, and graphene. The results show that none of the MNMs have both high production volumes and high ecotoxicity. Several refinements of the assessment are possible, such as higher resolution regarding the MNMs assessed (e.g., different allotropes) and different metrics (e.g., particle number and surface area). The proof of concept shows the feasibility of using proxy measures for environmental assessment of MNMs, in particular for novel MNMs in early technological development, when data is particularly scarce. PMID- 30422634 TI - Fixable Molecular Thermometer for Real-Time Visualization and Quantification of Mitochondrial Temperature. AB - A change of mitochondrial temperature can be an important indicator of mitochondrial metabolism that generates considerable heat. For this reason, development of fluorescent probes to detect mitochondrial temperature has become an attractive topic. Previous efforts have successfully addressed the major issues, such as temperature sensitivity and mitochondrial targetability. However, there remains a key obstacle to practical applications. Considering the highly dynamic features of mitochondria, especially the variation of the inner-membrane potential, it is quite necessary to permanently immobilize a temperature probe in mitochondria in order to avoid unstable intracellular localization along with the changes of mitochondrial status. Herein, we report Mito-TEM, the first fixable, fluorescent molecular thermometer. Mito-TEM is based on a positively charged rhodamine B fluorophore that has the tendency of being attracted to mitochondria, which have negative potential. This fluorophore containing rotatable substituents also contributes to the temperature-responsive fluorescence property. Most importantly, a benzaldehyde is introduced in Mito-TEM as an anchoring unit that condenses with aminos of the protein and thus immobilizes the probe in mitochondria. The specific immobilization of Mito-TEM in mitochondria is unambiguously demonstrated in colocalization imaging. By using Mito-TEM, a method of visualizing and quantifying a temperature distribution through grayscale imaging of mitochondria is established and further applied to monitor the temperature changes of live cells under light heating and PMA stimulation. PMID- 30422635 TI - Topological Transition in Spontaneously Formed Cellulosic Liquid-Crystalline Microspheres in a w/o Emulsion. AB - A cholesteric liquid crystal (ChLC) in a confined space has attracted significant scientific interest and has potential applications. ChLC microspheres have been obtained by devising processing such as a microfluidic technique. Herein, we adopted the self-assembly approach for the spontaneous formation of cellulosic ChLC microspheres. A functional block copolymer (BCP) was grafted to hydroxypropyl cellulose (HPC), making it amphiphilic to self-assembly in a w/o emulsion. The HPC segment aggregated in the aqueous phase under lyotropic conditions and produced the ChLC microspheres dispersed in the oil phase. The microspheres exhibited a topological transition between radial and bipolar while altering the molecular structure in terms of the molecular weight of BCP and the degree of substitution of HPC. The coexistence of inorganic salts in the aqueous HPC lyotropic phase changed the mesophase behavior as well. Such cellulosic ChLC microspheres will present opportunities to develop biobased optical devices and stimuli-responsive biomedical materials. PMID- 30422636 TI - A Dynamic Heterometal-Organic Rhomboid Exhibiting Thermochromic and Piezochromic Luminescence. AB - Heterometallic grids or rhomboids, in which two or more different metal ions are periodically segregated throughout a lattice, can give rise to emergent synergistic multifunctionalities but are typically static in nature because of strong metal-ligand binding. Here, a heterobimetallic C2-symmetric rhomboid, [Zn2Dy2] (1), was self-assembled from a naphthol-containing asymmetric ligand and 3d/4f mixed-metal ions. We show that a heavy structural twist of bridge ligands around the heterometallic centers can induce a translation ("stretch-elastic phase" behavior) related to the shape of the metallorhomboid and facilitates a luminescence response to external stimuli, such as temperature, mechanical pressure, etc. PMID- 30422637 TI - Specific lipid and metabolic profiles of R-CHOP-resistant diffuse large B-cell lymphoma elucidated by matrix-assisted laser desorption ionization mass spectrometry imaging and in vivo imaging. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell non-Hodgkin lymphoma. To treat this aggressive disease, R-CHOP, a combination of immunotherapy (R; rituximab) and chemotherapy (CHOP; cyclophosphamide, doxorubicin, vincristine and prednisone), remains the most commonly used regimen for newly diagnosed DLBCLs. However, up to one-third of patients ultimately becomes refractory to initial therapy or relapses after treatment, and the high mortality rate highlights the urgent need for novel therapeutic approaches based upon selective molecular targets. In order to understand the molecular mechanisms underlying relapsed DLBCL and to find better therapeutic targets, we studied differences in the chemical composition after R-CHOP treatment and tumor relapse, using a combination of in vivo DLBCL xenograft models and mass spectrometry imaging. Together, these techniques provide information regarding analyte composition and molecular distributions of therapy-resistant and sensitive areas. We found specific lipid and metabolic profiles for R-CHOP-resistant tumors such as a higher presence of phosphatidylinositol and sphingomyelin fragments. In addition, we investigated intratumor heterogeneity and identified specific lipid markers of viable and necrotic areas. Furthermore, we could monitor metabolic changes, and found reduced adenosine triphosphate and increased adenosine monophosphate in the R-CHOP-resistant tumors. This work highlights the power of combining in vivo imaging and MSI to track molecular signatures in DLBCL, which has potential application for other diseases. PMID- 30422638 TI - Influence of Chain Length on the Structures and Dynamic Behavior of Alkyl Tethered alpha,omega-Diphosphide Complexes of Lithium and Their Use in the Synthesis of P-Heterocyclic Stannylenes. AB - The alkyl-tethered alpha,omega-diphosphines (Dipp)PH(CH2) nPH(Dipp) ( n = 1 (3H), 2 (4H), 3 (5H), 4 (6H), and 5 (7H)) were prepared in good yield and characterized by multinuclear NMR spectroscopy [Dipp = 2,6- iPr2C6H3]. Treatment of 3H with 2 equiv of nBuLi and 2 equiv of TMEDA gives the diphosphide complex [CH2{P(Dipp)}2]Li2(TMEDA)2 (3Lia), which crystallizes as discrete monomers which do not exhibit temperature-dependent NMR behavior. Treatment of 4H-7H with 2 equiv of nBuLi in THF gives the diphosphides [[CH2{P(Dipp)}]2]2Li4(THF)2(OEt2)2 (4Li), [CH2{CH2P(Dipp)}2]Li2(THF)4 (5Li), [{CH2CH2P(Dipp)}2]Li2(THF)6 (6Li), and [CH2{CH2CH2P(Dipp)}2]2Li4(THF)6.PhMe (7Li) after crystallization. Compounds 4Li 7Li adopt either monomeric or dimeric structures in the solid state, depending on the length of the alkyl tether of the diphosphide ligand. In solution, compounds 4Li-7Li exhibit dynamic behavior: variable-temperature 31P{1H} and 7Li NMR spectroscopic studies indicate that this involves equilibria between monomeric and dimeric or higher oligomeric species with the nature of the equilibrium again depending on the length of the alkyl tether of the diphosphide ligand. The reactions between 3Li, 6Li, or 7Li and SnCl2 in THF give mixtures of products which could not be separated. In contrast, the reactions between 4Li or 5Li and 1 equiv of SnCl2 give the dimeric P-heterocyclic stannylenes [{CH2P(Dipp)}2Sn]2 (4Sn) and [CH2{CH2P(Dipp)}2Sn]2.1/2THF (5Sn), respectively. While compound 5Sn is isolated exclusively as the cis isomer, 4Sn is isolated as a mixture of cis and trans isomers in an approximate 5:1 ratio. The solid-state structures of trans 4Sn and cis-5Sn were obtained, and multinuclear NMR spectroscopy indicates that the dimeric structures of these compounds are maintained in solution. Compounds 4Sn and 5Sn represent the first P-heterocyclic stannylene dimers to be structurally characterized. PMID- 30422639 TI - Impact of Ferrocene Substitution on the Electronic Properties of BODIPY Derivatives and Analogues. AB - Bis(ferrocenyl)-functionalized boron dipyrromethene (BODIPY) compound 1 featuring direct Fc-B bonds was obtained via a "prefunctionalization strategy". UV-vis absorption, electrochemical, and transient absorption experiments were performed on compound 1 and its analogues to examine the impact of ferrocenyl substitution on the electronic properties. The ferrocene units were found to have little impact on the absorption spectrum of the BODIPY unit but significantly change the excited-state dynamics. PMID- 30422640 TI - A Nuclear Resonance Vibrational Spectroscopic Study of Oxy Myoglobins Reconstituted with Chemically Modified Heme Cofactors: Insights into the Fe-O2 Bonding and Internal Dynamics of the Protein. AB - The molecular mechanism of O2 binding to hemoglobin (Hb) and myoglobin (Mb) is a long-standing issue in the field of bioinorganic and biophysical chemistry. The nature of Fe-O2 bond in oxy Hb and Mb had been extensively investigated by resonance Raman spectroscopy, which assigned the Fe-O2 stretching bands at ~570 cm-1. However, resonance Raman assignment of the vibrational mode had been elusive due to the spectroscopic selection rule and to the limited information available about the ground-state molecular structure. Thus, nuclear resonance vibrational spectroscopy was applied to oxy Mbs reconstituted with 57Fe-labeled native heme cofactor and two chemically modified ones. This advanced spectroscopy in conjunction with DFT analyses gave new insights into the nature of the Fe-O2 bond of oxy heme by revealing the effect of heme peripheral substitutions on the vibrational dynamics of heme Fe atom, where the main Fe-O2 stretching band of the native protein was characterized at ~420 cm-1. PMID- 30422641 TI - Cyano-Based Materials with Giant Optical Anisotropy and Second Harmonic Generation Effect. AB - It is a huge challenge to achieve giant optical anisotropy (e.g., birefringence) over a wide region from infrared (IR) to ultraviolet (UV) spectroscopy. This is mainly due to the lack of ideal optical motifs, which should have giant structural anisotropy with a wide transparent range. Especially in the field of nonlinear optical (NLO) materials, polar motifs with giant optical anisotropy are extremely scarce, but they are favorable to exhibit strong second harmonic generation (SHG) effect and phase-matching capacity. On the basis of analysis of microstructure and macro optical property, in this study, we focus on one dimensional chained cyano (CN) motif and surprisingly find that it can exhibit sufficiently large optical anisotropy and SHG effect from IR to UV regions. Therefore, it is reasonable to believe that the CN motif can be considered as a novel NLO material gene, which was totally ignored in the previous studies. Interestingly, the CN-gene can be integrated into various coordination structures, such as metal cyanides, cyanogen halides, and cyanogen chalcogenides, to promote these materials to exhibit tunable NLO capabilities from IR to UV and deep-UV regions. Remarkably, the chained acentric CNI structure, which has already been obtained in the experiment, can achieve the IR and UV frequency conversion with a sufficiently large SHG effect (~17 pm/V) and a giant optical birefringence (~0.7 at 1064 nm). Therefore, the cyano-based compounds proposed in this article can not only enrich the structural chemistry of NLO materials, but also potentially advance the development of optical material genome project. PMID- 30422642 TI - Structural Manipulation of Triboluminescent Lanthanide Coordination Polymers by Side-Group Alteration. AB - Novel Eu(III) coordination polymers with furan-based bridging ligands [Eu(hfa)3(Cy)] n and [Eu(hfa)3(Tol)] n (hfa: hexafluoroacetylacetonato, Cy: 2,5 bis(dicyclohexylphosphoryl)furan), Tol: 2,5-bis(di- p-tolylphosphoryl)furan) are reported. The rigidity of assembly steric structures was controlled by intermolecular interactions through the side groups in bridging ligands. They exhibited one of the best performances (thermal stability above 320 degrees C and external photoluminescence quantum yields of up to 71%) among reported lanthanide(III) compounds. The triboluminescence activity was demonstrated to be dependent on the mechanical stability of the coordination polymers, which was proportional to the number of hydrogen atoms in the side groups. The second example of a large TL/PL spectral difference in [Tb,Eu(hfa)3(Tol)] n also revealed discrete photophysical processes under the conditions of grinding and UV irradiation. PMID- 30422643 TI - Stabilizing Copper for CO2 Reduction in Low-Grade Electrolyte. AB - We demonstrate herein a CO2 reduction electrocatalyst regeneration strategy based on the manipulation of the Cu(0)/Cu2+ equilibrium with high concentrations of ethylenediaminetetraacetic acid (EDTA). This strategy enables the sustained performance of copper catalysts in distilled and tap water electrolytes for over 12 h. The deposition of common electrolyte impurities such as iron, nickel, and zinc is blocked because EDTA can effectively bind the metal ions and negatively shift the electrode potential of M/M n+. The Cu/Cu2+ redox couple is >600 mV more positive than the other metal ions and therefore participates in an equilibrium of dissolution and redeposition from and to the electrode in high concentrations of EDTA. These dynamic equilibria serve to further regenerate the surface copper catalyst to prevent the deactivation of catalytic sites. On the basis of this strategy, we show that >95% of initial hydrocarbon production activity can be maintained for 12 h in KHCO3 (99% purity) enriched distilled water and 6 h in KHCO3 (99% purity) enriched tap water. PMID- 30422644 TI - Improving the Global Electrophilicity Index (GEI) as a Measure of Lewis Acidity. AB - The global electrophilicity index (GEI) has been further explored as a general and base-free metric for Lewis acidity. A number of computational methods, including post-Hartree-Fock, density functional theory, and time-dependent density functional theory, have been explored. In this fashion, we sought the method most applicable to a range of different Lewis acids with differing structural and electronic features, including boron trihalides, silicon tetrahalides, fluoroaryl boranes, and group 15 pentahalides. The most accurate and computationally efficient approach was found to use the energies of the orbitals from a geometry optimization at the B3LYP/def2-TZVP level of theory. In addition, the GEI is shown to act as an effective acidity metric that is complementary to the fluoride ion affinity. The GEI also proved to be a better gauge of Lewis acidity for softer bases, as confirmed by comparison to the iodide ion affinity of the group 15 pentahalides. PMID- 30422645 TI - Highly Efficient Desalting by Silica Isoporous Membrane-Based Microfluidic Chip for Electrospray Ionization Mass Spectrometry. AB - Nonvolatile buffers and inorganic salts used for isolation and stabilization of biological samples are essential to be cleaned up prior to mass spectrometry (MS) analysis because of their deleterious effects such as ion suppression and instrumental pollution. In this work, a centimeter-scale continuous silica isoporous membrane (SIM) was prepared and integrated into a facile microfluidic chip for the desalting of protein samples based on dialysis principle. Thanks to the uniform pore size (~2.3 nm in diameter), ultrasmall thickness (90 nm) and high pore density (4.0 * 1012 pores cm-2, corresponding to a porosity of 16.7%) of SIM, the device achieved ~99% desalting efficiency for the sample with 154 mM NaCl (isotonic saline) at a flow rate of 1 MUL min-1, while protein loss was only 5%. High-quality electrospray ionization (ESI)-MS spectra of cytochrome c dissolved in isotonic saline was obtained after the desalting treatment. In addition, the SIM-based microfluidic device was successfully online-coupled with microchip ESI-MS for real-time desalting and characterization of proteins. PMID- 30422646 TI - Determination and Prediction of Zinc Speciation in Estuaries. AB - Lowering of the estuarine Environmental Quality Standard for zinc in the UK to 121 nM reflects rising concern regarding zinc in ecosystems and is driving the need to better understand its fate and behavior and to develop and parametrize speciation models to predict the metal species present. For the first time, an extensive data set has been gathered for the speciation of zinc within an estuarine system with supporting physicochemical characterization, in particular dissolved organic carbon. WHAM/Model VII and Visual MINTEQ speciation models were used to simulate zinc speciation, using a combination of measured complexation variables and available defaults. Data for the five estuarine transects from freshwater to seawater endmembers showed very variable patterns of zinc speciation depending on river flows, seasons, and potential variations in metal and ligand inputs from in situ and ex situ sources. There were no clear relationships between free zinc ion concentration [Zn2+] and measured variables such as DOC concentration, humic and biological indices. Simulations of [Zn2+] carried out with both models at high salinities or by inputting site specific complexation capacities were successful, but overestimated [Zn2+] in low salinity waters, probably owing to an underestimation of the complexation strength of the ligands present. Uncertainties in predicted [Zn2+] are consistently smaller than standard deviations of the measured values, suggesting that the accuracy of the measurements is more critical than model uncertainty in evaluating the predictions. PMID- 30422647 TI - Concise Chemistry Modulation of the SMM Behavior within a Family of Mononuclear Dy(III) Complexes. AB - By means of the facile chemistry, structural assembly, and transformation of four mononuclear Dy(III) complexes, Dy(bpad)3.CH3OH.H2O (1), Dy(bpad)2(H2O)2.NO3 (2), [Dy(bpad)2(tmhd)] (3), and [Dy(bpad)2(btfa)] (4) (Hbpad = N3-benzoylpyridine-2 carboxamidrazone, tmhd = 2,2,6,6-tetramethylheptane-3,5-dione, btfa = 3-benzoyl 1,1,1-trifluoroacetone), with distinct architectures and local symmetries were established. The disparity of the coordination geometries around the Dy(III) ion among these complexes impacts the strength of the crystal field and the local tensor of anisotropy ( D) of each Dy site and their relative orientations, therefore giving rise to diverse SIM behaviors with distinguishing relaxation energy barriers of 106.93 K for 1, 52.55 K for 2, 48.16 K for 3, and 51.41 K for 4. The differences of the magnetic property and the magnetic anisotropy for four complexes have been explained by ab initio calculations, which are corresponding to the experimental results. PMID- 30422648 TI - Electrochemically Promoted Tyrosine-Click-Chemistry for Protein Labeling. AB - The development of new bio-orthogonal ligation methods for the conjugation of native proteins is of particular importance in the field of chemical biology and biotherapies. In this work, we developed a traceless electrochemical method for protein bioconjugation. The electrochemically promoted tyrosine-click (e-Y-CLICK) allowed the chemoselective Y-modification of peptides and proteins with labeled urazoles. A low potential is applied in an electrochemical cell to activate urazole anchors in situ and on demand, without affecting the electroactive amino acids from the protein. The versatility of the electrosynthetic approach was shown on biologically relevant peptides and proteins such as oxytocin, angiotensin 2, serum bovine albumin, and epratuzumab. The fully conserved enzymatic activity of a glucose oxidase observed after e-Y-CLICK further highlights the softness of the method. The e-Y-CLICK protocols were successfully performed in pure aqueous buffers, without the need for co-solvents, scavenger or oxidizing chemicals, and should therefore significantly broaden the scope of bioconjugation. PMID- 30422649 TI - Guiding Synthesis of Polymorphs of Materials Using Nanometric Phase Diagrams. AB - Conventionally, phase diagrams serve as road maps for the design and synthesis of materials. However, bulk phase diagrams are often not as predictive for the synthesis of nanometric materials, mainly due to the increased significance of surface energy. The change of surface energy can drastically alter the total energy of the nanocrystals and thus yields a polymorph or metastable phase different from the stable phase in bulk, providing a means for controlling the synthesis of metastable phases. To achieve a theoretical and systematical understanding on the polymorphism of nanomaterials, metallic cobalt was chosen as a model system, where the two polymorphs, fcc and hcp phases, can be tuned with 100% selectivity in a solvothermal reaction. Advanced in situ synchrotron X-ray diffraction (XRD) technique and density functional theory (DFT) calculations were complementarily employed to reveal the size- and surface-dependent polymorphism at nanometer scale. The nanometric phase diagram provides a general predictive approach to guide the synthesis of metastable materials. PMID- 30422650 TI - Nanometer Confinement-Driven Promotion and Stabilization of a Hexatic Phase Intervening between Ordered Rotator Phases. AB - Bulk phase binary mixture of two rotator phase forming alkanes, n-tricosane (C23H48) and n-octacosane (C28H58), has been previously studied. C23H48 exists in the RII and RI phases, whereas C28H58 exists in the RIII and RIV phases. Over a certain range of composition, this binary mixture was found to exist in RII, RI and an intervening mesophase was reported to be the hexatic phase, wherein the long-range two-dimensional in-plane hexagonal lattice order of the RII is lost and what remains is molecules present in hexagonal geometry without long-range positional correlation between individual hexagons. Upon confinement in cylindrical anodized alumina pores 200 nm wide, on the one hand, the temperature range of the hexatic phase was found to extend, and on the other hand, it underwent increased molecular ordering compared to the hexatic phase in bulk, exhibiting two counter-reacting behaviors in confinement. We provide here a temperature-dependent X-ray diffraction study and a theoretical approach combining the Landau and Flory-Huggins theories to, first, understand the underlying mechanism leading to emergence of the hexatic phase and then to explain the effect of confinement on it in the light of finite size and interfacial interaction between the alkanes and alumina pores. PMID- 30422651 TI - Synthesis and Computational Study of Semicroconaines and Nonsymmetric Croconaines. AB - The synthesis of two new dye families of croconic acid derivatives, semicroconaine and nonsymmetric croconaine dyes, is reported for the first time. These compounds show strong absorption in the UV-visible and NIR, respectively. Semicroconaine dyes were obtained by a scalable and efficient condensation of croconic acid with aromatic heterocyclic methylene-active compounds. The subsequent reaction of the semicroconaine dyes with aromatic heterocyclic compounds affords nonsymmetric croconaines. The structure and electronic properties of the synthesized compounds have been investigated by preliminary theoretical calculations at DFT level of approximation. PMID- 30422652 TI - Design, Synthesis, and Biological Evaluation of Cytochrome P450 1B1 Targeted Molecular Imaging Probes for Colorectal Tumor Detection. AB - Cytochrome P450 1B1 (CYP1B1) was found to be universally expressed in various tumors. Herein, we reported near-infrared fluorescent imaging probes for tumor detection via visualizing CYP1B1. After introducing the linker to a CYP1B1 selective inhibitor we found previously, we got the resulting compound 5b which kept strong inhibition ability against CYP1B1 (IC50 = 8.7 +/- 1.2 nM) and high selectivity. Then, in vitro microscope studies and cell binding assay of probes indicated that the corresponding probe 6b could specifically be accumulated in CYP1B1 overexpressed colorectal cancer cell HCT-15 and showed satisfying binding affinity to target. During the in vivo noninvasive optical imaging, 6b was proved to rapidly lighten tumor in vivo as early as 6 h after injection. This work is the first attempt to visualize CYP1B1 for noninvasive imaging of tumor which could provide new approach for tumor diagnosis. PMID- 30422653 TI - Adaptation of a Bacterial Multidrug Resistance System Revealed by the Structure and Function of AlbA. AB - To combat the rise of antimicrobial resistance, the discovery of new antibiotics is paramount. Albicidin and cystobactamid are related natural product antibiotics with potent activity against Gram-positive and, crucially, Gram-negative pathogens. AlbA has been reported to neutralize albicidin by binding it with nanomolar affinity. To understand this potential resistance mechanism, we determined structures of AlbA and its complex with albicidin. The structures revealed AlbA to be comprised of two domains, each unexpectedly resembling the multiantibiotic neutralizing protein TipA. Binding of the long albicidin molecule was shared pseudosymmetrically between the two domains. The structure also revealed an unexpected chemical modification of albicidin, which we demonstrate to be promoted by AlbA, and to reduce albicidin potency; we propose a mechanism for this reaction. Overall, our findings suggest that AlbA arose through internal duplication in an ancient TipA-like gene, leading to a new binding scaffold adapted to the sequestration of long-chain antibiotics. PMID- 30422654 TI - SMD-Based Interaction-Energy Fingerprints Can Predict Accurately the Dissociation Rate Constants of HIV-1 Protease Inhibitors. AB - Recent research has increasingly suggested that the crucial factors affecting drug potencies are related not only to the thermodynamic properties but also to the kinetic properties. Therefore, in silico prediction of ligand-binding kinetic properties, especially the dissociation rate constant ( koff), has aroused more and more attention. However, there are still a lot of challenges that need to be addressed. In this paper, steered molecular dynamics (SMD) combined with residue based energy decomposition was employed to predict the dissociation rate constants of 37 HIV-1 protease inhibitors (HIV-1 PIs). For the first time, a predictive model of the dissociation rate constant was established by using the interaction-energy fingerprints sampled along the ligand dissociation pathway. On the basis of the key fingerprints extracted it can be inferred that the dissociation rates of 37 HIV-1 PIs are basically determined in the first half of the dissociation processes and that the H-bond interactions with active-site Asp25 and van der Waals interactions with flap-region Ile47 and Ile50 have important influences on the dissociation processes. In general, the strategy established in this paper can provide an efficient way for the prediction of dissociation rate constants as well as the unbinding mechanism research. PMID- 30422655 TI - Copper Induced Radical Dimerization of alpha-Synuclein Requires Histidine. AB - Aggregation of the neuronal protein alpha-synuclein (alphaS) is a critical factor in the pathogenesis of Parkinson's disease. Analytical methods to detect post translational modifications of alphaS are under development, yet the mechanistic underpinnings of biomarkers like dityrosine formation within alphaS have yet to be established. In our work, we demonstrate that CuI-bound N-terminally acetylated alphaS (NAcalphaS) activates O2 resulting in both intermolecular dityrosine cross-linking within the fibrillar core as well as intramolecular cross-linking within the C-terminal region. Substitution of the H50 residue with a disease relevant Q mutation abolishes intermolecular dityrosine cross-linking and limits the CuI/O2 promoted cross-linking to the C-terminal region. Such a dramatic change in reaction behavior establishes a previously unidentified role for H50 in facilitating intermolecular cross-linking. Involvement of H50 in the reaction profile implies that long-range histidine coordination with the upstream CuI coordination site is necessary to stabilize the transition of CuI to CuII as is a required mechanistic outcome of CuI/O2 reactivity. The aggregation propensity of NAcH50Q-CuI is also enhanced in comparison to NAcalphaS-CuI, suggesting a potential functional role for both copper and intermolecular cross linking in attenuating NAcalphaS fibrillization. PMID- 30422656 TI - Monte Carlo Simulation of Strain-Enhanced Stereocomplex Polymer Crystallization. AB - We performed dynamic Monte Carlo simulations to investigate strain-induced polymer crystallization under separate enhancements of the driving forces for homocomponent and stereocomplex crystallization in the half-half symmetric racemic polymer blends. The results showed that the polymer strain significantly enhances the stereocomplex crystallization, in comparison to the parallel cases of template-induced crystal growth without any strain in the previous simulations. We attributed the results to the strain-induced polymer crystallization favoring intermolecular crystal nucleation at high temperatures, which benefits the stereocomplex crystallization. Our observations provided a molecular-level interpretation to the strain- or shear-enhanced stereocomplex crystallization in the racemic polylactide blends. PMID- 30422657 TI - Machine Learning Distinguishes with High Accuracy between Pan-Assay Interference Compounds That Are Promiscuous or Represent Dark Chemical Matter. AB - Assay interference compounds give rise to false-positives and cause substantial problems in medicinal chemistry. Nearly 500 compound classes have been designated as pan-assay interference compounds (PAINS), which typically occur as substructures in other molecules. The structural environment of PAINS substructures is likely to play an important role for their potential reactivity. Given the large number of PAINS and their highly variable structural contexts, it is difficult to study context dependence on the basis of expert knowledge. Hence, we applied machine learning to predict PAINS that are promiscuous and distinguish them from others that are mostly inactive. Surprisingly accurate models can be derived using different methods such as support vector machines, random forests, or deep neural networks. Moreover, structural features that favor correct predictions have been identified, mapped, and categorized, shedding light on the structural context dependence of PAINS effects. The machine learning models presented herein further extend the capacity of PAINS filters. PMID- 30422658 TI - A Dual Ionic Liquid-Based Low-Temperature Electrolyte System. AB - Ionic liquids (ILs) show a promising future as electrolytes in electrochemical devices. In particular, IL-based electrolytes bring operations at extreme temperatures to realization that conventional electrolytes fail to accomplish. Although IL electrolytes demonstrate considerable progress in high-temperature applications, their breakthroughs in devices operating at low temperatures are still very limited due to undesirable phase transitions and unsatisfying transport properties. In this study, we present an approach where, by tuning molecular interactions in the system, the designed electrolyte of an IL-based mixture can reach a lower operating temperature with improved transport properties. We have discovered that the incorporation of the IL, ethylammonium nitrate ([EA][N]), can contribute to reforming the molecular interactions within the system, which effectively resolve the crystallization accompanied with the excess of water and retain a low glass transition temperature. The reported liquid electrolyte systems based on a mixture of 1-butyl-3-methylimidazolium iodide ([BMIM][I]), [EA][N], water, and lithium iodide exhibit a glass transition temperature below -105 degrees C. Furthermore, the optimized electrolyte system shows significant viscosity reduction and ionic conductivity enhancement from 25 to -75 degrees C. The influence is also noticeable on the increased ionicity, which made the developed electrolyte comparable with other good ILs under the Walden rule. The electrochemical stability of the electrolyte system is revealed by a steady and reproducible profile of iodide/triiodide redox reactions at room temperature over a proper potential window via cyclic voltammetry. The results from this work not only provide a potential solution to applications of the iodide/triiodide redox couple-based electrochemical devices at low temperatures but also show a practical approach to obtain tailored properties of a mixture system via modifying molecular interactions. PMID- 30422659 TI - trans-Hydrogenation, gem-Hydrogenation, and trans-Hydrometalation of Alkynes: An Interim Report on an Unorthodox Reactivity Paradigm. AB - cis-Delivery of H2 to the pi-system of an unsaturated substrate is the canonical course of metal catalyzed hydrogenation reactions. The semireduction of internal alkynes with the aid of [Cp*Ru]-based catalysts violates this rule and affords E alkenes by direct trans-hydrogenation. A pathway involving sigma-complexes and metallacyclopropenes accounts for this unconventional outcome. Connected to this process is an even more striking reactivity mode, in which both H atoms of H2 are delivered to one and the same C atom. Such gem-hydrogenation of stable carbogenic compunds is a fundamentally new transformation that leads to the formation of discrete metal carbene complexes. Computational studies suggest that the trans- and the gem-pathway have similar barriers, but polar substituents in the vicinity of the reacting triple bond provide opportunities for imposing selectivity and control. Moreover, it is shown that catalytic trans-hydrogenation is by no means a singularity: rather, the underlying principle is also manifest in trans hydroboration, trans-hydrosilylation, trans-hydrogermylation, and trans hydrostannation, which are equally paradigm-changing processes. These reactions are robust and distinguished by excellent compatibility with many (reducible) functional groups and have already stood the test of natural product synthesis in a number of demanding cases. PMID- 30422660 TI - Multifunctional Structural Ultrabattery Composite. AB - Here we demonstrate a composite material exhibiting dual multifunctional properties of a structural material and a redox-active battery. This incorporates three-dimensional aligned carbon nanotube interfaces that weave together a structural frame, redox-active battery materials, and a Kevlar-infiltrated solid electrolyte that facilitates ion transfer. Relative to the total measured composite material mass, we demonstrate energy density up to ~1.4 Wh/kg, elastic modulus of 7 GPa, and tensile strength exceeding 0.27 GPa. Mechano electrochemical analysis demonstrates stable battery operation under mechanical loading that validates multifunctional performance. These findings demonstrate how battery materials that are normally packaged under compression can be reorganized as elements in a structurally reinforced composite material. PMID- 30422661 TI - Metal-Metal Bond Formations in [Au(CN)2-] n ( n = 3, 4, 5) Oligomers in Water Identified by Coherent Nuclear Wavepacket Motions. AB - Large oligomers of [Au(CN)2-] n including pentamer were favorably formed in an aqueous solution containing tetra-ethyl ammonium chloride (1.0 mol/dm3), and intense transient absorption in the visible region was recorded by a selective photoexcitation of the oligomers. Distinct oscillations at ~40-100 cm-1 were clearly observed in the temporal profile of the excited-state absorption signal, and the frequency-wavelength two-dimensional analysis of the oscillation clearly distinguishes the coherent nuclear motion of different oligomers. The observed nuclear motions were assigned to Au-Au stretch vibrations in trimer, tetramer and pen-tamer induced by the bond formation in the excited states. The transient absorption exhibits significant changes with the time constant of 3-20 ps, reflecting intersystem crossing and structural change. PMID- 30422662 TI - Impact of Zn2+ on ABC Transporter Function in Intact Isolated Rat Brain Microvessels, Human Brain Capillary Endothelial Cells, and in Rat in Vivo. AB - ABC transporters act as efflux pumps, thereby influencing the pharmacokinetics and efficacy of many drugs. Zinc (Zn) is an essential trace element contributing to cellular growth and differentiation. It is increasingly recognized as an intracellular messenger. The present study aims at investigating the impact of Zn2+ on the function and regulation of ABC transporters at the blood-brain barrier (BBB). ABC transporter function was first studied in isolated rat brain capillaries. Zn2+ rapidly stimulated the activity of the multidrug resistance related protein 2 (Mrp2), p-glycoprotein (P-gp), and breast cancer resistance protein (Bcrp). These short-term effects were independent of transporter de novo synthesis but based on Zn2+ triggering intracellular signaling to stimulate basal transport activity. Studies focused on Mrp2 and P-gp showed that Zn2+ induced signaling through an endothelin receptor type B (ETB)/nitric oxide synthase (NOS)/protein kinase C (PKC) pathway and caused, specifically, an activation of the isoform PKCalpha. Studies revealed signaling through the phosphatidylinositol 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) pathway, as well as induction of the downstream target serum- and glucocorticoid-inducible kinase 1 (SGK1). Short-term effects of Zn2+ were also demonstrated in human hCMEC/D3 cells. An initial in vivo study in rats suggested enhanced P-gp transport activity at the BBB due to elevated Zn2+ plasma levels. This work provides the first evidence for Zn2+ being a regulator of basal ABC transporter activity at the BBB, driving a rapid and nongenomic stimulation of transport function. PMID- 30422663 TI - Investigation on the Interaction of Dabrafenib with Human Serum Albumin Using Combined Experiment and Molecular Dynamics Simulation: Exploring the Binding Mechanism, Esterase-like Activity, and Antioxidant Activity. AB - Dabrafenib is a novel targeted antimelanoma drug. The present work explored the binding mechanism of dabrafenib-human serum albumin (HSA) and the effect on the esterase-like activity and antioxidant activity of HSA by using 19F NMR, spectroscopy methods, and molecular dynamics simulation. The results of 19F NMR, fluorescence, and time-resolved fluorescence spectroscopy revealed that dabrafenib spontaneously binds to the subdomain IIIA of the HSA by hydrophobic action and forms a static complex. The binding affects the esterase-like activity of HSA but not its antioxidant activity. According to the results of molecular dynamics simulation, dabrafenib interacts with Arg410 and Tyr411, which are the key residue associated with the esterase-like activity of HSA. Meanwhile, dabrafenib does not interact with Cys34, the key residue associated with the antioxidant activity of HSA. The results of circular dichroism spectroscopy and molecular dynamics simulation show that the conformation of HSA is not affected by the binding of dabrafenib. This study can provide useful information for understanding the pharmacokinetic properties of dabrafenib. PMID- 30422664 TI - High Performance Plasmonic Nanolasers with External Quantum Efficiency Exceeding 10. AB - Plasmonic nanolasers break the diffraction limit for an optical oscillator, which brings new capabilities for various applications ranging from on-chip optical interconnector to biomedical sensing and imaging. However, the inevitably accompanied metallic absorption loss could convert the input power to heat rather than radiations, leading to undesired low external quantum efficiency and device degradation. To date, direct characterization of quantum efficiency of plasmonic nanolasers is still a forbidden task due to its near-field surface plasmon emissions, divergent emission profile, and the limited emission power. Here, we develop a method to characterize the external quantum efficiency of plasmonic nanolasers by synergizing experimental measurement and theoretical calculation. With systematical device optimization, we demonstrate high performance plasmonic nanolasers with external quantum efficiency exceeding 10% at room temperature. This work fills in a missing yet essential piece of key metrics of plasmonic nanolasers. The demonstrated high external quantum efficiency of plasmonic nanolasers not only clarifies the long-standing debate, but also endorses the exploration of them in various practical applications such as near-field spectroscopy and sensing, integrated optical interconnects, solid-state lighting, and free-space optical communication. PMID- 30422665 TI - Bronsted Acid Mediated Cascade Reaction To Access 3-(2-Bromoethyl)benzofurans. AB - A unified protocol for the construction of 3-(2-bromoethyl)benzofurans and 2 (benzofuran-3-yl)ethylamines from bis[(trimethylsilyl)oxy]cyclobutene has been developed. This mild and facile strategy was applied for the synthesis of a series of 5-HT serotonin receptor agonists, underlining its potential for the syntheses of bioactive compounds and natural products. PMID- 30422666 TI - Orientation and Morphology Control of the Liquid Crystalline Block Copolymer Thin Film by Liquid Crystalline Solvent. AB - The critical challenge to engineer the morphological structures in the strongly phase-segregated block copolymer thin film is to overcome the preferential wetting of the blocks at the interface and direct the self-assembly process. Herein, we utilize surface activity and selective solvation of a nematic (N) liquid crystalline (LC) solvent, 5CB, to facilely alter the LC anchoring and the orientation of the nanophase separated structures of the smectic-nematic (S-N) LC block copolymer thin film. For the neat S-N diblock copolymer thin film, the nanostructures are parallel aligned. In contrast, with continuous introduction of 5CB into the system, the orientations of the characteristic nanostructures and the morphologies of the LC thin film can be consequently changed, yielding the perpendicularly oriented lamellar or cylindrical structures with the feature size below 10 nm. The homeotropic alignment of the 5CB nematics near the air interface plays a critical role to induce this unique behavior in the S-N/5CB systems, which offers an opportunity to fine-tune the interfacial structures and the morphological patterning in the block copolymer thin film. PMID- 30422667 TI - How Lattice Dynamics Moderate the Electronic Properties of Metal-Halide Perovskites. AB - Metal-halide perovskites have emerged as highly promising semiconductors with excellent optoelectronic properties. This Perspective outlines how the dynamic response of the ionic lattice affects key electronic properties such as exciton binding energies and charge-carrier mobilities in hybrid perovskites. Such links are shown to derive from the frequency-dependence of the dielectric function, which is governed by contributions from electronic interband transitions, polar vibrations of the metal-halide sublattice, organic cation collective reorientations, and ionic movement. The influence of each of these contributions to charge-carrier screening and carrier-lattice interactions is discussed, which allows for general trends with material composition to be revealed. Overall, this Perspective highlights the challenges and questions arising from the peculiar combination of a soft polar metal-halide sublattice interspersed with rotationally mobile dipolar molecules that is encountered in hybrid metal-halide perovskites. PMID- 30422668 TI - GM1-Binding Conjugates To Improve Intestinal Permeability. AB - Drugs and proteins with poor intestinal permeability have a limited oral bioavailability. To remediate this problem, a receptor-mediated endocytosis and transcytosis approach was explored. Indeed, the nontoxic beta subunit of cholera toxin (CTB) can cross the intestinal barrier by binding to receptor GM1. In this study, we explored the use of GM1-binding peptides and CTB as potential covalent carriers of poorly permeable molecules. GM1-binding peptides (G23, P3) and CTB were conjugated to poorly permeable fluorescent probes such as fluorescein isothiocyanate (FITC) and albumin-FITC using triethylene glycol spacers and click chemistry. The affinity of the peptide conjugates with receptor GM1 was confirmed by isothermal titration calorimetry or microscale thermophoresis, and the results suggested the involvement of nonspecific interactions. Conjugating the model drugs to G23 and P3 improved the internalization into Caco-2 and T84 cells, although the process was not dependent on the amount of GM1 receptor. However, conjugation of bovine serum albumin FITC to CTB increased the internalization in the same cells in a GM1-dependent pathway. Peptide conjugates demonstrated a limited permeability through a Caco-2 monolayer, whereas G23 and CTB conjugates slightly enhanced permeability through a T84 cell monolayer compared to model drugs alone. Since CTB can improve the permeability of large macromolecules such as albumin, it is an interesting carrier for the improvement of oral bioavailability of various other macromolecules such as heparins, proteins, and siRNAs. PMID- 30422669 TI - Tumor-Derived Autoantibodies Identify Malignant Pulmonary Nodules. AB - RATIONALE: Screening for non-small cell lung cancer is associated with earlier diagnosis and reduced mortality but also increased harm due to invasive follow up of benign pulmonary nodules. Lung tumorigenesis activates the immune system, components of which could serve as tumor specific biomarkers. OBJECTIVES: To profile tumor-derived autoantibodies as peripheral biomarkers of malignant pulmonary nodules. METHODS: High-density protein arrays were used to define the specificity of autoantibodies isolated from B cells of 10 resected lung tumors. These tumor-derived autoantibodies were also examined as free or complexed to antigen in the plasma of the same 10 patients and matched benign nodule controls. Promising autoantibodies were further analyzed in an independent cohort of 250 nodule positive patients. MEASUREMENTS AND MAIN RESULTS: Thirteen tumor B cell derived autoantibodies isolated ex vivo showed >=50% sensitivity and >=70% specificity for lung cancer. In plasma, 11/13 autoantibodies were present both complexed to and free from antigen. In the larger validation cohort, 5/13 tumor derived autoantibodies remained significantly elevated in cancers. A combination of 4 of these autoantibodies could detect malignant nodules with an AUC=0.74 and had an AUC=0.78 in a sub-cohort of indeterminate (8-20mm in the longest diameter) pulmonary nodules. CONCLUSIONS: Our novel pipeline identifies tumor-derived autoantibodies that could effectively serve as blood biomarkers for malignant pulmonary nodule diagnosis. This approach has future implications for both a cost effective and non-invasive approach to determine nodule malignancy for widespread LDCT screening. PMID- 30422670 TI - Anaphylatoxins Enhance Recruitment of Non-Classical Monocytes via Chemokines Produced by PMCs in Tuberculous Pleural Effusion. AB - OBJECTIVES: To elucidate the mechanism by which monocytes are migrated into the pleural space in the presence of anaphylatoxins in tuberculous pleural effusion (TPE). METHODS: Monocytes in both pleural effusion and blood was counted and its phenotypic characteristics were analysed. The activation of complements system was detected in TPE. The effect of Mpt64 and anaphylatoxins on the production of chemokines in PMCs was measured. The chemoattractant activity of chemokines produced by PMCs for monocytes was observed. MEASUREMENTS AND MAIN RESULTS: CD14+CD16+ monocytes were significantly higher in TPE than in blood. Three pathways of the complement system were activated in TPE. Both C3a-C3aR1, C5a C5aR1, CCL2-CCR2, CCL7-CCR2 and CX3CL1-CX3CR1 were co-expressed in PMCs and monocytes isolated from TPE. Moreover, we initially found Mpt64 stimulated the expression of C3a and C5a in PMCs. C3a and C5a not only induced CCL2, CCL7 and CX3CL1 expression in PMCs but also stimulated production of IL-1beta,IL-17 and IL 27 in monocytes. CONCLUSIONS: C3a and C5a stimulated PMCs to secrete CCL2, CCL7 and CX3CL1, which recruit CD14+CD16+ monocytes to the pleural cavity. As a result, the infiltration of CD14+CD16+ monocytes engaged in the pathogenesis of TPE by excessive production of inflammatory cytokines. Key words: Anaphylatoxins, Monocytes, Pleural mesothelial cells, Chemokines, Tuberculous pleural effusion. PMID- 30422672 TI - Cardiopulmonary Exercise Testing: Another Tool in the Prognostication Tool Kit for Cystic Fibrosis. PMID- 30422673 TI - Restoration of skeletal muscle homeostasis by hydrogen sulfide during hyperhomocysteinemia-mediated oxidative/ER-stress condition. AB - Elevated homocysteine (Hcy), i.e., hyperhomocysteinemia (HHcy) causes skeletal muscle myopathy. Among many cellular and metabolic alterations caused by HHcy, oxidative and endoplasmic reticulum (ER)-stress are considered the major ones; however, the precise molecular mechanism(s) in this process is unclear. Nevertheless, there is no treatment option available to treat HHcy-mediated muscle injury. Hydrogen sulfide (H2S) is increasingly recognized as a potent anti oxidant, anti-apoptotic/necrotic/pyroptotic, and anti-inflammatory compound and also has been shown to improve angiogenesis during ischemic injury. Patients with CBS mutation produce less H2S, making them vulnerable to Hcy-mediated cellular damage. Many studies reported bidirectional regulation of ER-stress in apoptosis through JNK activation, and concomitant attenuation of cell proliferation and protein synthesis via PI3K/AKT axis. Whether H2S mitigates these detrimental effects of HHcy on muscle remains unexplored. In this review, we discuss molecular mechanisms of HHcy-mediated oxidative/ER-stress responses, apoptosis, angiogenesis, and atrophic changes in skeletal muscle and how H2S can restore skeletal muscle homeostasis during HHcy condition. This review also highlights the molecular mechanisms on how H2S could be developed as a clinically relevant therapeutic option for chronic conditions that are aggravated by HHcy. PMID- 30422671 TI - Seventeen-Year Follow-up After Meniscal Repair With Concomitant Anterior Cruciate Ligament Reconstruction in a Pediatric and Adolescent Population. AB - BACKGROUND:: Studies have shown good and excellent clinical and radiographic results after meniscal repair. Limited published information exists on the long term outcomes, however, especially in a pediatric and adolescent population. PURPOSE:: To determine long-term results of meniscal repair and concomitant anterior cruciate ligament (ACL) reconstruction in a pediatric and adolescent population. Specifically, the aims were to determine the clinical success rate of meniscal repair with concomitant ACL reconstruction, compare results with midterm outcomes, and analyze risk factors for failure. STUDY DESIGN:: Case series; Level of evidence, 4. METHODS:: Cases of meniscal repair with concomitant ACL reconstruction between 1990 and 2005 were reviewed among patients aged <=18 years. Patient demographics, injury history, and surgical details were recorded, and risk factors for failure were analyzed. Physical examination findings and clinical outcomes at latest available follow-up were collected. Subjective knee outcomes were compared with midterm results. Descriptive statistics and univariate analysis were used to evaluate the available data. RESULTS:: Forty seven patients (30 females, 17 males) with a mean age of 16 years (SD, 1.37) and a mean follow-up of 16.6 years (SD, 3.57) were included in this study. Overall, 13 patients (28%) failed meniscal repair and required repeat surgery at the time of final follow-up. Of the 13 failures, 9 underwent a subsequent meniscectomy; 2, meniscectomy and revision ACL reconstruction; 1, meniscal repair and revision ACL reconstruction; and 1, meniscal repair and subsequent meniscectomy. Mean International Knee Documentation Committee scores improved from 47.9 preoperatively to 87.7 postoperatively ( P < .01), and the mean score at long term follow-up (87.7) did not significantly differ from that at the midterm follow-up (88.5) at a mean 7.4 years ( P = .97). Mean Tegner Activity Scale scores improved from 1.9 preoperatively to 6.3 postoperatively ( P < .01) and decreased from 8.3 at preinjury to 6.3 at final long-term follow-up ( P < .01). CONCLUSION:: In conclusion, the long-term overall clinical success rate (failure free survival) was 72% for repair of pediatric and adolescent meniscal tears in the setting of concomitant ACL reconstruction. Patients reported excellent knee subjective outcome scores that remained favorable when compared with midterm follow-up. PMID- 30422674 TI - Ameliorative effect of low-dose spironolactone on obesity and insulin resistance is through replenishment of estrogen in ovariectomized rats. AB - Women have a lower incidence of cardiovascular diseases (CVD) than men at a similar age but the reverse is the case after menopause, indicating a possible protective effect of estrogen on cardiometabolic function. Obesity with insulin resistance is closely linked to CVD risks while ovariectomized rodents have been shown to mimic obese-insulin resistant (IR) state. We therefore hypothesized that low-dose spironolactone, would ameliorate obese-IR in estrogen-deprived rats by replenishing estrogen and suppressing elevated glycogen synthase kinase-3 (GSK 3). Ten weeks old female Wistar rats were divided into four groups; sham-operated (SHM), spironolactone (SPL; 0.25 mg/kg) and ovariectomized (OVX) rats treated with or without spironolactone daily for 8 weeks. Results showed that estrogen deprivation through ovariectomy caused increased body weight gain and visceral adiposity that are accompanied by increased HOMA-IR, HOMA-beta, 1-hr postload glucose, platelet/lymphocyte ratio, plasma insulin, atherogenic dyslipidemia, uric acid, GSK-3, corticosterone, aldosterone and depressed 17beta-estradiol. Treatment of OVX rats with spironolactone ameliorated all these effects. Therefore, the results demonstrate that treatment with low-dose spironolactone improves obesity and IR, which appears to involve replenishment of estrogen and suppression of GSK-3 along with circulating mineralocorticoid and glucocorticoid. The findings imply a positive cardiometabolic effect of low-dose spironolactone usage in estrogen-deprived conditions. PMID- 30422676 TI - Obstructive Sleep Apnea, Hypoxia, and Nonalcoholic Fatty Liver Disease. AB - Recent studies have demonstrated that obstructive sleep apnea (OSA) is associated with the development and evolution of nonalcoholic fatty liver disease (NAFLD), independent of obesity or other shared risk factors. Like OSA, NAFLD is a prevalent disorder associated with major adverse health outcomes: Patients with NAFLD may develop cirrhosis, liver failure, and hepatocellular carcinoma. One major finding that has emerged from these studies is that the OSA/NAFLD association is related to the degree of nocturnal hypoxemia in OSA. Animal models have therefore largely focused on intermittent hypoxia, a key manifestation of OSA, in order to shed light on the mechanisms by which OSA may give rise to the complex metabolic disturbances that are seen in NAFLD. Intermittent hypoxia leads to tissue hypoxia, and can result in oxidative stress, mitochondrial dysfunction, inflammation, and over-activation of the sympathetic nervous system, among many other maladaptive effects. In such models, intermittent hypoxia has been shown to cause insulin resistance, dysfunction of key steps in hepatic lipid metabolism, atherosclerosis, and hepatic steatosis and fibrosis, each of which is pertinent to the development and/or progression of NAFLD. However, many intriguing questions remain unanswered: Principally, how aggressively should the clinician screen for NAFLD in OSA patients, and vice-versa? In this review we attempt to apply the best evidence from animal and human studies to highlight the relationship between these two disorders and to advocate for further trials aimed at defining these relationships more precisely. PMID- 30422675 TI - Stress and psychosomatic symptoms in Chinese adults with sleep complaints: mediation effect of self-compassion. AB - Although stress has been widely acknowledged to link to psychosomatic dysfunctioning, the underlying mechanism that transmits the impact is not adequately investigated. This study examined self-compassion as a potential mediator that may explain the pathway from stress to depressive and somatic symptoms. Data in the present study were drawn from a baseline survey of 998 Chinese participants who enrolled in an intervention study on sleep disturbance in Hong Kong. Participants completed measures of perceived stress, self compassion, depressive symptoms, and somatic symptoms. The results showed that stress was associated with depressive symptoms (r = .79, p < .01) and somatic symptoms (r = .47, p < .01). The path analyses showed that low levels of self compassion mediated the association between stress and psychosomatic symptoms. Our findings provide insight into the pathway how stress affects psychosomatic symptoms. The intervention programs for stress management to improve psychological and physical functioning are recommended to consider self compassion as a promising component in practice. PMID- 30422677 TI - Effect of nuts on energy intake, hunger, and fullness, a systematic review and meta-analysis of randomized clinical trials. AB - Despite high energy content, nut consumption has not been associated with weight gain in epidemiological and clinical investigations. Since a satiety effect a decreased sense of hunger in the following meals has been proposed as the mechanism of nuts against obesity, the present meta-analysis was performed to examine how nut consumption affects "energy intake", "hunger", and "fullness". "Weight" was not included among the search terms but weight data were extracted from the collected articles in order to help interpreting the results. A total of 1048 trials were found, of which 31 passed the eligibility process. Daily energy intake was mostly assessed by 3-day food records, and hunger and fullness were estimated by visual analog scale (VAS). Nut consumption was associated with increased energy intake (mean difference (MD) (nuts - control) = 76.3 kcal; 95% CI: 22.7, 130 kcal; P = 0.005). In contrast, hunger suppressed following nut consumption (MD = -6.54 mm VAS; 95% CI: -12.7, -0.42 mm VAS; P = 0.03). Nuts did not affect sense of fullness and weight in the overall estimate. Subgroup analysis based on participants' BMI revealed that energy intake of overweight/obese individuals was increased following nut consumption while such effect was not observed in normal weight participants. In conclusion, pooled estimates of available clinical trials showed increased energy intake following nut consumption in overweight/obese individuals but not in persons with normal weight. Nut consumption was associated with decreased hunger but no effect was observed on fullness and weight. PMID- 30422678 TI - Developmental Milestones in Pediatric Research; A Case for Including Efficacy as Part of Interventional Trials in Infants with Cystic Fibrosis. PMID- 30422679 TI - Correction. PMID- 30422680 TI - A New Quartet-Based Statistical Method for Comparing Sets of Gene Trees Is Developed Using a Generalized Hoeffding Inequality. AB - Extracting the strength of the tree signal that is encompassed by a collection of gene trees is an exceptionally challenging problem in phylogenomics. Often, this problem not only involves the construction of individual phylogenies based on different genes, which may be a difficult endeavor on its own, but is also exacerbated by many factors that create conflicts between the evolutionary histories of different gene families, such as duplications or losses of genes; hybridization events; incomplete lineage sorting; and horizontal gene transfer, the latter two play central roles in the evolution of eukaryotes and prokaryotes, respectively. In this work, we tackle the aforementioned problem by focusing on quartet trees, which are the most basic unit of information in the context of unrooted phylogenies. In the first part, we show how a theorem of Janson that generalizes the classical Hoeffding inequality can be used to develop a statistical test involving quartets. In the second part, we study real and simulated data using this theoretical advancement, thus demonstrating how the significance of the differences between sets of quartets can be assessed. Our results are particularly intriguing since they nonstandardly require the analysis of dependent random variables. PMID- 30422681 TI - Pharmacological effects of nanoencapsulation of human-based dosing of probucol on ratio of secondary to primary bile acids in gut, during induction and progression of type 1 diabetes. AB - INTRODUCTION: The ratio of secondary to primary bile acids changes during Type 1 Diabetes (T1D) development and these effects might be ameliorated by using cholesterol lowering drugs or hydrophilic bile acids. Probucol is a cholesterol lowering drug, while ursodeoxycholic acid is a hydrophilic bile acid. This study investigated whether nanoencapsulated probucol with ursodeoxycholic acid altered bile acid ratios and the development of diabetes. METHODS: Balb/c mice were divided into three groups and gavaged daily with either free probucol, nanoencapsulated probucol or nanoencapsulated probucol with ursodeoxycholic acid for seven days. Alloxan was injected and once T1D was confirmed the mice continued to receive daily gavages until euthanasia. Blood, tissues, faeces and urine were collected for analysis of insulin and bile acids. RESULTS AND CONCLUSIONS: Nanoencapsulated probucol-ursodeoxycholic acid resulted in significant levels of insulin in the blood, lower levels of secondary bile acids in liver and lower levels of primary bile acids in brain, while ratio of secondary to primary bile acids remains similar among all groups, except in the faeces. Findings suggests that nanoencapsulated probucol-ursodeoxycholic acid may exert a protective effect on pancreatic beta-cells and reserve systemic insulin load via modulation of bile acid concentrations in the liver and brain. PMID- 30422682 TI - Back In (Regulatory) Action. AB - October brought new guidance on state waivers, more litigation, and preparation for the next open enrollment period. PMID- 30422683 TI - Are procrastinators psychologically healthy? Association between psychosocial problems and procrastination among college students in Shanghai, China: a syndemic approach. AB - Procrastination has been closely linked to psychosocial health problems, such as depression and anxiety, among college students. However, few studies have focused on the magnifying effects of multiple psychosocial health problems on procrastination. We conducted a cross-sectional study by convenience sampling among 509 college students in Shanghai, China. Logistic regressions were performed to assess the relationship between psychosocial variables and procrastination and to verify the syndemic effect of psychosocial factors. Univariate analyses revealed that self-esteem, depression, and loneliness were associated with procrastination. In multivariate analyses, self-esteem and depression remained significant. College students with four psychosocial problems were approximately 2.5 times more vulnerable to procrastination compared with non syndemic (have no more than one problem) students. The study indicates that college students with more psychosocial health problems exhibit severer procrastination, which in turn suggests that psychosocial syndemic theory can be applied to procrastination. PMID- 30422684 TI - Response-Ability and the Trauma of Animal Rescue. PMID- 30422685 TI - Bioinspired benzoxanthene lignans as a new class of antimycotic agents: synthesis and Candida spp. growth inhibition. AB - In this work we synthetized the bioinspired benzoxanthene lignans (BXLs) 3, 14 22, and the phenazine derivative 23 as potential antimycotic agents. MICs and MFCs against Candida strains were determined. In a preliminary screening, compounds 3, 15, 20, 21, 22 were substantially inactive. Compounds 14 and 17 showed antifungal activity, being able to inhibit the growth of the majority of Candida strains with MIC values in the range 4.6-19.2 uM (14) and 26.0-104.3 uM (17); for three strains, the MICs were lower than those obtained using the antimycotic drug fluconazole. The three BXLs 18, 19 and 23 showed some MIC values lower than that of fluconazole; 18 was also active against two non-albicans Candida strains resistant to fluconazole. Phenazine 23, although active only against one strain (MIC = 1.3 uM), was one order of magnitude more potent than fluconazole. All the BXLs were fungicidal. PMID- 30422686 TI - Biofunctionalized MnFe2O4@Au core-shell nanoparticles for pH-responsive drug delivery and hyperthermal agent for cancer therapy. AB - Novel materials are explored very often by material scientists to design an efficient drug delivery system to target carcinoma cells. Among various nanosystem, functionalized Iron oxide Nanoparticles (IoNP) were definitely studied especially to target, endocyte and release drug moieties inside the cells. This IoNP platform is usually composed of an inorganic core and a highly biocompatible shell layer in order to perform numerous tasks at the same time, such as drug delivery, multimodal imaging, and instantaneous monitoring, along with collective therapeutic approaches. Hence, in this work, MnFe2O4@Au nanoparticles (Mf@A) are used as a structure for docking anti-cancer drug using a coupling molecule for the precise targeting. The formation of the core-shell structure was corroborated by high-angle annular dark-field scanning transmission electron microscopy and line mapping techniques. Superconducting quantum interference device confirms the fabricated nanostructure is favorably superparamagnetic. The stability of nanoparticles was examined by measuring the zeta-potential measurements. The binding efficiency of the drug onto the Mf@A was found to be >90%. Drug-release was carried out at different pH and found that the release is maximum at lower pH. Finally, at 2.45 GHz we employed as a magneto hyperthermal agent which produced heat to kill the cancerous cell. PMID- 30422687 TI - High Throughput screening reveals no significant changes in protein synthesis, processing and degradation machinery during passaging of mesenchymal stem cells. AB - Increasing reports of successful and safe application of bone marrow derived mesenchymal stem cells (MSCs) for cell therapy are pouring in through numerous studies. However, poor survival of transplanted cells in the recipient has impaired the benefits of MSCs based therapies. Therefore, cell product preparation procedures pertaining to MSC therapy need to be optimized to improve the survival of transplanted cells. One of the important ex vivo procedures in the preparation of cells for therapy is passaging of MSCs to ensure suitable number of cells for transplantation, which may affect the turn-over of proteins involved in regulation of cell survival/death pathways. In the current study, we investigated the effect of increase in passage number of MSCs in cell culture on the intracellular protein turn over (protein synthesis, processing and degradation machinery). We performed proteomic analysis of MSCs at different passages. There was no significant difference observed in the ribosomal, protein processing and proteasomal pathways related proteins in MSCs with an increase in passage number from P3 to P7. Therefore, expansion of MSCs in the cell culture with in clinically relevant passages (Passage 3-7) does not affect the quality of MSCs in terms of intracellular protein synthesis and turn over. PMID- 30422688 TI - Anti-biofilm effects of gold and silver nanoparticles synthesized by the Rhodiola rosea rhizome extracts. AB - Bacterial biofilm represents a major problem in medicine. They colonize and damage medical devices and implants and, in many cases, foster development of multidrug-resistant microorganisms. Biofilm development starts by bacterial attachment to the surface and the production of extracellular polymeric substances (EPS). The EPS forms a structural scaffold for dividing bacterial cells. The EPS layers also play a protective role, preventing the access of antibiotics to biofilm-associated microorganisms. The aim of this work was to investigate the production nanoparticles that could be used to inhibit biofilm formation. The applied production procedure from rhizome extracts of Rhodiola rosea is simple and environmentally friendly, as it requires no additional reducing, stabilizing and capping agents. The produced nanoparticles were stable and crystalline in nature with an average diameter of 13-17 nm for gold nanoparticles (AuNPs) and 15-30 nm for silver nanoparticles (AgNPs). Inductively coupled plasma mass spectrometry analysis revealed the concentration of synthesized nanoparticles as 3.3 and 5.3 mg/ml for AuNPs and AgNPs, respectively. Fourier-transform infrared spectroscopy detected the presence of flavonoids, terpenes and phenols on the nanoparticle surface, which could be responsible for reducing the Au and Ag salts to nanoparticles and further stabilizing them. Furthermore, we explored the AgNPs for inhibition of Pseudomonas aeruginosa and Escherichia coli biofilms. AgNPs exhibited minimum inhibitory concentrations of 50 and 100 ug/ml, against P. aeruginosa and E. coli, respectively. The respective minimum bactericidal concentrations were 100 and 200 ug/ml. These results suggest that using the rhizome extracts of the medicinal plant R. rosea represents a viable route for green production of nanoparticles with anti-biofilm effects. PMID- 30422689 TI - Finding diseases associated with amyotrophic lateral sclerosis: a total population-based case-control study. AB - OBJECTIVE: To investigate diseases associated with amyotrophic lateral sclerosis (ALS) by using a total population-based medical database. METHODS: This study included 705 ALS patients aged older than 15 years diagnosed from January 1, 2007, to December 31, 2013, along with 14,100 controls matching in sex, age, residence, and insurance premium. Data from the National Health Insurance Research Database (NHIRD) and Serious Disabling Diseases (SDD) database in Taiwan were used to conduct a total population-based case-control study. Prior diseases were categorized as being diagnosed 1, 3, 5, 7, or 9 years before first ALS diagnosis. Chi-square or t test was used to examine differences in demographic characteristics between the new patients with ALS and controls. Previous diseases were screened using a conditional logistic regression model. Multivariate analysis was performed using stepwise selection to evaluate the association between these diseases and the risk of ALS. The path analysis was conducted to analyze the pathway between prior diseases and ALS. RESULTS: In total, 28 diseases were associated with ALS, including 17 positive associations and 11 negative associations. The path analysis revealed that the 11 negatively associated diseases could be attributed to diabetes mellitus and its comorbidities. The 17 positively associated diseases could be categorized as metabolic syndrome, neuroinflammation, head trauma, sports injuries, infections, and their comorbidities. CONCLUSIONS: Our results support the hypothesis that diseases developing prior to ALS diagnoses are hypermetabolic disorders. Hypometabolic disorders may have a beneficial effect on ALS incidence. Defective energy metabolism may play a role in ALS pathogenesis. PMID- 30422690 TI - Trust of Information about Tobacco and E-Cigarettes from Health Professionals versus Tobacco or Electronic Cigarette Companies: Differences by Subgroups and Implications for Tobacco Messaging. AB - Smoking behavior may be influenced by perceived trust of information from tobacco and e-cigarette companies about their products. The purpose of this study was to identify sociodemographic subgroups with more trust in tobacco product (tobacco and e-cigarette) companies than health professionals and explore associations between this relative trust and tobacco product use. Health Information National Trends Survey (HINTS 4, FDA Cycle) data were analyzed (N = 3,738). Two relative trust measures were developed identifying respondents who trust tobacco companies or e-cigarette companies as much as or more than health professionals for information about the health effects of tobacco products or e-cigarettes versus those who place more trust in health professionals. Dependent variables were smoking status (current, former, never) and e-cigarette use (ever, never). Bivariate analyses and multivariable logistic regressions were conducted in SAS 9.4 using jackknife replicate weights. Respondents who trusted tobacco or e cigarette companies as much as or more than health professionals were disproportionately from racial/ethnic minority groups or had low levels of income or education (all p < 0.05). Relative trust was not associated with smoking status. After controlling for demographics, respondents who trusted e-cigarette companies as much as or more than health professionals had 87% greater odds (95% CI: 1.16, 3.00) of e-cigarette use, compared to respondents who placed higher trust in health professionals. Findings suggest that population subgroups with greater trust in e-cigarette companies relative to health professionals are more prone to e-cigarette use. Targeted communication strategies may be needed for underserved populations and to counter messaging from e-cigarette companies. PMID- 30422691 TI - Evolution of clinical neuropsychology: Four challenges. AB - Quantitative and evidence-based approaches fail to capture "the whole person," neglect the important contributions of nonquantitative variables to understanding behavior, and have limitations when assessing individuals who fall outside traditional normative groups. The emphasis on quantitative and evidence-based practices is one challenge facing the profession. The lack of consensual definitions for various domains of interest is a second challenge, because it hinders research, poses communication challenges, and impedes the accumulation of knowledge about human behavior. A third challenge the profession faces is an overemphasis on the biological basis of behavior. Finally, the forth challenge is the impact of technology on practice. Since the 1970s, there has been a rapid advance in our ability to investigate the brain, resulting in a significant increase of information about brain functioning, making it difficult for clinicians to stay abreast of changes in the field. Advances in technology have resulted in "assessments" being completed by nonpsychologists. To place these and related challenges in context, a brief review of the history of assessment and efforts to investigate brain functioning will be presented. It is suggested that failure to meet these challenges will contribute to the demise of the profession. Suggestions for meeting these challenges are offered. PMID- 30422692 TI - Disaster Preparedness and Response: Who Will Fund? PMID- 30422693 TI - Science as the Basis of Public Health Emergency Preparedness and Response Practice: The Slow but Crucial Evolution. AB - We discuss challenges to implementing evidence-based practice within the broad field of public health preparedness and response. We discuss the progress of public health preparedness and response in building and translating evidence to practice since the World Trade Center attacks of 9/11/2001. We briefly describe analogies to struggles that other professional disciplines face, and we highlight key factors that facilitate and impede the implementation of evidence-based practice. We recommend a partnership led by funding agencies and closely involving research organizations and professional associations as a means to ensure that the public health preparedness and response field continues to develop an evidence-based culture and practice. PMID- 30422694 TI - Preparedness Emergency Response Research Centers (PERRCs): Addressing Public Health Preparedness Knowledge Gaps Using a Public Health Systems Perspective. PMID- 30422695 TI - Experiential Adult Learning: A Pathway to Enhancing Medical Countermeasures Capabilities. PMID- 30422696 TI - Academic and Practice Partnerships: Building an Effective Public Health System Focusing on Public Health Preparedness and Response. PMID- 30422697 TI - Translation, Dissemination, and Implementation of Public Health Preparedness Research and Training: Introduction and Contents of the Volume. PMID- 30422698 TI - Implementing Innovations in Public Health Agency Preparedness and Response Programs. PMID- 30422699 TI - Expanding Methodologies to Identify High-Priority Emergency Preparedness Tools for Implementation in Public Health Agencies. PMID- 30422700 TI - Strategies From American Indian and Alaska Native Community Partners on Effective Emergency Response Collaboration. PMID- 30422701 TI - Preparing Public Health for the Unexpected. PMID- 30422702 TI - METABOLIC ENDOTOXEMIA PROMOTES ADIPOSE DYSFUNCTION AND INFLAMMATION IN HUMAN OBESITY. AB - Impaired adipose tissue (AT) lipid handling and inflammation is associated with obesity-related metabolic diseases. Circulating lipopolysaccharides (LPS) from gut microbiota (metabolic endotoxemia), proposed as a triggering factor for the low-grade inflammation in obesity, might also be the responsible for AT dysfunction. Nevertheless, this hypothesis has not been explored in human obesity. In order to analyze the relationship between metabolic endotoxemia and AT markers for lipogenesis, lipid handling and inflammation in human obesity, 33 obese patients scheduled for surgery were recruited and classified according to their LPS levels. Visceral and subcutaneous AT gene and protein expression were analyzed and adipocyte and AT in vitro assays performed. Obese subjects with a high degree of metabolic endotoxemia had lower expression of key genes for AT function and lipogenesis (SREBP1, FABP4, FASN and LEP), but higher expression of inflammatory genes in visceral and subcutaneous AT than subjects with low LPS levels. In vitro experiments corroborated that LPS are responsible for the adipocyte and AT inflammation and down-regulation of PPARG, SCD, FABP4 and LEP expression and LEP secretion. Thus, metabolic endotoxemia influences AT physiology in human obesity by decreasing the expression of factors involved in AT lipid handling and function as well as by increasing inflammation. PMID- 30422703 TI - Associations of increased physical performance and change in body composition with molecular pathways of heart disease and diabetes risk. AB - Higher physical activity is associated with a reduced hazard for a plethora of diseases. It has remained unknown how the two primary physical activity associated health effects, improved physical performance and change in body composition, independently modulate metabolic profiles towards a reduced risk for adverse outcomes.Here, we utilized a prospective cohort of 664 young men undergoing military service. We studied the metabolic associations of changes in muscle performance and body composition during military service (range 6-12 months). We subsequently replicated our results for body composition change in 234 population-based samples with a 7-year follow-up.We found that increased physical performance was associated with reduced very-low density lipoprotein (VLDL) related measures (change in VLDL cholesterol, Beta=-0.135, 95%CI=-0.217; 0.054, P=1.2x10-3) and lower inflammation (change in Glycoprotein acetyls, Beta= 0.138, 95% CI=-0.217;-0.059, P=6.5x10-4), independent of change in body composition. Lower body fat percentage, independent of change in muscle performance, was associated with metabolic changes including lower low-density lipoprotein (LDL) cholesterol measures (change in LDL cholesterol, Beta=-0.193, 95%CI=-0.295;-0.090, P=2.5x10-4), increased high-density lipoprotein (HDL) cholesterol measures (change in large HDL cholesterol, Beta=0.316, 95% CI=0.205;0.427, P=3.7x10-8) and decreased concentrations of amino acids (change in leucine concentration, Beta=-0.236, 95%CI=-0.341;-0.132, P=1.0x10-5) that are type 2 diabetes biomarkers. Importantly, all body fat percentage associations were replicated in a general population-based cohort.Our findings indicate that improved muscle performance showed weaker associations on the metabolic profiles than change in body composition and reduction in body fat percentage reduces cardiometabolic risk mediated by atherogenic lipoprotein particles and branched chain and aromatic amino acid concentrations. PMID- 30422704 TI - Berberine alleviates insulin resistance by reducing peripheral branched-chain amino acids. AB - Increased circulating branched-chain amino acids (BCAAs) have been involved in the pathogenesis of obesity and insulin resistance (IR). However, evidence relating berberine (BBR), gut microbiota, BCAAs and IR is limited. Here, we showed that BBR could effectively rectify steatohepatitis and glucose intolerance in high-fat diet (HFD)-fed mice. BBR reorganized gut microbiota populations under both the normal chow diet (NCD) and HFD. Particularly, BBR noticeably decreased the relative abundance of BCAA-producing bacteria, including order Clostridiales, families Streptococcaceae, Clostridiaceae and Prevotellaceae, and genera Streptococcus and Prevotella. Compared with the HFD group, predictive metagenomics indicated a reduction in the proportion of gut microbiota genes involved in BCAA biosynthesis, but the enrichment genes for BCAA degradation and transport by BBR treatment. Accordingly, the elevated serum BCAAs of HFD group were significantly decreased by BBR. Furthermore, the Western blotting results implied that BBR could promote the BCAA catabolism in the liver and epididymal white adipose tissues of HFD-fed mice by activation of the multienzyme branched chain alpha-ketoacid dehydrogenase complex (BCKDC), whereas by inhibition of the phosphorylation state of BCKDHA (E1alpha subunit) and branched-chain alpha ketoacid dehydrogenase kinase (BCKDK). The ex vivo assay further confirmed that BBR could increase BCAA catabolism in both AML12 hepatocytes and 3T3-L1 adipocytes. Finally, data from healthy subjects and diabetics confirmed that BBR could improve glycemic control and modulate circulating BCAAs. Together, our findings clarified BBR improving IR associated not only with gut microbiota alteration in BCAA biosynthesis, but also with BCAA catabolism in liver and adipose tissues. PMID- 30422705 TI - Ablation of Amyloid Precursor Protein Increases Insulin Degrading Enzyme Levels and Activity in Brain and Peripheral Tissues. AB - The amyloid precursor protein (APP) is a type-I transmembrane glycoprotein widely studied for its role as the source of beta-amyloid peptide, accumulation of which is causal in at least some cases of Alzheimer's disease (AD). APP is expressed ubiquitously and is involved in diverse biological processes. Growing bodies of evidence indicate connections between AD and somatic metabolic disorders related to type-2 diabetes, and App-/- mice show alterations in glycemic regulation. We find that App-/- have higher levels of insulin-degrading enzyme (IDE) mRNA, protein, and activity compared to wild-type controls. This regulation of IDE by APP was widespread across numerous tissues including liver, skeletal muscle, and brain as well as cell types within neural tissue including neurons, astrocytes, and microglia. RNAi-mediated knockdown of APP in the SIM-A9 microglia cell line elevated IDE levels. Fasting levels of blood insulin were lower in App-/- than App+/+ mice, but the former showed a larger increase in response to glucose. These low basal levels may enhance peripheral insulin sensitivity, as App-/- mice failed to develop impairment of glucose tolerance on a high-fat, high-sucrose ("western") diet. Insulin levels and insulin signaling were also lower in App-/- brain; synaptosomes prepared from App-/- hippocampus showed diminished insulin receptor phosphorylation compared to App+/+ mice when stimulated ex vivo. These findings represent a new molecular link connecting APP to metabolic homeostasis and demonstrate a novel role for APP as an upstream regulator of IDE in vivo. PMID- 30422706 TI - Evidence of Human Milk Oligosaccharides in maternal circulation already during pregnancy - a pilot study. AB - Human Milk Oligosaccharides (HMOs) are bioactive glycans linked with health benefits to both, breastfed infant and lactating mother. We hypothesized that HMOs are present prior to lactation, already during pregnancy, and are influenced by maternal body composition. In a pilot study, we investigated individual and temporal variations in HMO composition and concentration in maternal serum at gestational weeks 10-14, 20-24, and 30-35 (V1, V2, and V3, respectively), and associations with maternal body composition. HMOs were quantified by HPLC and confirmed by enzymatic digest and mass spectrometry. Associations of maternal pre pregnancy BMI, subcutaneous adipose tissue thickness (SAT) and adipokines with absolute and relative HMO concentrations were analyzed by spearman correlation. We identified 16 HMOs, and two oligosaccharides not common to human milk. HMO concentration and composition varied with gestational age and secretor status. HMO concentration increased with gestational age and changed from a predominantly sialylated profile at V1, to a more balanced fucosylated-to-sialylated ratio at V3, mostly due to a profound increase in 2'-fucosyllactose (2'FL), reflecting secretor phenotype. In secretor positive women, BMI was negatively correlated with 2'FL at V2. SAT at V1 and V2 were strongly negatively correlated with 2'FL concentrations. This pilot study shows that prenatal HMOs are present in maternal serum, suggesting roles for HMOs already during pregnancy. Our results that maternal body composition is associated with prenatal HMOs might indicate that maternal metabolism modulates HMO composition with unknown implications for maternal and fetal health already during pregnancy. PMID- 30422707 TI - CT Colonography in Preoperative Staging of Colon Cancer: Evaluation of FOxTROT Inclusion Criteria for Neoadjuvant Therapy. AB - OBJECTIVE: The purpose of the present study is to evaluate the diagnostic performance of and interreader agreement for CT colonography (CTC) in the local staging of colon cancer, with emphasis given to the FOxTROT (Fluoropyrimidine, Oxaliplatin, and Targeted-Receptor pre-Operative Therapy [Panitumumab]) trial inclusion criteria, which propose a new tailored treatment paradigm for colon cancer that uses neoadjuvant therapy for patients with a high-risk of locoregional disease as determined by imaging. MATERIALS AND METHODS: This biinstitutional retrospective study involved 89 patients (with 93 tumors) who had colon cancer and underwent presurgical CTC. Two radiologists reviewed the CTC studies for local staging, including measurement of the tumor beyond the muscularis propria on a true orthogonal plane. Histopathologic findings for surgical colectomy specimens served as the reference standard for local pathologic staging. The sensitivity, specificity, positive predictive value, and negative predictive value for local determination of the T category, N category, and extramural vascular invasion (EMVI) were calculated separately for each reader. High-risk T category tumors were the same as those as used in the FOxTROT trial. Interreader agreement was assessed using the kappa statistic. RESULTS: Thirty-five of 93 tumors (37.6%) were histologically classified as high-risk tumors (T3c, T3d, or T4 tumors). The interreader agreement was substantial (kappa = 0.68) for classifying high-risk tumors with the use of CTC, moderate for differentiating N0 from N1 and N2 (kappa = 0.44), and slight for detecting EMVI (kappa = 0.15). The diagnostic statistics for CTC for the two readers were as follows: for detection of high-risk tumors, sensitivity was 65.7% and 82.9%, and specificity was 81.0% and 87.9%; for detection of N category-positive disease, sensitivity was 50.9% and 69.8%, and specificity was 50.0% and 72.5%; and for detection of EMVI, sensitivity was 18.2% and 66.7%, and specificity was 60.0% and 91.7%. CONCLUSION: The present study shows that CTC might be a feasible imaging modality for preoperative local staging of higher-risk colon cancers for which neoadjuvant chemotherapy is more suitable on the basis of the FOxTROT trial criteria. However, further studies are required to allow a better generalization of our results. PMID- 30422708 TI - Gadolinium-Based Blood Volume Mapping From MRI With Ultrashort TE Versus CT and SPECT for Predicting Postoperative Lung Function in Patients With Non-Small Cell Lung Cancer. AB - OBJECTIVE: The purpose of this study is to directly compare the capability of gadolinium-based blood volume (BV) mapping from MRI (BV-MRI) with ultrashort TE (UTE) with that of CT and perfusion SPECT in predicting the postoperative lung function of patients with non-small cell lung cancer (NSCLC). SUBJECTS AND METHODS: Unenhanced and contrast-enhanced MRI with UTE, thin-section CT, and perfusion SPECT examinations and measurements of the percentage of forced expiratory volume in 1 second (FEV1) before and after lung resection were performed for 29 patients with NSCLC (16 men [mean age, 66 years] and 13 women [mean age, 66 years]). BV-MRI with UTE was generated as a percentage of the signal change between un-enhanced and contrast-enhanced MRI. The postoperative percentage of FEV1 was predicted from perfusion fractions derived from BV-MRI with UTE and from SPECT. Quantitatively and qualitatively predicted postoperative percentages of FEV1 from CT were calculated from the functional lung volumes and the number of segments. Each predicted postoperative percentage of FEV1 was then correlated with the actual postoperative percentage of FEV1, and the limits of agreement for each actual and predicted postoperative percentage of FEV1 were evaluated by Bland-Altman analysis. RESULTS: Correlations between actual and predicted postoperative percentages of FEV1 for all methods were strong and significant (0.88 <= r <= 0.95). The limits of agreement (mean +/- 1.96 * SD) for BV-MRI with UTE (4.2% +/- 6.5%) and quantitatively assessed CT (4.1% +/- 6.5%) were smaller than those for qualitatively assessed CT (4.2% +/- 9.8%) and perfusion SPECT (5.7% +/- 8.7%). CONCLUSION: BV-MRI with UTE has the potential to predict the postoperative lung function of patients with NSCLC more accurately than qualitatively assessed CT and SPECT, and it can be considered to be at least as useful as quantitatively assessed CT. PMID- 30422709 TI - Crohn Disease: A 5-Point MR Enterocolonography Classification Using Enteroscopic Findings. AB - OBJECTIVE: The objectives of our study were to establish the efficacy of a 5 point MR enterocolonography classification for assessing Crohn disease (CD) activity, compare this classification with a validated MRI score (i.e., the MR index of activity [MaRIA]), and compare both with endoscopic findings, which were assessed using the Crohn disease endoscopic index of severity (CDEIS). MATERIALS AND METHODS: Seventy (derivation cohort) and 50 (validation cohort) patients with CD were retrospectively enrolled in this study. We developed a 5-point MR enterocolonography classification that consists of visual assessments alone. MR enterocolonography results were evaluated for each bowel segment (rectum; sigmoid, descending, transverse, and ascending colon; terminal and proximal ileum; and jejunum) by one observer in the derivation phase and independently by three observers in the validation phase using the 5-point MR enterocolonography classification lexicon and MaRIA. Areas under the ROC curves (AUCs) in discriminating endoscopic deep ulcers were compared between the MR enterocolonography classification and MaRIA. Interobserver reproducibility was assessed using weighted kappa coefficients. RESULTS: The AUCs of the MR enterocolonography classification were 89.0% in the derivation phase and 88.5%, 81.0%, and 77.3% for the three observers in the validation phase. The AUCs of the MR enterocolonography classification were statistically noninferior to those of MaRIA (p < 0.001). The cross-validation accuracy was 81.9% in the derivation phase and 81.5% in the validation phase. The MR enterocolonography classification showed good reproducibility. CONCLUSION: The 5-point MR enterocolonography classification was shown to be effective for evaluating CD activity in the large and small bowel. PMID- 30422710 TI - Gender Differences in Leadership Positions Among Academic Nuclear Medicine Specialists in Canada and the United States. AB - OBJECTIVE: Despite equal representation of genders among medical students, women continue to be underrepresented in the field of academic diagnostic radiology. These differences are manifest across subspecialties in academic medicine and even in diagnostic radiology. There are limited data available addressing diversity among nuclear medicine specialists. Thus, our primary objective was to compare gender representation in academic and leadership positions among faculty members in nuclear medicine in Canada and the United States. Our secondary objective was to study the influences to account for the existing disparity in academic nuclear medicine. MATERIALS AND METHODS: Using the Fellowship and Residency Electronic Interactive Database (FREIDA) and Canadian Resident Matching Service (CaRMS), we created a database of faculty members in nuclear medicine. For assessment of academic performance, the h-index, number of publications, number of citations, and years of active research were extracted using Scopus. RESULTS: The academic ranks of 237 faculty members were used for analysis; of this group, 16.95% of associate professors were female. Women were less frequently represented in higher academic ranks, and women were also less frequently represented in leadership ranks (13.6% female vs 86.4% male). The h index was comparable across genders. CONCLUSION: Female nuclear medicine specialists are underrepresented in academic and leadership positions compared with their male counterparts. This difference in numbers is unlikely to be because of academic performance given that both genders had comparable academic performance metrics in our study. The results show the need for devising strategies to promote diversity in academic and leadership positions across nuclear medicine specialists. PMID- 30422711 TI - A Review of the Role of Augmented Intelligence in Breast Imaging: From Automated Breast Density Assessment to Risk Stratification. AB - OBJECTIVE: The goal of augmented intelligence is to increase efficiency and effectiveness in practice. To achieve this, augmented intelligence technologies are being asked to perform a range of tasks, from simple to complex and quantitative. The development of these systems is increasingly important as screening becomes more personalized. This article will provide an overview of augmented intelligence in a variety of breast imaging applications. CONCLUSION: The incorporation of AI and ML techniques in breast imaging provides important new tools that will deliver ways to "sharpen" trusted familiar tools (so-called "augmented intelligence") to support radiologists, not replace them. The first wave of medical imaging systems based on AI and ML has primarily used ML to fix the values of key imaging parameters to be adapted to the individual as part of personalized medicine. Artificial intelligence is the new tool in the radiologist's arsenal but will never replace the human qualities that are important in medicine-intellectual curiosity, passion, and drive. PMID- 30422712 TI - Lead Shielding in Pediatric Chest CT: Effect of Apron Placement Outside the Scan Volume on Radiation Dose Reduction. AB - OBJECTIVE: The purpose of this study was to quantify the dose reduction resulting from the use of lead aprons for pediatric chest CT as a function of the distance between the apron and the bottom of the scan range. MATERIALS AND METHODS: Semianthropomorphic phantoms of the head, abdomen, and pelvis were placed adjacent to a chest phantom to mimic the habitus of a 5-year-old child. A chest CT scan was performed, and a point dosimeter was used to measure the radiation dose at points within and outside the scan range. A lead apron was placed 1, 5, and 10 cm from the bottom of the CT scan range, and the measurements were repeated. The weighted-average dose was calculated for each measurement position. RESULTS: The weighted-average dose within and outside the scan range was 1.7 and 0.067 mGy, respectively. The mean (percentage) dose reduction outside the scan range resulting from use of the lead apron was 0.013 mGy (19.1%), 0.007 mGy (10.1%), and 0.003 mGy (4.3%) when the lead apron was placed at distances of 1, 5, and 10 cm from the bottom of the scan range, respectively. The corresponding total percentage dose reduction (including the dose from the primary scan) was 0.7%, 0.4%, and 0.2%, respectively. CONCLUSION: As the lead apron was placed farther from the scan range, the amount of dose reduction diminished. The reduction in dose was extremely small compared with the overall dose from the examination. The small dose reduction gained from the use of lead shielding over the abdomen and pelvis during chest CT examination of pediatric patients may not outweigh the associated potential risks of artifacts and infection. PMID- 30422713 TI - Dual-Energy CT Urography With 50% Reduced Iodine Dose Versus Single-Energy CT Urography With Standard Iodine Dose. AB - OBJECTIVE: The purpose of this study was to compare dual-energy CT (DECT) urography with a 50% reduced iodine dose to single-energy CT (SECT) urography with a standard iodine dose with respect to attenuation of renal vascular and urinary tract structures and with respect to image quality. SUBJECTS AND METHODS: The study included 62 patients undergoing evaluation of urinary tract lithiasis, tumor, or hematuria. Thirty-one patients underwent DECT urography with a 50% reduced iodine dose and reconstruction at 50 and 77 keV. These subjects were sex, age, and size matched to a group of 31 patients who underwent 120-kVp SECT urography with a standard iodine dose. The mean iodine dose was 22 g for DECT and 44 g for SECT. Attenuation was measured at seven locations in the renal arteries, renal veins, and urinary tract. Two reviewers subjectively scored the image quality parameters image noise, sharpness of urinary tract contours, enhancement of urinary structures, and streak artifacts. RESULTS: Mean DECT attenuation at 50 keV was the same as or greater than SECT attenuation at each of the seven locations. Measured image noise was highest at 50-keV DECT but was the same for 77-keV DECT and 120-kVp SECT. Mean subjective scores for DECT image quality parameters were the same as or higher than those of SECT, except for streak artifact and sharpness of urinary tract contours. CONCLUSION: DECT urography with a 50% reduced iodine dose may result in measured renal vascular and urinary tract attenuation the same as or higher than and image quality measurements and scores similar to those obtained with 120-kVp SECT urography with a standard iodine dose. PMID- 30422714 TI - Fetal Head and Neck Masses: MRI Prediction of Significant Morbidity. AB - OBJECTIVE: The purpose of this study is to determine which MRI parameters of fetal head and neck masses predict high-morbidity neonatal outcomes, including ex utero intrapartum treatment (EXIT) procedure. MATERIALS AND METHODS: This retrospective study (2004-2016) included parameters of polyhydramnios (based on largest vertical pocket), mass effect on the trachea, mass midline extension, and morphologic grade and size of masses. The morbid cohort included those requiring an EXIT procedure, difficult intubation at delivery, or lethal outcome. Predictive modeling with a multivariable logistic regression and ROC analysis was then performed. RESULTS: Of 36 fetuses, five were delivered by EXIT procedures, there was one neonatal death within 12 hours after delivery, and another neonate required multiple intubation attempts. The remaining 29 fetuses were delivered at outside institutions with no interventions or neonatal morbidity. The largest vertical pocket and mass effect on the trachea were selected as independent predictors by the logistic regression. The cross-validated ROC AUC was 0.951 (95% CI, 0.8795-1). CONCLUSION: The largest vertical pocket measurement and mass effect on the trachea were the most contributory MRI parameters that predicted significant morbidity in fetuses with masses of the face and neck, along with other significant parameters. These parameters predict significant morbid neonatal outcomes, including the need for EXIT procedures. PMID- 30422715 TI - Artificial Intelligence in Breast Imaging: Potentials and Limitations. AB - OBJECTIVE: The purpose of this article is to discuss potential applications of artificial intelligence (AI) in breast imaging and limitations that may slow or prevent its adoption. CONCLUSION: The algorithms of AI for workflow improvement and outcome analyses are advancing. Using imaging data of high quality and quantity, AI can support breast imagers in diagnosis and patient management, but AI cannot yet be relied on or be responsible for physicians' decisions that may affect survival. Education in AI is urgently needed for physicians. PMID- 30422716 TI - How Cognitive Machines Can Augment Medical Imaging. AB - OBJECTIVE: Artificial intelligence (AI) neural networks rapidly convert disparate facts and data into highly predictive analytic models. Machine learning maps image-patient phenotype correlations opaque to standard statistics. Deep learning performs accurate image-derived tissue characterization and can generate virtual CT images from MRI datasets. Natural language processing reads medical literature and efficiently reconfigures years of PACS and electronic medical record information. CONCLUSION: AI logistics solve radiology informatics workflow pain points. Imaging professionals and companies will drive health care AI technology insertion. Data science and computer science will jointly potentiate the impact of AI applications for medical imaging. PMID- 30422717 TI - FDG PET/MRI Coregistration Helps Predict Response to Gamma Knife Radiosurgery in Patients With Brain Metastases. AB - OBJECTIVE: The purpose of this study was to determine whether relative standardized uptake value (SUV) measurements at FDG PET/MRI coregistration are predictive of local tumor control in patients with brain metastases treated with stereotactic radiosurgery (SRS). MATERIALS AND METHODS: A retrospective review was conducted of the images and clinical characteristics of a cohort of patients with brain metastases from non-CNS neoplasms treated with gamma knife radiosurgery (GKRS) who underwent posttherapy FDG PET because of MRI findings concerning for progression. The PET and contrast-enhanced MR images were fused. Relative SUV measurements were calculated from ROIs placed in the area of highest FDG uptake within the enhancing lesion and in the contralateral normal-appearing white matter. Relative SUV was defined as the ratio of maximum SUV in the tumor to maximum SUV in healthy white matter. Two independent readers evaluated response to GKRS using serial posttherapy MRI performed at least 3 months after GKRS completion. The relation between relative SUV and local tumor progression was evaluated with respect to treatment effect. RESULTS: Eighty-five patients (48 [56.5%] women, 37 [43.5%] men; mean age at diagnosis, 60.5 +/- 11.3 years) met the inclusion criteria. Thirty-three (38.8%) lesions progressed after SRS. There was a significant association between relative SUV and local tumor control (p = 0.035). Relative SUV provided a diagnostic ROC AUC of 0.67 (95% CI, 0.55-0.79). CONCLUSION: Quantitative relative SUV at posttherapy FDG PET serves as a biomarker of response to SRS in patients with brain metastases in cases in which lesion growth is identified at follow-up MRI. This prognostic data may affect management, supporting the need for further therapeutic actions for selected patients. PMID- 30422718 TI - What is it like to have your loved one with a severe brain injury come to rehabilitation? The experiences of significant others. AB - PURPOSE: To investigate the experiences of significant others when their loved one with a severe brain injury is admitted to acquired brain injury (ABI) rehabilitation. MAIN MEASURES: A qualitative approach was undertaken; using in depth interviews and the drawing method to elicit information on the experiences of significant others who had loved ones enter an ABI unit, early in the sub acute rehabilitation admission. RESULTS: Nine significant others participated in interviews and completed drawings. Seven themes were identified from the two sources of data. Themes included: Trauma; Relief; Interactions; Change; Grief and loss; Journey, and Uncertainty. CONCLUSIONS: The whole experience for the significant other is traumatic as they try to understand changes to both their loved ones and their own roles. Healthcare providers have a key role in supporting significant others as their loved ones enter rehabilitation. The role of the drawing method appears to supplement and extend data received from interviews, shedding additional light into the lived experiences of significant others of those with an acquired brain injury. Implications for rehabilitation Early in the rehabilitation process, significant others experience emotional trauma resulting from their experience of their loved one's trauma. It is important that health professionals interactions with significant others are respectful and kind, and that interactions around processes and communication are clear. Expertise and a tailored environment reduce stress and increase feelings of confidence in significant others. Significant others may need time to talk about their experiences with health professional staff, to support them to adjust to this major life change. PMID- 30422719 TI - Pulmonary arterial hypertension: assessing risk to improve prognosis. PMID- 30422720 TI - Codon 14 (+T) (HBB: c.44_45insT): a Rare beta-Thalassemia Mutation Reported Only in Azerbaijan. AB - Codon 14 (+T) (HBB: c.44_45insT) is a very rare beta-thalassemia (beta-thal) mutation previously reported in three beta-thal major (beta-TM) patients of Azerbaijani origin. None of the previous reports described the genotype-phenotype correlation of the mutation. We here report the first case of homozygous codon 14 together with data of the heterozygous parents. PMID- 30422721 TI - Prevalence of alpha-Thalassemia in the Egyptian Population. AB - Hemoglobinopathies are the most common monogenic diseases in the world, causing many health problems worldwide. In Egypt, thalassemia is the most common cause of chronic hemolytic anemia and correlated with significant morbidity and mortality. One thousand Egyptian newborns were screened to detect alpha-thalassemia (alpha thal) deletions using polymerase chain reaction (PCR)-based DNA analysis of cord blood samples. Ninety-one cases (9.1%) of the studied samples were proved to have at least one of the alpha genes deleted and 851 cases (85.1%) were normal by PCR analysis, while 58 samples (5.8%) failed to be amplified so further DNA analysis could not be done. In the studied group with alpha gene deletions, we found different types including silent carriers with only one alpha-globin gene deleted (3.1%), alpha-thal trait with two alpha-globin genes deleted (4.2%), Hb H disease with three alpha-globin genes deleted (1.8%) and no cases carrying Hb Bart's disease with loss of four alpha-globin genes. We determined the deletional spectrum of alpha-thal, which might be used in the future for molecular investigations of the disease in susceptible patients in our population. PMID- 30422722 TI - Primary care networks and team effectiveness: the case of a large-scale quality improvement disparity reduction program. AB - Documentation of primary care teams' involvement in disparity reduction efforts exists, yet little is known about how teams interact or perceive their effectiveness. We investigated how the social network and structural ties among primary-care-clinic team members relate to their perceived team effectiveness (TE), in a large-scale disparity reduction intervention in Israel's largest insurer and provider of services. A mixed-method design of Social Network Analysis and qualitative data collection was employed. 108 interviews with medical, nursing, and administrative teams of 26 clinics and their respective managerial units were performed and information on the organizational ties, analyzing density and centrality, collected. Pearson correlations examined association between network measures and perceived TE. Clinics with strong intra clinic density and high clinic-subregional-management density were positively correlated with perceived TE. Clinic in-degree centrality was also positively associated with perceived TE. Qualitative analyses support these findings with teamwork emerging as a factor which can impede or facilitate teams' ability to design and implement disparity reduction interventions. The study demonstrates that in an organization-wide disparity reduction initiative, cohesive intra network structure and close relations with mid-level management increase the likelihood that teams perceive themselves as possessing the skills and resources needed to lead and implement disparity reduction efforts. List of abbreviations Team Effectiveness (TE); Clalit Health Services (Clalit); Social Network Analysis (SNA); Quality Improvement (QI); National Health Care Collaborative (NHPC); Tampa Bay Community Cancer Network (TBCCN). PMID- 30422723 TI - Comparison of patients with and without pre-existing lymphoma at diagnosis of primary Sjogren's syndrome. AB - OBJECTIVE: In the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjogren's syndrome (pSS), pre existing lymphoma is not an exclusion criterion for pSS diagnosis, as in earlier criteria. We aimed to explore whether there are differences between pSS patients with and without pre-existing lymphoma at pSS diagnosis. METHOD: Patients with ICD-7-10 codes for Sjogren's syndrome (SS) and a diagnosis of malignant lymphoma before or after SS diagnosis were identified by linking the Swedish Patient Register 1964-2007 with the Cancer Register 1990-2007 (n = 224). Clinical data were collected from medical records. Lymphoma diagnoses were evaluated by tissue review. Characteristics of pSS patients with and without pre-existing lymphoma were compared. RESULTS: We identified 107 patients with pSS as the reason for an SS diagnosis code and a verified lymphoma. Of these, 18 (17%) had a pre-existing lymphoma at pSS diagnosis, defined as lymphoma diagnosed before or within 6 months of pSS diagnosis. Male gender (39% vs 10%, p = 0.006), enlarged lymph nodes during the pSS disease (61% vs 27%, p = 0.01), mucosa-associated lymphoid tissue (MALT) lymphoma (50% vs 22%, p = 0.02), and salivary gland lymphoma (61% vs 26%, p = 0.006) were more common in patients with a pre-existing lymphoma at pSS diagnosis. Other pSS characteristics were similar. CONCLUSION: In a substantial proportion of patients, particularly in men, pSS remains undiagnosed until after lymphoma diagnosis. The study highlights the importance of pSS investigation in patients with lymphoma, especially MALT lymphoma, in the salivary glands. PMID- 30422724 TI - The role of EUS-guided fine needle aspiration in autoimmune pancreatitis: a single center prospective study. AB - OBJECTIVES: Histopathological examination is pivotal in diagnosing autoimmune pancreatitis (AIP). The usefulness of EUS-guided fine needle aspiration (EUS-FNA) in diagnosing AIP remains controversial worldwide. The authors conducted this study to evaluate the efficacy of EUS-FNA for AIP diagnosis using a 22-gauge needle. METHODS: Between January 2013 and May 2017, 37 patients had imaging studies suggestive of AIP at Tongji Hospital, and 27 patients of them were enrolled in this study. Tissue specimens acquired through EUS-FNA were analyzed for periductal lymphoplasmacytic infiltrate (LPI), storiform fibrosis (SF), obliterative phlebitis (OP) and immunoglobulin G4 (IgG4)-positive plasma cell counts. Clinical Trials.gov no: TJ-C20121220. RESULTS: LPI and SF were present in 18 (66.67%) and 18 (66.67%) of 27 patients, respectively. Abundant IgG4-positive plasmacyte infiltration >10/high-power field (HPF) was detected in 8 of 27 patients (29.63%). OP and the characteristic findings of idiopathic duct-centric chronic pancreatitis (IDCP) and granulocytic epithelial lesion (GEL) were not detected in this study. According to the International Consensus Diagnostic Criteria (ICDC) for AIP, 5 and 12 of 27 patients were assessed as having level 1 and level 2 histological findings, respectively, suggesting that 17 of 27 patients (62.96%) had lymphoplasmacytic sclerosing pancreatitis (LPSP) based on the ICDC. CONCLUSIONS: In 92.6% of patients, pancreatic tissues with >5 HPFs were obtained by EUS-FNA using a 22-G needle. In 63% of patients, histology was evaluated to be >= level 2 according to the ICDC. The study indicates that EUS FNA with a 22-G needle is valuable in the histopathological diagnosis of AIP. PMID- 30422725 TI - Diagnostic performance of a new anti-carbamylated protein assay in rheumatic diseases. PMID- 30422726 TI - Computational investigation of mechanistic insights of Abeta42 interactions against extracellular domain of nAChRalpha7 in Alzheimer's disease . AB - Amyloid beta (Abeta) 1-42, which is a basic constituent of amyloid plaques, binds with extracellular transmembrane receptor nicotine acetylcholine receptor alpha7 (nAChRalpha7) in Alzheimer's disease. In the current study, a computational approach was employed to explore the active binding sites of nAChRalpha7 through Abeta 1-42 interactions and their involvement in the activation of downstream signaling pathways. Sequential and structural analyses were performed on the extracellular part of nAChRalpha7 to identify its core active binding site. Results showed that a conserved residual pattern and well superimposed structures were observed in all nAChRs proteins. Molecular docking servers were used to predict the common interactive residues in nAChRalpha7 and Abeta1-42 proteins. The docking profile results showed some common interactive residues such as Glu22, Ala42 and Trp171 may consider as the active key player in the activation of downstream signaling pathways. Moreover, the signal communication and receiving efficacy of best-docked complexes was checked through DynOmic online server. Furthermore, the results from molecular dynamic simulation experiment showed the stability of nAChRalpha7. The generated root mean square deviations and fluctuations (RMSD/F), solvent accessible surface area (SASA) and radius of gyration (Rg) graphs of nAChRalpha7 also showed its backbone stability and compactness, respectively. Taken together, our predicted results intimated the structural insight on the molecular interactions of beta amyloid protein involved in the activation of nAChRalpha7 receptor. In future, a better understanding of nAChRalpha7 and their interconnected proteins signaling cascade may be consider as target to cure Alzheimer's disease. PMID- 30422727 TI - Preparation and in vivo pharmacokinetics of rhGH-loaded PLGA microspheres. AB - Recombinant human growth hormone (rhGH) therapy must be administered as a daily injection due to its short half-life. To achieve sustained release of rhGH, the preparation of rhGH-loaded PLGA microspheres was investigated, and the influence of various factors on encapsulation efficiency was tested, including rhGH concentration, the ratio of internal phase to organic phase, stirring speed, PVA concentration, surrounding pH value, and the type of emulsifier and organic solvent. A pharmacokinetic study was performed by subcutaneous administration to explore the sustained release effect. It was found that rhGH-loaded PLGA microspheres were prepared with a narrow size distribution, and optimization of the formulation could enhance encapsulation efficiency. FTIR analysis indicated that the activity of rhGH was maintained after encapsulation. The pharmacokinetic behavior of rhGH solutions was consistent with a two-compartment model, which showed fast absorption and distribution. RhGH-loaded PLGA microspheres achieved a higher bioavailability and a long-term effective concentration by controlling the release, and PLGA 50/50 demonstrated favorable AUC compared with PLGA 75/25. Nevertheless, the higher bioavailability of rhGH-loaded PLGA microspheres lacking Span 80 did not predicate better sustained release behavior, indicating that further investigation is needed to explore the use of bioavailability as the standard in evaluating the sustained release characteristics and in vivo behavior of microspheres. PMID- 30422728 TI - Protective effects of glucagon-like peptide-1 (GLP-1) analogue exenatide against glucose and fructose-induced neurotoxicity. AB - Diabetes mellitus (DM) is one of the most common metabolic disorders characterized by hyperglycemia due to insufficiency of insulin and/or insulin resistance. Clinical studies have revealed a higher risk of neurodegenerative disorders such as Alzheimer's disease or Parkinson's disease in diabetic patients. Recently, glucagon-like peptide-1 (GLP-1) is an attractive potential treatment modality for various neurodegenerative diseases. In our study, we aimed to investigate whether exenatide, a GLP-1 analogue, has neuroprotective effects against glucose and fructose-induced toxicity in human SH-SY5Y neuroblastoma cell line. Neurotoxicity was induced by incubating SH-SY5Y cells with different doses (25-100 mM) of glucose and fructose for 24, 48 and 72 h. Following determination of the significant toxic doses of glucose and fructose, the cells were treated with various doses of exenatide (10-250 nM) in the presence or absence of glucose and fructose. Neurotoxicity was evaluated by MTT assay and Hoechst 33258 staining. Caspase-3 activity and the levels of advanced glycation end products (AGEs) were determined in the cytosolic fractions of treated cells. Our results demonstrated that both glucose and fructose treatments decreased cell viability in neuronal cells dose and time-dependently. Glucose and fructose-treated groups showed increased numbers of apoptotic cells, caspase-3 activity and AGEs levels. Treatment of the cells with exenatide significantly prevented cell death. The most prominent effect was observed at 100 nM exenatide-treated cultures. Our results suggest that high doses of glucose and fructose may lead to neurotoxicity, and exenatide may have protective effects against neuronal damage through its anti-apoptotic feature. PMID- 30422730 TI - Erythema nodosum in a postpartum primigravida: a case report. PMID- 30422729 TI - 'Isn't biological treatment something healthy?' Lay people's perceptions of medical terms. PMID- 30422731 TI - Development and evaluation of a primary care interprofessional education intervention to support people with dementia. AB - International policy documents emphasize the need to develop interprofessional education (IPE) to support collaborative dementia care in the community. The aim of this short report is to describe the development and pilot evaluation of an interprofessional dementia education workshop for primary care healthcare professionals. A three-hour workshop was iteratively developed through consultation with an expert reference group and people with dementia. The workshop was piloted with three separate primary care teams. A total of fifty four primary care based healthcare staff who represented fourteen different health care roles in primary care participated in the pilot evaluation. The pilot workshops were evaluated using a mixed method approach which included post workshop questionnaires for participants (n= 54)and a post-workshop focus group (n=8) with the program design team and workshop facilitators. The results of the pilot phase indicated that the workshop was useful and feasible. The workshop improved participants' self-reported knowledge, understanding and confidence to support people with dementia and their families.Areas for improvement were identified and will be used to inform improvements to the workshop content and delivery in advance of a national roll-out. Future evaluations of the implementation of this interprofessional educational workshop will focus on its impact on healthcare professional behavior and outcomes for the person with dementia and their families. PMID- 30422732 TI - Levels of total antioxidant capacity and 8-hydroxy-2'-deoxyguanosine of serum and follicular fluid in women undergoing in vitro fertilization: focusing on endometriosis. AB - This study was designed to evaluate the levels of oxidative stress (OS) markers, total non-enzymatic antioxidant capacity (TAC) and 8-hydroxy-2'-deoxyguanosine (8 OHdG) in the serum and follicular fluid (FF) of patients undergoing in vitro fertilization (IVF). The impact of these biomarkers on IVF outcome was also analysed. Samples were obtained from 61 patients (age: 36.40 +/- 4.99 years; BMI: 22.54 +/- 2.46; infertility: 3.7 +/- 2.5 years [mean +/- SD]) before and after controlled ovarian hyperstimulation (COH). Patients with and without endometriosis were also evaluated separately. TAC was quantified by enhanced chemiluminescence assay and 8-OHdG was measured by enzyme-linked immunosorbent assay. It was demonstrated that these biomarkers responded to COH differently. No relationship could be detected in their FF levels, although their cumulative serum levels were inversely related. Both FF TAC and FF 8-OHdG had a negative impact on the number of good quality embryos, but an effect of Serum TAC and 8 OHdG could not be observed. When women with and without endometriosis were evaluated separately, inconsistent results were obtained. However, women without endometriosis had higher levels of serum and FF TAC when they progressed to clinical pregnancy. Our findings support the notion that OS has an important contribution to the reproductive potential in IVF patients, the ideal biomarkers of outcome measures, however, need to be further explored. PMID- 30422734 TI - Laparoscopic specimen retrieval and attitudes towards morcellation: a questionnaire survey of gynaecology consultants in the United Kingdom. AB - The aim of this study was to evaluate the practices of laparoscopic specimen retrieval among Gynaecologists in the United Kingdom and to determine any variation in practice. A survey of Consultant Gynaecologist members of the British Society of Gynaecological Endoscopy (BSGE) was conducted using Survey MonkeyTM. Of the 460 registered consultants, 187 (40%) responded to the questionnaire. Sixty-two percent (62%) of the respondents considered themselves to be advanced laparoscopic surgeons whilst 34% considered themselves to be intermediate laparoscopic surgeons. The umbilical port was the most commonly used port for specimen retrieval and it was used to remove 49% of ectopic pregnancies, 43% of ovarian cysts and 43% of endometrioma. Most respondents would not insert an extra port or extend the existing port just for the retrieval of a specimen. The level of laparoscopic experience and the gender did not affect the method of specimen retrieval in cases of ectopic pregnancies, endometrioma and ovarian cysts (p value >.05, not significant). The majority of respondents used power morcellation for a laparoscopic myomectomy (85% of respondents) and laparoscopic subtotal hysterectomy (93% of respondents), despite the recent concerns surrounding power morcellation. Impact statement What is already known on this subject? There is a paucity of literature regarding laparoscopic specimen retrieval in gynaecology. In view of recent controversy pertaining to the potential upstaging of leiomyosarcoma with morcellation, other methods of specimen retrieval are gaining an importance. What do the results of this study add? This study shows that the umbilical port is the most commonly used port for specimen retrieval among UK gynaecologists and that most gynaecologists would not insert an additional port purely for specimen retrieval. Most respondents would still use power morcellation for a laparoscopic myomectomy and subtotal hysterectomy, despite the recent concerns over morcellation and its safety. What are the implications of these findings for clinical practice and/or further research? This paper demonstrates the need for development of a database of morcellation practices to enable analysis of both benefits and potential adverse outcomes. This paper will also encourage future research and the audit of specimen retrieval. PMID- 30422733 TI - Structural progression rate decreases over time on serial radiography and magnetic resonance imaging of sacroiliac joints and spine in a five-year follow up study of patients with ankylosing spondylitis treated with tumour necrosis factor inhibitor. AB - OBJECTIVE: To investigate temporal changes in structural progression assessed by serial conventional radiography and magnetic resonance imaging (MRI) of the sacroiliac joints (SIJs) and spine in patients with ankylosing spondylitis (AS) treated with tumour necrosis factor (TNF) inhibitor for 5 years. METHOD: Forty two patients were included and 33 patients were followed for 5 years in a prospective investigator-initiated study. Conventional radiographs were required four times and MRI seven times. The modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS); Spondyloarthritis Research Consortium of Canada (SPARCC) MRI SIJ and Spine Inflammation, and SPARCC MRI SIJ Structural Score (SSS) for Fat, Erosion, Backfill, and Ankylosis; and the Canada-Denmark MRI scores for Spine Inflammation, Fat, Erosion, and New Bone Formation (NBF) were applied. RESULTS: Compared with baseline, MRI Inflammation had decreased significantly at week 22 (spine)/week 46 (SIJ) and thereafter. MRI SIJ Fat (from week 22), SIJ Ankylosis, Spine NBF, and mSASSS had increased significantly at week 46 and thereafter. SIJ Erosion had decreased from year 2. The annual progression rate in mSASSS was significantly higher during weeks 0-46 compared to week 46 to year 3. In multivariate regression analyses, baseline SIJ Inflammation and Backfill were independent predictors of 5 year progression in SIJ Ankylosis. Spine Erosion predicted progression in Spine NBF. Longitudinally, Ankylosing Spondylitis Disease Activity Score, Bath Ankylosing Spondylitis Disease Activity Index, MRI Spine Inflammation, Fat, and Erosion scores were significantly associated with mSASSS. SIJ Inflammation, Fat, Erosion, and Backfill scores were longitudinally associated with SIJ Ankylosis. Structural progression was not associated with body mass index, smoking, or Assessment of SpondyloArthritis international Society Non-Steroidal Anti-Inflammatory Drug Index. CONCLUSION: In a 5 year follow-up study of patients with AS treated with TNF inhibitor, structural progression decreased over time. PMID- 30422735 TI - Fatigue and microgap behaviour of a three-unit implant-fixed dental prosthesis combining conventional and dynamic abutments. AB - This is an in vitro study composed by a fatigue test followed by an optical microscopy analysis. Dynamic abutments concept, recently introduced on screw retained implant dental prosthesis, consists on the screw channel customisation according to the individual needs of each rehabilitation. Geometry and tightening torque differences advise the assessment of their mechanical performance. Clarify whether the combination of dynamic and conventional abutments in a three-unit implant-fixed prosthesis has detrimental effects either on the mechanical performance under cyclic loading or on the implant-abutment microgap dimensions. The fatigue test was performed in agreement with the ISO standard 14801. Then on the samples that resisted 5 million cycles, the implant-abutment microgap was measured on dynamic and conventional abutments using optical microscopy. Two unloaded samples were used as control group. The samples supported a load of 1050 N. The implant-abutment microgap measurement did not show statistically significant differences (p = .086) between loaded and unloaded groups, but the loaded conventional abutments showed a significant lower implant-abutment microgap (p = .05) than the loaded dynamic abutments. The combination of conventional and dynamic abutments do not seem to produce a decrease in fatigue resistance to a level below the mastication forces or an increase in the joint dimensions. PMID- 30422736 TI - Venous blood flow in maternal kidneys in third trimester of pregnancy. AB - OBJECTIVES: Maternal intra-abdominal pressure and hemodynamics change during pregnancy. The kidneys are susceptible to the adverse effects of elevated intra abdominal pressure. The aim of this study was to compare venous and arterial blood flow between the right and left kidney in the third trimester in women without known pregnancy complications. METHODS: We conducted a prospective cohort study in 50 women with uncomplicated third trimester pregnancies at Trondheim University Hospital, Norway, from January to April 2018. The arterial and venous blood flow were examined with pulsed wave Doppler in the hilum of the kidneys and the cross section of the area (CSA) of the vessels were measured from 3D acquisitions. Two diameters of the main vein and artery were measured after rotating the image of the vessels in the C-plane to be as circular as possible. CSA was calculated as pi * (mean diameter/2)2. Blood flow volume (ml/minute) in the vessels were calculated as 0.5*TAmax (cm/s) * CSA (cm2) * 60. The main outcome was venous and arterial blood flow volumes, and secondary outcomes were maximum velocity (Vmax), minimum velocity (Vmin), pulsatile index (PI), time averaged maximum flow (TAmax) and renal interolobar vein impedance index (RIVI). We also examined possible associations between blood flow and maternal age, BMI and blood pressure. RESULTS: We observed differences in venous flow parameters between the two kidneys. The mean total flow volume in the renal veins was 274 ml/min in the left vein versus 358 ml/min in the right vein (p = 0.10). Vmax, TAmax, PI and RIVI were all significantly lower in the left renal vein. No differences in arterial blood flow between the two kidneys were found. BMI was negatively correlated to flow in the left renal vein (r = -0.28; p < 0.05), but not associated to flow in the right renal vein. CONCLUSION: We found that venous flow pattern differs between left and right renal veins in uncomplicated late pregnancies, but the total flow was not significant different. New studies should be done in women with preeclampsia. PMID- 30422737 TI - Stenotrophomonas maltophilia - a low-grade pathogen with numerous virulence factors. AB - Stenotrophomonas maltophilia is an increasingly prevalent opportunistic pathogen responsible for a wide range of nosocomial infections in intensive care unit patients, life-threatening diseases in immunocompromised haematology-oncology patients and chronic pulmonary infections in individuals with cystic fibrosis. Therapy of these infections is problematic due to the remarkable intrinsic antimicrobial resistance of the species and to acquired resistance to multiple antimicrobial agents. As this organism is a low-grade pathogen, the pathogenesis of S. maltophilia infections involves numerous virulence factors as well as the ability of bacterial cells to form biofilms on abiotic surfaces and host tissues. The present review summarizes the literature data regarding extracellular and cell-associated virulence factors of S. maltophilia (some of which have still not been studied in detail) and considers the basic characteristics of biofilm formation. Many virulence features such as extracellular enzymes, bacterial motility and biofilm formation are finely controlled by quorum sensing (QS) that enable the bacteria to express these virulence factors in a coordinated, cell density-dependent manner and overwhelm the host defence mechanisms. Manipulating the QS regulatory system is a promising approach for development of new strategies for control of S. maltophilia infections. PMID- 30422738 TI - Biotechnology in ciliates: an overview. AB - Since their description and classification in the 19th century, ciliates have played an important role in science, leading to several fundamental discoveries in the areas of cellular and molecular biology. During the last decades, with the emergence of biotechnology, many new developments are also coming to light. In this review, we describe a range of applications in which ciliates have found a niche, ranging from the production of a vast array of proteins, lipids, metabolites, and antigens to their use in toxicity screening, biocontrol, bioremediation, and biotransformation of substrates into more valuable products. We highlight the benefits and drawbacks of their use in biotechnology, the latest developments in large-scale culture and state-of-the-art molecular-genetic techniques, as well as the estimations on the exploitation areas with better potential, i.e., the production of complex membrane proteins, and those less interesting or with less chances of success. PMID- 30422739 TI - Reply to N. Cerveira et al. PMID- 30422740 TI - Optimizing Cardiovascular Care in Children With Acute Myeloid Leukemia to Improve Cancer-Related Outcomes. AB - The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 14-year-old African American female presented with fatigue, easy bruising, and fever. On examination, she had scattered bruising, lymphadenopathy, and hepatosplenomegaly. Laboratory evaluation revealed pancytopenia with peripheral blasts, and acute myeloid leukemia (AML; French-American-British M2, t[8;21][q22;q22.1]) was diagnosed on bone marrow biopsy. A baseline echocardiogram revealed normal left ventricular (LV) systolic function (ejection fraction [EF], 60%; shortening fraction [SF], 32%), and conventional chemotherapy was initiated that consisted of two cycles of remission induction (cytarabine, etoposide, and daunorubicin [50 mg/m2 * 3 days per cycle]) followed by intensification 1 (high-dose cytarabine and etoposide), intensification 2 (high-dose cytarabine and mitoxantrone [12 mg/m2/dose daily; four total doses]), and intensification 3 (high-dose cytarabine and l asparaginase). Of note, an echocardiogram was not repeated before the start of intensification 1. During intensification 1, the patient developed Streptococcus viridans sepsis, which required 4 days in the intensive care unit with antimicrobial and inotropic support. Repeat echocardiogram after recovery from the sepsis episode demonstrated low-normal LV systolic function (EF, 53%; SF, 27%), and she subsequently began intensification 2. On day 3 of intensification 2, the patient developed afebrile tachypnea, tachycardia, and an increasing oxygen requirement. Chest x-ray revealed cardiomegaly and pulmonary vascular congestion. Cardiac troponins were normal, whereas N-terminal pro B-type natriuretic peptide was 10 times the upper limit of normal. Repeat echocardiogram showed an enlarged LV with moderate to severely depressed LV function (EF, 28%; SF, 14%). Day 4 mitoxantrone was omitted and a cardiology consult obtained. PMID- 30422741 TI - Evidence-Based Criteria for Tyrosine Kinase Inhibitor Interruption in Pregnancy. PMID- 30422742 TI - Deoxynivalenol detoxification in transgenic wheat confers resistance to Fusarium Head Blight and Crown Rot diseases. AB - Fusarium diseases, including Fusarium head blight (FHB) and Fusarium crown rot (FCR), reduce crop yield and grain quality and are major agricultural problems worldwide. These diseases also affect food safety, through fungal production of hazardous mycotoxins. Among these, deoxynivalenol (DON) acts as a virulence factor during pathogenesis on wheat. The principal mechanism underlying plant tolerance to DON is glycosylation by specific UDP-glucosyltransferases (UGTs), through which DON-3-beta-D-glucoside (D3G) is produced. In this work we tested whether DON-detoxification by UGT could confer to wheat a broad-spectrum resistance against F. graminearum and F. culmorum. These widespread Fusarium species affect different plant organs and developmental stages in the course of FHB and FCR. To assess DON-detoxification potential, we produced transgenic durum wheat plants constitutively expressing the barley HvUGT13248 and bread wheat plants expressing the same transgene in flower tissues. When challenged with F. graminearum, FHB symptoms were reduced in both types of transgenic plants, particularly evident during early-mid stages of the infection progress. The transgenic durum wheat displayed much higher DON-to-D3G conversion ability and a considerable decrease of total DON+D3G content in flour extracts. The transgenic bread wheat exhibited a UGT-dose-dependent efficacy of DON detoxification. In addition, we showed for the first time that DON-detoxification limits FCR caused by F. culmorum. FCR symptoms were reduced throughout the experiment by nearly 50% in seedlings of transgenic plants constitutively expressing HvUGT13248. Our results demonstrate that limiting the effect of the virulence factor DON via in planta glycosylation restrains FHB and FCR development. Therefore, ability for DON detoxification can be a trait of interest for wheat breeding targeting FHB and FCR resistance. PMID- 30422743 TI - Within-Season Shift in Fungicide Resistance Profiles of Botrytis cinerea in California Strawberry Fields. AB - Sensitivity of Botrytis cinerea to seven fungicide chemical classes was determined for 888 isolates collected in 2016 from 47 California strawberry fields. Isolates were collected early season (minimum fungicide exposure) and late season (maximum fungicide exposure) from the same planting block in each field. Resistance was determined using a mycelial growth assay, and variable frequencies of resistance were observed to each fungicide at both sampling times (early season %, late season %): boscalid (12, 35), cyprodinil (12, 46), fenhexamid (53, 91), fludioxonil (1, 4), fluopyram (2, 7), iprodione (25, 8), isofetamid (0, 1), penthiopyrad (8, 25), pyraclostrobin (77, 98), and thiophanate methyl (81, 96). Analysis of number of chemical class resistances (CCRs) revealed an increasing shift in CCR from the early to late season. Phenotypes of 40 isolates that were resistant or sensitive to different chemical classes were associated with presence or absence of mutations in target genes. Fungicide resistance phenotypes determined in the mycelial growth assay closely matched (93.8%) the genotype observed. Previously described resistance-conferring mutations were found for each gene. A survey of fungicide use from 32 of the sampled fields revealed an average of 15 applications of gray mold-labeled fungicides per season at an average interval of 12 days. The most frequently applied fungicides (average number of applications during the 2016 season) were captan (7.3), pyraclostrobin (2.5), cyprodinil (2.3), fludioxonil (2.3), boscalid (1.8), and fenhexamid (1.4). Multifungicide resistance is widespread in California. Resistance management tactics that reduce selection pressure by limiting fungicide use, rotating among Fungicide Resistance Action Committee codes, and mixing/rotating site-specific fungicides with multisite fungicides need to be improved and implemented. PMID- 30422744 TI - Thymoquinone Potently Enhances the Activities of Classically Activated Macrophages Pulsed with Necrotic Jurkat Cell Lysates and the Production of Antitumor Th1-/M1-Related Cytokines. AB - Antitumor activity of classically activated macrophage (Mphi) may be impaired within the tumors, spleen, and bone marrow. Thus, it is possible to boost its antitumor activity after its pulsing with necrotic tumor cell lysates combined with an adjuvant. We set out to determine the potential adjuvant effects of thymoquinone (TQ; 2-isopropyl-5-methyl-1,4-benzoquinone, C10H12O2) on both functional activities of classically activated Mphis, pulsed or not with necrotic Jurkat T cell line lysates (NecrJCL), and the balance of antitumor cytokines (ATCs) versus immunosuppressive cytokines (ISCs) during crosstalk with autologous human CD4+ T cells. We found that TQ treatment resulted in a significant upregulation of phagocytic activity, respiratory burst, the production of interleukin-2 (IL-2), IL-6, and IL-17 in NecrJCL-pulsed Mphi co-culture system, and, conversely, in downregulation of the production of IL-6, IL-17, nitric oxide (NO), and arginase activity in nonpulsed TQ-treated Mphis co-culture system. In addition, TQ has also shown low upregulation effect on the production of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and IL 1beta, pathogen killing capacity and H2O2 in NecrJCL-pulsed Mphis co-cultures. Moreover, TQ significantly downregulated arginase activity, and significantly upregulated inducible NO synthase (iNOS) activity-to-arginase activity ratio in NecrJCL-pulsed Mphi co-cultures. Furthermore, TQ downregulated IL-10-to-IL-17 ratio and total cellular cholesterol content (ttcCHOL), but upregulated the ratios of IL-1beta-to-IL-4, IL-1beta-to-IL-10, IFN-gamma-to-IL-4, IFN-gamma-to-IL 10, TNF-alpha-to-IL-4, TNF-alpha-to-IL-10, and combined proinflammatory cytokines (PICs)-to-anti-inflammatory cytokines (AICs) in NecrJCL-pulsed Mphis co-culture system, whereas significant differences were highlighted only for IL-10-to-IL-17, IFN-gamma-to-IL-10, and PICs-to-AICs ratios. Our outcomes demonstrated that TQ can act as potent adjuvant for enhancing both the functional activities of NecrJCL-pulsed Mphi and the production of ATCs during their interplay with CD4+ T cells. PMID- 30422745 TI - Phylogeography and Molecular Species Delimitation of Pratylenchus capsici n. sp., a New Root-Lesion Nematode in Israel on Pepper (Capsicum annuum). AB - Root-lesion nematodes of the genus Pratylenchus parasitize the roots of numerous plants and can cause severe damage and yield loss. Here, we report on a new species, Pratylenchus capsici n. sp., from the Arava rift, Israel, which was characterized by integrative methods, including detailed morphology, molecular phylogeny, population genetics and phylogeography. This species is widely spread across the Arava rift, causing significant infection in pepper (Capsicum annuum) roots and inhibiting plant growth. Both morphological and molecular species delimitation support the recovered species as a new species. We found high cytochrome oxidase subunit I haplotype diversity, and phylogeography analysis suggests that contemporary gene flow is prevented among different agricultural farms, while population dispersal from weeds (Chenopodium album and Sonchus oleraceus) to pepper occurs on a relatively small scale. Our results suggest that weeds are important reservoir for the dispersal of P. capsici n. sp., either as the original nematode source or at least in maintaining the population between growing seasons. PMID- 30422746 TI - Comparison of Genomic Driver Oncogenes in Vietnamese Patients With Non-Small-Cell Lung Cancer in the United States and Vietnam. AB - PURPOSE: Discoveries of oncogenic driver alterations in non-small-cell lung cancer (NSCLC) have been accompanied by the development of effective targeted therapies. The frequencies of these mutations vary between populations but are less well characterized in the Vietnamese population. In this study, we analyzed the frequencies of lung cancer driver oncogenic alterations in Vietnamese patients compared with Vietnamese patients treated in the United States. METHODS: We collected data on tumor and disease characteristics of Vietnamese patients with NSCLC treated at Stanford. In addition, we collected NSCLC tumor specimens from patients with NSCLC diagnosed in Hue, Vietnam, and performed next-generation based genotyping on these samples. The molecular and clinical characteristics of these groups were compared. RESULTS: Fifty-nine Vietnamese patients were identified at Stanford. Of the 44 patients with molecular testing results, there were 21 (47.7%) with EGFR alterations, six (13.6%) with ALK alterations, two (4.5%) with KRAS alterations, one (2.3%) with BRAF alterations, and no ROS1 or RET alterations. Across all stages, the median overall survival for patients with a tumor having a targetable genomic alteration driver mutation was 42.4 months, compared with 27.1 months for patients without such alterations. In the 45 genotyped samples from Vietnam, there were 26 (57.8%) with EGFR, 11 (24.4%) with KRAS, and one each (2.2%) with ALK, ROS1, and RET. CONCLUSION: The majority of tumors from both Stanford and Vietnam had targetable oncogenic alterations. This suggests that routine implementation of molecular testing may have a significant, positive impact on the treatment of Vietnamese patients with NSCLC, but affordability of testing and treatments remains a barrier to adoption. PMID- 30422747 TI - Abdominal aortic and iliac aneurysm presented as lower limb deep vein thrombosis: case report. AB - INTRODUCTION: We report a rare case of a symptomatic abdominal aneurysm presented as a lower limb deep vein thrombosis (DVT). CASE PRESENTATION: A 63-year old male presented to our hospital with a recent progressive onset of the right lower limb swelling and pain. The patient had a history of a previous cardiovascular disease. A Duplex ultrasound was performed, which confirmed a right lower limb DVT extending to the right iliac vein. The patient had a pulsatile abdominal mass. Computed tomography scan of the abdomen showed an abdominal aortic and a right iliac artery aneurysm compressing the thrombosed inferior caval and the right iliac vein. The patient was treated with low molecular weight heparin. After resolution of the DVT on day 3 of hospitalization, a surgery on the abdominal and iliac artery aneurysm was performed. The aneurysm was resected and an aortobifemoral bypass was placed using a Dacron prosthesis. The patient remained to be asymptomatic for 6 months after the surgery. Follow up computed tomography demonstrated a fully patent inferior caval and iliac vein and the absence of the aneurysmal disease. CONCLUSION: Although rare, our case confirms that the DVT should be considered as a possible symptom of an abdominal aneurysm in selected patients. PMID- 30422748 TI - Chimeric antigen receptor T-cell therapy: design improvements and therapeutic strategies in cancer treatment. AB - OBJECTIVES: To summarize important findings from research on chimeric antigen receptor (CAR) T-cell immunotherapy in cancer. We discuss CAR design, cell products, toxicity management, heterogenous solid tumors and allogeneic transfer. METHODS: A review of literature was conducted. The available literature was selected on original research, state-of-the art design, relevance to the objective and journal impact factor. RESULTS: First-generation CARs provide patient T cells with tumor-specific antigen recognition. Second- and third generation CARs incorporate costimulatory domains for enhanced T-cell persistence and antitumor activity. Fourth-generation CAR T cells (TRUCKs) include a cytokine production cassette, and hold promise in the treatment of heterogenous solid tumors. Transduced cell phenotype and subset composition are important factors. Suicide genes and safety switches are designed to decrease potential toxicity. Multi-specific CAR T cells can address heterogenous tumors. Allogeneic, off-the shelf CAR T cells might reduce the production delay. CONCLUSION: CAR T cells have revolutionized the immunotherapeutic treatment of cancer: exciting results in refractory and relapsed B-cell malignancies have been published. Neurologic complications, solid tumor management and allogeneic constructs require further research. In conclusion, further design adjustments will enable CAR T cells to decisively reshape the field of cancer immunotherapy. PMID- 30422749 TI - Posttraumatic Stress Disorder in Older Adults: A Conceptual Review. AB - OBJECTIVES: We provide a review of the literature on posttraumatic stress disorder (PTSD) in older adults, focusing largely on older U.S. military veterans in two primary areas: 1) assessment and diagnosis and 2) non-pharmacological treatment of PTSD in late life. METHODS: We performed a search using PubMed and Academic Search Premier (EBSCO) databases and reviewed reference sections of selected papers. We also drew on our own clinical perspectives and reflections of seven expert mental health practitioners. RESULTS: Rates of PTSD are lower in older compared with younger adults. The presence of sub-syndromal/partial PTSD is important and may impact patient functioning. Assessment requires awareness and adaptation for potential differences in PTSD experience and expression in older adults. Psychotherapies for late-life PTSD appear safe, acceptable and efficacious with cognitively intact older adults, although there are relatively few controlled studies. Treatment adaptations are likely warranted for older adults with PTSD and co-morbidities (e.g., chronic illness, pain, sensory, or cognitive changes). CONCLUSIONS: PTSD is an important clinical consideration in older adults, although the empirical database, particularly regarding psychotherapy, is limited. CLINICAL IMPLICATIONS: Assessment for trauma history and PTSD symptoms in older adults is essential, and may lead to increased recognition and treatment. PMID- 30422751 TI - Vanillic acid mitigates the ovalbumin (OVA)-induced asthma in rat model through prevention of airway inflammation. AB - Asthma is a chronic allergic ailment affecting a considerably large population of the world. The aim of this study is to evaluate the ameliorative effects of vanillic acid against ovalbumin (OVA)-induced asthma in rat model. Asthma was induced in Sprague Dawley rats and vanillic acid was orally administered at 25 and 50 mg/kg body weight for 28 days. Rats challenged with OVA showed heavy signs of airway inflammation and remodeling similar to chronic asthma, evidenced by the increased differential cell counts and presence of inflammatory cytokines in the bronchoalveolar lavage fluid (BALF), along with elevated serum immunoglobulin levels, and the histological results. However, vanillic acid dose-dependently attenuated the manifestation of OVA-induced asthma (p < 0.05) through suppression of inflammatory mediators and modulation of immunoglobulin levels in rats. The asthma mitigating properties of vanillic acid might be due to suppression of oxidative stress and prevention of lung airway inflammation. PMID- 30422750 TI - Effect of novel recovery garments utilising nanodiamond- and nanoplatinum-coated materials (DPV576-C) on physical and psychological stress in baseball players: A randomised, placebo-controlled trial. AB - Based on research suggesting that nanomaterial containing nanodiamond- and nanoplatinum-coated fibres (DPV576-C) may reduce the stress response, garments to enhance athletes' recovery from training-induced stress have been manufactured. This study examined the effects of wearing recovery garments on the physical and psychological stress of Japanese male baseball players. Thirty-eight players aged 18-21 (19.6 +/- 0.2 years) who participated in a two-week intensified training programme were randomly assigned to two groups: 19 wore recovery (DPV576-C) garments (RG group) and 19 wore non-recovery garments (placebo group). Both groups wore the garments overnight. Mood states, using the Profile of Mood States questionnaire, and salivary cortisol levels were measured before (day 0) and after (day 14) the training period. Saliva samples were collected from 07:00 07:30 am. Both groups' fatigue scores significantly increased after the training period (RG: 8.4 +/- 0.8-10.1 +/- 0.8 score; placebo: 9.8 +/- 1.0-11.7 +/- 1.0 score). The total mood disturbance (TMD) score increased significantly in the placebo group (21.0 +/- 2.3-27.2 +/- 3.0 score) but not in the RG group (17.4 +/- 2.7-20.2 +/- 2.2 score). Salivary cortisol concentrations decreased significantly in the RG group (0.71 +/- 0.08-0.49 +/- 0.05 MUg/dL) but not in the placebo group (0.61 +/- 0.06-0.58 +/- 0.10 MUg/dL). Therefore, wearing the DPV576-C garments overnight attenuated increases in TMD levels and decreased salivary cortisol levels following intensified training. DPV576-C garments may have beneficial effects on training-induced physical and psychological stress among athletes. PMID- 30422752 TI - The influence of biological maturity on motor performance among habitually barefoot versus habitually shod adolescents. AB - Biological maturation is associated with physiological changes which in turn affect motor performance. No study has assessed the association between growing up habitually shod versus habitually barefoot and motor performance in the context of maturation, so this approach is unique. The purpose of this study was to examine the influence of biological maturity on motor performance dependent on the participants' footwear habits. Sixty-five German habitually shod (mean age 13.28 +/- 0.83 years) and fifty-five South African habitually barefoot (mean age 13.38 +/- 0.87 years) participants were included. Dynamic postural control was determined via backward balancing, explosive strength by standing long jump and sprinting performance based on a 20-m sprinting test. All tests were performed barefoot and shod. Biological maturation was calculated by using the maturity offset value. Linear mixed models were used to analyse interactions between the maturity offset value, footwear habits and motor performance. Throughout maturation, there was a significant difference between habitually barefoot and habitually shod balance performance (P = 0.001). Maturation led to balance improvements in habitually barefoot adolescents, but not in habitually shod adolescents. No such differences could be observed for standing long jump and 20 m sprint performance. Maturity offset was a significant predictor for jumping and sprinting performances (P < 0.001), independent of being habitually barefoot or habitually shod. Better performances could be observed in more mature subjects. Biological maturation seems to be a relevant predictor for motor performance characteristics for the jumping and sprinting performance in adolescents. PMID- 30422754 TI - The Potential of Information Technology to Navigate Caregiving Systems: Perspectives from Dementia Caregivers. AB - Technologies designed to support caregivers of adults with Alzheimer's disease and related dementias (AD/RD) have been developing at an increasingly rapid pace. However, little remains known about caregivers' perspectives on how technologies can and should help them navigate larger service systems they interact with to engage in caregiving. This study involved in-depth interviews and a beta test of an AD/RD caregiver app to learn more about how they currently use technologies and how potential technological features and functions can best meet their needs. Thematic findings suggest a conceptual model for designing AD/RD caregiver technologies. The findings suggest that eHealth and individual technologies may not fully meet the needs of caregivers as they navigate the larger systems within which they provide care. Findings highlight the need to develop technologies for caregivers that are effective, easy to use, and more widely disseminated - especially for caregivers from disadvantaged backgrounds. PMID- 30422753 TI - Person-Environment Fit, Substance Use Attitudes, and Early Adolescent Substance Use. AB - BACKGROUND: Adolescent substance use is a national health concern. While the literature is clear on the prevalence of substance use during the adolescent developmental period, a dearth of literature is available on the developmental contexts, particularly the influence of school factors, in which substance use occurs. OBJECTIVES: This study examined the intermediary role of substance use attitudes on the relationship between school racial composition and alcohol and marijuana use in a sample of sixth to eighth graders. METHODS: The sample consisted of 4228 middle school students (89% White; 53% female) in the Midwest. A moderated mediation analysis was conducted on the relationship between school racial composition, substance use attitudes, and substance use, with race as the moderator. RESULTS: Results indicated a significant relationship between the percentage of White or Black students in a school and alcohol or marijuana use and that this relationship was mediated by substance use attitudes. These relationships did not differ significantly by student race. Conclusions/Importance: Preliminary findings indicate the importance of considering school racial composition as a systems level risk or promotive factor for attitudes toward substance use as well as substance use outcomes. PMID- 30422756 TI - Is Laser the Best Choice for the Treatment of Peri-Implantitis? PMID- 30422755 TI - Photobiomodulation Therapy in Bone Repair Associated with Bone Morphogenetic Proteins and Guided Bone Regeneration: A Histomorphometric Study. AB - OBJECTIVE: To evaluate the efficacy of photobiomodulation for bone repair of critical surgical wounds with implants of bone morphogenetic proteins (BMPs) and bovine biological membranes, using histological and histomorphometric analysis. BACKGROUND: Tissue engineering has been developing rapidly through the use of various biomaterials for the treatment of bone defects, such as mechanical barriers consisting of biological membranes and implants of biomaterials for bone supply. MATERIALS AND METHODS: Thirty-two male rats were divided into four groups (n = 8): group I-C: control; group II-PT: photobiomodulation therapy; group III PM: Gen-Pro(r) BMPs+Gen-Derm(r) membrane; and group IV-PMPT: Gen-Pro(r) BMPs+Gen Derm(r) membrane+photobiomodulation therapy. A 3 mm bone cavity was performed in the upper third of the lateral surface of the right rat femur to obtain a bone defect considered to be critical. The irradiated groups received seven applications of AlGaAs diode laser 830 nm, P = 40 mW, continuous wave (CW) emission mode, f ~ 0.6 mm, 4 J/cm2 per point (north, south, east, and west) at 48 h intervals, for a total of 16 J/cm2 per session (final dose: 112 J/cm2). Bone repair was evaluated at sacrifice 15 and 30 days after the procedure. The specimens were embedded in paraffin and stained with hematoxylin and eosin and Picrosirius for analysis by light microscopy and by the Leica interactive measurement module software. Statistical analysis was performed (p < 0.05%). RESULTS: Histological analysis confirmed the histomorphometric results, with the experimental groups showing bone neoformation of significantly higher quality and quantity at the end of 30 days compared with the control group. CONCLUSIONS: Photobiomodulation therapy was effective for bone repair mainly when associated with BMPs and a biological membrane. The results of this study are promising and stimulate further scientific and clinical research. PMID- 30422757 TI - Fat percentage cutoff values to define obesity and prevalence of sarcopenic obesity in community-dwelling older adults in Turkey. AB - PURPOSE: Sarcopenic-obesity (SO) is associated with low-functional-status and mortality. Few studies evaluated the definition and prevalence of SO. We aimed to investigate the fat-percentage cut-off values for obesity and prevalences of obesity, SO in community-dwelling older adults in Turkey. METHODS: Body composition was measured using bioimpedance-analysis. Sarcopenia was defined by European-Working-Group-on-Sarcopenia-in-Older-People criteria. Obesity was defined by two different methods, a fat-percentile above 60th percentile (Zoico method) or a BMI of >=30 kg/m2 (WHO-definition). RESULTS: We enrolled 992 subjects (308 men, 684 women). Body fat-percentage thresholds for obesity were 27.3% for men and 40.7% for women according to Zoico-method. The rates of obesity were about 40% in both genders by Zoico-method; 29.2% versus 53.7% for men and women by WHO definition. Prevalences-of-sarcopenia was 3.1% versus 0.4%; SO was 0.3% versus 0.1% when obesity was assessed with Zoico-method in men and women, respectively. No case of SO was defined when obesity was assessed using WHO definition. CONCLUSION: The threshold for obesity definition according to Zoico method was similar to other European-populations. While obesity-prevalences were considerably high, SO prevalences were low but comparable to other populations. This low-prevalence seems to be due to underestimation of sarcopenia in obese subjects when skeletal-muscle-mass was adjusted by height2 to recognize low muscle-mass. PMID- 30422758 TI - Synthesis, characterization and nucleic acid binding studies of mononuclear copper(II) complexes derived from azo containing O, O donor ligands. AB - Azo linked salicyldehyde and a new 2-hydroxy acetophenone based ligands (HL1 and HL2) with their copper(II) complexes [Cu(L1)2] (1) and [Cu(L2)2] (2) were synthesized and characterized by spectroscopic methods such as 1H, 13C NMR, UV Vis spectroscopy and elemental analyses. Calculation based on Density Functional Theory (DFT), have been performed to obtain optimized structures. Binding studies of these copper (II) complexes with calf thymus DNA (ct-DNA) and torula yeast RNA (t-RNA) were analyzed by absorption spectra, emission spectra and Viscosity studies and Molecular Docking techniques. The absorption spectral study indicated that the copper(II) complexes of 1 and 2 had intrinsic binding constants with DNA or RNA in the range of 7.6 +/- 0.2 * 103 M-1 or 6.5 +/- 0.3 * 103M-1 and 5.7 +/- 0.4 * 104 M-1 or 1.8 +/- 0.5 * 103 M-1 respectively. The synthesized compounds and nucleic acids were simulated by molecular docking to explore more details mode of interaction of the complexes and their orientations in the active site of the receptor. PMID- 30422759 TI - Responses to crizotinib can occur in c-MET overexpressing nonsmall cell lung cancer after developing EGFR-TKI resistance. AB - Evidence suggests that activation of the MET signaling pathway might be associated with EGFR-TKI resistance. EGFR TKI-resistant lung cancers often remain sensitive to inhibition of the EGFR pathway; thus, c-MET inhibitors are likely to be effective when combined with continued EGFR-TKI treatment. Here, we described a 56-year-old male who became refractory after first-line gefitinib therapy and was confirmed to have c-MET overexpression without a T790M mutation, c-MET amplification or MET exon 14 alterations. A complete response to crizotinib occurred in this patient. Our case report uncovered the underlying mechanism of c MET overexpression in affecting EGFR-TKI sensitivity, and crizotinib may assist in overcoming this problem. PMID- 30422760 TI - Beyond the band: A biomarker for pediatric MS? PMID- 30422761 TI - Deep Learning Electronic Cleansing for Single- and Dual-Energy CT Colonography. AB - Electronic cleansing (EC) is used for computational removal of residual feces and fluid tagged with an orally administered contrast agent on CT colonographic images to improve the visibility of polyps during virtual endoscopic "fly through" reading. A recent trend in CT colonography is to perform a low-dose CT scanning protocol with the patient having undergone reduced- or noncathartic bowel preparation. Although several EC schemes exist, they have been developed for use with cathartic bowel preparation and high-radiation-dose CT, and thus, at a low dose with noncathartic bowel preparation, they tend to generate cleansing artifacts that distract and mislead readers. Deep learning can be used for improvement of the image quality with EC at CT colonography. Deep learning EC can produce substantially fewer cleansing artifacts at dual-energy than at single energy CT colonography, because the dual-energy information can be used to identify relevant material in the colon more precisely than is possible with the single x-ray attenuation value. Because the number of annotated training images is limited at CT colonography, transfer learning can be used for appropriate training of deep learning algorithms. The purposes of this article are to review the causes of cleansing artifacts that distract and mislead readers in conventional EC schemes, to describe the applications of deep learning and dual energy CT colonography to EC of the colon, and to demonstrate the improvements in image quality with EC and deep learning at single-energy and dual-energy CT colonography with noncathartic bowel preparation. (c)RSNA, 2018. PMID- 30422762 TI - Pediatric Brain Tumor Genetics: What Radiologists Need to Know. AB - Brain tumors are the most common solid tumors in the pediatric population. Pediatric neuro-oncology has changed tremendously during the past decade owing to ongoing genomic advances. The diagnosis, prognosis, and treatment of pediatric brain tumors are now highly reliant on the genetic profile and histopathologic features of the tumor rather than the histopathologic features alone, which previously were the reference standard. The clinical information expected to be gleaned from radiologic interpretations also has evolved. Imaging is now expected to not only lead to a relevant short differential diagnosis but in certain instances also aid in predicting the specific tumor and subtype and possibly the prognosis. These processes fall under the umbrella of radiogenomics. Therefore, to continue to actively participate in patient care and/or radiogenomic research, it is important that radiologists have a basic understanding of the molecular mechanisms of common pediatric central nervous system tumors. The genetic features of pediatric low-grade gliomas, high-grade gliomas, medulloblastomas, and ependymomas are reviewed; differences between pediatric and adult gliomas are highlighted; and the critical oncogenic pathways of each tumor group are described. The role of the mitogen-activated protein kinase pathway in pediatric low-grade gliomas and of histone mutations as epigenetic regulators in pediatric high-grade gliomas is emphasized. In addition, the oncogenic drivers responsible for medulloblastoma, the classification of ependymomas, and the associated imaging correlations and clinical implications are discussed. (c)RSNA, 2018. PMID- 30422763 TI - Layered Approach to the Anterior Knee: Normal Anatomy and Disorders Associated with Anterior Knee Pain. AB - Anterior knee pain is a common complaint that can be caused by a wide spectrum of disorders affecting the many varied tissues at the anterior knee. The anatomy and pathologic conditions of the anterior knee can be approached systematically by organizing the region into four layers: (a) superficial layer of fat, fascia, and bursae; (b) functional layer composed of the extensor mechanism and patellar stabilizers; (c) intracapsular extrasynovial layer containing the fat pads; and (d) intra-articular layer. The superficial layer is composed of delicate tissues that are predisposed to blunt and penetrating trauma, irritation, and infection. The extensor mechanism forms the functional layer, is responsible for knee extension and patellar stabilization, and is engaged in repetitive movements; overuse disorders dominate in this layer. The fat pads of the anterior knee are discussed collectively as an extracapsular extrasynovial layer, functioning to improve congruence and protect the articular surfaces during motion. Diseases involving the fat pads can be primary or secondary to pathologic conditions in the rest of the joint. The synovial lining and cartilage surface are in the fourth and final intra-articular layer; pathologic conditions are centered around arthritides and internal derangement. Symptoms in the anterior knee may be due to conditions affecting one or more of these interrelated layers. (c)RSNA, 2018. PMID- 30422764 TI - US Findings of First-Trimester Pregnancy RadioGraphics Fundamentals | Online Presentation. PMID- 30422765 TI - Suspensory Ligaments of the Female Genital Organs: MRI Evaluation with Intraoperative Correlation. AB - The uterus, which plays an important role in the reproductive process, provides a home for the developing fetus and so must be in a stable, though flexible, location. Various structures with suspensory ligaments help provide this berth. MRI with high spatial resolution allows us to detect and evaluate these relatively fine structures. Under physiologic conditions, MRI can be used to depict uterine and ovarian ligaments (ie, the uterosacral, cardinal, and round ligaments, as well as the suspensory ligament of the ovary). In the presence of pathologic conditions (inflammation, endometriosis, tumors), the suspensory ligaments may appear thickened or invaded, which makes their delineation easier. Understanding the normal anatomy of the suspensory ligaments of the female genital organs and using a standardized nomenclature are essential for identifying and reporting related pathologic conditions. The female pelvic anatomy and the suspensory ligaments of the female genital organs are described as depicted with MRI. Also, the compartmental anatomy of the female pelvis is explained, including the extraperitoneal pelvic spaces. Finally, a checklist is provided for structured reporting of the MRI findings in the female pelvis. Online supplemental material is available for this article. (c)RSNA, 2018. PMID- 30422767 TI - Congratulations to the 2018 RSNA Outstanding Educator: David M. Yousem, MD, MBA. PMID- 30422766 TI - Extrahepatic Cholangiocarcinoma: What the Surgeon Needs to Know RadioGraphics Fundamentals | Online Presentation. PMID- 30422768 TI - Signs and Artifacts in Amyloid PET. AB - Establishing a diagnosis of Alzheimer dementia can be challenging, particularly early in the course of the disease. However, with disease-modifying therapies on the horizon, it is becoming increasingly important to achieve the correct diagnosis as soon as possible. In challenging presentations of dementia, such as patients with clinically atypical features or early-age onset of mild cognitive impairment, amyloid PET is a valuable tool in determining the diagnosis of Alzheimer dementia. Furthermore, preliminary data show that amyloid PET findings alter clinical management in patients who meet the appropriate use criteria. There are currently three U.S. Food and Drug Administration (FDA)-approved fluorine 18 (18F)-labeled radiopharmaceuticals that allow in vivo detection of cerebral amyloid deposition, which is a hallmark pathologic feature of Alzheimer dementia. Knowledge of the common imaging features among these three 18F-labeled radiopharmaceuticals in the normal and abnormal brain will enable the radiologist to more accurately interpret amyloid PET studies. As in other subspecialties of radiology, imaging signs in amyloid PET are helpful to distinguish if a region is normal or abnormal. This article reviews appropriate use criteria for amyloid PET, introduces the properties of the radiopharmaceuticals, explains the algorithmic approach to interpretation with examples of normal and abnormal amyloid PET scans with MRI correlation, and provides an atlas of regional amyloid PET signs and common artifacts. (c)RSNA, 2018. PMID- 30422769 TI - Imaging Features and Management of Stress, Atypical, and Pathologic Fractures. AB - Traumatic and atraumatic fractures are entities with distinct but often overlapping clinical manifestations, imaging findings, and management protocols. This article is a review of terminology, etiology, and key imaging features that affect management of atraumatic fractures including stress fractures, atypical femoral fractures, and pathologic fractures. The terminology of atraumatic fractures is reviewed, with an emphasis on the distinctions and similarities of stress, atypical, and pathologic fractures. The basic biomechanics of normal bone is described, with an emphasis on the bone remodeling pathway. This framework is used to better convey the shared etiologies, key differences, and important imaging findings of these types of fractures. Next, the characteristic imaging findings of this diverse family of fractures is discussed. For each type of fracture, the most clinically relevant imaging features that guide management by the multidisciplinary treatment team, including orthopedic surgeons, are reviewed. In addition, imaging features are reviewed to help discriminate stress fractures from pathologic fractures in patients with challenging cases. Finally, imaging criteria to risk stratify an impending pathologic fracture at the site of an osseous neoplasm are discussed. Special attention is paid to fractures occurring in the proximal femur because the osseous macrostructure and mix of trabecular and cortical bone of the proximal femur can function as a convenient framework to understanding atraumatic fractures throughout the skeleton. Atraumatic fractures elsewhere in the body also are used to illustrate key imaging features and treatment concepts. (c)RSNA, 2018. PMID- 30422770 TI - Recurrent Respiratory Papillomatosis. PMID- 30422771 TI - Coronary Artery Fistulas: Pathophysiology, Imaging Findings, and Management Erratum. PMID- 30422774 TI - Primary Lung Tumors in Children: Radiologic-Pathologic Correlation From the Radiologic Pathology Archives. AB - Primary lung tumors in children are rare, with a narrow range of diagnostic considerations. However, the overlapping imaging appearances of these tumors necessitate attention to key discriminating imaging and pathologic features. In the neonate and infant, the important considerations include pleuropulmonary blastoma (PPB), infantile fibrosarcoma, and fetal lung interstitial tumor. Among these tumors, imaging findings such as air-filled cysts in type 1 PPB and homogeneously low attenuation of fetal lung interstitial tumors are relatively specific. Key pathologic and genetic discriminators among this group of tumors include the DICER1 germline mutation found in PPB and the t(12,15)(p13;q25) translocation and ETV6-NTRK3 fusion gene seen in infantile fibrosarcoma. Primary lung tumors in older children include inflammatory myofibroblastic tumors (IMTs), carcinoid salivary gland-type tumors of the lung, recurrent respiratory papillomatosis, and other rare entities. IMT, a spindle-cell proliferation with inflammatory elements, is the most common lung tumor in children. Anaplastic lymphoma kinase, a receptor-type protein tyrosine kinase, is present in 50% of these tumors, and this finding may support an imaging diagnosis of IMT. Carcinoid tumors account for a substantial portion of childhood lung tumors, and their characteristic avid enhancement on images corresponds to the compressed fibrovascular stroma histologically. Furthermore, novel imaging agents used with somatostatin receptor analogs have an emerging role in the evaluation of carcinoid tumors. Although less common than mucoepidermoid carcinoma, adenoid cystic carcinoma tends to recur given the perineural spread seen histologically. Integrating radiologic and pathologic knowledge is critical to accurate diagnosis, treatment planning, and surveillance of primary lung tumors in children. PMID- 30422773 TI - US of Right Upper Quadrant Pain: Some Uncommon but Noteworthy Causes. PMID- 30422775 TI - Role of FDG PET/CT in the Eighth Edition of TNM Staging of Non-Small Cell Lung Cancer. AB - Lung cancer is the leading cause of cancer-related mortality in the United States, and accurate staging plays a vital role in determining prognosis and treatment. The recently revised eighth edition of the TNM staging system for lung cancer defines new T and M descriptors and updates stage groupings on the basis of substantial differences in survival. There are new T descriptors that are based on the findings at histopathologic examination, and T descriptors are reassigned on the basis of tumor size and extent. No changes were made to the N descriptors in the eighth edition of the TNM staging of lung cancer, because the four N categories that are based on the location of the diseased nodes can be used to consistently predict prognosis. The eighth edition includes a new M1b descriptor for patients with a single extrathoracic metastatic lesion in a single organ (M1b), because they have better survival and different treatment options, compared with those with multiple extrathoracic lesions (M1c). Examination with fluorine 18 fluorodeoxyglucose (FDG) PET/CT is the standard of care and is an integral part of the clinical staging of patients with lung cancer. To provide the treating physicians with accurate staging information, radiologists and nuclear medicine physicians should be aware of the updated classification system and should be cognizant of the site-specific strengths and limitations of FDG PET/CT. In this article, the eighth edition of the TNM staging system is reviewed, as well as the role of FDG PET/CT in the staging of non-small cell lung carcinoma. (c)RSNA, 2018. PMID- 30422776 TI - No Ordinary Addiction Scientist: Remembering Nancy Petry. PMID- 30422778 TI - Favorable Effects Under Irrelevant Conditions: A Commentary to Woodall et al. (2018). PMID- 30422777 TI - Results of a Randomized Trial of Web-Based Retail Onsite Responsible Beverage Service Training: WayToServe. AB - OBJECTIVE: Research in Responsible Beverage Service (RBS) training indicates that such training can prevent over-service of alcohol and reduce drunk driving. However, reviews of the RBS literature suggest that the quality of training methods and the stability of implementation are important factors in determining RBS training effectiveness. Most RBS classes have been taught live, where the quality of instruction varies across instructors and classes, and the stability of the implementation of an RBS curriculum is variable. Web-based RBS training may carry important advantages by stabilizing instruction and implementation factors. Randomized trial results of a web-based onsite RBS training program (WayToServe(r) [WTS]) are reported here. It was hypothesized that servers trained by WTS would refuse alcohol service at significantly higher rates compared with Usual and Customary (UC) live training. METHOD: On-site alcohol-serving establishments in New Mexico communities were randomized to receive WTS training (n = 154) or the Usual and Customary live RBS training (n = 155). Premises were assessed at baseline, immediate post-training, 6-months post-training, and 1-year post-training intervals. Pseudo-intoxicated patron protocols were used to assess premise alcohol service during the early to mid-evening hours of 6:30 P.M. to 8:30 P.M., with the percentage of alcohol service refusals to apparently intoxicated pseudo-patrons as the primary outcome variable. RESULTS: Results indicate significantly higher refusal rates for WTS than for UC premises at the immediate (WTS = 68% vs. UC = 49%) and the 1-year post-training assessment points (WTS = 68% vs. UC = 58%) but not at the 6-month post-training assessment (WTS = 69% vs. UC = 64%). Differences in refusal rates based on pseudo-patron age were observed where younger pseudo-patrons were consistently refused more often than older pseudo-patrons. CONCLUSIONS: Effective RBS training can be delivered online, making it a potentially cost-effective way of reaching large alcohol server populations. PMID- 30422779 TI - Serving Evidence Warrants Caution: A Commentary on Woodall et al. (2018). PMID- 30422780 TI - Responses to Commentaries by Miller (2018) and Buvik and Rossow (2018). PMID- 30422781 TI - A Meta-Analysis of Computer-Delivered Drinking Interventions for College Students: A Comprehensive Review of Studies From 2010 to 2016. AB - OBJECTIVE: Computer-delivered drinking interventions (CDIs) are administered to tens of thousands of college students each year, yet recent evidence for their efficacy has not been summarized. This meta-analysis extends the work of past reviews and investigates the efficacy of CDIs in reducing college students' alcohol consumption and alcohol-related harms. METHOD: Following the systematic review standards set by PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), the literature was searched for published and unpublished data available from 2010 to 2016. We reviewed 35 randomized controlled trials (64 CDIs, N = 20,068, 57% female) that compared CDIs with control conditions for college students and calculated between- and within-groups weighted mean effect sizes. We analyzed effects at three follow-up assessment points (short term = <=6 weeks, intermediate term = 7-26 weeks, long term = >=27 weeks). RESULTS: Within group effect sizes showed that CDI participants did make reductions in drinking over time; however, between-groups effect sizes revealed that these effects rarely differed from those of control participants. CDIs were associated with very small but statistically significant reductions in quantity (d = 0.06, 95% CI [0.02, 0.10]) and frequency (d = 0.07, 95% CI [0.02, 0.12]) of alcohol consumption when compared with controls at short-term follow-up. However, at intermediate (d = -0.07, 95% CI [-0.11, -0.02]) and long-term follow-ups (d = 0.06, 95% CI [-0.12, -0.01]), CDIs were associated with statistically significantly more alcohol-related problems than controls. CONCLUSIONS: Computer delivered drinking interventions result in small reductions in college students' alcohol consumption over time. However, these interventions rarely reduce drinking more than controls and may be associated with some increased risk of harm over time. PMID- 30422782 TI - Assessing Brief Intervention for Unhealthy Alcohol Use: A Comparison of Electronic Health Record Documentation and Patient Self-Report. AB - OBJECTIVE: Alcohol screening and brief intervention (BI) are recommended preventive health practices. Veterans Health Administration (VA) uses a performance measure to incentivize BI delivery. Concerns have been raised about the validity of the BI performance measure, which relies on electronic health record (EHR) documentation. Our objective was to assess concordance between EHR based documentation and patient-reported receipt of BI, and to examine correlates of concordance. METHOD: Patients with a documented positive screen for unhealthy alcohol use at VA Greater Los Angeles primary care clinics were surveyed (within 15 days on average) in 2013-2014. Documented BI was indicated by an EHR note that the patient was advised to drink within recommended limits or reduce or abstain from drinking. Patient-reported receipt of BI corresponded to an affirmative response to questions on whether a VA provider advised the patient to drink less or abstain. Patient report and documentation were assessed over the same period. RESULTS: Documented and patient-reported receipt of BI had low concordance. Almost all patients who reported receiving BI had documentation of BI (93%; 95% CI [90%, 95%]), but only 63% [59%, 67%] of patients with documented BI reported receiving it. BI concordance was associated with more severe unhealthy alcohol use and drinking-related consequences, mental health comorbidity, and greater readiness-to-change alcohol use. CONCLUSIONS: Discrepancies between EHR documentation and patient-reported BI raise concerns about performance measure validity. Patient-reported receipt of BI could be an alternative or complementary measure of BI. PMID- 30422783 TI - Identifying the Population Sources of Alcohol Impaired Driving: An Assessment of Context Specific Drinking Risks. AB - OBJECTIVE: High-risk drinkers who drink in high-risk contexts like bars are recognized as a primary source of alcohol-impaired drivers and motor vehicle crashes within communities. We assess the contributions of drinking in other contexts to these outcomes. METHOD: Self-report survey data from 8,553 adults in 50 California cities were used to estimate rates of driving after drinking (DAD; driving within 4 hours of drinking any alcohol) and a measure of alcohol-impaired driving (AID; driving when having had "too much" to safely drive home) associated with drinking in bars, homes, restaurants, parties, and other contexts. RESULTS: Frequent drinking (b = .0588, z = 2.17, p = .030) and drinking outside the home, chi2(4) = 74.46, p < .001, at bars (b = .1418, z = 1.97, p = .049), and at restaurants (b = .2694, z = 5.60, p < .001) were related to greater DAD; lower risks were associated with drinking at home (b = -.0607, z = -2.16, p = .031). AID frequency was directly proportional to DAD (b = .0863, z = 8.43, p < .001) with no differences observed across contexts. Within a community of 100,000 persons over 6 months, 879 AID events were attributed to drinking at 102 restaurants and 726 AID events to drinking at 15 bars. CONCLUSIONS: Drinking at bars and restaurants contributes about equally to DAD and AID, with AID events concentrated in small populations that frequent relatively few bars and broadly distributed across large populations that frequent many restaurants. High frequencies of drinking at home were also associated with surprisingly large numbers of DAD and AID events. Observed differences between individual and community risks for DAD and AID must be addressed in place-based community prevention programs. PMID- 30422784 TI - A Mobile Phone-Based Brief Intervention With Personalized Feedback and Text Messaging Is Associated With Reductions in Driving After Drinking Among College Drinkers. AB - OBJECTIVE: Driving after drinking (DAD) among college students remains a significant public health concern and is perhaps the single riskiest drinking related behavior. Counselor-delivered and web-based Brief Alcohol Interventions (BAIs) have been shown to reduce DAD among college students, but to date no study has evaluated the efficacy of a single-session mobile phone-based BAI specific to DAD. The present study examined whether a driving-specific BAI delivered via mobile phone would significantly decrease DAD among college students compared to an informational control. METHOD: Participants were 84 college students (67.1% women; average age = 23; 52.4% White) who endorsed driving after drinking two or more drinks at least twice in the past 3 months. After completing baseline measures, participants were randomly assigned to receive either (a) DAD information or (b) DAD mobile BAI that included personalized feedback and interactive text messaging. Participants completed outcome measures at 3-month follow-up. RESULTS: Repeated-measures mixed modeling analyses revealed that students receiving the mobile phone-based BAI reported significantly greater reductions in likelihood of DAD (three or more drinks) and the number of drinks consumed before driving than students in the information condition at 3-month follow-up. CONCLUSIONS: These findings provide preliminary support for the short term efficacy of a mobile phone-based BAI for reducing DAD among college students. PMID- 30422785 TI - Illicit Drug Use, Cigarette Smoking, and Eating Disorder Symptoms: Associations in an Adolescent Twin Sample. AB - OBJECTIVE: Twin studies have shown that genetic factors in part explain the established relation between alcohol use (i.e., problematic use or abuse/dependence) and eating disorder symptoms in adolescent and adult females. However, studies have yet to elucidate if there are similar shared genetic factors between other aspects of substance involvement, such as illicit drug use and repeated cigarette smoking. METHOD: For those sex-specific phenotypic correlations above our threshold of .20, we used a behavioral genetic design to examine potential shared genetic overlap between self-reported lifetime illicit drug use and repeated cigarette smoking and the eating disorder symptoms of drive for thinness (DT), bulimia (BU), and body dissatisfaction (BD), as assessed with the Eating Disorder Inventory-II, in 16- to 17-year-old female and male twin pairs. RESULTS: Only phenotypic correlations with illicit drug use met our threshold for twin modeling. Small to moderate genetic correlations were observed between illicit drug use and BU in both girls and boys and between illicit drug use and DT in girls. CONCLUSIONS: Similar etiological factors are at play in the overlap between illicit drug use and certain eating disorder symptoms in girls and boys during adolescence, such that genetic factors are important for covariance. Specifically, illicit drug use was associated with bulimia nervosa symptoms in girls and boys, which parallels previous substance use research finding a genetic overlap between alcohol use and bulimia nervosa symptoms. Future research should prospectively examine developmental trajectories to further understand the etiological overlap between substance involvement and eating disorder symptoms. PMID- 30422786 TI - Socioeconomic Status and Adolescent Alcohol Involvement: Evidence for a Gene Environment Interaction. AB - OBJECTIVE: Adolescence is an optimal developmental stage for examining the interplay of environmental factors and the genetic risk for alcohol involvement. The current study aimed to examine how socioeconomic status might interact with genetic risk for alcohol involvement among adolescents. METHOD: A total of 839 same-sex adolescent twin pairs (509 monozygotic and 330 dizygotic) from the 1962 National Merit Twin Study completed a questionnaire containing items assessing alcohol involvement. Twins were approximately 17 years old at the time of participation. Parents provided reports of family income and educational attainment. Models were fit examining parental education and family income as moderators of genetic and environmental influences on alcohol use. RESULTS: There was evidence for moderation of genetic and environmental influences on alcohol involvement by family income. For twins with the lowest levels of family income, genetic and shared environmental influences accounted for 50% and 26% of the variance in alcohol involvement, respectively, compared with 2% and 67% of the variance among those at the highest level of income. CONCLUSIONS: These findings suggest that etiological influences on alcohol involvement vary as a function of an adolescent's socioeconomic status. PMID- 30422787 TI - Positive Attitude Toward Alcohol Predicts Actual Consumption in Young Adults: An Ecological Implicit Association Test. AB - OBJECTIVE: Excessive alcohol drinking, particularly among college students, is a major health concern worldwide. The implicit associations between alcohol-related concepts and affective attributes have been repeatedly postulated as a reliable predictor of these drinking behaviors. The Implicit Association Test (IAT) is considered one of the most reliable tasks for measuring these associations and their impact on actual alcohol consumption. However, the majority of these tests used verbal materials as stimuli, thus being unadapted to some categories of participants. The present study aims to develop a new IAT, using pictures exclusively as stimuli, to provide a cross-cultural and language-independent evaluation of implicit associations that is more closely related to real-life drinking contexts. METHOD: Sixty-five undergraduate young adults took part in this study. A new visual IAT was used to measure the implicit association between alcohol cues and alcohol-related positive attributes. Pictorial stimuli, previously validated, were used to represent both target (alcohol vs. soft drinks) and attribute (positive vs. neutral affective states) categories in seven successive experimental blocks. The IAT was followed by self-reported measures of explicit alcohol-related expectancies and alcohol consumption. RESULTS: The new IAT highlighted significant implicit associations between positively valenced and alcohol-related representations conveyed by pictures, with good internal consistency, thus proving its validity and reliability. Importantly, regression analyses showed that these implicit associations are a strong predictor of self reported alcohol consumption. CONCLUSIONS: This visual IAT further underscores that positive implicit associations with alcohol constitute an important factor in predicting effective alcohol-related behaviors and offers a more ecological and cross-cultural way to test these associations in non-alcohol-dependent populations. Moreover, this version of the IAT might be implemented in prevention and prophylactic programs. PMID- 30422789 TI - Alcohol Advertising on Facebook and the Desire to Drink Among Young Adults. AB - OBJECTIVE: Social networking sites (SNSs) may influence the behavior of SNS users by exposing them to information about the number of other users who engaged with a SNS post (i.e., user engagement) and any comments left in response to a post (i.e., user-generated comments [UGCs]). The current study hypothesized that beer advertisements with higher user engagement levels and pro-drinking UGCs would be positively associated with the desire to drink and ad engagement. The effect of ad content in relation to regulatory compliance was also investigated. METHOD: A 2 (regulatory compliant vs. noncompliant) * 2 (low vs. high user engagement) * 2 (pro- vs. anti-alcohol UGC) mixed factorial experiment was used. A total of 120 young adults viewed two compliant and two noncompliant ads. Participants were randomized into four groups: ads with high or low user engagement values, which were paired with either pro- or anti-drinking UGCs. Dependent variables included desire to drink and engaging (i.e., Liking or Sharing) with the ad. RESULTS: When associated with high user engagement values, the desire to drink was 3.5 times greater in the pro-drinking UGC group compared with the anti-drinking UGC group (odds ratio = 3.48, 95% CI [1.60, 7.55]). Ad engagement was 2.3 times greater among those exposed to pro-drinking UGCs (odds ratio = 2.30, 95% CI [1.09, 4.85]). CONCLUSIONS: Pro-drinking comments may increase the desire to drink and ad engagement, both of which may be predictive of future drinking behavior. Regulations are needed to limit the ability of SNS users to engage with alcohol ads. PMID- 30422788 TI - Subgroups of Young Sexual Minority Women Based on Drinking Locations and Companions and Links With Alcohol Consequences, Drinking Motives, and LGBTQ Related Constructs. AB - OBJECTIVE: Sexual minority women (SMW; e.g., lesbians, bisexual women) are at increased risk for alcohol use disorders and related problems compared with heterosexual women. However, little is known about the social context in which drinking occurs in this high-risk population. This study used latent class analysis to identify subgroups of SMW based on drinking locations and companions and examined whether class membership was associated with consequences, drinking motives, and LGBTQ-related constructs (e.g., outness, discrimination). METHOD: A sample of 670 SMW reported on alcohol use, drinking locations and companions, and related measures as part of a larger study on women's health. RESULTS: Based on SMW's patterns of responding to drinking locations and companions, latent class analysis identified five classes: Infrequent Drinking Contexts (10% of sample, reference class), Private/Intimate Drinking (28%), Convivial Drinking (29%), Alone/Convivial Drinking (20%), and Multiple Drinking Contexts (13%). Greater consequences were associated with greater odds of membership in the Convivial, Alone/Convivial, and Multiple Drinking Contexts classes relative to the Infrequent Drinking Contexts Class. Drinking motives were associated with class membership, although significant group comparisons varied by motive. Higher LGBTQ community involvement was associated with greater odds of membership in the Convivial, Alone/Convivial, and Multiple Drinking Contexts classes. CONCLUSIONS: Drinking classes paralleled those found in the literature on heterosexual individuals (e.g., public versus private contexts). Women in the Alone/Convivial and Multiple Drinking Contexts classes may be at particular risk. The context within which SMW drink may be a useful way to identify women at highest risk for problematic drinking. PMID- 30422790 TI - Passing on Pot: High School Seniors' Reasons for Not Using Marijuana as Predictors of Future Use. AB - OBJECTIVE: Marijuana use is relatively common among youth and increases during the transition to adulthood. Yet a substantial number of adolescents and young adults do not use marijuana. The purpose of this study was to examine how high school seniors' reasons for intending not to use marijuana within the next 12 months were prospectively associated with marijuana use reported 1 year later. METHOD: Data were drawn from national longitudinal samples of U.S. high school seniors from the Monitoring the Future study (n = 3,044; 50% female; 65% White). Bivariate and multivariable logistic regression analyses were conducted to examine associations between reasons seniors indicated for intending not to use marijuana within the next 12 months and marijuana use reported 1 year later in the follow-up survey, controlling for sociodemographic characteristics and high school risk factors. Analyses were conducted separately among youth with and without lifetime marijuana use in high school. RESULTS: In multivariable models, reasons associated with marijuana abstinence 1 year later among prior marijuana use abstainers were concerns about becoming addicted, use being against ones' beliefs, not liking marijuana users, and not having friends who use marijuana. Among prior marijuana users, not enjoying marijuana was a significant predictor of marijuana abstinence 1 year later. CONCLUSIONS: Reasons for abstaining from marijuana have predictive utility in relation to later use, but these associations differ between those with and without prior marijuana use. Understanding the underlying reasons for stopping marijuana use or maintaining abstinence may inform youth substance use prevention and intervention programs. PMID- 30422791 TI - Teen Social Networks and Depressive Symptoms-Substance Use Associations: Developmental and Demographic Variation. AB - OBJECTIVE: The current study examined whether an adolescent's standing within a school-bounded social network moderated the association between depressive symptoms and substance use across adolescence as a function of developmental and demographic factors (gender, parental education, and race/ethnicity). METHOD: The sample of 6,776 adolescents participated in up to seven waves of data collection spanning 6th to 12th grade. RESULTS: Results of latent growth models showed that lower integration into the social network exacerbates risk for depression-related substance use in youth, particularly around the high school transition, but social status acted as both a risk factor and a protective factor at different points in development for different youth. Findings also varied as a function of youth gender and parental education status. CONCLUSIONS: Together these findings suggest that lower integration into the social network exacerbates risk for depression-related substance use in youth, particularly around the high school transition in general as well as just before the high school transition in those with lower parental education or just after the high school transition in males. Thus, the risky impact of social isolation appears more consistent across this period. Social status, however, showed a more varied pattern and further study is needed to understand the sometimes risky and sometimes protective effects of social status on depression-related substance use. PMID- 30422792 TI - Associations Between Past-Month Pain and Distress Intolerance Among Daily Cigarette Smokers. AB - OBJECTIVE: A growing body of research indicates that pain is associated with the maintenance of tobacco smoking. Distress intolerance (DI) may play an important role in the link between pain and smoking. The goal of this study was to examine the association between past-month pain status and DI among a sample of daily cigarette smokers. It was hypothesized that smokers who reported past-month pain (vs. those reporting no past-month pain) would have higher perceived DI (i.e., lower scores on the Distress Tolerance Scale [DTS]) and higher physical DI (i.e., shorter persistence during the Breath-Holding Duration Task), and would report greater subjective distress and physical sensations during the breath-holding task. METHOD: Participants (N = 126) were daily smokers (56.3% male) who attended a baseline session for a larger experimental study on smoking behavior. Participants self-reported the presence and severity of past-month pain and completed two breath-holding duration trials approximately 15 minutes after smoking. Data were cross-sectional in nature. RESULTS: Smokers with past-month pain had lower scores on the DTS relative to smokers without pain. No differences in breath-holding duration were observed. In addition, smokers with past-month pain, relative to those without, reported greater subjective distress and physical sensations during the initial, but not second, breath-holding trial. CONCLUSIONS: This is the first study to show that smokers with co-occurring pain may harbor beliefs about their inability to tolerate aversive psychological states, and are more emotionally reactive to physiological provocation (breath holding task), than smokers without co-occurring pain. DI among smokers with pain may represent one mechanism by which pain contributes to the maintenance of smoking behavior. PMID- 30422793 TI - Heavy, Problematic College Drinking Predicts Increases in Impulsivity. AB - OBJECTIVE: Impulsigenic personality traits are among the many factors demonstrated to predict drinking behavior among late adolescents. The current study tested the opposite possibility, that during the emerging adulthood developmental period, problematic drinking behavior predicts increases in impulsigenic traits. This possibility is important because such traits increase risk for multiple forms of dysfunction. METHOD: Using a prospective design, we studied the personality traits and drinking behavior of 458 traditional college freshmen over one year. RESULTS: We found that drinking problems predicted increases in urgency (the tendency to act rashly when highly emotional), lack of planning (the tendency to act without forethought), and lack of perseverance (difficulty maintaining focus on a task). CONCLUSIONS: Maladaptive personality change may be one mechanism that increases risk transdiagnostically for some individuals who drink problematically during college. Increases in impulsigenic traits predictable from problem drinking put individuals at risk for not only more drinking, but a host of other negative outcomes. PMID- 30422795 TI - The rise of genetically engineered mouse models of pancreatitis: A review of literature. AB - Pancreatitis is increasingly recognized as not merely a local inflammation of the pancreas but also a disease with high frequency of systemic sequelae. Current understanding of the cellular mechanisms that trigger it and affect the development of sequelae are limited. Genetically engineered mouse models can be a useful tool to study the pathophysiology of pancreatitis. This article gives an overview of the genetically engineered mouse models that spontaneously develop pancreatitis and discusses those that most closely replicate different pancreatitis hallmarks observed in humans. PMID- 30422796 TI - An unexpectedly prolonged severe hyperbilirubinemia in a patient with pre existing hepatitis A: a role of genetic predisposition? PMID- 30422794 TI - Polysubstance Use by Stimulant Users: Health Outcomes Over Three Years. AB - OBJECTIVE: Studies show that stimulant users have varied substance use patterns and that polysubstance use is associated with poorer past or concurrent medical, mental health, and substance use outcomes. This study examined outcomes of substance use patterns prospectively. METHOD: A latent class analysis was conducted to examine substance use patterns among adults using stimulants (n = 710; 38.6% women) at baseline, and the health and treatment utilization outcomes of different use patterns over the subsequent 3 years. To examine associations between latent class membership and outcomes, generalized estimating equation modeling was conducted. RESULTS: Four classes of substance use patterns at baseline were identified, involving high use of (a) methamphetamine and marijuana (23%); (b) crack cocaine and alcohol (25%); (c) powder cocaine, alcohol, and marijuana (23%); and (d) nonprescribed opioids, alcohol, marijuana, crack cocaine, and powder cocaine (i.e., polysubstance [29%]). Polysubstance class members had poorer physical health and mental health status, and more severe substance use, over the subsequent 3-year period, than other class members. Regarding treatment utilization, polysubstance class members had more medical care utilization than crack cocaine class members, and more substance use treatment utilization than powder cocaine class members. The methamphetamine, crack cocaine, and powder cocaine classes did not differ from each other on any health or treatment utilization outcome. CONCLUSIONS: People using stimulants commonly use other substances, and those whose polysubstance use includes nonprescribed opioids have especially poor health outcomes. PMID- 30422797 TI - Extracellular vesicle-associated miRNAs in ovarian cancer - design of an integrated NGS-based workflow for the identification of blood-based biomarkers for platinum-resistance. AB - Background Extracellular vesicle (EV)-associated microRNAs (miRNAs) have been suggested as promising biomarkers for blood-based cancer diagnosis. However, one of the major limitations for the use of EVs with diagnostic purpose is the lack of standardized EV-profiling techniques. In this regard, the objective of our study was to design an integrated next-generation sequencing (NGS)-based workflow for analyzing the signature of EV-associated miRNA in the plasma of platinum resistant ovarian cancer patients. Methods For EV-extraction, different enrichment methods were compared (ExoQuick vs. exoRNeasy). NGS was performed with the Illumina platform. Results We established an integrated NGS-based workflow, including EV-enrichment with the ExoQuick system, which resulted in an optimal RNA-yield and consistent small RNA libraries. We applied this workflow in a pilot cohort of clinically documented platinum-sensitive (n=15) vs. platinum-resistant (n=15) ovarian cancer patients, resulting in a panel of mature EV-associated miRNAs (including ovarian cancer associated miR-181a, miR-1908, miR-21, miR-486 and miR-223), which were differentially abundant in the plasma of platinum resistant patients. Conclusions This is the first study, analyzing the profile of EV-associated miRNAs in platinum-resistant ovarian cancer patients. We provide rationale to further validate these miRNA candidates in an independent set of patients, in order to characterize their biomarker potential as predictors for platinum-resistance. PMID- 30422798 TI - Perception of parenting styles by in-school adolescents in South-West Nigeria. AB - Background Parenting styles can be explained as behavioural strategies parents use to interact with their offspring. It is importance to understand the perception of parenting styles received by adolescents undergoing socio-cognitive development, however, there are few Nigerian studies exploring this topic. Objective To describe the perception of parenting styles received by in-school adolescents in South-West Nigeria. Methods A descriptive cross-sectional multistage study was conducted among students attending public and private schools in Ibadan, Nigeria. Data was collected by self-administered questionnaires, evaluating socio-demographic characteristics and perception of styles of parenting received by the adolescents. Result The prevalent perceived parenting style was the authoritative style (73.1%) and the least perceived was the permissive (3.8%) style. Female adolescents perceived fathers as being more negligent (65.2%), permissive (66.7%) and authoritarian (56.0%) but less authoritative (40.4%) than male adolescents (p = 0.01). Adolescents in lower social class perceived their mothers as more authoritarian (78.6%) and negligent (72.7%) in contrast to adolescents in higher social class (p = 0.889). Conclusion Perceived parenting style is the tendency of the adolescent to cognizance the behaviour of parents in a particular manner in all situations and develop a perception about their parents. The prevalent authoritative style is the ideal and most desirable style of parenting worldwide, as it describes parents who maintain a balance between high levels of demandingness and responsiveness, consistently supervising their adolescent's behaviour and practicing constructive criticism. Other styles of parenting can be perceived by adolescents and may prevail across socio-economic divide, as depicted by this study. PMID- 30422799 TI - The relationship between anxiety and social support in male and female students in high schools in the southeast of Iran. AB - Introduction Adolescence is associated with physical, social and personality changes. Adolescents usually face some fears during this period, the removal and adjustment of which requires family and teachers' support and the lack of attention to the issues of maturity will have negative effects on their health, awareness and self-esteem. The aim of this study was to investigate the relationship between anxiety and social support among male and femaille students in high schools in the southeast of Iran. Materials and methods In this cross sectional study that was conducted as a descriptive comparison, 452 students who were studying in the first period of high school in Kerman (junior high schools) were selected as the entire population by the cluster sampling method and the data collection instruments were: a demographic questionnaire, Philips Social Support Scale and the Cattle Anxiety Scale. As well as descriptive statistics, to test the hypothesis of this study by SPSS software, and in the case of abnormal distribution of each variable, non-parametric tests were used. Results The results showed that anxiety in girls is great than in boys, also data analysis through Pearson's test showed that there is a negative and significant relationship between anxiety and social support in girls (r = -0.428, n = 226, p < 0.001) and boys (r = -0.378, n = 226, p < 0.001). Conclusion The results of research showed that by increasing perceptions of social support in students, their anxiety decreases. Therefore, paying attention to the social determinants of health such as social support is important and necessary to reduce the anxiety of students. PMID- 30422800 TI - Pelvic inflammatory disease: management requires a patient, prudent, prejudice free provider. PMID- 30422801 TI - Influence of eugenol on oxidative stress biomarkers in the liver of carrageenan induced arthritis rats. AB - Background Eugenol is the foremost constituent of clove oil and widely distributed in many plants. It possesses many pharmaceutical applications, including antioxidant, anti-inflammatory, and anti-tumorigenic properties, among others. This study evaluates the influence of eugenol on oxidative stress biomarkers in the liver of carrageenan-induced arthritis (CIA) rats. Methods Sixty albino rats were randomly divided into 10 (n=6) groups. Group I is the control group that received saline solution orally. Groups II and VII rats received 2.5 mg/kg of eugenol orally (EUG-2.5). Rats in groups III/VIII and IV/IX received 5 and 10 mg/kg of eugenol orally (EUG-5 and EUG-10), respectively. Groups V and X received 0.2 mg/kg of dexamethasone (DEX-0.2) orally. Groups VI to X were injected with 1% carrageenan intra-articularly. Behavioral studies were conducted after 21 days of treatment. Thereafter, the animals were sacrificed, and the livers were isolated and used for biochemical analysis. Results Reduced body weight in arthritic rats was recorded compared to normal controls. Reduced tibiofemoral joint edema and increased spontaneous movement were observed in CIA rats with decreased superoxide dismutase, catalase, reduced glutathione (GSH), glutathione peroxidase, and GSH S-transferase activities compared with the normal control group. Increased endogenous enzyme activities and decreased elevated lipid peroxidation were also observed after eugenol treatment. Conclusion Eugenol ameliorates carrageenan-induced oxidative stress in the liver of arthritic rats. PMID- 30422802 TI - Assessment of heart rate variability for different somatotype category among adolescents. AB - Background Somatotype is a quantified expression of the morphological conformation of a person in terms of three-numeral rating each representing one component; fat (endomorphy), muscle mass (mesomorphy) and bone length (ectomorphy) in the same order. Certain somatotypes are more prone to develop the particular disease. Obesity and overweight are already epidemic among Indian adolescents and are increasing at an alarming rate, and obesity is linked to cardiovascular (CV) risk in this age group. Identifying the heart rate variability (HRV) is an established non-invasive test to identify the CV risk. The objective of this study is to record the HRV data for each somatotype category and to compare the HRV data among these somatotype categories in adolescents. Methods The volunteer adolescents in the age group of 12-17 years were classified into a different somatotyping categories based on the Heath Carter somatotyping method. The short-term HRV was recorded in all the subjects using wireless BioHarness 3.0. Results Based on the time domain and frequency domain parameters, the parasympathetic activity showed decreasing order as follows: central>ectomorphy>mesomorphy>endomorphy, whereas sympathetic activity showed increasing order as follows: central 0.05) for IGBT and VMAT, respectively. Mean D0.1cm3 to the mandible was 77.0% vs. 85.4% (p < 0.05). Dmean to ipsilateral and contralateral parotid glands was 4.6% vs. 4.6% and 3.0% vs. 3.9% (p > 0.05). Dmean to ipsilateral and contralateral submandibular glands was 16.4% vs. 21.9% (p > 0.05) and 8.2% vs. 16.9% (p < 0.05), respectively. Conclusions Both techniques showed excellent target coverage. With IGBT dose to normal tissues was lower than with VMAT. The results prove the superiority of IGBT in the protection of OARs and the important role of this invasive method in the era of new external beam techniques. PMID- 30422805 TI - Posttraumatic stress and autobiographical memory in chronic pain patients. AB - Background and aims Posttraumatic stress disorder (PTSD) is related to more severe pain among chronic pain patients. PTSD is also related to dysfunctions or biases in several cognitive processes, including autobiographical memory. The autobiographical memories are our memories of specific personal events taking place over a limited amount of time on a specific occasion. We investigated how two biases in autobiographical memory, overgeneral memory style and negative emotional bias were related to pain, PTSD and trauma exposure in chronic pain patients. Methods Forty-three patients with diverse chronic pain conditions were recruited from a specialist pain clinic. The patients were evaluated for psychiatric diagnosis, with a diagnostic interview Mini-International Neuropsychiatric Interview (M.I.N.I) and for exposure to the most common types of traumatic events with the Life Event Checklist (LEC). The patients were tested with the 15-cue-words version of the Autobiographical Memory Test (AMT). In this test the participants are presented verbally to five positive, five neutral and five negative cue words and asked to respond with a personal, episodic memory associated with the cue word. The participant's responses were coded according to level of specificity and emotional valence. Pain intensity was assessed on a Visual Analogy Scale (VAS) and extent of pain by marking affected body parts on a pre-drawn body figure. Comparisons on autobiographical memory were made between PTSD and non-PTSD groups, and correlations were computed between pain intensity and extent of pain, trauma exposure and autobiographical memory. Results PTSD and extent of pain were significantly related to more negatively emotionally valenced memory responses to positive and negative cue words. There were no significant difference in response to neutral cue words. PTSD status and pain intensity were unrelated to overgeneral autobiographical memory style. Conclusions A memory bias towards negatively emotionally valenced memories is associated with PTSD and extent of pain. This bias may sustain negative mood and thereby intensify pain perception, or pain may also cause this memory bias. Contrary to our expectations, pain, trauma exposure and PTSD were not significantly related to an overgeneral memory style. Implications Cognitive therapies that have an ingredient focusing on amending memory biases in persons with comorbid pain and PTSD might be helpful for this patient population. Further investigations of negative personal memories and techniques to improve the control over these memories could potentially be useful for chronic pain treatment. PMID- 30422806 TI - Pain assessment in hospitalized spinal cord injured patients - a controlled cross sectional study. AB - Background and aims Following spinal cord injury (SCI), a majority of individuals may develop neuropathic pain, which further reduces quality of life. Pain is difficult to treat by medication; in fact, medication overuse may aggravate neuropathic pain in SCI by causing central sensitization (CS): a mechanism of hyper-reactivity of the dorsal horn neurons in the spinal cord with amplified cerebral pain response. The purpose of this study was to examine the presence of neuropathic pain and CS above the spinal lesion in SCI, and to investigate whether injury characteristics or medication influenced pain response. Methods Twenty-four SCI patients with various injury characteristics (eight subacute, traumatic injuries, eight chronic, traumatic injuries, eight non-traumatic injuries) and 12 able-bodied controls underwent sensory testing:pressure algometry, Von Frey filaments (sensitivity), and repetitive pinprick stimulation (pain windup). SCI participants also fulfilled a modified version of the McGill Pain Questionnaire. Data were analyzed regarding (i) SCI patients compared with controlgroup and (ii) SCI subgroup comparison (grouped by a) injury characteristics and (b) intake of analgesics, where low-medicated subgroup were prescribed only non-opioids and high-medicated potent opioids). Results Neuropathic pain was present in 21 of 24 SCI patients. Chronic and non-traumatic SCI patients reported considerably higher present pain intensity than sub-acute traumatic SCI patients on a five-point scale (3.13+/-0.99, 1.75+/-1.75 and 0.13+/ 0.35, respectively, p<0.005). Reduced pressure pain detection thresholds (PPDT) were found in SCI patients at several supra-lesional anatomical points compared to controls. Contrarily, tactile detection thresholds were higher in SCI. SCI subgroup analyses showed that i) the low-medicated SCI subgroup displayed significantly lower PPDT compared to the high-medicated subgroup, ii) pain-windup was present in all subgroups although the sub-acute and non-traumatic subgroups displayed lesser pain windup than controls, and the chronic SCI subgroup mainly displayed higher pain windup. Conclusions The reduced PPDT found above lesion suggests the presence of CS in SCI. However, findings regarding SCI subgroup comparison did not support our hypothesis that more medication leads to increased CS. Implications The development of CS may complicate diagnosis and pain treatment following SCI. Prospective studies of SCI with a healthy control group are needed. PMID- 30422807 TI - The effects of auditory background noise and virtual reality technology on video game distraction analgesia. AB - Background and aims The present study was designed to evaluate the relative efficacy of two video game display modalities - virtual reality (VR) assisted video game distraction, in which the game is presented via a VR head-mounted display (HMD) helmet, versus standard video game distraction, in which the game is projected on a television - and to determine whether environmental context (quiet versus noisy) moderates the relative efficacy of the two display modalities in reducing cold pressor pain in healthy college students. Methods Undergraduate students (n=164) were stratified by sex and self-reported video game skill and were randomly assigned to a quiet or a noisy environment. Participants then underwent three cold pressor trials consisting of one baseline followed by two distraction trials differing in display modality (i.e. VR assisted or standard distraction) in counter-balanced order. Results Participants experienced improvement in pain tolerance from baseline to distraction in both display modality conditions (p<0.001, partial eta2=0.41), and there was a trend toward greater improvement in pain tolerance from baseline to distraction when using the VR HMD helmet than during standard video game distraction (p=0.057, partial eta2=0.02). Participants rated pain as more intense when experienced with concurrent experimental background noise (p=0.047, partial eta2=0.02). Pain tolerance was not influenced by the presence or absence of background noise, and there was not a significant interaction between display modality and noise condition. Though exploratory sex analyses demonstrated a significant three-way interaction between noise condition, sex, and display modality on pain intensity (p=0.040, partial eta2=0.040), follow-up post-hoc analyses conducted for males and females separately did not reveal significant differences in pain intensity based on the interaction between noise condition and display modality. Conclusions As expected, video game distraction both with and without an HMD helmet increased pain tolerance; however, the two display modalities only marginally differed in efficacy within the population under study. The effect of auditory background noise on pain was mixed; while pain tolerance did not vary as a function of the presence or absence of background noise, the addition of noise increased pain intensity ratings. The interaction between participant sex, noise condition, and distraction modality on pain intensity trended toward significance but would require replication in future research. Implications Results suggest that video game distraction via HMD helmet may be superior to standard video game distraction for increasing pain tolerance, though further research is required to replicate the trending findings observed in this study. Though it does not appear that background noise significantly impacted the relative efficacy of the two different video game display modalities, the presence of noise does appear to alter the pain response through amplified pain intensity ratings. Further research utilizing more sophisticated VR technology and clinically relevant background auditory stimuli is necessary in order to better understand the impact of these findings in real-world settings and to test the clinical utility of VR technology for pain management relative to standard video game distraction. PMID- 30422808 TI - Slo3 K+ channel blocker clofilium extends bull and mouse sperm-fertilizing competence. AB - For artificial insemination (AI) to be successful, it is essential that sperm delivery be perfectly timed relative to ovulation, as sperm lifespan is limited due to oxidative metabolism induced by capacitation. Extending the window of sperm capacitation could therefore increase sperm lifespan, prolong sperm fertilizing competence and increase AI efficiency. Hyperpolarization of sperm is a crucial step in capacitation and is induced by activation of the potassium calcium-activated channel subfamily U member 1 (KCNU1, also named Slo3 or KSper). Given the essential role played by KCNU1 in capacitation, this study assessed the impact of its pharmacological inhibition on sperm lifespan. We showed that treatment of murine sperm with sub-micromolar concentrations of clofilium, a specific inhibitor of KCNU1, slowed down capacitation, decreased the rate of acrosome reaction and extended the fertilizing competence of capacitated sperm for 12 h. Clofilium also extended fertilizing competence and motility of bovine capacitated sperm, and increased the rate of fertilization with sperm capacitated for 24 h by 100%, and the rate of blastocyst formation by 150%. Finally, toxicity experiments showed clofilium to have no impact on sperm DNA and no embryotoxicity at the concentration used to extend sperm lifespan. Our results demonstrate that clofilium prolongs fertilizing competence of aging capacitated sperm in vitro in both rodent and bovine species. To our knowledge, this is the first time the duration of sperm-fertilizing competence is shown to be extended by potassium channels blockers. PMID- 30422809 TI - Antitumor effects of beta-elemene via targeting the phosphorylation of insulin receptor. AB - Ewing sarcoma family tumors (ESFTs) are a group of aggressive and highly metastatic tumors lacking efficient therapies. Insulin-like growth factor 1 receptor (IGF1R) blockade is one of the most efficient targeting therapy for ESFTs. However, the appliance is obstructed by drug resistance and disease recurrence due to the activation of insulin receptor (IR) signaling induced by IGF1R blockade. Herein beta-elemene, a compound derived from natural plants, exhibited a remarkable proliferation repression on ESFT cells, which was weakened by a caspase inhibitor Z-VAD. beta-elemene in combination with IGF1R inhibitors enhanced markedly the repression on cellular proliferation and mTOR activation by IGF1R inhibitors, and suppressed the PI3K phosphorylation induced by IGF1R inhibitors. To investigate the mechanisms, we focused on the effects of beta elemene on IR signaling pathway. beta-elemene significantly suppressed the insulin-driven cell growth and the activation of mTOR and PI3K in tumor cells, while the toxicity to normal hepatocytes is much lower. Further, the phosphorylation of IR was found to be suppressed notably by beta-elemene specifically in tumor cells but not normal hepatocytes. In addition, beta-elemene inhibited the growth of ESFT xenografts in vivo, and the phosphorylation of IR and S6 ribosomal protein was significantly repressed in the beta-elemene-treated xenografts. These data suggest that beta-elemene targets IR phosphorylation to inhibit the proliferation of tumor cells specifically and enhace the effects of IGF1R inhibitors. Thus this study provides evidences for novel approaches by beta elemene alone or in combination with IGF1R blockades in ESFTs and IR signaling hyperactivated tumors. PMID- 30422810 TI - Titanium-oxide based nanoscale and embeddable subzero temperature sensor using MIT deformation characteristics. AB - In this research, we propose a nanoscale and embeddable subzero temperature sensor that is made with a temperature-dependent titanium-oxide based metal insulator-transition (MIT) device. For a nanoscale two-terminal structured MIT device, the MIT device's characteristics are noticeably changed from abrupt to gradual MIT under zero temperature, which is called MIT deformation. On the basis of the MIT deformation characteristics, subzero temperatures can be detected by reading current levels as temperature changes. Furthermore, this sensor has desirable sensing properties such as high-linearity and proper sensitivity. The obtained results strongly show that titanium-oxides with CMOS process compatibility, cost-effectiveness, nontoxicity, etc, can be applied at the nanoscale and embeddable on subzero temperature sensors on a chip. PMID- 30422811 TI - The electronic transport efficiency of a graphene charge carrier guider and an Aharanov-Bohm interferometer. AB - The electrostatic gating defined channel in graphene forms a charge carrier guider. We theoretically investigated electronic transport properties of a single channel and an Aharanov-Bohm (AB) interferometer, based on a charge carrier guider in a graphene nanoribbon. Quantized conductance is found in a single channel, and the guider shows high efficiency in the optical fiber regime, in good agreement with the experiment results. For an AB interferometer without a magnetic field, quantized conductance occurs when there are a few modes inside the channel. The local density of states (LDOS) inside the AB interferometer shows quantum scars when the scattering is strong. At low magnetic field, a periodical conductance oscillation appears. The conductance has a maximum value at zero magnetic field in the absence of intravalley scattering. The mechanism was investigated by LDOS calculations and a toy model. PMID- 30422812 TI - Emerging memory technologies for neuromorphic computing. AB - In this paper, we reviewed the recent trends on neuromorphic computing using emerging memory technologies. Two representative learning algorithms used to implement a hardware-based neural network are described as a bio-inspired learning algorithm and software-based learning algorithm, in particular back propagation. The requirements of the synaptic device to apply each algorithm were analyzed. Then, we reviewed the research trends of synaptic devices to implement an artificial neural network. PMID- 30422813 TI - Composite materials based on Ag nanoparticles in situ synthesized on the vaterite porous matrices. AB - We have designed sensors based on Ag nanoparticles synthesized in situ on the vaterite beads. In this article we demonstrate an approach to produce size controllable spherical and elliptical vaterite particles and discuss time dependent in situ Ag nanoparticles synthesis and its potential effect on surface enhanced Raman scattering. The time dependent silver reduction synthesis in inorganic porous particles allows to regulate the number and size of Ag nanoparticles. It is shown that the irregular surface and high porosity of vaterite particles and large amount (surface filling factor) of the Ag nanoparticles are the critical parameters to increase the SERS signal to 104 times. Such inorganic composites have a huge potential in medical applications; soon they provide an opportunity to study intracellular processes in vivo. The detailed characterization of the microstructure of these composites was studied by scanning and transmission electron microscopy, including 3D visualization and energy dispersive x-ray microanalysis. PMID- 30422814 TI - Quantum theory of spin waves for helical ground states in a hollandite lattice. AB - We perform spin-wave analysis of classical ground states of a model Hamiltonian proposed earlier (Mandal et al 2014 Phys. Rev. B 90 104420) for [Formula: see text] compounds. It is known that the phase diagram of the hollandite lattice (lattice of [Formula: see text] compounds) consists of four different helical phases (FH, A2H, C2H, CH phase) in the space of model parameters [Formula: see text]. The spin wave dispersion shows presence of gapless mode which interpolates between quadratic to linear depending on phases and values of J i . In most cases, the second lowest mode shows the existence of a roton-like minima mainly from [Formula: see text] to [Formula: see text] and [Formula: see text] to [Formula: see text] path and it appears at the value of [Formula: see text] for constant [Formula: see text]. Few higher modes also show similar minima. Each helical phase has its characteristic traits which can be used to determine the phases itself. The analytical expressions of eigenmodes at high symmetry points are obtained which can be utilized to extract the values of J i . Density of states, specific heat and susceptibilities at low temperature have been studied within spin-wave approximation. The specific heat shows departure from T 1.5(3) dependence found in three-dimensional unfrustrated ferromagnetic(anti ferromagnetic) system which seems to be the signature of incommensurate helical phase. The parallel susceptibility is maximum for FH phase and minimum for CH phase at low temperature. The perpendicular susceptibility is found to be independent of temperature at very low temperature. Our study can be used to compare experiments on magnon spectrum, elastic neutron scattering, and finite temperature properties mentioned above for clean [Formula: see text] system as well as determining the values of J i . PMID- 30422815 TI - On the interpretation of cathodoluminescence intensity maps of wide band gap nanowires. AB - It is commonly assumed in the spatially resolved cathodoluminescence (CL) studies of wide band gap (WBG) nanowires (NWs) that the CL intensity maps of deep-level (DL) and near band edge (NBE) emission reflect the spatial distribution of defects in these structures. On this basis, crucial conclusions about the technological growth conditions of NWs are drawn. However, here we showed using three-dimensional finite element analysis that in the case of WBG NWs, which exhibit surface band bending, the CL intensity maps of DL and NBE emission do not reflect the distribution of defects but, instead, the electric field strength in NWs. In particular, we found that independently of the defect concentration distribution, the DL emission intensity is always the highest in the areas where the electric field is the strongest and the lowest where the electric field is absent, while the NBE emission intensity exhibits the opposite trends. We explained this finding by the strong influence of the electric field on the spatial distribution of radiative recombination rates. Overall, our results indicate that (i) the frequently observed spatially inhomogeneous CL intensity distribution in WBG NWs can result from the presence of electric fields but not, as widely accepted, non-uniform defect distribution and (ii) spatially resolved CL spectroscopy measurements on the WBG NWs in most cases can not provide any quantitative information about the DL defect distribution. PMID- 30422816 TI - Magnetic anisotropy manipulation of the femtosecond laser-excited spin wave modes in full-Heusler Co2Fe1-x Mn x Al films. AB - Spin-wave dynamics in full-Heusler Co2Fe1-x Mn x Al films have been investigated using all-optical pump-probe magneto-optical polar Kerr spectroscopy. We find magnetic damping and anisotropy can be modulated by composition x. Damon-Eshbach (DE) spin wave occurs only in the samples which present intrinsic magnetic damping and have huge uniaxial magnetic anisotropy, implying that intrinsic magnetic damping and huge uniaxial magnetic anisotropy is the necessary conditions to excite coherent DE spin wave. Kittel spin wave appears in low uniaxial magnetic anisotropic samples and presents extrinsic magnetic damping. Therefore, laser-excited spin-wave modes can be manipulated by magnetic anisotropy, whose physical picture is discussed phenomenologically. PMID- 30422817 TI - Na-assisted fast growth of large single-crystal MoS2 on sapphire. AB - Monolayer molybdenum sulfide (MoS2), a typical semiconducting transition metal dichalcogenide, has emerged as a perfect platform for next-generation electronics and optoelectronics due to its sizeable band gap and strong light-matter interactions. Nevertheless, the controlled growth of a monolayer MoS2 single crystal with a large-domain size and high crystal quality still faces great challenges. Herein, we demonstrate the fast growth of a large-domain monolayer MoS2 on the c-plane sapphire substrate with the assistance of sodium chloride (NaCl) crystals as the intermediate promoter. Particularly, the volatilization temperature of the NaCl crystal and the growth temperature of MoS2 are established to be the key parameters that influence the growth efficiency of MoS2 at an optimized growth condition. Monolayer triangular MoS2 domain with an edge length ~300 MUm is obtained within 1 min, featured with a growth rate ~5 MUm s-1. The Na element from the NaCl crystal is found to be able to facilitate the two dimensional growth of monolayer MoS2. This work thus offers novel insights into the high-efficiency production of large-domain monolayer MoS2 on insulating growth substrates. PMID- 30422818 TI - P-type beta-MoO2 nanostructures on n-Si by hydrogenation process: synthesis and application towards self-biased UV-visible photodetection. AB - We report on the synthesis and UV-vis photodetection application of p-type MoO2 nanostructures (NSs) on Si substrate. beta-MoO2 NSs have been synthesized from previously grown alpha-MoO3 structures/n-type Si via a hydrogenation process at 450 degrees C. After hydrogenation, the alpha-MoO3 structures were completely converted into beta-MoO2 NSs without the presence of sub-oxidized phases of molybdenum oxide. The as-grown NSs exhibited very good p-type electrical conductivity of ~2.02 * 103 S-cm-1 with hole mobility of ~7.8 +/- 1.3 cm2-V-1-Sec 1. To explore optoelectronic properties of p-type beta-MoO2 NSs, we have fabricated a p-MoO2/n-Si heterojunction photodetector device with Au as the top and Al as the bottom contacts. The device exhibits peak photoresponsivity of ~0.155 A W-1 with maximum detectivity ~1.28 * 1011 cm-Hz1/2-W-1 and 44% external quantum efficiency around ~436 nm, following the highest photoresponse (I ph/I d ~ 6.4 * 102) and good response speed (rise time ~29 ms and decay time ~38 ms) at 1.5 V. Importantly, this device also shows good self-powered high-speed (rise time ~47 ms and decay time ~70 ms) photodetection performance with peak responsivity and detectivity of ~45 mA W-1 and ~4.05 * 1010 cm-Hz1/2-W-1, respectively. This broadband UV-visible light detection feature can be attributed to the coordinated effects of MoO2 band-edge absorption, interfacial defects and self absorption in Si. The photodetection behavior of the device has been understood by proposed energy-band diagrams with the help of an experimentally derived work function, band gap and valence band maximum position of MoO2 NSs. PMID- 30422819 TI - In vivo hematopoietic stem cell gene therapy ameliorates murine thalassemia intermedia. AB - Current thalassemia gene therapy protocols require the collection of hematopoietic stem/progenitor cells (HSPCs), in vitro culture, lentivirus vector transduction, and retransplantation into myelo-ablated patients. Because of cost and technical complexity, it is unlikely that such protocols will be applicable in developing countries where the greatest demand for a beta-thalassemia therapy lies. We have developed a simple in vivo HSPC gene therapy approach that involved HSPC mobilization and an intravenous injection of integrating HDAd5/35++ vectors. Transduced HSPCs homed back to the bone marrow where they persisted long-term. HDAd5/35++ vectors for in vivo gene therapy of thalassemia had a unique capsid that targeted primitive HSPCs through human CD46, a relatively safe SB100X transposase-based integration machinery, a micro-LCR driven gamma-globin gene and, a MGMT(P140K) system that allowed for increasing the therapeutic effect by short-term treatment with low-dose O6BG/BCNU. We showed in "healthy" human CD46 transgenic mice and in a mouse model of thalassemia intermedia that our in vivo approach resulted in stable gamma-globin expression in the majority of circulating red blood cells. The high marking frequency was maintained in secondary recipients. In the thalassemia model, a near complete phenotypic correction was achieved. The treatment was well tolerated. This cost-efficient and "portable" approach could permit a broader clinical application of thalassemia gene therapy. PMID- 30422820 TI - Type I IFN blockade uncouples immunotherapy-induced antitumor immunity and autoimmune toxicity. AB - Despite showing success in treating melanoma and haematological malignancies, adoptive cell therapy (ACT) has generated only limited effects in solid tumors. This is, in part, due to a lack of specific antigen targets, poor trafficking/infiltration and immunosuppression in the tumor microenvironment. In this study, we combined ACT with oncolytic virus vaccines (OVV) to drive expansion and tumor infiltration of transferred antigen-specific T cells, and demonstrated that the combination is highly potent for the eradication of established solid tumors. Consistent with other successful immunotherapies, this approach elicited severe autoimmune consequence when the antigen targeted was a self-protein. However, modulation of IFNalpha/beta signaling, either by functional blockade or rational choice of an OVV backbone, ameliorated autoimmune side effects without compromising antitumor efficacy. Our study uncovers a pathogenic role for IFNalpha/beta in facilitating autoimmune toxicity during cancer immunotherapy and offers a safe and powerful combinatorial regimen with immediate translational applications. PMID- 30422821 TI - Rescue of recurrent deep intronic mutation underlying cell type-dependent quantitative NEMO deficiency. AB - X-linked dominant incontinentia pigmenti (IP) and X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) are caused by loss-of function and hypomorphic NEMO mutations, respectively. We describe a European mother with mild IP and a Japanese mother without IP, whose three boys with EDA ID died of immunodeficiency. We identify the same private variant in an intron of IKBKG/NEMO, IVS4+866 C>T, which was inherited from and occurred de novo in the European and Japanese mothers, respectively. This mutation creates a new splicing donor site, giving rise to a 44-nucleotide pseudo-exon generating a frameshift. Its leakiness accounts for NF-kappaB activation being impaired, but not abolished in the boys' cells. However, aberrant splicing rates differ between cell types, with WT NEMO mRNA and protein levels ranging from barely detectable in leukocytes to residual amounts in iPSC-derived macrophages, and higher levels in fibroblasts and iPSC-derived neuronal precursor cells. Finally, SRSF6 binds to the pseudo exon, facilitating its inclusion. Moreover, SRSF6 knockdown or CLK inhibition restores WT NEMO expression and function in mutant cells. A recurrent deep intronic splicing mutation in IKBKG/NEMO underlies a purely quantitative NEMO defect in males that is most severe in leukocytes and can be rescued by the inhibition of SRSF6 or CLK. PMID- 30422822 TI - Endothelial progerin expression causes cardiovascular pathology through an impaired mechanoresponse. AB - Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder characterized by accelerated cardiovascular disease with extensive fibrosis. It is caused by a mutation in LMNA leading to expression of truncated prelamin A (progerin) in the nucleus. To investigate the contribution of the endothelium to cardiovascular HGPS pathology, we generated an endothelium-specific HGPS mouse model with selective endothelial progerin expression. Transgenic mice develop interstitial myocardial and perivascular fibrosis and left ventricular hypertrophy associated with diastolic dysfunction and premature death. Endothelial cells show impaired shear stress response and reduced levels of endothelial nitric oxide synthase (eNOS) and NO. On the molecular level, progerin impairs nucleocytoskeletal coupling in endothelial cells through changes in mechanoresponsive components at the nuclear envelope, increased F-/G-actin ratios and deregulation of mechanoresponsive myocardin-related transcription factor-A (MRTFA). MRTFA binds to the Nos3 promoter reducing eNOS expression, thereby mediating a pro-fibrotic paracrine response in fibroblasts. MRTFA inhibition rescues eNOS levels and ameliorates the pro-fibrotic effect of endothelial cells in vitro. Although this murine model lacks the key anatomical feature of vascular smooth muscle cell loss seen in HGPS patients, our data show that progerin induced impairment of mechanosignaling in endothelial cells contributes to excessive fibrosis and cardiovascular disease in HGPS patients. PMID- 30422823 TI - Scurvy-Characteristic Features and Forensic Issues. AB - Scurvy is a multisystem condition that arises from vitamin C deficiency. As humans cannot synthesize vitamin C, serum and tissue levels depend on bioavailability, utilization, and renal excretion. Deficiencies result in defective collagen formation with swelling of gums, leg ulceration, and bleeding manifestations. Death most often results from infection and hemorrhage. In a forensic context, scurvy may mimic inflicted injuries and may be responsible for sudden death by mechanisms that remain unclear. Cardiac failure and rhythm disturbances with chest pain, hypotension, cardiac tamponade, and dyspnea are associated with vitamin C deficiency. In addition, syncope and seizures may occur. Although far less common than in previous centuries, scurvy is still present in high-risk populations that include alcoholics, isolated elderly individuals, food faddists, institutionalized patients, those with mental illness, and those who have had bariatric surgery or with underlying gastrointestinal conditions. Scurvy should therefore be a diagnosis to consider in medicolegal cases of apparent trauma and sudden death. PMID- 30422824 TI - New insights into IgG4-related disease: emerging new CD4+ T-cell subsets. AB - PURPOSE OF REVIEW: New insights into IgG4-related disease (IgG4-RD) have recently been obtained. A better understanding of the mechanisms underlying this disease is important for identification of therapeutic targets, which will lead to the development of specific strategies for treatment. RECENT FINDINGS: Infiltration of activated T follicular helper (Tfh) cells is observed in affected tissues of IgG4-RD. Such Tfh cells have a greater capacity than tonsillar Tfh cells to help B cells produce IgG4. Circulating PD-1CXCR5 peripheral T helper (Tph)-like cells are also increased in patients with IgG4-RD. Because Tph-like cells express high levels of chemokine receptors and granzyme A, they have the capacity to infiltrate affected tissues and exert a cytotoxic function. Tph-like cells can also produce CXCL13, and CXCR5 Tfh cells and B cells are therefore preferentially recruited to form ectopic lymphoid structures in the sites. Tph cells may have a role to ignite inflammation and maintain persistent fibroinflammation in collaboration with Tfh cells in lesions of IgG4-RD. SUMMARY: Recent advances in understanding the pathogenesis of IgG4-RD are remarkable. In this review, we summarize and discuss the possible pathologic role of CD4 T-cell subsets in IgG4 RD. PMID- 30422826 TI - Is aerobic exercise training beneficial for adults with fibromyalgia? - A Cochrane Review summary with commentary. PMID- 30422825 TI - Carotid pulse wave analysis: left or right, does it matter? AB - INTRODUCTION: Pulse wave analysis (PWA) over the carotid artery is one of the available methodological options to obtain central arterial pressures and other important hemodynamic parameters. However, limited data exist relating the PWA estimates of one carotid artery over the contralateral one as the majority of the available data rely on measures over the right carotid artery. OBJECTIVE: To evaluate the agreement of the PWA estimates between the right carotid artery and the left carotid artery. PATIENTS AND METHODS: A cross-sectional study of 38 patients, with a mean age of 28.85+/-1.70 years, was carried out. Brachial blood pressure was evaluated using a sphygmomanometer. Subsequently, PWA was obtained randomly over the left or the right carotid arteries with the Complior Analyse. All the evaluations were performed by the same experienced operator. RESULTS: The overall mean differences observed by comparing the obtained parameters in each carotid territory were -1.50+/-8.06 mmHg for central systolic blood pressure (SBP), -1.63+/-7.98 mmHg for central pulse pressure, -3.37+/-27.80% for the augmentation index, and 1.50+/-8.06 mmHg for the SBP amplification, and were not statistically significant for all the parameters. The Bland-Altman analysis showed distinct correlations and concordance levels for different parameters: central SBP and central pulse pressure showed a very strong agreement (intraclass correlation of 0.926 and 0.886, respectively). In contrast, the concordance for the augmentation index and the SBP amplification was moderate (intraclass correlations between 0.5 and 0.8). CONCLUSION: PWA provides similar measures of central blood pressure, whether measured over the right or the left carotid arteries, even though the morphological features of the pulse waves showed moderate agreement. The advantages of PWA over each arterial territory and the requirements that should mediate the choice of one of the both sides require further investigation. PMID- 30422827 TI - Impairments in Postural Control and Re-test Reliability of Dynamic Posturographic Measures after Lung Transplantation. AB - OBJECTIVE: To classify impairments in postural control using computerized posturography in lung transplant recipients (LuTXr) undergoing subacute rehabilitation, and to examine the re-test reliability of these measures. METHODS: In a prospective repeated-measures study, 50 LuTXr underwent clinical and quantitative posturographic testing (SMART EquiTest), which included the Sensory Organisation Test (SOT), Motor Control Test (MCT) and Limits of Stability Test (LOS). Testing was repeated after 1-to-2 days and upon completion of rehabilitation, two months later. Main outcome measures were: SOT-composite score, MCT-latency and amplitude scaling, LOS-movement velocity (LOS-MV) and end point-excursion (LOS-EPE)/maximum-excursion (LOS-MXE). RESULTS: At the beginning of rehabilitation, the mean SOT-CS and LOS, but not the MCT scores were below normative reference values, and did not return to normal after rehabilitation. Intra-class correlation coefficients (ICC2,1) yielded excellent relative reliability for all posturographic tests. The smallest detectable differences observed for the SOT and LOS exceeded the mean changes observed upon completion of rehabilitation. CONCLUSION: Impairments in sensory and anticipatory postural control was insufficiently restored after subacute LuTX rehabilitation. The little sensitivity of the SOT-CS or LOS scores to detect a minimal change in performance due to rehabilitation limits the clinical applicability of these tests as objective outcome measures in LuTX rehabilitation. PMID- 30422828 TI - Hypopigmented Macules With Onychodystrophy: Challenge. PMID- 30422829 TI - Pathogenesis of Leprosy: An Insight Into B Lymphocytes and Plasma Cells. AB - The pathogenesis of leprosy is still not fully understood. Several studies have been performed on the involvement of T cells in leprosy and more recently have focused on genetic factors and innate immune response. There are still only few reports about the role of B cells in active leprosy lesions in different spectral forms of the disease. The literature on tuberculosis suggests that B cells play an important role in the regulation of the granulomas, in cytokine production, T cell response, and antigen presentation. Only few studies investigated the role of B cell in leprosy. We investigated the distribution of B cells in 85 leprosy biopsies covering all forms of the disease and compared results with 13 biopsies of tuberculosis and atypical mycobacteriosis, expanding the previous experiences. A statistically significant difference in the number of CD20 (P = 0.014) and CD138+ (P = 0.01) cells between the different forms of leprosy was observed. A remarkable amount of CD138+ cells could also be detected in borderline tuberculoid. The median of the CD20 cells decreased from the bacilloscopy negative samples to the bacilloscopy-positive samples by 50% (P = 0.004). Contrarily, the median of CD138+ cells showed an increase from bacilloscopy negative to bacilloscopy-positive samples of 966.67% (P = 0.001). In our experience, tuberculoid leprosy showed more B cells and less plasma cells than lepromatous leprosy. Our results show that B cells might be implicated in leprosy pathogenesis, not only in the lepromatous pole as previously postulated, but also in tuberculoid granuloma formation and type 1 reactions. PMID- 30422830 TI - Eosinophils Among the Histological Features of Psoriasis. AB - "Eosinophils are absent in psoriasis" has been dogma for generations; yet, there is little published to support this statement. Two recent studies examining the presence of eosinophils in psoriasis came to contrasting conclusions. We reviewed skin biopsies from 50 patients with clinically confirmed cases of psoriasis vulgaris to characterize the histologic features, with a focus on the number of eosinophils in the dermis. We noted the presence of eosinophils in nearly half of our study population (n = 23, 46.0%). There was no significant association between the presence of eosinophils and degree of spongiosis (P = 0.405). Eosinophil density ranged from 0 to 8 per tissue section. The mean average eosinophil density was 1.04 (range: 0-8) per tissue section. Among cases with eosinophils, there were 73.9% (n = 17/23) of cases with 1-2 eosinophils, and 26.1% (n = 6) with 3-8 eosinophils. Mild to moderate spongiosis was noted in the majority of cases (n = 48; 96.0%). Eosinophils were only present in psoriasis cases with evidence of spongiosis (n = 23; 47.9%). We conclude that eosinophils are not an uncommon finding in the dermis of psoriasis vulgaris, although the number is often few. The presence of eosinophils should not preclude a diagnosis of psoriasis, particularly if other histologic features are supportive. PMID- 30422831 TI - Pruritic Blistering Eruption: Challenge. PMID- 30422832 TI - A modified DAW-22 compound F-B1 inhibits Bcr/Abl and induces apoptosis in chronic myelogenous leukemia cells. AB - The Bcr/Abl kinase is an oncogenic fusion protein that plays a central role in the pathogenesis of chronic myeloid leukemia (CML). Some small-molecule kinase inhibitors such as imatinib were developed in the treatment of CML; however, resistant to imatinib is an emerging problem of CML therapy. Hence, additional approaches or compounds targeting leukemogenic cells are required. F-B1 is a new compound obtained by modifying DAW-22, a natural sesquiterpenoid coumarin, which was isolated from traditional Chinese medicine Ferula ferulaeoides (Steud.) Korov. F-B1 was found to inhibit the growth of myelogenous leukemia cell lines, that is, K562 cells bearing wild-type Bcr/Abl and imatinib-resistant K562G cells. F-B1 potently down-regulated the mRNA and protein levels of Bcr/Abl, followed by suppression of the downstream molecules such as Akt, externally regulated kinases, and nuclear factor kappaB. In addition, F-B1 also induced cell apoptosis by impairing the balance between proapoptotic protein Bax and antiapoptotic proteins Bcl-2 and Bcl-XL and increased the activity of mitochondrial-dependent apoptosis in nude mouse xenografts. Experimental validation results together demonstrated that F-B1 can inhibit Bcr/Abl fusion proteins in K562 and K562G cells, implying that F-B1 might be a promising drug to treat CML, especially the imatinib-resistant CML. PMID- 30422833 TI - Long-term renal outcomes and mortality following renal injury among myocardial infarction patients treated by primary percutaneous intervention. AB - OBJECTIVES: Limited data are present on persistent renal impairment following acute kidney injury (AKI) among ST elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). We evaluated the incidence and prognostic implications of acute kidney disease (AKD), defined as reduced kidney function for the duration of between 7 and 90 days after exposure to an AKI initiating event, as well as long-term renal outcomes among STEMI patients undergoing primary PCI who developed AKI. PATIENTS AND METHODS: We retrospectively studied 225 consecutive STEMI patients who developed AKI. Patients were assessed for the occurrence of AKD and long-term renal outcomes on the basis of serum creatinine levels measured at 7 days/hospital discharge and within 90-180 days of renal insult. Mortality was assessed at 90 days and over a period of 1271+/-903 days (range: 2-2130 days) following the renal insult. RESULTS: Progression to AKD occurred in 81/225 (36%) patients and was associated with higher 90-day (35 vs. 11%, P<0.001) and long term mortality (35 vs. 17%, P<0.001). Normalization of serum creatinine to a level equal/lower than hospital admission level at more than 90 days from renal insult occurred in 41% of patients with AKD, whereas 59% of these patients showed new/progressed chronic kidney disease. In contrast, only 7% of patients without AKD showed the progression of pre-existing renal disease while, in the rest, the serum creatinine level remained stable. CONCLUSION: Progression to AKD following an acute renal insult in STEMI is frequent and associated with worse survival and adverse long-term renal outcomes. PMID- 30422834 TI - Pharmacological treatment of attention-deficit hyperactivity disorder comorbid with an anxiety disorder: a systematic review. AB - The purpose of this study was to conduct a systematic review of the pharmacological options available to treat patients diagnosed with attention deficit hyperactivity disorder and anxiety disorder, for generating evidence on the safest, most-effective and tolerable pharmacotherapy. To this end, a systematic search was performed in three electronic databases (Medline, Scopus and Directory of Open Access Journals; December 2017). Randomized, double-blind, parallel-design clinical trials evaluating the efficacy, safety or tolerability of therapies for attention-deficit hyperactivity disorder and anxiety disorder in children and adolescents or adults were considered. A total of 1960 articles were retrieved from the databases, of which five studies were included in the qualitative synthesis. Two of these studies evaluated the drug atomoxetine, another study evaluated desipramine, and the remaining two studies evaluated methylphenidate, with fluvoxamine being associated with methylphenidate in one of the trials. Owing to the high heterogeneity among studies, it was not possible to combine data for meta-analyses. Although only few studies have been evaluated in this systematic review, the results point to a more significant benefit of atomoxetine. This is probably because this drug was studied in a wider age range and evaluated by more specific scales for both disorders. To further strengthen this evidence, randomized, controlled and multicenter clinical trials with larger sample sizes should be conducted. PMID- 30422835 TI - Impact of mental illness on outcomes of outpatients with community-acquired pneumonia. AB - According to the National Alliance on Mental Illness, one in five adults experience a mental health condition yearly. Community-acquired pneumonia (CAP) is often treated with QTc prolonging antibiotics. The primary outcome assessed is if psychiatric diagnosis contributed to treatment failure in CAP. Outpatients with International Statistical Classification of Diseases and Related Health Problems 9 and 10 codes for CAP from January 2008 to January 2018 were analyzed retrospectively by descriptive statistics. Bivariate analysis was used to compare baseline characteristics, treatment regimens, and outcomes between those with a psychiatric diagnosis and those without. A chi-test was used for analysis of categorical variables and either the independent Student's t-test or one-way analysis of variance was used was used for analysis of continuous variables. Criteria were met by 518 patients, of which, 49% had a psychiatric diagnosis. Patients with psychiatric comorbidity were not more likely to experience treatment failure, subsequent admission, or mortality. There was no statistically significant difference between patients with a psychiatric diagnosis and those without in early or late CAP treatment failure (P=0.34 and 0.12), 30-day subsequent admission rates (P=0.41), 30-day mortality (P=0.34), or 90-day mortality (P=0.38). Psychiatric diagnosis increased the likelihood of a concomitant QTc prolonging psychiatric medication (51.78 vs. 3.40% P<0.0001), however, the prescribing rate of a QTc prolonging antibiotic was not statistically significantly different (85.3 vs. 83.4% P=0.54). Outpatients with mental illness can be treated for CAP without fear of increased risk of treatment failure compared with those without such diagnosis. This study emphasizes the necessity to consider the full patient history and diagnosis when treating patients with outpatient infections. PMID- 30422836 TI - Dynamic Volume Change Rate and Aspect Ratio Are Correlated to the Formation of an Irregular Morphology of Unruptured Intracranial Aneurysm. AB - OBJECTIVE: The aim of this research was to study the factors influencing the formation of intracranial aneurysms with irregular morphology by observing the dynamic volume change rate of intracranial unruptured aneurysms and other aneurysm characteristics. METHOD: Sixty-five unruptured intracranial aneurysms of 51 consecutive patients from 1 center were included in this study. All patients underwent a dual-source computed tomography electrocardiogram-gated 4-dimensional computed tomography angiography examination. The original data at the end of the scan were reconstructed, and 20 sets of data packages through a cardiac cycle with 5% interval were obtained. Data packages were processed by a 3-dimensional software workstation to obtain 20 sets of images and dynamic diagrams. The volume of each aneurysm in the 20 sets of images was measured, and the volume change was calculated by a specific formula. The other data features of the aneurysm such as aneurysm neck, aneurysm height, aspect ratio (AR), location at bifurcation, and clinical features such as age, sex, hypertension history, type 2 diabetes history, smoking history, family history, multiple aneurysm history, and subarachnoid hemorrhage history, were documented in detail. After single factor analysis data, logistic regression analysis of the meaningful indicator was conducted to study the predictive factors of irregular aneurysms. RESULTS: Of the 65 aneurysms, 25 possessed an irregular shape and 40 were of regular shape; 51 were anterior circulatory aneurysms and 14 were posterior circulatory aneurysms. Single factor analysis showed that AR (P = 0.001), volume change rate (P = 0.002), and location of aneurysm at the bifurcation (P = 0.038) of the vessel were significantly correlated with irregular aneurysms, but not correlated with age, sex, hypertension history, type 2 diabetes history, smoking history, family history, multiple aneurysm history, and subarachnoid hemorrhage history. Multifactor analysis showed that volume change rate greater than 30% (P = 0.008; odds ratio, 6.934) and AR greater than 1.4 (P = 0.004; odds ratio, 8.258) were independent correlative factors of the formation of intracranial aneurysm with irregular shape. CONCLUSION: The volume change rate and AR are independent correlative factors of the formation of intracranial aneurysm with irregular shape. PMID- 30422837 TI - Failed Total Hip Arthroplasty. PMID- 30422838 TI - Mothers' Perspectives on Follow-up for Postpartum Depression Screening in Primary Care. AB - OBJECTIVE: To qualitatively assess mothers' perspectives on barriers to and facilitators of follow-up of at-risk postpartum depression (PPD) screening test results. METHODS: We conducted semistructured qualitative telephone interviews with 17 women who scored in the moderate or high-risk range on the Edinburgh Postnatal Depression Scale. Interviews explored personal experience with depressive symptoms, barriers and facilitators to receiving mental health care postpartum, and suggestions for primary care follow-up of at-risk screens. The team created a coding structure that was updated during review of transcripts. Findings were triangulated and external validity assessed via discussions with a mother who experienced PPD, a perinatal social worker, and a perinatal psychologist. RESULTS: Personal health/attitude, family/friends, community, and health care system factors influenced mothers' follow-up of at-risk PPD screening test results. Health and personal attitude factors included anxiety, physical and emotional exhaustion, self-care and recognition of symptoms, and living up to personal and family expectations. Family/friend factors included material and emotional support and competing priorities. Community factors included child care affordability and availability, access to transportation, geographic access to resources, social networks, and community mental health stigma. Health care factors included pediatrician taking the mother's symptoms seriously, adequate time with the pediatrician, mother and pediatrician focus on the child's health, and access to mental health referrals. CONCLUSION: Addressing barriers to follow up after PPD screening may enable better service access for at-risk families. PMID- 30422839 TI - Feasibility of Distinguishing Performance Among Provider Groups Using Patient reported Outcome Measures in Older Adults With Multiple Chronic Conditions. AB - OBJECTIVE: To examine minimum sample sizes and follow-up times required for patient-reported outcome-based performance measures (PMs) to achieve acceptable reliability as PMs. PARTICIPANTS: We used 2 groups of patients age 65+ with at least 2 of 13 chronic conditions. The first was a sample of Medicare Advantage beneficiaries, who reported health-related quality of life (HRQoL) at baseline and 2 years. The second was a sample of primary care patients, who reported HRQoL at baseline and 6 months. MEASURES: Medicare Advantage beneficiaries completed the Veterans RAND 12-Item Short Form (VR-12), while the primary care sample completed the Patient-Reported Outcomes Measurement Information System 29-Item Profile Measure (PROMIS-29). We constructed binary candidate PMs indicating stable or improved physical or mental HRQoL at follow-up, and continuous PMs measuring mean change over time. RESULTS: In the Medicare Advantage sample, with a sample size per entity profiled of 160, the most promising PM achieved a reliability of 0.32 as a PM. A sample size of 882 per entity would have been needed for this PM to achieve an acceptable reliability of 0.7. In the prospective sample, with a sample size of 27 per clinic, the most promising PM achieved a reliability of 0.16 as a PM. A sample size of 341 patients (at the clinic level) would have been needed for this PM to achieve a reliability of 0.7. CONCLUSIONS: Achieving acceptable reliability for these PMs and conditions would have required minimum sample sizes of 341 at the clinic level or 880 at the health plan level. These estimates can guide the design of future patient reported outcome-based PMs. PMID- 30422840 TI - Assessing Residual Bias in Estimating Influenza Vaccine Effectiveness: Comparison of High-dose Versus Standard-dose Vaccines. AB - BACKGROUND: Estimating influenza vaccine effectiveness using an unvaccinated comparison group may result in biased effect estimates. OBJECTIVES: To explore the reduction of confounding bias in an active comparison of high-dose versus standard-dose influenza vaccines, as compared with vaccinated versus unvaccinated comparisons. METHODS: Using Medicare data from the United States end-stage renal disease program (2009-2013), we compared the risk of all-cause mortality among recipients of high-dose vaccine (HDV) versus standard-dose vaccine (SDV), HDV versus no vaccine, and SDV versus no vaccine. To quantify confounding bias, analyses were restricted to the preinfluenza season, when the protective effect of vaccination should not yet be observed. We estimated the standardized mortality ratio-weighted cumulative incidence functions using Kaplan-Meier methods and calculated risk ratios (RRs) and risk differences between groups. RESULTS: Among 350,921 eligible patients contributing 825,642 unique patient preinfluenza seasons, 0.8% received HDV, 70.5% received SDV, and 28.7% remained unvaccinated. Comparisons with unvaccinated patients yielded spurious decreases in mortality risk during the preinfluenza period, for HDV versus none [RR, 0.60; 95% confidence interval (CI), 0.51-0.70)] and SDV versus none (RR, 0.72; 95% CI, 0.70-0.75). The effect estimate was attenuated in the HDV versus SDV comparison (RR, 0.89; 95% CI, 0.77-1.03). Estimates on the absolute scale followed a similar pattern. CONCLUSIONS: The HDV versus SDV comparison yielded less-biased estimates of the all-cause mortality before influenza season compared to those with nonuser comparison groups. Vaccine effectiveness and safety researchers should consider the active comparator design to reduce bias due to differences in underlying health status between vaccinated and unvaccinated individuals. PMID- 30422841 TI - Chyle Leak Following Autologous Breast Reconstruction: A Rare Complication of a Deep Inferior Epigastric Artery Perforator Flap. AB - BACKGROUND: While complications of deep inferior epigastric artery perforator flaps are known and well documented, a thorough literature review revealed no other reports of a patient developing a chyle leak following the use of the internal mammary vessels for recipient vessels in autologous breast reconstruction. CASE: A 55-year-old woman underwent free autologous breast reconstruction. She developed a chyle leak during the postoperative period. This was verified through a computed tomography scan and fluid analysis demonstrating a high triglyceride count and the presence of chylomicrons. The leak resolved with conservative measures including compression and a low-fat, high-protein diet. DISCUSSION: The presence of chyle leak following dissection of the internal mammary vessels is a unique complication of autologous breast reconstruction. There have been reports of lymph leaks following mastectomy, but these are mostly reported in the axilla. A history of radiation to the contralateral breast and aberrant anatomy may have contributed to the complication. Treatment of chyle leaks ranges from conservative management to the use of total parenteral nutrition and somatostatin analogs to surgical intervention. CONCLUSION: While altering practice patterns based on a single case is not usually suggested, this complication does intimate that dealing with lymphatic vessels and lymph nodes in the chest should be done deliberately to prevent lymphatic leaks. PMID- 30422842 TI - Assessment of Pelvic Floor Anatomy for Male-to-Female Vaginoplasty and the Role of Physical Therapy on Functional and Patient-Reported Outcomes. AB - BACKGROUND: Rapid increase in number of male-to-female vaginoplasties emphasizes the need for preoperative measures to optimize final surgical and patient reported outcomes. Hormonal therapy and socioeconomic factors may contribute to a higher incidence of pelvic floor dysfunction in patients undergoing male-to female vaginoplasty. The purpose of this study was to evaluate the incidence of pelvic floor dysfunction in this population and the role of physical therapy in its treatment. METHODS: From July 2016 to July 2018, patients scheduled to undergo male-to-female vaginoplasty were evaluated by a physical therapist for pelvic floor dysfunction. Patient charts were reviewed for demographics, comorbidities, and length of hormonal therapy. Those with and without symptoms were compared. Symptomatic patients underwent therapy. Assessment of symptom severity and its impact on daily living were completed at 2- to 3-month intervals with physical therapy using the 6-item Urinary Distress Index 6 and 8-item Colorectal Anal Distress Index components of the 20-item Pelvic Floor Distress Inventory (PFDI-20) before and after surgery. A third component of the PFDI-20, the 6-item Pelvic Organ Prolapse Distress Inventory, was also included in the postoperative assessment. RESULTS: Over a 24-month period, a total of 40 patients with a mean age of 40.7 (19-72) years and body mass index of 27.1 kg/m (22-39 kg/m) were enrolled. Comorbidities included 4 patients (10%) with diabetes and 6 patients (15%) with hypertension. Patients with symptoms had a significantly higher mean age (P < 0.01). Only 1 patient (2.5%) had new-onset pelvic floor dysfunction after surgery, and there was no significant increase in severity of symptoms in those with a previous pelvic floor dysfunction postoperatively. Physical therapy significantly (P < 0.01) reduced severity of symptoms and its impact on daily living as assessed by the Urinary Distress Index and Colorectal Anal Distress Index before and after surgery and by the PFDI-20 and 7-item Pelvic Floor Dysfunction Index postoperatively. CONCLUSIONS: A high incidence of pelvic floor dysfunction may exist in patients undergoing male-to-female vaginoplasty preoperatively. Screening at this early stage with both preoperative and postoperative therapy can significantly reduce pelvic floor dysfunction and improve symptoms and quality of life for this population. PMID- 30422843 TI - Determinants of Free Fasciocutaneous Flap Outcomes in Partial Hypopharyngeal Defects. AB - BACKGROUND: Most of the patients with hypopharyngeal cancer are still diagnosed with advanced stage, and total or partial pharyngectomy with free flap reconstruction is the mainstay of treatment. The aim of this study was to find out the possible risk factors related to surgical complications after free fasciocutaneous flap reconstruction for partial pharyngeal defect and its sequelae in the follow-up. PATIENTS AND METHODS: We retrospectively reviewed the charts of patients with advanced hypopharyngeal cancer who received free fasciocutaneous flaps for partial pharyngeal defects reconstruction. From 2005 to 2015, 79 free fasciocutaneous flaps (59 free fasciocutaneous flaps and 20 anterolateral thigh flaps) were performed in our department. The risk factors for free flap outcome and complications were evaluated with multivariant linear regression model. RESULTS: The mean age of patients was 60.8 years with male predominance. The mean follow-up duration was 39.6 months. Most of the cases (97.5%) were in stage III or IV. Patients with comorbidities showed significant correlation to flap failure (95% confidence interval [CI] = 0.038 to 0.264, P = 0.10). Anastomosis style (end-to-side vs end-to-end) was the only operation related factors significantly related to flap failure rate (18.8% vs 3.2%, 95% CI = 0.031 to 0.32, P = 0.18). Flap size was significantly associated with fistula formation (95% CI = -0.005 to 0.000, P = 0.38). CONCLUSIONS: In our experience, patients with comorbidities and end-to-side anastomosis illustrate significantly higher flap failure rate in free fasciocutaneous flap reconstruction of partial hypopharyngeal defect. Reconstruction with smaller flap size had higher possibility of fistula formation. PMID- 30422845 TI - Locked Thumb Metacarpophalangeal Joint Caused by Entrapment of the Sesamoid Bone: A Report of 2 Cases. AB - Locked thumb metacarpophalangeal joint caused by entrapment of the sesamoid bone is an uncommon entity. The intact volar plate, strong ligamentous attachment between the sesamoid bone and the joint, and altered axis of inserted muscle all contribute to failure of closed reduction. The patient's history, clinical presentation, and plain radiographic findings are all important clues to diagnosing this rare disease. We describe 2 patients with a similar mechanism of injury, where the sesamoid bones were displaced into the thumb metacarpophalangeal joint causing lock thumb. The anatomy, pathophysiology, and surgical management of the patients are also described and discussed. Both patients were successfully treated with meticulous open reduction. PMID- 30422844 TI - Extended Use of Chimeric Medial Sural Artery Perforator Flap for 3-Dimensional Defect Reconstruction. AB - BACKGROUND: The medial sural artery perforator (MSAP) flap has become increasingly popular because it is thin and pliable for small to moderate defect soft tissue reconstruction. Furthermore, chimeric MSAP flap, which includes a skin paddle and a separated piece of medial gastrocnemius muscle, allowed more freedom for flap insetting, especially in 3-dimensional defect reconstruction. Here we describe our experience regarding this clinical application. PATIENTS AND METHODS: From 2007 to 2016, 14 male patients (average age, 46.9 +/- 14.4 years) who received either a free or pedicled chimeric MSAP flap were included. Of these 14 patients, 7 received this flap for reconstruction in the head and neck, 2 in the upper extremities, and 5 in the lower extremities. Demographic data were collected and analyzed, and a literature review was performed. RESULTS: Ten patients received free chimeric MSAP flap, and 4 received the pedicled type. Thirteen of the 14 flaps (92.6%) survived, and 1 failed 2 days later owing to venous insufficiency. Venous congestion-related partial loss occurred in another case. CONCLUSIONS: The chimeric MSAP flap is a good alternative for deep space obliteration or reconstruction of adjacent but separate defects in both free and pedicled flap design. Donor site morbidity is limited. However, the perforator needs to be mobilized carefully to prevent postoperative venous compromise. PMID- 30422848 TI - This Month in Anesthesiology. PMID- 30422850 TI - Personalized PEEP: Options for Getting It Just Right. PMID- 30422852 TI - Daily Nitrous Oxide for "Pupblic" Patients of Dr. C. C. Haskell. PMID- 30422853 TI - Warding Off Quacks: Ward's Laudanum in Pittsburgh. PMID- 30422854 TI - York Dentist Kurwin Eisenhart Provided "Any Anesthetic Desired". PMID- 30422855 TI - Chloroforming a Hoosier Holiday Turkey. PMID- 30422856 TI - In-training Exams, Performance, and Exam Fatigue. PMID- 30422857 TI - Does the American Board of Anesthesiology BASIC Examination Really Affect Anesthesiology Resident Knowledge Acquisition? PMID- 30422858 TI - In Reply. PMID- 30422859 TI - In Reply. PMID- 30422860 TI - When Checklists Fail: Human Factors Learning from Aviation and Safety by Design. PMID- 30422861 TI - Extracorporeal Cardiopulmonary Resuscitation: One-Year Survival and Neurobehavioral Outcome Among Infants and Children With In-Hospital Cardiac Arrest. AB - OBJECTIVE: To describe neurobehavioral outcomes and investigate factors associated with survival and survival with good neurobehavioral outcome 1 year after in-hospital cardiac arrest for children who received extracorporeal cardiopulmonary resuscitation. DESIGN: Secondary analysis of the Therapeutic Hypothermia after Pediatric Cardiac Arrest In-Hospital trial. SETTING: Thirty seven PICUs in the United States, Canada, and the United Kingdom. PATIENTS: Children (n = 147) resuscitated with extracorporeal cardiopulmonary resuscitation following in-hospital cardiac arrest. INTERVENTIONS: Neurobehavioral status was assessed using the Vineland Adaptive Behavior Scales, Second Edition, at prearrest baseline and 12 months postarrest. Norms for Vineland Adaptive Behavior Scales, Second Edition, are 100 (mean) +/- 15 (SD). Higher scores indicate better functioning. Outcomes included 12-month survival, 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, decreased by less than or equal to 15 points from baseline, and 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, greater than or equal to 70. MEASUREMENTS AND MAIN RESULTS: Of 147 children receiving extracorporeal cardiopulmonary resuscitation, 125 (85.0%) had a preexisting cardiac condition, 75 (51.0%) were postcardiac surgery, and 84 (57.1%) were less than 1 year old. Duration of chest compressions was greater than 30 minutes for 114 (77.5%). Sixty-one (41.5%) survived to 12 months, 32 (22.1%) survived to 12 months with Vineland Adaptive Behavior Scales, Second Edition, decreased by less than or equal to 15 points from baseline, and 39 (30.5%) survived to 12 months with Vineland Adaptive Behavior Scales, Second Edition, greater than or equal to 70. On multivariable analyses, open-chest cardiac massage was independently associated with greater 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, decreased by less than or equal to 15 points and greater 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, greater than or equal to 70. Higher minimum postarrest lactate and preexisting gastrointestinal conditions were independently associated with lower 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, decreased by less than or equal to 15 points and lower 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, greater than or equal to 70. CONCLUSIONS: About one third of children survived with good neurobehavioral outcome 1 year after receiving extracorporeal cardiopulmonary resuscitation for in-hospital arrest. Open-chest cardiac massage and minimum postarrest lactate were associated with survival with good neurobehavioral outcome at 1 year. PMID- 30422862 TI - Prediction of Severe Maternal Outcome Among Pregnant and Puerperal Women in Obstetric ICU. AB - OBJECTIVE: World Health Organization recommends the use of maternal near miss as a tool to monitor and improve quality of obstetric care. Severe maternal outcome corresponds to the sum of maternal near miss and maternal death cases. This study was aimed at validating Acute Physiology and Chronic Health Evaluation II and IV, Simplified Acute Physiology Score III, and Sequential Organ Failure Assessment in pregnant and postpartum women in predicting severe maternal outcome. DESIGN: A retrospective cohort study. SETTING: Obstetric ICU in a tertiary care hospital in Brazil. PATIENTS: Pregnant and postpartum women admitted to the obstetric ICU during a 3-year period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 279 women were admitted to ICU, an admission rate of 34.6/1,000 live births, and the mortality index to severe maternal outcome (maternal death/maternal near miss + maternal death) was 7.7%. Total Sequential Organ Failure Assessment had a better overall performance than remaining scores for total hospitalizations (area under the curve, 0.86; standardized mortality ratio, 0.96; 95% CI, 0.74-1.22), for hypertensive direct causes (area under the curve, 0.81; standardized mortality ratio, 0.73; 95% CI, 0.31-1.43), and indirect causes (area under the curve, 0.89; standardized mortality ratio, 0.85; 95% CI, 0.59 1.19). The Acute Physiology and Chronic Health Evaluation II had a better overall performance than total Sequential Organ Failure Assessment for hemorrhagic causes (area under the curve, 0.75; standardized mortality ratio, 1.0; 95% CI, 0.61 1.54). CONCLUSIONS: Total Sequential Organ Failure Assessment may be used to predict severe maternal outcome in obstetric populations admitted to ICU. The Acute Physiology and Chronic Health Evaluation II may be applied to predict severe maternal outcome in hemorrhagic complications. We do not recommend Acute Physiology and Chronic Health Evaluation IV and Simplified Acute Physiology Score III for the prediction of severe maternal outcome. PMID- 30422864 TI - "Ghost DMEK" Technique: Circular Peripheral Staining of Descemet's Membrane Endothelial Keratoplasty Grafts. AB - PURPOSE: To describe the ghost Descemet's membrane endothelial keratoplasty (DMEK) technique that allows for real-time evaluation of DMEK graft orientation, location, and folding status within the anterior chamber, by simple observation at the surgical microscope. METHODS: This is a retrospective case series done in a university hospital. The study included 10 patients who underwent ghost DMEK surgery because of corneal endothelial insufficiency for Fuchs' endothelial dystrophy (N = 5), pseudophakic bullous keratopathy (N = 2), and failed previous posterior lamellar keratoplasty (N = 3). Cases were reviewed for feasibility of graft preparation, intra- and postoperative complications, postoperative clearing of the cornea, corrected distance visual acuity, and endothelial cell loss. RESULTS: All graft preparations were uneventful. The circular staining was readily apparent and did not fade away during surgery. Graft orientation and folding status were determined using only direct observation through the operating microscope. Complications included one intraoperative hyphema, one graft detachment requiring rebubbling, and one pupillary block on the first postoperative day, which was resolved surgically. At last visit, 8 of 10 eyes had visual acuity of 6/12 or better and 7 of 10 eyes had visual acuity of 6/8.5 or better. Mean cell loss rates 1 to 3 months postoperatively were 48% +/- 17% (range, 22%-71%). All corneas were clear by the first to second postoperative month. Mean follow-up time was 3 months (range, 1-8 months). CONCLUSIONS: Peripheral staining of DMEK grafts (ghost DMEK) is a simple and effective method for graft visualization in the anterior chamber, obviating the need for trypan blue staining and other techniques and devices currently used for the identification of graft orientation and folding status, thus simplifying and shortening surgery. PMID- 30422865 TI - Microbiological Evaluation of Bandage Soft Contact Lenses Used in Management of Persistent Corneal Epithelial Defects. AB - PURPOSE: To investigate the rate and agents of contamination in bandage soft contact lenses fitted for management of persistent corneal epithelial defects. METHODS: This prospective comparative case series enrolled 57 consecutive eyes fitted with bandage contact lenses for treatment of persistent corneal epithelial defects. The lenses were collected at the time of epithelial closure or when it was necessary to exchange contact lenses and were immediately placed in sterile tubes containing an enriched thioglycolate liquid medium. When contamination of the contact lens was detected, the microorganism was cultured in different media and identified based on various tests. All isolates were tested for susceptibility to various antibiotics. Univariate analyses were used to evaluate the influence of different variables (duration of contact lens use, use of topical corticosteroids, presence of blepharitis, contact lens deposits, and presence of sutures) on bandage contact lens contamination. RESULTS: Seventeen of the contact lenses (29.8%) were contaminated. The most commonly isolated pathogen was Staphylococcus epidermidis (n = 10), followed by Enterobacter cloacae (n = 3), Staphylococcus aureus (n = 1), Streptococcus viridans (n = 1), and Alcaligenes spp. (n = 1). One contact lens yielded a mixed infection with E. cloacae and Candida spp. Infectious keratitis was not observed in any eyes. Correlations between contact lens contamination and patient- and lens-related variables were not statistically significant. CONCLUSIONS: Most bandage contact lenses (70.2%) used for treatment of persistent corneal epithelial defects did not show bacterial growth. Staphylococcus epidermidis was the most common microorganism isolated from the contaminated contact lenses. PMID- 30422863 TI - Models of Peer Support to Remediate Post-Intensive Care Syndrome: A Report Developed by the Society of Critical Care Medicine Thrive International Peer Support Collaborative. AB - OBJECTIVES: Patients and caregivers can experience a range of physical, psychologic, and cognitive problems following critical care discharge. The use of peer support has been proposed as an innovative support mechanism. DESIGN: We sought to identify technical, safety, and procedural aspects of existing operational models of peer support, among the Society of Critical Care Medicine Thrive Peer Support Collaborative. We also sought to categorize key distinctions between these models and elucidate barriers and facilitators to implementation. SUBJECTS AND SETTING: Seventeen Thrive sites from the United States, United Kingdom, and Australia were represented by a range of healthcare professionals. MEASUREMENTS AND MAIN RESULTS: Via an iterative process of in-person and email/conference calls, members of the Collaborative defined the key areas on which peer support models could be defined and compared, collected detailed self reports from all sites, reviewed the information, and identified clusters of models. Barriers and challenges to implementation of peer support models were also documented. Within the Thrive Collaborative, six general models of peer support were identified: community based, psychologist-led outpatient, models based within ICU follow-up clinics, online, groups based within ICU, and peer mentor models. The most common barriers to implementation were recruitment to groups, personnel input and training, sustainability and funding, risk management, and measuring success. CONCLUSIONS: A number of different models of peer support are currently being developed to help patients and families recover and grow in the postcritical care setting. PMID- 30422866 TI - Efficacy of Luliconazole Against Broad-Range Filamentous Fungi Including Fusarium solani Species Complex Causing Fungal Keratitis. AB - PURPOSE: Fungal keratitis can be difficult to medically treat. Topical antifungals are usually applied empirically as the initial option in treating fungal keratitis. Natamycin (NAT) and/or voriconazole (VRCZ) have been widely used in the treatment of fungal keratitis. However, Fusarium solani species complex (FSSC), which are the dominant species of fungal keratitis, are resistant to VRCZ. This study investigated in vitro efficacy of luliconazole (LLCZ), a new imidazole antifungal, against FSSC and other filamentous fungi. METHODS: A total of 18 Fusarium isolates and 7 others were grown on potato dextrose agar at 30 and 37 degrees C. For Fusarium, species identification and phylogenetic tree analysis were performed based on elongation factor-1alpha (EF-1alpha) DNA sequencing. The broth microdilution method was used for antifungal susceptibility testing of 11 antifungal drugs including LLCZ. RESULTS: The 18 identified Fusarium isolates belonged to FSSC (n = 13), Fusarium oxysporum species complex (FOSC; n = 2), Fusarium chlamydosporum species complex (FCSC; n = 1), Fusarium incarnatum equiseti species complex (FIESC; n = 1), and Fusarium fujikuroi species complex (FFSC; n = 1). We further divided 13 FSSC isolates into 3 clades, FSSC5 (n = 8), FSSC3 + 4 (n = 4), and FSSC9-a (n = 1), with 8 FSSC strains growing at 37 degrees C. LLCZ showed lowest minimum inhibitory concentrations (MICs) against all tested filamentous fungi, with a MIC90 against the Fusarium species of 0.06 MUg/mL, whereas MIC90 for NAT and VRCZ were 4 and 8 MUg/mL, respectively. CONCLUSIONS: LLCZ has the strongest in vitro antifungal activity among all drugs used against broad-range filamentous fungi including FSSC. LLCZ may potentially be a new medical treatment option for fungal keratitis.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30422867 TI - Reply. PMID- 30422868 TI - Dose-dependent effect of propranolol on the hemodynamic response in cirrhotic patients with gastroesophageal varices. AB - OBJECTIVE: Propranolol is always titrated to the maximum tolerated dose to prevent gastroesophageal variceal bleeding. However, some patients do not achieve a hemodynamic response and experience more intolerance and discontinuation. This study evaluated the dose-dependent effect of propranolol on hemodynamic response and tolerance in cirrhotic patients. PATIENTS AND METHODS: This retrospective study included 95 consecutive patients recruited from our prospective database. After hepatic venous pressure gradient measurement, patients received propranolol 10 mg, twice daily increased 10 mg daily until to 80 or 120 mg/day. Secondary hepatic venous pressure gradient was also measured. For nonresponders at 80 mg/day, propranolol was titrated to 120 mg/day. RESULTS: For 58 patients, propranolol was titrated to 80 mg/day, whereas for 37 patients, it was titrated to 120 mg/day. Hemodynamic response was similar in both groups (50 vs. 54.1%, P=0.700). Eighteen of the 29 nonresponders at propranolol 80 mg/day received a dose of 120 mg/day. Two patients achieved a hemodynamic response, but two could not tolerate the dose. Nine (15.5%) patients achieved the target dose of propranolol at 80 mg/day, whereas 16 (43.2%) patients at 120 mg/day achieved this (P=0.003). The difference in patients achieving the target dose between responders and nonresponders was not significant (14 vs. 14, P=0.642). Reduction or discontinuation was required by two (6.9%) patients using 80 mg/day propranolol and six (30%) patients using 120 mg/day propranolol (P=0.032). CONCLUSION: There is no dose-dependent effect of 80-120 mg/day of propranolol on the hemodynamic response in cirrhotic patients with gastroesophageal varices. This indicates that low-dose propranolol below the target dose might lead to a considerable hemodynamic response and is much safer and well tolerated.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/. PMID- 30422869 TI - Decitabine attenuates nociceptive behavior in a murine model of bone cancer pain. AB - Bone cancer metastasis is extremely painful and decreases the quality of life of the affected patients. Available pharmacological treatments are not able to sufficiently ameliorate the pain and as cancer patients are living longer new treatments for pain management are needed. Decitabine (5-aza-2'-deoxycytidine), a DNA methyltransferases inhibitor, has analgesic properties in pre-clinical models of post-surgical and soft tissue oral cancer pain by inducing an up-regulation of endogenous opioids. In this study, we report that daily treatment with decitabine (2ug/g, i.p.) attenuated nociceptive behavior in the 4T1-luc2 mouse model of bone cancer pain. We hypothesized that the analgesic mechanism of decitabine involved activation of the endogenous opioid system through demethylation and reexpression of the transcriptionally silenced endothelin B receptor gene, Ednrb. Indeed, Ednrb was hypermethylated and transcriptionally silenced in the mouse model of bone cancer pain. We demonstrated that expression of Ednrb in the cancer cells lead to release of beta-endorphin in the cell supernatant which reduced the number of responsive DRG neurons in an opioid-dependent manner. Our study supports a role of demethylating drugs, such as decitabine, as unique pharmacological agents targeting the pain in the cancer microenvironment. PMID- 30422870 TI - Distinct functions of soluble guanylyl cyclase isoforms NO-GC1 and NO-GC2 in inflammatory and neuropathic pain processing. AB - A large body of evidence indicates that nitric oxide (NO)/cGMP signaling essentially contributes to the processing of chronic pain. In general, NO-induced cGMP formation is catalyzed by two isoforms of guanylyl cyclase, NO-sensitive guanylyl cyclase 1 (NO-GC1) and 2 (NO-GC2). However, the specific functions of the two isoforms in pain processing remain elusive. Here we investigated the distribution of NO-GC1 and NO-GC2 in the spinal cord and dorsal root ganglia, and we characterized the behavior of mice lacking either isoform in animal models of pain. Using immunohistochemistry and in situ hybridization we demonstrate that both isoforms are localized to interneurons in the spinal dorsal horn with NO-GC1 being enriched in inhibitory interneurons. In dorsal root ganglia, the distribution of NO-GC1 and NO-GC2 is restricted to non-neuronal cells with NO-GC2 being the major isoform in satellite glial cells. Mice lacking NO-GC1 demonstrated reduced hypersensitivity in models of neuropathic pain, whereas their behavior in models of inflammatory pain was normal. In contrast, mice lacking NO-GC2 exhibited increased hypersensitivity in models of inflammatory pain, but their neuropathic pain behavior was unaltered. Cre-mediated deletion of NO-GC1 or NO-GC2 in spinal dorsal horn neurons recapitulated the behavioral phenotypes observed in the global knockout. Together, these results indicate that cGMP produced by NO-GC1 or NO-GC2 in spinal dorsal horn neurons exert distinct, and partly opposing, functions in chronic pain processing. PMID- 30422871 TI - Preferred self-administered questionnaires to assess fear of movement, coping, self-efficacy and catastrophizing in patients with musculoskeletal pain - A modified Delphi study. AB - The way people with musculoskeletal disorders deal with pain influences their prognosis. Psychosocial factors that influence outcomes include fear of movement, coping, self-efficacy and catastrophizing. A three-round modified Delphi study was conducted with the aim to reach consensus on the most appropriate questionnaires to assess these four psychosocial factors in patients at risk of developing persistent musculoskeletal pain. The panel consisted of 36 experts, with track records in medicine, psychology and allied health. To be considered an expert, a minimum number of authorships was required on research papers using self-administered questionnaires to assess these psychosocial factors in relevant patient populations. In Round 1, the experts proposed 30 questionnaires to assess the four factors. In Round 2, experts rated the questionnaires on suitability, considering clinimetric properties, content, feasibility, personal experiences and expertise. The highest ranked questionnaires (maximally five per factor) were retained for Round 3, in which the experts made a final assessment of the questionnaires, and provided their positive and negative experiences with the questionnaires. Consensus was reached for the following questionnaires to assess (1) fear of movement: Fear Avoidance Beliefs Questionnaire and Tampa Scale (full version or 11-item version); (2) coping: Coping Strategies Questionnaire (initial or revised version) and Chronic Pain Coping Index; (3) self-efficacy: Pain Self Efficacy Questionnaire (full version or 2-item version); and (4) catastrophizing: Pain Catastrophizing Scale and the revised version of the Coping Strategies Questionnaire. Although other questionnaires can be considered in specific circumstances, these questionnaires are recommended in people with musculoskeletal pain. PMID- 30422872 TI - Behavioural discrimination of noxious stimuli in infants is dependent on brain maturation. AB - Changes in facial expression are an essential form of social communication, and in non-verbal infants are often used to alert care providers to pain-related distress. However, studies of early human brain development suggest that premature infants aged less than 34 weeks' gestation do not display discriminative brain activity patterns to equally salient noxious and innocuous events. Here we examine the development of facial expression in 105 infants, aged between 28 and 42 weeks' gestation. We show that the presence of facial expression change following noxious and innocuous stimulation is age-dependent and that discriminative facial expressions emerge from approximately 33 weeks' gestation. In a subset of 49 infants, we also recorded electroencephalographic (EEG) brain activity and demonstrate that the temporal emergence of facial discrimination mirrors the developmental profile of the brain's ability to generate discriminative responses. Furthermore, within individual infants, the ability to display discriminative facial expressions is significantly related to brain response maturity. This data demonstrates that the emergence of behavioural discrimination in early human life corresponds to our brain's ability to discriminate noxious and innocuous events and raises fundamental questions as to how best to interpret infant behaviours when measuring and treating pain in premature infants. PMID- 30422873 TI - It's not how you feel, it's what you know. PMID- 30422874 TI - Human trafficking: How nurse practitioners can help end modern-day slavery. AB - Nurse practitioners can be a powerful frontline force by collectively raising awareness of human trafficking (HT) through education; advocating for policy change at the local/state/federal level, providing primary prevention for contributory risk factors; and building a strong HT prevention program with the Social-Ecological Model. Together, NPs can lead through practice, education, advocacy, and research to promote optimal health outcomes and to end human trafficking. PMID- 30422875 TI - Hypophosphatasia: A rare disorder. AB - Hypophosphatasia is a rare, progressive metabolic disorder inherited in either an autosomal dominant or an autosomal recessive fashion. Affected individuals may have unusual bone development. Infants may be diagnosed with infantile rickets. Symptoms then abate during adolescence, with bony abnormalities manifesting again as mid-life osteopenia or osteoporosis. Long-term management is focused on minimizing complications, so consultations and periodic visits with a variety of specialists is often warranted. New therapies are on the horizon, but some agents used to treat bone diseases are contraindicated in this population. At-risk relatives should be referred to genetic professionals to determine mode of inheritance and discuss options. PMID- 30422877 TI - I serve 2: Identifying and caring for military-connected children in civilian primary care settings. PMID- 30422876 TI - Competencies for dermatology nurse practitioners. AB - The number of nurse practitioners (NPs) specializing in dermatology has been rapidly rising. Most dermatology NPs acquire their knowledge and skills through post-master's continuing education, select NP fellowship programs, and on-the-job training. However, the professional competencies for dermatology NPs have not been defined or standardized. Competencies require unique knowledge, skills, and judgment for the care of dermatology patients. A national task force and validation panel was convened to define the entry-level competencies for dermatology NP practice. PMID- 30422878 TI - Leveraging health care reform to accelerate nurse practitioner full practice authority: Corrigendum. PMID- 30422879 TI - Strategies for Mentoring Diverse Students. PMID- 30422880 TI - Stathmin is a potential therapeutic target but not a prognostic marker in melanoma: an immunohistochemical study of 323 melanocytic lesions. AB - In several solid tumors, an increased stathmin expression is associated with both poor prognosis and resistance to certain chemotherapy types. However, the data regarding melanocytic lesions are very limited. The goals of our study are as follows: the assessment of stathmin expression in benign and malignant melanocytic lesions, and the significance of its expression for the differential diagnostics between benign and malignant lesions; the analysis of the prognostic significance of stathmin expression in melanoma; and the evaluation of stathmin expression in melanoma and melanoma metastases with respect to possible therapeutic targeting. Immunohistochemical analysis of stathmin expression was done in 323 melanocytic lesions, including 205 primary cutaneous melanomas, 60 melanoma metastases, and 58 melanocytic nevi. Stathmin expression was found in all analyzed groups of melanocytic lesions. Using the H-scoring system, the observed intensity of expression was as follows: melanocytic nevi: 146.1 (mean) and 150 (median); melanomas: 116.7 (mean) and 110 (median); and melanoma metastases: 136.8 (mean) and 140 (median). The stathmin expression was significantly lower in the cohort of primary melanomas when compared with metastases and nevi (P=0.001). The stathmin expression showed no prognostic significance. The high stathmin expression in melanoma suggests that stathmin might be a promising marker for therapeutic targeting in ongoing clinical trials. Compared with several other solid tumors, stathmin expression in melanoma showed no prognostic significance. The potential use of stathmin expression in differential diagnostics is limited by its common expression, and despite the statistically significant differences between nevi and melanoma, it may not be used in this setting. PMID- 30422882 TI - North American Contact Dermatitis Group Patch Test Results: 2015-2016. AB - BACKGROUND: Patch testing is an important diagnostic tool for the assessment of allergic contact dermatitis (ACD). OBJECTIVE: This study documents the North American Contact Dermatitis Group (NACDG) patch testing results from January 1, 2015, to February 28, 2017. METHODS: At 13 centers in North America, patients were tested in a standardized manner with a screening series of 70 allergens. Data were manually verified and entered into a central database. Descriptive frequencies were calculated, and trends were analyzed using chi test. RESULTS: A total of 5597 patients were tested. There were 3725 patients (66.6%) who had at least 1 positive reaction, and 2798 patients (50.2%) were ultimately determined to have a primary diagnosis of ACD. A total of 572 patients (10.2%) had occupationally related skin disease. There were 10,983 positive allergic reactions. Nickel remained the most commonly detected allergen (17.5%). Methylisothiazolinone, which was added to the screening series for the 2013-2014 cycle, had the second highest positive reaction rate of allergens tested (13.4%). Compared with the previous reporting periods (2013-2014) and (2005-2014), positive reaction rates for the top 35 screening allergens statistically increased for only 1 allergen: hydroxyethyl methacrylate (3.4%; risk ratios, 1.24 [confidence interval, 1.00-1.54] and 1.46 [confidence interval, 1.23-1.73]). Three newly added allergen preparations-ammonium persulfate (1.7%), chlorhexidine (0.8%), and hydroquinone (0.3%)-all had a reaction rate of less than 2%. Twenty three percent of the tested patients had at least 1 relevant allergic reaction to an allergen not on the NACDG series; 12% of these were occupationally related. T.R.U.E. Test (SmartPractice Denmark, Hillerod, Denmark) would have hypothetically missed one quarter to almost 40% of reactions detected by the NACDG screening series. CONCLUSIONS: These results confirm that the epidemic of sensitivity to methylisothiazolinone has continued in North America. Patch testing with allergens beyond a screening tray is necessary for a complete evaluation of occupational and nonoccupational ACD. PMID- 30422883 TI - Trends in Patch Testing With the Mayo Clinic Standard Series, 2011-2015. AB - BACKGROUND: Patch testing to a standard (baseline) series of allergens is the screening tool used to identify culprit allergens in patients with contact dermatitis. The allergens and concentrations used in a standard series are constantly evolving to be most relevant to the patients being patch tested. OBJECTIVE: The aim of this study was to analyze the 2011-2015 patch test results of the Mayo Clinic standard series. METHODS: We retrospectively reviewed patch test reactions of standard series allergens from 2011 through 2015 and compared these results with the 2011-2012 and 2013-2014 North American Contact Dermatitis Group (NACDG) reports. CONCLUSIONS: Of 2582 patients included, 1566 (60.7%) had at least 1 positive reaction, and 516 (20.0%) had at least 1 irritant reaction. The 15 allergens with the highest reaction rates (from highest to lowest) were nickel sulfate hexahydrate, methylisothiazolinone, Myroxylon pereirae resin, neomycin sulfate, cobalt (II) chloride hexahydrate, benzalkonium chloride, fragrance mix I, potassium dichromate, bacitracin, methylchloroisothiazolinone/methylisothiazolinone, carba mix, formaldehyde, p phenylenediamine, quaternium-15, and methyldibromo glutaronitrile. Twelve (80%) of these allergens were also in the top 15 of the most recent NACDG report; the 3 allergens not in the NACDG top 15 allergens were potassium dichromate, benzalkonium chloride, and methyldibromo glutaronitrile (the latter 2 allergens are not included in their series). PMID- 30422884 TI - Associations of Nickel Co-Reactions and Metal Polysensitization in Adults. AB - BACKGROUND: Allergic contact dermatitis to metals is a significant clinical and public health problem. Little is known about the determinants of polysensitization to metals. OBJECTIVE: The aim of the study was to determine the frequency and predictors of nickel co-reactions and metal polysensitization. METHODS: This is a retrospective chart review of 686 adults (age >= 18 years) who were patch tested from 2014 to 2017. RESULTS: Overall, 267 patients (38.9%) had 1 or more positive patch-test reactions to a metal allergen, most commonly nickel (17.4%), mercury (12.3%), and palladium (9.2%). Nickel reactions were inversely associated with age (logistic regression; adjusted odds ratio [95% confidence interval], 0.39 [0.29-0.78]). Among patients with positive reactions to nickel, 34.5%, 15.1%, and 5.0% had positive reactions to 1, 2, or 3 additional metals, respectively. The most common nickel co-reactors were palladium, mercury, and gold. Polysensitization to metals occurred in 11.8% of patients. Polysensitization to metal allergens was associated with female sex (6.67 [1.01 44.21]) and inversely associated with age (0.40 [0.18-0.88]). CONCLUSIONS: Nickel sensitized patients have high rates of metal co-reactions. Polysensitization to metals is common in adults. These results may help guide future strategies for allergen avoidance. PMID- 30422885 TI - Comparison of Nickel Sulfate 2.5% and Nickel Sulfate 5% for Detecting Nickel Contact Allergy. AB - BACKGROUND: Nickel is among the most common contact allergens found on patch testing worldwide and, because of its ubiquitous nature in our environment, often has important implications for allergen avoidance strategies. In both North America and Europe, nickel positivity is found in approximately 20% of patients who undergo patch testing. Whereas in North America, nickel sulfate is typically tested at a concentration of 2.5%, in Europe, it is tested at a 5% concentration. OBJECTIVE: The primary objective was to assess the differences in patch test positivity to nickel sulfate 2.5% and 5%. METHODS: We investigated 205 consecutive patients between September 2017 and February 2018 who were tested to nickel sulfate at concentrations of both 2.5% and 5%. RESULTS: Among the 205 patients tested, 33% were positive (+, ++, or +++) to at least 1 concentration of nickel sulfate, 20% were positive to nickel sulfate 2.5%, and 31% were positive to nickel sulfate 5% (chi1(N = 205) = 16.1, P = 0.0001). Patients were 6.5 times more likely to have a positive reaction to nickel sulfate 5% than 2.5% (odds ratio 95% confidence interval, 2.3-25.6). CONCLUSIONS: Given our findings, we propose an additional evaluation of nickel sulfate 5% as a standard allergen for patch testing in North America. PMID- 30422886 TI - Skin Sensitization Induction Potential From Daily Exposure to Fragrances in Personal Care Products. AB - BACKGROUND: Many chemicals used for fragrance purposes in a diversity of products have allergenic potential. Based on such concerns, industry groups developed concentration limits for use of fragrance chemicals in personal care and cosmetic products. OBJECTIVE: The aim of this study was to use a quantitative risk assessment to evaluate the potential for skin sensitization induction resulting from daily exposure to fragrance chemicals present in personal care and cosmetic products. METHODS: Product-specific dermal consumer exposure levels were calculated based on product use data in US adult females and benchmarked against acceptable exposure levels based on reported no expected sensitization induction levels to determine a margin of safety for each fragrance under evaluation. CONCLUSIONS: The results demonstrate an increased risk of skin sensitization induction for several leave-on products (lipstick, solid antiperspirant, eye shadow, face cream) for most of the evaluated fragrance chemicals, particularly under high-use exposure scenarios. In contrast, rinse-off products (shampoo, conditioner, facial cleanser) were not associated with risk of skin sensitization induction. Because the approach was based on maximum use limits for fragrance chemicals with skin sensitization concerns, the results suggest these limits may not be protective, particularly in the United States. PMID- 30422887 TI - Cannabidiol-Induced Acute Generalized Exanthematous Pustulosis. PMID- 30422888 TI - Investigating the Effect of Demographics, Clinical Characteristics, and Polymorphism of MDR-1, CYP1A2, CYP3A4, and CYP3A5 on Clopidogrel Resistance. AB - Clopidogrel is an antiplatelet agent that is indicated for cardiovascular emergencies and procedures. The drug, however, is subject to response variability leading to therapy resistance. In this research, we explored the demographic, clinical, and genetic factors associated with clopidogrel resistance. Data analysis among our 280 subjects receiving clopidogrel showed some risk factors that are significantly associated with clopidogrel resistance compared with responders. Those were: female sex (P = 0.021), advanced age (P = 0.011), obesity (P = 0.002), and higher body mass index (P = 0.008) and higher platelets count (P = 0.002). However, known polymorphisms of MDR-1, CYP1A2, CYP3A4, and CYP3A5 were not associated with treatment resistance when compared to responders to clopidogrel therapy. Knowledge about such risk factors might provide recommendation in the future about starting doses or monitoring recommendations. PMID- 30422889 TI - Combined Antihypertensive Therapies That Increase Expression of Cardioprotective Biomarkers Associated With the Renin-Angiotensin and Kallikrein-Kinin Systems. AB - Antihypertensive pharmacological treatments focus on the use of angiotensin converting enzyme (ACE) inhibitors, AT1 receptor antagonists, and beta-blockers as single and combined treatments. The effect of single treatments on the mRNA expression of some components of the renin-angiotensin system has been studied, but not the effect of combined treatments. This study determined the expression of the AT1, AT2, B1, and B2 receptors and of the enzymes ACE and ACE2 in hypertensive rats treated with captopril-propranolol or losartan-propranolol. Methods: The mRNA expression of the receptors and enzymes was determined by reverse transcription-quantitative polymerase chain reaction in the aorta of spontaneously hypertensive rats under different treatments. Results: Rats under combined treatments showed a decrease in the expression of AT1 and ACE, and an increase in the expression of the B1 receptor (captopril + propranolol group: 0.43 +/- 0.046, 2.243 +/- 0.269, 3.356 +/- 0.418; Group: losartan + propranolol: 0.727 +/- 0.071, 0.852 +/- 0.102, 1.277 +/- 0.131 compared to the spontaneously hypertensive group: 1 +/- 0.212, 1 +/- 0.192, 1 +/- 0.214). This decrease in the expression of ACE and AT1 suggests a reduction in the expression of Ang II that could be related to a lower response to this vasoconstrictor. An increase in the expression of B1 would improve vasodilation, which would be a beneficial effect of combined therapies for hypertension. PMID- 30422890 TI - An Orally Available NLRP3 Inflammasome Inhibitor Prevents Western Diet-Induced Cardiac Dysfunction in Mice. AB - BACKGROUND: A diet rich in saturated fat and sugars (Western diet, WD) induces myocardial expression of the NLRP3 inflammasome and dysfunction in mice. We therefore hypothesized that a diet enriched with an orally available NLRP3 inflammasome inhibitor could prevent WD-induced cardiac dysfunction in mice. METHODS: Ten-week-old CD-1 male mice were fed WD or standard diet (SD) for 8 weeks. The compound 16673-34-0, an orally active NLRP3 inhibitor, was added to the diet at a concentration of 100 mg/Kg. The plasmatic levels of the NLRP3 inflammasome inhibitor were measured. Food intake, body weight, and glucose tolerance were assessed. Cardiac systolic and diastolic functions were measured by Doppler echocardiography at baseline, 4 weeks, and 8 weeks. RESULTS: WD induced a significant increase in body weight (+14%, P = 0.02), impaired glucose tolerance (+34%, P = 0.03), and a significant increase in isovolumetric relaxation time (+129%, P = 0.03) and reduction in left ventricular ejection fraction (-10%, P = 0.03), as compared to standard chow diet (SD). The treatment with NLRP3 inhibitor in the diet prevented cardiac systolic and diastolic dysfunction (P < 0.05 for left ventricular ejection fraction, isovolumetric relaxation time, and myocardial performance index in WD with drug vs. WD without drug), without significant changes in heart rate and metabolic parameters. CONCLUSIONS: An orally available NLRP3 inhibitor prevented WD-induced cardiac dysfunction in obese mice. PMID- 30422892 TI - Detection of putative functional SNPs in blood pressure loci and validation of association between SNP in WBP1L and hypertension in the Chinese Han population. AB - We have performed a gene-based association study and detected several important blood pressure (BP)-associated genes. In this study we explored functional variants in these genes by bioinformatics analysis and validated the associations between the functional SNPs and hypertension with public data and our in-house data of 857 cases and 927 controls. We found various functional variants in the BP-associated genes, including missense mutations, phosphorylation-related SNPs. Most of these SNPs were associated with expressions of the local genes. Some of these SNPs were associated with coronary artery disease or ischemic stroke. The associations between 12 functional SNPs in 7 genes and BP were validated (P < 5 * 10). The intronic SNP rs176185, which may influence promoter histone, enhancer histone, DNase and regulatory motifs and showed cis-eQTL effect on WBP1L, was associated with hypertension in the Chinese Han population (P = 0.0119). Our study detected plenty of potential functional SNPs in the BP-associated genes and demonstrated that rs176185 may be associated with hypertension in the Chinese Han population. PMID- 30422891 TI - Mitochondrial Dysfunction and Apoptosis are Attenuated upon kappa-Opioid Receptor Activation via AMPK/GSK-3beta Pathway Following Myocardial Ischemia and Reperfusion. AB - Previous studies have shown that kappa-opioid receptor activation possesses cardioprotection against myocardial ischemia and reperfusion (MI/R) injury. The current study was designed to investigate whether mitochondrial dysfunction following MI/R is regulated by the kappa-opioid receptor and to further explore the underlying mechanisms involved. MI/R rat model was established in vivo, and a hypoxia and reoxygenation cardiomyocytes model was utilized in vitro. Mitochondrial morphology and function, as well as myocardial apoptosis were determined. Our data indicated that treatment with U50,488H (a selective kappa opioid receptor agonist) not only reduced apoptosis but also significantly improved mitochondrial morphology and function. These effects were blocked by nor binaltorphimine (nor-BNI, a selective kappa-opioid receptor antagonist), Compound C (an AMPK inhibitor), and AR-A014418 (a GSK3beta inhibitor). Moreover, in cardiomyocytes, treatment with U50,488H significantly increased the expression in phosphorylation of AMPK and the phosphorylation of GSK3beta. Treatment of cardiomyocytes with AMPKalpha siRNA decreased the phosphorylation of AMPK and GSK3beta. Moreover, AMPK activation resulted in the phosphorylation of GSK3beta. Our findings suggested that U50,488H exerted cardioprotective effects by improving mitochondrial morphology and function against MI/R injury through activation of the kappa-opioid receptor-mediated AMPK/GSK3beta pathway. PMID- 30422893 TI - Late phases of cardioprotection during remote ischemic preconditioning and adenosine preconditioning involves activation of neurogenic pathway. AB - BACKGROUND: The role of neurogenic pathway in early phases of cardioprotection during remote ischemic preconditioning (RIPC) and adenosine preconditioning is reported AIM:: The present study was designed to explore the involvement of neurogenic pathway in late phases of cardioprotection during RIPC and adenosine preconditioning. MATERIAL ANDMETHODS: Fifty four Wistar rats were employed and divided into nine experimental groups. RIPC was induced by tying the blood pressure cuff around the hind limb and subjecting to four cycles of inflation and deflation of 5 minutes each. In early RIPC, the heart was isolated immediately after last episode of RIPC; while in late RIPC, heart was isolated 24 h after last cycle of RIPC. In a similar way, adenosine preconditioning was instituted in early and late phases by either isolating the heart forty minutes or 24 hours after adenosine (4 mg/kg, i.p.) administration. Isolated hearts were subjected to ischemia-reperfusion (I/R) injury on the Langendorff's system RESULTS:: Both early and late phases of RIPC and adenosine preconditioning significantly abrogated I/R-induced myocardial injury in terms of decrease in the release of lactate dehydrogenase (LDH), creatine kinase (CK) and decrease in infarct size. Pretreatment with hexamethonium, a ganglion blocker (20 mg/kg, i.p.), significantly abolished the cardioprotective effects of both early and late phases of RIPC and adenosine preconditioning CONCLUSION:: Apart from the involvement of neurogenic pathway in the early phases, there is a critical role of neurogenic pathway in late phase of cardioprotection during RIPC and adenosssssine preconditioning. PMID- 30422894 TI - Targeting lipid mediators in asthma: time for reappraisal. AB - PURPOSE OF REVIEW: In the past decades, cysteinyl leukotrienes (CysLTs) and prostaglandin D2 have been recognized as key mediators of asthma and comorbid conditions for their potent broncho-active and proinflammatory properties. However, both the development and initial positioning of small molecules targeting these lipid mediators [i.e., leukotriene-synthesis inhibitors, CysLT antagonists, and chemoattractant receptor homologous molecule on T-helper2-cells (CRTH2) antagonists] experienced drawbacks by lacking adequate biomarkers to define potential responders. RECENT FINDINGS: New insights into the mechanisms of airway inflammation in asthma including the interaction of leukotrienes and prostanoids has uncovered potential therapeutic targets. Emerging application of biomarkers in more recent clinical studies helped identify responders to therapies targeting lipid mediators and demonstrated their clinical efficacy in distinct asthma phenotypes and endotypes. SUMMARY: Interest in small molecules targeting lipid mediators in asthma and related conditions is emerging. Several clinical trials evaluating the efficacy and safety of CRTH2 (Prostaglandin D2 receptor 2) antagonists are ongoing. There is an urgent need for sensitive biomarkers to identify responders to such therapies and for monitoring of (long term) effects. Furthermore, evaluation of effectiveness of combining different agents targeting lipid mediators or combining them with available or emerging biologics may uncover other potential benefits in certain asthma populations warranting future research. PMID- 30422895 TI - New insights in neutrophilic asthma. AB - PURPOSE OF REVIEW: Recent advances in both murine models and clinical research of neutrophilic asthma are improving our understanding on the etiology and pathophysiology of this enigmatic endotype of asthma. We here aim at providing an overview of our current and latest insights on the pathophysiology and treatment of neutrophilic asthma. RECENT FINDINGS: Activation of the NLRP3 inflammasome pathway with increased IL-1beta has been demonstrated in various studies involving patients with asthma. It has been suggested that type 3 innate lymphoid cells are implicated in the inflammatory cascade leading to neutrophilic inflammation. The role of neutrophil extracellular traps is only at the start of being understood and might be an attractive novel therapeutic target. A diverse panel of nonallergic stimuli, such as cigarette smoke, intensive exercise, cold air or saturated fatty acids, have been linked with neutrophilic airway inflammation. Azithromycin treatment could reduce asthma exacerbations and quality of life in patients with persistent asthma. SUMMARY: Research of the last few years has accelerated our insights in mechanisms underlying neutrophilic asthma. This is in stark contrast with the lack of efficacy of different therapies targeting neutrophil chemotaxis and/or signalling cascade, such as IL 17A or CXCR2. Macrolide therapy might be a useful add-on therapy for patients with persistent asthma. PMID- 30422896 TI - Unravelling the complexity of tissue inflammation in uncontrolled and severe asthma. AB - PURPOSE OF REVIEW: The clinical and inflammatory heterogeneity in asthma constitutes a major challenge for improved treatment. This review describes the nature of the inflammatory complexity and how it can be decoded to yield improved disease understanding and personalized treatment. The focus is on the difficult task of revealing the immunological complexity as it occurs inside diseased patient tissues. RECENT FINDINGS: The inflammatory heterogeneity in asthma stretches beyond the classical division into allergic Th2 eosinophilic versus Th1 and/or Th17 neutrophilic (or paucigranulocytic) phenotypes. Rather than having one distinct type of inflammation, many patients display a patchwork of overlapping immune signatures. The patient diversity is further increased by differences in regard of distal lung involvement. Faced with this staggering complexity, calls have been made for a pragmatic biomarker-guided identification of treatable traits. In parallel, novel high-dimensional analyses and multiplex imaging aid the long-term goal of decoding the underlying molecular endotypes. SUMMARY: Asthma is vastly heterogeneous with multiple and superimposed inflammatory and anatomical phenotypes. Despite the intensive research and introduction of highly immune-selective dugs, basic questions remain; especially as still too many of today's uncontrolled patients remain poorly understood. Here, pragmatic biomarker strategies, combined with novel methodological approaches that ultimately reveal the complete immunological complexity, will pave the way for improved differential diagnosis and personalized medication. PMID- 30422897 TI - Strategies to prevent exacerbations of childhood asthma. AB - PURPOSE OF REVIEW: The goal of this review is to discuss strategies to prevent asthma exacerbations in children, focusing on recent advances in knowledge and understanding. RECENT FINDINGS: Asthma exacerbations are common, and their prevention is an important goal to avoid detrimental impacts such as loss of disease control and lung function and significant healthcare costs. A number of strategies have been studied as tools for prevention of asthma exacerbations. Daily inhaled corticosteroids (ICSs) are effective for many children with asthma. However, alternative strategies such as intermittent ICS therapy, antileukotrienes, and biologics have been studied as means to lessen corticosteroid exposure. Further, recent studies have examined add-on strategies for children not controlled with ICS alone. Finally, personalizing therapy with targeted approaches has provided significant benefit to those with moderate severe disease. SUMMARY: Recent research highlights many potentially effective treatment strategies to prevent asthma exacerbations in children. We have reviewed and summarized the data on treatment approaches to help provide a better understanding of the methods that can be utilized. An individualized approach with careful monitoring is essential to identify the most effective strategies to prevent asthma exacerbations in each child. PMID- 30422898 TI - Pituitary 18F-FDG uptake correlates with serum TSH levels in thyroid cancer patients on 18F-FDG PET/CT. AB - OBJECTIVE: The objective of this study was to evaluate the relationship between fluorine-18-fluorodeoxyglucose (F-FDG) uptake in the pituitary gland and serum thyroid-stimulating hormone (TSH) levels in differentiated thyroid cancer (DTC) patients on F-FDG PET/computed tomography (CT). PATIENTS AND METHODS: A total of 215 DTC patients and 215 age-paired and sex-paired healthy screening participants were included. DTC patients were divided into hypothyroid, euthyroid and subclinical hyperthyroid patients according to their serum TSH levels. The relationship between F-FDG uptake in the pituitary gland and serum TSH levels was evaluated the in DTC patients, and the pituitary F-FDG metabolism was compared in different thyroid status. RESULTS: The standardized uptake value of pituitary (SUVp) in all 430 patients was directly correlated with serum TSH levels (r=0.479 and 0.432, all P<0.05). The SUVp in DTC patients was higher than that in 215 healthy participants (z=-10.4, P<0.05). No significant difference of SUVp was observed between euthyroid patients and healthy participants (P=0.145). CONCLUSION: Our study established the positive correlation between pituitary F FDG uptake and serum TSH. TSH values should be measured in patients with incidental pituitary uptake during F-FDG PET/CT. L-T4 replacement for DTC patients may well have the same feedback on the thyroid-pituitary axis as the physiologic thyroid status. The diffuse F-FDG uptake with normal CT or MRI appearance of the pituitary in patients with DTC indicates physiologic uptake. PMID- 30422899 TI - Better outcomes among HIV-infected Rwandan children 18-60 months following the implementation of "treat all". AB - BACKGROUND: In 2012, Rwanda introduced a Treat All approach for HIV-infected children under age 5. We compared antiretroviral therapy (ART) initiation, outcomes, and retention, before and after this change. METHODS: We conducted a retrospective study of children enrolled into care between June 2009-December 2011 (Before Treat All cohort [BTA]) and between July 2012-April 2015 (Treat All cohort [TA]). SETTING: Medical records of a nationally representative sample were abstracted for all eligible aged 18-60 months from 100 Rwandan public health facilities. RESULTS: We abstracted 374 medical records: 227 in the BTA and 147 in the TA cohorts. Mean (SD) age at enrollment was (3 years [1.1]). Among BTA, 59% initiated ART within one year, vs. 89% in the TA cohort. Median time to ART initiation was 68 days (IQR 14-494) for BTA and 9 days (IQR 0-28) for TA (p<0.0001), with 9 (5%) undergoing same-day initiation in BTA compared to 50 (37%) in TA (p < 0.0001).Before ART initiation, 59% in the BTA reported at least one health condition compared to 35% in the TA cohort (p < 0.0001).While overall loss to follow-up (LTFU) was similar between cohorts (BTA: 13%, TA: 8%, p = 0.18), LTFU prior to ART was significantly higher in the BTA (8%) compared to the TA cohort (2%) (p = 0.02). CONCLUSIONS: Nearly 90% of Rwandan children started on ART within one year of enrollment; most within 1 month, with greater than 90% retention following implementation of TA. TA was also associated with fewer morbidities.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC ND) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30422900 TI - Efficacy and safety of tenofovir disoproxil fumarate versus low-dose stavudine over 96 weeks: a multi-country randomised, non-inferiority trial. AB - BACKGROUND: Reducing doses of antiretroviral drugs, including stavudine (d4T), may lower toxicity, while preserving efficacy. There are substantial concerns about renal and bone toxicities of tenofovir disoproxil fumarate (TDF). SETTING: HIV-1-infected treatment-naive adults in India, South Africa and Uganda METHODS: A phase-4, 96-week, randomized, double-blind, non-inferiority trial compared d4T 20mg BD and TDF, taken in combination with lamivudine (3TC) and efavirenz (EFV). The primary endpoint was the proportion of participants with HIV-1 RNA <50 copies/ml at 48 weeks. Adverse events assessments included measures of bone density and body fat. The trial is registered on Clinicaltrials.gov (NCT02670772). RESULTS: Between 2012 and 2014, 536 participants were recruited per arm. At week-96, trial completion rates were 75.7% with d4T/3TC/EFV (n=406) and 82.1% with TDF/3TC/EFV (n=440, p=0.011). Non-completion was largely due to virological failure (6.2% [33] with d4T/3TC/EFV versus 5.4% [29] with TDF/3TC/EFV; p=0.60). For the primary endpoint, d4T/3TC/EFV was non-inferior to TDF/3TC/EFV (79.3%, 425/536 versus 80.8% 433/536; difference=-1.49%, 95%CI= 6.3,3.3; p<0.001). Drug-related adverse event discontinuations were higher with d4T (6.7%, 36), than TDF (1.1%, 6; p<0.001). Lipodystrophy was more common with d4T (5.6%, 30) than TDF (0.2%, 1; p<0.001). Creatinine clearance increased in both arms, by 18.1 mL/min in the d4T arm and 14.2 mL/min with TDF (p=0.03). Hip bone density measures, however, showed greater loss with TDF. CONCLUSIONS: Low dose d4T combined with 3TC/EFV demonstrated non-inferior virological efficacy compared to TDF/3TC/EFV, but mitochondrial toxicity remained high. Little renal toxicity occurred in either arm. Implications of bone mineral density changes with TDF warrant investigation.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30422901 TI - Comfort discussing HIV pre-exposure prophylaxis with patients among physicians in an urban emergency department. PMID- 30422902 TI - S100a14 is Increased in Activated Nk Cells and Plasma of HIV-Exposed Seronegative People Who Inject Drugs and Promotes Monocyte-Nk crosstalk. AB - BACKGROUND: HIV-exposed sero-negative people who inject drugs (HESN-PWID) have been shown to have increased NK cell and myeloid activation when compared to control donors. METHODS: We investigated potential mechanisms maintaining NK activation by conducting quantitative proteome comparisons of NK cells from HESN PWID subjects and control donors. Proteins upregulated in NK cells were measured in the plasma of HESN-PWID subjects by ELISA and further investigated for their ability to induce innate immune activation in vitro. RESULTS: The NK cell proteome comparison showed markedly higher levels of Interferon-stimulated proteins and S100 proteins, including S100A14. Consistent with these results, we observed significantly higher levels of S100A14 in the plasma of HESN-PWID subjects compared to controls (p=0.033, n=25). In vitro, the addition of recombinant S100A14 protein significantly activated NK cells in a PBMC mixture (p=0.011, n=9), but not purified NK cells alone. Treatment of purified monocytes with recombinant S100A14 protein induced secretion of TNF-alpha and led to significantly higher NK CD69 activation (p=0.0156, n=7) in a co-culture through a TLR4 dependent interaction. CONCLUSIONS: Our study identified S100A14 as a novel protein increased within NK cells and plasma of HESN-PWID subjects with the capacity to sustain NK activation through TLR4-dependent activation of myeloid cells. PMID- 30422903 TI - Gut structural damage, an ongoing process in chronically untreated HIV infection. AB - OBJECTIVE: To investigate the longitudinal changes of gut structural damage in chronically untreated HIV infection. DESIGN: This is a 96-week prospective, single site, cohort study of antiretroviral therapy (ART)-naive HIV-infected participants. METHODS: Intestinal fatty acid-binding proteins (I-FABP) was used as a surrogate marker of gut structural damage. We assessed changes in I-FABP over 96 weeks and examined the associations between I-FABP, HIV variables, and inflammation. Spearman's correlations and linear mixed effect models were used to study relationships among variables. RESULTS: A total of 63 HIV-infected, ART naive patients were included in this analysis. At baseline, 76% were male; 62% were African American, with median age and BMI of 40 years and 27kg/m. Median HIV RNA and CD4+ T cell counts were 5520 copies/mL and 588 cells/mm. I-FABP significantly increased from baseline to week 96 (mean change +333.9 pg/mL; p=0.03), and this increase was associated with viral replication (rho=+0.4; p=0.03). I-FABP levels were found to be associated with markers of inflammation: sTNFR-II (rho=0.4, p=0.02) and sVCAM-1 (rho=0.04; p<0.01) at all study time points. Lower baseline CD4+ T cells counts was found to be independently associated with I-FABP progression after adjusting for baseline characteristics variables ( p=0.02). CONCLUSION: Gut structural damage is an ongoing process in the chronic phase of untreated HIV infection, and is largely dependent on viral replication. I-FABP was found to be associated with worse immune function, increase inflammation, and viremia in chronically untreated HIV infection, supporting its role as a biomarker of intestinal barrier dysfunction. PMID- 30422904 TI - Laboratory-reflex cryptococcal antigen screening is associated with a survival benefit in Tanzania. AB - BACKGROUND: Cryptococcal antigen (CrAg) screening in persons with advanced HIV/AIDS is recommended to prevent death. Implementing CrAg screening only in outpatients may underestimate the true CrAg prevalence and decrease its potential impact. Our previous 12-month survival/retention in CrAg-positive persons not treated with fluconazole was 0%. METHODS: HIV testing was offered to all ART naive outpatients and hospitalized patients in Ifakara, Tanzania, followed by laboratory-reflex CrAg screening for CD4<150 cells/MUL. CrAg-positive individuals were offered lumbar punctures, and antifungals were tailored to the presence/absence of meningitis. We assessed the impact on survival and retention in-care using multivariate Cox regression models. RESULTS: We screened 560 individuals for CrAg. The median CD4 count was 61 cells/MUL (IQR 26-103). CrAg prevalence was 6.1% (34/560) among individuals with CD4 <=150 and 7.5% among <=100 cells/MUL. CrAg prevalence was 2.3-fold higher among hospitalized participants than in outpatients (12% vs. 5.3%, p=0.02). We performed lumbar punctures in 94% (32/34), and 31% (10/34) had cryptococcal meningitis. Mortality did not differ significantly between treated CrAg-positive without meningitis and CrAg-negative individuals (7.3 vs 5.4 deaths per 100 persons-year, respectively, p=0.25). Independent predictors of 6-month death/lost to follow-up were low CD4, cryptococcal meningitis (adjusted hazard ratio (aHR) 2.76, 95% CI 1.31-5.82)), and no ART initiation (aHR 3.12, 95%CI 2.16-4.50). CONCLUSIONS: Implementing laboratory-reflex CrAg screening among outpatients and hospitalized-individuals resulted in a rapid detection of cryptococcosis and a survival benefit. These results provide a model of a feasible, effective and scalable CrAg screening and treatment strategy integrated into routine care in sub-Saharan Africa.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC) , where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. PMID- 30422905 TI - Body Mass Index and Cognitive Function among HIV-1 Infected Individuals in China, India and Nigeria. AB - BACKGROUND: Risk of cognitive impairment is increased among persons with high or low body mass index (BMI) in HIV- and HIV+ populations in resource-rich settings. We examined this association among HIV+ patients in three resource-limited settings. METHODS: This secondary analysis included data of 761 HIV+ volunteers pooled from 3 prospective cohort studies conducted in China (n=404; 53%), India (n=200; 26%) and Nigeria (n=157; 21%). World Health Organization (WHO) weight classifications were based on BMI. T scores, adjusted for demographics and practice effects, were derived from a 7-domain neuropsychological battery. Neurocognitive impairment (NCI) was defined as global deficit score (GDS) of >= 0.5. RESULTS: Overall prevalence of NCI at baseline was 27.7% (similar across all cohorts). The overweight/obese and underweight constituted 37.3% and 15.5% of the total participants respectively. In a multivariable logistic regression of pooled longitudinal data, adjusting for clinical and demographic variables, the odds of global neurocognitive impairment were 38% higher among the overweight/obese as compared to normal weight participants (OR: 1.38 [95% CI: 1.1, 1.72]; P=0.005). Similarly, the odds of global neurocognitive impairment were 39% higher among the underweight as compared to normal weight participants (OR: 1.39 [95% CI: 1.03, 1.87]; P=0.029). CONCLUSION: Neurocognitive impairment among HIV-1 infected patients was more prevalent in both overweight/obese and underweight than normal weight individuals in three resource-limited settings, confirming observations in resource rich settings. Mechanisms underlying these associations are unclear, but likely differ for underweight and overweight persons. PMID- 30422907 TI - Prediction OF HIV Transmission Cluster Growth with Statewide Surveillance Data. AB - BACKGROUND: Prediction of HIV transmission cluster growth may help guide public health action. We developed a predictive model for cluster growth in North Carolina (NC) using routine HIV surveillance data. METHODS: We identified putative transmission clusters with >=2 members via pairwise genetic distances <=1.5% from HIV-1 pol sequences sampled 11/2010-12/2017 in NC. Clusters established by a baseline of 01/2015 with any sequences sampled within two years before baseline were assessed for growth (new diagnoses) over 18 months. We developed a predictive model for cluster growth incorporating demographic, clinical, temporal, and contact tracing characteristics of baseline cluster members. We internally and temporally externally validated the final model in the periods 01/2015-06/2016 and 07/2016-12/2017. RESULTS: Cluster growth was predicted by larger baseline cluster size, shorter time between diagnosis and HIV care entry, younger age, shorter time since the most recent HIV diagnosis, higher proportion with no named contacts, and higher proportion with HIV viremia. The model showed areas under the receiver operating characteristic curves of 0.82 and 0.83 in the internal and temporal external validation samples. CONCLUSION: The predictive model developed and validated here is a novel means of identifying HIV transmission clusters that may benefit from targeted HIV control resources. PMID- 30422906 TI - Decreases in self-reported ART adherence predict HIV viremia among pregnant and postpartum South African women. AB - INTRODUCTION: Routine HIV viral load (VL) monitoring is recommended for patients on antiretroviral therapy (ART) but frequent VL testing, required in pregnant and postpartum women, is often not feasible. Self-reported adherence can be valuable, but little is known about its longitudinal characteristics. METHODS: We followed women living with HIV from ART initiation in pregnancy through 18 months postpartum in Cape Town, South Africa, with repeated measurement of VL and self reported adherence using a three-item scale. We used generalized estimating equations (with results presented as odds ratios [OR] with 95% confidence intervals [CI]) to investigate the association between viremia and change in adherence over pairs of consecutive visits. RESULTS: Among 2085 visit pairs from 433 women, a decrease in self-reported adherence relative to the previous visit on any of three self-report items, or the combined scale, was associated with VL >50 and >1000 copies/mL. The best performing thresholds to predict VL >50 copies/mL were a single level decrease on the Likert response item "how good a job did you do at taking your HIV medicines in the way that you were supposed to?" (OR 2.08 95% CI 1.48-2.91), and a decrease equivalent to >=5 missed doses or a one level decrease in score on either of two Likert items (OR 1.34 95% CI 1.06 1.69). CONCLUSION: Longitudinal changes in self-reported adherence can help identify patients with viremia. This approach warrants consideration in settings where frequent viral load monitoring or other objective adherence measures are not possible. PMID- 30422908 TI - The impact of home-based HIV testing services on progress towards the UNAIDS 90 90-90 targets in a hyperendemic area of South Africa. AB - BACKGROUND: In several sub-groups of South Africa, the percentage of HIV-positive individuals aware of their status falls well below the UNAIDS 90% target. This study examined the impact that home-based HIV testing services (HBHTS) had on knowledge of status in a hyperendemic area of South Africa. METHODS: We analysed data from the second cross-sectional HIV Incidence Provincial Surveillance System survey (2015/2016), a representative sample (n=10236) of individuals aged 15-49 years. Participants completed a questionnaire, provided blood samples for laboratory testing (used to estimate HIV prevalence) and were offered HBHTS. The proportion of people living with HIV (n=3870) made aware of their status through HBHTS was measured and factors associated with HBHTS uptake were identified. RESULTS: Knowledge of HIV-positive status at the time of the survey was 62.9% among men and 73.4% among women. Through HBHTS, the percentage of HIV-positive men and women who knew their status rose to 74.2% and 80.5% respectively. The largest impact was observed among youth (15-24 years). Knowledge of status increased from 36.6% to 59.3% and from 50.8% to 64.8% among young men and women respectively. Additionally, 51.4% of those who had previously never tested received their first test. Key reasons for declining HBHTS among undiagnosed HIV positive individuals included fear and self-report of a HIV-negative status. CONCLUSIONS: HBHTS was effective in increasing awareness of HIV-positive status, particularly among youth, men and those who had never tested. HBHTS could have a marked impact on progress towards the UNAIDS 90-90-90 targets within these sub groups. PMID- 30422909 TI - Perceived versus calculated HIV risk: Implications for Pre-exposure prophylaxis uptake in a randomized trial of men who have sex with men. AB - BACKGROUND: Inaccurate HIV risk perception by men who have sex with men (MSM) is a barrier to HIV prevention. Providing information about objective HIV risk could improve preexposure prophylaxis (PrEP) uptake. METHODS: PrEP Accessibility Research & Evaluation 2 (PrEPARE2) was a randomized controlled trial of MSM to determine if an objective risk score affects future PrEP uptake. Participants completed a baseline survey to assess demographics, risk behaviors and HIV self perceived risk (SPR). The survey generated a calculated HIV risk score (CalcR), estimating HIV risk based on reported condomless anal intercourse and sexually transmitted infections, and was provided to individuals in the intervention arm. Participants were contacted 8 weeks later to determine if they initiated PrEP. RESULTS: Of 171 participants (median age 32; 37% Hispanic or Non-Hispanic Black; median 5 sexual partners in past 6 months), 81% had heard of PrEP, and 57% thought they were good PrEP candidates. SPR had poor agreement with CalcR (kappa=0.176) with 38% underestimating their HIV risk. At week 8, only 14 of 135 participants had initiated PrEP with no difference between arms (CalcR 11%, control 10%, p>0.99). The most common reason for not starting PrEP was low HIV risk perception. There was a relative decrease in SPR over time (p=0.06) but no difference between arms (p=0.29). CONCLUSION: Providing an objective HIV risk score alone did not increase PrEP uptake. HIV testing performed at testing sites may be a crucial time to correct misperceptions about risk and initiate same-day PrEP given enthusiasm for PrEP on testing day to facilitate greater uptake. PMID- 30422910 TI - Impact of a youth-focused care model on retention and virologic suppression among young adults with HIV cared for in an adult HIV clinic. AB - BACKGROUND: Young adults with HIV (YAHIV) are less likely to be retained in care or achieve viral suppression when seen in adult clinics. We assessed outcomes of a youth focused care model versus standard of care within a large adult HIV clinic. SETTING: The Accessing Care Early (ACE) program for YAHIV is embedded within an adult clinic. Eligibility for ACE includes age 18-30 years with >=1 criteria: transfer from pediatric care, mental health diagnosis, substance use, or identified adherence barriers. Ineligible patients receive standard of care (SOC). METHODS: Retrospective analysis of patients entering ACE vs SOC from 2012 2014. Multivariable logistic regression assessed variables associated with retention and viral suppression (VS) < 200 copies/mL, and in separate analysis, clinical services utilization. RESULTS: 137 YAHIV entered care (2012-2014), 61 ACE and 76 SOC. Despite higher risk factors, ACE YAHIV were less likely to be lost to follow up compared to SOC (16% vs. 37%, p<0.01). At 24 months 49% in ACE vs. 26% in SOC met the retention measure, (p<0.01). In adjusted analysis ACE was associated with retention in care (AOR 3.26 [1.23-8.63]). Of those meeting the retention measure, 60% of ACE versus 89% of SOC had VS (AOR 0.63 [0.35-1.14]). Retention was associated with more frequent social work visits, nurse phone calls, and peer navigator interactions. CONCLUSIONS: Higher risk ACE YAHIV had better retention than SOC YAHIV in an adult clinic. Improved retention did not to lead to improved VS, underscoring the need for additional interventions to optimize VS for YAHIV. PMID- 30422911 TI - Impact of antiretroviral drugs on fracture risk in HIV-infected individuals: A case-control study nested within the French Hospital Database on HIV (FHDH-ANRS CO4). AB - BACKGROUND: HIV-infected patients have lower bone mineral density and a higher incidence of fractures than the general population of the same age and sex. To assess the impact of antiretroviral drugs (ARV) exposure on the risk of osteoporotic fractures, we conducted a nested case-control study. METHODS: Cases were individuals enrolled while ARV-naive, with a first prospectively recorded fracture between 2000 and 2010. Controls were randomly selected after matching for sex, age (+/-3years), period of HIV diagnosis (<1997/>=1997) and clinical centre. The risk of fracture was analysed with conditional logistic regression models, using different ways to model ARV exposure. All exposure variables and potential confounders were included in multivariable models. RESULTS: Among 861 reviewed cases, 261 fractures were osteoporotic and 254 of cases were matched to at least one control (376 controls). The median year of fracture diagnosis was 2007 (IQR 2004-2009): 49% of patients had been exposed to tenofovir disoproxil fumarate (TDF) and 82% to protease inhibitors (PIs).After taking into account the transmission group, AIDS status, geographic origin, BMI, current smoking status, alcohol consumption, exposure to systemic glucocorticoids, and the period of enrolment, there was no association between the risk of fracture and exposure to TDF (OR for cumulative exposure: 1.04 [0.86-1.27], similar results for ever exposed subjects), to NRTIs, or to PIs (OR for cumulative PI exposure: 1.02 [0.92 1.12]). CONCLUSION: We found no evidence of an excess risk of fracture following exposure to TDF or PIs. This has important implications for the debate concerning tenofovir alafenamide versus generic TDF. PMID- 30422913 TI - Depressive symptoms during childhood and cardiovascular risk factors in black and white men. AB - OBJECTIVE: Depressive symptoms and major depression predict cardiovascular disease (CVD) and CVD risk factors in adulthood. Evidence regarding the role of depression in the development of CVD risk in youth is minimal. The study evaluated the prospective relationship of depressive symptoms in childhood and adolescence with adult CVD risk factors in black and white men. METHODS: Health behaviors and medical history were measured in 165 black and 146 white men (mean age = 32); a subset in the Pittsburgh area had a fasting blood draw to measure metabolic syndrome and inflammation. Adult CVD risk factors were related to depressive symptoms and childhood socioeconomic status (SES) prospectively measured annually from ages 7 to 16 years, followed by adjustments for adult SES and depressive symptoms. RESULTS: Men with higher depressive symptoms ages 7 to 16 smoked more cigarettes, B = 0.28 (standard error, 0.12), p = .015, and ate fewer servings of fruits and vegetables, B = -0.08 (0.04), p = .040, as adults. The association for smoking was independent of adult depressive symptoms (concurrent) and childhood and adult SES as well as race. Depressive symptoms during childhood were unrelated to the metabolic syndrome or biomarkers of inflammation in adulthood. CONCLUSIONS: Depressive symptoms in childhood may predict later adverse health behaviors in black and white men. No evidence was found for an association between childhood depressive symptoms with metabolic syndrome or inflammation markers at ages around 32 years. The nature of the sample and lack of measurement of depressive disorder diagnosis tempers the conclusions, and future research is needed to determine associations with biological measures at later life span phases. PMID- 30422912 TI - Medical intensive care unit admission among patients with and without HIV, hepatitis C virus, and alcohol-related diagnoses in the United States: a national, retrospective cohort study, 1997-2014. AB - BACKGROUND: HIV, hepatitis C virus (HCV), and alcohol-related diagnoses (ARD) independently contribute increased risk for all-cause hospitalization. We sought to determine annual medical intensive care unit (MICU) admission rates and relative risk of MICU admission between 1997 and 2014 among people with and without HIV, HCV, and ARD, using data from the largest HIV and HCV care provider in the United States. SETTING: Veterans Health Administration. METHODS: Annual MICU admission rates were calculated among 155,550 patients in the Veterans Aging Cohort Study by HIV, HCV, and ARD status. Adjusted rate ratios (RR) and 95% confidence intervals (CI) were estimated with Poisson regression. Significance of trends in age-adjusted admission rates were tested with generalized linear regression. Models were stratified by calendar period to identify shifts in MICU admission risk over time. RESULTS: Compared to HIV-/HCV-/ARD- patients, relative risk for MICU admission decreased among HIV mono-infected patients from 61% (95% CI 1.56-1.65) in 1997-2009 to 21% (95% CI 1.16-1.27) in 2010-2014, increased among HCV mono-infected patients from 22% (95% CI 1.16-1.29) in 1997-2009 to 54% (95% CI 1.43-1.67) in 2010-2014, and remained consistent among patients with ARD only at 46% (95% CI 1.42-1.50). MICU admission rates decreased by 48% among HCV uninfected patients (p-trend<0.0001) but did not change among HCV+ patients (p trend=0.34). CONCLUSION: HCV infection and ARD remain key contributors to MICU admission risk. The impact of each of these conditions could be mitigated with combination of treatment of HIV, HCV, and interventions targeting unhealthy alcohol use. PMID- 30422914 TI - Effects of ABO Matching of Platelet Transfusions in Critically Ill Children. AB - OBJECTIVES: To determine if transfusing ABO compatible platelets has a greater effect on incremental change in platelet count as compared to ABO incompatible platelets in critically ill children. DESIGN: Secondary analysis of a prospective, observational study. Transfusions were classified as either ABO compatible, major incompatibility, or minor incompatibility. The primary outcome was the incremental change in platelet count. Transfusion reactions were analyzed as a secondary outcome. SETTING: Eighty-two PICUs in 16 countries. PATIENTS: Children (3 d to 16 yr old) were enrolled if they received a platelet transfusion during one of the predefined screening weeks. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Five-hundred three children were enrolled and had complete ABO information for both donor and recipient, as well as laboratory data. Three hundred forty-two (68%) received ABO-identical platelets, 133 (26%) received platelets with major incompatibility, and 28 (6%) received platelets with minor incompatibility. Age, weight, proportion with mechanical ventilation or underlying oncologic diagnosis did not differ between the groups. After adjustment for transfusion dose, there was no difference in the incremental change in platelet count between the groups; the median (interquartile range) change for ABO-identical transfusions was 28 * 10 cells/L (8-68 * 10 cells/L), for transfusions with major incompatibility 26 * 10 cells/L (7-74 * 10 cells/L), and for transfusions with minor incompatibility 54 * 10 cells/L (14-81 * 10 cells/L) (p = 0.37). No differences in count increment between the groups were noted for bleeding (p = 0.92) and nonbleeding patients (p = 0.29). There were also no differences observed between the groups for any transfusion reaction (p = 0.07). CONCLUSIONS: No differences were seen in the incremental change in platelet count nor in transfusion reactions when comparing major ABO incompatible platelet transfusions with ABO compatible transfusions in a large study of critically ill children. Studies in larger, prospectively enrolled cohorts should be performed to validate whether ABO matching for platelet transfusions in critically ill children is necessary. PMID- 30422915 TI - Coronary Artery Calcium Scoring: Current Status and Review of Literature. AB - Coronary artery calcium is a marker of overall atherosclerotic plaque burden, corresponding to approximately 20% overall atherosclerotic plaque burden. Coronary artery calcium screening, most commonly performed using the Agatston score, has been shown to be a predictor of future cardiovascular risk independent of conventional risk scores such as the Framingham risk score. Coronary artery calcium screening is also recommended on routine nongated, noncontrast chest computed tomography scans using several ordinal and visual scoring systems. PMID- 30422916 TI - Spectral Content of Electroencephalographic Burst-Suppression Patterns May Reflect Neuronal Recovery in Comatose Post-cardiac Arrest Patients. AB - PURPOSE: To assess the potential biologic significance of variations in burst suppression patterns (BSPs) after cardiac arrest in relation to recovery of consciousness. In the context of recent theoretical models of BSP, bursting frequency may be representative of underlying network dynamics; discontinuous activation of membrane potential during impaired cellular energetics may promote neuronal rescue. METHODS: We reviewed a database of 73 comatose post-cardiac arrest patients who underwent therapeutic hypothermia to assess for the presence of BSP and clinical outcomes. In a subsample of patients with BSP (n = 14), spectral content of burst and suppression periods were quantified using multitaper method. RESULTS: Burst-suppression pattern was seen in 45/73 (61%) patients. Comparable numbers of patients with (31.1%) and without (35.7%) BSP regained consciousness by the time of hospital discharge. In addition, in two unique cases, BSP initially resolved and then spontaneously reemerged after completion of therapeutic hypothermia and cessation of sedative medications. Both patients recovered consciousness. Spectral analysis of bursts in all patients regaining consciousness (n = 6) showed a prominent theta frequency (5-7 Hz) feature, but not in age-matched patients with induced BSP who did not recover consciousness (n = 8). CONCLUSIONS: The prognostic implications of BSP after hypoxic brain injury may vary based on the intrinsic properties of the underlying brain state itself. The presence of theta activity within bursts may index potential viability of neuronal networks underlying recovery of consciousness; emergence of spontaneous BSP in some cases may indicate an innate neuroprotective mechanism. This study highlights the need for better characterization of various BSP patterns after cardiac arrest. PMID- 30422918 TI - Nurse Empowerment in the New Year. PMID- 30422917 TI - Periodic Limb Movements in a Comatose Patient: Case Report. AB - Periodic limb movements (PLMs) may occur as a primary condition or be associated with other pathologies, such as sleep disorders. However, PLMs have not been described in comatose patients. We report the case of a 66-year-old man, with no history of sleep disorders, who presented PLMs during coma caused by an extensive right hemispheric abscess inducing midline shift. These movements were further characterized by video and electromyographic recordings, which displayed bilateral periodic bursts of the tibialis anterior muscles, occurring every 7 to 15 seconds, with no concomitant electroencephalographic correlate. After a long period of hospitalization, the patient eventually regained consciousness and PLMs seem to persist, only in sleep. To the best of our knowledge, this is the first report showing that PLMs may be observed in a setting where the networks supporting consciousness are lost, namely in a coma of structural etiology. PMID- 30422919 TI - Elucidating the End-of-Life Experience of Persons With Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease that occurs in 4 among 100 000 people in the United States. Individuals with ALS gradually lose their ability to control voluntary muscles, diminishing their ability to communicate. A comprehensive multidatabase search retrieved 31 qualitative research articles that addressed persons with end-of-life experiences with ALS. Inclusion/exclusion criteria were applied and a critical appraisal was applied for the final 8 included articles. First-person data extraction from the final articles represented emergence of 3 themes significant to persons with ALS: decisions for life-sustaining support, coping and fear of what is to come, and communication with providers. Tracheostomy and ventilation as a means of prolonging life were important considerations for individuals with ALS. Persons with ALS struggled emotionally with their sudden loss of control and facing their demise. Some facets in which they did exert control, such as living wills, were hindered by patient and health care provider communication. Effective communication in end-of-life circumstances is paramount to preserving patient autonomy and dignity. This can be achieved by the patients conveying their preferences with respect to end-of-life care in advance, as well the nurses and other health care providers supporting the patients emotionally as they cope with terminal illness. Understanding patients' views regarding end-of-life circumstances is pertinent to nurses and other health care providers as they plan for palliative care. PMID- 30422920 TI - Ubuntu-the Essence of Caring and Being: A Concept Analysis. AB - What is the South-African concept of caring? In Africa, the principle of Ubuntu introduces the concept of belonging and caring. The purpose of this concept analysis was thus to analyze the concept of Ubuntu. The 8 steps of a concept analysis by Walker and Avant were used. PMID- 30422921 TI - A Qualitative Study on Cancer Care Burden: Experiences of Iranian Family Caregivers. AB - The aim of this study was to explore the experiences of Iranian family caregivers with regard to the burden of caregiving. This is in the context of illuminating and identifying the experiences of family members from different contextual perspectives. In this qualitative study, purposive sampling was conducted in 2016. Data were collected using semistructured interviews and were analyzed using content analysis. Data analysis identified 4 categories and 8 subcategories: (1) burnout (physical problems and psychoemotional stress), (2) role conflict (balancing caring roles and family responsibilities; failure in professional or educational roles), (3) health system tensions (inadequate support from health professionals; ignorance of family members in health structure), and (4) social challenges of cancer (economic burden; taboo of cancer). In conclusion, nurses need to provide individualized support and counseling that address the sources of burden. This highlights the benefit of training health care professionals to provide culturally sensitive support based on family caregivers' needs and circumstances. PMID- 30422922 TI - Developing a Web-Based Smoking Cessation Program and Evaluating Its Effectiveness. AB - This study, which is based on the Stages of Change Model, aimed to develop a Web based smoking cessation program and to evaluate its effectiveness. An interventional study with 1 group was conducted with college students from Afyon Kocatepe University. First, the Web-Based Smoking Cessation Program was set up (www.sbp.aku.edu.tr). The sample in this study was composed of the 433 students who were site members. The appropriate stages of the program were then sent to members' e-mail addresses at monthly intervals over a period of 6 months. Second, the effectiveness of the program was evaluated at the baseline, the third, and the sixth months of the study. The study was completed with 314 students. The data were evaluated using descriptive statistics, 1-way analysis of variance, and analysis of variance for repeated measures. There were significant developments in the self-efficacy, cognitive, and behavioral processes of students in the third and sixth months of the study. Students (2.5%) had quit smoking by the third month and 4.5% by the sixth month. These results reveal that the program was able to help students quit smoking, increase their self-efficacy, and develop the process of change regarding smoking cessation. PMID- 30422923 TI - Prevalence and Correlates of the Use of Complementary and Alternative Medicine in Adults Living in a Rural Area. AB - There is growing interest in the use of complementary and alternative medicine (CAM) throughout the world; however, previous research performed in Turkey has not focused on CAM use in rural areas. The present study was aimed at determining CAM use among people aged 18 years or older living in Balikesir, a province in the western part of Turkey, and the correlates of CAM use. This cross-sectional study was conducted in Balikesir between January 2015 and April 2015. The sample group was reached with multistage cluster sampling method. The study included 410 people who agreed to participate. Data were collected with the questionnaire developed by the researchers from the households through face-to-face interviews. The data were analyzed using the descriptive statistics, chi-square test, and logistic regression analysis. Of the participants, 87.3% reported that they had used CAM in the past 12 months. While 39.4% of them preferred herbal products, 25.7% reported that they used CAM due to chronic pain. The results of the logistic regression model demonstrated that CAM use was 4.23 times higher in the age group of those 44 years of age and older, 7.32 times higher among the women, 11.11 times higher among those who had junior high school or lower education, 9.76 times higher among the employed participants and 15.12 times higher among those who had chronic diseases. The results of the study revealed that nearly 9 of every 10 participants used CAM methods and that the most commonly used method was the use of herbal products. PMID- 30422924 TI - Quitting Smoking in Mainland China: A New Role for Hospital-Based Nurses. AB - China has more than 300 million cigarette smokers and 1 million deaths every year attributed to smoking. Despite its huge economic implications, the lack of smoking and associated lifestyle-related data on China's outpatients makes it difficult for health care professionals to provide individualized assessments and targeted interventions. This study aimed to identify factors to inform nurse-led smoking behavioral assessments and cessation interventions. Clinical data from new patients attending the family medicine outpatient department from a large tertiary hospital in a major Southern China city were collected between March and December 2015. Data including basic demographics, medical history, vaccination history, current medication, and information on lifestyle risk factors were collected by frontline nurses during nursing assessment on their initial visit. Chi-square and Student's t tests were used as univariate analysis and post hoc regression analysis to explore which factors contributed toward smoking cessation. Of 7913 eligible visits, smokers and ex-smokers accounted for 13.5% and 2.4% of new patients, respectively, with a majority of them being young and male (gender ratio of 8:1) smokers. Multiple behavioral risks and comorbidities such as hypertension and diabetes mellitus in smokers were common; for example, 17.9% of smokers were also current drinkers, making alcohol users 8.5 to 16.7 times more likely to have smoked. Ex-smokers were more likely to be divorced, to be ex-drinkers, or to have higher diastolic blood pressure and concurrent hypertension. Smoking and associated lifestyle risk assessments run by registered nurses should be incorporated into current outpatient health histories and in targeted smoking cessation intervention programs. PMID- 30422926 TI - Natural Health Strategies for Pain Care, Part I: A Phytomedicine Compendium. PMID- 30422925 TI - Knowledge and Opinion of Obstetrician-Gynecologists and Midwives Regarding Complementary and Alternative Medicine in Spain. AB - The objective of this article is to present the results from a cross-sectional survey carried out to assess and compare knowledge, attitudes, and beliefs of the obstetrician-gynecologists and midwives, regarding a set of complementary and alternative therapies in the area of the Corredor del Henares in Spain. The results show a high percentage of acceptance regarding complementary and alternative therapies in the field of obstetrics and gynecology, and more than half of the Spanish professionals of reproductive health would like to learn more about these therapies. PMID- 30422927 TI - Nursing Now: Unleashing the Power of the Triple Impact Report. PMID- 30422928 TI - Envenomation by the common European adder (Vipera berus): a case series of 219 patients. AB - OBJECTIVES: Every year, several patients are bitten by the common European adder (Vipera berus). The aim of this study is to present a large consecutive case series of patients bitten by V. berus, and to identify signs and symptoms indicative of complicated illness. PATIENTS AND METHODS: This is a retrospective case series from the Hospital of South West Jutland, Denmark. All 219 patients bitten by V. berus (diagnosed by history or clinical findings) from 1994 to 2012 were identified through hospital databases. A severity grading from 1 to 5 was applied, and epidemiology, symptoms and signs, complications, treatment and laboratory data were extracted from the hospital databases. RESULTS: The most common complaints on admission were pain, nausea, abdominal pain, diarrhoea and dizziness, with discoloration and oedema being the most common symptoms. Few patients experienced syncope, palpitations or respiratory distress. Fifteen percent of all patients were transferred to the ICU and 2% (all children) were suspected of having compartment syndrome. Leucocytosis, gastrointestinal symptoms and hypotension were risk factors for complicated disease. CONCLUSION: Most patients only showed symptoms of no or mild envenomation. Fifteen percent were transferred to the ICU and five patients (all children) required fasciotomy because of suspected compartment syndrome. Only 10 patients received antivenom. PMID- 30422929 TI - A colorectal cancer diet quality index is inversely associated with colorectal cancer in the Malmo diet and cancer study. AB - The World Cancer Research Fund International has concluded strong evidence for that high intake of dairy products and foods containing dietary fiber and low intake of processed meat are associated with decreased risk of colorectal cancer (CRC). As food items are consumed together, it is important to study dietary patterns. The aim of the present study was to examine the association between an a priori constructed dietary index and incident CRC and between intake of processed meat, fiber, and dairy products and CRC. In the Malmo Diet and Cancer study cohort, 923 cases of CRC were identified, during 502 136 person-years of follow-up. A Colorectal Diet Quality Index (CDQI) was constructed regarding intakes of processed meat, fiber, and dairy products in relation to CRC. Higher index indicated a higher dietary quality. Higher CDQI was associated with lower risk of CRC [hazard ratios (HR): 0.57 for highest compared with lowest quintile; 95% confidence interval (CI): 0.43, 0.75; P<0.001]. Intake of dairy products was inversely associated with risk of CRC [HR for highest vs. lowest quintile was 0.77 (CI: 0.62, 0.96); P=0.008], as was dietary fiber (HR for highest vs. lowest quintile was 0.77 (CI: 0.61, 0.98); P=0.043). High intake of processed meat was associated with CRC (HR for highest vs. lowest quintile was 1.31; CI: 1.05, 1.63; P=0.012). High adherence to a predefined CRC-specific diet quality index was inversely associated with the risk of CRC and gave a stronger association with CRC, than when analyzing the components of the CDQI individually. PMID- 30422930 TI - What's New in Shock, December 2018? PMID- 30422931 TI - Clinical management of hypoactive sexual desire disorder. AB - Although a woman's healthcare provider has the best opportunity to address hypoactive sexual desire disorder (HSDD), most women are reluctant to discuss their loss of sexual desire. The feeling is often mutual, because limited education and misunderstanding persist, leaving few providers feeling competent to assess and treat this condition. The purpose of this Practice Pearl is to improve the clinician's understanding of and confidence in discussing HSDD, including symptoms, etiology, burden, diagnosis, and treatment. PMID- 30422932 TI - The burden of vulvovaginal atrophy on women's daily living: implications on quality of life from a face-to-face real-life survey. AB - OBJECTIVE: This subanalysis of the European Vulvovaginal Epidemiology Survey study aimed to assess the correlation of vulvovaginal atrophy (VVA) symptoms and severity, when confirmed by objective gynecologic examination, with the quality of life of postmenopausal women. METHODS: Women aged 45 to 75 years with confirmation of last menstrual period more than 12 months before, who attended menopause or gynecology centers, were included. Those women had at least one VVA symptom filled in a group of questionnaires, including EuroQol-EQ-5D-3L and Day to-Day Impact of Vaginal Aging (DIVA). To confirm the VVA diagnosis, an objective gynecologic examination was also performed. RESULTS: Of a total of 2,160 evaluable women, 66.3%, 30.5%, and 11.2% suffered from severe vaginal, vulvar, and urinary symptoms, respectively. VVA was confirmed in more than 90% of the participants. Mean (+/-SD) EQ-5D-3L score was 0.892 +/- 0.144 and mean (+/-SD) score on the associated visual analog scale was 71.7 +/- 16.0. Mean (+/-SD) DIVA score was 0.922 +/- 0.653. For both EQ-5D-3L and DIVA, the overall scores and most of the dimensions/components were statistically significantly worse for women with severe VVA symptoms (vulvar and urinary) compared with women not affected by severe symptoms. Quality of life questionnaires showed worse scores in women where the diagnosis of VVA was confirmed by gynecologic examination. CONCLUSIONS: Severe VVA symptoms showed a direct association with worse quality of life in postmenopausal women. This important effect on the quality of life of many women should be recognized as equivalent to those from other conditions and pathologies of which there is greater awareness. PMID- 30422933 TI - Sleep disturbance in women who undergo surgical menopause compared with women who experience natural menopause. AB - OBJECTIVE: Women who undergo surgical menopause (SM) experience a relatively more acute and precipitous drop of estrogen compared with women who experience natural menopause (NM). Few studies, however, have compared sleep quality in women who experience natural versus SM. METHODS: Participants were 526 postmenopausal women (mean age 60.2 +/- 7.64). All participants completed self-report questionnaires about insomnia symptoms, sleep-interfering behaviors, depression, sleep quality, and gynecological history. Analysis of covariance was conducted to compare women who experienced NM versus SM on sleep variables. Logistic regression analysis was used to determine whether NM or SM groups predicted insomnia status. Regression based moderation analysis was conducted to explore the moderating effect of type of menopause on the relationship between sleep-interfering behaviors and insomnia symptoms. RESULTS: Among the sample, 81.6% (n = 429) reported going through NM and 18.4% (n = 97) reported going through SM. The SM group was significantly younger by 7.2 years (P < 0.001). Women in the SM group reported significantly worse sleep quality (P = 0.007), especially for sleep duration (P = 0.001) and habitual sleep efficiency (P = 0.010) compared with women in the NM group. Regression analysis indicated that individuals in the SM group were 2.131 (95% CI 1.055-4.303) times more likely to have insomnia compared with the NM group (P = 0.027). In addition, women in the SM group who displayed more sleep-interfering behaviors also had a higher severity of insomnia symptoms compared with women who experience NM (beta = 0.26, P = 0.03). CONCLUSIONS: Menopause can be both physically and psychologically challenging, but women who undergo SM experience worse sleep quality compared with women who experience NM, and may benefit from behavioral interventions. PMID- 30422934 TI - The association of miR-25T>C, miR-32C>A, miR-125C>T, and miR-222G>T polymorphisms with a risk of primary ovarian insufficiency in Korean women. AB - OBJECTIVE: The purpose of this study was to investigate the association of microRNA polymorphisms (miR-25T>C, miR-32C>A, miR-125C>T, and miR-222G>T) with primary ovarian insufficiency (POI) in Korean women. METHODS: We conducted a case control study of Korean women: 142 participants with POI and 266 controls with at least 1 live birth and no history of pregnancy loss. RESULTS: The haplotype-based multifactor dimensionality reduction analysis revealed that the T-C-T-G (miR-25/ 32/-125/-222), T-A-C-G (miR-25/-32/-125/-222), C-T-G (miR-32/-125/-222), A-C-G (miR-32/-125/-222), T-G (miR-122/-222), C-T (miR-32/-125), and C-C (miR-25/-32) inferred haplotypes were significantly less frequent in POI (P < 0.05), which suggested potential protective effects. Participants with POI had significantly increased luteinizing hormone levels (P < 0.05), but hormonal levels, including luteinizing hormone, were not significantly different between POI women and control women with miR-32/-125/-222. CONCLUSIONS: After considering multiple comparisons, we concluded that miR-25T>C, miR-32C>A, miR-125C>T, and miR-222G>T had no relation with POI. PMID- 30422936 TI - Hormone therapy and carotid intima-media thickness: the thick and thin of it. PMID- 30422935 TI - Preventing postsmoking cessation weight gain: exercise helps, even if previously inactive. PMID- 30422937 TI - RELATIONSHIP BETWEEN ABNORMALITIES OF PHOTORECEPTOR MICROSTRUCTURES AND MICROVASCULAR STRUCTURES DETERMINED BY OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN EYES WITH BRANCH RETINAL VEIN OCCLUSION. AB - PURPOSE: To determine whether the size of the foveal avascular zone (FAZ) is significantly correlated with the best-corrected visual acuity (BCVA) and to examine the relationship between the size and microstructural changes of the photoreceptors in eyes with a branch retinal vein occlusion. METHODS: The medical records of 69 eyes of patients (mean age, 64.6 +/- 11.7 years) with a branch retinal vein occlusion were reviewed after the resolution of macular edema. All the patients underwent optical coherence tomography angiography for measurement of the FAZ area and spectral domain optical coherence tomography for determination of microstructural changes of the photoreceptors at the fovea. RESULTS: The superficial and deep FAZ areas in eyes with a branch retinal vein occlusion were 0.39 +/- 0.36 mm and 0.63 +/- 0.18 mm, respectively, and both were significantly larger than those observed in the fellow eyes (both, P < 0.001). The superficial FAZ area correlated with the posttreatment BCVA (r = 0.285, P = 0.027) but not with any parameters regarding the microstructures of the photoreceptors. Multivariate linear regression analysis showed that the pretreatment BCVA (beta = 0.519, P < 0.001) and integrity of the external limiting membrane (beta = -0.373, P = 0.001) were independent factors that significantly correlated with the posttreatment BCVA. CONCLUSION: There was no significant correlation between the FAZ area and microstructural parameters. However, the integrity of the external limiting membrane was significantly correlated with the posttreatment BCVA in eyes with a branch retinal vein occlusion. PMID- 30422938 TI - POSTTREATMENT POLYP REGRESSION AND RISK OF MASSIVE SUBMACULAR HEMORRHAGE IN EYES WITH POLYPOIDAL CHOROIDAL VASCULOPATHY. AB - PURPOSE: To study the association between the risk of massive submacular hemorrhage (SMH) and polyp regression after initial treatment of polypoidal choroidal vasculopathy using long-term follow-up data. METHODS: Retrospective study of 223 patients who were diagnosed with polypoidal choroidal vasculopathy and were followed up for up to 11 years. Subjects were categorized into "regression" and "no regression" groups, according to their polyp status after the initial treatment. Kaplan-Meier survival analyses were performed on development of massive SMH. The association between treatment methods and the occurrence of massive SMH was also analyzed. RESULTS: The incidence rates of massive SMH at 3, 6, and 9 years in the "no regression" group were 6.50, 22.59, and 38.03%, respectively, and in the "regression" group were 1.14, 6.47, and 10.92%, respectively (P = 0.005, log-rank test). The hazard ratio of massive SMH was 3.677 for cluster-type polyps and 0.271 for polyp regression after initial treatment. A higher rate of polyp regression was associated with photodynamic therapy (PDT) than anti-VEGF monotherapy (64.4 vs. 33.3%, P < 0.001). Additional anti-VEGF treatments after initial PDT showed lower risk of massive SMH than PDT only. (9.5 vs 38.5%, P = 0.005). CONCLUSION: The long-term risk of massive SMH after initial treatment on polypoidal choroidal vasculopathy is significantly higher in eyes with persistent polyps than those with regressed polyps. Ophthalmologists should pay attention to the risk of massive SMH and the polyp status when treating polypoidal choroidal vasculopathy. PMID- 30422939 TI - Resting-state electroencephalogram in learning-disabled children: power and connectivity analyses. AB - The neurophysiological underpinnings of learning disabilities remain unknown. In this clinical study, we recorded electroencephalograms for a large sample of children with learning disabilities (LD) and healthy control children (n=216) during resting states in which the eyes were either open or closed. We calculated the power and lagged phase coherence in six main frequency bands (delta, theta, lower and upper alpha, and lower and upper beta) to re-evaluate the question of whether children with LD show frontal theta power increases and posterior alpha band decreases on the basis of patterns of electroencephalogram oscillation, which could then be considered as evidence for the so-called 'maturational delay hypothesis.' We identified a general (not restricted to frontal electrodes) power increase in the theta band and no accompanying concomitant alpha band decrease at the posterior electrode position. In addition, we observed increased beta band power at frontal electrodes for LD children. With respect to lagged phase coherence, which is a coherence measure not influenced by volume conduction, we identified decreased coherence for children with LD in the upper alpha band during the eyes closed condition. We interpret this LD-specific resting-state activation pattern as indicating a suboptimally functioning neural resting-state network that provides a detrimental 'starting point' for task-specific brain activations. PMID- 30422940 TI - Protein disulphide isomerase is associated with mutant SOD1 in canine degenerative myelopathy. AB - Canine degenerative myelopathy (DM) is a fatal neurodegenerative disorder prevalent in the canine population. It may represent a unique, naturally occurring disease model for human amyotrophic lateral sclerosis (ALS) because of similar clinical signs and association with superoxide dismutase 1 gene (SOD1) mutations. Misfolded SOD1 aggregates and endoplasmic reticulum (ER) stress are major pathophysiological features associated with ALS. Interestingly, an ER foldase, protein disulphide isomerase (PDI) is upregulated during ALS and it co localizes with SOD1 inclusions in ALS patient tissues. Furthermore, mutations in the gene encoding PDI were recently associated with ALS. Given the genetic similarity between DM and ALS, we investigated whether ER stress and PDI were associated with DM. Protein extracts from spinal cord tissue of DM-affected dogs bearing a SOD1 mutation were examined for ER stress by western blotting. Immunohistochemical staining was also carried out to examine co-localization between endogenous PDI and SOD1 inclusions in spinal cord tissues of dogs affected with DM. PDI and CHOP, the proapoptotic protein induced during ER stress, were significantly upregulated in DM-affected dogs compared with controls. Furthermore, PDI co-localized with intracellular SOD1 aggregates in DM affected dogs in all motor neurons examined, indicating that PDI may be a cellular defence mechanism against SOD1 misfolding in DM. Our results imply that ER stress is induced in DM-affected dogs; hence, it is a common pathological mechanism associated with both ALS and DM. The possibility that PDI may be a therapeutic target to inhibit SOD1 aggregation in DM dogs is also raised by this study. PMID- 30422941 TI - Altered hippocampal function with preserved cognitive performance in treatment naive major depressive disorder. AB - The hippocampus is implicated in the pathophysiology of major depressive disorder (MDD), with evidence that morphological changes occur with disease progression. It was hypothesized that treatment-naive patients with depression would show performance deficits in hippocampus-dependent memory trials, with concurrent hippocampal activation deficits on functional magnetic resonance imaging, compared with control participants. Thirteen treatment-naive patients with MDD and 13 control participants completed a hippocampus-dependent memory functional magnetic resonance imaging process-dissociation task. On behavioural measures of habit memory and guessing, there were no significant differences between groups. Functional magnetic resonance imaging analysis indicated that compared with the control group, the MDD group showed increased activation in the parahippocampal gyrus and hippocampus on habit memory and nonitem trials. These alterations in hippocampal functioning with preserved cognitive performance on a test of hippocampus-dependent memory in MDD may be indicative of a compensatory mechanism. PMID- 30422942 TI - Tablet Computer as a Distraction Tool During Facial Laceration Repair: A Randomized Trial. AB - OBJECTIVES: Child life interventions reduce the anxiety of medical procedures but are not always available in emergency departments. In this study, we determined the effect of parent-directed tablet computer use without child life direction on patient anxiety and on parent and suturing clinician experience during pediatric facial laceration repair. METHODS: In a children's hospital emergency department, we enrolled children 2 to 12 years of age undergoing unsedated facial laceration repairs and randomized them to parent-directed tablet computer distraction or standard supportive care. We measured anxiety using the Observational Scale of Behavioral Distress-Revised (OSBD-R) for 5 procedure phases from videotaped laceration repairs. We compared OSBD-R scores for 5 phases and weighted averages between the tablet and standard care groups. Parents and suturing clinicians completed surveys about their experiences after the procedures. RESULTS: From April 2014 to July 2015, 77 patients (39 tablet, 38 standard) underwent repairs. Age, use of restraint, procedure duration, and number of sutures were similar between the 2 groups. The groups did not differ in procedure phase or weighted average OSBD-R scores. Parents in the tablet group reported less personal anxiety compared with parents in the standard group (P = 0.01). In a post hoc subgroup analysis, subjects in the unrestrained tablet group had lower OSBD-R scores during the anesthetic injection phase than did subjects in the unrestrained standard group (P = 0.04). If restrained, subjects in the tablet group had higher OSBD-R scores during the anesthetic injection phase than did subjects in the standard group (P = 0.048). CONCLUSIONS: Unrestrained children may benefit from parent-directed tablet computer distraction. Parents who operate the device are less anxious during their children's procedures. PMID- 30422944 TI - A Comprehensive Pediatric Acute Sexual Assault Protocol: From Emergency Department to Outpatient Follow-up. AB - OBJECTIVE: Close medical follow-up after pediatric acute sexual assault is recommended and may mitigate adverse consequences and decrease long-term comorbidities. The objectives are to (1) examine adherence to a comprehensive outpatient medical follow-up protocol after evaluation in the emergency department in a pediatric population and (2) identify characteristics associated with patient adherence to inform the utilization of a medical follow-up protocol after pediatric acute sexual assault. METHODS: A retrospective medical record review was conducted of patients younger than 18 years presenting to the emergency department from January 1, 2010, to December 31, 2013, with a discharge diagnosis suggestive of sexual assault/abuse. We examined differences in demographics, assault characteristics, and medical/legal needs of patients who were evaluated in follow-up versus patients who were not. RESULTS: Of 182 patients, 60.4% completed follow-up appointments with the child protection center. Younger patients had follow-up rates higher than older patients (70.2% vs 50%; odds ratio [OR], 0.42). For patients where child protective services or law enforcement were called, follow-up rates were 74.2% and 64.7%, respectively (OR, 2.5; OR, 3.1). All patients with anogenital injuries on initial examination were seen in follow-up. The majority of patients who followed-up were accompanied by a caregiver/relative (95%). CONCLUSIONS: (1) Caregivers should be integrated into the evaluation to facilitate compliance with follow-up; (2) child abuse specialists may be consulted to facilitate specific interventions and recommendations; (3) professionals should work as a multidisciplinary team; and (4) the patient's psychological status should be evaluated, and mental health interventions recommended. PMID- 30422945 TI - Acute Flaccid Paralysis in an 11-Year-Old. AB - Rhabdomyolysis is a syndrome caused by injury to skeletal muscle and subsequent release of intracellular components into the systemic circulation. We report a case of rhabdomyolysis causing acute paralysis from underlying and unrecognized hypothyroidism in an 11-year-old girl. To date, publications of rhabdomyolysis secondary to hypothyroidism have been limited, especially in the pediatric population. Early intervention with intravenous fluids and levothyroxine led to resolution of our patient's symptoms and is overall important in preventing the serious sequela of rhabdomyolysis including renal failure, cardiac dysrhythmias, compartment syndrome, and disseminated intravascular coagulation. PMID- 30422943 TI - Test Characteristics of Cerebrospinal Fluid Gram Stain to Identify Bacterial Meningitis in Infants Younger Than 60 Days. AB - In our cohort of 20,947 infants aged 60 days or younger, cerebrospinal fluid Gram stain had a sensitivity of 34.3% (95% confidence interval, 28.1%-41.1%) and a positive predictive value of 61.4% (95% confidence interval, 52.2%-69.8%) for positive cerebrospinal fluid culture, suggesting that Gram stain alone may lead to both underdiagnosis and overdiagnosis of bacterial meningitis. PMID- 30422946 TI - Consensus Statement on Urgent Care Centers and Retail Clinics in Acute Care of Children. AB - This article provides recommendations for pediatric readiness, scope of services, competencies, staffing, emergency preparedness, and transfer of care coordination for urgent care centers (UCCs) and retail clinics that provide pediatric care. It also provides general recommendations for the use of telemedicine in these establishments.With continuing increases in wait times and overcrowding in the nation's emergency departments and the mounting challenges in obtaining timely access to primary care providers, a new trend is gaining momentum for the treatment of minor illness and injuries in the form of UCCs and retail clinics. As pediatric visits to these establishments increase, considerations should be made for the type of injury or illnesses that can be safely treated, the required level training and credentials of personnel needed, the proper equipment and resources to specifically care for children, and procedures for safe transfer to a higher level of care, when needed. When used appropriately, UCCs and retail clinics can be valuable and convenient patient care resources. PMID- 30422947 TI - Outcomes for Children With a Nonvisualized Appendix on Ultrasound. AB - OBJECTIVES: Oftentimes while pursing the diagnosis of appendicitis, an ultrasound cannot visualize the appendix, and physicians must utilize other resources for evaluation. The primary objective of this study was to determine if there was a lower rate of appendicitis when the appendix was not visualized on ultrasound. Furthermore, we assessed the importance of specific clinical predictors in this population. METHODS: We conducted a retrospective chart review of all children who presented to our pediatric emergency department from 2011 to 2013 and had an abdominal ultrasound. We identified total numbers of ultrasounds with a nonvisualized appendix and then assessed follow-up for a randomly selected group of patients. We performed logistic regression to assess the predictive value of different clinical factors. RESULTS: A total of 3245 ultrasounds were analyzed, and in 54% of these, the appendix was nonvisualized. In total, 28% of the total patients and 11.9% of patients who received a nonvisualized ultrasound had appendicitis (95% confidence interval [CI], 8.3%-16.2%). Among those patients who had follow-up studies performed during the same visit, 21.2% had appendicitis (95% CI, 14.9%-28.8%), and of those discharged without a diagnosis, 1.5% had appendicitis (95% CI, 0.2%-5.4%). Male sex, leukocytosis, and an elevated absolute neutrophil count were each significantly associated with appendicitis after a nonvisualized appendix on ultrasound. CONCLUSIONS: A significant proportion of patients with suspected appendicitis who had an initial nonvisualized appendix on ultrasound were ultimately diagnosed with appendicitis. Clinicians must be vigilant about pursuing a definitive diagnosis if an initial ultrasound is nondiagnostic. PMID- 30422948 TI - Hypothermia in Young Infants: Frequency and Yield of Sepsis Workup. AB - OBJECTIVES: Serious bacterial infections (SBIs) in young infants can present with fever or hypothermia. There are substantial data on fever as a presentation for SBI that help to inform the clinical approach. In contrast, data on hypothermia are lacking, thus leaving clinicians without guidance. We aimed to describe the workup and findings, specifically the occurrence, of SBIs in infants younger than 60 days of life with hypothermia. METHODS: We reviewed the medical records of infants younger than 60 days of life with rectal temperature of less than 36.5 degrees C upon arrival to a children's hospital emergency department between January 2013 and December 2014. Comparisons were made between those who were found to have an SBI and those without. Serious bacterial infection was defined as bacteremia, bacterial meningitis, pneumonia, or urinary tract infection (UTI). RESULTS: From the 414 patients identified, 104 (25%) underwent a sepsis evaluation of blood, urine, and/or cerebrospinal fluid culture. Serious bacterial infections were identified in 9 patients: 4 with UTI, 1 with pneumonia, 2 with bacteremia, 1 with pneumonia and UTI, and 1 with meningitis and bacteremia. Compared with patients with negative cultures, patients with SBI were older and had elevated absolute band counts and elevated immature-to-total neutrophil ratio. CONCLUSIONS: Approximately a quarter of infants younger than 60 days with hypothermia were evaluated for SBI. Serious bacterial infection was identified in 9% of evaluated infants (2% of all hypothermic infants). Hypothermia can be a presenting sign of SBI. PMID- 30422949 TI - Use of the C-MAC Macintosh 0 Blade for Intubation of Infants in the Emergency Department. AB - First-pass success rates during intubation of infants in the emergency department have been shown to be low. Video laryngoscopy is being increasingly used during advanced airway management in the emergency department, but available data have not supported improved outcomes with use in pediatrics. The newly available Macintosh size 0 (curved) blade for the C-MAC video laryngoscope offers a narrower blade for use in infants. We describe the use of the new C-MAC Macintosh 0 blade for intubation of 2 infants with apnea secondary to respiratory syncytial virus bronchiolitis. The included video recording demonstrates the favorable glottic view and improved maneuverability offered by the narrower blade but also highlights the limitation in use beyond young infants given the short blade length. PMID- 30422950 TI - Rethinking the Utility of Head Computed Tomography in the Evaluation of Apparent Life Threatening Events. PMID- 30422951 TI - Oxygenated preservation solutions for organ preservation. PMID- 30422952 TI - Oxygenated UW solution decreases ATP decay and improves survival after transplantation of DCD liver grafts. AB - BACKGROUND: DCD liver grafts are known to be predisposed to primary nonfunction and ischemic cholangiopathy. Many DCD grafts are discarded because of older donor age or long warm ischemia times. Thus, it is critical to improve the quality of DCD liver grafts. Here, we have tested whether an enriched oxygen carrier added to the preservation solution can prolong graft survival and reduce biliary damage. METHODS: We assessed the ATP content decay of mouse liver grafts after cold ischemia, warm ischemia, and combined warm+cold ischemia. In addition, we used a rat model of liver transplantation to compare survival of DCD grafts preserved in high-oxygen solution (pre-oxygenated PFC+UW solution) vs. lower oxygen solution (pre-oxygenated UW solution). RESULTS: ATP levels under UW preservation fall to less than 10% after 30 min of warm ischemia. Pre-oxygenated UW solution with PFC reached a significantly higher PaO2. After 45min of warm ischemia in oxygenated UW+PFC solution, grafts showed 63% higher levels of ATP (p=0.011). In addition, this was associated with better preservation of morphology when compared to grafts stored in standard UW solution. Animals that received DCD grafts preserved in higher oxygenation solution showed improved survival: 4 out of 6 animals survived long-term whereas all control group animals died within 24 hours. CONCLUSIONS: The additional oxygen provided by PFC during static cold preservation of DCD livers can better sustain ATP levels, and thereby reduce the severity of ischemic tissue damage. PFC-based preservation solution extends the tolerance to warm ischemia, and may reduce the rate of ischemic cholangiopathy. PMID- 30422954 TI - Transplantation Society Consensus Statement on Immunosuppression in Liver Transplant Recipients: Erratum. PMID- 30422953 TI - Asian Liver Transplant Network Clinical Guidelines on Immunosuppression in Liver Transplantation. AB - Most management guidelines and much of the available clinical trial evidence for immunosuppressants in liver transplantation pertain to Western practice. While evidence from Western studies may not translate to Asian settings, there is a paucity of Asian randomized controlled trials of immunosuppression in liver recipients. Nonetheless, there are notable differences in the indications and procedures for liver transplantation between Western and Asian settings. The Asian Liver Transplant Network (ALTN) held its inaugural meeting in Singapore in November 2016 and aimed to provide an Asian perspective on aspects of immunosuppression following liver transplantation. Because of their importance to outcome following liver transplantation, the meeting focused on: (1) reducing the impact of renal toxicity, (2) hepatocellular carcinoma recurrence and (3) nonadherence with immunosuppressant therapy. PMID- 30422955 TI - Analysis of Differentially Expressed Proteins in Hepatocellular Carcinoma: Erratum. PMID- 30422956 TI - "Villagers collecting seafood in low tide from Nungwi, Zanzibar, Tanzania". PMID- 30422957 TI - Predicting Factors at Skeletal Maturity for Curve Progression and Low Back Pain in Adult Patients Treated Nonoperatively for Adolescent Idiopathic Scoliosis With Thoracolumbar/Lumbar Curves: A Mean 25-year Follow-up. AB - STUDY DESIGN: A retrospective, long-term follow-up study. OBJECTIVE: We aimed to clarify the predicting factors at skeletal maturity for future curve progression and low back pain (LBP) in adolescent idiopathic scoliosis (AIS) with thoracolumbar/lumbar (TL/L) curve. SUMMARY OF BACKGROUND DATA: TL/L curves are likely to progress after skeletal maturity and cause LBP. METHODS: Of 147 patients treated nonoperatively for AIS with TL/L curve, 56 (55 females; average age at the time of survey, 39.5 +/- 7.1 years; average follow-up duration after maturity, 24.9 +/- 6.9 years) completed questionnaires, including the visual analogue scale (VAS) for LBP and Oswestry disability index (ODI). Forty-nine patients underwent a radiological examination, and 48 underwent lumbar magnetic resonance imaging (MRI). RESULTS: The mean Cobb angle of the TL/L curve increased from 37.3 degrees +/- 7.5 degrees to 47.8 degrees +/- 12.6 degrees (0.41 degrees +/- 0.39 degrees per year). The factors at skeletal maturity that were associated with the annual progression of the TL/L curve included a cranially located apical vertebra, and great apical vertebral translation and L3 tilt. In addition, the VAS for LBP was positively correlated with L4 tilt, and the ODI was positively correlated with L4 tilt and apical vertebral rotation. Multivariate analyses and receiver-operating characteristic curves demonstrated that L3 tilt at skeletal maturity independently predicted a curve progression >=0.5 degrees per year (odds ratio [OR], 1.17), while L4 tilt at skeletal maturity independently predicted a VAS >=3 cm (OR, 1.20) and ODI >=21% (OR, 1.25) in adulthood, with a cutoff value of approximately 16 degrees for each factor. Moreover, lumbar disc degeneration on MRI was associated with L4 tilt at skeletal maturity and LBP in adulthood. CONCLUSION: Great L3 and L4 tilt at skeletal maturity, especially those >16 degrees , are predictors of future curve progression and LBP in adulthood, respectively. For adolescent patients with these risk factors, periodic follow-ups into adulthood should be considered. LEVEL OF EVIDENCE: 4. PMID- 30422959 TI - IN RESPONSE. PMID- 30422958 TI - Prediction Accuracy of Common Prognostic Scoring Systems for Metastatic Spine Disease: Results of a Prospective International Multicentre Study of 1469 Patients. AB - STUDY DESIGN: A prospective multicenter cohort study. OBJECTIVE: To assess the clinical accuracy of six commonly cited prognostic scoring systems for patients with spinal metastases. SUMMARY OF BACKGROUND DATA: There are presently several available methods for the estimation of prognosis in metastatic spinal disease, but none are universally accepted by surgeons for clinical use. These scoring systems have not been rigorously tested and validated in large datasets to see if they are reliable enough to inform day-to-day patient management decisions. We tested these scoring systems in a large cohort of patients. A total of 1469 patients were recruited into a secure internet database, and prospectively collected data were analyzed to assess the accuracy of published prognostic scoring systems. METHODS: We assessed six prognostic scoring systems, described by the first authors Tomita, Tokuhashi, Bauer, van der Linden, Rades, and Bollen. Kaplan-Meier survival estimates were created for different patient subgroups as described in the original publications. Harrell's C-statistic was calculated for the survival estimates, to assess the concordance between estimated and actual survival. RESULTS: All the prognostic scoring systems tested were able to categorize patients into separate prognostic groups with different overall survivals. However none of the scores were able to achieve "good concordance" as assessed by Harrell's C-statistic. The score of Bollen and colleagues was found to be the most accurate, with a Harrell's C-statistic of 0.66. CONCLUSION: No prognostic scoring system was found to have a good predictive value. The scores of Bollen and Tomita were the most effective with Harrell's C-statistic of 0.66 and 0.65, respectively. Prognostic scoring systems are calculated using data from previous years, and are subject to inaccuracies as treatments advance in the interim. We suggest that other methods of assessing prognosis should be explored, such as prognostic risk calculation. LEVEL OF EVIDENCE: 3. PMID- 30422960 TI - TO THE EDITOR. PMID- 30422961 TI - New mass spectrometric approaches for the quantitative evaluation of anticancer drug levels in treated patients. AB - Alternatively to the well consolidated LC-MS/MS approach employed for the evaluation of anticancer drug concentrations in treated patients, new mass spectrometric methods have been proposed and tested recently. They exhibited faster analysis time and, at first sight, simpler instrumental approaches. However, results obtained by these methods require an in-depth evaluation, due to their strong dependence on the experimental set up. In this short review, the quantification of irinotecan, sunitinib, and 6-alpha-hydroxy paclitaxel (the main metabolite of paclitaxel) by laser desorption ionization techniques (matrix assisted laser desorption/ionization MALDI, nanostructure-assisted laser desorption/ionization NALDI, and surface-assisted laser desorption/ionization SALDI) is reported and discussed, showing the advantages but also drawbacks of the methods. The MALDI approach led to the most reliable results and the cross validation for the quantitative analysis of irinotecan indicates that this method can be fruitfully employed for therapeutic drug monitoring (TDM) and pharmacokinetic studies. Another recently proposed technique, paper spray mass spectrometry, has been tested for the quantitative measurement of imatinib in plasma samples. Even if the approach is, at first sight, really simple, the parameterization of the analytical and instrumental aspects has required many efforts to reach satisfactory results. What it should be expected in the future is the evaluation of these methods, not only in scientific environments dedicated to instrument development, but also, in clinical chemistry laboratories, to evaluate their effectiveness and to give new and valid tools for TDM and for other qualitative or quantitative measurements of biomedical interest. PMID- 30422962 TI - Pharmacokinetics of Daclatasvir, Sofosbuvir and GS-331007 in a Prospective Cohort of HCV positive Kidney Transplant Recipients. AB - BACKGROUND: Limited data exist on the pharmacokinetic profile of novel direct acting antivirals in kidney transplant recipients. Daclatasvir is primarily eliminated via the biliary route and sofosbuvir via the renal route; here we report the pharmacokinetic profile of combined treatment with these compounds in a prospective study of hepatitis C virus positive kidney transplant recipients (EudraCT: 2014-004551-32). METHODS: In this study plasma samples of 16 HCV positive kidney transplant recipients receiving daclatasvir and sofosbuvir were collected at 4 time points at day 1, 7, 14, 21, 56, and 84 after start of treatment. Inclusion criteria were stable graft function and an estimated GFR (eGFR) > 30mL/min/1.73m. Daclatasvir, sofosbuvir and GS-331007 (inactive metabolite of sofosbuvir) plasma concentrations were determined using ultra performance liquid chromatography quadrupole time of flight mass spectrometry. RESULTS: All patients showed a rapid virological response with HCV RNA below the detection limit 21 days after the start of therapy (medium time to viral clearance). No difference of the areas under the concentration-time curve (AUC) of daclatsavir, sofosbuvir and GS-331007 was observed between patients with an eGFR below or >= 60mL/min. For GS-331007, no relevant changes of trough levels were observed over time. Mean GS-331007 trough levels were 339.5+/-174.9 ng/mL in patients with an eGFR >= 60mL/min and 404.3+/-226 ng/mL in patients with an eGFR < 60mL/min at day 7 (p=0.52). At day 84, GS-331007 trough levels were 357.8+/ 200.8 ng/mL and 404.2+/-70.2 ng/mL in patients with an eGFR >= 60 mL/min and in patients with an eGFR < 60 mL/min, respectively (p=0.51). The accumulation ratios of renally eliminated GS-331007 for AUC and Cmax did not significantly differ between the two eGFR groups at day 7. CONCLUSION: An impaired eGFR (30-60 mL/min) does not lead to a dose accumulation of daclatasvir, sofosbuvir and GS-331007. This study provides the rationale for future studies investigating the pharmacokinetic profile of sofosbuvir based HCV treatment in kidney transplant recipients with an eGFR < 30 mL/min. PMID- 30422963 TI - Catalase C-262T polymorphism is a risk factor for valproic acid-induced abnormal liver function in Chinese patients with epilepsy. AB - BACKGROUND: Individual susceptibility to valproic acid (VPA)-caused hepatotoxicity might result from genetic deficiencies in the detoxification and antioxidant enzymes including glutathione S-transferases (GSTs), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx). This study aimed to investigate the relationships between GST mu 1(GSTM1), GST theta 1(GSTT1), CAT C 262T, GPx1 Pro200Leu and SOD2 Val16Ala polymorphisms and the risk of abnormal liver function in Chinese epileptic patients treated with VPA monotherapy. METHODS: According to the levels of liver function indicators, a total of 267 epileptic patients between 1 and 65 years of age were divided into normal liver function group (NLFT) and abnormal liver function group (ANLFT). GSTM1 and GSTT1 polymorphisms were determined using PCR amplification based on the absence of a PCR amplification product. CAT, GPx1 and SOD2 polymorphisms were identified using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or direct automated DNA sequencing. RESULTS: Carriers of CAT had an increased risk of developing abnormal liver function compared with noncarriers in VPA-treated patients (odds ratio 3.968, P = 0.003). Logistic regression analyses indicated that the CAT genotype was a significant genetic risk factor for VPA-induced liver dysfunction. It suggests that individual susceptibility to VPA-induced liver dysfunction may at least partially result from genetic deficiencies in CAT C 262T. PMID- 30422964 TI - Clinical Faceoff: Irreparable Rotator Cuff Tears in Young, Active Patients: Tendon Transfer versus Superior Capsular Reconstruction? PMID- 30422965 TI - Value-based Healthcare: Applying Time-driven Activity-based Costing in Orthopaedics. PMID- 30422966 TI - Medicolegal Sidebar: Unnecessary Medical Care and Physician Liability. PMID- 30422967 TI - Increased Patellar Volume/Width and Decreased Femoral Trochlear Width Are Associated With Adolescent Patellofemoral Pain. AB - BACKGROUND: Patellofemoral pain is one of the most common forms of knee arthralgia in adolescent females. Unlike in adults, in whom the etiology of patellofemoral pain is considered to be multifactorial (eg, altered bone shape and musculoskeletal dynamics), the etiology of adolescent patellofemoral pain has been historically attributed to overuse. Although it is highly plausible that adolescent patellofemoral pain results from excessive maltracking, as suggested by recent research, an increase in patellar, relative to femoral, size could also contribute to patellofemoral pain through altered cartilage stresses/strains, resulting in overloading of the subchondral bone. Because the role of bone morphology in the genesis of patellofemoral pain in adolescent females remains largely unknown, research is needed in this area to improve our understanding of patellofemoral pain and advance diagnosis/treatment. QUESTIONS/PURPOSES: (1) Are patellar volume and width increased, and femoral trochlear width decreased, in female adolescents with patellofemoral pain compared with asymptomatic females? (2) Are measures of patellofemoral size correlated with patellofemoral tracking? METHODS: Twenty adolescent females with patellofemoral pain (age, 13.7 +/- 1.3 years) and 20 asymptomatic female control participants (age, 13.6 +/- 1.3 years) were enrolled in this case-control institutional review board-approved study. This study focused on a strict definition of patellofemoral pain, peripatellar pain in the absence of other structural pathologic conditions (eg, tendinitis, ligament injury, Osgood-Schlatter disease) or a history of dislocations/trauma. Control participants with no history of patellofemoral pain or other lower extremity pathology were matched for age (within 6 months) and body mass index (within 5 kg/m). Participants self-referred and were recruited through clinicaltrails.gov, printed advertisements, and word of mouth. Three-dimensional (3-D), static, T1-weighted, gradient recalled echo MR images were acquired, from which 3-D patellofemoral models were created. Patellar volume and width, patellar to-femoral volume and width ratios, and femoral trochlear width were compared across cohorts. In addition, 3-D patellofemoral tracking was quantified from dynamic MR images captured during cyclical flexion-extension volitional movements of the lower extremity. The size measures and ratios were correlated to patellofemoral tracking. RESULTS: Compared with control participants, the cohort with patellofemoral pain had greater patellar volume (13,792 +/- 2256 versus 11,930 +/- 1902 mm; 95% confidence interval [CI], 1336 mm; p = 0.004; d = 0.89) and width (38.4 +/- 3.0 versus 36.5 +/- 2.7 mm; 95% CI, 1.8 mm; p = 0.021; d = 0.67). The femoral trochlear width was smaller (32.0 +/- 1.8 versus 32.9 +/- 1.8 mm; p = 0.043, d = 0.54). The patellar-to-femoral volume ratio and the patellar to-trochlear width ratio were greater in adolescents with patellofemoral pain (0.15 +/- 0.02 versus 0.13 +/- 0.01, p = 0.006, d = 0.83 and 1.20 +/- 0.09 versus 1.11 +/- 0.09, p = 0.001, d = 1.02). No correlations were found between patellar size and patellofemoral tracking (r < 0.375, p > 0.103). CONCLUSIONS: In adolescent females with patellofemoral pain, the increased patellar volume/width and patellar-to-trochlear width ratio, along with the decreased femoral trochlear width, may initiate a pathway to pain through improper engagement of the patella within the femoral trochlea. Specifically, the mean differences between cohorts in patellar and femoral trochlear width (1.9 mm and 0.9 mm) are 58% and 37% of the mean patellar and femoral cartilage thickness in females, respectively, as reported in the literature. Further studies are needed to fully elucidate the mechanism of pain. LEVEL OF EVIDENCE: Level III, prognostic study. PMID- 30422968 TI - CORR Insights(r): What are the Demographics and Epidemiology of Legg-Calve Perthes Disease in a Large Southern California Integrated Health System? PMID- 30422969 TI - Human Immunodeficiency Virus/Sexually Transmitted Infection Counseling and Testing Services Received by Gay and Bisexual Men Using Preexposure Prophylaxis at Their Last PrEP Care Visit. AB - BACKGROUND: Preexposure prophylaxis (PrEP) reduces risk of human immunodeficiency virus infection for many gay and bisexual men (GBM); however, bacterial sexually transmitted infections associated with decreasing condom use among users is of concern. Center for Disease Control and Prevention's guidelines for PrEP use recommend bacterial sexually transmitted infection screening every 6 months. We sought to investigate comprehensive PrEP care, defined as: (1) discussion of sexual behavior, (2) blood sample, (3) urine sample, (4) rectal sample (rectal swab), and (5) throat sample (throat swab), provided at the user's last PrEP appointment. METHODS: The PrEP-using GBM in New York City (n = 104) were asked about their last PrEP care visit. We examined associations of demographics (age, race/ethnicity, and education), recent number of condomless anal sex events, time on PrEP, and health care provider type on receiving comprehensive care at last visit using fully adjusted binary logistic regression. RESULTS: At their last visit, nearly all men (94%) gave blood for testing, 88% provided a urine sample, and 77% discussed sexual behavior with their provider. However, only 51% reported having a rectal swab, and 48% an oral swab. Only 32% of men received comprehensive PrEP care at their last PrEP visit. Odds of receiving comprehensive care were significantly higher among younger men, men with a bachelor's degree or more education, and those who reported more condomless anal sex. CONCLUSIONS: Less than one third of GBM received comprehensive human immunodeficiency virus/sexually transmitted infection counseling and testing at their last visit. These findings indicate further efforts are needed to prepare health care providers for prescribing and managing patients on PrEP. PMID- 30422970 TI - Stable Low Hepatitis C Virus Antibody Prevalence Among HIV-Negative Men Who Have Sex With Men Attending the Sexually Transmitted Infection Outpatient Clinic in Amsterdam, 2007 to 2017. AB - BACKGROUND: In response to the increased hepatitis C virus (HCV) prevalence recently found among participants of the Amsterdam preexposure prophylaxis demonstration project, we evaluated HCV prevalence over time and the performance of the HCV-MOSAIC risk score for detection of HCV infection in HIV-negative men who have sex with men (MSM) attending the Amsterdam sexually transmitted infection (STI) clinic. METHODS: In October 2016, HIV-negative MSM were tested for anti-HCV and HCV RNA and completed the HCV-MOSAIC risk score. Anti-HCV prevalence was compared with that found in cross-sectional studies at the Amsterdam STI clinic (2007-2017). The time trend in HCV prevalence was modeled via logistic regression. The performance of the HCV-MOSAIC risk score, adjusted to identify prevalent HCV infection, was evaluated by calculating sensitivity and specificity. RESULTS: Of 504 HIV-negative MSM tested in October 2016, 5 were anti HCV positive (1.0%, 95% confidence interval [CI], 0.4%-2.3%) and all were HCV RNA negative. Sensitivity and specificity of the adjusted HCV-MOSAIC risk score for prevalent infection were 80.0% (95% CI, 37.6%-96.4%) and 56.1% (95% CI, 51.7% 60.4%), respectively. The overall anti-HCV prevalence among 3264 HIV-negative MSM participating in cross-sectional studies at the Amsterdam STI clinic (2007-2017) was 0.8% (95% CI, 0.5%-1.2%) and did not change over time (P = 0.55). CONCLUSIONS: Anti-HCV prevalence among HIV-negative MSM attending the Amsterdam STI clinic in October 2016 was 1.0% and remained stable over time. We would therefore not recommend routine HCV screening of HIV-negative MSM at the STI clinic. However, given the increased prevalence among MSM using preexposure prophylaxis, periodic monitoring of HCV prevalence remains important. PMID- 30422971 TI - Preexposure Prophylaxis for Human Immunodeficiency Virus (HIV) Prevention Among HIV-uninfected Pregnant Women: Estimated Coverage Using Risk-based Versus Regional Prevalence Approaches. AB - Antenatal register data from 62 clinics in 5 regions of Kenya were used to estimate women with human immunodeficiency virus (HIV) risk (partner HIV status, syphilis). With individual risk-guided preexposure prophylaxis (PrEP) offer in all regions, 39% of pregnant women would be offered PrEP nationally. Offering PrEP to all women in high-prevalence regions reached 26% of the pregnant women. PMID- 30422972 TI - Impact of Hyperbaric Oxygen on Tissue Healing around Dental Implants in Beagles. AB - BACKGROUND The impact of hyperbaric oxygen (HBO) on the healing of soft tissues around dental implants was studied in a beagle model. MATERIAL AND METHODS Beagle dogs were randomized to receive implants, followed by postoperative HBO therapy or not (n=10 per group). On postoperative days 3, 7, and 14, tissue specimens were paraffin-embedded and analyzed by hematoxylin-eosin and Masson staining, as well as immunohistochemistry against CD31. RESULTS Scores for inflammation pathology based on hematoxylin-eosin staining and mean optical density of collagen fibers were significantly different between the HBO and control groups on postoperative days 3 and 7 (P<0.05), but not on day 14. Mean optical density due to anti-CD31 staining was significantly higher in the HBO group on postoperative days 3, 7, and 14 (P<0.05). CONCLUSIONS These results suggest that HBO may promote early osteogenesis and soft tissue healing after implantation. PMID- 30422973 TI - On the importance of monitoring and valuing all forms of biodiversity. AB - Pauchard et al claim that non-native species should not be granted conservation value, as this could hinder effort to curtail novel introductions. In this response, Schlaepfer counters that the positive contributions of non-native species to biodiversity and conservation must be included to provide a complete and objective snapshot to policy makers. PMID- 30422974 TI - Comparing Bayesian and non-Bayesian accounts of human confidence reports. AB - Humans can meaningfully report their confidence in a perceptual or cognitive decision. It is widely believed that these reports reflect the Bayesian probability that the decision is correct, but this hypothesis has not been rigorously tested against non-Bayesian alternatives. We use two perceptual categorization tasks in which Bayesian confidence reporting requires subjects to take sensory uncertainty into account in a specific way. We find that subjects do take sensory uncertainty into account when reporting confidence, suggesting that brain areas involved in reporting confidence can access low-level representations of sensory uncertainty, a prerequisite of Bayesian inference. However, behavior is not fully consistent with the Bayesian hypothesis and is better described by simple heuristic models that use uncertainty in a non-Bayesian way. Both conclusions are robust to changes in the uncertainty manipulation, task, response modality, model comparison metric, and additional flexibility in the Bayesian model. Our results suggest that adhering to a rational account of confidence behavior may require incorporating implementational constraints. PMID- 30422975 TI - Moth olfactory receptor neurons adjust their encoding efficiency to temporal statistics of pheromone fluctuations. AB - The efficient coding hypothesis predicts that sensory neurons adjust their coding resources to optimally represent the stimulus statistics of their environment. To test this prediction in the moth olfactory system, we have developed a stimulation protocol that mimics the natural temporal structure within a turbulent pheromone plume. We report that responses of antennal olfactory receptor neurons to pheromone encounters follow the temporal fluctuations in such a way that the most frequent stimulus timescales are encoded with maximum accuracy. We also observe that the average coding precision of the neurons adjusted to the stimulus-timescale statistics at a given distance from the pheromone source is higher than if the same encoding model is applied at a shorter, non-matching, distance. Finally, the coding accuracy profile and the stimulus-timescale distribution are related in the manner predicted by the information theory for the many-to-one convergence scenario of the moth peripheral sensory system. PMID- 30422977 TI - Transforming health policy through machine learning. AB - In their Perspective, Ara Darzi and Hutan Ashrafian give us a tour of the future policymaker's machine learning toolkit. PMID- 30422976 TI - Biodiversity assessments: Origin matters. PMID- 30422979 TI - Bayesian phylodynamic inference with complex models. AB - Population genetic modeling can enhance Bayesian phylogenetic inference by providing a realistic prior on the distribution of branch lengths and times of common ancestry. The parameters of a population genetic model may also have intrinsic importance, and simultaneous estimation of a phylogeny and model parameters has enabled phylodynamic inference of population growth rates, reproduction numbers, and effective population size through time. Phylodynamic inference based on pathogen genetic sequence data has emerged as useful supplement to epidemic surveillance, however commonly-used mechanistic models that are typically fitted to non-genetic surveillance data are rarely fitted to pathogen genetic data due to a dearth of software tools, and the theory required to conduct such inference has been developed only recently. We present a framework for coalescent-based phylogenetic and phylodynamic inference which enables highly-flexible modeling of demographic and epidemiological processes. This approach builds upon previous structured coalescent approaches and includes enhancements for computational speed, accuracy, and stability. A flexible markup language is described for translating parametric demographic or epidemiological models into a structured coalescent model enabling simultaneous estimation of demographic or epidemiological parameters and time-scaled phylogenies. We demonstrate the utility of these approaches by fitting compartmental epidemiological models to Ebola virus and Influenza A virus sequence data, demonstrating how important features of these epidemics, such as the reproduction number and epidemic curves, can be gleaned from genetic data. These approaches are provided as an open-source package PhyDyn for the BEAST2 phylogenetics platform. PMID- 30422978 TI - Inferring interaction partners from protein sequences using mutual information. AB - Functional protein-protein interactions are crucial in most cellular processes. They enable multi-protein complexes to assemble and to remain stable, and they allow signal transduction in various pathways. Functional interactions between proteins result in coevolution between the interacting partners, and thus in correlations between their sequences. Pairwise maximum-entropy based models have enabled successful inference of pairs of amino-acid residues that are in contact in the three-dimensional structure of multi-protein complexes, starting from the correlations in the sequence data of known interaction partners. Recently, algorithms inspired by these methods have been developed to identify which proteins are functional interaction partners among the paralogous proteins of two families, starting from sequence data alone. Here, we demonstrate that a slightly higher performance for partner identification can be reached by an approximate maximization of the mutual information between the sequence alignments of the two protein families. Our mutual information-based method also provides signatures of the existence of interactions between protein families. These results stand in contrast with structure prediction of proteins and of multi-protein complexes from sequence data, where pairwise maximum-entropy based global statistical models substantially improve performance compared to mutual information. Our findings entail that the statistical dependences allowing interaction partner prediction from sequence data are not restricted to the residue pairs that are in direct contact at the interface between the partner proteins. PMID- 30422980 TI - Delta albumin is a better prognostic marker for complications following laparoscopic intestinal resection for Crohn's disease than albumin alone - A retrospective cohort study. AB - PURPOSE: Little is known about the perioperative dynamic of albumin and its effect on surgical outcome in Crohn's disease. Thus, we aimed to assess postoperative changes of albumin levels and their potentially predictive role for complications after laparoscopic intestinal resections. METHODS: We identified 182 patients who underwent laparoscopic intestinal resection for symptomatic Crohn's disease between 2000 and 2014 for this retrospective cohort study. Pre- and postoperative serum albumin levels (within 4 days) were recorded retrospectively and proportional postoperative reduction (delta (Delta) albumin) was calculated. Complications were defined according to the Clavien-Dindo classification. Univariate and multivariate analysis describing an eventful postoperative course were conducted. RESULTS: Complications were found in 22.5% (n = 41), 6% (n = 11) developed major complications defined as Clavien Dindo III V and 16.5% (n = 30) had minor complications (Clavien Dindo I-II). The median Delta albumin was 22.75% (range: -18.46-47.14%). Delta albumin was found to be significantly higher in patients who developed complications after surgery (p = 0.03). Notably, neither preoperative (p = 0.28) nor postoperative albumin levels (p = 0.41) taken as absolute numerical values correlated with an eventful course following intestinal resection. In the multivariate analysis, based on a cut-off of 24.27%, Delta albumin remained an independent factor for surgical complications (p = 0.04, OR 2.232) next to conversion rate (p<0.001, OR 5.577) and the presence of an inflammatory mass (p = 0.003, OR 0.280). CONCLUSION: Delta albumin is a better prognostic marker for an eventful postoperative course after laparoscopic surgery in patients with Crohn's disease in comparison to albumin alone. PMID- 30422981 TI - Rabies post-exposure prophylaxis started during or after travel: A GeoSentinel analysis. AB - BACKGROUND: Recent studies demonstrate that rabies post-exposure prophylaxis (RPEP) in international travelers is suboptimal, with only 5-20% of travelers receiving rabies immune globulin (RIG) in the country of exposure when indicated. We hypothesized that travelers may not be receiving RIG appropriately, and practices may vary between countries. We aim to describe the characteristics of travelers who received RIG and/or RPEP during travel. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a multi-center review of international travelers exposed to potentially rabid animals, collecting information on RPEP administration. Travelers who started RPEP before (Group A) and at (Group B) presentation to a GeoSentinel clinic during September 2014-July 2017 were included. We included 920 travelers who started RPEP. About two-thirds of Group A travelers with an indication for rabies immunoglobulin (RIG) did not receive it. Travelers exposed in Indonesia were less likely to receive RIG in the country of exposure (relative risk: 0.30; 95% confidence interval: 0.12-0.73; P = 0.01). Travelers exposed in Thailand [Relative risk (RR) 1.38, 95% Confidence Interval (95% CI): 1.0-1.8; P = 0.02], Sri Lanka (RR 3.99, 95% CI: 3.99-11.9; P = 0.013), and the Philippines (RR 19.95, 95% CI: 2.5-157.2; P = 0.01), were more likely to receive RIG in the country of exposure. CONCLUSIONS/SIGNIFICANCE: This analysis highlights gaps in early delivery of RIG to travelers and identifies specific countries where travelers may be more or less likely to receive RIG. More detailed country-level information helps inform risk education of international travelers regarding appropriate rabies prevention. PMID- 30422982 TI - The in vivo and in vitro roles of Trypanosoma cruzi Rad51 in the repair of DNA double strand breaks and oxidative lesions. AB - In Trypanosoma cruzi, the etiologic agent of Chagas disease, Rad51 (TcRad51) is a central enzyme for homologous recombination. Here we describe the different roles of TcRad51 in DNA repair. Epimastigotes of T. cruzi overexpressing TcRAD51 presented abundant TcRad51-labeled foci before gamma irradiation treatment, and a faster growth recovery when compared to single-knockout epimastigotes for RAD51. Overexpression of RAD51 also promoted increased resistance against hydrogen peroxide treatment, while the single-knockout epimastigotes for RAD51 exhibited increased sensitivity to this oxidant agent, which indicates a role for this gene in the repair of DNA oxidative lesions. In contrast, TcRad51 was not involved in the repair of crosslink lesions promoted by UV light and cisplatin treatment. Also, RAD51 single-knockout epimastigotes showed a similar growth rate to that exhibited by wild-type ones after treatment with hydroxyurea, but an increased sensitivity to methyl methane sulfonate. Besides its role in epimastigotes, TcRad51 is also important during mammalian infection, as shown by increased detection of T. cruzi cells overexpressing RAD51, and decreased detection of single-knockout cells for RAD51, in both fibroblasts and macrophages infected with amastigotes. Besides that, RAD51-overexpressing parasites infecting mice also presented increased infectivity and higher resistance against benznidazole. We thus show that TcRad51 is involved in the repair of DNA double strands breaks and oxidative lesions in two different T. cruzi developmental stages, possibly playing an important role in the infectivity of this parasite. PMID- 30422983 TI - Evolution at two time frames: Polymorphisms from an ancient singular divergence event fuel contemporary parallel evolution. AB - When environments change, populations may adapt surprisingly fast, repeatedly and even at microgeographic scales. There is increasing evidence that such cases of rapid parallel evolution are fueled by standing genetic variation, but the source of this genetic variation remains poorly understood. In the saltmarsh beetle Pogonus chalceus, short-winged 'tidal' and long-winged 'seasonal' ecotypes have diverged in response to contrasting hydrological regimes and can be repeatedly found along the Atlantic European coast. By analyzing genomic variation across the beetles' distribution, we reveal that alleles selected in the tidal ecotype are spread across the genome and evolved during a singular and, likely, geographically isolated divergence event, within the last 190 Kya. Due to subsequent admixture, the ancient and differentially selected alleles are currently polymorphic in most populations across its range, which could potentially allow for the fast evolution of one ecotype from a small number of random individuals, as low as 5 to 15, from a population of the other ecotype. Our results suggest that cases of fast parallel ecological divergence can be the result of evolution at two different time frames: divergence in the past, followed by repeated selection on the same divergently evolved alleles after admixture. These findings highlight the importance of an ancient and, likely, allopatric divergence event for driving the rate and direction of contemporary fast evolution under gene flow. This mechanism is potentially driven by periods of geographic isolation imposed by large-scale environmental changes such as glacial cycles. PMID- 30422984 TI - Tick-borne encephalitis: A 43-year summary of epidemiological and clinical data from Latvia (1973 to 2016). AB - BACKGROUND: The incidence of tick-borne encephalitis (TBE) varies significantly over time. To better understand the annual incidence of all TBE cases in Latvia we investigated the disease burden in the country from 1973-2016 using several available sources and case definitions. METHODS: We identified cases of TBE from an electronic database (maintained by the Centre for Disease Prevention and Control of Latvia [CDPC]) by the use of ICD-10 diagnosis codes for TBE (A84; A84.0; A84.1; A84.8; A84.9). In addition, previously unreported TBE cases were found by review of TBE diagnoses according to ICD-10 codes in four hospital databases. RESULTS: From 1973 to 2016 a total of 15,193 TBE cases were reported to the CDPC, 2,819 of which were reported from January 2007 through December 2016, additionally for this time period, 104 cases were identified via hospital survey. From all 2,923 reported cases (2007-2016), 1,973 met TBE case definition criteria and were included in the TBE study analysis. The highest average 10 year incidence was observed from 1990-1999 (27.9 cases per 100,000; range 4.6-53.0), however, the average 10-year incidence from 2007-2016 using officially adopted TBE case definition was 9.6 cases per 100,000 (range 5.8-14.6). For this 10-year time period most cases were adults (95.1%) and male (52.2%). The most common clinical form of TBE was meningitis (90.6%). A tick bite prior to TBE onset was reported in 60.6% of TBE cases and 98.2% of cases were not vaccinated against TBE. CONCLUSION: The data demonstrate that the incidence of TBE varies by about one third based on the case definition used. TBE occurs almost entirely in the unvaccinated population. Regular TBE awareness campaigns could encourage the population in Latvia to use protective measures to further control TBE in the country, either via vaccination or tick avoidance. PMID- 30422985 TI - Machine learning to identify pairwise interactions between specific IgE antibodies and their association with asthma: A cross-sectional analysis within a population-based birth cohort. AB - BACKGROUND: The relationship between allergic sensitisation and asthma is complex; the data about the strength of this association are conflicting. We propose that the discrepancies arise in part because allergic sensitisation may not be a single entity (as considered conventionally) but a collection of several different classes of sensitisation. We hypothesise that pairings between immunoglobulin E (IgE) antibodies to individual allergenic molecules (components), rather than IgE responses to 'informative' molecules, are associated with increased risk of asthma. METHODS AND FINDINGS: In a cross sectional analysis among 461 children aged 11 years participating in a population based birth cohort, we measured serum-specific IgE responses to 112 allergen components using a multiplex array (ImmunoCAP Immuno-Solid phase Allergy Chip [ISAC]). We characterised sensitivity to 44 active components (specific immunoglobulin E [sIgE] > 0.30 units in at least 5% of children) among the 213 (46.2%) participants sensitised to at least one of these 44 components. We adopted several machine learning methodologies that offer a powerful framework to investigate the highly complex sIgE-asthma relationship. Firstly, we applied network analysis and hierarchical clustering (HC) to explore the connectivity structure of component-specific IgEs and identify clusters of component-specific sensitisation ('component clusters'). Of the 44 components included in the model, 33 grouped in seven clusters (C.sIgE-1-7), and the remaining 11 formed singleton clusters. Cluster membership mapped closely to the structural homology of proteins and/or their biological source. Components in the pathogenesis-related (PR)-10 proteins cluster (C.sIgE-5) were central to the network and mediated connections between components from grass (C.sIgE-4), trees (C.sIgE-6), and profilin clusters (C.sIgE-7) with those in mite (C.sIgE-1), lipocalins (C.sIgE 3), and peanut clusters (C.sIgE-2). We then used HC to identify four common 'sensitisation clusters' among study participants: (1) multiple sensitisation (sIgE to multiple components across all seven component clusters and singleton components), (2) predominantly dust mite sensitisation (IgE responses mainly to components from C.sIgE-1), (3) predominantly grass and tree sensitisation (sIgE to multiple components across C.sIgE-4-7), and (4) lower-grade sensitisation. We used a bipartite network to explore the relationship between component clusters, sensitisation clusters, and asthma, and the joint density-based nonparametric differential interaction network analysis and classification (JDINAC) to test whether pairwise interactions of component-specific IgEs are associated with asthma. JDINAC with pairwise interactions provided a good balance between sensitivity (0.84) and specificity (0.87), and outperformed penalised logistic regression with individual sIgE components in predicting asthma, with an area under the curve (AUC) of 0.94, compared with 0.73. We then inferred the differential network of pairwise component-specific IgE interactions, which demonstrated that 18 pairs of components predicted asthma. These findings were confirmed in an independent sample of children aged 8 years who participated in the same birth cohort but did not have component-resolved diagnostics (CRD) data at age 11 years. The main limitation of our study was the exclusion of potentially important allergens caused by both the ISAC chip resolution as well as the filtering step. Clustering and the network analyses might have provided different solutions if additional components had been available. CONCLUSIONS: Interactions between pairs of sIgE components are associated with increased risk of asthma and may provide the basis for designing diagnostic tools for asthma. PMID- 30422986 TI - Rabies vaccine initiation and adherence among animal-bite patients in Haiti, 2015. AB - BACKGROUND: Approximately 59,000 people die from rabies worldwide annually. Haiti is one of the last remaining countries in the Western Hemisphere with endemic canine rabies. Canine-mediated rabies deaths are preventable with post-exposure prophylaxis (PEP): wound treatment, immunoglobulin, and vaccination. In countries where PEP is available, variability in healthcare seeking behaviors and lack of adherence to recommended treatment guidelines could also contribute to these deaths. Yet, few studies have addressed these issues. METHODS: We examined animal bite reporting and assessed adherence to treatment guidelines at nine healthcare facilities in Haiti. We analyzed individual-level, de-identified patient data (demographic characteristics, geographic location, healthcare facility type, vaccine administration, and bite injury information) using descriptive analyses and logistic regression to examine factors associated with receiving PEP. FINDINGS: During the 6 month study period, we found 2.5 times more animal-bite case-patients than reported by the national surveillance system (690 versus 274). Of the 690 animal-bite patients identified, 498 (72%) sought care at six PEP providing facilities. Of the case-patients that sought care, 110 (22%) received at least one rabies vaccine. Of the 110 patients, 60 (55%) received all five doses. Delays were observed for three events: when patients presented to a facility after an animal-bite (3.0 days, range: 0-34 days), when patients received their fourth dose (16.1 days, range: 13-52 days), and when patients received their fifth dose (29 days, range: 26-52). When comparing vaccination status and patient characteristics, we found a significant association for bite location (p < .001), severity rank score (p < .001), geographic location (p < .001), and healthcare facility type (p = .002) with vaccination. CONCLUSION: High levels of underreporting identified here are of concern since vaccine distribution may, in part, be based on the number of animal-bite cases reported. Given that the Haitian government provides PEP to the population for free and we found animal-bite victims are seeking care in a timely manner? reducing rabies deaths is an achievable goal. PMID- 30422987 TI - Machine learning assessment of myocardial ischemia using angiography: Development and retrospective validation. AB - BACKGROUND: Invasive fractional flow reserve (FFR) is a standard tool for identifying ischemia-producing coronary stenosis. However, in clinical practice, over 70% of treatment decisions still rely on visual estimation of angiographic stenosis, which has limited accuracy (about 60%-65%) for the prediction of FFR < 0.80. One of the reasons for the visual-functional mismatch is that myocardial ischemia can be affected by the supplied myocardial size, which is not always evident by coronary angiography. The aims of this study were to develop an angiography-based machine learning (ML) algorithm for predicting the supplied myocardial volume for a stenosis, as measured using coronary computed tomography angiography (CCTA), and then to build an angiography-based classifier for the lesions with an FFR < 0.80 versus >= 0.80. METHODS AND FINDINGS: A retrospective study was conducted using data from 1,132 stable and unstable angina patients with 1,132 intermediate lesions who underwent invasive coronary angiography, FFR, and CCTA at the Asan Medical Center, Seoul, Korea, between 1 May 2012 and 30 November 2015. The mean age was 63 +/- 10 years, 76% were men, and 72% of the patients presented with stable angina. Of these, 932 patients (assessed before 31 January 2015) constituted the training set for the algorithm, and 200 patients (assessed after 1 February 2015) served as a test cohort to validate its diagnostic performance. Additionally, external validation with 79 patients from two centers (CHA University, Seongnam, Korea, and Ajou University, Suwon, Korea) was conducted. After automatic contour calibration using the caliber of guiding catheter, quantitative coronary angiography was performed using the edge detection algorithms (CAAS-5, Pie-Medical). Clinical information was provided by the Asan BiomedicaL Research Environment (ABLE) system. The CCTA-based myocardial segmentation (CAMS)-derived myocardial volume supplied by each vessel (right coronary artery [RCA], left anterior descending [LAD], left circumflex [LCX]) and the myocardial volume subtended to a stenotic segment (CAMS-%Vsub) were measured for labeling. The ML for (1) predicting vessel territories (CAMS-%LAD, CAMS-%LCX, and CAMS-%RCA) and CAMS-%Vsub and (2) identifying the lesions with an FFR < 0.80 was constructed. Angiography-based ML, employing a light gradient boosting machine (GBM), showed mean absolute errors (MAEs) of 5.42%, 8.57%, and 4.54% for predicting CAMS-%LAD, CAMS-%LCX, and CAMS-%RCA, respectively. The percent myocardial volumes predicted by ML were used to predict the CAMS-%Vsub. With 5 fold cross validation, the MAEs between ML-predicted percent myocardial volume subtended to a stenotic segment (ML-%Vsub) and CAMS-%Vsub were minimized by the elastic net (6.26% +/- 0.55% for LAD, 5.79% +/- 0.68% for LCX, and 2.95% +/- 0.14% for RCA lesions). Using all attributes (age, sex, involved vessel segment, and angiographic features affecting the myocardial territory and stenosis degree), the ML classifiers (L2 penalized logistic regression, support vector machine, and random forest) predicted an FFR < 0.80 with an accuracy of approximately 80% (area under the curve [AUC] = 0.84-0.87, 95% confidence intervals 0.71-0.94) in the test set, which was greater than that of diameter stenosis (DS) > 53% (66%, AUC = 0.71, 95% confidence intervals 0.65-0.78). The external validation showed 84% accuracy (AUC = 0.89, 95% confidence intervals 0.83-0.95). The retrospective design, single ethnicity, and the lack of clinical outcomes may limit this prediction model's generalized application. CONCLUSION: We found that angiography-based ML is useful to predict subtended myocardial territories and ischemia-producing lesions by mitigating the visual-functional mismatch between angiographic and FFR. Assessment of clinical utility requires further validation in a large, prospective cohort study. PMID- 30422988 TI - Characterization of microbes and denitrifiers attached to two species of floating plants in the wetlands of Lake Taihu. AB - Biofilms are often observed at the solid-water interface. The leaves of many floating macrophytes have characteristics of both terrestrial plants and submerged macrophytes, because, in general, their upper and lower surfaces are exposed to air and water, respectively. However, little is known about the biofilms attached to floating plants. We investigated biofilms attached to the leaves, stems and roots of the floating plants Nymphoides peltata (in summer and winter) and Trapa natans (in summer) in the Gonghu Bay of Lake Taihu. Bacteria and algae were major components of the biofilm on the leaves of the two species of plants. In addition, 454 pyrosequencing analysis of bacterial 16S rRNA genes revealed that Proteobacteria was the dominant phylum, followed by Bacteroidetes, Firmicutes, Chloroflexi, Acidobacteria, and Verrucomicrobia. Cluster analysis showed that bacterial communities from the same plant source were clustered into the same group. A total of 677 genera were detected, and 47 genera were shared by all samples. Nitrifiers, including Nitrosomonas, Nitrosococcus and Nitrospira were detected in this study. Seven denitrifying genes (napA, napG, nirS, nirK, cnorB, qnorB and nosZ) were used to detect the abundance of denitrifiers. Genes nirK, nirS cnorB and nosZ were the four most abundant genes in all samples. Our results demonstrated that cultivation of floating plants in water column could enlarge the area for biofilm growth, and biofilms might play an important role in denitrification in eutrophic water. PMID- 30422989 TI - H3K36 trimethylation mediated by SETD2 regulates the fate of bone marrow mesenchymal stem cells. AB - During the aging process, bone marrow mesenchymal stem cells (BMSCs) exhibit declined osteogenesis accompanied by excess adipogenesis, which will lead to osteoporosis. Here, we report that the H3 lysine 36 trimethylation (H3K36me3), catalyzed by histone methyltransferase SET-domain-containing 2 (SETD2), regulates lineage commitment of BMSCs. Deletion of Setd2 in mouse bone marrow mesenchymal stem cells (mBMSCs), through conditional Cre expression driven by Prx1 promoter, resulted in bone loss and marrow adiposity. Loss of Setd2 in BMSCs in vitro facilitated differentiation propensity to adipocytes rather than to osteoblasts. Through conjoint analysis of RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) data, we identified a SETD2 functional target gene, Lbp, on which H3K36me3 was enriched, and its expression was affected by Setd2 deficiency. Furthermore, overexpression of lipopolysaccharide-binding protein (LBP) could partially rescue the lack of osteogenesis and enhanced adipogenesis resulting from the absence of Setd2 in BMSCs. Further mechanistic studies demonstrated that the trimethylation level of H3K36 could regulate Lbp transcriptional initiation and elongation. These findings suggest that H3K36me3 mediated by SETD2 could regulate the cell fate of mesenchymal stem cells (MSCs) in vitro and in vivo, indicating that the regulation of H3K36me3 level by targeting SETD2 and/or the administration of downstream LBP may represent a potential therapeutic way for new treatment in metabolic bone diseases, such as osteoporosis. PMID- 30422990 TI - Microvascular dysfunction determines infarct characteristics in patients with reperfused ST-segment elevation myocardial infarction: The MICROcirculation in Acute Myocardial Infarction (MICRO-AMI) study. AB - BACKGROUND: In patients with reperfused ST-elevation myocardial infarction (STEMI) both invasive and non-invasive assessments of microvascular dysfunction, the index of microcirculatory resistance (IMR), and microvascular obstruction (MVO) by cardiovascular magnetic resonance (CMR), independently predict poor long term outcomes. AIMS: The aims of this study were to investigate whether an invasive parameter (IMR), assessed at the time of primary percutaneous intervention (PPCI), could predict the extent of MVO in proportion to infarct size (MVO index). METHODS: 50 patients presenting with STEMI and TIMI flow <= I in the infarct related artery were prospectively recruited to the study, before undergoing PPCI. All patients underwent invasive IMR assessment at maximal hyperaemia using adenosine, and following stent insertion. CMR was performed on day 2 following STEMI, MVO was assessed both on first-pass rest perfusion (early MVO) and in the late gadolinium enhancement (LGE) images (late MVO) along with infarct size. The MVO index was calculated as the ratio of late MVO/infarct size. Differences between IMR quartiles and the MVO index were investigated. RESULTS: The median IMR was 38.5 (range 9 to 202). The median size of late MVO was 1.9% LV (range 0 to 21.0% LV). IMR predicted late MVO (p<0.01) and as IMR increased, the MVO index increased (r = 0.70, [95% CI 0.53, 0.82], p<0.001). An IMR cut-off of 40 significantly predicted the presence of late MVO on CMR (p<0.001). CONCLUSION: IMR measured at the time of PPCI in acutely reperfused STEMI is associated with the presence and severity of infarct damage as measured by the MVO index. TRIAL REGISTRATION: The Microcirculation in Acute Myocardial Infarction (MICRO-AMI). Clinicaltrials.gov NCT01552564. Registered 9th March 2012. PMID- 30422991 TI - The intergenerational transmission of partnering. AB - As divorce and cohabitation dissolution in the US have increased, partnering has expanded to the point that sociologists describe a merry-go-round of partners in American families. Could one driver of the increase in the number of partners be an intergenerational transmission of partnering? We discuss three theoretical perspectives on potential mechanisms that would underlie an intergenerational transmission of partnering: the transmission of economic hardship, the transmission of marriageable characteristics and relationship skills, and the transmission of relationship commitment. Using the National Longitudinal Survey of Youth 1979 Child and Young Adult study (NLSY79 CYA) and their mothers in the National Longitudinal Survey of Youth 1979 (NLSY79), we examined the intergenerational transmission of partnering, including both marital and cohabitating unions, using prospective measures of family and economic instability as well as exploiting sibling data to try to identify potential mechanisms. Even after controlling for maternal demographic characteristics and socioeconomic factors, the number of maternal partners was positively associated with offspring's number of partners. Hybrid sibling Poisson regression models that examined sibling differential experiences of maternal partners indicated that there were no differences between siblings who witnessed more or fewer maternal partners. Overall, results suggested that the transmission of poor marriageable characteristics and relationship skills from mother to child may warrant additional attention as a potential mechanism through which the number of partners continues across generations. PMID- 30422992 TI - Whole genome screen reveals a novel relationship between Wolbachia levels and Drosophila host translation. AB - Wolbachia is an intracellular bacterium that infects a remarkable range of insect hosts. Insects such as mosquitos act as vectors for many devastating human viruses such as Dengue, West Nile, and Zika. Remarkably, Wolbachia infection provides insect hosts with resistance to many arboviruses thereby rendering the insects ineffective as vectors. To utilize Wolbachia effectively as a tool against vector-borne viruses a better understanding of the host-Wolbachia relationship is needed. To investigate Wolbachia-insect interactions we used the Wolbachia/Drosophila model that provides a genetically tractable system for studying host-pathogen interactions. We coupled genome-wide RNAi screening with a novel high-throughput fluorescence in situ hybridization (FISH) assay to detect changes in Wolbachia levels in a Wolbachia-infected Drosophila cell line JW18. 1117 genes altered Wolbachia levels when knocked down by RNAi of which 329 genes increased and 788 genes decreased the level of Wolbachia. Validation of hits included in depth secondary screening using in vitro RNAi, Drosophila mutants, and Wolbachia-detection by DNA qPCR. A diverse set of host gene networks was identified to regulate Wolbachia levels and unexpectedly revealed that perturbations of host translation components such as the ribosome and translation initiation factors results in increased Wolbachia levels both in vitro using RNAi and in vivo using mutants and a chemical-based translation inhibition assay. This work provides evidence for Wolbachia-host translation interaction and strengthens our general understanding of the Wolbachia-host intracellular relationship. PMID- 30422995 TI - A (former) skeptic's view of bariatric surgery. PMID- 30422993 TI - Delayed oseltamivir plus sirolimus treatment attenuates H1N1 virus-induced severe lung injury correlated with repressed NLRP3 inflammasome activation and inflammatory cell infiltration. AB - Severe influenza A virus infection causes high mortality and morbidity worldwide due to delayed antiviral treatment and inducing overwhelming immune responses, which contribute to immunopathological lung injury. Sirolimus, an inhibitor of mammalian target of rapamycin (mTOR), was effective in improving clinical outcomes in patients with severe H1N1 infection; however, the mechanisms by which it attenuates acute lung injury have not been elucidated. Here, delayed oseltamivir treatment was used to mimic clinical settings on lethal influenza A (H1N1) pdm09 virus (pH1N1) infection mice model. We revealed that delayed oseltamivir plus sirolimus treatment protects mice against lethal pH1N1 infection by attenuating severe lung damage. Mechanistically, the combined treatment reduced viral titer and pH1N1-induced mTOR activation. Subsequently, it suppressed the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated secretion of interleukin (IL)-1beta and IL-18. It was noted that decreased NLRP3 inflammasome activation was associated with inhibited nuclear factor (NF)-kappaB activation, reduced reactive oxygen species production and increased autophagy. Additionally, the combined treatment reduced the expression of other proinflammatory cytokines and chemokines, and decreased inflammatory cell infiltration in lung tissue and bronchioalveolar lavage fluid. Consistently, it inhibited the mTOR-NF-kappaB-NLRP3 inflammasome-IL-1beta axis in a lung epithelial cell line. These results demonstrated that combined treatment with sirolimus and oseltamivir attenuates pH1N1-induced severe lung injury, which is correlated with suppressed mTOR-NLRP3-IL-1beta axis and reduced viral titer. Therefore, treatment with sirolimus as an adjuvant along with oseltamivir may be a promising immunomodulatory strategy for managing severe influenza. PMID- 30422994 TI - Impact of chronic total occlusion lesion length on six-month angiographic and 2 year clinical outcomes. AB - BACKGROUND: Successful management of chronic total occlusion (CTO)by percutaneous coronary intervention (PCI) is known to be associated with better clinical outcomes than failed PCI. However, whether angiographic and clinical outcomes following PCI for long CTO lesions differ from those following PCI for short CTO lesions in the drug eluting stent (DES) era remains unknown. We therefore investigated whether CTO lesion length can significantly influence6-month angiographic and 2-year clinical outcomes following successful CTO PCI. METHODS AND RESULTS: A total of 235 consecutive patients who underwent successful CTO intervention were allocated into either the long or short CTO group according to CTO lesion length. Six-month angiographic and 2-year clinical outcomes were then compared between the 2groups. We found that baseline clinical characteristics were generally similar between the 2 groups. Exceptions were prior PCI, which was more frequent in the long CTO group, and bifurcation lesions, which were more frequent in the short CTO group. Apart from intimal dissection, which was more frequent in the long than short CTO group, in-hospital complications were also similarly frequent between the 2groups. Furthermore, both groups had similar angiographic outcomes at 6 months and clinical outcomes at 2 years. However, the incidence of repeat PCI(predominantly target vessel revascularization),was higher in the long than short CTO group, with our multivariate analysis identifying long CTO as an important predictor of repeat PCI (odds ratio, 4.26;95% confidence interval, 1.53-11.9; p = 0.006). CONCLUSION: The safety profile, 6-month angiographic, and 2-year clinical outcomes of CTO PCI were similar between patients with long and short CTO. However, there was a higher incidence of repeat PCI in long CTO patients despite successful PCI with DESs. PMID- 30422996 TI - Obesity: When to consider surgery. AB - Bariatric surgery is underutilized despite an obesity epidemic. Here, 3 patients pursue a surgical option when they can't reach their target weight and optimal health by nonsurgical means. PMID- 30422997 TI - Take these steps to improve your flu season preparedness. AB - The 6 strategies outlined here can help you reduce the risk of illness and limit its severity if contracted. PMID- 30422998 TI - Strategies for caring for the well cancer survivor. AB - Surveillance of existing cancer, management of treatment-related adverse effects, and screening for second cancers are key to the care you'll provide. PMID- 30422999 TI - How to treat complicated grief. AB - Several DSM-5 criteria lasting 6 months or longer can help identify complicated grief, as can available assessment tools. Treatment has a unique focus. PMID- 30423000 TI - Nausea and vomiting . sensitivity to smell . history of hypertension and alcohol abuse . Dx? PMID- 30423001 TI - Photo Rounds: Chronic diarrhea in a 64-year-old woman. AB - Our patient presented with abdominal pain and worsening diarrhea. She had no significant medical history, but imaging studies helped us make the Dx. PMID- 30423002 TI - How effectively do ACE inhibitors and ARBs prevent migraines? PMID- 30423003 TI - Dehydration in terminal illness: Which path forward? AB - While our natural tendency is to restore full hydration to patients, how do we proceed when death is imminent and being fully hydrated may prolong discomfort? PMID- 30423004 TI - What's the best VTE treatment for patients with cancer? PMID- 30423005 TI - Ever-evolving Concepts in the Asthma Management Landscape in the United States. PMID- 30423006 TI - An Update on Treatment Options for Children and Adults With Asthma. PMID- 30423007 TI - Confronting the Challenges of Severe Asthma. PMID- 30423008 TI - COPD Management in the Primary Care Setting. PMID- 30423010 TI - Optimizing Adherence to Improve Clinical Outcomes in Patients with Chronic Obstructive Pulmonary Disease. PMID- 30423009 TI - Interpreting Recent Developments in COPD Treatments. PMID- 30423011 TI - Asthma-Chronic Obstructive Pulmonary Disease Overlap: Diagnostic and Management Challenges. PMID- 30423012 TI - Optimizing Insulin Therapy: Basal Insulin and Beyond. AB - Data suggest that in patients with type 2 diabetes, there has been little or no improvement in glycated hemoglobin (A1C) and other glycemic parameters over recent decades. In this digital roundtable discussion, the speakers address challenges faced every day in clinical practice, and provide practical advice regarding how primary care clinicians can overcome clinical inertia. The speakers particularly focus on how to manage patients who are treated with basal insulin, yet are unable to achieve good glycemic control. PMID- 30423013 TI - Mild Allergic Transfusion Reactions: Impact of Associated Clinical Symptoms? AB - Objectives: Transfusions are often needlessly aborted after occurrence of a mild allergic transfusion reaction (ATR), leading to wastage and reexposure of recipients to additional blood products (with potential alloimmunization). We aimed to determine the symptoms associated with such reactions (along with other parameters) as a possible reason of concern for transfusionists aborting such transfusions. Methods: We reviewed the symptomology of all mild ATRs (as well as the associated wastage and costs of aborted transfusions) at an academic medical center that occurred over a period of 1 year. Results: Of the patients, 52.3% had nonatopic-associated symptoms. The most common associated symptom was tachycardia (37.8%), followed by dyspnea (28.9%), hypotension (17.8%), and hypertension (13.3%). More than half of patients (54.7%) required retransfusion. The estimated cost of product wastage was $12,507. Conclusions: Understanding symptoms associated with mild ATRs may lead to improved management of patients, with fewer unnecessary transfusions and less wastage. PMID- 30423014 TI - Six-Year Prospective Outcomes of Primary Breast Augmentation With Nano Surface Implants. AB - Background: Motiva Implants (Establishment Labs Holdings Inc.) are a novel family of silicone breast implants using cutting-edge technologies engineered to optimize aesthetic and safety outcomes. Objectives: The authors sought to prospectively evaluate the safety and effectiveness of SmoothSilk/SilkSurface Motiva Implants over long-term follow-up. Methods: Surgeons at a single plastic surgery center undertook a 10-year follow-up study of SmoothSilk/SilkSurface Motiva Implants in women who underwent primary breast augmentation. Safety was assessed through identification of complications on follow-up and through magnetic resonance imaging (MRI) in a representative sample. Effectiveness outcomes were assessed by surgeons and patients using Likert scales and a Quality of Life tool. Results: This article reports the 6-year safety and effectiveness outcomes. A total of 35 patients were implanted between September and December 2010, and 71.9% of implants were placed submuscularly using inframammary incision. During the 6-year follow-up, there were no occurrences of capsular contracture, rupture, double capsules, or late seroma. MRI evaluation identified no signs of implant-related complications. Three revision surgeries were performed, all for aesthetic reasons; there were no implant replacements for medical reasons. The level of satisfaction for both patients and surgeons was high at all follow-up visits. Patient quality-of-life scores increased following breast augmentation by an average of 0.89% at 72 months. Conclusions: The results of this prospective long-term follow-up study demonstrate the excellent safety and effectiveness of SmoothSilk/SilkSurface Motiva Implants in primary breast augmentation through 6 years of follow-up. Level of Evidence 4: PMID- 30423016 TI - A high level of TGF-B1 promotes endometriosis development via cell migration, adhesiveness, colonization, and invasiveness. AB - Endometriosis is a prevalent gynecological disorder that eventually gives rise to painful invasive lesions. Increased levels of transforming growth factor-beta1 (TGF-B1) have been reported in endometriosis. However, details of the effects of high TGF-B1 on downstream signaling in ectopic endometrial tissue remain obscure. We induced endometriotic lesions in mice by surgical auto-transplantation of endometrial tissues to the peritoneal regions. We then treated endometriotic (ectopic and eutopic endometrial tissues) and non-endometriotic (only eutopic endometrial tissues) animal groups with either active TGF-B1 or PBS. Our results demonstrate that externally supplemented TGF-B1 increases the growth of ectopically implanted endometrial tissues in mice, possibly via SMAD2/3 activation and PTEN suppression. Adhesion molecules integrins (beta3 and beta8) and FAK were upregulated in the ectopic endometrial tissue when TGF-B1 was administered. Phosphorylated E-cadherin, N-cadherin, and vimentin were enhanced in the ectopic endometrial tissue in the presence of TGF-B1 in the mouse model, and correlated with Epithelial-Mesenchymal Transition (EMT) in ovarian endometriotic cells of human origin. Further, in response to TGF-B1, the expression of RHOGTPases (RAC1, RHOC and RHOG) were increased in the human endometriotic cells (ovarian cyst derived cells from endometriosis patient) and tissues from the mouse model of endometriosis (ectopic endometrial tissue). TGF B1 enhanced the migration, invasive, and colonizing potential of human endometriotic cells. Therefore, we conclude that TGF-B1 potentiates the adhesion of ectopic endometrial cells/tissues in the peritoneal region by enhancing the integrin- and FAK-signaling axis, and also migration via cadherin-mediated EMT and RHOGTPase-signaling cascades. PMID- 30423017 TI - Brain responses to anticipation and consumption of beer with and without alcohol. AB - Beer is a popular alcoholic beverage world-wide. Non-alcoholic beer is increasingly marketed. Brain responses to beer and non-alcoholic beer (NA-beer) have not been compared. It could be that the flavor of beer constitutes a conditioned stimulus associated with alcohol reward. Therefore, we investigated whether oral exposure to NA-beer with or without alcohol elicits similar brain responses in reward-related areas in a context where regular alcoholic beer is expected. Healthy men (n=21) who were regular beer drinkers were scanned using functional MRI. Participants were exposed to word cues signaling delivery of a 10 ml sip of chilled beer or carbonated water (control) and subsequent sips of NA beer with or without alcohol or water (control). Beer alcohol content was not signaled. The beer cue elicited less activation than the control cue in the primary visual cortex, supplementary motor area (reward-related region) and bilateral inferior frontal gyrus/frontal operculum. During tasting, there were no significant differences between the 2 beers. Taste activation after swallowing was significantly greater for alcoholic than for NA-beer in the inferior frontal gyrus/anterior insula and dorsal prefrontal cortex (superior frontal gyrus). This appears to be due to sensory stimulation by ethanol rather than reward processing. In conclusion, we found no differences in acute brain reward upon consumption of NA-beer with and without alcohol, when presented in a context where regular alcoholic beer is expected. This suggests that in regular consumers beer flavor rather than the presence of alcohol is the main driver of the consumption experience. PMID- 30423015 TI - A novel ATP1A2 mutation in a patient with hypokalaemic periodic paralysis and CNS symptoms. AB - Hypokalaemic periodic paralysis is a rare genetic neuromuscular disease characterized by episodes of skeletal muscle paralysis associated with low serum potassium. Muscle fibre inexcitability during attacks of paralysis is due to an aberrant depolarizing leak current through mutant voltage sensing domains of either the sarcolemmal voltage-gated calcium or sodium channel. We report a child with hypokalaemic periodic paralysis and CNS involvement, including seizures, but without mutations in the known periodic paralysis genes. We identified a novel heterozygous de novo missense mutation in the ATP1A2 gene encoding the alpha2 subunit of the Na+/K+-ATPase that is abundantly expressed in skeletal muscle and in brain astrocytes. Pump activity is crucial for Na+ and K+ homeostasis following sustained muscle or neuronal activity and its dysfunction is linked to the CNS disorders hemiplegic migraine and alternating hemiplegia of childhood, but muscle dysfunction has not been reported. Electrophysiological measurements of mutant pump activity in Xenopus oocytes revealed lower turnover rates in physiological extracellular K+ and an anomalous inward leak current in hypokalaemic conditions, predicted to lead to muscle depolarization. Our data provide important evidence supporting a leak current as the major pathomechanism underlying hypokalaemic periodic paralysis and indicate ATP1A2 as a new hypokalaemic periodic paralysis gene. PMID- 30423018 TI - KRAS mutations in ctDNA: a promising new biomarker in advanced pancreatic cancer. PMID- 30423019 TI - Female Cosmetic Genital Surgery: Patient Characteristics, Motivation, and Satisfaction. AB - Background: Female cosmetic genital surgery is rapidly growing. However, controversy reports raised around these procedures question their indications, motives, and safety. Warning against performing this surgery might unjustly restrict surgical alleviation of symptoms. Objectives: Through anonymous exploration, the authors explored patient characteristics and motivation, when women started to think about surgery, and effects of surgery on psychosocial and cosmetic aspects. Methods: Of 125 patients who underwent female cosmetic genital surgery at Oslo Plastic Surgery Clinic between 2010 and 2016, 69 patients were reachable by e-mail. A questionnaire with 40 questions was completed anonymously. Answers were processed by a third, independent party via QuestBack return mail system. Results: Response rate was 77%. Mean follow-up time was 31.4 months. Mean patient age was 30.8 years. Motivations for surgery were cosmetic (69.8%), physical/practical (62.3%), emotional (54.7%), and intimate (49.1%). When emotional reasons were involved, media (39.7%), pornography (31.5%), and negative comments (28.8%) influenced the decision to undergo surgery. Genital concerns had negative effects on self-esteem (63.2%) and sexual attractiveness (57.9%) among others; 90.5% thought about surgery for more than 1 year. Overall cosmetic result was satisfactory for 69.8%, and the operation as a whole was satisfactory for 75.5%. Conclusions: Age, level of education, and gross income of patients who underwent this surgery seem high compared with those of breast implant patients. Genital dissatisfaction arose early in life and affected various psychosexual aspects. Most patients are satisfied with the outcome of surgery and would recommend this surgery to others. Additional anonymous multicenter studies are recommended. PMID- 30423020 TI - Targeted expression of cyclin D2 ameliorates late stage anthracycline cardiotoxicity. AB - Background: Doxorubicin (DOX) is a widely used and effective anti-cancer therapeutic. DOX treatment is associated with both acute and late onset cardiotoxicity, limiting its overall efficacy. Here, the impact of cardiomyocyte cell cycle activation was examined in a juvenile model featuring aspects of acute and late onset DOX cardiotoxicity. Methods and Results: Two-week old MHC-cycD2 transgenic mice (which express cyclin D2 in postnatal cardiomyocytes and exhibit sustained cardiomyocyte cell cycle activity; D2 mice) and their wild type (WT) littermates received weekly DOX injections for 5 weeks (25 mg/kg cumulative dose). One week after the last DOX treatment (acute stage), cardiac function was suppressed in both groups. Acute DOX cardiotoxicity in D2 and WT mice was associated with similar increases in the levels of cardiomyocyte apoptosis and Ku70/Ku80 expression (markers of DNA damage and oxidative stress), as well as similar reductions in hypertrophic cardiomyocyte growth. Cardiac dysfunction persisted in WT mice for 13 weeks following the last DOX treatment (late stage), and was accompanied by increased levels of cardiomyocyte apoptosis, Ku expression and myocardial fibrosis. In contrast, D2 mice exhibited a progressive recovery in cardiac function, which was indistinguishable from saline-treated animals by 9 weeks following the last DOX treatment. Improved cardiac function was accompanied by reductions in the levels of late stage cardiomyocyte apoptosis, Ku expression and myocardial fibrosis. Conclusions: These data suggest that cardiomyocyte cell cycle activity can promote recovery of cardiac function and preserve cardiac structure following DOX treatment. PMID- 30423021 TI - Cost per Case Mix Index-Adjusted Hospital Day as a Measure of Effective Laboratory Utilization Efforts in a Growing Academic Medical Center. AB - Objectives: Traditional laboratory utilization measures are unable to detect the results of small-scale utilization improvement efforts in a background of rising patient volumes and acuity. However, accurate assessment is necessary to document effectiveness of these efforts. Methods: Test menu changes, physician education, and laboratory utilization feedback were used to address costs and overused tests. Effectiveness was evaluated using cost/case mix index (CMI)-adjusted hospital day and inpatient tests/CMI-adjusted discharge. These metrics were compared with the more traditional measures of cost/test and inpatient tests/discharge. Results: Cost/CMI-adjusted hospital day and inpatient tests/CMI adjusted discharge better demonstrated the impact of utilization improvement efforts compared with more traditional measures because they account for changes in patient volume and acuity. Conclusions: Cost/CMI-adjusted hospital day and tests/CMI-adjusted discharge show the effectiveness of laboratory utilization efforts despite increasing patient volume and acuity. PMID- 30423022 TI - Human Borreliosis Caused by a New World Relapsing Fever Borrelia-like Organism in the Old World. AB - Background: Relapsing fever is an infectious disease previously neglected in Africa, which imposes a large public health burden in the country. We aimed to investigate and report on a case of relapsing fever borreliosis in Zambia. Methods: A previously unknown Borrelia species was isolated from the blood of a febrile patient. Investigations of the presumptive vector ticks and natural hosts for the Borrelia species were conducted by culture isolation and/or DNA detection by Borrelia-specific polymerase chain reaction. Using culture isolates from the patient and bat specimens, genetic characterization was performed by multilocus sequence analysis based on the draft genome sequences. Results: The febrile patient was diagnosed with relapsing fever. The isolated Borrelia species was frequently detected in Ornithodoros faini (n = 20/50 [40%]) and bats (n = 64/237 [27%]). Multilocus sequence analysis based on a draft genome sequence revealed that the Borrelia species isolates from the patient and presumptive reservoir host (bats) formed a monophyletic lineage that clustered with relapsing fever borreliae found in the United States. Conclusions: A febrile illness caused by a Borrelia species that was treatable with erythromycin was identified in Zambia. This is the first study to report on relapsing fever Borrelia in Zambia and suggesting the likely natural reservoir hosts of the isolated Borrelia species. Interestingly, the isolated Borrelia species was more closely related to New World relapsing fever borreliae, despite being detected in the Afrotropic ecozone. PMID- 30423023 TI - Analytical and Clinical Performance Evaluation of the Elecsys HIV combi PT Assay on the cobas e 602 Analyzer for the Diagnosis of Human Immunodeficiency Virus. AB - Objectives: We evaluated the performance of the Elecsys HIV combi PT assay on the cobas e 602 analyzer for diagnosing human immunodeficiency virus (HIV; part of the US Food and Drug Administration [FDA] submission). Methods: The HIV combi PT and reference (ARCHITECT HIV Ag/Ab Combo) assays were assessed at four independent clinical laboratories/one reference laboratory (United States; July 2014 to November 2015). Clinical performance was evaluated using four reagent lots. Analytical performance was evaluated per Clinical and Laboratory Standards Institute EP05-A3 guidelines. Serum/plasma samples from 18 clinical sites/vendors (United States and outside the United States) were tested. Results: Sensitivity (95% confidence interval [CI]) in HIV-1 antibody-positive individuals (United States and outside the United States; n = 1,460) was 100.00% (99.75%-100.00%). Specificity was 99.94% (95% CI, 99.85%-99.98%) in low-risk individuals (United States; n = 6,843), 98.19% (95% CI, 96.93%-99.04%) in high-risk individuals (United States and outside the United States; n = 758), and 97.43% (95% CI, 95.32%-98.76%) in pregnant women (United States and outside the United States; n = 440). Analytical performance was acceptable. Conclusions: We demonstrate the robustness of the FDA-approved Elecsys HIV combi PT assay on the cobas e 602 analyzer for HIV testing in the United States. PMID- 30423024 TI - Loss of function of NF1 is a mechanism of acquired resistance to endocrine therapy in lobular breast cancer. AB - Background: Invasive lobular carcinoma (ILC) as a disease entity distinct from invasive ductal carcinoma (IDC) has merited focused studies of the genomic landscape, but those to date are largely limited to the assessment of early-stage cancers. Given that genomic alterations may develop as acquired resistance to endocrine therapy, studies on refractory ILC are needed. Patients and Methods: Tissue from 336 primary-enriched, breast-biopsied ILC and 485 ER-positive IDC and metastatic biopsy specimens from 180 ILC and 191 ER-positive IDC patients was assayed with hybrid-capture based comprehensive genomic profiling for short variant, indel, copy number variants, and rearrangements in 395 cancer-related genes. Results: Whereas ESR1 alterations are enriched in the metastases of both ILC and IDC compared to breast specimens, NF1 alterations are enriched only in ILC metastases (mILC). NF1 alterations are predominantly under loss of heterozygosity (11/14, 79%), are mutually exclusive with ESR1 mutations (OR = 0.24, <0.027), and are frequently polyclonal in ctDNA assays. Assessment of paired specimens show that NF1 alterations arise in the setting of acquired resistance. An in vitro model of CDH1 mutated ER-positive breast cancer demonstrates that NF1 knockdown confers a growth advantage in the presence of 4 hydroxy tamoxifen. Our study further identified a significant increase in tumor mutational burden (TMB) in mILCs relative to breast ILCs or metastatic IDCs (8.9% >20 mutations/mb; <0.001). Most TMB-high mILCs harbor an APOBEC trinucleotide signature (14/16; 88%). Conclusions: This study identifies alteration of NF1 as enriched specifically in mILC. Mutual exclusivity with ESR1 alterations, polyclonality in relapsed ctDNA, and de novo acquisition suggest a role for NF1 loss in endocrine therapy resistance. Since NF1 loss leads to RAS/RAF kinase activation, patients may benefit from a matched inhibitor. Moreover, for an independent subset of mILC, TMB was elevated relative to breast ILC, suggesting possible benefit from immune checkpoint inhibitors. PMID- 30423025 TI - Identification and characterization of Letm1 gene in Toxoplasma gondii. AB - Toxoplasma gondii is an obligate intracellular protozoan that causes toxoplasmosis. Previous studies have shown that the perturbation of mitochondrial metabolism in T. gondii results in growth deficiency in host cells and lack of virulence in animals. Members of this Letm1 protein family are inner mitochondrial membrane proteins which play a role in potassium and hydrogen ion exchange. Letm1 has not been characterized in T. gondii. In this study, a potential TgLetm1 gene (TgGT1_288400) with Letm1-like protein domain coding sequence was identified in T. gondii. Indirect immunofluorescence assays suggested that TgLetm1 localized to the mitochondria in tachyzoites, as indicated by the colocalization with mitochondrial marker Mitotracker. TgLetm1 was found in the membrane fraction by western blot analysis. To investigate the role of TgLetm1 in T. gondii, we generated a tetracycline-inducible TgLetm1-knock-down mutant. The conditional deletion of TgLetm1 resulted in mitochondrial swelling. Functional studies showed that the conditional deletion of TgLetm1 resulted in growth inhibition, deficiency in invasion and replication, and lack of virulence in mice. PMID- 30423026 TI - NF?B Regulates Muscle Development and Mitochondrial Function. AB - NF?B is a transcription factor that controls immune and inflammatory signaling pathways. In skeletal muscle, NF?B has been implicated in the regulation of metabolic processes and tissue mass; yet, its affects on mitochondrial function in this tissue are unclear. To investigate the role of NF?B on mitochondrial function and its relationship with muscle mass across the lifespan, we study a mouse model with muscle-specific NF?B suppression (MISR mice). In wild type mice there was a natural decline in muscle mass with aging that was accompanied by decreased mitochondrial function and mRNA expression of electron transport chain subunits. NF?B inactivation downregulated expression of PPARGC1A, while upregulating TFEB and PPARGC1B, as well as decreased gastrocnemius (but not soleus) muscle mass in early life (1-6 months old). Lower oxygen consumption rates occurred in gastrocnemius and soleus muscles from young MISR mice, whereas soleus (but not gastrocnemius) muscles from old MISR mice displayed increased oxygen consumption compared to age-matched controls. We conclude that the NF?B pathway plays an important role in muscle development and growth. The extent to which NF?B suppression alters mitochondrial function is age-dependent and muscle specific. Lastly, mitochondrial function and muscle mass are tightly associated in both genotypes and across the lifespan. PMID- 30423027 TI - Effects of Moderate Ethanol Consumption on Lipid Metabolism and Inflammation Through Regulation of Gene Expression in Rats. AB - Aims: Epidemiological studies and experimental data from rodent models have reported a non-linear relationship between consumption of alcohol and cardiovascular disease (CVD) risk that suggests that light-to-moderate drinking as opposed to excessive consumption may provide some cardiovascular benefits. The present study examined potential mechanisms by which moderate alcohol consumption may provide a protective effect against CVD. Short summary: Wistar rats exposed for 3 months to a 20% ethanol intermittent-access voluntary drinking paradigm displayed a reduction in epididymal fat, blood glucose and non-HDL and total cholesterol. These effects were accompanied by decreased expression of Hmgcr, Srebp-2, Cox-2 and RelA, indicating downregulation of genes involved in cholesterol synthesis and inflammation. Methods: Twenty-four male Wistar rats voluntarily consumed a 20% v/v ethanol solution on alternate days for 13 weeks (ethanol-treated) or were given access to water alone (non-ethanol-exposed control). Results: There was no difference in body weight gain between the two groups, however, epididymal fat weight was lower in ethanol-fed rats (P = 0.030). Blood glucose, total cholesterol, non-high-density lipoprotein (HDL) and oxidized low-density lipoprotein (LDL) levels were lower in the ethanol group compared to controls (P < 0.05). There was a significant reduction in the expression of hydroxymethylglutaryl-coenzyme A reductase and sterol regulatory element-binding protein-2 in ethanol-treated rats (P < 0.05), suggesting that ethanol may have lowered cholesterol levels via downregulation of genes involved in cholesterol synthesis. Paraoxonase-1, which is associated with inhibition of LDL cholesterol oxidation, was upregulated in the ethanol group (P = 0.029). Ethanol-treated rats exhibited significantly lower levels of high-mobility box group protein 1 (P <= 0.05). Cyclooxygenase-2 and RelA gene expression were significantly lower in ethanol-treated rats (P < 0.05), indicating possible anti-inflammatory effects. Conclusions: These findings suggest that moderate ethanol consumption may potentially contribute to improved cardiovascular outcomes by reducing body fat, improving blood cholesterol and blood glucose, and modulation of gene expression involved in inflammation and/or cholesterol synthesis. PMID- 30423028 TI - Comparison of Phenotypic Activated Protein C Resistance Testing With a Genetic Assay for Factor V Leiden. AB - Objectives: To compare the accuracy and reliability of phenotypic activated protein C resistance (aPC-R) assays with a genotypic assay for the factor V Leiden F5 p.R506Q (FVL) mutation. Methods: Data were obtained from an electronic data warehouse for FVL testing performed at an academic institution with a large referral laboratory service. In total, 1,596 patients were identified who had undergone both phenotypic aPC-R and genotypic FVL mutation testing. Results: Phenotypic testing showed a high level of sensitivity, specificity, and other biostatistical values compared with genotypic testing. Improvements in technology decreased the amount of equivocal phenotypic results. Conclusions: Phenotypic assays had close to total concordance with genotypic assays over 16 years of testing. Changing ordering practices could result in up to an 80% reduction in testing costs. PMID- 30423029 TI - Local structural connectivity is associated with social cognition in autism spectrum disorder. AB - The current theory implying local, short-range overconnectivity in autism spectrum disorder, contrasting with long-range underconnectivity, is based on heterogeneous results, on limited data involving functional connectivity studies, on heterogeneous paediatric populations and non-specific methodologies. In this work, we studied short-distance structural connectivity in a homogeneous population of males with high-functioning autism spectrum disorder and used a novel methodology specifically suited for assessing U-shaped short-distance tracts, including a recently developed tractography-based atlas of the superficial white matter fibres. We acquired diffusion-weighted MRI for 58 males (27 subjects with high-functioning autism spectrum disorder and 31 control subjects) and extracted the mean generalized fractional anisotropy of 63 short distance tracts. Neuropsychological evaluation included Wechsler Adult Intelligence Scale IV (WAIS-IV), Communication Checklist-Adult, Empathy Quotient, Social Responsiveness Scale and Behaviour Rating Inventory of Executive Function Adult (BRIEF-A). In contradiction with the models of short-range over connectivity in autism spectrum disorder, we found that patients with autism spectrum disorder had a significantly decreased anatomical connectivity in a component comprising 13 short tracts compared to controls. Specific short-tract atypicalities in temporal lobe and insula were significantly associated with clinical manifestations of autism spectrum disorder such as social awareness, language structure, pragmatic skills and empathy, emphasizing their importance in social dysfunction. Short-range decreased anatomical connectivity may thus be an important substrate of social deficits in autism spectrum disorder, in contrast with current models. PMID- 30423031 TI - Phosphatase regulatory subunits in beta-adrenergic signaling: a delicate balancing act. PMID- 30423030 TI - Characterization of Telomeric Repeat-Containing RNA (TERRA) localization and protein interactions in Primordial Germ Cells of the mouse. AB - Telomeres are dynamic nucleoprotein structures capping the physical ends of linear eukaryotic chromosomes. They consist of telomeric DNA repeats (TTAGGG), the shelterin protein complex, and Telomeric Repeat-Containing RNA (TERRA). Proposed TERRA functions are wide-ranging and include telomere maintenance, telomerase inhibition, genomic stability, and alternative lengthening of telomere. However, the presence and role of TERRA in primordial germ cells (PGCs), the embryonic precursors of germ cells, is unknown. Using RNA fluorescence in situ hybridization (RNA-FISH) we identify TERRA transcripts in female PGCs at 11.5, 12.5 and 13.5 days post-coitum. In male PGCs, the earliest detection TERRA was at 12.5 dpc where we observed cells with either zero or one TERRA focus. Using qRT-PCR we evaluated chromosome-specific TERRA expression. Female PGCs showed TERRA expression at 11.5 dpc from 8 different chromosome subtelomeric regions (Chromosomes 1, 2, 7, 9, 11, 13, 17 and 18) while in male PGCs, TERRA expression was confined to the chromosome 17. Most TERRA transcription in 13.5 dpc male PGCs arose from chromosomes 2 and 6. TERRA interacting proteins were evaluated using Identification of Direct RNA Interacting Proteins (iDRiP) which identified 48 in female and 26 in male protein interactors from PGCs at 13.5 dpc. We validated two different proteins the splicing factor, proline- and glutamine-rich (SFPQ) in PGCs and Non-POU domain containing octamer-binding protein (NONO) in somatic cells. Taken together, our data indicate that TERRA expression and interactome during PGC development are regulated in a dynamic fashion that is dependent on gestational age and sex. PMID- 30423033 TI - 'Quality of Care' Standards in Inflammatory Bowel Disease: A Systematic Review. AB - Background: Inflammatory bowel disease [IBD] includes chronic, disabling and progressive conditions that need a complex approach and management. Although several attempts have been made to standardize the care of IBD patients, no clear definitions of a global 'standard of care' are currently available. Methods: We performed a systematic review of the available literature, searching for all relevant data concerning three main domains of standards of quality of care in IBD patients: structure, process and outcomes. From the literature search, 2394 abstracts were retrieved, and 62 relevant papers were included in the final review. Results: Standards of quality of care in IBD include several aspects that can be summarized in three identified domains: structure, process and outcomes. The suggested structure of an IBD Unit includes a multi-disciplinary approach, effective referral processes, improved access using helplines, and departmental guidelines/pathways with identification of measurable quality indicators. Coordinated care models which incorporate a multi-disciplinary approach, structured clinical pathways or processes for the diagnosis, monitoring and treatment of IBD, fast-track recovery from IBD surgery, designated IBD clinics, virtual clinics and telemanagement are currently considered the main standards for process, although supporting data are limited. Several consensus statements on outcomes and quality indicators have been reported, focusing on outcomes in symptoms, function and quality of life restoration, survival and disease control, in addition to effective healthcare utilization. Conclusions: The results of this systematic review can provide the basis for general recommendations for standards of quality of care in IBD. PMID- 30423034 TI - Utility of DNA Flow Cytometric Analysis of Paraffin-Embedded Tissue in the Risk Stratification and Management of "Indefinite for Dysplasia" in Patients with Inflammatory Bowel Disease. AB - Background and Aims: The clinical significance of "indefinite for dysplasia" (IND) in patients with inflammatory bowel disease remains unclear. Currently, no biomarker can reliably differentiate reactive changes from true dysplasia and/or risk stratify IND. Methods: Fifty-two IND colon biopsies were analyzed by DNA flow cytometry. The follow-up result of each biopsy was determined by reviewing all subsequent biopsies and endoscopic reports for the occurrence of high-grade dysplasia (HGD) or colorectal cancer (CRC) at the site of prior biopsy or in the same segment of colon. Results: The overall 1-, 3-, 5-, and 7-year detection rates of HGD or CRC in all 52 IND cases were 4.6% (95% confidence interval [CI], 0.0%-10.6%), 18.2% (95% CI, 3.5%-30.7%), 26.3% (95% CI, 8.4%-40.7%), and 31.6% (95% CI, 11.2%-47.4%), respectively. More interestingly, 10.6% of IND cases with aneuploidy were subsequently found to have HGD or CRC within 1 year (95% CI, 0.0% 23.7%), with 36.4% (95% CI, 7.1%-56.5%), 51.7% (95% CI, 16.1%-72.2%), and 59.8% (95% CI, 21.4%-79.5%) detected within 3, 5, and 7 years, respectively. By comparison, in the setting of normal DNA content, 1-, 3-, 5-, and 7-year detection rates of HGD or CRC were 0.8% (95% CI, 0.0%-2.7%), 3.3% (95% CI, 0.0% 9.6%), 5.2% (95% CI, 0.0%-14.7%), and 6.5% (95% CI, 0.0%-18.1%), respectively. Only the presence of aneuploidy was found to be a significant predictor of HGD or CRC with the estimated univariate and multivariate hazard ratios of 13.8 (p = 0.016) and 50.3 (p = 0.010), respectively. Conclusions: IND may not be a low-risk condition for HGD or CRC. In this regard, the presence of aneuploidy can identify a subset of IND cases that are at increased risk for subsequent detection of HGD or CRC. PMID- 30423032 TI - European postgraduate curriculum in geriatric medicine developed using an international modified Delphi technique. AB - Background: the European Union of Medical Specialists (UEMS-GMS) recommendations for training in Geriatric Medicine were published in 1993. The practice of Geriatric Medicine has developed considerably since then and it has therefore become necessary to update these recommendations. Methods: under the auspices of the UEMS-GMS, the European Geriatric Medicine Society (EuGMS) and the European Academy of Medicine of Ageing (EAMA), a group of experts, representing all member states of the respective bodies developed a new framework for education and training of specialists in Geriatric Medicine using a modified Delphi technique. Thirty-two expert panel members from 30 different countries participated in the process comprising three Delphi rounds for consensus. The process was led by five facilitators. Results: the final recommendations include four different domains: 'General Considerations' on the structure and aim of the syllabus as well as quality indicators for training (6 sub-items), 'Knowledge in patient care' (36 sub-items), 'Additional Skills and Attitude required for a Geriatrician' (9 sub items) and a domain on 'Assessment of postgraduate education: which items are important for the transnational comparison process' (1 item). Conclusion: the current publication describes the development of the new recommendations endorsed by UEMS-GMS, EuGMS and EAMA as minimum training requirements to become a geriatrician at specialist level in EU member states. PMID- 30423035 TI - 2018 IDSA Clinical Practice Guideline for the Management of Outpatient Parenteral Antimicrobial Therapy. AB - A panel of experts was convened by the Infectious Diseases Society of America (IDSA) to update the 2004 clinical practice guideline on outpatient parenteral antimicrobial therapy (OPAT) [1]. This guideline is intended to provide insight for healthcare professionals who prescribe and oversee the provision of OPAT. It considers various patient features, infusion catheter issues, monitoring questions, and antimicrobial stewardship concerns. It does not offer recommendations on the treatment of specific infections. The reader is referred to disease- or organism-specific guidelines for such support. PMID- 30423036 TI - Two Birds, One Stone: Two Unusual Causes of Diarrhea in a Nonimmunocompromised Human Immunodeficiency Virus-Infected Patient. PMID- 30423038 TI - In the Literature. PMID- 30423039 TI - Bacterial Pathogens Differed Between Neutropenic and Non-neutropenic Patients in the Same Hematological Ward: An 8-Year Survey. AB - Background: Bacterial infections are very common among patients with hematological diseases. Scant data are available regarding differences in the epidemiology and biological features of bacterial infections in neutropenic and non-neutropenic patients. Methods: The aim of this survey was to compare the bacterial pathogens in neutropenic and non-neutropenic patients in the same ward during an 8-year period. Results: A total of 1139 bacterial strains were isolated from 1071 patients with hematological diseases. The percentage of Gram-negative bacteria was significantly higher in neutropenic patients than in non-neutropenic patients (70.4% vs. 55.0%, respectively, P < .01). In neutropenic patients, the most commonly-isolated bacterium was Pseudomonas aeruginosa, followed by Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Stenotrophomonas maltophilia. In respiratory exudates, Gram-negative bacteria were also more frequently isolated from neutropenic patients than from non neutropenic patients (79.1% vs. 56.1%, respectively, P < .01). The proportion of non-fermentative Gram-negative bacilli was significantly higher in neutropenic patients than in non-neutropenic patients (52.9% vs. 30.5%, respectively, P < .01). In blood culture samples from neutropenic patients, the most frequently identified pathogens, apart from coagulase negative staphylococcus, were Gram negative bacilli (58.2%). In addition, the proportion of Escherichia coli in neutropenic patients was significantly higher than that in non-neutropenic patients (P < .01). Escherichia coli and Klebsiella pneumoniae strains from neutropenic patients also produced extended-spectrum beta-lactamases at a higher rate of than those strains from non-neutropenic patients (Escherichia coli, 57.6% vs. 30.3%, respectively, P < .01; Klebsiella pneumonia, 31.9% vs. 13.0%, respectively, P < .01). Conclusions: This study showed that there are significant differences in the epidemiology and biological features of bacteria isolated from neutropenic and non-neutropenic patients. PMID- 30423041 TI - Antimicrobial Stewardship in China: Systems, Actions and Future Strategies. AB - Antimicrobial resistance (AMR) has become a serious global public health crisis, and AMR control has consequently become a priority in all countries. Specifically, the incidence of various common multidrug-resistant bacteria is high, and there are multiple problems concerning the irrational use of antimicrobial drugs. In the past decade, China has established a relatively comprehensive management system and technical support framework for antimicrobial stewardship, including regulations, guidelines, networks for the surveillance of AMR and antimicrobial consumption, and professional personnel training. In addition, the Ministry of Health has carried out a special campaign to promote the proper clinical use of antibiotics in medical institutions, which significantly improved outcomes. The use of antibacterial drugs without indication and the consumption of antibiotics have been significantly reduced. In consideration of the factors that contribute to AMR, the structure of the healthcare system in China, and the need for long-term sustaining efforts to control AMR, the strategy of "two steps and two hands" must be implemented to contain AMR. The first step is to generally promote the rational use of antimicrobial agents in order to promptly curb the rising momentum of resistance with high pressure from the government. The second step requires sustainable professional work with the implementation of precise AMR control. The "first hand" refers to the government-oriented active establishment and optimization of the system and infrastructure of rational antibiotic use and AMR control. The "second hand" refers to the cultivation of professional teams to ensure the establishment and development of sustainable processes in AMR control. PMID- 30423040 TI - A Prospective Multicenter Clinical Observational Study on Vancomycin Efficiency and Safety With Therapeutic Drug Monitoring. AB - Background: Vancomycin is a first-line antibiotic used for the treatment of severe gram-positive bacterial infections. Clinical guidelines recommend that the vancomycin trough concentration be 10-15 mg/L for regular infections and 15-20 mg/L for severe infections. We investigated whether increasing the vancomycin concentration would result in better clinical outcomes with sustainable adverse effects (AEs) in the Chinese population. Methods: A prospective, open, multicenter clinical observational study was performed in patients with gram positive bacterial infections from 13 teaching hospitals. Patients received vancomycin therapeutic drug monitoring. Clinical, microbiological, and laboratory data were collected. Results: In total, 510 patients were enrolled, and 470 were evaluable, of whom 370 were adults and 100 were children; 35.53% had methicillin resistant Staphylococcus aureus infections (vancomycin 50% minimum inhibitory concentration [MIC50] = 1, 90% minimum inhibitory concentration [MIC90] = 1), and 23.19% had Enterococcus species infections (vancomycin MIC50 = 1, MIC90 = 2). The average trough concentration was 10.54 +/- 8.08 mg/L in adults and 6.74 +/- 8.93 mg/L in children. The infection was eradicated in 86.22% of adults and 96% of children. Thirty-six vancomycin-related nephrotoxicity cases were reported in the enrolled population. No severe AEs or deaths were related to vancomycin therapy. Logistic regression analysis showed that trough concentration had no relationship with clinical outcomes (adults P = .75, children P = .68) but was correlated with adult nephrotoxicity (P < .0001). Vancomycin trough concentration had an applicable cut point at 13 mg/L. Conclusions: Our study shows that vancomycin trough concentration has no statistical correlation with clinical outcomes, and is an indicator of nephrotoxicity in the observed population. We found no evidence that increasing vancomycin trough concentration to 15-20 mg/L can benefit Chinese patients with complicated infections. Clinical Trials Registration: ChiCTR-OPC-16007920. PMID- 30423042 TI - Model-based Evaluation of the Clinical and Microbiological Efficacy of Vancomycin: A Prospective Study of Chinese Adult In-house Patients. AB - Background: Our aims in this prospective study were to evaluate the correlations between pharmacokinetic/pharmacodynamic (PK/PD) indices and the clinical/microbiological efficacy of vancomycin and to identify an appropriate PK/PD target in the Chinese population to guide vancomycin treatment in the clinic. Methods: Adult patients from 11 hospitals in China with gram-positive infections who received vancomycin therapy for >=5 days and who were under therapeutic drug monitoring (TDM) were enrolled in this study. A 1-compartment population PK model was established and validated. The correlations between PK/PD indices (Cmin, Cmax, 0-24 hour area under the curve (AUC0-24), and AUC0 24/minimum inhibitory concentration (MIC) and clinical outcomes (clinical efficacy and bacterial eradication) were evaluated. Results: In total, 402 adult Chinese patients were enrolled. Among them, 380 patients were evaluable for PK analysis, and 334 were evaluable for PK/PD analysis. In the final population PK model, creatinine clearance (CLCR) was the significant covariate on CL (typical value, 3.87 L/hour; between-subject variability (BSV), 12.5%), and age was the significant covariate on volume of distribution (V) (typical value, 45.1 L; BSV, 24.8%). The univariate analysis showed that Cmax, AUC0-24, and AUC0-24/MIC were significantly different or marginally significantly different (P values were 0.009, 0.0385, and 0.0509, respectively) between microbiological outcome groups with coagulase-negative Staphylococcus infections. However, there were no significant differences (P > .05) in the above PK parameters by multivariate logistic regression analysis, indicating there was no independently associated factor. Conclusions: No significant correlations were identified between PK/PD indices and the clinical or microbiological efficacy of vancomycin in Chinese patients. The necessity of vancomycin TDM based on trough concentration and the current treatment target of AUC0-24/MIC >=400 need to be further evaluated and confirmed in additional prospective studies. PMID- 30423044 TI - Antimicrobial Resistance in China: Challenges and Actions. PMID- 30423043 TI - In Vitro Activities of Ceftaroline/Avibactam, Ceftazidime/Avibactam, and Other Comparators Against Pathogens From Various Complicated Infections in China. AB - Background: We conducted a national antimicrobial surveillance study of both gram positive and gram-negative organisms isolated from hospitalized patients. This report presents data on antimicrobial susceptibility among 4998 organisms collected in China between 2012 and 2014. Method: The minimum inhibitory concentrations (MICs) and susceptibilities of ceftaroline/avibactam (CPA), ceftazidime/avibactam (CZA) and a range of comparative agents were determined according to guidelines established by the Clinical and Laboratory Standards Institute (CLSI). Results: The highest overall susceptibility levels for all Enterobacteriaceae during the study period were observed for CPA, CZA, doripenem (DOR), meropenem (MEM), and amikacin (AMK), which were all >90%. However, both CPT and CAZ alone and in combination with avibactam showed low activities for Acinetobacter spp., whereas CPA and CZA exhibited MIC90 values for Pseudomonas aeruginosa that were reduced by 4- and 8-fold, respectively, compared with those of CPT and CAZ. High susceptibilities of Acinetobacter spp. and P. aeruginosa to colistin and P. aeruginosa to AMK were observed. For the gram-positive strains, no significant activity changes were seen for Enterococcus, Staphylococcus, and viridans group streptococci to CPT or CAZ alone or in combination with avibactam, whereas Streptococcus pneumoniae and beta-hemolytic Streptococcus showed almost 100% susceptibility to both CPT and CPA. Conclusion: The addition of 4 mg/L avibactam greatly increased the activities of CPT and CAZ against most Enterobacteriaceae and P. aeruginosa isolates, whereas no significant changes were observed in Acinetobacter spp. or any of the gram-positive strains. PMID- 30423045 TI - Current Status and Trends of Antibacterial Resistance in China. AB - The bacterial resistance surveillance system is relatively well established at the national, provincial, and hospital levels in China. Two representative national surveillance networks for bacterial resistance are the China Antimicrobial Resistance Surveillance System (CARSS) and the China Antimicrobial Surveillance Network (CHINET), both established in 2005. CARSS data show the different bacterial resistance rates among different provinces and autonomous regions for each specific bacterium. CHINET data mainly represent the bacterial resistance profiles of teaching hospitals and show the changing trends of bacterial resistance in China. For clinical isolates, the ratio of gram-negative bacilli to gram-positive cocci is approximately 7 to 3. In general, gram-negative bacilli have higher antimicrobial resistance profiles in China. Regarding different bacterial species, antimicrobial resistance is multifaceted. The prevalence of extended-spectrum beta-lactamases is high; Acinetobacter baumannii has a high antimicrobial resistance profile; and, notably, the prevalence of CRKP has been showing a marked increase since 2005. In addition, the prevalence of vancomycin-resistant Enterococcus is low, and the prevalence of methicillin resistant Staphylococcus aureus and antimicrobial resistance in Pseudomonas aeruginosa showed decreasing trends from 2005 to 2017. PMID- 30423046 TI - An Emerging Clone (ST457) of Acinetobacter baumannii Clonal Complex 92 With Enhanced Virulence and Increasing Endemicity in South China. AB - Background: The global dissemination of carbapenem-resistant Acinetobacter baumannii clonal complex (CC) 92 has become an urgent public health concern. Methods: A. baumannii isolates were collected in 5 tertiary hospitals in south China during 2012-2015, and their clinical data were obtained. The clinical characterization was studied by statistical analysis. Whole-genome sequencing and a Galleria mellonella infection model were used to investigate the genetic characterization and pathogenicity of isolates, respectively. Results: Sequence type (ST)457, following ST195, become the second-most prevalent clone in our collection. Patients infected by ST457 had significantly higher 7-day mortality rates (44.4% vs 14.3%; P = .01) and proportions of 7-day deaths (70.6% vs 26.7%; P = .01) than those infected by the other STs of CC92, except for ST195 and ST208. Consistently, the day of death after culture was significantly sooner in patients infected with ST457 than those with the non-ST195/208 members of CC92 (8.71 +/- 15.27 vs 25.20 +/- 6.51; P = .02). This is accordant with results that ST457 had enhanced virulence with a high mortality rate through use of the G. mellonella larvae infection model. Genomic analysis suggests that ST457 evolved distinctly from the other CC92 members mainly via recombinations. This clone exclusively shared a few virulence factors with the hypervirulence strain LAC-4, including a capsule biosynthesis locus (KL49) that is supposed to be important for the hypervirulence in LAC-4. Conclusions: The rising trends in prevalence and enhanced virulence of ST457 highlight the urgent need for tailored surveillance to control the further dissemination of this clone. PMID- 30423047 TI - Transmission of mcr-1-Producing Multidrug-resistant Enterobacteriaceae in Public Transportation in Guangzhou, China. AB - Objectives: mcr-1-mediated colistin resistance in bacteria is concerning, as colistin is used in treating multidrug-resistant bacterial infections. And mcr-1 producing bacteria have been identified in multiple sources. Up to 248 million people use public transportation daily in China, however; public transportation hasn't been studied as a potential source of community-based transmission of mcr 1. Herein we investigated mcr-1-producing isolates from public transportation and explored the genomic characteristics of them. Methods: Surface samples were collected from public transportation in Guangzhou, China, from October 2016 to April 2017. Polymerase chain reaction was performed to detect mcr-1 gene, plasmid replicon type and phylogenetic group. Minimum inhibitory concentrations (MICs) were determined by microdilution method. S1-nuclease digestion and pulsed-field gel electrophoresis (S1-PFGE) and Southern blotting were performed with mcr-1 harboring plasmids. Whole-genome sequencing was performed with mcr-1-producing isolates. Results: Of the 737 samples with bacterial growth, 26 isolates were positive for mcr-1, including 23 Escherichia coli and 3 Klebsiella pneumoniae isolates. The E. coli isolates belonged to phylogroups A and B1. Most mcr-1 producing isolates were resistant to ampicillin (25), cefotaxime (21), fosfomycin (16), and gentamicin (15). S1-PFGE, Southern blotting and replicon typing showed that mcr-1 was mainly located on ~33.3 kb to ~220 kb IncX4, IncI2 and IncHI2 plasmids in E. coli, while located on ~33.3 kb untyped plasmid in K. pneumoniae. Several sequence types (ST), including ST2253, ST101, ST10 complex and ST37, were revealed. Between 53 and 66 (mean = 61.8) resistance genes were identified among mcr-1-producing isolates. Conclusions: Public transportation may serve as a source of mcr-1-producing bacteria. PMID- 30423048 TI - Microbiological Diagnostic Performance of Metagenomic Next-generation Sequencing When Applied to Clinical Practice. AB - Background: Metagenomic next-generation sequencing (mNGS) was suggested to potentially replace traditional microbiological methodology because of its comprehensiveness. However, clinical experience with application of the test is relatively limited. Methods: From April 2017 to December 2017, 511 specimens were collected, and their retrospective diagnoses were classified into infectious disease (347 [67.9%]), noninfectious disease (119 [23.3%]), and unknown cases (45 [8.8%]). The diagnostic performance of pathogens was compared between mNGS and culture. The effect of antibiotic exposure on detection rate was also assessed. Results: The sensitivity and specificity of mNGS for diagnosing infectious disease were 50.7% and 85.7%, respectively, and these values outperformed those of culture, especially for Mycobacterium tuberculosis (odds ratio [OR], 4 [95% confidence interval {CI}, 1.7-10.8]; P < .01), viruses (mNGS only; P < .01), anaerobes (OR, infinity [95% CI, 1.71-infinity]; P < .01) and fungi (OR, 4.0 [95% CI, 1.6-10.3]; P < .01). Importantly, for mNGS-positive cases where the conventional method was inconclusive, 43 (61%) cases led to diagnosis modification, and 41 (58%) cases were not covered by empirical antibiotics. For cases where viruses were identified, broad-spectrum antibiotics were commonly administered (14/27), and 10 of 27 of these cases were suspected to be inappropriate. Interestingly, the sensitivity of mNGS was superior to that of culture (52.5% vs 34.2%; P < .01) in cases with, but not without, antibiotic exposure. Conclusions: mNGS could yield a higher sensitivity for pathogen identification and is less affected by prior antibiotic exposure, thereby emerging as a promising technology for detecting infectious diseases. PMID- 30423049 TI - Microbial Etiology and Prognostic Factors of Ventilator-associated Pneumonia: A Multicenter Retrospective Study in Shanghai. AB - Background: The microbial etiology and mortality risk factors of ventilator associated pneumonia (VAP) have not been investigated extensively in Shanghai. Methods: VAP cases were identified from the patients hospitalized during the period from 1 January 2013 to 30 December 2017 in Shanghai. The relevant data were reviewed and analyzed retrospectively. Results: One hundred ninety-four VAP cases were included in this analysis. The overall mortality rate was 32.47%. The respiratory pathogens isolated from these patients included 212 bacterial strains and 54 fungal strains. The leading pathogens were Acinetobacter baumannii (33.96%), Klebsiella pneumoniae (23.58%), Pseudomonas aeruginosa (19.81%), and Staphylococcus aureus (7.08%). Candida colonization was associated with higher mortality of VAP patients compared to those without Candida colonization (45.45% vs 28.67%, P < .05). The VAP patients with Candida colonization also showed higher prevalence of P. aeruginosa, carbapenem-resistant P. aeruginosa (CRPA), K. pneumoniae, carbapenem-resistant K. pneumoniae (CRKP), A. baumannii, and carbapenem-resistant A. baumannii (CRAB) (P < .05). VAP nonsurvivors had higher prevalence of CRPA, K. pneumoniae, CRAB, and Candida than VAP survivors (P < .05). Multivariate analysis showed that prior antibiotic use was a significant risk factor for Candida colonization, while hypertension and length of hospital stay were significant risk factors of VAP mortality (P < .05). Conclusions: The top pathogens of VAP patients in Shanghai tertiary teaching hospitals are A. baumannii, K. pneumoniae, and P. aeruginosa, with high prevalence of carbapenem resistance. Carbapenem-resistant bacterial pathogens and Candida may predict poor outcome. PMID- 30423050 TI - A Case-Control Study: Clinical Characteristics of Nosocomial Bloodstream Infections Versus Non-bloodstream Infections of Acinetobacter spp. AB - Background: Acinetobacter spp. are among the most common causes of bacterial nosocomial infections, including pneumonia and bloodstream infections. Previous studies on the risk factors of bloodstream Acinetobacter spp. infections (BSAcIs) primarily compared uninfected patients to those with BSAcIs. However, the identified risk factors contribute to either BSIs or Acinetobacter spp. infections. To the best of our knowledge, this is the first study to analyze the risk factors of BSAcIs in comparison to non-bloodstream Acinetobacter infections (non-BSAcIs). Methods: We retrospectively reviewed 10 years of medical records of BSAcIs from a teaching hospital in Shanghai. Clinical characteristics and treatment outcomes were compared between BSAcIs and non-BSAcIs. Treatment outcomes of carbapenem- and sulbactam-based regimens were also evaluated. Results: Respiratory tract infections (43.1%, 44/102) were the most common source of BSAcIs. The in-hospital mortality rate of BSAcIs (22.5%, 23/102) was significantly higher than that of non-BSAcIs (10.8%, 24/204). Compared with non BSAcIs, the previous use of corticoids, proton pump inhibitor (PPI) usage, and the implementation of intracranial drainage were independent risk factors for BSAcIs. The clinical efficacy rate of antimicrobial treatment of carbapenem susceptible BSAcIs was significantly higher than that of carbapenem-non susceptible (CNS) BSAcIs (74.0% vs 44.3%). Sulbactam-based regimens had similar clinical efficacy rates as carbapenem-based regimens for treating CNS-BSAcIs (50.0% vs 45.8%). Conclusions: The in-hospital mortality rate of BSAcIs was significantly higher than that of non-BSAcIs. Glucocorticoids, PPI usage, and intracranial drainage were independent risk factors for BSAcIs. Sulbactam-based regimens had similar clinical efficacy rates as carbapenem-based regimens for treating CNS-BSAcIs. PMID- 30423051 TI - Using Core-genome Multilocus Sequence Typing to Monitor the Changing Epidemiology of Methicillin-resistant Staphylococcus aureus in a Teaching Hospital. AB - Background: This study was performed to elucidate the changing epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) in a Chinese teaching hospital. Methods: We performed whole-genome sequencing and phylogenetic analysis on MRSA isolates recovered at Sir Run Run Shaw Hospital (SRRSH) from 2013 to 2015. MRSA isolates underwent susceptibility testing, resistance determinant screening, virulence assays and clinical data analysis. Results: A total of 292 MRSA infections were identified during the study period. Of these, most belonged to sequence type (ST) 5 (51.4%; 150 of 292) and ST59 (23.3%; 68 of 292). The proportion of ST5 MRSA decreased from 68.3% in 2013 to 32.1% in 2015, and the proportion of ST59 MRSA increased from 8.9% to 41.0%. Core-genome phylogenetic analysis revealed that ST59 MRSA isolates exhibited wider genotypic diversity than ST5 MRSA isolates in both healthcare-onset and community-onset groups. Minimum spanning trees showed that a cluster of ST5 MRSA was circulating at SRRSH, whereas the ST59 MRSA infections were mostly sporadic. ST59 MRSA caused 45.2% of the 93 skin and soft-tissue infection cases and displayed lower levofloxacin (11.8%) and ciprofloxacin (19.1%) resistance rates than the ST239 and ST5 MRSA isolates. ST59 healthcare-onset MRSA displayed enhanced virulence in the skin infection model and hemolysis assays. Notably, these isolates had virulence levels similar to those of classic community-associated MRSA strains. Conclusions: ST59 MRSA strains with high virulence potential have been replacing ST5 MRSA in predominance in SRRSH and causing nosocomial infections. Whole-genome sequencing is a powerful tool to monitor changes in the epidemiology of MRSA in hospitals. PMID- 30423052 TI - In-hospital Medical Costs of Infections Caused by Carbapenem-resistant Klebsiella pneumoniae. AB - Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a major health threat, but the economic impact of carbapenem resistance in K. pneumoniae infections remains largely uninvestigated. Methods: We constructed a retrospective cohort of all patients hospitalized at West China Hospital in 2017 who had CRKP- or carbapenem-susceptible K. pneumoniae (CSKP)-positive clinical samples. Propensity score matching (PSM) was used to control the impact of potential confounding variables, including demographics, comorbidities, and treatment, and to observe the impact of factors other than length of stay (LOS). Patients who survived were subjected to subgroup analyses stratified by infection type. Results: There were 267 patients with CRKP and 1328 with CSKP. Patients with CRKP had a higher crude in-hospital mortality rate (14.61% vs 5.65%, P < .05) and longer LOS (median, 31 vs 19 days; P < .05). PSM for demographics, comorbidities, and treatment generated 237 pairs. Patients with CRKP had higher medical costs than those with CSKP during the entire hospitalization (median, in US dollars, $22962 vs $11755, respectively; P < .05) and during the period after infection (median, $9215 vs $6904, respectively; P < .05). When LOS was matched, patients with CRKP still had high excess costs compared to those with CSKP (median, $22917 vs $13851, respectively, for the entire hospitalization, P < .05; $9101 vs $7001, respectively, after infection, P < .05). For infection type, the sample size generated sufficient power to compare only the patients with pneumonia. For surviving patients, high excess costs were observed in those with pneumonia caused by CRKP as compared to CSKP ($21890 vs $11698, respectively, for the entire hospitalization, P < .05; $9773 vs $5298, respectively, after infection, P < .05). Medicines other than antibacterial agents and nonmedicinal therapies contributed most (57.8%) of the excess costs associated with CRKP. Conclusions: Carbapenem resistance in K. pneumoniae was associated with increased medical costs not accounted for by the cost of antimicrobial therapy. PMID- 30423053 TI - Carbapenem-resistant Isolates of the Klebsiella pneumoniae Complex in Western China: The Common ST11 and the Surprising Hospital-specific Types. AB - A genome sequence-based analysis of 74 carbapenem-resistant Klebsiella pneumoniae (CRKP) from 12 hospitals in Sichuan, China, revealed that the isolates carried blaKPC-2 (n = 48), blaNDM (n = 22), or blaIMP-4 (n = 4) were identified as K. pneumoniae (n = 67), Klebsiella variicola (n = 5), and Klebsiella quasipneumoniae (n = 2) and belonged to 19 sequence types. Both inter- and intrahospital transmission of multiple ST11 strains was identified. There is an urgent need for all hospitals in a given region to coordinate actions against CRKP. PMID- 30423054 TI - Incidence, Risk Factors, Microbiology and Outcomes of Pre-engraftment Bloodstream Infection After Haploidentical Hematopoietic Stem Cell Transplantation and Comparison With HLA-identical Sibling Transplantation. AB - Background: Bloodstream infection (BSI) is a common and serious complication after hematopoietic stem cell transplantation (HSCT). An investigation of the characteristics of pre-engraftment BSI after haploidentical HSCT compared with human leukocyte antigen (HLA)-identical sibling HSCT has not been conducted. Methods: A single-center cohort representing 1847 consecutive patients undergoing haploidentical or HLA-identical sibling HSCT from 2013 to 2016 was selected. We investigated the characteristics of pre-engraftment BSI after haploidentical HSCT and its impact on patient outcome, and we compared it with HLA-identical sibling HSCT. Results: After haploidentical HSCT, the cumulative incidence of pre engraftment BSI was higher (30-day: 9.2% [7.6, 10.8] vs 1.7% [0.5, 2.9], P < .0001) and median onset of BSI was earlier (day +3 vs day +9, P = .001) than HLA identical sibling HSCT. Escherichia coli, Klebsiella pneumoniae, and coagulase negative staphylococci were the most common isolates after haploidentical HSCT. However, Enterococcus faecium was the most common isolate after HLA-identical sibling HSCT. A multivariate analysis suggested that variables associated with BSI after haploidentical HSCT included a diagnosis of myelodysplastic syndrome (MDS), an interval from diagnosis to HSCT >=190 days, carbapenem therapy, and grade 3-4 intestinal mucositis. The same variables, except MDS, were also associated with BSI after HLA-identical sibling HSCT. The multivariate analysis also suggested that BSI was a risk factor for increased all-cause mortality at 3 months after haploidentical HSCT (hazard ratio = 2.281; 95% confidence interval: 1.334, 3.900; P = .003). Conclusions: Pre-engraftment BSI was more common after haploidentical HSCT than HLA-identical sibling HSCT. It was an independent factor associated with increased all-cause mortality at 3 months after haploidentical HSCT. PMID- 30423055 TI - The Current Epidemiological Landscape of Ventilator-associated Pneumonia in the Intensive Care Unit: A Multicenter Prospective Observational Study in China. AB - Background: Ventilator-associated pneumonia (VAP) is among the most important hospital-acquired infections in the intensive-care unit setting. However, clinical data regarding the epidemiology of VAP in China are limited. Methods: A multicenter, longitudinal, observational study was performed from March 2013 to December 2015 to prospectively collect data on patients diagnosed with VAP. Specifically, patients supported by invasive mechanical ventilation for longer than 48 hours were included. Clinical data were recorded for each VAP patient. The exact pathogen distribution and the incidence of VAP were calculated. Risk factors associated with mortality were analyzed using univariate and multivariate regression analyses. Results: A total of 2492 patients received mechanical ventilation for longer than 48 hours and were enrolled in the study. A total of 129 (5.0%) patients fulfilled the VAP criteria, and 38 (29.5%) patients were diagnosed with early-onset VAP. The incidence of VAP was 4.5 per 1000 ventilation days, with a 28-day mortality rate of 45%. Individual pathogens, including 115 bacteria and 2 fungi, were identified in 117 (90.7%) enrollees, and 87 (75.7%) bacteria were multidrug-resistant organisms. Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa were the most commonly detected pathogens causing VAP. No difference in the distribution of pathogens was observed between early- and late-onset VAP or between surviving and non-surviving patients. Multivariate regression revealed that older ages and Sequential Organ Failure Assessment Scores were correlated with increased 28-day mortality rates. Conclusions: High pathogen resistance and mortality were found in both early- and late-onset VAP. Clinical Trials Registration: NCT01943331. PMID- 30423056 TI - China-United States Research Collaborations in Antimicrobial Resistance. AB - A strong synergy can result from China-US antimicrobial resistance (AMR) collaborations given similarities and differences between their respective healthcare systems and research infrastructures. The Antibacterial Resistance Leadership Group has employed a model of realistic growth, starting with a feasible, relatively low-resource observational study in a critical priority pathogen. This and other observational studies will provide vital scientific information required for the rational design of future interventional trials. In addition, it provides a mutual, low-risk opportunity for determining the strengths and opportunities of the research collaboration. Issues identified during the observational studies can be addressed prior to the initiation of high resource interventional studies. Collaborative clinical AMR studies between China and the United States have tremendous potential to decrease AMR rates, improve responsible antibiotic use, and ultimately improve the lives of patients in both countries. PMID- 30423057 TI - Phenotypic and Genotypic Characterization of Carbapenem-resistant Enterobacteriaceae: Data From a Longitudinal Large-scale CRE Study in China (2012 2016). AB - Background: Carbapenem-resistant Enterobacteriaceae (CRE) strains are a major threat to global health. The development of effective control measures requires more detailed phenotypic and genotypic characterization of CRE. Methods: CRE isolates were collected from 65 hospitals in 25 provinces across China between January 1, 2012, and December 31, 2016. The isolates were characterized by antimicrobial susceptibility testing and multilocus sequence typing. Genes encoding carbapenemases, mobilized colistin resistance (mcr-1), and beta lactamases were detected by polymerase chain reaction and DNA sequencing. Results: A total of 1801 independent CRE isolates (1201 Klebsiella pneumoniae, 282 Escherichia coli, and 179 Enterobacter cloacae) were collected during the study period. Overall, 96.9%, 89.7%, 54.5%, 49.9%, and 40% of CRE strains were susceptible to colistin, tigecycline, amikacin, minocycline, and fosfomycin, respectively. Notably, 1091/1201 (91%) K. pneumoniae, 225/282 (80%) E. coli, and 129/179 (72%) E. cloacae harbored carbapenemase gene. K. pneumoniae carbapenemase (KPC) was predominant in K. pneumoniae (77%), whereas New Delhi metallo-beta lactamase (NDM) was predominant in E. coli (75%) and E. cloacae (53%). The mcr-1 gene was detected in 13 NDM-carrying E. coli isolates (4.6%). Sequence type (ST)11 and ST167 were predominant among the 100 K. pneumoniae and 47 E. coli STs, respectively. KPC-ST11, which accounted for 64% of K. pneumoniae isolates, had higher levels of resistance than non-ST11 strains to aztreonam, fosfomycin, and amikacin (P < .001). The proportions of KPC and NDM enzymes in CRE increased from 2012 to 2016 (54%-59% and 12%-28%, respectively). Conclusions: The number of CRE strains harboring carbapenemase is increasing. KPC-ST11 K. pneumoniae, the predominant strain, shows a reduced susceptibility to most available antibiotics. PMID- 30423058 TI - Understanding the evolution of functional redundancy in metabolic networks. AB - Motivation: Metabolic networks have evolved to reduce the disruption of key metabolic pathways by the establishment of redundant genes/reactions. Synthetic lethals in metabolic networks provide a window to study these functional redundancies. While synthetic lethals have been previously studied in different organisms, there has been no study on how the synthetic lethals are shaped during adaptation/evolution. Results: To understand the adaptive functional redundancies that exist in metabolic networks, we here explore a vast space of 'random' metabolic networks evolved on a glucose environment. We examine essential and synthetic lethal reactions in these random metabolic networks, evaluating over 39 billion phenotypes using an efficient algorithm previously developed in our lab, Fast-SL. We establish that nature tends to harbour higher levels of functional redundancies compared with random networks. We then examined the propensity for different reactions to compensate for one another and show that certain key metabolic reactions that are necessary for growth in a particular growth medium show much higher redundancies, and can partner with hundreds of different reactions across the metabolic networks that we studied. We also observe that certain redundancies are unique to environments while some others are observed in all environments. Interestingly, we observe that even very diverse reactions, such as those belonging to distant pathways, show synthetic lethality, illustrating the distributed nature of robustness in metabolism. Our study paves the way for understanding the evolution of redundancy in metabolic networks, and sheds light on the varied compensation mechanisms that serve to enhance robustness. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423060 TI - S-Cluster++: a fast program for solving the cluster containment problem for phylogenetic networks. AB - Motivation: Comparative genomic studies indicate that extant genomes are more properly considered to be a fusion product of random mutations over generations (vertical evolution) and genomic material transfers between individuals of different lineages (reticulate transfer). This has motivated biologists to use phylogenetic networks and other general models to study genome evolution. Two fundamental algorithmic problems arising from verification of phylogenetic networks and from computing Robinson-Foulds distance in the space of phylogenetic networks are the tree and cluster containment problems. The former asks how to decide whether or not a phylogenetic tree is displayed in a phylogenetic network. The latter is to decide whether a subset of taxa appears as a cluster in some tree displayed in a phylogenetic network. The cluster containment problem (CCP) is also closely related to testing the infinite site model on a recombination network. Both the tree containment and CCP are NP-complete. Although the CCP was introduced a decade ago, there has been little progress in developing fast algorithms for it on arbitrary phylogenetic networks. Results: In this work, we present a fast computer program for the CCP. This program is developed on the basis of a linear-time transformation from the small version of the CCP to the SAT problem. Availability and implementation: The program package is available for download on http://www.math.nus.edu.sg/~matzlx/ccp. PMID- 30423059 TI - An ontology-based method for assessing batch effect adjustment approaches in heterogeneous datasets. AB - Motivation: International consortia such as the Genotype-Tissue Expression (GTEx) project, The Cancer Genome Atlas (TCGA) or the International Human Epigenetics Consortium (IHEC) have produced a wealth of genomic datasets with the goal of advancing our understanding of cell differentiation and disease mechanisms. However, utilizing all of these data effectively through integrative analysis is hampered by batch effects, large cell type heterogeneity and low replicate numbers. To study if batch effects across datasets can be observed and adjusted for, we analyze RNA-seq data of 215 samples from ENCODE, Roadmap, BLUEPRINT and DEEP as well as 1336 samples from GTEx and TCGA. While batch effects are a considerable issue, it is non-trivial to determine if batch adjustment leads to an improvement in data quality, especially in cases of low replicate numbers. Results: We present a novel method for assessing the performance of batch effect adjustment methods on heterogeneous data. Our method borrows information from the Cell Ontology to establish if batch adjustment leads to a better agreement between observed pairwise similarity and similarity of cell types inferred from the ontology. A comparison of state-of-the art batch effect adjustment methods suggests that batch effects in heterogeneous datasets with low replicate numbers cannot be adequately adjusted. Better methods need to be developed, which can be assessed objectively in the framework presented here. Availability and implementation: Our method is available online at https://github.com/SchulzLab/OntologyEval. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423061 TI - Higher-order molecular organization as a source of biological function. AB - Motivation: Molecular interactions have widely been modelled as networks. The local wiring patterns around molecules in molecular networks are linked with their biological functions. However, networks model only pairwise interactions between molecules and cannot explicitly and directly capture the higher-order molecular organization, such as protein complexes and pathways. Hence, we ask if hypergraphs (hypernetworks), that directly capture entire complexes and pathways along with protein-protein interactions (PPIs), carry additional functional information beyond what can be uncovered from networks of pairwise molecular interactions. The mathematical formalism of a hypergraph has long been known, but not often used in studying molecular networks due to the lack of sophisticated algorithms for mining the underlying biological information hidden in the wiring patterns of molecular systems modelled as hypernetworks. Results: We propose a new, multi-scale, protein interaction hypernetwork model that utilizes hypergraphs to capture different scales of protein organization, including PPIs, protein complexes and pathways. In analogy to graphlets, we introduce hypergraphlets, small, connected, non-isomorphic, induced sub-hypergraphs of a hypergraph, to quantify the local wiring patterns of these multi-scale molecular hypergraphs and to mine them for new biological information. We apply them to model the multi-scale protein networks of bakers yeast and human and show that the higher-order molecular organization captured by these hypergraphs is strongly related to the underlying biology. Importantly, we demonstrate that our new models and data mining tools reveal different, but complementary biological information compared with classical PPI networks. We apply our hypergraphlets to successfully predict biological functions of uncharacterized proteins. Availability and implementation: Code and data are available online at http://www0.cs.ucl.ac.uk/staff/natasa/hypergraphlets. PMID- 30423062 TI - Discovering epistatic feature interactions from neural network models of regulatory DNA sequences. AB - Motivation: Transcription factors bind regulatory DNA sequences in a combinatorial manner to modulate gene expression. Deep neural networks (DNNs) can learn the cis-regulatory grammars encoded in regulatory DNA sequences associated with transcription factor binding and chromatin accessibility. Several feature attribution methods have been developed for estimating the predictive importance of individual features (nucleotides or motifs) in any input DNA sequence to its associated output prediction from a DNN model. However, these methods do not reveal higher-order feature interactions encoded by the models. Results: We present a new method called Deep Feature Interaction Maps (DFIM) to efficiently estimate interactions between all pairs of features in any input DNA sequence. DFIM accurately identifies ground truth motif interactions embedded in simulated regulatory DNA sequences. DFIM identifies synergistic interactions between GATA1 and TAL1 motifs from in vivo TF binding models. DFIM reveals epistatic interactions involving nucleotides flanking the core motif of the Cbf1 TF in yeast from in vitro TF binding models. We also apply DFIM to regulatory sequence models of in vivo chromatin accessibility to reveal interactions between regulatory genetic variants and proximal motifs of target TFs as validated by TF binding quantitative trait loci. Our approach makes significant strides in improving the interpretability of deep learning models for genomics. Availability and implementation: Code is available at: https://github.com/kundajelab/dfim. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423063 TI - Scalable and exhaustive screening of metabolic functions carried out by microbial consortia. AB - Motivation: The selection of species exhibiting metabolic behaviors of interest is a challenging step when switching from the investigation of a large microbiota to the study of functions effectiveness. Approaches based on a compartmentalized framework are not scalable. The output of scalable approaches based on a non compartmentalized modeling may be so large that it has neither been explored nor handled so far. Results: We present the Miscoto tool to facilitate the selection of a community optimizing a desired function in a microbiome by reporting several possibilities which can be then sorted according to biological criteria. Communities are exhaustively identified using logical programming and by combining the non-compartmentalized and the compartmentalized frameworks. The benchmarking of 4.9 million metabolic functions associated with the Human Microbiome Project, shows that Miscoto is suited to screen and classify metabolic producibility in terms of feasibility, functional redundancy and cooperation processes involved. As an illustration of a host-microbial system, screening the Recon 2.2 human metabolism highlights the role of different consortia within a family of 773 intestinal bacteria. Availability and implementation: Miscoto source code, instructions for use and examples are available at: https://github.com/cfrioux/miscoto. PMID- 30423064 TI - Towards an accurate and efficient heuristic for species/gene tree co-estimation. AB - Motivation: Species and gene trees represent how species and individual loci within their genomes evolve from their most recent common ancestors. These trees are central to addressing several questions in biology relating to, among other issues, species conservation, trait evolution and gene function. Consequently, their accurate inference from genomic data is a major endeavor. One approach to their inference is to co-estimate species and gene trees from genome-wide data. Indeed, Bayesian methods based on this approach already exist. However, these methods are very slow, limiting their applicability to datasets with small numbers of taxa. The more commonly used approach is to first infer gene trees individually, and then use gene tree estimates to infer the species tree. Methods in this category rely significantly on the accuracy of the gene trees which is often not high when the dataset includes closely related species. Results: In this work, we introduce a simple, yet effective, iterative method for co estimating gene and species trees from sequence data of multiple, unlinked loci. In every iteration, the method estimates a species tree, uses it as a generative process to simulate a collection of gene trees, and then selects gene trees for the individual loci from among the simulated gene trees by making use of the sequence data. We demonstrate the accuracy and efficiency of our method on simulated as well as biological data, and compare them to those of existing competing methods. Availability and implementation: The method has been implemented in PhyloNet, which is publicly available at http://bioinfocs.rice.edu/phylonet. PMID- 30423065 TI - Recognition of CRISPR/Cas9 off-target sites through ensemble learning of uneven mismatch distributions. AB - Motivation: CRISPR/Cas9 is driving a broad range of innovative applications from basic biology to biotechnology and medicine. One of its current issues is the effect of off-target editing that should be critically resolved and should be completely avoided in the ideal use of this system. Results: We developed an ensemble learning method to detect the off-target sites of a single guide RNA (sgRNA) from its thousands of genome-wide candidates. Nucleotide mismatches between on-target and off-target sites have been studied recently. We confirm that there exists strong mismatch enrichment and preferences at the 5'-end close regions of the off-target sequences. Comparing with the on-target sites, sequences of no-editing sites can be also characterized by GC composition changes and position-specific mismatch binary features. Under this novel space of features, an ensemble strategy was applied to train a prediction model. The model achieved a mean score 0.99 of Aera Under Receiver Operating Characteristic curve and a mean score 0.45 of Aera Under Precision-Recall curve in cross-validations on big datasets, outperforming state-of-the-art methods in various test scenarios. Our predicted off-target sites also correspond very well to those detected by high-throughput sequencing techniques. Especially, two case studies for selecting sgRNAs to cure hearing loss and retinal degeneration partly prove the effectiveness of our method. Availability and implementation: The python and matlab version of source codes for detecting off-target sites of a given sgRNA and the supplementary files are freely available on the web at https://github.com/penn-hui/OfftargetPredict. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423066 TI - Conditional generative adversarial network for gene expression inference. AB - Motivation: The rapid progress of gene expression profiling has facilitated the prosperity of recent biological studies in various fields, where gene expression data characterizes various cell conditions and regulatory mechanisms under different experimental circumstances. Despite the widespread application of gene expression profiling and advances in high-throughput technologies, profiling in genome-wide level is still expensive and difficult. Previous studies found that high correlation exists in the expression pattern of different genes, such that a small subset of genes can be informative to approximately describe the entire transcriptome. In the Library of Integrated Network-based Cell-Signature program, a set of ~1000 landmark genes have been identified that contain ~80% information of the whole genome and can be used to predict the expression of remaining genes. For a cost-effective profiling strategy, traditional methods measure the profiles of landmark genes and then infer the expression of other target genes via linear models. However, linear models do not have the capacity to capture the non-linear associations in gene regulatory networks. Results: As a flexible model with high representative power, deep learning models provide an alternate to interpret the complex relation among genes. In this paper, we propose a deep learning architecture for the inference of target gene expression profiles. We construct a novel conditional generative adversarial network by incorporating both the adversarial and l1-norm loss terms in our model. Unlike the smooth and blurry predictions resulted by mean squared error objective, the coupled adversarial and l1-norm loss function leads to more accurate and sharp predictions. We validate our method under two different settings and find consistent and significant improvements over all the comparing methods. PMID- 30423067 TI - Prioritising candidate genes causing QTL using hierarchical orthologous groups. AB - Motivation: A key goal in plant biotechnology applications is the identification of genes associated to particular phenotypic traits (for example: yield, fruit size, root length). Quantitative Trait Loci (QTL) studies identify genomic regions associated with a trait of interest. However, to infer potential causal genes in these regions, each of which can contain hundreds of genes, these data are usually intersected with prior functional knowledge of the genes. This process is however laborious, particularly if the experiment is performed in a non-model species, and the statistical significance of the inferred candidates is typically unknown. Results: This paper introduces QTLSearch, a method and software tool to search for candidate causal genes in QTL studies by combining Gene Ontology annotations across many species, leveraging hierarchical orthologous groups. The usefulness of this approach is demonstrated by re analysing two metabolic QTL studies: one in Arabidopsis thaliana, the other in Oryza sativa subsp. indica. Even after controlling for statistical significance, QTLSearch inferred potential causal genes for more QTL than BLAST-based functional propagation against UniProtKB/Swiss-Prot, and for more QTL than in the original studies. Availability and implementation: QTLSearch is distributed under the LGPLv3 license. It is available to install from the Python Package Index (as qtlsearch), with the source available from https://bitbucket.org/alex warwickvesztrocy/qtlsearch. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423068 TI - Ontology-based validation and identification of regulatory phenotypes. AB - Motivation: Function annotations of gene products, and phenotype annotations of genotypes, provide valuable information about molecular mechanisms that can be utilized by computational methods to identify functional and phenotypic relatedness, improve our understanding of disease and pathobiology, and lead to discovery of drug targets. Identifying functions and phenotypes commonly requires experiments which are time-consuming and expensive to carry out; creating the annotations additionally requires a curator to make an assertion based on reported evidence. Support to validate the mutual consistency of functional and phenotype annotations as well as a computational method to predict phenotypes from function annotations, would greatly improve the utility of function annotations. Results: We developed a novel ontology-based method to validate the mutual consistency of function and phenotype annotations. We apply our method to mouse and human annotations, and identify several inconsistencies that can be resolved to improve overall annotation quality. We also apply our method to the rule-based prediction of regulatory phenotypes from functions and demonstrate that we can predict these phenotypes with Fmax of up to 0.647. Availability and implementation: https://github.com/bio-ontology-research-group/phenogocon. PMID- 30423069 TI - PAIPline: pathogen identification in metagenomic and clinical next generation sequencing samples. AB - Motivation: Next generation sequencing (NGS) has provided researchers with a powerful tool to characterize metagenomic and clinical samples in research and diagnostic settings. NGS allows an open view into samples useful for pathogen detection in an unbiased fashion and without prior hypothesis about possible causative agents. However, NGS datasets for pathogen detection come with different obstacles, such as a very unfavorable ratio of pathogen to host reads. Alongside often appearing false positives and irrelevant organisms, such as contaminants, tools are often challenged by samples with low pathogen loads and might not report organisms present below a certain threshold. Furthermore, some metagenomic profiling tools are only focused on one particular set of pathogens, for example bacteria. Results: We present PAIPline, a bioinformatics pipeline specifically designed to address problems associated with detecting pathogens in diagnostic samples. PAIPline particularly focuses on userfriendliness and encapsulates all necessary steps from preprocessing to resolution of ambiguous reads and filtering up to visualization in a single tool. In contrast to existing tools, PAIPline is more specific while maintaining sensitivity. This is shown in a comparative evaluation where PAIPline was benchmarked along other well-known metagenomic profiling tools on previously published well-characterized datasets. Additionally, as part of an international cooperation project, PAIPline was applied to an outbreak sample of hemorrhagic fevers of then unknown etiology. The presented results show that PAIPline can serve as a robust, reliable, user friendly, adaptable and generalizable stand-alone software for diagnostics from NGS samples and as a stepping stone for further downstream analyses. Availability and implementation: PAIPline is freely available under https://gitlab.com/rki_bioinformatics/paipline. PMID- 30423070 TI - SPhyR: tumor phylogeny estimation from single-cell sequencing data under loss and error. AB - Motivation: Cancer is characterized by intra-tumor heterogeneity, the presence of distinct cell populations with distinct complements of somatic mutations, which include single-nucleotide variants (SNVs) and copy-number aberrations (CNAs). Single-cell sequencing technology enables one to study these cell populations at single-cell resolution. Phylogeny estimation algorithms that employ appropriate evolutionary models are key to understanding the evolutionary mechanisms behind intra-tumor heterogeneity. Results: We introduce Single-cell Phylogeny Reconstruction (SPhyR), a method for tumor phylogeny estimation from single-cell sequencing data. In light of frequent loss of SNVs due to CNAs in cancer, SPhyR employs the k-Dollo evolutionary model, where a mutation can only be gained once but lost k times. Underlying SPhyR is a novel combinatorial characterization of solutions as constrained integer matrix completions, based on a connection to the cladistic multi-state perfect phylogeny problem. SPhyR outperforms existing methods on simulated data and on a metastatic colorectal cancer. Availability and implementation: SPhyR is available on https://github.com/elkebir-group/SPhyR. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423071 TI - Computational enhancement of single-cell sequences for inferring tumor evolution. AB - Motivation: Tumor sequencing has entered an exciting phase with the advent of single-cell techniques that are revolutionizing the assessment of single nucleotide variation (SNV) at the highest cellular resolution. However, state-of the-art single-cell sequencing technologies produce data with many missing bases (MBs) and incorrect base designations that lead to false-positive (FP) and false negative (FN) detection of somatic mutations. While computational methods are available to make biological inferences in the presence of these errors, the accuracy of the imputed MBs and corrected FPs and FNs remains unknown. Results: Using computer simulated datasets, we assessed the robustness performance of four existing methods (OncoNEM, SCG, SCITE and SiFit) and one new method (BEAM). BEAM is a Bayesian evolution-aware method that improves the quality of single-cell sequences by using the intrinsic evolutionary information in the single-cell data in a molecular phylogenetic framework. Overall, BEAM and SCITE performed the best. Most of the methods imputed MBs with high accuracy, but effective detection and correction of FPs and FNs is a challenge, especially for small datasets. Analysis of an empirical dataset shows that computational methods can improve both the quality of tumor single-cell sequences and their utility for biological inference. In conclusion, tumor cells descend from pre-existing cells, which creates evolutionary continuity in single-cell sequencing datasets. This information enables BEAM and other methods to correctly impute missing data and incorrect base assignments, but correction of FPs and FNs remains challenging when the number of SNVs sampled is small relative to the number of cells sequenced. Availability and implementation: BEAM is available on the web at https://github.com/SayakaMiura/BEAM. PMID- 30423072 TI - Off-target predictions in CRISPR-Cas9 gene editing using deep learning. AB - Motivation: The prediction of off-target mutations in CRISPR-Cas9 is a hot topic due to its relevance to gene editing research. Existing prediction methods have been developed; however, most of them just calculated scores based on mismatches to the guide sequence in CRISPR-Cas9. Therefore, the existing prediction methods are unable to scale and improve their performance with the rapid expansion of experimental data in CRISPR-Cas9. Moreover, the existing methods still cannot satisfy enough precision in off-target predictions for gene editing at the clinical level. Results: To address it, we design and implement two algorithms using deep neural networks to predict off-target mutations in CRISPR-Cas9 gene editing (i.e. deep convolutional neural network and deep feedforward neural network). The models were trained and tested on the recently released off-target dataset, CRISPOR dataset, for performance benchmark. Another off-target dataset identified by GUIDE-seq was adopted for additional evaluation. We demonstrate that convolutional neural network achieves the best performance on CRISPOR dataset, yielding an average classification area under the ROC curve (AUC) of 97.2% under stratified 5-fold cross-validation. Interestingly, the deep feedforward neural network can also be competitive at the average AUC of 97.0% under the same setting. We compare the two deep neural network models with the state-of-the-art off-target prediction methods (i.e. CFD, MIT, CROP-IT, and CCTop) and three traditional machine learning models (i.e. random forest, gradient boosting trees, and logistic regression) on both datasets in terms of AUC values, demonstrating the competitive edges of the proposed algorithms. Additional analyses are conducted to investigate the underlying reasons from different perspectives. Availability and implementation: The example code are available at https://github.com/MichaelLinn/off_target_prediction. The related datasets are available at https://github.com/MichaelLinn/off_target_prediction/tree/master/data. PMID- 30423074 TI - A Boolean network inference from time-series gene expression data using a genetic algorithm. AB - Motivation: Inferring a gene regulatory network from time-series gene expression data is a fundamental problem in systems biology, and many methods have been proposed. However, most of them were not efficient in inferring regulatory relations involved by a large number of genes because they limited the number of regulatory genes or computed an approximated reliability of multivariate relations. Therefore, an improved method is needed to efficiently search more generalized and scalable regulatory relations. Results: In this study, we propose a genetic algorithm-based Boolean network inference (GABNI) method which can search an optimal Boolean regulatory function of a large number of regulatory genes. For an efficient search, it solves the problem in two stages. GABNI first exploits an existing method, a mutual information-based Boolean network inference (MIBNI), because it can quickly find an optimal solution in a small-scale inference problem. When MIBNI fails to find an optimal solution, a genetic algorithm (GA) is applied to search an optimal set of regulatory genes in a wider solution space. In particular, we modified a typical GA framework to efficiently reduce a search space. We compared GABNI with four well-known inference methods through extensive simulations on both the artificial and the real gene expression datasets. Our results demonstrated that GABNI significantly outperformed them in both structural and dynamics accuracies. Conclusion: The proposed method is an efficient and scalable tool to infer a Boolean network from time-series gene expression data. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423073 TI - iCFN: an efficient exact algorithm for multistate protein design. AB - Motivation: Multistate protein design addresses real-world challenges, such as multi-specificity design and backbone flexibility, by considering both positive and negative protein states with an ensemble of substates for each. It also presents an enormous challenge to exact algorithms that guarantee the optimal solutions and enable a direct test of mechanistic hypotheses behind models. However, efficient exact algorithms are lacking for multistate protein design. Results: We have developed an efficient exact algorithm called interconnected cost function networks (iCFN) for multistate protein design. Its generic formulation allows for a wide array of applications such as stability, affinity and specificity designs while addressing concerns such as global flexibility of protein backbones. iCFN treats each substate design as a weighted constraint satisfaction problem (WCSP) modeled through a CFN; and it solves the coupled WCSPs using novel bounds and a depth-first branch-and-bound search over a tree structure of sequences, substates, and conformations. When iCFN is applied to specificity design of a T-cell receptor, a problem of unprecedented size to exact methods, it drastically reduces search space and running time to make the problem tractable. Moreover, iCFN generates experimentally-agreeing receptor designs with improved accuracy compared with state-of-the-art methods, highlights the importance of modeling backbone flexibility in protein design, and reveals molecular mechanisms underlying binding specificity. Availability and implementation: https://shen-lab.github.io/software/iCFN. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423075 TI - Comparative Network Reconstruction using mixed integer programming. AB - Motivation: Signal-transduction networks are often aberrated in cancer cells, and new anti-cancer drugs that specifically target oncogenes involved in signaling show great clinical promise. However, the effectiveness of such targeted treatments is often hampered by innate or acquired resistance due to feedbacks, crosstalks or network adaptations in response to drug treatment. A quantitative understanding of these signaling networks and how they differ between cells with different oncogenic mutations or between sensitive and resistant cells can help in addressing this problem. Results: Here, we present Comparative Network Reconstruction (CNR), a computational method to reconstruct signaling networks based on possibly incomplete perturbation data, and to identify which edges differ quantitatively between two or more signaling networks. Prior knowledge about network topology is not required but can straightforwardly be incorporated. We extensively tested our approach using simulated data and applied it to perturbation data from a BRAF mutant, PTPN11 KO cell line that developed resistance to BRAF inhibition. Comparing the reconstructed networks of sensitive and resistant cells suggests that the resistance mechanism involves re establishing wild-type MAPK signaling, possibly through an alternative RAF isoform. Availability and implementation: CNR is available as a python module at https://github.com/NKI-CCB/cnr. Additionally, code to reproduce all figures is available at https://github.com/NKI-CCB/CNR-analyses. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423076 TI - DeepDiff: DEEP-learning for predicting DIFFerential gene expression from histone modifications. AB - Motivation: Computational methods that predict differential gene expression from histone modification signals are highly desirable for understanding how histone modifications control the functional heterogeneity of cells through influencing differential gene regulation. Recent studies either failed to capture combinatorial effects on differential prediction or primarily only focused on cell type-specific analysis. In this paper we develop a novel attention-based deep learning architecture, DeepDiff, that provides a unified and end-to-end solution to model and to interpret how dependencies among histone modifications control the differential patterns of gene regulation. DeepDiff uses a hierarchy of multiple Long Short-Term Memory (LSTM) modules to encode the spatial structure of input signals and to model how various histone modifications cooperate automatically. We introduce and train two levels of attention jointly with the target prediction, enabling DeepDiff to attend differentially to relevant modifications and to locate important genome positions for each modification. Additionally, DeepDiff introduces a novel deep-learning based multi-task formulation to use the cell-type-specific gene expression predictions as auxiliary tasks, encouraging richer feature embeddings in our primary task of differential expression prediction. Results: Using data from Roadmap Epigenomics Project (REMC) for ten different pairs of cell types, we show that DeepDiff significantly outperforms the state-of-the-art baselines for differential gene expression prediction. The learned attention weights are validated by observations from previous studies about how epigenetic mechanisms connect to differential gene expression. Availability and implementation: Codes and results are available at deepchrome.org. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423077 TI - Semantic Disease Gene Embeddings (SmuDGE): phenotype-based disease gene prioritization without phenotypes. AB - Motivation: In the past years, several methods have been developed to incorporate information about phenotypes into computational disease gene prioritization methods. These methods commonly compute the similarity between a disease's (or patient's) phenotypes and a database of gene-to-phenotype associations to find the phenotypically most similar match. A key limitation of these methods is their reliance on knowledge about phenotypes associated with particular genes which is highly incomplete in humans as well as in many model organisms such as the mouse. Results: We developed SmuDGE, a method that uses feature learning to generate vector-based representations of phenotypes associated with an entity. SmuDGE can be used as a trainable semantic similarity measure to compare two sets of phenotypes (such as between a disease and gene, or a disease and patient). More importantly, SmuDGE can generate phenotype representations for entities that are only indirectly associated with phenotypes through an interaction network; for this purpose, SmuDGE exploits background knowledge in interaction networks comprised of multiple types of interactions. We demonstrate that SmuDGE can match or outperform semantic similarity in phenotype-based disease gene prioritization, and furthermore significantly extends the coverage of phenotype-based methods to all genes in a connected interaction network. Availability and implementation: https://github.com/bio-ontology-research-group/SmuDGE. PMID- 30423078 TI - A deep neural network approach for learning intrinsic protein-RNA binding preferences. AB - Motivation: The complexes formed by binding of proteins to RNAs play key roles in many biological processes, such as splicing, gene expression regulation, translation and viral replication. Understanding protein-RNA binding may thus provide important insights to the functionality and dynamics of many cellular processes. This has sparked substantial interest in exploring protein-RNA binding experimentally, and predicting it computationally. The key computational challenge is to efficiently and accurately infer protein-RNA binding models that will enable prediction of novel protein-RNA interactions to additional transcripts of interest. Results: We developed DLPRB (Deep Learning for Protein RNA Binding), a new deep neural network (DNN) approach for learning intrinsic protein-RNA binding preferences and predicting novel interactions. We present two different network architectures: a convolutional neural network (CNN), and a recurrent neural network (RNN). The novelty of our network hinges upon two key aspects: (i) the joint analysis of both RNA sequence and structure, which is represented as a probability vector of different RNA structural contexts; (ii) novel features in the architecture of the networks, such as the application of RNNs to RNA-binding prediction, and the combination of hundreds of variable length filters in the CNN. Our results in inferring accurate RNA-binding models from high-throughput in vitro data exhibit substantial improvements, compared to all previous approaches for protein-RNA binding prediction (both DNN and non-DNN based). A more modest, yet statistically significant, improvement is achieved for in vivo binding prediction. When incorporating experimentally-measured RNA structure, compared to predicted one, the improvement on in vivo data increases. By visualizing the binding specificities, we can gain biological insights underlying the mechanism of protein RNA-binding. Availability and implementation: The source code is publicly available at https://github.com/ilanbb/dlprb. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423079 TI - Liquid-chromatography retention order prediction for metabolite identification. AB - Motivation: Liquid Chromatography (LC) followed by tandem Mass Spectrometry (MS/MS) is one of the predominant methods for metabolite identification. In recent years, machine learning has started to transform the analysis of tandem mass spectra and the identification of small molecules. In contrast, LC data is rarely used to improve metabolite identification, despite numerous published methods for retention time prediction using machine learning. Results: We present a machine learning method for predicting the retention order of molecules; that is, the order in which molecules elute from the LC column. Our method has important advantages over previous approaches: We show that retention order is much better conserved between instruments than retention time. To this end, our method can be trained using retention time measurements from different LC systems and configurations without tedious pre-processing, significantly increasing the amount of available training data. Our experiments demonstrate that retention order prediction is an effective way to learn retention behaviour of molecules from heterogeneous retention time data. Finally, we demonstrate how retention order prediction and MS/MS-based scores can be combined for more accurate metabolite identifications when analyzing a complete LC-MS/MS run. Availability and implementation: Implementation of the method is available at https://version.aalto.fi/gitlab/bache1/retention_order_prediction.git. PMID- 30423080 TI - DREAM-Yara: an exact read mapper for very large databases with short update time. AB - Motivation: Mapping-based approaches have become limited in their application to very large sets of references since computing an FM-index for very large databases (e.g. >10 GB) has become a bottleneck. This affects many analyses that need such index as an essential step for approximate matching of the NGS reads to reference databases. For instance, in typical metagenomics analysis, the size of the reference sequences has become prohibitive to compute a single full-text index on standard machines. Even on large memory machines, computing such index takes about 1 day of computing time. As a result, updates of indices are rarely performed. Hence, it is desirable to create an alternative way of indexing while preserving fast search times. Results: To solve the index construction and update problem we propose the DREAM (Dynamic seaRchablE pArallel coMpressed index) framework and provide an implementation. The main contributions are the introduction of an approximate search distributor via a novel use of Bloom filters. We combine several Bloom filters to form an interleaved Bloom filter and use this new data structure to quickly exclude reads for parts of the databases where they cannot match. This allows us to keep the databases in several indices which can be easily rebuilt if parts are updated while maintaining a fast search time. The second main contribution is an implementation of DREAM-Yara a distributed version of a fully sensitive read mapper under the DREAM framework. Availability and implementation: https://gitlab.com/pirovc/dream_yara/. PMID- 30423081 TI - IRSOM, a reliable identifier of ncRNAs based on supervised self-organizing maps with rejection. AB - Motivation: Non-coding RNAs (ncRNAs) play important roles in many biological processes and are involved in many diseases. Their identification is an important task, and many tools exist in the literature for this purpose. However, almost all of them are focused on the discrimination of coding and ncRNAs without giving more biological insight. In this paper, we propose a new reliable method called IRSOM, based on a supervised Self-Organizing Map (SOM) with a rejection option, that overcomes these limitations. The rejection option in IRSOM improves the accuracy of the method and also allows identifing the ambiguous transcripts. Furthermore, with the visualization of the SOM, we analyze the rejected predictions and highlight the ambiguity of the transcripts. Results: IRSOM was tested on datasets of several species from different reigns, and shown better results compared to state-of-art. The accuracy of IRSOM is always greater than 0.95 for all the species with an average specificity of 0.98 and an average sensitivity of 0.99. Besides, IRSOM is fast (it takes around 254 s to analyze a dataset of 147 000 transcripts) and is able to handle very large datasets. Availability and implementation: IRSOM is implemented in Python and C++. It is available on our software platform EvryRNA (http://EvryRNA.ibisc.univ-evry.fr). PMID- 30423082 TI - Accurate and adaptive imputation of summary statistics in mixed-ethnicity cohorts. AB - Motivation: Methods based on summary statistics obtained from genome-wide association studies have gained considerable interest in genetics due to the computational cost and privacy advantages they present. Imputing missing summary statistics has therefore become a key procedure in many bioinformatics pipelines, but available solutions may rely on additional knowledge about the populations used in the original study and, as a result, may not always ensure feasibility or high accuracy of the imputation procedure. Results: We present ARDISS, a method to impute missing summary statistics in mixed-ethnicity cohorts through Gaussian Process Regression and automatic relevance determination. ARDISS is trained on an external reference panel and does not require information about allele frequencies of genotypes from the original study. Our method approximates the original GWAS population by a combination of samples from a reference panel relying exclusively on the summary statistics and without any external information. ARDISS successfully reconstructs the original composition of mixed ethnicity cohorts and outperforms alternative solutions in terms of speed and imputation accuracy both for heterogeneous and homogeneous datasets. Availability and implementation: The proposed method is available at https://github.com/BorgwardtLab/ARDISS. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423083 TI - Learning structural motif representations for efficient protein structure search. AB - Motivation: Given a protein of unknown function, fast identification of similar protein structures from the Protein Data Bank (PDB) is a critical step for inferring its biological function. Such structural neighbors can provide evolutionary insights into protein conformation, interfaces and binding sites that are not detectable from sequence similarity. However, the computational cost of performing pairwise structural alignment against all structures in PDB is prohibitively expensive. Alignment-free approaches have been introduced to enable fast but coarse comparisons by representing each protein as a vector of structure features or fingerprints and only computing similarity between vectors. As a notable example, FragBag represents each protein by a 'bag of fragments', which is a vector of frequencies of contiguous short backbone fragments from a predetermined library. Despite being efficient, the accuracy of FragBag is unsatisfactory because its backbone fragment library may not be optimally constructed and long-range interacting patterns are omitted. Results: Here we present a new approach to learning effective structural motif presentations using deep learning. We develop DeepFold, a deep convolutional neural network model to extract structural motif features of a protein structure. We demonstrate that DeepFold substantially outperforms FragBag on protein structural search on a non redundant protein structure database and a set of newly released structures. Remarkably, DeepFold not only extracts meaningful backbone segments but also finds important long-range interacting motifs for structural comparison. We expect that DeepFold will provide new insights into the evolution and hierarchical organization of protein structural motifs. Availability and implementation: https://github.com/largelymfs/DeepFold. PMID- 30423084 TI - iTOP: inferring the topology of omics data. AB - Motivation: In biology, we are often faced with multiple datasets recorded on the same set of objects, such as multi-omics and phenotypic data of the same tumors. These datasets are typically not independent from each other. For example, methylation may influence gene expression, which may, in turn, influence drug response. Such relationships can strongly affect analyses performed on the data, as we have previously shown for the identification of biomarkers of drug response. Therefore, it is important to be able to chart the relationships between datasets. Results: We present iTOP, a methodology to infer a topology of relationships between datasets. We base this methodology on the RV coefficient, a measure of matrix correlation, which can be used to determine how much information is shared between two datasets. We extended the RV coefficient for partial matrix correlations, which allows the use of graph reconstruction algorithms, such as the PC algorithm, to infer the topologies. In addition, since multi-omics data often contain binary data (e.g. mutations), we also extended the RV coefficient for binary data. Applying iTOP to pharmacogenomics data, we found that gene expression acts as a mediator between most other datasets and drug response: only proteomics clearly shares information with drug response that is not present in gene expression. Based on this result, we used TANDEM, a method for drug response prediction, to identify which variables predictive of drug response were distinct to either gene expression or proteomics. Availability and implementation: An implementation of our methodology is available in the R package iTOP on CRAN. Additionally, an R Markdown document with code to reproduce all figures is provided as Supplementary Material. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423085 TI - An accurate and rapid continuous wavelet dynamic time warping algorithm for end to-end mapping in ultra-long nanopore sequencing. AB - Motivation: Long-reads, point-of-care and polymerase chain reaction-free are the promises brought by nanopore sequencing. Among various steps in nanopore data analysis, the end-to-end mapping between the raw electrical current signal sequence and the reference expected signal sequence serves as the key building block to signal labeling, and the following signal visualization, variant identification and methylation detection. One of the classic algorithms to solve the signal mapping problem is the dynamic time warping (DTW). However, the ultra long nanopore sequencing and an order of magnitude difference in the sampling speed complexify the scenario and make the classical DTW infeasible to solve the problem. Results: Here, we propose a novel multi-level DTW algorithm, continuous wavelet DTW (cwDTW), based on continuous wavelet transforms with different scales of the two signal sequences. Our algorithm starts from low-resolution wavelet transforms of the two sequences, such that the transformed sequences are short and have similar sampling rates. Then the peaks and nadirs of the transformed sequences are extracted to form feature sequences with similar lengths, which can be easily mapped by the original DTW. Our algorithm then recursively projects the warping path from a lower-resolution level to a higher-resolution one by building a context-dependent boundary and enabling a constrained search for the warping path in the latter. Comprehensive experiments on two real nanopore datasets on human and on Pandoraea pnomenusa demonstrate the efficiency and effectiveness of the proposed algorithm. In particular, cwDTW can gain remarkable acceleration with tiny loss of the alignment accuracy. On the real nanopore datasets, cwDTW can finish an alignment task in few seconds, which is about 3000 times faster than the original DTW. By successfully applying cwDTW on the tasks of signal labeling and ultra-long sequence comparison, we further demonstrate the power and applicability of cwDTW. Availability and implementation: Our program is available at https://github.com/realbigws/cwDTW. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423086 TI - fastp: an ultra-fast all-in-one FASTQ preprocessor. AB - Motivation: Quality control and preprocessing of FASTQ files are essential to providing clean data for downstream analysis. Traditionally, a different tool is used for each operation, such as quality control, adapter trimming and quality filtering. These tools are often insufficiently fast as most are developed using high-level programming languages (e.g. Python and Java) and provide limited multi threading support. Reading and loading data multiple times also renders preprocessing slow and I/O inefficient. Results: We developed fastp as an ultra fast FASTQ preprocessor with useful quality control and data-filtering features. It can perform quality control, adapter trimming, quality filtering, per-read quality pruning and many other operations with a single scan of the FASTQ data. This tool is developed in C++ and has multi-threading support. Based on our evaluation, fastp is 2-5 times faster than other FASTQ preprocessing tools such as Trimmomatic or Cutadapt despite performing far more operations than similar tools. Availability and implementation: The open-source code and corresponding instructions are available at https://github.com/OpenGene/fastp. PMID- 30423087 TI - piMGM: incorporating multi-source priors in mixed graphical models for learning disease networks. AB - Motivation: Learning probabilistic graphs over mixed data is an important way to combine gene expression and clinical disease data. Leveraging the existing, yet imperfect, information in pathway databases for mixed graphical model (MGM) learning is an understudied problem with tremendous potential applications in systems medicine, the problems of which often involve high-dimensional data. Results: We present a new method, piMGM, which can learn with accuracy the structure of probabilistic graphs over mixed data by appropriately incorporating priors from multiple experts with different degrees of reliability. We show that piMGM accurately scores the reliability of prior information from a given expert even at low sample sizes. The reliability scores can be used to determine active pathways in healthy and disease samples. We tested piMGM on both simulated and real data from TCGA, and we found that its performance is not affected by unreliable priors. We demonstrate the applicability of piMGM by successfully using prior information to identify pathway components that are important in breast cancer and improve cancer subtype classification. Availability and implementation: http://www.benoslab.pitt.edu/manatakisECCB2018.html. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423088 TI - Hierarchical HotNet: identifying hierarchies of altered subnetworks. AB - Motivation: The analysis of high-dimensional 'omics data is often informed by the use of biological interaction networks. For example, protein-protein interaction networks have been used to analyze gene expression data, to prioritize germline variants, and to identify somatic driver mutations in cancer. In these and other applications, the underlying computational problem is to identify altered subnetworks containing genes that are both highly altered in an 'omics dataset and are topologically close (e.g. connected) on an interaction network. Results: We introduce Hierarchical HotNet, an algorithm that finds a hierarchy of altered subnetworks. Hierarchical HotNet assesses the statistical significance of the resulting subnetworks over a range of biological scales and explicitly controls for ascertainment bias in the network. We evaluate the performance of Hierarchical HotNet and several other algorithms that identify altered subnetworks on the problem of predicting cancer genes and significantly mutated subnetworks. On somatic mutation data from The Cancer Genome Atlas, Hierarchical HotNet outperforms other methods and identifies significantly mutated subnetworks containing both well-known cancer genes and candidate cancer genes that are rarely mutated in the cohort. Hierarchical HotNet is a robust algorithm for identifying altered subnetworks across different 'omics datasets. Availability and implementation: http://github.com/raphael-group/hierarchical-hotnet. Supplementary information: Supplementary material are available at Bioinformatics online. PMID- 30423089 TI - Bayesian inference on stochastic gene transcription from flow cytometry data. AB - Motivation: Transcription in single cells is an inherently stochastic process as mRNA levels vary greatly between cells, even for genetically identical cells under the same experimental and environmental conditions. We present a stochastic two-state switch model for the population of mRNA molecules in single cells where genes stochastically alternate between a more active ON state and a less active OFF state. We prove that the stationary solution of such a model can be written as a mixture of a Poisson and a Poisson-beta probability distribution. This finding facilitates inference for single cell expression data, observed at a single time point, from flow cytometry experiments such as FACS or fluorescence in situ hybridization (FISH) as it allows one to sample directly from the equilibrium distribution of the mRNA population. We hence propose a Bayesian inferential methodology using a pseudo-marginal approach and a recent approximation to integrate over unobserved states associated with measurement error. Results: We provide a general inferential framework which can be widely used to study transcription in single cells from the kind of data arising in flow cytometry experiments. The approach allows us to separate between the intrinsic stochasticity of the molecular dynamics and the measurement noise. The methodology is tested in simulation studies and results are obtained for experimental multiple single cell expression data from FISH flow cytometry experiments. Availability and implementation: All analyses were implemented in R. Source code and the experimental data are available at https://github.com/SimoneTiberi/Bayesian-inference-on-stochastic-gene transcription-from-flow-cytometry-data. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423090 TI - CNEFinder: finding conserved non-coding elements in genomes. AB - Motivation: Conserved non-coding elements (CNEs) represent an enigmatic class of genomic elements which, despite being extremely conserved across evolution, do not encode for proteins. Their functions are still largely unknown. Thus, there exists a need to systematically investigate their roles in genomes. Towards this direction, identifying sets of CNEs in a wide range of organisms is an important first step. Currently, there are no tools published in the literature for systematically identifying CNEs in genomes. Results: We fill this gap by presenting CNEFinder; a tool for identifying CNEs between two given DNA sequences with user-defined criteria. The results presented here show the tool's ability of identifying CNEs accurately and efficiently. CNEFinder is based on a k-mer technique for computing maximal exact matches. The tool thus does not require or compute whole-genome alignments or indexes, such as the suffix array or the Burrows Wheeler Transform (BWT), which makes it flexible to use on a wide scale. Availability and implementation: Free software under the terms of the GNU GPL (https://github.com/lorrainea/CNEFinder). PMID- 30423091 TI - Predicting protein-protein interactions through sequence-based deep learning. AB - Motivation: High-throughput experimental techniques have produced a large amount of protein-protein interaction (PPI) data, but their coverage is still low and the PPI data is also very noisy. Computational prediction of PPIs can be used to discover new PPIs and identify errors in the experimental PPI data. Results: We present a novel deep learning framework, DPPI, to model and predict PPIs from sequence information alone. Our model efficiently applies a deep, Siamese-like convolutional neural network combined with random projection and data augmentation to predict PPIs, leveraging existing high-quality experimental PPI data and evolutionary information of a protein pair under prediction. Our experimental results show that DPPI outperforms the state-of-the-art methods on several benchmarks in terms of area under precision-recall curve (auPR), and computationally is more efficient. We also show that DPPI is able to predict homodimeric interactions where other methods fail to work accurately, and the effectiveness of DPPI in specific applications such as predicting cytokine receptor binding affinities. Availability and implementation: Predicting protein protein interactions through sequence-based deep learning): https://github.com/hashemifar/DPPI/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423093 TI - Insights on the alteration of functionality of a tyrosine kinase 2 variant: a molecular dynamics study. AB - Motivation: The tyrosine kinase 2 protein (Tyk2), encoded by the TYK2 gene, has a crucial role in signal transduction and the pathogenesis of many diseases. A single nucleotide polymorphism of the TYK2 gene, SNP rs34536443, is of major importance, since it has been shown to confer protection against various, mainly, autoimmune diseases. This polymorphism results in a Pro to Ala change at amino acid position 1104 of the encoded Tyk2 protein that affects its enzymatic activity. However, the details of the underlined mechanism are unknown. To address this issue, in this study, we used molecular dynamics simulations on the kinase domains of both wild type and variant Tyk2 protein. Results: Our MD results provided information, at atomic level, on the consequences of the Pro1104 to Ala substitution on the structure and dynamics of the kinase domain of Tyk2 and suggested reduced enzymatic activity of the resulting protein variant due to stabilization of inactive conformations, thus adding to knowledge towards the elucidation of the protection mechanism against autoimmune diseases associated with this point mutation. PMID- 30423092 TI - Fast characterization of segmental duplications in genome assemblies. AB - Motivation: Segmental duplications (SDs) or low-copy repeats, are segments of DNA > 1 Kbp with high sequence identity that are copied to other regions of the genome. SDs are among the most important sources of evolution, a common cause of genomic structural variation and several are associated with diseases of genomic origin including schizophrenia and autism. Despite their functional importance, SDs present one of the major hurdles for de novo genome assembly due to the ambiguity they cause in building and traversing both state-of-the-art overlap layout-consensus and de Bruijn graphs. This causes SD regions to be misassembled, collapsed into a unique representation, or completely missing from assembled reference genomes for various organisms. In turn, this missing or incorrect information limits our ability to fully understand the evolution and the architecture of the genomes. Despite the essential need to accurately characterize SDs in assemblies, there has been only one tool that was developed for this purpose, called Whole-Genome Assembly Comparison (WGAC); its primary goal is SD detection. WGAC is comprised of several steps that employ different tools and custom scripts, which makes this strategy difficult and time consuming to use. Thus there is still a need for algorithms to characterize within-assembly SDs quickly, accurately, and in a user friendly manner. Results: Here we introduce SEgmental Duplication Evaluation Framework (SEDEF) to rapidly detect SDs through sophisticated filtering strategies based on Jaccard similarity and local chaining. We show that SEDEF accurately detects SDs while maintaining substantial speed up over WGAC that translates into practical run times of minutes instead of weeks. Notably, our algorithm captures up to 25% 'pairwise error' between segments, whereas previous studies focused on only 10%, allowing us to more deeply track the evolutionary history of the genome. Availability and implementation: SEDEF is available at https://github.com/vpc-ccg/sedef. PMID- 30423095 TI - ECCB 2018 Organization. PMID- 30423094 TI - A fast adaptive algorithm for computing whole-genome homology maps. AB - Motivation: Whole-genome alignment is an important problem in genomics for comparing different species, mapping draft assemblies to reference genomes and identifying repeats. However, for large plant and animal genomes, this task remains compute and memory intensive. In addition, current practical methods lack any guarantee on the characteristics of output alignments, thus making them hard to tune for different application requirements. Results: We introduce an approximate algorithm for computing local alignment boundaries between long DNA sequences. Given a minimum alignment length and an identity threshold, our algorithm computes the desired alignment boundaries and identity estimates using kmer-based statistics, and maintains sufficient probabilistic guarantees on the output sensitivity. Further, to prioritize higher scoring alignment intervals, we develop a plane-sweep based filtering technique which is theoretically optimal and practically efficient. Implementation of these ideas resulted in a fast and accurate assembly-to-genome and genome-to-genome mapper. As a result, we were able to map an error-corrected whole-genome NA12878 human assembly to the hg38 human reference genome in about 1 min total execution time and <4 GB memory using eight CPU threads, achieving significant improvement in memory-usage over competing methods. Recall accuracy of computed alignment boundaries was consistently found to be >97% on multiple datasets. Finally, we performed a sensitive self-alignment of the human genome to compute all duplications of length >=1 Kbp and >=90% identity. The reported output achieves good recall and covers twice the number of bases than the current UCSC browser's segmental duplication annotation. Availability and implementation: https://github.com/marbl/MashMap. PMID- 30423097 TI - DeepDTA: deep drug-target binding affinity prediction. AB - Motivation: The identification of novel drug-target (DT) interactions is a substantial part of the drug discovery process. Most of the computational methods that have been proposed to predict DT interactions have focused on binary classification, where the goal is to determine whether a DT pair interacts or not. However, protein-ligand interactions assume a continuum of binding strength values, also called binding affinity and predicting this value still remains a challenge. The increase in the affinity data available in DT knowledge-bases allows the use of advanced learning techniques such as deep learning architectures in the prediction of binding affinities. In this study, we propose a deep-learning based model that uses only sequence information of both targets and drugs to predict DT interaction binding affinities. The few studies that focus on DT binding affinity prediction use either 3D structures of protein ligand complexes or 2D features of compounds. One novel approach used in this work is the modeling of protein sequences and compound 1D representations with convolutional neural networks (CNNs). Results: The results show that the proposed deep learning based model that uses the 1D representations of targets and drugs is an effective approach for drug target binding affinity prediction. The model in which high-level representations of a drug and a target are constructed via CNNs achieved the best Concordance Index (CI) performance in one of our larger benchmark datasets, outperforming the KronRLS algorithm and SimBoost, a state-of the-art method for DT binding affinity prediction. Availability and implementation: https://github.com/hkmztrk/DeepDTA. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423096 TI - FLYCOP: metabolic modeling-based analysis and engineering microbial communities. AB - Motivation: Synthetic microbial communities begin to be considered as promising multicellular biocatalysts having a large potential to replace engineered single strains in biotechnology applications, in pharmaceutical, chemical and living architecture sectors. In contrast to single strain engineering, the effective and high-throughput analysis and engineering of microbial consortia face the lack of knowledge, tools and well-defined workflows. This manuscript contributes to fill this important gap with a framework, called FLYCOP (FLexible sYnthetic Consortium OPtimization), which contributes to microbial consortia modeling and engineering, while improving the knowledge about how these communities work. FLYCOP selects the best consortium configuration to optimize a given goal, among multiple and diverse configurations, in a flexible way, taking temporal changes in metabolite concentrations into account. Results: In contrast to previous systems optimizing microbial consortia, FLYCOP has novel characteristics to face up to new problems, to represent additional features and to analyze events influencing the consortia behavior. In this manuscript, FLYCOP optimizes a Synechococcus elongatus Pseudomonas putida consortium to produce the maximum amount of bio-plastic (PHA, polyhydroxyalkanoate), and highlights the influence of metabolites exchange dynamics in a four auxotrophic Escherichia coli consortium with parallel growth. FLYCOP can also provide an explanation about biological evolution driving evolutionary engineering endeavors by describing why and how heterogeneous populations emerge from monoclonal ones. Availability and implementation: Code reproducing the study cases described in this manuscript are available on-line: https://github.com/beatrizgj/FLYCOP. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423098 TI - Approximate, simultaneous comparison of microbial genome architectures via syntenic anchoring of quiver representations. AB - Motivation: A long-standing limitation in comparative genomic studies is the dependency on a reference genome, which hinders the spectrum of genetic diversity that can be identified across a population of organisms. This is especially true in the microbial world where genome architectures can significantly vary. There is therefore a need for computational methods that can simultaneously analyze the architectures of multiple genomes without introducing bias from a reference. Results: In this article, we present Ptolemy: a novel method for studying the diversity of genome architectures-such as structural variation and pan-genomes across a collection of microbial assemblies without the need of a reference. Ptolemy is a 'top-down' approach to compare whole genome assemblies. Genomes are represented as labeled multi-directed graphs-known as quivers-which are then merged into a single, canonical quiver by identifying 'gene anchors' via synteny analysis. The canonical quiver represents an approximate, structural alignment of all genomes in a given collection encoding structural variation across (sub-) populations within the collection. We highlight various applications of Ptolemy by analyzing structural variation and the pan-genomes of different datasets composing of Mycobacterium, Saccharomyces, Escherichia and Shigella species. Our results show that Ptolemy is flexible and can handle both conserved and highly dynamic genome architectures. Ptolemy is user-friendly-requires only FASTA formatted assembly along with a corresponding GFF-formatted file-and resource friendly-can align 24 genomes in ~10 mins with four CPUs and <2 GB of RAM. Availability and implementation: Github: https://github.com/AbeelLab/ptolemy. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423099 TI - CisPi: a transcriptomic score for disclosing cis-acting disease-associated lincRNAs. AB - Motivation: Long intergenic noncoding RNAs (lincRNAs) have risen to prominence in cancer biology as new biomarkers of disease. Those lincRNAs transcribed from active cis-regulatory elements (enhancers) have provided mechanistic insight into cis-acting regulation; however, in the absence of an enhancer hallmark, computational prediction of cis-acting transcription of lincRNAs remains challenging. Here, we introduce a novel transcriptomic method: a cis-regulatory lincRNA-gene associating metric, termed 'CisPi'. CisPi quantifies the mutual information between lincRNAs and local gene expression regarding their response to perturbation, such as disease risk-dependence. To predict risk-dependent lincRNAs in neuroblastoma, an aggressive pediatric cancer, we advance this scoring scheme to measure lincRNAs that represent the minority of reads in RNA Seq libraries by a novel side-by-side analytical pipeline. Results: Altered expression of lincRNAs that stratifies tumor risk is an informative readout of oncogenic enhancer activity. Our CisPi metric therefore provides a powerful computational model to identify enhancer-templated RNAs (eRNAs), eRNA-like lincRNAs, or active enhancers that regulate the expression of local genes. First, risk-dependent lincRNAs revealed active enhancers, over-represented neuroblastoma susceptibility loci, and uncovered novel clinical biomarkers. Second, the prioritized lincRNAs were significantly prognostic. Third, the predicted target genes further inherited the prognostic significance of these lincRNAs. In sum, RNA-Seq alone is sufficient to identify disease-associated lincRNAs using our methodologies, allowing broader applications to contexts in which enhancer hallmarks are not available or show limited sensitivity. Availability and implementation: The source code is available on request. The prioritized lincRNAs and their target genes are in the Supplementary Material. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423100 TI - Single cell network analysis with a mixture of Nested Effects Models. AB - Motivation: New technologies allow for the elaborate measurement of different traits of single cells under genetic perturbations. These interventional data promise to elucidate intra-cellular networks in unprecedented detail and further help to improve treatment of diseases like cancer. However, cell populations can be very heterogeneous. Results: We developed a mixture of Nested Effects Models (M&NEM) for single-cell data to simultaneously identify different cellular subpopulations and their corresponding causal networks to explain the heterogeneity in a cell population. For inference, we assign each cell to a network with a certain probability and iteratively update the optimal networks and cell probabilities in an Expectation Maximization scheme. We validate our method in the controlled setting of a simulation study and apply it to three data sets of pooled CRISPR screens generated previously by two novel experimental techniques, namely Crop-Seq and Perturb-Seq. Availability and implementation: The mixture Nested Effects Model (M&NEM) is available as the R-package mnem at https://github.com/cbg-ethz/mnem/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423102 TI - ECCB 2018: The 17th European Conference on Computational Biology. PMID- 30423101 TI - Quantitative trait loci identification for brain endophenotypes via new additive model with random networks. AB - Motivation: The identification of quantitative trait loci (QTL) is critical to the study of causal relationships between genetic variations and disease abnormalities. We focus on identifying the QTLs associated to the brain endophenotypes in imaging genomics study for Alzheimer's Disease (AD). Existing research works mainly depict the association between single nucleotide polymorphisms (SNPs) and the brain endophenotypes via the linear methods, which may introduce high bias due to the simplicity of the models. Since the influence of QTLs on brain endophenotypes is quite complex, it is desired to design the appropriate non-linear models to investigate the associations of genotypes and endophenotypes. Results: In this paper, we propose a new additive model to learn the non-linear associations between SNPs and brain endophenotypes in Alzheimer's disease. Our model can be flexibly employed to explain the non-linear influence of QTLs, thus is more adaptive for the complex distribution of the high throughput biological data. Meanwhile, as an important computational learning theory contribution, we provide the generalization error analysis for the proposed approach. Unlike most previous theoretical analysis under independent and identically distributed samples assumption, our error bound is based on m dependent observations, which is more appropriate for the high-throughput and noisy biological data. Experiments on the data from Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort demonstrate the promising performance of our approach for identifying biological meaningful SNPs. Availability and implementation: An executable is available at https://github.com/littleq1991/additive_FNNRW. PMID- 30423104 TI - Analysis of single amino acid variations in singlet hot spots of protein-protein interfaces. AB - Motivation: Single amino acid variations (SAVs) in protein-protein interaction (PPI) sites play critical roles in diseases. PPI sites (interfaces) have a small subset of residues called hot spots that contribute significantly to the binding energy, and they may form clusters called hot regions. Singlet hot spots are the single amino acid hot spots outside of the hot regions. The distribution of SAVs on the interface residues may be related to their disease association. Results: We performed statistical and structural analyses of SAVs with literature curated experimental thermodynamics data, and demonstrated that SAVs which destabilize PPIs are more likely to be found in singlet hot spots rather than hot regions and energetically less important interface residues. In contrast, non-hot spot residues are significantly enriched in neutral SAVs, which do not affect PPI stability. Surprisingly, we observed that singlet hot spots tend to be enriched in disease-causing SAVs, while benign SAVs significantly occur in non-hot spot residues. Our work demonstrates that SAVs in singlet hot spot residues have significant effect on protein stability and function. Availability and implementation: The dataset used in this paper is available as Supplementary Material. The data can be found at http://prism.ccbb.ku.edu.tr/data/sav/ as well. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423105 TI - Protein pocket detection via convex hull surface evolution and associated Reeb graph. AB - Motivation: Protein pocket information is invaluable for drug target identification, agonist design, virtual screening and receptor-ligand binding analysis. A recent study indicates that about half holoproteins can simultaneously bind multiple interacting ligands in a large pocket containing structured sub-pockets. Although this hierarchical pocket and sub-pocket structure has a significant impact to multi-ligand synergistic interactions in the protein binding site, there is no method available for this analysis. This work introduces a computational tool based on differential geometry, algebraic topology and physics-based simulation to address this pressing issue. Results: We propose to detect protein pockets by evolving the convex hull surface inwards until it touches the protein surface everywhere. The governing partial differential equations (PDEs) include the mean curvature flow combined with the eikonal equation commonly used in the fast marching algorithm in the Eulerian representation. The surface evolution induced Morse function and Reeb graph are utilized to characterize the hierarchical pocket and sub-pocket structure in controllable detail. The proposed method is validated on PDBbind refined sets of 4414 protein-ligand complexes. Extensive numerical tests indicate that the proposed method not only provides a unique description of pocket-sub-pocket relations, but also offers efficient estimations of pocket surface area, pocket volume and pocket depth. Availability and implementation: Source code available at https://github.com/rdzhao/ProteinPocketDetection. Webserver available at http://weilab.math.msu.edu/PPD/. PMID- 30423106 TI - Topology independent structural matching discovers novel templates for protein interfaces. AB - Motivation: Protein-protein interactions (PPI) are essential for the function of the cellular machinery. The rapid growth of protein-protein complexes with known 3D structures offers a unique opportunity to study PPI to gain crucial insights into protein function and the causes of many diseases. In particular, it would be extremely useful to compare interaction surfaces of monomers, as this would enable the pinpointing of potential interaction surfaces based solely on the monomer structure, without the need to predict the complete complex structure. While there are many structural alignment algorithms for individual proteins, very few have been developed for protein interfaces, and none that can align only the interface residues to other interfaces or surfaces of interacting monomer subunits in a topology independent (non-sequential) manner. Results: We present InterComp, a method for topology and sequence-order independent structural comparisons. The method is general and can be applied to various structural comparison applications. By representing residues as independent points in space rather than as a sequence of residues, InterComp can be applied to a wide range of problems including interface-surface comparisons and interface-interface comparisons. We demonstrate a use-case by applying InterComp to find similar protein interfaces on the surface of proteins. We show that InterComp pinpoints the correct interface for almost half of the targets (283 of 586) when considering the top 10 hits, and for 24% of the top 1, even when no templates can be found with regular sequence-order dependent structural alignment methods. Availability and implementation: The source code and the datasets are available at: http://wallnerlab.org/InterComp. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423107 TI - MDPbiome: microbiome engineering through prescriptive perturbations. AB - Motivation: Recent microbiome dynamics studies highlight the current inability to predict the effects of external perturbations on complex microbial populations. To do so would be particularly advantageous in fields such as medicine, bioremediation or industrial scenarios. Results: MDPbiome statistically models longitudinal metagenomics samples undergoing perturbations as a Markov Decision Process (MDP). Given a starting microbial composition, our MDPbiome system suggests the sequence of external perturbation(s) that will engineer that microbiome to a goal state, for example, a healthier or more performant composition. It also estimates intermediate microbiome states along the path, thus making it possible to avoid particularly undesirable/unhealthy states. We demonstrate MDPbiome performance over three real and distinct datasets, proving its flexibility, and the reliability and universality of its output 'optimal perturbation policy'. For example, an MDP created using a vaginal microbiome time series, with a goal of recovering from bacterial vaginosis, suggested avoidance of perturbations such as lubricants or sex toys; while another MDP provided a quantitative explanation for why salmonella vaccine accelerates gut microbiome maturation in chicks. This novel analytical approach has clear applications in medicine, where it could suggest low-impact clinical interventions that will lead to achievement or maintenance of a healthy microbial population, or alternately, the sequence of interventions necessary to avoid strongly negative microbiome states. Availability and implementation: Code (https://github.com/beatrizgj/MDPbiome) and result files (https://tomdelarosa.shinyapps.io/MDPbiome/) are available online. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423109 TI - Improving the visualization, interpretation and analysis of two-sample summary data Mendelian randomization via the Radial plot and Radial regression. PMID- 30423108 TI - Branch-recombinant Gaussian processes for analysis of perturbations in biological time series. AB - Motivation: A common class of behaviour encountered in the biological sciences involves branching and recombination. During branching, a statistical process bifurcates resulting in two or more potentially correlated processes that may undergo further branching; the contrary is true during recombination, where two or more statistical processes converge. A key objective is to identify the time of this bifurcation (branch or recombination time) from time series measurements, e.g. by comparing a control time series with perturbed time series. Gaussian processes (GPs) represent an ideal framework for such analysis, allowing for nonlinear regression that includes a rigorous treatment of uncertainty. Currently, however, GP models only exist for two-branch systems. Here, we highlight how arbitrarily complex branching processes can be built using the correct composition of covariance functions within a GP framework, thus outlining a general framework for the treatment of branching and recombination in the form of branch-recombinant Gaussian processes (B-RGPs). Results: We first benchmark the performance of B-RGPs compared to a variety of existing regression approaches, and demonstrate robustness to model misspecification. B-RGPs are then used to investigate the branching patterns of Arabidopsis thaliana gene expression following inoculation with the hemibotrophic bacteria, Pseudomonas syringae DC3000, and a disarmed mutant strain, hrpA. By grouping genes according to the number of branches, we could naturally separate out genes involved in basal immune response from those subverted by the virulent strain, and show enrichment for targets of pathogen protein effectors. Finally, we identify two early branching genes WRKY11 and WRKY17, and show that genes that branched at similar times to WRKY11/17 were enriched for W-box binding motifs, and overrepresented for genes differentially expressed in WRKY11/17 knockouts, suggesting that branch time could be used for identifying direct and indirect binding targets of key transcription factors. Availability and implementation: https://github.com/cap76/BranchingGPs. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30423110 TI - Non-steroids anti-inflammatory drugs and risk of peritonsillar abscess in pharyngitis: a French longitudinal study in primary care. AB - Background: The safety of non-steroids anti-inflammatory drugs (NSAIDs) in the context of pharyngitis is doubtful with contradictory results in the literature. Objective: To evaluate the risk of peritonsillar abscess (PTA) associated to NSAIDs consumption during a pharyngitis episode observed in primary care. Method: A retrospective cohort study using Observatory of General Medicine Datalink from 1995 to 2010. All patients consulting a GP from the Datalink network for pharyngitis have been included. The occurrence of a PTA in the 15 days following the consultation for pharyngitis was matched. The association between PTA and prescriptions of NSAIDs was studied via an adjusted logistic regression model. Results: During the study period, 105 802 cases of pharyngitis and 48 cases of PTA following a pharyngitis were reported, concerning respectively 67 765 and 47 patients. In the multivariate analysis, the risk of PTA was associated positively with a NSAIDs prescription (OR = 2.9, 95% CI = 1.6-5.2). Other factors associated with PTA occurrence were the prescription of corticosteroids (OR = 3.1, 95% CI = 1.3-7.6) and an age between 20 and 40 years (OR = 5.7, 95% CI = 2.5-13.0). The prescription of antibiotics was not significantly associated with PTA (P = 0.7). Conclusion: Prescription of NSAIDs in pharyngitis may increase the risk of PTA. This study encourages considering cautiously the balance between benefits and harms before prescription of NSAIDs for pharyngitis. PMID- 30423111 TI - Genomic Prediction for Crossbred Performance using Metafounders. AB - Future genomic evaluation models to be used routinely in breeding programs for pigs and poultry need to be able to optimally use information of crossbred animals to predict breeding values for crossbred performance of purebred selection candidates. Important challenges in the commonly used single-step genomic best linear unbiased prediction (ssGBLUP) model, are the definition of relationships between the different line compositions and the definition of the base generation per line. The use of metafounders (MFs) in ssGBLUP has been proposed to overcome these issues. When relationships between lines are known to be different from 0, the use of MFs generalizes the concept of genetic groups relying on the genotype data. Our objective was to investigate the effect of using MFs in genomic prediction for crossbred performance on estimated variance components, and accuracy and bias of genomic estimated breeding values. This was studied using stochastic simulation to generate data representing a three-way crossbreeding scheme in pigs, with the parental lines being either closely related or unrelated. Results show that using MFs, the variance components should be scaled appropriately, especially when basing them on estimates obtained with e.g. a pedigree based model. The accuracies of genomic estimated breeding values that were obtained using MFs were similar to accuracies without using MFs, regardless whether the lines involved in the crossbred were closely related or unrelated. The use of MFs resulted in a model that had similar or somewhat better convergence properties compared to other models. We recommend the use of MFs in ssGBLUP for genomic evaluations in crossbreeding schemes. PMID- 30423112 TI - Height as a clinical biomarker of disease burden in adult mitochondrial disease. AB - Context: Abnormal growth and short stature are observed in patients with mitochondrial disease but it is unclear whether there is a relationship between final adult height, and disease severity. Objective: To determine whether patients with genetically confirmed mitochondrial disease are shorter than their peers and whether stature is related to disease severity. Design: Analysis of final adult height in relation to disease severity determined by the Newcastle Mitochondrial Disease Adult Scale (NMDAS). Setting: United Kingdom (UK) Mitochondrial Disease Patient Cohort. Patients: 575 patients were identified with recorded height, weight and molecular genetic diagnosis of mitochondrial disease within the UK Mitochondrial Disease Patient Cohort. Main Outcome Measures: Adult Height, BMI and their association with genetic subgroup and disease severity. Results: Adults with mitochondrial disease were short with a mean height of -0.49 standard deviations (SD) (95% CI; -0.58 to -0.39, n=575) compared to UK reference data. Patients were overweight with a BMI SD 0.52 (95% CI; 0.37 to 0.67, n=472). The most common genetic subgroup (m.3243A>G mutation) had a height SD of -0.70 (95% CI; -0.85 to -0.54, n=234) and BMI SD of 0.12 (95% CI; -0.10 to 0.34, n=212). NMDAS scores were negatively correlated with height SD (r= -0.25, 95% CI; -0.33 to -0.17, p<0.001, n=533).Rate of disease progression also correlated negatively with adult height (p<0.001). Conclusion: Final height in mitochondrial disease reflects disease severity and rate of disease progression. Mitochondrial dysfunction and associated subclinical comorbidities affect growth plate physiology. PMID- 30423113 TI - The muscle protein synthetic response to whey protein ingestion is greater in middle-aged women when compared with men. AB - Rationale: Muscle mass maintenance is largely regulated by the postprandial rise in muscle protein synthesis rates. It remains unclear whether postprandial protein handling differs between women and men. Methods: Healthy men (43+/-3 y; BMI: 23.4+/-0.4 kg/m2; n=12) and women (46+/-2 y; BMI: 21.3+/-0.5 kg/m2; n=12) received primed continuous infusions of L-[ring-2H5]-phenylalanine and L-[ring 3,5-2H2]-tyrosine and ingested 25 g intrinsically L-[1-13C]-phenylalanine-labeled whey protein. Blood samples and muscle biopsies were collected to assess dietary protein digestion and amino acid absorption kinetics as well as basal and postprandial myofibrillar protein synthesis rates. Results: Plasma phenylalanine and leucine concentrations rapidly increased following protein ingestion (both P<0.001), with no differences between middle-aged women and men (Time*Sex P=0.307 and 0.529, respectively). The fraction of dietary protein-derived phenylalanine that appeared in the circulation over the 5 h postprandial period averaged 56+/-1 and 53+/-1% in the women and men, respectively (P=0.145). Myofibrillar protein synthesis rates increased (Time P=0.010) from 0.035+/-0.004 and 0.030+/-0.002 %/h in the post-absorptive state (t-test P=0.319) to 0.045+/-0.002 and 0.034+/-0.002 %/h in the 5 h postprandial phase in middle-aged women and men, respectively, with higher postprandial myofibrillar protein synthesis rates in women compared with men (t-test P=0.005). Middle-aged women showed a greater increase in myofibrillar protein synthesis rates during the early (0-2 h) postprandial period when compared with men (Time*Sex P=0.001). Conclusions: There are no differences in post-absorptive myofibrillar protein synthesis rates between middle-aged women and men. The myofibrillar protein synthetic response to the ingestion of 25 g whey protein is greater in women when compared with men. PMID- 30423114 TI - Genetic Influences on Susceptibility to Rheumatoid Arthritis in African Americans. AB - Large meta-analyses of RA susceptibility in European and East Asian populations have identified >100 RA risk loci, but genome-wide studies of RA in African Americans are absent. To address this disparity, we performed an analysis of 916 African-American RA patients and 1392 controls, and aggregated our data with genotyping data from >100,000 European and Asian RA patients and controls. We identified two novel risk loci that appear to be specific to African-Americans: GPC5 and RBFOX1 (pAA < 5 x 10-9). Most RA risk loci are shared across different ethnicities, but among discordant loci, we observed strong enrichment of variants having large effect sizes. We found strong evidence of effect concordance for only 3 of the 21 largest effect index variants in Europeans. We used the trans ethnic fine-mapping algorithm PAINTOR3 to prioritize risk variants in >90 RA risk loci. Addition of African-American data to those of European and East Asian descent enabled identification of 7 novel high confidence candidate pathogenic variants (defined by posterior probability > 0.8). In summary, our trans-ethnic analyses are the first to include African-Americans, identified several new RA risk loci, and point to candidate pathogenic variants that may underlie this common autoimmune disease. These findings may lead to better ways to diagnose or stratify treatment approaches in RA. PMID- 30423115 TI - Scientific communication strategies of microbiologists in the era of social media. AB - Over the last decades, the world of communication underwent drastic changes, and internet and social media emerged as essential vehicles for exchanging information. Following these trends, it is important that scientists adapt to changes and adopt optimal strategies to communicate with colleagues, lay people and institutions. We conducted an online survey to investigate the communication strategies of microbiologists and their colleagues from other disciplines. We collected data from 527 scholars from 57 countries, with ~42% of them being microbiologists. We focused particularly on social media and found that >80% of participants used them for work, and that ~50% of interviewed actively shared and gathered scientific contents from social media. Compared to colleagues from other fields, microbiologists were less averse to use social media for work and were also less accustomed to use pre-prints as a source and vehicle of information. However, a large proportion of microbiologists declared to have planned pre-print publications in the future. Surprisingly, our data revealed that age is a poor predictor of social media usage, but it is strongly associated with the type of social media used, the activity undertaken on them and the attitude towards pre print publications. Considering the kaleidoscopic variety of scientific communication tools, our data might help to optimize the scientific promotion strategies among microbiologists. PMID- 30423116 TI - The crystal structure of homoserine dehydrogenase complexed with L-homoserine and NADPH in a closed form. AB - Homoserine dehydrogenase from Thermus thermophilus (TtHSD) is a key enzyme in the aspartate pathway that catalyzes the reversible conversion of L-aspartate-beta semialdehyde to L-homoserine (L-Hse) with NAD(P)H. We determined the crystal structures of unliganded TtHSD, TtHSD complexed with L-Hse and NADPH, and Lys99Ala and Lys195Ala mutant TtHSDs, which have no enzymatic activity, complexed with L-Hse and NADP+ at 1.83, 2.00, 1.87, and 1.93 A resolutions, respectively. Binding of L-Hse and NADPH induced the conformational changes of TtHSD from an open to a closed form: The mobile loop containing Glu180 approached to fix L-Hse and NADPH, and both Lys99 and Lys195 could make hydrogen bonds with the hydroxy group of L-Hse. The ternary complex of TtHSDs in the closed form mimicked a Michaelis complex better than the previously reported open form structures from other species. In the crystal structure of Lys99Ala TtHSD, the productive geometry of the ternary complex was almost preserved with one new water molecule taking over the hydrogen bonds associated with Lys99, while the positions of Lys195 and L-Hse were significantly retained with those of the wild-type enzyme. These results propose new possibilities that Lys99 is the acid-base catalytic residue of HSDs. PMID- 30423117 TI - Using genetics to understand the causal influence of higher BMI on depression. AB - Background: Depression is more common in obese than non-obese individuals, especially in women, but the causal relationship between obesity and depression is complex and uncertain. Previous studies have used genetic variants associated with BMI to provide evidence that higher body mass index (BMI) causes depression, but have not tested whether this relationship is driven by the metabolic consequences of BMI nor for differences between men and women. Methods: We performed a Mendelian randomization study using 48 791 individuals with depression and 291 995 controls in the UK Biobank, to test for causal effects of higher BMI on depression (defined using self-report and Hospital Episode data). We used two genetic instruments, both representing higher BMI, but one with and one without its adverse metabolic consequences, in an attempt to 'uncouple' the psychological component of obesity from the metabolic consequences. We further tested causal relationships in men and women separately, and using subsets of BMI variants from known physiological pathways. Results: Higher BMI was strongly associated with higher odds of depression, especially in women. Mendelian randomization provided evidence that higher BMI partly causes depression. Using a 73-variant BMI genetic risk score, a genetically determined one standard deviation (1 SD) higher BMI (4.9 kg/m2) was associated with higher odds of depression in all individuals [odds ratio (OR): 1.18, 95% confidence interval (CI): 1.09, 1.28, P = 0.00007) and women only (OR: 1.24, 95% CI: 1.11, 1.39, P = 0.0001). Meta-analysis with 45 591 depression cases and 97 647 controls from the Psychiatric Genomics Consortium (PGC) strengthened the statistical confidence of the findings in all individuals. Similar effect size estimates were obtained using different Mendelian randomization methods, although not all reached P < 0.05. Using a metabolically favourable adiposity genetic risk score, and meta analysing data from the UK biobank and PGC, a genetically determined 1 SD higher BMI (4.9 kg/m2) was associated with higher odds of depression in all individuals (OR: 1.26, 95% CI: 1.06, 1.50], P = 0.010), but with weaker statistical confidence. Conclusions: Higher BMI, with and without its adverse metabolic consequences, is likely to have a causal role in determining the likelihood of an individual developing depression. PMID- 30423118 TI - Effect of family-oriented diabetes programs on glycemic control: A meta-analysis. AB - Background: Efficacy of programs for patients with diabetes mellitus (DM) that have promoted family members to help with patients' self-care activities has been largely inconsistent. This meta-analysis aims to assess the effect of family oriented diabetes programs for glycemic control (GC). Methods: Electronic literature searches were conducted for clinical trials with a parallel design wherein there were two groups according to whether family members were included (intervention group) or not included (control group) and changes in glycohemoglobin A1C (A1C) were assessed as a study outcome. Each effect size (i.e. difference in A1C change between the intervention and control group) was pooled with a random-effects model. Results: There were 31 eligible trials consisting of 1466 and 1415 patients in the intervention and control groups, respectively. Pooled A1C change [95% confidence interval (CI)] was -0.45% (-0.64% to -0.26%). Limiting analyses to 21 trials targeted at patients with type 1 DM or 9 trials targeted at patients with type 2 DM, the pooled A1C changes (95% CI) were -0.35% (-0.55% to -0.14%) and -0.71% (-1.09% to -0.33%), respectively. Conclusion: This meta-analysis suggests that focusing on the family as well as the individual patient in self-management diabetes programs to improve the performance of self-care activities of patients with DM is effective in terms of proper GC. PMID- 30423119 TI - Ageism Amplifies Cost and Prevalence of Health Conditions. AB - Background and Objectives: The persistent status of ageism as one of the least acknowledged forms of prejudice may be due in part to an absence of quantifying its costs in economic terms. In this study, we calculated the costs of ageism on health conditions for all persons aged 60 years or older in the United States during 1 year. Research Design and Materials: The ageism predictors were discrimination aimed at older persons, negative age stereotypes, and negative self-perceptions of aging. Health care costs of ageism were computed by combining analyses of the impact of the predictors with comprehensive health care spending data in 1 year for the eight most-expensive health conditions, among all Americans aged 60 years or older. As a secondary analysis, we computed the number of these health conditions experienced due to ageism. Results: It was found that the 1-year cost of ageism was $63 billion, or one of every seven dollars spent on the 8 health conditions (15.4%), after adjusting for age and sex as well as removing overlapping costs from the three predictors. Also according to our model, ageism resulted in 17.04 million cases of these health conditions. Discussion and Implications: This is the first study to identify the economic cost that ageism imposes on health. The findings suggest that a reduction of ageism would not only have a monetary benefit for society, but also have a health benefit for older persons. PMID- 30423120 TI - Prevalence of tick-borne viruses in Ixodes ricinus assessed by high-throughput real-time PCR. AB - Ticks are one of the principal arthropod vectors of human and animal infectious diseases. Whereas the prevalence of tick-borne encephalitis virus in ticks in Europe is well studied, there is less information available on the prevalence of the other tick-borne viruses (TBVs) existing worldwide. The aim of this study was to improve the epidemiological survey tools of TBVs by the development of an efficient high-throughput test to screen a wide range of viruses in ticks.In this study, we developed a new high-throughput virus-detection assay based on parallel real-time PCRs on a microfluidic system, and used it to perform a large scale epidemiological survey screening for the presence of 21 TBVs in 18 135 nymphs of Ixodes ricinus collected from five European countries. This extensive investigation has (i) evaluated the prevalence of four viruses present in the collected ticks, (ii) allowed the identification of viruses in regions where they were previously undetected.In conclusion, we have demonstrated the capabilities of this new screening method that allows the detection of numerous TBVs in a large number of ticks. This tool represents a powerful and rapid system for TBVs surveillance in Europe and could be easily customized to assess viral emergence. PMID- 30423121 TI - Cholestyramine decreases apparent total tract macronutrient digestibility and alters fecal characteristics and metabolites of healthy adult dogs. AB - Absorption of dietary lipids in the small intestine is dependent on the emulsification by bile acids (BA) and the formation of chylomicrons. Cholestyramine is a common drug used in humans - and potentially dogs - to treat BA malabsorption associated with chronic diarrhea. It is known to bind BA to form insoluble complexes, preventing their reabsorption and possibly proper emulsification and absorption of dietary fats. The objective of this study was to evaluate the effects of cholestyramine on 1) macronutrient apparent total tract digestibility (ATTD), and 2) fecal characteristics and metabolites of healthy adult dogs. We hypothesized that cholestyramine would decrease ATTD of fat and organic matter (OM), increase fecal dry matter (DM) content, and increase fecal output. Twelve healthy beagles (3.2 +/- 0.8 yr; 10.4 +/- 0.9 kg) were used in a randomized crossover design. All procedures were approved by the University of Illinois Institutional Animal Care and Use Committee before the study. The study included a baseline period and two 14-d experimental periods separated by a 14-d washout. All dogs were fed the same experimental diet, formulated to meet all nutrient needs recommended by AAFCO, throughout the study. Dogs were randomized into two groups [diet only (control) or diet + 11.4 g/d cholestyramine (8 g/d active ingredient)] in Period 1 and received the other treatment in Period 2. During the washout, all dogs were fed the diet only. Dogs were fed once daily (08:00) to maintain BW. Total fecal output was collected during the last 4 d of each period for ATTD analysis. On d14 of each of period, fresh fecal and blood samples were collected for metabolite analysis. Dogs fed cholestyramine had lower (P < 0.001) ATTD of DM, OM, energy, crude protein, and fat and lower (P <0.01) fecal scores (firmer stools) than controls. Dogs fed cholestyramine had greater (P <0.01) as-is and dry fecal output than controls. Dogs fed cholestyramine had lower (P <0.05) fecal ammonia and phenol concentrations, but greater (P <0.05) fecal indole, acetate, butyrate, and total short-chain fatty acid concentrations than controls. Fecal DM% and pH were greater (P <0.01) in dogs fed cholestyramine. Our results indicate that cholestyramine, when given with a meal, is safe and well tolerated but significantly decreases nutrient digestibility and alters fecal characteristics. Future studies are required to explore the effects of cholestyramine on dogs with gastrointestinal disease. PMID- 30423122 TI - ER Stress Activated by Androgen Enhances Apoptosis of Granulosa Cells via Induction of Death Receptor 5 in PCOS. AB - Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism and growth arrest of antral follicles. Previously, we found that endoplasmic reticulum (ER) stress is activated in granulosa cells of antral follicles in PCOS, evidenced by activation of unfolded protein response (UPR) genes. Based on this observation, we hypothesized that ER stress is activated by androgens in granulosa cells of antral follicles, and that activated ER stress promotes apoptosis via induction of the UPR transcription factor C/EBP homologous protein (CHOP) and subsequent activation of death receptor (DR) 5. In this study, we found that testosterone induced expression of various UPR genes, including CHOP, as well as DR5, in cultured human granulosa-lutein cells (GLCs). Pretreatment with the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) inhibited testosterone-induced apoptosis and expression of DR5 and CHOP. Knockdown of CHOP inhibited testosterone-induced DR5 expression and apoptosis, and knockdown of DR5 inhibited testosterone-induced apoptosis. Pretreatment with flutamide, as well as knockdown of androgen receptor (AR), decreased testosterone-induced DR5 and CHOP expression, as well as apoptosis. Expression of DR5 and CHOP was upregulated in GLCs obtained from PCOS patients, and in granulosa cells of antral follicles in ovarian sections obtained from PCOS patients and dehydroepiandrosterone (DHEA) induced PCOS mice. Treatment of PCOS mice with TUDCA decreased apoptosis and DR5 expression in granulosa cells of antral follicles, with a concomitant reduction in CHOP expression. Together, our findings indicate that ER stress activated by hyperandrogenism in PCOS promotes apoptosis of granulosa cells of antral follicles via induction of DR5. PMID- 30423124 TI - Optimization of cardiac resynchronisation therapy: LV Lead position, qLV, or paced effects? PMID- 30423123 TI - Association between cortical bone microstructure and statin use in older women. AB - Context: Treatment with statins has been associated with increased bone mineral density (BMD), but if this association depends on differences in cortical or trabecular volumetric bone microstructure is unknown. Objective: The aim of this study was to investigate if treatment with statins is associated with bone microstructure and geometry in older women. Design setting and participants: Older women were included in a population-based study of 3,028 women (mean age +/ SD: 77.8 +/- 1.6 years) from the greater Gothenburg area in Sweden. Information regarding medical history, medication and life-style factors was obtained from validated questionnaires. Main outcome: Bone geometry and microstructure were measured at the ultradistal and distal (14%) site of radius and tibia using high resolution peripheral quantitative computed tomography (HR-pQCT; XtremeCT). Results: The 803 women in the cohort who used statins had higher body weight, worse physical function and more frequently cardiovascular disease and diabetes than nonusers (p<0.05). Statin users had lower cortical porosity (radius 2.2+/- 1.9 vs. 2.5+/- 2.0%; tibia 5.2+/- 2.4 vs. 5.4+/- 2.5, p=0.01), higher cortical bone density (radius 1008 +/- 39.1 vs. 1001 +/- 38.4 mg/cm3; tibia 919 +/- 42.6 vs. 914 +/- 41.5, p<0.01), and greater cortical area (radius 60.5 +/- 9.6 vs. 58.6 +/- 9.7 mm2; tibia 150.0 +/- 23.6 vs. 146.7 +/- 23.8, p<0.01) than non users, also after adjustment for a large number of confounders, including age, weight, smoking, other medications and prevalent diseases. Conclusions: Use of statins was associated with better cortical bone characteristics in older women. PMID- 30423125 TI - An improved genome assembly for Drosophila navojoa, the basal species in the mojavensis cluster. AB - Three North American cactophilic Drosophila species, D. mojavensis, D. arizonae, and D. navojoa are of considerable evolutionary interest owing to the shift from breeding in Opuntia cacti to columnar species. The three species form the "mojavensis cluster" of Drosophila. The genome of D. mojavensis was sequenced in 2007 and the genomes of D.navojoa and D. arizonae were sequenced together in 2016 using the same technology (Illumina) and assembly software (AllPaths-LG). Yet, unfortunately, the D. navojoa genome was considerably more fragmented and incomplete than its sister species, rendering it less useful for evolutionary genetic studies. The D. navojoa read dataset does not fully meet the strict insert size required by the assembler used (AllPaths-LG) and this incompatibility might explain its assembly problems. Accordingly, when we re-assembled the genome of D. navojoa with the SPAdes assembler, which does not have the strict AllPaths LG requirements, we obtained a substantial improvement in all quality indicators such as N50 (from 84 kb to 389 kb) and BUSCO coverage (from 77% to 97%). Here we share a new, improved reference assembly for D. navojoa genome, along with a RNAseq transcriptome. Given the basal relationship of the Opuntia breeding D. navojoa to the columnar breeding D. arizonae and D. mojavensis, the improved assembly and annotation will allow researchers to address a range of questions associated with the genomics of host shifts, chromosomal rearrangements and speciation in this group. PMID- 30423127 TI - Lethal and Repellent Effects of the Botanical p-Anisaldehyde on Musca domestica (Diptera: Muscidae). AB - The house fly, Musca domestica L., is a globally distributed nuisance and disease carrying urban and livestock pest. Control mostly relies on synthetic insecticides but resistance to them has become problematic. p-Anisaldehyde, a compound found in many edible plants, was assessed for its effects on different life stages of M. domestica. Whereas p-anisaldehyde, applied as an adult contact spray, caused >80% mortality by 30 min at a 30% concentration, egg mortality on treated substrate was complete at 0.1%, and the LC90 was 0.024%. Only 0.5 and 1 ml of 1.5% p-anisaldehyde mixed into 100 g of cow manure curtailed pupation. When the amount of p-anisaldehyde was increased to 2 ml, 0.75% p-anisaldehyde reduced pupation by 95.5%. In static air olfactometer tubes, 0.075% p-anisaldehyde repelled substantial numbers of adult M. domestica within 30 min. Repellency of 60-78% was maintained throughout the 4-h bioassay. This study demonstrates that p anisaldehyde is strongly bioactive against M. domestica in terms of lethal and nonlethal effects. PMID- 30423126 TI - An acute challenge with a deoxynivalenol-contaminated diet has short- and long term effects on performance and feeding behavior in finishing pigs. AB - Mycotoxins are toxic secondary metabolites produced by various fungi and are known to contaminate animal feed ingredients especially cereals. One of the most common mycotoxins in swine diets is deoxynivalenol (DON) which is known to decrease growth performance. The objective of the present study was to evaluate the effects of single or repeated short-term DON challenges on growth performance, and feeding behavior in finishing pigs. A total of 160 pigs were distributed to four experimental groups in two successive replicates with each pig individually measured for live BW and individually fed using an electronic feeding station. The pigs in control group CC were fed with a standard finisher diet during the whole duration of the experimental period. Groups DC, CD, and DD were given the DON-contaminated diet (3.02 mg DON/kg feed) for 7 d at 113 d, at 134 d, and at 113 and 134 d of age, respectively. The DON-contaminated diet was formulated with a naturally contaminated corn. During challenge periods, ADFI was decreased by 26% to 32% (P < 0.05) and ADG by 40% to 60% (P < 0.05). The drop in ADFI during DON challenges was associated with changes in the feeding behavior: when compared to the nonchallenged pigs, pigs fed with DON-contaminated diet had lower number of meals per day (9.6 versus 8.2 meals per day on average; P < 0.05) and slower feeding rate (42.0 g/min versus 39.9 g/min on average; P < 0.05). For the whole trial period, pigs submitted to the DON challenge at the end of the experiment (i.e., first time for CD group and second time for DD group) had a lower (P < 0.05) ADFI (2.67 and 2.59 kg/d, respectively) when compared to the control CC group of pigs (2.87 kg/d). An intermediate value was reported for the DC groups (2.79 kg/d). All challenged groups, i.e., DC, CD, and DD pigs, had lower (P < 0.05) overall ADG (970, 940, and 900 g/day, respectively) than CC (1,050 g/day) for the whole trial period. Pigs challenged early in the trial, i.e., DC and DD groups, had a higher (P < 0.05) FCR than CC group (3.00 and 3.06 versus 2.80, respectively) while group CD showed intermediate results (2.92). This study demonstrates that the severity of DON toxicity in pig performance can be related to the age of exposure (113 or 134 d) and the number of exposures to the toxin (one or two). Exposure to DON also resulted to long-term effects because challenged pigs showed limited ability to recover after the DON-induced reduction of feed intake. PMID- 30423128 TI - Pharmacokinetics and In Vivo Efficacy of Pyrazolopyrimidine, Pyrrolopyrimidine and 5-Aminopyrazole-4-Carboximide Bumped Kinase Inhibitors against Toxoplasmosis. AB - Bumped kinase inhibitors have been shown to be potent inhibitors of Toxoplasma gondii calcium dependent protein kinase 1. Pyrazolopyrimidine and 5-aminopyrazole 4-carboxamide scaffold-based BKIs are effective in acute and chronic experimental models of toxoplasmosis. Through further exploration of these two scaffolds and a new pyrrolopyrimidine scaffold, additional compounds have been identified that are extremely effective against acute experimental toxoplasmosis. The in vivo efficacy of these BKIs demonstrates that the cyclopropyloxynaphthyl, cyclopropyloxyquinoline, and 2-ethoxyquinolin-6-yl substituents are associated with efficacy across scaffolds. In addition, a broad range of plasma concentrations after oral dosing resulted from small structural changes to the BKIs. These select BKIs include anti-Toxoplasma compounds that are effective against acute experimental toxoplasmosis and are not toxic in human cell assays, nor to mice when administered for therapy. The BKIs described here are promising late leads for improving anti-Toxoplasma therapy. PMID- 30423129 TI - Functional Analysis of Genetic Variation In The Secis Element Of Thyroid Hormone Activating Type 2 Deiodinase. AB - Context: Thyroid hormone (TH) is important for normal brain development. The type 2 deiodinase (D2) controls TH action in the brain by activating T4 to T3. The enzymatic activity of D2 depends on the incorporation of selenocysteine (Sec) for which the SECIS element located in the 3'UTR is indispensable. We hypothesized that mutations in the SECIS element could impact on D2 function, resulting in a neurocognitive phenotype. Objective: To identify mutations in the SECIS element of DIO2 in patients with intellectual disability (ID) and to test their functional consequences. Design, setting and patients: The SECIS element of DIO2 was sequenced in 387 patients with unexplained ID, based on a predefined pattern of thyroid function tests. SECIS element read-through in wild-type (WT) or mutant D2 was quantified by a luciferase reporter system in transfected cells. Functional consequences were assessed by quantifying D2 activity in cell lysate or intact cell metabolism studies. Results: Sequence analysis revealed 2 heterozygous mutations: c.5703C>T and c.5730A>T, which were also present in unaffected family members. Functional evaluation showed that both mutations did not affect D2 enzyme activity in cell lysates or intact cells, although the 5730A>T mutation decreased SECIS element read-through by 75%. In the patient harboring the c.5730A>T variant, whole genome sequencing revealed a pathogenic deletion of the STXBP1 gene. Conclusion: We report 2 families with mutations in the SECIS element of D2. Although functional analysis shows that nucleotide 5730 is important for normal SECIS element read-through, both variants do not segregate with a distinct phenotype. PMID- 30423130 TI - Accelerating aligner treatment using low-frequency vibration: a single-centre, randomized controlled clinical trial. AB - Background: Low-frequency vibrations have been proposed as a means of accelerating tooth movement and reducing orthodontic treatment times. Objective: To determine any differences in the accuracy of dental movement in patients treated with a low-frequency vibration aligner protocol and/or by reducing the aligner replacement interval with respect to a conventional protocol. Design: This trial was designed as a single-centre, randomized controlled clinical trial. Methods: Participants: Patients (aged 27.1 +/- 9.0 years) who required orthodontic treatment with aligners. Randomization: Patients were randomly allocated to three arms as determined by a computer-randomization scheme. Group A were assigned a conventional protocol (aligners replaced every 14 days); group B also used a low-frequency vibration device for 20 minutes per day; group C followed the same vibration protocol but replaced their aligners every 7 days. Blinding: The operator who performed the set-up and the one who analysed the data were blinded to the group of the patients. Outcome: Pre- and post-treatment digital models were analysed using VAM software to identify the accuracy/imprecision of dental movements. One-way analysis of variance (P < 0.05) and the Bonferroni post hoc test were used to identify any statistically significant differences between the three arms in terms of the accuracy of tooth movement versus the prescription. Results: Numbers analysed: A total of 45 patients (15 for group) were analysed (i.e. 2286 dental movements). Outcome: No statistically significant differences emerged between groups A and C in the upper arch, or among groups A, B, and C in the lower. Group B displayed significantly greater accuracy with respect to group A in upper incisor rotation (P = 0.016), and to group C in vestibulolingual (P = 0.007) and mesiodistal tipping (P = 0.029) of the upper canines, and vestibulolingual tipping of the upper molars (P = 0.0001). Harms: No adverse events or side-effects were registered. Conclusions: There was no difference in accuracy between replacing the aligners accompanied by low-frequency vibration every 7 days and replacing them every 14 days without vibration. Moreover, low-frequency vibration seemed to improve the accuracy of a conventional protocol in terms of upper incisor rotation. Trial registration: The German Clinical Trials Register (DRK00015613). PMID- 30423131 TI - The unbearable ease of expression-how avoidance of spurious transcription can shape G+C content in bacterial genomes. PMID- 30423132 TI - Plasma acylcarnitines and risk of type 2 diabetes in a Mediterranean population at high cardiovascular risk. AB - Context: The potential associations between acylcarnitine profiles and incidence of T2D, and whether acylcarnitines can be used to improve diabetes prediction remains unclear. Objective: To evaluate the associations between baseline and 1 year changes in acylcarnitines, and their diabetes predictive ability beyond traditional risk factors. Design, setting and participants: We designed a case cohort study within the PREDIMED Study including all incident cases of T2D(n=251) and 694 randomly selected participants at baseline(follow-up:3.8-years).Plasma acylcarnitines were measured using a targeted approach by liquid chromatography tandem mass spectrometry(LC-MS).We tested the associations between baseline and 1 year changes in individual acylcarnitines and T2D risk using weighted Cox regression models.We used elastic net regressions to select acylcarnitines for T2D prediction and compute a weighted score using a cross-validation approach. Results: An acylcarnitine profile, especially including short-chain and long chain, was significantly associated with a higher risk of T2D independent of traditional risk factors.The relative risk of T2D per SD increment of the predictive model scores were 4.03(95%CI,3.00-5.42;P<0.001) for the conventional model, and 4.85(95%,3.65-6.45;P<0.001) for the model including acylcarnitines, with a HR of 1.33 (95%CI,1.08-1.63;P<0.001) attributed to the acylcarnitines.Including the acylcarnitines into the model did not significantly improve the area under the receiver operator characteristic(ROC) curve (0.86 to 0.88,P=0.61).One-year increase in C4OH-carnitine was associated with higher risk of T2D[per SD increment: 1.44(1.03-2.01)]. Conclusions: An acylcarnitines profile, mainly including short- and long- chain acylcarnitines, was significantly associated with higher T2D risk in participants at high cardiovascular risk.The inclusion of acylcarnitines into the model did not significantly improve the T2D prediction c-statistics beyond traditional risk factors including fasting glucose. PMID- 30423133 TI - Repellent Effects of Methyl Anthranilate on Western Corn Rootworm Larvae (Coleoptera: Chrysomelidae) in Soil Bioassays. AB - Methyl anthranilate (MA), a compound in maize roots that is repellent to western corn rootworm larvae (Diabrotica virgifera virgifera LeConte) was tested in behavioral bioassays in a soil environment. MA prevented larvae from locating roots of a maize seedling, and the repellency strengthened with increasing rates of MA. In a simple push-pull strategy between an MA-treated seedling and an untreated seedling, granules containing 0.1 mg/g MA pushed larvae to the untreated seedling. This push effect increased with dose, with 90% repellency observed for the highest dose tested (100 mg/g). Chemical analysis showed that MA concentrations remained high for 4 wk in dry, sterilized or unsterilized soil, but declined rapidly in moist soil. After 7 d, 50% less MA was recovered in moist, sterilized soil than in dry soil, and only a trace of MA remained in unsterilized moist soil, suggesting that both moisture and microbial activity contributed to the loss of MA. Various (MA) carrier granules were tested in bioassays after aging in moist soil. After 1 d, all of the MA granules were repellent at the 10 mg/g rate and clay granules were also effective at 1 mg/g. After 1 wk, only molecular sieve granules elicited repellency, but that activity disappeared after 2 wk. These results demonstrate that MA is repellent to western corn rootworm larvae in the soil environment and may have potential as a rootworm treatment if formulations can be developed that protect the material from decomposition in the soil. PMID- 30423134 TI - A quality improvement project to improve pediatric medical provider sleep and communication during night shifts. AB - Quality problem or issue: Night-shift medical providers frequently experience limited sleep resulting in fatigue, often because of paging activity. Streamlined medical-specific communication interventions are known to improve sleep and communication among these providers. Initial assessment: We found that non-urgent paging communication occurred frequently during night-shifts, leading to provider sleep disturbances within our institution. We tested a quality improvement (QI) intervention to improve paging practices and determined its effect on provider sleep. Choice of solution: We used a Plan-Do-Study-Act QI model aimed at improving clinician sleep and paging communications. Implementation: We initially conducted focus groups of nurses and physician trainees to inform the creation of a standardized paging intervention. We collected actigraphy and sleep log data from physicians, nurse practitioners, and physician trainees and performed electronic collection of paging frequency data. Evaluation: Data were collected between December 2015 and March 2017 from pediatric residents, pediatric hematology/oncology (PHO) fellows, hospitalist medicine nocturnists and nurses working during night-shift hours in PHO inpatient units. We collected baseline data before implementation of the QI intervention and at 1 month post implementation. Although objective measures and provider reports demonstrated improved medical-specific communication paging practices, provider sleep was not affected. Lessons learned: Provider-based standardization of paging communication was associated with improved medical-specific communication between nurses and providers; however, provider sleep was not affected. The strategies used in this intervention may be transferable to other clinics and institutions to streamline medical-specific communication. PMID- 30423135 TI - Incidence and Risk Factors of Foot and Ankle Disorders in Male Finnish Conscripts. AB - Introduction: Many studies focusing on musculoskeletal disorders or injuries have been performed in countries where the army is recruited as volunteers. Little is known about foot and ankle disorders among young men in conscript armies. Materials and methods: We studied the incidence and risk factors of foot and ankle disorders in 4,029 Finnish army male conscripts of the same age among five different cohorts born in 1969, 1974, 1979, 1984, or 1989. Data were collected from the medical reports of the Finnish Defence Forces. Self-reported symptoms and diseases detected in the health examination prior to military service, and information obtained from visits to garrison health care centers were analyzed. Results: A total of 1,623 conscripts visited health care professionals due to foot or ankle disorders during their military service. About 511 (31.5%) of those had suffered an injury. The majority of the visits to garrison health care centers due to foot or ankle disorders occurred during the first few months of military service. Smoking, flatfoot deformity, previous injuries, and Class A military service were statistically significantly related with the incidence of foot or ankle disorders. There were statistically significantly less foot and ankle disorders if previous mental symptoms were reported. The data suggest that poor adaptation to physically demanding military training may cause foot and ankle disorders among many conscripts. Conclusions: The study shows that foot and ankle disorders are common in this population. Most of them occur in the first 2 months of the military service. Further analysis of different conditions was not possible, as many of the diagnostic codes were missing. PMID- 30423136 TI - Suicide in the Military: Understanding Rates and Risk Factors Across the United States' Armed Forces. AB - This paper presents data from the United States Department of Defense Suicide Event Report System for years 2012-2015 to detail descriptive, longitudinal rate data and risk factor profiles associated with military suicide. The annual findings were aggregated from all U.S. military suicide deaths and suicide attempts. Data elements included the most common method of suicide (firearms), most common behavioral health diagnoses (substance abuse/dependence), common life stressors (failed intimate-partner relationships), and an individual's history of operational deployment. Age- and sex-adjusted rates for the Services were compared with rates for the U.S. adult population. Results showed that the current reporting period (2015) is similar to patterns that have been observed over the preceding years and to patterns reported in the overall U.S. adult population. Suicide rates remain elevated but stable for both the Active and Reserve Components of the Military Services compared to historical levels observed prior to 2003. Finally, we discuss common errors and misinterpretations that can occur when analyzing surveillance data. PMID- 30423137 TI - The Effectiveness of an Upper Extremity Neuromuscular Training Program on the Shoulder Function of Military Members With a Rotator Cuff Tendinopathy: A Pilot Randomized Controlled Trial. AB - Introduction: Shoulder pain, a leading reason to consult a physician or physiotherapist, continues to be a challenge to rehabilitate, particularly with a military population. A rotator cuff (RC) tendinopathy, the most important source of shoulder pain, is one of the leading reasons for sick leave or a discharge from active military service. Research encourages the use of exercise prescription for the management of a RC tendinopathy, however the ideal method of delivery (group setting versus one-on-one) remains uncertain. The purpose of this single-blind (evaluator) pilot randomized clinical trial was to compare two 6 week rehabilitation programs, a newly developed group-supervised neuromuscular training program and usual one-on-one physiotherapy care, on the pain and symptoms of Canadian soldiers affected by a RC tendinopathy. Materials and Methods: Thirty-one soldiers with the Canadian Armed Forces were randomly assigned to (1) a group-supervised neuromuscular training program (UPEx-NTP) or; (2) one-on-one usual physiotherapy care (UPC). The primary outcome was the Disability of Arm, Hand and Shoulder (DASH) questionnaire. Secondary outcomes included the Western Ontario Rotator Cuff (WORC) Index, pain levels at rest, and maximum isometric voluntary contractions (MIVC) of the abductors and external (lateral) rotators of the affected shoulder. Both were assessed at baseline (T0), 6 (T6) and 12 (T12) weeks. Analysis included two-way repeated measures of variance for intention-to-treat (ITT) and per-protocol analyses. Results: Eighty military members with a RC tendinopathy were contacted, resulting in 31 participants who were randomized for their active intervention, in the UPEx-NTP or UPC, respectively. No significant group (p >= 0.16) or group * time interactions (p >= 0.11) were found for either ITT or per-protocol analyses. A statistically significant time effect (p < 0.001) was established for the DASH and WORC, showing that both groups improved over time. Conclusions: Our preliminary data demonstrates that both rehabilitation approaches, grounded in active exercises, were not statistically different from each other, and derived similar benefits over time for a military population. This suggests that a group intervention for a RC tendinopathy has potential to be just as effective as a one on-one approach for a military population, an interesting avenue for an active working population. Larger sample sizes and further investigation are warranted regarding the cost and clinical resource benefits of a supervised group approach. PMID- 30423138 TI - Radiation resistance of normal human astrocytes: the role of non-homologous end joining DNA repair activity. AB - Radiotherapy is a common modality for treatment of brain cancers, but it can induce long-term physiological and cognitive deficits. The responses of normal human brain cells to radiation is not well understood. Astrocytes have been shown to have a variety of protective mechanisms against oxidative stress and have been shown to protect neurons. We investigated the response of cultured normal human astrocytes (NHAs) to X-ray irradiation. Following exposure to 10 Gy X irradiation, NHAs exhibited DNA damage as indicated by the formation of gamma H2AX foci. Western blotting showed that NHAs displayed a robust increase in expression of non-homologous end joining DNA repair enzymes within 15 min post irradiation and increased expression of homologous recombination DNA repair enzymes ~2 h post-irradiation. The cell cycle checkpoint protein p21/waf1 was upregulated from 6-24 h, and then returned to baseline. Levels of DNA repair enzymes returned to basal ~48 h post-irradiation. NHAs re-entered the cell cycle and proliferation was observed at 6 days. In contrast, normal human mesenchymal stem cells (MSCs) failed to upregulate DNA repair enzymes and instead displayed sustained upregulation of p21/waf1, a cell cycle checkpoint marker for senescence. Ectopic overexpression of Ku70 was sufficient to protect MSCs from sustained upregulation of p21/waf1 induced by 10 Gy X-rays. These findings suggest that increased expression of Ku70 may be a key mechanism for the radioresistance of NHAs, preventing their accelerated senescence from high-dose radiation. These results may have implications for the development of novel targets for radiation countermeasure development. PMID- 30423139 TI - Corrigendum to: Final grain weight is not limited by the activity of key starchsynthesising enzymes during grain filling in wheat. PMID- 30423140 TI - A Preliminary Study of Carrion Insects and Their Succession in Luanda, Angola. AB - The study of the arthropod fauna involved in carcass decomposition is crucial for medicolegal forensic purposes. This knowledge is especially needed in countries with high levels of criminality and where the arthropod fauna is still under recorded and not well known, such as Angola. We present data from the first survey on sarcosaprophagous flies and beetles in Angola, conducted in Luanda over a 17-d period, in the wet summer season. In total, 881 adult and immature specimens, belonging to 18 species, were collected from three pig carcasses that were sampled daily. Three species were not previously known from Angola. The dominant flies were Chrysomya albiceps (Wiedemann, 1819) (Diptera: Calliphoridae) and Chrysomya megacephala (Fabricius, 1794), but Chrysomya marginalis (Wiedemann, 1830), Chrysomya putoria (Wiedemann, 1830), and Liosarcophaga emmrichiana (Lehrer, 2002) (Diptera: Sarcophagidae) also bred on the carcasses. The dominant beetles were Dermestes maculatus De Geer, 1774 (Coleoptera: Dermestidae), Saprinus splendens (Paykull 1811) (Coleoptera: Histeridae), and Necrobia rufipes (De Geer, 1775) (Coleoptera: Cleridae). Because of the hot weather during the experimental period (~27 degrees C), decomposition was extremely fast. Periods of insect activity on carcasses are presented and comparisons are made with other carrion communities reported from the Afrotropical region. PMID- 30423141 TI - Role of INSL4 Signaling in Sustaining the Growth and Viability of LKB1 Inactivated Lung Cancer. AB - Background: The LKB1 tumor suppressor gene is commonly inactivated in non-small cell lung carcinomas (NSCLC), a major form of lung cancer. Targeted therapies for LKB1-inactivated lung cancer are currently unavailable. Identification of critical signaling components downstream of LKB1 inactivation has the potential to uncover rational therapeutic targets. Here we investigated the role of INSL4, a member of the insulin/IGF/relaxin superfamily, in LKB1-inactivated NSCLCs. Methods: INSL4 expression was analyzed using global transcriptome profiling, quantitative reverse transcription PCR, western blotting, enzyme-linked immunosorbent assay, and RNA in situ hybridization in human NSCLC cell lines and tumor specimens. INSL4 gene expression and clinical data from The Cancer Genome Atlas lung adenocarcinomas (n = 515) were analyzed using log-rank and Fisher exact tests. INSL4 functions were studied using short hairpin RNA (shRNA) knockdown, overexpression, transcriptome profiling, cell growth, and survival assays in vitro and in vivo. All statistical tests were two-sided. Results: INSL4 was identified as a novel downstream target of LKB1 deficiency and its expression was induced through aberrant CRTC-CREB activation. INSL4 was highly induced in LKB1-deficient NSCLC cells (up to 543-fold) and 9 of 41 primary tumors, although undetectable in all normal tissues except the placenta. Lung adenocarcinomas from The Cancer Genome Atlas with high and low INSL4 expression (with the top 10th percentile as cutoff) showed statistically significant differences for advanced tumor stage (P < .001), lymph node metastasis (P = .001), and tumor size (P = .01). The INSL4-high group showed worse survival than the INSL4-low group (P < .001). Sustained INSL4 expression was required for the growth and viability of LKB1-inactivated NSCLC cells in vitro and in a mouse xenograft model (n = 5 mice per group). Expression profiling revealed INSL4 as a critical regulator of cell cycle, growth, and survival. Conclusions: LKB1 deficiency induces an autocrine INSL4 signaling that critically supports the growth and survival of lung cancer cells. Therefore, aberrant INSL4 signaling is a promising therapeutic target for LKB1-deficient lung cancers. PMID- 30423142 TI - miRBase: from microRNA sequences to function. AB - miRBase catalogs, names and distributes microRNA gene sequences. The latest release of miRBase (v22) contains microRNA sequences from 271 organisms: 38 589 hairpin precursors and 48 860 mature microRNAs. We describe improvements to the database and website to provide more information about the quality of microRNA gene annotations, and the cellular functions of their products. We have collected 1493 small RNA deep sequencing datasets and mapped a total of 5.5 billion reads to microRNA sequences. The read mapping patterns provide strong support for the validity of between 20% and 65% of microRNA annotations in different well-studied animal genomes, and evidence for the removal of >200 sequences from the database. To improve the availability of microRNA functional information, we are disseminating Gene Ontology terms annotated against miRBase sequences. We have also used a text-mining approach to search for microRNA gene names in the full text of open access articles. Over 500 000 sentences from 18 542 papers contain microRNA names. We score these sentences for functional information and link them with 12 519 microRNA entries. The sentences themselves, and word clouds built from them, provide effective summaries of the functional information about specific microRNAs. miRBase is publicly and freely available at http://mirbase.org/. PMID- 30423143 TI - Using a mobile application to detect health needs among children and adolescents who are newly arrived migrants in Europe. AB - Background: Unprecedented numbers of migrants have arrived in Europe, including children and adolescents. Little is known about their unique health needs. Prospective data collection has been sparse. Mobile applications may help to facilitate global health surveillance. Methods: A pre-validated survey instrument was converted into a mobile application covering self-reported exposures and disruptions of healthcare before/during migration, communicable and non communicable diseases. Participation was voluntary, anonymous and confidential. Results: Data were obtained from 405 migrant children and adolescents in Berlin, Germany, between 7 October 2015 and 15 March 2016 (median age 19 years, range: 1 24; 80.7% males) with the majority from Syria (62.5%), Afghanistan (9.1%) and Iraq (8.2%). In total, 55% were without family, 64% registered asylum-seekers with access to healthcare; 54% had seen a doctor since arrival, with colds or respiratory complaints (37.5 and 13.6%), followed by pain (26.7%) gastrointestinal (12.4%) and skin problems (11.1%). Underlying conditions were reported in 15.6%, predominantly asthma. Overall, 73% reported being up-to date on immunizations, but only 22% held a vaccination record with 46.4% having lost it during migration. Conclusions: The lack of medical and immunization records among newly arrived migrants provides a challenge to healthcare systems. Mobile applications offer rapid screening tools in times of crisis, helping stakeholders with timely information. PMID- 30423144 TI - Stunting, dietary diversity and household food insecurity among children under 5 years in ethnic communities of northern Thailand. AB - Background: The aim of this study was to describe stunting in infants and young children in the ethnic communities of northern Thailand and to explore associations with dietary diversity and household factors including food security. Methods: A cross-sectional survey of households with children under 5 years from eight villages. Adult respondents provided information on foods consumed by each child and details of the household. Heights and weights of children were measured. Results: Adults from 172 households and 208 children participated. Overall, 38% of children were stunted. Exclusive breastfeeding was rare, but the proportion consuming breastmilk at 24 months (75%) was high. Few children (7%) aged 6-11 months met minimum dietary diversity. Stunted children were less likely than non-stunted children to meet minimum dietary diversity (63 versus 82%). Widespread food insecurity did not discriminate between stunted and non-stunted children. Stunting was elevated when households had little land and few animals. Conclusions: Stunting was widespread in children under 5 years of age, in part reflecting poor dietary diversity, especially at age 6-11 months. Stunting was worst in households with least assets. Small increases in land or animals, or equivalent resources, appear to be required to improve child nutrition in extremely poor families. PMID- 30423145 TI - Effects of repeated arthrocentesis on systemic cytokine expression and leukocyte population in young horses challenged with intra-articular lipopolysaccharide. AB - Osteoarthritis (OA) is a prevalent and economically costly source of lameness in the athletic horse. Previous studies investigating OA pathology have focused on localized trauma to the articular cartilage of a joint, largely ignoring the systemic immune status of the animal. In this study, yearling Quarter Horses were used to evaluate systemic cytokine gene expression and circulating leukocytes following a localized intra-articular inflammatory insult of the endotoxin, lipopolysaccharide (LPS). Treatments for the 35-d experiment included an intra articular injection of 0.25 ng (n = 7) or 0.50 ng (n = 6) of LPS obtained from Escherichia coli O55:B5 or sterile lactated Ringer's solution (n = 6; control) into the radial carpal joint. Blood and synovial fluid samples were collected at pre-injection h 0 and 2, 6, 12, and 24 h post-injection. Synovial fluid was obtained for a companion study. Total RNA was isolated from plasma leukocytes and real-time PCR was used to determine relative gene expression of the cytokines interleukin (IL)-1beta (beta), IL-6, IL-8, IL-10, and tumor necrosis factor-alpha (TNF-alpha). Total leukocyte subpopulations and differentials was performed using a cell counter. Data were analyzed using the PROC MIXED procedure of SAS. Gene expression of all cytokines were unaffected by intra-articular treatment. However, IL-1beta increased above baseline beginning at h 6 and remained elevated to 24 h (P = 0.04). In contrast, IL-6 decreased from h 6 to 12 and then increased to 24 h (P = 0.02). Levels of TNF-alpha increased at 6 and 12 h (P = 0.01) post injection. Only IL-8 exceeded a 2-fold change in expression (P = 0.01), peaking at 12 h and indicating greater responsiveness to arthrocentesis when compared to other cytokines. No treatment effects on the leukocyte population were observed; however, total circulating leukocytes increased over time (P = 0.04), peaking at 6 h post-injection. Similarly, an increase over time was observed in monocytes (P = 0.02) and in platelets (P = 0.01) at 24 h post-injection. The results indicate that regardless of treatment, a mild immune response was elicited, that may be due to repeated arthrocentesis. Future experiments should consider the effects of arthrocentesis and potential systemic inflammatory response, even in control animals, when administering intra-articular LPS to young horses. PMID- 30423146 TI - Development of a GeXP-Based Multiplex RT-PCR Assay for Detection of Long Noncoding RNA in Hepatocellular Carcinoma. AB - Objective: To develop a multiplex quantitative polymerase chain reaction (qPCR) assay based on the GenomeLabTM GeXP Genetic Analysis System (GeXP) for detection of long noncoding RNA in hepatocellular carcinoma (HCC). Methods: From PubMed database articles published between 2011 and 2016, we selected 8 kinds of long noncoding RNAs (lncRNAs) related to HCC. Further, we examined 23 pairs of HCC and adjacent noncancerous tissues, using the optimized GeXP multiplex reverse transcription polymerase chain reaction (RT-PCR) assay. Results: The expression level of lncRNA NEAT1, H19, MALAT1, HOTAIR, DANCR, UCA1, and BCAR4 were significantly decreased, compared with that in adjacent noncancerous tissues (all P <.05). The expression level of lncRNA GAS5 was statistically significantly increased (P <.05). For the quantitative polymerase chain reaction (qPCR) assay, 8 kinds of lncRNAs were detected as a result of the GeXP assay. Conclusions: The GeXP-based multiplex RT-PCR assay may be used as an alternative method for assisting in the histopathological diagnosis of HCC in liver lesions. PMID- 30423147 TI - Severe Progressive Mycobacterium avium Complex Infection Associated With Brentuximab Vedotin Therapy. PMID- 30423148 TI - Molecular-targeted therapies and precision medicine for endometrial cancer. AB - The overall survival rate of patients with early-stage endometrial cancer is relatively high; however, there are few treatment options for patients with advanced or recurrent endometrial cancer, and the prognosis of such patients remains poor. Recent progress in molecular-targeted therapies demonstrated that they have the potential to improve the long-term survival of cancer patients with appropriate biomarkers. However, the median progression-free survival of patients who received single-agent molecular-targeted therapy was <5 months, and the development of molecular-targeted therapies for endometrial cancer patients is urgently needed. This review highlights the previous efforts, including antiangiogenesis therapy, PI3K/AKT/mTOR pathway inhibitor treatment and epidermal growth factor receptor inhibitor treatment and reports on ongoing phase 2 clinical trials, including immune checkpoint inhibitor and PARP inhibitor. We also summarized the genetic background of endometrial cancer according to The Cancer Genome Atlas data and considered the theoretical background for future efforts to prolong the survival of patients with refractory endometrial cancer and for other interesting challenges. PMID- 30423149 TI - Open Surgery for Extraction of an Embolized Pellet in the Middle Cerebral Artery From a Shotgun Injury. AB - BACKGROUND AND IMPORTANCE: Embolization of shotgun pellet from the peripheral vasculature to the cerebral vessels has been a known phenomenon that has been reported previously in the literature. However, there is no consensus on clinical indications for intervention, best modality of intervention or management upon leaving the hospital. We describe a case of a shotgun pellet in the neck that embolized to the middle cerebral artery that was treated with open surgery. Discussed is the initial management on presentation, timing of intervention from surgery and detailed surgical technique. CLINICAL PRESENTATION: A 20-yr-old man presented after being shot at close range with a shotgun. He was neurologically intact on exam. Initial screening computed tomography (CT) of the brain noted a shotgun pellet in the region of the sylvian fissure without intracranial hemorrhage. Computed tomography angiography again displayed pellet in the vicinity of the left middle cerebral artery. He was emergently taken for an awake cerebral angiogram and subsequent surgical extraction of the shotgun pellet. CONCLUSION: Missile embolization of a bullet fragment to the intracranial vasculature is rare and requires difficult decisions regarding management. Critical factors that are to be considered prior to treatment include neurological clinical presentation, timing of the trauma, and anatomic location of injury. Patients who are without neurological deficit that display compromised blood flow require immediate cerebral angiogram followed by surgical intervention depending on location. PMID- 30423150 TI - Primary and Repeated Respiratory Viral Infections Among Infants in Rural Nepal. AB - Background: Respiratory viruses cause significant morbidity and death in infants; 99% of such deaths occur in resource-limited settings. Risk factors for initial and repeated respiratory viral infections in young infants in resource-limited settings have not been well described. Methods: From 2011 to 2014, a birth cohort of infants in rural Nepal was enrolled and followed with weekly household-based active surveillance for respiratory symptoms until 6 months of age. Respiratory illness was defined as having any of the following: fever, cough, wheeze, difficulty breathing, and/or a draining ear. We tested nasal swabs of infants with respiratory illness for multiple respiratory viruses by using a reverse transcription polymerase chain reaction assay. The risk of primary and repeated infections with the same virus was evaluated using Poisson regression. Results: Of 3528 infants, 1726 (49%) had a primary infection, and 419 (12%) had a repeated infection. The incidences of respiratory viral infection in infants were 1816 per 1000 person-years for primary infections and 1204 per 1000 person-years for repeated infection with the same virus. Exposure to other children and male sex were each associated with an increased risk for primary infection (risk ratios, 1.13 [95% confidence interval (CI), 1.06-1.20] and 1.14 [95% CI, 1.02-1.27], respectively), whereas higher maternal education was associated with a decreased risk for both primary and repeated infections (risk ratio, 0.96 [95% CI, 0.95 0.98]). The incidence of subsequent infection did not change when previous infection with the same or another respiratory virus occurred. Illness duration and severity were not significantly different in the infants between the first and second episodes for any respiratory virus tested. Conclusions: In infants in rural Nepal, repeated respiratory virus infections were frequent, and we found no decrease in illness severity with repeated infections and no evidence of replacement with another virus. Vaccine strategies and public health interventions that provide durable protection in the first 6 months of life could decrease the burden of repeated infections by multiple respiratory viruses, particularly in low-resource countries. PMID- 30423151 TI - Work-related asthma from cleaning agents versus other agents. AB - Background: Cleaning agents have been commonly implicated as causative or triggering factors in work-related asthma (WRA), mainly from epidemiologic studies. Relatively few clinical series have been reported. Aims: We aimed to compare socio-demographic and clinical features among tertiary clinic patients with WRA exposed to cleaning and non-cleaning products. Methods: Analyses were conducted on a patient database containing 208 patients with probable WRA referred to the asthma and airway centre at a tertiary centre hospital in Canada from 2000 to 2014. Chi-squared and independent samples t-tests were used to analyse categorical and continuous data, respectively. Results: Twenty-two (11%) WRA cases were attributed to a variety of cleaning product exposures, 12 were diagnosed as occupational asthma (OA) and 10 as work-exacerbated asthma (WEA) (10% of all OA and 11% of all WEA). There were multiple exposures and the responsible agent(s) could seldom be clearly identified. Most frequent categories of exposure were surfactants, alcohols, disinfectants and acids. Compared to WRA with other exposures, those with cleaning agent exposures had a significantly larger proportion of females (82 versus 35%, P < 0.001), included a higher percentage of workers in healthcare (41 versus 4%, P < 0.001), and submitted more workers' compensation claims (86 versus 64%, P = 0.05). Other characteristics were comparable. Conclusions: In a tertiary referral clinic, patients with WRA from cleaning agent exposure had clinical characteristics that were similar to those with WRA from other causes. Most frequent exposures were surfactants, alcohols, disinfectants and acids. PMID- 30423152 TI - Reply to the Letter to the Editor: Ultrasound-Guided Plantar Fascia Injections: (Where) Are You Putting the Gas or Steroids? PMID- 30423153 TI - New TNM classification (AJCC eighth edition) of bone and soft tissue sarcomas: JCOG Bone and Soft Tissue Tumor Study Group. AB - The Cancer Staging Manual of the American Joint Committee on Cancer (AJCC) has recently been revised and updated to its eighth edition. This review focuses on the new staging system of bone and soft tissue sarcomas and outlines the revision points and caveats in the latest edition. The major changes in the eighth edition of the AJCC staging for bone and soft tissue sarcomas are the following four points. (i) Tumors are described separately according to the primary sites. For bone sarcoma, three tumor locations are described: (a) appendicular skeleton, trunk, skull and facial bones; (b) spine and (c) pelvis. Meanwhile, four tumor locations are described for soft tissue sarcoma: (1) trunk and extremity; (2) retroperitoneum; (3) head and neck and (4) visceral sites. (ii) Histologic grading system in bone sarcoma is changed to three-grade classifications. (iii) For soft tissue sarcoma, AnyTN1M0 tumor in the trunk and extremity is classified as stage IV, whereas for the retroperitoneal tumor, anyTN1M0 remains as stage IIIB. (iv) For soft tissue sarcomas in the trunk, extremity and retroperitoneum, tumor size was classified into four categories: (a) <=5 cm; (b) >5 cm and <=10 cm; (c) >10 cm and <=15 cm and (d) >15 cm. In addition, the notation about the depth of the tumor (superficial or deep from the superficial fascia) has been eliminated. PMID- 30423154 TI - Hemoglobin San Diego: An Uncommon Cause of Hereditary Erythrocytosis Discovered Incidentally in a Military Trainee. AB - High-affinity hemoglobinopathies are a rare clinical entity that commonly presents as an isolated erythrocytosis in asymptomatic individuals. We report such a case involving an 18-year-old active duty military trainee who presented to the hematology clinic after an isolated erythrocytosis was incidentally discovered during a flight physical. The patient was asymptomatic but did report a family history of erythrocytosis in his mother and maternal grandmother which intermittently required venesection. Initial history and physical exam were unremarkable. P50 RBC Oxygen Dissociation showed a left-shifted oxygen dissociation curve, although hemoglobin electrophoresis did not reveal an abnormal hemoglobin variant. A beta-globin variant was identified via mass spectrometry and sequencing that was consistent with the rare high-oxygen affinity hemoglobin variant designated hemoglobin San Diego. This patient was medically cleared to return to training without limitations and counseled regarding the potential significance of being a carrier of this rare hemoglobin variant. This case represents the first observation of hemoglobin San Diego in the U.S. military population. PMID- 30423155 TI - Preoperative Resectability Estimates of Nonenhancing Glioma by Neurosurgeons and a Resection Probability Map. AB - BACKGROUND: Preoperative interpretation of resectability of diffuse nonenhancing glioma is primarily based on individual surgical expertise. OBJECTIVE: To compare the accuracy and precision between observed resections and preoperative estimates of neurosurgeons and a resection probability map (RPM). We hypothesize that the RPM estimates is as good as senior neurosurgeons. METHODS: A total of 234 consecutive patients were included from 2 centers, who had resective surgery with functional mapping between 2006 and 2012 for a supra-tentorial nonenhancing glioma. Extent of resection (EOR) and residual tumor volume (RTV) were segmented and an RPM was constructed in standard brain space. Three junior and three senior neurosurgeons estimated EOR and RTV, blinded for postoperative results. We determined the agreement between the estimates and calculated the diagnostic accuracy of the neurosurgeons and the RPM to predict the observed resections. RESULTS: Preoperative estimates of resection results by junior and senior neurosurgeons were significantly biased towards overestimation of EOR (4.2% and 11.2%) and underestimation of RTV (4.3 and 9.0 mL), whereas estimates of the RPM were unbiased (-2.6% and -.2 mL, respectively). The limits of agreement were wide for neurosurgeons and for the RPM. The RPM was significantly more accurate in identifying patients in whom an EOR >40% was observed than neurosurgeons. CONCLUSION: Neurosurgeons estimate preoperative resectability before surgery of a nonenhancing glioma rather accurate-with a small bias-and imprecise-with wide limits of agreement. An RPM provides unbiased resectability estimates, which can be useful for surgical decision-making, planning, and education. PMID- 30423156 TI - Proteinase-activated Receptor 1 Antagonism Ameliorates Experimental Pulmonary Hypertension. AB - Aims: Pulmonary hypertension is characterized by progressive increases in pulmonary vascular resistance. Thrombotic lesions are common pathological findings. The pulmonary artery has a unique property regarding the vasoconstrictive response to thrombin, which is mediated by proteinase-activated receptor 1 (PAR1). We aim to elucidate the role of PAR1 in the development and progression of pulmonary hypertension. Methods and Results: A rat model of monocrotaline-induced pulmonary hypertension and a mouse model of hypoxia-induced pulmonary hypertension were used to investigate the effects of atopaxar (a PAR1 antagonist) and PAR1 knockout on hemodynamic parameters, right ventricular hypertrophy, vascular remodeling and survival. In perfused lung preparations, the pressor response to PAR1 agonist was significantly augmented in monocrotaline induced pulmonary hypertension. Both the preventive and therapeutic administration of atopaxar significantly inhibited the increase in pulmonary vascular resistance and the development of right ventricular hypertrophy and prolonged survival. A real-time PCR revealed that the level of PAR1 mRNA in the pulmonary artery was significantly higher than that in any of the systemic arteries examined in control rats, and the level was significantly upregulated in monocrotaline-induced pulmonary hypertension. PAR1 gene knockout significantly attenuated the hemodynamic and histological findings in the mouse model of hypoxia-induced pulmonary hypertension. Conclusions: The specific expression of PAR1 in the pulmonary artery and its upregulation were suggested to play a critical role in the development and progression of experimental pulmonary hypertension in murine models. PAR1 is a potential therapeutic target for the treatment of pulmonary hypertension. PMID- 30423157 TI - Hell's itch due to sunburn. PMID- 30423158 TI - Diagnostic accuracy and treatment approach to depression in primary care: predictive factors. AB - Objective: The study assessed the predictive factors of diagnostic accuracy and treatment approach (antidepressants versus active monitoring) for depression in primary care. Methods: This is a cross-sectional study that uses information from a naturalistic prospective controlled trial performed in Barcelona (Spain) enrolling newly diagnosed patients with mild to moderate depression by GPs. Treatment approach was based on clinical judgement. Diagnosis was later assessed according to DSM-IV criteria using Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) interview by an external researcher. Patients (sociodemographic, psychiatric diagnosis, severity of depression and anxiety, health-related quality of life, disability, beliefs about medication and illness and comorbidities) and GP factors associated with diagnostic accuracy and treatment approach were assessed using multilevel logistic regression. Variables with missing data were imputed through multiple imputations. Results: Two hundred sixty-three patients were recruited by 53 GPs. Mean age was 51 years (SD = 15). Thirty percent met DSM-IV criteria for major depression. Mean depression symptomatology was moderate-severe. Using multivariate analyses, patients' beliefs about medicines were the only variable associated with the antidepressant approach. Specialization in general medicine and being a resident tutor were associated with a more accurate diagnosis. Conclusions: Clinical depression diagnosis by GPs was not always associated with a formal diagnosis through a SCID I. GPs' training background was central to an adequate depression diagnosis. Patients' beliefs in medication were the only factor associated with treatment approach. More resources should be allocated to improving the diagnosis of depression. PMID- 30423159 TI - A Comparison of Mentorship Attitudes and Attributes Between Civilian and Army Healthcare Leaders. AB - Introduction: The purpose of this study is to compare the differences in mentorship expectations and attitudes between Army and civilian healthcare leaders, and to review cultural differences between the Army and civilian sectors. Materials and Methods: This study used survey data from Army Medical Service Corps officers and members of a regional chapter of the American College of Healthcare Executives (ACHE) to compare attributes of, and attitudes toward, mentorship. A principal component analysis was used to develop three broad mentorship factors, and a comparison of individual attributes was conducted between populations. Institutional approval (IRB) was granted by the University of New Hampshire (IRB #: 6676). Results: The principal component analysis showed similar underlying factors for both populations. An attribute level comparison demonstrated important differences in attitudes toward mentors and mentoring between the Army and civilian participants. Conclusion: The differences between the Army and civilian samples appear to arise from differences in their respective cultures. The utilization by the Army of formal training programs such as the Army's Basic Officer Leadership Course (BOLC), fill a need provided by mentors in civilian organizations. The common experience of professional training like BOLC is part of what creates and sustains the "thick" culture of the Army. Former Army members making the transition to a civilian career should bear in mind that they are leaving behind a thick culture, and that individual relationships may have greater impact on their future careers than they had experienced in the Army. PMID- 30423160 TI - Acute Kidney Injury in Patients Receiving Systemic Treatment for Cancer: A Population-Based Cohort Study. AB - Background: Patients undergoing treatment for cancer are at increased risk of acute kidney injury (AKI). There are few data on AKI incidence and risk factors in the current era of cancer treatment. Methods: We conducted a population-based study of all patients initiating systemic therapy (chemotherapy or targeted agents) for a new cancer diagnosis in Ontario, Canada (2007-2014). The primary outcome was hospitalization with AKI or acute dialysis. We estimated the cumulative incidence of AKI and fitted Fine and Gray models, adjusting for demographics, cancer characteristics, comorbidities, and coprescriptions. We modeled exposure to systemic therapy (the 90-day period following treatments) as a time-varying covariate. We also assessed temporal trends in annual AKI incidence. Results: We identified 163 071 patients initiating systemic therapy of whom 10 880 experienced AKI. The rate of AKI was 27 per 1000 person-years, with overall cumulative incidence of 9.3% (95% CI = 9.1% to 9.6%). Malignancies with the highest 5-year AKI incidence were myeloma (26.0%, 95% CI = 24.4% to 27.7%), bladder (19.0%, 95% CI = 17.6% to 20.5%), and leukemia (15.4%, 95% CI = 14.3% to 16.5%). Advanced cancer stage, chronic kidney disease, and diabetes were associated with increased risk of AKI (adjusted hazard ratios [aHR] = 1.41, 95% CI = 1.28 to 1.54; 1.80, 95% CI = 1.67 to 1.93; and 1.43, 95% CI = 1.37 to 1.50, respectively). In patients aged 66 years or older with universal drug benefits, diuretic, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker coprescription was associated with higher AKI risk (aHR = 1.20, 95% CI = 1.14 to 1.28; 1.30, 95% CI = 1.23 to 1.38). AKI risk was further accentuated during the 90-day period following systemic therapy (aHR = 2.34, 95% CI = 2.24 to 2.45). The annual incidence of AKI increased from 18 to 52 per 1000 person-years between 2007 and 2014. Conclusion: Cancer-related AKI is common and associated with advanced stage, chronic kidney disease, diabetes, and concomitant receipt of diuretics or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. Risk is heightened in the 90 days after systemic therapy. Preventive strategies are needed to address the increasing burden of AKI in this population. PMID- 30423162 TI - A framework for systematic evaluation and quantitative integration of mechanistic data in assessments of potential human carcinogens. AB - Recently, the key characteristics of carcinogens (KCC) have been proposed as an organizational approach for the evaluation of mechanistic data related to carcinogenicity. Our objective was to develop a framework to systematically and quantitatively integrate KCC data using elements that are important to risk assessment. Methods for developing the framework included: defining objectives, identifying and accommodating key considerations for components, input, and output of the framework, and operational development via iterative testing by a multidisciplinary team. The proposed framework involves three steps: (1) a structured, yet flexible, appraisal of individual studies and endpoints, (2) a structured and transparent evaluation of the body of evidence for each key characteristic, and (3) an evaluation of all of the KCC-relevant data relative to tumors and/or cancer types. In step 1, data are assessed and scored for reliability, strength, and activity. In step 2, a mathematical algorithm is used to integrate (and weight) the quality, relevance, and activity for each of the KCCs. These scores facilitate subsequent evaluations related to the overall body of evidence in Step 3 in which KCCs can be linked, assessing potential adverse outcome pathways or networks, and finally, considered in the context of observed carcinogenic responses in animals and/or humans. The output is an overall conclusion regarding KCC activity as it relates to carcinogenic responses. The proposed framework provides a flexible solution to quantitively integrate KCC data in a systematic and transparent manner that provides weighting of data most well-suited for the assessment of potential human carcinogenicity. PMID- 30423161 TI - BIODOSIMETRY AND BIODOSIMETRY NETWORKS FOR MANAGING RADIATION EMERGENCY. AB - Biological dosimetry enables individual dose reconstruction in the case of unclear or inconsistent radiation exposure situations, especially when a direct measurement of ionizing radiation is not or is no longer possible. To be prepared for large-scale radiological incidents, networking between well-trained laboratories has been identified as a useful approach for provision of the fast and trustworthy dose assessments needed in such circumstances. To this end, various biodosimetry laboratories worldwide have joined forces and set up regional and/or nationwide networks either on a formal or informal basis. Many of these laboratories are also a part of global networks such as those organized by World Health Organization, International Atomic Energy Agency or Global Health Security Initiative. In the present report, biodosimetry networks from different parts of the world are presented, and the partners, activities and cooperation actions are detailed. Moreover, guidance for situational application of tools used for individual dosimetry is given. PMID- 30423163 TI - Acute Psychosis and Wilson's Disease. AB - Wilson's Disease is an inborn error of metabolism associated with accumulation of copper in the body manifesting as hepatic, neurological and behavioural symptoms. Almost 20% patients initially present with behavioural symptoms such as depression, personality changes or even mania. Schizophrenia and catatonia are less common. We describe the case of a 35 year old female with behavioural abnormalities diagnosed as a case of Schizophrenia and started on antipsychotics, which led to further worsening of her primary complaints. Physical examination was significant for ascites, splenomegaly and a right sided cataract. Hematological evaluation revealed pancytopenia. With a suspicion of underlying chronic liver disease associated with metabolic encephalopathy, she was evaluated for Wilson's disease, which was confirmed by biochemical and radiological evidence. Chelation therapy was initiated which led to complete reversal of her behavioural changes. PMID- 30423164 TI - Concentrations of Serum Free Light Chains in Kappa and Lambda Lesions in Light Chain Myelomas. AB - Background: Concentration of serum free light chains has been promoted as an assay in the evaluation of monoclonal gammopathic manifestations. A high false positive rate in patients without monoclonal gammopathic manifestations and a high false-negative rate in patients with those manifestations have been reported. The false-negative rate for lambda chain-associated lesions is higher than that for kappa chain-associated lesions. Objective: To assess the serum free light chains in light-chain myelomas. Methods: Concentrations of involved and uninvolved serum free light chains were retrospectively reviewed in patients with light-chain myelomas. Results: The highest recorded levels of involved light chains in kappa-chain myelomas and lambda-chain myelomas were comparable. The levels of uninvolved light chains were higher, although not statistically significantly, in lambda-chain lesions. Conclusions: The results of serum free light chains in light-chain myelomas support the clinical usefulness of the assay in monitoring patients with light chain myeloma. PMID- 30423165 TI - Outcomes associated with non-recommended dosing of rivaroxaban: results from the XANTUS study. AB - Aims: In Europe, the approved rivaroxaban dose for stroke prevention in patients with atrial fibrillation is 20 mg once daily (od), with 15 mg od recommended in patients with creatinine clearance [CrCl] 15-49 mL/min. Non-recommended doses are prescribed in real-world practice. This analysis of the XANTUS study assessed outcomes associated with non-recommended dosing and patient characteristics that may have impacted dose choice. Methods and results: Baseline characteristics and 1-year outcomes were compared in 4464/6784 patients with known CrCl, receiving recommended or non-recommended rivaroxaban doses; 3608 (80.8%) patients received recommended doses (mean CHADS2 score 1.9) and 856 (19.2%) non-recommended doses (mean CHADS2 score 2.5). Incidence rate (events/100 patient-years) for the composite of treatment-emergent adjudicated major bleeding, stroke/systemic embolism and death was 7.5 (95% confidence interval [CI] 5.7-9.8) and 4.8 (95% CI 4.1-5.7) with non-recommended and recommended doses, respectively (hazard ratio 1.55; 95% CI 1.2-2.1; P = 0.004). Incidence rates for the components of the composite were 3.7 and 2.6, 1.4 and 0.9, and 3.5 and 1.9, respectively. Adjustment for baseline characteristics showed similar rates of the composite outcome (hazard ratio 1.06; 95% CI 0.77-1.45; P = 0.719). Multivariable analysis identified age, anaemia, congestive heart failure, diabetes mellitus, CrCl, lower body weight, atrial fibrillation type, and vascular disease as predictors of non recommended dosing. Conclusion: Non-recommended rivaroxaban dosing was associated with less favourable outcomes, possibly due to baseline characteristics, in addition to renal function, that may also affect physicians' dosing decisions. Trial registration number: Clinicaltrials.gov: NCT01606995. PMID- 30423166 TI - The Rising Physicians Program: A Novel Approach for Mentoring Medical Students. AB - Introduction: The transition to medical school is a particularly challenging time for new students as they are faced with significant academic responsibilities. Moreover, for many students at the Uniformed Services University they are adjusting to being on active duty in the military. Mentoring has been considered a way to help with the transition and professional development. Prior to 2015, there was no formal mentoring program for new students at the Uniformed Services University. Materials and Methods: In order to address the demands and challenges facing matriculating medical students, the Rising Physicians Program was created. This student initiated program enabled pre-clerkship medical students to connect with residents at the Walter Reed National Military Medical Center via a secure database with resident profiles. Residents were recruited and voluntarily agreed to serve as mentors. Students were then able to access the database and reach out to mentors based on their specific goals. The program was introduced to students during orientation and student participation was completely voluntary. A survey was designed using best survey practices and sent to the 175 students participating in the program for the 2015 academic (class of 2019) year to determine participation and characteristics of the program. Results: Sixty-four percent (112/175) of the students from the class of 2019 participated in the post implementation survey. Fifteen percent of the class (26/175) reported participating in the voluntary mentoring program. The three most commonly used communication methods with mentors in precedence were in-person, e-mail, and text messages. The majority of the students found their interactions in this program were beneficial and did not get in the way of their academic performance. The most common topics of discussion were academics (20%), mentor's past experience (22%), military lifestyle (7%), medical school pathways (23%), and specialty selections (23%). Limitations of the program included a lack of U.S. Air Force mentors and mentors within certain residency specialties. Conclusions: The Rising Physician Program provides a near-peer mentoring model for new medical students. Students preferred to communicate with their mentors in person, but the flexibility of communication appears to be important. New students have a variety of academic and professional development concerns that could partially be addressed through mentoring by residents. PMID- 30423167 TI - Kinlessness Around the World. AB - Objectives: The first and second demographic transitions have led to profound changes in family networks. However, the timing and extent of these transitions vary widely across contexts. We examine how common it is for contemporary older adults to lack living kin and whether such individuals are uniformly disadvantaged around the world. Method: Using surveys from 34 countries that together contain 69.6% of the world's population over age 50 and come from all regions of the world, we describe the prevalence and correlates of lacking immediate kin. We examine macro-level demographic indicators associated with the prevalence of kinlessness as well as micro-level associations between kinlessness and sociodemographic and health indicators. Results: There is great variation in levels of kinlessness, from over ten percent with neither a spouse nor a biological child in Canada, Ireland, the Netherlands and Switzerland to levels below two percent in China and the Republic of Korea. There are strong macro level relationships between kinlessness and lagged or contemporaneous fertility, mortality, and nuptiality measures and more marginal relationships with other demographic forces. Micro-level associations between kinlessness and respondent attributes are varied. The kinless are more likely to live alone than those with kin in all countries. In most countries they have equivalent or worse self-rated health and lower education, although there are notable exceptions. There is substantial variation in the gender composition of the kinless population. Discussion: As demographic changes affecting kinlessness continue, we expect the scale of the kinless population to grow around the world. PMID- 30423168 TI - Lztfl1/BBS17 controls energy homeostasis by regulating the leptin signaling in the hypothalamic neurons. AB - Leptin receptor (LepRb) signaling pathway in the hypothalamus of the forebrain controls food intake and energy expenditure in response to an altered energy state. Defects in the LepRb signaling pathway can result in leptin-resistance and obesity. Leucine zipper transcription factor like 1 (Lztfl1)/BBS17 is a member of the Bardet-Biedl syndrome (BBS) gene family. Human BBS patients have a wide range of pathologies including obesity. The cellular and molecular mechanisms underlying Lztfl1-regulated obesity are unknown. Here, we generated Lztfl1f/f mouse model in which Lztfl1 can be deleted globally and in tissue-specific manner. Global Lztfl1 deficiency resulted in pleiotropic phenotypes including obesity. Lztfl1-/- mice are hyperphagic and showed similar energy expenditure as WT littermates. The obese phenotype of Lztfl1-/- mice is caused by the loss of Lztfl1 in the brain but not in the adipocytes. Lztfl1-/- mice are leptin resistant. Inactivation of Lztfl1 abolished phosphorylation of Stat3 in the LepRb signaling pathway in the hypothalamus upon leptin stimulation. Deletion of Lztfl1 had no effect on LepRb membrane localization. Furthermore, we observed that Lztfl1-/- mouse embryonic fibroblasts (MEFs) have significantly longer cilia than WT MEFs. We identified several proteins that potentially interact with Lztfl1. As these proteins are known to be involved in regulation of actin/cytoskeleton dynamics, we suggest that Lztfl1 may regulate leptin signaling and ciliary structure via these proteins. Our study identified Lztfl1 as a novel player in the LepRb signaling pathway in the hypothalamus that controls energy homeostasis. PMID- 30423169 TI - New insights into neurobiology. PMID- 30423170 TI - DNA methylation of Tumour Suppressor Genes in Pituitary Neuroendocrine Tumours. AB - Context: Epigenetic alterations may play a role in the development and behaviour of Pituitary Neuroendocrine Tumours (PitNETs). Objective: To evaluate the effect of methylation of Tumour Suppressor Genes (TSGs) in their gene expression and in the behaviour of PitNETs. Material and Methods: We use MS-MLPA and q-RT-PCR techniques to analyse the DNA-promoter hypermethylation and the gene expression of 35 TSGs in 105 PitNETs. We define functionality, size and invasiveness of tumours according to their clinical manifestations, Hardy's classification and MRI invasion of the cavernous sinus, respectively. Results: We observed different methylation patterns among PitNET subtypes. CASP8 was the most hypermethylated gene in all PitNET subtypes. The methylation status of TP73 correlated negatively with their gene expression in the overall series (p=0.013) and in some subtypes. MSH6 and CADM1 showed higher methylation frequency in macro than in microadenomas in the overall series and in corticotroph PitNETs (all p<=0.053). ESR1 and RASSF1 were higher methylated in non-invasive than in invasive tumours in the overall series (p=0.054 and p=0.031, respectively) and in the gonadotroph subtype (sGT) (p=0.055 and p=0.050, respectively). ESR1 and CASP8 appeared more hypermethylated in functioning than in sCT (p=0.034 and p=0.034, respectively). Conclusions: DNA methylation of TSGs has a selective effect on their gene expression and on the growth and invasiveness of PitNETs. Its involvement in their functionality is biased because all silent operated tumours are macroadenomas while all operated microadenomas are functioning ones. Therefore, the subtypes of PitNETs should be considered as different entities. PMID- 30423171 TI - Bed Bug (Hemiptera: Cimicidae) Attraction to Human Odors: Validation of a Two Choice Olfactometer. AB - Bed bugs (Cimex lectularius L.) (Hemiptera: Cimicidae) are obligate hematophagous ectoparasites, and, therefore, must locate suitable hosts to ensure survival and reproduction. Their largely nocturnal activity suggests that chemosensory and thermosensory cues would play critical roles in host location. Yet, the importance of olfaction in host attraction of bed bugs remains unclear. We developed and validated a Y-tube, two-choice olfactometer and tested its suitability for investigating attraction to human odors (from skin swabs). Olfactometer orientation significantly affected the percentage of bed bugs that were activated by human odors, with significantly more bed bugs responding when the olfactometer was oriented vertically (bug introduced at bottom of the olfactometer) compared with all other orientations. Starved (7-10 d) adult males, mated females, and nymphs responded (47-77% moved up the olfactometer and made a choice) when human odors were present in the olfactometer, while starved, unmated females did not respond. Skin swabs from all five human participants elicited high response rates (65-82%), and bed bugs from four different populations responded to skin swabs (40-82% response rate). However, in all assays including those resulting in relatively low response rates, bed bugs exhibited >90% preference for human odors over blank controls. These results provide strong evidence that bed bugs can respond and orient towards human odors, independently of all other host cues. Furthermore, the validated olfactometer should enable rapid and efficient evaluations of bed bug behavioral responses to semiochemicals. PMID- 30423172 TI - Introduction of novel agents in the treatment of Primary CNS Lymphoma. AB - Novel insights into the pathophysiology of Primary Central Nervous System Lymphoma (PCNSL) have identified the B-cell receptor and Toll-like receptor pathway as well as immune evasion and suppressed tumor immune microenvironment as a key mechanism in the pathogenesis of PCNSL. Small molecules and novel agents targeting these aberrant pathways have been introduced into clinical trials targeting the recurrent or refractory PCNSL patient population. Agents like the Bruton Tyrosine Kinase (BTK) inhibitor ibrutinib or immunomodulatory drugs (IMiDs) like pomalidomide and lenalidomide have shown promising high response rates in the salvage setting. Here, we give an overview about the recent, exciting developments in PCNSL and summarize the results of clinical trials using novel agents in the recurrent and refractory salvage setting, which includes immune checkpoint inhibitors, IMiDs, as well as BTK, PI3K, and mTOR inhibitors. PMID- 30423173 TI - Predictors of Postdeployment Prescription Opioid Receipt and Long-term Prescription Opioid Utilization Among Army Active Duty Soldiers: Corrigendum. PMID- 30423174 TI - Giant cell arteritis: new concepts, treatments and the unmet need that remains. PMID- 30423175 TI - Clinical manifestations and molecular aspects of phosphoribosylpyrophosphate synthetase superactivity in females. AB - Objectives: Phosphoribosylpyrophosphate synthetase (PRPS1) superactivity is an X linked disorder characterized by urate overproduction Online Mendelian Inheritance in Man (OMIM) gene reference 300661. This condition is thought to rarely affect women, and when it does, the clinical presentation is mild. We describe a 16-year-old African American female who developed progressive tophi, nephrolithiasis and acute kidney failure due to urate overproduction. Family history included a mother with tophaceous gout who developed end-stage kidney disease due to nephrolithiasis and an affected sister with polyarticular gout. The main aim of this study was to describe the clinical manifestations of PRPS1 superactivity in women. Methods: Whole exome sequencing was performed in affected females and their fathers. Results: Mutational analysis revealed a new c.520 G > A (p.G174R) mutation in the PRPS1 gene. The mutation resulted in decreased PRPS1 inhibition by ADP. Conclusion: Clinical findings in previously reported females with PRPS1 superactivity showed a high clinical penetrance of this disorder with a mean serum urate level of 8.5 (4.1) mg/dl [506 (247) MUmol/l] and a high prevalence of gout. These findings indicate that all women in families with PRPS1 superactivity should be genetically screened for a mutation (for clinical management and genetic counselling). In addition, women with tophaceous gout, gout presenting in childhood, or a strong family history of severe gout should be considered for PRPS1 mutational analysis. PMID- 30423176 TI - Genetic Variation of the Long-Legged Flies Phacaspis mitis Complex (Diptera: Dolichopodidae) in Peninsular Thailand Inferred From Three Mitochondrial Genes. AB - Phacaspis (Meuffels and Grootaert 1988) is a true marine dolichopodid fly genus. They are common on the mud flats in the front of mangroves where they deal with extreme conditions. The genus is represented in southern Thailand by Phacaspis mitis (Grootaert and Meuffels 2001) (Diptera: Dolichopodidae). Previous studies have focused on both taxonomy and classification of this genus, but there are a few studies focusing on this species in terms of molecular genetics. The objective of the present study was to investigate genetic variation and phylogenetic relationships of P. mitis using ribosomal DNA subunit 12S, ribosomal DNA subunit 16S, and cytochrome oxidase subunit I of mitochondrial genes. The specimens were collected in six coastal provinces from the Andaman Sea and the Gulf of Thailand. The phylogenetic relationship of combined mitochondrial genes revealed that P. mitis in peninsular Thailand is a monophyletic group that can be divided into two distinct clades. According to the haplotype network, 16 haplotype patterns were observed in P. mitis, but P. mitis was separated into two major haplotype networks. In addition, a positive correlation between genetic distance (FST) and geographical distance (km) was found among the populations of peninsular Thailand. The level of genetic differentiation between populations is influenced by geographic isolation. Moreover, P. mitis arose in late Eocene (35.5 Mya) and it diversified during the Plio-Pleistocene (3.14 Mya). Although, P. mitis is divided into two populations in this study, it is a well-supported monophyletic group. PMID- 30423177 TI - Habitual light exposure relative to circadian timing in delayed sleep-wake phase disorder. AB - Study Objectives: To compare melatonin timing, a well-validated marker for endogenous circadian phase, and habitual light-exposure patterns in adults with delayed sleep-wake phase disorder (DSWPD) and intermediate chronotype controls. Methods: Twelve individuals with DSWPD (five females, mean age: 31.1) and 12 age matched controls (six females, mean age: 33.6) underwent a minimum of 7 days of light and activity monitoring followed by an inpatient hospital stay, where blood was taken to assess melatonin timing (calculated as dim light melatonin onset DLMO). Habitual light-exposure patterns were then compared with a human phase response curve (PRC) to light. Results: Relative to clock time, individuals with DSWPD had a later light-exposure pattern compared with controls, but their light exposure pattern was earlier relative to DLMO. According to the human PRC to light, individuals with DSWPD had less daily advancing light exposure compared with controls. The primary difference was seen in the late portion of the advancing window, in which individuals with DSWPD were exposed to fewer pulses of light of equivalent duration and intensity compared with controls. Conclusions: Diminished advancing light exposure may play a role in the development and perpetuation of delayed sleep-wake timing in individuals with DSWPD. Enhancing light exposure during the later portion of the advancing window represents an innovative and complementary strategy that has the potential to improve the effectiveness of bright light therapy in DSWPD. PMID- 30423178 TI - A cluster randomized controlled trial of a theory-based sleep hygiene intervention for adolescents. AB - Study Objectives: To use theory to design and evaluate an intervention to promote sleep hygiene and health among adolescents. Methods: The Theory of Planned Behavior (TPB) and the Health Action Process Approach (HAPA) were used to develop an intervention, which was then evaluated in a cluster randomized trial. Participants were high school students (N = 2,841, M age = 15.12, SD = 1.50). Adolescents in the intervention group received four face-to-face sessions providing behavior change techniques targeting the theoretical determinants of sleep hygiene. Adolescents in the control group only received educational material at the end of the study. The primary outcome was sleep hygiene measured at 1 and 6 months postintervention. A number of secondary outcomes were also measured, including beliefs about sleep, self-regulatory processes, and outcomes related to health and wellbeing. Results: Sleep hygiene was improved in the intervention group when compared with the control group at both follow-up points (coefficients = 0.16 and 0.19, 95% CIs = 0.12-0.20 and 0.15-0.23 at 1 and 6 months, respectively, for scores on the Adolescent Sleep Hygiene Scale), as were psychosocial and general aspects of health. Mediation analyses suggested that beliefs about sleep hygiene as specified by the TPB, along with self-regulatory processes from HAPA, both mediated the effect of the intervention on outcomes. In turn, the effects of the intervention on sleep hygiene mediated its impact on general health. Conclusions: Healthcare practitioners might consider intervention programs based on the TPB and the HAPA to improve sleep among adolescents. Clinical Trial Registration: Clinicaltrials.gov (NCT02551913) https://clinicaltrials.gov/ct2/show/NCT02551913. PMID- 30423179 TI - Functional determinants of enhanced and depressed interareal information flow in nonrapid eye movement sleep between neuronal ensembles in rat cortex and hippocampus. AB - Compared with wakefulness, neuronal activity during nonrapid eye movement (NREM) sleep is characterized by a decreased ability to integrate information, but also by the reemergence of task-related information patterns. To investigate the mechanisms underlying these seemingly opposing phenomena, we measured directed information flow by computing transfer entropy between neuronal spiking activity in three cortical regions and the hippocampus of rats across brain states. State dependent information flow was jointly determined by the anatomical distance between neurons and by their functional specialization. We distinguished two regimes, operating at short and long time scales, respectively. From wakefulness to NREM sleep, transfer entropy at short time scales increased for interareal connections between neurons showing behavioral task correlates. Conversely, transfer entropy at long time scales became stronger between nontask modulated neurons and weaker between task-modulated neurons. These results may explain how, during NREM sleep, a global interareal disconnection is compatible with highly specific task-related information transfer. PMID- 30423180 TI - Power versus phenotyping precision of genome-wide association studies on sleep traits. PMID- 30423181 TI - Manifestations of Pain Sensitization Across Different Painful Knee Disorders: A Systematic Review Including Meta-analysis and Metaregression. AB - Objectives: Previous reviews have reported that manifestations of pain sensitization may play an important role in the pain experienced by people with knee osteoarthritis. However, it is unknown if manifestations of pain sensitization are common features across other painful knee disorders or if sensitization requires targeted intervention. This review aims to synthesize the published research investigating manifestations of pain sensitization in painful knee disorders and to evaluate if the manifestations of pain sensitization change in response to treatment. Methods: The systematic review protocol was registered with PROSPERO (CRD42015024211). We searched Medline, Embase, CINAHL, Web of Science, Sportsdiscus, and Cochrane Central for studies that investigated between group differences (knee pain vs pain-free subjects) or the effect of treatment on manifestations of pain sensitization. Two reviewers independently assessed studies for inclusion and quality. Available data were synthesized via predetermined levels of evidence, meta-analysis, and metaregression where possible. Results: Fifty-two studies investigating evidence related to pain sensitization distributed across four different painful knee disorders were identified. Conclusions: Our meta-analysis provides evidence of pain sensitization in people with knee osteoarthritis (strong evidence), people with patellofemoral pain (moderate evidence), and postmeniscectomy patients (very limited evidence). However, conflicting evidence exists in patellar tendinopathy. Metaregression indicates that pain is associated with pressure pain thresholds in knee osteoarthritis. In people with knee osteoarthritis and patellofemoral pain, several interventions were found to reduce manifestations of pain sensitization. This review highlights that pain sensitization may be amenable to treatment through exercise therapy, mobilization, and pharmacological and surgical intervention. PMID- 30423182 TI - Thinking Fast Is Clinically Important, but Thinking Slow Is Just as Important. PMID- 30423183 TI - The Truth About Obesity, Exercise, and Nutrition. AB - There is a plethora of misinformation regarding obesity, diet, and exercise due to lack of supporting evidence on these topics. There are myths and facts about what exactly encompasses a healthy lifestyle that interfere with the ability to lose weight and stay healthy. These include topics such as the effects of small sustained increases in energy intake or expenditure, establishment of realistic goals, rapid weight loss, readiness for weight loss, physical activity, breast feeding as well as the effects of eating breakfast daily, early childhood experiences, eating fruits and vegetables, weight that cycles up and down, snacking, and the environment. There are evidence-based approaches that can help guide people in their pursuit of a healthy lifestyle, weight loss, and physical activity. Pediatricians and health care providers should be aware of these approaches when counseling patients on a healthy lifestyle. [Pediatr Ann. 2018;47(11):e427-e430.]. PMID- 30423184 TI - Pediatric Hepatology: An Update. PMID- 30423185 TI - Neonatal Cholestasis: A Primer of Selected Etiologies. AB - Cholestasis refers to impairment in formation or excretion of bile. This can be due to defects in intrahepatic production of bile, defects in the transmembrane transport of bile, or mechanical obstruction to bile flow. Clinical features of cholestasis reflect the retention of components of bile (bilirubin, bile acids, cholesterol) in the body. In the neonatal period, hyperbilirubinemia can be categorized as either unconjugated (and often benign) hyperbilirubinemia, or conjugated hyperbilirubinemia due to cholestasis. It is for this reason that the first laboratory evaluation in a patient with jaundice, dark urine, and/or acholic stool is a fractionated bilirubin. This article serves as a practical primer for pediatric and neonatology trainees and covers common causes of neonatal cholestasis, as well as the diagnostic work-up and treatment. Causes that are discussed include biliary atresia, idiopathic neonatal hepatitis, gestational alloimmune liver disease, metabolic and genetic diseases, total parenteral nutrition cholestasis, and congenital infection. [Pediatr Ann. 2018;47(11):e433-e439.]. PMID- 30423186 TI - Wilson's Disease: A Review for the General Pediatrician. AB - Wilson's disease, also known as hepatolenticular degeneration, is an autosomal recessive genetic disorder due to a mutation of the ATP7B gene resulting in impaired hepatic copper excretion and copper accumulation in various tissues. It is associated with the classic triad of cirrhosis, neurological manifestations, and the ocular finding of Kayser-Fleischer rings; however, the clinical presentation can vary greatly from incidental findings of abnormal liver enzymes to acute liver failure necessitating liver transplant. Pediatric patients may present with subtle findings including asymptomatic hepatomegaly, transaminitis, changes in behavior, movement disorders, or school failure. The general pediatrician may be the first to recognize these symptoms and should consider Wilson's disease in their differential diagnosis. Wilson's disease can be managed with lifelong chelation or zinc therapy in patients who present early in the disease; therefore, pediatricians should have a low threshold for referral to a pediatric hepatologist for further evaluation when it is suspected. [Pediatr Ann. 2018;47(11):e440-e444.]. PMID- 30423187 TI - Nutrition in Pediatric Chronic Liver Disease. AB - More than one-half of children with chronic liver disease suffer from malnutrition, which leads not only to a poor quality of life and even possibly catastrophic complications, but also to poor outcomes after a liver transplantation. These children have increased metabolic demands but often decreased intake with malabsorption and altered nutrient utilization, all of which make it difficult to keep up with nutritional demands. Assessment of a patient's nutritional status should be timely, and it should be performed routinely and proactively. When specific nutritional needs are identified, these should be addressed with a multidisciplinary team approach and with the close guidance of an experienced pediatric dietician. The assessment includes anthropometric and laboratory assessments, in addition to a careful physical examination and a detailed patient history. The specific nutritional needs vary, but generally dietary intervention focuses on increasing caloric intake, supplementation with medium-chain triglycerides, and prevention of essential fatty acid and fat-soluble vitamin deficiencies. [Pediatr Ann. 2018;47(11):e445 e451.]. PMID- 30423188 TI - Autoimmune Liver Diseases in Children. AB - Autoimmune liver disease remains difficult to diagnose, and distinguishing the various causes is difficult as well. In children, it can present with wide variation, including autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and the "overlap syndrome" of AIH/PSC, also known as autoimmune sclerosing cholangitis. These liver disorders are thought to be immune-mediated, but their etiology remains unclear. They are not secondary to inherited or acquired diseases and they are not associated with any drugs, so they can only be diagnosed if these other diseases or conditions are excluded. Because there is considerable commonality in the clinical presentation of these diseases but differences in their management, appropriate treatment may be delayed, increasing the risk for liver transplantation. Further education for general pediatricians and trainees is needed. This article reviews the differences between AIH and PSC, as well as the newly recognized overlap syndrome of both of these diseases. [Pediatr Ann. 2018;47(11):e452-e457.]. PMID- 30423189 TI - Hepatobiliary Manifestations in Systemic Disease. AB - Liver disease in children occurs via a multitude of primary illnesses such as autoimmune hepatopathy, biliary atresia, and nonalcoholic fatty liver disease. However, jaundice, hepatitis, and alterations in liver tests can often be a manifestation of systemic diseases. The liver is involved in many critical functions such as circulation, immunity, toxin clearance, and metabolism; when the heart, lungs, gastrointestinal tract, immune system, or endocrine systems are compromised, the liver will be affected. This article reviews common causes of liver injury as well as highlights key associations that should not be missed when diagnosing and managing children with liver disease. Becoming familiar with patterns of liver injury and arranging clues in the context of a thorough history and physical examination can help providers navigate the broad differential diagnosis of secondary liver disease. [Pediatr Ann. 2018;47(11):e458-e464.]. PMID- 30423190 TI - Assessing Nutritional Risk Among Infants and Toddlers in Primary Care Practice. AB - Traditionally, nutritional risk has been defined by growth failure, with clinical intervention indicated when a child falls below the third to fifth percentile on growth charts. Although the velocity of linear growth and weight gain during the first years are unparalleled at any other time of life, this period is also unique for other reasons. Nutrition not only supports increased bone length, muscle mass, and tissue growth, but also continued development of several highly metabolic organs such as the gastrointestinal tract, the immune system, the cardiorespiratory system, the kidneys, and the central nervous system. Just as growth depends on consistent nutrients, so too does organ development, especially the brain. The undernourished child may exhibit compromised optimal development and future cognitive performance, irrespective of weight status. It is often challenging in early childhood to ensure that a child is receiving high-quality nutrition. Primary care clinicians are positioned to identify the child with potential nutritional risk and design an appropriate intervention that promotes optimal development. [Pediatr Ann. 2018;47(11):e465-e469.]. PMID- 30423191 TI - Comparative safety and effectiveness of direct oral anticoagulants in patients with atrial fibrillation in clinical practice in Scotland. AB - AIMS: To compare the clinical effectiveness and safety of direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) in routine clinical practice. METHODS: Retrospective cohort study using linked administrative data. The study population (n=14,577) included patients with a diagnosis of AF (confirmed in hospital) who initiated DOAC treatment in Scotland between August 2011 and December 2015. Multivariate Cox proportional hazard models were used to estimate hazard ratios of thromboembolic events, mortality, and bleeding events. RESULTS: No differences between the DOACs were observed in the risks of stroke, systemic embolism, or cardiovascular death. In contrast, the risk of myocardial infarction was higher among apixaban patients in comparison to rivaroxaban (1.67 [1.02 - 2.71]), and all-cause mortality was higher among rivaroxaban patients in contrast to both apixaban (1.22 [1.01 - 1.47]) and dabigatran (1.55 [1.16 - 2.05]); rivaroxaban patients also had a higher risk of pulmonary embolism than apixaban patients (5.27 [1.79 - 15.53]). The risk of other major bleeds was higher among rivaroxaban patients compared to apixaban (1.50 [1.10 - 2.03]) and dabigatran (1.58 [1.01 - 2.48]); the risks of gastro intestinal bleeds and overall bleeding were higher among rivaroxaban patients than among apixaban patients (1.48 [1.01 - 2.16] and 1.52[1.21 - 1.92], respectively). CONCLUSIONS: All DOACs were similarly effective in preventing strokes and systemic embolisms, while patients being treated with rivaroxaban exhibited the highest bleeding risks. Observed differences in the risks of all cause mortality, myocardial infarction, and pulmonary embolism warrant further research. PMID- 30423192 TI - The antitumor effects of entinostat in ovarian cancer require adaptive immunity. AB - BACKGROUND: Ovarian cancer is poorly immunogenic; however, increased major histocompatibility complex class II (MHCII) expression correlates with improved immune response and prolonged survival in patients with ovarian cancer. The authors previously demonstrated that the histone deacetylase inhibitor entinostat increases MHCII expression on ovarian cancer cells. In the current study, they evaluated whether entinostat treatment and resultant MHCII expression would enhance beneficial immune responses and impair tumor growth in mice with ovarian cancer. METHODS: C57BL/6 mice bearing intraperitoneal ID8 tumors were randomized to receive entinostat 20 mg/kg daily versus control. Changes in messenger RNA (mRNA) expression of 46 genes important for antitumor immunity were evaluated using NanoString analysis, and multicolor flow cytometry was used to measure changes in protein expression and tumor-infiltrating immune cells. RESULTS: Entinostat treatment decreased the growth of both subcutaneously and omental ID8 tumors and prolonged survival in immunocompetent C57BL/6 mice. NanoString analysis revealed significant changes in mRNA expression in 21 of 46 genes, including increased expression of the MHCI pathway, the MHCII transactivator (CIITA), interferon gamma, and granzyme B. C57BL/6 mice that received entinostat had increased MHCII expression on omental tumor cells and a higher frequency of tumor-infiltrating, CD8-positive T cells by flow cytometry. In immunocompromised mice, treatment with entinostat had no effect on tumor size and did not increase MHCII expression. CONCLUSIONS: In the current murine ovarian cancer model, entinostat treatment enhances beneficial immune responses. Moreover, these antitumor effects of entinostat are dependent on an intact immune system. Future studies combining entinostat with checkpoint inhibitors or other immunomodulatory agents may achieve more durable antitumor responses in patients with ovarian cancer. PMID- 30423193 TI - Outcomes of very high-risk prostate cancer after radical prostatectomy: Validation study from 3 centers. AB - BACKGROUND: Among men with localized high-risk prostate cancer (PCa), patients who meet very high-risk (VHR) criteria have been shown to experience worse outcomes after radical prostatectomy (RP) in a previous study. Variations of VHR criteria have been suggested to be prognostic in other single-center cohorts, but multicenter outcomes validating VHR criteria have not been described. This study was designed to validate VHR criteria for identifying which PCa patients are at greatest risk for cancer progression. METHODS: Patients with high-risk PCa undergoing RP (2005-2015) at 3 tertiary centers were pooled. The outcomes of men with VHR PCa were compared with the outcomes of those who did not meet VHR criteria. The high-risk criteria were a clinical stage of T3 to T4, a prostate specific antigen level > 20 ng/mL, or a biopsy Gleason grade sum of 8 to 10. The VHR criteria were multiple high-risk features, >4 biopsy cores with a Gleason grade sum of 8 to 10, or primary Gleason grade pattern 5. Biochemical recurrence, metastasis (METS), and cancer-specific mortality (CSM) were assessed with competing risks regressions. Overall mortality was assessed with Cox survival models. RESULTS: Among 1981 patients with high-risk PCa, men with VHR PCa (n = 602) had adverse pathologic outcomes: 37% versus 25% for positive margins and 37% versus 15% for positive lymph nodes (P < .001 for both comparisons). Patients with VHR PCa also had higher adjusted hazard ratios for METS (2.78; 95% confidence interval [CI], 2.08-3.72), CSM (6.77; 95% CI, 2.91-15.7), and overall mortality (2.44; 95% CI, 1.56-3.80; P < .001 for all comparisons). CONCLUSIONS: In a validation study of patients who underwent treatment for high-risk PCa, VHR criteria were strongly associated with adverse pathologic and oncologic outcomes. PMID- 30423194 TI - Update on Medication Use Quality and Safety in Older Adults, 2017. AB - Improving the quality of medication use and medication safety in older adults is an important public health priority and is of paramount importance for clinicians who care for them. We selected four important articles from 2017 that address these issues to annotate and critique, and we discuss the broader implications for optimizing medication use. A longer list of articles is given in an online appendix. The first study provides national data on the prevalence of central nervous system-active medication polypharmacy in older adults and how this has changed over a 9-year period (2004-2013). The second study characterizes prevalence of and factors associated with nonadherence to antiepileptic drugs in 36,912 older adults with epilepsy, with an emphasis on minorities. The third study describes the extent of antibiotic use in residents of 381 long-term care facilities (LTCF) in British Columbia, Canada, from 2007 to 2014. Finally, we discuss a meta-analysis of 42 studies that evaluated the prevalence of hospital admissions caused by adverse drug reactions in older adults. This article is intended to provide a narrative review of important publications on medication use quality and safety for clinicians and researchers committed to optimizing medication use in older adults. PMID- 30423195 TI - Sensing alpha-Synuclein From the Outside via the Prion Protein: Implications for Neurodegeneration. AB - Parkinson's disease and other synucleinopathies are characterized by the accumulation of aggregated alpha-synuclein in intracellular proteinaceous inclusions. The progressive nature of synucleinopathies seems to be related to the cell-to-cell spreading of alpha-synuclein pathology, and several possible mechanisms have been put forward to explain this phenomenon. In our recent study, we found that alpha-synuclein oligomers interact with cellular prion protein in glutamatergic synapses. This interaction triggered a signaling cascade involving phosphorylation of Fyn kinase and activation of the N-methyl-d-aspartate receptor, thereby leading to synaptic dysfunction. Here, we present relevant plasma membrane proteins that have been described to interact with alpha synuclein and discuss the possible pathological implications. We focus primarily on the prion protein and propose a pathological mechanism in which the interaction between alpha-synuclein and prion protein leads to the formation of cofilin/actin rods, culminating in long-term potentiation impairment and cognitive dysfunction. We posit that deciphering the mechanisms involved in sensing specific forms of extracellular alpha-synuclein and transducing this information may prove invaluable in our quest to devise novel diagnostic and therapeutic approaches in PD and other synucleinopathies. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 30423196 TI - Loss of ATRX/DAXX expression and alternative lengthening of telomeres in uterine leiomyomas. AB - BACKGROUND: Uterine leiomyomas (ULs) are the most common gynecologic tumors and affect 3 of every 4 women by the age of 50 years. The majority of ULs are classified as conventional tumors, whereas 10% represent various histopathological subtypes with features that mimic malignancy. These subtypes include cellular and mitotically active ULs and ULs with bizarre nuclei. Uterine leiomyosarcoma (ULMS), the malignant counterpart of UL, is an aggressive cancer with poor overall survival. The early diagnosis and preoperative differentiation of ULMS from UL are often challenging because their symptoms and morphology resemble one another. Recent studies have shown frequent loss of alpha thalassemia/mental retardation syndrome X-linked (ATRX) or death domain associated protein (DAXX) expression in ULMS, and this is often associated with an alternative lengthening of telomeres (ALT) phenotype. METHODS: To investigate ATRX and DAXX expression and the presence of ALT in UL subtypes, immunohistochemical and telomere-specific fluorescence in situ hybridization analyses were performed. The study material consisted of 142 formalin-fixed, paraffin-embedded tissue samples representing various UL subtypes and 64 conventional ULs. RESULTS: A loss of ATRX or DAXX and/or ALT was detected in 6.3% of the histopathological UL subtype samples (9 of 142). Two patients whose ULs showed either ATRX loss or ALT were later diagnosed with a pulmonary smooth muscle tumor. Pulmonary tumors displayed molecular alterations found in the corresponding uterine tumors, which indicated metastasis to the lungs. All conventional ULs displayed normal ATRX, DAXX, and telomeres. CONCLUSIONS: These results highlight the differences between conventional and histopathologically atypical ULs and indicate that some UL subtype tumors may harbor long-term malignant potential. PMID- 30423197 TI - Hospital-Associated Complications of Older People: A Proposed Multicomponent Outcome for Acute Care. AB - OBJECTIVES: To propose a new multicomponent measure of hospital-associated complications of older people (HAC-OP) and evaluate its validity in a large hospital sample. DESIGN: Observational study using baseline (pre-intervention) data from the Collaboration for Hospitalised Elders Reducing the Impact of Stays in Hospital cluster randomized controlled trial. SETTING: Acute medical and surgical wards in 4 hospitals in Queensland, Australia. PARTICIPANTS: Individuals aged 65 and older (mean age 76, 48% female) with a hospital stay of 72 hours or longer (N=434). MEASUREMENTS: We developed a multicomponent measure including 5 well-recognized hospital-associated complications of older people: hospital associated delirium, functional decline, incontinence, falls, and pressure injuries. To evaluate construct validity, we examined associations with common risk factors (aged >=75, functional impairment, cognitive impairment, history of falls). To evaluate predictive validity, we examined the association between length of stay, facility discharge, and 6-month mortality and any HAC-OP and total number of HAC-OP. RESULTS: Overall, 192 (44%) participants had 1 or more HAC-OP during their admission. Any HAC-OP was strongly associated with the proposed shared risk factors, and there was a strong and graded association between HAC-OP and length of stay (9.1+/-7.4 days for any HAC-OP vs 6.8 +/-4.1 days with none, p < .001), facility discharge (59/192 (31%) vs 27/242 (11%), p < .001) and 6-month mortality (26/192 (14%) vs 17/242 (7%), p = .02). CONCLUSION: This study provides evidence of construct and predictive validity of the proposed measure of HAC-OP as a potential outcome measure for research investigating and improving hospital care of older people. PMID- 30423198 TI - Long-Term Trend of Polypharmacy in Older People in Taiwan From 2000 to 2013. PMID- 30423199 TI - Anodal tDCS over prefrontal cortex improves dual-task walking in Parkinsonian patients with freezing. PMID- 30423200 TI - Ten-year change in neighborhood socioeconomic status and colorectal cancer. AB - BACKGROUND: A growing body of research has demonstrated that individuals who live in neighborhoods with more severe socioeconomic deprivation may have higher risks for colorectal cancer (CRC). However, previous studies have examined neighborhood socioeconomic status (SES) at only 1 point in time, and it is unclear whether changes in neighborhood SES also can influence the risks of CRC. METHODS: Cox regression analysis was used to examine different trajectories of change in neighborhood SES over 10 years in relation to the incidence of CRC among 266,804 participants (ages 51-70 years) in the National Institutes of Health-AARP Diet and Health Study. Eligible participants reported living in the same neighborhood at baseline (1995-1996) and from 2004 to 2006 according to a follow-up questionnaire. Changes in neighborhood SES were measured between 1990 and 2000 by SES indices derived from Census data. Neighborhoods were grouped into 4 categories based on median SES indices in 1990 and 2000 (low-low, low-high, high low, and high-high). RESULTS: Compared with residents whose neighborhoods were in the higher SES group at both time points (reference category), those whose neighborhoods were consistently in the low SES group had a 7% higher risk of developing CRC (hazard ratio, 1.07; 95% confidence interval, 1.00-1.14). Moreover, the risk of CRC was 15% higher (hazard ratio, 1.15; 95% confidence interval, 1.02-1.28) for those living in neighborhoods with decreasing SES (high low) over time. CONCLUSIONS: The current findings suggest that exposure to consistently low SES neighborhoods and/or a decrease in neighborhood SES over a period of time may be associated with higher risks of CRC. PMID- 30423201 TI - Ratios of proteins in cerebrospinal fluid in Parkinson's disease cognitive decline: prospective study. AB - BACKGROUND: There is a need for biomarkers of dementia in PD. OBJECTIVES: To determine if the levels of the main CSF proteins and their ratios are associated with deterioration in cognition and progression to dementia in the short to mid term. METHODS: The Parkinson's Progression Markers Initiative database was used as an exploratory cohort, and a center-based cohort was used as a replication cohort. Amyloid beta1-42, total tau, threonine-181 phosphorylated tau, and alpha synuclein in the CSF and the ratios of these proteins were assessed. RESULTS: In the Parkinson's Progression Markers Initiative cohort (n = 281), the total tau/amyloid beta1-42, total tau/alpha-synuclein, total tau/amyloid beta1-42+alpha synuclein, and amyloid beta1-42/total tau ratios were associated with a risk of progression to dementia over a 3-year follow-up. In the replication cohort (n = 40), the total tau/alpha-synuclein and total tau/amyloid beta1-42+alpha-synuclein ratios were associated with progression to dementia over a 41-month follow-up. CONCLUSION: Ratios of the main proteins found in PD patient brain inclusions that can be measured in the CSF appear to have value as short- to mid-term predictors of dementia. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 30423202 TI - Prodromal features of Parkinson's disease: Self-reported symptoms versus clinically assessed signs. PMID- 30423203 TI - Entinostat finds a path: A new study elucidates effects of the histone deacetylase inhibitor on the immune system. PMID- 30423204 TI - Parkinsonism due to A53E alpha-synuclein gene mutation: Clinical, genetic, epigenetic, and biochemical features. AB - BACKGROUND: SNCA mutations cause autosomal dominant parkinsonism and inform our understanding of the molecular underpinnings of synucleinopathies. The most recently identified mutation, p.Ala53Glu (A53E), has only been observed in Finland. The objectives of this study were to examine clinical, genetic, epigenetic, and biochemical features of the first family outside Finland with A53E. METHODS: We examined a Canadian family with parkinsonism because of A53E using haplotype and DNA methylation analyses. We assessed aggregation properties of A53E alpha-synuclein in vitro. RESULTS: Family members with parkinsonism shared a common haplotype distinct from Finnish patients with A53E. Increased acceleration of DNA methylation age was accompanied by earlier age at onset in the family members. We demonstrate that A53E alpha-synuclein has a propensity to form oligomers and phosphorylation promotes fibrillation. CONCLUSIONS: A53E as a cause of parkinsonism is not restricted to Finnish individuals. DNA methylation may contribute to disease age at onset. A53E enriches alpha-synuclein oligomers and fibrils dependent on the phosphorylation state. PMID- 30423205 TI - Effectiveness and safety of 110 or 150 mg dabigatran versus vitamin K antagonists in non-valvular atrial fibrillation. AB - BACKGROUND: We compared the 1-year safety and effectiveness of dabigatran 110 mg (D110) or 150 mg (D150) to vitamin K antagonists (VKA) in patients with non valvular atrial fibrillation (NVAF), METHODS: New user cohort study of patients dispensed D110 or D150 vs. VKA in 2013 for NVAF, followed 1 year in the French Systeme National des Donnees de Sante (SNDS, 66 million persons). D110 and D150 users were matched 1:1 with VKA users on sex, age, date of first drug dispensing, and high-dimensional propensity score (hdPS). Hazard ratios (HR [95% confidence intervals]) for stroke and systemic embolism (SSE), major bleeding (MB), and death were computed using Cox proportional hazards or Fine and Gray models during exposure. RESULTS: In 14,442 matched D110 and VKA patients, mean age 79, 49% male, 91% with CHA2 DS2 -VASc >=2 and 8% with HAS-BLED >3, incidence rates of SSE were 1.9% and 2.6% person-years (HR 0.69 [0.56-0.84]), MB 1.8% and 2.9% (0.62 [0.51-0.76]), death 7.2% and 8.6% (0.84 [0.76-0.94]). In 8,389 matched D150 and VKA patients, mean age 67, 67% male, 65% with CHA2 DS2 -VASC >= 2; < 5% HAS-BLED > 3, incidence rates were for SSE 1.4% and 1.9% (0.76 [0.56-1.04]), MB 0.6 % and 1.9% (0.30 [0.20-0.46]), death 1.6% and 3.6% (0.46 [0.35-0.59]). Numbers needed to treat to observe one fewer death were 78 for D110, 88 for D150 CONCLUSION: In real life D110 and D150 were at least as effective and safer than VKA. PMID- 30423206 TI - On the Design of Radical-Radical Cocrystals. AB - Formation of radical-radical cocrystals is an important step towards the design of organic ferrimagnets. We describe a simple approach to generate radical radical cocrystals through the identification and implementation of well-defined supramolecular synthons which favor cocrystallization over phase separation. In the current paper we implement the structure-directing interactions of the E-E bond (E=S, Se) of dithiadiazolyl (DTDA) and diselenadiazolyl (DSDA) radicals to form close contacts to electronegative groups. This is exemplified through the preparation and structural characterization of three sets of radical cocrystals; the 2:2 cocrystal [PhCNSSN]2 [MBDTA]2 (4) [MBDTA=methyl benzodithiazolyl] and the 2:1 cocrystals [C6 F5 CNEEN]2 [TEMPO] (E=S, 5; E=Se, 6). In 4 the two types of radical are linked via bifurcated inter-dimer delta+ S???Ndelta- interactions whereas 5 and 6 exhibit a set of five-centre delta+ E???Odelta- contacts (E=S, Se). PMID- 30423207 TI - Admitting privileges and hospital-based care after presenting for abortion: A retrospective case series. AB - OBJECTIVE: To examine the pathways of care for abortion patients transferred or referred to emergency departments (EDs) or hospitals before and after abortion providing physicians obtained hospital admitting privileges. DATA SOURCES: This case series was based on retrospective chart review at three abortion clinics in which physicians had obtained admitting privileges in the previous 5 years. STUDY DESIGN: We identified patients who were transferred or referred to a hospital or ED. Patients were grouped according to the pathway by which their care was transferred or referred to the ED/hospital. PRINCIPAL FINDINGS: Both before and after admitting privileges, the majority of patients were referred to a hospital before the abortion was attempted and most were for suspected ectopic pregnancy or to perform the abortion in a hospital. Direct ambulance transfer from the facility to the ED/hospital was the least common pathway. We observed few changes in practice from before to after admitting privileges. Preexisting mechanisms of coordination and communication facilitated care that was tailored for the specific patient. CONCLUSIONS: We did not find evidence that physician admitting privileges influenced the pathways through which abortion patients obtain hospital-based care, as existing mechanisms of collaboration between hospitals and abortion facilities allowed for management of patients who sought hospital based care. PMID- 30423208 TI - Deep ultraviolet lasers for flow cytometry. AB - Modern flow cytometers require multiple laser wavelengths to excite the wide variety of fluorescent probes now available for high-dimensional analysis. Ultraviolet (UV) lasers (typically solid state 355 nm) have become a critical excitation source for the Brilliant Ultraviolet (BUV) series of polymer fluorochromes. The BUV dyes have pushed the number of fluorescent probes available for simultaneous analysis to nearly 30, allowing an unprecedented level of precision for immune cell analysis. However, immunologists are already seeking analyze more than 30 simultaneous parameters, requiring both new fluorochromes and corresponding laser wavelengths. A group of polymer dyes requiring deep ultraviolet (UV) excitation (~280-300 nm) is currently under development, allowing the expansion of high-dimensional cytometry beyond the current 30 color limit. In this study, we evaluated a newly available laser emitting at 280 nm as a possible laser source for exciting these dyes. Since deep UV polymer dyes are not yet available, we used quantum nanoparticles (Qdots) as a surrogate probe to assess the utility of this laser wavelength for flow cytometry. Deep UV laser light was found to excite Qdots as well as traditional UV sources. Deep UV 280 nm did not excite BUV dyes well, suggesting that BUV and deep UV polymers will be spectrally compatible with low crossbeam spillover issues. Deep UV excitation did excite considerable autofluorescence in the violet to blue range, a limitation that will need to guide deep UV fluorochrome development. A deep UV 280 nm laser may therefore be the next essential wavelength for high-dimensional flow cytometry. (c) 2018 International Society for Advancement of Cytometry. PMID- 30423209 TI - The role of mass spectrometry in studies of glycation processes and diabetes management. AB - In the last decade, mass spectrometry has been widely employed in the study of diabetes. This was mainly due to the development of new, highly sensitive, and specific methods representing powerful tools to go deep into the biochemical and pathogenetic processes typical of the disease. The aim of this review is to give a panorama of the scientifically valid results obtained in this contest. The recent studies on glycation processes, in particular those devoted to the mechanism of production and to the reactivity of advanced glycation end products (AGEs, AGE peptides, glyoxal, methylglyoxal, dicarbonyl compounds) allowed to obtain a different view on short and long term complications of diabetes. These results have been employed in the research of effective markers and mass spectrometry represented a precious tool allowing the monitoring of diabetic nephropathy, cardiovascular complications, and gestational diabetes. The same approaches have been employed to monitor the non-insulinic diabetes pharmacological treatments, as well as in the discovery and characterization of antidiabetic agents from natural products. (c) 2018 Wiley Periodicals, Inc. Mass Spec Rev XX:XX-XX, 2018. PMID- 30423210 TI - Gold-Catalyzed Facile Synthesis and Crystal Structures of Benzene-/Naphthalene based Bispentalenes as Organic Semiconductors. AB - We describe the gold-catalyzed facile synthesis of U-shaped and S-shaped bispentalenes from easily available tetra(arylethynyl)-benzenes and naphthalenes. The optoelectronic and transistor properties were also investigated. The selectivity between the U-shaped and S-shaped bispentalene isomers can be tuned by the bulkiness of the ligand and the substrates. The S shaped naphthalene-based bispentalene shows a one dimensional face-to-face packing pattern in solid state and a good hole mobility, indicating that the S shaped bispentalene core is highly suitable for transistor applications. The gold catalyzed annulation of tetraynes provides a useful protocol in the synthesis of bispentalenes for organic semiconductors. PMID- 30423211 TI - Molecular monitoring of therapeutic milestones and clinical outcomes in patients with chronic myeloid leukemia. AB - BACKGROUND: In the current study, the authors determined whether adhering to molecular monitoring guidelines in patients with chronic myeloid leukemia (CML) is associated with major molecular response (MMR) and assessed barriers to adherent monitoring. METHODS: Newly treated patients with CML from the Quebec province-wide CML registry from 2005 to 2016 were included. Timely polymerase chain reaction (tPCR) was defined as the molecular assessment of BCR -ABL1 at the 3-month, 12-month, and 18-month time points from the initiation of tyrosine kinase inhibitor (TKI) therapy. The cohort was analyzed as a nested case-control study. Cases with a first-ever MMR (BCR-ABL1 <=0.1%, assessed at any time during follow-up) were matched to up to 5 controls by duration of TKI therapy, volume of patients with CML at the treatment center, year of cohort entry, and age. Odds ratios (ORs) for the performance of tPCR and MMR were adjusted for sex, comorbidities, type of TKI, and other important covariates. RESULTS: The cohort included 496 patients. Of 392 MMR events, 67.9% occurred before 18 months. The performance of tPCR was associated with a doubling of the MMR rate (OR, 2.23; 95% confidence interval [95% CI], 1.56-3.21) and was similar with 1 to 3 tPCRs performed (P = .67). Furthermore, tPCRs at 3 months (OR, 2.77; 95% CI, 1.81-4.23) and 12 months (OR, 3.00; 95% CI, 1.64-5.49) were associated with achieving early MMR, whereas tPCRs at 18 months were not (OR, 1.23; 95% CI, 0.80-1.89). Low volume centers were found to have lower adherence to tPCR (OR, 0.60; 95% CI, 0.40 0.89). CONCLUSIONS: Timely molecular assessment at 3 months and 12 months appears to benefit patients with CML. Adherence to timely monitoring should be encouraged, especially in low-volume treatment centers. PMID- 30423212 TI - Life span pigmentation changes of the substantia nigra detected by neuromelanin sensitive MRI. AB - BACKGROUND: Neuromelanin is a pigment with strong iron-chelating properties preferentially found in dopaminergic neurons of the substantia nigra pars compacta (SNpc). Parkinson's disease is characterized by pronounced, MRI detectable neuromelanin loss, but the neuroprotective or neurotoxic role of neuromelanin remains debated. Histological studies have demonstrated neuromelanin increases with age, but this has not been confirmed in vivo, and there is uncertainty whether neuromelanin declines, stabilizes, or increases from middle age. METHODS: This study aimed to establish physiological changes of pigmentation of the SNpc using a pooled data set of neuromelanin-sensitive 3T MRI from 134 healthy individuals aged 5-83 years. Neuromelanin-related brightness (regional contrast to ratio) and calibrated hyperintense volumes were analyzed using linear and nonlinear regression models to characterize age effects. Laterality, sex, and subregional effects were also assessed. RESULTS: For brightness, age effects were best described as a quadratic trajectory explaining 81.5% of the observed variance in the SNpc showing a strong increase from childhood to adolescence, with plateauing in middle age and a decline in older age. Similar but less pronounced effects were seen in hyperintense volumes. We also show an anterior posterior gradient in SNpc contrast, larger normalized neuromelanin-rich volume in women > 47 years old, but no laterality effect. CONCLUSIONS: Using optimized neuromelanin MRI in a life span sample, we demonstrate a strong age effect with inverted U-shaped SNpc pigmentation-related contrast from childhood to old age. This age trajectory of physiological SNpc pigmentation needs to be taken into account for diagnostic applications of depigmentation. The study also paves the way for systematic investigations of the mechanisms of neuromelanin in healthy and pathological brain development and aging. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 30423213 TI - Present and future temporal profiles and their relationship to health intentions and behaviors: A test on a Norwegian general population sample. AB - We investigated the temporal profiles of a Norwegian general population sample and their relation to health behaviors and intentions. The profiles were based on variables from the present and future dimensions of the Zimbardo Time Perspective Inventory (ZTPI), the Consideration of Future Consequences Scale (CFCS), and the combination of both scales. The analysis revealed that there were only two stable clusters that corresponded to the present and the future profiles. Generally, CFCS-based present and future profiles were more effective at predicting health behaviors and intentions than ZTPI-based profiles. Profiles based on the CFCS variables were more predictive of eating behaviors. However, the profiles based on the combination of both CFCS and ZTPI were more predictive of smoking, exercising, and health intentions than the profiles based solely on the CFCS. The variation in walking was explained only by the profiles based on a combination of CFCS and ZTPI. PMID- 30423214 TI - Hierarchical Microboxes Constructed by SnS Nanoplates Coated with Nitrogen-Doped Carbon for Efficient Sodium Storage. AB - We demonstrate the delicate design and synthesis of hierarchical microboxes assembled from SnS nanoplates coated with nitrogen-doped carbon (NC) as an anode material for sodium-ion batteries. The template-engaged multistep synthesis of the SnS@NC microboxes involves sequential phase transformation, polydopamine coating, and thermal annealing in N2. The SnS@NC composite with two-dimensional nanosized subunits rationally integrates several advantages including shortening the diffusion path of electrons/Na+ ions, improving electric conductivity and alleviating volume variation of the electrode material. As a result, the SnS@NC microboxes manifest efficient sodium storage performance with high capacity, good cycling stability, and excellent rate capability. PMID- 30423215 TI - Building a Global Culture of Science - The Vietnam Experience. AB - We detail the lessons learned, challenges, achievements, and outlook in building a chemistry research center in Vietnam. Through the principles of 'global science', we provide specific insight into the process behind establishing an internationally-competitive research program - a model that is scalable and adaptable to countries beyond Vietnam. Furthermore, we highlight the prospects for success in advancing global science education, research capacity building, and mentorship. PMID- 30423216 TI - Exploiting the Cellular Redox Control System for Activatable Photodynamic Therapy. AB - Photodynamic therapy (PDT) has been successfully used for treating a variety of cancers. However, one drawback has been the adverse side effects experienced by patients during therapy, as a result from the destruction of normal tissues upon irradiation. To overcome this issue, we describe the design, synthesis and characterization of a photosensitizer whereby in addition to light, is also dependent on the over active redox system present in cancer cells for its activation. Our probe consists of the photosensitizer, protoporphyrin IX, and a FRET-based quencher dye, BHQ-3, on a scaffold containing a disulfide bond. The close proximity of BHQ-3 to protoporphyrin IX quenches its ability to fluoresce and produce reactive oxygen species, while non-enzymatic or enzymatic reduction can recover its native properties. We further demonstrate its ability to be activated in cancer cells in a thiol-dependent manner, and can destroy breast and lung cancer cells upon red-light irradiation. PMID- 30423217 TI - Ultra-high-frequency deep brain stimulation at 10,000 Hz improves motor function. PMID- 30423218 TI - Doping control analysis of four JWH-250 metabolites in equine urine by LC-MS/MS. AB - JWH-250 is a synthetic cannabinoid. Its use is prohibited in equine sport according to the Association of Racing Commissioners International (ARCI) and the Federation Equestre Internationale (FEI). A doping control method to confirm the presence of four JWH-250 metabolites (JWH-250 4-OH-pentyl, JWH-250 5-OH-pentyl, JWH-250 5-OH-indole and JWH-250 N-pentanoic acid) in equine urine was developed and validated. Urine samples were treated with acetonitrile and evaporated to concentrate the analytes prior to the analysis by LC-MS/MS. The chromatographic separation was carried out using a Phenomenex Lux(r) 3 MUm AMP column (150 x 3.0 mm). A triple quadrupole mass spectrometer was used for detection of the analytes in positive mode electrospray ionization using multiple reaction monitoring (MRM). The limits of detection, quantification and confirmation for these metabolites were 25, 50 and 50 pg/mL, respectively. The linear dynamic range of quantification was 50-10000 pg/mL. Enzymatic hydrolysis indicated that JWH-250 4 OH-pentyl, JWH-250 5-OH-pentyl, and JWH-250 5-OH indole are highly conjugated whereas JWH-250 N-pentanoic acid is not conjugated. Relative retention time and product ion intensity ratios were employed as the criteria to confirm the presence of these metabolites in equine urine. The method was successfully applied to post-race urine samples collected from horses suspected of being exposed to JWH-250. All four JWH-250 metabolites were confirmed in these samples, demonstrating the method applicability for equine doping control analysis. PMID- 30423220 TI - As commissions on ACA plans vanish, some brokers stop selling them. PMID- 30423219 TI - Insurer withdrawals in Iowa set off alarms for individual market. AB - If Medica calls it quits, many Iowans will have no ACA-compliant plan options, an unprecedented situation with no clear fix. PMID- 30423221 TI - Medicare Advantage plans score several wins in rates for 2018. PMID- 30423224 TI - Special report: The Transformation Imperative: Hospital-based venture funds bet big on health startups. AB - Health systems have muscled into the venture capital space to support innovations that will help them thrive under value-based reimbursement. PMID- 30423222 TI - GOP lawmakers may face voter fury as they return home for Easter break. PMID- 30423223 TI - Special Report The Transformation Imperative: Why the social and economic forces disrupting healthcare are here to stay: Costs, consumerism driving innovation. AB - Healthcare systems are moving on multiple fronts to innovate in the ways they deliver care. The movement is being driven not just by the national imperative to improve quality and lower costs, but by the growing realization that patient facing digital technologies could soon disrupt the traditional ways of providing care. PMID- 30423225 TI - Which Scott Gottlieb will run the FDA? AB - Dr. Scott Gottlieb is by far the most conflicted person nominated to run the 111 year-old Food and Drug Administration. He's received payments from or invested in dozens of companies with business before the agency, earning millions of dollars in the process. PMID- 30423226 TI - Everyone agrees the ACA isn't perfect, but let's 'fix and innovate; not 'repeal and replace'. AB - The House Republicans' campaign to repeal the Affordable Care Act and shrink Medicaid funding has produced a lot of drama-and an unexpected realization for repeal proponents: People like the ACA. And they're pretty fond of Medicaid, too. PMID- 30423227 TI - Using caution with copy and paste. AB - Copy-and-pasting safely. Implement mechanisms that clearly identify copy-and pasted content and offer data on the source of the text. Train staff on when it's safe to copy and when it's important to manually replicate text. Monitor copy-and paste use among your staff and warn staff who may be abusing the functionality. PMID- 30423228 TI - 'Systems are looking to partner with other players to help them vet these deals'. AB - Karen Griffith Gryga is a partner and chief investment officer at Dreamit Ventures, one of the nation's largest accelerators for technology startups. The Philadelphia-based company also invests in early-stage health technology firms. A third of Dreamit's 80- plus companies are involved in population health management. Southern Bureau Chief Dave Barkholz interviewed Griffith Gryga. The following is an edited transcript. PMID- 30423229 TI - Confidence in 'selecting the winners'. AB - Catholic-sponsored Ascension was among the first health systems to set up a venture capital arm to invest in health technology companies. Since 2001, Ascension Ventures has raised $800 million with hospital partners to nurture startup companies. Today, more than 60 health systems have their own venture capital units. Modern Healthcare Southern Bureau Chief Dave Barkholz spoke with managing director Matt Hermann about the promise and pitfalls awaiting hospital systems just getting into the venture capital game. The following is an edited transcript. PMID- 30423230 TI - Healthcare systems accelerating innovations: Ranked by number of innovation projects. PMID- 30423231 TI - Obamacare Lite looms as alternative for GOP. AB - GOP leaders may decide an ACA deal with Dems would save them a lot of trouble, but they'll have a hard time convincing their right wing. PMID- 30423232 TI - GOP governors fight uphill battle to save Medicaid expansion. AB - Republican governors who tout the economic benefits of expanding Medicaid in their states aren't likely to influence their party's members in Congress who want to repeal the Affordable Care Act. PMID- 30423233 TI - The rhetoric over repeal and replace. PMID- 30423234 TI - Abbott-St. Jude merger gives providers what they want: fewer vendors. AB - The Abbott-St. Jude merger will help hospitals consolidate vendor relationships, but it has the potential to lead to higher supply costs in the long term. PMID- 30423235 TI - Moving dental health into primary care. AB - Growing recognition that improved dental health leads to better overall health is leading some providers to look for ways to integrate dental care into primary care, which tends to be more accessible for patients. PMID- 30423236 TI - First impressions matter most for millennials. AB - If you think keeping millennials from job-hopping is hard, try keeping them tied to your provider network if you've got old equipment, ratty gowns and long appointment wait times. PMID- 30423237 TI - Seeking solutions for behavioral healthcare shortage. AB - .A shortage of mental and behavioral health specialists is forcing healthcare systems to look for alternatives such as offering those services within primary care practices. PMID- 30423238 TI - Venture capital's bold move into population health. AB - Population health management is now one of the top six fields in healthcare attracting new money from venture capital firms, thanks in large part to the aging of the baby boomer population. PMID- 30423239 TI - The high-deductible plan trap. AB - Republicans seem intent on pursuing a disastrous Obamacare replacement plan that couples catastrophic coverage with subsidized health savings accounts. PMID- 30423240 TI - Devil is in the details for determining how to apply social determinants of health. AB - The 21st Century Cures Act, now law, is best known for funding prominent medical research initiatives and for accelerating the review of drugs and devices at the U.S. Food and Drug Administration. PMID- 30423241 TI - A social media platform docs can trust. PMID- 30423243 TI - Fastest-growing industry sectors in healthcare Ranked by percentage change in spending from 2014 to 2015. PMID- 30423242 TI - "We're seeing business models predicated on building value". AB - Dr. Farzad Mostasharl helped shape the electronic health record landscape from 2011 to 2013 as head of the Office of the National Coordinator for Health Information Technology. Today, he is CEO of Aledade, a Bethesda, Md.-based startup with 150 employees that manages physician-led accountable care organizations. Editor Merrill Goozner recently spoke with Mostashari about how the coming regulatory and political changes will affect his business, which manages ACOs for over 1,000 primary-care doctors in 15 states. The following is an edited excerpt. PMID- 30423244 TI - Unravelling the Role of Topological Defects on Catalytic Unzipping of Single Walled Carbon Nanotubes by Single Transition Metal Atom. AB - Catalytic unzipping of single-walled carbon nanotubes (SWCNTs) has been experimentally shown to be a viable method to produce graphene nanoribbons (GNRs) with clean and smooth edges for advanced applications, while topological defects (TDs) are inevitably presented in mass produced CNTs (especially the tube end/cap), which may affect the catalytic unzipping. Herein, we theoretically investigate the roles of TDs on the catalytic unzipping of SWCNTs by a single Fe atom in the H2 environment. Our computation shows that the threshold reaction barriers to the catalytic SWCNT unzipping can be notably reduced by ~20%-40%, resulting from weakened and elongated local C-C bonds associated with TDs. The curvature energy of a SWCNT released during the unzipping can support the continuous unzipping and enable the chirality- and diameter-dependent unzipping. The important roles of H2 are also identified. The suggested tear-from-end-defect mechanism can markedly improve the controllability of the catalytic unzipping of SWCNTs. PMID- 30423245 TI - Less Is More: Enhancement of Second-Harmonic Generation from Metasurfaces by Reduced Nanoparticle Density. AB - We investigate optical second-harmonic generation (SHG) from metasurfaces where noncentrosymmetric V-shaped gold nanoparticles are ordered into regular array configurations. In contrast to expectations, a substantial enhancement of the SHG signal is observed when the number density of the particles in the array is reduced. More specifically, by halving the number density, we obtain over 5-fold enhancement in SHG intensity. This striking result is attributed to favorable interparticle interactions mediated by the lattice, where surface-lattice resonances lead to spectral narrowing of the plasmon resonances. Importantly, however, the results cannot be explained by the improved quality of the plasmon resonance alone. Instead, the lattice interactions also lead to further enhancement of the local fields at the particles. The experimental observations agree very well with results obtained from numerical simulations including lattice interactions. PMID- 30423246 TI - Plasmon Rulers as a Probe for Real-Time Microsecond Conformational Dynamics of Single Molecules. AB - Biopolymers such as DNA, RNA, and proteins exploit conformational changes to modulate their function. Although state-of-the-art single-molecule approaches enable identification of conformational states, the transition path and metastable intermediates often remain elusive because they occur on microsecond time scales. Here we introduce a method to probe conformational dynamics with microsecond integration times based on a heterodimer of plasmonic particles. By combining Brownian dynamics and electromagnetic simulations, we find that integration times of 1 MUs can be routinely achieved, providing the capability to identify short-lived intermediates and transition paths at the single-molecule level in real-time. Importantly, plasmon rulers require no specialized equipment but can be probed on existing fluorescence microscopes equipped with a fast camera. The approach combines the advantages of fluorescent probes (zero-force, parallelization) and mechanical probes such as optical tweezers (continuous microsecond integration times). They offer a unique opportunity to study conformational dynamics and compare measurements to full-atom simulations, where computational demands limit the simulation time. PMID- 30423247 TI - Nanoengineered Peptide-Grafted Hyperbranched Polymers for Killing of Bacteria Monitored in Real Time via Intrinsic Aggregation-Induced Emission. AB - Facing the global health crisis caused by drug-resistant bacteria, antimicrobial peptides and their analogues offer exciting solutions to this widespread problem. Without additionally introducing a fluorescent probe, novel nanoengineered peptide-grafted hyperbranched polymers (NPGHPs) are constructed for their combined outstanding antimicrobial activity and sensitive bacterial detection in real time. Hyperbranched polyamide amine (H-PAMAM) that exhibits aggregation induced emission (AIE) effects is synthesized. Then, NPGHPs are prepared by ring opening polymerization of alpha-amino acid N-carboxyanhydrides on the periphery of the H-PAMAM. The NPGHPs exhibit high-efficiency antibacterial properties against a wide spectrum of bacteria, especially against Gram-negative bacteria. On the basis of the AIE effect of NPGHPs, the interaction between NPGHPs and Escherichia coli is explored and the fluorescence intensity of NPGHPs is dependent on the number of E. coli present. Thus, a method for monitoring E. coli concentration is developed, and the detection limit is 1 * 104 CFU mL-1. Furthermore, NPGHPs are used as fluorescent probes to visualize antibacterial process via lighting-up bacteria. NPGHPs can penetrate the membrane of bacteria and cause cell rupture and apoptosis. In addition, the excellent selectivity of NPGHPs toward bacteria over mammalian cells makes them bright prospects for clinical applications. PMID- 30423248 TI - Identification of Cyanamide-Based Janus Kinase 3 (JAK3) Covalent Inhibitors. AB - Ongoing interest in the discovery of selective JAK3 inhibitors led us to design novel covalent inhibitors that engage the JAK3 residue Cys909 by cyanamide, a structurally and mechanistically differentiated electrophile from other cysteine reacting groups previously incorporated in JAK3 covalent inhibitors. Through crystallography, kinetic, and computational studies, interaction of cyanamide 12 with Cys909 was optimized leading to potent and selective JAK3 inhibitors as exemplified by 32. In relevant cell-based assays and in agreement with previous results from this group, 32 demonstrated that selective inhibition of JAK3 is sufficient to drive JAK1/JAK3-mediated cellular responses. The contribution from extrahepatic processes to the clearance of cyanamide-based covalent inhibitors was also characterized using metabolic and pharmacokinetic data for 12. This work also gave key insights into a productive approach to decrease glutathione/glutathione S-transferase-mediated clearance, a challenge typically encountered during the discovery of covalent kinase inhibitors. PMID- 30423249 TI - On-Chip Monolithically Fabricated Plasmonic-Waveguide Nanolaser. AB - Plasmonic-waveguide lasers, which exhibit subdiffraction limit lasing and light propagation, are promising for the next-generation of nanophotonic devices in computation, communication, and biosensing. Plasmonic lasers supporting waveguide modes are often based on nanowires grown with bottom-up techniques that need to be transferred and aligned for use in optical circuits. Here, we demonstrate a monolithically fabricated ZnO/Al plasmonic-waveguide nanolaser compatible with the fabrication requirements of on-chip circuits. The nanolaser is designed with a plasmonic metal layer on the top of the laser cavity only, providing highly efficient energy transfer between photons, excitons, and plasmons, and achieving lasing in the ultraviolet region up to 330 K with a low threshold intensity (0.20 mJ/cm2 at room temperature). This work demonstrates the realization of a plasmonic-waveguide nanolaser without the need for transfer and positioning steps, which is the key for on-chip integration of nanophotonic devices. PMID- 30423250 TI - Metal-Organic Framework-Assisted Construction of TiO2/Co3O4 Highly Ordered Necklace-like Heterostructures for Enhanced Ethanol Vapor Sensing Performance. AB - In this work, we report a metal-organic framework (MOF)-assisted strategy to synthesize necklace-like TiO2/Co3O4 nanofibers with highly ordered heterostructures via a facile approach including electrospinning and subsequent calcination. Polycrystalline TiO2 nanofibers and Co3O4 nanocages are consummately interconnected to form a highly ordered heterogeneous nanostructure, which can be of benefit for precisely accommodating the interface resistance of the p-n heterojunctions and the future realization of improved material performance. The ethanol-gas-sensing investigation showed that TiO2/Co3O4 nanofiber sensors exhibited a strong ethanol response ( Rair/ Rgas -1 = 16.7 @ 150 ppm) and a low operating temperature of 150 degrees C. The sensing enhancement mechanism of the TiO2/Co3O4 nanofibers is related to the formation of heterojunctions at interfaces and the high catalytic activity of MOF-derived Co3O4. Furthermore, this versatile method is a promising approach to constructing ordered heterostructures and extending the MOF-based heterogeneous materials toward wide applications. PMID- 30423251 TI - Mild Synthesis of Copper Nanoparticles with Enhanced Oxidative Stability and Their Application in Antibacterial Films. AB - Copper nanoparticles possess unique physical and chemical properties; however, their application is often restricted, owing to their tendency to oxidize. In this work, we prepared copper nanoparticles with enhanced oxidative stability via a simple and low-cost method, where a modified starch was used as an environmentally friendly reducing agent and biocompatible polyethylenimine was used as a stabilizer. The prepared copper nanoparticles could be stored in air for at least 6 months without any oxidation in a dried state. Interestingly, our synthesis could even be performed at room temperature with a longer reaction time. We used various characterization methods to study the reaction mechanism. The prepared copper nanoparticles were further uniformly doped into an agar film, and this composite showed excellent bacterial killing efficiency, owing to the antibacterial properties of the copper nanoparticles. Our composite film shows potential for various clinical applications, such as wound dressing materials. PMID- 30423252 TI - Broadband Achromatic Metasurface-Refractive Optics. AB - Existing methods of correcting for chromatic aberrations in optical systems are limited to two approaches: varying the material dispersion in refractive lenses or incorporating grating dispersion via diffractive optical elements. Recently, single-layer broadband achromatic metasurface lenses have been demonstrated but are limited to diameters on the order of 100 MUm due to the large required group delays. Here, we circumvent this limitation and design a metacorrector by combining a tunable phase and artificial dispersion to correct spherical and chromatic aberrations in a large spherical plano-convex lens. The tunability results from a variation in light confinement in sub-wavelength waveguides by locally tailoring the effective refractive index. The effectiveness of this approach is further validated by designing a metacorrector, which greatly increases the bandwidth of a state-of-the-art immersion objective (composed of 14 lenses and 7 types of glasses) from violet to near-infrared wavelengths. This concept of hybrid metasurface-refractive optics combines the advantages of both technologies in terms of size, scalability, complexity, and functionality. PMID- 30423253 TI - Effectiveness of Multilevel Risk Management Emergency Response Activities To Ensure Free Chlorine Residual in Household Drinking Water in Southern Syria. AB - To provide safe drinking water and reduce the risk of disease, emergency responders in southern Syria are implementing a multilevel risk reduction strategy with the aim of ensuring free chlorine residual (FCR) in household drinking water. Responders implemented activities across the water chain (from chlorination station and well operators to water vendors to household members), including distribution of supplies for chlorination and training on chlorine use; activities varied by responder. We evaluated the effectiveness of these interventions in a cross-sectional observation study including interviews and observations with 24 chlorination station operators and 63 well owners/managers; interviews, observations, and water quality testing with 220 water truckers; and surveys and water quality testing with 1006 households. Across all responders, activities successfully ensured FCR in household drinking water (61-96% of households with FCR >= 0.1 mg/L compared to 21% in nonintervention households, p < 0.001). Centralized interventions led to the highest FCR results. Household FCR was associated with access to piped water systems (aOR 3.5, 95% CI 1.8-6.7) and chlorine distribution (aOR 6.1, 95% CI 3.4-11.0). We recommend continuing activities, emphasizing central-level activities, and supplementing with household-level activities. These results will help to optimize current interventions and guide future response design in similar contexts. PMID- 30423254 TI - Give Me a Fork: Can Autophagy Research Solve the Riddle of Airway Remodeling in Asthma? PMID- 30423255 TI - Non-invasive evaluation of periodontal ligament stiffness during orthodontic tooth movement. AB - OBJECTIVES:: To evaluate the longitudinal changes in periodontal ligament (PDL) stiffness during orthodontic tooth movement using the Advanced System for Implant Stability Testing (ASIST). MATERIALS AND METHODS:: ASIST measurements of maxillary canines that were actively retracted into an extraction space were collected approximately once per month for 12 adolescent female patients. The ASIST Stability Coefficient (ASC) values, which are directly related to PDL stiffness, were determined for each visit to examine longitudinal changes for individual canines as they were exposed to different forces (approximately 80 and 150 g) during retraction. RESULTS:: The pattern of longitudinal changes in ASC was similar for both canines (regardless of the two force levels applied) in individual patients and across patients. All patients showed some decrease in ASC, with an average maximum reduction in stiffness of 73.4 +/- 7.7%. Some recovery was observed for most patients; however, none of the patients had the PDL stiffness return to the pre-treatment value at the final measurement appointment which was some time close after space closure was completed. On average, the ASC value at the final measured visit was 48.1 +/- 12.2% of the initial value. No measurements are available after removal of orthodontic appliances and during retention. CONCLUSIONS:: The ASIST was able to detect changes in PDL stiffness during orthodontic treatment, providing some insight into the mechanical changes that occur at the tooth root interface. PMID- 30423256 TI - Reliability of different three-dimensional cephalometric landmarks in cone-beam computed tomography : A systematic review. AB - OBJECTIVES:: Conventional two-dimensional (2D) cephalometric radiography is an integral part of orthodontic patient diagnosis and treatment planning. One must be mindful of its limitations as it indeed is a 2D representation of a vaster three-dimensional (3D) object. Issues with projection errors, landmark identification, and measurement inaccuracies impose significant limitations, which may now be overcome with the advent of cone-beam computed tomography (CBCT). A systematic review of the reliability of different 3D cephalometric landmarks in CBCT imaging was conducted. MATERIALS AND METHODS:: Electronic database searches were administered until October 2017 using PubMed, MEDLINE via OvidSP, EBMR and EMBASE via OvidSP, Scopus, and Web of Science. Google Scholar was used as an adjunctive search tool. RESULTS:: Thirteen articles considering CBCT scans of human subjects from preexisting data sets were selected and reviewed. Most of the studies had methodological limitations and were of moderate quality. Because of their heterogeneity, key data from each could not be combined and were reported qualitatively. Overall, in 3D, midsagittal plane landmarks demonstrated greater reliability compared with bilateral landmarks. A minimum number of dental landmarks were reported, although most were recommended for use. CONCLUSIONS:: Further research is required to evaluate the reliability of 3D cephalometric landmarks when evaluating 3D craniofacial complexes. PMID- 30423257 TI - On the Move: The Commander IL-4 Leads the Cell Army in Collective Migration. PMID- 30423258 TI - Recommended Reading from University of Colorado Anesthesia Critical Care Medicine Fellows. PMID- 30423259 TI - Identification of a novel caspase cleavage site in huntingtin that regulates mutant huntingtin clearance. AB - Huntington disease (HD) is a progressive neurodegenerative disease that initially affects the striatum and leads to changes in behavior and loss of motor coordination. It is caused by an expansion in the polyglutamine repeat at the N terminus of huntingtin (HTT) that leads to aggregation of mutant HTT. The loss of wild-type function, in combination with the toxic gain of function mutation, initiates various cell death pathways. Wild-type and mutant HTT are regulated by different posttranslational modifications that can positively or negatively regulate their function or toxicity. In particular, we have previously shown that caspase cleavage of mutant HTT at amino acid position aspartate 586 (D586) by caspase-6 is critical for the pathogenesis of the disease in an HD mouse model. Herein, we describe the identification of a new caspase cleavage site at position D572 that is mediated by caspase-1. Inhibition of caspase-1 also appeared to decrease proteolysis at D586, likely by blocking the downstream activation of caspase-6 through caspase-1. Inhibition of caspase cleavage at D572 significantly decreased mutant HTT aggregation and significantly increased the turnover of soluble mutant HTT. This suggests that caspase-1 may be a viable target to inhibit caspase cleavage of mutant HTT at both D572 and D586 to promote mutant HTT clearance.-Martin, D. D. O., Schmidt, M. E., Nguyen, Y. T., Lazic, N., Hayden, M. R. Identification of a novel caspase cleavage site in huntingtin that regulates mutant huntingtin clearance. PMID- 30423260 TI - Hyperglycemia promotes microvillus membrane expression of DMT1 in intestinal epithelial cells in a PKCalpha-dependent manner. AB - Excessive iron increases the incidence of diabetes and worsens diabetic complications. Reciprocally, diabetes induces iron loading, partially attributable to elevated intestinal iron export according to a recent report. Herein, we show that iron uptake and the mRNA expression of iron importer divalent metal transporter 1 (DMT1) were significantly increased in the duodenum of streptozotocin-induced diabetic mice. Immunofluorescence staining of human intestinal biopsies revealed increased brush border membrane (BBM) and decreased cytoplasmic DMT1 expression in patients with diabetes, suggesting translocation of DMT1. This pattern of DMT1 regulation was corroborated by immunoblotting results in diabetic mice showing that BBM DMT1 expression was increased by 210%, in contrast to a 60% increase in total DMT1. PKC mediates many diabetic complications, and PKCalpha activity was increased in diabetic mouse intestine. Intriguingly, diabetic mice with PKCalpha deficiency did not show increases in iron uptake and BBM DMT1 expression. High-glucose treatment increased plasma membrane DMT1 expression via the activation of PKCalpha in cultured IECs. Inhibition of PKCalpha potentiated the ubiquitination and degradation of DMT1 protein. We further showed that high glucose suppressed membrane DMT1 internalization. These findings demonstrate that PKCalpha promotes microvillus membrane DMT1 expression and intestinal iron uptake, contributing to diabetic iron loading.-Zhao, L., Bartnikas, T., Chu, X., Klein, J., Yun, C., Srinivasan, S., He, P. Hyperglycemia promotes microvillus membrane expression of DMT1 in intestinal epithelial cells in a PKCalpha-dependent manner. PMID- 30423261 TI - The RNA-binding protein LIN28 controls progenitor and neuronal cell fate during postnatal neurogenesis. AB - The RNA-binding protein LIN28 is known to regulate cell fate, tissue growth, and pluripotency; however, a unified understanding of its role at the cellular level has not been achieved. Here, we address its developmental activity in mammalian postnatal neurogenesis. Constitutive expression of LIN28 in progenitor cells of the mouse subventricular zone (SVZ) caused several distinct effects: 1) the number of differentiated neurons in the olfactory bulb was dramatically reduced, whereas the relative abundance of 2 neuronal subtypes was significantly altered, 2) the population of proliferating neural progenitors in the SVZ was reduced, whereas the proportion of neuroblasts was increased, and 3) the number of astrocytes was reduced, occasionally causing them to appear early. Thus, LIN28 acts at a poststem cell/predifferentiation step, and its continuous expression caused a precocious phenotype unlike in other experimental systems. Furthermore, for the first time in a vertebrate system, we separate the majority of the biologic role of LIN28 from its known activity of blocking the microRNA let-7 by using a circular RNA sponge. We find that although LIN28 has a multifaceted role in the number and types of cells produced during postnatal neurogenesis, it appears that its action through let-7 is responsible for only a fraction of these effects.-Romer-Seibert, J. S., Hartman, N. W., Moss, E. G. The RNA-binding protein LIN28 controls progenitor and neuronal cell fate during postnatal neurogenesis. PMID- 30423262 TI - Exogenous adrenocorticotropic hormone affects genome-wide DNA methylation and transcriptome of corpus luteum in sows. AB - Stress is known to cause corpus luteum (CL) dysfunction, and stress hormones play a critical role in this process. However, the mechanism remains unclear. In this study, weaned sows were injected with synthetic adrenocorticotropic hormone (ACTH) for 7 d; whole-genome bisulfite sequencing (WGBS) and RNA-sequencing was used respectively to investigate the systematic association between ACTH administration and DNA methylation in CL and its relationship to gene expression. Results showed that ACTH treatment significantly increased the concentrations of cortisol ( P < 0.05). The genome-wide DNA methylation maps of CL were provided, and the global analysis showed the difference between the 2 groups exists in the chromosomes and feature regions of the genome. A total of 88,559 DMRs were identified and the most DMR-related genes were gathered in terms of metabolic biologic processes, and some DMR-related genes were involved in cellular differentiation. Nine differentially expressed genes were screened out of coexpressed genes and 4 DMR-associated genes that were also differentially expressed ( P < 0.05). In summary, our study firstly provides insight into the regulation of ACTH administration on genomic DNA methylation and gene expression in CL. We revealed a remarkable alteration of DNA methylation in CL caused by ACTH treatment, and identified 4 DMR-related genes that may be involved in the CL function under stress conditions.-Zhao, F., Wu, W., Wei, Q., Shen, M., Li, B., Jiang, Y., Liu, K., Liu, H. Exogenous adrenocorticotropic hormone affects genome wide DNA methylation and transcriptome of corpus luteum in sows. PMID- 30423263 TI - Collaborative Physician-Pharmacist-Managed Multiple Myeloma Clinic Improves Guideline Adherence and Prevents Treatment Delays. AB - PURPOSE:: We hypothesized that a multidisciplinary collaborative physician pharmacist multiple myeloma clinic would improve adherence to treatment and supportive care guidelines as well as reduce delays in receiving oral antimyeloma therapy. METHODS:: From March 2014 to February 2015, an oncology pharmacist provided consultation for all patients in a specialist myeloma clinic. This included reviewing medications, ensuring physician adherence to supportive care guidelines, managing treatment-related adverse effects, and navigating issues involving access to oral specialty medications (collaborative clinic). RESULTS:: Outcome measures were retrospectively compared with those of patients being treated by the same physician during the previous year, in which ad hoc pharmacist consultation was available upon request (traditional clinic). The collaborative clinic led to significant improvements in adherence to supportive medications, such as bisphosphonates (96% v 68%; P < .001), calcium and vitamin D (100% v 41%; P < .001), acyclovir (100% v 58%; P < .001), and Pneumocystis jirovecii pneumonia prophylaxis (100% v 50%; P < .001). Appropriate venous thromboembolism prophylaxis in immunomodulatory drug-treated patients was prescribed in 100% versus 83% of cases ( P = .0035). The median time to initiation of bisphosphonate (5.5 v 97.5 days; P < .001) and P jirovecii pneumonia prophylaxis after autologous transplantation was shortened in the collaborative clinic (11 v 40.5 days; P < .001). Furthermore, the number (85% v 21%; P < .001) and duration (7 v 15 days; P = .002) of delays in obtaining immunomodulatory drug therapy were also significantly reduced. CONCLUSION:: Our collaborative clinic model could potentially be applied to other practice sites to improve the management of patients with multiple myeloma. Prospective studies analyzing clinical outcomes, patient satisfaction, and cost effectiveness of this approach are warranted. PMID- 30423264 TI - Window of Opportunity: Patient Portals and Cancer. PMID- 30423265 TI - The Sin of Exclusion: Applicability of Trials Encouraging Omission of Radiation Therapy to Nonwhite Patients With Breast Cancer. PMID- 30423266 TI - Burkitt's Lymphoma: Challenges and Practical Considerations for Modern Therapy. PMID- 30423267 TI - Approach to the Diagnosis and Treatment of Adult Burkitt's Lymphoma. AB - Burkitt's lymphoma is a rarely encountered, aggressive B-cell lymphoma that is highly curable in children and young adults. In middle-aged and older adults, however, administering curative therapy may be challenging because standard Burkitt's lymphoma platforms are associated with high treatment-related toxicity in these age groups. Because of its high curability, the testing of alternative, less toxic approaches in Burkitt's lymphoma has been challenging. Although the critical role of MYC in Burkitt's lymphoma has been well described, recent biologic insights have identified several new mutations that cooperate with MYC in driving lymphomagenesis, paving the way for novel drug testing in this disease. Recently, intermediate-intensity approaches have been tested in Burkitt's lymphoma. Early multicenter results demonstrate good tolerability while maintaining high cure rates in all patient and age groups. PMID- 30423268 TI - DA-EPOCH-R for Adult Burkitt's Lymphoma: Pros and Cons. PMID- 30423269 TI - Treatment of Acute Promyelocytic Leukemia With No or Minimal Chemotherapy: Now a Reality in Common Clinical Practice. PMID- 30423270 TI - Treatment of Acute Promyelocytic Leukemia in Adults. AB - The treatment of acute promyelocytic leukemia (APL) has evolved rapidly in the past two decades after the introduction of highly active drugs, including tretinoin (all- trans-retinoic acid) and arsenic trioxide. It is now possible to treat this disease without the use of traditional cytotoxic chemotherapy. Today's clinical guidelines include multiple regimens, some of which continue to use cytotoxic chemotherapy. This leaves the practicing oncologist with multiple treatment options when faced with a new case of APL. In an effort to standardize our approach to the treatment of newly diagnosed APL, we sought to develop a set of treatment recommendations at our institution. We identified eight major controversial issues in the treatment of APL. These controversial issues include the optimal dose and schedule of both all- trans-retinoic acid and arsenic trioxide, the optimal regimen for high-risk APL, the need for intrathecal prophylaxis, the use of prophylactic corticosteroids, and the need for maintenance therapy after consolidation. We reviewed the relevant literature and used the Delphi method among the coauthors to reach consensus for recommendations on the basis of the best available data and our own clinical experience. In this clinical review, we present our consensus recommendations, the reasoning behind them, and the grading of the evidence that supports them. PMID- 30423271 TI - Share of Oncology Versus Nononcology Spending in Episodes Defined by the Centers for Medicare & Medicaid Services Oncology Care Model. AB - PURPOSE:: Performance-based payments to oncology providers participating in the Centers for Medicare & Medicaid Services (CMS) Oncology Care Model (OCM) are based, in part, on overall spending in 6-month episodes of care, including spending unrelated to oncology care. The amount of spending likely to occur outside of oncologists' purview is unknown. METHODS:: Following the OCM definition of an episode, we used SEER-Medicare data from 2006 to 2013 to identify episodes of cancer care for the following diagnoses: breast cancer (BC), non-small-cell lung cancer, renal cell carcinoma, multiple myeloma (MM), and chronic myeloid leukemia. Claims were categorized by service type and, separately, whether the content fell within the purview of oncology providers (classified as oncology, with all other claims nononcology). We calculated the shares of episode spending attributable to oncology versus nononcology services. RESULTS:: The percentage of oncology spending within OCM episodes ranged from 62.4% in BC to 85.5% in MM. The largest source of oncology spending was antineoplastic drug therapy, ranging from 21.8% of total episode spending in BC to 67.6% in chronic myeloid leukemia. The largest source of nononcology spending was acute hospitalization and inpatient physician costs, ranging from 6.6% of overall spending for MM to 10.4% for non-small-cell lung cancer; inpatient oncology spending contributed roughly similar shares to overall spending. CONCLUSION:: Most spending in OCM-defined episodes was attributable to services related to cancer care, especially antineoplastic drug therapy. Inability to control nononcology spending may present challenges for practices participating in the OCM, however. PMID- 30423272 TI - Utility of Droplet Digital PCR Assay for Quantitative Detection of Norovirus in Shellfish, from Production to Consumption in Guangxi, China. AB - OBJECTIVE: Shellfish are recognized as important vehicles of norovirus-associated gastroenteritis. The present study aimed to monitor norovirus contamination in oysters along the farm-to-fork continuum in Guangxi, a major oyster production area in Southwestern China. METHODS: Oyster samples were collected monthly from farms, markets, and restaurants, from January to December 2016. Norovirus was detected and quantified by one-step reverse transcription-droplet digital polymerase chain reaction (RT-ddPCR). RESULTS: A total of 480 oyster samples were collected and tested for norovirus genogroups I and II. Norovirus was detected in 20.7% of samples, with genogroup II predominating. No significant difference was observed in norovirus prevalence among different sampling sites. The norovirus levels varied widely, with a geometric mean of 19,300 copies/g in digestive glands. Both norovirus prevalence and viral loads showed obvious seasonality, with a strong winter bias. CONCLUSION: This study provides a systematic analysis of norovirus contamination 'from the farm to the fork' in Guangxi. RT-ddPCR can be a useful tool for detection and quantification of low amounts of norovirus in the presence of inhibitors found particularly in foodstuffs. This approach will contribute to the development of strategies for controlling and reducing the risk of human illness resulting from shellfish consumption. PMID- 30423273 TI - Neutralizing Antibody Titer Test of Ebola Recombinant Protein Vaccine and Gene Vector Vaccine pVR-GP-FC. AB - OBJECTIVE: In previous studies, we immunized mice with Ebola recombinant protein vaccine and gene vector vaccine. Both stimulated high levels of humoral immunity. In this work, we constructed a pseudovirus containing Ebola membrane proteins to verify whether the two immunization strategies can induce neutralizing antibodies in mice. METHODS: A pseudovirus containing an Ebola virus membrane protein based on the HIV-1 viral gene sequence was constructed and evaluated using a known neutralizing antibody. The titer of the neutralizing antibody in the sera of mice immunized with the recombinant protein and the gene vector vaccine was examined using a neutralization test. RESULTS: Ebola pseudovirus was successfully prepared and applied for neutralizing antibody detection. Immunological experiments showed that recombinant protein GP-Fc and gene vaccine pVR-modGP-Fc had good immunogenicity. The titer of the bound antibody in the serum after 8 weeks of immunization in mice was more than 1:105, and the recombinant protein induced greater humoral immunity. The results of the neutralization test based on the Ebola pseudovirus system demonstrated that both vaccines induced production of protective antibodies, while the gene vaccine induced a higher titer of neutralizing antibodies. CONCLUSION: An Ebola pseudovirus detection system was successfully established and used to evaluate two Ebola vaccines. Both produced good immunogenicity. The findings lay the foundation for the development of new Ebola vaccines and screening for neutralizing monoclonal antibodies. PMID- 30423274 TI - A Scan of Obesogenic Environments and a Spatial Inference of Obesity Prevalence in Chinese Children and Adolescents: Based on the Chinese Health and Nutrition Survey 2011 Data. AB - OBJECTIVE: To identify the characteristics of Chinese obesogenic environments at a provincial level, infer a spatial distribution map of obesity prevalence in 31 provinces, and provide a foundation for development of policy to reduce obesity in children and adolescents. METHODS: After scanning obesity data on subjects aged 7-17 years from 12 provinces in the China Health and Nutrition Survey 2011 and environmental data on 31 provinces from the China Statistical Yearbook 2011 and other sources, we selected 12 predictors. We used the 12 surveyed provinces as a training sample to fit an analytical model with partial least squares regression and prioritized the 12 predictors using variable importance in projection. We also fitted a predictive model with Bayesian analysis. RESULTS: We identified characteristics of obesogenic environments. We fitted the predictive model with a deviance information criterion of 61.96 and with statistically significant (P < 0.05) parameter estimates of intercept [95% confidence interval (CI): 329.10, 963.11], log(oil) (CI: 13.11, 20.30), log(GDP) (CI: 3.05, 6.93), log(media) (CI: -234.95, -89.61), and log(washing-machine) (CI: 0.92, 5.07). The total inferred average obesity prevalence among those aged 7-17 was 9.69% in 31 Chinese provinces in 2011. We also found obvious clustering in occurrences of obesity in northern and eastern provinces in the predicted map. CONCLUSION: Given complexity of obesity in children and adolescents, concerted efforts are needed to reduce consumption of edible oils, increase consumption of vegetables, and strengthen nutrition, health, and physical activity education in Chinese schools. The northern and eastern regions are the key areas requiring intervention. PMID- 30423275 TI - Influence of Familiarity on Energy Intake and Plasma Gut Hormone Concentration in Lean and Overweight Young Male Students. AB - OBJECTIVE: This study is to examine the influence of familiarity on energy intake, eating behavior, and concentration of the plasma gut hormones in lean and overweight young male subjects. METHODS: Twenty-eight lean and twenty-eight overweight participants were recruited. Their food consumption was documented and analyzed when they had a test meal while they were paired with friends or strangers at the same weight stature. Their eating behavior was recorded with cameras hidden in the carton, and postprandial plasma gut hormone concentration were measured. RESULTS: Compared with overweight strangers (OS), overweight friends (OF) had increased food consumption, prolonged and decreased number of chews per 10 g food. Compared with OS, postprandial plasma concentration of cholecystokinin-8 was significantly lower in OF group at 30, 60, and 90 min, whereas the concentration of glucagon-like peptide 1 was significantly lower at 60 and 90 min. Plasma ghrelin concentration was significantly higher in the OF group than that in the OS group at 90 and 120 min. No significant differences in gut hormone concentration were observed between lean strangers (LS) and lean friends (LF) groups at all time points. CONCLUSION: Familiarity plays an important role in increasing energy intake and in changing of postprandial gut hormone concentration in overweight individuals. PMID- 30423276 TI - Clustering of Cardiovascular Risk Factors and Diabetes: A Prospective Cohort Study on the Inner Mongolian Population in China. AB - OBJECTIVE: To evaluate the effect of clustering of cardiovascular risk factors (CVRFs) on type 2 diabetes mellitus (T2DM) incidence and identify some high predictive clusters in the Inner Mongolian population in China. METHODS: A total of 1,884 Mongolian individuals aged 20 years or above were followed up from 2002 to 2013 and included in the final analysis. We categorized the participants into two subgroups according to the study outcome event. A Cox proportional hazards model was used to evaluate the effect of clustering of CVRFs on the incidence of T2DM. Areas under the curve were used to compare the effect of every cluster on T2DM and identify those having higher predictive value. RESULTS: We found 203 persons with T2DM. Subjects with incident T2DM tended to be older, had a higher prevalence of drinking, had higher systolic and diastolic pressures; total cholesterol, triglyceride, low-density lipoprotein cholesterol, and C-reactive protein levels; waist circumference; body mass index; and heart rate and lower HDL-C level than did those without T2DM. The multivariable adjusted hazard ratio (95% confidence interval) of T2DM was calculated based on comparisons with subjects with 0 CVRFs; in participants with 2 and ? 3 factors, the adjusted hazard ratios were 2.257 (1.448, 3.518) and 3.316 (2.119, 5.188), respectively. CONCLUSION: The clustering of CVRFs increased the risk of T2DM. On the basis of fast heart rate, the cluster of abdominal obesity and other CVRFs had higher predictive value for T2DM than the other three CVRF clusters. PMID- 30423277 TI - Effects of Simulated Heat Wave and Ozone on High Fat Diet ApoE Deficient Mice. AB - OBJECTIVE: To discuss the cardiac toxicities of a heat waves and ozone exposure on cardiovascular diseases (CVDs) and explore a possible mechanism. METHODS: The incidence of ozone exposure combined with heat wave was simulated in the Shanghai Meteorological and Environmental Animal Exposure System (Shanghai-METAS). A total of 64 ApoE-/- mice, matched by weight, were randomly divided into 8 groups and exposed to heat wave conditions or ozone. The levels of creatine kinase (CK), D lactate dehydrogenase (D-LDH), intercellular adhesion molecule 1 (sICAM-1), tumor necrosis factor alpha (TNF-alpha), nitric oxide (NO), endothelin-1 (ET-1), D dimer (D2D), plasminogen activator inhibitor-1 (PAI-1) and blood lipid in plasma and heat shock protein-60 (HSP60), hypoxia inducible factor 1 alpha (HIF-1alpha), interleukin-6 (IL-6), C-reactive protein (CRP), superoxide dismutase (SOD), and malondialdehyde (MDA) in hearts were measured after exposure. RESULTS: The levels of all indicators, except for SOD, increased with the ozone-only exposure. However, cardiac damage was most significant when the heat wave conditions were combined with severe ozone exposure. Moreover, the levels of CK, D-LDH, NO, PAI 1, sICAM-1, and TNF-alpha in plasma increased significantly (P < 0.05), and the contents of HSP60, HIF-1alpha, CRP, and MDA in hearts increased considerably (P < 0.05), but the activity of SOD decreased significantly. In addition, the levels of four blood lipid items remarkably increased (except the level of HDL-C which decreased significantly) with ozone exposure. CONCLUSION: A short-term exposure to a heat wave and ozone causes severe toxic effects on the heart. Cardiac damage was most significant under combined heat wave and severe ozone exposure simulations. PMID- 30423278 TI - Association between Physical Activity and Higher Serum Creatinine/Uric Acid by Dose-response Association. PMID- 30423279 TI - Epidemiological Analysis on Reported Hepatitis C Cases in China from 2012 to 2016. PMID- 30423280 TI - Hormetic Effects of Yttrium on Male Sprague-Dawley Rats. AB - To evaluate hormesis induced by Yttrium (Y) nitrate in male rats, Y was offered to F0 mother rats and F1 offspring at concentrations of 0, 20, 80, and 320 ppm daily from gestational day (GD) 0 through postnatal day 70 (PND 70). The F1 offspring were evaluated with respect to motor function, learning and memory, and histopathology. Administration of Y improved motor function in a dose dependent manner. In the 20 ppm group, body weight and spatial learning and memory were increased, while the latter was decreased in the 320 ppm group. Additionally, in the 20 ppm and 80 ppm, but not the 320 ppm groups, Y reduced the anogenital distance, which indicated an anti-androgen effect. These results suggest that Y follows a hormetic concentration-related trend with an inverted U-shape. PMID- 30423281 TI - Challenges Brought about by Rapid Changes in Chinese Diets: Comparison with Developed Countries and Implications for Further Improvement. PMID- 30423282 TI - Identifying palliative care needs in residential care. AB - The aim of this study is to determine the accuracy, feasibility and acceptability of the surprise question (SQ) in combination with a clinical prediction tool (Supportive and Palliative Care Indicator Tool (SPICT)) in identifying residents who have palliative care needs in residential aged care facilities (RACFs) in Australia. A prospective cohort study in two RACFs containing both high-level care (including dementia) and low-level care beds. Directors of Nursing screened 187 residents at risk of dying by 12 months using first the SQ, and if positive, then the SPICT. At 12-months follow-up, deaths, hospitalisations, use of palliative care services, end-of-life care and clinical indicators were recorded. The SQ had a sensitivity of 70%, a specificity of 69.6%, a positive predictive value of 40.6% and a negative predictive value of 88.7% for death. All residents identified by the SQ had at least two general indicators of deterioration, while 98.8% had at least one disease-specific indicator on the SPICT. The SPICT marginally increased the ability to identify residents in need of proactive end of-life planning. A combination of the SQ and the SPICT is effective in predicting palliative care needs in residents of aged care facilities, and may trigger timely care planning. PMID- 30423283 TI - Deprescribing for older adults in Australia: factors influencing GPs. AB - Polypharmacy is increasing among older Australians, raising their risk of experiencing medication-related harm. As part of the prescribing continuum, deprescribing is a strategy proposed to reduce inappropriate polypharmacy. This study explored factors that influence deprescribing among Australian GPs using a new 21-item survey to measure GP attitudes and practices. The 85 GP responses indicated that many factors are supportive of deprescribing. GPs suggest that they are willing to explore their older patients' deprescribing preferences; they believe that they have enough information about the potential harms and benefits of medication to inform their deprescribing decisions and are confident to communicate this information to their patients. GPs did not consider their patients would interpret deprescribing as being 'given up on'. Limited time to review medications, poor communication between prescribers and a perception that other prescribers do not respect their role as overall coordinators of their older patients' medications were considered by respondents to be unsupportive of deprescribing. Overall, despite GPs reporting many supportive factors for deprescribing, the influence of unsupportive factors appears to remain strong, as deprescribing is not routinely considered in practice. PMID- 30423284 TI - MicroRNA profile comparison of testicular tissues derived from successful and unsuccessful microdissection testicular sperm extraction retrieval in non obstructive azoospermia patients. AB - Non-obstructive azoospermia (NOA) is the most severe clinical diagnosis in cases of male infertility. Although in some cases of NOA spermatozoa can be retrieved by microdissection testicular sperm extraction (micro-TESE) to fertilise eggs through intracytoplasmic sperm injection (ICSI), there remains a lack of potential biomarkers for non-invasive diagnosis before micro-TESE surgery. To determine predictive biomarkers for successful sperm retrieval before micro-TESE, the aim of this study was to explore whether microRNAs (miRNAs) were differentially expressed in testicular tissues in NOA patients in whom sperm retrieval had been successful (SSR) versus those in whom it had been unsuccessful (USR) using next-generation small RNA sequencing (RNA-Seq). In all, 180 miRNAs were identified with significantly altered expression levels between SSR and USR testicular tissues. Of these, the expression of 13 miRNAs was upregulated and that of 167 miRNAs was downregulated in the USR compared with SSR group. Unexpectedly, 86 testicular miRNAs were found to be completely absent in the USR group, but showed high expression in the SSR group, suggesting that these miRNAs may serve as biomarkers for micro-TESE and may also play an essential role in spermatogenesis. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that the miRNAs that differed significantly between the USR and SSR groups were involved in cell apoptosis, proliferation and differentiation, which are of considerable importance during spermatogenesis. In summary, this study identified a panel of miRNAs highly expressed in testicular tissues of SSR but not USR NOA patients, providing new insights into specific miRNAs that may play important roles in epigenetic regulation during spermatogenesis. The findings provide a basis for further elucidation of the regulatory role of miRNAs in spermatogenesis and clues to identifying useful biomarkers to predict residual spermatogenic loci in NOA patients during treatment with assisted reproductive technologies. PMID- 30423285 TI - Mitochondrial DNA replication is initiated at blastocyst formation in equine embryos. AB - Intracytoplasmic sperm injection is the technique of choice for equine IVF and, in a research setting, 18-36% of injected oocytes develop to blastocysts. However, blastocyst development in clinical programs is lower, presumably due to a combination of variable oocyte quality (e.g. from old mares), suboptimal culture conditions and marginal fertility of some stallions. Furthermore, mitochondrial constitution appears to be critical to developmental competence, and both maternal aging and in vitro embryo production (IVEP) negatively affect mitochondrial number and function in murine and bovine embryos. The present study examined the onset of mitochondrial (mt) DNA replication in equine embryos and investigated whether IVEP affects the timing of this important event, or the expression of genes required for mtDNA replication (i.e. mitochondrial transcription factor (TFAM), mtDNA polymerase gamma subunit B (mtPOLB) and single stranded DNA binding protein (SSB)). We also investigated whether developmental arrest was associated with low mtDNA copy number. mtDNA copy number increased (P < 0.01) between the early and expanded blastocyst stages both in vivo and in vitro, whereas the mtDNA : total DNA ratio was higher in in vitro-produced embryos (P = 0.041). Mitochondrial replication was preceded by an increase in TFAM but, unexpectedly, not mtPOLB or SSB expression. There was no association between embryonic arrest and lower mtDNA copy numbers. PMID- 30423286 TI - Reductions in quality of life and increased economic burden associated with mental disorders in an Australian adult sample. AB - Objective The aim of this study was to determine the effect of a broad range of common mental disorders and their comorbidity on health-related quality of life and functional disability.Methods In all, 2734 Australians aged >=18 years, recruited from the general community via Facebook during August-December 2014, completed an online survey assessing demographic characteristics, nine mental disorders, suicidal ideation and attempt. Outcome measures were health-related quality of life (assessed using the Assessment of Quality of Life (AQoL)-4D measure and functional disability (days out of role).Results Overall, 53.1% of the sample met criteria for at least one mental disorder. Participants with each of the 11 mental health problems had significantly lower mean AQoL-4D scores and significantly greater functional disability compared with not having the disorder (P<0.001). A monotonic decrease in quality of life and an increase in functional disability were observed with an increased total number of comorbid disorders (P<0.001). Accounting for disorder prevalence, annual economic burden for each mental disorder was estimated to be in the range of A$870 million-A$17 billion.Conclusions Mental disorders negatively affect health-related quality of life and functional disability, exacerbated by increased comorbidity. The economic burden to participants and employers estimated in this study is of concern, and highlights the importance of evidence-based treatment and prevention approaches.What is known about the topic? Mental disorders are associated with poorer health-related quality of life, increased functional disability and increased economic costs.What does this paper add? This paper furthers our understanding of the associations of nine mental disorders, suicidal ideation and suicide attempts with quality of life in an Australian setting, highlighting the considerable economic implications of these associations. Further, it reveals that comorbidity of mental disorders exacerbates reductions in quality of life and increased functional disability.What are the implications for practitioners? The economic burden associated with lost productivity and quality of life for individuals with mental disorders is considerable. Therefore, prioritising funding to prevention and treatment using evidence-based approaches will have significant effect in terms of economic productivity and personal well-being for individuals. PMID- 30423287 TI - Comparison of multi-walled carbon nanotube and nitrogen-doped multi-walled carbon nanotube effects on lung function and airway reactivity in rats. AB - Incorporation of multi-wall carbon nanotubes (MWCNT) into materials has raised concerns about their potential hazards to manufacturing workers. In animal models, airway inflammation and lung fibrosis follow aspiration, instillation, and inhalation exposures to MWCNT. However, the effects of MWCNT on pulmonary function, airway reactivity and airway epithelium function following inhalation exposure has not been studied. We investigated whether inhaled MWCNT affects lung resistance (RL) and dynamic compliance (Cdyn), reactivity to inhaled methacholine (MCh), epithelial regulation of airway reactivity to MCh in vitro, and airway epithelial ion transport. Male rats were exposed by whole body inhalation for 6 h to air or aerosolized MWCNT (0.5, 1 or 5 mg/m3) for one or nine days. Eighteen h after 1 d exposure to 5 mg/m3 MWCNT, basal RL was increased and basal Cdyn was decreased; changes did not persist for 7 d. Reactivity to MCh (RL) was increased and Cdyn responses were decreased at 18 h, but not 7 d after exposure to 1 and 5 mg/m3 MWCNT. The effects of i.t.-instilled MWCNT and nitrogen-doped MWCNT (N MWCNT) on pulmonary function and reactivity to MCh at doses comparable to deposition after inhalation of 5 mg/m3 at 1 d and 0.5, 1, and 5 mg/m3 MWCNT 9 d exposures were compared. Both nanoparticles increased airway reactivity (RL); N MWCNT did not affect Cdyn responses. Lung function and airway reactivity are altered following a single MWCNT inhalation and generally subside over time. Given i.t., MWCNT's and N-MWCNT's effects were comparable, but N-MWCNT evoke smaller changes in Cdyn responses. PMID- 30423288 TI - Activation of local bone RAS by maternal excessive glucocorticoid participated in the fetal programing of adult osteopenia induced by prenatal caffeine exposure. AB - This study was aimed to investigate whether and how prenatal caffeine exposure (PCE) could induce osteopenia in the adult offspring. Pregnant rats were treated with prenatal caffeine 12 mg/100 g body weight per day from pregnant day 9 to 20, while rat bone marrow mesenchymal stem cells (BMSCs) were treated with exogenous corticosterone during osteogenic induction. Shorter femur and primary ossification center was observed in the PCE offspring, as well as less bone trabecular and poor biomechanical intensity. Local gene expression of glucocorticoid receptor (GR) and angiotensin converting enzyme (ACE), as well as angiotensin 2 content, was found to be stimulated, while the expression of bone gamma-carboxyglutamate protein (BGLAP), alkaline phosphatase (ALP) and bone sialoprotein (BSP) was found to be suppressed, with hypomethylation of ACE promoter. Corticosterone (1250 nM) suppressed osteogenic differentiation of BMSCs and gene expression of BGLAP, ALP and BSP, which was attenuated by enalapril, while it stimulated ACE mRNA expression and induced hypomethylation of ACE promoter, which was attenuated by mifepristone. It indicated that PCE caused bone growth retardation and adult osteopenia in offspring, which might be triggered by the activation of local RAS induced by excessive maternal glucocorticoid, while the hypomethylation of ACE gene might be the key point of the sustained activation of the local RAS. PMID- 30423290 TI - CHAF1B Overexpression: A Brake for the Differentiation of Leukemia Cells. AB - In this issue of Cancer Cell, Volk et al. report that overexpression of CHAF1B displaces myeloid transcription factors from chromatin, and deletion of CHAF1B promotes differentiation of leukemia cells and suppresses leukemogenesis in a murine model, revealing a causal role of and an unexpected mechanism for CHAF1B overexpression in tumorigenesis. PMID- 30423289 TI - GPR37 and GPR37L1 differently interact with dopamine 2 receptors in live cells. AB - Receptor-receptor interactions are essential to fine tune receptor responses and new techniques enable closer characterization of the interactions between involved proteins directly in the plasma membrane. Fluorescence cross-correlation spectroscopy (FCCS), which analyses concurrent movement of bound molecules with single-molecule detection limit, was here used to, in live N2a cells, study interactions between the Parkinson's disease (PD) associated orphan receptor GPR37, its homologue GPR37L1, and the two splice variants of the dopamine 2 receptor (D2R). An interaction between GPR37 and both splice forms of D2R was detected. 4-phenylbutyrate (4-PBA), a neuroprotective chemical chaperone known to increase GPR37 expression at the cell surface, increased the fraction of interacting molecules. The interaction was also increased by pramipexole, a D2R agonist commonly used in the treatment of PD, indicating a possible clinically relevance. Cross-correlation, indicating interaction between GPR37L1 and the short isoform of D2R, was also detected. However, this interaction was not changed with 4-PBA or pramipexole treatment. Overall, these data provide further evidence that heteromeric GPR37-D2R exist and can be pharmacologically modulated, which is relevant for the treatment of PD. PMID- 30423291 TI - Metabolic Flexibility in Leukemia-Adapt or Die. AB - In this issue of Cancer Cell, Jones et al. demonstrate that LSCs are metabolically inflexible. LSCs rely on amino acid metabolism to fuel oxidative phosphorylation and cannot compensate with other fuel sources following amino acid depletion. Combined venetoclax and azacitidine reduces amino acid uptake, partly explaining the anti-LSC effects. PMID- 30423292 TI - Accurate and Reproducible Diagnosis of Canine Soft Tissue Sarcoma Using Mass Spectrometry: A Step in the Right Direction. AB - In this issue of Cancer Cell, Saudemont et al. describe the real-time ex vivo molecular diagnosis and histologic subtyping of canine soft tissue sarcomas using SpiderMass, a technology using water-assisted laser desorption/ionization mass spectrometry. In the future, SpiderMass has the potential to aid in diagnosis and intraoperative margin assessment. PMID- 30423293 TI - A CHAF1B-Dependent Molecular Switch in Hematopoiesis and Leukemia Pathogenesis. AB - CHAF1B is the p60 subunit of the chromatin assembly factor (CAF1) complex, which is responsible for assembly of histones H3.1/H4 heterodimers at the replication fork during S phase. Here we report that CHAF1B is required for normal hematopoiesis while its overexpression promotes leukemia. CHAF1B has a pro leukemia effect by binding chromatin at discrete sites and interfering with occupancy of transcription factors that promote myeloid differentiation, such as CEBPA. Reducing Chaf1b activity by either heterozygous deletion or overexpression of a CAF1 dominant negative allele is sufficient to suppress leukemogenesis in vivo without impairing normal hematopoiesis. PMID- 30423294 TI - Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells. AB - In this study we interrogated the metabolome of human acute myeloid leukemia (AML) stem cells to elucidate properties relevant to therapeutic intervention. We demonstrate that amino acid uptake, steady-state levels, and catabolism are all elevated in the leukemia stem cell (LSC) population. Furthermore, LSCs isolated from de novo AML patients are uniquely reliant on amino acid metabolism for oxidative phosphorylation and survival. Pharmacological inhibition of amino acid metabolism reduces oxidative phosphorylation and induces cell death. In contrast, LSCs obtained from relapsed AML patients are not reliant on amino acid metabolism due to their ability to compensate through increased fatty acid metabolism. These findings indicate that clinically relevant eradication of LSCs can be achieved with drugs that target LSC metabolic vulnerabilities. PMID- 30423296 TI - RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer. AB - Pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance and immunotherapeutic resistance. We discovered upregulation of receptor-interacting serine/threonine protein kinase 1 (RIP1) in tumor-associated macrophages (TAMs) in PDA. To study its role in oncogenic progression, we developed a selective small-molecule RIP1 inhibitor with high in vivo exposure. Targeting RIP1 reprogrammed TAMs toward an MHCIIhiTNFalpha+IFNgamma+ immunogenic phenotype in a STAT1-dependent manner. RIP1 inhibition in TAMs resulted in cytotoxic T cell activation and T helper cell differentiation toward a mixed Th1/Th17 phenotype, leading to tumor immunity in mice and in organotypic models of human PDA. Targeting RIP1 synergized with PD1-and inducible co-stimulator-based immunotherapies. Tumor-promoting effects of RIP1 were independent of its co association with RIP3. Collectively, our work describes RIP1 as a checkpoint kinase governing tumor immunity. PMID- 30423295 TI - JARID2 Functions as a Tumor Suppressor in Myeloid Neoplasms by Repressing Self Renewal in Hematopoietic Progenitor Cells. AB - How specific genetic lesions contribute to transformation of non-malignant myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDSs) to secondary acute myeloid leukemia (sAML) are poorly understood. JARID2 is lost by chromosomal deletions in a proportion of MPN/MDS cases that progress to sAML. In this study, genetic mouse models and patient-derived xenografts demonstrated that JARID2 acts as a tumor suppressor in chronic myeloid disorders. Genetic deletion of Jarid2 either reduced overall survival of animals with MPNs or drove transformation to sAML, depending on the timing and context of co-operating mutations. Mechanistically, JARID2 recruits PRC2 to epigenetically repress self renewal pathways in hematopoietic progenitor cells. These studies establish JARID2 as a bona fide hematopoietic tumor suppressor and highlight potential therapeutic targets. PMID- 30423297 TI - PEGylated IL-10 (Pegilodecakin) Induces Systemic Immune Activation, CD8+ T Cell Invigoration and Polyclonal T Cell Expansion in Cancer Patients. AB - Tumor-reactive T cell exhaustion prevents the success of immune therapies. Pegilodecakin activates intratumoral CD8+ T cells in mice and induces objective tumor responses in patients. Here we report that pegilodecakin induces hallmarks of CD8+ T cell immunity in cancer patients, including elevation of interferon gamma and GranzymeB, expansion and activation of intratumoral CD8+ T cells, and proliferation and expansion of LAG-3+ PD-1+ CD8+ T cells. On pegilodecakin, newly expanded T cell clones, undetectable at baseline, become 1%-10% of the total T cell repertoire in the blood. Elevation of interleukin-18, expansion of LAG-3+ PD 1+ T cells and novel T cell clones each correlated with objective tumor responses. Combined pegilodecakin with anti-PD-1 increased the expansion of LAG 3+ PD-1+ CD8+ T cells. PMID- 30423298 TI - KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism. AB - Our recent ERK1/2 inhibitor analyses in pancreatic ductal adenocarcinoma (PDAC) indicated ERK1/2-independent mechanisms maintaining MYC protein stability. To identify these mechanisms, we determined the signaling networks by which mutant KRAS regulates MYC. Acute KRAS suppression caused rapid proteasome-dependent loss of MYC protein, through both ERK1/2-dependent and -independent mechanisms. Surprisingly, MYC degradation was independent of PI3K-AKT-GSK3beta signaling and the E3 ligase FBWX7. We then established and applied a high-throughput screen for MYC protein degradation and performed a kinome-wide proteomics screen. We identified an ERK1/2-inhibition-induced feedforward mechanism dependent on EGFR and SRC, leading to ERK5 activation and phosphorylation of MYC at S62, preventing degradation. Concurrent inhibition of ERK1/2 and ERK5 disrupted this mechanism, synergistically causing loss of MYC and suppressing PDAC growth. PMID- 30423300 TI - beta2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer. PMID- 30423301 TI - CARM1 Is Essential for Myeloid Leukemogenesis but Dispensable for Normal Hematopoiesis. PMID- 30423302 TI - Rate and Determinants of Completing Neoadjuvant Chemotherapy in Medicare Beneficiaries With Bladder Cancer: A SEER-Medicare Analysis. AB - OBJECTIVE: To determine the rate and determinants of neoadjuvant chemotherapy noncompletion in patients with muscle-invasive bladder cancer. METHODS: Using Surveillance, Epidemiology, and End Results-Medicare data, we identified all patients who underwent cystectomy between 2008-2013 and received chemotherapy within 6 months. Of these, 594 patients received neoadjuvant chemotherapy, defined as the presence of a claim for chemotherapy within the 180 days preceding cystectomy. Our primary outcome was noncompletion of neoadjuvant chemotherapy. We determined regimen-specific cut points for noncompletion based on clinical trials and national guidelines. RESULTS: Over the study period, 174 of 594 patients (29%) did not complete neoadjuvant chemotherapy. Noncompleters and completers received a median interquartile range of 4.4 (3.0-8.0) and 10.0 (7.7-11.2) weeks of chemotherapy, respectively. A total of 391 (66%) patients received a cisplatin based regimen and 203 (34%) patients received an alternative regimen, with 27% and 33% not completing chemotherapy, respectively. After adjusting for covariates, age and geographic region were independently associated with failing to complete chemotherapy. CONCLUSION: Nearly 30% of patients who received neoadjuvant chemotherapy did not complete their regimen. Advanced age and nonclinical factors, such as practice patterns in certain geographic regions, may influence a patient's likelihood of successfully completing chemotherapy. PMID- 30423299 TI - The Osteogenic Niche Is a Calcium Reservoir of Bone Micrometastases and Confers Unexpected Therapeutic Vulnerability. AB - The fate of disseminated tumor cells is largely determined by microenvironment (ME) niche. The osteogenic niche promotes cancer cell proliferation and bone metastasis progression. We investigated the underlying mechanisms using pre clinical models and analyses of clinical data. We discovered that the osteogenic niche serves as a calcium (Ca) reservoir for cancer cells through gap junctions. Cancer cells cannot efficiently absorb Ca from ME, but depend on osteogenic cells to increase intracellular Ca concentration. The Ca signaling, together with previously identified mammalian target of rapamycin signaling, promotes bone metastasis progression. Interestingly, effective inhibition of these pathways can be achieved by danusertib, or a combination of everolimus and arsenic trioxide, which provide possibilities of eliminating bone micrometastases using clinically established drugs. PMID- 30423303 TI - Dermatofibrosarcoma Protuberans in a Male Infant. AB - Dermtofibrosarcoma protuberans is a rare cutaneous malignancy known to be locally aggressive. It is uncommonly seen in the pediatric population and can be difficult to distinguish from other benign skin lesions. We present a case of dermatofibrosarcoma protuberans of the penis in a 6-month-old child managed with surgical resection. This case highlights the challenges of diagnosis of genital lesions in children and the complexities of genitourinary reconstruction following surgical resection. PMID- 30423304 TI - Long noncoding RNA IGF2AS is acting as an epigenetic tumor suppressor in human prostate cancer. AB - OBJECTIVE: To assess the expression profile and functional mechanism of long non coding RNA (lncRNA) insulin growth factor 2 antisense, IGF2AS in human prostate cancer (PCa). METHODS: QRT-PCR was applied to assess IGF2AS expression in immortal PCa cell lines and in situ human PCa tumors. IGF2AS was overexpressed in VCaP and PC3 cells to assess its effect on PCa cell proliferation and invasion in vitro, and xenograft in vivo. The effect of IGF2AS overexpression on IGF2 was also assessed in PCa cells. Then, IGF2 was upregulated in IGF2AS-overexpressed PCa cells to assess the functional involvement of IGF2 in IGF2AS-mediated PCa cell development. RESULTS: IGF2AS was downregulated in both PCa cell lines and human PCa tumors. In VCaP and PC3 cells, lentivirus-induced IGF2AS overexpression suppressed cancer cell proliferation and invasion in vitro, and xenograft development in vivo. IGF2 was downregulated by IGF2AS overexpression. Conversely, IGF2 upregulation revered the suppressing function of IGF2AS on PCa proliferation and invasion. CONCLUSION: LncRNA IGF2AS is acting as an epigenetic tumor suppressor in human prostate cancer, likely through inverse regulation on IGF2. IGF2AS/IGF2 axis may be a future therapeutic target for PCa treatment. PMID- 30423305 TI - Analysis of phenotypic- and Estimated Breeding Values (EBV) to dissect the genetic architecture of complex traits in a Scots pine three-generation pedigree design. AB - In forest tree breeding, family-based Quantitative Trait Loci (QTL) studies are valuable as methods to dissect the complexity of a trait and as a source of candidate genes. In the field of conifer research, our study contributes to the evaluation of phenotypic and predicted breeding values for the identification of QTL linked to complex traits in a three-generation pedigree population in Scots pine (Pinus sylvestris L.). A total of 11 470 open pollinated F2-progeny trees established at three different locations, were measured for growth and adaptive traits. Breeding values were predicted for their 360 mothers, originating from a single cross of two grand-parents. A multilevel LASSO association analysis was conducted to detect QTL using genotypes of the mothers with the corresponding phenotypes and Estimated Breeding Values (EBV). Different levels of genotype-by environment (G * E) effects among sites at different years, were detected for survival and height. Moderate-to-low narrow sense heritabilities and EBV accuracies were found for all traits and all sites. We identified 18 AFLPs and 12 SNPs to be associated with QTL for one or more traits. 62 QTL were significant with percentages of variance explained ranging from 1.7 to 18.9%. In those cases where the same marker was associated to a phenotypic or an ebvQTL, the ebvQTL always explained higher proportion of the variance, maybe due to the more accurate nature of Estimated Breeding Values (EBV). Two SNP-QTL showed pleiotropic effects for traits related with hardiness, seed, cone and flower production. Furthermore, we detected several QTL with significant effects across multiple ages, which could be considered as strong candidate loci for early selection. The lack of reproducibility of some QTL detected across sites may be due to environmental heterogeneity reflected by the genotype- and QTL-by environment effects. PMID- 30423306 TI - Interaction between epidemic spread and collective behavior in scale-free networks with community structure. AB - Many real-world networks exhibit community structure: the connections within each community are dense, while connections between communities are sparser. Moreover, there is a common but non-negligible phenomenon, collective behaviors, during the outbreak of epidemics, are induced by the emergence of epidemics and in turn influence the process of epidemic spread. In this paper, we explore the interaction between epidemic spread and collective behavior in scale-free networks with community structure, by constructing a mathematical model that embeds community structure, behavioral evolution and epidemic transmission. In view of the differences among individuals' responses in different communities to epidemics, we use nonidentical functions to describe the inherent dynamics of individuals. In practice, with the progress of epidemics, individual behaviors in different communities may tend to cluster synchronization, which is indicated by the analysis of our model. By using comparison principle and Gersgorin theorem, we investigate the epidemic threshold of the model. By constructing an appropriate Lyapunov function, we present the stability analysis of behavioral evolution and epidemic dynamics. Some numerical simulations are performed to illustrate and complement our theoretical results. It is expected that our work can deepen the understanding of interaction between cluster synchronization and epidemic dynamics in scale-free community networks. PMID- 30423307 TI - Human papillomavirus infection is not involved in esophageal verrucous carcinoma. AB - Verrucous carcinoma of the esophagus (VCE) is a rare variant of squamous cell cancer, with a puzzling clinical, etiological, and molecular profile. The etiological involvement of human papillomavirus (HPV) in the cancer's natural history is controversial. This study considers nine cases of VCE, focusing on patients' clinical history before surgery, histological phenotype, immunophenotype (EGFR, E-cadherin, cyclin D1, p16, and p53 expression), HPV infection, and TP53 gene mutational status (exons 5-8). Using three different molecular test methods, not one of these cases of VCE featured HPV infection. The only case with synchronous nodal metastasis was characterized by a TP53 missense point mutation in association with high EGFR and low E-cadherin expression levels. In conclusion, HPV infection is probably not involved VCE, while TP53 gene mutation, EGFR overexpression, and E-cadherin loss might fuel the tumor's proliferation and lend it a metastatic potential. PMID- 30423308 TI - A meta-analysis of dysregulated miRNAs in coronary heart disease. AB - AIMS: To combine the results of dysregulated miRNAs in individual coronary heart disease (CHD) studies and to identify potential miRNA biomarkers. MAIN METHODS: MiRNA profiling studies of CHD were extracted from Pubmed, Embase, Web of Science and China National Knowledge Internet (CNKI) databases if they met the inclusion criteria. The meta-analysis was conducted using a random effects model to identify the effect of each multiple-reported miRNA. We also performed subgroup analysis according to miRNA detecting methods, tissues and subtypes of CHD. Sensitivity analysis was performed on the sample size. Bioinformatic analysis was performed to identify the potential biomatic functions. All results were represented as log10 odds ratios (logORs). KEY FINDINGS: A total of 239 miRNAs were reported to be dysregulated in all 25 studies analyzed herein, and meta analysis identified 48 statistically significant miRNAs. Bioinformatic analysis showed they were closely related with CHD. The most reported up-regulated miRNA was miR-122-5p (logOR: 2.7924, P < 0.001). A total of 7, 6, 4 and 9 miRNAs were detected to be differentially expressed in myocardial infarction (MI), unstable angia (UA), stable angina (SA) and pre-CHD subjects, respectively. 32 miRNAs were dysregulated in blood sample. The dysregulation of miR-133a-3p in whole blood and plasma/serum was contrary. In sensitivity analysis, 37 out of 48 (77.08%) miRNAs were consistently dysregulated. SIGNIFICANCE: A total of 48 dysregulated miRNAs were confirmed in this meta-analysis. MiR-122-5p and miR-133a-3p may be valuable biomarkers for CHD. PMID- 30423310 TI - Thank you to Klavs Berzins, Editor Acta Tropica. PMID- 30423309 TI - Are WHO recommendations to perform two consecutive semen analyses for reliable diagnosis of male infertility still valid? AB - PURPOSE: To evaluate whether a second semen analysis as suggested by the World Health Organization (WHO) Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction improves diagnostic reliability in the evaluation of male infertility. MATERIALS AND METHODS: Analysis of 5132 semen samples from 2566 men receiving at least two consecutive semen analyses at a University Fertility Center. Reproducibility and correlation between first and second analysis for sperm concentration, motility, and morphology according to WHO criteria as well as total motile sperm count (TMSC) were evaluated. RESULTS: Altogether, 51.2% of the second analyses confirmed the initial findings according to WHO criteria; and 60% when applying TMSC criteria. A total of 27% of second semen analysis after normozoospermia in the initial analysis were pathological. Following a first pathological semen analysis, 23% of the second analyses were normal and 77% pathological. The coefficient of variation (CVw) ranged from 0.23 to 0.60. Spearman's correlation coefficient was high for sperm concentration (rs = 0.84), as well as normal morphology (rs = 0.80), and lower for progressive motility (rs = 0.57). The discriminating capacity of each semen parameter to distinguish between men with a normal and men with a pathological second semen analysis was rather limited, with an area under the ROC curve (AUC) of 0.72 to 0.79. CONCLUSION: In accordance with WHO recommendations, two consecutive semen analysis should be performed. PMID- 30423311 TI - Epidemiological and genetic characteristics of porcine reproductive and respiratory syndrome virus circulating in central and South China in 2016. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is a leading cause of reproductive failure in sows and respiratory disorders in all ages of pigs; PRRSV is one of the most serious threats to the global pig industry. Continuously monitoring the epidemiological and genetic characteristics of PRRSV epidemic strains is beneficial for PRRSV prevention and control. In this study, we detected PRRSV from different types of porcine samples collected from 257 pig farms in Central (Henan Province) and South China (Fujian, Guangdong, and Guangxi Provinces) in 2016. Of the 1047 samples collected, 530 (50.62%) were positive for PRRSV by RT-PCR. The positive rates of virus detection for each of the geographical regions were higher than 44.25%. These findings suggest that the prevalence of PRRSV continues to be a major problem for the pig industry in China. Phylogenetic analysis showed that PRRSV2 was still the prevalent species in Central and South China, and highly pathogenic PRRSV (HP-PRRSV) was the predominate PRRSV type. However, the emergence and circulation of novel PRRSV strains such as the GM2-like strains and NADC30-like strains is worrisome and should receive more attention. In terms of different geographical regions, HP PRRSV strains were the predominate PRRSV strains circulating in South China, while both HP-PRRSV strains and NADC30-like strains appeared to be the predominate PRRSV strains in Central China (Henan Province). These findings demonstrate that PRRSV types circulating in different regions in China are some different. In addition, a number of amino acid mutation types including amino acid changes and deletions were observed in both the GP5 and Nsp2 proteins. Our study provides important information on the epidemiological and genetic characteristics of PRRSV strains currently circulating in China. PMID- 30423312 TI - Glycomics in rare diseases: from diagnosis to mechanism. AB - The National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP) studies rare genetic disorders not only to achieve diagnoses, but to understand human biology. To ascertain the contribution of protein glycosylation to rare diseases, the NIH UDP used mass spectrometry to agnostically identify abnormalities of N-linked and O-linked glycans in plasma and free oligosaccharides in the urine of 207 patients. 60% of UDP patients had a glycome profile that deviated from control values in at least 1 fluid. Additional evaluation of the fibroblast glycome in 66 patients with abnormalities in plasma and/or urine revealed a consistent glycome phenotype in 83% of these cases. Many of these patients may have secondary glycosylation defects, since it is unlikely that they all have congenital disorders of glycosylation (CDGs). In fact, whole exome sequencing revealed only a few patients with CDGs, along with several others having disorders indirectly altering glycosylation. In summary, we describe a biochemical phenotyping screen to identify defects in protein glycosylation that can elucidate mechanisms of disease among NIH UDP patients. PMID- 30423313 TI - Isoform-specific therapeutic control of sulfonation in humans. AB - The activities of hundreds, perhaps thousands, of metabolites are regulated by human cytosolic sulfotransferases (SULTs) - a 13-member family of disease relevant enzymes that catalyze transfer of the sulfuryl moiety (-SO3) from PAPS (3'-phosphoadenosine 5'-phosphosulfonate) to the hydroxyls and amines of acceptors. SULTs harbor two independent allosteric sites, one of which, the focus of this work, binds non-steroidal anti-inflammatory drugs (NSAIDs). The structure of the first NSAID-binding site - that of SULT1A1 - was elucidated recently and homology modeling suggest that variants of the site are present in all SULT isoforms. The objective of the current study was to assess whether the NSAID binding site can be used to regulate sulfuryl transfer in humans in an isoform specific manner. Mefenamic acid (Mef) is a potent (Ki 27 nM) NSAID-inhibitor of SULT1A1 - the predominant SULT isoform in small intestine and liver. Acetaminophen (APAP), a SULT1A1 specific substrate, is extensively sulfonated in humans. Dehydroepiandrosterone (DHEA) is specific for SULT2A1, which we show here is insensitive to Mef inhibition. APAP and DHEA sulfonates are readily quantified in urine and thus the effects of Mef on APAP and DHEA sulfonation could be studied non-invasively. Compounds were given orally in a single therapeutic dose to a healthy, adult male human with a typical APAP-metabolite profile. Mef profoundly decreased APAP sulfonation during first pass metabolism and substantially decreased systemic APAP sulfonation without influencing DHEA sulfonation; thus, it appears the NSAID site can be used to control sulfonation in humans in a SULT-isoform specific manner. PMID- 30423314 TI - Lactic acid induced microRNA-744 enhances motility of SiHa cervical cancer cells through targeting ARHGAP5. AB - High-risk (hr) human papillomaviruses (HPV) infection and integration has caused the majority of cervical cancer, of which E6 and E7 oncogenes are invariably retained and expressed to immortalize cells probably via affecting cell migration and invasion, and tumor metastasis. However, the underlying mechanism that mediates the procedure such as motility of cervical cancer cells within the tumor microenvironment is not well understood. Herein, we examined one possible factor extracellular lactic acid, an end up chemical in glycolytic tumor cells, on the motility in HPV16 positive SiHa cells. The results showed that lactic acid enhanced cell migration and invasion behavior via stimulating the expression of miR-744. ARHGAP5 was confirmed to be a target of miR-744, and silencing ARHGAP5 exhibited an inhibiting effect on cell migration and invasion as that observed by suppressing miR-744. In addition, lactic acid down-regulated E6 and E7 protein levels, and overexpression of either miR-744 or ARHGAP5 could also reduce E6 and E7 levels. Overall, our findings suggest that the miR-774/ARHGAP5 axis may provide a vital role in triggering lactic acid-induced migration and invasion in SiHa cells, regardless of the diminished effect due to the partial inhibition of E6 and E7 expression. PMID- 30423315 TI - Genome-wide DNA methylation assessment of 'BRCA1-like' early-onset breast cancer: Data from the Australian Breast Cancer Family Registry. AB - Breast cancers arising in women carrying a germline mutation in BRCA1 are typically high-grade, early-onset and have distinct morphological features (BRCA1 like). However, the majority of early-onset breast cancers of this morphological type are not associated with germline BRCA1 mutations or constitutional BRCA1 promoter methylation. We aimed to assess DNA methylation across the genome for associations with the "BRCA1-like" morphology. Genome-wide methylation in blood derived DNA was measured using the Infinium HumanMethylation450K BeadChip assay for women under the age of 40 years participating in the Australian Breast Cancer Family Study (ABCFS) diagnosed with: i) BRCA1-like breast cancer (n = 30); and ii) breast cancer without BRCA1-like morphological features (non BRCA1-like; n = 30), and age-matched unaffected women (controls; n = 30). Corresponding tumour derived DNA from 43 of the affected women was also assessed. Methylation of blood derived DNA was found to be elevated across 17 consecutive marks in the BRCA1 promoter region and decreased at several other genomic regions (including TWIST2 and CTBP1) for 7 women (23%) diagnosed with BRCA1-like breast cancer compared with women in the other groups. Corresponding tumour-derived DNA available from 5 of these 7 women had elevated methylation within the BRCA1 and SPHK2 promoter region and decreased methylation within the ADAP1, IGF2BP3 and SPATA13 promoter region when compared with the other breast tumours. These methylation marks could be biomarkers of risk for BRCA1-like breast cancer, and could be responsible in part for their distinctive morphological features and biology. As such, they may assist with prevention and targeted therapies for this cancer subtype. PMID- 30423316 TI - Co-localization of mu-opioid and dopamine D1 receptors in the medial preoptic area and bed nucleus of the stria terminalis across seasonal states in male European starlings. AB - In seasonally breeding animals, changes in photoperiod and sex-steroid hormones may modify sexual behavior in part by altering the activity of neuromodulators, including opioids and dopamine. In rats and birds, activation of mu-opioid receptors (MOR) and dopamine D1 receptors in the medial preoptic area (mPOA) often have opposing effects on sexual behavior, yet mechanisms by which the mPOA integrates these opposing effects to modulate behavior remain unknown. Here, we used male European starlings (Sturnus vulgaris) to provide insight into the hypothesis that MOR and D1 receptors modify sexual behavior seasonally by altering activity in the same neurons in the mPOA. To do this, using fluorescent immunohistochemistry, we examined the extent to which MOR and D1 receptors co localize in mPOA neurons and the degree to which photoperiod and the sex-steroid hormone testosterone alter co-localization. We found that MOR and D1 receptors co localize throughout the mPOA and the bed nucleus of the stria terminalis, a region also implicated in the control of sexual behavior. Numbers of single and co-labeled MOR and D1 receptor labeled cells were higher in the rostral mPOA in photosensitive males (a condition observed just prior to the breeding season) compared to photosensitive males treated with testosterone (breeding season condition). In the caudal mPOA co-localization of MOR and D1 receptors was highest in photosensitive males compared to photorefractory males (a post breeding season condition). Seasonal shifts in the degree to which neurons in the mPOA integrate signaling from opioids and dopamine may underlie seasonal changes in the production of sexual behavior. PMID- 30423317 TI - Morphomechanic phenotypic variability of sarcomeric cardiomyopathies: A multifactorial polygenic perspective. AB - Morphology underlies subdivision of the primary/heritable sarcomeric cardiomyopathies (CMs) into hypertrophic (HCM) and dilated (DCM). Next-generation DNA-sequencing (NGS) has identified important disease-variants, improving CM diagnosis, management, genetic screening, and prognosis. Although monogenic (Mendelian) analyses directly point at downstream studies, they disregard coexisting genomic variations and gene-by-gene interactions molding detailed CM phenotypes. In-place of polygenic models, in accounting for observed defective genotype-phenotype correlations, fuzzy concepts having gradations of significance and unsharp domain-boundaries are invoked, including pleiotropy, genetic heterogeneity, incomplete penetrance, and variable expressivity. HCM and DCM undoubtedly entail cooperativity of unidentified/elusive causative genomic variants. Modern genomics can exploit comprehensive electronic/digital health records, facilitating consideration of multifactorial variant-models. Genome-wide association studies entailing high-fidelity solid-state catheterization, multimodal-imaging, molecular cardiology, systems biology and bioinformatics, will decipher accurate genotype-phenotype correlations and identify novel therapeutic-targets, fostering personalized medicine/cardiology. This review surveys successes and challenges of genetic/genomic approaches to CMs, and their impact on current and future clinical care. PMID- 30423318 TI - Inhibition of TRPC1 prevents cardiac hypertrophy via NF-kappaB signaling pathway in human pluripotent stem cell-derived cardiomyocytes. AB - Cardiac hypertrophy is an adaptive response against increased workload featuring by an increase in left ventricular mass and a thickening left ventricle wall. Here, we showed the expression of transient receptor potential canonical 1 (TRPC1) is higher in hearts of patients with hypertrophic cardiomyopathy (HCM) or heart failure (HF) than that of normal hearts. To better understand the mechanisms of TRPC1 in regulating cellular hypertrophy of human-based cardiomyocytes, we generated human pluripotent stem cell lines of TRPC1 knockout by CRISPR/Cas9. We demonstrated that knockout of TRPC1 significantly attenuated cardiomyocyte hypertrophy phenotype induced by phorbol 12-myristate 13-acetate, which was associated with abnormal activation of NF-kappaB. In contrast, overexpression of TRPC1 induced cardiomyocyte hypertrophy, which can be reversed by inhibition of NF-kappaB. Taken together, we established a stable human-based cardiomyocyte hypertrophy model and highlighted molecular mechanisms underlying TRPC1-mediated hypertrophy, aiding the development of therapeutic drugs for HCM and HF by targeting TRPC1. PMID- 30423320 TI - Hormonal contraception, breastfeeding, and bedside advocacy: the case for patient centered care. AB - Postpartum contraceptive decision-making is complex, and recommendations may be influenced by breastfeeding intentions. While biologically plausible, concerns about the adverse impact of hormonal contraception on breast milk production have not been supported by the clinical evidence to date. However, the data have limitations. Which can lead providers with different priorities around contraception and breastfeeding to interpret the data in a way that advances their personal priorities. Discrepancies in interpretations can lead to divergent recommendations for individual women, and may cause conflict. Furthermore, providers must recognize that decision-making about contraception and breastfeeding takes place in complex cultural, historical, and socioeconomic contexts. Implicit bias may influence a provider's counseling. Unrecognized biases toward one patient or another, or one practice or another, may influence a provider's counseling. It is crucial for providers to strive to recognize their own biases. Providers need to respectfully recognize each patient's values and preferences regarding hormonal contraception and breastfeeding. Developing a patient-centered decision tool or implementing patient-centered interview techniques specifically around breastfeeding and contraception could help to minimize provider-driven variability in care. PMID- 30423319 TI - Apatinib exerts anti-tumor activity to non-Hodgkin lymphoma by inhibition of the Ras pathway. AB - Apatinib is a tyrosine kinase inhibitor that selectively targets vascular endothelial growth factor receptor-2 (VEGFR-2). Although apatinib has shown promising anti-tumor activity against several types of tumor, its role and underlying mechanism against non-Hodgkin lymphoma (NHL) remain to be explored. Here, we report that apatinib dramatically inhibited in vitro the proliferation of various human NHL cell lines, including Burkitt lymphoma (BL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL), in a dose-dependent manner. Moreover, administration of apatinib markedly delayed tumor growth in vivo in a xenograft mouse model derived from human DLBCL OCI-ly3 cells, in association with significantly prolonged survival of tumor-bearing mice. Mechanistically, apatinib suppressed activation of VEGFR2 (manifested by reduced VEGFR2 phosphorylation), accompanied by inhibition of the Ras pathway (reflected by down-regulation Ras, Raf, pMEK1/2, pERK1/2) in OCI-ly1 (GCB subtype of DLBCL) and SU-DHL2 (ABC subtype of DLBCL) cells. Of note, apatinib sharply impaired angiogenesis in vivo in tumor tissues. Together, these results indicate that apatinib displays a marked cytotoxic activity against various types of NHL cells (including BL, MCL, and GCB- or ABC-DLBCL) both in vitro and in vivo. They also suggest that anti-NHL activity of apatinib might be associated with inhibition of tumor cell growth and induction of apoptosis as well as anti-angiogenesis by targeting VEGFR2 and its downstream Ras/Raf/MEK/ERK pathway. PMID- 30423321 TI - Analysis of butterfly reproductive proteins using capillary electrophoresis and mass spectrometry. AB - A method for analysis of proteins from spermatophores transferred from male to female Pieris napi butterflies during mating has been developed. The proteins were solubilized from the dissected spermatophores using different solubilization agents (water, methanol, acetonitrile and hexafluoroisopropanol). Capillary electrophoresis (CE) analysis was performed using an acidic background electrolyte containing a fluorosurfactant to avoid protein-wall adsorption, and to increase separation performance. The samples were also analyzed with matrix assisted laser desorption/ionization mass spectrometry (MALDI-MS), in a lower m/z range (1000-6000) and a higher m/z range (6000-12000). Solubilization with different solvents and the use of alternative matrices gave partly complementary profiles. PMID- 30423322 TI - Corticotropin hormone assay interference: A case series. AB - Measuring the plasma corticotropin (ACTH) concentration is an important step in determining the underlying cause in patients with hypercortisolemia. Interfering substances in immunoassays can lead to erroneous results impacting clinical management. We describe a case series of 12 patients, the majority of whom were being investigated for possible Cushing's syndrome and in whom inconsistencies between the clinical picture and biochemical testing raised concerns of assay interference. ACTH assay interference resulted in falsely elevated ACTH concentrations using the Siemens Immulite assay and consequently led to additional unnecessary testing. Communication between physician and laboratory as well as appropriate investigation (including sample dilution, use of blocking antibodies and testing on an alternate platform) resulted in assay interference identification. Recognition of biochemical results which are clinically discrepant remains an essential step in patient assessment. PMID- 30423323 TI - Clinical outcomes after more conservative management of patent ductus arteriosus in preterm infants. AB - OBJECTIVE: Management of patent ductus arteriosus is still controversial. This study aimed to describe the impact of a more conservative approach on treatment rates and on main outcomes of prematurity, especially in preterm infants with <26 weeks of gestation. METHOD: Clinical charts review of infants <=30 weeks with patent ductus arteriosus between 2009 and 2016 at two centers. In 2011, the authors changed patent ductus arteriosus management: in first period (2009-2011), patients who failed medical treatment underwent surgical closure; in second period (2012-2016), only those with cardiopulmonary compromise underwent surgical ligation. Medical treatment, surgical closure, mortality, and survival-without morbidity were compared. RESULTS: This study included 188 patients (27+/-2 weeks, 973+/-272 grams); 63 in P1 and 125 in P2. In P2, significantly lower rates of medical treatment (85.7% P1 versus 56% P2, p<0.001) and surgical closure (34.5% P1 versus 16.1% P2, p<0.001) were observed. No differences were found in chronic lung disease (28.8% versus 13.9%, p=0.056), severe retinopathy of prematurity (7.5% versus 11.8%, p=0.403), necrotizing enterocolitis (15.5% versus 6.9%, p=0.071), severe intraventricular hemorrhage (25.4% versus 18.4%, p=0.264), mortality (17.5% versus 15.2%, p=0.690) or survival-without-morbidity adjusted OR=1.10 (95% CI: 0.55-2.22); p=0.783. In P2, 24.5% patients were discharged with patent ductus arteriosus. The subgroup born between 23 and 26 weeks (n=82) showed significant differences: lower incidence of chronic lung disease (50% versus 19.6%, p=0.019) and more survival-without-morbidity (20% versus 45.6%, p=0.028) were found. CONCLUSION: A conservative approach in preterm infants with patent ductus arteriosus can avoid medical and surgical treatments, without a significant impact in survival-without-morbidity. However, two-thirds of preterm infants under 26 weeks are still treated. PMID- 30423324 TI - Enhanced expression of the Epithelial Sodium Channel in neutrophils from hypertensive patients. AB - Hypertension (HTN), i.e. abnormally high blood pressure, is a major risk factor for heart attack, stroke, and kidney failure. The Epithelial Sodium Channel (ENaC), one of the main transporters regulates blood pressure by tightly controlling the sodium reabsorption along the nephron. Recently, we have shown an alpha-ENaC overexpression in platelets from hypertensive patients compared to platelets from normotensive subjects, suggesting it makes a contribution to the activation state of platelets and the physiopathology of hypertension. However, the involvement of the alpha-ENaC localized in neutrophils to this disease remains unknown. Neutrophils are the first leukocytes to be recruited to an inflammatory site and are equipped with a strong ability to eliminate intra- or extracellular pathogens using reactive oxygen species or antibacterial proteins contained in their granules. Using the Western blotting (Wb), flow cytometry, and qRT-PCR approaches; we determined alpha-ENaC neutrophil overexpression at the protein and messenger RNA (mRNA) levels. By confocal and cytometry analysis, we determined the alpha-ENaC distribution and the heterogeneity of HTN neutrophils population, respectively. Immunoprecipitation and Wb assays demonstrated the presence of both alpha-ENaC and caveolin-1 phosphorylated forms, compared with neutrophils from healthy individuals. Although neutrophils from hypertensive subjects circulating in an activated state were exhibiting important oxidative stress and modifications registered by confocal, atomic force, and scanning electron microscope, they conserved their defense capabilities. The features described above for neutrophils from hypertensive patients could be attributed to alpha-ENaC overexpression, as its drug inhibition diminished their activation state modulating the actin cytoskeleton reorganization triggered during the activation process. PMID- 30423325 TI - Sequence and length optimization of membrane active coiled coils for triggered liposome release. AB - Defined and tunable peptide-lipid membrane interactions that trigger the release of liposome encapsulated drugs may offer a route to improve the efficiency and specificity of liposome-based drug delivery systems, but this require means to tailor the performance of the membrane active peptides. In this paper, the membrane activity of a de novo designed coiled coil peptide has been optimized with respect to sequence and size to improve release efficiency of liposome encapsulated cargo. The peptides were only membrane active when covalently conjugated to the liposomes. Two amino acid substitutions were made to enhance the amphipathic characteristics of the peptide, which increased the release by a factor of five at 1 MUM. Moreover, the effect of peptide length was investigated by varying the number of heptad repeats from 2 to 5, yielding the peptides KVC2 KVC5. The shortest peptide (KVC2) showed the least interaction with the membrane and proved less efficient than the longer peptides in releasing the liposomal cargo. The peptide with three heptads (KVC3) caused liposome aggregation whereas KVC4 proved to effectively release the liposomal cargo without causing aggregation. The longest peptide (KVC5) demonstrated the most defined alpha helical secondary structure and the highest liposome surface concentration but showed slower release kinetics than KVC4. The four heptad peptide KVC4 consequently displayed optimal properties for triggering the release and is an interesting candidate for further development of bioresponsive and tunable liposomal drug delivery systems. PMID- 30423326 TI - Structural characterization of the L0 cytoplasmic loop of human multidrug resistance protein 6 (MRP6). AB - ABCC6 is a member of the C subfamily of ATP-binding cassette transporters whose mutations are correlated to Pseudoxanthoma elasticum, an autosomal recessive, progressive disorder characterized by ectopic mineralization and fragmentation of elastic fibers. Structural studies of the entire protein have been hindered by its large size, membrane association, and domain complexity. Studies previously performed have contributed to shed light on the structure and function of the nucleotide binding domains and of the N-terminal region. Here we report the expression in E. coli of the polypeptide E205-G279 contained in the cytoplasmic L0 loop. For the first time structural studies in solution were performed. Far-UV CD spectra showed that L0 is structured, assuming predominantly alpha-helix in TFE solution and turns in phosphate buffer. Fluorescence spectra indicated some flexibility of the regions containing aromatic residues. 1H NMR spectroscopy identified three helical regions separated by more flexible regions. PMID- 30423327 TI - Smad7 ameliorates TGFbeta-mediated skin inflammation and associated wound healing defects but not the susceptibility to experimental skin carcinogenesis. AB - We assessed roles of Smad7 in skin inflammation and wound healing using genetic and pharmacological approaches. In K5.TGFbeta1/K5.Smad7 bigenic (double transgenic) mice, Smad7 transgene expression reversed TGFbeta1 transgene-induced inflammation, fibrosis and subsequent epidermal hyperplasia, and molecularly abolished TGFbeta and NF-kappaB activation. Next, we produced recombinant human Smad7 protein with a Tat-tag (Tat-Smad7) that rapidly enters cells. Subcutaneous injection of Tat-Smad7 attenuated infiltration of F4/80+ and CD11b+ leukocytes and alphaSMA+ fibroblasts prior to attenuating epidermal hyperplasia in K5.TGFbeta1 skin. Further, topically applied Tat-Smad7 on K5.TGFbeta1 skin wounds accelerated wound closure with improved re-epithelialization and reductions in inflammation and fibrotic response. A short treatment with Tat-Smad7 was also sufficient to reduce TGFbeta and NF-kappaB signaling in K5.TGFbeta1 skin and wounds. Relevant to clinic, we found that human diabetic wounds had elevated TGFbeta and NF-kappaB signaling compared to normal skin. To assess the oncogenic risk of a potential Smad7-based therapy, we exposed K5.Smad7 skin to chemical carcinogenesis and found reduced myeloid leukocyte infiltration in tumors but not accelerated carcinogenesis compared to wildtype littermates. Our study suggests the feasibility of using exogenous Smad7 below an oncogenic level to alleviate skin inflammation and wound healing defects associated with excessive activation of TGFbeta and NF-kappaB. PMID- 30423328 TI - Biological effects of IL-26 on T cell-mediated skin inflammation including psoriasis. AB - Psoriasis is a chronic inflammatory skin disease mainly characterized by epidermal hyperplasia, scaling and erythema, with Th17 cells having a role in its pathogenesis. Although IL-26, known as a Th17 cytokine, is upregulated in psoriatic skin lesions, its precise role is unclear. We now investigate the role of IL-26 in the imiquimod (IMQ)-induced psoriasis-like murine model using human IL-26 transgenic (hIL-26Tg) mice. Erythema symptoms induced by daily applications of IMQ dramatically increased in hIL-26Tg mice as compared with controls. Vascularization and immune cell infiltration were prominent in skin lesions of hIL-26Tg mice. Levels of fibroblast growth factor (FGF)-1, FGF2 and FGF7 were significantly upregulated in the skin lesions of IMQ-treated hIL-26Tg mice and psoriasis patients. In vitro analysis demonstrated that FGF1, FGF2 and FGF7 levels were elevated in human keratinocytes and vascular endothelial cells following IL-26 stimulation. Furthermore, IL-26 directly acted on vascular endothelial cells, promoting proliferation and tube formation, possibly through Akt, ERK and NF-kB pathways. Moreover, similar effects of IL-26 were observed in the murine contact hypersensitivity model, indicating that these effects are not restricted to psoriasis. Altogether, our data indicate that IL-26 may be a promising therapeutic target in T cell-mediated skin inflammation including psoriasis. PMID- 30423329 TI - Resident memory and recirculating memory T cells cooperate to maintain disease in a mouse model of vitiligo. AB - Tissue resident memory T cells (Trm) form in the skin in vitiligo and persist to maintain disease, as white spots often recur rapidly after discontinuing therapy. We and others have recently described melanocyte-specific autoreactive Trm in vitiligo lesions. Here, we characterize the functional relationship between Trm and recirculating memory T cells (Tcm) in our vitiligo mouse model. We found that both Trm and Tcm sensed autoantigen in the skin long after stabilization of disease, producing IFNgamma, CXCL9, and CXCL10. Blockade of Tcm recruitment to the skin with FTY720 or depletion of Tcm with low dose Thy1.1 antibody reversed disease, indicating that Trm cooperate with Tcm to maintain disease. Taken together, our data provide characterization of skin memory T cells in vitiligo, demonstrate that Trm and Tcm work together during disease, and indicate that targeting their survival or function may provide novel, durable treatment options for patients. PMID- 30423331 TI - Clinical Outcomes of Mitral Valve Reoperations in the United States (Commentary). PMID- 30423330 TI - Risk of second primary cancer in survivors of in situ melanoma. AB - Invasive melanoma survivors have an increased risk of developing second primary cancers, however, similar risks associated with in situ melanoma haven't been established. We evaluated 43,829 first primary in situ melanoma survivors diagnosed from 1982-2012 in Queensland, Australia. Risk of second non-melanoma primary cancers was estimated from standardized incidence ratios with 95% confidence intervals. A total of 4,917 (11.3%) in situ melanoma survivors developed a second primary cancer. No net increased risk compared with the general population was found. In those aged <50 years, risk was increased by 13% for all cancers combined. In situ melanoma survivors had significantly increased risks of developing lip, brain, and thyroid cancers, and decreased risks of head and neck, lung, bladder, and colorectal cancers. Male in situ melanoma survivors had a significantly increased risk of prostate cancer; female survivors had an increased risk of thyroid cancer and lymphoid leukaemia, and a decreased risk of gynaecological cancers. Findings indicate in situ melanoma may predict the diagnosis of certain second primary cancers. This altered risk may be due to biological, behavioural or genetic factors, or increased medical surveillance, and requires further investigation, particularly among people aged under 50 years. PMID- 30423332 TI - Hospital Distribution and Patient Travel Patterns for Congenital Heart Surgery in the United States (Commentary). PMID- 30423333 TI - Perioperative Exposure to Suspect Neurotoxicants from Medical Devices in Newborns with CHD (Commentary). PMID- 30423335 TI - The Society of Thoracic Surgeons Adult Cardiac Surgery Database: 2019 Update on Outcomes and Quality. AB - The Society of Thoracic Surgeons Adult Cardiac Surgery Database is one of the most mature, comprehensive and respected clinical data registries in health care. Through nearly three decades of growth and refinement, it is widely recognized for accurately benchmarking risk-adjusted outcomes in cardiac surgery and serves as the foundation for all quality measurement and improvement activities of the Society of Thoracic Surgeons. This is the fourth in a series of annual reports that provides updated national outcomes, volume trends and database-related developments in quality measurement and performance improvement. PMID- 30423334 TI - Reintervention after Heller Myotomy for Achalasia: Is It Inevitable? AB - BACKGROUND: Few studies of reintervention after Heller myotomy for achalasia set patients' expectations, assist therapeutic decision-making, and direct follow-up. Therefore, we investigated the frequency and type of symptoms and reinterventions post-myotomy based on achalasia type. METHODS: From 1/2006-3/2013, 248 patients who had preoperative high-resolution manometry and a timed barium esophagram (TBE) underwent Heller myotomy, 62 (25%) for type I, 162 (65%) type II, and 24 (10%) type III achalasia. Postoperative surveillance, including TBE, was performed at 8 weeks, then annually. Median follow-up was 36 months. Endpoints were all symptom types and modes of reintervention, endoscopic or surgical. Reintervention was based on both symptoms and objective TBE measurements. RESULTS: Eventually most patients (169/218; 69%) developed at least 1 symptom post-myotomy. Fifty patients underwent 85 reinterventions, 41 endoscopic only, 4 surgical only, and 5 both. Five-year freedom from reintervention was 62% for type I, 74% type II, and 87% type III, most occurring within 6 months, although later in type III. At 5 years, number of reinterventions per 100 patients was 72 for type I, 51 for type II, and 13 for type III. After each reintervention, there was approximately a 50% chance of another within 2 years. CONCLUSIONS: Patients' expectations when undergoing Heller myotomy for achalasia must be that symptoms will only be palliated, and those who have worse esophageal function-achalasia type I-may require 1 or more postoperative reinterventions. Thus, we recommend that patients with achalasia have lifelong annual surveillance after Heller myotomy that includes a TBE. PMID- 30423336 TI - Cognition and Cerebral Infarction in Older Adults After Surgical Aortic Valve Replacement. AB - BACKGROUND: Aortic valve replacement (AVR) for calcific aortic stenosis is associated with high rates of perioperative stroke and "silent" cerebral infarcts on diffusion-weighted magnetic resonance imaging (MRI), but cognitive outcomes in elderly AVR patients compared with individuals with cardiac disease who do not undergo surgery are uncertain. METHODS: One hundred ninety AVR patients (mean age=76+/-6y) and 198 non-surgical participants with cardiovascular disease (mean age=74+/-6y) completed comprehensive cognitive testing at baseline (pre-surgery), and 4-6 weeks and 1-year postoperatively. Surgical participants also completed perioperative stroke evaluations, including postoperative brain MRI. Mixed model analyses and reliable change scores examined cognitive outcomes. Stroke outcomes were evaluated in participants with and without postoperative cognitive dysfunction. RESULTS: Based on reliable change scores, only 12.4% of the surgical group demonstrated postoperative cognitive dysfunction at 4-6 weeks and 7.5% at 1 year. Although the surgical group had significantly lower scores in working memory/inhibition 4-6 weeks after surgery, the groups did not differ at 1-year. In surgical participants, postoperative cognitive dysfunction was associated with more acute cerebral infarct number (p<0.01) and total volume (p<0.01) on MRI. CONCLUSIONS: In high-risk, aged participants undergoing surgical AVR for aortic stenosis, post-operative cognitive dysfunction was surprisingly limited and was resolved by 1-year in most. Post-operative cognitive dysfunction at 4-6 weeks was associated with more and larger acute cerebral infarcts. PMID- 30423337 TI - Robotic-Assisted Surgical Ablation of Atrial Fibrillation Combined with Mitral Valve Surgery (Commentary). PMID- 30423338 TI - Fifty-eight Years and Counting: High-Impact Publishing in Computational Pharmaceutical Sciences and Mechanism-based Modeling. PMID- 30423339 TI - Predicting the changes in oral absorption of weak base drugs under elevated gastric pH using an in vitro - in silico - in vivo approach: case examples dipyridamole, prasugrel and nelfinavir. AB - The aim of the current research was to develop an in silico oral absorption model coupled with an in vitro dissolution/precipitation testing to predict gastric pH dependent drug-drug interactions for weakly basic drugs. The effects of elevated gastric pH on the plasma profiles of dipyridamole, prasugrel, and nelfinavir were simulated and compared with pharmacokinetic data reported in humans with or without use of proton pump inhibitors or histamine H2 receptor antagonists. The in vitro dissolution and precipitation data for the weakly basic drugs in biorelevant media were obtained using paddle apparatus. An in silico prediction model based on STELLA software was designed and simulations were conducted to predict the oral pharmacokinetic profiles of the three drugs under both usual (low) and elevated gastric pH conditions. The changes in oral absorption of dipyridamole and prasugrel in subjects with elevated gastric pH compared with those with low stomach pH were predicted well using the in vitro - in silico - in vivo approach. The proposed approach could become a powerful tool in the formulation development of poorly soluble weak base drugs. PMID- 30423340 TI - Application of Physiologically-Based Pharmacokinetic Modeling to Predict the Effects of FcRn Inhibitors in Mice, Rats, and Monkeys. AB - There is a growing interest in developing inhibitors of the neonatal Fc-receptor, FcRn, for use in the treatment for humoral autoimmune conditions. We have developed a new physiological based pharmacokinetic (PBPK) model that is capable of characterizing the pharmacokinetics and pharmacodynamics (PK/PD) of anti-FcRn monoclonal antibodies (mAb) in mice, rats, and monkeys. The model includes incorporation of FcRn recycling of immune gamma globulin (IgG) in hematopoietic cells in addition to FcRn recycling of IgG in vascular endothelial cells, and considers FcRn turnover and intracellular cycling. The model captured antibody disposition in wild-type and FcRn knockout mice and rats, and also predicted the effects of intravenous immune globulin (IVIG) and anti-FcRn mAb on IgG disposition. Simulations predicted the change in IgG clearance in response to IVIG with good accuracy in rats (mean prediction error of 7.15+/-7.67%). In monkeys, prediction windows for simulated IgG concentration vs. time data, as generated through Monto Carlo simulation, were able to capture the effects of anti-FcRn mAb on endogenous IgG. The model may have utility in guiding preclinical evaluations of anti-FcRn therapies in development, potentially assisting in the identification of optimal dosing strategies for this emerging class of immunosuppressive drugs. PMID- 30423341 TI - Semimechanistically Based Modeling of Pembrolizumab Time Varying Clearance Using Four Longitudinal Covariates in Patients with Non-Small Cell Lung Cancer. AB - Time varying clearance has been recently recognized in FDA drug labels for oncology monoclonal antibodies (mAbs). Pembrolizumab population CL at steady state decreased about 20% from the first dose, and individual CL changes varied from 75% decrease to 25% increase, which were correlating with disease conditions. From mechanism of action perspective, this research explored the longitudinal covariate effect on pembrolizumab CL based on data from a Phase II/III clinical trial in patients with non-small cell lung cancer (NSCLC). Time courses of tumor size (SLD), lymphocyte count (LC), albumin (ALB) and lactate dehydrogenase (LDH) were first characterized separately and the post-hoc parameters of each individual patient were fixed in the subsequent semi mechanistically-based modeling (Msmb) analysis. Pembrolizumab time varying clearance was assumed to be associated with the patient's SLD, LC, ALB and LDH, and tumor related pembrolizumab CL (CLtumor) was assumed to be a fraction (FCL) of total pembrolizumab clearance in the Msmb. PMID- 30423342 TI - Molecular Drivers of Crystallization Kinetics for Drugs in Supersaturated Aqueous Solutions. AB - In this study, we explore molecular properties of importance in solution-mediated crystallization occurring in supersaturated aqueous drug solutions. Furthermore, we contrast the identified molecular properties with those of importance for crystallization occurring in the solid state. A literature dataset of 54 structurally diverse compounds for which crystallization kinetics from supersaturated aqueous solutions and in melt-quenched solids were reported, was used to identify molecular drivers for crystallization kinetics observed in solution and contrast these to those observed for solids. The compounds were divided into fast, moderate and slow crystallizers and in silico classification was developed using a molecular K-nearest neighbor (KNN) model. The topological equivalent of Grav3 (T_Grav3; related to molecular size and shape) was identified as the most important molecular descriptor for solution crystallization kinetics; the larger this descriptor, the slower the crystallization. Two electrotopological descriptors (the Atom-type E-state index for -Caa groups and the sum of absolute values of pi Fukui(+) indices on C) were found to separate the moderate and slow crystallizers in solution. The larger these descriptors, the slower the crystallization. With these three descriptors, the computational model correctly sorted the crystallization tendencies from solutions with an overall classification accuracy of 77% (test set). PMID- 30423343 TI - Anti-persister activity of squalamine against Acinetobacter baumannii. AB - Squalamine is a natural polycationic aminosterol extracted from Squalus acanthias. It displays a remarkable efficacy against Gram- and Gram+ bacteria which are resistant to antimicrobials. Its membranolytic activity and its low cytotoxicity make squalamine one of the most promising agents to fight against nosocomial pathogens such as Acinetobacter baumannii. In the context of chronic diseases and therapeutic failures associated to this pathogen, the presence of dormant cells, i.e. persisters and viable but not culturable cells (VBNCs), highly tolerant to antimicrobial compounds is problematic. The aim of this study was to investigate the antibacterial activity of squalamine against this bacterial population of A. baumannii. Bacterial dormancy was induced by cold shocks and nutriment starvation in the presence of high doses of either colistin, ciprofloxacin, or squalamine. Persisters and VBNCs induced by these treatments were then challenged by 100 mg/L of squalamine. The efficacy of each treatment was determined by evaluating the culturability on agar medium, the membrane integrity (Live/DeadTMBacLightTM staining) and the respiratory activity (CTC BacLightTM RedoSensorTM staining) of bacteria. We showed that A. baumannii ATCC 17978 generated persisters as well as VBNCs in the presence of high doses of ciprofloxacin whereas colistin and squalamine did not. We demonstrated that squalamine at 100 mg/L (below its hemolytic concentration) was able to kill dormant cells. Squalamine did not induce persisters nor VBNCs formation in A. baumannii ATCC 17978. Interestingly, it was significantly active against this type of dormant population generated by ciprofloxacin, making it a very promising anti-persister agent. PMID- 30423344 TI - HMGB1 from Lampetra japonica promotes inflammatory activation in supraneural body cells. AB - High mobility group box protein 1 (HMGB1) acts as a potent proinflammatory cytokine that involves in the pathogenesis of diverse inflammatory and infectious disorders. In previous study, we identified a homolog of HMGB1 in the Lampetra japonica(L-HMGB1), and further revealed that L-HMGB1 was able to induce the production of tumor necrosis factor-alpha (TNF-alpha) in activated human acute monocytic leukemia cells. However, the role of L-HMGB1 played in lamprey was unknown. Here, we found that L-HMGB1 was located in the cytoplasm of lamprey leukocytes and supraneural body (SB) cells. Importantly, we demonstrated that L HMGB1 participated in activation of various key molecules in inflammation signaling pathway. LPS also promoted the release of L-HMGB1 from SB cells similar to Hu-HMGB1, and then extracellular L-HMGB1 in turn induced the release of cytokines. This study revealed that the synergistic action of LPS and L-HMGB1 played a crucial role in inflammation in lamprey. Our results suggested that lampreys used L-HMGB1 to activate their innate immunity for the purpose of pathogen defense. PMID- 30423345 TI - Identification of factors involved in Enterococcus faecalis biofilm under quercetin stress. AB - Enterococcus faecalis is a gram positive enteric commensal bacteria or opportunistic pathogen and its infection involves biofilm formation. Quercetin, a plant origin polyphenol was found to inhibit E. faecalis biofilm. Crystal violet assay, SEM and CLSM microscopy confirmed biofilm inhibition by quercetin. Proteomics was used to elucidate the changes occurred in bacterial cell by quercetin treatment. 2D-Electrophorosis and MALDI-TOF analysis revealed that nineteen proteins were differentially expressed in quercetin treated sample. Glycolytic pathways, protein translation-elongation pathways and protein folding pathways were under differential expression after treatment. Real Time-PCR (RT PCR) validated the proteomic data at genomic level except for the translation elongation factor G which showed opposite data to proteomics. Protein-protein interaction networks constructed using STRING 10.0 demonstrated strong connection of translation-elongation proteins with many important proteins. The results of the comparative analysis indicate that quercetin exerts its inhibitory effect by disturbing glycolytic, protein translation-elongation and protein folding pathways. This disturbs bacterial physiology and stops transition of planktonic cells to biofilm state. PMID- 30423346 TI - In vitro evaluation of adherence and anti-infective property of probiotic Lactobacillus plantarum DM 69 against Salmonella enterica. AB - Gastrointestinal infections are a global health problem, and the potential use of probiotic Lactobacillus species to control such infections represents a promising approach. To exert the health benefits on the host, studying the colonization and adherence properties of probiotic bacteria in vitro is crucial. In this context, investigation was carried out to evaluate adhesion, aggregation and anti infective effect of an indigenous probiotic Lactobacillus plantarum DM 69 against an enteric pathogen Salmonella enterica subsp. enterica ATCC 35640. The results obtained in this study indicated the strong hydrophobic property of the probiotic candidate. In addition, probiotic strain L. plantarum DM 69 also showed higher percentage of self aggregation (58.66%) and low co-aggregation with S. enterica (23.5%). Investigation on antimicrobial property of the probiotic strain revealed its broad-spectrum activity against S. enterica which may have the potential as antibiotics. On analyzing the antimicrobial compound, infrared (IR) spectroscopy indicated the proteinaceous nature of the compound with a molecular weight of 12010.2751 Da. On evaluating the competitive exclusion properties of probiotic strain we observed that L. plantarum DM 69 and its purified antimicrobial compound could control and inhibit pathogen adhesion and penetration into HCT-116 cells. Probiotic L. plantarum DM 69 and its therapeutic properties must be evaluated further. PMID- 30423347 TI - Defining the transcription landscape of the Gram-negative marine bacterium Vibrio harveyi. AB - Vibrio harveyi is a Gram-negative pathogenic bacterium ubiquitously present in natural aquatic systems. Although environmental adaptability in V. harveyi may be enabled by profound reprogramming of gene expression previously observed during responses to starvation, suboptimal temperatures and other stress factors, the key characteristics of V. harveyi transcripts and operons, such as their boundaries and size as well as location of small RNA genes, remain largely unknown. To reveal the main features of the V. harveyi transcriptome, total RNA of this organism was analyzed by differential RNA sequencing (dRNA-seq). Analysis of the dRNA-seq data made it possible to define the primary transcriptome of V. harveyi along with cis-acting regulatory elements (riboswitches and leader sequences) and new genes. The latter encode a number of putative polypeptides and new phylogenetically conserved antisense RNAs potentially involved in the post transcriptional control of gene expression. PMID- 30423348 TI - Synergistic improved efficacy of Gymnadenia orchidis root Salep and pumpkin seed on induced diabetic complications. AB - OBJECTIVE: Diabetes mellitus occurs due to either deficiency of insulin or resistance to insulin. Synthetic drugs and insulin therapy against diabetes possess numerous drawbacks. Diabetic people are advised to choose low-glycemic food and herbal products to control diabetes. This study aims to examine the synergistic effects of aqueous root Salep ofGymnadenia orchidis Lindl and pumpkin seed powder on Streptozotocin induced diabetic mice. METHODS: Out of 6 groups, animals in 2 groups were kept as control and rest 4 groups were made diabetic by Streptozotocin. Animals in one diabetic group were supplemented with effective dose (200 mg/kg of body weight) of root Salep, one with pumpkin seed powder (5%) mixed food, and another with Salep and pumpkin seed food. Changes in various biochemical parameters, DNA damage and liver and kidney structures were noted after 21 days treatment. RESULTS: Salep with pumpkin seed supplementation significantly normalized the alterations of different biochemical parameters of diabetic mice. The DNA damage in blood cells of diabetic mice was recovered by this supplementation. Terpenoids of root Salep and anti-oxidants of pumpkin seed may play the active role against diabetes. CONCLUSION: The root Salep and pumpkin seed synergistically prevent diabetic complications and could be better supplementation against type-2 diabetes. PMID- 30423349 TI - Pakistan and diabetes-A country on the edge. AB - The rising burden of diabetes is mainly ascribed to environmental and emotional changes. The main contributors are sedentary lifestyle including internet and TV usage, caloric rich diets leading to increasing obesity. The National Diabetes Survey of Pakistan (NDSP 2016-2017) has reported the prevalence of diabetes as 26.3% in Pakistan. Pakistan with very high numbers of prevalent diabetes needs a cost-effective population based approach for screening. Proper governance system has to be adopted to facilitate multi sectoral collaboration, including transparency and evaluation for achieving Non-Communicable Disease (NCD) associated targets. According to health economists, if a country invests 1$ per person in interventions for NCDs now, it shall expect a return of 7$ per person in NCDs by 2030. Increase NCDs with increasing age is not unexpected but premature morbidity and mortality with NCDs must be efficiently and diligently tackled. Finally, though the numbers to treat are really high, but human resources and evidence based solutions are enough to call multi stake holders to ACT NOW. PMID- 30423350 TI - Variability and uncertainty in the rodent controlled cortical impact model of traumatic brain injury. AB - BACKGROUND: Controlled cortical impact (CCI) has emerged as one of the most flexible and clinically applicable approaches for the induction of traumatic brain injury (TBI) in rodents and other species. Although this approach has been shown to model cognitive and functional outcomes associated with TBI in humans, recent work has shown that CCI is limited by excessive variability in lesion size despite attempts to control velocity, impact depth, and dwell time. NEW METHOD: Thus, this work used high-speed imaging to evaluate the delivery of cortical impact and permit the identification of specific parameters associated with technical variability in the CCI model. RESULTS: Variability is introduced by vertical oscillations that result in multiple impacts of varying depths, lateral movements after impact, and changes in velocity, particularly at the prescribed impact depth. CONCLUSIONS: Together these data can inform future work to design modifications to commonly used CCI devices that produce TBI with less variability in severity and lesion size. PMID- 30423351 TI - Increased cell number with reduced nitric oxide level and augmented superoxide dismutase activity in the anterior-pituitary region of young suicide completers. AB - Suicidal behavior is a complex human behavior and current data suggests that suicide is an increasing cause of death among young people. The neurobiology of suicide is unknown and data investigating the role of the pituitary in suicidal behavior is scarce. Imaging data suggests that this gland increases in size in patients with major depression and recent data implicates hyperactivity of the hypothalamus-pituitary-adrenal axis in suicidal behavior. In this study, we evaluate the size and number of cells as well as markers related to oxidative stress and lipid peroxidation of the anterior and posterior sections of the pituitary gland of male suicide completers. Stereological analysis is used to quantify the total cell number in anterior- and posterior-pituitary regions. We examined nitric oxide (NO) levels, Zinc (Zn) levels, superoxide dismutase (SOD) activity, 4-hydroxy-alkenals (4-HDA), malondialdehyde (MDA) and metallothioneins (MTs). Our results indicate that the anterior-pituitary region of suicide completers exhibits increased weight, likely due to an enhanced number of cells compared to the control group. In addition, we found a reduction of NO levels with higher SOD activity in the anterior-pituitary region of suicide victims. No changes in Zn, MDA, MTs, 4-HDA or MDA were observed in tissue of suicide completers compared to the control group. This study demonstrates that there is an increased number of cells, with an imbalance in oxidative stress without a process of lipid peroxidation in the anterior-pituitary region of young male suicide completers. PMID- 30423352 TI - Individual Smad2 linker region phosphorylation sites determine the expression of proteoglycan and glycosaminoglycan synthesizing genes. AB - Growth factors such as thrombin and transforming growth factor (TGF)-beta facilitate glycosaminoglycan (GAG) chain hyperelongation on proteoglycans, a phenomenon that increases lipoprotein binding in the vessel wall and the development of atherosclerosis. TGF-beta signals via canonical carboxy terminal phosphorylation of R-Smads and also non-canonical linker region phosphorylation of R-Smads. The G protein coupled receptor agonist, thrombin, can transactivate the TGF-beta receptor leading to both canonical and non-canonical Smad signalling. Linker region phosphorylation drives the expression of genes for the synthesis of the proteoglycan, biglycan. Proteoglycan synthesis involves core protein synthesis, the initiation of GAG chains and the subsequent elongation of GAG chains. We have explored the relationship between the thrombin stimulated phosphorylation of individual serine and threonine sites in the linker region of Smad2 and the expression of GAG initiation xylosyltransferase-1 (XT-1) and GAG elongation chondroitin 4-sulfotransferase-1 (C4ST-1) and chondroitin synthase-1 (CHSY-1) genes. Thrombin stimulated the phosphorylation of all four target residues (Thr220, Ser245, Ser250 and Ser255 residues) with a similar temporal pattern - phosphorylation was maximal at 15 min (the earliest time point studied) and the level of the phospho-proteins declined thereafter over the following 4 h. Jnk, p38 and PI3K, selectively mediated the phosphorylation of the Thr220 residue whereas the serine residues were variously phosphorylated by multiple kinases. Thrombin stimulated the expression of all three genes - XT-1, C4ST-1 and CHSY-1. The three pathways mediating Thr220 phosphorylation were also involved in the expression of XT-1. The target pathways (excluding Jnk) were involved in the expression of the GAG elongation genes (C4ST-1 and CHSY-1). These findings support the contention that individual Smad linker region phosphorylation sites are linked to the expression of genes for the initiation and elongation of GAG chains on proteoglycans. The context of this work is that a specific inhibitor of GAG elongation represents a potential therapeutic agent for preventing GAG elongation and lipid binding and the results indicate that the specificity of the pathways is such that it might be therapeutically feasible to specifically target GAG elongation without interfering with other physiological processes with which proteoglycans are involved. PMID- 30423353 TI - A Cynomolgus monkey model of temporal lobe epilepsy. AB - Temporal lobe epilepsy (TLE) with hippocampal sclerosis is the most common type of drug-resistant epilepsy. Non-human primates are attractive models for studying the pathogenic mechanisms of TLE, with the goal of developing new drugs and interventions. In this study, we developed and tested a Cynomolgus monkey (Macaca fascicularis) model of TLE. A total of 5 Cynomolgus monkeys received3-4 weekly unilateral hippocampal injections of kainic acid (KA) to induce repetitive acute seizures. Animals were monitored via video and electroencephalography (EEG) to assess KA-induced acute seizures and subsequent spontaneous recurrent epileptiform discharges (SREDs). During acute seizures, EEG recording showed bursts of generalized spike discharges arising from the temporal lobe ipsilateral to the KA injection. Three months later, we detected abundant interictal epileptiform discharges (IEDs) during pentobarbital induced anesthesia. Furthermore, two monkeys exhibited synchronized epileptiform discharges accompanied by symptoms mimicking absence seizures. No obvious convulsive symptoms were observed in any monkeys. Overall, our data indicate successful development of a Cynomolgus monkey model of TLE via unilateral hippocampal injection of KA. PMID- 30423355 TI - Nanocomplexes of carboxymethyl chitosan/amorphous calcium phosphate reduce oral bacteria adherence and biofilm formation on human enamel surface. AB - OBJECTIVES: This study investigated the effect of CMC/ACP on oral bacteria adherence and biofilm formation on the enamel surface as well as the underlying mechanism to determine the anti-cariogenic potential of CMC/ACP. METHODS: A mineral solution of CMC/ACP was characterised by transmission electron microscope. The bactericidal activity of CMC/ACP was evaluated with the plate count method. An in vitro biofilm model was established on saliva-coated enamel blocks; the effect of CMC/ACP on the adherence of Streptococcus mutans and Streptococcus gordonii to and biofilm formation on these blocks, as well as co aggregation of Fusobacterium nucleatum was assessed by scanning electron microscopy, crystal violet staining, and confocal microscopy. Bacterial surface charge was estimated with the cytochrome c binding assay and by zeta potential measurement. RESULTS: CMC/ACP nanocomplexes inhibited S. mutans and S. gordonii adherence to enamel blocks by 90% and 86% (P < 0.01), respectively, and biofilm formation by 45% and 44% (P < 0.01), respectively, after 24 h without bactericidal activity. CMC/ACP reduced F. nucleatum attachment to streptococcal biofilm by 75% (P < 0.01) while also altering cytochrome c binding to bacteria and reducing the zeta potential of the bacterial suspension. CONCLUSIONS: CMC/ACP nanocomplexes inhibit cariogenic bacterial adherence, co-adhesion, and biofilm formation on the enamel surface, possibly by altering bacterial surface charge and enhancing the flocculation effect. As an agent that promotes remineralisation and has anti-cariogenic effects, CMC/ACP can be used to prevent and treat early caries and white spot lesions. PMID- 30423354 TI - Strong antibacterial dental resin composites containing cellulose nanocrystal/zinc oxide nanohybrids. AB - OBJECTIVE: The aim is to explore the reinforcing and antibacterial effect of cellulose nanocrystal/zinc oxide (CNC/ZnO) nanohybrids on dental resin composites (DRCs). METHODS: CNC/ZnO nanohybrids were prepared through precipitating Zn2+ on the surface of CNC and then introduced into the DRCs. The mechanical properties of DRCs including compressive strength, flexural modulus, flexural strength, and Vickers microhardness were characterized. The antibacterial activity of DRCs to Streptococcus mutans was determined and the morphology of Streptococcus mutans on the surface of DRCs after incubation was observed. The morphology of fractured surface after flexural test and Zn content in DRCs were analyzed. RESULTS: Compared with DRCs without CNC/ZnO nanohybrids, DRCs containing 2 wt.% CNC/ZnO nanohybrids possess higher compressive strength and flexural modulus and there is no significantly statistical difference (P>0.05) on the flexural strength and Vickers microhardness. The excess use of CNC/ZnO nanohybrids decreases the mechanical properties of DRCs except flexural modulus. DRCs containing CNC/ZnO nanohybrids show excellent antibacterial properties and a 78% reduction in bacterial number is obtained when 2% CNC/ZnO nanohybrids are added. CONCLUSION: The small amounts of CNC/ZnO nanohybrids have a positive influence on the mechanical and antibacterial properties of DRCs. SIGNIFICANCE: The prepared DRCs are promising to address bulk fracture and secondary caries. PMID- 30423356 TI - Reward association alters brain responses to emotional stimuli: ERP evidence. AB - We investigated the effects of reward learning on the processing of emotional faces using event-related potentials (ERPs). A simple choice game was used to imbue angry and happy faces with a high or low probability of reward. ERPs were recorded in a subsequent test phase in which participants performed a visual search task to discriminate the emotion of a face singleton as being angry or happy without any reward. Results revealed a significant interaction between reward-history and emotion for the N1 and P2 components, in which the difference between the mean amplitudes for angry and happy faces was smaller in the high reward association condition than in the low-reward association condition. This reward-modulation effect indicates that reward association reduced the initial visual awareness and hence attentional allocation to angry faces. Moreover, we found a positive relationship between the personal trait of reward sensitivity and the reward-modulation effect for the late-latency response-selection related slow positive wave (SPW) component and the behavioral response accuracy, suggesting that participants with higher reward sensitivity may employ more cognitive resources to evaluate the reward history during the late decision stage of emotional processing. Our study contributes to a better understanding of how reward-association history affects both the perceptual and executive levels of emotional face processing. PMID- 30423357 TI - Mechanisms underlying acquired platinum resistance in high grade serous ovarian cancer - a mini review. AB - BACKGROUND: Advanced epithelial ovarian cancer is one of the hardest human malignancies to treat. Standard treatment involves cytoreductive surgery and platinum-based chemotherapy, however, median progression-free survival for patients diagnosed with advanced stage disease (FIGO stages III and IV) is approximately 18 months. There has been little improvement in overall survival over the past decade and less than half of women with advanced stage disease will be living 5 years after diagnosis. A majority of patients initially have a favourable response to platinum-based chemotherapy, but most will eventually relapse and their disease will become platinum resistant. SCOPE OF REVIEW: Here, we review our current understanding of mechanisms that promote recurrence and acquired resistance in epithelial ovarian cancer with particular focus on studies that describe differences observed between untreated primary tumors and recurrent tumors, post-first-line chemotherapy. Multiple molecular mechanisms contribute to recurrence in patients following initial treatment for advanced epithelial ovarian cancer including those involving the tumor microenvironment, tumor immune status, cancer stem cells, DNA repair/cell survival pathways and extracellular matrix. MAJOR CONCLUSIONS: Due to the adaptive nature of recurrent tumors, the major contributing and specific resistance pattern may largely depend on the nature of the primary tumor itself. GENERAL SIGNIFICANCE: Future work that aims to elucidate the complex pattern of acquired resistance will be useful for predicting chemotherapy response/recurrence following primary diagnosis and to develop novel treatment strategies to improve the survival of patients with advanced epithelial ovarian cancer, especially in tumors not harbouring homologous DNA recombination repair deficiencies. PMID- 30423358 TI - c-Fos, DeltaFosB, BDNF, trkB and Arc Expression in the Limbic System of Male Roman High- and Low-Avoidance Rats that Show Differences in Sexual Behavior: Effect of Sexual Activity. AB - Male Roman High- (RHA) and Low-Avoidance (RLA) rats display significant differences in sexual behavior (RHA rats exhibit higher sexual motivation and better copulatory performance than RLA rats). These differences are very evident in sexually naive rats (which copulate with a receptive female rat for the first time), and are still present, although reduced, after five copulatory tests, when sexual experience has been acquired. Since sexual activity is a natural reward that induces neural activation and synaptic plastic changes in limbic brain areas, we studied whether the differences in sexual activity between these rat lines are accompanied by changes in the expression of markers of neural activation and plasticity, i.e., c-Fos, DeltaFosB (a truncated form of FosB), Brain-Derived Neurotrophic Factor (BDNF) and its tyrosine kinase receptor B (trkB) and Activity regulated cytoskeleton-associated (Arc) protein in the ventral tegmental area (VTA), nucleus accumbens (Acb) (core and shell) and medial prefrontal cortex (mPFC) of sexually naive and experienced RHA and RLA rats by Western Blot and/or immunohistochemistry. This study shows that these markers changed differentially in the VTA, Acb and mPFC of RHA and RLA rats, after sexual activity. In both rat lines, the changes were very evident in naive rats, tended to disappear in experienced rats and were higher in RHA than RLA rats. These findings confirm that sexual activity induces neural activation in limbic brain areas involved in motivation and reward, leading to changes in synaptic plasticity with sexual experience acquisition, and show that these depend on the animals' genotypic/phenotypic characteristics. PMID- 30423359 TI - Reliability, validity and minimal detectable change of 2-minute walk test, 6 minute walk test and 10-meter walk test in frail older adults with dementia. AB - BACKGROUND: Walk tests are commonly used to evaluate walking ability in frail older adults with dementia but their psychometric evidence in this population is lacking. OBJECTIVES: 1) To examine test-retest and inter-rater reliability, construct and known-group validity, and minimal detectable change at 95% level of confidence (MDC95) of walk tests in frail older adults with dementia, and 2) to examine the feasibility and consistency of a cueing system in facilitating participants in completing walk tests. DESIGN: Psychometric study with repeated measures. SETTING: Day care and residential care facilities. PARTICIPANTS: Thirty nine frail older adults with a mean age 87.1 and a diagnosis of dementia or Alzheimer's disease who were able to walk independently for at least 15 m. METHODS: The participants underwent a 2-minute walk test (2MWT), 6-minute walk test (6MWT) and 10-meter walk test (10MeWT) on 6 separate occasions under 2 independent assessors using a cueing system. Functional status was measured using the Elderly Mobility Scale (EMS), Berg Balance Scale (BBS) and Modified Barthel Index (MBI). RESULTS: Excellent test-retest (ICC = 0.91-0.98) and inter-rater reliability (ICC = 0.86-0.96) were shown in the 2MWT, 6MWT and 10MeWT. The walk tests were strongly correlated with each other (rho = 0.85-0.94). The correlations between the walk tests and the functional measures were moderate in general (rho = 0.34-0.55). All the walk tests were able to distinguish between those who could walk outdoor and indoor only (p <= .036). The MDC95 were 9.1 m in the 2MWT, 28.1 m in the 6MWT, and.16 m/s in the 10MeWT. The cues provided by the assessors in the walk tests were generally consistent (ICC = 0.62-0.89). CONCLUSIONS: The 2MWT, 6MWT and 10MeWT are reliable and valid measures in evaluating walking ability in frail older adults with dementia. The MDC95 of the walk tests has been established. The cueing system is feasible and reliable to facilitate the administration of the walk tests in this population group. PMID- 30423360 TI - Detection of an animal-derived G4P[6] group A rotavirus strain in a symptomatic child, in Italy. AB - During 2017, a G4P[6] group A rotavirus strain was identified in the feces of an Italian child hospitalized for acute gastroenteritis in Southern Italy. Nucleotide sequencing of the 11 genomic segments, revealed the G4-P[6]-I1-R1-C1 M1-A1-N1-T1-E1-H1 genotype constellation. Phylogenetic analyses of the gene segments investigated revealed high nucleotide sequence identities with G4P[6] RVA strains detected previously in pigs and in humans. The human strains related to the Italian G4P[6] were mainly reported from Asia, and were detected after an inter-species transmission event from swine. This study reports the genotyping and phylogenetic analysis of a G4P[6] RVA strain presenting a genomic constellation never detected before in Italy. In addition, this strain was able to cause AGE symptoms in a healthy child, successively hospitalized. The molecular characterization suggested zoonotic origin and inter-species transmission of this strain from swine, living open the possibility of its importation from abroad. PMID- 30423361 TI - microRNA response in potato virus Y infected tobacco shows strain-specificity depending on host and symptom severity. AB - The present study demonstrates how different potato virus Y (PVY) strains affect the miRNA balance in tobacco cv. Samsun. The two prevalent strains PVYNTN and PVYN-Wi caused severe and mild veinal necrosis (VN) respectively, and the unique PVYZ-NTN strain induced milder vein clearing (VCl) in the upper non-inoculated leaves. A single amino acid polymorphisms (SAPs) I252V and a Q412 to R412 substitution in the HC-Pro cistron of the PVYZ-NTN strain might relate to the loss of VN in tobacco. The abundance of 18 out of the 26 tested miRNAs was increased upon infection by the severe strains PVYNTN and PVYN-Wi. Expression of a group of defense related transcripts were increased accordingly. Two miRNAs, nta-miR6020a-5p and nta-miR6164a/b, which target the TIR-NBS-LRR type resistant TMV N genes involving in signal transduction, might correlate with the PVYNTN and PVYN-Wi induced VN. The down-regulated mRNAs, e.g., RAP2-7 and TOE3, PXC3, LRR RLK, ATHB-14 and TCP4 targeted by nta-miR172, nta-miR390, nta-miR482, nta-miR166 and nta-miR319/159 respectively, were related to regulation of transcription, protein phosphorylation and cell differentiation. The observed strain-specific alteration of miRNAs and their targets are host dependent and corresponds to the symptom severity and the viral HC-Pro RNA levels. PMID- 30423362 TI - HBV antigen and DNA loss from mouse serum is associated with novel vaccine induced HBV surface antigen-specific cell-mediated immunity and cytokine production. AB - Therapeutic vaccination is a promising strategy for controlling chronic hepatitis B virus (HBV). Here, we tested whether several novel vaccination strategies could be used to induce HBV-specific adaptive immune responses and control/eradicate HBV in a mouse model. Robust HBV antigen-specific antibody responses were elicited by several vaccination strategies using a novel particle vaccine (HBSS1), which expresses a fusion of the S (amino acids [aa] 1-223) and preS1 (aa 21-47) antigens, and/or a recombinant adenovirus rAdSS1 vaccine. However, antigen specific cell-mediated immunity and high levels of production of multiple cytokines were elicited only by heterologous prime-boost immunization; i.e., priming with the HBSS1 vaccine followed by a rAdSS1 boost. Furthermore, the most rapid loss of serum HBsAg, HBeAg and DNA was achieved by the novel vaccination regimen (priming with HBSS1 formulated with adjuvants [alum plus PolyI:C]), which was strongly associated with more potent and functional HBsAg-specific CD4+ and CD8+ T-cell responses and increased production of interleukin (IL)-2, interferon (IFN)-gamma, tumor necrosis factor-alpha, IL-12, and IFN-gamma-induced protein (IP)-10. Thus, our novel heterogeneous prime-boost vaccine regimen shows promise as a therapeutic strategy against HBV. PMID- 30423363 TI - Detection of carbapenemases, AmpC and ESBL genes in Acinetobacter isolates from ICUs by DNA microarray. AB - The accumulation of multiple inherent and acquired resistance mechanisms in Acinetobacter spp. results in emergence of "pandrug resistant" strains which is one of the major concerns in healthcare sectors worldwide. Surveillance of the carbapenemase/ extended-spectrum beta-lactamases (ESBLs) genes in A. baumannii by phenotypic methods is challenging especially in developing countries, like Pakistan. In this context, a novel microarray (CT 103XL Check-MDR) assay was used for simultaneous detection of genes encoding clinically important carbapenemases and ESBLs. The results were compared with the phenotypic methods including MHT, Rapidec Carba NP, EDTA+DDST and Rosco (KPC/MBL). The results of the microarray were also confirmed by PCR. All of the strains of A. baumannii (47) were resistant to imipenem and meropenem. Microarray and PCR results showed presence of OXA-23 in all the isolates of A. baumannii while 36.17% also harbored PER. Rosco kit test showed 100% sensitivity to detect carbapenemases but exhibited low specificity to classify them. Rapidec Carba NP test has 100% sensitivity and specificity to detect the carbapenemases when compared with microarray. Sensitivity and specificity of microarray assay were 100% for bla-genes in comparison to PCR. This reveals that Check-MDR CT103 XL assay is an accurate method for the identification of ESBLs and carbapenemase genes in A. baumannii in comparison to the other methods. PMID- 30423364 TI - Detection of microbial genes in a single leukocyte by polymerase chain reaction following laser capture microdissection. AB - Although isolation and identification of bacteria in a clinical specimen constitute essential steps for the diagnosis of bacterial infection, positive results of the bacterial culture are not always attained, despite observing the bacteria by Gram staining. As bacteria phagocytosed by the leukocytes are considered as the causative agents of infectious diseases, this study aims to introduce a new approach for the collection of only bacteria phagocytosed by the neutrophils in an animal model using laser capture microdissection (LCM) followed by the DNA identification using polymerase chain reaction (PCR). We inoculated representative bacteria (Escherichia coli and Staphylococcus aureus) into the abdominal cavities of specific pathogen-free C57BL/6 J mice. After 6 h inoculation, we collected the fluid samples from the peritoneal cavities of mice and demonstrated peritonitis by the increase of neutrophils. Then, we smeared the neutrophils on the membrane slides and collected single-cell phagocytosing bacteria by LCM. The supernatant of the cell lysate was supplied for the PCR reaction to amplify the 16S rRNA gene, and we validated the DNA sequences specific for the inoculated bacteria. In addition, PCR using specific primers for E. coli and S. aureus identified each species of bacteria. Hence, this study suggests that the combination of LCM and PCR could be a novel approach to determine bacteria in infectious diseases. Nevertheless, further investigation is warranted to test various additional bacterial taxa to demonstrate the general applicability of this method to clinical samples. PMID- 30423365 TI - Cytotoxicity and global transcriptional responses induced by zinc oxide nanoparticles NM 110 in PMA-differentiated THP-1 cells. AB - Despite a wide production and use of zinc oxide nanoparticles (ZnONP), their toxicological study is only of limited number and their impact at a molecular level is seldom addressed. Thus, we have used, as a model, zinc oxide nanoparticle NM110 (ZnO110NP) exposure to PMA-differentiated THP-1 macrophages. The cell viability was studied at the cellular level using WST-1, LDH and Alamar Blue(r) assays, as well as at the molecular level by transcriptomic analysis. Exposure of cells to ZnO110NP for 24 h decreased their viability in a dose dependent manner with mean inhibitory concentrations (IC50) of 8.1 ug/mL. Transcriptomic study of cells exposed to two concentrations of ZnO110NP: IC50 and a quarter of it (IC50/4) for 4 h showed that the expressions of genes involved in metal metabolism are perturbed. In addition, expression of genes acting in transcription regulation and DNA binding, as well as clusters of genes related to protein synthesis and structure were altered. It has to be noted that the expressions of metallothioneins genes (MT1, MT2) and genes of heat-shock proteins genes (HSP) were strongly upregulated for both conditions. These genes might be used as an early marker of exposition to ZnONP. On the contrary, at IC50 exposure, modifications of gene expression involved in inflammation, apoptosis and mitochondrial suffering were noted indicating a less specific cellular response. Overall, this study brings a resource of transcriptional data for ZnONP toxicity for further mechanistic studies. PMID- 30423366 TI - Caffeine attenuates brain injury but increases mortality induced by high intensity blast wave exposure. AB - Caffeine is a substance that is consumed worldwide, and it may exert neuroprotective effects against various cerebral insults, including neurotrauma, which is the most prevalent injury among military personnel. To investigate the effects of caffeine on high-intensity blast wave-induced severe blast injury in mice, three different paradigms of caffeine were applied to male C57BL/6 mice with severe whole body blast injury (WBBI). The results demonstrated that chronic caffeine treatment alleviated blast-induced traumatic brain injury (bTBI); however, both chronic and acute caffeine treatments exacerbated blast-induced lung injuries and, more importantly, increased both the cumulative and time segmented mortalities postinjury. Interestingly, withdrawing caffeine intake preinjury resulted in favorable outcomes in mortality and lung injury, similar to the findings in water-treated mice, and had the trend to attenuate brain injury. These findings demonstrated that although drinking coffee or caffeine preparations attenuated blast-induced brain trauma, these beverages may place personnel in the battlefield at high risk of casualties, which will help us re evaluate the therapeutic strategy of caffeine application, particularly in multiple-organ-trauma settings. Furthermore, these findings provided possible strategies for reducing the risk of casualties with caffeine consumption, which may help to change the coffee-drinking habits of military personnel. PMID- 30423367 TI - Combined effects of glycosylation precursors and lactate on the glycoprofile of IgG produced by CHO cells. AB - The glycosylation profile of therapeutic monoclonal antibodies (mAbs) is a crucial quality parameter for industrial Immunoglobulin G (IgG) production. Several alternative carbon sources, which function as glycosylation precursors, have been reported to impact the glycosylation pattern. Since the cells give priority to glucose uptake, the presence of this substrate can lower the effects of alternative sugars on the glycosylation. In order to get a better understanding of the influence of alternative sugars on the glycosylation and to investigate how they impact each other, combinations of mannose, fructose, galactose and fucose were fed to Chinese hamster ovary (CHO) cells in batch culture when the glucose became depleted and the lactate, accumulated in the culture, was used as carbon source. Feeding with a feed containing mannose or glucose decreased by 3-7% the percentage of high mannose glycans compared to a feed without mannose or glucose. Feeding with a feed containing galactose led to 8-20% increase of monogalactoglycans (G1) glycans and 2-6% rise of digalactoglycans (G2) glycans compared to feeding without galactose or glucose. The cells fed with fucose exhibited a significantly higher concentration of intracellular GDP-Fucose. This work indicates that a feeding strategy based on non-glucose sugars and potentially lactate, could be adopted to obtain a targeted glycosylation profile. PMID- 30423368 TI - Encapsulated drug system based on the gels obtained from callus cultures modified pectins. AB - The aims of this research were to obtain modified pectins of callus cultures using various culture conditions, to evaluate the relationship between the chemical characteristics of pectins, the swelling behavior and the release of prednisolone from calcium pectinate gel (CaPG) beads. An increase of the calcium concentration in the culture media correlated significantly with the rhamnogalacturonan I (RG-I) branching of the pectin. The beads from the pectin with a higher RG-I branching had the lower prednisolone release in a gastric fluid. The beads produced from the pectins obtained from callus cultured with a higher calcium concentration showed the lower prednisolone release. The swelling of the CaPG beads from pectin with a lower molecular weight (Mw) or linearity occurred to a lower degree. All beads prepared from modified pectins showed a high stability and a slow liberation of prednisolone in the simulated gastric and intestinal fluids, whereas rapid drug release in a colonic fluid. An applied strategy involving modification of the pectic structure using the abiotic factors allows obtaining the pectic gels with modified functional properties, in particular, with enhanced gastric and small intestinal resistance and a low drug release. These CaPG beads can be applied as the carriers for colon delivery of the drugs. PMID- 30423369 TI - An addition to the differential diagnosis of AV Wenckebach in the His-bundle pacing era! PMID- 30423370 TI - ADRB2 gene polymorphism modulates the retention of fear extinction memory. AB - Individual differences in regulation of fear and extinction memory play significant roles in the aetiology development of post-traumatic stress disorder (PTSD). Previous animal based studies showed that the activity of beta-adrenergic receptors (beta-ARs) are involved in memory modulation. However in humans it is not clear that whether genetic variability in beta-ARs contributes to individual differences of fear and extinction memory. In the current study, we investigated the role of a common single-nucleotide polymorphism of beta2-adrenergic receptor (ADRB2) gene in fear memory acquisition, fear memory extinction, extinction recall and fear generalization in human participants. Ninety-one male participants were exposed to a Pavlovian fear conditioning and their fear responses were assessed by the skin conductance response. Participants were genotyped for a polymorphism (rs2400207) located within the promoter region of the human ADRB2. Differences between genotypes were observed in the extinction memory recall test but not in fear acquisition, extinction learning and fear generalization. Particularly, A-allele carriers of rs2400707 displayed successful retention of extinction memory and prevented the return of fear during recall test. The results revealed the involvement of human noradrenergic system in the retention of extinction memory and genetic variability in this system may underlie individual differences in PTSD. Furthermore, rs2400207 polymorphism of ADRB2 gene may play a key role in the treatment efficacy of PTSD and can be a basis for future studies investigating a personalized medicine for fear memory related disorders. PMID- 30423371 TI - Chlorpyrifos disturbs hepatic metabolism associated with oxidative stress and gut microbiota dysbiosis in adult zebrafish. AB - Chlorpyrifos (CPF) is widely used in agriculture and is considered one of the most toxic pesticides to fish. In this study, adult male zebrafish were exposed to CPF at concentrations of 30, 100 and 300 MUg/L for 21 days. It was observed that CPF not only induced oxidative stress but also caused gut microbiota dysbiosis in the gut. The malondialdehyde (MDA) levels increased, and the glutathione (GSH) contents decreased in the gut of the CPF-treated group. For the gut microbiota, at the phylum level, the relative abundance of Proteobacteria showed a significant change after CPF exposure. At the genus level, approximately 25 types of bacteria in the gut changed significantly. In addition, based on a gas chromatography combined with mass spectrometry (GC/MS) analysis, we found that 98 metabolites significantly influenced the zebrafish liver, and these changed metabolites were tightly related to several pathways, including glucose and lipid metabolism, the tricarboxylic acid (TCA) cycle, and amino acid metabolism. Furthermore, the transcriptional levels of some genes related to glycolysis and lipid metabolism decreased significantly in the livers of CPF treated zebrafish. These results indicated that CPF exposure could induce hepatic glucose and lipid metabolism disorders in adult zebrafish. Taken together, our results suggest that CPF exposure causes hepatic lipid metabolism disorders that are associated with gut oxidative stress and microbiota dysbiosis in adult zebrafish. PMID- 30423372 TI - What if "Cabrol" Lost Half of Its Mustache? PMID- 30423373 TI - A cross-sectional bibliometric study showed suboptimal journal endorsement rates of STROBE and its extensions. AB - OBJECTIVE: The STrengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement provides guidance on reporting observational studies. Many extensions have been created for specialized methods or fields. We determined endorsement prevalence and typology by journals in extension-related fields. STUDY DESIGN AND SETTING: A published protocol defined search strategies to identify journals publishing observational studies (2007 - 2017) across seven fields relating to STROBE extensions. We extracted text regarding STROBE, 7 STROBE extensions, reporting guidelines CONSORT and PRISMA, and transparent reporting documents/groups: ICMJE, COPE, and the EQUATOR Network. Relationships between endorsing STROBE, endorsing other guidelines and journal impact factor were tested using Chi-square and Mann-Whitney. RESULTS: Of 257 unique journals, 12 (5%) required STROBE on submission, 22 (9%) suggested use, 12 (5%) recommended a "relevant guideline", 72 (28%) mentioned it indirectly (via editorial policies or ICMJE Recommendations), and 139 (54%) did not mention STROBE. The relevant extension was required by 2 (<1%) journals; 4 (1%) suggested use. STROBE endorsement was not associated with journal impact indices but was with CONSORT and PRISMA endorsement. CONCLUSION: Reporting guideline endorsement rates are low; information is vague and scattered. Unambiguous language is needed to improve adherence to reporting guidelines and increase the quality of reporting. PMID- 30423374 TI - Response to letter to the editor "Only ITT analysis provides information about the actual effects of a health policy". PMID- 30423375 TI - Marginal structural models and other analyses allow multiple estimates of treatment effects in randomized clinical trials: meta-epidemiological analysis. AB - OBJECTIVE: To determine how marginal structural models (MSMs), which are increasingly used to estimate causal effects, are used in randomized clinical trials (RCTs) and compare their results with those from intention-to-treat (ITT) or other analyses. DESIGN: and Setting: We searched PubMed, Scopus, citations of key references, and Clinicaltrials.gov. Eligible RCTs reported clinical effects based on MSMs and at least one other analysis. RESULTS: We included 12 RCTs reporting 138 analyses for 24 clinical questions. In 19/24 (79%), MSM-based and other effect estimates were all in the same direction, 22/22 had overlapping 95%CIs, and in 19/22 (86%), the MSM-effect estimate lay within all 95%CIs of all other effects (in two cases no CIs were reported). For the same clinical question, the largest effect estimate from any analysis was 1.19-fold (median; IQR 1.13-1.34) larger than the smallest. All MSM and ITT-effect estimates were in the same direction and had overlapping 95% CIs. In 71% (12/17), they also agreed on the presence of statistical significance. MSM-based effect estimates deviated more from the null than those based on ITT (p=0.18). The effect estimates of both approaches differed 1.12-fold (median; IQR 1.02-1.22). CONCLUSIONS: MSMs provided largely similar effect estimates as other available analyses. Nevertheless, some of the differences in effect estimates or statistical significance may become important in clinical decision-making and the multiple estimates require utmost attention of possible selective reporting bias. PMID- 30423376 TI - "Only ITT analysis provides information about the actual effects of a health policy". PMID- 30423377 TI - Model Based Economic Evaluations of Diagnostic Point of Care Tests Were Rarely Fit for Purpose. AB - OBJECTIVE: Linked evidence models are recommended to predict health benefits and cost-effectiveness of diagnostic tests. We considered how published models accounted for changes in patient pathways that occur with point of care tests (POCTs), and their impact of on patient health and costs. STUDY DESIGN AND SETTING: Model based evaluations of diagnostic POCTs published from 2004-2017 were identified from searching six databases. For each model we assessed the outcomes considered, and whether reduced time to diagnosis and increased access to testing affected patient health and costs. RESULTS: Seventy-four model based evaluations were included: 95% incorporated evidence on test accuracy, but 34% only assessed intermediate outcomes such as rates of correct diagnosis. Of 54 models where POCTs reduced testing time, 39% addressed the economic and 37% the health benefits of faster diagnosis. No model considered differences in access to tests. CONCLUSIONS: Many models fail to capture the effects of POCTs in increasing access, advancing speed of diagnosis and treatment, reducing anxiety and the associated costs. Many only consider the impact of testing from changes in accuracy. Ensuring models incorporate changes in patient pathways from faster and more accessible testing will lead to economic evaluations that better reflect the impact of POCTs. PMID- 30423378 TI - Susceptibility Weighted Imaging in infants with staged embolization of Vein of Galen Aneurysmal Malformations. AB - BACKGROUND AND PURPOSE: The vein of Galen aneurysmal malformation (VGAM) is a rare congenital vascular malformation with a higher morbidity and mortality, especially in neonates. Ultrasound, CT and MR are usually used in diagnosis and treatment monitoring of these disorders. In this current study we aim to examine utility of SWI in evaluation of treatment response in infants with VGAM. MATERIALS AND METHODS: We performed a retrospective chart analysis of children with VGAM in our institution between January 2008 and December 2016. Inclusion criteria included; confirmed VGAM on DSA; available SWI sequence at baseline and at follow up after at least a single embolization session; age at initial MR of 18 years or younger. Signal intensity and Angioarchitecture of VGAM and cerebral veins on SWI, as well as hydrocephalus and clinical outcome were evaluated. RESULTS: Of 11 patients identified with VGAM in our institution, 5 children (3 males and 2 females) satisfied the inclusion criteria. The average age at initial MR was 29 days (range 1-120). Fourteen MRI were available for review. All children had VGAM of mural type. Intramedullary veins were dilated and SWI hypointense in all children, while subependymal and sulcal veins were dilated and SWI-hypointense in 4 patients on initial MRI. On the first available follow up MRI, cerebral veins have mostly normalized in 4 children and remained mostly dilated and SWI-hypointense in 1 child; even after complete treatment of the VGAM. CONCLUSION: Our preliminary findings show that SWI seems to offer a beneficial non-invasive tool in evaluating passive venous congestion patterns in pediatric patients with VGAM. It remains to be determined in larger studies, the clinical significance of these SWI changes. PMID- 30423379 TI - Thromboembolic delayed event after a WEB device implantation managed by mechanical thrombectomy and stenting. PMID- 30423380 TI - The vestibular aqueduct sign: Magnetic resonance imaging can detect abnormalities in both ears of patients with unilateral Meniere's disease. AB - BACKGROUND AND PURPOSE: In patients with Meniere's disease (MD), saccular hydrops can only be studied by magnetic resonance imaging (MRI) at a late stage when the disease is already responsible for moderate to severe hearing loss. However, these patients may also present vestibular aqueduct (VA) abnormalities. MATERIALS AND METHODS: In this prospective study (38RC14.428 for healthy subjects/38RC15.173 for patients), imaging was carried out on a 3T MRI scanner. Twenty healthy subjects (13 women, median age 53.5 [52.2-66.7]) and twenty MD patients (9 women, median age 54.5 [52-66.7]) had MRI scans with 3D-FLAIR sequences without injection, then 4 hours after a single intra-venous dose of contrast agent. Two radiologists independently ranked the morphology of the VA in the healthy subjects and in MD patients, using a three-level score (completely visible, discontinuous and not visible). Each subject was then graded, based on both the VA's appearance and on saccular hydrops presence. Inter-reader agreement tests were performed. RESULTS: In controls and patients, VA modifications were symmetrical without significant difference between the symptomatic and asymptomatic ears. The presence of at least one ear with discontinuous VA showed a correlation with clinical MD (P < 0.001) with a sensitivity of 90%. Ten patients had saccular hydrops, but only in the symptomatic ears. The evaluation of VA did not differ between MRI, both within MRI series or between the two radiologists (kappa without and with contrast agent = 0.9 and 0.92 respectively). CONCLUSION: Analysis of the vestibular aqueduct by MRI detects abnormalities in both ears of patients with unilateral MD. PMID- 30423381 TI - A helical shape anatomical variation of carotid siphon: A case report. PMID- 30423382 TI - Optic chiasm and oculomotor nerves involvement in active multiple sclerosis. PMID- 30423383 TI - Descending musculospinal branch of the ascending pharyngeal artery as a feeder of carotid body tumors: Angio-architecture and embryological consideration. AB - INTRODUCTION: Although the ascending pharyngeal artery (APhA) is known as a main feeder of carotid body tumors (CBTs), its detailed architecture and embryological consideration have not been described. The objective of this study was to describe the architecture of a descending feeder of the APhA and to consider its origin embryologically through a review of our CBT embolizations. METHODS: We retrospectively analyzed data from patients with CBTs who underwent transarterial embolization or angiographic examination-only between July 2010 and February 2017. The arterial supply of the tumors, the number of feeder pedicles, the mean tumor size, embolization materials, complication of embolization, and extent of tumor removal were assessed. The embryological origin of feeding artery was considered based on the literature. RESULTS: Eighteen patients with 20 CBTs underwent preoperative embolization or angiographic examination. The number of feeder pedicles was significantly related to the size of the CBT (P = 0.0002). The main feeding artery was the descending branch of APhA, which was hypertrophied and tortuous (18/20, 90%). Embryologically, this artery originated from the musculospinal branch and is termed the "descending musculospinal branch". CONCLUSION: The main feeder of the CBTs was the "descending musculospinal branch" of the APhA and needs special consideration such as dangerous anastomosis for embolization. PMID- 30423384 TI - Associations between HMGB1 gene polymorphisms and susceptibility and clinical outcomes in Chinese Han sepsis patients. AB - OBJECTIVES: High mobility group box 1 protein (HMGB1) is an important late inflammatory mediator in the body. In recent years, studies have found that it plays an important pathogenic role in various diseases such as sepsis. However, it is unclear whether the genetic variation of the HMGB1 gene is related to the susceptibility to sepsis. This study investigated the relationship between susceptibility and outcome of the HMGB1 gene rs2249825, rs1045411, and rs1360485 single nucleotide polymorphisms (SNPs) in Chinese Han patients with sepsis. METHODS: The HMGB1 gene rs2249825, rs1045411, and rs1360485 genotypes were detected by the direct sequencing method in 345 patients with sepsis and 345 healthy controls. Serum HMGB1 levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The HMGB1 gene rs2249825 and rs1045411 site SNPs were associated with sepsis risk, but the rs1360485 site SNP was not associated with sepsis risk. Subjects with the HMGB1 gene rs2249825 and rs1045411 site mutations had higher serum HMGB1 levels, and patients with mutant genotype sepsis had higher APACHE II scores and lower 30-day survival rates. There were no correlations among the rs1360485 site SNP, sepsis risk, and patient 30-day survival. CONCLUSION: The HMGB1 gene rs2249825 and rs1045411 site SNPs are associated with susceptibility and outcomes of Chinese Han patients with sepsis. The rs2249825 locus C allele and the rs1045411 locus A allele are high risk factors for sepsis and severity in the Chinese Han population, and are associated with adverse outcomes in patients with sepsis. PMID- 30423385 TI - Phylogenetic, molecular evolution and structural analyses of the WFDC1/prostate stromal protein 20 (ps20). AB - The WFDC1 gene is frequently down-regulated or lost in prostate cancer, and the encoded protein, ps20, has been implicated in epithelial cell behaviour and angiogenesis. However, ps20 remains largely uncharacterised with respect to its structure and interacting partners. This study characterised the evolution, functionality and structural characteristics of WFDC1/ps20 using phylogenetic reconstruction and other computational approaches. Bayesian phylogenetic analyses suggested that ps20 appeared in a common ancestor of deuterostomes-protostomes. The rate of evolutionary change within the coding regions of vertebrate WFDC1 genes and the synteny conservation in mammals differed from that of other vertebrate clades, indicating a possible functional diversity of ps20 homologues. A gene set enrichment analysis of the genes around WFDC1 (conserved synteny) showed functional relationships between the WFDC1, CDH13, CRISPLD2, IRF8 and TFPI2 genes. The molecular evolution of ps20 has been driven by purifying selection, particularly in the segments corresponding to exons 3 and 4, which encode the most conserved regions of the protein. A co-evolution analysis showed that residues within these regions co-vary with each other during the evolution of ps20. These results show that the regions corresponding to exons 3 and 4 are ps20-specific structure-function modules. Homology modelling of the exon 2 encoded polypeptide and subsequent dynamics calculus using a Gaussian network model showed that residues with high conformational flexibility are part of a loop region involved in protein-protein recognition, given the similarity with other serine protease inhibitors. Residues C96, R94, L105, and C66 are critical for the integrity and functionality of this ps20 region. PMID- 30423386 TI - miR-10b-5p regulates 3T3-L1 cells differentiation by targeting Apol6. AB - MicroRNAs (miRNAs) are small, non-coding RNAs that have been proposed to control or fine-tune complex genetic pathways by post-transcriptional regulation of target genes. It was proved that numerous miRNAs have influence on the biology of adipocytes as well as on the function of adipose tissues. This study shows that miR-10b-5p expression was decreased in mice, rats, and human under obesity. In addition, the obtained results indicated that the expression level of miR-10b-5p was increased in 3T3-L1 pre-adipocytes without manifesting a significant role in 3T3-L1 cells proliferation. On the other hand, the downregulation of miR-10b-5p by the inhibitor played a role in 3T3-L1 cells differentiation and adipogenesis. Our results strongly suggest that Apol6 was the target gene of miR-10b-5p. The inhibition of miR-10b-5p promoted the differentiation of 3T3-L1 cells and adipogenesis by upregulating the Apol6 expression. Then, the upregulated Apol6 acted as an oncogene in certain obesity-related cancers. These results indicate that miR-10b-5p may have a therapeutic significance for obesity and obesity related cancers. PMID- 30423387 TI - Evidence that hydrogen peroxide, a component of oxidative stress, induces high anxiety-related behaviour in mice. AB - The link between oxidative stress and high-anxiety-related behaviour is uncontested; but the cause-effect relationship has yet to be completely elucidated. Here, the behavioural effects of hydrogen peroxide (H2O2), given to mice (n = 10 per group) in drinking water at 1%, were assessed in the light/dark choice test, the open field, the elevated-plus maze and the hole-board test. Compared to controls (drinking only water), subacute exposure (10-15 days) of mice to H2O2, the major component of reactive oxygen species (ROS) and the precursor of potent oxidants (hydroxyl radical and hypochlorous acid), affected emotional responses by inducing an anxious behaviour associated with hyperactivity. Our findings clearly showed that H2O2-treated mice exhibited anxiogenic behaviour in the light/dark choice test and in the hole-board test. Moreover, H2O2-treated mice displayed a hyperactive behaviour, revealed by a significant increase in the number of crossings made in the open field test relative to controls. Although H2O2-exposed mice made significantly less head dippings in the open arms than controls, H2O2-induced hyperactivity may have blurred anxiogenic-like behaviour in H2O2-treated mice in the elevated-plus maze. Our findings provide the evidence that H2O2, an oxidizing component, caused high anxiety-related behaviour associated with hyperactivity in mice. Antioxidants may play a role in preventing or attenuating oxidative stress-related anxiety. PMID- 30423388 TI - Possible mechanisms of prenatal cold stress induced-anxiety-like behavior depression in offspring rats. AB - Environmental factors and prenatal stress have long-term effects on offspring behavior, physical development, hypothalamic-pituitary-adrenal (HPA) axis regulation, immune activity, and disease susceptibility. To further understand the effects of prenatal cold stress on offspring, we investigated the behavior change; the expression of glucocorticoid receptor (GR), mineralocorticoid receptor (MR), brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 receptor (IGF1R), neuronal nuclei (NEUN), glial fibrillary acidic protein (GFAP), corticotropin-releasing hormone receptor 1 (CRHR1), Gamma aminobutyric acid B receptor, 2 (GABAB2) proteins in hippocampus; the ratio of CD4/CD8 lymphocyte subsets and the level of norepinephrine (NE), dopamine (DA) in the peripheral blood of weaned offspring rats using behavioral tests and biology analysis methods. The results showed that prenatal cold stress affected offspring HPA axis activity, inhibited the expression of MR, BDNF and IGF1R in the hippocampus of male offspring, and lowered the expression of GR in female offspring. The expression levels of NEUN and GFAP in the hippocampus of male and female offspring were also reduced, which may have affected the growth and development of neurons. Moreover, prenatal cold stress inhibited the expression of CRHR1 and GABAB2 in the hippocampus of male offspring, leading to decreased anxiety-like behavior in offspring; a reduced ratio of CD4 and CD8 lymphocyte subsets in the peripheral blood of male offspring; and inhibition of offspring cell immunity. In summary, prenatal cold stress inhibits the growth and development of hippocampal neurons in weaned offspring rats, and induces offspring anxiety-like behavior reduced. PMID- 30423389 TI - The link between social context-dependent anxious behavior and habenular mast cells in fear-conditioned rats. AB - Affiliative social behavior relieves the physiological reactivity to stressors, while social inequity, represented by unfairness in the social environment, causes emotional distress in animals. Mast cells are immune cells found in the brain that affect both the nervous system and emotional behavior. To determine the role of neuro-immunity in the programming of emotional behaviors, we observed brain mast cells and anxiety-like behaviors in female rats exposed to electrical foot shocks in different social environments. The following groups of rats were used in this study: control (unshocked) rats, solitarily shock-exposed rats, and shock-exposed rats in the presence of unshocked (unequal) or shocked (equal) conspecifics. An absence of significant difference in body weight or sucrose preference was seen among the different groups. Additionally, fear memory was augmented in rats shocked in the presence of either unshocked or shocked conspecifics than rats in the solitarily shocked group. Furthermore, rats shocked in the presence of unshocked conspecifics showed intensified anxiety-like behaviors after fear conditioning. Finally, we found an increase in the number of habenular mast cells in the intensified anxiogenic group, which had a significant correlation with the decreasing rate of anxiety-like behaviors. This provides evidence that habenular mast cells might be of importance in relieving the amplified biopsychological responses caused by social stress. PMID- 30423390 TI - The association between NCAM1 levels and behavioral phenotypes in children with autism spectrum disorder. AB - Autism spectrum disorders (ASDs) are neuropsychiatric disorders associated with synaptic function and plasticity. Neural cell adhesion molecule (NCAM1) dysfunction impairs synapse formation, synaptic activity and plasticity. To explore the relationship between NCAM1 and ASD, a case-control study was conducted. This research included 40 ASD children and 39 healthy children aged 2 6 years old. We measured the levels of plasma NCAM1 in ASD and healthy control groups by ELISA kits. The severity and behavioral problems of autistic children were also examined. The level of plasma NCAM1 in ASD children was significantly lower than that in controls (p < 0.05). Additionally, NCAM1 levels were negatively correlated with social motivation, social communication and the total scores assessed by Social Responsiveness Scale (SRS). NCAM1 levels positively correlated with gross motor ability and developmental quotient in the ASD group. The area under the ROC curve of NCAM1 was 0.647. These results indicated that NCAM1 levels are associated with behavioral problems in children with ASD. These include phenotypes relating to social motivation, social communication, gross motor ability and developmental quotient. These results suggest that future studies exploring the function of NCAM1 in the context of etiology of ASD may be needed. PMID- 30423391 TI - 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. PMID- 30423392 TI - Use of Risk Assessment Tools to Guide Decision-Making in the Primary Prevention of Atherosclerotic Cardiovascular Disease: A Special Report From the American Heart Association and American College of Cardiology. AB - Risk assessment is a critical step in the current approach to primary prevention of atherosclerotic cardiovascular disease. Knowledge of the 10-year risk for atherosclerotic cardiovascular disease identifies patients in higher-risk groups who are likely to have greater net benefit and lower number needed to treat for both statins and antihypertensive therapy. Current U.S. prevention guidelines for blood pressure and cholesterol management recommend use of the pooled cohort equations to start a process of shared decision-making between clinicians and patients in primary prevention. The pooled cohort equations have been widely validated and are broadly useful for the general U.S. clinical population. But, they may systematically underestimate risk in patients from certain racial/ethnic groups, those with lower socioeconomic status or with chronic inflammatory diseases, and overestimate risk in patients with higher socioeconomic status or who have been closely engaged with preventive healthcare services. If uncertainty remains for patients at borderline or intermediate risk, or if the patient is undecided after a patient-clinician discussion with consideration of risk enhancing factors (e.g., family history), additional testing with measurement of coronary artery calcium can be useful to reclassify risk estimates and improve selection of patients for use or avoidance of statin therapy. This special report summarizes the rationale and evidence base for quantitative risk assessment, reviews strengths and limitations of existing risk scores, discusses approaches for refining individual risk estimates for patients, and provides practical advice regarding implementation of risk assessment and decision-making strategies in clinical practice. PMID- 30423393 TI - 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. PMID- 30423394 TI - Systematic Review for the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. AB - BACKGROUND: The 2013 American College of Cardiology/American Heart Association guidelines for the treatment of blood cholesterol found little evidence to support the use of nonstatin lipid-modifying medications to reduce atherosclerotic cardiovascular disease (ASCVD) events. Since publication of these guidelines, multiple randomized controlled trials evaluating nonstatin lipid modifying medications have been published. METHODS: We performed a systematic review to assess the magnitude of benefit and/or harm from additional lipid modifying therapies compared with statins alone in individuals with known ASCVD or at high risk of ASCVD. We included data from randomized controlled trials with a sample size of >1,000 patients and designed for follow-up >1 year. We performed a comprehensive literature search and identified 10 randomized controlled trials for intensive review, including trials evaluating ezetimibe, niacin, cholesterol ester transfer protein inhibitors, and PCSK9 inhibitors. The prespecified primary outcome for this review was a composite of fatal cardiovascular events, nonfatal myocardial infarction, and nonfatal stroke. RESULTS: The cardiovascular benefit of nonstatin lipid-modifying therapies varied significantly according to the class of medication. There was evidence for reduced ASCVD morbidity but not mortality with ezetimibe and 2 PSCK9 inhibitors. Reduced ASCVD mortality rate was reported for 1 PCSK9 inhibitor. The use of ezetimibe/simvastatin versus simvastatin in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) reduced the primary outcome by 1.8% over 7 years (hazard ratio: 0.90; 95% CI: 0.84-0.96], 7-year number needed to treat: 56). The PSCK9 inhibitor evolocumab in the FOURIER study (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) decreased the primary outcome by 1.5% over 2.2 years (hazard ratio: 0.80; 95% CI: 0.73-0.88; 2.2=year number needed to treat: 67). In ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), alirocumab reduced the primary outcome by 1.6% over 2.8 years (hazard ratio: 0.86; 95% CI: 0.79-0.93; 2.8-year number needed to treat: 63). For ezetimibe and the PSCK9 inhibitors, rates of musculoskeletal, neurocognitive, gastrointestinal, or other adverse event risks did not differ between the treatment and control groups. For patients at high risk of ASCVD already on background statin therapy, there was minimal evidence for improved ASCVD risk or adverse events with cholesterol-ester transfer protein inhibitors. There was no evidence of benefit for the addition of niacin to statin therapy. Direct comparisons of the results of the 10 randomized controlled trials were limited by significant differences in sample size, duration of follow-up, and reported primary outcomes. CONCLUSIONS: In a systematic review of the evidence for adding nonstatin lipid-modifying therapies to statins to reduce ASCVD risk, we found evidence of benefit for ezetimibe and PCSK9 inhibitors but not for niacin or cholesterol-ester transfer protein inhibitors. PMID- 30423395 TI - Secretion of the recombination alpha-amylase in Escherichia coli and purification by the gram-positive enhancer matrix (GEM) particles. AB - alpha-Amylases are important enzymes in industry. A recombinant alpha-amylase with a secretion signal peptide and an AcmA tag was expressed in Escherichia coli to improve the yield. The induction concentrations were optimized, and the temperature had a significant influence on soluble expression and secretion. A visible band could be obtained when the induction was conducted at 16 degrees C. The gram-positive enhancer matrix (GEM) particles could separate and purify the recombinant alpha-amylase with the AcmA tag, and no visible band could be seen in the culture even after the culture was concentrated ten times. The solution and concentration of the recombinant alpha-amylase could be adjusted by GEM particles. The recombinant untagged alpha-amylase was obtained after digestion. The alpha-amylase was characterized. The recombinant alpha-amylase was a thermophilic enzyme with a broad pH tolerance. In addition, the enzyme activity of the recombinant alpha-amylase was independent of Ca2+. The recombinant alpha amylase contained the OmpA signal peptide and the AcmA tag and was expressed and purified quickly and easily. PMID- 30423396 TI - Lipase-catalyzed selective enrichment of omega-3 polyunsaturated fatty acids in acylglycerols of cod liver and linseed oils: Modeling the binding affinity of lipases and fatty acids. AB - Present study employed molecular modeling method to elucidate the binding affinity of lipases with fatty acids of different chain lengths; and investigated the effects of lipases positional and fatty acids specificity on omega-3 polyunsaturated fatty acids (omega-3 PUFAs) enrichment in cod liver and linseed oils. Among the lipases studied, molecular modeling showed the active sites of Candida rugosa lipase (CRL) had a low C-Docker interactive energy for saturated (SFA) and monounsaturated (MUFA) fatty acids which predicted CRL to have highest preferences to selectively hydrolyze resulting in efficient enrichment of omega-3 PUFAs. Verification experiments showed the SFA and MUFA in the acylglycerol fraction includes monoacylglcyerols (MAG), diacyglycerols (DAG), and triacylglycerols (TAG) of CRL-hydrolyzed cod liver oil decreased from the initial 25.21 to 16.88% and 45.25 to 32.17%, respectively. In addition, CRL-hydrolyzed cod liver oil demonstrated 88.36% of omega-3 PUFAs enrichment. The regio distribution of fatty acids in CRL-hydrolyzed cod liver oil were not significantly different than that of cod liver oil indicating the omega-3 PUFAs enrichment was due to fatty acids selectivity and not positional selectivity of CRL. PMID- 30423397 TI - Preparation of an injectable modified chitosan-based hydrogel approaching for bone tissue engineering. AB - This research aimed to design an injectable chitosan-based hydrogel for bone tissue engineering. To this end, chitosan should not only be soluble in water but also be thixotropic. Therefore, it can be used as an injectable liquid that can form a hydrogel under physiological conditions. Accordingly, chitosan was modified with carboxymethyl chloride and the resultant carboxymethyl chitosan (CMCTS) was conjugated to alpha-cyclodextrin (alpha-CD) to yield CMCTSCD. The alpha-CD conjugation improved the water solubility and the hydrophobic cavities to function as crosslinking points by forming an inclusion complex with poly(ethylene glycol) (PEG). The optimum mole ratio of alpha-CD (as CMCTSCD) to PEG was found to be 2 to 4 with a threading number of ~2.5. The sol-to-gel transition was formed within 450 +/- 10 min. The interconnecting porous structure of the gel was observed by scanning electron microscope. Therefore, CMCTSCD/PEG is a potential novel design that can be used as an injectable hydrogel for bone tissue engineering. PMID- 30423398 TI - Cytokine variations within brain structures in rats selected for differences in aggression. AB - The present study examined the content of cytokines (IL-1beta, IL-2, IL-6, IL-10) in the brain structures (the hypothalamus, striatum, frontal cortex, and hippocampus) in two rat lines selected for differences in fear-induced aggression at 2, 4, and 24 h after a peripheral injection of saline or lipopolysaccharide (LPS, 250 MUg/kg). LPS stimulation elevated cytokine activity above baseline levels in both aggressive and nonaggressive rats, but the pattern, time course of cytokine changes, and their regional characteristics varied according to the animal aggressiveness. After LPS administration, aggressive rats showed increased levels of IL-1beta in the hypothalamus at 2 and 4 h and in the frontal cortex at 4 and 24 h compared to LPS-treated nonaggressive line. IL-2 was increased in the frontal cortex and striatum of aggressive rats within 24 h, while IL-6 elevation in the hypothalamus was found at 4 h and in the frontal cortex at 2 and 4 h. In the hippocampus, the levels of IL-1beta, IL-2, and IL-6 were lower in LPS-treated aggressive rats than in nonaggressive animals. The levels of anti-inflammatory cytokine IL-10 were also decreased in all brain structures of aggressive rats receiving LPS. The results indicate that genetic predisposition to increased aggression is associated with a time and region-dependent changes in the levels of pro- and anti-inflammatory cytokines. PMID- 30423399 TI - Phosphorylation of serine 305 in tau inhibits aggregation. AB - Alzheimer's disease and other tauopathies are characterized by the brain accumulation of hyperphosphorylated aggregated tau protein forming pathological inclusions. Although elevated tau phosphorylated at many amino acid residues is a hallmark of pathological tau, some evidence suggest that tau phosphorylation at unique sites, especially within its microtubule-binding domain, might inhibit aggregation. In this study, the effects of phosphorylation of two unique residues within this domain, serine 305 (S305) and serine 320 (S320), were examined in the context of established aggregation and seeding models. It was found that the S305E phosphomimetic significantly inhibited both tau seeding and tau aggregation in this model, while S320E did not. To further explore S305 phosphorylation in vivo, a monoclonal antibody (2G2) specific for tau phosphorylated at S305 was generated and characterized. Consistent with inhibition of tau aggregation, phosphorylation of S305 was not detected in pathological tau inclusions in Alzheimer's disease brain tissue. This study indicates that phosphorylation of unique tau residues can be inhibitory to aggregate formation, and has important implications for potential kinase therapies. Additionally, it creates new tools for observing these changes in vivo. PMID- 30423400 TI - Diagnostic value of NT-proCNP compared to NSE and S100B in cerebrospinal fluid and plasma of patients with sepsis-associated encephalopathy. AB - Sepsis-associated encephalopathy (SAE) has significant impact on the neurocognitive outcome of sepsis survivors. This study was conducted to analyze the amino-terminal propeptide of the C-type natriuretic peptide (NT-proCNP) as a biomarker for SAE in comparison to neuron-specific enolase (NSE) and S100B protein. Cerebrospinal fluid (CSF) and plasma samples from twelve septic patients with SAE and nine non-septic controls without encephalopathy were analyzed. The assessment of SAE comprised a neuropsychiatric examination, delirium screening using the confusion assessment method in the ICU (CAM-ICU) and magnetic resonance imaging (MRI) in all participants. NSE, S100B and NT-proCNP were measured in plasma at study days 1, 3 and 7 in sepsis patients, once in controls and once in the CSF of both groups. The long-term outcome was assessed using the validated Barthel index (BI). Plasma NT-proCNP levels were significantly higher in the sepsis cohort compared to controls with peak concentrations at study day 1 (10.1 +/- 6.6 pmol/l vs. 3.3 +/- 0.9 pmol/l; p < 0.01) and a decrease over time. Plasma NT-proCNP levels at day 7 correlated with NT-proCNP in CSF (r = 0.700, p < 0.05). A comparable decrease of significantly higher plasma S100B values in sepsis patients compared to controls was observed. Plasma NSE levels were not significantly different between both groups. CSF NT-proCNP levels just tended to be higher in sepsis patients compared to controls and tended to be higher in patients with septic brain lesions seen on MRI. In the sepsis cohort CSF NT proCNP levels correlated with CSF Interleukin-6 (IL-6) levels (r = 0.616, p < 0.05) and systemic inflammation represented by high plasma procalcitonin (PCT) levels at day 3 (r = 0.727, p < 0.05). The high peak concentration of plasma NT proCNP in the early phase of sepsis might help to predict the emergence of SAE during the further course of disease. NT-proCNP in plasma might, in contrast to CSF, indicate neurological impairment in patients with SAE. PMID- 30423401 TI - Changes in white matter and the effects of fluoxetine on such changes in the CUS rat model of depression. AB - OBJECTIVE: To explore the pathogenesis of depression and the possible mechanism of the effects of selective serotonin reuptake inhibitors (SSRIs) on the myelinated fibers and myelin sheaths in the white matter during the antidepressant action of fluoxetine. METHODS: In this study, Sprague Dawley (SD) rats were divided into a Control group, a group treated with CUS and no drugs (CUS/Standard group) and a group treated with CUS and fluoxetine (CUS/FLX group). The CUS/FLX group was treated with fluoxetine at dose of 5 mg/kg for 21 days. The white matter volume, the myelinated fiber parameters and the myelin sheath volume in the white matter were calculated from transmission electron microscope images through unbiased stereological methods. RESULTS: The total volume and total length of myelinated fibers;and mean volume of white matter of the CUS/Standard group were significantly decreased compared to values from the control group (p = 0.025, p = 0.007, p = 0.000), whereas no significant differences in these stereological parameters were found between the CUS/Standard and CUS/FLX groups (p > 0.05). CONCLUSIONS: Fluoxetine successfully treated depression-like behavior but had no effects on the white matter or its component myelinated fibers in the CUS rat model of depression. PMID- 30423402 TI - Tetrahydrocurcumin and octahydrocurcumin, the primary and final hydrogenated metabolites of curcumin, possess superior hepatic-protective effect against acetaminophen-induced liver injury: Role of CYP2E1 and Keap1-Nrf2 pathway. AB - Acetaminophen (APAP) overdose-induced hepatotoxicity is tightly associated with oxidative stress. Tetrahydrocurcumin (THC) and octahydrocurcumin (OHC), the primary and final hydrogenated metabolites of curcumin (CUR), possess stronger antioxidant activity in vitro. The present study was performed to investigate the potential and mechanism of OHC and THC against APAP-induced hepatotoxicity in parallel to CUR. Our results showed that OHC and THC dose-dependently enhanced liver function (ALT and AST levels) and alleviated histopathological deterioration. Besides, OHC and THC significantly restored the hepatic antioxidant status by miring level of MDA and ROS, and elevated levels of GSH, SOD, CAT and T-AOC. In addition, OHC and THC markedly suppressed the activity and expressions of CYP2E1, and bound to the active sites of CYP2E1. Moreover, OHC and THC activated the Keap1-Nrf2 pathway and enormously enhanced the translational activation of Nrf2-targeted gene (GCLC, GCLM, NQO1 and HO-1) against oxidative stress, via inhibiting the expression of Keap1 and blocking the interaction between Keap1 and Nrf2. Particularly, OHC and THC exerted superior hepato protective and antioxidant activities to CUR. In conclusion, OHC and THC possess favorable hepato-protective effect through restoring antioxidant status, inhibiting CYP2E1 and activating Keap1-Nrf2 pathway, which might represent promising antioxidants for the treatment of APAP-induced hepatotoxicity. PMID- 30423403 TI - Neferine suppresses diethylnitrosamine-induced lung carcinogenesis in Wistar rats. AB - Neferine is a bisbenzylisoquinoline alkaloid isolated from the embryos of lotus which has attracted attention for its anti-inflammatory and anti-cancer activities. The aim of this study was to evaluate the anti-cancer effect of neferine against diethylnitrosamine (DEN)-induced lung carcinogenesis in Wistar rats and to explore the underlying molecular mechanism. DEN-induced oxidative stress is mediated by alterations in the levels of pulmonary reactive-oxygen species, lipid peroxidation, protein carbonyl content and antioxidant status. Thus, treatment with neferine restored cellular normalcy, highlighting the antioxidant potential of neferine in mitigating the oxidative stress-mediated damage produced during DEN-induced lung carcinogenesis. Histopathological analysis showed disorganized alveolar structure, thickened alveolar wall, infiltration of inflammatory cells in DEN-induced rats, the damage was significantly reduced upon neferine treatment. DEN-induced rats exhibited increased gene expression of NF-kappaB, COX-2, CYP2E1, VEGF, Bcl-2, PI3K/AKT/mTOR and significantly decreased the gene expression of p53, Bax, caspase-9 and caspase-3. Neferine treatment restored the DEN- induced alteration of these gene expression levels. Further, blotting analysis also revealed increased expression of NF-kappaB, COX-2, Bcl-2 and decreased expression of Bax, caspase-9 and caspase 3 proteins in DEN-induced rats. Neferine treatment restored the expression of these proteins in DEN- induced lung carcinogenesis. PMID- 30423404 TI - L-arginine/5-fluorouracil combination treatment approaches cells selectively: Rescuing endothelial cells while killing MDA-MB-468 breast cancer cells. AB - Reducing the adverse effects of chemotherapy on normal cells such as endothelial cells is a determinant factor of treatment success especially in pregnant women. In this regard, modulatory effect of L-arginine on various cancers is still a controversial topic in cancer therapy. So, this study aimed to compare the effect of L-arginine treatment alone and in combination with 5-fluorouracil (5-FU) on the survival and angiogenesis of primary human umbilical vein endothelial cells (HUVECs) and the breast cancer cell line of MDA-MB-468. Combinations of L arginine and 5-FU increased cell survival in HUVECs but induced cell death in MDA MB-468 cells. Nitric oxide assay showed an increase of this molecule in both cell lines. Assessments of metabolic changes as well as molecular docking indicated a decrease in glycolytic activity of cancer cells but not normal cells. Angiogenesis induction in HUVECs was confirmed through VEGF and MMP-2,9 up regulated gene expressions. However, a down-regulation of the above-mentioned genes expression was observed in MDA-MB-468. Furthermore, an in vivo increased angiogenesis and decreased embryo toxicity was observed in combination treatment. Altogether, these findings clearly suggest that L-arginine inhibits cell death induced by 5-FU in HUVECs through attenuating the adverse effects of 5-FU, while it does not do so in breast cancer cells. PMID- 30423405 TI - Toxic effects of mineral oil saturated hydrocarbons (MOSH) and relation to accumulation in rat liver. AB - Humans are daily exposed to mineral oil saturated hydrocarbons (MOSH) from the diet. We exposed female Fischer 344 rats to a broad mixture and sub-fractions of MOSH. Chemical characterization of the MOSH mixture used and material accumulated in rat tissues were previously reported. Rats were exposed to feed containing 0 4000 mg/kg broad MOSH mixture for 30, 60, 90 and 120 days; and for 120 days to feed containing different MOSH fractions: i) mainly molecular masses < C25 (S C25), ii) dewaxed, mainly molecular masses > C25 (L-C25) and iii) the L-C25 fraction mixed with wax largely consisting of n-alkanes > C25 (L-C25W). Treatments related effects were increased liver and spleen weight, as well as vacuolization and granuloma formation with lymphoid cell clusters in the liver, but effects varied strongly between the MOSH fractions tested. We conclude that increased liver and spleen weights were mainly related to accumulated iso-alkanes and substituted cycloalkanes, but also wax n-alkanes. Induction of liver granuloma appeared to be related to n-alkanes > C25 and not to the accumulated amount of MOSH. Immune responses to an injected antigen were not affected. MOSH fractions associated with increased liver and spleen weights were similar to those accumulating in humans. PMID- 30423406 TI - SRC-3 inhibition blocks tumor growth of pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant and lethal disease with few treatment options. Steroid receptor coactivator-3 (SRC-3, also known as NCOA3, AIB1, pCIP, ACTR, RAC3, TRAM1) sits at the nexus of many growth signaling pathways and has been pursued as a therapeutic target for breast, prostate and lung cancers. In this study, we find that SRC-3 is overexpressed in PDAC and inversely correlates with patient overall survival. Knockdown of SRC-3 reduces pancreatic cancer cell proliferation, migration and invasion in vitro. Additionally, inhibition of SRC-3 using either shRNA or a small molecule inhibitor can significantly inhibit tumor growth in orthotopic pancreatic cancer mouse models. Collectively, this study establishes SRC-3 as a promising therapeutic target for pancreatic cancer treatment. PMID- 30423407 TI - Targeting AR-Beclin 1 Complex-Modulated Growth Factor Signaling Increases the Antiandrogen-Enzalutamide Sensitivity to Better Suppress the Castration-Resistant Prostate Cancer Growth. AB - While the recently developed antiandrogen Enzalutamide (Enz) can extend survival for 4.8 months in castration-resistant prostate cancer (CRPC) patients, eventually most of these CRPC patients may develop resistance to the Enz without a clear mechanism. Here we found the expression of Beclin 1 was decreased in both Enz-resistant (EnzR) cell lines (EnzR1-C4-2 and EnzR2-C4-2B) as compared to their parental Enz-sensitive (EnzS) (EnzS1-C4-2 and EnzS2-C4-2B) cells, and targeting the Beclin 1 could lead to increase the Enz-sensitivity in these two CRPC cell lines. Mechanism dissection revealed that Enz might function via altering the interaction between Beclin 1 and the androgen receptor (AR) to decrease the activity of Beclin 1-Vps15-Vps34 complex thus increasing the ERK-mediated growth factor signaling to alter the Enz sensitivity. Interrupting the AR-Beclin 1/ERK signaling with ectopic BECN1 or ERK inhibitor led to alter the Enz sensitivity in both EnzR1/S1-C4-2 and EnzR2/S2-C4-2B cells. Together, these results suggest that targeting this newly identified AR-Beclin 1 complex-mediated ERK growth factor signaling with small molecule inhibitor may help potentially develop new therapies to better suppress the EnzR CRPC. PMID- 30423408 TI - YTHDF2 suppresses cell proliferation and growth via destabilizing the EGFR mRNA in hepatocellular carcinoma. AB - N6-methyladenosin (m6A) is one of the most pervasive modification of mRNA in eukaryotes and the m6A methyltransferases and demethylases play critical roles in many types of cancer. However the role of m6A-binding proteins in cancer remains elusive. Here we report that the down-regulation of YTHDF2 was specifically induced by hypoxia in hepatocellular carcinoma (HCC) cells, and that overexpression of YTHDF2 suppressed cell proliferation, tumor growth and activation of MEK and ERK in HCC cells. Mechanistically, YTHDF2 directly bound the m6A modification site of EGFR 3'-UTR to promote the degradation of EGFR mRNA in HCC cells. This is the first report showing that YTHDF2 may act as a tumor suppressor to repress cell proliferation and growth via destabilizing the EGFR mRNA in HCC. PMID- 30423409 TI - Healthcare Burden of Probable and Proven Invasive Mucormycosis: A Multicenter Cost-of-Illness Analysis of Patients Treated in Tertiary Care Hospitals between 2003 - 2016. AB - BACKGROUND: Invasive mucormycosis (IM) is a rare invasive fungal infection with high mortality rates. However, data concerning the clinical and economic burden of IM are scarce. AIM: To evaluate the direct treatment costs and additional expenditures of patients with IM. METHODS: We performed a retrospective cost-of illness analysis of cases with IM extracted from FungiScopeTM- Global Registry for Emerging Fungal Infections, accessible through the epidemiological research platform www.ClinicalSurveys.net. Results of patients with IM were compared to matched patients with similar underlying conditions based on the German Diagnosis Related Group (G-DRG) coding. FINDINGS: Out of 46 patients with probable/proven IM included, 31 (67%) patients were male and median age was 53 years (range 11 - 88 years). Forty-two patients (92%) had haematological diseases as the most common risk factor. Analysis of cost factors identified antifungal treatment due to IM as the primary cost driver ?22,816 (95% CI: ?15,036 - ?32,346), resulting in mean overall direct treatment costs of ?53,261 (95% CI: ?39,660 - ?68,825). Compared to matched patients, patients with IM were treated in hospital for 26.5 (SD 31.8 days; P< 0.001) additional days, resulting in mean additional costs of ?32,991 (95% CI: ?21,558 - ?46,613; P< 0.001). Probable IM, as well as absence of chemotherapy, surgical measures due to IM, and antifungal prophylaxis were associated with lower overall costs. Nineteen patients (41.3%) died during hospitalization. CONCLUSION: Our study demonstrates the considerable healthcare burden of IM. The choice of an antifungal agent for treatment of IM had no impact on overall cost. PMID- 30423410 TI - Microbial water quality management of dental unit water lines at a dental school. AB - Contaminated dental unit water lines (DUWLs) are a possible source for spreading micro-organisms in the dental practice. This study reports the microbial load of the water from DUWLs of a large dental school over time. The water quality of 231 dental chairs was tested three times over 1.5 years; 175 DUWLs at student clinics and 56 DUWLs at staff clinics. DUWLs at the staff clinics met the Dutch requirement of 100 cfu/ml. An increasing amount of DUWLs at the student clinics complied with this requirement, indicating that the local protocols were adequate, but that the compliance can be improved. PMID- 30423411 TI - Instrument cleanliness and protein misfolding disorders. PMID- 30423412 TI - Broad-spectrum antibiotic prescriptions are unevenly discontinued throughout the week. AB - To investigate prescribing patterns of in-hospital broad-spectrum antibiotics (anti-meticillin-resistant Staphylococcus aureus drugs, carbapenems, and piperacillin/tazobactam), we analysed data of the distribution of antibiotic initiations and discontinuations throughout the week at Osaka University Hospital, Japan. There were no statistical differences in the number of initiations among weekdays. However, the broad-spectrum antibiotics were disproportionately discontinued on Tuesday or on the second day after a holiday. This study suggested that the broad-spectrum antibiotics tend to be continued over weekends or holidays and discontinued thereafter, probably due to behavioural factors beyond medical indications that need to be addressed in future antimicrobial stewardship initiatives. PMID- 30423413 TI - Surgical instruments complex design as barrier for cleaning effectiveness, favouring biofilm formation. AB - AIM: Determine the cumulative effect of 20 cycles of contamination, cleaning (manual or manual followed by automated) and steam sterilisation on high-complex design reusable surgical instruments (RSI) used for orthopaedic surgery. METHOD: New flexible medullary reamers and depth gauges were contaminated by soaking in tryptone soya broth, containing 5% sheep blood and 109CFU/mL of Staphylococcus aureus (ATCC 25923), for 5 minutes. To mimic a worse-case scenario, RSI were dried seven hours and subjected to either a) rinsing in distilled water, b) manual cleaning or c) manual plus automated cleaning (gold standard), and steam sterilisation. The contamination, cleaning and sterilisation cycle was repeated 20 times. Adenosine Triphosphate (ATP) was measured after cleaning procedures, while microbial load and residual protein were measured following the 10th and 20th reprocessing, in triplicate. Scanning electron microscopy (SEM) was used to confirm soil and biofilm presence on the RSI after the 20th reprocessing. FINDINGS: Manual and manual plus automated cleaning significantly reduced the amount of ATP and protein residues for all RSI. Viable bacteria were not detected following sterilisation. However, SEM detected soil after automated cleaning, and soil, including biofilms, after manual cleaning. CONCLUSION: Soil and/or biofilms were evident on complex-design RSI following 20 cycles of contamination and reprocessing, even using the gold standard method of cleaning. Although the depth gauges could be disassembled, biological residues and biofilm accumulated in its lumen. The current design of these RSI prevents removal of all biological soil and this may have an adverse effect on patient outcome. PMID- 30423414 TI - Multifunctional magnetic-gold nanoparticles for efficient combined targeted drug delivery and interstitial photothermal therapy. AB - Abundant efforts have recently been made to design potent theranostic nanoparticles, which combine diagnostic and therapeutic agents, for the effective treatment of cancer. In this study, we developed multifunctional magnetic gold nanoparticles (MGNPs) that are able to (i) selectively deliver the drug to the tumor site in a controlled-release manner, either passively or by using magnetic targeting; (ii) induce photothermal therapy by producing heat by near-infrared (NIR) laser absorption; and (iii) serve as contrast agents for magnetic resonance imaging (MRI) (imaging-guided therapy). The prepared MGNPs were characterized by different physical techniques. They were then coated and conjugated with polyethylene glycol (PEG) and doxorubicin (DOX) to form MGNP-DOX conjugates. The high efficacy of MGNP-DOX for combined chemo-photothermal therapy was observed both in vitro and in vivo. The effectiveness of MGNP-DOX as theranostic nanoparticles was confirmed by histopathological examination and immunohistochemical studies. Moreover, MGNP-DOX showed good potential as MRI contrast agents for guided chemo-photothermal synergistic therapy. PMID- 30423415 TI - Transdermal drug delivery of triptolide-loaded nanostructured lipid carriers: Preparation, pharmacokinetic, and evaluation for rheumatoid arthritis. AB - The objective of this present study was to develop and evaluate the triptolide loaded nanostructured lipid carriers (TPL-NLCs) for transdermal drug delivery system (TDDS). TPL-NLCs was prepared with emulsification technique and optimized by central composite design of a response surface methodology (CCD-RSM). The optimized TPL-NLCs were spherical and physically stable with the average size of 139.6.0 +/- 2.53 nm and Zeta potential of -36.03 +/- 2.41 mV. The encapsulation efficiency and drug loading were 97.15% +/- 9.46 and 10.35% +/- 1.12, respectively. Moreover, the in vitro release study showed that TPL-NLCs had a sustained release profiles and the in vitro penetration study indicated that TPL NLCs could effectively penetrate into skin. Besides, the methodology of skin blood synchronous microdialysis was established to evaluate the pharmacokinetics of TPL-NLCs in vivo and the results displayed that the TPL concentration in skin was higher than that in blood. And TPL-NLCs presented a remarkable effect of decreasing knee edema, inhibiting inflammation by regulating the levels of TNF alpha, IL-1beta and IL-6, which indicated that TPL-NLCs was a promising topical administration in treatment of edema and inflammation associated with rheumatoid arthritis (RA). PMID- 30423416 TI - Modulation of Alendronate release from a calcium phosphate bone cement: An in vitro osteoblast-osteoclast co-culture study. AB - In this study, we loaded a biomimetic calcium phosphate bone cement (CPC) with relatively high amounts of a bisphosphonate through the use of Solid Lipid Microparticles (MPs) and investigated bone cells response to the composite cements. 10, 20 and 30% w/w of Alendronate (AL) were successfully introduced into microparticles of Cutina HR and Precirol, which were prepared by means of spray congealing technique. Addition of AL-loaded MPs to the cement composition provoked a lengthening of the setting and of the hardening processes. However, setting times were still in a range useful for clinical applications, except for the cements at the highest Alendronate content. The composite cements displayed a sustained drug release over time. Cements with the best performances in terms of setting, hardening, mechanical properties and drug release were submitted to in vitro tests using a co-culture model of osteoblast and osteoclast. The results showed that the use of MPs to enrich the cement composition with Alendronate provides materials able to inhibit osteoclast viability and activity, while promoting osteoblast viability and earlier differentiation, indicating that the MPs-cements are good delivery systems for bisphosphonates. PMID- 30423417 TI - Vaginal residence and pharmacokinetic preclinical study of topical vaginal mucoadhesive W/S emulsions containing ciprofloxacin. AB - The aim of this work is to test the in vivo behavior of a mucoadhesive vaginal emulsion resistant to the clearance of vaginal fluids using ciprofloxacin (CPX) as an anti-infective model of drug. CPX is a broad-spectrum antibiotic used in the treatment of sexual tissues infections, as intravenous injection in a dose of 20 mg every 12 h. In this study, CPX was incorporated in water in silicone (W/S) mucoadhesive emulsions and the in vivo residence time and the CPX in vivo absorption and distribution to the sexual organs was studied using the rat as animal model. W/S emulsion shows excellent in vitro bioadhesion having high resistance to the vaginal fluids clearance. The drug release profiles show a constant release of CPX during at least 6 h according to a zero-order kinetics. In vivo computerized PET/CT Image Analysis after intravaginal administration to rats indicates that W/S emulsions remain in the vaginal area for a long time and shows a good absorption of the radiotracers used as markers through the vaginal mucosa. Ciprofloxacin pharmacokinetic studies developed after the single intravaginal administration of W/S emulsion shows a good absorption and distribution of CPX on the uterus and ovarian tissue. A significant concentration of CPX in the sexual tissues was observed after 24 h of administration of W/S emulsion. Therefore, W/S emulsions have a good in vivo residence and drug release in the vaginal mucosae showing a great potential for the treatment of sexual tissues infections, as vaginal bioadhesive delivery systems of antinfectious drugs. PMID- 30423418 TI - Optimization of a novel in situ gel for sustained ocular drug delivery using Box Behnken design: In vitro, ex vivo, in vivo and human studies. AB - The aim of the present research work was to formulate, optimize and evaluate the in-situ gel for the ophthalmic drug delivery using the combination of gellan gum and carbopol 934P. The Box-Behnken design was applied to optimize the concentration of gellan gum (X1), carbopol 934P (X2) and benzododecenium bromide (X3) to achieve the maximum viscosity [at physiological condition; 35 degrees C, pH 7.4, and simulated tear fluid (STF)], mucoadhesive strength, permeability coefficient and sustained release of the drug from the gel with constraint on the viscosity under the non-physiological condition (25 degrees C, pH 5). Response surface plots were drawn, the statistical validity of the polynomials was established, and optimized formulation was selected by the feasibility and grid search. The design proposed the optimized batch by selecting the independent variables as gellan gum (0.55% w/v), carbopol 934P (0.35% w/v) and benzododecenium bromide (0.013% w/v) to achieve the maximum viscosity (3363 cps) at physiological condition, mucoadhesive strength (22.35 dyn/cm2), t90% (1200 min), permeability coefficient (1.36 * 10-5 sq.cm/sec), with minimum viscosity (131 cps) under the non-physiological condition. The combination of gellan gum and carbopol 934P improved the gelation (synergistic effect) characteristics of the in situ gel. The optimized in situ gel was clear, isotonic, pH 4.7 and showed pseudoplastic flow, high in vitro gelling capacity, low contact angle, acceptable hardness (51018 gm), compressibility (64617 gm) and adhesiveness (74 gm) values for the ocular application. The ex vivo study showed the significant protection of the mast cell from the degranulation. The ocular irritation and histopathology studies in the rabbit eyes confirmed the safety of in situ gel for human use. The in vivo drug release studies showed the presence of drug in the rabbit tear fluid up to 3 h in comparison to just 1 h with the eye drop solution. The contact time of the in situ gel in the human eye was 15.0 +/- 2.5 min, which was >2 folds higher than the marketed gel (6.0 +/- 3.2 min), which could reduce the dosing frequency and total dose of drug. The Box-Behnken design facilitated the optimization of in situ gel for sustained ophthalmic drug delivery. PMID- 30423419 TI - Illness and drug modifiable factors associated with violent behavior in homeless people with severe mental illness: results from the French Housing First (FHF) program. AB - OBJECTIVE: The aim of this study was to investigate the factors associated with violent behavior in a large multicenter sample of Homeless Schizophrenia (SZ) and Bipolar Disorder (BD) (HSB) subjects. METHODS: This multicenter study was conducted in 4 French cities: Lille, Marseille, Paris and Toulouse. Violent behavior was defined by at least one episode of verbal or physical violence in the last 6 months. RESULTS: Overall, 675 HSB patients, mean aged 38 years and 82.5% men were included, 458 SZ (68.4%) and 212 BD (31.6%). During the 6 months before evaluation, 213 (34.3%) committed at least one physical or verbal violence. In multivariate analysis, violence has been associated with younger age (aOR = 0.96[0.94-0.99], p = .001), number of nights in the street (aOR = 1.01[1.01-1.01]), BD diagnosis (aOR = 1.63[1.01-2.65], p = .04), higher current illness severity (CGI score) (aOR = 1.32[1.07-1.64], p = .01), higher rates of current manic episode (aOR = 2.24[1.32-3.81], p = .002), current alcohol use disorder (aOR = 2.05 [1.33-3.15], p = .001), antisocial personality disorder (aOR = 2.51[1.55-4.07], p < .001) and with antidepressant consumption (aOR = 2.01[1.01 4.04], p = .04). No specific antipsychotic or mood stabilizer has been associated with decreased rates of violent behavior, however clozapine, lithium and carbamazepine remained poorly prescribed. CONCLUSION: In case of violent behavior in HSB subjects, clinicians should focus in priority on the treatment of mania, antidepressant iatrogenic effect and alcohol use disorder by pharmacological and non-pharmacological treatments. Clozapine, lithium and carbamazepine should be chosen as the treatments of reference in this population but may be hard to manage in some cases. The current clinical trial number is NCT01570712. PMID- 30423420 TI - Changes in motor cortical excitability in schizophrenia following transcranial direct current stimulation. AB - Schizophrenia is a disorder associated with cortical inhibition deficits. Transcranial direct current stimulation (tDCS) induces changes in cortical excitability in healthy subjects and individuals with neuropsychiatric disorders depending on the stimulation parameters. Our aim was to investigate whether a previously published tDCS protocol associated with symptomatic improvement in schizophrenia would induce changes in motor cortical excitability, assessed by transcranial magnetic stimulation paradigms, i.e., short-interval intracortical inhibition (SICI) and intra-cortical facilitation (ICF). We assessed cortical excitability measurements in 48 subjects with schizophrenia before and after a single session of active tDCS (20 min, 2 mA, anode over left dorsolateral prefrontal cortex, cathode over left temporoparietal cortex) or sham. Those who received active tDCS had a significant increase of SICI in the left motor cortex compared to those who received sham stimulation (Cohen's d = 0.54, p = .019). No changes were observed for ICF. In addition, lower SICI was associated with higher age (beta = -0.448, p < .01). Increase in intracortical inhibition may indicate a mechanism of action of tDCS in this population. Future studies should investigate whether this finding is a biomarker of treatment response for schizophrenia. PMID- 30423421 TI - Circadian clock genes link photoperiodic signals to lipid accumulation during diapause preparation in the diapause-destined female cabbage beetles Colaphellus bowringi. AB - Many organisms have evolved a series of adaptions, such as dormancy or diapause in insects that enable them to withstand seasonally adverse conditions. In insects, photoperiodic signals received during the diapause induction phase have irreversible effect on diapause initiation. Insects continue to be exposed to diapause-inducing photoperiod after the diapause induction phase during diapause preparation before they enter diapause. However, how photoperiodic signals experienced during the diapause preparation phase (DPP) regulate diapause remains largely unclear. In this paper, we investigate this in the cabbage beetle Colaphellus bowringi. The cabbage beetle is in many respects an ideal experimental model in which to investigate the effect of photoperiodic signals on the DPP because it has facultative reproductive diapause induced by long-day length and has differentiable diapause induction and preparation phases. We found that the lipid content of female cabbage beetles decreased after diapause destined (DD) individuals were exposed to a diapause-inhibiting photoperiod during the DPP. Two circadian clock negative regulators, per and tim, were probably involved in the photoperiodic response of beetles during the DPP. Per and tim presented obvious oscillation of circadian rhythm and photoperiodic response during the DPP in DD females and knock-down of these genes in DD females caused their lipid content to decrease. Per and tim probably promote lipid accumulation by regulating the expression of genes that regulate lipogenesis and lipolysis. Moreover, decreased lipid accumulation caused by exposure to different photoperiods during the DPP was independent of juvenile hormone. In summary, these results suggest that photoperiodic signals received during the DPP influence lipid accumulation in DD insects. DD insects still have some ability to monitor photoperiodic changes during the DPP and per and tim are probably involved in regulating physiological responses to photoperiodic signals during diapause preparation. These results shed light on the relationship between photoperiodic signals and diapause preparation, and may provide new insights on both how to better utilize insects as resources and for pest management. PMID- 30423422 TI - Functional characterization of odorant-binding proteins from the scarab beetle Holotrichia oblita based on semiochemical-induced expression alteration and gene silencing. AB - With the advent of next-generation sequencing, it is now possible to rapidly identify the entire repertoire of olfactory genes likely to be involved in chemical communication of an insect species. It remains, however, a challenge to identify olfactory proteins, such as odorant receptors and odorant-binding proteins (OBPs), vis-a-vis the odorants they detect. It has been reported that exposing the olfactory system to a physiologically relevant odorant alters the transcript levels of odorant receptor(s) involved in the detection of the tested odorant. We applied this paradigm in an attempt to identify putative OBPs from the scarab beetle Holotrichia oblita involved in the reception of plant-derived kairomones. Twenty-nine OBP genes were identified in the H. oblita transcriptome, 20 of which were enriched in antennae compared with nonolfactory tissues. Of these, 2 OBP genes, HoblOBP13 and HoblOBP9, were upregulated upon exposure to one of the female attractants (E)-2-hexenol and phenethyl alcohol; none of the OBP transcripts changed upon exposure to methyl anthranilate, which does not attract H. oblita females. Binding assays showed that HoblOBP13 and HoblOBP9 have high affinity for (E)-2-hexenol and phenethyl alcohol, respectively. RNAi treatment showed that transcripts of both HoblOBP13 and HoblOBP9 declined in a time-course manner 24-72 h postinjection. OBP-dsRNA-treated female beetles showed significantly lower attraction to (E)-2-hexenol and phenethyl alcohol than did water-injected beetles and those treated with GFP-dsRNA. We, therefore, concluded that HoblOBP13 and HoblOBP9 are essential for H. oblita reception of the plant derived kairomones (E)-2-hexenol and phenethyl alcohol. PMID- 30423423 TI - Microglia metabolism in health and disease. AB - In the last decade tremendous progress has been made in understanding how the immune system reacts to insults. During this progress it became obvious that those immune responses are tightly regulated and cross-linked with distinct metabolic changes in immune cells. Extensive research has been conducted mainly on subtypes of T cells, which use different metabolic pathways during differentiation processes and activation states. In addition, it has also been established later, that the innate immune cell lineage of myeloid cells includes a variety of different subsets of bone marrow-derived as well as tissue-specific macrophages, which elicit much more functions than simply killing bacteria. To execute this high variety of functions, also macrophages use different metabolic pathways and are tightly regulated by key metabolic regulators, such as the mechanistic target of rapamycin (mTOR). Upon activation, metabolic changes within the cell occur to meet the requirements of the phenotypic switch. In addition, metabolic changes correlate with the ability of innate immune cells to show hallmarks of adaptive immune responses. Little is known about specific metabolic changes of myeloid cells and specifically microglia in vivo. Microglia are key players in neurodegenerative and neuroinflammatory diseases and have become a major target of medical research. Here, we review the existing data on microglia metabolism and the connection of microglia phenotypes with neuroinflammatory and neurodegenerative diseases. Lastly, we will discuss how our knowledge about the cellular metabolism might be used to develop new treatment options for neurological diseases. PMID- 30423424 TI - Long-term challenge of methylphenidate changes the neuronal population and membrane property of dopaminergic neuron in rats. AB - Attention deficit hyperactivity disorder (ADHD) has a prevalence of 7.5% in school-age children in Taiwan. A number of ADHD patients start taking medications in elementary school and continue their treatment until they are in college or adulthood. Methylphenidate is the most frequently used medication prescribed for ADHD treatment. The influence of long-term treatment of methylphenidate on neuro development, especially dopaminergic neurons, in rats would be explored. This study investigated the impact of long-term treatment of methylphenidate on different neurons. Rats aged 1 month were divided into three groups: Normal group receiving only sucrose solution, Low-dose group receiving 2 mg/kg methylphenidate, and High-dose group receiving 10 mg/kg methylphenidate; for each group, the drug was administreted twice per day. After 7 months of the treatment period, then the alterations in number of norepinephrine, serotonergic, cholinergic and dopaminergic neurons were quantified. The number of dopaminergic neurons in the substantia nigra (SN), the serotonergic neurons in the dorsal raphe nucleus, and the cholinergic neurons in the tegmental nucleus significantly decreased as compared with Normal group, whereas the noradrenergic neurons in the locus coeruleus substantially increased. The whole-cell recording was made from dopaminergic neurons residing in the SN for examination of their firing activity. The recorded dopaminergic neurons in SN were categorized into slow and fast firing using 10 Hz as a classified index. The results displayed that the ratio of dopaminergic neurons with fast firing in the High-dose group was less as compared with those in the Normal and the Low-dose group. Furthermore, the amplitude of action potential of the dopaminergic neurons with slow firing was higher in the High-dose group than those in the Normal and Low-dose groups. The firing behavior of dopaminergic neurons and dopamine concentration in the brain is affected by the long-term challenge of methylphenidate. PMID- 30423425 TI - Pentobarbital and other anesthetic agents induce opposite regulations of MAP kinases p-MEK and p-ERK, and upregulate p-FADD/FADD neuroplastic index in brain during hypnotic states in mice. AB - Midazolam and ketamine-induced anesthesia were recently shown to induce a disruption of MEK/ERK sequential phosphorylation with parallel upregulation of p FADD in the mouse brain. The present study was designed to assess whether other structurally diverse anesthetic agents (pentobarbital, ethanol, chloral hydrate, isoflurane) also impair brain p-MEK to p-ERK signal and increase p-FADD during the particular time course of 'sleep' in mice. Pentobarbital (50 mg/kg)-, ethanol (4000 mg/kg)-, chloral hydrate (400 mg/kg)-, and isoflurane (2% in O2)-induced anesthesia (range: 24-60 min) were associated with unaltered or increased p MEK1/2 (up to +155%) and decreased p-ERK1/2 (up to -60%) contents, revealing disruption of MEK to ERK activation in mouse brain cortex. These anesthetic agents also upregulated cortical p-FADD (up to +110%), but not total FADD (moderately decreased), which resulted in increased neuroplastic/survival p FADD/FADD ratios (up to +2.8 fold). The inhibition of pentobarbital metabolism with SKF525-A (a cytochrome P450 inhibitor) augmented barbiturate anesthesia (2.6 times) and induced a greater and sustained upregulation of p-MEK with p-ERK downregulation, as well as prolonged increases of p-FADD content and p-FADD/FADD ratio (effects lasting for more than 240 min). Pentobarbital also upregulated significantly the cortical contents of other markers of neuroplasticity such as the ERK inhibitor p-PEA-15 (up to +46%), the transcription factor NF-kappaB (up to +27%) and the synaptic density protein PSD-95 (up to +20%) during 'sleep'. The results reveal a paradoxical stimulation of p-MEK without the concomitant (canonical) activation of p-ERK (e.g. with pentobarbital and isoflurane), for which various molecular mechanisms are discussed. The downregulation of brain p ERK may participate in the manifestations of adverse effects displayed by most hypnotic/anesthetic agents in clinical use (e.g. amnesia). PMID- 30423426 TI - Of Old Lyme, ticks, and new Borrelia. PMID- 30423427 TI - Modeling of dynamic cerebrovascular reactivity to spontaneous and externally induced CO2 fluctuations in the human brain using BOLD-fMRI. AB - In this work, we investigate the regional characteristics of the dynamic interactions between arterial CO2 and BOLD (dynamic cerebrovascular reactivity - dCVR) during normal breathing and hypercapnic, externally induced step CO2 challenges. To obtain dCVR curves at each voxel, we use a custom set of basis functions based on the Laguerre and gamma basis sets. This allows us to obtain robust dCVR estimates both in larger regions of interest (ROIs), as well as in individual voxels. We also implement classification schemes to identify brain regions with similar dCVR characteristics. Our results reveal considerable variability of dCVR across different brain regions, as well as during different experimental conditions (normal breathing and hypercapnic challenges), suggesting a differential response of cerebral vasculature to spontaneous CO2 fluctuations and larger, externally induced CO2 changes that are possibly associated with the underlying differences in mean arterial CO2 levels. The clustering results suggest that anatomically distinct brain regions are characterized by different dCVR curves that in some cases do not exhibit the standard, positive valued curves that have been previously reported. They also reveal a consistent set of dCVR cluster shapes for resting and forcing conditions, which exhibit different distribution patterns across brain voxels. PMID- 30423428 TI - Human or not human? Performance monitoring ERPs during human agent and machine supervision. AB - Performance monitoring is a critical process which allows us to both learn from our own errors, and also interact with other human beings. However, our increasingly automated world requires us to interact more and more with automated systems, especially in risky environments. The present EEG study aimed at investigating and comparing the neuro-functional correlates associated with performance monitoring of an automated system and a human agent using a vertically-oriented arrowhead version of the flanker task. Given the influence of task difficulty on performance monitoring, two levels of difficulty were considered in order to assess their impact on supervision activity. A large N2-P3 complex in fronto-central regions was observed for both human agent error detection and system error detection during supervision. Using a cluster-based permutation analysis, a significantly decreased P3-like component was found for system compared to human agent error detection. This variation is in line with various psychosocial behavioral studies showing a difference between human-human and human-machine interactions, even though it was not clearly anticipated. Finally, the activity observed during error detection was significantly reduced in the difficult condition compared to the easy one, for both system and human agent supervision. Overall, this study is a first step towards the characterization of the neurophysiological correlates underlying system supervision, and a better understanding of their evolution in more complex environments. To go further, these results need to be replicated in other experiments with various paradigms to assess the robustness of the pattern and decrease during system supervision. PMID- 30423429 TI - Control freaks: Towards optimal selection of control conditions for fMRI neurofeedback studies. AB - fMRI Neurofeedback research employs many different control conditions. Currently, there is no consensus as to which control condition is best, and the answer depends on what aspects of the neurofeedback-training design one is trying to control for. These aspects can range from determining whether participants can learn to control brain activity via neurofeedback to determining whether there are clinically significant effects of the neurofeedback intervention. Lack of consensus over criteria for control conditions has hampered the design and interpretation of studies employing neurofeedback protocols. This paper presents an overview of the most commonly employed control conditions currently used in neurofeedback studies and discusses their advantages and disadvantages. Control conditions covered include no control, treatment-as-usual, bidirectional regulation control, feedback of an alternative brain signal, sham feedback, and mental-rehearsal control. We conclude that the selection of the control condition(s) should be determined by the specific research goal of the study and best procedures that effectively control for relevant confounding factors. PMID- 30423430 TI - Prenatal metformin exposure or organic cation transporter 3 knock-out curbs social interaction preference in male mice. AB - Poorly managed gestational diabetes can lead to severe complications for mother and child including fetal overgrowth, neonatal hypoglycemia and increased autism risk. Use of metformin to control it is relatively new and promising. Yet safety concerns regarding gestational metformin use remain, as its long-term effects in offspring are unclear. In light of beneficial findings with metformin for adult mouse social behavior, we hypothesized gestational metformin treatment might also promote offspring sociability. To test this, metformin was administered to non diabetic, lean C57BL/6 J female mice at mating, with treatment discontinued at birth or wean. Male offspring exposed to metformin through birth lost social interaction preference relative to controls by time in chambers, but not by sniffing measures. Further, prenatal metformin exposure appeared to enhance social novelty preference only in females. However due to unbalanced litters and lack of statistical power, firm establishment of any sex-dependency of metformin's effects on sociability was not possible. Since organic cation transporter 3 (OCT3) transports metformin and is dense in placenta, social preferences of OCT3 knock-out males were measured. Relative to wild-type, OCT3 knock-outs had reduced interaction preference. Our data indicate gestational metformin exposure under non-diabetic conditions, or lack of OCT3, can impair social behavior in male C57BL6/J mice. Since OCT3 transports serotonin and tryptophan, impaired placental OCT3 function is one common mechanism that could persistently impact central serotonin systems and social behavior. Yet no gross alterations in serotonergic function were evident by measure of serotonin transporter density in OCT3, or serotonin turnover in metformin-exposed offspring brains. Mechanisms underlying the behavioral outcomes, and if with gestational diabetes the same would occur, remain unclear. Metformin's impacts on placental transporters and serotonin metabolism or AMPK activity in fetal brain need further investigation to clarify benefits and risks to offspring sociability from use of metformin to treat gestational diabetes. PMID- 30423431 TI - Some thoughts about the possibility of diet-derived exogenous small RNAs. PMID- 30423432 TI - Lipid-hyaluronan synergy strongly reduces intrasynovial tissue boundary friction. AB - Hyaluronan (HA)-lipid layers on model (mica) surfaces massively reduce friction as the surfaces slide past each other, and have been proposed, together with lubricin, as the boundary layers accounting for the extreme lubrication of articular cartilage. The ability of such HA-lipid complexes to lubricate sliding biological tissues has not however been demonstrated. Here we show that HA-lipid layers on the surface of an intrasynovial tendon can strongly reduce the friction as the tendon slides within its sheath. We find a marked lubrication synergy when combining both HA and lipids at the tendon surface, relative to each component alone, further enhanced when the polysaccharide is functionalized to attach specifically to the tissue. Our results shed light on the lubricity of sliding biological tissues, and indicate a novel approach for lubricating surfaces such as tendons and, possibly, articular cartilage, important, respectively, for alleviating function impairment following tendon injury and repair, or in the context of osteoarthritis. STATEMENT OF SIGNIFICANCE: Lubrication breakdown between sliding biological tissues is responsible for pathologies ranging from dry eye syndrome to tendon-injury repair impairment and osteoarthritis. These are increasing with human longevity and impose a huge economic and societal burden. Here we show that synergy of hyaluronan and lipids, molecules which are central components of synovial joints and of the tendon/sheath system, can strongly reduce friction between sliding biological tissues (the extrasynovial tendon sliding in its sheath), relative to untreated tissue or to either component on its own. Our results point to the molecular origins of the very low friction in healthy tendons and synovial joints, as well as to novel treatments of lubrication breakdown in these organs. PMID- 30423433 TI - Phoenixin: Expression at different ovarian development stages and effects on genes ralated to reproduction in spotted scat, Scatophagus argus. AB - Phoenixin (Pnx), a recently discovered neuropeptide, has been implicated in reproduction. Pnx mainly exists in two active isoforms, phoenixin-14 (Pnx-14) and phoenixin-20 (Pnx-20). However, little is known about the functions of Pnx in teleosts. To determine the roles of Pnx in the regulation of reproduction in Scatophagus argus, the physiological characterization of the Pnx was analyzed. During ovary development, the expression of pnx in phase IV was higher than in phase II and III in the hypothalamus. In the pituitary, pnx expression was highest in phase IV, moderate in phase III, and lowest in phase II. When hypothalamus and pituitary fragments were cultured in vitro with Pnx-14 and Pnx 20 (10 nM and 100 nM) for 6 h, the expression of GnRHR (gonadotropin releasing hormone receptor), lh (luteinizing hormone) and fsh (follicular stimulating hormone) in the pituitary increased significantly, except GnRH (gonadotropin releasing hormone) in the hypothalamus. Similarly, the expression of GnRHR, lh and fsh in the pituitary increased significantly after injecting S. argus with Pnx-14 and Pnx-20 (10 ng/g and 100 ng/g body weight (bw)), except GnRHR and fsh treated with 10 ng/gbw Pnx-20 in the pituitary and GnRHs in the hypothalamus. These results indicate that Pnx may not only stimulate the reproduction of the S. argus through the hypothalamic-pituitary-gonadal (HPG) axis, but also directly through the pituitary. PMID- 30423434 TI - Pilot-scale expression, purification, and bioactivity of recombinant human TGF beta3 from Escherichia coli. AB - TGF-beta3, a subtype of transforming growth factor-beta (TGF-beta), is essential to various biological processes, including endoderm development, organogenesis, epithelial hyperplasia, synthesis of extracellular matrix, and immune response. Essentially, TGF-beta3 engages the TGF-beta1/Smad signaling pathway to stimulate mesenchymal lineage cells, inhibit epithelial or neuroectodermal lineage cells, and regulate repair, remodeling, and potential scarring after cutaneous wounding. We have now expressed recombinant human TGF-beta3 in Escherichia coli Origami B (DE3), with yield 300 +/- 17 mg/L monomeric protein at pilot scale. Identity was confirmed by western blot and HPLC-based peptide mapping. After purification and refolding, dimeric proteins were found to induce chondro-related genes in adipose derived stem cells, and to suppress scarring in injured rabbit ears. Thus, the recombinant protein has excellent potential for medical applications. PMID- 30423436 TI - Production of xylanolytic enzymes by Moesziomyces spp. using xylose, xylan and brewery's spent grain as substrates. AB - Xylanases play a crucial role in the hydrolysis of xylan-rich hemicelluloses and have wide industrial applications in the fuel, food, feed and pulp and paper industries. The production of these enzymes at low cost is of paramount importance for their commercial deployment. Moesziomyces antarcticus PYCC 5048T and M. aphidis PYCC 5535T were screened for their ability to produce xylanolytic enzymes when grown on d-xylose, xylan (beechwood) and brewery's spent grain (BSG). The extracellular crude extracts produced were characterized and tested in xylan hydrolysis. The yeasts produced xylanolytic enzymes without cellulolytic activity on all the substrates tested. The highest xylanase volumetric activity was obtained with M. aphidis PYCC 5535T grown on BSG, reaching 518.2 U/ml, a value 8.4- and 4.7-fold higher than those achieved on xylan and d-xylose, respectively. The xylanase activities were characterized in relation to pH and temperature with optima at 4.5 and 50 degrees C, respectively. The extracts from both M. antarcticus PYCC 5048Tand M. aphidis PYCC 5535T were used in xylan hydrolysis, producing d-xylose as the major end product (0.43 and 0.34-0.47 gD xylose/gxylan, respectively, at 50 degrees C) and relatively low or no xylobiose accumulation (from no detection to 0.12 gD-xylobiose/gxylan at 50 degrees C). PMID- 30423435 TI - Population pharmacokinetic modeling to establish the role of P-glycoprotein on ciprofloxacin distribution to lung and prostate following intravenous and intratracheal administration to Wistar rats. AB - Ciprofloxacin (CIP) is indicated for clinical treatment of urinary and respiratory tract infections. Poor infection site penetration and consequent insufficient exposure to the antimicrobial agent may be the reason for some therapeutic failures. Ciprofloxacin is reported as a substrate for efflux transporters, such as P-glycoprotein, which could be related to the presence of sub-therapeutic drug concentration at the infection site. In the present work we evaluated CIP pharmacokinetics (PK) in plasma and lung and prostate tissues of Wistar rats after intravenous (i.v.) and intratracheal (i.t.) dosing (7 mg/Kg) in the presence and absence of P-gp inhibitor tariquidar (TAR, 15 mg/Kg). Microdialysis was applied to determine free tissue concentration-time profiles and the obtained data were analyzed by non-compartmental and population PK (popPK) analysis. A sequential strategy was used to develop the popPK model: characterization of CIP PK in tissues (Tissue model) was performed subsequently to CIP PK modeling in plasma (Plasma model). Two and three compartmental models were used to simultaneously characterize plasma concentrations after i.t. and i.v. dosing; the distribution model was developed by separating the central compartment into venous and arterial compartment and by adding lung and prostate; TAR was identified as a significant covariate for clearance and volume of distribution of central compartment as well as for inter-compartmental clearance. Our results indicate an impact of P-gp on plasma PK, likely by acting on renal active secretion of CIP. Regarding CIP exposure in lung and prostate tissues, our results suggest a complex interplay between drug transporters; P-gp inhibition by TAR was likely counterbalanced by the activity of other efflux/influx transporters, which could not be fully characterized by our model. PMID- 30423437 TI - Effects of sub-minimal inhibitory concentrations of antibiotics on the morphology and surface hydrophobicity of periodontopathic anaerobes. AB - It has been reported that sub-minimal inhibitory concentrations (sub-MICs) of antibiotics are capable of altering bacterial surface properties and phenotype. In this study, the effects of sub-MICs of certain antibiotics on surface hydrophobicity, cell morphology, and protein profile were ascertained using Fusobacterium nucleatum, Porphyromonas gingivalis and Treponema denticola strains, which are pathogenic bacterial species in periodontal diseases. The MICs of antibiotics were determined by culturing bacteria in media supplemented with serially diluted antibiotic solutions, and sub-MIC of antibiotics was used. The effect of sub-MIC of antibiotics on cell morphology was determined by scanning electron microscopy. Microscopic observation of F. nucleatum and P. gingivalis grown at a sub-MIC of amoxicillin revealed cell enlargement. T. denticola grown at a sub-MIC of doxycycline also showed cell elongation. The relative surface hydrophobicity determined by measuring the ability of the bacteria to absorb n hexadecane revealed an increase in surface hydrophobicity of F. nucleatum grown at sub-MIC of penicillin and amoxicillin, but a decrease with metronidazole; whereas increased hydrophobicity was observed in T. denticola grown at sub-MIC of doxycycline, metronidazole and tetracycline. The surface hydrophobicity of P. gingivalis increased only when grown in sub-MIC of metronidazole. The protein expression profile of the treated bacteria differed from their respective controls. These results confirmed that sub-MIC concentrations of antibiotics can affect the phenotype, surface properties and morphology of periodontal pathogenic anaerobic bacteria. PMID- 30423438 TI - Four hundred shades of brown: Higher level phylogeny of the problematic Euptychiina (Lepidoptera, Nymphalidae, Satyrinae) based on hybrid enrichment data. AB - Relationships within satyrine butterflies have been notoriously difficult to resolve using both morphology and Sanger sequencing methods, and this is particularly true for the mainly Neotropical subtribe Euptychiina, which contains about 400 described species. Known larvae of Euptychiina feed on grasses and sedges, with the exception of the genus Euptychia, which feed on mosses and lycopsids, and the butterflies occur widely in rainforest, cloudforest and grassland habitats, where they are often abundant. Several previous molecular and morphological studies have made significant progress in tackling the systematics of the group, but many relationships remain unresolved, with long-branch attraction artifacts being a major problem. Additionally, the monophyly of the clade remains uncertain, with Euptychia possibly not being closely related to the remainder of the clade. Here we present a backbone phylogeny of the subtribe based on 106 taxa, 368 nuclear loci, and over 180,000 bps obtained through hybrid enrichment. Using both concatenation and species tree approaches (IQ-TREE, EXABAYES, ASTRAL), we can for the first time strongly confirm the monophyly of Euptychiina with Euptychia being the sister group to the remainder of the clade. The Euptychiina is divided into nine well supported clades, but the placement of a few genera such as Hermeuptychia, Pindis and the Chloreuptychia catharina group still remain uncertain. As partially indicated in previous studies, the genera Cissia, Chloreuptychia, Magneuptychia, Megisto, Splendeuptychia and Euptychoides, among others, were found to be highly polyphyletic and revisions are in preparation. The phylogeny will provide a strong backbone for the analysis of datasets in development that are much more taxonomically comprehensive but have orders of magnitude fewer loci. This study therefore represents a critical step towards resolving the higher classification and studying the evolution of this highly diverse lineage. PMID- 30423439 TI - Molecular phylogeny of Caudofoveata (Mollusca) challenges traditional views. AB - The shell-less, worm-shaped Caudofoveata (=Chaetodermomorpha) is one of the least known group of molluscs. The taxon consists of 141 recognized species found from intertidal environments to the deep-sea where they live burrowing in sediment. Evolutionary relationships of the group have been debated, but few studies based on morphological or molecular data have investigated the phylogeny of the group. Here we use molecular phylogenetics to resolve relationships among and within families of Caudofoveata. Phylogenetic analyses were performed using selected mitochondrial and nuclear genes from species from all recognized families of Caudofoveata. In resulting trees and contrary to traditional views, Prochaetodermatidae forms the sister clade to a clade containing the other two currently recognized families, Chaetodermatidae and Limifossoridae. The monophyly of Prochaetodermatidae is highly supported, but Limifossoridae and Chaetodermatidae are not recovered as monophyletic. Most of the caudofoveate genera are also not recovered as monophyletic in our analyses. Thus results from our molecular data suggest that the current classification of Caudofoveata is in need of revision, and indicate evolutionary scenarios that differ from previously proposed hypotheses based on morphology. PMID- 30423440 TI - Core genome phylogenetic analysis of the avian associated Borrelia turdi indicates a close relationship to Borrelia garinii. AB - Borrelia burgdorferi sensu lato comprises a species complex of tick-transmitted bacteria that includes the agents of human Lyme borreliosis. Borrelia turdi is a genospecies of this complex that exists in cryptic transmission cycles mainly between ornithophilic tick vectors and their avian hosts. The species has been originally discovered in avian transmission cycles in Asia but has increasingly been found in Europe. Next generation sequencing was used to sequence the genome of B. turdi isolates obtained from ticks feeding on birds in Portugal to better understand the evolution and phylogenetic relationship of this avian and ornithophilic tick-associated genospecies. Here we use draft genomes of these B. turdi isolates for comparative analysis and to determine the taxonomic position within the B. burgdorferi s.l. species complex. The main chromosomes showed a maximum similarity of 93% to other Borrelia species whilst most plasmids had lower similarities. All three isolates had nine or 10 plasmids and, interestingly, one plasmid with a novel partitioning protein; this plasmid was termed lp30. Phylogenetic analysis of multilocus sequence typing housekeeping genes and 113 single copy orthologous genes revealed that the isolates clustered according to their classification as B. turdi. In phylogenies generated from these 113 genes the isolates cluster together with other Eurasian genospecies and form a sister clade to the avian associated B. garinii and the rodent associated B. bavariensis. These findings show that Borrelia species maintained in cryptic ecological cycles need to be included to fully understand the complex ecology and evolutionary history of this bacterial species complex. PMID- 30423441 TI - The complex study of complexes: The first well-supported phylogeny of two species complexes within genus Caridina (Decapoda: Caridea: Atyidae) sheds light on evolution, biogeography, and habitat. AB - Atyid shrimps, a key component of tropical freshwater ecosystems, face multiple anthropogenic threats and thus need special attention. With more than 300 described species, the genus Caridina is the most speciose of all the Caridea infra-order. Caridina spp. occupy diverse habitats in tropical freshwaters of the Indo-West Pacific region. Several species complexes have been recognized, based on common morphological features, but little is known about how well these morphological characteristics align with phylogenetic characteristics. Furthermore, no phylogeny of the genus Caridina published so far has provided well-resolved and supported relationships among different species, thus impeding the possibility of proposing evolutionary hypotheses. In this study we used next generation sequencing (NGS) to provide new insights into the phylogenetic relationships among the genus Caridina, focusing on two complexes: 'Caridina nilotica' and 'Caridina weberi'. We collected 92 specimens belonging to these two groups from most of their known geographical range, representing 50 species, for which we sequenced seven mitochondrial genes and two nuclear markers using ion torrent NGS. We performed a phylogenetic analysis, which yielded the first well supported tree for the genus Caridina. On this tree were mapped the geographic ranges and the habitats used by the different species, and a time calibration was tested. We found the driving factors that most likely account for separation of clades are differences in habitat and to a lesser extent geography. This work provides new insights into the taxonomy of this group and identifies opportunities for further studies in order to fill knowledge gaps that currently impede the management and conservation of atyid species. PMID- 30423442 TI - A novel PDE6D mutation in a patient with Joubert syndrome type 22 (JBTS22). AB - Joubert syndrome (JS) is an autosomal or X-linked recessive syndrome principally characterized by hypotonia, ataxia, cognitive impairment, and a specific finding on brain imaging called a "molar tooth sign" (MTS), which can be isolated or in conjunction with variable organ involvement. The genetic basis of JS is heterogeneous, with over 35 ciliary genes being implicated in its pathogenesis. However, some of these genes (such as PDE6D) have been associated to JS only in single families, seeking confirmation. Here we report a boy, born to first cousin parents, presenting with developmental delay, hypotonia, microcephaly, post axial polydactyly, oculomotor apraxia, and MTS. Whole exome sequencing revealed the presence of a novel homozygous truncating variant in the PDE6D gene: NM_002601.3:c.367_368insG [p.(Leu123Cysfs*13)]. The variant was confirmed by Sanger sequencing and found at the heterozygous state in both parents. A review of the literature pertaining to the role of PDE6D in JS is discussed. PMID- 30423443 TI - Diverse phenotype in patients with complex I deficiency due to mutations in NDUFB11. AB - Mitochondrial complex I deficiency is the most frequent mitochondrial disorder presenting in childhood and the mutational spectrum is highly heterogeneous. The NDUFB11 gene is one of the recently identified genes, which is located in the short arm of the X-chromosome. Here we report clinical, biochemical, functional and genetic findings of two male patients with lactic acidosis, hypertrophic cardiomyopathy and isolated complex I deficiency due to de novo hemizygous mutations (c.286C > T and c.328C > T) in the NDUFB11 gene. Neither of them had any skin manifestations. The NDUFB11 gene encodes a relatively small integral membrane protein NDUFB11, which is essential for the assembly of an active complex I. The expression levels of this protein was decreased in both patient cells and a lentiviral complementation experiment also supported the notion that the complex I deficiency in those two patients is caused by NDUFB11 genetic defects. Our findings together with a review of the thirteen previously described patients demonstrate a wide spectrum of clinical features associated with NDUFB11 related complex I deficiency. However, histiocytoid cardiomyopathy and/or congenital sideroblastic anemia could be indicative for mutation in the NDUFB11 gene, while the clinical manifestation of the same mutation can be highly variable. PMID- 30423444 TI - Recessive multiple epiphyseal dysplasia - Clinical characteristics caused by rare compound heterozygous SLC26A2 genotypes. AB - Pathogenic sequence variants in the solute carrier family 26 member 2 (SLC26A2) gene result in lethal (achondrogenesis Ib and atelosteogenesis II) and non-lethal (diastrophic dysplasia and recessive multiple epiphyseal dysplasia, rMED) chondrodysplasias. We report on two new patients with rMED and very rare compound heterozygous mutation combinations in non-consanguineous families. Patient I presented in childhood with waddling gait and joint stiffness. Radiographs showed epiphyseal changes, bilateral coxa plana-deformity and knee valgus deformity, for which he underwent surgeries. At present 33 years his height is 165 cm. Patient II presented with cleft palate, small jaw, short limbs, underdeveloped thumbs and on radiographs, cervical kyphosis with an underdeveloped C4. He also developed severe scoliosis but has grown at -2.9 SD curve. Molecular analysis revealed that patient I is heterozygous for two known pathogenic variants in SLC26A2, a splice site variant c.-26+2T > C and a missense variant c.1957T > A (p.Cys653Ser), while patient II is compound heterozygous for missense variants c.835C > T (p.Arg279Trp) and c.1535C > A (p.Thr512Lys). These patients further elucidate the variability of the phenotypic and genetic presentations of rMED. PMID- 30423445 TI - Molecular characterization of a recurrent 10.9 kb CYP24A1 deletion in Idiopathic Infantile Hypercalcemia. AB - Loss-of-function mutations in CYP24A1 (MIM 126065 20q13.2), the gene encoding the 24-hydroxylase responsible for 25-OH-D and 1,25-(OH)2D degradation, are identified in about 20% of patients presenting Idiopathic Infantile Hypercalcemia (IIH) (MIM 143880). Common features of this autosomal recessive condition included hypercalcemia with hypercalciuria, suppressed PTH and a high 25-OH D3:24,25-(OH)2D3 ratio. Medical care mainly relies on sun protection and life long contraindication of vitamin D to avoid complications such as early nephrocalcinosis and renal failure. Molecular diagnosis therefore keeps a crucial place in the diagnosis of IIH, and genetic counseling should be systematically recommended to prevent vitamin D administration in affected siblings. In this report is described the molecular characterization of a CYP24A1 deletion identified in two unrelated families. This highlights the potential role of CYP24A1 copy number variations (CNV) in IIH. Considering the presence of CNV affecting CYP24A1 in public databases, CNV analysis should be systematically added to the sequencing studies in IIH. Targeted Massively Parallel Sequencing (MPS) study coupled with a CNV detection tool called CovCop is a powerful method to detect genic rearrangement and improve genetic analysis. PMID- 30423446 TI - Metabolomics in the study of retinal health and disease. AB - Metabolomics is the qualitative and quantitative assessment of the metabolites (small molecules < 1.5 kDa) in body fluids. The metabolites are the downstream of the genetic transcription and translation processes and also downstream of the interactions with environmental exposures; thus, they are thought to closely relate to the phenotype, especially for multifactorial diseases. In the last decade, metabolomics has been increasingly used to identify biomarkers in disease, and it is currently recognized as a very powerful tool with great potential for clinical translation. The metabolome and the associated pathways also help improve our understanding of the pathophysiology and mechanisms of disease. While there has been increasing interest and research in metabolomics of the eye, the application of metabolomics to retinal diseases has been limited, even though these are leading causes of blindness. In this manuscript, we perform a comprehensive summary of the tools and knowledge required to perform a metabolomics study, and we highlight essential statistical methods for rigorous study design and data analysis. We review available protocols, summarize the best approaches, and address the current unmet need for information on collection and processing of tissues and biofluids that can be used for metabolomics of retinal diseases. Additionally, we critically analyze recent work in this field, both in animal models and in human clinical disease, including diabetic retinopathy and age-related macular degeneration. Finally, we identify opportunities for future research applying metabolomics to improve our current assessment and understanding of mechanisms of vitreoretinal diseases, and to hence improve patient assessment and care. PMID- 30423447 TI - Sprouting and anastomosis in the Drosophila trachea and the vertebrate vasculature: Similarities and differences in cell behaviour. AB - Branching morphogenesis is a fascinating process whereby a simple network of biological tubes increases its complexity by adding new branches to existing ones, generating an enlarged structure of interconnected tubes. Branching morphogenesis has been studied extensively in animals and much has been learned about the regulation of branching at the cellular and molecular level. Here, we discuss studies of the Drosophila trachea and of the vertebrate vasculature, which have revealed how new branches are formed and connect (anastomose), leading to the establishment of complex tubular networks. We briefly describe the cell behaviour underlying tracheal and vascular branching. Although similar at many levels, the branching and anastomosis processes characterized thus far show a number of differences in cell behaviour, resulting in somewhat different tube architectures in these two organs. We describe the similarities and the differences and discuss them in the context of their possible developmental significance. We finish by highlighting some old and new data, which suggest that live imaging of the development of capillary beds in adult animals might reveal yet unexplored endothelial behaviour of endothelial cells. PMID- 30423448 TI - Role of amino acid metabolism in angiogenesis. AB - The role of endothelial metabolism represents a crucial element governing the formation and the differentiation of blood vessels, termed angiogenesis. Besides glycolysis and fatty acid oxidation, endothelial cells rely on specific amino acids to proliferate, migrate, and survive. In this review we focus on the metabolism of those amino acids and the intermediates that hold an established function within angiogenesis and endothelial pathophysiology. We also discuss recent work which provides a rationale for specific amino acid-restricted diets and its beneficial effects on vascular tissues, including extending the life span and preventing the development of a variety of diseases. PMID- 30423449 TI - Efficacy, safety, and quality of life in a multi-center, randomized, placebo controlled trial of low-dose peanut oral immunotherapy in peanut allergic children. AB - BACKGROUND: Only two, small placebo-controlled trials on peanut- oral immunotherapy (OIT) have been published. OBJECTIVE: We examined the efficacy, safety, immunological parameters, quality of life (QoL) and burden of treatment (BoT) of low-dose peanut- OIT in a multicenter, double-blind, randomized placebo controlled trial. METHODS: 62 children aged 3-17 years with IgE-mediated, challenge-proven peanut allergy were randomized (1:1) to receive peanut-OIT with a maintenance dose of 125-250 mg peanut protein or placebo. The primary outcome was the proportion of children tolerating >=300 mg peanut protein at oral food challenge (OFC) after 16 months of OIT. We measured occurrence of adverse events (AEs), immunological changes, QoL prior and post OIT and BoT during OIT. RESULTS: 23/31 (74.2%) children of the active group tolerated at least 300 mg peanut protein at final OFC compared to 5 /31 (16.1%) in the placebo group (p<.001). 13/31 (41.9%) children of the active versus 1/31 (3.2%) of the placebo group tolerated the highest dose of 4.5 g peanut protein at final OFC (p<.001). There was no significant difference between the groups in the occurrence of AE-related drop-outs or in the number, severity and treatment of objective AEs. In the peanut-OIT group, we noted a significant reduction in peanut specific IL-4, IL-5, IL10 and IL-2 production by PBMCs compared to the placebo group, as well as a significant increase in peanut specific-IgG4 levels and a significant improvement of QoL. 86% of children evaluated the BoT positively. DISCUSSION: Low-dose OIT is a promising, effective and safe treatment option for peanut allergic children, leading to improvement of QoL, a low BoT and immunological changes showing tolerance development. PMID- 30423450 TI - Association between asthma and depression: A National Cohort Study. AB - BACKGROUND: Patients with asthma often suffer from depression and vice versa. However, the temporal relationship between the two diseases has remained elusive. OBJECTIVE: The aim of this study was to determine the bidirectional relationship between asthma and depression in adults using national cohort samples in Korea. METHODS: Using the national cohort from the study by the Korean Health Insurance Review and Assessment Service, asthma patients and control participants were selected and matched by age group, sex, income group, region of residence, and prior medical histories. A stratified Cox proportional hazards model was used to analyze the hazard ratio (HR) of asthma with depression (Study I) and depression with asthma (Study II). RESULTS: In Study I, the HR of depressive disorders was significantly higher in the patients with asthma than in the patients without asthma (HR = 1.35, 95% confidence interval [CI] = 1.31-1.40). In Study II, the HR of asthma in the patients with depression was significantly higher than that in the patients without depression (HR = 1.25, 95% CI = 1.21-1.29). CONCLUSION: A bidirectional association between asthma and depression was observed in this study. PMID- 30423452 TI - Assessment of associations between mitochondrial DNA haplogroups and attention deficit and hyperactivity disorder in Korean children. AB - Attention deficit hyperactivity disorder (ADHD) is a multifactorial disorder with multiple environmental and biological etiologies, including genetic factors. Until now, several genetic variants have been reported to be significantly associated with ADHD. Recently, the relationship between mitochondrial DNA (mtDNA) haplogroups and psychiatric disorders such as schizophrenia has also been reported. However, currently there are no reports pertaining to the genetic association between mtDNA haplogroups and ADHD. Therefore, we performed an mtDNA haplogroup analysis of a total of 472 Korean children (150 Children with ADHD and 322 controls). The 20 East Asian specific mtDNA haplogroups were determined using the SNaPshot assay. We also sequenced the displacement loop (D-loop) region, position 15,971-613. Our results showed that haplogroup B4 was significantly associated with ADHD (OR, 1.90; 95% CI, 1.055-3.429; p = 0.031). A marginally significant association was found in subjects with ADHD and haplogroup B5 (OR, 0.26; 95% CI, 0.059-1.139; p = 0.041). When stratified based on gender, an association was also observed between haplogroup B5 and boys diagnosed with ADHD (OR, 0.17; 95% CI, 0.022-1.340; p = 0.048). Compared with boys, girls with ADHD carried an excess of the haplogroup D4b (OR, 4.83; 95% CI, 1.352-17.272; p = 0.014). Stratified analysis of subtypes also showed significant results (combined: haplogroup B4, p = 0.007; inattentive: haplogroup F, p = 0.022). Our results showed a possible role of mtDNA haplogroups in the genetic etiology of ADHD and ADHD symptoms in Korean children. PMID- 30423453 TI - Congenital diaphragmatic hernia in newborn infants: Variable endotracheal tube and umbilical venous catheter positions. AB - We reviewed the radiographs of 131 infants with congenital diaphragmatic hernia and report that the umbilical venous catheter usually deviates to the ipsilateral and the endotracheal tube to the contralateral side of the defect. The trachea and the umbilical vein, however, can be found on either side of the midline. PMID- 30423451 TI - The frequency of mitochondrial polymerase gamma related disorders in a large Polish population cohort. AB - Diseases related to DNA polymerase gamma dysfunction comprise of heterogeneous clinical presentations with variable severity and age of onset. Molecular screening for the common POLG variants: p.Ala467Thr, p.Trp748Ser, p.Gly848Ser, and p.Tre251Ile has been conducted in a large population cohort (n = 3123) and in a clinically heterogeneous group of 1289 patients. Recessive pathogenic variants, including six novel ones were revealed in 22/26 patients. Infantile Alpers Huttenlocher syndrome and adulthood ataxia spectrum were the most common found in our group. Distinct molecular profile identified in the Polish patients with significant predominance of p.Trp748Ser variant (50% of mutant alleles) reflected strikingly low population frequency of the three remaining variants and slightly higher p.Trp748Ser allele frequency in the general Polish population as compared to the non-Finish European population. PMID- 30423454 TI - l-proline supplementation improves nitric oxide bioavailability and counteracts the blood pressure rise induced by angiotensin II in rats. AB - We evaluated whether l-proline (Pro) supplementation improves redox status and nitric oxide (NO) bioavailability and prevents or delays angiotensin II (AngII) induced hypertension. Male Sprague-Dawley rats were distributed to four experimental groups: Pro + AngII (Pro-Ang), Pro + Saline (Pro-Sal), Vehicle + AngII (Veh-Ang) and Veh + Saline (Veh-Sal). Pro solution (2 g.kg-1.day-1) or water (vehicle) were orally administered, from day 0 to day 21. AngII (200 ng.kg 1.min-1) or saline were infused (s.c.) from day 7 to day 21. Systolic blood pressure (SBP) was measured by the tail-cuff method. From day 20-21, animals were kept on metabolic cages for 24h-urine collection. On day 21, urine and blood were collected for further quantification of redox status biomarkers, NO-related markers (urinary nitrates and nitrites, U-NOx; plasma asymmetric dimethylarginine, P-ADMA), metabolic and renal parameters. Pro prevented the AngII-induced SBP rise [mean (95% CI), Day 19: Pro-AngII, 137 (131; 143) vs. Veh AngII, 157 (151; 163) mm Hg, P < 0.001]. Pro-AngII rats also had increased values of U-NOx, systemic and urinary total antioxidant status (TAS), urinary H2O2 and plasma urea, as well as reduced P-ADMA and unaltered urinary isoprostanes. Plasma Pro was inversely correlated with P-ADMA (r = -0.52, p = 0.0009) and positively correlated with urinary TAS (r = 0.55, p = 0.0005) which, in turn, was inversely correlated with P-ADMA (r = -0.56, p = 0.0004). Furthermore, urinary H2O2 values decreased across P-ADMA tertiles (p for linear trend = 0.023). These results suggest that Pro reduces P-ADMA levels and improves redox status, thereby increasing NO bioavailability and counteracting the AngII-induced SBP rise. H2O2 and TAS modulation by Pro may contribute to the reduced P-ADMA concentration. PMID- 30423455 TI - Dietary Lactobacillus plantarum ST-III alleviates the toxic effects of triclosan on zebrafish (Danio rerio) via gut microbiota modulation. AB - The probiotics, Lactobacillus plantarum ST-III, plays an important role in modulating microbiota and alleviating intestinal metabolic disorders. Herein, we reported that Lactobacillus increases biodiversity of zebrafish gut flora, and attenuates toxic effects from chronic triclosan (TCS) exposure. Lactobacillus feeding recovered the species and amount of microorganisms in the intestines of zebrafish, and inhibited toxin production by saprophytic bacterial growth. Abnormal physiological indexes and malonaldeyhde content resulting from TCS exposure were effectively alleviated. Additionally, lipid-metabolism disorders, such as increased triglyceride and total cholesterol levels, were attenuated by a probiotics diet. The number of CD4+ T cell lymphocytes in the lamina propria of the duodenal mucosa was decreased in zebrafish receiving a Lactobacillus diet compared to the TCS-exposed group, showing a consistent expression trend for six immune genes (NF-kappaB, IL-1beta, TNF-alpha, lysozyme, TLR4alpha, IL-10) in the intestinal mucosa. Histopathological observations of intestines, spleen and kidney showed that TCS exposure produced severe damage to the morphology and structure of immune and metabolism-related organs. Lactobacillus was capable of mitigating this damage, but bile salt hydrolase, an active extract of Lactobacillus, was not an effective mitigation strategy. The Lactobacillus induced decrease in the number of inflammatory cells confirmed its role in preventing inflammatory injury. Three behavioral tests (T-maze, bottom dwelling and social interaction) indicated that a probiotics diet improved zebrafish movement and learning/memory capacity, effectively alleviating anxiety behavior due to TCS exposure. These findings inform development of beneficial strategies to alleviate intestinal metabolic syndromes and neurodegenerative diseases resulting from exposure to environmental contaminants through modifying gut flora with a probiotics diet. PMID- 30423456 TI - MicroRNAs profiles of Chinese Perch Brain (CPB) cells infected with Siniperca chuatsi rhabdovirus (SCRV). AB - MicroRNAs are non-coding RNAs, which widely participate in biological processes. In recent years, Siniperca chuatsi rhabdovirus (SCRV) has caused mass mortality in Chinese perch (Siniperca chuatsi). To identify specific miRNAs involved in SCRV infection, deep sequencing of microRNA on Chinese perch brain cell line (CPB) with or without SCRV infection were performed at 6 and 12 h post of infection (hpi). Totally 382 miRNAs were identified, including 217 known miRNA aligned with zebrafish miRNAs and 165 novel miRNAs by MiRDeep2 program. Of which 15 and 35 differentially-expressed miRNAs were determined respectively to 6 and 12 hpi. Nine miRNAs were selected randomly from the differentially-expressed miRNAs and validated by quantitative real-time PCR (qRT-PCR). These results were consistent with the microRNA sequencing results. Besides, target genes of 98 differentially-expressed miRNAs were predicted. Three of miRNAs (miR-122, miR 214, miR-135a) were selected, and its effects were analyzed in CPC cells transfected with appropriate miRNA mimics/inhibitors to evaluate its regulation effects by qRT-PCR and western blot. The results demonstrated that miR-214 inhibited the replication of SCRV, while miR-122 promoted the replication of SCRV and there was no correlation between the miR-135a and SCRV replication. These results will pave a new way for the development of effective strategies against the SCRV infection. PMID- 30423457 TI - Heart Failure Epidemiology in Patients With Diabetes Mellitus Without Coronary Heart Disease. AB - BACKGROUND: Epidemiology of patients with comorbid heart failure (HF) and diabetes mellitus (DM) without coronary heart disease (CHD) is not well described. METHODS AND RESULTS: We assessed HF incidence and outcomes in 2896 participants of the Health ABC Study (age 74.0 +/- 3.0 years, 48.4% men, 41.1% black, 34.6% with DM) in relation to prio DM and CHD status. During a median follow-up of 11.4 years, 484 participants (16.7%) developed incident HF; 214 (44.2%) had DM of whom 71 (33.1%) had no prio CHD. Incident HF rate was 2.5% per 100 person-years in those with and 1.5% in those without DM (hazard ratio [HR] 1.66, 95% CI 1.39-1.99). In those with DM, incident HF rate was 4.6% in those with and 1.3% in those without CHD (HR 3.75, 95% CI 2.81-4.99). During a median follow-up of 2.1 years after HF onset, 329 (68.0%) of the participants died. Amongst those with DM, annual mortality was 22.6% in those with versus 25.9% without CHD (HR 0.86, 95% CI 0.61-1.22). All-cause hospitalizations after incident HF in DM patients were 55.0 per 100 person-years in those with and 33.3 in those without CHD (rate ratio [RR] 1.64, 95% CI 1.24-2.16); HF hospitalizations were 42.7 and 30.7 per 100-person years (RR 1.39, 95% CI 1.03 1.86) in those with and without CHD. Reduced ejection fraction was seen in 49.6% of HF patients with DM and CHD and in 34.7% of those without CHD (P = .08); mortality but not hospitalization risk tended to be lower in those with reduced compared with preserved ejection fraction regardless of CHD status. CONCLUSIONS: A sizeable proportion of HF in patients with DM develops in the absence of prior CHD; these patients are at risk for mortality similar to those with CHD. These data underscore the importance of modulating risk beyond atherosclerosis in patients with comorbid HF and DM. PMID- 30423458 TI - Sero-molecular epidemiology of enterovirus-associated encephalitis in Zhejiang Province, China, from 2014 to 2017. AB - BACKGROUND: Recently, both sporadic and outbreak aseptic meningitis caused by enteroviruses have been reported in Zhejiang Province based on a surveillance system. METHODS: This study analysed the epidemiologic features, phylogenetic characteristics and prevalence of enterovirus neutralizing antibodies (nAbs) from 2014 to 2017 in Zhejiang Province. RESULTS: A total of 584 samples were collected. Males accounted for 66.07% while females accounted for 33.93%. The median age was 6 years (range: 1 to 15 years). Cases peaked in May and August (81.17%) and 162 cases (28.93%) occurred in June. We detected 15 serotypes, some of which (E6, E9, E18 and E30) were the dominate serotypes prevalent in different years and geographical regions. Phylogenetic results revealed that all of the isolates from this study belonged to the human enterovirus B family. A total of 329 subjects sampled from a healthy population were tested for nAbs against B5, E6 and E30 in Rui'an county in 2015. The seropositive rate of E30 in each age group was significantly higher than that of the other serotypes. CONCLUSION: Enterovirus-associated encephalitis pathogens circulating in Zhejiang caused sporadic aseptic meningitis in children. The level of nAbs against human enterovirus reflects the history of previous infections in different age groups. Therefore, additional surveillance sites and more precise seroprevalence studies based on these populations are required to gain better insight into the epidemiology of enterovirus-associated encephalitis in Zhejiang Province. PMID- 30423459 TI - Inflammatory profiles revealed the dysregulation of cytokines in adult patients of HFMD. AB - BACKGROUND: Adult patients of HFMD might act as potential enterovirus reservoirs. As enterovirus infection will cause acute inflammatory response, identifying the association between the dysregulation of cytokines and the development and prognosis of HFMD in adult patients has the vital clinical significance. METHODS: 60 patients from 266 laboratory-confirmed adult HFMD cases were included in this study, with 40 healthy adult subjects served as the control. Social-demographic data was collected through follow-up phone calls. Serum samples were collected from the participates. Enterovirus genotype was tested by RT-PCR, and the expression of cytokines were examined according to the manufacturer's instructions. Cases were classified using the cytokine profiles with machine learning algorithm. RESULTS: Adult patients of HFMD presented with dysregulation of cytokines. 15 cytokines of adult patients were significantly elevated and 11 cytokines were decreased comparing with those of controls. Correlation analysis showed some cytokines have positive correlation with the clinical characteristics and others have negative correlation. All the enteroviral genotype presented cytokines dysregulation, and five cytokines were significantly differ between genotype. Using Random forest algorithm, we could classify the cytokine profiles into HFMD class and control class with a very high accuracy. CONCLUSION: These findings suggested that cytokine expression was correlated with the enteroviral infection, genotype and clinical presentation. The inflammatory profiles could be developed as markers to identified HFMD case with machine learning algorithm. PMID- 30423460 TI - Human African Trypanosomiasis Caused by Trypanosoma brucei gambiense: The First Case Report in China. AB - We report the first imported case in China of human African trypanosomiasis, caused by Trypanosoma brucei gambiense after returning from Gabon in 2014. The diagnosis was delayed and relapse lead to death, despite treatment with Eflornithine, as recommended by WHO for late-stage HAT. The case given to us indicates that early diagnosis of HAT and close follow-up, proper retreatment are critical. PMID- 30423461 TI - Etiological Role of Human Papillomavirus Infection in the Development of Penile Cancer. AB - BACKGROUND AND AIMS: To examine an association between human papillomavirus (HPV) infection and penile cancer among Japanese patients. METHODS: Thirty-four patients with penile cancer were enrolled in this study. DNA was extracted from paraffin-embedded tumor-tissue samples, and HPV-DNA tests and genotyping were performed. In all of samples, in situ hybridization (ISH) was performed to locate HPV-DNA in tumor tissue; expression levels of p16-INK4a, mini-chromosome maintenance protein-7(mcm-7), HPV-L1, and Ki-67 were analyzed using immunohistochemical methods. RESULTS: HPV and high-risk (HR)-HPV were detected in 14 (41.2%; 95% confidence intervals [CI], 24.6-57.7%) and 12 (35.2%; 95%CI, 19.2 51.4%) cases, respectively. HPV16 was the most frequently detected HPV type. Among the HR-HPV-positive cases, a punctate HR-HPV-DNA signal pattern was detected by ISH in tumor-cell nuclei. P16-INK4a expression was expressed in 66.7% (95%CI, 42.8-90.1%) of HR-HPV positive-cases, and was significantly frequent and stronger in HR-HPV-positive cases than in HPV-negative cases. There were no significant differences in the occurrence and distribution of mcm-7 and Ki-67 expression between HPV-positive and HPV-negative cases. HPV-L1 expression was not observed in any of the examined cases. CONCLUSIONS: HPV infection may have had an etiological role in 41% examined cases of penile cancer in Japan. PMID- 30423462 TI - Digging deeper in the differential effects of inflammatory and psychosocial stressors in remitted depression: Effects on cognitive functioning. AB - BACKGROUND: Major Depressive Disorder (MDD) covers a wide spectrum of symptoms, including cognitive dysfunction, which can persist during remission. Both inflammatory states and psychosocial stress play a role in MDD pathogenesis. METHODS: The effects of inflammatory (i.e., Salmonella typhi vaccine) and psychosocial stressor (i.e., Trier Social Stress Test), as well as their combination were investigated on cognition in women (aged 25-45 years, n = 21) with (partially) remitted MDD and healthy controls (n = 18) in a single-blind placebo-controlled study. In a crossover design, patients received on the first day one of the aforementioned interventions and on the other day a placebo, or vice versa, with a washout period of 7-14 days. Short-term and verbal memory, working memory, attention, verbal fluency, information processing speed, psychomotor function, and measures of attentional bias to emotions were measured. Exploratory analyses were performed to assess the correlation between biomarkers of inflammation and the Hypothalamic-Pituitary-Adrenal axis and cognitive functioning. RESULTS: In patients, inflammatory stress decreased information processing speed and verbal memory, and increased working memory; after psychosocial stress, there was an increase in attention. There was also an increased negative attentional bias in patients after inflammatory stress. Neither stressor had any effect in controls. LIMITIATIONS: Limitations are the relatively small sample size and antidepressant use by a part of the participants. The effects of the stressors were also measured a relatively short period after administration. CONCULSION: Patients were sensitive to the cognitive effects of inflammation and psychosocial stress on cognition, while controls were not. PMID- 30423463 TI - Omega-3 polyunsaturated fatty acids and psychological intervention for workers with mild to moderate depression: A double-blind randomized controlled trial. AB - BACKGROUND: This study assessed whether a combined intervention of omega-3 polyunsaturated fatty acids (PUFAs) and psychoeducation better improved mild to moderate depression in workers compared to psychoeducation alone. METHODS: This study was a double-blinded, parallel group, randomized controlled trial that compared the intervention group, receiving omega-3 fatty acids, with a control group, receiving a placebo supplement. Participants receiving omega-3 fatty acids took 15 * 300 mg capsules per day for 12 weeks. The total daily dose of omega-3 PUFAs was 500 mg docosahexaenoic acid and 1000 mg eicosapentaenoic acid (EPA). The Beck Depression Inventory(r)-II (BDI-II) was used to assess the severity of depression after treatment. RESULTS: After 12 weeks of treatment, BDI-II scores were significantly lower in the placebo and omega-3 group, when compared to their respective baseline scores (Placebo: t = - 4.6, p < 0.01; Omega-3: t = - 7.3, p < 0.01). However, after 12 weeks of treatment, we found no significant difference between both groups with respect to changes in the BDI-II scores (0.7; 95% CI, - 0.7 to 2.1; p = 0.30). LIMITATIONS: This study did not measure blood omega-3 fatty acid concentration and presented a high-dropout rate. Moreover, our results may not be generalizable to other regions. CONCLUSIONS: The results show that a combination of omega-3 fatty acids and psychoeducation and psychoeducation alone can contribute to an improvement in symptoms in people with mild to moderate depression. However, there is no difference between the interventions in ameliorating symptoms of depression. PMID- 30423464 TI - Effect of grip strength on mental health. AB - BACKGROUND: This study is to longitudinally investigate the association between grip strength and mental health disorders in middle aged and aged population from the Korean Longitudinal Study of Aging. METHODS: Data from the Korean Longitudinal Study of Aging (KLoSA) from 2006 to 2016 was assessed using longitudinal data analysis and out of the 9279 research subjects gathered 1549 (16.7%) participants were reported as Q1 group and 2074 (22.4%) participants were reported as Q5 group. To analyze the association between grip strength and mental health disorders, generalized estimating equation (GEE) model was used. RESULTS: The association between grip strength and cognitive decline was statistically significant, with the following Odds ratio (OR) predicting decreased cognitive decline: OR = 4.99 (p < .0001) for Q1 group vs. Q5 group. The association between grip strength and MMSE and CESD was also statistically significant, with the following estimate (B) predicting decreased MMSE score: B = -0.12 (p < .0001) for Q1 group vs. Q5 group. In terms of CESD, CESD score was higher for Q1 group (B = 0.34, p < .0001) compared to Q5 group. CONCLUSION: This study shows a significant association between grip strength and risk of mental illness in Korean middle aged and aged population. Therefore, grip strength should be given more focus in terms of resistance training programs. PMID- 30423465 TI - Effect of bifidobacterium breve A-1 on anxiety and depressive symptoms in schizophrenia: A proof-of-concept study. AB - BACKGROUND: Studies of probiotics have suggested they have a positive effect on anxiety and depressive symptoms in humans. This study investigated the effect of consuming the probiotic Bifidobacterium breve A-1 on anxiety and depressive symptoms in patients with schizophrenia and explored its effect on immune products such as cytokines and chemokines. METHODS: In this open-label single-arm study, all participants received B. breve strain A-1 (1011 cfu/day) for 4 weeks followed by 4 weeks of observation. The primary outcome was the Hospital Anxiety and Depression Scale (HADS) score. Secondary outcomes were anxiety and depressive symptoms on the Positive and Negative Syndrome Scale (PANSS), blood test findings, and fecal microbiome composition. RESULTS: Twenty-nine outpatients completed the study. HADS total score and PANSS anxiety/depression score were significantly improved at 4 weeks. Based on the criterion of a greater than 25% reduction in HADS total score at 4 weeks from baseline, there were 12 responders and 17 non-responders. Responders were found to have fewer negative symptoms, reduced intake of dairy products, and higher relative abundance of Parabacteroides in the gut microbiome than non-responders. Moreover, IL-22 and TRANCE expression was significantly increased at 4 weeks from baseline in responders but not in non-responders. LIMITATIONS: This open-label, single-arm study cannot exclude a placebo effect. CONCLUSIONS: The results suggest the potential effect of B. breve A-1 in improving anxiety and depressive symptoms in patients with schizophrenia. Further studies should investigate this effect in patients with other psychiatric conditions and assess dietary habits and the gut microbiome. PMID- 30423466 TI - Depression disorder in patients with cerebellar damage: Awareness of the mood state. AB - BACKGROUND: Although depressive symptoms are often reported to be comorbid with degenerative cerebellar diseases, the role of the cerebellum in depressive disorder needs to be elucidated. To address this aim, we investigated self perception of the negative mood state in patients with cerebellar pathology and depressive symptoms. METHODS: Thirty-eight patients with cerebellar damage (10 with depressive symptoms - CB-DP and 28 with no depressive symptoms - CB-nDP), 11 subjects with depressive disorders without cerebellar damage (DP) and 29 healthy controls (CTs) were enrolled. A device for self-monitoring of the mood state (MoMo) and validated scales such as the Profile of Mood States questionnaire (POMS), the Self-Report Symptom Inventory-Revised (SCL-90-R) and the Hamilton Depression Rating Scale (HDRS) were used to evaluate depressive symptoms. RESULTS: Both CB-DP and DP patients showed higher scores than CTs on the POMS and SCL-90-R for depressive factors and on the HDRS. DP patients showed a lower frequency of 'good' mood and a higher frequency of 'bad' mood than CTs when using the MoMo device. However, although the two depressed populations showed comparable scores on these validated scales, CB-DP patients showed impaired self awareness of the mood experience in 'the here and now', as evidenced by the absence of significant differences, compared with CTs, in the subjective mood evaluation performed with the MoMo device. LIMITATIONS: The number of CB patients and inhomogeneity across MRI scans were study limitations. CONCLUSION: Cerebellar dysfunction might slow the data integration necessary for mood state awareness, resulting in difficulty of depressed CB patients in explicitly recognizing their mood "in the here and now". PMID- 30423467 TI - Altered amygdala circuits underlying valence processing among manic and depressed phases in bipolar adults. AB - BACKGROUND: Disruptions in affective processing characterize mood disorders, yet the neural mechanisms underlying internal state dependency in affective processes are not well understood. The present work presents a pilot investigation into state dependency among neural circuits known to be involved in processing affective information, by examining acute manic and depressive mood phases in adults with bipolar disorder and major depressive disorder. METHODS: The present study probed affective processes with a well-validated passive picture-viewing task amongst acutely manic (n = 8) or acutely depressed (bipolar depression: n = 11; major depression: n = 15) mood-disordered adults during functional magnetic resonance imaging . RESULTS: Beta-series correlation analyses seeded from the amygdala revealed distinct neural circuits distinguished across current mood state rather than diagnostic boundaries. We delineated an amygdala-striatum pathway that distinguished depressed from manic mood phase, rather than between diagnostic boundaries, in processing valenced information. Specifically, we found differences in this neural response to negative, but not positive, images across clinical mood states. LIMITATIONS: As a preliminary investigation of state dependent affective processes, the current investigation is predominantly limited by the small sample size. While it provides direction and generates hypotheses for further work, future studies need to replicate and expand the reported effects with larger samples. CONCLUSIONS: These findings demonstrate the conditions under which mood state-dependent affective processes cut cross traditional diagnostic boundaries, speaking to recent advances in transdiagnostic disease mechanisms, and can guide future work examining the neural mechanisms driving symptomatology in affective disorders. PMID- 30423468 TI - Desvenlafaxine vs. placebo in the treatment of persistent depressive disorder. AB - INTRODUCTION: Pharmacotherapy of non-major persistent depressive disorder (PDD) is little studied. We report a study of the serotonin-norepinephrine reuptake inhibitor (SNRI) desvenlafaxine (DVLX) for PDD. METHOD: Non-psychotic, non bipolar outpatients aged 20-65 having PDD without concurrent major depression (MDD) were randomized double-blind to desvenlafaxine or placebo for 12 weeks. All had Hamilton Depression Rating Scale (HDRS-24) score >= 12. Open-label DVLX was offered for 12 weeks following the acute trial. RESULTS: Seventy-one subjects having mean baseline HDRS-24 20.27 +/- 4.77 were eligible, of whom post-RZ data was available for all 59 randomized. The primary 12 week analysis did not differentiate DVLX-treated subjects' mean HDRS scores from those on placebo (6.53 +/- 3.98 vs. 8.24 +/- 4.96, F = 3.33, df = 1, p = .07). Several secondary analyses yielded statistically significant results, including Responder, CGI and QIDS. DISCUSSION: As the primary analysis did not reach statistical significance, this is a negative study which does not support the use of DVLX for non-major PDD. Nevertheless, statistically significant secondary analyses suggest the overall negative result could be due to sample size or sampling, suggesting further studies of this medication might be appropriate in this population. PMID- 30423469 TI - Insomnia and risk for suicidal behavior: A test of a mechanistic transdiagnostic model in veterans. AB - BACKGROUND: Insomnia has been shown to have direct and indirect associations with suicidal ideation, attempts, and death in U.S. military and veteran populations. However, transdiagnostic models of insomnia and psychopathology have not been used to examine the contribution of psychopathology. METHOD: The present study is a secondary analysis examining the associations among insomnia symptoms, posttraumatic stress disorder (PTSD) and depressive symptoms, interpersonal theory of suicide variables, and risk for suicidal behavior in community veterans (n = 392). Serial mediation was used to test sequential associations, allowing for examination of direct and indirect associations. RESULTS: The model with insomnia, PTSD, and depressive symptoms, and thwarted belongingness, accounted for 29% of the variance in risk. Insomnia symptoms had an indirect association through PTSD and depressive symptoms, and thwarted belongingness. The model with insomnia, PTSD, and depressive symptoms, and perceived burdensomeness accounted for 35% of the variance in risk. Insomnia symptoms had an indirect association through PTSD and depressive symptoms, and perceived burdensomeness. LIMITATIONS: Data are cross-sectional, precluding the testing of causal associations. CONCLUSIONS: In veterans, insomnia symptoms may be associated with increased PTSD and depressive symptoms, which may be associated with increased risk for suicidal behavior directly and indirectly through relationship disruptions. PMID- 30423470 TI - Understanding the effects of emotional reactivity on depression and suicidal thoughts and behaviors: Moderating effects of childhood adversity and resilience. AB - BACKGROUND: Early adulthood is a period of increased risk for depression and suicide. Emotional reactivity (a tendency to react to stress with increases in negative affect and maladaptive interpretations of events) is an important risk factor for these outcomes that has been under-studied. We hypothesized that elevated emotional reactivity would be associated with higher levels of depressive symptoms and suicidal thoughts and behaviors. Further, we hypothesized that experiences of childhood maltreatment would amplify this relationship, whereas the presence of resilience would act as a buffer. METHODS: 1703 young adults (Mean Age = 19.56 years), 71% female) completed well-validated self-report questionnaires at a single time point. RESULTS: Higher emotional reactivity was directly associated with higher levels of depressive symptoms and suicidal thoughts and behaviors. Further, resilience levels significantly moderated the relationships between emotional reactivity and depressive symptoms and suicidal thoughts and behaviors. Finally, childhood trauma significantly moderated the relationship between emotional reactivity and suicidal thoughts and behaviors only. LIMITATIONS: This study was cross-sectional in design and relied upon self report measures only. CONCLUSIONS: The current study demonstrates an association between emotional reactivity, depressive symptoms, and suicidal thoughts and behaviors during emerging adulthood. Whereas a history of childhood maltreatment may amplify the relationship between emotional reactivity, depression, and suicidal thoughts and behaviors, certain qualities associated with resilience may buffer against the effects of emotional reactivity. Future studies can identify the resilience-promoting factors that are most protective and develop and test interventions that can potentially augment those factors. PMID- 30423471 TI - The effect of complementary medicines and therapies on maternal anxiety and depression in pregnancy: A systematic review and meta-analysis. AB - BACKGROUND: Depression and anxiety are common during the antenatal and postnatal period, and are known to have a significant impact on the woman and her unborn infant. Pregnant women state a preference for non-pharmacological treatment options, and use complementary medicines and therapies to manage these symptoms. We examined the effectiveness and safety of these modalities on depression and anxiety during pregnancy. METHODS: CENTRAL, EMBASE and PubMed databases were searched for randomised controlled trials comparing complementary therapies and medicines to a control, for pregnant women with depression or anxiety. The primary outcome measure was antenatal depression or anxiety. RESULTS: Twenty randomised controlled trials containing 1092 women were included in the review. We found some evidence of reduced antenatal depression from three modalities. Acupuncture reduced the number of women diagnosed with antenatal depression (RR 1.68, 95% CI 1.06-2.66, 1 trial). Massage reduced the severity of antenatal depression in one trial of 149 women (SMD -0.73, 95%CI -1.07--0.39). One small trial of bright light therapy found reduced antenatal depression (RR 4.80, 95% CI -8.39--1.21, 27 women). There was no evidence of a reduction in depression and anxiety from relaxation, yoga, mindfulness and fish oils. Overall the risk of bias was high or unclear for the majority of studies. LIMITATIONS: There are few high quality randomised controlled trials of complementary medicines and therapies examining the effect on anxiety and depression. CONCLUSION: Acupuncture, bright light therapy, and massage may reduce antenatal depression. There is a need for high quality and larger studies that include postnatal follow up and maternal and neonatal outcomes. PMID- 30423472 TI - Cognitive functions associated with developing prefrontal cortex during adolescence and developmental neuropsychiatric disorders. AB - Cognitive functions including social cognition improve significantly during adolescence, the time period during which the brain typically handles a large volume of incoming information from the outside environment. Processing information and responding to environmental challenges allow the prefrontal cortex, a brain region important for cognition, to mature further and establish self-identity, social skills, and other cognitive abilities, thus helping individuals to function in society. People with vulnerable circuitries predisposed by either genetic or early environmental insults, may not be able to deal with social situations appropriately, and develop network dysfunction that may lead to the onset of schizophrenia, which often occurs during this period. Populations with higher risk for developing schizophrenia present "prodromal" phenotypes, including cognitive deficits, even before the onset of the disorder. Modulating circuit plasticity when the prefrontal cortex is particularly vulnerable allows us to support the development of cognitive functions in such populations and prevent them from transitioning into full-blown schizophrenia. For this approach to be successful, we need to conduct both human and animal studies side by side to better understand the neurobiology underlying the disorder, especially changes that occur over the disease trajectory that may be clinically relevant. By taking a multidisciplinary approach, there is a hope for precision medicine for schizophrenia in the future. PMID- 30423473 TI - Mitochondrial dysfunction in preclinical genetic prion disease: A target for preventive treatment? AB - Mitochondrial malfunction is a common feature in advanced stages of neurodegenerative conditions, as is the case for the accumulation of aberrantly folded proteins, such as PrP in prion diseases. In this work, we investigated mitochondrial activity and expression of related factors vis a vis PrP accumulation at the subclinical stages of TgMHu2ME199K mice, modeling for genetic prion diseases. While these mice remain healthy until 5-6 months of age, they succumb to fatal disease at 12-14 months. We found that mitochondrial respiratory chain enzymatic activates and ATP/ROS production, were abnormally elevated in asymptomatic mice, concomitant with initial accumulation of disease related PrP. In parallel, the expression of Cytochrome c oxidase (COX) subunit IV isoform 1(Cox IV-1) was reduced and replaced by the activity of Cox IV isoform 2, which operates in oxidative neuronal conditions. At all stages of disease, Cox IV-1 was absent from cells accumulating disease related PrP, suggesting that PrP aggregates may directly compromise normal mitochondrial function. Administration of Nano-PSO, a brain targeted antioxidant, to TgMHu2ME199K mice, reversed functional and biochemical mitochondrial functions to normal conditions regardless of the presence of misfolded PrP. Our results therefore indicate that in genetic prion disease, oxidative damage initiates long before clinical manifestations. These manifest only when aggregated PrP levels are too high for the compensatory mechanisms to sustain mitochondrial activity. PMID- 30423474 TI - Microsomal prostaglandin E synthase-1 is a critical factor in dopaminergic neurodegeneration in Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder of uncertain pathogenesis characterized by the loss of nigrostriatal dopaminergic neurons. Although increased production of prostaglandin E2 (PGE2) has been implicated in tissue damage in several pathological settings, the role of microsomal prostaglandin E synthase-1 (mPGES-1), an inducible terminal enzyme for PGE2 synthesis, in dopaminergic neurodegeneration remains unclear. Here we show that mPGES-1 is up-regulated in the dopaminergic neurons of the substantia nigra of postmortem brain tissue from PD patients and in neurotoxin 6-hydroxydopamine (6 OHDA)-induced PD mice. The expression of mPGES-1 was also up-regulated in cultured dopaminergic neurons stimulated with 6-OHDA. The genetic deletion of mPGES-1 not only abolished 6-OHDA-induced PGE2 production but also inhibited 6 OHDA-induced dopaminergic neurodegeneration both in vitro and in vivo. Nigrostriatal projections, striatal dopamine content, and neurological functions were significantly impaired by 6-OHDA administration in wild-type (WT) mice, but not in mPGES-1 knockout (KO) mice. Furthermore, in cultured primary mesencephalic neurons, addition of PGE2 to compensate for the deficiency of 6-OHDA-induced PGE2 production in mPGES-1 KO neurons recovered 6-OHDA toxicity to almost the same extent as that seen in WT neurons. These results suggest that induction of mPGES 1 enhances 6-OHDA-induced dopaminergic neuronal death through excessive PGE2 production. Thus, mPGES-1 may be a valuable therapeutic target for treatment of PD. PMID- 30423475 TI - Calpain activation and neuronal death during early epileptogenesis. AB - Epilepsy is a brain disorder characterized by a predisposition to suffer epileptic seizures. Acquired epilepsy might be the result of brain insults like head trauma, stroke, brain infection, or status epilepticus (SE) when one of these triggering injuries starts a transformative process known as epileptogenesis. There is some data to suggest that, during epileptogenesis, seizures themselves damage the brain but there is no conclusive evidence to demonstrate that spontaneous recurrent seizures themselves injure the brain. Our recent evidence indicates that calpain overactivation might be relevant for epileptogenesis. Here, we investigated if spontaneous recurrent seizures that occur during an early period of epileptogenesis show any correlation with the levels of calpain activation and/or expression. In addition, we also investigated a possible association between the occurrence of spontaneous seizures and increased levels of cell death, gliosis and inflammation (typical markers associated with epileptogenesis). We found that the number of spontaneous seizures detected prior to sample collection was correlated with altered calpain activity and expression. Moreover, the levels of hippocampal neurodegeneration were also correlated with seizure occurrence. Our findings suggest that, at least during early epileptogenesis, there is a correlation between seizure occurrence, calpain activity and neurodegeneration. Thus, this study opens the possibility that aberrant calpain reactivation by spontaneous seizures might contribute to the manifestation of future spontaneous seizures. PMID- 30423476 TI - Deep brain stimulation of the pedunculopontine nucleus modulates subthalamic pathological oscillations. AB - Low frequency deep brain stimulation (DBS) of the pedunculopontine nucleus area (PPNa) has been proposed as a novel surgical target for gait dysfunction in the late stage of Parkinson's disease (PD). Since the mid-2000s, we have shown that intrasurgical delivery of stimulation in the pontine tegmentum affects the firing activity in the subthalamic nucleus (STN), but its effect on STN oscillatory rhythms has not been studied. Neuronal oscillations detected by local field potential (LFPs) have great importance, since they express complex movement related behavior such as locomotion. Therefore, we examined the effect of three PPNa-DBS stimulation protocols (at 10, 25 and 80 Hz) on the STN oscillatory activity of PD patients. We focused on the anti-kinetic beta (beta, 15-30 Hz), the pro-kinetic gamma (gamma, 60-90 Hz) and "gait-related" alpha (alpha, 7-12 Hz) bands. We hypothesized that modulation of STN oscillations might have clinical relevance in the PPNa-mediated effects. PPNa stimulation at 25 and 80 Hz decreased the power of the STN beta band by 33.94 and 40.22%, respectively. PPNa DBS did not affect the other two bands with a tendency to suppress alpha power, while gamma oscillation increased. Our results suggest that the anti-kinetic beta band is the oscillation most sensitive to PPNa-DBS despite the negligible clinical efficacy on bradykinesia. However, how these changes interact reciprocally with the cortex or are counterbalanced by lower brainstem/spinal pathways remain to be elucidated. Our observation might turn out to be helpful in new protocols designed with adaptive DBS supporting the addition of PPN implantation in PD patients experiencing declining efficacy of STN-DBS. PMID- 30423477 TI - Apoliporotein L3 interferes with endothelial tube formation via regulation of ERK1/2, FAK and Akt signaling pathway. AB - BACKGROUND AND AIMS: Endothelial cells are main actors in vascular homeostasis as they regulate vascular pressure and permeability as well as hemostasis and inflammation. Disturbed stimuli delivered to and by endothelial cells correlate with the so-called endothelial dysfunction and disrupt this homeostasis. As constituents of the inner layer of blood vessels, endothelial cells are also involved in angiogenesis. Apolipoprotein Ls (APOL) comprise a family of newly discovered apolipoproteins with yet poorly understood function, and are suggested to be involved in inflammatory processes and cell death mechanisms. Here we investigate the role of APOLs in endothelial cells stimulated with factors known to be involved in atherogenesis and their possible contribution to endothelial dysfunction with an emphasis on inflammation driven-angiogenesis in vitro. METHODS: Using the CRISPR/Cas9 technique, we analyzed the effect of APOL3 gene knock out in HMEC-1 endothelial cells on cell migration, tubulogenesis, endothelial permeability, intracellular signal transduction as assessed by kinase phosphorylation, and angiogenesis gene expression (measured by qRT-PCR). RESULTS: Our results indicate that among the family, APOL3 was the only member induced by myeloperoxidase, oxidized LDL, VEGF and FGF treatments. APOL3 invalidation increased endothelial permeability, reduced wound repair and tubule formation in vitro, the latter only in MPO and VEGF-induced conditions. Accordingly, some pro angiogenic signaling pathways (ERK1/2 and FAK but not Akt) and some pro angiogenic genes were partially inhibited in APOL3 knock out cells. CONCLUSIONS: These findings suggest the involvement of APOL3 in angiogenesis in vitro and as a modulator of MAPK and FAK signaling in endothelial cells. PMID- 30423478 TI - Studies on effectiveness of PTT on 3D tumor model under microfluidic conditions using aptamer-modified nanoshells. AB - Herein, we present the research focused on the synthesis and application of aptamer-modified gold nanoshells for photothermal therapy (PTT). NIR-absorbing hollow gold nanoshells were synthetized and conjugated with anti-MUC1 aptamer (HGNs@anti-MUC1). MUC1 (Mucin 1) is a transmembrane glycoprotein, which is overexpressed in a variety of epithelial cancers (eg. breast, lung, pancreatic). In order to evaluate the efficiency of PTT with HGNs@anti-MUC1 we used 3D cell culture model - multicellular spheroids. The selected cell culture model is considered as the best in vitro model for cancer research (similar morphology, metabolite and oxygen gradients, cellular interactions and cell growth kinetics in the spheroids are similar to the early stage of a nonvascular tumor). We conducted our research on human normal (MRC-5, MCF-10A) and tumor (A549, MCF-7) cell lines using a microfluidic system. Aptamer-modified nanoparticles were accumulated selectively in tumor cells (A549, MCF-7) and this fact contributed to the reduction of tumor spheroids viability and size. It should be underlined, that it is the first example of photothermal therapy carried out in a microsystem on multicellular spheroids. PMID- 30423479 TI - Clinical Implications of t(11;14) in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation. AB - Conventional cytogenetic analyses and fluorescent in situ hybridization (FISH) are helpful for stratifying patients with multiple myeloma (MM) into high-risk [t(4;14), t(14;16), and/or del 17p] and standard-risk [t(11;14)] categories. However, the prognosis of patients with MM treated with autologous stem cell transplantation (ASCT) stratified according to these categories remains unclear. This retrospective observational study analyzed 97 patients with MM who received a single, planned ASCT after treatment with 200 mg/m2 melphalan between 2001 and 2011. The patients were grouped according to chromosomal abnormality, including t(11;14) (n = 45), t(4;14) (n = 31), del 17p (n = 10), t(11;14) with del 17p (n = 7), and t(4;14) with del 17p (n = 4). Median overall survival (OS) of the t(11;14) group (64.1 months) was not significantly different from that of the t(4;14) group (not reached), but it was significantly longer than that of the del 17p group (23.0 months; P = .002). G-banding revealed that the median OS of the t(11;14) group with additional chromosomal abnormalities (ACAs) (46.2 months) was significantly shorter than that of the t(11;14) group without ACAs (not reached; P = .005) and the t(4;14) group (not reached; P = .010). These findings highlight the importance of G-banding in patients with t(11;14) MM. PMID- 30423482 TI - Testosterone, risk, and socioeconomic position in British men: Exploring causal directionality. AB - Lower testosterone levels in men are observationally associated with worse health, but it is unclear whether they contribute to well-established social gradients in health. Mendelian Randomization studies suggest positive testosterone-health associations may not be causal, with some intervention studies suggesting testosterone administration could be harmful. Since testosterone is rarely measured in general population studies, very little is known about how testosterone varies by social position. Differences by education and household income in British men aged 60-64y were recently reported, but it is unclear whether this reflects an influence of socioeconomic position (SEP) on testosterone, influence of testosterone on SEP, or confounding. In the UK Household Longitudinal Study, a nationally-representative survey of UK adults, we examine social differences in testosterone in 3663 men aged 16-97y in 2010-12. We consider diverse dimensions of SEP: education, employment status, equivalized household income and personal earnings. Multivariable regression is used to explore social differences in testosterone across the adult life-span (16-97y). Secondly, Mendelian Randomization (MR), an approach which uses gene variants as instrumental variables for endogenous exposures, is used to investigate causal directionality. We examine associations with risk-taking, a plausible mediator of testosterone-SEP associations. In observational models no social differences in testosterone are seen, but MR models suggest a positive influence of testosterone on earnings (increase in log-transformed monthly earnings (GBP) per standard deviation increase in testosterone: 0.51, 95%CI: 0.03,1.05, p = 0.07) and probability of being in work (probit coefficient:0.25, 95%CI: 0.01,0.51, p = 0.06). Though MR estimates are less precise, results are consistent with previous literature linking testosterone with labour market success. The discrepancy may reflect suppression of observational associations by factors positively correlated with testosterone and negatively correlated with SEP, or indicate an influence of typical lifetime testosterone, which may be better indexed by genetic variants than by single testosterone measurements subject to noise. PMID- 30423481 TI - Effect of Conditioning Regimen Dose Reduction in Obese Patients Undergoing Autologous Hematopoietic Cell Transplantation. AB - Data are limited on whether to adjust high-dose chemotherapy before autologous hematopoietic cell transplant (autoHCT) in obese patients. This study explores the effects of dose adjustment on the outcomes of obese patients, defined as body mass index (BMI) >= 30 kg/m2. Dose adjustment was defined as a reduction in standard dosing >= 20%, based on ideal, reported dosing and actual weights. We included 2 groups of US patients who had received autoHCT between 2008 and 2014. Specifically, we included patients with multiple myeloma (MM, n = 1696) treated with high-dose melphalan and patients with Hodgkin or non-Hodgkin lymphomas (n = 781) who received carmustine, etoposide, cytarabine, and melphalan conditioning. Chemotherapy dose was adjusted in 1324 patients (78%) with MM and 608 patients (78%) with lymphoma. Age, sex, BMI, race, performance score, comorbidity index, and disease features (stage at diagnosis, disease status, and time to transplant) were similar between dose groups. In multivariate analyses for MM, adjusting for melphalan dose and for center effect had no impact on overall survival (P = .894) and treatment-related mortality (TRM) (P = .62), progression (P = .12), and progression-free survival (PFS; P = .178). In multivariate analyses for lymphoma, adjusting chemotherapy doses did not affect survival (P = .176), TRM (P = .802), relapse (P = .633), or PFS (P = .812). No center effect was observed in lymphoma. This study demonstrates that adjusting chemotherapy dose before autoHCT in obese patients with MM and lymphoma does not influence mortality. These results do not support adjusting chemotherapy dose in this population. PMID- 30423483 TI - Effects of chronic gamma-irradiation on growth and sexual maturation of the Tohoku hynobiid salamander, Hynobius lichenatus. AB - There are still considerable gaps in knowledge regarding the biological effects of chronic ionising radiation exposure in amphibians. To fill these gaps, Tohoku hynobiid salamanders, Hynobius lichenatus (Amphibia, Caudata), were chronically irradiated with 137Cs gamma-rays from embryonic to adult stages over 1954 days, and the effects on their growth and sexual maturation were examined under laboratory conditions. Irradiation at a dose rate of 33 MUGy h-1 had some stimulatory effects on growth (body weight increase) of H. lichenatus, while growth was temporarily or permanently suppressed at 150 or 510 MUGy h-1, respectively. On day 1802, secondary sexual characteristics (a tubercle at the anterior angle of the cloacal vent for males and ovisac development for females) were observed in 91% of the salamanders irradiated at 33 MUGy h-1, and in a similar percentage of non-irradiated controls. At 150 and 510 MUGy h-1, secondary sexual characteristics were not observed in any individuals. These results suggest that the derived consideration reference level (DCRL) of the International Commission on Radiological Protection (ICRP) for Reference Frog, i.e. 40-400 MUGy h-1, is applicable for the protection of H. lichenatus, and that growth and sexual maturation of this salamander may not have been adversely affected even in the most severely contaminated area in Fukushima, where the highest dose rate to salamanders was estimated to be 50 MUGy h-1. However, observations in the contaminated area are required to confirm this conclusion, considering the possible confounding factors which may make this salamander more sensitive to radiation in the natural environment than under laboratory conditions. PMID- 30423480 TI - Effect of Aging and Predonation Comorbidities on the Related Peripheral Blood Stem Cell Donor Experience: Report from the Related Donor Safety Study. AB - The development of reduced-intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RDs) of peripheral blood stem cells (PBSCs). The effects of age on donation efficacy, toxicity, and long-term recovery in RDs are poorly understood. To address this we analyzed hematologic variables, pain, donation-related symptoms, and recovery in 1211 PBSC RDs aged 18 to 79 enrolled in the Related Donor Safety Study. RDs aged > 60 had a lower median CD34+ level before apheresis compared with younger RDs (age > 60, 59 * 106/L; age 41 to 60, 81 * 106/L; age 18 to 40, 121 * 106/L; P < .001). This resulted in older donors undergoing more apheresis procedures (49% versus 30% >= 2 collections, P < .001) and higher collection volumes (52% versus 32% > 24 L, P < .001), leading to high percentages of donors aged > 60 with postcollection thrombocytopenia <50 * 109/L (26% and 57% after 2 and 3 days of collection, respectively). RDs aged 18 to 40 had a higher risk of grades 2 to 4 pain and symptoms pericollection, but donors over age 40 had more persistent pain at 1, 6, and 12 months (odds ratio [OR], 1.7; P = 0.02) and a higher rate of nonrecovery to predonation levels (OR, 1.7; P = .01). Donors reporting comorbidities increased significantly with age, and those with comorbidities that would have led to deferral by National Marrow Donor Program unrelated donor standards had an increased risk for persistent grades 2 to 4 pain (OR, 2.41; P < .001) and failure to recover to predonation baseline for other symptoms (OR, 2.34; P = .004). This information should be used in counseling RDs regarding risk and can assist in developing practice approaches aimed at improving the RD experience for high-risk individuals. PMID- 30423484 TI - Enhanced long-wavelength light utilization with polyaniline/bismuth-rich bismuth oxyhalide composite towards photocatalytic degradation of antibiotics. AB - Antibiotics in natural waters have posed serious threats to our ecosystem due to its potent biological toxicity. In the present work, a visible-light-driven PANI/Bi4O5Br2 composite photocatalyst was fabricated and used for the degradation of ciprofloxacin (CIP) and tetracycline (TC) antibiotics under visible light (lambda > 420 nm). The PANI/Bi4O5Br2 composite presented a significantly improved ability of CIP and TC photodegradation, which is about 2.2 times and 1.6 times to that of Bi4O5Br2, respectively. The promoted photocatalytic activity results from the interface interaction between PANI and Bi4O5Br2, which contributes to the electron-hole separation. The degradation process of CIP was monitored by mass spectrometry, and a possible degradation pathway was proposed based on the analysis of the product. A microbiological antibacterial experiment was designed, proving that the degraded products of CIP and TC have lower toxicity. Furthermore, long wavelength light irradiated (lambda > 550 nm) experiment indicated that the introduction of PANI helps to extend the light absorption region and use the long wavelength light more efficiently, thereby promoting the photocatalytic ability. The optimal composite applied for TC degradation was 0.1% PANI/Bi4O5Br2. Its reaction rate constant was 2.8 times to that of Bi4O5Br2 (lambda > 550 nm). Eventually, a possible photocatalytic mechanism over PANI/Bi4O5Br2 composite was proposed. PMID- 30423485 TI - Uniform mesoporous carbon hollow microspheres imparted with surface-enriched gold nanoparticles enable fast flow adsorption and catalytic reduction of nitrophenols. AB - Adsorption and catalytic conversion of nitrophenols (NPs) over carbon-based materials have attracted wide interest. Batch adsorption and catalytic reduction of NPs have been widely reported, but less attention has been paid to flow systems, which require high particle size uniformity and superior active site accessibility. Herein, uniform mesoporous carbon hollow microspheres with their surfaces enriched by Au nanoparticles (denoted as Au@UMCHMs) are synthesized. The surface-enriched Au nanoparticle loading is promoted by the unique feature, that is, relatively dense external layers and mesoporous inner shells, of the carbon microspheres and the simple impregnation-reduction method. The Au@UMCHMs possess uniform sizes of ~82 MUm, small shell thickness of ~5.8 MUm, high specific surface area (~1587 m2/g), and uniform mesopores (2.1 and 5.8 nm). They show excellent performance for flow adsorption and catalytic reduction of 4 nitrophenol (4-NP), superior to that of conventional Au-loaded carbon materials. In flow adsorption of 4-NP, the Au@UMCHMs show a fast and complete removal efficiency with high adsorption capacities (~223 mg/g at breakthrough). They show outstanding performance in flow catalytic reduction of 4-NP. 4-NP with high concentrations (up to 100 mg/L) can be ultrafast and completely catalytically reduced to 4-aminophenol (4-AP) under rapid flow rates (up to ~25 mL/min). PMID- 30423486 TI - Armoured nanobubbles; ultrasound contrast agents under pressure. AB - HYPOTHESIS: Robust methods for differentiating long-lived nanobubbles from other nanoparticles are required. Evaluation of the density and compressibility of nanoparticles should enable nanobubbles to be differentiated from other nanoparticles, although the response of nanobubbles to pressure can be strongly influenced by a coating of insoluble surfactant. Here we evaluate the response of nanobubbles armoured with a coating of insoluble surfactants in order to determine if they can be differentiated from other nanoparticles. EXPERIMENTS: Dynamic light scattering was used to size candidate nanoparticles under the influence of external pressure and resonant mass measurements were employed to assess the density of candidate nanoparticles. FINDINGS: The resonant mass measurement revealed a significant population of lipid-coated gas nanobubbles. These nanobubbles are proven to be gas entities, by their response to application of pressure. The pressure at which the gas within the nanobubbles condenses is shifted to higher pressure due to the mechanical resistance of the lipid shell, which shields the bubble contents from up to ~0.8 atm. of the external pressure The presence of lipids of low solubility at the nanobubble-solution interface effectively results in a negative Laplace pressure, which stabilizes these nanobubbles against dissolution. PMID- 30423487 TI - Towards highly efficient and low-cost oxygen evolution reaction electrocatalysts: An effective method of electronic waste management by utilizing waste Cu cable wires. AB - Currently, electronic waste (e-waste) is the world's most challenging and rapidly growing problem in the waste stream. To develop an alternative way to use e-waste (waste copper (Cu) wires) to accelerate the oxygen evolution reaction (OER) of water electrolysis, the waste Cu wires are used as a low-cost current collector. We demonstrate a simple electrodeposition process to deposit nickel-iron hydroxide (NiFe LDH) nanosheets on self-supported copper hydroxide (Cu(OH)2/Cu) nanowires grown via chemical-oxidation on waste Cu wire. Benefiting from the efficient electron transport, high mass activity, and surface area this electrocatalyst exhibits an efficient OER performance with a low overpotential of 275 mV and 390 mV at 20 and 100 mA cm-2 respectively, with excellent stability. This work provides a promising pathway to recycle e-waste into value-added resources in various energy conversion applications. PMID- 30423488 TI - Nickel induced in situ growth of nickel hydroxide nanoflakes on reduced graphite oxide with high energy and power density. AB - Layered hexagonal Ni(OH)2 nanoflakes have been successfully fabricated on the surface of reduce graphite oxide (rGO) via nickel induced in situ growth in this study. The layers number and size of Ni(OH)2 nanoflakes could be controlled by adjusting the concentration of Ni2+ precursors with nickel as active site on rGO surface. In the three electrode systems, the composite showed a relatively high specific capacitance achieved 1012.2 F?g-1 at current density of 1 A?g-1 with coulombic efficiency of 98.3%. As assembled in asymmetric devices (Ni(OH)2 nanoflakes loaded on rGO as positive electrode and active carbon as negative electrode), the maximum specific capacitance reaches to 260.9 F?g-1 at current density of 0.5 A?g-1 and the energy density can be maintained at 71.1 Wh?kg-1 at power density of 26.95 kW?kg-1 with good rate capability and acceptable cycling stability. PMID- 30423489 TI - Synthesis of three dimensional N&S co-doped rGO foam with high capacity and long cycling stability for supercapacitors. AB - Inspired by steaming bread, a novel three dimensional N and S co-doped reduced graphene oxide (3D NS-rGO) foam is fabricated via a gas foaming method similar to steaming bread procedure, in which (NH4)2S2O3 is selected as the foaming agent as well as N and S source. Such cross-linked 3D structure not only has the high specific surface area also enable more transport channels for electrons/ions transport. Furthermore, introducing of N and S-containing functional groups creates lattice defects in graphene, which provides more active sites where the Faradaic pseudocapacitance occurs. Consequently, the electrochemical test of 3D NS-rGO sample in a three-electrode system demonstrates a high specific capacity of 306.3 F g-1 at 1 A g-1, two times higher than that of rGO prepared at the same temperature. Moreover, 3D NS-rGO sample reveals the superb cycling stability with less than 2% capacitance loss after 10,000 cycles and it exhibits potential application for high performance supercapacitors. PMID- 30423490 TI - Well-designed Ag/ZnO/3D graphene structure for dye removal: Adsorption, photocatalysis and physical separation capabilities. AB - In this research, adsorption and photocatalytic degradation process were utilized to remove organic dye from wastewater. To accomplish that, a newly-designed ternary nanostructure based on Ag nanoparticles/ZnO nanorods/three-dimensional graphene network (Ag NPs/ZnO NRs/3DG) was prepared using a combined hydrothermal photodeposition method. The three-dimensional structure of graphene hydrogel as a support for growth of ZnO nanorods was characterized using field emission scanning electron microscopy (FESEM). In addition, diameter of silver nanoparticles grown on the ZnO nanorods with the average aspect ratio of 5 was determined in the range of 30-80 nm by using transmission electron microscopy (TEM). The X-ray diffraction (XRD) pattern was revealed hexagonal Wurtzite structure of ZnO nanorods and the (1 1 1) lattice plane of the face-centered cubic (FCC) of the silver nanoparticles. The dye adsorption capacity of the synthesized 3DG was evaluated at about 300 mg/g using kinetic study. The photocatalytic dye degradation under both UV and visible light irradiation exhibited an enhanced activity of the prepared ternary Ag/ZnO/3DG sample in comparison to ZnO/3DG and 3DG structures. Different charge-carrier scavengers were utilized to elucidate the synergistic effect of adsorption and visible-light photocatalytic degradation mechanism for dye removal. The facile photocatalyst recovery as well as the high elimination rate of dye is promising for future applications such as efficient removal of organic contaminants from industrial wastewater under solar irradiation. PMID- 30423491 TI - One-step synthesis of palladium oxide-functionalized tin dioxide nanotubes: Characterization and high nitrogen dioxide gas sensing performance at room temperature. AB - Mesoporous palladium oxide (PdO)-functionalized tin dioxide (SnO2) composite nanotubes (SPCTs) were prepared via one-step synthesis by electrospinning technology using ethanol and N,N-dimethylformamide (DMF) as solvents. Compared with pure SnO2 nanotubes, there were abundant mesopores and multiheterojunctions in PdO-functionalized SnO2 nanotubes. The sample with the molar ratio of SnO2:PdO of 100:3 (3-SPCT) exhibited excellent response (~20.30) as a sensor with fast gas response speed (~1.33 s) to 100 ppm nitrogen dioxide (NO2) at room temperature (RT), and the detection limit reached to 10 ppb. The improved gas sensing performance of the 3-SPCT sensor was mainly attributed to the synergistic effect: the unique SnO2 tubular structure and well-dispersed mesopores provided the gas diffusion and adsorption channels, oxygen defects and chemisorbed oxygen were taken as the electron trap and charge transfer active sites, and a large number of heterojunctions acted as electron transport channels, thereby increasing the transfer rate. PMID- 30423493 TI - Forensic Science UK - We need solutions, let's hear them. PMID- 30423492 TI - Fabrication of highly durable polysiloxane-zinc oxide (ZnO) coated polyethylene terephthalate (PET) fabric with improved ultraviolet resistance, hydrophobicity, and thermal resistance. AB - Developing a universal strategy to improve the properties of polyethylene terephthalate (PET) fibers, such as UV resistance, hydrophobicity, and thermal resistance, is highly desirable in expanding the application of PET fibers. Herein, a highly durable and robust ZnO layer was deposited onto PET fabric via radiation-induced graft polymerization (RIGP) of gamma-methacryloxypropyl trimethoxysilane (MAPS) and the subsequent sol-gel in situ mineralization with zinc acetate to produce wurtzite nanocrystalline ZnO. The as-obtained material, denoted as PET-g-PMAPS/ZnO. The interfacial layer consisted of Zn-O-Si and Si-O Si covalent bonds not only leads to an improvement in adhesion between ZnO nanoparticles and its support, but it also overcomes the poor film-forming ability of inorganic particles. Most importantly, photocatalytic self-degradation of its organic support caused by the high photocatalytic activity of ZnO can be eliminated because of high bond energy of the organic-inorganic hybrid structure. PET-g-PMAPS/ZnO exhibited excellent thermal resistance, UV resistance and durability. Superhydrophobicity was achieved by simply annealing the PET-g PMAPS/ZnO fabric at 200 degrees C in ambient air, and the coated fabric still retains its superhydrophobicity after 40 laundering cycles test and even stored for a few weeks. This study presents an effective method to overcome the bottle necks in growing inorganic nanocrystals on polymeric supports surface. PMID- 30423494 TI - Evaluating novel fungal secretomes for efficient saccharification and fermentation of composite sugars derived from hydrolysate and molasses into ethanol. AB - This paper evaluates the ability of secretome from two thermotolerant fungal strains (Aspergillus terreus 9DR and Achaetomium strumarium 10DR) for boosting the hydrolytic efficiency of benchmark cellulolytic preparation (Cellic CTec2). Further we report enhanced saccharification of different agro-residues under semi aerobic when compared to aerobic conditions. The mass spectroscopic analysis of the hydrolysates indicates the role of auxiliary oxidative enzymes present in A. terreus and A. strumarium secretomes for enhancing the capability of the cellulolytic cocktails. The paper further demonstrate positive effect of using the cocktails for enhanced saccharification and subsequent fermentation to ethanol of acid pre-treated rice straw, corn residues and sugarcane bagasse at higher substrate loading rates (20% w/v). The paper also reports co-utilization of composite sugars derived from molasses and enzymatic hydrolysate obtained from agnostic lignocellulosics for efficient bioconversion to ethanol applicable for developing BOLT-ON technology. PMID- 30423495 TI - Efficacy of Cu(II) as an electron-shuttle mediator for improved bioelectricity generation and Cr(VI) reduction in microbial fuel cells. AB - Cu(II) ion was employed as an electron-shuttle mediator to enhance bioelectricity output and accelerate reduction rate of Cr(VI) in a dual-chamber microbial fuel cell (MFC). In the presence of Cu(II), power density and the Cr(VI) reduction rate were 1235.53 mW m-2 and 1.191 g m-3 h-1, respectively, which were 1.44 times and 1.17 times than that of MFC in the absence of Cu(II). A series of electrochemical analysis confirmed the presence of Cu(II) can diminish overpotential and diffusional resistance of MFC, further accelerating electrochemical reduction process of Cr(VI) via an indirect mechanism. After reduction, Cr(VI) and Cu(II) in this work were mainly deposited on cathode electrodes in the form of Cr(OH)3 and little Cu, thus wastewater containing Cr(VI) was successfully treated by bio-electrochemical technology. The aim of this work was to study the efficacy of Cu(II) as an electron-shuttle mediator for improved bioelectricity generation and Cr(VI) reduction in MFCs. PMID- 30423496 TI - Both cell envelope and cytoplasm were the locations for chromium(VI) reduction by Bacillus sp. M6. AB - Biotreatment is an effective way in remediation of chromium(VI) (Cr(VI)) contamination, but its mechanism and reaction sites are still not clear. Herein, Bacillus sp. M6 was used as a model bacterium in this study to investigate the removal mechanism of Cr(VI) in solution. The results showed that the removal of Cr(VI) was attributed to direct reduction by Bacillus sp. M6, and the reduction locations occurred both on the cell envelope and in the cytoplasm. Meanwhile, bioanalysis of Bacillus sp. M6 by SEM-EDS and TEM-EDS, indicated that Cr(III) containing precipitates distributed both on the surface and in the cytoplasm of Bacillus sp. In addition, XPS analysis demonstrated that the chromium could be bound to cells by coordination with functional groups (C-based and O-based) on the bacterial surface. This work offers a new and deep insight into the mechanism of Cr(VI) reduction by Bacillus sp. PMID- 30423497 TI - Microwave assisted hydrothermal preparation of rice straw hydrochars for adsorption of organics and heavy metals. AB - A series of rice straw hydrochars were produced through a microwave-assisted hydrothermal treatment method, characterized and used for the adsorption of three organics and two heavy metals from aqueous solutions. The hydrochars have carbon contents from 37.44% to 43.31%, are rich in oxygen containing functional groups, and the equilibrium of hydrothermal carbonization reactions could be reached rapidly in microwave environment. The hydrochars can effectively adsorb the model pollutants, the maximum adsorption capacities of Congo red, berberine hydrochloride and 2-naphthol at 298 K and initial concentration of 0.5 mg/mL were 222.1, 174.0 and 48.7 mg/g, respectively, and those of Zn2+ and Cu2+ were 112.8 and 144.9 mg/g, respectively. Adsorption thermodynamic parameters were calculated. These results suggest that microwave-assisted hydrothermal treatment is an effective method for the rapid production of hydrochars, and rice straw hydrochars are promising adsorbents for the removal of water pollutants such as organics and heavy metals. PMID- 30423498 TI - Pulse-rate discrimination deficit in cochlear implant users: is the upper limit of pitch peripheral or central? AB - Cochlear implant (CI) users do not reliably associate an increase in pulse rate above 300 pulses per second (pps) with an increase in pitch. The locus of this upper limit of pitch remains unknown. The present study tested the hypothesis that this deficit resides at least initially at the auditory nerve. The hypothesis was tested by comparing pulse rate discrimination in different neural excitation patterns, in which a large versus small population of auditory nerve fibers was activated. If poorer pulse rate discrimination was found under conditions where narrower spread of neural excitation (SOE) was anticipated where a relatively small neural population was activated, then it would support the hypothesis that the rate processing deficit found in CI users is related to peripheral neural degeneration. Nine listeners (12 ears) implanted with the Cochlear Americas Nucleus(r) devices participated in the study. Different SOE conditions were created by (1) selecting electrodes that showed narrow versus broad forward-masked psychophysical spatial tuning curves, and (2) by measuring these electrodes in monopolar (MP) and narrow bipolar (BP0) electrode configurations. Rate discrimination difference limen (DL) was measured at the selected electrodes in two electrode configurations at three base rates (200, 300 and 500 pps). Consistent with the prediction, group mean DL was better (1) at stimulation sites measured with broader tuning, and (2) in MP relative to BP stimulation. These effects were more salient at the more challenging base rates. There was a weak relationship between rate discrimination (above thresholds) and the effect of rate on detection thresholds. Finally, rate discrimination at rates above the known upper limit (i.e., 500 pps) was correlated with duration of deafness and highly predicted the subjects' speech recognition performance in noise. These findings support that pulse rate discrimination depends, at least partially, on neural conditions at the auditory periphery and this peripheral limit predicts speech recognition outcomes with a CI. PMID- 30423499 TI - Neuronal competition: microcircuit mechanisms define the sparsity of the engram. AB - Extensive work in computational modeling has highlighted the advantages for employing sparse yet distributed data representation and storage Kanerva (1998), properties that extend to neuronal networks encoding mnemonic information (memory traces or engrams). While neurons that participate in an engram are distributed across multiple brain regions, within each region, the cellular sparsity of the mnemonic representation appears to be quite fixed. Although technological advances have enabled significant progress in identifying and manipulating engrams, relatively little is known about the region-dependent microcircuit rules governing the cellular sparsity of an engram. Here we review recent studies examining the mechanisms that help shape engram architecture and examine how these processes may regulate memory function. We speculate that countervailing forces in local microcircuits contribute to the generation and maintenance of engrams and discuss emerging questions regarding how engrams are formed, stored and used. PMID- 30423500 TI - Hold-relax and contract-relax stretching for hamstrings flexibility: A systematic review with meta-analysis. AB - OBJECTIVE: To synthesize evidence on the effects of hold-relax and contract-relax stretching (HR and CR) on hamstrings flexibility compared with no intervention and other stretching techniques. DESIGN: Electronic databases (PubMed, PEDro, Cochrane CENTRAL, Scopus, LILACS) were searched from inception until March 31, 2014 and updated until May 31, 2017. Randomized controlled trials involving HR and CR to improve hamstrings flexibility in adults (aged >=18 years old) with or without a pathological condition were included. Two reviewers independently searched literature, assessed risk of bias, and extracted data, while a third reviewer settled disagreements. RESULTS: Thirty-nine trials (n = 1770 healthy adults; median PEDro score = 4/10) were included. Meta-analysis showed large effects compared to control immediately after 1 session (6 trials, SMD = 1.02, 95% CI = 0.69 to 1.35, I2 = 2%) and multiple sessions (4 trials, SMD = 1.02, 95% CI = 0.64 to 1.40, I2 = 0%). Meta-analysis showed conflicting results compared to static stretching, while individual trials demonstrated conflicting results compared to other techniques. CONCLUSIONS: The immediate effects of HR and CR on hamstrings flexibility in adults are better against control. The long-term effects against other stretching types, and optimal exercise prescription parameters require further research. PMID- 30423501 TI - Denoising and spatial resolution enhancement of 4D flow MRI using proper orthogonal decomposition and lasso regularization. AB - 4D-Flow MRI has emerged as a powerful tool to non-invasively image blood velocity profiles in the human cardio-vascular system. However, it is plagued by issues such as velocity aliasing, phase offsets, acquisition noise, and low spatial and temporal resolution. In imaging small blood vessel malformations such as intra cranial aneurysms, the spatial resolution of 4D-Flow is often inadequate to resolve fine flow features. In this paper, we address the problem of low spatial resolution and noise by combining 4D-Flow MRI and patient specific computational fluid dynamics using Least Absolute Shrinkage and Selection Operator. Extensive experiments using numerical phantoms of two actual intra-cranial aneurysms geometries show the applicability of the proposed method in recovering the flow profile. Comparisons with the state-of-the-art denoising methods for 4D-Flow show lower error metrics. This method can enable more accurate computation of flow derived patho-physiological parameters such as wall shear stresses, pressure gradients, and viscous dissipation. PMID- 30423502 TI - Anode materials for sulfide oxidation in alkaline wastewater: An activity and stability performance comparison. AB - Electrochemical sulfide removal can be attractive as a zero-chemical-input approach for treatment of waste streams such as spent caustics coupled to caustic recovery. A key concern is possible decline in catalytic activity, due to passivation from deposited elemental sulfur (S0) on the anode surface and stability limitation, due to sulfide oxidation under highly alkaline conditions. In this study, six commercially available electrode materials (Ir Mixed Metal Oxide (MMO), Ru MMO, Pt/IrOx, Pt, PbOx and TiO2/IrTaO2 coated titanium-based electrodes) were tested to investigate the impact of the electrocatalyst on the process efficiency in terms of sulfide removal and final product of sulfide oxidation, as well as to determine the stability of the electrocatalyst under high sulfide concentrations (50 mM Na2S) and high alkalinity (pH > 12). Short term experiments showed that the catalyst type impacts the anode potential and the sulfide oxidation reaction products. Longer-term experiments under current densities up to 200 A m-2 showed a high differentiation in stability performance among the catalysts. Ru MMO was the most active towards sulfide oxidation with a coulombic efficiency of 63.2 +/- 0.5% at an average anode potential of 0.92 +/- 0.17 V vs SHE. Ir MMO was the most stable, preserving 100% of its original catalyst loading during the tests. The results demonstrated that Ru MMO and Ir MMO were the most suitable electrode materials for sulfide oxidation under highly alkaline conditions, while the need for establishing a good trade-off between activity, stability and cost still persists. PMID- 30423503 TI - Assessing the effect of abiotic variables and zooplankton on picocyanobacterial dominance in two tropical mesotrophic reservoirs by means of evolutionary computation. AB - Evolutionary computation has been applied to predict the occurrence of massive cyanobacteria proliferations; in the present study, this tool was further used to explore the factors responsible for maintaining picocyanobacterial dominance. Aiming to increase the understanding of factors that promote dominance of picocyanobacteria in tropical reservoirs, we chose two reservoirs used for water supplies located in different regions of Brazil and subjected to climate changes such as warmer winters that intensify water column stratification and prolonged dry seasons that cause water level decreases. This study focused on the diagnosis of the relationships among picocyanobacteria (1-2 MUm), zooplankton and environmental variables using evolutionary computation. The integrated data analysis performed here was very successful in elucidating the dynamics of picocyanobacterial density variation influenced by both abiotic and biotic factors by the modeling approach. Relative water column stability - RWCS and electrical conductivity were highlighted as the most important environmental drivers for picocyanobacterial peaks. Hybrid Evolutionary Analysis (HEA) models for the two reservoirs indicated for the first time in the literature that rotifers, small-sized cladocerans and copepods (mainly nauplii) can directly or indirectly control picocyanobacteria in tropical mesotrophic reservoirs, depending on RWCS conditions and electrical conductivity. However, this control is modulated by pH, water transparency and water temperature thresholds. PMID- 30423504 TI - The QuantiPhage assay: A novel method for the rapid colorimetric detection of coliphages using cellulose pad materials. AB - Assessment of viral contamination is essential for monitoring the microbial quality of water and protection of public health, as human virus presence is not accurately determined using bacterial indicators. Currently, the time required for conventional viral testing means that water contaminated with human pathogens may be used (e.g. for drinking, recreation or irrigation) days before results are available. Here we report a new rapid method for coliphage enumeration, the QuantiPhage (QP) assay. The novelty of the assay is the use of cellulose absorbent pad materials to support coliphage growth and colorimetric detection, in place of agar that is used in the plaque assay. In addition to saving time associated with agar preparation and tempering, the QP assay enabled enumeration of somatic coliphages in 1.5-2 h and F+ coliphages in 2.5-3 h. The assays were highly sensitive, with a lower detection limit of 1 plaque forming unit (PFU) per mL where 1 mL sample volumes were analysed, and 1 PFU per 10 mL where 10 mL sample volumes were analysed. This is the first rapid culture assay to enable low numbers of coliphages to be reliably detected and to produce directly equivalent results to agar-based plaque assays. A novel gelatin-immobilisation method is also reported, that reduces time to prepare bacterial cells from ~20 h to 40-60 min (depending on the assay format), and provides a ready to use form of cells, that is compatible with rapid detection and kit formats. When applied to analysis of somatic coliphages in wastewater samples and surface water samples, mean differences in results of the QP assay and the conventional plaque assay were not statistically significant (mean difference <= 0.15 log10 PFU/L and 0.5 PFU/10 mL respectively, P > 0.05). The QP is a valuable tool for assessing microbial water quality, which may assist in improving the management of water resources. PMID- 30423505 TI - The design and the performance of an ultrahigh vacuum 3He fridge-based scanning tunneling microscope with a double deck sample stage for in-situ tip treatment. AB - Scanning tunneling microscope (STM) is a powerful tool for studying the structural and electronic properties of materials at the atomic scale. The combination of low temperature and high magnetic field for STM and related spectroscopy techniques allows us to investigate the novel physical properties of materials at these extreme conditions with high energy resolution. Here, we present the construction and the performance of an ultrahigh vacuum 3He fridge based STM system with a 7 Tesla superconducting magnet. It features a double deck sample stage on the STM head so we can clean the tip by field emission or prepare a spin-polarized tip in situ without removing the sample from the STM. It is also capable of in situ sample and tip exchange and preparation. The energy resolution of scanning tunneling spectroscopy at T = 310 mK is determined to be 400 mK by measuring the superconducting gap with a niobium tip on a gold surface. We demonstrate the performance of this STM system by imaging the bicollinear magnetic order of Fe1+xTe at T = 5 K. PMID- 30423506 TI - Planar conformity of movements in 3D reaching tasks for persons with Multiple Sclerosis. AB - Robotic rehabilitation of the upper limb has been proved beneficial for people with Multiple Sclerosis (MS). In order to provide task-specific therapy for MS, given its complex impairing nature, it is desired to take advantage of the robots' ability to move and provide force feedback in generic three-dimensional motions. Previous investigations have shown that hand motion during reaching tasks is piecewise planar, therefore, it is possible to simplify the design of robotic rehabilitation trajectories by confining them on planes oriented in space. To do so, it must first be established whether this natural tendency for tracking a plane during hand movement is affected by the presence of neurological impairment, such as Multiple Sclerosis. This work hypothesizes that in the case of people with MS, planar mapping is not dependent on the resulting impairment. Furthermore, it is investigated whether neurophysiological models such as Fitts' law and Minimum Jerk Model remain in effect when considering the plane-mapped trajectories and also how these are affected by MS in contrast to natural movement. To test the hypotheses a group of healthy people and a group of people with MS at various stages of the disease have performed reaching tasks in the context of a haptic-interface based Nine-Hole-Pegboard-Test (NHPT) which facilitates the generation of trajectories with various distances and durations in the three-dimensional space. The results suggest that, despite the neurological impairments, the planar adaptation of people with MS is almost as persistent as in the case of healthy people. Furthermore it is shown that Fitts' law and MJM apply for plane-mapped trajectories and can be utilized in the design of simplified robotic rehabilitation schemes. PMID- 30423507 TI - Assessment of mindfulness by self-report. AB - Assessment of mindfulness is essential to understanding its relationships with psychological functioning. Currently, mindfulness is most often assessed with self-report questionnaires. Although additional work is required, mindfulness questionnaires have reasonable psychometric properties and are making important contributions to the understanding of mindfulness and its effects on health and wellbeing. For example, measurement of mindfulness as a multidimensional construct shows that present-moment awareness can be unhelpful unless accompanied by a nonjudgmental, nonreactive stance; moreover, nonjudgment and nonreactivity may be only weakly related to present-moment awareness in people with no meditation experience. Differences between psychological and Buddhist conceptions of mindfulness, though often a source of criticism of mindfulness questionnaires, are argued here to be inevitable and not necessarily problematic. PMID- 30423508 TI - Clinical, mammographic, and ultrasonographic characteristics of diabetic mastopathy: A case series. AB - PURPOSE: Diabetic mastopathy (DMP) is a rare benign breast lesion that mimics breast cancer on ultrasound. Our aims were to identify patient characteristics and imaging features of the disease. METHODS: We conducted retrospective searches of our database for DMP lesions that were pathologically confirmed between January 2004 and November 2015. Mammographic and ultrasound features were reviewed by two experienced radiologists. RESULTS: Twelve women were identified with 16 lesions. Most patients (83%) had type 2 diabetes mellitus (DM) and over half were insulin-dependent (58.3%), with a mean time of 16.9 years between the diagnosis of DM and that of DMP. There were negative findings on mammography for 46.7% of the lesions, including larger-sized lesions. Ultrasound revealed various features, including irregular shape (81.3%), indistinct margins (100%), parallel orientation to the chest wall (93.8%), marked hypoechogenicity (87.5%), and posterior shadowing (62.5%). CONCLUSIONS: DMP was more common in patients with longstanding DM; in particular, type 2 DM and insulin-dependent patients. DMP lesions were usually occult on mammography, despite the relatively large size of DMP, which may help distinguish DMP from invasive cancer. Ultrasound detected several features that are also present in invasive cancer, making tissue sampling necessary to distinguish these. PMID- 30423509 TI - Chemical and microbiological characterization of cruise vessel wastewater discharges under repair conditions. AB - Cruise ship wastewater discharges are pollution sources towards the marine environment that are poorly characterized. In this study, wastewater samples from cruise ships have been obtained during repair works in a shipyard. Different organic pollutants have been analyzed and their concentrations were similar to those in urban wastewaters for pharmaceuticals and fragrances, but higher for UV filters and PAHs. For the first time, cypermethrin, a pesticide highly toxic towards aquatic species, was found at relevant concentrations (>1 ug L^-1). The faecal microorganisms were for all parameters higher than 10^4 CFU 100 mL^-1, which together with the presence of antibiotic compounds in wastewater (e.g., triclosan), could potentially lead to the generation of antibiotic resistance bacteria (ARB). The historical position of cruise ships, determined from the Automatic Identification System (AIS), were used to define the time ships were underway, at port, or in repair. From ship's passenger and crew load, and from estimates of discharges the total volume of wastewater produced by these ships (371,000 m^3 year^-1) and the average flow (0.15 +/- 0.03 m^3crew^-1 day^-1) were calculated. PMID- 30423510 TI - Triphenyltin exposure affects mating behaviors and attractiveness to females during mating in male guppies (Poecilia reticulata). AB - The impacts of triphenyltin (TPT) on ecological health have been of great concern due to their widespread use and ubiquity in aquatic ecosystems. However, little is known about the effects of TPT on the reproductive behaviors of fishes. Therefore, the present study was conducted to investigate the effects of TPT at environmentally relevant concentrations (0, 1 and 10 ng Sn/L) on the mating behaviors and the attractiveness to females during mating in male guppies (Poecilia reticulata). The results showed that TPT exposure disturbed the mating behaviors; the TPT-exposed male fish performed more sneaking attempts, but no changes in sigmoid courtship were displayed. The increases in sneaking attempts might be related to increases in testosterone levels induced by TPT exposure. In the context of a competing male, the TPT-exposed males were less attractive to females during mating. The decreases in attractiveness might be related to decreases in carotenoid-based coloration, shown as decreases in caudal fin redness values and skin carotenoid contents. In addition, TPT-induced total antioxidant capacities, the activities of superoxide dismutase and catalase, and the contents of malondialdehyde in liver and intestinal tissues indicated increases in oxidative stress. Both oxidative stress and coloration are linked to carotenoids. Thus, we speculated that the TPT-exposed males might use carotenoids to cope with increases in oxidative stress at the expense of carotenoid-based coloration. The disruption of mating behaviors and the decrease in attractiveness to females in male fish could result in reproductive failure. The present study underscores the importance of using behavioral tests as a sensitive tool in assessing the impact of pollutants present in aquatic environments. PMID- 30423511 TI - Abnormal processing of prosodic boundary in adults who stutter: An ERP study. AB - Characterized by involuntary disruptions in fluency speech, adults who stutter (AWS) are different from normally fluent speakers (NFS) in speech-language processing indices of phonological, semantic, and syntactic information coding. However, the neural base of the prosodic information (i.e. prosodic boundary) processing in AWS is still elusive at this point. To investigate this question, Chinese temporarily ambiguous phrases (narrative-object/modifier-noun construction) were presented in pairs to AWS and NFS in both lexical judgment and structural judgment task by using structural priming paradigm. Results showed that both AWS and NFS produced prosodic priming in the two tasks, however, AWS were more sensitive to the priming than NFS in the midline. Besides, unlike the greater right hemisphere involvement of priming effect for NFS, AWS exhibited a left hemisphere asymmetry in the lateral areas. In addition, structural judgment task elicited stronger prosodic priming effect than lexical judgment task for both groups. These results indicate that the mode of prosodic priming for AWS is different from NFS, and the priming effect is influenced by the experimental task that participants completed. PMID- 30423512 TI - Difenoconazole and linuron dissipation kinetics in carrots under open-field conditions. AB - The dissipation of difenoconazole and linuron using an open-field experimental approach with carrots exposed to one-, two- and fivefold the recommended dose of the pesticides was evaluated to provide safe recommendation to ensure food safety of carrots. The pesticide residue analysis was performed with solid-liquid extraction with low temperature partitioning technique (SLE/LTP) followed by gas chromatography analysis. The recovery percentages of extracts obtained from samples of carrot passed through SLE/LTP extraction and fortified with difenoconazole and linuron pesticides varied from 93.4% to 106.3% and from 95.1% to 116.6%, respectively. The limit of detection for difenoconazole was 0.02 and 0.12 mg kg-1 for linuron. The limit of quantification for difenoconazole was 0.05 and 0.36 mg kg-1 for linuron. The degradation time for fifty percent of the applied pesticide at the different doses ranged from 2.4 to 3.6 days for difenoconazole and from 7.5 to 10.5 days for linuron. At the end of the pre harvest interval, carrots treated with fivefold the recommended dose of both pesticides were considered unfit for consumption. Despite monitoring the degradation products of the applied pesticides by gas chromatography coupled to mass spectrometer, none degradation product was identified on the carrots. PMID- 30423513 TI - Selenite mitigates cadmium-induced oxidative stress and affects Cd uptake in rice seedlings under different water management systems. AB - Cadmium (Cd) is toxic throughout the food chain. Selenium (Se) can mitigate Cd accumulation in rice plants, although it is unclear why it has such effect. The objectives of this study were to investigate the effects of Se application on Cd induced oxidative stress and antioxidant activities, and the combined effects of Se application and water management on the formation of iron plaque on the rice surface and Fe, Cd, and Se accumulation in rice plants. Rice seedlings were grown in Cd-contaminated soil with or without the addition of Se, and in aerobic or flooded conditions. Exogenous Se reduced Cd-induced oxidative stress. In the flooded treatment, exogenous selenite significantly decreased Cd concentrations in rice tissues, whereas it noticeably enhanced Cd concentrations in rice tissues in the aerobic treatment. Furthermore, selenite addition and flooding promote the formation of iron plaque and increase Fe concentrations in rice tissues. Pearson correlation analysis shows that plant Cd was significantly negatively correlated with Fe concentrations in rice tissues, and plant Fe was significantly positively correlated with Se concentrations in rice tissues, but no significant correlation was found between Cd and Se concentrations Thus, exogenous selenite may indirectly affect Cd uptake by influencing the formation of iron plaque on rice root surface, Fe uptake and Fe levels in rice. PMID- 30423514 TI - Safety and wellbeing as spatial capacities: An analysis from two ethnographic studies in primary care and palliative care contexts. AB - Patient safety and quality of care are increasing concerns for healthcare internationally. This paper examines the spatial achievement of safety and wellbeing by healthcare staff, patients and their carers within UK primary care and Australian palliative care contexts. Two key socio-spatial modes of safety and wellbeing were found across these healthcare contexts. The technical mode was spatially managed by staff and driven by formal approaches to safety with a limited focus on wellbeing. In contrast, the relational mode was driven by attentiveness to the wellbeing and spatial engagement of staff, patients and carers that drew on informal elements of safety. Both modes extended across public, private, biomedical and administrative spaces, with technical and relational safety-wellbeing configurations often inhabiting the same spaces. Differences also existed across primary and palliative care contexts that reflected the unique pressures present within each context, and the ability of people and places to adapt to these demands. In the context of increasing workloads in healthcare internationally, this study highlights the benefits of attending as much to the relational dimensions of safety and quality of care as to the technical ones through increased focus on the safety and wellbeing of healthcare staff, patients and carers within and beyond traditional sites of care. PMID- 30423515 TI - How crickets become freeze tolerant: The transcriptomic underpinnings of acclimation in Gryllus veletis. AB - Some ectotherms can survive internal ice formation. In temperate regions, freeze tolerance is often induced by decreasing temperature and/or photoperiod during autumn. However, we have limited understanding of how seasonal changes in physiology contribute to freeze tolerance, and how these changes are regulated. During a six week autumn-like acclimation, late-instar juveniles of the spring field cricket Gryllus veletis (Orthoptera: Gryllidae) become freeze tolerant, which is correlated with accumulation of low molecular weight cryoprotectants, elevation of the temperature at which freezing begins, and metabolic rate suppression. We used RNA-Seq to assemble a de novo transcriptome of this emerging laboratory model for freeze tolerance research. We then focused on gene expression during acclimation in fat body tissue due to its role in cryoprotectant production and regulation of energetics. Acclimated G. veletis differentially expressed >3000 transcripts in fat body. This differential expression may contribute to metabolic suppression in acclimated G. veletis, but we did not detect changes in expression that would support cryoprotectant accumulation or enhanced control of ice formation, suggesting that these latter processes are regulated post-transcriptionally. Acclimated G. veletis differentially regulated transcripts that likely coordinate additional freeze tolerance mechanisms, including upregulation of enzymes that may promote membrane and cytoskeletal remodelling, cryoprotectant transporters, cytoprotective proteins, and antioxidants. Thus, while accumulation of cryoprotectants and controlling ice formation are commonly associated with insect freeze tolerance, our results support the hypothesis that many other systems contribute to surviving internal ice formation. Together, this information suggests new avenues for understanding the mechanisms underlying insect freeze tolerance. PMID- 30423516 TI - Antagonism of adenosinergic system decrease SWD occurrence via an increment in thalamic NFkB and IL-6 in absence epilepsy. AB - Epilepsy is a major pathological condition, characterized by recurrent seizures and affecting approximately 1% of the population. Many studies have shown a relationship between epilepsy and inflammation. The adenosinergic system contributes to inflammation and epilepsy by regulating the release of neurotransmitters through its various receptors. This study investigates the effect of agonist and antagonist of adenosinergic system on seizure activity and cytokine levels in the WAG/Rij strain, a genetic animal model of absence epilepsy. The WAG/Rij rats used in our study were assigned to saline, Tween 20, adenosine, and caffeine groups. Tripolar electrodes were implanted on the skull, and EEG activities recorded for 3 h. ELISA was used to determine the NFkB, TNF alpha, IL-1beta, and IL-6 levels in the cortical and thalamic brain regions, as well as the TNF-alpha, IL-1beta, and IL-6 levels in the blood samples. Administration of caffeine to rats resulted in a decreased SWD number at 30 and 60 min as determined by EEG recording after baseline (p < .05), and a significant increase in NFkB and IL-6 levels in the thalamic tissue (p < .05). Administration of adenosine to rats did not change seizures and cytokine levels. Our results show that an increase in thalamic IL-6 and NFkB levels may related with a decrement in absence epilepsy. This study clearly shows the contribution of adenosinergic system in absence seizure in WAG/Rij rats. These results also support the importance of the thalamus on occurrence of SWD in the thalamocortical loop. PMID- 30423517 TI - Definition of phosphoinositide distribution in the nanoscale. AB - New functionalities of phosphoinositides (PIs) are being revealed continuously, and the scale of the membrane area studied is becoming smaller, from the micrometer range like the entire surface of organelles to the nanometer range as in subdomains of organelles. Concurrently, function of less abundant PIs, such as PI(3,4)P2 and PI(3,5)P2, attracts increasing attention. In accordance with the progress, finer and more accurate information on PI distribution is required. The fluorescence biosensor method utilizing PI-binding domains and/or immunolabeling with anti-PI antibodies are used for this purpose in most studies but both methods are known to have caveats. In this article, we examined how PI distribution was defined in recent studies and discussed whether methodological uncertainty has any bearing on the results. PMID- 30423518 TI - Allicin induces beige-like adipocytes via KLF15 signal cascade. AB - Under specific conditions, white adipose tissue (WAT) depots are readily converted to a brown-like state, which is associated with weight loss. However, whether diet-derived factors directly induce browning of white adipocytes has yet to be established. Thus, we investigated the effects of allicin, one of the major components of garlic, on brown-like adipocyte formation in inguinal WAT (iWAT), and prevention of obesity and related complications in animal models. Allicin significantly increased mRNA and/or protein expression of brown adipocyte markers including uncoupling protein 1 (UCP1) in differentiated mouse embryonic fibroblast cell line 3T3-L1 and differentiated iWAT stromal vascular cells (SVC), suggesting that allicin induced brown-like adipocyte formation in vitro. Concomitantly, allicin markedly enhanced the protein expression of KLF-15 and its interaction with UCP-1 promoter region. Such changes were absent in cells lacking KLF-15, suggesting the critical role of KLF15 in allicin action. Allicin also induced brown-like adipogenesis in vivo along with the appearance of multilocular adipocytes, increased UCP1 expression and increased lipid oxidation. In summary, our data suggest that allicin potentially prevents obesity and associated metabolic disorders such as type 2 diabetes mellitus by enhancing the expression of brown adipocyte-specific genes, including UCP-1, through KLF15 signal cascade. PMID- 30423519 TI - Adsorption of micronutrient metal ion onto struvite to prepare slow release multielement fertilizer: Copper(II) doped-struvite. AB - In this study, struvite (MgNH4PO4.6H2O) sample was prepared by precipitation. Synthetic struvite was used as an adsorbent to remove Cu(II) from aqueous solution. Struvite was characterized by X-ray diffraction, FTIR, particle size analysis, SEM-EDX, surface area and true density. Solubility of struvite in water and acid solutions was investigated. Batch adsorption experiments were carried out by changing the initial Cu(II) concentration, contact time, struvite dosage and temperature. Cu(II) adsorption was found to be highly pH-dependent, and maximum adsorption was observed in the basic pH range. Equilibrium data were applied to Langmuir, Freundlich and D-R adsorption isotherms. Kinetic data were also analyzed for pseudo-first, pseudo-second and intraparticle diffusion models. Langmuir adsorption isotherm and pseudo-second kinetic models fit best to the data. Maximum adsorption capacity was found to be 158.73 mg g-1 at 20 degrees C, pH of 6 and adsorbent dosage of 1 g L-1 for a contact time of 240 min. Activation energy, mean adsorption energy (from D-R isotherm) and thermodynamic parameters were evaluated, and the nature of adsorption was found to be physical, endothermic and spontaneous. On the basis of characterization upon struvite before and after adsorption, it was found that the electrostatic attraction supported the ion sorption on struvite surface, and the transformation of Cu(II) ion into copper phosphate and copper hydroxide occurred on struvite surface. After its adsorption, solubility study was carried out. Release of P, N, Mg and Cu into extracts was studied. Phosphorus, nitrogen, magnesium and copper solubility in pure water was lower than about 1%. PMID- 30423520 TI - Degradation of refractory organic contaminants in membrane concentrates from landfill leachate by a combined coagulation-ozonation process. AB - Landfill leachate is a typical refractory wastewater for which research into rapid and efficient treatment methods has become very topical. In this study, a coagulation-ozonation process was developed to treat the concentrate arising from membrane treatment of landfill leachate. The effect of coagulant type and initial pH on treatment efficiencies was investigated. Results showed that many of organics were effectively removed in the coagulation process. Thereafter, ozone was applied to further treat the coagulation-resistant organic substances. Our results revealed that the degradation rate of these coagulation-resistant substances followed the trend (color number) CN > (light absorbance at 254 nm) UV254 > (chemical oxygen demand) COD, and the residual coagulation-resistant substances were oxidized rapidly in the ozone process. Ozone first destroyed the molecular structure of fulvic acid and the by-products generated, such as protein like substances. In addition, the molecular weight, organic condensation degree, and concentration of benzene ring compounds were considerably decreased. Moreover, the macro molecular organics (i.e., humic acid and fulvic acid) within the size range 1-100 kDa were effectively degraded and partially transformed into bicarbonate. Overall, the combined coagulation-ozonation process reduced COD, UV254, and CN in the landfill leachate concentrate by 88.32%, 94.37%, and 98.83%, respectively, and thus the biodegradability of the treated leachate also was significantly improved. This excellent performance proved the feasibility of the combined coagulation-ozonation process for the removal of recalcitrant organic substances contained in landfill leachate concentrate, benefiting subsequent biological treatment. PMID- 30423521 TI - Nitrogen dioxide air pollution and preterm birth in Shanghai, China. AB - BACKGROUND: Nitrogen dioxide (NO2) is a typical indicator of traffic-related air pollution, and few studies with exposure assessment of high resolution have been conducted to explore its association with preterm birth in China. OBJECTIVES: To investigate the association between NO2 exposure based on a land use regression (LUR) model and preterm birth in Shanghai, China. METHODS: A retrospective cohort study was performed among 25,493 singleton pregnancies in a major maternity hospital in Shanghai, China, from 2014 to 2015. A temporally adjusted LUR model was used to predict the prenatal exposure to NO2 based on residence address of each gravida. Logistic regression was performed to evaluate the associations of ambient NO2 exposure with preterm birth during six exposure periods, including the entire pregnancy, the first trimester, the second trimester, the third trimester, the last month, and the last week before delivery. Sensitivity analysis with a matched case-control design was conducted to test the robustness of the association between NO2 exposure and preterm birth. RESULTS: The average NO2 concentrations during the entire pregnancy was 48.23 ug/m3 among all participants. A 10 ug/m3 increase in NO2 concentrations was associated with preterm birth, with an adjusted odds ratio of 1.03 (95% confidence interval [CI]: 0.96,1.10) for exposures during the entire pregnancy, 1.00 (95%CI: 0.95,1.06) in the first trimester, 1.01 (95%CI: 0.96,1.07) in the second trimester, 1.07 (95%CI: 1.02,1.13) in the third trimester, 1.10 (95%CI: 1.04,1.15) and 1.05 (95%CI: 1.00,1.09) in the month and week before delivery, respectively. The results of the matched case-control analysis were generally consistent with those of main analyses. CONCLUSION: NO2 may increase the risk of preterm birth, especially for exposures during the third trimester, the month and the week before delivery in Shanghai, China. PMID- 30423522 TI - Effect of artificial shade on saliva cortisol concentrations of heat-stressed dairy calves. AB - Responses to heat stress have not been evaluated in dairy cattle by noninvasive techniques such as analysis of saliva cortisol concentrations. The aim of the present study was the assessment of saliva cortisol levels in Holstein bull calves with (n = 8) or without supplemental shade (n = 8) in response to acute heat stress. Measurements were carried out during a 5-d period [temperature, average/max ( degrees C); day 1 (control, all calves shaded): 22.9/29.4, day 2 (heat stress day): 28.3/38.8, day 3: 26.2/33.5, day 4: 23.7/28.7, and day 5: 21.2/24.7]. The level of thermal stress was characterized with a temperature humidity index (THI). Saliva cortisol levels did not differ between groups during the control day. On the heat stress day, saliva cortisol levels increased from 8:00 to 12:00 by 51% and 342% in shaded and nonshaded calves, respectively, and nonshaded calves showed higher cortisol concentrations at 12:00, 16:00, and 24:00. Saliva cortisol levels peaked at 12:00 on day 3 in both groups. On days 4 and 5, saliva cortisol did not show significant daytime elevations in either group; however, group differences remained significant until 20:00 on day 4. Based on our results, measurement of saliva cortisol concentrations is a promising approach to detect acute heat stress in dairy calves, which could be reduced by artificial shading. PMID- 30423523 TI - Keeping pace with the increasing demand for high quality drug candidates in pharmaceutical research: Development of a new two-step preparative tandem high performance chromatographic system for the purification of antibodies. AB - In the area of biological drug development, high throughput (HT) technologies are key to identifying the most promising therapeutic candidate in a time-efficient and market-competitive manner. While efficient cloning and expression methods exist, HT downstream processing mainly relies on liquid handling workstations applying miniaturized chromatography columns or resin-based 96-well plates to shorten process development time. However, there is still a lack of generic, preparative chromatographic methods devoid of aggregates and endotoxins with sufficient throughput. The only truly generic antibody purification strategy including an efficient dimer removal consists of Protein A capture followed by size exclusion chromatography (SEC) as a polishing step. Other polishing methods, including IEX, HIC, and CHT, require an antibody-specific fine tuning. However, standard preparative SEC setups tend to be rather time-consuming, and so limit throughput. In this work, we devised a unique chromatography setup enabling an unattended two-step purification of IgGs on the milligram scale directly from 35 mL clarified cell supernatants, processing up to 48 samples in 44.0 h. By introducing a silica-based SEC column, preparative SEC could be accelerated. By further developing an HT two-step preparative Protein A/alternating column regeneration SEC system using Agilent 1260 Infinity LC components, mAbs can be purified generically by two chromatographic steps in 55 min. In this way, by using a 2-position/10-port valve and two quaternary pumps, two SEC columns can be run in parallel, excluding the cleaning and equilibrating phase from the actual cycle time. By further applying a third pump, the Protein A step can be run independently, resulting in a time-optimized process nesting. By introducing a CETAC ASX-520 autosampler, 48 samples can be run automatically without any user intervention over two working days. The developed system is highly reproducible for all tested human IgG1 antibodies, easily generating milligram scale material sufficient for full characterization of the antibodies and for their use in in vitro and in vivo activity assessments. PMID- 30423525 TI - Factors associated with pain in the pelvic girdle in pregnant adolescents: A case control study. AB - BACKGROUND: Due to biological immaturity and unfavorable psychosocial conditions, it is conjectured that teenage pregnancy may be associated with disorders such as pelvic girdle pain. The evidence for risk factors for pelvic girdle pain in pregnant adolescents remains unclear. OBJECTIVES: To evaluate the factors associated with pelvic girdle pain related to pregnancy in adolescents. DESIGN: Case-control study. METHOD: Seventy three pregnant women with presence of pelvic girdle pain (case group) and 331 pregnant women without pelvic girdle pain (control group) aged between 10 and 19 years, with gestational age between 28 and 40 weeks were included. RESULTS/FINDINGS: A logistic regression model was used to identify factors associated with the occurrence of pelvic girdle pain. The following aspects were considered for the model: sociodemographic, anthropometric, gynecological and obstetrical, related to lifestyle, musculoskeletal and psychosocial factors. The results showed that suspected common mental disorder (OR: 2.27; 95% CI: 1.23 to 4.18), low back pain during menstruation (OR: 2.10; 95% CI: 1.16 to 3.80) and strenuous work (OR: 1.95; 95% CI: 1.13 to 3.35) were associated with pelvic girdle pain among pregnant adolescents. CONCLUSIONS: Attention must be given to pregnant adolescents with suspected common mental disorder, low back pain during menstruation and strenuous work in order to ensure referral to the appropriate healthcare professional for early prevention of pelvic girdle pain. PMID- 30423524 TI - Pharmacokinetics, tissue distribution and excretion of ACT001 in Sprague-Dawley rats and metabolism of ACT001. AB - This study investigated pharmacokinetics, tissue distribution and excretion of ACT001 in Sprague-Dawley rats. Stability study and metabolism study of ACT001 are conducted. The absolute bioavailability of ACT001 is 50.82%. ACT001 has no accumulation effect and displayed wide tissue distribution. ACT001 can be rapidly distributed to tissues after oral administration and can diffuse through the blood-brain barrier. The total cumulative excretion of ACT001 in feces, urine and bile were found to be 0.05, 3.42 and 0.012%, respectively. UPLC/ESI-QTOF-MS coupled with MetaboLynx XS software was utilized to detect the metabolites of ACT001 in vitro. Five metabolites (M1, M2, M3, M4 and M5) were detected. M2 wasn't discovered in human liver microsome samples and bile samples. M1 and M2 weren't discovered in rat plasma and human plasma. M3, M4 and M5 weren't discovered in bile samples. M5 is an active metabolite named micheliolide (MCL). There is no significant difference in half-life, type of identified metabolites and the amount of each metabolites between using rat plasma and human plasma. Owing to the species differences of hepatomicrosome enzymes, significant differences were shown in half-life, type of identified metabolites and the amount of each metabolites between using rat liver microsome and human liver microsome. PMID- 30423526 TI - Perceptions of physiotherapists towards the management of non-specific chronic low back pain from a biopsychosocial perspective: A qualitative study. AB - BACKGROUND: Physiotherapists have been urged to embrace a patient-oriented biopsychosocial (BPS) framework for the management of non-specific chronic low back pain (NSCLBP). However, recent evidence suggests that providing broader BPS interventions demonstrates small differences in pain or disability compared to usual care. Little is known about how to integrate a BPS model into physiotherapy practice and the challenges it presents. OBJECTIVE: To explore the perceptions of physiotherapists' in primary care in England adopting a BPS approach to managing NSCLBP patients. METHOD: Qualitative semi-structured interviews were conducted with ten physiotherapists working in primary care. A purposive sampling method was employed to seek the broadest perspectives. Thematic analysis was used to analyse the interview transcripts and capture the emergent themes. RESULTS: Three main themes emerged: (1) physiotherapists recognised the multi-dimensional nature of NSCLBP and the need to manage the condition from a BPS perspective, (2) addressing psychological factors was viewed as challenging due to a lack of training and guidance, (3) engaging patients to self-manage their NSCLBP was seen as a key objective. CONCLUSION: Although employing a BPS approach is recognised by physiotherapists in the management of NSCLBP, this study highlights the problems of implementing evidence based guidelines recommending that psychological factors be addressed but providing limited support for this. It also supports the need to allocate more time to explore these domains in distressed individuals. Engaging patients to self-manage was seen as a key objective, which was not a straightforward process, requiring careful negotiation. PMID- 30423527 TI - Clarifying distinct models of modern human origins in Africa. AB - Accumulating genomic, fossil and archaeological data from Africa have led to a renewed interest in models of modern human origins. However, such discussions are often discipline-specific, with limited integration of evidence across the different fields. Further, geneticists typically require explicit specification of parameters to test competing demographic models, but these have been poorly outlined for some scenarios. Here, we describe four possible models for the origins of Homo sapiens in Africa based on published literature from paleoanthropology and human genetics. We briefly outline expectations for data patterns under each model, with a special focus on genetic data. Additionally, we present schematics for each model, doing our best to qualitatively describe demographic histories for which genetic parameters can be specifically attached. Finally, it is our hope that this perspective provides context for discussions of human origins in other manuscripts presented in this special issue. PMID- 30423528 TI - Covalent interactions between lignin and hemicelluloses in plant secondary cell walls. AB - The plant secondary cell wall is a complex structure composed of polysaccharides and lignin, and is a key evolutionary innovation of vascular land plants. Although cell wall composition is well understood, the cross-linking of the different polymers is only now yielding to investigation. Cross-linking between hemicelluloses and lignin occurs via two different mechanisms: incorporation into lignin by radical coupling of ferulate substitutions on xylan in commelinid monocots, and incorporation of hemicellulosic glycosyl residues by re aromatisation of lignification intermediates. Recent genetic evidence indicates that hemicellulose:lignin cross-linking has a substantial impact on plant cell wall recalcitrance. Engineering plant biomass with modified frequencies of cross links will have significant impacts on biomass utilisation. PMID- 30423529 TI - An analytical method to create patient-specific deformed bone models using X-ray images and a healthy bone model. AB - Generation of patient-specific bone models from X-ray images is useful for various medical applications such as total hip replacement, implant manufacturing, knee kinematic studies and deformity correction. These models may provide valuable information required for a more reliable operation. In this work, we propose a new algorithm for generating patient-specific 3D models of femur and tibia with deformity, using only a generic healthy bone model and some simple measurements taken on the X-ray images of the diseased bone. Using the X ray measurements, an interpolation function (a polynomial or a cubic spline) is fit to the mid-diaphyseal curve of the actual bone and the generic bone model is deformed in the guidance of this function with free form deformation method. The created models are intended to be used mainly for the visualization of fixation procedure in software-supported external fixation systems. An error measure is defined to quantify the error in this matching procedure. The method is found to be capable of producing deformed tibia models that satisfactorily reflect the actual bones, as confirmed by two orthopaedic surgeons who use software-supported external fixation systems regularly. PMID- 30423530 TI - Peripapillary retinal nerve fiber layer thickness measured by optical coherence tomography in different clinical subtypes of multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory demyelinating autoimmune disease of the central nervous system (CNS) with axonal degeneration as major determinant of neurological disability. Assessment of unmyelinated retinal nerve fibers using optical coherence tomography (OCT) may be useful for diagnosing the onset and rate of progression of neurodegeneration. OBJECTIVE: To assess the incidence and severity of damage of the peripapillary retinal nerve fiber layer (RNFL) in two different MS subtypes: non-progressive [Prog(-)MS] and progressive [Prog(+)MS]. METHODS: 48 patients (96 eyes) with MS were included: 13 males, 35 females; aged 22-62 years (mean 38.8; SD +/- 10.02) in two subgroups: 26 Prog(-)MS and 22 Prog(+)MS. 3 subtypes of Prog(+)MS were identified by neurologist, according to Lublin criteria: 3 patients had PPMS (14%), 7 had SPMS(32%), 12 had PRMS(54%). RRMS subtype was considered a non-progressive phenotype, designated as Prog(-)MS. All 22 patients with progressive MS phenotypes were included in one group, designated as Prog(+)MS. Progressive disease can be defined over 1 year. The expanded EDSS score was determined by the treating MS specialist and confirmed by the study investigators through the records review. Definition included a 3-strata progression magnitude in the absence of a relapse, confirmed after 3 months within the leading Functional System and required an Expanded Disability Status Scale step>=4 and pyramidal score>=2. 11 Prog(-)MS (16 eyes) and 10 Prog(+)MS (13 eyes) patients had a history of optic neuritis (ON). EDSS score was 1.5-6.5 (mean 3.83 +/- 1.62) in the Prog(+)MS group and 1.0-3.5 (mean 1.40 +/- 0.57) in the Prog(-)MS. CONTROL GROUP: 31 healthy volunteers (3 males, 28 females), aged 20-62 years (mean 37.4 +/- 10.88). Peripapillary RNFL thickness was measured around the optic nerve head (ONH) using spectral-domain OCT (Topcon OCT 1000 MarkII, FastMap v. 3.40, Topcon, Japan). Scans were obtained according to OSCAR-IB consensus criteria. The generalized estimating equation model (GEE) was used in the statistical analysis to assess differences in RNFL thickness between Prog(-)MS and Prog(+)MS patients, taking into consideration history of ON, EDSS score, immunomodulatory therapy, MS progression, MS duration, age and gender. The protocol was approved by the Ethical Committee of the Medical Centre of Postgraduate Education, Warsaw, Poland and informed consent was obtained from all subjects. RESULTS: There was a significant difference between Prog(-)MS and Prog(+)MS groups for mean, nasal and superior quadrant of RNFL thickness. For individuals with a history of ON, significant differences were found between the two MS phenotypes regardless of RNFL thickness measurements. CONCLUSIONS: A significant correlation was established between RNFL thickness and progression of neurodegeneration in MS patients with no regard to history of ON. RNFL thickness may be considered a MS biomarker and potential diagnostic tool for assessment of disease progression. PMID- 30423531 TI - Uncovering the association between fatigue and fatigability in multiple sclerosis using cognitive control. AB - BACKGROUND: Fatigue and cognitive dysfunction are two common symptoms experienced by patients with multiple sclerosis (MS). The relationship between subjective and objective fatigue (fatigability) in MS is poorly understood. Cognitive control tasks might be more conducive to fatigability and more likely to show associations between subjective and objective cognitive fatigue in MS. OBJECTIVE: To study the association between objective fatigability, as induced by a cognitive control task called the Blocked Cyclic Naming Task (BCNT), subjective fatigue and baseline cognitive functioning in patients with MS. METHODS: Twenty one patients with MS completed baseline questions about their disease, the Montreal Cognitive Assessment (MoCA) battery and self-reported questionnaires on trait fatigue, sleep and depression. Disability was captured using the expanded disability status scale (EDSS). Participants then performed the BCNT and were asked about their level of state momentary fatigue before and after the BCNT. The BCNT consists of several blocks of either related or unrelated pictures that participants name as quickly as possible. The pictures cycled 4 times in each block and the difference in the response times (RTs) between related and unrelated blocks was captured. Data were analyzed using repeated measures analysis of variance and Pearson correlations. RESULTS: MS participants' performance declined for the related, but not unrelated blocks. The difference in RTs between related and unrelated conditions increased with repetition across cycles (p < 0.001). Participants also showed objective fatigability with less repetition priming (p = 0.02) in the 4th quarter and with greater differences between related and unrelated conditions in the later part of the task. Objective fatigability was strongly associated with participants' assessment of their level of momentary state fatigue (r = 0.612, p = 0.007). CONCLUSION: Using the appropriate tools, this study showed an association between subjective and objective cognitive fatigue in people with MS. The BCNT and cognitive control are useful tools in assessing patients with MS and should be explored in future, larger studies in this population. PMID- 30423532 TI - Community variation in adolescent cannabis use in Australia and the Netherlands. AB - BACKGROUND: While controversial, cannabis use is common, and often begins in adolescence. In Australia and the Netherlands, cannabis use is understood and legislated within a harm-minimisation framework. In Australia it is illegal to purchase or consume cannabis. Cannabis use in the Netherlands is illegal, except in licensed coffee shops where the sale and consumption of small amounts (5 g) are permitted. METHODS: Secondary school aged children in Victoria, Australia and the Netherlands were surveyed using the same culturally adapted questionnaire, designed to measure community rates of substance use and risk factors. Youth cannabis use and predictors of use were compared between the two countries. RESULTS: Similar levels of cannabis use in the last month were reported in Australia and the Netherlands (4.5%), with slightly lower use amongst girls, compared to boys. Common predictors of use were found in both the Australian and Netherlands sample. CONCLUSIONS: The findings suggest that interventions that effectively target similar risk factors to reduce or prevent cannabis use may have applications cross-nationally. PMID- 30423534 TI - Nitrification inhibitor DMPSA mitigated N2O emission and promoted NO sink in rainfed wheat. AB - Fertilized cropping systems are important sources of nitrous oxide (N2O) and nitric oxide (NO) to the atmosphere, and biotic and abiotic processes control the production and consumption of these gases in the soil. In fact, the inhibition of nitrification after application of urea or an ammonium-based fertilizer to agricultural soils has resulted in an efficient strategy to mitigate both N2O and NO in aerated agricultural soils. Therefore, the NO and N2O mitigation capacity of a novel nitrification inhibitor (NI), 2-(3,4-dimethyl-1H-pyrazol-1-yl) succinic acid isomeric mixture (DMPSA), has been studied in a winter wheat crop. A high temporal resolution of fluxes of NO and NO2, obtained by using automatic chambers for urea (U) and urea with DMPSA, allowed a better understanding of the temporal net emissions of these gases under field conditions. Seventy-five days after fertilization, the effective reduction of nitrification by DMPSA significantly decreased the production of NO with respect to the treatment without it, giving net consumption of NO in the soil (-61.72 g-N ha-1) for U + DMPSA in comparison to net production (227.44 g-N ha-1) for U. The explanation of NO deposition after NI application, due to biotic and abiotic processes in the soil-plant system, supposes a challenge that needs to be studied in the future. In the case of N2O, the addition of DMPSA significantly mitigated the emissions of this gas by 71%, though the total N2O emissions in both fertilized treatments were significantly greater than those of the control (43.69 g-N ha-1). Regarding the fertilized treatments, no significant effect of DMPSA in comparison to urea alone was observed on grain yield nor bread-making wheat quality. To sum up, we got a significant reduction of N2O and NO with the addition of DMPSA, without a loss in yield and quality parameters in wheat. PMID- 30423535 TI - Insight into interaction between biochar and soil minerals in changing biochar properties and adsorption capacities for sulfamethoxazole. AB - Biochars produced from wheat straw at 400 degrees C (BC400) and 700 degrees C (BC700) were treated with three typical soil minerals to examine the effects of soil minerals on biochar properties and adsorption capacity for sulfamethoxazole (SMX). Mineral treatment enlarged the surface area and pore size of biochar, and the electron donating capacity (EDC) of the mineral-treated biochars also increased due to the increased phenolic group in BC400 and the enhanced conjugated pi-electron system in BC700, respectively, which in turn affected the adsorption capacity of biochars for SMX. The adsorption of SMX on BC700 was increased after mineral treatment due to the facilitating effect of pi-pi electron donor-acceptor interaction as indicated by the positive correlation of surface adsorption amount (QA) of SMX with EDC of biochars (R2 = 0.92-0.96). In contrast, mineral treatment decreased SMX adsorption on BC400, which could be attributed to the potential association of organic matter with minerals via coprecipitation and adsorption, in addition to the weak adsorption capacities of soil minerals for SMX. These results can provide a new insight for better understanding the interaction between biochar and soil minerals and its effect on adsorption capacity of biochar for organic pollutants. PMID- 30423533 TI - Erythrocytic bioactivation of nitrite and its potentiation by far-red light. AB - BACKGROUND: Nitrite is reduced by heme-proteins and molybdenum-containing enzymes to form the important signaling molecule nitric oxide (NO), mediating NO signaling. Substantial evidence suggests that deoxygenated hemoglobin within red blood cells (RBCs) is the main erythrocytic protein responsible for mediating nitrite-dependent NO signaling. In other work, infrared and far red light have been shown to have therapeutic potential that some attribute to production of NO. Here we explore whether a combination of nitrite and far red light treatment has an additive effect in NO-dependent processes, and whether this effect is mediated by RBCs. METHODS AND RESULTS: Using photoacoustic imaging in a rat model as a function of varying inspired oxygen, we found that far red light (660 nm, five min. exposure) and nitrite feeding (three weeks in drinking water at 100 mg/L) each separately increased tissue oxygenation and vessel diameter, and the combined treatment was additive. We also employed inhibition of human platelet activation measured by flow cytometry to assess RBC-dependent nitrite bioactivation and found that far red light dramatically potentiates platelet inhibition by nitrite. Blocking RBC-surface thiols abrogated these effects of nitrite and far-red light. RBC-dependent production of NO was also shown to be enhanced by far red light using a chemiluminescence-based nitric oxide analyzer. In addition, RBC-dependent bioactivation of nitrite led to prolonged lag times for clotting in platelet poor plasma that was enhanced by exposure to far red light. CONCLUSIONS: Our results suggest that nitrite leads to the formation of a photolabile RBC surface thiol-bound species such as an S-nitrosothiol or heme nitrosyl (NO-bound heme) for which far red light enhances NO signaling. These findings expand our understanding of RBC-mediated NO production from nitrite. This pathway of NO production may have therapeutic potential in several applications including thrombosis, and, thus, warrants further study. PMID- 30423536 TI - Contamination by perfluoroalkyl substances and microbial community structure in Pearl River Delta sediments. AB - Environmental microbiota play essential roles in the maintenance of many biogeochemical processes, including nutrient cycling and pollutant degradation. They are also highly susceptible to changes in environmental stressors, with environmental pollutants being key disruptors of microbial dynamics. In the present study, a scientific cruise was launched on July 2017 around Pearl River Delta, a suitable studying site for perfluoroalkyl substances (PFASs) in the wake of the severe PFAS pollution. Surface sediment samples were collected from 18 representative stations to assess PFAS accumulation and profile microbial community. PFAS concentrations ranged from 24.2 to 181.4 pg/g dry weight in sediment, and perfluorooctanesulfonic acid (PFOS) was the dominant homologue. The concentrations of PFAS homologues in the current study were much lower than those reported in previous studies, implying effective management and control of pollution from PFAS-related industries. 16S rRNA gene amplicon sequencing revealed that Proteobacteria was the dominant phylum, while nitrogen-metabolizing Nitrosopumilus and sulfate-reducing Desulfococcus genera were the most abundant. Variations in microbial communities among sampling stations were mainly due to the differences in abundances of Escherichia, Nitrosopumilus, and Desulfococcus. The outbreak of Escherichia bacteria at specific coastal stations potentially indicated the discharge of fecal matter into the marine environment. Dissolved oxygen (DO) in bottom seawater significantly influenced the structure of microbial communities in the sediment, while current study failed to observe significant effects from PFAS pollutants. Positive correlations were found between DO and sulfate-reducing bacteria in Desulfococcus and GOUTA19 genera. Overall, this study explored relationships between environmental variables (e.g., PFAS pollutants) and sediment bacteria. Biogeochemical parameters significantly influenced the structure and composition of microbial communities in sediment. PMID- 30423537 TI - Characterization of the chemical components and bioreactivity of fine particulate matter produced during crop-residue burning in China. AB - Five types of crop residue (rice, wheat, corn, sorghum, and sugarcane) collected from different provinces in China were used to characterize the chemical components and bioreactivity properties of fine particulate matter (PM2.5) emissions during open-burning scenarios. Organic carbon (OC) and elemental carbon (EC) were the most abundant components, contributing 41.7%-54.9% of PM2.5 emissions. The OC/EC ratio ranged from 8.8 to 31.2, indicating that organic matter was the dominant component of emissions. Potassium and chloride were the most abundant components in the portion of PM2.5 composed of water-soluble ions. The coefficient of divergence ranged from 0.27 to 0.51 among various emissions profiles. All samples exposed to a high PM2.5 concentration (150 MUg/mL) exhibited a significant reduction in cell viability (A549 lung alveolar epithelial cells) and increase in lactic dehydrogenase (LDH) and interleukin 6 levels compared with those exposed to 20 or 0 MUg/mL. Higher bioreactivity (determined according to LDH and interleukin 6 level) was observed for the rice, wheat, and corn samples than for the sorghum straw samples. Pearson's correlation analysis suggested that OC, heavy metals (chromium, manganese, iron, nickel, copper, zinc, tin, and barium), and water-soluble ions (fluoride, calcium, and sulfate) are the components potentially associated with LDH production. PMID- 30423538 TI - Contribution of plant species to the high N retention capacity of a subalpine meadow undergoing elevated N deposition and warming. AB - While numerous studies have examined the effect of N deposition on ecosystem N retention, few have analyzed the involvement of plant species and climate warming in this process. We experimentally investigated the effects of increasing N deposition (Nexo) and climate warming on the fate of Nexo in a subalpine meadow and established the involvement of plant species. Using 15N tracer, we tracked Nexo sprayed on the vegetation in belowground and aboveground plant biomasses (AGB) and in bulk soil over three growing seasons. We assessed the Nexo absorption capacity of plant species and the contribution of Nexo to their AGB N pool. The meadow retained a large proportion of Nexo (~65%, mostly in AGB) for depositions up to four times the background N rate. Nexo present in the meadow compartments in year 2 was still present in year 3, suggesting that the ecosystem was unsaturated after three years of high N input. Nexo retention resulted more from an increase in N concentration in plant tissues than from the increase in AGB. The species-specific Nexo absorption capacity was inversely related to their AGB N concentration. Nexo accounted for up to 40% of total AGB N depending on the species and the N treatments. The contribution of species to ecosystem Nexo retention more contingent on their AGB than on their relative cover in the community, ranked as follows: C. vulgaris (14.0%) > N. stricta (7.0%) > other Poaceae = C. caryophyllea (2.5%) > other Eudicotyledons (1.5%) > non-vascular species = P. erecta > Fabaceae (0.8-0.2%). Climate warming increased AGB and decreased tissue N concentration. No warming-Nexo interaction was observed. Thus, Pyrenean subalpine meadows that have not undergone a decline in plant species richness in recent decades paradoxically display a high potential to sequester atmospheric N deposition. PMID- 30423539 TI - Fish on steroids: Temperature-dependent effects of 17beta-trenbolone on predator escape, boldness, and exploratory behaviors. AB - Hormonal growth promoters (HGPs), widely used in beef cattle production globally, make their way into the environment as agricultural effluent-with potential impacts on aquatic ecosystems. One HPG of particular concern is 17beta trenbolone, which is persistent in freshwater habitats and can affect the development, morphology and reproductive behaviors of aquatic organisms. Despite this, few studies have investigated impacts of 17beta-trenbolone on non reproductive behaviors linked to growth and survival, like boldness and predator avoidance. None consider the interaction between 17beta-trenbolone and other environmental stressors, such as temperature, although environmental challenges confronting animals in the wild seldom, if ever, occur in isolation. Accordingly, this study aimed to test the interactive effects of trenbolone and temperature on organismal behavior. To do this, eastern mosquitofish (Gambusia holbrooki) were subjected to an environmentally-relevant concentration of 17beta-trenbolone (average measured concentration 3.0 +/- 0.2 ng/L) or freshwater (i.e. control) for 21 days under one of two temperatures (20 and 30 degrees C), after which the predator escape, boldness and exploration behavior of fish were tested. Predator escape behavior was assayed by subjecting fish to a simulated predator strike, while boldness and exploration were assessed in a separate maze experiment. We found that trenbolone exposure increased boldness behavior. Interestingly, some behavioral effects of trenbolone depended on temperature, sex, or both. Specifically, significant effects of trenbolone on male predator escape behavior were only noted at 30 degrees C, with males becoming less reactive to the simulated threat. Further, in the maze experiment, trenbolone-exposed fish explored the maze faster than control fish, but only at 20 degrees C. We conclude that field detected concentrations of 17beta-trenbolone can impact ecologically important behaviors of fish, and such effects can be temperature dependent. Such findings underscore the importance of considering the potentially interactive effects of other environmental stressors when investigating behavioral effects of environmental contaminants. PMID- 30423540 TI - Population-based incidence of lymphoid neoplasms: Twenty years of epidemiological data in the Girona province, Spain. AB - BACKGROUND: The aim of this study was to describe incidence patterns of lymphoid neoplasms in the Girona province (Spain) (1996-2015), and to predict the number of cases in Spain during 2020. METHODS: Data were extracted from the Girona cancer registry. Incident cases were classified using the ICD-O-3, third revision, and grouped according to the WHO 2008 classification scheme. Age adjusted incidence rates to the European standard population (ASRE) were estimated and incidence trends were modeled using Joinpoint. RESULTS: 4367 lymphoid neoplasms were diagnosed in the Girona province. The ASRE for overall lymphoma was 37.1 (95% CI: 36.0; 38.2), with a marked male predominance in almost all subtypes. During 1996-2015, incidence trends remained stable for broader lymphoma categories. According to our predictions, 17,950 new cases of LNs will be diagnosed in Spain in 2020. CONCLUSIONS: This 'real-world' data will provide valuable information to better inform etiological hypotheses and plan future health-care services. PMID- 30423541 TI - Effect of istradefylline on mood disorders in Parkinson's disease. AB - Depression is the most common psychiatric complication in patients with Parkinson's disease (PD). Istradefylline, a new anti-parkinsonian agent with completely different mechanism, improves depression-like symptoms in an experimental disease model; however, there is no report of its effects in PD patients. In this study, the effectiveness of istradefylline for treatment of mood disorders in patients with PD was examined in an open-label trial. Thirty PD patients were enrolled. All patients had scores of higher than cut-off level in at least one of the following batteries: Snaith-Hamilton Pleasure Scale Japanese version (SHAPS-J), Apathy scale, or Beck Depression Inventory-2nd edition (BDI). Following study enrollment, all patients received 20 mg of istradefylline, and the dose was increased to 40 mg after 4 weeks. Results from these 3 batteries and the Unified Parkinson's Disease Rating Scale (UPDRS) score were assessed every 2 4 weeks until 12 weeks and the changes in these scores were analyzed. Following administration of istradefylline, the scores of SHAPS-J, Apathy scale, and BDI were significantly improved over time. Significant improvement was also found in the UPDRS score; however, no significant correlation was observed between the score change in these 3 batteries and UPDRS motor function. This is the first study to show the effectiveness of istradefylline for treatment of mood disorders in PD independent of improvement of parkinsonian motor symptoms. In the future, this should be confirmed in a double-blind placebo-controlled trial. PMID- 30423542 TI - Concurrent Guillain-Barre syndrome, transverse myelitis and encephalitis post Zika: A case report and review of the pathogenic role of multiple arboviral immunity. PMID- 30423543 TI - Endometriosis of the appendix presenting as acute appendicitis with unusual appearance. AB - INTRODUCTION: Endometriosis of the appendix is an uncommon mimicker of acute appendicitis which makes for a diagnostic dilemma. PRESENTATION OF CASE: We present a rare case of a menstruating woman presenting with classic symptoms of appendicitis, without the characteristic inflammatory changes seen on laparoscopy consistent with appendicitis. Instead, the appendix appeared unusually contracted on itself. Pathologic review of the appendix revealed microscopic findings of endometriosis. DISCUSSION: We theorize the growth and shedding of the endometrial tissue during menstruation caused compression of the neural plexi in the wall of the appendix leading to the presentation mimicking acute appendicitis. CONCLUSION: Given the potential for endometrial appendicitis, we propose appendectomy in reproductive age female patients with right lower quadrant pain, regardless of appendix appearance on laparoscopy. PMID- 30423544 TI - Municipal solid waste recycling by burning it as part of composite fuel with energy generation. AB - In this work, it has been shown that the involvement of composite fuels in thermal power engineering will enable to recycle both industrial and municipal combustible wastes while saving fossil fuels. The ignition and combustion stability of composite fuel droplets up to their complete burnout was experimentally substantiated under the conditions typical of boiler furnaces, using the example of several fuel compositions with wood, food waste, plastic, and cardboard, each added separately. The values of the guaranteed delay times for the ignition of droplets with a size of about 1 mm were established for the considered fuel compositions in a wide range of the ambient temperature variation (600-1000 degrees C). The minimum values of ignition delay times were about 3 s, the maximum values were about 25 s. It was established experimentally that the concentration of nitrogen and sulfur oxides in flue gases was lower for the fuel compositions containing municipal solid waste (MSW) in comparison with those without it. The maximum difference between NOx and SOx concentrations for such fuel compositions was about 60% and 35% (in absolute units about 110 ppm and 45 ppm). As a result of the theoretical analysis, it was found that partial replacement of coal (50% of energy generation) by composite fuel in the amount equivalent in terms of energy generation will save about 1 billion tons/year of high-quality solid fossil fuel in the course of 20 years (the regulated period of safe operation of a boiler in thermal power engineering). PMID- 30423545 TI - Negative effect of flocculant (cationic acrylamide) on detectability of the nematode eggs in sewage sludge. AB - The use of sewage sludge in agriculture brings the risk of microbiological and parasitological contamination of soil, ground and surface water, as well as cultivated plants. Therefore prior the application to the soil, sewage sludge must be examined, among others, for the presence of live eggs of intestinal parasites. However, the efficiency of commonly used for this purpose parasitological methods is not satisfactory. This is probably due to the presence of flocculants in the sediments used in the dehydration process. The objective of the study was analysis of the effect of flocculant (cationic acrylamide) on the possibilities of isolation of parasite eggs from dehydrated sewage sludge. For this purpose 10 samples of sewage sludge were prepared: 5 containing flocculant and 5 without flocculant. Samples were tested by flotation method according to Quinn. From sewage sludge free of flocculant, 67.8 eggs were isolated, on average, whereas from sludge containing flocculant - only 2.8 eggs. The experiments confirmed that the isolation of eggs from sewage sludge containing flocculant (cationic acrylamide) is much more difficult than from sludge free from this substance and therefore the simple parasitological methods should not be used to examine the dehydrated sewage sludge. PMID- 30423546 TI - Optimal design of selective catalyst reduction denitrification system using numerical simulation. AB - The performance of selective catalyst reduction systems highly depends on the degree of mixing between NH3 and NOx and the flow uniformity of velocity and concentration, which are sensitive to several parameters such as the installment of gate leafs, a hybrid grid, a straightener, and the ammonia injection method. In this work, computational fluid dynamics was applied to investigate these parameters in heat recovery steam generators. Performance of gate leafs and a new type of hybrid grid was considered. Analyses showed that gate leafs significantly improved the uniformity of velocity distribution and that the new type of hybrid grid improved the uniformity of concentration distribution. The velocity relative standard deviation decreased from 19.6% to 5.4%, and the concentration relative standard deviation decreased from 70% to 12.7%. Experiments also qualitatively confirmed the reliability of simulation results. Moreover, the hybrid grid was optimized with different structures. Results indicated that a 30 degrees crossed angle could obtain a better mixing between NH3 and NOx with a slight decrease in pressure. In addition, an optimal injection method of the ammonia injection grid was designed, and it was helpful in conducting the field operation. The relationship between the thickness of the straightener and the incident angle at the entrance of catalyst layer was discussed. PMID- 30423547 TI - Effectiveness of a mitigation measure for the lesser kestrel (Falco naumanni) in wind farms in Spain. AB - Central-eastern Spain is characterised as being a flat and relatively open landscape, greatly used for agricultural purposes and with a high density of wind installations. This landscape also hosts a large population of the lesser kestrel (Falco naumanni), one of the species most threatened by collisions with wind turbines. During a ten-year period, we analysed bird mortality by recording deaths on three wind farms (WF), Cerro del Palo, Cerro Calderon and La Muela I, located in the province of Cuenca (Spain) and containing a total of 99 turbines. The aim of the study was to determine the variables associated with mortalities caused by these types of devices. Subsequently, the information obtained allowed a mitigation measure to be implemented for avoiding and minimising collisions. The procedure involved superficially tilling the soil around the base of turbines with a high collision rate. This measure was monitored for two years before and after implementation in order to compare its effectiveness, and involved making the areas around the turbines less attractive to kestrels by tilling and reducing the amount of vegetation and consequently the abundance of potential prey, mainly Orthoptera. If effective, the lack of prey would decrease the number of dead kestrels, as the birds of prey would need to search for food in other less dangerous areas (approximately 80 m away from the turbines). After monitoring the mitigation measure it was found that the number of collisions decreased by 75 100%. In fact, no collisions were registered during the two year period for all of the wind turbines with tilled surroundings. Based on these results it can be safely stated that this mitigation measure is an easy and inexpensive procedure that significantly and effectively reduces the number of kestrels that collide into wind turbines. PMID- 30423548 TI - Christian Orthodox fasting in practice: A comparative evaluation between Greek Orthodox general population fasters and Athonian monks. AB - OBJECTIVES: Christian Orthodox fasting (COF), a periodical vegetarian subset of the Mediterranean diet, has been proven to exert beneficial effects on human health. Athonian fasting is a pescetarian COF variation, where red meat is strictly restricted throughout the year. Previous studies have examined the COF nutritional synthesis and health effects in general population fasters (GF) and Athonian monks (AM), separately. The aim of this study is to comparatively evaluate the characteristics and effects of this nutritional advocacy between the two populations. METHODS: The study included 43 male GFs (20-45 y of age) and 57 age-matched male AMs following COF. Dietary intake data were collected in both groups during a restrictive (RD) and a nonrestrictive (NRD) day. Nutritional, cardiometabolic, and anthropometric parameters were compared between the two cohorts. RESULTS: AM presented lower daily total caloric intake for both RD (1362.42 +/- 84.52 versus 1575.47 +/- 285.96 kcal, P < 0.001) and NRD (1571.55 +/ 81.07 versus 2137.80 +/- 470.84 kcal, P < 0.001) than GF.They also demonstrated lower body mass index (23.77 +/- 3.91 versus 28.92 +/- 4.50 kg/m2, P <0.001), body fat mass (14.57 +/- 8.98 versus 24.61 +/- 11.18 kg, P = 0.001), and homeostatic model assessment for insulin resistance values (0.98 +/- 0.72 versus 2.67 +/- 2.19 mmol/L, P < .001) than GF. Secondary hyperparathyroidism (parathyroid hormone concentrations: 116.08 +/- 49.74 pg/mL), as a result of profound hypovitaminosis D [25(OH)D: 9.27 +/- 5.81 ng/mL], was evident in the AM group. CONCLUSIONS: The results of the present study highlight the unique characteristics of Athonian fasting and its value as a health-promoting diet. The effects of limitation of specific vitamins and minerals during fasting warrants further investigation. PMID- 30423549 TI - Bortezomib Comes to the Rescue: Comment on the Article by Nachmias et al. Entitled "A Bortezomib-Based Protocol Induces a High Rate of CR with Minor Toxicity in Adult Patients with Relapsed/Refractory ALL". PMID- 30423550 TI - Coronary Artery Calcification in Hemodialysis and Peritoneal Dialysis. AB - BACKGROUND: Vascular calcification is seen in most patients on dialysis and is strongly associated with cardiovascular mortality. Vascular calcification is promoted by phosphate, which generally reaches higher levels in hemodialysis than in peritoneal dialysis. However, whether vascular calcification develops less in peritoneal dialysis than in hemodialysis is currently unknown. Therefore, we compared coronary artery calcification (CAC), its progression, and calcification biomarkers between patients on hemodialysis and peritoneal dialysis. METHODS: We measured CAC in 134 patients who had been treated exclusively with hemodialysis (n = 94) or peritoneal dialysis (n = 40) and were transplantation candidates. In 57 of them (34 on hemodialysis and 23 on peritoneal dialysis), we also measured CAC progression annually up to 3 years and the inactive species of desphospho uncarboxylated matrix Gla protein (dp-ucMGP), fetuin-A, osteoprotegerin. We compared CAC cross-sectionally with Tobit regression. CAC progression was compared in 2 ways: with linear mixed models as the difference in square root transformed volume score per year (DeltaCAC SQRV) and with Tobit mixed models. We adjusted for potential confounders. RESULTS: In the cross-sectional cohort, CAC volume scores were 92 mm3 in hemodialysis and 492 mm3 in peritoneal dialysis (adjusted difference 436 mm3; 95% CI -47 to 919; p = 0.08). In the longitudinal cohort, peritoneal dialysis was associated with significantly more CAC progression defined as DeltaCAC SQRV (adjusted difference 1.20; 95% CI 0.09 to 2.31; p = 0.03), but not with Tobit mixed models (adjusted difference in CAC score increase per year 106 mm3; 95% CI -140 to 352; p = 0.40). Peritoneal dialysis was associated with higher osteoprotegerin (adjusted p = 0.02) but not with dp-ucMGP or fetuin-A. CONCLUSIONS: Peritoneal dialysis is not associated with less CAC or CAC progression than hemodialysis, and perhaps with even more progression. This indicates that vascular calcification does not develop less in peritoneal dialysis than in hemodialysis. PMID- 30423552 TI - The Impact of Midodrine on Outcomes in Patients with Intradialytic Hypotension. AB - BACKGROUND: Intradialytic hypotension (IDH) is a frequent complication of hemodialysis, and is associated with significant morbidity and mortality. Off label use of the alpha-1 andrenergic receptor agonist midodrine to reduce the frequency and severity of IDH is common. However, limited data exist to support this practice. This study sought to examine real-world efficacy of midodrine with respect to relevant clinical and hemodynamic outcomes. METHODS: Here, we compared a variety of clinical and hemodynamic outcomes among adult patients who were prescribed midodrine (n = 1,046) and matched controls (n = 2,037), all of whom were receiving in-center hemodialysis treatment at dialysis facilities in the United States (July 2015 - September 2016). Mortality, all-cause hospitalization, cardiovascular hospitalization, and hemodynamic outcomes were considered from the month following the initiation of midodrine (or corresponding month for controls) until censoring for discontinuation of dialysis, transplant, loss to follow-up, or study end (September 30, 2016). Rate outcomes were compared using Poisson models and quantitative outcomes using linear mixed models; all models were adjusted for imbalanced patient characteristics. RESULTS: Compared to non-use, midodrine use was associated with higher rates of death (adjusted incidence rate ratio 1.37, 95% CI 1.15-1.62), all-cause hospitalization (1.31, 1.19-1.43) and cardiovascular hospitalization (1.41, 1.17-1.71). During follow-up, midodrine use tended to be associated with lower pre-dialysis systolic blood pressure (SBP), lower nadir SBP, greater fall in SBP during dialysis, and a greater proportion of treatments affected by IDH. CONCLUSION: Although residual confounding may have influenced the results, the associations observed here are not consistent with a potent beneficial effect of midodrine with respect to either clinical or hemodynamic outcomes. PMID- 30423551 TI - Constitutively Photomorphogenic 1 Reduces the Sensitivity of Chronic Lymphocytic Leukemia Cells to Fludarabine Through Promotion of Ubiquitin-Mediated P53 Degradation. AB - BACKGROUND/AIMS: Chronic Lymphocytic leukemia (CLL) is characterized by accumulation of cells in the G0/G1 phase of the cell cycle and resistance to apoptosis due to gene mutation or abnormal gene expression. In our previous study, constitutively photomorphogenic 1 (COP1) was shown to be upregulated in Binet C-phase CLL patients. Based on the negative regulation of COP1 in the repair of DNA damage, we further studied the function of COP1 in CLL cell apoptosis induced by fludarabine in vitro and in vivo. METHODS: We analyzed the sensitivity of primary CLL cells to the fludarabine by CCK-8, and detected the expression of p53 in cells after drug treatment by western blot. Next, we constructed COP1 overexrpessing CLL cell line HG3, and analyzed the effect of COP1 overexpression on the HG3 cell's apoptosis, and HG3 transplant mice survival with drug treatment. RESULTS: Here, we found that primary CLL cells with high expression of COP1 showed low sensitivity to the drug and presented delayed enrichment of p53 protein than cells with low COP1 expressed. COP1 overexpression reduced HG3 cell sensitivity to the fludarabine treatment and inhibited cell apoptosis, and also retarded itself via autoubiquitination. The further study showed that COP1 promoted ubiquitin-dependent p53 degradation, which further disrupts the formation of the p53-Brn-3a complex and activation of Bcl-2 transcription. Moreover, mice engrafted with cells overexpressing COP1 showed a shortened survival, increased tumor cells burden in spleen and bone marrow (BM), and reduced tumor cell apoptosis even when fludarabine combined cyclophosphamide (F+C) therapy was administered. CONCLUSION: This study demonstrates that COP1 contributes to drug resistance of CLL cells to the fludarabine treatment in vitro and in vivo. PMID- 30423553 TI - Long-Noncoding RNA Colorectal Neoplasia Differentially Expressed Gene as a Potential Target to Upregulate the Expression of IRX5 by miR-136-5P to Promote Oncogenic Properties in Hepatocellular Carcinoma. AB - BACKGROUND/AIMS: The long-noncoding RNA colorectal neoplasia differentially expressed (CRNDE) gene was first found to be activated in colorectal neoplasia. Now, it also has been found to be upregulated in many other solid tumors. Whether CRNDE affects tumorigenesis remains unknown. METHODS: We conducted bioinformatics, real-time polymerase chain reaction (PCR), Western blot analysis, cell proliferation assay, colony formation assay, wound healing assay, cell migration and invasion assays, RNA immunoprecipitation, and reporter vector construction and luciferase assays. RESULTS: CRNDE was upregulated in hepatocellular carcinoma (HCC). The overexpression of CRNDE promoted HCC cellular proliferation, migration, and invasion in intro and in vivo, and acted as an oncogene in HCC progression. Furthermore, CRNDE impaired miR-136-5P expression in a RISC manner, and a reciprocal repression feedback loop was possible between CRNDE and miR-136-5P. We found that the neighboring mRNA of CRNDE was IRX5, and IRX5 increased the tumorigenicity of HCC cells. IRX5 was a potential downstream target gene of miR-136-5P. MiR-136 regulated IRX5 by interacting with its 3'UTR. In addition, miR-136-5P was involved in the CRNDE-regulated expression of IRX5. CONCLUSION: CRNDE acted as a tumor oncogene by exhibiting oncogenic properties of human HCC and revealed a novel CRNDE-miR-136-5P-IRX5 regulatory network in HCC. CRNDE may be considered to be a potential target for HCC therapies based on its ability to upregulate IRX5, and it deserves further investigation. PMID- 30423555 TI - Crosstalk between Estrogen Withdrawal and NFkappaB Signaling following Penetrating Brain Injury. AB - OBJECTIVES: Characterized by neuroinflammation, traumatic brain injury (TBI) induces neuropathological changes and cognitive deficits. Estrogens are neuroprotective by increasing cell survival and this increase is mediated by a decrease in neuroinflammation. To further explore the relationship between estrogens, brain injury, and neuroinflammation, we examined the expression of the IKK/NFkappaB complex. The IKK/NFkappaB complex is a pleiotropic regulator of many cellular signaling pathways linked to inflammation, as well as three major cytokines (IL-1beta, IL-6, and TNF-alpha). We hypothesized that NFkappaB expression would be upregulated following injury and that this increase would be exacerbated when circulating estrogens were decreased with fadrozole (aromatase inhibitor). METHODS: Using adult zebra finches, we first determined the expression of major components of the NFkappaB complex (NFkappaB, IkappaB-alpha, and IkappaB-beta) following injury using qPCR. Next, male and female finches were collected at 2 time points (2 or 24 h after injury) and brain tissue was analyzed to determine whether NFkappaB expression was differentially expressed in males and females at either time point. Finally, we examined how the expression of NFkappaB changed when estrogen levels were decreased immediately after injury. RESULTS: Our study documented an increase in the expression of the major components of the NFkappaB complex (NFkappaB, IkappaB-alpha, and IkappaB-beta) following injury. Decreasing estrogen levels resulted in a surprising decrease in the NFkappaB complex studied here. DISCUSSION: These data further expand the model of how estrogens and other steroid hormones interact with the inflammatory pathways following injury and may prove beneficial when developing therapies for treatment of TBI. PMID- 30423554 TI - Peperomin E Induces Promoter Hypomethylation of Metastatic-Suppressor Genes and Attenuates Metastasis in Poorly Differentiated Gastric Cancer. AB - BACKGROUND/AIMS: Peperomin E (PepE), a natural secolignan isolated from the whole plant of Peperomia dindygulensis, has been reported by ourselves and others to display potent anti-cancer effects in many types cancer cells, especially gastric cancer. However, the effects of PepE on the metastasis of poorly-differentiated gastric cancer cells and the underlying molecular mechanisms have not been well elucidated. METHODS: We evaluated PepE effects on gastric cancer cell invasion and migration in vitro via wound healing and transwell assays and those on growth and metastasis in vivo using an orthotopic xenograft NOD-SCID mouse model. DNA methyltransferase (DNMT) activity was determined using a colorimetric DNMT activity/inhibition assay kit. PepE binding kinetics to DNMTs were determined using the bio-layer interferometry binding assay. Gene and protein levels of DNMTs, AMPKalpha-Sp1 signaling molecules, and metastatic-suppressor genes in PepE treated gastric cancer cells were determined using quantitative reverse transcription-PCR arrays and western blotting. The effect of PepE on Sp1 binding to the DNMT promoter was determined by electrophoretic mobility-shift assay. Global DNA methylation levels were determined using liquid chromatography coupled with electrospray ionization tandem mass spectrometry. The methylation status of silenced metastatic-suppressor genes (MSGs) in gastric cancer cells was investigated by methylation-specific PCR. RESULTS: PepE can dose-dependently suppress invasion and migration of poorly-differentiated gastric cancer cells in vitro and in vivo with low toxicity against normal cells. Mechanistically, PepE not only covalently binds to the catalytic domain of DNMT1 and inhibits its activity (IC50 value 3.61 MUM) but also down-regulates DNMT1, 3a, and 3b mRNA and protein expression in in gastric cancer cells, by disruption of the physical interaction of Sp1 with the DNMT1, 3a, and 3b promoter and mediation of the AMPKalpha-Sp1 signaling pathway. The dual inhibition activity of PepE toward DNMTs renders a relative global DNA hypomethylation, which induces MSG promoter hypomethylation (e.g., E-cadherin and TIMP3) and enhances their expression in gastric cancer cells. CONCLUSION: Collectively, our data indicated that PepE may represent a promising therapeutic lead compound for intervention in gastric cancer metastasis and may also exhibit potential as a DNA methylation inhibitor for use in epigenetic cancer therapy. PMID- 30423556 TI - The Clinical Effects of Sildenafil for Erection in Patients after Kidney Transplantation: A Meta-Analysis. AB - BACKGROUND: With the wide use of sildenafil in kidney-transplanted patients, it is vital to recognize the effectiveness and safety in clinical practice. METHODS: Full-text articles involving the application of sildenafil after renal transplantation searched out in multiple databases were reviewed. All the meta analyses were performed with Review Manager 5.0 software and bias analysis of the studies were conducted to examine the quality of articles. In addition, to estimate possible publication bias, funnel plot and the Egger's test were used. RESULT: Finally 7 articles eventually satisfied the inclusion criteria. The penetration ability and maintenance frequency in sildenafil group were much larger than those of control group. Except orgasmic function, domains of the International Index of Erectile Function have showed larger scores in sildenafil group than those of control group. No significant difference of the concentration of cyclosporine was observed between sildenafil and control group. CONCLUSION: In conclusion, this study showed that treatment with sildenafil in renal allograft recipients with erectile dysfunction is a valid and safe option. PMID- 30423557 TI - The Pathophysiology of Respiratory Failure: Control of Breathing, Respiratory Load, and Muscle Capacity. AB - The purpose of this review is to provide an overview on how interactions between control of breathing, respiratory load, and muscle function may lead to respiratory failure. The mechanisms involved vary according to the underlying pathology, but respiratory failure is most often the result of an imbalance between the muscular pump and the mechanical load placed upon it. Changes in respiratory drive and response to CO2 seem to be important contributors to the pathophysiology of respiratory failure. Inspiratory muscle dysfunction is also frequent but is not a mandatory prerequisite to respiratory failure since increased load may also be sufficient to precipitate it. It is crucial to recognize these interactions to be able to timeously establish patients on mechanical ventilation and adapt the ventilator settings to their respiratory system physiology. PMID- 30423559 TI - 28th Annual Congress of European Childhood Obesity Group (ECOG), Porto, November 14-17, 2018 - Selected Abstracts. PMID- 30423558 TI - High-Conductance Channel Formation in Yeast Mitochondria is Mediated by F-ATP Synthase e and g Subunits. AB - BACKGROUND/AIMS: The permeability transition pore (PTP) is an unselective, Ca2+ dependent high conductance channel of the inner mitochondrial membrane whose molecular identity has long remained a mystery. The most recent hypothesis is that pore formation involves the F-ATP synthase, which consistently generates Ca2+-activated channels. Available structures do not display obvious features that can accommodate a channel; thus, how the pore can form and whether its activity can be entirely assigned to F-ATP synthase is the matter of debate. In this study, we investigated the role of F-ATP synthase subunits e, g and b in PTP formation. METHODS: Yeast null mutants for e, g and the first transmembrane (TM) alpha-helix of subunit b were generated and evaluated for mitochondrial morphology (electron microscopy), membrane potential (Rhodamine123 fluorescence) and respiration (Clark electrode). Homoplasmic C23S mutant of subunit a was generated by in vitro mutagenesis followed by biolistic transformation. F-ATP synthase assembly was evaluated by BN-PAGE analysis. Cu2+ treatment was used to induce the formation of F-ATP synthase dimers in the absence of e and g subunits. The electrophysiological properties of F-ATP synthase were assessed in planar lipid bilayers. RESULTS: Null mutants for the subunits e and g display dimer formation upon Cu2+ treatment and show PTP-dependent mitochondrial Ca2+ release but not swelling. Cu2+ treatment causes formation of disulfide bridges between Cys23 of subunits a that stabilize dimers in absence of e and g subunits and favors the open state of wild-type F-ATP synthase channels. Absence of e and g subunits decreases conductance of the F-ATP synthase channel about tenfold. Ablation of the first TM of subunit b, which creates a distinct lateral domain with e and g, further affected channel activity. CONCLUSION: F-ATP synthase e, g and b subunits create a domain within the membrane that is critical for the generation of the high-conductance channel, thus is a prime candidate for PTP formation. Subunits e and g are only present in eukaryotes and may have evolved to confer this novel function to F-ATP synthase. PMID- 30423560 TI - Intradialytic Hypotension: Is Midodrine the Answer? PMID- 30423562 TI - Recent Advances in Experimental Allergy. AB - Atopic disorders are on the rise and pose a great burden on society. A better understanding of the underlying mechanisms is required for the development of improved or novel therapeutic strategies. Here we aim to highlight recent advances in experimental allergy, with a particular focus on proposed treatment alternatives for airway disorders, atopic dermatitis, and food allergy. Furthermore, we discuss recent work focusing on molecular and cellular mechanisms that might offer candidates for future preventive or therapeutic intervention. PMID- 30423561 TI - An Open-Labeled Study on Fecal Microbiota Transfer in Irritable Bowel Syndrome Patients Reveals Improvement in Abdominal Pain Associated with the Relative Abundance of Akkermansia Muciniphila. AB - BACKGROUND/AIMS: The gut microbiota is altered in irritable bowel syndrome (IBS), and microbiota manipulations by diet or antibiotics can reduce its symptoms. As fecal microbiota transfer (FMT) in IBS is still controversial, we investigated the clinical and side effects of FMT in a cohort of IBS patients with recurrent, treatment refractory symptoms, and studied gut microbiota signatures. METHODS: Using an observational, prospective study design, we applied FMTs from one unrelated, healthy donor to 13 IBS patients. Fecal samples of patients and the donor were analyzed by 16S ribosomal RNA amplicon sequencing. RESULTS: On a symptom level, primarily abdominal pain symptoms were reduced after FMT, and no adverse effects were observed. Studying the microbiome, we found an increase in alpha diversity and changes in the composition of the gut microbiota after FMT. Beta diversity changes after FMT were prominent in a subset of 7 patients with microbiota profiles coming very close to the donor. These patients also showed most pronounced visceral pain reduction. The relative abundance of Akkermansia muciniphila was inversely correlated with pain reduction in our cohort. CONCLUSION: Although exploratory in nature and with a pilot character, this study highlights the potential role of microbiota manipulations in IBS and describes a novel association of intestinal Akkermansia and pain modulation. PMID- 30423563 TI - Contrast-Enhanced Sonography in Patients with Hyposplenia: A Retrospective Analysis in Forty-Three Patients. AB - PURPOSE: In contrast to splenomegaly, the clinical value of a small spleen (hyposplenia) is unclear. Contrast-enhanced ultrasound (CEUS) has not been investigated systematically in hyposplenia. METHODS: Between February 2005 and January 2017, 43 patients with hyposplenia (< 7 * 3 cm) were examined by B-mode ultrasound (US) and CEUS. A retrospective data analysis was performed. RESULTS: A total of 39 (91%) patients had an underlying disease (UD; allogenic stem cell transplantation, n = 16; autoimmune-diseases, n = 7; sickle cell anemia, n = 5; solid tumors, n = 5; others, n = 6). In 4 (9%) cases, hyposplenia was an incidental finding. The echogenicity of the spleen was normal (homogeneous, isoechogenic) in 17 (39.5%) and abnormal in 26 (60.5%) cases (inhomogeneous, n = 26 and hyperechoic, n = 9). In CEUS, 21 (49%) patients presented a normal isoenhancement. An abnormal enhancement was detected in 22 (51%) patients with UD (arterial/parenchymal inhomogeneous, n = 1; no [arterial, n = 3 and parenchymal, n = 6]; reduced [arterial, n = 8 and parenchymal, n = 15]). CONCLUSIONS: Hyposplenia is a rare pathologic finding and often associated with hematological/oncological and autoimmune diseases. Furthermore, altered B-mode US appearance and a pathological CEUS pattern are frequently found. However, the clinical implication, especially regarding splenic function remains obscure to date. PMID- 30423564 TI - Low Bone Mineral Density Is Not Associated with Subclinical Atherosclerosis: A Population-Based Study in Rural China. AB - OBJECTIVES: Loss of bone mass may affect the progression of atherosclerosis. We investigated the relationship between low bone mineral density (BMD) and subclinical atherosclerosis in rural China. METHODS: In total, 333 men and 421 postmenopausal women aged 55-65 years were enrolled. BMD was measured in the lumbar spine, femoral neck, and total hip using dual-energy X-ray absorptiometry. Subclinical atherosclerosis was defined as increased carotid artery intima-media thickness (CIMT >=0.9 mm), the presence of carotid plaques, high brachial-ankle pulse wave velocity (baPWV >=1,400 cm/s), and low ankle-brachial index (ABI <=1). Binary logistic regression analyses were used to estimate the association between low BMD and subclinical atherosclerosis. RESULTS: There was no significant difference in BMD between the normal group and the subclinical atherosclerosis group. After full adjustment for the relevant covariates, a boundary significant association was found between low BMD in the femoral neck and baPWV in postmenopausal women (odds ratio = 1.77, p = 0.049). After full adjustment, neither BMD nor low BMD were significantly associated with subclinical atherosclerosis in men or postmenopausal women. CONCLUSIONS: Low BMD is not associated with subclinical atherosclerosis in Chinese individuals aged 55-65 years resident in rural China. PMID- 30423565 TI - Mice Deficient in Cyp4a14 Have An Increased Number of Goblet Cells and Attenuated Dextran Sulfate Sodium-Induced Colitis. AB - BACKGROUND/AIMS: Cyp4a14 is a member of cytochrome P450 (Cyp450) enzyme superfamily that possesses NADPH monooxygenase activity, which catalyzes omega hydroxylation of medium-chain fatty acids and arachidonic acid. Study suggests that down-regulation of Cyp4a14 has an anti-inflammatory response in intestine. The present study was to test the function of Cyp4a14 in dextran sulfate sodium (DSS)-induced colitis. METHODS: Female Cyp4a14-knockout (KO) and wild-type (WT) mice were treated with DSS for 6 days to induce colitis. The colon of mice was histologically observed by hematoxylin and eosin (H&E) and periodic acid Schiff (PAS) staining. The serum malondialdehyde (MDA), an endogenous indicator of oxidative stress, was chemically measured. Proinflammatory and NADPH oxidase genes were examined by quantitative polymerase chain reaction (qPCR). RESULTS: Cyp4a14-KO mice had a significantly higher number of goblet cells in the colon and were more resistant to DSS-induced colitis compared with the WT mice. The DSS treated KO mice had lower levels of MDA. Consistent with the milder inflammatory pathological changes, DSS-treated KO mice had lower levels of IL-1beta, IL-6 and TNF-alpha mRNA in the liver and the colon. Moreover, the colon of DSS-treated Cyp4a14-KO and WT mice had higher mRNA levels of two members of NADPH oxidases, Nox2 and Nox4, suggesting that both Nox2 and Nox4 are inflammatory markers. By contrast, DSS-treated WT and KO mice had drastically decreased epithelium localized Nox1 and dual oxidase (Duox) 2 mRNA levels, coinciding with the erosion of the mucosa induced by DSS. CONCLUSION: These results suggests a hypothesis that the increased goblet cell in the colon of Cyp4a14-KO mice provides protection from mucosal injury and Cyp4a14-increased oxidative stress exacerbates DSS-induced colitis. Therefore, Cyp4a14 may represent a potential target for treating colitis. PMID- 30423566 TI - Ovarian Clear Cell Carcinoma Detected During Long-Term Management of Endometriotic Cysts in Young Patients: Possible Heterogeneity of this Tumor. AB - Ovarian endometriotic cysts have been identified as the possible origin of ovarian clear cell carcinoma (OCCC), so predicting or preventing future transformation is important. Early detection of clear cell carcinoma is important because it shows low sensitivity to chemotherapy and the prognosis is worse than for other histologic types. We recently treated 2 patients with OCCC. They were both young women with no family history of cancer who received long-term oral contraceptive therapy for endometriotic cysts, and the histologic diagnosis was typical clear cell carcinoma in both patients. However, in Case 1, the tumor was detected by periodic examination, tumor expression of WT1 was positive, and the stage was IA. On the other hand, Case 2 presented with fever of unknown origin, her tumor showed expression of p53, and the stage was IVB. Case 1 is alive with no evidence of disease at 38 months after surgery, while Case 2 died after 19 months despite intensive treatment. These contrasting cases suggest that we need to be aware of the risk of cancer in young women receiving long-term hormone therapy for endometriotic cysts and that OCCC may show greater heterogeneity than what has been reported previously. PMID- 30423567 TI - Acute-Phase Plasma PCSK9 Levels and Recurrent Cardiovascular Events in a Chinese Acute Myocardial Infarction Cohort. AB - BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising target for lowering plasma low-density lipoprotein cholesterol and preventing cardiovascular (CV) disease. Whether plasma PCSK9 measured during the acute phase predicts recurrent CV events in patients with acute myocardial infarction (AMI) remains unresolved. METHODS AND RESULTS: Plasma PCSK9 levels were measured in 1,646 patients with AMI from the China PEACE-Prospective AMI Study at the acute phase. Additionally, 248 patients were resampled and measured at 1 month post AMI. Associations of acute-phase PCSK9 tertiles with clinical characteristics and recurrent CV events within 1 year were assessed. Female gender (OR 1.94, 95% CI 1.24-3.03), premature coronary heart disease (CHD; OR 2.12, 95% CI 1.37-3.26), higher high-sensitivity C-reactive protein (OR 1.67, 95% CI 1.44-1.95), and higher triglycerides (OR 1.46, 95% CI 1.03-2.09) were associated with higher baseline PCSK9. Plasma PCSK9 levels in the highest tertile (versus lowest) did not have an increased risk of 1-year recurrent CV events in the AMI cohort (HR 0.78, 95% CI 0.52-1.16) or any subgroup. There was also no association between percentage changes in PCSK9 over the first month and 1-year recurrent events, although there was a trend of differences between patients in the upper versus lower tertiles. CONCLUSION: Plasma PCSK9 levels measured during the acute phase were associated with high-sensitivity C-reactive protein, triglycerides, premature CHD, and gender in patients with AMI but did not predict recurrent CV events within 1 year. Dynamic changes in PCSK9 suggested a trend yet no significance value in predicting recurrent CV events. PMID- 30423568 TI - Efficacy of Magnifying Narrow Band Imaging for Delineating Horizontal Margins of Early Gastric Cancer. AB - BACKGROUND/AIMS: The aim of this study was to evaluate the diagnostic accuracy of magnifying narrow-band imaging (M-NBI) with histopathological confirmation in identifying the demarcation line (DL) of early gastric cancer (EGC). METHODS: EGCs resected by endoscopic submucosal dissection after identifying the DL using M-NBI following histopathological confirmation were included. After determining the DL for the entire EGC lesion using M-NBI, at least 4 biopsies were taken from non-cancerous tissues outside the EGC lesion for histopathological confirmation. RESULTS: A total of 330 EGCs were analyzed in this study. The rate of biopsy negative and negative horizontal margin were 96.7% (319/330) and 97.9% (323/330) in EGC respectively. Tumors larger than 20 mm showed a higher risk for showing remnant cancer cells on biopsies taken outside the DL. Risk factors for a positive horizontal resection margin were tumor size > 20 mm and moderately or poorly differentiated adenocarcinomas. CONCLUSION: The assessment of demarcation of EGC using M-NBI was excellent in well-differentiated (WD) adenocarcinoma and lesions below 20 mm in size. However, histopathological confirmation is needed to assess the demarcation of non-WD adenocarcinomas and EGC over 20 mm in size. PMID- 30423569 TI - Mammalian Target of Rapamycin Complex 1 Activation Disrupts the Low-Density Lipoprotein Receptor Pathway: A Novel Mechanism for Extracellular Matrix Accumulation in Human Peritoneal Mesothelial Cells. AB - Peritoneal fibrosis (PF) is characterized by progressive extracellular matrix (ECM) accumulation. Increasing evidence has suggested that ECM synthesis was increased in human peritoneal mesothelial cells (HPMCs) under high-glucose conditions, but the effects of high-glucose peritoneal dialysis solution (PDS) on ECM synthesis have not been fully elucidated. The aim of this study was to explore the potential mechanisms of high-glucose PDS-induced production of ECM in HPMCs. HPMCs were stimulated by high-glucose PDS. The activity of mammalian target of rapamycin complex 1 (mTORC1) was inhibited by rapamycin or regulatory associated protein of mTOR (raptor) siRNA. Morphological changes in the cells were observed under an inverted microscope. Oil red O, filipin staining and high performance liquid chromatography were used to examine lipid accumulation. The expression of low-density lipoprotein receptor (LDLr) regulation, the mTORC1 pathway and ECM-associated markers were assessed by real-time polymerase chain reaction and western blot analysis. The results showed that after treatment with PDS, HPMCs showed notable elongation consistent with the morphology of myofibroblasts, and the expression of ECM proteins such as alpha-smooth muscle actin, fibroblast specific protein-1 and collagen I was increased. In addition, there was a parallel increase in the ECM and lipid accumulation. Moreover, the effect of intracellular lipid deposition was closely correlated with the dysregulation of LDLr, which was mediated through the upregulation of LDLr, sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP), and SREBP-2 and through the enhanced coexpression of the SCAP with the Golgin. Further analysis showed that PDS enhanced the protein phosphorylation of mTOR, eukaryotic initiation factor 4E-binding protein 1, and p70 S6 kinase. Interestingly, blocking mTORC1 activity reversed the dysregulation of LDLr, even in the presence of PDS. These effects were also accompanied by a decrease in the expression of ECM components. Our findings demonstrated that increased mTORC1 activity exacerbated ECM formation in HPMCs by disrupting LDLr regulation, which contributed to lipid disorder-mediated PF. PMID- 30423570 TI - Extramedullary Haematopoiesis in Axillary Lymph Nodes of Breast Carcinoma Patients Receiving Neoadjuvant Chemotherapy: A Potential Diagnostic Pitfall. AB - Extramedullary haematopoiesis (EMH) in the axillary lymph node of breast cancer patients is extremely rare but when encountered can represent a diagnostic challenge. We aim to highlight this incidental finding as a diagnostic pitfall which can be mistaken for metastatic carcinoma (particularly of the metaplastic type). We report the case of a 68-year-old Caucasian female with a family history of cancer. Core biopsy revealed that she had grade II oestrogen receptor negative, Her2-positive invasive ductal carcinoma. She was offered neoadjuvant chemotherapy with Herceptin and subsequently underwent breast-conserving surgery. Microscopic examination of the post-treatment breast surgical specimen showed a partial pathological response with large areas of tumour regression. The sentinel lymph node showed frequent large single and multinucleate giant cells with hyperchromatic nuclei located predominantly within the subcapsular and medullary sinuses. The morphological differentials of metastatic carcinoma, sinus histiocytosis and extramedullary haematopoiesis were considered. A panel of immunohistochemistry showed these large cells to be negative for epithelial markers and CD68. They were strongly positive for CD42b (megakaryocyte marker). Smaller myeloperoxidase and factor VIII-positive cells were identified. The findings confirmed EMH. Sentinel nodes are often well scrutinised by pathologists for evidence of metastatic carcinoma as an important prognostic parameter both in the standard and neoadjuvant setting. Nodal megakaryocytes have been described in response to neoadjuvant chemotherapy particularly in association with Herceptin treatment. Pathologists' awareness of this finding in the neoadjuvant setting is crucial to avoid a mistaken diagnosis of malignancy. A relevant immunohistochemical panel together with careful attention to morphology should help establish the correct diagnosis. PMID- 30423572 TI - Stimulation of Eryptosis, the Suicidal Erythrocyte Death, by Costunolide. AB - BACKGROUND/AIMS: The sesquiterpene lactone Costunolide is effective against various disorders including inflammation and malignancy. The substance is effective in part by triggering suicidal death or apoptosis of tumor cells. Mechanisms involved include altered function of transcription factors and mitochondria. Erythrocytes lack nuclei and mitochondria but are - in analogy to apoptosis of nucleated cells - able to enter suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress and ceramide. The present study explored, whether Costunolide induces eryptosis and, if so, to shed light on the mechanisms involved. METHODS: Phosphatidylserine exposure at the cell surface was estimated from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, reactive oxygen species (ROS) formation from 2',7'-dichlorodihydrofluorescein (DCF)-dependent fluorescence, and ceramide abundance utilizing specific antibodies. RESULTS: A 48 hours exposure of human erythrocytes to Costunolide (15 ug/ml) significantly enhanced the percentage of annexin-V-binding cells, significantly decreased forward scatter and significantly increased Fluo3-fluorescence, DCF-fluorescence, and ceramide abundance. The effect of Costunolide on annexin-V-binding was significantly blunted by removal of extracellular Ca2+. CONCLUSION: Costunolide triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part due to Ca2+ entry and paralleled by oxidative stress and ceramide formation. PMID- 30423571 TI - Global mRNA and Long Non-Coding RNA Expression in the Placenta and White Adipose Tissue of Mice Fed a High-Fat Diet During Pregnancy. AB - BACKGROUND/AIMS: Gestational diabetes mellitus (GDM) is a common complication of pregnancy, but the mechanisms underlying the disorders remain unclear. The study aimed to identify mRNA and long non-coding RNA (lncRNA) profiles in placenta and gonadal fat of pregnant mice fed a high-fat diet and to investigate the transcripts and pathways involved in the development of gestational diabetes mellitus. METHODS: Deep and broad transcriptome profiling was performed to assess the expression of mRNAs and lncRNAs in placenta and gonadal fat from 3 mice fed an HFD and chow during pregnancy. Then, differentially expressed mRNAs and lncRNAs were validated by quantitative real-time PCR. The function of the differentially expressed mRNAs was determined by pathway and Gene Ontology (GO) analyses, and the physical or functional relationships between the lncRNAs and the corresponding mRNAs were determined. RESULTS: Our study revealed that 82 mRNAs and 52 lncRNAs were differentially expressed in the placenta of mice fed an HFD during pregnancy, and 202 mRNAs and 120 lncRNAs were differentially expressed in gonadal fat. GO and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed differentially expressed mRNAs of placenta were closely related to extracellular matrix interactions, digestion, adhesion, and metabolism, whereas the differentially expressed mRNAs in adipose tissue were related to metabolic and insulin signalling pathways. The gene network demonstrated that Actg2, Cnfn, Muc16, Serpina3k, NONMMUT068202, and NONMMUT068203, were the core of the network in placental tissue, and the genes Tkt, Acss2, and Elovl6 served as the core of the network in gonadal fat tissue. CONCLUSION: These newly identified key genes and pathways in mice might provide valuable information regarding the pathogenesis of GDM and might be used to improve early diagnosis, prevention, drug design, and clinical treatment. PMID- 30423573 TI - MicroRNA-200a Affects the Proliferation of Airway Smooth Muscle Cells and Airway Remodeling by Targeting FOXC1 via the PI3K/AKT Signaling Pathway in Ovalbumin Induced Asthmatic Mice. AB - BACKGROUND/AIMS: The etiology of asthma, which is a complicated disorder with various symptoms, including wheezing, coughing, and airflow obstruction, remains poorly understood. In addition, the effects of microRNAs (miRs) have not been explored. This study explored the effect of microRNA-200a (miR-200a) on airway smooth muscle cells (ASMCs) and airway remodeling in asthmatic mice. Furthermore, we speculated that miR-200a achieves its effect by targeting FOXC1 via the PI3K/AKT signaling pathway based on differentially expressed gene screening, target miR predictions and a bioinformatics analysis. METHODS: Eighty mice were assigned to a saline group or an ovalbumin (OVA) group, and the OVA group was transfected with a series of inhibitors, activators, and siRNAs to test the established mouse model. Airway reactivity and the ratio of eosinophils (EOSs) to leukocytes were detected. An ELISA was adopted to measure the levels of interleukin (IL)-4, IL-6, IL-8, tumor necrosis factor (TNF)-alpha, and immunoglobulin E (IgE). Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to determine the expression of FOXC1, PI3K, AKT, NF-kappaB, cyclin D1, TGF-beta1 and p-AKT in ASMCs. Finally, CCK-8 assays were performed to detect cell proliferation and flow cytometry to detect apoptosis and cell cycle entry. RESULTS: The bioinformatics analysis indicated that miR-200a mediated the PI3K/AKT signaling pathway by targeting FOXC1. In addition, mouse models of asthma were established. An elevated expression of miR-200a, a decreased mRNA and protein expression of FOXC1, PI3K, AKT, NF-kappaB, cyclin D1 and TGF-beta1, a decreased expression of p-AKT, suppressed cell proliferation, accelerated apoptosis, and an increased number of cells at the G0/G1 phase were observed following the upregulation of miR-200a and downregulation of FOXC1. CONCLUSION: The overexpression of miR-200a may downregulate FOXC1, thereby inhibiting the activation of the PI3K/AKT signaling pathway and ultimately suppressing ASMC proliferation and airway remodeling in asthmatic mice. This evidence supports the potential that miR-200a represents a new approach to treating asthma. PMID- 30423575 TI - The Impact of the Opioid Antagonist Naloxone on Experimentally Induced Craving in Nicotine-Dependent Individuals. AB - OBJECTIVE: Preclinical and clinical findings suggest a substantial association of the endogenous opioid system in nicotine dependence. The present study investigates the possible dose-dependent influence of naloxone, an unspecific opioid-receptor-antagonist, combined with cue exposure on the physiological state, locomotor activity, craving and the hypothalamic-pituitary-adrenal axis in nicotine-dependent humans. METHODS: Twenty nicotine-dependent, outpatient participants were deprived of nicotine for over 4 h, before receiving challenges with naloxone (1.6 mg or 3.2 mg q70 kg IV) or the placebo. Additionally, following drug administration, either smoking-related cues or neutral images were presented. Nicotine withdrawal was monitored by evaluating the following objective signs - skin conductance, heart rate, temperature, respiration, locomotor activity, cortisol, prolactin and ACTH levels as well as craving. RESULTS: With respect to subjective effects, participants administered a higher dosage of naloxone and those who were shown smoking-related cues were significantly less pleased (p = 0.019), felt more depressed (p = 0.033) and thought smoking would make them feel better (p = 0.028) than participants given naloxone and shown neutral cues. Participants given no naloxone but with smoking related cues felt a higher urge to smoke than participants given naloxone and shown neutral cues (p = 0.042). Naloxone - in both dosages - also decreased the desire and intention to smoke in comparison to placebo. Compared to the placebo group, significantly higher cortisol, prolactin and ACTH values were observed after administration of lower and higher dosage of naloxone followed by smoking related cues. CONCLUSION: Naloxone influenced nicotine withdrawal and strengthened significantly by cue exposure, both on objective measurement and on craving scales. These findings suggest an involvement of the endogenous opioid system in the development and maintenance of nicotine dependence. PMID- 30423574 TI - Effects of Triple-Mutated Hypoxia-Inducible Factor-1alpha on Angiogenesis and Cardiac Function Improvement in Rats with Myocardial Infarction. AB - BACKGROUND/AIMS: The effects of hypoxia-inducible factor-1alpha (HIF-1alpha) on angiogenesis and cardiac function improvement in rats with myocardial infarction (MI) is unknown and our current study was to evaluate whether HIF-1alpha would be beneficial for angiogenesis and cardiac function improvement in MI rats. METHODS: A mutant of adenovirus HIF-1alpha (Ad-HIF-1alpha-Trip) was constructed by three sites mutation (Pro402, Pro564 and Asn803) in HIF-1alpha. The rat MI model was produced by permanent ligation of left anterior descending artery and 1*109 PFU adenovirus (Ad) vector particles of Ad-Null, Ad- HIF-1a-564/402, Ad- HIF-1a-Trip, 250ng vascular endothelial growth factor (VEGF) in 0.5ml saline or only 0.5 ml saline were injected intramuscularly around the infarct border zone. Real-time PCR, ELISA and western blotting were used to evaluate angiogenesis factors expression. Capillary density and necrotic areas were detected by immunohistochemistry staining and TTC staining, respectively. Cardiac function assessment was done by echocardiography before operation and on day 7, 14 and 28 after MI. Blood samples were drawn for the measurement of cardiac biomarkers, liver function and kidney function. RESULTS: On day 7, compared to the other groups, the expressions of HIF-1alpha and angiogenesis factors, and the capillary density were all significantly higher in the Ad-HIF-1alpha-Trip group. However, on day 28, no significant between-group differences were observed. After 72 hours of MI, serum level of cardiac biomarkers and the necrotic areas were significantly lower in the Ad-HIF-1a-Trip group compared to the other groups. Echocardiography showed that on day 7, cardiac functions were significantly reduced in all groups compared to the baseline. Cardiac function in the Ad-HIF 1alpha-Trip group was decreased less profoundly through day 7 to day 28 compared to the other groups. Importantly, no significant differences in liver and renal function were observed. CONCLUSION: Mutation of Pro402, Pro564 and Asn803 are beneficial for enhancement of the efficacy of HIF-1alpha. Ad-HIF-1alpha-Trip is able to improve angiogenesis and cardiac function, which may be a promising avenue for treatment of ischemic heart disease in the future. PMID- 30423576 TI - miR-423-5p Inhibits Osteosarcoma Proliferation and Invasion Through Directly Targeting STMN1. AB - BACKGROUND/AIMS: Increasing evidences suggest that dysregulated expression of miRNAs contributes to the progression of various tumors. However, the underlying function of miR-423-5p in osteosarcoma remains unexplored. METHODS: The expression of miR-423-5p and STMN1 were determined in osteosarcoma samples and cell lines via quantitative real-time PCR. Colony formation and Cell Counting Kit 8 (CCK-8) assays were performed to measure cell proliferation ability and transwell analysis was used to detect cell invasion, and dual luciferase reporter assay was perform to analysis the interaction between the miR-423-5p and STMN1. RESULTS: The expression levels of miR-423-5p and STMN1 in the osteosarcoma tissues and cell lines were measured by qRT-PCR. Cell viability was determined using the clone formation and CCK-8 assays. A dual-luciferase reporter and Western blot were performed to stdudy the target gene of miR-423-5p. Here, we showed that miR-423-5p expression was downregulated in osteosarcoma tissues and cell lines. However, the expression of stathmin1 (STMN1) was downregulated in osteosarcoma tissues and cell lines. Moreover, STMN1 expression level was negatively correlated with the miR-423-5p expression in the osteosarcoma tissues. We identified STMN1 was a direct target gene of miR-423-5p in osteosarcoma cell. Overexpression of miR-423-5p inhibited osteosarcoma cell proliferation, colony formation and invasion. Furthermore, we demonstrated that STMN1 was involved in miR-423-5p-mediated cell behavior such as cell proliferation, colony formation and invasion in the osteosarcoma cell. CONCLUSION: Our present study indicated that miR-423-5p acted as a tumor suppressor gene in osteosarcoma partly through inhibiting STMN1 expression. PMID- 30423577 TI - Ca2+ Signaling Triggered by Shear-Autocrine P2X Receptor Pathway in Rat Atrial Myocytes. AB - BACKGROUND/AIMS: The atrium is exposed to high shear stress during heart failure and valvular diseases. We aimed to understand atrial shear-induced Ca2+ signaling and its underlying mechanisms. METHODS: Pressurized micro-flow was applied to single rat atrial myocytes, and Ca2+ signal, membrane potential, and ATP release were assessed using confocal imaging, patch clamp technique, and luciferin luciferase assay, respectively. RESULTS: Shear stress (~16 dyn/cm2) induced global Ca2+ waves (~0.1 events/s) from the periphery to the center of cells in a transverse direction ("T-wave"; ~145 MUm/s). Pharmacological interventions and simultaneous recording of membrane potential and Ca2+ demonstrated that shear induced T-waves resulted from action potential (AP)-triggered Ca2+ release from the sarcoplasmic reticulum. T-waves were not sensitive to inhibitors of known shear signaling mechanisms except connexin hemichannels and ATP release. Shear stress caused ATP release from these myocytes (~1.1x10-17 moles/unit membrane, um2); ATP release was increased by enhancement of connexin hemichannels and suppressed by inhibition of the hemichannels, but not affected by inhibitors of other ATP release pathways. Blockade of P2X receptor, but not pannexin or the Na+ Ca2+ exchanger, eliminated shear-induced T-wave initiation. CONCLUSION: Our data suggest that shear stress triggers APs and concomitant Ca2+ signaling via activation of P2X receptors by connexin hemichannel-mediated ATP release in atrial myocytes. PMID- 30423578 TI - Genome-Wide Analysis of mRNAs and lncRNAs of Intramuscular Fat Related to Lipid Metabolism in Two Pig Breeds. AB - BACKGROUND/AIMS: Long non-coding RNAs (lncRNAs) can regulate adipogenesis and lipid accumulation. Intramuscular fat deposition appears to vary in different pig breeds, and the regulation mechanism has not yet been fully elucidated at molecular level. Moreover, little is known about the function and profile of lncRNAs in intramuscular fat deposition and metabolism in pig. The aim of this study was thus to explore the regulatory functions of lncRNAs in intramuscular fat deposition. METHODS: In this study, Laiwu (LW) pig and Large White (LY) pig with significant difference in fat deposition were selected for use. RNA-seq technology and bioinformatics methods were used to comparatively analyze the gene expression profiles of intramuscular fat between LW and LY pigs to identify key mRNAs and lncRNAs associated with lipid metabolism and adipogenesis. Real-time fluorescence-based quantitative PCR was applied to verify the expression level of the differentially expressed mRNAs and lncRNAs. RESULTS: A total of 513 mRNAs and 55 lncRNAs were differentially expressed between two pig breeds. By co-expression network construction as well as cis- and trans-regulated target gene analysis, 31 key lncRNAs were identified. Gene Ontology and KEGG pathway analyses revealed that differentially expressed genes and lncRNAs were mainly involved in the biological processes and pathways related to adipogenesis and lipid metabolism. CONCLUSION: XLOC_046142, XLOC_004398 and XLOC_015408 may target MAPKAPK2, NR1D2 and AKR1C4, respectively, and play critical regulatory roles in intramuscular adipogenesis and lipid accumulation in pig. XLOC_064871 and XLOC_011001 may play a role in lipid metabolism-related disease via regulating TRIB3 and BRCA1. This study provides a valuable resource for lncRNA study and improves our understanding of the biological roles of lipid metabolism- related genes and molecular mechanism of intramuscular fat metabolism and deposition. PMID- 30423579 TI - Icodextrin is Associated with a Lower Risk of Stroke in Peritoneal Dialysis Patients. AB - BACKGROUND/AIMS: This study investigated whether peritoneal dialysis (PD) patients using icodextrin were at a reduced risk of stroke. METHODS: From Taiwan National Health Insurance data, it was found that there were 6,796 new end-stage renal disease patients undergoing dialysis between 2005 and 2011. We compared the risk of stroke between PD patients with or without icodextrin treatment. The follow-up period began from the date of PD initiation to the end of 2011. The time-dependent Cox proportional hazards regression models were used to analyze the risk of stroke. RESULTS: Among PD patients, the icodextrin users had both a lower incidence and risk of stroke than icodextrin non-users (incidence: 22.4 vs. 25.2/1,000 person-years) with an adjusted hazard ratio of 0.76 (95% CI 0.63 0.93). The results were similar in models considering death a competing risk (overall: adjusted subhazard ratio [SHR] 0.78, 95% CI 0.63-0.94). Icodextrin users also had a lower risk of ischemic stroke with or without considering death a competing risk (adjusted SHR 0.71, 95% CI 0.57-0.89 and adjusted HR 0.74, 95% CI 0.59-0.93, respectively), compared to non-users. CONCLUSION: The use of icodextrin is associated with a lower incidence and risk of stroke in PD patients. PMID- 30423580 TI - Biochemical Markers, Genotype, and Inflammation in Pediatric Inflammatory Bowel Disease: A Danish Population-Based Study. AB - BACKGROUND: Our aim was to characterize the biochemical markers at diagnosis in patients with inflammatory bowel disease (IBD), to assess the utility of these to predict disease course and investigate if genotype influences biochemical markers of inflammation. SUMMARY: Patients were included from a population-based pediatric IBD cohort from Eastern Denmark. Data on biochemical markers and medical as well as surgical treatment were registered at diagnosis, 30 days, 6 and 12 months after diagnosis. Fifty-two single nucleotide polymorphisms (SNPs) known to be associated with IBD were selected for genotyping based on previous genetic studies. Key messages: A total of 190 IBD patients (97 ulcerative colitis [UC], 87 Crohn's disease [CD], and 6 IBD unclassified) were included. UC patients with extensive disease had higher C-reactive protein, erythrocyte sedimentation rate, and platelet count at diagnosis compared to UC patients with less extensive disease. No similar differences between disease extent groups were found in CD. Low albumin at diagnosis was associated with an increased risk of surgery in both UC (OR 1.35; 95% CI: 1.05-1.75) and CD patients (OR 1.23; 95% CI: 1.01-1.48) and increased use of azathioprine and anti-tumor necrosis factor alpha use in the total IBD cohort (OR 1.15; 95% CI: 1.04-1.27 and OR 1.19 [1.08-1.34]). One SNP (rs4986791 in the TLR-4 locus) and 2 SNPs (rs6785049 in the Pregnane-x-receptor gene and rs10500264 in the SLCA10 gene) were associated with a change in albumin and hemoglobin over time respectively in our IBD cohort. Our study confirms albumin to be a marker of severe disease course. Furthermore, the patient's genotype possibly affects the inflammatory response. Future studies in larger pediatric cohorts are needed to confirm our findings. PMID- 30423581 TI - Microarray Profiling of TGF-beta1-Induced Long Non-Coding RNA Expression Patterns in Human Lung Bronchial Epithelial BEAS-2B Cells. AB - BACKGROUND/AIMS: TGF-beta1 mediated radiation-induced bystander effects (RIBE) have been linked with malignant transformation and tumorigenesis. However, the underlying mechanisms are not fully understood. METHODS: To reveal new molecules of regulatory functions in this process, lncRNA microarray was performed to profile both lncRNA and mRNA expression patterns in human lung bronchial epithelial BEAS-2B cells treated with TGF-beta1 at a concentration measured in the medium conditioned by directly irradiated BEAS-2B cells. The potential functions of the differentially expressed lncRNAs were predicted by GO and KEGG pathway analyses of their co-expressed mRNAs. Cis- and trans-regulation of the lncRNAs were analyzed and the interaction networks were constructed using Cytoscape. qRT-PCR was conducted to validate the results of microarray profiling. CCK-8 assay was employed for functional validation of 3 identified lncRNAs. RESULTS: 224 lncRNAs were found to be dysregulated, among which 6 lncRNAs were chosen for expression validation by qRT-PCR assay. Pathway analyses showed that differentially expressed lncRNAs are highly correlated with cell proliferation, transformation, migration, etc. Trans-regulation analyses showed that the differentially expressed lncRNAs most likely participate in the pathways regulated by four transcriptional factors, FOS, STAT3, RAD21 and E2F1, which have been identified to be involved in the modulation of oncogenic transformation, cell cycle progression, genomic instability, etc. lnc-THEMIS-2 and lnc-ITGB6-4, predicted to be regulated by STAT3 and E2F1 respectively, were found to rescue the decrease of cell viability induced by TGF-beta1 treatment. CONCLUSION: Our findings suggest that the differentially expressed lncRNAs induced by TGF-beta1 play crucial roles in the oncogenic transformation and tumorigenesis, which provide a better understanding of the underlying mechanisms related to tumorigensis induced by LD/LDR radiations. PMID- 30423582 TI - Altered Retinal Nerve Fiber Layer Thickness and Choroid Thickness in Patients with Migraine. AB - BACKGROUND: Migraine is a chronic neurological disorder. However, its pathogenesis is still unclear. This study aimed to measure the posterior ocular structure in patients with migraine using enhanced depth imaging (EDI)-optical coherence tomography (OCT) and explore the probable pathogenesis of migraine. METHODS: A total of 115 patients diagnosed with migraine and 50 healthy volunteers were recruited. These participants underwent an ocular examination to exclude the ocular diseases. Retinal nerve fiber layer thickness, macular thickness, and choroid thickness were assessed using EDI-OCT. RESULTS: The nasal peripapillary retinal nerve fiber layer (pRNFL) was significantly thinner in the migraine with aura group (p = 0.001) than that in the control group. The inferior inner macular layer was thinner in the migraine with aura group (p = 0.005). The 3 subfields of choroid were significantly thinner in the migraine with aura group (p = 0.044, 0.008, and 0.029). However, there was no difference between the migraine without aura group and the control group. The nasal pRNFL in migraine with aura was negatively correlated with the product of duration (months) and number of attacks/month (p = 0.039). CONCLUSION: The changes in the ocular posterior structure may serve as evidence of the trigeminovascular system mechanism underlying migraine and transneuronal retrograde degeneration of the primary visual cortex, which reflects the cortical spreading depression. PMID- 30423583 TI - Novel Zinc Finger Transcription Factor ZFP580 Facilitates All-Trans Retinoic Acid -Induced Vascular Smooth Muscle Cells Differentiation by Raralpha-Mediated PI3K/Akt and ERK Signaling. AB - BACKGROUND/AIMS: Phenotypic switching of vascular smooth muscle cells (VSMC) plays a vital role in the development of vascular diseases. All-trans retinoic acid (ATRA) is known to regulate VSMC phenotypes. However, the underlying mechanisms remain completely unknown. Here, we have investigated the probable roles and underlying mechanisms of the novel C2H2 zinc finger transcription factor ZFP580 on ATRA-induced VSMC differentiation. METHODS: VSMCs were isolated, cultured, and identified. VSMCs were infected with an adenovirus encoding ZFP580 or Ad-siRNA to silence ZFP580. The expression levels of ZFP580, SMalpha-actin, SM22alpha, SMemb, RARalpha, RARbeta, and RARgamma were assayed by Q-PCR and western blot. A rat carotid artery injury model and morphometric analysis of intimal thickening were also used in this study. RESULTS: ATRA caused a significant reduction of VSMC proliferation and migration in a doseand time dependent manner. Moreover, it promoted VSMC differentiation by enhancing expression of differentiation markers and reducing expression of dedifferentiation markers. This ATRA activity was accompanied by up-regulation of ZFP580, with concomitant increases in RARalpha expression. In contrast, silencing of the RARalpha gene or inhibiting RARalpha with its antagonist Ro41-5253 abrogated the ATRA-induced ZFP580 expression. Furthermore, ATRA binding to RARalpha induced ZFP580 expression via the PI3K/Akt and ERK pathways. Adenovirusmediated overexpression of ZFP580 promoted VSMC differentiation by enhancing expression of SM22alpha and SMalpha-actin and reducing expression of SMemb. In contrast, silencing ZFP580 dramatically reduced the expression of differentiation markers and increased expression of dedifferentiation markers. The classic rat carotid artery balloon injury model demonstrated that ZFP580 inhibited proliferation and intimal hyperplasia in vivo. CONCLUSION: The novel zinc finger transcription factor ZFP580 facilitates ATRA-induced VSMC differentiation by the RARalpha-mediated PI3K/Akt and ERK signaling pathways. This might represent a novel mechanism of regulation of ZFP580 by ATRA and RARalpha, which is critical for understanding the biological functions of retinoids during VSMC phenotypic modulation. PMID- 30423584 TI - No Survival Benefit in Octogenarians and Nonagenarians with Extended Hemodialysis Treatment Time. AB - BACKGROUND: The population of elderly end-stage renal disease patients initiating dialysis is rapidly growing. Although longer treatment is supposed to benefit for hemodialysis (HD) patients through more solute clearance and slower fluid removal, it is not yet clear how treatment session length affects mortality risk in octogenarians and nonagenarians. METHODS: In a cohort of 112,026 incident HD patients between 2007 and 2011, we examined the association of treatment session length with all-cause mortality, adjusting for demographics and comorbid conditions. We also used restricted spline functions for age to evaluate continuous changes in the association of short (< 210 min) and extended (>=240 min) HD treatment (vs. 210 to < 240 min) with all-cause mortality over continuous age. RESULTS: During the first 91 days of dialysis, patients aged >=80 years tended to have the lowest treatment session length (median [interquartile range] 211 [193-230] min, r > 0.5). Longer treatment was associated with better survival in patients < 65 and 65 to < 80 years but not in octogenarians/nonagenarians. The association of extended treatment (>=240 min) with better survival was attenuated across age and not significant among patients aged >=80 years with a hazard ratio of 1.10 (95% CI 0.99-1.20). Shorter treatment sessions (< 210 min) was associated with higher mortality across all age groups. CONCLUSION: Extended HD was not associated with lower mortality among octogenarians and nonagenarians, while it was associated with better survival among younger patients. Further studies are needed to determine the optimal treatment session length in elderly incident HD patients. PMID- 30423585 TI - Cerebrospinal Fluid Level of Soluble CD27 Is Associated with Disease Severity in Neuromyelitis Optica Spectrum Disorder. AB - OBJECT: CD27 belongs to the tumor necrosis factor receptor family and is constitutively expressed on T cells. The concentration of cerebrospinal fluid (CSF) soluble (s)CD27 is elevated in patients with multiple sclerosis (MS). However, whether the level of CSF sCD27 is elevated in neuromyelitis optica spectrum disorder (NMOSD) remains unknown. The aim of this study was to measure the CSF concentration of sCD27 and to determine its relationship with NMOSD disease activity. METHODS: CSF CXCL13 was measured by ELISA in neuromyelitis optica (NMO) (n = 31) and MS (n = 23) patients and in controls (CTLs) (n = 22). RESULTS: The concentration of sCD27 was higher in the NMO group than in the MS (p = 0.082) and CTL (p = 0.002) groups, and there was a positive correlation with CSF IL-6 (p = 0.000) and a negative correlation with IL-10 (p = 0.073). In the NMO group, patients with higher sCD27 concentrations exhibited worse disease disability in their CSF (p = 0.006). Moreover, the sCD27 concentrations had a significantly positive correlation with the level of CSF total protein (p = 0.030). Furthermore, the patients positive for AQP4-IgG (n = 26) seemed to have higher levels of sCD27 in their CSF (p = 0.069) than those negative for AQP4-IgG (n = 5). CONCLUSIONS: We revealed that the level of CSF sCD27 was elevated in NMOSD and correlated with NMOSD disease activity. PMID- 30423586 TI - A Review: Mealtime Difficulties following Frontotemporal Lobar Degeneration. AB - BACKGROUND: Frontotemporal lobar degeneration (FTLD) can result in a decline in behavior, language, and motor function. Mealtime disturbances are a common and significant outcome of FTLD. Disturbances during mealtimes can arise from dysphagia or may occur secondary to behavioral changes such as rapid eating, mealtime rigidity, and altered diet preferences. SUMMARY: Few studies have comprehensively evaluated eating behavior or dysphagia in individuals presenting with FTLD pathology despite the potential impact on medical safety and individual quality of life. Dysphagia is reported in the late stages of frontotemporal dementia and early in the motor subtypes of FTLD. The identification of dysphagia can alert individuals and medical teams to disease progression and provide insight into the nature and spread of the underlying neuropathology. Improved understanding of eating behaviors can improve individual care and may enhance diagnostic accuracy. Key Message: Aberrant eating behavior and swallowing difficulties are reported in the conditions associated with FTLD neuropathology. The consequences of mealtime disturbances include health risks associated with an increased BMI and aspiration, reduction of an individual's independence, and an increase in caregiver stress and burden. Here we review and summarize the literature on eating behavior and swallow impairments (dysphagia) in each of the syndromes caused by FTLD. PMID- 30423587 TI - Efficacy and Safety of Botulinum Toxin Type A in Spasticity Caused by Spinal Cord Injury: A Randomized, Controlled Trial. AB - BACKGROUND Baclofen is approved by the US FDA to treat spasticity, but its sustained use may cause drug addiction. The objective of this study was to compare the efficacy and safety of botulinum toxin type A versus baclofen in spasticity. MATERIAL AND METHODS A total of 336 patients who had spasticity caused by spinal cord injury were enrolled in a randomized (in 1: 1: 1: ratio) for placebo, controlled trial. Patients had received baclofen (BA group, n=112), local intramuscular injection of 500 U Botulinum toxin type A (BTI group, n=112), or physical therapies alone (placebo group, n=112). Modified Ashworth scale (mAS) score, disability assessment scale (DAS) score, modified medical research council (mMRC) score, the Barthel Index (BI) score, and treatment-emergent adverse effects were evaluated during the follow-up period. Wilcoxon test or one-way ANOVA/Tukey post hoc tests were performed at 95% of confidence level. RESULTS Baclofen (1.504+/-0.045 vs. 1.53+/-0.06, p=0.003, q=4.068) and botulinum toxin type A (1.49+/-0.09 vs. 1.528+/-0.15, p=0.0224, q=3.5541) had improved mAS scores after 2 weeks. Baclofen had a more strongly improved DAS score than botulinum toxin type A at 4 (p=0.0496, q=3.48) and 6 (p<0.0001, q=6.48) weeks. Baclofen and botulinum toxin type A had consistently improved BI scores. Baclofen caused asthenia and sleepiness, while botulinum toxin type A caused bronchitis and elevated blood pressure. CONCLUSIONS Botulinum toxin type A may be an effective therapeutic option for spasticity caused by spinal cord injury. PMID- 30423589 TI - Fetal Abdominal Aorta: Doppler and Structural Evaluation of Endothelial Function in Intrauterine Growth Restriction and Controls. PMID- 30423588 TI - Illumina sequencing analysis of the ruminal microbiota in high-yield and low yield lactating dairy cows. AB - In this study, differences in the ruminal bacterial community between high-yield and low-yield lactating dairy cows under the same dietary conditions were investigated. Sixteen lactating dairy cows with similar parity and days in milk were divided into high-yield (HY) and low-yield (LY) groups based on their milk yield. On day 21, rumen content samples were collected, and their microbiota compositions were determined using high-throughput sequencing of the 16S rRNA gene by the Illumina MiSeq platform. During the study period, dry matter intake (DMI) and milk yield were measured daily, and milk composition was assessed 3 times per week. The results showed that the milk of the LY group tended to have higher fat (P = 0.08), protein (P = 0.01) and total solid contents (P = 0.04) than that of the HY group, while the HY group had higher ruminal propionate (P = 0.08) proportion and volatile fatty acid (VFA) (P = 0.02) concentrations. Principal coordinate analysis indicated significant differences in ruminal bacterial community compositions and structures between the HY group and LY group. The abundances of Ruminococcus 2, Lachnospiraceae and Eubacterium coprostanoligenes were significantly higher in the HY group than in the LY group. In addition, Bacteroides, Ruminococcus 2 and Candidatus-Saccharimonas were positively correlated with ruminal propionate proportion (r>0.4, P<0.05). These findings enhance the understanding of bacterial synthesis within the rumen and reveal an important mechanism underlying differences in milk production in dairy cows. PMID- 30423590 TI - A Retrospective Comparative Study of Different Methods of Blood Management in Total Knee Replacement. AB - Perioperative blood management is essential to minimize allogeneic blood transfusion in total knee replacement. The effect of preoperative administration of erythropoietin, intraoperative cell saver, tranexamic acid, and restrictive transfusion strategies on allogeneic transfusion is studied in total knee replacement. A retrospective comparative study of 106 patients who underwent total knee replacement in different time periods was performed. Group A (n 1 = 45) underwent restrictive strategies of transfusion between 2009 and 2010. Group B (n 2 = 24) includes patients where erythropoietin of either 10.000 IU or 20.000 IU was given preoperatively. Patients of Group C (n 3 = 21) underwent autologous washed erythrocytes transfusion through a cell saver. Lastly, in Group D (n 4 = 15) tranexamic acid dose of 1 gr IV was given intraoperatively. The preoperative and discharge hemoglobin together with total units of blood transfusion and creatinine levels was studied. Tranexamic acid noted the least units of blood transfusion (mean = 0.82 units/patient, p < 0.001, CI 95%) in contrast to the two regimens of erythropoietin (1.16 units/patient) OrthoPAT (1.43 units/patient) and restrictive strategies (1.92 units/patient). The mean preoperative hemoglobin was 13.37 g/dL with no statistical difference among the groups of patients. The postoperative mean hemoglobin was 10.59 with no statistical difference among the groups of patients too. Additionally, the mean creatinine level was 0.93 mg/dL; however, no statistical difference among the groups of patients was noted. Finally, tranexamic acid seemed to be the most cost-effective regime. In our study, tranexamic acid proved its superiority concerning the postoperative blood transfusion on patients undergoing total knee replacement, in comparison with the other existing methods of perioperative blood management. This is a Level III, retrospective comparative study. PMID- 30423591 TI - The Use of Platelet-Rich Plasma in Symptomatic Knee Osteoarthritis. AB - With average life expectancy and the rising prevalence of obesity, osteoarthritis (OA) is creating an increasingly large financial and physical burden on the U.S. population today. As the body ages and experiences trauma, articular cartilage surfaces in joints are gradually worn away, leading to OA. Traditionally, treatment options have included lifestyle modifications, pain management, and corticosteroid injections, with joint replacement reserved for those who have exhausted nonsurgical measures. More recently, hyaluronic acid, micronized dehydrated human amniotic/chorionic membrane tissue, and platelet-rich plasma (PRP) injections have started to gain traction. PRP has been shown to have both anti-inflammatory effects through growth factors such as transforming growth factor-beta and insulin-like growth factor 1, and stimulatory effects on mesenchymal stem cells and fibroblasts. Multiple studies have indicated that PRP is superior to hyaluronic acid and corticosteroids in terms of improving patient reported pain and functionality scores. Unfortunately, there are many variations in PRP preparation, and lack of standardization in factors, such as speed and duration of centrifugation, leads to wide ranges of platelet and leukocyte concentrations. This review examines the current literature addressing the use of PRP in symptomatic knee OA and addresses suggestions for future studies in this area. PMID- 30423592 TI - [Muscle Cramps: Superficial Knowledge Versus Evidence]. AB - BACKGROUND: Muscle cramps are common in the population, especially in athletes. However, various ideas exist as to how to treat cramps. OBJECTIVE: The aim of this investigation is to compare and contrast the common conceptions with the results of evidence-based studies. METHOD: Scientific literature research. RESULTS: The knowledge of the population seems insufficient and does not reflect the current scientific evidence. CONCLUSION: It is necessary to spread current scientific knowledge among the population, especially via coaches and doctors acting as multipliers. PMID- 30423594 TI - ? PMID- 30423595 TI - [Neurointensive Care: Aneurysmal Subarachnoid Hemorrhage - State of the Art]. AB - The aneurysmal subarachnoid hemorrhage is a life threatening disorder associated with high morbidity and mortality. Identification and treatment of the bleeding source is mandatory within the first 24 hours to prevent rebleeding. Patients suffering from subarachnoid hemorrhage should be managed on an intensive care unit experienced in the treatment of this condition. Most frequent complications in the clinical course are hydrocephalus, requiring temporary or permanent shunting, and delayed cerebral ischemia. Consequent monitoring of the patients including transcranial doppler sonography and undelayed treatment of complications can improve the outcome of the patient substantially. Longterm neuropsychological sequelae may hamper the patient and thwart his reconstitution, thus requiring psychological intervention. PMID- 30423593 TI - Performance measures for endoscopy services: a European Society of Gastrointestinal Endoscopy (ESGE) Quality Improvement Initiative. AB - The European Society of Gastrointestinal Endoscopy (ESGE) and United European Gastroenterology present a list of key performance measures for endoscopy services. We recommend that these performance measures be adopted by all endoscopy services across Europe. The measures include those related to the leadership, organization, and delivery of the service, as well as those associated with the patient journey. Each measure includes a recommendation for a minimum and target standard for endoscopy services to achieve. We recommend that all stakeholders in endoscopy take note of these ESGE endoscopy services performance measures to accelerate their adoption and implementation. Stakeholders include patients and their advocacy groups; service leaders; staff, including endoscopists; professional societies; payers; and regulators. PMID- 30423596 TI - [Pain Therapy Aspects in Tumour Surgery]. AB - Due to preexisting pain or surgically induced sensitization patients undergoing oncological surgery are predisposed for a postoperative high pain intensity with the risk of developing persistent pain. In oncological surgery, pain therapy should be adapted to the underlying pain mechanism. Different treatment principles should be applied in a graded concept of acute pain therapy. The rationale implies the "conventional" use of the WHO step scheme, the administration of opioids as PCA as well as regional analgesia and agents with anti-hypersensitizing properties. Anti-hypersensitizing and anti-neuropathic treatment principles may include the use of antidepressants, anticonvulsants, intravenous lidocaine and s-ketamine. Before using such treatment, pain mechanisms should be verified by an adequate pain diagnostic. The impact of perioperative regional analgesia on the oncological outcome is subject to controversy. Opioids reveal both: tumor promoting and tumor inhibiting properties. PMID- 30423597 TI - [Traumatic Injuries of the Central Nervous System]. AB - The term "traumatic injuries of the central nervous system" (CNS) refers to both traumatic brain injury (TBI) as well as traumatic spinal cord injury (SCI). Both types of injuries substantially contribute to morbidity and mortality in developed as well as developing countries. The underlying pathophysiological processes are very complex and despite extensive research efforts they are still not completely understood. Therefore, traumatic injuries to the CNS pose special challenges for preclinical and clinical management. Thus, in order to treat these conditions effectively an interdisciplinary treatment approach consisting of intensive conservative as well as operative treatment options in specialized centers experienced in the treatment of patients with traumatic injuries of the CNS is necessary. This review summarizes the epidemiology, pathophysiology, diagnostic approaches as well as current preclinical and clinical treatment options based on current guidelines and literature. Finally, the prognosis for both conditions is outlined. PMID- 30423598 TI - [Multimodal Neuromonitoring and its Impact on Therapeutic and Diagnostic Decisions in Critical Ill Patients]. AB - Patients with acute cerebral injuries for various reasons (traumatic, ischemic, hemorrhagic) are at risc for developing secondary brain damage and further neurological deterioration. The aim of neuromonitoring is to recognize subtile changes in intracranial physiology as early as possible to initiate adequate diagnostic and therapeutic measures to prevent secondary brain damage. Beside the classic method of clinical neuromonitoring in awake patients, implantation of intracranial probes to monitor intracranial pressure, brain tissue oxygenation and brain metabolism are used in comatose patients. Electrophysiological monitoring by electrocorticography or evoked potentials and measurement of cerebral blood flow provide additional information.The indications and clinical impact of these various monitoring techniques are discussed to ensure optimal medical care in patients with acute brain injury. PMID- 30423599 TI - [A Process-Oriented Approach at Current Recommendations for Obstetric Anesthesia and Postoperative Monitoring After C-Section]. AB - The known guidelines before a planned operation on aspiration, fasting and preoperative risk evaluation also apply in obstetrics. Extended measures are only justified under concrete anamnestic or specific symptoms. Neuraxial anesthesia techniques should be offered to the mother as early as possible, as waiting for a certain opening of the cervix is not justified. Catheter procedures offer numerous advantages and are useful for possible emergency situations. Low-dose local anesthetic concentrations in combination with an opioid are still recommended. The benefit of pencil-point spinal needles in minimizing the risk of post-puncture headache has been demonstrated. Predictable emergencies are airway emergencies, hemorrhagic emergencies and cardiopulmonary resuscitation with emergency cesarean if appropriate (> 20 SSW). PMID- 30423600 TI - [Metabolic Acidosis under Acetaminophen Intake - an Unordinary Side Effect]. AB - Metabolic acidosis is common among hospitalized patients. However, in a few cases a long-term administration of acetaminophen can lead to transient 5-oxoproline accumulation and causes metabolic acidosis with high anion gap in adults. A 73 year-old man was hospitalized with Staph. aureus sepsis after right knee prosthesis infection and received analgesic treatment with acetaminophen 2 g/d and antibiotic therapy with flucloxacillin over several weeks. The patient had a protracted course of illness and was transferred to intensive care unit with progressing vigilance reduction and for metabolic acidosis with high anion gap. Further medical investigation confirmed an increased concentration of 5 oxoproline in urine. A change in antibiotic treatment, interruption of acetaminophen and administration of acetylcysteine lead to a normalization of the acid-base balance. In a patient with metabolic acidosis under acetaminophen administration, particularly in the context of sepsis, malnutrition, liver and kidney diseases as well as antibiotic treatment with flucloxacillin an accumulation of 5-oxoproline must be considered. The treatment with acetaminophen must be interrupted and acetylcysteine should be administered. PMID- 30423601 TI - Evaluating the integration of a pregnancy weight gain chart into routine antenatal care: a mixed method study design. AB - Monitoring pregnancy weight can reduce excess gestational weight gain (GWG), and is recommended in clinical practice guidelines as part of routine care. This study aimed to evaluate the implementation of routine weight monitoring using a pregnancy weight gain chart (PWGC), and assess Healthcare Professionals (HCPs) attitudes and practices around its use. A semi-quantitative survey was conducted with a consecutive sample of antenatal women at 16 and 36 weeks gestation. Women were weighed and a PWGC audit done at 36 weeks gestation to assess adherence to chart use and GWG. A cross-sectional survey of antenatal HCPs at the Australian facility assessed staff attitudes and practices relating to weight monitoring and PWGC use. Of the 291 women surveyed, 68% reported being given a PWGC. Of the audited PWGCs (n=258), 54% had less than three weights recorded, 36% had errors and 3% were unused. All HCPs surveyed (n=42) were aware of the PWGC, 63% reported using it to track GWG regularly, and 26% believed it to be only the woman's responsibility (i.e. not the midwives role) to complete it. Seventy-seven percent reported they needed more training in counselling pregnant women, and insufficient time was a main barrier to weighing and conversing with women. It is feasible to implement a PWGC into routine antenatal care. Clarity over women's and HCPs responsibility for monitoring GWG and completion of the PWGC is needed. Training on correct PWGC use and counselling, and workforce engagement are required to overcome barriers and support healthy GWG. PMID- 30423603 TI - [Pathological diagnosis on newly recognized rare tumors or diseases in childhood]. PMID- 30423602 TI - Porphyromonas gingivalis induces the production of interleukin-31 by human mast cells, resulting in dysfunction of the gingival epithelial barrier. AB - Interleukin (IL)-31 is important for innate immunity in mucosal tissues and skin, and increased IL-31 expression participates in the pathogenesis of chronic inflammatory diseases affecting the skin, airways, lungs, and intestines. We investigated the contribution of mast cells to the induction of IL-31 production following infection with the periodontal pathogen, Porphyromonas gingivalis. We found that oral infection with P. gingivalis increased IL-31 expression in the gingival tissues of wild-type mice but not in those of mast cell-deficient mice. The P. gingivalis-induced IL-31 production by human mast cells occurred through the activation of the JNK and NF-kappaB signalling pathways and was dependent on the P. gingivalis lysine-specific protease gingipain-K. P. gingivalis infection induced IL-31 receptor alpha and oncostatin M receptor beta expression in human gingival epithelial cells. Notably, the P. gingivalis-induced IL-31 production by mast cells led to the downregulation of claudin-1, a tight junction molecule, in gingival epithelial cells, resulting in an IL-31-dependent increase in the paracellular permeability of the gingival epithelial barrier. These findings suggest that IL-31 produced by mast cells in response to P. gingivalis infection causes gingival epithelial barrier dysfunction, which may contribute to the chronic inflammation observed in periodontitis. PMID- 30423604 TI - [HER2 status in gastric adenocarcinoma of Chinese: a multicenter study of 40 842 patients]. AB - Objective: To investigation HER2 status in gastric adenocarcinoma of Chinese and contributing factors to the HER2 expression. Methods: HER2 status of 40 842 gastric adenocarcinomas and clinical data were retrospectively collected from 23 hospitals dated from 2013 to 2016. The association between HER2 positivity and clinicopathologic features was analyzed. Results: Of the 40 842 patients the median age was 62 years, the male female ratio was 2.6?1.0. The rate of HER2 positivity was 8.8% (3 577/40 842). HER2 expression was related to the tissue type, tumor location, Lauren classification and tumor differentiation (P values: 0.009, 0.001, <0.01 and <0.01, respectively). Different HER2 expression status was observed between primary and recurrent tumors in 7.6% (48/635) cases. The rates of HER2 positivity ranged from 2% to 10% among different institutions. The rates of HER2 FISH amplification were dramatically different among the 23 hospitals (0-100%) with an average rate of 10% (810/8 156) in patients with HER2 IHC 2+ . Conclusions: HER2 expression is associated with clinicopathologic characteristics. HER2 re-assessment of tumor tissue and use of in situ hybridization techniques increase HER2 positivity. The current retrospective study should reflect the HER2 status in gastric adenocarcinoma of Chinese patients. PMID- 30423605 TI - [Correlation between mismatch-repair protein expression and clinicopathologic features in 658 colorectal cancers]. AB - Objective: To investigate the expression of mismatch repair (MMR) proteins (MLH1, MSH2, MSH6 and PMS2) in colorectal cancers and to explore the relationship between MMR expression and clinicopathologic features. Methods: Six hundred and fifty-eight colon cancers were collected from January 2016 to January 2017 at Shengjing Hospital of China Medical University. Of the 658 patients there were 409 male and 249 female. The patients were 20 to 92 years old, with average age of (63+/-5) years old. Expression of MLH1, MSH2, MSH6 and PMS2 protein was detected by immunohistochemical method. Immunohistochemistry for BRAF V600E was performed in colorectal cancers with loss of MLH1 protein expression. Relationship between MMR protein expression and clinicopathologic features was analyzed statistically. Results: Forty-four cases of 658 cases (6.7%) lost at least one MMR protein expression. Expression deficiency rates of MLH1, MSH2, MSH6 and PMS2 were 4.1%(27/658), 2.3%(15/658), 2.4% (16/658), and 4.3% (28/658), respectively. MMR expression deficiency mainly consisted of combined loss of MLH1/PMS2 (61.4%, 27/44) and MSH2/MSH6 (34.1%, 15/44). Two unique mutations were identified including one MSH6-deficient(2.3%, 1/44) and PMS2-deficient(2.3%, 1/44). Seven cases (25.9%, 7/27) had positive BRAF V600E expression, suggesting BRAF gene mutation related sporadic colorectal cancers. No correlation was observed between the expression of MMR and depth of tumor infiltration, lymph node metastasis, vascular tumor emboli, clinical stage or hematogenous metastasis (P>0.05). MMR status was associated with tumor cell differentiation, histological type and tumor location (P<0.01). Tumors with combined MLH1 and PMS2 loss were associated with mucinous differentiation (P=0.049, P=0.013) and located in the right hemi-colon (P=0.006, P=0.002). Combined MSH2 and PMS2 loss was related to gender, while loss of MSH2 protein was observed more frequently in female patients (P=0.048) and loss of PMS2 protein was seen more frequently in male patients (P=0.031). Conclusions: Patients with MMR protein deficiency have a younger onset age and poorly differentiated tumors. Most tumors are located in the right hemi-colon and have mucinous differentiation. PMID- 30423606 TI - [Expression of cytokeratin(CK)7, CK8/18, CK19 and p40 in esophageal squamous cell carcinoma and their correlation with prognosis]. AB - Objective: To evaluate the expression of cytokeratin (CK)7, CK8/18, CK19 and p40 in esophageal squamous cell carcinoma (ESCC) and its significances. Methods: One hundred and ninety cases of surgically resected ESCCs and 154 normal esophageal tissues as control were collected at the First Affiliated Hospital of Zhengzhou University in 2012.Of the 190 ESCC cases including 116 male and 74 female, aged 28-82 (60.3+/-8.6) years, 88 cases <60 years old and 102 cases >=60 years old. Tissue sections were immunostained for CK7, CK8/18, CK19 and p40, and the expression was evaluated and correlated with the clinicopathologic findings and outcome. Results: CK19 and p40 were expressed in 190 cases of ESCCs; with 147 cases (77.4%) and 151 cases (79.5%) showing high p40 and CK19 expression, respectively; while 43 cases (22.6%) and 39 cases (20.5%) showed low p40 and CK19 expression, respectively. The low expression groups showed more lymph node metastases and higher pTNM stages compared to the high expression groups. The high CK19 expression group showed better prognosis than the low expression group (P<0.01); p40 expression was not correlated with prognosis(P>0.05). In contrast, CK7 and CK8/18 expression was only seen in 29 cases (15.3%) and 59 cases (31.1%) of ESCCs, respectively, and their expression correlated significantly with the degree of tumor differentiation and lymph node metastasis (P<0.05). The prognosis in the CK7 negative group was better than that in the CK7 positive group. Similar results were found in CK8/18 expression. Multivariate analysis revealed that pTNM stages, low CK19 expression and CK8/18 expression were independent prognostic factors. Conclusions: Low p40 expression and the expression of CK7 and CK8/18 cannot exclude poorly-differentiated ESCCs.CK7 and CK8/18 expression and low CK19 and p40 expression in the ESCCs are associated with lymph node metastasis and poor prognosis. Decreased expression of CK19 and positive expression of CK8/18 in ESCCs are independent prognostic markers. PMID- 30423607 TI - [Consistency of PD-L1 immunohistochemical detection platforms in biopsy samples with advanced lung adenocarcinoma: a multicenter study]. AB - Objective: To analyze the expression of programmed death ligand 1 (PD-L1) in patients with advanced lung adenocarcinoma and the consistency of four PD-L1 immunohistochemical detection platforms, with an aim of establishing baseline information to predict and select patients for programmed death 1 (PD-1)/PD-L1 immune inhibitor therapy. Methods: This was a multi-center retrospective study, collecting totally 57 advanced lung adenocarcinoma biopsy specimens from four centers from August 2017 to December 2017.The mean age of 57 patients was 59 (range 34-81) years, and 29 cases were male, 28 cases were female. Four PD-L1 immunohistochemical stains were done for each case, including 22C3 (Dako), 28-8 (Abcam), SP263 (Ventana), and SP142 (Ventana). Among them, 22C3 staining was done using Dako autostainer, and for the other three antibodies, Ventana Ultraview detection system and autostainer was used. The immunohistochemical slides were read by two trained histopathologists in a double-blinded way, and the percentage of PD-L1 positive tumor cells was assessed as <1%, 1%-24%, 25%-49% and more than 50%. Results: The Dako 22C3 was used as the standard. There were eight cases in which the PD-L1 staining was more than 50% (14.0%, 8/57). The staining consistency of tumor cells was higher in 22C3, 28-8 and SP263 (rho=0.729-0.809). The two scoring doctors had a high degree of concordance in PD-L1 positive tumor cells (rho=0.707-0.896), and this was most noticeable in 22C3 and SP263. Conclusions: 22C3, 28-8 and SP263 show high consistency in tumor cell staining. The study can provide an effective basis for screening for potential patient population that may benefit from immunotherapy. PMID- 30423608 TI - [Synchronous mucinous metaplasia and neoplasia of the female genital tract]. AB - Objective: To describe the clinicopathological features of synchronous mucinous metaplasia and neoplasia of the female genital tract (SMMN-FGT). Methods: The sample consisted of 7 cases of SMMN-FGT recorded from November 2014 to September 2017 at Obstetrics and Gynecology Hospital, Fudan University.PAP method was used in immunohistochemistry.Clinical histories were retrieved and pathological slides were reviewed. Results: The patients were 37 to 70 years old(mean 54 years old). All patients showed endometrial mucinous lesions associated with cervical lesions. Three cases were an admixture of minimal deviation adenocarcinoma(MDA) and gastrictype adenocarcinoma(GAS). Three cases were an admixture of lobular endocervical glandular hyperplasia (LEGH), atypical LEGH and focal gastrictype adenocarcinoma in situ, one of which had early invasive gastrictype adenocarcinoma.Endometrium showed a structure of LEGH in one patient with focal simple gastric mucinous metaplasia in her cervix. Gastric mucinous differentiation was found in unilateral fallopian tube in 6 patients. Ovarian mucinous lesions were found in 3 patients. p16 was negative staining in 6 cases and positive in 1 case. CK7 was diffusely positive in all lesions. CK20 and CDX2 were negative or only focally positive.The expression of MUC6 was strongly positive staining or focal staining. p53 in GAS and GAS in situ had mutant expression, but wild expression in MDA region. Patients were followed up for 2 to 34 months and no recurrence was found. Conclusions: SMMN-FGT is a series of rare mucinous lesions involving multiple areas of the female genital tract, including benign or malignant lesions with gastric differentiation. It is not related to infection with high-risk human papilloma virus. When cervical gastrictype lesions are found, SMMN-FGT should be considered and should be differentiated from metastatic mucinous adenocarcinoma. PMID- 30423609 TI - [Clinicopathologic features of primary renal neuroendocrine carcinoma]. AB - Objective: To investigate the clinicopathologic characteristics, diagnostic features and prognosis of primary renal neuroendocrine carcinoma (NEC). Methods: The clinicopathologic data of eight cases of renal NEC was collected from January 2008 to December 2017 from Affiliated Hospital of Qingdao University. Immunohistochemical staining was performed, and follow-up information was analyzed, and the relevant literature reviewed. Results: The patients' mean age at diagnosis was 45 years (range, 27-66 years); five were women, and three were men. The tumors located on the left side in five patients, and on the right side in three. Five cases were detected incidentally, and three patients presented with loin pain. Microscopically, these cases included five well-differentiated NECs (three carcinoids, two atypical carcinoids), two small cell NECs, and one large cell NEC according to the World Health Organization classification of 2016. The tumors infiltrated the renal capsule in six cases. Necrosis was found in five cases. Vascular invasion with tumor emboli was seen in three cases. Lymph node metastasis was identified in one case. Immunohistochemically, the expression rates of neuroendocrine markers CD56, chromogranin A (CgA) and synaptophysin (Syn) were 6/8, 4/8, and 8/8 respectively. Some of the NECs were positive for epithelial markers CKpan (6/8, with three cases showing focal positivity) and CAM5.2 (4/8) of variable degrees. The Ki-67 proliferation index was<=3% in the carcinoids; >=50% in the small cell carcinoma and large cell carcinoma; and 5% and 8% for the two cases of atypical carcinoid, respectively. All cases were negative for EMA, CK7, CA9, CD10, CD117, PAX2, PAX8, WT1, p63, S-100 and TTF1. Three patients (two with small cell carcinoma and one with large cell carcinoma) died of extensive metastases at 3 months, 4 months and 9 months after operation, while five patients were well, without recurrence or distant metastasis for follow-up period of one to nine years. Conclusions: Primary renal NEC is rare. Carcinoid is the most common histological type. The pathomorphological features and neuroendocrine markers (CD56, CgA, Syn), epithelial markers (CKpan, CAM5.2) and nephrogenic markers (PAX2, PAX8) are important for the diagnosis. Renal carcinoid tumors are indolent and prone to early metastasis, but are associated with prolonged survival. The small cell renal cell carcinoma and large cell carcinoma are highly malignant renal tumors with poor prognosis and short survival. PMID- 30423610 TI - [Clinicpathologic studies of cases with tracheobronchopathia osteochondroplastica]. PMID- 30423611 TI - [Effects of immunohistochemical staining in the suspicious malignancy cell blocks]. PMID- 30423612 TI - [Primary cutaneous marginal zone B cell lymphoma: a clinicopathologic study of 11 cases]. PMID- 30423613 TI - [Cytological pathological diagnosis of T lymphoblastic lymphoma:a clinicopathologic analysis]. PMID- 30423615 TI - [Effects of waxing time on the quality of fatty tissue preparation]. PMID- 30423614 TI - [Key points of standardized procedure for making Gastrointestinal biopsy and early Gastrointestinal tumor specimens]. PMID- 30423616 TI - [Gliosarcoma with multi-directional differentiation: report of a case]. PMID- 30423617 TI - [Primary desmoplastic medulloblastoma of the ovary: report of a case]. PMID- 30423618 TI - [Urine cytological diagnosis of embryonic rhabdomyosarcoma: report of a case]. PMID- 30423619 TI - [Nodular fasciitis of the tongue: report of a case]. PMID- 30423621 TI - [Pathological diagnosis of hysterectomy for postpartum hemorrhage]. PMID- 30423620 TI - [With abundant myxoid matrix of invasive bladder urothelial carcinoma:report of a case]. PMID- 30423622 TI - [Research progress of mismatch repair deficiency/microstatellites instability status and immune checkpoint inhibitors in colorectal cancer]. PMID- 30423623 TI - [Detection of PD-L1 expression in non-small cell lung cancer: current status]. PMID- 30423624 TI - [Research progress on the role and relationship of MUC1/EMA and sLex in tumor metastasis]. PMID- 30423625 TI - [Molecular mechanisms of resistance to tyrosine kinas inhibitors in renal cell carcinoma]. PMID- 30423626 TI - [Diagnostic value of serum cardiac biomarkers for right ventricular dysfunction in non-high-risk patients with acute pulmonary thromboembolism]. AB - Objective: To investigate the diagnostic value of N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin I (TnI) for detecting right ventricular dysfunction (RVD) in patients with non-high-risk acute pulmonary thromboembolism (APE). Methods: A retrospective analysis was performed in 96 adult patients [44 males, 52 females, aged (61+/-14) years] with non-high-risk APE from January 2015 to June 2016. All patients were divided into RVD group and non-RVD group according to whether there was right ventricular enlargement on echocardiography. The baseline data, serumTnI and NT-proBNP levels were compared between the 2 groups and the diagnostic value of the 2 cardiac markers for RVD was analyzed. Results: There were no significant differences in age, gender, body mass index between the 2 groups (P>0.05). The creatinine clearance rate of the RVD group was lower than that of the non-RVD group [96.4 (77.5,99.6) vs 101.7 (95.1,106.5), P=0.021]. NT-proBNP [2 300 (1 056,3 396) vs 188 (61,535), P<0.01] and TnI [0.13 (0.09,0.25) vs 0.00 (0.00,0.02), P<0.01] were significant higher in the RVD group than in the non-RVD group. The univariate logistic regression analyses showed that NT-proBNP (per 100 ng/L, OR 1.199, 95%CI 1.117-1.287), TnI (per 0.01 MUg/L, OR 1.164, 95%CI 1.079-1.256) and creatinine clearance rate (OR 0.968, 95% CI 0.938-0.998) were significantly associated with RVD. Multivariate regression analysis showed that NT-proBNP (per 100 ng/L, OR 1.155, 95%CI 1.074 1.241) and TnI (per 0.01 MUg/L, OR 1.079, 95% CI 1.011-1.151) were independently associated with RVD. The areas under the ROC curve (AUC) of NT-proBNP, TnI, and the combination of them were 0.908 (95% CI 0.841-0.976), 0.896 (95% CI 0.826 0.966) and 0.925 (95% CI 0.862-0.988), respectively. The cut-off value of NT proBNP was 503.5 ng/L, with a sensitivity of 85.7%, specificity of 75.4%, positive predictive value (PPV) of 66.7% and negative predictive value (NPV) of 90.2%.The cut-off value of TnI was 0.05 MUg/L, and the sensitivity, specificity, PPV and NPV was 80.0%, 86.9%, 77.8% and 88.3%, respectively. The optimal probability derived from the logistic regression model in which the 2 biomarkers were the independent variables was 0.779, with a sensitivity, specificity, PPV and NPV of 65.7%, 96.7%, 92.0%, 83.1%, respectively. Conclusion: Both NT-proBNP and TnI had preferably good diagnostic value for RVD in patients with non-high risk APE, but their clinical application needed comprehensive evaluation combined with the overall manifestations of the patients and experimental methods. The diagnostic value was higher when the 2 biomarkers were evaluated together. PMID- 30423627 TI - [Measurement of rifampicin concentrations in tuberculous pleural effusion before and after combination treatment with oral and local rifampicin]. AB - Objective: To investigate the changes of rifampin concentrations in pleural effusion before and after combination treatment with oral and pleural administration of rifampicin by electro-phonophoresis(EP). Methods: A self control study was performed in 32 cases of tuberculous pleurisy treated in the Second Department of Respiratory Medicine of Affiliated Hospital of Zunyi Medical College between September 2016 and January 2018. Based on the weight of each patient, an oral administration of isoniazid (0.3-0.4 g/d), rifampicin (0.45-0.60 g/d),ethambutol(0.75 g/d),and pyrazinamide (1.0-1.5 g/d) were given. After a 5 day traditional anti-tuberculosis treatment, an additional EP treatment was applied by penetrating chest wall to deliver 3 ml of rifampicin. The concentration of rifampicin in 5 ml pleural effusion was measured at 0, 0.5, 1, 2, 4 and 8h after applying EP treatment using high performance liquid chromatography. The measurement data were analyzed by using statistic software SPSS 20.0. The results were expressed by x+/-s and t test was conducted, with a statistical significance of P<0.05. Results: The average concentration of rifampicin in pleural effusion was (2.2+/-1.1) MUg/ml by oral rifampicin alone. The concentration of rifampicin was (2.7+/-1.1) MUg/ml, (3.0+/-1.4) MUg/ml, (3.2+/-1.2) MUg/ml, (2.8+/-1.2) MUg/ml and (1.3+/-1.1) MUg/ml, respectively, at 0.5 h, 1, 2, 4, 8 h after combining local EP treatment. The results indicated that combining local EP treatment significantly increased the drug concentration in pleural effusion, which lasted for about 5 hours. Conclusions: By applying rifampicin into pleural cavity through EP treatment with penetration of the chest wall, the concentration of rifampicin in pleural effusion of patients with tuberculous pleurisy could be increased. Combined with oral administration of rifampicin, this treatment could prolong the effective drug concentration in pleural effusion, which was beneficial to the bactericidal effects of rifampicin. PMID- 30423628 TI - [Efficacy and safety of cryotherapy combined with balloon dilatation through electronic bronchoscope in the management of airway occlusion caused by scar stenosis type of tracheobronchial tuberculosis]. AB - Objective: To investigate the efficacy and safety of cryotherapy combined with balloon dilatation through electronic bronchoscope in the management of airway occlusion caused by scar stenosis type of tracheobronchial tuberculosis (TBTB). Methods: From December 2008 to May 2016, 98 cases of airway occlusion caused by scar stenosis of TBTB were diagnosed by microbiology, histopathology, CT (computer tomography), bronchial reconstructions and bronchoscopy. All patients underwent routine anti-tuberculosis chemotherapy and cryotherapy through bronchoscope. The patients whose airways were reopened successfully received balloon dilatation through bronchoscope subsequently. The treatment effects were estimated by indexes including clinical efficacy, modified medical research council (mMRC) dyspnea scale and complications. Results: Among the 98 patients, airway occlusion in 87 cases were reopened successfully by cryotherapy for (10+/ 4) times, and then these patients received balloon dilatation through bronchoscope for (7+/-3) times subsequently. The total effective rates were 76.53% and 72.45% after 3 and 12 months after the treatments respectively. Analysis of the disease courses of patients with different therapeutic efficacy showed that the median disease course was 3 months in healed cases, 5 months in effective cases and 9 months in ineffective cases. There was a significant difference between the ineffective and the total effective cases in disease courses (t=-15.012, P<0.01). The average of mMRC score changed from (3.8+/-0.5) before the procedure, to (1.1+/-0.7), (1.2+/-0.7) and (1.2+/-0.7) immediately, 3 and 12 months after the treatments. The difference was significant between the scores before and after therapy (t=30.398-31.058, P<0.01), but not among the 3 scores after treatments. No serious complications were observed in all cases. Conclusions: Cryotherapy combined with balloon dilatation through electronic bronchoscope was a very safe and effective method in the management of airway occlusion caused by scar stenosis of tracheobronchial tuberculosis. A shorter course of disease indicated more benefits for patients. PMID- 30423629 TI - [Clinical characteristics and prognosis of overweight and obese patients with pulmonary thromboembolism]. AB - Objective: To investigate the clinical characteristics and outcomes of overweight and obese patients with pulmonary embolism. Methods: This was a retrospective study of patients with pulmonary thromboembolism(PTE) in Beijing Hospital between 2009 and 2017. Data were analyzed and compared based on body mass index (BMI), and patients were classified into normal weight, overweight, and obese. Results: Among 372 patients with PTE, 159 were normal, 143 were overweight and 70 were obese. The mean age was (67.8+/-13.4) years, and 159(47.0%) were males. There was no significant difference in age, sex, smoking ratio, and underlying disease between the 3 groups (all P>0.05). Chest pain was less frequent in the obese group than the overweight group (P<0.05), and swollen of lower limbs was more prevalent in the obese group than the first 2 groups (all P<0.05). The levels of hemoglobin and hematocrit in the obese group were significantly higher than those in the normal group(P<0.05), while the serum uric acid levels were significantly higher than that in the normal group (P<0.05). Anticoagulation was more frequent in the overweight than the normal group(P<0.05) and Warfarin use was more frequent in the overweight and the obese than the normal group(both P<0.05). The mortality rate was higher in the normal group than those in the overweight and the obese groups (both P<0.01). Multiple logistic regression analysis after adjusting for age and sex showed that malignancy (OR=3.716, 95%CI: 1.733-7.972, P=0.001) and high risk PTE (OR=13.815, 95%CI: 4.093-46.624, P<0.001) were predictors of mortality, whereas anticoagulation (OR=0.155, 95%CI: 0.056-0.428, P<0.001), BMI>=24 (OR=0.142, 95%CI: 0.045-0.446, P=0.001) and BMI>=28 (OR=0.272, 95%CI: 0.085-0.872, P=0.029) were the predictors of survival. Conclusions: Proportion of hypertension, diabetes, coronary heart disease and hyperlipidemia were not significantly different in patients with overweight and obesity compared to patients with normal weight. Obese patients had higher levels of uric acid and hemoglobin than normal weight. Overweight and obese patients had a better survival. PMID- 30423630 TI - [The effects of different activators on the release curve of human platelet-rich plasma]. AB - Objective: To compare and analyze the effects of different activators on the release curve of TGF-beta(1) and PDGF-AB in platelet rich plasma(PRP). Methods: A total of 36 ml peripheral venous blood was obtained from 10 healthy adult volunteers, and the PRP was made by secondary centrifugation. The platelet activator was made by bovine thrombin 1 000 U in 1 ml 10% calcium chloride solution. The Thrombin-PRP group was made by PRP and the activator in a ratio of 10?1.The Calcium chloride-PRP group was made in a ratio of 10?1 by PRP and 10% calcium chloride solution instead. The fresh whole blood(whole blood group) and inactived PRP(PRP group) were used as the control groups. The 4 groups were incubated in warm water of 37 C for 0, 1, 8, 24,72 and 168 h. A quantitative sandwich enzyme-linked immunosorbent assays(ELISA) was used to examine the amount of TGF-beta(1) and PDGF-AB in different time points of each group. The release curves of TGF-beta(1) and PDGF-AB were based on afore-mentioned data, and then comparisons of the release curves of TGF-beta(1) and PDGF-AB in different groups were performed by repeated measurement variance analysis. Results: (1)The levels of TGF-beta(1) and PDGF-AB in the whole blood group and the PRP group continued to increase within 168 h. PRP immediately formed into a gel after mixture with thrombin combined and calcium chloride, and the concentrations of TGF-beta(1) and PDGF-AB reached the peak in 1 h after activation; increased from (42+/-21)ng/ml and (77+/-18)ng/ml to (84+/-21)ng/ml and (124+/-35)ng/ml, respectively, and then decreased gradually. The release curve was direct and rapid. The PRP became a gel state in approximate 1 h after mixture with calcium chloride, and the concentrations of TGF-beta(1) and PDGF-AB were slowly rising and remained high at 168 h. (2)The AUC(0-168h) of TGF-beta(1) and PDGF-AB in the PRP group was higher than that in the whole blood group (all P<0.05) , and the AUC(0-168h) of TGF beta(1) in the Calcium chloride-PRP group was higher than that in the Thrombin PRP group(Z=-2.26, P<0.05).However, there was no significant difference in the AUC(0-168h) of PDGF-AB between the Calcium chloride-PRP group and the Thrombin PRP group(Z=-1.512, P=0.131). Conclusion: Using calcium chloride as activator can get a higher release concentration of TGF-beta(1) and PDGF-AB and a longer release time, with the largest area under the curve. PMID- 30423631 TI - [Airway epithelial ATG5 suppresses asthmatic inflammation in mice]. AB - Objective: To explore the role and mechanisms of airway epithelium-localized ATG5 in asthmatic airway injury and inflammation. Methods: CC10-rtTA/(tetO)7-cre ATG5(f/f)(atg5(?/?)) mice and atg5(+/+) mice were randomly assigned to control and asthma groups, respectively. Mice of the asthma group were treated with house dust mite extract (HDM), and allergic inflammation, mucus hyperproduction, and markers of autophagy, apoptosis, and necroptosis were examined. Results: Airway epithelium-specific ATG5 deficiency significantly increased the number of BALF total inflammatory cells (171.25+/-41.50) and eosinophils (114.54+/-19.61), compared with the control asthma group (42.64+/-8.72) (P<0.01) and (18.71+/-7.54) (P<0.01), respectively. Histological analyses showed that airway inflammation deteriorated significantly in atg5(?/?) asthma group (2.00+/-0.45) compared to atg5(+/+) group (1.23+/-0.26) (P<0.01). Meanwhile, Th2-related cytokines and mucus production were increased in atg5(?/?) asthma group. These mice displayed enhanced necroptosis markers RIP and RIP3, while the autophagic protein LC3B and apoptotic markers caspase-9 and -3 were not significantly changed. Conclusion: Airway epithelium-localized ATG5 suppresses allergic airway inflammation, likely via modulation of necroptosis, while independent of autophagy and apoptosis. PMID- 30423632 TI - [Recent development of fibrotic pulmonary sarcoidosis]. PMID- 30423633 TI - [Progress of liquid biopsy technique and clinical application in lung cancer]. PMID- 30423634 TI - [Catathrenia: a new understanding of the old members of sleep breathing disorder]. PMID- 30423635 TI - Custom-made triflanged acetabular components in the treatment of major acetabular defects. Short-term results and clinical experience. AB - We report on the Belgian experience with the aMace(r) custom-made triflange acetabular component in revision total hip arthroplasty between September 2009 and November 2014. We focused on (1) the complexity of the preoperative planning and reimbursement procedure; (2) the surgical problems and operative experience; and (3) the early outcome. We collected 20 patients' reviews and 22 surgeons' reviews, with a mean follow-up of 25 months. The preoperative planning and reimbursement procedures were rated as time-consuming and cumbersome. In 6/22 cases, the operation was difficult or very difficult. Technical problems occurred in 8/22 cases, including problematic fitting in four. However, all aMace(r) components could be implanted successfully. The mean postoperative Harris Hip Score (HHS) was 68/100; patients' satisfaction was high and most patients experienced no or mild pain. Complications occurred in 8/22 cases, half of them dislocations. The aMace(r) implant can provide a solution for complex acetabular revisions. As dislocations were common, the use of dual-mobility cups should be considered. Because of the high cost and the lack of bone stock restoration, we suggest using custom-made triflange acetabular implants only in cases with large cavitational and segmental defects, which would be difficult to reconstruct with alternative methods. PMID- 30423636 TI - External Fixation Versus Hemiartroplasty In Unstable Intertrochanteric Hip Fractures Of The Elderly. AB - To compare two alternative methods : external fixation (EF) and hemiarthroplasty (HA) in elderly patients with unstable intertrochanteric hip fractures. Forty-two patients with Orthopaedic Trauma Association type 31A2-2 or 31A2-3 fractures treated between January 2007 and December 2010 were included. Twenty-two patients underwent hemiarthroplasty and twenty patients underwent external fixation. The mean length of stay in the operation room was 45 minutes and 108 minutes in the EF and HA groups, respectively (p<0.05). The mean postoperative length of hospital stay was 2.7 days in the EF group and 4.9 days in the HA group (p<0.05). The total length of hospital stay, functional scores and mortality rates were not different. Findings of the current study comparing EF and HA in a limited number of non-randomized elderly patients with unstable intertrochanteric fracture indicated that the EF method, when performed in a sufficiently stable manner, might be a valuable alternative to HA since it is less aggressive and cheaper. PMID- 30423637 TI - Changes In Pelvic Orientation After Total Hip Arthroplasty : A Prospective Study With EOSTM. AB - Changes in pelvic orientation after THA could alter the relationship between the femoral stem and the acetabular component and may be responsible of dislocation and implant degeneration. EOSTM technology allows three-dimensional analysis of the pelvis in functional position with low irradiation. The purpose of the study was to evaluate changes in pelvic orientation after THA in standing position with EOSTM. In a prospective study, EOSTM was performed in standing position preoperatively and 3 months after computer assisted THA for primary hip osteoarthritis. Differences between pre- and postoperative pelvic parameters values were analyzed. 40 patients were included. Changes greater than 5 degrees was noted in 12,5% of cases for pelvic incidence, 35% of cases for sacral slope and in 22,5% of cases for pelvic version. In conclusion, pelvic parameters could be modified after THA. PMID- 30423638 TI - Patellar Instability - An Update. AB - This review is a current concept on the topic of patellofemoral instability purposing to highlight, reflect and in cooperate both recent important findings regarding the patellofemoral joint. In the past decade numerous studies have significantly contributed to our understanding of both the epidemiology, symptomatology and underlying pathomorphology of patella instability. The topic of patella instability is very complex and several biomechanical important factor have been elucidated and consequently treatment strategies are changing. Both non surgical as well as surgical algorithms are evolving, but still there is a lot of controversies and generally there is lack of consensus. Many different surgical options exist primarily based upon repair what have been torn, or by correcting the underlining pathomorphology. Reconstruction of the medial patellofemoral ligament is the most common surgical procedure, nevertheless in cases with more severe underlining pathomorphologic factors such as trochlear dysplasia, patella alta and increased femoral anteversion, subsequent procedures correcting those abnormalities should be corrected. PMID- 30423639 TI - Minimally Invasive Versus Open Surgery For Acute Achilles Tendon Ruptures A Systematic Review And Meta-Analysis. AB - The minimally invasive surgery (MIS) approach has been popularised as an alternative to the standard open approach in acute Achilles tendon repair. Advocates of MIS suggest earlier functional recovery, due to reduced trauma to adjacent soft tissues. Critics, however, argue that due to inadequate surgical exposure, complications of such surgery are higher compared to an open technique. A systematic review and meta-analysis of randomised, prospective studies weas conducted to compare MIS and open surgery in acute Achilles tendon ruptures. Thirteen studies were included in the meta-analysis with a total of 854 patients. Although re-rupture rates were not significantly different between the groups (P = 0.43), there were significantly more complications in the open surgery group (P = <.00001). MIS in acute Achilles tendon ruptures result in similar re-rupture rates, sural nerve injury rates and return to sport time in comparison with open surgical method, but with significantly less post-operative complications. PMID- 30423640 TI - Open Reduction And Internal Fixation Versus Primary Partial Arthrodesis For Lisfranc Injuries Accompanied By Comminution Of The Second Metatarsal Base. AB - The objective of this retrospective study was to compare open reduction and internal fixation (ORIF) with primary partial arthrodesis for the treatment of Lisfranc injuries accompanied by comminution of the second metatarsal base. Thirty-four patients were treated with ORIF or primary partial arthrodesis from 2007 to 2013. The patients were followed for an average of 28.5 months. Evaluation was performed with clinical examination, radiography, Visual Analogue Scale (VAS), the American Orthopedic Foot and Ankle Society (AOFAS) Midfoot Score, and the Short Form 36 (SF-36). Fifteen patients were treated with ORIF, and nineteen patients were treated with primary partial arthrodesis. Anatomical reduction was obtained in all patients. At two years postoperatively, the mean AOFAS Midfoot score was 84.33 points in the ORIF group and 85.05 points in the primary partial arthrodesis group (P> 0.05). Also, no significant differences were seen in the VAS for pain (1.20 vs 1.05 points), SF-36 physical component (79.60 vs 79.89 points) or SF-36 mental component (77.07 vs 79.21 points). With longer and conservative postoperative management, ORIF as well as primary partial arthrodesis for Lisfranc injuries accompanied by comminution of the second metatarsal base led to similar medium-term outcome. PMID- 30423641 TI - Efficacy of the Wallis interspinous implant for primary lumbar disc herniation : a prospective randomised controlled trial. AB - PURPOSE: To investigate the efficacy of the Wallis implant after lumbar discectomy compared with discectomy alone for primary lumbar disc herniation. Seventy-seven patients with primary lumbar disc herniation were randomly assigned to undergo either posterior lumbar discectomy with (n=40, Wallis group) or without (n=37, control group) Wallis implantation. The primary outcomes were visual analogue scale score, Japanese Orthopedics Association score, and Oswestry Disability Index. The secondary outcomes were intervertebral disc height, range of motion of the operated segments, complications, and operating time. The primary outcomes at 1 week after treatment (P> 0.05) were not different between groups. The Wallis group had better scores at 12 months (P< 0.05) and the last follow-up visit (P< 0.05), higher disc height (P< 0.001), and significantly longer operating time (P =0.006) than the control group. Combined treatment appears beneficial for pain relief and lumbar function improvement by maintaining intervertebral disc height and limiting the range of motion of the spine compared with lumbar discectomy alone. However, its actual clinical benefit remains controversial because of the longer operating time and the relatively small difference in the visual analogue scale score and Oswestry Disability Index between the groups. PMID- 30423642 TI - Greater Tuberosity Sclerosis: A Radiographic Sign Of Rotator Cuff Tear? AB - The study had been carried out to investigate the relation of sclerosis of the greater tuberosity to cuff tear, or whether this may signify partial or complete tear.This retrospective study conducted on 425 patients, 250 Females (58.8%) and 175 males (41.2%). Dominant side was affected in 342 Patients (80%). The average age in males was 46 years (24-68 years) and 54.5 years in Females (44-65 years). Greater tuberosity sclerosis had 93.5% sensitivity for rotator cuff tear, 67.5% specificity, 90.4% positive predictive value (PPV), 51.9% negative Predictive value (NPV) and 85.2% accuracy Greater tuberosity sclerosis had both high sensitivity and positive Predictive value for rotator cuff tears ; however, more in-depth evaluation was required to better understand the relation between greater tuberosity sclerosis and rotator cuff tear. Level of evidence III. PMID- 30423643 TI - Latarjet reconstruction in patients with anterior shoulder instability and significant Hill-Sachs lesion. AB - Management of glenohumeral instability with large Hill-Sachs lesions remains controversial either to address or just grafting the glenoid rim defects. This study was done to investigate if open Latarjet is sufficient to prevent recurrent instability in patients with significant Hill-Sachs defects without addressing these lesions. In the period between October 2009 and November 2014 twenty three patients with shoulder instability and significant bone loss were treated by open Latarjet. All patients were followed up for a period ranged from 17 to 58 months (median +/- SD : 30 +/- 13.9).The mean preoperative Rowe score was significantly increased from 45.4 to 91.5 (p value <0,001). At the final follow up there was 17 patients with excellent result, 5 patients with good result and 2 patients with fair result. In conclusion, Latarjet provides a reliable and effective stabilization for anteroinferior glenohumeral instability with significant bone loss and engaging Hill-Sachs lesion. PMID- 30423644 TI - Operative Techniques For Treatment Of Chronic Massive Rotator Cuff Lesions : Deltoid Flap Transfer Versus Arthroscopic Debridement. AB - The treatment of chronic massive rotator cuff lesions remains challenging. Extensive reconstruction techniques as deltoid flap transfer as well as low invasive arthroscopic debridement techniques were established and showed good results. In present study 106 patients with massive rotator cuff lesions were treated by deltoid muscle flap transfer (n = 47 group I) and by arthroscopic debridement (n = 59 group II). Postoperative outcome was determined by amount of pain, range of motion, shoulder functionality according to Constant-Murley Shoulder Score and radiological assessment of acromiohumeral distance (AHD). Statistically analysis was done by the T-Test and Mann-Whitney-U-Test. Both groups showed significant improvement of range of motion compared to preoperative situation, but statistical analysis revealed no significant difference between both groups either in flexion or abduction. Overall shoulder functionality increased significantly in group I (30,2 points) and group II (20,6 points) postoperative, however group I improved significantly more in overall functionality compared to group II (p < 0,01). Therefore, present study showed that surgical treatment with arthroscopic debridement or deltoid muscle flap transfer can improve shoulder function in patients with chronic massive rotator cuff lesions. Deltoid muscle flap showed significantly better results in overall shoulder function and seems superior regarding clinical outcome. However, in regard to the good outcome a detailed risk-benefit analysis should be done before a deltoid-flap transfer is performed. PMID- 30423645 TI - The Outcome Of Surgical Management Of Chronic Pectoralis Major Ruptures In Weightlifters. AB - Pectoralis major repair is increasing in frequency due to the uptake of weight training. Chronic tendon injuries tend not to have as favourable outcomes. We report our outcome of chronic pectoralis major ruptures following surgical repair. Retrospective analysis of 8 patients who were weightlifters, treated for primary pectoralis major repair by one surgeon. Surgical repair was direct via suture anchors and one additionally required fascia lata graft due to tendon retraction. Outcome was assessed by comparing strength to the contralateral pectoralis muscle and the Oxford Shoulder Score. All patients were male with mean age of 36 years. Mean delay to surgery was 25.6 months. Mean followup was 19.6 months and mean Oxford Shoulder Score was 43.7. Six out of eight patients had full strength compared to the contralateral side. Complications included visible skin tethering not associated with weakness, stiffness associated with weakness and a seroma at fascia lata donor site. This is the largest documented study of Chronic Pectoralis Major repair showing excellent outcomes with repair, even if delayed. PMID- 30423646 TI - Long-Term Efficiency Of Extracorporeal Shockwave Therapy On Lateral Epicondylitis. AB - Lateral epicondilytis is a frequent cause of elbow pain in the adult age population. The purpose of this study was to determine the effects of extracorporeal shock wave therapy (ESWT) effective on long term clinical and functional results in the treatment on patients with lateral epicondylitis. Forty six patients suffering from lateral epicondylitis for at least 3 months were treated in this study. Clinical evaluation scoring system tests were used before an done year after the treatment for each patients. The VAS improved from 9,3 to 1.8, and the Nirschl values improved from 6,4 to 4.3. In the control group, VAS improved from 8,4 to 7, and the Nirschl values improved from 6,8 to 6,1. ESWT application to LE patients those are resistent to the theraphy, carries beneficial effects to the long term which was previously stated fort he short term, both clinically and functionally. PMID- 30423647 TI - Extension Casting For Both-Bone Forearm Fractures In Children. AB - Paediatric forearm fractures are commonly treated with closed reduction and cast immobilization. Determining the best way to cast these fractures during the initial presentation may prevent the need for re-manipulation . An analysis of casting technique for all patients under eighteen years of age treated with closed reduction and cast immobilization for both-bone fractures of the forearm at a regional tertiary referral hospital over 7 years was undertaken. One-hundred and eighty-nine consecutive patients with 207 fractures were reviewed. No significant association was found between casting technique and failure rates (p=0.124). However, if manipulation and plaster was performed by a trainee, failure rates were significantly reduced when extension casting was utilized (p=0.029). Closed reduction and cast immobilization with the elbow in an extended position is an effective treatment option for both-bone forearm fractures in a paediatric population and is a safer option when performed by more junior staff members. PMID- 30423648 TI - The Role Of The Carpometacarpal Ligaments Of The Thumb In Stability And The Development Of Osteoarthritis Lesions : An Anatomical Study. AB - This study aims to assess ligament lesions and subluxations of the carpometacarpal (CMC) joint of the thumbs and the role that these ligament ruptures play in the pathophysiology of osteoarthritis (OA). Twenty-five fresh frozen cadaver hands were dissected. There were 14 female and 11 male with mean age 65 years (51-92 years old). The origin, insertion, and fibre orientation of the ligaments were identified based on Berger's anatomical descriptions. Length, thickness and width of the main ligaments were measured. The ligament ruptures and the metacarpal translation associated with these ruptures were measured (mm). Cartilage thickness in the trapezium and metacarpal of specimens was assessed. We investigated the relationship between the ligament ruptures and the area of chondromalacia and OA. In the specimens that showed an isolated or combined rupture in DRL we found a significant increase in the dorsal translation of metacarpal with a mean of 1.7 mm. Statistical analysis of data demonstrates a significant difference (P = 0.006). There was a relationship between the presence of a tear in the DRL and OA in the radial quadrants (P = 0.032). These observations suggest a translation of metacarpal on trapezium in the production of arthritic lesions and support a hypothesis that pathologic joint instability could be a cause of CMC osteoarthritis. This study suggests that repairing the DRL during ligament reconstruction of the CMC joint should be considered. PMID- 30423649 TI - Limits Of Indications Of The Morrison Wrap-Around Procedure In Thumb Reconstruction. AB - The thumb contributes approximately 40 percent of hand function. In the case of an amputation, where replantation/revascularisation is impossible, a reconstruction should be planned as the second best treatment. Morrison described in 1980 the technique of a wrap-around partial great toe transfer. According to Morrison, the technique is best suited for reconstruction of the thumb distal to the metacarpophalangeal joint (MCPJ). In this study, we retrospectively report on 10 thumb reconstructions using the wraparound flap from the great toe. Functional results according to the level of amputation are compared. We found in our limited series, that although better results are achieved when the amputation was distal to the MCPJ, the 'wraparound' reconstruction technique still yielded acceptable functional results and outcome in amputation levels through or proximal to the MCPJ. PMID- 30423650 TI - Flexor Pollicis Longus Tendon Rupture After Volar Wrist Plating : Reconstruction With Palmaris Longus Interposition Graft. AB - Rupture of the flexor pollicis longus tendon is a rare complication after volar plating of distal radius fractures. Several surgical treatment options have been proposed but postoperative results are not well documented. The authors retrospectively studied the clinical outcome of 4 patients after flexor pollicis longus tendon reconstruction with a palmaris longus interposition graft. Minimal follow-up was 12 months. Mean active interphalangeal joint flexion (44 degrees ) and thumb opposition (Kapandji 8/10) were significantly reduced compared to the opposite side. Mean power grip (32 kg) and key pinch strength (8kg) of the operated hand were comparable to the contralateral hand. The mean Visual Analogue Scale for pain was 2.5/10. The mean DASH score was 14 points. Although flexion and opposition of the thumb did not return to normal after surgery, patients reported excellent functional results. PMID- 30423651 TI - Trapeziumectomy And Mini Tightrope Stabilization Of The First Metacarpal For Thumb Carpometacarpal Osteoarthritis : A Prospective Case Series. AB - Our purpose was to investigate the short-term results of trapeziumectomy and stabilization of the first metacarpal by using the TightRope(c) device, at a maximum follow-up of 1 year post-op. This is a novel method in treating first carpometacarpal joint osteoarthritis and an alternative to the variety of other methods that have been previously reported. We recruited 21 patients and assessed them at regular intervals, comparing pre-operative and postoperative variables. We recorded all complications during the study period. There was a statistically significant improvement in pain, hand grip and tip pinch power and functional outcome scores. Patients were very satisfied at 12 months after surgery. No significant change in thumb opposition was noted. There was subsidence of the first metacarpal at 1 year after surgery. Despite the existence of a significant number of alternative procedures, we feel that the procedure described in this paper has promising short-term results and is safe. PMID- 30423652 TI - Percutaneous Cementoplasty For Acetabulum In Patients With Bone Metastasis. AB - The purpose of this study is to demonstrate the surgical technique and to show the results of percutaneous cementoplasty (PC) for acetabular metastases using lateral approach under regional anesthesia. Forty-two cases underwent PC for acetabular metastases. The PC was performed using spinal anesthesia, lateral approach and fluoroscopic guidance. We assessed visual analogue scale (VAS) and revised musculoskeletal tumor society (MSTS) rating system and maximum standardized uptake value (SUVmax) of the acetabular lesion using F-18-FDG PET/CT before and after the PC. The mean injected volume of polymethylmethacrylamide to the pelvis was 21+/-11.8 ml. The mean of regional VAS (6.2+/-1.1 vs. 3.1+/-2.7, p<0.001), MSTS (10.3+/-3.9 vs. 18.3+/-3.2, p<0.001) and local SUVmax (8.6+/-5.2 vs. 5.7+/-3.6 , p = 0.012) on PET/CT showed significant reductions after surgery. Twenty-three patients (55%) died of disease at mean 11.8+/-4.8 months after surgery. PC using lateral approach and regional anesthesia could be a simple and safe surgical method for relieving pain and maintaining skeletal stability against acetabular metastasis. PMID- 30423653 TI - Fracture Management In Osteopetrosis : An Intriguing Enigma A Guide For Surgeons. AB - Osteopetrosis is a disorder of diminished bone resorption with hard and brittle bones resulting in high rates of perioperative complications during an operative intervention. We present a series of 4 Subtrochanteric fractures treated surgically in 3 patients of Osteopetrosis in a tertiary level Orthopaedic centre over the last 3 years with an aim to highlight our preparation and technique, especially as a guide to other surgeons, to minimize the complication rates and optimise the results. The patients had a mean Harris Hip Score of 85, at a mean follow up of 21.5 months ; the fractures united and all patients successfully returned to their normal activities of daily living. PMID- 30423654 TI - A New 3D Reconstruction Method To Assess Anatomical Restoration In Vertebral Compression Fractures. AB - Deformation of the spine following vertebral compression fracture (VCF) can be associated with severe spinal dysfunction. Anatomical restoration is described as the complete reduction and stable fixation of the fracture with the goal to restore the pre-fracture local and global spine properties. The essential need to obtain endplate reduction, and consider the whole vertebral body in the management of vertebral fractures is pointed out. A new 3D imaging technique is described. A new assessment method based on CT scans 3D reconstructions was developed. This new method was used to assess the anatomical restoration of the fractured vertebrae. A procedure consisting in placing two expandable titanium implants for fracture reduction, together with stabilization with a high viscosity PMMA cement was used to demonstrate the method. The cases presented here are demonstrating that this 3D-mapping software is a tool which can address the lack of a valid, reproducible and user-friendly method to evaluate the anatomical restoration in VCF. The evaluation of the anatomical restoration of the fractured vertebrae raises some issues in terms of interpretation because of a lack of consensus in the existing reporting methods. A 3D-reconstruction method, using CT scans and a newly-developed software, is proposed to evaluate the anatomical restoration in a clear, valid, reproducible and user-friendly way. PMID- 30423655 TI - The Appropriate Management Of Osteoporotic Vertebral Compression Fractures : A Single Institute Evaluation Using The VCF Monitor. AB - From the Department of Orthopaedics and Trauma Surgery, Klinikum Bayreuth, Bayreuth, Germany Osteoporosis-related vertebral compression fractures (OVCF) are commonly seen in clinical practice. Treatment choice is often challenging due to heterogeneity of the patient population. A European multidisciplinary expert panel developed patient-specific recommendations for reatment choice that were embedded in an online evaluation tool (VCF Monitor). This study aimed to evaluate the appropriateness of treatment choice in patients with OVCF in a German hospital. The prospective observational study included 190 patients with OCVF (2013-2015). Using the VCF Monitor, treatment choices were compared with the recommendations of the European expert panel. Treatment choices included balloon kyphoplasty (61%), non-surgical management (36%) and other surgical procedures (3%). Compared to the panel recommendations, 70% of treatment choices were appropriate, 24% uncertain, and 3% inappropriate. Less appropriate choices were partly due to patient preferences. The VCF Monitor proved to be a helpful tool for quality assurance in the management of OVCF. PMID- 30423656 TI - Acute Injuries Sustained By Racing Drivers: A Cross-Sectional Study. AB - Aim of the present study was to investigate the prevalence and type of acute injuries sustained by 137 racing drivers. An ad hoc questionnaire was developed and was completed by 137 drivers with a mean age (SD) of 42 (15) years. Approximately half of the drivers had < 10 years of experience in auto racing (49%). Multiple logistic regression analyses were performed. There was a wide distribution of injuries of the knee (n=17, 12%), shoulder injuries (n=15, 11%), thorax/rib or ankle (n=13, 9%), hand (n=11, 8%), forearm (n=9, 7%) and neck or wrist injuries (n=7, 5%). Long-distance racing, more than 10 days per month spent on testing, short-distance racing, and full-time occupation were associated with increased incidence of injuries on multivariable analyses. The high incidence of acute injuries in race car driving indicates the need for further improvements. PMID- 30423657 TI - Antibiotic Impregnated Cement Coated Ilizarov Rod For The Management Of Infected Non Union Of Long Bone. AB - The infected non union of the long bones in the presence of the intramedullary nail is a dreaded complication of fracture management. Around 7% patients may develop an infected non union of the long bones in intramedullary nailing. Amongst the various grades of infection, grade three infection is the most difficult to cure and manage as it involves an osteomyelitic bone. Amongst an array of therapeutic modalities, the two stage methods are commonly used with the first stage aimed at controlling the infection and the second stage at inducing union. This increases the number of surgical procedures. We used an Ilizarov threaded rod coated with antibiotic impregnated cement to replace the intramedullary nail with the idea of delivering higher concentration of antibiotic locally as well as provide stability. We achieved a union rate of 91% in a relatively small number of patients with this single procedure. The antibiotic impregnated cement coated Ilizarov rod that we used in our study achieves both infection control and union simultaneously and does not allow cement debonding at removal. PMID- 30423658 TI - Is Parathyroid Hormone A Viable Solution For Nonunion? A Systematic Review And Pooled Analysis. AB - We conducted a systematic review and pooled analysis of published studies to evaluate the clinical results of parathyroid hormone (PTH) in the treatment of nonunion and delayed union and assess whether there are any adverse effects of PTH. Four electronic databases (PubMed, Web of Science, EMBASE, and Cochrane library) were searched from 1950 to 2016. A total of 24 patients from 13 published studies were identified. The mean age of the patients was 57 years (range, 19-91 years). Mean duration of nonunion after initial treatment (surgical or conservative) was 8.4 months (range, 3-36 months). PTH was given to the patients for 1.5 months to 10 months (mean, 5.3 months) for various types of fractures. The union rates after using PTH was 96%. Mean time to union after PTH therapy was 7.3 months (range, 3-15 months). No patients reported any side effects during the entire period of PTH treatment. Our study has helped to further elucidate the outcomes of PTH therapy in the treatment of nonunion. We believe that PTH is a viable option that is a promising, safe, and effective anabolic treatment for delayed union and nonunion. PMID- 30423659 TI - Results Of The Treatement Of Intracapsular Femoral Neck Fractures With A New Dynamic Locking Plate. AB - The purpose of this study was to evaluate the outcomes in patients with intracapsular femoral neck fractures treated with the novel Targon FN implant. Sixty two patients (mean age: 57 years) were included. The clinical and radiological results were investigated. Radiological and clinical followup (mean time: 21,2 months) was available for 51 patients; in 36 patients, Harris Hip Score (HHS) outcome data were additionally assessed. The overall complication rate was 8%. The median Harris Hip Score was 92 (range 30-100). The results of the Harris Hip Score were rated excellent or good in 26 (72%) patients and fair or poor in 10 (28%). The HHS was correlated significantly with age at trauma, time from admission to operation, preexisting cardiovascular risk factors and disease of the ipsilateral leg. The positive experience with Targon FN suggests that this implant is an advance in treatment of intracapsular femoral neck fractures with head-preserving surgery. PMID- 30423660 TI - Comparison Of Acetabulum Posterior Wall Fractures And Fracture Dislocations: Dislocation Does Not Affect Clinical And Radiological Outcomes. AB - The aim of this study was to compare radiological and clinical outcomes of posterior wall acetabulum fractures and posterior wall fracture dislocations. Data were including 52 acetabulum fractures and fracture dislocations. Twenty-six patients (%50) had posterior acetabulum fractures and fracture dislocations who were operatively treated. Radiographic evaluations were performed before and after the operation and at the last follow up. Clinical outcome evaluation was performed at the last follow up. Clinical and radiological outcomes were evaluated including Merle D'aubigne clinical assessment score and Matta' s radiologic measurement score. Brooker classification was used to measure heterotopic ossification. Both Merle D'aubigne and Matta scores were found higher in the acetabulum posterior wall fracture group. But there wasn't significantly difference of clinical and radiological outcomes between two groups (p > 0,05). Reduction quality and Matta radiologic scores were correlated significantly in 2 groups. Posterior dislocation may not negatively affect clinical and radiologic outcomes. PMID- 30423661 TI - Is There Any Difference Between The Biomechanical Strengths Of The Current Fixation Techniques For Comminuted Distal Patellar Fractures? (Comparison Of Distal Patella Fracture Fixation Techniques). AB - In this biomechanical study, the strength of five different fixation techniques anterior tension band wiring with K-wires, separate vertical wiring, headless compression screws with anterior tension band wiring, cannulated screws with tension band wiring and memory shape patellar fixator- for distal patellar fractures were compared. Forty calf knees were used for the biomechanical testing. Each specimen was pre-loaded with 10 N at 1 N/s. The distraction forces were applied consistently with the velocity of 5 mm/s. The ultimate load (N) and displacement (mm) values were recorded. The headless compression screw with anterior tension band wiring (656.9+/-167.9 N) and the cannulated screws with anterior tension band wiring (642.6+/-166.0 N) obtained significantly higher ultimate loading values compared to the other fixation methods (p<0.05). Fixation via cannulated screws with anterior tension band wiring techniques are more stabile than the patellar shape memory fixator and anterior K wire fixation. PMID- 30423662 TI - Atypical Femoral Fractures : Three Cases And A Review Of Literature AB - In recent years, bisphosphonates and RANK-ligand inhibitors have become the mainstay of treatment for multiple types of osteoporosis, as well as several other metabolic bone diseases. Although rare, atypical femoral fracture is a recent but clearly defined complication of antiresorptive therapy with bisphosphonates, and likely also with denosumab. In this article, we present 3 different cases of atypical femoral fracture: an incomplete fracture linked to a bisphosphonate, an incomplete fracture linked to denosumab, and a complete atypical femoral fracture. Specific diagnostic steps and therapy are described. We also offer a complete overview of available literature concerning diagnosis, epidemiology, pathogenesis, treatment and future outlooks concerning this entity. Although antiresorptive therapy offers a very significant benefit in the prevention of osteoporotic fractures, clinicians should be aware of the possible complications, especially with long-term therapy. PMID- 30423663 TI - Fixation Of Tibial Pilon Fractures Based On Column Concept :A Prospective Study. AB - Distal tibia fractures are complex injuries with high complication rates. Limited soft tissue, poor vascularity and complexity of fracture pattern impose limitations for traditional plating techniques. Better understanding of fracture patterns using 3D-CT reconstruction, optimum pre-op planning and availability of anatomical locking plates have certainly improved the outcome in these fractures. We report the functional and radiological outcome in 12 patients of complex tibial pilon fractures, who were treated on the basis of the novel column concept. PMID- 30423664 TI - Do Patients With Acute Isolated Pubic Ramus Fractures Have To Be Hospitalized? AB - A total of 129 patients were included in the study. Haemoglobin levels on admission and at 24 hours were evaluated. Radiographs and computed tomography of the pelvis were also evaluated. The patients were divided into subgroups, according to the accompanying occult posterior pelvic injuries, whether they received anticoagulant-antiaggregant treatment, the number of pubic ramus fractures (single or multiple), the level of energy (low or high) and the zone(s) of the fracture(s). The mean haemoglobin decrease was 1.21 g/dL. Forty-six of the patients were under anticoagulant or antiaggregant treatment. Fifty-one of the fractures occurred due to low energy trauma. Posterior ring injuries were observed in 75 of the patients. Haemoglobin level decreases were statistically significant in injuries with high energy trauma aetiology, in patients using antiaggregant or anticoagulant and in fractures of the lateral half of the superior pubic ramus. It is important to follow all pubic ramus fractures closely because, even in low energy trauma, haemoglobin levels could decrease significantly. We recommend hospitalization to monitor this group of patients. PMID- 30423665 TI - Radiation Exposure From Computed Tomography Of The Upper Limbs. AB - To investigate exposure to radiation we identified a cohort of 312 patients who underwent standardized CT of an upper limb within a three years period. The effective dose per dose length product coefficient was used to calculate the effective doses of radiation. Mean effective doses were as follows: shoulder CT, 10.83 (SD 6.36) mSv; wrist CT, 0.15 (SD 0.07) mSv; elbow CT performed with the arm above the head, 0.21 (SD 0.11) mSv and with the arm adjacent to the torso, 13.1 (SD 10.8) mSv. The corresponding lifetime attributable risk of cancer was 0.6/1000 for males and 0.73/1000 for females for shoulder CT and 0.75/1000 for males and 0.96/1000 for females for elbow CT with the arm adjacent to torso. The effective doses for CT scans of the wrist and of the elbow performed with the arm above the head were low. For elbow CT scans, elevating the arm above the head decreases the radiation doses. PMID- 30423666 TI - The Efficacy Of 1,2- Intercompartmental Supraretinacular Artery Pedicled Vascularised Bone Graft For Scaphoid Proximal End Non-Union And Avascular Necrosis. AB - The aim is to show the efficacy of 1,2-intercompartmental supraretinacular artery pedicled vascularised bone graft in treatment of scaphoid non-union with concomitant proximal end avascular necrosis retrospectively. Twentytwo cases of scaphoid nonunion with concomitant proximal end avascular necrosis were evaluated. Radiographic evaluation was made with radiographs, computed tomography, and magnetic resonance imaging. Clinical evaluation was made according to the Disabilities of the Arm, Shoulder and Hand (DASH) score, the Mayo wrist score, and the Short Form-36. Union was achieved in 18 81.8%. The mean age was 31.13 +/- 5.29 years and the mean follow-up was 34.95+/-16.87 months. The median wrist flexionextension range was 123.5 degrees (100 degrees -144 degrees ) preoperatively and 128 degrees (82 degrees -146 degrees ) postoperatively. The median radial-ulnar deviation was measured as 41.5 degrees (24 degrees - 55 degrees ) preoperatively and 42 degrees (24 degrees -58 degrees ) postoperatively. The dominant hand was measured as 92% (p = 0.061) grip strength compared to the healthy side and the non-dominant side as 74% (p = 0.012). Improvement was observed in all patients in SF-36,DASH,Mayo score and in patients with union (p < 0.001). The radiological and clinical results of this study showed that 1,2- intercompartmental supraretinacular artery pedicled vascularised bone graft is an effective method in the treatment of scaphoid nonunion with concomitant proximal end avascular necrosis. PMID- 30423667 TI - The Latarjet Procedure For Anterior Shoulder Instability : A Consecutive Prospective Series Of 50 Cases. AB - The Latarjet is a successful primary and revision option for anterior shoulder instability. However, recent reports have highlighted varying complication rates. Our study prospectively collected clinical, functional and radiological outcomes of patients undergoing the procedure. Forty-eight consecutive patients (fifty shoulders) underwent the Latarjet procedure in a single UK centre. Clinical, radiological and functional follow-up was performed. Mean clinical follow-up was 32 months and radiological follow-up 20 months. 95% shoulders were subjectively graded "excellent" or "good" and 5% "fair". Mean Rowe, Oxford Shoulder Instability Score, American Shoulder and Elbow selfassessment Score and Subjective Shoulder Value Score all improved post-operatively (p<0.001). No infections, dislocations, revisions or metalworkrelated complications occurred. There was one intra-operative coracoid fracture and five transient neurological injuries, resolving within three months. The long-term complication rate was 2%. The Latarjet procedure is safe and reliable for treating anterior shoulder instability with a very low long-term complication rate providing excellent clinical and functional outcomes. PMID- 30423668 TI - Inter- And Intraobserver Reliability In The Assessment Of Glenoid Fracture Classifications. AB - Throughout literature a number of glenoid classification systems have been described but lack clear correlation with the fracture patterns found in clinical cases. This study aimed to evaluate the intra- and interobserver agreement for fracture classifications of the glenoid, using either plain radiographs, computed tomography (CT) scans. The study was retrospective, using images with a variety of fracture types. Six observers classified the fracture patterns. Classifications of Ideberg, OTAAO, Mayo and Euler/Ruedi were used. Agreement was determined using kappa coefficients. Currently used glenoid fracture classification systems have a fair to moderate intraobserver reliability. Combining plain radiographs and CT scans led to a better observer agreement. For interoberserver reliability, the system of Euler scored slightly better than other systems. Although Ideberg's classification is the most widely used system, this study does not support superiority of it. Based on this study there is need for a more reliable glenoid classification system. PMID- 30423669 TI - The Use Of Suture Anchors In Akin Osteotomy : A New Surgical Technique. AB - To perform an Akin osteotomy using suture anchors to achieve stability of the osteotomy line and avoid the need for a further operation to remove an implant. Akin osteotomy using suture anchors was performed on 35 feet of 30 patients (21 female, 9 male ; mean age 45 years, range 18-60 yrs) diagnosed with hallux valgus. In bilateral cases, surgery was firstly carried out on the foot in the more serious condition, followed by the second foot 2 months later. Preoperative and postoperative clinical evaluation of the patients was made using American Orthopaedic Foot and Ankle Society (AOFAS) scores. Preoperative AOFAS values for pain, function and alignment were measured. Pain values were 8 patients 20 points, 27 patients 0 points. Function values were, activity, 14 patients 4 points, 21 patients 0 points ; footwear requirements, 18 patients 5 points, 17 patients 0 points, MTP joint movement, 11 patients 5 points, 24 patients 0 points, Post-operative AOFAS values were measured and evaluated as follows. Pain values were 33 patients 40 points, 2 patients 30 points. Function values were, activity, 30 patients 10 points, 5 patients 7 points ; footwear requirements,32 patients 10 points, 13 patients 5 points, MTP joint movement, 22 patients 10 points, 13 patients 5 pointsThese results were found to be statisically highly significant (p<0.001). Rigid fixation was achieved with suture anchors and patients made an early return to normal activities. Postoperative shoes were used for early mobilisation. PMID- 30423670 TI - Achievement Of Primary Stability Using 3D-CT Guided Custom Design Femoral Stems In Patients With Proximal Femoral Deformity : EBRA-FCA Analysis. AB - Hip replacement in patients with proximal femoral deformity and end stage arthrosis is technically challenging. The purpose of this study was to measure the subsidence rate of custom femoral stems using EBRA-Femoral Component Analysis (FCA) software, as an indicator of achievement of primary stability. We retrospectively reviewed 14 hips in 12 consecutive patients who underwent this procedure between June 2008 and Feb. 2011. There were 7 males and 5 females with a mean age 41 years (22-60). The primary diagnosis in the majority of the cases was Perthes and DDH with secondary osteoarthritis. The average follow up period was 36 +/- 10 months (19-51 months). Average subsidence was the 0.96 mm +/- 0.95mm (0- 2.9 mm). All patients had signs of osteointegration at the metaphyseal level. We conclude that the 3D-CT guided custom made femoral stem produces reliable proximal 'fit and fill' and osteointegration without the need of a corrective osteotomy in patients with proximal femoral deformity but long term studies are needed to assess the performance of this femoral stem. PMID- 30423671 TI - Neopterin, Interleukin-6, Procalcitonin, C-Reactive Protein And PET-CT Staining As Markers In Infected Total Knee Prosthesis, A Retrospective Analysis. AB - Diagnosis in prosthetic joint infections is challenging as symptoms are variable, and currently most of the diagnostic tests are non-specific. Normal inflammatory reactions after orthopedic prosthetic surgery may generate false positives, as these tests have high sensitivity but low specificity. Thus, specific tests, as alpha defensin, are needed to distinguish bacterial infections from reactions to surgical trauma. The aim of this study was to determine the sensitivity and specificity of several diagnostic tools for detecting bacterial infection in prostheses. Between April 2010 and December 2012, we analyzed white blood cell count, erythrocyte sedimentation rate, C-reactive protein, neopterin, interleukin 6, and procalcitonin in 45 patients with prosthetic infection confirmed by positive cultures of joint aspirate and deep tissue biopsy. In addition, these patients underwent PET-CT imaging, in accordance with infection protocols in place at our clinic. The suitability and diagnostic power of these tests were assessed by using Shapiro-Wilk test, Mann-Whitney U test, and ROC curve analysis, and by comparing to 40 age- and gender-matched volunteers who underwent unilateral total knee prosthesis with normal serum indices and without known diseases. Significant differences were observed between infected patients and control volunteers (p < 0.05) for all parameters examined. Highest sensitivity (99%) and specificity (98%) were achieved using a combination of interleukin-6 and C-reactive protein. However, PET-CT imaging had diagnostic accuracy of 93.3%. A combination of interleukin-6 and C-reactive protein also enables accurate diagnosis. PET-CT may be an important imaging modality for detecting prosthesis infection. But, these markers were found neither sensitive nor specific in the diagnosis of periprosthetic infection as alpha defensin. PMID- 30423672 TI - Cement Anchors With Screw Holes For Liner Cementation Into Cementless Acetabular Metal Shells. AB - This mechanical study was conducted with the shellcement interface in order to construct an acetabular metal shell, and to fix a polyethylene liner with bone cement. Six types of models were tested, with all cementations performed under similar conditions. The "lever out" test was conducted 3 times for each group in order to measure the dissociation strength. The average dissociation strength values were 11.5 N* m for those without screw holes; 33.6, 34.7, and 78.7 N* m for those with single holes at 1, 3, and 6 mm depth, respectively; and 41.3 and 101.1 N* m for 2 different configurations with 3 holes at 3 mm depth. The strength of adhesion increased with the use of a cement anchor, and with an increasing length and number of anchors. The application of a cement anchor with a screw hole is clinically useful for increasing the mechanical strength of the shellcement interface. PMID- 30423673 TI - Bilateral Early Knee Osteoarthritis Treated With Unilateral Proximal Tibial Osteotomy And Contralateral Non-Surgical Technique. AB - Some non-surgical techniques that decrease the mechanical load of the knee may be effective in treating early primary knee osteoarthritis. Thirtysix consecutive patients with bilateral early primary knee osteoarthritis and genu varum were treated with unilateral proximal tibial osteotomy in the more degenerated knee. After the osteotomized bone healed, ambulation with protected weight bearing using a cane in the contralateral hand was advised continuously for at least three months or until knee pain subsided bilaterally. Thirty-one patients were followed for an average of 4.6 years (range, 2.1-7.8 years). All osteotomized bones healed. Twenty patients (64.5%) had satisfactory knee function bilaterally. Eight patients (25.8%) only had satisfactory knee function in the operated knee. Thus, 28 patients (90.3%) improved operated knee function (p < 0.001). Non operated knees improved to satisfactory function from 38.7% initially to 71.0% at the latest follow-up (p = 0.01). Bilateral early primary knee osteoarthritis may be successfully treated with unilateral proximal tibial osteotomy. PMID- 30423674 TI - Is There Any Correlation Between Short-Term MRI And Mid-Term Clinical Resultsin Patients Undergoing An Osteochondral Autograft In The Knee? AB - Thirthy three patients (mean age 32 years) undergoing OA were retrospectively evaluated. All patients had MRI at mean 6.6 months. Lysholm, International Knee Documentation Committee (IKDC), and Tegner scores. The aim is to evaluate Magnetic Resonance Imaging (MRI) in patients who underwent an Osteochondal Autograft (OA) and correlate them with their clinical results-evaluated at mean followup of 28 months (12-88). Tegner Pre-operatively: 6.6, Post-operative: 7.4 (p<0.001). Mean Lysholm: 87, mean IKDC: 86. MRI: complete filling of the lesion in 25 (75.7%) patients, complete integration of the graft in 5 (15.1%) and intact repair tissue in 22 (66.6%. Positive correlation between the degree of repair and filling of the defect and higher Lysholm and IKDC (p<0.05). There is a minor association between short-term MRI and mid-term clinical results after an OA being the degree of repair and filling of the chondral defect the only parameters correlated with patient's evolution. PMID- 30423675 TI - Tibial Component In Total Knee Replacement :The Effect Of Overhang And Sizing On Outcome. AB - The aim of this study was to find a relationship between tibial overhang, malpositioning and oversizing, and the functional outcome. 188 patients were included in this retrospective study. All patients completed an Oxford knee score questionnaire at mean followup of 5 years. Anteroposterior radiographs of the total knee replacements were reviewed for medial and lateral overhang and oversizing. Lateral overhang was seen in 32.9% of patients with a mean Oxford knee score of 24.7. However lateral overhang proved no significant correlation with the functional outcome. Oversizing was seen in 31.9% of patients and, with a mean of 25.6, oversizing did have a correlation with Oxford Knee score. This study confirms that neither medial or lateral overhang of the tibial component influences functional outcome, independent of the severity of overhang. Oversizing the tibial component however, does show worse functional outcome scores at a 5 year review. PMID- 30423676 TI - Vitamin D Deficiency Is Associated With Longer Hospital Stay And Lower Functionaloutcome After Total Knee Arthroplasty. AB - High vitamin D deficiency prevalence has been found in hip and knee osteoarthritis, and a correlation between low vitamin D levels and worse functional outcome after hip arthroplasty was published before. Our goal was to examine the relation between vitamin D levels and outcome after knee arthroplasty on short and long term. In 138 patients with knee replacements preoperative vitamin D levels were recorded. 33 patients were vitamin D deficient (median 32 nmol/l, range 6-40 nmol/l) and 105 patients were vitamin D sufficient (median 65 nmol/l, range 41-177 nmol/l). After correction for confounders, vitamin D deficient patients had significant (p = 0.03) longer hospital stay (+1.0 day, range 0.2-1.6 day), and significant (p = 0.04) worse functional outcome also at long term follow up after eight years (WOMAC : +5.0, range 0.2-9.8). More research is needed to evaluate if rehabilitation and postoperative outcome can be improved by preoperative vitamin D suppletion. PMID- 30423677 TI - Comparison Of Isokinetic Muscle Strength And Clinical Outcomebetween Isolated And Combined PCL Reconstruction. AB - The purposes of this study was to 1) compare the functional result and muscle strength between patients who underwent reconstruction by isolated posterior cruciate ligament (PCL) and combined PCLposeterolateral corner sling (PLCS) reconstruction. Nineteen (Group I: isolated PCL reconstruction) and 30 (Group II: combined PCL-PLCS reconstruction) were compared. The clinical results and isokinetic muscle strength were compared between groups. The clinical results were comparable between groups and posterior stability was not different between the two groups, either. The isokinetic strength test result was not significantly different between the two groups, although absolute values of the flexion strength in Group I was higher than those in Group II. The HQ ratio of the affected side in Group I was similar to that of the contralateral side. Isokinetic muscle strength, especially flexion, was not fully recovered as compared with the contralateral side in both groups, although clinical and stability results were improved. However, the isolated PCL reconstruction group that was managed with the accelerated rehabilitation protocol showed an HQ ratio similar to that of the contralateral side. Therefore, an earlier active strengthening program would be also necessary in PCL-PLCS reconstructed groups, and justification for prevention of early weight bearing in PCL-PLCS reconstruction should be re-evaluated because weight bearing is helpful for muscle strengthening. PMID- 30423678 TI - Which Unicondylar Prosthesis Is Better In The Mid-Term In Obese Patients : Fixed Or Mobile? AB - As it is mentioned in the literature, rates of complications and revision are higher in the obese compared to non-obese patients, although obesity does not a contraindication for unicompartmental knee arthroplasty and successful outcomes are achieved. However, there is not any study in the literature comparing the outcomes of fixed and mobile unicompartmental prostheses which are applied in the obese patients. Objective of this study was to compare outcomes of our obese patients who we applied fixed or mobile unicompartmental arthroplasty and followed up for 8 years and over. Of 293 patients in whom we performed unicompartmental knee prosthesis due to medial gonarthrosis between 2003 and 2014, 239 patients who were regularly followed-up at least for 18 months were included in this study. Total 248 knees with 193 (77.8%) fixed including bilateral prosthesis in 9 patients and 55 (22.2%) mobile prostheses were retrospectively assessed. The study included 57 patients having BMI >30 kg/ m2 who were regularly followed-up. In the final controls; mean flexion was found as 107 degrees (100-128 degrees )(p<0.05), mean extension as 3 degrees (0-5 degrees ) and mean tibio femoral angle as 4 degrees (1-5 degrees ) (p<0.05) valgus. Postoperative mean WOMAC value was found as 91.23 +/- 3.02 (92-96) (p<0.05) and mean KSS score as 88.3 +/- 3.94 (85-100) (p<0.05). In the final controls, respective knee flexions were seen to be 105 degrees (100- 125 degrees ) and 108 degrees (105-128 degrees ) in the fixed and mobile insert subgroups (p>0.05). Unicompartmental knee prosthesis is a good treatment option which can be applied also in obese patients and has high survival rates. No significant difference was found between the prostheses with fixed and mobile insert in terms of function and knee scores. However, fixed unicompartmental prosthesis should primarily be preferred in obese patients because of the challenging surgical technique, difficult learning curve and insert dislocation that we encounter with mobile prostheses. PMID- 30423679 TI - Open Meniscus Repair In Full And Partial Horizontal Meniscal Lesions : A Biomechanical Cadaver Study. AB - Horizontal meniscal tears are often treated by partial meniscectomy. Some clinical studies have shown successful repair. The purpose of this study was to show that axial loading causes less horizontal displacement in partial than in total horizontal lesions and that suture of those lesions prevents horizontal displacement. Forty menisci were tested : sutured partial horizontal lesions (ten), sutured total horizontal lesions (ten) and matched unsutured control groups (ten each). Samples were put in a custom made fixation device. 1000 cycles with axial loading, simulating partial weight-bearing of 15kg, were applied. Displacement was measured and construct stiffness was calculated. No suture failure or pullout occurred. Horizontal displacement was insignificantly lower in partial then in full lesions as well as in sutured samples than in the control groups. Horizontal displacement is low in both sutured and unsutured menisci in our test setting. Further studies with higher loads are required. PMID- 30423680 TI - Is There A Difference In Outcome Between Two Types Of Valgus Unloading Braces? A Randomized Controlled Trial. AB - The short-term clinical and radiographic outcomes of two different valgus unloading braces were compared in patients with medial knee osteoarthritis (OA) and a varus leg alignment. A RCT was performed in 100 patients (50 Bledsoe Thruster brace, 50 SofTec OA brace) with symptomatic medial knee OA and a varus leg alignment. Outcomes were the visual analogue scale pain and satisfaction, Dutch Western Ontario and McMaster Universities Osteoarthritis Index, SF-12, 6 Minutes Walking Test, hip-knee-ankle alignment, analgesic use, complications and compliance after a follow-up of 2 and 12 weeks. The clinical and radiographic outcomes were not significant different between both groups. Almost all clinical outcomes improved in both groups at follow-up compared to baseline. 24% of the patients discontinued using the brace. No significant differences in clinical and radiographic outcomes were found between both groups after 2 and 12 weeks follow up. Both braces were effective in the treatment of varus medial knee OA. Complications and compliance remains a problem. PMID- 30423681 TI - Nanostructured titanium surfaces fabricated by hydrothermal method: Influence of alkali conditions on the osteogenic performance of implants. AB - Hydrothermal method is an easy-to-use approach for creating nanostructured surfaces on titanium (Ti). However, whether the alkali conditions of this method influence the osteogenic potential of the modified surfaces remains unknown. In this study, we fabricated nanostructured surfaces, termed the Ti-1, Ti-5, and Ti 10 groups, by using the hydrothermal method in 1 M, 5 M, and 10 M NaOH aqueous solutions, respectively. An untreated Ti surface served as a control. The osteogenic performance of modified surfaces was systemically investigated, including the proliferation and osteogenic differentiation of human osteoblast like MG63 cells in vitro and the osteointegration of implants in a rabbit femoral condyle defect model. After hydrothermal treatment, the hydrophilicity of modified surfaces was greatly enhanced. The Ti-1 group showed a nanowire-like topography, while the Ti-5 and Ti-10 groups exhibited a nanopetal-like topography with different pore sizes. Compared with the untreated Ti surface, the modified surfaces showed good cytocompatibility and enhanced the osteogenic differentiation of MG-63 cells. Compared with the other modified surfaces, the Ti 5 group was the most favourable for the osteogenic differentiation of cells, showing higher levels of alkaline phosphatase activity, osteogenic gene expression, mineralization and osteoprotegerin secretion. Twelve weeks after implantation at the bone defects, the Ti-5 group showed superior peri-implant bone regeneration and higher peak push-out force than the other groups. Overall, this study revealed the crucial role of alkali conditions of hydrothermal method in modulating the material characteristics of modified surfaces and their osteogenic performance in vitro and in vivo, highlighting the need for optimizing the processing conditions of hydrothermal method for enhanced osteointegration. PMID- 30423682 TI - Controlled release of glibenclamide from monolithic silica subdermal implants produced by the sol-gel process and its use for hyperglycaemia treatment in a murine model. AB - Glibenclamide is an anti-hyperglycaemic drug that is commonly used for the treatment of type 2 diabetes mellitus and has promising new medical indications. However, this drug is associated with high rates of serious hypoglycaemic episodes as a result of its pharmacological activity. Administering the drug through controlled release delivery systems could reduce the incidence of these episodes. In this study, glibenclamide silica monolithic xerogel implants for subdermal application (GMSIx) were developed using the sol-gel technique for matrix synthesis with TEOS with different drying conditions (environmental, 60, 90, and 120 degrees C, which were named as GMSIE, GMSI60, GMSI90, and GMSI120, respectively). The inclusion of the drug in monoliths was monitored by DSC, FTIR, and PXRD. The effect of drying conditions on the morphology, moisture content, hardness, dosage uniformity, surface characteristics, and drug release mechanism of glibenclamide from the matrices was systematically investigated. Oral Glucose Tolerance Tests were performed with mice to evaluate the efficacy of the GMSI in maintaining blood glucose levels. Glibenclamide was completely included in a non crystalline solid form in the matrixes. The moisture content, hardness, dosage uniformity, and surface characteristics depend on the drying conditions. The monolithic matrices showed a mesoporous surface with high surface area, and a narrower pore size distribution occurred for GMSI60. GMSIE and GMSI60 showed non Fickian anomalous Korsmeyer-Peppas glibenclamide release kinetics. GMSI90 and GMSI120 showed controlled release of the drug through dissolution. When GMSI60 was administered to mice, glucose blood levels were effectively maintained despite a high oral glucose load in the animals, showing a sustained effect of the drug released from this new sol-gel drug delivery system. PMID- 30423683 TI - A novel antibacterial acellular porcine dermal matrix cross-linked with oxidized chitosan oligosaccharide and modified by in situ synthesis of silver nanoparticles for wound healing applications. AB - Not only are the physicochemical properties and biocompatibility of biomaterials important considerations, but also their antibacterial properties. In this study, a novel chemically-cross-linked antibacterial porcine acellular dermal matrix (pADM) scaffold was fabricated according to a two-step method. A naturally derived oxidized chitosan oligosaccharide (OCOS) was used to cross-linked pADM (termed OCOS-pADM) to improve its physicochemical properties. Residual aldehyde groups within the OCOS-pADM were used in a redox reaction with Ag ions to produce Ag nanoparticles (AgNPs) in situ. As the AgNPs were tightly adhered onto the scaffold fibrils (termed OCOS-AgNPs-pADM), this effectively functionalized scaffold with antibacterial properties. The generated AgNPs were characterized by UV-Vis diffuse reflectance spectroscopy, XPS and SEM. The results of DSC, TG and enzymatic degradation demonstrated that OCOS-AgNPs-pADM possessed improved thermal stability and resistance to enzymatic degradation compared with pADM scaffolds. The kinetic experiment of the release of silver showed that silver was released in a controllable way. After introducing AgNPs into scaffolds, the OCOS AgNPs-pADM possessed wide-spectrum antibacterial activity against Escherichia coli and Staphylococcus aureus. Furthermore, MTT assay and CLSM showed that the scaffolds had good biocompatibility. Pieces of OCOS-AgNPs-pADM were implanted into Sprague-Dawley rats to characterize their ability to repair full-thickness skin wounds. And results showed that the OCOS-AgNPs-pADM could accelerate the wound healing process. Overall, this work contributes new insight into the chemical cross-linking and functionalization of pADM scaffolds. In addition, as novel antibacterial scaffolds, OCOS-AgNPs-pADMs have the potential for development as wound dressing materials. PMID- 30423684 TI - Impact of activator incorporation on red emitting rods of ZnGa2O4:Cr3+ phosphor. AB - Chromium doped zinc gallium oxide (ZnGa2O4:Cr3+) microrods were synthesized by simple solid state reaction method. The transformation on crystal structure and optical properties with molar concentration of Cr3+ were analyzed. The cubic spinel nature of ZnGa2O4:Cr3+phosphor and their crystalline nature were confirmed from x- ray diffractogram. The average grain size of the samples range between 24 and 29 nm, with lattice parameter values greater than that of bulk. Lattice strain produced in the lattice on doping was estimated from the Williamson-Hall plot. It increases on Cr3+ doping up to 3 mol% and then decreases. Rod like nature of zinc gallate was observed from the surface morphological analysis using SEM. X-ray photoelectron spectroscopy was used for the chemical state identification of the constituent elements in the compound. The photoluminescense spectra consists of various emission lines originated from the chromium ion in the spinel lattice. The purity of red emissions were observed from chromaticity diagram with a concentration quenching initiated from the dipole-dipole interaction, with increase in dopant concentration. Band gap of the samples were estimated using Kubelka-Munk equation which exhibited red shift compared to bulk due to band tailing effect. PMID- 30423686 TI - Characterization of the microstructure of hydrazone crosslinked polysaccharide based hydrogels through rheological and diffusion studies. AB - Microstructure plays an essential role in the control of hydrogel properties. It is also an important factor when cells or drugs are encapsulated inside the hydrogel. In this work, the microstructures of hydrazone crosslinked hyaluronan-, alginate- and gellan gum-based hydrogels were evaluated thoroughly for the first time by using rheology- and diffusion (fluorescence recovery after photobleaching, FRAP)-based methods. The effect of gel parameters on the viscoelastic and diffusion properties of hydrogels, and further on their structural parameters (mesh size, average molecular weight of the polymer chain between neighboring crosslinks, crosslinking density) are shown. Results further show that diffusivity decreased when larger dextran sizes were used, which were equivalent to the mesh sizes of hydrogels (15 nm to 47 nm) evaluated by the rheological method. This mesh size range allows the transportation of smaller molecules, but also peptides and most of the proteins. A correlation between the storage modulus and the structural parameters was also shown. Overall, hydrazone crosslinking offers an easy way to produce polysaccharide-based hydrogels with variable microstructures by altering the gel parameters. PMID- 30423685 TI - Encapsulation of bovine serum albumin within novel xanthan gum based hydrogel for protein delivery. AB - Aim of the present study is to investigate synthesis of novel hydrogel as a potential protein carrier, intended for controlled release formulation. The hydrophilic bovine serum albumin (BSA) was chosen as a model protein to be encapsulated within xanthan gum (XG)/poly (N-vinyl imidazole (PVI) hydrogel. Both XG/PVI hydrogel and XG/PVI/BSA matrix structures were elucidated via different analysis tools such as FTIR, XRD, FE-SEM and EDX. Both BSA loading and release profiles were determined. Cytotoxicity of XG/PVI hydrogel was investigated against normal cell line (VERO cells). The obtained results revealed that % Drug (BSA) loading (% DL) and Encapsulation Efficiency (% EE) increased with increasing both gelation time and loaded BSA concentration, while %DL and %EE decreased with increasing the polymer concentration. The maximum value of %DL and %EE was 59.50% and 99.17%, respectively. Results of in-vitro BSA release in PBS showed that increase in the polymer (XG and PVI) concentrations led to increase in BSA release. Kinetic studies of the in-vitro release of BSA from XG/PVI/BSA matrix followed non-Fickian and case II transport mechanism. Moreover, Cytotoxicity results showed good biocompatibility of this novel hydrogel. SDS PAGE analysis confirmed that the structural integrity of BSA was not affected by the encapsulation or release conditions. Consequently, this novel hydrogel can be used as an efficient BSA carrier for protein delivery. PMID- 30423687 TI - Bilayered heparinized vascular graft fabricated by combining electrospinning and freeze drying methods. AB - Small diameter vascular grafts (<6 mm) are highly demanded for patients suffering from severe occluded arteries to be used as a bypass or substituted conduit. Fabricating a graft with appropriate structural, mechanical and cell growth properties which has simultaneously anti-thrombogenic trait is a challenge nowadays. Here, we proposed a bilayer heparinized vascular graft that can mimic the structural and mechanical characteristics close to those of the native coronary artery by combining electrospinning and freeze drying methods. In this study, the inner layer was made by co-electrospinning of synthetic polymer, poly caprolactone (PCL) and the natural polymer, gelatin (Gel). Also, heparin which is widely used as an anticoagulant drug, was loaded by blending in gelatin solution and emulsion electrospinning of PCL fibers. Adding heparin resulted in better endothelial cell attachment and proliferation while fewer platelets attached to the scaffold. This indicates that that probability of graft failure as a result of thrombosis can be reduced. The outer layer was fabricated using freeze-drying of gelatin hydrogel. With average pore diameter size of >200 MUm, large smooth muscle cells (SMC) could proliferate easily along this layer. Mechanical tests demonstrated the more appropriate mechanical properties of the bilayer scaffold in comparison with the freeze dried or electrospun layer individually. PMID- 30423688 TI - Dual layered wound dressing with simultaneous temperature & antibacterial regulation properties. AB - Scald first-aid needs to reduce the local temperature as well as the bacterial colonization. Bacteria resistant problem has become a major challenge that global public health workers face. Long-term and high dosage use of antibacterial agents is the main reason. In this study, temperature-regulated release antibacterial nanoparticles were applied to poly(n-isopropyl acrylamide) and sodium polyacrylate. This hypothermia coverage could be used as an ideal scald first-aid wound dressing with spontaneous Temperature & Antibacterial regulation properties. PMID- 30423689 TI - A novel approach to enhance the spinnability of collagen fibers by graft polymerization. AB - Collagen is an important natural biopolymer that cannot be electrospun easily due to the lost properties occurs in the associated degrading chains while dissolving and spinning. Grafting polymerization of methyl methacrylate-co-Ethyl Acrylate was applied to modify the surface of acid soluble collagen (ASC). The branched copolymer on the surface of collagen significantly influenced the initial viscosity. Since chain entanglement is crucial for fiber formation during electrospinning, the dependency of entanglement concentration on branch densities possessing the approximate same viscosity was investigated; in which the mean fiber diameters of all considered samples remained broadly constant. Increasing the number of branching onto ASC chains significantly decreased the deteriorative impact of the electrospinning conditions. It has also increased the stability of the collagen-based fibers under high humidity conditions. The short chain branched ASC-g-P(MMA-co-EA) can effectively influence the thermal stability of electrospun collagen fibers while the long chain branched ASC-g-P(MMA-co-EA) can provide a higher chain entanglement density leading to the more fiber uniformity. PMID- 30423690 TI - Polylactide-based materials science strategies to improve tissue-material interface without the use of growth factors or other biological molecules. AB - In a large number of medical devices, a key feature of a biomaterial is the ability to successfully bond to living tissues by means of engineered mechanisms such as the enhancement of biomineralization on a bone tissue engineering scaffold or the mimicking of the natural structure of the extracellular matrix (ECM). This ability is commonly referred to as "bioactivity". Materials sciences started to grow interest in it since the development of bioactive glasses by Larry Hench five decades ago. As the main goal in applications of biomedical devices and tissue scaffolds is to obtain a seamless tissue-material interface, achieving optimal bioactivity is essential for the success of most biomaterial based tissue replacement and regenerative approaches. Polymers derived from lactic acid are largely adopted in the biomedical field, they are versatile, FDA approved and relatively cost-effective. However, as for many other widespread biomedical polymers, they are hydrophobic and lack the intrinsic ability of positively interacting with surrounding tissues. In the last decades scientists have studied many solutions to exploit the positive characteristics of polylactide-based materials overcoming this bottleneck at the same time. The efforts of this research fruitfully produced many effective tissue engineering technologies based on PLA and related biopolymers. This review aims to give an overview on the latest and most promising strategies to improve the bioactivity of lactic acid-based materials, especially focusing on biomolecule-free bulk approaches such as blending, copolymerization or composite fabrication. Avenues for future research to tackle current needs in the field are identified and discussed. PMID- 30423691 TI - Solution rheological parameters modulate calcium phosphate mineralization in a microfluidic device. AB - Mineralization of calcium phosphate and other materials in vivo and in natural water sources occurs in solutions that are not stagnant, but are flowing. Flow conditions could influence solution mixing and, therefore, mineralization kinetics or mechanism. This work describes the design and characterization of a multi-stream parallel flow microfluidic device that allows for controlled solution mixing and indirect control of laminar flow by altering the microfluidic device width, shape, length, flow rate, and flow velocity. Measurement of solution mixing was accomplished using the protonation of quinine to produce a fluorescent molecule and the rate of calcium phosphate mineralization was monitored by optical microscopy and analysis with Image J software. Experiments were designed to hold the flow rate constant, allowing the solution velocity to vary and to hold the velocity constant, allowing the flow rate to vary. It was found that small changes in laminar flow conditions do not correlate to mineral growth, but solution velocity and flow rate have a substantial effect on calcium phosphate mineralization. AFM and SEM characterization of the mineral produced shows an amorphous material and varying degrees of mineralization possibly due to variation in supersaturation conditions across the solution mixing area. This microfluidic device and analysis procedure allows for improved study of mineralization and the effect of flow conditions relevant to those seen in biological settings. PMID- 30423692 TI - Reconstructing nanofibers from natural polymers using surface functionalization approaches for applications in tissue engineering, drug delivery and biosensing devices. AB - Previously, the nanofibers were predominantly fabricated from synthetic polymers due to their excellent mechanical properties. Understanding the different complex processes in fabrication and various process parameters involved have not only allowed the use of natural polymers for fabricating nanofibers but also broadened the scope of applications. To date, many of the natural polymeric composites have been fabricated by different functionalization techniques to increase their applicability. Nanofibers fabricated from natural polymers have been chemically functionalized by a variety of molecules like drugs, enzymes, metal ions etc. by techniques such as plasma treatment, wet chemical method, graft polymerization and co-electrospinning of surface-active molecules. Furthermore, the nanofibers derived from natural polymers have been surface-coated on the synthetic polymers to induce extracellular matrix mirroring properties like cell adhesion, migration, proliferation and differentiation. In this review, we have not only investigated the various novel and facile functionalization approaches but potential properties and applications are discussed as well. The various surface chemistry modifications of the natural polymeric nanofibers and their potential applications in drug delivery, enzymology, catalysis, filtration, biosensing and tissue engineering are discussed. In addition, a brief presentation of an overview of challenges and future scope with the aim of making them a clinical success has been presented. PMID- 30423693 TI - In vitro biocompatibility of new bioactive lithia-silica glass-ceramics. AB - Glass-ceramics based on the Li2O-SiO2 system have been extensively used as restorative dental materials due to their excellent chemical durability, aesthetics, inertness in the buccal environment, and high fracture strength; but they are not bioactive. On the other hand, all known bioactive glasses show ability to bond to bone, teeth and cartilage coupled to osteoconduction and osteoinduction, but their fracture strength and toughness are rather low. The aim of this study is to develop and evaluate the in vitro biocompatibility of a new type of (bioactive and strong) lithia-silica glass-ceramic. For these purposes, two types of glass-ceramics based on a multicomponent lithia-silica system were studied: lithium metasilicate (LM) and lithium disilicate (LD). The in vitro bioactivity study was conducted in a SBF solution, before and after different times of immersion; the new materials were analyzed by XRD, FTIR, and SEM. Some samples were subjected to in vitro biodegradation tests to quantify the release of lithium and the weight loss. Cytotoxicity, adhesion, and cell proliferation on different samples were examined by using the Methyl Tetrazolium salt (MTS) and Alizarin Red. For ~40 vol% crystallinity, lithium metasilicate was detected as the major phase, whereas for ~80 vol% crystallinity, lithium disilicate was the major phase. The LD proved to be strong (3p-bending strength of 233 +/- 12 MPa) and bioactive after 14 days of immersion in SBF. In terms of lithium ion release, the LD was outside the toxic range (>8.3 ppm). The LM and LD are not cytotoxic. The LD shows the best cellular adhesion and proliferation, leading to the formation of a mineralized matrix after 21 days. These results clearly suggest that the new LD brand is strong and highly biocompatible and warrants further study. PMID- 30423694 TI - Bi-layered silane-TiO2/collagen coating to control biodegradation and biointegration of Mg alloys. AB - Magnesium alloys have shown high potential as biodegradable implants for bone repair applications. However, their fast degradation in physiological media demands tuning their corrosion rate to accompany the natural tissue healing processes. Here, a new bi-layered silane-TiO2/collagen coating efficient in stabilizing and biofunctionalizing the surface of AZ31 and ZE41 Mg alloys is presented. Corrosion tests performed in cell culture medium over 7 weeks showed that the bi-layered coating promotes the formation of a stable layer of Mg(OH)2/MgCO3/CaCO3 that provides effective protection to the alloys at advanced immersion stages. The intrinsic reactivity of each alloy plus formation of transitory calcium phosphate phases, resulted in distinct corrosion behavior in the short term. Cell experiments showed that the bi-layered coating improved osteoblasts and fibroblasts proliferation compared to bare and silane-TiO2-coated alloys. Different responses in terms of cell adhesion could be related to the intrinsic corrosion rate of each alloy and some toxicity from the alloying elements. The results evidenced the complex interplay between alloy nature, coating-alloy combination and cell type. The silane-TiO2/collagen coating showed to be a promising strategy to improve cell response and viability and to control degradation rate of Mg alloys in the long term. PMID- 30423695 TI - Microencapsulation of garlic oil by beta-cyclodextrin as a thermal protection method for antibacterial action. AB - The present study investigated the encapsulation process of garlic oil in beta cyclodextrin (betaCD) and the antibacterial properties of the betaCD-garlic oil complex against Escherichia coli and Staphylococcus aureus. The encapsulation method increased the thermal stability of garlic oil with a formation constant (Kc) value of 253.78 L.mol-1 for of the betaCD-garlic oil complex, which confirmed the success of the encapsulation process. Scanning electron microscopy analysis showed that the dimensions of the structures formed by the inclusion complex of betaCD-garlic oil had values ranging from 5 to 10 MUm. After thermal treatment of the betaCD-garlic oil complex at 60 degrees C for 1 h, the complex retained significant antibacterial action. The minimum inhibitory concentration (MIC) and agar diffusion results showed that the microcapsules containing 81.73 mmol.L-1 garlic oil exhibited excellent antibacterial action. PMID- 30423696 TI - Evaluation of surface properties of low density polyethylene (LDPE) films tailored by atmospheric pressure non-thermal plasma (APNTP) assisted co polymerization and immobilization of chitosan for improvement of antifouling properties. AB - This work describes the development of antifouling functional coatings on the surface of low density polyethylene (LDPE) films by means of atmospheric pressure non-thermal plasma (APNTP) assisted copolymerization using a mixture of acrylic acid and poly (ethylene glycol). The aim of the study was to investigate the antifouling properties of the plasma copolymerized LDPE films and the same was carried out as a function of deposition time with fixed applied potential of 14 kV. In a second stage, the plasma copolymerized LDPE films were functionalized with chitosan (CHT) to further enhance its antifouling properties. The surface hydrophilicity, structural, topographical and chemistry of the plasma copolymerized LDPE films were examined by contact angle (CA), X-ray diffraction (XRD), atomic force microscopy (AFM), Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). Coating stability was also studied in detail over a storage time of 15 days by storing in water and air. The antifouling properties of the plasma copolymerized LDPE films were examined via protein adsorption and platelet adhesion studies. CA study showed significant changes in surface wettability after the coating process. XPS and FTIR analysis proved the presence of a dense multifunctional coating and an efficient immobilization of CHT. Substantial amendments in surface topography were observed, positively enhancing the overall surface hydrophilicity. Finally, in vitro analysis showed excellent antifouling behavior of the surface modified LDPE films. PMID- 30423697 TI - Optimization of silver-containing bioglass nanoparticles envisaging biomedical applications. AB - Bioglass nanoparticles (BGs) are of outmost importance in the biomedical field, because their unique characteristics, namely osteoconductivity and osteoinductivity, and also in certain conditions, angiogenic and bactericidal properties. In this work, novel bioglass nanoparticles containing silver (AgBGs) were synthesized by a sol-gel method, adopting different thermal treatments to obtain new nanoparticles with bioactive and antibacterial features. This is the first systematic study of the effect of the thermal treatment on the properties of AgBGs. The effect of the studied thermal treatments on the properties of synthesized nanoparticles was analyzed by several characterization techniques: FT IR, XRD, S-TEM, SEM-EDS and Zeta potential. FT-IR allowed the identification of the characteristic peaks of the nanoparticles and XRD revealed the presence of the characteristic peaks of an apatite-like phase. By S-TEM analysis it was found that the produced nanoparticles are dense and have a diameter <200 nm. The SEM micrographs showed their surface morphology and Zeta potential measurements were performed to study their suspension stability. Additionally, in vitro bioactivity tests confirmed their bioactive potential and the microbiological tests evidenced their bactericidal effect. These promising AgBGs could be incorporated either in 2D or 3D structures for several biomedical applications, namely in the orthopedic and dental fields. PMID- 30423698 TI - pH-sensitive amphiphilic triblock copolymers containing ortho ester main-chains as efficient drug delivery platforms. AB - Triblock copolymer PEG-block-poly(ortho ester urethane)-block-PEG (PEG-POEU-PEG) was conveniently prepared via polycondensation reaction between the ortho ester containing diol and hexamethylene diisocyanate (HDI) at varying reaction time followed by termination with polyethylene glycol monomethyl ether (mPEG). PEG POEU-PEG could further self-assemble into nano-scaled micelles. Ortho ester degradation in these micelles was significantly accelerated at pH 5.0 due to its pH sensitivity. In vitro drug release profiles showed that only a small amount of the loaded DOX was released in PBS solution at pH 7.4, while DOX could be quickly released at pH 5.0. MTT assay reveals that the micelles were completely nontoxic to cultured cells. Moreover, DOX-loaded micelles exhibited efficient antitumor efficiency against cancer cells. Therefore, the micelles may be potential drug carriers in cancer therapy. PMID- 30423699 TI - Melanin incorporated electroactive and antioxidant silk fibroin nanofibrous scaffolds for nerve tissue engineering. AB - Nerve restoration and repair in the central nervous system is complicated and requires several factors to be considered while designing the scaffolds like being bioactive as well as having neuroinductive, neuroconductive and antioxidant properties. Aligned electrospun nanofibers provide necessary guidance and topographical cues required for directing the axonal and neurite outgrowth during regeneration. Conduction of nerve impulses is a mandatory feature of a typical nerve. The neuro-conductive property can be imparted by blending the biodegradable, bioactive polymers with conductive polymers. This will provide additional features, i.e., electrical cues to the already existing topographical and bioactive cues in order to make it a more multifaceted neuroregenerative approach. Hence in the present study, we used a combination of silk fibroin and melanin for the fabrication of random and aligned electrospun nanofibrous composite scaffolds. We performed the physico-chemical characterization and also assessed their antioxidant properties. We also evaluated their neurogenic potential using human neuroblastoma cells (SH-SY5Y) for their cellular viability, proliferation, adhesion and differentiation levels. Designed nanofibrous scaffolds had adequate physical properties suitable as neural substrates to promote neuronal growth and regeneration. They stimulated the neuroblastoma cell attachment and viability indicating their biocompatible nature. Silk/melanin composite scaffolds have specifically exhibited high antioxidant nature proven by the radical scavenging activity. Additionally, the melanin incorporated aligned silk fibroin scaffolds promoted the cell differentiation into neurons and orientation along their axis. Our results confirmed the potential of melanin incorporated aligned silk fibroin scaffolds as the promising candidates for effective nerve regeneration and recovery. PMID- 30423700 TI - Silk scaffolds with gradient pore structure and improved cell infiltration performance. AB - Electrospun scaffold with three-dimensional (3D) geometry and appropriate pore structure is an important challenge to mimic natural tissues such as skin, cartilage, etc. In this work, 3D silk fibroin (SF) electrospun scaffolds with gradient pore size were prepared by combining multi-step electrospinning with low temperature (LTE) collecting. The LTE electrospun scaffolds achieved 3D macro structure with large pore size. The effects of relative humidity (RH), collecting temperature on the morphology of the scaffolds were investigated by scanning electron microscopy and computed tomography. The pore size of the scaffolds was tailored by adjusting SF concentration, electric field, flow rate, needle gauge and collector temperature during electrospinning at 50% RH. L929 cell infiltration results of the scaffolds showed that conventional electrospun scaffolds with small pore size (average diameter 5.9 +/- 1.4 MUm) restrained cell proliferation and infiltration. On the contrary, LTE electrospun scaffolds with medium pore size (average diameter 11.6 +/- 1.4 MUm) improved cell proliferation obviously. Large pore size scaffolds (average diameter 37.2 +/- 12.9 MUm) was beneficial to cell infiltration depth in the thickness direction of the scaffolds. The scaffolds, which were integrated with layers of small, medium and large pores, are promising in the repair of tissue with gradient pore structures. PMID- 30423701 TI - Polypyrrole-coated poly(l-lactic acid-co-epsilon-caprolactone)/silk fibroin nanofibrous nerve guidance conduit induced nerve regeneration in rat. AB - According to our previous study, polypyrrole (Ppy) possessed good conductivity and non-cytotoxicity. In this study, the surface of electrospun poly(l-lactic acid-co-epsilon-caprolactone)/silk fibroin (PLCL/SF) was coated with Ppy to fabricate Ppy-coated nerve guidance conduit (NGC). Firstly, the presence of Ppy on the prepared NGC was characterized and confirmed by scanning electron microscopy (SEM), X-ray photoelectron spectroscopic spectra (XPS) and Fourier transforms infrared spectroscopy (FTIR). Subsequently, Ppy-coated NGC was used to repair a 10 mm sciatic nerve gap in vivo. 4 and 12 weeks after implantation, the regenerated nerve tissues on defect sites were removed and sectioned for further evaluation. Histological analysis with hematoxylin-eosin (HE), toluidine blue (TB), and luxol fast blue (LFB) staining indicated that the coated Ppy could promote SCs proliferation in early post-surgery, and enhance myelin formation in later post-surgery. In consideration of immunofluorescence and morphology observation with SEM and TEM, it showed that the nerve regeneration of Ppy-coated NGC group was close to autograft group, which was better than PLCL/SF NGC. In addition, walking track analysis indicated that Ppy-coated NGC group showed a similar performance compared with the autograft group, and significantly better than PLCL/SF NGC group. These promising results showed the potential of Ppy coated NGC in peripheral nerve regeneration. PMID- 30423702 TI - Effects of acid-alkali treatment on bioactivity and osteoinduction of porous titanium: An in vitro study. AB - BACKGROUND: To elucidate the bioactivity and bone regeneration of porous titanium surfaces treated using acid-alkali combination, and to define the optimal alkali reaction time. METHODS: Ten groups of porous Ti with at least 3 per group undergoing different acid-alkali treated time were prepared. The surface was characterized by scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), bicinchoninic acid method (BCA), optical contact angle measurement and Raman spectrometry. Compression testing was performed with a universal testing machine. The bioactivity and osteoinduction were evaluated by a series of biological tests using a simulated body fluid (SBF) test, cell proliferation test, vinculin, ALP and OCN expression, and cell mineralization. RESULTS: The acid-alkali treatment formed micro- and nano-scale structures on the sample surfaces. The alkali treatment for 12 h achieved the sharpest nano-scale surface relief and the most protein absorption. The treated porous surface was coated with a NaHTiO3 layer. The acid-alkali etching did not compromise the elastic modulus and compressive strength of the porous Ti samples. In addition to hydroxyapatite, a perovskite phase was also formed on the treated porous samples in SBF. Non-treated dense Ti showed more cell adhesion and proliferation (P < 0.05), while osteoinduction and mineralization were more pronounced on the treated porous sample (P < 0.05). CONCLUSION: Acid-alkali treatment is an effective means of generating nano-scale relief on porous Ti surface, and is beneficial for bioactivity and bone regeneration. The 15 min acid and 12 h alkali etching is the optimal combination. The osteoinductive efficacy may be attributable to the surface physical chemistry and the formation of hydroxyapatite and perovskite layers, rather than direct cell adhesion and proliferation. PMID- 30423703 TI - Enhanced oxidation stability of highly cross-linked ultrahigh molecular weight polyethylene by tea polyphenols for total joint implants. AB - Despite being currently state-of-the-art to prevent the oxidation of irradiated ultrahigh molecular weight polyethylene (UHMWPE) bearings, vitamin E (VE) poses concerns in the loss of cross-linking efficiency and is limited to be used at very low concentrations. It thus emphasizes the urgent demand for more efficient stabilizers. In this study, oxidation stability of highly cross-linked UHMWPE was demonstrated to be enhanced by tea polyphenols, such as lipid-soluble tea polyphenols (lsPPT), epigallocatechin gallate (EGCG), and lipid-soluble epigallocatechin gallate (lsEGCG). These antioxidants were blended with UHMWPE granules and consolidated by compression molding prior to E-beam irradiation. The presence of tea polyphenols substantially prolonged oxidation induction time of the irradiated UHMWPE before and after accelerated aging. Especially, lsEGCG was significantly superior to VE in terms of stabilizing capacity. Explained by the hydrogen donation mechanism, tea polyphenols with multiple phenolic hydroxyls could scavenge more radiation-induced free radicals than VE with only one phenolic hydroxyl, which was verified by the electron spin resonance spectra. Intriguingly, tea polyphenols showed less inhibitive effect on the cross-link density of irradiated UHMWPE than VE. Besides, there is no significant difference in crystallinity, mechanical performance as well as in vitro biocompatibility between the irradiated UHMWPE stabilized by tea polyphenols and VE. These findings highlight tea polyphenols, especially lsEGCG, are promising alternatives to extend the life span of UHMWPE implants. PMID- 30423704 TI - Phthalocyanine photosensitizer in polyethylene glycol-block-poly(lactide-co benzyl glycidyl ether) nanocarriers: Probing the contribution of aromatic donor acceptor interactions in polymeric nanospheres. AB - For best photosensitizer activity phthalocyanine dyes used in photodynamic therapy should be molecularly dispersed. Polyethylene glycol-block-polylactide derivatives presenting benzyl side-groups were synthesized to encapsulate a highly lipophilic phthalocyanine dye (AlClPc) and evaluate the effect of pi-pi interactions on the nanocarrier colloidal stability and dye dispersion. Copolymers with 0, 1, 2 and 6 mol% of benzyl glycidyl ether (BGE) were obtained via polyethylene glycol initiated ring-opening copolymerization of D,l-lactide with BGE. The block copolymers formed stable, monodisperse nanospheres with low in vitro cytotoxicity. AlClPc loading increased the nanosphere size and affected their colloidal stability. The photo-physical properties of the encapsulated dye, studied in batch and after separation by field flow fractionation, demonstrated the superiority of plain PEG-PLA over BGE-containing copolymers in maintaining the dye in its monomeric (non-aggregated) form in aqueous suspension. High dye encapsulation and sustained dye release suggest that these nanocarriers are good candidates for photodynamic therapy. PMID- 30423705 TI - In silico and in vitro study of magnetic niosomes for gene delivery: The effect of ergosterol and cholesterol. AB - A low transfection efficiency and failure to deliver therapeutic genes to target organs limit the use of vesicular systems in gene therapy. In this study, magnetic niosomes were used to improve transfection efficiency and overcome limitations. In this light, Tween 60 and Span 60 molecules were employed as the bilayer component and ergosterol and/or cholesterol as membrane-stabilizing agents. We studied the structural and dynamical properties of cholesterol containing niosomes (ST60/Chol) and ergosterol-containing vesicles (ST60/Ergo) using the molecular dynamics (MD) simulation technique. In in vitro experiments, the protamine-condensed DNA along with magnetic nanoparticles were prepared and incorporated into the niosome to form magnetic niosome-entrapped protamine condensed DNA (M-NPD). The MD simulation comparison of two bilayers showed that the ST60/Ergo vesicles have better properties for gene delivery. Our in vitro results confirmed the in silico results and revealed that Ergo-niosomes have smaller size, better polydispersity, and slower release of plasmid than Chol niosome. Moreover, M-NPD-Ergo showed higher cellular uptake and gene expresssion in HEK-293T cell line compared to M-NPD-Chol vesicles. PMID- 30423706 TI - Targeting graphene quantum dots to epidermal growth factor receptor for delivery of cisplatin and cellular imaging. AB - The unique properties of graphene quantum dots (GQDs) which include high loading capacity, excellent physiological stability, strong photoluminescence, biocompatibility, and facile production make them attractive nanomaterials for biomedical applications. In this work, GQDs have been explored as dual-functional targeted drug carriers and cellular bioimaging agents. The GQDs were conjugated to single chain variable fragment of antibody (scFv), which had been engineered with high affinity (B10) to epidermal growth factor receptor (EGFR), via amide covalent linkages (GQDs-scFvB10). The morphology and surface modification of GQDs were characterized by HRTEM, SDS-PAGE, FT-IR, UV-vis and fluorescence spectroscopies. Western blot analysis along with the confocal imaging of EGFR overexpressing breast cancer cells (MDA-MB-231) demonstrated the targeting functionality of scFvB10 after conjugation to the GQDs, as well as the potential application of GQDs-scFvB10 in targeted bioimaging. The surface of targeted GQDs had a high cisplatin (CDDP) loading capacity of 50% and a pH-dependent release with slower release rate at neutral conditions, which can reduce the commonly observed systemic toxicity of CDDP. The targeted CDDP-loaded nanocarriers ((CDDP)GQDs-scFvB10) exhibited significantly higher toxicity on MDA-MB-231 cells compared to non-targeted ones suggesting their efficient uptake through EGFR. In contrast, cells with saturated EGFR showed lower uptake and cytotoxic effect of (CDDP)GQDs-scFvB10, demonstrating selectivity of the nanocarriers towards EGFR overexpressing cells. The scFvB10-functionalized GQD is a promising platform for targeted cellular imaging and delivery of CDDP through interactions with EGFRs. PMID- 30423707 TI - Nano-curcumin incorporated polyethersulfone membranes for enhanced anti biofouling in treatment of sewage plant effluent. AB - Biofouling is a severe problem in membrane systems which hampers their broad applications because it requires regular chemical cleaning, reduces membrane life, and also decreases product quality. In this study, nanocurcumin (CCM) was prepared by sonication-assisted wet-milling technique and then incorporated in polyethersulfone (PES) membrane to enhance the anti-biofouling property. TEM analysis of the curcumin showed that nanomaterials are spherical. FTIR studies confirmed that the presence of CCM nanomaterial in PES membrane. Zone inhibition studies revealed that PES/CCM nanocomposite membranes exhibited the better anti biofouling propensity against Escherichia coli and Pseudomonas aeruginosa. Static adhesion studies also showed that PES/CCM nanocomposite membranes prevented the attachment and proliferation of E. coli cells. Also, PES/2 wt% CCM nanocomposite membrane had a high thermal degradation temperature of 575.62 degrees C and tensile strength of 1.87 MPa. Moreover, addition of CCM nanomaterial in casting solution altered the membrane morphology and hydrophilicity. Further, pure water flux was increased up to 64.48 L.m-2.h-1 for PES/2 wt% CCM nanocomposite membrane. Filtration of raw sewage treatment plant effluent was also carried out. The incorporation of curcumin in membranes was effectively improved the antifouling tendency without compromised affecting the chemical oxygen demand reduction. This study highlights the anti-biofouling potential of CCM incorporated PES nanocomposite membranes, which could be utilized for various filtration applications. PMID- 30423708 TI - The first one-pot synthesis of undoped and Eu doped beta-NaYF4 nanocrystals and their evaluation as efficient dyes for nanomedicine. AB - Polygonal-shaped about 75 nm sized and highly crystallized Eu3+-doped beta-NaYF4 particles were directly prepared under mild conditions using the polyol process. A set of operating parameters were optimized for such a purpose. A conventional heating under reflux for 30 min of a mixture of Y(III) and Eu(III) acetate, ammonium fluoride, sodium hydroxide and oleic acid (OA) dissolved in ethyleneglycol offered a pertinent material processing route if a large excess of NH4F and an enough amount of OA were used. Typically, the former parameter provides an exclusive stabilization of the desired beta allotropic form, while the latter allows a significant size decrease of the particles. Thanks to their coating by a double OA layer, the produced particles exhibited a hydrophilic surface feature when dispersed in water and when excited under UV light they emitted a very intense red photoluminescence. Additionally, they did not evidence any accurate cytotoxicity when incubated with healthy human foreskin fibroblast (BJH) cells for doses as high as 50 MUg.mL-1 and contact time as long as 48 h, highlighting the ability of the prepared particles to be used as efficient down converter light sources for cell labelling. PMID- 30423709 TI - A facile surface modification strategy for fabrication of fluorescent silica nanoparticles with the aggregation-induced emission dye through surface-initiated cationic ring opening polymerization. AB - Fluorescent silica nanoparticles (FSNPs) have attracted great interest for potential applications in biological and biomedical fields because they possess higher fluorescence quantum yield and better fluorescence stability as comparison with small organic fluorescent molecules. The encapsulation of covalent linkage with fluorescent organic dyes or fluorescent metal complexes has demonstrated to be the commonly adopted strategies for fabrication of FSNPs previously. However, it is still challengeable to obtain FSNPs based polymer composites with intensive fluorescence and good water dispersibility through a one-pot surface modification strategy. In this paper, we developed a facile method to fabricate novel FSNPs based polymer composites (PhE@MSNs-PEtOx) through introducing the aggregation induced emission (AIE) dye (PhE-OH) and poly(2-ethyl-2-oxazoline) (PEtOx) onto mesoporous silica nanoparticles (MSNs) based on cationic ring opening polymerization (CROP). The resulting PhE@MSNs-PEtOx composites possess strong fluorescence emission, excellent hydrophilicity and biocompatibility. These features make the final FSNPs based polymer composites great potential for biomedical applications. Taken together, we have developed for the first time that FSNPs based polymer composites can be facilely prepared through the one-pot introduction of AIE dyes and hydrophilic PEtOx on MSNs. Moreover, the novel FSNPs based composites could also be utilized for other biomedical applications considered their properties. PMID- 30423710 TI - Structural, physico-mechanical and in-vitro bioactivity studies on SiO2-CaO-P2O5 SrO-Al2O3 bioactive glasses. AB - Strontium based bioactive glasses have shown a better biocompatibility than calcia based bioactive glasses. In this report, we have shown that the bioactivity is found to be even more when we incorporate Al2O3 upto 1.5 mol% in SiO2-CaO-P2O5-SrO bioactive glass. We have studied the structural, physico mechanical and bioactive properties in these glasses with varying alumina concentration from 0.5 to 2.5 mol%. The bioactivity of the glasses is evaluated by in vitro test in simulated body fluid (SBF). The formation of hydroxy carbonated apatite layer (HCA) on the surface of glasses after immersion in SBF is identified by the XRD, FTIR and SEM. The substitution of Al2O3 for SrO in these glasses demonstrates a significant enhancement in compressive strength and elastic modulus. However cytotoxicity and cell viability assessed using human osteosarcoma U2-OS cell lines show the growth of the cells without causing any significant loss of viability and cell death upto 1.5 mol% addition of Al2O3. Osteosarcoma cells grow on the surface of bioglasses which make them biocompatible and fit for use in clinical trials. PMID- 30423711 TI - Synthesis of multifunctional Fe3O4@PLGA-PEG nano-niosomes as a targeting carrier for treatment of cervical cancer. AB - A new folic acid (FA)-conjugated poly (lactic-co-glycolicacid) (PLGA) polyethylene glycol (PEG) nano-noisome was prepared. The noisome was employed as a drug delivery system to load curcumin (Cur) as a model drug and fluorescent probe for cervical cancer therapy and cell imaging. The Fe3O4@PLGA-PEG@FA noisomes were prepared through facile emulsion solvent evaporation and conjugation chemistry method, possessing the properties of high rapid magnetic separation and targeting character. X-ray photoelectron spectroscopy (XRD), Fourier transform infrared spectroscopy (FTIR), dynamic light scattering (DLS), thermogravimetric analysis (TGA), and vibrating sample magnetometer (VSM) were adopted to characterize the chemical structure and properties of these niosomes. MTT assay revealed that the blank noisomes exhibited excellent biocompatibility. The in vitro drug loading and release behavior studier showed the as prepared nano-noisome presented ultrahigh performance as drug carrier. The confocal laser scanning microscopy (CLSM) and flow cytometry (FCM) experiments demonstrated that Cur-loaded Fe3O4@PLGA-PEG@FA niosomes achieved significantly high targeting efficiency for cervical cancer. Additionally, the FA-targeted niosomes exhibited higher antitumor efficiency than free Cur. Cell morphology, the mitochondrial membrane potential and cell cycle changes indicated that Cur-loaded niosomes induced HeLa229 cells to apoptosis by destroying mitochondrion of cervical tumor cells, simultaneously changing nuclear morphology and blocking tumor cell proliferation. These results demonstrate that Fe3O4@PLGA-PEG@FA noisomes have promising applications as targeted drug delivery system for sustained drug release in cancer treatment. PMID- 30423712 TI - Development and evaluation of novel nanophotosensitizers as photoantimicrobial agents against Staphylococcus aureus. AB - The main aim of the present study was to synthetize polyacrylamide nanoparticles and to use them as photosensitizer carriers. The new monobrominated derivatives (monobrominated neutral red and monobrominated azure B) were the photosensitizers used for antimicrobial photodynamic therapy. They were loaded into the nanocarriers and their antibacterial and oxidative activities were evaluated. The polyacrylamide nanoparticles were evaluated and prepared by inverse microemulsion polymerization. The nanoparticles obtained were characterized by size, polydispersity index, and zeta potential analysis. The Dynamic Light Scattering indicated that the diameter of the particle (z-average) was optimal, with an acceptable polydispersity index. The antibacterial activity of the polyacrylamide nanoparticles loaded with photosensitizers was evaluated against Staphylococcus aureus. Both photosensitizers loaded into the nanoparticles showed great potential as antibacterial agents since they suppressed the bacterial growth. The maximum percentage of growth reduction was 35.5% (>2 Log CFU/mL), with the monobrominated azure B loaded into the nanocarrier with 2 hydroxyethyl methacrylate against methicillin resistant S. aureus. The improved physicochemical and photophysical properties of these photosensitizers were accompanied by a significant increase in the photoantimicrobial action, in conventional-sensitive and-methicillin resistant S. aureus. The results obtained clearly suggest that polyacrylamide nanoparticles loaded with photosensitizers have great potential for further application in antimicrobial photodynamic therapy. PMID- 30423713 TI - Fabrication and biological imaging of hydrazine hydrate cross-linked AIE-active fluorescent polymeric nanoparticles. AB - Amphiphilic copolymers play a paramount role in the fabrication of fluorescent polymeric nanoparticles (FPNs) through the self-assembly procedure. In this work, novel hydrazine hydrate cross-linked amphiphilic poly(PEG-co-FHMA) copolymers were constructed via reversible addition-fragmentation chain transfer (RAFT) polymerization, containing an aggregation-induced emission (AIE) active hydrophobic moiety and a hydrophilic poly(ethylene glycol) (PEG) group. Different characterization techniques have been employed to confirm their successful synthesis. Due to their amphiphilic property, the resulting poly(PEG-co-FHMA) copolymers can self-assemble into FPNs in aqueous solution and form poly(PEG-co FHMA) FPNs with size ranging from 100 to 200 nm. The investigation of photophysical properties demonstrated poly(PEG-co-FHMA) FPNs possess strong fluorescence, large Stokes shift, excellent AIE characteristic, low critical micelle concentration and remarkable photostability. Biological assay results suggested that these cross-linked AIE-active FPNs are of low toxicity and excellent cell dyeing performances. All of these features make them promising candidates for biomedical applications. As compared with typical AIE-active FPNs based on the synthetic AIE-active compounds, the novel cross-linked AIE-active FPNs based on the Schiff base is rather simple, good designable and universal. More importantly, this strategy could also be adopted for preparation of a large number of AIE-active FPNs because of the well designability of copolymers and salicylaldehyde derivatives. Thus this work will provide a novel route for preparation of multifunctional AIE-active FPNs in a rather facile manner. PMID- 30423714 TI - Designing cotton fibers impregnated with photocatalytic graphene oxide/Fe, N doped TiO2 particles as prospective industrial self-cleaning and biocompatible textiles. AB - Our study reports the fabrication and characterization (surface morphology, hydrophobicity/hydrophilicity, photocatalytic efficiency) of cotton fibers treated by various methods with graphene oxide decorated with Fe, N-doped TiO2 nanoparticles. Designed as prospective industrial self-cleaning, antimicrobial and biocompatible textiles, microbiological and cytotoxicity tests were performed on these particles-treated fibers to validate their qualities. The photocatalytic effect was dependent on chemicals used to disperse the nanoparticles, the parameters of the treatment, the fiber structure and composition of the material. The double and triple treatment of the textiles with the same particle dispersion resulted in a relatively uniform coverage of cotton fibers with relatively large amounts of particles. A larger amount of doped TiO2 particles demonstrated a better photocatalytic effect under visible light. The material's hydrophobicity increased with the number of treatments due to the deposition of successive layers of reduced graphene, ensuring self-cleaning properties. The photocatalyst treated cotton fabrics exhibited an increased resistance to Enterococcus faecalis and Escherichia coli colonization, and also high biocompatibility, as they did not affect the cell viability, membrane integrity and morphology, nor induce inflammation. All these data confirm the improved properties of cotton fibers treated with graphene oxide decorated with Fe, N-doped TiO2 particles in order to be used as industrial self-cleaning and biocompatible textiles. PMID- 30423715 TI - Self-assembling antimicrobial peptides on nanotubular titanium surfaces coated with calcium phosphate for local therapy. AB - Bacterial infection is a serious medical problem leading to implant failure. The current antibiotic based therapies rise concerns due to bacterial resistance. The family of antimicrobial peptides (AMP) is one of the promising candidates as local therapy agents due to their broad-spectrum activity. Despite AMPs receive increasing attention to treat infection, their effective delivery to the implantation site has been limited. Here, we developed an engineered dual functional peptide which delivers AMP as a biomolecular therapeutic agent onto calcium phosphate (Ca-P) deposited nanotubular titanium surfaces. Dual functionality of the peptide was achieved by combining a hydroxyapatite binding peptide-1 (HABP1) with an AMP using a flexible linker. HABP functionality of the peptide provided a self-coating property onto the nano-topographies that are designed to improve osteointegration capability, while AMP offered an antimicrobial protection onto the implant surface. We successfully deposited calcium phosphate minerals on nanotubular titanium oxide surface using pulse electrochemical deposition (PECD) and characterized the minerals by XRD, FT-IR, FE-SEM. Antimicrobial activity of the engineered peptide was tested against S. mutans (gram- positive) and E. coli (gram-negative) both in solution and on the Ca-P coated nanotubular titanium surface. In solution activity of AMP and dual functional peptide have the same Minimum Inhibitory Concentration (MIC) (32 mg/mL). The peptide also resulted in the reduction of the number of bacteria both for E.coli and S. mutans compare to control groups on the surface. Antimicrobial features of dual functional peptides are strongly correlated with their structures suggesting tunability in design through linkers regions. The dual function peptide offers single-step solution for implant surface functionalization that could be applicable to any implant surface having different topographies. PMID- 30423716 TI - pH responsive selective protein adsorption by carboxylic acid functionalized large pore mesoporous silica nanoparticles SBA-1. AB - Cubic mesoporous silica nanoparticles (MSNs) with the SBA-1 moiety, functionalized with carboxylic acid (COOH) groups as well as enlarged mesopores, are successfully synthesized using tetraethyl orthosilicate (TEOS) and carboxyethylsilanetriol sodium salt (CES) as silica sources, complexes formed by polyacrylic acid (PAA) and hexadecylpyridinium chloride (CPC) as templates, and trimethylbenzene (TMB) as pore expander. The successful incorporation of organic functionalities are confirmed by 13C and 29Si solid-state NMR. The structural properties of cubic mesostructures are characterized by powder XRD, N2 adsorption desorption isotherms, and TEM measurements. The prepared MSNs exhibit a remarkably high adsorption capacity of 1138 mg g-1 at pH 8.2 when they are used as the supports to immobilize papain. Both factors of the large pore size of the support and the favorable electrostatic attractions between the carboxylate groups on the adsorbent surface and the papain molecules play important roles in reaching such a high adsorption capacity. The immobilized papain possesses better thermal stability, pH tolerance, and heat resistance in comparison to the free papain. The materials are also used for selective adsorption of a single protein (papain) from the binary mixture of two different types of proteins (papain and hemoglobin). Our results demonstrate that proteins such as papain and hemoglobin with different isoelectric points and shapes can be effectively separated from their binary mixture by simply tuning the pH of the buffer. PMID- 30423717 TI - Silk fibroin/collagen/hyaluronic acid scaffold incorporating pilose antler polypeptides microspheres for cartilage tissue engineering. AB - A silk fibroin/collagen/hyaluronic acid (SF/COL/HA) composite scaffold was prepared via admixing, crosslinking, and lyophilizing processes. We studied its physicochemical and biological properties, such as water absorption, porosity, weight loss, and biocompatibility. The optimal ratio of SF/COL/HA scaffold was 3:6.5:0.5. Then, the optimal ratio of scaffold incorporating pilose antler polypeptides (PAPs)-PLGA microspheres was prepared, and their compatibility was studied. PAP-SF/COL/HA scaffold had favorable adhesion and proliferation. A rabbit cartilage defect model was established. The repair effect of cartilage defects was observed and evaluated among PAP-SF/COL/HA, SF/COL/HA, and sham operation groups. The defects were almost completely repaired after 13 weeks in the PAP-SF/COL/HA group, thereby indicating that the PAP-SF/COL/HA composite had a favorable effect on articular cartilage repair. PMID- 30423718 TI - Investigation of the wear and corrosion behaviors of Ti5Al2.5Fe and Ti6Al4V alloys produced by mechanical alloying method in simulated body fluid environment. AB - In this study, wear and electrochemical corrosion behaviors of the Ti5Al2.5Fe and Ti6Al4V alloys produced with the mechanical alloying method were examined in simulated body fluid environment. Ti5Al2.5Fe and Ti6Al4V powders were produced by grinding elemental powders in the mechanical alloying device for 120 min. The sintered alloys were characterized SEM, XRD, hardness and density measurements. Wear tests were performed in simulated body fluid environment using a pin-on-disk type wear testing device, under three different loads at four different sliding distances with 1 ms-1 sliding speed. Corrosion tests were performed using the potentiodynamic polarization technique and a cyclic polarization measurement. The density of the MA'ed Ti5Al2.5Fe and Ti6Al4V alloys respectively was measured as 4.314 g/cm3 and 4.427 g/cm3 and its hardness was found as 706.6 HV and 630 HV. Also, it was found dominant alpha-Ti phase in the alloys' structure. The wear resistance of Ti5Al2.5Fe alloy is higher than that of Ti6Al4V alloy. According to the corrosion test results, the Icorr value of the Ti5Al2.5Fe alloy was measured to be 18.24 mA/cm2, and the Icorr value of the Ti6Al4V alloy was measured to be 43.58 mA/cm2. The corrosion resistance of Ti5Al2.5Fe alloy is higher than that of Ti6Al4V alloy. After corrosion tests, formation of pits of different sizes on the surface of Ti5Al2.5Fe and Ti6Al4V alloys was found to dominate the pitting corrosion mechanism. PMID- 30423719 TI - Mechanically-enhanced polysaccharide-based scaffolds for tissue engineering of soft tissues. AB - Collagen-based materials are probably among the most used class of biomaterials in tissue engineering and regenerative medicine. Although collagen is often privileged for providing a suitable substrate on which cells can be cultured or a matrix in which cells can be dispersed, its mechanical properties represent a major limitation for clinical translation and even for handling of the obtained regenerated tissue. In this work, the combination of polysaccharides chitosan (Ch) and xanthan gum (X) was investigated as an alternative for scaffolds for soft tissue engineering. Moreover, in an attempt to reach a compromise between obtaining highly porous biomaterials while maintaining appropriate mechanical properties, a surfactant (Kolliphor(r) P188, K) was added to Ch-X matrices to generate pores, while silicone rubber (Silpuran(r) 2130A/B, S) was used to balance their mechanical properties. Addition of K (10 or 25% w/w) increased the porosity and pore-dimensions, while addition of S improved by up to 156% and 85% the elastic moduli and the elastic behavior of Ch-X-based scaffolds, under both compressive and tensile loads, respectively, at 50% strain. Relaxation tests confirmed that these materials do have a viscoelastic behavior. The presence of S increased thickness and microscale surface roughness and did not affect liquid uptake and stability, thrombogenicity, biodegradation and cytotoxicity of polysaccharide-based scaffolds. In conclusion, this work shows that Ch-X-S porous blends constitute suitable scaffolds for soft tissue engineering. PMID- 30423720 TI - Anti-bacterium influenced corrosion effect of antibacterial Ti-3Cu alloy in Staphylococcus aureus suspension for biomedical application. AB - Titanium and titanium alloys have been widely used as dental and orthopedic materials. The infection and the bacterium influenced corrosion both are concerned problems. Ti-3Cu alloy exhibits strong antibacterial properties against E. coli and S. aureus. The strong antibacterial properties of Ti-3Cu provides with a potential new method to reduce the bacterium influenced corrosion. S. aureus suspension was selected to simulate a serious bacterial condition. The corrosion behavior of Ti-3Cu alloy in S. aureus suspension was investigated by an electrochemical testing and an immersion test in comparison with pure titanium. Electrochemical results showed that Ti-3Cu exhibited a much better anti-corrosion property than cp-Ti in S. aureus suspension. Surface observation demonstrated that no corrosion pit was observed on Ti-3Cu alloy after 30 days immersion in the suspension while lots of corrosion pits were found on cp-Ti. The biofilm formation on the surface was observed by scanning electronic microscopy (SEM) in different periods. It has been revealed that S. aureus could grow and gather on the surface of cp-Ti to form biofilm after 18 h immersion, but only several bacteria were found on Ti-3Cu alloy even after 24 h immersion, displaying that Ti 3Cu alloy exhibits very strong anti-adhesion properties against S. aureus. It was concluded that Ti-3Cu performs a super anti-corrosion property due to the strong anti-adhesion property, in which Ti2Cu precipitate plays a critical role. PMID- 30423721 TI - Incorporation of chitosan-alginate complex into injectable calcium phosphate cement system as a bone graft material. AB - Calcium phosphate brushite type of cements have been used to replace bone graft materials because of their biocompatibility and other attractive features. Especially, injectability of cement allows easy handling of minimally invasive surgical techniques. New calcium phosphate cement (CPC) system, brushite based cement incorporated into polyelectrolyte complex, was developed in this study. Chitosan-alginate complex produced by an interaction between a cationic polymer (chitosan) and an anionic polymer (alginate) was loaded in the cement. This improved the functional properties and biocompatibility of the final cement. We optimized the liquid/solid (L/S) ratio of the cement components and investigated the compressive strength, setting time, pH change of CPC0 (with only citric acid) and CPC0.5, 1, and 1.5 (0.5, 1, and 1.5 v/v % chitosan-alginate complex in citric acid solution, respectively). The L/S ratio did not affect structural formation, while the addition of polymer complex showed new formation of macro-pores within CPC. However, a lower L/S ratio and higher amount of added polymer complex shortened the setting time and improved the compressive strength. The appropriate conditions for the injectable bone substitute were CPC1 with an L/S ratio of 0.45. To investigate the effect of the chitosan-alginate complex on CPC system in physiological conditions, CPC0 and CPC1 were implanted in a rabbit femoral head defect model for 1 and 3 months. Micro-computed tomography revealed improved bone formation in CPC1 compared to CPC0 3 months after implantation. Histological analysis revealed newly formed bone tissues around the peripheral sides of CPC0 and CPC1. The results indicate the potential value of the CPC system containing polymer complex as an injectable bone substitute. The study of the CPC-polymer complex system incorporating drugs or cells can be further developed into a controlled release system for faster bone regeneration. PMID- 30423722 TI - Development and evaluation of antibacterial electrospun pea protein isolate polyvinyl alcohol nanocomposite mats incorporated with cinnamaldehyde. AB - Electrospun film is developed from an electrically charged ultrafine jet of a polymer solution or melt as a matrix of thin/nano fibers struck on to a target surface. The objective of this work was to obtain homogeneous nanofibers from pea protein isolate (PPI) in polyvinyl alcohol (PVA) by hybrid electrospinning as well as incorporating cinnamaldehyde (CA) into the matrix to obtain an antibacterial mat. The effect of processing conditions, pH, polymer and CA concentrations on formulation properties and nanofiber morphology were investigated and the mats were visualized by scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). Rheological evaluation indicated a pseudoplastic behavior for all formulations. Alkaline pH formulation led to a decreasing apparent viscosity and an increasing electrical conductivity resulting in the formation of more homogeneous fibers. The 50:50 mass percentage ratio of PPI/PVA solutions produced homogeneous nanofibers with the average fiber diameter of 485 +/- 85 nm. FTIR spectroscopy confirmed uniform dispersion of PPI and PVA. The minimum concentration of CA to inhibit both Gram negative and Gram positive bacteria was 1%. The average diameter of nanofibers decreased from 257 +/- 51 nm to 219 +/- 31 nm by increasing CA content from 0.25 to 1.5%. PMID- 30423723 TI - New chemically modified carbon paste sensor for nanomolar concentration measurement of rifampicin in biological and pharmaceutical media. AB - A new carbon paste electrode for rifampicin (RIF) drug was prepared and fully characterized in terms of composition, usable pH range and temperature. The sensor is based on 2-hydroxypropyl beta-cyclodextrin as a good ionophore in the carbon paste matrix. The modified electrode showed a Nernstian slope of 59.2 mV/decade over the concentration range of 3.2 * 10-8 to 2.2 * 10-4 M with a limit of detection 2.3 * 10-8 M. The electrode has a short and stable response time of 4 s. The sensor manifested advantages of simple design, low cost, wide concentration range, excellent selectivity to rifampicin, applicable as an indicator electrode and renewability. The sensor was successfully used for determination of rifampicin in tablet and blood serum samples. Temperature dependence of the sensor potential response was examined in the temperature range of 15-55 degrees C. The sensor showed a very low thermal coefficient within the studied temperature range. PMID- 30423724 TI - A new selective optode for the determination of iron(III) based on the immobilization of morin on triacetylcellulose: A combined experimental and computational study. AB - Accurate and fast measurement of the iron ion in biological, pharmaceutical and medical samples is of great applied importance. In this work, a novel optical sensor (optode) for the Fe(III) ion is fabricated based on the immobilization of morin (2',3,4',5,7-pentahydroxyflavone) on a triacetylcellulose membrane. Chemical binding of the Fe(III) ion with the immobilized morin is monitored spectrophotometrically at 334 nm. The prepared optode shows excellent response over a wide range of concentrations from 1.06 * 10-10 to 4.73 * 10-5 M with a detection limit of 4.23 * 10-11 M Fe(III). Effects of the factors determining sensitivity of the optode are studied and optimized. The prepared optical sensor shows good selectivity toward the Fe(III) ion in the presence of a number of other metal ions. The developed sensor is applied successfully and satisfactorily for the determination of iron in three pharmaceutical, one plasma and two serum samples. In addition, concentration of the Fe(III) ion in two tap water samples is measured using standard addition method. Density functional theory (TD) B3LYP/6-311++G** method is used to investigate structure and binding characteristics, and calculate the UV-Vis spectrum of the Fe(III)-morin complex. PMID- 30423725 TI - Towards the production of natural rubber-calcium phosphate hybrid for applications as bioactive coatings. AB - This paper assesses the morphological, structural and bio-physicochemical stability of natural rubber (NR) Hevea brasiliensis coatings incorporated with microparticles of calcium phosphate-based (CaP) bioactive ceramics. Optical and electronic spectroscopic imaging techniques were employed to successfully evaluate the NR encapsulation capability and the stability of the coating in a biologically relevant media for bio-related application, i.e., simulated body fluid (SBF). The chemical structure of the natural polymer, the microchemical environment at the NR-CaP interface and the morphology of the CaP clusters were fully characterized. Further, the response of the hybrid coating to SBF was evaluated by incubating the samples for 30 days. The hybrid coating formed on Si surface (inert substrate) exhibited both stability and biodegradability in different levels (time dependence), thus opening horizons for applications as coatings for both biomaterials and drug delivery systems. PMID- 30423726 TI - Novel sintering-free scaffolds obtained by additive manufacturing for concurrent bone regeneration and drug delivery: Proof of concept. AB - Advances on the fabrication of sintering-free biphasic calcium phosphate (BCP)/natural polymer composite scaffolds using robocasting as additive manufacturing technique are presented in the present work. Inks with high amounts of BCP powders (45 vol%) containing different HA/beta-TCP ratios, in presence of crosslinked polymer, were successfully fine-tuned for extrusion by robocasting. The non-existence of sintering step opened the possibility to obtain drug loaded scaffolds by adding levofloxacin to the extrudable inks. The drug presence induced slightly changes on the rheological behaviour of the inks, more emphasized for the BCP compositions with higher amounts of beta-TCP, and consequently, on the microstructure and on the mechanical properties of the final scaffolds. The strong interaction of beta-TCP with chitosan difficult the preparation of suitable rheological inks for printing. Drug delivery studies revealed a fast release of levofloxacin with a high burst of drug within the first 30 min. Levofloxacin loaded samples also presented bacteria growth inhibition ability, proving that antibiotic was not degraded during the fabrication process and its bactericidal efficacy was preserved. From the results obtained, the composite scaffolds containing higher amounts of HA (around 80% HA/20% beta-TCP) constitute a promising bi-functional synthetic bone substitute for simultaneous local bone regeneration and infection treatments. PMID- 30423727 TI - Preparation of silver nanoparticles in the presence of polyoxometalates. AB - The mechanisms of reduction of silver ions and subsequently oxidation of silver atoms in the presence of polyoxometalates (POMs) are discussed. A step-by-step room temperature electron reduction of silver ions and its subsequent reactions has been used in this work to monitor oxidation of silver atoms and its clusters. The silver atoms can transfer electron to POMs is revealed by decrease in the yield of silver clusters and increase in their decay rates. The results of continuous gamma-irradiation are compared using UV-visible (UV-Vis) absorption spectra, underlying the effect of silver atoms accumulation in the absence of POMs. Silver nanoparticles (Ag NPs) prepared by reduced silicotungstic acid (STA) were used as Raman substrate and also for antibacterial studies against panel of human pathogenic bacteria. The Ag NPs exhibited antibacterial activity against both Gram-positive and Gram-negative bacterial pathogens evaluated by well diffusion assay. The inhibition zones were within the range of 10 to 14 mm. We have also explored the surface enhanced Raman scattering (SERS) activity of the Ag NPs substrates using 1.0 * 10-7 M solution of crystal violet (CV) as Raman probe molecule. It was possible to detect SERS spectral pattern of CV on Ag NPs substrate with a high signal-to-noise ratio. Both SERS and antibacterial studies show that this simple, low cost, and greener method for synthesizing Ag NPs may be valuable in future studies about SERS sensor development and bio-applications. PMID- 30423728 TI - Preparation and characterization of Aloe vera acetate and electrospinning fibers as promising antibacterial properties materials. AB - In this work, the anti-bacterial effect of Aloe vera derivate fibers produced by the electrospinning method was reported. Aloe vera Polyvinylpyrrolidone (Av/PVP) and Aloe vera acetate-Polyvinylpyrrolidone (AvAc/PVP) electrospun fibers were prepared with different concentrations and their microstructure and mechanical properties were studied. Various methods such as differential scanning calorimetry (DSC), thermogravimetry analysis (TGA), water contact angle (CA) tests, Fourier-Transform Nuclear Magnetic Resonance (FT-NMR), scanning electron microscope (SEM), X-ray diffraction (XRD), CHNSO and Fourier-Transform Infrared Spectroscopy (FT-IR) were used to characterize prepared samples. (Av/PVP) electrospun fibers were prepared with different concentrations (6-10 wt%) of PVP and 0.2 wt% Av blended and tested in medicinal herb for wound healing, antibacterial and anti-inflammatory properties. For further study, the effect of AvAc film on the properties of composite film was studied. AvAc increased the thermal stability and crystallite size percentage of samples. Antibacterial and antiviral test studies on the scaffold displayed no bacterial and viral growth. These results suggest that AvAc/PVP scaffolds could be promising candidates for wound healing applications. PMID- 30423729 TI - Experimental and statistical analysis on a nanostructured sensor for determination of p-hydroxybenzoic acid in cosmetics. AB - In this research, differential pulse voltammetry (DPV) coupled with experimental design, was used for determination of p-hydroxybenzoic acid (PHB) in cosmetics. Optimization of effecting parameters was carried out based on rotatable central composite design (RCCD) and response surface methodology (RSM) at the surface of a nanostructured electrode for achieving the best sensitivity. Sol-gel process was used for synthesize of nickel titanate (NiTiO3) nanoceramics. The structural and morphological characterization of the nanoparticles was studied by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM). Then the NiTiO3 nanopowders were used for surface modification of a carbon paste modified electrode (CPE). Surface characterization of the electrode was accomplished using SEM, electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) techniques. Under the optimized conditions, the voltammograms exhibited two linear dynamic ranges of 0.7-80.0 MUM and 80.0-1000.0 MUM for PHB with the detection limit of 62.0 nM (S/N = 3). Finally the NiTiO3 nanoceramics modified carbon paste electrode (NiTiO3/CPE) could be employed for the determination of PHB in real samples with satisfactory results. PMID- 30423730 TI - Evaluation of biomimetically synthesized mesoporous silica nanoparticles as drug carriers: Structure, wettability, degradation, biocompatibility and brain distribution. AB - Herein, three kinds of mesoporous silica nanoparticles (BMSs) were biomimetically synthesized by using heterocyclic amino acid derivatives as template and their the basic capacity in being drug carriers that covered structure, wettability, degradation, brain uptake, hemocompatibility and toxicity were systematically evaluated. The results indicated that BMSs were kinds of spherical nanoparticles with good biocompatibility. Their in vitro and in vivo behaviors, including degradation, biodistribution and biocompatibility were mainly governed by the wettability which was closely related to the structure and pore diameter of mesoporous silica nanoparticles. BMSs can degrade completely under simulated physiological environments through a time period of 2-13 weeks. They showed the tendency of brain distribution, and the distribution amount peaked at 4 h post administration. Particularly, Trp-BMS (BMS templated by C16-l-tryptophan) with the largest amount of OH groups on the surface exhibited highest wettability, fastest degradation rate and the lowest brain distribution ability. Besides, His BMS (BMS templated by C16-l-histidine) and Pro-BMS (BMS templated by C16-l poline) were silica materials with good biocompatibility. Both in vitro and in vivo studies uncovered no significantly toxicity for BMSs and they were proved to be safe when they circulated into the blood. However, Trp-BMS might induce severe hemolysis and cell cycle arrest due to the high wettability. It is believed that appropriate wettability is required for the in vivo application of nanomaterials and the in vivo evaluation of mesoporous silica nanoparticles will provide useful information for understanding the underlining toxicity of biomaterials and bring new insights on designing efficient drug delivery systems. PMID- 30423731 TI - Designing heparan sulfate-based biocompatible polymers and their application for intracellular stimuli-sensitive drug delivery. AB - Heparan sulfate (HS) is a kind of natural polysaccharides with good biocompatibility. And as drug carriers, it has some advantages compared to heparin. However, the preparation of HS is cumbersome and difficult, which limits its application in drug delivery. Here, we use modern separation technique combined with chromatography to establish a new preparation method of HS. The molecular weight and degree of dispersion of HS were (1.03 * 104 +/- 107) kDa and 1.106, respectively. HS also showed low anticoagulation activity in comparison with heparin. Subsequently, novel redox-sensitive heparan sulfate-cystamine vitamin E succinate (HS-SS-VES, HSV) micelles were designed to increase tumor selectivity and improve the therapeutic effect of doxorubicin (DOX). DOX-loaded HSV micelles (DOX/HSV) with spherical morphology had average particle size of 90 120 nm and good redox-triggered release behavior. The cell viabilities of blank micelles were >90% in both human breast cancer (MCF7) cells and African green monkey SV40-transformed kidney fibroblast (COS7) cells. However, the cytotoxicity of DOX/HSV in MCF7 cells was higher than that of COS7 cells. Flow cytometry analyses and confocal laser scanning microscopy observation indicated that DOX/HSV micelles were internalized by endocytosis, and then the drug was released quickly and entered the nuclei of tumor cells. The results demonstrate that high purity HS can be prepared and has the potential to be further used for drug delivery in antitumor applications. PMID- 30423732 TI - N-acetylcysteine side-chain functionalization of poly(globalide-co-epsilon caprolactone) through thiol-ene reaction. AB - N-Acetylcysteine (NAC) is a drug well known for its antimucolytic action, antioxidant activity and ability to protect cells from oxidative stress. Conjugation of NAC with double bonds in the main polymer chain of poly(globalide co-epsilon-caprolactone) (PGlCL) through thiol-ene reaction is reported. Different globalide (Gl) (an unsaturated macrolactone) to epsilon-caprolactone (CL) ratios were employed for PGlCL synthesis. The polymeric materials (PGlCL NAC) were evaluated in terms of the number of functionalized double bonds, thermal properties, affinity for water and antioxidant potential. PGlCL-NAC containing more globalide repeating units presented higher degree of functionalization, due to the higher number of double bonds available to react through thiol-ene coupling. For high globalide contents (Gl/CL ratios above 50/50), NAC coupling in PGlCL chains resulted in completely amorphous copolymers with a more hydrophilic character, which should enhance bioresorption and cell adhesion characteristics. Functionalization also gave rise to a thioether linkage, conferring to PGlCL-NAC an antioxidant character, important for biomedical applications, where the material could combat cellular oxidative stress. PMID- 30423733 TI - Ultrasonicated graphene oxide enhances bone and skin wound regeneration. AB - In the present study, we investigated the applications of ultrasonicated graphene oxide (UGO) for bone regeneration and skin wound healing. Ultrasonication of a GO suspension increased the dispersion and stability (by increasing the zeta potential) of the GO suspension. UGO has fewer oxygen-containing groups but still displays excellent water dispersion. The UGO supension showed high biocompatibility for human fetal osteoblast (hFOB cells), human endothelial cells (EA.hy 926 cells), and mouse embryonic fibroblasts. Importantly, UGO could support cell attachment and proliferation, in addition to promoting the osteogenesis of seeded cells and the promotion of new bone formation. In addition, a 1% UGO supension enhanced cell migration in an in vitro skin scratch assay and promoted wound closure in an in vivo rat excisional skin defect model. These results showed that UGO offers a good environment for cells involved in bone and skin healing, suggesting its potential application in tissue regeneration. PMID- 30423734 TI - Mononuclear copper(II) complexes with 2-thiophene carboxylate and N-N donors; DNA interaction, antioxidant/anti-inflammatory and antitumor activity. AB - Redox-active compounds such as copper-phenanthroline are known as artificial/chemical nucleases with a great impact and potential for their applications as metallotherapeutics. In that vein, the mononuclear copper(II) complexes [Cu(L)2(bipy)] (1), [Cu(L)2(bipy)(H2O)] (2) and [Cu(L)2(phen)(H2O)] (3), where L = 2-thiophene carboxylate, bipy = 2,2?-bipyridine and phen = 1,10 phenanthroline, have been prepared and pharmacochemically studied, while the crystal structure of 1 is also reported. All the tested complexes preferably bind to CT-DNA via minor groove as resulted from UV spectroscopy studies, luminescent titration, EB competition assays and viscosity measurements. Complexes 2 and 3 in aqua behave like a "light switch" for DNA. The intensity enhancement, with the increase of DNA concentration, reached about 3-fold for 2 and 10-fold for 3. In vitro antioxidant activity of compounds 1-3, was evaluated using two different antioxidant assays: a) interaction with 1,1-diphenyl-2-picryl-hydrazyl (DPPH) stable free radical and b) inhibition of lipid peroxidation. Moreover, their inhibitory activity on soybean lipoxygenase (LOX) was evaluated for their anti inflammatory potency. The tested complexes showed good activity on both lipid peroxidation and soybean LOX inhibition while complex 2 exhibited the best antioxidant/anti-inflammatory activity. A computational analysis over the LOX protein structure 1JNQ was performed, in an effort to support their possible mode of action. The cytotoxicity of the complexes was determined and their efficacy against several human cancer cell lines (ovarian, OAW-42; lung, A549; colon, HT29; breast, MDA-MB-231; kidney, Caki-2; and cervical, Hela) and human non-tumor cell lines (lung, MRC-5; and breast, MTSV1-7) were evaluated. The best cytotoxic activity was appeared for complex 3. In silico, computational methods support antiestrogen activity of the administered complexes on normal breast cells. PMID- 30423735 TI - Strontium functionalized scaffold for bone tissue engineering. AB - Drug functionalized scaffolds are currently being employed to improve local delivery of osteoprotective drugs with the aim of reducing their loading dose as well as unwanted systemic complications. In this study we tested a poly-(epsilon) caprolactone (PCL)-laponite-strontium ranelate (SRA) composite scaffold (PLS3) for its abilities to support growth and osteogenic differentiation of human marrow derived stromal stem cells (hMSC). The in vitro experiments showed the PLS3 scaffold supported cell growth and osteogenic differentiation. The in vivo implantation of hMSC seeded PLS3 scaffold in immunocompromised mice revealed vascularized ectopic bone formation. PLS3 scaffolds can be useful in bone regenerative applications in the fields of orthopaedics and dentistry. PMID- 30423736 TI - Fabrication, multi-scale characterization and in-vitro evaluation of porous hybrid bioactive glass polymer-coated scaffolds for bone tissue engineering. AB - Bioactive glass-based scaffolds are commonly used in bone tissue engineering due to their biocompatibility, mechanical strength and adequate porous structure. However, their hydrophobicity and brittleness limits their practical application. In this study, to improve nanomechanical properties of such scaffolds, pure bioactive hybrid glass and two bioactive hybrid glass-polymer coated composites were fabricated. A complementary micro and nanoscale characterization techniques (SEM, AFM, MUCT, FTIR, compressive test, goniometer) were implemented for detailed description of architecture and physicochemical properties of hybrid bioactive glass-based scaffolds with emphasis on nano-mechanics. The final step was in-vitro evaluation of three dimensional macroporous structures. Our findings show that after polymer addition, architecture, topography and surface properties of the scaffolds were changed and promoted favoured behaviour of the cells. PMID- 30423737 TI - A facile approach for the reduction of 4-nitrophenol and degradation of congo red using gold nanoparticles or laccase decorated hybrid inorganic nanoparticles/polymer-biomacromolecules vesicles. AB - Catalytic reduction of toxic 4-nitrophenol to 4-aminophenol and dye wastewater treatment over rapid, convenient gold nanoparticles or laccase decorated hybrid vesicles catalysts has attracted much attention. In current work, a stable building block was designed with inorganic gold nanoparticles and nano conjugates; and a hybrid giant vesicles (AuNPs@vesicles) was self-assembled by using Pickering emulsion method. The vesicles were characterized by SEM, TEM, UV vis and DLS measurements. The results showed that a temperature-responsive multifunctional building block based on BSA-PNIPAAm and gold nanoparticles was obtained. DLS results also indicated that the length of chains on the surface of AuNPs could change shorter with increasing of temperature (>32 degrees C) and also obtain an average diameter to ~190 nm. A substrate-rich (high concentration of 4-nitrophenol) microenvironment can be created around AuNPs, which can dramatically accelerate the interfacial AuNPs-catalyzed reactions. The AuNPs@vesicles as catalyst in the presence of freshly prepared NaBH4 has excellent catalytic performance for reduction of 4-nitrophenol (almost 100%). After laccase was capsulated into AuNPs@vesicles, the obtained active hybrid laccase?AuNPs@vesicles demonstrated high catalytic decolouration efficiency (>98.5%, nearly 2.3 times higher than that of free laccase) and excellent reusability. The possible mechanisms of reduction of 4-nitrophenol and dye decolouration was proposed. These novel giant vesicles could provide some new opportunities in wastewater treatment, bottom-up synthetic biology, bioinspired microstorage/microreactor and drug/gene delivery. PMID- 30423738 TI - Polyhydroxybutyrate-co-hydroxyvalerate copolymer modified graphite oxide based 3D scaffold for tissue engineering application. AB - In this study, we have fabricated the PHBV functionalized graphite oxide using freeze drying technique, followed by 'in situ' pay loading of Fe3O4 nanoparticles onto the hydrophobic plate of the composite basal plane; thereby, mechanically and thermally stable, bio-imaging Fe3O4/GO-g-PHBV composites have been developed. The synthesis of Fe3O4/GO-g-PHBV composite was confirmed by field emission SEM and TEM analyses, X-ray diffraction and Fourier transform infrared spectroscopy. The wrapping of PHBV copolymer into the graphene layers was investigated by atomic force microscopy and Raman spectral analyses which provided the shifting of the 2D band with low signal intensity in the range of 2600-3000 cm-1. The bactericidal activities of the Fe3O4/GO-g-PHBV composite films were found to exhibit more efficiency against Gram-negative bacteria strains compared to Gram positive strains. In vibrating sample magnetometer (VSM) analysis, the zero value of coercivity revealed the super-paramagnetic nature of the Fe3O4/GO-g-PHBV composites. The Phantom agar magnetic resonance imaging analysis revealed the efficiency of Fe3O4 nanoparticles as a negative contrast (T2 contrast) along with higher relaxivity value. The significant fibroblast cell (NIH 3T3) adhesion and proliferation (85%) on the Fe3O4/GO-g-PHBV composite surface indicated the physiological and biocompatible stability of that composite along with the presence of large pi conjugated aromatic domain. PMID- 30423739 TI - Biomimetic fabrication of new bioceramics-introduced fibrous scaffolds: From physicochemical characteristics to in vitro biological properties. AB - The combination of biodegradable polymers and bioactive inorganic materials is a promising method to mimic native tissue in bone regeneration. Toward this direction, electrospun fibrous scaffolds were successfully fabricated in the silk fibroin (SF) matrix containing new bioceramics on the basis of mesoporous bioactive glass/hydroxyapatite nanocomposite (MGHA). The physicochemical properties and surface hydrophilicity of these biphasic composite could be tailored by the addition of MGHA content. The increase in surface hydrophilicity and bioactivity of the as-spun composite fibers were observed with the increasing the nanoparticle contents while decreasing their tensile strength. In vitro cytotoxicity evaluation based on human bone marrow-derived mesenchymal stem cells (hMSCs) revealed that a positive osteogenic differentiation effect on SF/MGHA7 sample as evidenced by an increased alkaline phosphatase (ALP) activity, and upregulated osteoblastic gene expression compared with SF samples. These findings supported the suitability of the SF/MGHA composite system for its potential application in cell-material combination in bone tissue engineering. PMID- 30423740 TI - Bacteria killer enzyme attached magnetic nanoparticles. AB - The objective of the present work was to develop immobilized lysozyme systems through adsorption on magnetic nanoparticles for potential usage in bacteria killing studies. For this, magnetic poly(HEMA-GMA) nanoparticles were prepared by surfactant free emulsion polymerization technique and functionalized with dye ligand Reactive Green 5. Synthesized magnetic nanoparticles were then characterized by FTIR, SEM, EDX and ESR studies. Particle size range of the polymers was found to be as 90-120 nm. Magnetic behavior was also demonstrated by ESR with the g value of 2.48. Maximum lysozyme loading was found to be as 1045.1 mg/g nanopolymer. Repeated usability of the magnetic nanoparticles was also studied. Immobilized form of lysozyme protected 85.85% of its initial activity at the end of the immobilization process. Bacteria killing capacity of the lysozyme immobilized magnetic nanoparticles were investigated by using Micrococcus lysodeikticus bacteria and it was demonstrated that all bacteria were successfully destroyed by the lysozyme immobilized magnetic nanoparticles within 5 min. PMID- 30423741 TI - Surface engineered Amphora subtropica frustules using chitosan as a drug delivery platform for anticancer therapy. AB - Drug delivery using synthetic mesoporous nanomaterials, including porous silicon, has been extensively used to ameliorate the constraints currently experienced with conventional chemotherapy. Owing to the amazing potential, the silica based nanomaterials have been used widely. Nevertheless, synthetic nanomaterial involves high cost, lack of scalability, and the use of toxic substances limits its utilization. These issues can be overcome by the use of nature generated nanoscale materials, such as diatoms would serve as a boon for pharmaceutical industries. In this study we investigate the use of a mesoporous, biodegradable nanomaterial obtained from the natural silica found in the diatom species Amphora subtropica (AMPS) for drug delivery applications. AMPS cultures cleaned and chemically treated to obtain Amphora frustules (exoskeleton) (AF), followed by surface functionalization with chitosan (Chi). Results of our experiments demonstrate high drug loading, strong luminescence, biodegradable and biocompatible nature of the doxorubicin tethered diatom. Further, toxicity studies employing immortalized lung cancer cell line (A549) indicates sustained drug delivery and less toxic compared to the free doxorubicin (DOX), suggesting AF could be an excellent substitute for synthetic nanomaterials used in drug delivery applications. PMID- 30423742 TI - In situ preparation of multicomponent polymer composite nanofibrous scaffolds with enhanced osteogenic and angiogenic activities. AB - Bioactive ceramics are extensively used for bone repair and regeneration, which release ions to initiate apatite formation and promote osteogenic differentiation eventually resulting in strong bonding to bone. Toward enhancing the bioactivity of polymeric nanofibrous scaffolds, this work presents a one-step in situ sol-gel method to fabricate electrospun composite nanofibrous scaffolds encapsulating well dispersed ceramic nanoparticles overcoming the limitations of current preparation techniques. Transmission electron micrographs revealed uniform distribution of ceramic nanoparticles within the polymer nanofibers. The multicomponent scaffolds were found to release calcium, silicon and phosphate ions that mimic the dissolution and bioactivity of conventional bioactive glasses. The scaffolds enhanced the bioactivity of PCL fibers as observed through enhanced apatite formation in simulated body fluid. The released ions markedly enhanced the proliferation and osteogenic differentiation of human mesenchymal stem cells and the angiogenic activity of human endothelial cells in vitro. This work has important implications for engineering the next-generation nanostructured scaffolds that exhibit multi-biofunctional activities for bone tissue regeneration. PMID- 30423743 TI - Cholesterol derived carbon quantum dots as fluorescence probe for the specific detection of hemoglobin in diluted human blood samples. AB - In the current decade, carbon quantum dots (CQDs) are promising fluorescence probe in bio/analytical chemistry due to its unique properties. The functional groups of CQDs can be tuning the optical properties and selectively make a strong bond with target molecules. The interactions between Hb and cholesterol through hydrophobic batches are more favorable than the usual pi-pi interaction between CQDs and Hb. Hence we prepared highly stable CQDs with a fluorescence quantum yield of 45% from cholesterol by the hydrothermal method to make hydrophobic interactions with Hb. Concurrently the CQDs possess graphitic crystalline and amphiphilic structure in nature. The fluorescence at 440 nm arises from the intrinsic core of CQDs and it will not affect by solution pH and excitation wavelengths. This fluorescence intensity was selectively quenched by Hb owing to the formation of fluorescence inactive complex (CQDs-Hb) through strong hydrophobic interactions. The quenching mechanism complies with the Forster non radiative energy transfer (FRET) theory. This method shows good linearity from 0.1 MUM to 2.9 MUM with a limit of detection of 24 nM (S/N = 3). This observation is used for the quenchometric determination of Hb in diluted human blood samples. PMID- 30423745 TI - Synthesis, characterization and cytocompatibility assessment of hydroxyapatite polypyrrole composite coating synthesized through pulsed reverse electrochemical deposition. AB - Composite coating of hydroxyapatite-polypyrrole is synthesized with the help of pulsed reverse electrochemical deposition method from aqueous bath through in situ formation and co-deposition of both phases simultaneously over metallic stainless steel surface. The inter phase bonding along with surface energy variation and morphology is tuned with the help of deposition current density, deposition time and reverse duty cycle. Hydroxyapatite (HA) lattice exhibits unidirectional growth along the highest atomic plane of <111> parallel to the coating surface. Different kind of deposited hydroxyapatite structures, namely lamellar and spherical particle scaffold, are observed at moderate and high current densities respectively together with the incorporation of polypyrrole (PPy) phase in between. Pyrrole ring stretching and bond strengthening represent the bonding with hydroxyapatite lattice, which in turn helps to increase the overall corrosion resistance of composite coating by ten-fold as compared to bare PPY coating. The coating deposited with moderate current density (10 mA/cm2) seems to be the optimum one regarding the faster-interconnected growth of MG63 cells over the coating surface along with highest corrosion resistance and anodic passivation capability. Presence of sub-micron level ceramic hydroxyapatite scaffold along with polymer filler material makes this composite biocompatible coating as a potential candidate to use over the load bearing metallic implant surfaces due to its sufficient elasticity along with superior toughness. PMID- 30423744 TI - Novel dental composite with capability to suppress cariogenic species and promote non-cariogenic species in oral biofilms. AB - Recurrent caries often occurs and is a primary reason for the failure of dental composite restorations. The objectives of this study were to: (1) develop a bioactive composite containing dimethylaminohexadecyl methacrylate (DMAHDM), (2) investigate its antibacterial effects and suppression on biofilm growth, and (3) investigate its ability to modulate biofilm species composition for the first time. DMAHDM was incorporated into a composite at mass% of 0%, 0.75%, 1.5%, 2.25% and 3%. A commercial composite Heliomolar served as a comparative control. A biofilm model consisting of Streptococcus mutans (S. mutans), Streptococcus sanguinis (S. sanguinis) and Streptococcus gordonii (S. gordonii) was tested by growing biofilms for 48 h and 72 h on composites. Colony-forming units (CFUs), metabolic activity and live/dead staining were evaluated. Lactic acid and polysaccharide productions were measured to assess biofilm cariogenicity. TaqMan real-time polymerase chain reaction was used to determine the proportion of each species in the biofilm. DMAHDM-containing composite had a strong anti-biofilm function, reducing biofilm CFU by 2-3 orders of magnitude, compared to control composite. Biofilm metabolic activity, lactic acid and polysaccharides were decreased substantially, compared to control (p < 0.05). At 72 h, the cariogenic S. mutans proportion in the biofilm on the composite with 3% DMAHDM was 19.9%. In contrast, an overwhelming S. mutans proportion of 92.2% and 91.2% existed in biofilms on commercial control and 0% DMAHDM, respectively. In conclusion, incorporating DMAHDM into dental composite: (1) yielded potent anti-biofilm properties; (2) modulated the biofilm species composition toward a non-cariogenic tendency. The new DMAHDM composite is promising for applications in a wide range of tooth cavity restorations to modulate oral biofilm species and combat caries. PMID- 30423746 TI - Multifunctional magnetic cargo-complexes with radical scavenging properties. AB - Core-shell magnetic nanoparticle synthesis offers the opportunity to engineering their physical properties for specific applications when the intrinsic magnetic properties can be associated with other interesting ones. The purpose of this study was to design, synthesize, and characterize core-shell magnetic nanoparticles that mimic superoxide dismutase activity offering the possibility of guidance and therapeutic action. We proposed, for the first time, the synthesis and characterization of the nanocarriers comprised of magnetite nanoparticles functionalized with branched polyethyleneimine of low molecular weight (1.8 kDa) permitting the loading of the protocatechuic acid or its inclusion complex with anionic sulfobutylether-beta-cyclodextrin for active drug delivery, in order to combine the useful properties of the magnetite and the protocatechuic acid antioxidant effect. NMR and DSC analyses confirmed the formation of the inclusion complex between sulfobutylether-beta-cyclodextrin and protocatechuic acid, while structural and compositional analyses (FT-IR, TEM, XRD) revealed the synthesis of the multifunctional magnetic systems. Due to the possibility of being formulated as blood system injectable suspensions, antioxidant activity (using DPPH test) and cytotoxicity (using MTS assay on normal human dermal fibroblasts cells) were also measured, showing adequate properties to be used in biomedical applications. Moreover, we proposed a nanocarrier that would be able to load unstable active principles and with very low solubility in biological fluids to increase their biological ability. PMID- 30423747 TI - Comparative study on Ti-Nb binary alloys fabricated through spark plasma sintering and conventional P/M routes for biomedical application. AB - The main purpose of this work is to obtain homogenous, single beta phase in binary Ti-xNb (x = 18.75, 25, and 31.25 at.%) alloys by simple mixing of pure elemental powders using different sintering techniques such as spark plasma sintering (pressure-assisted sintering) and conventional powder metallurgy (pressure-less sintering). Synthesis parameters such as sintering temperature and holding time etc. are optimized in both techniques in order to get homogenous microstructure. In spark plasma sintering (SPS), complete homogeneous beta phase is achieved in Ti25at.%Nb using 1300 degrees C sintering temperature with 60 min holding time under 50 MPa pressure. On the other hand, complete beta phase is obtained in Ti25at.%Nb through conventional powder metallurgy (P/M) route using sintering temperature of 1400 degrees C for 120 min holding time which are adopted from the dilatometry studies. Nano-indentation is carried out for mechanical properties such as Young's modulus and nano-hardness. Elastic properties of binary Ti-xNb compositions are fallen within the range of 80-90 GPa. Cytotoxicity as well as cell adhesion studies carried out using MG63, osteoblast-like cells showed excellent biocompatibility of thus developed Ti25at.%Nb surface irrespective of fabrication route. PMID- 30423748 TI - Selective laser fiber welding on woven polymer fabrics for biomedical applications. AB - Localized cartilage damage is a common problem for younger patients. This can heal, but often results in a painful condition that requires intervention. A welded-woven three-dimensional polymer fabric has been suggested as a suitable cartilage replacement because such materials closely match the mechanical properties of cartilage. However, such materials fare poorly when evaluated with respect to wear. A microscopic investigation of wear mechanisms showed that it is critical that the fibers not deflect laterally under a normal load. This observation led to the use of a new process for selective laser welding of the surface layers of three-dimensional fabrics in order to improve their wear resistance. Experimental evaluations were made in a pin-on-disc arrangement with a biomimetic loading. All materials used in the studies have previously been used in orthopedic devices or meet the requirements for United States Pharmacopeial Convention (USP) Class VI biocompatibility approval. The wear rates were significantly reduced and the lifespan of the fabrics was markedly improved due to surface welding, making this a viable option for cartilage replacement in vivo. PMID- 30423749 TI - Dynamic constitutional chemistry towards efficient nonviral vectors. AB - Dynamic constitutional chemistry has been used to design nonviral vectors for gene transfection. Their design has been thought in order to fulfill ab initio the main requirements for gene therapy. As building blocks were used hyperbranched PEI as hydrophilic part and benzentrialdehyde and a diamine linear siloxane as hydrophobic part, connected through reversible imine linkages. The obtaining of the envisaged structures has been confirmed by NMR and FTIR spectroscopy. The dynamic synthesized amphiphiles proved to be able to self assemble in nano-sized spherical entities as was demonstrated by TEM and DLS, characterized by a narrow dimensional polydispersity. Agarose gel electrophoresis proved the ability of the synthesized compounds to bind DNA, while TEM revealed the spherical morphology of the formed polyplexes. As a proof of the concept, the nonviral vectors promoted an efficient transfection on HeLa cells, demonstrating that dynamic constitutional chemistry can be an important tool in the development of this domain. PMID- 30423750 TI - Magnetically targetable microcapsules display subtle changes in permeability and drug release in response to a biologically compatible low frequency alternating magnetic field. AB - High frequency alternating magnetic fields (AMF) have been widely used as a non invasive method to induce local hyperthermia for antitumor treatment and to efficiently trigger drug release from various carriers. However, few studies have exploited the potential of targeted drug delivery to healthy cells or tissue and the use of low frequency AMF (LF-AMF) for intracellular triggered release. To achieve this goal, doxycycline was delivered with the layer-by-layer (LbL) assembled magnetic microcapsules, and AMF with low frequency (50 Hz) was applied. The low frequency AMF had little effect on morphology of microcapsules, which upon exposure for 360 min caused no significant damage and had the advantage of minimizing heating effects. Nonetheless, microcapsule permeability increased as a function of exposure time when assessed using FITC-dextran (70 kDa) with the number of permeable microcapsules increased from 13.5% (20 min) to 52.8% (360 min). Increased permeability also enhanced in vitro doxycycline release in genetically engineered myoblast cells where EGFP expression is regulated by the tetracycline system, while targeted EGFP expression was observed by magnetically navigating the microcapsules to a site of interest. Upon LF-AMF exposure of 30 min, no cytotoxicity was observed, but intracellular doxycycline release was promoted and enhanced EGFP expression as demonstrated by EGFP fluorescence intensity measurement. This study reveals the possibility of targeted drug delivery and using LF-AMF as a non-cytotoxic intracellular trigger of drug release from microcapsules without alteration in cell viability. PMID- 30423751 TI - Synergistically enhanced osteoconductivity and anti-inflammation of PLGA/beta TCP/Mg(OH)2 composite for orthopedic applications. AB - Synthetic biodegradable polymers including poly(lactide-co-glycolide) (PLGA) have been widely used as alternatives to metallic implantable materials in the orthopedic field due to their superior biocompatibility and biodegradability. However, weak mechanical properties of the biodegradable polymers and inflammatory reaction caused by the acidic degradation products have limited their biomedical applications. In this study, we have developed a PLGA composite containing beta-tricalcium phosphate (beta-TCP) and magnesium hydroxide (Mg(OH)2) as additives to improve mechanical, osteoconductivity, and anti-inflammation property of the biopolymer composite simultaneously. The beta-TCP has an osteoconductive effect and the Mg(OH)2 has a pH neutralizing effect. The PLGA/inorganic composites were uniformly blended via a twin extrusion process. The mechanical property of the PLGA/beta-TCP/Mg(OH)2 composite was improved compared to the pure PLGA. In particular, the addition of Mg(OH)2 suppressed the inflammatory reaction of normal human osteoblast (NHOst) cells and also inhibited the differentiation of pre-osteoclastic cells into osteoclasts. Moreover, synergistically upregulated late osteogenic differentiation of NHOst cells was observed on the PLGA/beta-TCP/Mg(OH)2 composite. Taken all together, we believe that the use of beta-TCP and Mg(OH)2 as additives with synthetic biodegradable polymers has great potential by the synergistic effect in orthopedic applications. PMID- 30423752 TI - Design of antimicrobial polycaprolactam nanocomposite by immobilizing subtilisin conjugated Au/Ag core-shell nanoparticles for biomedical applications. AB - Preparation of the gold core and silver shell NP (AuAgNP) is challenging because of the facile oxidation of silver. Here such a NP is carefully synthesized and conjugated with subtilisin to arrive at a stable spherical material of 120-130 nm in diameter (AuAgSNP). A biomaterial prepared by immobilizing AuAgSNP on polycaprolactam (PCL) exhibits antibiofilm properties against S. aureus and E. coli, but with lesser potency than the one prepared with bare AuAgNP. Subtilisin degrades the adhesive surface proteins of the bacteria thereby preventing the biofilm formation. Subtilisin conjugated AuAgSNP is not cytotoxic to 3T3 cells at its MIC, in contrast to AuAgNP. The presence of subtilisin promotes the fibroblast proliferation. This study indicates that AuAgSNP has antibacterial/antibiofilm activities as well as biocompatibility unlike NPs which are very cytotoxic to cells. Hence AuAgSNP can be used in medical implants and devices. PMID- 30423753 TI - Human adipose-derived stem cells loaded with drug-coated magnetic nanoparticles for in-vitro tumor cells targeting. AB - Magnetic nanoparticles (MNPs) functionalized with different therapeutics delivered by mesenchymal stem cells represent a promising approach to improve the typical drug delivery methods. This innovative method, based on the "Trojan horse" principle, faces however important challenges related to the viability of the MNPs-loaded cells and drug stability. In the present study we report about an in vitro model of adipose-derived stem cells (ADSCs) loaded with palmitate-coated MNPs (MNPsPA) as antitumor drug carriers targeting a 3D tissue-like osteosarcoma cells. Cell viability, MNPsPA-drug loading capacity, cell speed, drug release rate, magnetization and zeta potential were determined and analysed. The results revealed that ADSCs loaded with MNPsPA-drug complexes retained their viability at relatively high drug concentrations (up to 1.22 pg antitumor drug/cell for 100% cell viability) and displayed higher speed compared to the targeted tumor cells in vitro. The magnetization of the sterilized MNPsPA complexes was 67 emu/g within a magnetic field corresponding to induction values of clinical MRI devices. ADSCs payload was around 9 pg magnetic material/cell, with an uptake rate of 6.25 fg magnetic material/min/cell. The presented model is a proof-of concept platform for stem cells-mediated MNPs-drug delivery to solid tumors that could be further correlated with MRI tracking and magnetic hyperthermia for theranostic applications. PMID- 30423754 TI - Selective response of dopamine on 3-thienylphosphonic acid modified gold electrode with high antifouling capability and long-term stability. AB - In this work, an Au electrode modified with self-assembled monolayers (SAMs) of 3 thienylphosphonic acid (TPA) was used as a novel functional interface to selectively sense dopamine (DA) in the presence of excess ascorbic acid (AA). Ellipsometry, X-ray photoelectron spectroscopic (XPS) and electrochemical measurements proved the immobilization of TPA on the gold surface. Interestingly, the Au electrode modified with TPA substantially improved the antifouling and renewal capabilities towards the oxidation of dopamine (DA) after 15 days of storage in undeoxygenated phosphate buffer solution (PBS pH 7.4). Moreover, the TPA-SAMs modified Au electrode could afford a selective electrochemical response for the DA oxidation in the presence of ascorbic acid (AA). Based on this result, a high sensitive detection limit of 2.0 * 10-7 M for DA could be obtained in the presence of high concentration of AA. PMID- 30423755 TI - Modification of mesoporous silica with molecular imprinting technology: A facile strategy for achieving rapid and specific adsorption. AB - In order to improve the diffusion kinetics of molecularly imprinted materials (MIMs), applying imprinting technology to mesoporous materials is a promising strategy. In the present study, an imprinting approach based on the combination of mesoporous silica materials and molecular imprinting technology is reported. Molecularly imprinted material (MIM) for 2,4-dichlorophenoxyacetic acid (2,4-D) was prepared by using 2,4-D as the template molecule, alkyne-modified beta cyclodextrin and propargyl amine as the combinatorial functional monomers and SBA 15 as the supporter. The functional monomers were anchored to the azide-modified SBA-15 by azide-alkyne Click reaction. The synthesized MIM was characterized by transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), elemental analysis (EA), thermal gravimetric analysis (TGA), low-angle X ray diffraction (XRD) and N2 adsorption-desorption analysis. The interactions between template and functional monomers were studied by proton NMR analysis and UV-vis experiments. The results of the equilibrium binding experiments and selective tests showed that the prepared MIM has binding affinity and specificity for a group of analytes which have similar size and shape to those of template. Binding kinetic experiments demonstrated that the present imprinting approach can effectively enhance the mass transfer rate. The solid phase extraction of 2,4-D using MIM as the adsorbent was investigated. The extraction conditions for the processes of loading, washing and eluting were optimized. The recoveries of the molecularly imprinted solid phase extraction (MISPE) column for 2,4-D were 76.3 88.9% with relative standard deviations (RSD) of 3.48-7.64%. PMID- 30423756 TI - Long-lasting anti-platelet activity of cilostazol from poly(epsilon-caprolactone) poly(ethylene glycol) blend nanocapsules. AB - Cilostazol (CLZ) acts as a vasodilator and antiplatelet agent and is the main drug for the treatment of intermittent claudication (IC) related to peripheral arterial disease (PAD). The usual oral dose is 100 mg twice a day, which represents a disadvantage in treatment compliance. CLZ presents several side effects, such as headache, runny nose, and dizziness. This paper aimed to obtain novel polymeric nanocapsules prepared from poly(epsilon-caprolactone) poly(ethylene glycol) (PCL-PEG) blend containing CLZ. Nanocapsules showed pH values between 6.1 and 6.3, average size lower than 137 nm, low polydispersity index (<0.22) and negative zeta potential. These nanoformulations demonstrated spherical shape with smooth surface. Results achieved by X-ray diffraction (XRD) and differential scanning calorimetry (DSC) indicated drug amorphization compared to pure CLZ. Fourier-transformed infrared spectroscopy (FTIR) showed no chemical bonds between drug and polymers. Formulations presented suitable stability for physical parameters. The in vitro drug release demonstrated prolonged release with no burst effect. Drug release was controlled by both mechanisms of polymer relaxation/degradation and Fickian diffusion. Moreover, chosen CLZ-loaded nanocapsules provided an in vivo prolonged antiplatelet effect for CLZ statistically similar to aspirin. These formulations can be further used as a feasible oral drug delivery carrier for controlled release of CLZ in order to treat PAD and IC events. PMID- 30423757 TI - Enhanced osteodifferentiation of MSC spheroids on patterned electrospun fiber mats - An advanced 3D double strategy for bone tissue regeneration. AB - 2D cell culture has been widely developed with various micropatterning and microfabrication techniques over the past few decades for creating and controlling cellular microenvironments including cell-matrix interactions, cell cell interactions, and bio-mimicking the in-vivo tissue hierarchy and functions. However, the drawbacks of 2D culture have currently paved the way to 3D cell culture which is considered clinically and biologically more relevant. Here we report a 3D double strategy for osteodifferentiation of MSC spheroids on nano- and micro-patterned PLGA/Collagen/nHAp electrospun fiber mats. A comparison of cell alignment, proliferation and differentiation of 2D and 3D MSCs on patterned and non-patterned substrate was done. The study demonstrates the synergistic effect of geometric cues and 3D culture on differentiation of MSC spheroids into osteogenic lineage even in absence of osteoinduction medium. PMID- 30423758 TI - Investigating the mechanical, physiochemical and osteogenic properties in gelatin chitosan-bioactive nanoceramic composite scaffolds for bone tissue regeneration: In vitro and in vivo. AB - The aim of this work was to compare the efficacy of gelatin-chitosan based bone scaffolds after incorporation of three different bioactive nanoparticles such as hydroxyapatite (HAp), beta-tricalcium phosphate (beta-TCP) and 58s bio active glass by evaluating its physicochemical, mechanical and osteogenic properties. Gelatin-chitosan based scaffolds made of gelatin-chitosan (GC) and GC composites containing 30 wt% HAp, beta-TCP and 58s bioactive glass nanoparticles were fabricated using freeze drying technique. The porosity and compressive strength of all the prepared scaffolds were evaluated. The average pore size of all the prepared composite scaffolds was in the range between 90 and 125 MUm. Most frequent pore size in GCT 30 scaffold was the highest of 120 MUm whereas that for GCH 30 was the lowest of 96 MUm as suggested by Hg porosimetry analysis. GCH30 scaffolds showed the highest average compressive strength of 3.45 MPa as opposed to 2.24 MPa exhibited by GCB 30, with high degree of interconnected porosity appropriate for cellular colonization. To study the effect of different bioceramic phases on MSCs differentiation, scaffolds were cell cultured for up to 14 days in osteogenic medium. GCB30 scaffold showed higher capacity to proliferate MSCs cultured onto it as compared to other composite scaffolds. Degree of differentiation of MSCs into osteoblast was higher in GCB30 scaffolds than in the GCH30 and GCT30 composite scaffold as evident from higher amount of RUNX2 and osteocalcin expression in the former up to 14 days of cell culture. Inclusion of 58s bioactive glass particles showed positive effects on cell differentiation. In coherence with the in vitro appearance, histomorphometric analysis and fluorochrome study in a rabbit tibia model showed a significantly greater amount of new bone formation in GCB30 compared to other composite scaffolds. The results demonstrated that the prepared GCB30 scaffold could be a better candidate as bone substitute material for its higher bioactivity in bone tissue regeneration. PMID- 30423759 TI - A facile method to synthesize mussel-inspired polydopamine nanospheres as an active template for in situ formation of biomimetic hydroxyapatite. AB - In this study, Mussel-inspired polydopamine (PDA) nanospheres were synthesized via spontaneous oxidative polymerization of dopamine hydrochloride (dopa-HCl) in a deionized water-alcohol mixed solvent at room temperature and atmospheric air, under alkaline condition. Field-emission scanning electron microscopy (FE-SEM) demonstrated production of sphere-like shape with a smooth surface and tunable size, while monodispersity increased by utilizing isopropanol instead of ethanol owing to lower Ra values based on Hansen solubility parameter (HSP) theory. Dropwise addition of monomer played an undeniable role in the fabrication of uniform and smaller spheres. The difference of the charge repulsion of constructs in the range of pH led to different dispersive behavior in a variety of solvents, exhibiting versatile applications. The presence of active functional groups on the surface of PDA spheres made them an appropriate option for PDA-assisted biomimetic mineralization of hydroxyapatite (HA), which is the result of the interaction between abundant catecholamine moieties in PDA and Ca+2 ions in simulated body fluid. Bio-adhesive nature of PDA in water and the presence of amino and hydroxyl functional groups support desirable L929 mouse fibroblast cell spreading. The viability of >90% fibroblast cells proved the biocompatibility of polymerized structure. All the achievements indicated that PDA nanospheres provide a biocompatible and bioactive template for green synthesizing hydroxyapatite and the innovative basis for further tissue engineering applications. PMID- 30423760 TI - Electrospun nanofibrous thermoplastic polyurethane/poly(glycerol sebacate) hybrid scaffolds for vocal fold tissue engineering applications. AB - Vocal fold tissue engineering requires biomimetic scaffolds with an appropriate matrix stiffness closely matching that of the natural vocal folds to maintain function. Traditionally, poly(E-caprolactone) (PCL) and thermoplastic polyurethane (TPU) have been employed as the primary matrix materials for vocal fold electrospun scaffolds. However, not all of the scaffolds fabricated thus far matched the human vocal fold tissues. Poly(glycerol sebacate) (PGS) is a non cytotoxic and biodegradable soft elastomer that has shown promising results for soft tissue engineering applications. However, no work has been done to employ this biomaterial to construct vocal fold scaffolds. In this study, PGS has been synthesized and blended with thermoplastic polyurethane (TPU) to produce vocal fold scaffolds with improved hydrophilicity and compliance by electrospinning. The resulting scaffolds were found to have mechanical properties mimicking those of the vocal fold lamina propria extracellular matrix (ECM). An unusual leaf-like structure was obtained when using 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as the solvent. Other suitable fibrous scaffolds were also obtained when using acetic acid and 2,2,2-trifluoroethanol (TFE) as binary solvents. A biological evaluation of these TPU/PGS scaffolds showed better cell spreading and significantly improved cell proliferation as compared to TPU-only scaffolds (p < 0.01), thereby suggesting potential applications for vocal fold tissue engineering. PMID- 30423761 TI - Fabrication and in vitro behavior of dual-function chitosan/silver nanocomposites for potential wound dressing applications. AB - We report the synthesis and in vitro evaluation of dual-function chitosan-silver nanoparticles (CTS-AgNPs) films with potential applications as wound dressings. We attempted to formulate nanocomposite films with appropriate AgNPs concentrations to simultaneously display antibacterial activity and suitability for cell culture. Nanocomposites were obtained by CTS-mediated in situ chemical reduction of AgNO3. Circular-shape AgNPs (sizes ca. 7-50 nm) well distributed within the CTS matrices were obtained in concentrations from 0.018 to 0.573 wt%. Efficacy (bacteriostatic and bactericidal properties) of CTS-AgNPs films to decrease planktonic and biofilm bacterial growth was AgNPs concentration- and bacteria strain-dependent. Films showed significant antibacterial activity against Gram-negative E. coli and P. aeruginosa and Gram-positive S. aureus. Antibacterial activity against S. epidermidis was moderated. Films suitability for cell culture was characterized using primary human fibroblasts (HF). HF displayed cell viability higher than 90% and the characteristic fusiform morphology of adhered fibroblast upon culture on films with AgNPs concentration <= 0.036 wt%. HF cultured on these films also showed positive expression of tropoelastin, procollagen type I and Ki-67, characteristic proteins of extracellular matrix and proliferative cells, respectively. In vitro assays demonstrated that cytocompatibility/antibacterial properties decreased/increased as silver concentration increased, suggesting that CTS-AgNPS nanocomposite films with ~0.04-0.20 wt% might be considered as potential temporary dual-function wound dressings. PMID- 30423762 TI - Biological, thermal and mechanical characterization of modified glass ionomer cements: The role of nanohydroxyapatite, ciprofloxacin and zinc l-carnosine. AB - The study evaluated the effects of 4 wt% nanohydroxyapatite (HA), 6 wt% zinc l carnosine (MDA) and 1.5 wt% Ciprofloxacin (AB) on the mechanical, thermal and biological properties of glass ionomer cements (GIC). Filler and additive concentrations were selected after a previous study had tested single components and different percentages. Specimens included five silicon molds of each GIC cement for all tests. They were stored at room temperature for 24 h from specimen collection to analysis. Mechanical tests, calorimetric analysis, morphological investigation, antibacterial and cell viability assays were conducted. One-way analysis of variance (ANOVA) was used for data analysis with significance set at p < 0.05. Adding HA, MDA and AB to GICs modified their thermal, mechanical and microbiological properties. Polymerization increased. A slight decrease in the compressive strength of modified GICs was observed in dry condition (p < 0.05). Cement extracts affected cell viability in relation to extract dilution. Mechanical behavior improved in modified glass ionomer cements, especially with the powder formulated antibiotic. Overall cytotoxicity was reduced. Therefore adding nanohydroxyapatite, antibiotic and a mucosal defensive agent to conventional glass ionomer cement in special need patients could improve the clinical, preventive and therapeutic performance of the cements, without altering their mechanical properties. PMID- 30423763 TI - Gradient platform for combinatorial screening of thermoset polymers for biomedical applications. AB - The goal of this work was to design a device for rapid screening of crosslinked thermoset polymers. This gradient curing platform is capable of yielding a library of polyesters with systematically varying mechanical and physicochemical properties and the resultant cellular response. A library of poly(xylitolsebacate) polyesters was prepared in this device by differential curing to yield a gradient polymer. The resultant polymer exhibits a gradient in the storage modulus (1 to 5 MPa), wettability (70 degrees < water contact angle < 110 degrees ), degree of crosslinking, degradation rate (3-25% in 7 days), drug release and biological response (ability to support stem cell proliferation and differentiation) from one end of the polymer to the other. Primary human mesenchymal stem cells were cultured to assess the cellular response in vitro. Maximal stem cell proliferation and osteogenesis was observed on the highly crosslinked polyester segments that provide high stiffness, are hydrophobic and are slow degrading as compared to the lower cured counterparts. Under in vivo conditions, this material showed differential response across the gradient without displaying significant concerns for inflammation or infection. This gradient curing device is capable of ascertaining suitable curing conditions to obtain appropriate polymers for application specific requirements. This gradient platform was further used to identify optimal processing parameters to prepare three-dimensional tissue scaffolds such as electrospun fiber mats and porous foams. Thus, this versatile combinatorial platform is well suited for rapid screening of thermoset polymers for biomedical applications. PMID- 30423764 TI - Studies on the interaction of mononuclear metal(II) complexes of amino naphthoquinone with bio-macromolecules. AB - Three metal(II) complexes [CoLCl2], [CuLCl2] and [ZnL2Cl2] {L = 2-chloro-3-((3 dimethylamino)propylamino)naphthalene-1,4-dione} have been synthesized and characterized using analytical, thermal and spectral techniques (FT-IR, UV-Vis, ESR and ESI-MS). The structure of the L has been confirmed by single crystal XRD study. The complexes show good binding propensity to bovine serum albumin (BSA) having relatively higher binding constant values (104 M-1) than the ligand. Fluorescence spectral studies indicate that [CoLCl2] binds relatively stronger with CT DNA through intercalative mode, exhibiting higher binding constant (2.22 * 105 M-1). Agarose gel electrophoresis run on plasmid DNA (pUC18) prove that all the complexes showed efficient DNA cleavage via hydroxyl radical mechanism. The complexes were identified as potent anticancer agents against two human cancer cell lines (MCF7 and A549) by comparing with cisplatin. Co(II) complex demonstrated greater cytotoxicity against MCF7 and A549 cells with IC50 values at 19 and 22 MUM, respectively. PMID- 30423765 TI - Decellularized bovine small intestinal submucosa-PCL/hydroxyapatite-based multilayer composite scaffold for hard tissue repair. AB - This study involved the development of a multilayer osteogenic tissue scaffold by assembling decellularized bovine small intestinal submucosa (bSIS) layers, together with synthetic hydroxyapatite microparticles (HAp) and poly(epsilon caprolactone) (PCL) as the binder. As a first step, the surface and mechanical properties of the developed scaffold was determined, after which the biocompatibility was evaluated through seeding with isolated rat bone marrow mesenchymal stem cells (BM-MSCs). Then, a 21-day culture study was performed to investigate the in vitro osteoinductive potential of the scaffold on BM-MSCs under standard and osteogenic culture conditions. The SEM findings indicated that a uniform multilayer and perforated structure was acquired; that the HAp microparticles were homogenously distributed within the structure; and that the PCL-bound laminar scaffold had structural integrity. Mechanical tests revealed that the scaffold maintained its mechanical stability for at least 21 days in culture, with no changes in the first-day maximum strength and maximum stress values of 625.123 +/- 70.531 N and 6.57762 +/- 0.742 MPa, respectively. MTT and SEM analyses together revealed that BM-MSCs preserved their viability and proliferated during a 14-day culture period on the multilayer scaffold. Immunofluorescence analyses indicated that cells on the scaffold differentiated into the osteogenic lineage, by the culture-time-dependent increase in osteogenic markers' expression, i.e. Alkaline phosphatase, Osteopontin, and Osteocalcin. It was also clear that, the osteoinductive effect by the composite scaffold on BM MSCs could be achieved even without the use of any external osteogenic inducers. PMID- 30423766 TI - Gold is for the mistress, silver for the maid: Enhanced mechanical properties, osteoinduction and antibacterial activity due to iron doping of tricalcium phosphate bone cements. AB - Self-hardening calcium phosphate cements present ideal bone tissue substitutes from the standpoints of bioactivity and biocompatibility, yet they suffer from (a) weak mechanical properties, (b) negligible osteoinduction without the use of exogenous growth factors, and (c) a lack of intrinsic antibacterial activity. Here we attempt to improve on these deficiencies by studying the properties of self-setting Fe-doped bone-integrative cements containing two different concentrations of the dopant: 0.49 and 1.09 wt% Fe. The hardening process, which involved the transformation of Fe-doped beta-tricalcium phosphate (Fe-TCP) to nanocrystalline brushite, was investigated in situ by continuously monitoring the cements using the Energy Dispersive X-Ray Diffraction technique. The setting time was 20 min and the hardening time 2 h, but it took 50 h for the cement to completely stabilize compositionally and mechanically. Still, compared to other similar systems, the phase transformation during hardening was relatively fast and it also followed a relatively simple reaction path, virtually free of complex intermediates and noisy background. Mossbauer spectrometry demonstrated that 57Fe atoms in Fe-TCP were located in two non-equivalent crystallographic sites and distributed over positions with a strong crystal distortion. The pronounced presence of ultrafine crystals in the final, brushite phase contributed to the reduction of the porosity and thereby to the enhancement of the mechanical properties. The compressive strength of the hardened TCP cements increased by more than twofold when Fe was added as a dopant, i.e., from 11.5 +/- 0.5 to 24.5 +/- 2.0 MPa. The amount of iron released from the cements in physiological media steadied after 10 days and was by an order of magnitude lower than the clinical threshold that triggers the toxic response. The cements exhibited osteoinductive activity, as observed from the elevated levels of expression of genes encoding for osteocalcin and Runx2 in both undifferentiated and differentiated MC3T3-E1 cells challenged with the cements. The osteoinductive effect was inversely proportional to the content of Fe ions in the cements, indicating that an excessive amount of iron can have a detrimental effect on the induction of bone growth by osteoblasts in contact with the cement. In contrast, the antibacterial activity of the cement in the agar assay increased against all four bacterial species analysed (E. coli, S. enteritidis, P. aeruginosa, S. aureus) in direct proportion with the concentration of Fe ions in it, indicating their key effect on the promotion of the antibacterial effect in this material. This effect was less pronounced in broth assays. Experiments involving co-incubation of cements with cells in an alternate magnetic radiofrequency field for 30 min demonstrated a good potential for the use of these magnetic cements in hyperthermia cancer therapies. Specifically, the population of human glioblastoma cells decreased six fold at the 24 h time point following the end of the magnetic field treatment, while the population of the bone cancer cells dropped approximately twofold. The analysis of the MC3T3-E1 cell/cement interaction reiterated the effects of iron in the cement on the bone growth marker expression by showing signs of adverse effects on the cell morphology and proliferation only for the cement containing the higher concentration of Fe ions (1.09 wt%). Biological testing concluded that the effects of iron are beneficial from the perspective of a magnetic hyperthermia therapy and antibacterial prophylaxis, but its concentration in the material must be carefully optimized to avoid the adverse effects induced above a certain level of iron concentrations. PMID- 30423767 TI - Microstructure, mechanical properties and springback behaviour of Ti-6Al-4V alloy connection rod for spinal fixation device. AB - The effect of annealing condition on microstructure, mechanical properties and springback behaviour was examined in the connection rod of Ti-6Al-4V alloy for spinal fixation devices. Compared with the deformed microstructure in the sample before annealing, relatively few equiaxed grains were present after annealing at 1003 K after 1.8 ks, and a considerable amount appeared at 7.2 ks. When annealing time was extended to 36 ks, the recrystallised grains further grew. Vickers hardness, tensile strength and bending strength decreased with increasing annealing time, whereas the elastic and bending moduli showed no significant change with annealing time of up to 7.2 ks and then slightly decreased at 36 ks. The springback ratio was closely associated with strength and modulus and applied bending deflection. The springback ratio reached the highest and lowest values in the sample before and after annealing for 7.2 ks, respectively. A good combination of strength, modulus and springback ratio was obtained in the sample after annealing for 7.2 ks. PMID- 30423768 TI - Electrochemical corrosion behavior of a non-vascular, bi-stent combination, surgical esophageal nitinol stent in phosphate-buffered saline solution. AB - In the present work, the corrosion behavior of a bi-stent combination, which is the combination of an uncoated outer stent and silicone-coated body stent, was assessed by the use of electrochemical methods in phosphate-buffered saline at 37 degrees C. Although each stent comprising the bi-stent combination showed favorable corrosion properties, the bi-stent combination showed significant decreases in these corrosion properties. Corrosion was concentrated on the uncoated outer stent of the bi-stent combination. The cathodic reaction was activated on the outer stent of the bi-stent combination by the galvanic effect, and the hydrogen generated was detrimental to the surface film on the outer stent. In addition, hydrogen had a synergic effect with chloride and accelerated the corrosion reaction on the outer stent. PMID- 30423769 TI - Silver-gold-apoferritin nanozyme for suppressing oxidative stress during cryopreservation. AB - Reactive oxygen species (ROS) cause oxidative stress, which involves in the pathogenesis of many serious diseases. Apoferittin containing gold-silver nanoparticles (Au-Ag-AFT) was designed and evaluated as a nanozyme for scavenging the ROS. The nanozyme consisting of silver-gold nanohybrid in apoferittin cage represents superoxide dismutase, catalase and peroxidase mimetic activities. The Au-Ag-AFT nanozyme was characterized by spectroscopy, FESEM, TEM and dynamic light scattering. The inhibition process for pyrogallol autoxidation was used for assaying the superoxide dismutase mimetic activity and measuring the kinetic parameters of Au-Ag-AFT nanozyme. Additionally, Aebi method and standard protocol was used for evaluating the catalase and peroxidase mimetic activity. The kcat values for superoxide dismutase, catalase and peroxidase mimetics activity were 1.4 * 106, 0.1 and 9 * 103 s-1 respectively. These values indicated that Au-Ag AFT nanozyme could act as a suitable ROS scavenger. Additionally, Au-Ag-AFT nanozyme was examined as a protective agent for human sperm against oxidative stress induced during the cryopreservation process. Presence of the nanozyme in the sperm media significantly increased the motility and viability of the cells and also decreased the ROS, apoptosis and necrosis (P < 0.05) compare to the control group. PMID- 30423770 TI - Improvement of physicochemical properties of nanocolloidal carrier loaded with low water solubility drug for parenteral cancer treatment by Response Surface Methodology. AB - Nanoemulsions have been used as a drug carrier system, particularly for poorly water-soluble drugs. Sorafenib is a poorly soluble drug and also there is no parenteral treatment. The aim of this study is the development of nanoemulsions for intravenous administration of Sorafenib. The formulations were prepared by high energy emulsification method and optimized by using Response Surface Methodology (RSM). Here, the effect of independent composition variables of lecithin (1.16-2.84%, w/w), Medium-Chain Triglycerides (2.32-5.68%, w/w) and polysorbate 80 (0.58-1.42%, w/w) amounts on the properties of Sorafenib-loaded nanoemulsion was investigated. The three responses variables were particle size, zeta potential, and polydispersity index. Optimization of the conditions according to the three dependent variables was performed for the preparation of the Sorafenib-loaded nanoemulsions with the minimum value of particle size, suitable rage of zeta potential, and polydispersity index. A formulation containing 0.05% of Sorafenib kept its properties in a satisfactory range over the evaluated period. The composition with 3% Medium-Chain Triglycerides, 2.5% lecithin and 1.22% polysorbate 80 exhibited the smallest particle size and polydispersity index (43.17 nm and 0.22, respectively) with the zeta potential of -38.8 mV was the optimized composition. The fabricated nanoemulsion was characterized by the transmission electron microscope (TEM), viscosity, and stability assessment study. Also, the cytotoxicity result showed that the optimum formulations had no significant effect on a normal cell in a low concentration of the drug but could eliminate the cancer cells. The dose-dependent toxicity made it a suitable candidate for parenteral applications in the treatment of breast cancer. Furthermore, the optimized formulation indicated good storage stability for 3 months at different temperatures (4 +/- 2 degrees C, 25 +/- 2 degrees C and 45 +/- 2 degrees C). PMID- 30423771 TI - Green synthesis of copper oxide nanoparticles decorated reduced graphene oxide for high sensitive detection of glucose. AB - A non-enzymatic glucose sensor based on pencil graphite electrode (PGE) modified by copper oxide nanoparticles decorated reduced graphene oxide (CuO(NP)/rGO-PGE) was prepared. XRD patterns showed partially electrochemically reduction of GO and monoclinic structure of CuO on the PGE. The prepared CuO(NP)/rGO exhibited a nanoporous structure by scanning electron microscopy (SEM). Transmittance electron microscopy (TEM) revealed copper oxide nanoparticles were well distributed on rGO and had semispherical shapes with diameter 3-5 nm. Cyclic voltammetry at CuO(NP)/rGO-PGE showed the immobilized CuO(NP)s were highly stable in alkaline solutions and had high electrocatalytic activity toward glucose oxidation. Using amperometry, the detection limit of [0.091 (+/-0.003) MUM] and concentration sensitivity of [4760 (+/-3.2) MUA mM-1 cm-2] for glucose was obtained at optimum conditions. The applicability of the sensor was evaluated to determine the glucose concentration in human blood serum samples and the experimental results were comparable with those measured by traditional spectrophotometric methods. The preparation of CuO(NP)/rGO-PGE was reproducible, very simple, fast and inexpensive for practical application. PMID- 30423772 TI - Co3O4/CuO hollow nanocage hybrids with high oxidase-like activity for biosensing of dopamine. AB - Here, we report the synthesis, characterization, and oxidase-like activity of Co3O4/CuO hollow nanocage (HNC) nanocomposites. The Co3O4/CuO HNCs were successfully prepared by hydrothermal treatment of ZIF-67 in copper nitrate solution, followed by carbonization in air. The obtained nanocomposites were characterized by scanning electron microscopy, transmission electron microscopy, X-ray photoelectron spectroscopy, and X-ray diffraction. The Co3O4/CuO HNCs possess enhanced oxidase-like activity compared with pure Co3O4 and CuO, and they can catalytically oxidize the 3,3',5,5'-tetramethylbenzidine (TMB) substrate in the absence of H2O2 to produce an intense blue product. Reactive oxygen species (ROS) measurements indicate that 1O2 and O2- radicals are the major ROS in catalytic oxidation of TMB by dissolved oxygen in the TMB-Co3O4/CuO HNC system. We then developed a simple, sensitive, visual, and colorimetric biosensing method for dopamine (DA) based on its inhibiting effect on TMB oxidation. The proposed method allows for DA detection with a limit of detection of 0.027 MUM and a dynamic range of 0.05-8 MUM. This new colorimetric method was successfully used to detect DA in biological samples. The present work demonstrates a simple strategy to fabricate an efficient oxidase mimic with potential applications in bioanalysis and clinical diagnosis. PMID- 30423773 TI - Preparation of gentamicin sulfate eluting fiber mats by emulsion and by suspension electrospinning. AB - This work investigates the immobilization of the antibiotic gentamicin sulfate (GS) in electrospun fiber mats composed of poly(lactic acid) (PLA), poly(epsilon caprolactone) (PCL) and the copolymer poly(lactic-co-glycolic acid) (PLGA). Since GS is highly water soluble but weakly soluble in the organic solvents commonly used in the electrospinning process, two methods of immobilization were investigated: by suspension electrospinning, in which GS particles were directly dispersed in the polymeric organic solutions, and by emulsion electrospinning, in which GS was solubilized in an aqueous phase that was then dispersed in the organic polymeric solution containing the surfactant SPAN80. Fibers with distinct diameters and morphologies were obtained for the different methods and compositions. Contrary to the fibers prepared by suspension electrospinning, emulsion electrospinning based fibers exhibited an excellent wettability, allegedly due to the effect of the surfactant SPAN80. Despite the differences between both methods the produced mats presented similar GS release profiles, with a considerable burst release in the first 8 h followed by a gradual release of the remaining drug during the next 4-6 days. Finally, all GS loaded fiber mats proved to have an antibacterial effect against the bacterial strain Staphylococcus aureus. PMID- 30423774 TI - Polymeric 3D scaffolds for tissue regeneration: Evaluation of biopolymer nanocomposite reinforced with cellulose nanofibrils. AB - Biopolymers such as gelatin (Gel) and cellulose nanofibrils (CNF) have many of the essential requirements for being used as scaffolding materials in tissue regeneration; biocompatibility, surface chemistry, ability to generate homogeneous hydrogels and 3D structures with suitable pore size and interconnection, which allows cell colonization and proliferation. The purpose of this study was to investigate whether the mechanical behaviour of the Gel matrix can be improved by means of functionalization with cellulose nanofibrils and proper cross-linking treatments. Blending processes were developed to achieve a polymer nanocomposite incorporating the best features of both biopolymers: biomimicry of the Gel and structural reinforcement by the CNF. The designed 3D structures underline interconnected porosity achieved by freeze-drying process, improved mechanical properties and chemical stability that are tailored by CNF addition and different cross-linking approaches. In vitro evaluations reveal the preservation of the biocompatibility of Gel and its good interaction with cells by promoting cell colonization and proliferation. The results support the addition of cellulose nanofibrils to improve the mechanical behaviour of 3D porous structures suitable as scaffolding for tissue regeneration. PMID- 30423775 TI - Application of a nano-structured molecularly imprinted polymer as an efficient modifier for the design of captopril drug selective sensor: Mechanism study and quantitative determination. AB - In the present study, electrochemical studies and potentiometric determination of captopril (CAP) drug were presented using a glassy carbon electrode (GCE) and carbon paste electrode (CPE), respectively; which is modified with a synthetic nano-structured molecularly imprinted polymer (MIP). CAP-MIP sample with an average particle size of 95 nm was synthesized using a precipitation polymerization method. The electrochemical behavior of CAP was studied on a MIP modified GCE, in an aqueous solution at pH 3.0. The electron transfer coefficient (alpha) was determined for the CAP drug, using electrochemical approaches. The prepared CAP-MIP was also used as a modifier in a CPE to design a selective CAP sensor, before its potentiometric determination. The modified CPE exhibits a good electrochemical response with a Nernstian slope of 59.15 +/- 1.5 mV per decade over a wide linearity in the concentration range of 3.0 * 10-9-1.0 * 10-1 mol L 1. The cyclic voltammetry results were in good agreement with the electrochemical studies for the 1H+/1e- process. The designed electrode indicates a reasonable selectivity for CAP over other studied drugs such as ibuprofen, paracetamol, acyclovir, pyrazinamide, dimenhydrinate, and naproxen as well as with an excellent applicability in some pharmaceutical products. PMID- 30423776 TI - Preparation of pillar[5]arene immobilized trypsin and its application in microwave-assisted digestion of Cytochrome c. AB - This work presents the immobilization of trypsin on the synthesized pillar[5]arene derivative (P5) containing ten iodo-terminals. The characterization has been carried out by Thermogravimetric Analysis (TGA), Fourier Transform Infrared (FTIR) and Raman spectra, Scanning Electron Microscopy (SEM) and Zeta Potential. Furthermore, Cytochrome c (Cyt c) was chosen as a model protein for evaluation of the performance of the pillar[5]arene-immobilized trypsin (P5-T), and its microwave-assisted digestion conditions were investigated by using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) for 15 second. The peptide numbers of 10 and sequence coverage of 93% for 15 second microwave-assisted digestion were obtained for P5-T. The results can be further applied in future proteomics studies due to high efficiency, good reproducibility and stability of the pillar[5]arene-immobilized trypsin. PMID- 30423777 TI - Cowries derived aragonite as raw biomaterials for bone regenerative medicine. AB - Carbonate apatites are sought as a bone substitute due to their biocompatibility and excellent resorbability. The present study deals with Cowrie's shell derived powder (CSDP) as natural biomaterial for bone regenerative medicine. Structural and physicochemical analysis showed that Cowrie's shells, presenting brick and mortar microstructures, were mainly composed of aragonite crystals, which were converted into poorly crystalline B-type carbonate apatite once soaked, at 37 degrees C, in simulated body fluid for 7 days, reflecting bioactive features. Cytotoxic assays showed that CSDP boosted human stem cell proliferation over the study time compared to nacre derived powder (NDP), used as positive control. Human stem cells adopted a flattened morphology and established physical contact with CSDP, signature of a good biocompatibility. Thus, these results suggested that CSDP presents a great interest for bone regenerative medicine, and could be a useful and versatile carrier/scaffold for bone tissue engineering or a raw material for 3D printed orthopedic devices. PMID- 30423778 TI - The design of additively manufactured lattices to increase the functionality of medical implants. AB - The rise of antibiotic resistant bacterial species is driving the requirement for medical devices that minimise infection risks. Antimicrobial functionality may be achieved by modifying the implant design to incorporate a reservoir that locally releases a therapeutic. For this approach to be successful it is critical that mechanical functionality of the implant is maintained. This study explores the opportunity to exploit the design flexibilities possible using additive manufacturing to develop porous lattices that maximise the volume available for drug loading while maintaining load-bearing capacity of a hip implant. Eight unit cell types were initially investigated and a volume fraction of 30% was identified as the lowest level at which all lattices met the design criteria in ISO 13314. Finite element analysis (FEA) identified three lattice types that exhibited significantly lower displacement (10-fold) compared with other designs; Schwartz primitive, Schwartz primitive pinched and cylinder grid. These lattices were additively manufactured in Ti-6Al-4V using selective laser melting. Each design exceeded the minimum strength requirements for orthopaedic hip implants according to ISO 7206-4. The Schwartz primitive (Pinched) lattice geometry, with 10% volume fill and a cubic unit cell period of 10, allowed the greatest void volume of all lattice designs whilst meeting the fatigue requirements for use in an orthopaedic implant (ISO 7206-4). This paper demonstrates an example of how additive manufacture may be exploited to add additional functionality to medical implants. PMID- 30423779 TI - Identification of the critical viscoelastic factor in the performance of submucosal injection materials. AB - High-performance submucosal injection materials (SIMs) contribute to the success of endoscopic therapy for early-stage gastrointestinal neoplasms. This study aimed to identify the most important factor (viscoelastic parameter) that determines SIM performance and the ease of injection. To determine the ideal viscoelastic parameters of SIMs, submucosal elevation heights (SEHs) and the ease of submucosal injection [characterized by injection pressures (IPs)] were evaluated using a newly developed ex vivo model, in which a constant tension was applied to the studied specimen. The strongest positive correlation was observed between the loss modulus determined at an oscillation frequency of 0.1 rad/s and SEH (correlation coefficient > 0.9) and between the loss modulus at 10 rad/s and IP (correlation coefficient > 0.9). SIMs with high loss moduli (0.1 rad/s) also contributed to maintenance of the submucosal elevation. Moreover, the SEHs of pseudoplastic fluid SIMs (whose loss moduli increased slightly with increasing angular frequency) were greater than those of Newtonian fluid SIMs (whose loss modulus increased drastically with increasing angular frequency). In this study, the ideal viscoelastic SIM parameters were clarified. The loss modulus (0.1 rad/s) was the most important viscoelastic factor affecting SIM performance. Additionally, the development of pseudoplastic fluid SIMs may lead to the creation of next-generation SIMs, with a performance superior to that of sodium hyaluronate, which is currently used widely in endoscopic treatments. PMID- 30423780 TI - Functionalized graphene oxide coating on Ti6Al4V alloy for improved biocompatibility and corrosion resistance. AB - The present study focused on the development of magnesium-functionalized graphene oxide (FGO) coating on titanium alloy (Ti6Al4V) by electrophoretic deposition. Graphene oxide (GO) was synthesized by modified Hummers' method and functionalized with magnesium ions. X-ray diffraction, infrared spectroscopy (IR) and Raman spectroscopy were employed to confirm the synthesis of GO and GO coatings on Ti6Al4V. Functionalization of GO with Mg ions was confirmed by energy dispersive X-ray spectroscopy. The surface morphology of coated samples was examined through scanning electron microscopy. Reduction of FGO coating (labelled as rFGO) by heating at 200 degrees C was confirmed by IR. The rFGO coated Ti6Al4V was found to be hydrophilic in nature as determined by contact angle measurement which showed reduction in the contact angle of Ti6Al4V from 95.4 degrees to 42.1 degrees . The percent cell viability over the coated sample was appreciably improved compared to as-received Ti6Al4V sample owing to hydrophilicity of the former. The positive shift in open circuit potential and increase in polarization resistance was observed after coating Ti6Al4V samples with FGO. The significant decrease in the corrosion current density and negative polarization loop in the reverse scan of samples also confirmed the improved corrosion resistance of rFGO-coated Ti6Al4V over uncoated Ti6Al4V in the PBS solution. Furthermore, the impedance spectroscopy revealed that the preferential adsorption of ionic species (indicated by large Rads) at the surface improved the barrier characteristics of rFGO coated samples and exhibited an order of magnitude higher Rct compared to as-received samples. PMID- 30423781 TI - Drug release and biodegradability of electrospun cellulose nanocrystal reinforced polycaprolactone. AB - In this paper, high molecular weight cellulose was used as the starting material for the synthesis of cellulose nanocrystal (CNC). Different analysis techniques such as FTIR, XRD, TGA, DLS, and AFM were used to characterize CNC synthesis. The synthesized CNC was incorporated in polycaprolactone solution and nanofibers were prepared under different conditions. Production conditions were optimized based on the diameter of nanofibers using response surface methodology (RSM). Based on our results, the optimal condition is electrospinning of 16% PCL polymer solution at 17 kV and a 0.9 ml/h feed rate, which yields nanofibers with a diameter of 233 nm. The effects of CNC content on morphological, mechanical and thermal properties were investigated. Results also showed that CNC incorporation in PCL nanofibers enhances biodegradability. SEM, DSC, tensile, and biodegradability results showed that the nanofibers prepared from PCL solution containing 1% CNC have optimal mechanical and degradation behaviors. We also studied and modeled release of tetracycline from nanofiber mats, based on the assumption of rate limiting diffusion from the nanofibers, with a fraction of release delayed by drug sequestration. Results showed that the final drug release is decreased in CNC-incorporated nanofibers. PMID- 30423782 TI - Regeneration of different types of tissues depends on the interplay of stem cells laden constructs and microenvironments in vivo. AB - The ability of repair and regeneration of tissues or organs has been significantly improved by using biomaterials-based constructs. Our previous studies found the regeneration of both articular cartilage and subchondral bone by implantation of a poly(lactide-co-glycolide) (PLGA)/fibrin gel/bone marrow stem cells (BMSCs)/(lipofectamine/pDNA-transforming growth factor (TGF)-beta1) construct in vivo, without the step of pre-induced differentiation of the laden stem cells in vitro. To substantiate the ability to regenerate multi-types of tissues by the same constructs, in this study the constructs were implanted into three types of tissues or tissue defects in vivo, including subcutaneous fascia layer, and ear cartilage and eyelid tarsal plate defects. The ear cartilage and eyelid tarsal plate defects were fully regenerated 8 w post-implantation, showing a similar morphology to the corresponding native tissues. In the neo ear cartilage, abundant chondrocytes with obvious lacunas and cartilage-specific extracellular matrices (ECMs) were found. Neo eyelid tarsal plate with mature meibomian gland acinar units was regenerated. Furthermore, expressions of the ECMs-specific genes and proteins, as well as the cell behavior modulatory factors, Sry related HMG box 9 (Sox9) and TGF-beta1 were significantly up regulated in the regenerated ear cartilages and eyelid tarsal plate than those in the subcutaneously implanted constructs, which were filled with fibrocytes, inflammatory cells, obvious vascularization and slight ECMs deposition. These results confirm firmly the ability to regenerate multi-types of tissues by a stem cells-laden construct via adapting to the microenvironments of corresponding tissues. PMID- 30423783 TI - Impact of styrene maleic anhydride (SMA) based hydrogel on rat fallopian tube as contraceptive implant with selective antimicrobial property. AB - Development of non-hormonal female contraception is a need to combat against increasing population growth. The presently available short term or long term female contraceptives and sterilization methods have their own restrictions and side effects. With this objective, herein, we describe an innovative insight about the use of hydrogel formulation consisting of Styrene Maleic Anhydride (SMA) dissolved in Dimethyl Sulfoxide (DMSO) as non-hormonal fallopian tube contraceptive implant. Firstly, in vitro behavior of SMA hydrogel was evaluated by in vitro swelling and rheological properties to comprehend the polymeric hydrogel property post implantation inside the fallopian tube. Simulated Uterine Fluid (SUF) was used to simulate female reproductive tract environment in this study. Mechanical strength of the hydrogel when subjected to dynamic environment post implantation in the fallopian tube was estimated by the G' values demonstrated. SMA hydrogel expressed selective antimicrobial activity against opportunistic pathogens (Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus) while having limited consequence over the growth of Lactobacillus spp. After confirmation of cytocompatibility against primary rat endometrial cell lines, the polymeric hydrogel was implanted inside the uterine horns of Sprague-Dawley rats. In vivo biocompatibility of the hydrogel was confirmed by histological and immunohistochemical evaluation of uterine tissue sections. Hematology, blood biochemistry and organ toxicity (kidney, liver, spleen, lungs and heart) also revealed biocompatibility of SMA hydrogel. The results of the current study indicated that the SMA copolymer dissolved in DMSO to form hydrogel has excellent biocompatibility for application as female contraceptive gel which can be implanted in the fallopian tube. PMID- 30423784 TI - Novel of nano delivery system for Linalool loaded on gold nanoparticles conjugated with CALNN peptide for application in drug uptake and induction of cell death on breast cancer cell line. AB - Linalool is a monoterpene alcohol which occurs naturally in several aromatic plants. The aims of this study are to load Linalool on gold nanoparticles, conjugate the complex with CALNN peptide, and investigate them for in-vitro anticancer activities against breast cancer (MCF-7) cell line. Linalool was obtained with 98% purity while gold nanoparticles and CALNN peptide were chemically synthesized. The formation of LIN-GNPs and LIN-GNPs-CALNN was observed through a color change. These compounds were confirmed and characterized using SEM, DLS, AFM, UV-VIS spectrophotometer, XRD, and FTIR. The free radical scavenging potential of each compound was confirmed based on its stable antioxidant effects using different parameters. Blood compatibility on red blood cells was confirmed by hemolytic and in vitro cytotoxicity assays. The in-vitro anticancer activity of each compound towardMCF-7 cell line was investigated using various parameters. From the results, Linalool, GNPs, LIN-GNPs, and LIN-GNPs CALNN were found to exert cell growth arrest against MCF-7 cell line. The anti proliferative effect of these compounds was due to cell death and induction of apoptosis confirmed using acridine orange-Ethidium bromide dual staining, DAPI staining, and electrophoresis analysis of DNA fragmentation. High fluorescent signals specific for the cellular uptake of LIN-GNPs and LIN-GNPs-CALNN into the cytoplasm of the cell line were confirmed. To study the toxicity of LIN-GNPs CALNN in animal models, the hematological, histopathological, and body weight changes were estimated after 4 weeks of intraperitoneal injection of the compounds into the animal models. Our results demonstrate that Linalool, GNPs, Linalool-GNPs, and Linalool-GNPs-CALNN peptide had no side effects and could be clinically used for future therapeutic purposes. PMID- 30423785 TI - A facile restructuring of 3D high water absorption aerogels from methoxy polyethylene glycol-polycaprolactone (mPEG-PCL) nanofibers. AB - High water absorption aerogels with three-dimensional porous structures and high specific surface areas have been fabricated from methoxy polyethylene glycol polycaprolactone block copolymer (mPEG-PCL) via a facile approach by electrospinning, mechanical homogeneous shearing and dispersing short fibers in the water, freeze-drying, and heat crosslinking. The three-dimensional nanofiber aerogels (TNAs) exhibit continuous porous structures which are restructured with crisscrossed and dispersed nanofibers. The aerogel displays a low density (36 +/- 3 mg/cm3), a high specific surface area (230 m2/g), a high pore volume (5.9 cm3/g), a high porosity of 85% as well as an average pore diameter (1.12 MUm). The as-made mPEG-PCL TNAs deliver a high average water-absorption capacity of 24.11 g/g and a good retention ability owing to the three-dimensional porous structures and large micropores population. The water absorption could still reach approximately 25 g/g after 10 compression cycles of TNAs. The average dehydration weight loss of 3.1% demonstrates that the materials are hardly soluble in the water, and the structural characteristic would not be changed after water adsorption. The antimicrobial activity against the bacteria Staphylococcus aureus and Escherichia coli are assessed that the TNAs are suitable carriers of antimicrobial agents. Moreover, as showed by cytotoxic tests, the TNAs are neglectable toxic, which are suitable for applications in environmental bioengineering. Based on the high water absorption and biocompatibility, the TNAs could be suitable candidates for health care materials and medical products. PMID- 30423786 TI - Modulatory effect of simultaneously released magnesium, strontium, and silicon ions on injectable silk hydrogels for bone regeneration. AB - Injectable silk hydrogels are ideal carriers of therapeutic agents due to their biocompatibility and low immunogenicity. Injectable silk hydrogels for bone regeneration have been previously developed but often utilize expensive biologics. In this study, we have developed an injectable silk composite incorporated with a triphasic ceramic called MSM-10 (54 Mg2SiO4, 36 Si3Sr5 and 10 MgO (wt%)) capable of simultaneously releasing magnesium, silicon, and strontium ions into its environment. These ions have been previously reported to possess therapeutic effects for bone regeneration. MSM-10 particles were incorporated into the silk hydrogels at various weight percentages [0.1 (SMH-0.1), 0.6 (SMH 0.6), 1 (SMH-1) and 2 (SMH-2)]. The effects of the released ions on the physicochemical and biological properties of the silk hydrogel were comprehensively evaluated. Increased MSM-10 loading was found to hinder the gelation kinetics of the silk hydrogel through the reduction of beta-sheet phase formation, which in turn affected the required sonication time for gelation, compressive strength, force of injection, microstructure and in vitro degradation rate. Primary human osteoblasts seeded on SMH-0.6 demonstrated increased proliferation and early alkaline phosphatase activity, as well as enhanced osteogenic gene expression compared to pure silk hydrogel and SMH-0.1. In vivo results in subcutaneous mouse models showed both decreased fibrous capsule formation and increased number of new blood vessels around the injected SMH-0.1 and SMH-0.6 implants compared to pure silk hydrogels. The results in this study indicate that the ions released from MSM-10 is able to influence the physicochemical and biological properties of silk hydrogels, and SMH-0.6 in particular shows promising properties for bone regeneration. PMID- 30423787 TI - Effects of creep and creep-recovery on ratcheting strain of articular cartilage under cyclic compression. AB - Since the accumulations of ratcheting strain combined with creep deformation, which are produced in normal activities, can accelerate the fatigue damage of cartilage in joint, the creep-ratcheting and creep-recovery-ratcheting behaviors of articular cartilage are experimentally investigated under creep-fatigue loads. The effect of pre-creep on ratcheting behavior of cartilage was probed firstly and it is found that the initial ratcheting strain of cartilage presents the larger value (30% and 35%) due to its pre-creep deformation in spite of the short pre-creep time applied. With the increasing pre-creep time the ratcheting strain of sample increases while the ratcheting strain rate decreases. The effects of pre-creep and recovery on ratcheting behavior of cartilage were also investigated and it is noted that the strain of cartilage increases fast at first, decreases partly and then changes periodically with cyclic stress. The ratcheting strain evolutions of different layers are not coincident for cartilage sample after the pre-creep or pre-creep-recovery and the ratcheting strains of different layers with pre-creep are larger than them with pre-creep-recovery. Finally the creep ratcheting strain of cartilage with different peak-holding time during cyclic compression was studied and it is found that the creep-ratcheting strain with peak-holding time is significantly greater than that without peak-holding time. The creep-ratcheting strain increases with increase of peak-holding time or stress amplitude, while it reduces with rising of stress rate. The creep ratcheting behavior of cartilage is dependent on its depth. These findings point out that the accumulated deformations, including creep deformation and ratcheting deformation, can accelerate the cartilage's damage. PMID- 30423788 TI - PLGA-amoxicillin-loaded layer formed on anodized Ti alloy as a hybrid material for dental implant applications. AB - In this paper, the preparation of a functional hybrid coating loaded with a drug (amoxicillin) on a promising titanium alloy - Ti-15Mo alloy is presented. The titanium alloy surface was anodized in solution with bioactive compounds to obtain a porous oxide layer favorable for MG-63 osteoblast-like cell adhesion. Then, a poly(lactide-co-glycolide) (PLGA) loaded with amoxicillin layer was formed using a dip-coating technique to cover the oxide layer, without filling in all of the pores. The morphology of the surface was evaluated using scanning electron microscopy supported by 3D Roughness Reconstruction software. The surface treatment of the Ti-15Mo alloy surface caused the surface roughness to increase up to 1.71 MUm. The anodization process caused the Ti-15Mo alloy surface to become slightly more hydrophilic; however, the formation of the PLGA layer loaded with drug increased the contact angle to 96.5 degrees +/- 2.2 degrees , respectively. After 4 weeks of polymer layer degradation, the registered signals on the 1H NMR spectrum were identical to the signals registered for lactic acid (LAc), which confirms that the polymer layer was degraded within a short period of time. The concentration of drug released into the artificial saliva was investigated using high-performance liquid chromatography (HPLC) up to 12 h of coatings immersion. During the first hour of coating degradation in artificial saliva, and the concentration of the drug (13 MUg/ml) was enough to inhibit bacterial growth of S. aureus and S. epidermidis. These results were confirmed by agar plate diffusion method and evaluation of the minimal inhibitory concentration (MIC). The cytocompatibility of the materials was determined using the osteoblast-like cells MG-63, and the viability and cell morphology (live/dead staining) were also evaluated. The results showed that amoxicillin influences the osteoblast-like MG-63 cells' behavior during cell culture, especially for the first few hours. The influence on the type of surface treatment on MG-63 cell behavior during 7 days of culture is discussed in this paper. To the best of our knowledge, this is the first time that a fast-degrading layer with amoxicillin has been deposited on previously anodized Ti surface. The formation of functional coating may find application as a cytocompatible coating to prevent bacterial adhesion on long-term implant surfaces. PMID- 30423789 TI - Editorial. PMID- 30423790 TI - Optimizing Evidence-based Opioid-prescribing After General Surgery. PMID- 30423792 TI - Biomaterials in Abdominal Wall Surgery: Change Your Mind!: Erratum. PMID- 30423791 TI - Reply to: "Relationship Between Sarcopenic Obesity and Outcomes of Hepatectomy for Hepatocellular Carcinoma". PMID- 30423793 TI - In the Next Issue. PMID- 30423794 TI - The Internal Relation between Quantum Chemical Descriptors and Empirical Constants of Polychlorinated Compounds. AB - Quantum chemical descriptors and empirical parameters are two different types of chemical parameters that play the fundamental roles in chemical reactivity and model development. However, previous studies have lacked detail regarding the relationship between quantum chemical descriptors and empirical constants. We selected polychlorinated biphenyls (PCBs) as an object to investigate the intrinsic correlation between 16 quantum chemical descriptors and Hammett constants. The results exhibited extremely high linearity for ? with Qxx/yy/zz, alpha and EHOMO based on the meta-position grouping. Polychlorinated dibenzodioxins (PCDDs) and polychlorinated naphthalenes (PCNs) congeners, as two independent compounds, validated the reliability of the relationship. The meta substituent grouping method between ? and alpha was successfully used to predict the rate constant (k) for *OH oxidation of PCBs, as well as the octanol/water partition coefficient (logKOW) and aqueous solubility (-logSW) of PCDDs, and exhibited excellent agreement with experimental measurements. Revealing the intrinsic correlation underlying the empirical constant and quantum chemical descriptors can develop simpler and higher efficient model application in predicting the environmental behavior and chemical properties of compounds. PMID- 30423795 TI - Retraction: Yang, C., et al. miR-126 Functions as a Tumor Suppressor in Osteosarcoma by Targeting Sox2. Int. J. Mol. Sci. 2014, 15, 423-437, doi:10.3390/ijms15010423. AB - Experimental results from [...]. PMID- 30423796 TI - An Unusual Presentation of Pectoralis Major Pyomyositis Presenting as Septic Arthritis of the Shoulder: A Case Report and Review of the Literature. AB - Pyomyositis is a relatively rare condition and often requires a low index of suspicion. We present a case of an otherwise fit and well woman who had pyomyositis of the pectoralis major muscle and presented as an acute septic arthritis of the shoulder. We present the conundrums that arose in arriving at this diagnosis, and how we successfully managed this condition through our multidisciplinary approach. We urge all clinicians to bear in mind this potential diagnosis, even in those patients not deemed to be immunocompromised. PMID- 30423797 TI - Polyamidoamine Nanoparticles for the Oral Administration of Antimalarial Drugs. AB - Current strategies for the mass administration of antimalarial drugs demand oral formulations to target the asexual Plasmodium stages in the peripheral bloodstream, whereas recommendations for future interventions stress the importance of also targeting the transmission stages of the parasite as it passes between humans and mosquitoes. Orally administered polyamidoamine (PAA) nanoparticles conjugated to chloroquine reached the blood circulation and cured Plasmodium yoelii-infected mice, slightly improving the activity of the free drug and inducing in the animals immunity against malaria. Liquid chromatography with tandem mass spectrometry analysis of affinity chromatography-purified PAA ligands suggested a high adhesiveness of PAAs to Plasmodium falciparum proteins, which might be the mechanism responsible for the preferential binding of PAAs to Plasmodium-infected erythrocytes vs. non-infected red blood cells. The weak antimalarial activity of some PAAs was found to operate through inhibition of parasite invasion, whereas the observed polymer intake by macrophages indicated a potential of PAAs for the treatment of certain coinfections such as Plasmodium and Leishmania. When fluorescein-labeled PAAs were fed to females of the malaria mosquito vectors Anopheles atroparvus and Anopheles gambiae, persistent fluorescence was observed in the midgut and in other insect's tissues. These results present PAAs as a versatile platform for the encapsulation of orally administered antimalarial drugs and for direct administration of antimalarials to mosquitoes, targeting mosquito stages of Plasmodium. PMID- 30423798 TI - DNA Methylation Analysis of Dormancy Release in Almond (Prunus dulcis) Flower Buds Using Epi-Genotyping by Sequencing. AB - DNA methylation and histone post-translational modifications have been described as epigenetic regulation mechanisms involved in developmental transitions in plants, including seasonal changes in fruit trees. In species like almond (Prunus dulcis (Mill.) D.A: Webb), prolonged exposure to cold temperatures is required for dormancy release and flowering. Aiming to identify genomic regions with differential methylation states in response to chill accumulation, we carried out Illumina reduced-representation genome sequencing on bisulfite-treated DNA from floral buds. To do this, we analyzed almond genotypes with different chilling requirements and flowering times both before and after dormancy release for two consecutive years. The study was performed using epi-Genotyping by Sequencing (epi-GBS). A total of 7317 fragments were sequenced and the samples compared. Out of these fragments, 677 were identified as differentially methylated between the almond genotypes. Mapping these fragments using the Prunus persica (L.) Batsch v.2 genome as reference provided information about coding regions linked to early and late flowering methylation markers. Additionally, the methylation state of ten gene-coding sequences was found to be linked to the dormancy release process. PMID- 30423799 TI - Matrix Metalloproteinase-1 and Acid Phosphatase in the Degradation of the Lamina Propria of Eruptive Pathway of Rat Molars. AB - The comprehension of dental pathogenesis and disorders derived from eruption failure requires a deep understanding of the molecular mechanisms underlying normal tooth eruption. As intense remodelling is needed during tooth eruption, we hypothesize that matrix metalloproteinase-1 (MMP-1) and acid phosphatase (ACP) play a role in the eruptive pathway degradation. We evaluated MMP-1 immunoexpression and the collagen content in the lamina propria at different eruptive phases. Immunohistochemistry and ultrastructural cytochemistry for detection of ACP were also performed. In the maxillary sections containing first molars of 9-, 11-, 13-, and 16-day-old rats, the birefringent collagen of eruptive pathway was quantified. MMP-1 and ACP-2 immunohistochemical reactions were performed and the number of MMP-1-immunolabelled cells was computed. Data were analyzed by one-way ANOVA and Tukey post-test (p <= 0.05). ACP cytochemistry was evaluated in specimens incubated in sodium beta-glycerophosphate. In the eruptive pathway of 13- and 16-day-old rats, the number of MMP-1-immunolabelled cells increased concomitantly to reduction of collagen in the lamina propria. Enhanced ACP-2-immunolabelling was observed in the lamina propria of 13- and 16 day-old rats. Fibroblasts and macrophages showed lysosomes and vacuoles containing fragmented material reactive to ACP. MMP-1 degrades extracellular matrix, including collagen fibers, being responsible for the reduction in the collagen content during tooth eruption. The enhanced ACP activity at the mucosal penetration stage indicates that this enzyme plays a role in the degradation of remnant material, which is engulfed by macrophages and fibroblasts of the eruptive pathway. Therefore, enzymatic failure in the eruptive pathway may disturbs tooth eruption. PMID- 30423800 TI - Effect of Diet Supplementation with Quinoa Seed and/or Linseed on Immune Response, Productivity and Meat Quality in Merinos Derived Lambs. AB - In the last years several studies have investigated the strong relation between nutrition and immune response in the livestock production, particularly in dairy cattle and sheep. The aim of this study was to evaluate the effects of supplementation based on linseed, quinoa seeds and their combination on welfare, productivity and quality of meat from merinos derived lambs. 32 weaned lambs were divided into 4 experimental groups: quinoa (Q), linseed (LS) and combination of quinoa and linseed (LS + Q) that received the respective supplementation and control group (C) without supplementation. Lambs from all supplemented groups showed lower plasma urea, creatinine and cholesterol than control. Both linseed and quinoa supplementation enhanced the cell-mediated immune responses of lambs, furthermore, linseed supplementation resulted in the lowest level of cortisol secretion after handling, loading and transport. Meat from lambs supplemented with linseed and LS + Q showed the highest pH, at 1 and 3 h post-mortem, while, meat from all supplemented groups was more tender than meat from control. Results indicated that linseed and quinoa seeds supplementation can help the animal to cope with stressful events due to the close link between stress responses and the immune system and for improving meat quality in terms of better tenderness. PMID- 30423802 TI - Detailed Characterization of Early HIV-1 Replication Dynamics in Primary Human Macrophages. AB - Macrophages are natural target cells of human immunodeficiency virus type 1 (HIV 1). Viral replication appears to be delayed in these cells compared to lymphocytes; however, little is known about the kinetics of early post-entry events. Time-of-addition experiments using several HIV-1 inhibitors and the detection of reverse transcriptase (RT) products with droplet digital PCR (ddPCR) revealed that early replication was delayed in primary human monocyte-derived macrophages of several donors and peaked late after infection. Direct imaging of reverse-transcription and pre-integration complexes (RTC/PIC) by click-labeling of newly synthesized DNA further confirmed our findings and showed a concomitant shift to the nuclear stage over time. Altering the entry pathway enhanced infectivity but did not affect kinetics of viral replication. The addition of viral protein X (Vpx) enhanced productive infection and accelerated completion of reverse transcription and nuclear entry. We propose that sterile alpha motif (SAM) and histidine/aspartate (HD) domain-containing protein 1 (SAMHD1) activity lowering deoxyribonucleotide triphosphate (dNTP) pools is the principal factor delaying early HIV-1 replication in macrophages. PMID- 30423803 TI - Microwave-Assisted Expeditious Synthesis of 2-Alkyl-2-(N-arylsulfonylindol-3-yl) 3-N-acyl-5-aryl-1,3,4-oxadiazolines Catalyzed by HgCl2 under Solvent-Free Conditions as Potential Anti-HIV-1 Agents. AB - A series of 2-alkyl-2-(N-arylsulfonylindol-3-yl)-3-N-acyl-5-aryl-1,3,4 oxadiazolines were expeditious prepared under microwave-assisted, catalyzed by HgCl2 and solvent-free conditions. This method has the advantage of low catalyst loading and recovering catalyst, ease reaction and repaid reaction times, easy separation products and excellent yields, and more conducive to the large-scale synthesis products. Furthermore, compounds 3s, 3y, 3a', 3b', 3f', 3i', 3q', and 3r' exhibited more potent anti-HIV-1 activity with EC50 values of 3.35, 6.12, 3.63, 9.54, 1.79, 0.51, 3.00, and 4.01 MUg/mL, and TI values of 32.66, >32.68, 31.22, 13.94, 24.27, 39.59, 26.01, and 24.51, respectively. Especially compound 3i' displayed the highest anti-HIV-1 activity with TI values of 39.59. PMID- 30423801 TI - Molecular Basis of Aquaporin-7 Permeability Regulation by pH. AB - The aquaglyceroporin AQP7, a family member of aquaporin membrane channels, facilitates the permeation of water and glycerol through cell membranes and is crucial for body lipid and energy homeostasis. Regulation of glycerol permeability via AQP7 is considered a promising therapeutic strategy towards fat related metabolic complications. Here, we used a yeast aqy-null strain for heterologous expression and functional analysis of human AQP7 and investigated its regulation by pH. Using a combination of in vitro and in silico approaches, we found that AQP7 changes from fully permeable to virtually closed at acidic pH, and that Tyr135 and His165 facing the extracellular environment are crucial residues for channel permeability. Moreover, instead of reducing the pore size, the protonation of key residues changes AQP7's protein surface electrostatic charges, which, in turn, may decrease glycerol's binding affinity to the pore, resulting in decreased permeability. In addition, since some pH-sensitive residues are located at the monomer-monomer interface, decreased permeability may result from cooperativity between AQP7's monomers. Considering the importance of glycerol permeation via AQP7 in multiple pathophysiological conditions, this mechanism of hAQP7 pH-regulation may help the design of selective modulators targeting aquaglyceroporin-related disorders. PMID- 30423804 TI - Unlocking the Potential of 46 New Bacteriophages for Biocontrol of Dickeya Solani. AB - Modern agriculture is expected to face an increasing global demand for food while also needing to comply with higher sustainability standards. Therefore, control of crop pathogens requires new, green alternatives to current methods. Potatoes are susceptible to several bacterial diseases, with infections by soft rot Enterobacteriaceae (SRE) being a significant contributor to the major annual losses. As there are currently no efficient ways of combating SRE, we sought to develop an approach that could easily be incorporated into the potato production pipeline. To this end, 46 phages infecting the emerging potato pathogen Dickeya solani were isolated and thoroughly characterized. The 46 isolated phages were grouped into three different groups based on DNA similarity, representing two distinct clusters and a singleton. One cluster showed similarity to phages previously used to successfully treat soft rot in potatoes, whereas the remaining phages were novel and showed only very limited similarity to previously isolated phages. We selected six diverse phages in order to create the hereto most complex phage cocktail against SRE. The cocktail was applied in a proof-of-principle experiment to treat soft rot in potatoes under simulated storage conditions. We show that the phage cocktail was able to significantly reduce the incidence of soft rot as well as disease severity after 5 days of storage post-infection with Dickeya solani. This confirms results from previous studies that phages represent promising biocontrol agents against SRE infection in potato. PMID- 30423805 TI - Comparison of College Students' Energy Expenditure, Physical Activity, and Enjoyment during Exergaming and Traditional Exercise. AB - This study evaluated the effects of exergaming on college students' energy expenditure (EE), moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), rating of perceived exertion (RPE), and enjoyment compared to traditional treadmill exercise, and sex differences. Sixty college students (30 female; X - age = 23.6 +/- 4.1 years) completed three 20-min exercise sessions on Xbox 360 Kinect Just Dance (Microsoft, Redmond, WA, USA), Xbox 360 Kinect Reflex Ridge (Microsoft, Redmond, WA, USA), and treadmill walking. Their EE and PA were assessed by ActiGraph accelerometers (ActiGraph Co.; Pensacola, FL, USA); RPE every four min; enjoyment via an established scale. Significant exercise-type by sex interaction effects were observed for RPE (p < 0.01): females reported significantly lower RPE during exergaming sessions but significantly higher RPE during treadmill walking. Results revealed significant main effects for all outcomes between exercise sessions (all p < 0.01): treadmill walking resulted in significantly higher metabolic equivalents (METs), MVPA, and EE (p < 0 .01), yet lower LPA (p < 0.01), compared to the two exergaming sessions. Participants' RPE was significantly higher during treadmill walking than during exergaming sessions, with exergaming eliciting significantly higher enjoyment (all p < 0.01). College students find exergaming more enjoyable and report lower RPE compared to traditional treadmill exercise, though not yet matching the moderate physiological intensity level. PMID- 30423807 TI - Inhibition of Microglia-Derived Oxidative Stress by Ciliary Neurotrophic Factor Protects Dopamine Neurons In Vivo from MPP+ Neurotoxicity. AB - We demonstrated that capsaicin (CAP), an agonist of transient receptor potential vanilloid subtype 1 (TRPV1), inhibits microglia activation and microglia-derived oxidative stress in the substantia nigra (SN) of MPP+-lesioned rat. However, the detailed mechanisms how microglia-derived oxidative stress is regulated by CAP remain to be determined. Here we report that ciliary neurotrophic factor (CNTF) endogenously produced by CAP-activated astrocytes through TRPV1, but not microglia, inhibits microglial activation and microglia-derived oxidative stress, as assessed by OX-6 and OX-42 immunostaining and hydroethidine staining, respectively, resulting in neuroprotection. The significant increase in levels of CNTF receptor alpha (CNTFRalpha) expression was evident on microglia in the MPP+ lesioned rat SN and the observed beneficial effects of CNTF was abolished by treatment with CNTF receptor neutralizing antibody. It is therefore likely that CNTF can exert its effect via CNTFRalpha on microglia, which rescues dopamine neurons in the SN of MPP+-lesioned rats and ameliorates amphetamine-induced rotations. Immunohistochemical analysis revealed also a significantly increased expression of CNTFRalpha on microglia in the SN from human Parkinson's disease patients compared with age-matched controls, indicating that these findings may have relevance to the disease. These data suggest that CNTF originated from TRPV1 activated astrocytes may be beneficial to treat neurodegenerative disease associated with neuro-inflammation such as Parkinson's disease. PMID- 30423806 TI - Chronic Consumption of Fructose Induces Behavioral Alterations by Increasing Orexin and Dopamine Levels in the Rat Brain. AB - It has been widely described that chronic intake of fructose causes metabolic alterations which can be associated with brain function impairment. In this study, we evaluated the effects of fructose intake on the sleep-wake cycle, locomotion, and neurochemical parameters in Wistar rats. The experimental group was fed with 10% fructose in drinking water for five weeks. After treatment, metabolic indicators were quantified in blood. Electroencephalographic recordings were used to evaluate the sleep architecture and the spectral power of frequency bands. Likewise, the locomotor activity and the concentrations of orexin A and monoamines were estimated. Our results show that fructose diet significantly increased the blood levels of glucose, cholesterol, and triglycerides. Fructose modified the sleep-wake cycle of rats, increasing the waking duration and conversely decreasing the non-rapid eye movement sleep. Furthermore, these effects were accompanied by increases of the spectral power at different frequency bands. Chronic consumption of fructose caused a slight increase in the locomotor activity as well as an increase of orexin A and dopamine levels in the hypothalamus and brainstem. Specifically, immunoreactivity for orexin A was increased in the ventral tegmental area after the intake of fructose. Our study suggests that fructose induces metabolic changes and stimulates the activity of orexinergic and dopaminergic neurons, which may be responsible for alterations of the sleep-wake cycle. PMID- 30423809 TI - Characterization of Ecklonia cava Alginate Films Containing Cinnamon Essential Oils. AB - In this study, Ecklonia cava alginate (ECA) was used as a base material for biodegradable films. Calcium chloride (CaCl2) was used as a cross-linking agent, and various concentrations (0%, 0.4%, 0.7%, and 1.0%) of cinnamon leaf oil (CLO) or cinnamon bark oil (CBO) were incorporated to prepare active films. The ECA film containing 3% CaCl2 had a tensile strength (TS) of 17.82 MPa and an elongation at break (E) of 10.36%, which were higher than those of the film without CaCl2. As the content of essential oils (EOs) increased, TS decreased and E increased. Addition of CLO or CBO also provided antioxidant and antimicrobial activities to the ECA films. The antioxidant activity of the ECA film with CBO was higher than that of the film containing CLO. In particular, the scavenging activities of the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis (3 ethylbenzothiazoline-6-sulphonic acid) (ABTS) radicals in the ECA film containing 1% CBO were 50.45% and 99.37%, respectively. In contrast, the antimicrobial activities against Escherichia coli O157:H7, Salmonella Typhimurium, Staphylococcus aureus, and Listeria monocytogenes were superior in the ECA films with CLO. These results suggest that ECA films containing CLO or CBO can be applied as new active packaging materials. PMID- 30423808 TI - Immunohistochemical Evaluation of Aquaporin-4 and its Correlation with CD68, IBA 1, HIF-1alpha, GFAP, and CD15 Expressions in Fatal Traumatic Brain Injury. AB - Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide. Our understanding of its pathobiology has substantially increased. Following TBI, the following occur, edema formation, brain swelling, increased intracranial pressure, changes in cerebral blood flow, hypoxia, neuroinflammation, oxidative stress, excitotoxicity, and apoptosis. Experimental animal models have been developed. However, the difficulty in mimicking human TBI explains why few neuroprotective strategies, drawn up on the basis of experimental studies, have translated into improved therapeutic strategies for TBI patients. In this study, we retrospectively examined brain samples in 145 cases of death after different survival times following TBI, to investigate aquaporin-4 (AQP4) expression and correlation with hypoxia, and neuroinflammation in human TBI. Antibodies anti-glial fibrillary acid protein (GFAP), aquaporin-4 (AQP4), hypoxia induced factor-1alpha (HIF-1alpha), macrophage/phagocytic activation (CD68), ionized calcium-binding adapter molecule-1 (IBA-1), and neutrophils (CD15) were used. AQP4 showed a significant, progressive increase between the control group and groups 2 (one-day survival) and 3 (three-day survival). There were further increases in AQP4 immunopositivity in groups 4 (seven-day survival), 5 (14-dayssurvival), and 6 (30-day survival), suggesting an upregulation of AQP4 at 7 to 30 days compared to group 1. GFAP showed its highest expression in non-acute cases at the astrocytic level compared with the acute TBI group. Data emerging from the HIF-1alpha reaction showed a progressive, significant increase. Immunohistochemistry with IBA-1 revealed activated microglia starting three days after trauma and progressively increasing in the next 15 to 20 days after the initial trauma. CD68 expression demonstrated basal macrophage and phagocytic activation mostly around blood vessels. Starting from one to three days of survival after TBI, an increase in the number of CD68 cells was progressively observed; at 15 and 30 days of survival, CD68 showed the most abundant immunopositivity inside or around the areas of necrosis. These findings need to be developed further to gain insight into the mechanisms through which brain AQP4 is upregulated. This could be of the utmost clinicopathological importance. PMID- 30423811 TI - NVP-BEZ235 Attenuated Cell Proliferation and Migration in the Squamous Cell Carcinoma of Oral Cavities and p70S6K Inhibition Mimics its Effect. AB - NVP-BEZ235 or BEZ235 is a dual inhibitor of adenosine triphosphate (ATP) competitive phosphoinositide 3-kinase (PI3K)/mammalian-target-of-rapamycin (mTOR) and is promising for cancer treatment. Because it targets more than one downstream effector, a dual approach is promising for cancer treatment. The aim of this study was to evaluate the efficacy of NVP-BEZ235 in treating oral cavity squamous cell carcinoma (OSCC). Two human OSCC cell lines, SCC-4 and SCC-25, were used in this study. PI3K-AKT signaling, proliferation, and cell migratory and invasion capabilities of OSCC cells were examined. In NVP-BEZ235-treated SCC-4 and SCC-25 cells, the phosphorylation of 70-kDa ribosomal S6 kinase (p70S6K), but not mTOR, decreased within 24 h. NVP-BEZ235 inhibited OSCC-cell proliferation, migration, and invasion possibly by directly deregulating the phosphorylation of p70S6K. The phospho-p70S6K inhibitor mimicked the effects of NVP-BEZ235 for preventing proliferation and weakening the migratory and invasion abilities of SCC-4 and SCC-25 cells. This study further confirmed the effect of NVP-BEZ235 on OSCC cells and provided a new strategy for controlling the proliferation, migration, and invasion of OSCC cells using the phopho-p70S6K inhibitor. PMID- 30423812 TI - Role of Overexpressed Transcription Factor FOXO1 in Fatal Cardiovascular Septal Defects in Patau Syndrome: Molecular and Therapeutic Strategies. AB - Patau Syndrome (PS), characterized as a lethal disease, allows less than 15% survival over the first year of life. Most deaths owe to brain and heart disorders, more so due to septal defects because of altered gene regulations. We ascertained the cytogenetic basis of PS first, followed by molecular analysis and docking studies. Thirty-seven PS cases were referred from the Department of Pediatrics, King Abdulaziz University Hospital to the Center of Excellence in Genomic Medicine Research, Jeddah during 2008 to 2018. Cytogenetic analyses were performed by standard G-band method and trisomy13 were found in all the PS cases. Studies have suggested that genes of chromosome 13 and other chromosomes are associated with PS. We, therefore, did molecular pathway analysis, gene interaction, and ontology studies to identify their associations. Genomic analysis revealed important chr13 genes such as FOXO1, Col4A1, HMGBB1, FLT1, EFNB2, EDNRB, GAS6, TNFSF1, STARD13, TRPC4, TUBA3C, and TUBA3D, and their regulatory partners on other chromosomes associated with cardiovascular disorders, atrial and ventricular septal defects. There is strong indication of involving FOXO1 (Forkhead Box O1) gene-a strong transcription factor present on chr13, interacting with many septal defects link genes. The study was extended using molecular docking to find a potential drug lead for overexpressed FOXO1 inhibition. The phenothiazine and trifluoperazine showed efficiency to inhibit overexpressed FOXO1 protein, and could be potential drugs for PS/trisomy13 after validation. PMID- 30423813 TI - Interferons and Dry Eye in Sjogren's Syndrome. AB - Various cytokines, including interferon (IFN)-gamma and IL-17, are augmented, and autoreactive T cells and B cells are activated in the immune pathogenesis of Sjogren's syndrome (SS). In particular, IFNs are involved in both the early stages of innate immunity by high level of type I IFN in glandular tissue and sera and the later stages of disease progression by type I and type II IFN producing T cells and B cells through B cell activating factor in SS. Genetically modified mouse models for some of these molecules have been reported and will be discussed in this review. New findings from human SS and animal models of SS have elucidated some of the mechanisms underlying SS-related dry eye. We will discuss IFN-gamma and several other molecules that represent candidate targets for treating inflammation in SS-related dry eye. PMID- 30423814 TI - Pretreatment of Lignocellulosic Materials as Substrates for Fermentation Processes. AB - Lignocellulosic biomass is an abundant and renewable resource that potentially contains large amounts of energy. It is an interesting alternative for fossil fuels, allowing the production of biofuels and other organic compounds. In this paper, a review devoted to the processing of lignocellulosic materials as substrates for fermentation processes is presented. The review focuses on physical, chemical, physicochemical, enzymatic, and microbiologic methods of biomass pretreatment. In addition to the evaluation of the mentioned methods, the aim of the paper is to understand the possibilities of the biomass pretreatment and their influence on the efficiency of biofuels and organic compounds production. The effects of different pretreatment methods on the lignocellulosic biomass structure are described along with a discussion of the benefits and drawbacks of each method, including the potential generation of inhibitory compounds for enzymatic hydrolysis, the effect on cellulose digestibility, the generation of compounds that are toxic for the environment, and energy and economic demand. The results of the investigations imply that only the stepwise pretreatment procedure may ensure effective fermentation of the lignocellulosic biomass. Pretreatment step is still a challenge for obtaining cost-effective and competitive technology for large-scale conversion of lignocellulosic biomass into fermentable sugars with low inhibitory concentration. PMID- 30423810 TI - Therapeutic Microbiology: The Role of Bifidobacterium breve as Food Supplement for the Prevention/Treatment of Paediatric Diseases. AB - The human intestinal microbiota, establishing a symbiotic relationship with the host, plays a significant role for human health. It is also well known that a disease status is frequently characterized by a dysbiotic condition of the gut microbiota. A probiotic treatment can represent an alternative therapy for enteric disorders and human pathologies not apparently linked to the gastrointestinal tract. Among bifidobacteria, strains of the species Bifidobacterium breve are widely used in paediatrics. B. breve is the dominant species in the gut of breast-fed infants and it has also been isolated from human milk. It has antimicrobial activity against human pathogens, it does not possess transmissible antibiotic resistance traits, it is not cytotoxic and it has immuno stimulating abilities. This review describes the applications of B. breve strains mainly for the prevention/treatment of paediatric pathologies. The target pathologies range from widespread gut diseases, including diarrhoea and infant colics, to celiac disease, obesity, allergic and neurological disorders. Moreover, B. breve strains are used for the prevention of side infections in preterm newborns and during antibiotic treatments or chemotherapy. With this documentation, we hope to increase knowledge on this species to boost the interest in the emerging discipline known as "therapeutic microbiology". PMID- 30423815 TI - A Novel Hybrid of a Fading Filter and an Extreme Learning Machine for GPS/INS during GPS Outages. AB - In this paper, a novel algorithm based on the combination of a fading filter (FF) and an extreme learning machine (ELM) is presented for Global Positioning System/Inertial Navigation System (GPS/INS) integrated navigation systems. In order to increase the filtering accuracy of the model, a variable fading factor fading filter based on the fading factor is proposed. It adjusts the fading factor by the ratio of the estimated covariance before and after the moment which proves to have excellent performance in our experiment. An extreme learning machine based on a Fourier orthogonal basis function is introduced that considers the deterioration of the accuracy of the navigation system during GPS outages and has a higher positioning accuracy and faster learning speed than the typical neural network learning algorithm. In the end, a simulation and real road test are performed to verify the effectiveness of this algorithm. The results show that the accuracy of the fading filter based on a variable fading factor is clearly improved, and the proposed improved ELM algorithm can provide position corrections during GPS outages more effectively than the other algorithms (ELM and the traditional radial basis function neural network). PMID- 30423816 TI - Two Decades of Invasive Western Corn Rootworm Population Monitoring in Croatia. AB - Western corn rootworm (WCR) is the worst pest of maize in the United States, and since its spread through Europe, WCR is now recognized as the most serious pest affecting maize production. After the beetle's first detection in Serbia in 1992, neighboring countries such as Croatia have established a national monitoring program. For more than two decades WCR adult population abundance and variability was monitored. With traditional density monitoring, more recent genetic monitoring, and the newest morphometric monitoring of WCR populations, Croatia possesses a great deal of knowledge about the beetle's invasion process over time and space. Croatia's position in Europe is unique as no other European nation has demonstrated such a detailed and complete understanding of an invasive insect. The combined use of traditional monitoring (attractant cards), which can be effectively used to predict population abundance, and modern monitoring procedures, such as population genetics and geometric morphometrics, has been effectively used to estimate inter- and intra-population variation. The combined application of traditional and modern monitoring techniques will enable more efficient control and management of WCR across Europe. This review summarizes the research on WCR in Croatia from when it was first detected in 1992 until 2018. An outline of future research needs is provided. PMID- 30423817 TI - Local Pressure of Supercritical Adsorbed Hydrogen in Nanopores. AB - An overview is given of the development of sorbent materials for hydrogen storage. Understanding the surface properties of the adsorbed film is crucial to optimize hydrogen storage capacities. In this work, the lattice gas model (Ono Kondo) is used to determine the properties of the adsorbed hydrogen film from a single supercritical hydrogen isotherm at 77 K. In addition, this method does not require a conversion between gravimetric excess adsorption and absolute adsorption. The overall average binding energy of hydrogen is 4.4 kJ/mol and the binding energy at low coverage is 9.2 kJ/mol. The hydrogen film density at saturation is 0.10 g/mL corresponding to a local pressure of 1500 bar in the adsorbed phase. PMID- 30423818 TI - miR-103/miR-195/miR-15b Regulate SALL4 and Inhibit Proliferation and Migration in Glioma. AB - Glioma is the common highly malignant primary brain tumor. However, the molecular pathways that result in the pathogenesis of glioma remain elusive. In this study, we found that microRNA-103 (miR-103), microRNA-195 (miR-195), or microRNA-15b (miR-15b), which all have the same 5' "seed" miRNA portion and share common binding sites in the SALL4 3'-untranslated region (UTR), were downregulated in glioma tissues and cell lines. These miRNAs suppressed glioma cell proliferation, migration, and invasion, induced cell apoptosis, and decreased the level of the SALL4 protein, but not that of SALL4 mRNA, which was identified as a direct target of all three miRNAs. The caspase-3/7 activity expression in U251 cells overexpressing these miRNAs was rescued during SALL4 upregulation. An obvious inverse correlation was observed between SALL4 and miR-103 or miR-195 expression levels in clinical glioma samples. Moreover, enforced expression of SALL4 stimulated cell proliferation, migration, and invasion. In conclusion, these data suggest that miR-103, miR-195, and miR-15b post-transcriptionally downregulated the expression of SALL4 and suppressed glioma cell growth, migration, and invasion, and increased cell apoptosis. These results provide a potential therapeutic target that may downregulate SALL4 in glioma. PMID- 30423819 TI - A Situation-Aware Indoor Localization (SAIL) System Using a LF and RF Hybrid Approach. AB - Recently, studies focusing on identifying user's current location for use in a wide variety of differentiated location-based and localization services have steadily increased. In particular, location awareness using wireless communication is gaining attention in indoor environments composed of many obstacles, where GPS signals cannot reach. Previously, studies have focused mostly on location precision, which resulted in using many beacon nodes, not considering the initial installation and maintenance costs, communication robustness, or power consumption. This makes it difficult to apply existing methods to various fields, especially in mobile nodes (i.e., wearable devices, mobile tags, etc.) with limited battery capacity. In this paper, we propose a hybrid situation-aware indoor localization (SAIL) system for real-time indoor localization using a combination of low frequency (LF) and Bluetooth Low Energy (BLE) 4.0. This approach allows us to work with limited battery capacity mobile devices, and identify tagged mobile nodes and their current location in relevance to the anchor node. In our experiment, we attached one anchor node at the entrance to indoor areas such as office or factory settings. Using our hybrid SAIL system, we were able to detect the passing of a mobile node through the entrance and recognize whether the node is entering or exiting the room by calculating the direction of movement as well as the distance from the entrance. This allowed us to distinguish the precise position in an indoor environment with the margin of error being 0.5 m. The signal attenuation due to obstacles is overcome by using LF communication in the 125-kHz band. This approach enables us to reduce the number of initially installed anchor nodes as well as the power consumption of the mobile node. We propose an indoor position recognition system, namely, the hybrid SAIL system, that can be applied to mobile nodes with limited battery capacity by reducing the system complexity and power consumption. PMID- 30423820 TI - A Novel Method for the Determination of Vancomycin in Serum by High-Performance Liquid Chromatography-Tandem Mass Spectrometry and Its Application in Patients with Diabetic Foot Infections. AB - A novel, precise, and accurate high-performance liquid chromatography-tandem mass spectrometry (Q-trap-MS) method was developed, optimized, and validated for determination of vancomycin in human serum using norvancomycin as an internal standard. Effect of different parameters on the analysis was evaluated. ZORBAX SB C18 column (150 * 4.6 mm, 5 MUm) using water (containing 0.1% formic acid, v/v) acetonitrile (containing 0.1% formic acid, v/v) as a mobile phase was chosen. The calibration curve was linear over the concentration ranges of 1 to 2000 ng/mL for vancomycin. The limit of detection (LOD) and limit of quantification (LOQ) for vancomycin were 0.3 and 1.0 ng/mL. Recoveries were between 87.2 and 102.3%, which gave satisfactory precision. A total of 100 serum samples (from 50 patients with diabetic foot proven Gram-positive infection and 50 nondiabetic patients with pneumonia requiring hospitalization and antibiotic therapy) were analyzed by this method. The trough vancomycin concentrations of diabetic foot infection (DFI) patients and nondiabetic patients were 8.20 +/- 2.83 MUg/mL (range: 4.80-14.2 MUg/mL) and 15.80 +/- 5.43 MUg/mL (range: 8.60-19.5 MUg/mL), respectively. The method is sensitive, precise, and reproducible, it could be applied for routine laboratory analysis of vancomycin in serum samples. PMID- 30423822 TI - Co-Administered Polymeric Nano-Antidotes for Improved Photo-Triggered Response in Glioblastoma. AB - Polymer-based nanoparticles (NPs) are useful vehicles in treating glioblastoma because of their favorable characteristics such as small size and ability to cross the blood-brain barrier, as well as reduced immunogenicity and side effects. The use of a photosensitizer drug such as Verteporfin (BPD), in combination with a pan-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), Cediranib (CED), encapsulated in NPs will provide the medical field with new research on the possible ways to treat glioblastoma. Concomitant administration of BPD and CED NPs have the potential to induce dual photocytotoxic and cytostatic effects in U87 MG cells by (1) remotely triggering BPD through photodynamic therapy by irradiating laser at 690 nm and subsequent production of reactive oxygen species and (2) inhibiting cell proliferation by VEGFR interference and growth factor signaling mechanisms which may allow for longer progression free survival in patients and fewer systemic side effects. The specific aims of this research were to synthesize, characterize and assess cell viability and drug interactions for polyethylene-glycolated (PEGylated) polymeric based CED and BPD NPs which were less than 100 nm in size for enhanced permeation and retention effects. Synergistic effects were found using the co-administered therapies compared to the individual drugs. The major goal of this research was to investigate a new combination of photodynamic chemotherapy drugs in nano-formulation for increased efficacy in glioblastoma treatment at reduced concentrations of therapeutics for enhanced drug delivery in vitro. PMID- 30423823 TI - Dynamic Pose Estimation Using Multiple RGB-D Cameras. AB - Human poses are difficult to estimate due to the complicated body structure and the self-occlusion problem. In this paper, we introduce a marker-less system for human pose estimation by detecting and tracking key body parts, namely the head, hands, and feet. Given color and depth images captured by multiple red, green, blue, and depth (RGB-D) cameras, our system constructs a graph model with segmented regions from each camera and detects the key body parts as a set of extreme points based on accumulative geodesic distances in the graph. During the search process, local detection using a supervised learning model is utilized to match local body features. A final set of extreme points is selected with a voting scheme and tracked with physical constraints from the unified data received from the multiple cameras. During the tracking process, a Kalman filter based method is introduced to reduce positional noises and to recover from a failure of tracking extremes. Our system shows an average of 87% accuracy against the commercial system, which outperforms the previous multi-Kinects system, and can be applied to recognize a human action or to synthesize a motion sequence from a few key poses using a small set of extremes as input data. PMID- 30423821 TI - Effects of a Change from an Indoor-Based Total Mixed Ration to a Rotational Pasture System Combined With a Moderate Concentrate Feed Supply on Rumen Fermentation of Dairy Cows. AB - In spring, transition from a total mixed ration (TMR) to pasture requires rumen adaptions for the cow. It had been shown that transition period does not necessarily mean an increased risk for subacute ruminal acidosis (SARA). After adaption to pasture, however, supplying low amounts of concentrate did indicate increased risk, but caused no adverse effects on rumen morphology and absorption capacity. The present study aimed to investigate the effect of transition, and how a supply of 4.5 kg dry matter concentrate.cow-1 . day-1 during fulltime grazing influenced different rumen parameters. During a 12-week trial eleven rumen-cannulated dairy cows were observed during transition from confinement to pasture (PG; n = 6) and compared to cows fed TMR indoors (CG; n = 5). The CG stayed on a TMR based ration (35% corn silage, 35% grass silage, 30% concentrate; dry matter basis), whereas the PG slowly switched to a pasture-based ration (week 0 and 1 = TMR, week 2 = TMR and 3 h pasture.day-1, week 3 and 4 = TMR and 12 h pasture.day-1, and week 5 to 11 = pasture combined with 4.5 kg DM concentrate . cow-1.day-1). Papillae surface area decreased during transition and increased again during fulltime grazing, while the fractional absorption rate of volatile fatty acids (VFA) was not influenced. This suggests only a limited effect of papillae surface area on VFA absorption rate. Feeding changes resulted in different fermentation profiles of VFA. Changing ratio of starch to sugar during transition to fulltime grazing plus concentrate supply did not lead to lower rumen pH. In conclusion, the concentrate supply combined with high fermentable grass during fulltime grazing increased papillae surface area but did not affect absorption rate or rumen pH, so that risk for SARA was not increased. PMID- 30423824 TI - Effects of Endosymbiont Disruption on the Nutritional Dynamics of the Pea Aphid Acyrthosiphon pisum. AB - Pea aphid (Acyrthosiphon pisum) is a worldwide pest that feeds exclusively on the phloem sap of numerous host plants. It harbours a well-known primary endosymbiont Buchnera aphidicola that helps to overcome the nutritional deficiency of a plant based diet. However, how the Buchnera contributes to the nutritional and energy metabolism of its aphid host is unclear to date. In the current study, the function of Buchnera in relation to nutritional synthesis of pea aphid was investigated by disrupting the primary endosymbiont with an antibiotic rifampicin. Our findings revealed that the disruption of Buchnera led to infertility and higher loss in body mass of aphid hosts. Body length and width were also decreased significantly compared to healthy aphids. The detection of nutrition indicated that the quantity of proteins, soluble sugars, and glycogen in aposymbiotic pea aphids increased slowly with the growth of the aphid host. In comparison, the quantities of all the nutritional factors were significantly lower than those of symbiotic pea aphids, while the quantity of total lipid and neutral fat in aposymbiotic pea aphids were distinctly higher than those of symbiotic ones. Thus, we concluded that the significant reduction of the total amount of proteins, soluble sugars, and glycogen and the significant increase of neutral fats in aposymbiotic pea aphids were due to the disruption of Buchnera, which confirmed that the function of Buchnera is irreplaceable in the pea aphid. PMID- 30423825 TI - Synthesis of a Novel alpha-Glucosyl Ginsenoside F1 by Cyclodextrin Glucanotransferase and Its In Vitro Cosmetic Applications. AB - Ginsenosides from Panax ginseng (Korean ginseng) are unique triterpenoidal saponins that are considered to be responsible for most of the pharmacological activities of P. ginseng. However, the various linkage positions cause different pharmacological activities. In this context, we aimed to synthesize new derivatives of ginsenosides with unusual linkages that show enhanced pharmacological activities. Novel alpha-glycosylated derivatives of ginsenoside F1 were synthesized from transglycosylation reactions of dextrin (sugar donor) and ginsenoside F1 (acceptor) by the successive actions of Toruzyme(r)3.0L, a cyclodextrin glucanotransferase. One of the resultant products was isolated and identified as (20S)-3beta,6alpha,12beta-trihydroxydammar-24ene-(20-O-beta-D glucopyranosyl-(1->2)-alpha-D-glucopyranoside) by various spectroscopic characterization techniques of fast atom bombardment-mass spectrometry (FAB-MS), infrared spectroscopy (IR), proton-nuclear magnetic resonance (1H-NMR), 13C-NMR, gradient heteronuclear single quantum coherence (gHSQC), and gradient heteronuclear multiple bond coherence (gHMBC). As expected, the novel alpha glycosylated ginsenoside F1 (G1-F1) exhibited increased solubility, lower cytotoxicity toward human dermal fibroblast cells (HDF), and higher tyrosinase activity and ultraviolet A (UVA)-induced inhibitory activity against matrix metalloproteinase-1 (MMP-1) than ginsenoside F1. Since F1 has been reported as an antiaging and antioxidant agent, the enhanced efficacies of the novel alpha glycosylated ginsenoside F1 suggest that it might be useful in cosmetic applications after screening. PMID- 30423826 TI - Cellular and Molecular Events in the Airway Epithelium Defining the Interaction Between House Dust Mite Group 1 Allergens and Innate Defences. AB - Serodominant group 1 allergens of house dust mites (HDMs) are cysteine protease digestive enzymes. By increasing the detection of any allergen by dendritic antigen presenting cells, upregulating inflammatory signalling molecules, and activating cells crucial to the transition from innate to acquired immune responses, the proteolytic activity of these HDM allergens also underlies their behaviour as inhalant allergens. The significance of this property is underlined by the attenuation of allergic responses to HDMs by novel inhibitors in experimental models. The group 1 HDM allergens act as prothrombinases, enabling them to operate the canonical stimulation of protease activated receptors 1 and 4. This leads to the ligation of Toll-like receptor 4, which is an indispensable component in HDM allergy development, and reactive oxidant-regulated gene expression. Intermediate steps involve epidermal growth factor receptor ligation, activation of a disintegrin and metalloproteases, and the opening of pannexons. Elements of this transduction pathway are shared with downstream signalling from biosensors which bind viral RNA, suggesting a mechanistic linkage between allergens and respiratory viruses in disease exacerbations. This review describes recent progress in the characterisation of an arterial route which links innate responses to inhaled allergens to events underpinning the progression of allergy to unrelated allergens. PMID- 30423827 TI - Pyruvate Treatment Restores the Effectiveness of Chemotherapeutic Agents in Human Colon Adenocarcinoma and Pleural Mesothelioma Cells. AB - Emerging evidence supports the idea that a dysfunction in cell metabolism could sustain a resistant phenotype in cancer cells. As the success of chemotherapeutic agents is often questioned by the occurrence of multidrug resistance (MDR), a multiple cross-resistance towards different anti-cancer drugs represent a major obstacle to cancer treatment. The present study has clarified the involvement of the carbon metabolites in a more aggressive tumor colon adenocarcinoma phenotype and in a chemoresistant mesothelioma, and the role of pyruvate treatment in the reversion of the potentially related resistance. For the first time, we have shown that human colon adenocarcinoma cells (HT29) and its chemoresistant counterpart (HT29-dx) displayed different carbon metabolism: HT29-dx cells had a higher glucose consumption compared to HT29 cells, whereas human malignant mesothelioma (HMM) cells showed a lower glucose consumption compared to HT29 cells, accompanied by a lower pyruvate production and, consequently, a higher production of lactate. When treated with pyruvate, both HT29-dx and HMM cells exhibited a re-established accumulation of doxorubicin and a lower survival ability, a decreased activity of multidrug resistance protein 1 (MRP1) and a restored mitochondrial respiratory chain function, improving the effectiveness of the chemotherapeutic agents in these resistant cancer cells. PMID- 30423828 TI - A Multisensor Fusion Method for Tool Condition Monitoring in Milling. AB - Tool fault diagnosis in numerical control (NC) machines plays a significant role in ensuring manufacturing quality. Tool condition monitoring (TCM) based on multisensors can provide more information related to tool condition, but it can also increase the risk that effective information is overwhelmed by redundant information. Thus, the method of obtaining the most effective feature information from multisensor signals is currently a hot topic. However, most of the current feature selection methods take into account the correlation between the feature parameters and the tool state and do not analyze the influence of feature parameters on prediction accuracy. In this paper, a multisensor global feature extraction method for TCM in the milling process is researched. Several statistical parameters in the time, frequency, and time-frequency (Wavelet packet transform) domains of multiple sensors are selected as an alternative parameter set. The monitoring model is executed by a Kernel-based extreme learning Machine (KELM), and a modified genetic algorithm (GA) is applied in order to search the optimal parameter combinations in a two-objective optimization model to achieve the highest prediction precision. The experimental results show that the proposed method outperforms the Pearson's correlation coefficient (PCC) based, minimal redundancy and maximal relevance (mRMR) based, and Principal component analysis (PCA)-based feature selection methods. PMID- 30423829 TI - Wind-Induced Fatigue and Asymmetric Damage in a Timber Bridge. AB - The transformation of a 30 m long timber pedestrian bridge into a wobbly (laterally swaying) bridge with a dramatically reduced first lateral modal frequency has been monitored by seven annual, multi-sensor surveys. This evidence, in combination with analysis of the wind record, observations of local damage and evidence of wind-induced excitations from other bridges, is used to present a multi-stage scenario of the extraordinary structural weakening of our study bridge in only a few years. Our analysis is constrained by observations of asymmetric damage (longitudinal splitting cracks around metallic connections along the south side of the deck, not explained by ordinary, essentially symmetric lateral oscillations) and over-threshold analysis of strong northerly wind events, including gusts. The proposed scenario is that an unexpected for the area icing event took advantage of construction vicissitudes and produced damage that reduced the lateral stiffness of the bridge, especially of the arch superstructure. In addition, strong winds sharing common direction with gusts produced a combination of semi-static lateral bending and of dynamic oscillations, leading to numerous cycles of asymmetric high amplitude lateral deflections producing tensile stress normal to grain, cracks localized in connections, and fatigue. The vertical stiffness of the bridge was only slightly affected. PMID- 30423830 TI - The Impact of Mechanically-Imposed Shear on Clogging, Fouling and Energy Demand for an Immersed Membrane Bioreactor. AB - The impact of the application of mechanically-imposed shear on the propensity for fouling and clogging (or "sludging"-the agglomeration of sludge solids in the membrane channel) of an immersed flat sheet (iFS) membrane bioreactor (MBR) was studied. The bench-scale test cell used contained a single flat sheet fitted with a crank and motor to allow the membrane to be oscillated (or reciprocated) vertically at a low rate (20 RPM). The membrane was challenged with sludge samples from a local MBR installation treating petroleum industry effluent, the sludge having previously been demonstrated as having a high sludging propensity. Sludging was measured by direct visual observation of membrane surface occlusion by the agglomerated solids, with fouling being notionally represented by the rate of transmembrane pressure increase. Results demonstrated membrane reciprocation to have a more beneficial impact on sludging amelioration than on suppressing fouling. Compared with the stationary membrane, sludging was reduced by an average of 45% compared with only 13% for fouling suppression at the reference flux of 15 L.m-2.h-1 applied. The specific energy demand of the mechanical shear application was calculated as being around 0.0081 kWh.m-3, significantly lower than values reported from a recent pilot scale study on a reciprocated immersed hollow fibre MBR. Whilst results appear promising in terms of energy efficiency, it is likely that the mechanical complexity of applying membrane movement would limit the practical application to low flows, and a correspondingly small number of membrane modules. PMID- 30423831 TI - A Practical Evaluation on RSA and ECC-Based Cipher Suites for IoT High-Security Energy-Efficient Fog and Mist Computing Devices. AB - The latest Internet of Things (IoT) edge-centric architectures allow for unburdening higher layers from part of their computational and data processing requirements. In the specific case of fog computing systems, they reduce greatly the requirements of cloud-centric systems by processing in fog gateways part of the data generated by end devices, thus providing services that were previously offered by a remote cloud. Thanks to recent advances in System-on-Chip (SoC) energy efficiency, it is currently possible to create IoT end devices with enough computational power to process the data generated by their sensors and actuators while providing complex services, which in recent years derived into the development of the mist computing paradigm. To allow mist computing nodes to provide the previously mentioned benefits and guarantee the same level of security as in other architectures, end-to-end standard security mechanisms need to be implemented. In this paper, a high-security energy-efficient fog and mist computing architecture and a testbed are presented and evaluated. The testbed makes use of Transport Layer Security (TLS) 1.2 Elliptic Curve Cryptography (ECC) and Rivest-Shamir-Adleman (RSA) cipher suites (that comply with the yet to come TLS 1.3 standard requirements), which are evaluated and compared in terms of energy consumption and data throughput for a fog gateway and two mist end devices. The obtained results allow a conclusion that ECC outperforms RSA in both energy consumption and data throughput for all the tested security levels. Moreover, the importance of selecting a proper ECC curve is demonstrated, showing that, for the tested devices, some curves present worse energy consumption and data throughput than other curves that provide a higher security level. As a result, this article not only presents a novel mist computing testbed, but also provides guidelines for future researchers to find out efficient and secure implementations for advanced IoT devices. PMID- 30423832 TI - Enhanced Stability of DNA Oligonucleotides with Partially Zwitterionic Backbone Structures in Biological Media. AB - Deficient stability towards nuclease-mediated degradation is one of the most relevant tasks in the development of oligonucleotide-derived biomedical agents. This hurdle can be overcome through modifications to the native oligonucleotide backbone structure, with the goal of simultaneously retaining the unique hybridization properties of nucleic acids. The nucleosyl amino acid (NAA) modification is a recently introduced artificial cationic backbone linkage. Partially zwitterionic NAA-modified oligonucleotides had previously shown hybridization with DNA strands with retained base-pairing fidelity. In this study, we report the significantly enhanced stability of NAA-modified oligonucleotides towards 3'- and 5'-exonuclease-mediated degradation as well as in complex biological media such as human plasma and whole cell lysate. This demonstrates the potential versatility of the NAA-motif as a backbone modification for the development of biomedically active oligonucleotide analogues. PMID- 30423833 TI - Reaction between Indazole and Pd-Bound Isocyanides-A Theoretical Mechanistic Study. AB - The mechanism of the addition of indazole (Ind)-a bifunctional aromatic N,NH nucleophile-to cyclohexyl isocyanide coordinated to the palladium(II) center in the model complex cis-[PdCl2(CNMe)(CNCy)] (1) to give the corresponding aminocarbene ligand was investigated in detail by theoretical (DFT) methods. The most plausible mechanism of this reaction is that of the associative type involving nucleophilic attack of Ind by its unprotonated N atom at the isocyanide carbon atom followed by the stepwise proton transfer from the nucleophile molecule to the isocyanide N atom via deprotonation/protonation steps. Two reaction channels based on two tautomeric forms of indazole were found. The channel leading to the experimentally isolated aminocarbene product is based on the less stable tautomeric form. Another channel based on the more stable tautomer of Ind is slightly kinetically more favorable but it is endergonic. Thus, the regioselectivity of this reaction is thermodynamically rather than kinetically driven. The bonding situation in key species was analyzed. PMID- 30423834 TI - Specification and Performance Indicators of AeroRing-A Multiple-Ring Ethernet Network for Avionics Embedded Systems. AB - The complexity and costs of the avionics communication architecture are increasing exponentially with the increasing number of embedded computers over the last few decades. To limit the cabling complexity and the deployment costs of such a communication architecture, we specify a new Gigabit multiple-ring Ethernet network, called AeroRing, while meeting the avionics requirements. First, we describe the current Aircraft Data Communication Network (ADCN) to highlight the main characteristics and requirements that have to be fulfilled by our solution. Then, we give an overview of the most relevant solutions to improve ADCN performance and relate them to AeroRing. Afterwards, we detail the specifications and the main Performance Indicators (PIs) of AeroRing. Finally, sensitivity and validation analyses of AeroRing are conducted through a realistic avionics application, regarding the various PIs, in comparison to the backbone network of the ADCN, the Avionics Full DupleX Switched Ethernet (AFDX). The computed AeroRing performance metrics show its ability to guarantee the avionics requirements. PMID- 30423835 TI - Missing RRI Interpolation Algorithm based on Locally Weighted Partial Least Squares for Precise Heart Rate Variability Analysis. AB - The R-R interval (RRI) fluctuation in electrocardiogram (ECG) is called heart rate variability (HRV), which reflects activities of the autonomic nervous system (ANS) and has been used for various health monitoring services. Accurate R wave detection is crucial for success in HRV-based health monitoring services; however, ECG artifacts often cause missing R waves and deteriorate the accuracy of HRV analysis. The present work proposes a new missing RRI interpolation technique based on Just-In-Time (JIT) modeling. In the JIT modeling framework, a local regression model is built by weighing samples stored in the database according to the distance from a query and output is estimated only when an estimate is requested. The proposed method builds a local model and estimates missing RRI only when an RRI detection error is detected. Locally weighted partial least squares (LWPLS) is adopted for local model construction. The proposed method is referred to as LWPLS-based RRI interpolation (LWPLS-RI). The performance of the proposed LWPLS-RI was evaluated through its application to RRI data with artificial missing RRIs. We used the MIT-BIH Normal Sinus Rhythm Database for nominal RRI dataset construction. Missing RRIs were artificially introduced and they were interpolated by the proposed LWPLS-RI. In addition, MEAN that replaces the missing RRI by a mean of the past RRI data was compared as a conventional method. The result showed that the proposed LWPLS-RI improved root mean squared error (RMSE) of RRI by about 70% in comparison with MEAN. In addition, the proposed method realized precise HRV analysis. The proposed method will contribute to the realization of precise HRV-based health monitoring services. PMID- 30423836 TI - Predicting Profile Soil Properties with Reflectance Spectra via Bayesian Covariate-Assisted External Parameter Orthogonalization. AB - In situ, diffuse reflectance spectroscopy (DRS) profile soil sensors have the potential to provide both rapid and high-resolution prediction of multiple soil properties for precision agriculture, soil health assessment, and other applications related to environmental protection and agronomic sustainability. However, the effects of soil moisture, other environmental factors, and artefacts of the in-field spectral data collection process often hamper the utility of in situ DRS data. Various processing and modeling techniques have been developed to overcome these challenges, including external parameter orthogonalization (EPO) transformation of the spectra. In addition, Bayesian modeling approaches may improve prediction over traditional partial least squares (PLS) regression. The objectives of this study were to predict soil organic carbon (SOC), total nitrogen (TN), and texture fractions using a large, regional dataset of in situ profile DRS spectra and compare the performance of (1) traditional PLS analysis, (2) PLS on EPO-transformed spectra (PLS-EPO), (3) PLS-EPO with the Bayesian Lasso (PLS-EPO-BL), and (4) covariate-assisted PLS-EPO-BL models. In this study, soil cores and in situ profile DRS spectrometer scans were obtained to ~1 m depth from 22 fields across Missouri and Indiana, USA. In the laboratory, soil cores were split by horizon, air-dried, and sieved (<2 mm) for a total of 708 samples. Soil properties were measured and DRS spectra were collected on these air-dried soil samples. The data were randomly split into training (n = 308), testing (n = 200), and EPO calibration (n = 200) sets, and soil textural class was used as the categorical covariate in the Bayesian models. Model performance was evaluated using the root mean square error of prediction (RMSEP). For the prediction of soil properties using a model trained on dry spectra and tested on field moist spectra, the PLS-EPO transformation dramatically improved model performance relative to PLS alone, reducing RMSEP by 66% and 53% for SOC and TN, respectively, and by 76%, 91%, and 87% for clay, silt, and sand, respectively. The addition of the Bayesian Lasso further reduced RMSEP by 4-11% across soil properties, and the categorical covariate reduced RMSEP by another 2-9%. Overall, this study illustrates the strength of the combination of EPO spectral transformation paired with Bayesian modeling techniques to overcome environmental factors and in-field data collection artefacts when using in situ DRS data, and highlights the potential for in-field DRS spectroscopy as a tool for rapid, high resolution prediction of soil properties. PMID- 30423837 TI - 3DAirSig: A Framework for Enabling In-Air Signatures Using a Multi-Modal Depth Sensor. AB - In-air signature is a new modality which is essential for user authentication and access control in noncontact mode and has been actively studied in recent years. However, it has been treated as a conventional online signature, which is essentially a 2D spatial representation. Notably, this modality bears a lot more potential due to an important hidden depth feature. Existing methods for in-air signature verification neither capture this unique depth feature explicitly nor fully explore its potential in verification. Moreover, these methods are based on heuristic approaches for fingertip or hand palm center detection, which are not feasible in practice. Inspired by the great progress in deep-learning-based hand pose estimation, we propose a real-time in-air signature acquisition method which estimates hand joint positions in 3D using a single depth image. The predicted 3D position of fingertip is recorded for each frame. We present four different implementations of a verification module, which are based on the extracted depth and spatial features. An ablation study was performed to explore the impact of the depth feature in particular. For matching, we employed the most commonly used multidimensional dynamic time warping (MD-DTW) algorithm. We created a new database which contains 600 signatures recorded from 15 different subjects. Extensive evaluations were performed on our database. Our method, called 3DAirSig, achieved an equal error rate (EER) of 0 . 46 %. Experiments showed that depth itself is an important feature, which is sufficient for in-air signature verification. The dataset will be publicly available (https://goo.gl/yFdfdL). PMID- 30423838 TI - A Facile Way to Prolong Service Life of Double Base Propellant. AB - The safe storage time for double base propellant (DBP or DB propellant) with stabilizers could usually be calculated to be greater than 40 years. However, the actual service life is far below that, which is largely caused by the decline of propellant mechanical performance. In this work polytetrafluoroethylene (PTFE) was introduced into the double base propellant formula as an additive. The tensile properties of this propellant before and after artificial aging were determined. The evaporation and diffusion characteristics of nitroglycerin (NG) in propellant were evaluated by thermogravimetry analysis (TGA). The results showed that mechanical properties of propellant were improved due to PTFE, especially for elongation at -40 degrees C, which was greatly increased by 115%. Moreover, the results of TGA showed that NG migration was reduced due to PTFE, which delayed the decline of propellant mechanical performance during aging. The reduction in elongation at -40 degrees C caused by aging was decreased by 68.5% for PTFE modified DBP. Enhanced mechanical properties and reduced NG migration could potentially prolong propellant service life. PMID- 30423839 TI - Aromatherapy for Managing Pain in Primary Dysmenorrhea: A Systematic Review of Randomized Placebo-Controlled Trials. AB - Aromatherapy, the therapeutic use of essential oils, is often used to reduce pain in primary dysmenorrhea. Eleven databases, including four English (PubMed, AMED, EMBASE, and the Cochrane Library) and seven Korean medical databases, were searched from inception through August 2018 without restrictions on publication language. Randomized controlled trials (RCTs) testing aromatherapy for pain reduction in primary dysmenorrhea were considered. Data extraction and risk-of bias assessments were performed by two independent reviewers. All of the trials reported superior effects of aromatherapy for pain reduction compared to placebo (n = 1787, standard mean difference (SMD): -0.91, 95% CI: -1.17 to -0.64, p < 0.00001) with high heterogeneity (I2 = 88%). A sub-analysis for inhalational aromatherapy for the alleviation of pain also showed superior effects compared to placebo (n = 704, SMD: -1.02, 95% CI: -1.59 to -0.44, p = 0.0001, I2 = 95%). With regard to aromatherapy massage, the pooled results of 11 studies showed favorable effects of aromatherapy massage on pain reduction compared to placebo aromatherapy massage (n = 793, SMD: -0.87, 95% CI: -1.14 to -0.60, p < 0.00001, I2 = 70%). Oral aromatherapy had superior effects compared to placebo (n = 290, SMD: -0.61, 95% CI: -0.91 to -0.30, p < 0.0001, I2 = 0%). In conclusion, our systemic review provides a moderate level of evidence on the superiority of aromatherapy (inhalational, massage, or oral use) for pain reduction over placebo in primary dysmenorrhea. PMID- 30423841 TI - A Novel Method for Breath Detection via Stepped-Frequency Continuous Wave Ultra Wideband (SFCW UWB) Radars Based on Operational Bandwidth Segmentation. AB - Human being detection via ultra-wideband (UWB) radars has shown great prospects in many areas, such as biomedicine, military operation, public security, emergency rescue, and so on. When a person stays stationary, the main feature that separates him/her from surroundings is the movement of chest wall due to breath. There have been many algorithms developed for breath detection while using UWB radars. However, those algorithms were almost based on a basic scheme that focused on processing in the time dimension of UWB data. They did not utilize the benefits from the wide operational bandwidth of UWB radars to show potential superiority over those narrowband systems such as a continuous wave (CW) Doppler radar. In this paper, a breath detection method was proposed based on operational bandwidth segmentation. A basic theoretical model was firstly introduced, indicating that characteristics of breath signals contained in UWB echoes were consistent among the operational frequencies, while those of clutters were not. So, the method divided a set of UWB echo data into a number of subsets, each of which corresponded to a sub-band within the operational bandwidth of the UWB radar. Thus information about the operational frequency is provided for subsequent processing. With the aid of the information, a breath enhancement algorithm was developed mainly by averaging the segmented UWB data along the operational frequency. The algorithm's performance was verified by data measured by a stepped-frequency CW (SFCW) UWB radar. The experimental results showed that the algorithm performed better than that without the segmentation. They also showed its feasibility for fast detection of breath based on a short duration of data. Moreover, the method's potential for target identification and impulse radio (IR) UWB radar was investigated. In summary, the method provides a new processing scheme for UWB radars when they are used for breath detection. With this scheme, the UWB radars have a benefit of greater flexibility in data processing over those narrowband radars, and thus will perform more effectively and efficiently in practical applications. PMID- 30423842 TI - Development of a Protein Microarray Chip with Enhanced Fluorescence for Identification of Semen and Vaginal Fluid. AB - The detection of body fluids has been used to identify a suspect and build a criminal case. As the amount of evidence collected at a crime site is limited, a multiplex identification system for body fluids using a small amount of sample is required. In this study, we proposed a multiplex detection platform using an Ag vertical nanorod metal enhanced fluorescence (MEF) substrate for semen and vaginal fluid (VF), which are important evidence in cases of sexual crime. The Ag nanorod MEF substrate with a length of 500 nm was fabricated by glancing angle deposition, and amino functionalization was conducted to improve binding ability. The effect of incubation time was analyzed, and an incubation time of 60 min was selected, at which the fluorescence signal was saturated. To assess the performance of the developed identification chip, the identification of semen and VF was carried out. The developed sensor could selectively identify semen and VF without any cross-reactivity. The limit of detection of the fabricated microarray chip was 10 times better than the commercially available rapid stain identification (RSID) Semen kit. PMID- 30423840 TI - Spices and Atherosclerosis. AB - Cardiovascular disease is one of the leading causes of death and disability in the world. Atherosclerosis, characterized by lipid accumulation and chronic inflammation in the vessel wall, is the main feature of cardiovascular disease. Although the amounts of fruits and vegetables present in the diets vary by country, diets, worldwide, contain large amounts of spices; this may have positive or negative effects on the initiation and development of atherosclerosis. In this review, we focused on the potential protective effects of specific nutrients from spices, such as pepper, ginger, garlic, onion, cinnamon and chili, in atherosclerosis and atherosclerotic cardiovascular disease. The mechanisms, epidemiological analysis, and clinical studies focusing on a variety of spices are covered in this review. Based on the integrated information, we aimed to raise specific recommendations for people with different dietary styles for the prevention of atherosclerotic cardiovascular disease through dietary habit adjustments. PMID- 30423845 TI - Design of a Measurement System for Simultaneously Measuring Six-Degree-Of-Freedom Geometric Errors of a Long Linear Stage. AB - This study designs and characterizes a novel precise measurement system for simultaneously measuring six-degree-of-freedom geometric motion errors of a long linear stage of a machine tool. The proposed measurement system is based on a method combined with the geometrical optics method and laser interferometer method. In contrast to conventional laser interferometers using only the interferometer method, the proposed measurement system can simultaneously measure six-degree-of-freedom geometric motion errors of a long linear stage with lower cost and faster operational time. The proposed measurement system is characterized numerically using commercial software ZEMAX and mathematical modeling established by using a skew-ray tracing method, a homogeneous transformation matrix, and a first-order Taylor series expansion. The proposed measurement system is then verified experimentally using a laboratory-built prototype. The experimental results show that, compared to conventional laser interferometers, the proposed measurement system better achieves the ability to simultaneously measure six-degree-of-freedom geometric errors of a long linear stage (a traveling range of 250 mm). PMID- 30423844 TI - Biochemical and Anti-Triple Negative Metastatic Breast Tumor Cell Properties of Psammaplins. AB - Breast tumors reprogram their cellular metabolism, nutrient uptake, and utilization-associated biochemical processes. These processes become further transformed as genetically predisposed metastatic breast tumor cells colonize specific organs. Breast tumor cells often metastasize to the brain, bone, lung and liver. Massague and colleagues isolated organotropic subclones and established organ-specific gene signatures associated with lung-, bone-, and brain-specific metastatic triple-negative breast cancer (TNBC) MDA-MB-231 cells. Using these genetically characterized metastatic subclones specific to lung (LM4175), bone (BoM1833), and brain (BrM-2a), we evaluated marine natural products for the ability to differentially suppress metastatic breast cancer cells in a target organ-dependent manner. Psammaplin-based histone deacetylase (HDAC) inhibitors were found to differentially inhibit HDAC activity, induce activation of hypoxia-inducible factor-1 (HIF-1), and disrupt organotropic metastatic TNBC subclone growth. Further, psammaplins distinctly suppressed the outgrowth of BoM1833 tumor spheroids in 3D-culture systems. Similar results were observed with the prototypical HDAC inhibitor trichostatin A (TSA). These organotropic tumor cell-based studies suggest the potential application of HDAC inhibitors that may yield new directions for anti-metastatic breast tumor research and drug discovery. PMID- 30423846 TI - Short-Term Effects of Healthy Eating Pattern Cycling on Cardiovascular Disease Risk Factors: Pooled Results from Two Randomized Controlled Trials. AB - Adherence to healthy eating patterns (HEPs) is often short-lived and can lead to repetitive attempts of adopting-but not maintaining-HEPs. We assessed effects of adopting, abandoning, and readopting HEPs (HEP cycling) on cardiovascular disease risk factors (CVD-RF). We hypothesized that HEP cycling would improve, worsen, and again improve CVD-RF. Data were retrospectively pooled for secondary analyses from two randomized, crossover, controlled feeding trials (n = 60, 52 +/- 2 years, 30.6 +/- 0.6 kg/m2) which included two 5-6 week HEP interventions (Dietary Approaches to Stop Hypertension-style or Mediterranean-style) separated by a four week unrestricted eating period. Ambulatory and fasting blood pressures (BP), fasting serum lipids, lipoproteins, glucose, and insulin were measured before and during the last week of HEP interventions. Fasting systolic BP and total cholesterol decreased (-6 +/- 1 mm Hg and -19 +/- 3 mg/dL, respectively, p < 0.05), returned to baseline, then decreased again (-5 +/- 1 mm Hg and -13 +/- 3 mg/dL, respectively, p < 0.05) when adopting, abandoning, and readopting a HEP; magnitude of changes did not differ. Ambulatory and fasting diastolic BP and high density lipoprotein cholesterol concentrations followed similar patterns; glucose and insulin remained unchanged. Low-density lipoprotein cholesterol concentrations decreased with initial adoption but not readoption (-13 +/- 3 and 6 +/- 3, respectively, interaction p = 0.020). Healthcare professionals should encourage individuals to consistently consume a HEP for cardiovascular health but also encourage them to try again if a first attempt is unsuccessful or short lived. PMID- 30423847 TI - Diagnostic Performance of Initial Serum Albumin Level for Predicting In-Hospital Mortality among Necrotizing Fasciitis Patients. AB - BACKGROUND: Hypoalbuminemia is known to be associated with adverse outcomes in critical illness. In this study, we attempted to identify whether hypoalbuminemia on emergency department (ED) arrival is a reliable predictor for in-hospital mortality in necrotizing fasciitis (NF). PATIENTS: METHOD: A retrospective cohort study of hospitalized adult patients with NF was conducted in a tertiary teaching hospital in Taiwan between March 2010 and March 2018. Blood samples were collected in the ED upon arrival, and serum albumin levels were determined. We evaluated the predictive value of serum albumin level at ED presentation for in hospital mortality. All collected data were statistically analyzed. RESULT: Of the 707 NF patients, 40 (5.66%) died in the hospital. The mean serum albumin level was 3.1 +/- 0.9 g/dL and serum albumin levels were significantly lower in the non-survivor group than in the survivor group (2.8 +/- 0.7 g/dL vs. 3.5 +/- 0.8 g/dL). In the multivariable logistic regression model, albumin was significantly associated with in-hospital mortality (odds ratio (OR) 0.92, 95% confidence interval (CI) 0.88-0.96, p < 0.001). The area under-the-receiver operating-characteristic curve (AUC) for in-hospital survival was 0.77 (95% CI 0.72-0.82) and corresponding sensitivity, specificity, positive predictive value, negative predictive value, and positive and negative likelihood ratio were 66%, 74%, 33%, 88%, 2.25, and 0.48, respectively. High sensitivity (96%) for survival was shown at albumin level of 4.0 g/dL and high specificity (91%) for mortality was shown at a level of 2.5 g/dL. CONCLUSION: Initial serum albumin levels strongly predicted in-hospital mortality among patients with necrotizing fasciitis. NF patients with hypoalbuminemia on ED arrival should be closely monitored for signs of deterioration and early and aggressive intervention should be considered to prevent mortality. PMID- 30423848 TI - Comparison of Low Glycaemic Index and High Glycaemic Index Potatoes in Relation to Satiety: A Single-Blinded, Randomised Crossover Study in Humans. AB - High glycaemic index (GI) foods have been proposed to reduce satiety and thus promote overweight and obesity. Generally, potatoes have a high GI, but they also provide many beneficial nutrients and they are a highly important food source globally. In this study, we investigated how a low GI potato affected subjective satiety as compared to a high GI potato. Twenty healthy men (aged 18-40 years; body mass index (BMI) 18-27 kg/m2) participated in this single-blinded, controlled, randomised crossover trial. On each of the two trial days, the subjects were given a 500-gram portion of either a low or high GI potato variety (Carisma(r) low GI and Arizona high GI). Subjective appetite sensations were measured at baseline and at +15 min, +45 min, +75 min, +105 min, and +135 min after consumption of the test meal until an ad libitum meal was served at +150 min. No significant differences in the primary endpoint, satiety, were found between the two potato varieties (all p > 0.05). Furthermore, no significant differences were found in the secondary endpoints; hunger, fullness, and prospective food consumption, or ad libitum energy intake (all p > 0.05). In conclusion, the results of this study do not indicate that the GI of potatoes is important for satiety in normal-weight men. PMID- 30423849 TI - BCAbox Algorithm Expands Capabilities of Raman Microscope for Single Organelles Assessment. AB - Raman microspectroscopy is a rapidly developing technique, which has an unparalleled potential for in situ proteomics, lipidomics, and metabolomics, due to its remarkable capability to analyze the molecular composition of live cells and single cellular organelles. However, the scope of Raman spectroscopy for bio applications is limited by a lack of software tools for express-analysis of biomolecular composition based on Raman spectra. In this study, we have developed the first software toolbox for immediate analysis of intracellular Raman spectra using a powerful biomolecular component analysis (BCA) algorithm. Our software could be easily integrated with commercial Raman spectroscopy instrumentation, and serve for precise analysis of molecular content in major cellular organelles, including nucleoli, endoplasmic reticulum, Golgi apparatus, and mitochondria of either live or fixed cells. The proposed software may be applied in broad directions of cell science, and serve for further advancement and standardization of Raman spectroscopy. PMID- 30423843 TI - Hedgehog Signaling in Cancer: A Prospective Therapeutic Target for Eradicating Cancer Stem Cells. AB - The Hedgehog (Hh) pathway is a signaling cascade that plays a crucial role in many fundamental processes, including embryonic development and tissue homeostasis. Moreover, emerging evidence has suggested that aberrant activation of Hh is associated with neoplastic transformations, malignant tumors, and drug resistance of a multitude of cancers. At the molecular level, it has been shown that Hh signaling drives the progression of cancers by regulating cancer cell proliferation, malignancy, metastasis, and the expansion of cancer stem cells (CSCs). Thus, a comprehensive understanding of Hh signaling during tumorigenesis and development of chemoresistance is necessary in order to identify potential therapeutic strategies to target various human cancers and their relapse. In this review, we discuss the molecular basis of the Hh signaling pathway and its abnormal activation in several types of human cancers. We also highlight the clinical development of Hh signaling inhibitors for cancer therapy as well as CSC targeted therapy. PMID- 30423850 TI - Deep CNNs with Robust LBP Guiding Pooling for Face Recognition. AB - Pooling layer in Convolutional Neural Networks (CNNs) is designed to reduce dimensions and computational complexity. Unfortunately, CNN is easily disturbed by noise in images when extracting features from input images. The traditional pooling layer directly samples the input feature maps without considering whether they are affected by noise, which brings about accumulated noise in the subsequent feature maps as well as undesirable network outputs. To address this issue, a robust Local Binary Pattern (LBP) Guiding Pooling (G-RLBP) mechanism is proposed in this paper to down sample the input feature maps and lower the noise impact simultaneously. The proposed G-RLBP method calculates the weighted average of all pixels in the sliding window of this pooling layer as the final results based on their corresponding probabilities of being affected by noise, thus lowers the noise impact from input images at the first several layers of the CNNs. The experimental results show that the carefully designed G-RLBP layer can successfully lower the noise impact and improve the recognition rates of the CNN models over the traditional pooling layer. The performance gain of the G-RLBP is quite remarkable when the images are severely affected by noise. PMID- 30423851 TI - Photobiomodulation Therapy in the Treatment of Oral Mucositis, Dysgeusia and Oral Dryness as Side-Effects of Head and Neck Radiotherapy in a Cancer Patient: A Case Report. AB - Successful management of oral mucositis, dysgeusia and oral dryness was made with fivesessions of photobiomodulation. The severity of oral mucositis was measured according to the World Health Organization scale for the assessment of oral mucositis. Dysgeusia testing was performed according to the International Standards Organization (ISO). For the assessment of oral dryness or hyposalivation, quantity of the total resting and stimulated saliva (Q-sal, mL/min) was measured.Photobiomodulation parameters, applications, and treatment protocol used were suggested by an international multidisciplinary panel of clinicians and researchers with expertise in the area of supportive care in cancer and/or PBM clinical application and dosimetry. This case report confirms the effectiveness of photobiomodulation therapy in the management of oral mucositis, dysgeusia, and oral dryness. PMID- 30423852 TI - New Photodegradation Products of the Fungicide Fluopyram: Structural Elucidation and Mechanism Identification. AB - Identifying the fate of agrochemicals is important to understand their potential risk for living organisms. We report here new photodegradation products (PPs) of the fungicide fluopyram. The PPs were produced by irradiating a fluopyram standard in 0.1% acetonitrile aqueous media by a 150-W medium pressure Hg-lamp that emits wavelengths between 200-280 nm. The structural elucidation of PPs was achieved by combining the retention time, isotopic pattern, targeted fragmentation, and accurate mass measurements using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and high resolution-MS (HRMS). In addition to previously known PPs, seven new PPs of fluopyram were identified in this work: mainly dihydroxyl and hydroxylimide fluopyram as well as mono, di, and trihydroxyl lactam. Additionally, two PPs were found to be formed by rearrangement after the loss of H2C=CH2. Hence, the results of the work contribute to extending the current knowledge regarding the photoinduced fate of agrochemicals, and fluopyram in particular. PMID- 30423853 TI - Risk Stratification of Sudden Cardiac Death in Patients with Heart Failure: An update. AB - Heart failure (HF) is a complex clinical syndrome in which structural/functional myocardial abnormalities result in symptoms and signs of hypoperfusion and/or pulmonary or systemic congestion at rest or during exercise. More than 80% of deaths in patients with HF recognize a cardiovascular cause, with most being either sudden cardiac death (SCD) or death caused by progressive pump failure. Risk stratification of SCD in patients with HF and preserved (HFpEF) or reduced ejection fraction (HFrEF) represents a clinical challenge. This review will give an update of current strategies for SCD risk stratification in both HFrEF and HFpEF. PMID- 30423855 TI - Clinical Characteristics of Nursing- and Healthcare-Associated Tuberculosis. AB - : Tuberculosis remains a serious health problem worldwide. Patients with tuberculosis who also require nursing care due to aging and underlying diseases are considered to have a high mortality rate; however, there are few studies describing detailed examinations of such disease conditions. OBJECTIVE: The present study was conducted to investigate differences in clinical features of elderly tuberculosis patients according to the levels of nursing and healthcare required. DESIGN: The study participants included 146 elderly (>=65 years) patients diagnosed with active tuberculosis among patients hospitalized with tuberculosis at a single center. The patients were classified into two groups: a nursing- and healthcare-associated tuberculosis group (n = 71) and a community acquired tuberculosis group (n = 75). RESULTS: The nursing- and healthcare associated tuberculosis patients were older and had a higher frequency of comorbidities compared with the community-acquired tuberculosis group. Patients in the nursing- and healthcare-associated tuberculosis group had markedly lower levels of serum albumin and hemoglobin, and higher levels of C-reactive protein. The rate of in-hospital death was significantly higher in the nursing- and healthcare-associated tuberculosis group. This was attributed to malnutrition and comorbid conditions rather than the severity of tuberculosis. CONCLUSION: The prognosis was poor in elderly tuberculosis patients receiving nursing and healthcare. PMID- 30423854 TI - Gluten-Free Diet and Its 'Cousins' in Irritable Bowel Syndrome. AB - Functional disorders are common, with irritable bowel syndrome (IBS) being the commonest and most extensively evaluated functional bowel disorder. It is therefore paramount that effective therapies are available to treat this common condition. Diet appears to play a pivotal role in symptom generation in IBS, with a recent interest in the role of dietary therapies in IBS. Over the last decade, there has been a substantial increase in awareness of the gluten-free diet (GFD), with a recent focus of the role of a GFD in IBS. There appears to be emerging evidence for the use of a GFD in IBS, with studies demonstrating the induction of symptoms following gluten in patients with IBS. However, there are questions with regards to which components of wheat lead to symptom generation, as well as the effect of a GFD on nutritional status, gut microbiota and long-term outcomes. Further studies are required, although the design of dietary studies remain challenging. The implementation of a GFD should be performed by a dietitian with a specialist interest in IBS, which could be achieved via the delivery of group sessions. PMID- 30423857 TI - Social Disadvantage, Maternal Psychological Distress, and Difficulties in Children's Social-Emotional Well-Being. AB - This study used data from wave four of the United Kingdom (U.K.) Millennium Cohort Study to examine whether there is an individual (i.e., maternal education) and area-level social disadvantage (i.e., neighborhood deprivation) gradient to difficulties in social-emotional well-being (SEW) in 7-year-old English children. We then investigated to what extent maternal psychological distress (Kessler 6 score) explains the relationship between social disadvantage indicators and boys' and girls' SEW difficulties. Subjects consisted of 3661 child-mother dyads (1804 boys and 1857 girls). Results discerned gender differences in the effect social disadvantage indicators have on child SEW difficulties. Maternal education had a comparable effect on boys' and girls' SEW difficulties, but a steeper neighborhood deprivation gradient was evident for boys' SEW difficulties compared to girls' SEW difficulties. The effect of each social disadvantage indicator on boys' and girls' SEW difficulties was for most part direct and strong (p <= 0.001) rather than through maternal psychological distress, suggesting that the theoretical framework was incomplete. Here we demonstrate that where children are positioned on the social disadvantage gradient matters greatly to their SEW. Improving the living conditions and health of mothers with psychological distress may offer a pathway to improve child SEW. PMID- 30423858 TI - Leptodactylus latrans Amphibian Skin Secretions as a Novel Source for the Isolation of Antibacterial Peptides. AB - Amphibians' skin produces a diverse array of antimicrobial peptides that play a crucial role as the first line of defense against microbial invasion. Despite the immense richness of wild amphibians in Argentina, current knowledge about the presence of peptides with antimicrobial properties is limited to a only few species. Here we used LC-MS-MS to identify antimicrobial peptides with masses ranging from 1000 to 4000 Da from samples of skin secretions of Leptodactylus latrans (Anura: Leptodactylidae). Three novel amino acid sequences were selected for chemical synthesis and further studies. The three synthetic peptides, named P1-Ll-1577, P2-Ll-1298, and P3-Ll-2085, inhibited the growth of two ATCC strains, namely Escherichia coli and Staphylococcus aureus. P3-Ll-2085 was the most active peptide. In the presence of trifluoroethanol (TFE) and anionic liposomes, it adopted an amphipathic alpha-helical structure. P2-Ll-1298 showed slightly lower activity than P3-Ll-2085. Comparison of the MIC values of these two peptides revealed that the addition of seven amino acid residues (GLLDFLK) on the N terminal of P2-Ll-1298 significantly improved activity against both strains. P1 Ll-1577, which remarkably is an anionic peptide, showed interesting antimicrobial activity against E. coli and S. aureus strain, showing marked membrane selectivity and non-hemolysis. Due to this, P1-L1-1577 emerges as a potential candidate for the development of new antibacterial drugs. PMID- 30423856 TI - Aquaporins: More Than Functional Monomers in a Tetrameric Arrangement. AB - Aquaporins (AQPs) function as tetrameric structures in which each monomer has its own permeable pathway. The combination of structural biology, molecular dynamics simulations, and experimental approaches has contributed to improve our knowledge of how protein conformational changes can challenge its transport capacity, rapidly altering the membrane permeability. This review is focused on evidence that highlights the functional relationship between the monomers and the tetramer. In this sense, we address AQP permeation capacity as well as regulatory mechanisms that affect the monomer, the tetramer, or tetramers combined in complex structures. We therefore explore: (i) water permeation and recent evidence on ion permeation, including the permeation pathway controversy-each monomer versus the central pore of the tetramer-and (ii) regulatory mechanisms that cannot be attributed to independent monomers. In particular, we discuss channel gating and AQPs that sense membrane tension. For the latter we propose a possible mechanism that includes the monomer (slight changes of pore shape, the number of possible H-bonds between water molecules and pore-lining residues) and the tetramer (interactions among monomers and a positive cooperative effect). PMID- 30423859 TI - Association of Serum 25-Hydroxyvitamin D Concentration with Pulmonary Function in Young Adults. AB - The role of vitamin D on pulmonary function is unclear and is mostly studied in patients, smokers and elderly people. The aim of this paper was to evaluate the association between serum 25-hydroxyvitamin D [25(OH)D] concentration and pulmonary function in young adults. Cross-sectional analysis of 499 individuals that were evaluated at 21 years of age as part of the population-based cohort Epidemiological Health Investigation of Teenagers in Porto (EPITeen). Serum 25(OH)D was categorized according to the Institute of Medicine. Pulmonary function was evaluated using spirometry. Linear regression models were used to estimate the regression coefficients (beta) and its 95% confidence intervals (95% CI), and were adjusted for confounders. Education, smoking, body mass index, and season of evaluation were determinants of serum 25(OH)D concentration. Prevalence of serum 25(OH)D concentration <50 nmol/L was 48.9%. A decrease in all pulmonary function parameters, with the decrease of serum 25(OH)D, was observed. The higher effect was found for peak expiratory flow (PEF). Having as reference participants with serum 25(OH)D concentration >=50 nmol/L, PEF was significantly lower for those with a concentration of 30 to <50 nmol/L (beta= -0.576; 95% CI: -0.943, 0.210), and for those with a concentration of <30 nmol/L (beta= -0.650; 95% CI: 1.155, -0.146). Although only PEF attained statistical significance, the consistent results with the other parameters support the role of serum 25(OH)D to promote better pulmonary function in young adults. PMID- 30423860 TI - Quantitative Ultrasound Imaging Pixel Analysis of the Intrinsic Plantar Muscle Tissue between Hemiparesis and Contralateral Feet in Post-Stroke Patients. AB - Quantitative ultrasound imaging of the muscle tissue may be applied in the neurology field, due to B-mode grayscale pixels values could be used as potential biomarkers for disease progression and intervention effects in poststroke patients. Thus, the study aim was to compare and analyze the ultrasound imaging B mode pixels differences between the intrinsic plantar muscles cross-sectional area (CSA) in hemiparetic and contralateral feet from poststroke patients by means of the Image J software. A case-control design and a convenience sampling method were used in order to recruit 22 feet from 11 poststroke patients. This total sample was divided into 11 hemiparetic feet and 11 contralateral feet. The Image J software was used in order to evaluate the interface distance, CSA as well as measure the pixels mean, standard deviation (SD) and count from all offline images in the flexor digitorum brevis, abductor hallucis (AbH), and flexor hallucis brevis muscles. Statistically significant differences (p = 0.003) were only shown for the pixels count in the AbH muscle. The rest of outcome measurements did not show any statistically significant difference (p > 0.05). Therefore, B-mode ultrasound imaging Image J software differences for the pixels count reduction were shown in the AbH muscle between hemiparetic and contralateral feet from poststroke patients. Further studies are necessary in order to apply our findings as potential biomarkers during the stroke disease course. PMID- 30423861 TI - The Role of Statins in the Management of Patients Undergoing Coronary Artery Bypass Grafting. AB - Each year, a large number of patients undergo coronary artery bypass grafting surgery (CABG) worldwide. Accumulating evidence suggests that the preoperative administration of statins might be useful in preventing adverse events after CABG. In the present review, we discuss the role of statins in the perioperative management of patients undergoing CABG. Preoperative administration of statins in these patients substantially reduces the risk of postoperative atrial fibrillation and shortens hospital and intensive care unit (ICU) stay. Atorvastatin appears to be more effective, particularly when administered at high doses. Given these benefits and the safety of statins, their administration should be considered in patients undergoing CABG, even though the statins do not appear to affect the incidence of cardiovascular events and overall mortality perioperatively. PMID- 30423862 TI - Radiobiological Characterization of 64CuCl2 as a Simple Tool for Prostate Cancer Theranostics. AB - 64CuCl2 has recently been proposed as a promising agent for prostate cancer (PCa) theranostics, based on preclinical studies in cellular and animal models, and on the increasing number of human studies documenting its use for PCa diagnosis. Nevertheless, the use of 64CuCl2 raises important radiobiological questions that have yet to be addressed. In this work, using a panel of PCa cell lines in comparison with a non-tumoral prostate cell line, we combined cytogenetic approaches with radiocytotoxicity assays to obtain significant insights into the cellular consequences of exposure to 64CuCl2. PCa cells were found to exhibit increased 64CuCl2 uptake, which could not be attributed to increased expression of the main copper cellular importer, hCtr1, as had been previously suggested. Early DNA damage and genomic instability were also higher in PCa cells, with the tumoral cell lines exhibiting deficient DNA-damage repair upon exposure to 64CuCl2. This was corroborated by the observation that 64CuCl2 was more cytotoxic in PCa cells than in non-tumoral cells. Overall, we showed for the first time that PCa cells had a higher sensitivity to 64CuCl2 than healthy cells, supporting the idea that this compound deserved to be further evaluated as a theranostic agent in PCa. PMID- 30423863 TI - Innovative DendrisChips(r) Technology for a Syndromic Approach of In Vitro Diagnosis: Application to the Respiratory Infectious Diseases. AB - Clinical microbiology is experiencing the emergence of the syndromic approach of diagnosis. This paradigm shift will require innovative technologies to detect rapidly, and in a single sample, multiple pathogens associated with an infectious disease. Here, we report on a multiplex technology based on DNA-microarray that allows detecting and discriminating 11 bacteria implicated in respiratory tract infection. The process requires a PCR amplification of bacterial 16S rDNA, a 30 min hybridization step on species-specific oligoprobes covalently linked on dendrimers coated glass slides (DendriChips(r)) and a reading of the slides by a dedicated laser scanner. A diagnostic result is delivered in about 4 h as a predictive value of presence/absence of pathogens using a decision algorithm based on machine-learning method, which was constructed from hybridization profiles of known bacterial and clinical isolated samples and which can be regularly enriched with hybridization profiles from clinical samples. We demonstrated that our technology converged in more than 95% of cases with the microbiological culture for bacteria detection and identification. PMID- 30423864 TI - Inshore Ship Detection Based on Level Set Method and Visual Saliency for SAR Images. AB - Inshore ship detection is an important research direction of synthetic aperture radar (SAR) images. Due to the effects of speckle noise, land clutters and low signal-to-noise ratio, it is still challenging to achieve effective detection of inshore ships. To solve these issues, an inshore ship detection method based on the level set method and visual saliency is proposed in this paper. First, the image is fast initialized through down-sampling. Second, saliency map is calculated by improved local contrast measure (ILCM). Third, an improved level set method based on saliency map is proposed. The saliency map has a higher signal-to-noise ratio and the local level set method can effectively segment images with intensity inhomogeneity. In this way, the improved level set method has a better segmentation result. Then, candidate targets are obtained after the adaptive threshold. Finally, discrimination is employed to get the final result of ship targets. The experiments on a number of SAR images demonstrate that the proposed method can detect ship targets with reasonable accuracy and integrity. PMID- 30423865 TI - Nutrient Intakes and Food Sources of Filipino Infants, Toddlers and Young Children are Inadequate: Findings from the National Nutrition Survey 2013. AB - Comprehensive assessment of nutrient intakes and food sources of nutrients in Filipino children under 5 years old are lacking. We studied energy and nutrient intakes and food sources in 4218 children aged 6-59.9 months using two 24-h dietary recalls. Usual energy and nutrient intakes were estimated using the PC SIDE program. Reported foods and beverages were assigned to one of 85 food groups. Percentage contribution of each food group to nutrient intake was calculated. The results showed that the intake of total fat as a percentage of energy and of most micronutrients were highly inadequate. The prevalence of inadequate nutrient intakes, defined as the percent of children with intakes less than the estimated average requirements (EAR) ranged from 60-90% for iron, calcium, vitamin C, and zinc and ranged from 30-50% for others such as vitamin A, thiamine, riboflavin, niacin, vitamin B6, and phosphorus. The diets of these children were composed of limited foods, namely a large amount of refined rice and other low-nutrient-dense foods (cookies and sugar), while vegetables, fruits, meats, and eggs made little contribution to daily energy or nutrients. These findings provide direction to health professionals developing food-based recommendations and strategies to tackle the shortfalls in the diet of this population. PMID- 30423866 TI - Development of a System Measurement Model of the Brazilian Hospital Accreditation System. AB - The purpose of this study is to develop and validate a measurement model that evaluates the Brazilian hospital accreditation methodology (ONA), based on a multivariate model using structural equation modeling (SEM). The information used to develop the model was obtained from a questionnaire sent to all organizations accredited by the ONA methodology. A model was built based on the data obtained and tested through a structural equation modeling (SEM) technique using the LISREL(r) software (Scientific Software International, Inc., Skokie, IL, USA). Four different tests were performed: Initial, calibrated, simulated, and cross validation models. By analyzing and validating the proposed measurement model, it can be verified that the selected factors satisfy the required criteria for the development of a structural model. The results show that leadership action is one of the most important factors in the process of health services accredited by ONA. Although, leadership, staff management, quality management, organizational culture, process orientation, and safety are strongly linked to the development of health organizations, and directly influence the accreditation process. PMID- 30423867 TI - Oral Intake of Collagen Peptide Attenuates Ultraviolet B Irradiation-Induced Skin Dehydration In Vivo by Regulating Hyaluronic Acid Synthesis. AB - Collagen peptide (CP) has beneficial effects on functions of the skin, such as skin barrier function and skin elasticity, in vivo. However, there are few studies investigating the mechanism underlying the potential effects of CP in skin epidermal moisturization after ultraviolet B (UVB) irradiation. In this study, we examined whether orally-administered CP affects the loss of skin hydration induced by UVB irradiation in hairless mice. SKH-1 hairless mice were orally administered CP at two doses (500 and 1000 mg/kg) for nine weeks, and the dorsal skin was exposed to UVB. The potential effects of CP were evaluated by measuring the transepidermal water loss (TEWL), skin hydration, wrinkle formation, and hyaluronic acid expression in the dorsal mice skin. We found that oral administration of CP increased skin hydration and decreased wrinkle formation compared to the UVB-irradiated group. Treatment of CP increased the mRNA and protein expression of hyaluronic acid synthases (HAS-1 and -2) concomitant with an increased hyaluronic acid production in skin tissue. The expression of hyaluronidase (HYAL-1 and 2) mRNA was downregulated in the CP treated group. In addition, the protein expression of skin-hydrating factors, filaggrin and involucrin, was upregulated via oral administration of CP. In summary, these results show that oral administration of CP increases hyaluronic acid levels, which decreases during UVB photoaging. Therefore, we suggest that CP can be used as a nutricosmetic ingredient with potential effects on UVB-induced skin dehydration and moisture loss in addition to wrinkle formation. PMID- 30423868 TI - The Memory of the Heart. AB - The embryological development of the heart is one of the most fascinating phenomena in nature and so is its final structure and function. The various ontogenetic passages form the evolutive basis of the final configuration of the heart. Each key step can be recognized in the final features, as the heart maintains a kind of "memory" of these passages. We can identify the major lines of development of the heart and trace these lines up to the mature organ. The aim of this review is to identify these key parameters of cardiac structure and function as essential elements of the heart's proper functioning and bases for its treatment. We aim to track key steps of heart development to identify what it "remembers" and maintains in its final form as positively selected. A new vision based on the whole acquired knowledge must guide an in-depth scientific approach in future papers and guidelines on the topic and a complete, farsighted therapeutic conduct able to ensure the physiological correction of cardiac pathologies. The application of this modern, functional vision of the heart could improve the clinical treatment of heart disease, filling the gaps still present. PMID- 30423869 TI - The Relationship between Vitamin D Status and the Menstrual Cycle in Young Women: A Preliminary Study. AB - BACKGROUND: The aim of this study was to evaluate serum vitamin D levels and to compare these with the menstrual cycle in young women with different body weights. METHODS: Eighty-four students were recruited into the study of which 77 remained at the study's completion. Women were assigned to one of two subgroups, according to their 25-hydroxy vitamin D test level [25(OH)D] in which 60 women had low 25(OH)D levels (LD < 30 ng/mL) and 17 had normal levels (ND > 30 ng/mL <= 80 ng/mL). RESULTS: In the LD group, 40% of participants reported having long cycles, 27% were classified as having oligomenorrhoea, and 13% as having amenorrhoea. In the ND group, only 12% reported menstrual cycle disorders, 6% had oligomenorrhoea, and 6% had amenorrhoea. Women who did not meet the recommended level of 30 ng/mL of 25(OH)D had almost five times the odds of having menstrual cycle disorders as women who were above the recommended vitamin D level. CONCLUSION: A relationship was demonstrated between the frequency of menstrual disorders and low levels of vitamin D. Supplementation is necessary in women with low levels of vitamin D in order to compensate for this deficiency and to assess its effect in regulating menstrual disorders. PMID- 30423870 TI - Detrimental Effects of Doping Al and Ba on the Thermoelectric Performance of GeTe. AB - GeTe-based materials are emerging as viable alternatives to toxic PbTe-based thermoelectric materials. In order to evaluate the suitability of Al as dopant in thermoelectric GeTe, a systematic study of thermoelectric properties of Ge1 xAlxTe (x = 0-0.08) alloys processed by Spark Plasma Sintering are presented here. Being isoelectronic to Ge1-xInxTe and Ge1-xGaxTe, which were reported with improved thermoelectric performances in the past, the Ge1-xAlxTe system is particularly focused (studied both experimentally and theoretically). Our results indicate that doping of Al to GeTe causes multiple effects: (i) increase in p type charge carrier concentration; (ii) decrease in carrier mobility; (iii) reduction in thermopower and power factor; and (iv) suppression of thermal conductivity only at room temperature and not much significant change at higher temperature. First principles calculations reveal that Al-doping increases the energy separation between the two valence bands (loss of band convergence) in GeTe. These factors contribute for Ge1-xAlxTe to exhibit a reduced thermoelectric figure of merit, unlike its In and Ga congeners. Additionally, divalent Ba-doping [Ge1-xBaxTe (x = 0-0.06)] is also studied. PMID- 30423871 TI - Non-Alcoholic Fatty Liver Disease among Type-2 Diabetes Mellitus Patients in Abha City, South Western Saudi Arabia. AB - The objective of this study was to determine the prevalence and the factors associated with non-alcoholic fatty liver disease (NAFLD) among type-2 diabetes mellitus (T2DM) patients in Abha City, Southwestern Saudi Arabia. Using a cross sectional study design, a representative sample of 245 T2DM patients were recruited from all primary healthcare centers in Abha city. A detailed medical history as well as laboratory investigations were done. NAFLD was diagnosed using abdominal ultrasound examination. The overall prevalence of NAFLD was 72.8% (95% CI: 66.6%-78.1%). In a multivariable regression analysis, the risk of NAFLD was significantly higher among overweight T2DM patients (aOR = 6.112, 95% CI: 1.529 4.432), Obese (aOR = 10.455, 95% CI: 2.645-41.326), with high ALT of more than 12 IU/L (aOR = 2.335, 95% CI: 1.096-5.062), moderate diet-compliant patients (aOR = 2.413, 95% CI: 1.003-5.805) and poor diet-compliant patients (aOR = 6.562, 95% CI: 2.056-20.967). On the other hand, high HDL (high density cholesterol) (in mg/dL) was a protective factor for NAFLD (aOR = 0.044, 95% CI: 0.005-0.365). It was concluded that NAFLD is a common association of T2DM. Increasing BMI (Body mass index), lower HDL level, and poor dietary control are significant factors associated with NAFLD among T2DM patients. Health education to improve dietary control and avoid excessive weight gain, testing for NAFLD among diabetic patients, especially those with abnormal BMI and HDL, are recommended for early detection and to ensure optimal levels of HDL. PMID- 30423873 TI - Single Chiral Skyrmions in Ultrathin Magnetic Films. AB - The stability and sizes of chiral skyrmions in ultrathin magnetic films are calculated accounting for the isotropic exchange, Dzyaloshinskii-Moriya exchange interaction (DMI), and out-of-plane magnetic anisotropy within micromagnetic approach. Bloch skyrmions in ultrathin magnetic films with B20 cubic crystal structure (MnSi, FeGe) and Neel skyrmions in ultrathin films and multilayers Co/X (X = Ir, Pd, Pt) are considered. The generalized DeBonte ansatz is used to describe the inhomogeneous skyrmion magnetization. The single skyrmion metastability/instability area, skyrmion radius, and skyrmion width are found analytically as a function of DMI strength d . It is shown that the single chiral skyrmions are metastable in infinite magnetic films below a critical value of DMI d c , and do not exist at d > d c . The calculated skyrmion radius increases as d increases and diverges at d -> d c - 0 , whereas the skyrmion width increases monotonically as d increases up to d c without any singularities. The calculated skyrmion width is essentially smaller than the one calculated within the generalized domain wall model. PMID- 30423874 TI - Geographic Analysis of Motor Neuron Disease Mortality and Heavy Metals Released to Rivers in Spain. AB - The etiology of motor neuron disease (MND) is still unknown. The aims of this study were to: (1) analyze MND mortality at a fine-grained level; and (2) explore associations of MND and heavy metals released into Spanish river basins. MND deaths were extracted from the Spanish nationwide mortality registry (2007-2016). Standardized mortality ratios (SMRs) for MND were estimated at a municipal level. Sites that emitted quantities of heavy metals above the regulatory thresholds were obtained from the European Pollutant Release and Transfer Register database (2007-2015). The relative risks for non-exposed and exposed municipalities (considering a downstream 20 km river section) by type of heavy metal were analyzed using a log-linear model. SMRs were significantly higher in central and northern municipalities. SMRs were 1.14 (1.10-1.17) higher in areas exposed to heavy metals than in non-exposed areas: 0.95 (0.92-0.96). Considering the different metals, we found the following increased MND death risks in exposed areas: 20.9% higher risk for lead, 20.0% for zinc, 16.7% for arsenic, 15.7% for chromium, 15.4% for cadmium, 12.7% for copper, and 12.4% for mercury. This study provides associations between MND death risk and heavy metals in exposed municipalities. Further studies investigating heavy metal exposure are needed to progress in MND understanding. PMID- 30423875 TI - Image Segmentation Based on Dynamic Particle Swarm Optimization for Crystal Growth. AB - In order to realize the intelligent production of sapphire crystal, it is important to obtain the growth status from the furnace by charge coupled device (CCD). However, a significant challenge is that traditional approaches are often not valid to separate the images of the melting interface well due to the low contrast and uneven brightness from the heater. In this paper, an improved Otsu algorithm based on dynamic particle swarm optimization (DPSO) is proposed to find the exact threshold band as contour of the crystal. In this method, the Otsu method is constructed firstly, then DPSO is used to find the optimal threshold band. Experimental results show that the proposed algorithm can separate the texture of crystal growth images well and has high robustness. PMID- 30423872 TI - Cancer-Associated Function of 2-Cys Peroxiredoxin Subtypes as a Survival Gatekeeper. AB - Cancer cells are abnormal cells that do not comply with tissue homeostasis but undergo uncontrolled proliferation. Such abnormality is driven mostly by somatic mutations on oncogenes and tumor suppressors. Cancerous mutations show intra tumoral heterogeneity across cancer types and eventually converge into the self activation of proliferative signaling. While transient production of intracellular reactive oxygen species (ROS) is essential for cell signaling, its persistent production is cytotoxic. Thus, cancer cells require increased levels of intracellular ROS for continuous proliferation, but overexpress cellular peroxidase enzymes, such as 2-Cys peroxiredoxins, to maintain ROS homeostasis. However, suppression of 2-Cys peroxiredoxins has also been reported in some metastatic cancers. Hence, the cancer-associated functions of 2-Cys peroxiredoxins must be illuminated in the cellular context. In this review, we describe the distinctive signaling roles of 2-Cys peroxiredoxins beyond their intrinsic ROS-scavenging role in relation to cancer cell death and survival. PMID- 30423876 TI - Electrochemical Comparison of SAN/PANI/FLG and ZnO/GO Coated Cast Iron Subject to Corrosive Environments. AB - ZnO/GO (Graphene Oxide) and SAN (Styrene Acrylonitrile)/PANI (Polyaniline)/FLG (Few Layers Graphene) nanocomposite coatings were produced by solution casting and sol-gel methods, respectively, to enhance corrosion resistance of ferrous based materials. Corrosive seawater and 'produced crude oil water' environments were selected as electrolytes for this study. Impedance and coating capacitance values obtained from Electrochemical Impedance Spectroscopy (EIS) Alternating Current (AC technique) showed enhanced corrosion resistance of nanocomposites coatings in the corrosive environments. Tafel scan Direct Current (DC technique) was used to find the corrosion rate of nanocomposite coating. SAN/PANI/FLG coating reduced the corrosion of bare metal up to 90% in seawater whereas ZnO/GO suppressed the corrosion up to 75% having the impedance value of 100 Omega. In produced water of crude oil, SAN/PANI/FLG reduced the corrosion up to 95% while ZnO/GO suppressed the corrosion up to 10%. Hybrid composites of SAN/PANI/FLG coatings have demonstrated better performances compared to ZnO/GO in the corrosive environments under investigation. This study provides fabrication of state-of-the-art novel anti corrosive nanocomposite coatings for a wide range of industrial applications. Reduced corrosion will result in increased service lifetime, durability and reliability of components and system and will in turn lead to significant cost savings. PMID- 30423877 TI - Photoacoustic Energy Sensor for Nanosecond Optical Pulse Measurement. AB - We demonstrate a photoacoustic sensor capable of measuring high-energy nanosecond optical pulses in terms of temporal width and energy fluence per pulse. This was achieved by using a hybrid combination of a carbon nanotube-polydimethylsiloxane (CNT-PDMS)-based photoacoustic transmitter (i.e., light-to-sound converter) and a piezoelectric receiver (i.e., sound detector). In this photoacoustic energy sensor (PES), input pulsed optical energy is heavily absorbed by the CNT-PDMS composite film and then efficiently converted into an ultrasonic output. The output ultrasonic pulse is then measured and analyzed to retrieve the input optical characteristics. We quantitatively compared the PES performance with that of a commercial thermal energy meter. Due to the efficient energy transduction and sensing mechanism of the hybrid structure, the minimum-measurable pulsed optical energy was significantly lowered, ~157 nJ/cm2, corresponding to 1/760 of the reference pyroelectric detector. Moreover, despite the limited acoustic frequency bandwidth of the piezoelectric receiver, laser pulse widths over a range of 6-130 ns could be measured with a linear relationship to the ultrasound pulse width of 22-153 ns. As CNT has a wide electromagnetic absorption spectrum, the proposed pulsed sensor system can be extensively applied to high-energy pulse measurement over visible through terahertz spectral ranges. PMID- 30423878 TI - Long-Term Influence of Laser-Processing Parameters on (Super)hydrophobicity Development and Stability of Stainless-Steel Surfaces. AB - Controlling the surface wettability represents an important challenge in the field of surface functionalization. Here, the wettability of a stainless-steel surface is modified by 30-ns pulses of a Nd:YAG marking laser (lambda = 1064 nm) with peak fluences within the range 3.3-25.1 J cm-2. The short- (40 days), intermediate- (100 days) and long-term (1 year) superhydrophilic-to (super)hydrophobic transition of the laser-textured surfaces exposed to the atmospheric air is examined by evaluating its wettability in the context of the following parameters: (i) pulse fluence; (ii) scan line separation; (iii) focal position and (iv) wetting period due to contact angle measurements. The results show that using solely a short-term evaluation can lead to wrong conclusions and that the faster development of the hydrophobicity immediately after laser texturing usually leads to lower final contact angle and vice versa, the slower this transition is, the more superhydrophobic the surface is expected to become (possibly even with self-cleaning ability). Depending on laser fluence, the laser textured surfaces can develop stable or unstable hydrophobicity. Stable hydrophobicity is achieved, if the threshold fluence of 12 J cm-2 is exceeded. We show that by nanosecond-laser texturing a lotus-leaf-like surface with a contact angle above 150 degrees and roll-off angle below 5 degrees can be achieved. PMID- 30423879 TI - Variables Influencing the Accuracy of 3D Modeling of Existing Roads Using Consumer Cameras in Aerial Photogrammetry. AB - Point cloud (PC) generation from photogrammetry-remotely piloted aircraft systems (RPAS) at high spatial and temporal resolution and accuracy is of increasing importance for many applications. For several years, photogrammetry-RPAS has been used to recover civil engineering works such as digital elevation models (DEMs), triangle irregular networks (TINs), contour levels, orthophotographs, etc. This study analyzes the influence of variables involved in the accuracy of PC generation over asphalt shapes and determines the most influential variable based on the development of an artificial neural network (ANN) with patterns identified in the test flights. The input variables were those involved, and output was the three-dimension root mean square error (3D-RMSE) of the PC in each ground control point (GCP). The result of the study shows that the most influential variable over PC accuracy is the modulation transfer function 50 (MTF50). In addition, the study obtained an average 3D-RMSE of 1 cm. The results can be used by the scientific and civil engineering communities to consider MTF50 variables in obtaining images from RPAS cameras and to predict the accuracy of a PC over asphalt based on the ANN developed. Also, this ANN could be the beginning of a large database containing patterns from several cameras and lenses in the world market. PMID- 30423880 TI - Packaged Droplet Microresonator for Thermal Sensing with High Sensitivity. AB - Liquid droplet and quasi-droplet whispering gallery mode (WGM) microcavities have been widely studied recently for the enhanced spatial overlap between the liquid and WGM field, especially in sensing applications. However, the fragile cavity structure and the evaporation of liquid limit its practical applications. Here, stable, packaged, quasi-droplet and droplet microcavities are proposed and fabricated for thermal sensing with high sensitivity. The sensitivity and electromagnetic field intensity distribution are analyzed by Mie theory, and a quantified definition of the quasi-droplet is presented for the first time to the best of our knowledge. By doping dye material directly into the liquid, lasing packaged droplet and quasi-droplet microcavity sensors with a high thermal sensitivity of up to 205.3 pm/ degrees C are experimentally demonstrated. The high sensitivity, facile fabrication, and mechanically robust properties of the optofluidic, packaged droplet microresonator make it a promising candidate for future integrated photonic devices. PMID- 30423881 TI - Hypothalamic AMPK as a Mediator of Hormonal Regulation of Energy Balance. AB - As a cellular energy sensor and regulator, adenosine monophosphate (AMP) activated protein kinase (AMPK) plays a pivotal role in the regulation of energy homeostasis in both the central nervous system (CNS) and peripheral organs. Activation of hypothalamic AMPK maintains energy balance by inducing appetite to increase food intake and diminishing adaptive thermogenesis in adipose tissues to reduce energy expenditure in response to food deprivation. Numerous metabolic hormones, such as leptin, adiponectin, ghrelin and insulin, exert their energy regulatory effects through hypothalamic AMPK via integration with the neural circuits. Although activation of AMPK in peripheral tissues is able to promote fatty acid oxidation and insulin sensitivity, its chronic activation in the hypothalamus causes obesity by inducing hyperphagia in both humans and rodents. In this review, we discuss the role of hypothalamic AMPK in mediating hormonal regulation of feeding and adaptive thermogenesis, and summarize the diverse underlying mechanisms by which central AMPK maintains energy homeostasis. PMID- 30423882 TI - Anti-Acanthamoeba Activity of Brominated Sesquiterpenes from Laurencia johnstonii. AB - Focused on our interest to develop novel antiparasistic agents, the present study was aimed to evaluate the biological activity of an extract of Laurencia johnstonii collected in Baja California Sur, Mexico, against an Acantamoeba castellanii Neff strain. Bioassay-guided fractionation allowed us to identify the amoebicidal diastereoisomers alpha-bromocuparane (4) and alpha-isobromocuparane (5). Furthermore, bromination of the inactive laurinterol (1) and isolaurinterol (2) yielded four halogenated derivatives, (6)-(9), which improved the activity of the natural sesquiterpenes. Among them, the most active compound was 3alpha bromojohnstane (7), a sesquiterpene derivative which possesses a novel carbon skeleton johnstane. PMID- 30423883 TI - Microscopic Three-Dimensional Measurement Based on Telecentric Stereo and Speckle Projection Methods. AB - Three-dimensional (3D) measurement of microstructures has become increasingly important, and many microscopic measurement methods have been developed. For the dimension in several millimeters together with the accuracy at sub-pixel or sub micron level, there is almost no effective measurement method now. Here we present a method combining the microscopic stereo measurement with the digital speckle projection. A microscopy experimental setup mainly composed of two telecentric cameras and an industrial projection module is established and a telecentric binocular stereo reconstruction procedure is carried out. The measurement accuracy has firstly been verified by performing 3D measurements of grid arrays at different locations and cylinder arrays with different height differences. Then two Mitutoyo step masters have been used for further verification. The experimental results show that the proposed method can obtain 3D information of the microstructure with a sub-pixel and even sub-micron measuring accuracy in millimeter scale. PMID- 30423884 TI - Anisotropic Pinning-Effect of Inclusions in Mg-Based Low-Carbon Steel. AB - In this study, the effect of austenite grain size on acicular ferrite (AF) nucleation in low-carbon steel containing 13 ppm Mg is determined. The average austenite grain size was calculated using OM Leica software. Results show that the predicted and experimental values of austenite grain size are extremely close, with a deviation of less than 20 um. AF formation is difficult to induce by either excessively small and large austenite grain sizes; that is, an optimal austenite grain size is required to promote AF nucleation probability. The austenite grain size of 164 um revealed the highest capacity to induce AF formation. The effects of the maximum distance of carbon diffusion and austenite grain size on the microstructure of Mg-containing low carbon steel are also discussed. Next, the pinning ability of different inclusion types in low-carbon steel containing 22 Mg is determined. The in situ observation shows that not every inclusion could inhibit austenite grain migration; the inclusion type influences pinning ability. The grain mobility of each inclusion was calculated using in situ micrographs of confocal scanning laser microscopy (CSLM) for micro analysis. Results show that the austenite grain boundary can strongly be pinned by Mg-based inclusions. MnS inclusions are the least effective in pinning austenite grain boundary migration. PMID- 30423885 TI - Tolerance to Drought, Low pH and Al Combined Stress in Tibetan Wild Barley Is Associated with Improvement of ATPase and Modulation of Antioxidant Defense System. AB - Aluminum (Al) toxicity and drought are two major constraints on plant growth in acidic soils, negatively affecting crop performance and yield. Genotypic differences in the effects of Al/low pH and polyethyleneglycol (PEG) induced drought stress, applied either individually or in combination, were studied in Tibetan wild (XZ5, drought-tolerant; XZ29, Al-tolerant) and cultivated barley (Al tolerant Dayton; drought-tolerant Tadmor). Tibetan wild barley XZ5 and XZ29 had significantly higher H+-ATPase, Ca2+Mg2+-ATPase, and Na+K+-ATPase activities at pH 4.0+Al+PEG than Dayton and Tadmor. Moreover, XZ5 and XZ29 possessed increased levels in reduced ascorbate and glutathione under these conditions, and antioxidant enzyme activities were largely stimulated by exposure to pH 4.0+PEG, pH 4.0+Al, and pH 4.0+Al+PEG, compared to a control and to Dayton and Tadmor. The activity of methylglyoxal (MG) was negatively correlated with increased levels of glyoxalase (Gly) I and Gly II in wild barley. Microscopic imaging of each genotype revealed DNA damage and obvious ultrastructural alterations in leaf cells treated with drought or Al alone, and combined pH 4.0+Al+PEG stress; however, XZ29 and XZ5 were less affected than Dayton and Tadmor. Collectively, the authors findings indicated that the higher tolerance of the wild barley to combined pH 4.0+Al+PEG stress is associated with improved ATPase activities, increased glyoxalase activities, reduced MG, and lower reactive oxygen species levels (like O2- and H2O2) due to increased antioxidant enzyme activities. These results offer a broad comprehension of the mechanisms implicated in barley's tolerance to the combined stress of Al/low pH and drought, and may provide novel insights into the potential utilization of genetic resources, thereby facilitating the development of barley varieties tolerant to drought and Al/low pH stress. PMID- 30423887 TI - Microstructure and Mechanical Properties of Hot- Rolled and Cold-Rolled Medium-Mn TRIP Steels. AB - This study investigated the microstructure and mechanical properties of hot rolled and cold-rolled medium-Mn transformation-induced plasticity (TRIP) steel. The experimental steel, processed by quenching and tempering (Q & T) heat treatment, exhibited excellent mechanical properties for hot-rolled and Q & T steels (strength of 1050-1130 MPa and ductility of 16-34%), as well as for cold rolled and Q & T steels (strength of 878-1373 MPa and ductility of 18-40%). The mechanical properties obtained after isothermal holding at 775 degrees C for one hour for cold-rolled/Q & T steel were superior to that of hot-rolled/Q & T steel. Excellent mechanical properties were attributed to the large amount of retained austenite, which produced a discontinuous TRIP effect. Additionally, the differences in mechanical properties correlated with the morphology, stability and content of retained austenite. The cold-rolled sample, quenched from 650 degrees C (CR 650 degrees C) had extensive TRIP effects in the middle and late stages of the deformation, leading to better mechanical properties. The fracture modes of the hot-rolled sample, quenched from 650 degrees C, and the cold-rolled sample quenched from 650 degrees C, were ductile fractures, resulting in excellent ductility. PMID- 30423886 TI - Novel Bioactive Peptides from Meretrix meretrix Protect Caenorhabditis elegans against Free Radical-Induced Oxidative Stress through the Stress Response Factor DAF-16/FOXO. AB - The hard clam Meretrix meretrix, which has been traditionally used as medicine and seafood, was used in this study to isolate antioxidant peptides. First, a peptide-rich extract was tested for its protective effect against paraquat induced oxidative stress using the nematode model Caenorhabditis elegans. Then, three novel antioxidant peptides; MmP4 (LSDRLEETGGASS), MmP11 (KEGCREPETEKGHR) and MmP19 (IVTNWDDMEK), were identified and were found to increase the resistance of nematodes against paraquat. Circular dichroism spectroscopy revealed that MmP4 was predominantly in beta-sheet conformation, while MmP11 and MmP19 were primarily in random coil conformation. Using transgenic nematode models, the peptides were shown to promote nuclear translocation of the DAF-16/FOXO transcription factor, a pivotal regulator of stress response and lifespan, and induce the expression of superoxide dismutase 3 (SOD-3), an antioxidant enzyme. Analysis of DAF-16 target genes by real-time PCR reveals that sod-3 was up regulated by MmP4, MmP11 and MmP19 while ctl-1 and ctl-2 were also up-regulated by MmP4. Further examination of daf-16 using RNA interference suggests that the peptide-increased resistance of C. elegans to oxidative stress was DAF-16 dependent. Taken together, these data demonstrate the antioxidant activity of M. meretrix peptides, which are associated with activation of the stress response factor DAF-16 and regulation of the antioxidant enzyme genes. PMID- 30423888 TI - Time- and Space-Varying Atmospheric Phase Correction in Discontinuous Ground Based Synthetic Aperture Radar Deformation Monitoring. AB - Ground-based synthetic aperture radar (GB-SAR) uses active microwave remote sensing observation mode to achieve two-dimensional deformation measurement and deformation trend extraction, which shows great prospects in the field of deformation monitoring. However, in the process of GB-SAR deformation monitoring, the disturbances caused by atmospheric effect cannot be neglected, and the atmospheric phases will seriously affect the precision of deformation monitoring. In discontinuous GB-SAR deformation monitoring mode, the atmospheric phases are particularly affected by changes of time and space, so the traditional models of atmospheric phase correction are no longer applicable. In this paper, the interferometric phase signal model considering atmospheric phase is first established. Then, the time- and space-varying characteristics of the atmospheric phase are analyzed, and a novel time- and space-varying atmospheric phase correction algorithm, based on coherent scatterers analysis, is proposed. Finally, slope deformation monitoring experiments are carried out to verify the validity and robustness of the proposed algorithm. PMID- 30423889 TI - One Major Challenge of Sequencing Large Plant Genomes Is to Know How Big They Really Are. AB - Any project seeking to deliver a plant or animal reference genome sequence must address the question as to the completeness of the assembly. Given the complexity introduced particularly by the presence of sequence redundancy, a problem which is especially acute in polyploid genomes, this question is not an easy one to answer. One approach is to use the sequence data, along with the appropriate computational tools, the other is to compare the estimate of genome size with an experimentally measured mass of nuclear DNA. The latter requires a reference standard in order to provide a robust relationship between the two independent measurements of genome size. Here, the proposal is to choose the human male leucocyte genome for this standard: its 1C DNA amount (the amount of DNA contained within unreplicated haploid chromosome set) of 3.50 pg is equivalent to a genome length of 3.423 Gbp, a size which is just 5% longer than predicted by the most current human genome assembly. Adopting this standard, this paper assesses the completeness of the reference genome assemblies of the leading cereal crops species wheat, barley and rye. PMID- 30423890 TI - Blood-Brain Barrier Pathology and CNS Outcomes in Streptococcus pneumoniae Meningitis. AB - Streptococcus pneumoniae is a major meningitis-causing pathogen globally, bringing about significant morbidity and mortality, as well as long-term neurological sequelae in almost half of the survivors. Subsequent to nasopharyngeal colonisation and systemic invasion, translocation across the blood brain barrier (BBB) by S. pneumoniae is a crucial early step in the pathogenesis of meningitis. The BBB, which normally protects the central nervous system (CNS) from deleterious molecules within the circulation, becomes dysfunctional in S. pneumoniae invasion due to the effects of pneumococcal toxins and a heightened host inflammatory environment of cytokines, chemokines and reactive oxygen species intracranially. The bacteria-host interplay within the CNS likely determines not only the degree of BBB pathological changes, but also host survival and the extent of neurological damage. This review explores the relationship between S. pneumoniae bacteria and the host inflammatory response, with an emphasis on the BBB and its roles in CNS protection, as well as both the acute and long-term pathogenesis of meningitis. PMID- 30423891 TI - An Intelligent Nanoscale Insulin Delivery System. AB - Insulin injection relies on strict blood glucose monitoring. However, existing techniques and algorithms for blood glucose monitoring cannot be completed in a timely way. In this study, we have developed a new intelligent glucose-sensitive insulin delivery system to stabilize blood glucose levels in the body. This system does not require real-time detection of blood glucose. First, we successfully synthesized a nanoscale material called PAM-PAspPBA-b-PEG by using chemical methods. We then conducted TEM, DLS, and 1H-NMR analyses to characterize the physicochemical properties, such as size, molecular composition, and configuration of the nanomaterial. We verified the glucose responsibility of the insulin loading nanoscale material in vitro and evaluated its safety and effect on mice in vivo. Results showed that insulin-loaded PAM-PAspPBA-b-PEG is glucose sensitive, safer and more effective than regular insulin injection. This study provides a basis for future development of smart insulin delivery systems. PMID- 30423892 TI - Ultrasonic Sensing and Actuation in Laminate Structures Using Bondline-Embedded d35 Piezoelectric Sensors. AB - Ultrasonic systems employing embedded piezoelectric transducers have seen increased interest in recent years. The ability to sense, actuate, and analyze the wave propagation modes in engineering structures has been fundamental to the advancement of ultrasonic structural health monitoring (SHM). This paper presents a study into the sensing and actuation properties of shear-mode (d35) piezoelectric transducers made of lead zirconate titanate (PZT) that are internally embedded in the bondline of laminate structures. The manuscript presents analytical analysis, finite element simulation, and experimental validation building from an individual piezoelectric element to a full laminate structure. The validated model was then used to perform a parametric study into the effects of d35 PZT transducer size on the strength of actuation and sensing output signal. The selectivity of d35 PZT sensors was also investigated by generating multiple wave modes in the laminate structure and inspecting the output signals. The d35 PZT sensors were found to selectively detect only certain modes of the wave propagation providing a fundamental hardware filter that could be employed to simplify signal analysis and processing. The results of this study indicate that d35 PZTs embedded in the bondline have multiple properties that can potentially be employed for ultrasonic SHM. PMID- 30423893 TI - Optimized Gateway Placement for Interference Cancellation in Transmit-Only LPWA Networks. AB - We study the placement of gateways in a low-power wide-area sensor network, when the gateways perform interference cancellation and when the model of the residual error of interference cancellation is proportional to the power of the packet being canceled. For the case of two sensor nodes sending packets that collide, by which we mean overlap in time, we deduce a symmetric two-crescent region wherein a gateway can decode both collided packets. For a large network of many sensors and multiple gateways, we propose two greedy algorithms to optimize the locations of the gateways. Simulation results show that the gateway placements by our algorithms achieve lower average contention, which means higher packet delivery ratio in the same conditions, than when gateways are naively placed, for several area distributions of sensors. PMID- 30423894 TI - Emotion Recognition Based on Multichannel Physiological Signals with Comprehensive Nonlinear Processing. AB - Multichannel physiological datasets are usually nonlinear and separable in the field of emotion recognition. Many researchers have applied linear or partial nonlinear processing in feature reduction and classification, but these applications did not work well. Therefore, this paper proposed a comprehensive nonlinear method to solve this problem. On the one hand, as traditional feature reduction may cause the loss of significant amounts of feature information, Kernel Principal Component Analysis (KPCA) based on radial basis function (RBF) was introduced to map the data into a high-dimensional space, extract the nonlinear information of the features, and then reduce the dimension. This method can provide many features carrying information about the structure in the physiological dataset. On the other hand, considering its advantages of predictive power and feature selection from a large number of features, Gradient Boosting Decision Tree (GBDT) was used as a nonlinear ensemble classifier to improve the recognition accuracy. The comprehensive nonlinear processing method had a great performance on our physiological dataset. Classification accuracy of four emotions in 29 participants achieved 93.42%. PMID- 30423895 TI - A DIC-Based Study on Fatigue Damage Evolution in Pre-Corroded Aluminum Alloy 2024 T4. AB - This paper investigates the fatigue damage and cracking behavior of aluminum alloy 2024-T4 with different levels of prior corrosion. Damage evolution, crack initiation and propagation were experimentally analyzed by digital image correlation, scanning electron microscopy and damage curves. Prior corrosion is shown to cause accelerated damage accumulation, inducing premature fatigue crack initiation, and affecting crack nucleation location, crack orientation and fracture path. For the pre-corrosion condition, although multiple cracks were observed, only one corrosion-initiated primary crack dominates the failure process, in contrast to the plain fatigue cases, where multiple cracks propagated simultaneously leading to final coalescence and fracture. Based on the experimental observations, a mixed-mode fracture model is proposed and shown to successfully predict fatigue crack growth and failure from the single dominant localized corrosion region. PMID- 30423896 TI - Targeted Energy Intake Is the Important Determinant of Clinical Outcomes in Medical Critically Ill Patients with High Nutrition Risk. AB - The clinical conditions of critically ill patients are highly heterogeneous; therefore, nutrient requirements should be personalized based on the patient's nutritional status. However, nutritional status is not always considered when evaluating a patient's nutritional therapy in the medical intensive care unit (ICU). We conducted a retrospective cross-sectional study to assess the effect of ICU patients' nutrition risk status on the association between energy intake and clinical outcomes (i.e., hospital, 14-day and 28-day mortality). The nutrition risk of critically ill patients was classified as either high- or low-nutrition risk using the modified Nutrition Risk in the Critically Ill score. There were 559 (75.3%) patients in the high nutrition risk group, while 183 patients were in the low nutrition risk group. Higher mean energy intake was associated with lower hospital, 14-day and 28-day mortality rates in patients with high nutrition risk; while there were no significant associations between mean energy intake and clinical outcomes in patients with low nutrition risk. Further examination of the association between amount of energy intake and clinical outcomes showed that patients with high nutrition risk who consumed at least 800 kcal/day had significantly lower hospital, 14-day and 28-day mortality rates. Although patients with low nutrition risk did not benefit from high energy intake, patients with high nutrition risk are suggested to consume at least 800 kcal/day in order to reduce their mortality rate in the medical ICU. PMID- 30423897 TI - Indium Nitrite (InN)-Based Ultrasensitive and Selective Ammonia Sensor Using an External Silicone Oil Filter for Medical Application. AB - Ammonia is an essential biomarker for noninvasive diagnosis of liver malfunction. Therefore, selective detection of ammonia is essential for medical application. Here, we demonstrate a portable device to selectively detect sub-ppm ammonia gas. The presented gas sensor is composed of a Pt coating on top of an ultrathin Indium nitrite (InN) epilayer with a lower detection limit of 0.2 ppm, at operating temperature of 200 degrees C, and detection time of 1 min. The sensor connected with the external filter of nonpolar 500 CS silicone oil to diagnose liver malfunction. The absorption of 0.7 ppm acetone and 0.4 ppm ammonia gas in 10 cc silicone oil is 80% (0.56 ppm) and 21.11% (0.084 ppm), respectively, with a flow rate of 10 cc/min at 25 degrees C. The absorption of acetone gas is 6.66 fold higher as compared to ammonia gas. The percentage variation in response for 0.7 ppm ammonia and 0.7 ppm acetone with and without silicone oil on InN sensor is 17.5% and 4%, and 22.5%, and 14% respectively. Furthermore, the percentage variation in response for 0.7 ppm ammonia gas with silicone oil on InN sensor is 4.3-fold higher than that of 0.7 ppm acetone. The results show that the InN sensor is suitable for diagnosis of liver malfunction. PMID- 30423898 TI - Using Google Trends to Examine the Spatio-Temporal Incidence and Behavioral Patterns of Dengue Disease: A Case Study in Metropolitan Manila, Philippines. AB - Dengue is a major public health concern and an economic burden in the Philippines. Despite the country's improved dengue surveillance, it still suffers from various setbacks and needs to be complemented with alternative approaches. Previous studies have demonstrated the potential of Internet-based surveillance such as Google Dengue Trends (GDT) in supplementing current epidemiological methods for predicting future dengue outbreaks and patterns. With this, our study has two objectives: (1) assess the temporal relationship of weekly GDT and dengue incidence in Metropolitan Manila from 2009-2014; and (2) examine the health seeking behavior based on dengue-related search queries of the population. The study collated the population statistics and reported dengue cases in Metropolitan Manila from respective government agencies to calculate the dengue incidence (DI) on a weekly basis for the entire region and annually per city. Data processing of GDT and dengue incidence was performed by conducting an 'adjustment' and scaling procedures, respectively, and further analyzed for correlation and cross-correlation analyses using Pearson's correlation. The relative search volume of the term 'dengue' and top dengue-related search queries in Metropolitan Manila were obtained and organized from the Google Trends platform. Afterwards, a thematic analysis was employed, and word clouds were generated to examine the health behavior of the population. Results showed that weekly temporal GDT pattern are closely similar to the weekly DI pattern in Metropolitan Manila. Further analysis showed that GDT has a moderate and positive association with DI when adjusted or scaled, respectively. Cross-correlation analysis revealed a delayed effect where GDT leads DI by 1-2 weeks. Thematic analysis of dengue-related search queries indicated 5 categories namely; (a) dengue, (b) sign and symptoms of dengue, (c) treatment and prevention, (d) mosquito, and (e) other diseases. The majority of the search queries were classified in 'signs and symptoms' which indicate the health-seeking behavior of the population towards the disease. Therefore, GDT can be utilized to complement traditional disease surveillance methods combined with other factors that could potentially identify dengue hotspots and help in public health decisions. PMID- 30423899 TI - Preparation of Renewable Bio-Polyols from Two Species of Colliguaja for Rigid Polyurethane Foams. AB - In this study, we investigated the potential of two non-edible oil extracts from seeds of Colliguaja integerrima (CIO) and Colliguaja salicifolia (CSO) to use as a renewable source for polyols and, eventually, polyurethane foams or biodiesel. For this purpose, two novel polyols from the aforementioned oils were obtained in a one-single step reaction using a mixture of hydrogen peroxide and acetic acid. The polyol derivatives obtained from the two studied oils were characterized by spectral (FTIR, 1H NMR, and 13C NMR), physicochemical (e.g., chromatographic analysis, acid value, oxidizability values, iodine value, peroxide value, saponification number, kinematic viscosity, density, theorical molecular weight, hydroxyl number, and hydroxyl functionality) and thermal (TGA) analyses according to standard methods. Physicochemical results revealed that all parameters, with the exception of the iodine value, were higher for bio-polyols (CSP and CIP) compared to the starting oils. The NMR, TGA, and FTIR analyses demonstrated the formation of polyols. Finally, the OH functionality values for CIP and CSP were 4.50 and 5.00, respectively. This result indicated the possible used of CIP and CSP as a raw material for the preparation of polyurethane rigid foams. PMID- 30423900 TI - Design, Modeling, and Evaluation of the Eddy Current Sensor Deeply Implanted in the Human Body. AB - Joint replacement surgeries have enabled motion for millions of people suffering from arthritis or grave injuries. However, over 10% of these surgeries are revision surgeries. We have first analyzed the data from the worldwide orthopedic registers and concluded that the micromotion of orthopedic implants is the major reason for revisions. Then, we propose the use of inductive eddy current sensors for in vivo micromotion detection of the order of tens of MU m. To design and evaluate its characteristics, we have developed efficient strategies for the accurate numerical simulation of eddy current sensors implanted in the human body. We present the response of the eddy current sensor as a function of its frequency and position based on the robust curve fit analysis. Sensitivity and Sensitivity Range parameters are defined for the present context and are evaluated. The proposed sensors are fabricated and tested in the bovine leg. PMID- 30423901 TI - Baseline Mapping of Schistosomiasis and Soil Transmitted Helminthiasis in the Northern and Eastern Health Regions of Gabon, Central Africa: Recommendations for Preventive Chemotherapy. AB - In order to follow the Preventive Chemotherapy (PC) for the transmission control as recommended by WHO, Gabon initiated in 2014 the mapping of Schistosomiasis and Soil Transmitted Helminthiasis (STH). Here, we report the results of the Northern and Eastern health regions, representing a third of the land area and 12% of its total population. All nine departments of the two regions were surveyed and from each, five schools were examined with 50 schoolchildren per school. The parasitological examinations were realized using the filtration method for urine and the Kato-Katz technique for stool samples. Overall 2245 schoolchildren (1116 girls and 1129 boys), mean aged 11.28 +/- 0.04 years, were examined. Combined schistosomiasis and STH affected 1270 (56.6%) with variation between regions, departments, and schools. For schistosomiasis, prevalence were 1.7% across the two regions, with no significant difference (p > 0.05) between the Northern (1.5%) and the Eastern (1.9%). Schistosomiasis is mainly caused by Schistosoma haematobium with the exception of one respective case of S. mansoni and S. guineensis. STH are more common than schistosomiasis, with an overall prevalence of 56.1% significantly different between the Northern (58.1%) and Eastern (53.6%) regions (p = 0.034). Trichuris trichiura is the most abundant infection with a prevalence of 43.7% followed by Ascaris lumbricoides 35.6% and hookworms 1.4%. According to these results, an appropriate PC strategy is given. In particular, because of the low efficacy of a single recommended drug on T. trichiura and hookworms, it is important to include two drugs for the treatment of STH in Gabon, due to the high prevalence and intensities of Trichuris infections. PMID- 30423902 TI - Experimental Study of Rubberized Concrete Stress-Strain Behavior for Improving Constitutive Models. AB - Inclusion of rubber into concrete changes its behavior and the established shape of its stress-strain curve. Existing constitutive stress-strain models for concrete are not valid in case of rubberized concrete, and currently available modified models require additional validation on a larger database of experimental results, with a wider set of influential parameters. By executing uniaxial compressive tests on concrete with rubber substituting 10%, 20%, 30%, and 40% of aggregate, it was possible to study and evaluate the influence of rubber content on its mechanical behavior. The stress-strain curve was investigated in its entirety, including compressive strength, elastic modulus, strains at significant levels of stress, and failure patterns. Experimental results indicated that increase of rubber content linearly decreases compressive strength and elastic modulus, but increases ductility. By comparing experimental stress-strain curves with those plotted using available constitutive stress strain models it was concluded that they are inadequate for rubberized concrete with high rubber content. Based on determined deviations an improvement of an existing model was proposed, which provides better agreement with experimental curves. Obtained research results enabled important insights into correlations between rubber content and changes of the stress-strain curve required when utilizing nonlinear material properties. PMID- 30423903 TI - Interfacial Microstructure and Properties of Si3N4 Ceramics/Cu/304 Stainless Steel Brazed by Ti40Zr25B0.2Cu Amorphous Solder. AB - Si3N4 ceramics and 304 stainless steel were brazed by Ti40Zr25B0.2Cu amorphous solder, and the interfacial microstructure of brazed joint Si3N4 ceramics/Ti40Zr25B0.2Cu/Cu/Ti40Zr25B0.2Cu/304 stainless steel was analyzed. The mechanical properties of the brazed joint were overtly affected by the brazing temperature and Cu foil thickness. The results revealed that the interface structure of the brazed joint might be 304 stainless steel/FeTi/Cu-Zr+Cu-Ti+Fe Ti/Cu(s,s)/Cu-Zr+Cu-Ti+Fe-Ti/Ti-Si+Zr-Si/TiN/Si3N4 ceramics. The four-point bending strength of the brazed joint decreased sharply as the brazing temperature increased and reached a maximum of 76 MPa at 1223 K. Furthermore, as the Cu foil thickness was increased from 500 MUm to 1000 MUm, the joint strength rose to 90 MPa at 1223 K. PMID- 30423904 TI - Using Risk Communication Strategies for Zika Virus Prevention and Control Driven by Community-Based Participatory Research. AB - Background: In this study, we use community-based participatory processes to engage community and academic partners in a meaningful exchange to identify and pilot test risk communication strategies for Zika virus prevention and control. Methods: Community members were actively involved in planning, developing, and implementing a risk communication initiative. Qualitative and quantitative data gathered through individual interviews, focus groups, and community advisory board input provided information for the identification of relevant risk communication strategies to increase the understanding about Zika virus and to promote behavior change. To examine its impact we obtained baseline and follow-up data from a random sample of 75 community residents. A face-to-face interview was conducted to assess community members' knowledge, attitudes, and behaviors regarding Zika virus infection. Results: Study activities focused on three risk communication strategies: Zika awareness health fair, health education through theater, and community forums and workshops. The risk communication initiative was implemented over a two-month period. Findings from baseline and follow-up data demonstrated significant positive changes in respondents' recognition of personal and community responsibility for the prevention of Zika infection, increased knowledge of prevention strategies, and enhanced engagement in preventive behaviors for mosquito control. Conclusion: Our findings sustain the benefits of community based participatory research for the design and implementation of risk communication strategies that are relevant to enable residents in low-income communities to take informed decisions for the protection against Zika virus and other mosquito-borne diseases. PMID- 30423905 TI - Hypoxic Microenvironment and Metastatic Bone Disease. AB - Hypoxia is a common feature of solid tumors and is associated with an increased risk of metastasis and a poor prognosis. Recent imaging techniques revealed that bone marrow contains a quite hypoxic microenvironment. Low oxygen levels activate hypoxia signaling pathways such as hypoxia-inducible factors, which play critical roles in the key stages of metastatic dissemination including angiogenesis, epithelial-mesenchymal transition, invasion, maintenance of cancer stem cells, tumor cell dormancy, release of extracellular vesicles, and generation of pre metastatic niches. Hypoxia also affects bone cells, such as osteoblasts and osteoclasts, and immune cells, which also act to support the development and progression of bone metastases. Paradoxically, hypoxia and related signaling molecules are recognized as high-priority therapeutic targets and many candidate drugs are currently under preclinical and clinical investigation. The present review focuses on our current knowledge of the potential roles of hypoxia in cancer metastasis to bone by considering the interaction between metastatic cancer cells and the bone microenvironment. Current therapeutic approaches targeting hypoxia are also described. PMID- 30423906 TI - Comparative Assessment of Tungsten Toxicity in the Absence or Presence of Other Metals. AB - Tungsten is a refractory metal that is used in a wide range of applications. It was initially perceived that tungsten was immobile in the environment, supporting tungsten as an alternative for lead and uranium in munition and military applications. Recent studies report movement and detection of tungsten in soil and potable water sources, increasing the risk of human exposure. In addition, experimental research studies observed adverse health effects associated with exposure to tungsten alloys, raising concerns on tungsten toxicity with questions surrounding the safety of exposure to tungsten alone or in mixtures with other metals. Tungsten is commonly used as an alloy with nickel and cobalt in many applications to adjust hardness and thermal and electrical conductivity. This review addresses the current state of knowledge in regard to the mechanisms of toxicity of tungsten in the absence or presence of other metals with a specific focus on mixtures containing nickel and cobalt, the most common components of tungsten alloy. PMID- 30423908 TI - Development and Application of an Additively Manufactured Calcium Chloride Nebulizer for Alginate 3D-Bioprinting Purposes. AB - Three-dimensional (3D)-bioprinting enables scientists to mimic in vivo micro environments and to perform in vitro cell experiments under more physiological conditions than is possible with conventional two-dimensional (2D) cell culture. Cell-laden biomaterials (bioinks) are precisely processed to bioengineer tissue three-dimensionally. One primarily used matrix material is sodium alginate. This natural biopolymer provides both fine mechanical properties when gelated and high biocompatibility. Commonly, alginate is 3D bioprinted using extrusion based devices. The gelation reaction is hereby induced by a CaCl2 solution in the building chamber after material extrusion. This established technique has two main disadvantages: (1) CaCl2 can have toxic effects on the cell-laden hydrogels by oxygen diffusion limitation and (2) good printing resolution in the CaCl2 solution is hard to achieve, since the solution needs to be removed afterwards and substituted by cell culture media. Here, we show an innovative approach of alginate bioprinting based on a CaCl2 nebulizer. The device provides CaCl2 mist to the building platform inducing the gelation. The necessary amount of CaCl2 could be decreased as compared to previous gelation strategies and limitation of oxygen transfer during bioprinting can be reduced. The device was manufactured using the MJP-3D printing technique. Subsequently, its digital blueprint (CAD file) can be modified and additive manufactured easily and mounted in various extrusion bioprinters. With our approach, a concept for a more gentle 3D Bioprinting method could be shown. We demonstrated that the concept of an ultrasound-based nebulizer for CaCl2 mist generation can be used for 3D bioprinting and that the mist-induced polymerization of alginate hydrogels of different concentrations is feasible. Furthermore, different cell-laden alginate concentrations could be used: Cell spheroids (mesenchymal stem cells) and single cells (mouse fibroblasts) were successfully 3D printed yielding viable cells and stable hydrogels after 24 h cultivation. We suggest our work to show a different and novel approach on alginate bioprinting, which could be useful in generating cell-laden hydrogel constructs for e.g., drug screening or (soft) tissue engineering applications. PMID- 30423909 TI - Atomistic Analysis of ToxN and ToxI Complex Unbinding Mechanism. AB - ToxIN is a triangular structure formed by three protein toxins (ToxNs) and three specific noncoding RNA antitoxins (ToxIs). To respond to stimuli, ToxI is preferentially degraded, releasing the ToxN. Thus, the dynamic character is essential in the normal function interactions between ToxN and ToxI. Here, equilibrated molecular dynamics (MD) simulations were performed to study the stability of ToxN and ToxI. The results indicate that ToxI adjusts the conformation of 3' and 5' termini to bind to ToxN. Steered molecular dynamics (SMD) simulations combined with the recently developed thermodynamic integration in 3nD (TI3nD) method were carried out to investigate ToxN unbinding from the ToxIN complex. The potentials of mean force (PMFs) and atomistic pictures suggest the unbinding mechanism as follows: (1) dissociation of the 5' terminus from ToxN, (2) missing the interactions involved in the 3' terminus of ToxI without three nucleotides (G31, A32, and A33), (3) starting to unfold for ToxI, (4) leaving the binding package of ToxN for three nucleotides of ToxI, (5) unfolding of ToxI. This work provides information on the structure-function relationship at the atomistic level, which is helpful for designing new potent antibacterial drugs in the future. PMID- 30423907 TI - Novel Agents for Acute Myeloid Leukemia. AB - Acute myeloid leukemia (AML) is a complex hematological disease characterized by genetic and clinical heterogeneity. Recent advances in the understanding of AML pathogenesis have paved the way for the development of new agents targeting specific molecules or mechanisms that contribute to finally move beyond the current standard of care, which is "3 + 7" regimen. In particular, new therapeutic options such as targeted therapies (midostaurin and enasidenib), monoclonal antibodies (gemtuzumab ozogamicin), and a novel liposomal formulation of cytarabine and daunorubicin (CPX-351) have been recently approved, and will be soon available for the treatment of adult patients with AML. In this review, we will present and describe these recently approved drugs as well as selected novel agents against AML that are currently under investigation, and show the most promising results as monotherapy or in combination with chemotherapy. The selection of these emerging treatments is based on the authors' opinion. PMID- 30423910 TI - Comparative Transcriptome Analysis Provides Novel Insight into Morphologic and Metabolic Changes in the Fat Body during Silkworm Metamorphosis. AB - The fat body plays key roles in energy storage and utilization as well as biosynthetic and metabolic activities in insects. During metamorphosis from larva to pupa, the fat body undergoes dramatic changes in morphology and metabolic processes. However, the genetic basis underlying these changes has not been completely understood. In this study, the authors performed a time-course transcriptome analysis of the fat body during silkworm metamorphosis using RNA sequencing. A total of 5217 differentially expressed genes (DEGs) were identified in the fat body at different developmental time points. DEGs involved in lipid synthesis and degradation were highly expressed at the third day of the last larval instar and during the prepupal-pupal transition, respectively. DEGs involved in the ecdysone signaling and bone morphogenetic protein (BMP) signaling pathways that modulate organ development exhibited a high expression level during the fat body remodeling process from prepupa to pupa. Intriguingly, the RNA interference-mediated knockdown of either decapentaplegic (Dpp) or protein 60A (Gbb), two DEGs involved in the BMP signaling pathway, inhibited fat body dissociation but promoted lipid mobilization, suggesting that the BMP signaling pathway not only is required for fat body remodeling, but also moderately inhibits lipid mobilization to ensure an appropriate lipid supply during the pupal-adult transition. In conclusion, the comparative transcriptome analysis provides novel insight into morphologic and metabolic changes in the fat body during silkworm metamorphosis. PMID- 30423911 TI - Use and Propensity to Use Substances as Cognitive Enhancers in Italian Medical Students. AB - International media has paid attention to the use of substances by healthy subjects to enhance cognitive performance. Medical students are liable to use cognitive enhancers (CE) with the aim of improving academic performance. The study explored use and attitudes toward the use of CE in Italian medical students. The authors anonymously surveyed 433 medical students of the University of Modena and Reggio Emilia with an ad hoc 36-items questionnaire. CE were broadly defined as any substance taken with the purpose of improving cognitive functions, from readily available beverages and substances, such as coffee, tea, energy drinks, and supplements to prescription only medication, such as psychostimulants and modafinil. Response rate was 83.8% (n = 363). While the majority of the students (74.7%; n = 271) said that they had used substances to improve cognitive functions, only 2 students (0.6%) reported the use of prescription-only medications in the last 30 days. Main reasons for not taking prescription-only drugs were concerns about safety and side effects, reported by 83.3% of students (n = 295). A positive attitude toward use was held by 60.3% (n = 219) subjects. The surveyed Italian medical students used many substances as CE, but this did not seem to apply significantly to psychostimulants. A multivariable analysis showed that the following variables were related to the propensity to use substances as CE: male gender, self-reported memory impairment, concerns about worsening of cognitive performance, lifetime use of at least one illegal substance, use of any substance (both legal or illegal) in the last 30 days. PMID- 30423912 TI - Reply to the Comment from Watson, K.M. "Letter to the Editor Re: Kipperman, B.S. and German, A.J. Animals 2018, 8, 143" Animals 2018, 8, 179. AB - We appreciate the interest [1] in our opinion paper [2] regarding companion animal obesity and, although there is limited published evidence, agree that some pet owners might respond negatively when this issue is addressed [...]. PMID- 30423913 TI - Characterization of Microbiota in Bronchiectasis Patients with Different Disease Severities. AB - The applications of the 16S rRNA gene pyrosequencing has expanded our knowledge of the respiratory tract microbiome originally obtained using conventional, culture-based methods. In this study, we employed DNA-based molecular techniques for examining the sputum microbiome in bronchiectasis patients, in relation to disease severity. Of the sixty-three study subjects, forty-two had mild and twenty-one had moderate or severe bronchiectasis, which was classified by calculating the FACED score, based on the FEV1 (forced expiratory volume in 1 s, %) (F, 0-2 points), age (A, 0-2 points), chronic colonization by Pseudomonas aeruginosa (C, 0-1 point), radiographic extension (E, 0-1 point), and dyspnoea (D, 0-1 point). Bronchiectasis was defined as mild, at 0-2 points, moderate at 3 4 points, and severe at 5-7 points. The mean age was 68.0 +/- 9.3 years; thirty three patients were women. Haemophilus (p = 0.005) and Rothia (p = 0.043) were significantly more abundant in the mild bronchiectasis group, whereas Pseudomonas (p = 0.031) was significantly more abundant in the moderate or severe group. However, in terms of the alpha and beta diversity, the sputum microbiota of the two groups did not significantly differ, i.e., the same dominant genera were found in all samples. Further large-scale studies are needed to investigate the sputum microbiome in bronchiectasis. PMID- 30423914 TI - Optimization of Vortex-Assisted Dispersive Liquid-Liquid Microextraction for the Simultaneous Quantitation of Eleven Non-Anthocyanin Polyphenols in Commercial Blueberry Using the Multi-Objective Response Surface Methodology and Desirability Function Approach. AB - In the present study, 11 non-anthocyanin polyphenols, gallic acid, protocatechuate, vanillic acid, syringic acid, ferulic acid, quercetin, catechin, epicatechin, epigallocatechin gallate, gallocatechin gallate and epicatechin gallate-were firstly screened and identified from blueberries using an ultra performance liquid chromatography-time of flight mass spectrography (UPLC-TOF/MS) method. Then, a sample preparation method was developed based on vortex-assisted dispersive liquid-liquid microextraction. The microextraction conditions, including the amount of ethyl acetate, the amount of acetonitrile and the solution pH, were optimized through the multi-objective response surface methodology and desirability function approach. Finally, an ultra performance liquid chromatography-triple quadrupole mass spectrography (UPLC-QqQ/MS) method was developed to determine the 11 non-anthocyanin polyphenols in 25 commercial blueberry samples from Sichuan province and Chongqing city. The results show that this new method with high accuracy, good precision and simple operation characteristics, can be used to determine non-anthocyanin polyphenols in blueberries and is expected to be used in the analysis of other fruits and vegetables. PMID- 30423915 TI - Recent Studies on Ponatinib in Cancers Other Than Chronic Myeloid Leukemia. AB - Ponatinib is a third line drug for the treatment of chronic myeloid leukemia patients, especially those that develop the gatekeeper mutation T315I, which is resistant to the first and the second line drugs imatinib, nilotinib, dasatinib and bosutinib. The compound was first identified as a pan Bcr-Abl and Src kinase inhibitor. Further studies have indicated that it is a multitargeted inhibitor that is active on FGFRs, RET, AKT, ERK1/2, KIT, MEKK2 and other kinases. For this reason, the compound has been evaluated on several cancers in which these kinases play important roles, including thyroid, breast, ovary and lung cancer, neuroblastoma, rhabdoid tumours and in myeloproliferative disorders. Ponatinib is also being tested in clinical trials to evaluate its activity in FLT3-ITD acute myelogenous leukemia, head and neck cancers, certain type of lung cancer, gastrointestinal stromal tumours and other malignancies. In this review we report the most recent preclinical and clinical studies on ponatinib in cancers other than CML, with the aim of giving a complete overview of this interesting compound. PMID- 30423916 TI - Assessment of Nutrient and Food Group Intakes across Sex, Physical Activity, and Body Mass Index in an Urban Brazilian Population. AB - The burden of preventable diet-related diseases is significant and becoming worse. Thus, accurately assessing food intake is crucial to guide public health policies and actions. Using food dietary recalls, we evaluated usual dietary intake according to physical activity and nutritional status in an adult urban population from Brasilia, Brazil. The usual nutrient and energy intakes distributions were estimated using the Iowa State University (ISU) method. Energy and nutrient intakes were stratified by gender, age group, body mass index (BMI), and physical activity (PA). The prevalence of inadequate intake was highest for vitamins E and D. Both men and women had excessive sodium intake. The percentage of intakes below daily serving recommendations for food groups were 96% for cereals, 74% for vegetables, and 87% for dairy products, whereas percentage of intakes above daily serving recommendations were 97% for meat, 93% for pulses, and 99% for fat/oils. Energy and nutrient intakes were highest in overweight and physically active individuals within the categories of BMI and physical activity, respectively. Our study found that high-income urban Brazilians consume large quantities of meat, beans, fat/oils, and exhibit a low prevalence of nutrient inadequacies but have excessive sodium intake. Energy and nutrient intakes are highest among men, as well as overweight and physically active individuals. PMID- 30423917 TI - CoAR: Congestion-Aware Routing Protocol for Low Power and Lossy Networks for IoT Applications. AB - The IPv6 routing protocol for low power and lossy networks (RPL) was designed to satisfy the requirements of a wide range of Internet of Things (IoT) applications, including industrial and environmental monitoring. In most scenarios, different from an ordinary environment, the industrial monitoring system under emergency scenarios needs to not only periodically collect the information from the sensing region, but also respond rapidly to some unusual situations. In the monitoring system, particularly when an event occurs in the sensing region, a surge of data generated by the sensors may lead to congestion at parent node as data packets converge towards the root. Congestion problem degrades the network performance that has an impact on quality of service. To resolve this problem, we propose a congestion-aware routing protocol (CoAR) which utilizes the selection of an alternative parent to alleviate the congestion in the network. The proposed mechanism uses a multi-criteria decision-making approach to select the best alternative parent node within the congestion by combining the multiple routing metrics. Moreover, the neighborhood index is used as the tie-breaking metric during the parent selection process when the routing score is equal. In order to determine the congestion, CoAR adopts the adaptive congestion detection mechanism based on the current queue occupancy and observation of present and past traffic trends. The proposed protocol has been tested and evaluated in different scenarios in comparison with ECRM and RPL. The simulation results show that CoAR is capable of dealing successfully with congestion in LLNs while preserving the required characteristics of the IoT applications. PMID- 30423918 TI - Highly Cancer Selective Antiproliferative Activity of Natural Prenylated Flavonoids. AB - Xanthohumol (XN) and four minor hops prenylflavonoids: alpha,beta dihydroxanthohumol (2HXN), isoxanthohumol (IXN), 8-prenylnaringenin (8PN), and 6 prenylnaringenin (6PN), were tested for antiproliferative activity towards human cancer and normal cell lines. Nonprenylated naringenin (NG) was used as a model compound. Xanthohumol, alpha,beta-dihydroxanthohumol and 6-prenylnaringenin were the most active compounds. Xanthohumol exhibited higher antiproliferative activity than cisplatin (CP) against five cancer cell lines: ovarian resistant to cisplatin A2780cis, breast MDA-MB-231 and T-47D, prostate PC-3, and colon HT-29. Isoxanthohumol was more potent than cisplatin against breast cancer cell lines MDA-MB-231 and T-47D whereas 6-prenylnaringenin was stronger than cisplatin against breast cancer cell line T-47D. It was found that tested chalcones possessed highly selective antiproliferative activity towards all tested breast cancer lines compared to the normal breast MCF 10A cell line (the calculated selectivity index ranged from 5 to 10). Low antiproliferative activity of naringenin indicates the importance of the prenyl group with respect to antiproliferative activity. PMID- 30423919 TI - Hybrid TSR-PSR Alternate Energy Harvesting Relay Network over Rician Fading Channels: Outage Probability and SER Analysis. AB - In this research, we investigate a hybrid time-switching relay (TSR)-power splitting relay (PSR) alternate energy harvesting (EH) relaying network over the Rician fading channels. For this purpose, the amplify-and-forward (AF) mode is considered for the alternative hybrid time TSR-PSR. The system model consists of one source, one destination and two alternative relays for signal transmission from the source to the destination. In the first step, the exact and asymptotic expressions of the outage probability and the symbol errors ratio (SER) are derived. Then, the influence of all system parameters on the system performance is investigated, and the Monte Carlo simulation verifies all results. Finally, the system performances of TSR-PSR, TSR, and PSR cases are compared in connection with all system parameters. PMID- 30423920 TI - Genome-Wide Investigation of the Auxin Response Factor Gene Family in Tartary Buckwheat (Fagopyrum tataricum). AB - Auxin signaling plays an important role in plant growth and development. It responds to various developmental and environmental events, such as embryogenesis, organogenesis, shoot elongation, tropical growth, lateral root formation, flower and fruit development, tissue and organ architecture, and vascular differentiation. However, there has been little research on the Auxin Response Factor (ARF) genes of tartary buckwheat (Fagopyrum tataricum), an important edible and medicinal crop. The recent publication of the whole-genome sequence of tartary buckwheat enables us to study the tissue and expression profile of the FtARF gene on a genome-wide basis. In this study, 20 ARF (FtARF) genes were identified and renamed according to the chromosomal distribution of the FtARF genes. The results showed that the FtARF genes belonged to the related sister pair, and the chromosomal map showed that the duplication of FtARFs was related to the duplication of the chromosome blocks. The duplication of some FtARF genes shows conserved intron/exon structure, which is different from other genes, suggesting that the function of these genes may be diverse. Real-time quantitative PCR analysis exhibited distinct expression patterns of FtARF genes in various tissues and in response to exogenous auxin during fruit development. In this study, 20 FtARF genes were identified, and the structure, evolution, and expression patterns of the proteins were studied. This systematic analysis laid a foundation for the further study of the functional characteristics of the ARF genes and for the improvement of tartary buckwheat crops. PMID- 30423921 TI - Moral or Dirty Leadership: A Qualitative Study on How Juniors Are Managed in Dutch Consultancies. AB - Professional service firms in Western Europe have a reputation for putting huge pressures on their junior employees, resulting in very long work hours, and as a consequence health risks. This study explores moral leadership as a possible response to the stigma of such dirty leadership. We conducted semi-structured interviews with 12 consultant managers and with each one of their juniors, and found that managers put several pressures on their juniors; these pressures bring high levels of stress, lowered wellbeing and burnout. Society considers such a pressuring leadership style morally dirty. To counteract the experience of being seen as morally dirty, we found that consultant managers were normalizing such criticisms as commonly assumed in dirty work literature. However, they also employed several moral leadership tactics to counteract the negative consequences criticized in society. However, in addition to the well-known individual-level tactics, consultant managers and their juniors also reported moral leadership support at the organizational level, like institutionalized performance talks after every project, trainings, specific criteria for hiring juniors, and policies to recognize and compliment high performance. Still, we cannot conclude these moral leadership approaches are moral by definition. They can be used in an instrumental way as well, to further push performance. PMID- 30423922 TI - Tip-Enhanced Raman Spectroscopy with High-Order Fiber Vector Beam Excitation. AB - We investigated tip-enhanced Raman spectra excited by high-order fiber vector beams. Theoretical analysis shows that the high-order fiber vector beams have stronger longitudinal electric field components than linearly polarized light under tight focusing conditions. By introducing the high-order fiber vector beams and the linearly polarized beam from a fiber vector beam generator based on an electrically-controlled acoustically-induced fiber grating into a top illumination tip-enhanced Raman spectroscopy (TERS) setup, the tip-enhanced Raman signal produced by the high-order fiber vector beams was 1.6 times as strong as that produced by the linearly polarized light. This result suggests a new type of efficient excitation light beams for TERS. PMID- 30423923 TI - The Two-Faced Cytokine IL-6 in Host Defense and Diseases. AB - Interleukein-6 (IL-6), is produced locally from infectious or injured lesions and is delivered to the whole body via the blood stream, promptly activating the host defense system to perform diverse functions. However, excessive or sustained production of IL-6 is involved in various diseases. In diseases, the IL-6 inhibitory strategy begins with the development of the anti-IL-6 receptor antibody, tocilizumab (TCZ). This antibody has shown remarkable effects on Castleman disease, rheumatoid arthritis and juvenile idiopathic arthritis. In 2017, TCZ was proven to work effectively against giant cell arteritis, Takayasu arteritis and cytokine releasing syndrome, initiating a new era for the treatment of these diseases. In this study, the defensive functions of IL-6 and various pathological conditions are compared. Further, the diseases of which TCZ has been approved for treatment are summarized, the updated results of increasing off label use of TCZ for various diseases are reviewed and the conditions for which IL-6 inhibition might have a beneficial role are discussed. Given the involvement of IL-6 in many pathologies, the diseases that can be improved by IL-6 inhibition will expand. However, the important role of IL-6 in host defense should always be kept in mind in clinical practice. PMID- 30423924 TI - A Comparative Analysis of Residential Energy Consumption in Urban and Rural China: Determinants and Regional Disparities. AB - Residential energy consumption (REC) has become increasingly important in constructing an energy-saving and environment-friendly society in China. The main purpose of this study is to provide a more in-depth analysis of the determinants of REC from an urban-rural segregation perspective, and quantify the contributions of individual determinants to the regional disparities of REC. Based on the extended STIRPAT (the stochastic impacts by regression on population, affluence, and technology) model, seemingly unrelated regression (SUR) estimation is employed to examine the impacts of various determinants of urban REC per capita (URECP) and rural REC per capita (RRECP) in a sample of China's 30 provinces over the period 2007-2016. Then, following the results of SUR, this paper tries to explore the reasons for interprovincial disparities of URECP and RRECP by using the Shapley value decomposition. The empirical results show that income level and heating lead to an increase in URECP, while other factors, including the share of natural gas, average temperature, child dependency ratio and gross dependency ratio, significantly decrease URECP. In terms of RRECP, it is shown that old-age dependency ratio, income level and the share of coal consumption positively influence RRECP, while average temperature has a negative effect on RRECP. Specially, the effect of gross dependency ratio on RRECP is positive, indicating the non-working-age population causes more energy use than the working-age population in rural areas. According to the Shapley decomposition, rather than social-economic variables, climate and heating factors contribute the most to the interprovincial differences in URECP. Furthermore, it is found that income level is the most important factor accounting for inter-provincial differences in RRECP. The findings of this research are of great interest, not only to scholars in REC-related fields, but also to decision makers. PMID- 30423925 TI - Preparation and Characterization of Phenolic Foam Modified with Bio-Oil. AB - Bio-oil was added as a substitute for phenol for the preparation of a foaming phenolic resin (PR), which aimed to reduce the brittleness and pulverization of phenolic foam (PF). The components of bio-oil, the chemical structure of bio-oil phenolic resin (BPR), and the mechanical performances, and the morphological and thermal properties of bio-oil phenolic foam (BPF) were investigated. The bio-oil contained a number of phenols and abundant substances with long-chain alkanes. The peaks of OH groups, CH2 groups, C=O groups, and aromatic skeletal vibration on the Fourier transform infrared (FT-IR) spectrum became wider and sharper after adding bio-oil. These suggested that the bio-oil could partially replace phenol to prepare resin and had great potential for toughening resin. When the substitute rate of bio-oil to phenol (B/P substitute rate) was between 10% and 20%, the cell sizes of BPFs were smaller and more uniform than those of PF. The compressive strength and flexural strength of BPFs with a 10-20% B/P substitute rate increased by 10.5-47.4% and 25.0-50.5% respectively, and their pulverization ratios decreased by 14.5-38.6% in comparison to PF. All BPFs maintained good flame-retardant properties, thermal stability, and thermal isolation, although the limited oxygen index (LOI) and residual masses by thermogravimetric (TG) analysis of BPFs were lower and the thermal conducticity was slightly greater than those of PF. This indicated that the bio-oil could be used as a renewable toughening agent for PF. PMID- 30423926 TI - Effect of the Preparation Method (Sol-Gel or Hydrothermal) and Conditions on the TiO2 Properties and Activity for Propene Oxidation. AB - Since the two most commonly used methods for TiO2 preparation are sol-gel (SG) and hydrothermal (HT) synthesis, this study attempts to compare both methods in order to determine which one is the most suitable to prepare photocatalysts for propene oxidation. In addition, this work studies how the concentration of the HCl used for hydrolysis of the TiO2 precursor affects the properties of the obtained materials. Also, the effect of avoiding the post-synthesis heat treatment in a selection of samples is investigated. The photocatalysts are characterized by XRD, N2 adsorption-desorption isotherms and UV-vis spectroscopy, and the study tries to correlate the properties with the photocatalytic performance of the prepared TiO2 samples in propene oxidation. TiO2 materials with high crystallinity, between 67% and 81%, and surface area (up to 134 m2/g) have been obtained both by SG and HT methods. In general, the surface area and pore volume of the TiO2-HT samples are larger than those of TiO2-SG ones. The TiO2-HT catalysts are, in general, more active than TiO2-SG materials or P25 in the photo-oxidation of propene. The effect of HCl presence during the TiO2 synthesis and of the post synthesis heat treatment are much more marked in the case of the SG materials. PMID- 30423927 TI - Structural Studies of the 3',3'-cGAMP Riboswitch Induced by Cognate and Noncognate Ligands Using Molecular Dynamics Simulation. AB - Riboswtich RNAs can control gene expression through the structural change induced by the corresponding small-molecule ligands. Molecular dynamics simulations and free energy calculations on the aptamer domain of the 3',3'-cGAMP riboswitch in the ligand-free, cognate-bound and noncognate-bound states were performed to investigate the structural features of the 3',3'-cGAMP riboswitch induced by the 3',3'-cGAMP ligand and the specificity of ligand recognition. The results revealed that the aptamer of the 3',3'-cGAMP riboswitch in the ligand-free state has a smaller binding pocket and a relatively compact structure versus that in the 3',3'-cGAMP-bound state. The binding of the 3',3'-cGAMP molecule to the 3',3' cGAMP riboswitch induces the rotation of P1 helix through the allosteric communication from the binding sites pocket containing the J1/2, J1/3 and J2/3 junction to the P1 helix. Simultaneously, these simulations also revealed that the preferential binding of the 3',3'-cGAMP riboswitch to its cognate ligand, 3',3'-cGAMP, over its noncognate ligand, c-di-GMP and c-di-AMP. The J1/2 junction in the 3',3'-cGAMP riboswitch contributing to the specificity of ligand recognition have also been found. PMID- 30423929 TI - Herbs and Spices in the Treatment of Functional Gastrointestinal Disorders: A Review of Clinical Trials. AB - More than fifty percent of all new patient visits to pediatric gastroenterology clinics consult for functional abdominal pain disorders (FAPDs). In 2005, a technical report of the American Academy of Pediatrics and the North American Pediatric Gastroenterology, Hepatology and Nutrition society (NASPGHAN) found limited or inconclusive evidence for most therapeutic interventions for this group of disorders. The report did not include studies on herbs and spices. Since then, there has been an increasing interest in the use of complementary and alternative medicine (CAM) for the treatment of chronic pain disorders in children. About 40% of parents of pediatric gastroenterology patients have utilized CAM. This review evaluated the published literature on the effectiveness of CAM, specifically the use of herbs and spices, for the treatment of FAPDs. We found little evidence for most of the commonly used herbs and spices. Despite its common use, research on the efficacy, safety, and optimal dosage remains limited. There is evidence to suggest the benefit of peppermint oil and STW 5 for the treatment of FAPDs in children. The paucity of data on most therapies underscores the need for large clinical trials to assess their efficacy. PMID- 30423928 TI - miR-338-3p Is Regulated by Estrogens through GPER in Breast Cancer Cells and Cancer-Associated Fibroblasts (CAFs). AB - Estrogens acting through the classic estrogen receptors (ERs) and the G protein estrogen receptor (GPER) regulate the expression of diverse miRNAs, small sequences of non-coding RNA involved in several pathophysiological conditions, including breast cancer. In order to provide novel insights on miRNAs regulation by estrogens in breast tumor, we evaluated the expression of 754 miRNAs by TaqMan Array in ER-negative and GPER-positive SkBr3 breast cancer cells and cancer associated fibroblasts (CAFs) upon 17beta-estradiol (E2) treatment. Various miRNAs were regulated by E2 in a peculiar manner in SkBr3 cancer cells and CAFs, while miR-338-3p displayed a similar regulation in both cell types. By METABRIC database analysis we ascertained that miR-338-3p positively correlates with overall survival in breast cancer patients, according to previous studies showing that miR-338-3p may suppress the growth and invasion of different cancer cells. Well-fitting with these data, a miR-338-3p mimic sequence decreased and a miR-338 3p inhibitor sequence rescued the expression of genes and the proliferative effects induced by E2 through GPER in SkBr3 cancer cells and CAFs. Altogether, our results provide novel evidence on the molecular mechanisms by which E2 may regulate miR-338-3p toward breast cancer progression. PMID- 30423930 TI - Rituximab and Fibrillary Glomerulonephritis: Interest of B Cell Reconstitution Monitoring. AB - Fibrillary glomerulonephritis (FGN) is a rare glomerular disease characterized by glomerular deposition of randomly arranged non-amyloid fibrils. FGN has a poor renal prognosis and its optimal treatment is a medical challenge. Rituximab therapy has recently emerged as a promising approach even though its mechanism of action remains hypothetical. We describe the case of a 55-year-old woman with FGN successfully treated by rituximab. During the 36-month follow-up, she had three relapses of FGN, occurring each time in the context of B cell recovery. Investigation of the distribution of B cell subpopulations at the time of the third relapse showed, as previously described for some immunological diseases, an increase in the proportion of switched memory B cells relative to healthy subjects, whereas global memory B cell pool was not yet recovered. This case suggests that B cell reconstitution should be carefully monitored in the management of FGN treated with rituximab. PMID- 30423932 TI - An Inductive Sensing System to Measure In-Socket Residual Limb Displacements for People Using Lower-Limb Prostheses. AB - The objective of this research was to assess the performance of an embedded sensing system designed to measure the distance between a prosthetic socket wall and residual limb. Low-profile inductive sensors were laminated into prosthetic sockets and flexible ferromagnetic targets were created from elastomeric liners with embedded iron particles for four participants with transtibial amputation. Using insights from sensor performance testing, a novel calibration procedure was developed to quickly and accurately calibrate the multiple embedded sensors. The sensing system was evaluated through laboratory tests in which participants wore sock combinations with three distinct thicknesses and conducted a series of activities including standing, walking, and sitting. When a thicker sock was worn, the limb typically moved further away from the socket and peak-to-peak displacements decreased. However, sensors did not measure equivalent distances or displacements for a given sock combination, which provided information regarding the fit of the socket and how a sock change intervention influenced socket fit. Monitoring of limb-socket displacements may serve as a valuable tool for researchers and clinicians to quantitatively assess socket fit. PMID- 30423931 TI - Comparative Effects of Coenzyme Q10 or n-3 Polyunsaturated Fatty Acid Supplementation on Retinal Angiogenesis in a Rat Model of Oxygen-Induced Retinopathy. AB - Neonatal intermittent hypoxia (IH) or apnea afflicts 70% to 90% of all preterm infants <28 weeks gestation, and is associated with severe retinopathy of prematurity (ROP). We tested the hypotheses that coenzyme Q10 (CoQ10) or omega-3 polyunsaturated fatty acids (n-3 PUFAs) supplementation during neonatal IH reduces the severity of oxygen-induced retinopathy (OIR). Newborn rats were exposed to two IH paradigms: (1) 50% O2 with brief hypoxia (12% O2); or (2) 21% O2 with brief hypoxia, until postnatal day 14 (P14), during which they received daily oral CoQ10 in olive oil, n-3 PUFAs in fish oil, or olive oil only and compared to room air (RA) treated groups. Pups were examined at P14, or placed in RA until P21. Retinal angiogenesis, histopathology, and morphometry were determined. Both IH paradigms produced severe OIR, but these were worsened with 50/12% O2 IH. CoQ10 and n-3 PUFAs reduced the severity of OIR, as well as ocular growth factors in both IH paradigms, but CoQ10 was more effective in 50/12% O2 IH. Supplementation with either CoQ10 or n-3 PUFAs targeting IH-induced retinal injury is individually effective for ameliorating specific characteristics consistent with ROP. Given the complexity of ROP, further studies are needed to determine whether combined CoQ10 and n-3 PUFAs supplementation would optimize their efficacy and result in a better outcome. PMID- 30423933 TI - A Genomic Survey of Angiotensin-Converting Enzymes Provides Novel Insights into Their Molecular Evolution in Vertebrates. AB - Angiotensin-converting enzymes, ACE and ACE2, are two main elements in the renin angiotensin system, with a crucial role in the regulation of blood pressure in vertebrates. Previous studies paid much attention to their physiological functions in model organisms, whereas the studies on other animals and related evolution have been sparse. Our present study performed a comprehensive genomic investigation on ace and ace2 genes in vertebrates. We successfully extracted the nucleotide sequences of ace and ace2 genes from high-quality genome assemblies of 36 representative vertebrates. After construction of their evolutionary tree, we observed that most of the phylogenetic positions are consistent with the species tree; however, certain differences appear in coelacanths and frogs, which may suggest a very slow evolutionary rate in the initial evolution of ace and ace2 in vertebrates. We further compared evolutionary rates within the entire sequences of ace and ace2, and determined that ace2 evolved slightly faster than ace. Meanwhile, we counted that the exon numbers of ace and ace2 in vertebrates are usually 25 and 18 respectively, while certain species may occur exon fusion or disruption to decrease or increase their exon numbers. Interestingly, we found three homologous regions between ace and ace2, suggesting existence of gene duplication during their evolutionary process. In summary, this report provides novel insights into vertebrate ace and ace2 genes through a series of genomic and molecular comparisons. PMID- 30423936 TI - The Long Journey of Pollen Tube in the Pistil. AB - In non-cleistogamous plants, the male gametophyte, the pollen grain is immotile and exploits various agents, such as pollinators, wind, and even water, to arrive to a receptive stigma. The complex process of pollination involves a tubular structure, i.e., the pollen tube, which delivers the two sperm cells to the female gametophyte to enable double fertilization. The pollen tube has to penetrate the stigma, grow in the style tissues, pass through the septum, grow along the funiculus, and navigate to the micropyle of the ovule. It is a long journey for the pollen tube and its two sperm cells before they meet the female gametophyte, and it requires very accurate regulation to perform successful fertilization. In this review, we update the knowledge of molecular dialogues of pollen-pistil interaction, especially the progress of pollen tube activation and guidance, and give perspectives for future research. PMID- 30423934 TI - Cow's Milk Protein Allergy in Infancy: A Risk Factor for Functional Gastrointestinal Disorders in Children? AB - The role and prevalence of cow's milk protein allergy (CMA) in functional gastrointestinal disorders remains unclear. The aim of this review is to update knowledge on the relationship between CMA and functional abdominal pain disorders (FAPDs) in children. Cochrane Database and Pubmed were searched from inception using general and specific terms for CMA and functional gastrointestinal disorders. CMA is reported as a predisposing or coexisting factor in a wide range of functional gastrointestinal disorders in infants and children. Pathogenesis of both conditions is complex and multiple mechanisms including dysmotility and hypersensitivity might contribute to the clinical manifestations. Data supporting the possible role of food allergies in the pathogenesis of FAPDs are limited. CMA may predispose to early life inflammation and visceral hypersensitivity, which in turn might manifest as FAPDs. The diagnosis of either CMA or FAPDs and distinction between them is challenging because of nonspecific and overlapping symptoms. Lack of accurate allergy tests in non-IgE (immunoglobulin E) mediated cases is also problematic. Oral food challenge, following an elimination diet, should be performed to diagnose a suspected non-IgE CMA allergy in children with FAPDs. In the management of FAPDs, an elimination diet should be considered for a limited period to verify if the symptoms improve or resolve. PMID- 30423935 TI - Calcium Pathways in Human Neutrophils-The Extended Effects of Thapsigargin and ML 9. AB - In neutrophils, intracellular Ca2+ levels are regulated by several transporters and pathways, namely SERCA [sarco(endo)plasmic reticulum Ca2+-ATPase], SOCE (store-operated calcium entry), and ROCE (receptor-operated calcium entry). However, the exact mechanisms involved in the communication among these transporters are still unclear. In the present study, thapsigargin, an irreversible inhibitor of SERCA, and ML-9, a broadly used SOCE inhibitor, were applied in human neutrophils to better understand their effects on Ca2+ pathways in these important cells of the immune system. The thapsigargin and ML-9 effects in the intracellular free Ca2+ flux were evaluated in freshly isolated human neutrophils, using a microplate reader for monitoring fluorimetric kinetic readings. The obtained results corroborate the general thapsigargin-induced intracellular pattern of Ca2+ fluctuation, but it was also observed a much more extended effect in time and a clear sustained increase of Ca2+ levels due to its influx by SOCE. Moreover, it was obvious that ML-9 enhanced the thapsigargin induced emptying of the internal stores. Indeed, ML-9 does not have this effect by itself, which indicates that, in neutrophils, thapsigargin does not act only on the influx by SOCE, but also by other Ca2+ pathways, that, in the future, should be further explored. PMID- 30423937 TI - Noise-Seeded Developmental Pattern Formation in Filamentous Cyanobacteria. AB - Under nitrogen-poor conditions, multicellular cyanobacteria such as Anabaena sp. PCC 7120 undergo a process of differentiation, forming nearly regular, developmental patterns of individual nitrogen-fixing cells, called heterocysts, interspersed between intervals of vegetative cells that carry out photosynthesis. Developmental pattern formation is mediated by morphogen species that can act as activators and inhibitors, some of which can diffuse along filaments. We survey the limitations of the classical, deterministic Turing mechanism that has been often invoked to explain pattern formation in these systems, and then, focusing on a simpler system governed by birth-death processes, we illustrate pedagogically a recently proposed paradigm that provides a much more robust description of pattern formation: stochastic Turing patterns. We emphasize the essential role that cell-to-cell differences in molecular numbers-caused by inevitable fluctuations in gene expression-play, the so called demographic noise, in seeding the formation of stochastic Turing patterns over a much larger region of parameter space, compared to their deterministic counterparts. PMID- 30423938 TI - Cathepsin S Alters the Expression of Pro-Inflammatory Cytokines and MMP-9, Partially through Protease-Activated Receptor-2, in Human Corneal Epithelial Cells. AB - Cathepsin S (CTSS) activity is increased in tears of Sjogren's syndrome (SS) patients. This elevated CTSS may contribute to ocular surface inflammation. Human corneal epithelial cells (HCE-T cells) were treated with recombinant human CTSS at activity comparable to that in SS patient tears for 2, 4, 8, and 24 h. Acute CTSS significantly increased HCE-T cell gene and protein expression of interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-alpha (TNF alpha), and interleukin-1beta (IL-1beta) from 2 to 4 h, while matrix metalloproteinase 9 (MMP-9), CTSS, and protease-activated receptor-2 (PAR-2) were increased by chronic CTSS (24 h). To investigate whether the increased pro inflammatory cytokines and proteases were induced by CTSS activation of PAR-2, HCE-T cells were transfected with PAR-2 siRNA, reducing cellular PAR-2 by 45%. Cells with reduced PAR-2 expression showed significantly reduced release of IL-6, TNF-alpha, IL-1beta, and MMP-9 into culture medium in response to acute CTSS, while IL-6, TNF-alpha, and MMP-9 were reduced in culture medium, and IL-6 and MMP 9 in cell lysates, after chronic CTSS. Moreover, cells with reduced PAR-2 expression showed reduced ability of chronic CTSS to induce gene expression of pro-inflammatory cytokines and proteases. CTSS activation of PAR-2 may represent a potential therapeutic target for amelioration of ocular surface inflammation in SS patients. PMID- 30423939 TI - Molecular Modeling and Design Studies of Purine Derivatives as Novel CDK2 Inhibitors. AB - Cyclin-dependent kinase 2 (CDK2) is a potential target for treating cancer. Purine heterocycles have attracted particular attention as the scaffolds for the development of CDK2 inhibitors. To explore the interaction mechanism and the structure-activity relationship (SAR) and to design novel candidate compounds as potential CDK2 inhibitors, a systematic molecular modeling study was conducted on 35 purine derivatives as CDK2 inhibitors by combining three-dimensional quantitative SAR (3D-QSAR), virtual screening, molecular docking, and molecular dynamics (MD) simulations. The predictive CoMFA model (q2 = 0.743, r pred 2 = 0.991), the CoMSIA model (q2 = 0.808, r pred 2 = 0.990), and the Topomer CoMFA model (q2 = 0.779, r pred 2 = 0.962) were obtained. Contour maps revealed that the electrostatic, hydrophobic, hydrogen bond donor and steric fields played key roles in the QSAR models. Thirty-one novel candidate compounds with suitable predicted activity (predicted pIC50 > 8) were designed by using the results of virtual screening. Molecular docking indicated that residues Asp86, Glu81, Leu83, Lys89, Lys33, and Gln131 formed hydrogen bonds with the ligand, which affected activity of the ligand. Based on the QSAR model prediction and molecular docking, two candidate compounds, I13 and I60 (predicted pIC50 > 8, docking score > 10), with the most potential research value were further screened out. MD simulations of the corresponding complexes of these two candidate compounds further verified their stability. This study provided valuable information for the development of new potential CDK2 inhibitors. PMID- 30423940 TI - Deoxynivalenol Affects Cell Metabolism and Increases Protein Biosynthesis in Intestinal Porcine Epithelial Cells (IPEC-J2): DON Increases Protein Biosynthesis. AB - Deoxynivalenol (DON) is a toxin found in cereals as well as in processed products such as pasta, and causes substantial economic losses for stock breeding as it induces vomiting, reduced feeding, and reduced growth rates in piglets. Oxidative phosphorylation, TCA-cycle, transcription, and translation have been hypothesized to be leading pathways that are affected by DON. We used an application of high and low glucose to examine oxidative phosphorylation and anaerobic glycolysis. A change in the metabolic status of IPEC-J2 was observed and confirmed by microarray data. Measurements of oxygen consumption resulted in a significant reduction, if DON attacks from the basolateral. Furthermore, we found a dose dependent effect with a significant reduction at 2000 ng/mL. In addition, SLC7A11 and PHB, the genes with the highest regulation in our microarray analyses under low glucose supply, were investigated and showed a variable regulation on protein level. Lactate production and glucose consumption was investigated to examine the impact of DON on anaerobic glycolysis and we observed a significant increase in 2000 blhigh and a decrease in 2000 aphigh. Interestingly, both groups as well as 200 blhigh showed a significant higher de novo protein synthesis when compared to the control. These results indicate the direct or indirect impact of DON on metabolic pathways in IPEC-J2. PMID- 30423941 TI - Experimental and Modeling Study of Drug Release from HPMC-Based Erodible Oral Thin Films. AB - In this work hydroxypropyl methylcellulose (HPMC) fast-dissolving thin films for oral administration are investigated. Furosemide (Class IV of the Biopharmaceutical Classification System) has been used as a model drug for in vitro release tests using three different set-ups: the Franz cell, the millifluidic flow-through device, and the paddle type dissolution apparatus (USP II). In order to enable drug incorporation within HPMC films, a multifunctional excipient, hydroxypropyl- beta -cyclodextrin (HP- beta -CD) has been included in the formulation, and the influence of HP- beta -CD on film swelling, erosion, and release properties has been investigated. Mathematical models capable of describing the swelling and release processes from HPMC erodible thin films in different apparatuses have been developed. In particular, we propose a new model for the description of drug transport and release in a Franz cell that accounts for the effect of the unavoidable imperfect mixing of the receptor chamber. PMID- 30423942 TI - Effects of a Pasty Bone Cement Containing Brain-Derived Neurotrophic Factor Functionalized Mesoporous Bioactive Glass Particles on Metaphyseal Healing in a New Murine Osteoporotic Fracture Model. AB - The development of new and better implant materials adapted to osteoporotic bone is still urgently required. Therefore, osteoporotic muscarinic acetylcholine receptor M3 (M3 mAChR) knockout (KO) and corresponding wild type (WT) mice underwent osteotomy in the distal femoral metaphysis. Fracture gaps were filled with a pasty alpha-tricalcium phosphate (alpha-TCP)-based hydroxyapatite (HA) forming bone cement containing mesoporous bioactive CaP-SiO2 glass particles (cement/MBG composite) with or without Brain-Derived Neurotrophic Factor (BDNF) and healing analyzed after 35 days. Histologically, bone formation was significantly increased in WT mice that received the BDNF-functionalized cement/MBG composite compared to control WT mice without BDNF. Cement/MBG composite without BDNF increased bone formation in M3 mAChR KO mice compared to equally treated WT mice. Mass spectrometric imaging showed that the BDNF functionalized cement/MBG composite implanted in M3 mAChR KO mice was infiltrated by newly formed tissue. Leukocyte numbers were significantly lower in M3 mAChR KO mice treated with BDNF-functionalized cement/MBG composite compared to controls without BDNF. C-reactive protein (CRP) concentrations were significantly lower in M3 mAChR KO mice that received the cement/MBG composite without BDNF when compared to WT mice treated the same. Whereas alkaline phosphatase (ALP) concentrations in callus were significantly increased in M3 mAChR KO mice, ALP activity was significantly higher in WT mice. Due to a stronger effect of BDNF in non osteoporotic mice, higher BDNF concentrations might be needed for osteoporotic fracture healing. Nevertheless, the BDNF-functionalized cement/MBG composite promoted fracture healing in non osteoporotic bone. PMID- 30423944 TI - Better Resolution of High-Spin Cobalt Hyperfine at Low Frequency: Co-Doped Ba(Zn1/3Ta2/3)O3 as a Model Complex. AB - Low-frequency electron paramagnetic resonance (EPR) is used to extract the EPR parameter A-mid and support the approximate X-band value of g-mid for Ba(CoyZn1/3 yTa2/3)O3. Although the cobalt hyperfine structure for the |+/-1/2⟩ state is often unresolved at X-band or S-band, it is resolved in measurements on this compound. This allows for detailed analysis of the molecular orbital for the |+/ 1/2⟩ state, which is often the ground state. Moreover, this work shows that the EPR parameters for Co substituted into Zn compounds give important insight into the properties of zinc binding sites. PMID- 30423943 TI - Multifunctional Platform Based on Electroactive Polymers and Silica Nanoparticles for Tissue Engineering Applications. AB - Poly(vinylidene fluoride) nanocomposites processed with different morphologies, such as porous and non-porous films and fibres, have been prepared with silica nanoparticles (SiNPs) of varying diameter (17, 100, 160 and 300 nm), which in turn have encapsulated perylenediimide (PDI), a fluorescent molecule. The structural, morphological, optical, thermal, and mechanical properties of the nanocomposites, with SiNP filler concentration up to 16 wt %, were evaluated. Furthermore, cytotoxicity and cell proliferation studies were performed. All SiNPs are negatively charged independently of the pH and more stable from pH 5 upwards. The introduction of SiNPs within the polymer matrix increases the contact angle independently of the nanoparticle diameter. Moreover, the smallest ones (17 nm) also improve the PVDF Young's modulus. The filler diameter, physico chemical, thermal and mechanical properties of the polymer matrix were not significantly affected. Finally, the SiNPs' inclusion does not induce cytotoxicity in murine myoblasts (C2C12) after 72 h of contact and proliferation studies reveal that the prepared composites represent a suitable platform for tissue engineering applications, as they allow us to combine the biocompatibility and piezoelectricity of the polymer with the possible functionalization and drug encapsulation and release of the SiNP. PMID- 30423945 TI - Preparation and Thermal Performance Enhancement of Low Temperature Eutectic Composite Phase Change Materials Based on Na2SO4.10H2O. AB - In this paper, a series of Na2SO4.10H2O-KCl eutectic mixtures were prepared by adding different mass fractions of KCl (1 wt.%, 3 wt.%, 5 wt.%, or 7 wt.%) to Na2SO4.10H2O. Polyacrylamide (PAM) was proposed as the thickener, sodium tetraborate decahydrate (STD) was proposed as the nucleating agent, and expanded graphite (EG) was proposed as the high thermal conductivity medium for Na2SO4.10H2O-5 wt.% KCl eutectics. The results showed that in Na2SO4.10H2O-5 wt.% KCl eutectics with 5 wt.% PAM and 5 wt.% STD, almost no phase separation occurred, and the degree of supercooling was reduced to 0.4 degrees C. The thermal performance of Na2SO4.10H2O-5 wt.% KCl composite phase change materials (CPCMs) with varying contents of EG was explored. The results showed that EG could improve the thermal conductivity effectively and that the mass fraction of EG should be no more than 3%, otherwise the crystallization value and supercooling would deteriorate. The thermal reliability of the Na2SO4.10H2O-5 wt.% KCl eutectic CPCMs containing 5 wt.% PAM, 5 wt.% STD, and 3 wt.% EG was investigated, mainly through the ambient temperature, thermal cycling test, and TGA analysis. The results demonstrated that these CPCMs showed perfect thermal reliability. PMID- 30423946 TI - Imaging the Polymorphic Transformation in a Single Cu6Sn5 Grain in a Solder Joint. AB - In-situ observations of the polymorphic transformation in a single targeted Cu6Sn5 grain constrained between Sn-0.7 wt % Cu solder and Cu-Cu3Sn phases and the associated structural evolution during a solid-state thermal cycle were achieved via a high-voltage transmission electron microscope (HV-TEM) technique. Here, we show that the monoclinic eta'-Cu6Sn5 superlattice reflections appear in the hexagonal eta-Cu6Sn5 diffraction pattern upon cooling to isothermal 140 degrees C from 210 degrees C. The in-situ real space imaging shows that the eta' Cu6Sn5 contrast pattern is initiated at the grain boundary. This method demonstrates a new approach for further understanding the polymorphic transformation behavior on a real solder joint. PMID- 30423947 TI - Quinazolin-4(3H)-ones and 5,6-Dihydropyrimidin-4(3H)-ones from beta-Aminoamides and Orthoesters. AB - Quinazolin-4(3H)-ones have been prepared in one step from 2-aminobenzamides and orthoesters in the presence of acetic acid. Simple 2-aminobenzamides were easily converted to the heterocycles by refluxing in absolute ethanol with 1.5 equivalents of the orthoester and 2 equivalents of acetic acid for 12-24 h. Ring substituted and hindered 2-aminobenzamides as well as cases incorporating an additional basic nitrogen required pressure tube conditions with 3 equivalents each of the orthoester and acetic acid in ethanol at 110 degrees C for 12-72 h. The reaction was tolerant towards functionality on the benzamide and a range of structures was accessible. Workup involved removal of the solvent under vacuum and either recrystallization from ethanol or trituration with ether-pentane. Several 5,6-dihydropyrimidin-4(3H)-ones were also prepared from 3-amino-2,2 dimethylpropionamide. All products were characterized by melting point, FT-IR, 1H NMR, 13C-NMR, and HRMS. PMID- 30423948 TI - Challenges and Opportunities for UAV-Based Digital Elevation Model Generation for Flood-Risk Management: A Case of Princeville, North Carolina. AB - Among the different types of natural disasters, floods are the most devastating, widespread, and frequent. Floods account for approximately 30% of the total loss caused by natural disasters. Accurate flood-risk mapping is critical in reducing such damages by correctly predicting the extent of a flood when coupled with rain and stage gage data, supporting emergency-response planning, developing land use plans and regulations with regard to the construction of structures and infrastructures, and providing damage assessment in both spatial and temporal measurements. The reliability and accuracy of such flood assessment maps is dependent on the quality of the digital elevation model (DEM) in flood conditions. This study investigates the quality of an Unmanned Aerial Vehicle (UAV)-based DEM for spatial flood assessment mapping and evaluating the extent of a flood event in Princeville, North Carolina during Hurricane Matthew. The challenges and problems of on-demand DEM production during a flooding event were discussed. An accuracy analysis was performed by comparing the water surface extracted from the UAV-derived DEM with the water surface/stage obtained using the nearby US Geologic Survey (USGS) stream gauge station and LiDAR data. PMID- 30423949 TI - Tuneable Q-Factor of MEMS Cantilevers with Integrated Piezoelectric Thin Films. AB - In atomic force microscopes (AFM) a resonantly excited, micro-machined cantilever with a tip is used for sensing surface-related properties. When targeting the integration of AFMs into vacuum environments (e.g., for enhancing the performance of scanning electron microscopes), a tuneable Q-factor of the resonating AFM cantilever is a key feature to enable high speed measurements with high local resolution. To achieve this goal, in this study an additional mechanical stimulus is applied to the cantilever with respect to the stimulus provided by the macroscopic piezoelectric actuator. This additional stimulus is generated by an aluminum nitride piezoelectric thin film actuator integrated on the cantilever, which is driven by a phase shifted excitation. The Q-factor is determined electrically by the piezoelectric layer in a Wheatstone bridge configuration and optically verified in parallel with a laser Doppler vibrometer. Depending on the measurement technique, the Q-factor is reduced by a factor of about 1.9 (electrically) and 1.6 (optically), thus enabling the damping of MEMS structures with a straight-forward and cheap electronic approach. PMID- 30423950 TI - Spray Deposition of Ag Nanowire-Graphene Oxide Hybrid Electrodes for Flexible Polymer-Dispersed Liquid Crystal Displays. AB - We investigated the effect of different spray-coating parameters on the electro optical properties of Ag nanowires (NWs). Highly transparent and conductive Ag NW graphene oxide (GO) hybrid electrodes were fabricated by using the spray-coating technique. The Ag NW percolation network was modified with GO and this led to a reduced sheet resistance of the Ag NW-GO electrode as the result of a decrease in the inter-nanowire contact resistance. Although electrical conductivity and optical transmittance of the Ag NW electrodes have a trade-off relationship, Ag NW-GO hybrid electrodes exhibited significantly improved sheet resistance and slightly decreased transmittance compared to Ag NW electrodes. Ag NW-GO hybrid electrodes were integrated into smart windows based on polymer-dispersed liquid crystals (PDLCs) for the first time. Experimental results showed that the electro optical properties of the PDLCs based on Ag NW-GO electrodes were superior when compared to those of PDLCs based on only Ag NW electrodes. This study revealed that the hybrid Ag NW-GO electrode is a promising material for manufacturing the large-area flexible indium tin oxide (ITO)-free PDLCs. PMID- 30423951 TI - 20-Nor-Isopimarane Epimers Produced by Aspergillus wentii SD-310, a Fungal Strain Obtained from Deep Sea Sediment. AB - Four new uncommon 20-nor-isopimarane diterpenoid epimers, aspewentins I-L (1-4), together with a new methylated derivative of 3, aspewentin M (5), were isolated from the deep sea sediment-derived fungus Aspergillus wentii SD-310. The very similar structures of these epimers made the separation and purification procedures difficult. The structures of compounds 1-5 were illustrated based on spectroscopic analysis, and the absolute configurations of compounds 1-5 were unambiguously determined by the combination of NOESY, time-dependent density functional (TDDFT)-ECD calculations, and X-ray crystallographic analysis. These metabolites represented the rare examples of 20-nor-isopimarane analogues possessing a cyclohexa-2,5-dien-1-one moiety. These compounds were tested for antimicrobial activities against human and aquatic pathogenic bacteria, as well as plant-pathogenic fungi. While compounds 1 and 2 exhibited inhibitory activities against zoonotic pathogenic bacteria such as Escherichia coli, Edwardsiella tarda, Vibrio harveyi, and V. parahaemolyticus, compound 5 showed potent activity against the plant pathogen Fusarium graminearum. PMID- 30423952 TI - Anticancer Activity of Natural Compounds from Plant and Marine Environment. AB - This paper describes the substances of plant and marine origin that have anticancer properties. The chemical structure of the molecules of these substances, their properties, mechanisms of action, their structure-activity relationships, along with their anticancer properties and their potential as chemotherapeutic drugs are discussed in this paper. This paper presents natural substances from plants, animals, and their aquatic environments. These substances include the vinca alkaloids, mistletoe plant extracts, podophyllotoxin derivatives, taxanes, camptothecin, combretastatin, and others including geniposide, colchicine, artesunate, homoharringtonine, salvicine, ellipticine, roscovitine, maytanasin, tapsigargin, and bruceantin. Compounds (psammaplin, didemnin, dolastin, ecteinascidin, and halichondrin) isolated from the marine plants and animals such as microalgae, cyanobacteria, heterotrophic bacteria, invertebrates (e.g., sponges, tunicates, and soft corals) as well as certain other substances that have been tested on cells and experimental animals and used in human chemotherapy. PMID- 30423954 TI - Online Moisture Measurement of Bio Fuel at a Paper Mill Employing a Microwave Resonator. AB - This paper investigates online moisture measurement of biofuel employing a strip line cavity resonator at approximately 366 MHz, attached above and below the conveyor belt. An existing sensor design is modified for the factory assembly, and the correct operation has been tested prior to this paper with a small number of measurement points and collected reference samples (n = 67). The purpose is now to concentrate on the accuracy of the measurement and increase the number of measurement points (n = 367). The measurements were made in 5 different lots, and the thickness and moisture properties of the biomaterial mat were varied between minimum and maximum levels by adjusting the settings of the belt filter press that presses pulp slush into a mat. In order to further reduce inaccuracy, at the maximum one standard deviation was allowed from the average height of the equivalent water layer for each dataset, and consequently the number of samples was reduced to 235. A linear fit and a parabola fit were determined for thickness of the equivalent water layer vs. the relative resonant frequency shift: R2 = 0.82 and R2 = 0.78. PMID- 30423953 TI - A Process Evaluation of a Multi-Component Intervention in Dutch Dietetic Treatment to Improve Portion Control Behavior and Decrease Body Mass Index in Overweight and Obese Patients. AB - The SMARTsize intervention embeds an evidence-based portion control intervention in regular dietetic care. This intervention was evaluated to explore (1) which patients participated, (2) the implementation process, and (3) the outcomes of the intervention. The intervention was evaluated with an observational study design including measures at baseline, and three, six, and nine months after the start of the program. Data concerning the process (participation, dose delivered, dose received, satisfaction) and the outcomes (self-efficacy, intention, portion control strategies, and Body Mass Index (BMI) were collected with forms and questionnaires filled out by dietitians and patients. Descriptive analyses, comparison analyses, and cluster analyses were performed. Patients were mainly obese, moderately to highly educated women of Dutch ethnicity. Use of the intervention components varied from 50% to 100% and satisfaction with the SMARTsize intervention was sufficient to good (grades 7.2-8.0). Statistically significant (p < 0.001) improvements were observed for self-efficacy (+0.5), portion control strategies (+0.7), and BMI (-2.2 kg/m2), with no significant differences between patients with or without counselling. Three clusters of patients with different levels of success were identified. To conclude, implementing an evidence-based portion control intervention in real-life dietetic practice is feasible and likely to result in weight loss. PMID- 30423955 TI - Increased Plasma Levels of Gut-Derived Phenolics Linked to Walking and Running Following Two Weeks of Flavonoid Supplementation. AB - Using a randomized, double-blinded, placebo-controlled, parallel group design, this investigation determined if the combination of two weeks of flavonoid supplementation (329 mg/day, quercetin, anthocyanins, flavan-3-ols mixture) and a 45-minute walking bout (62.2 +/- 0.9% VO2max (maximal oxygen consumption rate)) enhanced the translocation of gut-derived phenolics into circulation in a group of walkers (n = 77). The walkers (flavonoid, placebo groups) were randomized to either sit or walk briskly on treadmills for 45 min (thus, four groups: placebo sit, placebo-walk, flavonoid-sit, flavonoid-walk). A comparator group of runners (n = 19) ingested a double flavonoid dose for two weeks (658 mg/day) and ran for 2.5 h (69.2 +/- 1.2% VO2max). Four blood samples were collected (pre- and post supplementation, immediately post- and 24 h post-exercise/rest). Of the 76 metabolites detected in this targeted analysis, 15 increased after the 2.5 h run, and when grouped were also elevated post-exercise (versus placebo-sit) for the placebo- and flavonoid-walking groups (p < 0.05). A secondary analysis showed that pre-study plasma concentrations of gut-derived phenolics in the runners were 40% higher compared to walkers (p = 0.031). These data indicate that acute exercise bouts (brisk walking, intensive running) are linked to an increased translocation of gut-derived phenolics into circulation, an effect that is amplified when combined with a two-week period of increased flavonoid intake or chronic training as a runner. PMID- 30423956 TI - Enhanced In Vitro Antitumor Activity of GnRH-III-Daunorubicin Bioconjugates Influenced by Sequence Modification. AB - Receptors for gonadotropin releasing hormone (GnRH) are highly expressed in various human cancers including breast, ovarian, endometrial, prostate and colorectal cancer. Ligands like human GnRH-I or the sea lamprey analogue GnRH-III represent a promising approach for the development of efficient drug delivery systems for targeted tumor therapy. Here, we report on the synthesis and cytostatic effect of 14 oxime bond-linked daunorubicin GnRH-III conjugates containing a variety of unnatural amino acids within the peptide sequence. All compounds demonstrated a reduced cell viability in vitro on estrogen receptor alpha (ERalpha) positive and ERalpha negative cancer cells. The best candidate revealed an increased cancer cell growth inhibitory effect compared to our lead compound GnRH-III-[4Lys(Bu),8Lys(Dau=Aoa)]. Flow cytometry and fluorescence microscopy studies showed that the cellular uptake of the novel conjugate is substantially improved leading to an accelerated delivery of the drug to its site of action. However, the release of the active drug-metabolite by lysosomal enzymes was not negatively affected by amino acid substitution, while the compound provided a high stability in human blood plasma. Receptor binding studies were carried out to ensure a high binding affinity of the new compound for the GnRH-receptor. It was demonstrated that GnRH-III-[2DeltaHis,3d Tic,4Lys(Bu),8Lys(Dau=Aoa)] is a highly potent and promising anticancer drug delivery system for targeted tumor therapy. PMID- 30423957 TI - Comparison of Secular Trends in Road Injury Mortality in China and the United States: An Age-Period-Cohort Analysis. AB - This study aimed to identify and compare the mortality trends for road injuries in China and the United States, and evaluate the contributions of age, period, and cohort effects to the trends from 1990 to 2014. Using the 2016 Global Burden of Disease Study database, the mortality trends were analyzed by joinpoint regression and age-period-cohort modeling. Overall, the mortality for road injuries was higher in China than in the United States. The mortality in China increased from 1992 to 2002 (annual percent change [APC] was 1.9%), and then decreased from 2002 to 2015 (APC2002-2009 was 1.5%; APC2009-2015 was 3.5%). For the United States, the mortality decreased from 1990 to 2010 (APC1990-1997 was 1.8%; APC1997-2005 was 0.7%; APC2005-2010 was 4.2%). Age-period-cohort modeling revealed significant period and cohort effects. Compared with the period 2002 2004, the period risk ratios (RRs) in 2010-2014 period declined by 14.62% for China and 18.86% for the United States. Compared with the 1955-1959 birth cohort, the cohort RRs for China and the United States in the 2010-2014 cohort reduced by 47.60% and 75.94%, respectively. Period and cohort effects could not be ignored for reducing road injury mortalities. PMID- 30423958 TI - Dual-Emission Fluorescent Microspheres for the Detection of Biothiols and Hg2. AB - Dual-emission nanosensor for Hg2+ detection was prepared by coupling CA-AEAPMS on the surface of RBS-doped modified silica microspheres. The CA-AEAPMS was synthesized by using N-(beta-aminoethyl)-gamma-aminopropyl methyldimethoxysilane (AEAPMS) and citric acid as the main raw material. The obtained nanosensor showed characteristic fluorescence emissions of Rhodamine B (red) and CA-AEAPMS (blue) under a single excitation wavelength (360 nm). Upon binding to Hg2+, only the fluorescence of CA-AEAPMS was quenched, resulting in the ratiometric fluorescence response of the dual-emission silica microspheres. This ratiometric nanosensor exhibited good selectivity to Hg2+ over other metal ions, because of the amide groups on the surface of CA-AEAPMS serving as the Hg2+ recognition sites. The ratio of F450/F580 linearly decreased with the increasing of Hg2+ concentration in the range of 0 to 3 * 10-6 M, and a detection limit was as low as 97 nM was achieved. Then, the addition of three thiol-containing amino acids (Cys, Hcy, GSH) to the quenched fluorescence solution with Hg2+ can restore the fluorescence, and the detection limits of the three biothiols (Cys, Hcy, GSH) are 0.133 MUM, 0.086 MUM, and 0.123 MUM, respectively. PMID- 30423959 TI - CMV2b-Dependent Regulation of Host Defense Pathways in the Context of Viral Infection. AB - RNA silencing (or RNA interference, RNAi) plays direct roles in plant host defenses against viruses. Viruses encode suppressors of RNAi (VSRs) to counteract host antiviral defenses. The generation of transgenic plants expressing VSRs facilitates the understanding of the mechanisms of VSR-mediated interference with the endogenous silencing pathway. However, studying VSRs independent of other viral components simplifies the complex roles of VSRs during natural viral infection. While suppression of transgene silencing by the VSR 2b protein encoded by cucumber mosaic virus (CMV) requires 2b-small RNA (sRNA) binding activity, suppression of host antiviral defenses requires the binding activity of both sRNAs and AGOs proteins. This study, aimed to understand the functions of 2b in the context of CMV infection; thus, we performed genome-wide analyses of differential DNA methylation regions among wild-type CMV-infected, CMVDelta2b infected, and 2b-transgenic Arabidopsis plants. These analyses, together with transcriptome sequencing and RT-qPCR analyses, show that while the majority of induced genes in 2b-transgenic plants were involved in extensive metabolic pathways, CMV-infection 2b-dependent induced genes were enriched in plant immunity pathways, including salicylic acid (SA) signaling. Together with infection with CMV mutants that expressed the 2b functional domains of sRNA or AGO binding, our data demonstrate that CMV-accelerated SA signaling depends on 2b sRNA binding activity which is also responsible for virulence. PMID- 30423960 TI - Protective Effect of Pyrogallol-Phloroglucinol-6,6-Bieckol from Ecklonia cava on Monocyte-Associated Vascular Dysfunction. AB - Ecklonia cava (E. cava) can alleviate vascular dysfunction in diseases associated with poor circulation. E. cava contains various polyphenols with different functions, but few studies have compared the effects of these polyphenols. Here, we comparatively investigated four major compounds present in an ethanoic extract of E. cava. These four major compounds were isolated and their effects were examined on monocyte-associated vascular inflammation and dysfunctions. Pyrogallol-phloroglucinol-6,6-bieckol (PPB) significantly inhibited monocyte migration in vitro by reducing levels of inflammatory macrophage differentiation and of its related molecular factors. In addition, PPB protected against monocyte associated endothelial cell death by increasing the phosphorylations of PI3K-AKT and AMPK, decreasing caspase levels, and reducing monocyte-associated vascular smooth muscle cell proliferation and migration by decreasing the phosphorylations of ERK and AKT. The results of this study show that four compounds were effective for reduction of monocyte-associated vascular inflammation and dysfunctions, but PPB might be more useful for the treatment of vascular dysfunction in diseases associated with poor circulation. PMID- 30423961 TI - Investigation of New Orexin 2 Receptor Modulators Using In Silico and In Vitro Methods. AB - The neuropeptides, orexin A and orexin B (also known as hypocretins), are produced in hypothalamic neurons and belong to ligands for orphan G protein coupled receptors. Generally, the primary role of orexins is to act as excitatory neurotransmitters and regulate the sleep process. Lack of orexins may lead to sleep disorder narcolepsy in mice, dogs, and humans. Narcolepsy is a neurological disorder of alertness characterized by a decrease of ability to manage sleep-wake cycles, excessive daytime sleepiness, and other symptoms, such as cataplexy, vivid hallucinations, and paralysis. Thus, the discovery of orexin receptors, modulators, and their causal implication in narcolepsy is the most important advance in sleep-research. The presented work is focused on the evaluation of compounds L1-L11 selected by structure-based virtual screening for their ability to modulate orexin receptor type 2 (OX2R) in comparison with standard agonist orexin-A together with their blood-brain barrier permeability and cytotoxicity. We can conclude that the studied compounds possess an affinity towards the OX2R. However, the compounds do not have intrinsic activity and act as the antagonists of this receptor. It was shown that L4 was the most potent antagonistic ligand to orexin A and displayed an IC50 of 2.2 uM, offering some promise mainly for the treatment of insomnia. PMID- 30423962 TI - Road Surface Monitoring Using Smartphone Sensors: A Review. AB - Road surface monitoring is a key factor to providing smooth and safe road infrastructure to road users. The key to road surface condition monitoring is to detect road surface anomalies, such as potholes, cracks, and bumps, which affect driving comfort and on-road safety. Road surface anomaly detection is a widely studied problem. Recently, smartphone-based sensing has become increasingly popular with the increased amount of available embedded smartphone sensors. Using smartphones to detect road surface anomalies could change the way government agencies monitor and plan for road maintenance. However, current smartphone sensors operate at a low frequency, and undersampled sensor signals cause low detection accuracy. In this study, current approaches for using smartphones for road surface anomaly detection are reviewed and compared. In addition, further opportunities for research using smartphones in road surface anomaly detection are highlighted. PMID- 30423964 TI - Inter- and Intra-Host Nucleotide Variations in Hepatitis A Virus in Culture and Clinical Samples Detected by Next-Generation Sequencing. AB - The accurate virus detection, strain discrimination, and source attribution of contaminated food items remains a persistent challenge because of the high mutation rates anticipated to occur in foodborne RNA viruses, such as hepatitis A virus (HAV). This has led to predictions of the existence of more than one sequence variant between the hosts (inter-host) or within an individual host (intra-host). However, there have been no reports of intra-host variants from an infected single individual, and little is known about the accuracy of the single nucleotide variations (SNVs) calling with various methods. In this study, the presence and identity of viral SNVs, either between HAV clinical specimens or among a series of samples derived from HAV clone1-infected FRhK4 cells, were determined following analyses of nucleotide sequences generated using next generation sequencing (NGS) and pyrosequencing methods. The results demonstrate the co-existence of inter- and intra-host variants both in the clinical specimens and the cultured samples. The discovery and confirmation of multi-viral RNAs in an infected individual is dependent on the strain discrimination at the SNV level, and critical for successful outbreak traceback and source attribution investigations. The detection of SNVs in a time series of HAV infected FRhK4 cells improved our understanding on the mutation dynamics determined probably by different selective pressures. Additionally, it demonstrated that NGS could potentially provide a valuable investigative approach toward SNV detection and identification for other RNA viruses. PMID- 30423963 TI - Ursolic Acid Attenuates Hepatic Steatosis, Fibrosis, and Insulin Resistance by Modulating the Circadian Rhythm Pathway in Diet-Induced Obese Mice. AB - The aim of the current study was to elucidate the effects of long-term supplementation with dietary ursolic acid (UR) on obesity and associated comorbidities by analyzing transcriptional and metabolic responses, focusing on the role of UR in the modulation of the circadian rhythm pathway in particular. C57BL/6J mice were divided into three groups and fed a normal diet, high-fat diet, or high-fat + 0.05% (w/w) UR diet for 16 weeks. Oligonucleotide microarray profiling revealed that UR is an effective regulator of the liver transcriptome, and canonical pathways associated with the "circadian rhythm" and "extracellular matrix (ECM)-receptor interactions" were effectively regulated by UR in the liver. UR altered the expression of various clock and clock-controlled genes (CCGs), which may be linked to the improvement of hepatic steatosis and fibrosis via lipid metabolism control and detoxification enhancement. UR reduced excessive reactive oxygen species production, adipokine/cytokine dysregulation, and ECM accumulation in the liver, which also contributed to improve hepatic lipotoxicity and fibrosis. Moreover, UR improved pancreatic islet dysfunction, and suppressed hepatic gluconeogenesis, thereby reducing obesity-associated insulin resistance. Therapeutic approaches targeting hepatic circadian clock and CCGs using UR may ameliorate the deleterious effects of diet-induced obesity and associated complications such as hepatic fibrosis. PMID- 30423965 TI - Estimation of Neonatal Intestinal Perforation Associated with Necrotizing Enterocolitis by Machine Learning Reveals New Key Factors. AB - Intestinal perforation (IP) associated with necrotizing enterocolitis (NEC) is one of the leading causes of mortality in premature neonates; with major nutritional and neurodevelopmental sequelae. Since predicting which neonates will develop perforation is still challenging; clinicians might benefit considerably with an early diagnosis tool and the identification of critical factors. The aim of this study was to forecast IP related to NEC and to investigate the predictive quality of variables; based on a machine learning-based technique. The Back propagation neural network was used to train and test the models with a dataset constructed from medical records of the NICU; with birth and hospitalization maternal and neonatal clinical; feeding and laboratory parameters; as input variables. The outcome of the models was diagnosis: (1) IP associated with NEC; (2) NEC or (3) control (neither IP nor NEC). Models accurately estimated IP with good performances; the regression coefficients between the experimental and predicted data were R2 > 0.97. Critical variables for IP prediction were identified: neonatal platelets and neutrophils; orotracheal intubation; birth weight; sex; arterial blood gas parameters (pCO2 and HCO3); gestational age; use of fortifier; patent ductus arteriosus; maternal age and maternal morbidity. These models may allow quality improvement in medical practice. PMID- 30423966 TI - A Spatio-Temporal Pattern and Socio-Economic Factors Analysis of Improved Sanitation in China, 2006-2015. AB - Ensuring an adequate and safe access to sanitation is essential to prevent diseases. Using provincial spatial panel data reported in the China Health Statistical Yearbook and the China Statistical Yearbook, this paper analyzed the spatio-temporal characteristics of improved rural sanitation in 30 Chinese provinces during the period 2006-2015, and analyzed factors that may affect improved sanitation rates in rural China. Spatial autocorrelations of improved sanitation rates were computed via Global and Local Moran's I firstly, and then, inter-provincial disparities of improved sanitation were assessed by using the Theil index estimator; finally, the spatial panel model was employed to examine the potential socio-economic factors. Spatial autocorrelations results suggested that the provincial improved sanitation rates changes affect both the provinces themselves and the adjacent regions; Analysis of the spatial panel model revealed that factors such as GDP per capita, investment proportion ratio, centralized water supply, rural residents' expenditure were positively associated with improved sanitation rates, and illiteracy rate of people older than 15 was negatively related with improved sanitation rates. Socio-economic factors had affected the improved sanitation rates in 30 provinces in rural China. Thus, a series of policies, socio-economic measures and personal latrine literacy education should be given to improve the status of improved sanitation rates in rural China. PMID- 30423967 TI - A Low-Cost Resource Re-Allocation Scheme for Increasing the Number of Guaranteed Services in Resource-Limited Vehicular Networks. AB - Vehicular networks are becoming increasingly dense due to expanding wireless services and platooning has been regarded as a promising technology to improve road capacity and on-road safety. Constrained by limited resources, not all communication links in platoons can be allocated to the resources without suffering interference. To guarantee the quality of service, it is required to determine the set of served services at which the scale of demand exceeds the capability of the network. To increase the number of guaranteed services, the resource allocation has to be adjusted to adapt to the dynamic environment of the vehicular network. However, resource re-allocation results in additional costs, including signal overhead and latency. To increase the number of guaranteed services at a low-cost in a resource-limited vehicular network, we propose a time dynamic optimization method that constrains the network re-allocation rate. To decrease the computational complexity, the time dynamic optimization problem is converted into a deterministic optimization problem using the Lyapunov optimization theory. The simulation indicates that the analytical results do approximate the reality, and that the proposed scheme results in a higher number of guaranteed services as compared to the results of a similar algorithm. PMID- 30423968 TI - Web-Based System for the Remote Monitoring and Management of Precision Irrigation: A Case Study in an Arid Region of Argentina. AB - This article presents a description of the design, development, and implementation of web-based software and dedicated hardware which allows for the remote monitoring and control of a drip irrigation system. The hardware consists of in-field stations which are strategically distributed in the field and equipped with different sensors and communication devices; a weather station and drip irrigation system complete the setup. The web-based software makes it possible to remotely access and process the information gathered by all the stations and the irrigation controller. The proposed system was implemented in a young olive orchard, located in the province of San Juan, an arid region of Argentina. The system was installed and evaluated during the seasons 2014-2015 and 2015-2016. Four regulated irrigation strategies were proposed in the olive orchard to test its behavior. In this pilot experiment, the precision irrigation system was a useful tool for precisely managing the irrigation process, applying only the required amount of water (precise irrigation). Regulated deficit irrigation experiments, on the other hand, have demonstrated the sensitivity of olives to water restriction. The precision irrigation system made it possible to control soil moisture levels, avoiding water stress in the control treatment. PMID- 30423969 TI - Collagen-Polyvinyl Alcohol-Indomethacin Biohybrid Matrices as Wound Dressings. AB - The aim of this study is to design, develop and evaluate new biohybrid sponges based on polymers (collagen and polyvinyl alcohol) with and without indomethacin as anti-inflammatory drug model to be used for tissue regeneration in wound healing. Type I fibrillar collagen in the form of a gel and different concentrations of polyvinyl alcohol were mixed together to prepare composite gels. Both control samples, without indomethacin and with indomethacin, were obtained. All samples were crosslinked with glutaraldehyde. By freeze-drying of hydrogels, the spongious forms (matrices) were obtained. The matrices were characterized by FT-IR spectroscopy, scanning electron microscopy (SEM), water absorption, enzymatic degradation and in vitro indomethacin release. The pharmacological effect of the spongious biohybrid matrices was determined on an experimental model of burns induced to Wistar rats. The SEM images showed a porous structure with interconnected pores. Collagen sponges present a structure with pore sizes between 20 and 200 um, which became more and more compact with polyvinyl alcohol addition. The FT-IR showed interactions between collagen and polyvinyl alcohol. The enzymatic degradation indicated that the most stable matrix is the one with the ratio 75:25 of collagen:polyvinyl alcohol (ACI75), the other ones being degradable in time. The kinetic data of indomethacin release from matrices were fitted with different kinetic models and highlighted a biphasic release of the drug. Such kinetic profiles are targeted in skin wound healing for which important aspects are impaired inflammation and local pain. The treatment with sponges associated with anti-inflammatory drug had beneficial effects on the healing process in experimentally induced burns compared to the corresponding matrices without indomethacin and the classical treated control group. PMID- 30423971 TI - Structure and Physiological Regulation of AMPK. AB - Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a heterotrimeric alphabetagamma complex that functions as a central regulator of energy homeostasis. Energy stress manifests as a drop in the ratio of adenosine triphosphate (ATP) to AMP/ADP, which activates AMPK's kinase activity, allowing it to upregulate ATP-generating catabolic pathways and to reduce energy-consuming catabolic pathways and cellular programs. AMPK senses the cellular energy state by competitive binding of the three adenine nucleotides AMP, ADP, and ATP to three sites in its gamma subunit, each, which in turn modulates the activity of AMPK's kinase domain in its alpha subunit. Our current understanding of adenine nucleotide binding and the mechanisms by which differential adenine nucleotide occupancies activate or inhibit AMPK activity has been largely informed by crystal structures of AMPK in different activity states. Here we provide an overview of AMPK structures, and how these structures, in combination with biochemical, biophysical, and mutational analyses provide insights into the mechanisms of adenine nucleotide binding and AMPK activity modulation. PMID- 30423970 TI - Preoperative Albuminuria and Intraoperative Chloride Load: Predictors of Acute Kidney Injury Following Major Abdominal Surgery. AB - BACKGROUND: Postoperative Acute Kidney Injury (AKI) is a common and serious complication associated with significant morbidity and mortality. While several pre- and intra-operative risk factors for AKI have been recognized in cardiac surgery patients, relatively few data are available regarding the incidence and risk factors for perioperative AKI in other surgical operations. The aim of the present study was to determine the risk factors for perioperative AKI in patients undergoing major abdominal surgery. METHODS: This was a prospective, observational study of patients undergoing major abdominal surgery in a tertiary care center. Postoperative AKI was diagnosed according to the Acute Kidney Injury Network criteria within 48 h after surgery. Patients with chronic kidney disease stage IV or V were excluded. Logistic regression analysis was used to evaluate the association between perioperative factors and the risk of developing postoperative AKI. RESULTS: Eleven out of 61 patients developed postoperative AKI. Four intra-operative variables were identified as predictors of AKI: intra operative blood loss (p = 0.002), transfusion of fresh frozen plasma (p = 0.004) and red blood cells (p = 0.038), as well as high chloride load (p = 0.033, cut off value > 500 mEq). Multivariate analysis demonstrated an independent association between AKI development and preoperative albuminuria, defined as a urinary Albumin to Creatinine ratio >= 30 mg.g-1 (OR = 6.88, 95% CI: 1.43-33.04, p = 0.016) as well as perioperative chloride load > 500 mEq (OR = 6.87, 95% CI: 1.46-32.4, p = 0.015). CONCLUSION: Preoperative albuminuria, as well as a high intraoperative chloride load, were identified as predictors of postoperative AKI in patients undergoing major abdominal surgery. PMID- 30423972 TI - Improving Worst-Case Delay Analysis for Traffic of Additional Stream Reservation Class in Ethernet-AVB Network. AB - With the increase in the number of Electronic Control Units (ECUs) and future requirements for vehicle functions, two SR (Stream Reservation) traffic classes may not be sufficient to ensure fulfilment of constraints for multiple traffic types with individual timing requirements transmitted in the Ethernet-AVB (Audio Video Bridging) networks. The goal of this paper is to determine the worst-case delay for an additional SR traffic class under the CBS (Credit-Based Shaper) algorithm. Delay evaluation is based on the impact analysis of CBS on different priority flows, particularly depending on when the credits of both SR class A and B drain from the worst-case perspective. More specifically, both the impact of CBS and the evolution trends of credit on different priority class flows are first analyzed from the worst-case perspective. Then, for an additional SR class, two types of worst-case delay models are established with the CBS configuration suggestions. Finally, an approach to calculate the worst-case queuing delay is proposed. Moreover, the worst-case end-to-end delay is determined by the network calculus approach and simulation. Numerical results show that the delay bounds of our models are tighter than those of other models, which is beneficial to the development of Ethernet-AVB for in-vehicle networking. PMID- 30423973 TI - Hydration Thermodynamics of Non-Polar Aromatic Hydrocarbons: Comparison of Implicit and Explicit Solvation Models. AB - The precise description of solute-water interactions is essential to understand the chemo-physical nature in hydration processes. Such a hydration thermodynamics for various solutes has been explored by means of explicit or implicit solvation methods. Using the Poisson-Boltzmann solvation model, the implicit models are well designed to reasonably predict the hydration free energies of polar solutes. The implicit model, however, is known to have shortcomings in estimating those for non-polar aromatic compounds. To investigate a cause of error, we employed a novel systematic framework of quantum-mechanical/molecular-mechanical (QM/MM) coupling protocol in explicit solvation manner, termed DFT-CES, based on the grid based mean-field treatment. With the aid of DFT-CES, we delved into multiple energy parts, thereby comparing DFT-CES and PB models component-by-component. By applying the modified PB model to estimate the hydration free energies of non polar solutes, we find a possibility to improve the predictability of PB models. We expect that this study could shed light on providing an accurate route to study the hydration thermodynamics for various solute compounds. PMID- 30423974 TI - THz Sensing With Anomalous Extraordinary Optical Transmission Hole Arrays. AB - Subwavelength hole array (HA) metasurfaces support the so-called extraordinary optical transmission (EOT) resonance that has already been exploited for sensing. In this work, we demonstrate the superior performance of a different resonant regime of HA metasurfaces called anomalous EOT, by doing a thorough numerical and experimental study of its ability in thin-film label-free sensing applications in the terahertz (THz) band. A comprehensive analysis using both the regular and anomalous EOT resonances is done by depositing thin layers of dielectric analyte slabs of different thicknesses on the structures in different scenarios. We carry out a detailed comparison and demonstrate that the best sensing performance is achieved when the structure operates in the anomalous EOT resonance and the analyte is deposited on the non-patterned side of the metasurface, improving by a factor between 2 and 3 the results of the EOT resonance in any of the considered scenarios. This can be explained by the comparatively narrower linewidth of the anomalous EOT resonance. The results presented expand the reach of subwavelength HAs for sensing applications by considering the anomalous EOT regime that is usually overlooked in the literature. PMID- 30423975 TI - Prevalence and Predictors of Food Insecurity among Older People in Canada. AB - Background: Food insecurity research has been mainly examined among young people. The root causes of food insecurity are closely linked to poverty, and social policies and income supplements, including public and private pensions, have been shown to sharply curb food insecurity into later life. However, social, economic, and political trends that are closely connected to social and health inequalities threaten to undermine the conditions that have limited food insecurity among older people until now. Exploring the prevalence and predictors of food insecurity among older people across Canada has important implications for domestic policies concerning health, healthcare, and social welfare. Methods: Data come from the Canadian Community Health Survey 2012 Annual Component (n = 14,890). Descriptive statistics and a generalized linear model approach were used to determine prevalence and estimate the associations between food insecurity-as measured by the Household Food Security Survey Module-and social, demographic, geographic, and economic factors. Results: Approximately 2.4% of older Canadians are estimated to be moderately or severely food insecure. Income was by far the strongest predictor of food insecurity (total household income <$20,000 compared to >$60,000, OR: 46.146, 95% CI: 12.523-170.041, p < 0.001). Younger older people, and those with a non-white racial background also had significantly greater odds of food insecurity (ages 75+ compared to 65-74, OR: 0.322, 95% CI: 0.212-0.419, p < 0.001; and OR: 2.429, 95% CI: 1.438-4.102, p < 0.001, respectively). Sex, home ownership, marital status, and living arrangement were all found to confound the relationship between household income and food insecurity. Prevalence of food insecurity varied between provinces and territories, and odds of food insecurity were approximately five times greater for older people living in northern Canada as compared to central Canada (OR: 5.189, 95% CI: 2.329-11.562, p < 0.001). Conclusion: Disaggregating overall prevalence of food insecurity among older people demonstrates how disparities exist among sub-groups of older people. The seemingly negligible existence of food insecurity among older people has obscured the importance, practicality, and timeliness of including this age group in research on food insecurity. The current research underscores the critical importance of an income floor in preventing food insecurity among older people, and contributes a Canadian profile of the prevalence and predictors of food insecurity among older people to the broader international literature. PMID- 30423976 TI - Temperature-Corrected Fluidic Glucose Sensor Based on Microwave Resonator. AB - In this paper, a fluidic glucose sensor that is based on a complementary split ring resonator (CSRR) is proposed for the microwave frequency region. The detection of glucose with different concentrations from 0 mg/dL to 400 mg/dL in a non-invasive manner is possible by introducing a fluidic system. The glucose concentration can be continuously monitored by tracking the transmission coefficient S 21 as a sensing parameter. The variation tendency in S 21 by the glucose concentration is analyzed with equivalent circuit model. In addition, to eradicate the systematic error due to temperature variation, the sensor is tested in two temperature conditions: the constant temperature condition and the time dependent varying temperature condition. For the varying temperature condition, the temperature correction function was derived between the temperature and the variation in S 21 for DI water. By applying the fitting function to glucose solution, the subsidiary results due to temperature can be completely eliminated. As a result, the S 21 varies by 0.03 dB as the glucose concentration increases from 0 mg/dL to 400 mg/dL. PMID- 30423978 TI - Three-Dimensional Holographic Electromagnetic Imaging for Accessing Brain Stroke. AB - The authors recently developed a two-dimensional (2D) holographic electromagnetic induction imaging (HEI) for biomedical imaging applications. However, this method was unable to detect small inclusions accurately. For example, only one of two inclusions can be detected in the reconstructed image if the two inclusions were located at the same XY plane but in different Z-directions. This paper provides a theoretical framework of three-dimensional (3D) HEI to accurately and effectively detect inclusions embedded in a biological object. A numerical system, including a realistic head phantom, a 16-element excitation sensor array, a 16-element receiving sensor array, and image processing model has been developed to evaluate the effectiveness of the proposed method for detecting small stroke. The achieved 3D HEI images have been compared with 2D HEI images. Simulation results show that the 3D HEI method can accurately and effectively identify small inclusions even when two inclusions are located at the same XY plane but in different Z directions. This preliminary study shows that the proposed method has the potential to develop a useful imaging tool for the diagnosis of neurological diseases and injuries in the future. PMID- 30423977 TI - The Heterochromatin Landscape in Migrating Cells and the Importance of H3K27me3 for Associated Transcriptome Alterations. AB - H3K9me3, H3K27me3, and H4K20me1 are epigenetic markers associated with chromatin condensation and transcriptional repression. Previously, we found that migration of melanoma cells is associated with and dependent on global chromatin condensation that includes a global increase in these markers. Taken together with more recent reports by others suggests it is a general signature of migrating cells. Here, to learn about the function of these markers in migrating cells, we mapped them by ChIP-seq analysis. This analysis revealed that induction of migration leads to expansion of these markers along the genome and to an increased overlapping between them. Significantly, induction of migration led to a higher increase in H3K9me3 and H4K20me1 signals at repetitive elements than at protein-coding genes, while an opposite pattern was found for H3K27me3. Transcriptome analysis revealed 182 altered genes following induction of migration, of which 33% are dependent on H3K27me3 for these changes. H3K27me3 was also required to prevent changes in the expression of 501 other genes upon induction of migration. Taken together, our results suggest that heterochromatinization in migrating cells is global and not restricted to specific genomic loci and that H3K27me3 is a key component in executing a migration-specific transcriptional plan. PMID- 30423979 TI - Data Fusion Using Improved Support Degree Function in Aquaculture Wireless Sensor Networks. AB - For monitoring the aquaculture parameters in pond with wireless sensor networks (WSN), high accuracy of fault detection and high precision of error correction are essential. However, collecting accurate data from WSN to server or cloud is a bottleneck because of the data faults of WSN, especially in aquaculture applications, limits their further development. When the data fault occurs, data fusion mechanism can help to obtain corrected data to replace abnormal one. In this paper, we propose a data fusion method using a novel function that is Dynamic Time Warping time series strategy improved support degree (DTWS-ISD) for enhancing data quality, which employs a Dynamic Time Warping (DTW) time series segmentation strategy to the improved support degree (ISD) function. We use the DTW distance to replace Euclidean distance, which can explore the continuity and fuzziness of data streams, and the time series segmentation strategy is adopted to reduce the computation dimension of DTW algorithm. Unlike Gauss support function, ISD function obtains mutual support degree of sensors without the exponent calculation. Several experiments were finished to evaluate the accuracy and efficiency of DTWS-ISD with different performance metrics. The experimental results demonstrated that DTWS-ISD achieved better fusion precision than three existing functions in a real-world WSN water quality monitoring application. PMID- 30423981 TI - Sleep Duration and Sleep Quality Are Associated with Physical Activity in Elderly People Living in Nursing Homes. AB - The main purpose of the study was to explore the associations of sleep duration and sleep quality with physical activity (PA). In this cross-sectional study, participants were 894 elderly individuals (mean age 80 +/- 3 years; 56.0% women) living in nursing homes. PA, sleep duration, and sleep quality (based on the Pittsburgh Sleep Quality Index (PSQI)) were self-reported. The associations of sleep duration and sleep quality with PA at the nursing home level were analyzed using generalized estimating equations with clustering. Participants reporting short sleep duration (<6 h; OR = 0.45; 95% CI 0.25-0.80) were less likely to report sufficient PA, yet those reporting long sleep duration (>9 h; OR = 2.61; 95% CI 1.35-5.02) and good sleep quality (<5 points; OR = 1.59; 95% CI 1.19-2.12) were more likely to report sufficient PA. When sleep duration and sleep quality were entered into the same model, the same associations remained. This study shows that elderly individuals who report short sleep duration are less likely to meet PA guidelines, while those who report long sleep duration and good sleep quality are more likely to meet PA guidelines. Strategies aiming to improve sleep duration and sleep quality are warranted. PMID- 30423980 TI - Effects of Macrolide Treatment during the Hospitalization of Children with Childhood Wheezing Disease: A Systematic Review and Meta-Analysis. AB - Children are susceptible to a variety of respiratory infections. Wheezing is a common sign presented by children with respiratory infections. Asthma, bronchiolitis, and bronchitis are common causes of childhood wheezing disease (CWD) and are regarded as overlapping disease spectra. Macrolides are common antimicrobial agents with anti-inflammatory effects. We conducted a comprehensive literature search and a systematic review of studies that investigated the influences of macrolide treatment on CWD. The primary outcomes were the impact of macrolides on hospitalization courses of patients with CWD. Data pertaining to the study population, macrolide treatment, hospital courses, and recurrences were analyzed. Twenty-three studies with a combined study population of 2210 patients were included in the systematic review. Any kind of benefit from macrolide treatment was observed in approximately two-thirds of the studies (15/23). Eight studies were included in the meta-analysis to investigate the influence of macrolides on the length of stay (LOS), duration of oxygen demand (DOD), symptoms and signs of respiratory distress, and re-admission rates. Although the benefits of macrolide treatment were reported in several of the studies, no significant differences in LOS, DOD, symptoms and signs of respiratory distress, or re admission rates were observed in patients undergoing macrolide treatment. In conclusion, any kind of benefit of macrolide treatment was observed in approximately two-thirds of the studies; however, no obvious benefits of macrolide treatment were observed in the hospitalization courses of children with CWD. The routine use of macrolides to improve the hospitalization course of children with CWD is not suggested. PMID- 30423982 TI - The Expected and Unexpected Roles of Nitrate Transporters in Plant Abiotic Stress Resistance and Their Regulation. AB - Nitrate transporters are primarily responsible for absorption of nitrate from soil and nitrate translocation among different parts of plants. They deliver nitrate to where it is needed. However, recent studies have revealed that nitrate transporters are extensively involved in coping with adverse environmental conditions besides limited nitrate/nitrogen availability. In this review, we describe the functions of the nitrate transporters related to abiotic stresses and their regulation. The expected and unexpected roles of nitrate transporters in plant abiotic stress resistance will also be discussed. PMID- 30423983 TI - Factors Affecting Trailer Thermal Environment Experienced by Market Pigs Transported in the US. AB - Extreme weather conditions challenge pig thermoregulation during transport and are addressed by the National Pork Board (NPB) Transport Quality Assurance(r) (TQA) program that provides guidelines for trailer boarding, bedding, and misting. These guidelines are widely applied, yet very little is known about the microenvironment within the trailer. In this study, TQA guidelines (V4) were evaluated via extensive thermal environment measurements during transport in order to evaluate spatial variability and implications on ventilation pattern. Effects of trailer management strategies including bedding, boarding, and misting were examined and the trailer was monitored for interior temperature rise and THI responses within six separate zones. The trailer thermal environment was not uniformly distributed in the colder trips with the top front and bottom zones were the warmest, indicating these zones had the majority of outlet openings and experienced air with accumulated sensible and latent heat of the pigs. Relatively enhanced thermal environment uniformity was observed during hot trips, suggesting that ventilation patterns and ventilation rate were different for colder vs. warmer weather conditions. Misting applied prior to transport cooled interior air temperature, but also created high THI conditions in some cases. Neither boarding and bedding combinations in the TQA nor boarding position showed impacts on trailer interior temperature rise or spatial distribution of temperature inside the trailer. PMID- 30423984 TI - Effect of Plasma Treatment and Its Post Process Duration on Shear Bonding Strength and Antibacterial Effect of Dental Zirconia. AB - We have investigated the effect of non-thermal atmospheric pressure plasma (NTAPP) treatment and the post process time on the bonding strength and surface sterilization of dental zirconia. Presintered zirconia specimens were manufactured as discs, and then subjected to a 30-min argon treatment (Ar, 99.999%; 10 L/min) using an NTAPP device. Five post-treatment durations were evaluated: control (no treatment), P0 (immediate), P1 (24 h), P2 (48 h), and P3 (72 h). The surface characteristics, shear bonding strength (SBS) with two resin cements, and Streptococcus mutans biofilm formation of these plasma-treated dental zirconia were tested. Plasma did not change the roughness, and caused surface element changes and surface energy increase. Due to this increase in surface energy, SBS increased significantly (p < 0.05) within 48 h when RelyXTM U200 was used. However, the increase of surface oxygen significantly decreased (p < 0.05) the SBS of Panavia F 2.0 when using plasma immediately (P0). S. mutans adhesion decreased significantly (p < 0.05) for the P0, P1, and P2 groups compared to the control. The P0 group exhibited lower biofilm thickness than the other experimental groups due to the increased hydrophilicity (p < 0.05). Our study suggests that there is a suitable time window for the post NTAPP treatment regarding bonding strength and antimicrobial growth persist. PMID- 30423985 TI - Design of Azomethine Diols for Efficient Self-Healing of Strong Polyurethane Elastomers. AB - Azomethine diols (AMDs) were synthesized by condensation between a terephthalic aldehyde, polyether diamine, and ethanol amine. The synthesized AMDs were employed to introduce azomethine groups into the backbones of polyurethane elastomers (PUEs). Different AMDs were designed to control the concentration and distribution of azomethine groups in PUEs. In this study, we explored the intrinsic self-healing of AMD-based PUEs by azomethine metathesis. Particularly, the effects of the concentration and distribution of the azomethine groups on the AMD-based PUEs were considered. Consequently, as the azomethine group concentration increased and the distribution became denser, the self-healing properties improved. With AMD3-40, the self-healing efficiency reached 86% at 130 degrees C after 30 min. This represents a 150% improvement over the control PUE. Additionally, as the AMD content increased, the mechanical properties improved. With AMD3-40, the tensile strength reached 50 MPa. Therefore, we concluded that the self-healing and mechanical properties of PUEs can potentially be tailored for applications by adjusting the concentration and design of AMD structure for PUEs. PMID- 30423986 TI - The Prognostic Value of the Combination of Low VEGFR-1 and High VEGFR-2 Expression in Endothelial Cells of Colorectal Cancer. AB - Research on tumor angiogenesis has mainly focused on the vascular endothelial growth factor (VEGF) family and on methods to block its actions. However, reports on VEGF receptor (VEGFR) expression in tumor-associated endothelial cells (ECs) are limited. Thus, we evaluated VEGF, VEGFR-1 and VEGFR-2 expression in ECs of colorectal cancer (CRC) using immunohistochemistry. VEGF, VEGFR-1 and -2 expression in ECs was quantitatively evaluated by digital image analysis in a retrospective series of 204 tumor tissue samples and related to clinical variables. The data show that the VEGF, VEGFR-1 and VEGFR-2 expression in ECs is heterogeneous. Multivariate analysis including a set of clinicopathological variables reveals that high EC VEGFR-1 expression is an independent prognostic factor for overall survival (OS). The combination of low VEGFR-1 and high VEGFR-2 expression in ECs outperforms models integrating VEGFR-1 and VEGFR-2 as separate markers. Indeed, this VEGFR-1_VEGFR-2 combination is an independent negative prognostic factor for OS (p = 0.012) and metastasis-free survival (p = 0.007). In conclusion, this work illustrates the importance of studying the distribution of VEGF members in ECs of CRC. Interestingly, our preliminary data suggest that high VEGFR-1 and low VEGFR-2 expression in ECs appear to be involved in the progression of CRC, suggesting that targeting EC VEGFR-1 could offer novel opportunities for CRC treatment. However, a prospective validation study is needed. PMID- 30423987 TI - An Adaptive Prediction Target Search Algorithm for Multi-AUVs in an Unknown 3D Environment. AB - For a target search of autonomous underwater vehicles (AUVs) in a completely unknown three-dimensional (3D) underwater environment, a multi-AUV collaborative target search algorithm based on adaptive prediction is proposed in this paper. The environmental information sensed by the forward-looking sonar is used to judge the current state of view, and the AUV system uses this environmental information to perform the target search task. If there is no target in the field of view, the AUV system will judge whether all sub-regions of the current layer have been searched or not. The next sub-region for searching is determined by the evaluation function and the task assignment strategy. If there are targets in the field of view, the evaluation function and the estimation function of the adaptive predictive optimization algorithm is used to estimate the location of the unknown target. At the same time, the algorithm also can reduce the positioning error caused by the noise of the sonar sensor. In this paper, the simulation results show that the proposed algorithm can not only deal with static targets and random dynamic interference target search tasks, but it can also perform target search tasks under some random AUV failure conditions. In this process, the underwater communication limits are also considered. Finally, simulation experiments indicate the high efficiency and great adaptability of the proposed algorithm. PMID- 30423988 TI - A Portable, Wireless Photoplethysomography Sensor for Assessing Health of Arteriovenous Fistula Using Class-Weighted Support Vector Machine. AB - A portable, wireless photoplethysomography (PPG) sensor for assessing arteriovenous fistula (AVF) by using class-weighted support vector machines (SVM) was presented in this study. Nowadays, in hospital, AVF are assessed by ultrasound Doppler machines, which are bulky, expensive, complicated-to-operate, and time-consuming. In this study, new PPG sensors were proposed and developed successfully to provide portable and inexpensive solutions for AVF assessments. To develop the sensor, at first, by combining the dimensionless number analysis and the optical Beer Lambert's law, five input features were derived for the SVM classifier. In the next step, to increase the signal-noise ratio (SNR) of PPG signals, the front-end readout circuitries were designed to fully use the dynamic range of analog-digital converter (ADC) by controlling the circuitries gain and the light intensity of light emitted diode (LED). Digital signal processing algorithms were proposed next to check and fix signal anomalies. Finally, the class-weighted SVM classifiers employed five different kernel functions to assess AVF quality. The assessment results were provided to doctors for diagonosis and detemining ensuing proper treatments. The experimental results showed that the proposed PPG sensors successfully achieved an accuracy of 89.11% in assessing health of AVF and with a type II error of only 9.59%. PMID- 30423989 TI - Bioavailability Study of Maqui Berry Extract in Healthy Subjects. AB - Several health promoting effects have been reported for maqui berry, rich in anthocyanins. Direct effects of anthocyanins as well as bioactive metabolites might be involved. Within the study, bioavailability of a proprietary standardized maqui berry extract Delphinol(r) was investigated based on two selected anthocyanins (delphinidin-3-O-glucoside (DS) + cyanidin-3-O-sambubioside (CS)) and two breakdown products (protocatechuic acid (PCA) + gallic acid (GA)) after a single-dose supplementation in humans. Pharmacokinetic parameters were calculated from individual concentration time curves. In all 12 subjects a significant increase was noted in plasma values of DG and CS after intake of maqui berry extract. Maximum concentration of DG was observed after 1.0 +/- 0.3 h and CS after 2.0 +/- 1.1 h. Within 8 h, concentrations nearly returned to baseline levels. The results confirm a fast uptake and metabolism of the two selected key substances. Additionally, the phenolic acids GA and PCA were observed as breakdown products of anthocyanins. In summary, the study clearly confirms the bioavailability of maqui berry extract and its specific anthocyanin compounds and related breakdown products in healthy subjects. PMID- 30423990 TI - OsYSL13 Is Involved in Iron Distribution in Rice. AB - The uptake and transport of iron (Fe) in plants are both important for plant growth and human health. However, little is known about the mechanism of Fe transport in plants, especially for crops. In the present study, the function of yellow stripe-like 13 (YSL13) in rice was analyzed. OsYSL13 was highly expressed in leaves, especially in leaf blades, whereas its expression was induced by Fe deficiency both in roots and shoots. Furthermore, the expression level of OsYSL13 was higher in older leaves than that in younger leaves. OsYSL13 was located in the plasma membrane. Metal measurement revealed that Fe concentrations were lower in the youngest leaf and higher in the older leaves of the osysl13 mutant under both Fe sufficiency and deficiency conditions, compared with the wild type and two complementation lines. Moreover, the Fe concentrations in the brown rice and seeds of the osysl13 mutant were also reduced. Opposite results were found in OsYSL13 overexpression lines. These results suggest that OsYSL13 is involved in Fe distribution in rice. PMID- 30423991 TI - Hepatitis C Virus Infection at Primary Healthcare Level in Abha City, Southwestern Saudi Arabia: Is Type 2 Diabetes Mellitus an Associated Factor? AB - BACKGROUND: There is an increasing concern about the relation between hepatitis C virus infection (HCV) and type 2 diabetes mellitus (T2DM). The present study aims to determine the prevalence of HCV infection among T2DM patients and non-diabetic patients attending primary healthcare centers (PHCCs) in Abha city, southwestern Saudi Arabia, and to explore the possible association between T2DM and HCV infection. METHODS: A cross-sectional study targeting a random sample of T2DM and non-diabetic patients attending PHCCs in Abha City was conducted. Patients were interviewed using a structured questionnaire and screened for HCV infection using fourth-generation ELISA kits. All positive cases were confirmed by qualitative RT PCR immune assay. RESULTS: The study revealed an overall seroprevalence of HCV infection of 5% (95% CI: 2.9-7.9%). Among T2DM and non-diabetics, a seroprevalence of 8.0% and 2.0% was found, respectively. Using multivariable regression analysis, the only significant associated factor for HCV infection was T2DM (aOR = 4.185, 95% CI: 1.074-16.305). CONCLUSIONS: There is strong positive association between T2DM and HCV infection. Yet, the direction of relationship is difficult to establish. Patients with T2DM have higher prevalence of HCV infection than non-diabetic group. It is highly recommended for primary health care providers to screen for HCV infection among T2DM patients and to increase the level of HCV awareness among them. PMID- 30423992 TI - Mapping Soil Alkalinity and Salinity in Northern Songnen Plain, China with the HJ 1 Hyperspectral Imager Data and Partial Least Squares Regression. AB - In arid and semi-arid regions, identifying and monitoring of soil alkalinity and salinity are in urgently need for preventing land degradation and maintaining ecological balances. In this study, physicochemical, statistical, and spectral analysis revealed that potential of hydrogen (pH) and electrical conductivity (EC) characterized the saline-alkali soils and were sensitive to the visible and near infrared (VIS-NIR) wavelengths. On the basis of soil pH, EC, and spectral data, the partial least squares regression (PLSR) models for estimating soil alkalinity and salinity were constructed. The R2 values for soil pH and EC models were 0.77 and 0.48, and the root mean square errors (RMSEs) were 0.95 and 17.92 dS/m, respectively. The ratios of performance to inter-quartile distance (RPIQ) for the soil pH and EC models were 3.84 and 0.14, respectively, indicating that the soil pH model performed well but the soil EC model was not considerably reliable. With the validation dataset, the RMSEs of the two models were 1.06 and 18.92 dS/m. With the PLSR models applied to hyperspectral data acquired from the hyperspectral imager (HSI) onboard the HJ-1A satellite (launched in 2008 by China), the soil alkalinity and salinity distributions were mapped in the study area, and were validated with RMSEs of 1.09 and 17.30 dS/m, respectively. These findings revealed that the hyperspectral images in the VIS-NIR wavelengths had the potential to map soil alkalinity and salinity in the Songnen Plain, China. PMID- 30423993 TI - Investigative Study on Nitric Oxide Production in Human Dermal Fibroblast Cells under Normal and High Glucose Conditions. AB - Diabetic foot ulcers (DFU) are a major health problem associated with diabetes mellitus. Impaired nitric oxide (NO) production has been shown to be a major contributor to the dysregulation of healing in DFU. The level of impairment is not known primarily due to challenges with measuring NO. Herein, we report the actual level of NO produced by human dermal fibroblasts cultured under normal and high glucose conditions. Fibroblasts produce the extracellular matrix, which facilitate the migration of keratinocytes to close wounds. The results show that NO production was significantly higher in normal glucose compared to high glucose conditions. The real-time NO detected was compared to the nitrite present in the culture media and there was a direct correlation between real-time NO and nitrite in normal glucose conditions. However, real-time NO detection and nitrite measurement did not correlate under high glucose conditions. The inducible nitric oxide synthase (iNOS) enzyme responsible for NO production was upregulated in normal and high glucose conditions and the proliferation rate of fibroblasts was not statistically different in all the treatment groups. Relying only on nitrite to assess NO production is not an accurate determinant of the NO present in the wound bed in pathological states such as diabetes mellitus. PMID- 30423994 TI - Alkaloid-Rich Crude Extracts, Fractions and Piperamide Alkaloids of Piper guineense Possess Promising Antibacterial Effects. AB - Piper guineense is a food and medicinal plant commonly used to treat infectious diseases in West-African traditional medicine. In a bid to identify new antibacterial compounds due to bacterial resistance to antibiotics, twelve extracts of P. guineense fruits and leaves, obtained by sequential extraction, as well as the piperine and piperlongumine commercial compounds were evaluated for antibacterial activity against human pathogenic bacteria. HPLC-DAD and UHPLC/Q TOF MS analysis were conducted to characterize and identify the compounds present in the extracts with promising antibacterial activity. The extracts, with the exception of the hot water decoctions and macerations, contained piperamide alkaloids as their main constituents. Piperine, dihydropiperine, piperylin, dihydropiperylin or piperlonguminine, dihydropiperlonguminine, wisanine, dihydrowisanine and derivatives of piperine and piperidine were identified in a hexane extract of the leaf. In addition, some new piperamide alkaloids were identified, such as a piperine and a piperidine alkaloid derivative and two unknown piperamide alkaloids. To the best of our knowledge, there are no piperamides reported in the literature with similar UVlambda absorption maxima and masses. A piperamide alkaloid-rich hexane leaf extract recorded the lowest MIC of 19 ug/mL against Sarcina sp. and gave promising growth inhibitory effects against S. aureus and E. aerogenes as well, inhibiting the growth of both bacteria with a MIC of 78 ug/mL. Moreover, this is the first report of the antibacterial activity of P. guineense extracts against Sarcina sp. and E. aerogenes. Marked growth inhibition was also obtained for chloroform extracts of the leaves and fruits against P. aeruginosa with a MIC value of 78 ug/mL. Piperine and piperlongumine were active against E. aerogenes, S. aureus, E. coli, S. enterica, P. mirabilis and B. cereus with MIC values ranging from 39-1250 ug/mL. Notably, the water extracts, which were almost devoid of piperamide alkaloids, were not active against the bacterial strains. Our results demonstrate that P. guineense contains antibacterial alkaloids that could be relevant for the discovery of new natural antibiotics. PMID- 30423995 TI - Lignin Degradation Efficiency of Chemical Pre-Treatments on Banana Rachis Destined to Bioethanol Production. AB - Valuable biomass conversion processes are highly dependent on the use of effective pretreatments for lignocellulose degradation and enzymes for saccharification. Among the nowadays available treatments, chemical delignification represents a promising alternative to physical-mechanical treatments. Banana is one of the most important fruit crops around the world. After harvesting, it generates large amounts of rachis, a lignocellulosic residue, that could be used for second generation ethanol production, via saccharification and fermentation. In the present study, eight chemical pretreatments for lignin degradation (organosolv based on organic solvents, sodium hypochlorite, hypochlorous acid, hydrogen peroxide, alkaline hydrogen peroxide, and some combinations thereof) have been tested on banana rachis and the effects evaluated in terms of lignin removal, material losses, and chemical composition of pretreated material. Pretreatment based on lignin oxidation have demonstrated to reach the highest delignification yield, also in terms of monosaccharides recovery. In fact, all the delignified samples were then saccharified with enzymes (cellulase and beta-glucosidase) and hydrolysis efficiency was evaluated in terms of final sugars recovery before fermentation. Analysis of Fourier transform infrared spectra (FTIR) has been carried out on treated samples, in order to better understand the structural effects of delignification on lignocellulose. Active chlorine oxidations, hypochlorous acid in particular, were the best effective for lignin removal obtaining in the meanwhile the most promising cellulose-to-glucose conversion. PMID- 30423996 TI - Fetal Bovine Serum-Derived Extracellular Vesicles Persist within Vesicle-Depleted Culture Media. AB - It is known that culture media (CM) promotes cellular growth, adhesion, and protects explanted primary brain cells from in vitro stresses. The fetal bovine serum (FBS) supplement used in most CM, however, contains significant quantities of extracellular vesicles (EVs) that confound quantitative and qualitative analyses from the EVs produced by the cultured cells. We quantitatively tested the ability of common FBS EV-depletion protocols to remove exogenous EVs from FBS supplemented CM and evaluated the influence such methods have on primary astrocyte culture growth and viability. We assessed two methodologies utilized for FBS EV removal prior to adding to CM: (1) an 18-h ultracentrifugation (UC); and (2) a commercial EV-depleted FBS (Exo-FBSTM). Our analysis demonstrated that Exo-FBSTM CM provided the largest depletion (75%) of total FBS EVs, while still providing 6.92 * 108 +/- 1.39 * 108 EVs/mL. In addition, both UC and Exo-FBSTM CM resulted in poor primary astrocyte cell growth and viability in culture. The two common FBS EV-depletion methods investigated, therefore, not only contaminate in vitro primary cell-derived EV analyses, but also provide a suboptimal environment for primary astrocyte cell growth and viability. It appears likely that future CM optimization, using a serum-free alternative, might be required to advance analyses of cell-specific EVs isolated in vitro. PMID- 30423997 TI - Excretion of Urinary Metabolites of the Phthalate Esters DEP and DEHP in 16 Volunteers after Inhalation and Dermal Exposure. AB - Phthalate esters are suspected endocrine disruptors that are found in a wide range of applications. The aim of this study was to determine the excretion of urinary metabolites in 16 individuals after inhalation and/or dermal exposure to 100-300 ug/m3 of deuterium-labelled diethyl phthalate (D4-DEP) and bis(2 ethylhexyl) phthalate (D4-DEHP). Dermal exposure in this study represents a case with clean clothing acting as a barrier. After inhalation, D4-DEP and D4-DEHP metabolites were excreted rapidly, though inter-individual variation was high. D4 DEP excretion peaked 3.3 h (T1/2 of 2.1 h) after combined inhalation and dermal exposure, with total excreted metabolite levels ranging from 0.055 to 2.351 nmol/nmol/m3 (nmol of urinary metabolites per phthalates air concentration in (nmol/m3)). After dermal exposure to D4-DEP, metabolite excretion peaked 4.6 h (T1/2 of 2.7 h) after exposure, with excreted metabolite levels in between 0.017 and 0.223 nmol/nmol/m3. After combined inhalation and dermal exposure to D4-DEHP, the excretion of all five analysed metabolites peaked after 4.7 h on average (T1/2 of 4.8 h), and metabolite levels ranged from 0.072 to 1.105 nmol/nmol/m3 between participants. No dermal uptake of particle phase D4-DEHP was observed. In conclusion, the average excreted levels of metabolites after combined inhalation and dermal exposure to D4-DEP was three times higher than after combined exposure to D4-DEHP; and nine times higher than after dermal exposure of D4-DEP. This study was made possible due to the use of novel approaches, i.e., the use of labelled phthalate esters to avoid the background concentration, and innovative technique of phthalate generation, both in the particle and the gas phase. PMID- 30423999 TI - A Raster-Based Subdividing Indicator to Map Urban Heat Vulnerability: A Case Study in Sydney, Australia. AB - Assessing and mapping urban heat vulnerability has developed significantly over the past decade. Many studies have mapped urban heat vulnerability with a census unit-based general indicator (CGI). However, this kind of indicator has many problems, such as inaccurate assessment results and lacking comparability among different studies. This paper seeks to address this research gap and proposes a raster-based subdividing indicator to map urban heat vulnerability. We created a raster-based subdividing indicator (RSI) to map urban heat vulnerability from 3 aspects: exposure, sensitivity and adaptive capacity. We applied and compared it with a raster-based general indicator (RGI) and a census unit-based general indicator (CGI) in Sydney, Australia. Spatial statistics and analysis were used to investigate the performance among those three indicators. The results indicate that: (1) compared with the RSI framework, 67.54% of very high heat vulnerability pixels were ignored in the RGI framework; and up to 83.63% of very high heat vulnerability pixels were ignored in the CGI framework; (2) Compared with the previous CGI framework, a RSI framework has many advantages. These include more accurate results, more flexible model structure, and higher comparability among different studies. This study recommends using a RSI framework to map urban heat vulnerability in the future. PMID- 30423998 TI - Transitions in Tobacco Product Use by U.S. Adults between 2013-2014 and 2014 2015: Findings from the PATH Study Wave 1 and Wave 2. AB - In 2013-2014, nearly 28% of adults in the United States (U.S.) were current tobacco users with cigarettes the most common product used and with nearly 40% of tobacco users using two or more tobacco products. We describe overall change in prevalence of tobacco product use and within-person transitions in tobacco product use in the U.S. between 2013-2014 and 2014-2015 for young adults (18-24 years) and older adults (25+ years). Data from Wave 1 (W1, 2013-2014) and Wave 2 (W2, 2014-2015) of the Population Assessment of Tobacco and Health (PATH) Study were analyzed (N = 34,235). Tobacco product types were categorized into: (1) combustible (cigarettes, cigars, pipe tobacco, hookah), (2) noncombustible (smokeless tobacco, snus pouches, dissolvable tobacco), and (3) electronic nicotine delivery systems (ENDS). Transitions for individual combustible-product types, and for single- and multiple-product use, were also considered. Overall prevalence of current tobacco use decreased from 27.6% to 26.3%. Among W1 non tobacco users, 88.7% of young adults and 95.8% of older adults were non-tobacco users at W2. Among W1 tobacco users, 71.7% of young adults transitioned, with 20.7% discontinuing use completely, and 45.9% of older adults transitioned, with 12.5% discontinuing use completely. Continuing with/transitioning toward combustible product(s), particularly cigarettes, was more common than continuing with/transitioning toward ENDS. Tobacco use behaviors were less stable among young adults than older adults, likely reflecting greater product experimentation among young adults. Relative stability of cigarette use compared to other tobacco products (except older adult noncombustible use) demonstrates high abuse liability for cigarettes. PMID- 30424000 TI - Virtual Torque Sensor for Low-Cost RC Servo Motors Based on Dynamic System Identification Utilizing Parametric Constraints. AB - We propose a novel virtual torque sensor for commercial low-cost radio-controlled (RC) servo motors. The virtual torque sensor has played an important role for conventional robots. It has been used for torque-required control applications such as human-robot interaction and under-actuated robots. However, most virtual torque sensors are based on the inversion of actuators or robot dynamics with the assumption that entire dynamics are known. This is not applicable to the RC servo motors that have unknown control structures. As RC servo motors enable researchers and hobbyists to create lightweight but high performance robots in an easy and cost-effective manner, the development of a virtual torque sensor for these motors is necessary. In this study, we propose a design method of a virtual torque sensor for RC servo motors. First, the virtual sensor is derived mathematically based on internal dynamic models with parametric constraints and compared to the conventional model. Second, a dedicated system identification method is developed for the proposed virtual sensor to implement the sensor in actual experiments. Finally, we compare experimental results with the measurements obtained by an actual sensor. PMID- 30424001 TI - An Intelligent Fault Diagnosis Method for Bearings with Variable Rotating Speed Based on Pythagorean Spatial Pyramid Pooling CNN. AB - Deep learning methods have been introduced for fault diagnosis of rotating machinery. Most methods have good performance when processing bearing data at a certain rotating speed. However, most rotating machinery in industrial practice has variable working speed. When processing the bearing data with variable rotating speed, the existing methods have low accuracies, or need complex parameter adjustments. To solve this problem, a fault diagnosis method based on continuous wavelet transform scalogram (CWTS) and Pythagorean spatial pyramid pooling convolutional neural network (PSPP-CNN) is proposed in this paper. In this method, continuous wavelet transform is used to decompose vibration signals into CWTSs with different scale ranges according to the rotating speed. By adding a PSPP layer, CNN can process CWTSs in different sizes. Then the fault diagnosis of variable rotating speed bearing can be carried out by a single CNN model without complex parameter adjustment. Compared with a spatial pyramid pooling (SPP) layer that has been used in CNN, a PSPP layer locates as front layer of CNN. Thus, the features obtained by PSPP layer can be delivered to convolutional layers for further feature extraction. According to experiment results, this method has higher diagnosis accuracy for variable rotating speed bearing than other methods. In addition, the PSPP-CNN model trained by data at some rotating speeds can be used to diagnose bearing fault at full working speed. PMID- 30424002 TI - Contemporary Ribonomics Methods for Viral microRNA Target Analysis. AB - Numerous cellular processes are regulated by microRNAs (miRNAs), both cellular and viral. Elucidating the targets of miRNAs has become an active area of research. An important method in this field is cross-linking and immunoprecipitation (CLIP), where cultured cells or tissues are UV-irradiated to cross-link protein and nucleic acid, the RNA binding protein of interest is immunoprecipitated, and the RNAs pulled down with the protein are isolated, reverse-transcribed, and analyzed by sequencing. CLIP using antibody against Argonaute (Ago), which binds to both miRNA and mRNA as they interact in RISC, has allowed researchers to uncover a large number of miRNA targets. Coupled with high throughput sequencing, CLIP has been useful for revealing miRNA targetomes for the gamma-herpesviruses Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV). Variants on the CLIP protocol are described, with the benefits and drawbacks of each. In particular, the most recent methods involving RNA-RNA ligation to join the miRNA and its RNA target have aided in target identification. Lastly, data supporting biologically meaningful interactions between miRNAs and long non-coding RNAs (lncRNAs) are reviewed. In summary, ribonomics-based miRNA targetome analysis has expanded our understanding of miRNA targeting and has provided a rich resource for EBV and KSHV research with respect to pathogenesis and tumorigenesis. PMID- 30424003 TI - Population Connectivity and Traces of Mitochondrial Introgression in New Zealand Black-Billed Gulls (Larus bulleri). AB - Black-billed gulls (Larus bulleri) are endemic to New Zealand and are suspected to be undergoing substantial population declines. They primarily breed on open gravel beds in braided rivers of the South Island-a habitat that is diminishing and becoming increasingly modified. Although management of this species is increasing, little has been published on their movements and demographics. In this study, both mitochondrial DNA (mtDNA) control region domain I and nuclear single nucleotide polymorphisms (SNPs) were examined to help understand the connectivity and population structure of black-billed gulls across the country and to help inform management decisions. Mitochondrial DNA showed no population structure, with high haplotype and low nucleotide diversity, and analyses highlighted mitochondrial introgression with the closely related red-billed gulls (Larus novaehollandiae scopulinus). Nuclear DNA analyses, however, identified two groups, with Rotorua birds in the North Island being distinct from the rest of New Zealand, and isolation-by-distance evident across the South Island populations. Gene flow primarily occurs between nearby colonies with a stepwise movement across the landscape. The importance from a genetic perspective of the more isolated North Island birds (1.6% of total population) needs to be further evaluated. From our results, we infer that the South Island black-billed gull management should focus on maintaining several populations within each region rather than focusing on single specific colonies or river catchments. Future study is needed to investigate the genetic structure of populations at the northern limit of the species' range, and identify the mechanisms behind, and extent of, the hybridisation between red-billed and black-billed gulls. PMID- 30424004 TI - Contribution of the Economic Crisis to the Risk Increase of Poor Mental Health in a Region of Spain. AB - Previous research suggests that the economic crisis can affect mental health. The purpose of this study was to analyse the association of risk of poor mental health with various socioeconomic, demographic, health, quality of life, and social support variables; and to evaluate the contribution of socioeconomic variables most affected by the beginning of the economic crisis (employment situation and income) on the changes in the prevalence of the risk of poor mental health between 2005 and 2010. A study of prevalence evolution in adult population residents of the Valencian Community in the Spanish Mediterranean was conducted. We studied 5781 subjects in 2005 and 3479 in 2010. Logistic regression models have been adjusted to analyse the association between variables. A standardisation procedure was carried out to evaluate which part of the changes in overall prevalence could be attributed to variations in the population structure by age, sex, employment status, and income between the years under study. The prevalence of GHQ+ increased from 2005 to 2010, in both men and women. Several variables were closely associated with the risk of poor mental health (sex, age, country of birth, number of nonmental chronic diseases, social support, disability, cohabitation in couple, employment status, and income). The changes produced as a result of the onset of the economic crisis in income and unemployment (increase in low income and in unemployment rates) contributed to the increase of poor mental health risk. This could confirm the sensitivity of mental health to the economic deterioration caused by the crisis. PMID- 30424005 TI - Visitors' Perceived Place Value and the Willingness to Pay in an Urban Lake Park. AB - As highly developed nature, an urban lake park will be a place required to integrate various functions such as health promotion, recreation, and cultural exchange by focusing on ecological aspects. We applied latent profile analysis (LPA) to identify latent classes based on visitors' perceived place value, and to estimate the willingness to pay (WTP) by these classifications. Park visitors were classified according to place value into three groups: Local Seekers (LS), Ecology Seekers (ES), and Recreation Seekers (RS). To compare the WTP of the three groups and examine differences in attributes between the groups, we used a choice experiment (CE). The results from the CE revealed that the WTP for attributes was ranked in the order of basic infrastructure, advanced services, and ecological activities. These differences in the WTP of visitors in an urban lake park may be useful for park management, such as providing strategies for zoning and ecotourism, which is specialized by visitor type. PMID- 30424007 TI - Repression of Transcriptional Activity of Forkhead Box O1 by Histone Deacetylase Inhibitors Ameliorates Hyperglycemia in Type 2 Diabetic Rats. AB - : Type 2 diabetes mellitus (T2DM) is a chronic disease manifested by hyperglycemia. It is essential to effectively control hyperglycemia to prevent complications of T2DM. Here, we hypothesize that repression of transcriptional activity of forkhead box O1 (FoxO1) via histone deacetylase inhibitors (HDACi) ameliorates hyperglycemia in T2DM rats. METHODS: Male Long-Evans Tokushima Otsuka (LETO) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats aged 14 weeks were administered sodium valproate (VPA, 0.71% w/v) dissolved in water for 20 weeks. Electrophoretic mobility shift assay (EMSA) and luciferase assay were performed for elucidation of transcriptional regulation through acetylation of FoxO1 by HDACi. RESULTS: VPA attenuated blood glucose levels in accordance with a decrease in the expression of gluconeogenic genes in hyperglycemic OLETF rats. It has been shown that HDAC class I-specific and HDAC class IIa-specific inhibitors, as well as pan-HDAC inhibitors decrease FoxO1 enrichment at the cis-element of target gene promoters. Mutations in FoxO1 prevent its acetylation, thereby increasing its transcriptional activity. HDAC3 and HDAC4 interact with FoxO1, and knockdown of HDAC3, HDAC4, or their combination increases FoxO1 acetylation, thereby decreasing the expression of gluconeogenic genes. CONCLUSIONS: These results indicate that HDACi attenuates the transcriptional activity of FoxO1 by impeding deacetylation, thereby ameliorating hyperglycemia in T2DM rats. PMID- 30424008 TI - Integrated Proteomics and Lipidomics Investigation of the Mechanism Underlying the Neuroprotective Effect of N-benzylhexadecanamide. AB - Macamides are very important secondary metabolites produced by Lepidium meyenii Walp, which possess multiple bioactivities, especially in the neuronal system. In a previous study, we observed that macamides exhibited excellent effects in the recovery of injured nerves after 1-methyl-4-phenylpyridinium (MPP+)-induced dopaminergic neuronal damage in zebrafish. However, the mechanism underlying this effect remains unclear. In the present study, we observed that N benzylhexadecanamide (XA), which is a typical constituent of macamides, improved the survival rate of neurons in vitro. We determined the concentration of neurotransmitters in MN9D cells and used it in conjunction with an integrated proteomics and lipidomics approach to investigate the mechanism underlying the neuroprotective effects of XA in an MPP+-induced neurodegeneration cell model using QqQ MS, Q-TOF MS, and Orbitrap MS. The statistical analysis of the results led to the identification of differentially-expressed biomarkers, including 11 proteins and 22 lipids, which may be responsible for the neuron-related activities of XA. All these potential biomarkers were closely related to the pathogenesis of neurodegenerative diseases, and their levels approached those in the normal group after treatment with XA. Furthermore, seven lipids, including five phosphatidylcholines, one lysophosphatidylcholine, and one phosphatidylethanolamine, were verified by a relative quantitative approach. Moreover, four proteins (Scarb2, Csnk2a2, Vti1b, and Bnip2) were validated by ELISA. The neurotransmitters taurine and norepinephrine, and the cholinergic constituents, correlated closely with the neuroprotective effects of XA. Finally, the protein-lipid interaction network was analyzed. Based on our results, the regulation of sphingolipid metabolism and mitochondrial function were determined to be the main mechanisms underlying the neuroprotective effect of XA. The present study should help us to better understand the multiple effects of macamides and their use in neurodegenerative diseases. PMID- 30424006 TI - The Effect of Dietary Mushroom Agaricus bisporus on Intestinal Microbiota Composition and Host Immunological Function. AB - A study was designed to determine the potential prebiotic effect of dietary mushrooms on the host immune response, and intestinal microbiota composition and function. Thirty-one six-week-old pigs were fed a pig grower diet alone or supplemented with either three or six servings of freeze-dried white button (WB) mushrooms for six weeks. Host immune response was evaluated in peripheral blood mononuclear cells (PBMC), and alveolar macrophages (AM) after stimulation with Salmonella typhymurium-Lipopolysaccharide (LPS). Isolated DNA from fecal and proximal colon contents were used for 16S rDNA taxonomic analysis and linear discriminant analysis effect size (LEfSe) to determine bacterial abundance and metabolic function. Pigs gained weight with no difference in body composition or intestinal permeability. Feeding mushrooms reduced LPS-induced IL-1beta gene expression in AM (P < 0.05) with no change in LPS-stimulated PBMC or the intestinal mucosa transcriptome. LEfSe indicated increases in Lachnospiraceae, Ruminococcaceae within the order Clostridiales with a shift in bacterial carbohydrate metabolism and biosynthesis of secondary metabolites in the mushroom fed pigs. These results suggested that feeding WB mushrooms significantly reduced the LPS-induced inflammatory response in AM and positively modulated the host microbiota metabolism by increasing the abundance of Clostridiales taxa that are associated with improved intestinal health. PMID- 30424009 TI - Rapid Determination of Cadmium Contamination in Lettuce Using Laser-Induced Breakdown Spectroscopy. AB - Quick access to cadmium (Cd) contamination in lettuce is important to supervise the leafy vegetable growth environment and market. This study aims to apply laser induced breakdown spectroscopy (LIBS) technology for fast determination of Cd content and diagnosis of the Cd contamination degree in lettuce. Emission lines Cd II 214.44 nm, Cd II 226.50 nm, and Cd I 228.80 nm were selected to establish the univariate analysis model. Multivariate analysis including partial least squares (PLS) regression, was used to establish Cd content calibration models, and PLS model based on 22 variables selected by genetic algorithm (GA) obtained the best performance with correlation coefficient in the prediction set Rp2 = 0.9716, limit of detection (LOD) = 1.7 mg/kg. K-Nearest Neighbors (KNN) and random forest (RF) were used to analyze Cd contamination degree, and RF model obtained the correct classification rate of 100% in prediction set. The preliminary results indicate LIBS coupled with chemometrics could be used as a fast, efficient and low-cost method to assess Cd contamination in the vegetable industry. PMID- 30424010 TI - Theranostics Applications of Nanoparticles in Cancer Immunotherapy. AB - With the advancement in the mechanism of immune surveillance and immune evasion in cancer cells, cancer immunotherapy shows promising results for treating cancer with established efficacy and less toxicity. As a result of the off-target effect, the approach for delivering vaccines, adjuvants, or antibodies directly to tumor sites is gaining widespread attention. An effective alternative is to utilize nanoengineered particles, functioning as drug-delivery systems or as antigens themselves. This article reviews the practical implementation of nanotechnology in cancer immunotherapy. PMID- 30424011 TI - A Brief History of Charcot-Leyden Crystal Protein/Galectin-10 Research. AB - Eosinophils are present in tissues, such as the respiratory tract, spleen, lymph nodes and blood vessels. The significant presence of eosinophils in these tissues are associated with various diseases, including asthma, allergies, acute myeloid leukemia, etc. Charcot-Leyden crystal protein/galectin-10 is overexpressed in eosinophils and has also been identified in basophils and macrophages. In human body, this protein could spontaneously form Charcot-Leyden crystal in lymphocytes or in the lysates of lymphocytes. At present, the role of Charcot-Leyden crystal protein/galectin-10 in lymphocytes is not fully understood. This review summarizes research progress on Charcot-Leyden crystal protein/galectin-10, with emphasis on its history, cellular distributions, relations to diseases, structures and ligand binding specificity. PMID- 30424012 TI - Bioactive Sphene-Based Ceramic Coatings on cpTi Substrates for Dental Implants: An In Vitro Study. AB - Titanium implant surface modifications have been widely investigated to favor the process of osseointegration. The present work aimed to evaluate the effect of sphene (CaTiSiO5) biocoating, on titanium substrates, on the in vitro osteogenic differentiation of Human Adipose-Derived Stem Cells (hADSCs). Sphene bioceramic coatings were prepared using preceramic polymers and nano-sized active fillers and deposited by spray coating. Scanning Electron Microscopy (SEM) analysis, surface roughness measurements and X-ray diffraction analysis were performed. The chemical stability of the coatings in Tris-HCl solution was investigated. In vitro studies were performed by means of proliferation test of hADSCs seeded on coated and uncoated samples after 21 days. Methyl Thiazolyl-Tetrazolium (MTT) test and immunofluorescent staining with phalloidin confirmed the in vitro biocompatibility of both substrates. In vitro osteogenic differentiation of the cells was evaluated using Alizarin Red S staining and quantification assay and real-time PCR (Polymerase Chain Reaction). When hADSCs were cultured in the presence of Osteogenic Differentiation Medium, a significantly higher accumulation of calcium deposits onto the sphene-coated surfaces than on uncoated controls was detected. Osteogenic differentiation on both samples was confirmed by PCR. The proposed coating seems to be promising for dental and orthopedic implants, in terms of composition and deposition technology. PMID- 30424013 TI - Optimization of Gas Sensors Based on Advanced Nanomaterials through Split-Plot Designs and GLMMs. AB - This paper deals with the planning and modeling of a split-plot experiment to improve novel gas sensing materials based on Perovskite, a nano-structured, semi conductor material that is sensitive to changes in the concentration of hazardous gas in the ambient air. The study addresses both applied and theoretical issues. More precisely, it focuses on (i) the detection of harmful gases, e.g., NO 2 and CO, which have a great impact on industrial applications as well as a significantly harmful impact on human health; (ii) the planning and modeling of a split-plot design for the two target gases by applying a dual-response modeling approach in which two models, e.g., location and dispersion models, are estimated; and (iii) a robust process optimization conducted in the final modeling step for each target gas and for each gas sensing material, conditioned to the minimization of the working temperature. The dual-response modeling allows us to achieve satisfactory estimates for the process variables and, at the same time, good diagnostic valuations. Optimal solutions are obtained for each gas sensing material while also improving the results achieved from previous studies. PMID- 30424014 TI - Assessing Configurational Sampling in the Quantum Mechanics/Molecular Mechanics Calculation of Temoporfin Absorption Spectrum and Triplet Density of States. AB - The absorption properties of Temoporfin, a second-generation photosensitizer employed in photodynamic therapy, are calculated with an electrostatic-embedding quantum mechanics/molecular mechanics (QM/MM) scheme in methanol. The suitability of several ensembles of geometries generated by different sampling techniques, namely classical-molecular-dynamics (MD) and QM/MM-MD thermal sampling, Wigner quantum sampling and a hybrid protocol, which combines the thermal and quantum approaches, is assessed. It is found that a QM description of the chromophore during the sampling is needed in order to achieve a good agreement with respect to the experimental spectrum. Such a good agreement is obtained with both QM/MM MD and Wigner samplings, demonstrating that a proper description of the anharmonic motions of the chromophore is not relevant in the computation of the absorption properties. In addition, it is also found that solvent organization is a rather fast process and a long sampling is not required. Finally, it is also demonstrated that the same exchange-correlation functional should be employed in the sampling and in the computation of the excited states properties to avoid unphysical triplet states with relative energies close or below 0 eV. PMID- 30424015 TI - Development of an Improved Carotenoid Extraction Method to Characterize the Carotenoid Composition under Oxidative Stress and Cold Temperature in the Rock Inhabiting Fungus Knufia petricola A95. AB - Black yeasts are a highly specified group of fungi, which are characterized by a high resistance against stress factors. There are several factors enabling the cells to survive harsh environmental conditions. One aspect is the pigmentation, the melanin black yeasts often display a highly diverse carotenoid spectrum. Determination and characterization of carotenoids depend on an efficient extraction and separation, especially for black yeast, which is characterized by thick cell walls. Therefore, specific protocols are needed to ensure reliable analyses regarding stress responses in these fungi. Here we present both. First, we present a method to extract and analyze carotenoids and secondly we present the unusual carotenoid composition of the black yeast Knufia petricola A95. Mechanical treatment combined with an acetonitrile extraction gave us very good extraction rates with a high reproducibility. The presented extraction and elution protocol separates the main carotenoids (7) in K. petricola A95 and can be extended for the detection of additional carotenoids in other species. K. petricola A95 displays an unusual carotenoid composition, with mainly didehydrolycopene, torulene, and lycopene. The pigment composition varied in dependency to oxidative stress but remained relatively constant if the cells were cultivated under low temperature. Future experiments have to be carried out to determine if didehydrolycopene functions as a protective agent itself or if it serves as a precursor for antioxidative pigments like torulene and torularhodin, which could be produced after induction under stress conditions. Black yeasts are a promising source for carotenoid production and other substances. To unravel the potential of these fungi, new methods and studies are needed. The established protocol allows the determination of carotenoid composition in black yeasts. PMID- 30424016 TI - Peroxisome Proliferator-Activated Receptors (PPAR)gamma Agonists as Master Modulators of Tumor Tissue. AB - In most clinical trials, thiazolidinediones do not show any relevant anti-cancer activity when used as mono-therapy. Clinical inefficacy contrasts ambiguous pre clinical data either favoring anti-tumor activity or tumor promotion. However, if thiazolidinediones are combined with additional regulatory active drugs, so called 'master modulators' of tumors, i.e., transcriptional modulators, metronomic low-dose chemotherapy, epigenetically modifying agents, protein binding pro-anakoinotic drugs, such as COX-2 inhibitors, IMiDs, etc., the results indicate clinically relevant communicative reprogramming of tumor tissues, i.e., anakoinosis, meaning 'communication' in ancient Greek. The concerted activity of master modulators may multifaceted diversify palliative care or even induce continuous complete remission in refractory metastatic tumor disease and hematologic neoplasia by establishing novel communicative behavior of tumor tissue, the hosting organ, and organism. Re-modulation of gene expression, for example, the up-regulation of tumor suppressor genes, may recover differentiation, apoptosis competence, and leads to cancer control-in contrast to an immediate, 'poisoning' with maximal tolerable doses of targeted/cytotoxic therapies. The key for uncovering the therapeutic potential of Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists is selecting the appropriate combination of master modulators for inducing anakoinosis: Now, anakoinosis is trend setting by establishing a novel therapeutic pillar while overcoming classic obstacles of targeted therapies, such as therapy resistance and (molecular-)genetic tumor heterogeneity. PMID- 30424017 TI - Reinforcement Learning-Based Multi-AUV Adaptive Trajectory Planning for Under-Ice Field Estimation. AB - This work studies online learning-based trajectory planning for multiple autonomous underwater vehicles (AUVs) to estimate a water parameter field of interest in the under-ice environment. A centralized system is considered, where several fixed access points on the ice layer are introduced as gateways for communications between the AUVs and a remote data fusion center. We model the water parameter field of interest as a Gaussian process with unknown hyper parameters. The AUV trajectories for sampling are determined on an epoch-by-epoch basis. At the end of each epoch, the access points relay the observed field samples from all the AUVs to the fusion center, which computes the posterior distribution of the field based on the Gaussian process regression and estimates the field hyper-parameters. The optimal trajectories of all the AUVs in the next epoch are determined to maximize a long-term reward that is defined based on the field uncertainty reduction and the AUV mobility cost, subject to the kinematics constraint, the communication constraint and the sensing area constraint. We formulate the adaptive trajectory planning problem as a Markov decision process (MDP). A reinforcement learning-based online learning algorithm is designed to determine the optimal AUV trajectories in a constrained continuous space. Simulation results show that the proposed learning-based trajectory planning algorithm has performance similar to a benchmark method that assumes perfect knowledge of the field hyper-parameters. PMID- 30424018 TI - DTM-Aided Adaptive EPF Navigation Application in Railways. AB - The diverse operating environments change GNSS measurement noise covariance in real time, and different GNSS techniques hold different measurement noise covariance as well. Mismodelling the covariance causes undependable filtering results and even degenerates the GNSS/INS Particle Filter (PF) process, due to the fact that INS error-state noise covariance is much smaller than that of GNSS measurement noise. It also makes the majority of existing methods for adaptively adjusting filter parameters incapable of performing well. In this paper, a feasible Digital Track Map-aided (DTM-aided) adaptive extended Kalman particle filter method is introduced in GNSS/INS integration in order to adjust GNSS measurement noise covariance in real time, and the GNSS down-direction offset is also estimated along with every sampling period through making full use of DTM information. The proposed approach is successfully examined in a railway environment, and the on-site experimental results reveal that the adaptive approach holds better positioning performance in comparison to the methods without adaptive adjustment. Improvements of 62.4% and 14.9% in positioning accuracy are obtained in contrast to Standard Point Positioning (SPP) and Precise Point Positioning (PPP), respectively. The proposed adaptive method takes advantage of DTM information and is able to automatically adapt to complex railway environments and different GNSS techniques. PMID- 30424019 TI - Frequency Dependence of Receiving Sensitivity of Ultrasonic Transducers and Acoustic Emission Sensors. AB - Receiving displacement sensitivities (Rx) of ultrasonic transducers and acoustic emission (AE) sensors are evaluated using sinewave packet excitation method and compared to the corresponding data from pulse excitation method with a particular emphasis on low frequency behavior below 20 kHz, down to 10 Hz. Both methods rely on the determination of transmitter displacement characteristics using a laser interferometric method. Results obtained by two calibration methods are in good agreement, with average spectral differences below 1 dB, indicating that the two calibration methods yield identical receiving sensitivities. At low test frequencies, effects of attenuation increase substantially due to increasing sensor impedance and Rx requires correction in order to evaluate the inherent sensitivity of a sensor, or open-circuit sensitivity. This can differ by more than 20 dB from results that used common preamplifiers with ~10 kOmega input impedance, leading to apparent velocity response below 100 kHz for typical AE sensors. Damped broadband sensors and ultrasonic transducers exhibit inherent velocity response (Type 1) below their main resonance frequency. In sensors with under-damped resonance, a steep sensitivity decrease occurs showing frequency dependence of f2~f5 (Type 2), while mass-loaded sensors exhibit flat displacement response (Type 0). Such behaviors originate from sensor characteristics that can best be described by the damped harmonic oscillator model. This model accounts for the three typical behaviors. At low frequencies, typically below 1 kHz, receiving sensitivity exhibits another Type 0 behavior of frequency independent Rx. Seven of 12 sensors showed this flat region, while three more appear to approach the Type 0 region. This appears to originate from the quasi-static piezoelectric response of a sensing element. In using impulse method, a minimum pulse duration is necessary to obtain spectral fidelity at low frequencies and an approximate rule is given. Various factors for sensitivity improvement are also discussed. PMID- 30424020 TI - Extraction, Purification, and Hydrolysis Behavior of Apigenin-7-O-Glucoside from Chrysanthemum Morifolium Tea. AB - Apigenin-7-O-glucoside is an active phenolic compound in Asteraceae flowers and possesses remarkable therapeutic applications. However, its high price and low abundance in plants limit its use, meanwhile it would hydrolyze in the purification process. In this study, apigenin-7-O-glucoside extracted with ultrasound and purified with preparative HPLC from Chrysanthemum morifolium 'Huangju' was investigated, as well as its hydrolysis behavior and bioactivities. The optimized extraction conditions were: solid/liquid ratio: 1:20, extraction time: 35 min, temperature: 50 degrees C, and ultrasound power: 350 W. The content of apigenin-7-O-glucoside was up to 16.04 mg/g. Apigenin-7-O-glucoside was then purified with preparative HPLC from the extract, and confirmed by Q TOF/MS. Apigenin-7-O-glucoside was partially hydrolyzed in acidic condition, and the hydrolysis rate depended on the pH value and temperature. The antioxidant activity increased as a result of the hydrolysis process. This study provided a green and effective way to obtain apigenin-7-O-glucoside and would be beneficial for further investigations into nutritional and functional aspects apigenin-7-O glucoside and other glycosides. PMID- 30424021 TI - Dose and Exposure Time-Dependent Renal and Hepatic Effects of Intraperitoneally Administered Fumonisin B1 in Rats. AB - Male Wistar rats were treated intraperitoneally (i.p.) with fumonisin B1 (FB1; 0, 20, 50 and 100 mg/kg dietary dose equivalent) for 5 and 10 days (n = 24-24 in each setting) to gain dose- and time-dependent effects on antioxidant status and oxidative stress response, clinical chemical endpoints and liver, kidney and lung histopathology and lymphocyte damage (genotoxicity). FB1 decreased feed intake, body weight gain and absolute liver weight, irrespective of the toxin dose. Relative kidney weight increased in the 10-day setting. Linear dose response was found for plasma aspartate aminotransferase, alanine aminotransferase, total cholesterol, urea and creatinine, and exposure time-dependence for plasma creatinine level. The latter was coupled with renal histopathological findings, tubular degeneration and necrosis and the detachment of tubular epithelial cells. The pronounced antioxidant response (reduced glutathione accretion, increasing glutathione peroxidase activity) referred to renal cortical response (5-10 days exposure at 50-100 ppm FB1). Hepatic alterations were moderate, referring to initial phase lipid peroxidation (exposure time dependent difference of conjugated diene and triene concentrations), and slight functional disturbance (? total cholesterol). Lymphocyte DNA damage was moderate, supporting a mild genotoxic effect of FB1. PMID- 30424022 TI - Synthesis of Reduced Graphene Oxide/Titanium Dioxide Nanotubes (rGO/TNT) Composites as an Electrical Double Layer Capacitor. AB - Composites of synthesized reduced graphene oxide (rGO) and titanium dioxide nanotubes (TNTs) were examined and combined at different mass proportions (3:1, 1:1, and 1:3) to develop an electrochemical double layer capacitor (EDLC) nanocomposite. Three different combination methods of synthesis-(1) TNT introduction during GO reduction, (2) rGO introduction during TNT formation, and (3) TNT introduction in rGO sheets using a microwave reactor-were used to produce nanocomposites. Among the three methods, method 3 yielded an EDLC nanomaterial with a highly rectangular cyclic voltammogram and steep electrochemical impedance spectroscopy plot. The specific capacitance for method 3 nanocomposites ranged from 47.26-165.22 F/g while that for methods 1 and 2 nanocomposites only ranged from 14.03-73.62 F/g and 41.93-84.36 F/g, respectively. Furthermore, in all combinations used, the 3:1 graphene/titanium dioxide-based samples consistently yielded the highest specific capacitance. The highest among these nanocomposites is 3:1 rGO/TNT. Characterization of this highly capacitive 3:1 rGO/TNT EDLC composite revealed the dominant presence of partially amorphous rGO as seen in its XRD and SEM with branching crystalline anatase TNTs as seen in its XRD and TEM. Such property showed great potential that is desirable for applications to capacitive deionization and energy storage. PMID- 30424023 TI - BLocate: A Building Identification Scheme in GPS Denied Environments Using Smartphone Sensors. AB - Indoor localization systems assume that the user's current building is known by the GPS (Global Positioning System). However, such assumptions do not hold true in GPS denied environments or where the GPS cannot determine the user's definite location. We present a novel solution to identify the building where the user is present now. The proposed building identification method works on the pervasive magnetic field using a smartphone. The accelerometer data determines the user's activity of being stationary or walking. An Artificial Neural Network is used to identify the user's activities and it shows good results. The magnetometer data is used to identify the user's current building using the fingerprinting approach. Contrary to a traditional fingerprinting approach which stores intensity values, we utilize the patterns formed by the magnetic field strength in the form of a Binary Grid (BG). The BG approach overcomes the limitation of Dynamic Time Warping (DTW) whose performance is degraded when the magnitude of the magnetic data is changed. The experiments are performed with Samsung Galaxy S8 for eight various buildings with different altitudes and number of floors in Yeungnam University, Korea. The results demonstrate that the proposed building identification method can potentially be deployed for building identification. The precision, UAR (Unweighted Average Recall), F score, and Cohen's Kappa values are used to determine the performance of the proposed system. The proposed systems shows very promising results. The system operates without any aid from any infrastructure dependent technologies like GPS or WiFi. Furthermore, we performed many experiments to investigate the impact of isolated points data to build fingerprint database on system's accuracy with 1 m and 2 m distance. Results illustrate that by trading off a minor accuracy, survey labor can be reduced by 50 percent. PMID- 30424024 TI - Ethanolic Extract of Folium Sennae Mediates the Glucose Uptake of L6 Cells by GLUT4 and Ca2. AB - In today's world, diabetes mellitus (DM) is on the rise, especially type 2 diabetes mellitus (T2DM), which is characterized by insulin resistance. T2DM has high morbidity, and therapies with natural products have attracted much attention in the recent past. In this paper, we aimed to study the hypoglycemic effect and the mechanism of an ethanolic extract of Folium Sennae (FSE) on L6 cells. The glucose uptake of L6 cells was investigated using a glucose assay kit. We studied glucose transporter 4 (GLUT4) expression and AMP-activated protein kinase (AMPK), protein kinase B (PKB/Akt), and protein kinase C (PKC) phosphorylation levels using western blot analysis. GLUT4 trafficking and intracellular Ca2+ levels were monitored by laser confocal microscopy in L6 cells stably expressing IRAP mOrange. GLUT4 fusion with plasma membrane (PM) was observed by myc-GLUT4 mOrange. FSE stimulated glucose uptake; GLUT4 expression and translocation; PM fusion; intracellular Ca2+ elevation; and the phosphorylation of AMPK, Akt, and PKC in L6 cells. GLUT4 translocation was weakened by the AMPK inhibitor compound C, PI3K inhibitor Wortmannin, PKC inhibitor Go6983, G protein inhibitor PTX/Gallein, and PLC inhibitor U73122. Similarly, in addition to PTX/Gallein and U73122, the IP3R inhibitor 2-APB and a 0 mM Ca2+-EGTA solution partially inhibited the elevation of intracellular Ca2+ levels. BAPTA-AM had a significant inhibitory effect on FSE-mediated GLUT4 activities. In summary, FSE regulates GLUT4 expression and translocation by activating the AMPK, PI3K/Akt, and G protein-PLC-PKC pathways. FSE causes increasing Ca2+ concentration to complete the fusion of GLUT4 vesicles with PM, allowing glucose uptake. Therefore, FSE may be a potential drug for improving T2DM. PMID- 30424025 TI - Parametric Analysis and Optimization of Radially Layered Cylindrical Piezoceramic/Epoxy Composite Transducers. AB - Radially layered cylindrical piezoceramic/epoxy composite transducers have been designed by integrating the excellent performance of piezoelectric/polymer composites and the radial radiation ability of cylindrical configurations, which are promising in developing novel ultrasonic and underwater sound techniques. Our previous study has explored the effects of the external resistance on the electromechanical characteristics of the transducer, and obtained some valuable findings. To clearly understand the electromechanical characteristics of the transducer and to guide the device design, in this paper, parametric analysis was performed to reveal the effects of multiple key factors on the electromechanical characteristics. These factors include material parameters of epoxy layers, piezoceramic material types, and locations of piezoceramic rings. In order to better analyze the influence of these factors, a modified theoretical model, in which every layer has different geometric and material parameters, was developed based on the model given in the previous work. Furthermore, the reliability of the model was validated by the ANSYS simulation results and the experimental results. The present investigation provides some helpful guidelines to design and optimize the radially layered cylindrical piezoceramic/epoxy composite transducers. PMID- 30424026 TI - Electrowetting Using a Microfluidic Kelvin Water Dropper. AB - The Kelvin water dropper is an electrostatic generator that can generate high voltage electricity through water dripping. A conventional Kelvin water dropper converts the gravitational potential energy of water into electricity. Due to its low current output, Kelvin water droppers can only be used in limited cases that demand high voltage. In the present study, microfluidic Kelvin water droppers (MKWDs) were built in house to demonstrate a low-cost but accurately controlled miniature device for high voltage generation. The performance of the MKWDs was characterized using different channel diameters and flow rates. The best performed MKWD was then used to conduct experiments of the electrowetting of liquid on dielectric surfaces. Electrowetting is a process that has been widely used in manipulating the wetting properties of a surface using an external electric field. Usually electrowetting requires an expensive DC power supply that outputs high voltage. However, in this research, it was demonstrated that electrowetting can be conducted by simply using an MKWD. Additionally, an analytic model was developed to simulate the electrowetting process. Finally, the model's ability to well predict the liquid deformation during electrowetting using MKWDs was validated. PMID- 30424027 TI - Wafer-Level Packaging Method for RF MEMS Applications Using Pre-Patterned BCB Polymer. AB - A radio-frequency micro-electro-mechanical system (RF MEMS) wafer-level packaging (WLP) method using pre-patterned benzo-cyclo-butene (BCB) polymers with a high resistivity silicon cap is proposed to achieve high bonding quality and excellent RF performance. In this process, the BCB polymer was pre-defined to form the sealing ring and bonding layer by the spin-coating and patterning of photosensitive BCB before the cavity formation. During anisotropic wet etching of the silicon wafer to generate the housing cavity, the BCB sealing ring was protected by a sputtered Cr/Au (chromium/gold) layer. The average measured thickness of the BCB layer was 5.9 MUm. In contrast to the conventional methods of spin-coating BCB after fabricating cavities, the pre-patterned BCB method presented BCB bonding layers with better quality on severe topography surfaces in terms of increased uniformity of thickness and better surface flatness. The observation of the bonded layer showed that no void or gap formed on the protruding coplanar waveguide (CPW) lines. A shear strength test was experimentally implemented as a function of the BCB widths in the range of 100 400 MUm. The average shear strength of the packaged device was higher than 21.58 MPa. A RF MEMS switch was successfully packaged using this process with a negligible impact on the microwave characteristics and a significant improvement in the lifetime from below 10 million to over 1 billion. The measured insertion loss of the packaged RF MEMS switch was 0.779 dB and the insertion loss deterioration caused by the package structure was less than 0.2 dB at 30 GHz. PMID- 30424028 TI - Prediction of Necrotic Core and Hypoxic Zone of Multicellular Spheroids in a Microbioreactor with a U-Shaped Barrier. AB - Microfluidic devices have been widely used for biological and cellular studies. Microbioreactors for three-dimensional (3D) multicellular spheroid culture are now considered as the next generation in in vitro diagnostic tools. The feasibility of using 3D cell aggregates to form multicellular spheroids in a microbioreactor with U-shaped barriers has been demonstrated experimentally. A barrier array is an alternative to commonly used microwell traps. The present study investigates oxygen and glucose concentration distributions as key parameters in a U-shaped array microbioreactor using finite element simulation. The effect of spheroid diameter, inlet concentration and flow rate of the medium are systematically studied. In all cases, the channel walls are considered to be permeable to oxygen. Necrotic and hypoxic or quiescent regions corresponding to both oxygen and glucose concentration distributions are identified for various conditions. The results show that the entire quiescent and necrotic regions become larger with increasing spheroid diameter and decreasing inlet and wall concentration. The shear stress (0.5-9 mPa) imposed on the spheroid surface by the fluid flow was compared with the critical values to predict possible damage to the cells. Finally, optimum range of medium inlet concentration (0.13-0.2 mM for oxygen and 3-11 mM for glucose) and flow rate (5-20 MUL/min) are found to form the largest possible multicellular spheroid (500 MUm), without any quiescent and necrotic regions with an acceptable shear stress. The effect of cell-trap types on the oxygen and glucose concentration inside the spheroid was also investigated. The levels of oxygen and glucose concentration for the microwell are much lower than those for the other two traps. The U-shaped barrier created with microposts allows for a continuous flow of culture medium, and so improves the glucose concentration compared to that in the integrated U-shaped barrier. Oxygen concentration for both types of U-shaped barriers is nearly the same. Due to the advantage of using U-shaped barriers to culture multicellular spheroids, the results of this paper can help to choose the experimental and design parameters of the microbioreactor. PMID- 30424029 TI - Theoretical Studies of the Spin-Dependent Electronic Transport Properties in Ethynyl-Terminated Ferrocene Molecular Junctions. AB - The spin-dependent electron transport in the ferrocene-based molecular junctions, in which the molecules are 1,3-substituted and 1,3'-substituted ethynyl ferrocenes, respectively, is studied by the theoretical simulation with nonequilibrium Green's function and density functional theory. The calculated results suggest that the substitution position of the terminal ethynyl groups has a great effect on the spin-dependent current-voltage properties and the spin filtering efficiency of the molecular junctions. At the lower bias, high spin filtering efficiency is found in 1,3'-substituted ethynyl ferrocene junction, which suggests that the spin filtering efficiency is also dependent on the bias voltage. The different spin-dependent transport properties for the two molecular junctions originate from their different evolutions of spin-up and spin-down energy levels. PMID- 30424030 TI - Fabrication of a Micro-Lens Array Mold by Micro Ball End-Milling and Its Hot Embossing. AB - Hot embossing is an efficient technique for manufacturing high-quality micro-lens arrays. The machining quality is significant for hot embossing the micro-lens array mold. This study investigates the effects of micro ball end-milling on the machining quality of AISI H13 tool steel used in the micro-lens array mold. The micro ball end-milling experiments were performed under different machining strategies, and the surface roughness and scallop height of the machined micro lens array mold are measured. The experimental results showed that a three dimensional (3D) offset spiral strategy could achieve a higher machining quality in comparison with other strategies assessed in this study. Moreover, the 3D offset spiral strategy is more appropriate for machining the micro-lens array mold. With an increase of the cutting speed and feed rate, the surface roughness of the micro-lens array mold slightly increases, while a small step-over can greatly reduce the surface roughness. In addition, a hot embossing experiment was undertaken, and the obtained results indicated higher-quality production of the micro-lens array mold by the 3D offset spiral strategy. PMID- 30424031 TI - Optofluidic Tunable Lenses for In-Plane Light Manipulation. AB - Optofluidics incorporates optics and microfluidics together to construct novel devices for microsystems, providing flexible reconfigurability and high compatibility. Among many novel devices, a prominent one is the in-plane optofluidic lens. It manipulates the light in the plane of the substrate, upon which the liquid sample is held. Benefiting from the compatibility, the in-plane optofluidic lenses can be incorporated into a single chip without complicated manual alignment and promises high integration density. In term of the tunability, the in-plane liquid lenses can be either tuned by adjusting the fluidic interface using numerous microfluidic techniques, or by modulating the refractive index of the liquid using temperature, electric field and concentration. In this paper, the in-plane liquid lenses will be reviewed in the aspects of operation mechanisms and recent development. In addition, their applications in lab-on-a-chip systems are also discussed. PMID- 30424032 TI - The Design of Rare-Earth Giant Magnetostrictive Ultrasonic Transducer and Experimental Study on Its Application of Ultrasonic Surface Strengthening. AB - Ultrasonic transducer based on rare-earth giant magnetostrictive materials was designed in accordance with the technical requirements of ultrasonic surface strengthening. The whole structure of the transducer was designed. Modal analysis is made to get the natural frequency of the compound oscillator. The working frequency of the transducer should be guaranteed at about 15.2 kHz and the composite oscillator should have relatively better vibration mode. The magnetic field of the transducer is well sealed and the transducer will not show obvious magnetic flux leakage phenomenon. Which shows the rationality of structural design. Based on this transducer, the ultrasonic surface strengthening experiment on 40 steel was conducted. The surface roughness and hardness of the parts were analyzed after the experiment. The results show that the surface of the parts reach the mirror surface result after the ultrasonic strengthening. When compared to the previous process, the roughness decreases by about 75%, and the surface hardness increases by more than 20%. PMID- 30424033 TI - Editorial for the Special Issue on MEMS Mirrors. AB - MEMS mirrors can steer, modulate, and switch light, as well as control the wavefront for focusing or phase modulation.[...]. PMID- 30424035 TI - Fabrication of 3D Capillary Vessel Models with Circulatory Connection Ports. AB - Bionic microscopic vessel models can contribute to the development of vascular treatment skills and techniques for clinical training. Most microscopic vessel models are limited to two dimensions, but three-dimensional (3D) models are important for surgery, such as on retina microscopic vessels, for the observation of colon microvessels, for measuring the deformability of red blood cell (RBC), and so on. Therefore, bionic 3D blood vessel models are increasingly in demand. For this reason, it is necessary to establish 3D fabrication techniques for microchannels. In this study, we established two fabrication methods for 3D microfluidic devices for the development of microscopic vessel models. First, we employed an exposure method using photolithographic technology. Second, we employed a 3D method using femtosecond laser and mask hybrid exposure (FMEx). Both methods made it possible to fabricate a millimeter-scale 3D structure with a submicrometer resolution and achieve an easy injection of solution. This is because it was possible to fabricate typical microfluidic channels used for model inlet and outlet ports. Furthermore, in the FMEx method, we employed an acid diffusion effect using a chemically amplified resist to form a circular channel cross-section. The acid-diffusion effect made it realizable to fabricate a smooth surface independent of the laser scanning line width. Thus, we succeeded in establishing two methods for the fabrication of bionic 3D microfluidic devices with microfluidic channels having diameters of 15-16 um for mimicking capillary vessels. PMID- 30424034 TI - Liquid Biopsy in Lung Cancer: Clinical Applications of Circulating Biomarkers (CTCs and ctDNA). AB - Lung cancer is by far the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Recent advances in the understanding of the biology of tumors and in highly sensitive detection technologies for molecular analysis offer targeted therapies, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. However, our understanding of an individual patient's lung cancer is often limited by tumor accessibility because of the high risk and invasive nature of current tissue biopsy procedures. "Liquid biopsy", the analysis of circulating biomarkers from peripheral blood, such as circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), offers a new source of cancer-derived materials that may reflect the status of the disease better and thereby contribute to more personalized treatment. In this review, we examined the clinical significance and uniqueness of CTCs and ctDNA from NSCLC patients, isolation and detection methods developed to analyze each type of circulating biomarker, and examples of clinical studies of potential applications for early diagnosis, prognosis, treatment monitoring, and prediction of resistance to therapy. We also discuss challenges that remain to be addressed before such tools are implemented for routine use in clinical settings. PMID- 30424036 TI - On AC-Field-Induced Nonlinear Electroosmosis next to the Sharp Corner-Field Singularity of Leaky Dielectric Blocks and Its Application in on-Chip Micro Mixing. AB - Induced-charge electroosmosis has attracted lots of attention from the microfluidic community over the past decade. Most previous researches on this subject focused on induced-charge electroosmosis (ICEO) vortex streaming actuated on ideally polarizable surfaces immersed in electrolyte solutions. Starting from this point, we conduct herein a linear asymptotic analysis on nonlinear electroosmotic flow next to leaky dielectric blocks of arbitrary electrical conductivity and dielectric permittivity in harmonic AC electric fields, and theoretically demonstrate that observable ICEO fluid motion can be generated at high field frequencies in the vicinity of nearly insulating semiconductors, a very low electrical conductivity, of which can evidently increase the double layer relaxation frequency (inversely proportional to the solid permittivity) to be much higher than the typical reciprocal RC time constant for induced double layer charging on ideally polarizable surfaces. A computational model is developed to study the feasibility of this high-frequency vortex flow field of ICEO for sample mixing in microfluidics, in which the usage of AC voltage signal at high field frequencies may be beneficial to suppress electrochemical reactions to some extent. The influence of various parameters for developing an efficient mixer is investigated, and an integrated arrangement of semiconductor block array is suggested for achieving a reliable mixing performance at relatively high sample fluxes. Our physical demonstration with high-frequency ICEO next to leaky dielectric blocks using a simple channel structure offers valuable insights into the design of high-throughput micromixers for a variety of lab-on-a-chip applications. PMID- 30424037 TI - Experimental Research on Fluid Coupling Flexible Actuator. AB - In the field of micromechanics, piezoelectric actuator has attracted great attention for its high-frequency response, high displacement resolution, and high output force. However, its prospect of practical application has been largely limited by the displacement of micrometer. A fluid coupling flexible actuator was proposed, which utilizes resonance to enlarge the output displacement. The actuator uses a piezoelectric oscillator as an excitation source, fluid as the transmission medium and a flexible diaphragm for the displacement output. On the condition that the fluid is inviscid and incompressible, mathematical formulation of the membrane vibration theory has been analyzed. Then, the prototype is made. The displacement is amplified 21 times to 1.106 mm when driving frequency is 127 Hz. The flexible diaphragm appears the largest displacement output when driving frequency is close to one of the system's natural frequency. Then, the points with zero amplitude form a circle on the surface of flexible diaphragm and the movement direction of the flexible diaphragm is opposite on different sides of the circle. In fact, rather than vibrates at the first resonance frequency, the membrane in the essay is vibrating at a certain higher-order resonance frequency. The experimental results are mainly consistent with the theoretical analysis. PMID- 30424038 TI - Design, Fabrication, and Implementation of an Array-Type MEMS Piezoresistive Intelligent Pressure Sensor System. AB - To meet the radiosonde requirement of high sensitivity and linearity, this study designs and implements a monolithically integrated array-type piezoresistive intelligent pressure sensor system which is made up of two groups of four pressure sensors with the pressure range of 0-50 kPa and 0-100 kPa respectively. First, theoretical models and ANSYS (version 14.5, Canonsburg, PA, USA) finite element method (FEM) are adopted to optimize the parameters of array sensor structure. Combing with FEM stress distribution results, the size and material characteristics of the array-type sensor are determined according to the analysis of the sensitivity and the ratio of signal to noise (SNR). Based on the optimized parameters, the manufacture and packaging of array-type sensor chips are then realized by using the standard complementary metal-oxide-semiconductor (CMOS) and microelectromechanical system (MEMS) process. Furthermore, an intelligent acquisition and processing system for pressure and temperature signals is achieved. The S3C2440A microprocessor (Samsung, Seoul, Korea) is regarded as the core part which can be applied to collect and process data. In particular, digital signal storage, display and transmission are realized by the application of a graphical user interface (GUI) written in QT/E. Besides, for the sake of compensating the temperature drift and nonlinear error, the data fusion technique is proposed based on a wavelet neural network improved by genetic algorithm (GA WNN) for average measuring signal. The GA-WNN model is implemented in hardware by using a S3C2440A microprocessor. Finally, the results of calibration and test experiments achieved with the temperature ranges from -20 to 20 degrees C show that: (1) the nonlinear error and the sensitivity of the array-type pressure sensor are 8330 * 10-4 and 0.052 mV/V/kPa in the range of 0-50 kPa, respectively; (2) the nonlinear error and the sensitivity are 8129 * 10-4 and 0.020 mV/V/kPa in the range of 50-100 kPa, respectively; (3) the overall error of the intelligent pressure sensor system is maintained at +/-0.252% within the hybrid composite range (0-100 kPa). The involved results indicate that the developed array-type composite pressure sensor has good performance, which can provide a useful reference for the development of multi-range MEMS piezoresistive pressure sensor. PMID- 30424039 TI - An Adaptable Interface Conditioning Circuit Based on Triboelectric Nanogenerators for Self-Powered Sensors. AB - In order to solve the limited life problem of typical battery power supply, a self-powered method that is based on the environmental energy harvesting has emerged as an amazing power supply approach. The Tribo-electric-Nano-generator (TENG) has been widely studied because of its high efficiency, low fabrication cost, and high output voltage. However, low output power conversion efficiency has restricted its practical application because of its own extremely high output impedance. In order to match the high output impedance of TENG and increase the output power, this paper presents an adaptable interface conditioning circuit, which is composed of an impedance matching circuit, a synchronous rectifier bridge, a control circuit, and an energy storage device. In the impedance matching circuit, the energy loss of coupling inductance could be reduced by using the bi-directional switch to increase the frequency, and impedance matching circuit can be used to increase the output efficiency of TENG. Experimental results show that, in about 3.6 s, the storing capacitor voltage was basically stable at 5.5 V by using the proposed adapted interface conditioning circuit in this paper. The charging efficiency has increased by 50%. PMID- 30424040 TI - Deterministic Capture of Individual Circulating Tumor Cells Using a Flow Restricted Microfluidic Trap Array. AB - Circulating tumor cells (CTCs) are regarded as a strong biomarker which includes clinically valuable information. However, CTCs are very rare and require precise separation and detection for effective clinical applications. Furthermore, downstream analysis has become necessary to identify the distinct sub-population of CTCs that causes metastasis. Here, we report a flow-restricted microfluidic trap array capable of deterministic single-cell capture of CTCs. The extent of flow restriction, correlating with the device geometry, was then optimized using a highly invasive breast cancer cell line (LM2 MDA-MB-231) to achieve 97% capture efficiency with a single-cell capture rate of 99%. Single-cell capture of CTCs from mice with full-blown metastasis was also demonstrated. The single-CTC capturing ability of the flow-restricted trap array not only showed cell enumerating ability but also high prospects for application in future automated downstream analysis. PMID- 30424041 TI - Mixing Enhancement in Serpentine Micromixers with a Non-Rectangular Cross Section. AB - In this numerical study, a new type of serpentine micromixer involving mixing units with a non-rectangular cross-section is investigated. Similar to other serpentine/spiral shaped micromixers, the design exploits the formation of transversal vortices (Dean flows) in pressure-driven systems, associated with the centrifugal forces experienced by the fluid as it is confined to move along curved geometries. In contrast with other previous designs, though, the use of non-rectangular cross-sections that change orientation between mixing units is exploited to control the center of rotation of the transversal flows formed. The associated extensional flows that thus develop between the mixing segments complement the existent rotational flows, leading to a more complex fluid motion. The fluid flow characteristics and associated mixing are determined numerically from computational solutions to Navier-Stokes equations and the concentration diffusion equation. It is found that the performance of the investigated mixers exceeds that of simple serpentine channels with a more consistent behavior at low and high Reynolds numbers. An analysis of the mixing quality using an entropic mixing index indicates that maximum mixing can be achieved at Reynolds numbers as small as 20 in less than four serpentine mixing units. PMID- 30424042 TI - Analytical, Numerical and Experimental Study of a Horizontal Electrothermal MEMS Microgripper for the Deformability Characterisation of Human Red Blood Cells. AB - Microgrippers are typical microelectromechanical systems (MEMS) that are widely used for micromanipulation and microassembly in both biological and micromanufacturing fields. This paper presents the design, modelling, fabrication and experimental testing of an electrothermal microgripper based on a 'hot and cold arm' actuator design that is suitable for the deformability characterisation of human red blood cells (RBCs). The analysis of the mechanical properties of human RBCs is of great interest in the field of medicine as pathological alterations in the deformability characteristics of RBCs have been linked to a number of diseases. The study of the microgripper's steady-state performance is initially carried out by the development of a lumped analytical model, followed by a numerical model established in CoventorWare(r) (Coventor, Inc., Cary, NC, USA) using multiphysics finite element analysis. Both analytical and numerical models are based on an electothermomechanical analysis, and take into account the internal heat generation due to the applied potential, as well as conduction heat losses through both the anchor pads and the air gap to the substrate. The models are used to investigate key factors of the actuator's performance including temperature distribution, deflection and stresses based on an elastic analysis of structures. Results show that analytical and numerical values for temperature and deflection are in good agreement. The analytical and computational models are then validated experimentally using a polysilicon microgripper fabricated by the standard surface micromachining process, PolyMUMPsTM (Durham, NC, USA). The microgripper's actuation is characterised at atmospheric pressure by optical microscopy studies. Experimental results for the deflection of the microgripper arm tips are found to be in good agreement with the analytical and numerical results, with process-induced variations and the non-linear temperature dependence of the material properties accounting for the slight discrepancies observed. The microgripper is shown to actuate to a maximum opening displacement of 9 MU m at an applied voltage of 3 V, thus being in line with the design requirement of an approximate opening of 8 MU m for securing and characterising a RBC. PMID- 30424044 TI - Multi-Objective Optimizations of a Serpentine Micromixer with Crossing Channels at Low and High Reynolds Numbers. AB - In order to maximize the mixing performance of a micromixer with an integrated three-dimensional serpentine and split-and-recombination configuration, multi objective optimizations were performed at two different Reynolds numbers, 1 and 120, based on numerical simulation. Numerical analyses of fluid flow and mixing in the micromixer were performed using three-dimensional Navier-Stokes equations and convection-diffusion equation. Three dimensionless design variables that were related to the geometry of the micromixer were selected as design variables for optimization. Mixing index at the exit and pressure drop through the micromixer were employed as two objective functions. A parametric study was carried out to explore the effects of the design variables on the objective functions. Latin hypercube sampling method as a design-of-experiment technique has been used to select design points in the design space. Surrogate modeling of the objective functions was performed by using radial basis neural network. Concave Pareto optimal curves comprising of Pareto-optimal solutions that represents the trade off between the objective functions were obtained using a multi-objective genetic algorithm at Re = 1 and 120. Through the optimizations, maximum enhancements of 18.8% and 6.0% in mixing index were achieved at Re = 1 and 120, respectively. PMID- 30424045 TI - Modeling and Closed Loop Flight Testing of a Fixed Wing Micro Air Vehicle. AB - This paper presents the nonlinear six degrees of freedom dynamic modeling of a fixed wing micro air vehicle. The static derivatives of the micro air vehicle are obtained through the wind tunnel testing. The propeller effects on the lift, drag, pitching moment and side force are quantified through wind tunnel testing. The dynamic derivatives are obtained through empirical relations available in the literature. The trim conditions are computed for a straight and constant altitude flight condition. The linearized longitudinal and lateral state space models are obtained about trim conditions. The variations in short period mode, phugoid mode, Dutch roll mode, roll subsidence mode and spiral mode with respect to different trim operating conditions is presented. A stabilizing static output feedback controller is designed using the obtained model. Successful closed loop flight trials are conducted with the static output feedback controller. PMID- 30424043 TI - Turing Instability-Driven Biofabrication of Branching Tissue Structures: A Dynamic Simulation and Analysis Based on the Reaction-Diffusion Mechanism ?. AB - Four-dimensional (4D) biofabrication techniques aim to dynamically produce and control three-dimensional (3D) biological structures that would transform their shapes or functionalities with time, when a stimulus is imposed or cell post printing self-assembly occurs. The evolution of 3D branching patterns via self assembly of cells is critical for the 4D biofabrication of artificial organs or tissues with branched geometry. However, it is still unclear how the formation and evolution of these branching patterns are biologically encoded. Here, we study the biofabrication of lung branching structures utilizing a simulation model based on Turing instability that raises a dynamic reaction-diffusion (RD) process of the biomolecules and cells. The simulation model incorporates partial differential equations of four variables, describing the tempo-spatial distribution of the variables in 3D over time. The simulation results present the formation and evolution process of 3D branching patterns over time and also interpret both the behaviors of side-branching and tip-splitting as the stalk grows and the fabrication style under an external concentration gradient of morphogen, through 3D visualization. This provides a theoretical framework for rationally guiding the 4D biofabrication of lung airway grafts via cellular self organization, which would potentially reduce the complexity of future experimental research and number of trials. PMID- 30424046 TI - Editorial for the Special Issue on Wireless Microdevices and Systems for Biomedical Applications. AB - Wireless microdevices are getting smaller and smaller, and in this special issue seven papers address a few miniaturization challenges in the biomedical field, which are common across different applications. Kargaran et al. [1] proposes a new ultra-low-voltage ultra-low-power LNA, where the reduced current consumption of only 160 MUA, on a supply as low as 0.18 V, has potential to enable future RF receivers for ultra-low-power implantable devices [...]. PMID- 30424047 TI - Adaptive Absolute Ego-Motion Estimation Using Wearable Visual-Inertial Sensors for Indoor Positioning. AB - This paper proposes an adaptive absolute ego-motion estimation method using wearable visual-inertial sensors for indoor positioning. We introduce a wearable visual-inertial device to estimate not only the camera ego-motion, but also the 3D motion of the moving object in dynamic environments. Firstly, a novel method dynamic scene segmentation is proposed using two visual geometry constraints with the help of inertial sensors. Moreover, this paper introduces a concept of "virtual camera" to consider the motion area related to each moving object as if a static object were viewed by a "virtual camera". We therefore derive the 3D moving object's motion from the motions for the real and virtual camera because the virtual camera's motion is actually the combined motion of both the real camera and the moving object. In addition, a multi-rate linear Kalman-filter (MR LKF) as our previous work was selected to solve both the problem of scale ambiguity in monocular camera tracking and the different sampling frequencies of visual and inertial sensors. The performance of the proposed method is evaluated by simulation studies and practical experiments performed in both static and dynamic environments. The results show the method's robustness and effectiveness compared with the results from a Pioneer robot as the ground truth. PMID- 30424048 TI - Design, Preparation and Performance Study of On-Chip Flow-Through Amperometric Sensors with an Integrated Ag/AgCl Reference Electrode. AB - To improve the reference potential stability of on-chip amperometric sensors, we propose a novel integrated Ag/AgCl reference electrode structure. This structure can refresh the saturated potassium chloride filling solution surrounding the Ag/AgCl electrode. We then designed a flow-through amperometric sensor and a multilayer microfluidic chip based on the integrated reference electrode. In order to improve the detection signal strength of the flow-through sensor, a numerical simulation model was established. The simulation results showed that a combination of (1) using a step-type detection cell structure that maintains micro-channel width while reducing micro-channel height, and (2) controlling the sample flow rate to limit the mass transfer of the sensor surface effectively, improves the detection signal strength. The step-type detection cell structure had dimensions of 200 MUm * 200 MUm * 100 MUm (length * width * height), and the electroosmotic flow driving voltage was 120 V/cm. Finally, successful trace detection of Mg2+ and Pb2+ in the water was achieved using the amperometric sensor and microfluidic chip: detection limits were 5 MUmol/L and 84 MUmol/L. The preparation of an on-chip flow-through amperometric sensor with an integrated Ag/AgCl reference electrode will facilitate improved portability of microfluidic detection technology. PMID- 30424049 TI - Highly Fluorinated Methacrylates for Optical 3D Printing of Microfluidic Devices. AB - Highly fluorinated perfluoropolyether (PFPE) methacrylates are of great interest for transparent and chemically resistant microfluidic chips. However, so far only a few examples of material formulations for three-dimensional (3D) printing of these polymers have been demonstrated. In this paper we show that microfluidic chips can be printed using these highly fluorinated polymers by 3D stereolithography printing. We developed photocurable resin formulations that can be printed in commercial benchtop stereolithography printers. We demonstrate that the developed formulations can be printed with minimal cross-sectional area of 600 um for monolithic embedded microfluidic channels and 200 um for open structures. The printed and polymerized PFPE methacrylates show a good transmittance above 70% at wavelengths between 520-900 nm and a high chemical resistance when being exposed to organic solvents. Microfluidic mixers were printed to demonstrate the great variability of different designs that can be printed using stereolithography. PMID- 30424050 TI - Characterization of 3D-Printed Moulds for Soft Lithography of Millifluidic Devices. AB - Increased demand for inexpensive and rapid prototyping methods for micro- and millifluidic lab-on-a-chip (LOC) devices has stimulated considerable interest in alternative cost-effective fabrication techniques. Additive manufacturing (AM) also called three-dimensional (3D) printing-provides an attractive alternative to conventional fabrication techniques. AM has been used to produce LOC master moulds from which positive replicas are made using soft-lithography and a biocompatible elastomer, poly(dimethylsiloxane) (PDMS). Here we characterize moulds made using two AM methods-stereolithography (SLA) and material-jetting (MJ)-and the positive replicas produced by soft lithography and PDMS moulding. The results showed that SLA, more than MJ, produced finer part resolution and finer tuning of feature geometry. Furthermore, as assessed by zebrafish (Danio rerio) biotoxicity tests, there was no toxicity observed in SLA and MJ moulded PDMS replicas. We conclude that SLA, utilizing commercially available printers and resins, combined with PDMS soft-lithography, is a simple and easily accessible technique that lends its self particularly well to the fabrication of biocompatible millifluidic devices, highly suited to the in-situ analysis of small model organisms. PMID- 30424051 TI - Monitoring of Non-Ferrous Wear Debris in Hydraulic Oil by Detecting the Equivalent Resistance of Inductive Sensors. AB - Wear debris in hydraulic oil contains important information on the operation of equipment, which is important for condition monitoring and fault diagnosis in mechanical equipment. A micro inductive sensor based on the inductive coulter principle is presented in this work. It consists of a straight micro-channel and a 3-D solenoid coil wound on the micro-channel. Instead of detecting the inductance change of the inductive sensor, the equivalent resistance change of the inductive sensor is detected for non-ferrous particle (copper particle) monitoring. The simulation results show that the resistance change rate caused by the presence of copper particles is greater than the inductance change rate. Copper particles with sizes ranging from 48 MUm to 150 MUm were used in the experiment, and the experimental results are in good agreement with the simulation results. By detecting the inductive change of the micro inductive sensor, the detection limit of the copper particles only reaches 70 MUm. However, the detection limit can be improved to 48 MUm by detecting the equivalent resistance of the inductive sensor. The equivalent resistance method was demonstrated to have a higher detection accuracy than conventional inductive detection methods for non-ferrous particle detection in hydraulic oil. PMID- 30424052 TI - Determination of the Three-Dimensional Rate of Cancer Cell Rotation in an Optically-Induced Electrokinetics Chip Using an Optical Flow Algorithm. AB - Our group has reported that Melan-A cells and lymphocytes undergo self-rotation in a homogeneous AC electric field, and found that the rotation velocity of these cells is a key indicator to characterize their physical properties. However, the determination of the rotation properties of a cell by human eyes is both gruesome and time consuming, and not always accurate. In this paper, a method is presented to more accurately determine the 3D cell rotation velocity and axis from a 2D image sequence captured by a single camera. Using the optical flow method, we obtained the 2D motion field data from the image sequence and back-project it onto a 3D sphere model, and then the rotation axis and velocity of the cell were calculated. After testing the algorithm on animated image sequences, experiments were also performed on image sequences of real rotating cells. All of these results indicate that this method is accurate, practical, and useful. Furthermore, the method presented there can also be used to determine the 3D rotation velocity of other types of spherical objects that are commonly used in microfluidic applications, such as beads and microparticles. PMID- 30424053 TI - Study of the Operational Safety of a Vascular Interventional Surgical Robotic System. AB - This paper proposes an operation safety early warning system based on LabView (2014, National Instruments Corporation, Austin, TX, USA) for vascular interventional surgery (VIS) robotic system. The system not only provides intuitive visual feedback information for the surgeon, but also has a safety early warning function. It is well known that blood vessels differ in their ability to withstand stress in different age groups, therefore, the operation safety early warning system based on LabView has a vascular safety threshold function that changes in real-time, which can be oriented to different age groups of patients and a broader applicable scope. In addition, the tracing performance of the slave manipulator to the master manipulator is also an important index for operation safety. Therefore, we also transformed the slave manipulator and integrated the displacement error compensation algorithm in order to improve the tracking ability of the slave manipulator to the master manipulator and reduce master-slave tracking errors. We performed experiments "in vitro" to validate the proposed system. According to previous studies, 0.12 N is the maximum force when the blood vessel wall has been penetrated. Experimental results showed that the proposed operation safety early warning system based on LabView combined with operating force feedback can effectively avoid excessive collisions between the surgical catheter and vessel wall to avoid vascular puncture. The force feedback error of the proposed system is maintained between +/-20 mN, which is within the allowable safety range and meets our design requirements. Therefore, the proposed system can ensure the safety of surgery. PMID- 30424054 TI - Design, Fabrication, and Performance Characterization of LTCC-Based Capacitive Accelerometers. AB - In this paper, two versions of capacitive accelerometers based on low-temperature co-fired ceramic (LTCC) technology are developed, different with respect to the detection technique, as well as the mechanical structure. Fabrication of the key structure, a heavy proof mass with thin beams embedded in a large cavity, which is extremely difficult for the conventional LTCC process, is successfully completed by the optimized process. The LC resonant accelerometer, using coupling resonance frequency sensing which is first applied to LTCC accelerometer and may facilitate application in harsh environments, demonstrates a sensitivity of 375 KHz/g over the full scale range 1 g, with nonlinearity less than 6%, and the telemetry distance is 5 mm. The differential capacitive accelerometer adopting differential capacitive sensing presents a larger full scale range 10 g and lower nonlinearity less than 1%, and the sensitivity is 30.27 mV/g. PMID- 30424055 TI - A Novel High-Precision Digital Tunneling Magnetic Resistance-Type Sensor for the Nanosatellites' Space Application. AB - Micro-electromechanical system (MEMS) magnetic sensors are widely used in the nanosatellites field. We proposed a novel high-precision miniaturized three-axis digital tunneling magnetic resistance-type (TMR) sensor. The design of the three axis digital magnetic sensor includes a low-noise sensitive element and high performance interface circuit. The TMR sensor element can achieve a background noise of 150 pT/Hz1/2 by the vertical modulation film at a modulation frequency of 5 kHz. The interface circuit is mainly composed of an analog front-end current feedback instrumentation amplifier (CFIA) with chopper structure and a fully differential 4th-order Sigma-Delta (SigmaDelta) analog to digital converter (ADC). The low-frequency 1/f noise of the TMR magnetic sensor are reduced by the input-stage and system-stage chopper. The dynamic element matching (DEM) is applied to average out the mismatch between the input and feedback transconductor so as to improve the gain accuracy and gain drift. The digital output is achieved by a switched-capacitor SigmaDelta ADC. The interface circuit is implemented by a 0.35 MUm CMOS technology. The performance test of the TMR magnetic sensor system shows that: at a 5 V operating voltage, the sensor can achieve a power consumption of 120 mW, a full scale of +/-1 Guass, a bias error of 0.01% full scale (FS), a nonlinearity of x-axis 0.13% FS, y-axis 0.11% FS, z-axis 0.15% FS and a noise density of x-axis 250 pT/Hz1/2 (at 1 Hz), y-axis 240 pT/Hz1/2 (at 1 Hz), z-axis 250 pT/Hz1/2 (at 1 Hz), respectively. This work has a less power consumption, a smaller size, and higher resolution than other miniaturized magnetometers by comparison. PMID- 30424056 TI - Advances of Optofluidic Microcavities for Microlasers and Biosensors. AB - Optofluidic microcavities with high Q factor have made rapid progress in recent years by using various micro-structures. On one hand, they are applied to microfluidic lasers with low excitation thresholds. On the other hand, they inspire the innovation of new biosensing devices with excellent performance. In this article, the recent advances in the microlaser research and the biochemical sensing field will be reviewed. The former will be categorized based on the structures of optical resonant cavities such as the Fabry-Perot cavity and whispering gallery mode, and the latter will be classified based on the working principles into active sensors and passive sensors. Moreover, the difficulty of single-chip integration and recent endeavors will be briefly discussed. PMID- 30424057 TI - Three-Dimensional Reservoir-Based Dielectrophoresis (rDEP) for Enhanced Particle Enrichment. AB - Selective enrichment of target species is crucial for a wide variety of engineering systems for improved performance of subsequent processes. Dielectrophoresis (DEP) is a powerful electrokinetic method that can be used to focus, trap, concentrate, and separate a variety of species in a label-free manner. The commonly employed methods for DEP suffer from limitations such as electrode fouling and high susceptibility to Joule heating effects. Recently, our group has demonstrated DEP-based manipulations of particles and cells using a novel method of reservoir-based dielectrophoresis (rDEP) which exploits the naturally produced electric field gradients at the reservoir-microchannel junction. Although this method reasonably addresses the limitations mentioned above while maintaining a high simplicity of fabrication, all of our demonstrations so far have used a two-dimensional rDEP, which limits the performance of the devices. This work aims to improve their performance further by making the DEP three-dimensional. Through detailed experimental and numerical analysis, we demonstrate a six-fold increase in the enrichment performance of latex beads and a significant reduction in the power consumption for the new devices, which would allow a more reliable integration of the same into micro total analysis systems. PMID- 30424058 TI - Microstructure Formation of Functional Polymers by Evaporative Self-Assembly under Flexible Geometric Confinement. AB - Polymer microstructures are widely used in optics, flexible electronics, and so forth. We demonstrate a cost-effective bottom-up manner for patterning polymer microstructures by evaporative self-assembly under a flexible geometric confinement at a high temperature. Two-parallel-plates confinement would become curve-to-flat shape geometric confinement as the polydimethylsiloxane (PDMS) cover plate deformed during solvent swelling. We found that a flexible cover plate would be favorable for the formation of gradient microstructures, with various periodicities and widths obtained at varied heights of clearance. After thermal annealing, the edge of the PMMA (Poly-methylmethacrylate) microstructures would become smooth, while the RR-P3HT (regioregular-poly(3-hexylthiophene)) might generate nanocrystals. The morphologies of RR-P3HT structures included thick films, straight lines, hierarchical stripes, incomplete stripes, and regular dots. Finally, a simple field-effect transistor (FET) device was demonstrated with the RR-P3HT micropattern as an active layer. PMID- 30424059 TI - Digital Manufacturing of Selective Porous Barriers in Microchannels Using Multi Material Stereolithography. AB - We have developed a sequential stereolithographic co-printing process using two different resins for fabricating porous barriers in microfluidic devices. We 3D printed microfluidic channels with a resin made of poly(ethylene glycol) diacrylate (MW = 258) (PEG-DA-258), a UV photoinitiator, and a UV sensitizer. The porous barriers were created within the microchannels in a different resin made of either PEG-DA (MW = 575) (PEG-DA-575) or 40% (w/w in water) PEG-DA (MW = 700) (40% PEG-DA-700). We showed selective hydrogen ion diffusion across a 3D-printed PEG-DA-575 porous barrier in a cross-channel diffusion chip by observing color changes in phenol red, a pH indicator. We also demonstrated the diffusion of fluorescein across a 3D-printed 40% PEG-DA-700 porous barrier in a symmetric channel diffusion chip by measuring fluorescence intensity changes across the porous barrier. Creating microfluidic chips with integrated porous barriers using a semi-automated 3D printing process shortens the design and processing time, avoids assembly and bonding complications, and reduces manufacturing costs compared to micromolding processes. We believe that our digital manufacturing method for fabricating selective porous barriers provides an inexpensive, simple, convenient and reproducible route to molecule delivery in the fields of molecular filtration and cell-based microdevices. PMID- 30424060 TI - Micro-UFO (Untethered Floating Object): A Highly Accurate Microrobot Manipulation Technique. AB - A new microrobot manipulation technique with high precision (nano level) positional accuracy to move in a liquid environment with diamagnetic levitation is presented. Untethered manipulation of microrobots by means of externally applied magnetic forces has been emerging as a promising field of research, particularly due to its potential for medical and biological applications. The purpose of the presented method is to eliminate friction force between the surface of the substrate and microrobot. In an effort to achieve high accuracy motion, required magnetic force for the levitation of the microrobot was determined by finite element method (FEM) simulations in COMSOL (version 5.3, COMSOL Inc., Stockholm, Sweden) and verified by experimental results. According to position of the lifter magnet, the levitation height of the microrobot in the liquid was found analytically, and compared with the experimental results head-to head. The stable working range of the microrobot is between 30 um to 330 um, and it was confirmed in both simulations and experimental results. It can follow the given trajectory with high accuracy (<1 um error avg.) at varied speeds and levitation heights. Due to the nano-level positioning accuracy, desired locomotion can be achieved in pre-specified trajectories (sinusoidal or circular). During its locomotion, phase difference between lifter magnet and carrier magnet has been observed, and relation with drag force effect has been discussed. Without using strong electromagnets or bulky permanent magnets, our manipulation approach can move the microrobot in three dimensions in a liquid environment. PMID- 30424061 TI - Experimental Investigation on Ductile Mode Micro-Milling of ZrO2 Ceramics with Diamond-Coated End Mills. AB - ZrO2 ceramics are currently used in a broad range of industrial applications. However, the machining of post-sintered ZrO2 ceramic is a difficult task, due to its high hardness and brittleness. In this study, micro-milling of ZrO2 with two kinds of diamond-coated end mills has been conducted on a Kern MMP 2522 micro milling center (Kern Microtechnik GmbH, Eschenlohe, Germany). To achieve a ductile mode machining of ZrO2, the feed per tooth and depth of cut was set in the range of a few micrometers. Cutting force and machined surface roughness have been measured by a Kistler MiniDynamometer (Kistler Group, Winterthur, Switzerland) and a Talysurf 120 L profilometer (Taylor Hobson Ltd., Leicester, UK), respectively. Machined surface topography and tool wear have been examined under SEM. Experiment results show that the material can be removed in ductile mode, and mirror quality surface with Ra low as 0.02 MUm can be achieved. Curled and smooth chips have been collected and observed. The axial cutting force Fz is always bigger than Fx and Fy, and presents a rising trend with increasing of milling length. Tool wear includes delamination of diamond coating and wear of tungsten carbide substrate. Without the protection of diamond coating, the tungsten carbide substrate was worn out quickly, resulting a change of tool tip geometry. PMID- 30424063 TI - Method of Measuring the Mismatch of Parasitic Capacitance in MEMS Accelerometer Based on Regulating Electrostatic Stiffness. AB - For the MEMS capacitive accelerometer, parasitic capacitance is a serious problem. Its mismatch will deteriorate the performance of accelerometer. Obtaining the mismatch of the parasitic capacitance precisely is helpful for improving the performance of bias and scale. Currently, the method of measuring the mismatch is limited in the direct measuring using the instrument. This traditional method has low accuracy for it would lead in extra parasitic capacitive and have other problems. This paper presents a novel method based on the mechanism of a closed-loop accelerometer. The strongly linear relationship between the output of electric force and the square of pre-load voltage is obtained through theoretical derivation and validated by experiment. Based on this relationship, the mismatch of parasitic capacitance can be obtained precisely through regulating electrostatic stiffness without other equipment. The results can be applied in the design of decreasing the mismatch and electrical adjusting for eliminating the influence of the mismatch. PMID- 30424062 TI - A Label Free Disposable Device for Rapid Isolation of Rare Tumor Cells from Blood by Ultrasounds. AB - The use of blood samples as liquid biopsy is a label-free method for cancer diagnosis that offers benefits over traditional invasive biopsy techniques. Cell sorting by acoustic waves offers a means to separate rare cells from blood samples based on their physical properties in a label-free, contactless and biocompatible manner. Herein, we describe a flow-through separation approach that provides an efficient separation of tumor cells (TCs) from white blood cells (WBCs) in a microfluidic device, "THINUS-Chip" (Thin-Ultrasonic-Separator-Chip), actuated by ultrasounds. We introduce for the first time the concept of plate acoustic waves (PAW) applied to acoustophoresis as a new strategy. It lies in the geometrical chip design: different to other microseparators based on either bulk acoustic waves (BAW) or surface waves (SAW, SSAW and tSAW), it allows the use of polymeric materials without restrictions in the frequency of work. We demonstrate its ability to perform high-throughput isolation of TCs from WBCs, allowing a recovery rate of 84% +/- 8% of TCs with a purity higher than 80% and combined viability of 85% at a flow rate of 80 MUL/min (4.8 mL/h). The THINUS-Chip performs cell fractionation with low-cost manufacturing processes, opening the door to possible easy printing fabrication. PMID- 30424064 TI - Crack-Configuration Analysis of Metal Conductive Track Embedded in Stretchable Elastomer. AB - This paper reports the analysis of the crack configuration of a stretched metal conductive track that is embedded in a stretchable elastomer. The factor determining the crack configurations is analyzed by modeling as well as experiments. The modeling analysis indicates that the crack configuration is determined by the ratio of the elongation stiffness of the track and elastomer, and is classified into two types: multiple-crack growth and single-crack growth. When the track stiffness is considerably lower than the elastomer stiffness, multiple-crack growth type occurs; in the opposite case, single-crack growth type occurs. Hence, to verify the modeling analysis, metal conductive tracks with different thicknesses are fabricated, and the cracks are studied with respect to the crack width, number of cracks, and crack propagation speed. In this study, two conventional metal-track shapes are studied: straight-shaped tracks with track thickness of 0.04-1.17 um, and wave-shaped tracks with track thickness of 2 10 um. For straight-shaped tracks, multiple-crack growth type occurred, when the track thickness was 0.04 um, and the crack configuration gradually changed to a single crack, with the increase in the track thickness. For wave-shaped tracks with track thickness of 2-10 um, only single-crack growth type occurred; however, the crack propagation speed decreased and the maximum stretchability of the track increased, with the increase in the track thickness. PMID- 30424065 TI - Silicon-Based Microfabrication of Free-Floating Neural Probes and Insertion Tool for Chronic Applications. AB - Bidirectional neural interfaces for multi-channel, high-density recording and electrical stimulation of neural activity in the central nervous system are fundamental tools for neuroscience and medical applications. Especially for clinical use, these electrical interfaces must be stable over several years, which is still a major challenge due to the foreign body response of neural tissue. A feasible solution to reduce this inflammatory response is to enable a free-floating implantation of high-density, silicon-based neural probes to avoid mechanical coupling between the skull and the cortex during brain micromotion. This paper presents our latest development of a reproducible microfabrication process, which allows a monolithic integration of a highly-flexible, polyimide based cable with a silicon-stiffened neural probe at a high resolution of 1 um. For a precise and complete insertion of the free-floating probes into the cortex, a new silicon-based, vacuum-actuated insertion tool is presented, which can be attached to commercially available electrode drives. To reduce the electrode impedance and enable safe and stable microstimulation an additional coating with the electrical conductive polymer PEDOT:PSS is used. The long-term stability of the presented free-floating neural probes is demonstrated in vitro and in vivo. The promising results suggest the feasibility of these neural probes for chronic applications. PMID- 30424066 TI - Single-Wall Carbon Nanotube-Coated Cotton Yarn for Electrocardiography Transmission. AB - We fabricated a type of conductive fabric, specifically single-wall carbon nanotube-coated cotton yarns (SWNT-CYs), for electrocardiography (ECG) signal transmission utilizing a "dipping and drying" method. The conductive cotton yarns were prepared by dipping cotton yarns in SWNTs (single-wall carbon nanotubes) solutions and then drying them at room temperature-a simple process that shows consistency in successfully coating cotton yarns with conductive carbon nanotubes (CNTs). The influence of fabrication conditions on the conductivity properties of SWNT-CYs was investigated. The results demonstrate that our conductive yarns can transmit weak bio-electrical (i.e., ECG) signals without significant attenuation and distortion. Our conductive cotton yarns, which combine the flexibility of conventional fabrics and the good conductivity of SWNTs, are promising materials for wearable electronics and sensor applications in the future. PMID- 30424067 TI - Fabrication and Study of Micro Monolithic Tungsten Ball Tips for Micro/Nano-CMM Probes. AB - Micro ball tips with high precision, small diameter, and high stiffness stems are required to measure microstructures with high aspect ratio. Existing ball tips cannot meet such demands because of their weak qualities. This study used an arc discharge melting method to fabricate a micro monolithic tungsten ball tip on a tungsten stylus. The principles of arc discharge and surface tension phenomenon were introduced. The experimental setup was designed and established. Appropriate process parameters, such as impulse voltage, electro discharge time, and discharge gap were determined. Experimental results showed that a ball tip of approximately 60 um in diameter with less than 0.6 um roundness error and 0.6 um center offset could be realized on a 100 um-diameter tungsten wire. The fabricated micro ball tip was installed on a homemade probe, touched by high precision gauge blocks in different directions. A repeatability of 41 nm (K = 2) was obtained. Several interesting phenomena in the ball-forming process were also discussed. The proposed method could be used to fabricate a monolithic probe ball tip, which is necessary for measuring microstructures. PMID- 30424068 TI - Modeling and Analysis of an Opto-Fluidic Sensor for Lab-on-a-Chip Applications. AB - In this work modeling and analysis of an integrated opto-fluidic sensor, with a focus on achievement of single mode optical confinement and continuous flow of microparticles in the microfluidic channel for lab-on-a-chip (LOC) sensing application is presented. This sensor consists of integrated optical waveguides, microfluidic channel among other integrated optical components. A continuous flow of microparticles in a narrow fluidic channel is achieved by maintaining the two sealed chambers at different temperatures and by maintaining a constant pressure of 1 Pa at the centroid of narrow fluidic channel geometry. The analysis of silicon on insulator (SOI) integrated optical waveguide at an infrared wavelength of 1550 nm for single mode sensing operation is presented. The optical loss is found to be 5.7 * 10-4 dB/cm with an effective index of 2.3. The model presented in this work can be effectively used to detect the nature of microparticles and continuous monitoring of pathological parameters for sensing applications. PMID- 30424069 TI - Dielectrophoretic Microfluidic Device for in Vitro Fertilization. AB - The aim of this work was to create a microfluidic platform that uses in vitro fertilization (IVF) and avoids unnecessary damage to oocytes due to the dielectrophoretic force manipulation of the sperms and oocytes that occurs in a traditional IVF operation. The device from this research can serve also to decrease medium volumes, as well as the cost of cell culture under evaporation, and to prevent unnecessary risk in intracytoplasmic sperm injection (ICSI). To decrease the impact and destruction of the oocyte and the sperm, we adopted a positive dielectrophoretic force to manipulate both the sperms and the oocyte. The mouse oocytes were trapped with a positive dielectrophoretic (p-DEP) force by using Indium Tin Oxide (ITO)-glass electrodes; the ITO-glass electrode chip was fabricated by wet etching the ITO-glass. The polydimethylsiloxane (PDMS) flow focusing microfluidic device was used to generate microdroplets of micrometer size to contain the zygotes. The volume of the microdroplets was controlled by adjusting the flow rates of both inlets for oil and the DEP buffer. As a result, the rate of fertilization was increased by about 5% beyond that of the DEP treatment in traditional IVF, and more than 20% developed to the blastocyst stage with a low sperm-oocyte ratio. PMID- 30424071 TI - Topology Optimization of Passive Micromixers Based on Lagrangian Mapping Method. AB - This paper presents an optimization-based design method of passive micromixers for immiscible fluids, which means that the Peclet number infinitely large. Based on topology optimization method, an optimization model is constructed to find the optimal layout of the passive micromixers. Being different from the topology optimization methods with Eulerian description of the convection-diffusion dynamics, this proposed method considers the extreme case, where the mixing is dominated completely by the convection with negligible diffusion. In this method, the mixing dynamics is modeled by the mapping method, a Lagrangian description that can deal with the case with convection-dominance. Several numerical examples have been presented to demonstrate the validity of the proposed method. PMID- 30424072 TI - Fabrication of Through via Holes in Ultra-Thin Fused Silica Wafers for Microwave and Millimeter-Wave Applications. AB - Through via holes in fused silica are a key infrastructure element of microwave and millimeter-wave circuits and 3D integration. In this work, etching through via holes in ultra-thin fused silica wafers using deep reactive-ion etching (DRIE) and laser ablation was developed and analyzed. The experimental setup and process parameters for both methods are presented and compared. For DRIE, three types of mask materials including KMPR 1035 (Nippon Kayaku, Tokyo, Japan) photoresist, amorphous silicon and chromium-with their corresponding optimized processing recipes-were tested, aiming at etching through a 100 MUm fused silica wafer. From the experiments, we concluded that using chromium as the masking material is the best choice when using DRIE. However, we found that the laser ablation method with a laser pulse fluence of 2.89 J/cm2 and a pulse overlap of 91% has advantages over DRIE. The laser ablation method has a simpler process complexity, while offering a fair etching result. In particular, the sidewall profile angle is measured to be 75 degrees to the bottom surface of the wafer, which is ideal for the subsequent metallization process. As a demonstration, a two-inch wafer with 624 via holes was processed using both technologies, and the laser ablation method showed better efficiency compared to DRIE. PMID- 30424070 TI - Optofluidics Refractometers. AB - Refractometry is a classic analytical method in analytical chemistry and biosensing. By integrating advanced micro- and nano-optical systems with well developed microfluidics technology, optofluidics are shown to be a powerful, smart and universal platform for refractive index sensing applications. This paper reviews recent work on optofluidic refractometers based on different sensing mechanisms and structures (e.g., photonic crystal/photonic crystal fibers, waveguides, whisper gallery modes and surface plasmon resonance), and traces the performance enhancement due to the synergistic integration of optics and microfluidics. A brief discussion of future trends in optofluidic refractometers, namely volume sensing and resolution enhancement, are also offered. PMID- 30424073 TI - Mode Transition of Droplet Formation in a Semi-3D Flow-Focusing Microfluidic Droplet System. AB - Uniform droplets have significant potential in many biological applications due to their higher surface area to volume ratio. This paper proposed a semi-three dimensional (sime-3D) flow-focusing microfluidic system, which was fabricated using the multi-layer soft lithography method. Based on the semi-3D structure, we focus on droplets formation modes and droplet uniformity at different bulk concentration of surfactant. The relationships between droplets uniformity, droplets breakup processes (jetting mode, dripping mode and tip-streaming mode) and surfactant concentration was investigated. It was found that three droplet generation modes occur through adjusting the pressure ratio in two inlet channels and the concentration of surfactant in continuous phase liquid. The jetting mode would transform to the dripping mode or the tip-streaming mode as the pressure ratio in different surfactant concentrations increased. Furthermore, the uniformity of droplets could be improved through the transition of jetting to dripping mode. We assumed that the uniformity declined through the transition of jetting to tip-streaming, and explored the specific transitions from jetting to dripping mode and tip-streaming mode. Dripping mode leads to high droplet uniformity, and generation frequency decreases with increasing pressure ratio. Tip-streaming mode is considered as an extreme state of jetting mode, leading to higher formation frequency and smaller droplet size at low uniformity. PMID- 30424074 TI - A Microfluidic Lab-on-a-Disc (LOD) for Antioxidant Activities of Plant Extracts. AB - Antioxidants are an important substance that can fight the deterioration of free radicals and can easily oxidize when exposed to light. There are many methods to measure the antioxidant activity in a biological sample, for example 2,2-diphenyl 1-picrylhydrazyl (DPPH) antioxidant activity test, which is one of the simplest methods used. Despite its simplicity, the organic solvent that has been used to dilute DPPH is easily evaporated and degraded with respect to light exposure and time. Thus, it needs to be used at the earliest convenient time prior to the experiment. To overcome this issue, a rapid and close system for antioxidant activity is required. In this paper, we introduced the Lab-on-a-Disc (LoD) method that integrates the DPPH antioxidant activity test on a microfluidic compact disc (CD). We used ascorbic acid, quercetin, Areca catechu, Polygonum minus, and Syzygium polyanthum plant extracts to compare the results of our proposed LoD method with the conventional method. Contrasted to the arduous laborious conventional method, our proposed method offer rapid analysis and simple determination of antioxidant. This proposed LoD method for antioxidant activity in plants would be a platform for the further development of antioxidant assay. PMID- 30424075 TI - Robotic Cell Rotation Based on Optimal Poking Direction. AB - It is essential to have three-dimensional orientation of cells under a microscope for biological manipulation. Conventional manual cell manipulation is highly dependent on the operator's experience. It has some problems of low repeatability, low efficiency, and contamination. The current popular robotic method uses an injection micropipette to rotate cells. However, the optimal poking direction of the injection micropipette has not been established. In this paper, a strategy of robotic cell rotation based on optimal poking direction is proposed to move the specific structure of the cell to the desired orientation. First, analysis of the force applied to the cell during rotation was done to find the optimal poking direction, where we had the biggest moment of force. Then, the moving trajectory of the injection micropipette was designed to exert rotation force based on optimal poking direction. Finally, the strategy was applied to oocyte rotation in nuclear transfer. Experimental results show that the average completion time was up to 23.6 s and the success rate was 93.3% when the moving speed of the injection micropipette was 100 MUm/s, which demonstrates that our strategy could overcome slippage effectively and with high efficiency. PMID- 30424076 TI - Matrix Effect Study and Immunoassay Detection Using Electrolyte-Gated Graphene Biosensor. AB - Significant progress has been made on the development of electrolyte-gated graphene field effect transistor (EGGFET) biosensors over the last decade, yet they are still in the stage of proof-of-concept. In this work, we studied the electrolyte matrix effects, including its composition, pH and ionic strength, and demonstrate that variations in electrolyte matrices have a significant impact on the Fermi level of the graphene channel and the sensitivity of the EGGFET biosensors. This is attributed to the polarization-induced interaction between the electrolyte and the graphene at the interface which can lead to considerable modulation of the Fermi level of the graphene channel. As a result, the response of the EGGFET biosensors is susceptible to the matrix effect which might lead to high uncertainty or even false results. Then, an EGGFET immunoassay is presented which aims to allow good regulation of the matrix effect. The multichannel design allows in-situ calibration with negative control, as well as statistical validation of the measurement results. Its performance is demonstrated by the detection of human immunoglobulin G (IgG) from serum. The detection range is estimated to be around 2-50 nM with a coefficient of variation (CV) of less than 20% and the recovery rate for IgG detection is around 85-95%. Compared with traditional immunoassay techniques, the EGGFET immunoassay is label-free and ready to be integrated with microfluidics sensor platforms, suggesting its great prospect for point-of-care applications. PMID- 30424077 TI - Improving Electrophoretic Particle Motion Control in Electrophoretic Displays by Eliminating the Fringing Effect via Driving Waveform Design. AB - Electrophoretic display is realized by controlling colored nanoparticles moving in micrometer spaces via electrophoresis. The quality of information display is therefore affected by the unsynchronized particle moving speed and the mismatched electric signal according to the crosstalk of the electric field and inhomogeneous material distribution. In this work, we analyzed the mechanism of a fringe phenomenon that affected the information display quality of electrophoretic displays (EPDs). Electrical driving waveforms (voltage signals) are designed to reduce the fringe phenomenon. By using the optimizing driving waveform, we proposed that the fringe phenomenon is quantified as gray value that can be diminished by 25.5, while keeping a response time of 200 ms. PMID- 30424078 TI - A Magnetic-Field-Assisted Milli-Scale Robotic Assembly Machine: An Approach to Parallel Robotic Automation Systems. AB - Utilizing large numbers of microrobots to heterogeneously integrate small devices to build advanced structures has long been a goal in the field of manufacturing automation. In this paper, we demonstrate a novel milli-scale robotic assembly machine with highly parallel capabilities and assisted with a programmable magnetic field. The prototype machine consists of a 16 * 16 array of electromagnets. Using this machine, we have successfully demonstrated the manipulation of up to nine milli-scale robots simultaneously. Moreover, two microrobots have been operated to demonstrate the proof of concept of two simultaneous pick-and-place light-emitting diodes (LEDs). The design and modeling of the microrobots is discussed. PMID- 30424080 TI - Investigation on Surface Integrity of Rapidly Solidified Aluminum RSA 905 by Magnetic Field-Assisted Finishing. AB - RSA 905, a rapidly solidified aluminum alloy, has been widely utilized in optical, automotive, and aerospace industries owing to its superior mechanical properties such as hardness and strength compared to conventional aluminum alloys. However, the surface finishing of RSA 905 to achieve submicron surface roughness is quite challenging and was rarely addressed. This paper presents an experimental and analytical study on magnetic field-assisted finishing (MFAF) of RSA 905 through a systematic investigation on surface integrity in relation to the MFAF process parameters. The effect of abrasive and polishing speed conditions on material removal and surface roughness was quantitatively investigated. The surface and subsurface quality were evaluated by optical microscope and scanning electron microscope (SEM) observations, residual stress measurement, surface microhardness and tribology test. The results show that relatively high material removal and low surface roughness were obtained under conditions using the SiC abrasive with a grit size of 12 um at polishing speed of 400 rpm or using the Al2O3 abrasive with a grit size of 5 um at polishing speed of 800 rpm. Heat melt layer caused by wire electrical discharge machining (EDM) during the sample preparation was removed by MFAF without inducing new subsurface damage. The MFAF process also helps release the surface residual stress and improve the tribological performance although the surface microhardness was slightly reduced. PMID- 30424079 TI - Optofluidics in Microstructured Optical Fibers. AB - In this paper, we review the development and applications of optofluidics investigated based on the platform of microstructured optical fibers (MOFs) that have miniature air channels along the light propagating direction. The flexibility of the customizable air channels of MOFs provides enough space to implement light-matter interaction, as fluids and light can be guided simultaneously along a single strand of fiber. Different techniques employed to achieve the fluidic inlet/outlet as well as different applications for biochemical analysis are presented. This kind of miniature platform based on MOFs is easy to fabricate, free of lithography, and only needs a tiny volume of the sample. Compared to optofluidics on the chip, no additional waveguide is necessary to guide the light since the core is already designed in MOFs. The measurements of flow rate, refractive index of the filled fluids, and chemical reactions can be carried out based on this platform. Furthermore, it can also demonstrate some physical phenomena. Such devices show good potential and prospects for applications in bio-detection as well as material analysis. PMID- 30424081 TI - A DLC-Punch Array to Fabricate the Micro-Textured Aluminum Sheet for Boiling Heat Transfer Control. AB - A diamond-like carbon (DLC) film, coated on an SKD11 (alloy tool steel) substrate, was shaped by plasma oxidation to form an assembly of DLC macro pillars and to be used as a DLC-punch array that is micro-embossed into aluminum sheets. First, the SKD11 steel die substrate was prepared and DLC-coated to have a film thickness of 10 MUm. This DLC coating worked as a punch material. The two dimensional micro-patterns were printed onto this DLC film by maskless lithography. The unprinted DLC films were selectively removed by plasma oxidation to leave the three-dimensional DLC-punch array on the SKD11 substrate. Each DLC punch had a head of 3.5 MUm * 3.5 MUm and a height of 8 MUm. This DLC-punch array was fixed into the cassette die set for a micro-embossing process using a table top servo-stamper. Furthermore, through numerically controlled micro-embossing, an alignment of rectangular punches was transcribed into a micro-cavity array in the aluminum sheet. The single micro-cavity had a bottom surface of 3.2 MUm * 3.2 MUm and an average depth of 7.5 MUm. A heat-transfer experiment in boiling water was also performed to investigate the effect of micro-cavity texture on bubbling behavior and the boiling curve. PMID- 30424082 TI - Advanced Fabrication of Single-Crystal Diamond Membranes for Quantum Technologies. AB - Many promising applications of single crystal diamond and its color centers as sensor platform and in photonics require free-standing membranes with a thickness ranging from several micrometers to the few 100 nm range. In this work, we present an approach to conveniently fabricate such thin membranes with up to about one millimeter in size. We use commercially available diamond plates (thickness 50 MU m) in an inductively coupled reactive ion etching process which is based on argon, oxygen and SF 6 . We thus avoid using toxic, corrosive feed gases and add an alternative to previously presented recipes involving chlorine based etching steps. Our membranes are smooth (RMS roughness <1 nm) and show moderate thickness variation (central part: <1 MU m over ~200 * 200 MU m 2 ). Due to an improved etch mask geometry, our membranes stay reliably attached to the diamond plate in our chlorine-based as well as SF 6 -based processes. Our results thus open the route towards higher reliability in diamond device fabrication and up-scaling. PMID- 30424084 TI - Paper-Based Sensor Chip for Heavy Metal Ion Detection by SWSV. AB - Heavy metal ion pollution problems have had a terrible influence on human health and the environment. Therefore, the monitoring of heavy metal ions is of great practical significance. In this paper, an electrochemical three-electrode system was fabricated and integrated on nitrocellulose membrane (NC) by the use of magnetron sputtering technology, which exhibited a uniform arrangement of porous structure without further film modification. This paper-based sensor chip was used for Cu2+ detection by square-wave stripping voltammetry (SWSV). Within the ranges of 5~200 MUg.L-1 and 200~1000 MUg.L-1, it showed good linearity of 99.58% and 98.87%, respectively. The limit of detection was 2 MUg.L-1. On the basis of satisfying the detection requirements (10 MUg.L-1), the integrated sensor was small in size and inexpensive in cost. Zn2+, Cd2+, Pb2+ and Bi3+ were also detected by this paper-based sensor chip with good linearity. PMID- 30424083 TI - Microfluidic Devices Developed for and Inspired by Thermotaxis and Chemotaxis. AB - Taxis has been reported in many cells and microorganisms, due to their tendency to migrate toward favorable physical situations and avoid damage and death. Thermotaxis and chemotaxis are two of the major types of taxis that naturally occur on a daily basis. Understanding the details of the thermo- and chemotactic behavioral response of cells and microorganisms is necessary to reveal the body function, diagnosing diseases and developing therapeutic treatments. Considering the length-scale and range of effectiveness of these phenomena, advances in microfluidics have facilitated taxis experiments and enhanced the precision of controlling and capturing microscale samples. Microfabrication of fluidic chips could bridge the gap between in vitro and in situ biological assays, specifically in taxis experiments. Numerous efforts have been made to develop, fabricate and implement novel microchips to conduct taxis experiments and increase the accuracy of the results. The concepts originated from thermo- and chemotaxis, inspired novel ideas applicable to microfluidics as well, more specifically, thermocapillarity and chemocapillarity (or solutocapillarity) for the manipulation of single- and multi-phase fluid flows in microscale and fluidic control elements such as valves, pumps, mixers, traps, etc. This paper starts with a brief biological overview of the concept of thermo- and chemotaxis followed by the most recent developments in microchips used for thermo- and chemotaxis experiments. The last section of this review focuses on the microfluidic devices inspired by the concept of thermo- and chemotaxis. Various microfluidic devices that have either been used for, or inspired by thermo- and chemotaxis are reviewed categorically. PMID- 30424086 TI - A Control and Detecting System of Micro-Near-Infrared Spectrometer Based on a MOEMS Scanning Grating Mirror. AB - Based on the scanning grating mirror we developed, this paper presents a method of the precise control of a scanning grating mirror and of high-speed spectrum data detection. In addition, the system circuit of the scanning grating mirror control and spectrum signal detecting is designed and manufactured in this paper. The mirror control system includes a drive generator module, an amplitude detection module, a feedback control module, and a variable gain amplification (VGA) module; the detecting system includes a field programmable gate array (FPGA) main control module, a synchronous trigger module, an analog-digital conversion (ADC) module, and a universal serial bus (USB) interface module. The final results of the experiment show that the control system has successfully realized the precision control of the swing of the scanning grating mirror and that the detecting system has successfully realized the high-speed acquisition and transmission of the spectral signal and the angle signals. The spectrum has been reconstructed according to the mathematical relationship between the wavelength lambda and the angle beta of the mirror. The resolution of the spectrometer reaches 10 nm in the wavelength range of 800-1800 nm, the signal-to noise ratio (SNR) of the spectrometer is 4562 at full scale, the spectrum data drift is 0.9% in 24 h, and the precision of the closed loop control is 0.06%. PMID- 30424085 TI - Deformation of Red Blood Cells, Air Bubbles, and Droplets in Microfluidic Devices: Flow Visualizations and Measurements. AB - Techniques, such as micropipette aspiration and optical tweezers, are widely used to measure cell mechanical properties, but are generally labor-intensive and time consuming, typically involving a difficult process of manipulation. In the past two decades, a large number of microfluidic devices have been developed due to the advantages they offer over other techniques, including transparency for direct optical access, lower cost, reduced space and labor, precise control, and easy manipulation of a small volume of blood samples. This review presents recent advances in the development of microfluidic devices to evaluate the mechanical response of individual red blood cells (RBCs) and microbubbles flowing in constriction microchannels. Visualizations and measurements of the deformation of RBCs flowing through hyperbolic, smooth, and sudden-contraction microchannels were evaluated and compared. In particular, we show the potential of using hyperbolic-shaped microchannels to precisely control and assess small changes in RBC deformability in both physiological and pathological situations. Moreover, deformations of air microbubbles and droplets flowing through a microfluidic constriction were also compared with RBCs deformability. PMID- 30424087 TI - Capillary Rise of Nanostructured Microwicks. AB - Capillarity refers to the driving force to propel liquid through small gaps in the absence of external forces, and hence enhanced capillary force has been pursued for various applications. In this study, flower like ZnO nanostructures are successfully deposited to enhance capillarity of microwick structures that are specially designed to augment boiling heat transfer performance. Microreactor assisted nanomaterial deposition, MANDTM, is employed with a flow cell to deposit the ZnO nanostructures on a large sized microwick (4.3 cm * 10.7 cm) with dual channel configuration. A capillary rise experiment based on the mass gain method is first performed using water and ethanol (EtOH) as the working liquids to demonstrate the enhanced capillary force induced by the ZnO nanostructure on the microwick structure. It is found that the coating of ZnO nanostructure effectively propels the working fluids through the nano- or micro pores created from the ZnO nanostructure and consequently improves the capillary force. In order to investigate the wicking mechanism of the ZnO coated microwick structure, the capillary rise result based on height measurement was compared with analytical models. It is found that the gravity effect and viscous force play an important role in wicking rise of the coated wick structure. This study aims at demonstrating the capability of the integrated MAND process with a flow cell for producing a large scaled nanostructured surface, which eventually has a great potential for enhanced boiling heat transfer. PMID- 30424088 TI - DC-25 GHz and Low-Loss MEMS Thermoelectric Power Sensors with Floating Thermal Slug and Reliable Back Cavity Based on GaAs MMIC Technology. AB - Wideband and low-loss microwave power measurements are becoming increasingly important for microwave communication and radar systems. To achieve such a power measurement, this paper presents the design and measurement of wideband DC-25 GHz and low-loss MEMS thermoelectric power sensors with a floating thermal slug and a reliable back cavity. In the sensors, the microwave power is converted to thermovoltages via heat. The collaborative design of the thermal slug and the back cavity, i.e., two thermal flow paths, is utilized to improve the efficiency of heat transfer and to ensure reliable applications. These sensors are required to operate up to 25 GHz. In order to achieve low microwave losses at the bandwidth, the floating thermal slug is designed instead of the grounded one. The effects of the floating slug on the reflection losses are analyzed by the simulation. The fabrication of these sensors is completed by GaAs monolithic microwave integrated circuits (MMIC) and micro-electro-mechanical systems (MEMS) technology. Measured reflection losses are less than -25.6 dB up to 12 GHz and 18.6 dB up to 25 GHz. The design of the floating thermal slug reduces the losses, which is equivalent to improving the sensitivity. At 10 and 25 GHz, experiments exhibit that the sensors result in sensitivities of about 51.13 and 35.28 MUV/mW for the floating slug and 81.68 and 55.20 MUV/mW for the floating slug and the cavity. PMID- 30424089 TI - Electroosmotic Flow of Viscoelastic Fluid in a Nanoslit. AB - The electroosmotic flow (EOF) of viscoelastic fluid in a long nanoslit is numerically studied to investigate the rheological property effect of Linear Phan Thien-Tanner (LPTT) fluid on the fully developed EOF. The non-linear Poisson Nernst-Planck equations governing the electric potential and the ionic concentration distribution within the channel are adopted to take into account the effect of the electrical double layer (EDL), including the EDL overlap. When the EDL is not overlapped, the velocity profiles for both Newtonian and viscoelastic fluids are plug-like and increase sharply near the charged wall. The velocity profile resembles that of pressure-driven flow when the EDL is overlapped. Regardless of the EDL thickness, apparent increase of velocity is obtained for viscoelastic fluid of larger Weissenberg number compared to the Newtonian fluid, indicating the shear thinning behavior of the LPTT fluid. The effect of the Weissenberg number on the velocity distribution is less significant as the degree of EDL overlapping increases, due to the overall decrease of the shear rate. The increase (decrease) of polymer extensibility (viscosity ratio) also enhances the EOF of viscoelastic fluid. PMID- 30424090 TI - An FEP Microfluidic Reactor for Photochemical Reactions. AB - Organic syntheses based on photochemical reactions play an important role in the medical, pharmaceutical, and polymeric chemistry. For years, photochemistry was performed using high-pressure mercury lamps and immersion-wells. However, due to excellent yield, control of temperature, selectivity, low consumption of reagents and safety, the microreactors made of fluorinated ethylene propylene (FEP) tubings have recently been used more frequently. Fluoropolymers are the material of choice for many types of syntheses due to their chemical compatibility and low surface energy. The use of tubing restricts the freedom in designing 2D and 3D geometries of the sections of the microreactors, mixing sections, etc., that are easily achievable in the format of a planar chip. A chip microreactor made of FEP is impracticable to develop due to its high chemical inertness and high melting temperature, both of which make it difficult (or impossible) to bond two plates of polymer. Here, we demonstrate a 'click' system, where the two plates of FEP are joined together mechanically using a tenon and a mortise. The concept was presented by us previously for a preparation polytetrafluoroethylene (PTFE) microreactor (Szymborski et al. Sensors Actuators, B Chem. 2017, doi:10.1016/j.snb.2017.09.035). Here, we use the same strategy for FEP plates, test the use of the chips in photochemistry and also describe a custom-designed non-transparent polyethylene (PE) mask-holder with a circular opening to guide and focus the ultraviolet (UV) illumination. The solutions that we describe offer tight microreactor chips, preventing any leakage either of the liquid reagents or of UV light outside the reactor. This allows for conducting photochemical synthesis without a fume hood and without special protection against UV radiation. PMID- 30424091 TI - A Microfluidic Chip with Double-Slit Arrays for Enhanced Capture of Single Cells. AB - The application of microfluidic technology to manipulate cells or biological particles is becoming one of the rapidly growing areas, and various microarray trapping devices have recently been designed for high throughput single-cell analysis and manipulation. In this paper, we design a double-slit microfluidic chip for hydrodynamic cell trapping at the single-cell level, which maintains a high capture ability. The geometric effects on flow behaviour are investigated in detail for optimizing chip architecture, including the flow velocity, the fluid pressure, and the equivalent stress of cells. Based on the geometrical parameters optimized, the double-slit chip enhances the capture of HeLa cells and the drug experiment verifies the feasibility of the drug delivery. PMID- 30424092 TI - Optofluidic Technology for Water Quality Monitoring. AB - Water quality-related incidents are attracting attention globally as they cause serious diseases and even threaten human lives. The current detection and monitoring methods are inadequate because of their long operation time, high cost, and complex process. In this context, there is an increasing demand for low cost, multiparameter, real-time, and continuous-monitoring methods at a higher temporal and spatial resolution. Optofluidic water quality sensors have great potential to satisfy this requirement due to their distinctive features including high throughput, small footprint, and low power consumption. This paper reviews the current development of these sensors for heavy metal, organic, and microbial pollution monitoring, which will breed new research ideas and broaden their applications. PMID- 30424093 TI - Optofluid-Based Reflective Displays. AB - Displays can present information like text, images, or videos in a different color (visible light) by activating the materials in pixels. In a display device, pixels are typically of micrometer size and filled with displaying materials that are aligned and controlled by a display driver integrated circuit. Typical reflective displays can show designed information by manipulating ambient light via the microfluidic behavior in pixels driven by electrophoresis, electrowetting, or electromechanical forces. In this review, we describe the basic working principles and device structures of three reflective displays of electrophoresis display (EPD), electrowetting display (EWD), and interferometric modulator display (IMOD). The optofluidic behavior and controlling factors relating to the display performance are summarized. PMID- 30424094 TI - Passive Mixing inside Microdroplets. AB - Droplet-based micromixers are essential units in many microfluidic devices for widespread applications, such as diagnostics and synthesis. The mixers can be either passive or active. When compared to active methods, the passive mixer is widely used because it does not require extra energy input apart from the pump drive. In recent years, several passive droplet-based mixers were developed, where mixing was characterized by both experiments and simulation. A unified physical understanding of both experimental processes and simulation models is beneficial for effectively developing new and efficient mixing techniques. This review covers the state-of-the-art passive droplet-based micromixers in microfluidics, which mainly focuses on three aspects: (1) Mixing parameters and analysis method; (2) Typical mixing element designs and the mixing characters in experiments; and, (3) Comprehensive introduction of numerical models used in microfluidic flow and diffusion. PMID- 30424095 TI - Electric Power Self-Supply Module for WSN Sensor Node Based on MEMS Vibration Energy Harvester. AB - This paper proposes an electric power self-supply module for the wireless sensor network (WSN) sensor node. The module includes an electromagnetic vibration energy harvester based on micro-electro-mechanical system (MEMS) technology and a processing circuit. The vibration energy harvester presented in this paper is fabricated by an integrated microfabrication process and consists of four similar and relatively independent beam vibration elements. The main functions of the processing circuit are to convert the output of the harvester from unstable alternating current (AC) to stable direct current (DC), charge the super capacitor, and ensure the stable output of the super capacitor. The preliminary test results of the harvester chip show that the chip can output discontinuous pulse voltage, and the range of the voltage value is from tens to hundreds of millivolts in the vibration frequency range of 10-90 Hz. The maximum value that can be reached is 563 mV (at the vibration frequency of 18 Hz). The results of the test show that the harvester can output a relatively high voltage, which can meet the general electric power demand of a WSN sensor node. PMID- 30424096 TI - SF6 Optimized O2 Plasma Etching of Parylene C. AB - Parylene C is a widely used polymer material in microfabrication because of its excellent properties such as chemical inertness, biocompatibility and flexibility. It has been commonly adopted as a structural material for a variety of microfluidics and bio-MEMS (micro-electro-mechanical system) applications. However, it is still difficult to achieve a controllable Parylene C pattern, especially on film thicker than a couple of micrometers. Here, we proposed an SF6 optimized O2 plasma etching (SOOE) of Parylene C, with titanium as the etching mask. Without the SF6, noticeable nanoforest residuals were found on the O2 plasma etched Parylene C film, which was supposed to arise from the micro-masking effect of the sputtered titanium metal mask. By introducing a 5-sccm SF6 flow, the residuals were effectively removed during the O2 plasma etching. This optimized etching strategy achieved a 10 MUm-thick Parylene C etching with the feature size down to 2 MUm. The advanced SOOE recipes will further facilitate the controllable fabrication of Parylene C microstructures for broader applications. PMID- 30424098 TI - PDMS-PDMS Micro Channels Filled with Phase-Change Material for Chip Cooling. AB - This paper reports on a chip cooling solution using polydimethylsiloxane (PDMS) based microfluidic devices filled with n-Octadecane. A thick SU-8 layer of 150 um is used as the master mold for patterning PDMS fabrication. With the SU-8 mold, patterns with straight lines at microscale have been fabricated with standard micro-electro-mechanical system (MEMS) technology. Thermal polymer bonding technique is used to bond the PDMS pattern directly to a flat polydimethylsiloxane (PDMS) film which results in the sealed microchannels. n Octadecane as a phase-change material has been successfully filled in the microchannels using a dispensing machine. Infrared thermal image shows a sharp contrast of the temperature distribution between the chip with n-Octadecane and the empty chip during the same heating process. This result indicates an efficient cooling performance of the microchannel device with phase-change material. A thermal stimulation test demonstrates that a 16 degrees C-lower temperature difference can be achieved. This microchannel device, benefited from the flexibility of PDMS substrate, shows specific advantages in meeting the need for the heat dissipation of flexible electronics such as flexible displays, electronic skins, and wearable electronics. Latent heat of the phase-change material can keep the temperature of devices relatively lower over a period of time, which shows potential application values on discontinuously active flexible electronic devices. PMID- 30424097 TI - Light Manipulation in Inhomogeneous Liquid Flow and Its Application in Biochemical Sensing. AB - Light manipulation has always been the fundamental subject in the field of optics since centuries ago. Traditional optical devices are usually designed using glasses and other materials, such as semiconductors and metals. Optofluidics is the combination of microfluidics and optics, which brings a host of new advantages to conventional solid systems. The capabilities of light manipulation and biochemical sensing are inherent alongside the emergence of optofluidics. This new research area promotes advancements in optics, biology, and chemistry. The development of fast, accurate, low-cost, and small-sized biochemical micro sensors is an urgent demand for real-time monitoring. However, the fluid flow in the on-chip sensor is usually non-uniformed, which is a new and emerging challenge for the accuracy of optical detection. It is significant to reveal the principle of light propagation in an inhomogeneous liquid flow and the interaction between biochemical samples and light in flowing liquids. In this review, we summarize the current state of optofluidic lab-on-a-chip techniques from the perspective of light modulation by the unique dynamic properties of fluid in heterogeneous media, such as diffusion, heat transfer, and centrifugation etc. Furthermore, this review introduces several novel photonic phenomena in an inhomogeneous liquid flow and demonstrates their application in biochemical sensing. PMID- 30424099 TI - Manufacturing of a Compact Micro Air Bearing Device for Power Micro Electro Mechanical System (MEMS) Applications Using Silica Film Assisted Processing. AB - The focus of this study is on the manufacturing of micro air bearings (MABs) using silica film assisted processing. Structure of the three-layer micro air bearing is described in detail and the salient process flow of etching and bonding is illustrated. The main manufacturing challenges and the methods adopted to overcome them are also presented. The uniformity of wet etching for nozzles with 20 MUm in diameter to silica film is improved by adopting an ultrasound assisted method. Particular attention is given to the novel fabrication procedures for the second layer of MAB (with three depths on aft side). This paper develops new applications of silica film in Micro Electro Mechanical System (MEMS) processing for MABs to realize the etching of multi-depth on the same side and efficient three-layer bonding with increased bonding areas. A silica etch mask is proven to achieve a higher accuracy in surface topography when compared to a photoresist mask for multi-depth etching, resulting in precise depth and vertical control. The bonding rate of three-layer direct bonding for MAB is increased by 50% from 0.05 to 0.1 with the novel silica film protection method. PMID- 30424100 TI - A Visualization Technique of a Unique pH Distribution around an Ion Depletion Zone in a Microchannel by Using a Dual-Excitation Ratiometric Method. AB - The ion depletion zone of ion concentration polarization has a strong potential to act as an immaterial barrier, separating delicate submicron substances, including biomolecules, without causing physical damage. However, the detailed mechanisms of the barrier effect remain incompletely understood because it is difficult to visualize the linked behavior of protons, cations, anions, and charged molecules in the thin ion depletion zone. In this study, pH distribution in an ion depletion zone was measured to estimate the role of proton behavior. This was done in order to use it as a tool with good controllability for biomolecule handling in the future. As a result, a unique pH peak was observed at several micrometers distance from the microchannel wall. The position of the peak appeared to be in agreement with the boundary of the ion depletion zone. From this agreement, it is expected that the pH peak has a causal connection to the barrier effect of the ion depletion zone. PMID- 30424101 TI - Analytical Model and Experimental Evaluation of the Micro-Scale Thermal Property Sensor for Single-Sided Measurement. AB - We report a new analytical model of the MEMS-based thermal property sensor for samples which are difficult to handle and susceptible to damage by thermal stimulus, such as living cells. Many sensor designs had been reported for thermal property measurements, but only a few of them have considered the analytical model of the single-sided measurement in which a measurement sample is placed on the sensor substrate. Even in the few designs that have considered the analytical model, their applicable limits are restricted to more than 1 mm length in practical situations. Our new model considers both the sample and the sensor substrate thermal properties and is applicable to a sensor length less than 1 um. In order to minimize the influence of the heat stimulus to the sample, the model formulates the required heat dissipating time for different sensor geometries. We propose fast and precise detection circuit architecture to realize our model, and we discuss the sensor performance for a number of different designs. PMID- 30424102 TI - Effect of Substrate Support on Dynamic Graphene/Metal Electrical Contacts. AB - Recent advances in graphene and other two-dimensional (2D) material synthesis and characterization have led to their use in emerging technologies, including flexible electronics. However, a major challenge is electrical contact stability, especially under mechanical straining or dynamic loading, which can be important for 2D material use in microelectromechanical systems. In this letter, we investigate the stability of dynamic electrical contacts at a graphene/metal interface using atomic force microscopy (AFM), under static conditions with variable normal loads and under sliding conditions with variable speeds. Our results demonstrate that contact resistance depends on the nature of the graphene support, specifically whether the graphene is free-standing or supported by a substrate, as well as on the contact load and sliding velocity. The results of the dynamic AFM experiments are corroborated by simulations, which show that the presence of a stiff substrate, increased load, and reduced sliding velocity lead to a more stable low-resistance contact. PMID- 30424104 TI - Spiral Microchannels with Trapezoidal Cross Section Fabricated by Femtosecond Laser Ablation in Glass for the Inertial Separation of Microparticles. AB - The fabrication and testing of spiral microchannels with a trapezoidal cross section for the passive separation of microparticles is reported in this article. In contrast to previously reported fabrication methods, the fabrication of trapezoidal spiral channels in glass substrates using a femtosecond laser is reported for the first time in this paper. Femtosecond laser ablation has been proposed as an accurate and fast prototyping method with the ability to create 3D features such as slanted-base channels. Moreover, the fabrication in borosilicate glass substrates can provide high optical transparency, thermal resistance, dimensional stability, and chemical inertness. Post-processing steps of the laser engraved glass substrate are also detailed in this paper including hydrogen fluoride (HF) dipping, chemical cleaning, surface activation, and thermal bonding. Optical 3D images of the fabricated chips confirmed a good fabrication accuracy and acceptable surface roughness. To evaluate the particle separation function of the microfluidic chip, 5 MUm, 10 MUm, and 15 MUm particles were focused and recovered from the two outlets of the spiral channel. In conclusion, the new chemically inert separation chip can be utilized in biological or chemical processes where different sizes of cells or particles must be separated, i.e., red blood cells, circulating tumor cells, and technical particle suspensions. PMID- 30424105 TI - Millimeter-Wave Substrate Integrated Waveguide Using Micromachined Tungsten Coated Through Glass Silicon Via Structures. AB - A millimeter-wave substrate integrated waveguide (SIW) has been demonstrated using micromachined tungsten-coated through glass silicon via (TGSV) structures. Two-step deep reactive ion etching (DRIE) of silicon vias and selective tungsten coating onto them using a shadow mask are combined with glass reflow techniques to realize a glass substrate with metal-coated TGSVs for millimeter-wave applications. The proposed metal-coated TGSV structures effectively replace the metallic vias in conventional through glass via (TGV) substrates, in which an additional individual glass machining process to form micro holes in the glass substrate as well as a time-consuming metal-filling process are required. This metal-coated TGSV substrate is applied to fabricate a SIW operating at Ka-band as a test vehicle. The fabricated SIW shows an average insertion loss of 0.69 +/- 0.18 dB and a return loss better than 10 dB in a frequency range from 20 GHz to 45 GHz. PMID- 30424103 TI - Stretchable Tattoo-Like Heater with On-Site Temperature Feedback Control. AB - Wearable tissue heaters can play many important roles in the medical field. They may be used for heat therapy, perioperative warming and controlled transdermal drug delivery, among other applications. State-of-the-art heaters are too bulky, rigid, or difficult to control to be able to maintain long-term wearability and safety. Recently, there has been progress in the development of stretchable heaters that may be attached directly to the skin surface, but they often use expensive materials or processes and take significant time to fabricate. Moreover, they lack continuously active, on-site, unobstructive temperature feedback control, which is critical for accommodating the dynamic temperatures required for most medical applications. We have developed, fabricated and tested a cost-effective, large area, ultra-thin and ultra-soft tattoo-like heater that has autonomous proportional-integral-derivative (PID) temperature control. The device comprises a stretchable aluminum heater and a stretchable gold resistance temperature detector (RTD) on a soft medical tape as fabricated using the cost and time effective "cut-and-paste" method. It can be noninvasively laminated onto human skin and can follow skin deformation during flexure without imposing any constraint. We demonstrate the device's ability to maintain a target temperature typical of medical uses over extended durations of time and to accurately adjust to a new set point in process. The cost of the device is low enough to justify disposable use. PMID- 30424106 TI - A Study on Measurement Variations in Resonant Characteristics of Electrostatically Actuated MEMS Resonators. AB - Microelectromechanical systems (MEMS) resonators require fast, accurate, and cost effective testing for mass production. Among the different test methods, frequency domain analysis is one of the easiest and fastest. This paper presents the measurement uncertainties in electrostatically actuated MEMS resonators, using frequency domain analysis. The influence of the applied driving force was studied to evaluate the measurement variations in resonant characteristics, such as the natural frequency and the quality factor of the resonator. To quantify the measurement results, measurement system analysis (MSA) was performed using the analysis of variance (ANOVA) method. The results demonstrate that the resonant frequency ( f r ) is mostly affected by systematic error. However, the quality (Q) factor strongly depends on the applied driving force. To reduce the measurement variations in Q factor, experiments were carried out to study the influence of DC and/or AC driving voltages on the resonator. The results reveal that measurement uncertainties in the quality factor were high for a small electrostatic force. PMID- 30424107 TI - Comprehensive Die Shear Test of Silicon Packages Bonded by Thermocompression of Al Layers with Thin Sn Capping or Insertions. AB - Thermocompression bonding for wafer-level hermetic packaging was demonstrated at the lowest temperature of 370 to 390 degrees C ever reported using Al films with thin Sn capping or insertions as bonding layer. For shrinking the chip size of MEMS (micro electro mechanical systems), a smaller size of wafer-level packaging and MEMS-ASIC (application specific integrated circuit) integration are of great importance. Metal-based bonding under the temperature of CMOS (complementary metal-oxide-semiconductor) backend process is a key technology, and Al is one of the best candidates for bonding metal in terms of CMOS compatibility. In this study, after the thermocompression bonding of two substrates, the shear fracture strength of dies was measured by a bonding tester, and the shear-fractured surfaces were observed by SEM (scanning electron microscope), EDX (energy dispersive X-ray spectrometry), and a surface profiler to clarify where the shear fracture took place. We confirmed two kinds of fracture mode. One mode is Si bulk fracture mode, where the die shear strength is 41.6 to 209 MPa, proportionally depending on the area of Si fracture. The other mode is bonding interface fracture mode, where the die shear strength is 32.8 to 97.4 MPa. Regardless of the fracture modes, the minimum die shear strength is practical for wafer-level MEMS packaging. PMID- 30424108 TI - Microfabricated Vapor Cells with Reflective Sidewalls for Chip Scale Atomic Sensors. AB - We investigate the architecture of microfabricated vapor cells with reflective sidewalls for applications in chip scale atomic sensors. The optical configuration in operation is suitable for both one-beam and two-beam (pump & probe) schemes. In the miniaturized vapor cells, the laser beam is reflected twice by the aluminum reflectors on the wet etched 54.7 degrees sidewalls to prolong the optical length significantly, thus resulting in a return reflectance that is three times that of bare silicon sidewalls. To avoid limitations faced in the fabrication process, a simpler, more universal and less constrained fabrication process of microfabricated vapor cells for chip scale atomic sensors with uncompromised performance is implemented, which also decreases the fabrication costs and procedures. Characterization measurements show that with effective sidewall reflectors, mm3 level volume and feasible hermeticity, the elongated miniature vapor cells demonstrate a linear absorption contrast improvement by 10 times over the conventional micro-electro-mechanical system (MEMS) vapor cells at ~50 degrees C in the rubidium D1 absorption spectroscopy experiments. At the operating temperature of ~90 degrees C for chip scale atomic sensors, a 50% linear absorption contrast enhancement is obtained with the reflective cell architecture. This leads to a potential improvement in the clock stability and magnetometer sensitivity. Besides, the coherent population trapping spectroscopy is applied to characterize the microfabricated vacuum cells with 46.3 kHz linewidth in the through cell configuration, demonstrating the effectiveness in chip scale atomic sensors. PMID- 30424109 TI - Mechanical Response of MEMS Inductor with Auxiliary Pillar under High-g Shock. AB - Micro-electromechanical system (MEMS) suspended inductors have excellent radio frequency (RF) performance, but poor mechanical properties. To improve their reliability, auxiliary pillars have been used. However, few studies have been carried out on the response of a suspended inductor with auxiliary pillars under high mechanical shock. In this paper, a theoretical method is proposed that combines a single-degree-of-freedom (SDOF) model and a method for solving statically indeterminate structures. The calculated results obtained by this proposed method were verified by finite-element analysis (ANSYS). The calculated results obtained by the proposed method were found to agree well with the results of ANSYS simulation. Finally, this method was extended to a suspended inductor with double auxiliary pillars. The method proposed in this paper provides a theoretical reference for mechanical performance evaluation and reliability optimization design for MEMS suspended inductors with auxiliary pillars. PMID- 30424111 TI - Fabrication Technology and Characteristics Research of the Acceleration Sensor Based on Li-Doped ZnO Piezoelectric Thin Films. AB - An acceleration sensor based on piezoelectric thin films is proposed in this paper, which comprises the elastic element of a silicon cantilever beam and a piezoelectric structure with Li-doped ZnO piezoelectric thin films. The Li-doped ZnO piezoelectric thin films were prepared on SiO2/Si by radio frequency (RF) magnetron sputtering method. The microstructure and micrograph of ZnO piezoelectric thin films is analysed by a X-ray diffractometer (XRD), scanning electron microscope (SEM), X-ray photoelectron spectroscopy (XPS), and piezoresponse force microscopy (PFM), respectively. When the sputtering power of 220 W and Li-doped concentration of 5%, ZnO piezoelectric thin films have a preferred (002) orientation. The chips of the sensor were fabricated on the <100> silicon substrate by micro-electromechanical systems (MEMS) technology, meanwhile, the proposed sensor was packaged on the printed circuit board (PCB). The experimental results show the sensitivity of the proposed sensor is 29.48 mV/g at resonant frequency (1479.8 Hz). PMID- 30424110 TI - Microfluidic Line-Free Mass Sensor Based on an Antibody-Modified Mechanical Resonator. AB - This research proposes a mass sensor based on mechanical resonance that is free from power supply lines (line-free) and incorporates both microfluidic mechanisms and label-free techniques to improve its sensitivity and reusability. The microfluidic line-free mass sensor comprises a disk-shaped mechanical resonator, a separate piezoelectric element used to excite vibrations in the resonator, and a microfluidic mechanism. Electrical power is used to actuate the piezoelectric element, leaving the resonator free from power lines. The microfluidic mechanism allows for rapid, repeat washings to remove impurities from a sample. The microfluidic line-free mass sensor is designed as a label-free sensor to enable high-throughput by modifying and dissociating an antibody on the resonator. The resonator was fabricated by photolithography and the diameter and thickness were 4 mm and 0.5 mm, respectively. The line-free mass sensor enabled a high Q-factor and resonance frequency of 7748 MHz and 1.402 MHz, respectively, to be achieved even in liquids, facilitating the analysis of human salivary cortisol. The line free mass sensor could be used for repeated measurements with the microfluidic mechanism, and the resonator could be fully washed out. It was concluded that the microfluidic line-free mass sensor was suitable to analyze the concentration of a salivary hormone, cortisol, in human saliva samples, and that it provided high throughput suitable for point-of-care testing. PMID- 30424112 TI - On Developing Field-Effect-Tunable Nanofluidic Ion Diodes with Bipolar, Induced Charge Electrokinetics. AB - We introduce herein the induced-charge electrokinetic phenomenon to nanometer fluidic systems; the design of the nanofluidic ion diode for field-effect ionic current control of the nanometer dimension is developed by enhancing internal ion concentration polarization through electrochemical transport of inhomogeneous inducing-counterions resulting from double gate terminals mounted on top of a thin dielectric layer, which covers the nanochannel connected to microfluidic reservoirs on both sides. A mathematical model based on the fully-coupled Poisson Nernst-Plank-Navier-Stokes equations is developed to study the feasibility of this structural configuration causing effective ionic current rectification. The effect of various physiochemical and geometrical parameters, such as the native surface charge density on the nanochannel sidewalls, the number of gate electrodes (GE), the gate voltage magnitude, and the solution conductivity, permittivity, and thickness of the dielectric coating, as well as the size and position of the GE pair of opposite gate polarity, on the resulted rectification performance of the presented nanoscale ionic device is numerically analyzed by using a commercial software package, COMSOL Multiphysics (version 5.2). Three types of electrohydrodynamic flow, including electroosmosis of 1st kind, induced charge electroosmosis, and electroosmosis of 2nd kind that were originated by the Coulomb force within three distinct charge layers coexist in the micro/nanofluidic hybrid network and are shown to simultaneously influence the output current flux in a complex manner. The rectification factor of a contrast between the 'on' and 'off' working states can even exceed one thousand-fold in the case of choosing a suitable combination of several key parameters. Our demonstration of field-effect-tunable nanofluidic ion diodes of double external gate electrodes proves invaluable for the construction of a flexible electrokinetic platform for ionic current control and may help transform the field of smart, on-chip, integrated circuits. PMID- 30424113 TI - Quantitative Evaluation of Dielectric Breakdown of Silicon Micro- and Nanofluidic Devices for Electrophoretic Transport of a Single DNA Molecule. AB - In the present study, we quantitatively evaluated dielectric breakdown in silicon based micro- and nanofluidic devices under practical electrophoretic conditions by changing the thickness of the insulating layer. At higher buffer concentration, a silicon nanofluidic device with a 100 nm or 250 nm silicon dioxide layer tolerated dielectric breakdown up to ca. 10 V/cm, thereby allowing successful electrophoretic migration of a single DNA molecule through a nanochannel. The observed DNA migration behavior suggested that parameters, such as thickness of the insulating layer, tolerance of dielectric breakdown, and bonding status of silicon and glass substrate, should be optimized to achieve successful electrophoretic transport of a DNA molecule through a nanopore for nanopore-based DNA sequencing applications. PMID- 30424114 TI - Bonding-Based Wafer-Level Vacuum Packaging Using Atomic Hydrogen Pre-Treated Cu Bonding Frames. AB - A novel surface activation technology for Cu-Cu bonding-based wafer-level vacuum packaging using hot-wire-generated atomic hydrogen treatment was developed. Vacuum sealing temperature at 300 degrees C was achieved by atomic hydrogen pre treatment for Cu native oxide reduction, while 350 degrees C was needed by the conventional wet chemical oxide reduction procedure. A remote-type hot-wire tool was employed to minimize substrate overheating by thermal emission from the hot wire. The maximum substrate temperature during the pre-treatment is lower than the temperature of Cu nano-grain re-crystallization, which enhances Cu atomic diffusion during the bonding process. Even after 24 h wafer storage in atmospheric conditions after atomic hydrogen irradiation, low-temperature vacuum sealing was achieved because surface hydrogen species grown by the atomic hydrogen treatment suppressed re-oxidation. Vacuum sealing yield, pressure in the sealed cavity and bonding shear strength by atomic hydrogen pre-treated Cu-Cu bonding are 90%, 5 kPa and 100 MPa, respectively, which are equivalent to conventional Cu-Cu bonding at higher temperature. Leak rate of the bonded device is less than 10-14 Pa m3 s-1 order, which is applicable for practical use. The developed technology can contribute to low-temperature hermetic packaging. PMID- 30424115 TI - Photopatternable Magnetic Hollowbots by Nd-Fe-B Nanocomposite for Potential Targeted Drug Delivery Applications. AB - In contrast to traditional drug administration, targeted drug delivery can prolong, localize, target and have a protected drug interaction with the diseased tissue. Drug delivery carriers, such as polymeric micelles, liposomes, dendrimers, nanotubes, and so on, are hard to scale-up, costly, and have short shelf life. Here we show the novel fabrication and characterization of photopatternable magnetic hollow microrobots that can potentially be utilized in microfluidics and drug delivery applications. These magnetic hollowbots can be fabricated using standard ultraviolet (UV) lithography with low cost and easily accessible equipment, which results in them being easy to scale up, and inexpensive to fabricate. Contact-free actuation of freestanding magnetic hollowbots were demonstrated by using an applied 900 G external magnetic field to achieve the movement control in an aqueous environment. According to the movement clip, the average speed of the magnetic hollowbots was estimated to be 1.9 mm/s. PMID- 30424117 TI - Topology Optimization of Spatially Compliant Mechanisms with an Isomorphic Matrix of a 3-UPC Type Parallel Prototype Manipulator. AB - A novel topology optimization approach is proposed in this paper for the design of three rotational degree-of-freedom (DOF) spatially compliant mechanisms, combining the Jacobian isomorphic mapping matrix with the solid isotropic material with penalization (SIMP) topological method. In this approach, the isomorphic Jacobian matrix of a 3-UPC (U: universal joint, P: prismatic joint, C: cylindrical joint) type parallel prototype manipulator is formulated. Subsequently, the orthogonal triangular decomposition and differential kinematic method is applied to uncouple the Jacobian matrix to construct a constraint for topology optimization. Firstly, with respect to the 3-UPC type parallel prototype manipulator, the Jacobian matrix is derived to map the inputs and outputs to be used for initializing the topology optimization process. Secondly, the orthogonal triangular decomposition with the differential kinematic method is used to reconstruct the uncoupled mapping matrix to derive the 3-UPC type parallel prototype manipulator. Finally, a combination of the solid isotropic material with penalization (SIMP) method and the isomorphic mapping matrix is applied to construct the topological model. A typical three rotational DOF spatially compliant mechanism is reported as a numerical example to demonstrate the effectiveness of the proposed method. PMID- 30424118 TI - Research and Analysis of MEMS Switches in Different Frequency Bands. AB - Due to their high isolation, low insertion loss, high linearity, and low power consumption, microelectromechanical systems (MEMS) switches have drawn much attention from researchers in recent years. In this paper, we introduce the research status of MEMS switches in different bands and several reliability issues, such as dielectric charging, contact failure, and temperature instability. In this paper, some of the following methods to improve the performance of MEMS switches in high frequency are summarized: (1) utilizing combinations of several switches in series; (2) covering a float metal layer on the dielectric layer; (3) using dielectric layer materials with high dielectric constants and conductor materials with low resistance; (4) developing MEMS switches using T-match and pi-match; (5) designing MEMS switches based on bipolar complementary metal-oxide-semiconductor (BiCMOS) technology and reconfigurable MEMS' surfaces; (6) employing thermal compensation structures, circularly symmetric structures, thermal buckle-beam actuators, molybdenum membrane, and thin-film packaging; (7) selecting Ultra-NanoCrystalline diamond or aluminum nitride dielectric materials and applying a bipolar driving voltage, stoppers, and a double-dielectric-layer structure; and (8) adopting gold alloying with carbon nanotubes (CNTs), hermetic and reliable packaging, and mN-level contact. PMID- 30424116 TI - High-Throughput Optofluidic Acquisition of Microdroplets in Microfluidic Systems. AB - Droplet optofluidics technology aims at manipulating the tiny volume of fluids confined in micro-droplets with light, while exploiting their interaction to create "digital" micro-systems with highly significant scientific and technological interests. Manipulating droplets with light is particularly attractive since the latter provides wavelength and intensity tunability, as well as high temporal and spatial resolution. In this review study, we focus mainly on recent methods developed in order to monitor real-time analysis of droplet size and size distribution, active merging of microdroplets using light, or to use microdroplets as optical probes. PMID- 30424119 TI - Fabrication of an Anti-Reflective and Super-Hydrophobic Structure by Vacuum Ultraviolet Light-Assisted Bonding and Nanoscale Pattern Transfer. AB - The application of subwavelength, textured structures to glass surfaces has been shown to reduce reflectivity and also results in self-cleaning due to super hydrophobicity. However, current methods of producing such textures are typically either expensive or difficult to scale up. Based on prior work by the authors, the present study employed a combination of vacuum ultraviolet (VUV) light assisted bonding and release agent-free pattern transfer to fabricate a moth-eye texture on a glass substrate. This was accomplished by forming a cyclic olefin polymer mold master with a moth-eye pattern, transferring this pattern to a polydimethylsiloxane (PDMS) spin coating, activating both the PDMS and a glass substrate with VUV light, and then bonding the PDMS to the glass before releasing the mold. Atomic force microscopy demonstrated that the desired pattern was successfully replicated on the PDMS surface with a high degree of accuracy, and the textured glass specimen exhibited approximately 3% higher transmittance than untreated glass. Contact angle measurements also showed that the hydrophobicity of the textured surface was significantly increased. These results confirm that this new technique is a viable means of fabricating optical nanostructures via a simple, inexpensive process. PMID- 30424120 TI - Progress on the Use of Commercial Digital Optical Disc Units for Low-Power Laser Micromachining in Biomedical Applications. AB - The development of organ-on-chip and biological scaffolds is currently requiring simpler methods for microstructure biocompatible materials in three dimensions, to fabricate structural and functional elements in biomaterials, or modify the physicochemical properties of desired substrates. Aiming at addressing this need, a low-power CD-DVD-Blu-ray laser pickup head was mounted on a programmable three axis micro-displacement system in order to modify the surface of polymeric materials in a local fashion. Thanks to a specially-designed method using a strongly absorbing additive coating the materials of interest, it has been possible to establish and precisely control processes useful in microtechnology for biomedical applications. The system was upgraded with Blu-ray laser for additive manufacturing and ablation on a single platform. In this work, we present the application of these fabrication techniques to the development of biomimetic cellular culture platforms thanks to the simple integration of several features typically achieved with traditional, less cost-effective microtechnology methods in one step or through replica-molding. Our straightforward approach indeed enables great control of local laser microablation or polymerization for true on-demand biomimetic micropatterned designs in transparent polymers and hydrogels and is allowing integration of microfluidics, microelectronics, surface microstructuring, and transfer of superficial protein micropatterns on a variety of biocompatible materials. PMID- 30424122 TI - Position-Space-Based Design of a Symmetric Spatial Translational Compliant Mechanism for Micro-/Nano-Manipulation. AB - Symmetry enables excellent motion performance of compliant mechanisms, such as minimized parasitic motion, reduced cross-axis coupling, mitigated buckling, and decreased thermal sensitivity. However, most existing symmetric compliant mechanisms are heavily over-constrained due to the fact that they are usually obtained by directly adding over-constraints to the associated non-symmetric compliant mechanisms. Therefore, existing symmetric compliant mechanisms usually have relatively complex structures and relatively large actuation stiffness. This paper presents a position-space-based approach to the design of symmetric compliant mechanisms. Using this position-space-based approach, a non-symmetric compliant mechanism can be reconfigured into a symmetric compliant mechanism by rearranging the compliant modules and adding minimal over-constraints. A symmetric spatial translational compliant parallel mechanism (symmetric XYZ compliant parallel mechanism (CPM)) is designed using the position-space-based design approach in this paper. Furthermore, the actuation forces of the symmetric XYZ CPM are nonlinearly and analytically modelled, which are represented by the given primary translations and the geometrical parameters. The maximum difference, between the nonlinear analytical results and the nonlinear finite element analysis (FEA) results, is less than 2.58%. Additionally, a physical prototype of the symmetric XYZ CPM is fabricated, and the desirable motion characteristics such as minimized cross-axis coupling are also verified by FEA simulations and experimental testing. PMID- 30424121 TI - A Horizontal Magnetic Tweezers and Its Use for Studying Single DNA Molecules. AB - We report the development of a magnetic tweezers that can be used to micromanipulate single DNA molecules by applying picoNewton (pN)-scale forces in the horizontal plane. The resulting force-extension data from our experiments show high-resolution detection of changes in the DNA tether's extension: ~0.5 pN in the force and <10 nm change in extension. We calibrate our instrument using multiple orthogonal techniques including the well-characterized DNA overstretching transition. We also quantify the repeatability of force and extension measurements, and present data on the behavior of the overstretching transition under varying salt conditions. The design and experimental protocols are described in detail, which should enable straightforward reproduction of the tweezers. PMID- 30424123 TI - Electrostatically Driven In-Plane Silicon Micropump for Modular Configuration. AB - In this paper, an in-plane reciprocating displacement micropump for liquids and gases which is actuated by a new class of electrostatic bending actuators is reported. The so-called "Nano Electrostatic Drive" is capable of deflecting beyond the electrode gap distance, enabling large generated forces and deflections. Depending on the requirements of the targeted system, the micropump can be modularly designed to meet the specified differential pressures and flow rates by a serial and parallel arrangement of equally working pumping base units. Two selected, medium specific micropump test structure devices for pumping air and isopropanol were designed and investigated. An analytical approach of the driving unit is presented and two-way Fluid-Structure Interaction (FSI) simulations of the micropump were carried out to determine the dynamic behavior. The simulation showed that the test structure device designed for air expected to overcome a total differential pressure of 130 kPa and deliver a flow rate of 0.11 sccm at a 265 Hz driving frequency. The isopropanol design is expected to generate 210 kPa and pump 0.01 sccm at 21 Hz. The device is monolithically fabricated by CMOS-compatible bulk micromachining processes under the use of standard materials only, such as crystalline silicon, silicon dioxide and alumina. PMID- 30424124 TI - Open Design 3D-Printable Adjustable Micropipette that Meets the ISO Standard for Accuracy. AB - Scientific communities are drawn to the open source model as an increasingly utilitarian method to produce and share work. Initially used as a means to develop freely-available software, open source projects have been applied to hardware including scientific tools. Increasing convenience of 3D printing has fueled the proliferation of open labware projects aiming to develop and share designs for scientific tools that can be produced in-house as inexpensive alternatives to commercial products. We present our design of a micropipette that is assembled from 3D-printable parts and some hardware that works by actuating a disposable syringe to a user-adjustable limit. Graduations on the syringe are used to accurately adjust the set point to the desired volume. Our open design printed micropipette is assessed in comparison with a commercial pipette and meets the ISO 8655 standards. PMID- 30424125 TI - Multiple Electrohydrodynamic Effects on the Morphology and Running Behavior of Tiny Liquid Metal Motors. AB - Minimized motors can harvest different types of energy and transfer them into kinetic power to carry out complex operations, such as targeted drug delivery, health care, sensing and so on. In recent years, the liquid metal motor is emerging as a very promising tiny machine. This work is dedicated to investigate the motion characteristics of self-powered liquid metal droplet machines under external electric field, after engulfing a small amount of aluminum. Two new non dimensional parameters, named A and O , are put forward for the first time to evaluate the ratio of the forces resulting from the electric field to the fluidic viscous force and the ratio of the friction force to the fluidic viscous force. Forces exerted on liquid metal droplets, the viscosity between the droplet and the surrounding fluid, the pressure difference on both ends, the friction between the bottom of the droplet and the sink base, and bubble propulsion force are evaluated and estimated regarding whether they are impetus or resistance. Effects of electric field intensity, droplet size, solution concentration and surface roughness etc. on the morphology and running behavior of such tiny liquid metal motors are clarified in detail. This work sheds light on the moving mechanism of the liquid metal droplet in aqueous solutions, preparing for more precise and complicated control of liquid metal soft machines. PMID- 30424126 TI - Parametric Excitation of Optomechanical Resonators by Periodical Modulation. AB - Optical excitation of mechanical resonators has long been a research interest, since it has great applications in the physical and engineering field. Previous optomechanical methods rely on the wavelength-dependent, optical anti-damping effects, with the working range limited to the blue-detuning range. In this study, we experimentally demonstrated the excitation of optomechanical resonators by periodical modulation. The wavelength working range was extended from the blue detuning to red-detuning range. This demonstration will provide a new way to excite mechanical resonators and benefit practical applications, such as optical mass sensors and gyroscopes with an extended working range. PMID- 30424127 TI - Particle-Based Microfluidic Quartz Crystal Microbalance (QCM) Biosensing Utilizing Mass Amplification and Magnetic Bead Convection. AB - Microfluidic quartz crystal microbalances (QCM) can be used as powerful biosensors that not only allow quantifying a target analyte, but also provide kinetic information about the surface processes of binding and release. Nevertheless, their practical use as point-of-care devices is restricted by a limit of detection (LoD) of some ng/cm2. It prohibits the measurement of small molecules in low concentrations within the initial sample. Here, two concepts based on superparamagnetic particles are presented that allow enhancing the LoD of a QCM. First, a particle-enhanced C-reactive protein (CRP) measurement on a QCM is shown. The signal response could be increased by a factor of up to five by utilizing the particles for mass amplification. Further, a scheme for sample pre preparation utilizing convective up-concentration involving magnetic bead manipulation is investigated. These experiments are carried out with a glass device that is fabricated by utilizing a femtosecond laser. Operation regimes for the magnetic manipulation of particles within the microfluidic channel with integrated pole pieces that are activated by external permanent magnets are described. Finally, the potential combination of the concepts of mass amplification and up-concentration within an integrated lab-on-a chip device is discussed. PMID- 30424128 TI - Maskless Surface Modification of Polyurethane Films by an Atmospheric Pressure He/O2 Plasma Microjet for Gelatin Immobilization. AB - A localized maskless modification method of polyurethane (PU) films through an atmospheric pressure He/O2 plasma microjet (APPMUJ) was proposed. The APPMUJ system combines an atmospheric pressure plasma jet (APPJ) with a microfabricated silicon micronozzle with dimension of 30 MUm, which has advantages of simple structure and low cost. The possibility of APPMUJ in functionalizing PU films with hydroxyl (-OH) groups and covalent grafting of gelatin for improving its biocompatibility was demonstrated. The morphologies and chemical compositions of the modified surface were analyzed by scanning electronic microscopy (SEM), Raman spectroscopy, and X-ray photoelectron spectroscopy (XPS). The fluorescent images show the modified surface can be divided into four areas with different fluorescence intensity from the center to the outside domain. The distribution of the rings could be controlled by plasma process parameters, such as the treatment time and the flow rate of O2. When the treatment time is 4 to 5 min with the oxygen percentage of 0.6%, the PU film can be effectively local functionalized with the diameter of 170 MUm. In addition, the modification mechanism of PU films by the APPMUJ is investigated. The localized polymer modified by APPMUJ has potential applications in the field of tissue engineering. PMID- 30424130 TI - Integrated Electromechanical Transduction Schemes for Polymer MEMS Sensors. AB - Polymer Micro ElectroMechanical Systems (MEMS) have the potential to constitute a powerful alternative to silicon-based MEMS devices for sensing applications. Although the use of commercial photoresists as structural material in polymer MEMS has been widely reported, the integration of functional polymer materials as electromechanical transducers has not yet received the same amount of interest. In this context, we report on the design and fabrication of different electromechanical schemes based on polymeric materials ensuring different transduction functions. Piezoresistive transduction made of carbon nanotube-based nanocomposites with a gauge factor of 200 was embedded within U-shaped polymeric cantilevers operating either in static or dynamic modes. Flexible resonators with integrated piezoelectric transduction were also realized and used as efficient viscosity sensors. Finally, piezoelectric-based organic field effect transistor (OFET) electromechanical transduction exhibiting a record sensitivity of over 600 was integrated into polymer cantilevers and used as highly sensitive strain and humidity sensors. Such advances in integrated electromechanical transduction schemes should favor the development of novel all-polymer MEMS devices for flexible and wearable applications in the future. PMID- 30424129 TI - Emerging Anti-Fouling Methods: Towards Reusability of 3D-Printed Devices for Biomedical Applications. AB - Microfluidic devices are used in a myriad of biomedical applications such as cancer screening, drug testing, and point-of-care diagnostics. Three-dimensional (3D) printing offers a low-cost, rapid prototyping, efficient fabrication method, as compared to the costly-in terms of time, labor, and resources-traditional fabrication method of soft lithography of poly(dimethylsiloxane) (PDMS). Various 3D printing methods are applicable, including fused deposition modeling, stereolithography, and photopolymer inkjet printing. Additionally, several materials are available that have low-viscosity in their raw form and, after printing and curing, exhibit high material strength, optical transparency, and biocompatibility. These features make 3D-printed microfluidic chips ideal for biomedical applications. However, for developing devices capable of long-term use, fouling-by nonspecific protein absorption and bacterial adhesion due to the intrinsic hydrophobicity of most 3D-printed materials-presents a barrier to reusability. For this reason, there is a growing interest in anti-fouling methods and materials. Traditional and emerging approaches to anti-fouling are presented in regard to their applicability to microfluidic chips, with a particular interest in approaches compatible with 3D-printed chips. PMID- 30424131 TI - Analysis and Design of a Polygonal Oblique Beam for the Butterfly Vibratory Gyroscope with Improved Robustness to Fabrication Imperfections. AB - This paper focuses on structural optimization of a Butterfly vibratory gyroscope (BFVG). An oblique suspension beam adopting polygonal cross-section is proposed in order to enhance the sensitivity and robustness. The operation principles of the BFVG are introduced. The suspension beam, which was found to be the key component, is selectively stressed. Varying cross sections of the suspension beam, including parallelogram, pentagon, hexagon, platform of pentagon, L-shaped and convex shapes are compared with each other. In particular, in order to show the advantages of the proposed polygonal cross-section, the convex cross-section is used as a reference. The influence of fabrication imperfections, which includes alignment error, silicon thickness error, etching depth error, upper width error, bottom width error and deep reactive-ion etching (DRIE) verticality error, on the oblique beam's spindle azimuth angle of the two cross-sections is analyzed. Further, the quadrature error of two cross-sections with a fabrication defect is analyzed. The theoretical arithmetic results suggest that a polygonal cross-section beam is much more stable than a convex cross-section beam in most cases. The robustness of the fabrication imperfection is improved nine-fold and the quadrature error due to fabrication defect is reduced by 70 percent with a polygonal cross-section. It could be a better candidate for BFVG's oblique beam, which would provide a gyroscope with good robustness and repeatability. PMID- 30424132 TI - Mixing Performance of a 3D Micro T-Mixer with Swirl-Inducing Inlets and Rectangular Constriction. AB - In this paper, three novel 3D micro T-mixers, namely, a micro T-mixer with swirl inducing inlets (TMSI), a micro T-mixer with a rectangular constriction (TMRC), and a micro T-mixer with swirl-inducing inlets and a rectangular constriction (TMSC), were proposed on the basis of the original 3D micro T-mixer (OTM). The flow and mixing performance of these micromixers was numerically analyzed using COMSOL Multiphysics package at a range of Reynolds numbers from 10 to 70. Results show that the three proposed 3D micro T-mixers have achieved better mixing performance than OTM. Due to the coupling effect of two swirl-inducing inlets and a rectangular constriction, the maximum mixing index and pressure drop appeared in TMSC among the four micromixers especially; the mixing index of TMSC reaches 91.8% at Re = 70, indicating that TMSC can achieve effective mixing in a short channel length, but has a slightly higher pressure drop than TMSI and TMRC. PMID- 30424134 TI - Flexible Tactile Sensor Array Based on Aligned MWNTs-PU Composited Sub Microfibers. AB - This present paper describes a novel method to fabricate tactile sensor arrays by producing aligned multi-walled carbon nanotubes (MWNTs)-polyurethane (PU) composite sub-microfiber (SMF) arrays with the electrospinning technique. The proposed sensor was designed to be used as the artificial skin for a tactile sensation system. Although thin fibers in micro- and nanoscale have many good mechanical characteristics and could enhance the alignment of MWNTs inside, the high impedance as a consequence of a small section handicaps its application. In this paper, unidirectional composite SMFs were fabricated orthogonally to the parallel electrodes through a low-cost method to serve as sensitive elements (SEs), and the impedances of SEs were measured to investigate the changes with deformation caused by applied force. The particular piezoresistive mechanism of MWNTs disturbed in SMF was analyzed. The static and dynamic test results of the fabricated tactile sensor were also presented to validate the performance of the proposed design. PMID- 30424136 TI - Fabrication of a Metal Micro Mold by Using Pulse Micro Electroforming. AB - Microfluidic devices have been widely used for biomedical and biochemical applications. Due to its unique characteristics, polymethyl methacrylate (PMMA) show great potential in fabricating microfluidic devices. Hot embossing technology has established itself as a popular method of preparing polymer microfluidic devices in both academia and industry. However, the fabrication of the mold used in hot embossing is time-consuming in general and often impractical for economically efficient prototyping. This paper proposes a modified technology for preparing metal micro molds by using pulse micro electroforming directly on metallic substrate, which could save time and reduce costs. In this method, an additive was used to avoid surface defect on deposited nickel. A chemical etching process was performed on the metallic substrate before the electroforming process in order to improve the bonding strength between the deposited structure and substrate. Finally, with the aim of obtaining a metal micro mold with high surface quality (low surface roughness), an orthogonal experiment was designed and conducted to optimize the electroforming parameters. Additionally, metal micro molds with different structures were well prepared by using the optimized parameters. PMID- 30424133 TI - Particle Manipulation by Optical Forces in Microfluidic Devices. AB - Since the pioneering work of Ashkin and coworkers, back in 1970, optical manipulation gained an increasing interest among the scientific community. Indeed, the advantages and the possibilities of this technique are unsubtle, allowing for the manipulation of small particles with a broad spectrum of dimensions (nanometers to micrometers size), with no physical contact and without affecting the sample viability. Thus, optical manipulation rapidly found a large set of applications in different fields, such as cell biology, biophysics, and genetics. Moreover, large benefits followed the combination of optical manipulation and microfluidic channels, adding to optical manipulation the advantages of microfluidics, such as a continuous sample replacement and therefore high throughput and automatic sample processing. In this work, we will discuss the state of the art of these optofluidic devices, where optical manipulation is used in combination with microfluidic devices. We will distinguish on the optical method implemented and three main categories will be presented and explored: (i) a single highly focused beam used to manipulate the sample, (ii) one or more diverging beams imping on the sample, or (iii) evanescent wave based manipulation. PMID- 30424135 TI - Recent Microdevice-Based Aptamer Sensors. AB - Since the systematic evolution of ligands by exponential enrichment (SELEX) method was developed, aptamers have made significant contributions as bio recognition sensors. Microdevice systems allow for low reagent consumption, high throughput of samples, and disposability. Due to these advantages, there has been an increasing demand to develop microfluidic-based aptasensors for analytical technique applications. This review introduces the principal concepts of aptasensors and then presents some advanced applications of microdevice-based aptasensors on several platforms. Highly sensitive detection techniques, such as electrochemical and optical detection, have been integrated into lab-on-a-chip devices and researchers have moved towards the goal of establishing point-of-care diagnoses for target analyses. PMID- 30424137 TI - Numerical and Experimental Study on Mixing Performances of Simple and Vortex Micro T-Mixers. AB - Vortex flow increases the interface area of fluid streams by stretching along with providing continuous stirring action to the fluids in micromixers. In this study, experimental and numerical analyses on a design of micromixer that creates vortex flow were carried out, and the mixing performance was compared with a simple micro T-mixer. In the vortex micro T-mixer, the height of the inlet channels is half of the height of the main mixing channel. The inlet channel connects to the main mixing channel (micromixer) at the one end at an offset position in a fashion that creates vortex flow. In the simple micro T-mixer, the height of the inlet channels is equal to the height of the channel after connection (main mixing channel). Mixing of fluids and flow field have been analyzed for Reynolds numbers in a range from 1-80. The study has been further extended to planar serpentine microchannels, which were combined with a simple and a vortex T-junction, to evaluate and verify their mixing performances. The mixing performance of the vortex T-mixer is higher than the simple T-mixer and significantly increases with the Reynolds number. The design is promising for efficiently increasing mixing simply at the T-junction and can be applied to all micromixers. PMID- 30424139 TI - Study of the Carrier-Aided Thin Film Electrode Array Design for Cochlear Insertion. AB - The micro-fabricated thin film electrode array (TFEA) has been a promising design for cochlear implants (CIs) because of its cost-effectiveness and fabrication precision. The latest polymer-based cochlear TFEAs have faced difficulties for cochlear insertion due to the lack of structural stiffness. To stiffen the TFEA, dissolvable stiffening materials, TFEAs with different structures, and TFEAs with commercial CIs as carriers have been invested. In this work, the concept of enhancing a Parylene TFEA with Kapton tape as a simpler carrier for cochlear insertion has been proved to be feasible. The bending stiffness of the Kapton aided TFEA was characterized with an analytical model, a finite element model, and a cantilever bending experiment, respectively. While the Kapton tape increased the bending stiffness of the Parylene TFEA by 103 times, the 6-MUm thick TFEA with a similar Young's modulus, as a polyimide, in turn significantly increased the bending stiffness of the 170-MUm-thick Kapton carrier by 60%. This result indicated that even the TFEA is ultra-flexible and that its bending stiffness should not be neglected in the design or selection of its carrier. PMID- 30424138 TI - Preparation and Characteristics of MAPbBr3 Perovskite Quantum Dots on NiOx Film and Application for High Transparent Solar Cells. AB - In this work, a MAPbBr3 quantum dot (QD-MAPbBr3) layer was prepared by a simple and rapid method. Octylammonium bromide (OABr) gives the MAPbBr3 better exciton binding energy, good surface morphology, and stability. To form a nanocrystalline thin film on indium tin oxide (ITO) glass, the QD-MAPbBr3 film was coated by a spin-coating method in a nitrogen-filled glove box and the NiOx film was used as an adhesive layer and hole transport layer. The highest transmittance of MAPbBr3 on NiOx/ITO glass was around 75% at 700 nm. This study also reported a high transparent and perovskite bulk-free ITO/NiOx/QD-MAPbBr3/C60/Ag solar cell where the NiOx, QD-MAPbBr3, and C60 were used as a hole transport layer, active layer, and electron transport layer, respectively. PMID- 30424140 TI - High Temperature AlGaN/GaN Membrane Based Pressure Sensors. AB - A highly sensitive Gallium Nitride (GaN) diaphragm based micro-scale pressure sensor with an AlGaN/GaN heterostructure field effect transistor (HFET) deflection transducer has been designed and fabricated for high temperature applications. The performance of the pressure sensor was studied over a pressure range of 20 kPa, which resulted in an ultra-high sensitivity of ~0.76%/kPa, with a signal-to-noise ratio as high as 16 dB, when biased optimally in the subthreshold region. A high gauge factor of 260 was determined from strain distribution in the sensor membrane obtained from finite element simulations. A repeatable sensor performance was observed over multiple pressure cycles up to a temperature of 200 degrees C. PMID- 30424141 TI - Fabrication of a Hydrophilic Line on a Hydrophobic Surface by Laser Ablation Processing. AB - A hydrophilic line on a hydrophobic surface was fabricated by using plasma etching and laser ablation processing in this paper. We fabricated the nanospikes on a polyimide surface by using the plasma etching processing. CHF3 plasma treatment for hydrophobic coating was conducted on these nanospikes. We fabricated the microgrooves on the hydrophobic nanospikes surface using laser ablation processing. The microgroove had hydrophilic characteristics. In order to measure the hydrophilic characteristics of the microgroove, a solution that was dispersed with silver nanoparticles was used. The hydrophilic line on the hydrophobic surface was dipped in the silver nanoparticle solution. The silver nanoparticles were attached on the hydrophilic microgroove and not on the hydrophobic surface. We concluded that the laser heat affected zone should be reduced for reducing the hydrophilic line width. This hydrophilic pattern on the hydrophobic surface can be used for cell growth, protein manipulation, the spotting of biomolecules, micro-fluidics and water collection. This functional surface can especially be used for an electric flexible circuit, which is newly proposed in this paper. PMID- 30424143 TI - Performance Analysis and Numerical Evaluation of Mixing in 3-D T-Shape Passive Micromixers. AB - In micromixer devices, laminar characteristics of the flow domain and small diffusion constants of the fluid samples that are mixed characterize the mixing process. The advection dominant flow and transport processes that develop in these devices not only create significant challenges for numerical solution of the problem, but they are also the source of numerical errors which may lead to confusing performance evaluations that are reported in the literature. In this study, the finite volume method (FVM) and finite element method (FEM) are used to characterize these errors and critical issues in numerical performance evaluations are highlighted. In this study, we used numerical methods to evaluate the mixing characteristics of a typical T-shape passive micromixer for several flow and transport parameters using both FEM and FVM, although the numerical procedures described are also equally applicable to other geometric designs as well. The outcome of the study shows that the type of stabilization technique used in FEM is very important and should be documented and reported. Otherwise, erroneous mixing performance may be reported since the added artificial diffusion may significantly affect the mixing performance in the device. Similarly, when FVM methods are used, numerical diffusion errors may become important for certain unstructured discretization techniques that are used in the idealization of the solution domain. This point needs to be also analyzed and reported when FVM is used in performance evaluation of micromixer devices. The focus of this study is not on improving the mixing performance of micromixers. Instead, we highlight the bench scale characteristics of the solutions and the mixing evaluation procedures used when FVM and FEM are employed. PMID- 30424142 TI - Applications of Laser Welding in Dentistry: A State-of-the-Art Review. AB - The dental industry without lasers is inconceivable right now. This captivating technology has outlasted other possible alternative technologies applied in dentistry in the past due to its precision, accuracy, minimal invasive effect as well as faster operating time. Other alternatives such as soldering, resistance (spot) welding, plasma (torch) welding, and single pulse tungsten inert gas welding have their pros and cons; nevertheless, laser welding remains the most suitable option so far for dental application. This paper attempts to give an insight into the laser principle and types of lasers used for dental purposes, types of dental alloys used by the dentist, and effect of laser parameters on prosthesis/implants. It is apparent from the literature review that laser assisted dental welding will continue to grow and will become an unparalleled technology for dental arena. PMID- 30424144 TI - Novel EMD-Based Extraction Approach of Electric Field Fringe Impacts on a Micro Capacitive Displacement Sensor. AB - This paper presents an EMD (empirical mode decomposition)-based extraction approach to decouple the electric field fringe component impacts on the nonlinearity errors of a micro encoder-like capacitive displacement sensor. A calculated capacitance model built under Maxwell's equations against the impacts of electric field fringe component indicates that signals of this sensor are all in periodic co-sinusoidal waveforms. Applying the proposed EMD scheme, signals are decomposed into sets of intrinsic mode functions (IMFs) and a residual, in which a fundamental component represents all the features of sensor signal and reserves the local information. Interpreting sensor information from the extracted component instead of the original signal drastically diminishes the impacts of electric field fringe effect. Results from a test bench shows that after applying the EMD-based extraction approach, waveform errors were decreased from over 4.18% to less than 0.89%. Nonlinearity of the interpreted displacement was decreased from 1.54% to 0.29% for 8 mm stroke. PMID- 30424145 TI - Fabricating and Characterizing the Microfluidic Solid Phase Extraction Module Coupling with Integrated ESI Emitters. AB - Microfluidic chips coupling with mass spectrometry (MS) will be of great significance to the development of relevant instruments involving chemical and bio-chemical analysis, drug detection, food and environmental applications and so on. In our previous works, we proposed two types of microfluidic electrospray ionization (ESI) chip coupling with MS: the two-phase flow focusing (FF) ESI microfluidic chip and the corner-integrated ESI emitter, respectively. However the pretreatment module integrated with these ESI emitters is still a challenging problem. In this paper, we concentrated on integrating the solid phase micro extraction (SPME) module with our previous proposed on-chip ESI emitters; the fabrication processes of such SPME module are fully compatible with our previous proposed ESI emitters based on the multi-layer soft lithography. We optimized the structure of the integrated chip and characterized its performance using standard samples. Furthermore, we verified its abilities of salt removal, extraction of multiple analytes and separation through on-chip elution using mimic biological urine spiked with different drugs. The results indicated that our proposed integrated module with ESI emitters is practical and effective for real biological sample pretreatment and MS detection. PMID- 30424146 TI - Technology for 3D System Integration for Flexible Wireless Biomedical Applications. AB - This paper presents a new 3D bottom-up packing technology for integrating a chip, an induction coil, and interconnections for flexible wireless biomedical applications. Parylene was used as a flexible substrate for the bottom-up embedding of the chip, insulation layer, interconnection, and inductors to form a flexible wireless biomedical microsystem. The system can be implanted on or inside the human body. A 50-MUm gold foil deposited through laser micromachining by using a picosecond laser was used as an inductor to yield a higher quality factor than that yielded by thickness-increasing methods such as the fold-and bond method or thick-metal electroplating method at the operation frequency of 1 MHz. For system integration, parylene was used as a flexible substrate, and the contact pads and connections between the coil and chip were generated using gold deposition. The advantage of the proposed process can integrate the chip and coil vertically to generate a single biocompatible system in order to reduce required area. The proposed system entails the use of 3D integrated circuit packaging concepts to integrate the chip and coil. The results validated the feasibility of this technology. PMID- 30424147 TI - FR4-Based Electromagnetic Scanning Micromirror Integrated with Angle Sensor. AB - This paper presents a flame retardant 4 (FR4)-based electromagnetic scanning micromirror, which aims to overcome the limitations of conventional microelectromechanical systems (MEMS) micromirrors for the large-aperture and low frequency scanning applications. This micromirror is fabricated through a commercial printed circuit board (PCB) technology at a low cost and with a short process cycle, before an aluminum-coated silicon mirror plate with a large aperture is bonded on the FR4 platform to provide a high surface quality. In particular, an electromagnetic angle sensor is integrated to monitor the motion of the micromirror in real time. A prototype has been assembled and tested. The results show that the micromirror can reach the optical scan angle of 11.2 ? with a low driving voltage of only 425 mV at resonance (361.8 Hz). At the same time, the signal of the integrated angle sensor also shows good signal-to-noise ratio, linearity and sensitivity. Finally, the reliability of the FR4 based micro-mirror has been tested. The prototype successfully passes both shock and vibration tests. Furthermore, the results of the long-term mechanical cycling test (50 million cycles) suggest that the maximum variations of resonant frequency and scan angle are less than 0.3% and 6%, respectively. Therefore, this simple and robust micromirror has great potential in being useful in a number of optical microsystems, especially when large-aperture or low-frequency is required. PMID- 30424149 TI - CO2 Laser-Based Rapid Prototyping of Micropumps. AB - The fabrication of microdevices for fluidic control often requires the use of flexible diaphragms in a way that requires cleanroom equipment and compromises performance. We use a CO 2 laser to perform the standard ablative techniques of cutting and engraving materials, but we also apply a method that we call laser placement. This allows us to fabricate precisely-positioned and precisely-sized, isolated diaphragms. This in turn enables the rapid prototyping of integrated multilayer microfluidic devices to form complex structures without the need for manual positioning or cleanroom equipment. The fabrication process is also remarkably rapid and capable of being scaled to manufacturing levels of production. We explore the use of these devices to construct a compact system of peristaltic pumps that can form water in oil droplets without the use of the non pulsatile pumping systems typically required. Many devices can be fabricated at a time on a sheet by sheet basis with a fabrication process that, to our knowledge, is the fastest reported to date for devices of this type (requiring only 3 h). Moreover, this system is unusually compact and self-contained. PMID- 30424150 TI - A Non-Resonant Kinetic Energy Harvester for Bioimplantable Applications. AB - A linear non-resonant kinetic energy harvester for implantable devices is presented. The design contains a metal platform with permanent magnets, two stators with three-dimensional helical coils for increased power generation, ball bearings, and a polydimethylsiloxane (PDMS) package for biocompatibility. Mechanical excitation of this device within the body due to daily activities leads to a relative motion between the platform and stators, resulting in electromagnetic induction. Initial prototypes without packaging have been fabricated and characterized on a linear shaker. Dynamic tests showed that the friction force acting on the platform is on the order of 0.6 mN. The resistance and the inductance of the coils were measured to be 2.2 Omega and 0.4 uH, respectively. A peak open circuit voltage of 1.05 mV was generated per stator at a platform speed of 5.8 cm/s. Further development of this device offers potential for recharging the batteries of implantable biomedical devices within the body. PMID- 30424148 TI - Single-Molecule Tethered Particle Motion: Stepwise Analyses of Site-Specific DNA Recombination. AB - Tethered particle motion/microscopy (TPM) is a biophysical tool used to analyze changes in the effective length of a polymer, tethered at one end, under changing conditions. The tether length is measured indirectly by recording the Brownian motion amplitude of a bead attached to the other end. In the biological realm, DNA, whose interactions with proteins are often accompanied by apparent or real changes in length, has almost exclusively been the subject of TPM studies. TPM has been employed to study DNA bending, looping and wrapping, DNA compaction, high-order DNA-protein assembly, and protein translocation along DNA. Our TPM analyses have focused on tyrosine and serine site-specific recombinases. Their pre-chemical interactions with DNA cause reversible changes in DNA length, detectable by TPM. The chemical steps of recombination, depending on the substrate and the type of recombinase, may result in a permanent length change. Single molecule TPM time traces provide thermodynamic and kinetic information on each step of the recombination pathway. They reveal how mechanistically related recombinases may differ in their early commitment to recombination, reversibility of individual steps, and in the rate-limiting step of the reaction. They shed light on the pre-chemical roles of catalytic residues, and on the mechanisms by which accessory proteins regulate recombination directionality. PMID- 30424151 TI - Liquid-Metal Enabled Droplet Circuits. AB - Conventional electrical circuits are generally rigid in their components and working styles, which are not flexible and stretchable. As an alternative, liquid metal-based soft electronics offer important opportunities for innovation in modern bioelectronics and electrical engineering. However, their operation in wet environments such as aqueous solution, biological tissue or allied subjects still encounters many technical challenges. Here, we propose a new conceptual electrical circuit, termed as droplet circuit, to fulfill the special needs described above. Such unconventional circuits are immersed in a solution and composed of liquid metal droplets, conductive ions or wires, such as carbon nanotubes. With specifically-designed topological or directional structures/patterns, the liquid-metal droplets composing the circuit can be discrete and disconnected from each other, while achieving the function of electron transport through conductive routes or the quantum tunneling effect. The conductive wires serve as electron transfer stations when the distance between two separate liquid-metal droplets is far beyond that which quantum tunneling effects can support. The unique advantage of the current droplet circuit lies in the fact that it allows parallel electron transport, high flexibility, self healing, regulation and multi-point connectivity without needing to worry about the circuit break. This would extend the category of classical electrical circuits into newly emerging areas like realizing room temperature quantum computing, making brain-like intelligence or nerve-machine interface electronics, etc. The mechanisms and potential scientific issues of the droplet circuits are interpreted and future prospects in this direction are outlined. PMID- 30424152 TI - Gimbal-Less Two-Axis Electromagnetic Microscanner with Twist Mechanism. AB - We present an electromagnetically driven microscanner based on a gimbal-less twist mechanism. In contrast to conventional microscanners using a gimbal-less leverage mechanism, our device utilizes a gimbal-less twist mechanism to increase the scan angle in optical applications requiring a large scanning mirror. The proposed gimbal-less scanner with twist mechanism increases the scan angle by 1.55 and 1.97 times for the slow and fast axes, respectively, under the same force; 3.64 and 1.97 times for the slow and fast axes, respectively, under the same maximum stress, compared to the gimbal-less leverage mechanism. The scanner with a 3-mm-diameter mirror and a current path composed of a single-turn coil was fabricated, and it showed the maximum scan angle of 5 degrees (quasi-static) and 22 degrees (resonant) for the slow and fast axes, respectively. The experimentally estimated crosstalk was as small as 0.47% and 0.97% for the fast and slow axes affected by the other axes, respectively, which was determined using a newly employed methodology based on fast Fourier transform. PMID- 30424153 TI - Features in Microfluidic Paper-Based Devices Made by Laser Cutting: How Small Can They Be? AB - In this paper, we determine the smallest feature size that enables fluid flow in microfluidic paper-based analytical devices (uPADs) fabricated by laser cutting. The smallest feature sizes fabricated from five commercially available paper types: Whatman filter paper grade 50 (FP-50), Whatman 3MM Chr chromatography paper (3MM Chr), Whatman 1 Chr chromatography paper (1 Chr), Whatman regenerated cellulose membrane 55 (RC-55) and Amershan Protran 0.45 nitrocellulose membrane (NC), were 139 +/- 8 um, 130 +/- 11 um, 103 +/- 12 um, 45 +/- 6 um, and 24 +/- 3 um, respectively, as determined experimentally by successful fluid flow. We found that the fiber width of the paper correlates with the smallest feature size that has the capacity for fluid flow. We also investigated the flow speed of Allura red dye solution through small-scale channels fabricated from different paper types. We found that the flow speed is significantly slower through microscale features and confirmed the similar trends that were reported previously for millimeter-scale channels, namely that wider channels enable quicker flow speed. PMID- 30424154 TI - A Handy Liquid Metal Based Non-Invasive Electrophoretic Particle Microtrap. AB - A handy liquid metal based non-invasive particle microtrap was proposed and demonstrated in this work. This kind of microtrap can be easily designed and fabricated at any location of a microfluidic chip to perform precise particle trapping and releasing without disturbing the microchannel itself. The microsystem demonstrated in this work utilized silicon oil as the continuous phase and fluorescent particles (PE-Cy5, SPHEROTM Fluorescent Particles, BioLegend, San Diego, CA, USA, 10.5 MUm) as the target particles. To perform the particle trapping, the micro system utilized liquid-metal-filled microchannels as noncontact electrodes to generate different patterns of electric field inside the fluid channel. According to the experimental results, the target particle can be selectively trapped and released by switching the electric field patterns. For a better understanding the control mechanism, a numerical simulation of the electric field was performed to explain the trapping mechanism. In order to verify the model, additional experiments were performed and are discussed. PMID- 30424155 TI - Surface Modification of Electroosmotic Silicon Microchannel Using Thermal Dry Oxidation. AB - A simple fabrication method for the surface modification of an electroosmotic silicon microchannel using thermal dry oxidation is presented. The surface modification is done by coating the silicon surface with a silicon dioxide (SiO2) layer using a thermal oxidation process. The process aims not only to improve the surface quality of the channel to be suitable for electroosmotic fluid transport but also to reduce the channel width using a simple technique. Initially, the parallel microchannel array with dimensions of 0.5 mm length and a width ranging from 1.8 um to 2 um are created using plasma etching on the 2 cm * 2 cm silicon substrate <100>. The oxidation of the silicon channel in a thermal chamber is then conducted to create the SiO2 layer. The layer properties and the quality of the surface are analyzed using scanning electron microscopy (SEM) and a surface profiler, respectively. The results show that the maximum oxidation growth rate occurs in the first 4 h of oxidation time and the rate decreases over time as the oxide layer becomes thicker. It is also found that the surface roughness is reduced with the increase of the process temperature and the oxide thickness. The scallop effect on the vertical wall due to the plasma etching process also improved with the presence of the oxide layer. After oxidation, the channel width is reduced by ~40%. The demonstrated method is suggested for the fabrication of a uniform channel cross section with high aspect ratio in sub-micro and nanometer scale that will be useful for the electroosmotic (EO) ion manipulation of the biomedical fluid sample. PMID- 30424156 TI - Continuous-Flow Cell Dipping and Medium Exchange in a Microdevice using Dielectrophoresis. AB - Medium exchange is the process of changing the suspension medium of cells/particles, and has applications in washing, surface modifications, nutrient replenishment, or simply changing the environment of the target entities. Dipping involves diverting the path of target cells in the carrying fluid to immerse them in another fluid for a short duration, and pushing them again into the original medium. In this paper, a simple microfluidic platform is introduced that employs dielectrophoresis to achieve medium exchange and dipping of micro-objects in a continuous manner. The essential feature of the platform is a microchannel that includes two arrays of microelectrodes that partly enter the bottom surface from both sides. In the first step, numerous finite element-based parametric studies are carried out to obtain the optimized geometrical and operational parameters ensuring successful dipping and medium exchange processes. The results of those studies are utilized to fabricate the platform using standard photolithography techniques. The electrodes are patterned on a glass substrate, while the channel, made out of polydimethylsiloxane, is bonded on top of the glass. Trajectories of blood cells from numerical studies and experimentations are reported, and both results exhibited close agreement. PMID- 30424157 TI - Study on Micro-Crack Induced Precision Severing of Quartz Glass Chips. AB - It is difficult to cut hard and brittle quartz glass chips. Hence, a method involving micro-crack-induced severing along a non-crack microgroove-apex by controlling the loading rate is proposed. The objective is to realize the rapid and precision severing of the hardest quartz glass in chip materials. Firstly, micro-grinding was employed to machine smooth microgrooves of 398-565 MU m in depth; then the severing force was modelled by the microgroove shape and size; finally, the severing performance of a 4-mm thick substrate was investigated experimentally. It is shown that the crack propagation occurred at the same time from the microgroove-apex and the loading point during 0.5 ms in micro-crack induced severing. The severing efficiency is dominated by the severing time rather than the crack propagation time. When the loading rate is less than 20-60 mm/min, the dynamic severing is transferred to static severing. With increasing microgroove-apex radius, the severing force decreases to the critical severing force of about 160-180 N in the static severing, but it increases to the critical severing force in the dynamic severing. The static severing force and time are about two times and about nine times larger than the dynamic ones, respectively, but the static severing form error of 16.3 MU m/mm and surface roughness of 19.7 nm are less. It is confirmed that the ideal static severing forces are identical to the experimental results. As a result, the static severing is controllable for the accurate and smooth separation of quartz glass chips in 4 s and less. PMID- 30424158 TI - Theoretical and Experimental Research on Bubble Actuated Micro-Pumps. AB - Bubble actuated micro-pumps have great potential to be integrated into microfluidic systems to allow the independence of peripheral equipment. Previous studies on bubble actuated valveless micro-pumps have been mainly limited to experimental studies and numerical simulations due to the complex behavior of bubbles. In this paper, the construction of a mathematical model for a bubble actuated valveless micro-pump considering fluid dynamics, heat and mass transfer and bubble dynamics is described. A prototype was fabricated and tested to verify this theoretical model. The morphological evolution of the driving bubbles during the heating process was observed by a high-speed charge-coupled device (CCD) camera, the flow rate produced by the micro-pump under different working conditions was recorded and the test results were explained by the heat dissipation model. The model in this study was able to precisely predict the flow of micro-pumps in different drive modes. The principle behind defining the heating frequency and the duty cycle based on the pump chamber volume was determined. The study shows the mechanism of bubble controlling and the good prospects of bubble actuated valveless micro-pumps. PMID- 30424159 TI - Optimization of Pulley-Type Ring Resonator with Waveguide Offset. AB - In this work, we dealt with the optimization of the pulley-type ring resonator using the offset of the straight input and output waveguide at the junction with the curved waveguide. We adopted the finite-difference time-domain method to simulate the structure. It was found that the coupling loss could be significantly reduced and the critical coupling could be precisely tuned. This results in the possibility of the Q-factor being higher than that of the structure without waveguide offset. In this study, the Q-factor of the ring resonator is increased from 9180 to 11,302. The corresponding enhancement is 23.1%. PMID- 30424160 TI - High-Precision Lens-Less Flow Cytometer on a Chip. AB - We present a flow cytometer on a microfluidic chip that integrates an inline lens free holographic microscope. High-speed cell analysis necessitates that cells flow through the microfluidic channel at a high velocity, but the image sensor of the in-line holographic microscope needs a long exposure time. Therefore, to solve this problem, this paper proposes an S-type micro-channel and a pulse injection method. To increase the speed and accuracy of the hologram reconstruction, we improve the iterative initial constraint method and propose a background removal method. The focus images and cell concentrations can be accurately calculated by the developed method. Using whole blood cells to test the cell counting precision, we find that the cell counting error of the proposed method is less than 2%. This result shows that the on-chip flow cytometer has high precision. Due to its low price and small size, this flow cytometer is suitable for environments far away from laboratories, such as underdeveloped areas and outdoors, and it is especially suitable for point-of-care testing (POCT). PMID- 30424162 TI - Electroosmotic Flow in Microchannel with Black Silicon Nanostructures. AB - Although electroosmotic flow (EOF) has been applied to drive fluid flow in microfluidic chips, some of the phenomena associated with it can adversely affect the performance of certain applications such as electrophoresis and ion preconcentration. To minimize the undesirable effects, EOF can be suppressed by polymer coatings or introduction of nanostructures. In this work, we presented a novel technique that employs the Dry Etching, Electroplating and Molding (DEEMO) process along with reactive ion etching (RIE), to fabricate microchannel with black silicon nanostructures (prolate hemispheroid-like structures). The effect of black silicon nanostructures on EOF was examined experimentally by current monitoring method, and numerically by finite element simulations. The experimental results showed that the EOF velocity was reduced by 13 +/- 7%, which is reasonably close to the simulation results that predict a reduction of approximately 8%. EOF reduction is caused by the distortion of local electric field at the nanostructured surface. Numerical simulations show that the EOF velocity decreases with increasing nanostructure height or decreasing diameter. This reveals the potential of tuning the etching process parameters to generate nanostructures for better EOF suppression. The outcome of this investigation enhances the fundamental understanding of EOF behavior, with implications on the precise EOF control in devices utilizing nanostructured surfaces for chemical and biological analyses. PMID- 30424163 TI - Development of a Fully Flexible Sheet-Type Tactile Display Based on Electrovibration Stimulus. AB - Tactile displays have been extensively studied for several decades. However, owing to their bulkiness and stiffness, it has been difficult to integrate these displays with information devices to enable tactile communication between the devices and their users. This paper proposes a novel sheet-type electrovibration tactile display that consists of poly(3,4-ethylenedioxythiophene) polystyrene sulfonate conductive layers and an insulation layer of polydimethylsiloxane. The tactile display is sufficiently thin and flexible for attaching onto various surfaces. In this study, the tactile display was micro-fabricated and characterized through experiments. The experimental results indicated that the tactile display exhibited good durability under bending and that it could present various tactile sensations depending on the type of voltage waveform. In addition, the effect of using a combination of electrovibration and thermal stimuli was also demonstrated. The sheet-type display was attached onto a Peltier element; the thinness of the structure enabled the display to conform to the element and ensure good heat transfer. In the experiment, subjects were asked to scan the display with their fingertips. The results showed that multiple tactile stimuli were also successfully perceived by the subjects. PMID- 30424161 TI - A Microfluidic Platform for Investigating Transmembrane Pressure-Induced Glomerular Leakage. AB - Transmembrane pressure across the glomerular filter barrier may underlie renal failure. However, studies of renal failure have been difficult owing to a lack of in vitro models to capture the transmembrane pressure in a controlled approach. Here we report a microfluidic platform of podocyte culture to investigate transmembrane pressure induced glomerular leakage. Podocytes, the glomerular epithelial cells essential for filtration function, were cultivated on a porous membrane supplied with transmembrane pressure DeltaP. An anodic aluminum oxide membrane with collagen coating was used as the porous membrane, and the filtration function was evaluated using dextrans of different sizes. The results show that dextran in 20 kDa and 70 kDa can penetrate the podocyte membrane, whereas dextran in 500 kDa was blocked until DeltaP >= 60 mmHg, which resembles the filtration function when DeltaP was in the range of a healthy kidney (DeltaP < 60 mmHg) as well as the hypertension-induced glomerular leakage (DeltaP >= 60 mmHg). Additionally, analysis showed that synaptopodin and actin were also downregulated when DeltaP > 30 mmHg, indicating that the dysfunction of renal filtration is correlated with the reduction of synaptopodin expression and disorganized actin cytoskeleton. Taking together, our microfluidic platform enables the investigation of transmembrane pressure in glomerular filter membrane, with potential implications for drug development in the future. PMID- 30424164 TI - Hard-Baked Photoresist as a Sacrificial Layer for Sub-180 degrees C Surface Micromachining Processes. AB - This letter proposes a method for utilizing a positive photoresist, Shipley 1805, as a sacrificial layer for sub-180 degrees C fabrication process flows. In the proposed process, the sacrificial layer is etched at the end to release the structures using a relatively fast wet-etching technique employing resist remover and a critical point dryer (CPD). This technique allows high etching selectivity over a large number of materials, including silicon-based structural materials such as silicon-carbide, metals such as titanium and aluminum, and cured polymers. This selectivity, as well as the low processing thermal budget, introduces more flexibility in material selection for monolithic integration above complementary metal oxide semiconductor (CMOS) as well as flexible substrates. PMID- 30424166 TI - Acceleration Sensitivity in Bulk-Extensional Mode, Silicon-Based MEMS Oscillators. AB - Acceleration sensitivity in silicon bulk-extensional mode oscillators is studied in this work, and a correlation between the resonator alignment to different crystalline planes of silicon and the observed acceleration sensitivity is established. It is shown that the oscillator sensitivity to the applied vibration is significantly lower when the silicon-based lateral-extensional mode resonator is aligned to the <110> plane compared to when the same resonator is aligned to <100>. A finite element model is developed that is capable of predicting the resonance frequency variation when a distributed load (i.e., acceleration) is applied to the resonator. Using this model, the orientation-dependent nature of acceleration sensitivity is confirmed, and the effect of material nonlinearity on the acceleration sensitivity is also verified. A thin-film piezoelectric-on substrate platform is chosen for the implementation of resonators. Approximately, one order of magnitude higher acceleration sensitivity is measured for oscillators built with a resonator aligned to the <100> plane versus those with a resonator aligned to the <110> plane (an average of ~5.66 * 10-8 (1/g) vs. ~3.66 * 10-9 (1/g), respectively, for resonators on a degenerately n-type doped silicon layer). PMID- 30424165 TI - Controlled Mechanical Motions of Microparticles in Optical Tweezers. AB - Optical tweezers, formed by a highly focused laser beam, have intriguing applications in biology and physics. Inspired by molecular rotors, numerous optical beams and artificial particles have been proposed to build optical tweezers trapping microparticles, and extensive experiences have been learned towards constructing precise, stable, flexible and controllable micromachines. The mechanism of interaction between particles and localized light fields is quite different for different types of particles, such as metal particles, dielectric particles and Janus particles. In this article, we present a comprehensive overview of the latest development on the fundamental and application of optical trapping. The emphasis is placed on controllable mechanical motions of particles, including rotation, translation and their mutual coupling under the optical forces and torques created by a wide variety of optical tweezers operating on different particles. Finally, we conclude by proposing promising directions for future research. PMID- 30424167 TI - Side-Group Effect on Electron Transport of Single Molecular Junctions. AB - In this article, we have investigated the influence of the nitro side-group on the single molecular conductance of pyridine-based molecules by scanning tunneling microscopy break junction. Single molecular conductance of 4,4' bipyridine (BPY), 3-nitro-4-(pyridin-4-yl)pyridine (BPY-N), and 3-nitro-4-(3 nitropyridin-4-yl)pyridine (BPY-2N) were measured by contact with Au electrodes. For the BPY molecular junction, two sets of conductance were found with values around 10-3.1 G0 (high G) and 10-3.7 G0 (low G). The addition of nitro side group(s) onto the pyridine ring resulted in lower conductance of 10-3.8 G0 for BPY-N and 10-3.9 G0 for BPY-2N, respectively, which can be attributed to the twist angle of two pyridine rings. Moreover, the steric hindrance of nitro group(s) also affects the contacting configuration of electrode-molecule electrode. As a consequence, only one set of conductance value was observed for BPY-N and BPY-2N. Our work clearly shows the important role of side-groups on the electron transport of single-molecule junctions. PMID- 30424168 TI - Assembly and Connection of Micropatterned Single Neurons for Neuronal Network Formation. AB - Engineering of neuronal network geometry by micropatterning technology is a key future technology for creating artificial brains on a chip. However, engineering of network geometry at the single-cell-level with functional morphology (axon/dendrite) and connectivity (synapses) is still challenging. Here, we describe a method for controlling the axon and dendrite morphology of single primary-cultured neurons and assembling a neural circuit using mobile microplates. The microplates enabled morphological control of neurons by their shapes and bringing their ends into contact caused the formation of physical connections. Functional synapse formation at the connection was indicated by immunostaining of synapse-related proteins and intracellular Ca2+ imaging of neural activity. We believe that the method will be useful in engineering neural circuits with selected neurons and defined morphology. PMID- 30424169 TI - Decoupling Research of a Novel Three-Dimensional Force Flexible Tactile Sensor Based on an Improved BP Algorithm. AB - Decoupling research on flexible tactile sensors play a very important role in the intelligent robot skin and tactile-sensing fields. In this paper, an efficient machine learning method based on the improved back-propagation (BP) algorithm is proposed to decouple the mapping relationship between the resistances of force sensitive conductive pillars and three-dimensional forces for the 6 * 6 novel flexible tactile sensor array. Tactile-sensing principles and numerical experiments are analyzed. The tactile sensor array model accomplishes the decomposition of the force components by its delicate structure, and avoids direct interference among the electrodes of the sensor array. The force components loaded on the tactile sensor are decoupled with a very high precision from the resistance signal by the improved BP algorithm. The decoupling results show that the k-cross validation (k-CV) algorithm is a highly effective method to improve the decoupling precision of force components for the novel tactile sensor. The large dataset with the k-CV method obtains a better decoupling accuracy of the force components than the small dataset. All of the decoupling results are fairly good, and they indicate that the improved BP model with a strong non-linear approaching ability has an efficient and valid performance in decoupling force components for the tactile sensor. PMID- 30424170 TI - Editorial for the Special Issue on Piezoelectric MEMS. AB - Electromechanical transducers that utilize the piezoelectric effect have been increasingly used in micro-electromechanical systems (MEMS) either as substrates or as thin films[...]. PMID- 30424171 TI - An Organic Flexible Artificial Bio-Synapses with Long-Term Plasticity for Neuromorphic Computing. AB - Artificial synapses, with synaptic plasticity, are the key components of constructing the neuromorphic computing system and mimicking the bio-synaptic function. Traditional synaptic devices are based on silicon and inorganic materials, while organic electronics can open up new opportunities for flexible devices. Here, a flexible artificial synaptic device with an organic functional layer was proposed. The organic device showed good switching behaviors such as ON/OFF ratio over 100 at low operation voltages. The set and reset voltages were lower than 0.5 V and -0.25 V, respectively. The long-term plasticity, spike timing-dependent plasticity learning rules (STDP), and forgetting function were emulated using the device. The retention times of the excitatory and inhibitory post-synaptic currents were both longer than 60 s. The long-term plasticity was repeatable without noticeable degradation after the application of five voltage pulse cycles to the top electrode. These results indicate that our organic flexible device has the potential to be applied in bio-inspired neuromorphic systems. PMID- 30424172 TI - Fabrication and Characterization of Inhomogeneous Curved Artificial Compound Eye. AB - Compared with the conventional compound eye processing method, a new fabrication method-namely, a mold casting method-was presented. This method is simple, low cost, easy to implement, and can be reused. A bionic compound eye array model with 61 ommatidia arranged inhomogeneously onto a curved surface was fabricated. The curved surface had a radius of 9 mm and a thickness of 0.5 mm. The margin imaging quality was improved significantly by the analysis of light beam focus and the optical imaging properties of the fabricated compound eye. The sub-image of each ommatidium had a high resolution. There was 5% error between the collecting spot brightness and simulation analysis results, which proved that the production method is feasible. PMID- 30424173 TI - How Hydrogen Dielectric Strength Forces the Work Voltage in the Electric Discharge Machining. AB - An electro-thermal model based on the Joule heating effect is proposed to simulate a single discharge in an electric discharge machining process. Normally, the dielectric strength of the hydrocarbons oil is approximately 20 MV/m, but it varies with both the thickness of the film and its decomposition. After the breakdown, the hydrocarbon oil has an average dielectric strength value of 2 MV/m. This value is close to the dielectric strength of the hydrogen, which is the main gas that results from the hydrocarbon oil decomposition, at temperatures between 6000 K and 9000 K. Therefore, the electric discharge occurs in a hydrogen atmosphere that imposes both the discharge gap and the work voltage. A 200 V voltage is associated to a 100 MUm discharge gap, leading to a 20 V work voltage. Therefore, the 3 V work voltage control corresponds to approximately 15 MUm. In other words, the increase of the discharge gap originates other discharge during the discharge pulse. The work voltage control, together with the multiple discharge method, is taken into account. The 100 MUm discharge gap corresponds to the higher value of the transitory discharge gap that over evaluates the material removal and the tool wear rates. The results of the numerical simulations are validated with experimental data. PMID- 30424174 TI - Hysteresis Compensation and Sliding Mode Control with Perturbation Estimation for Piezoelectric Actuators. AB - Based on the background of atomic force microscope (AFM) driven by piezoelectric actuators (PEAs), this paper proposes a sliding mode control coupled with an inverse Bouc-Wen (BW) hysteresis compensator to improve the positioning performance of PEAs. The intrinsic hysteresis and creep characteristics degrade the performance of the PEA and cause accuracy loss. Although creep effect can be eliminated by the closed-loop control approach, hysteresis effects need to be compensated and alleviated by hysteresis compensators. For the purpose of dealing with the estimation errors, unmodeled vibration, and disturbances, a sliding mode control with perturbation estimation (SMCPE) method is adopted to enhance the performance and robustness of the system. In order to validate the feasibility and performance of the proposed method, experimental studies are carried out, and the results show that the proposed controller performs better than a proportional integral-derivative (PID) controller at 1 and 2 Hz, reducing error to 1.2% and 1.4%, respectively. PMID- 30424175 TI - Micromachined Planar Supercapacitor with Interdigital Buckypaper Electrodes. AB - In this work, a flexible micro-supercapacitor with interdigital planar buckypaper electrodes is presented. A simple fabrication process involving vacuum filtration method and SU-8 molding techniques is proposed to fabricate in-plane interdigital buckypaper electrodes on a membrane filter substrate. The proposed process exhibits excellent flexibility for future integration of the micro supercapacitors (micro-SC) with other electronic components. The device's maximum specific capacitance measured using cyclic voltammetry was 107.27 mF/cm2 at a scan rate of 20 mV/s. The electrochemical stability was investigated by measuring the performance of charge-discharge at different discharge rates. Devices with different buckypaper electrode thicknesses were also fabricated and measured. The specific capacitance of the proposed device increased linearly with the buckypaper electrode thickness. The measured leakage current was approximately 9.95 uA after 3600 s. The device exhibited high cycle stability, with 96.59% specific capacitance retention after 1000 cycles. A Nyquist plot of the micro-SC was also obtained by measuring the impedances with frequencies from 1 Hz to 50 kHz; it indicated that the equivalent series resistance value was approximately 18 Omega. PMID- 30424177 TI - Energy Harvesting Combat Boot for Satellite Positioning. AB - Most portable electronic devices are power-limited by battery capacity, and recharging these batteries often interrupts the user's experience with the device. The product presented in this paper provides an alternative to powering portables by converting regular human walking motion to electricity. The device harvests electric power using air bulbs, distributed in the sole of a shoe to drive a series of micro-turbines connected to small DC motors. The number and position of air bulbs is optimized to harvest the maximum airflow from each foot strike. The system is designed to continuously drive the micro-turbines by utilizing both outflow and inflow from the air bulbs. A prototype combat boot was fitted on the right foot of a 75 kg test subject, and produced an average continuous power on the order of 10 s of mW over a 22 Omega load during walking at 3.0 mph. This combat boot provides enough electric power to a passive GPS tracker that periodically relays geographical coordinates to a smartphone via satellite without battery replacement. PMID- 30424178 TI - Manipulation of Biological Cells Using a Robot-Aided Optical Tweezers System. AB - This article reviews the autonomous manipulation strategies of biological cells utilizing optical tweezers, mainly including optical direct and indirect manipulation strategies. The typical and latest achievements in the optical manipulation of cells are presented, and the existing challenges for autonomous optical manipulation of biological cells are also introduced. Moreover, the integrations of optical tweezers with other manipulation tools are presented, which broadens the applications of optical tweezers in the biomedical manipulation areas and will also foster new developments in cell-based physiology and pathology studies, such as cell migration, single cell surgery, and preimplantation genetic diagnosis (PGD). PMID- 30424176 TI - Nanostructure-Enabled and Macromolecule-Grafted Surfaces for Biomedical Applications. AB - Advances in nanotechnology and nanomaterials have enabled the development of functional biomaterials with surface properties that reduce the rate of the device rejection in injectable and implantable biomaterials. In addition, the surface of biomaterials can be functionalized with macromolecules for stimuli responsive purposes to improve the efficacy and effectiveness in drug release applications. Furthermore, macromolecule-grafted surfaces exhibit a hierarchical nanostructure that mimics nanotextured surfaces for the promotion of cellular responses in tissue engineering. Owing to these unique properties, this review focuses on the grafting of macromolecules on the surfaces of various biomaterials (e.g., films, fibers, hydrogels, and etc.) to create nanostructure-enabled and macromolecule-grafted surfaces for biomedical applications, such as thrombosis prevention and wound healing. The macromolecule-modified surfaces can be treated as a functional device that either passively inhibits adverse effects from injectable and implantable devices or actively delivers biological agents that are locally based on proper stimulation. In this review, several methods are discussed to enable the surface of biomaterials to be used for further grafting of macromolecules. In addition, we review surface-modified films (coatings) and fibers with respect to several biomedical applications. Our review provides a scientific update on the current achievements and future trends of nanostructure enabled and macromolecule-grafted surfaces in biomedical applications. PMID- 30424179 TI - Improved Morphological Filter Based on Variational Mode Decomposition for MEMS Gyroscope De-Noising. AB - An adaptive multi-scale method based on the combination generalized morphological filter (CGMF) is presented for de-noising of the output signal from a MEMS gyroscope. A variational mode decomposition is employed to decompose the original signal into multi-scale modes. After choosing a length selection for the structure element (SE), the adaptive multi-scale CGMF method reduces the noise corresponding to the different modes, after which a reconstruction of the de noised signal is obtained. From an analysis of the effect of de-noising, the main advantages of the present method are that it: (i) effectively overcomes deficiencies arising from data deviation compared with conventional morphological filters (MFs); (ii) effectively targets the different components of noise and provides efficacy in de-noising, not only primarily eliminating noise but also smoothing the waveform; and (iii) solves the problem of SE-length selection for a MF and produces feasible formulae of indicators such as the power spectral entropy and root mean square error for mode evaluations. Compared with the other current signal processing methods, the method proposed owns a simpler construction with a reasonable complexity, and it can offer better noise suppression effect. Experiments demonstrate the applicability and feasibility of the de-noising algorithm. PMID- 30424180 TI - Fluorescent Nanodiamond Applications for Cellular Process Sensing and Cell Tracking. AB - Diamond nanocrystals smaller than 100 nm (nanodiamonds) are now recognized to be highly biocompatible. They can be made fluorescent with perfect photostability by creating nitrogen-vacancy (NV) color centers in the diamond lattice. The resulting fluorescent nanodiamonds (FND) have been used since the late 2000s as fluorescent probes for short- or long-term analysis. FND can be used both at the subcellular scale and the single cell scale. Their limited sub-diffraction size allows them to track intracellular processes with high spatio-temporal resolution and high contrast from the surrounding environment. FND can also track the fate of therapeutic compounds or whole cells in the organs of an organism. This review presents examples of FND applications (1) for intra and intercellular molecular processes sensing, also introducing the different potential biosensing applications based on the optically detectable electron spin resonance of NV- centers; and (2) for tracking, firstly, FND themselves to determine their biodistribution, and secondly, using FND as cell tracking probes for diagnosis or follow-up purposes in oncology and regenerative medicine. PMID- 30424182 TI - Motion Constraints and Vanishing Point Aided Land Vehicle Navigation. AB - In the typical Inertial Navigation System (INS)/ Global Navigation Satellite System (GNSS) setup for ground vehicle navigation, measures should be taken to maintain the performance when there are GNSS signal outages. Usually, aiding sensors are utilized to reduce the INS drift. A full motion constraint model is developed allowing the online calibration of INS frame with respect to (w.r.t) the motion frame. To obtain better heading and lateral positioning performance, we propose to use of vanishing point (VP) observations of parallel lane markings from a single forward-looking camera to aid the INS. In the VP module, the relative attitude of the camera w.r.t the road frame is derived from the VP coordinates. The state-space model is developed with augmented vertical attitude error state. Finally, the VP module is added to a modified motion constrains module in the Extended Kalman filter (EKF) framework. Simulations and real-world experiments have shown the validity of VP-based method and improved heading and cross-track position accuracy compared with the solution without VP. The proposed method can work jointly with conventional visual odometry to aid INS for better accuracy and robustness. PMID- 30424181 TI - Micro Droplet Formation towards Continuous Nanoparticles Synthesis. AB - In this paper, micro droplets are generated in a microfluidic focusing contactor and then they move sequentially in a free-flowing mode (no wall contact). For this purpose, two different micro-flow glass devices (hydrophobic and hydrophilic) were used. During the study, the influence of the flow rate of the water phase and the oil phase on the droplet size and size distribution was investigated. Moreover, the influence of the oil phase viscosity on the droplet size was analyzed. It was found that the size and size distribution of the droplets can be controlled simply by the aqueous phase flow rate. Additionally, 2D simulations to determine the droplet size were performed and compared with the experiment. PMID- 30424183 TI - Editorial for the Special Issue on Passive Micromixers. AB - Micromixers are important components of microfluidic systems [...]. PMID- 30424184 TI - Simultaneous Measurement of Viscosity and Optical Density of Bacterial Growth and Death in a Microdroplet. AB - Herein, we describe a novel method for the assessment of droplet viscosity moving inside microfluidic channels. The method allows for the monitoring of the rate of the continuous growth of bacterial culture. It is based on the analysis of the hydrodynamic resistance of a droplet that is present in a microfluidic channel, which affects its motion. As a result, we were able to observe and quantify the change in the viscosity of the dispersed phase that is caused by the increasing population of interacting bacteria inside a size-limited system. The technique allows for finding the correlation between the viscosity of the medium with a bacterial culture and its optical density. These features, together with the high precision of the measurement, make our viscometer a promising tool for various experiments in the field of analytical chemistry and microbiology, where the rigorous control of the conditions of the reaction and the monitoring of the size of bacterial culture are vital. PMID- 30424185 TI - A Micromachined Coupled-Cantilever for Piezoelectric Energy Harvesters. AB - This paper presents a demonstration of the feasibility of fabricating micro cantilever harvesters with extended stress distribution and enhanced bandwidth by exploiting an M-shaped two-degrees-of-freedom design. The measured mechanical response of the fabricated device displays the predicted dual resonance peak behavior with the fundamental peak at the intended frequency. This design has the features of high energy conversion efficiency in a miniaturized environment where the available vibrational energy varies in frequency. It makes such a design suitable for future large volume production of integrated self powered sensors nodes for the Internet-of-Things. PMID- 30424186 TI - Microfluidic Formation of Double-Stacked Planar Bilayer Lipid Membranes by Controlling the Water-Oil Interface. AB - This study reports double-stacked planar bilayer lipid membranes (pBLMs) formed using a droplet contact method (DCM) for microfluidic formation with five-layered microchannels that have four micro guide pillars. pBLMs are valuable for analyzing membrane proteins and modeling cell membranes. Furthermore, multiple pBLM systems have broadened the field of application such as electronic components, light-sensors, and batteries because of electrical characteristics of pBLMs and membrane proteins. Although multiple-stacked pBLMs have potential, the formation of multiple-pBLMs on a micrometer scale still faces challenges. In this study, we applied a DCM strategy to pBLM formation using microfluidic techniques and attempted to form double-stacked pBLMs in micro-meter scale. First, microchannels with micro pillars were designed via hydrodynamic simulations to form a five-layered flow with aqueous and lipid/oil solutions. Then, pBLMs were successfully formed by controlling the pumping pressure of the solutions and allowing contact between the two lipid monolayers. Finally, pore-forming proteins were reconstituted in the pBLMs, and ion current signals of nanopores were obtained as confirmed by electrical measurements, indicating that double-stacked pBLMs were successfully formed. The strategy for the double-stacked pBLM formation can be applied to highly integrated nanopore-based systems. PMID- 30424187 TI - Absolute Copy Numbers of beta-Actin Proteins Collected from 10,000 Single Cells. AB - Semi-quantitative studies have located varied expressions of beta-actin proteins at the population level, questioning their roles as internal controls in western blots, while the absolute copy numbers of beta-actins at the single-cell level are missing. In this study, a polymeric microfluidic flow cytometry was used for single-cell analysis, and the absolute copy numbers of single-cell beta-actin proteins were quantified as 9.9 +/- 4.6 * 105, 6.8 +/- 4.0 * 105 and 11.0 +/- 5.5 * 105 per cell for A549 (ncell = 14,754), Hep G2 (ncell = 36,949), and HeLa (ncell = 24,383), respectively. High coefficients of variation (~50%) and high quartile coefficients of dispersion (~30%) were located, indicating significant variations of beta-actin proteins within the same cell type. Low p values (?0.01) and high classification rates based on neural network (~70%) were quantified among A549, Hep G2 and HeLa cells, suggesting expression differences of beta actin proteins among three cell types. In summary, the results reported here indicate significant variations of beta-actin proteins within the same cell type from cell to cell, and significant expression differences of beta-actin proteins among different cell types, strongly questioning the properties of using beta actin proteins as internal controls in western blots. PMID- 30424188 TI - PDMS-Parylene Hybrid, Flexible Microfluidics for Real-Time Modulation of 3D Helical Inertial Microfluidics. AB - Inertial microfluidics has drawn much attention for its applications for circulating tumor cell separations from blood. The fluid flows and the inertial particle focusing in inertial microfluidic systems are highly dependent on the channel geometry and structure. Flexible microfluidic systems can have adjustable 3D channel geometries by curving planar 2D channels into 3D structures, which will enable tunable inertial separation. We present a poly(dimethylsiloxane) (PDMS)-parylene hybrid thin-film microfluidic system that can provide high flexibility for 3D channel shaping while maintaining the channel cross-sectional shape. The PDMS-parylene hybrid microfluidic channels were fabricated by a molding and bonding technique using initiated chemical vapor deposition (iCVD) bonding. We constructed 3D helical inertial microfluidic channels by coiling a straight 2D channel and studied the inertial focusing while varying radius of curvature and Reynolds number. This thin film structure allows for high channel curvature and high Dean numbers which leads to faster inertial particle focusing and shorter channel lengths than 2D spiral channels. Most importantly, the focusing positions of particles and cells in the microchannel can be tuned in real time by simply modulating the channel curvature. The simple mechanical modulation of these 3D structure microfluidic systems is expected to provide unique advantages of convenient tuning of cell separation thresholds with a single device. PMID- 30424189 TI - Fabrication of Random Microwell Arrays as Pseudo-Thermal Speckle Light Source. AB - Quantum correlated imaging using the intensity fluctuations of thermal light possesses advantages of high resolution and strong anti-interference ability. The common method to produce pseudo-thermal light source is using a rotary ground glass and transmission of laser beam. In the present work, we propose a method for the fabrication of microwell arrays with randomly varied diameters, which could be used as a new structural element for pseudo-thermal speckle light source. If these are etched with random sizes then they may also have random and complex varying curvatures (diffusion limited etching) leading to random destructive interference of the coherent beam which could be a good thing. The microwell arrays, with diameters randomly varying from 5 MUm to 40 MUm, height varying from 200 nm to 20 MUm, were fabricated by photolithography combined with acid etching. The experimental conditions are simple and can be scaled up to for large structures. The produced microwell arrays can transform the laser beam to a pseudo-thermal light source with a certain divergent angle by rational designing of mask and adjustable process parameters. PMID- 30424190 TI - A Low Power Energy-Efficient Precision CMOS Temperature Sensor ?. AB - This paper presents a low power, energy-efficient precision CMOS temperature sensor. The front-end circuit is based on bipolar junction transistors, and employs a pre-bias circuit and bipolar core. To reduce measurement errors arising from current ratio mismatch, a new dynamic element-matching mode is proposed, which dynamically matches all current sources in the front-end circuit. The first order fitting and third-order fitting are used to calibrate the output results. On the basis of simulation results, the sensor achieves 3sigma-inaccuracies of +0.18/-0.13 degrees C from -55 degrees C to +125 degrees C. Measurement results demonstrate sensor 3sigma-inaccuracies of +/-0.2 degrees C from 0 degrees C to +100 degrees C. The circuit is implemented in 0.18 MUm CMOS, and consumes 6.1 MUA with a 1.8 V supply voltage. PMID- 30424191 TI - Self-Assembly Behavior and pH-Stimuli-Responsive Property of POSS-Based Amphiphilic Block Copolymers in Solution. AB - Stimuli-responsive polymeric systems containing special responsive moieties can undergo alteration of chemical structures and physical properties in response to external stimulus. We synthesized a hybrid amphiphilic block copolymer containing methoxy polyethylene glycol (MePEG), methacrylate isobutyl polyhedral oligomeric silsesquioxane (MAPOSS) and 2-(diisopropylamino)ethyl methacrylate (DPA) named MePEG-b-P(MAPOSS-co-DPA) via atom transfer radical polymerization (ATRP). Spherical micelles with a core-shell structure were obtained by a self-assembly process based on MePEG-b-P(MAPOSS-co-DPA), which showed a pH-responsive property. The influence of hydrophobic chain length on the self-assembly behavior was also studied. The pyrene release properties of micelles and their ability of antifouling were further studied. PMID- 30424192 TI - Development of Multiple Capsule Robots in Pipe. AB - Swallowable capsule robots which travel in body cavities to implement drug delivery, minimally invasive surgery, and diagnosis have provided great potential for medical applications. However, the space constraints of the internal environment and the size limitations of the robots are great challenges to practical application. To address the fundamental challenges of narrow body cavities, a different-frequency driven approach for multiple capsule robots with screw structure manipulated by external electromagnetic field is proposed in this paper. The multiple capsule robots are composed of driven permanent magnets, joint permanent magnets, and a screw body. The screw body generates a propulsive force in a fluidic environment. Moreover, robots can form new constructions via mutual docking and release. To provide manipulation guidelines for active locomotion, a dynamic model of axial propulsion and circumferential torque is established. The multiple start and step-out frequencies for multiple robots are defined theoretically. Moreover, the different-frequency driven approach based on geometrical parameters of screw structure and the overlap angles of magnetic polarities is proposed to drive multiple robots in an identical electromagnetic field. Finally, two capsule robots were prototyped and experiments in a narrow pipe were conducted to verify the different motions such as docking, release, and cooperative locomotion. The experimental results demonstrated the validity of the driven approach for multiple capsule robots in narrow body cavities. PMID- 30424193 TI - Numerical Investigation of DC Dielectrophoretic Deformable Particle-Particle Interactions and Assembly. AB - In a non-uniform electric field, the surface charge of the deformable particle is polarized, resulting in the dielectrophoretic force acting on the surface of the particle, which causes the electrophoresis. Due to dielectrophoretic force, the two deformable particles approach each other, and distort the flow field between them, which cause the hydrodynamic force correspondingly. The dielectrophoresis (DEP) force and the hydrodynamic force together form the net force acting on the particles. In this paper, based on a thin electric double layer (EDL) assumption, we developed a mathematical model under the arbitrary Lagrangian-Eulerian (ALE) numerical approach method to simulate the flow field, electric field, and deformable particles simultaneously. Simulation results show that, when two deformable particles' distances are in a certain range, no matter the initial position of the two particles immersed in the fluid field, the particles will eventually form a particle-particle chain parallel to the direction of the electric field. In actual experiments, the biological cells used are deformable. Compared with the previous study on the DEP motion of the rigid particles, the research conclusion of this paper provides a more rigorous reference for the design of microfluidics. PMID- 30424194 TI - 3D Shape Reconstruction of 3D Printed Transparent Microscopic Objects from Multiple Photographic Images Using Ultraviolet Illumination. AB - We propose and demonstrate a simple, low-cost, three-dimensional (3D) shape acquisition method for transparent 3D printed microscopic objects. Our method uses ultraviolet (UV) illumination to obtain high-contrast silhouette images of transparent 3D printed polymer objects. Multiple silhouette images taken from different viewpoints make it possible to reconstruct the 3D shape of this transparent object. A 3D shape acquisition system consisting of a UV light emitting diode, charge-coupled device camera and a rotation stage was constructed and used to successfully reconstruct the 3D shape of a transparent bunny model produced using micro-stereolithography. In addition, 3D printed pillar array models, with different diameters on the order of several hundred micrometers, were reconstructed. This method will be a promising tool for the 3D shape reconstruction of transparent 3D objects on both the micro- and macro-scale by changing the imaging lens. PMID- 30424195 TI - Electromagnetic Regulation of Electrolyte Solution Heat Convection in Microchannels. AB - With the rapid development of microelectronics and micro-electromechanical system technology, the electronic components have become smaller and the performance has become higher. Under this condition, however, their energy consumption and heat production have also increased continuously, which poses a great challenge to heat dissipation. In this paper, electromagnetic driving technology is applied to drive the electrolyte solution flow within a microchannel to realize efficient heat convection with microchannel walls. By changing the magnitude and direction of electric-magnetic field, the regulation of heat convection performance is studied. The results show that the Nu number of microchannel increases as the Ha number and magnetic direction angle increases, while it decreases as the potential difference increases. According to the average index of the four factors, it was determined that the electrolyte solution had the best heat convection performance with Ha = 0.05, Vb = 0.00006, Pe = 90, and alpha = 90 degrees . After that, sensitivity analysis of the Ha number, potential difference and magnetic direction angle was used to regulate the heat convection performance. This paper may provide some theoretical support for the design of microelectronics and micro-electromechanical systems. PMID- 30424197 TI - Effect of Heat Accumulation on Femtosecond Laser Reductive Sintering of Mixed CuO/NiO Nanoparticles. AB - Direct laser-writing techniques have attracted attention for their use in two- and three-dimensional printing technologies. In this article, we report on a micropatterning process that uses femtosecond laser reductive sintering of mixed CuO/NiO nanoparticles. The writing speed, laser fluence, and incident total energy were varied to investigate the influence of heat accumulation on the micropatterns formed by these materials. Heat accumulation and the thermal history of the laser irradiation process significantly affected the material composition and the thermoelectric properties of the fabricated micropatterns. Short laser irradiation durations and high laser fluences decrease the amount of metal oxide in the micropatterns. Selective fabrication of p-type and n-type thermoelectric micropatterns was demonstrated to be possible with control of the reduction and reoxidization reactions through the control of writing speed and total irradiation energy. PMID- 30424196 TI - Novel Nano-Materials and Nano-Fabrication Techniques for Flexible Electronic Systems. AB - Recent progress in fabricating flexible electronics has been significantly developed because of the increased interest in flexible electronics, which can be applied to enormous fields, not only conventional in electronic devices, but also in bio/eco-electronic devices. Flexible electronics can be applied to a wide range of fields, such as flexible displays, flexible power storages, flexible solar cells, wearable electronics, and healthcare monitoring devices. Recently, flexible electronics have been attached to the skin and have even been implanted into the human body for monitoring biosignals and for treatment purposes. To improve the electrical and mechanical properties of flexible electronics, nanoscale fabrications using novel nanomaterials are required. Advancements in nanoscale fabrication methods allow the construction of active materials that can be combined with ultrathin soft substrates to form flexible electronics with high performances and reliability. In this review, a wide range of flexible electronic applications via nanoscale fabrication methods, classified as either top-down or bottom-up approaches, including conventional photolithography, soft lithography, nanoimprint lithography, growth, assembly, and chemical vapor deposition (CVD), are introduced, with specific fabrication processes and results. Here, our aim is to introduce recent progress on the various fabrication methods for flexible electronics, based on novel nanomaterials, using application examples of fundamental device components for electronics and applications in healthcare systems. PMID- 30424198 TI - Approximate Solution for Electroosmotic Flow of Power-Law Fluids in a Planar Microchannel with Asymmetric Electrochemical Boundary Conditions. AB - Electroosmotic flow (EOF) is widely used in microfluidic systems and chemical analysis. It is driven by an electric force inside microchannel with highly charged boundary conditions. In practical applications, electrochemical boundary conditions are often inhomogeneous because different materials as walls are commonly utilized in routine fabrication methods. In the present study, we focus on the analytic solutions of the EOF generated in a planar microchannel with asymmetric electrochemical boundary conditions for non-Newtonian fluids. The velocity profile and flow rate are approximated by employing the power-law model of fluids in the Cauchy momentum equation. The hydrodynamic features of the EOF under asymmetric zeta potentials are scrutinized as a function of the fluid behavior index of the power-law fluid, thickness of Debye length, and zeta potential ratios between planes. The approximate solutions of the power-law model are comparable to the numerically obtained solutions when the Debye length is small and the fluid behavior index is close to unity. This study provides insights into the electrical control of non-Newtonian fluids, such as biological materials of blood, saliva, and DNA solution, in lab-on-a-chip devices. PMID- 30424199 TI - Design and Application of a High-G Piezoresistive Acceleration Sensor for High Impact Application. AB - In this paper, we present our work developing a family of silicon-on-insulator (SOI)-based high-g micro-electro-mechanical systems (MEMS) piezoresistive sensors for measurement of accelerations up to 60,000 g. This paper presents the design, simulation, and manufacturing stages. The high-acceleration sensor is realized with one double-clamped beam carrying one transversal and one longitudinal piezoresistor on each end of the beam. The four piezoresistors are connected to a Wheatstone bridge. The piezoresistors are defined to 4400 Omega, which results in a width-to-depth geometry of the pn-junction of 14 MUm * 1.8 MUm. A finite element method (FEM) simulation model is used to determine the beam length, which complies with the resonance frequency and sensitivity. The geometry of the realized high-g sensor element is 3 * 2 * 1 mm3. To demonstrate the performance of the sensor, a shock wave bar is used to test the sensor, and a Polytec vibrometer is used as an acceleration reference. The sensor wave form tracks the laser signal very well up to 60,000 g. The sensor can be utilized in aerospace applications or in the control and detection of impact levels. PMID- 30424200 TI - Research on PF-SLAM Indoor Pedestrian Localization Algorithm Based on Feature Point Map. AB - Recently, the map matching-assisted positioning method based on micro electromechanical systems (MEMS) inertial devices has become a research hotspot for indoor pedestrian positioning; however, these are based on existing indoor electronic maps. In this paper, without prior knowledge of the map and through building an indoor main path feature point map combined with the simultaneous localization and map building (SLAM) particle filter (PF-SLAM) algorithm idea, a PF-SLAM indoor pedestrian location algorithm based on a feature point map was proposed through the inertial measurement unit to improve indoor pedestrian positioning accuracy. Aiming at the problem of inaccurate heading angle estimation in the pedestrian dead reckoning (PDR) algorithm, a turn-straight state threshold detection method was proposed that corrected the difference of the heading angles during the straight-line walking of pedestrians to suppress the error accumulation of the heading angle. Aiming at the particles that are severely divergent at the corners, a feature point matching algorithm was proposed to correct the pedestrian position error. Furthermore, the turning point extracted the main path that failed to match the current feature point map as a new feature point was added to update the map. Through the mutual modification of SLAM and an inertial navigation system (INS) the long-time, high-precision, and low-cost positioning functions of indoor pedestrians were realized. PMID- 30424201 TI - Effect of Machining Parameters and Tool Wear on Surface Uniformity in Micro Milling. AB - In micro-milling, the periodically varying chip thickness, which varies with tool rotation, leads to varying degrees of minimum chip thickness effect and ploughing effect during surface generation. This results in a change of roughness in the cross-sectional direction of the micro-grooves, giving a non-uniform surface quality. However, the factors influencing surface uniformity in micro-milling are not fully understood. In the present work, the effect of the machining parameters and tool wear on surface uniformity in micro-milling is theoretically and experimentally studied. A mathematical model is proposed to predict the varying surface roughness in the cross-sectional direction of the micro-grooves, which is experimentally validated by fabricating a set of 800 um wide micro-grooves. The theoretical and experimental results reveal that, compared to the normally adopted Ra or Sa, the relative standard deviation of roughness (RSDS) is more appropriate to evaluating surface uniformity. When machining under small feed rates and small cutting depths, the surface uniformity deteriorates as the feed rate increases and improves as the cutting depth increases. The blunt cutting edge induced by tool wear enhances the surface uniformity and increases the surface roughness at the same time. This research furthers understanding of the various cutting mechanisms in micro-milling and can be applied to the optimization of machining parameters in micro-milling. PMID- 30424202 TI - Fabricating Microstructures on Glass for Microfluidic Chips by Glass Molding Process. AB - Compared with polymer-based biochips, such as polydimethylsiloxane (PDMS), glass based chips have drawn much attention due to their high transparency, chemical stability, and good biocompatibility. This paper investigated the glass molding process (GMP) for fabricating microstructures of microfluidic chips. The glass material was D-ZK3. Firstly, a mold with protrusion microstructure was prepared and used to fabricate grooves to evaluate the GMP performance in terms of roughness and height. Next, the molds for fabricating three typical microfluidic chips, for example, diffusion mixer chip, flow focusing chip, and cell counting chip, were prepared and used to mold microfluidic chips. The analysis of mold wear was then conducted by the comparison of mold morphology, before and after the GMP, which indicated that the mold was suitable for GMP. Finally, in order to verify the performance of the molded chips by the GMP, a mixed microfluidic chip was chosen to conduct an actual liquid filling experiment. The study indicated that the fabricating microstructure of glass microfluidic chip could be finished in 12 min with good surface quality, thus, providing a promising method for achieving mass production of glass microfluidic chips in the future. PMID- 30424203 TI - Towards Controlled Single-Molecule Manipulation Using "Real-Time" Molecular Dynamics Simulation: A GPU Implementation. AB - Molecular electronics saw its birth with the idea to build electronic circuitry with single molecules as individual components. Even though commercial applications are still modest, it has served an important part in the study of fundamental physics at the scale of single atoms and molecules. It is now a routine procedure in many research groups around the world to connect a single molecule between two metallic leads. What is unknown is the nature of this coupling between the molecule and the leads. We have demonstrated recently (Tewari, 2018, Ph.D. Thesis) our new setup based on a scanning tunneling microscope, which can be used to controllably manipulate single molecules and atomic chains. In this article, we will present the extension of our molecular dynamic simulator attached to this system for the manipulation of single molecules in real time using a graphics processing unit (GPU). This will not only aid in controlled lift-off of single molecules, but will also provide details about changes in the molecular conformations during the manipulation. This information could serve as important input for theoretical models and for bridging the gap between the theory and experiments. PMID- 30424204 TI - High-Precision Solvent Vapor Annealing for Block Copolymer Thin Films. AB - Despite its efficacy in producing well-ordered, periodic nanostructures, the intricate role multiple parameters play in solvent vapor annealing has not been fully established. In solvent vapor annealing a thin polymer film is exposed to a vapor of solvent(s) thus forming a swollen and mobile layer to direct the self assembly process at the nanoscale. Recent developments in both theory and experiments have directly identified critical parameters that govern this process, but controlling them in any systematic way has proven non-trivial. These identified parameters include vapor pressure, solvent concentration in the film, and the solvent evaporation rate. To explore their role, a purpose-built solvent vapor annealing chamber was designed and constructed. The all-metal chamber is designed to be inert to solvent exposure. Computer-controlled, pneumatically actuated valves allow for precision timing in the introduction and withdrawal of solvent vapor from the film. The mass flow controller-regulated inlet, chamber pressure gauges, in situ spectral reflectance-based thickness monitoring, and low flow micrometer relief valve give real-time monitoring and control during the annealing and evaporation phases with unprecedented precision and accuracy. The reliable and repeatable alignment of polylactide cylinders formed from polystyrene-b-polylactide, where cylinders stand perpendicular to the substrate and span the thickness of the film, provides one illustrative example. PMID- 30424205 TI - Effects of Microchannel Shape and Ultrasonic Mixing on Microfluidic Padlock Probe Rolling Circle Amplification (RCA) Reactions. AB - The fluorescence in situ hybridization (FISH)-based padlock probe and rolling circle amplification (RCA) method allows for the detection of point mutations. However, it requires multiple reaction steps and solution exchanges, making it costly, labor-intensive, and time-consuming. In this study, we aimed to improve the efficiency of padlock/RCA by determining the effects of microchannel shape and ultrasonic solution mixing. Using a circular-shaped microchamber and ultrasonic mixing, the efficiency of microfluidic padlock/RCA was improved, and the consumption of the expensive probe solution was reduced from 10 uL to approximately 3.5 uL. Moreover, the fluorescent probe hybridization time was reduced to 5 min, which is four times faster than that of the standard protocol. We used this method to successfully detect mitochondrial DNA and transcripts of beta-actin and K-ras proto-oncogene codon 12 in cells. Our method offers improvements over current padlock/RCA methods and will be helpful in optimizing other microfluidics-based FISH-related analyses. PMID- 30424206 TI - Artificial Cochlear Sensory Epithelium with Functions of Outer Hair Cells Mimicked Using Feedback Electrical Stimuli. AB - We report a novel vibration control technique of an artificial auditory cochlear epithelium that mimics the function of outer hair cells in the organ of Corti. The proposed piezoelectric and trapezoidal membrane not only has the acoustic/electric conversion and frequency selectivity of the previous device developed mainly by one of the authors and colleagues, but also has a function to control local vibration according to sound stimuli. Vibration control is achieved by applying local electrical stimuli to patterned electrodes on an epithelium made using micro-electro-mechanical system technology. By choosing appropriate phase differences between sound and electrical stimuli, it is shown that it is possible to both amplify and dampen membrane vibration, realizing better control of the response of the artificial cochlea. To be more specific, amplification and damping are achieved when the phase difference between the membrane vibration by sound stimuli and electrical stimuli is zero and pi , respectively. We also demonstrate that the developed control system responds automatically to a change in sound frequency. The proposed technique can be applied to mimic the nonlinear response of the outer hair cells in a cochlea, and to realize a high-quality human auditory system. PMID- 30424207 TI - Highly Sensitive Label-Free Detection of Small Molecules with an Optofluidic Microbubble Resonator. AB - The detection of small molecules has increasingly attracted the attention of researchers because of its important physiological function. In this manuscript, we propose a novel optical sensor which uses an optofluidic microbubble resonator (OFMBR) for the highly sensitive detection of small molecules. This paper demonstrates the binding of the small molecule biotin to surface-immobilized streptavidin with a detection limit reduced to 0.41 pM. Furthermore, binding specificity of four additional small molecules to surface-immobilized streptavidin is shown. A label-free OFMBR-based optical sensor has great potential in small molecule detection and drug screening because of its high sensitivity, low detection limit, and minimal sample consumption. PMID- 30424208 TI - Developing a MEMS Device with Built-in Microfluidics for Biophysical Single Cell Characterization. AB - This study combines the high-throughput capabilities of microfluidics with the sensitive measurements of microelectromechanical systems (MEMS) technology to perform biophysical characterization of circulating cells for diagnostic purposes. The proposed device includes a built-in microchannel that is probed by two opposing tips performing compression and sensing separately. Mechanical displacement of the compressing tip (up to a maximum of 14 um) and the sensing tip (with a quality factor of 8.9) are provided by two separate comb-drive actuators, and sensing is performed with a capacitive displacement sensor. The device is designed and developed for simultaneous electrical and mechanical measurements. As the device is capable of exchanging the liquid inside the channel, different solutions were tested consecutively. The performance of the device was evaluated by introducing varying concentrations of glucose (from 0.55 mM (0.1%) to 55.5 mM (10%)) and NaCl (from 0.1 mM to 10 mM) solutions in the microchannel and by monitoring changes in the mechanical and electrical properties. Moreover, we demonstrated biological sample handling by capturing single cancer cells. These results show three important capabilities of the proposed device: mechanical measurements, electrical measurements, and biological sample handling. Combined in one device, these features allow for high-throughput multi-parameter characterization of single cells. PMID- 30424209 TI - On the Possibility of Miniature Diamond-Based Magnetometers Using Waveguide Geometries. AB - We propose the use of a diamond waveguide structure to enhance the sensitivity of magnetometers relying on the detection of the spin state of nitrogen-vacancy ensembles in diamond by infrared optical absorption. An optical waveguide structure allows for enhanced optical path-lengths avoiding the use of optical cavities and complicated setups. The presented design for diamond-based magnetometers enables miniaturization while maintaining high sensitivity and forms the basis for magnetic field sensors applicable in biomedical, industrial and space-related applications. PMID- 30424210 TI - Micro-Dumbbells-A Versatile Tool for Optical Tweezers. AB - Manipulation of micro- and nano-sized objects with optical tweezers is a well established, albeit still evolving technique. While many objects can be trapped directly with focused laser beam(s), for some applications indirect manipulation with tweezers-operated tools is preferred. We introduce a simple, versatile micro tool operated with holographic optical tweezers. The 40 um long dumbbell-shaped tool, fabricated with two-photon laser 3D photolithography has two beads for efficient optical trapping and a probing spike on one end. We demonstrate fluids viscosity measurements and vibration detection as examples of possible applications. PMID- 30424211 TI - The Fabrication of Au@C Core/Shell Nanoparticles by Laser Ablation in Solutions and Their Enhancements to a Gas Sensor. AB - A convenient and flexible route is presented to fabricate gold noble metal nanoparticles wrapped with a controllable ultrathin carbon layer (Au@C) in one step based on laser ablation of the noble metal targets in toluene-ethanol mixed solutions. The obtained metal nanoparticles were <20 nm in size after ablation, and the thickness of the wrapped ultrathin carbon layer was 2 nm in a typical reaction. The size of the inner noble metal nanoparticles could be controlled by adjusting the power of laser ablation, and the thickness of the ultrathin carbon layer can be controlled from 0.6 to 2 nm by laser ablation in different components of organic solution. Then the resultant Au@C core/shell nanoparticles were modified on the surface of In2O3 films through a sol-gel technique, and the hydrogen sulfide (H2S) gas-sensing characteristics of the products were examined. Compared to pure and Au-modified In2O3, the Au@C-modified In2O3 materials exhibited a revertible and reproducible performance with good sensitivity and very low response times (few seconds) for H2S gas with a concentrations of 1 to 5 ppm at room temperature. Evidence proved that the ultrathin carbon layer played an important role in the improved H2S sensor performance. Other noble metals wrapped by the homogeneous carbon shell, such as Ag@C, could also be prepared with this method. PMID- 30424212 TI - Elucidating the Mechanisms of Two Unique Phenomena Governed by Particle-Particle Interaction under DEP: Tumbling Motion of Pearl Chains and Alignment of Ellipsoidal Particles. AB - Particle-particle interaction plays a crucial role in determining the movement and alignment of particles under dielectrophoresis (DEP). Previous research efforts focus on studying the mechanism governing the alignment of spherical particles with similar sizes in a static condition. Different approaches have been developed to simulate the alignment process of a given number of particles from several up to thousands depending on the applicability of the approaches. However, restricted by the simplification of electric field distribution and use of identical spherical particles, not much new understanding has been gained apart from the most common phenomenon of pearl chain formation. To enhance the understanding of particle-particle interaction, the movement of pearl chains under DEP in a flow condition was studied and a new type of tumbling motion with unknown mechanism was observed. For interactions among non-spherical particles, some preceding works have been done to simulate the alignment of ellipsoidal particles. Yet the modeling results do not match experimental observations. In this paper, the authors applied the newly developed volumetric polarization and integration (VPI) method to elucidate the underlying mechanism for the newly observed movement of pearl chains under DEP in a flow condition and explain the alignment patterns of ellipsoidal particles. The modeling results show satisfactory agreement with experimental observations, which proves the strength of the VPI method in explaining complicated DEP phenomena. PMID- 30424213 TI - UWB Bandpass Filter with Dual Notched Bands Using T-Shaped Resonator and L-Shaped Defected Microstrip Structure. AB - In this paper, an ultra-wideband (UWB) bandpass filter (BPF) with dual notched bands using a T-shaped resonator and L-shaped defected microstrip structure (DMS) is proposed and fabricated. First, the principle of generating notched bands by using a T-shaped resonator and L-shaped defected microstrip structure to determine the size parameters of the structure is analyzed. High frequency structure simulator (HFSS) software is used to analyze the performance of the filter, and advanced design system (ADS) is used to extract the equivalent circuit model parameters. The two simulation results are consistent, which further verifies the correctness of the circuit model. Finally, the filter is fabricated and measured. The measured results are in good agreement with simulated results, demonstrating good insertion loss and return loss. The proposed filter has dual independently controllable notched bands which are implemented by coupling the T-shaped resonator to the transmission line and by etching the L-shaped defected microstrip structure respectively. The proposed filter can suppress dispensable bands at 3.5 GHz and 7.5 GHz in WiMAX band and X band to improve the performance of the ultra-wideband communication system. By adjusting the parameters of the T-shaped resonator and L-shaped defected microstrip structure, the UWB bandpass filter with dual notched bands working at WiMAX band and X-band can be designed and applied to the wireless communication system. PMID- 30424214 TI - Silicon-Vacancy Centers in Ultra-Thin Nanocrystalline Diamond Films. AB - Color centers in diamond have shown excellent potential for applications in quantum information processing, photonics, and biology. Here we report the optoelectronic investigation of shallow silicon vacancy (SiV) color centers in ultra-thin (7-40 nm) nanocrystalline diamond (NCD) films with variable surface chemistry. We show that hydrogenated ultra-thin NCD films exhibit no or lowered SiV photoluminescence (PL) and relatively high negative surface photovoltage (SPV) which is ascribed to non-radiative electron transitions from SiV to surface related traps. Higher SiV PL and low positive SPV of oxidized ultra-thin NCD films indicate an efficient excitation-emission PL process without significant electron escape, yet with some hole trapping in diamond surface states. Decreasing SPV magnitude and increasing SiV PL intensity with thickness, in both cases, is attributed to resonant energy transfer between shallow and bulk SiV. We also demonstrate that thermal treatments (annealing in air or in hydrogen gas), commonly applied to modify the surface chemistry of nanodiamonds, are also applicable to ultra-thin NCD films in terms of tuning their SiV PL and surface chemistry. PMID- 30424215 TI - Measuring Single-Molecule Conductance at An Ultra-Low Molecular Concentration in Vacuum. AB - We report on systematic investigation of single-molecule detection mechanisms in break junction experiments in vacuum. We found molecular feature in the conductance traces at an extremely low concentration of molecules of 10 nM. This was attributed to condensation of the molecular solution on the junction surface upon evaporation of the solvent during evacuation. Furthermore, statistical analyses of the temporal dependence of molecular junction formation probabilities suggested accumulation effects of the contact mechanics to concentrate molecules absorbed on a remote area to the tunneling current sensing zone, which also contributed to the capability of molecular detections at the low concentration condition. The present findings can be used as a useful guide to implement break junction measurements for studying electron and heat transport through single molecules in vacuum. PMID- 30424216 TI - Design and Experimental Research of a Miniature Digital Hydraulic Valve. AB - A digital hydraulic valve is an important component of the digital hydraulic system, and its performance is directly related to the system function. In order to make the valve system more competitive in dimension, digital valve miniaturization is an important research point. A new micro digital valve is designed, which is analyzed from the mechanical structure and magnetic circuit mechanism, and the design difficulties are also expounded. The four subsystems and switching characteristics of the valve are theoretically analyzed and simulated. In order to test the performance of the valve, a test system is designed, and performance of the new micro valve is tested. The test results show that the switch characteristic analysis of the valve is correct. The comparison between the test curve and the simulation curve is carried out, which demonstrates that the accuracy of the simulation model is reasonable. The theoretical analysis of the new micro digital valve is consistent with experiments. PMID- 30424217 TI - Selected Papers from the 2017 International Conference on Micro/Nanomachines. AB - Thanks to their capabilities of converting various energy into motions, micro/nanomachines are believed to bring about revolutionary changes in many fields[...]. PMID- 30424218 TI - Fab on a Package: LTCC Microfluidic Devices Applied to Chemical Process Miniaturization. AB - Microfluidics has brought diverse advantages to chemical processes, allowing higher control of reactions and economy of reagents and energy. Low temperature co-fired ceramics (LTCC) have additional advantages as material for fabrication of microfluidic devices, such as high compatibility with chemical reagents with typical average surface roughness of 0.3154 MUm, easy scaling, and microfabrication. The conjugation of LTCC technology with microfluidics allows the development of micrometric-sized channels and reactors exploiting the advantages of fast and controlled mixing and heat transfer processes, essential for the synthesis and surface functionalization of nanoparticles. Since the chemical process area is evolving toward miniaturization and continuous flow processing, we verify that microfluidic devices based on LTCC technology have a relevant role in implementing several chemical processes. The present work reviews various LTCC microfluidic devices, developed in our laboratory, applied to chemical process miniaturization, with different geometries to implement processes such as ionic gelation, emulsification, nanoprecipitation, solvent extraction, nanoparticle synthesis and functionalization, and emulsion diffusion/solvent extraction process. All fabricated microfluidics structures can operate in a flow range of mL/min, indicating that LTCC technology provides a means to enhance micro- and nanoparticle production yield. PMID- 30424219 TI - Nanoliter Centrifugal Liquid Dispenser Coupled with Superhydrophobic Microwell Array Chips for High-Throughput Cell Assays. AB - Microfluidic systems have been regarded as a potential platform for high throughput screening technology in drug discovery due to their low sample consumption, high integration, and easy operation. The handling of small-volume liquid is an essential operation in microfluidic systems, especially in investigating large-scale combination conditions. Here, we develop a nanoliter centrifugal liquid dispenser (NanoCLD) coupled with superhydrophobic microwell array chips for high-throughput cell-based assays in the nanoliter scale. The NanoCLD consists of a plastic stock block with an array of drilled through holes, a reagent microwell array chip (reagent chip), and an alignment bottom assembled together in a fixture. A simple centrifugation at 800 rpm can dispense ~160 nL reagents into microwells in 5 min. The dispensed reagents are then delivered to cells by sandwiching the reagent chip upside down with another microwell array chip (cell chip) on which cells are cultured. A gradient of doxorubicin is then dispensed to the cell chip using the NanoCLD for validating the feasibility of performing drug tests on our microchip platform. This novel nanoliter-volume liquid dispensing method is simple, easy to operate, and especially suitable for repeatedly dispensing many different reagents simultaneously to microwells. PMID- 30424220 TI - 3D Integrated Circuit Cooling with Microfluidics. AB - Using microfluidic cooling to achieve thermal management of three-dimensional integrated circuits (ICs) is recognized as a promising method of extending Moore law progression in electronic components and systems. Since the U.S. Defense Advanced Research Projects Agency launched Intra/Inter Chip Enhanced Cooling thermal packaging program, the method of using microfluidic cooling in 3D ICs has been under continuous development. This paper presents an analysis of all publications available about the microfluidic cooling technologies used in 3D IC thermal management, and summarized these research works into six categories: cooling structure design, co-design issues, through silicon via (TSV) influence, specific chip applications, thermal models, and non-uniform heating and hotspots. The details of these research works are given, future works are suggested. PMID- 30424221 TI - Miniaturized Optical Resolution Photoacoustic Microscope Based on a Microelectromechanical Systems Scanning Mirror. AB - In this paper, we report a miniaturized optical resolution photoacoustic microscopy system based on a microelectromechanical system (MEMS) scanning mirror. A two-dimensional MEMS scanning mirror was used to achieve raster scanning of the excitation optical focus. The wideband photoacoustic signals were detected by a flat ultrasound transducer with a center frequency of 10 MHz and an active area of 2 mm in diameter. The size and weight of this device were 60 mm * 30 mm * 20 mm and 40 g, respectively. We evaluated this system using sharp blades, carbon fibers, and a silver strip target. In vivo experiments of imaging vasculatures in the mouse ear, brain, and human lip were completed to demonstrate its potential for biological and clinical applications. PMID- 30424222 TI - Chopper-Stabilized Instrumentation Amplifier with Automatic Frequency Tuning Loop. AB - A variable-gain chopper-stabilized instrumentation amplifier (chopper IA), which employs a low pass filter (LPF) to attenuate the up-converted noise at the chopping frequency, is presented. The circuit is designed and fabricated with Taiwan Semiconductor Manufacturing Company (TSMC) (Hsinchu, Taiwan) 0.18 MUm complementary metal-oxide-semiconductor (CMOS) technology. Consuming 1.1 mW from a 1.2 V supply voltage, the chopper IA achieves a variable gain of 20.7-48.5 dB, with a minimum bandwidth of 6.7 kHz and a common-mode rejection ratio (CMRR) of 95 dB below 10 kHz. By using the chopper technique, the input-referred noise of the chopper IA can be reduced to 0.28 MUVrms (0~96 kHz), with a chopping frequency of 83.3 kHz. An automatic frequency tuning loop (ATL) is employed to adjust the corner frequency of the LPF dynamically so that the frequency ratio between the chopping frequency and the LPF corner frequency is 8.3, ensuring a noise reduction of 36.7 dB. PMID- 30424223 TI - Noise Source Visualization for Small DC Motors Using Current Reference without a Reference Microphone. AB - Noise and vibration sources from small direct current (DC) motors should be clearly visualized for optimal design of low noise motors. For accurate visualization, relatively good reference measurements at optimal locations are required. For some very small motors, the optimal position for a stationary reference microphone may not be accessible during measurement. However, strategies for small motor noise visualization without using a reference microphone have been developed in this study. Only scanning microphones and current measurements of a small motor were used to visualize sound sources. Scanning microphone signals combined with current measurements were used as moving reference signals. Motor noise visualization results based on different moving reference locations have been estimated and reported. Consistent motor noise visualization results from motor current and different, moving reference locations for the major electro-magnetic force excitation frequencies have been shown. Furthermore, for frequencies with relatively low current amplitude, clear motor noise visualization results have been produced for a moving reference located at the center of the motor. Also, the relationship between motor noise and current has been shown, and motor noise has been reduced by connecting an optimal capacitor to the motor power input. PMID- 30424224 TI - High Frequency Needle Ultrasonic Transducers Based on Lead-Free Co Doped Na0.5Bi4.5Ti4O15 Piezo-Ceramics. AB - This paper describes the design, fabrication, and characterization of tightly focused (f-number close to 1) high frequency needle-type transducers based on lead-free Na0.5Bi4.5Ti3.975Co0.025O15 (NBT-Co) piezo-ceramics. The NBT-Co ceramics, are fabricated through solid-state reactions, have a piezoelectric coefficient d33 of 32 pC/N, and an electromechanical coupling factor kt of 35.3%. The high Curie temperature (670 degrees C) indicates a wide working temperature range. Characterization results show a center frequency of 70.4 MHz and a -6 dB bandwidth of 52.7%. Lateral resolution of 29.8 MUm was achieved by scanning a 10 MUm tungsten wire target, and axial resolution of 20.8 MUm was calculated from the full width at half maximum (FWHM) of the pulse length of the echo. This lead free ultrasonic transducer has potential applications in high resolution biological imaging. PMID- 30424225 TI - Magnetic Isotropy/Anisotropy in Layered Metal Phosphorous Trichalcogenide MPS3 (M = Mn, Fe)Single Crystals. AB - Despite the fact that two-dimensional layered magnetic materials hold immense potential applications in the field of spintronic devices, tunable magnetism is still a challenge due to the lack of controllable synthesis. Herein, high-quality single crystals MPS3 (M= Mn, Fe) of millimeter size were synthesized through the chemical vapor transport method. After systemic structural characterizations, magnetic properties were studied on the bulk MPS3 layers through experiments, along with first principle theoretical calculations. The susceptibilities as well as the EPR results evidently revealed unique isotropic and anisotropic behavior in MnPS3 and FePS3 crystals, respectively. It is worth noting that both of these materials show antiferromagnetic states at measured temperatures. The estimated antiferromagnetic transition temperature is 78 K for bulk MnPS3 and 123 K for FePS3 crystals. The spin polarized density functional theory calculations confirmed that the band gap of the antiferromagnetic states could be generated owing to asymmetric response all over the energy range. The ferromagnetic state in MnPS3 and FePS3 is less stable as compared to the antiferromagnetic state, resulting in antiferromagnetic behavior. Additionally, frequency-dependent dielectric functions for parallel and perpendicular electric field component vectors, along with the absorption properties of MPS3, are thoroughly investigated. PMID- 30424226 TI - Micro-Injection Moulding In-Line Quality Assurance Based on Product and Process Fingerprints. AB - Micro-injection moulding (MUIM) is a replication-based process enabling the cost effective production of complex and net-shaped miniaturized plastic components. The micro-scaled size of such parts poses great challenges in assessing their dimensional quality and often leads to time-consuming and unprofitable off-line measurement procedures. In this work, the authors proposed a novel method to verify the quality of a three-dimensional micro moulded component (nominal volume equal to 0.07 mm3) based on the combination of optical micro metrology and injection moulding process monitoring. The most significant dimensional features of the micro part were measured using a focus variation microscope. Their dependency on the variation of uIM process parameters was studied with a Design of Experiments (DoE) statistical approach. A correlation study allowed the identification of the product fingerprint, i.e., the dimensional characteristic that was most linked to the overall part quality and critical for product functionality. Injection pressure and velocity curves were recorded during each moulding cycle to identify the process fingerprint, i.e., the most sensitive and quality-related process indicator. The results of the study showed that the dimensional quality of the micro component could be effectively controlled in line by combining the two fingerprints, thus opening the door for future uIM in line process optimization and quality assessment. PMID- 30424227 TI - Micro-Fabricated Resonator Based on Inscribing a Meandered-Line Coupling Capacitor in an Air-Bridged Circular Spiral Inductor. AB - This letter presents a high-performance micro-fabricated resonator based on inscribing a meandered-line square coupling capacitor in an air-bridged circular spiral inductor on the GaAs-integrated passive device (IPD) technology. The main advantages of the proposed method, which inserts a highly effective coupling capacitor between the two halves of a circular spiral inductor, are the miniaturized size, enhanced coupling coefficient, and improved selectivity. Moreover, using an air-bridge structure utilizes the enhanced mutual inductance in which it maximizes the self-inductance by a stacking inductor layout to obtain a high coupling effect. The simulated and measured S-parameters of a prototype resonator with an effective overall circuit size of 1000 um * 800 um are in good agreement. The measured insertion and return losses of 0.41 and 24.21 dB, respectively, at a measured central frequency of 1.627 GHz, as well as an upper band transmission zero with a suppression level of 38.7 dB, indicate the excellent selectivity of the developed resonator. PMID- 30424228 TI - Flexible Transparent Conductive Film Based on Random Networks of Silver Nanowires. AB - We synthesized silver nanowires (AgNWs) with a mean diameter of about 120 nm and 20-70 MUm in length using a polyol process. The flexible transparent conductive AgNWs films were prepared using the vacuum filtration-transferring process, in which random AgNWs networks were transferred to a polyethylene terephthalate (PET) substrate after being deposited on mixed cellulose esters (MCEs). Furthermore, the photoelectric and mechanical properties of the AgNWs films were studied. The scanning electron microscopy images show that the AgNWs randomly, uniformly distribute on the surface of the PET substrate, which indicates that the AgNWs structure was preserved well after the transfer process. The film with 81% transmittance at 550 nm and sheet resistance about 130 Omega.sq-1 can be obtained. It is sufficient to be used as a flexible transparent conductive film. However, the results of the bending test and tape test show that the adhesion of AgNWs and PET substrate is poor, because the sheet resistance of film increases during the bending test and tape test. The 0.06 W LED lamp with a series fixed on the surface of the AgNWs-PET electrode with conductive adhesive was luminous, and it was still luminous after bent. PMID- 30424229 TI - Progress in Photo-Responsive Polypeptide Derived Nano-Assemblies. AB - Stimuli-responsive polymeric materials have attracted significant attention in a variety of high-value-added and industrial applications during the past decade. Among various stimuli, light is of particular interest as a stimulus because of its unique advantages, such as precisely spatiotemporal control, mild conditions, ease of use, and tunability. In recent years, a lot of effort towards the synthesis of a biocompatible and biodegradable polypeptide has resulted in many examples of photo-responsive nanoparticles. Depending on the specific photochemistry, those polypeptide derived nano-assemblies are capable of crosslinking, disassembling, or morphing into other shapes upon light irradiation. In this mini-review, we aim to assess the current state of photo responsive polypeptide based nanomaterials. Firstly, those 'smart' nanomaterials will be categorized by their photo-triggered events (i.e., crosslinking, degradation, and isomerization), which are inherently governed by photo-sensitive functionalities, including O-nitrobenzyl, coumarin, azobenzene, cinnamyl, and spiropyran. In addition, the properties and applications of those polypeptide nanomaterials will be highlighted as well. Finally, the current challenges and future directions of this subject will be evaluated. PMID- 30424230 TI - A Facile Interfacial Self-Assembly of Crystalline Colloidal Monolayers by Tension Gradient. AB - Many self-assembly approaches of colloidal monolayers have flourished but with some shortages, such as complexity, time-consumption, parameter sensitivity, and high-cost. This paper presents a facile, rapid, well-controlled, and low-cost method to prepare monolayers by directly adding silica particle suspensions containing water and ethanol to different liquids. A detailed analysis of the self-assembly process was conducted. The particles dove into water firstly, then moved up under the effect of the buoyancy and the tension gradient. The tension gradient induced the Marangoni convection and the relative motion between the water and the particles. At last, the particles were adsorbed at the air-water interface to minimize the free energy. The quality of the monolayers depended on the addition of sodium dodecyl sulfonate or ethanol in the water subphase. An interfacial polymerization of ethyl 2-cyanoacrylate was used to determine the contact angles of the particles at different subphase surfaces. The value of the detachment energy was positively associated with the contact angle and the surface tension. When the detachment energy decreased to a certain value, some particles detached from the surface, leading to the formation of a quasi-double layer. We also observed that the content of ethanol in suspensions influenced the arrangement of particles. PMID- 30424231 TI - Multiscale Analysis of Size Effect of Surface Pit Defect in Nanoindentation. AB - The nanoindentation on a pit surface has been simulated using the quasicontinuum method in order to investigate the size effect of surface pit defect on the yield load of thin film. Various widths and heights of surface pit defect have been taken into account. The size coefficient has been defined as an index to express the influence of the width or height of surface pit defect. The results show that as the size coefficient of width (of height) increases, at first the yield load of thin film decreases extremely slowly, until the size coefficient of width equals approximately one unit (half unit), at which point the yield load experiences an obvious drop. When the size coefficient of width (of height) reaches approximately two units (one unit), the yield load is almost the same as that of the nanoindentation on a stepped surface. In addition, the height of surface pit defect has more influence than the width on the yield load of thin film. PMID- 30424232 TI - Improving the Electrical Contact Performance for Amorphous Wire Magnetic Sensor by Employing MEMS Process. AB - This paper presents a novel fabrication method for amorphous alloy wire giant magneto-impedance (GMI) magnetic sensor based on micro electro mechanical systems (MEMS) technology. In this process, negative SU-8 thick photoresist was proposed as the solder mask due to its excellent properties, such as good stability, mechanical properties, etc. The low melting temperature solder paste was used for the electrical connections with the amorphous alloy wire and the electrode pads. Compared with the conventional welding fabrication methods, the proposed micro electro mechanical systems (MEMS) process in this paper showed the advantages of good impedance consistency, and can be fabricated at a low temperature of 150 degrees C. The amorphous alloy wire magnetic sensor made by the conventional method and by the micro electro mechanical systems (MEMS) process were tested and compared, respectively. The minimum resistance value of the magnetic sensor made by the conventional welding method is 19.8 Omega and the maximum is 28.1 Omega. The variance of the resistance is 7.559 Omega2. The minimum resistance value of the magnetic sensor made by micro electro mechanical systems (MEMS) process is 20.1 Omega and the maximum is 20.5 Omega. The variance of the resistance is 0.029 Omega2. The test results show that the impedance consistency by micro electro mechanical systems (MEMS) process is better than that of the conventional method. The sensor sensitivity is around 150 mV/Oe and the nonlinearity is less than 0.92% F.S. PMID- 30424234 TI - Miniaturization and High-Density Arrangement of Microcantilevers in Proximity and Tactile Sensor for Dexterous Gripping Control. AB - In this paper, in order to perform delicate and advanced grip control like human, a proximity and tactile combination sensor using miniaturized microcantilevers one-fifth the size of previous one as the detection part was newly developed. Microcantilevers were arranged with higher spatial density than in previous works and an interdigitated array electrode to enhance light sensitivity was added. It is found that the interdigitated array electrode can detect light with 1.6 times higher sensitivity than that in previous works and the newly fabricated microcantilevers have enough sensitivity to applied normal and shear loads. Therefore, more accurate detection of proximity distance and spatial distribution of contact force become available for dexterous gripping control to prevent 'overshooting', 'force control error', and 'slipping'. PMID- 30424235 TI - Editorial for the Special Issue on Advances in Optofluidics. PMID- 30424233 TI - Liquid Biopsy in Colorectal Cancer-Current Status and Potential Clinical Applications. AB - Colorectal cancer is one of the most frequent solid malignancies worldwide. The treatment is either surgical or multimodal and depends on the stage of the disease at diagnosis. Accurate disease assessment is thus of great importance for choosing the most optimal treatment strategy. However, the standard means of disease assessment by radiological imaging or histopathological analysis of the removed tumor tissue lack the sensitivity in detecting the early systemic spread of the disease. To overcome this deficiency, the concept of liquid biopsy from the peripheral blood of patients has emerged as a new, very promising diagnostic tool. In this article, we provide an overview of the current status of clinical research on liquid biopsy in colorectal cancer. We also highlight the clinical situations in which the concept might be of the greatest benefit for the management of colorectal cancer patients in the future. PMID- 30424236 TI - Formation of Branched and Chained Alginate Microfibers Using Theta-Glass Capillaries. AB - This study proposes a microfluidic spinning method to form alginate microfibers with branched and chained structures by controlling two streams of a sodium alginate solution extruded from a theta-glass capillary (a double-compartmented glass capillary). The two streams have three flow regimes: (i) a combined flow regime (single-threaded stream), (ii) a separated flow regime (double-threaded stream), and (iii) a chained flow regime (stream of repeating single- and double threaded streams). The flow rate of the sodium alginate solution and the tip diameter of the theta-glass capillary are the two parameters which decide the flow regime. By controlling the two parameters, we form branched (a Y-shaped structure composed of thick parent fiber and permanently divided two thin fibers) and chained (a repeating structure of single- and double-threaded fibers with constant frequency) alginate microfibers with various dimensions. Furthermore, we demonstrate the applicability of the alginate microfibers as sacrificial templates for the formation of chain-shaped microchannels with two inlets. Such microchannels could mimic the structure of blood vessels and are applicable for the research fields of fluidics including hemodynamics. PMID- 30424237 TI - Manipulation of the Superhydrophobicity of Plasma-Etched Polymer Nanostructures. AB - The manipulation of droplet mobility on a nanotextured surface by oxygen plasma is demonstrated by modulating the modes of hydrophobic coatings and controlling the hierarchy of nanostructures. The spin-coating of polytetrafluoroethylene (PTFE) allows for heterogeneous hydrophobization of the high-aspect-ratio nanostructures and provides the nanostructured surface with "sticky hydrophobicity", whereas the self-assembled monolayer coating of perfluorodecyltrichlorosilane (FDTS) results in homogeneous hydrophobization and "slippery superhydrophobicity". While the high droplet adhesion (stickiness) on a nanostructured surface with the spin-coating of PTFE is maintained, the droplet contact angle is enhanced by creating hierarchical nanostructures via the combination of oxygen plasma etching with laser interference lithography to achieve "sticky superhydrophobicity". Similarly, the droplet mobility on a slippery nanostructured surface with the self-assembled monolayer coating of FDTS is also enhanced by employing the hierarchical nanostructures to achieve "slippery superhydrophobicity" with modulated slipperiness. PMID- 30424238 TI - A Generic Control Architecture for Hybrid Micro-Machines. AB - Hybrid micro-machining, which integrates several micro-manufacturing processes on one platform, has emerged as a solution to utilize the so-called "1 + 1 = 3" effect to tackle the manufacturing challenges for high value-added 3D micro products. Hybrid micro-machines tend to integrate multiple functional modules from different vendors for the best value and performance. However, the lack of plug-and-play solutions leads to tremendous difficulty in system integration. This paper proposes a novel three-layer control architecture for the first time for the system integration of hybrid micro-machines. The interaction of hardware is encapsulated into software components, while the data flow among different components is standardized. The proposed control architecture enhances the flexibility of the computer numerical control (CNC) system to accommodate a broad range of functional modules. The component design also improves the scalability and maintainability of the whole system. The effectiveness of the proposed control architecture has been successfully verified through the integration of a six-axis hybrid micro-machine. Thus, it provides invaluable guidelines for the development of next-generation CNC systems for hybrid micro-machines. PMID- 30424239 TI - Rapid Detection and Trapping of Extracellular Vesicles by Electrokinetic Concentration for Liquid Biopsy on Chip. AB - Exosomes have gained immense importance since their proteomic and genetic contents could potentially be used for disease diagnostics, monitoring of cancer progression, metastasis, and drug efficacy. However, establishing the clinical utility of exosomes has been restricted due to small sizes and high sample loss from extensive sample preparation. Sample loss is particularly critical for body fluids limited in volume and difficult to access, e.g., cerebrospinal fluid. We present a microfluidic technique that locally enhances the concentration of extracellular vesicles extracted from MDA-MB-231 human breast cancer cell lines by using an ion concentration polarization (ICP)-based electrokinetic concentrator. Our design incorporates a trapping mechanism near the conductive polymer membrane; therefore, we can preconcentrate and capture extracellular vesicles simultaneously. Compared with standard fluorescence detection, our method increased the limit of detection (LOD) of extracellular vesicles by two orders of magnitude in 30 min. Our concentrator increased the extracellular vesicle concentration for 5.0 * 107 particles/1 mL (LOD), 5.0 * 108 particles/1 mL, and 5.0 * 108 particles/1 mL by ~100-fold each within 30 min using 45 V. This study demonstrates an alternative platform to simultaneously preconcentrate and capture extracellular vesicles that can be incorporated as part of a liquid biopsy-on-a-chip system for the detection of exosomal biomarkers and analysis of their contents for early cancer diagnosis. PMID- 30424241 TI - Rigid-Flex PCB Technology with Embedded Fluidic Cavities and Its Application in Electromagnetic Energy Harvesters. AB - A technology platform based on commercial printed circuit boards (PCB) technology is developed and presented. It integrates rigid flame retardant (FR)-4 boards, flexible polyimide (PI) structures, and embedded cavities for micro- and meso scale applications. The cavities or channels can be filled with fluids for microfluidic and lab-on-chip systems. In this study, an electromagnetic energy harvester with enhanced output was designed and implemented in the platform. To enhance harvester output, the embedded cavities were filled with ferrofluid (FF) to improve the overall magnetic circuit design and electromechanical coupling of the device. The fabricated PCB-based harvester had a dimension of 20 mm * 20 mm * 4 mm. Vibration tests of the harvesters were conducted with different magnet sizes and different FF. Test results showed up to a 70% enhancement of output voltage and a 195% enhancement of output power when the cavities were filled with oil-based FF as compared with harvesters without FF. When the cavities were filled with water-based FF, the enhancement of voltage and power increased to 25% and 50%, respectively. The maximum output power delivered to a matched load at a 196-Hz resonance frequency and 1 grms vibration was estimated to be 2.3 uW, corresponding to an area power density of 0.58 uW/cm2 and a volume power density of 1.4 uW/cm3, respectively. PMID- 30424240 TI - Self-Assembled Mucin-Containing Microcarriers via Hard Templating on CaCO3 Crystals. AB - Porous vaterite crystals of CaCO3 are extensively used for the fabrication of self-assembled polymer-based microparticles (capsules, beads, etc.) utilized for drug delivery and controlled release. The nature of the polymer used plays a crucial role and discovery of new perspective biopolymers is essential to assemble microparticles with desired characteristics, such as biocompatibility, drug loading efficiency/capacity, release rate, and stability. Glycoprotein mucin is tested here as a good candidate to assemble the microparticles because of high charge due to sialic acids, mucoadhesive properties, and a tendency to self assemble, forming gels. Mucin loading into the crystals via co-synthesis is twice as effective as via adsorption into preformed crystals. Desialylated mucin has weaker binding to the crystals most probably due to electrostatic interactions between sialic acids and calcium ions on the crystal surface. Improved loading of low-molecular-weight inhibitor aprotinin into the mucin-containing crystals is demonstrated. Multilayer capsules (mucin/protamine)3 have been made by the layer by-layer self-assembly. Interestingly, the deposition of single mucin layers (mucin/water)3 has also been proven, however, the capsules were unstable, most probably due to additional (to hydrogen bonding) electrostatic interactions in the case of the two polymers used. Finally, approaches to load biologically active compounds (BACs) into the mucin-containing microparticles are discussed. PMID- 30424242 TI - A Flexible Annular Sectorial Sensor for Detecting Contact Position Based on Constant Electric Field. AB - To achieve tactile detection on the irregular surface of a robot link, a flexible annular sectorial sensor with a five-layer structure was proposed that could be wrapped on the surface of a truncated cone-shaped link. The sensor was designed for the detection of a contact position when robots collide with other objects during movement. The sensor obtains the coordinates of the contact position by exerting a constant electric field on the upper and lower conductive layers. The mathematical model linking the coordinates of the contact position and the corresponding electric potential on the conductive layer was established, based on the uniqueness of the electric field. The design of the sensor was simulated using COMSOL software, and the detection error of the contact position was discussed. A sensor sample was fabricated and wrapped on the mechanical arm. The results of the simulations and experiments indicated that the flexible sensor performed very well when wrapped on the robot link. PMID- 30424243 TI - Fatigue Assessment by Blink Detected with Attachable Optical Sensors of Dye Sensitized Photovoltaic Cells. AB - This paper demonstrates fatigue assessment based on eye blinks that are detected by dye-sensitized photovoltaic cells. In particular, the sensors were attached to the temple of eyeglasses and positioned at the lateral side of the eye. They are wearable, did not majorly disturb the user's eyesight, and detected the position of the eyelid or the eye state. The optimal location of the sensor was experimentally investigated by evaluating the detection accuracy of blinks. We conducted fatigue assessment experiments using the developed wearable system, or smart glasses. Several parameters, including the frequency, duration, and velocity of eye blinks, were extracted as fatigue indices. Successful fatigue assessment by the proposed system will be of great benefit for maximizing performance and maintenance of physical/mental health. PMID- 30424244 TI - Design and Performance Test of an Ocean Turbulent Kinetic Energy Dissipation Rate Measurement Probe. AB - Ocean turbulent kinetic energy dissipation rate is an essential parameter in marine environmental monitoring. Numerous probes have been designed to measure the turbulent kinetic energy dissipation rate in the past, and most of them utilize piezoelectric ceramics as the sensing element. In this paper, an ocean turbulent kinetic energy dissipation rate measurement probe utilizing a microelectromechanical systems (MEMS) piezoresistor as the sensing element has been designed and tested. The triangle cantilever beam and piezoresistive sensor chip are the core components of the designed probe. The triangle cantilever beam acts as a velocity-force signal transfer element, the piezoresistive sensor chip acts as a force-electrical signal transfer element, and the piezoresistive sensor chip is bonded on the triangle cantilever beam. One end of the triangle cantilever beam is a nylon sensing head which contacts with fluid directly, and the other end of it is a printed circuit board which processes the electrical signal. A finite element method has been used to study the effect of the cantilever beam on probe performance. The Taguchi optimization methodology is applied to optimize the structure parameters of the cantilever beam. An orthogonal array, signal-to-noise ratio, and analysis of variance are studied to analyze the effect of these parameters. Through the use of the designed probe, we can acquire the fluid flow velocity, and to obtain the ocean turbulent dissipation rate, an attached signal processing system has been designed. To verify the performance of the designed probe, tests in the laboratory and in the Bohai Sea are designed and implemented. The test results show that the designed probe has a measurement range of 10-8-10-4 W/kg and a sensitivity of 3.91 * 10-4 (Vms2)/kg. The power spectrum calculated from the measured velocities shows good agreement with the Nasmyth spectrum. The comparative analysis between the designed probe in this paper and the commonly used PNS probe has also been completed. The designed probe can be a strong candidate in marine environmental monitoring. PMID- 30424245 TI - Frequency Tuning of Graphene Nanoelectromechanical Resonators via Electrostatic Gating. AB - In this article, we report on a comprehensive modeling study of frequency tuning of graphene resonant nanoelectromechanical systems (NEMS) via electrostatic coupling forces induced by controlling the voltage of a capacitive gate. The model applies to both doubly clamped graphene membranes and circumference-clamped circular drumhead device structures. Frequency tuning of these devices can be predicted by considering both capacitive softening and elastic stiffening. It is shown that the built-in strain in the device strongly dictates the frequency tuning behavior and tuning range. We also find that doubly clamped graphene resonators can have a wider frequency tuning range, while circular drumhead devices have higher initial resonance frequency with same device characteristic parameters. Further, the parametric study in this work clearly shows that a smaller built-in strain, smaller depth of air gap or cavity, and larger device size or characteristic length (e.g., length for doubly clamped devices, and diameter for circular drumheads) help achieve a wider range of electrostatic frequency tunability. This study builds a solid foundation that can offer important device fabrication and design guidelines for achieving radio frequency components (e.g., voltage controlled oscillators and filters) with the desired frequencies and tuning ranges. PMID- 30424246 TI - Friction Determination by Atomic Force Microscopy in Field of Biochemical Science. AB - Atomic force microscopy (AFM) is an analytical nanotechnology in friction determination between microscale and nanoscale surfaces. AFM has advantages in mechanical measurement, including high sensitivity, resolution, accuracy, and simplicity of operation. This paper will introduce the principles of mechanical measurement by using AFM and reviewing the progress of AFM methods in determining frictions in the field of biochemical science over the past decade. While three friction measurement assays-friction morphology, friction curve and friction process in experimental cases-are mainly introduced, important advances of technology, facilitating future development of AFM are also discussed. In addition to the principles and advances, the authors also give an overview of the shortcomings and restrictions of current AFM methods, and propose potential directions of AFM techniques by combining it with other well-established characterization techniques. AFM methods are expected to see an increase in development and attract wide attention in scientific research. PMID- 30424247 TI - 3D-Printed Capillary Circuits for Calibration-Free Viscosity Measurement of Newtonian and Non-Newtonian Fluids. AB - Measuring viscosity is important for the quality assurance of liquid products, as well as for monitoring the viscosity of clinical fluids as a potential hemodynamic biomarker. However, conventional viscometers and their microfluidic counterparts typically rely on bulky and expensive equipment, and lack the ability for rapid and field-deployable viscosity analysis. To address these challenges, we describe 3D-printed capillary circuits (3D-CCs) for equipment- and calibration-free viscosity measurement of Newtonian and non-Newtonian fluids. A syringe, modified with an air chamber serving as a pressure buffer, generates and maintains a set pressure to drive the pressure-driven flows of test fluids through the 3D-CCs. The graduated fluidic chambers of the 3D-CCs serve as a flow meter, enabling simple measurement of the flow rates of the test fluids flowing through the 3D-CCs, which is readable with the naked eye. The viscosities of the test fluids can be simply calculated from the measured flow rates under a set pressure condition without the need for peripheral equipment and calibration. We demonstrate the multiplexing capability of the 3D-CC platform by simultaneously measuring different Newtonian-fluid samples. Further, we demonstrate that the shear-rate dependence of the viscosity of a non-Newtonian fluid can be analyzed simultaneously under various shear-rate conditions with the 3D-CC platform. PMID- 30424248 TI - Design of Substrate Stretchability Using Origami-Like Folding Deformation for Flexible Thermoelectric Generator. AB - A stretchable thermoelectric (TE) generator was developed by using rigid BiTe based TE elements and a non-stretchable substrate with origami-like folding deformation. Our stretchable TE generator contains flat sections, on which the rigid TE elements are arranged, and folded sections, which produce and guarantee the stretchability of a device. First, a simple stretchable device with a single pair of p-type and n-type BiTe-based TE elements was designed and fabricated. The TE elements were sandwiched between two folded polyimide-copper substrates. The length of the wiring between the flat sections changed from 1.0 mm in the folded state to 1.8 mm in the deployed state. It was also confirmed that the single-pair device could generate power in both the folded and deployed states. After this, a stretchable TE generator with eight pairs of p-type and n-type BiTe-based TE elements connected in series was created. The stretchable TE generator was capable of withstanding a stretching deformation of 20% and could also produce an output voltage in both the folded and deployed states. PMID- 30424249 TI - Erbium Luminescence Centres in Single- and Nano-Crystalline Diamond-Effects of Ion Implantation Fluence and Thermal Annealing. AB - We present a fundamental study of the erbium luminescence centres in single- and nano-crystalline (NCD) diamonds. Both diamond forms were doped with Er using ion implantation with the energy of 190 keV at fluences up to 5 * 1015 ions.cm-2, followed by annealing at controllable temperature in Ar atmosphere or vacuum to enhance the near infrared photoluminescence. The Rutherford Backscattering Spectrometry showed that Er concentration maximum determined for NCD films is slightly shifted to the depth with respect to the Stopping and Range of Ions in Matter simulation. The number of the displaced atoms per depth slightly increased with the fluence, but in fact the maximum reached the fully disordered target even in the lowest ion fluence used. The post-implantation annealing at 800 degrees C in vacuum had a further beneficial effect on erbium luminescence intensity at around 1.5 MUm, especially for the Er-doped NCD films, which contain a higher amount of grain boundaries than single-crystalline diamond. PMID- 30424250 TI - Encapsulation of NEM Memory Switches for Monolithic-Three-Dimensional (M3D) CMOS NEM Hybrid Circuits. AB - Considering the isotropic release process of nanoelectromechanical systems (NEMSs), defining the active region of NEM memory switches is one of the most challenging process technologies for the implementation of monolithic-three dimensional (M3D) CMOS-NEM hybrid circuits. In this paper, we propose a novel encapsulation method of NEM memory switches. It uses alumina (Al2O3) passivation layers which are fully compatible with the CMOS baseline process. The Al2O3 bottom passivation layer can protect intermetal dielectric (IMD) and metal interconnection layers from the vapor hydrogen fluoride (HF) etching process. Thus, the controllable formation of the cavity for the mechanical movement of NEM devices can be achieved without causing any damage to CMOS baseline circuits as well as metal interconnection lines. As a result, NEM memory switches can be located in any place and metal layer of an M3D CMOS-NEM hybrid chip, which makes circuit design easier and more volume efficient. The feasibility of our proposed method is verified based on experimental results. PMID- 30424251 TI - Multiple and Periodic Measurement of RBC Aggregation and ESR in Parallel Microfluidic Channels under On-Off Blood Flow Control. AB - Red blood cell (RBC) aggregation causes to alter hemodynamic behaviors at low flow-rate regions of post-capillary venules. Additionally, it is significantly elevated in inflammatory or pathophysiological conditions. In this study, multiple and periodic measurements of RBC aggregation and erythrocyte sedimentation rate (ESR) are suggested by sucking blood from a pipette tip into parallel microfluidic channels, and quantifying image intensity, especially through single experiment. Here, a microfluidic device was prepared from a master mold using the xurography technique rather than micro-electro-mechanical-system fabrication techniques. In order to consider variations of RBC aggregation in microfluidic channels due to continuous ESR in the conical pipette tip, two indices (aggregation index (AI) and erythrocyte-sedimentation-rate aggregation index (EAI)) are evaluated by using temporal variations of microscopic, image based intensity. The proposed method is employed to evaluate the effect of hematocrit and dextran solution on RBC aggregation under continuous ESR in the conical pipette tip. As a result, EAI displays a significantly linear relationship with modified conventional ESR measurement obtained by quantifying time constants. In addition, EAI varies linearly within a specific concentration of dextran solution. In conclusion, the proposed method is able to measure RBC aggregation under continuous ESR in the conical pipette tip. Furthermore, the method provides multiple data of RBC aggregation and ESR through a single experiment. A future study will involve employing the proposed method to evaluate biophysical properties of blood samples collected from cardiovascular diseases. PMID- 30424252 TI - The Design and Positioning Method of a Flexible Zoom Artificial Compound Eye. AB - The focal lengths of the sub-eyes in a single-layer uniform curved compound eye are all the same, resulting in poor imaging quality for the compound eye. A non uniform curved compound eye can effectively solve the problem of poor edge imaging quality, however, it suffers from a large spherical aberration, and is unable to achieve zoom imaging. To solve these problems, a new type of aspherical artificial compound eye structure with variable focal length is proposed in this paper. The structure divides the surface compound eye into three fan-shaped areas with different focal lengths of the microlens in different areas, which allow the artificial compound eye to zoom in a certain range. The focal length and size of the microlens is determined by the area and the location of the microlens. The aspherical optimization of the microlens is calculated, and spherical aberration in each area is reduced to one percent of the initial value. Through simulation analysis, the designed artificial compound eye structure realizes focal length adjustment and effectively reduces the problem of the poor imaging quality of the curved compound eye edge. As a result, an aspherical artificial compound eye sample-where the number of sub-eyes is n = 61, and the diameter of the base is Phi = 8.66 mm-was prepared by using a molding method. Additionally, the mutual relationship between the eyes of the child was calibrated, and hence, a mathematical model for the simultaneous identification of multiple sub-eyes was established. This study set up an experimental artificial compound eye positioning system, and through a number of microlens capture target point settlement coordinates, achieved an error value of less than 10%. PMID- 30424253 TI - Admittance of Atomic and Molecular Junctions and Their Signal Transmission. AB - Atom-sized contacts of metals are usually characterized by their direct current (DC) conductance. However, when atom-sized contacts are used as device interconnects and transmit high frequency signals or fast pulses, the most critical parameter is not their DC conductance but their admittance Y(omega), in particular its imaginary part ImY(omega). In this article, I will present a brief survey of theoretical and experimental results on the magnitude of Y(omega) for atom-sized contacts of metals. Theoretical contact models are first described and followed by numerical evaluation of ImY(omega) based on these models. As for experiments on Y(omega), previous experiments conducted under time-varying biases are surveyed, and then the results of direct signal transmission through atom sized contacts are discussed. Both theoretical and experimental results indicate that ImY(omega) is negligibly small for typical atom-sized contacts for signal frequencies up to 1 GHz. PMID- 30424255 TI - Characterization of Cotton Ball-like Au/ZnO Photocatalyst Synthesized in a Micro Reactor. AB - Noble metal/metal oxide nanostructures are an efficient system in photocatalysis. Continuous and scalable production of advanced particle systems will be a requirement for commercial-scale deployment for many applications, including photocatalysis. In this work, Au/ZnO structures were synthesized in a continuous flow micro-reactor at room temperature and the detailed characteristics of the product indicate a specific cotton ball-like core-shell microstructure that showcases specific advantages compared to traditional batch synthesis methods. The formation pathway of the core-shell Au/ZnO structures is discussed with the pH-dependent speciation diagram, and photocatalytic activity was assessed under simulated sunlight, demonstrating the enhanced performance of the cotton ball like Au/ZnO microstructures in photocatalytic dye degradation. This work describes the application of microreaction technology in the continuous production of metal/metal oxide photocatalysts. PMID- 30424256 TI - The Evolution of Integrated Interfaces for MEMS Microphones. AB - Over the last decade, MEMS microphones have become the leading solution for implementing the audio module in most portable devices. One of the main drivers for the success of the MEMS microphone has been the continuous improvement of the corresponding integrated interface circuit performance in terms of both dynamic range and power consumption, which enabled the introduction in mobile devices of additional functionalities, such as Hi-Fi audio recording or voice commands. As a result, MEMS microphone interface circuits evolved from just simple amplification stages to complex mixed-signal circuits, including A/D converters, with ever improving performance. This paper provides an overview of such evolution based on actual design examples, focusing, finally, on the latest cutting-edge solutions. PMID- 30424254 TI - Recent Advances in Tactile Sensing Technology. AB - Research on tactile sensing technology has been actively conducted in recent years to pave the way for the next generation of highly intelligent devices. Sophisticated tactile sensing technology has a broad range of potential applications in various fields including: (1) robotic systems with tactile sensors that are capable of situation recognition for high-risk tasks in hazardous environments; (2) tactile quality evaluation of consumer products in the cosmetic, automobile, and fabric industries that are used in everyday life; (3) robot-assisted surgery (RAS) to facilitate tactile interaction with the surgeon; and (4) artificial skin that features a sense of touch to help people with disabilities who suffer from loss of tactile sense. This review provides an overview of recent advances in tactile sensing technology, which is divided into three aspects: basic physiology associated with human tactile sensing, the requirements for the realization of viable tactile sensors, and new materials for tactile devices. In addition, the potential, hurdles, and major challenges of tactile sensing technology applications including artificial skin, medical devices, and analysis tools for human tactile perception are presented in detail. Finally, the review highlights possible routes, rapid trends, and new opportunities related to tactile devices in the foreseeable future. PMID- 30424257 TI - Analysis of Shape Geometry and Roughness of Ti6Al4V Parts Fabricated by Nanosecond Laser Ablation. AB - Laser milling is a micro-machining process that uses a laser beam as a tool to remove material through the layer-by-layer ablation mechanism. Generally in laser ablation, the quality of parts is reduced by melt accretions and thermal damage; therefore, this problem is reduced with shorter pulse duration, although ablation efficiency decreases as well. Thus, laser ablation in the nanosecond range still offers a good compromise between process quality and efficiency. Therefore, laser milling with nanosecond laser ablation requires an accurate study to reduce geometric defects induced by the process. The aim of this paper was to study the shape geometry and roughness of Ti6Al4V parts fabricated by laser milling using a nanosecond Nd:YAG laser source. The impact of the laser processing parameters on machining outcomes was studied in order to determine the optimized processing conditions for reducing geometrical defects and improving surface quality. In particular, the influence of average laser power, frequency, and scanning speed was investigated. The geometry of micro-parts was revealed using a 3D digitizing system, the Optimet Mini Conoscan 4000, which combines a non-contact, single point measuring sensor based on conoscopic holography technology. The use of this measurement technology yielded complete information of the shape geometry and dimensions of the built parts. In addition, the roughness of manufactured surfaces was assessed to complete the analysis. PMID- 30424258 TI - Development of a Sensor Network System with High Sampling Rate Based on Highly Accurate Simultaneous Synchronization of Clock and Data Acquisition and Experimental Verification ?. AB - In this paper, we develop a new sensor network system with a high sampling rate (over 500 Hz) based on the simultaneous synchronization of clock and data acquisition for integrating the data obtained from various sensors. Hence, we also propose a method for the synchronization of clock and data acquisition in the sensor network system. In the proposed scheme, multiple sensor nodes including PCs are connected via Ethernet for data communication and for clock synchronization. The timing of the data acquisition of each sensor is locally controlled based on the PC's clock locally provided in the node, and the clocks are globally synchronized over the network. We construct three types of high speed sensor network systems using the proposed method: the first one is composed of a high-speed tactile sensor node and a high-speed vision node; the second one is composed of a high-speed tactile sensor node and three acceleration sensor nodes; and the last one is composed of a high-speed tactile sensor node, two acceleration sensor nodes, and a gyro sensor node. Through experiments, we verify that the timing error between the sensor nodes for data acquisition is less than 15 MUs, which is significantly smaller than the time interval of 2 ms or a shorter sampling time (less than 2 ms). We also confirm the effectiveness of the proposed method and it is expected that the system can be applied to various applications. PMID- 30424259 TI - 3D Printed Microfluidic Features Using Dose Control in X, Y, and Z Dimensions. AB - Interest has grown in recent years to leverage the possibilities offered by three dimensional (3D) printing, such as rapid iterative changes; the ability to more fully use 3D device volume; and ease of fabrication, especially as it relates to the creation of complex microfluidic devices. A major shortcoming of most commercially available 3D printers is that their resolution is not sufficient to produce features that are truly microfluidic (<100 * 100 MUm2). Here, we test a custom 3D printer for making ~30 MUm scale positive and negative surface features, as well as positive and negative features within internal voids (i.e., microfluidic channels). We found that optical dosage control is essential for creating the smallest microfluidic features (~30 um wide for ridges, ~20 um wide for trenches), and that this resolution was achieved for a number of different exposure approaches. Additionally, we printed various microfluidic particle traps, showed capture of 25 um diameter polymer beads, and iteratively improved the trap design. The rapid feedback allowed by 3D printing, as well as the ability to carefully control optical exposure conditions, should lead to new innovations in the types and sizes of devices that can be created for microfluidics. PMID- 30424260 TI - Engineering of Removing Sacrificial Materials in 3D-Printed Microfluidics. AB - Three-dimensional (3D) printing will create a revolution in the field of microfluidics due to fabricating truly three-dimensional channels in a single step. During the 3D-printing process, sacrificial materials are usually needed to fulfill channels inside and support the printed chip outside. Removing sacrificial materials after printing is obviously crucial for applying these 3D printed chips to microfluidics. However, there are few standard methods to address this issue. In this paper, engineering techniques of removing outer and inner sacrificial materials were studied. Meanwhile, quantification methods of removal efficiency for outer and inner sacrificial materials were proposed, respectively. For outer sacrificial materials, a hot bath in vegetable oil can remove 89.9% +/- 0.1% of sacrificial materials, which is better than mechanics removal, hot oven heating, and an ethanol bath. For inner sacrificial materials, injecting 70 degrees C vegetable oil for 720 min is an optimized approach because of the uniformly high transmittance (93.8% +/- 6.8%) and no obvious deformation. For the industrialization of microfluidics, the cost-effective removing time is around 10 min, which considers the balance between time cost and chip transmittance. The optimized approach and quantification methods presented in this paper show general engineering sacrificial materials removal techniques, which promote removing sacrificial materials from 3D-printed microfluidics chips and take 3D printing a step further in microfluidic applications. PMID- 30424261 TI - A Novel Self-Calibration Method and Experiment of MEMS Gyroscope Based on Virtual Coriolis Force. AB - This paper proposes an effective method to calibrate the microelectromechanical systems (MEMS) vibratory gyroscope based on the virtual Coriolis force. This method utilizes a series of voltage signals to simulate the Coriolis force input, and the gyroscope output is monitored to obtain the scale factor characteristics of the gyroscopes. The scale factor and bias parameters of the gyroscope can be calibrated conveniently and efficiently in the sense-mode open loop. The calibration error of the scale factor based on the turntable and the virtual Coriolis force method is only 1.515%, which proves the correction of the method proposed in this paper. Meanwhile, the non-linearity and bias value of the turntable and the virtual Coriolis force method are 742 ppm and 42.04 mV and 3389 ppm and 0.66 mV, respectively. PMID- 30424262 TI - Multi-axis Response of a Thermal Convection-based Accelerometer. AB - A thermal convection-based accelerometer was fabricated, and its characteristics were analyzed in this study. To understand the thermal convection of the accelerometer, the Grashof and Prandtl number equations were analyzed. This study conducted experiments to improve not only the sensitivity, but also the frequency band. An accelerometer with a more voluminous cavity showed better sensitivity. In addition, when the accelerometer used a gas medium with a large density and small viscosity, its sensitivity also improved. On the other hand, the accelerometer with a narrow volume cavity that used a gas medium with a small density and large thermal diffusivity displayed a larger frequency band. In particular, this paper focused on a Z-axis response to extend the performance of the accelerometer. PMID- 30424263 TI - Simulation and Experiment on Droplet Formation and Separation for Needle-Type Micro-Liquid Jetting Dispenser. AB - The needle-type droplet jetting dispenser has wide applications in the field of microelectronic packaging, and for which the good quality of droplet formation and separation is the key to successful dispensing. This paper simulates the droplet jetting process which has been divided into 5 stages named backflow, growth, droplet extension, breakage, and separation, and analyses the combined effects of system parameters, such as pressure, viscosity, needle stroke, and nozzle diameter, on the changes of morphologies of ejected droplets, which is verified by experiments. The simulation and experiment results show that a higher driving pressure is quite suitable for the high-viscosity liquid to form normal droplets by avoiding adhesion. When increasing the needle stroke, the pressure should also be lowered properly to prevent the flow-stream. Besides, the nozzle with a large diameter is much more likely to cause sputtering or satellite droplet problems. The results have a great significance for guiding the parameter settings of the needle-type dispensing approach. PMID- 30424264 TI - A Closed System for Pico-Liter Order Substance Transport from a Giant Liposome to a Cell. AB - In single cell analysis, transport of foreign substances into a cell is an important technique. In particular, for accurate analysis, a method to transport a small amount (pico-liter order) of substance into the cell without leakage while retaining the cell shape is essential. Because the fusion of the cell and the giant liposome is a closed system to the outside, it may be possible to transport a precise, small amount of substances into the cell. Additionally, there is no possibility that a leaked substance would affect other systems. To develop the liposome-cell transportation system, knowledge about the behavior of substances in the liposome and the cell is important. However, only a few studies have observed the substance transport between a liposome and a cell. Here, we report observation of small amount of substance transport into a single C2C12 cell by using a giant liposome. Substance transport occurred by electrofusion between the cell and the giant liposome containing the substance, which is a closed system. First, to observe the electrofusion and substance transport from the moment of voltage application, we fabricated a microfluidic device equipped with electrodes. We introduced suspensions of cells and liposomes into the microfluidic device and applied alternating current (AC) and direct current (DC) voltages for electrofusion. We observed a small amount (22.4 +/- 0.1%, 10.3 +/- 0.4% and 9.1 +/- 0.1%) of fluorescent substance (Calcein) contained in the liposomes was transported into the cell without leakage outside the cell, and we obtained the diffusion coefficient of Calcein in the cell as 137 +/- 18 MUm2/s. We anticipate that this system and the knowledge acquired will contribute to future realization of more accurate single cell analysis in a wide range of fields. PMID- 30424265 TI - Development of Porous Coatings Enriched with Magnesium and Zinc Obtained by DC Plasma Electrolytic Oxidation. AB - Coatings with developed surface stereometry, being based on a porous system, may be obtained by plasma electrolytic oxidation, PEO (micro arc oxidation, MAO). In this paper, we present novel porous coatings, which may be used, e.g., in micromachine's biocompatible sensors' housing, obtained in electrolytes containing magnesium nitrate hexahydrate Mg(NO3)2.6H2O and/or zinc nitrate hexahydrate Zn(NO3)2.6H2O in concentrated phosphoric acid H3PO4 (85% w/w). Complementary techniques are used for coatings' surface characterization, such as scanning electron microscopy (SEM), for surface imaging as well as for chemical semi-quantitative analysis via energy dispersive X-ray spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), glow discharge optical emission spectroscopy (GDOES), and X-ray powder diffraction (XRD). The results have shown that increasing contents of salts (here, 250 g/L Mg(NO3)2.6H2O and 250 g/L Zn(NO3)2.6H2O) in electrolyte result in increasing of Mg/P and Zn/P ratios, as well as coating thickness. It was also found that by increasing the PEO voltage, the Zn/P and Mg/P ratios increase as well. In addition, the analysis of XPS spectra revealed the existence in 10 nm top of coating magnesium (Mg2+), zinc (Zn2+), titanium (Ti4+), and phosphorus compounds (PO43-, or HPO42-, or H2PO4-, or P2O74-). PMID- 30424266 TI - Novel Disc Hydrodynamic Polishing Process and Tool for High-Efficiency Polishing of Ultra-Smooth Surfaces. AB - Nowadays, large aspheric surfaces, including non-rotationally symmetric surfaces, are increasingly used in ground- and space-based astronomical instruments. The fabrication of these surfaces with sub-micrometric form accuracy and nanometric surface finish, especially for hard and difficult-to-machine materials, has always been a challenge to the optics industry. To produce ultra-smooth surfaces efficiently without subsurface damage and surface scratches, a novel disc hydrodynamic polishing (DHDP) process is proposed through the combination of elastic emission machining and fluid jet polishing. Firstly, the polishing tool for DHDP was carefully designed and the feasibility of the proposed method was experimentally verified. The liquid film was found to act as a carrier of abrasive grains between the polishing tool and the polished surface. Next, computational fluid dynamics (CFD) was used to study the effects of process parameters on the slurry film flow in DHDP. Finally, preliminary experiments were conducted to verify the CFD simulations. The experimental data reasonably agree with the simulation results, which show that increasing rotational speed has no influence on the film thickness for the polishing tool without grooves, but leads to increased film thickness for the polishing tool with grooves. Moreover, DHDP can efficiently reduce the surface roughness and acquire ultra-smooth surfaces without subsurface damage and scratches. PMID- 30424267 TI - Kinematics Error Compensation for a Surface Measurement Probe on an Ultra Precision Turning Machine. AB - In order to enhance the measurement availability for manufacturing applications, on-machine surface measurement (OMSM) is integrated onto the machine tools, which avoids the errors caused by re-positioning workpieces and utilizes the machine axes to extend the measuring range as well. However, due to the fact that measurement probe actuation is performed using the machine tool axes, the inherent kinematics error will inevitably induce additional deviations onto the OMSM results. This paper presents a systematic methodology of kinematics error modelling, measurement, and compensation for OMSM on an ultra-precision turning lathe. According to the measurement task, a selective kinematics error model is established with four primary error components in the sensitive measurement direction, based on multi-body theory and a homogeneous transformation matrix (HTM). In order to separate the artefact error from the measurement results, the selected error components are measured using the reversal method. The measured error value agrees well with the machine tool's specification and a kinematics error map is generated for further compensation. To verify the effectiveness of the proposed kinematics error modelling, measurement, and compensation, an OMSM experiment of an optically flat mirror is carried out. The result indicates the OMSM is the superposition of the sample surface form error and the machine tool kinematics error. With the implementation of compensation, the accuracy of the characterized flatness error from the OMSM improves by 67%. PMID- 30424268 TI - Resist Filling Study for UV Nanoimprint Lithography Using Stamps with Various Micro/Nano Ratios. AB - Mixed micro- and nanoscale structures are gaining popularity in various fields due to their rapid advances in patterning. An investigation in stamp resist filling with multiscale cavities via ultraviolet (UV) nanoimprint lithography (UV NIL) is necessary to improve stamp design. Here, simulations at the level of individual features were conducted to explain different filling behaviors of micro- and nanoscale line patterns. There were noticeable interactions between the micro-/nanoscale cavities. These delayed the resist filling process. Several chip-scale simulations were performed using test patterns with different micro/nano ratios of 1:1, 1:2, and 1:3. There were some minor influences that changed the micro/nano ratios on overall imprint qualities. During the imprinting process, the pressure difference at the boundary between micro- and nanoscale patterns became obvious, with a value of 0.04 MPa. There was a thicker residual layer and worse cavity filling when the proportion of nanoscale structures increased. PMID- 30424269 TI - Design and Fabrication of a Three-Dimensional Artificial Compound Eye Using Two Photon Polymerization. AB - Microlens arrays have been widely used in the fields of micro-optics because of the advantages of their high diffraction efficiency, high fill factor, and wide operating band. However, the microlens array still has problems with its smaller field of view (FOV) and lower utilization of light energy. In this paper, a 3D compound eye system consisting of a microlens array and a pinhole array was designed according to the optical principle of insect compound eye. The artificial compound eye structure was processed in two-photon polymerization processing technology. Ray tracing and optical system simulation of the designed artificial compound eye structure were performed. The results showed that the artificial compound eye structure had a wider FOV and higher light energy utilization than a conventional 2D microlens array. This thesis may lay a theoretical foundation for the structural optimization design of microlens arrays. PMID- 30424270 TI - A Review of the Precision Glass Molding of Chalcogenide Glass (ChG) for Infrared Optics. AB - Chalcogenide glass (ChG) is increasingly demanded in infrared optical systems owing to its excellent infrared optical properties. ChG infrared optics including ChG aspherical and freeform optics are mainly fabricated using the single point diamond turning (SPDT) technique, which is characterized by high cost and low efficiency. This paper presents an overview of the ChG infrared optics fabrication technique through precision glass molding (PGM). It introduces the thermo-mechanical properties of ChG and models the elastic-viscoplasticity constitutive of ChG. The forming accuracy and surface defects of the formed ChG are discussed, and the countermeasures to improve the optics quality are also reviewed. Moreover, the latest advancements in ChG precision molding are detailed, including the aspherical lens molding process, the ChG freeform optics molding process, and some new improvements in PGM. PMID- 30424271 TI - Adaptive Backstepping Design of a Microgyroscope. AB - This paper presents a novel algorithm for the design and analysis of an adaptive backstepping controller (ABC) for a microgyroscope. Firstly, Lagrange-Maxwell electromechanical equations are established to derive the dynamic model of a z axis microgyroscope. Secondly, a nonlinear controller as a backstepping design approach is introduced and deployed in order to drive the trajectory tracking errors to converge to zero with asymptotic stability. Meanwhile, an adaptive estimator is developed and implemented with the backstepping controller to update the value of the parameter estimates in the Lyapunov framework in real-time. In addition, the unknown system parameters including the angular velocity may be estimated online if the persistent excitation (PE) requirement is met. A robust compensator is incorporated in the adaptive backstepping algorithm to suppress the parameter variations and external disturbances. Finally, simulation studies are conducted to prove the validity of the proposed ABC scheme with guaranteed asymptotic stability and excellent tracking performance, as well as consistent parameter estimates in the presence of model uncertainties and disturbances. PMID- 30424272 TI - Possibility of Controlling Self-Organized Patterns with Totalistic Cellular Automata Consisting of Both Rules like Game of Life and Rules Producing Turing Patterns. AB - The basic rules of self-organization using a totalistic cellular automaton (CA) were investigated, for which the cell state was determined by summing the states of neighboring cells, like in Conway's Game of Life. This study used a short range and long-range summation of the cell states around the focal cell. These resemble reaction-diffusion (RD) equations, in which self-organizing behavior emerges from interactions between an activating factor and an inhibiting factor. In addition, Game-of-Life-type rules, in which a cell cannot survive when adjoined by too many or too few living cells, were applied. Our model was able to mimic patterns characteristic of biological cells, including movement, growth, and reproduction. This result suggests the possibility of controlling self organized patterns. Our model can also be applied to the control of engineering systems, such as multirobot swarms and self-assembling microrobots. PMID- 30424274 TI - Comprehensive Simulations for Ultraviolet Lithography Process of Thick SU-8 Photoresist. AB - Thick SU-8 photoresist has been a popular photoresist material to fabricate various mechanical, biological, and chemical devices for many years. The accuracy and precision of the ultraviolet (UV) lithography process of thick SU-8 depend on key parameters in the set-up, the material properties of the SU-8 resist, and the thickness of the resist structure. As feature sizes get smaller and pattern complexity increases, accurate control and efficient optimization of the lithography process are significantly expected. Numerical simulations can be employed to improve understanding and process design of the SU-8 lithography, thereby allowing rapid related product and process development. A typical comprehensive lithography of UV lithography of thick SU-8 includes aerial image simulation, exposure simulation, post-exposure bake (PEB) simulation, and development simulation, and this article presents an overview of the essential aspects in the comprehensive simulation. At first, models for the lithography process of the SU-8 are discussed. Then, main algorithms for etching surface evolvement, including the string, ray tracing, cellular automaton, and fast marching algorithms, are introduced and compared with each other in terms of performance. After that, some simulation results of the UV lithography process of the SU-8 are presented, demonstrating the promising potential and efficiency of the simulation technology. Finally, a prospect is discussed for some open questions in three-dimensional (3D) comprehensive simulation of the UV lithography of the SU-8. PMID- 30424273 TI - Salivary Exosome and Cell-Free DNA for Cancer Detection. AB - Liquid biopsies are easier to acquire patient derived samples than conventional tissue biopsies, and their use enables real-time monitoring of the disease through continuous sampling after initial diagnosis, resulting in a paradigm shift to customized treatment according to the patient's prognosis. Among the various liquid biopsy samples, saliva is easily obtained by spitting or swab sucking without needing an expert for sample collection. In addition, it is known that disease related biomarkers that exist in the blood and have undergone extensive research exist in saliva even at a lower concentration than the blood. Thus, interest in the use of saliva as a liquid biopsy has increased. In this review, we focused on the salivary exosome and cell-free DNA (cfDNA) among the various biomarkers in saliva. Since the exosome and cfDNA in saliva are present at lower concentrations than the biomarkers in blood, it is important to separate and concentrate them before conducting down-stream analyses such as exosome cargo analysis, quantitative polymerase chain reaction (qPCR), and sequencing. However, saliva is difficult to apply directly to microfluidics-based systems for separation because of its high viscosity and the presence of various foreign substances. Therefore, we reviewed the microfluidics-based saliva pretreatment method and then compared the commercially available kit and the microfluidic chip for isolation and enrichment of the exosome and cfDNA in saliva. PMID- 30424275 TI - AFM-Based Characterization Method of Capacitive MEMS Pressure Sensors for Cardiological Applications. AB - Current CMOS-micro-electro-mechanical systems (MEMS) fabrication technologies permit cardiological implantable devices with sensing capabilities, such as the iStents, to be developed in such a way that MEMS sensors can be monolithically integrated together with a powering/transmitting CMOS circuitry. This system on chip fabrication allows the devices to meet the crucial requirements of accuracy, reliability, low-power, and reduced size that any life-sustaining medical application imposes. In this regard, the characterization of stand-alone prototype sensors in an efficient but affordable way to verify sensor performance and to better recognize further areas of improvement is highly advisable. This work proposes a novel characterization method based on an atomic force microscope (AFM) in contact mode that permits to calculate the maximum deflection of the flexible top plate of a capacitive MEMS pressure sensor without coating, under a concentrated load applied to its center. The experimental measurements obtained with this method have allowed to verify the bending behavior of the sensor as predicted by simulation of analytical and finite element (FE) models. This validation process has been carried out on two sensor prototypes with circular and square geometries that were designed using a computer-aided design tool specially-developed for capacitive MEMS pressure sensors. PMID- 30424276 TI - Resonant Directly Coupled Inductors-Capacitors Ladder Network Shows a New, Interesting Property Useful for Application in the Sensor Field, Down to Micrometric Dimensions. AB - The study of ladder networks made by sequences of directly coupled inductor capacitor single cells has led us to discover a new property, which may be of certain interest in the sensor field. In the case of n cells, the n-frequencies vector characterizing each node may allow for the identification of that capacitor (sensor), which has experienced a variation of its nominal value. This localization is possible independently from the observable node of the ladder network as proven by the application of the following multivariate data analysis techniques: principal component analysis and partial least square discriminant analysis. This property can be applied on a large scale down to micrometric dimensions in agreement with the technologic ability to shrink the capacitive sensor dimensions. PMID- 30424277 TI - Frequency Characteristic of Resonant Micro Fluidic Chip for Oil Detection Based on Resistance Parameter. AB - Monitoring the working condition of hydraulic equipment is significance in industrial fields. The abnormal wear of the hydraulic system can be revealed by detecting the variety and size of micro metal debris in the hydraulic oil. We thus present the design and implementation of a micro detection system of hydraulic oil metal debris based on inductor capacitor (LC) resonant circuit in this paper. By changing the resonant frequency of the micro fluidic chip, we can detect the metal debris of hydraulic oil and analyze the sensitivity of the micro fluidic chip at different resonant frequencies. We then obtained the most suitable resonant frequency. The chip would generate a positive resistance pulse when the iron particles pass through the detection area and the sensitivity of the chip decreased with resonant frequency. The chip would generate a negative resistance pulse when the copper particles pass through the detection area and the sensitivity of the chip increased with resonant frequency. The experimental results show that the change of resonant frequency has a great effect on the copper particles and little on the iron particles. Thus, a relatively big resonant frequency can be selected for chip designing and testing. In practice, we can choose a relatively big resonant frequency in this micro fluidic chip designing. The resonant micro fluidic chip is capable of detecting 20-30 MUm iron particles and 70-80 MUm copper particles at 0.9 MHz resonant frequency. PMID- 30424278 TI - 2D Optical Gratings Based on Hexagonal Voids on Transparent Elastomeric Substrate. AB - A chromatic vectorial strain sensor constituted by hexagonal voids on transparent elastomeric substrate has been successfully fabricated via soft colloidal lithography. Initially a highly ordered 1.6 microns polystyrene spheres monolayer colloidal crystal has been realized by wedge-shaped cell method and used as a suitable mold to replicate the periodic structure on a polydimethylsiloxane sheet. The replicated 2D array is characterized by high periodicity and regularity over a large area, as evidenced by morphological and optical properties obtained by means of SEM, absorption and reflectance spectroscopy. In particular, the optical features of the nanostructured elastomer have been investigated in respect to uniaxial deformation up to 10% of its initial length, demonstrating a linear, tunable and reversible response, with a sensitivity of 4.5 +/- 0.1 nm/%. Finally, it has been demonstrated that the specific geometrical configuration allows determining simultaneously the vectorial strain-stress information in the x and y directions. PMID- 30424280 TI - Reconfigurable Sensor Analog Front-End Using Low-Noise Chopper-Stabilized Delta Sigma Capacitance-to-Digital Converter. AB - This paper proposes a reconfigurable sensor analog front-end using low-noise chopper-stabilized delta-sigma capacitance-to-digital converter (CDC) for capacitive microsensors. The proposed reconfigurable sensor analog front-end can drive both capacitive microsensors and voltage signals by direct conversion without a front-end amplifier. The reconfigurable scheme of the front-end can be implemented in various multi-mode applications, where it is equipped with a fully integrated temperature sensor. A chopper stabilization technique is implemented here to achieve a low-noise characteristic by reducing unexpected low-frequency noises such as offsets and flicker noise. The prototype chip of the proposed sensor analog front-end is fabricated by a standard 0.18-MUm 1-poly-6-metal (1P6M) complementary metal-oxide-semiconductor (CMOS) process. It occupies a total active area of 5.37 mm2 and achieves an effective resolution of 16.3-bit. The total power consumption is 0.843 mW with a 1.8 V power supply. PMID- 30424279 TI - Recent Progress in Rapid Sintering of Nanosilver for Electronics Applications. AB - Recently, nanosilver pastes have emerged as one of the most promising high temperature bonding materials for high frequency and high power applications, which provide an effective lead-free electronic packaging solution instead of high-lead and gold-based solders. Although nanosilver pastes can be sintered at lower temperature compared to bulk silver, applications of nanosilver pastes are limited by long-term sintering time (20-30 min), relative high sintering temperature (>250 degrees C), and applied external pressure, which may damage chips and electronic components. Therefore, low temperature rapid sintering processes that can obtain excellent nanosilver joints are anticipated. In this regard, we present a review of recent progress in the rapid sintering of nanosilver pastes. Preparation of nanosilver particles and pastes, mechanisms of nanopastes sintering, and different rapid sintering processes are discussed. Emphasis is placed on the properties of sintered joints obtained by different sintering processes such as electric current assisted sintering, spark plasma sintering, and laser sintering, etc. Although the research on rapid sintering processes for nanosilver pastes has made a great breakthrough over the past few decades, investigations on mechanisms of rapid sintering, and the performance of joints fabricated by pastes with different compositions and morphologies are still far from enough. PMID- 30424281 TI - Improved Virtual Gyroscope Technology Based on the ARMA Model. AB - In view of the large output noise and low precision of the Micro-electro mechanical Systems (MEMS) gyroscope, the virtual gyroscope technology was used to fuse the data of the MEMS gyroscope to improve its output precision. Random error model in the conventional virtual gyroscopes contained an angular rate random walk and angle random walk ignoring other noise items and the virtual gyroscope technology can not compensate all random errors of MEMS gyroscope. So, the improved virtual gyroscope technology based on the autoregressive moving average (ARMA) model was proposed. First, the conventional virtual gyroscope technology was used to model the random error of three MEMS gyroscopes, and the data fusion was carried out by a Kalman filter to get the output of the virtual gyroscope. After that, the ARMA model was used to model the output of the virtual gyroscope, the random error model was improved with the ARMA model, and the Kalman filter was designed based on the improved random error model for data fusion of the MEMS gyroscopes. The experimental results showed that the 1sigma standard deviation of the output of the virtual gyroscope based on the ARMA model was 1.4 times lower than that of the conventional virtual gyroscope output. PMID- 30424282 TI - Effects of Process Parameters on Material Removal in Vibration-Assisted Polishing of Micro-Optic Mold. AB - Process parameter conditions such as vibrating motion, abrasives, pressure and tool wear play an important role in vibration-assisted polishing of micro-optic molds as they strongly affect material removal efficiency and stability. This paper presents an analytical and experimental investigation on the effects of process parameters, aimed at clarifying interrelations between material removal and process parameters which affect polishing quantitatively. The material removal rate (MRR) and surface roughness which represent the polishing characteristics were examined under different vibrating motions, grain sizes of abrasives and polishing pressure. The effects of pressure and tool wear conditions on tool influence function were analyzed. The results showed that 2D vibrating motion generated better surface roughness with higher material removal efficiency while a smaller grain size of abrasives created better surface roughness but lower material removal efficiency. MRR gradually decreases with the increase of polishing pressure when it exceeds 345 kPa, and it was greatly affected by the wear of polisher when wear diameter on the polisher's head exceeds 300 MUm. PMID- 30424285 TI - Tongue Pressure Sensing Array Integrated with a System-on-Chip Embedded in a Mandibular Advancement Splint. AB - Obstructive sleep apnea (OSA), which is caused by obstructions of the upper airway, is a syndrome with rising prevalence. Mandibular advancement splints (MAS) are oral appliances for potential treatment of OSA. This work proposes a highly-sensitive pressure sensing array integrated with a system-on-chip (SoC) embedded in a MAS. The device aims to measure tongue pressure distribution in order to determine the efficacy of the MAS for treating OSA. The flexible sensing array consists of an interdigital electrode pair array assembled with conductive polymer films and an SoC capable of retrieving/storing data during sleep, and transmitting data for analysis after sleep monitoring. The surfaces of the conductive polymer films were patterned with microdomed structures, which effectively increased the sensitivity and reduced the pressure sensing response time. The measured results also show that the crosstalk effect between the sensing elements of the array was negligible. The sensitivity of the sensing array changed minimally after the device was submerged in water for up to 100 h. PMID- 30424283 TI - Graphene-Based Semiconductor Heterostructures for Photodetectors. AB - Graphene transparent conductive electrodes are highly attractive for photodetector (PD) applications due to their excellent electrical and optical properties. The emergence of graphene/semiconductor hybrid heterostructures provides a platform useful for fabricating high-performance optoelectronic devices, thereby overcoming the inherent limitations of graphene. Here, we review the studies of PDs based on graphene/semiconductor hybrid heterostructures, including device physics/design, performance, and process technologies for the optimization of PDs. In the last section, existing technologies and future challenges for PD applications of graphene/semiconductor hybrid heterostructures are discussed. PMID- 30424284 TI - Updated Tactile Feedback with a Pin Array Matrix Helps Blind People to Reduce Self-Location Errors. AB - Autonomous navigation in novel environments still represents a challenge for people with visual impairment (VI). Pin array matrices (PAM) are an effective way to display spatial information to VI people in educative/rehabilitative contexts, as they provide high flexibility and versatility. Here, we tested the effectiveness of a PAM in VI participants in an orientation and mobility task. They haptically explored a map showing a scaled representation of a real room on the PAM. The map further included a symbol indicating a virtual target position. Then, participants entered the room and attempted to reach the target three times. While a control group only reviewed the same, unchanged map on the PAM between trials, an experimental group also received an updated map representing, in addition, the position they previously reached in the room. The experimental group significantly improved across trials by having both reduced self-location errors and reduced completion time, unlike the control group. We found that learning spatial layouts through updated tactile feedback on programmable displays outperforms conventional procedures on static tactile maps. This could represent a powerful tool for navigation, both in rehabilitation and everyday life contexts, improving spatial abilities and promoting independent living for VI people. PMID- 30424286 TI - Progress in Circulating Tumor Cell Research Using Microfluidic Devices. AB - Circulating tumor cells (CTCs) are a popular topic in cancer research because they can be obtained by liquid biopsy, a minimally invasive procedure with more sample accessibility than tissue biopsy, to monitor a patient's condition. Over the past decades, CTC research has covered a wide variety of topics such as enumeration, profiling, and correlation between CTC number and patient overall survival. It is important to isolate and enrich CTCs before performing CTC analysis because CTCs in the blood stream are very rare (0-10 CTCs/mL of blood). Among the various approaches to separating CTCs, here, we review the research trends in the isolation and analysis of CTCs using microfluidics. Microfluidics provides many attractive advantages for CTC studies such as continuous sample processing to reduce target cell loss and easy integration of various functions into a chip, making "do-everything-on-a-chip" possible. However, tumor cells obtained from different sites within a tumor exhibit heterogenetic features. Thus, heterogeneous CTC profiling should be conducted at a single-cell level after isolation to guide the optimal therapeutic path. We describe the studies on single-CTC analysis based on microfluidic devices. Additionally, as a critical concern in CTC studies, we explain the use of CTCs in cancer research, despite their rarity and heterogeneity, compared with other currently emerging circulating biomarkers, including exosomes and cell-free DNA (cfDNA). Finally, the commercialization of products for CTC separation and analysis is discussed. PMID- 30424287 TI - Selective Detection of NO and NO2 with CNTs-Based Ionization Sensor Array. AB - The accurate detection of NOx is an important issue, because nitrogen oxides are not only environmental pollutants, but also harm to human health. An array composed of two carbon nanotubes (CNTs)-based ionization sensors with different separations is proposed for NO and NO2 selective detection. The experimental results indicate that the CNTs-based ionization sensor has an intrinsic, monotonically decreasing response to NO or NO2. The sensor with 80 um separations and 100 um separations exhibited the highest sensitivity of -0.11 nA/ppm to 300 ppm NO and -0.49 nA /ppm to 70 ppm NO2, respectively. Although the effect of the NO2 concentration on the NO response is much stronger than that of NO on NO2, the array of these two sensors still exhibits the ability to simultaneously detect the concentrations of NO and NO2 in a gas mixture without component separation. PMID- 30424288 TI - Injection Compression Molded Microlens Arrays for Hyperspectral Imaging. AB - In this work, a polymer microlens array (MLA) for a hyperspectral imaging (HSI) system is produced by means of ultraprecision milling (UP-milling) and injection compression molding. Due to the large number of over 12,000 microlenses on less than 2 cm2, the fabrication process is challenging and requires full process control. The study evaluates the process chain and optimizes the single process steps to achieve high quality polymer MLAs. Furthermore, design elements like mounting features are included to facilitate the integration into the final HSI system. The mold insert was produced using ultraprecision milling with a diamond cutting tool. The machining time was optimized to avoid temperature drifts and enable high accuracy. Therefore, single immersions of the diamond tool at a defined angle was used to fabricate each microlens. The MLAs were replicated using injection compression molding. For this process, an injection compression molding tool with moveable frame plate was designed and fabricated. The structured mold insert was used to generate the compression movement, resulting in a homogeneous pressure distribution. The characterization of the MLAs showed high form accuracy of the microlenses and the mounting features. The functionality of the molded optical part could be demonstrated in an HIS system by focusing light spectrums onto a CCD image sensor. PMID- 30424289 TI - Compound Glass Microsphere Resonator Devices. AB - In recent years, compound glass microsphere resonator devices have attracted increasing interest and have been widely used in sensing, microsphere lasers, and nonlinear optics. Compared with traditional silica resonators, compound glass microsphere resonators have many significant and attractive properties, such as high-Q factor, an ability to achieve high rare earth ion, wide infrared transmittance, and low phonon energy. This review provides a summary and a critical assessment of the fabrication and the optical characterization of compound glasses and the related fabrication and applications of compound glass microsphere resonators. PMID- 30424290 TI - A Study on Microturning with Electrochemical Assistance of the Cutting Process. AB - The paper investigated an electrochemically-assisted microturning process. Depending on the variant of electrochemical assistance, material can be removed with simultaneous electrochemical and mechanical action or electrochemical assistance can change the conditions of the cutting by changing the mechanical properties of the machined material. The experimental part includes discussion of the study methodology and a comparison of straight turning results in the case of machining 1.4301 stainless steel with and without electrochemical assistance. Based on this study, we can confirm that electrochemical assistance brings significant benefits in both variants, especially when the depth-of-cut is in the range of 1 um. PMID- 30424291 TI - Fabrication of Magnetically Actuated Fluidic Drug Delivery Device Using Polyvinyl Chloride Adhesive Stencils. AB - In this paper, a polydimethylsiloxane (PDMS) fabrication method is introduced. It eliminates the need for conventional fabrication methods, such as photolithography and etching. Only a series of oxygen plasma treatments, silanization, and polyvinyl chloride (PVC) adhesive stencils were used to develop multi-layer designs. The fabrication method was applied to fabricate a PDMS-based drug delivery device with an actively controllable, magnetically actuated valve. Above all, this fabrication method eliminated the use of a power-consuming pump. Fluidic substances were injected into the circular shaped primary chamber through a syringe. A secondary chamber, similar to the primary chamber's structure but with a smaller radius and thinner membrane, was connected via a microchannel to regulate the amount released. When actuated with a permanent magnet for one second, the volume in the secondary chamber first depletes. As the magnet is removed, the valve closes. Subsequently, the primary chamber replenishes the secondary chamber. This process can be repeated until the primary chamber reaches a saturation state that can no longer inflate the secondary chamber. The device could release a few microliters per actuation. Various combinations of size and thickness of primary, and secondary chambers can realize release rate of desired amount. PMID- 30424292 TI - Performance Evaluation of Thermoelectric Energy Harvesting System on Operating Rolling Stock. AB - During rolling stock operation, various kinds of energy such as vibration, heat, and train-induced wind are dissipated. The amount of energy dissipation cannot be overlooked when a heavy railroad vehicle operates at high speed. Therefore, if the wasted energy is effectively harvested, it can be used to power components like low power sensor nodes. This study aims to review a method of collecting waste heat, caused by the axle bearing of bogie in a rolling stock. A thermoelectric module (TEM) was used to convert the temperature gradient between the surface of the axle bearing housing and the outdoor air into electric energy. In this study, the output performance by temperature difference in the TEM was lab-tested and maximized by computational fluid analysis of the cooling fins. The optimized thermoelectric energy harvesting system (TEHS) was designed and applied on a rolling stock to analyze the power-generating performance under operation. When the rolling stock was operated for approximately 57 min including an interval of maximum speed of 300 km/h, the maximum open circuit voltage was measured at approximately 0.4 V. Based on this study, the system is expected to be utilized as a self-powered independent monitoring system if applied to a low power sensor node in the future. PMID- 30424294 TI - Topic Review: Application of Raman Spectroscopy Characterization in Micro/Nano Machining. AB - The defects and subsurface damages induced by crystal growth and micro/nano machining have a significant impact on the functional performance of machined products. Raman spectroscopy is an efficient, powerful, and non-destructive testing method to characterize these defects and subsurface damages. This paper aims to review the fundamentals and applications of Raman spectroscopy on the characterization of defects and subsurface damages in micro/nano-machining. Firstly, the principle and several critical parameters (such as penetration depth, laser spot size, and so on) involved in the Raman characterization are introduced. Then, the mechanism of Raman spectroscopy for detection of defects and subsurface damages is discussed. The Raman spectroscopy characterization of semiconductor materials' stacking faults, phase transformation, and residual stress in micro/nano-machining is discussed in detail. Identification and characterization of phase transformation and stacking faults for Si and SiC is feasible using the information of new Raman bands. Based on the Raman band position shift and Raman intensity ratio, Raman spectroscopy can be used to quantitatively calculate the residual stress and the thickness of the subsurface damage layer of semiconductor materials. The Tip-Enhanced Raman Spectroscopy (TERS) technique is helpful to dramatically enhance the Raman scattering signal at weak damages and it is considered as a promising research field. PMID- 30424293 TI - Liquid Metal Enabled Electrobiology: A New Frontier to Tackle Disease Challenges. AB - In this article, a new conceptual biomedical engineering strategy to tackle modern disease challenges, called liquid metal (LM) enabled electrobiology, is proposed. This generalized and simple method is based on the physiological fact that specially administrated electricity induces a series of subsequent desired biological effects, either shortly, transitionally, or permanently. Due to high compliance within biological tissues, LM would help mold a pervasive method for treating physiological or psychological diseases. As highly conductive and non toxic multifunctional flexible materials, such LMs can generate any requested electric treating fields (ETFields), which can adapt to various sites inside the human body. The basic mechanisms of electrobiology in delivering electricity to the target tissues and then inducing expected outputs for disease treatment are interpreted. The methods for realizing soft and conformable electronics based on LM are illustrated. Furthermore, a group of typical disease challenges are observed to illustrate the basic strategies for performing LM electrobiology therapy, which include but are not limited to: tissue electronics, brain disorder, immunotherapy, neural functional recovery, muscle stimulation, skin rejuvenation, cosmetology and dieting, artificial organs, cardiac pacing, cancer therapy, etc. Some practical issues regarding electrobiology for future disease therapy are discussed. Perspectives in this direction for incubating a simple biomedical tool for health care are pointed out. PMID- 30424295 TI - An Improved Phase-Robust Configuration for Vibration Amplitude-Phase Extraction for Capacitive MEMS Gyroscopes. AB - This paper presents for the first time an improved algorithm for vibration amplitude-phase information extraction of capacitive microelectromechanical systems (MEMS) gyroscopes. Amplitude and phase information resulting from the improved algorithm is insensitive to the phase variation of an interface capacitance-voltage (CV) circuit, thus both long time drift of the gyroscope and bias instability have been improved. Experimental results show that both the phase and amplitude information extracted using this improved algorithm is insensitive to phase variation of CV circuit which is in accordance with theory. Bias instability using this improved configuration is 0.64 degrees /h, which is improved two times more than the configuration using traditional double-side-band (DSB) demodulation configuration, and 4.3 times more than the configuration using single-side-band (SSB) demodulation, respectively. Allan deviation analysis shows that the slow varying drift term using D&S configuration is effectively reduced due to its robustness to CV phase variation compared to test results using DSB or SSB configuration. PMID- 30424296 TI - Stabilization of Microrobot Motion Characteristics in Liquid Media. AB - Magnetically actuated microrobot in a liquid media is faced with the problem of head-tilting reaction caused by its hydrodynamic structure and its speed while moving horizontally. When the instance microrobot starts a lateral motion, the drag force acting on it increases. Thus, the microrobot is unable to move parallel to the surface due to the existence of drag force that cannot be neglected, particularly at high speeds such as >5 mm/s. The effect of it scales exponentially at different speeds and the head-tilting angle of the microrobot changes relative to the reference surface. To the best of our knowledge, there is no prior study on this problem, and no solution has been proposed so far. In this study, we developed and experimented with 3 control models to stabilize microrobot motion characteristics in liquid media to achieve accurate lateral locomotion. The microrobot moves in an untethered manner, and its localization is carried out by a neodymium magnet (grade N48) placed inside its polymer body. This permanent magnet is called a carrier-magnet. The fabricated microrobot is levitated diamagnetically using a pyrolytic graphite placed under it and an external permanent magnet, called a lifter-magnet (grade N48), aligned above it. The lifter-magnet is attached to a servo motor mechanism which can control carrier-magnet orientation along with roll and pitch axes. Controlling the angle of this servo motor, together with the lifter-magnet, allowed us to cope with the head-tilting reaction instantly. Based on the finite element method (FEM), analyses that were designed according to this experimental setup, the equations giving the relation of microrobot speed with servo motor angle along with the microrobot head-tilting angle with servo motor angle, were derived. The control inputs were obtained by COMSOL(r) (version 5.3, COMSOL Inc., Stockholm, Sweden). Using these derived equations, the rule-based model, laser model, and hybrid model techniques were proposed in this study to decrease the head-tilting angle. Motion control algorithms were applied in di-ionized water medium. According to the results for these 3 control strategies, at higher speeds (>5 mm/s) and 5 mm horizontal motion trajectory, the average head-tilting angle was reduced to 2.7 degrees with the ruled-based model, 1.1 degrees with the laser model, and 0.7 degrees with the hybrid model. PMID- 30424297 TI - Poly(ionic liquid)s Based Brush Type Nanomotor. AB - A brush type nanomotor was fabricated via assembly assistant polymerization of poly(ionic liquid) and surface grafting polymerization. The method for large scale fabrication of brush nanomotors with soft surfaces is described. These soft locomotive particles are based on core-shell brush nanoparticles assembled from poly(ionic liquid) as core and thermoresponsive PNIPAM as brush shells on which platinum nanoparticle (PtNP) were grown in situ. The particles show non-Brownian motion in H2O2 solution. PMID- 30424298 TI - Micro Motion Amplifiers for Compact Out-of-Plane Actuation. AB - Small-scale, out-of-plane actuators can enable tactile interfaces; however, achieving sufficient actuator force and displacement can require larger actuators. In this work, 2-mm2 out-of-plane microactuators were created, and were demonstrated to output up to 6.3 um of displacement and 16 mN of blocking force at 170 V. The actuators converted in-plane force and displacement from a piezoelectric extensional actuator into out-of-plane force and displacement using robust, microelectromechanical systems (MEMS)-enabled, half-scissor amplifiers. The microscissors employed two layers of lithographically patterned SU-8 epoxy microstructures, laminated with a thin film of structural polyimide and adhesive to form compact flexural hinges that enabled the actuators' small area. The self aligned manufacture minimized assembly error and fabrication complexity. The scissor design dominated the actuators' performance, and the effects of varying scissor angle, flexure thickness, and adhesive type were characterized to optimize the actuators' output. Reducing the microscissor angle yielded the highest actuator performance, as it maximized the amplification of the half scissor's displacement and minimized scissor deformation under externally applied loads. The actuators' simultaneously large displacements and blocking forces for their size were quantified by a high displacement-blocking force product per unit area of up to 50 mN.um/mm2. For a linear force-displacement relationship, this corresponds to a work done per unit area of 25 mN.um/mm2. PMID- 30424299 TI - Long Period Grating-Based Fiber Coupling to WGM Microresonators. AB - A comprehensive model for designing robust all-in-fiber microresonator-based optical sensing setups is illustrated. The investigated all-in-fiber setups allow light to selectively excite high-Q whispering gallery modes (WGMs) into optical microresonators, thanks to a pair of identical long period gratings (LPGs) written in the same optical fiber. Microspheres and microbubbles are used as microresonators and evanescently side-coupled to a thick fiber taper, with a waist diameter of about 18 um, in between the two LPGs. The model is validated by comparing the simulated results with the experimental data. A good agreement between the simulated and experimental results is obtained. The model is general and by exploiting the refractive index and/or absorption characteristics at suitable wavelengths, the sensing of several substances or pollutants can be predicted. PMID- 30424301 TI - A New Grinding Force Model for Micro Grinding RB-SiC Ceramic with Grinding Wheel Topography as an Input. AB - The ability to predict the grinding force for hard and brittle materials is important to optimize and control the grinding process. However, it is a difficult task to establish a comprehensive grinding force model that takes into account the brittle fracture, grinding conditions, and random distribution of the grinding wheel topography. Therefore, this study developed a new grinding force model for micro-grinding of reaction-bonded silicon carbide (RB-SiC) ceramics. First, the grinding force components and grinding trajectory were analysed based on the critical depth of rubbing, ploughing, and brittle fracture. Afterwards, the corresponding individual grain force were established and the total grinding force was derived through incorporating the single grain force with dynamic cutting grains. Finally, a series of calibration and validation experiments were conducted to obtain the empirical coefficient and verify the accuracy of the model. It was found that ploughing and fracture were the dominate removal modes, which illustrate that the force components decomposed are correct. Furthermore, the values predicted according to the proposed model are consistent with the experimental data, with the average deviation of 6.793% and 8.926% for the normal and tangential force, respectively. This suggests that the proposed model is acceptable and can be used to simulate the grinding force for RB-SiC ceramics in practice. PMID- 30424300 TI - The Development of an Effective Bacterial Single-Cell Lysis Method Suitable for Whole Genome Amplification in Microfluidic Platforms. AB - Single-cell sequencing is a powerful technology that provides the capability of analyzing a single cell within a population. This technology is mostly coupled with microfluidic systems for controlled cell manipulation and precise fluid handling to shed light on the genomes of a wide range of cells. So far, single cell sequencing has been focused mostly on human cells due to the ease of lysing the cells for genome amplification. The major challenges that bacterial species pose to genome amplification from single cells include the rigid bacterial cell walls and the need for an effective lysis protocol compatible with microfluidic platforms. In this work, we present a lysis protocol that can be used to extract genomic DNA from both gram-positive and gram-negative species without interfering with the amplification chemistry. Corynebacterium glutamicum was chosen as a typical gram-positive model and Nostoc sp. as a gram-negative model due to major challenges reported in previous studies. Our protocol is based on thermal and chemical lysis. We consider 80% of single-cell replicates that lead to >5 ng DNA after amplification as successful attempts. The protocol was directly applied to Gloeocapsa sp. and the single cells of the eukaryotic Sphaerocystis sp. and achieved a 100% success rate. PMID- 30424302 TI - Flexible Thermo-Optic Variable Attenuator based on Long-Range Surface Plasmon Polariton Waveguides. AB - A flexible thermo-optic variable attenuator based on long-range surface plasmon polariton (LRSPP) waveguide for microwave photonic application was investigated. Low-loss polymer materials and high-quality silver strip were served as cladding layers and core layer of the LRSPP waveguide, respectively. By using finite element method (FEM), the thermal distribution and the optical field distribution have been carefully optimized. The fabricated device was characterized by end fire excitation with a 1550 nm laser. The transmission performance of high-speed data and microwave modulated optical signal was measured while using a broadband microwave photonics link. The results indicated that the propagation loss of the LRSPP waveguide was about 1.92 dB/cm. The maximum attenuation of optical signal was about 28 dB at a driving voltage of 4.17 V, and the variable attenuation of microwave signals was obviously observed by applying different driving voltage to the heater. This flexible plasmonic variable attenuator is promising for chip scale interconnection in high-density photonic integrated circuits and data transmission and amplitude control in microwave photonic systems. PMID- 30424303 TI - Adenosine Triphosphate Measurement in Deep Sea Using a Microfluidic Device. AB - Total ATP (adenosine triphosphate) concentration is a useful biochemical parameter for detecting microbial biomass or biogeochemical activity anomalies in the natural environment. In this study, we describe the development and evaluation of a new version of in situ ATP analyzer improved for the continuous and quantitative determination of ATP in submarine environments. We integrated a transparent microfluidic device containing a microchannel for cell lysis and a channel for the bioluminescence L-L (luciferin-luciferase) assay with a miniature pumping unit and a photometry module for the measurement of the bioluminescence intensity. A heater and a temperature sensor were also included in the system to maintain an optimal temperature for the L-L reaction. In this study, the analyzer was evaluated in deep sea environments, reaching a depth of 200 m using a remotely operated underwater vehicle. We show that the ATP analyzer successfully operated in the deep-sea environment and accurately quantified total ATP within the concentration lower than 5 * 10-11 M. PMID- 30424304 TI - Microchannels Fabrication in Alumina Ceramic Using Direct Nd:YAG Laser Writing. AB - Ceramic microchannels have important applications in different microscale systems like microreactors, microfluidic devices and microchemical systems. However, ceramics are considered difficult to manufacture owing to their wear and heat resistance capabilities. In this study, microchannels are developed in alumina ceramic using direct Nd:YAG laser writing. The laser beam with a characteristic pulse width of 10 us and a beam spot diameter of 30 um is used to make 200 um width microchannels with different depths. The effects of laser beam intensity and pulse overlaps on dimensional accuracy and material removal rate have been investigated using different scanning patterns. It is found that beam intensity has a major influence on dimensional accuracy and material removal rate. Optimum parameter settings are found using grey relational grade analysis. It is concluded that low intensity and low to medium pulse overlap should be used for better dimensional accuracy. This study facilitates further understanding of laser material interaction for different process parameters and presents optimum laser process parameters for the fabrication of microchannel in alumina ceramic. PMID- 30424305 TI - A High-Dynamic-Range Switched-Capacitor Sigma-Delta ADC for Digital Micromechanical Vibration Gyroscopes. AB - This paper presents a multi-stage noise shaping (MASH) switched-capacitor (SC) sigma-delta (SigmaDelta) analog-to-digital converter (ADC) composed of an analog modulator with an on-chip noise cancellation logic and a reconfigurable digital decimator for MEMS digital gyroscope applications. A MASH 2-1-1 structure is employed to guarantee an absolutely stable modulation system. Based on the over sampling and noise-shaping techniques, the core modulator architecture is a cascade of three single-loop stages containing feedback paths for systematic optimization to avoid deterioration in conversion accuracy caused by capacitor mismatch. A digital noise cancellation logic is also included to eliminate residual quantization errors in the former two stages, and those in the last stage are shaped by a fourth-order modulation. A multi-rate decimator follows the analog modulator to suit variable gyroscope bandwidth. Manufactured in a standard 0.35 MUm CMOS technology, the whole chip occupies an area of 3.8 mm2. Experimental results show a maximum signal-to-noise ratio (SNR) of 100.2 dB and an overall dynamic range (DR) of 107.6 dB, with a power consumption of 3.2 mW from a 5 V supply. This corresponds to a state-of-the-art figure-of-merit (FoM) of 165.6 dB. PMID- 30424306 TI - Random Error Analysis of MEMS Gyroscope Based on an Improved DAVAR Algorithm. AB - In view that traditional dynamic Allan variance (DAVAR) method is difficult to make a good balance between dynamic tracking capabilities and the confidence of the estimation. And the reason is the use of a rectangular window with the fixed window length to intercept the original signal. So an improved dynamic Allan variance method was proposed. Compared with the traditional Allan variance method, this method can adjust the window length of the rectangular window adaptively. The data in the beginning and terminal interval was extended with the inverted mirror extension method to improve the utilization rate of the interval data. And the sliding kurtosis contribution coefficient and kurtosis were introduced to adjust the length of the rectangular window by sensing the content of shock signal in terminal interval. The method analyzed the window length change factor in different stable conditions and adjusted the rectangular window's window length according to the kurtosis, sliding kurtosis contribution coefficient. The test results show that the more the kurtosis stability threshold was close to 3, the stronger the dynamic tracking ability of DAVAR would be. But the kurtosis stability threshold was too close to 3, there was a misjudgement in kurtosis analysis of signal stability, resulting in distortion of DAVAR analysis results. When using the improved DAVAR method, the kurtosis stability threshold can be close to 3 to improve the tracking ability and the estimation confidence in stable interval. Therefore, it solved the problem that the dynamic Allan variance tracking ability and confidence level were difficult to take into account, and also solved the problem of misjudgement in the stability analysis of kurtosis. PMID- 30424307 TI - Extrusion-Based 3D Printing of Microfluidic Devices for Chemical and Biomedical Applications: A Topical Review. AB - One of the most widespread additive manufacturing (AM) technologies is fused deposition modelling (FDM), also known as fused filament fabrication (FFF) or extrusion-based AM. The main reasons for its success are low costs, very simple machine structure, and a wide variety of available materials. However, one of the main limitations of the process is its accuracy and finishing. In spite of this, FDM is finding more and more applications, including in the world of micro components. In this world, one of the most interesting topics is represented by microfluidic reactors for chemical and biomedical applications. The present review focusses on this research topic from a process point of view, describing at first the platforms and materials and then deepening the most relevant applications. PMID- 30424308 TI - Design and Fabrication of a Microfluidic Viscometer Based on Electrofluidic Circuits. AB - This paper reports a microfluidic viscometer based on electrofluidic circuits for measuring viscosities of liquid samples. The developed micro-device consists of a polydimethylsiloxane (PDMS) layer for electrofluidic circuits, a thin PDMS membrane, another PDMS layer for sample pretreatment, and a glass substrate. As the sample flows inside the microfluidic channel, its viscosity causes flow resistance and a pressure drop along this channel. This pressure drop, in turn, generates a hydraulic pressure which deforms the PDMS membrane, causing changes in the cross-sectional area and the electrical resistance of the electrofluidic resistor. This small resistance change is then measured via the electrofluidic Wheatstone bridge to relate the measured voltage difference to the fluidic viscosity. The performance of this viscometer was first tested by flowing nitrogen gas with controllable pressures into the device. The relationship between measured voltage difference and input gas pressure was analyzed to be linear in the pressure range of 0-15 psi. Another test using pure water indicated good linearity between measured voltage difference and flow rate in the rate range of 20-100 MUL/min. Viscosities of glycerol/water solutions with volume/volume (v/v) concentrations ranging from 0 to 30% were measured, and these values were close to those obtained using commercially available viscometers. In addition, the sample-pretreatment layer can be used to mix and/or dilute liquid samples to desired concentrations. Therefore, this microfluidic device has potential for measurements of fluidic viscosity in a fast, accurate, and high throughput manner. PMID- 30424309 TI - Direct Metal Forming of a Microdome Structure with a Glassy Carbon Mold for Enhanced Boiling Heat Transfer. AB - The application of microtechnology to traditional mechanical industries is limited owing to the lack of suitable micropatterning technology for durable materials including metal. In this research, a glassy carbon (GC) micromold was applied for the direct metal forming (DMF) of a microstructure on an aluminum (Al) substrate. The GC mold with microdome cavities was prepared by carbonization of a furan precursor, which was replicated from the thermal reflow photoresist master pattern. A microdome array with a diameter of 8.4 MUm, a height of ~0.74 MUm, and a pitch of 9.9 MUm was successfully fabricated on an Al substrate by using DMF at a forming temperature of 645 degrees C and an applied pressure of 2 MPa. As a practical application of the proposed DMF process, the enhanced boiling heat transfer characteristics of the DMF microdome Al substrate were analyzed. The DMF microdome Al substrate showed 20.4 +/- 2.6% higher critical heat flux and 34.1 +/- 5.3% higher heat transfer coefficient than those of a bare Al substrate. PMID- 30424310 TI - Effects of Annealing Temperature on Optical Band Gap of Sol-gel Tungsten Trioxide Films. AB - Tungsten trioxide (WO3) is a wide band gap semiconductor material that is used as an important electrochromic layer in electrochromic devices. In this work, the effects of the annealing temperature on the optical band gap of sol-gel WO3 films were investigated. X-ray Diffraction (XRD) showed that WO3 films were amorphous after being annealed at 100 degrees C, 200 degrees C and 300 degrees C, respectively, but became crystallized at 400 degrees C and 500 degrees C. An atomic force microscope (AFM) showed that the crystalline WO3 films were rougher than the amorphous WO3 films (annealed at 200 degrees C and 300 degrees C). An ultraviolet spectrophotometer showed that the optical band gap of the WO3 films decreased from 3.62 eV to 3.30 eV with the increase in the annealing temperature. When the Li+ was injected into WO3 film in the electrochromic reaction, the optical band gap of the WO3 films decreased. The correlation between the optical band gap and the electrical properties of the WO3 films was found in the electrochromic test by analyzing the change in the response time and the current density. The decrease in the optical band gap demonstrates that the conductivity increases with the corresponding increase in the annealing temperature. PMID- 30424311 TI - A Simulation Study of Debris Removal Process in Ultrasonic Vibration Assisted Electrical Discharge Machining (EDM) of Deep Holes ?. AB - When machining a small hole with high aspect ratio in EDM, it is hard for the flushing liquid entering the bottom gap and the debris could hardly be removed, which results in the accumulation of debris and affects the machining efficiency and machining accuracy. The assisted ultrasonic vibration can improve the removal of debris in the gap. Based on dynamics simulation software, Fluent, a three dimensional (3D) model of debris movement in the gap flow field of EDM small hole machining assisted with side flushing and ultrasonic vibration is established in this paper. The laws of different amplitudes and frequencies and different aspect ratios on debris distribution and movement are quantitatively analyzed. The motion height of debris was observed under different conditions. The research results show that periodic ultrasonic vibration can promote the movement of debris, which is beneficial to the removal of debris in the machining gap. When compared to traditional small hole machining in EDM, the debris in the machining gap were greatly reduced, which ensures the stability of the machining process and improves the machining efficiency. PMID- 30424312 TI - Glassy Microspheres for Energy Applications. AB - Microspheres made of glass, polymer, or crystal material have been largely used in many application areas, extending from paints to lubricants, to cosmetics, biomedicine, optics and photonics, just to mention a few. Here the focus is on the applications of glassy microspheres in the field of energy, namely covering issues related to their use in solar cells, in hydrogen storage, in nuclear fusion, but also as high-temperature insulators or proppants for shale oil and gas recovery. An overview is provided of the fabrication techniques of bulk and hollow microspheres, as well as of the excellent results made possible by the peculiar properties of microspheres. Considerations about their commercial relevance are also added. PMID- 30424313 TI - Ag-Sensitized Yb3+ Emission in Glass-Ceramics. AB - Rare earth doped materials play a very important role in the development of many photonic devices, such as optical amplifiers and lasers, frequency converters, solar concentrators, up to quantum information storage devices. Among the rare earth ions, ytterbium is certainly one of the most frequently investigated and employed. The absorption and emission properties of Yb3+ ions are related to transitions between the two energy levels 2F7/2 (ground state) and 2F5/2 (excited state), involving photon energies around 1.26 eV (980 nm). Therefore, Yb3+ cannot directly absorb UV or visible light, and it is often used in combination with other rare earth ions like Pr3+, Tm3+, and Tb3+, which act as energy transfer centres. Nevertheless, even in those co-doped materials, the absorption bandwidth can be limited, and the cross section is small. In this paper, we report a broadband and efficient energy transfer process between Ag dimers/multimers and Yb3+ ions, which results in a strong PL emission around 980 nm under UV light excitation. Silica-zirconia (70% SiO2-30% ZrO2) glass-ceramic films doped by 4 mol.% Yb3+ ions and an additional 5 mol.% of Na2O were prepared by sol-gel synthesis followed by a thermal annealing at 1000 degrees C. Ag introduction was then obtained by ion-exchange in a molten salt bath and the samples were subsequently annealed in air at 430 degrees C to induce the migration and aggregation of the metal. The structural, compositional, and optical properties were investigated, providing evidence for efficient broadband sensitization of the rare earth ions by energy transfer from Ag dimers/multimers, which could have important applications in different fields, such as PV solar cells and light emitting near-infrared (NIR) devices. PMID- 30424314 TI - Vibration Identification of Folded-MEMS Comb Drive Resonators. AB - Natural frequency and frequency response are two important indicators for the performances of resonant microelectromechanical systems (MEMS) devices. This paper analytically and numerically investigates the vibration identification of the primary resonance of one type of folded-MEMS comb drive resonator. The governing equation of motion, considering structure and electrostatic nonlinearities, is firstly introduced. To overcome the shortcoming of frequency assumption in the literature, an improved theoretical solution procedure combined with the method of multiple scales and the homotopy concept is applied for primary resonance solutions in which frequency shift due to DC voltage is thoroughly considered. Through theoretical predictions and numerical results via the finite difference method and fourth-order Runge-Kutta simulation, we find that the primary frequency response actually includes low and high-energy branches when AC excitation is small enough. As AC excitation increases to a certain value, both branches intersect with each other. Then, based on the variation properties of frequency response branches, hardening and softening bending, and the ideal estimation of dynamic pull-in instability, a zoning diagram depicting extreme vibration amplitude versus DC voltage is then obtained that separates the dynamic response into five regions. Excellent agreements between the theoretical predictions and simulation results illustrate the effectiveness of the analyses. PMID- 30424315 TI - Stretchability-The Metric for Stretchable Electrical Interconnects. AB - Stretchable circuit technology, as the name implies, allows an electronic circuit to adapt to its surroundings by elongating when an external force is applied. Based on this, early authors proposed a straightforward metric: stretchability the percentage length increase the circuit can survive while remaining functional. However, when comparing technologies, this metric is often unreliable as it is heavily design dependent. This paper aims to demonstrate this shortcoming and proposes a series of alternate methods to evaluate the performance of a stretchable interconnect. These methods consider circuit volume, material usage, and the reliability of the technology. This analysis is then expanded to the direct current (DC) resistance measurement performed on these stretchable interconnects. A simple dead reckoning approach is demonstrated to estimate the magnitude of these measurement errors on the final measurement. PMID- 30424316 TI - Editorial for the Special Issue on Micro/Nano-Chip Electrokinetics, Volume II. PMID- 30424318 TI - Anti-Reflectance Optimization of Secondary Nanostructured Black Silicon Grown on Micro-Structured Arrays. AB - Owing to its extremely low light absorption, black silicon has been widely investigated and reported in recent years, and simultaneously applied to various disciplines. Black silicon is, in general, fabricated on flat surfaces based on the silicon substrate. However, with three normal fabrication methods-plasma dry etching, metal-assisted wet etching, and femtosecond laser pulse etching-black silicon cannot perform easily due to its lowest absorption and thus some studies remained in the laboratory stage. This paper puts forward a novel secondary nanostructured black silicon, which uses the dry-wet hybrid fabrication method to achieve secondary nanostructures. In consideration of the influence of the structure's size, this paper fabricated different sizes of secondary nanostructured black silicon and compared their absorptions with each other. A total of 0.5% reflectance and 98% absorption efficiency of the pit sample were achieved with a diameter of 117.1 MUm and a depth of 72.6 MUm. In addition, the variation tendency of the absorption efficiency is not solely monotone increasing or monotone decreasing, but firstly increasing and then decreasing. By using a statistical image processing method, nanostructures with diameters between 20 and 30 nm are the majority and nanostructures with a diameter between 10 and 40 nm account for 81% of the diameters. PMID- 30424317 TI - Assessment of the Deformability and Velocity of Healthy and Artificially Impaired Red Blood Cells in Narrow Polydimethylsiloxane (PDMS) Microchannels. AB - Malaria is one of the leading causes of death in underdeveloped regions. Thus, the development of rapid, efficient, and competitive diagnostic techniques is essential. This work reports a study of the deformability and velocity assessment of healthy and artificially impaired red blood cells (RBCs), with the purpose of potentially mimicking malaria effects, in narrow polydimethylsiloxane microchannels. To obtain impaired RBCs, their properties were modified by adding, to the RBCs, different concentrations of glucose, glutaraldehyde, or diamide, in order to increase the cells' rigidity. The effects of the RBCs' artificial stiffening were evaluated by combining image analysis techniques with microchannels with a contraction width of 8 um, making it possible to measure the cells' deformability and velocity of both healthy and modified RBCs. The results showed that healthy RBCs naturally deform when they cross the contractions and rapidly recover their original shape. In contrast, for the modified samples with high concentration of chemicals, the same did not occur. Additionally, for all the tested modification methods, the results have shown a decrease in the RBCs' deformability and velocity as the cells' rigidity increases, when compared to the behavior of healthy RBCs samples. These results show the ability of the image analysis tools combined with microchannel contractions to obtain crucial information on the pathological blood phenomena in microcirculation. Particularly, it was possible to measure the deformability of the RBCs and their velocity, resulting in a velocity/deformability relation in the microchannel. This correlation shows great potential to relate the RBCs' behavior with the various stages of malaria, helping to establish the development of new diagnostic systems towards point-of-care devices. PMID- 30424319 TI - Molecular Dynamics Investigation of Residual Stress and Surface Roughness of Cerium under Diamond Cutting. AB - Machined surface quality in terms of residual stress and surface roughness has an important influence on the performance of devices and components. In the present work, we elucidate the formation mechanisms of residual stress and surface roughness of single crystalline cerium under ultraprecision diamond cutting by means of molecular dynamics simulations. Influences of machining parameters, such as the rake angle of a cutting tool, depth of cut, and crystal orientation of the workpiece on the machined surface quality were also investigated. Simulation results revealed that dislocation activity and lattice distortion are the two parallel factors that govern the formation of both residual stress and surface roughness. It was found that both distributions of residual stress and surface roughness of machined surface are significantly affected by machining parameters. The optimum machining parameters for achieving high machined surface quality of cerium by diamond cutting are revealed. PMID- 30424320 TI - Micropipette-Based Microfluidic Device for Monodisperse Microbubbles Generation. AB - Microbubbles have various applications including their use as carrier agents for localized delivery of genes and drugs and in medical diagnostic imagery. Various techniques are used for the production of monodisperse microbubbles including the Gyratory, the coaxial electro-hydrodynamic atomization (CEHDA), the sonication methods, and the use of microfluidic devices. Some of these techniques require safety procedures during the application of intense electric fields (e.g., CEHDA) or soft lithography equipment for the production of microfluidic devices. This study presents a hybrid manufacturing process using micropipettes and 3D printing for the construction of a T-Junction microfluidic device resulting in simple and low cost generation of monodisperse microbubbles. In this work, microbubbles with an average size of 16.6 to 57.7 MUm and a polydispersity index (PDI) between 0.47% and 1.06% were generated. When the device is used at higher bubble production rate, the average diameter was 42.8 MUm with increased PDI of 3.13%. In addition, a second-order polynomial characteristic curve useful to estimate micropipette internal diameter necessary to generate a desired microbubble size is presented and a linear relationship between the ratio of gaseous and liquid phases flows and the ratio of microbubble and micropipette diameters (i.e., Qg/Ql and Db/Dp) was found. PMID- 30424321 TI - Disposable Optical Stretcher Fabricated by Microinjection Moulding. AB - Microinjection moulding combined with the use of removable inserts is one of the most promising manufacturing processes for microfluidic devices, such as lab-on chip, that have the potential to revolutionize the healthcare and diagnosis systems. In this work, we have designed, fabricated and tested a compact and disposable plastic optical stretcher. To produce the mould inserts, two micro manufacturing technologies have been used. Micro electro discharge machining (uEDM) was used to reproduce the inverse of the capillary tube connection characterized by elevated aspect ratio. The high accuracy of femtosecond laser micromachining (FLM) was exploited to manufacture the insert with perfectly aligned microfluidic channels and fibre slots, facilitating the final composition of the optical manipulation device. The optical stretcher operation was tested using microbeads and red blood cells solutions. The prototype presented in this work demonstrates the feasibility of this approach, which should guarantee real mass production of ready-to-use lab-on-chip devices. PMID- 30424322 TI - Glancing Angle Deposition Effect on Structure and Light-Induced Wettability of RF Sputtered TiO2 Thin Films. AB - Crystalline TiO2 films were prepared on unheated glass substrates by radio frequency (RF) reactive magnetron sputtering at normal angle of incidence (a = 0 degrees ) and at glancing angle (a = 87 degrees ). The effect of the glancing angle on the structure, microstructure, and wetting properties of the films was investigated. The inclination of the substrate led to phase transformation of the deposited films from rutile to either rutile/anatase or anatase, depending on the working pressure. Extreme shadowing at 87 degrees results in a remarkable increase of the films' porosity and surface roughness. The mechanism of the glancing-angle-induced crystalline phase formation is thoroughly discussed based on the thermodynamic, kinetic, and geometrical aspects of the nucleation and is related with the microstructural changes. Both crystalline phase and microstructure significantly affect the wetting properties of the TiO2 films. Glancing-angle-deposited anatase TiO2 exhibits a high degree of porosity and roughness, a high rate of UV-induced wettability conversion, and a long-term highly hydrophilic nature in dark. Therefore, anatase TiO2 is potentially a good candidate for applications as dye-sensitized solar cells (DSSC)/perovskite solar cells, microfluidic devices, and self-cleaning surfaces prepared on thermosensitive substrates. PMID- 30424323 TI - Novel High-Capacitance-Ratio MEMS Switch: Design, Analysis and Performance Verification. AB - This paper proposes a novel high-capacitance-ratio radio frequency micro electromechanical systems (RF MEMS) switch. The proposed RF MEMS mainly consists of serpentine flexure MEMS metallic beam, comprised of coplanar waveguide (CPW) transmission line, dielectric and metal-insulator-metal (MIM) floating metallic membrane. Comparing the proposed high-capacitance-ratio MEMS switch with the ones in available literature, an acceptable insertion loss insulation, acceptable response time and high capacitance ratio (383.8) are achieved. PMID- 30424324 TI - Asymmetrical Induced Charge Electroosmotic Flow on a Herringbone Floating Electrode and Its Application in a Micromixer. AB - Enhancing mixing is of significant importance in microfluidic devices characterized by laminar flows and low Reynolds numbers. An asymmetrical induced charge electroosmotic (ICEO) vortex pair generated on the herringbone floating electrode can disturb the interface of two-phase fluids and deliver the fluid transversely, which could be exploited to accomplish fluid mixing between two neighbouring fluids in a microscale system. Herein we present a micromixer based on an asymmetrical ICEO flow induced above the herringbone floating electrode array surface. We investigate the average transverse ICEO slip velocity on the Ridge/Vee/herringbone floating electrode and find that the microvortex generated on the herringbone electrode surface has good potential for mixing the miscible liquids in microfluidic systems. In addition, we explore the effect of applied frequencies and bulk conductivity on the slip velocity above the herringbone floating electrode surface. The high dependence of mixing performance on the floating electrode pair numbers is analysed simultaneously. Finally, we investigate systematically voltage intensity, applied frequencies, inlet fluid velocity and liquid conductivity on the mixing performance of the proposed device. The microfluidic micromixer put forward herein offers great opportunity for fluid mixing in the field of micro total analysis systems. PMID- 30424325 TI - The Conformal Design of an Island-Bridge Structure on a Non-Developable Surface for Stretchable Electronics. AB - Conformal design of the island-bridge structure is the key to construct high performance inorganic stretchable electronics that can be conformally transferred to non-developable surfaces. Former studies in conformal problems of epidermal electronics are mainly focused on soft surfaces that can adapt to the deformation of the electronics, which are not suitable for applications in hard, non developable surfaces because of their loose surface constraints. In this paper, the conformal design problem for the island-bridge structure on a hard, non developable surface was studied, including the critical size for island and stiffness and the demand for stretchability for the bridge. Firstly, the conformal model for an island on a part of torus surface was established to determine the relationship between the maximum size of the island and the curvatures of the surface. By combining the principle of energy minimization and the limit of material failure, a critical non-dimensional width for conformability was given for the island as a function of its thickness and interfacial adhesion energy, and the ratio of two principal curvatures of the surface. Then, the dependency of the tensile stiffness of the bridge on its geometric parameters was studied by finite element analysis (FEA) to guide the deterministic assembly of the islands on the surface. Finally, the location dependent demands for the stretchability of the bridges were given by geometric mapping. This work will provide a design rule for stretchable electronics that fully conforms to the non-developable surface. PMID- 30424326 TI - Micro Magnetic Field Sensors Manufactured Using a Standard 0.18-MUm CMOS Process. AB - Micro magnetic field (MMF) sensors developed employing complementary metal oxide semiconductor (CMOS) technology are investigated. The MMF sensors, which are a three-axis sensing type, include a magnetotransistor and four Hall elements. The magnetotransistor is utilized to detect the magnetic field (MF) in the x-axis and y-axis, and four Hall elements are used to sense MF in the z-axis. In addition to emitter, bases and collectors, additional collectors are added to the magnetotransistor. The additional collectors enhance bias current and carrier number, so that the sensor sensitivity is enlarged. The MMF sensor fabrication is easy because it does not require post-CMOS processing. Experiments depict that the MMF sensor sensitivity is 0.69 V/T in the x-axis MF and its sensitivity is 0.55 V/T in the y-axis MF. PMID- 30424328 TI - Development of a Thermoelectric and Electromagnetic Hybrid Energy Harvester from Water Flow in an Irrigation System. AB - A hybrid energy harvester is presented in this paper to harvest energy from water flow motion and temperature difference in an irrigating pipe at the same time. The harvester is based on the integration of thermoelectric and electromagnetic mechanisms. To harvest the water flow motion, a turbine fan with magnets that are attached on the blades is placed inside of the water pipe. Multiple coils turn the water flow energy into electricity with the rotation of the turbine. The thermoelectric generators (TEGs) are attached around the pipe, so as to harvest energy due to temperature difference. For a maximum temperature difference of 55 degrees C (hot side 80 degrees C and room temperature 25 degrees C), twelve serial-connected TEGs can generate voltage up to 0.346 V. Under a load resistance of 20 Omega, the power output of 1.264 mW can be achieved. For a maximum water flow rate of 49.9 L/min, the electromagnetic generator (EMG) can produce an open circuit voltage of 0.911 V. The EMG can be potentially used as a water flow meter due to the linear relationship between water flow rate and output voltage. Under the joint action of TEG and EMG, the maximum terminal voltage for TEG is 66 mV and for EMG is 241 mV at load resistances of 10 and 100 Omega, respectively, resulting in a corresponding power output of 0.435 and 0.584 mW. PMID- 30424327 TI - 3D-Printed Biosensor Arrays for Medical Diagnostics. AB - While the technology is relatively new, low-cost 3D printing has impacted many aspects of human life. 3D printers are being used as manufacturing tools for a wide variety of devices in a spectrum of applications ranging from diagnosis to implants to external prostheses. The ease of use, availability of 3D-design software and low cost has made 3D printing an accessible manufacturing and fabrication tool in many bioanalytical research laboratories. 3D printers can print materials with varying density, optical character, strength and chemical properties that provide the user with a vast array of strategic options. In this review, we focus on applications in biomedical diagnostics and how this revolutionary technique is facilitating the development of low-cost, sensitive, and often geometrically complex tools. 3D printing in the fabrication of microfluidics, supporting equipment, and optical and electronic components of diagnostic devices is presented. Emerging diagnostics systems using 3D bioprinting as a tool to incorporate living cells or biomaterials into 3D printing is also reviewed. PMID- 30424329 TI - An Improved Large Signal Model for 0.1 MUm AlGaN/GaN High Electron Mobility Transistors (HEMTs) Process and Its Applications in Practical Monolithic Microwave Integrated Circuit (MMIC) Design in W band. AB - An improved empirical large signal model for 0.1 um AlGaN/GaN high electron mobility transistor (HEMT) process is proposed in this paper. The short channel effect including the drain induced barrier lowering (DIBL) effect and channel length modulation has been considered for the accurate description of DC characteristics. In-house AlGaN/GaN HEMTs with a gate-length of 0.1 MUm and different dimensions have been employed to validate the accuracy of the large signal model. Good agreement has been achieved between the simulated and measured S parameters, I-V characteristics and large signal performance at 28 GHz. Furthermore, a monolithic microwave integrated circuit (MMIC) power amplifier from 92 GHz to 96 GHz has been designed for validation of the proposed model. Results show that the improved large signal model can be used up to W band. PMID- 30424331 TI - Detection of Particulate Matter of Size 2.5 MUm with a Surface-Acoustic-Wave Sensor Combined with a Cyclone Separator. AB - A device to monitor particulate matter of size 2.5 MUm (PM2.5) that has been designed and developed includes a surface-acoustic-wave sensor operating in a shear horizontal mode (SH-SAW) combined with a cyclone separator. In our tests, aerosols generated as incense smoke were first separated and sampled inside a designed cyclone separator; the sampled PM2.5 was then introduced into the sensing area of an SH-SAW sensor for detection. The use of microcentrifuge tubes as a cyclone separator effectively decreases the size and power consumption of the device; the SAW sensor in a well design and operating at 122 MHz was fabricated with MEMS techniques. After an explanation of the design of the cyclone separator, a simulation of the efficiency and the SAW sensor detection are discussed. A microcentrifuge tube (volume 0.2 mL, inlet and outlet diameters 0.5 mm) as a separator has separation cutoff diameters 50% (d50) at 2.5 MUm; the required rate of volumetric flow at the inlet is 0.125 LPM, according to simulation with computational fluid dynamics (CFD) software; the surface-acoustic wave (SAW) sensor exhibits sensitivity approximately 9 Hz/ng; an experiment for PM2.5 detection conducted with the combined device shows a strong positive linear correlation with a commercial aerosol monitor. The limit of detection (LOD) is 11 MUg/m3 with sample time 160 s and total detection duration about 5 min. PMID- 30424332 TI - On-Chip Asymmetric Microsupercapacitors Combining Reduced Graphene Oxide and Manganese Oxide for High Energy-Power Tradeoff. AB - Given the rapid miniaturization of technology, it is of interest to produce viable on-chip micro-electrochemical energy storage systems. In this study, interdigitated asymmetric microsupercapacitors were fabricated using photolithography, lift-off and electrodeposition methods. Manganese oxide (MnOx) and reduced graphene oxide (rGO) comprised the pseudocapacitive and the double layer component, respectively. Symmetric MnOx//MnOx, rGO//rGO as well as asymmetric rGO//MnOx microsupercapacitors with three different MnOx thicknesses were constructed and characterized in aqueous media. The asymmetric microsupercapacitor with the intermediate MnOx film thickness displayed the optimal energy-power trade-off superior to that of both the symmetric and well as the other asymmetric configurations. The optimal microsupercapacitor exhibited a high stack energy density of 1.02 mWh.cm-3 and a maximal power density of 3.44 W.cm-3. The high energy-power trade-off of the device is attributed to the synergistic effects of utilizing double layer and pseudocapacitive charge storage mechanisms along with in-plane interdigital microelectrode design within one optimized micro-device. PMID- 30424330 TI - The Use of Microfluidic Technology for Cancer Applications and Liquid Biopsy. AB - There is growing awareness for the need of early diagnostic tools to aid in point of-care testing in cancer. Tumor biopsy remains the conventional means in which to sample a tumor and often presents with challenges and associated risks. Therefore, alternative sources of tumor biomarkers is needed. Liquid biopsy has gained attention due to its non-invasive sampling of tumor tissue and ability to serially assess disease via a simple blood draw over the course of treatment. Among the leading technologies developing liquid biopsy solutions, microfluidics has recently come to the fore. Microfluidic platforms offer cellular separation and analysis platforms that allow for high throughout, high sensitivity and specificity, low sample volumes and reagent costs and precise liquid controlling capabilities. These characteristics make microfluidic technology a promising tool in separating and analyzing circulating tumor biomarkers for diagnosis, prognosis and monitoring. In this review, the characteristics of three kinds of circulating tumor markers will be described in the context of cancer, circulating tumor cells (CTCs), exosomes, and circulating tumor DNA (ctDNA). The review will focus on how the introduction of microfluidic technologies has improved the separation and analysis of these circulating tumor markers. PMID- 30424334 TI - Array of Resonant Electromechanical Nanosystems: A Technological Breakthrough for Uncooled Infrared Imaging. AB - Microbolometers arethe most common uncooled infrared techniques that allow 50 mK temperature resolution to be achieved on-scene. However, this approach struggles with both self-heating, which is inherent to the resistive readout principle, and 1/f noise. We present an alternative approach that consists of using micro/nanoresonators vibrating according to a torsional mode, and whose resonant frequency changes with the incident IR-radiation. Dense arrays of such electromechanical structures were fabricated with a 12 um pitch at low temperature, allowing their integration on complementary metal-oxide semiconductor (CMOS) circuits according to a post-processing method. H-shape pixels with 9 um-long nanorods and a cross-section of 250 nm * 30 nm were fabricated to provide large thermal responses, whose experimental measurements reached up to 1024 Hz/nW. These electromechanical resonators featured a noise equivalent power of 140 pW for a response time of less than 1 ms. To our knowledge, these performances are unrivaled with such small dimensions. We also showed that a temperature sensitivity of 20 mK within a 100 ms integration time is conceivable at a 12 um pitch by co-integrating the resonators with their readout electronics, and suggesting a new readout scheme. This sensitivity could be reached short-term by depositing on top of the nanorods a vanadium oxide layer that had a phase-transition that could possibly enhance the thermal response by one order of magnitude. PMID- 30424333 TI - Core-Shell Structures of Upconversion Nanocrystals Coated with Silica for Near Infrared Light Enabled Optical Imaging of Cancer Cells. AB - Optical imaging of cancer cells using near infrared (NIR) light is currently an active area of research, as this spectral region directly corresponds to the therapeutic window of biological tissues. Upconversion nanocrystals are photostable alternatives to conventional fluorophores. In our work, we have prepared upconversion nanocrystals of NaYF4:Yb/Er and encapsulated them in silica to form core-shell structures. The as-prepared core-shell nanostructures have been characterized for their structure, morphology, and optical properties using X-ray diffraction, transmission electron microscopy coupled with elemental mapping, and upconversion luminescence spectroscopy, respectively. The cytotoxicity examined using cell viability assay indicated a low level of toxicity of these core-shell nanostructures. Finally, these core-shell nanostructures have been utilized as photostable probes for NIR light enabled optical imaging of human breast cancer cells. This work paves the way for the development of advanced photostable, biocompatible, low-toxic core-shell nanostructures for potential optical imaging of biological cells and tissues. PMID- 30424335 TI - Experimental Research on Machining Localization and Surface Quality in Micro Electrochemical Milling of Nickel-Based Superalloy. AB - Micro electrochemical machining is becoming increasingly important in the microfabrication of metal parts. In this paper, the machining characteristics of micro electrochemical milling with nanosecond pulse were studied. Firstly, a mathematical model for the localization control of micro electrochemical milling with nanosecond pulse was established. Secondly, groups of experiments were conducted on nickel-based superalloy and the effects of parameters such as applied voltage, pulse on time, pulse period, electrolyte concentration and electrode diameter on machining localization and surface roughness were analyzed. Finally, by using the optimized machining parameters, some 2D complex shapes and 3D square cavity structures with good shape precision and good surface quality were successfully obtained. It was proved that the micro electrochemical milling with nanosecond pulse technique is an effective machining method to fabricate metal microstructures. PMID- 30424336 TI - From Lab on a Chip to Point of Care Devices: The Role of Open Source Microcontrollers. AB - Microcontrollers are programmable, integrated circuit chips. In the last two decades, their applications to industrial instruments, vehicles, and household appliances have reached the extent that microcontrollers are now the number-one selling electronic chip of all kinds. Simultaneously, the field of lab-on-a-chip research and technology has seen major technological leaps towards sample handling, sample preparation, and sensing for use in molecular diagnostic devices. Yet, the transformation from a laboratory based lab-on-a-chip technology to actual point-of-care device products has largely been limited to a fraction of the foreseen potential. We believe that increased knowledge of the vast possibilities that becomes available with open source microcontrollers, especially when embedded in easy-to-use development environments, such as the Arduino or Raspberry Pi, could potentially solve and even bridge the gap between lab-on-a-chip technology and real-life point of care applications. The profuse availability and extraordinary capabilities of microcontrollers, namely within computation, communication, and networking, combined with easy-to-use development environments, as well as a very active and fast moving community of makers, who are eager to share their knowledge, could potentially be the difference between a dreadful "chip-in-a-lab"-situation, and the next successful start-up. Here follows a brief insight into how open source microcontrollers could potentially have a transformative effect on the field of lab-on-a-chip research and technology. Details in some specific areas of application are briefly treated before addressing challenges and future perspectives. PMID- 30424338 TI - Alkali Vapor MEMS Cells Technology toward High-Vacuum Self-Pumping MEMS Cell for Atomic Spectroscopy. AB - The high-vacuum self-pumping MEMS cell for atomic spectroscopy presented here is the result of the technological achievements of the author and the research group in which he works. A high-temperature anodic bonding process in vacuum or buffer gas atmosphere and the influence of the process on the inner gas composition inside a MEMS structure were studied. A laser-induced alkali vapor introduction method from solid-state pill-like dispenser is presented as well. The technologies mentioned above are groundbreaking achievements that have allowed the building of the first European miniature atomic clock, and they are the basis for other solutions, including high-vacuum optical MEMS. Following description of the key technologies, high-vacuum self-pumping MEMS cell construction and preliminary measurement results are reported. This unique solution makes it possible to achieve a 10-6 Torr vacuum level inside the cell in the presence of saturated rubidium vapor, paving the way to building a new class of optical reference cells for atomic spectroscopy. Because the level of vacuum is high enough, experiments with cold atoms are potentially feasible. PMID- 30424337 TI - Acoustofluidic Measurements on Polymer-Coated Microbubbles: Primary and Secondary Bjerknes Forces. AB - The acoustically-driven dynamics of isolated particle-like objects in microfluidic environments is a well-characterised phenomenon, which has been the subject of many studies. Conversely, very few acoustofluidic researchers looked at coated microbubbles, despite their widespread use in diagnostic imaging and the need for a precise characterisation of their acoustically-driven behaviour, underpinning therapeutic applications. The main reason is that microbubbles behave differently, due to their larger compressibility, exhibiting much stronger interactions with the unperturbed acoustic field (primary Bjerknes forces) or with other bubbles (secondary Bjerknes forces). In this paper, we study the translational dynamics of commercially-available polymer-coated microbubbles in a standing-wave acoustofluidic device. At increasing acoustic driving pressures, we measure acoustic forces on isolated bubbles, quantify bubble-bubble interaction forces during doublet formation and study the occurrence of sub-wavelength structures during aggregation. We present a dynamic characterisation of microbubble compressibility with acoustic pressure, highlighting a threshold pressure below which bubbles can be treated as uncoated. Thanks to benchmarking measurements under a scanning electron microscope, we interpret this threshold as the onset of buckling, providing a quantitative measurement of this parameter at the single-bubble level. For acoustofluidic applications, our results highlight the limitations of treating microbubbles as a special case of solid particles. Our findings will impact applications where knowing the buckling pressure of coated microbubbles has a key role, like diagnostics and drug delivery. PMID- 30424339 TI - Fluorosilicone as an Omnimold for Microreplication. AB - Soft lithography and replica molding have been an integral part of polymer basic microfabrication for over 20 years. The use of silicone rubber materials as either molds or directly molded parts are well described in the literature and have provided researchers with an easily accessible technique to reproduce complex micro and nanostructures with minimal costs and technical challenges. Yet, for many applications, the use of standard silicones may not necessarily be the best choice, either as a mold material or as a replicated surface. For those instances where a mold is required that is high temperature tolerant, flexible, durable and capable of being used as a mold for multiple materials including silicone rubber, the most commonly used silicone rubber, Sylgard-184, has substantial deficiencies. In this work, we introduce a new material, Fluorosilicone that has not been described in the microfabrication field in detail and determine it is capable of reproducing micro structures via soft lithography techniques and being used as a mold for thermoplastic and thermosetting polymers, including silicone rubbers. Material compatibility, appropriate processing conditions for quality replicas and demonstration of extremely fast production of silicone microstructures are reported. PMID- 30424340 TI - Effects of Embedded TiO2-x Nanoparticles on Triboelectric Nanogenerator Performance. AB - Triboelectric nanogenerators (TENGs) are used as self-power sources for various types of devices by converting external waves, wind, or other mechanical energies into electric power. However, obtaining a high-output performance is still of major concern for many applications. In this study, to enhance the output performance of polydimethylsiloxane (PDMS)-based TENGs, highly dielectric TiO2-x nanoparticles (NPs) were embedded as a function of weight ratio. TiO2-x NPs embedded in PDMS at 5% showed the highest output voltage and current. The improved output performance at 5% is strongly related to the change of oxygen vacancies on the PDMS surface, as well as the increased dielectric constant. Specifically, oxygen vacancies in the oxide nanoparticles are electrically positive charges, which is an important factor that can contribute to the exchange and trapping of electrons when driving a TENG. However, in TiO2-x NPs containing over 5%, the output performance was significantly degraded because of the increased leakage characteristics of the PDMS layer due to TiO2-x NPs aggregation, which formed an electron path. PMID- 30424341 TI - A Mini-System Integrated with Metal-Oxide-Semiconductor Sensor and Micro-Packed Gas Chromatographic Column. AB - In this work, a mini monitoring system integrated with a microfabricated metal oxide array sensor and a micro packed gas chromatographic (GC) column was developed for monitoring environmental gases. The microfabricated packed GC column with a 1.6 m length was used to separate the environmental gas, and the metal oxide semiconductor (MOS) array sensor, fabricated with nano-sized SnO-SnO2 sensitive materials, was able to effectively detect each component separated by GC column. The results demonstrate that the monitoring system can detect environmental gas with high precision. PMID- 30424342 TI - Rapid Laser Manufacturing of Microfluidic Devices from Glass Substrates. AB - Conventional manufacturing of microfluidic devices from glass substrates is a complex, multi-step process that involves different fabrication techniques and tools. Hence, it is time-consuming and expensive, in particular for the prototyping of microfluidic devices in low quantities. This article describes a laser-based process that enables the rapid manufacturing of enclosed micro structures by laser micromachining and microwelding of two 1.1-mm-thick borosilicate glass plates. The fabrication process was carried out only with a picosecond laser (Trumpf TruMicro 5*50) that was used for: (a) the generation of microfluidic patterns on glass, (b) the drilling of inlet/outlet ports into the material, and (c) the bonding of two glass plates together in order to enclose the laser-generated microstructures. Using this manufacturing approach, a fully functional microfluidic device can be fabricated in less than two hours. Initial fluid flow experiments proved that the laser-generated microstructures are completely sealed; thus, they show a potential use in many industrial and scientific areas. This includes geological and petroleum engineering research, where such microfluidic devices can be used to investigate single-phase and multi phase flow of various fluids (such as brine, oil, and CO2) in porous media. PMID- 30424343 TI - Design and Fabrication of a Visible-Light-Compatible, Polymer-Based Photonic Crystal Resonator and Waveguide for Sensing Applications. AB - In this paper, we have proposed a polymer-based photonic crystal (PhC) resonator, with multiple sizes of cavities, and a waveguide to be used as highly sensitive optical sensor components. Properties of the proposed PhC were simulated by the finite-difference time-domain method, and the polymer-based PhC resonator and waveguide were fabricated on a photoresist (polymer) by electron beam lithography, which was prepared on an Au-layer-deposited Si substrate. We detected the resonant light that penetrated through the waveguide and was trapped in the PhC resonator. Optical characteristics of the fabricated PhC were evaluated by detecting the polymer layer deposition process by using the layer-by layer (LbL) method to deposit polymer layers. As a result, by using an optimized design of a polymer-based PhC resonator with a long cavity (equivalent to a defect of three holes), the PhC structure changes caused by LbL deposition lead to changes in resonant light wavelength (peak shift: 5.26 nm/layer). Therefore, we suggest that a PhC resonator and a waveguide is applicable as an optical sensor. PMID- 30424344 TI - Design of Ensemble Stacked Auto-Encoder for Classification of Horse Gaits with MEMS Inertial Sensor Technology. AB - This paper discusses the classification of horse gaits for self-coaching using an ensemble stacked auto-encoder (ESAE) based on wavelet packets from the motion data of the horse rider. For this purpose, we built an ESAE and used probability values at the end of the softmax classifier. First, we initialized variables such as hidden nodes, weight, and max epoch using the options of the auto-encoder (AE). Second, the ESAE model is trained by feedforward, back propagation, and gradient calculation. Next, the parameters are updated by a gradient descent mechanism as new parameters. Finally, once the error value is satisfied, the algorithm terminates. The experiments were performed to classify horse gaits for self-coaching. We constructed the motion data of a horse rider. For the experiment, an expert horse rider of the national team wore a suit containing 16 inertial sensors based on a wireless network. To improve and quantify the performance of the classification, we used three methods (wavelet packet, statistical value, and ensemble model), as well as cross entropy with mean squared error. The experimental results revealed that the proposed method showed good performance when compared with conventional algorithms such as the support vector machine (SVM). PMID- 30424346 TI - Wide Acoustic Bandgap Solid Disk-Shaped Phononic Crystal Anchoring Boundaries for Enhancing Quality Factor in AlN-on-Si MEMS Resonators. AB - This paper demonstrates the four fold enhancement in quality factor (Q) of a very high frequency (VHF) band piezoelectric Aluminum Nitride (AlN) on Silicon (Si) Lamb mode resonator by applying a unique wide acoustic bandgap (ABG) phononic crystal (PnC) at the anchoring boundaries of the resonator. The PnC unit cell topology, based on a solid disk, is characterized by a wide ABG of 120 MHz around a center frequency of 144.7 MHz from the experiments. The resulting wide ABG described in this work allows for greater enhancement in Q compared to previously reported PnC cell topologies characterized by narrower ABGs. The effect of geometrical variations to the proposed PnC cells on their corresponding ABGs are described through simulations and validated by transmission measurements of fabricated delay lines that incorporate these solid disk PnCs. Experiments demonstrate that widening the ABG associated with the PnC described herein provides for higher Q. PMID- 30424345 TI - Demonstration of a Robust All-Silicon-Carbide Intracortical Neural Interface. AB - Intracortical neural interfaces (INI) have made impressive progress in recent years but still display questionable long-term reliability. Here, we report on the development and characterization of highly resilient monolithic silicon carbide (SiC) neural devices. SiC is a physically robust, biocompatible, and chemically inert semiconductor. The device support was micromachined from p-type SiC with conductors created from n-type SiC, simultaneously providing electrical isolation through the resulting p-n junction. Electrodes possessed geometric surface area (GSA) varying from 496 to 500 K MUm2. Electrical characterization showed high-performance p-n diode behavior, with typical turn-on voltages of ~2.3 V and reverse bias leakage below 1 nArms. Current leakage between adjacent electrodes was ~7.5 nArms over a voltage range of -50 V to 50 V. The devices interacted electrochemically with a purely capacitive relationship at frequencies less than 10 kHz. Electrode impedance ranged from 675 +/- 130 kOmega (GSA = 496 um2) to 46.5 +/- 4.80 kOmega (GSA = 500 K um2). Since the all-SiC devices rely on the integration of only robust and highly compatible SiC material, they offer a promising solution to probe delamination and biological rejection associated with the use of multiple materials used in many current INI devices. PMID- 30424347 TI - Spray Pyrolysis Technique; High-K Dielectric Films and Luminescent Materials: A Review. AB - The spray pyrolysis technique has been extensively used to synthesize materials for a wide variety of applications such as micro and sub-micrometer dimension MOSFET's for integrated circuits technology, light emitting devices for displays, and solid-state lighting, planar waveguides and other multilayer structure devices for photonics. This technique is an atmospheric pressure chemical synthesis of materials, in which a precursor solution of chemical compounds in the proper solvent is sprayed and converted into powders or films through a pyrolysis process. The most common ways to generate the aerosol for the spraying process are by pneumatic and ultrasonic systems. The synthesis parameters are usually optimized for the materials optical, structural, electric and mechanical characteristics required. There are several reviews of the research efforts in which spray pyrolysis and the processes involved have been described in detail. This review is intended to focus on research work developed with this technique in relation to high-K dielectric and luminescent materials in the form of coatings and powders as well as multiple layered structures. PMID- 30424348 TI - Roughness Evolution and Charging in Plasma-Based Surface Engineering of Polymeric Substrates: The Effects of Ion Reflection and Secondary Electron Emission. AB - The interaction of plasma with polymeric substrates generates both roughness and charging on the surface of the substrates. This work, toward the comprehension and, finally, the control of plasma-induced surface roughness, delves into the intertwined effects of surface charging, ion reflection, and secondary electron electron emission (SEEE) on roughness evolution during plasma etching of polymeric substrates. For this purpose, a modeling framework consisting of a surface charging module, a surface etching model, and a profile evolution module is utilized. The case study is etching of a poly(methyl methacrylate) (PMMA) substrate by argon plasma. Starting from an initial surface profile with microscale roughness, the results show that the surface charging contributes to a faster elimination of the roughness compared to the case without charging, especially when ion reflection is taken into account. Ion reflection sustains roughness; without ion reflection, roughness is eliminated. Either with or without ion reflection, the effect of SEEE on the evolution of the rms roughness over etching time is marginal. The mutual interaction of the roughness and the charging potential is revealed through the correlation of the charging potential with a parameter combining rms roughness and skewness of the surface profile. A practical implication of the current study is that the elimination or the reduction of surface charging will result in greater surface roughness of polymeric, and generally dielectric, substrates. PMID- 30424349 TI - Liquid Crystal Elastomer-Based Microelectrode Array for In Vitro Neuronal Recordings. AB - Polymer-based biomedical electronics provide a tunable platform to interact with nervous tissue both in vitro and in vivo. Ultimately, the ability to control functional properties of neural interfaces may provide important advantages to study the nervous system or to restore function in patients with neurodegenerative disorders. Liquid crystal elastomers (LCEs) are a class of smart materials that reversibly change shape when exposed to a variety of stimuli. Our interest in LCEs is based on leveraging this shape change to deploy electrode sites beyond the tissue regions exhibiting inflammation associated with chronic implantation. As a first step, we demonstrate that LCEs are cellular compatible materials that can be used as substrates for fabricating microelectrode arrays (MEAs) capable of recording single unit activity in vitro. Extracts from LCEs are non-cytotoxic (>70% normalized percent viability), as determined in accordance to ISO protocol 10993-5 using fibroblasts and primary murine cortical neurons. LCEs are also not functionally neurotoxic as determined by exposing cortical neurons cultured on conventional microelectrode arrays to LCE extract for 48 h. Microelectrode arrays fabricated on LCEs are stable, as determined by electrochemical impedance spectroscopy. Examination of the impedance and phase at 1 kHz, a frequency associated with single unit recording, showed results well within range of electrophysiological recordings over 30 days of monitoring in phosphate-buffered saline (PBS). Moreover, the LCE arrays are shown to support viable cortical neuronal cultures over 27 days in vitro and to enable recording of prominent extracellular biopotentials comparable to those achieved with conventional commercially-available microelectrode arrays. PMID- 30424350 TI - Electromagnetically Induced Transparency (EIT) Like Transmission Based on 3 * 3 Cascaded Multimode Interference Resonators. AB - We propose a method for generating the electromagnetically induced transparency (EIT) like-transmission by using microring resonator based on cascaded 3 * 3 multimode interference (MMI) structures. Based on the Fano resonance unit created from a 3 * 3 MMI coupler with a feedback waveguide, two schemes of two coupled Fano resonator unit (FRU) are investigated to generate the EIT like transmission. The theoretical and numerical analysis based on the coupled mode theory and transfer matrix is used for the designs. Our proposed structure has advantages of compactness and ease of fabrication. We use silicon waveguide for the design of the whole device so it is compatible with the existing Complementary Metal-Oxide Semiconductor (CMOS) circuitry foundry. The fabrication tolerance and design parameters are also investigated in this study. PMID- 30424351 TI - A Simple Imaging Device for Fluorescence-Relevant Applications. AB - This article unveiled the development of an inexpensive, lightweight, easy-to use, and portable fluorescence imaging device for paper-based analytical applications. We used commercial fluorescent dyes, as proof of concept, to verify the feasibility of our fluorescence imaging device for bioanalysis. This approach may provide an alternative method for nucleotide detection and semen analysis, using a miniaturized fluorescence reader that is more compact and portable than conventional analytical equipment. PMID- 30424352 TI - Outstanding Photoluminescence in Pr3+-Doped Perovskite Ceramics. AB - Ba (Zr0.2Ti0.8) O3-50% (Ba0.7Ca0.3) TiO3 (BZT-0.5BCT) ceramics with different doping contents of Pr3+ were prepared by the conventional solid-state reaction. The phase structure and crystallinity of the fabricated ceramics were investigated by X-ray diffraction, Raman spectroscopy, and scanning electron microscopy. Photoluminescence (PL) emission spectra were measured to analyze the PL characteristics. The strong intensities of a green band at 489 nm and a red band at 610 nm were observed. The maximum emission intensity of the PL spectrum was achieved in the BZT-0.5BCT ceramic with 0.2% mol of Pr3+ ions. Furthermore, the PL spectra of BZT-0.5BCT ceramics were found to be sensitive to polarization of the ferroelectric ceramics. Compared with the unpoled ceramics, the green emission increased about 42% and a new emission peak at 430 nm appeared for the poled ceramics. With excellent intrinsic ferroelectricity and an enhanced PL property, such material has potential to realize multifunctionality in a wide application range. PMID- 30424353 TI - Rapid Fabrication of Epidermal Paper-Based Electronic Devices Using Razor Printing. AB - This work describes the use of a benchtop razor printer to fabricate epidermal paper-based electronic devices (EPEDs). This fabrication technique is simple, low cost, and compatible with scalable manufacturing processes. EPEDs are fabricated using paper substrates rendered omniphobic by their cost-effective silanization with fluoroalkyl trichlorosilanes, making them inexpensive, water-resistant, and mechanically compliant with human skin. The highly conductive inks or thin films attached to one of the sides of the omniphobic paper makes EPEDs compatible with wearable applications involving wireless power transfer. The omniphobic cellulose fibers of the EPED provide a moisture-independent mechanical reinforcement to the conductive layer. EPEDs accurately monitor physiological signals such as ECG (electrocardiogram), EMG (electromyogram), and EOG (electro-oculogram) even in high moisture environments. Additionally, EPEDs can be used for the fast mapping of temperature over the skin and to apply localized thermotherapy. Our results demonstrate the merits of EPEDs as a low-cost platform for personalized medicine applications. PMID- 30424354 TI - One-Dimensional Control System for a Linear Motor of a Two-Dimensional Nanopositioning Stage Using Commercial Control Hardware. AB - A two-dimensional (2D) nanopositioning platform stage (NanoPla) is in development at the University of Zaragoza. To provide a long travel range, the actuators of the NanoPla are four Halbach linear motors. These motors present many advantages in precision engineering, and they are custom made for this application. In this work, a one-dimensional (1D) control strategy for positioning a Halbach linear motor has been developed, implemented, and experimentally validated. The chosen control hardware is a commercial Digital Motor Control (DMC) Kit from Texas Instruments that has been designed to control the torque or the rotational speed of rotative motors. Using a commercial control hardware facilitates the applicability of the developed control system. Nevertheless, it constrains the design, which needs to be adapted to the hardware and optimized. Firstly, a dynamic characterization of the linear motor has been performed. By leveraging the dynamic properties of the motor, a sensorless controller is proposed. Then, a closed-loop control strategy is developed. Finally, this control strategy is implemented in the control hardware. It was verified that the control system achieves the working requirements of the NanoPla. It is able to work in a range of 50 mm and perform a minimum incremental motion of 1 MUm. PMID- 30424355 TI - Techniques and Considerations in the Microfabrication of Parylene C Microelectromechanical Systems. AB - Parylene C is a promising material for constructing flexible, biocompatible and corrosion-resistant microelectromechanical systems (MEMS) devices. Historically, Parylene C has been employed as an encapsulation material for medical implants, such as stents and pacemakers, due to its strong barrier properties and biocompatibility. In the past few decades, the adaptation of planar microfabrication processes to thin film Parylene C has encouraged its use as an insulator, structural and substrate material for MEMS and other microelectronic devices. However, Parylene C presents unique challenges during microfabrication and during use with liquids, especially for flexible, thin film electronic devices. In particular, the flexibility and low thermal budget of Parylene C require modification of the fabrication techniques inherited from silicon MEMS, and poor adhesion at Parylene-Parylene and Parylene-metal interfaces causes device failure under prolonged use in wet environments. Here, we discuss in detail the promises and challenges inherent to Parylene C and present our experience in developing thin-film Parylene MEMS devices. PMID- 30424356 TI - Transport of a Micro Liquid Plug in a Gas-Phase Flow in a Microchannel. AB - Micro liquid droplets and plugs in the gas-phase in microchannels have been utilized in microfluidics for chemical analysis and synthesis. While higher velocities of droplets and plugs are expected to enable chemical processing at higher efficiency and higher throughput, we recently reported that there is a limit of the liquid plug velocity owing to splitting caused by unstable wetting to the channel wall. This study expands our experimental work to examine the dynamics of a micro liquid plug in the gas phase in a microchannel. The motion of a single liquid plug, 0.4-58 nL in volume, with precise size control in 39- to 116-m-diameter hydrophobic microchannels was investigated. The maximum velocity of the liquid plug was 1.5 m/s, and increased to 5 m/s with splitting. The plug velocity was 20% of that calculated using the Hagen-Poiseuille equation. It was found that the liquid plug starts splitting when the inertial force exerted by the fluid overcomes the surface tension, i.e., the Weber number (ratio of the inertial force to the surface tension) is higher than 1. The results can be applied in the design of microfluidic devices for various applications that utilize liquid droplets and plugs in the gas phase. PMID- 30424357 TI - Development, Modeling, Fabrication, and Characterization of a Magnetic, Micro Spring-Suspended System for the Safe Electrical Interconnection of Neural Implants. AB - The development of innovative tools for neuroscientific research is based on in vivo tests typically applied to small animals. Most often, the interfacing of neural probes relies on commercially available connector systems which are difficult to handle during connection, particularly when freely behaving animals are involved. Furthermore, the connectors often exert high mechanical forces during plugging and unplugging, potentially damaging the fragile bone structure. In order to facilitate connector usage and increase the safety of laboratory animals, we developed a new magnetic connector system circumventing the drawbacks of existing tools. The connector system uses multiple magnet pairs and spring suspended electrical contact pads realized using micro-electromechanical systems (MEMS) technologies. While the contact pad suspension increases the system tolerance in view of geometrical variations, we achieved a reliable self alignment of the connector parts at +/-50 um provided by the specifically oriented magnet pairs and without the need of alignment pins. While connection forces are negligible, we can adjust the forces during connector release by modifying the magnet distance. With the connector test structures developed here, we achieved an electrical connection yield of 100%. Based on these findings, we expect that in vivo experiments with freely behaving animals will be facilitated with improved animal safety. PMID- 30424358 TI - New Detector Sensitivity Calibration and the Calculation of the Interaction Force between Particles Using an Optical Tweezer. AB - We propose a new approach to calculate the sensitivity factor of the detector in optical tweezers. In this work, we used a charge-coupled device (CCD) camera and a quadrant photodiode (QPD) for the extraction of the various positions occupied by the trapped object (in this case, silica beads of different diameters). Image J software and the Boltzmann statistical method were then used to estimate the sensitivity of the detector. Silica beads of diameter 0.8 um, 2 um, a system of 2 um bead stuck to 4.5 um one and another system of 2 um beads stuck to 2 um one, were studied. This work contributes significantly to making better calibration of the detector without taking into account the geometry of the object imprisoned in the optical trap. We further developed an approach to calculate the interaction force between two microbeads. This approach does not require any knowledge of solvent viscosity and works for all types of samples. PMID- 30424359 TI - A Laser-Engraving Technique for Portable Micropneumatic Oscillators. AB - Microfluidic automation technology is at a stage where the complexity and cost of external hardware control often impose severe limitations on the size and functionality of microfluidic systems. Developments in autonomous microfluidics are intended to eliminate off-chip controls to enable scalable systems. Timing is a fundamental component of the digital logic required to manipulate fluidic flow. The authors present a self-driven pneumatic ring oscillator manufactured by assembling an elastomeric sheet of polydimethylsiloxane (PDMS) between two laser engraved polymethylmethacrylate (PMMA) layers via surface activation through treatment with 3-aminopropyltriethoxysilane (APTES). The frequency of the fabricated oscillators is in the range of 3-7.5 Hz with a maximum of 14 min constant frequency syringe-powered operation. The control of a fluidic channel with the oscillator stages is demonstrated. The fabrication process represents an improvement in manufacturability compared to previous molding or etching approaches, and the resulting devices are inexpensive and portable, making the technology potentially applicable for wider use. PMID- 30424360 TI - Electrospun Three-Dimensional Nanofibrous Structure via Probe Arrays Inducing. AB - The fast and precise direct-printing of micro three-dimensional (3D) structures is the important development trend for micro/nano fabrication technique. A novel method with probe arrays was built up to realize the controllable deposition of 3D electrospun nanofibrous structures. Firstly, several 3D nanofibrous structures were built on a single probe and 2-, 3-probes, which indicated that the probe height and probe interval played a key role on the 3D structure morphology. Then, different stereo nanofibrous structures based on multiprobe arrays were achieved accurately and the effects of processing parameters, including the probe height, probe interval, applied voltage and flow rate on the deposition behaviors of electrospun nanofiber over the probe arrays were investigated. The deposition area of 3D electrospun nanofibrous structures decreased with the increase of probe interval, applied voltage, and flow rate. Several 3D nanofibrous structures of special shapes including convex, triangle wave, inverted cone and complex curved surface were demonstrated by controlling the configuration of probe arrays and electrospinning parameters. This work provides an effective and simple way for the construction of 3D electrospun nanofibrous structures, which has great potentials in various medical and industrial applications. PMID- 30424362 TI - Oocyte Positional Recognition for Automatic Manipulation in ICSI. AB - Polar body position detection is a necessary process in the automation of micromanipulation systems specifically used in intracytoplasmic sperm injection (ICSI) applications. The polar body is an intracellular structure, which accommodates the chromosomes, and the injection must not only avoid this structure but be at the furthest point away from it. This paper aims to develop a vision recognition system for the recognition of the oocyte and its polar body in order to be used to inform the automated injection mechanism to avoid the polar body. The novelty of the paper is its capability to determine the position and orientation of the oocyte and its polar body. The gradient-weighted Hough transform method was employed for the detection of the location of the oocyte and its polar body. Moreover, a new elliptical fitting method was employed for size measurement of the polar bodies and oocytes for the allowance of morphological variance of the oocytes and their polar bodies. The proposed algorithm has been designed to be adaptable with typical commercial inverted microscopes with different criteria. The successful experimental results for this algorithm produce maximum errors of 5% for detection and 10% for reporting respectively. PMID- 30424361 TI - Opportunities and Challenges for Single-Unit Recordings from Enteric Neurons in Awake Animals. AB - Advanced electrode designs have made single-unit neural recordings commonplace in modern neuroscience research. However, single-unit resolution remains out of reach for the intrinsic neurons of the gastrointestinal system. Single-unit recordings of the enteric (gut) nervous system have been conducted in anesthetized animal models and excised tissue, but there is a large physiological gap between awake and anesthetized animals, particularly for the enteric nervous system. Here, we describe the opportunity for advancing enteric neuroscience offered by single-unit recording capabilities in awake animals. We highlight the primary challenges to microelectrodes in the gastrointestinal system including structural, physiological, and signal quality challenges, and we provide design criteria recommendations for enteric microelectrodes. PMID- 30424363 TI - Chronically Implanted Intracranial Electrodes: Tissue Reaction and Electrical Changes. AB - The brain-electrode interface is arguably one of the most important areas of study in neuroscience today. A stronger foundation in this topic will allow us to probe the architecture of the brain in unprecedented functional detail and augment our ability to intervene in disease states. Over many years, significant progress has been made in this field, but some obstacles have remained elusive notably preventing glial encapsulation and electrode degradation. In this review, we discuss the tissue response to electrode implantation on acute and chronic timescales, the electrical changes that occur in electrode systems over time, and strategies that are being investigated in order to minimize the tissue response to implantation and maximize functional electrode longevity. We also highlight the current and future clinical applications and relevance of electrode technology. PMID- 30424364 TI - Large-Field-of-View Visualization Utilizing Multiple Miniaturized Cameras for Laparoscopic Surgery. AB - The quality and the extent of intra-abdominal visualization are critical to a laparoscopic procedure. Currently, a single laparoscope is inserted into one of the laparoscopic ports to provide intra-abdominal visualization. The extent of this field of view (FoV) is rather restricted and may limit efficiency and the range of operations. Here we report a trocar-camera assembly (TCA) that promises a large FoV, and improved efficiency and range of operations. A video stitching program processes video data from multiple miniature cameras and combines these videos in real-time. This stitched video is then displayed on an operating monitor with a much larger FoV than that of a single camera. In addition, we successfully performed a standard and a modified bean drop task, without any distortion, in a simulator box by using the TCA and taking advantage of its FoV which is larger than that of the current laparoscopic cameras. We successfully demonstrated its improved efficiency and range of operations. The TCA frees up a surgical port and potentially eliminates the need of physical maneuvering of the laparoscopic camera, operated by an assistant. PMID- 30424365 TI - A High-Throughput Electrokinetic Micromixer via AC Field-Effect Nonlinear Electroosmosis Control in 3D Electrode Configurations. AB - In this study, we make use of the AC field-effect flow control on induced-charge electroosmosis (ICEO), to develop an electrokinetic micromixer with 3D electrode layouts, greatly enhancing the device performance compared to its 2D counterpart of coplanar metal strips. A biased AC voltage wave applied to the central gate terminal, i.e., AC field-effect control, endows flow field-effect-transistor of ICEO the capability to produce arbitrary symmetry breaking in the transverse electrokinetic vortex flow pattern, which makes it fascinating for microfluidic mixing. Using the Debye-Huckel approximation, a mathematical model is established to test the feasibility of the new device design in stirring nanoparticle samples carried by co-flowing laminar streams. The effect of various experimental parameters on constructing a viable micromixer is investigated, and an integrated microdevice with a series of gate electrode bars disposed along the centerline of the channel bottom surface is proposed for realizing high-flux mixing. Our physical demonstration on field-effect nonlinear electroosmosis control in 3D electrode configurations provides useful guidelines for electroconvective manipulation of nanoscale objects in modern microfluidic systems. PMID- 30424366 TI - Assessment of Lagrangian Modeling of Particle Motion in a Spiral Microchannel for Inertial Microfluidics. AB - Inertial microfluidics is a promising tool for a label-free particle manipulation for microfluidics technology. It can be utilized for particle separation based on size and shape, as well as focusing of particles. Prediction of particles' trajectories is essential for the design of inertial microfluidic devices. At this point, numerical modeling is an important tool to understand the underlying physics and assess the performance of devices. A Monte Carlo-type computational model based on a Lagrangian discrete phase model is developed to simulate the particle trajectories in a spiral microchannel for inertial microfluidics. The continuous phase (flow field) is solved without the presence of a discrete phase (particles) using COMSOL Multi-physics. Once the flow field is obtained, the trajectory of particles is determined in the post-processing step via the COMSOL MATLAB interface. To resemble the operation condition of the device, the random inlet position of the particles, many particles are simulated with random initial locations from the inlet of the microchannel. The applicability of different models for the inertial forces is discussed. The computational model is verified with experimental results from the literature. Different cases in a spiral channel with aspect ratios of 2.0 and 9.0 are simulated. The simulation results for the spiral channel with an aspect ratio of 9.0 are compared against the experimental data. The results reveal that despite certain limitations of our model, the current computational model satisfactorily predicts the location and the width of the focusing streams. PMID- 30424368 TI - About the Implementation of Frequency Conversion Processes in Solar Cell Device Simulations. AB - Solar cells are electrical devices that can directly convert sunlight into electricity. While solar cells are a mature technology, their efficiencies are still far below the theoretical limit. The major losses in a typical semiconductor solar cell are due to the thermalization of electrons in the UV and visible range of the solar spectrum, the inability of a solar cell to absorb photons with energies below the electronic band gap, and losses due to the recombination of electrons and holes, which mainly occur at the contacts. These prevent the realization of the theoretical efficiency limit of 85% for a generic photovoltaic device. A promising strategy to harness light with minimum thermal losses outside the typical frequency range of a single junction solar cell could be frequency conversion using rare earth ions, as suggested by Trupke. In this work, we discuss the modelling of generic frequency conversion processes in the context of solar cell device simulations, which can be used to supplement experimental studies. In the spirit of a proof-of-concept study, we limit the discussion to up-conversion and restrict ourselves to a simple rare earth model system, together with a basic diode model for a crystalline silicon solar cell. The results of this show that these simulations are very useful for the development of new types of highly efficient solar cells. PMID- 30424367 TI - Single Cell Isolation Using Optical Tweezers. AB - Optical tweezers offer a non-contact method for selecting single cells and translocating them from one microenvironment to another. We have characterized the optical tweezing of yeast S. cerevisiae and can manipulate single cells at 0.41 +/- 0.06 mm/s using a 26.8 +/- 0.1 mW from a 785 nm diode laser. We have fabricated and tested three cell isolation devices; a micropipette, a PDMS chip and a laser machined fused silica chip and we have isolated yeast, single bacteria and cyanobacteria cells. The most effective isolation was achieved in PDMS chips, where single yeast cells were grown and observed for 18 h without contamination. The duration of budding in S. cerevisiae was not affected by the laser parameters used, but the time from tweezing until the first budding event began increased with increasing laser energy (laser power * time). Yeast cells tweezed using 25.0 +/- 0.1 mW for 1 min were viable after isolation. We have constructed a micro-consortium of yeast cells, and a co-culture of yeast and bacteria, using optical tweezers in combination with the PDMS network of channels and isolation chambers, which may impact on both industrial biotechnology and understanding pathogen dynamics. PMID- 30424369 TI - Scalable, Modular Three-Dimensional Silicon Microelectrode Assembly via Electroless Plating. AB - We devised a scalable, modular strategy for microfabricated 3-D neural probe synthesis. We constructed a 3-D probe out of individual 2-D components (arrays of shanks bearing close-packed electrodes) using mechanical self-locking and self aligning techniques, followed by electroless nickel plating to establish electrical contact between the individual parts. We detail the fabrication and assembly process and demonstrate different 3-D probe designs bearing thousands of electrode sites. We find typical self-alignment accuracy between shanks of <0.2 degrees and demonstrate orthogonal electrical connections of 40 um pitch, with thousands of connections formed electrochemically in parallel. The fabrication methods introduced allow the design of scalable, modular electrodes for high density 3-D neural recording. The combination of scalable 3-D design and close packed recording sites may support a variety of large-scale neural recording strategies for the mammalian brain. PMID- 30424371 TI - High-Performance Resistive Pressure Sensor Based on Elastic Composite Hydrogel of Silver Nanowires and Poly(ethylene glycol). AB - Improved pressure sensing is of great interest to enable the next-generation of bioelectronics systems. This paper describes the development of a transparent, flexible, highly sensitive pressure sensor, having a composite sandwich structure of elastic silver nanowires (AgNWs) and poly(ethylene glycol) (PEG). A simple PEG photolithography was employed to construct elastic AgNW-PEG composite patterns on flexible polyethylene terephthalate (PET) film. A porous PEG hydrogel structure enabled the use of conductive AgNW patterns while maintaining the elasticity of the composite material, features that are both essential for high-performance pressure sensing. The transparency and electrical properties of AgNW-PEG composite could be precisely controlled by varying the AgNW concentration. An elastic AgNW-PEG composite hydrogel with 0.6 wt % AgNW concentration exhibited high transmittance including T550nm of around 86%, low sheet resistance of 22.69 Omega.sq-1, and excellent bending durability (only 5.8% resistance increase under bending to 10 mm radius). A flexible resistive pressure sensor based on our highly transparent AgNW-PEG composite showed stable and reproducible response, high sensitivity (69.7 kPa-1), low sensing threshold (~2 kPa), and fast response time (20-40 ms), demonstrating the effectiveness of the AgNW-PEG composite material as an elastic conductor. PMID- 30424370 TI - Spin Readout Techniques of the Nitrogen-Vacancy Center in Diamond. AB - The diamond nitrogen-vacancy (NV) center is a leading platform for quantum information science due to its optical addressability and room-temperature spin coherence. However, measurements of the NV center's spin state typically require averaging over many cycles to overcome noise. Here, we review several approaches to improve the readout performance and highlight future avenues of research that could enable single-shot electron-spin readout at room temperature. PMID- 30424372 TI - Nano and Microsensors for Mammalian Cell Studies. AB - This review presents several sensors with dimensions at the nano- and micro-scale used for biological applications. Two types of cantilever beams employed as highly sensitive temperature sensors with biological applications will be presented. One type of cantilever beam is fabricated from composite materials and is operated in the deflection mode. In order to achieve the high sensitivity required for detection of heat generated by a single mammalian cell, the cantilever beam temperature sensor presented in this review was microprocessed with a length at the microscale and a thickness in the nanoscale dimension. The second type of cantilever beam presented in this review was operated in the resonant frequency regime. The working principle of the vibrating cantilever beam temperature sensor is based on shifts in resonant frequency in response to temperature variations generated by mammalian cells. Besides the cantilever beam biosensors, two biosensors based on the electric cell-substrate impedance sensing (ECIS) used to monitor mammalian cells attachment and viability will be presented in this review. These ECIS sensors have dimensions at the microscale, with the gold films used for electrodes having thickness at the nanoscale. These micro/nano biosensors and their mammalian cell applications presented in the review demonstrates the diversity of the biosensor technology and applications. PMID- 30424373 TI - A Molecular Dynamics Study of the Mechanical Properties of Twisted Bilayer Graphene. AB - Graphene is one of the most important nanomaterials. The twisted bilayer graphene shows superior electronic properties compared to graphene. Here, we demonstrate via molecular dynamics simulations that twisted bilayer graphene possesses outstanding mechanical properties. We find that the mechanical strain rate and the presence of cracks have negligible effects on the linear elastic properties, but not the nonlinear mechanical properties, including fracture toughness. The "two-peak" pattern in the stress-strain curves of the bilayer composites of defective and pristine graphene indicates a sequential failure of the two layers. Our study provides a safe-guide for the design and applications of multilayer grapheme-based nanoelectronic devices. PMID- 30424374 TI - Luminescent Properties of Eu3+-Doped Hybrid SiO2-PMMA Material for Photonic Applications. AB - Hybrid organic-inorganic materials are of great interest for various applications. Here, we report on the synthesis and optical characterization of silica-PMMA samples with different Eu3+ molar concentrations. The optical properties of this material make it suitable for photonic applications. The samples were prepared using the sol-gel method, mixing tetraethyl orthosilicate (TEOS) as a silica glass precursor and methyl methacrylate (PMMA) as a polymer component. Europium nitrate pentahydrate was then added in six different molar concentrations (0.0, 0.1, 0.25, 0.5, 0.75, and 1%) to obtain as many different samples of the material. The absorption spectra were obtained applying the Kubelka-Munk formula to the diffuse reflectance spectra of the samples, all in the wavelength range between 240 and 2500 nm. The emission and excitation measurements were made in the visible range. Five bands could be identified in the emission spectra, related to electronic transitions of the ion Eu3+ (4D0 >7Fi, i from 0 to 4). In the excitation spectra, the following bands were detected: 7F0->5G3 (379 nm), 7F0->5G2 (380 nm), 7F0->5L6 (392 nm), 7F0->5D3 (407 nm), 7F0->5D2 (462 nm), and 7F0->5D1 (530 nm). The emission decay times were measured for the different samples and showed an inverse dependence with the Eu3+ concentration. PMID- 30424375 TI - MEMS Inertial Sensors Based Gait Analysis for Rehabilitation Assessment via Multi Sensor Fusion. AB - Gait and posture are regular activities which are fully controlled by the sensorimotor cortex. In this study, fluctuations of joint angle and asymmetry of foot elevation in human walking stride records are analyzed to assess gait in healthy adults and patients affected with gait disorders. This paper aims to build a low-cost, intelligent and lightweight wearable gait analysis platform based on the emerging body sensor networks, which can be used for rehabilitation assessment of patients with gait impairments. A calibration method for accelerometer and magnetometer was proposed to deal with ubiquitous orthoronal error and magnetic disturbance. Proportional integral controller based complementary filter and error correction of gait parameters have been defined with a multi-sensor data fusion algorithm. The purpose of the current work is to investigate the effectiveness of obtained gait data in differentiating healthy subjects and patients with gait impairments. Preliminary clinical gait experiments results showed that the proposed system can be effective in auxiliary diagnosis and rehabilitation plan formulation compared to existing methods, which indicated that the proposed method has great potential as an auxiliary for medical rehabilitation assessment. PMID- 30424376 TI - A Meta-Analysis of Intracortical Device Stiffness and Its Correlation with Histological Outcomes. AB - Neural implants offer solutions for a variety of clinical issues. While commercially available devices can record neural signals for short time periods, they fail to do so chronically, partially due to the sustained tissue response around the device. Our objective was to assess the correlation between device stiffness, a function of both material modulus and cross-sectional area, and the severity of immune response. Meta-analysis data were derived from nine previously published studies which reported device material and geometric properties, as well as histological outcomes. Device bending stiffness was calculated by treating the device shank as a cantilevered beam. Immune response was quantified through analysis of immunohistological images from each study, specifically looking at fluorescent markers for neuronal nuclei and astrocytes, to assess neuronal dieback and gliosis. Results demonstrate that the severity of the immune response, within the first 50 um of the device, is highly correlated with device stiffness, as opposed to device modulus or cross-sectional area independently. In general, commercially available devices are around two to three orders of magnitude higher in stiffness than devices which induced a minimal tissue response. These results have implications for future device designs aiming to decrease chronic tissue response and achieve increased long-term functionality. PMID- 30424377 TI - A SigmaDelta Closed-Loop Interface for a MEMS Accelerometer with Digital Built-In Self-Test Function. AB - Sigma-delta (SigmaDelta) closed-loop operation is the best candidate for realizing the interface circuit of MEMS accelerometers. However, stability and reliability problems are still the main obstacles hindering its further development for high-end applications. In situ self-testing and calibration is an alternative way to solve these problems in the current process condition, and thus, has received a lot of attention in recent years. However, circuit methods for self-testing of SigmaDelta closed-loop accelerometers are rarely reported. In this paper, we propose a fifth-order SigmaDelta closed-loop interface for a capacitive MEMS accelerometer. The nonlinearity problem of the system is detailed discussed, the source of it is analyzed, and the solutions are given. Furthermore, a built-in self-test (BIST) unit is integrated on-chip for in situ self-testing of the loop distortion. In BIST mode, a digital electrostatic excitation is generated by an on-chip digital resonator, which is also SigmaDelta modulated. By single-bit SigmaDelta-modulation, the noise and linearity of excitation is effectively improved, and a higher detection level for distortion is easily achieved, as opposed to the physical excitation generated by the motion of laboratory equipment. PMID- 30424379 TI - Investigation of Growth Factor and Tenocyte Proliferation Induced by Platelet Rich Plasma (PRP) in a 3-Chamber Co-Culture Device. AB - The platelet-rich plasma (PRP) has become an attractive topic for soft tissue healing therapy recently. While some clinical reports revealed the effective treatments for knee osteoarthritis, lateral epicondylitis, and rotator cuff tears, other case studies showed that there was no statistically significant healing improvement. The efficacy of the PRP therapy is still unclear clinically. Thus, a significant amount of basic studies should be conducted to optimize the preparation procedure and the platelet concentration of the PRP. In this work, a 3-chamber co-culture device was developed for the PRP study in order to reduce the usage of primary cells and to avoid the PRP gelation effect. The device was a culture, well partitioning into 3 sub-chambers. Tenocytes and PRP could be respectively loaded into the sub-chambers and co-cultured under the interlinked medium. The results showed that a higher platelet number in the PRP could diffuse higher concentration of the growth factors in the medium and induce higher tenocyte proliferation. The 3-chamber co-culture device provides a simple and practical tool for the PRP study. It is potentially applied for optimizing the preparation procedure and platelet concentration of the PRP therapy. PMID- 30424380 TI - Quantifying Discretization Errors in Electrophoretically-Guided Micro Additive Manufacturing. AB - This paper presents process models for a new micro additive manufacturing process termed Electrophoretically-guided Micro Additive Manufacturing (EPMUAM). In EPMUAM, a planar microelectrode array generates the electric potential distributions which cause colloidal particles to agglomerate and deposit in desired regions. The discrete microelectrode array nature and the used pulse width modulation (PWM) technique for microelectrode actuation create unavoidable process errors-space and time discretization errors-that distort particle trajectories. To combat this, we developed finite element method (FEM) models to study trajectory deviations due to these errors. Mean square displacement (MSD) analysis of the computed particle trajectories is used to compare these deviations for several electrode geometries. The two top-performing electrode geometries evaluated by MSD were additionally investigated through separate case studies via geometry variation and MSD recomputation. Furthermore, separate time discretization error simulations are also studied where electrode actuating waveforms were simulated. The mechanical impulse of the electromechanical force, generated from these waveforms is used as the basis for comparison. The obtained results show a moderate MSDs variability and significant differences in the computed mechanical impulses for the actuating waveforms. The observed limitations of the developed process model and of the error comparison technique are briefly discussed and future steps are recommended. PMID- 30424378 TI - The History and Horizons of Microscale Neural Interfaces. AB - Microscale neural technologies interface with the nervous system to record and stimulate brain tissue with high spatial and temporal resolution. These devices are being developed to understand the mechanisms that govern brain function, plasticity and cognitive learning, treat neurological diseases, or monitor and restore functions over the lifetime of the patient. Despite decades of use in basic research over days to months, and the growing prevalence of neuromodulation therapies, in many cases the lack of knowledge regarding the fundamental mechanisms driving activation has dramatically limited our ability to interpret data or fine-tune design parameters to improve long-term performance. While advances in materials, microfabrication techniques, packaging, and understanding of the nervous system has enabled tremendous innovation in the field of neural engineering, many challenges and opportunities remain at the frontiers of the neural interface in terms of both neurobiology and engineering. In this short communication, we explore critical needs in the neural engineering field to overcome these challenges. Disentangling the complexities involved in the chronic neural interface problem requires simultaneous proficiency in multiple scientific and engineering disciplines. The critical component of advancing neural interface knowledge is to prepare the next wave of investigators who have simultaneous multi-disciplinary proficiencies with a diverse set of perspectives necessary to solve the chronic neural interface challenge. PMID- 30424381 TI - Utilization of 2:1 Internal Resonance in Microsystems. AB - In this paper, the nonlinear mode coupling at 2:1 internal resonance has been studied both analytically and experimentally. A modified micro T-beam structure is proposed, and the equations of motion are developed using Lagrange's energy method. A two-variable expansion perturbation method is used to describe the nonlinear behavior of the system. It is shown that in a microresonator with 2:1 internal resonance, the low-frequency mode is autoparametrically excited after the excitation amplitude reaches a certain threshold. The effect of damping on the performance of the system is also investigated. PMID- 30424382 TI - Interrogation Techniques and Interface Circuits for Coil-Coupled Passive Sensors. AB - Coil-coupled passive sensors can be interrogated without contact, exploiting the magnetic coupling between two coils forming a telemetric proximity link. A primary coil connected to the interface circuit forms the readout unit, while a passive sensor connected to a secondary coil forms the sensor unit. This work is focused on the interrogation of sensor units based on resonance, denoted as resonant sensor units, in which the readout signals are the resonant frequency and, possibly, the quality factor. Specifically, capacitive and electromechanical piezoelectric resonator sensor units are considered. Two interrogation techniques, namely a frequency-domain technique and a time-domain technique, have been analyzed, that are theoretically independent of the coupling between the coils which, in turn, ensure that the sensor readings are not affected by the interrogation distance. However, it is shown that the unavoidable parasitic capacitance in parallel to the readout coil introduces, for both techniques, an undesired dependence of the readings on the interrogation distance. This effect is especially marked for capacitance sensor units. A compensation circuit is innovatively proposed to counteract the effects of the parasitic input capacitance, and advantageously obtain distance-independent readings in real operating conditions. Experimental tests on a coil-coupled capacitance sensor with resonance at 5.45 MHz have shown a deviation within 1.5 kHz, i.e., 300 ppm, for interrogation distances of up to 18 mm. For the same distance range, with a coil-coupled quartz crystal resonator with a mechanical resonant frequency of 4.432 MHz, variations of less than 1.8 Hz, i.e., 0.5 ppm, have been obtained. PMID- 30424383 TI - Activity Monitoring with a Wrist-Worn, Accelerometer-Based Device. AB - This study condenses huge amount of raw data measured from a MEMS accelerometer based, wrist-worn device on different levels of physical activities (PAs) for subjects wearing the device 24 h a day continuously. In this study, we have employed the device to build up assessment models for quantifying activities, to develop an algorithm for sleep duration detection and to assess the regularity of activity of daily living (ADL) quantitatively. A new parameter, the activity index (AI), has been proposed to represent the quantity of activities and can be used to categorize different PAs into 5 levels, namely, rest/sleep, sedentary, light, moderate, and vigorous activity states. Another new parameter, the regularity index (RI), was calculated to represent the degree of regularity for ADL. The methods proposed in this study have been used to monitor a subject's daily PA status and to access sleep quality, along with the quantitative assessment of the regularity of activity of daily living (ADL) with the 24-h continuously recorded data over several months to develop activity-based evaluation models for different medical-care applications. This work provides simple models for activity monitoring based on the accelerometer-based, wrist worn device without trying to identify the details of types of activity and that are suitable for further applications combined with cloud computing services. PMID- 30424384 TI - Correction: Bernardin E.K.; et al. Demonstration of a Robust All-Silicon-Carbide Intracortical Neural Interface. Micromachines, 2018, 9, 412. AB - The authors would like to indicate the following financial support they received to the Acknowledgement Section of their published paper [...]. PMID- 30424386 TI - Characterization and Integration of Terahertz Technology within Microfluidic Platforms. AB - In this work, the prospects of integrating terahertz (THz) time-domain spectroscopy (TDS) within polymer-based microfluidic platforms are investigated. The work considers platforms based upon the polar polymers polyethylene terephthalate (PET), polycarbonate (PC), polymethyl-methacrylate (PMMA), polydimethylsiloxane (PDMS), and the nonpolar polymers fluorinated ethylene propylene (FEP), polystyrene (PS), high-density polyethylene (HDPE), and ultra high-molecular-weight polyethylene (UHMWPE). The THz absorption coefficients for these polymers are measured. Two microfluidic platforms are then designed, fabricated, and tested, with one being based upon PET, as a representative high loss polar polymer, and one being based upon UHMWPE, as a representative low-loss nonpolar polymer. It is shown that the UHMWPE microfluidic platform yields reliable measurements of THz absorption coefficients up to a frequency of 1.75 THz, in contrast to the PET microfluidic platform, which functions only up to 1.38 THz. The distinction seen here is attributed to the differing levels of THz absorption and the manifestation of differing f for the systems. Such findings can play an important role in the future integration of THz technology and polymer-based microfluidic systems. PMID- 30424385 TI - Introduction to Photonics: Principles and the Most Recent Applications of Microstructures. AB - Light has found applications in data transmission, such as optical fibers and waveguides and in optoelectronics. It consists of a series of electromagnetic waves, with particle behavior. Photonics involves the proper use of light as a tool for the benefit of humans. It is derived from the root word "photon", which connotes the tiniest entity of light analogous to an electron in electricity. Photonics have a broad range of scientific and technological applications that are practically limitless and include medical diagnostics, organic synthesis, communications, as well as fusion energy. This will enhance the quality of life in many areas such as communications and information technology, advanced manufacturing, defense, health, medicine, and energy. The signal transmission methods used in wireless photonic systems are digital baseband and RoF (Radio over-Fiber) optical communication. Microwave photonics is considered to be one of the emerging research fields. The mid infrared (mid-IR) spectroscopy offers a principal means for biological structure analysis as well as nonintrusive measurements. There is a lower loss in the propagations involving waveguides. Waveguides have simple structures and are cost-efficient in comparison with optical fibers. These are important components due to their compactness, low profile, and many advantages over conventional metallic waveguides. Among the waveguides, optofluidic waveguides have been found to provide a very powerful foundation for building optofluidic sensors. These can be used to fabricate the biosensors based on fluorescence. In an optical fiber, the evanescent field excitation is employed to sense the environmental refractive index changes. Optical fibers as waveguides can be used as sensors to measure strain, temperature, pressure, displacements, vibrations, and other quantities by modifying a fiber. For some application areas, however, fiber-optic sensors are increasingly recognized as a technology with very interesting possibilities. In this review, we present the most common and recent applications of the optical fiber-based sensors. These kinds of sensors can be fabricated by a modification of the waveguide structures to enhance the evanescent field; therefore, direct interactions of the measurand with electromagnetic waves can be performed. In this research, the most recent applications of photonics components are studied and discussed. PMID- 30424387 TI - Design, Simulation and Experimental Study of the Linear Magnetic Microactuator. AB - This paper reports the design, simulation and experimental study of a linear magnetic microactuator for portable electronic equipment and microsatellite high resolution remote sensing technology. The linear magnetic microactuator consists of a planar microcoil, a supporter and a microspring. Its bistable mechanism can be kept without current by external permanent magnetic force, and can be switched by the bidirectional electromagnetic force. The linearization and threshold of the bistable mechanism was optimized by topology structure design of the microspring. The linear microactuator was then fabricated based on non-silicon technology and the prototype was tested. The testing results indicated that the bistable mechanism was realized with a fast response of 0.96 ms, which verified the simulation and analysis. PMID- 30424388 TI - Fabrication and Characterization of PZT Fibered-Epitaxial Thin Film on Si for Piezoelectric Micromachined Ultrasound Transducer. AB - This paper presents a fibered-epitaxial lead zirconate titanate (PZT) thin film with intermediate features between the monocrystalline and polycrystalline thin films for piezoelectric micromachined ultrasound transducer (pMUT). The grain boundaries confirmed by scanning electron microscopy, but it still maintained the in-plane epitaxial relationship found by X-ray diffraction analyses. The dielectric constant (epsilonr33 = 500) was relatively high compared to those of the monocrystalline thin films, but was lower than those of conventional polycrystalline thin films near the morphotropic phase boundary composition. The fundamental characterizations were evaluated through the operation tests of the prototyped pMUT with the fibered-epitaxial thin film. As a result, its piezoelectric coefficient without poling treatment was estimated to be e31,f = 10--11 C/m2, and thus reasonably high compared to polycrystalline thin films. An appropriate poling treatment increased e31,f and decreased epsilonr33. In addition, this unique film was demonstrated to be mechanically tougher than the monocrystalline thin film. It has the potential ability to become a well-balanced piezoelectric film with both high signal-to-noise ratio and mechanical toughness for pMUT. PMID- 30424389 TI - Electrohydrodynamic Direct-Writing Micropatterns with Assisted Airflow. AB - Electrohydrodynamic direct-writing (EDW) is a developing technology for high resolution printing. How to decrease the line width and improve the deposition accuracy of direct-written patterns has been the key to the promotion for the further application of EDW. In this paper, an airflow-assisted spinneret for electrohydrodynamic direct-writing was designed. An assisted laminar airflow was introduced to the EDW process, which provided an additional stretching and constraining force on the jet to reduce the surrounding interferences and enhance jet stability. The flow field and the electric field around the spinneret were simulated to direct the structure design of the airflow-assisted spinneret. Then, a series of experiments were conducted, and the results verified the spinneret design and demonstrated a stable ejection of jet in the EDW process. With assisted airflow, the uniformity of printed patterns and the deposition position accuracy of a charged jet can be improved. Complex patterns with positioning errors of less than 5% have been printed and characterized, which provide an effective way to promote the integration of micro/nanosystems. PMID- 30424390 TI - Thermal-Flow Characteristics of Ferrofluids in a Rotating Eccentric Cylinder under External Magnetic Force. AB - Heat dissipation has become an important issue due to the miniaturization of various electronic devices. Various methods such as spray and nozzle coolers, heat sinks and so on are used for heat dissipation. However, the emergence of ferrofluids drastically improves the operating characteristics of electromagnetic systems and devices. A ferrofluid is a suspension containing 10-nm magnetic particles in a colloidal solution. This material exhibits paramagnetic behavior and is sensitive to magnetic field and temperature. In this study, heat transfer characteristics of ferrofluids in a rotating eccentric cylinder were investigated using the commercial code, COMSOL Multiphysics. Numerical results of the local Nusselt number, magnetophoretic force and velocity distributions were obtained from various eccentricities of the cylinder, and the results were graphically depicted with various flow conditions. PMID- 30424391 TI - LSS-RM: Using Multi-Mounted Devices to Construct a Lightweight Site-Survey Radio Map for WiFi Positioning. AB - A WiFi-received signal strength index (RSSI) fingerprinting-based indoor positioning system (WiFi-RSSI IPS) is widely studied due to advantages of low cost and high accuracy, especially in a complex indoor environment where performance of the ranging method is limited. The key drawback that limits the large-scale deployment of WiFi-RSSI IPS is time-consuming offline site surveys. To solve this problem, we developed a method using multi-mounted devices to construct a lightweight site-survey radio map (LSS-RM) for WiFi positioning. A smartphone was mounted on the foot (Phone-F) and another on the waist (Phone-W) to scan WiFi-RSSI and simultaneously sample microelectromechanical system inertial measurement-unit (MEMS-IMU) readings, including triaxial accelerometer, gyroscope, and magnetometer measurements. The offline site-survey phase in LSS-RM is a client-server model of a data collection and preprocessing process, and a post calibration process. Reference-point (RP) coordinates were estimated using the pedestrian dead-reckoning algorithm. The heading was calculated with a corner detected by Phone-W and the preassigned site-survey trajectory. Step number and stride length were estimated using Phone-F based on the stance-phase detection algorithm. Finally, the WiFi-RSSI radio map was constructed with the RP coordinates and timestamps of each stance phase. Experimental results show that our LSS-RM method can reduce the time consumption of constructing a WiFi-RSSI radio map from 54 min to 7.6 min compared with the manual site-survey method. The average positioning error was below 2.5 m with three rounds along the preassigned site-survey trajectory. LSS-RM aims to reduce offline site-survey time consumption, which would cut down on manpower. It can be used in the large-scale implementation of WiFi-RSSI IPS, such as shopping malls, hospitals, and parking lots. PMID- 30424392 TI - A Dynamic Model of Drag Force for Catalytic Micromotors Based on Navier-Stokes Equations. AB - In past decades, considerable advances have been achieved in micro and nanomotors. Particular attention has been given to self-propelled catalytic micromotors, which have been widely used in cell separation, drug delivery, microsurgery, lithography and environmental remediation. Fast moving, long life micromotors appear regularly, however it seems there are no solutions yet that thoroughly clarify the hydrodynamic behavior of catalytic micromotors moving in fluid. Dynamic behavior of this kind of micromotors is mainly determined by the driving force and drag force acting on the micromotors. Based on the hydromechanics theory, a hydrodynamic model is established to predict the drag force for a conical micromotor immersed in the flow field. By using the computational fluid dynamics software Fluent 18.0 (ANSYS), the drag force and the drag coefficient of different conical micromotors are calculated. A mathematical model was proposed to describe the relationship among Reynolds numbers Re, the ratio lambda, the semi-cone angle delta and the drag coefficient Cd of the micromotors. This work provides theoretical support and reference for optimizing the design and development of conical micromotors. PMID- 30424393 TI - Fluorescence Enhancement Using Bimetal Surface Plasmon-Coupled Emission from 5 Carboxyfluorescein (FAM). AB - We demonstrate the enhancement of fluorescence emission from a dye, 5 carboxyfluorescein (FAM), which couples with surface plasmons at the spectral channels of excitation and emission. Experiments and calculations revealed that bimetallic (gold-silver) plasmon, as compared to the monometallic ones, allowed such coupling to be enhanced, at both the spectral channels. We achieved the maximum fluorescence enhancement level of 46.5-fold, with markedly high reproducibility (coefficient of variation ~ 0.5%) at a FAM concentration of 10 nM. We also found that higher fluorescence enhancement was more likely to be reproducible. This encourages the use of this technology for practical applications in fluorescence-based biochemical assays. Moreover, we investigated a FAM concentration-dependent enhancement of fluorescence. It was found that fluorescence enhancement decreased and saturated at above 10 nM concentration possibly due to partial photo-bleaching of FAM molecules. PMID- 30424394 TI - Low-Cost, Accessible Fabrication Methods for Microfluidics Research in Low Resource Settings. AB - Microfluidics are expected to revolutionize the healthcare industry especially in developing countries since it would bring portable, easy-to-use, self-contained diagnostic devices to places with limited access to healthcare. To date, however, microfluidics has not yet been able to live up to these expectations. One non negligible factor can be attributed to inaccessible prototyping methods for researchers in low-resource settings who are unable to afford expensive equipment and/or obtain critical reagents and, therefore, unable to engage and contribute to microfluidics research. In this paper, we present methods to create microfluidic devices that reduce initial costs from hundreds of thousands of dollars to about $6000 by using readily accessible consumables and inexpensive equipment. By including the scientific community most embedded and aware of the requirements of healthcare in developing countries, microfluidics will be able to increase its reach in the research community and be better informed to provide relevant solutions to global healthcare challenges. PMID- 30424395 TI - A Novel Approach to Droplet's 3D Shape Recovery Based on Mask R-CNN and Improved Lambert-Phong Model. AB - Aiming at the demand for extracting the three-dimensional shapes of droplets in microelectronic packaging, life science, and some related fields, as well as the problems of complex calculation and slow running speed of conventional shape from shading (SFS) illumination reflection models, this paper proposes a Lambert-Phong hybrid model algorithm to recover the 3D shapes of micro-droplets based on the mask regions with convolutional neural network features (R-CNN) method to extract the highlight region of the droplet surface. This method fully integrates the advantages of the Lambertian model's fast running speed and the Phong model's high accuracy for reconstruction of the highlight region. First, the Mask R-CNN network is used to realize the segmentation of the highlight region of the droplet and obtain its coordinate information. Then, different reflection models are constructed for the different reflection regions of the droplet, and the Taylor expansion and Newton iteration method are used for the reflection model to get the final height of all positions. Finally, a three-dimensional reconstruction experimental platform is built to analyze the accuracy and speed of the algorithm on the synthesized hemisphere image and the actual droplet image. The experimental results show that the proposed algorithm based on mask R CNN had better precision and shorter running time. Hence, this paper provides a new approach for real-time measurement of 3D droplet shape in the dispensing state. PMID- 30424396 TI - A High-Frequency-Compatible Miniaturized Bandpass Filter with Air-Bridge Structures Using GaAs-Based Integrated Passive Device Technology. AB - This paper reports on the use of gallium arsenide-based integrated passive device technology for the implementation of a miniaturized bandpass filter that incorporates an intertwined circle-shaped spiral inductor and an integrated center-located capacitor. Air-bridge structures were introduced to the outer inductor and inner capacitor for the purpose of space-saving, thereby yielding a filter with an overall chip area of 1178 MUm * 970 MUm. Thus, not only is the chip area minimized, but the magnitude of return loss is also improved as a result of selective variation of bridge capacitance. The proposed device possesses a single passband with a central frequency of 1.71 GHz (return loss: 32.1 dB), and a wide fractional bandwidth (FBW) of 66.63% (insertion loss: 0.50 dB). One transmission zero with an amplitude of 43.42 dB was obtained on the right side of the passband at 4.48 GHz. Owing to its miniaturized chip size, wide FBW, good out-band suppression, and ability to yield high-quality signals, the fabricated bandpass filter can be implemented in various L-band applications such as mobile services, satellite navigation, telecommunications, and aircraft surveillance. PMID- 30424398 TI - Magnetorheological Fluids Actuated Haptic-Based Teleoperated Catheter Operating System. AB - During conventional catheter endovascular procedures, surgeons needs to adjust the catheter intervention moving direction and velocity according to the direct sensation. Moreover, in the conventional method, both the surgeon and the patient are inevitable exposed to a large amount of, and for a long period of time, X-ray radiation during the surgical procedure. The purpose of this paper is to ensure surgical safety and to protect the surgeon from X-ray radiation during the surgical procedure by adopting a novel haptic-based robot-assisted master-slave system mode. In this paper, a kind of magnetorheological fluids (MR fluids)-based haptic interface has been developed to generate a kind of controllable haptic sensation providing to the catheter operator, and the catheter intervention kinematics parameters measured the motion capture part to control the salve robotic catheter operating system following the master side kinematics. The slave catheter operating the mechanical system has also been designed and manufactured to manipulate the clinical catheter by mimicking the surgeon operating the catheter intervention surgical procedure, which has a 2-DOF (advance, retreat, and rotate) catheter motion characteristic; in addition, the interaction force between the catheter and inner wall of vasculature can be measured by its force sensing unit and the feedback to the master system. The catheter intervention synchronous evaluation experiments between the master and slave system are tested. Also, the advantages of integrating the controllable haptic sensation to the master-slave system experimental evaluations have been done in vitro. The experimental results demonstrated that the proposed haptic-based robot-assisted master-slave system mode can reduce the surgical time and protect the surgeon from X-ray radiation. PMID- 30424399 TI - A Plantar Pressure Sensing System with Balancing Sensitivity Based on Tailored MWCNTs/PDMS Composites. AB - This paper presents a flexible plantar pressure sensor with a simple structure and easy accessibility, suitable for everyday use. In this study, the design, fabrication, and characteristics of both the composite and the sensor were involved. By using the solution method, the piezoresistive composite was fabricated by uniform dispersion of multiwall carbon nanotubes (MWCNTs) into the polydimethylsiloxane (PDMS) matrix. The proposed sensor consists of eight sensing elements with a laminated structure. The upper layer is a sensing layer made of the piezoresistive composite, and the lower layer is a flexible printed circuit board working as electrodes. A particular design of sensing elements was carried out by using different doping concentrations according to arrangement positions under the feet to obtain balancing sensitivity. A signal processing system to convert the variable resistance signal into voltages by the current-to-voltage method was designed. Experimental results prove that the designed sensor shows a repeatable response with a sensitivity of 11.5 mV/kPa within the range of 265 kPa. Also, an actual application verifies that the designed plantar pressure sensor can measure the pressure under the foot and can be used for gait detection and disease diagnosis purposes. PMID- 30424397 TI - Nanoscale-Textured Tantalum Surfaces for Mammalian Cell Alignment. AB - Tantalum is one of the most important biomaterials used for surgical implant devices. However, little knowledge exists about how nanoscale-textured tantalum surfaces affect cell morphology. Mammalian (Vero) cell morphology on tantalum coated comb structures was studied using high-resolution scanning electron microscopy and fluorescence microscopy. These structures contained parallel lines and trenches with equal widths in the range of 0.18 to 100 MUm. Results showed that as much as 77% of adherent cell nuclei oriented within 10 degrees of the line axes when deposited on comb structures with widths smaller than 10 MUm. However, less than 20% of cells exhibited the same alignment performance on blanket tantalum films or structures with line widths larger than 50 MUm. Two types of line-width-dependent cell morphology were observed. When line widths were smaller than 0.5 MUm, nanometer-scale pseudopodia bridged across trench gaps without contacting the bottom surfaces. In contrast, pseudopodia structures covered the entire trench sidewalls and the trench bottom surfaces of comb structures with line-widths larger than 0.5 MUm. Furthermore, results showed that when a single cell simultaneously adhered to multiple surface structures, the portion of the cell contacting each surface reflected the type of morphology observed for cells individually contacting the surfaces. PMID- 30424400 TI - Microfluidic-Based Technique for Measuring RBC Aggregation and Blood Viscosity in a Continuous and Simultaneous Fashion. AB - Hemorheological properties such as viscosity, deformability, and aggregation have been employed to monitor or screen patients with cardiovascular diseases. To effectively evaluate blood circulating within an in vitro closed circuit, it is important to quantify its hemorheological properties consistently and accurately. A simple method for measuring red blood cell (RBC) aggregation and blood viscosity is proposed for analyzing blood flow in a microfluidic device, especially in a continuous and simultaneous fashion. To measure RBC aggregation, blood flows through three channels: the left wide channel, the narrow channel and the right wide channel sequentially. After quantifying the image intensity of RBCs aggregated in the left channel () and the RBCs disaggregated in the right channel (), the RBC aggregation index (AIPM) is obtained by dividing by . Simultaneously, based on a modified parallel flow method, blood viscosity is obtained by detecting the interface between two fluids in the right wide channel. RBC aggregation and blood viscosity were first evaluated under constant and pulsatile blood flows. AIPM varies significantly with respect to blood flow rate (for both its amplitude and period) and the concentration of the dextran solution used. According to our quantitative comparison between the proposed aggregation index (AIPM) and the conventional aggregation index (AICM), it is found that AIPM provides consistent results. Finally, the suggested method is employed to obtain the RBC aggregation and blood viscosity of blood circulating within an in vitro fluidic circuit. The experimental results lead to the conclusion that the proposed method can be successfully used to measure RBC aggregation and blood viscosity, especially in a continuous and simultaneous fashion. PMID- 30424401 TI - Structural Formation of Oil-in-Water (O/W) and Water-in-Oil-in-Water (W/O/W) Droplets in PDMS Device Using Protrusion Channel without Hydrophilic Surface Treatment. AB - This paper presents a simple method of droplet formation using liquids that easily wet polydimethylsiloxane (PDMS) surfaces without any surface treatment. Using only structural features and uniform flow focusing, Oil-in-Water (O/W) and Water-in-Oil-in-Water (W/O/W) droplets were formed in the full PDMS structure. Extrusion channel and three-dimensional flow focusing resulted in effective fluidic conditions for droplet formation and the droplet size could be precisely controlled by controlling the flow rate of each phase. The proposed structure can be utilized as an important element for droplet based research, as well as a droplet generator. PMID- 30424402 TI - Continuous Recirculation of Microdroplets in a Closed Loop Tailored for Screening of Bacteria Cultures. AB - Emerging microfluidic technology has introduced new precision controls over reaction conditions. Owing to the small amount of reagents, microfluidics significantly lowers the cost of carrying a single reaction. Moreover, in two phase systems, each part of a dispersed fluid can be treated as an independent chemical reactor with a volume from femtoliters to microliters, increasing the throughput. In this work, we propose a microfluidic device that provides continuous recirculation of droplets in a closed loop, maintaining low consumption of oil phase, no cross-contamination, stabilized temperature, a constant condition of gas exchange, dynamic feedback control on droplet volume, and a real-time optical characterization of bacterial growth in a droplet. The channels (tubing) and junction cubes are made of Teflon fluorinated ethylene propylene (FEP) to ensure non-wetting conditions and to prevent the formation of biofilm, which is particularly crucial for biological experiments. We show the design and operation of a novel microfluidic loop with the circular motion of microdroplet reactors monitored with optical sensors and precision temperature controls. We have employed the proposed system for long term monitoring of bacterial growth during the antibiotic chloramphenicol treatment. The proposed system can find applications in a broad field of biomedical diagnostics and therapy. PMID- 30424403 TI - Measurement of Carcinoembryonic Antigen in Clinical Serum Samples Using a Centrifugal Microfluidic Device. AB - Carcinoembryonic antigen (CEA) is a broad-spectrum tumor marker used in clinical applications. The primarily clinical method for measuring CEA is based on chemiluminescence in serum during enzyme-linked immunosorbent assays (ELISA) in 96-well plates. However, this multi-step process requires large and expensive instruments, and takes a long time. In this study, a high-throughput centrifugal microfluidic device was developed for detecting CEA in serum without the need for cumbersome washing steps normally used in immunoreactions. This centrifugal microdevice contains 14 identical pencil-like units, and the CEA molecules are separated from the bulk serum for subsequent immunofluorescence detection using density gradient centrifugation in each unit simultaneously. To determine the optimal conditions for CEA detection in serum, the effects of the density of the medium, rotation speed, and spin duration were investigated. The measured values from 34 clinical serum samples using this high-throughput centrifugal microfluidic device showed good agreement with the known values (average relative error = 9.22%). These results indicate that the high-throughput centrifugal microfluidic device could provide an alternative approach for replacing the classical method for CEA detection in clinical serum samples. PMID- 30424404 TI - Liquid Cladding Mediated Optical Fiber Sensors for Copper Ion Detection. AB - We present a label-free optical fiber based sensor device to detect copper ions (Cu2+) in water. A multimode optical fiber, with its polymer cladding removed along a 1-cm length, is used for the optical sensor head, where the injected Cu2+ in the liquid phase acts as a liquid cladding for the optical mode. The various Cu2+ concentrations modulate the numerical aperture (NA) of the liquid cladding waveguide part. The degree of NA mismatch between the liquid cladding and solid cladding guided parts gives rise to an optical power transmittance change, forming the sensing principle. The presented liquid cladding fiber sensor exhibits a minimum resolvable refractive index of 2.48 * 10-6. For Cu2+ detection, we functionalize the sensor head surface (fiber core) using chitosan conjugated ethylenediaminetetraacetic acid (EDTA) which captures Cu2+ effectively due to the enhanced chelating effects. We obtain a limit of detection of Cu2+ of 1.62 nM (104 ppt), which is significantly lower than the tolerable level in drinking water (~30 uM), and achieve a dynamic range of 1 mM. The simple structure of the sensor head and the sensing system ensures the potential capability of being miniaturized. This may allow for in-situ, highly-sensitive, heavy metal sensors in a compact format. PMID- 30424405 TI - A 3D-Printed Millifluidic Platform Enabling Bacterial Preconcentration and DNA Purification for Molecular Detection of Pathogens in Blood. AB - Molecular detection of pathogens in clinical samples often requires pretreatment techniques, including immunomagnetic separation and magnetic silica-bead-based DNA purification to obtain the purified DNA of pathogens. These two techniques usually rely on handling small tubes containing a few millilitres of the sample and manual operation, implying that an automated system encompassing both techniques is needed for larger quantities of the samples. Here, we report a three-dimensional (3D)-printed millifluidic platform that enables bacterial preconcentration and genomic DNA (gDNA) purification for improving the molecular detection of target pathogens in blood samples. The device consists of two millichannels and one chamber, which can be used to preconcentrate pathogens bound to antibody-conjugated magnetic nanoparticles (Ab-MNPs) and subsequently extract gDNA using magnetic silica beads (MSBs) in a sequential manner. The platform was able to preconcentrate very low concentrations (1-1000 colony forming units (CFU)) of Escherichia coli O157:H7 and extract their genomic DNA in 10 mL of buffer and 10% blood within 30 min. The performance of the platform was verified by detecting as low as 1 CFU of E. coli O157:H7 in 10% blood using either polymerase chain reaction (PCR) with post gel electrophoresis or quantitative PCR. The results suggest that the 3D-printed millifluidic platform is highly useful for lowering the limitations on molecular detection in blood by preconcentrating the target pathogen and isolating its DNA in a large volume of the sample. PMID- 30424407 TI - The Use of a Water Soluble Flexible Substrate to Embed Electronics in Additively Manufactured Objects: From Tattoo to Water Transfer Printed Electronics. AB - The integration of electronics into the process flow of the additive manufacturing of 3D objects is demonstrated using water soluble films as a temporary flexible substrate. Three process variants are detailed to evaluate their capabilities to meet the additive manufacturing requirements. One of them, called water transfer printing, shows the best ability to fabricate electronics onto 3D additively manufactured objects. Moreover, a curved capacitive touchpad hidden by color films is successfully transferred onto the 3D objects, showing a potential application of this technology to fabricate fully additively manufactured discrete or even hidden electronic devices. PMID- 30424406 TI - LED Optrode with Integrated Temperature Sensing for Optogenetics. AB - In optogenetic studies, the brain is exposed to high-power light sources and inadequate power density or exposure time can cause cell damage from overheating (typically temperature increasing of 2 ? C). In order to overcome overheating issues in optogenetics, this paper presents a neural tool capable of assessing tissue temperature over time, combined with the capability of electrical recording and optical stimulation. A silicon-based 8 mm long probe was manufactured to reach deep neural structures. The final proof-of-concept device comprises a double-sided function: on one side, an optrode with LED-based stimulation and platinum (Pt) recording points; and, on the opposite side, a Pt based thin-film thermoresistance (RTD) for temperature assessing in the photostimulation site surroundings. Pt thin-films for tissue interface were chosen due to its biocompatibility and thermal linearity. A single-shaft probe is demonstrated for integration in a 3D probe array. A 3D probe array will reduce the distance between the thermal sensor and the heating source. Results show good recording and optical features, with average impedance magnitude of 371 k Omega , at 1 kHz, and optical power of 1.2 mW.mm - 2 (at 470 nm), respectively. The manufactured RTD showed resolution of 0.2 ? C at 37 ? C (normal body temperature). Overall, the results show a device capable of meeting the requirements of a neural interface for recording/stimulating of neural activity and monitoring temperature profile of the photostimulation site surroundings, which suggests a promising tool for neuroscience research filed. PMID- 30424408 TI - A Disposable Blood-on-a-Chip for Simultaneous Measurement of Multiple Biophysical Properties. AB - Biophysical properties are widely used to detect pathophysiological processes of vascular diseases or clinical states. For early detection of cardiovascular diseases, it is necessary to simultaneously measure multiple biophysical properties in a microfluidic environment. However, a microfluidic-based technique for measuring multiple biophysical properties has not been demonstrated. In this study, a simple measurement method was suggested to quantify three biophysical properties of blood, including red blood cell (RBC) deformability, RBC aggregation, and hematocrit. To demonstrate the suggested method, a microfluidic device was constructed, being composed of a big-sized channel (BC), a parallel micropillar (MP), a main channel, a branch channel, inlet, and outlets. By operating a single syringe pump, blood was supplied into the inlet of the microfluidic device, at a periodic on-off profile (i.e., period = 240 s). The RBC deformability index (DI) was obtained by analyzing the averaged blood velocity in the branch channel. Additionally, the RBC aggregation index (AIN) and the hematocrit index (HiBC) were measured by analyzing the image intensity of blood flows in the MP and the BC, respectively. The corresponding contributions of three influencing factors, including the turn-on time (Ton), the amplitude of blood flow rate (Q0), and the hematocrit (Hct) on the biophysical indices (DI, AIN, and HiBC) were evaluated quantitatively. As the three biophysical indices varied significantly with respect to the three factors, the following conditions (i.e., Ton = 210 s, Q0 = 1 mL/h, and Hct = 50%) were maintained for consistent measurement of biophysical properties. The proposed method was employed to detect variations of biophysical properties depending on the concentrations of autologous plasma, homogeneous hardened RBCs, and heterogeneous hardened RBCs. Based on the observations, the proposed method exhibited significant differences in biophysical properties depending on base solutions, homogeneous hardened RBCs (i.e., all RBCs fixed with the same concentration of glutaraldehyde solution), and heterogeneous hardened RBCs (i.e., partially mixed with normal RBCs and homogeneous hardened RBCs). Additionally, the suggested indices (i.e., DI, AIN, and HiBC) were effectively employed to quantify three biophysical properties, including RBC deformability, RBC aggregation, and hematocrit. PMID- 30424409 TI - Genetic Modulation at the Neural Microelectrode Interface: Methods and Applications. AB - The use of implanted microelectrode arrays (MEAs), in the brain, has enabled a greater understanding of neural function, and new treatments for neurodegenerative diseases and psychiatric disorders. Glial encapsulation of the device and the loss of neurons at the device-tissue interface are widely believed to reduce recording quality and limit the functional device-lifetime. The integration of microfluidic channels within MEAs enables the perturbation of the cellular pathways, through defined vector delivery. This provides new approaches to shed light on the underlying mechanisms of the reactive response and its contribution to device performance. In chronic settings, however, tissue ingrowth and biofouling can obstruct or damage the channel, preventing vector delivery. In this study, we describe methods of delivering vectors through chronically implanted, single-shank, "Michigan"-style microfluidic devices, 1-3 weeks, post implantation. We explored and validated three different approaches for modifying gene expression at the device-tissue interface: viral-mediated overexpression, siRNA-enabled knockdown, and cre-dependent conditional expression. We observed a successful delivery of the vectors along the length of the MEA, where the observed expression varied, depending on the depth of the injury. The methods described are intended to enable vector delivery through microfluidic devices for a variety of potential applications; likewise, future design considerations are suggested for further improvements on the approach. PMID- 30424410 TI - Acquisition of Neural Action Potentials Using Rapid Multiplexing Directly at the Electrodes. AB - Neural recording systems that interface with implanted microelectrodes are used extensively in experimental neuroscience and neural engineering research. Interface electronics that are needed to amplify, filter, and digitize signals from multichannel electrode arrays are a critical bottleneck to scaling such systems. This paper presents the design and testing of an electronic architecture for intracortical neural recording that drastically reduces the size per channel by rapidly multiplexing many electrodes to a single circuit. The architecture utilizes mixed-signal feedback to cancel electrode offsets, windowed integration sampling to reduce aliased high-frequency noise, and a successive approximation analog-to-digital converter with small capacitance and asynchronous control. Results are presented from a 180 nm CMOS integrated circuit prototype verified using in vivo experiments with a tungsten microwire array implanted in rodent cortex. The integrated circuit prototype achieves <0.004 mm2 area per channel, 7 uW power dissipation per channel, 5.6 uVrms input referred noise, 50 dB common mode rejection ratio, and generates 9-bit samples at 30 kHz per channel by multiplexing at 600 kHz. General considerations are discussed for rapid time domain multiplexing of high-impedance microelectrodes. Overall, this work describes a promising path forward for scaling neural recording systems to numbers of electrodes that are orders of magnitude larger. PMID- 30424411 TI - Miniaturized NIR Spectrometer Based on Novel MOEMS Scanning Tilted Grating. AB - This paper presents a dispersive near-infrared spectrometer with features of miniaturization, portability and low cost. The application of a resonantly-driven scanning grating mirror (SGM) as a dispersive element in a crossed Czerny-Turner configuration enables the design of a miniaturized spectrometer that can detect the full spectra using only one single InGaAs diode. In addition, a high accuracy recalculation is realized, which can convert time-dependent measurements to spectrum information by utilizing the deflection position detector integrated on SGM and its associated closed-loop control circuit. Finally, the spectrometer prototype is subjected to a series of tests to characterize the instrument's performance fully. The results of the experiment show that the spectrometer works in a spectral range of 800 nm-1800 nm with a resolution of less than 10 nm, a size of 9 * 7 * 7 cm3, a wavelength stability better than +/-1 nm and a measuring time of less than 1 ms. Furthermore, the power consumption of the instrument is 3 W at 5 V DC, and the signal-to-noise ratio is 3267 at full scale. Therefore, this spectrometer could be a potential alternative to classical spectrometers in process control applications or could be used as a portable or airborne spectroscopic sensor. PMID- 30424412 TI - Dynamic Flow Characteristics and Design Principles of Laminar Flow Microbial Fuel Cells. AB - Laminar flow microbial fuel cells (MFCs) are used to understand the role of microorganisms, and their interactions with electrodes in microbial bioelectrochemical systems. In this study, we reported the flow characteristics of laminar flow in a typical MFC configuration in a non-dimensional form, which can serve as a guideline in the design of such microfluidic systems. Computational fluid dynamics simulations were performed to examine the effects of channel geometries, surface characteristics, and fluid velocity on the mixing dynamics in microchannels with a rectangular cross-section. The results showed that decreasing the fluid velocity enhances mixing but changing the angle between the inlet channels, only had strong effects when the angle was larger than 135 degrees . Furthermore, different mixing behaviors were observed depending on the angle of the channels, when the microchannel aspect ratio was reduced. Asymmetric growth of microbial biofilm on the anode side skewed the mixing zone and wall roughness due to the bacterial attachment, which accelerated the mixing process and reduced the efficiency of the laminar flow MFC. Finally, the magnitude of mass diffusivity had a substantial effect on mixing behavior. The results shown here provided both design guidelines, as well as better understandings of the MFCs due to microbial growth. PMID- 30424414 TI - A Novel, Hybrid-Integrated, High-Precision, Vacuum Microelectronic Accelerometer with Nano-Field Emission Tips. AB - In this paper, a novel, hybrid-integrated, high-precision, vacuum microelectronic accelerometer is put forward, based on the theory of field emission; the accelerometer consists of a sensitive structure and an ASIC interface (application-specific integrated circuit). The sensitive structure has a cathode cone tip array, a folded beam, an emitter electrode, and a feedback electrode. The sensor is fabricated on a double-sided polished (1 0 0) N-type silicon wafer; the tip array of the cathode is shaped by wet etching with HNA (HNO3, HF, and CH3COOH) and metalized by TiW/Au thin film. The structure of the sensor is finally released by the ICP (inductively coupled plasma) process. The ASIC interface was designed and fabricated based on the P-JFET (Positive-Junction Field Effect Transistor) high-voltage bipolar process. The accelerometer was tested through a static field rollover test, and the test results show that the hybrid-integrated vacuum microelectronic accelerometer has good performance, with a sensitivity of 3.081 V/g, the non-linearity is 0.84% in the measuring range of 1 g~1 g, the average noise spectrum density value is 36.7 MUV/ Hz in the frequency range of 0-200 Hz, the resolution of the vacuum microelectronic accelerometer can reach 1.1 * 10-5 g, and the zero stability reaches 0.18 mg in 24 h. PMID- 30424413 TI - Amorphous Silicon Carbide Platform for Next Generation Penetrating Neural Interface Designs. AB - Microelectrode arrays that consistently and reliably record and stimulate neural activity under conditions of chronic implantation have so far eluded the neural interface community due to failures attributed to both biotic and abiotic mechanisms. Arrays with transverse dimensions of 10 um or below are thought to minimize the inflammatory response; however, the reduction of implant thickness also decreases buckling thresholds for materials with low Young's modulus. While these issues have been overcome using stiffer, thicker materials as transport shuttles during implantation, the acute damage from the use of shuttles may generate many other biotic complications. Amorphous silicon carbide (a-SiC) provides excellent electrical insulation and a large Young's modulus, allowing the fabrication of ultrasmall arrays with increased resistance to buckling. Prototype a-SiC intracortical implants were fabricated containing 8 - 16 single shanks which had critical thicknesses of either 4 um or 6 um. The 6 um thick a SiC shanks could penetrate rat cortex without an insertion aid. Single unit recordings from SIROF-coated arrays implanted without any structural support are presented. This work demonstrates that a-SiC can provide an excellent mechanical platform for devices that penetrate cortical tissue while maintaining a critical thickness less than 10 um. PMID- 30424415 TI - Enhancement of Virus Infection Using Dynamic Cell Culture in a Microchannel. AB - With increasing interest in induced pluripotent stem cells (iPSCs) in the field of stem cell research, highly efficient infection of somatic cells with virus factors is gaining importance. This paper presents a method of employing microfluidic devices for dynamic cell culture and virus infection in a microchannel. The closed space in the microchannel provided a better environment for viruses to diffuse and contact cell surfaces to infect cells. The microfluidic devices were fabricated by photolithography and soft lithography. NIH/3T3 fibroblast cells were cultured in the microfluidic device in static and dynamic conditions and compared with the conventional culture method of using Petri dishes. Virus infection was evaluated using an enhanced green fluorescent protein virus as a model. Dynamic culture in the microchannel showed similar growth of cells to that in Petri dish culture, but the virus infection efficiency was four-times higher. The proposed dynamic culture system could be useful in iPSC research by providing efficient virus infection tools. PMID- 30424416 TI - Evaluation of Electrovibration Stimulation with a Narrow Electrode. AB - Recently, electrovibration tactile displays were studied and applied to several use cases by researchers. The high-resolution electrode for electrovibration stimulus will contribute to the presentation of a more realistic tactile sensation. However, the sizes of the electrodes that have been used thus far are of the millimeter-order. In this study, we evaluated whether a single narrow electrode was able to provide the electrovibration stimulus adequately. The widths of the prepared electrodes were 10, 20, 50, 100, 200, and 500 MUm. We conducted a sensory experiment to characterize each electrode. The electrodes with widths of 50 MUm or less were not durable or suitable for the applied signal, although the subjects perceived the stimulus. Therefore, we conducted the experiment without using these non-durable electrodes. The voltage waveform condition affected perception, and the subjects were not sensitive to the electrovibration stimulus at low frequencies. In addition, the stroke direction of the fingertip had a significant effect on perception under certain conditions. The results indicate that electrovibration stimulation requires an electrode with a width of only a few hundred micrometers for stimulation. PMID- 30424417 TI - A 0.35-MUm CMOS-MEMS Oscillator for High-Resolution Distributed Mass Detection. AB - This paper presents the design, fabrication, and electrical characterization of an electrostatically actuated and capacitive sensed 2-MHz plate resonator structure that exhibits a predicted mass sensitivity of ~250 pg.cm-2.Hz-1. The resonator is embedded in a fully on-chip Pierce oscillator scheme, thus obtaining a quasi-digital output sensor with a short-term frequency stability of 1.2 Hz (0.63 ppm) in air conditions, corresponding to an equivalent mass noise floor as low as 300 pg.cm-2. The monolithic CMOS-MEMS sensor device is fabricated using a commercial 0.35-MUm 2-poly-4-metal complementary metal-oxide-semiconductor (CMOS) process, thus featuring low cost, batch production, fast turnaround time, and an easy platform for prototyping distributed mass sensors with unprecedented mass resolution for this kind of devices. PMID- 30424418 TI - Surface Finish and Back-Wall Dross Behavior during the Fiber Laser Cutting of AZ31 Magnesium Alloy. AB - Magnesium alloys are of increasing interest in the medical industry due to their biodegradability properties and better mechanical properties as compared to biodegradable polymers. Fiber laser cutting of AZ31 magnesium alloy tubes was carried out to study the effect of cutting conditions on wall surface roughness and back-wall dross. During the experiments, an argon gas chamber was adapted in order to avoid material reactivity with oxygen and thus better control the part quality. A surface response methodology was applied to identify the significance of pulse overlapping and pulse energy. Our results indicate minimum values of surface roughness (Ra < 0.7 MUm) when the spot overlapping is higher than 50%. A back-wall dross range of 0.24% to 0.94% was established. In addition, a reduction in back-wall dross accumulations was obtained after blowing away the dross particles from inside the tube using an argon gas jet, reaching values of 0.21%. Laser cutting experimental models show a quadratic model for back-wall dross related with the interaction of the pulse energy, and a linear model dependent on pulse overlapping factor for surface roughness. PMID- 30424420 TI - Development of a Contactless Air Conveyor System for Transporting and Positioning Planar Objects. AB - In this study, we developed a completely contactless air conveyor system for transporting and positioning planar objects. The air conveyor forms a thin film underneath the object for support and simultaneously generates a controlled airflow that results in viscous traction. It is potentially applicable in the manufacturing process for semiconductor wafer or flat foodstuffs, where mechanical contact is expected to be avoided during transportation of the products to minimize contamination. The air conveyor employs duplicated arrays of actuating cells that are square pockets with a surrounding dam. A simple model is proposed to characterize the viscous force. The theoretical analysis reveals that the total force is the composition of an actuating force generated in the pocket areas and the side areas and a drag force generated in the dam areas. Experimental investigations are conducted on the basic characteristics of the film pressure distribution and the viscous force. The results show that the air film pressure is symmetrically distributed in the width direction but nonsymmetrically distributed in the length direction. The viscous force increases if the suction flow rate is enlarged or the gap thickness is narrowed. Comparison of the experimental results and the calculated results indicates that the model can provide an accurate prediction. A proportional-integral-derivative (PID) controller is applied for 1D-position control and position tracking. The actuating direction is selected using fast switching valves and the amplitude of the actuating force is adjusted using a control valve to vary the suction flow rate. The simulated and the experimental results verify the feasibility of the air conveyor system and the control method. PMID- 30424421 TI - On Frequency-Based Interface Circuits for Capacitive MEMS Accelerometers. AB - Interface circuits for capacitive MEMS accelerometers are conventionally based on charge-based approaches. A promising alternative to these is provided by frequency-based readout techniques that have some unique advantages as well as a few challenges associated with them. This paper addresses these techniques and presents a derivation of the fundamental resolution limits that are imposed on them by phase noise. Starting with an overview of basic operating principles, associated properties and challenges, the discussions then focus on the fundamental trade-offs between noise, power dissipation and signal bandwidth (BW) for the LC-oscillator-based frequency readout and for the conventional charge based switched-capacitor (SC) readout. Closed-form analytical formulas are derived to facilitate a fair comparison between the two approaches. Benchmarking results indicate that, with the same bandwidth requirement, charge-based readout circuits are more suitable when optimizing for noise performance, while there is still some room for frequency-based techniques when optimizing for power consumption, especially when flicker phase noise can be mitigated. PMID- 30424419 TI - Characterization of the Neuroinflammatory Response to Thiol-ene Shape Memory Polymer Coated Intracortical Microelectrodes. AB - Thiol-ene based shape memory polymers (SMPs) have been developed for use as intracortical microelectrode substrates. The unique chemistry provides precise control over the mechanical and thermal glass-transition properties. As a result, SMP substrates are stiff at room temperature, allowing for insertion into the brain without buckling and subsequently soften in response to body temperatures, reducing the mechanical mismatch between device and tissue. Since the surface chemistry of the materials can contribute significantly to the ultimate biocompatibility, as a first step in the characterization of our SMPs, we sought to isolate the biological response to the implanted material surface without regards to the softening mechanics. To accomplish this, we tightly controlled for bulk stiffness by comparing bare silicon 'dummy' devices to thickness-matched silicon devices dip-coated with SMP. The neuroinflammatory response was evaluated after devices were implanted in the rat cortex for 2 or 16 weeks. We observed no differences in the markers tested at either time point, except that astrocytic scarring was significantly reduced for the dip-coated implants at 16 weeks. The surface properties of non-softening thiol-ene SMP substrates appeared to be equally-tolerated and just as suitable as silicon for neural implant substrates for applications such as intracortical microelectrodes, laying the groundwork for future softer devices to improve upon the prototype device performance presented here. PMID- 30424422 TI - Single-Layered Microfluidic Network-Based Combinatorial Dilution for Standard Simplex Lattice Design. AB - In this paper, we presented a straightforward strategy to generate 15 combinations of three samples based on an experimental simplex lattice design using a single-layer microfluidic network. First, we investigated the performances of the plain structural and the groove structural combinatorial devices by computational simulation (CFD-ACE+). The simulated output concentrations were extremely close to the desirable values within an absolute error of less than 1%. Based on the simulated designs, polydimethylsiloxane (PDMS) devices were fabricated with soft lithography and tested with fluorescent dye (sodium salt). The mixing results for 15 combinations showed good performance, with an absolute error of less than 4%. We also investigated two liquid handling methods (bottom-up and top-down) for high-throughput screening and assay. The liquid-handling methods were successfully accomplished by adding the systematic structured groove sets on the mixing channels. PMID- 30424423 TI - Development and Characterization of Non-Evaporable Getter Thin Films with Ru Seeding Layer for MEMS Applications. AB - Mastering non-evaporable getter (NEG) thin films by elucidating their activation mechanisms and predicting their sorption performances will contribute to facilitating their integration into micro-electro-mechanical systems (MEMS). For this aim, thin film based getters structured in single and multi-metallic layered configurations deposited on silicon substrates such as Ti/Si, Ti/Ru/Si, and Zr/Ti/Ru/Si were investigated. Multilayered NEGs with an inserted Ru seed sub layer exhibited a lower temperature in priming the activation process and a higher sorption performance compared to the unseeded single Ti/Si NEG. To reveal the gettering processes and mechanisms in the investigated getter structures, thermal activation effect on the getter surface chemical state change was analyzed with in-situ temperature XPS measurements, getter sorption behavior was measured by static pressure method, and getter dynamic sorption performance characteristics was measured by standard conductance (ASTM F798-97) method. The correlation between these measurements allowed elucidating residual gas trapping mechanism and prediction of sorption efficiency based on the getter surface poisoning. The gettering properties were found to be directly dependent on the different changes of the getter surface chemical state generated by the activation process. Thus, it was demonstrated that the improved sorption properties, obtained with Ru sub-layer based multi-layered NEGs, were related to a gettering process mechanism controlled simultaneously by gas adsorption and diffusion effects, contrarily to the single layer Ti/Si NEG structure in which the gettering behavior was controlled sequentially by surface gas adsorption until reaching saturation followed then by bulk diffusion controlled gas sorption process. PMID- 30424424 TI - Microfabrication of Nonplanar Polymeric Microfluidics. AB - For four decades, microfluidics technology has been used in exciting, state-of the-art applications. This paper reports on a novel fabrication approach in which micromachining is used to create nonplanar, three-dimensional microfluidic chips for experiments. Several parameters of micromachining were examined to enhance the smoothness and definition of surface contours in the nonplanar poly(methyl methacrylate) (PMMA) mold inserts. A nonplanar PMMA/PMMA chip and a nonplanar polydimethylsiloxane (PDMS)/PMMA chip were fabricated to demonstrate the efficacy of the proposed approach. In the first case, a S-shape microchannel was fabricated on the nonplanar PMMA substrate and sealed with another nonplanar PMMA via solvent bonding. In the second case, a PDMS membrane was casted from two nonplanar PMMA substrates and bonded on hemispherical PMMA substrate via solvent bonding for use as a microlens array (MLAs). These examples demonstrate the effectiveness of micromachining in the fabrication of nonplanar microfluidic chips directly on a polymeric substrate, as well as in the manufacture of nonplanar mold inserts for use in creating PDMS/PMMA microfluidic chips. This technique facilitates the creation of nonplanar microfluidic chips for applications requiring a three-dimensional space for in vitro characterization. PMID- 30424425 TI - Universal Testing Apparatus Implementing Various Repetitive Mechanical Deformations to Evaluate the Reliability of Flexible Electronic Devices. AB - A requirement of flexible electronic devices is that they maintain their electrical performance during and after repetitive mechanical deformation. Accordingly, in this study, a universal test apparatus is developed for in-situ electrical conductivity measurements for flexible electrodes that are capable of applying various mechanical deformations such as bending, twisting, shearing, sliding, stretching, and complex modes consisting of two simultaneous deformations. A novel method of deforming the specimen in an arc to induce uniform bending stress in single and alternating directions is also proposed with a mathematically derived control method. As an example of the arc bending method, the changes in the resistance of the printed radio frequency identification (RFID) tag antennas were measured by applying repetitive inner bending, outer bending, and alternating inner-outer bending. After 5000 cycles, the increases in resistance of the specimens that were subjected to inner or outer bending only were under 30%; however, specimens that were subjected to alternating inner-outer bending showed an increase of 135% in resistance. It is critical that the reliability of flexible electronic devices under various mechanical deformations be determined before they can be commercialized. The proposed testing apparatus can readily provide various deformations that will be useful to inform the design of device shapes and structures to accommodate deformations during use. PMID- 30424428 TI - Midwave FTIR-Based Remote Surface Temperature Estimation Using a Deep Convolutional Neural Network in a Dynamic Weather Environment. AB - Remote measurements of thermal radiation are very important for analyzing the solar effect in various environments. This paper presents a novel real-time remote temperature estimation method by applying a deep learning-based regression method to midwave infrared hyperspectral images. A conventional remote temperature estimation using only one channel or multiple channels cannot provide a reliable temperature in dynamic weather environments because of the unknown atmospheric transmissivities. This paper solves the issue (real-time remote temperature measurement with high accuracy) with the proposed surface temperature deep convolutional neural network (ST-DCNN) and a hyperspectral thermal camera (TELOPS HYPER-CAM MWE). The 27-layer ST-DCNN regressor can learn and predict the underlying temperatures from 75 spectral channels. Midwave infrared hyperspectral image data of a remote object were acquired three times a day (10:00, 13:00, 15:00) for 7 months to consider the dynamic weather variations. The experimental results validate the feasibility of the novel remote temperature estimation method in real-world dynamic environments. In addition, the thermal stealth properties of two types of paint were demonstrated by the proposed ST-DCNN as a real-world application. PMID- 30424427 TI - Design Choices for Next-Generation Neurotechnology Can Impact Motion Artifact in Electrophysiological and Fast-Scan Cyclic Voltammetry Measurements. AB - Implantable devices to measure neurochemical or electrical activity from the brain are mainstays of neuroscience research and have become increasingly utilized as enabling components of clinical therapies. In order to increase the number of recording channels on these devices while minimizing the immune response, flexible electrodes under 10 um in diameter have been proposed as ideal next-generation neural interfaces. However, the representation of motion artifact during neurochemical or electrophysiological recordings using ultra-small, flexible electrodes remains unexplored. In this short communication, we characterize motion artifact generated by the movement of 7 um diameter carbon fiber electrodes during electrophysiological recordings and fast-scan cyclic voltammetry (FSCV) measurements of electroactive neurochemicals. Through in vitro and in vivo experiments, we demonstrate that artifact induced by motion can be problematic to distinguish from the characteristic signals associated with recorded action potentials or neurochemical measurements. These results underscore that new electrode materials and recording paradigms can alter the representation of common sources of artifact in vivo and therefore must be carefully characterized. PMID- 30424429 TI - Post-Release Deformation and Motion Control of Photonic Waveguide Beams by Tuneable Electrothermal Actuators in Thick SiO2. AB - Photonic packaging, which includes high-precision assembly of photonic sub systems, is currently a bottleneck in the development of commercially-available integrated photonic products. In the pursuit of a fully-automated, high precision, and cost-effective photonic alignment scheme for two multi-channel photonic chips, this paper explores different designs of the on-chip electrothermal actuators for positioning mechanically-flexible waveguide structures. The final alignment goal is ~100 nm waveguide to waveguide. The on chip actuators, particularly for out-of-plane actuation, are built in a 16 MUm thick SiO 2 photonic-material stack with 5 MUm-thick poly-Si as an electrothermal element. A major challenge of out-of-plane positioning is a 6 MUm height difference of the waveguides to be aligned, due to different built-up material stacks, together with a misalignment tolerance of 1 MUm-2 MUm from the pre assembly (flip-chip) process. Therefore, the bimorph-actuator design needs to compensate this height difference, and provide sufficient motion to align the waveguides. We propose to exploit the post-release deformation of so-called short loop bimorph actuator designs to meet these joint demands. We explore different design variants based on the heater location and the integration of actuator beams with waveguide beams. The actuator design (with 30 MUm poly-Si and 900 MUm SiO 2 in length) has ~8 MUm out-of-plane deflection and is able to generate ~4 MUm motion, which meets the design goal. PMID- 30424426 TI - Microfluidic-Based 3D Engineered Microvascular Networks and Their Applications in Vascularized Microtumor Models. AB - The microvasculature plays a critical role in human physiology and is closely associated to various human diseases. By combining advanced microfluidic-based techniques, the engineered 3D microvascular network model provides a precise and reproducible platform to study the microvasculature in vitro, which is an essential and primary component to engineer organ-on-chips and achieve greater biological relevance. In this review, we discuss current strategies to engineer microvessels in vitro, which can be broadly classified into endothelial cell lining-based methods, vasculogenesis and angiogenesis-based methods, and hybrid methods. By closely simulating relevant factors found in vivo such as biomechanical, biochemical, and biological microenvironment, it is possible to create more accurate organ-specific models, including both healthy and pathological vascularized microtissue with their respective vascular barrier properties. We further discuss the integration of tumor cells/spheroids into the engineered microvascular to model the vascularized microtumor tissue, and their potential application in the study of cancer metastasis and anti-cancer drug screening. Finally, we conclude with our commentaries on current progress and future perspective of on-chip vascularization techniques for fundamental and clinical/translational research. PMID- 30424430 TI - Novel Preparation of Monodisperse Microbubbles by Integrating Oscillating Electric Fields with Microfluidics. AB - Microbubbles generated by microfluidic techniques have gained substantial interest in various industries such as cosmetics, food engineering, and the biomedical field. The microfluidic T-junction provides exquisite control over processing parameters, however, it relies on pressure driven flows only; therefore, bubble size variation is limited especially for viscous solutions. A novel set-up to superimpose an alternating current (AC) oscillation onto a direct current (DC) field is invented in this work, capitalising on the possibility to excite bubble resonance phenomenon and properties, and introducing relevant parameters such as frequency, AC voltage, and waveform to further control bubble size. A capillary embedded T-junction microfluidic device fitted with a stainless steel capillary was utilised for microbubble formation. Furthermore, a numerical model of the T-junction was developed by integrating the volume of fluid (VOF) method with the electric module; simulation results were attained for the formation of the microbubbles with a particular focus on the flow fields along the detachment of the emerging bubble. Two main types of experiments were conducted in this framework: the first was to test the effect of applied AC voltage magnitude and the second was to vary the applied frequency. Experimental results indicated that higher frequencies have a pronounced effect on the bubble diameter within the 100 Hz and 2.2 kHz range, whereas elevated AC voltages tend to promote bubble elongation and growth. Computational results suggest there is a uniform velocity field distribution along the bubble upon application of a superimposed field and that microbubble detachment is facilitated by the recirculation of the dispersed phase. Furthermore, an ideal range of parameters exists to tailor monodisperse bubble size for specific applications. PMID- 30424431 TI - Modelling and Analysis of Characteristics of a Piezoelectric-Actuated Micro-/Nano Compliant Platform Using Bond Graph Approach. AB - The piezoelectric-actuated flexure-based compliant platform is commonly adopted in many fields of micro and nanotechnology. In this paper, bond graph modeling, and kinematic and dynamic characteristics of a piezoelectric-actuated micro-/nano compliant platform system are investigated. During modeling, the bond graph model of the piezoelectric actuator (PZT) is derived by considering both the electrical domain and the mechanical domain. Considering the compliances of flexure hinges and elastic linkages, as well as the input ends, the bond graph model for the bridge-type displacement amplification mechanism in the compliant platform is established by combining pseudo-rigid-body (PRB) model theory and elastic beam theory. Based on the interactions between the PZT subsystem and compliant platform subsystem, the kinematic performance of the proposed compliant platform system is evaluated through both computer simulations and experimental tests. Furthermore, the frequency responses, dynamic responses and load capacity of the compliant platform system are studied. This paper explores a new modeling method for a piezoelectric-actuated compliant platform system, which can provide an effective solution when analyzing the micro-/nano system. PMID- 30424432 TI - Vibration-Assisted Roll-Type Polishing System Based on Compliant Micro-Motion Stage. AB - This paper aims to create a high-quality surface based on the linear contact material removal mechanism. For this paper, a piezo-driven, flexure-based micro motion stage was developed for the vibration-assisted roll-type precision polishing system. Meanwhile, the compliance matrix method was employed to establish the amplification ratio and compliance model of the flexure mechanism. The dimensions of the mechanism were optimized using the grey wolves optimization (GWO) algorithm, aiming to maximize the natural frequencies. Using the optimal parameters, the established models for the mechanical performance evaluation of the flexure stage were verified with the finite-element method. Through closed loop test, it was proven that the proposed micro-motion stage performs well in positioning micro motions. Finally, high quality surface using silicon carbide (SiC) ceramic with 36 nm Sa was generated by the independently developed vibration-assisted roll-type polishing machine to validate the performance of the established polishing system. PMID- 30424434 TI - Shear Mode Bulk Acoustic Resonator Based on Inclined c-Axis AlN Film for Monitoring of Human Hemostatic Parameters. AB - Measurement of hemostatic parameters is essential for patients receiving long term oral anticoagulant agents. In this paper, we present a shear mode bulk acoustic resonator based on an inclined c-axis aluminum nitride (AlN) film for monitoring the human hemostatic parameters. During the blood coagulation process, the resonant frequency of the device decreases along with a step-ladder profile due to the viscosity change during the formation of fibers in blood, revealing the sequential coagulation stages. Two hemostatic parameters with clinical significance, prothrombin time (PT) along with its derived measure of international normalized ratio (INR), are determined from time-frequency curves of the device. Furthermore, the resonator is compared with a commercial coagulometer by monitoring the hemostatic parameters for one month in a patient taking the oral anticoagulant. The results are consistent. In addition, thanks to the excellent potential for integration, miniaturization and the availability of direct digital signals, the proposed device has promising application for point of care coagulation monitoring. PMID- 30424433 TI - Chronic Intracortical Recording and Electrochemical Stability of Thiol ene/Acrylate Shape Memory Polymer Electrode Arrays. AB - Current intracortical probe technology is limited in clinical implementation due to the short functional lifetime of implanted devices. Devices often fail several months to years post-implantation, likely due to the chronic immune response characterized by glial scarring and neuronal dieback. It has been demonstrated that this neuroinflammatory response is influenced by the mechanical mismatch between stiff devices and the soft brain tissue, spurring interest in the use of softer polymer materials for probe encapsulation. Here, we demonstrate stable recordings and electrochemical properties obtained from fully encapsulated shape memory polymer (SMP) intracortical electrodes implanted in the rat motor cortex for 13 weeks. SMPs are a class of material that exhibit modulus changes when exposed to specific conditions. The formulation used in these devices softens by an order of magnitude after implantation compared to its dry, room-temperature modulus of ~2 GPa. PMID- 30424435 TI - Fabrication of a Malaria-Ab ELISA Bioassay Platform with Utilization of Syringe Based and 3D Printed Assay Automation. AB - We report on the fabrication of a syringe-based platform for automation of a colorimetric malaria-Ab assay. We assembled this platform from inexpensive disposable plastic syringes, plastic tubing, easily-obtainable servomotors, and an Arduino microcontroller chip, which allowed for system automation. The automated system can also be fabricated using stereolithography (SLA) to print elastomeric reservoirs (used instead of syringes), while platform framework, including rack and gears, can be printed with fused deposition modeling (FDM). We report on the optimization of FDM and SLA print parameters, as well as post production processes. A malaria-Ab colorimetric test was successfully run on the automated platform, with most of the assay reagents dispensed from syringes. Wash solution was dispensed from an SLA-printed elastomeric reservoir to demonstrate the feasibility of both syringe and elastomeric reservoir-based approaches. We tested the platform using a commercially available malaria-Ab colorimetric assay originally designed for spectroscopic plate readers. Unaided visual inspection of the assay solution color change was sufficient for qualitative detection of positive and negative samples. A smart phone application can also be used for quantitative measurement of the assay color change. PMID- 30424436 TI - Mechanical Fatigue Resistance of Piezoelectric PVDF Polymers. AB - The fatigue resistance of piezoelectric PVDF has been under question in recent years. While some report that a significant degradation occurs after 106 cycles of repeated voltage input, others report that the reported degradation originates from the degraded metal electrodes instead of the piezoelectric PVDF itself. Here, we report the piezoelectric response and remnant polarization of PVDF during 107 cycles of repeated compression and tension, with silver paste-based electrodes to eliminate any electrode effect. After applying repeated tension and compression of 1.8% for 107 times, we do not observe any notable decrease in the output voltage generated by PVDF layers. The results from tension experiments show stable remnant polarization of 5.5 MUC/cm2, however, the remnant polarization measured after repeated compression exhibits a 7% decrease as opposed to the tensed PVDF. These results suggest a possible anisotropic response to stress direction. The phase analyses by Raman spectroscopy reveals no significant change in the phase content, demonstrating the fatigue resistance of PVDF. PMID- 30424437 TI - An Exact Solution for Power-Law Fluids in a Slit Microchannel with Different Zeta Potentials under Electroosmotic Forces. AB - Electroosmotic flow (EOF) is one of the most important techniques in a microfluidic system. Many microfluidic devices are made from a combination of different materials, and thus asymmetric electrochemical boundary conditions should be applied for the reasonable analysis of the EOF. In this study, the EOF of power-law fluids in a slit microchannel with different zeta potentials at the top and bottom walls are studied analytically. The flow is assumed to be steady, fully developed, and unidirectional with no applied pressure. The continuity equation, the Cauchy momentum equation, and the linearized Poisson-Boltzmann equation are solved for the velocity field. The exact solutions of the velocity distribution are obtained in terms of the Appell's first hypergeometric functions. The velocity distributions are investigated and discussed as a function of the fluid behavior index, Debye length, and the difference in the zeta potential between the top and bottom. PMID- 30424438 TI - Unexpected Phase Behavior of Pluronic Polymer-Organic Derivative Mixtures Depending on Temperature in Aqueous Solution. AB - The phase behavior of amphiphilic Pluronic block copolymers in aqueous solution is of importance for a broad spectrum of practical applications but has not been fully exploited yet. Here, the phase behavior of the mixture of the Pluronic P65 and P105 triblock copolymer, (which have the same composition of PEO and PPO but the different molecular weight) and organic derivative, 5-methyl salicylic acid (5mS), in aqueous solution has been investigated by using small angle neutron scattering (SANS). According to the temperature and the 5mS concentration, SANS measurements showed that the P65-5mS mixtures sequentially transform into a random coil, sphere, vesicle, cylinder, and vesicle again, while the P105-5mS mixtures form spherical particles with two different sizes without any topological phase transition. Upon heating, the formation of two different kinds of the vesicle structure of amphiphilic block copolymer in aqueous solution is very unusual. This phase behavior was explained as the coupled effect of the simultaneous increase of the hydrophobicity of the polymer and the solubility of 5mS molecules upon heating. This result gives fundamental information for the practical use of Pluronic polymers in nano- and bio-science and it provides a simple route for the fabrication of the nanostructure without a complicated procedure. PMID- 30424439 TI - A Plasmonic Fiber Based Glucometer and Its Temperature Dependence. AB - We present the plasmonic fiber based optical glucometer. A thin gold layer is coated on clad-free core of multimode optical fiber along 3 cm length to excite surface plasmons at 632.8 nm wavelength. Glucose oxidase is immobilized on the metal surface for glucose sensing. The effective surface refractive index increases by gluconic acid and hydrogen peroxide that are generated upon glucose injection, leading to plasmonic condition change with a consequence of optical power change at the fiber output. We obtain limit of detection of glucose concentration of 6.75 mg/dL, indicating higher sensitivity than the wavelength interrogating SPR glucometer that uses a spectrometer of 1nm spectral resolution. The coefficient of variation is 8.6% at a glucose concentration of 80 mg/dL at room temperature. We also examine the effects of ambient temperature variations from -10 degrees C to 40 degrees C on the performance of the presented sensor and compared them with those on commercially available glucometers that are based on enzyme electrodes. We find that the presented fiber sensor produced standard deviation of 12.1 mg/dL at a glucose concentration of 80 mg/dL under such varying temperature, which is, even without additional temperature correction function, comparable to the commercialized ones. PMID- 30424440 TI - A Novel Electronic Interface for Micromachined Si-Based Photomultipliers. AB - In this manuscript, the authors propose a novel interface for silicon photomultipliers based on a second-generation voltage conveyor as an active element, performing as a transimpedance amplifier. Due to the absence of internal feedback, this solution offers a static bandwidth regardless of the tunable gain level. The simulation results have shown good performances, confirming the possibility of the proposed interface being effectively used in different scenarios. A preliminary hybrid solution has also been developed using second generation current conveyors and measurements conducted on an equivalent discrete elements board, which is promising. PMID- 30424441 TI - Generation of Color Images by Utilizing a Single Composite Diffractive Optical Element. AB - This paper presents an approach that is capable of producing a color image using a single composite diffractive optical element (CDOE). In this approach, the imaging function of a DOE and the spectral deflection characteristics of a grating were combined together to obtain a color image at a certain position. The DOE was designed specially to image the red, green, and blue lights at the same distance along an optical axis, and the grating was designed to overlay the images to an off-axis position. We report the details of the design process of the DOE and the grating, and the relationship between the various parameters of the CDOE. Following the design and numerical simulations, a CDOE was fabricated, and imaging experiments were carried out. Both the numerical simulations and the experimental verifications demonstrated a successful operation of this new approach. As a platform based on coaxial illumination and off-axis imaging, this system is featured with simple structures and no cross-talk of the light fields, which has huge potentials in applications such as holographic imaging. PMID- 30424442 TI - Photolithographic Patterning of Cytop with Limited Contact Angle Degradation. AB - Cytop is a commercially available amorphous fluoropolymer with excellent characteristics including electric insulation, water and oil repellency, chemical resistance, and moisture-proof property, making it an attractive material as hydrophobic layers in electrowetting-on-dielectric (EWOD) devices. However, its highly hydrophobic surface makes it difficult for photoresists to be directly coated on the surface. To pattern Cytop, plasma treatment prior to applying photoresists is required to promote the adhesion between the photoresist and the Cytop coating. This approach inevitably causes hydrophobicity loss in the final EWOD devices. Thus, a damage-reduced recipe for Cytop patterning is urgently needed. In this paper, we first characterized the damage caused by two categories of surface treatment methods: plasma treatment and metal treatment. Parameters such as plasma gas source (Ar/O2), plasma treatment time (0-600 s), metal target (Al/Cu/Cr/Au), metal deposition process (magnetron sputtering or e-beam evaporation) were varied. Film thickness, wettability, and roughness were quantified by ellipsometry measurements, contact angle measurements, and atom force microscope (AFM), respectively. We then evaluated the effectiveness of annealing in damage reduction. Experimental results show that: (1) annealing is necessary in restoring hydrophobicity as well as smoothing surfaces; (2) specified film thickness can be obtained by controlling plasma treatment time; (3) "Ar/O2 plasma treatment + an AZ5214 soft mask + annealing" is a feasible recipe; (4) "an Al/Cu/Cr/Au hard mask + annealing" is feasible as well. PMID- 30424444 TI - Automatic Frequency Tuning Technology for Dual-Mass MEMS Gyroscope Based on a Quadrature Modulation Signal. AB - In order to eliminate the frequency mismatch of MEMS (Microelectromechanical Systems) gyroscopes, this paper proposes a frequency tuning technology based on a quadrature modulation signal. A sinusoidal signal having a frequency greater the gyroscope operating bandwidth is applied to the quadrature stiffness correction combs, and the modulation signal containing the frequency split information is then excited at the gyroscope output. The effects of quadrature correction combs and frequency tuning combs on the resonant frequency of gyroscope are analyzed. The tuning principle based on low frequency input excitation is analyzed, and the tuning system adopting this principle is designed and simulated. The experiments are arranged to verify the theoretical analysis. The wide temperature range test (-20 ? C -60 ? C ) demonstrates the reliability of the tuning system with a maximum mismatch frequency of less than 0.3 Hz. The scale factor test and static test were carried out at three temperature conditions (-20 ? C, room temperature, 60 ? C), and the scale factor, zero-bias instability, and angle random walk are improved. Moreover, the closed-loop detection method is adopted, which improves the scale factor nonlinearity and bandwidth under the premise of maintaining the same static performances compared with the open-loop detection by tuning. PMID- 30424443 TI - Integrity Assessment of a Hybrid DBS Probe that Enables Neurotransmitter Detection Simultaneously to Electrical Stimulation and Recording. AB - Deep brain stimulation (DBS) is a successful medical therapy for many treatment resistant neuropsychiatric disorders such as movement disorders; e.g., Parkinson's disease, Tremor, and dystonia. Moreover, DBS is becoming more and more appealing for a rapidly growing number of patients with other neuropsychiatric diseases such as depression and obsessive compulsive disorder. In spite of the promising outcomes, the current clinical hardware used in DBS does not match the technological standards of other medical applications and as a result could possibly lead to side effects such as high energy consumption and others. By implementing more advanced DBS devices, in fact, many of these limitations could be overcome. For example, a higher channels count and smaller electrode sites could allow more focal and tailored stimulation. In addition, new materials, like carbon for example, could be incorporated into the probes to enable adaptive stimulation protocols by biosensing neurotransmitters in the brain. Updating the current clinical DBS technology adequately requires combining the most recent technological advances in the field of neural engineering. Here, a novel hybrid multimodal DBS probe with glassy carbon microelectrodes on a polyimide thin-film device assembled on a silicon rubber tubing is introduced. The glassy carbon interface enables neurotransmitter detection using fast scan cyclic voltammetry and electrophysiological recordings while simultaneously performing electrical stimulation. Additionally, the presented DBS technology shows no imaging artefacts in magnetic resonance imaging. Thus, we present a promising new tool that might lead to a better fundamental understanding of the underlying mechanism of DBS while simultaneously paving our way towards better treatments. PMID- 30424445 TI - Investigating Tungsten Carbide Micro-Hole Drilling Characteristics by Desktop Micro-ECM with NaOH Solution. AB - Due to their hardness and low tool wear, tungsten carbides are widely used in industrial applications, such as spray nozzles, wire drawing dies and spinning nozzles. However, there is no conventional machining process that is capable of fabricating micro-holes, slots and complicated shapes in tungsten carbide. In this study, a low-cost desktop micro electro-chemical machining (ECM) was developed to investigate the characteristics of tungsten carbide micro-hole drilling. The performance parameters of the machining conditions by desktop micro ECM, such as the machining time, material removal rate, relative tool wear rate, surface quality and dimensional accuracy, were also investigated in this study. The experimental results demonstrate that the low-cost desktop micro-ECM could fabricate micro-holes in the tungsten cemented carbide (WC-Co) workpiece. PMID- 30424446 TI - Size-Dependent and Property-Independent Passive Microdroplet Sorting by Droplet Transfer on Dot Rails. AB - A fully passive microdroplet sorting method is presented in this paper. On the rails with dot patterns, the droplets were sorted in different ways depending on their size. However, the effect of droplet properties on the threshold size of the sorting was eliminated. The droplet positions on two railways and the Laplace pressure of the droplets on the dot patterns allowed selective droplet transfer according to size. Different gaps between the rails altered the threshold size of the transfer. However, the threshold size was independent of the droplet's surface tension and viscosity because the droplet transfer utilized only the droplet position and Laplace pressure without lateral flow to sort targets. This feature has a high potential for bio/chemical applications requiring categorization of droplet targets consisting of various mixtures as pre- or post elements. PMID- 30424447 TI - Thermal Performance of Micro Hotplates with Novel Shapes Based on Single-Layer SiO2 Suspended Film. AB - In this paper, two kinds of suspended micro hotplate with novel shapes of multibeam structure and reticular structure are designed. These designs have a reliable mechanical strength, so they can be designed and fabricated on single layer SiO2 suspended film through a simplified process. Single-layer suspended film helps to reduce power consumption. Based on the new film shapes, different resistance heaters with various widths and thicknesses are designed. Then, the temperature uniformity and power consumption of different micro hotplates are compared to study the effect of these variables and obtain the one with the optimal thermal performance. We report the simulations of temperature uniformity and give the corresponding infrared images in measurement. The experimental temperature differences are larger than those of the simulation. Experimental results show that the lowest power consumption and the minimum temperature difference are 43 mW and 50 degrees C, respectively, when the highest temperature on the suspended platform (240 * 240 MUm2) is 450 degrees C. Compared to the traditional four-beam micro hotplate, temperature non-uniformity is reduced by about 30-50%. PMID- 30424448 TI - Ultrahigh Frequency Ultrasonic Transducers Design with Low Noise Amplifier Integrated Circuit. AB - This paper describes the design of an ultrahigh frequency ultrasound system combined with tightly focused 500 MHz ultrasonic transducers and high frequency wideband low noise amplifier (LNA) integrated circuit (IC) model design. The ultrasonic transducers are designed using Aluminum nitride (AlN) piezoelectric thin film as the piezoelectric element and using silicon lens for focusing. The fabrication and characterization of silicon lens was presented in detail. Finite element simulation was used for transducer design and evaluation. A custom designed LNA circuit is presented for amplifying the ultrasound echo signal with low noise. A Common-source and Common-gate (CS-CG) combination structure with active feedback is adopted for the LNA design so that high gain and wideband performances can be achieved simultaneously. Noise and distortion cancelation mechanisms are also employed in this work to improve the noise figure (NF) and linearity. Designed by using a 0.35 MUm complementary metal oxide semiconductor (CMOS) technology, the simulated power gain of the echo signal wideband amplifier is 22.5 dB at 500 MHz with a capacitance load of 1.0 pF. The simulated NF at 500 MHz is 3.62 dB. PMID- 30424449 TI - Rapid Prototyping of Polymer-Based Rolled-Up Microfluidic Devices. AB - This work presents the simple and rapid fabrication of a polymer-based microfluidic prototype manufactured by rolling up thin films of polymer. The thin films were fabricated via a casting method and rolled up around a center core with the aid of plasma activation to create a three-dimensional (3D) spiral microchannel, hence reducing the time and cost of manufacture. In this work, rolled-up devices with single or dual fluidic networks fabricated from a single or two films were demonstrated for heat sink or heat exchanger applications, respectively. The experimental results show good heat transfer in the rolled-up system at various flow rates for both heat sink and heat exchanger devices, without any leakages. The rolled-up microfluidic system creates multiple curved channels, allowing for the generation of Dean vortices, which in turn lead to an enhancement of heat and mass transfer and prevention of fouling formation. These benefits enable the devices to be employed for many diverse applications, such as heat-transfer devices, micromixers, and sorters. To our knowledge, this work would be the first report on a microfluidic prototype of 3D spiral microchannel made from rolled-up polymeric thin film. This novel fabrication approach may represent the first step towards the development of a pioneering prototype for roll-to-roll processing, permitting the mass production of polymer-based microchannels from single or multiple thin films. PMID- 30424450 TI - Pseudo-Continuous Flow FTIR System for Glucose, Fructose and Sucrose Identification in Mid-IR Range. AB - In this paper, we present a new FTIR-based microfluidic system for Glucose, Fructose and Sucrose detection. The proposed microfluidic system is based on a pseudo-continuous flow coupled to a microscope-FTIR instrument. The detection and characterization of sugar samples were performed by recording their absorption spectrum in the wavelength range 700-1000 cm - 1 of the Mid-IR region. The proposed pseudo-continuous flow system is designed to improve the uniformity of the sample distribution in the analyzed area versus conventional systems. The obtained results for different sugars concentrations, show a very low measurement error of 4.35% in the absorption peak intensity, which is ten times lower than the error obtained using the conventional measurements. PMID- 30424452 TI - Tunnel Encapsulation Technology for Durability Improvement in Stretchable Electronics Fabrication. AB - Great diversity of process technologies and materials have been developed around stretchable electronics. A subset of them, which are made up of zigzag metal foil and soft silicon polymers, show advantages of being easy to manufacture and low cost. However, most of the circuits lack durability due to stress concentration of interconnects entirely embedded in elastic polymer silicone such as polydimethylsiloxane (PDMS). In our demonstration, tunnel encapsulation technology was introduced to relieve stress of these conductors when they were stretched to deform in and out of plane. It was realized by dissolving the medium of Polyvinyl Alcohol (PVA), previous cured together with circuits in polymer, to form the micro-tunnel which not only guarantee the stretchability of interconnect, but also help to improve the durability. With the protection of tunnel, the serpentine could stably maintain the designed shape and electrical performance after 50% strain cycling over 20,000 times. Finally, different materials for encapsulation were employed to provide promising options for applications in portable biomedical devices which demand duplicate distortion. PMID- 30424451 TI - Nanoindentation of Bi2Se3 Thin Films. AB - The nanomechanical properties and nanoindentation responses of bismuth selenide (Bi2Se3) thin films are investigated in this study. The Bi2Se3 thin films are deposited on c-plane sapphire substrates using pulsed laser deposition. The microstructural properties of Bi2Se3 thin films are analyzed by means of X-ray diffraction (XRD). The XRD results indicated that Bi2Se3 thin films are exhibited the hexagonal crystal structure with a c-axis preferred growth orientation. Nanoindentation results showed the multiple "pop-ins" displayed in the loading segments of the load-displacement curves, suggesting that the deformation mechanisms in the hexagonal-structured Bi2Se3 films might have been governed by the nucleation and propagation of dislocations. Further, an energetic estimation of nanoindentation-induced dislocation associated with the observed pop-in effects was made using the classical dislocation theory. PMID- 30424453 TI - Assessing the Reusability of 3D-Printed Photopolymer Microfluidic Chips for Urine Processing. AB - Three-dimensional (3D) printing is emerging as a method for microfluidic device fabrication boasting facile and low-cost fabrication, as compared to conventional fabrication approaches, such as photolithography, for poly(dimethylsiloxane) (PDMS) counterparts. Additionally, there is an increasing trend in the development and implementation of miniaturized and automatized devices for health monitoring. While nonspecific protein adsorption by PDMS has been studied as a limitation for reusability, the protein adsorption characteristics of 3D-printed materials have not been well-studied or characterized. With these rationales in mind, we study the reusability of 3D-printed microfluidics chips. Herein, a 3D printed cleaning chip, consisting of inlets for the sample, cleaning solution, and air, and a universal outlet, is presented to assess the reusability of a 3D printed microfluidic device. Bovine serum albumin (BSA) was used a representative urinary protein and phosphate-buffered solution (PBS) was chosen as the cleaning agent. Using the 3-(4-carboxybenzoyl)quinoline-2-carboxaldehyde (CBQCA) fluorescence detection method, the protein cross-contamination between samples and the protein uptake of the cleaning chip were assessed, demonstrating a feasible 3D-printed chip design and cleaning procedure to enable reusable microfluidic devices. The performance of the 3D-printed cleaning chip for real urine sample handling was then validated using a commercial dipstick assay. PMID- 30424454 TI - Multiple Light Coupling and Routing via a Microspherical Resonator Integrated in a T-Shaped Optical Fiber Configuration System. AB - We demonstrate a three-port, light guiding and routing T-shaped configuration based on the combination of whispering gallery modes (WGMs) and micro-structured optical fibers (MOFs). This system includes a single mode optical fiber taper (SOFT), a slightly tapered MOF and a BaTiO3 microsphere for efficient light coupling and routing between these two optical fibers. The BaTiO3 glass microsphere is semi-immersed into one of the hollow capillaries of the MOF taper, while the single mode optical fiber taper is placed perpendicularly to the latter and in contact with the equatorial region of the microsphere. Experimental results are presented for different excitation and reading conditions through the WGM microspherical resonator, namely, through single mode optical fiber taper or the MOF. The experimental results indicate that light coupling between the MOF and the single mode optical fiber taper is facilitated at specific wavelengths, supported by the light localization characteristics of the BaTiO3 glass microsphere, with spectral Q-factors varying between 4.5 * 103 and 6.1 * 103, depending on the port and parity excitation. PMID- 30424455 TI - Experimental Study of the Influence of Ink Properties and Process Parameters on Ejection Volume in Electrohydrodynamic Jet Printing. AB - Electrohydrodynamic jet (e-jet) printing has very promising applications due to its high printing resolution and material compatibility. It is necessary to know how to choose the printing parameters to get the right ejection volume. The previous scaling law of the ejection volume in e-jet printing borrows the scaling law of the ejection volume of an unstable isolated droplet charged to the Rayleigh limit. The influence of viscosity, applied voltage amplitude, and nozzle to-substrate distance on the ejection volume in e-jet printing was not taken into account in the scaling law. This study investigated the influence of viscosity, conductivity, applied voltage, and nozzle-to-substrate distance on the ejection volume. The ejection volume increases with viscosity and decreases with applied voltage and nozzle-to-substrate distance. The average electric field was kept unchanged while changing the nozzle-to-substrate distance by changing the applied voltage according to the electric field model of a semi-infinite wire perpendicular to an infinite large planar counter electrode. The ejection volume decreases with conductivity as V ~ K - 0.6 , which is different from the previous scaling law, which concludes that V ~ K - 1 . Finally, a model about the relation between the ejection volume and four parameters was established by regression analysis using a third-order polynomial. Two more experiments were done, and the predicted results of the fitted model accorded well with the experiments. The model can be used to choose the ink properties and process parameters to get the right ejection volume. PMID- 30424456 TI - Dual Sacrificial Molding: Fabricating 3D Microchannels with Overhang and Helical Features. AB - Fused deposition modeling (FDM) has become an indispensable tool for 3D printing of molds used for sacrificial molding to fabricate microfluidic devices. The freedom of design of a mold is, however, restricted to the capabilities of the 3D printer and associated materials. Although FDM has been used to create a sacrificial mold made with polyvinyl alcohol (PVA) to produce 3D microchannels, microchannels with free-hanging geometries are still difficult to achieve. Herein, dual sacrificial molding was devised to fabricate microchannels with overhang or helical features in PDMS using two complementary materials. The method uses an FDM 3D printer equipped with two extruders and filaments made of high- impact polystyrene (HIPS) and PVA. HIPS was initially removed in limonene to reveal the PVA mold harboring the design of microchannels. The PVA mold was embedded in PDMS and subsequently removed in water to create microchannels with 3D geometries such as dual helices and multilayer pyramidal networks. The complementary pairing of the HIPS and PVA filaments during printing facilitated the support of suspended features of the PVA mold. The PVA mold was robust and retained the original design after the exposure to limonene. The resilience of the technique demonstrated here allows us to create microchannels with geometries not attainable with sacrificial molding with a mold printed with a single material. PMID- 30424457 TI - Automatic Manipulation of Magnetically Actuated Helical Microswimmers in Static Environments. AB - Electromagnetically actuated microswimmers have been widely used in various biomedical applications due to their minor invasive traits and their easy access to confined environments. In order to guide the microswimmers autonomously towards a target, an obstacle-free path must be computed using path planning algorithms, meanwhile a motion controller must be formulated. However, automatic manipulations of magnetically actuated microswimmers are underdeveloped and still are challenging topics. In this paper, we develop an automatic manipulation system for magnetically actuated helical microswimmers in static environments, which mainly consists of a mapper, a path planner, and a motion controller. First, the mapper processes the captured image by morphological transformations and then labels the free space and the obstacle space. Second, the path planner explores the obstacle-free space to find a feasible path from the start to the goal by a global planning algorithm. Last, the motion controller guides the helical microswimmers along the desired path by a closed-loop algorithm. Experiments are conducted to verify the effectiveness of the proposed automatic manipulation. Furthermore, our proposed approach presents the first step towards applications of microswimmers for targeted medical treatments, such as micromanipulation, targeted therapy, and targeted drug delivery. PMID- 30424458 TI - Controlling Normal Stiffness in Droplet-Based Linear Bearings. AB - While capillary forces are negligible relative to gravity at the macroscale, they provide adequate force to effectively manipulate millimeter to micro meter objects. The fluidic actuation can be accomplished using droplets that also act as bearings. While rotary droplet bearings have been previously demonstrated, this paper addresses the positioning accuracy of a droplet-based bearing consisting of a droplet between a moving plate and a stationary substrate with constrained wetting region under a normal load. Key wetting cases are analyzed using both closed form analytical approximations and numerical simulations. The vertical force and stiffness characteristics are analyzed in relation to the wetting boundaries of the supporting surface. Case studies of different wetting boundaries are presented and summarized. Design strategies are presented for maximizing load carrying capability and stiffness. These results show that controlled wetting and opposing droplet configurations can create much higher stiffness fluidic bearings than simple droplets. PMID- 30424459 TI - Remote Microwave and Field-Effect Sensing Techniques for Monitoring Hydrogel Sensor Response. AB - This paper presents two novel techniques for monitoring the response of smart hydrogels composed of synthetic organic materials that can be engineered to respond (swell or shrink, change conductivity and optical properties) to specific chemicals, biomolecules or external stimuli. The first technique uses microwaves both in contact and remote monitoring of the hydrogel as it responds to chemicals. This method is of great interest because it can be used to non invasively monitor the response of subcutaneously implanted hydrogels to blood chemicals such as oxygen and glucose. The second technique uses a metal-oxide hydrogel field-effect transistor (MOHFET) and its associated current-voltage characteristics to monitor the hydrogel's response to different chemicals. MOHFET can be easily integrated with on-board telemetry electronics for applications in implantable biosensors or it can be used as a transistor in an oscillator circuit where the oscillation frequency of the circuit depends on the analyte concentration. PMID- 30424460 TI - Editorial for the Special Issue on Interface Circuits for Microsensor Integrated Systems. AB - Recent advances in sensing technologies, especially those for Microsensor Integrated Systems, have led to several new commercial applications. [...]. PMID- 30424461 TI - Fabrication and Optimization of High Aspect Ratio Through-Silicon-Vias Electroplating for 3D Inductor. AB - In this study, the filling process of high aspect ratio through-silicon-vias (TSVs) under dense conditions using the electroplating method was efficiently achieved and optimized. Pulsed power was used as the experimental power source and the electroplating solution was prepared with various additive concentrations. Designed control variable experiments were conducted to determine the optimized method. In the control variable experiments, the relationship of multiple experimental variables, including current density (0.25-2 A/dm2), additive concentration (0.5-2 mL/L), and different shapes of TSVs (circle, oral, and square), were systematically analyzed. Considering the electroplating speed and quality, the influence of different factors on experimental results and the optimized parameters were determined. The results showed that increasing current density improved the electroplating speed but decreased the quality. Additives worked well, whereas their concentrations were controlled within a suitable range. The TSV shape also influenced the electroplating result. When the current density was 1.5 A/dm2 and the additive concentration was 1 mL/L, the TSV filling was relatively better. With the optimized parameters, 500-MUm-deep TSVs with a high aspect ratio of 10:1 were fully filled in 20 h, and the via density reached 70/mm2. Finally, optimized parameters were adopted, and the electroplating of 1000-MUm-deep TSVs with a diameter of 100 MUm was completed in 45 h, which is the deepest and smallest through which a three-dimensional inductor has ever been successfully fabricated. PMID- 30424463 TI - A Trace C2H2 Sensor Based on an Absorption Spectrum Technique Using a Mid Infrared Interband Cascade Laser. AB - In this study, tunable diode laser absorption spectroscopy (TDLAS) combined with wavelength modulation spectroscopy (WMS) was used to develop a trace C2H2 sensor based on the principle of gas absorption spectroscopy. The core of this sensor is an interband cascade laser that releases wavelength locks to the best absorption line of C2H2 at 3305 cm-1 (3026 nm) using a driving current and a working temperature control. As the detected result was influenced by 1/f noise caused by the laser or external environmental factors, the TDLAS-WMS technology was used to suppress the 1/f noise effectively, to obtain a better minimum detection limit (MDL) performance. The experimental results using C2H2 gas with five different concentrations show a good linear relationship between the peak value of the second harmonic signal and the gas concentration, with a linearity of 0.9987 and detection accuracy of 0.4%. In total, 1 ppmv of C2H2 gas sample was used for a 2 h observation experiment. The data show that the MDL is low as 1 ppbv at an integration time of 63 s. In addition, the sensor can be realized by changing the wavelength of the laser to detect a variety of gases, which shows the flexibility and practicability of the proposed sensor. PMID- 30424464 TI - Bending Limit Tests for Ultra-Thin Liquid Crystal Polymer Substrate Based on Flexible Microwave Components. AB - In this paper, bending limit tests for one ultra-thin liquid crystal polymer (LCP) substrate (Rogers 3850) based on the mechanical properties of flexible microwave microstrip components are presented. First, a set of 50 Omega microstrip lines, a band-pass filter, and a stepped impedance filter in X-band, are designed by using double clapped LCPs with 50 MUm thickness of substrate and 18 MUm thickness of copper, which is fabricated by conventional photolithography. Then, the limit tests of the flexibility of the LCP microwave microstrip components are presented, and the range of the bending limit radius, from 1 mm to 0.75 mm, is demonstrated from the testing results. It is found that the cause for component failure is fracture of the copper (18 MUm thickness) laminate, according to the bending limit test experiments. Finally, the analysis of the reasons for the collapse of the microwave components, under bending situations, is explored. The results from this work would be useful for further designs of the flexible microwave devices and systems on LCP substrates, with compact sizes and good performance. PMID- 30424462 TI - Tunable Adhesion for Bio-Integrated Devices. AB - With the rapid development of bio-integrated devices and tissue adhesives, tunable adhesion to soft biological tissues started gaining momentum. Strong adhesion is desirable when used to efficiently transfer vital signals or as wound dressing and tissue repair, whereas weak adhesion is needed for easy removal, and it is also the essential step for enabling repeatable use. Both the physical and chemical properties (e.g., moisture level, surface roughness, compliance, and surface chemistry) vary drastically from the skin to internal organ surfaces. Therefore, it is important to strategically design the adhesive for specific applications. Inspired largely by the remarkable adhesion properties found in several animal species, effective strategies such as structural design and novel material synthesis were explored to yield adhesives to match or even outperform their natural counterparts. In this mini-review, we provide a brief overview of the recent development of tunable adhesives, with a focus on their applications toward bio-integrated devices and tissue adhesives. PMID- 30424465 TI - The Progress of PVDF as a Functional Material for Triboelectric Nanogenerators and Self-Powered Sensors. AB - Ever since a new energy harvesting technology, known as a triboelectric nanogenerator (TENG), was reported in 2012, the rapid development of device fabrication techniques and mechanical system designs have considerably made the instantaneous output power increase up to several tens of mW/cm2. With this innovative technology, a lot of researchers experimentally demonstrated that various portable/wearable devices could be operated without any external power. This article provides a comprehensive review of polyvinylidene fluoride (PVDF) based polymers as effective dielectrics in TENGs for further increase of the output power to speed up commercialization of the TENGs, as well as the fundamental issues regarding the materials. In the end, we will also review PVDF based sensors based on the triboelectric and piezoelectric effects of the PVDF polymers. PMID- 30424466 TI - Numerical Demonstration of In-Tube Liquid-Column Migration Driven by Photoisomerization. AB - Droplet manipulation by light-induced isomerization was numerically demonstrated and investigated regarding the driving mechanism. Such a non-invasive manipulation of a droplet in a microchannel can be realized, for example, by the use of watery solution of photoresponsive surfactant that exhibits the isomerization. Due to variable fluid properties between the cis and trans isomers, one-side light irradiation on a liquid column in a tube would lead to some kind of imbalance between the two ends of the liquid column and then drive droplet migration. The present numerical simulations of air-liquid two-phase flow and its scalar transport of the isomer, considering the variable static contact angle, agreed quantitatively with the experimental results in terms of the migration speed. This fact supports the contention that the droplet migration is more likely to be driven by an imbalance in the wettability, or the contact angle. The migration speed was found to be less dependent on the liquid-column length, but proportional to the tube diameter. PMID- 30424467 TI - MagIO: Magnetic Field Strength Based Indoor- Outdoor Detection with a Commercial Smartphone. AB - A wide range of localization techniques has been proposed recently that leverage smartphone sensors. Context awareness serves as the backbone of these localization techniques, which helps them to shift the localization technologies to improve efficiency and energy utilization. Indoor-outdoor (IO) context sensing plays a vital role for such systems, which serve both indoor and outdoor localization. IO systems work with collaborative technologies including the Global Positioning System (GPS), cellular tower signals, Wi-Fi, Bluetooth and a variety of smartphone sensors. GPS- and Wi-Fi-based systems are power hungry, and their accuracy is severed by limiting factors like multipath, shadowing, etc. On the other hand, various built-in smartphone sensors can be deployed for environmental sensing. Although these sensors can play a crucial role, yet they are very less studied. This research aims at investigating the use of ambient magnetic field data alone from a smartphone for IO detection. The research first investigates the feasibility of utilizing magnetic field data alone for IO detection and then extracts different features suitable for IO detection to be used in machine learning-based classifiers to discriminate between indoor and outdoor environments. The experiments are performed at three different places including a subway station, a shopping mall and Yeungnam University (YU), Korea. The training data are collected from one spot of the campus, and testing is performed with data from various locations of the above-mentioned places. The experiment involves Samsung Galaxy S8, LG G6 and Samsung Galaxy Round smartphones. The results show that the magnetic data from smartphone magnetic sensor embody enough information and can discriminate the indoor environment from the outdoor environment. Naive Bayes (NB) outperforms with a classification accuracy of 83.26%, as against Support vector machines (SVM), random induction (RI), gradient boosting machines (GBM), random forest (RF), k-nearest neighbor (kNN) and decision trees (DT), whose accuracies are 67.21%, 73.38%, 73.40%, 78.59%, 69.53% and 68.60%, respectively. kNN, SVM and DT do not perform well when noisy data are used for classification. Additionally, other dynamic scenarios affect the attitude of magnetic data and degrade the performance of SVM, RI and GBM. NB and RF prove to be more noise tolerant and environment adaptable and perform very well in dynamic scenarios. Keeping in view the performance of these classifiers, an ensemble-based stacking scheme is presented, which utilizes DT and RI as the base learners and naive Bayes as the ensemble classifier. This approach is able to achieve an accuracy of 85.30% using the magnetic data of the smartphone magnetic sensor. Moreover, with an increase in training data, the accuracy of the stacking scheme can be elevated by 0.83%. The performance of the proposed approach is compared with GPS-, Wi-Fi- and light sensor-based IO detection. PMID- 30424468 TI - Design and Implementation of a Novel Single-Driven Ultrasonic Elliptical Vibration Assisted Cutting Device. AB - In this paper, a novel single-driven ultrasonic elliptical vibration cutting (SDUEVC) device with a succinct structure and a simple assembly is proposed and investigated. A tailored horn with a tilted-slot structure was employed in the designed SDUEVC device. Also, the elliptical trajectory formation mechanism of the designed SDUEVC device was described by using the theory of mechanical vibration. Furthermore, the finite element method (FEM) was used to optimize the tilted-slot structure parameters and there are four parameters selected as the optimization factors. The results indicated that the proposed SDUEVC device can generate larger vertical amplitude than previous SDUEVC devices, which provides an important and positive effect for the cutting performance of the proposed SDUEVC device. According to the optimized results, a prototype SDUEVC device was fabricated and its vibration characteristic was tested. When the excitation signal voltage was 500 Vp-p, the test results indicated that the amplitudes in the axial and vertical directions were 8.7 MUm and 6.8 MUm, respectively. Furthermore, an elliptical trajectory was generated at the cutting tool tip. Finally, the proposed SDUEVC device was used to fabricate microdimple patterns as the initial application to confirm the feasibility of the proposed SDUEVC device. PMID- 30424471 TI - Single-Blind Placebo-Controlled Response Test with Phenytoin 10% Cream in Neuropathic Pain Patients. AB - BACKGROUND: Phenytoin cream applied topically has been explored in neuropathic pain conditions. In several case series, phenytoin 5% and 10% cream could reduce pain in a clinically relevant way with a fast onset of action within 30 min, and with positive effects on sleep. OBJECTIVE: To evaluate a single-blind placebo controlled response test (SIBRET) for use in clinical practice. MATERIALS AND METHODS: Patients with localized neuropathic pain, having an equal pain intensity in at least 2 areas (e.g., both feet), and a pain intensity of at least 4 on the 11-point numerical rating scale (NRS), were selected to perform the SIBRET. In one area, placebo cream consisting of the base cream was applied, and on the other area, phenytoin 10% cream was applied with separate hands to avoid contamination. Responders were defined as patients who experienced within 30 min at least 2-points difference as scored on the NRS, between the phenytoin 10% and the placebo cream applied areas, in favor of the former. Responders were subsequently prescribed phenytoin 10% cream. RESULTS: Of the 21 patients, 15 patients (71.45%) were classified as responders. The mean pain reduction after 30 min as measured with the NRS in the phenytoin 10% cream area was 3.3 (SD: 1.3) and in the placebo cream area 1.2 (SD: 1.1). The difference of the mean percentage pain reduction between phenytoin 10% cream and placebo cream was 33.2% (SD: 17.6, p < 0.001). Using a 50% reduction on the NRS as a full response criterion, we could identify 57.1% of responders on phenytoin 10% cream and only 9.5% responders on placebo cream. CONCLUSIONS: The SIBRET helps patients and clinicians to quickly identify the appropriate treatment and can thus be seen as an important contributor to the domain of personalized medicine in pain. These results can also be regarded as a proof of principle for the analgesic activity of 10% phenytoin cream. PMID- 30424469 TI - Organs-on-a-Chip Module: A Review from the Development and Applications Perspective. AB - In recent years, ever-increasing scientific knowledge and modern high-tech advancements in micro- and nano-scales fabrication technologies have impacted significantly on various scientific fields. A micro-level approach so-called "microfluidic technology" has rapidly evolved as a powerful tool for numerous applications with special reference to bioengineering and biomedical engineering research. Therefore, a transformative effect has been felt, for instance, in biological sample handling, analyte sensing cell-based assay, tissue engineering, molecular diagnostics, and drug screening, etc. Besides such huge multi functional potentialities, microfluidic technology also offers the opportunity to mimic different organs to address the complexity of animal-based testing models effectively. The combination of fluid physics along with three-dimensional (3-D) cell compartmentalization has sustained popularity as organ-on-a-chip. In this context, simple humanoid model systems which are important for a wide range of research fields rely on the development of a microfluidic system. The basic idea is to provide an artificial testing subject that resembles the human body in every aspect. For instance, drug testing in the pharma industry is crucial to assure proper function. Development of microfluidic-based technology bridges the gap between in vitro and in vivo models offering new approaches to research in medicine, biology, and pharmacology, among others. This is also because microfluidic-based 3-D niche has enormous potential to accommodate cells/tissues to create a physiologically relevant environment, thus, bridge/fill in the gap between extensively studied animal models and human-based clinical trials. This review highlights principles, fabrication techniques, and recent progress of organs-on-chip research. Herein, we also point out some opportunities for microfluidic technology in the future research which is still infancy to accurately design, address and mimic the in vivo niche. PMID- 30424470 TI - A Review of Fast Bubble-Driven Micromotors Powered by Biocompatible Fuel: Low Concentration Fuel, Bioactive Fluid and Enzyme. AB - Micromotors are extensively applied in various fields, including cell separation, drug delivery and environmental protection. Micromotors with high speed and good biocompatibility are highly desirable. Bubble-driven micromotors, propelled by the recoil effect of bubbles ejection, show good performance of motility. The toxicity of concentrated hydrogen peroxide hampers their practical applications in many fields, especially biomedical ones. In this paper, the latest progress was reviewed in terms of constructing fast, bubble-driven micromotors which use biocompatible fuels, including low-concentration fuels, bioactive fluids, and enzymes. The geometry of spherical and tubular micromotors could be optimized to acquire good motility using a low-concentration fuel. Moreover, magnesium- and aluminum-incorporated micromotors move rapidly in water if the passivation layer is cleared in the reaction process. Metal micromotors demonstrate perfect motility in native acid without any external chemical fuel. Several kinds of enzymes, including catalase, glucose oxidase, and ureases were investigated to serve as an alternative to conventional catalysts. They can propel micromotors in dilute peroxide or in the absence of peroxide. PMID- 30424472 TI - Exercise and Redox Status Responses Following Alpha-Lipoic Acid Supplementation in G6PD Deficient Individuals. AB - G6PD deficiency renders cells more susceptible to oxidative insults, while antioxidant dietary supplementation could restore redox balance and ameliorate exercise-induced oxidative stress. To examine the effects of alpha-lipoic acid (ALA) supplementation on redox status indices in G6PD deficient individuals, eight male adults with G6PD deficiency (D) participated in this randomized double blind placebo-controlled crossover trial. Participants were randomly assigned to receive ALA (600 mg/day) or placebo for 4 weeks separated by a 4-week washout period. Before and at the end of each treatment period, participants exercised following an exhaustive treadmill exercise protocol. Blood samples were obtained before (at rest), immediately after and 1h after exercise for later analysis of total antioxidant capacity (TAC), uric acid, bilirubin, thiobarbituric acid reactive substances (TBARS) and protein carbonyls (PC). ALA resulted in significantly increased resting TAC and bilirubin concentrations. Moreover, TAC increased immediately and 1h after exercise following both treatment periods, whereas bilirubin increased immediately after and 1h after exercise following only ALA. No significant change in uric acid, TBARS or PC was observed at any time point. ALA supplementation for 4 weeks may enhance antioxidant status in G6PD individuals; however, it does not affect redox responses to acute exercise until exhaustion or exercise performance. PMID- 30424473 TI - Identification of Potential Key Genes Associated with Adipogenesis through Integrated Analysis of Five Mouse Transcriptome Datasets. AB - Adipose tissue is the most important energy metabolism and secretion organ, and these functions are conferred during the adipogenesis process. However, the cause and the molecular events underlying adipogenesis are still unclear. In this study, we performed integrated bioinformatics analyses to identify vital genes involved in adipogenesis and reveal potential molecular mechanisms. Five mouse high-throughput expression profile datasets were downloaded from the Gene Expression Omnibus (GEO) database; these datasets contained 24 samples of 3T3-L1 cells during adipogenesis, including 12 undifferentiated samples and 12 differentiated samples. The five datasets were reanalyzed and integrated to select differentially expressed genes (DEGs) during adipogenesis via the robust rank aggregation (RRA) method. Functional annotation of these DEGs and mining of key genes were then performed. We also verified the expression levels of some potential key genes during adipogenesis. A total of 386 consistent DEGs were identified, with 230 upregulated genes and 156 downregulated genes. Gene Ontology (GO) analysis showed that the biological functions of the DEGs primarily included fat cell differentiation, lipid metabolic processes, and cell adhesion. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that these DEGs were mainly associated with metabolic pathways, the peroxisome proliferator-activated receptor (PPAR) signaling pathway, regulation of lipolysis in adipocytes, the tumor necrosis factor (TNF) signaling pathway, and the FoxO signaling pathway. The 30 most closely related genes among the DEGs were identified from the protein protein interaction (PPI) network and verified by real-time quantification during 3T3-L1 preadipocyte differentiation. In conclusion, we obtained a list of consistent DEGs during adipogenesis through integrated analysis, which may offer potential targets for the regulation of adipogenesis and treatment of adipose dysfunction. PMID- 30424474 TI - Clinical Outcomes of Monolithic Zirconia Crowns with CAD/CAM Technology. A 1-Year Follow-Up Prospective Clinical Study of 65 Patients. AB - Aim/Purpose: The primary aim of this study was to examine the clinical performance of posterior monolithic single crowns in terms of failure or complications and the secondary aim was to assess the quality of these restorations according to the United States Public Health Service (USPHS) criteria. Methods: Iotan a private dental clinic, 65 patients with need of posterior crowns were restored with monolithic zirconia crowns. All the restorations were evaluated 6 and 12 months after their cementation. The modified United States Public Health Service (USPHS) criteria and periodontal parameters were applied for the clinical evaluation of the crowns. Restorations with Alpha or Bravo rating were considered a success. Results: Descriptive statistics and nonparametric tests were used for statistical analysis. Sixty-five patients (mean age: 49.52) were restored with 65 monolithic zirconia crowns. No fracture of the restorations was recorded. The overall success rate was 98.5%. The clinical quality of all crowns was acceptable except for the marginal discoloration of one crown at the 6- and 12-month follow-up examination. Conclusions: In this study, no fracture of single-tooth monolithic crowns occurred and the success rate was high. Monolithic zirconia restorations fabricated is a viable option for the restoration of single posterior teeth. PMID- 30424475 TI - The Dilemma of Cure and Damage in Oligodendroglioma: Ways to Tip the Balance Away from the Damage. AB - Current treatments for oligodendrogliomas are powerful but have a negative impact on the rest of the body. The bone marrow is damaged by the chemotherapeutics, but other parts of the body are also affected. In this paper, the current treatment method and its collateral damage is described. Therefore, therapies are needed that are more effective against the tumor while having less negative effects on the patient's quality of life. Some potential therapies include optimal removal of the tumor by fluorescent-guided surgery (FGS), intraoperative desorption electrospray ionization-mass spectrometry (DESI-MS), better monitoring of the effects of therapy by pseudo-coloring shades of gray of MRI pictures, and using recent data from RNA sequencing of single cells and immunotherapy. These are all open new ways of treating this tumor. The RNA sequencing of single tumor cells unravels specific tumor antigens present in the differentiation status of the cancer cell. Stem cell antigens were expressed in dividing cells, while hypoxia inducible factor-alpha (HIF-1alpha) is expressed in all tumor cells. Cancer stem cell antigens can be loaded on dendritic cells to induce cytotoxic T-cells directed to cancer stem cells. These recent discoveries suggest a better quality of life with the same overall survival. PMID- 30424476 TI - AMP-Activated Protein Kinase as a Key Trigger for the Disuse-Induced Skeletal Muscle Remodeling. AB - Molecular mechanisms that trigger disuse-induced postural muscle atrophy as well as myosin phenotype transformations are poorly studied. This review will summarize the impact of 5' adenosine monophosphate -activated protein kinase (AMPK) activity on mammalian target of rapamycin complex 1 (mTORC1)-signaling, nuclear-cytoplasmic traffic of class IIa histone deacetylases (HDAC), and myosin heavy chain gene expression in mammalian postural muscles (mainly, soleus muscle) under disuse conditions, i.e., withdrawal of weight-bearing from ankle extensors. Based on the current literature and the authors' own experimental data, the present review points out that AMPK plays a key role in the regulation of signaling pathways that determine metabolic, structural, and functional alternations in skeletal muscle fibers under disuse. PMID- 30424477 TI - CRISPR/Cas9 for Cancer Therapy: Hopes and Challenges. AB - Cancer is the second leading cause of death globally and remains a major economic and social burden. Although our understanding of cancer at the molecular level continues to improve, more effort is needed to develop new therapeutic tools and approaches exploiting these advances. Because of its high efficiency and accuracy, the CRISPR-Cas9 genome editing technique has recently emerged as a potentially powerful tool in the arsenal of cancer therapy. Among its many applications, CRISPR-Cas9 has shown an unprecedented clinical potential to discover novel targets for cancer therapy and to dissect chemical-genetic interactions, providing insight into how tumours respond to drug treatment. Moreover, CRISPR-Cas9 can be employed to rapidly engineer immune cells and oncolytic viruses for cancer immunotherapeutic applications. Perhaps more importantly, the ability of CRISPR-Cas9 to accurately edit genes, not only in cell culture models and model organisms but also in humans, allows its use in therapeutic explorations. In this review, we discuss important considerations for the use of CRISPR/Cas9 in therapeutic settings and major challenges that will need to be addressed prior to its clinical translation for a complex and polygenic disease such as cancer. PMID- 30424478 TI - Characteristics of Indoor PM2.5 Concentration in Gers Using Coal Stoves in Ulaanbaatar, Mongolia. AB - Coal combustion in ger areas is the main source of ambient air pollution in Ulaanbaatar (Mongolia). This study determined the characteristics of indoor PM2.5 concentrations in gers using coal stoves during winter. The study population consisted of 60 gers in the Chingeltei district of Ulaanbaatar. The indoor particle number concentration (PNC) in each ger was measured using a Dylos DC1700 particle counter for 24 h in January and February 2016. The PNC by Dylos was converted into the mass concentration using a calibration equation developed using a collocated real-time light scattering monitor adjusted by gravimetric measurement. The average 24 h PM2.5 concentration was 203.9 +/- 195.1 MUg/m3 in gers with traditional stoves (n = 29) and 257.5 +/- 204.4 MUg/m3 in those with improved stoves (n = 31). In the daily profile, concentrations were lower at night, increased in the early morning, and peaked up to noon. The temperature in gers was slightly higher than that recommended in winter. Many development assistance programs have supported the installation of improved energy-efficient stoves. Better control measures are needed to improve the indoor air quality of gers. PMID- 30424479 TI - Solid Phase Extraction Purification of Saliva Samples for Antipsychotic Drug Quantitation. AB - Saliva is far less popular as a diagnostic material than blood. This has resulted in a lack of procedures for the sampling and handling of saliva, e.g., effective ways to purify endogenous compounds from saliva to enable a simultaneous determination of xenobiotics such as neuroleptics. Therefore, the aim of this study was to develop an analytical procedure to purify saliva samples so that it is then possible to simultaneously determine five neuroleptics (aripiprazole, clozapine, olanzapine, quetiapine and risperidone) and the antiepileptic drug carbamazepine, and their respective metabolites (dehydroaripiprazole, N desmethylclozapine, N-demethylolanzapine, norquetiapine, 9-OH-risperidone and carbamazepine-10,11-epoxide). A study of three types of solid-phase extraction (SPE) columns showed that the purest eluates were obtained using columns containing ion exchange sorbent. The sorbents were first washed with water then with a mixture of water and methanol (1:1), and the adsorbed residue was eluted with a 5% ammonia solution in methanol. Saliva samples for SPE were diluted with 2% formic acid and a mixture of methanol and water (1:1). This procedure was developed to purify a saliva sample spiked with a mixture of neuroleptics and carbamazepine, and their respective metabolites. A chromatographic analysis confirmed the isolation of all compounds, indicating that this procedure can be used in further development and validation for a method designed to monitor the levels of neuroleptic drugs in saliva and to monitor their uptake by patients. PMID- 30424480 TI - QTL Mapping Reveals the Relationship between Pasting Properties and Malt Extract in Barley. AB - Pasting properties are important characteristics of barley starch from a processing standpoint. Many studies reported the close relationship between pasting properties and malting quality, especially malt extract. However, most conclusions were derived from the correlation between pasting properties and malting quality using a set of cultivars or breeding lines. In this study, a doubled haploid population of 150 lines from a cross between a Japanese malting barley and a Chinese feed barley was grown in four different environments (two sites * two years). Based on average values from all different environments, 17 significant quantitative trait loci (QTL) were identified for pasting properties. The genetic variance explained by these QTL varied from 7.0 to 23.2%. Most QTL controlling pasting properties were located on 1H, 2H, 5H, and 7H. Results confirmed the linkage between pasting properties and malt extract, with most of the QTL for pasting properties becoming nonsignificant when using malt extract as a covariate. Breakdown showed the closest correlation with malt extract. Molecular markers closely linked to the QTL can be used to select desired pasting properties to improve malting quality. PMID- 30424481 TI - Special Issue on Mechanisms of Mesothelioma Heterogeneity: Highlights and Open Questions. AB - This editorial aims to synthesize the eleven papers that have contributed to this special issue, where the mechanisms of mesothelioma heterogeneity have been tackled from different angles. PMID- 30424482 TI - Effect of New Zealand Blackcurrant Extract on Physiological Responses at Rest and during Brisk Walking in Southeast Asian Men: A Randomized, Double-Blind, Placebo Controlled, Crossover Study. AB - New Zealand blackcurrant (NZBC) extract affects cardiovascular and metabolic responses during rest and exercise in Caucasian men. Ethnicity and nutritional habits may affect responses to nutritional ergogenic aids. We examined the effects of NZBC extract on cardiovascular, metabolic, and physiological responses during seated rest and moderate-intensity exercise in Southeast Asian men. Seventeen healthy Thai men (age: 22 +/- 3 years; body mass index (BMI): 21.8 +/- 1.1 kg.m-2) participated. Resting metabolic equivalent (1-MET) was measured (OxyconTM mobile, Germany), and an incremental walking protocol was completed to establish the relationship between walking speed and MET. In a double-blind, randomized, placebo-controlled, crossover design, cardiovascular (Physioflow, n = 12) and physiological responses (Oxycon, n = 17) were measured during both seated rest and a 30-min treadmill walk at five metabolic equivalent (5-MET), with either a seven-day intake of placebo (PL) or two capsules of NZBC extract (each 300 mg capsule contains 35% blackcurrant extract) with a 14-day washout. Paired t tests were used with significance accepted at p < 0.05 and a trend for 0.05 > p <= 0.10. During 30 min of treadmill walking at 5-MET, no differences were observed for heart rate and substrate oxidation. With intake of NZBC during treadmill walking, there was a trend for increased stroke volume by 12% (PL: 83.2 +/- 25.1; NZBC: 93.0 +/- 24.3 mL; p = 0.072) and cardiac output increased by 12% (PL: 9.2 +/- 2.6; NZBC: 10.3 +/- 2.8 L.min-1; p = 0.057). Systemic vascular resistance decreased by 10% (PL: 779 +/- 267; NZBC: 697 +/- 245 dyn.s.cm-5; p = 0.048). NZBC extract had no effect on metabolic, physiological, and cardiovascular parameters during seated rest and exercise-induced fat oxidation in Thai men, in contrast to observations in Caucasian men. During treadmill walking, Thai men showed cardiovascular response, indicating vasodilatory effects during moderate-intensity exercise with the intake of NZBC extract. Our findings suggest that the ergogenic responses to anthocyanin intake from New Zealand blackcurrant may be ethnicity-dependent. PMID- 30424483 TI - On the Performance of an Aerosol Electrometer with Enhanced Detection Limit. AB - An aerosol electrometer with enhanced detection limit was developed for measuring the collected particles electrical current ranging from -50 pA to 50 pA with no range switching necessary. The detection limit was enhanced by suppressing the electric current measurement noise and improving the detection efficiency. A theoretical model for the aerosol electrometer has been established to investigate the noise effect factors and verified experimentally. The model showed that the noise was a function of ambient temperature, and it was affected by the characteristics of feedback resistor and operational amplifier simultaneously. The Faraday cup structure of the aerosol electrometer was optimized by adopting a newly designed cup-shaped metal filter which increased the surface area of the cup; thus the particle interception efficiency was improved. The aerosol electrometer performance-linearity, noise and the particle detection efficiency, were evaluated experimentally. When compared with TSI 3068B, a 99.4% ( R 2 ) statistical correlation was achieved. The results also showed that the root mean square noise and the peak-to-peak noise were 0.31 fA and 1.55 fA, respectively. The particle detection efficiency was greater than 99.3% when measuring particle diameter larger than 7.0 nm. PMID- 30424484 TI - Pathogenic Viruses Commonly Present in the Oral Cavity and Relevant Antiviral Compounds Derived from Natural Products. AB - Many viruses, such as human herpesviruses, may be present in the human oral cavity, but most are usually asymptomatic. However, if individuals become immunocompromised by age, illness, or as a side effect of therapy, these dormant viruses can be activated and produce a variety of pathological changes in the oral mucosa. Unfortunately, available treatments for viral infectious diseases are limited, because (1) there are diseases for which no treatment is available; (2) drug-resistant strains of virus may appear; (3) incomplete eradication of virus may lead to recurrence. Rational design strategies are widely used to optimize the potency and selectivity of drug candidates, but discovery of leads for new antiviral agents, especially leads with novel structures, still relies mostly on large-scale screening programs, and many hits are found among natural products, such as extracts of marine sponges, sea algae, plants, and arthropods. Here, we review representative viruses found in the human oral cavity and their effects, together with relevant antiviral compounds derived from natural products. We also highlight some recent emerging pharmaceutical technologies with potential to deliver antivirals more effectively for disease prevention and therapy. PMID- 30424485 TI - Deep Profiling of the Aggregated Proteome in Alzheimer's Disease: From Pathology to Disease Mechanisms. AB - Hallmarks of Alzheimer's disease (AD), a progressive neurodegenerative disease causing dementia, include protein aggregates such as amyloid beta plaques and tau neurofibrillary tangles in a patient's brain. Understanding the complete composition and structure of protein aggregates in AD can shed light on the as yet unidentified underlying mechanisms of AD development and progression. Biochemical isolation of aggregates coupled with mass spectrometry (MS) provides a comprehensive proteomic analysis of aggregates in AD. Dissection of these AD specific aggregate components, such as U1 small nuclear ribonucleoprotein complex (U1 snRNP), provides novel insights into the deregulation of RNA splicing in the disease. In this review, we summarize the methodologies of laser capture microdissection (LCM) and differential extraction to analyze the aggregated proteomes in AD samples, and discuss the derived novel insights that may contribute to AD pathogenesis. PMID- 30424486 TI - Paraquat-Mediated Oxidative Stress in Anopheles gambiae Mosquitoes Is Regulated by An Endoplasmic Reticulum (ER) Stress Response. AB - Paraquat is a potent superoxide (O2-)-inducing agent that is capable of inducing an oxidative imbalance in the mosquito midgut. This oxidative imbalance can super stress the malaria parasite, leading to arrested development in the mosquito midgut and reduced transmission. While several studies have explored the effect of paraquat on malaria parasites, a fundamental understanding of the mosquito response to this compound remains unknown. Here, we quantified the mosquito midgut proteomic response to a paraquat-laced sugar meal, and found that An. gambiae midguts were enriched in proteins that are indicative of cells under endoplasmic reticulum (ER) stress. We also carried out qRT-PCR analyses for nine prominent thioredoxin (Trx) and glutathione (GSH)-dependent genes in mosquito midguts post P. falciparum blood meal ingestion to evaluate the concordance between transcripts and proteins under different oxidative stress conditions. Our data revealed an absence of significant upregulation in the Trx and GSH-dependent genes following infected blood meal ingestion. These data suggest that the intrinsic tolerance of the mosquito midgut to paraquat-mediated oxidative stress is through an ER stress response. These data indicate that mosquitoes have at least two divergent pathways of managing the oxidative stress that is induced by exogenous compounds, and outline the potential application of paraquat-like drugs to act selectively against malaria parasite development in mosquito midguts, thereby blocking mosquito-to-human transmission. PMID- 30424487 TI - White-Light Emitting Di-Ureasil Hybrids. AB - White-light emitting materials have emerged as important components for solid state lighting devices with high potential for the replacement of conventional light sources. Herein, amine-functionalized organic-inorganic di-ureasil hybrids consisting of a siliceous skeleton and oligopolyether chains codoped with lanthanide-based complexes, with Eu3+ and Tb3+ ions and 4,4'-oxybis(benzoic acid) and 1,10-phenanthroline ligands, and the coumarin 1 dye were synthesized by in situ sol-gel method. The resulting luminescent di-ureasils show red, green, and blue colors originated from the Eu3+, Tb3+, and C1 emissions, respectively. The emission colors can be modulated either by variation of the relative concentration between the emitting centers or by changing the excitation wavelength. White light emission is achieved under UV excitation with absolute quantum yields of 0.148 +/- 0.015, 0.167 +/- 0.017, and 0.202 +/- 0.020 at 350, 332, and 305 nm excitation, respectively. The emission mechanism was investigated by photoluminescence and UV-visible absorption spectroscopy, revealing an efficient energy transfer from the organic ligands to the Ln3+ ions and the organic dye, whereas negligible interaction between the dopants is discerned. The obtained luminescent di-ureasils have potential for optoelectronic applications, such as in white-light emitting diodes. PMID- 30424488 TI - Comparative Study on Conductive Knitted Fabric Electrodes for Long-Term Electrocardiography Monitoring: Silver-Plated and PEDOT:PSS Coated Fabrics. AB - Long-term monitoring of the electrical activity of the heart helps to detect the presence of potential dysfunctions, enabling the diagnosis of a wide range of cardiac pathologies. However, standard electrodes used for electrocardiogram (ECG) acquisition are not fully integrated into garments, and generally need to be used with a gel to improve contact resistance. This article is focused on the development of washable screen-printed cotton, with and without Lycra, textile electrodes providing a medical quality ECG signal to be used for long-term electrocardiography measurements. Several samples with different Poly(3,4 ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) concentrations were investigated. Silver-plated knitted fabric electrodes were also used for comparison, within the same process of ECG signal recording. The acquisition of ECG signals carried out by a portable medical device and a low-coast Arduino based device on one female subject in a sitting position. Three textile electrodes were placed on the right and left forearms and a ground electrode was placed on the right ankle of a healthy female subject. Plastic clamps were applied to maintain electrodes on the skin. The results obtained with PEDOT:PSS used for electrodes fabrication have been presented, considering the optimal concentration required for medical ECG quality and capacity to sustain up to 50 washing cycles. All the ECG signals acquired and recorded, using PEDOT:PSS and silver-plated electrodes, have been reviewed by a cardiologist in order to validate their quality required for accurate diagnosis. PMID- 30424489 TI - Aircraft-Assisted Pilot Suicides in the General Aviation Increased for One-Year Period after 11 September 2001 Attack in the United States. AB - Pilot aircraft-assisted suicides (AAS) are rare, and there is limited understanding of copycat phenomenon among aviators. The aim of this study was to evaluate the possible effect the 11 September 2001, terrorist attacks had on pilot AASs in the U.S. Fatal aviation accidents in the National Transportation Safety Board (NTSB) database were searched using the following search words: "suicide", "murder-suicide" and "homicide-suicide". The timeline between 11 September 1996, and 11 September 2004, was analyzed. Only those accidents in which NTSB judged that the cause of the accident was suicide were included in the final analysis. The relative risk (RR) of the pilot AASs in all fatal accidents in the U.S. was calculated in order to compare the one, two, and three-year periods after the September 11 terrorist attacks with five years preceding the event. The RR of a fatal general aviation aircraft accident being due to pilot suicide was 3.68-fold (95% confidence interval 1.04-12.98) during the first year after 11 September 2001, but there was not a statistically significant increase in the later years. This study showed an association, albeit not determinate causal effect, of a very specific series of simultaneous terrorist murder suicides with subsequent pilot AASs. PMID- 30424490 TI - Enhanced Ferroelectric and Piezoelectric Properties of (1-x)PMN-xPT Ceramics Based on a Partial Oxalate Process. AB - The pyrochlore phase in ferroelectric and piezoelectric materials is the main obstacle device application due to its poor electrical properties. Especially, the pyrochlore phase is frequently observed in the perovskite-based metal-oxide materials including piezoelectric and ferroelectric ceramics, which are based on solid-state reaction methods for fabrication. To overcome these problems, advanced innovative methods such as partial oxalate process will be investigated. In this method, crystalized magnesium niobite (MN) and lead titanate (PT) powders will be coated with a certain amount of lead oxalate and, then, the calcination process can be carried out to form the PMN-PT without pyrochlore phase. In this study, (1-x)PMN-xPT ceramics near the morphotropic phase boundary (MPB), with compositions of x = 0.25-0.40, have been prepared employing the partial oxalate method at various temperatures. The crystalline, microstructure, and piezoelectric properties of (1-x)PMN-xPT ceramics depending on the sintering temperature were intensively investigated and discussed. By optimizing the sintering temperature and compositions from the PMN-PT ceramics, the maximum value of the piezoelectric charge coefficient (d33) of 665pC/N, planar electromechanical coupling factor (kp) of 77.8%, dielectric constant (epsilonr) of 3230, and remanent polarization (Pr) of 31.67 MUC/cm2 were obtained. PMID- 30424491 TI - Incidence, Risk Factors, and Outcomes of Arterial Thromboembolism in Patients with Pancreatic Cancer Following Palliative Chemotherapy. AB - BACKGROUND: Few studies have explored the association between pancreatic cancer and arterial thromboembolism (aTE). METHODS: A total of 838 consecutive patients receiving palliative chemotherapy for pancreatic cancer between 2010 and 2016 were retrospectively enrolled. The clinical characteristics of patients were analyzed to determine the incidence, risk factors, and survival outcome of aTE in patients with pancreatic cancer. RESULTS: aTE occurred in 42 (5.0%) of 838 patients. Patients with aTE had a worse survival outcome than those without (5.1 months versus 7.8 months, hazard ratio 1.53, 95% confidence interval [CI]: 1.12 2.09). Stage IV disease, high aspartate transaminase level, and comorbidity with hypertension or atrial fibrillation were four independent predictors of aTE. A concise predictive model stratified patients into low (0-1 predictor), intermediate (2 predictors), and high (3-4 predictors) risk groups. The hazard ratios for the comparison of patients in intermediate and high risk groups with those in low risk group were 4.55 (95% CI: 2.31-8.98), and 13.3 (95% CI: 5.63 31.6), respectively. CONCLUSION: Patients with pancreatic cancer undergoing palliative chemotherapy have an increased risk of aTE. A predictive model showed that patients presented with 3 or 4 predictors had the highest risk for developing aTE. PMID- 30424492 TI - Effects of the Application of a Program of Adapted Utilitarian Judo (JUA) on the Fear of Falling Syndrome (FOF) for the Health Sustainability of the Elderly Population. AB - This research analyzes the fall history of a group of elderly people and studies the effects of an intervention program based on Adapted Utilitarian Judo (JUA) to teach fall control in subjects with fear of falling syndrome (FOF). We adopted a quasi-experimental research design with pre-post measurement of the experimental group, in a healthy, pre-fragile sample of 12 women aged 71.5 +/- 8 years, chosen using non-probabilistic-incidental accessibility sampling. The WHO questionnaire was used for the functional assessment of the fall. To evaluate FOF, we applied the 16-item version of the Falls Efficacy Scale-International (FES-I), (pretest and posttest). This intervention program was based on Adapted Utilitarian Judo and conducted over 8 weeks, with two 60-minute sessions each week. After analyzing the scores obtained by the subjects in the pre and post FES-I, we found that the intervention with the JUA program had been significant for the experimental group with p <= 0.004, and there was an 11.9% decrease in the fear of falling (FES-I pos = 18.17). The results show that after the application of the JUA program there were significant improvements in subjects' perception of FOF, with this being greater in those who had the highest levels of fear of falling before the intervention. PMID- 30424494 TI - Synthesis of Ge1-xSnx Alloy Thin Films by Rapid Thermal Annealing of Sputtered Ge/Sn/Ge Layers on Si Substrates. AB - In this work, nanocrystalline Ge1-xSnx alloy formation from a rapid thermal annealed Ge/Sn/Ge multilayer has been presented. The multilayer was magnetron sputtered onto the Silicon substrate. This was followed by annealing the layers by rapid thermal annealing, at temperatures of 300 degrees C, 350 degrees C, 400 degrees C, and 450 degrees C, for 10 s. Then, the effect of thermal annealing on the morphological, structural, and optical characteristics of the synthesized Ge1-xSnx alloys were investigated. The nanocrystalline Ge1-xSnx formation was revealed by high-resolution X-ray diffraction (HR-XRD) measurements, which showed the orientation of (111). Raman results showed that phonon intensities of the Ge-Ge vibrations were improved with an increase in the annealing temperature. The results evidently showed that raising the annealing temperature led to improvements in the crystalline quality of the layers. It was demonstrated that Ge-Sn solid-phase mixing had occurred at a low temperature of 400 degrees C, which led to the creation of a Ge1-xSnx alloy. In addition, spectral photo-responsivity of a fabricated Ge1-xSnx metal-semiconductor-metal (MSM) photodetector exhibited its extending wavelength into the near-infrared region (820 nm). PMID- 30424493 TI - Nutrient Supplement Use among the Chinese Population: A Cross-Sectional Study of the 2010-2012 China Nutrition and Health Surveillance. AB - Nutrient supplements play a key role in managing malnutrition/chronic diseases and are commonly used in the world, but few studies described the prevalence of nutrient supplement use at the national level in China. To our knowledge, this study provides the first detailed investigation of nutrient supplement use in a nationally representative sample of the Chinese population. This study aimed to describe the prevalence of the nutrient supplement use among the Chinese population aged 6 years or older in 2010-2012. A stratified multistage cluster sampling method was conducted to recruit participants from 150 surveillance sites. The demographic characteristics and information about nutrient supplement use were collected through an interview-administrative questionnaire. A total of 74,501 children and adults (excluding the pregnant women) were included in the study (mean age, 35.7 years; male, 47.0%, female, 53.5%). Only 0.71% of the participants reported using nutrient supplements in the previous month. Participants aged 6-11 years and 60 years and above, female, living in large urban, with higher education level and higher family incomes were more likely to use nutrient supplements than their counterparts (p < 0.05). The prevalence of nutrient supplement use increased with age in Chinese adults. The highest usage among the nutrient supplements was multi-vitamins and minerals with 0.37%. More females used single vitamin, multi-mineral, multi-vitamins and minerals than males (p < 0.05). The nutrient supplement use proportion was highest amongst the participants with a health problem, and the participants who had no idea about their health conditions were the least likely to use the nutrient supplements (p < 0.05). The prevalence of nutrient supplement use was low among the Chinese population in 2010-2012. Further research is required to understand the social cognition, usage reasons, dosage and consumption motivation of NS, and the relationships with health effects, to ensure that the nutrient supplements can be appropriately promoted in China. PMID- 30424495 TI - Chokeberry Extract and Its Active Polyphenols Suppress Adipogenesis in 3T3-L1 Adipocytes and Modulates Fat Accumulation and Insulin Resistance in Diet-Induced Obese Mice. AB - Berries of Aronia melanocarpa (chokeberry) are known to be a rich source of biologically active polyphenols. In the present study, the effects of seven anti adipogenic polyphenolic phytochemicals isolated from A. melanocarpa methanol extract on adipogenic transcription factors were investigated. Amygdalin and prunasin were found to inhibit 3T3-L1 adipocyte differentiation by suppressing the expressions of PPARgamma (peroxisome proliferator-activated receptor gamma), C/EBPalpha (CCAAT/enhancer binding protein alpha), SREBP1c (sterol regulatory element binding protein 1c), FAS (fatty acid synthase), and aP2 (adipocyte fatty acid-binding protein). A. melanocarpa extract-treated (100 or 200 mg/kg/day on body weight) high fat diet (HFD)-induced obese mice showed significant decreases in body weight, serum triglyceride (TG), and low-density lipoprotein cholesterol (LDLC) levels and improved insulin sensitivity as compared with HFD controls. This research shows A. melanocarpa extract is potentially beneficial for the suppression of HFD-induced obesity. PMID- 30424496 TI - Levels of Physical Activity in Lithuanian Adolescents. AB - BACKGROUND AND OBJECTIVE: Population levels of physical activity are an international concern. The purpose of the present study was to describe and analyse physical activity levels in Lithuanian adolescents. MATERIALS AND METHODS: With this aim in mind, the Physician-based Assessment and Counselling for Exercise (PACE) questionnaire was administered to 5141 adolescents residing in Lithuania, 2502 boys (48.7%) and 2639 girls (51.3%), aged between 11 and 19 years. RESULTS: It was found that adolescents studied met the physical activity guideline, of 60 min of moderate-to-vigorous physical activity a day, on average 3.6 days/week (SD = 2.1). A total of 3426 adolescents (66.6%) were inactive as classified by the PACE questionnaire (at least 1 h of physical activity/day < 5 days/week). In the present sample there were more active (at least 1 h of physical activity/day >= 5 days/week) boys (n = 994, 39.7%) than girls (n = 721, 27.3%) (p < 0.001; OR 1.75, 95% CI 1.56 to 1.97), and, on average, boys were more likely to meet daily recommendations of physical activity than girls, 0.7 days more a week (p < 0.001; IRRs 1.21, 95% CI 1.17 to 1.25). According to age, younger adolescents (11-12 years) were significantly more active than older adolescents (13-19 years) and a curvilinear relationship between age and physical activity was observed with significant linear (unstandardized beta (B) = -0.807; standardized beta (beta) = -0.796; p < 0.001) and quadratic terms (unstandardized beta (B) = 0.024; standardized beta (beta) = 0.704; p < 0.001). CONCLUSIONS: It is necessary to increase the level of physical activity in Lithuanian adolescents and intervention programs should be carried out considering these results. PMID- 30424497 TI - Spread of an Experimental Salmonella Derby Infection in Antibiotic-Treated or Lawsonia intracellularis Vaccinated Piglets. AB - Lawsonia intracellularis infections are a common reason for antibiotic treatment in pig production. Experimental studies in animals naturally infected with Lawsonia intracellularis comparing the course of an experimental Salmonella infection in piglets previously treated with tylosin or vaccinated against Lawsonia intracellularis are scarce. A total of 72 seven-week-old Salmonella-free pigs were taken from a herd with a Lawsonia intracellularis history in piglet rearing. The pigs were divided into two groups with three replicates each. Animals had either been previously treated with tylosin (10 mg/kg body weight) for seven days (AB+VAC-) or had been vaccinated as suckling pigs by drenching (Enterisol(r)Ileitis; AB-VAC+). Two animals per replicate were primarily infected with Salmonella Derby (1.04 * 108 colony-forming units per animal). The detection of Salmonella in faeces (p < 0.0001, odds ratio: 3.8364) and in the ileocaecal lymph nodes (p = 0.0295, odds ratio: 3.5043) was significantly more frequent in AB+VAC- animals. Overall, the odds ratio for detecting Salmonella in any substrate or organ was significantly higher in the AB+VAC- group animals (p = 0.0004, odds ratio: 5.9091). Treatment with tylosin can significantly increase the spread of a Salmonella infection, which is not observed after early Lawsonia intracellularis vaccination. PMID- 30424498 TI - Serum Renalase Levels Are Predicted by Brain-Derived Neurotrophic Factor and Associated with Cardiovascular Events and Mortality after Percutaneous Coronary Intervention. AB - Circulating brain-derived neurotrophic factor (BDNF) predicts survival rate in patients with coronary artery disease (CAD). We examined the relationship between BDNF and renalase before and after percutaneous coronary intervention (PCI) and the role of renalase in patients with CAD. Serum BDNF and renalase levels were determined using blood samples collected before and after PCI. Incident myocardial infarction, stroke, and mortality were followed up longitudinally. A total of 152 patients completed the assessment. BDNF levels were not significantly changed after PCI compared to baseline levels (24.7 +/- 11.0 vs. 23.5 +/- 8.3 ng/mL, p = 0.175), although renalase levels were significantly reduced (47.5 +/- 17.3 vs. 35.9 +/- 11.3 ng/mL, p < 0.001). BDNF level before PCI was an independent predictor of reduction in renalase (95% confidence interval (CI): -1.371 to -0.319). During a median 4.1 years of follow-up, patients with serum renalase levels of >=35 ng/mL had a higher risk of myocardial infarction, stroke, and death than those with renalase of <35 ng/mL (hazard ratio = 5.636, 95% CI: 1.444-21.998). In conclusion, our results show that serum BDNF levels before PCI were inversely correlated with the percentage change in renalase levels after PCI. Nevertheless, post-PCI renalase level was a strong predictor for myocardial infarction, stroke, and death. PMID- 30424499 TI - Metal Organic Frameworks Based Materials for Heterogeneous Photocatalysis. AB - The increase in environmental pollution due to the excessive use of fossil fuels has prompted the development of alternative and sustainable energy sources. As an abundant and sustainable energy, solar energy represents the most attractive and promising clean energy source for replacing fossil fuels. Metal organic frameworks (MOFs) are easily constructed and can be tailored towards favorable photocatalytic properties in pollution degradation, organic transformations, CO2 reduction and water splitting. In this review, we first summarize the different roles of MOF materials in the photoredox chemical systems. Then, the typical applications of MOF materials in heterogeneous photocatalysis are discussed in detail. Finally, the challenges and opportunities in this promising field are evaluated. PMID- 30424500 TI - Alien Species and Human Health: Austrian Stakeholder Perspective on Challenges and Solutions. AB - No saturation in the introduction, acceleration of spread and the increasing impacts of alien species are a characteristic feature of the Anthropocene. Concomitantly, alien species affecting human health are supposed to increase, mainly due to increasing global trade and climate change. In this study, we assess challenges and solutions posed by such species to the public health sector in Austria over the next few decades. We did so using an online questionnaire circulated to 131 experts and stakeholders working on human health and biological invasions, supplemented by in-depth interviews with eleven selected experts. Results from the online survey and in-depth interviews largely support and complement each other. Experts and stakeholders suggest that (i) the allergenic Ambrosia artemisiifolia (common ragweed), the photodermatoxic Heracleum mantegazzianum (giant hogweed), and vectors of diseases such as Aedes albopictus (Asian tiger mosquito) are considered the alien species posing the most severe challenges; (ii) challenges are expected to increase in the next few decades and awareness in the public health sector is not sufficient; (iii) effective and efficient solutions are mainly related to prevention. Specific solutions include pathway management of introduction and spread by monitoring and controlling established populations of ragweed, hogweed and mosquitos. PMID- 30424501 TI - Optimized Chitosan/Anion Polyelectrolyte Complex Based Inserts for Vaginal Delivery of Fluconazole: In Vitro/In Vivo Evaluation. AB - (1) Background: Fluconazole, used orally for vaginal candidiasis, has reported gastrointestinal side effects. Therefore, researchers directed towards the drug vaginal delivery. However, vaginal delivery is limited by poor retention and leakage. Thus, this work aimed at exploring chitosan/anion polyelectrolyte complex (PEC) for the formulation of fluconazole vaginal inserts with controlled release and appreciable mucoadhesion. (2) Methods: PECs were prepared and assessed for interactions. Fluconazole PEC based vaginal inserts were prepared by lyophilization using mannitol. 3151 factorial design was applied to investigate the effect of the anion type and Chitosan/anion ratio on the inserts mucoadhesion and release properties. The optimized insert [based on 5:5 chitosan: anionic polymer (sodium alginate)] release was modulated by the release retardant; Compritol(r) 888. The selected formulation was subjected to microbiological and histological evaluation. (3) Results: Fluconazole inserts showed satisfactory drug content, acceptable friability percentages and highest swelling indices at six hours. Statistical analysis showed significant effect of the studied factors on detachment force and release properties. Microbiological assays revealed significantly higher antifungal activity of inserts compared to fluconazole solution. Reduced inflammatory cells were confirmed by histological evaluation. (4) Conclusion: CH/Alg based vaginal insert could be a promising platform for vaginal delivery of antifungal drugs used for vaginal candidiasis treatment. PMID- 30424502 TI - Effects of Red Ginseng Extract on the Pharmacokinetics and Elimination of Methotrexate via Mrp2 Regulation. AB - We aimed to investigate the effects of red ginseng extract (RGE) on the expression of efflux transporters and to study the pharmacokinetics of representative substrate. For this, rats received single or repeated administration of RGE (1.5 g/kg/day) for 1 and 2 weeks via oral gavage. mRNA and protein levels of multidrug resistance-associated protein2 (Mrp2), bile salt export pump (Bsep), and P-glycoprotein (P-gp) in the rat liver were measured via real-time polymerase chain reaction and Western blot analysis. Ginsenosides concentrations from the rat plasma were also monitored using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) system. Plasma concentrations of ginsenoside Rb1, Rb2, Rc, and Rd following repeated administration of RGE for 1 and 2 weeks were comparable but significantly higher than those after single administration of RGE. These dosing regimens did not induce significant biochemical abnormalities in the liver, kidneys, and lipid homeostasis. In the RGE repeated oral administration groups, the mRNA and protein levels of Mrp2 significantly decreased. Accordingly, we investigated the changes in the pharmacokinetics of methotrexate, a probe substrate for Mrp2, following intravenous administration of 3 mg/kg methotrexate to rats in the RGE 1-week repeated oral administration group, compared to that in the control group. Biliary excretion, but not urinary excretion, of methotrexate decreased in the RGE repeated administration group, compared to that in the control group. Consequently, the plasma concentrations of methotrexate slightly increased in the RGE repeated administration group. In conclusion, repeated administration of RGE for 1 week resulted in a decrease in Mrp2 expression without inducing significant liver or kidney damage. Pharmacokinetic herb-drug interaction between RGE and methotrexate might occur owing to the decrease in the mRNA and protein levels of Mrp2. PMID- 30424503 TI - Development and Application of an Atmospheric Pollutant Monitoring System Based on LoRa-Part I: Design and Reliability Tests. AB - At present, as growing importance continues to be attached to atmospheric environmental problems, the demand for real-time monitoring of these problems is constantly increasing. This article describes the development and application of an embedded system for monitoring of atmospheric pollutant concentrations based on LoRa (Long Range) wireless communication technology, which is widely used in the Internet of Things (IoT). The proposed system is realized using a combination of software and hardware and is designed using the concept of modularization. Separation of each function into independent modules allows the system to be developed more quickly and to be applied more stably. In addition, by combining the requirements of the remote atmospheric pollutant concentration monitoring platform with the specific requirements for the intended application environment, the system demonstrates its significance for practical applications. In addition, the actual application data also verifies the sound application prospects of the proposed system. PMID- 30424504 TI - Factors Associated with Cervical Cancer Screening among Married Female Immigrants with Korean Husbands in South Korea. AB - Background. The purpose of this study was to identify factors associated with the national cervical cancer screening behaviors of married female immigrants living in South Korea. Methods. The present study dataset was collected by the National Health Insurance Services in 2014-2015. A final study population of 15,935 was considered eligible for inclusion in this study if they met the criteria for participation in the national cervical cancer screening program in 2014-2015. Results. Of the 15,935 subjects, 7837 (49%) participated in cervical cancer screening. Based on the results of the logistic regression analysis of the association between cervical cancer screening behaviors and related factors, the odds ratio (OR) for participation in cervical cancer screening among individuals older than 50 years was the highest (OR: 2.13; 95% confidence interval (CI): 1.82 2.51), and the OR increased as their duration of stay in South Korea decreased. The OR of Chinese women for cervical cancer screening participation was higher than that of non-Chinese women (OR: 1.83; 95% CI: 1.69-1.99). The OR value was 29.4 (95% CI: 25.9-33.3) among those who participated in the general health screening compared with those who did not participate. Conclusions. To improve awareness about cervical cancer screening and reduce disparities in access to healthcare, appropriate programs should be developed to promote cervical cancer screening participation to socially vulnerable classes. Continuous social attention is needed to address these issues and encourage participation in general health screening to improve the rate of cervical cancer screening. PMID- 30424505 TI - Effects of Royal Jelly Administration on Endurance Training-Induced Mitochondrial Adaptations in Skeletal Muscle. AB - We investigated the effect of royal jelly (RJ), a natural secretion from worker bees, on the endurance training-induced mitochondrial adaptations in skeletal muscles of ICR mice. Mice received either RJ (1.0 mg/g body weight) or distilled water for three weeks. The mice in the training group were subjected to endurance training (20 m/min; 60 min; 5 times/week). There was a main effect of endurance training on the maximal activities of the mitochondrial enzymes, citrate synthase (CS), and beta-hydroxyacyl coenzyme Adehydrogenase (beta-HAD), in the plantaris and tibialis anterior (TA) muscles, while no effect of RJ treatment was observed. In the soleus muscle, CS and beta-HAD maximal activities were significantly increased by endurance training in the RJ-treated group, while there was no effect of training in the control group. Furthermore, we investigated the effects of acute RJ treatment on the signaling cascade involved in mitochondrial biogenesis. In the soleus, phosphorylation of 5'-AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) were additively increased by a single RJ treatment and endurance exercise, while only an exercise effect was found in the plantaris and TA muscles. These results indicate that the RJ treatment induced mitochondrial adaptation with endurance training by AMPK activation in the soleus muscles of ICR mice. PMID- 30424506 TI - Rapid Simultaneous Determination of Paraquat and Creatinine in Human Serum Using a Piece of Paper. AB - Paraquat intoxication is characterized by acute kidney injury and multi-organ failure, causing substantial mortality and morbidity. This study aims to develop a 2-in-1 paper-based analytical device to detect the concentrations of paraquat and creatinine in human serum, which can help clinicians diagnose patients with paraquat poisoning in a more rapid and geographically unrestricted manner. The procedure involves fabrication of a paper-based analytical device, i.e., printing of design on a filter paper, heating of wax-printed micro zone plates so as molten wax diffusing into and completely through the paper to the other side, forming hydrophobic boundaries that could act as detection zones for the paraquat colorimetric assay, and finally analysis using ImageJ software. The paper employed a colorimetric sodium dithionite assay to indicate the paraquat level in a buffer or human serum system in less than 10 min. In this study, colorimetric changes into blue color could be observed by the naked eye. By curve fitting models of sodium dithionite in normal human serum, we evaluated the serum paraquat levels for five paraquat patients. In the sodium dithionate assay, the measured serum paraquat concentrations in patients 1-5 were 22.59, 5.99, 26.52, 35.19 and 25.00 ppm, respectively. On the other hand, by curve fitting models of the creatinine assay in normal human serum, the measured serum creatinine concentrations were 16.10, 12.92, 13.82, 13.58 and 12.20 ppm, respectively. We found that the analytical performance of this device can compete with the standard of Clinical Laboratory of Chang Gung Memorial Hospital, with a less complicated sample preparation process and more rapid results. In conclusion, this 2-in-1 paper-based analytical device has the advantage of being simple and cheap, enabling rapid detection of paraquat intoxication as well as assessment of renal prognosis. PMID- 30424507 TI - Effect of Plyometric Training on Speed and Change of Direction Ability in Elite Field Hockey Players. AB - This study investigated the effects of two plyometric training protocols on sprint and change of direction (COD) performance in elite hockey players. A parallel-group randomized controlled trial design was used and seventeen elite male and female field hockey players were randomly allocated into either low-to high (L-H, n = 8) or high-to-low (H-L, n = 9) training groups. Each group performed separate variations of the drop jump exercise twice weekly for six weeks, with an emphasis on either jump height (L-H) or drop height (H-L). Performance variables assessed included sprint times over 10 m and 20 m, as well as 505 time. A two-way repeated measures analysis of variance was performed and Cohen's d effect sizes (ESs) were calculated. The H-L group displayed a significant small ES improvement from baseline to post-training in the 10 m sprint (1.893 +/- 0.08 s pre vs. 1.851 +/- 0.06 s post) (ES = -0.44) (p < 0.05). Differences between groups for 10 m and 20 m sprint performance failed to reach statistical significance, and no significant differences were observed within or between groups for 505 time. These findings highlight the difficulty in substantially enhancing speed and COD ability in highly trained athletic populations through the addition of a low volume, short duration plyometric training protocol. PMID- 30424508 TI - IL-24 Promotes Apoptosis through cAMP-Dependent PKA Pathways in Human Breast Cancer Cells. AB - Interleukin 24 (IL-24) is a tumor-suppressing protein, which inhibits angiogenesis and induces cancer cell-specific apoptosis. We have shown that IL-24 regulates apoptosis through phosphorylated eukaryotic initiation factor 2 alpha (eIF2alpha) during endoplasmic reticulum (ER) stress in cancer. Although multiple stresses converge on eIF2alpha phosphorylation, the cellular outcome is not always the same. In particular, ER stress-induced apoptosis is primarily regulated through the extent of eIF2alpha phosphorylation and activating transcription factor 4 (ATF4) action. Our studies show for the first time that cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) activation is required for IL-24-induced cell death in a variety of breast cancer cell lines and this event increases ATF4 activity. We demonstrate an undocumented role for PKA in regulating IL-24-induced cell death, whereby PKA stimulates phosphorylation of p38 mitogen-activated protein kinase and upregulates extrinsic apoptotic factors of the Fas/FasL signaling pathway and death receptor 4 expression. We also demonstrate that phosphorylation and nuclear import of tumor suppressor TP53 occurs downstream of IL-24-mediated PKA activation. These discoveries provide the first mechanistic insights into the function of PKA as a key regulator of the extrinsic pathway, ER stress, and TP53 activation triggered by IL-24. PMID- 30424509 TI - Isolated Mammillary Bodies Damage-An Atypical Presentation of Wernicke Syndrome. AB - We report atypical magnetic resonance imaging (MRI) lesions in a case of Wernicke encephalopathy. The patient presented with isolated anterograde amnesia following a partial colectomy complicated by peritonitis. Fluid-attenuated inversion recovery and T2 MRI sequences were normal. However, bilateral contrast enhancement of mammillary bodies was shown on T1 gadolinium-enhanced sequences. Blood tests revealed thiamine deficiency. The diagnosis of Wernicke encephalopathy was made and thiamine supplementation was given, resulting in complete recovery of the memory functions. PMID- 30424510 TI - Electrical Characteristics and pH Response of a Parylene-H Sensing Membrane in a Si-Nanonet Ion-Sensitive Field-Effect Transistor. AB - We report the electrical characteristics and pH responses of a Si-nanonet ion sensitive field-effect transistor with ultra-thin parylene-H as a gate sensing membrane. The fabricated device shows excellent DC characteristics: a low subthreshold swing of 85 mV/dec, a high current on/off ratio of ~107 and a low gate leakage current of ~10-10 A. The low interface trap density of 1.04 * 1012 cm-2 and high field-effect mobility of 510 cm2V-1s-1 were obtained. The pH responses of the devices were evaluated in various pH buffer solutions. A high pH sensitivity of 48.1 +/- 0.5 mV/pH with a device-to-device variation of ~6.1% was achieved. From the low-frequency noise characterization, the signal-to-noise ratio was extracted as high as ~3400 A/A with the lowest noise equivalent pH value of ~0.002 pH. These excellent intrinsic electrical and pH sensing performances suggest that parylene-H can be promising as a sensing membrane in an ISFET-based biosensor platform. PMID- 30424511 TI - Are There Non-Responders to the Ergogenic Effects of Caffeine Ingestion on Exercise Performance? AB - I have read with interest the recent review paper by Southward and colleagues [...]. PMID- 30424512 TI - Identifying Free-Living Physical Activities Using Lab-Based Models with Wearable Accelerometers. AB - The purpose of this study was to classify, and model various physical activities performed by a diverse group of participants in a supervised lab-based protocol and utilize the model to identify physical activity in a free-living setting. Wrist-worn accelerometer data were collected from ( N = 152 ) adult participants; age 18-64 years, and processed the data to identify and model unique physical activities performed by the participants in controlled settings. The Gaussian mixture model (GMM) and the hidden Markov model (HMM) algorithms were used to model the physical activities with time and frequency-based accelerometer features. An overall model accuracy of 92.7% and 94.7% were achieved to classify 24 physical activities using GMM and HMM, respectively. The most accurate model was then used to identify physical activities performed by 20 participants, each recorded for two free-living sessions of approximately six hours each. The free living activity intensities were estimated with 80% accuracy and showed the dominance of stationary and light intensity activities in 36 out of 40 recorded sessions. This work proposes a novel activity recognition process to identify unsupervised free-living activities using lab-based classification models. In summary, this study contributes to the use of wearable sensors to identify physical activities and estimate energy expenditure in free-living settings. PMID- 30424513 TI - Characterizing Longitudinal Changes in the Impedance Spectra of In-Vivo Peripheral Nerve Electrodes. AB - Characterizing the aging processes of electrodes in vivo is essential in order to elucidate the changes of the electrode-tissue interface and the device. However, commonly used impedance measurements at 1 kHz are insufficient for determining electrode viability, with measurements being prone to false positives. We implanted cohorts of five iridium oxide (IrOx) and six platinum (Pt) Utah arrays into the sciatic nerve of rats, and collected the electrochemical impedance spectroscopy (EIS) up to 12 weeks or until array failure. We developed a method to classify the shapes of the magnitude and phase spectra, and correlated the classifications to circuit models and electrochemical processes at the interface likely responsible. We found categories of EIS characteristic of iridium oxide tip metallization, platinum tip metallization, tip metal degradation, encapsulation degradation, and wire breakage in the lead. We also fitted the impedance spectra as features to a fine-Gaussian support vector machine (SVM) algorithm for both IrOx and Pt tipped arrays, with a prediction accuracy for categories of 95% and 99%, respectively. Together, this suggests that these simple and computationally efficient algorithms are sufficient to explain the majority of variance across a wide range of EIS data describing Utah arrays. These categories were assessed over time, providing insights into the degradation and failure mechanisms for both the electrode-tissue interface and wire bundle. Methods developed in this study will allow for a better understanding of how EIS can characterize the physical changes to electrodes in vivo. PMID- 30424515 TI - Poly(Urethane-Acrylate) Aerogels via Radical Polymerization of Dendritic Urethane Acrylate Monomers. AB - The purpose of this work was to investigate the effect of multifunctionality on material properties of synthetic polymer aerogels. For this purpose, we present the synthesis and characterization of monolithic dendritic-type urethane-acrylate monomers based on an aliphatic/flexible (Desmodur N3300), or an aromatic/rigid (Desmodur RE) triisocyanate core. The terminal acrylate groups (three at the tip of each of the three branches, nine in total) were polymerized with 2,2' azobis(isobutyronitrile) (AIBN) via free radical chemistry. The resulting wet gels were dried with supercritical fluid (SCF) CO2. Aerogels were characterized with ATR-FTIR and solid-state 13C NMR. The porous network was probed with N2 sorption and scanning electron microscopy (SEM). The thermal stability of aerogels was studied with thermogravimetric analysis (TGA). Most aerogels were macroporous materials (porosity > 80%), with high thermal stability (up to 300 degrees C). Aerogels were softer at low monomer concentrations and more rigid at higher concentrations. The material properties were compared with those of analogous aerogels bearing only one acrylate moiety at the tip of each branch and the same cores, and with those of analogous aerogels bearing norbornene instead of acrylate moieties. The nine-terminal acrylate-based monomers of this study caused rapid decrease of the solubility of the growing polymer and made possible aerogels with much smaller particles and much higher surface areas. For the first time, aliphatic/flexible triisocyanate-based materials could be made with similar properties in terms of particle size and surface areas to their aromatic/rigid analogues. Finally, it was found that with monomers with a high number of crosslinkable groups, material properties are determined by multifunctionality and thus aerogels based on 9-acrylate- and 9-norbornene-terminated monomers were similar. Materials with aromatic cores are carbonizable with satisfactory yields (20-30% w/w) to mostly microporous materials (BET surface areas: 640-740 m2 g-1; micropore surface areas: 360-430 m2 g-1). PMID- 30424514 TI - Oral Adjuvant Curcumin Therapy for Attaining Clinical Remission in Ulcerative Colitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - Curcumin has demonstrated anti-inflammatory properties and has been investigated as an adjuvant therapy of ulcerative colitis (UC). The scope of this study was to systematically review and meta-analyze the efficacy of oral curcumin administration as an adjuvant therapy of UC. MEDLINE, Cochrane/CENTRAL, ClinicalTrials.gov, WHO-ICT Registry, EMBASE and grey literature were searched for relevant randomized controlled trials (RCTs). The primary outcome was clinical remission (attainment) and the secondary outcome was clinical response (maintenance/failure). Risk of bias was assessed with the Cochrane tool. Odds ratios (OR) were calculated with a Mantel-Haenszel (M-H) random effects model and with a beta-binomial (B-B) random effects model when zero events/cells occurred. Four RCTs met the criteria, but one was removed from the analyses due to inconsistency in protocol details. With the M-H method, treatment with curcumin was significantly superior to placebo in attaining remission in the per-protocol (PP) analysis (OR = 5.83, 95%CI = 1.24-27.43), but not in the intention-to-treat (ITT) analysis (OR = 4.33, 95%CI = 0.78-24.00). However, with the more accurate B B method, both analyses were insignificant (for PP OR = 4.26, 95%CI = 0.59-31.00, for ITT OR = 3.80, 95%CI = 0.55-26.28). Based on the current available evidence, oral curcumin administration does not seem superior to placebo in attaining remission in patients with UC. Future RCTs should be planned more cautiously with sufficient size and adhere to the ITT analysis in all outcomes. PMID- 30424516 TI - Intake of Saturated Fatty Acids Affects Atherogenic Blood Properties in Young, Caucasian, Overweight Women Even without Influencing Blood Cholesterol. AB - Despite a general relation between fat intake and cardiovascular risk factors, the association is often not observed in studies conducted in heterogenic populations, as for population groups, it may differ. The aim of the study was to analyze the associations between dietary fat intake and lipoprotein cholesterol fractions, as well as atherogenic blood properties, in young and middle-aged overweight Caucasian women. In a group of 138 overweight women, the three-day dietary records were assessed, under-reporters were excluded, and lipoprotein cholesterol fractions were analyzed. For the included 24 young (aged 20-40) and 42 middle-age women (aged 40-60), the intakes of fat, saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA), and cholesterol, as well as the PUFA/SFA ratio, were assessed. Afterwards, the analysis of associations with blood levels of total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride, as well as the TC/HDL ratio, HDL/LDL, ratio and Atherogenic Index of Plasma (AIP), were conducted. It was stated that the influence of the dietary fat level on lipoprotein cholesterol fractions as well as atherogenic blood properties in overweight Caucasian women is age dependent. For young, overweight, Caucasian women, the influence of the dietary fat level on the lipoprotein cholesterol fractions was not observed; however, SFA intake influenced atherogenic blood properties. For middle-aged, overweight, Caucasian women, the PUFA intake had an especially important influence in increasing the HDL cholesterol level. For overweight Caucasian women, not only should lipoprotein cholesterol fractions be controlled, but also the AIP calculated-especially for younger women. PMID- 30424517 TI - The Impact of Backpack Loads on School Children: A Critical Narrative Review. AB - Background: Backpack loads of school students during school days have been suggested to range from 10% to as high as 25% of their body weight and may have a negative impact on their body. The aim of this review was to identify and review studies that have examined impacts of contemporary backpack loads on school children. Methods: A systematic search was conducted of the literature using key search terms. After relevant studies published in recent years were selected using strict inclusion and exclusion criteria, the studies were critically appraised and relevant data were extracted and tabulated prior to conducting a critical narrative synthesis of findings. Results: Twenty-one studies were included, ranging in methodological quality from poor to good (critical appraisal scores 22% to 77%). Students carried on average over 15% of their own body weight, which caused biomechanical and physiological adaptations that could increase musculoskeletal injury risk, fatigue, redness, swelling and discomfort. Conclusion: Considering the limited methodological quality and variations in foci across studies, further research is needed to elucidate: (1) the loads students carry around on a school day in their school backpacks and; (2) the biomechanical, physiological and physical effects of load carriage on students. PMID- 30424518 TI - Transcriptome Analysis Provides Insights into the Markers of Resting and LPS Activated Macrophages in Grass Carp (Ctenopharyngodon idella). AB - Macrophages are very versatile immune cells, with the characteristics of a proinflammatory phenotype in response to pathogen-associated molecular patterns. However, the specific activation marker genes of macrophages have not been systematically investigated in teleosts. In this work, leukocytes (WBC) were isolated using the Percoll gradient method. Macrophages were enriched by the adherent culture of WBC, then stimulated with lipopolysaccharide (LPS). Macrophages were identified by morphological features, functional activity and authorized cytokine expression. Subsequently, we collected samples, constructed and sequenced transcriptomic libraries including WBC, resting macrophage (Mo) and activated macrophage (M(LPS)) groups. We gained a total of 20.36 Gb of clean data including 149.24 million reads with an average length of 146 bp. Transcriptome analysis showed 708 differential genes between WBC and Mo, 83 differentially expressed genes between Mo and M(LPS). Combined with RT-qPCR, we proposed that four novel cell surface marker genes (CD22-like, CD63, CD48 and CD276) and two chemokines (CXCL-like and CCL39.3) would be emerging potential marker genes of macrophage in grass carp. Furthermore, CD69, CD180, CD27, XCL32a.2 and CXCL8a genes can be used as marker genes to confirm whether macrophages are activated. Transcriptome profiling reveals novel molecules associated with macrophages in C. Idella, which may represent a potential target for macrophages activation. PMID- 30424519 TI - Generation of Highly Efficient Equine-Derived Antibodies for Post-Exposure Treatment of Ricin Intoxications by Vaccination with Monomerized Ricin. AB - Ricin, a highly lethal toxin derived from the seeds of Ricinus communis (castor beans) is considered a potential biological threat agent due to its high availability, ease of production, and to the lack of any approved medical countermeasure against ricin exposures. To date, the use of neutralizing antibodies is the most promising post-exposure treatment for ricin intoxication. The aim of this work was to generate anti-ricin antitoxin that confers high level post-exposure protection against ricin challenge. Due to safety issues regarding the usage of ricin holotoxin as an antigen, we generated an inactivated toxin that would reduce health risks for both the immunizer and the immunized animal. To this end, a monomerized ricin antigen was constructed by reducing highly purified ricin to its monomeric constituents. Preliminary immunizing experiments in rabbits indicated that this monomerized antigen is as effective as the native toxin in terms of neutralizing antibody elicitation and protection of mice against lethal ricin challenges. Characterization of the monomerized antigen demonstrated that the irreversibly detached A and B subunits retain catalytic and lectin activity, respectively, implying that the monomerization process did not significantly affect their overall structure. Toxicity studies revealed that the monomerized ricin displayed a 250-fold decreased activity in a cell culture-based functionality test, while clinical signs were undetectable in mice injected with this antigen. Immunization of a horse with the monomerized toxin was highly effective in elicitation of high titers of neutralizing antibodies. Due to the increased potential of IgG-derived adverse events, anti-ricin F(ab')2 antitoxin was produced. The F(ab')2-based antitoxin conferred high protection to intranasally ricin-intoxicated mice; ~60% and ~34% survival, when administered 24 and 48 h post exposure to a lethal dose, respectively. In line with the enhanced protection, anti-inflammatory and anti-edematous effects were measured in the antitoxin treated mice, in comparison to mice that were intoxicated but not treated. Accordingly, this anti-ricin preparation is an excellent candidate for post exposure treatment of ricin intoxications. PMID- 30424520 TI - Global Identification of HIF-1alpha Target Genes in Benzene Poisoning Mouse Bone Marrow Cells. AB - Benzene is a hematopoietic toxicant, and hematopoietic cells in bone marrow (BM) are one of the main targets for its action, especially hematopoietic stem cells (HSCs). Hypoxia-inducible factor-1alpha (HIF-1alpha) is associated with the metabolism and physiological functions of HSCs. We previously found that the mechanism of regulation of HIF-1alpha is involved in benzene-induced hematopoietic toxicity. In this study, chromatin immunoprecipitation sequencing (ChIP-Seq) technologies were used to analyze the genome-wide binding spectrum of HIF-1alpha in mouse BM cells, and specific HIF-1alpha target genes and pathways associated with benzene toxicity were screened and validated. By application of the ChIP-Seq technique, we identified target genes HIF-1alpha directly binds to and regulates. Forty-two differentially down-regulated genes containing the HIF 1alpha specific binding site hypoxia response element (HRE) were found, of which 25 genes were with biological function. Moreover, the enrichment analysis of signal pathways indicated that these genes were significantly enriched in the Jak STAT signaling pathway, Natural killer cell mediated cytotoxicity, the Fc epsilon RI signaling pathway, Pyrimidine metabolism, the T cell receptor signaling pathway, and Transcriptional misregulation in cancer. After verification, 11 genes involved in HSC self-renewal, cell cycle, differentiation, and apoptosis pathways were found to be significantly reduced, and may participate in benzene induced hematotoxicity. Our study provides a new academic clue for the mechanism of benzene hematotoxicity. PMID- 30424521 TI - Antibiotic Therapy Using Phage Depolymerases: Robustness Across a Range of Conditions. AB - Phage-derived depolymerases directed against bacterial capsules are showing therapeutic promise in various animal models of infection. However, individual animal model studies are often constrained by use of highly specific protocols, such that results may not generalize to even slight modifications. Here we explore the robustness of depolymerase therapies shown to succeed in a previous study of mice. Treatment success rates were reduced by treatment delay, more so for some enzymes than others: K1- and K5 capsule-degrading enzymes retained partial efficacy on delay, while K30 depolymerase did not. Phage were superior to enzymes under delayed treatment only for K1. Route of administration (intramuscular versus intraperitoneal) mattered for success of K1E, possibly for K1F, not for K1H depolymerase. Significantly, K1 capsule-degrading enzymes proved highly successful when using immune-suppressed, leukopenic mice, even with delayed treatment. Evolution of bacteria resistant to K1-degrading enzymes did not thwart therapeutic success in leukopenic mice, likely because resistant bacteria were avirulent. In combination with previous studies these results continue to support the efficacy of depolymerases as antibacterial agents in vivo, but system-specific details are becoming evident. PMID- 30424522 TI - Chemical Composition and Antioxidant Characteristic of Traditional and Industrial Zhenjiang Aromatic Vinegars during the Aging Process. AB - Zhenjiang aromatic vinegar (ZAV) is one of the well-known fermented condiments in China, which is produced by solid-state fermentation. It can be classified into traditional Zhenjiang aromatic vinegar (TZAV) and industrial Zhenjiang aromatic vinegar (IZAV) because of different production methods. The purpose of the study was to evaluate the variations and differences on chemical compositions and antioxidant activities of TZAV and IZAV during the aging process. The proximate composition, organic acids content, total phenolic content (TPC), total flavonoid content (TFC), total antioxidant activity (TAA) and phenolic compounds composition of TZAV and IZAV were detected during the aging process. Organic acids contents, TPC, TFC, TAA and phenolic compounds contents in ZAV were increased during the aging process. Acetic acid, lactic acid and pyroglutamic acid in ZAV were major organic acids. With the extension of aging time, TZAV and IZAV had similar proximate compositions and organic acids content. The values of TPC, TFC and TAA were higher in TZAV than in IZAV when aging is more than 3 years. Rutin and p-coumaric acid were detected in TZAV but not in IZAV. In principal component analysis (PCA), TZAV and IZAV can be divided into two groups according to their phenolic compounds composition. These findings provide references for evaluating TZAV and IZAV on the basis of their characterizations. PMID- 30424523 TI - Raman Spectroscopy and Microscopy Applications in Cardiovascular Diseases: From Molecules to Organs. AB - Noninvasive and label-free vibrational spectroscopy and microscopy methods have shown great potential for clinical diagnosis applications. Raman spectroscopy is based on inelastic light scattering due to rotational and vibrational modes of molecular bonds. It has been shown that Raman spectra provide chemical signatures of changes in biological tissues in different diseases, and this technique can be employed in label-free monitoring and clinical diagnosis of several diseases, including cardiovascular studies. However, there are very few literature reviews available to summarize the state of art and future applications of Raman spectroscopy in cardiovascular diseases, particularly cardiac hypertrophy. In addition to conventional clinical approaches such as electrocardiography (ECG), echocardiogram (cardiac ultrasound), positron emission tomography (PET), cardiac computed tomography (CT), and single photon emission computed tomography (SPECT), applications of vibrational spectroscopy and microscopy will provide invaluable information useful for the prevention, diagnosis, and treatment of cardiovascular diseases. Various in vivo and ex vivo investigations can potentially be performed using Raman imaging to study and distinguish pathological and physiological cardiac hypertrophies and understand the mechanisms of other cardiac diseases. Here, we have reviewed the recent literature on Raman spectroscopy to study cardiovascular diseases covering investigations on the molecular, cellular, tissue, and organ level. PMID- 30424524 TI - Flubendiamide Enhances Adipogenesis and Inhibits AMPKalpha in 3T3-L1 Adipocytes. AB - Flubendiamide, a ryanoid class insecticide, is widely used in agriculture. Several insecticides have been reported to promote adipogenesis. However, the potential influence of flubendiamide on adipogenesis is largely unknown. The current study was therefore to determine the effects of flubendiamide on adipogenesis utilizing the 3T3-L1 adipocytes model. Flubendiamide treatment not only enhanced triglyceride content in 3T3-L1 adipocytes, but also increased the expression of cytosine-cytosine-adenosine-adenosine-thymidine (CCAAT)/enhancer binding protein alpha and peroxisome proliferator-activated receptor gamma-gamma, two important regulators of adipocyte differentiation. Moreover, the expression of the most important regulator of lipogenesis, acetyl coenzyme A carboxylase, was also increased after flubendiamide treatment. Further study revealed that 5 aminoimidazole-4-carboxamide ribonucleotide (AICAR) or A769662, two Adenosine 5' monophosphate (AMP)-activated protein kinase alpha activators, subverted effects of flubendiamide on enhanced adipogenesis. Together, these results suggest that flubendiamide promotes adipogenesis via an AMPKalpha-mediated pathway. PMID- 30424525 TI - A Rare Pediatric Case of Severe Bird Fancier's Lung Presented with Viral Pneumonitis-Like Picture. AB - Bird Fancier's Lung (BFL) is a rare, nonatopic immunologic response to repeated or intense inhalation of avian (bird) proteins/antigens found in the feathers or droppings of many species of birds, which leads to an immune-mediated inflammatory reaction in the respiratory system. Although this is the most common type of hypersensitivity pneumonitis (HP) reported in adults, it is one of the classifications of a rare subtype of interstitial lung disease that occurs in the pediatric age group of which few case reports are available in the literature. The pathophysiology of HP is complex; numerous organic and inorganic antigens can cause immune dysregulation, leading to an immune-related antigen-antibody response (immunoglobulin G-IgG- against the offending antigen). Diagnosing BFL in the pediatric age group is challenging due to the history of exposure usually being missed by health care providers, symptoms and clinical findings in such cases being nonspecific and often misdiagnosed during the acute illness with other common diseases such asthma or acute viral lower respiratory tract infection, and the lack of standardization of criteria for diagnosing such a condition or sensitive radiological or laboratory tests. Treatment, on the other hand, is also controversial. Avoidance of the offending antigen could be the sole or most important part of treatment, particularly in acute mild and moderate cases. Untreated cases can result in irreversible lung fibrosis. In this case report, we highlight how children presenting with an acute viral lower respiratory tract infection can overlap with the acute/subacute phase of HP. Early intervention with pulse steroids markedly improves the patient's clinical course. PMID- 30424526 TI - Recent Hydrophobic Metal-Organic Frameworks and Their Applications. AB - The focus of discussion of this review is the application of the most recent synthesized hydrophobic metal-organic frameworks (MOFs). The most promising hydrophobic MOFs are mentioned with their applications and discussed. The various MOFs considered are sub-sectioned into the main application areas, namely alcohol adsorption and oil/water-alcohol/water separation, gas separation and storage, and other applications such as self-cleaning and liquid marbles. Again, the methods of synthesis are briefly described, showing how the features of the end product aid in their applications. The efficiency of the MOF materials and synthesis methods are highlighted and briefly discussed. Lastly, the summary and outlook section concludes the write-up giving suggestions that would be useful to present-day researchers. PMID- 30424527 TI - Production of a Novel Functional Fruit Beverage Consisting of Cornelian Cherry Juice and Probiotic Bacteria. AB - The present study describes the development of a novel functional beverage through the application of probiotic Lactobacillus plantarum ATCC (American Type Culture Collection) 14917 in Cornelian cherry juice fermentation. The probiotic was employed in free and immobilized in a delignified wheat bran carrier (DWB) form. Cornelian cherry juice was fermented for 24 h and then it was stored at 4 degrees C for 4 weeks. Several parameters were evaluated such as residual sugar, organic acid and alcohol levels, total phenolics content, and cell viability as well as consumers acceptance. Regarding sugar and organic acids analyses, it was proved that the probiotic free or immobilized biocatalyst was effective. The concentration of ethanol was maintained at low levels (0.3-0.9% v/v). The total phenolic content of fermented Cornelian cherry juice with immobilized cells was recorded in higher levels (214-264 mg GAE/100 mL) for all the cold storage time compared to fermented juice with free cells (165-199 mg GAE/100 mL) and non fermented juice (135-169 mg GAE/100 mL). Immobilized cells retained their viability in higher levels (9.95 log cfu/mL at the 4th week) compared to free cells (7.36 log cfu/mL at the 4th week). No significant sensory differences were observed among the fermented and the non-fermented samples. PMID- 30424528 TI - Anticoagulant Properties of a Green Algal Rhamnan-type Sulfated Polysaccharide and Its Low-molecular-weight Fragments Prepared by Mild Acid Degradation. AB - The active sulfated polysaccharide from seaweed possesses important pharmaceutical and biomedical potential. In the study, Monostroma sulfated polysaccharide (MSP) was obtained from Monostroma angicava, and the low-molecular weight fragments of MSP (MSP-Fs: MSP-F1-MSP-F6) were prepared by controlled acid degradation. The molecular weights of MSP and MSP-F1-MSP-F6 were 335 kDa, 240 kDa, 90 kDa, 40 kDa, 24 kDa, 12 kDa, and 6.8 kDa, respectively. The polysaccharides were sulfated rhamnans that consisted of ->3)-alpha-l-Rhap-(1-> and ->2)-alpha-l-Rhap-(1-> units with partial sulfation at C-2 of ->3)-alpha-l Rhap-(1-> and C-3 of ->2)-alpha-l-Rhap-(1->. Anticoagulant properties in vitro of MSP and MSP-F1-MSP-F6 were evaluated by studying the activated partial thromboplastin time, thrombin time, and prothrombin time. Anticoagulant activities in vivo of MSP and MSP-F4 were further evaluated; their fibrin(ogen)olytic activities in vivo and thrombolytic properties in vitro were also assessed by D-dimer, fibrin degradation products, plasminogen activator inhibitior-1, and clot lytic rate assays. The results showed that MSP and MSP-F1 MSP-F4 with molecular weights of 24-240 kDa had strong anticoagulant activities. A decrease in the molecular weight of MSP-Fs was accompanied by a decrease in the anticoagulant activity, and higher anticoagulant activity requires a molecular weight of over 12 kDa. MSP and MSP-F4 possessed strong anticoagulant activities in vivo, as well as high fibrin(ogen)olytic and thrombolytic activities. MSP and MSP-F4 have potential as drug or helpful food supplements for human health. PMID- 30424529 TI - Main Olfactory and Vomeronasal Epithelium Are Differently Affected in Niemann Pick Disease Type C1. AB - INTRODUCTION: Olfactory impairment is one of the earliest symptoms in neurodegenerative disorders that has also been documented in Niemann-Pick disease type C1 (NPC1). NPC1 is a very rare, neurovisceral lipid storage disorder, characterized by a deficiency of Npc1 gene function that leads to progressive neurodegeneration. Here, we compared the pathologic effect of defective Npc1 gene on the vomeronasal neuroepithelium (VNE) with that of the olfactory epithelium (OE) in an NPC1 mouse model. METHODS: Proliferation in the VNE and OE was assessed by applying a bromodeoxyuridine (BrdU) protocol. We further compared the immunoreactivities of anti-olfactory marker protein (OMP), and the lysosomal marker cathepsin-D in both epithelia. To investigate if degenerative effects of both olfactory systems can be prevented or reversed, some animals were treated with a combination of miglustat/allopregnanolone/2-hydroxypropyl-cyclodextrin (HPbetaCD), or a monotherapy with HPbetaCD alone. RESULTS: Using BrdU to label dividing cells of the VNE, we detected a proliferation increase of 215% +/- 12% in Npc1-/- mice, and 270% +/- 10% in combination- treated Npc1-/- animals. The monotherapy with HPbetaCD led to an increase of 261% +/- 10.5% compared to sham treated Npc1-/- mice. Similar to the OE, we assessed the high regenerative potential of vomeronasal progenitor cells. OMP reactivity in the VNE of Npc1-/- mice was not affected, in contrast to that observed in the OE. Concomitantly, cathepsin-D reactivity in the VNE was virtually absent. Conclusion: Vomeronasal receptor neurons are less susceptible against NPC1 pathology than olfactory receptor neurons. Compared to control mice, however, the VNE of Npc1-/- mice displays an increased neuroregenerative potential, indicating compensatory cell renewal. PMID- 30424530 TI - Following in the Footsteps of the Chikungunya Virus in Brazil: The First Autochthonous Cases in Amapa in 2014 and Its Emergence in Rio de Janeiro during 2016. AB - Currently, Brazil lives a triple arboviruses epidemic (DENV, ZIKV and CHIKV) making the differential diagnosis difficult for health professionals. Here, we aimed to investigate chikungunya cases and the possible occurrence of co infections during the epidemic in Amapa (AP) that started in 2014 when the first autochthonous cases were reported and in Rio de Janeiro (RJ) in 2016. We further performed molecular characterization and genotyping of representative strains. In AP, 51.4% of the suspected cases were confirmed for CHIKV, 71.0% (76/107). Of those, 24 co-infections by CHIKV/DENV, two by CHIKV/DENV-1, and two by CHIKV/DENV 4 were observed. In RJ, 76.9% of the suspected cases were confirmed for CHIKV and co-infections by CHIKV/DENV (n = 8) and by CHIKV/ZIKV (n = 17) were observed. Overall, fever, arthralgia, myalgia, prostration, edema, exanthema, conjunctival hyperemia, lower back pain, dizziness, nausea, retroorbital pain, and anorexia were the predominating chikungunya clinical symptoms described. All strains analyzed from AP belonged to the Asian genotype and no amino acid changes were observed. In RJ, the East-Central-South-African genotype (ECSA) circulation was demonstrated and no E1-A226V mutation was observed. Despite this, an E1-V156A substitution was characterized in two samples and for the first time, the E1 K211T mutation was reported in all samples analyzed. PMID- 30424531 TI - Effect of Comorbidity Assessed by the Charlson Comorbidity Index on the Length of Stay, Costs and Mortality among Older Adults Hospitalised for Acute Stroke. AB - The burden of comorbidity among stroke patients is high. The aim of this study was to examine the effect of comorbidity on the length of stay (LOS), costs, and mortality among older adults hospitalised for acute stroke. Among 776 older adults (mean age 80.1 +/- 8.3 years; 46.7% female) hospitalised for acute stroke during July 2013 to December 2015 at a tertiary hospital in Melbourne, Australia, we collected data on LOS, costs, and discharge outcomes. Comorbidity was assessed via the Charlson Comorbidity Index (CCI), where a CCI score of 0-1 was considered low and a CCI >= 2 was high. Negative binomial regression and quantile regression were applied to examine the association between CCI and LOS and cost, respectively. Survival was evaluated with the Kaplan-Meier and Cox regression analyses. The median LOS was 1.1 days longer for patients with high CCI than for those with low CCI. In-hospital mortality rate was 18.2% (22.1% for high CCI versus 11.8% for low CCI, p < 0.0001). After controlling for confounders, high CCI was associated with longer LOS (incidence rate ratio [IRR]; 1.35, p < 0.0001) and increased likelihood of in-hospital death (hazard ratio [HR]; 1.91, p = 0.003). The adjusted median, 25th, and 75th percentile costs were AUD$2483 (26.1%), AUD$1446 (28.1%), and AUD$3140 (27.9%) higher for patients with high CCI than for those with low CCI. Among older adults hospitalised for acute stroke, higher global comorbidity (CCI >= 2) was associated adverse clinical outcomes. Measures to better manage comorbidities should be considered as part of wider strategies towards mitigating the social and economic impacts of stroke. PMID- 30424532 TI - Development of a Diagnostic Marker for Phlebotomus papatasi to Initiate a Potential Vector Surveillance Program in North America. AB - Phlebotomus papatasi, an Old World sand fly species, is primarily responsible for the transmission of leishmaniasis, a highly infectious and potentially lethal disease. International travel, especially military rotations, between domestic locations and P. papatasi-prevalent regions in the Middle East poses an imminent threat to the public health of US citizens. Because of its small size and cryptic morphology, identification of P. papatasi is challenging and labor-intensive. Here, we developed a ribosomal DNA-polymerase chain reaction (PCR)-based diagnostic assay that is capable of detecting P. papatasi genomic DNA from mixed samples containing multiple sand flies native to the Americas. Serial dilution of P. papatasi samples demonstrated that this diagnostic assay could detect one P. papatasi from up to 255 non-target sand flies. Due to its simplicity, sensitivity and specificity, this rapid identification tool is suited for a long-term surveillance program to screen for the presence of P. papatasi in the continental United States and to reveal geographical regions potentially vulnerable to sand fly-borne diseases. PMID- 30424534 TI - A Blockchain-Based Location Privacy Protection Incentive Mechanism in Crowd Sensing Networks. AB - Crowd sensing is a perception mode that recruits mobile device users to complete tasks such as data collection and cloud computing. For the cloud computing platform, crowd sensing can not only enable users to collaborate to complete large-scale awareness tasks but also provide users for types, social attributes, and other information for the cloud platform. In order to improve the effectiveness of crowd sensing, many incentive mechanisms have been proposed. Common incentives are monetary reward, entertainment & gamification, social relation, and virtual credit. However, there are rare incentives based on privacy protection basically. In this paper, we proposed a mixed incentive mechanism which combined privacy protection and virtual credit called a blockchain-based location privacy protection incentive mechanism in crowd sensing networks. Its network structure can be divided into three parts which are intelligence crowd sensing networks, confusion mechanism, and blockchain. We conducted the experiments in the campus environment and the results shows that the incentive mechanism proposed in this paper has the efficacious effect in stimulating user participation. PMID- 30424535 TI - Graphene Nanomaterials: Synthesis, Biocompatibility, and Cytotoxicity. AB - Graphene, graphene oxide, and reduced graphene oxide have been widely considered as promising candidates for industrial and biomedical applications due to their exceptionally high mechanical stiffness and strength, excellent electrical conductivity, high optical transparency, and good biocompatibility. In this article, we reviewed several techniques that are available for the synthesis of graphene-based nanomaterials, and discussed the biocompatibility and toxicity of such nanomaterials upon exposure to mammalian cells under in vitro and in vivo conditions. Various synthesis strategies have been developed for their fabrication, generating graphene nanomaterials with different chemical and physical properties. As such, their interactions with cells and organs are altered accordingly. Conflicting results relating biocompatibility and cytotoxicity induced by graphene nanomaterials have been reported in the literature. In particular, graphene nanomaterials that are used for in vitro cell culture and in vivo animal models may contain toxic chemical residuals, thereby interfering graphene-cell interactions and complicating interpretation of experimental results. Synthesized techniques, such as liquid phase exfoliation and wet chemical oxidation, often required toxic organic solvents, surfactants, strong acids, and oxidants for exfoliating graphite flakes. Those organic molecules and inorganic impurities that are retained in final graphene products can interact with biological cells and tissues, inducing toxicity or causing cell death eventually. The residual contaminants can cause a higher risk of graphene induced toxicity in biological cells. This adverse effect may be partly responsible for the discrepancies between various studies in the literature. PMID- 30424536 TI - Genetic Testing by Sports Medicine Physicians in the United States: Attitudes, Experiences, and Knowledge. AB - It remains unknown whether and how sports medicine physicians currently utilize genetic testing in their clinical practice. This study sought to assess knowledge of, experience with, and attitudes towards genetic testing by sports medicine physicians in the United States (US). An email with a survey hyperlink was distributed twice to members of the American Medical Society for Sports Medicine (AMSSM) listserv in September 2016, with approximately a 10% response rate. Questions focused on knowledge of, experience with, and attitudes towards testing for different genes related to sports proficiency, injury risk, and disease risk. Few AMSSM physicians believe that genetic testing to adapt training (12%) or to choose a sport (2%) is ready for clinical adoption. Most respondents self reported minimal knowledge about, and limited experience with, genetic testing. The main exception was screening for sickle cell trait (SCT) for which most (84%) reported moderate/significant/expert knowledge and over two-thirds had ordered testing. Although most respondents thought it appropriate to counsel and test for health conditions associated with cardiac and connective tissue disorders in the setting of a positive family history, only a minority had been asked to do so. Five or fewer respondents (2%) had been asked to test for performance-associated variants (Angiotensin Converting Enzyme (ACE) II and Alpha-Actinin 3 (ACTN3)), and five or fewer (2%) would recommend changes based on the results. Our study provides a baseline of current US sports medicine physicians' minimal experiences with, and knowledge of, genetic testing. The findings of our study indicate that sports medicine physicians require further genetics education as it relates to sports and exercise in order to be prepared to competently engage with their patients and to develop sound professional organizational policies. PMID- 30424533 TI - Food-Derived Bioactive Peptides in Human Health: Challenges and Opportunities. AB - Recent scientific evidence suggests that food proteins not only serve as nutrients, but can also modulate the body's physiological functions. These physiological functions are primarily regulated by some peptides that are encrypted in the native protein sequences. These bioactive peptides can exert health beneficial properties and thus are considered as a lead compound for the development of nutraceuticals or functional foods. In the past few decades, a wide range of food-derived bioactive peptide sequences have been identified, with multiple health beneficial activities. However, the commercial application of these bioactive peptides has been delayed because of the absence of appropriate and scalable production methods, proper exploration of the mechanisms of action, high gastro-intestinal digestibility, variable absorption rate, and the lack of well-designed clinical trials to provide the substantial evidence for potential health claims. This review article discusses the current techniques, challenges of the current bioactive peptide production techniques, the oral use and gastrointestinal bioavailability of these food-derived bioactive peptides, and the overall regulatory environment. PMID- 30424537 TI - Subjective Satiety Following Meals Incorporating Rice, Pasta and Potato. AB - The satiating capacity of carbohydrate staples eaten alone is dependent upon the energy density of the food but relative satiety when starchy staples are incorporated into mixed meals is uncertain. Our aim was to assess the satiating effects of three carbohydrate staples; jasmine rice, penne pasta, and Agria potato, each consumed within a standard mixed meal. Cooked portions of each staple containing 45 g carbohydrate were combined with 200 g of meat sauce and 200 g of mixed vegetables in three mixed meals. The quantities of staple providing 45 g carbohydrate were: Rice, 142 g; pasta, 138 g and potato 337 g. Participants (n = 14) consumed each of the mixed meals in random order on separate days. Satiety was assessed with using visual analogue scales at baseline and for 3 h post meal. In an area-under-the-curve comparison, participants felt less hungry (mean (SD)) following potato 263 (230) than following rice 374 (237) or pasta 444 (254) mm?min, and felt fuller, more satisfied, and wanted to eat less following the potato compared with the rice and pasta meals (p for all <0.01). The superior satiating effect of potato compared with rice and pasta in a mixed meal was consistent with its lower energy density. PMID- 30424538 TI - Supplementation with Beef Extract Improves Exercise Performance and Reduces Post Exercise Fatigue Independent of Gut Microbiota. AB - Beef extract (BE) is a nutritional supplement obtained by cooking beef meat. Compared with traditional chicken essence or clam extract, BE is cheaper to produce and may be used for wound healing, as a chemotherapy supplement, or to prevent fatigue. In this study, we evaluated the potential beneficial effects of BE on exercise performance and the related role of the gut microbiota. Pathogen free male BALB/c mice were divided into three groups to receive vehicle or BE (0, 12.3, or 24.6 mL/kg) by oral gavage for 28 days. Exercise performance was evaluated using forelimb grip strength, swimming time to exhaustion, and physiological levels of fatigue-related biomarkers (serum lactate, blood urea nitrogen, and glucose levels) after physical challenges. BE supplementation elevated endurance and grip strength in a dose-dependent manner; significantly decreased lactate and blood urea nitrogen levels after physical challenge; and significantly increased muscle glycogen content. The germ-free mice supplemented with BE or an equal-calorie portion of albumin did not show significant differences from the other groups in exercise performance and levels of related biomarkers. Therefore, BE supplementation improved endurance and reduced fatigue, which might be related to BE composition, but had no correlation with the gut microbiota. PMID- 30424540 TI - Preparation of LiFePO4/C Cathode Materials via a Green Synthesis Route for Lithium-Ion Battery Applications. AB - In this work, LiFePO4/C composite were synthesized via a green route by using Iron (III) oxide (Fe2O3) nanoparticles, Lithium carbonate (Li2CO3), glucose powder and phosphoric acid (H3PO4) solution as raw materials. The reaction principles for the synthesis of LiFePO4/C composite were analyzed, suggesting that almost no wastewater and air polluted gases are discharged into the environment. The morphological, structural and compositional properties of the LiFePO4/C composite were characterized by X-ray diffraction (XRD), scanning electron microscope (SEM), transmission electron microscopy (TEM), Raman and X ray photoelectron spectroscopy (XPS) spectra coupled with thermogravimetry/Differential scanning calorimetry (TG/DSC) thermal analysis in detail. Lithium-ion batteries using such LiFePO4/C composite as cathode materials, where the loading level is 2.2 mg/cm2, exhibited excellent electrochemical performances, with a discharge capability of 161 mA h/g at 0.1 C, 119 mA h/g at 10 C and 93 mA h/g at 20 C, and a cycling stability with 98.0% capacity retention at 1 C after 100 cycles and 95.1% at 5 C after 200 cycles. These results provide a valuable approach to reduce the manufacturing costs of LiFePO4/C cathode materials due to the reduced process for the polluted exhaust purification and wastewater treatment. PMID- 30424541 TI - Editorial for the Special Issue "Dietary Fibre: New Insights on Biochemistry and Health Benefits". AB - When the term dietary fibre was first coined, over sixty years ago, it only referred to plant cell walls in the diet. [...]. PMID- 30424542 TI - Regulation of Leptin Methylation Not via Apoptosis by Melatonin in the Rescue of Chronic Programming Liver Steatosis. AB - We examined the mechanisms of chronic liver steatosis after prenatal dexamethasone exposure and whether melatonin rescues adult offspring with liver steatosis. Melatonin rescued prenatal dexamethasone-exposed livers with steatosis in young rats. Sprague-Dawley rats pregnant at gestational day 14-21 were administered with intraperitoneal dexamethasone (DEX) or prenatal dexamethasone and melatonin between gestational day 14 and postnatal day ~120 (DEX+MEL). Chronic programming effects in the liver were assessed at day ~120. Liver steatosis increased in the DEX compared with that in the vehicle group and decreased in the DEX+MEL group (p < 0.05), with no changes in cellular apoptosis. Expression of leptin and its receptor decreased in the DEX (p < 0.05) and increased in the DEX+MEL group (p < 0.05), as revealed by RT-PCR and Western blotting. Tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-6 expression increased in the DEX group compared with that in the vehicle group and decreased in the DEX+MEL group (p < 0.05). Liver DNA methyltransferase activity and leptin methylation increased in the DEX group (p < 0.05) and decreased in the DEX+MEL group (p < 0.05), with no changes in HDAC activity. Thus, prenatal dexamethasone induces liver steatosis at ~120 days via altered leptin expression and liver inflammation without leptin resistance. Melatonin reverses leptin methylation and expression and decreases inflammation and chronic liver steatosis not via apoptosis or histone deacetylation (HDAC). PMID- 30424543 TI - Extensive Distribution of the Lyme Disease Bacterium, Borrelia burgdorferi Sensu Lato, in Multiple Tick Species Parasitizing Avian and Mammalian Hosts across Canada. AB - Lyme disease, caused by the spirochetal bacterium, Borrelia burgdorferi sensu lato (Bbsl), is typically transmitted by hard-bodied ticks (Acari: Ixodidae). Whenever this tick-borne zoonosis is mentioned in medical clinics and emergency rooms, it sparks a firestorm of controversy. Denial often sets in, and healthcare practitioners dismiss the fact that this pathogenic spirochetosis is present in their area. For distribution of Bbsl across Canada, we conducted a 4-year, tick host study (2013-2016), and collected ticks from avian and mammalian hosts from Atlantic Canada to the West Coast. Overall, 1265 ticks representing 27 tick species belonging to four genera were collected. Of the 18 tick species tested, 15 species (83%) were positive for Bbsl and, of these infected ticks, 6 species bite humans. Overall, 13 of 18 tick species tested are human-biting ticks. Our data suggest that a 6-tick, enzootic maintenance cycle of Bbsl is present in southwestern B.C., and five of these tick species bite humans. Biogeographically, the groundhog tick, Ixodes cookei, has extended its home range from central and eastern Canada to southwestern British Columbia (B.C.). We posit that the Fox Sparrow, Passerella iliaca, is a reservoir-competent host for Bbsl. The Bay breasted Warbler, Setophaga castanea, and the Tennessee Warbler, Vermivora peregrina, are new host records for the blacklegged tick, Ixodes scapularis. We provide the first report of a Bbsl-positive Amblyomma longirostre larva parasitizing a bird; this bird parasitism suggests that a Willow Flycatcher is a competent reservoir of Bbsl. Our findings show that Bbsl is present in all provinces, and that multiple tick species are implicated in the enzootic maintenance cycle of this pathogen. Ultimately, Bbsl poses a serious public health contagion Canada-wide. PMID- 30424544 TI - Application of Direct Immersion Solid-Phase Microextraction (DI-SPME) for Understanding Biological Changes of Mediterranean Fruit Fly (Ceratitis capitata) During Mating Procedures. AB - Samples from three different mating stages (before, during and after mating) of the Mediterranean fruit fly Ceratitis capitata were used in this experiment. Samples obtained from whole insects were subjected to extraction with the two mixtures of solvents (acetonitrile/water (A) and methanol/acetonitrile/water (B)) and a comparative study of the extractions using the different solvents was performed. Direct immersion-solid phase microextraction (DI-SPME) was employed, followed by gas chromatographic-mass spectrometry analyses (GC/MS) for the collection, separation and identification of compounds. The method was validated by testing its sensitivity, linearity and reproducibility. The main compounds identified in the three different mating stages were ethyl glycolate, alpha farnesene, decanoic acid octyl ester, 2,6,10,15-tetramethylheptadecane, 11 tricosene, 9,12-(Z,Z)-octadecadienoic acid, methyl stearate, 9-(Z)-tricosene, 9,11-didehydro-lumisterol acetate; 1,54-dibromotetrapentacontane, 9-(Z) hexadecenoic acid hexadecyl ester, 9-(E)-octadecenoic acid and 9-(Z)-hexadecenoic acid octadecyl ester. The novel findings indicated that compound compositions were not significantly different before and during mating. However, new chemical compounds were generated after mating, such as 1-iodododecane, 9-(Z)-tricosene and 11,13-dimethyl-12-tetradecen-1-acetate which were extracted with both (A) and (B) and dodecanoic acid, (Z)-oleic acid, octadecanoic acid and hentriacontane which were extracted with (A) and ethyl glycolate, 9-hexadecenoic acid hexadecyl ester, palmitoleic acid and 9-(E)-octadecenoic acid, which were extracted with solvent (B). This study has demonstrated that DI-SPME is useful in quantitative insect metabolomics by determining changes in the metabolic compounds in response to mating periods. DI-SPME chemical extraction technology might offer analysis of metabolites that could potentially enhance our understanding on the evolution of the medfly. PMID- 30424539 TI - Cell Origins of High-Grade Serous Ovarian Cancer. AB - High-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), is the most common and deadliest type of ovarian cancer. HGSC appears to arise from the ovary, fallopian tube, or peritoneum. As most HGSC cases present with widespread peritoneal metastases, it is often not clear where HGSC truly originates. Traditionally, the ovarian surface epithelium (OSE) was long believed to be the origin of HGSC. Since the late 1990s, the fallopian tube epithelium has emerged as a potential primary origin of HGSC. Particularly, serous tubal intraepithelial carcinoma (STIC), a noninvasive tumor lesion formed preferentially in the distal fallopian tube epithelium, was proposed as a precursor for HGSC. It was hypothesized that STIC lesions would progress, over time, to malignant and metastatic HGSC, arising from the fallopian tube or after implanting on the ovary or peritoneum. Many clinical studies and several mouse models support the fallopian tube STIC origin of HGSC. Current evidence indicates that STIC may serve as a precursor for HGSC in high-risk women carrying germline BRCA1 or 2 mutations. Yet not all STIC lesions appear to progress to clinical HGSCs, nor would all HGSCs arise from STIC lesions, even in high-risk women. Moreover, the clinical importance of STIC remains less clear in women in the general population, in which 85-90% of all HGSCs arise. Recently, increasing attention has been brought to the possibility that many potential precursor or premalignant lesions, though composed of microscopically-and genetically cancerous cells, do not advance to malignant tumors or lethal malignancies. Hence, rigorous causal evidence would be crucial to establish that STIC is a bona fide premalignant lesion for metastatic HGSC. While not all STICs may transform into malignant tumors, these lesions are clearly associated with increased risk for HGSC. Identification of the molecular characteristics of STICs that predict their malignant potential and clinical behavior would bolster the clinical importance of STIC. Also, as STIC lesions alone cannot account for all HGSCs, other potential cellular origins of HGSC need to be investigated. The fallopian tube stroma in mice, for instance, has been shown to be capable of giving rise to metastatic HGSC, which faithfully recapitulates the clinical behavior and molecular aspect of human HGSC. Elucidating the precise cell(s) of origin of HGSC will be critical for improving the early detection and prevention of ovarian cancer, ultimately reducing ovarian cancer mortality. PMID- 30424545 TI - miRNA Mediated Noise Making of 3'UTR Mutations in Cancer. AB - Somatic mutations in 3'-untranslated regions (3'UTR) do not alter amino acids and are considered to be silent in cancers. We found that such mutations can promote tumor progression by altering microRNA (miRNA) targeting efficiency and consequently affecting miRNA-mRNA interactions. We identified 67,159 somatic mutations located in the 3'UTRs of messenger RNAs (mRNAs) which can alter miRNA mRNA interactions (functional somatic mutations, funcMutations), and 69.3% of these funcMutations (the degree of energy change > 12 kcal/mol) were identified to significantly promote loss of miRNA-mRNA binding. By integrating mRNA expression profiles of 21 cancer types, we found that the expression of target genes was positively correlated with the loss of absolute affinity level and negatively correlated with the gain of absolute affinity level. Functional enrichment analysis revealed that genes carrying funcMutations were significantly enriched in the MAPK and WNT signaling pathways, and analysis of regulatory modules identified eighteen miRNA modules involved with similar cellular functions. Our findings elucidate a complex relationship between miRNA, mRNA, and mutations, and suggest that 3'UTR mutations may play an important role in tumor development. PMID- 30424546 TI - Relative Contribution of PIN-Containing Secretory Vesicles and Plasma Membrane PINs to the Directed Auxin Transport: Theoretical Estimation. AB - The intercellular transport of auxin is driven by PIN-formed (PIN) auxin efflux carriers. PINs are localized at the plasma membrane (PM) and on constitutively recycling endomembrane vesicles. Therefore, PINs can mediate auxin transport either by direct translocation across the PM or by pumping auxin into secretory vesicles (SVs), leading to its secretory release upon fusion with the PM. Which of these two mechanisms dominates is a matter of debate. Here, we addressed the issue with a mathematical modeling approach. We demonstrate that the efficiency of secretory transport depends on SV size, half-life of PINs on the PM, pH, exocytosis frequency and PIN density. 3D structured illumination microscopy (SIM) was used to determine PIN density on the PM. Combining this data with published values of the other parameters, we show that the transport activity of PINs in SVs would have to be at least 1000* greater than on the PM in order to produce a comparable macroscopic auxin transport. If both transport mechanisms operated simultaneously and PINs were equally active on SVs and PM, the contribution of secretion to the total auxin flux would be negligible. In conclusion, while secretory vesicle-mediated transport of auxin is an intriguing and theoretically possible model, it is unlikely to be a major mechanism of auxin transport in planta. PMID- 30424547 TI - Transcriptomic Insight into Terpenoid Biosynthesis and Functional Characterization of Three Diterpene Synthases in Scutellaria barbata. AB - Scutellaria barbata (Lamiaceae) is an important medicinal herb widely used in China, Korea, India, and other Asian countries. Neo-clerodane diterpenoids are the largest known group of Scutellaria diterpenoids and show promising cytotoxic activity against several cancer cell lines. Here, Illumina-based deep transcriptome analysis of flowers, the aerial parts (leaf and stem), and roots of S. barbata was used to explore terpenoid-related genes. In total, 121,958,564 clean RNA-sequence reads were assembled into 88,980 transcripts, with an average length of 1370 nt and N50 length of 2144 nt, indicating high assembly quality. We identified nearly all known terpenoid-related genes (33 genes) involved in biosynthesis of the terpenoid backbone and 14 terpene synthase genes which generate skeletons for different terpenoids. Three full length diterpene synthase genes were functionally identified using an in vitro assay. SbTPS8 and SbTPS9 were identified as normal-CPP and ent-CPP synthase, respectively. SbTPS12 reacts with SbTPS8 to produce miltiradiene. Furthermore, SbTPS12 was proven to be a less promiscuous class I diterpene synthase. These results give a comprehensive understanding of the terpenoid biosynthesis in S. barbata and provide useful information for enhancing the production of bioactive neo-clerodane diterpenoids through genetic engineering. PMID- 30424548 TI - Receiver-Initiated Handshaking MAC Based on Traffic Estimation for Underwater Sensor Networks ?. AB - In underwater sensor networks (UWSNs), the unique characteristics of acoustic channels have posed great challenges for the design of medium access control (MAC) protocols. The long propagation delay problem has been widely explored in recent literature. However, the long preamble problem with acoustic modems revealed in real experiments brings new challenges to underwater MAC design. The overhead of control messages in handshaking-based protocols becomes significant due to the long preamble in underwater acoustic modems. To address this problem, we advocate the receiver-initiated handshaking method with parallel reservation to improve the handshaking efficiency. Despite some existing works along this direction, the data polling problem is still an open issue. Without knowing the status of senders, the receiver faces two challenges for efficient data polling: when to poll data from the sender and how much data to request. In this paper, we propose a traffic estimation-based receiver-initiated MAC (TERI-MAC) to solve this problem with an adaptive approach. Data polling in TERI-MAC depends on an online approximation of traffic distribution. It estimates the energy efficiency and network latency and starts the data request only when the preferred performance can be achieved. TERI-MAC can achieve a stable energy efficiency with arbitrary network traffic patterns. For traffic estimation, we employ a resampling technique to keep a small computation and memory overhead. The performance of TERI-MAC in terms of energy efficiency, channel utilization, and communication latency is verified in simulations. Our results show that, compared with existing receiver-initiated-based underwater MAC protocols, TERI-MAC can achieve higher energy efficiency at the price of a delay penalty. This confirms the strength of TERI-MAC for delay-tolerant applications. PMID- 30424549 TI - An Invertebrate Host to Study Fungal Infections, Mycotoxins and Antifungal Drugs: Tenebrio molitor. AB - Faced with ethical conflict and social pressure, researchers have increasingly chosen to use alternative models over vertebrates in their research. Since the innate immune system is evolutionarily conserved in insects, the use of these animals in research is gaining ground. This review discusses Tenebrio molitor as a potential model host for the study of pathogenic fungi. Larvae of T. molitor are known as cereal pests and, in addition, are widely used as animal and human feed. A number of studies on mechanisms of the humoral system, especially in the synthesis of antimicrobial peptides, which have similar characteristics to vertebrates, have been performed. These studies demonstrate the potential of T. molitor larvae as a model host that can be used to study fungal virulence, mycotoxin effects, host immune responses to fungal infection, and the action of antifungal compounds. PMID- 30424550 TI - Knowledge Management for Fostering Biostatistical Collaboration within a Research Network: The RTRN Case Study. AB - Purpose: While the intellectual and scientific rationale for research collaboration has been articulated, a paucity of information is available on a strategic approach to facilitate the collaboration within a research network designed to reduce health disparities. This study aimed to (1) develop a conceptual model to facilitate collaboration among biostatisticians in a research network; (2) describe collaborative engagement performed by the Network's Data Coordinating Center (DCC); and (3) discuss potential challenges and opportunities in engaging the collaboration. Methods: Key components of the strategic approach will be developed through a systematic literature review. The Network's initiatives for the biostatistical collaboration will be described in the areas of infrastructure, expertise and knowledge management and experiential lessons will be discussed. Results: Components of the strategic approach model included three Ps (people, processes and programs) which were integrated into expert management, infrastructure management and knowledge management, respectively. Ongoing initiatives for collaboration with non-DCC biostatisticians included both web-based and face-to-face interaction approaches: Network's biostatistical capacities and needs assessment, webinar statistical seminars, mobile statistical workshop and clinics, adjunct appointment program, one-on-one consulting, and on site workshop. The outreach program, as a face-to-face interaction approach, especially resulted in a useful tool for expertise management and needs assessment as well as knowledge exchange. Conclusions: Although fostering a partnered research culture, sustaining senior management commitment and ongoing monitoring are a challenge for this collaborative engagement, the proposed strategies centrally performed by the DCC may be useful in accelerating the pace and enhancing the quality of the scientific outcomes within a multidisciplinary clinical and translational research network. PMID- 30424551 TI - State-of-the-Art Extraction Methodologies for Bioactive Compounds from Algal Biome to Meet Bio-Economy Challenges and Opportunities. AB - Over the years, significant research efforts have been made to extract bioactive compounds by applying different methodologies for various applications. For instance, the use of bioactive compounds in several commercial sectors such as biomedical, pharmaceutical, cosmeceutical, nutraceutical and chemical industries, has promoted the need of the most suitable and standardized methods to extract these bioactive constituents in a sophisticated and cost-effective manner. In practice, several conventional extraction methods have numerous limitations, e.g., lower efficacy, high energy cost, low yield, etc., thus urges for new state of-the-art extraction methodologies. Thus, the optimization along with the integration of efficient pretreatment strategies followed by traditional extraction and purification processes, have been the primary goal of current research and development studies. Among different sources, algal biome has been found as a promising and feasible source to extract a broader spectrum of bioactive compounds with point-of-care application potentialities. As evident from the literature, algal bio-products includes biofuels, lipids, polyunsaturated fatty acids, pigments, enzymes, polysaccharides, and proteins. The recovery of products from algal biomass is a matter of constant development and progress. This review covers recent advancements in the extraction methodologies such as enzyme-assisted extraction (EAE), supercritical-fluid extraction (SFE), microwave-assisted extraction (MAE) and pressurized-liquid extraction (PLF) along with their working mechanism for extracting bioactive compounds from algal-based sources to meet bio-economy challenges and opportunities. A particular focus has been given to design characteristics, performance evaluation, and point-of-care applications of different bioactive compounds of microalgae. The previous and recent studies on the anticancer, antibacterial, and antiviral potentialities of algal-based bioactive compounds have also been discussed with particular reference to the mechanism underlying the effects of these active constituents with the related pathways. Towards the end, the information is also given on the possible research gaps, future perspectives and concluding remarks. PMID- 30424552 TI - An Improved ACKF/KF Initial Alignment Method for Odometer-Aided Strapdown Inertial Navigation System. AB - For a land-vehicle strapdown inertial navigation system (SINS), the problem of initial alignment with large misalignment angle in-motion needs to be solved urgently. This paper proposes an improved ACKF/KF initial alignment method for SINS aided by odometer. The SINS error equation with large misalignment angle is established first in the form of an Euler angle. The odometer/gyroscope dead reckoning (DR) error equation is deduced, which makes the observation equation linear when the position is taken as the observation of the Kalman filter. Then, based on the cubature Kalman filter, the Sage-Husa adaptive filter and the characteristics of the observation equation, an improved ACKF/KF method is proposed, which can accomplish initial alignment well in the case of unknown measurement noise. Computer simulation results show that the performance of the proposed ACKF/KF algorithm is superior to EKF, CKF and AEKF method in accuracy and stability, and the vehicle test validates its advantages. PMID- 30424553 TI - Impact of Machine Perfusion on Biliary Complications after Liver Transplantation. AB - We describe in this review the different types of injuries caused to the biliary tree after liver transplantation. Furthermore, we explain underlying mechanisms and why oxygenated perfusion concepts could not only protect livers, but also repair high-risk grafts to prevent severe biliary complications and graft loss. Accordingly, we summarize experimental studies and clinical applications of machine liver perfusion with a focus on biliary complications after liver transplantation. Key points: (1) Acute inflammation with subsequent chronic ongoing liver inflammation and injury are the main triggers for cholangiocyte injury and biliary tree transformation, including non-anastomotic strictures; (2) Hypothermic oxygenated perfusion (HOPE) protects livers from initial oxidative injury at normothermic reperfusion after liver transplantation. This is a unique feature of a cold oxygenation approach, which is effective also end-ischemically, e.g., after cold storage, due to mitochondrial repair mechanisms. In contrast, normothermic oxygenated perfusion concepts protect by reducing cold ischemia, and are therefore most beneficial when applied instead of cold storage; (3) Due to less downstream activation of cholangiocytes, hypothermic oxygenated perfusion also significantly reduces the development of biliary strictures after liver transplantation. PMID- 30424554 TI - Effect of Mixture Variables on Durability for Alkali-Activated Slag Cementitious. AB - In this study, the influence of three mixture variables named Sand/Aggregate ratio, Liquid/Binder ratio, and Paste/Aggregate ratio on the cementitious properties were studied. The durability of cementitious including absorption, absorption rate, resistivity, rapid chloride permeability index, and carbonation rate were examined. Results showed that the alkali-activated slag cementitious has superior durability. The trends of influences on the composites properties for these three mixture variables are similar to those for the ordinary Portland cement concrete. It means that the experiences for making the ordinary Portland cement concrete should be able to be used for the alkali-activated slag cementitious. This paper also provides a lot of data for the alkali-activated slag cementitious for future development of the mix design. PMID- 30424555 TI - Sources and Characteristics of Particulate Matter in Subway Tunnels in Seoul, Korea. AB - Hazards related to particulate matter (PM) in subway systems necessitate improvement of the air quality. As a first step toward establishing a management strategy, we assessed the physicochemical characteristics of PM in a subway system in Seoul, South Korea. The mean mass of PM10 and PM2.5 concentrations (n = 13) were 213.7 +/- 50.4 and 78.4 +/- 8.8 ug/m3, with 86.0% and 85.9% of mass concentration. Chemical analysis using a thermal-optical elemental/organic carbon (EC-OC) analyzer, ion chromatography (IC), and inductively coupled plasma (ICP) spectroscopy indicated that the chemical components in the subway tunnel comprised 86.0% and 85.9% mass concentration of PM10 and PM2.5. Fe was the most abundant element in subway tunnels, accounting for higher proportions of PM, and was detected in PM with diameters >94 nm. Fe was present mostly as iron oxides, which were emitted from the wheel-rail-brake and pantograph-catenary wire interfaces. Copper particles were 96-150 nm in diameter and were likely emitted via catenary wire arc discharges. Furthermore, X-ray diffraction analysis (XRD) showed that the PM in subway tunnels was composed of calcium carbonate (CaCO3), quartz (SiO2), and iron oxides (hematite (alpha-Fe2O3) and maghemite-C (gamma Fe2O3)). Transmission electron microscopy images revealed that the PM in subway tunnels existed as agglomerates of iron oxide particle clusters a few nanometers in diameter, which were presumably generated at the aforementioned interfaces and subsequently attached onto other PM, enabling the growth of aggregates. Our results can help inform the management of PM sources from subway operation. PMID- 30424557 TI - Targeting Cancer with Phytochemicals via Their Fine Tuning of the Cell Survival Signaling Pathways. AB - The role of phytochemicals as potential prodrugs or therapeutic substances against tumors has come in the spotlight in the very recent years, thanks to the huge mass of encouraging and promising results of the in vitro activity of many phenolic compounds from plant raw extracts against many cancer cell lines. Little but important evidence can be retrieved from the clinical and nutritional scientific literature, where flavonoids are investigated as major pro-apoptotic and anti-metastatic compounds. However, the actual role of these compounds in cancer is still far to be fully elucidated. Many of these phytochemicals act in a pleiotropic and poorly specific manner, but, more importantly, they are able to tune the reactive oxygen species (ROS) signaling to activate a survival or a pro autophagic and pro-apoptosis mechanism, depending on the oxidative stress responsive endowment of the targeted cell. This review will try to focus on this issue. PMID- 30424556 TI - Effects of Resveratrol on the Renin-Angiotensin System in the Aging Kidney. AB - The renin-angiotensin system (RAS), especially the angiotensin II (Ang II)/angiotensin II type 1 receptor (AT1R) axis, plays an important role in the aging process of the kidney, through increased tissue reactive oxygen species production and progressively increased oxidative stress. In contrast, the angiotensin 1-7 (Ang 1-7)/Mas receptor (MasR) axis, which counteracts the effects of Ang II, is protective for end-organ damage. To evaluate the ability of resveratrol (RSV) to modulate the RAS in aging kidneys, eighteen-month-old male C57BL/6 mice were divided into two groups that received either normal mouse chow or chow containing resveratrol, for six months. Renal expressions of RAS components, as well as pro- and antioxidant enzymes, were measured and mouse kidneys were isolated for histopathology. Resveratrol-treated mice demonstrated better renal function and reduced albuminuria, with improved renal histologic findings. Resveratrol suppressed the Ang II/AT1R axis and enhanced the AT2R/Ang 1 7/MasR axis. Additionally, the expression of nicotinamide adenine dinucleotide phosphate oxidase 4, 8-hydroxy-2'-deoxyguanosine, 3-nitrotyrosine, collagen IV, and fibronectin was decreased, while the expression of endothelial nitric oxide synthase and superoxide dismutase 2 was increased by resveratrol treatment. These findings demonstrate that resveratrol exerts protective effects on aging kidneys by reducing oxidative stress, inflammation, and fibrosis, through Ang II suppression and MasR activation. PMID- 30424558 TI - Sensor-Based Safety Performance Assessment of Individual Construction Workers. AB - Over the last decade, researchers have explored various technologies and methodologies to enhance worker safety at construction sites. The use of advanced sensing technologies mainly has focused on detecting and warning about safety issues by directly relying on the detection capabilities of these technologies. Until now, very little research has explored methods to quantitatively assess individual workers' safety performance. For this, this study uses a tracking system to collect and use individuals' location data in the proposed safety framework. A computational and analytical procedure/model was developed to quantify the safety performance of individual workers beyond detection and warning. The framework defines parameters for zone-based safety risks and establishes a zone-based safety risk model to quantify potential risks to workers. To demonstrate the model of safety analysis, the study conducted field tests at different construction sites, using various interaction scenarios. Probabilistic evaluation showed a slight underestimation and overestimation in certain cases; however, the model represented the overall safety performance of a subject quite well. Test results showed clear evidence of the model's ability to capture safety conditions of workers in pre-identified hazard zones. The developed approach presents a way to provide visualized and quantified information as a form of safety index, which has not been available in the industry. In addition, such an automated method may present a suitable safety monitoring method that can eliminate human deployment that is expensive, error prone, and time-consuming. PMID- 30424559 TI - Electrolytic Surface Treatment for Improved Adhesion between Carbon Fibre and Polycarbonate. AB - To achieve good mechanical properties of carbon fibre-reinforced polycarbonate composites, the fibre-matrix adhesion must be dialled to an optimum level. The electrolytic surface treatment of carbon fibres during their production is one of the possible means of adapting the surface characteristics of the fibres. The production of a range of tailored fibres with varying surface treatments (adjusting the current, potential, and conductivity) was followed by contact angle, inverse gas chromatography and X-ray photoelectron spectroscopy measurements, which revealed a significant increase in polarity and hydroxyl, carboxyl, and nitrile groups on the fibre surface. Accordingly, an increase in the fibre-matrix interaction indicated by a higher interfacial shear strength was observed with the single fibre pull-out force-displacement curves. The statistical analysis identified the correlation between the process settings, fibre surface characteristics, and the performance of the fibres during single fibre pull-out testing. PMID- 30424560 TI - The Phytochemistry of Cherokee Aromatic Medicinal Plants. AB - Background: Native Americans have had a rich ethnobotanical heritage for treating diseases, ailments, and injuries. Cherokee traditional medicine has provided numerous aromatic and medicinal plants that not only were used by the Cherokee people, but were also adopted for use by European settlers in North America. Methods: The aim of this review was to examine the Cherokee ethnobotanical literature and the published phytochemical investigations on Cherokee medicinal plants and to correlate phytochemical constituents with traditional uses and biological activities. Results: Several Cherokee medicinal plants are still in use today as herbal medicines, including, for example, yarrow (Achillea millefolium), black cohosh (Cimicifuga racemosa), American ginseng (Panax quinquefolius), and blue skullcap (Scutellaria lateriflora). This review presents a summary of the traditional uses, phytochemical constituents, and biological activities of Cherokee aromatic and medicinal plants. Conclusions: The list is not complete, however, as there is still much work needed in phytochemical investigation and pharmacological evaluation of many traditional herbal medicines. PMID- 30424561 TI - Could Robots Help Older People with Age-Related Nutritional Problems? Opinions of Potential Users. AB - Background: The rapid development of new technologies has recently raised interest in the use of assistive robots in the care of older people. The success or failure of robots' implementation is mediated by their acceptance by users. The aim of the study was to answer the question of how both older people and caregivers perceive the possibility of using an assistive robot for nutritional support. Methods: Opinions of 252 respondents (126 older-aged 65 and above; 126 younger ones-aged below 65) from five European countries were collected using the Users' Needs, Requirements, and Abilities Questionnaire. Results: The majority of participants positively assessed the possibility of using a robot to improve the diet of older people by giving advice on healthy eating or monitoring the amount of food consumed by the owner. An age-related difference was observed, as older people less frequently accepted the reminding of meal times or drinking liquids than younger participants. Four key categories related to the robot's role in the diet of older people were identified: matching the needs, robot's characteristics, ethical issues and technical/financial issues. Conclusions: Our preliminary research has shown a positive approach to robots in the context of their nutrition-related aspects. An indication has been made of the need to include older people and other stakeholders in the process of designing these functionalities and modeling human-robot interactions based on communication theories. PMID- 30424562 TI - Dissecting the Contribution of Release Factor Interactions to Amber Stop Codon Reassignment Efficiencies of the Methanocaldococcus jannaschii Orthogonal Pair. AB - Non-canonical amino acids (ncAAs) are finding increasing use in basic biochemical studies and biomedical applications. The efficiency of ncAA incorporation is highly variable, as a result of competing system composition and codon context effects. The relative quantitative contribution of the multiple factors affecting incorporation efficiency are largely unknown. This manuscript describes the use of green fluorescent protein (GFP) reporters to quantify the efficiency of amber codon reassignment using the Methanocaldococcus jannaschii orthogonal pair system, commonly employed for ncAA incorporation, and quantify the contribution of release factor 1 (RF1) to the overall efficiency of amino acid incorporation. The efficiencies of amber codon reassignments were quantified at eight positions in GFP and evaluated in multiple combinations. The quantitative contribution of RF1 competition to reassignment efficiency was evaluated through comparisons of amber codon suppression efficiencies in normal and genomically recoded Escherichia coli strains. Measured amber stop codon reassignment efficiencies for eight single stop codon GFP variants ranged from 51 to 117% in E. coli DH10B and 76 to 104% in the RF1 deleted E. coli C321.DeltaA.exp. Evaluation of efficiency changes in specific sequence contexts in the presence and absence of RF1 suggested that RF1 specifically interacts with +4 Cs and that the RF1 interactions contributed approximately half of the observed sequence context dependent variation in measured reassignment efficiency. Evaluation of multisite suppression efficiencies suggests that increasing demand for translation system components limits multisite incorporation in cells with competing RF1. PMID- 30424563 TI - Rapid Solar-Light Driven Superior Photocatalytic Degradation of Methylene Blue Using MoS2-ZnO Heterostructure Nanorods Photocatalyst. AB - Herein, MoS2-ZnO heterostructure nanorods were hydrothermally synthesized and characterized in detail using several compositional, optical, and morphological techniques. The comprehensive characterizations show that the synthesized MoS2/ZnO heterostructure nanorods were composed of wurtzite hexagonal phase of ZnO and rhombohedral phase of MoS2. The synthesized MoS2/ZnO heterostructure nanorods were used as a potent photocatalyst for the decomposition of methylene blue (MB) dye under natural sunlight. The prepared MoS2/ZnO heterostructure nanorods exhibited ~97% removal of MB in the reaction time of 20 min with the catalyst amount of 0.15 g/L. The kinetic study revealed that the photocatalytic removal of MB was found to be in accordance with pseudo first-order reaction kinetics with an obtained rate constant of 0.16262 min-1. The tremendous photocatalytic performance of MoS2-ZnO heterostructure nanorods could be accredited to an effective charge transportation and inhibition in the recombination of photo-excited charge carriers at an interfacial heterojunction. The contribution of active species towards the decomposition of MB using MoS2-ZnO heterostructure nanorods was confirmed from scavenger study and terephthalic acid fluorescence technique. PMID- 30424564 TI - Multiscale Analysis of CFRP Laminates with MMF3 Criterion under Different Off Axis Loading Conditions. AB - A multiscale analysis strategy with physical modified-micromechanics of failure (MMF3) criterion was proposed to analyze the failure behaviors of carbon fiber reinforced plastic (CFRP) laminates. The quantitative relationship between the macro- and micro- stresses was determined considering two typical fiber distributions. Thermal residual stress was taken into account in the stress transformation. The failures were defined and the properties of damaged elements were degraded at the constituent level. The back-calculation method based on the iteration algorithm was proposed to determine the micro strength with macro mechanical tests. A series of off-axis loading tests were conducted to verify the established multiscale models. The predicted strength was also compared with the results using micromechanics of failure (MMF) criterion to present accuracy improvements. Thermal residual stress was found to affect the strength by contributing to the matrix damage status. Meanwhile, sensitivity analysis was provided for the matrix-dominant micro strength to investigate its physical meaning. Results suggest that the micro tensile and compressive strength of the matrix influenced the off-axis tensile and compressive strengths respectively, with relative large off-axis angles, while the micro shear strength of the matrix dominated when the off-axis angles were relative small. PMID- 30424566 TI - A Comparative Study of Interdigitated Electrode and Quartz Crystal Microbalance Transduction Techniques for Metal-Organic Framework-Based Acetone Sensors. AB - We present a comparative study of two types of sensor with different transduction techniques but coated with the same sensing material to determine the effect of the transduction mechanism on the sensing performance of sensing a target analyte. For this purpose, interdigitated electrode (IDE)-based capacitors and quartz crystal microbalance (QCM)-based resonators were coated with a zeolitic imidazolate framework (ZIF-8) metal-organic framework thin films as the sensing material and applied to the sensing of the volatile organic compound acetone. Cyclic immersion in methanolic precursor solutions technique was used for depositing the ZIF-8 thin films. The sensors were exposed to various acetone concentrations ranging from 5.3 to 26.5 vol % in N2 and characterized/compared for their sensitivity, hysteresis, long-term and short-term stability, selectivity, detection limit, and effect of temperature. Furthermore, the IDE substrates were used for resistive transduction and compared using capacitive transduction. PMID- 30424565 TI - Microfluidic Analyzer Enabling Quantitative Measurements of Specific Intracellular Proteins at the Single-Cell Level. AB - This paper presents a microfluidic instrument capable of quantifying single-cell specific intracellular proteins, which are composed of three functioning modules and two software platforms. Under the control of a LabVIEW platform, a pressure module flushed cells stained with fluorescent antibodies through a microfluidic module with fluorescent intensities quantified by a fluorescent module and translated into the numbers of specific intracellular proteins at the single-cell level using a MATLAB platform. Detection ranges and resolutions of the analyzer were characterized as 896.78-6.78 * 105 and 334.60 nM for Alexa 488, 314.60-2.11 * 105 and 153.98 nM for FITC, and 77.03-5.24 * 104 and 37.17 nM for FITC-labelled anti-beta-actin antibodies. As a demonstration, the numbers of single-cell beta actins of two paired oral tumor cell types and two oral patient samples were quantified as: 1.12 +/- 0.77 * 106/cell (salivary adenoid cystic carcinoma parental cell line (SACC-83), ncell = 13,689) vs. 0.90 +/- 0.58 * 105/cell (salivary adenoid cystic carcinoma lung metastasis cell line (SACC-LM), ncell = 15,341); 0.89 +/- 0.69 * 106/cell (oral carcinoma cell line (CAL 27), ncell = 7357) vs. 0.93 +/- 0.69 * 106/cell (oral carcinoma lymphatic metastasis cell line (CAL 27-LN2), ncell = 6276); and 0.86 +/- 0.52 * 106/cell (patient I) vs. 0.85 +/ 0.58 * 106/cell (patient II). These results (1) validated the developed analyzer with a throughput of 10 cells/s and a processing capability of ~10,000 cells for each cell type, and (2) revealed that as an internal control in cell analysis, the expressions of beta-actins remained stable in oral tumors with different malignant levels. PMID- 30424567 TI - Triple-Band Dual-Sense Circularly Polarized Hybrid Dielectric Resonator Antenna. AB - In this paper, a triple-band dual-sense circularly polarized (CP) hybrid dielectric resonator antenna is proposed. A modified hexagonal dielectric resonator (DR) is top-loaded with a square microstrip ring (SMR). A vertical tapered-strip connected to a 50- Omega microstrip line is used to excite the proposed antenna. It is found that the lower and central CP bands correspond to left-handed circular polarization and are produced by the TM 11 and TE 111 modes of the SMR and modified hexagonal DR, respectively. The upper CP band is formed by the combination of the quasi-TM 21 mode of the SMR and quasi-TE 111 mode of the DR that exhibits right-handed circular polarization. The measurement results of the fabricated prototype show triple-band response for |S 11 | < -10 dB with impedance bandwidths (IBWs) of 17.4% (1.75-2.03 GHz), 28.13% (2.23-2.96 GHz), and 2.97% (3.65-3.76 GHz) in the lower, central, and upper bands, respectively. The measured 3 dB axial ratio bandwidths lying within -10 dB IBWs are 3.69% (1.86 1.93 GHz), 5.46% (2.67-2.82 GHz), and 2.15% (3.68-3.76 GHz) along with the peak gains of 5 dBic, 5.28 dBic, and 2.36 dBic in the lower, central, and upper bands, respectively. PMID- 30424568 TI - Correction Method for the Observed Global Navigation Satellite System Ultra-Rapid Orbit Based on Dilution of Precision Values. AB - For ultra-rapid orbits provided by the Global Navigation Satellite System (GNSS), the key parameters, accuracy and timeliness, must be taken into consideration in real-time and near real-time applications. However, insufficient observations in later epochs appear to generate low accuracy in observed orbits, for which a correlation between the Dilution of Precision (DOP) of the orbit parameters and their accuracy is found. To correct the observed GNSS ultra-rapid orbit, a correction method based on the DOP values is proposed by building the function models between DOP values and the orbit accuracy. With 10-day orbit determination experiments, the results show that the observed ultra-rapid-orbit errors, generated by insufficient observations, can be corrected by 12-22% for the last three hours of the observed orbits. Moreover, considering the timeliness constraints in ultra-rapid-orbit determination, a DOP amplification factor is defined to weight the contribution of each tracking station and optimize the station distribution in the orbit determination procedure. Finally, six schemes are designed to verify the method and strategy in determining the ultra-rapid orbit based on one-month observations. The orbit accuracy is found to decrease by 1.27-6.34 cm with increasing amplification factor from 5-20%. Thus, the observed ultra-orbit correction method proposed is ideal when considering accuracy and timeliness in ultra-rapid orbit determination. PMID- 30424570 TI - The Protective Role of Dormant Origins in Response to Replicative Stress. AB - Genome stability requires tight regulation of DNA replication to ensure that the entire genome of the cell is duplicated once and only once per cell cycle. In mammalian cells, origin activation is controlled in space and time by a cell specific and robust program called replication timing. About 100,000 potential replication origins form on the chromatin in the gap 1 (G1) phase but only 20-30% of them are active during the DNA replication of a given cell in the synthesis (S) phase. When the progress of replication forks is slowed by exogenous or endogenous impediments, the cell must activate some of the inactive or "dormant" origins to complete replication on time. Thus, the many origins that may be activated are probably key to protect the genome against replication stress. This review aims to discuss the role of these dormant origins as safeguards of the human genome during replicative stress. PMID- 30424569 TI - Association of Muscular Fitness and Body Fatness with Cardiometabolic Risk Factors: The FUPRECOL Study. AB - This study investigated the associations of muscular fitness and various indicators of body fatness with cardio-metabolic risk factors and determined the muscular strength and body fatness thresholds for detecting a high risk of cardio metabolic dysfunction in young adults. A cross-sectional study was conducted on 1798 collegiate students (61.5% females, mean age 20.5 years). Muscular fitness was determined by using a handgrip strength test and normalized grip strength (NGS = handgrip (kg)/body mass (kg)). Body mass index (BMI), waist circumference (WC), percentage of fat mass (BF%), fat-mass index (FMI), and waist-to-height ratio (WHR) were also included as body fatness measurements. A high cardio metabolic risk cluster was derived by assessing triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, fasting glucose, and blood pressure. Logistic regression models showed that men and women with lower NGS had an increased cardio-metabolic risk odds ratio (OR) = 1.8, 95% confidence interval (CI) 1.1 to 2.9, p = 0.006, and OR = 1.6, 95% CI 1.0 to 2.5, p = 0.036, respectively). In both sexes, higher levels of all fatness parameters were also associated with increased cardio-metabolic risk (p < 0.001). In both men and women, high FMI had the highest OR for clustered risk (OR = 4.7, 95% CI 2.6 to 8.4, and OR = 7.3, 95% CI 3.4 to 9.7, p < 0.001, respectively). Combined analysis showed that unfitness (lower NGS) and high fat had the highest OR for WC and FMI in men and women, respectively (OR = 5.5, 95% CI 2.6 to 11.4, OR = 7.7, 95% CI 2.3 to 15.8, p < 0.01). Muscular strength and body fatness are independently and jointly associated with increased cardiometabolic risk in young adults, which suggests that both are predictor variables for this. PMID- 30424571 TI - Aluminum Patterned Electroplating from AlCl3-[EMIm]Cl Ionic Liquid towards Microsystems Application. AB - Electroplating process is being used to deposit a relatively thick film of metallic materials for various microsystems applications, such as for the wafer level bonding sealing frame and as a thermal actuator. Recently, the Al electroplating process from ionic liquid has been an attractive deposition method for anti-corrosion coatings. To extend the utilization of the film, in particular for microsystems application, a microstructure formation by patterned electroplating of Al from AlCl 3 -1-ethyl-3-methylimidazolium chloride ((EMIm)Cl) ionic liquid is investigated in this study. The influences of each deposition parameters to the electroplating process as well as the resulting surface morphology are evaluated. Electroplated Al deposits on both Au and Al seed layers are both studied. It is also found that a recurrent galvanic pulse plating process yields in a higher current efficiency. Finally, Al electroplating on a 2 um-trenched 100 mm-wafer is also demonstrated. PMID- 30424572 TI - Pretreatment with NaCl Promotes the Seed Germination of White Clover by Affecting Endogenous Phytohormones, Metabolic Regulation, and Dehydrin-Encoded Genes Expression under Water Stress. AB - This study was designed to examine the effects of NaCl pretreatment on the seed germination of white clover (Trifolium repens cv. Ladino) under water stress induced by 19% polyethylene glycol (PEG) 6000. Lower concentrations of NaCl (0.5, 1, and 2.5 mM) pretreatment significantly alleviated stress-induced decreases in germination percentage, germination vigor, germination index, and radicle length of seedlings after seven days of germination under water stress. The soaking with 1 mM of NaCl exhibited most the pronounced effects on improving seed germination and alleviating stress damage. NaCl-induced seeds germination and growth could be associated with the increases in endogenous gibberellic acid (GA) and indole-3 acetic acid (IAA) levels through activating amylases leading to improved amylolysis under water stress. Seedlings pretreated with NaCl had a significantly lower osmotic potential than untreated seedlings during seed germination, which could be related to significantly higher soluble sugars and free proline content in NaCl-treated seedlings under water stress. For antioxidant metabolism, NaCl pretreatment mainly improved superoxide dismutase, peroxidase, ascorbate peroxidase, and glutathione reductase activities, transcript levels of FeSOD, APX, and DHAR, and the content of ascorbic acid, reduced glutathione, and oxidized glutathione during seed germination under water stress. The results indicated that seeds soaking with NaCl could remarkably enhance antioxidant metabolism, thereby decreasing the accumulation of reactive oxygen species and membrane lipid peroxidation during germination under water stress. In addition, NaCl-upregulated dehydrin-encoded genes SK2 expression could be another important mechanism of drought tolerance during seeds germination of white clover in response to water stress. PMID- 30424573 TI - Spin Rate Effects in a Micromachined Electrostatically Suspended Gyroscope. AB - Spin rate of a high-speed spinning-rotor gyroscope will make a significant impact on angular rate sensor performances such as the scale factor, resolution, measurement range, and bias stability. This paper presents the spin rate effects on performance indicators of a microelectromechanical systems (MEMS) gyroscope where a free-spinning rotor is electrostatically suspended in an evacuated vacuum cavity and functions as a dual-axis angular rate sensor. Theoretical models of the scale factor and measurement range of such a spinning-rotor gyroscope are derived. The experimental results indicate that the measured scale factors at different settings of the spin rate match well with the theoretical predication. In order to separate the disturbance component of the rotation control loop on the gyroscope output, a testing strategy is proposed by operating the gyroscope at different spin rates. Experimental results on a prototype gyroscope show that the squared drive voltage generated by the rotation control loop is approximately proportional to the noise of the gyroscope output. It was further investigated that an improved performance of such spinning-rotor gyroscopes can be achieved by operating the gyroscope rotor at an optimal spin rate. PMID- 30424574 TI - The Melting Diagram of Protein Solutions and Its Thermodynamic Interpretation. AB - Here we present a novel method for the characterization of the hydration of protein solutions based on measuring and evaluating two-component wide-line 1H NMR signals. We also provide a description of key elements of the procedure conceived for the thermodynamic interpretation of such results. These interdependent experimental and theoretical treatments provide direct experimental insight into the potential energy surface of proteins. The utility of our approach is demonstrated through the examples of two proteins of distinct structural classes: the globular, structured ubiquitin; and the intrinsically disordered ERD10 (early response to dehydration 10). We provide a detailed analysis and interpretation of data recorded earlier by cooling and slowly warming the protein solutions through thermal equilibrium states. We introduce and use order parameters that can be thus derived to characterize the distribution of potential energy barriers inhibiting the movement of water molecules bound to the surface of the protein. Our results enable a quantitative description of the ratio of ordered and disordered parts of proteins, and of the energy relations of protein-water bonds in aqueous solutions of the proteins. PMID- 30424575 TI - Measurements and Accuracy Evaluation of a Strapdown Marine Gravimeter Based on Inertial Navigation. AB - The strapdown gravimetry system uses the combination of an Inertial Measuring Unit (IMU) and a Global Navigation Satellite System (GNSS) to measure the Earth's gravity field. Due to limited accuracies of IMU and GNSS, early strapdown gravimetry systems were more often used in airborne surveys, but less used in marine surveys. We developed a strapdown inertial navigation system (SINS), the Sea-Air Gravimeter-2Marine (SAG-2M), using novel IMU components, whose accuracy was further improved with the application of Precise Point Positioning (PPP) and enhanced algorithm, making it possible to be used in marine gravity survey. The testing results of the SAG-2M were compared to those of the Lacoste and Romberg S 129 gravimeter on the same ship in the South China Sea basin. The cruise lasted for 50 days, during which 134 effective gravity profiles were measured, resulting in 174 crossover points. The results showed that, for the SAG-2M, the root mean square (RMS) crossover points were 1.35 mGal before difference adjustment and 0.69 mGal after difference adjustment; for the S-129 gravimeter, they were 5.62 mGal and 0.95 mGal, correspondingly. In calm sea conditions, the results of the two systems were relatively consistent at all wavelengths. However, in rough sea conditions, since the SAG-2M was not affected by the cross-coupling effect, its data demonstrated less high-frequency jump. A physical platform adopted in SAG-2M can further make the transition data effective when the ship is turning around. Therefore, SAG-2M was able to improve the proportion of valid data and the efficiency of data post-processing for measurements taken during the cruise. The testing results indicate that in terms of accuracy and efficiency in the marine gravity survey, SAG-2M is better than S-129. In addition, as the miniaturization and precision of inertial components are developing continuously, SAG-2M also shows great potential in miniaturization. PMID- 30424576 TI - Exploring Solanum tuberosum Epoxide Hydrolase Internal Architecture by Water Molecules Tracking. AB - Several different approaches are used to describe the role of protein compartments and residues in catalysis and to identify key residues suitable for the modification of the activity or selectivity of the desired enzyme. In our research, we applied a combination of molecular dynamics simulations and a water tracking approach to describe the water accessible volume of Solanum tuberosum epoxide hydrolase. Using water as a molecular probe, we were able to identify small cavities linked with the active site: (i) one made up of conserved amino acids and indispensable for the proper positioning of catalytic water and (ii) two others in which modification can potentially contribute to enzyme selectivity and activity. Additionally, we identified regions suitable for de novo tunnel design that could also modify the catalytic properties of the enzyme. The identified hot-spots extend the list of the previously targeted residues used for modification of the regioselectivity of the enzyme. Finally, we have provided an example of a simple and elegant process for the detailed description of the network of cavities and tunnels, which can be used in the planning of enzyme modifications and can be easily adapted to the study of any other protein. PMID- 30424577 TI - A Classification-Lock Tracking Strategy Allowing a Person-Following Robot to Operate in a Complicated Indoor Environment. AB - Person-following technology is an important robot service. The major trend of person-following is to utilize computer vision technology to localize the target person, due to the wide view and rich information that is obtained from the real world through a camera. However, most existing approaches employ the detecting-by tracking strategy, which suffers from low speed, accompanied with more complicated detecting models and unstable region of interest (ROI) outputs in unexpressed situations. In this paper, we propose a novel classification-lock strategy to localize the target person, which incorporates the visual tracking technology with object detection technology, to adapt the localization model to different environments online, and to keep a high frame-per-second (FPS) on the mobile platform. This person-following approach consists of three key parts. In the first step, a pairwise cluster tracker is employed to localize the person. A positive and negative classifier is then utilized to verify the tracker's result and to update the tracking model. In addition, a detector pre-trained by a CPU optimized convolutional neural network is used to further improve the result of tracking. In the experiment, our approach is compared with other state-of-art approaches by a Vojir tracking dataset, with three sequences in the items of human to prove the quality of person localization. Moreover, the common challenges during the following task are evaluated by several image sequences in a static scene, and a dynamic scene is used to evaluate the improvement from the classification-lock strategy. Finally, our approach is deployed on a mobile robot to test its performance on the function of the person-following. Compared with other state-of-art methods, our approach achieves the highest score (0.91 recall rate). In the static and dynamic scene, the output of the ROI based on the classification-lock strategy is significantly better than that without it. Our approach also succeeds in a long-term following task in an indoor multi-floor scenario. PMID- 30424578 TI - Assembly of a Complete Mitogenome of Chrysanthemum nankingense Using Oxford Nanopore Long Reads and the Diversity and Evolution of Asteraceae Mitogenomes. AB - Diversity in structure and organization is one of the main features of angiosperm mitochondrial genomes (mitogenomes). The ultra-long reads of Oxford Nanopore Technology (ONT) provide an opportunity to obtain a complete mitogenome and investigate the structural variation in unprecedented detail. In this study, we compared mitogenome assembly methods using Illumina and/or ONT sequencing data and obtained the complete mitogenome (208 kb) of Chrysanthemum nankingense based on the hybrid assembly method. The mitogenome encoded 19 transfer RNA genes, three ribosomal RNA genes, and 34 protein-coding genes with 21 group II introns disrupting eight intron-contained genes. A total of seven medium repeats were related to homologous recombination at different frequencies as supported by the long ONT reads. Subsequently, we investigated the variations in gene content and constitution of 28 near-complete mitogenomes from Asteraceae. A total of six protein-coding genes were missing in all Asteraceae mitogenomes, while four other genes were not detected in some lineages. The core fragments (~88 kb) of the Asteraceae mitogenomes had a higher GC content (~46.7%) than the variable and specific fragments. The phylogenetic topology based on the core fragments of the Asteraceae mitogenomes was highly consistent with the topologies obtained from the corresponding plastid datasets. Our results highlighted the advantages of the complete assembly of the C. nankingense mitogenome and the investigation of its structural variation based on ONT sequencing data. Moreover, the method based on local collinear blocks of the mitogenomes could achieve the alignment of highly rearrangeable and variable plant mitogenomes as well as construct a robust phylogenetic topology. PMID- 30424579 TI - Effects of Cardiovascular Risk Factors on Cardiac STAT3. AB - Nuclear, mitochondrial and cytoplasmic signal transducer and activator of transcription 3 (STAT3) regulates many cellular processes, e.g., the transcription or opening of mitochondrial permeability transition pore, and its activity depends on the phosphorylation of Tyr705 and/or Ser727 sites. In the heterogeneous network of cardiac cells, STAT3 promotes cardiac muscle differentiation, vascular element formation and extracellular matrix homeostasis. Overwhelming evidence suggests that STAT3 is beneficial for the heart, plays a role in the prevention of age-related and postpartum heart failure, protects the heart against cardiotoxic doxorubicin or ischaemia/reperfusion injury, and is involved in many cardioprotective strategies (e.g., ischaemic preconditioning, perconditioning, postconditioning, remote or pharmacological conditioning). Ischaemic heart disease is still the leading cause of death worldwide, and many cardiovascular risk factors contribute to the development of the disease. This review focuses on the effects of various cardiovascular risk factors (diabetes, aging, obesity, smoking, alcohol, depression, gender, comedications) on cardiac STAT3 under non-ischaemic baseline conditions, and in settings of ischaemia/reperfusion injury with or without cardioprotective strategies. PMID- 30424580 TI - Kat2a and Kat2b Acetyltransferase Activity Regulates Craniofacial Cartilage and Bone Differentiation in Zebrafish and Mice. AB - Cranial neural crest cells undergo cellular growth, patterning, and differentiation within the branchial arches to form cartilage and bone, resulting in a precise pattern of skeletal elements forming the craniofacial skeleton. However, it is unclear how cranial neural crest cells are regulated to give rise to the different shapes and sizes of the bone and cartilage. Epigenetic regulators are good candidates to be involved in this regulation, since they can exert both broad as well as precise control on pattern formation. Here, we investigated the role of the histone acetyltransferases Kat2a and Kat2b in craniofacial development using TALEN/CRISPR/Cas9 mutagenesis in zebrafish and the Kat2ahat/hat (also called Gcn5) allele in mice. kat2a and kat2b are broadly expressed during embryogenesis within the central nervous system and craniofacial region. Single and double kat2a and kat2b zebrafish mutants have an overall shortening and hypoplastic nature of the cartilage elements and disruption of the posterior ceratobranchial cartilages, likely due to smaller domains of expression of both cartilage- and bone-specific markers, including sox9a and col2a1, and runx2a and runx2b, respectively. Similarly, in mice we observe defects in the craniofacial skeleton, including hypoplastic bone and cartilage and altered expression of Runx2 and cartilage markers (Sox9, Col2a1). In addition, we determined that following the loss of Kat2a activity, overall histone 3 lysine 9 (H3K9) acetylation, the main epigenetic target of Kat2a/Kat2b, was decreased. These results suggest that Kat2a and Kat2b are required for growth and differentiation of craniofacial cartilage and bone in both zebrafish and mice by regulating H3K9 acetylation. PMID- 30424581 TI - Alcoholic Liver Disease: Alcohol Metabolism, Cascade of Molecular Mechanisms, Cellular Targets, and Clinical Aspects. AB - Alcoholic liver disease is the result of cascade events, which clinically first lead to alcoholic fatty liver, and then mostly via alcoholic steatohepatitis or alcoholic hepatitis potentially to cirrhosis and hepatocellular carcinoma. Pathogenetic events are linked to the metabolism of ethanol and acetaldehyde as its first oxidation product generated via hepatic alcohol dehydrogenase (ADH) and the microsomal ethanol-oxidizing system (MEOS), which depends on cytochrome P450 2E1 (CYP 2E1), and is inducible by chronic alcohol use. MEOS induction accelerates the metabolism of ethanol to acetaldehyde that facilitates organ injury including the liver, and it produces via CYP 2E1 many reactive oxygen species (ROS) such as ethoxy radical, hydroxyethyl radical, acetyl radical, singlet radical, superoxide radical, hydrogen peroxide, hydroxyl radical, alkoxyl radical, and peroxyl radical. These attack hepatocytes, Kupffer cells, stellate cells, and liver sinusoidal endothelial cells, and their signaling mediators such as interleukins, interferons, and growth factors, help to initiate liver injury including fibrosis and cirrhosis in susceptible individuals with specific risk factors. Through CYP 2E1-dependent ROS, more evidence is emerging that alcohol generates lipid peroxides and modifies the intestinal microbiome, thereby stimulating actions of endotoxins produced by intestinal bacteria; lipid peroxides and endotoxins are potential causes that are involved in alcoholic liver injury. Alcohol modifies SIRT1 (Sirtuin-1; derived from Silent mating type Information Regulation) and SIRT2, and most importantly, the innate and adapted immune systems, which may explain the individual differences of injury susceptibility. Metabolic pathways are also influenced by circadian rhythms, specific conditions known from living organisms including plants. Open for discussion is a 5-hit working hypothesis, attempting to define key elements involved in injury progression. In essence, although abundant biochemical mechanisms are proposed for the initiation and perpetuation of liver injury, patients with an alcohol problem benefit from permanent alcohol abstinence alone. PMID- 30424582 TI - Molecular Modeling and In Vitro Studies of a Neutral Oxime as a Potential Reactivator for Acetylcholinesterase Inhibited by Paraoxon. AB - The present work aimed to compare the small, neutral and monoaromatic oxime, isatin-3-oxime (isatin-O), to the commercial ones, pralidoxime (2-PAM) and obidoxime, in a search for a new potential reactivator for acetylcholinesterase (AChE) inhibited by the pesticide paraoxon (AChE/POX) as well as a novel potential scaffold for further synthetic modifications. The multicriteria decision methods (MCDM) allowed the identification of the best docking poses of those molecules inside AChE/POX for further molecular dynamic (MD) studies, while Ellman's modified method enabled in vitro inhibition and reactivation assays. In corroboration with the theoretical studies, our experimental results showed that isatin-O have a reactivation potential capable of overcoming 2-PAM at the initial moments of the assay. Despite not achieving better results than obidoxime, this molecule is promising for being an active neutral oxime with capacity of crossing the blood-brain barrier (BBB), to reactivate AChE/POX inside the central and peripheral nervous systems. Moreover, the fact that isatin-O can also act as anticonvulsant makes this molecule a possible multipotent reactivator. Besides, the MCDM method showed to be an accurate method for the selection of the best docking poses generated in the docking studies. PMID- 30424583 TI - A Novel Dynamic Spectrum-Sharing Method for Integrated Wireless Multimedia Sensors and Cognitive Satellite Networks. AB - With the growing demand, Wireless Multimedia Sensor Networks (WMSNs) play an increasingly important role, which enhances the capacity of typical Wireless Sensor Networks (WSNs). Additionally, integrating satellite systems into WMSNs brings about the beneficial synergy, especially in rural and sparsely populated areas. However, the available spectrum resource is scarce, which contradicts the high-speed content required for multimedia. Cognitive radio is a promising solution to address the conflict. In this context, we propose a novel spectrum sharing method for the integrated wireless multimedia sensor and cognitive satellite network based on the dynamic frequency allocation. Specifically, the Low Earth Orbit (LEO) satellite system plays the role of the auxiliary to connect sensor nodes and the remote control host, and it shares the same frequency with the Geostationary Earth Orbit (GEO) system in the downlink. Because the altitudes of GEO and LEO satellites differ greatly, the beam size of GEO is much larger than that of LEO, which provides the opportunity for LEO beam to reuse the frequency that was allocated to the GEO beam. A keep-out region is defined to guarantee the spectral coexistence based on the interference analysis in the worst case. In addition, a dynamic frequency allocation algorithm is presented to deal with the dynamic configuration caused by the satellite motion. Numerical results demonstrate that the dynamic spectrum-sharing method can improve the throughput. PMID- 30424584 TI - Diabetes in Pregnancy and MicroRNAs: Promises and Limitations in Their Clinical Application. AB - Maternal diabetes is associated with an increased risk of complications for the mother and her offspring. The latter have an increased risk of foetal macrosomia, hypoglycaemia, respiratory distress syndrome, preterm delivery, malformations and mortality but also of life-long development of obesity and diabetes. Epigenetics have been proposed as an explanation for this long-term risk, and microRNAs (miRNAs) may play a role, both in short- and long-term outcomes. Gestation is associated with increasing maternal insulin resistance, as well as beta-cell expansion, to account for the increased insulin needs and studies performed in pregnant rats support a role of miRNAs in this expansion. Furthermore, several miRNAs are involved in pancreatic embryonic development. On the other hand, maternal diabetes is associated with changes in miRNA both in maternal and in foetal tissues. This review aims to summarise the existing knowledge on miRNAs in gestational and pre-gestational diabetes, both as diagnostic biomarkers and as mechanistic players, in the development of gestational diabetes itself and also of short- and long-term complications for the mother and her offspring. PMID- 30424585 TI - What is the Evidence That Parkinson's Disease is a Prion Disorder, Which Originates in the Gut? AB - Parkinson's disease (PD) is a neurodegenerative disorder resulting from degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). PD is characterized by motor dysfunctions as well as gastrointestinal symptoms and mental impairment. The pathological hallmark of PD is an accumulation of misfolded alpha-synuclein aggregates within the brain. The etiology of PD and related synucleinopathy is poorly understood, but recently, the hypothesis that alpha-synuclein pathology spreads in a prion-like fashion originating in the gut has gained much scientific attention. A crucial clue was the appearance of constipation before the onset of motor symptoms, gut dysbiosis and synucleinopathy in PD patients. Another line of evidence, demonstrating accumulation of alpha-synuclein within the peripheral autonomic nervous system (PANS), including the enteric nervous system (ENS), and the dorsal motor nucleus of the vagus (DMV) support the concept that alpha-synuclein can spread from the ENS to the brain by the vagus nerve. The decreased risk of PD following truncal vagotomy supports this. The convincing evidence of the prion-like behavior of alpha-synuclein came from postmortem observations that pathological alpha synuclein inclusions appeared in healthy grafted neurons. In this review, we summarize the available data from human subjects' research and animal experiments, which seem to be the most suggestive for explaining the hypotheses. PMID- 30424586 TI - Anesthetic management of video-assisted thoracic surgery using the combination of midazolam and remifentanil with ketamine for spontaneous breathing. PMID- 30424587 TI - The assignment of ASA-physical status relates to anesthesiologist's experience: a survey-based national-study. AB - Background: The American Society of Anesthesiologists physical status (ASA-PS) is a grading system adopted worldwide by anesthesiologists to classify the overall health status of patients. Its importance is demonstrated not only by its routinely use in clinical practice, but also by its deployment in other healthcare-related environments. However, a weak/moderate inter-observer agreement for ASA-PS has been previously shown and, although definitions and clinical examples of each class were provided by ASA, doubts remain on the individual factors influencing the assignment to an ASA-PS class. The aim of this study was to investigate whether and how an anesthesiologist's experience conditions the classification into a specific ASA-PS class. Methods: An online survey presenting 8 fictitious patients was administered to a group of Italian anesthesiologists and residents of different experience. Respondents were asked to assign each one of the 8 patients to a specific ASA-PS class. For the comparisons, anesthesiologists were subdivided into 5 classes according to the experience as anesthesiologists. Results: Six hundred one surveys were correctly completed. The highest mean number of correct answers was obtained by residents, and this number decreased progressively with increasing work experience. The lowest value was recorded in the most experienced group (>= 20 years of experience). Conclusions: Low inter-reliability and experience-dependence of ASA PS must be taken into account when evaluating a patient, particularly in settings where wide differences in experience are present. PMID- 30424588 TI - Spinal anesthesia and postoperative epidural analgesia in a patient with congenital central hypoventilation sydrome. AB - Congenital central hypoventilation syndrome (CCHS), also known as Ondine's Curse, is a rare disorder characterized by alveolar hypoventilation and autonomic dysregulation. Patients with CCHS have adequate ventilation while awake but exhibit hypoventilation while asleep. More severely affected patients exhibit hypoventilation both when awake and when asleep. In patients with CCHS, anesthesia is used with the goal of minimizing respiratory depression to avoid prolonged mechanical ventilation. Regional anesthesia should be considered where appropriate. Continuous oxygen saturation and end-tidal carbon dioxide monitoring must be available. Here, we report a case of successful spinal anesthesia and postoperative epidural analgesia in a patient with CCHS who underwent orthostatic surgery. PMID- 30424589 TI - Coexisting Mucinous Cystic Neoplasm of the Pancreas and Type 1 Autoimmune Pancreatitis. AB - Type 1 autoimmune pancreatitis (AIP1) is an IgG4-related systemic disease that mimics tumors. We report a rare case of AIP1 accompanied by mucinous cystic neoplasm (MCN). A pancreatic lesion was incidentally detected in a woman in her 60s. After 6 years of follow-up, the lesion abruptly increased in size. Computed tomography showed a 3.5-cm unilocular cyst in the tail of the pancreas and distal pancreatectomy was performed. On microscopic examination, the cyst was lined by mucinous and non-mucinous epithelial cells with mild cytologic atypia. The surrounding stroma comprised ovarian-type spindle cells with progesterone receptor positivity. The pericystic pancreas exhibited multifocal lymphoid follicles, lymphoplasmacytic infiltrations, obliterative phlebitis, and storiform fibrosis. IgG4-positive plasma cell infiltration (215 cells/HPF) and the IgG4/IgG ratio (57%) were increased. Cases of MCN coexisting with AIP1 are extremely rare; only two such cases have been reported in the English-language literature. This third case featured low-grade MCN with AIP1. PMID- 30424590 TI - Wharton Jelly Hair in a Case of Umbilical Cord Stricture and Fetal Death. PMID- 30424591 TI - Loss of Human Leukocyte Antigen Class I Expression Is Associated with Poor Prognosis in Patients with Advanced Breast Cancer. AB - Background: Human leukocyte antigen class I (HLA-I) molecules play important roles in regulating immune responses. Loss or reduction of HLA-I expression has been shown to be associated with prognosis in several cancers. Regulatory T-cells (Tregs) also play critical functions in immune response regulation. Evaluation of HLA-I expression status by the EMR8-5 antibody and its clinical impact in breast cancer have not been well studied, and its relationship with Tregs remains unclear. Materials and Methods: We evaluated HLA-I expression and Treg infiltration by immunohistochemistry in 465 surgically resected breast cancer samples. We examined the correlation between HLA-I expression and Treg infiltration and clinicopathologic characteristics and survival analyses were performed. Results: Total loss of HLA-I expression was found in 84 (18.1%) breast cancer samples. Univariate survival analysis revealed that loss of HLA-I expression was significantly associated with worse disease-specific survival (DSS) (p = 0.029). HLA-I was not an independent prognostic factor in the entire patient group, but it was an adverse independent prognostic factor for DSS in patients with advanced disease (stage II-IV) (p = 0.031). Treg numbers were significantly higher in the intratumoral stroma of HLA-I-positive tumors than in HLA-I-negative tumors (median 6.3 cells/high power field vs. 2.1 cells/high power field, p < 0.001). However, Tregs were not an independent prognostic factor in our cohort. Conclusion: Our findings suggest that the loss of HLA-I expression is associated with poor prognosis in breast cancer patients, highlighting the role of HLA-I alterations in immune evasion mechanisms of breast cancer. HLA-I could be a promising marker that enables the application of more effective and precise immunotherapies for patients with advanced breast cancer. PMID- 30424592 TI - PLAG1, SOX10, and Myb Expression in Benign and Malignant Salivary Gland Neoplasms. AB - Background: Recent findings in molecular pathology suggest that genetic translocation and/or overexpression of oncoproteins is important in salivary gland tumorigenesis and diagnosis. We investigated PLAG1, SOX10, and Myb protein expression in various salivary gland neoplasm tissues. Materials and Methods: A total of 113 cases of surgically resected salivary gland neoplasms at the National Cancer Center from January 2007 to March 2017 were identified. Immunohistochemical staining of PLAG1, SOX10, and Myb in tissue samples was performed using tissue microarrays. Results: Among the 113 cases, 82 (72.6%) were benign and 31 (27.4%) were malignant. PLAG1 showed nuclear staining and normal parotid gland was not stained. Among 48 cases of pleomorphic adenoma, 29 (60.4%) were positive for PLAG1. All other benign and malignant salivary gland neoplasms were PLAG1-negative. SOX10 showed nuclear staining. In normal salivary gland tissues SOX10 was expressed in cells of acinus and intercalated ducts. In benign tumors, SOX10 expression was observed in all pleomorphic adenoma (48/48), and basal cell adenoma (3/3), but not in other benign tumors. SOX10 positivity was observed in 9 of 31 (29.0%) malignant tumors. Myb showed nuclear staining but was not detected in normal parotid glands. Four of 31 (12.9%) malignant tumors showed Myb positivity: 3 adenoid cystic carcinomas (AdCC) and 1 myoepithelial carcinoma with focal AdCC-like histology. Conclusion: PLAG1 expression is specific to pleomorphic adenoma. SOX10 expression is helpful to rule out excretory duct origin tumor, but its diagnostic value is relatively low. Myb is useful for diagnosing AdCC when histology is unclear in the surgical specimen. PMID- 30424593 TI - Late Subaxial Lesion after Overcorrected Occipitocervical Reconstruction in Patients with Rheumatoid Arthritis. AB - Study Design: Retrospective case-control study, level 4. Purpose: To clarify the risk factors for late subaxial lesion after occipitocervical (O-C) reconstruction. We examined cases requiring fusion-segment-extended (FE) reconstruction in addition to/after O-C reconstruction. Overview of Literature: Patients with rheumatoid arthritis (RA) frequently require O-C reconstruction surgery for cranio-cervical lesions. Acceptable outcomes are achieved via indirect decompression using cervical pedicle screws and occipital plate-rod systems. However, late subaxial lesions may develop occasionally following O-C reconstruction. Methods: O-C reconstruction using cervical pedicle screws and occipital plate-rod systems was performed between 1994 and 2007 in 113 patients with RA. Occipito-atlanto-axial (O-C2) reconstruction was performed for 89 patients, and occipito-subaxial cervical (O-under C2) reconstruction was performed for 24 patients. We reviewed the cases of patients requiring FE reconstruction (fusion extended group, FEG) and 26 consecutive patients who did not require FE reconstruction after a follow-up of >5 years (non-fusion extended group, NEG) as controls. Results: FE reconstructions were performed for nine patients at an average of 45 months (range, 24-180 months) after O-C reconstruction. Of the 89 patients, three (3%) underwent FE reconstruction in cases of O-C2 reconstruction. Of the 24 patients, five (21%) underwent FE reconstruction in cases of O-under C2 reconstruction (p=0.003, Fisher exact test). Age, sex, RA type, and neurological impairment stage were not significantly different between FEG and NEG. O-under C2 reconstruction, larger correction angle (4 degrees per number of unfixed segment), and O-C7 angle change after O-C reconstruction were the risk factors for late subaxial lesions on radiographic assessment. Conclusions: Overcorrection of angle at fusion segments requiring O-C7 angle change was a risk factor for late subaxial lesion in patients with RA with fragile bones and joints. Correction should be limited, considering the residual mobility of the cervical unfixed segments. PMID- 30424594 TI - Efficacy of the Erector Spinae Plane Block for Lumbar Spinal Surgery: A Retrospective Study. AB - Study Design: A retrospective study. Purpose: The first research on the erector spinae plane (ESP) block was published in 2016. To our knowledge, no cohort studies or randomized controlled trials of the ESP block were performed in 2016 and 2017. Overview of Literature: This study retrospectively investigated the efficacy of the ESP block in pain management after lumbar spinal surgery. Methods: Patients who underwent lumbar spinal surgery in 2017 were enrolled in the study. Those who underwent secondary surgery with local anesthesia other than the ESP block were excluded. The primary outcome was the Numerical Rating Scale (NRS) pain score at various time points until the morning of postoperative day 2. The secondary outcomes were the amount of intravenous fentanyl administered during the first 24 hours following the surgery and the number of patients with complaints of complications such as nausea and vomiting until the morning of postoperative day 2. Results: The data of 41 patients undergoing lumbar spinal surgery were retrospectively analyzed. Of these, 23 received only general anesthesia (G group), whereas the other 18 patients received the ESP block in addition to general anesthesia (E group). The NRS pain scores and the amount of fentanyl administered were lower in the G group than in the E group at all measured time points (all data were less than p<0.05). There was no significant difference in the incidence of complications between the two groups (p=0.11). Conclusions: The ESP block provides effective postoperative analgesic effect for 24 hours in patients undergoing lumbar spinal surgery. PMID- 30424595 TI - Tunable Hydrogels Derived from Genetically Engineered Extracellular Matrix Accelerate Diabetic Wound Healing. AB - Hydrogels composed of solubilized decellularized extracellular matrix (ECM) are attractive materials because they combine the complexity of native ECM with injectability and ease of use. Nevertheless, these materials are typically only tunable by altering the concentration, which alters the ligand landscape, or by incorporating synthetic components, which can result in an unfavorable host response. Herein, we demonstrate the fabrication of genetically tunable ECM derived materials, by utilizing wild type (WT) and (thrombospondin-2 knockout) TSP-2 KO decellularized skins to prepare hydrogels. The resulting materials exhibited distinct mechanical properties characterized by rheology and different concentrations of collagens when characterized by quantitative proteomics. Mixtures of the gels achieved intermediate effects between the WT and the KO, permitting tunability of the gel properties. In vivo, the hydrogels exhibited tunable cell invasion with a correlation between the content of TSP-2 KO hydrogel and the extent of cell invasion. Additionally, TSP-2 KO hydrogels significantly improved diabetic wound healing at 10 and 21 days. Furthermore, hydrogels derived from genetically engineered in vitro cell-derived matrix mimicked the trends observed for tissue-derived matrix, providing a platform for faster screening of novel manipulations and easier clinical translation. Overall, we demonstrate that genetic engineering approaches impart tunability to ECM-based hydrogels and can result in materials capable of enhanced regeneration. PMID- 30424596 TI - Selective Enrichment of Slow-Growing Bacteria in a Metabolism-Wide CRISPRi Library with a TIMER Protein. AB - Construction of pooled genetic variant libraries has become very fast and versatile. The current limitation of this technique is to select cells with a desired phenotype from very large libraries. Especially cells with poor fitness and slow growth are difficult to select because they are rapidly outcompeted by fitter cells. Here, we demonstrate selective and high-throughput enrichment of slow-growing strains using a fluorescent TIMER protein and flow cytometry. As a proof of principle, we created a metabolism-wide CRISPR interference library for Escherichia coli and enriched targets that interfere with amino acid metabolism. After enrichment of slow-growing cells, the CRISPRi library consisted almost entirely of targets that block amino acid biosynthesis. These results provide general guidelines for how to enrich slow-growing strains from a large pool of genetic variants, with applications in genetic screens, metabolic engineering, and synthetic biology. PMID- 30424597 TI - Harnessing Lysosomal pH through PLGA Nanoemulsion as a Treatment of Lysosomal Related Neurodegenerative Diseases. AB - Most neurodegenerative disorders are characterized by deposits of misfolded proteins and neuronal degeneration in specific brain regions. Growing evidence indicates that lysosomal impairment plays a primary pathogenic role in these diseases, in particular, the occurrence of increased lysosomal pH. Thus, therapeutic development aiming at restoring lysosomal function represents a novel, precise, and promising strategy for the treatment of these pathologies. Herein we demonstrate that acidic oil-in-water nanoemulsions loaded with poly(dl lactide- co-glycolide) (PLGA) are able to rescue impaired lysosomal pH in genetic cellular models of Parkinson's disease. For in vivo assays, nanoemulsions were labeled with an original synthetic hydrophobic far red-emitting dye to allow fluorescence monitoring. Following stereotaxic injection in the mouse brain, widespread diffusion of the nanocarrier was observed, up to 500 MUm from the injection site, as well as internalization into the lysosomal compartment in brain cells. Finally, promising preliminary assays of systemic administration demonstrate that a fraction of the formulation crosses the blood brain barrier, penetrates the brain parenchyma, is internalized by cells, and colocalizes with lysosomal markers. Overall, these results suggest the feasibility and the therapeutic potential of this new nanoformulation as an effective drug delivery tool to the brain, with the potential to rescue pathological lysosomal deficits. PMID- 30424598 TI - Electronic Structure Modulation of Graphitic Carbon Nitride by Oxygen Doping for Enhanced Catalytic Degradation of Organic Pollutants through Peroxymonosulfate Activation. AB - Oxygen-doped graphitic carbon nitride (O-CN) was fabricated via a facile thermal polymerization method using urea and oxalic acid dehydrate as the graphitic carbon nitride precursor and oxygen source, respectively. Experimental and theoretical results revealed that oxygen doping preferentially occurred on the two-coordinated nitrogen positions, which create the formation of low and high electron density areas resulting in the electronic structure modulation of O-CN. As a result, the resultant O-CN exhibits enhanced catalytic activity and excellent long-term stability for peroxymonosulfate (PMS) activation toward the degradation of organic pollutants. The O-CN with modulated electronic structure enables PMS oxidation over the electron-deficient C atoms for the generation of singlet oxygen (1O2) and PMS reduction around the electron-rich O dopants for the formation of hydroxyl radical (?OH) and sulfate radical (SO4?-), in which 1O2 is the major reactive oxygen species (ROS), contributing to the selective reactivity of the CN-DM1.0/PMS system. Our findings not only propose a novel PMS activation mechanism in terms of simultaneous PMS oxidation and reduction for the production of nonradical and radical species but also provide a valuable insight for the development of efficient metal-free catalysts through nonmetal doping toward the persulfate-based environmental cleanup. PMID- 30424599 TI - Green Tea Catechins Effectively Altered Hepatic Fibrogenesis in Rats by Inhibiting ERK and Smad1/2 Phosphorylation. AB - Polyphenols derived from green tea have been reported to have a wide range of profound functions. Tea catechins, including epicatechin, epigallocatechin (EGC), epicatechin-3- O-gallate (ECG), and epigallocatechin-3- O-gallate (EGCG), are considered as the major bioactive polyphenols in tea. The present study was designed to elucidate the potential antifibrogenic role of three abundant tea catechins (ECG, EGC, and EGCG) in a CCl4-induced fibrotic rat and their underlying molecular mechanisms. Tea catechins, especially groups of ECG, EGC, and EGCG, effectively induced several beneficial alterations of liver injury markers, oxidative status, and liver histology. Furthermore, catechins ameliorated liver fibrosis, as evidenced by the reduced expression of desmin, alpha-smooth muscle actin, transforming growth factor beta (TGF-beta), and downstream ERK1/2 and Smad1/2 phosphorylation. The most significant inhibitory effect on those proteins was observed in ECG (300 mg/kg) and EGCG (300 mg/kg) groups. In addition, catechins conferred their protective role by downregulating the proinflammation cytokines TGF-beta, tumor necrosis factor alpha, and interleukin 17. It is postulated that tea catechins, particularly ECG and EGCG, are potential therapeutic candidates in antifibrotic therapy. PMID- 30424600 TI - Mechanisms of Interaction between Persulfate and Soil Constituents: Activation, Free Radical Formation, Conversion, and Identification. AB - Persulfate-based in situ chemical oxidation (ISCO) for soil remediation has received great attention in recent years. However, the mechanisms of interaction between persulfate (PS) and soil constituents are not fully understood. In this study, PS decomposition, activation, free radical formation and conversion processes in 10 different soils were examined. The results showed that soil organic matter (SOM) was the dominant factor affecting PS decomposition in soil, but Fe/Mn-oxides were mainly responsible for PS decomposition when SOM was removed. Electron paramagnetic resonance (EPR) spectroscopy analysis showed that sulfate radicals (SO4*-) and hydroxyl radicals (*OH) generated from PS decomposition subsequently react with SOM to produce alkyl-like radicals (R*), and this process is dependent on SOM content. R* and SO4*-/*OH radicals predominated in soil with high and low SOM, respectively, and all three radicals coexist in soil with medium SOM. Chemical probe analysis further identified the types of radicals, and R* can reductively degrade hexachloroethane in high SOM soil, while SO4*- and *OH oxidatively degrade phenol in low SOM soil. These findings provide valuable information for PS-ISCO, and new insight into the role of SOM in the remediation of contaminated soil. PMID- 30424601 TI - pySBOL: A Python Package for Genetic Design Automation and Standardization. AB - This paper presents pySBOL, a software library for computer-aided design of synthetic biological systems in the Python scripting language. This library provides an easy-to-use, object-oriented, application programming interface (API) with low barrier of entry for synthetic biology application developers. The pySBOL library enables reuse of genetic parts and designs through standardized data exchange with biological parts repositories and software tools that communicate using the Synthetic Biology Open Language (SBOL). In addition, pySBOL supports data management of design-build-test-learn workflows for individual laboratories as well as large, distributed teams of synthetic biologists. PySBOL also lets users add custom data to SBOL files to support the specific data requirements of their research. This extensibility helps users integrate software toolchains and develop workflows for new applications. These features and others make the pySBOL library a valuable tool for supporting engineering practices in synthetic biology. PMID- 30424602 TI - Prenyl Praxis: A Method for Direct Photocatalytic Defluoroprenylation. AB - The prenyl fragment is the quintessential constituent of terpenoid natural products, a diverse family which contains numerous members with diverse biological properties. In contrast, fluorinated and multifluorinated arenes make up an important class of anthropogenic molecules which are highly relevant to material, agricultural, and pharmaceutical industries. While allylation chemistry is well developed, effective prenylation strategies have been less forthcoming. Herein, we describe the photocatalytic defluoroprenylation, a powerful method that provides access to "hybrid molecules" that possess both the functionality of a prenyl group and fluorinated arenes. This approach involves direct prenyl group transfer under very mild conditions, displays excellent functional group tolerance, and includes relatively short reaction times (<4 h), which is the fastest photocatalytic C-F functionalization developed to date. Additionally, the strategy can be extended to include allyl and geranyl (10 carbon fragment) transfers. Another prominent finding is a reagent-dependent switch in regioselectivity of the major product from para to ortho C-F functionalization. PMID- 30424603 TI - Nosyl (2-Nitrobenzenesulfonyl) Annulation Strategy toward Winding Vine-Shaped Bithiophenes. AB - Winding vine-shaped bithiophene was synthesized through the nosyl (2 nitrobenzenesulfonyl) cyclization protocol. The reaction of bithiophene bearing bromomethyl groups at the 3,3'-positions with nosylated 1,2-ethylenediamine in the presence of potassium carbonate afforded the annulated product in excellent yield. The obtained bithiophene was found to contain a 10-membered ring, which was confirmed by X-ray analysis. The related nosyldiamine bearing a tri- or tetramethylene group also reacted in a similar manner, affording an 11- or 12 membered macrocycle, respectively. PMID- 30424604 TI - Assembly of Metallacages into Soft Suprastructures with Dimensions of up to Micrometers and the Formation of Composite Materials. AB - This work provides a platform for the rapid generation of superstructure assemblies with a wide range of lengths that can be used to access a variety of metal-organic complex-based soft superstructures. Metallacage-based microneedles that are nanometers in diameter and millimeters in length were generated in dichloromethane and ethyl acetate; their size could be controlled by adjusting the ratio of the two solvents. Interestingly, microflower structures could be formed by further assembly of the microneedles during solvent evaporation. Our study establishes a feasible method designed to broaden the range of suprastructures with emissions from blue and green to red through the co-assembly of lysine-modified perylene. Similar to the co-assembly of lysine-modified perylene with microflowers, chlorophyll-a and vitamin B12 were introduced into the microflowers during the assembly process, which may be exploited in studies of energy capture and nerve repair in the future. PMID- 30424605 TI - Co-delivery of hydrophobic and hydrophilic drugs by graphene decorated magnetic dendrimer. AB - In this study, a nanocarrier was prepared for co-delivery of hydrophilic (doxorubicin) and hydrophobic drug (curcumin) to cancer cells. In this nanocarrier the edges of graphene oxide sheets were decorated by magnetic functionalized polyamidoamine dendrimer with the hydrazone groups at the end of polymer. The edge functionalization of graphene sheets not only improved the solubility and dispersibility of graphene sheets but also induced the magnetic properties to the nanocarrier. The resulted nanocarrier was loaded by doxorubicin through the covalent linkage and curcumin through the pi-pi stacking. The nanocarrier showed a pH-sensitive release for both drugs and the drug release behavior was also improved by co-immobilization of both drugs. The cytotoxicity assay of nanocarier showed low toxicity toward MCF-7 cell compared to un-modified graphene oxide which was attributed to the presence of magnetic dendrimer. Besides, the drugs loaded nanocarrier was highly toxic for cells even more than the free drugs. The cellular uptake images revealed higher drug internalization for co-loaded nanocarrier than the nanocarrier loaded with one drug alone. All of the results showed that the co-delivery of curcumin and doxorubicin by the presence nanocarrier was more effective in chemotherapy than the nanocarrier loaded with one drug. PMID- 30424606 TI - Unveiling the Role of Defects on Oxygen Activation and Photodegradation of Organic Pollutants. AB - The status of defects of TiO2 are of fundamental importance in determining its physicochemical properties. Here we report a simple chemical deposition method for controllable synthesis of defective anatase TiO2 nanocrystals under various calcination atmospheres. XPS and ESR analysis reveals that both the oxygen vacancies ( VO) and the trivalent titanium (Ti3+) defects exist in TiO2 after N2 treatment (N-TiO2). Meanwhile, mainly VO defects can be obtained in TiO2 with air calcination (A-TiO2). ESR spectra for reactive oxygen species determination, clearly show that the visible light catalytic activity is mainly caused by the efficient activation of oxygen molecules to *O2- species for A-TiO2, which play an important role in hindering the accumulation of intermediates during p chlorophenol (4-CP) photodegradation process. However, the oxygen molecules cannot be activated for N-TiO2 even with superior visible light absorption and thus the photogenerated electron are reductant, which participated in the transformation of BQ to HQ via electron shuttle mechanism. Moreover, A-TiO2 exhibits higher separation efficiency of photogenerated carriers than that of N TiO2, showing the critical role of VO with a suitable concentration in transferring photogenerated charges. PMID- 30424607 TI - Hydrophobic Nature of Methacrylate-POSS in Combination with 2 (Methacryloyloxy)ethyl Phosphorylcholine for Enhanced Solubility and Controlled Release of Paclitaxel. AB - Amphiphilic copolymers consisting of 2-(methacryloyloxy)ethyl phosphorylcholine (MPC) and hydrophobic monomers are known as biomaterials for the administration of poorly water-soluble drugs such as paclitaxel (PTX). However, the hydrophobic monomers to be copolymerized with MPC have not been optimized for PTX solubilization and its dosage forms. Here, we show the enhanced PTX solubility by only an MPC-based amphiphilic copolymer using a polyhedral oligomeric silsesquioxane (POSS) methacrylate (MA) bearing an ethyl (C2H5) group as a vertex group. MPC was copolymerized with POSS methacrylates bearing different vertex groups of ethyl (C2H5), hexyl (C6H13), and octyl (C8H17) via radical polymerization. We found that the strong interaction between C2H5-POSS and PTX contributed to the slow release of PTX without any burst release. The C2H5-POSS MA MPC copolymer was internalized into the cultured HeLa cells, which was confirmed by using a fluorescein-4-isothiocyanate (FITC)-labeled PTX, and the PTX dissolved copolymer induced cell death. We anticipate that the C2H5-POSS-MA MPC copolymer is a good solubilizer bearing a controlled release function for PTX. PMID- 30424608 TI - Activation CuFe2O4 by Hydroxylamine for Oxidation of Antibiotic Sulfamethoxazole. AB - A new potential oxidation process is provided by CuFe2O4/hydroxylamine (HA) system for degradation of antibiotics in water. The CuFe2O4/HA system can generate reactive oxygen species (ROS) for the degradation of sulfamethoxazole (SMX). The addition of radical scavengers, including benzoquinone (BQ) and catalase (CAT), inhibited the oxidation of SMX in CuFe2O4/HA system. Electron transfer in the CuFe2O4/HA system played a key function for the generation of ROS and the degradation of SMX. The main ROS, was the superoxide radical (O2*-) mainly generated from adsorbed oxygen (O2(A)), which came from the oxidation of the lattice oxygen (O2-(L)) in CuFe2O4. The CuFe2O4/HA system was effectively applicable for a broad pH range (approximately 5-10). In addition, the activation mechanism for CuFe2O4/HA system was studied with the target contaminant SMX. Finally, the degradation pathways of SMX were proposed under the optimal conditions in CuFe2O4/HA system. PMID- 30424609 TI - Introduction: Optogenetics and Photopharmacology. PMID- 30424611 TI - Robust and accurate measurements of gold nanoparticle concentrations using UV visible spectrophotometry. AB - This paper provides an empirical formula to calculate the extinction efficiencies of gold nanoparticles over the size range 1-1000 nm in fluids with refractive indexes which extend from n = 1 to n = 1.62. The formula contains a shape factor to account for nonspherical particles and aggregates. The empirical curves are fitted to values calculated from accurate Mie and T-Matrix theory and confirm previous descriptions which are restricted to nearly spherical particles in water of diameter between 5 and 100 nm. This paper demonstrates that these previous descriptions will be in error for fluids other than water and for nonspherical particles greater than 100 nm in size. An empirical description is provided which matches calculated values to within a few percent across most of the range. The description also matches experimental data to within the standard relative error, currently 5% at best, using other methods which directly measure the particle concentration. These extinction efficiencies can be used to validate the concentration of gold nanoparticles in a wide range of situations to support the drive for reproducibility in nanoparticle research. PMID- 30424612 TI - Vocal instabilities in a three-dimensional body-cover phonation model. AB - The goal of this study is to identify vocal fold conditions that produce irregular vocal fold vibration and the underlying physical mechanisms. Using a three-dimensional computational model of phonation, parametric simulations are performed with co-variations in vocal fold geometry, stiffness, and vocal tract shape. For each simulation, the cycle-to-cycle variations in the amplitude and period of the glottal area function are calculated, based on which the voice is classified into three types corresponding to regular, quasi-steady or subharmonic, and chaotic phonation. The results show that vocal folds with a large medial surface vertical thickness and low transverse stiffness are more likely to exhibit irregular vocal fold vibration when tightly approximated and subject to high subglottal pressure. Transition from regular vocal fold vibration to vocal instabilities is often accompanied by energy redistribution among the first few vocal fold eigenmodes, presumably due to nonlinear interaction between eigenmodes during vocal fold contact. The presence of a vocal tract may suppress such contact-related vocal instabilities, but also induce new instabilities, particularly for less constricted vocal fold conditions, almost doubling the number of vocal fold conditions producing irregular vibration. PMID- 30424613 TI - Influence of sampling rate on voice analysis for assessment of Parkinson's disease. AB - Parkinson's diagnosis through voice analysis (PDVA) has been attracting increasing attention. In this paper, the influence of sampling rate on PDVA is studied. By analyzing the main difficulties that hamper the development of PDVA, the significance of seeking guidelines on sampling rate is discussed. Then voices from both healthy controls and patients with Parkinson's disease are recorded, for which the sampling rate used is given special consideration. Recordings of other sampling rates are generated via down sampling the recorded voices. Then it is proposed to adopt six metrics from four levels to assess the impacts of sampling rate, which are information entropy, reconstruction error, feature correlation, classification accuracy, computational cost, and the storage cost. Through extensive experiments, basic guideline to seek an appropriate sampling rate is provided. It is concluded that a sampling rate of 96 kHz is preferred when no limits of storage and computational costs are imposed. However, a lower sampling rate may be needed if the storage size and computational complexity are the main concerns. PMID- 30424614 TI - Erratum: Cognitive disruption by noise-vocoded speech stimuli: Effects of spectral variation [J. Acoust. Soc. Am. 143(3), 1407-1416 (2018)]. PMID- 30424615 TI - Calibration of vertical array tilt using snapping shrimp sound. AB - Snapping shrimp are the dominant biological source of high-frequency (>2 kHz) ambient noise in warm coastal waters. In a recent experiment, the highly impulsive signals produced by shrimp snaps were recorded continually by a large aperture vertical array (56 m) that was bottom-moored in 100-m deep shallow water. Assuming the array vertical, initial localization of individual snaps based on wavefront curvature along the array indicated that all snaps came from either above or beneath the flat seabed. By constraining all snaps to originate from the seabed, several hundred snaps within a radius of 500 m from the array over a 20-s window were detected successfully and localized in the three dimensional space of time-of-arrival, range, and array tilt. Since the estimated array tilt for each snap is a projection of the absolute array tilt onto the nominal array-snap plane, the maximal tilt in the range and tilt domain corresponds to the absolute array tilt. Both simulations and data demonstrate that snapping shrimp can be exploited as a source of opportunity for calibration of vertical array tilt. PMID- 30424616 TI - Spherical expansions of sound radiation from resilient and rigid disks with reduced error. AB - This paper derives expressions for the sound pressure due to free-space resilient and rigid disks using a spherical harmonic expansion. A method is derived for improving the convergence and reducing the error of the expansions for radii less than the disk radius. Low-frequency approximations are also derived which simplify calculation at low frequencies. The results are verified by comparison with numerical solutions and the error is compared with existing paraxial solutions. PMID- 30424617 TI - ACOUSTICAL STANDARDS NEWS. AB - American National Standards (ANSI Standards) developed by Accredited Standards Committees S1, S2, S3, S3/SC 1, and S12 in the areas of acoustics, mechanical vibration and shock, bioacoustics, animal bioacoustics, and noise, respectively, are published by the Acoustical Society of America (ASA). In addition to these standards, ASA publishes a catalog of Acoustical American National Standards. To receive a copy of the latest Standards catalog, please contact asastds@acousticalsociety.org.Comments are welcomed on all material in Acoustical Standards News.This Acoustical Standards News section in JASA and other information on the Standards Program of the Acoustical Society of America are available via the ASA home page: http://acousticalsociety.org. PMID- 30424618 TI - Partial-field decomposition analysis of full-scale supersonic jet noise using optimized-location virtual references. AB - Supersonic jet noise reduction efforts benefit from targeted source feature extraction and high-resolution acoustic imaging. Another useful tool for feature extraction is partial field decomposition of sources into independent contributors. Since such decomposition processes are nonunique, care must be taken in the physical interpretation of decomposed partially coherent aeroacoustic fields. The optimized-location virtual reference method (OLVR) is a partial field decomposition designed to extract physically meaningful source and field information through the strategic placement of virtual references within a reconstructed field. The OLVR method is applied here to obtain spatially distinct and ordered partial sources at multiple frequencies of a full-scale, high performance supersonic jet engine operating at 100% engine power. Partial sources are shown to mimic behaviors of the total source distributions including monotonic growth and decay. Because of finite spatial coherence, multiple partial sources are used to reproduce far-field radiation away from the main lobe, and the number of required sources increases with increasing frequency. An analytical multiwavepacket model is fitted to the partial sources to demonstrate how OLVR partial fields can be leveraged to produce reduced-order models. PMID- 30424620 TI - ACOUSTICAL NEWS. AB - Editor's Note: Readers of this journal are encouraged to submit news items on awards, appointments, and other activities about themselves or their colleagues. Deadline dates for news and notices are 2 months prior to publication. PMID- 30424619 TI - Influence of tube geometry on the performance of standing-wave acoustic resonators. AB - A general and simple calculation method is presented to investigate the effects of tube shape on the resonant frequency and performance of a resonator. First, the resonant frequency of a variable cross-section resonator is modeled using a transfer matrix. Then, the amplification ratio of the pressure amplitude (ARPA), defined as the ratio of the pressure amplitude at the small end to that at the large end of the resonator, is used to evaluate its performance. The ARPA value for a variable cross-section resonator can be directly calculated from its resonant frequency. It is shown that the ARPA value is closely related to the compression ratio. However, its value is only determined by the resonator itself and is independent of the working conditions. Therefore, the ARPA index is potentially a more convenient tool for evaluating the performance of resonators compared with other indexes. Additionally, the presented method is validated by a comparison with analytical results and experimental data. Moreover, the harmonic frequencies for cylindrical, exponential, conical, half-cosine, 3/4 cosine, and Horn-Cone shape tubes are numerically investigated, in addition to the influence of the resonator shape on the resonance frequency and ARPA. Finally, optimal shape parameters for several types of resonators are suggested. PMID- 30424621 TI - Modulation spectrum-constrained trajectory error training for mixture density network-based speech synthesis. AB - In statistical parametric speech synthesis, a mixture density network is employed to address the limitations of a linear output layer such as pre-computed fixed variances and the unimodal assumption. However, it also has a defect, i.e., it cannot deploy a static-dynamic constraint needed in the training phase for high quality speech synthesis. To cope with this problem, this paper proposes a training algorithm based on the minimum trajectory error for a mixture density network. And a modulation spectrum-constrained loss function is also proposed to alleviate the over-smoothing effect. The experimental results confirm meaningful improvement both in objective and subjective performance measures. PMID- 30424622 TI - On-site acoustical characterization of Baroque tapestries: The Barberini collection at St. John the Divine Cathedral. AB - Tapestries represent an important and valuable cultural heritage. In the past they played a significant role in enriching indoor environments, as well as contributing to change the indoor characteristics of the space. Considering typical mounting conditions, acoustics was likely to be strongly affected by hung tapestries. Even though their acoustic properties could be ideally inferred from their physical features, a proper characterization would be preferable to understand how they could modify sound propagation. However, given their dimensions and their delicacy, on-site measurements are often the only option. In the present paper, absorption coefficients of the Barberini tapestries were measured during a temporary exhibition held in the Cathedral of St. John the Divine in New York City. Measurements were carried out in a large chapel with and without the tapestries installed. The effect of acoustical coupling with the adjacent cathedral volume was investigated using Bayesian methods to exclude unwanted influence on the measurements. Results were obtained using either the classical reverberation time formula or the indirect approach based on the use of geometrical acoustic modeling. Finally, results proved to be in good agreement with predictions based on theoretical formulas, once the relevant non-acoustical parameters were estimated. PMID- 30424623 TI - Estimating relative channel impulse responses from ships of opportunity in a shallow water environment. AB - The uncertainty of estimating relative channel impulse responses (CIRs) obtained using the radiated signature from a ship of opportunity is investigated. The ship observations were taken during a 1.4 km (11 min) transect in a shallow water environment during the Noise Correlation 2009 (NC09) experiment. Beamforming on the angle associated with the direct ray-path yields an estimate of the ship signature, subsequently used in a matched filter. Relative CIRs are estimated every 2.5 s independently at three vertical line arrays (VLAs). The relative arrival-time uncertainty is inversely proportional to source bandwidth and CIR signal-to-noise ratio, and reached a minimum standard deviation of 5 MUs (equivalent to approximately 1 cm spatial displacement). Time-series of direct path relative arrival-times are constructed for each VLA element across the 11 min observation interval. The overall structure of these time-series compares favorably with that predicted from an array element localization model. The short term standard deviations calculated on the direct-path (7 MUs) and bottom reflected-path (17 MUs) time-series are in agreement with the predicted arrival time accuracies. The implications of these observed arrival-time accuracies in the context of estimating sound speed perturbations and bottom-depth are discussed. PMID- 30424624 TI - Comparison of sound speed and attenuation measurements to the corrected effective density fluid model for gassy sediments. AB - To validate the corrected effective density fluid model for gassy sediments, an acoustic experiment was undertaken to measure the sound speed and attenuation in the frequency band of 10 to 120 kHz in a laboratory tank. Sound speed and attenuation each have four peaks, with a one-to-one correspondence between them. The optimal bubble size distribution modeled by five continuous modified Gaussian functions is obtained from inversion of sound speed and attenuation data. The measured sound speed and attenuation are in good agreement with the predicted results. PMID- 30424625 TI - A deep learning based segregation algorithm to increase speech intelligibility for hearing-impaired listeners in reverberant-noisy conditions. AB - Recently, deep learning based speech segregation has been shown to improve human speech intelligibility in noisy environments. However, one important factor not yet considered is room reverberation, which characterizes typical daily environments. The combination of reverberation and background noise can severely degrade speech intelligibility for hearing-impaired (HI) listeners. In the current study, a deep learning based time-frequency masking algorithm was proposed to address both room reverberation and background noise. Specifically, a deep neural network was trained to estimate the ideal ratio mask, where anechoic clean speech was considered as the desired signal. Intelligibility testing was conducted under reverberant-noisy conditions with reverberation time T 60 = 0.6 s, plus speech-shaped noise or babble noise at various signal-to-noise ratios. The experiments demonstrated that substantial speech intelligibility improvements were obtained for HI listeners. The algorithm was also somewhat beneficial for normal-hearing (NH) listeners. In addition, sentence intelligibility scores for HI listeners with algorithm processing approached or matched those of young-adult NH listeners without processing. The current study represents a step toward deploying deep learning algorithms to help the speech understanding of HI listeners in everyday conditions. PMID- 30424626 TI - The dynamics of voiceless sibilant fricative production in children between 7 and 13 years old: An ultrasound and acoustic study. AB - This study reports on dynamic tongue shape and spectral characteristics of sibilant fricatives /s/ and /?/ in Scottish English speaking children aged between 7 and 13 years old. The sequences /eCa/ and /eCi/ were produced by 40 children, with ten participants in each age group, and two-year intervals between successive groups. Productions of the same sequences by ten adults were used for comparison with the children's data. Quantitative dynamic analyses were carried out on spectral information and on ultrasound imaging data on tongue shape. All age groups differentiated between the two consonants in the fricative centroid and in tongue shape. Vowel-on-consonant effects showed consonant-specific patterns across age groups without a consistent increase or decrease in the extent of coarticulation with increasing age. The extent of discriminability between the two fricatives increased with age on both acoustic and articulatory measures. Younger speakers were generally more variable than older speakers. Complementary findings from the centroid and tongue shape measures suggest that age-related differences are due to the ongoing maturation of controlling the tongue in coordination with other articulators, particularly the jaw, throughout childhood. PMID- 30424627 TI - Automatic classification of grouper species by their sounds using deep neural networks. AB - In this paper, the effectiveness of deep learning for automatic classification of grouper species by their vocalizations has been investigated. In the proposed approach, wavelet denoising is used to reduce ambient ocean noise, and a deep neural network is then used to classify sounds generated by different species of groupers. Experimental results for four species of groupers show that the proposed approach achieves a classification accuracy of around 90% or above in all of the tested cases, a result that is significantly better than the one obtained by a previously reported method for automatic classification of grouper calls. PMID- 30424628 TI - Acoustic scattering by finite composite plates. AB - Trailing edge scattering is a significant source of sound, and elasticity is known to decrease the radiated sound by a process involving coupled acoustic and bending waves. Most of the analysis available in the literature to deal with this problem is limited to structures of isotropic material. A numerical method is extended, based on the solution of a boundary element method with boundary conditions given by the structural problem, to account for anisotropic composite plates, restricted to symmetric laminates. These conditions are recast in terms of the vibration modes of a rectangular plate. To obtain these modes, the hierarchical finite element method is used to model an elastic flat plate. Expressions for bending waves propagating in such plates are derived, and how the solution of the problem is modified to account for these effects is shown. Results show modifications in the scattered sound as a function of ply orientation and stacking sequence. Composite materials are shown to be advantageous, since laminates lead to lower acoustic scattering when compared to structurally equivalent metallic plates. This is due to a lower specific mass, leading to higher coupling between fluid and solid, and thus to more significant elasticity effects, decreasing substantially the radiated sound. PMID- 30424629 TI - Assimilation of mobile phone measurements for noise mapping of a neighborhood. AB - Noise maps are a key asset in the elaboration of urban noise mitigation policies. However, simulation-based noise maps are subject to high uncertainties, and the estimation of population exposition to noise pollution generally relies on static averages over an extended period of time. This paper introduces a method to produce hourly noise maps based on temporally averaged simulation maps and mobile phone audio recordings. The data assimilation method produces an analysis noise map which is the so-called best linear unbiased estimator: it merges the simulated map and the measurements based on respective uncertainties so that the analysis map has minimum error variance. The method is illustrated through a neighborhood-wide experiment. A systematic study of the errors associated with both the simulation map and the observations (measurement error, temporal representativeness error, location error) is carried out. Two LAeq,1h maps are produced, corresponding, respectively, to a morning and an evening time slot. The analysis maps achieve a reduction of at least 25% of root-mean-square error. The a posteriori error variance of the maps are generally around 50% of the a priori error variance in the vicinity of the observed locations. PMID- 30424630 TI - Vibroacoustic behavior of an infinitely long cylindrical shell with periodic internal lengthwise ribs. AB - The vibroacoustic behavior of an infinitely long cylindrical shell with periodic lengthwise ribs is studied. The shell motion is described by the Donnell equations, and the lengthwise rib is modeled as an elastic beam whose motion is decomposed into longitudinal and flexural vibrations. Analytical expressions are obtained for the shell motion via a circumferential mode expansion based on the periodicity in the circumferential direction and the Fourier transform in the longitudinal direction. Furthermore, the far-field radiated pressure is obtained via the stationary-phase approach. The shell vibration and sound radiation are analyzed using discrete circumferential wavenumbers. Multi-order flexural Bloch waves exist in the circumferential direction when the cylindrical shell is equipped with periodic lengthwise ribs. The supersonic components of the flexural Bloch waves radiate efficiently and lead to acoustic radiation resonances in the far field. PMID- 30424631 TI - Unmanned aerial vehicle-based sounding of subsurface concrete defects. AB - A sounding technique that uses an unmanned aerial vehicle (UAV) equipped with two microphones can detect subsurface concrete defects. Use of flexural vibration frequency as a basis for defect depth estimation is evaluated. While many non destructive tests for concrete can detect depth, current UAV-based inspection methods like optical and thermal imaging are typically limited to two-dimensional subsurface defect information. Acoustic signals from sounding and UAV noise are known to exist in similar frequency ranges. Accordingly, three noise reduction measures for this sounding technique are assessed. Given adequate distance between the microphones and UAV, a two microphone signal subtraction technique is slightly effective for some noise, but a spectral noise gating procedure is shown to substantially decrease noise in the frequency range of interest. PMID- 30424632 TI - Lower-level acoustics underlie higher-level phonological categories in lexical tone perception. AB - The pitch-processing deficit associated with congenital amusia has been shown to be transferable to lexical tone processing. However, it remains unclear whether the tone perception difficulties of amusics are merely due to the domain-general deficit in acoustic processing or additionally caused by impaired higher-level phonological operations. Answers to this question can shed light on the influence of lower-level acoustic processing on higher-level phonological processing. Using a modified categorical perception paradigm, the present study indicates that the acoustic processing deficit systematically extends to higher-level phonological processing. These findings suggest that lower-level acoustics underlie higher level phonological categories in lexical tone perception. PMID- 30424634 TI - Investigation of nonlinear ultrasonic guided waves in open waveguides based on perfectly matched layers. AB - Nonlinear ultrasonic guided waves have been investigated widely in closed waveguides such as plates, pipes, etc. However, the description of nonlinear ultrasonic guided waves remains challenging for open waveguides, as energy may leak into the surrounding medium. In this work, the properties of nonlinear ultrasonic guided waves in open waveguides are investigated. Mathematical framework is first established based on real reciprocity relation and modal expansion with perfectly matched layers. Numerical models are then implemented, including nonlinear semi-analytical finite element (SAFE) method to predict the properties of nonlinear ultrasonic guided waves, and time domain finite element models to simulate the nonlinear guided wave propagation and cross validate the predictions from the nonlinear SAFE method. Two examples, an aluminum plate attached to an elastomer and an aluminum plate with water loaded on one side, are studied to demonstrate the proposed methods and reveal some interesting phenomena that only exist in open waveguides. It is interesting to find out that the amplitude of the attenuated second harmonic wave in immersed waveguides can keep constant with propagation distance, only if the primary wave is non-leaky, which may bring potential non-destructive test applications for underwater inspections. Such a feature is validated by well-designed experiments in one-sidedly immersed plates. PMID- 30424633 TI - Compressive sensing method to leverage prior information for submerged target echoes. AB - Reducing data volume and improving signal-to-noise ratio (SNR) is of great importance for echoes from submerged targets, affected by serious marine environment noise. The echo from a target is made of its response to the incident wave with the superposition of highlights (sub-echoes from main constituents of the target). Each of these highlights can be seen as a block, and the echo therefore has a block-sparse feature. This paper proposes a compressive sensing method to leverage prior information (CSPI), in which knowledge of the incident wave and the block-sparse feature are leveraged into the dictionary structure and signal reconstruction. CSPI is illustrated with simulations and field measurements of backscattering for a 1:20 model of the Benchmark Target Strength Simulation Submarine. For simulated signals with different noise levels, CSPI can reconstruct an almost invisible signal (original SNR = 0 dB), and improve SNR by up to 13 dB (for an original SNR of 4 dB) down to a still significant SNR of 7 dB (for an original SNR of 0 dB). For field measurements, CSPI can obtain the same SNR as the original signal using only 13% of the data, increasing the SNR to 15 dB using 30% data, and increasing with the compression ratio. PMID- 30424635 TI - Acoustic inversion for Monin-Obukhov similarity parameters from wind noise in a convective boundary layer. AB - The prediction accuracy of outdoor sound is in large part limited by uncertainties in the state of the atmosphere. These uncertainties can potentially be reduced by inferring scaling parameters of the atmospheric surface layer from wind noise. Screened microphones sense wind noise as a result of mean atmospheric flow, turbulent eddy interaction with the windscreen, and pressure fluctuations within the turbulent flow. Under conditions of terrain homogeneity and atmospheric quasi-steadiness, the Monin-Obukhov similarity theory (MOST) states that only a handful of parameters governs the dynamics of the atmospheric surface layer. This study explores the relationships of atmospheric similarity parameters to the acoustic spectrum of wind noise in a convective boundary layer. Ambient noise data collected in a high desert during a 2007 long-range sound propagation experiment are analyzed for the purposes of establishing a nondimensional empirical relationship between the acoustic power spectrum and MOST parameters. Furthermore, this paper examines the consequences of inferring surface-layer scaling parameters with different parameter priors. This study shows that, for minimizing the variance in the inversion, the most important parameter to constrain is the Obukhov length. PMID- 30424636 TI - Interactions of azimuthal acoustic modes with an unsteady heat source in an annular duct. AB - The interactions of azimuthal acoustic modes with an unsteady heat source in an annular duct is studied in the present paper. Based on a linear analysis, two methods are given. One is the untruncated low order method in which the linear equations with full terms are solved. Another is the truncated low order method in which terms of order O(M) or higher are neglected, where M denotes the mean flow Mach number. From investigations, the quantities of disturbances, including reflected, transmitted acoustic waves, generated entropy waves, and vorticity waves are calculated. Results show that the amplitudes of reflected and transmitted acoustic waves dramatically depend on the temperature ratio across the heat source and the non-dimensional frequencies of incident acoustic waves. Furthermore, mean flow effects are investigated. The flow Mach number has significant effects on flow disturbances, especially on vorticity waves. Based on analytical results, the energy fluxes of disturbances are investigated. It is found that the energy flux contributed from an entropy fluctuation is much higher than the acoustic energy flux. The energy flux associated with a vortical mode becomes comparable with the acoustic energy flux only when the flow Mach number is large. PMID- 30424637 TI - Prediction of three articulatory categories in vocal sound imitations using models for auditory receptive fields. AB - Vocal sound imitations provide a new challenge for understanding the coupling between articulatory mechanisms and the resulting audio. In this study, the classification of three articulatory categories, phonation, supraglottal myoelastic vibrations, and turbulence, have been modeled from audio recordings. Two data sets were assembled, consisting of different vocal imitations by four professional imitators and four non-professional speakers in two different experiments. The audio data were manually annotated by two experienced phoneticians using a detailed articulatory description scheme. A separate set of audio features was developed specifically for each category using both time domain and spectral methods. For all time-frequency transformations, and for some secondary processing, the recently developed Auditory Receptive Fields Toolbox was used. Three different machine learning methods were applied for predicting the final articulatory categories. The result with the best generalization was found using an ensemble of multilayer perceptrons. The cross-validated classification accuracy was 96.8% for phonation, 90.8% for supraglottal myoelastic vibrations, and 89.0% for turbulence using all the 84 developed features. A final feature reduction to 22 features yielded similar results. PMID- 30424638 TI - An ideal quantized mask to increase intelligibility and quality of speech in noise. AB - Time-frequency (T-F) masks represent powerful tools to increase the intelligibility of speech in background noise. Translational relevance is provided by their accurate estimation based only on the signal-plus-noise mixture, using deep learning or other machine-learning techniques. In the current study, a technique is designed to capture the benefits of existing techniques. In the ideal quantized mask (IQM), speech and noise are partitioned into T-F units, and each unit receives one of N attenuations according to its signal-to-noise ratio. It was found that as few as four to eight attenuation steps (IQM4, IQM8) improved intelligibility over the ideal binary mask (IBM, having two attenuation steps), and equaled the intelligibility resulting from the ideal ratio mask (IRM, having a theoretically infinite number of steps). Sound-quality ratings and rankings of noisy speech processed by the IQM4 and IQM8 were also superior to that processed by the IBM and equaled or exceeded that processed by the IRM. It is concluded that the intelligibility and sound-quality advantages of infinite attenuation resolution can be captured by an IQM having only a very small number of steps. Further, the classification-based nature of the IQM might provide algorithmic advantages over the regression-based IRM during machine estimation. PMID- 30424639 TI - Explicit approximation of the wavenumber for lined ducts. AB - For acoustic waves in lined ducts, at given frequencies, the dispersion relation leads to a transcendental equation for the wavenumber that has to be solved by numerical methods. Based on an Eckart explicit expression initially derived for water waves, accurate explicit approximations are proposed for the wavenumber of the fundamental mode in lined ducts. While the Eckart expression is 5% accurate, some improved approximations can reach maximum relative errors of less than 10-8. The cases with small dissipation parts in the admittance of the liner and/or axisymmetric ducts are also considered. PMID- 30424640 TI - Prediction of fluid flow and acoustic field of a supersonic jet using vorticity confinement. AB - In this study, the numerical simulation of the fluid flow and acoustic field of a supersonic jet is performed by using high-order discretization and the vorticity confinement (VC) method on coarse grids. The three-dimensional Navier-Stokes equations are considered in the generalized curvilinear coordinate system and the high-order compact finite-difference scheme is applied for the space discretization, and the time integration is performed by the fourth-order Runge Kutta scheme. A low-pass high-order filter is applied to stabilize the numerical solution. The non-reflecting boundary conditions are adopted for all the free boundaries, and the Kirchhoff surface integration is utilized to obtain the far field sound pressure levels in a number of observer locations. Comparisons of the jet mean flow and jet aeroacoustics results with the other numerical and experimental data at similar flow conditions are made and show a reasonable agreement. The study shows that the proposed solution methodology based on the high-order compact finite-difference scheme in conjunction with the VC method can reasonably predict the near-field flow and the far-field noise of high Reynolds number jets with a fairly coarser grid than that used in the large eddy simulations and, thus, the computational cost can be significantly decreased. PMID- 30424641 TI - Effect of bevel angle on the reflection coefficient from open unflanged pipes. AB - Pipes terminating in bevel angled cuts are popular for automotive and motorcycle exhaust systems. This letter provides measured reflection coefficients and end impedances obtained from two-microphone experiments using unflanged open-ended pipes with bevel angles of 0 degrees , 30 degrees , and 60 degrees for 0.03 < ka < 0.27, where k is the acoustic wave number and a is the pipe radius. The measurements at 0 degrees match classical pipe reflection coefficient results within uncertainty. However, as the bevel angle increases to 60 degrees , the magnitude of the reflection coefficient decreases by 2%, the end reactance increases by 130%, and the end resistance increases by 24%. PMID- 30424642 TI - Analytical coupled vibro-acoustic modeling of a cavity-backed duct-membrane system with uniform mean flow. AB - Sound propagation in a flow duct is a complex and technically challenging problem. The presence of flexible vibrating walls inside the duct creates additional difficulties to the problem due to the complex vibro-acoustic and aero acoustic couplings involved in the system. An accurate prediction of the coupled system response is of great importance for a good understanding of the underlying physics as well as the optimal design of relevant noise suppression devices. In the present work, a unified energy formulation is proposed for the fully coupled structural-acoustic modelling of a duct-mounted membrane backed by an acoustic cavity with a grazing flow. Sufficiently smoothed admissible functions, taking the form of a combination of Fourier series and supplementary polynomials, are constructed to overcome the differential discontinuities for various boundary and/or coupling conditions. The formulation allows the obtention of all relevant vibro-acoustic field information in conjunction with the generalized Lighthill equation and Rayleigh-Ritz procedure. The validation and convergence studies show the accuracy and the efficiency of the proposed model. Results show the strong structural-acoustic interaction in such a duct-membrane-cavity system, and the flow affects resonant amplitude of membrane-dominant modes significantly. Some cross-zones can be observed for the membrane kinetic energy frequency response with low Mach number cases, especially when a higher tension is applied to the membrane. Analyses on the structural-acoustic coupling strength indicate that the coupling between the odd-even structural modes becomes more significant at a higher Mach number compared with odd-odd and even-even mode pairs. It is also shown that adjusting the boundary constraint of the membrane or imposing a higher tensile force allows impairing the adverse influence of the flow in the duct on sound attenuation. PMID- 30424643 TI - Broadband transmission losses and time dispersion maps from time-domain numerical simulations in ocean acoustics. AB - In this letter, a procedure for the calculation of transmission loss maps from numerical simulations in the time domain is presented. It can be generalized to arbitrary time sequences and to elastic media and provides an insight into how energy spreads into a complex configuration. In addition, time dispersion maps can be generated. These maps provide additional information on how energy is distributed over time. Transmission loss and time dispersion maps are generated at a negligible additional computational cost. To illustrate the type of transmission loss maps that can be produced by the time-domain method, the problem of the classical two-dimensional upslope wedge with a fluid bottom is addressed. The results obtained are compared to those obtained previously based on a parabolic equation. Then, for the same configuration, maps for an elastic bottom and maps for non-monochromatic signals are computed. PMID- 30424644 TI - Coupling between a fiber-reinforced model and a Hill-based contractile model for passive and active tissue properties of laryngeal muscles: A finite element study. AB - In this work, a three-dimensional fiber-reinforced model was used to simulate passive stress response of vocal fold muscle tissue undergoing a series of isometric force measurement and a dynamic stretching. It was found that, with proper material constants, the fiber-reinforced model is able to reproduce literature data with acceptable deviation. A Hill-based contractile model was then coupled with the fiber-reinforced model to enable simulations of stretching induced and activation-induced stress at the same time. For dynamic, concurrent tissue stimulation and stretching, the coupled model demonstrated a good agreement with past experimental data. PMID- 30424645 TI - Three-dimensional modeling and numerical predictions of multimodal nonlinear behavior in damaged concrete blocks. AB - In this paper, the multimodal nonlinear elastic behavior of concrete, which is representative of a consolidated granular material, is modeled numerically. Starting from a local three-dimensional softening law, the initial stiffness properties are re-estimated according to the local strain field. The experiments deal with samples of thermally damaged concrete blocks successively excited around their first three modes of vibration. The geometry of these samples cannot be described by a one-dimensional approximation in these experiments where compressional and shear motions are strongly coupled. Despite this added complexity, the nonlinear behavior for the three modes of vibration of the samples is well captured by the simulations using a single scalar nonlinear parameter appropriately integrated into the elasticity equations. It is shown that without sufficient attention paid to the latter, the conclusions would have brought erroneous statements such as nonlinearity dispersion or strain type dependence. PMID- 30424646 TI - Effects of geometry dependent diffraction on the performance of object-mounted Linear Differential Microphone Arrays. AB - Effects of geometry-dependent diffraction on the performance of object-mounted Linear Differential Microphone Arrays (LDMAs) for far-field sound waves are investigated through the Finite Element Method. This is done by studying the acoustic pressure gradients corresponding to different orders of LDMAs and placement (azimuthal and radial) on an object (such as human head or voice activated devices). An optimized frequency-dependent adaptive-dimension finite element technique, innovated by the authors, is used to simulate acoustic scattering for two simple head-model geometries (sphere and ellipsoid). These simulations are conducted for frequencies ranging from 20 to 20 000 Hz. Verification of results is done by comparisons to analytical solutions (for the sphere) and literature data. Results show that object-mounted second order radial LDMAs are greatly affected by object geometry. Maps of directivity patterns show that object-mounted first order azimuthal LDMAs completely attenuate sound from sources located at the sides of the listener. A modified LDMA signal processing method is proposed to lessen the effects of scattering for object-mounted first order azimuthal LDMAs by incorporating frequency-dependent weighting functions. The findings of this article provide an understanding of using object-mounted LDMAs for designing directional sound-sensing devices. PMID- 30424647 TI - Sparse representation-based classification of mysticete calls. AB - This paper presents an automatic classification method dedicated to mysticete calls. This method relies on sparse representations which assume that mysticete calls lie in a linear subspace described by a dictionary-based representation. The classifier accounts for noise by refusing to assign the observed signal to a given class if it is not included into the linear subspace spanned by the dictionaries of mysticete calls. Rejection of noise is achieved without feature learning. In addition, the proposed method is modular in that, call classes can be appended to or removed from the classifier without requiring retraining. The classifier is easy to design since it relies on a few parameters. Experiments on five types of mysticete calls are presented. It includes Antarctic blue whale Z calls, two types of "Madagascar" pygmy blue whale calls, fin whale 20 Hz calls and North-Pacific blue whale D-calls. On this dataset, containing 2185 calls and 15 000 noise samples, an average recall of 96.4% is obtained and 93.3% of the noise data (persistent and transient) are correctly rejected by the classifier. PMID- 30424648 TI - Lombard effect, ambient noise, and willingness to spend time and money in a restaurant. AB - The objective of this study is to determine the minimum level of noise in a restaurant that starts the Lombard effect, and how it relates to the perceived communication disturbance and the willingness to spend time and money for a meal. Twenty-eight participants were instructed to read a passage in the presence of restaurant noise from 35 to 85 dB(A). As the noise level increased, participants began to be disturbed by the noise at 52 dB(A) and began to raise their voice at 57 dB(A). The willingness to spend time and money decreased starting at 52 dB(A). PMID- 30424649 TI - Macroscopic observations of diel fish movements around a shallow water artificial reef using a mid-frequency horizontal-looking sonar. AB - The twilight feeding migration of fish around a shallow water artificial reef (a shipwreck) was observed by a horizontal-looking, mid-frequency sonar. The sonar operated at frequencies between 1.8 and 3.6 kHz and consisted of a co-located source and horizontal line array deployed at 4 km from the reef. The experiment was conducted in a well-mixed shallow water waveguide which is conducive to characterizing fish aggregations at these distances. Large aggregations of fish were repeatedly seen to emerge rapidly from the shipwreck at dusk, disperse into the surrounding area during the night, and quickly converge back to the shipwreck at dawn. This is a rare, macroscopic observation of an ecologically-important reef fish behavior, delivered at the level of aggregations, instead of individual fish tracks that have been documented previously. The significance of this observation on sonar performance associated with target detection in the presence of fish clutter is discussed based on analyses of echo intensity and statistics. Building on previous studies of long-range fish echoes, this study further substantiates the unique utility of such sonar systems as an ecosystem monitoring tool, and illustrates the importance of considering the impact of the presence of fish on sonar applications. PMID- 30424650 TI - Prediction of some vibro-acoustic properties of sandwich plates with honeycomb and foam cores. AB - A sixth-order differential equation governing the flexural vibration of sandwich plates is derived. The sandwich plates considered consist of laminates bonded to honeycomb or foam cores. The structures are assumed to be symmetric. Shear and rotation in core are included in the model. The effect on the bending stiffness of rotation and shear in the core is discussed. Shear effects are of great importance, whereas rotation of the core has only a marginal effect on the bending stiffness of lightweight sandwich plates. The bending stiffness of a sandwich plate is found to strongly depend on frequency. The bending stiffness of a structure determines its acoustical coupling to any surrounding fluid and thus its sound transmission loss and sound radiation ratio. Loss factors of sandwich plates are discussed. Boundary conditions are formulated for rectangular plates having simply supported, clamped, or free edges. There are five boundary conditions to be satisfied at each edge of the plate. The bending stiffness of simply supported and infinite plates is presented as a function of frequency. Expressions for the point mobility for infinite or simply supported finite panels are given. PMID- 30424651 TI - Time-domain spline interpolation in a simulation of N-wave propagation through turbulence. AB - A fully time-domain solution of the Khokhlov-Zabolotskaya-Kuznetzov propagation equation is illustrated using cubic spline interpolation of an exact implicit solution for nonlinearity, temperature fluctuations, and advection in the propagation direction. The spline interpolation method is benchmarked against a frequency-domain solution and found to have similar accuracy while offering about a 50% or higher speedup. The methods are evaluated by propagating Taylor shocks through turbulence in one dimension and by propagating N-waves through turbulence in two dimensions including relaxation and diffraction. The performance is superior to implicit finite differences. PMID- 30424653 TI - Active control of outgoing noise fields in rooms. AB - Current active noise control systems can cancel noises in a duct effectively. However, they are insufficient for suppressing complex noise fields in time varying rooms. This paper develops an active noise control system that can cancel tonal noise fields produced by a primary source in a room. The problem of tonal noise field control is formulated as estimating and canceling the outgoing field on a sphere surrounding the primary source. The proposed system limits the energy of the primary source radiating out of the sphere, thereby creating a global quiet zone inside the room. In addition, it removes the need for online secondary path estimation with reduced influence on desired sound fields in the room. A method for estimating the outgoing field on a sphere is presented, together with a wave-domain algorithm for controlling the outgoing field. Simulations and hardware demonstrations show the proposed system can reduce tonal noise fields in a room and over a wide frequency range. PMID- 30424652 TI - Spherical harmonics based generalized image source method for simulating room acoustics. AB - Allen and Berkley's image source method (ISM) is proven to be a very useful and popular technique for simulating the acoustic room transfer function (RTF) in reverberant rooms. It is based on the assumption that the source and receiver of interest are both omnidirectional. With the inherent directional nature of practical loudspeakers and the increasing use of directional microphones, the above assumption is often invalid. The main objective of this paper is to generalize the frequency domain ISM in the spherical harmonics domain such that it could simulate the RTF between practical transducers with higher-order directivity. This is achieved by decomposing transducer directivity patterns in terms of spherical harmonics and by applying the concept of image sources in spherical harmonics based propagation patterns. Therefore, from now on, any transducer can be modeled in the spherical harmonics domain with a realistic directivity pattern and incorporated with the proposed method to simulate room acoustics more accurately. We show that the proposed generalization also has an alternate use in terms of enabling RTF simulations for moving point-transducers inside pre-defined source and receiver regions. PMID- 30424654 TI - Erratum: The development of a modified spectral ripple test [J. Acoust. Soc. Am. 134(2), EL217-EL222 (2013)]. PMID- 30424655 TI - Clear speech adaptations in spontaneous speech produced by young and older adults. AB - The study investigated the speech adaptations by older adults (OA) with and without age-related hearing loss made to communicate effectively in challenging communicative conditions. Acoustic analyses were carried out on spontaneous speech produced during a problem-solving task (diapix) carried out by talker pairs in different listening conditions. There were 83 talkers of Southern British English. Fifty-seven talkers were OAs aged 65-84, 30 older adults with normal hearing (OANH), and 27 older adults with hearing loss (OAHL) [mean pure tone average (PTA) 0.250-4 kHz: 27.7 dB HL]. Twenty-six talkers were younger adults (YA) aged 18-26 with normal hearing. Participants were recorded while completing the diapix task with a conversational partner (YA of the same sex) when (a) both talkers heard normally (NORM), (b) the partner had a simulated hearing loss, and (c) both talkers heard babble noise. Irrespective of hearing status, there were age-related differences in some acoustic characteristics of YA and OA speech produced in NORM, most likely linked to physiological factors. In challenging conditions, while OANH talkers typically patterned with YA talkers, OAHL talkers made adaptations more consistent with an increase in vocal effort. The study suggests that even mild presbycusis in healthy OAs can affect the speech adaptations made to maintain effective communication. PMID- 30424656 TI - Contextually dependent cue realization and cue weighting for a laryngeal contrast in Shanghai Wu. AB - Phonological categories are often differentiated by multiple phonetic cues. This paper reports a production and perception study of a laryngeal contrast in Shanghai Wu that is not only cued in multiple dimensions, but also cued differently on different manners (stops, fricatives, sonorants) and in different positions (non-sandhi, sandhi). Acoustic results showed that, although this contrast has been described as phonatory in earlier literature, its primary cue is in tone in the non-sandhi context, with vowel phonation and consonant properties appearing selectively for specific manners of articulation. In the sandhi context where the tonal distinction is neutralized, these other cues may remain depending on the manner of articulation. Sonorants, in both contexts, embody the weakest cues. The perception results were largely consistent with the aggregate acoustic results, indicating that speakers adjust the perceptual weights of individual cues for a contrast according to manner and context. These findings support the position that phonological contrasts are formed by the integration of multiple cues in a language-specific, context-specific fashion and should be represented as such. PMID- 30424657 TI - Structural contributions to phantom partial generation in the piano. AB - The results of experiments designed to determine the origin of the anomalous frequency components in the sound of the piano commonly referred to as phantom partials are reported. It is shown that these overtones, which occur at the sum and difference frequencies associated with the transverse string motion, are produced by nonlinearities in both the string and the wooden components of the piano. However, the contribution from the string is significantly smaller than the contributions from other components. PMID- 30424658 TI - Behavioral measurements of auditory streaming and build-up by budgerigars (Melopsittacus undulatus). AB - The perception of the build-up of auditory streaming has been widely investigated in humans, while it is unknown whether animals experience a similar perception when hearing high (H) and low (L) tonal pattern sequences. The paradigm previously used in European starlings (Sturnus vulgaris) was adopted in two experiments to address the build-up of auditory streaming in budgerigars (Melopsittacus undulatus). In experiment 1, different numbers of repetitions of low-high-low triplets were used in five conditions to study the build-up process. In experiment 2, 5 and 15 repetitions of high-low-high triplets were used to investigate the effects of repetition rate, frequency separation, and frequency range of the two tones on the birds' streaming perception. Similar to humans, budgerigars subjectively experienced the build-up process in auditory streaming; faster repetition rates and larger frequency separations enhanced the streaming perception, and these results were consistent across the two frequency ranges. Response latency analysis indicated that the budgerigars needed a longer amount of time to respond to stimuli that elicited a salient streaming perception. These results indicate, for the first time using a behavioral paradigm, that budgerigars experience a build-up of auditory streaming in a manner similar to humans. PMID- 30424659 TI - A measuring instrument for the auditory perception of rooms: The Room Acoustical Quality Inventory (RAQI). AB - With the Room Acoustical Quality Inventory (RAQI), a measuring instrument for the perceptual space of performance venues for music and speech has been developed. First, a focus group with room acoustical experts determined relevant aspects of room acoustical impression in the form of a comprehensive list of 50 uni- and bipolar items in different categories. Then, n = 190 subjects rated their acoustical impression of 35 binaurally simulated rooms from 2 listening positions, with symphonic orchestra, solo trumpet, and dramatic speech as audio content. Subsequent explorative and confirmative factor analyses of the questionnaire data resulted in three possible solutions with four, six, and nine factors of room acoustical impression. The factor solutions, as well as the related RAQI items, were tested in terms of reliability, validity, and several types of measurement invariance, and were cross-validated by a follow-up experiment with a subsample of 46% of the original participants, which provided re-test reliabilities and stability coefficients for all RAQI constructs. The resulting psychometrically evaluated measurement instrument can be used for room quality assessment, acoustical planning, and the further development of room acoustical parameters in order to predict primary acoustical qualities of venues for music and speech. PMID- 30424660 TI - Differences in cue weights for speech perception are correlated for individuals within and across contrasts. AB - Speech perception requires multiple acoustic cues. Cue weighting may differ across individuals but be systematic within individuals. The current study compared individuals' cue weights within and across contrasts. Forty-two listeners performed a two-alternative forced choice task for four out of five sets of minimal pairs, each varying orthogonally in two dimensions. Individuals' cue weights within a contrast were positively correlated for bet-bat, Luce-lose, and sock-shock, but not for bog-dog and dear-tear. Importantly, individuals' cue weights were also positively correlated across contrasts. This indicates that some individuals are better able to extract and use phonetic information across different dimensions. PMID- 30424661 TI - Exact solution for the acoustical impulse response of a line source above an absorbing plane. AB - The solution of the two-dimensional (2D) wave equation excited by a Dirac delta function above an infinite plane is the 2D impulse response of the half-space. Equivalently, it can be considered as the sound field generated by an infinite line source in three-dimensional (3D) space. For a point source in 3D, it is possible to express the resulting impulse function in closed form if the infinite plane is characterized by a masslike or pure absorbing behavior. Based on the 3D impulse response above an absorbing plane, a closed form solution for a line source over absorbing ground is found. This solution consists of the direct pressure contribution plus a reflected signal. The analytical expression for the reflection factor R is the main result of the work. R is a simple algebraic function of impedance, time, and spatial coordinates. The acoustical field generated by a line source with a general time dependence can be constructed by convolution. For a Gaussian signal, the resulting pressure is computed numerically. For a rectangular pulse, an analytical solution in 3D and 2D is derived. The deviations from the numerically obtained results are very small. PMID- 30424662 TI - Broadband shock-associated noise from a high-performance military aircraft. AB - Broadband shock-associated noise (BBSAN) is a prominent noise component from nonideally expanded jets in the forward and sideline directions. BBSAN from laboratory-scale jets has been studied extensively, and spatial trends in BBSAN spectral peak characteristics-frequency, level, and width-have been established. These laboratory-scale trends are compared to those for BBSAN from a tied-down F 35B operated at four engine conditions. While the peak frequency varies as expected, both spatially and across engine condition, the peak level and width do not, pointing to the need for additional research into BBSAN for high-performance military aircraft. PMID- 30424664 TI - Complex eigenvalues of slotted arbitrary cylindrical cavities: Sound-soft elliptic cavity with variably placed longitudinal slit. AB - A generalization of the rigorous method of regularization is implemented to calculate the complex eigenvalues for a two dimensional arbitrarily shaped acoustically soft cavity with a longitudinal slit. The problem is reduced to the finding of non-trivial solutions of the coupled homogeneous well-conditioned Fredholm second kind infinite systems of linear algebraic equations that are solved numerically by the truncation method. The guaranteed fast convergence of the solution of the truncated system to the exact solution allows one to achieve any pre-determined accuracy by proper choice of truncation number. Formally, the complex eigenvalues coincide with the complex roots of the characteristic equation of the truncated infinite system. All calculations are performed with an accuracy of six significant decimal digits. The algorithm is free from limitations on the slit width, frequency band, and slit location along the bounding contour of a cavity. As an example, the spectrum of the complex eigenvalues for open elliptic cavity with moveable longitudinal slit is accurately investigated for various ellipse eccentricities, including the case of degenerated elliptic cavity-circular cavity. The slit width varies from zero value (closed cavity) to open semi-elliptic cavity. PMID- 30424663 TI - Dependence of inertial cavitation induced by high intensity focused ultrasound on transducer F-number and nonlinear waveform distortion. AB - Pulsed high intensity focused ultrasound was shown to enhance chemotherapeutic drug uptake in tumor tissue through inertial cavitation, which is commonly assumed to require peak rarefactional pressures to exceed a certain threshold. However, recent studies have indicated that inertial cavitation activity also correlates with the presence of shocks at the focus. The shock front amplitude and corresponding peak negative pressure (p -) in the focal waveform are primarily determined by the transducer F-number: less focused transducers produce shocks at lower p -. Here, the dependence of inertial cavitation activity on the transducer F-number was investigated in agarose gel by monitoring broadband noise emissions with a coaxial passive cavitation detector (PCD) during pulsed exposures (pulse duration 1 ms, pulse repetition frequency 1 Hz) with p- varying within 1-15 MPa. Three 1.5 MHz transducers with the same aperture, but different focal distances (F-numbers 0.77, 1.02, 1.52) were used. PCD signals were processed to extract cavitation probability, persistence, and mean noise level. At the same p -, all metrics indicated enhanced cavitation activity at higher F numbers; specifically, cavitation probability reached 100% when shocks formed at the focus. These results provide further evidence supporting the excitation of inertial cavitation at reduced p - by waveforms with nonlinear distortion and shocks. PMID- 30424665 TI - Two-dimensional multizone sound field reproduction using a wave-domain method. AB - This paper addresses a two-dimensional multizone sound field reproduction approach using a wave-domain method. The desired sound fields in the bright and dark zones are described as orthogonal expansions of basis functions over the regions. The loudspeaker weights are obtained by maximizing the contrast among multiple zones in the wave domain. Simulation results demonstrate that compared with the conventional acoustic contrast control approach, the proposed method improves the level of acoustic contrast and array gain over the entire control region and is less sensitive to the selection of the regularization parameter. PMID- 30424666 TI - Enhancing the sound transmission loss through acoustic double panel using sonic crystal and porous material. AB - Acoustic panels are widely used for sound insulation in various applications. Sound transmission loss (STL) through the panel is due to a change in acoustic impedance as sound travels from one medium to another. In double panels, STL further increases due to multiple reflections in air cavity. Recently the sonic crystal (SC) has emerged as an interesting research topic which provides sound attenuation in specific frequency bands. The present paper aims at combining the property of a SC with the acoustic panel for enhancing the STL through the double panel. Initially, an analytical method is developed to obtain the STL through the double panel. Further finite element (FE) simulations are performed using acoustic structure interaction to obtain the STL through the double panel which is in good agreement with the analytical predictions. The SC, along with the double panel, is analyzed using the FE method for the combined effect of both sound attenuators. Further, glass wool is considered as a filler material between the double panel as well as between the double panel and the SC assembly. It is found that the combined structure of the double panel and the SC with glass wool as filler gives the best STL for all different cases for the same external dimensions. PMID- 30424667 TI - Passive guided waves measurements using fiber Bragg gratings sensors. AB - Guided elastic waves are often studied as an effective solution for Structural Health Monitoring (SHM) systems of plate-like structures thanks to the capacity to propagate on large distances. In typical applications such as monitoring delaminations in aircraft fuselage, a network made of piezoelectric transducer (PZT) is used to emit and receive such waves in the structure. Fiber Bragg grating (FBG) sensors on optical fibers are a promising alternative to PZT for guided waves measurements in practical applications due to the capacity for dense multiplexing and robustness with respect to the environment. However, unlike conventional PZT transducers, FBG sensors cannot emit waves. It is demonstrated here that FBG sensors can be used in combination with a passive diffuse noise cross-correlation technique in order to extract the coherent guided waves propagating between two sensors. This could lead to a system using only FBG sensors in the near future. The reconstructed signals can then be analyzed with usual guided waves algorithms, like in active SHM systems, keeping all the advantages of this kind of monitoring in terms of fine diagnosis. The experimental demonstration shown in this paper is performed at ultrasonic frequencies (20-100 kHz) typically used in guided waves based SHM systems showing the potential of the approach. PMID- 30424669 TI - Loudness of an auditory scene composed of multiple talkers. AB - Normal hearing listeners judged loudness differences between two complex speech sounds, one consisting of "n" consonant-vowel (CV) pairs each spoken by a different talker and one consisting of "2n" CV pairs. When n was less than four, listeners' judgments of loudness differences between the two sounds was based on the level of the individual CVs within each sound, not the overall level of the sounds. When n was four or more, listeners' judgments of loudness differences between the two sounds was based on the overall level of the two sounds consisting of n or 2n CVs. PMID- 30424670 TI - A modified spectrogram with possible application as a visual hearing aid for the deaf. AB - A modified spectrogram was developed, substantially improving visual word recognition over that of traditional spectrograms from 23% to 80%. Traditional spectrograms are difficult to interpret quickly due partly to poor contrast, subtle cues, and extraneous detail. Improvements developed here include increased frequency resolution, enhancement of inconspicuous but relevant information, and elimination of extraneous detail. Log-frequency and especially, sone-amplitude scaling were subjectively easier to interpret visually than linear-frequency, dB amplitude, and linear-amplitude scaling. The spectrogram was made sufficiently small to fit into the center of vision, emulating written language in which individual words are recognized as discrete patterns. PMID- 30424671 TI - Computer-based auditory training improves second-language vowel production in spontaneous speech. AB - The current study examined the effectiveness of computer-based auditory training on Greek speakers' production of English vowels in read sentences and in spontaneous speech. Another group of Greek speakers served as controls. Improvement was evaluated pre- and post-training via an identification task performed by English listeners and by an acoustic analysis of vowel quality using a combined F1/F2 measure. Auditory training improved English vowel production in read sentences and in spontaneous speech for the trained group, with improvement being larger in read sentences. The results indicate that auditory training can have ecological validity since it enhances learners' production beyond the (read) sentence level. PMID- 30424672 TI - Acoustic source characterization for a logging while drilling tool: Theoretical and experimental modeling. AB - The development of acoustic source technology has been an important task for acoustic logging while drilling (LWD) and various source designs have been implemented. Using a multipole wave expansion theory, this study demonstrates that a LWD acoustic source can be represented as a combination of monopole, dipole, and quadrupole constituents and characterized by the contribution of each constituent. The theoretical analysis is experimentally demonstrated with a cylindrical pipe simulating the LWD collar. The result of this study can be used to provide a method for evaluating the performance of a LWD acoustic source. PMID- 30424673 TI - Sound power and timbre as cues for the dynamic strength of orchestral instruments. AB - In a series of measurements, the sound power of 40 musical instruments, including all standard modern orchestral instruments, as well as some of their historic precursors from the classical and the baroque epoch, was determined using the enveloping surface method with a 32-channel spherical microphone array according to ISO 3745. Single notes were recorded at the extremes of the dynamic range (pp and ff) over the entire pitch range. In a subsequent audio content analysis, audio features were determined for all 3482 single notes using the timbre toolbox. In order to analyze the relative contributions of timbre- and amplitude related properties to the expression of musical dynamics in different instruments, Bayesian linear discriminant analysis and generalized linear mixed modelling were employed to determine those audio features discriminating best between extremes of dynamics both within and across instruments. The results from these measurements and statistical analyses thus deliver a comprehensive picture of the acoustical manifestation of "musical dynamics" with respect to sound power and timbre for all standard orchestral instruments. PMID- 30424675 TI - Spectral change and duration as cues in Australian English listeners' front vowel categorization. AB - Australian English /i?/, /i/, and /ie/ exhibit almost identical average first (F1) and second (F2) formant frequencies and differ in duration and vowel inherent spectral change (VISC). The cues of duration, F1 * F2 trajectory direction (TD) and trajectory length (TL) were assessed in listeners' categorization of /i?/ and /ie/ compared to /i/. Duration was important for distinguishing both /i?/ and /ie/ from /i/. TD and TL were important for categorizing /i?/ versus /i/, whereas only TL was important for /ie/ versus /i/. Finally, listeners' use of duration and VISC was not mutually affected for either vowel compared to /i/. PMID- 30424676 TI - Erratum: Species-level classification of beaked whale echolocation signals detected in the northern Gulf of Mexico [J. Acoust. Soc. Am. 144, 387-396 (2018)]. PMID- 30424674 TI - The relationship between acoustical and perceptual measures of vocal effort. AB - Excessive vocal effort is a common clinical voice symptom, yet the acoustical manifestation of vocal effort and how that is perceived by speakers and listeners has not been fully elucidated. Here, 26 vocally healthy adults increased vocal effort during the production of the utterance /ifi/, followed by self-ratings of effort on a 100 mm visual analog scale. Twenty inexperienced listeners assessed the speakers' vocal effort using the visual sort-and-rate method. Previously proposed acoustical correlates of vocal effort were calculated, including: mean sound pressure level (SPL), mean fundamental frequency (f o), relative fundamental frequency (RFF) offset cycle 10 and onset cycle 1, harmonics-to-noise ratio (HNR), cepstral peak prominence and its standard deviation (SD), and low-to high (L/H) spectral ratio and its SD. Two separate mixed-effects regression models yielded mean SPL, L/H ratio, and HNR as significant predictors of both speaker and listener ratings of vocal effort. RFF offset cycle 10 and mean f o were significant predictors of listener ratings only. Therefore, speakers and listeners attended to similar acoustical cues when making judgments of vocal effort, but listeners also used additional time-based information. Further work is needed to determine how vocal effort manifests in the speech signal in speakers with voice disorders. PMID- 30424677 TI - Acoustic scattering comparison of Kirchhoff approximation to Rayleigh-Fourier method for sinusoidal surface waves at low grazing angles. AB - The Fourier series method for implementing the Rayleigh hypothesis [Rayleigh Fourier method (RFM)] is used as a reference solution to assess the Kirchhoff approximation of the Helmholtz integral [Helmholtz-Kirchhoff approximation (HKA)] for modeling broadband scatter from sinusoidal surfaces at low grazing angles. The HKA is a valuable solution because it has an eigen-ray interpretation without unbounded caustic amplitudes and discontinuous shadow zones. Plane wave studies of the HKA, however, show it becomes inaccurate at low grazing angles. This study quantifies how this limitation manifests with increasing transmission distance for time domain scattering simulations. Scattering results are compared over a complete surface wave cycle with parameters modeling sea surface-swell. The HKA agrees reasonably well with the RFM in point source calculations for limited extensions of transmission distances beyond where plane wave comparisons begin to diverge. Past these distances, HKA solutions begin to show significant over prediction of the acoustic amplitude around late arrivals. This over-prediction is frequency dependent and eigen-ray interference offers an explanation of this behavior. Further extending the transmission range leads to a significant HKA error, and a range is found at which flat surface reflections have less error. PMID- 30424678 TI - A descriptive monitoring study of a non-anesthetist sedation quality program. AB - INTRODUCTION: sedation substantially improves the quality of digestive endoscopy procedures but may result in severe complications. METHODS: a joint commission based multidisciplinary protocol was used to define a protocol for sedation by non-anesthesiologists. ASA 4 patients were excluded, as well as patients with a difficult airway, complex procedures and deep sedation. Quality based on the analysis of 9 indicators were monitored. Incomplete procedures were also monitored in order to assess efficacy. RESULTS: patient safety was established based on a very low incidence of complications and a rate of respiratory events of 1.07. Furthermore, a low rate of hypotension and bradycardia was found, as well as a low rate of pain, either during or after endoscopy and an incidence of unexpected admissions lower than 0.5%. The quality indicators measured reflect the evolution of the results of the program. CONCLUSIONS: ongoing sedation program monitoring in endoscopy allows the control of different quality dimensions and the implementation of steps for process improvement. PMID- 30424679 TI - Appropriateness of task of public health doctors in South Korea. AB - INTRODUCTION: Public health doctors (PHDs) in South Korea serve the medically underserved region of South Korea as part of national service duty, but their number has declined in recent years (due to changes in the medical education system). Therefore, there is an increasing need to deploy PHDs efficiently. Consisting of 2138 medical doctors of different specialties, they serve as both primary care physicians and public health experts. METHODS: The purpose of this study was to investigate the appropriateness of tasks of PHDs in South Korea. RESULTS: Of the 2138 PHDs invited, 1015 participated in the survey. Most PHDs performed primary care and vaccination duties (96.8% and 85.8%). PHDs evaluated the appropriateness of tasks and number of PHDs as above the midpoint of a five point Likert scale (3.5±1.1 and 3.4±1.1). The majority of offices were located within 5 km of private clinics and hospitals (72.7% and 45.2%). CONCLUSIONS: PHDs on remote islands highly value the validity and deployment needs of PHDs, while PHDs in close proximity to private clinics or hospitals give a low score. This suggests that there is a need to more efficiently deploy PHDs depending on local characteristics and the presence or absence of nearby private medical clinics and hospitals. PMID- 30424680 TI - Evaluating the cost-effectiveness of percutaneous closure of a patent foramen ovale versus medical management in patients with a cryptogenic stroke: from the UK payer perspective. AB - AIMS: Percutaneous closure of a patent foramen ovale (PFO) is known to lower the risk of recurrent stroke in patients with a cryptogenic stroke. However, the economic implications of transcatheter PFO closure are less well known. From a UK payer perspective, a detailed economic appraisal of PFO closure was performed for prevention of recurrent ischemic stroke in patients with a PFO who had experienced a cryptogenic stroke. MATERIALS AND METHODS: A Markov cohort model was constructed using a 5-year time-horizon with a patient mean age of 45.2 years, reflecting the characteristics reported in the REDUCE trial. Transition probabilities, clinical inputs, costs, and utility values were ascertained from published and national costing sources. Total costs, incremental costs, quality adjusted life-years (QALYs), and incremental cost-effectiveness ratios were calculated, utilizing a discount rate of 3.5%. A range of univariate and probabilistic sensitivity analyses were also performed. RESULTS: When applying a willingness-to-pay (WTP) threshold of L20,000/QALY in accordance with NICE guidelines, PFO closure compared with antiplatelet therapy alone showed a beneficial cost/QALY of L18,584, attained at 4 years. Applying discount rates of 0% and 6% had a negligible effect on the base-case model findings. PFO closure demonstrated a 76.9% probability of being cost-effective at a WTP threshold of L20,000/QALY at a 5-year time-horizon. LIMITATIONS: This model focused specifically on UK stroke patients and typically enrolled young (mean age <65 years old) patients. Hence, caution should be taken when comparing data vs non-UK populations, and it remains unclear how older patients might have affected cost effectiveness findings, as the risk of paradoxical embolism can persist as patients age. CONCLUSION: Percutaneous closure of a PFO is cost-effective compared with antiplatelet therapy alone, underlining the economic benefits potentially afforded by this treatment in selected patients. PMID- 30424681 TI - Immunization with plasmids encoding M2 acetylcholine muscarinic receptor epitopes impairs cardiac function in mice and induces autophagy in the myocardium. AB - Autoantibodies against the M2 subtype of muscarinic acetylcholine receptors with functional activities have been found in the sera of patients with dilated cardiomyopathy (DCM), and the second extracellular loop has been established as the predominant epitope. However, it has been shown that the third intracellular loop is recognized by Chagas disease patients with severe cardiac dysfunction. In this work, BALB/c mice were immunized with plasmids encoding these two epitopes, and a control group received the empty plasmid (pcDNA3 vector). Serum from these DNA-immunized animals had elevated and persistent titres of antibodies against respective antigens. Heart echocardiography indicated diminished left ventricular wall thickness and reduced ejection fraction for both epitope-immunized groups, and ergospirometry tests showed a significant decrease in the exercise time and oxygen consumption. Transfer of serum from these immunized mice into naive recipients induced the same alterations in cardiac structure and function. Furthermore, electron microscopy analysis of donor-immunized animals revealed several ultrastructural alterations suggestive of autophagy and mitophagy, suggesting novel roles for these autoantibodies. Overall, greater functional and structural impairment was observed in the donor and recipient epitope groups, implicating the third intracellular loop epitope in the pathological effects for the first-time. Therefore, the corresponding peptides could be useful for autoimmune DCM diagnosis and targeted therapy. PMID- 30424682 TI - The interrelationship of functional skills in individuals living in the community, following moderate to severe traumatic brain injury. AB - OBJECTIVE: The Adaptive Behaviour and Community Competency Scale was used to investigate the interrelationship of 22 basic and instrumental activities of daily living (ADL/IADL) in individuals with moderate to severe traumatic brain injury (TBI). The relationship of self-awareness to task performance was also investigated. RESEARCH DESIGN: Prospective descriptive study. METHOD: The profiles of 100 community dwelling individuals were used to compare the degree to which independence in each ADL/IADL was associated with independence in every other ADL/IADL. The interrelationship of these skills was further explored in a factor analysis, and comparisons made between the degree of self-awareness of those who could and could not complete IADL independently. RESULTS: We found evidence of a hierarchy of skills: individuals who were independent in IADL were more able to perform ADL, than vice versa. Factor analysis supported a two-factor solution distinguishing ADL and IADL. Self-awareness was more strongly associated with IADL than with ADL independence. CONCLUSIONS: A subset of individuals with moderate to severe TBI are able to perform a range of IADL. This group appears to have higher levels of self-awareness than those who are limited to performing only ADL skills. Implications for the applications of functional retraining interventions are discussed. PMID- 30424683 TI - Rates and Causes of Death among Adult Diabetes Patients in Romania. AB - AIMS: To study the age and sex-dependent mortality rates and causes of death in a large Romanian diabetes cohort as compared with the general population. METHODS: All adult patients aged 20-64 years, receiving a free diabetes prescription in a major urban area during 2001-2008 were included and followed-up for death until December 31, 2011. Crude mortality rates and standardized mortality rate ratios (SMR) against general population (data from the National Institute of Statistics) were calculated. Years lost due to diabetes were computed assuming the general population mortality rates for ages below 20 and above 64 years. RESULTS: During the 11 years study period, 49,328 diabetes patients (mean age at baseline 53.0 +/ 8.8 years) contributed 297,370 person-years and 5,053 deaths. All cause mortality rates (per 1000 person years) increased with age and was 3.4 in 20-24 years age group and 25.7 in 60-64 year age group, while the corresponding SMR decreased from 6.0 to 1.5. Diabetes patients aged 20-24 years had a life expectancy of 48.6 years, which was 6.6 years less compared with the corresponding general population (55.2 years). The gap was 7.0 years in women and 5.8 years in men. Diabetes patients aged 20-24 years lost 196 minutes of life daily due to diabetes in women and 182 minutes in men. CONCLUSIONS: Mortality rates increased, while mortality rate ratios against general population decreased with age. Men had higher mortality rates, but women had higher mortality rate ratios in the gender analysis. PMID- 30424684 TI - The Effect of Functional Home-Based Strength Training Programs on the Mechano Morphological Properties of the Plantar Flexor Muscle-Tendon Unit in Children With Spastic Cerebral Palsy. AB - PURPOSE: The purpose of this study was to investigate the effects of functional progressive resistance training (PRT) and high-intensity circuit training (HICT) on the mechano-morphological properties of the plantar flexor muscle-tendon unit in children with spastic cerebral palsy. METHODS: Twenty-two children (12.8 [2.6] y old, Gross Motor Function Classification System levels I/II = 19/3) were randomly assigned to either a PRT group or an HICT group. The interventions consisted of functional lower limb exercises, which were performed at home 3 times per week for 8 weeks. Measurements at baseline, preintervention, postintervention, and follow-up were taken to assess ankle joint range of motion and the properties of the gastrocnemius medialis, vastus lateralis, rectus femoris, and Achilles tendon (eg, thickness, strength, stiffness). RESULTS: Despite a nonsignificant increase in active torque in the HICT group, neither gastrocnemius medialis morphology nor Achilles tendon properties were significantly altered after the interventions. Vastus lateralis thickness increased following PRT only. CONCLUSIONS: Functional home-based strength training did not lead to significant changes at the muscular level in children with cerebral palsy. We therefore assume that a more specific stimulus of higher intensity combined with a longer training duration might be necessary to evoke changes in muscles and tendons in individuals with cerebral palsy. PMID- 30424686 TI - ? PMID- 30424685 TI - [Point-of-Care Ultrasound: Teaching and Learning in Ifakara, Tanzania]. AB - Point-of-Care Ultrasound: Teaching and Learning in Ifakara, Tanzania Abstract. Presentation of two practical cases from the point-of-care ultrasound class in Ifakara, Tanzania. The first case shows the sonographic findings of tuberculosis with findings in the lungs, heart, abdominal lymph nodes and spleen. In the second case, detection of an enterobiliary fistula by sonographic live imaging of air passing from the intestine into the gall bladder and causing non-iatrogenic pneumobilia. PMID- 30424687 TI - [Pneumonia: Does Ultrasound Replace Chest X-Ray?] AB - Pneumonia: Does Ultrasound Replace Chest X-Ray? Abstract. Pneumonic lung consolidations are characterized by typical changes in terms of sonomorphology: echopoor lesions with blurred margins, bronchoaerograms, regular vascularization, and parapneumonic effusions. Pneumonias may be first discovered at bedside. Reventilation is well correlated with clinical progression. Compared with CT in four metaanalyses, lung ultrasound shows accuracy with a sensitivity of 88-97 % and a specificity of 90-96 %. Chest x-ray on the other hand has a pooled sensitivity of 77 % and a specificity of 91 %. Thus, lung ultrasound should replace chest x-ray in the diagnosis of pneumonia aquired by out-patients. PMID- 30424688 TI - ? PMID- 30424689 TI - [CME Sonography 84: Scrotal Node Palpated]. PMID- 30424690 TI - [Practical Ultrasound Skills in Medical School]. AB - Practical Ultrasound Skills in Medical School Abstract. A more competency-based medical education is addressed in the German National Competence Based Catalogue of Learning Objectives (NKLM) for Undergraduate Medical Education. This catalogue defines a wide range of competencies in communication, knowledge and skills that enable a medical professional to act effectively and responsibly for the benefit of individual patients and the community. Currently, the cataloque has the status of recommendations for restructuring medical curricula. Medical faculties are called upon to gain practical experience over the next years. Ultrasound is implemented in the preclinical and clinical parts of the NKLM. However, the acquisition of practical ultrasound skills for students is not addressed. PMID- 30424691 TI - [CME: Significance of Thoracic Sonography in Thoracic Trauma]. AB - CME: Significance of Thoracic Sonography in Thoracic Trauma Abstract. Trauma patients should be treated according to international guidelines. Depending on the severity of the trauma, an immediate threat to life must be ruled out and sonography is part of the complementation of diagnostics. The EFAST investigation includes the exclusion of fluid in the thorax, the exclusion of pneumothorax and the exclusion of fluid in the pericardium. Thorax ultrasound is becoming increasingly important in the evaluation of the outcome in thoracic trauma patients as well as in the control of the initiated therapy. PMID- 30424692 TI - [CME Answers: 'Thyrotoxicosis and Thyroiditis', Praxis No. 22]. PMID- 30424693 TI - [Teaching Technical Basics in Ultrasound for Medical Students - Outline of the Viennese 'Teach Us Sound' Concept]. AB - Teaching Technical Basics in Ultrasound for Medical Students - Outline of the Viennese 'Teach Us Sound' Concept Abstract. Teaching technical ultrasound basics in regular medical curricula is possible to small extent only and not adequate. This contribution will give a survey of the lectures focussed on "ultrasound" at the Medical University of Vienna and presents a concept how to impart basic technical competences in practice. The contents of the concept and some detail aspects of it will be presented and the benefit for students discussed. PMID- 30424694 TI - [Ultrasound in Student Education]. AB - Ultrasound in Student Education Abstract. The subject 'Ultrasound in Medicine', already introduced during the studies increases the motivation of students by its practical character and combines basic medical knowledge (anatomy, physiology) and imaging with clinical applications in a unique way. This is done on the one hand as a point of care method (POCUS) at the point of decision-making, and on the other hand as a 'radiological' method with intervention options. POCUS is the use of ultrasound by physicians to correctly identify problems and implement solutions at the point of action. Both the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) and the World Federation for Ultrasound in Medicine and Biology (WFUMB) have published position papers on the targeted application of ultrasound technology (point of care), the status of which is reported here. PMID- 30424695 TI - [CME ENT 29/Answer: Infraauricular Node on the Right]. PMID- 30424696 TI - ? PMID- 30424697 TI - [Blended Learning Basic Course Sonography - A SGUM Accredited Ultrasound Course Based on Peer-Tutoring]. AB - Blended Learning Basic Course Sonography - A SGUM Accredited Ultrasound Course Based on Peer-Tutoring Abstract. In various countries, students organize themselves to teach each other practical sonography skills through peer tutoring. A joint project of the Swiss universities and the SGUM is actively supporting this movement. In an e-learning course with a basic part and twelve organ specific lessons, the anatomy and the standards of practical examination are demonstrated with videos. For each lesson, the students complete practical training sessions with a peer tutor and document these in a logbook. Students will be accredited to the SGUM Abdomen Sonography Basic Course after passing the practical final exam. This article describes some strategic and didactic considerations about this innovative project as well as the current state of implementation. PMID- 30424698 TI - [SGUM/SSUM Course System. A Joint Basic Course with Students and Universities - an Opportunity as a Continuation of an Eventful History]. AB - SGUM/SSUM Course System. A Joint Basic Course with Students and Universities - an Opportunity as a Continuation of an Eventful History Abstract. In the ultrasound course, the basic course Sonography Blended Learning is starting an interesting and promising cooperation between universities, students and the SGUM/SSUM. It is hoped that we will seize this opportunity. We are well on the way to it. PMID- 30424699 TI - Chronic myelomonocytic leukemia treated with 5-azacytidine - results from the Hellenic 5-Azacytidine Registry: proposal of a new risk stratification system. AB - Hypomethylating agents are widely used in chronic myelomonocytic leukemia (CMML). We analyzed the characteristics of 88 patients with CMML homogeneously treated with 5-azacytidine (Hellenic 5-Azacytidine Registry). The overall response rate was 48.9% and the median overall survival (OS) 29.7 months. Out of the seven most widely used prognostic scoring systems for CMML, the Dusseldorf score (DUSS) showed the best prognostic capability (HR, 2.27; p < .001). Forty-one (48.8%) patients progressed to acute myeloid leukemia (AML) after a median time of 15.2 months following treatment initiation. High serum ferritin levels at diagnosis were independently correlated with low OS (HR, 2.84; p = .022), as were circulating blasts (HR, 3.47; p = .014), while a platelet count <100 * 109/L was marginally predictive of lower OS (HR, 1.45; p = .06). We selected these three factors to create a new risk stratification system for CMML with three risk groups. Finally, we highlighted for the first time the prognostic significance of serum ferritin levels in CMML. PMID- 30424700 TI - Inherited anxiety-related parent-infant dyads alter LHPA activity. AB - The pathogenesis of post-traumatic stress disorder (PTSD) is incompletely understood. We hypothesize that disruptions in mother-child relations may be a key contributor to development of PTSD. A normal and healthy separation individuation process requires adaptations of self- and interactive contingency in both the mother and her child, especially in early childhood development. Anxious mothers are prone to overprotection, which may hinder the individuation process in their children. We examined long-term stress hormones and other stress markers in subjects three generations removed from the Holocaust, to assess the long-term consequences of inherited behavioral and physiological responses to prior stress and trauma. Jewish subjects who recalled overprotective parental behavior had higher hairsteroid-concentrations and dampened limbic-hypothalamic pituitary-adrenal (LHPA) axis reactivity compared to German and Russian-German subjects with overprotective parents. We suggest that altered LHPA axis activity in maternally overprotected Jewish subjects may indicate a transmitted pathomechanism of "frustrated individuation" resulting from cross-generational anti-Semitic experiences. Thus measurements of hairsteroid-concentrations and parenting practices may have clinical value for diagnosis of PTSD. We propose that this apparent inherited adaptivity of LHPA axis activity could promote higher individual stress resistance, albeit with risk of an allostatic overload. PMID- 30424701 TI - A Test of Perfectionistic Vulnerability Following Competitive Failure Among College Athletes. AB - Perfectionism purportedly bestows vulnerability to distress through an interaction with achievement and interpersonal stress. The authors test this by assessing athletes' perfectionism and subsequent self-conscious emotion following repeated competitive failure. A total of 60 college athletes undertook three 4 min competitive sprint trials on a cycle ergometer and were instructed that they had performed the worst of all competitors on each occasion. Measures of perfectionism (self-oriented and socially prescribed) were taken at baseline and measures of pride, guilt, and shame were taken at baseline and three times following each successive failure. Across the successive failures, self-oriented perfectionism predicted within-person trajectories of decreasing pride and increasing guilt. Socially prescribed perfectionism predicted within-person trajectories of increasing shame and guilt. Furthermore, a combination of high self-oriented and high socially prescribed perfectionism predicted the steepest within-person increases in shame and guilt. Findings support an achievement specific vulnerability hypothesis whereby those higher in perfectionism experience pronounced distress following competitive failure. PMID- 30424703 TI - Targeting Primary Sjogren's Syndrome. AB - Primary Sjogren's syndrome (pSS) is a chronic autoimmune disease that is estimated to affect 35 million people worldwide. Hallmarks of the disease are a loss of salivary and lacrimal gland function as well as lymphocytic infiltration, elevated proinflammatory cytokines, and circulating autoantibodies. Patients often experience significant fatigue and a decrease in their quality of life. Approximately 30-50% of pSS patients develop extra-glandular manifestations including malignant lymphoma. Although therapeutic approaches for pSS target both dryness and systemic manifestations, effective treatments are limited. However, new therapies targeting specific immune pathways associated with pSS are being developed. This review describes current and future targeted therapies against pSS. PMID- 30424702 TI - CD4+/CD8+ immunophenotype switching as a marker for intraocular and CNS involvement in mycosis fungoides. PMID- 30424704 TI - Bacterial vaginosis: a primer for clinicians. AB - Bacterial vaginosis (BV) affects approximately one third of women in the United States. While often asymptomatic, BV infection may be accompanied by serious health consequences, such as preterm birth and pelvic inflammatory disease, and may facilitate acquisition of sexually transmitted infections. Identifying appropriate patients for screening, such as pregnant women, women planning pregnancy, and women with multiple and/or new sexual partners, is imperative for treatment. Diagnosis of BV has traditionally depended on the presence of vaginal discharge and odor, elevated pH, and clue cells as determined by microscopy, but newer diagnostic modalities that utilize molecular techniques allow for more convenient and accurate testing for BV. Approved treatment options consist of antibiotics administered as oral or intravaginal formulations. Patient counseling and education regarding treatment options, including adherence to prescribed treatments, appropriate hygienic practices, and treatment of symptomatic same-sex partners, are crucial to optimize patient outcomes and prevent recurrence. PMID- 30424706 TI - Mutations and prognosis in myeloproliferative neoplasms. PMID- 30424705 TI - A novel approach to eliminate therapy-resistant mantle cell lymphoma: synergistic effects of Vorinostat with Palbociclib. AB - Mantle cell lymphoma (MCL) represents an aggressive B-cell lymphoma with frequent relapse and poor survival. Recently, dysregulated histone-deacetylases (HDACs) and cell cycle CDK-Rb pathway have been shown to be commonly associated with MCL pathogenesis, and are considered promising targets for relapsed-lymphoma therapy. Therefore, we investigated the single agents and combination efficacy of HDACs inhibitor Vorinostat, CDK4/6 dual-inhibitor Palbociclib on MCL cell growth/survival and underlying molecular mechanism(s) using MCL cell lines including therapy-resistant MCL cell lines. Our results showed that both inhibitors as single agents or combined, significantly suppressed the cell growth and induced apoptosis in therapy-resistant and parental MCL lines. In addition, the combination of Vorinostat and Palbociclib significantly inhibited the activation of the key molecules of the CDK4/6-Rb pathway and HDAC activity and subsequently decreased the expression of Cyclin-D1 and Bcl-2. These studies demonstrated the potential for combining these two inhibitors as a novel therapeutic approach in refractory MCL therapy. PMID- 30424707 TI - Dacryocystosclerotherapy as an alternative to dacryocystectomy. AB - PURPOSE: The aim of this study was to perform a histopathological assessment of the efficacy of sclerosing agents in dacryocystosclerotherapy (DCST) and to evaluate its role as an alternative to dacryocystectomy (DCT) in a specific group of patients. METHODS: Thirteen lacrimal drainage systems of 10 patients with primary acquired nasolacrimal duct obstruction (PANDO) were studied. All patients were awaiting a DCT, indications being repeated attacks of dacryocystitis with severe systemic or ocular co-morbidities and/or refusal for a dacryocystorhinostomy. Fluorescent labelled sodium tetradecyl sulphate (SDS) or bleomycin were used as sclerosing agents for a DCST taking specific precautions. All patients underwent a DCT after 4 weeks and histopathological evaluation was performed to assess the changes and extent of DCST. RESULTS: There were nine females and one male, and all patients were above the age of 60 years. Of the 13 lacrimal systems studied, the mean duration of PANDO was 1.3 years. All the patients had associated systemic and/or ocular co-morbidities. SDS and bleomycin were used in 6 and 7 lacrimal systems, respectively. The mean doses used for SDS and bleomycin were 0.26 and 0.31 cc, respectively. The post-injection phase was uneventful except for one patient who had a moderate inflammation, which resolved with low dose oral steroids. Histopathological features were more marked in the SDS group and included loss of epithelium, luminal closure, gross fibrosis across the lacrimal sac wall, congestion and hyalinization of blood vessels, and multiple areas of haemorrhages in the sac wall. CONCLUSIONS: DCST is a safe and effective alternative to DCT in very carefully selected patients. Histopathology demonstrates SDS to be more effective as compared to bleomycin. PMID- 30424708 TI - "The Thrill of Victory . . . and the Agony of Defeat": Passion and Emotional Reactions to Success and Failure Among Recreational Golfers. AB - The dualistic model of passion proposes two distinct forms of passion: obsessive (OP) and harmonious (HP). The purpose of this research was to test if emotional reactivity following athletic successes and failures was related to one's levels of HP and OP for sport. The authors recruited recreational golfers (N = 115) to report how they typically felt after they experienced successes and failures on the golf course. Results of multilevel modeling analyses supported the hypotheses and revealed that OP moderated the effects of success and failure on both positive and negative affect: OP was associated with higher levels of positive affect following success, as well as higher levels of negative affect following failure. These results suggest that OP, but not HP, is associated with greater emotional reactivity to the experience of success and failure in sport. PMID- 30424709 TI - "TRPV1 is a component of the atrial natriuretic signaling complex, and using orally delivered antagonists, presents a valid therapeutic target in the longitudinal reversal and treatment of cardiac hypertrophy and heart failure". AB - Background Activation of the atrial natriuretic signaling pathway is intrinsic to the pathological responses associated with a range of cardiovascular diseases that stress the heart, especially those involved in sustained cardiac pressure overload which induces hypertrophy and the pathological remodeling that frequently leads to heart failure. We identify transient receptor potential cation channel, subfamily V, member 1, as a regulated component, and therapeutic target of this signaling system. Methods We undertook biochemical, calcium imaging and electrophysiological experiments to analyze interactions and regulation of TRPV1. Pressure overload cardiac hypertrophy was modeled in mice using transthoracic aortic constriction, after which TRPV1 antagonists were delivered orally, to assess any reversal in the loss of function associated with pressure overload cardiac hypertrophy. Results The data show that TRPV1 is a physical component of the natriuretic peptide A, cGMP, PKG signaling complex, interacting with the natriuretic peptide receptor 1 (NPR1), and upon binding its ligand, natriuretic peptide A (NPPA, ANP) TRPV1 activation is subsequently suppressed through production of cGMP and PKG mediated phosphorylation of the channel. Further, drug inhibition of TRPV1 suppresses chamber and myocyte hypertrophy, and improves in vivo heart function in mice exposed to chronic pressure overload induced by transverse aortic constriction, reversing pre established hypertrophy induced by pressure load while restoring chamber function. Conclusions TRPV1 is a physical and regulated component of the natriuretic peptide signaling system, and TRPV1 inhibition may provide a new treatment strategy for treating the loss of function associated with cardiac hypertrophy and remodeling. PMID- 30424710 TI - Patient understanding, expectations, outcomes, and satisfaction regarding surgical management of shoulder instability. AB - Shoulder instability is a common condition encountered by sports medicine and shoulder surgeons. Management can be challenging, both with regards to the underlying pathology and the high expectations associated with the very active patient population that this condition typically affects. High-performance athletes who are used to performing at activity levels which typically challenge the normal physiologic limits of the glenohumeral joint may be particularly difficult to treat. As physicians increasingly evaluate patient reported outcomes (PROs), a growing body of literature has emerged related to patient expectations for a variety of orthopaedic conditions, including shoulder instability. Physicians may face difficulty when using the literature to counsel patients due to the difference between a successful PRO and true patient satisfaction. Having a better understanding of patient expectations may improve preoperative evaluation, patient counseling, postoperative PROs, and patient satisfaction with shoulder instability surgery. The purpose of this paper was to review the literature regarding patient understanding of shoulder instability injuries, expectations following surgical repair of shoulder instability pathology, and satisfaction with operative intervention. Additionally, we sought to determine the effect of patient expectations on outcomes. PMID- 30424711 TI - Clinical prognostic scores are poor predictors of overall survival in various types of malignant lymphomas. PMID- 30424712 TI - Time Course of Subretinal Proliferation after Scleral Buckling for Rhegmatogenous Retinal Detachment Repair. AB - PURPOSE: To observe course of subretinal proliferation (SRP) after scleral buckling (SB) for the rhegmatogenous retinal detachment. METHODS: Fundus photographs and serial optical coherence tomographies (OCTs) were retrospectively analyzed in 10 cases from 9 patients. RESULTS: Preoperative SRP locations were beneath the retina in six cases, intraretinal in one, and between the retina and retinal pigment epithelium (RPE) in one. One demonstrated SRP heterogeneity. Final SRP locations were intraretinal in two, on the RPE in seven, and beneath the retina in one. In two, the SRP invaginated into the retina while being absorbed. CONCLUSIONS: Detached retina can be reattached following retinal break occlusion by SB, although the remaining SRP can disturb the reattachment. OCT images of SRP demonstrated various features. Before surgery, the SRPs were typically strand-like types located beneath the retina. Postoperatively, they were located on the RPE. In some cases, they invaginated into the retina. PMID- 30424713 TI - Changes in support for the continuation of female genital mutilation/cutting and religious views on the practice in 19 countries. AB - Campaigns to end female genital mutilation/cutting (FGM/C) have been ongoing for decades. Many countries have adopted legislation that criminalises the practice and programmatic interventions aim to reduce support for it by presenting it as a violation of human rights and by highlighting associated health risks. We used Demographic and Health Survey data from 19 countries to measure national-level trends in the prevalence of FGM/C, reported support for the continuation of the practice, and the belief that it is a religious requirement among men and women. Levels and patterns in each of these outcomes vary markedly between countries. More than half of men and women born in recent years in Guinea and Mali support the continuation of the practice and believe that it is a religious requirement. Support for the continuation of FGM/C has fallen in Benin, Burkina Faso, Chad, Egypt, Ethiopia, Kenya, Senegal, and Tanzania, but has risen in Guinea, Niger, Nigeria, and Sierra Leone. The belief that FGM/C is a religious requirement is common, particularly in countries with high prevalence of cutting. Changes in support for cutting mirror those in the belief that it is a religious requirement. PMID- 30424714 TI - Pancreatic fistula rates after internal and external stenting of the pancreatojejunostomy anastomosis following pancreatoduodenectomy. AB - BACKGROUND: This retrospective comparative case series study aims to analyze the pancreatic fistula rates of internal and external stenting of the pancreatojejunostomy (PJ) anastomosis in patients who underwent pancreatoduodenectomy (PD) for periampullary tumors. METHODS: Ninety-eight patients with periampullary tumors who were operated between 2010 and 2017 were enrolled in this study. A classic open PD with Roux-en-Y PJ reconstruction was performed in all cases. RESULTS: The PJ anastomosis of 53 patients (54%) were stented internally whereas in 45 patients (46%) external stenting was preferred. Pancreatic fistula was observed in 29 patients (29.6%). Internal stenting and soft pancreatic tissue were found to be related to higher pancreatic fistula rates with odds ratios of 3.27 (p = .024) and 3.4 (p = .017), respectively. When only grade B and grade C fistulas were taken into account, the type of stenting has lost its significance but the texture of the remnant pancreas was still associated with 'clinically important' pancreatic fistula. CONCLUSIONS: We concluded that the external stenting of the PJ anastomosis may be considered as an effective approach for reducing postoperative pancreatic leaks in PD-planned patients for periampullary tumors. Although our study was retrospectively designed, we used standard charts to gather patient data and compared two stenting methods among homogeneous patient groups. PMID- 30424715 TI - Small-sided games can discriminate perceptual-cognitive-motor capability and predict disposal efficiency in match performance of skilled Australian footballers. AB - This study determined if small-sided games could discriminate perceptual cognitive-motor skill in Australian Rules Footballers. Higher skilled Western Australian Football League (WAFL) (n = 17) and lesser skilled Amateur (n = 23) players were recruited. Participants played three small-sided games of three minutes. Each disposal was scored for decision-making and motor skill execution, with these scores combined for a total score. Mann-Whitney U tests indicated significantly superior mean decision-making by higher skilled (M = 2.9, SD = 0.02) over lesser skilled (M = 2.7, SD = 0.04) (p = .012) players. Execution score was not significantly different between groups. Linear mixed model analysis found higher skilled players (M = 5.3, SD = 0.08) scored significantly higher than lower skilled players (M = 4.9, SD = 0.13) on total score (p = .009). Large effect sizes were found for decision-making and total score relative to games and position played in WAFL players. High agreement of scoring was observed for an elite (inter-rater) and a novice (intra-rater) coaches. Linear mixed model analysis indicated mean total scores of WAFL players significantly predicted disposal efficiency in match performance (p = .011). Small-sided games can be easily implemented to identify talented players and assess perceptual-cognitive motor skill. Mann-Whitney U tests indicated significantly superior median decision-making by higher skilled (Median = 2.90, Range = 0.30) and lower skilled (Median = 2.80, Range = 0.73) (p = .012). PMID- 30424716 TI - Human T-cell lymphotropic virus type I and II seroprevalence among volunteer blood donors in Thailand. AB - Human T-cell lymphotrophic virus type I and II (HTLV-I/II) are closely related but distinct retroviruses that can infect humans. Both the viruses can be transmitted via transfusion of contaminated blood components. HTLV pre transfusion screening is not mandatory in Thailand until now. Current epidemiological data for HTLV prevalence is still lacking since the past surveys were done more than a decade ago. The main objective of this study was to determine the seroprevalence of HTLV-I/II among voluntary blood donors in Thailand. 11,057 volunteer blood donors were screened for HTLV-I/II antibodies using the ARCHITECT rHTLV-I/II chemiluminescent immunoassay (CLIA). Initial reactive (IR) samples were subjected to repeat duplicate testing and were also sent for confirmatory testing at Korean Red Cross Society (KRC), Seoul or National Serology Reference Laboratories (NRL), Australia using alternate HTLV serological assays and immunoblot and/or specific nucleic acid testing respectively. Out of 11,057 plasma samples, 10,080 were low-risk seronegative donors and 977 were first-time/high-risk donors. Twenty of 24 IR samples were repeatedly reactive (RR) in low-risk seronegative donors group. On confirmatory testing of these 24 IR by immunoblot, 13 indeterminate and 11 negative results were observed. One out of 977 samples from first-time/high-risk donors was RR for anti-HTLV-I/II antibodies. This sample was co-reactive for HBsAg, but negative for HTLV by EIA or in-house HTLV-I qPCR. The ARCHITECT rHTLV-I/II assay exhibited a specificity of 99.93% in low-risk donors and 99.90% among high-risk donors. This study concluded that HTLV-I/II prevalence is low among blood donors in Thailand. But periodic surveillance should be continually conducted to ensure high blood safety standards in the country. PMID- 30424717 TI - Social work-based transitional care intervention for super utilizers of medical care: a retrospective analysis of the bridge model for super utilizers. AB - The present study was a retrospective evaluation of a social worker-led transitional care intervention that addresses the medical and social needs of inpatient super utilizers with >=5 inpatient admissions in a 12-month period. Bivariate analyses revealed significant reductions in the total number of hospital admissions, 30-day readmission rates, number of emergency department visits, average hospital charges per episode, and total hospital charges per person after the intervention. This social work intervention may be of interest to providers and payers, particularly regarding addressing the psychosocial needs of complex patients who account for most of health care costs. PMID- 30424718 TI - Preface. PMID- 30424719 TI - Patent Selections. PMID- 30424720 TI - Numerical analysis of intracellular amino acid profiles of breast cancer cells with K-Ras or PI3K mutation in response to kinase inhibitors. AB - BACKGROUND: Various efforts to understand the relationship between biological information and disease have been done using many different types of highthroughput data such as genomics and metabolomics. However, information obtained from previous studies was not satisfactory, implying that new direction of studies is in need. Thus, we have tried profiling intracellular free amino acids in normal and cancerous cells to extract some information about such relationship by way of the change in IFAA levels in response to the treatment of three kinase inhibitors. We define two measures such as relative susceptibility (RS) and relative efficacy (RE) to numerically quantify susceptibility of cell line to treatment and efficacy of treatment on cell line, respectively. METHODS: We applied principal component analysis (PCA) to the intracellular free amino acids (IFAAs) of isogenic breast cells with oncogenic mutation in K-Ras or PI3K genes to investigate the change in IFAA levels in response to the treatment of three kinase inhibitors. Two-dimensional plot, which was graphically represented by using the first two principal components (PCs), enabled us to evaluate the treatment efficacy in cancerous cells in terms of the quantitative distance of two IFAA profiles from cancerous and normal cells with the same treatment condition. RESULTS: The biggest change in metabolic states in K-Ras mutant cell was caused by REGO for both treatment time (RS=2.31 (24 h) and 1.64 (48 h)). Regarding RE, REGO was the most effective on K-Ras/PI3K mutant cell line for treatment time 24h (RE=1.28) while PI3K inhibitor had good effect on K-Ras mutant cell line for 48h (RE=1.1). CONCLUSIONS: Numerical study on the link between amino acid profile and cancer has been done in two different dimensions. We then summarized such link in terms of two new metrics such as RS and RE, which we first define in this work. Although our study based on those metrics seems to work, we think that the usefulness of the metrics in cancer study of this kind need to be further investigated. PMID- 30424721 TI - The predictive powers of plasma trefoil factor 3 or its related micro RNAs for patients with hepatocellular carcinoma. AB - BACKGROUND: Earlier diagnosis is beneficial for the prognosis of hepatocellular carcinoma (HCC). Alpha fetoprotein (AFP) is the most widely used biomarker for HCC, but its sensitivity and specificity are only 60 and 90%, respectively. Therefore, it is of great clinical significance to identify early prognostic biomarkers for HCC, especially a blood-based biomarker as it offers several advantages over tissue-based biomarkers. Trefoil factor 3 (TFF3), a novel secretory protein, was over-expressed in HCC tissues, indicating it might be a blood-based biomarker for HCC. In addition, circulating microRNAs have been investigated as biomarkers for HCC, indicating that miR-7-5p and miR-203a-3p, which are reported or predicted to target TFF3, also hold promise as blood-based biomarkers for HCC. METHODS: We enrolled 43 patients who were firstly diagnosed HCC and matched 47 control subjects without HCC. The levels of TFF3, miR-7-5p and miR-203a-3p were tested in the plasma of HCC patients. Moreover, we assayed the correlation of TFF3 with its related micro RNAs, miR-7-5p and miR-203a-3p, and evaluated their predictive powers for HCC. RESULTS: Decrease of TFF3 was associated with increase of miR-203a-3p in the plasma of HCC patients and they displayed potent predictive powers for HCC diagnosis. However, there was no significant change of plasma miR-7-5p between HCC and control group. CONCLUSION: Decrease of TFF3 correlated with increase of miR-203a-3p in the plasma of HCC patients and they could be additional biomarkers to improve sensitivity and specificity in the diagnosis of HCC. PMID- 30424722 TI - Prophylactic intervention of probiotics (L.acidophilus, L.rhamnosus GG) and celecoxib modulate Bax-mediated apoptosis in 1,2-dimethylhydrazine-induced experimental colon carcinogenesis. AB - BACKGROUND: Colorectal cancer has been found to be attenuated either with prophylactic manipulation of gut microbiome with probiotics or celecoxib, a non steroidal anti-inflammatory drug mainly by suppressing early pro-carcinogenic markers in various experimental studies. Therefore, the present study was designed to assess the prophylactic potential of combinatorial administration of probiotics (Lactobacillus rhamnosus GG, Lactobacillus acidophilus) and celecoxib in experimental colon carcinogenesis. METHODS: Six groups of Spraugue Dawely rats received probiotics L.rhamnosus GG or/and L.acidophilus in combination with celecoxib one week prior to the inducement of tumor by 1,2-dimethylhydrazine (DMH) and the treatment continued for 18 weeks. Prophylactic potentials of probiotics and celecoxib were determined by employing various methods such as tumor incidence, tumor burden, tumor multiplicity, apoptosis, caspase activity, expression of proto-oncogene K-ras and tumor suppressor p53 gene in colonic tumors. RESULTS: Interestingly, it was found that one week prior supplementation of both probiotics and celecoxib reduced tumor burden, tumor multiplicity, down regulated the expression of anti-apoptotic Bcl-2, proto-oncogene K-ras and up regulated pro-apoptotic Bax as well as tumor suppressor p53 in L.rhamnosus GG + celecoxib+DMH animals compared with counter controls and DMH-treated. CONCLUSIONS: It can be concluded that such combinatorial approach may be useful in reducing the burden and severity of disease in highly susceptible individuals but needs to be validated clinically. PMID- 30424724 TI - Genetic architecture of common bunt resistance in winter wheat using genome-wide association study. AB - BACKGROUND: Common bunt (caused by Tilletia caries and T. foetida) has been considered as a major disease in wheat (Triticum aestivum) following rust (Puccinia spp.) in the Near East and is economically important in the Great Plains, USA. Despite the fact that it can be easily controlled using seed treatment with fungicides, fungicides often cannot or may not be used in organic and low-input fields. Planting common bunt resistant genotypes is an alternative. RESULTS: To identify resistance genes for Nebraska common bunt race, the global set of differential lines were inoculated. Nine differential lines carrying nine different genes had 0% infected heads and seemed to be resistant to Nebraska race. To understand the genetic basis of the resistance in Nebraska winter wheat, a set of 330 genotypes were inoculated and evaluated under field conditions in two locations. Out of the 330 genotypes, 62 genotypes had different degrees of resistance. Moreover, plant height, chlorophyll content and days to heading were scored in both locations. Using genome-wide association study, 123 SNPs located on fourteen chromosomes were identified to be associated with the resistance. Different degrees of linkage disequilibrium was found among the significant SNPs and they explained 1.00 to 9.00% of the phenotypic variance, indicating the presence of many minor QTLs controlling the resistance. CONCLUSION: Based on the chromosomal location of some of the known genes, some SNPs may be associated with Bt1, Bt6, Bt11 and Bt12 resistance loci. The remaining significant SNPs may be novel alleles that were not reported previously. Common bunt resistance seems to be an independent trait as no correlation was found between a number of infected heads and chlorophyll content, days to heading or plant height. PMID- 30424725 TI - Mixed methods developmental evaluation of the CHOICE program: a relationship centred mealtime intervention for long-term care. AB - BACKGROUND: Mealtimes are important to quality of life for residents in long-term care (LTC). CHOICE (which stands for Connecting, Honouring dignity, Offering support, supporting Identity, Creating opportunities, and Enjoyment) is a multi component intervention to improve relationship-centred care (RCC) and overall mealtime experience for residents. The objective of this developmental evaluation was to determine: a) if the dining experience (e.g. physical, social and RCC practices) could be modified with the CHOICE Program, and b) how program components needed to be adapted and/or if new components were required. METHODS: A mixed methods study conducted between April-November 2016 included two home areas (64 residents; 25 care staff/home management) within a single LTC home in Ontario. Mealtime Scan (MTS), which measures mealtime experience at the level of the dining room, was used to evaluate the effectiveness of CHOICE implementation at four time points. Change in physical, social, RCC dining environment ratings and overall quality of the mealtime experience over time was determined with linear mixed-effects analyses (i.e., repeated measures). Semi-structured interviews (n = 9) were conducted with home staff to identify what components of the intervention worked well and what improvements could be made. RESULTS: Physical and overall mealtime environment ratings showed improvement over time in both areas; one home area also improved social ratings (p < 0.05). Interviews revealed in-depth insights into the program and implementation process: i) Knowing the context and culture to meet staff and resident needs; ii) Getting everyone on board, including management; iii) Keeping communication lines open throughout the process; iv) Sharing responsibility and accountability for mealtime goals and challenges; v) Empowering and supporting staff's creative mealtime initiatives. CONCLUSIONS: This developmental evaluation demonstrated the potential value of CHOICE. Findings suggest a need to: extend the time to tailor program components; empower home staff in change management; and provide increased coaching. PMID- 30424727 TI - HIV prevalence, related risk behaviors, and correlates of HIV infection among people who use drugs in Cambodia. AB - BACKGROUND: Although HIV prevalence in Cambodia has declined to 0.6% among the general population, the prevalence remains high among female sex workers (14.0%) and men who have sex with men (2.3%). Over the past 10 years, the number of people who use drugs (PWUDs) has increased considerably. PWUDs, especially people who inject drugs (PWIDs), who have multiple sex partners or unprotected sex contribute to a higher HIV prevalence. This paper aims to estimate the prevalence of HIV across PWUD groups and to identify factors associated with HIV infection. METHODS: Respondent-driven sampling (RDS) was used to recruit 1626 consenting PWUDs in 9 provinces in 2012. Questionnaires and blood specimens were collected. HIV prevalence estimates were calculated using RDSAT 7.1. Individual weightings for HIV were generated with RDSAT and used for a weighted analysis in STATA 13. Multivariate logistic regression was used to identify the independent factors associated with HIV prevalence. RESULTS: Most of the PWUDs were men (82.0%), and 7.3% were PWIDs. Non-PWIDs, especially users of amphetamine-type stimulants (ATS), represented the larger proportion of the participants (81.5%). The median age for of the PWUDs was 24.0 years (IQR: 20-29). The HIV prevalence among the PWUDs was 5.1% (95% CI: 4.1-6.2), 24.8%, among PWIDs and 4.0% among non-PWIDs. The HIV prevalence among female PWIDs was 37.5, and 22.5% among male PWIDs. Four factors were independently associated with HIV infection: female sex, with AOR = 7.8 (95% CI: 3.00-20.35); age groups 21-29 and older (AOR = 10.3, 95% CI: 1.2 20.4); and using drugs for >=12 months (AOR = 4.0, 95% CI: 1.38-11.35). Finally, injecting drugs remained a strong predictor of HIV infection, with an AOR = 4.1 (95% CI: 1.53-10.96). CONCLUSION: HIV prevalence remains high among PWIDs. Harm reduction efforts, such as needle and syringe provision programs, must improve their coverage. Innovative strategies are needed to reach sub-groups of PWUDs, especially women who inject drugs. Furthermore, the large proportion of non PWIDs, especially ATS users, should not be ignored. Therefore, combined HIV prevention and harm reduction programs should integrate ATS users. PMID- 30424726 TI - Whole genome sequencing of Trypanosoma cruzi field isolates reveals extensive genomic variability and complex aneuploidy patterns within TcII DTU. AB - BACKGROUND: Trypanosoma cruzi, the etiologic agent of Chagas disease, is currently divided into six discrete typing units (DTUs), named TcI-TcVI. TcII is among the major DTUs enrolled in human infections in South America southern cone, where it is associated with severe cardiac and digestive symptoms. Despite the importance of TcII in Chagas disease epidemiology and pathology, so far, no genome-wide comparisons of the mitochondrial and nuclear genomes of TcII field isolates have been performed to track the variability and evolution of this DTU in endemic regions. RESULTS: In the present work, we have sequenced and compared the whole nuclear and mitochondrial genomes of seven TcII strains isolated from chagasic patients from the central and northeastern regions of Minas Gerais, Brazil, revealing an extensive genetic variability within this DTU. A comparison of the phylogeny based on the nuclear or mitochondrial genomes revealed that the majority of branches were shared by both sequences. The subtle divergences in the branches are probably consequence of mitochondrial introgression events between TcII strains. Two T. cruzi strains isolated from patients living in the central region of Minas Gerais, S15 and S162a, were clustered in the nuclear and mitochondrial phylogeny analysis. These two strains were isolated from the other five by the Espinhaco Mountains, a geographic barrier that could have restricted the traffic of insect vectors during T. cruzi evolution in the Minas Gerais state. Finally, the presence of aneuploidies was evaluated, revealing that all seven TcII strains have a different pattern of chromosomal duplication/loss. CONCLUSIONS: Analysis of genomic variability and aneuploidies suggests that there is significant genomic variability within Minas Gerais TcII strains, which could be exploited by the parasite to allow rapid selection of favorable phenotypes. Also, the aneuploidy patterns vary among T. cruzi strains and does not correlate with the nuclear phylogeny, suggesting that chromosomal duplication/loss are recent and frequent events in the parasite evolution. PMID- 30424723 TI - Effectiveness of contrast-associated acute kidney injury prevention methods; a systematic review and network meta-analysis. AB - BACKGROUND: Different methods to prevent contrast-associated acute kidney injury (CA-AKI) have been proposed in recent years. We performed a mixed treatment comparison to evaluate and rank suggested interventions. METHODS: A comprehensive Systematic review and a Bayesian network meta-analysis of randomised controlled trials was completed. Results were tabulated and graphically represented using a network diagram; forest plots and league tables were shown to rank treatments by the surface under the cumulative ranking curve (SUCRA). A stacked bar chart rankogram was generated. We performed main analysis with 200 RCTs and three analyses according to contrast media and high or normal baseline renal profile that includes 173, 112 & 60 RCTs respectively. RESULTS: We have included 200 trials with 42,273 patients and 44 interventions. The primary outcome was CI-AKI, defined as >=25% relative increase or >= 0.5 mg/dl increase from baseline creatinine one to 5 days post contrast exposure. The top ranked interventions through different analyses were Allopurinol, Prostaglandin E1 (PGE1) & Oxygen (0.9647, 0.7809 & 0.7527 in the main analysis). Comparatively, reference treatment intravenous hydration was ranked lower but better than Placebo (0.3124 VS 0.2694 in the main analysis). CONCLUSION: Multiple CA-AKI preventive interventions have been tested in RCTs. This network evaluates data for all the explored options. The results suggest that some options (particularly allopurinol, PGE1 & Oxygen) deserve further evaluation in a larger well-designed RCTs. PMID- 30424729 TI - Genome-wide identification of LRR-containing sequences and the response of these sequences to nematode infection in Arachis duranensis. AB - BACKGROUND: Leucine-rich repeat (LRR)-containing genes are involved in responses to various diseases. Recently, RNA-seq data from A. duranensis after nematode (Meloidogyne arenaria) infection were released. However, the number of LRR containing genes present in A. duranensis and the response of LRR-containing genes to nematode infection are poorly understood. RESULTS: In this study, we found 509 amino acid sequences containing nine types of LRR domains in A. duranensis. The inferred phylogenetic relationships revealed that the nine types of LRR domains had two originations. The inferred selective pressure was mainly consistent with LRR domains undergoing purifying selection. Twenty-one LRR containing genes were associated with possible resistance to nematode infection after 3, 6, and 9 days. Among them, Aradu.T5WNW, Aradu.JM17V, and Aradu.MKP1A were up-regulate at these three time points, while Aradu.QD5DS and Aradu.M0ENQ were up-regulated 6 and 9 days after nematode infection. The expression of the above mentioned five genes was significantly and negatively correlated with the number of LRR8 domain, indicating that fewer LRR8 domains are associated with the promotion of LRR-containing genes that resist nematode infection. Patterns of co expression and cis-acting elements indicated that WRKY possibly regulate the responses of LRR-containing genes to nematode infection and that expansin genes may work together with LRR-containing genes in response to nematode infection. CONCLUSIONS: We identified the number and type of LRR-containing genes in A. duranensis. The LRR-containing genes that were found appear to be involved in responses to nematode infection. The number of LRR8 domains was negatively correlated with expression after nematode infection. The WRKY transcription factor may regulate resistance to nematode infection based on LRR-containing genes. Our results could improve the understanding of resistance to nematodes and molecular breeding in peanuts. PMID- 30424730 TI - Respiratory variation in peripheral arterial blood flow peak velocity to predict fluid responsiveness in mechanically ventilated patients: a systematic review and meta-analysis. AB - BACKGROUND: Fluid overloading is detrimental to organ function and results in a poor prognosis. It is necessary to evaluate fluid responsiveness before fluid loading. We performed a systematic meta-analysis to evaluate the diagnostic value of the respiratory variation in peripheral arterial blood flow peak velocity (?Vpeak PA) in predicting fluid responsiveness in mechanically ventilated patients. METHODS: PubMed, Embase and The Cochrane Library databases were searched for studies that used ?Vpeak PA to predict fluid responsiveness in mechanically ventilated patients. We calculated the pooled values of sensitivity, specificity and the area of the summary receiver operating characteristic curve by Meta-Disc 14.0 software. RESULTS: Nine studies with a total of 402 patients were included. Two low quality studies were deleted in further analysis. Moreover, because of different locations of peripheral artery, the rest included studies were divided into brachial site group and carotid site group for meta analysis individually. The pooled sensitivity, specificity and area under curve were 0.85 (95% confidence interval (CI) 0.77-0.92), 0.86 (95% CI 0.77-0.92) and 0.9268 in carotid site group. The pooled sensitivity, specificity and area under curve were 0.72 (95% CI 0.60-0.81), 0.85 (95% CI 0.74-0.93) and 0.8587 in brachial site group. CONCLUSIONS: ?Vpeak of carotid and brachial artery had a diagnostic value in predicting fluid responsiveness respectively. Moreover, ?Vpeak of carotid artery had more value than brachial artery in predicting fluid responsiveness. However, there was some clinical heterogeneity; therefore, further studies are needed to confirm diagnostic accuracy. PMID- 30424728 TI - Gut microbiota of preterm infants supplemented with probiotics: sub-study of the ProPrems trial. AB - BACKGROUND: The ProPrems trial, a multi-center, double-blind, placebo-controlled randomized trial, previously reported a 54% reduction in necrotizing enterocolitis (NEC) of Bell stage 2 or more from 4.4 to 2.0% in 1099 infants born before 32 completed weeks' gestation and weighing < 1500 g, receiving probiotic supplementation (with Bifidobacterium longum subsp. infantis BB-02, Streptococcus thermophilus TH-4 and Bifidobacterium animalis subsp. lactis BB-12). This sub study investigated the effect of probiotic supplementation on the gut microbiota in a cohort of very preterm infants in ProPrems. RESULTS: Bifidobacterium was found in higher abundance in infants who received the probiotics (AOR 17.22; 95% CI, 3.49-84.99, p < 0.001) as compared to the placebo group, and Enterococcus was reduced in infants receiving the probiotic during the supplementation period (AOR 0.27; 95% CI, 0.09-0.82, p = 0.02). CONCLUSION: Probiotic supplementation with BB 02, TH-4 and BB-12 from soon after birth increased the abundance of Bifidobacterium in the gut microbiota of very preterm infants. Increased abundance of Bifidobacterium soon after birth may be associated with reducing the risk of NEC in very preterm infants. PMID- 30424731 TI - Comparative study of virulence factors among methicillin resistant Staphylococcus aureus clinical isolates. AB - BACKGROUND: Methicillin resistant Staphylococcus aureus (MRSA) is recognized worldwide as a leading cause of hospital and community infections. Biofilm formation by MRSA is an extremely important virulence factor to be understood. Our aim was to establish phenotypic and genotypic characterization of virulence factors among 43 MRSA clinical isolates in a Tunisian hospital. METHODS: We investigated enzymatic profiles, biofilm production and prevalences of genes encoding intracellular adhesion molecules (icaA and icaD), Microbial Surface Components Recognizing Adhesive Matrix Molecules genes (fnbA, fnbB and cna) and exoenzymes genes (geh, sspA and sspB). RESULTS: Our findings revealed that caseinase, gelatinase, lipase and lecithinase activities were detected in 100%, 100%, 76.6% and 93.3% of cases respectively. This study showed that 23 strains (76.7%) were slime producers on Congo red medium. Furthermore, 46.5% and 53.5% of isolates were respectively highly and moderately biofilm-forming on polystyrene. Significant association was found between both biofilm tests. PCR detection showed that 74.4%, 18.6%, 69.8%, 65.1% and 74.4% of isolates harbored fnbA, fnbB, icaA, icaD and cna genes respectively. In addition, 34.9%, 18.6% and 30.2% of MRSA strains were found positive for sspA, sspB and geh genes respectively. Further, statistical data showed that the presence of the fnbA and fnbB genes was significantly associated with a high biofilm production on polystyrene. However, no statistical association was observed for the icaA, icaD and cna genes. CONCLUSIONS: This study indicates that the detection of fnbA and fnbB contributing to the first step of biofilm formation has been predictable of high biofilm production. As studied factors contribute to MRSA virulence, this research could be of value in orienting towards the development of new preventive and therapeutic measures. PMID- 30424732 TI - Biaryl scaffold-focused virtual screening for anti-aggregatory and neuroprotective effects in Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease (AD) is a primary cause of dementia in ageing population affecting more than 35 million people around the globe. It is a chronic neurodegenerative disease caused by defected folding and aggregation of amyloid beta (Abeta) protein. Abeta is formed by the cleavage of membrane embedded amyloid precursor protein (APP) by using enzyme 'transmembrane aspartyl protease, beta-secretase'. Inhibition of beta-secretase is a viable strategy to prevent neurotoxicity in AD. Another strategy in the treatment of AD is inhibition of acetylcholinesterase. This inhibition reduces the degradation of acetylcholine and temporarily restores the cholinergic function of neurons and improves cognitive function. Monoamine oxidase and higher glutamate levels are also found to be linked with Abeta peptide related oxidative stress. Oxidative stress leads to reduced activity of glutamate synthase resulting in significantly higher level of glutamate in brain. The aim of this study is to perform in silico screening of a virtual library of biaryl scaffold containing compounds potentially used for the treatment of AD. Screening was done against the primary targets of AD therapeutics, acetylcholinesterase, beta-secretase (BACE1), Monoamine oxidases (MAO) and N-Methyl-D-aspartate (NMDA) receptor. Compounds were screened for their inhibitory potential by employing molecular docking approach using AutoDock vina. Binding energy scores were embodied in the heatmap to display varies strengths of interactions of the ligands targeting AD. RESULTS: Several ligands showed notable interaction with at least two targets, but the strong interaction with all the targets is shown by very few ligands. The pharmacokinetics of the interacting ligands was also predicted. The interacting ligands have good drug-likeness and brain availability essential for drugs with intracranial targets. CONCLUSION: These results suggest that biaryl scaffold may be pliable to drug development for neuroprotection in AD and that the synthesis of further analogues to optimize these properties should be considered. PMID- 30424733 TI - Dynamics of the Phanerochaete carnosa transcriptome during growth on aspen and spruce. AB - BACKGROUND: The basidiomycete Phanerochaete carnosa is a white-rot species that has been mainly isolated from coniferous softwood. Given the particular recalcitrance of softwoods to bioconversion, we conducted a comparative transcriptomic analysis of P. carnosa following growth on wood powder from one softwood (spruce; Picea glauca) and one hardwood (aspen; Populus tremuloides). P. carnosa was grown on each substrate for over one month, and mycelia were harvested at five time points for total RNA sequencing. Residual wood powder was also analyzed for total sugar and lignin composition. RESULTS: Following a slightly longer lag phase of growth on spruce, radial expansion of the P. carnosa colony was similar on spruce and aspen. Consistent with this observation, the pattern of gene expression by P. carnosa on each substrate converged following the initial adaptation. On both substrates, highest transcript abundances were attributed to genes predicted to encode manganese peroxidases (MnP), along with auxiliary activities from carbohydrate-active enzyme (CAZy) families AA3 and AA5. In addition, a lytic polysaccharide monooxygenase from family AA9 was steadily expressed throughout growth on both substrates. P450 sequences from clans CPY52 and CYP64 accounted for 50% or more of the most highly expressed P450s, which were also the P450 clans that were expanded in the P. carnosa genome relative to other white-rot fungi. CONCLUSIONS: The inclusion of five growth points and two wood substrates was important to revealing differences in the expression profiles of specific sequences within large glycoside hydrolase families (e.g., GH5 and GH16), and permitted co-expression analyses that identified new targets for study, including non-catalytic proteins and proteins with unknown function. PMID- 30424734 TI - CC-type glutaredoxins mediate plant response and signaling under nitrate starvation in Arabidopsis. AB - BACKGROUND: Nitrogen is an essential nutrient in plants. Despite the importance of nitrogen for plant growth and agricultural productivity, signal transduction pathways in response to nitrate starvation have not been fully elucidated in plants. RESULTS: Gene expression analysis and ectopic expression were used to discover that many CC-type glutaredoxins (ROXYs) are differentially expressed in response to nitrate deprivation. A gain-of-function approach showed that ROXYs may play a role in nutrient sensing through the regulation of chlorophyll content, root hair growth, and transcription of nitrate-related genes such as NRT2.1 under low or high nitrate conditions. Reactive oxygen species (ROS) were produced in plant roots under nitrate starvation and H2O2 treatment differentially regulated the expression of the ROXYs, suggesting the involvement of ROS in signaling pathways under nitrate deficiency. CONCLUSION: This work adds to what is known about nitrogen sensing and signaling through the findings that the ROXYs and ROS are likely to be involved in the nitrate deprivation signaling pathway. PMID- 30424735 TI - Association of TLR8 and TLR9 polymorphisms with tuberculosis in a Chinese Han population: a case-control study. AB - BACKGROUND: Toll-like receptor (TLR) single nucleotide polymorphisms (SNPs) have been associated with regulation of TLR expression and development of active tuberculosis (TB). The objectives of this study were to determine whether TLR8 and TLR9 SNPs were associated with the development of latent TB infection (LTBI) and the subsequent pulmonary TB (PTB) in a Chinese Han population. METHODS: Two independent samples were enrolled. The first sample contained 584 TB cases and 608 controls; the second sample included 204 healthy controls, 201 LTBI subjects and 209 bacteria-confirmed active PTB patients. Three SNPs (rs3764880, rs187084 and rs5743836) were genotyped. The associations between the SNPs and risk of LTBI or PTB were investigated using unconditional logistic regression analysis. RESULTS: The A-allele of TLR8 rs3764880 SNP was protective against the development of TB in males (A vs G, OR = 0.58, 95%CI = 0.37-0.91). The AA genotype of rs3764880 SNP was found to increase the risk of PTB among females with an OR of 4.81 (1.11-20.85). The G allele of TLR9 SNP rs187084 was found to increase the risk of PTB (G vs A, P = 0.01, OR = 1.48, 95% CI = 1.10-2.00), the significance was also observed under dominant genetic models. The GA-genotype of TLR9 rs187084 SNP was found to increase the risk of PTB with an OR of 1.68 (1.07 2.65), but was found to decrease the risk of MTB infection with an OR = 0.64 (0.41-0.98). TLR9_rs5743836 SNP was excluded from the data analyses, because the minimum allele frequency was< 1%. CONCLUSIONS: Our findings in two independent samples indicated that SNPs in TLR8 and TLR9 were associated with the development of TB, and highlight that SNPs may have different effects on disease pathogenesis and progression. PMID- 30424736 TI - Multistate recursively imputed survival trees for time-to-event data analysis: an application to AIDS and mortality post-HIV infection data. AB - BACKGROUND: This study aimed to introduce recursively imputed survival trees into multistate survival models (MSRIST) to analyze these types of data and to identify the prognostic factors influencing the disease progression in patients with intermediate events. The proposed method is fully nonparametric and can be used for estimating transition probabilities. METHODS: A general algorithm was provided for analyzing multi-state data with a focus on the illness-death and progressive multi-state models. The model considered both beyond Markov and Non Markov settings. We also proposed a multi-state random survival method (MSRSF) and compared their performance with the classical multi-state Cox model. We applied the proposed method to a dataset related to HIV/AIDS patients based on a retrospective cohort study extracted in Tehran from April 2004 to March 2014 consist of 2473 HIV-infected patients. RESULTS: The results showed that MSRIST outperformed the classical multistate method using Cox Model and MSRSF in terms of integrated Brier score and concordance index over 500 repetitions. We also identified a set of important risk factors as well as their interactions on different states of HIV and AIDS progression. CONCLUSIONS: There are different strategies for modelling the intermediate event. We adapted two newly developed data mining technique (RSF and RIST) for multistate models (MSRSF and MSRIST) to identify important risk factors in different stages of the diseases. The methods can capture any complex relationship between variables and can be used as a useful tool for identifying important risk factors in different states of this disease. PMID- 30424737 TI - Study protocol of the iMPaCT project: a longitudinal cohort study assessing psychological determinants, sexual behaviour and chlamydia (re)infections in heterosexual STI clinic visitors. AB - BACKGROUND: Chlamydia trachomatis (chlamydia), the most commonly reported sexually transmitted infection (STI) in the Netherlands, can lead to severe reproductive complications. Reasons for the sustained chlamydia prevalence in young individuals, even in countries with chlamydia screening programs, might be the asymptomatic nature of chlamydia infections, and high reinfection rates after treatment. When individuals are unaware of their infection, preventive behaviour or health-care seeking behaviour mostly depends on psychological determinants, such as risk perception. Furthermore, behaviour change after a diagnosis might be vital to reduce reinfection rates. This makes the incorporation of psychological determinants and behaviour change in mathematical models estimating the impact of interventions on chlamydia transmission especially important. Therefore, quantitative real-life data to inform these models is needed. METHODS: A longitudinal cohort study will be conducted to explore the link between psychological and behavioural determinants and chlamydia (re)infection among heterosexual STI clinic visitors aged 18-24 years. Participants will be recruited at the STI clinics of the public health services of Amsterdam, Hollands Noorden, Kennemerland, and Twente. Participants are enrolled for a year, and questionnaires are administrated at four time points: baseline (before an STI consultation), three-week, six-month and at one-year follow-up. To be able to link psychological and behavioural determinants to (re)infections, participants will be tested for chlamydia at enrolment and at six-month follow-up. Data from the longitudinal cohort study will be used to develop mathematical models for curable STI incorporating these determinants to be able to better estimate the impact of interventions. DISCUSSION: This study will provide insights into the link between psychological and behavioural determinants, including short-term and long-term changes after diagnosis, and chlamydia (re)infections. Our mathematical model, informed by data from the longitudinal cohort study, will be able to estimate the impact of interventions on chlamydia prevalence, and identify and prioritise successful interventions for the future. These interventions could be implemented at STI clinics tailored to psychological and behavioural characteristics of individuals. TRIAL REGISTRATION: Dutch Trial Register NTR-6307 . Retrospectively registered 11-nov-2016. PMID- 30424738 TI - Effects, costs and feasibility of the 'Stay Active at Home' Reablement training programme for home care professionals: study protocol of a cluster randomised controlled trial. AB - BACKGROUND: According to the principles of Reablement, home care services are meant to be goal-oriented, holistic and person-centred taking into account the capabilities and opportunities of older adults. However, home care services traditionally focus on doing things for older adults rather than with them. To implement Reablement in practice, the 'Stay Active at Home' programme was developed. It is assumed that the programme leads to a reduction in sedentary behaviour in older adults and consequently more cost-effective outcomes in terms of their health and wellbeing. However, this has yet to be proven. METHODS/ DESIGN: A two-group cluster randomised controlled trial with 12 months follow-up will be conducted. Ten nursing teams will be selected, pre-stratified on working area and randomised into an intervention group ('Stay Active at Home') or control group (no training). All nurses of the participating teams are eligible to participate in the study. Older adults and, if applicable, their domestic support workers (DSWs) will be allocated to the intervention or control group as well, based on the allocation of the nursing team. Older adults are eligible to participate, if they: 1) receive homecare services by the selected teams; and 2) are 65 years or older. Older adults will be excluded if they: 1) are terminally ill or bedbound; 2) have serious cognitive or psychological problems; or 3) are unable to communicate in Dutch. DSWs are eligible to participate if they provide services to clients who fulfil the eligibility criteria for older adults. The study consists of an effect evaluation (primary outcome: sedentary behaviour in older adults), an economic evaluation and a process evaluation. Data for the effect and economic evaluation will be collected at baseline and 6 and/or 12 months after baseline using performance-based and self-reported measures. In addition, data from client records will be extracted. A mixed-methods design will be applied for the process evaluation, collecting data of older adults and professionals throughout the study period. DISCUSSION: This study will result in evidence about the effectiveness, cost-effectiveness and feasibility of the 'Stay Active at Home' programme. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03293303 , registered on 20 September 2017. PMID- 30424739 TI - A novel splicing mutation in the PKD1 gene causes autosomal dominant polycystic kidney disease in a Chinese family: a case report. AB - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic renal disorder in humans, affecting 1 in 400 to 1000 individuals. Mutations PKD1 (which accounts for 85% of ADPKD and produces polycystin-1) and PKD2 (produces polycystin-2) are responsible for this disease. These two polycystins are critical for maintaining normal renal tubular structures during kidney development. CASE PRESENTATION: We performed genetic analysis on a family with ADPKD. DNA samples extracted from ADPKD patient blood were subject to targeted Next generation sequencing for human a panel of renal disease-related genes. A splicing mutation, c.2854-3C > G (also known as IVS11-3C > G), in the PKD1 gene was found in the 3 patients from the family, but was not found in four unaffected relatives and 100 normal control samples. Reverse transcription-PCR (RT-PCR) was performed to analyse the relative mRNA expression in the patient samples. mRNA sequencing showed that 29 bases inserted into the 3' end of exon 11 in the PKD1 gene lead to a frameshift mutation. CONCLUSIONS: The PKD1 c.2854-3C > G mutation leads to a frameshift mutation during translation of the polycystin-1 protein, which eventually led to ADPKD in the Chinese family. PMID- 30424740 TI - Burden and factors associated with clinical neonatal sepsis in urban Uganda: a community cohort study. AB - BACKGROUND: Neonatal sepsis is one of the most important causes of mortality in developing countries and yet the most preventable. In developing countries clinical algorithms are used to diagnose clinical neonatal sepsis because of inadequate microbiological services. Most information on incidence and risk factors of neonatal sepsis are from hospital studies which may not be generalized to communities where a significant proportion of mothers do not deliver from health facilities. This study, conducted in urban Uganda, sought to determine the community based incidence of clinical neonatal sepsis and the factors associated. METHODS: This was a cohort of mother-neonate pairs in Kampala, Uganda from March to May 2012. The enrolled neonates were assessed for clinical sepsis and factors associated, and followed up till the end of the neonatal period. STATA version 10 was used to analyse the data. RESULTS: The community based incidence of neonatal sepsis was 11% (95% CI: 7.6-14.4). On bivariate analysis, lack of financial support from the father (OR 4.09, 95% CI 1.60-10.39) and prolonged rupture of membranes more than 18 h prior to delivery (OR 11.7, 95% CI 4.0-31.83) were significantly associated with neonatal sepsis. Maternal hand washing prior to handling the baby was found to be protective of neonatal sepsis (OR 0.41, 95% CI 0.18-0.94). Of the 317 infants who completed the follow up period, one died within the neonatal period giving a neonatal mortality of 0.003%. CONCLUSION: The high incidence of clinical neonatal sepsis in this urban community with high rates of antenatal care attendance and health facility delivery places a demand on the need to improve the quality of antenatal, perinatal and postnatal care in health facilities with regards to infection prevention including promoting simple practices like hand washing. The astoundingly low mortality rate is most likely because this was a low risk cohort. However it may also suggest that the neonatal mortality in developing countries may be reduced with promotion of simple low cost interventions like community follow up of neonates using village health teams or domiciliary care. PMID- 30424741 TI - Bubble effect: including internet search engines in systematic reviews introduces selection bias and impedes scientific reproducibility. AB - BACKGROUND: Using internet search engines (such as Google search) in systematic literature reviews is increasingly becoming a ubiquitous part of search methodology. In order to integrate the vast quantity of available knowledge, literature mostly focuses on systematic reviews, considered to be principal sources of scientific evidence at all practical levels. Any possible individual methodological flaws present in these systematic reviews have the potential to become systemic. MAIN TEXT: This particular bias, that could be referred to as (re)search bubble effect, is introduced because of inherent, personalized nature of internet search engines that tailors results according to derived user preferences based on unreproducible criteria. In other words, internet search engines adjust their user's beliefs and attitudes, leading to the creation of a personalized (re)search bubble, including entries that have not been subjected to rigorous peer review process. The internet search engine algorithms are in a state of constant flux, producing differing results at any given moment, even if the query remains identical. There are many more subtle ways of introducing unwanted variations and synonyms of search queries that are used autonomously, detached from user insight and intent. Even the most well-known and respected systematic literature reviews do not seem immune to the negative implications of the search bubble effect, affecting reproducibility. CONCLUSION: Although immensely useful and justified by the need for encompassing the entirety of knowledge, the practice of including internet search engines in systematic literature reviews is fundamentally irreconcilable with recent emphasis on scientific reproducibility and rigor, having a profound impact on the discussion of the limits of scientific epistemology. Scientific research that is not reproducible, may still be called science, but represents one that should be avoided. Our recommendation is to use internet search engines as an additional literature source, primarily in order to validate initial search strategies centered on bibliographic databases. PMID- 30424742 TI - Cost-effectiveness of a complex intervention to reduce children's exposure to second-hand smoke in the home. AB - BACKGROUND: Second-hand smoke (SHS) causes numerous health problems in children such as asthma, respiratory tract infections and sudden infant death syndrome. The home is the main source of exposure to SHS for children, particularly for young children. We estimated the cost-effectiveness of a complex intervention designed to reduce SHS exposure of children whose primary caregiver feels unable or unwilling to quit smoking. METHODS: A cost-effectiveness analysis was carried out alongside an open-label, parallel, randomised controlled trial in deprived communities in Nottingham, England. A complex intervention combining behavioural support, nicotine replacement therapy and personalised feedback on home air quality was compared with usual care. A total number of 205 households were recruited, where the main caregivers were aged 18 and over, with a child aged under five years living in their household reporting smoking inside their home. Analyses for this study were undertaken from the National Health Service/Personal Social Services perspective. All costs were estimated in UK pounds (L) at 2013/14 prices. The primary outcome was the incremental cost-effectiveness of change in air quality in the home, measured as average 16-24 h levels of particulate matter of < 2.5 MUm diameter (PM2.5), between baseline and 12 weeks. Secondary outcomes included incremental cost per quitter, quit attempts and cigarette consumption in the home. A non-parametric bootstrap re-sampling technique was employed to explore uncertainty around the calculated incremental cost-effectiveness ratios. RESULTS: The complex intervention achieved reduced PM2.5 by 21.6 MUg/m3 (95% CI: 5.4 to 37.9), with an incremental cost of L283 (95% CI: L254-L313), relative to usual care. The incremental cost-effectiveness ratio was L131 (bootstrapped 95% CI: L72-L467) per additional 10MUg/m3 reduction in PM2.5, or L71 (bootstrapped 95% CI: -L57-L309) per additional quitter. CONCLUSIONS: This trial targeted a socio-economically disadvantaged population that has been neglected within the literature. The complex intervention was more costly but more effective in reducing PM2.5 compared with the usual care. It offers huge potential to reduce children's' tobacco-related harm by reducing exposure to SHS in the home. The intervention is considered cost-effective if the decision maker is willing to pay L131 per additional 10MUg/m3 of PM2.5 reduction. TRIAL REGISTRATION: The Smoke Free Homes trial was registered with isrctn.com on 29 January 2013 with the identifier ISRCTN81701383 . PMID- 30424743 TI - De novo variant of TRRAP in a patient with very early onset psychosis in the context of non-verbal learning disability and obsessive-compulsive disorder: a case report. AB - BACKGROUND: TRRAP encodes a multidomain protein kinase that works as a genetic cofactor to influence DNA methylation patterns, DNA damage repair, and chromatin remodeling. TRRAP protein is vital to early neural developmental processes, and variants in this gene have been associated with schizophrenia and childhood disintegrative disorder. CASE PRESENTATION: Here, we report on a patient with a de novo nonsynonymous TRRAP single-nucleotide variant (EST00000355540.3:c.5957G > A, p.Arg1986Gln) and early onset major depression accompanied by a psychotic episode (before age 10) that occurred in the context of longer standing nonverbal learning disability and a past history of obsessions and compulsions. CONCLUSIONS: The de novo variant and presentation of very early onset psychosis indicate a rare Mendelian disorder inheritance model. The genotype and behavioral abnormalities of this patient are reviewed. PMID- 30424745 TI - Cardiovascular risk factors with an emphasis on hypertension in the Mura Indians from Amazonia. AB - BACKGROUND: The Brazilian indigenous population is currently undergoing a process of epidemiological transition regarding the occurrence of communicable diseases, malnutrition and non-communicable chronic diseases. Chronic non-infectious diseases are the most common causes of death worldwide, and hypertension is one of the main cardiovascular risk factors. Thus, the main objective of this paper was to evaluate the prevalence of cardiovascular risk factors, with an emphasis on hypertension, in the Mura Indians living in the municipality of Autazes in the northern Brazilian state of Amazonas. METHODS: This cross-sectional study was conducted among 455 natives (57.8% women, 42.2 +/- 16.7 years) selected by simple random sampling. Sociodemographic variables, habits and lifestyles, anthropometric data, fasting glycaemia and lipid profiles were evaluated. Blood pressure was measured with a validated automatic device. Values of p <= 0.05 were considered significant. RESULTS: The prevalence of hypertension was 26.6%. The other cardiovascular risk factors were as follows: increased waist-hip ratio (85.1%); increased neck circumference (60.2%); increased waist circumference (48.6%); overweight (57.1%); physical inactivity (52.7%); use of alcoholic beverages (40.2%); high total cholesterol (27.5%); increased triglycerides (23.5%); smoking (20.4%); and diabetes mellitus (3.0%). In relation to non hypertensive individuals, indigenous hypertensive individuals were (p <= 0.05) older and had a higher proportion of individuals living with partners and individuals who were retired, as well as a lower level of schooling and higher family income. The indigenous people living in urban areas had a higher prevalence of hypertension than did those living in rural areas. In relation to habits and lifestyles, hypertensive Indians had a lower prevalence of smoking, higher frequency of the use of animal fat during meal preparation, lower frequency of vegetable oil use and lower frequency of salt addition to already prepared meals. An assessment of anthropometric variables and laboratory markers showed that the hypertensive indigenous individuals had higher values of body mass index, neck circumference, waist circumference, visceral fat, Conicity Index, and body fat than did the non-hypertensive individuals. CONCLUSION: The prevalence of hypertension and other important cardiovascular risk factors in the Mura Indians was high. This finding is probably due to the adoption of inappropriate habits and lifestyles. PMID- 30424744 TI - MALDI-TOF mass spectrometry-based serotyping of V. parahaemolyticus isolated from the Zhejiang province of China. AB - BACKGROUND: Vibrio parahaemolyticus is as an important food-borne pathogen circulating in China. Since 1996, the core serotype has become O3:K6, which has specific genetic markers. This serotype causes the majority of outbreaks worldwide. Until now, nearly 21 serotypes were considered as serovariants of O3:K6. Among these, O4:K68, O1:K25 and O1:KUT have caused pandemic outbreaks. O4:K8, a serovariant of O3:K6, has become the second most dominant serotype circulating in China after O3:K6. In this study, we report the use of matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) to analyze and characterize 146 V. parahaemolyticus isolates belonging to 23 serotypes. RESULTS: Upon mass spectral analysis, isolates belonging to O4:K8 formed a distinct group among the five main pandemic groups (O3:K6, O4:K8, O4:K68, O1:K25 and O1:KUT). Two major protein peaks (m/z 4383 and 4397) were significantly different between serotype O4:K8 and the four other pandemic strains. Both of these peaks were present in 32 out of 36 O4:K8 isolates, but were absent in 105 out of 110 non-O4:K8 isolates. These peaks were also absent in all 74 pandemic serotypes (O3:K6, O4:K68, O1:K25 and O1:KUT). CONCLUSION: Our results highlight the threat of O4:K8 forming a distinct group, which differs significantly from pandemic serotypes on the proteomic level. The use of MALDI TOF MS has not been reported before in a study of this nature. Mass spectrum peaks at m/z 4383 and 4397 may be specific for O4:K8. However, we cannot conclude that MALDI-TOF MS can be used to serotype V. parahaemolyticus. PMID- 30424746 TI - Risk factors of brucellosis seropositivity in Bactrian camels of Mongolia. AB - BACKGROUND: More information on brucellosis epidemiology in Bactrian camels is needed due to their growing economic and livelihood importance for herders and renewed efforts in Mongolia to eliminate brucellosis through mass vaccination of ruminants excluding camels. Brucellosis prevalence in camels increased over the past two decades. Random multi-stage cluster surveys were done in the Eastern provinces of Dornod and Sukhbaatar in 2013 and 2014 and in the Southern & Western provinces of Dornogobi, Umnogobi and Khovd in 2014 and 2015. A total of 1822 camels, 1155 cattle, and 3023 small ruminant sera were collected and tested with the Rose Bengal Test. In addition, 195 vaginal swabs and 250 milk samples for bacteriological culture were taken from livestock with history of abortion. RESULTS: The overall apparent seroprevalence in camels was 2.3% (95% confidence interval 1.6-3.3). The main risk factor for camel seropositivity was being in an Eastern province when compared to Southern & Western provinces (odds ratio 13.2, 95% CI 5.3-32.4). Camel seroprevalences were stable over the two consecutive survey years, despite introduction of ruminant vaccination: 5.7% (95% CI 3.1 10.2%) and 5.8% (3.3-10.1%) in Eastern provinces and 0.4% (0.2-1.2%) and 0.5% (0.1-2.0%) in Southern & Western provinces. We isolated Brucella abortus from camels and cattle. Camel seropositivity was associated to keeping cattle together with camels. Monitoring of vaccination campaigns showed that coverage in cattle was insufficient because animals could not be adequately restrained. CONCLUSIONS: The present study reveals that brucellosis is present with important seroprevalence in Mongolian camels and was endemic in Eastern provinces. Camel herd seropositivity was most closely associated to infection in cattle. Longer term monitoring is needed to assess whether camel seroprevalance decreases with ongoing vaccination in Mongolia. This should be coupled with further confirmation on Brucella spp. isolates. To date, only Brucella abortus was isolated, but camels are also susceptible to Brucella melitensis. Clear verbal and written information on disease prevention in livestock and household members is important, particularly for remote camel herders who had only moderate knowledge on brucellosis epidemiology and preventive measures. PMID- 30424747 TI - Isolation of Streptococcus agalactiae in a female llama (Lama glama) in South Tyrol (Italy). AB - BACKGROUND: Streptococcus agalactiae is pathogenic for both animals and humans. In dairy cattle it commonly causes mastitis, with great economic losses, and there is scientific evidence of mastitis, caseous lymphadenitis, contagious skin necrosis and purulent infections associated with S. agalactiae in camels (Camelus dromedarius) as well. In humans, it is a common component of the respiratory and gastrointestinal microflora, but it can also act as a pathogen, especially in elderly people and immunocompromised patients, as well as in pregrant women and newborns. CASE PRESENTATION: A 10-year old non-pregnant female llama (Lama glama) was conferred to the Institute for Animal Health Control, in Bolzano for necropsy after sudden death. The animal had not shown unusual behaviour and had a low to normal nutritional condition (body condition score 2/5). The breeder had reported a chronic suppurative subcutaneous infection in the intermandibular area, resistant to therapy (therapy unknown). After necropsy, several samples were processed for histological, bacteriological and parasitological examinations. CONCLUSIONS: This report describes, to the best of our knowledge, the first isolation of S. agalactiae in llamas (Lama glama). The animal came from a herd that counts approximately 200 South American camelids (llamas, alpacas) along with several horses, chicken, rabbits, cats and dogs; this farm offers services, such as trekking and pet therapy activities. PMID- 30424748 TI - Bicycling participation in people with a lower limb amputation: a scoping review. AB - BACKGROUND: To review literature on bicycling participation, as well as facilitators and barriers for bicycling in people with a lower limb amputation (LLA). METHODS: Peer-reviewed, primary, full text, studies about bicycling in people with a LLA from midfoot level to hemipelvectomy were searched in Pubmed, Embase, Cinahl, Cochrane library, and Sportdiscus. No language or publication date restrictions were applied. Included full-text studies were assessed for methodological quality using the Effective Public Health Practice Project tool. Data were extracted, synthesized and reported following Preferred Reporting Items for Systematic Review. RESULTS: In total, 3144 papers were identified and 14 studies were included. The methodological quality of 13 studies was weak and 1 was moderate. Bicycling participation ranged from 4 to 48%. A shorter time span after LLA and a distal amputation were associated with a higher bicycling participation rate particularly for transportation. In people with a transtibial amputation, a correct prosthetic foot or crank length can reduce pedalling asymmetry during high-intensity bicycling. People with limitations in knee range of motion or skin abrasion can use a hinged crank arm or a low profile prosthetic socket respectively. CONCLUSION: People with a LLA bicycled for transportation, recreation, sport and physical activity. Adaptation of prosthetic socket, pylon and foot as well as bicycle crank can affect pedalling work and force, range of motion, and aerodynamic drag. Because the suggestions from this review were drawn from evidences mostly associated to competition, prosthetists should carefully adapt the existing knowledge to clients who are recreational bicyclists. PMID- 30424749 TI - Effects of acupuncture on vascular dementia (VD) animal models: a systematic review and meta-analysis. AB - BACKGROUND: Vascular dementia is the second most common type of dementia that causes cognitive dysfunction. Acupuncture, an ancient therapy, has been mentioned for the treatment of vascular dementia in previous studies. This study aimed to evaluate the effects of acupuncture in animal models of vascular dementia. METHODS: Experimental animal studies of treating vascular dementia with acupuncture were gathered from Embase, PubMed and Ovid Medline (R) from the dates of the databases' creation to December 2016. We adopted the CAMARADES 10-item checklist to evaluate the quality of the included studies. The Morris water maze test was considered as an outcome measure. The software Stata12.0 was used for the meta-analysis. Heterogeneity was examined using I2 statistics, and we conducted subgroup analyses to determine the causes of heterogeneity for escape latency and duration in original platform. RESULTS: Sixteen studies involving 363 animals met the inclusion criteria. The included studies scored between 4 and 8 points, and the mean was 5.44. The results of the meta-analysis indicated remarkable differences with acupuncture on increasing the duration in the former platform quadrant both in EO models (SMD = 1.56, 95% CI: 1.02 ~ 2.11; p < 0.00001) and 2-VO models (SMD 4.29, 95% CI 3.23 ~ 5.35; p < 0.00001) compared with the control groups. CONCLUSIONS: Acupuncture may be effective in improving cognitive function in vascular dementia animal models. The mechanisms of acupuncture for vascular dementia are multiple such as anti-apoptosis, antioxidative stress reaction, and metabolism enhancing of glucose and oxygen. PMID- 30424750 TI - Prevalence of orthorexia nervosa in university students and its relationship with psychopathological aspects of eating behaviour disorders. AB - INTRODUCTION: Orthorexia nervosa (ON) is characterized by an obsession with healthy eating, which may lead to severe physical, psychological and social disorders. It is particularly important to research this problem in populations that do not receive clinical care in order to improve early detection and treatment. OBJECTIVE: The aim of this study was to research the prevalence of ON in a population of Spanish university students and to analyze the possible associations between ON and psychological traits and behaviors that are common to ED. METHOD: A cross-sectional study with 454 students from the University of Castilla La Mancha, Spain. In total, 295 women and 159 men participated, aged between 18 and 41 years. The ORTO-11-ES questionnaire and the Eating Disorder Inventory (EDI-2) were used for this study. The chi squared test was used to compare the homogeneity among the different groups. RESULTS: The scores on the ORTO-11-ES suggested that 17% of students were at risk of ON. The scores on the EDI-2 for the group at risk of ON were significant, compared to the remaining individuals, regarding their drive for thinness (17.1% vs 2.1%), bulimia (2.6% vs 0%), body dissatisfaction (26.3% vs. 12.4%), perfectionism (14.5% vs 4.8%), interoceptive awareness (13.2% vs 1.3%), asceticism (15.8% vs 3.7%) and impulsiveness (9.2% vs 1.9%). DISCUSSION AND CONCLUSION: These findings suggest that many of the psychological and behavioral aspects of ED are shared by people who are at risk of ON. Future research should use longitudinal data, examining the temporal relationship among these variables or other underlying variables that may contribute to the concurrence of ED and ON. PMID- 30424751 TI - Pattern of varicocele vein blood gases in patients undergoing microsurgical Varicocelectomy. AB - BACKGROUND: Varicocele is known to be associated with infertility and sperm disorders. The exact cause of this ailment is not fully understood. There are limited numbers of studies where venous blood gases (VBGs) of varicocele veins were determined with conflicting results. Therefore, we have investigated the pattern of VBGs in both internal spermatic and external spermatic varicocele veins and correlation with semen quality parameters in infertile individuals who underwent left microsurgical varicocelectomy. METHODS: Patients (n = 27) undergoing left microsurgical varicocelectomy at a tertiary care hospital, were included in the study. Before surgery, semen parameters and scrotal color Doppler ultrasonography was performed. During surgery, blood sample was drawn from varicocele veins (internal spermatic and external spermatic veins) and a peripheral arm vein of the same patient as a control. The VBGs of all veins under study were estimated and compared with each other. The VBGs were also correlated with various semen quality parameters. Data, expressed as Mean +/- SD, regarding VBGs in three veins were analyzed using one-way ANOVA. The correlation between VBGs and semen quality parameters was determined using Pearson's correlation. Differences were considered significant at p < 0.05. RESULTS: The pH was found to be higher (p < 0.01) in the internal spermatic vein compared with the external spermatic and the peripheral veins. Partial pressure of oxygen (pO2) and oxygen saturation (sO2) were higher (p < 0.01) in the internal spermatic vein compared with the peripheral vein. However, concentration of bicarbonate (HCO3) was lower (p < 0.01) in both veins compared with the peripheral vein. Partial pressure of carbon dioxide (pCO2) was also lower (p < 0.01) in the varicocele veins compared with the control vein. CONCLUSION: The internal spermatic veins had higher pH and oxygen tension, but lower HCO3 and pCO2 levels compared with the control peripheral veins. External spermatic veins had lower pCO2 and HCO3 but other VBGs were similar to the peripheral veins. The shift of VBGs of internal spermatic vein toward arterial blood pattern may be a missing link to understand the pathophysiology of varicocele. PMID- 30424752 TI - Correlations between serum concentration of three bone-derived factors and obesity and visceral fat accumulation in a cohort of middle aged men and women. AB - BACKGROUND: The aim of this study was to investigate the interrelationships between three bone-derived factors [serum osteocalcin (OCN), fibroblast growth factor (FGF) 23, and neutrophil gelatinase-associated lipocalin (NGAL) levels] and body fat content and distribution, in order to reveal the potential endocrine function of bone in the development of obesity. METHODS: We recruited 1179 people (aged 59.5 +/- 6.2 years) from communities in Shanghai. Serum OCN levels were determined using an electrochemiluminescence immunoassay. Serum FGF23 and NGAL levels were determined using a sandwich enzyme-linked immunosorbent assay. The abdominal fat distribution, including visceral fat area (VFA), was assessed by magnetic resonance imaging. Visceral obesity was defined as a VFA >= 80 cm2. RESULTS: Serum OCN levels were inversely correlated with body fat parameters, while FGF23 and NGAL were positively correlated (P < 0.05). After adjusting for confounders, waist circumference (W) and VFA had a closer relationship with serum OCN, FGF23, and NGAL levels than body mass index (BMI) and body fat percentage (fat%, all P < 0.05). The risk of visceral obesity significantly increased with higher FGF23 and/or NGAL levels, as well as with reduced OCN levels (all P < 0.05). In addition, serum OCN, FGF23, and NGAL levels were independently associated with visceral obesity (all P < 0.01). The relationships persisted among subjects with normal glucose tolerance or subjects with hyperglycaemia (both P < 0.05). CONCLUSIONS: Compared to the indicators of overall adiposity such as BMI or fat%, visceral adiposity indicators (W or VFA) were more closely related to serum OCN, FGF23 and NGAL levels. There was no interaction among the relationship of three bone-derived factors with visceral obesity, which revealed the independent relationship of endocrine function of skeleton with body fat. PMID- 30424753 TI - Weighing benefits and risks in aspects of security, privacy and adoption of technology in a value-based healthcare system. AB - BACKGROUND: Technology can potentially enable the implementation of a value-based healthcare system, where the impact of quality of care is offered at optimised cost for maximised patient benefit. Technology can deliver value by aiding in data collection to evaluate outcomes and measure costs on a patient and population level. Healthcare organisations, however, face several challenges and risks that result almost exclusively from the use of these technologies. DISCUSSION: Some challenges associated with healthcare technology include their unsustainability, due to lack of scale-up plans and timely evaluations. Other risks include noncompliance with data protection policies, inadequate data governance, and overestimated expectations resulting from the rapid introduction of new technologies. CONCLUSION: Organisations need to consider the risks and challenges associated with the use of technology and develop comprehensive strategies that mitigate factors leading to non-adoption and to realise benefits for achieving a value-based healthcare system. PMID- 30424754 TI - Innovation to impact in spatial epidemiology. AB - Spatial epidemiology is a rapidly advancing field, pushing our abilities to measure, monitor and map pathogens at increasingly finer spatiotemporal scales. However, these scales often do not align with the abilities of control programmes to act at them, building a disconnect between academia and implementation. Efforts are being made to feed innovations into government, build spatial data skills, and strengthen links between disease control programmes and universities, yet work remains to be done if goals for disease control, elimination and 'leaving no one behind' are to be met. PMID- 30424755 TI - Expression and clinical significance of Caveolin-1 in prostate Cancer after transurethral surgery. AB - BACKGROUND: Prostate cancer is a common malignancy of the male genitourinary system that occurs worldwide. The current research aims to investigate caveolin-1 expression in prostate cancer tissue and its relationship with pathological grade, clinical pathologic staging, and preoperative prostate-specific antigen (PSA) levels. METHODS: From January 2012 to December 2014, samples from 47 patients with prostate cancer who had received transurethral prostatic resection (TURP) and 20 patients with benign prostatic hyperplasia were collected at the First Affiliated Hospital of Guangxi Medical University. Caveolin-1 was detected by streptavidin-perosidase (SP) immunohistochemical staining in pathological tissue slices. The results were statistically analyzed for pathological grade, clinical stage, and preoperative PSA level. RESULTS: The expression of caveolin-1 was significantly higher in prostate cancer samples than in benign prostatic hyperplasia samples (P < 0.05), and caveolin-1 expression was significantly different among the pathological grades of poorly, moderately and well differentiated prostate cancer (P < 0.05). The difference in caveolin-1 expression was significant for different clinical stages (T1-T2 and T3-T4) of prostate cancer (P < 0.05). The difference in caveolin-1 expression was not significant among samples with different preoperative PSA levels (0-10, 10-100 and > 100 MUg/L) (P > 0.05). CONCLUSIONS: Caveolin-1 is closely related to the pathological grade and clinical stage of prostate cancer after transurethral surgery, and it may be a novel tumor marker for prostate cancer. The expression of caveolin-1 is not associated with preoperative serum PSA levels. PMID- 30424756 TI - X-search: an open access interface for cross-cohort exploration of the National Sleep Research Resource. AB - BACKGROUND: The National Sleep Research Resource (NSRR) is a large-scale, openly shared, data repository of de-identified, highly curated clinical sleep data from multiple NIH-funded epidemiological studies. Although many data repositories allow users to browse their content, few support fine-grained, cross-cohort query and exploration at study-subject level. We introduce a cross-cohort query and exploration system, called X-search, to enable researchers to query patient cohort counts across a growing number of completed, NIH-funded studies in NSRR and explore the feasibility or likelihood of reusing the data for research studies. METHODS: X-search has been designed as a general framework with two loosely-coupled components: semantically annotated data repository and cross cohort exploration engine. The semantically annotated data repository is comprised of a canonical data dictionary, data sources with a data dictionary, and mappings between each individual data dictionary and the canonical data dictionary. The cross-cohort exploration engine consists of five modules: query builder, graphical exploration, case-control exploration, query translation, and query execution. The canonical data dictionary serves as the unified metadata to drive the visual exploration interfaces and facilitate query translation through the mappings. RESULTS: X-search is publicly available at https://www.x search.net/ with nine NSRR datasets consisting of over 26,000 unique subjects. The canonical data dictionary contains over 900 common data elements across the datasets. X-search has received over 1800 cross-cohort queries by users from 16 countries. CONCLUSIONS: X-search provides a powerful cross-cohort exploration interface for querying and exploring heterogeneous datasets in the NSRR data repository, so as to enable researchers to evaluate the feasibility of potential research studies and generate potential hypotheses using the NSRR data. PMID- 30424757 TI - Utilization of somatic specialist services among psychiatric immigrant patients: the Norwegian patient registry study. AB - BACKGROUND: Amongst psychiatric patients, the leading causes of reduced quality of life and premature death are chronic viral infections and cardiovascular diseases. In spite of this, there are extremely high levels of disparity in somatic healthcare amongst such populations. Little research has explored patterns of healthcare utilisation and, therefore, this study aims to examine the use of somatic specialist healthcare for infectious diseases and diseases of circulatory system among psychiatric patients from different immigrant groups and ethnic Norwegians. METHODS: Register data from the Norwegian Patient Registry and Statistics Norway were used. The sample (ages 0-90+) consisted of 276,890 native born Norwegians and 52,473 immigrants from five world regions - Western countries, East Europe, Africa, Asia, and Latin America, all of whom had contacts with specialist mental healthcare during the period 2008-2011. Statistical analyses were applied using logistic regression models. RESULTS: Rates of outpatient consultation for circulatory system diseases were significantly lower amongst patients from Africa, Asia and Latin America compared with ethnic Norwegian psychiatric patients. Only patients from Eastern Europeans had a higher rate. With regard to hospital admission, all psychiatric patients had a lower rate than ethnic Norwegians with the exception of those from Africa where the finding was non-significant. In terms of infectious diseases, patients from African countries had significantly higher outpatient and admission rates than ethnic Norwegians. Outpatient consultation rates were lower amongst those from Western and Latin America and hospital admission rates were lower amongst those from Eastern Europe and Asia. CONCLUSIONS: The findings suggest that the majority of immigrant psychiatric patients have lower hospitalization rates for circulatory system diseases than Norwegian psychiatric patients. This may suggest that poor access for immigrants is a contributing factor, though the findings were less pronounced for infectious diseases. PMID- 30424759 TI - Letter to editor: careful literature search and exact data extraction are milestones of a meta-analysis: the case of dairy consumption and hip fracture. AB - In a recent issue of the BMC Public Health journal, Bian et al. described the results of an interesting meta-analysis on the association between dairy products consumption and risk of hip fracture. Although the results are important and valuable, some critical points should be noticed in the explanation of these findings. We prepared these critical points in a letter to the editor and hope to be an interest of you. PMID- 30424758 TI - Primary care physicians' attitudes to the adoption of electronic medical records: a systematic review and evidence synthesis using the clinical adoption framework. AB - BACKGROUND: Recent decades have seen rapid growth in the implementation of Electronic Medical Records (EMRs) in healthcare settings in both developed regions as well as low and middle income countries. Yet despite substantial investment, the implementation of EMRs in some primary care systems has lagged behind other settings, with piecemeal adoption of EMR functionality by primary care physicians (PCPs) themselves. We aimed to review and synthesise international literature on the attitudes of PCPs to EMR adoption using the Clinical Adoption (CA) Framework. METHODS: MEDLINE, PsycINFO, and EMBASE were searched from 1st January 1996 to 1st August 2017 for studies investigating PCP attitudes towards EMR adoption. Papers were screened by two independent reviewers, and eligible studies selected for further assessment. Findings were categorised against the CA Framework and the quality of studies assessed against one of three appropriate tools. RESULTS: Out of 2263 potential articles, 33 were included, based in North and South America, Europe, Middle East and Hong Kong. Concerns about the accessibility, reliability and EMR utility exerted an adverse influence on PCPs' attitudes to adoption. However many were positive about their potential to improve clinical productivity, patient safety and care quality. Younger, computer-literate PCPs, based in large/multi-group practices, were more likely to be positively inclined to EMR use than older physicians, less-skilled in technology use, based in solo practices. Adequate training, policies and procedures favourably impacted on PCPs' views on EMR implementation. Financial factors were common system level influencers shaping EMR adoption, from start-up costs to the resources required by ongoing use. CONCLUSIONS: By using the CA Framework to synthesise the evidence, we identified a linked series of factors influencing PCPs attitudes to EMR adoption. Findings underline the need to involve end-users in future implementation programmes from the outset, to avoid the development of an EMR which is neither feasible nor acceptable for use in practice. TRIAL REGISTRATION: PROSPERO CRD42016038790 . PMID- 30424760 TI - Practice intentions at entry to and exit from medical schools aspiring to social accountability: findings from the Training for Health Equity Network Graduate Outcome Study. AB - BACKGROUND: Understanding the impact of selection and medical education on practice intentions and eventual practice is an essential component of training a fit-for-purpose health workforce distributed according to population need. Existing evidence comes largely from high-income settings and neglects contextual factors. This paper describes the practice intentions of entry and exit cohorts of medical students across low and high income settings and the correlation of student characteristics with these intentions. METHODS: The Training for Health Equity Network (THEnet) Graduate Outcome Study (GOS) is an international prospective cohort study tracking learners throughout training and ten years into practice as part of the longitudinal impact assessment described in THEnet's Evaluation Framework. THEnet is an international community of practice of twelve medical schools with a social accountability mandate. Data presented here include cross-sectional entry and exit data obtained from different cohorts of medical students involving eight medical schools in six countries and five continents. Binary logistic regression was used to create adjusted odds ratios for associations with practice intent. RESULTS: Findings from 3346 learners from eight THEnet medical schools in 6 countries collected between 2012 and 2016 are presented. A high proportion of study respondents at these schools come from rural and disadvantaged backgrounds and these respondents are more likely than others to express an intention to work in underserved locations after graduation at both entry and exit from medical school. After adjusting for confounding factors, rural and low income background and regional location of medical school were the most important predictors of intent to practice in a rural location. For schools in the Philippines and Africa, intention to emigrate was more likely for respondents from high income and urban backgrounds. CONCLUSIONS: These findings, from a diverse range of schools with social accountability mandates in different settings, provide preliminary evidence for the selection and training of a medical workforce motivated to meet the needs of underserved populations. These respondents are being followed longitudinally to determine the degree to which these intentions translate into actual practice. PMID- 30424761 TI - The effect of HIV educational interventions on HIV-related knowledge, condom use, and HIV incidence in sub-Saharan Africa: a systematic review and meta-analysis. AB - BACKGROUND: As high stigmatization of HIV and relatively low knowledge of HIV transmission and prevention measures persist in Sub-Saharan Africa, the improvement of HIV-related knowledge, and the evaluation of which types of interventions are most effective in this regard, is an important aspect of further prevention efforts. In addition, it is of interest to assess whether improvements in HIV-related knowledge may actually lead to increased engagement in preventive behaviours and ultimately lower HIV transmission. This study therefore aims to systematically review and meta-analyse the evidence for the effect of HIV-related knowledge interventions on 1) the improvement of HIV related knowledge, 2) subsequent risk reduction behaviour (condom use), 3) lower incidence of HIV infection. METHODS: A literature search was conducted using the Embase and Medline databases, returning 746 after duplicate removal. Following abstract and full-text screening, 36 studies were ultimately included in the final review. Meta-analyses were conducted in R, using random-effects models, for the HIV-related knowledge, condom use, and HIV incidence outcomes, where sufficient data were available. RESULTS: Interventions assessed in the reviewed studies varied, including computer-based interventions, mass media campaigns, and peer education interventions. The interventions were generally found to be effective at improving HIV-related knowledge in the target population, with 10 studies reporting improved knowledge of risk reduction through condom use in the intervention group (out of 11 studies reporting data for this outcome), with 6 reporting these differences as significant (p < 0.05). Regarding knowledge of transmission routes, studies assessing peer education interventions often reported significant improvements in the intervention group. Meta-analysis results showed significantly higher odds among the intervention groups of correct knowledge of: risk reduction through condom use (OR: 3.09, 95%CI: 1.83-5.22, p < 0.0001), sexual transmission of HIV (OR: 5.86, 95%CI: 2.65-12.97, p < 0.001) and transmission through sharps (OR: 4.35, 95%CI = 3.21-5.90, p < 0.001), but non significantly lower odds of HIV infection (OR: 0.97, 95%CI: 0.66-1.41, p = 0.854). CONCLUSION: Peer-education-based interventions appear to be particularly effective in facilitating the uptake of HIV-related knowledge, particularly pertaining to transmission routes. There is some evidence that improved knowledge of HIV transmission and prevention facilitates increased subsequent engagement in preventive measures, although this requires further exploration. TRIAL REGISTRATION: PROSPERO Number: CRD42018090600. PMID- 30424762 TI - Female trainees believe that having children will negatively impact their careers: results of a quantitative survey of trainees at an academic medical center. AB - BACKGROUND: Medical training occurs during peak childbearing years. However, the intense workload, long work hours, and limited financial compensation are potential barriers to having children during this time. Here, we aimed to identify gender-based differences in beliefs and experiences of having children during graduate medical education. We hypothesized that both genders face significant challenges, but women are more likely to experience stressors related to work-family conflicts. METHODS: We administered an anonymous web-based survey to all trainees at an academic medical center. Primary outcomes were gender differences in beliefs and experiences of having children during training. Multivariate logistic regression was performed using independent variables of gender, specialty type (surgical vs. medical), and parental status. RESULTS: In total, 56% of trainees responded (60% women, 40% men; n = 435). Women were more often concerned about the negative impact of having children and taking maternity leave on their professional reputation and career. The majority of women expressed concern about the potential negative impact of the physical demands of their jobs on pregnancy. Among parents, women were more likely than men to be the primary caregivers on weeknights and require weekday childcare from a non-parent. CONCLUSIONS: Women face greater work-related conflicts in their beliefs and experiences of having a family during graduate medical education. Trainees should be aware of these potential challenges when making life and career decisions. We recommend that institutions employ solutions to accommodate the needs and wellbeing of trainees with families while optimizing training and workload equity for all trainees. PMID- 30424763 TI - Tending the 'monthly flower:' a qualitative study of menstrual beliefs in Tigray, Ethiopia. AB - BACKGROUND: Menstruation is a universal aspect of human female reproductive life. Management of menstrual flow presents hygiene challenges to girls and women in low-income countries, especially when they first start their periods. As part of a project to improve menstrual hygiene management in the Tigray Region of Ethiopia, we explored the local understanding of menstruation through focus-group discussions and individual interviews. METHODS: A detailed ethnographic survey of menstrual beliefs was carried out through 40 focus group discussions, 64 in-depth key informant interviews, and 16 individual case histories in the Tigray Region of northern Ethiopia. A total of 240 individuals participated in six types of focus groups (pre-menarchal girls, menstruating adolescents, married women of reproductive age, post-menopausal women, adolescent males, and married men). In depth interviews were also carried out with 80 individuals, including Orthodox Christian priests, imams from the Muslim community, principals of primary and secondary schools, teachers and nurses, as well as menstruating schoolgirls and women. Audio data were transcribed and translated, then broken down into discrete codes using Atlas Ti software (version 7.5.4, Atlas.ti Scientific Software Development Mnbh, Berlin) and further grouped into related families and sub families based on their content. The results were then synthesized to produce a cohesive narrative concerning menstruation in Tigray. RESULTS: Recurrent themes identified by participants included descriptions of the biology of menstruation (which were sometimes fanciful); the general unpreparedness of girls for menarche; cultural restrictions imposed by menstruation on females (particularly the stigma of ritual uncleanliness in both Christian and Muslim religious traditions); the prevalence and challenges of unmet menstrual hygiene needs at schools (including lack of access to sanitary pads and the absence of acceptable toilet/washing facilities); and the stigma and shame associated with menstrual hygiene accidents in public. CONCLUSIONS: Changes in the educational system in northern Ethiopia are required to improve student understanding of the biology of menstruation, to foster gender equity, to overcome the barriers to school attendance presented by poor menstrual hygiene management, and to create a society that is more understanding and more accepting of menstruation. PMID- 30424764 TI - Zerumbone from Zingiber zerumbet (L.) smith: a potential prophylactic and therapeutic agent against the cariogenic bacterium Streptococcus mutans. AB - BACKGROUND: Essential oil obtained from rhizomes of the Zingiber zerumbet (L.) Smith (popularly known in Brazil as bitter ginger) is mainly constituted by the biomolecule zerumbone, which exhibit untapped antimicrobial potential. The aim of this study was to investigate the antimicrobial activity of the zerumbone from bitter ginger rhizomes against the cariogenic agent Streptococcus mutans. METHODS: Firstly, the essential oil from rhizomes of Zingiber zerumbet (L.) Smith extracted by hydrodistillation was submitted to purification and recrystallization process to obtain the zerumbone compound. The purity of zerumbone was determined through high-performance liquid chromatography analysis. Different concentrations of zerumbone were tested against the standard strain S. mutans (ATCC 35668) by using microdilution method. The speed of cidal activity was determined through a time kill-curve assay. The biological cytotoxicity activity of zerumbone was assessed using Vero cell line through MTT assay. RESULTS: The zerumbone showed a minimum inhibitory concentration (MIC) of 250 MUg/mL and a minimum bactericidal concentration (MBC) of 500 MUg/mL against S. mutans. After six hours of bacteria-zerumbone interaction, all concentrations tested starts to kill the bacteria and all bacteria were killed between 48 and 72 h period at the concentration of 500 MUg/mL (99,99% of bacteria were killed in comparison with original inoculum). In addition, zerumbone showed no cytotoxicity activity on mammalian continuous cells line. CONCLUSIONS: These results draw attention to the potential of zerumbone as antimicrobial agent against S. mutans infection, indicating its possible use in the phyto-pharmaceutical formulations as new approach to prevent and treat tooth decay disease. PMID- 30424765 TI - How to perform the dusting technique for calcium oxalate stone phantoms during Ho:YAG laser lithotripsy. AB - BACKGROUND: To determine the most efficacious setting of Holmium:yttrium-aluminum garnet (Ho:YAG) laser with a maximum power output of 120 W with in vitro phantom stone dusting technique. METHODS: A laser was used to treat two 4 * 3 * 3 mm3 sized phantom stones in 5 mL syringes with 1 mm-sized holes at the bottom. According to the pulse width (short 500, middle 750, long pulse 1000 MUsec), maximal pulse repetition rates from 50 to 80 Hz were tested with pulse energy of 0.2, 0.4, 0.5, and 0.8 J. Six times of the mean dusting times were measured at each setting. Dusting was performed at continuous firing of the laser until the stones become dusts < 1 mm. RESULTS: The mean Hounsfield unit of phantom stones was 1309.0 +/- 60.8. The laser with long pulse generally showed shorter dusting times than short or middle pulse width. With increasing the pulse energy to 0.5 J, the dusting time decreased. However, the pulse energy of 0.8 J showed longer dusting times than those of 0.5 J. On the post-hoc analysis, the pulse energy of 0.5 J, long pulse width, and the repetition rates of 70 Hz demonstrated significantly shorter dusting times than other settings. CONCLUSIONS: The results suggest that long pulse width with 0.5 J and 70 Hz would be the most efficacious setting for dusting techniques of plaster stone phantoms simulating calcium oxalate stones using the 120 W Ho:YAG laser. PMID- 30424766 TI - Enhancing 3-hydroxypropionic acid production in combination with sugar supply engineering by cell surface-display and metabolic engineering of Schizosaccharomyces pombe. AB - BACKGROUND: Economical production of value-added chemicals from renewable biomass is a promising path to sustainability. 3-Hydroxypropionic acid (3-HP) is an important chemical for building a bio-sustainable society. Establishment of 3-HP production from renewable resources such as glucose would provide a bio sustainable alternative to the production of acrylic acid from fossil resources. RESULTS: Here, we describe metabolic engineering of the fission yeast Schizosaccharomyces pombe to enhance 3-HP production from glucose and cellobiose via the malonyl-CoA pathway. The mcr gene, encoding the malonyl-CoA reductase of Chloroflexus aurantiacus, was dissected into two functionally distinct fragments, and the activities of the encoded protein were balanced. To increase the cellular supply of malonyl-CoA and acetyl-CoA, we introduced genes encoding endogenous aldehyde dehydrogenase, acetyl-CoA synthase from Salmonella enterica, and endogenous pantothenate kinase. The resulting strain produced 3-HP at 1.0 g/L from a culture starting at a glucose concentration of 50 g/L. We also engineered the sugar supply by displaying beta-glucosidase (BGL) on the yeast cell surface. When grown on 50 g/L cellobiose, the beta-glucosidase-displaying strain consumed cellobiose efficiently and produced 3-HP at 3.5 g/L. Under fed-batch conditions starting from cellobiose, this strain produced 3-HP at up to 11.4 g/L, corresponding to a yield of 11.2% (g-3-HP/g-glucose; given that 1 g cellobiose corresponds to 1.1 g glucose upon digestion). CONCLUSIONS: In this study, we constructed a series of S. pombe strains that produced 3-HP via the malonyl-CoA pathway. Our study also demonstrated that BGL display using cellobiose and/or cello-oligosaccharides as a carbon source has the potential to improve the titer and yield of malonyl-CoA- and acetyl-CoA-derived compounds. PMID- 30424767 TI - Epimedium sagittatum inhibits TLR4/MD-2 mediated NF-kappaB signaling pathway with anti-inflammatory activity. AB - BACKGROUND: Epimedium sagittatum (Sieb.et Zucc.) Maxim., Ying-Yang-Huo in Chinese has been used as a traditional Chinese medicine and is deemed to "reinforce the kidney Yang". Previous studies showed that E. sagittatum could modulate the immune system and treat some chronic disease such as rheumatic arthritis, cardiovascular diseases and osteoporosis. The aim of this study is to evaluate the anti-inflammatory effects of ethyl acetate extracts (YYHs) of E. sagittatum and its mechanisms of action. METHODS: In order to explore the composition of YYHs, YYHs was analyzed using high performance liquid chromatography-mass spectrometry-mass spectrometry (HPLC-MS/MS) and in comparison with reference standards. Anti-inflammatory model was established in LPS-induced RAW264.7 cells. The levels of nitric oxide (NO) were measured with the Griess reagent. Production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-2 (IL-2) were measured by enzyme-linked immunosorbent assays (ELISA). In addition, expression of p-p65 protein and TLR4/MD-2 complex was detected by western blots and flow cytometric, respectively. Nuclear factor kappa B (NF-kappaB) nuclear translocation was observed by fluorescence microscope. RESULTS: A total of eight compounds were identified, of which icariside II was the most abundant compound. YYHs (12.5-50 MUg/mL) had no obvious cytotoxic effect on cells, and remarkably inhibited LPS induced production of NO, TNF-alpha and IL-2 with a dose-dependent manner. Additionally, YYHs up-regulated expression of p-p65 and TLR4/MD-2 complex. Further research showed that YYHs significantly suppressed NF-kappaB p65 nuclear translocation. CONCLUSION: In brief, YYHs contributed to the inhibition of LPS induced inflammatory response through the TLR4/MD-2-mediated NF-kappaB pathway and may be a potential choice to combat inflammation diseases. It includes a schema of pathways at the end of the paper. PMID- 30424768 TI - The ratio of AGE to sRAGE independently associated with albuminuria in hypertensive patients. AB - BACKGROUND: Soluble receptor for advanced glycation end-products (sRAGE) and advanced glycation end-products (AGE) have been associated with risks of cardiovascular disease. Because sRAGE is regarded as a scavenger to AGE, we hypothesized that the ratio of AGE to sRAGE (AGE/sRAGE) is associated with albuminuria in hypertensive patients. METHODS: In this cross-sectional study, a total of 104 patients with essential hypertension were recruited. Hypertension was defined as a systolic blood pressure >= 140 mmHg, a diastolic blood pressure >= 90 mmHg, or use of antihypertensive treatment. Albuminuria was defined as albumin excretion rate ? 20 MUg/min. Multivariate logistic regression analyses were performed to evaluate the association between AGE/sRAGE and albuminuria. RESULTS: Among the 104 patients, 30 (28.8%) patients had albuminuria and 74 (71.2%) patients did not. Patients with albuminuria had higher AGE (2.15 vs. 1.71 MUg/mL), lower sRAGE (424.5 vs. 492.5 pg/ml) and higher AGE/sRAGE (3.79 vs. 3.29 MUg/pg) than those without albuminuria. Multivariate logistic regression model revealed that AGE/sRAGE (OR = 1.131, 95% CI = 1.001-1.278, P = 0.048) was independently associated with albuminuria. There was no significant relationship between AGE and sRAGE alone with albuminuria. CONCLUSION: This study suggests that the ratio of AGE to sRAGE may be a surrogate biomarker for microvascular injury. Further prospective studies of the prognostic value of the ratio in relation to microvasular injury are needed. PMID- 30424769 TI - A decision support system to follow up and diagnose primary headache patients using semantically enriched data. AB - BACKGROUND: Headache disorders are an important health burden, having a large health-economic impact worldwide. Current treatment & follow-up processes are often archaic, creating opportunities for computer-aided and decision support systems to increase their efficiency. Existing systems are mostly completely data driven, and the underlying models are a black-box, deteriorating interpretability and transparency, which are key factors in order to be deployed in a clinical setting. METHODS: In this paper, a decision support system is proposed, composed of three components: (i) a cross-platform mobile application to capture the required data from patients to formulate a diagnosis, (ii) an automated diagnosis support module that generates an interpretable decision tree, based on data semantically annotated with expert knowledge, in order to support physicians in formulating the correct diagnosis and (iii) a web application such that the physician can efficiently interpret captured data and learned insights by means of visualizations. RESULTS: We show that decision tree induction techniques achieve competitive accuracy rates, compared to other black- and white-box techniques, on a publicly available dataset, referred to as migbase. Migbase contains aggregated information of headache attacks from 849 patients. Each sample is labeled with one of three possible primary headache disorders. We demonstrate that we are able to reduce the classification error, statistically significant (rho<=0.05), with more than 10% by balancing the dataset using prior expert knowledge. Furthermore, we achieve high accuracy rates by using features extracted using the Weisfeiler-Lehman kernel, which is completely unsupervised. This makes it an ideal approach to solve a potential cold start problem. CONCLUSION: Decision trees are the perfect candidate for the automated diagnosis support module. They achieve predictive performances competitive to other techniques on the migbase dataset and are, foremost, completely interpretable. Moreover, the incorporation of prior knowledge increases both predictive performance as well as transparency of the resulting predictive model on the studied dataset. PMID- 30424770 TI - A perioperative surgeon-controlled open-lung approach versus conventional protective ventilation with low positive end-expiratory pressure in cardiac surgery with cardiopulmonary bypass (PROVECS): study protocol for a randomized controlled trial. AB - BACKGROUND: Postoperative pulmonary complications (PPCs) are frequent after on pump cardiac surgery. Cardiac surgery results in a complex pulmonary insult leading to high susceptibility to perioperative pulmonary atelectasis. For technical reasons, ventilator settings interact with the surgical procedure and traditionally, low levels of positive end-expiratory pressure (PEEP) have been used. The objective is to compare a perioperative, multimodal and surgeon controlled open-lung approach with conventional protective ventilation with low PEEP to prevent PPCs in patients undergoing cardiac surgery. METHODS/DESIGN: The perioperative open-lung protective ventilation in cardiac surgery (PROVECS) trial is a multicenter, two-arm, randomized controlled trial. In total, 494 patients scheduled for elective cardiac surgery with cardiopulmonary bypass (CPB) and aortic cross-clamp will be randomized into one of the two treatment arms. In the experimental group, systematic recruitment maneuvers and perioperative high PEEP (8 cmH2O) are associated with ultra-protective ventilation during CPB. In this group, the settings of the ventilator are controlled by surgeons in relation to standardized protocol deviations. In the control group, no recruitment maneuvers, low levels of PEEP (2 cmH2O) and continuous positive airway pressure during CPB (2 cmH2O) are used. Low tidal volumes (6-8 mL/kg of predicted body weight) are used before and after CPB in each group. The primary endpoint is a composite of the single PPCs evaluated during the first 7 postoperative days. DISCUSSION: The PROVECS trial will be the first multicenter randomized controlled trial to evaluate the impact of a perioperative and multimodal open-lung ventilatory strategy on the occurrence of PPCs after on-pump cardiac surgery. The trial design includes standardized surgeon-controlled protocol deviations that guarantee a pragmatic approach. The results will help anesthesiologists and surgeons aiming to optimize ventilatory settings during cardiac surgery. TRIAL REGISTRATION: Clinical Trials.gov, NCT 02866578 . Registered on 15 August 2016. Last updated 11 July 2017. PMID- 30424771 TI - Are smokers who are regularly exposed to e-cigarette use by others more or less motivated to stop or to make a quit attempt? A cross-sectional and longitudinal survey. AB - BACKGROUND: Concerns have been raised that observing other people using e cigarettes may undermine motivation to quit by renormalising smoking. This study aimed to explore associations between regular exposure to other people's e cigarette use and motivation to stop smoking and quit attempts in smokers. METHODS: Data were from 12,787 smokers in England who participated in the Smoking Toolkit Study between November 2014 and May 2018. At baseline, respondents were asked whether anyone other than themselves regularly used an e-cigarette in their presence, whether they had made a quit attempt in the past year and how motivated they were to stop. Data at 6-month follow-up were available for 1580 respondents, who reported on whether they had attempted to quit in the past 6 months. RESULTS: Smokers who reported regular exposure to e-cigarette use by others were more likely than those who did not to have tried to stop smoking in the past year (32.3% vs. 26.8%; unadjusted RR 1.21, 95% CI 1.11-1.31) and have high motivation to quit (16.6% vs. 14.2%; unadjusted RR 1.17, 95% CI 1.05-1.30) but were not significantly more or less likely to make a quit attempt over the subsequent 6 months (34.4% vs. 31.3%; unadjusted RR 1.10, 95% CI 0.88-1.38). In models that adjusted for participants' own current e-cigarette use and unadjusted and adjusted models excluding current e-cigarette users from the sample, there were no significant associations between exposure to e-cigarette use by others and past quit attempts (RR 0.97-1.00), high current motivation to quit (RR 0.97-1.00) or prospective quit attempts (RR 0.94-1.12). In contrast, exposure to use of cigarettes was associated with low motivation to quit even after adjustment (RR 0.89) but not with quit attempts. Participants' own use of e-cigarette was strongly associated with high motivation to quit (RR 1.95) and past quit attempts (RR 2.14) and appeared to account for the bivariate associations with reported exposure to e-cigarettes. CONCLUSION: Smokers who report regular exposure to other people using e-cigarettes are more likely to report past quit attempts and high current motivation to quit, but there does not appear to be an independent association with motivation or quit attempts after adjustment for their own current use of e-cigarettes. In contrast, reported exposure to other people using cigarettes was independently and negatively associated with high motivation. PMID- 30424773 TI - A novel patient-specific three-dimensional-printed external template to guide iliosacral screw insertion: a retrospective study. AB - BACKGROUND: Iliosacral screw fixation is a popular method for the management of posterior pelvic ring fractures or dislocations, providing adequate biomechanical stability. Our aim in this study was to describe the use of a new patient specific external template to guide the insertion of iliosacral screws and to evaluate the efficacy and safety of this technique compared with the conventional fluoroscopy-guided technique. METHODS: This was a retrospective study of patients with incomplete or complete posterior pelvic ring disruptions who required iliosacral screw fixation. For analysis, patients were divided into two groups: the external template group (37 screws in 22 patients) and the conventional group (28 screws in 18 patients). The operative time per screw, radiation exposure time and the rate of screw perforation (accuracy) were compared between groups. In the external template group, the difference between the actual and planned iliosacral screw position was also compared. RESULTS: In the conventional group, the average operative time per screw was 39.7 +/- 10.6 min, with an average radiation exposure dose of 1904.0 +/- 844.5 cGy/cm2, with 4 cases of screw perforation. In the external template group, the average operative time per screw was 17.9 +/- 4.7 min, with an average radiation exposure dose of 742.8 +/- 230.6 cGy/cm2 and 1 case of screw perforation. In the template group, the mean deviation distance between the actual and planned screw position was 2.75 +/- 1.0 mm at the tip, 1.83 +/- 0.67 mm in the nerve root tunnel zone and 1.52 +/- 0.48 mm at the entry point, with a mean deviation angle of 1.73 +/- 0.80 degrees . CONCLUSIONS: The external template provides an accurate and safe navigation tool for percutaneous iliosacral screw insertion that could decrease the operative time and radiation exposure. PMID- 30424772 TI - Genetic disease risks can be misestimated across global populations. AB - BACKGROUND: Accurate assessment of health disparities requires unbiased knowledge of genetic risks in different populations. Unfortunately, most genome-wide association studies use genotyping arrays and European samples. Here, we integrate whole genome sequence data from global populations, results from thousands of genome-wide association studies (GWAS), and extensive computer simulations to identify how genetic disease risks can be misestimated. RESULTS: In contrast to null expectations, we find that risk allele frequencies at known disease loci are significantly different for African populations compared to other continents. Strikingly, ancestral risk alleles are found at 9.51% higher frequency in Africa, and derived risk alleles are found at 5.40% lower frequency in Africa. By simulating GWAS with different study populations, we find that non African cohorts yield disease associations that have biased allele frequencies and that African cohorts yield disease associations that are relatively free of bias. We also find empirical evidence that genotyping arrays and SNP ascertainment bias contribute to continental differences in risk allele frequencies. Because of these causes, polygenic risk scores can be grossly misestimated for individuals of African descent. Importantly, continental differences in risk allele frequencies are only moderately reduced if GWAS use whole genome sequences and hundreds of thousands of cases and controls. Finally, comparisons between uncorrected and corrected genetic risk scores reveal the benefits of considering whether risk alleles are ancestral or derived. CONCLUSIONS: Our results imply that caution must be taken when extrapolating GWAS results from one population to predict disease risks in another population. PMID- 30424775 TI - LLIN Evaluation in Uganda Project (LLINEUP): factors associated with ownership and use of long-lasting insecticidal nets in Uganda: a cross-sectional survey of 48 districts. AB - BACKGROUND: Long-lasting insecticidal nets (LLINs) are a key malaria control intervention. To investigate factors associated with ownership and use of LLINs in Uganda, a cross-sectional community survey was conducted in March-June 2017, approximately 3 years after a national Universal Coverage Campaign (UCC). METHODS: Households from 104 clusters (health sub-districts) in 48 districts were randomly selected using two-staged cluster sampling; 50 households were enrolled per cluster. Outcomes were household ownership of LLINs (at least one LLIN), adequate LLIN coverage (at least one LLIN per 2 residents), and use of LLINs (resident slept under a LLIN the previous night). Associations between variables of interest and outcomes were made using multivariate logistic regression. RESULTS: In total, 5196 households, with 29,627 residents and 6980 bed-nets, were included in the analysis. Overall, 65.0% of households owned at least one LLIN (down from 94% in 2014). In the adjusted analysis, factors most strongly associated with LLIN ownership were living in a wealthier household (highest tercile vs lowest; adjusted odds ratio [aOR] 1.94, 95% CI 1.66-2.28, p < 0.001) and time since the last UCC (29-37 vs 42-53 months; aOR 1.91, 95% CI 1.60-2.28, p < 0.001). Only 17.9% of households had adequate LLIN coverage (down from 65% in 2014). Factors most strongly associated with adequate coverage were fewer residents (2-4 vs >= 7; aOR 6.52, 95% CI 5.13-8.29, p < 0.001), living in a wealthier household (highest tercile vs lowest; aOR: 2,32, 95% CI 1.88-2.85, p < 0.001) and time since the last UCC (29-37 vs 42-53 months; aOR 2.13, 95% CI 1.61 2.81, p < 0.001). Only 39.5% of residents used a LLIN the previous night. Age was strongly associated with LLIN use, as were household wealth and time since the last UCC. Children < 5 years (44.7%) and residents > 15 years (44.1%) were more likely to use nets than children aged 5-15 years (30.7%; < 5 years: aOR 1.71, 95% CI 1.62-1.81, p < 0.001; > 15 years: aOR 1.37, 95% CI 1.29-1.45, p < 0.001). CONCLUSIONS: Long-lasting insecticidal net ownership and coverage have reduced markedly in Uganda since the last net distribution campaign in 2013/14. Houses with many residents, poorer households, and school-aged children should be targeted to improve LLIN coverage and use. Trial registration This study is registered with ISRCTN (17516395). PMID- 30424776 TI - Biosynthesis of flower-shaped Au nanoclusters with EGCG and their application for drug delivery. AB - BACKGROUND: In the last decade, the biosynthesis of metal nanoparticles using organisms have received more and more considerations. However, the complex composition of organisms adds up to a great barrier for the characterization of biomolecules involved in the synthesis process and their biological mechanisms. RESULTS: In this research, we biosynthesized a kind of flower-shaped Au nanoclusters (Au NCs) using one definite component-epigallocatechin gallate (EGCG), which was the main biomolecules of green tea polyphenols. Possessing good stability for 6 weeks and a size of 50 nm, the Au NCs might be a successful candidate for drug delivery. Hence, both methotrexate (MTX) and doxorubicin (DOX) were conjugated to the Au NCs through a bridge of cysteine (Cys). The introduction of MTX provided good targeting property for the Au NCs, and the conjugation of DOX provided good synergistic effect. Then, a novel kind of dual drug loaded, tumor-targeted and highly efficient drug delivery system (Au-Cys MTX/DOX NCs) for combination therapy was successfully prepared. The TEM of HeLa cells incubated with Au-Cys-MTX/DOX NCs indicated that the Au-Cys-MTX/DOX NCs could indeed enter and kill cancer cells. The Au-Cys-MTX/DOX NCs also possessed good targeting effect to the FA-receptors-overpressed cancer cells both in vitro and in vivo. Importantly, the Au-Cys-MTX/DOX NCs resulted in an excellent anticancer activity in vivo with negligible side effects. CONCLUSIONS: These results suggest that the biosynthesized Au-Cys-MTX/DOX NCs could be a potential carrier with highly efficient anticancer properties for tumor-targeted drug delivery. PMID- 30424774 TI - The population genetics of parasitic nematodes of wild animals. AB - Parasitic nematodes are highly diverse and common, infecting virtually all animal species, and the importance of their roles in natural ecosystems is increasingly becoming apparent. How genes flow within and among populations of these parasites - their population genetics - has profound implications for the epidemiology of host infection and disease, and for the response of parasite populations to selection pressures. The population genetics of nematode parasites of wild animals may have consequences for host conservation, or influence the risk of zoonotic disease. Host movement has long been recognised as an important determinant of parasitic nematode population genetic structure, and recent research has also highlighted the importance of nematode life histories, environmental conditions, and other aspects of host ecology. Commonly, factors influencing parasitic nematode population genetics have been studied in isolation, such that an integrated view of the drivers of population genetic structure of parasitic nematodes is still lacking. Here, we seek to provide a comprehensive, broad, and integrative picture of these factors in parasitic nematodes of wild animals that will be a useful resource for investigators studying non-model parasitic nematodes in natural ecosystems. Increasingly, new methods of analysing the population genetics of nematodes are becoming available, and we consider the opportunities that these afford in resolving hitherto inaccessible questions of the population genetics of these important animals. PMID- 30424777 TI - Enhancing the production of cephalosporin C through modulating the autophagic process of Acremonium chrysogenum. AB - BACKGROUND: Autophagy is used for degradation of cellular components and nutrient recycling. Atg8 is one of the core proteins in autophagy and used as a marker for autophagic detection. However, the autophagy of filamentous fungi is poorly understood compared with that of Saccharomyces cerevisiae. Our previous study revealed that disruption of the autophagy related gene Acatg1 significantly enhanced cephalosporin C yield through reducing degradation of cephalosporin biosynthetic proteins in Acremonium chrysogenum, suggesting that modulation of autophagic process is one promising way to increase antibiotic production in A. chrysogenum. RESULTS: In this study, a S. cerevisiae ATG8 homologue gene Acatg8 was identified from A. chrysogenum. Acatg8 could complement the ATG8 mutation in S. cerevisiae, indicating that Acatg8 is a functional homologue of ATG8. Microscope observation demonstrated the fluorescently labeled AcAtg8 was localized in the cytoplasm and autophagosome of A. chrysogenum, and the expression of Acatg8 was induced by nutrient starvation. Gene disruption and genetic complementation revealed that Acatg8 is essential for autophagosome formation. Disruption of Acatg8 significantly reduced fungal conidiation and delayed conidial germination. Localization of GFP-AcAtg8 implied that autophagy is involved in the early phase of conidial germination. Similar to Acatg1, disruption of Acatg8 remarkably enhanced cephalosporin C yield. The cephalosporin C biosynthetic enzymes (isopenicillin N synthase PcbC and isopenicillin N epimerase CefD2) and peroxisomes were accumulated in the Acatg8 disruption mutant (?Acatg8), which might be the main reasons for the enhancement of cephalosporin C production. However, the biomass of DeltaAcatg8 decreased drastically at the late stage of fermentation, suggesting that autophagy is critical for A. chrysogenum cell survival under nutrition deprived condition. Disruption of Acatg8 also resulted in accumulation of mitochondria, which might produce more reactive oxygen species (ROS) which promotes fungal death. However, the premature death is unfavorable for cephalosporin C production. To solve this problem, a plasmid containing Acatg8 under control of the xylose/xylan-inducible promoter was introduced into ?Acatg8. Conidiation and growth of the recombinant strain restored to the wild-type level in the medium supplemented with xylose, while the cephalosporin C production maintained at a high level even prolonged fermentation. CONCLUSIONS: Our results demonstrated inducible expression of Acatg8 and disruption of Acatg8 remarkably increased cephalosporin C production. This study provides a promising approach for yield improvement of cephalosporin C in A. chrysogenum. PMID- 30424778 TI - Inpatient burden of juvenile dermatomyositis among children in the United States. AB - BACKGROUND: Juvenile dermatomyositis (JDM) is a rare autoimmune disease that causes significant morbidity and quality of life impairment. Little is known about the inpatient burden of JDM in the US. Our goal was to determine the prevalence and risk factors for hospitalization with juvenile dermatomyositis and assess inpatient burden of JDM. METHODS: Data on 14,401,668 pediatric hospitalizations from the 2002-2012 Nationwide Inpatient Sample (NIS) was analyzed. ICD-9-CM coding was used to identify hospitalizations with a diagnosis of JDM. RESULTS: There were 909 and 495 weighted admissions with a primary or secondary diagnosis of JDM, respectively. In multivariable logistic regression models with stepwise selection, female sex (logistic regression; adjusted odds ratio [95% confidence interval]) (2.22 [2.05-2.42]), non-winter season (fall: 1.18[1.06-1.33]; spring (1.13 [1.01-1.27]; summer (1.53 [1.37-1.71]), non Medicaid administered government insurance coverage (2.59 [2.26-2.97]), and multiple chronic conditions (2-5: 1.41[1.30-1.54]; 6+: 1.24[1.00-1.52]) were all associated with higher rates of hospitalization for JDM. The weighted total length of stay (LOS) and inflation-adjusted cost of care for patients with a primary inpatient diagnosis of JDM was 19,159 days and $49,339,995 with geometric means [95% CI] of 2.50 [2.27-2.76] days and $7350 [$6228-$8674], respectively. Costs of hospitalization in primary JDM and length of stay and cost in secondary JDM were significantly higher compared to those without JDM. Notably, race/ethnicity was associated with increased LOS (log-linear regression; adjusted beta [95% confidence interval]) (Hispanic: 0.28 [0.14-0.41]; other non-white: 0.59 [0.31-0.86]) and cost of care (Hispanic: 0.30 [0.05-0.55]). CONCLUSION: JDM contributes to both increased length of hospitalization and inpatient cost of care. Non-Medicaid government insurance was associated with higher rates of hospitalization for JDM while Hispanic and other non-white racial/ethnic groups demonstrated increased LOS and cost of care. PMID- 30424779 TI - Pathological characteristics and genetic features of melanin-producing medullary thyroid carcinoma. AB - OBJECTIVE: To study the clinicopathological characteristics and genetic features of melanin-producing medullary thyroid carcinoma (MP-MTC). METHODS: The immunophenotype of MP-MTC was studied using the immunohistochemical method, and its genetic features were assayed using an amplification refractory mutation system or PCR method. RESULTS: A 71-year-old man presented with a slowly growing 5-cm mass on the left side of the neck for approximately two months. The cut surface of the neoplasm was brown and black. Melanin was found in the cytoplasm of tumor cells or the extracellular matrix. The tumor cells were positive for AE1/AE3, S-100 protein, melan A, HMB-45, synaptophysin, calcitonin, chromogranin A, melanoma, and thyroid transcription factor-1 (TTF-1) and negative for thyroglobulin. No typical genetic features were observed in this case. The patient showed no symptoms and recurrence at 12 months after the operation. CONCLUSIONS: The tumor cells of MP-MTC were positive for melanin biomarkers, TTF 1 and exhibited no genetic features. Histopathology and immunohistochemistry of the tumor cells will aid accurate diagnosis. PMID- 30424780 TI - In vivo assessment of neuroinflammation in progressive multiple sclerosis: a proof of concept study with [18F]DPA714 PET. AB - BACKGROUND: Over the past decades, positron emission tomography (PET) imaging has become an increasingly useful research modality in the field of multiple sclerosis (MS) research, as PET can visualise molecular processes, such as neuroinflammation, in vivo. The second generation PET radioligand [18F]DPA714 binds with high affinity to the 18-kDa translocator-protein (TSPO), which is mainly expressed on activated microglia. The aim of this proof of concept study was to evaluate this in vivo marker of neuroinflammation in primary and secondary progressive MS. METHODS: All subjects were genotyped for the rs6971 polymorphism within the TSPO gene, and low-affinity binders were excluded from participation in this study. Eight patients with progressive MS and seven age and genetic binding status matched healthy controls underwent a 60 min dynamic PET scan using [18F]DPA714, including both continuous on-line and manual arterial blood sampling to obtain metabolite-corrected arterial plasma input functions. RESULTS: The optimal model for quantification of [18F]DPA714 kinetics was a reversible two tissue compartment model with additional blood volume parameter. For genetic high affinity binders, a clear increase in binding potential was observed in patients with MS compared with age-matched controls. For both high and medium affinity binders, a further increase in binding potential was observed in T2 white matter lesions compared with non-lesional white matter. Volume of distribution, however, did not differentiate patients from healthy controls, as the large non displaceable compartment of [18F]DPA714 masks its relatively small specific signal. CONCLUSION: The TSPO radioligand [18F]DPA714 can reliably identify increased focal and diffuse neuroinflammation in progressive MS when using plasma input-derived binding potential, but observed differences were predominantly visible in high-affinity binders. PMID- 30424781 TI - Lymphatic filariasis transmission in Rufiji District, southeastern Tanzania: infection status of the human population and mosquito vectors after twelve rounds of mass drug administration. AB - BACKGROUND: Control of lymphatic filariasis (LF) in most of the sub-Saharan African countries is based on annual mass drug administration (MDA) using a combination of ivermectin and albendazole. Monitoring the impact of this intervention is crucial for measuring the success of the LF elimination programmes. This study assessed the status of LF infection in Rufiji district, southeastern Tanzania after twelve rounds of MDA. METHODS: Community members aged between 10 and 79 years were examined for Wuchereria bancrofti circulating filarial antigens (CFA) using immunochromatographic test cards (ICTs) and antigen positive individuals were screened for microfilaraemia. All study participants were examined for clinical manifestation of LF and interviewed for drug uptake during MDA rounds. Filarial mosquito vectors were collected indoor and outdoor and examined for infection with W. bancrofti using a microscope and quantitative real-time polymerase chain reaction (qPCR) techniques. RESULTS: Out of 854 participants tested, nine (1.1%) were positive for CFA and one (0.1%) was found to be microfilaraemic. The prevalence of hydrocele and elephantiasis was 4.8% and 2.9%, respectively. Surveyed drug uptake rates were high, with 70.5% of the respondents reporting having swallowed the drugs in the 2014 MDA round (about seven months before this study). Further, 82.7% of the respondents reported having swallowed the drugs at least once since the inception of MDA programme in 2000. Of the 1054 filarial vectors caught indoors and dissected to detect W. bancrofti infection none was found to be infected. Moreover, analysis by qPCR of 1092 pools of gravid Culex quinquefasciatus collected outdoors resulted in an estimated infection rate of 0.1%. None of the filarial vectors tested with qPCR were found to be infective. CONCLUSION: Analysis of indices of LF infection in the human population and filarial mosquito vectors indicated a substantial decline in the prevalence of LF and other transmission indices, suggesting that local transmission was extremely low if occurring at all in the study areas. We, therefore, recommend a formal transmission assessment survey (TAS) to be conducted in the study areas to make an informed decision on whether Rufiji District satisfied WHO criteria for stopping MDA. PMID- 30424782 TI - A practical approach to estimating optic disc dose and macula dose without treatment planning in ocular brachytherapy using 125I COMS plaques. AB - BACKGROUND: It has been reported that proximity of the tumor to the optic disc and macula, and radiation dose to the critical structures are substantial risk factors for vision loss following plaque brachytherapy. However, there is little dosimetry data published on this. In this study, therefore, the relationship between distance from tumor margin and radiation dose to the optic disc and macula in ocular brachytherapy using 125I Collaborative Ocular Melanoma Study (COMS) plaques was comprehensively investigated. From the information, this study aimed to allow for estimation of optic disc dose and macula dose without treatment planning. METHODS: An in-house brachytherapy dose calculation program utilizing the American Association of Physicists in Medicine Task Group-43 U1 formalism with a line source approximation in a homogenous water phantom was developed and validated against three commercial treatment planning systems (TPS). Then optic disc dose and macula dose were calculated as a function of distance from tumor margin for various tumor basal dimensions for seven COMS plaques (from 10 mm to 22 mm in 2 mm increments) loaded with commercially available 125I seeds models (IAI-125A, 2301 and I25.S16). A prescribed dose of 85 Gy for an irradiation time of 168 h was normalized to a central-axis depth of 5 mm. Dose conversion factors for each seed model were obtained by taking ratios of total reference air kerma per seed at various prescription depths (from 1 mm to 10 mm in 1 mm intervals) to that at 5 mm. RESULTS: The in-house program demonstrated relatively similar accuracy to commercial TPS. Optic disc dose and macula dose decreased as distance from tumor margin and tumor basal dimension increased. Dose conversion factors increased with increasing prescription depth. There existed dose variations (<8%) among three 125I seed models. Optic disc dose and macula dose for each COMS plaque and for each seed model are presented in a figure format. Dose conversion factors for each seed model are presented in a tabular format. CONCLUSIONS: The data provided in this study would enable clinicians in any clinic using 125I COMS plaques to estimate optic disc dose and macula dose without dose calculations. PMID- 30424783 TI - Evaluation of osteopenia and osteoporosis in younger breast cancer survivors compared with cancer-free women: a prospective cohort study. AB - BACKGROUND: Osteoporosis, an indicator of significant bone loss, has been consistently reported among older breast cancer survivors. Data are limited on the incidence of osteopenia, an earlier indicator of bone loss, and osteoporosis in younger breast cancer survivors compared with cancer-free women. METHODS: We prospectively examined bone loss in 211 breast cancer survivors (mean age at breast cancer diagnosis = 47 years) compared with 567 cancer-free women in the same cohort with familial risk for breast cancer. Multivariable-adjusted Cox proportional hazards models were used to estimate HRs and 95% CIs of osteopenia and/or osteoporosis incidence based on physician diagnosis. RESULTS: During a mean follow-up of 5.8 years, 66% of breast cancer survivors and 53% of cancer free women reported having a bone density examination, and 112 incident cases of osteopenia and/or osteoporosis were identified. Breast cancer survivors had a 68% higher risk of osteopenia and osteoporosis compared to cancer-free women (HR = 1.68, 95% CI = 1.12-2.50). The association was stronger among recent survivors after only 2 years of follow-up (HR = 2.74, 95% CI = 1.37-5.47). A higher risk of osteopenia and osteoporosis was also observed among survivors aged <= 50 years, estrogen receptor-positive tumors, and those treated with aromatase inhibitors alone or chemotherapy plus any hormone therapy relative to cancer-free women. CONCLUSIONS: Younger breast cancer survivors are at higher risk for osteopenia and osteoporosis compared to cancer-free women. Studies are needed to determine effective approaches to minimize bone loss in this population. PMID- 30424784 TI - Fear of disease progression in carriers of the m.3243A > G mutation. AB - BACKGROUND: Being diagnosed with mitochondrial disease due to the m.3243A > G mutation is frequently preceded by a long diagnostic process. The disease itself is characterized by heterogeneous course and expression, so leaving patients with considerable uncertainty regarding their prognosis and treatment possibilities. This could easily result in fear of disease progression. This study investigated the presence of this fear and its correlates with genetic characteristics and clinical disease severity in m.3243A > G carriers. METHODS: In total 125 eligible m.3243A > G mutation carriers were invited to participate in this cross-sectional study. After informed consent, participants completed questionnaires including items on socio-demographics, fear of progression, depression, anxiety, and quality of life. Clinical disease severity was assessed by the NMDAS questionnaire. Heteroplasmy levels were assessed in leucocytes, urine epithelial cells and buccal mucosa. RESULTS: Seventy-six carriers participated in this study. Results showed that 18% reported high fear of progression. Fear of progression was significantly related to all domains of quality of life. Furthermore, fear of progression was moderately correlated with feelings of depression (r = .37), and anxiety (r = .44). Patients with moderate or severe clinical symptoms on the NMDAS experienced more fear of progression than patients with mild clinical symptoms. Fear of progression was weakly correlated with heteroplasmy in leucocytes (r = .27) and buccal mucosa (r = .31). CONCLUSIONS: A substantial part of m.3243A > G mutation carriers experience high levels of fear of progression which coincide with significantly lower quality of life. Only a small relation with disease characteristics was found. The impact of receiving a diagnosis without therapeutic possibilities on fear is important to consider. PMID- 30424785 TI - Functional alterations of myeloid cells during the course of Alzheimer's disease. AB - BACKGROUND: Neuroinflammation is a hallmark of neurodegenerative disease and a significant component of the pathology of Alzheimer's disease (AD). Patients present with extensive microgliosis along with elevated pro-inflammatory signaling in the central nervous system and periphery. However, the role of peripheral myeloid cells in mediating and influencing AD pathogenesis remains unresolved. METHODS: Peripheral myeloid cells were isolated from peripheral blood of patients with prodromal AD (n = 44), mild AD dementia (n = 25), moderate/severe AD dementia (n = 28), and age-matched controls (n = 54). Patients were evaluated in the clinic for AD severity and categorized using Clinical Dementia Rating (CDR) scale resulting in separation of patients into prodromal AD (CDR0.5) and advancing forms of AD dementia (mild-CDR1 and moderate/severe CDR2/3). Separation of peripheral myeloid cells into mature monocytes or immature MDSCs permitted the delineation of population changes from flow cytometric analysis, RNA phenotype analysis, and functional studies using T cell suppression assays and monocyte suppression assays. RESULTS: During stages of AD dementia (CDR1 and 2/3) peripheral myeloid cells increase their pro-inflammatory gene expression while at early stages of disease (prodromal AD-CDR0.5) pro inflammatory gene expression is decreased. MDSCs are increased in prodromal AD compared with controls (16.81% vs 9.53%) and have markedly increased suppressive functions: 42.4% suppression of activated monocyte-produced IL-6 and 78.16% suppression of T cell proliferation. In AD dementia, MDSC populations are reduced with decreased suppression of monocyte IL-6 (5.22%) and T cell proliferation (37.61%); the reduced suppression coincides with increased pro-inflammatory signaling in AD dementia monocytes. CONCLUSIONS: Peripheral monocyte gene expression is pro-inflammatory throughout the course of AD, except at the earliest, prodromal stages when pro-inflammatory gene expression is suppressed. This monocyte biphasic response is associated with increased numbers and suppressive functions of MDSCs during the early stages and decreased numbers and suppressive functions in later stages of disease. Prolonging the early protective suppression and reversing the later loss of suppressive activity may offer a novel therapeutic strategy. PMID- 30424786 TI - HIF prolyl hydroxylase inhibition protects skeletal muscle from eccentric contraction-induced injury. AB - BACKGROUND: In muscular dystrophy and old age, skeletal muscle repair is compromised leading to fibrosis and fatty tissue accumulation. Therefore, therapies that protect skeletal muscle or enhance repair would be valuable medical treatments. Hypoxia-inducible factors (HIFs) regulate gene transcription under conditions of low oxygen, and HIF target genes EPO and VEGF have been associated with muscle protection and repair. We tested the importance of HIF activation following skeletal muscle injury, in both a murine model and human volunteers, using prolyl hydroxylase inhibitors that stabilize and activate HIF. METHODS: Using a mouse eccentric limb injury model, we characterized the protective effects of prolyl hydroxylase inhibitor, GSK1120360A. We then extended these studies to examine the impact of EPO modulation and infiltrating immune cell populations on muscle protection. Finally, we extended this study with an experimental medicine approach using eccentric arm exercise in untrained volunteers to measure the muscle-protective effects of a clinical prolyl hydroxylase inhibitor, daprodustat. RESULTS: GSK1120360A dramatically prevented functional deficits and histological damage, while accelerating recovery after eccentric limb injury in mice. Surprisingly, this effect was independent of EPO, but required myeloid HIF1alpha-mediated iNOS activity. Treatment of healthy human volunteers with high-dose daprodustat reduced accumulation of circulating damage markers following eccentric arm exercise, although we did not observe any diminution of functional deficits with compound treatment. CONCLUSION: The results of these experiments highlight a novel skeletal muscle protective effect of prolyl hydroxylase inhibition via HIF-mediated expression of iNOS in macrophages. Partial recapitulation of these findings in healthy volunteers suggests elements of consistent pharmacology compared to responses in mice although there are clear differences between these two systems. PMID- 30424787 TI - Bioinformatics analysis of differentially expressed genes in rotator cuff tear patients using microarray data. AB - BACKGROUND: Rotator cuff tear (RCT) is a common shoulder disorder in the elderly. Muscle atrophy, denervation and fatty infiltration exert secondary injuries on torn rotator cuff muscles. It has been reported that satellite cells (SCs) play roles in pathogenic process and regenerative capacity of human RCT via regulating of target genes. This study aims to complement the differentially expressed genes (DEGs) of SCs that regulated between the torn supraspinatus (SSP) samples and intact subscapularis (SSC) samples, identify their functions and molecular pathways. METHODS: The gene expression profile GSE93661 was downloaded and bioinformatics analysis was made. RESULTS: Five hundred fifty one DEGs totally were identified. Among them, 272 DEGs were overexpressed, and the remaining 279 DEGs were underexpressed. Gene ontology (GO) and pathway enrichment analysis of target genes were performed. We furthermore identified some relevant core genes using gene-gene interaction network analysis such as GNG13, GCG, NOTCH1, BCL2, NMUR2, PMCH, FFAR1, AVPR2, GNA14, and KALRN, that may contribute to the understanding of the molecular mechanisms of secondary injuries in RCT. We also discovered that GNG13/calcium signaling pathway is highly correlated with the denervation atrophy pathological process of RCT. CONCLUSION: These genes and pathways provide a new perspective for revealing the underlying pathological mechanisms and therapy strategy of RCT. PMID- 30424788 TI - ResistanceSim: development and acceptability study of a serious game to improve understanding of insecticide resistance management in vector control programmes. AB - The use of insecticides is the cornerstone of effective malaria vector control. However, the last two decades has seen the ubiquitous use of insecticides, predominantly pyrethroids, causing widespread insecticide resistance and compromising the effectiveness of vector control. Considerable efforts to develop new active ingredients and interventions are underway. However, it is essential to deploy strategies to mitigate the impact of insecticide resistance now, both to maintain the efficacy of currently available tools as well as to ensure the sustainability of new tools as they come to market. Although the World Health Organization disseminated best practice guidelines for insecticide resistance management (IRM), Rollback Malaria's Vector Control Working Group identified the lack of practical knowledge of IRM as the primary gap in the translation of evidence into policy. ResistanceSim is a capacity strengthening tool designed to address this gap. The development process involved frequent stakeholder consultation, including two separate workshops. These workshops defined the learning objectives, target audience, and the role of mathematical models in the game. Software development phases were interspersed with frequent user testing, resulting in an iterative design process. User feedback was evaluated via questionnaires with Likert-scale and open-ended questions. The game was regularly evaluated by subject-area experts through meetings of an external advisory panel. Through these processes, a series of learning domains were identified and a set of specific learning objectives for each domain were defined to be communicated to vector control programme personnel. A simple "game model" was proposed that produces realistic outputs based on player strategy and also runs in real-time. Early testing sessions revealed numerous usability issues that prevented adequate player engagement. After extensive revisions, later testing sessions indicated that the tool would be a valuable addition to IRM training. PMID- 30424789 TI - A simple method for determining dosimetric leaf gap with cross-field dose width for rounded leaf-end multileaf collimator systems. AB - PURPOSE: The dosimetric leaf gap (DLG) and multileaf collimator (MLC) transmission are two important systematic parameters used to model the rounded MLC leaf ends effect when commissioning an Eclipse treatment planning system (TPS). Determining the optimal DLG is a time consuming process. This study develops a simple and reliable method for determining the DLG using the cross field dose width. METHODS AND MATERIALS: A Varian TrueBeam linac with 6 MV, 10 MV, 6 MV flattening filter free (FFF) and 10 MV FFF photon beams and equipped with the 120 Millennium MLC and the EclipseTM TPS was used in this study. Integral sliding fields and static slit MLC field doses with different gap widths were measured with an ionization chamber and GAFCHROMIC EBT3 films, respectively. Measurements were performed for different beam energies and at depths of 5 and 10 cm. DLGs were derived from a linear extrapolation to zero dose and intercepting at the gap width axis. In the ion chamber measurements method, the average MLC leaf transmission to the gap reading for each gap (RgT) were calculated with nominal and cross-field dose widths, respectively. The cross-field dose widths were determined according to the dose profile measured with EBT3 films. Additionally, the optimal DLG values were determined using plan dose measurements, as the value that produced the closest agreement between the planned and measured doses. DLGs derived from the nominal and cross-field dose width, the film measurements, and the optimal process, were obtained and compared. RESULTS: The DLG values are insensitive to the variations in depth (within 0.07 mm). DLGs derived from nominal gap widths showed a significantly lower values (with difference about 0.5 mm) than that from cross-field dose widths and from film measurements and from plan optimal values. The method in deriving DLGs by correcting the nominal gap widths to the cross-field dose widths has shown good agreements to the plan optimal values (with difference within 0.21 mm). CONCLUSIONS: The DLG values derived from the cross-field dose width method were consistent with the values derived from film measurements and from the plan optimal process. A simple and reliable method to determine DLG for rounded leaf end MLC systems was established. This method provides a referable DLG value required during TPS commissioning. PMID- 30424790 TI - Graphene quantum dots in alveolar macrophage: uptake-exocytosis, accumulation in nuclei, nuclear responses and DNA cleavage. AB - BACKGROUND: Given the tremendous potential for graphene quantum dots (QDs) in biomedical applications, a thorough understanding of the interaction of these materials with macrophages is essential because macrophages are one of the most important barriers against exogenous particles. Although the cytotoxicity and cellular uptake of graphene QDs were reported in previous studies, the interaction between nuclei and the internalized graphene QDs is not well understood. We thus systematically studied the nuclear uptake and related nuclear response associated with aminated graphene QDs (AG-QDs) exposure. RESULTS: AG-QDs showed modest 24-h inhibition to rat alveolar macrophages (NR8383), with a minimum inhibitory concentration (MIC) of 200 MUg/mL. Early apoptosis was significantly increased by AG-QDs (100 and 200 MUg/mL) exposure and played a major role in cell death. The internalization of AG-QDs was mainly via energy dependent endocytosis, phagocytosis and caveolae-mediated endocytosis. After a 48 h clearance period, more than half of the internalized AG-QDs remained in the cellular cytoplasm and nucleus. Moreover, AG-QDs were effectively accumulated in nucleus and were likely regulated by two nuclear pore complexes genes (Kapbeta2 and Nup98). AG-QDs were shown to alter the morphology, area, viability and nuclear components of exposed cells. Significant cleavage and cross-linking of DNA chains after AG-QDs exposure were confirmed by atomic force microscopy investigation. Molecular docking simulations showed that H-bonding and pi-pi stacking were the dominant forces mediating the interactions between AG-QDs and DNA, and were the important mechanisms resulting in DNA chain cleavage. In addition, the generation of reactive oxygen species (ROS) (e.g., *OH), and the up regulation of caspase genes also contributed to DNA cleavage. CONCLUSIONS: AG-QDs were internalized by macrophages and accumulated in nuclei, which further resulted in nuclear damage and DNA cleavage. It is demonstrated that oxidative damage, direct contact via H-bonding and pi-pi stacking, and the up-regulation of caspase genes are the primary mechanisms for the observed DNA cleavage by AG-QDs. PMID- 30424791 TI - Characterization of two ETFDH mutations in a novel case of riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. AB - BACKGROUND: Deficiency of electron transfer flavoprotein dehydrogenase (ETFDH) is associated with multiple acyl-CoA dehydrogenase deficiency (MADD). This disorder is an autosomal recessive lipid storage myopathy (LSM) that exhibits a wide range of clinical features, including myopathy, weakness and multisystem dysfunctions. Many patients with late onset of MADD improve when treated with riboflavin and are also referred to as RR-MADD (riboflavin-responsive multiple Acyl-CoA dehydrogenase disorder). METHODS: In this study, we report the clinical and genetic characterization of a novel RR-MADD patient. Biochemical data were obtained from analysis of muscle and plasma samples. DNA and RNA were extracted from peripheral blood, and sequence analysis and expression study of ETFDH gene were performed. Finally, the impact of mutations on ETFDH folding was evaluated using bioinformatic tools. RESULTS: Patient initially presented with vomiting, muscle weakness, and acidosis. Muscle biopsy revealed typical myopathological patterns of lipid storage myopathy and blood acylcarnitine profiles showed a combined elevation of long and medium chain acylcarnitines, supporting the diagnosis of RR-MADD. Molecular analysis of ETFDH gene revealed two heterozygous mutations, a novel splice variation in intron 10, c.1285 + 1G > A, and the previously reported c.560C > T missense mutation. RT-PCR analysis showed an alteration of ETFDH RNA splicing which in turn should lead to the production of a truncated protein. The in silico prediction analysis of ETFDH tridimensional structure demonstrated that the missense mutation resulted in instability and loss of protein activation, while the splice site variation induced a dramatic conformational change of the truncated protein. After MCT diet supplemented with carnitine and riboflavin, the patient showed significant biochemical and clinical improvement, in spite of severe molecular defect. CONCLUSION: This case report extends the spectrum of ETFDH mutations in MADD, providing further evidence that patients presenting at least one missense mutation in the FAD-binding domain may respond to either carnitine or riboflavin treatment, due to the recovery of some enzymatic activity. PMID- 30424793 TI - Bright environmental light improves the sleepiness of nightshift ICU nurses. AB - BACKGROUND: Shift work can disturb circadian homeostasis and result in fatigue, excessive sleepiness, and reduced quality of life. Light therapy has been shown to impart positive effects in night shift workers. We sought to determine whether or not prolonged exposure to bright light during a night shift reduces sleepiness and enhances psychomotor performance among ICU nurses. METHODS: This is a single center randomized, crossover clinical trial at a surgical trauma ICU. ICU nurses working a night shift were exposed to a 10-h period of high illuminance (1500 2000 lx) white light compared to standard ambient fluorescent lighting of the hospital. They then completed the Stanford Sleepiness Scale and the Psychomotor Vigilance Test. The primary and secondary endpoints were analyzed using the paired t test. A p value <0.05 was considered significant. RESULTS: A total of 43 matched pairs completed both lighting exposures and were analyzed. When exposed to high illuminance lighting subjects experienced reduced sleepiness scores on the Stanford Sleepiness Scale than when exposed to standard hospital lighting: mean (sem) 2.6 (0.2) vs. 3.0 (0.2), p = 0.03. However, they committed more psychomotor errors: 2.3 (0.2) vs. 1.7 (0.2), p = 0.03. CONCLUSIONS: A bright lighting environment for ICU nurses working the night shift reduces sleepiness but increases the number of psychomotor errors. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03331822 . Retrospectively registered on 6 November 2017. PMID- 30424792 TI - Spatio-temporal expression profile of matrix metalloproteinase (Mmp) modulators Reck and Sparc during the rat ovarian dynamics. AB - BACKGROUND: Matrix metalloproteinases (Mmps) and their tissue inhibitors (Timps) are widely recognized as crucial factors for extracellular matrix remodeling in the ovary and are involved in follicular growth, ovulation, luteinization, and luteolysis during the estrous cycle. Recently, several genes have been associated to the modulation of Mmps activity, including Basigin (Bsg), which induces the expression of Mmps in rat ovaries; Sparc, a TGF-beta modulator that is related to increased expression of Mmps in cancer; and Reck, which is associated with Mmps inhibition. However, the expression pattern of Mmp modulators in ovary dynamics is still largely uncharacterized. METHODS: To characterize the expression pattern of Mmps network members in ovary dynamics, we analyzed the spatio-temporal expression pattern of Reck and Sparc, as well as of Mmp2, Mmp9 and Mmp14 proteins, by immunohistochemistry (IHC), in pre-pubertal rat ovaries obtained from an artificial cycle induced by eCG/hCG, in the different phases of the hormone-induced estrous cycle. We also determined the gene expression profiles of Mmps (2, 9, 13 14), Timps (1, 2, 3), Sparc, Bsg, and Reck to complement this panel. RESULTS: IHC analysis revealed that Mmp protein expression peaks at the early stages of folliculogenesis and ovulation, decreases during ovulation luteogenesis transition and luteogenesis, increasing again during corpus luteum maintenance and luteolysis. The protein expression patterns of these metalloproteinases and Sparc were inverse relative to the pattern displayed by Reck. We observed that the gene expression peaks of Mmps inhibitors Reck and Timp2 were closely paraleled by Mmp2 and Mmp9 suppression. The opposite was also true: increased Mmp2 and Mmp9 expression was concomitant to reduced Reck and Timp2 levels. CONCLUSION: Therefore, our results generate a spatio-temporal expression profile panel of Mmps and their regulators, suggesting that Reck and Sparc seem to play a role during ovarian dynamics: Reck as a possible inhibitor and Sparc as an inducer of Mmps. PMID- 30424794 TI - The preoperative predictors for subsequent degeneration in L5-S1 disc after long fusion arthrodesis terminating at L5 in patients with adult scoliosis: focus on spinopelvic parameters. AB - BACKGROUND: The subsequent L5-S1 disc degeneration associated with long fusion arthrodesis terminating at L5 in patients with adult scoliosis has been a common concern. However, few studies paid attention to its preoperative predictors, especially in spinopelvic parameters. The purpose of the present study was to clarify the preoperative predictors of subsequent L5-S1 disc degeneration after long fusion arthrodesis terminating at L5 in patients with adult scoliosis on spinopelvic parameters. METHODS: In this retrospective study, we enrolled 67 patients with adult scoliosis, and the patients were divided into disc degeneration group (DD) and no disc degeneration group (NDD), based on the presence or absence of subsequent L5-S1 disc degeneration. The status of L5-S1 disc was evaluated by a modified version of radiographic classification. Characteristics and spinopelvic parameters of preoperative patients were collected as potential predictors for subsequent lumbosacral disc degeneration after long fusion arthrodesis terminating at L5 in patients with adult scoliosis. Multivariate logistic regression analysis and the receiver operating characteristic curve were used to identify the preoperative predictors, with an adjusted odds ratio (OR) and 95% confidence intervals (CI). RESULTS: Thirty-six patients (53.73%) with subsequent L5-S1 disc degeneration were divided into group DD (preoperative score 0.81 +/- 0.57, last follow-up score 1.83 +/- 0.60, P < 0.001), and the other 31 patients were divided into group NDD (preoperative and last follow-up score 0.87 +/- 0.49). There was no statistical difference in preoperative score (P = 0.583) of lumbosacral disc between two groups; however, significant statistical difference showed in last follow-up score (P < 0.001). Multivariate logistic regression identified three preoperative predictors: pelvic incidence (PI) (P = 0.018), sagittal vertical axis (SVA) (P = 0.024), and sacrum femoral distance (SFD) (P = 0.023). PI < 48.5 degrees (OR = 0.911, 95% CI = 0.843-0.984), SVA > 4.43 cm (OR = 1.308, 95% CI = 1.036-1.649), and SFD > 5.65 cm (OR = 1.337, 95% CI = 1.041-1.718) showed satisfied accuracy for predicting subsequent L5-S1 disc degeneration. CONCLUSION: The prevalence of the subsequent L5-S1 disc degeneration after long fusion arthrodesis terminating at L5 in patients with adult scoliosis was 57.3% (36 of 67 patients). PI < 48.5 degrees , SVA > 4.43 cm, and SFD > 5.65 cm were preoperative predictors for the subsequent L5-S1 disc degeneration. More attention should be paid to prevent the L5-S1 disc from degeneration when these preoperative predictors exist, especially with two or more. PMID- 30424795 TI - Reduced AMPK activation and increased HCAR activation drive anti-inflammatory response and neuroprotection in glaucoma. AB - BACKGROUND: Glaucoma is a chronic degenerative disease for which inflammation is considered to play a pivotal role in the pathogenesis and progression. In this study, we examined the impact of a ketogenic diet on the inflammation evident in glaucoma as a follow-up to a recent set of experiments in which we determined that a ketogenic diet protected retinal ganglion cell structure and function. METHODS: Both sexes of DBA/2J (D2) mice were placed on a ketogenic diet (keto) or standard rodent chow (untreated) for 8 weeks beginning at 9 months of age. DBA/2J Gpnmb+ (D2G) mice were also used as a non-pathological genetic control for the D2 mice. Retina and optic nerve (ON) tissues were micro-dissected and used for the analysis of microglia activation, expression of pro- and anti-inflammatory molecules, and lactate- or ketone-mediated anti-inflammatory signaling. Data were analyzed by immunohistochemistry, quantitative RT-PCR, ELISA, western blot, and capillary tube-based electrophoresis techniques. RESULTS: Microglia activation was observed in D2 retina and ON as documented by intense microglial-specific Iba1 immunolabeling of rounded-up and enlarged microglia. Ketogenic diet treatment reduced Iba1 expression and the activated microglial phenotype. We detected low energy-induced AMP-activated protein kinase (AMPK) phosphorylation in D2 retina and ON that triggered NF-kappaB p65 signaling through its nuclear translocation. NF-kappaB induced pro-inflammatory TNF-alpha, IL-6, and NOS2 expression in D2 retina and ON. However, treatment with the ketogenic diet reduced AMPK phosphorylation, NF-kappaB p65 nuclear translocation, and expression of pro-inflammatory molecules. The ketogenic diet also induced expression of anti inflammatory agents Il-4 and Arginase-1 in D2 retina and ON. Increased expression of hydroxycarboxylic acid receptor 1 (HCAR1) after ketogenic diet treatment was observed. HCAR1 stimulation by lactate or ketones from the ketogenic diet reduced inflammasome formation, as shown by reduced mRNA and protein expression of NLRP3 and IL-1beta. We also detected increased levels of Arrestin beta-2 protein, an adapter protein required for HCAR1 signaling. CONCLUSION: Our data demonstrate that the AMPK activation apparent in the glaucomatous retina and ON triggers NF kappaB signaling and consequently induces a pro-inflammatory response. The ketogenic diet resolves energy demand and ameliorates the inflammation by inhibition of AMPK activation and stimulation of HCAR1-ARRB2 signaling that inhibits NLRP3 inflammasome-mediated inflammation. Thus, these findings depict a neuroprotective mechanism of the ketogenic diet in controlling inflammation and suggest potential therapeutic targets for inflammatory neurodegenerative diseases, including glaucoma. PMID- 30424796 TI - Cost-effectiveness of procalcitonin testing to guide antibiotic treatment duration in critically ill patients: results from a randomised controlled multicentre trial in the Netherlands. AB - BACKGROUND: Procalcitonin (PCT) testing can help in safely reducing antibiotic treatment duration in intensive care patients with sepsis. However, the cost effectiveness of such PCT guidance is not yet known. METHODS: A trial-based analysis was performed to estimate the cost-effectiveness of PCT guidance compared with standard of care (without PCT guidance). Patient-level data were used from the SAPS trial in which 1546 patients were randomised. This trial was performed in the Netherlands, which is a country with, on average, low antibiotic use and a short duration of hospital stay. As quality of life among sepsis survivors was not measured during the SAPS, this was derived from a Dutch follow up study. Outcome measures were (1) incremental direct hospital cost and (2) incremental cost per quality-adjusted life year (QALY) gained from a healthcare perspective over a one-year time horizon. Uncertainty in outcomes was assessed with bootstrapping. RESULTS: Mean in-hospital costs were ?46,081/patient in the PCT group compared with ?46,146/patient with standard of care (i.e. - ?65 (95% CI - ?6314 to ?6107); - 0.1%). The duration of the first course of antibiotic treatment was lower in the PCT group with 6.9 vs. 8.2 days (i.e. - 1.2 days (95% CI - 1.9 to - 0.4), - 14.8%). This was accompanied by lower in-hospital mortality of 21.8% vs. 29.8% (absolute decrease 7.9% (95% CI - 13.9% to - 1.8%), relative decrease 26.6%), resulting in an increase in mean QALYs/patient from 0.47 to 0.52 (i.e. + 0.05 (95% CI 0.00 to 0.10); + 10.1%). However, owing to high costs among sepsis survivors, healthcare costs over a one-year time horizon were ?73,665/patient in the PCT group compared with ?70,961/patient with standard of care (i.e. + ?2704 (95% CI - ?4495 to ?10,005), + 3.8%), resulting in an incremental cost-effectiveness ratio of ?57,402/QALY gained. Within this time frame, the probability of PCT guidance being cost-effective was 64% at a willingness-to-pay threshold of ?80,000/QALY. CONCLUSIONS: Although the impact of PCT guidance on total healthcare-related costs during the initial hospitalisation episode is likely negligible, the lower in-hospital mortality may lead to a non significant increase in costs over a one-year time horizon. However, since uncertainty remains, it is recommended to investigate the long-term cost effectiveness of PCT guidance, from a societal perspective, in different countries and settings. PMID- 30424797 TI - Body image dissatisfaction in patients with inflammatory bowel disease: a systematic review protocol. AB - BACKGROUND: Inflammatory bowel disease (IBD) is a debilitating chronic disease characterised by inflammation and ulceration of the gastrointestinal tract. It is associated with a range of debilitating symptoms and reduced quality of life. People living with IBD may also be at risk of body image dissatisfaction (BID). BID is a distorted and negative view of the physical self, which in turn can adversely affect mental health and quality of life. To date, there have been no systematic reviews of the evidence on BID in IBD patients. Therefore, the aim of this systematic review is to clarify the evidence base on BID in *IBD patients including (i) the tools used to measure BID, (ii) the prevalence and severity of BID, (iii) the risk factors associated with BID and (iv) the relationship between BID and quality of life. METHODS: Bibliographic databases (EMBASE, MEDLINE, PsycINFO, Cochrane CENTRAL) will be searched using a sensitive search strategy aiming to identify any quantitative study reporting on body image in the context of IBD. This will be supplemented by searches of ongoing trials registers and checking of reference lists. Studies will be assessed for eligibility using predetermined selection criteria for each question. Data will be extracted using a predefined data extraction form, and risk of bias (quality) of included studies will be assessed based on checklists appropriate to the study designs identified. Key methodological steps will be undertaken in duplicate to minimise bias and error. Synthesis will be undertaken separately for the different systematic review sub-questions. Given the anticipated heterogeneity of evidence on each question, it is likely that synthesis will be mostly narrative. DISCUSSION: To the best of our knowledge, this will be the first systematic review to collate the existing evidence on BID in IBD patients. Understanding the impact of BID, its relationship with quality of life, and which patients may be at greater risk, may ultimately lead to the development of interventions to prevent or treat BID and to better patient care. Any gaps in the identified evidence will help to inform the research agenda in this area. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: (CRD42018060999). PMID- 30424798 TI - A brief comment on the predictive value of myeloperoxidase-conjugated DNA level in patients with septic shock. PMID- 30424801 TI - Impact of season on the association between muscle strength/volume and physical activity among community-dwelling elderly people living in snowy-cold regions. AB - BACKGROUND: Although the benefits of physical activity are well-known, levels of physical inactivity are increasing in many countries. Physical activity, particularly for preventive care of the elderly, must be encouraged. The level of physical activity undertaken by people is influenced by season; however, little is known about seasonal fluctuations of physical activity and its relation to muscle strength/mass. Consequently, we clarified the association between physical activity levels and muscle strength/skeletal muscle mass during non-snowy and snowy seasons in northern Japan. METHODS: Participants were community-dwelling elderly people aged 65 years or older living in Tobetsu, northern Japan. A 30-s chair-stand test (CS-30) and body composition measurements using bioelectrical impedance analysis were conducted prior to physical activity measurement using a three-dimensional acceleration sensor in both non-snowy and snowy seasons. Daily steps for the non-snowy and snowy seasons were compared using Welch's t test. The association between the CS-30/skeletal muscle index and daily steps in both seasons was estimated by fitting multiple linear regression models, with age and sex as covariates. RESULTS: Average daily step counts were significantly lower during the snowy season, compared to the non-snowy season (P < .01). The CS-30 in the snowy season alone was significantly associated with daily step counts. Multiple linear regression analyses results revealed that, for the same muscle strength in both seasons, the daily step counts during the snowy season were fewer than those during the non-snowy season. CONCLUSIONS: The muscle strength required to perform adequate physical activity depended on season. This study obtained basic knowledge to ensure health promotion for elderly people living in snowy-cold regions. PMID- 30424800 TI - Healthcare provider knowledge, attitudes, beliefs, and practices surrounding the prescription of opioids for chronic non-cancer pain in North America: protocol for a mixed-method systematic review. AB - BACKGROUND: Evidence from diverse areas of medicine (e.g., cardiovascular disease, diabetes) indicates that healthcare providers (HCPs) often do not adhere to clinical practice guidelines (CPGs) despite a clear indication to implement recommendations-a phenomenon commonly termed clinical inertia. There are a variety of reasons for clinical inertia, but HCP-related factors (e.g., knowledge, motivation, agreement with guidelines) are the most salient and amenable to intervention aimed to improve adherence. CPGs have been developed to support the safe and effective prescription of opioid medication for the management of chronic non-cancer pain. The extent of physician uptake and adherence to such guidelines is not yet well understood. The purpose of this review is to synthesize the published evidence about knowledge, attitudes, beliefs, and practices that HCPs hold regarding the prescription of opioids for chronic non-cancer pain. METHODS: An experienced information specialist will perform searches of CINAHL, Embase, MEDLINE, and PsycINFO bibliographic databases. The Cochrane library, PROSPERO, and the Joanna Briggs Institute will be searched for systematic reviews. Searches will be performed from inception to the present. Quantitative and qualitative study designs that report on HCP knowledge, attitudes, beliefs, or practices in North America will be eligible for inclusion. Studies reporting on interventions to improve HCP adherence to opioid prescribing CPGs will also be eligible for inclusion. Two trained graduate-level research assistants will independently screen articles for inclusion, perform data extraction, and perform risk of bias and quality assessment using recommended tools. Confidence in qualitative evidence will be evaluated using the Grades of Recommendation, Assessment, Development, and Evaluation-Confidence in the Evidence from Qualitative Reviews (GRADE-CERQual) approach. Confidence in quantitative evidence will be assessed using the GRADE approach. DISCUSSION: The ultimate goal of this work is to support interventions aiming to optimize opioid prescribing practices in order to prevent opioid-related morbidity and mortality without restricting a HCP's ability to select the most appropriate treatment for an individual patient. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018091640 . PMID- 30424802 TI - Protocol for a systematic review of venous coupler devices versus hand-sewn anastomosis for microsurgical free flap reconstruction. AB - BACKGROUND: A patent microvascular anastomosis is of paramount importance in free tissue transfer. Anastomotic coupler devices provide an alternative to technically demanding hand-sewn venous anastomosis. Various advantages of these devices have been discussed but previous systematic reviews had methodological flaws or did not perform a meta-analysis. This review aims to evaluate the quality of the evidence and quantify the efficacy and safety of venous couplers compared to hand-sewn anastomosis. METHODS: A PRISMA-compliant systematic review and meta-analysis will be performed. A comprehensive search strategy has been developed and will be applied to the databases MEDLINE and Embase from inception to October 2018. All clinical studies using anastomotic coupler devices for venous anastomoses in free tissue transfer will be eligible for inclusion. Screening of studies and data extraction will be performed independently by two authors. Our primary outcome is anastomotic venous thrombosis. Secondary outcomes will include time to complete the venous anastomosis, tearing of veins, anastomotic leakage, flap loss/failure and fiscal outcomes. The risk of bias for included studies will be assessed by using the ROBINS-I tool, and recommendations based on the evidence will be made using the GRADE approach. Descriptive statistical analyses will be used and if two or more studies report the same outcome, data will be pooled for comparative analysis. A direct comparison meta analysis will be performed if possible. DISCUSSION: There has been no comparison of coupled and hand-sewn venous anastomoses using a robust and validated methodology preceded by a protocol and performing meta-analysis. Included studies are expected to be mainly observational and prone to bias; however, there is value in summarising the evidence, assessing its risk of bias and performing meta analysis to guide clinicians. By using a broad approach including all types of flaps, we foresee inherent differences regarding the unit of analysis and different anatomic sites. This will limit the validity of our conclusions but is unavoidable. We will seek unpublished data from authors and perform subgroup analysis where appropriate. Limitations and areas of uncertainty will be discussed to guide future research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018110111. PMID- 30424799 TI - Whole-genome epidemiology, characterisation, and phylogenetic reconstruction of Staphylococcus aureus strains in a paediatric hospital. AB - BACKGROUND: Staphylococcus aureus is an opportunistic pathogen and a leading cause of nosocomial infections. It can acquire resistance to all the antibiotics that entered the clinics to date, and the World Health Organization defined it as a high-priority pathogen for research and development of new antibiotics. A deeper understanding of the genetic variability of S. aureus in clinical settings would lead to a better comprehension of its pathogenic potential and improved strategies to contrast its virulence and resistance. However, the number of comprehensive studies addressing clinical cohorts of S. aureus infections by simultaneously looking at the epidemiology, phylogenetic reconstruction, genomic characterisation, and transmission pathways of infective clones is currently low, thus limiting global surveillance and epidemiological monitoring. METHODS: We applied whole-genome shotgun sequencing (WGS) to 184 S. aureus isolates from 135 patients treated in different operative units of an Italian paediatric hospital over a timespan of 3 years, including both methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) from different infection types. We typed known and unknown clones from their genomes by multilocus sequence typing (MLST), Staphylococcal Cassette Chromosome mec (SCCmec), Staphylococcal protein A gene (spa), and Panton-Valentine Leukocidin (PVL), and we inferred their whole genome phylogeny. We explored the prevalence of virulence and antibiotic resistance genes in our cohort, and the conservation of genes encoding vaccine candidates. We also performed a timed phylogenetic investigation for a potential outbreak of a newly emerging nosocomial clone. RESULTS: The phylogeny of the 135 single-patient S. aureus isolates showed a high level of diversity, including 80 different lineages, and co-presence of local, global, livestock-associated, and hypervirulent clones. Five of these clones do not have representative genomes in public databases. Variability in the epidemiology is mirrored by variability in the SCCmec cassettes, with some novel variants of the type IV cassette carrying extra antibiotic resistances. Virulence and resistance genes were unevenly distributed across different clones and infection types, with highly resistant and lowly virulent clones showing strong association with chronic diseases, and highly virulent strains only reported in acute infections. Antigens included in vaccine formulations undergoing clinical trials were conserved at different levels in our cohort, with only a few highly prevalent genes fully conserved, potentially explaining the difficulty of developing a vaccine against S. aureus. We also found a recently diverged ST1-SCCmecIV-t127 PVL- clone suspected to be hospital-specific, but time-resolved integrative phylogenetic analysis refuted this hypothesis and suggested that this quickly emerging lineage was acquired independently by patients. CONCLUSIONS: Whole genome sequencing allowed us to study the epidemiology and genomic repertoire of S. aureus in a clinical setting and provided evidence of its often underestimated complexity. Some virulence factors and clones are specific of disease types, but the variability and dispensability of many antigens considered for vaccine development together with the quickly changing epidemiology of S. aureus makes it very challenging to develop full-coverage therapies and vaccines. Expanding WGS-based surveillance of S. aureus to many more hospitals would allow the identification of specific strains representing the main burden of infection and therefore reassessing the efforts for the discovery of new treatments and clinical practices. PMID- 30424803 TI - Closing the gaps in opioid use disorder research, policy and practice: conference proceedings. AB - Drug overdose deaths involving opioids have surged in recent years and the economic cost of the opioid epidemic is estimated to be over $500 billion annually. In the midst of calls for declaring a national emergency, health policy decision makers are considering the best ways to allocate resources to curb the epidemic. On June 9, 2017, 116 invited health researchers, clinicians, policymakers, health system leaders, and other stakeholders met at the University of Pennsylvania to discuss approaches to address the gaps in evidence-based substance use disorder policy and practice, with an emphasis on the opioid epidemic. The conference was sponsored by the Center for Health Economics of Treatment Interventions for Substance Use Disorder, HCV, and HIV (CHERISH), a NIDA-funded National Center of Excellence, and hosted by the Leonard Davis Institute of Health Economics of the University of Pennsylvania. The conference aims were to: (1) foster new relationships between researchers and policymakers through a collaborative work process and (2) generate evidence-based policy recommendations to address the opioid epidemic. The conference concluded with an interactive work session during which attendees self-identified as researchers or policymakers and were divided equally among 13 tables. These groups met to develop and present policy recommendations based on an opioid use disorder case study. Thirteen policy recommendations emerged across four themes: (1) quality of treatment, (2) continuity of care, (3) opioid prescribing and pain management, and (4) consumer engagement. This conference serves as a proposed model to develop equitable, working relationships among researchers, clinicians, and policymakers. PMID- 30424804 TI - Targeting myeloid-inflamed tumor with anti-CSF-1R antibody expands CD137+ effector T-cells in the murine model of pancreatic cancer. AB - BACKGROUND: The pancreatic cancer vaccine, GVAX, induces novel lymphoid aggregates in the otherwise immune quiescent pancreatic ductal adenocarcinoma (PDAC). GVAX also upregulates the PD-1/PD-L1 pathway, and a pre-clinical model demonstrated the anti-tumor effects of combination GVAX and anti-PD-1 antibody therapy (GVAX/alphaPD-1). Resistance to GVAX was associated with an immune suppressive myeloid cell infiltration, which may limit further therapeutic gains of GVAX/alphaPD-1 therapy. The expression of CSF-1R, a receptor important for myeloid cell migration, differentiation and survival, and the effect of its therapeutic blockade in the context of GVAX in PDAC has not been investigated. METHODS: Lymphoid aggregates appreciated in 24 surgically resected PDAC from patients who received one dose of neoadjuvant GVAX were analyzed with multiplex immunohistochemistry. Flow cytometry analysis of tumor infiltrating T-cells in a murine model of PDAC was performed to investigate the therapeutic effects and mechanism of anti-CSF-1R/anti-PD-1/GVAX combination immunotherapy. RESULTS: High CSF-1R expression in resected PDAC from patients who received neoadjuvant GVAX was associated with a higher myeloid to lymphoid cell ratio (p < 0.05), which has been associated with poorer survival. This higher CSF-1R expression was associated with a higher intra-tumoral infiltration of immature dendritic cells (p < 0.05), but not mature dendritic cells (p = 0.132). In the pre-clinical murine model, administering anti-CSF-1R antibody prior to and after GVAX/alphaPD 1 ("pre/post-alphaCSF-1R + alphaPD-1 + GVAX") enhanced the survival rate compared to GVAX/alphaPD-1 dual therapy (p = 0.005), but administering anti-CSF-1R only before GVAX/alphaPD-1 did not (p = 0.41). The "pre/post-alphaCSF-1R + alphaPD-1 + GVAX" group also had higher intra-tumoral infiltration of PD-1 + CD8+ and PD-1 + CD4+ T-cells compared to alphaPD-1/GVAX (p < 0.001). Furthermore, this regimen increased the intra-tumoral infiltration of PD-1 + CD137 + CD8+, PD-1 + CD137 + CD4+ and PD-1 + OX40 + CD4+ T-cells (p < 0.001). These PD-1 + CD137 + CD8+ T cells expressed high levels of interferon-gamma (median 80-90%) in response to stimulation with CD3/CD28 activation beads, and this expression was higher than that of PD-1 + CD137-CD8+ T-cells (p < 0.001). CONCLUSIONS: The conversion of exhausted PD-1+ T-cells to CD137+ activated effector T-cells may contribute to the anti-tumor effects of the anti-CSF-1R/anti-PD-1/GVAX combination therapy. Anti-CSF-1R antibody with anti-PD-1 antibody and GVAX have the potential be an effective therapeutic strategy for treatment of PDAC. PMID- 30424805 TI - Perceptions of students in health and molecular life sciences regarding pharmacogenomics and personalized medicine. AB - BACKGROUND: Increasing evidence is demonstrating that a patient's unique genetic profile can be used to detect the disease's onset, prevent its progression, and optimize its treatment. This led to the increased global efforts to implement personalized medicine (PM) and pharmacogenomics (PG) in clinical practice. Here we investigated the perceptions of students from different universities in Bosnia and Herzegovina (BH) towards PG/PM as well as related ethical, legal, and social implications (ELSI). This descriptive, cross-sectional study is based on the survey of 559 students from the Faculties of Medicine, Pharmacy, Health Studies, Genetics, and Bioengineering and other study programs. RESULTS: Our results showed that 50% of students heard about personal genome testing companies and 69% consider having a genetic test done. A majority of students (57%) agreed that PM represents a promising healthcare model, and 40% of students agreed that their study program is well designed for understanding PG/PM. This latter opinion seems to be particularly influenced by the field of study (7.23, CI 1.99-26.2, p = 0.003). Students with this opinion are also more willing to continue their postgraduate education in the PM (OR = 4.68, CI 2.59-8.47, p < 0.001). Furthermore, 45% of students are aware of different ethical aspects of genetic testing, with most of them (46%) being concerned about the patient's privacy. CONCLUSIONS: Our results indicate a positive attitude of biomedical students in Bosnia and Herzegovina towards genetic testing and personalized medicine. Importantly, our results emphasize the key importance of pharmacogenomic education for more efficient translation of precision medicine into clinical practice. PMID- 30424806 TI - Estrogen-mediated gut microbiome alterations influence sexual dimorphism in metabolic syndrome in mice. AB - BACKGROUND: Understanding the mechanism of the sexual dimorphism in susceptibility to obesity and metabolic syndrome (MS) is important for the development of effective interventions for MS. RESULTS: Here we show that gut microbiome mediates the preventive effect of estrogen (17beta-estradiol) on metabolic endotoxemia (ME) and low-grade chronic inflammation (LGCI), the underlying causes of MS and chronic diseases. The characteristic profiles of gut microbiome observed in female and 17beta-estradiol-treated male and ovariectomized mice, such as decreased Proteobacteria and lipopolysaccharide biosynthesis, were associated with a lower susceptibility to ME, LGCI, and MS in these animals. Interestingly, fecal microbiota-transplant from male mice transferred the MS phenotype to female mice, while antibiotic treatment eliminated the sexual dimorphism in MS, suggesting a causative role of the gut microbiome in this condition. Moreover, estrogenic compounds such as isoflavones exerted microbiome-modulating effects similar to those of 17beta-estradiol and reversed symptoms of MS in the male mice. Finally, both expression and activity of intestinal alkaline phosphatase (IAP), a gut microbiota-modifying non classical anti-microbial peptide, were upregulated by 17beta-estradiol and isoflavones, whereas inhibition of IAP induced ME and LGCI in female mice, indicating a critical role of IAP in mediating the effects of estrogen on these parameters. CONCLUSIONS: In summary, we have identified a previously uncharacterized microbiome-based mechanism that sheds light upon sexual dimorphism in the incidence of MS and that suggests novel therapeutic targets and strategies for the management of obesity and MS in males and postmenopausal women. PMID- 30424807 TI - Small ruminant lentivirus infection influences expression of acute phase proteins and cathelicidin genes in milk somatic cells and peripheral blood leukocytes of dairy goats. AB - The aim of the study was to analyze acute phase protein and cathelicidin gene responses to small ruminant lentivirus (SRLV) infection in goats. In uninfected goats, we found higher Cp and lower Fbgamma mRNA levels in blood leucocytes (BL) than in milk somatic cells (MSC), as well as lower SAA, Hp, and CRP and higher Cp and AGP concentrations in blood serum than in milk. In SRLV-infected goats, we found higher Fbgamma and MAP28 and lower Cp expression in MSC than in BL, and higher SAA, Hp, Fb, and MAP28 and lower AGP concentrations in milk than in blood serum. Higher SAA and Hp expressions in BL and Hp expression in MSC were found in SRLV-infected goats. In SRLV-infected goats, we observed a higher concentration of SAA in blood serum, while in milk, lower SAA, Cp, and MAP28 and higher MAP34 concentrations were observed. The expression profiles of the studied genes differed between BL/serum and MSC/milk. The elevated SAA concentration in blood serum was accompanied by a decreased concentration of SAA and Cp in the milk of infected goats. No differences in the expression of the other studied genes may mean that the SRLV has the ability to evade the immune system, continuing to replicate. The elevated concentration of SAA in blood serum may promote viral multiplication. This higher concentration of SAA in blood serum and simultaneous reduced concentration of SAA and Cp in milk may be additive indicators of this infection. PMID- 30424808 TI - Barriers to access and utilization of emergency obstetric care at health facilities in sub-Saharan Africa: a systematic review of literature. AB - BACKGROUND: Nearly 15% of pregnancies end in fatal perinatal obstetric complications including bleeding, infections, hypertension, obstructed labour and complications of abortion. Globally, an estimated 10.7 million women have died due to obstetric complications in the last two decades, and two thirds of these deaths occurred in sub-Saharan Africa. Though the majority of maternal mortalities can be prevented, different factors can hinder women's access to emergency obstetric services. Therefore, this review is aimed at synthesizing current evidence on barriers to access and utilization of emergency obstetric care in sub-Saharan Africa. METHODS: Articles were searched from MEDLINE, CINAHL, EMBASE, and Maternity and Infant Care databases using predefined search terms and strategies. Articles published in English, between 2010 and 2017, were included. Two reviewers (AG and AM) independently screened the articles, and data extraction was conducted using the Joanna Briggs Institute data extraction format. The quality of the included studies was assessed using the Mixed Methods Appraisal Tool. The identified barriers were qualitatively synthesized and reported using the Three Delays analytical framework. The PRISMA checklist was employed to present the findings. RESULT: The search of the selected databases returned 3534 articles. After duplicates were removed and further screening undertaken, 37 studies fulfilled the inclusion criteria. The identified key barriers related to the first delay included younger age, illiteracy, lower income, unemployment, poor health service utilization, a lower level of assertiveness among women, poor knowledge about obstetric danger signs, and cultural beliefs. Poorly designed roads, lack of vehicles, transportation costs, and distance from facilities led to the second delay. Barriers related to the third delay included lack of emergency obstetric care services and supplies, shortage of trained staff, poor management of emergency obstetric care provision, cost of services, long waiting times, poor referral practices, and poor coordination among staff. CONCLUSIONS: A number of factors were found to hamper access to and utilization of emergency obstetric care among women in sub-Saharan Africa. These barriers are inter-dependent and occurred at multiple levels either at home, on the way to health facilities, or at the facilities. Therefore, country-specific holistic strategies including improvements to healthcare systems and the socio-economic status of women need to be strengthened. Further research should focus on the assessment of the third delay, as little is known about facility-readiness. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017074102. PMID- 30424809 TI - Systematic review of the surgical management of rotator cuff repair with an augmentative patch: a feasibility study protocol. AB - BACKGROUND: Shoulder pain is a common problem in the general population and is responsible for prolonged periods of disability, loss of productivity, absence from work and inability to carry out household activities. Rotator cuff problems account for up to 70% of shoulder pain problems and are the third most prevalent musculoskeletal disorder after those occurring in the lower back and neck. Rotator cuff surgery has high failure rates (25-50% within 12 months), and as a result, there is a pressing need to improve the outcome of rotator cuff surgery. Patch augmented surgery for rotator cuff repairs has recently been developed and is increasingly being used within the UK National Health Service. Patch augmented surgery could lead to a dramatic improvement in patient and surgical outcomes, but its clinical and cost effectiveness needs rigorous evaluation. The existing evidence on the use of patches may be at risk of bias as currently only a small number of single-centre comparative studies appear to have been carried out. Additionally, it is unclear for which patches a clinical study (comparative and non-comparative) has been conducted. This paper outlines the protocol for a systematic review intended to summarise the best available clinical evidence and will indicate what further research is required. METHODS: Electronic databases (Medline, Embase and Cochrane) will be systematically searched between April 2006 and the present day for relevant publications using a specified search strategy, which can be adapted for the use in multiple electronic databases, and inclusion criteria. Screening of both titles and abstracts will be done by two independent reviewers with any discrepancies resolved by a third independent reviewer. Data extraction will include information regarding the type of participants, type of intervention and outcomes including but not limited to shoulder-specific function and pain scores, patch-related adverse events and type of study. The results will be summarised in a narrative review where qualitative analysis is not possible. DISCUSSION: This review aims to collate the current evidence base regarding the use of patches to augment rotator cuff repair. The results of this review will help to develop, using consensus methods, the design of a definitive randomised trial assessing the clinical and cost-effectiveness of a patch to augment surgical repair of the rotator cuff that is both acceptable to stakeholders and is feasible. SYSTEMATIC REVIEW REGISTRATION: CRD42017057908. PMID- 30424810 TI - Transportable system enabling multiple irradiation studies under simultaneous hypoxia in vitro. AB - BACKGROUND: Cells in solid tumours are variably hypoxic and hence resistant to radiotherapy - the essential role of oxygen in the efficiency of irradiation has been acknowledged for decades. However, the currently available methods for performing hypoxic experiments in vitro have several limitations, such as a limited amount of parallel experiments, incapability of keeping stable growth conditions and dependence on CO2 incubator or a hypoxia workstation. The purpose of this study was to evaluate the usability of a novel portable system (Minihypoxy) in performing in vitro irradiation studies under hypoxia, and present supporting biological data. MATERIALS AND METHODS: This study was conducted on cancer cell cultures in vitro. The cells were cultured in normoxic (~ 21% O2) or in hypoxic (1% O2) conditions either in conventional hypoxia workstation or in the Minihypoxy system and irradiated at dose rate 1.28 Gy/min +/- 2.9%. The control samples were sham irradiated. To study the effects of hypoxia and irradiation on cell viability and DNA damage, western blotting, immunostainings and clonogenic assay were used. The oxygen level, pH, evaporation rate and osmolarity of the culturing media on cell cultures in different conditions were followed. RESULTS: The oxygen concentration in interest (5, 1 or 0% O2) was maintained inside the individual culturing chambers of the Minihypoxy system also during the irradiation. The radiosensitivity of the cells cultured in Minihypoxy chambers was declined measured as lower phosphorylation rate of H2A.X and increased clonogenic capacity compared to controls (OER~ 3). CONCLUSIONS: The Minihypoxy system allows continuous control of hypoxic environment in multiple wells and is transportable. Furthermore, the system maintains the low oxygen environment inside the individual culturing chambers during the transportation and irradiation in experiments which are typically conducted in separate facilities. PMID- 30424811 TI - The impact of thigh and shank marker quantity on lower extremity kinematics using a constrained model. AB - BACKGROUND: Musculoskeletal models are commonly used to quantify joint motions and loads during human motion. Constraining joint kinematics simplifies these models but the implications of the placement and quantity of markers used during data acquisition remains unclear. The purpose of this study was to establish the effects of marker placement and quantity on lower extremity kinematics calculated using a constrained-kinematic model. We hypothesized that a constrained-kinematic model would produce lower-extremity kinematics errors that correlated with the number of tracking markers removed from the thigh and shank. METHODS: Healthy young adults (N = 10) walked on a treadmill at slow, moderate, and fast speeds while skin-mounted markers were tracked using motion capture. Lower extremity kinematics were calculated for 256 combinations of leg and shank markers to establish the implications of marker placement and quantity on joint kinematics. Marker combinations that yielded differences greater than 5 degrees were tested with paired t-tests and the relationship between number of markers and kinematic errors were modeled with polynomials to determine goodness of fit (R2). RESULTS: Sagittal joint and hip coronal kinematics errors were smaller than documented errors caused by soft-tissue artifact, which tends to be approximately 5 degrees, when excluding thigh and shank markers. Joint angle and center kinematic errors negatively correlated with the number of markers included in the analyses (R2 > 0.97) and typically showed the greatest error reductions when two markers were included on the thigh or shank segments. Further, we demonstrated that a simplified marker set that included markers on the pelvis, lateral knee condyle, lateral malleolus, and shoes produced kinematics that strongly agreed with the traditional marker set that included 3 tracking markers for each segment. CONCLUSION: Constrained-kinematic models are resilient to marker placement and quantity, which has implications on study design and post-processing workflows. PMID- 30424812 TI - A systematic review and synthesis of theories of change of school-based interventions integrating health and academic education as a novel means of preventing violence and substance use among students. AB - BACKGROUND: Schools can play an important role in promoting health. However, many education policies and institutions are increasingly emphasising academic attainment targets, which appear to be diminishing the time available for health education lessons. Interventions that integrate both health and academic learning may present an ideal solution, simultaneously addressing health education and academic development. The theories of change underlying these interventions are therefore of interest, but are poorly studied. METHODS: A systematic review of evaluations of interventions that integrate academic and health education for reduced substance use and/or violence was carried out. As part of this, reports describing theory were assessed for quality and data extracted. Theoretical data were synthesised within and across individual interventions using reciprocal translation and meta-ethnographic line of argument synthesis to produce an overall theory of change for interventions that integrate health and academic education to prevent substance use and violence. RESULTS: Forty-eight reports provided theoretical descriptions of 18 interventions. An overarching theory that emerged was that eroding 'boundaries' at multiple and mutually reinforcing levels by integrating academic and health education, by transforming relationships between teachers and students, by generalising learning from classrooms to the wider school environment and by ensuring consistent messages from schools and families-is intended to lead to the development of a community of engaged students oriented towards pro-social behaviour and away from substance use, violence and other risk behaviours. CONCLUSIONS: Eroding 'boundaries' between health and academic education, teachers and students, classrooms and the wider school and schools and families were seen to be the most critical to establishing new frameworks of family, classroom or school organisation that are conducive to promoting both academic and social-emotional outcomes. Whether such interventions are feasible to implement and effective in reducing risk behaviours will be examined in other reports arising from the review. PMID- 30424813 TI - One-year mortality among hospital survivors of cholinesterase inhibitor poisoning based on Taiwan National Health Insurance Research Database from 2003 to 2012. AB - BACKGROUND: Acute cholinesterase inhibitor (CI) poisoning, including organophosphate and carbamate poisoning, is a crucial problem in developing countries. Acute intoxication results in a cholinergic crisis, neurological symptoms, or respiratory failure. However, the short-term and long-term outcomes of CI poisoning are seldom reported. METHODS: Data from the National Health Insurance Research Database were used to investigate the outcomes after organophosphate and carbamate poisoning. Patients who were hospitalized for a first episode of acute CI poisoning between 2003 and 2012 were enrolled in this study. Outcomes of acute CI poisoning with or without mechanical ventilation were analyzed. RESULTS: Among 6832 patients with CI poisoning, 2010 developed respiratory failure requiring mechanical ventilation, and the other 4822 patients did not require mechanical ventilation. The hospital mortality rate was higher in patients requiring mechanical ventilation than in those not requiring mechanical ventilation (33.3% versus 4.7%, p < 0.0001). In patients with respiratory failure with mechanical ventilation, the patients without pneumonia had higher mortality rate than those with pneumonia. (36.0% versus 19.9%, p < 0.0001). The 1-year mortality rate the survivors of CI poisoning was 6.7%. Among 5932 survivors after cholinesterase inhibitor poisoning, the one-year mortality rate in patients with mechanical ventilation during hospitalization was higher than those without mechanical ventilation during hospitalization (11.4% versus 5.4% respectively, p < 0.0001). CONCLUSIONS: The one-year mortality rate of survivors after CI poisoning was 6.7%. Meanwhile, age, pneumonia, and mechanical ventilation may be predictive factors for the one-year mortality among the survivors after CI poisoning. Diabetes mellitus was not a risk factor for hospital mortality in patients with CI poisoning. PMID- 30424814 TI - Anaphylaxis in atypical cold urticaria: case report and review of literature. AB - BACKGROUND: Cold-induced urticaria is a kind of physical urticaria characterized by the appearance of wheals after exposure to cold. The atypical form is a rare sub-type characterized by appearance of hives even in areas not directly exposed to the cold and by a negative cold stimulation test. Its diagnosis is often challenging because of the lack of specific tests and it is usually based on the patient's clinical history. Hypotension due to generalized exposure to the cold is described both in the typical and the atypical forms. CASE PRESENTATION: We describe a 9-year-old boy who, at the beginning of the summer after the first swim in the sea, developed generalized urticaria, dyspnea, conjunctival hyperemia, blurred vision and loss of strength. The child was treated with intramuscular steroid and intravenous antihistamine, and the symptoms quickly resolved. Insect bite, contact with fish and drug ingestion were denied, and no unusual food had been eaten before the swim. A tentative diagnosis was made of either aquagenic urticaria or cold urticaria, but the specific tests were negative. Although the cause was unknown, prophylactic treatment with antihistamines was prescribed but in spite of this, wheals developed all over the body, after every swim in the sea. The child then came to our attention and relying on clinical history a diagnosis of atypical cold urticaria was made: development of hives even in areas not directly exposed to cold and a negative response to the cold stimulation test, are the characteristic features of this rare form of cold urticaria. CONCLUSION: Atypical cold urticaria should be suspected in all cases of anaphylaxis related to cold exposure (i.e. contact with water) with a negative cold stimulation test. PMID- 30424815 TI - A CpG oligodeoxynucleotide enhances the immune response to rabies vaccination in mice. AB - BACKGROUND: Rabies is a fatal disease that is preventable when post exposure prophylaxis (PEP) is administered in a timely fashion. CpG oligodeoxynucleotides (ODNs) can trigger cells that express Toll-like receptor 9, and their immunopotentiation activity in an inactivated aluminum-adjuvanted rabies vaccine for dogs has been identified using mouse and dog models. METHODS: A human diploid cell rabies vaccine (HDCV) of humans and a CpG ODNs with cross-immunostimulatory activity in humans and mice were used to evaluate the immunogenicity and protective efficacy of CpG ODN in a mouse model that simulates human PEP. RESULTS: HDCV combined with CpG ODN (HDCV-CpG) stimulated mice to produce rabies virus-specific neutralizing antibody (RVNA) earlier and increased the seroconversion rate. Compared with HDCV alone, either HDCV-1.25 MUg CpG or HDCV-5 MUg CpG increased the levels of RVNA. In particular, 5 MUg CpG ODN per mouse significantly boosted the levels of RVNA compared with HDCV alone. IFN-gamma producing splenocytes generated in the HDCV-5 MUg CpG group were significantly increased compared to the group treated with HDCV alone. When the immunization regimen was reduced to three injections or the dose was reduced to half of the recommended HDCV combined with CpG ODN, the RVNA titers were still higher than those induced by HDCV alone. After viral challenge, 50% of mice immunized with a half-dose HDCV-CpG survived, while the survival rate of mice immunized with HDCV alone was 30%. CONCLUSIONS: The immunopotentiation activity of CpG ODNs for a commercially available human rabies vaccine was first evaluated in a mouse model on the basis of the Essen regimen. Our results suggest that the CpG ODN used in this study is a potential adjuvant to rabies vaccines for human use. PMID- 30424816 TI - CircRNA circRNA_102171 promotes papillary thyroid cancer progression through modulating CTNNBIP1-dependent activation of beta-catenin pathway. AB - BACKGROUND: As a type of recently discovered noncoding RNA, circular RNAs (circRNAs) exert pivot biological functions in diverse cancers. However, the role of circRNA_102171 in papillary thyroid cancer (PTC) has not been investigated. Our study was focused on the functional investigation toward circRNA_102171 in PTC progression. And we also aimed to reveal its potential molecular mechanism. METHODS: The expression pattern of circRNA_102171 was determined using quantitative polymerase chain reaction (qPCR) in PTC samples and cell lines. Cell proliferation was examined utilizing CCK8, colony formation and EdU incorporation assays. Apoptosis was analyzed by Annexin V/PI staining and FACS detection. Cell migration and invasion was measured using Transwell assay. Tumor growth in vivo was determined through a xenograft assay. RNA-pulldown, RNA-IP (RIP) and RNA-EMSA were used to analyze the interaction between circRNA_102171 and CTNNBIP1. RESULTS: CircRNA_102171 expression was upregulated in tumor tissues and cell lines. CircRNA_102171 silencing suppressed PTC cell proliferation, migration and invasion while promoting apoptosis. CircRNA_102171 knockdown inhibited PTC growth in vivo. CircRNA_102171 interacted with CTNNBIP1 to block its interaction with the beta-catenin/TCF3/TCF4/LEF1 complex, leading to activation of Wnt/beta catenin pathway. CONCLUSIONS: CircRNA_102171 overexpression promotes PTC progression through activating Wnt/beta-catenin pathway in a CTNNBIP1-dependent way. PMID- 30424817 TI - The effect of bi-annual community-directed treatment with ivermectin on the incidence of epilepsy in onchocerciasis endemic villages in South Sudan: a study protocol. AB - BACKGROUND: Nodding syndrome (NS) is a devastating epileptic illness of unknown aetiology mainly affecting children 5-15 years of age. Head nodding distinguishes NS from other forms of epilepsy. Other manifestations of the illness include mental and physical growth retardation. Many children die as a result of falling in fires or drowning. Recently, it was shown that NS is only one of the phenotypic presentations of onchocerciasis associated epilepsy (OAE). Despite the strong epidemiological association between epilepsy and onchocerciasis, the causal mechanism is unknown. After implementation of bi-annual community directed treatment with ivermectin (CDTi) and larviciding of rivers in northern Uganda, new cases of NS have ceased, while new cases continue to emerge in South Sudanese onchocerciasis-endemic areas with an interrupted CDTi programme. This study is designed to evaluate the potential effects of bi-annual CDTi on reducing the incidence of NS/OAE in onchocerciasis-endemic areas in South Sudan. METHODS: A pre-intervention door-to-door population-based household survey will be conducted in selected onchocerciasis-endemic villages in Mundri and Maridi Counties, which have a high prevalence of epilepsy. Using a validated questionnaire, the entire village will be screened by community research assistants for suspected epilepsy cases. Suspected cases will be interviewed and examined by a trained clinical officer or medical doctor who will confirm or reject the diagnosis of epilepsy. Bi-annual CDTi will be implemented in the villages and a surveillance system for epilepsy set up. By implementing an epilepsy onchocerciasis awareness campaign we expect to obtain > 90% CDTi coverage of eligible individuals. The door-to-door survey will be repeated two years after the baseline survey. The incidence of NS/OAE will be compared before and after bi-annual CDTi. DISCUSSION: Our study is the first population-based study to evaluate the effect of bi-annual CDTi to reduce the incidence of NS/OAE. If the study demonstrates such a reduction, these findings are expected to motivate communities in onchocerciasis-endemic regions to participate in CDTi, and will encourage policy makers, funders and other stakeholders to increase their efforts to eliminate onchocerciasis. PMID- 30424819 TI - An atypical presentation of an ovarian lymphoma: a case report. AB - BACKGROUND: Ovarian lymphoma has a varied clinical presentation and rarely presents with heavy menstrual bleeding. It may occur de novo or secondary to systemic disease and macroscopically appear as solid ovarian tumors. CASE PRESENTATION: A 32-year-old Tamil woman presented with heavy menstrual bleeding of 4 months' duration. On examination she was anemic with no lymphadenopathy. A large immobile pelvic mass and three firm nodules were found involving her vaginal walls. Ultrasonography suggested a fibroid uterus with two large pedunculated fibroids. Following preoperative optimization an endometrial sampling and biopsy of the nodules were done. Subsequently, histology revealed proliferative phase endometrium. The vaginal nodules showed lymphoid tissue. She presented a week later with an undulating fever and features of acute abdomen with clinical evidence of ascites. During an emergency laparotomy two large solid ovarian masses, gross ascites, pelvic lymph nodes, para-aortic lymph nodes, mesenteric lymph nodes, omental deposits, and a 24-week-size uterus were found. Bilateral oophorectomy was done. Laboratory investigations revealed raised lactate dehydrogenase with normal serum beta-human chorionic gonadotropin, alpha fetoprotein, and cancer antigen-125 levels. Histology of ovarian specimens revealed a diffuse large B cell lymphoma. A bone marrow biopsy revealed more than 80% infiltration with lymphoid cells. Two weeks after the laparotomy a computed tomography of her chest, abdomen, and pelvis revealed a pelvic mass, gross ascites, omental deposits, hepatosplenomegaly, and enlarged lymph nodes above and below her diaphragm. Immunohistochemistry confirmed the diagnosis of B cell lymphoblastic lymphoma. She was classified as stage IV E non-Hodgkin's lymphoma on the Ann Arbor staging system. CONCLUSION: This is an atypical presentation of an ovarian lymphoma. The atypical presentations of ovarian lymphomas can lead to diagnostic dilemmas. PMID- 30424820 TI - Relationship between volume and outcome for congenital diaphragmatic hernia: a systematic review protocol. AB - BACKGROUND: Congenital diaphragmatic hernia is a rare and life-threatening anomaly that occurs during fetal development and results in an incomplete or incorrect formation of the diaphragm. Surgical therapy of the diaphragm should be performed after clinical stabilization of the neonate. Higher hospital or surgeon volume has previously been found to be associated with better clinical outcomes for different especially high-risk, low-volume procedures. Therefore, we aim to examine the relationship between hospital or surgeon volume and outcomes for congenital diaphragmatic hernia. METHODS: This systematic review protocol has been designed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol. We will perform a systematic literature search in MEDLINE, Embase, CINAHL and Biosis Previews without applying any limitations. In addition, we will search for relevant conference abstracts. We will screen titles and abstracts of retrieved studies, obtain potentially relevant full texts, and assess the eligibility of those full texts against our inclusion criteria. We will include comparative studies analyzing the relationship between hospital or surgeon volume and clinical outcomes. We will systematically assess risk of bias of included studies and extract data on the study design, patient characteristics, case-mix adjustments, statistical methods, hospital and surgeon volume, and outcomes into standardized tables. Title and abstract screening, full text screening, critical appraisal, and data extraction of results will be conducted by two reviewers independently. Other data will be extracted by one reviewer and checked for accuracy by a second one. Any disagreements will be resolved by discussion. We will not perform a meta-analysis as we expect included studies to be clinically and methodologically very diverse. We will synthesize findings from primary studies in a structured narrative way and using GRADE. DISCUSSION: Given the lack of a comprehensive summary of findings on the relationship between hospital or surgeon volume and outcomes for congenital diaphragmatic hernia, this systematic review will put things right. Results can be used to inform decision makers or clinicians and to adapt medical care. SYSTEMATIC REVIEW REGISTRATION: PROSPERO ( CRD42018090231 ). PMID- 30424821 TI - Succession and persistence of microbial communities and antimicrobial resistance genes associated with International Space Station environmental surfaces. AB - BACKGROUND: The International Space Station (ISS) is an ideal test bed for studying the effects of microbial persistence and succession on a closed system during long space flight. Culture-based analyses, targeted gene-based amplicon sequencing (bacteriome, mycobiome, and resistome), and shotgun metagenomics approaches have previously been performed on ISS environmental sample sets using whole genome amplification (WGA). However, this is the first study reporting on the metagenomes sampled from ISS environmental surfaces without the use of WGA. Metagenome sequences generated from eight defined ISS environmental locations in three consecutive flights were analyzed to assess the succession and persistence of microbial communities, their antimicrobial resistance (AMR) profiles, and virulence properties. Metagenomic sequences were produced from the samples treated with propidium monoazide (PMA) to measure intact microorganisms. RESULTS: The intact microbial communities detected in Flight 1 and Flight 2 samples were significantly more similar to each other than to Flight 3 samples. Among 318 microbial species detected, 46 species constituting 18 genera were common in all flight samples. Risk group or biosafety level 2 microorganisms that persisted among all three flights were Acinetobacter baumannii, Haemophilus influenzae, Klebsiella pneumoniae, Salmonella enterica, Shigella sonnei, Staphylococcus aureus, Yersinia frederiksenii, and Aspergillus lentulus. Even though Rhodotorula and Pantoea dominated the ISS microbiome, Pantoea exhibited succession and persistence. K. pneumoniae persisted in one location (US Node 1) of all three flights and might have spread to six out of the eight locations sampled on Flight 3. The AMR signatures associated with beta-lactam, cationic antimicrobial peptide, and vancomycin were detected. Prominent virulence factors were cobalt zinc-cadmium resistance and multidrug-resistance efflux pumps. CONCLUSIONS: There was an increase in AMR and virulence gene factors detected over the period sampled, and metagenome sequences of human pathogens persisted over time. Comparative analysis of the microbial compositions of ISS with Earth analogs revealed that the ISS environmental surfaces were different in microbial composition. Metagenomics coupled with PMA treatment would help future space missions to estimate problematic risk group microbial pathogens. Cataloging AMR/virulence characteristics, succession, accumulation, and persistence of microorganisms would facilitate the development of suitable countermeasures to reduce their presence in the closed built environment. PMID- 30424824 TI - Effects of Intraoperative Vagal Nerve Stimulation on the Gastrointestinal Microbiome in a Mouse Model of Amyotrophic Lateral Sclerosis. AB - The gastrointestinal microbiota (GM) plays a fundamental role in health and disease and contributes to the bidirectional signaling between the gastrointestinal system and brain. The direct line of communication between these organ systems is through the vagus nerve. Therefore, vagal nerve stimulation (VNS), a commonly used technique for multiple disorders, has potential to modulate the enteric microbiota, enabling investigation and possibly treatment of numerous neurologic disorders in which the microbiota has been linked with disease. Here we investigate the effect of VNS in a mouse model of amyotrophic lateral sclerosis (ALS). B6SJL-Tg(SOD1*G93A)dl1Gur (SOD1dl) and wildtype mice underwent ventral neck surgeryto access the vagus nerve. During surgery, the experimental group received 1 h of VNS, whereas the sham group underwent 1 h of sham treatment. The third (control) group did not undergo any surgical manipulation. Fecal samples were collected before surgery and at 8 d after the initial collection. Microbial DNA was sequenced to determine the GM profiles at both time points. GM profiles did not differ between genotypes at either the initial or end point. In addition, VNS did not alter GM populations, according to the parameters chosen in this study, indicating that this short intraoperative treatment is safeand has no lasting effects on the GM. Future studies are warranted to determine whether different stimulation parametersor chronic use of VNS affect GM profiles. PMID- 30424823 TI - What influences women's movement and the use of different positions during labour and birth: a systematic review protocol. AB - BACKGROUND: Women want to give birth in a safe and supportive environment where they are free to move and adopt different positions. Moving freely and using different positions in labour results in a range of physical and psychological benefits for women. However, many women report that they are restricted from moving freely during labour and birth and it is important to understand the factors that are influencing this. METHODS: A mixed-methods systematic review will be undertaken. Qualitative, quantitative and mixed-methods primary empirical studies will be identified by systematically searching seven electronic databases using a search strategy that includes medical subject headings (MeSH) and keywords to cover synonyms and related terms. In addition, reference-tracking will be undertaken, and expert researchers will be contacted to locate relevant studies. Two reviewers will be involved in the assessment of the studies against eligibility criteria, formal quality appraisal and data extraction. A results based convergent synthesis will be undertaken, using narrative synthesis if the quantitative data are too heterogeneous for meta-analysis, meta-ethnography for the synthesis of the qualitative data and the production of a line of argument synthesis. Finally, confidence in the findings will be formally assessed and conclusions drawn. DISCUSSION: The findings of this review will allow researchers, practitioners and policy makers to better understand the factors influencing women's movement and the use of different positions during labour and birth. This will inform future research and the development of maternity services designed to implement best-evidence concerning movement and positioning during labour and birth into clinical practice. SYSTEMATIC REVIEW REGISTRATION: In accordance with the PRISMA-P guidelines (Moher et al. Syst Rev 4:1, 2015), the systematic review protocol was registered with the International Prospective Register of Systematic reviews (PROSPERO) on July 17, 2018 (CRD42018103354). PMID- 30424825 TI - How tuberculosis programs can navigate the world of social health insurance. AB -

SUMMARY

Many countries with a high tuberculosis (TB) burden are adopting social health insurance (SHI) schemes. However, the national TB programs (NTPs) of these countries are only just starting to grapple with the effects of SHI on their operations. Here, we review the rationale for analyzing TB programs in light of the changes brought by SHI. We consider the influence of certain purchasing decisions on TB care and prevention, and the opportunities that SHI may present for NTPs to broaden private sector engagement, extract TB data across the health sector, and facilitate quality improvement efforts. We also explore which functions are likely to be performed by SHI systems, which require special attention with the advent of SHI, and the metrics that indicate how much of TB care seeking and treatment can be reached and influenced by SHI. SHI presents certain risks for TB programs, but also opportunities to adapt to a more modern health system and to bring quality TB care and treatment to more people. PMID- 30424826 TI - Differentiation of Various Snake Bile Derived from Different Genus by High Performance Thin-Layer Chromatography Coupled with Quadrupole Time-of-Flight Mass Spectrometry. AB - Background: Snake bile originates from nearly 20 species from three families (Elapidae, Colubridae, and Viperidae). However, the components of various snake bile were not compared with one another. Objecive: The aim of the study was to develop a TLC-MS method for differentiation of various snake bile derived from a different genus. Method: As a type of traditional identification method for Chinese herbs, TLC has considerable advantages as a multicomponent separation system. Results: In this paper, TLC was used to separate the components in snake bile. It was found that the snake bile from Colubridae family and Cobra species is different from the others using TLC. The molecular formulas of the bands were elucidated with TLC coupled with quadrupole-time-of-flight-MS by the TLC-MS interface. Two bands on the plate were identified with the reference substance, and the other three bands were analyzed by the TLC-MS method without the reference substance. The corresponding molecular formulas of these bands were given according to accurate molecular weights. Conclusions: The results from this study indicate that the proposed method is reliable, and it has been successfully applied to the identification of snake bile samples. PMID- 30424822 TI - Effectiveness of the physical activity intervention program in the PREDIMED-Plus study: a randomized controlled trial. AB - BACKGROUND: The development and implementation of effective physical activity (PA) intervention programs is challenging, particularly in older adults. After the first year of the intervention program used in the ongoing PREvencion con DIeta MEDiterranea (PREDIMED)-Plus trial, we assessed the initial effectiveness of the PA component. METHODS: PREDIMED-Plus is an ongoing randomized clinical trial including 6874 participants randomized to an intensive weight-loss lifestyle intervention based on an energy-restricted Mediterranean diet (MedDiet), physical activity promotion and behavioral support and to a control group using MedDiet recommendations but without calorie restriction or PA advice. Body mass index (BMI) and waist circumference (WC) are measured by standard clinical protocols. Duration and intensity of PA is self-reported using the validated REGICOR Short Physical Activity Questionnaire. The primary endpoint of the PREDIMED-Plus trial is a combined cardiovascular outcome: myocardial infarction (acute coronary syndromes with positive troponin test), stroke, or cardiovascular mortality. The present study involved secondary analysis of PA data (n = 6059; mean age 65 +/- 4.9 years) with one-year changes in total, light, and moderate-to-vigorous PA within and between intervention groups as the outcome. Generalized estimating equation models were fitted to evaluate time trends of PA, BMI, and WC within groups and differences between intervention and control groups. RESULTS: After 12 months, average daily MVPA increased by 27.2 (95%CI 5.7;48.7) METs-min/day and 123.1 (95%CI 109.7-136.6) METs-min/day in the control and intervention groups, respectively. Total-PA, light-PA, and MVPA increased significantly (p < 0.01) in both groups. A significant (p < 0.001) time*intervention group interaction was found for Total-PA and MVPA, meaning the PA trajectory over time differed between the intervention and control groups. Age, sex, education level, and BMI did not moderate the effectiveness of the PA intervention. BMI and WC decreased significantly with increasing MVPA, compared with participants who reported no changes in MVPA. CONCLUSION: After one year of follow-up, the PREDIMED-Plus PA intervention has been effective in increasing daily PA in older adults. TRIAL REGISTRATION: Retrospectively registered at the International Standard Randomized Controlled Trial ( http://www.isrctn.com/ISRCTN89898870 ), registration date: 24 July 2014. PMID- 30424818 TI - Improving care at scale: process evaluation of a multi-component quality improvement intervention to reduce mortality after emergency abdominal surgery (EPOCH trial). AB - BACKGROUND: Improving the quality and safety of perioperative care is a global priority. The Enhanced Peri-Operative Care for High-risk patients (EPOCH) trial was a stepped-wedge cluster randomised trial of a quality improvement (QI) programme to improve 90-day survival for patients undergoing emergency abdominal surgery in 93 hospitals in the UK National Health Service. METHODS: The aim of this process evaluation is to describe how the EPOCH intervention was planned, delivered and received, at both cluster and local hospital levels. The QI programme comprised of two interventions: a care pathway and a QI intervention to aid pathway implementation, focussed on stakeholder engagement, QI teamwork, data analysis and feedback and applying the model for improvement. Face-to-face training and online resources were provided to support senior clinicians in each hospital (QI leads) to lead improvement. For this evaluation, we collated programme activity data, administered an exit questionnaire to QI leads and collected ethnographic data in six hospitals. Qualitative data were analysed with thematic or comparative analysis; quantitative data were analysed using descriptive statistics. RESULTS: The EPOCH trial did not demonstrate any improvement in survival or length of hospital stay. Whilst the QI programme was delivered as planned at the cluster level, self-assessed intervention fidelity at the hospital level was variable. Seventy-seven of 93 hospitals responded to the exit questionnaire (60 from a single QI lead response on behalf of the team); 33 respondents described following the QI intervention closely (35%) and there were only 11 of 37 care pathway processes that > 50% of respondents reported attempting to improve. Analysis of qualitative data suggests QI leads were often attempting to deliver the intervention in challenging contexts: the social aspects of change such as engaging colleagues were identified as important but often difficult and clinicians frequently attempted to lead change with limited time or organisational resources. CONCLUSIONS: Significant organisational challenges faced by QI leads shaped their choice of pathway components to focus on and implementation approaches taken. Adaptation causing loss of intervention fidelity was therefore due to rational choices made by those implementing change within constrained contexts. Future large-scale QI programmes will need to focus on dedicating local time and resources to improvement as well as on training to develop QI capabilities. EPOCH TRIAL REGISTRATION: ISRCTN80682973 https://doi.org/10.1186/ISRCTN80682973 Registered 27 February 2014 and Lancet protocol 13PRT/7655. PMID- 30424827 TI - Congenital brain abnormalities during a Zika virus epidemic in Salvador, Brazil, April 2015 to July 2016. AB - BackgroundNorth-eastern Brazil was the region most affected by the outbreak of congenital Zika syndrome that followed the 2015 Zika virus (ZIKV) epidemics, with thousands of suspected microcephaly cases reported to the health authorities, mostly between late 2015 and early 2016. Aim: To describe clinical and epidemiological aspects of the outbreak of congenital brain abnormalities (CBAs) and to evaluate the accuracy of different head circumference screening criteria in predicting CBAs.MethodBetween April 2015 and July 2016, the Centers for Information and Epidemiologic Surveillance of Salvador, Brazil investigated the reported cases suspected of microcephaly and, based on intracranial imaging studies, confirmed or excluded a diagnosis of CBA. Sensitivity, specificity and positive and negative predictive values of different head circumference screening criteria in predicting CBAs were calculated.ResultsOf the 365 investigated cases, 166 (45.5%) had confirmed CBAs. The most common findings were intracranial calcifications and ventriculomegaly in 143 (86.1%) and 111 (66.9%) of the 166 CBA cases, respectively. Prevalence of CBAs peaked in December 2015 (2.24 cases/100 live births). Cases of CBAs were significantly more likely to have been born preterm and to mothers who had clinical manifestations of arboviral infection during pregnancy. None of the head circumference screening criteria performed optimally in predicting CBAs.ConclusionThis study highlights the magnitude of neurological consequences of the ZIKV epidemic and the limitations of head circumference in accurately identifying children with CBA. Gestational symptoms compatible with ZIKV infection should be combined with imaging studies for efficient detection of suspect CBAs during ZIKV epidemics. PMID- 30424828 TI - High rates of meticillin-resistant Staphylococcus aureus among asylum seekers and refugees admitted to Helsinki University Hospital, 2010 to 2017. AB - IntroductionAntimicrobial resistance is increasing rapidly in countries with low hygiene levels and poorly controlled antimicrobial use. The spread of resistant bacteria poses a threat to healthcare worldwide. Refugees and migrants from high prevalence countries may add to a rise in multidrug-resistant (MDR) bacteria in low-prevalence countries. However, respective data are scarce.MethodsWe retrospectively collected microbiological and clinical data from asylum seekers and refugees treated at Helsinki University Hospital between January 2010 and August 2017.ResultsOf 447 asylum seekers and refugees (Iraq: 46.5%; Afghanistan: 10.3%; Syria: 9.6%, Somalia: 6.9%); 45.0% were colonised by MDR bacteria: 32.9% had extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE), 21.3% meticillin-resistant Staphylococcus aureus (MRSA), 0.7% carbapenemase producing Enterobacteriaceae (CPE), 0.4% multiresistant Pseudomonas aeruginosa (MRPA), 0.4% multiresistant Acinetobacter baumannii (MRAB); no vancomycin resistant Enterococcus (VRE) were found. Two or more MDR bacteria strains were recorded for 12.5% of patients. Multivariable analysis revealed geographical region and prior surgery outside Nordic countries as risk factors of MRSA colonisation. Young age (< 6 years old), short time from arrival to first sample, and prior hospitalisation outside Nordic countries were risk factors of ESBL-PE colonisation.ConclusionWe found MDR bacterial colonisation to be common among asylum seekers and refugees arriving from current conflict zones. In particular we found a high prevalence of MRSA. Refugees and migrants should, therefore, be included among risk populations requiring MDR screening and infection control measures at hospitals. PMID- 30424829 TI - Tick-borne encephalitis in Europe, 2012 to 2016. AB - Since 2012, tick-borne encephalitis (TBE) is a notifiable in the European Union. The European Centre for Disease Prevention and Control annually collects data from 28 countries plus Iceland and Norway, based on the EU case definition. Between 2012 and 2016, 23 countries reported 12,500 TBE cases (Ireland and Spain reported none), of which 11,623 (93.0%) were confirmed cases and 878 (7.0%) probable cases. Two countries (Czech Republic and Lithuania) accounted for 38.6% of all reported cases, although their combined population represented only 2.7% of the population under surveillance. The annual notification rate fluctuated between 0.41 cases per 100,000 population in 2015 and 0.65 in 2013 with no significant trend over the period. Lithuania, Latvia and Estonia had the highest notification rates with 15.6, 9.5 and 8.7 cases per 100,000 population, respectively. At the subnational level, six regions had mean annual notification rates above 15 cases per 100,000 population, of which five were in the Baltic countries. Approximately 95% of cases were hospitalised and the overall case fatality ratio was 0.5%. Of the 11,663 cases reported with information on importation status, 156 (1.3%) were reported as imported. Less than 2% of cases had received two or more doses of TBE vaccine. PMID- 30424830 TI - Echovirus type 6 transmission clusters and the role of environmental surveillance in early warning, the Netherlands, 2007 to 2016. AB - BackgroundIn the Netherlands, echovirus type 6 (E6) is identified through clinical and environmental enterovirus surveillance (CEVS and EEVS). AimWe aimed to identify E6 transmission clusters and to assess the role of EEVS in surveillance and early warning of E6. MethodsWe included all E6 strains from CEVS and EEVS from 2007 through 2016. CEVS samples were from patients with enterovirus illness. EEVS samples came from sewage water at pre-specified sampling points. E6 strains were defined by partial VP1 sequence, month and 4-digit postcode. Phylogenetic E6 clusters were detected using pairwise genetic distances. We identified transmission clusters using a combined pairwise distance in time, place and phylogeny dimensions. ResultsE6 was identified in 157 of 3,506 CEVS clinical episodes and 92 of 1,067 EEVS samples. Increased E6 circulation was observed in 2009 and from 2014 onwards. Eight phylogenetic clusters were identified; five included both CEVS and EEVS strains. Among these, identification in EEVS did not consistently precede CEVS. One phylogenetic cluster was dominant until 2014, but genetic diversity increased thereafter. Of 14 identified transmission clusters, six included both EEVS and CEVS; in two of them, EEVS identification preceded CEVS identification. Transmission clusters were consistent with phylogenetic clusters, and with previous outbreak reports. ConclusionAlgorithms using combined time-place-phylogeny data allowed identification of clusters not detected by any of these variables alone. EEVS identified strains circulating in the population, but EEVS samples did not systematically precede clinical case surveillance, limiting EEVS usefulness for early warning in a context where E6 is endemic. PMID- 30424832 TI - Treating Children with ASD: The Perspective of Caregivers. AB - PURPOSE: Treatment of Autism Spectrum Disorders (ASD) is challenging. Parents/caregivers' perspective on the effectiveness of therapies and services available to their children is important but neglected in the literature on ASD. This study investigated such perspective through questionnaire-guided interviews with a group of parents in the province of Manitoba (Canada). A secondary objective of the study was to explore how health care professionals and specifically pharmacists can assist in providing better care to children with ASD. Methods: Informed consent was obtained from all participants. Data on diagnoses and prescribed medications were collected from medical charts. Parents/caregivers completed questionnaires during interviews scheduled at their convenience. Specific questions were asked to gather caregivers/parents' perspectives on the effectiveness of medications and non-pharmacological interventions in controlling symptoms experienced by their children. Information on access to education and health services was also assessed. Common themes were identified using thematic analysis. RESULTS: All children attended school, 88% were males, 50% experienced eating/sleeping difficulties; 69% reported Attention Deficit Hyperactivity Disorder comorbidity. Risperidone was reported to be effective in controlling aggressive behaviours. Methylphenidate and aripiprazole were often discontinued. Melatonin and occupational therapy services were said to be very useful. Access to behavioural therapy was often limited. Parents were concerned about lack of trained professionals in schools, limited understanding of their children's needs, and uncertainty for the future. CONCLUSIONS: Better education and awareness are necessary to help ASD children and their families. Pharmacists should explore opportunities to provide better services. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 30424833 TI - Eustachian Tube Dysfunction and Wideband Absorbance Measurements at Tympanometric Peak Pressure and 0 daPa. AB - BACKGROUND: Although wideband absorbance (WBA) provides important information about middle ear function, there is limited research on the use of WBA to evaluate eustachian tube dysfunction (ETD). To date, WBA obtained under pressurized condition has not been used to evaluate ETD. PURPOSE: The objective of the study was to compare WBA at 0 daPa and tympanometric peak pressure (TPP) conditions in healthy ears and ears with ETD. Research Design: A cross-sectional study design was used. Study Sample: A total of 102 healthy ears from 79 participants (mean age = 10.0 yr) and 43 ears from 32 patients with ETD (mean age = 16.0 yr) were included in this cross-sectional study. WBA was measured at 0 daPa (WBA0) and TPP WBA at TPP (WBATPP). DATA COLLECTION AND ANALYSIS: WBA results were analyzed using descriptive statistics and t-tests with the Bonferroni correction. An analysis of variance with repeated measures was applied to the data. RESULTS: WBA0 was significantly lower in the ETD group than in the control group. The WBA0 of the control group demonstrated a broad peak between 1.25 and 4 kHz, whereas the WBA0 of the ETD group had a peak between 2.5 and 4 kHz. WBATPP of the ETD group approached values close to that of the control group. In the control group, WBATPP was only 0.06 to 0.09 higher than WBA0, whereas in the ETD group, WBATPP was 0.29 to 0.42 higher than WBA0 between 0.6 and 1.5 kHz. A differential pattern of WBA at TPP relative to 0 daPa was observed between ears with ETD and ears with otitis media with effusion (OME) and negative middle ear pressure (NMEP). CONCLUSIONS: Hence, a comparison of WBA0 and WBATPP can provide potentially useful diagnostic information, and hence can be used as an adjunct tool to evaluate ETD. This is important especially in young children or some adults who are unable to perform maneuvers such as Toynbee or Valsalva during ETD assessment. Further research is needed to verify the results using test performance measures to determine whether WBA0 and WBATPP can objectively determine the presence of ETD or OME with NMEP. PMID- 30424831 TI - High prevalence of carriage of mcr-1-positive enteric bacteria among healthy children from rural communities in the Chaco region, Bolivia, September to October 2016. AB - BackgroundThe mcr-1 gene is a transferable resistance determinant against colistin, a last-resort antimicrobial for infections caused by multi-resistant Gram-negatives.AimTo study carriage of antibiotic-resistant bacteria in healthy school children as part of a helminth control and antimicrobial resistance survey in the Bolivian Chaco region.MethodsFrom September to October 2016 we collected faecal samples from healthy children in eight rural villages. Samples were screened for mcr-1- and mcr-2 genes. Antimicrobial susceptibility testing was performed, and a subset of 18 isolates representative of individuals from different villages was analysed by whole genome sequencing (WGS).ResultsWe included 337 children (mean age: 9.2 years, range: 7-11; 53% females). The proportion of mcr-1 carriers was high (38.3%) and present in all villages; only four children had previous antibiotic exposure. One or more mcr-1-positive isolates were recovered from 129 positive samples, yielding a total of 173 isolates (171 Escherichia coli, 1 Citrobacter europaeus, 1 Enterobacter hormaechei). No mcr-2 was detected. Co-resistance to other antimicrobials varied in mcr-positive E. coli. All 171 isolates were susceptible to carbapenems and tigecycline; 41 (24.0%) were extended-spectrum beta-lactamase producers and most of them (37/41) carried bla CTX-M-type genes. WGS revealed heterogeneity of clonal lineages and mcr-genetic supports.ConclusionThis high prevalence of mcr-1 like carriage, in absence of professional exposure, is unexpected. Its extent at the national level should be investigated with priority. Possible causes should be studied; they may include unrestricted use of colistin in veterinary medicine and animal breeding, and importation of mcr-1-positive bacteria via food and animals. PMID- 30424834 TI - Dizziness, Vertigo, and Mental Health Comorbidity in Gulf War Veterans. AB - BACKGROUND: Gulf War Illness (GWI) is a chronic condition involving symptoms across multiple body systems. Previous research has implicated the vestibular system as a potential underlying factor in the symptoms experienced by veterans with GWI, due in part to exposure to potentially ototoxic chemicals and events. PURPOSE: To characterize the presence of vertigo and dizziness symptoms in a sample of veterans with GWI using validated self-report instruments, accounting for mental health comorbidities. RESEARCH DESIGN: This is a case series, follow up, prospective interview of clinical veterans; results presented are purely descriptive. STUDY SAMPLE: Our sample of 50 veterans was a follow-up to a case series of clinical Gulf War veterans evaluated at the War Related Illness and Injury Study Center. DATA COLLECTION AND ANALYSIS: Veterans participated in a 70 min phone interview where the following questionnaires were administered: Vertigo Symptom Scale (VSS), Patient Health Questionnaire (depression scale), Patient Health Questionnaire (somatization scale), Beck Anxiety Inventory, Posttraumatic Stress Disorder (PTSD) Checklist, Defense and Veterans Brain Injury Center Traumatic Brain Injury Questionnaire, and GWI (Kansas) Questionnaire. We used descriptive (mean/median, standard deviation, interquartile range, and percentage) statistics to describe our sample and illuminate possible relationships between measures. RESULTS: Our primary finding is a substantial report of vertigo symptoms in our sample, according to the VSS. Ninety percent of participants scored above the VSS threshold (>12), suggesting "severe dizziness." The most commonly endorsed symptom on the VSS was "headache or pressure in the head." CONCLUSIONS: We conclude that there is significant burden of vertigo symptoms in veterans with GWI, suggesting a need for objective tests of vestibular function in this population. Furthermore, the relationship between symptoms of vertigo and dizziness, vestibular function, and PTSD warrants further exploration using objective measures. PMID- 30424835 TI - Impact of Unilateral Hearing Loss on Behavioral and Evoked Potential Measures of Auditory Function in Adults. AB - BACKGROUND: A unilateral hearing loss (UHL) can have a significant functional and social impact on children and adults, affecting their quality of life. In adults, UHL is typically associated with difficulties understanding speech in noise and sound localization, and UHL increases the self-perception of auditory disability for a range of listening situations. Furthermore, despite evidence for the negative effects of reduced unilateral auditory input on the neural encoding of binaural cues, the perceptual consequences of these changes are still not well understood. PURPOSE: Determine effects of UHL on auditory abilities and speech evoked cortical auditory evoked potentials (CAEPs). RESEARCH DESIGN: CAEPs, sound localization, speech perception in noise and self-perception of auditory abilities (speech, spatial, and qualities hearing scale) were assessed. STUDY SAMPLE: Thirteen adults with UHL with a range of etiologies, duration of hearing loss, and severity and a control group of eleven binaural listeners with normal hearing. RESULTS: Participants with UHL varied greatly in their ability to localize sound and reported speech recognition and listening effort were the greatest problem. There was a greater effect of right ear than left ear hearing loss on N1 amplitude hemispheric asymmetry and N1 latencies evoked by speech syllables in noise. As duration of hearing loss increased, contralateral dominance (N1 amplitude asymmetry) decreased. N1 amplitudes correlated with speech scores, larger N1 amplitudes were associated with better speech recognition in noise scores. N1 latencies are delayed (in the better ear) and amplitude hemisphere asymmetry differed across UHL participants as function of side of deafness, mainly for right-sided deafness. CONCLUSION: UHL affects a range of auditory abilities, including speech detection in noise, sound localization, and self-perceived hearing disability. CAEPs elicited by speech sounds are sensitive enough to evidence changes within the auditory cortex due to an UHL. PMID- 30424836 TI - The brain-structural correlates of mathematical expertise. AB - Studies in several domains of expertise have established that experience dependent plasticity brings about both functional and anatomical changes. However, little is known about how such changes come to shape the brain in the case of expertise acquired by professional mathematicians. Here, we aimed to identify cognitive and brain-structural (grey and white matter) characteristics of mathematicians as compared to non-mathematicians. Mathematicians and non mathematician academics from the University of Oxford underwent structural and diffusion MRI scans, and were tested on a cognitive battery assessing working memory, attention, IQ, numerical and social skills. At the behavioural level, mathematical expertise was associated with better performance in domain-general and domain-specific dimensions. At the grey matter level, in a whole-brain analysis, behavioural performance correlated with grey matter density in left superior frontal gyrus - positively for mathematicians but negatively for non mathematicians; in a region of interest analysis, we found in mathematicians higher grey matter density in the right superior parietal lobule, but lower grey matter density in the right intraparietal sulcus and in the left inferior frontal gyrus. In terms of white matter, there were no significant group differences in fractional anisotropy or mean diffusivity. These results reveal new insights into the relationship between mathematical expertise and grey matter metrics in brain regions previously implicated in numerical cognition, as well as in regions that have so far received less attention in this field. Further studies, based on longitudinal designs and cognitive training, could examine the conjecture that such cross-sectional findings arise from a bidirectional link between experience and structural brain changes that is itself subject to change across the lifespan. PMID- 30424837 TI - Influence of altered geometry and material properties on tissue stress distribution under load in tendinopathic Achilles tendons - A subject-specific finite element analysis. AB - Achilles tendon material properties and geometry are altered in Achilles tendinopathy. The purpose of this study was to determine the relative contributions of altered material properties and geometry to free Achilles tendon stress distribution during a sub-maximal contraction in tendinopathic relative to healthy tendons. Tendinopathic (n = 8) and healthy tendons (n = 8) were imaged at rest and during a sub-maximal voluntary isometric contraction using three dimensional freehand ultrasound. Images were manually segmented and used to create subject-specific finite element models. The resting cross-sectional area of the free tendon was on average 31% greater for the tendinopathic compared to healthy tendons. Material properties for each tendon were determined using a numerical parameter optimisation approach that minimised the difference in experimentally measured longitudinal strain and the strain predicted by the finite element model under submaximal loading conditions for each tendon. The mean Young's modulus for tendinopathic tendons was 53% lower than the corresponding control value. Finite element analyses revealed that tendinopathic tendons experience 24% less stress under the same submaximal external loading conditions compared to healthy tendons. The lower tendon stress in tendinopathy was due to a greater influence of tendon cross-sectional area, which alone reduced tendon stress by 30%, compared to a lower Young's modulus, which alone increased tendon stress by 8%. These findings suggest that the greater tendon cross-sectional area observed in tendinopathy compensates for the substantially lower Young's modulus, thereby protecting pathological tendon against excessive stress. PMID- 30424838 TI - The effects of fall history on kinematic synergy during walking. AB - To prevent falls, control of the swing foot during walking is crucial. Recently, some studies demonstrated that the coordinated movement of lower limbs by kinematic synergy is important for stable walking. However, no study has been carried out to reveal the relation between falls and kinematic synergy, and it is unclear whether fall history alters the kinematic synergy. Thus, the purpose of this study was to test the effects of fall history on kinematic synergy using uncontrolled manifold (UCM) analysis. Older adults were divided into two groups: older adults without fall history (non-fallers, n = 14) and older adults with fall history of at least one fall in the 12 months prior to the measurements (fallers, n = 10). Subjects walked at their own comfortable speed on a pathway and kinematic data were collected. UCM analysis was performed to assess how variability of segmental configurations in the frontal plane, the mediolateral and vertical directions, affects the frontal trajectory of the swing foot. Fallers had a greater variability of segmental configurations than non-fallers in all phases. In the mediolateral direction, the kinematic synergy in fallers was significantly greater than that in non-fallers during the early and late swing phases. On the other hands, fallers continuously had greater kinematic synergy compared to non-fallers in the vertical direction. The results revealed that fall history increased the kinematic synergy, although fallers needed a greater variability of segmental configurations as a compensatory strategy to ensure kinematic synergy. PMID- 30424839 TI - Sarcopenia predicts poor outcomes in urgent exploratory laparotomy. AB - BACKGROUND: Emergent laparotomies are associated with higher rates of morbidity and mortality. Recent studies suggest sarcopenia predicts worse outcomes in elective operations. The purpose of this study is to examine outcomes following urgent exploratory laparotomy in sarcopenic patients. METHODS: This was a retrospective review of patients in a rural tertiary care facility between 2010 and 2014. Patients underwent a laparotomy within 72 h of admission and had an abdomen/pelvis CT scan were included. Primary outcomes were predictors of morbidity and mortality. Sarcopenia is the lowest quartile cross sectional area of the psoas muscles. RESULTS: Multivariate analysis of 967 patients found that sarcopenic patients had higher mortality, complication rate, were less likely to be discharged home, were more likely to undergo unplanned re-operation, and had a longer length of stay. Increasing abdominal wall fat has favorable outcomes in mortality, discharge destination, and complications. CONCLUSIONS: Sarcopenia is measured from CT scans, making it an accessible outcome predictor. In urgent laparotomies, sarcopenia was associated with higher morbidity, mortality, length of stay, and worse discharge destination. PMID- 30424840 TI - Proposal for the classification of peri-implant femoral fractures: Retrospective cohort study. AB - Background Peri-implant fractures occur in association with an implant used to treat a previous injury and that is still attached to the bone. Peri-implant fractures are considered to be relatively "new" fractures and they lack any classification system that is accepted in practice. Generally, the fracture classification systems currently used in our clinical practice were not developed or validated using rigorous scientific evaluation methods. Aim To provide data for a proposed classification of peri-implant femoral fractures. Methods This is an international and multicentre study (12 centres) based on a cohort of consecutive peri-implant fractures with the criterion being: a fracture in any segment of the femur in association with previously-used osteosynthesis material, whether a nail, plate or screws. A proposed system for the classification was tested, based on a topographical classification using alphanumeric coding, following a similar nomenclature to that explained in the "Vancouver Classification-for-Total-Hip-Arthroplasty-Periprosthetic-Fractures", and classified according to whether the implant is a nail, a screw or a plate, and the location of the fracture in relation to the original implant and the affected femoral segment. The study coordinator performed the first classification exercise, which was discussed subsequently for the study coordinator group to reach a consensus. A descriptive analysis of the fractures was produced. The proportion of peri-implant femoral fractures was estimated, and 95% confidence interval (95%CI) was calculated. Results Between January 2013 and December 2016, data on a total of 143 peri-implant femoral fractures were collected. Only 5 (3.5%) fractures had to be discussed to reach a consensus. The most common peri implant femoral fractures were located at the diaphyseal segment (#32) and associated with nails or plates: 51%, 73/143, 95%CI:43-59%; at the proximal segment (#31): 39%, 56/143, 95%CI:32-47%; and at the distal femoral segment (#33): 10%, 14/143, 95%CI:6-16%. The highest proportion of peri-implant femoral fractures corresponded to #31-AN (trochanteric and neck area) and #32-CNP (diaphysis fractures distant from the implant, often distal and spiral). Conclusion The proposed classification for peri-implant femoral fractures appears to be useful and easy to accomplish. Future studies will be necessary to validate it and demonstrate the effectiveness of its application in clinical practice. PMID- 30424841 TI - Regional passivity for switched nonlinear systems and its application. AB - A framework of regional passivity theory for switched systems is set up using multiple barrier storage functions. The "energy" stored in each subsystem is described by the corresponding individual barrier storage function which is only well defined on an open region associated with regional passivity. The key feature is that the "energy" grows to infinity when the trajectory tends to the region boundary. Firstly, a sufficient condition guaranteeing regional passivity for a switched system is derived under the designed switching law, where all subsystems are not assumed to be regionally passive. Secondly, asymptotic stability can be reached if a switched system is strictly regionally passive or regionally passive plus asymptotic detectability, and meanwhile the system trajectory remains in the corresponding open region. Thirdly, regional passivity is also shown to be preserved under feedback interconnection. Finally, as an application of the theory provided, the stabilization problem for state constrained strict-feedback switched nonlinear systems is solved, where no subsystem is required to be stabilizable. PMID- 30424842 TI - Should Helicopters Transport Patients Who Become Sick After a Chemical, Biological, Radiologic, Nuclear, and Explosive Attack? No but . . . PMID- 30424843 TI - Policy Changes. PMID- 30424844 TI - A 79-Year-Old Man With Angioedema. PMID- 30424845 TI - Ketamine: Good Drug. . .Bad Rap. PMID- 30424846 TI - Articles That May Change Your Practice: Steroids and Septic Shock. PMID- 30424847 TI - You Call, They Come, and You Say "Help Us". PMID- 30424848 TI - Forum. PMID- 30424849 TI - Out-Of-Hospital Blood Product Administration Considerations. PMID- 30424850 TI - Ultrasound in the Air Medical Environment. PMID- 30424851 TI - Operational Impact of a Critical Care Transport Duty Time Tool Implementation: A Quality Improvement Project to Enhance Crew and Patient Safety. AB - OBJECTIVE: The Commission on Accreditation of Medical Transport Systems requires transport programs to have operational risk assessment tools that must address issues such as transport acceptance with tools for assessing pilot/driver and crew alertness and fatigue, aviation decision making, and mission acceptance/medical decision making. The objective of this study was to evaluate the impact the implementation of this tool has on programmatic operations. METHODS: This hospital-based dedicated pediatric/neonatal transport team has experienced rapid increase in volume as well as an expanding response area. Data related to calls resulting in excessive on-duty time were evaluated for 2 years before and after the implementation of a formal risk assessment program that included duty time assessment. RESULTS: Since the implementation of the duty time assessment tool, there has been a 48% decrease in calls resulting in crews being held over 1 hour past their shift. Additionally, there has been no decline in transport requests, and the resultant increased safety awareness has led to a decreased risk of incidents related to crew and driver fatigue. CONCLUSION: The implementation of a risk assessment tool not only increases crew safety and subsequently patient safety, but also it has no negative impact on referral pattern or volume. PMID- 30424852 TI - Clinical Interventions Account for Scene Time in a Helicopter Emergency Medical Service in South Africa. AB - INTRODUCTION: Helicopter emergency medical services (HEMS) have been associated with a prolonged scene time, compromising the time benefit in an urban setting. Therefore, the clinical benefit offered through additional equipment, skills, and experience of HEMS crews must be investigated to propose the value of HEMS. This study aimed at establishing whether HEMS scene time was associated with the number of clinical interventions performed and improved patient stability. METHOD: This retrospective, cross-sectional chart review included all primary HEMS cases from June 1, 2013, to May 31, 2015, from a South African helicopter service and extracted the number of clinical interventions and patient stability using the Mainz Emergency Evaluation Score (MEES). We correlated this with scene time using analysis of variance. RESULTS: Five hundred fourteen clinical interventions were performed on 204 patients. A median of 2 clinical interventions per patient was performed on scene. Performing 1 additional clinical intervention was associated with an approximate 4-minute increase in on scene time. Some improvement in patient stability was shown by a mean change in the MEES of 0.65 after on-scene intervention, but this did not reach MEES clinical cutoff measures. CONCLUSION: The number of clinical interventions performed by helicopter crews can account for scene time in a South African HEMS. The clinical interventions performed by helicopter crews tend to have a positive effect on patient stability. PMID- 30424853 TI - Critical Care Skill Triad for Tactical Evacuations. AB - OBJECTIVE: Providing medical support to French soldiers deployed on war theater everywhere around the world is the first mission of the French Military Medical Service (FMMS). En-route critical care is critical to maintain the continuum of care and safety during forward and tactical medical evacuation (MEDEVAC). The FMMS has developed specific training programs to ensure optimal en-route critical care air transport. These courses need to be continuously adjusted to the returns of experience and to the operational changes. The aim of our survey was to characterize the critical care skills required for tactical MEDEVAC on fixed wing aircraft. METHODS: A 10-items survey was sent to 22 flight surgeons previously deployed in the Sahel-Saharan Strip. Eight questions focused on basic critical care skills. The 2 last items assessed the flight surgeons' willingness to follow a pre deployment course in a critical care unit and in a transfusion center. RESULTS: Fourteen of the 22 flight surgeons responded to the survey. All but one responder had to deal with at least one critical care skill. The most frequent critical care skills required were the management of mechanical ventilation, catecholamine infusion and blood product transfusion. Five of the 14 responders reported on-board blood product transfusion, including red blood cells, lyophilized plasma and fresh whole blood. CONCLUSION: Our survey highlights the need for the MEDEVAC teams to be skilled in critical care medicine. We defined a triad of critical care skills required for the management of severe casualties, including the management of mechanical ventilation, catecholamine infusion and blood product transfusion. PMID- 30424854 TI - Helicopter Emergency Medical Services in Buenos Aires: An Operational Overview. AB - As part of the emergency medical care system, helicopter emergency medical services (HEMS) have a different crew composition from the traditional team. HEMS consist of a pilot, doctor, and firefighter with rescue skills and training in basic life support on board an air ambulance. This allows the adaptation to different environments and increases the varieties of air procedures normally performed. HEMS began operating relatively recently in Buenos Aires. Yet, in 3 years, its use grew to such an extent that in 2015 it tripled, and by 2016 the number of medical assists was 4 times greater than in 2014. Furthermore, over the 3-year study period, 92% to 95% of assisted victims were traffic accident casualties requiring primary care. The HEMS crew is informed about the availability of resources in the acute care general hospitals and can therefore transfer patients to the most appropriate trauma center in the shortest time. However, 75% to 85% of the time, the choice of destination is strongly influenced by the availability of a helipad and the operational safety that it provides. PMID- 30424855 TI - Endotracheal Intubation for Traumatic Cardiac Arrest by an Australian Air Medical Service. AB - OBJECTIVE: Traumatic cardiac arrest (TCA) has been associated with poor outcome, but there are survivors with good neurological outcome. Treatment of hypoxia plays a key part in resuscitation algorithms, but little evidence exists on the ideal method of airway management in TCA. METHODS: LifeFlight Retrieval Medicine is an aeromedical retrieval service based in Queensland, Australia. Data regarding all intubations performed over a 28-month period were accessed from an electronic airway registry. RESULTS: 13/22 TCA patients were male, age range 2-81 years. 7/22 (31.8%) survived to hospital admission. During the same period 271 patients were intubated due to trauma, but were not in cardiac arrest (N-TCA). There was no difference in the likelihood of difficult laryngoscopy in the TCA group (16/22 (72.7%) compared to N-TCA (215/271 (79.3%); p = 0.46). The first attempt success rate was similar in TCA group (19/22 (86.4%)) and N-TCA (241/271 (88.9%) p = 0.71.). TCA patients were more likely to be intubated while lying on the ground than the N-TCA group (11/22 (50%) versus 17/271 (6.3%) p = <0.001). CONCLUSION: Resuscitation for predominantly blunt TCA is not futile. The endotracheal intubation first attempt success rate for TCA is comparable to that of N-TCA trauma patients. PMID- 30424856 TI - Transporting the Deceased: Partnering With the Organ Recovery Center to Improve Transplant Outcomes. PMID- 30424857 TI - Resuscitative Airway Management for Massive Gastrointestinal Hemorrhage. AB - Massive upper gastrointestinal hemorrhage represents a highly morbid, resource intensive disease entity that requires rapid diagnostic and therapeutic delivery in parallel with mobilization of in-hospital providers for definitive intervention. This report details a unique case demonstrating exceptional collaboration spanning multiple healthcare systems, a novel use of resuscitative endovascular balloon occlusion of the aorta, and a discussion on resuscitative airway management in the setting of massive upper gastrointestinal hemorrhage. PMID- 30424858 TI - A 15-Year-Old Male With Wide Complex Tachyarrhythmia. AB - A 15-year-old male presented with exertional syncope and was found to be in an unstable regular wide complex tachyarrhythmia (WCT). After a trial of antiarrhythmic medication, his clinical condition declined, necessitating synchronized cardioversion. Although he noted symptomatic improvement after cardioversion, he was found to be in third-degree heart block. The patient was transported by rotor wing aircraft to a pediatric cardiac intensive care unit where he was ultimately diagnosed with Lyme disease. He was treated with a course of intravenous antibiotics, his heart block resolved, and he was discharged home with a good neurologic outcome. PMID- 30424859 TI - Multiple Patients With Heatstroke Air Evacuated by Agreement Concerning Collaboration. AB - On August 30, 2017, the wet-bulb globe temperature was 30 degrees C. Three female military personnel fell unconscious almost simultaneously around noon after a long-distance march that had started at 6 am. The fire department in Gotenba received a 119 call [at 1:16 PM] and requested dispatch of the eastern Shizuoka doctor helicopter (DH) because it would take about 1 hour from the scene to arrive at our hospital by ground ambulance. At that time, the DH of eastern Shizuoka was transporting an injured patient to Kanagawa Prefecture, so the flight dispatcher of the DH of eastern Shizuoka decided to request support DHs from Kanagawa Prefectures based on an agreement concerning collaboration using the DH. The DH of Kanagawa Prefecture met 1 of the patients and transported her to its base hospital. The remaining 2 patients were then transported by the DH of eastern Shizuoka to its base hospital after completing the previous mission. All patients obtained a survival discharge without major complications after receiving proper treatment and rehabilitation. The agreement concerning collaboration using multiple DHs was important in this case, and dispersion transportation was successfully achieved. PMID- 30424861 TI - Concern Network. PMID- 30424860 TI - Prehospital Blood Product Transfusion in Mountain Rescue Operations. AB - Severely injured patients with hemorrhage present major challenges for emergency medical services, especially during mountain rescue missions in which harsh environmental conditions and long out-of-hospital times are frequent. Because uncontrolled hemorrhage is the leading cause of death within the first 48 hours after severe trauma, initiating damage control resuscitation (DCR) as early as possible after severe trauma and exporting the concept of DCR to the out-of hospital arena is pivotal for patient survival. Appropriate bleeding control, management of coagulopathy, and transfusion of blood products are core aspects of DCR. This review summarizes the available evidence on out-of-hospital blood product transfusion and the management of coagulopathy with a special focus on mountain rescue missions. An overview of upcoming trials and possible future trends in the management of coagulopathy during rescue operations is provided. PMID- 30424862 TI - [Behavior disorders in the childhood and adolescence of schizophrenic patients: A retrospective study]. AB - OBJECTIVE: Usually Schizophrenia starts in late adolescence or early adulthood. However in childhood it is associated with significant impairment. The aim of this study is to investigate behavior disorders of schizophrenic patients in this particular period of life, and whether the presence of these disorders leads to predict a subsequent development of schizophrenia. METHODS: Our study is retrospective, about a group of patients with schizophrenia, conducted in the university department of psychiatry of Fez. The study of the behavior of our patients during their childhood and adolescence is based on interviews with the parents of the subjects. We also used the teen version of the Child Behavior Cheklist 4-18 (CBCL). RESULTS: The sample included a total of 100 patients with a schizophrenia disorder, of which 80 were male, the average age was 25.36+/--3.54 years. According to parents, 60 % of our patients were shy and too wise; a third of them had a preference for solitary games, and they were disobedient at home and school, frequently fighting, breaking the laws, taking drugs. Finally 20 % were very aggressive, attacking and hitting others - they even destroyed their personal possessions - and had run away from home. The average CBCL score was 41.69+/--26,397, with 47 % above the threshold. Several factors were significantly related to a high CBCL score: gender, early age of onset of schizophrenia, and a traumatic event in childhood. CONCLUSION: Childhood and adolescence are characterized by the presence of many symptoms and behavior disorders. Although they are not very specific, their presence should alert the clinician to the significant probability of developing schizophrenia, especially in a risky population. PMID- 30424863 TI - [First trends of change in mortality by suicide in Nord-Pas-de-Calais since VigilanS]. AB - INTRODUCTION: In terms of suicide prevention, population-based prevention devices often struggle to demonstrate an effect in terms of reducing suicidal acts of suicide, often focusing on the evolution of the number of suicide attempts, on time too short to statistically interpret changes in mortality. The consolidated figures for mortality in France are provided by the CepiDC with a delay of approximately three years. We therefore had to try to work with an approximation of the phenomenon, and we tested the proxy value of the enumeration of corpses, body examinations and medico-legal autopsies for suicide by the forensic doctors of the Nord-Pas-de-Calais region in France. In parallel, we conducted a comprehensive mortality study for 2016 in the VigilanS cohort. METHOD: By measuring the evolution of the number of body lifts for suicide by the Department of Forensic Medicine of the region, for the 3 years before VigilanS (2012-2014) compared to the 3 years since VigilanS (2015-2017). The deaths of patients of the VigilanS cohort were identified by calling the city halls of birth and domicile of all patients integrating the device in 2016. The cause of death was then characterized by contact of the attending physician. RESULTS: We observe an average decrease in suicide mortality of 9.9% (-12% for men, +0.3% for women). The exhaustive analysis of suicide mortality in the VigilanS cohort in 2016 found 19 deaths, of which 14 by suicide, or 0.4% of patients. This observed mortality rate in the VigilanS cohort in 2016 is significantly below the expected threshold in the literature (1 to 2% in the year following TS). CONCLUSION: It seems possible to reach the 2020 target for a 10% decrease in suicidal behavior in industrialized countries by 2020. The VigilanS device could therefore be protective in terms of suicide mortality. PMID- 30424864 TI - Mechanisms of Antidepressant Response to Electroconvulsive Therapy Studied With Perfusion Magnetic Resonance Imaging. AB - BACKGROUND: Converging evidence suggests that electroconvulsive therapy (ECT) induces neuroplasticity in patients with severe depression, though how this relates to antidepressant response is less clear. Arterial spin-labeled functional magnetic resonance imaging tracks absolute changes in cerebral blood flow (CBF) linked with brain function and offers a potentially powerful tool when observing neurofunctional plasticity with functional magnetic resonance imaging. METHODS: Using arterial spin-labeled functional magnetic resonance imaging, we measured global and regional CBF associated with clinically prescribed ECT and therapeutic response in patients (n = 57, 30 female) before ECT, after two treatments, after completing an ECT treatment "index" (~4 weeks), and after long term follow-up (6 months). Age- and sex-matched control subjects were also scanned twice (n = 36, 19 female), ~4 weeks apart. RESULTS: Patients with lower baseline global CBF were more likely to respond to ECT. Regional CBF increased in the right anterior hippocampus in all patients irrespective of clinical outcome, both after 2 treatments and after ECT index. However, hippocampal CBF increases postindex were more pronounced in nonresponders. ECT responders exhibited CBF increases in the dorsomedial thalamus and motor cortex near the vertex ECT electrode, as well as decreased CBF within lateral frontoparietal regions. CONCLUSIONS: ECT induces functional neuroplasticity in the hippocampus, which could represent functional precursors of ECT-induced increases in hippocampal volume reported previously. However, excessive functional neuroplasticity within the hippocampus may not be conducive to positive clinical outcome. Instead, our results suggest that although hippocampal plasticity may contribute to antidepressant response in ECT, balanced plasticity in regions relevant to seizure physiology including thalamocortical networks may also play a critical role. PMID- 30424865 TI - Polygenic Risk Scores Derived From a Tourette Syndrome Genome-wide Association Study Predict Presence of Tics in the Avon Longitudinal Study of Parents and Children Cohort. AB - BACKGROUND: Tourette syndrome (TS) has a well-established genetic background, but its genetic architecture remains largely unknown. The authors investigated the role of polygenic risk scores (PRSs) derived from a TS genome-wide association study in relation to the occurrence of tics and associated traits in a general population cohort. METHODS: Using the most recent TS genome-wide association study (n = 4819 cases; n = 9488 controls) as the discovery sample, PRSs were calculated in Avon Longitudinal Study of Parents and Children participants (n = 8941). Regression analyses were used to assess whether PRS predicted the presence and chronicity of tics, and symptom severity of obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, and autism spectrum disorder in Avon Longitudinal Study of Parents and Children participants. RESULTS: Following correction for multiple testing, the PRS significantly predicted the presence (R2 = .48%, p empirical = .01, Q = .04) but not the chronicity (R2 = .16%, p empirical = .07, Q = .14) of tics in the Avon Longitudinal Study of Parents and Children cohort; it did not predict the severity of obsessive-compulsive disorder (R2 = .11%, p empirical = .11, Q = .15), attention-deficit/hyperactivity disorder (R2 = .09%, p empirical = .19, Q = .21), or autism spectrum disorder (R2 = .12%, p empirical = .09, Q = .14). CONCLUSIONS: The authors found a significant polygenic component of tics occurring in a general population cohort based on PRS derived from a genome-wide association study of individuals with a TS diagnosis. This finding supports the notion that tics along a spectrum from nonclinical to clinical symptom levels share a similar genetic background. PMID- 30424866 TI - Usefulness of a Computerized Reminder System to Improve Inferior Vena Cava Filter Retrieval and Complications. AB - Inferior vena cava filters (IVCF) are associated with complications which may be due to delayed retrieval. Initiation of an automated reminder system may improve retrieval rates and reduce complications. A computerized reminder system, which provides interactive email reminders after implantation while collecting IVCF use data, was implemented. IVCF retrieval was compared before ("reminder not provided" group) and after ("reminder provided" group) implementation. Data regarding implantation, retrieval, and complications were collected. The primary efficacy outcome was retrieval rate, and the primary safety outcome was indwelling complication rate. Secondary outcomes were time to retrieval and a composite adverse outcome defined as IVCF thrombosis, deep venous thrombosis (DVT), pulmonary embolism, and death. A total of 1,070 IVCF insertions were included, 715 in the "reminder not provided" group and 355 in the "reminder provided" group. Patient age (61 vs 64 years, p = 0.95) and gender (42% vs 40% female, p = 0.55) were similar in the "reminder not provided" and "reminder provided" groups, respectively. In the "reminder provided" group, the retrieval rate was higher (148/297 [49.8%] vs 223/715 [31.2%], p = 0.0001), the indwelling complication rate was lower (30/319 [9.4%] vs 115/715 [16.1%], p = 0.005), and the time to retrieval was shorter (112 days vs 146 days, p = 0.02). The composite adverse outcome occurred less frequently in the "reminder provided" group: (85/355 [23.9%] vs 297/715 [41.5%], p = 0.0001). The system was associated with increased odds of IVCF retrieval (odds ratio 2.56; 95% confidence interval: 1.82 to 3.59; p <0.0001) and reduced odds of the composite adverse outcome (odds ratio 0.72; 95% confidence interval: 0.60 to 0.80; p <0.0001). In conclusion, implementing a computerized email reminder system was associated with higher IVCF retrieval rates, fewer indwelling complications, and shorter dwell times. PMID- 30424867 TI - Subclinical Burden of Coronary Artery Calcium in Patients With Coarctation of the Aorta. AB - Coronary computed tomography (CT) angiography is often performed in adults with coarctation of the aorta (CoA) for anatomic assessment. As this population ages, assessment of atherosclerotic cardiovascular disease burden is important. Thus, quantitative and qualitative coronary artery calcium (CAC) scores were assessed for patients with CoA >=16 years of age, who were seen at a referral center. CoA patients had either coronary CT angiography or chest CT with interpretable coronary information performed for clinical indications (follow-up, preoperative, or for symptoms) from 2004 to 2017. Qualitative CAC was determined based on low dose CT and lung cancer screening protocols. Quantitative CAC scores were compared with an age- and gender-matched control cohort of patients chosen from an emergency department database of patients who received coronary CT angiography for chest pain evaluation. Atherosclerotic cardiovascular disease 10-year predicted risk scores were calculated for both cohorts. Out of 131 patients with CoA (mean age 46.1 +/- 15.3 years), 22 patients (17%) had multivessel atherosclerotic disease on qualitative assessment. In the subgroup of patients >=40 years, those with CoA were more likely to have a quantitative CAC score >=400 compared with those without CoA (14% vs 4%, p = 0.02). Median atherosclerotic cardiovascular disease risk score was 8% (interquartile range 2% to 12%) for CoA patients >=40 years, and 5% (interquartile range 2% to 9%) for patient without CoA >=40 years. In conclusion, we determined that CoA patients have subclinical atherosclerosis identifiable on CT in high rates when compared with patients without CoA. Atherosclerotic cardiovascular disease should be assessed in these patients for prevention and treatment. PMID- 30424868 TI - Relation of Ratio of Left Ventricular Ejection Fraction to Left Ventricular End Diastolic Pressure to Long-Term Prognosis After ST-Segment Elevation Acute Myocardial Infarction. AB - Risk stratification of patients with ST-segment elevation acute myocardial infarction (STEMI) is suboptimal. We assessed the prognostic value of the left ventricular ejection fraction to left ventricular end-diastolic pressure (LVEF/LVEDP) ratio in patients with STEMI who underwent primary percutaneous coronary intervention (PPCI). The study included 1,283 patients with STEMI. LVEF and LVEDP were measured at the time of PPCI. The primary outcome was 8-year cardiac mortality. Patients were divided into 3 groups: a group with a LVEF/LVEDP ratio within the first tertile (LVEF/LVEDP ratio <2; n = 437 patients), a group with a LVEF/LVEDP ratio within the second tertile (LVEF/LVEDP ratio 2 to 3; n = 422 patients), and a group with a LVEF/LVEDP ratio within third tertile (LVEF/LVEDP ratio >3; n = 424 patients). There were 109 cardiac deaths during the follow-up: 55 (17.1%), 36 (10.9%), and 18 (6.5%) deaths occurring in patients of the first, second, and third LVEF/LVEDP ratio tertiles, respectively (adjusted hazard ratio = 0.80, 95% confidence interval 0.66 to 0.97, p = 0.022 for 1 unit increment in the LVEF/LVEDP ratio). LVEF/LVEDP ratio (p = 0.035) but not LVEF (p = 0.290) or LVEDP (p = 0.145) alone improved the risk prediction of the models for cardiac mortality (p values show the difference in C-statistics between the models without and with LVEF/LVEDP ratio, LVEF or LVEDP). In conclusion, in patients with STEMI who underwent PPCI, a lower LVEF/LVEDP ratio was independently associated with increased risk of cardiac mortality up to 8 years after PPCI. The LVEF/LVEDP ratio, but not LVEF or LVEDP alone improved predictivity of multivariable models with respect to long-term cardiac mortality. PMID- 30424869 TI - Relation of Elevated Resting Heart Rate in Mid-Life to Cognitive Decline Over 20 Years (from the Atherosclerosis Risk in Communities [ARIC] Study). AB - Resting heart rate (RHR) is independently associated with cardiovascular disease (CVD) risk. We determined whether RHR, measured in mid-life, is also associated with cognitive decline. We studied 13,720 middle-aged white and black ARIC participants without a history of stroke or atrial fibrillation. RHR was obtained from a 12-lead resting electrocardiogram at the baseline visit (1990 to 1992) and categorized into groups as <60 (reference), 60 to 69, 70 to 79 and >=80 beats/min. Cognitive scores were obtained at baseline and at up to 2 additional visits (1996 to 1998 and 2011 to 2013). The primary outcome was a global composite cognitive score (Z-score) derived from 3 tests: delayed word recall, digit symbol substitution, and word fluency. The associations of RHR with cognitive decline and incident dementia were examined using linear mixed-effects and Cox hazard models, respectively, adjusting for sociodemographics, CVD risk factors, and AV-nodal blockade use. Multiple imputation methods were used to account for attrition over follow-up. Participants had mean +/- SD age of 58 +/- 6 years; 56% were women, 24% black. Average RHR was 66 +/- 10 beats/min. Over a mean follow-up of 20 years, those with RHR >=80 beats/min had greater global cognitive decline (average adjusted Z-score difference -0.12 [95% confidence interval -0.21, -0.03]) and increased risk for incident dementia (hazard ratio 1.28 (1.04, 1.57), compared with those with RHR <60 beats/min. In conclusion, elevated RHR is independently associated with greater cognitive decline and incident dementia over 20 years. Further studies are needed to determine whether the associations are causal or secondary to another underlying process, and whether modification of RHR can affect cognitive decline. PMID- 30424870 TI - Acute Myocardial Infarction Outcomes in Systemic Lupus Erythematosus (from the Nationwide Inpatient Sample). AB - One of the major causes of mortality in systemic lupus erythematosus (SLE) is acute myocardial infarction. Whether in-hospital outcomes and management of ST segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) are different in SLE patients compared with those without SLE from large, recent dataset is unclear. We queried the Nationwide Inpatient Database from 2005 to 2014 and identified STEMI and NSTEMI admissions with and without SLE. The primary outcome was in-hospital mortality. Secondary outcomes were revascularization strategy (percutaneous coronary intervention, coronary artery bypass surgery, or thrombolytics), medical therapy rates (no reperfusion), and major adverse clinical events. A propensity-matched cohort was created to compare these outcomes. Odds ratio (OR) was calculated from the propensity-matched cohort. A total of 321,048 STEMI admissions, of which 1,001 (0.31%) and 572,971 NSTEMI admissions, of which 2,134 (0.37%) were SLE, were identified. In those with STEMI, 882 SLE and non-SLE admissions were propensity-matched. In-hospital mortality (9.1% vs 11.8%, OR 0.75, p = 0.07), revascularization strategy, medical therapy rates, and major adverse events were similar. Similarly, in those with NSTEMI, 1,770 SLE and 1,775 non-SLE were matched. In-hospital mortality (4.1% vs 4.50%, OR 0.90, p = 0.51), coronary artery bypass surgery, medical therapy rates, and major adverse events were mostly similar but the rate of percutaneous coronary intervention was higher in SLE (32.9% vs 29.6%, OR 1.16, p = 0.04). For both STEMI and NSTEMI, hospital cost and length of stay were similar between SLE and non-SLE cohorts. From a large administrative database in the United States, revascularization strategies and in-hospital outcomes of acute coronary syndrome were mostly similar between SLE and non-SLE. PMID- 30424871 TI - Impact of Dialysis on the Prognosis of Patients Undergoing Transcatheter Aortic Valve Implantation. AB - End-stage renal disease (ESRD) affects approximately 2% to 4% of patients with severe aortic stenosis. It is because these patients have been excluded from clinical trials, the impact of transcatheter aortic valve implantation (TAVI) in this patient group has not been thoroughly investigated. Between April 2008 and March 2015, 2,000 patients (dialysis group, n = 56 [2.8%]) were consecutively enrolled when diagnosed with severe aortic stenosis and eligible to undergo TAVI. Procedural and longer-term outcomes were analyzed and adjusted for differences in baseline characteristics. Patients on dialysis had a higher periprocedural mortality (10.7% vs 1.7%; adjusted odds ratio [adjOR] 5.65, 95% confidence interval [CI] 1.91 to 16.67; p = 0.002) and a lower Valve Academic Research Consortium (VARC)-II (VARC) defined device success (adjOR 0.34, 95% CI 0.15 to 0.79; p = 0.012). At 30 days, there was an increased rate of all-cause mortality (21.4 vs 4.8%; adjOR 4.90, 95% CI 1.96 to 12.26; p = 0.001), cardiovascular (adjOR 3.67, 95% CI 1.43 to 9.41; p = 0.007) and noncardiovascular mortality (adjOR 6.28, 95% CI 1.36 to 9.41; p = 0.019), myocardial infarction (adjOR 9.39, 95% CI 1.84 to 48.03; p = 0.007), bleeding (adjOR 2.48, 95% CI 1.06 to 5.83; p = 0.036) as well as the VARC-II defined early safety combined end point (adjOR 2.97, 95% CI 1.28 to 6.90; p = 0.012) associated with dialysis. Dialysis was associated with poor survival at one (57.1% vs 84.2%) and 3 years (26.8% vs 66.9%) with or without the consideration of the first 72 hours (p <0.001; adjusted p <0.001). Although, in the multivariable regression analysis, reduced ejection fraction, peripheral arterial disease, pulmonary hypertension (PH), frailty and dialysis were associated with 1-year mortality, only PH (>60 mm Hg) remained significant in an analysis restricted to the dialysis patients (adjusted hazard ratio 2.68; 95% CI 1.18 to 5.88; p = 0.018). PH had a sensitivity of 45.8%, a specificity of 81.3%, and a positive predictive value of 64.7%. In conclusion, dialysis is an independent predictor of mortality in patients who underwent TAVI. Long-term mortality in dialysis patients appears to be largely determined by the kidney disease and/or dialysis itself whereas VARC-II defined complications are largely unaffected. An increased short-term mortality still calls for (pre-) procedural optimization. PMID- 30424872 TI - Corrigendum "The CCCH-type transcription factor BnZFP1 is a positive regulator to control oleic acid levels through the expression of diacylglycerol O acyltransferase 1 gene in Brassica napus" [Plant Physiology and Biochemistry Volume 132, November 2018, Pages 633-640]. PMID- 30424875 TI - Eruptive sebaceous hyperplasias secondary to ciclosporin in a renal transplant patient. PMID- 30424873 TI - Intracellular and extracellular effector activity of mouse neutrophils in response to cutaneous and visceral Leishmania parasites. AB - Neutrophils are short-lived phagocytic cells equipped with several receptors for pathogen recognition and phagocytosis and have intracellular and extracellular effector mechanisms that can inactivate pathogens. Leishmaniases are diseases caused by different species of Leishmania that mainly afflicts poorer populations of tropical and subtropical regions and immunocompromised individuals. Thus, the present study aims to investigate the effector response of murine neutrophils to species of Leishmania causing American cutaneous leishmaniasis and zoonotic visceral leishmaniasis by evaluating pattern recognition receptors (PRR) and intracellular and extracellular effector microbicide activity. When exposed to Leishmania parasites, mouse neutrophils produced superoxide, released enzymes in the extracellular space and generated neutrophil extracellular traps, although PRR gene expression is negatively regulated. L. infantum, L. guyanensis, and L. shawi inhibited enzymatic activity, whereas L. amazonensis reduced the emission of extracellular structures. These findings indicate that although neutrophils trigger several microbicide mechanisms, Leishmania parasites can manipulate extracellular effector mechanisms. The present study also provides evidence that neutrophils can internalize parasites by coiling phagocytosis. PMID- 30424876 TI - Special Issue on Advanced Drug Delivery Approaches for Inner Ear Therapeutics. PMID- 30424877 TI - Circular RNA-100290 promotes cell proliferation and inhibits apoptosis in acute myeloid leukemia cells via sponging miR-203. AB - Circular RNA (CirRNA) is a type of noncoding RNA that has been shown to play a unique role in tumor development and other fields in recent years. In this study, we aimed to explore the biological role of hsa_circ_100290 in acute myeloid leukemia (AML). First, we found that the expression of hsa_circ_100290 was increased in human AML samples and cell lines. Down-regulation of hsa_circ_100290 significantly suppressed cell proliferation of AML cells. Silencing hsa_circ_100290 also dramatically induced cell cycle arrest and apoptosis. Bioinformatic prediction and luciferase assay revealed that hsa_circ_100290 and Rab10 were targeted by miR-203. Validation experiments verified that hsa_circ_100290 was co-expressed with Rab10 and was negatively correlated with miR-203 expression. Moreover, rescue experiments demonstrated that miR-203 inhibitor could reverse the role of hsa_circ_100290 knockdown on proliferation and apoptosis in AML cells. Overall, the present study identifies the crucial regulation of hsa_circ_100290 in AML cell proliferation and apoptosis via targeting the miR-203/Rab10 axis. PMID- 30424878 TI - Revalidation of recombinant aequorin as a light emission standard: Estimation of specific activity of Gaussia luciferase. AB - To validate the use of recombinant aequorin (reAequorin) as a light emission standard, the protein concentrations of highly purified reAequorin were determined by amino acid composition analysis, and the presence of active reAequorin was confirmed by the ratio of absorbance peak at 460 nm to that at 280 nm. The high correlation of the luminescence intensity with the protein concentration showed that reAequorin could be used for a light emission standard to study the luminescence properties of luciferases and to evaluate the detection sensitivity of luminometers. The specific activity of Gaussia luciferase with Imax was 7.5-fold higher than that of reAequorin and was calculated to be 3.8 * 1016 quanta/mg protein. PMID- 30424879 TI - Home sperm testing device versus laboratory sperm quality analyzer: comparison of motile sperm concentration. AB - OBJECTIVE: To test the ability of the smartphone-based YO Home Sperm Test to accurately and precisely measure motile sperm concentration (MSC) versus the SQA Vision, an automated laboratory semen analyzer. DESIGN: MSC compared for the YO device on Galaxy and iPhone smartphones versus the SQA-Vision in a double-blind manner. SETTING: Academic medical center. PATIENT(S): Donor semen samples from 24 men in 144 aliquots. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Accuracy, precision, and agreement assessed between the YO device and the SQA-Vision for MSC results. RESULT(S): The YO device demonstrated good correlation and good to moderate agreement with the SQA-Vision for MSC results up to a range of 94 * 106/mL with Pearson and concordance correlation coefficient above 0.92. The YO also showed a very high level of accuracy (97.8%) with positive and negative percent agreement above 94%. The difference in coefficient of variation between the YO and the SQA-Vision was low (between 9.4% and 11.2%) and not statistically significant. The precision among the YO phone devices was lower (16.0%) than the manufacturer's claim of <=20%. CONCLUSION(S): The smartphone-based device has a high level of accuracy and precision when compared with the SQA-Vision. It can detect samples with abnormally "low" MSC (below 6 * 106/mL cutoff), which supports its use as an effective home sperm test for screening "low" and "moderate/normal" MSC cases. In addition, the device effectively identifies varying levels of normal MSC in a precise manner over a wide range of normal MSC. Thus, the YO Score can improve patient satisfaction and empowerment. PMID- 30424880 TI - Commentary: when embryos hit the brakes. PMID- 30424881 TI - What are patients doing with their mosaic embryos? Decision making after genetic counseling. AB - OBJECTIVE: To assess patient decisions regarding mosaic embryos and their impact on clinical outcomes. DESIGN: Review of patients who had genetic counseling regarding mosaic embryos. SETTING: Academic department. PATIENT(S): Ninety-eight patients who had mosaic embryos but no euploid embryos. INTERVENTION(S): Genetic counseling to discuss mosaic-embryo transfer (MET) after preimplantation genetic testing for aneuploidy. MAIN OUTCOME MEASURE(S): Patient decisions regarding MET. Outcomes for patients who pursued MET were compared with those for patients who pursued additional in vitro fertilization or intrauterine insemination cycles. Decisions regarding prenatal testing after MET were assessed. RESULT(S): Initially, 29.6% of patients pursued MET and 41.8% attempted a new treatment cycle. Only 6.1% of patients discarded their mosaic embryos without further treatment. Of the remaining patients, 2.0% transported their mosaic embryos to a different facility and 20.5% had not taken further action while their embryos remain stored. Patients who pursued additional cycles were more likely to have an ongoing pregnancy compared with those who pursued MET (51.2% vs. 27.6%; P<.05); however, there was no statistically significant difference in the percentage of patients who had at least one biochemical pregnancy or spontaneous abortion. Ultimately, 32.7% of patients underwent MET, and 54.5% of pregnant patients pursued amniocentesis. CONCLUSION(S): MET is desired by a substantial proportion of patients who do not have euploid embryos. Patients who opt for additional treatment cycles have a greater chance of achieving an ongoing pregnancy compared with those who pursue MET; however, future studies are needed to compare the cost effectiveness for both options. PMID- 30424882 TI - Transfer of embryos with segmental mosaicism is associated with a significant reduction in live-birth rate. AB - OBJECTIVE: To evaluate the impact of segmental mosaicism on pregnancy outcomes from the transfer of embryos previously designated as euploid. DESIGN: Retrospective cohort analysis. SETTING: Single, private, high-volume fertility center. PATIENT(S): Three hundred and twenty-seven women who underwent 377 frozen single euploid embryo transfers. INTERVENTION(S): Trophectoderm biopsy of embryos cultured to the blastocyst stage, where all transferred embryos were designated euploid by high-density oligonucleotide array comparative genomic hybridization (aCGH); after ascertaining all outcomes, revaluation of aCGH results for evidence of segmental mosaicism (defined as mosaicism on a portion of a chromosome). MAIN OUTCOME MEASURE(S): Live-birth rate and spontaneous abortion rate. RESULT(S): Of the 377 embryos transferred, 357 were euploid with no mosaicism, and 20 embryos had segmental mosaicism. Segmental mosaics had a statistically significantly lower live-birth rate compared with euploid controls (30.0% vs. 53.8%). When controlling for age and day of Trophectoderm biopsy, the odds for live birth after transfer of segmental mosaics were reduced by 66% compared with euploid controls (0.34; 95% confidence interval, 0.13-0.92). The spontaneous abortion rate was statistically significantly higher after transfer of segmental mosaics compared with euploid controls (40.0% vs. 18.2%). CONCLUSION(S): Blastocysts with segmental mosaicism have reduced reproductive potential but retain the ability to result in live birth. These results support reporting segmental mosaicism to optimize selection of a single embryo for transfer that will maximize the chance of life birth. PMID- 30424883 TI - Editorial training in radiology. PMID- 30424884 TI - No MELAS syndrome without heteroplasmy levels or multisystem examination. PMID- 30424885 TI - Measurement of ambient dose equivalent rates by walk survey around Fukushima Dai ichi Nuclear Power Plant using KURAMA-II until 2016. AB - Ambient dose equivalent rates in various environments related to human lives were measured by walk surveys using the KURAMA-II systems from 2013 to 2016 within an 80-km radius of the Fukushima Dai-ichi Nuclear Power Plant. The dose rate of the locations where the walk survey was performed decreased to about 38% of its initial value in the 42 months from June 2013 to the December 2016, which was beyond that attributable to the physical decay of radiocaesium. The ecological half-life of the slow decreasing component was evaluated to be 4.1 +/- 0.2 y. The air dose rates decreased depending on the level of the evacuation areas, and the decrease in the dose rates was slightly larger in populated areas where humans are active. The dose rates as measured by walk surveys exhibited a good correlation with those by car-borne surveys, suggesting that car-borne survey data are reflecting the air dose rates in living environments surrounding roads. The comparison of walk survey data with car-borne survey data indicated that the air dose rate varies largely even within a 100 m square area, and the variation is enhanced by human activities. The dose rates measured by the walk surveys were estimated to be medial of those along roads and those of undisturbed flat ground, and they were found to be decreasing quickly compared with the air dose rate from the flat ground fixed-point measurements. PMID- 30424886 TI - Income-based inequities in access to psychotherapy and other mental health services in Canada and Australia. AB - This paper compares income-based inequities in access to psychotherapy and other mental health services in Canada and Australia, two federal parliamentary systems with sharply contrasting responses to high rates of unmet need. Income-based inequity is measured by need-standardized concentration indices, using comparable data from the Canadian Community Health Survey 2011-2012 and the Australian National Survey of Mental Health and Well-Being 2007. The results indicate that utilization of psychologist services is more concentrated at higher income levels (i.e. pro-rich) than the other provider groups in both countries, and may be more pro-rich in Canada than in Australia. While the distribution of unmet need for psychotherapy was expected (as a negative indicator of access) to be more concentrated at lower income levels (i.e. pro-poor) under Canada's two-tier system, unmet need was not more equitable in Australia despite expanded public insurance coverage. As psychotherapy was made universally affordable for the first time in Australia in 2006, a possible backlog effect may have driven up both service utilization and unmet need, particularly among lower-income Australians. The impact of different Medicare co-payment policies also warrants further exploration. PMID- 30424887 TI - The Public Health Status and Foresight report 2014: Four normative perspectives on a healthier Netherlands in 2040. AB - Policy-oriented foresight reports aim to inform and advise decision-makers. In value-laden areas such as public health and healthcare, deliberative scenario methods are clearly needed. For the sixth Dutch Public Health Status and Forecasts-report (PHSF-2014), a new approach of co-creation was developed aiming to incorporate different societal norms and values in the description of possible future developments. The major future trends in the Netherlands were used as a starting point for a deliberative dialogue with stakeholders to identify the most important societal challenges for public health and healthcare. Four societal challenges were identified: 1) To keep people healthy as long as possible and cure illness promptly, 2) To support vulnerable people and enable social participation, 3) To promote individual autonomy and freedom of choice, and 4) To keep health care affordable. Working with stakeholders, we expanded these societal challenges into four corresponding normative scenarios. In a survey the normative scenarios were found to be recognizable and sufficiently distinctive. We organized meetings with experts to explore how engagement and policy strategies in each scenario would affect the other three societal challenges. Possible synergies and trade-offs between the four scenarios were identified. Public health foresight based on a business-as-usual scenario and normative scenarios is clearly practicable. The process and the outcomes support and elucidate a wide range of strategic discussions in public health. PMID- 30424888 TI - Dengue vaccine: WHO position paper, September 2018 - Recommendations. AB - This article presents the World Health Organization's (WHO) recommendations on the use of dengue vaccine excerpted from the WHO position paper on dengue vaccine - September 2018, published in the Weekly Epidemiological Record [1]. This position paper replaces the July 2016 WHO position paper concerning the first licensed dengue vaccine, CYD-TDV [2]. The position paper presents new evidence that became available in November 2017. A retrospective analysis of data from clinical trials, using a new serological assay classified trial participants according to their dengue serostatus prior to receipt of the first vaccine dose. The analysis revealed an excess risk of severe dengue in seronegative vaccine recipients compared to seronegative non-vaccinated individuals, while confirming long-term protection in seropositive individuals [3]. The paper provides revised guidance on dengue vaccination strategies from a population health perspective. Footnotes to this paper provide a number of core references including references to grading tables that assess the quality of the scientific evidence, and to the evidence-to-recommendation table. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO's current position on the use of vaccines in the global context. Recommendations on the use of dengue vaccine CYD-TDV were discussed by SAGE in April 2018; evidence presented at the meeting can be accessed at: http://www.who.int/immunization/sage/meetings/2018/april/presentations_background docs/en/. PMID- 30424889 TI - 69-Year-Old Woman With Fatigue, Dyspnea, and Lower Extremity Pain. PMID- 30424890 TI - Radiologic assessment of gastric emptying of water-soluble contrast media: New data security from a longitudinal study. AB - BACKGROUND AND OBJECTIVES: Practice guidelines for preoperative fasting have not clearly established the fasting time needed after oral administration of water soluble contrast media. The aim of this study was to determine the time required for the gastric emptying during the water-soluble contrast media in patients with acute abdominal pain. METHODS: This prospective longitudinal study included sixty eight patients older than 18 years of age with acute abdominal pain, who required a water-soluble contrast media enhanced abdominal computed tomography study. Plain radiographs were obtained hourly until complete the gastric emptying. Patients with probable bowel obstruction were not included in the study. RESULTS: A total of 31 (45,6%), 54 (79,4%), and 64 (94,1%) patients achieved a complete gastric clearance of barium in 1, 2 and 3 hours, respectively. All patients achieved complete emptying of water-soluble contrast media within 6 hours. Gastric emptying time was not associated with gender (P=0,44), body mass index (P=.35), fasting time prior to water-soluble contrast media intake (P=0,12), administration of opioids in the emergency room (P=0,7), and the presence of comorbidities (P=0,36). CONCLUSION: Ninety-four percent of the patients with acute abdominal pain achieved complete gastric emptying within 3hours after the administration of water-soluble contrast media. All of them achieved complete gastric emptying within 6hours. The results suggested 6hours after oral intake of the contrast media is enough to complete transit of water-soluble contrast media through the stomach and avoid unnecessary risks. PMID- 30424891 TI - Pump, pipes, and filter: do SGLT2 inhibitors cover it all? PMID- 30424892 TI - SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. AB - BACKGROUND: The magnitude of effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on specific cardiovascular and renal outcomes and whether heterogeneity is based on key baseline characteristics remains undefined. METHODS: We did a systematic review and meta-analysis of randomised, placebo-controlled, cardiovascular outcome trials of SGLT2i in patients with type 2 diabetes. We searched PubMed and Embase for trials published up to Sept 24, 2018. Data search and extraction were completed with a standardised data form and any discrepancies were resolved by consensus. Efficacy outcomes included major adverse cardiovascular events (myocardial infarction, stroke, or cardiovascular death), the composite of cardiovascular death or hospitalisation for heart failure, and progression of renal disease. Hazard ratios (HRs) with 95% CIs were pooled across trials, and efficacy outcomes were stratified by baseline presence of atherosclerotic cardiovascular disease, heart failure, and degree of renal function. FINDINGS: We included data from three identified trials and 34 322 patients (60.2% with established atherosclerotic cardiovascular disease), with 3342 major adverse cardiovascular events, 2028 cardiovascular deaths or hospitalisation sfor heart failure events, and 766 renal composite outcomes. SGLT2i reduced major adverse cardiovascular events by 11% (HR 0.89 [95% CI 0.83 0.96], p=0.0014), with benefit only seen in patients with atherosclerotic cardiovascular disease (0.86 [0.80-0.93]) and not in those without (1.00 [0.87 1.16], p for interaction=0.0501). SGLT2i reduced the risk of cardiovascular death or hospitalisation for heart failure by 23% (0.77 [0.71-0.84], p<0.0001), with a similar benefit in patients with and without atherosclerotic cardiovascular disease and with and without a history of heart failure. SGLT2i reduced the risk of progression of renal disease by 45% (0.55 [0.48-0.64], p<0.0001), with a similar benefit in those with and without atherosclerotic cardiovascular disease. The magnitude of benefit of SGLT2i varied with baseline renal function, with greater reductions in hospitalisations for heart failure (p for interaction=0.0073) and lesser reductions in progression of renal disease (p for interaction=0.0258) in patients with more severe kidney disease at baseline. INTERPRETATION: SGLT2i have moderate benefits on atherosclerotic major adverse cardiovascular events that seem confined to patients with established atherosclerotic cardiovascular disease. However, they have robust benefits on reducing hospitalisation for heart failure and progression of renal disease regardless of existing atherosclerotic cardiovascular disease or a history of heart failure. FUNDING: None. PMID- 30424893 TI - Assessment and management of pesticide pollution at a river basin level part II: Optimization of pesticide monitoring networks on surface aquatic ecosystems by data analysis methods. AB - The high cost of extensive pesticide monitoring studies, required for the protection of water resources, and the necessity of early identification of environmental threats, highlighted the need for prioritization of pesticides and sampling sites to be monitored. The aim of this study was to develop an optimum surface water monitoring network at a catchment scale including only the sites of a catchment vulnerable to pesticide pollution. The identification of sampling sites vulnerable to pesticide pollution (VPS) was based on the data of an intensive monitoring survey of 302 pesticides in 102 stationary sampling sites located on the surface water network of a river basin. In the proposed methodology the left-censored data of the analytical results derived from the above mentioned monitoring campaign were included in the statistical analyses by transforming all the raw data into categorical variables and arranging them in ordinal scales based on ecotoxicological thresholds derived from pesticide toxicity tests on aquatic non-target organisms. The categorized data were subjected to Categorical Principal Component Analysis with Optimal Scaling. For the identification of the VPS, the Squared Mahalanobis Distance criterion was applied on the extracted values (scores) of the significant principal components. With this methodology a 46% reduction in the number of the monitoring stations was achieved. This approach will be valuable in establishing more cost effective monitoring schemes in the future in other basins and in developing targeted measures to eliminate or limit the effect of critical pollution sources in surface aquatic systems. Moreover, by applying the proposed methodology, historical monitoring data can be used to initiate more efficient pesticide monitoring campaigns in the future. PMID- 30424894 TI - External validation of a prognostic model incorporating quantitative PET image features in oesophageal cancer. AB - AIM: Enhanced prognostic models are required to improve risk stratification of patients with oesophageal cancer so treatment decisions can be optimised. The primary aim was to externally validate a published prognostic model incorporating PET image features. Transferability of the model was compared using only clinical variables. METHODS: This was a Transparent Reporting of a multivariate prediction model for Individual Prognosis Or Diagnosis (TRIPOD) type 3 study. The model was validated against patients treated with neoadjuvant chemoradiotherapy according to the Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS) trial regimen using pre- and post harmonised image features. The Kaplan-Meier method with log-rank significance tests assessed risk strata discrimination. A Cox proportional hazards model assessed model calibration. Primary outcome was overall survival (OS). RESULTS: Between 2010 and 2015, 449 patients were included in the development (n = 302), internal validation (n = 101) and external validation (n = 46) cohorts. No statistically significant difference in OS between patient quartiles was demonstrated in prognostic models incorporating PET image features (X2 = 1.42, df = 3, p = 0.70) or exclusively clinical variables (age, disease stage and treatment; X2 = 1.19, df = 3, p = 0.75). The calibration slope beta of both models was not significantly different from unity (p = 0.29 and 0.29, respectively). Risk groups defined using only clinical variables suggested differences in OS, although these were not statistically significant (X2 = 0.71, df = 2, p = 0.70). CONCLUSION: The prognostic model did not enable significant discrimination between the validation risk groups, but a second model with exclusively clinical variables suggested some transferable prognostic ability. PET harmonisation did not significantly change the results of model validation. PMID- 30424895 TI - Trends and comparative effectiveness of inpatient radical hysterectomy for cervical cancer in the United States (2012-2015). AB - OBJECTIVE: Report the up-to-date trends in surgical approach for cervical cancer and compare outcomes between open and minimally invasive routes. METHODS: Radical Hysterectomy (RH) cases from the National Inpatient Sample (NIS) dataset between 2012 and 2015 were grouped into abdominal (ARH) and Minimally Invasive Surgery (MIS). The MIS group was subdivided as "Laparoscopic", "Robotic", and "Converted". Univariate and multivariable logistic regression were used to analyze differences in complication rates. The National Surgical Quality Improvement Dataset 2015 was used for validation. RESULTS: A total of 7180 cases from NIS were identified. Overall, there was 44% decline in RH cases from 2012 (n = 2220) to 2015 (n = 1255). A proportionate increase in robotic cases from 31.5% in 2012 to 41.4% in 2015 was noted. By intention to treat analysis, the rate of at least one complication for abdominal cases was 24.8% compared to 10% for MIS (p < 0.001). On multivariate analysis, abdominal cases had higher odd of any one complication (aOR 2.9,95% CI 2.12-4.00), medical complication (aOR 3.25,95% CI 2.15-4.19), infectious complication (aOR 3.76,95% CI 2.1-6.1) but not for surgical complications (aOR 1.7,95% CI 0.5-5.6). AH resulted in longer hospital stay compared to MIS (4.3 vs 1.9 days, p < 0.001). Median cost of AH was $12,624, laparoscopic $12,873, robotic $14,029 and converted cases $17,036. NSQIP analysis supplemented the outcomes to 30-days and showed similar findings. CONCLUSIONS: Perioperative complications are significantly lower for MIS procedures. These data should be used for contemporary cost-effective analysis and comprehensive counseling regarding risks and benefits of the surgical approach for cervical cancer. PMID- 30424896 TI - Perceptions of Genetically Engineered Technology in Developed Areas. AB - Consumer doubts and concerns about genetically engineered (GE) foods have been identified through surveys and calls for labeling. Comparing American, Canadian, and European consumer perceptions about GE technology provides insights to stakeholders interested in possible hurdles associated with technology adoption, which is especially important given the emerging growth of genome editing. PMID- 30424897 TI - Reply to: "Hip fracture risk in patients with alcoholic cirrhosis: Do comorbidities and complications matter?" PMID- 30424898 TI - Combined strategy of siRNA and osteoclast actin cytoskeleton automated imaging to identify novel regulators of bone resorption shows a non-mitotic function for anillin. AB - Osteoclasts are the main cells responsible for the resorption of mineralized extracellular matrices. They are the major targets for anti-resorptive therapies to manage osteoporosis, a major public health problem. Osteoclasts are giant multinucleated cells that can organize their a unique adhesion structure based on a belt of podosomes, which is the keystone of the bone resorption apparatus. We combined differential transcriptomics and siRNA screening approaches to get a broader view of cytoskeletal regulators that participate in the control of osteoclast cytoskeleton and identify novel regulators of bone resorption by osteoclasts. We identified 20 new candidate regulators of osteoclasts cytoskeleton including Fkbp15, Spire1, Tacc2 and RalA, for which we confirmed they are necessary for proper organization of the podosome belt. We also showed that Anillin, well known for its role during cytokinesis, is essential in osteoclasts for correct podosome patterning and efficient bone resorption. In particular, Anillin controls the levels of the GTPase RhoA, a known regulator of osteoclast cytoskeleton and resorption activity. Finally, we set up and validated an automated imaging strategy based on open-source software for automatic and objective measurement of actin cytoskeleton organization in osteoclasts. We provide these pipelines that are useful to automatically assess the effect of collections of siRNAs or chemical compounds on osteoclast cytoskeleton or differentiation. PMID- 30424899 TI - [Motives and perceptions of family care for dependent elderly]. AB - OBJECTIVE: To identify and analyze the motives that lead people to take care of a dependent relative and their perceptions of the care situation. DESIGN: Phenomenological qualitative study. LOCATION: The study was conducted in the Jaen Norte Sanitary District, during 2013 and 2014. PARTICIPANTS: A total of 13 primary caregivers of dependent elderly relatives with a minimum experience of one year in care participated, selected by intentional sampling. METHOD: Discourse analysis of 13 in-depth interviews considering the semantic and pragmatic content and field notes. Triangulation was performed in the analysis to favor the credibility of the study. RESULTS: The motives for caring for a dependent relative are:'Familism','Material gains' and'Social pressure'. In turn, the'Familism' include 7 dimensions/motives:'Family obligation','Affection to the person taken care of','Return the received','Well-being of the person taken care of','Respect to the decision of the person taken care of','Agreement','Habit'. When the main motive to take care of is the'Family obligation', the'Material gains' or the'Social pressure' caregivers do not manifest positive perceptions for caring, and vice versa. CONCLUSION: This study has identified that'Familism','Material gains' and'Social pressure' are reasons why people care for a dependent relative in our sociocultural environment, as well as the relationship with the perception of the care situation. This will facilitate the identification of caregivers with greater predisposition to suffer negative consequences for caring and the development of interventions aimed at the prevention of such consequences. PMID- 30424900 TI - Depression and African Americans in the First Decade of Midlife: The Consequences of Social Roles and Gender. AB - OBJECTIVE: This study examined gender differences in how three social roles - marriage, parenthood, and employment - impact depressive symptoms and clinically significant depression for African Americans in the first decade of midlife, from 40 to 50 years old. Specifically, we sought to understand the associations between roles configurations (e.g., married parent versus employed only) and depressed mood as well as diagnosable depression. METHOD: The data for this study were extracted from the National Longitudinal Survey of Youth 1979 cohort (NLSY79). Constituting a representative sample of non-institutionalized Americans, NLSY respondents were interviewed each year from 1979 to 1994 and biennially thereafter. Our study included 2372 African Americans. We used ordinary least squares regression to estimate depressive symptoms and logistic regression to model the probability of clinically significant depression. RESULTS: African American men who were married/cohabiting only, employed only, or married/cohabiting, employed parents experienced lower levels of depressed mood, compared to African American women. Holding none of the roles under consideration in this study resulted in higher levels of depressive symptoms for African American women than for African American men. For diagnosable depression, the role combinations of married/cohabiting, employed and married/cohabiting, employed parent resulted in a lower probability of depression for African American men, compared to their female counterparts. Regardless of gender, role configurations that included employment produced the lowest levels of depressive symptoms and the lowest likelihood of clinically significant depression. CONCLUSIONS: Overall, the pattern of findings showed that role configurations are important in shaping mental health for both African American men and women. Multiple role combinations that included employment make individuals less vulnerable to depressive symptoms and clinically significant depression. Having no roles (e.g., unmarried, unemployed, non-parent) was more problematic for the well-being of African American women compared to African American men, but not as detrimental to African American mental health as prior studies focused on other racial and ethnic groups have suggested. PMID- 30424901 TI - Authors Reply. PMID- 30424902 TI - Family caregivers experiences of the pre-diagnostic stage in frontotemporal dementia. AB - Frontotemporal dementia (FTD) is a neurodegenerative disease with symptoms that differs from other dementias. Commonly early symptoms in FTD are changes in personality and behavior, which can be interpreted as psychiatric disease. The delay in FTD diagnosis contributes to the burden of family caregivers. Therefore, it is important to have more knowledge about the pre-diagnostic stage. In this qualitative interview study, we explored fourteen family caregiver's experiences of the pre-diagnostic stage of frontotemporal dementia (FTD). Our findings suggest that the family caregivers experienced the pre-diagnostic stage of FTD as changes in the interpersonal relationship with their loved one. These changes were often subtle and difficult for family caregivers to explain to others. The findings from our study illuminate the importance of medical staff paying attention when a next of kin is concerned about subtle changes in a loved one. The findings also illuminate that awareness of FTD should be raised. PMID- 30424903 TI - Small-incision lenticule extraction for the correction of myopic astigmatism. AB - PURPOSE: To report the outcomes of small-incision lenticule extraction (SMILE) in myopic eyes with astigmatism of 1.0 to 3.0 diopters (D). SETTING: Center for Refractive Surgery, Eye Department, St. Francis Hospital, Muenster, Germany. DESIGN: Retrospective case series. METHODS: Inclusion criteria were myopia of 0.5 D or more, astigmatism between -1.0 D and 3.0 D, and decimal corrected distance visual acuity (CDVA) of 1.0 or better. RESULTS: The study comprised 206 eyes. Preoperatively, the mean attempted spherical equivalent (SE) correction was -5.45 +/- 2.37 D (range -1.25 to -11.38 D) and the mean cylinder was -1.52 +/- 0.57 D (range -1.0 to -3.0 D). Three months postoperatively, the mean SE refraction was -0.07 +/- 0.38 D (range -1.25 to +1.00 D) and the mean cylinder was -0.32 +/- 0.29 D (range 0.0 to -1.5 D). The mean decimal uncorrected distance visual acuity (UDVA) was 1.13, the mean efficacy index was 0.87, and the mean safety index was 1.00. The UDVA was the same as or better than the CDVA in 67% of cases. The angle of error was +/-5 degrees in 67% and +/-15 degrees in 94% of cases, and the residual astigmatism was 0.5 D or less in 88% and 1.0 D or less in all patients. CONCLUSION: Small-incision lenticule extraction for the correction of myopic astigmatism was safe and effective, with outcomes comparable to those reported for laser in situ keratomileusis using modern eye-tracking systems. PMID- 30424904 TI - Femtosecond laser-assisted cataract surgery versus conventional phacoemulsification: Refractive and aberrometric outcomes with a diffractive multifocal intraocular lens. AB - PURPOSE: To compare the outcomes of conventional phacoemulsification and femtosecond laser-assisted cataract surgery followed by multifocal intraocular lens (IOL) implantation. SETTING: Asan Medical Center, Seoul, South Korea. DESIGN: Retrospective case series. METHODS: Depending on their preference, patients had femtosecond laser-assisted cataract surgery or conventional phacoemulsification. Patients in the femtosecond group with corneal astigmatism greater than 0.75 diopter also had arcuate keratotomy. All eyes had multifocal IOL implantation. One month after treatment, the uncorrected distance and near visual acuities, spherical equivalent, corneal and refractive astigmatism, aberrometry results, and questionnaire results were compared between groups. Correlations between target-induced astigmatism (TIA) and surgically induced astigmatism (SIA) were also compared between the groups. RESULTS: The femtosecond group comprised 17 patients (23 eyes), with arcuate keratotomy performed in 14 eyes. The conventional phacoemulsification group comprised 22 patients (26 eyes). In the femtosecond group, the difference in corneal astigmatism between preoperatively and postoperatively was statistically significant. The correlation between TIA and SIA was greater in the femtosecond group. Corneal root-mean square higher-order aberrations (RMS HOAs) (P < .01) and total trefoil (P = .043) were significantly higher in the femtosecond laser group. However, internal total RMS (P = .05), tilt (P = .041), and RMS HOAs (P = .047) were significantly lower in the femtosecond group. Satisfaction scores were significantly higher in the femtosecond group. CONCLUSIONS: Astigmatic change was more predictable in the femtosecond laser-assisted cataract surgery group. Internal aberrations, including total RMS, tilt, and RMS HOAs, were lower in the femtosecond group, and patients in that group were more satisfied. PMID- 30424905 TI - Revealing Real-Life Experiences With Antifibrotic Drugs in Idiopathic Pulmonary Fibrosis. PMID- 30424906 TI - Cystic Adenocarcinoma of the Lung. PMID- 30424907 TI - Lysosomal Ion Channels as Decoders of Cellular Signals. AB - Lysosomes, the degradation center of the cell, are filled with acidic hydrolases. Lysosomes generate nutrient-sensitive signals to regulate the import of H+, hydrolases, and endocytic and autophagic cargos, as well as the export of their degradation products (catabolites). In response to environmental and cellular signals, lysosomes change their positioning, number, morphology, size, composition, and activity within minutes to hours to meet the changing cellular needs. Ion channels in the lysosome are essential transducers that mediate signal initiated Ca2+/Fe2+/Zn2+ release and H+/Na+/K+-dependent changes of membrane potential across the perimeter membrane. Dysregulation of lysosomal ion flux impairs lysosome movement, membrane trafficking, nutrient sensing, membrane repair, organelle membrane contact, and lysosome biogenesis and adaptation. Hence, activation and inhibition of lysosomal channels by synthetic modulators may tune lysosome function to maintain cellular health and promote cellular clearance in lysosome storage disorders. PMID- 30424908 TI - [Pinch-off syndrom or costo clavicular forceps syndrom]. AB - Implantable catheter systems are the most common procedure used for patients requiring chemotherapy or long-term drug administration. Several procedures are used for the installation of these systems. Patients with long-term subclavian venous catheters described a progressive rupture of the catheter which is a rare complication. This rupture is most often due to costoclavicular forceps or Pinch off syndrome (POS). We report 07 cases of Pinch-off syndrome to evaluate our diagnostic and therapeutic approach. PMID- 30424909 TI - AQUA1 is a mercury sensitive poplar aquaporin regulated at transcriptional and post-translational levels by Zn stress. AB - Aquaporins are water channel proteins that regulate plant development, growth, and response to environmental stresses. Populus trichocarpa is one of the plants with the highest number of aquaporins in its genome, but only few of them have been characterized at the whole plant functional level. Here we analyzed a putative aquaporin gene, aqua1, a gene that encodes for a protein of 257 amino acid with the typical NPA (Asp-Pro-Ala) signature motif of the aquaporin gene family. aqua1 was down-regulated of ~10 fold under excess Zn in both leaves and roots, and conferred Zn tolerance when expressed in yeast Zn hypersensitive strain. In vivo localization of AQUA1-GFP in Arabidopsis protoplast showed a heterogeneous distribution of this protein on different membranes destined to form aggregates related to autophagic multivesicular bodies. Zn-dependent AQUA1 GFP re-localization was perturbed by phosphatases' and kinases' inhibitors that could affect both intracellular trafficking and aquaporins' activity. Exposed to high concentration of Zn, AQUA1 also co-localized with AtTIP1;1, a well-known Arabidopsis vacuolar marker, probably in pro-vacuolar multivesicular bodies. These findings suggest that high concentration of Zn down-regulates aqua1 and causes its re-localization in new forming pro-vacuoles. This Zn-dependent re localization appears to be mediated by mechanisms regulating intracellular trafficking and aquaporins' post-translational modifications. This functional characterization of a poplar aquaporin in response to excess Zn will be a useful reference for understanding aquaporins' roles and regulation in response to high concentration of Zn in poplar. PMID- 30424910 TI - Conjunctival papillomatosis in children treated with co-adjuvant topical interferon alpha-2b. AB - A series of paediatric patients is presented in whom topical interferon alpha-2b was used as a co-adjuvant treatment for conjunctival papilloma. This condition is frequently associated with human papillomavirus infection. There is little information on the pediatric population with the use of interferon for the treatment of these lesions. In this case series, adjuvant treatment with topical interferon alpha-2b in paediatric patients showed no recurrence and good tolerance. PMID- 30424911 TI - Oxidant and antioxidant levels and DNA damage in tuberous sclerosis. AB - OBJECTIVE: The pathogenesis of inherited diseases is thought to involve oxidative stress and the associated DNA damage, which are also implicated in many other conditions including cancer. Tuberous sclerosis is a genetic disease with autosomal dominant inheritance pattern that is characterized by the development of hamartomas in multiple organ systems. Oxidative stress and the related DNA damage are also likely to play a significant role in the pathogenesis of this condition. Thus, our study aimed to assess total oxidant-antioxidant level, oxidative stress index and DNA damage in patients diagnosed with tuberous sclerosis. METHODS: The study included 30 patients with tuberous sclerosis between the ages of 0 and 16 years. The control group consisted of 29 age-matched healthy children. Blood samples obtained from each subject were centrifuged to separate the sera. The Total Antioxidant Status (TAS) and Total Oxidant Status (TOS) were measured in serum samples with a Thermo Scientific Multiscan plate reader (FC, 2011-06, USA) at wavelengths of 240 nm and 520 nm, respectively. The measured TAS and TOS values were used to calculate the Oxidative Stress Index (OSI). In addition, the Comet Assay Method was used to determine DNA damage in the samples. Data were analyzed using SPSS software. RESULTS: Patients with tuberous sclerosis complex (TSC) and controls were compared with respect to TAS, TOS, and OSI. TAS was significantly lower (p < 0.01), while TOS and OSI were significantly higher (p < 0.01, for both) in patients as compared to controls. In addition, patients had significantly higher DNA damage as shown by the Comet Assay (p < 0.01). CONCLUSIONS: Increased oxidative stress and DNA damage may contribute to the pathogenesis of tuberous sclerosis. PMID- 30424912 TI - Three Japanese patients with 3p13 microdeletions involving FOXP1. AB - BACKGROUND: FOXP1 is known as the gene responsible for neurodevelopmental delay associated with language impairment. Broad clinical findings also include feeding difficulty, muscular hypotonia, and distinctive features. These findings are common between patients with loss-of-function mutations in FOXP1 and 3p13 microdeletion involving FOXP1. Thus, "FOXP1-related intellectual disability syndrome" is now recommended. METHODS: After obtaining informed consent, chromosomal microarray testing was performed for patients with unknown etiology. RESULTS: We identified three Japanese patients with 3p13 microdeletions involving FOXP1. One of the patients showed an additional 1q31.3q32.1 deletion as de novo, which was rather considered as a benign copy number variant. CONCLUSION: This is the first report of patients with 3p13 microdeletions from Japan. All patients showed growth delay, moderate to severe developmental delay, hearing loss, and distinctive facial features including prominent forehead and mid facial hypoplasia. In addition, "square shaped face" commonly observed in all three patients may be a characteristic finding undescribed previously. From the obtained findings, "FOXP1-related intellectual disability syndrome" was considered to be clinically recognizable. PMID- 30424913 TI - Cutaneous adverse drug reactions to psychotropic drugs and their risk factors - a case-control study. AB - Cutaneous adverse drug reactions (CADRs) in patients with psychotropic drugs are common. Large studies on the relevant drugs and other risk factors are still scarce. 594 cases of severe CADRs ("cases") were compared with 8085 cases of other adverse drug reactions ("non-cases") documented in a pharmacovigilance program in psychiatry (AMSP) from 1993 to 2014. Logistic regression was carried out to determine risk factors and between-drug differences. CADRs were relatively more prevalent in patients treated with clomipramine, maprotiline, carbamazepine, lamotrigine, acamprosate, clomethiazole and disulfiram as well as with antidepressants and anticonvulsants as drug classes (p < 0.01). For these drugs, significantly more women were found in patients using maprotiline, lamotrigine (not carbamazepine) and in the groups of antidepressants, tricyclics and anticonvulsants (p < 0.01). Women were more vulnerable to CADRs (67% in cases and 56% in non-cases, p < 0.01). The significantly higher rate of CADRs in women was mainly observed under age of 50 years, i.e. during female reproductive years. In a multivariate logistic regression, female sex, the diagnostic group ICD F1 (substance abuse), maprotiline, carbamazepine, lamotrigine and clomethiazole were identified as risk factors of CADRs. The case/non-case approach allowed to identify risk factors based on empirical data rather than experts' evaluations. The new findings of substance abuse and clomethiazole as risk factors for CADRs have to be confirmed in further studies. Since CADRs can be life-threatening, it is important to be aware of risk factors, especially women during their reproductive period and with lamotrigine treatment. PMID- 30424914 TI - Immediate Effects of the Semi-Occluded Ventilation Mask on Subjects Diagnosed With Functional Dysphonia and Subjects With Normal Voices. AB - PURPOSE: The present study was designed to assess the immediate effects of the semi-occluded ventilation mask (SOVM) in subjects with functional dysphonia and subjects with normal voice. METHODS: Sixty-four participants were included in this study (48 women and 16 men). Thirty-one of them were diagnosed with functional dysphonia and 33 with normal voice. All subjects were randomly assigned to one of two conditions: an experimental condition using the SOVM (n = 33) and a control condition with participants not using the SOVM (n = 31). Thus, within both conditions, participants could be either dysphonic or normal-voiced. This produced a total of four different groups: (1) subjects with normal voice with SOVM (n = 17), (2) subjects with normal voice without SOVM (n = 16), (3) dysphonic subjects with SOVM (n = 16), and (4) dysphonic subjects without SOVM (n = 15). All participants underwent aerodynamic, electroglottographic (EGG), and acoustic assessments, and were also asked to assess their own voice, before and after voice exercises. RESULTS: Significant differences were found for aerodynamic, EGG, and acoustic variables when comparing SOVM conditions (dysphonic and normal) against control. Cepstral peak prominence and EGG contact quotient showed an increase among dysphonic participants with SOVM. L1-L0 showed an increase for all participants in SOVM condition (dysphonic and normal). Self perceived resonant voice quality showed an increase for both groups in SOVM condition. Glottal airflow showed a decrease for the dysphonic participants in SOVM condition. Phonation threshold pressure and subglottic pressure showed a decrease for both groups in SOVM condition. CONCLUSION: The present study suggests that immediate positive effect could be produced by connected speech phonatory tasks using the SOVM in both dysphonic subjects and subjects with normal voice, the change being greater among the former. SOVM seems to promote an easy voice production and a more efficient phonation. PMID- 30424915 TI - Estimated GFR Decline and Tubular Injury Biomarkers With Intensive Blood Pressure Control. PMID- 30424916 TI - Kidney Function and Hospital-Acquired Infections: Worth a Deeper Look. PMID- 30424917 TI - Calcium phosphate coatings elaborated by the soaking process on titanium dental implants: Surface preparation, processing and physical-chemical characterization. AB - OBJECTIVE: Dental implant manufacturers are looking for new surfaces to improve osseointegration. It is accepted that calcium phosphate coatings favor bone healing. Among all the techniques, the soaking process seems attractive because of its ability in producing a bioactive coating at low temperature. The objective of this study is to improve the titanium implant surface roughness and chemistry by optimizing the surface preparation and the soaking process parameters to produce a bioactive and adherent calcium phosphate coating. METHODS: Titanium samples were sandblasted and acid etched. Coatings were realized by an alternate soaking process including a centrifugation step to create a phosphate solution thin film on the implant that reacts with the calcium of the second bath. We performed a characterization of the sample surface with complementary physical and physico-chemical techniques to assess the effect of surface preparation and coating process operating parameters on coating formation and characteristics. RESULTS: Surface preparation led to a roughness around 1.6MUm, micro-porosities, high surface wettability and removed the embedded sandblasting particles. We showed that the centrifugation step is critical and determines the coating formation, coverage and thickness. A thin coating (~2MUm) composed of apatite analogous to bone mineral was deposited. The coating adhesion was demonstrated by screwing/unscrewing test in an artificial jawbone. SIGNIFICANCE: The titanium dental implant pre-treatment and coating developed in this study is expected to favor early implant osseointegration through coating dissolution in vivo and could be associated with biological active agents to confer additional functionality to the coating. PMID- 30424918 TI - Assessing the osteogenic potential of zirconia and titanium surfaces with an advanced in vitro model. AB - OBJECTIVES: In recent years, zirconia dental implants have gained increased attention especially for patients with thin gingival biotypes or patients seeking metal-free restoration. While physical and chemical material surface properties govern the blood-material interaction and subsequent osseointegration processes, the organizational principles underlying the interplay of biochemical and biophysical cues are still not well understood. Therefore, this study investigated how the interaction of a microstructured zirconia surface with blood influences its osseointegration potential compared to microstructured titanium with or without additional nanostructures. METHODS: Microstructured zirconia and micro- (and nano)structured titanium surfaces were fabricated via sandblasting followed by acid etching and their topographical as well as physico-chemical features were thoroughly characterized. Following, an advanced in vitro approach mimicking the initial blood interaction of material surfaces upon implantation was applied. Fibrinogen adsorption, human blood coagulation as well as their influence on cell fate decisions of primary human bone and progenitor cells (HBC) were studied. RESULTS: Obtained surface micro- and nanostructures on titanium surfaces were sharp with rugged peaks whereas zirconia surfaces were less rough with structures being shallower, more round and granular. Compared to titanium surfaces, the zirconia surface showed increased fibrinogen adsorption, higher levels of total accessible fibrinogen gamma-chain moieties yielding in increased platelet adhesion and activation and consequently thrombogenicity. Mineralization of HBC on microstructured surfaces was significantly higher on zirconia than on titanium, but was significantly lower compared to titanium surfaces with nanostructures. SIGNIFICANCE: This study provides insights into blood-material interaction and subsequent cellular events that are important for implant surface development. PMID- 30424919 TI - 234th ENMC International Workshop: Chaperone dysfunction in muscle disease Naarden, The Netherlands, 8-10 December 2017. PMID- 30424920 TI - Nursing Guide to Management of Major Symptoms in Patients with Malignant Glioma. AB - OBJECTIVES: To provide an overview of the symptoms commonly experienced by patients with malignant glioma, and discuss the pathophysiology and interventions associated with those. DATA SOURCES: A review of published scientific literature and clinical literature, and online information from National Comprehensive Cancer Network, Oncology Nursing Society, Epilepsy Foundation of America, and the American Brain Tumor Association. CONCLUSION: The unique symptom burden associated with a malignant glioma diagnosis often disrupts the lives of patients and their caregivers. Clinical support and interventions addressing malignant glioma-related focal deficits, seizures, headaches, venous thromboembolism, mood disturbances, fatigue, and sleep-wake disturbance can positively impact patient and caregiver experiences while living with malignant glioma. IMPLICATIONS FOR NURSING PRACTICE: Understanding the pathophysiology of these symptoms and reviewing nursing-led and supported interventions will empower the nurse in providing comprehensive care to patients with malignant glioma and their caregivers. PMID- 30424921 TI - End-of-Life Care for Patients with Glioma. AB - OBJECTIVE: To describe best practices and guidelines in symptom management at the end of life for adults with malignant glioma. DATA SOURCES: Journal articles, evidence-based reviews, textbooks, and clinical guidelines. CONCLUSION: Symptom management is an essential element of end-of-life care that aims to preserve dignity and quality of life for patients with glioma and their family caregivers. IMPLICATIONS FOR NURSING PRACTICE: Advance care planning using a holistic approach to the patient's symptoms experience and goals of care are necessary to develop, implement, and evaluate outcomes of an evidence-based plan of care tailored for each patient and family. PMID- 30424923 TI - Disagreement: Should the duration of primary hyperparathyroidism impact guidelines for evaluation and treatment? PMID- 30424922 TI - Corrigendum to "A Drosophila model of GDAP1 function reveals the involvement of insulin signalling in the mitochondria-dependent neuromuscular degeneration" [Biochim. Biophys. Acta 1863 (2017) 801-809]. PMID- 30424924 TI - Building community resilience: A scalable model for hemorrhage-control training at a mass gathering site, using the RE-AIM framework. AB - BACKGROUND: In a decade, the US military reduced deaths from uncontrolled bleeding on the battlefield by 67%. This success, coupled with an increased incidence of mass shootings in the US, has led to multiple initiatives intent on translating hemorrhage-control readiness to the civilian sector. However, the best method to achieve widespread population-level hemorrhage-control readiness for civilians has not yet been elucidated. This study evaluates the implementation of American College of Surgeons Bleeding Control training at a National Football League stadium as a prospective model for general mass gathering site implementation. METHODS: The American College of Surgeons' Bleeding Control Basic layperson hemorrhage-control training was implemented at Gillette Stadium in Massachusetts. The five domains are as follows: reach (demographics of study participants), effectiveness (correct tourniquet application after intervention), adoption (investigator, leadership, and participant efforts for sustainability of intervention), implementation (course details), and maintenance (correct tourniquet application at retention testing at 3 to 9 months). RESULTS: A total of 562 employees were included in the study. Of those included employees, 58.7% reported having taken first-aid training and 17.3% reported having taken hemorrhage-control training. There was an increased mean likelihood to help (4.39 vs 4.09, P < .01) and comfort level to control hemorrhage (4.26 vs 3.60, P < .01) after training compared with before training, on a Likert scale (1-5). The stadium operations team located hemorrhage control kits with automatic external defibrillators, integrated layperson immediate response awareness into its Web site, and developed a public safety announcement. The training, performed by physicians, nurses, and emergency medical technicians, consisted of a 30-minute lecture and a 30-minute hands-on skills-training course, with a class size of 24. The total number of sessions was 24. CONCLUSION: Achieving initial hemorrhage-control readiness and maintenance at a mass gathering site through American College of Surgeons Bleeding Control training is feasible but requires significant commitment from training staff, site leadership, and financial resources. PMID- 30424925 TI - Mortality and morbidity after pancreatoduodenectomy in patients undergoing hemodialysis: Analysis using a national inpatient database. AB - BACKGROUND: Whether patients undergoing hemodialysis have greater risks of mortality and morbidity after pancreatoduodenectomy remains unknown. METHODS: We used the Diagnosis Procedure Combination database, a national Japanese inpatient database, to identify patients who underwent pancreatoduodenectomy from July 2010 to March 2015. We conducted propensity-score-matching analyses to compare the outcomes, including postoperative complications and 30- and 90-day mortality after pancreatoduodenectomy between patients with and without hemodialysis. RESULTS: Of 30,495 eligible patients, 307 (1.0%) received hemodialysis. In the unmatched cohort, the proportions of male sex, younger age, pancreatic cancer, ischemic heart disease, diabetes mellitus, and hypertension were greater in patients with hemodialysis than those without hemodialysis. A 1-to-4 propensity score matching created a total of 1,535 patients, including 307 with hemodialysis and 1,228 without hemodialysis. Patients undergoing hemodialysis had greater proportions of postoperative complications, including peritonitis (8.8% vs 4.8%, P = .012), sepsis or disseminated intravascular coagulation (3.6% vs 0.7%, P = .001), intra-abdominal bleeding (4.9% vs 0.7%, P < .001), and acute coronary event (4.2% vs 1.7%, P = .015). Propensity score matching showed that patients undergoing hemodialysis had an increased risk of postoperative complications (OR, 1.62; 95% CI, 1.23-2.14; P = .001), 30-day mortality (OR, 7.45; 95% CI, 3.26 17.0; P < .001), and 90-day mortality (OR, 10.9; 95% CI, 6.58-18.2; P < .001) than those not undergoing hemodialysis. CONCLUSION: Patients undergoing hemodialysis had a significantly increased risk of postoperative complications and death after pancreatoduodenectomy. In particular, surgeons should consider the increased risk of intra-abdominal bleeding, peritonitis, sepsis or disseminated intravascular coagulation, and acute coronary event in patients with hemodialysis. PMID- 30424926 TI - Inhibitory effects of Kampo medicines, Keishibukuryogan and Shakuyakukanzoto, on the substrate uptake activities of solute carrier organic anion transporters. AB - The aim of this study was to assess the effects of Keishibukuryogan (K-06) and Shakuyakukanzoto (TJ-68), commercial herbal medicines, on the substrate uptake activities of renal organic anion transporters. We performed transporter uptake and cell viability assays in Xenopus oocytes and HEK293 human kidney embryonic cells treated with K-06 or TJ-68. K-06 and TJ-68 markedly inhibited the substrate uptake activities of URAT1, OAT1, and OAT3, while they did not exhibit non cytotoxic effects. Our findings demonstrated that K-06 and TJ-68 inhibited the substrate uptake activities of renal transporters, suggesting their mechanism of action as nephroprotective agents. PMID- 30424927 TI - For how long do denervated muscles in children retain the ability to regenerate?: Restoration of elbow flexion and shoulder function by partial nerve transfer in a child with long-standing poliomyelitis-like paralysis. AB - BACKGROUND: In infant poliomyelitis or poliomyelitis-like paresis, there has been no means of treating residual paralysis and the policy has been to wait until an affected infant has grown sufficiently to enable tendon transfer or arthrodesis. However, recent reports have described relatively good results for early surgical intervention in the form of nerve transfer. METHODS: In a 4-year and 6-month-old child we transferred a partial ulnar nerve for elbow flexor reconstruction even 3 years and 10 months after the onset of poliomyelitis-like palsy and also transferred partial accessory and radial nerves for shoulder function restoration 6 months after the first operation. RESULTS: Elbow flexor restored M4 on the British Medical Research Council scale. The shoulder subluxation resolved, however, the strengths of the deltoid and infraspinatus remained almost M1. At the most recent clinical examination, the patient was 18 years old and the active range of motion of patient's left elbow was 0 degrees -125 degrees , and those of the whole shoulder girdle were abduction 35 degrees , flexion 60 degrees , extension 30 degrees and external rotation 0 degrees . CONCLUSIONS: The outcomes we achieved may support partial nerve transfer techniques as viable treatment options for persistent long-standing motor deficits following poliomyelitis-like palsy in children. However, we recommend performing partial nerve transfer as early as possible after recovery from flaccid paralysis and also use of nerves that derive from narrow spinal cord segments. After denervation, children's neuromuscular systems seem to have the ability to regenerate after a much longer period than has generally been believed. This speculation is based on only a single case report; thus, more experience is needed before this generalization can confidently be made. PMID- 30424928 TI - Quantitative measurements of hip abduction strength in lumbar surgery patients. AB - BACKGROUND: We sought to evaluate the hip abduction strength in patients before and after lumbar surgery. MATERIALS AND METHODS: Eighty-four patients (51 males and 33 females) undergoing surgery for lumbar disc herniation or lumbar canal stenosis were selected. Mean age was 64.7 +/- 13.8 years. Seven patients (8.3%) had surgery at multiple levels, including L2-L3 (group A), 27 (32.1%) patients had surgery at multiple levels including L3-L4 (group B), 32 (38.1%) patients had surgery at the L4-L5 level only (group C), and 18 (21.4%) patients had surgery at the L5-S1 level only (group D). Hip abduction strength was measured in the 84 patients preoperatively and in 49 patients postoperatively. RESULTS: In all patients, preoperative mean hip abduction strength on the symptomatic side and the asymptomatic side was 71.4 +/- 34.5 N and 90.7 +/- 36.5 N, respectively (p = 0.0008). In groups A and B, there were no significant differences between the mean hip abduction strength on the symptomatic and contralateral side. In group C, those on the symptomatic and contralateral side were 68.0 +/- 33.5 N and 89.3 +/- 34.8 N, respectively (p = 0.0181). In group D, those on the symptomatic and contralateral side were 74.3 +/- 42.4 N and 101.7 +/- 44.7 N, respectively (p = 0.0314). In the 49 patients of all groups that could be measured postoperatively, there were no significant differences between the mean hip abduction strength on both sides. CONCLUSIONS: It was confirmed that the gluteus medius, which was main hip abductor, was mainly innervated by L5 and its mean strength significantly improved postoperatively. The possibility of improvement of hip abduction strength, especially with unchanged tibialis anterior strength, could be very useful for operative decisions. PMID- 30424929 TI - Therapeutic Targeting of Connexin Channels: New Views and Challenges. AB - Connexins, in particular connexin 43 (Cx43), function as gap junction channels (GJCs) and hemichannels (HCs). Only recently, specific tools have been developed to study their pleiotropic functions. Based on various protein interaction sites, distinct connexin-mimetic peptides have been established that enable discrimination between the function of HCs and GJCs. Although the precise mechanism of action of most of these peptides is still a matter of debate, an increasing number of studies report on important effects of those compounds in disease models. In this review, we summarize the structure, life cycle, and the most important physiological and pathological functions of both connexin GJCs and HCs. We provide a critical overview on the use of connexin-targeting peptides, in particular targeting Cx43, with a special focus on the remaining questions and hurdles to be taken in the research field of connexin channels. PMID- 30424930 TI - Analysis of morphological measurements of the trigeminal nerve in the linac stereotactic radiosurgery simulation targeting the root entry zone in trigeminal neuralgia. AB - PURPOSE: To describe the anatomical measurements of the trigeminal nerve in patients with trigeminal neuralgia (TN) during Linac (linear accelerator)-based stereotactic radiosurgery (SRS) simulation, targeting the root entry zone (REZ), with a 30% isodose line tangential to the pons, using 4-mm and 6-mm collimators. METHODS: In this retrospective study, 53 TN patients, who underwent Fiesta sequence scanning prior to any treatment modality, were assessed. Bilateral measurements were obtained from the cisternal segment of the trigeminal nerve, the trigeminal-pontine angle, and the lateral width of the pontine cistern on the Fiesta MRI sequence. Linac-based SRS simulations were estimated with a radiation dosage of 90Gy to 30% isodose line tangential to the pons, with both 4- and 6-mm collimators. Distances from the calculated targets to the pons and the Gasserian ganglion were measured for later analysis. The statistical analysis was performed comparing the affected side against the unaffected side. RESULTS: Right trigeminal nerve was affected in 36 patients (67.9%), and left one in 17 (32.1%) patients. The mean length of the trigeminal nerve was 9.8mm (range: 4.6-16.8mm) on the affected side, and 10.5mm (range: 5.6-18.4mm) on the unaffected side (p=.02). The mean trigeminal-pontine angle was 12.5 degrees (range: 5.4 degrees to 19.5 degrees ) on the affected side, and 10.2 degrees (range: 5.0 degrees to 30.5 degrees ) on the unaffected side (p=.01). In the simulations, the distances from the estimated targets to the pons and the Gasserian ganglion were not statistically different between sides. The variation of target-pons and target ganglion distances was statistically significant on the affected side with the change of collimators (p<.001). CONCLUSIONS: In this anatomical study, significant differences were identified in the length of the affected trigeminal nerve and trigeminal-pontine angle compared to the unaffected side in TN patients in Fiesta sequences prior to surgery or radiosurgery. Significant variation of the target location was found on the REZ between the 4- and 6-collimators during the Linac-based SRS simulations with the estimated radiation dosage of 90Gy and 30% isodose line tangential to the pons. PMID- 30424931 TI - Endothelial cell-specific overexpression of endothelial nitric oxide synthase in Ins2Akita mice exacerbates diabetic nephropathy. AB - Previous studies demonstrated that global deficiency of eNOS in diabetic mice exacerbated renal lesions and that overexpression of eNOS may protect against tissue injury. Our study revealed for the first time overexpression of eNOS leads to disease progression rather than protection. Transgenic mice selectively expressing eNOS in endothelial cells (eNOSTg) were cross bred with Ins2Akita type 1 (AK) diabetic mice to generate eNOS overexpressing eNOSTg/AK mice. Wild type, eNOSTg, AK and eNOSTg/AK mice were assessed for kidney function and blood glucose levels. Remarkably, overexpressing eNOSTg mice showed evidence of unpredicted glomerular injury with segmental mesangiolysis and occasional microaneurysms. Notably, in eNOSTg/AK mice overexpression of eNOS led to increased glomerular/endothelial injury that was associated with increased superoxide levels and renal dysfunction. Results indicate for the first time that overexpressing eNOS in endothelial cells cannot ameliorate diabetic lesions, but paradoxically leads to progression of nephropathy likely due to eNOS uncoupling and superoxide upsurge. This novel finding has a significant impact on current therapeutic strategies to improve endothelial function and prevent progression of diabetic renal disease. Further, the eNOSTg/AK model developed in this study has significant translational potentials for elucidating the underlying mechanism implicated in the deflected function of eNOS in diabetic nephropathy. PMID- 30424932 TI - Gastric MALT lymphoma and Helicobacter pylori. AB - Marginal zone lymphomas of the MALT type are a type of B-cell neoplasms that involve extranodal tissues and have an indolent clinical behaviour. The stomach is the most common site and most patients are infected by Helicobacter pylori. An increase in the resistance of this bacterium to several antibiotics has been observed in the last years and this fact has determined the review of treatment guidelines. In areas with resistance to clarithromycin greater than 15%, classical triple therapy should be abandoned and quadruple regimens with or without bismuth are currently recommended. Thus, these new guidelines for eradication treatment should be applied to patients with gastric MALT lymphoma associated with H. pylori infection. PMID- 30424933 TI - Disease of the holobiont, the example of multiple sclerosis. AB - In recent years there has been a revolution regarding the role of the microbiota in different diseases, most of them within the spectrum of inflammatory and autoimmune diseases, associated with the development of metagenomics and the concept of holobiont, a large organism together with its microbiota. Specifically, in Multiple Sclerosis, multiple evidence points to the role of the microbiota in experimental autoimmune encephalomyelitis, animal model of the disease, and several articles have been published in recent years about differences in intestinal microbiota among patients with multiple sclerosis and control subjects. We review in this article the concept of holobiont and the gut microbiota functions, as well as the evidence accumulated about the role of the microbiota in experimental autoimmune encephalomyelitis and multiple sclerosis. Nowadays, there is a lot of evidence showing the role of the microbiota in the genesis, prevention and treatment of experimental autoimmune encephalomyelitis based mainly on three immunological pillars, the Th1-Th17 / Th2 balance, the Treg cells and the humoral immunity. It is also well documented that there are differences in the microbiota of patients with MS that are associated with a different expression of genes related to inflammation. PMID- 30424934 TI - Central retinal artery occlusion as an onset form of Takayasu's arteritis. PMID- 30424935 TI - Reactivation of hepatitis B associated with immunosuppressants and chemotherapy. Natural history, risk factors and recommendations for prevention. AB - Although the risk of reactivation of hepatitis B in patients treated with immunosuppressants has been known for years and, if there are recommendations, data from some surveys indicate that the study of the serological profile of HBV infection before starting immunosuppressive treatment is not universal practice. Taking into account the serious consequences that the reactivation of the infection with HBV may entail, we believe that it is necessary to disclose the importance of this problem among the health professionals who prescribe these treatments as well as the recommendations to be followed. In fact, in recent years, the use of chemotherapy and potent immunosuppressants in patients with neoplastic processes and in non-neoplastic pathology of various specialties has been increasingly frequent, increasing the population of patients at risk of reactivation of HBV. PMID- 30424936 TI - Percutaneous endoscopic gastrostomy. Indications, care and complications. AB - Percutaneous endoscopic gastrostomy (PEG) is an effective and safe method for nutritional support in patients with malnutrition and impossibility of oral intake with an estimated survival higher than the months that require enteral nutrition beyond four weeks. The main indications include neoplasms of the upper air-digestive tract and neurological diseases, with dementia currently considered a controversial indication. Anatomical alterations and infectious diseases are the most frequent contraindications. There are different endoscopic techniques; the most widely used being the "pull" method, with a low mortality. Complications are more frequent in patients with multiple pathologies and the elderly. Wound infection, extraction of the tube, tube blockage and bronchoaspiratory pneumonia are the most prevalent complications. Adequate prior preparation of the patient and exhaustive maintenance of the tube can reduce the appearance of these. PMID- 30424937 TI - The impact of maternal lifestyle factors on periconception outcomes: a systematic review of observational studies. AB - The main risk factors for important reproductive health issues such as subfertility and perinatal mortality largely originate in the periconception period. To evaluate associations between modifiable maternal lifestyle factors and periconception outcomes, a systematic search was conducted for relevant studies published from 1990 to February 2017 on Embase, Medline, Web of Science, Cochrane database, PubMed and Google Scholar. The initial search identified 6166 articles, of which 49 studies were eligible for inclusion. Fecundity (the capacity to have a live birth) showed significant inverse associations with smoking, alcohol use and poor diet. Studies regarding time to pregnancy showed a decline in fecundity ratios (the monthly conception rate among exposed relative to unexposed couples) with increasing body mass index (BMI). Furthermore, risk of first-trimester miscarriage was found to be increased in smokers, alcohol and caffeine consumers, and with increasing BMI. Vitamin supplement use showed a decrease in this risk. This review demonstrates that maternal modifiable lifestyle factors affect periconception outcomes. If couples planning a pregnancy are more aware and supported to adopt healthy lifestyles during the periconceptional 'window of opportunity', short-term reproductive health as well as health in later life and even of future generations can be further improved. PMID- 30424938 TI - Angiogenic and immunological pathways in metastatic renal cell carcinoma: A counteracting paradigm or two faces of the same medal? The GIANUS Review. AB - In the so-called "antiangiogenic era" of recent years, a number of targeted therapies have been approved for the treatment of metastatic renal cell carcinoma (mRCC). Emerging information about the immunological features of mRCC and the immunomodulating properties of antiangiogenic agents, one of the standard treatments for mRCC, indicates that a more rational design of potentially synergistic combinations should be pursued. Indeed, immunotherapy has undergone a resurgence in clinical practice. In this narrative review, we discuss the immunological features of mRCC and the potential interactions that antiangiogenic agents may also exert on host immunity and tumor immunogenicity, possibly working on both sides of this complex cross-talk. Hence, the recall to Gianus, the ancient two-faced Roman God who was looking both at the future and the past. Treatment strategies will be also critically discussed. PMID- 30424939 TI - Opioid-Free Ultra-Fast-Track On-Pump Coronary Artery Bypass Grafting Using Erector Spinae Plane Catheters. PMID- 30424940 TI - Bidirectional roles of IL-22 in the pathogenesis of allergic airway inflammation. AB - Asthma is the most prevalent allergic disease of the airway, which is characterized by eosinophilic inflammation, mucus hyperproduction, and airway hyper-responsiveness. Although these pathognomonic features are mainly mediated by antigen-specific Th2 cells and their cytokines, such as IL-4, IL-5, and IL-13, recent studies have revealed that other inflammatory cells, including Th17 cells and innate lymphoid cells (ILCs), also play a critical role in the pathogenesis of asthma. IL-22, one of the cytokines produced by Th17 cells and type 3 ILCs, has distinct functional properties, as IL-22 exclusively acts on non hematopoietic cells including epithelial cells of mucosal surface and exhibits a broad range of action in regeneration and host protection. In accordance with the fact that lung epithelial cells play a critical role in the pathogenesis of asthma, we and other groups have shown that IL-22 is involved in the regulation of allergic airway inflammation. In this review, we discuss recent advances in the biology of IL-22 and its involvement in the pathogenesis of allergic airway inflammation. PMID- 30424941 TI - Association of SNCA variants with alpha-synuclein of gastric and colonic mucosa in Parkinson's disease. AB - BACKGROUND: Alpha-synuclein (alpha-Syn) immunostaining in the enteric nervous system (ENS) has been investigated to determine the role of diagnostic biomarker of Parkinson's disease (PD). However, determining factors for alpha-synuclein (alpha-Syn) deposition in the ENS of humans are still unclear. We aimed to investigate a possible association between SNCA variants and the presence of alpha-Syn immunostaining in the ENS in patients with PD and healthy individuals. METHODS: The study subjects consisted of 38 patients with PD and 46 healthy individuals. alpha-Syn immunohistochemistry was performed for gastric and colonic mucosal tissues of patients with PD and controls. Mucosal biopsy tissues of the ENS were obtained using standard biopsy forceps by endoscopic gastroduodenoscopy or colonoscopy. Two variants within the SNCA gene (the single nucleotide polymorphism [SNP] rs11931074 and the microsatellite REP1) were genotyped. RESULTS: In patients with PD, the rs11931074 (G allele) was significantly associated with the presence of alpha-Syn immunostaining in the ENS (OR = 5.96, 95% CI = 1.70-20.97, P = 0.01). In an interaction analysis, SNP rs11931074-PD status interaction was significantly associated with positive alpha-Syn immunostaining in the ENS (OR = 7.33, 95% CI = 1.58-33.88, P = 0.01). Longer SNCA REP1 alleles were not associated with positive alpha-Syn immunostaining in the ENS. CONCLUSION: This exploratory study demonstrated that alpha-Syn deposition in the ENS may be associated with SNCA variants in patients with PD. PMID- 30424942 TI - A bioassay-based protocol for chemical neutralization of human faecal wastes treated by physico-chemical disinfection processes: A case study on benzalkonium chloride. AB - In situ physico-chemical disinfection of high risk faecal waste is both effective and widely used as a sanitation management strategy for infection prevention and control. Systematic tests where the performance of alternative physico-chemical disinfection methods is systematically compared and optimized must be based on reliable protocols. These protocol are currently not adequately addressing the neutralization related issues: the neutralization of the tested disinfectant after specified conditions of concentration and contact time (CT) is necessary to prevent continued disinfection after the intended contact time; moreover such neutralization is often necessary in practice and on a large scale to prevent adverse health and ecological impacts from remaining disinfectant after the target CT is achieved. Few studies adequately assess the extent of neutralization of the chemical disinfectant and are intended to optimize on-site disinfection practices for waste matrices posing high microbial risks. Hence, there is a need for effective and reproducible neutralization protocols in chemical disinfection trials and practice. Furthermore, for most of chemical disinfectants used in healthcare settings there is no practical methodology to reliably and conveniently measure the residual disinfectant concentration after its neutralization and also determine the optimum concentration of the neutralizer. Because some neutralizing compounds can themselves be toxic to the test microorganisms, it is necessary to optimize neutralization procedures in disinfection experiments for the development of infection control practices using accepted positive control microbes. In the presented work, a stepwise bioassay based protocol using representative faecal indicator microbes is described for optimizing chemical disinfection and subsequent disinfectant neutralization of any infectious faecal waste matrix. The example described is for the quaternary ammonium compound benzalkonium chloride and its recommended chemical neutralizer in a high strength human faecal waste matrix. PMID- 30424943 TI - Spatial and daily variations of nitrous oxide emissions from biological reactors in a full-scale activated sludge anoxic/oxic process. AB - Nitrous oxide (N2O) is an important greenhouse gas that can be emitted from wastewater treatment plants (WWTPs). Such emissions are reportedly process specific and related to operational parameters. This study was conducted to clarify spatial and daily variations of N2O in a full-scale activated sludge anoxic/oxic process that consisted of an anoxic tank and three oxic tanks (oxic 1, oxic-2 and oxic-3), all of which except the final sedimentation tank were fully covered. Higher dissolved N2O (D-N2O) loading and gaseous N2O (G-N2O) emissions were observed for oxic-3 than for the anoxic, oxic-1, and oxic-2 tanks, implying that there was higher N2O production potential via nitrification in the latter stage of the oxic tank. Moreover, the sudden decrease in dissolved oxygen concentration after the peak was found to lead to abrupt production of D-N2O at oxic-3 in the anoxic/oxic process. The increases in AOB amoA, AOB nirK and the following AOB norB gene transcripts at the end of the oxic-2 tank suggested that nitrifier denitrification occurred to produce N2O under low dissolved oxygen conditions when the N2O peak was observed. Additionally, the much lower transcription levels of the two nosZ genes suggested lower N2O consumption. The N2O emission factors ranged from 0.087% to 0.302%, and lower N2O emission factors were observed during summer. PMID- 30424944 TI - Penfield's stimulation for direct cortical motor mapping: An outdated technique? PMID- 30424945 TI - Concentrated Bone Marrow Aspirate May Decrease Postoperative Cyst Occurrence Rate in Autologous Osteochondral Transplantation for Osteochondral Lesions of the Talus. AB - PURPOSE: To clarify if the use of concentrated bone marrow aspirate (CBMA) would affect both postoperative functional outcomes and magnetic resonance imaging (MRI) outcomes compared with those of autologous osteochondral transplantation (AOT) alone; in addition, to assess the efficacy of CBMA reducing the presence of postoperative cyst formation following AOT in the treatment of osteochondral lesions of the talus. METHODS: Fifty-four (92%) of 59 eligible patients who underwent AOT between 2004 and 2008 were retrospectively assessed at a minimum of 5-year follow-up. Twenty-eight patients were treated with AOT and CBMA (AOT/CBMA group) and 26 patients were treated with AOT alone (AOT-alone group). Clinical outcomes were evaluated using the Foot and Ankle Outcome Scores (FAOS) and Short Form 12 (SF-12) preoperatively and at final follow-up. Postoperative MRI was evaluated with the modified Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scoring system. Cyst formation was also evaluated on postoperative MRI. RESULTS: The mean FAOS and SF-12 significantly improved in both the AOT/CBMA and AOT-alone groups, but there were no statistical differences between groups in FAOS (80.5 vs 75.5, P = .225) and SF-12 (71.1 vs 69.6, P = .756) at final follow-up. Additionally, there was no difference in the mean MOCART score (80.4 vs 84.3, P = .484); however, AOT/CBMA did result in a statistically lower rate of cyst formation (46.4% vs 76.9%, P = .022). No significant differences were found in the mean postoperative FAOS and SF-12 between patients with and without cysts postoperatively. CONCLUSIONS: CBMA reduced postoperative cyst occurrence rate in patients treated with AOT; however, CBMA did not result in significant differences in medium term functional outcomes and MOCART score in patients who underwent AOT. LEVEL OF EVIDENCE: Level III, retrospective comparative trial. PMID- 30424946 TI - Triage education in rural remote settings: A scoping review. AB - BACKGROUND: Triage is a complex nursing task to prioritise patient care, based on acuity. Triage decisions can affect patient safety and must employ critical thinking. Graduate registered nurses are expected to triage in rural facilities, which is in contrast to current guidelines. The purpose of this review was; to discover how effective education support programs were in developing clinical decision-making skills for graduates at triage; and to determine what is known about triage education support programs for graduate or novice registered nurses undertaking triage in rural and remote settings. METHOD: A scoping review was undertaken to identify and analyse primary research articles following PRISMA guidelines, sourced from four electronic databases. RESULTS: 6158 retrieved articles were found, after duplicate removal and screening against inclusion/exclusion criteria; fourteen articles were included. Themes included 'variability of triage accuracy and assessment'; 'education qualifications and experience'; and 'training and supervision'. CONCLUSION: This review demonstrates significant gaps in the literature reporting on this topic area, particularly in the rural context. Common recommendations include standardised triage education strategies, and strategies that account for differences in resourcing levels. Further research is required to attempt to link education strategies in rural contexts to acceptable triage outcomes like triage accuracy. PMID- 30424947 TI - Effect of multi-ethnicity and ancestry on prevalence of allergic disease. AB - BACKGROUND/PURPOSE: Differences exist among racial and ethnic groups in the prevalence and severity of allergic diseases. However, influence of population admixing on allergic disease has not been studied. We examined the effect of population admixing on the occurrence of allergic disease. METHODS: We reviewed the data of 68,043 adolescents who participated in the 11th Korea Youth Risk Behavior Web-based Survey, which provides a sample that is representative of the entire Korean middle school and high school student population. Multi-ethnic status was determined by using parental country of birth and prevalence of asthma, allergic rhinitis (AR), and atopic dermatitis (AD) was determined by questionnaire. RESULTS: Multi-ethnic adolescents accounted for approximately 0.9% of the total adolescents. Prevalence of asthma was significantly higher in multi ethnic group than non multi-ethnic group while that of AR and AD was significantly higher in non multi-ethnic group than multi-ethnic group. Parental region of country at birth showed a significant difference in prevalence of allergic disease. Univariate analysis found that urbanity, perceived economic status (PES), parental region of country at birth, and environmental tobacco smoke (ETS) showed a significant odds ratio (OR) in asthma, AR, and AD. Body mass index (BMI) showed a significant OR in asthma and AD. After adjusting for urbanity, PES, BMI and ETS, multiethnicity showed significantly lower OR in AR and AD. CONCLUSION: Population admixing appears to have significant effect on the prevalence of allergic disease. Further study will be needed to clarify the effect of population admixing on prevalence of allergic disease. PMID- 30424948 TI - Identification and antifungal sensitivity of two new species of Diaporthe isolated. AB - Diaporhte species are plant pathogens rarely involved in human diseases, especially eye diseases. We report our findings in two undescribed Diaporhte species. Both were identified by their morphological characteristics and by DNA sequence analyses. In Case 1, an 81-year-old male farmer who had pterygium surgery 7 years earlier developed keratitis and the causal fungus was identified as a new species of Diaporthe, D. oculi. This species can be distinguished from the closely related D. limonicola on Citrus limon (Rutaceae) by the ITS, tef1, and TUB (515/520 = 99.0% in ITS, 315/324 = 97.2% in tef1, and 601/614 = 97.9% in TUB). The isolate from Case 2, a 68-year-old man with a rose thorn injury, was also identified as a new Diaporthe species, D. pseudooculi. Phylogenetically, D. pseudooculi is different from the closely related D. podocarpi-macrophylli by the ITS, tef1, and TUB (525/531 = 98.9% in ITS, 314/333 = 94.3% in tef1, and 436/442 = 98.6% in TUB). We report on the identification, drug sensitivity, and treatment outcomes for these two new species of Diaporthe, D. oculi and D. pseudooculi. PMID- 30424949 TI - Correlation between vancomycin penetration into cerebrospinal fluid and protein concentration in cerebrospinal fluid/serum albumin ratio. AB - Bacterial meningitis is a life-threatening condition. Vancomycin (VCM) is one of the antibiotics used as empirical therapy for bacterial meningitis. It is essential to maintain an adequate concentration of VCM in cerebrospinal fluid (CSF) to treat bacterial meningitis effectively. VCM administered intravenously must pass the blood-brain barrier (BBB) to enter the CSF and the extent of VCM penetration into CSF varies widely among patients. Previous report indicated that CSF albumin level is useful for estimation of VCM CSF penetration. However, CSF albumin level is not measured in routine practice. We focused on CSF protein concentration that is generally examined at the beginning of diagnosis and treatment of bacterial meningitis. We examined the relationship between CSF protein concentration/serum albumin ratio and the extent of VCM penetration into CSF. This retrospective study involved 7 patients admitted to our hospital who were treated with VCM for suspected bacterial meningitis. The VCM concentrations in serum and CSF were 17.6 +/- 7.2 MUg/mL and 3.31 +/- 3.14 MUg/mL, respectively. The serum VCM concentrations showed no significant correlation with CSF VCM concentrations. On the other hand, the protein concentration in CSF/serum albumin ratio showed a strong positive correlation with the VCM CSF/serum ratio (r = 0.877, p < 0.005). Our study indicates that the ratio of CSF protein concentration/serum albumin is likely useful for estimating the approximate VCM CSF/serum ratio. This could contribute to an improvement in the treatment of bacterial meningitis. PMID- 30424950 TI - Detection of beta-lactamase-negative ampicillin resistance in Haemophilus influenzae in Belgium. AB - Haemophilus influenzae, a frequent colonizer of the respiratory tract, is the causative agent of several clinically important infections. In cases that require therapeutic intervention, laboratory susceptibility testing can detect beta lactam antibiotic resistance and guide the best treatment course. In the absence of a beta-lactamase, beta-lactam resistance may be due to an altered form of the PBP3 protein, encoded by the ftsI gene. While these so-called beta-lactamase negative ampicillin-resistant (BLNAR) strains are of serious clinical interest, identification in the clinical laboratory is not always straightforward. In the current study, the ftsI genes of a set of phenotypic BLNAR H. influenzae isolates taken from samples collected in the UZ Brussel hospital in Belgium were sequenced and re-tested at the National Reference Laboratory (NRC). Non-silent mutations in the ftsI gene were found in 100% of the isolates. Although 30% of the isolates were classified by the NRC as beta-lactamase-negative ampicillin-sensitive (BLNAS) strains based on the EUCAST guidelines on ampicillin minimal inhibitory concentration (MIC), all isolates showed MIC values >=1 mg/L. These relatively high MIC values indicate a decreased susceptibility to ampicillin, and suggest that sequencing of the ftsI gene should be used as part of an antibiotic susceptibility testing (AST) algorithm in the clinical laboratory. This would allow clinicians to make better informed decisions regarding patient treatment. PMID- 30424951 TI - Vitamin B6 in Pediatric Renal Transplant Recipients. AB - OBJECTIVES: Our aim was to assess the vitamin B6 intake and biochemical status in a sample of children who have undergone renal transplantation. METHODS: A prospective observational study was performed in 10 pediatric renal transplant recipients to determine their vitamin B6 status through dietary assessment and serum Pyridoxal 5'-phosphate (PLP) measurement. RESULTS: Ten children (mean age of 11.9 years) had median serum PLP concentrations of 62.45 nmol/L (interquartile range +/-83.40). Two children (20%) had values above the reference range, and none below. Mean vitamin B6 intake was 138.7% of reference nutrient intake (standard deviation +/-35.2%). No children were in receipt of vitamin B6 supplementation. CONCLUSION: There is no previous literature on vitamin B6 status in children who have undergone renal transplantation. In adult transplant recipients, elevated serum PLP concentrations have been described and ascribed to possible excessive intakes. In this sample, no children appeared biochemically deficient, but 20% had elevated concentrations. Dietary intakes were not excessive, and no children reported oral Vitamin B6 supplementation. Exploration of vitamin B6 metabolism in this population is required. PMID- 30424952 TI - [Child abuse in the Emergency department: Epidemiology, management, and follow up]. AB - OBJECTIVE: To describe the clinical and epidemiological features, management, and follow-up of child abuse suspicions diagnosed in the Paediatric Emergency Unit. METHODS: A single-centre, observational and retrospective study was conducted between 2008 and 2017. Clinical, epidemiological and follow-up data were collected in those patients younger than 16 that were reported as child abuse suspicions. A descriptive and analytic study was performed, as well as a bivariate and multivariate analysis. RESULTS: A total of 404 out of 570,648 emergency patients (0.07%) were diagnosed with potential abuse. Physical abuse was the most frequent kind of abuse (40.3%). The median age was 4.3 years (IQR 1.6-10.2), and 55% were girls, with sexual abuse being more common in them (OR 3.71; 95% CI: 2.23-6.17), and physical abuse more frequent in boys (OR 1.72; 95% CI: 1.15-2.57). A total of 89 patients (22%) required admission. Age and type of abuse were independently associated with risk of admission. More than half (56%) of the cases required additional follow-up, with sexual (OR 3.98; 95% CI: 1.93 7.03) and emotional abuse (OR 4.93; 95% CI: 1.82-13.35) requiring more mental health follow-up, and physical abuse requiring more social services follow-up (OR 4.39; 95% CI: 1.61-11.98). CONCLUSIONS: In our study, child abuse is more frequent in pre-school children. Age and type of abuse are associated with the need of admission. The kind of follow-up is determined by the type of abuse. PMID- 30424953 TI - Optimization of CRISPR/Cas9 Delivery to Human Hematopoietic Stem and Progenitor Cells for Therapeutic Genomic Rearrangements. AB - Editing the beta-globin locus in hematopoietic stem cells is an alternative therapeutic approach for gene therapy of beta-thalassemia and sickle cell disease. Using the CRISPR/Cas9 system, we genetically modified human hematopoietic stem and progenitor cells (HSPCs) to mimic the large rearrangements in the beta-globin locus associated with hereditary persistence of fetal hemoglobin (HPFH), a condition that mitigates the clinical phenotype of patients with beta-hemoglobinopathies. We optimized and compared the efficiency of plasmid , lentiviral vector (LV)-, RNA-, and ribonucleoprotein complex (RNP)-based methods to deliver the CRISPR/Cas9 system into HSPCs. Plasmid delivery of Cas9 and gRNA pairs targeting two HPFH-like regions led to high frequency of genomic rearrangements and HbF reactivation in erythroblasts derived from sorted, Cas9+ HSPCs but was associated with significant cell toxicity. RNA-mediated delivery of CRISPR/Cas9 was similarly toxic but much less efficient in editing the beta globin locus. Transduction of HSPCs by LVs expressing Cas9 and gRNA pairs was robust and minimally toxic but resulted in poor genome-editing efficiency. Ribonucleoprotein (RNP)-based delivery of CRISPR/Cas9 exhibited a good balance between cytotoxicity and efficiency of genomic rearrangements as compared to the other delivery systems and resulted in HbF upregulation in erythroblasts derived from unselected edited HSPCs. PMID- 30424954 TI - LDR-Induced miR-30a and miR-30b Target the PAI-1 Pathway to Control Adverse Effects of NSCLC Radiotherapy. AB - Radiotherapy has been a central part in curing non-small cell lung cancer (NSCLC). However, it is possible that not all of the tumor cells are destroyed by radiation; therefore, it is important to effectively control residual tumor cells that could become aggressive and resistant to radiotherapy. In this study, we aimed to investigate the molecular mechanism of decreased NSCLC radioresistance by low-dose radiation (LDR) pretreatment. The results indicated that miR-30a and miR-30b, which effectively inhibited plasminogen activator inhibitor-1 (PAI-1), were overexpressed by treatment of LDR to NSCLC cells. Phosphorylation of Akt and ERK, the downstream survival signals of PAI-1, was decreased by PAI-1 inhibition. Reduced cell survival and epithelial-mesenchymal transition by PAI-1 inhibition were confirmed in NSCLC cells. Moreover, in vivo orthotopic xenograft mouse models with 7C1 nanoparticles to deliver miRNAs showed that tumor growth and aggressiveness were efficiently decreased by LDR treatment followed by radiotherapy. Taken together, the present study suggested that PAI-1, whose expression is regulated by LDR, was critical for controlling surviving tumor cells after radiotherapy. PMID- 30424955 TI - [Decision-making regarding treatment limitation after severe traumatic brain injury: A survey of French neurosurgeons]. AB - BACKGROUND/INTRODUCTION: In France, the law defines and prohibits "unreasonable obstinacy" and provides a framework for the subsequent decision to limit or to cease treatment. It also gives the person the right to appoint a trusted person and to draft advance directives regarding this issue. There have been few studies of neurosurgeons' involvement in decision-making in regard to treatment limitation after severe traumatic brain injury. AIM OF THE STUDY: The first aim of the study was to assess French neurosurgeons' adherence to the law on patients' rights and end of life which governs such decision-making. The second aim was to assess the prognostic and decision-making criteria applied by neurosurgeons. METHODS: A declarative practice and opinion survey, using a self administered questionnaire emailed to all practising neurosurgeons members of the French Society of Neurosurgery, was conducted from April to June 2016. RESULTS: Of the 197 neurosurgeons contacted, 62 filled in the questionnaire. Discussions regarding treatment limitation were in all cases collegial, as required under the law, and the patient's neurosurgeon was always involved. The trusted person and/or family were always informed and consulted, but their opinions were not consistently taken into account. Advance directives were most often lacking (68%) [56; 80] or inappropriate (27%) [16; 38]. The most frequently used prognostic criteria were clinical parameters, intracranial pressure, cerebral perfusion pressure, and imaging, with significant interindividual variation in their use. The main decision-making criteria were foreseeable disability, expected future quality of life, and age. CONCLUSIONS: Neurosurgeons showed good compliance with legal requirements, except in the matter of calling for the opinion of an external consultant. Furthermore, this survey confirmed variability in the use of prognosis predictors, and the need for further clinical research so as to achieve more-standardized practices to minimise the subjectivity in decision-making. PMID- 30424957 TI - Prostate brachytherapy under hypnosedation: A prospective evaluation. AB - PURPOSE: Hypnosedation (HS) for brachytherapy has been proposed in patients with prostate cancer and has been evaluated. MATERIALS AND METHODS: 79 patients were treated with brachytherapy under HS. The Visual Analog Scale questionnaire was used to assess comfort and anxiety and the lowest, mean, and highest level of pain. Data for 79 patients who underwent general anesthesia (GA) and 37 patients who underwent spinal anesthesia (SA) treated at the same period were compared with HS group in terms of medication and treatment duration. RESULTS: 11 patients (13.9%) requested a GA, because they did not reach the hypnotic level. For the remaining 68 patients, the mean pain and comfort scores evaluated just after the intervention were 3.1 and 7.4, respectively. At 8 weeks, the scores were 2.8 and 7.5, respectively. 66 patients (97%) would choose this approach again and recommend it to other patients. The patients in the HS group received significant less medications than in the GA (remifentanil, propofol, ketamine, phenylephrine, ephedrine...) or SA (sufentanil, midazolam, morphine, bupivacaine...) groups with mean values of 3.1 vs. 7.9 vs. 5.6 (p < 0.0001), respectively. HS increased the mean time of surgery room occupation by 12 min vs. GA and by 20 min vs. SA. However, the recovery room occupation is avoided with HS (GA = 61 min and SA = 67 min) and a shorter duration of a need for a urinary catheter was noted. CONCLUSIONS: HS is a feasible and comfortable method of anesthesia and a good alternative to GA and SA for patients undergoing prostate brachytherapy, with reduced treatment duration and number of medications. PMID- 30424958 TI - A Serendipitous Case for Shorter Steroid Course in Infantile Spasms. PMID- 30424956 TI - [Interest of robotic stereotactic radiosurgery in the management of brain metastases: Results of a retrospective, single center analysis]. AB - PURPOSE: The management of malignant brain metastases becomes a main issue for the treatment of patients, because of the survival extension related to the improvement in systemic treatments. Robotic stereotactic radiosurgery (RSR) is a new approach in this indication. The purpose of this analysis was to define the efficacy of RSR, in order to determine prognostic factors of survival and factors of response. PATIENTS AND METHODS: It was a retrospective, single center (polyclinique de Bordeaux Nord Aquitaine) analysis performed from 2012 to 2015, involving patients with malignant brain metastases treated by RSR using the Cyberknife(r) technique. We analyzed the following parameters: response to RSR, prognostic and predictive factors of response, and survival. RESULTS: A total of 72 RSRs were performed among 55 analyzed patients; 62 treatments were assessable with a median follow-up of 9.4 months. The main delivered dose on the 80%-isodose was 20Gy. A complete response was achieved in 40.3% of patients (stability or regression=83.9%). The overall survival was 13 months. The risk of failure was significantly correlated with the increase in metastasis size and non adenocarcinoma histology. A performance status<2 was the main prognostic factor of survival. CONCLUSIONS: The RSR allowed treating 3 to 5 brain metastases, avoiding an entire brain irradiation, and maintaining survival and quality of life. PMID- 30424959 TI - Short Takes. PMID- 30424960 TI - Childhood Moyamoya: Looking Back to the Future. AB - Moyamoya is a chronic, progressive steno-occlusive arteriopathy that typically affects the anterior circulation arteries of the circle of Willis. A network of deep thalamoperforating and lenticulostriate collaterals develop to by-pass the occlusion giving rise to the characteristic angiographic "puff of smoke" appearance. Moyamoya confers a lifelong risk of stroke and neurological demise, with peak age of presentation in childhood ranging between five and 10 years. Moyamoya disease refers to patients who do not have a comorbid condition, whereas moyamoya syndrome refers to patients in whom moyamoya occurs in association with an acquired or inherited disorder such as sickle cell disease, neurofibromatosis type-1 or trisomy 21. The incidence of moyamoya disease and moyamoya syndrome demonstrates geographic and ethnic variation, with a predominance of moyamoya disease in East-Asian populations. Antiplatelet therapy and surgical revascularization procedures are the mainstay of management, as there are no available treatments to slow the progression of the arteriopathy. Future research is required to address the major gaps that remain in our understanding of the pathologic basis, optimal timing for surgery, and determinants of outcome in this high-stroke risk condition of childhood. PMID- 30424961 TI - Genetic Evaluation of Common Neurocutaneous Syndromes. AB - The neurocutaneous syndromes are a group of multisystem disorders that affect the skin and central nervous system. Neurofibromatosis 1, neurofibromatosis 2, tuberous sclerosis complex and Sturge-Weber syndrome are the four major neurocutaneous disorders that mainly present in childhood. In this review, we discuss the clinical findings and genetic diagnosis, related genes/pathways and genotype-phenotype correlations of these four neurocutaneous syndromes. PMID- 30424962 TI - Longitudinal Effects of Everolimus on White Matter Diffusion in Tuberous Sclerosis Complex. AB - OBJECTIVE: We studied the longitudinal effects of everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), on callosal white matter diffusion tensor imaging (DTI) in patients with tuberous sclerosis complex (TSC). METHODS: Serial imaging data spanning nine years were used from the open label, Phase I/II trial (NCT00411619) and open-ended extension phase of everolimus for the treatment of subependymal giant cell astrocytoma associated with TSC. From 28 patients treated with everolimus and 25 untreated control patients, 481 MRI scans were available. Rigorous quality control resulted in omission of all scans with diffusion weighted imaging data in less than 15 directions or more than eight artifacted volumes, and all postsurgical scans. We applied a linear mixed-effects model to the remaining 125 scans (17 treated, 24 controls) for longitudinal analysis of each DTI metric of manually drawn callosal regions of interest. RESULTS: On a population level, mTOR inhibition was associated with a decrease in mean diffusivity. In addition, in treated patients only, a decrease of radial diffusivity was observed; in untreated patients only, an increase of axial diffusivity was seen. In patients below age 10, effect-sizes were consistently greater, and longer treatment was associated with greater rate of diffusion change. There was no correlation between DTI metrics and reduction of subependymal giant cell astrocytoma volume, or everolimus serum levels. CONCLUSIONS: Effects from mTOR overactivity on white matter microstructural integrity in TSC were modified through pharmacologic inhibition of mTOR. These changes sustained over time, were greater with longer treatment and in younger patients during a time of rapid white matter maturation. PMID- 30424963 TI - Potential application of ultrasound-guided thermal ablation in rare liver tumors. AB - BACKGROUND: With the advances of imaging techniques, the detection rate of rare liver tumor is increased. However, the therapeutic strategies of the rare liver tumors remain limited. METHODS: We analyzed twelve pathologically confirmed rare liver tumors in 8 patients. All of the patients underwent ultrasound (US) guided biopsy and subsequent thermal ablation. The tumors were ablated according to the preoperative plans and monitored by real-time US. CT/MRI fused with contrast enhanced US (CEUS) or three-dimensional (3D) US-CEUS images were used to guide and assess the ablation zone more accurately during thermal ablation. The rate of technical efficacy was assessed based on the contrast-enhance CT/MRI (CECT/MRI) results one month after ablation. Local tumor progression (LTP), recurrence and complications were followed up and recorded. RESULTS: Among these twelve nodules, nine were subject to US-guided thermal ablation, whereas the other three inconspicuous nodules were subject to CEUS-guided thermal ablation. Intra procedure CT/MRI-CEUS or 3D US-CEUS fusion imaging assessments demonstrated that the ablation zone sufficiently covered the original tumor, and no immediate supplementary ablation was required. Additionally, no major complications were observed during the follow-up period. The postoperative CECT/MRI confirmed that the technique success rate was 100%. Within the surveillance period of 13 months, no LTP or recurrence was noted. CONCLUSIONS: US-guided thermal ablation was feasible and safe for rare liver tumors. The use of fusion imaging technique might make US-guided thermal ablation as effective as surgical resection, and this technique might serve as a potential therapeutic modality for rare liver tumors in the future. PMID- 30424964 TI - Silica-based hybrid porous layers to enhance the retention and efficiency of open tubular capillary columns with a 5 MUm inner diame9ter. AB - We report on possibility to enhance the hydrophobicity of octadecylsilylated silica-based porous layered open tubular (PLOT) columns with an inner diameter (i.d.) of 5 MUm by applying hybrid tetramethoxysilane (TMOS)/methyltrimethoxysilane (MTMS) layers with inserted methyl groups. Due to this higher hydrophobicity, thinner porous layers suffice to achieve similar retention factor (k) as in octadecylsilylated silica-based PLOT columns synthesized using TMOS only. Since thinner layers have a lower intra-layer mass transfer resistance, this in turn allows to obtain superior column efficiencies in comparison with separations carried out with TMOS-based PLOT columns at the same retention. Since layer thickness contributes to the C-term type of band broadening, this is most pronounced at high velocities. Typical gains in column efficiency at a reduced velocity of nui = 30 are on the order of 15%. Preparing the hybrid PLOT columns in 5 MUm i.d.-capillaries with a length of 0.4 m using different TMOS/MTMS preparation mixtures leads to different layer thickness in the capillaries. It is shown that column efficiencies for the most retained compound (k = 0.9-1.5) went from N = 101,000 for PLOT columns with a layer thickness (df) of 250 nm, over N = 95,000 for df = 320 nm to N = 89,000 for df = 400 nm, corresponding to plate heights (H) in the order of 3.5-3.9 MUm (reduced plate heights (h = 0.8-1.0)). By applying the same preparation mixtures for much longer capillaries of 1.3 m, a high repeatability of the volumetric phase ratio (m) (difference <1%) and the k-values (difference <5%) was observed between the 0.4 m and 1.3 m PLOT columns. In addition, also a very similar band broadening was obtained, as the h-values in the longer columns coincided well (order of a few % difference) with the reduced plate height curves measured in the shorter columns. The effect of the retention factor and layer thickness on these reduced plate height curves furthermore fits well with the Golay-Aris theory. Depending on the layer thickness, plate numbers in the longer capillary columns were varying from N = 282,000 to N = 379,000 for the most retained compound. PMID- 30424965 TI - Matrix solid-phase dispersion based on magnetic ionic liquids: An alternative sample preparation approach for the extraction of pesticides from vegetables. AB - In this study, we propose, for the first time, the direct use of a magnetic ionic liquid (MIL) in a matrix solid-phase extraction procedure. Because of the magnetic properties, the MIL can be harvested directly after the extraction step, using a magnet, while its hydrophobic nature makes feasible the extraction of analytes. Raw vegetables of high water content can be analyzed without any pretreatment. The viscous nature of the selected MIL assists in blending with the matrix, while its hydrophobicity facilitates easier separation and retrieval. Additionally, no solid dispersing materials or co-sorbents are needed. A simple, low-cost analytical method for the determination of multi-class pesticides residues in raw vegetables was developed, with satisfactory recoveries. PMID- 30424966 TI - Constant-pattern design method for the separation of ternary mixtures of rare earth elements using ligand-assisted displacement chromatography. AB - A constant-pattern design method for separating ternary mixtures using ligand assisted displacement chromatography was developed for non-ideal systems. The general correlation for the minimum column length required to achieve the constant-pattern state for binary separations from our previous study was extended to ternary separations. Additionally, an equation for the yield of a target component as a function of key dimensionless groups was derived based on the constant-pattern mass transfer zone lengths. The column length and operating velocity solved from the two equations ensured the yields and the constant pattern state for the target components. A selectivity weighted composition factor was developed to allow the design method to specify a minimum target yield for one or multiple components. The design method was verified using simulations and experiments for different targeted yields (70-95%), ligand concentrations (0.03-0.06 M), and feed compositions (1/12-5/6). The targeted yields were achieved or exceeded in all cases tested. The minimum column length required to achieve a constant pattern-state and the productivity of LAD are limited by the lowest selectivity or by a minority component with a low concentration in the feed, even when it does not have the lowest selectivity. Sacrificing the yields of minor components can increase the total productivity significantly. The productivities achieved using this design method are 839 times higher than literature results for ternary separations with the same purity and similar yields. PMID- 30424967 TI - Polyethyleneimine-modified hybrid silica sorbent for hydrophilic solid-phase extraction of thyreostats in animal tissues. AB - In this work, a novel polyethyleneimine-modified hybrid silica material was developed and utilized as a solid support for hydrophilic solid-phase extraction (HILIC SPE) of thyreostats in animal tissue samples. The effects of critical parameters of extraction, including acetonitrile content, pH, sample loading volume, elution volume, sample loading flow rate and elution flow rate were completely optimized. It was found that the polyethyleneimine-modified hybrid silica sorbent displayed a high adsorption capacity of 15.8 mg/g, and the breakthrough volume was up to 40 mL. The proposed HILIC SPE method provided low detection limits of 0.5-2.2 MUg/kg, and excellent recoveries of 93.4-103.1% with relative standard deviations of 3.6-9.6% (n = 3). Importantly, compared with the traditional clean-up methods for determination of thyreostats in complex matrices, the developed HILIC SPE method eliminated drying and redissolving steps. In the further, the proposed HILIC SPE method is expected to be widely applied for the clean-up of small polar and hydrophilic compounds in complex matrices. PMID- 30424968 TI - Technical nuances of percutaneous sacroiliac joint fixation: A cadaveric study. AB - Sacroiliac (SI) joint can produce debilitating lower back pain with radiation to groin, buttocks, and lower extremities. SI joint dysfunction poses a clinical challenge to the spine surgeons. Studies entailing surgical arthrodesis utilizing Titanium implants have been reported with reputedly high level of patient satisfaction. Authors have described technical aspects of surgical technique with use of titanium screw implants. The transarticular technique is used to places SI joint screw implants across the articular portion of SI joint. Cadaveric SI joint instrumentation is performed under fluoroscopic guidance. Moreover, Medline literature search is conducted to study surgical outcome, and patient satisfaction. 4 cadavers are prepped prone for the percutaneous approach. Bilaterally 6 screws are placed using transarticular placement technique under fluoroscopic guidance. The posterior technique utilizes alignment guide to place the screws inline on the inlet view, parallel in the outlet view, and parallel to the dorsal aspect of the sacral body in the lateral view. One C-arm is used in the entire technique. The technical aspects of surgical technique have been described in a stepwise fashion for easy reproducibility in the operating room. Each screw track is checked with tactile feel of a blunt K-wire before final deployment. All bilateral screws were checked on a set of fluoroscopic views. A detail clinical examination, diagnostic joint injection, with the radiological imaging must be considered before surgical consideration. SI Joint fusion utilizing 3 transarticular sacral screws is equally effective and safe procedure to treat chronic lower back pain ensuing from SI joint dysfunction. PMID- 30424969 TI - Primary idiopathic CNS non-amyloidogenic light chain deposition disease complicated by treatment-resistant focal seizure disorder. AB - Light chain deposition disease (LCDD) is a systemic disorder characterised by the pathologic deposition of immunoglobulin light chains, which is histologically distinguished from amyloidosis by failure to stain with Congo red. Central nervous system (CNS)-restricted LCDD is among the rarest manifestations. We describe a unique case complicated by focal onset epilepsy with impaired awareness for which control with anticonvulsant therapy proved difficult. PMID- 30424971 TI - Trends of weight gain and prevalence of overweight and obesity from birth to three years of age. AB - OBJECTIVE: To examine the changes in children's weight-for-height at six monthly intervals between birth and three years old (3yo) from different counties across Chile and to determine if children had overweight or obesity, and if so, whether it was a transient or persistent change. SUBJECTS AND METHODS: Longitudinal data were obtained from routine medical check-ups and 8,373 children were selected from nine counties in Chile through a non-randomised sample design. Weight-for height z-scores (WHZ) were generated and categorized as wasted, normal, overweight, and obese using WHO standards. Repeated-measures ANOVA were used to analyse the changes in WHZ over the seven measurements as well as based on having normal, overweight, or obese WHZ at 3yo. The number of times having overweight or obesity was counted (from 0 to 7 times). The timing of having overweight and obesity was computed as well as all combinations of the patterns. RESULTS: Mean WHZ significantly increased up to 18months of age and declined thereafter (p<<0.001). Overall mean WHZ was 0.743, prevalence of overweight 31.2% and prevalence of obesity 10.0%. Children categorised with overweight or obesity at 3yo showed significantly higher and sustained pattern of weight gain compared with children with normal WHZ. Once a child had overweight or obesity they tended to remain with it and did not return to a weight-for-height in the normal range. CONCLUSION: The increasing prevalence of overweight and obesity in Chilean children is of concern. There is a need for greater healthcare promotion and prevention of this disease from infancy. PMID- 30424970 TI - Decreased rates of 30-day perioperative complications following ASD-corrective surgery: A modified Clavien analysis of 3300 patients from 2010 to 2014. AB - The Clavien-Dindo grading allows for broad comparison of perioperative surgical complications, and a temporal analysis of complications following ASD-corrective surgery. NSQIP database was utilized from 2010 to 2014 to isolate patients. Complications were stratified by Clavien complication (Cc) grade, and patients grouped by highest Cc grade: I, II, III, IV, V. Secondary analysis grouped by minor (I, II, III) and severe (IV, V). Comorbidity burden was assessed with a NSQIP-modified Charlson Comorbidity Index (CCI) and frailty was measured with a 5 factor modified frailty index (mFI). From 2010 to 2014, 2971 patients (57 yrs, 58% F) underwent surgery for ASD (3.4 +/- 4.1 levels; surgical approach: 46% anterior, 44% posterior, 10% combined), the rate of which increased 0.01% to 0.13. 32% suffered >1 complication. Patient breakdown by Cc grade: 0% I, 25% II, 3% III, 4% IV, 1% V. Severe Cc patients were more comorbid than minor Cc (CCI 2.8 vs 1.8), had longer operative times (394 min vs 251), and higher rates of osteotomy (29% vs 13%) and iliac fixation (16% vs 5%). Overall CCI (2.1-1.7) and perioperative complication rates (55-29%) decreased, despite increasing surgical invasiveness (2.8-4.5) and increasing frailty score (0.14 +/- 0.15 vs 0.16 +/- 0.16). Rates of Clavien grade II (39.80-22.20%) and IV (9.40-3.50%) complications also decreased, indicative of surgical improvements and effective preoperative patient selection. The decrease in CCI and increase in the modified frailty score may show that we are becoming more cognizant of discerning of comorbidities, but likely to not to have taken into account frailty, which may have an impact on future health socioeconomics. PMID- 30424972 TI - Aortic dilatation in patients with large vessel vasculitis: A longitudinal case control study using PET/CT. AB - OBJECTIVE: To evaluate aortic diameter and predictors of aortic dilatation using 18FDG-PET/CT in a longitudinally followed cohort of patients with large vessel vasculitis (LVV) compared with controls. METHODS: All consecutive patients with LVV who underwent at least 2 PET/CT scans between January 2008 and May 2015 were included. The first and last PET/CT study was evaluated by a radiologist and a nuclear medicine physician. Diameter and FDG uptake of the aorta was measured at 4 different levels: ascending, descending thoracic, suprarenal and infrarenal abdominal aorta. Twenty-nine age- and sex-matched patients with lymphoma who underwent at least 2 PET/CT scans in the same time interval were selected as controls. RESULTS: 93 patients with LVV were included in the study. In the time interval between first and last PET/CT study (median time 31 months), the diameter of the ascending, descending thoracic and suprarenal abdominal aorta significantly increased in LVV patients but not in controls. At last PET/CT, patients with LVV compared with controls had higher diameter of ascending [35.41 (5.54) vs 32.97 (4.11) mm, p = 0.029], descending thoracic [28.42 (4.82) vs 25.72 (3.55) mm, p = 0.007] and suprarenal abdominal aorta, mean [25.34 (7.01) vs 22.16 (3.26) mm, p = 0.005] and more frequently had aortic dilatation [19% vs 3%, p = 0.023]. Significant predictors of aortic dilatation were male sex [OR 7.27, p = 0.001] and, only for GCA, hypertension [OR 6.30, p = 0.031]. Finally, GCA patients with aortic FDG uptake grade 3 at first PET/CT, compared to those with aortic FDG uptake <=2, had significantly higher aortic diameter. CONCLUSIONS: Patients with LVV are at increased risk of aortic dilatation compared with age- and sex-matched controls. Significant predictors of aortic dilatation are male sex and, only for GCA, hypertension. GCA patients with aortic FDG uptake grade 3 are at increased risk of aortic dilatation. PMID- 30424973 TI - A prospective study of obesity and risk of systemic lupus erythematosus (SLE) among Black women. AB - BACKGROUND: Obesity may influence systemic lupus erythematous (SLE) pathogenesis via stimulation of systemic inflammation, but the relationship between obesity and SLE risk is unclear. Past studies have predominantly assessed White women, while Black women have higher prevalence of both obesity and SLE. METHODS: We prospectively assessed the relationship between Body Mass Index (BMI, kg/m2) and incident SLE within the Black Women's Health Study (median age 38 at entry in 1995). Height and weight at age 18 and during follow-up were self-reported. We confirmed incident SLE cases by updated American College of Rheumatology criteria and collected covariates prospectively. Cox proportional hazards regression models, adjusted for potential confounders, estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for categories of updated BMI and risk of SLE, relative to BMI 20-24.9 ("normal" BMI). Secondary analyses investigated BMI at age 18, BMI in 1995 at cohort entry, cumulative updated BMI and "lagged" BMI (>=4 years prior to outcome window to address possible reverse causation). RESULTS: Adult obesity was not related to SLE risk: HR for BMI >=30 ("obesity") relative to normal BMI at >=4 years prior to SLE diagnosis was 0.90 (95% CI 0.53-1.54). However, obesity at age 18 was associated with increased risk: HR 2.38 (95% CI 1.26-4.51) for >=30 vs. normal BMI. CONCLUSIONS: Among these Black women, obesity as a teenager was associated with increased SLE risk in adulthood. Further studies are necessary to understand the biologic mechanisms and windows of exposure for the relationship of obesity to SLE pathogenesis. PMID- 30424974 TI - Aggressive metastatic malignant pilomatrixoma followed by 18F-FDG PET/CT. PMID- 30424975 TI - Sentinel node biopsy for melanoma: New Zealand indication guidelines in practice?. PMID- 30424976 TI - Differential visualization of arterial and venous flow in deep inferior epigastric perforator imaging with vector-flow perforator Phase Contrast Angiography (pPCA). PMID- 30424977 TI - Single surgeon series of outcomes of 897 consecutive endoscopic carpal tunnel releases stratified by disease severity. PMID- 30424978 TI - Control of bacterial attachment by fracture topography. AB - In the biomedical arena, bacterial fouling is a precursor to complications such as implant infection and nosocomial infection. These complications are further compounded by biochemical mechanisms of resistance that threaten the action of traditional antibacterial strategies. Accordingly, antibacterial property by physical, not biochemical, mechanisms of action is becoming increasingly popular and promising. The present work falls in line with this paradigm shift. Here, microtextured Ti-6Al-4V surfaces were manufactured by destructive tension at three different cross-head speeds, probed with scanning electron microscopy (SEM) and multifocus optical microscopy, and treated with Staphylococcus aureus to study bacterial attachment. The fractographic study revealed the presence of dual mode fracture, typical of Ti-6Al-4V, comprising regions of both ductile, microvoid coalescence and brittle, cleavage faceting . Based on load-extension curves, quantitative roughness data, and qualitative SEM visualisation, it was evident that cross-head speed modulated fracture behaviour such that increased speed produced more brittle fracture whilst lower speeds produced more ductile fracture. The topography associated with ductile fracture was found to possess notable antibiofouling property due to geometric constrains imposed by the coalesced microvoids. Accordingly, fracture at low cross-head speeds (1 mm/min and 10 mm/min) yielded significant reduction in bacterial attachment, whilst fracture at high cross-head speeds (100 mm/min) did not. The greatest reduction (~72%) was achieved at a cross-head speed of 1 mm/min. These findings suggest that antibiofouling property can be elicited by fracture and further 'tuned' by fracture speed. Discovery of this novel, albeit simple, avenue for topography mediated antibacterial property calls for further research into alternate techniques for the manufacture of 'physical antibacterial surfaces'. PMID- 30424979 TI - Advances in behavioral animal models of alcohol use disorder. AB - Alcohol use disorder (AUD) is a multifaceted neuropsychiatric disease that combines behavioral, psychosocial, and neurobiological aspects. Over the previous decade, animal models have advanced in modeling the major psychological constructs that characterize AUD. These advances pave the road for more sophisticated behavioral models that capture addiction-related aspects, such as alcohol craving, compulsive seeking and intake, dependence, and relapse. In this review, we survey the recent progress in behavioral animal modeling of five aspects of AUD: alcohol consumption, dependence, and seeking; compulsivity in alcohol intake despite adverse outcomes; vulnerability and resilience factors in alcohol addiction; relapse despite treatment; and relapse prevention by manipulating alcohol-associated memory reconsolidation. These advances represent a general attempt to grasp the complexity and multidimensional nature of AUD, and to focus on behavioral characteristics that better reflect and model this disorder. PMID- 30424980 TI - Three Nurse-administered Protocols Reduce Nutritional Decline and Frailty in Older Gastrointestinal Surgery Patients: A Cluster Randomized Trial. AB - OBJECTIVE: To evaluate the effects of the modified Hospital Elder Life Program (mHELP) comprising 3 nurse-administered protocols in older patients undergoing gastrointestinal (GI) surgery. DESIGN: Cluster randomized trial. SETTING: Two 36 bed GI wards at a university-affiliated medical center in Taiwan. PARTICIPANTS: Older patients (>=65 years, N = 377) were recruited if they were scheduled for elective GI surgery with an expected length of hospital stay >6 days. After transferring to the GI ward after surgery, participants were randomly assigned to the mHELP or control group (1:1) by room rather than individually because most patient units are double- or triple-occupancy rooms. INTERVENTION: The mHELP protocols (early mobilization, oral and nutritional assistance, and orienting communication) were administered daily with usual care by a trained nurse until hospital discharge. The control group received usual care only. MEASURES: Outcomes were in-hospital nutritional decline, measured by body weight and Mini Nutritional Assessment (MNA) scores, and Fried's frailty phenotype. Return of GI motility was examined as a potential mechanism contributing to observed outcomes. RESULTS: Participants (mean age = 74.5 years; 56.8% male) primarily underwent colorectal (56.5%), gastric (21.2%), and pancreatobiliary (13.8%) surgery. Participants who received the mHELP [for a median of 7 days (interquartile range = 6-10 days)] had significantly lower in-hospital weight loss and decline in MNA scores (weight -2.1 vs -4.0 lb, P = .002; score -3.2 vs -4.0, P = .03) than the control group. The mHELP group also had significantly lower rates of incident frailty during hospitalization (12.0% vs 21.7%, P = .022), and persistent frailty (50.0% vs 92.9%, P = .03). Participants in the mHELP group had trends toward an accelerated return of GI motility. CONCLUSION AND IMPLICATIONS: The mHELP effectively reduced nutritional decline, prevented new frailty, and promoted recovery of frailty present before admission. These nurse-administered protocols might be useful in other settings, including conditions managed at home or in nursing facilities. PMID- 30424981 TI - Preventing Alzheimer's Disease: Why Not Targeting the Muscle First? PMID- 30424982 TI - Healthcare Costs of Frailty: Implications for Long-term Care. PMID- 30424983 TI - [Contraception for women after 40: CNGOF Contraception Guidelines]. AB - INTRODUCTION: Choosing contraception for women over 40 can be sometimes difficult but it is crucial since fertility and pregnancy's risks still exist. It requires a thorough evaluation of the situation, in order to identify any vascular and metabolic risk factors, along with the uterine and mammary benign pathologies already diagnosed. OBJECTIVE: The objective of this review was to elaborate some guidelines for clinical practice regarding contraception's prescription for women over 40. METHODS: A systematic review of the French and English existing literature was conducted. Pubmed and the Cochrane library were used to identify studies about contraception for perimenopausal women. International guidelines published by scientific societies were also reviewed (RCOG, FSRH, ESHRE, ACOG, WHO, HAS). RESULTS: No contraceptive methods are contraindicated on the sole basis of age alone. However, because age is a risk factor for vascular and metabolic diseases, combined hormonal contraception and DMPA should not be prescribed at first intention. Copper IUD and progestin-only contraceptives (pill, implant, intrauterine device) should primarily be considered, since they offer good efficacy with lower risks. CONCLUSIONS: Contraception for women over 40 should not be put aside. Long acting reversible contraception and progestin only pill have to be prescribed as first-ine. Contraception is no longer needed for women over 50 who use non-hormonal contraception, after a 12 month amenorrhea. Patients treated with combined hormonal contraception must stop using it over 50. Measuring hormonal levels while using hormonal contraception is not recommended. An hormonal-contraception-free interval must be considered, while using barrier contraception method. If an ovarian activity persists, a non hormonal contraception or progestin-only contraception (except for DMPA) should be (re-)established. PMID- 30424984 TI - Off-Pump Plicating Ascending Aortoplasty With External Wrapping: Magnum In Parvo. AB - BACKGROUND: Isolated, fusiform aneurysms, exclusively affecting the tubular portion of the ascending aorta, are rare. Surgical treatment aims to change their natural course, reducing individual and cumulative risks of rupture, dissection and death. Open tubular graft replacement still remains the procedure of choice, despite significant risks. In permanent pursuit for optimal, alternative surgical strategy in high-risk patients, less invasive and off-pump plicating ascending aortoplasty with modified external Dacron graft wrapping seems to be a reliable choice. METHODS: Two consecutive patients were operated on. The same preoperative calculations and slightly different operative techniques were applied regarding surgical exposure and wrapping graft orientation. Immediate and late follow-up (5 years) results were compared. RESULTS: Absolute and indexed target ascending aortic diameters remained acceptable (<2.1cm/m2 considered the upper normal range for adults). There were no significant changes in proximal and distal aortic diameters. Ascending aortic silhouette on contrast enhanced multi-detector CT was better with Dacron wrapping graft tailored to have its grooves in the longitudinal direction. Upper mini-sternotomy was quite appropriate for this procedure, from a surgical point of view, and was safe for the patient. CONCLUSIONS: Careful patient selection and using the current model of preoperative calculations and surgical technique resulted in acceptable and stable ascending aortoplasty in high-risk patients 5 years after surgery. PMID- 30424985 TI - The Relationship Between Renal Artery Involvement in Stanford B-Type Aortic Dissection and the Short-Term Prognosis: A Single-Centre Retrospective Cohort Study. AB - BACKGROUND: Renal artery involvement has not received sufficient attention despite the fact that aortic computed tomography angiography (CTA) examinations of Stanford B-type aortic dissection patients usually show renal artery involvement [3]. To study the influence of renal artery involvement on aortic dissection, we performed a retrospective study on acute Stanford B-type aortic dissection patients with or without renal artery involvement to investigate its effect on the prognosis of aortic dissection. METHODS: A total of 221 patients with acute Stanford-B type aortic dissection between January 2012 and January 2014 were enrolled. The patients were divided into a renal artery involvement group and a non-renal artery involvement group based on aortic computed tomography angiography (CTA) results. The clinical data of the two groups were compared. Univariate analyses and multiple logistic regression analyses were performed to determine risk factors related to in-hospital mortality. The effect of renal artery involvement on the prognosis of Stanford B-type aortic dissection patients was analysed. RESULTS: Among the 221 patients with acute Stanford type-B aortic dissection, 100 patients (45.2%) exhibited renal artery involvement. The percentage of patients with a past history of hypertension in the renal artery involvement group was significantly higher than that in the non-renal artery involvement group (84.0% vs. 74.8%, p=0.025). The estimated glomerular filtration rate (eGFR), creatinine level, and urea nitrogen level at admission were not significantly different between the renal artery involvement group and the non renal artery involvement group. The in-hospital mortality rate in the renal artery involvement group was higher than that in the non-renal artery involvement group; the difference in the percentage of in-hospital mortality between these two groups was statistically significant (12.0% vs. 4.1%, p<0.05). The results of multiple logistic regression analysis showed that renal artery involvement was a risk factor for in-hospital mortality in acute Stanford B-type aortic dissection patients (odds ratio (OR)=3.536 (1.127~11.095)). In the renal artery involvement group, the in-hospital mortality rate in the conservative treatment group was significantly higher than that in the interventional treatment group (30.8% vs. 5.4%, p=0.001). CONCLUSIONS: Although renal artery involvement was not associated with short-term renal function damage, it was a risk factor for in-hospital mortality after acute Stanford B-type aortic dissection. PMID- 30424986 TI - Is injury to the inferior alveolar nerve still common during orthognathic surgery? Manual twist technique for sagittal split ramus osteotomy. AB - The osteotomy in a bilateral sagittal split ramus osteotomy (BSSRO) is made in close proximity to the inferior alveolar nerve (IAN), so direct damage to the nerve and irreversible neurosensory deficit may result. The aim of this study was to compare the incidence of injury to the nerve when a conventional osteotomy using an osteotome was made, with that after manual twist splitting. We retrospectively reviewed the casenotes of 769 consecutive patients who had bilateral SSRO either alone or with a simultaneous maxillary procedure by a single surgeon from May 2009 - October 2016. Patients were divided into two groups based on the technique used. Those in the first group had conventional split osteotomy using an osteotome and hammer for splitting (conventional group, 736 sides), and in those in the second group the manual twist technique was used (manual group, 802 sides). Patients who sustained Sunderland fifth degree injuries were identified from an existing record of nerve repairs. Fisher's exact test was used to evaluate the significance of the number of injuries to the nerve in each group. Conventional osteotomy and hammer-assisted SSRO resulted in 8/736 (1.1%) injuries to the IAN, whereas the manual twist splitting technique resulted in 1/802 injuries (0.1%). Our results confirm that the manual twist splitting technique significantly reduces the incidence of injury to the IAN, though the overall incidence was low. PMID- 30424987 TI - Thyrotoxic periodic paralysis complicated by life-threatening acute hypercapnic respiratory failure in a Chinese male with painless thyroiditis. AB - CONTEXT: Thyrotoxic periodic paralysis (TPP) is a relatively common complication seen in Asian hyperthyroid patients. However, it is a rare occurrence to find a TPP case comprised of acute hypercapnic respiratory failure in patients with painless thyroiditis. PATIENT: A 29-year-old Chinese man presented with flaccid paralysis of all four limbs and he was brought to emergency room. Severe hypokalemia was found on admission. Although treatment had been initiated with potassium chloride supplementation, he went on to develop acute hypercapnic respiratory failure likely due to muscle fatigue. The patient was intubated for mechanical ventilatory support. Once his serum potassium levels were normalized, he was able to be weaned off ventilator support. Thyroid function tests showed elevated free thyroxine concentration and low thyroid-stimulating hormone concentration. He underwent a thyroid uptake scan with 131I which revealed decreased uptake rate of thyroid area. Based on the patient's clinical presentation and associated findings, we diagnosed him with TPP due to painless thyroiditis. We have reviewed TPP cases caused by painless thyroiditis and TPP cases associated with acute hypercapnic respiratory failure. CONCLUSION: It is important to note that potentially fatal complications such as acute hypercapnic respiratory failure might occur in acute attacks of TPP even in cases of TPP due to painless thyroiditis. PMID- 30424988 TI - Corrigendum to "Surface modifications and oxidative degradation in MPC-grafted highly cross-linked polyethylene liners retrieved from short-term total hip arthroplasty" [Acta Biomater. 66 (2018) 157-165]. PMID- 30424989 TI - Free radial forearm flap and anterolateral thigh flap for reconstruction of hemiglossectomy defects: A comparison of quality of life. AB - OBJECTIVES: The purpose of the retrospective study was to compare the differences of quality of life (QOL) outcomes 2 or more years postoperatively between the free radial forearm flap (FRFF) and anterolateral thigh flap (ALTF) in reconstruction of defects of a hemiglossectomy. METHODS: Ninety patients who had a lapse >=2 years since the reconstructive flap surgery were evaluated by the University of Washington quality of life scale (UW-QOL), and Performance Status Scale for Head and Neck (PSS-HN). RESULTS: Patients in the FRFF group reported statistically and clinically significantly better scores in the recreation, swallowing, chewing and speech domains of the UW-QOL compared with those in the ALTF group (P < .05). Similarly, FRFF provided better results in the understandability of speech and normalcy of diet of the PSS-HN, than the ALTF (P < .05). CONCLUSIONS: FRFF had the advantage of oral functions, such as chewing, speech and swallowing, over the ALTF for reconstruction of defect of half of the tongue. These results may provide useful information for surgeons to select a suitable free flap for tongue reconstruction. PMID- 30424991 TI - US Health Care Companies Exploring Blockchain Technologies. PMID- 30424990 TI - Usefulness of perampanel with concomitant levetiracetam for patients with drug resistant epilepsy. AB - PURPOSE: The purpose was to evaluate the efficacy of treatment and the occurrence of aggression-related adverse events among children receiving perampanel (PER) with concomitant levetiracetam (LEV). METHODS: Patients were selected according to the following criteria: 1) between 12 and 18 years old; 2) seizures refractory to at least 2 first-line drugs; 3) at least 4 seizures a month before PER administration; and 4) at least 12 months of follow-up. Patients were subdivided into groups with and without LEV as concomitant treatment. PER was administered at a dose of 2 mg/day, increasing by 2 mg/day every 2 weeks up to 12 mg/day if seizures appeared. In comparison with the baseline seizure frequency, response to PER treatment was classified as follows: complete cessation (100% seizure control); response (>=50% reduction in seizures); and exacerbation (>=50% increase in seizures). Responders were identified as patients showing complete cessation or response. RESULTS: The study group comprised 39 outpatients with a mean age of 13.7 years at enrollment. Responder status was seen in 13 of the 19 patients with LEV and 4 of the 20 patients without LEV. PER appeared significantly more effective in patients with LEV than in those without LEV (p = 0.0076). Seizure-free status was significantly more frequent among patients with LEV (47.4%) than among those without LEV (15.0% (p = 0.0407)). Aggression was present in 2 patients without LEV, but none with LEV. CONCLUSION: The present study suggests the utility of PER with concomitant LEV for children with drug resistant epilepsy. PMID- 30424992 TI - The Helper's High. AB - The concept of the "helper's high" arose in the 1980s, and has been confirmed in various studies since then. It consists of positive emotions following selfless service to others. Greater health and increased longevity are associated with this psychological state. Generosity, selflessness, and an extended sense of self favor our ability to confront successfully the environmental challenges we face on our planet. PMID- 30424993 TI - Testing of A Caregiver Support Team. AB - CONTEXT: Healthcare clinicians often endure stress over long periods of time. The burden of witnessing death and disability, complex work duties, long and irregular hours, the threat of errors, and tensions between colleagues result in emotional strain, anxiety, depression, burnout and in the worst case: suicide. The Caregiver Support Team was designed to provide emotional first aid to clinicians in the healthcare environment in the moment of need and triage those who would benefit from ongoing care. OBJECTIVE/INTERVENTION: To test the feasibility of providing a Caregiver Support Team to provide emotional first aid in the workplace. This project is an extension of our previously reported Code Lavender initiative. HYPOTHESES: After stressful events in the workplace, staff will provide, receive, and recommend the Caregiver Support Team to others. The Caregiver Support Team will be used and accepted by clinicians, improve Professional Quality of Life Scale (ProQoL) scores, general job satisfaction and feeling cared for in the workplace. METHOD/SAMPLE: We describe a pilot program. Following the completion of a Code Lavender pilot, physicians and staff on 4 hospital units provided nominations for peer supporters: someone they would trust in a time of emotional need. These peer supporters were provided 8 hours of training by a psychologist and voluntarily sought to find those in the workplace who were affected by workplace stress and provide emotional support. Feasibility data and ProQoL scores were collected at baseline and 3 months. RESULTS: At baseline, 59% (n = 44) reported symptomatic stress caused by the workplace. Main causes of stress were emotional responses of patients/families, disputes with colleagues, and negative clinical outcomes. Colleagues were reported as the most frequently used source of support following workplace stress. A Caregiver Support Team intervention was received by 40% of respondents; 100% found it helpful and 100% would recommend it to others. No significant changes were demonstrated before and after the intervention in ProQoL Scores, or job satisfaction. The emotion of feeling cared-for improved. Staff spontaneously requested emotional debriefings through peer supporters. One suicide was prevented. CONCLUSIONS: The Caregiver Support Team was positively received. The organization received budgetary support from our hospital to disseminate the program system-wide. Additional interventions are needed to overcome the root cause of workplace stressors. A formal link between Risk Management is being developed to identify cases which warrant emotional (vs. clinical only or both) debriefing/group processing. PMID- 30424994 TI - The Association Between C-Reactive Protein and Postoperative Delirium Differs by Catechol-O-Methyltransferase Genotype. AB - OBJECTIVE: Catechol-O-methyltransferase (COMT), a key enzyme in degrading catecholamines associated with the stress response, may influence susceptibility to delirium. Individuals with the COMT (rs4680) Val/Val genotype (designated "warriors") withstand the onset of neuropsychiatric disorders and cognitive decline, whereas individuals with Met/Met and Val/Met genotypes ("nonwarriors") are more susceptible to these conditions. We evaluated whether COMT genotype modifies the established association between acute phase reactant (stress marker) C-reactive protein (CRP) and postoperative delirium. METHODS: This was a prospective cohort study conducted at two academic medical centers. The study involved 547 patients aged 70 or older undergoing major noncardiac surgery. We collected blood, extracted DNA, and performed COMT genotyping using allele specific polymerase chain reaction assays, considering warriors versus nonwarriors. High plasma CRP, measured on postoperative day 2 using enzyme-linked immunosorbent assay, was defined by the highest sample-based quartile (>=234.12 mg/L). Delirium was determined using the Confusion Assessment Method, augmented by a validated chart review. We used generalized linear models adjusted for age, sex, surgery type, and race/ethnicity, stratified by COMT genotype, to determine whether the association between CRP and delirium differed by COMT. RESULTS: Prevalence of COMT warriors was 26%, and postoperative delirium occurred in 23%. Among COMT warriors, high CRP was not associated with delirium (relative risk [RR] 1.0, 95% confidence interval [CI] 0.4-2.6). In contrast, among nonwarriors, we found the expected relationship of high CRP and delirium (RR 1.5, 95% CI 1.1 2.2). CONCLUSION: COMT warriors may be protected against the increased risk of delirium associated with high CRP on postoperative day 2. With further confirmation, COMT genotype may help target interventions for delirium prevention in the vulnerable nonwarrior group. PMID- 30424995 TI - Interdisciplinary Team Perspectives on Mental Health Care in VA Home-Based Primary Care: A Qualitative Study. PMID- 30424996 TI - December Solstice. PMID- 30424997 TI - Effect of Adjunct Repetitive Transcranial Magnetic Stimulation in Elderly Patients with Acute Depressive Episode: Supporting Evidence from a Real-World Observation. PMID- 30424998 TI - Influence of Artificial Intelligence on Canadian Medical Students' Preference for Radiology Specialty: A National Survey Study. AB - RATIONALE AND OBJECTIVES: Artificial intelligence (AI) has the potential to transform the clinical practice of radiology. This study investigated Canadian medical students' perceptions of the impact of AI on radiology, and their influence on the students' preference for radiology specialty. MATERIALS AND METHODS: In March 2018, an anonymous online survey was distributed to students at all 17 Canadian medical schools. RESULTS: Among 322 respondents, 70 students considered radiology as the top specialty choice, and 133 as among the top three choices. Only a minority (29.3%) of respondents agreed AI would replace radiologists in foreseeable future, but a majority (67.7%) agreed AI would reduce the demand for radiologists. Even among first-choice respondents, 48.6% agreed AI caused anxiety when considering the radiology specialty. Furthermore, one-sixth of respondents who would otherwise rank radiology as the first choice would not consider radiology because of the anxiety about AI. Prior significant exposure to radiology and high confidence in understanding of AI were shown to decrease the anxiety level. Interested students valued the opinions of local radiologists, radiology conferences, and journals. Students were most interested in "expert opinions on AI" and "discussing AI in preclinical radiology lectures" to understand the impact of AI. CONCLUSION: Anxiety related to "displacement" (not "replacement") of radiologists by AI discouraged many medical students from considering the radiology specialty. The radiology community should educate medical students about the potential impact of AI, to ensure radiology is perceived as a viable long-term career choice. PMID- 30424999 TI - Diagnostic Accuracy of CT for Prediction of Bladder Cancer Treatment Response with and without Computerized Decision Support. AB - RATIONALE AND OBJECTIVES: To evaluate whether a computed tomography (CT)-based computerized decision-support system for muscle-invasive bladder cancer treatment response assessment (CDSS-T) can improve identification of patients who have responded completely to neoadjuvant chemotherapy. MATERIALS AND METHODS: Following Institutional Review Board approval, pre-chemotherapy and post chemotherapy CT scans of 123 subjects with 157 muscle-invasive bladder cancer foci were collected retrospectively. CT data were analyzed with a CDSS-T that uses a combination of deep-learning convolutional neural network and radiomic features to distinguish muscle-invasive bladder cancers that have fully responded to neoadjuvant treatment from those that have not. Leave-one-case-out cross validation was used to minimize overfitting. Five attending abdominal radiologists, four diagnostic radiology residents, two attending oncologists, and one attending urologist estimated the likelihood of pathologic T0 disease (complete response) by viewing paired pre/post-treatment CT scans placed side-by side on an internally-developed graphical user interface. The observers provided an estimate without use of CDSS-T and then were permitted to revise their estimate after a CDSS-T-derived likelihood score was displayed. Observer estimates were analyzed with multi-reader, multi-case receiver operating characteristic methodology. The area under the curve (AUC) and the statistical significance of the difference were estimated. RESULTS: The mean AUCs for assessment of pathologic T0 disease were 0.80 for CDSS-T alone, 0.74 for physicians not using CDSS-T, and 0.77 for physicians using CDSS-T. The increase in the physicians' performance was statistically significant (P < .05). CONCLUSION: CDSS-T improves physician performance for identifying complete response of muscle-invasive bladder cancer to neoadjuvant chemotherapy. PMID- 30425000 TI - Texture Analysis Based on Preoperative Magnetic Resonance Imaging (MRI) and Conventional MRI Features for Predicting the Early Recurrence of Single Hepatocellular Carcinoma after Hepatectomy. AB - RATIONALE AND OBJECTIVES: To investigate the value of texture analysis and conventional magnetic resonance imaging (MRI) features for predicting the early recurrence (ER) of single hepatocellular carcinoma (HCC) after hepatectomy. MATERIALS AND METHODS: A total of 100 HCC patients were first divided into group A (tumor diameter <=3 cm) and group B (tumor diameter >3 cm) and then classified into two subgroups with ER or nonearly recurrence. Textural parameters (skewness, kurtosis, uniformity, energy, entropy, and correlation) based on MR images and conventional MRI features were compared between the ER and nonearly recurrence subgroups. Predictive factors for ER were further assessed with multivariate logistic regression analysis. Receiver operating characteristic curve was performed to assess the predictive power. RESULTS: There were 53 patients in group A and 47 patients in group B. On arterial phase analysis, tumors with ER displayed significantly lower uniformity and higher entropy in group A, and higher skewness and entropy in group B. On portal venous phase analysis, tumors with ER had significantly lower kurtosis and energy in group A, and higher entropy in group B. Irregular margin in groups A and B, and arterial peritumoral enhancement and capsule presence in group B were associated with ER. In multivariate logistic regression analysis, uniformity and entropy based on arterial phase images and irregular margin in group A, and skewness and entropy based on arterial phase images and arterial peritumoral enhancement in group B were independent predictors for ER. Entropy displayed higher predictive power for ER. CONCLUSION: Texture analysis based on preoperative MRI are potential quantitative predictors of ER in HCC patients after hepatectomy, and may provide more information for preoperative treatment decision-making and follow up. PMID- 30425001 TI - Evaluation of Urinary Renal Biomarkers for Early Prediction of Acute Kidney Injury Following Partial Nephrectomy: A Feasibility Study. AB - BACKGROUND: Partial nephrectomy (PN) is the gold standard for the treatment of small renal masses. Urinary biomarkers (UBMs) may serve as early indicators of acute kidney injury (AKI) following PN. OBJECTIVE: To evaluate the timing, specificity, and sensitivity of several candidate UBMs after PN to determine the most promising UBMs in this setting. We hypothesize that some UBMs will have utility as early markers of AKI. DESIGN, SETTING, AND PARTICIPANTS: Twenty-two patients undergoing on-clamp robotic or open PN underwent paired urine collection via ureteral catheterization of the affected kidney and Foley catheterization for the unaffected kidney obtained preoperatively, after anesthesia, and at several points in time after renovascular occlusion. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Measured UBMs included albumin, alpha-glutathione S-transferase, B2M, calbindin, clusterin, cystatin C, epidermal growth hormone, kidney injury molecule 1, neutrophil gelatinase-associated lipocalin, osteoactivin, osteopontin, total protein, trefoil factor 3, uromodulin, and vascular endothelial growth factor. RESULTS AND LIMITATIONS: The largest fold changes in UBM levels were observed between the baseline values and just prior to vascular occlusion (time "0"). Albumin, clusterin, and calbindin were among the most consistently and significantly increased UBMs. After vascular occlusion and subsequent reperfusion, some UBMs, most notably albumin, calbindin, and total protein, continued to increase in the affected kidney, peaking at 60-90min, followed by decrease to time "0" measurements after 1 d and to baseline levels 14 42 d after surgery. No striking association of UBMs with parameters such as duration of surgery, ischemia time, and tumor complexity was observed. CONCLUSIONS: The most significant UBM increases were observed when comparing samples obtained at preoperative visit and after anesthesia, but before clamp time. Albumin, clusterin, and calbindin were the most consistently and significantly altered UBMs; further investigation will be necessary to determine whether UBMs can identify AKI earlier in nephrectomy patients. PATIENT SUMMARY: Factors (biomarkers) measured in the blood or urine can indicate the presence and amount of kidney injury. We evaluated 15 different biomarkers at several points in time prior to, during, and after surgery for kidney cancer. We found that three of these biomarkers were most consistently elevated in patients undergoing partial nephrectomy. Interestingly, the largest increases were observed when comparing samples obtained prior to surgery with those obtained just after anesthesia. PMID- 30425002 TI - Reasons for underutilization of bariatric surgery: The role of insurance benefit design. AB - Despite the effectiveness of bariatric surgery, both with respect to weight loss and improvements in obesity-related co-morbidities, it remains underused. Only 1% of the currently eligible population undergoes surgical treatment for obesity, with roughly 228,000 individuals receiving bariatric surgery in the United States each year. Several barriers to bariatric surgery have been identified, including limited patient and referring physician knowledge and attitudes regarding the effectiveness and safety of bariatric surgery. However, the role of insurance coverage and benefit design as a barrier to access to care has received less attention to date. Bariatric surgery is cost-effective compared with nonsurgical treatments among individuals with extreme obesity and type 2 diabetes. While it may not result in cost savings among all bariatric surgery eligible patients, for certain patient subgroups, bariatric surgery may be cost neutral compared with traditional treatment options. In addition, longer-term outcomes of bariatric surgery suggest decreased or stable costs in the long run. The purpose of this review paper was to synthesize the existing knowledge on why bariatric surgery remains largely underused in the United States with a focus on health insurance benefits and design. In addition, the review discusses the applicability of value based insurance design to bariatric surgery. Value-based insurance design has been previously applied to bariatric surgery coverage with use of incentive-based cost-sharing adjustments. Its application could be further extended because the postoperative clinical outcomes and costs vary among the different subgroups of bariatric surgery eligible patients. PMID- 30425003 TI - Results of a Prospective Phase 2 Pilot Trial of 177Lu-PSMA-617 Therapy for Metastatic Castration-Resistant Prostate Cancer Including Imaging Predictors of Treatment Response and Patterns of Progression. AB - BACKGROUND: 177Lu-PSMA-617 (Lu-PSMA) is an emerging therapy in men with metastatic castration-resistant prostate cancer. Paired theranostic agents have the potential to visually identify phenotypes that will respond to targeted therapy. This study examined the value of 68Ga-HBEDD PSMA-11; prostate-specific membrane antigen (PSMA) positron emission tomography (PET) in predicting treatment response and disease progression in Lu-PSMA therapy within the context of a phase 2 prospective pilot trial. PATIENTS AND METHODS: Men with progressive, symptomatic metastatic castration-resistant prostate cancer previously treated with antiandrogens (abiraterone and/or enzalutamide) and taxane-based chemotherapy were prospectively enrolled. Eligibility criteria included uptake on PSMA PET above or equal to liver activity, with no 18F-Fluoro-deoxyglucose (FDG) PET-discordant disease. Men received up to 4 cycles of Lu-PSMA at 6 weekly intervals. Repeat FDG/PSMA PET imaging was performed after completion of therapy or at prostate-specific antigen (PSA) progression. The study assessed treatment response to Lu-PSMA using PSA response and correlated treatment response (PSA) to molecular imaging parameters at enrollment. RESULTS: Fourteen of 18 men screened underwent Lu-PSMA therapy. Ten (71%) of 14 had a PSA response (mean reduction, 59%). A >= 50% reduction in PSA occurred in 5 (36%), and >= 30% in 9 (64%). PSMA PET standardized uptake value (SUV) at screening was predictive of >= 30% PSA reduction: SUV max value 17 +/- 9 versus 44 +/- 15 (P < .007), and PSMA SUV mean 6 +/- 4 versus 10 +/- 4 (P < .04). FDG parameters alone, and volume or site of disease did not predict PSA response. No imaging parameters predicted >= 50% PSA reduction. Nine of 14 men were reimaged after treatment, revealing 3 distinct patterns of progression. CONCLUSION: PSMA PET plays an important role in predicting treatment response to Lu-PSMA and in identifying subsequent patterns of failure, which may aid in determining the next best treatment options. PMID- 30425004 TI - miRNA arm switching identifies novel tumour biomarkers. AB - BACKGROUND: microRNAs have been reported to play critical roles in cancer and to have potential as diagnostic biomarkers. During miRNA biogenesis, one strand of the miRNA hairpin precursor is preferentially selected as a functionally mature miRNA, while the other strand is typically degraded. Arm switching occurs when the strand preference is changed. This preference can be different and can change dynamically depending upon the species, tissue types, or development stages. Due to recent advances in next-generation sequencing methods, arm switching has been observed in a variety of cancers. METHODS: A tumour miRNA-Seq dataset was collected from The Cancer Genome Atlas (TCGA). The support vector machine (SVM) method combined with 5-fold cross validation was applied to select the best combination of arm-switched miRNA tumour markers. Survival analysis was also applied to identify patient survival associated miRNA markers. FINDINGS: We observed 51 arm-switched miRNAs and of these, 7 were associated with patient survival. Twenty-three 1-combination arm switching miRNAs with excellent diagnostic value were identified. Interestingly, ovarian cancer showed a significant difference in arm switching pattern compared with 32 other cancers. INTERPRETATION: These results suggest that arm switching miRNAs could be used as potential biomarkers for various cancers. FUND: This work was partially supported by the National Natural Science Foundation of China (no. 61472158, 61572227), and University of Macau Faculty of Health Sciences (MYRG2016-00101-FHS). PMID- 30425005 TI - Lumbar Vertebrae Morphological Analysis and an Additional Approach for Vertebrae Identification in Lumbar Spine DXA Images. AB - INTRODUCTION: Bone mineral density measured by dual-energy X-ray absorptiometry (DXA) is the gold standard for diagnosis of osteoporosis. However, DXA interpretation can be influenced by analytic errors which can, in turn, interfere with diagnostic accuracy. One such source of potential error is the accurate identification of specific lumbar vertebrae on lumbar spine DXA images. Although the International Society for Clinical Densitometry has introduced several approaches to aid with this process, there remain individuals whose lumbar vertebrae cannot be labeled with certainty using these approaches. We designed the present study to systematically evaluate lumbar spine DXA images among a large cohort of Chinese patients and present an additional simple strategy for identifying L5 named the "em dash"-shaped L5 or "-"-shaped L5, based upon the two dimensional relationship between the bilateral pedicles with the central spinous process on DXA images. METHODOLOGY: Lumbar spine posteroanterior DXA images from adult patients receiving care at a large tertiary hospital in Beijing, China from May to August 2016 were retrospectively reviewed. For each patient, data were collected regarding key anatomic features seen on DXA (positions of the most superior portions of the iliac crests, the lowest vertebra with ribs, and the longest transverse processes) and the proportion of patients presenting with "H" shaped L4 and "-"-shaped L5. Chi-squared analyses were used to compare proportions across age strata. RESULTS: DXA images from 1125 patients (79.6% female) were evaluated. The mean age of patients was 52.5 +/- 14.8 yr (range: 19 90 yr). A horizontal line drawn across the superior-most portions of the iliac crests crossed the disk space between L4 and L5 among 78.3% of patients. The lowest ribs were most frequently (83.9%) observed at T12. Almost 80% of individuals had the longest transverse processes at L3. L4 was predominantly "H" shaped (73.3%), however we found that the proportion of individuals with "H" shaped L4 decreased steadily after 50 yr of age (p < 0.001). By contrast we observed that L5 was predominantly "-"-shaped (80.3%), with no significant differences in proportions across all age strata (p = 0.063). CONCLUSIONS: The " "-shaped L5 can be incorporated as an additional reference tool for lumbar spine DXA image analysis and may be particularly helpful for lumbar vertebrae identification among patients over 50 yr of age. PMID- 30425006 TI - Greater Visceral Fat but No Difference in Measures of Total Body Fat in Ambulatory Children With Spastic Cerebral Palsy Compared to Typically Developing Children. AB - BACKGROUND: Individuals with cerebral palsy (CP) are at increased risk for obesity and obesity-related complications. Studies of total body fat in those with CP are inconsistent and studies of abdominal fat are lacking in children with CP. The objective of this study was to determine if ambulatory children with spastic CP have greater central adiposity compared to typically developing children. METHODOLOGY: Eighteen ambulatory children with spastic CP (n = 5 girls; 8.6 +/- 2.9 yr) and 18 age-, sex-, and race-matched typically developing children (controls; 8.9 +/- 2.1 yr) participated in this cross-sectional study. Children with CP were classified as I or II using the Gross Motor Function Classification System. Dual-energy X-ray absorptiometry assessed body composition, including total body, trunk and abdominal fat mass, fat-free mass, fat mass index (FMI), and fat-free mass index (FFMI). RESULTS: There were no group differences in fat mass, fat-free mass, FMI, and FFMI in the total body, fat mass, fat-free mass, and FFMI in the trunk, or fat mass, visceral fat mass, and subcutaneous fat mass in the abdomen (p > 0.05). Compared to controls, children with CP had higher trunk FMI, abdominal FMI, and visceral FMI (p < 0.05). Although marginally insignificant (p = 0.088), children with CP had higher subcutaneous FMI. CONCLUSIONS: Ambulatory children with spastic CP have elevated central adiposity, especially in the visceral region, despite no differences in measures of total body fat. How this relates to cardiometabolic disease progression in those with CP requires further investigation. PMID- 30425008 TI - The use of goal attainment scaling during clinical medication review in older persons with polypharmacy. AB - BACKGROUND: Studies have shown that a clinical medication review (CMR) reduces drug-related problems (DRPs), but the effects on clinical outcomes are less clear. Perhaps, CMRs in older persons could me more effective when they focus on patients' personal goals and health-related complaints. OBJECTIVE: The aim of this study was to investigate whether goal attainment scaling (GAS) is a useful tool for determining goals and monitoring their attainment during CMR. METHODS: This study was an analysis based on data of the intervention group of the DREAMeR study; a randomised controlled trial investigating the effects of CMR in primary care. 315 persons aged >=70 years using >=7 drugs were randomised to the intervention: a CMR focused on personal goals using GAS. Outcome measures were: percentage of persons with health-related goals, attainment of goals measured with GAS-scores after three and six months, type of health-related goals and implementation rates of recommendations for GAS-related DRPs and other DRPs. RESULTS: A total of 406 health-related goals were set for 283 of 315 included persons (90%). Of the 350 evaluated goals (86%), 37% was attained after three months and 43% after six months. The goals 'reduce pain' (n = 66, 16%), 'improve mobility' (n = 57, 14%) and 'reduce number of pills' (n = 37, 9.1%) were most prevalent. The implementation rate of recommendations for GAS-related DRPs was 81% compared to 62% for not GAS-related DRPs (p < 0.05). CONCLUSION: Goal setting is important for prioritizing the most important problems during clinical medication review and Goal Attainment Scaling seems to be a useful tool for monitoring the attainment of these goals. PMID- 30425007 TI - Assessment of Bone and Muscle Measurements by Peripheral Quantitative Computed Tomography in Geriatric Patients. AB - The loss of bone and muscle mass increases the risk of osteoporotic fractures. Dual energy X-ray absorptiometry (DXA) loses sensitivity in older age. The purpose of this study was to evaluate bone and muscle measurements of peripheral quantitative computed tomography (pQCT) in a geriatric cohort with osteoporosis. Bone mineral density and muscle area of 168 patients aged 65 years and older (76.3 +/- 6.5) were measured with pQCT at distal forearm additionally to an osteoporosis assessment consisting of anamnesis, blood test and DXA of lumbar spine and hip. Prior fractures were categorized in minor and major osteoporotic fractures. Logistic regression was used to show the association of bone mineral density and muscle area with major fractures. 54.8% of the participants had at least one major fracture. Bone mineral density measured with pQCT and muscle area were significantly associated with these fractures (total and trabecular bone mineral density OR 2.243 and 2.195, p < 0.01; muscle area OR 2.378, p < 0.05), whereas DXA bone mineral density showed no significant association. These associations remained after adjustment for age, sex, BMI, physical activity and other factors. In all models for patients >75 years only muscle area was significantly associated (OR 5.354, p < 0.05) with major fractures. Measurement of bone mineral density and muscle area with pQCT seems to have advantage over DXA in fracture association in geriatric patients. Measuring muscle area also adds useful information to estimate the presence of osteosarcopenia. PMID- 30425009 TI - Re: Below Safety Limits, Every Unit of Glomerular Filtration Rate Counts: Assessing the Relationship between Renal Function and Cancer-specific Mortality in Renal Cell Carcinoma. PMID- 30425010 TI - Cost-effectiveness Analysis of Active Surveillance Strategies for Men with Low risk Prostate Cancer. AB - BACKGROUND: Active surveillance (AS) has become the recommended management strategy for men with low-risk prostate cancer. However, there is considerable uncertainty about the optimal follow-up schedule in terms of the tests to perform and their frequency. OBJECTIVE: To assess the costs and benefits of different AS follow-up strategies compared to watchful waiting (WW) or immediate treatment. DESIGN, SETTING, AND PARTICIPANTS: A state-transition Markov model was developed to simulate the natural history (ie, no testing or intervention) of prostate cancer for a hypothetical cohort of 50-yr-old men newly diagnosed with low-risk prostate cancer. Following diagnosis, men were hypothetically managed with immediate treatment, watchful waiting, or one of several AS strategies. AS follow up was performed either with transrectal ultrasound-guided biopsy or magnetic resonance imaging (MRI) which was scheduled annually, biennially, every 3yrs, according to the PRIAS protocol (yrs 1, 4, 7, and 10, and then every 5yr) or every 5yr. Diagnosis of higher-grade or -stage disease while on AS resulted in curative treatment. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We measured discounted quality-adjusted life years (QALYs), discounted lifetime medical costs (2017 US$), and incremental cost-effectiveness ratios (ICERs). RESULTS AND LIMITATIONS: Compared to WW, MRI-based surveillance performed every 5yr improved quality-adjusted survival by 4.47 quality-adjusted months and represented high value health care at the Medicare reimbursement rate using standard cost effectiveness metrics. Biopsy-based strategies were less effective and less costly than the corresponding MRI-based strategies for each testing interval. MRI based surveillance at more frequent intervals had ICERs greater than $800000 per QALY and would not be considered cost-effective according to standard metrics. Our results were sensitive to the diagnostic accuracy and costs of both biopsy modes in detecting clinically significant cancer. CONCLUSIONS: Incorporation of MRI into surveillance protocols at Medicare reimbursement rates and decreasing the intensity of repeat testing may be cost-effective options for men opting for conservative management of low-risk prostate cancer. PATIENT SUMMARY: Our study modeled outcomes for men with low-risk prostate cancer undergoing watchful waiting, immediate treatment, or active surveillance with different follow-up schedules. We found that conservative management of low-risk disease optimizes health outcomes and costs. Furthermore, we showed that decreasing the intensity of active surveillance follow-up and incorporating magnetic resonance imaging (MRI) into surveillance protocols can be cost-effective, depending on the MRI costs. PMID- 30425011 TI - Arteriovenous Graft for Hemodialysis: Effect of Cryotherapy on Postoperative Pain and Edema. AB - BACKGROUND: Arteriovenous grafting offers an alternative for patients whose vessels are unsuitable for arteriovenous fistula. However, as a result of subcutaneous tunnel dissection, postoperative pain and edema of the operated limb present early after surgery. As a traditional therapeutic approach, cryotherapy has the ability to suppress postoperative pain and edema. AIMS: The purpose of the study was to investigate the feasibility of cryotherapy after arteriovenous graft surgery to decrease perioperative medication usage. DESIGN: This study was a randomized controlled trial. SETTING: A large integrated health care facility in South China. PARTICIPANTS: /Subjects: A total of 85 hemodialysis patients who received arteriovenous graft surgery from March 2011 to February 2017 were enrolled. METHODS: The participants were divided into an intervention group and a control group according to the postoperative management. Ice packs were applied covering the operative forearm for 120 minutes after wound closure in the intervention group. General information, pain score, analgesic consumption, wound inflammation, forearm edema, and participant satisfaction were compared between the two groups. RESULTS: Cryotherapy-treated patients required less analgesia (26.19% vs. 48.84%, p < .05), reported lower pain score from 30 minutes to 48 hours postoperative (p < .05), less wound inflammation (11.90% vs. 25.58%, p < .05), and higher participant satisfaction (8.92 +/- 0.57 vs. 6.52 +/- 0.63, p < .05), whereas the incidence of forearm edema was equivalent (p > .05). No adverse events were reported in either group. CONCLUSIONS: Cryotherapy is a preferable intervention for patients after arteriovenous graft implantation as a result of its favorable cost, convenience, and fewer side effects. PMID- 30425012 TI - The effect of Therapeutic Touch on Back Pain in Adults on a Neurological Unit: An Experimental Pilot Study. AB - BACKGROUND: Chronic back pain affects many aspects of everyday life and is a common reason for medical visits, leading to high direct and indirect health care costs. Innovative and cost-effective nonpharmacologic pain management methods should be promoted to ensure adequate treatment. AIMS: The aim of this pilot study was to investigate the pain-relieving effect of Therapeutic Touch in adult neurologic patients with back pain. DESIGN: A pretest-post-test randomized controlled trial. SETTINGS: A university hospital in Austria. PARTICIPANTS/SUBJECTS: Patients with back pain diagnosis (n = 29) on hospital admission. METHODS: A pilot study was conducted for 3 months. The control group (n = 14) received the pharmacologic pain management recommended by the World Health Organization; patients in the intervention group (n = 15) received additionally four Therapeutic Touch treatments on 4 consecutive days. The Quebec Back Pain Disability Scale and the Numeric Pain Rating Scale were used as outcome measures to evaluate activity domains affected by back pain and pain intensity. RESULTS: Pain improvement was found in the intervention group according to the mean score of the Quebec Back Pain Disability Scale (day 1: 72.53, standard deviation [SD] +/- 14.10; day 4: 39.47, SD +/- 8.77; p < .001). The Numerical Pain Rating Scale score averaged 4.33 points (SD +/- 2.09) on the first day and 2.47 points (SD +/- 1.12) on the fourth day. The long-term effect of Therapeutic Touch was significant and indicated a major effect (Pillai's trace = .641, F(3.12) = 7.1, p = .005, etap2 = .641). CONCLUSIONS: Therapeutic Touch seems to be a noninvasive nursing intervention for back pain management to provide more professional patient care. PMID- 30425013 TI - Pain Management by Nurses in Level 2 and Level 3 Hospitals in China. AB - BACKGROUND: Pain management practice differs among hospitals in China; however, no studies have examined the association between hospital level and nursing practice of pain management. AIMS: To evaluate the nursing practice of pain management in orthopedics wards of level 3 and 2 hospitals and compare the differences in pain management regulations, policies, and perceived barriers. DESIGN: This was a cross-sectional descriptive study. SETTING: This study was conducted during the 10th International Congress of the Chinese Orthopedic Association, November 19-22, 2015. PARTICIPANTS: Subjects: The sample included 121 nurses from China. METHODS: Quantitative research methods were used to assess pain management practice by 121 Chinese nurses as well as barriers to nursing practice. RESULTS: Nurses in level 3 hospitals were more likely to evaluate patients' pain intensity (85.23% vs. 65.38%, p < .05) and quality (77.27% vs. 53.85%, p < .05) than those in level 2 hospitals. Compared with level 2 hospitals, level 3 hospitals were more likely to participate in the Painless Orthopedics Ward program (53.41% vs. 23.08%, p < .01), conduct pain management knowledge training (88.64% vs. 69.23%, p < .05), and establish pain management regulations (68.18% vs. 34.62%, p < .01). Level 2 hospital nurses reported a higher score for barriers than level 3 hospital nurses (3.27 vs. 2.45, p < .05). CONCLUSIONS: Nurses from level 2 hospitals received less education on pain management and also paid less attention to and faced more restrictions for pain management than nurses from level 3 hospitals. PMID- 30425014 TI - Influencing Vaccinations: A Buzzy Approach to Ease the Discomfort of a Needle Stick-a Prospective, Randomized Controlled Trial. AB - BACKGROUND: The rate of annual influenza immunization in both the general public and health care workers is less than desirable. Mechanisms to improve compliance with recommendations are needed; prevention of immunization site pain has been suggested as a viable route because fear of pain and needles has been cited as a barrier. AIMS: This study aimed to evaluate the impact of thermomechanical stimulation (Buzzy) on postprocedure pain ratings during vaccination in adults. DESIGN: This was a randomized controlled trial of Buzzy during immunization. SETTINGS: Three hospitals and two community health centers which are part of a large, integrated health system. PARTICIPANTS/SUBJECTS: Employees presenting to employer-sponsored annual influenza vaccination clinics. METHODS: A 10-cm visual analog scale was used to rate preinjection anxiety and expectation of pain as well as postprocedure pain scores; participants also rated their satisfaction with the vaccine injection on a 10-point Likert scale. RESULTS: In total, 497 employee volunteers were recruited to participate. Preprocedure anxiety was similar between the experimental and control groups (1.53 vs. 1.48, p = .82), whereas self-reported postprocedure pain scores were significantly lower in the group that received the Buzzy during injection (0.87 vs. 1.12, p = .035). Mean satisfaction scores did not vary between the intervention and control groups (9.11 vs. 9.09, p = .87); however, more participants rated their experience as better than previous vaccination experiences in the Buzzy group than control (62.0% vs. 23.9%, p < .0001). CONCLUSIONS: These results suggest that Buzzy reduced pain experienced by adults undergoing annual influenza vaccination and may improve overall experience. Buzzy can be used in adult patients to reduce pain during immunization and is especially effective in those with high levels of anxiety. PMID- 30425015 TI - Validation of the Spanish Version of the Pain Assessment in Advanced Dementia Scale (PAINAD-Sp) in Hospitalized Patients with Neurologic Disorders and Oncologic Patients Unable to Self-Report Their Pain. AB - BACKGROUND: Pain has a significant impact on hospitalized patients and is a quality indicator for nursing care. The Pain Assessment in Advanced Dementia (PAINAD) scale measures pain in people with communication disorders and advanced dementia, but it has not been validated in any other population. AIMS: The aim of this study was to validate the Spanish version (PAINAD-Sp) in hospitalized patients with neurologic disorders and in end-of-life cancer patients with difficulty self-reporting. DESIGN: The study had two phases: (1) analysis of the content by a committee of experts and (2) a cross-sectional study. SETTINGS: We collected phase 2 data from January 2017 to December 2017 in four hospitals in Barcelona: Hospital Germans Trias i Pujol, Institut Catala d'Oncologia, Hospital Vall d'Hebron, and Hospital de Bellvitge. PARTICIPANTS/SUBJECTS: We included all adults who had either a neurological disorder affecting language or an oncological disease with an end-of-life prognosis and difficulty self-reporting pain. We excluded patients with a diagnosis of dementia. METHODS: The cross sectional study included 325 patients who were simultaneously evaluated by two observers both at rest and in movement. We analyzed psychometric properties in terms of construct validity, reliability, and sensitivity to change. RESULTS: We obtained Cronbach alpha > .70 in both situations and an inter-rater reliability of 0.80. Confirmatory factor analysis indicated that the model adjusted adequately to a unidimensional structure. In terms of sensitivity to change, the mean difference was greater in movement than at rest (difference in means was 1.15). CONCLUSIONS: The PAINAD-Sp_Hosp scale had good psychometric qualities in terms of validity and reliability in neurology and oncology patients unable to self-report pain. PMID- 30425016 TI - Harm from left bundle branch block: We are the tortoise, not the hare. PMID- 30425017 TI - Supplemental Nutrition Assistance Program size and timing and hypertension related emergency department claims among Medicaid enrollees. AB - The Supplemental Nutrition Assistance Program (SNAP) is a public policy program that aims to reduce food insecurity-a social determinant of health that has been associated with suboptimal blood pressure control in the United States. The aim of the article was to explore the association between SNAP benefit timing and size and probability of hypertension-related emergency department (ED) claims. This study used the SNAP data from the Missouri's Department of Social Services for January 2010 to December 2013 linked to Medicaid ED claims data. The dependent variable was probability of hypertension-related and hypertensive emergency ED claims. The independent variables of interest were week of calendar and SNAP benefit months and SNAP benefit amount. Probit regression analyses were conducted. Average marginal effects are reported.In a sample of 6,013,951 Medicaid-insured SNAP beneficiaries, 11,709 hypertension-related claims were submitted for every 100,000 claims. The average marginal effect of SNAP benefit amount on hypertension-related ED claims was -0.0000638 (P < .001); thus, a $100 increase in SNAP benefits will reduce hypertension-related claims by 638 claims per 100,000 claim. The reduction in ED claims was higher for lower SNAP benefit amounts than at higher SNAP benefit amounts. There was no statistically significant association between week of calendar month in which SNAP benefit was received and probability of hypertension-related ED claims. Higher SNAP benefit amount was associated with a decreased probability of hypertension-related ED claims. The impact of an additional dollar of SNAP benefits was larger at lower SNAP benefit amounts. PMID- 30425018 TI - Postexercise hypotension as a clinical tool: a "single brick" in the wall. AB - After an exercise session, a reduction of blood pressure (BP) is expected, a phenomenon called postexercise hypotension (PEH). PEH as a predictor of chronic training responses for BP has been broadly explored. It suggests that when PEH occurs after each exercise sessions, its benefits may summate over time, contributing to the chronic adaptation. Thus, PEH is an important clinical tool, acting as a "single brick" in the wall, and building the chronic effect of decreasing BP. However, there is large variation in the literature regarding methodology and results, creating barriers for understanding comparisons among PEH studies. Thus, the differences among subjects' and exercise protocols' characteristics observed in the studies investigating PEH must be considered when readers interpret the results. Furthermore, understanding of these factors of influence might be useful for avoiding misinterpretations in future comparisons and how the subjacent mechanisms contribute to the BP reduction after exercise. PMID- 30425019 TI - A dose-response association of night sleep duration with hypertension in a Chinese rural population: the Henan Rural Cohort Study. AB - The purpose of the study was to determine if there was a relationship between night sleep duration and hypertension, and to evaluate as to whether blood lipid levels played a role in this relationship. A total of 37,317 participants aged 18 79 years were included in this study. Night sleep duration was classified as <5, 5-, 6-, 7-, 8-, 9-, and >=10 hours. Logistic regression and restricted cubic spline analysis was carried out to evaluate the association of sleep duration with hypertension. Compared with reference sleep duration (7 hours), in males, the multivariate odds ratios (ORs) (95% confidence interval [95% CI]) of the groups with longest sleep duration (>=10 hours) and shortest sleep duration (<5 hours) for hypertension was 1.52 (1.25-1.84) and 1.07 (0.80-1.44), respectively. Similarly, the longest sleep duration was associated with diagnosed hypertension (1.21, 1.00-1.45) in females. The OR for an indirect effect of sleep duration through low-density lipoprotein cholesterol (LDL-C) on hypertension was 1.085 (95% CI 1.038-1.137). Overall, a 3.5% possibility of hypertension being associated with sleep duration was attributable to LDL-C. In summary, a relationship between sleep duration and hypertension was observed in this rural population. LDL-C appeared to partially mediate the effect of sleep duration on hypertension in males. PMID- 30425020 TI - Almost a century of oblivion: Integrative taxonomy allows the resurrection of the longnose skate Zearaja brevicaudata (Marini, 1933) (Rajiformes; Rajidae). AB - Zearaja chilensis has been reported from Southern Brazil in the Southwest Atlantic (SWA) to northern Chile in the Southeast Pacific (SEP), and it was listed as vulnerable by the IUCN. Recent molecular studies have called into question the conspecificity between specimens from these opposite coasts of South America, which can have implications for the conservation status of the species. To verify the identity of specimens identified as Z. chilensis, 47 individuals from SWA and 22 from SEP were examined. By comparing external morphology, spinulation pattern, clasper, egg cases, and mitochondrial cytochrome c oxidase I (COI) sequence data, differences between groups were found. Adults from SWA presented longer snout length and shorter tail than those from SEP. Dermal denticles were restricted to the rostral area in SWA skates, whereas in SEP skates most of the dorsal surface was covered with denticles. Marked differences in the morphology of several components of clasper were noticeable. Egg cases of SWA skates had thinner lateral keels than those of SEP. Molecular analysis revealed two well-defined cohesive clusters, corresponding to SWA and SEP specimens, respectively. Average K2P distance between groups was 3.4%, higher than expected for intraspecific differences, and sequences were assigned to different BINs. These integrative approaches strongly support that specimens from SWA known as Z. chilensis correspond to a different nominal species than those from SEP. Herein, Z. brevicaudata (Marini 1933) is resurrected from synonymy with Z. chilensis. PMID- 30425021 TI - What happens to the posterior comminution in extra-articular fractures of the distal radius treated with volar locking plates? AB - Extra-articular fractures of the distal radius with posterior displacement are typically treated with volar locking plates. However, this fixation method does not address the posterior comminution, which seems to have no impact on the final result. The purpose of this study was to determine the fate of the posterior comminution. This was a retrospective study of 22 patients over 50 years old with a distal radius fracture. A preoperative computed tomography (CT) scan was performed to evaluate the comminution. All fractures were fixed with a volar locking plate. All patients underwent a bone density scan. Patients were reviewed at 6 months post-operative to determine their clinical, radiological and functional outcomes. The CT scan was performed again to determine the fate of the comminution. At 6 months post-operative, 82% of patients had an oval metaphyseal defect. The mean volume of this defect was 1.86 mL. The contents of this defect most closely resembled fat. There was no statistical link between the defect's volume and the various parameters studied. On the other hand, the defect's density was positively related to the functional outcome and negatively related to the patients' body mass index. Because of the compression experienced by the cancellous bone, a distal metaphyseal defect often persists after consolidation in dorsally displaced distal radius fractures. The posterior comminution is ultimately of little consequence. PMID- 30425022 TI - Association of Tumor Mutational Burden With DNA Repair Mutations and Response to Anti-PD-1/PD-L1 Therapy in Non-Small-Cell Lung Cancer. AB - PURPOSE: To examine clinical predictors of tumor mutational burden (TMB), to explore the association between TMB and DNA repair mutations, and to analyze TMB as a biomarker for response to immune checkpoint blockade in non-small-cell lung cancer. PATIENTS AND METHODS: TMB scores were determined retrospectively for 72 consecutive patients at our institution with next-generation sequencing comprehensive genomic profiling testing by Foundation Medicine. TMB scores were correlated with a number of clinical variables and presence of DNA repair mutations. Thirty-four patients were treated with anti-programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) therapies, and survival analyses based on TMB score were performed. In addition, tissue immunohistochemical analysis was performed for a subset of patients. RESULTS: History of smoking, but not other clinical variables, including prior treatment lines, stage of disease, and number of metastatic sites, predicted higher TMB score. Higher TMB score was significantly associated with greater number of DNA repair mutations. In the subset of patients treated with immune checkpoint blockade, higher TMB score significantly predicted overall survival, but not progression-free survival (hazard ratio = 0.10, P = .003; hazard ratio 1.1, P = .84, respectively). In a small subset of patients, PD-1/PD-L1 staining did not independently predict progression-free survival or overall survival. CONCLUSION: Tissue TMB was significantly associated with smoking history and number of DNA repair mutations. TMB is a promising biomarker for response to anti-PD-1/PD-L1 therapy, with higher TMB score predicting longer overall survival. PMID- 30425023 TI - Vagal Nerve Palsy After Transarterial Embolization of Transverse-Sigmoid Dural Arteriovenous Fistula Using Onyx. AB - OBJECTIVE: We report a case of a 70-year-old man who developed a transverse sigmoid dural arteriovenous fistula (TS-DAVF) that was successfully treated by transarterial embolization (TAE) with Onyx. CASE PRESENTATION: The patient presented with sudden and progressive disturbance of consciousness and left hemiparesis. Magnetic resonance imaging (MRI) revealed venous infarction and hemorrhagic changes with brain swelling in the right parietal lobe. Angiography revealed a right TS-DAVF and multiple occlusions with retrograde leptomeningeal venous drainage into the cortical veins. The TS-DAVF was graded as Borden type III and Cognard type IIa+b. Because of its progressive clinical nature and wide distribution of DAVF in the occluded sinus wall, he underwent emergent TAE with liquid embolic materials including n-butyl cyanoacrylate and Onyx under informed consent by his family. Complete obliteration of the TS-DAVF was achieved, leading to a marked amelioration of symptoms, and MRI after treatment confirmed a decrease in the brain swelling. However, he suffered transient dysphagia due to right vagal nerve palsy caused by occlusion of vasa nervorum of ascending pharyngeal artery. He returned home 5 months later with a modified Rankin Scale of 1. CONCLUSIONS: TAE with Onyx appears to be effective for aggressive TS-DAVF with a widely distributed shunt. However, the blood supply to the cranial nerves and potentially dangerous anastomoses between the external-internal carotid artery and vertebral artery should be taken into account to avoid serious complications. PMID- 30425024 TI - Positional Vertigo After Isolated Cerebellar Nodulus Stroke: A Report of 3 Cases. AB - We report 3 cases (69-year-old man, 71-year-old man, and 82-year-old woman) of isolated cerebellar nodulus stroke patients, who presented with positional vertigo alone that lasted only for 2-4 days. Brain magnetic resonance imaging helped diagnosing these cases. Although rare, clinicians should be aware of isolated cerebellar nodulus stroke, when facing with patients with paroxysmal vertigo of acute onset. PMID- 30425025 TI - Electronic Health Records as an Educational Tool: Viewpoint. AB - BACKGROUND: Electronic health records (EHRs) have been adopted by most hospitals and medical offices in the United States. Because of the rapidity of implementation, health care providers have not been able to leverage the full potential of the EHR for enhancing clinical care, learning, and teaching. Physicians are spending an average of 49% of their working hours on EHR documentation, chart review, and other indirect tasks related to patient care, which translates into less face time with patients. OBJECTIVE: The purpose of this article is to provide a preliminary framework to guide the use of EHRs in teaching and evaluation of residents. METHODS: First we discuss EHR educational capabilities that have not been reviewed in sufficient detail in the literature and expand our discussion for each educational activity with examples. We emphasize quality improvement of clinical notes as a basic foundational skill using a spreadsheet-based application as an assessment tool. Next, we integrate the six Accreditation Council for Graduate Medical Education (ACGME) Core Competencies and Milestones (CCMs) framework with the Reporter-Interpreter Manager-Educator (RIME) model to expand our assessments of other areas of resident performance related to EHR use. Finally, we discuss how clinical utility, clinical outcome, and clinical reasoning skills can be assessed in the EHR. RESULTS: We describe a pilot conceptual framework-CCM framework-to guide and demonstrate the use of the EHR for education in a clinical setting. CONCLUSIONS: As EHRs and other supporting technologies evolve, medical educators should continue to look for new opportunities within the EHR for education. Our framework is flexible to allow adaptation and use in most training programs. Future research should assess the validity of such methods on trainees' education. PMID- 30425026 TI - Patient-Reported Outcome of Physical Therapy in Amyotrophic Lateral Sclerosis: Observational Online Study. AB - BACKGROUND: Physical therapy is an essential component of multidisciplinary treatment in amyotrophic lateral sclerosis (ALS). However, the meaning of physical therapy beside preservation of muscular strength and functional maintenance is not fully understood. OBJECTIVE: The purpose of this study was to examine patients' perception of physical therapy during symptom progression using an internet assessment approach. METHODS: A prospective, longitudinal, observational study was performed. Recruitment took place in an ALS center in Berlin, Germany. Online self-assessment was established on a case management platform over 6 months. Participants self-assessed the progression of the disease with the ALS Functional Rating Scale-Revised (ALSFRS-R) and tracked the efficacy of targeted physical therapy using Measure Yourself Medical Outcome Profile (MYMOP). We used the net promoter score (NPS) to inquire into recommendation levels of physical therapy. RESULTS: Forty-five participants with ALS were included in the study. Twenty-seven (60.0%) started the online assessment. The mean duration of physical therapy sessions per week was 142.7 minutes (SD 60.4) with a mean frequency of 2.9 (SD 1.2) per week. As defined by MYMOP input, the most concerning symptoms were reported in the legs (62.2%), arms (31.1%), and less frequently in the torso (6.7%). As expected for a progressive disease, there was a functional decline of 3 points in the ALSFRS-R at the end of the observation period (n=20). Furthermore, the MYMOP showed a significant loss of 0.8 in the composite score, 0.9 in the activity score and 0.8 in the targeted symptom. In spite of functional decline, the recommendation for physical therapy jumped from a baseline value of 20 NPS points to a very high 50 points at the end of study (P=.05). CONCLUSIONS: Physical therapy is perceived as an important treatment method by patients with ALS. Despite functional deterioration, patients are satisfied with physical therapy and recommend this intervention. The results also underline how the meaning of physical therapy changes throughout the disease. Physical therapy in ALS has to be regarded as a supportive and palliative health care intervention beyond functional outcome parameters. PMID- 30425027 TI - The Ready to Reduce Risk (3R) Study for a Group Educational Intervention With Telephone and Text Messaging Support to Improve Medication Adherence for the Primary Prevention of Cardiovascular Disease: Protocol for a Randomized Controlled Trial. AB - BACKGROUND: Poor adherence to cardiovascular medications is associated with worse clinical outcomes. Evidence for effective education interventions that address medication adherence for the primary prevention of cardiovascular disease is lacking. The Ready to Reduce Risk (3R) study aims to investigate whether a complex intervention, involving group education plus telephone and text messaging follow-up support, can improve medication adherence and reduce cardiovascular risk. OBJECTIVE: This protocol paper details the design and rationale for the development of the 3R intervention and the study methods used. METHODS: This is an open and pragmatic randomized controlled trial with 12 months of follow-up. We recruited participants from primary care and randomly assigned them at a 1:1 frequency, stratified by sex and age, to either a control group (usual care from a general practitioner) or an intervention group involving 2 facilitated group education sessions with telephone and text messaging follow-up support, with a theoretical underpinning and using recognized behavioral change techniques. The primary outcome was medication adherence to statins. The primary measure was an objective, novel, urine-based biochemical measure of medication adherence. We also used the 8-item Morisky Medication Adherence Scale to assess medication adherence. Secondary outcomes were changes in total cholesterol, blood pressure, high-density lipoprotein, total cholesterol to high-density lipoprotein ratio, body mass index, waist to hip ratio, waist circumference, smoking behavior, physical activity, fruit and vegetable intake, patient activation level, quality of life, health status, health and medication beliefs, and overall cardiovascular disease risk score. We also considered process outcomes relating to acceptability and feasibility of the 3R intervention. RESULTS: We recruited 212 participants between May 2015 and March 2017. The 12-month follow-up data collection clinics were completed in April 2018, and data analysis will commence once all study data have been collected and verified. CONCLUSIONS: This study will identify a potentially clinically useful and effective educational intervention for the primary prevention of cardiovascular disease. Medication adherence to statins is being assessed using a novel urine assay as an objective measure, in conjunction with other validated measures. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number ISRCTN16863160; http://www.isrctn.com/ISRCTN16863160 (Archived by WebCite at http://www.webcitation.org/734PqfdQw). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/11289. PMID- 30425028 TI - Key Elements of mHealth Interventions to Successfully Increase Physical Activity: Meta-Regression. AB - BACKGROUND: Mobile technology gives researchers unimagined opportunities to design new interventions to increase physical activity. Unfortunately, it is still unclear which elements are useful to initiate and maintain behavior change. OBJECTIVE: In this meta-analysis, we investigated randomized controlled trials of physical activity interventions that were delivered via mobile phone. We analyzed which elements contributed to intervention success. METHODS: After searching four databases and science networks for eligible studies, we entered 50 studies with N=5997 participants into a random-effects meta-analysis, controlling for baseline group differences. We also calculated meta-regressions with the most frequently used behavior change techniques (behavioral goals, general information, self monitoring, information on where and when, and instructions on how to) as moderators. RESULTS: We found a small overall effect of the Hedges g=0.29, (95% CI 0.20 to 0.37) which reduced to g=0.22 after correcting for publication bias. In the moderator analyses, behavioral goals and self-monitoring each led to more intervention success. Interventions that used neither behavioral goals nor self monitoring had a negligible effect of g=0.01, whereas utilizing either technique increased effectiveness by Deltag=0.31, but combining them did not provide additional benefits (Deltag=0.36). CONCLUSIONS: Overall, mHealth interventions to increase physical activity have a small to moderate effect. However, including behavioral goals or self-monitoring can lead to greater intervention success. More research is needed to look at more behavior change techniques and their interactions. Reporting interventions in trial registrations and articles need to be structured and thorough to gain accurate insights. This can be achieved by basing the design or reporting of interventions on taxonomies of behavior change. PMID- 30425029 TI - Issues in Child and Adolescent Inpatient Assessment and Evaluation After Discharge: Protocol for App Development and a Randomized Controlled Trial. AB - BACKGROUND: New methods are needed for collecting data of in- and outpatients and for improving outpatient compliance after discharge. Mobile technologies, such as smartphone apps, have shown promising results, (eg, helping unwell people by offering support and resources). Screening for the condition, including comorbidities, is a vital part of psychiatric care. Comorbid conditions, especially in emergency evaluation, are often missed, leading to inaccurate diagnosis and treatment. One way of improving diagnostic accuracy is to use a structured diagnostic process. Digitalized screening and follow-up have the advantage of making administration and scoring easier and less time consuming, thereby increasing response rate. To address these problems, we decided to create a smartphone app called The Blue App. The Blue App was developed through 6 steps, described in the manuscript. OBJECTIVE: The aim of this paper is to describe (1) the development of The Blue App and (2) 2 planned research studies to evaluate the app. METHODS: Two studies will be performed. Study 1 has a descriptive design, mapping comorbidities before and after the introduction of The Blue App. Study 2 has a randomized controlled design, measuring compliance with outpatient treatments as well as depressive symptoms, rated as changes in Montgomery-Asberg Depression Scale scores during a 1-year follow-up. RESULTS: We have described app development. Data collection for Study 1 started in autumn 2017. Study 2 will start in autumn 2018. We expect to have enrolled the 150 patients in Study 2 by December 2019. Final results will be published in a scientific journal. CONCLUSIONS: A technically advanced and easy-to-use Web-based mobile phone app corresponding to the unit's needs was developed, and 2 studies are planned to evaluate its usefulness. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1 10.2196/10121. PMID- 30425030 TI - Automatic Classification of Online Doctor Reviews: Evaluation of Text Classifier Algorithms. AB - BACKGROUND: An increasing number of doctor reviews are being generated by patients on the internet. These reviews address a diverse set of topics (features), including wait time, office staff, doctor's skills, and bedside manners. Most previous work on automatic analysis of Web-based customer reviews assumes that (1) product features are described unambiguously by a small number of keywords, for example, battery for phones and (2) the opinion for each feature has a positive or negative sentiment. However, in the domain of doctor reviews, this setting is too restrictive: a feature such as visit duration for doctor reviews may be expressed in many ways and does not necessarily have a positive or negative sentiment. OBJECTIVE: This study aimed to adapt existing and propose novel text classification methods on the domain of doctor reviews. These methods are evaluated on their accuracy to classify a diverse set of doctor review features. METHODS: We first manually examined a large number of reviews to extract a set of features that are frequently mentioned in the reviews. Then we proposed a new algorithm that goes beyond bag-of-words or deep learning classification techniques by leveraging natural language processing (NLP) tools. Specifically, our algorithm automatically extracts dependency tree patterns and uses them to classify review sentences. RESULTS: We evaluated several state-of the-art text classification algorithms as well as our dependency tree-based classifier algorithm on a real-world doctor review dataset. We showed that methods using deep learning or NLP techniques tend to outperform traditional bag of-words methods. In our experiments, the 2 best methods used NLP techniques; on average, our proposed classifier performed 2.19% better than an existing NLP based method, but many of its predictions of specific opinions were incorrect. CONCLUSIONS: We conclude that it is feasible to classify doctor reviews. Automatically classifying these reviews would allow patients to easily search for doctors based on their personal preference criteria. PMID- 30425031 TI - Living With Inflammatory Bowel Disease: Protocol for a Longitudinal Study of Factors Associated With Symptom Exacerbations. AB - BACKGROUND: There has been limited longitudinal research that has comprehensively evaluated possible factors in the exacerbation of inflammatory bowel disease (IBD) symptoms with or without associated inflammation. Evolving Web-based technologies facilitate frequent monitoring of patients' experiences and allow a fine-grained assessment of disease course. OBJECTIVE: We aimed to prospectively identify factors associated with symptom exacerbation and inflammation in IBD including psychological functioning, diet, health behaviors, and medication adherence. METHODS: Between June 2015 and May 2017, we enrolled adults with IBD, recruited from multiple sources, who had been symptomatically active at least once within the prior 2 years. They completed a Web-based survey every 2 weeks for 1 year and submitted a stool sample at baseline, 26 weeks, and 52 weeks. Any participant reporting a symptom exacerbation was matched to a control within the cohort, based on disease type, sex, age, and time of enrollment; both were sent a supplemental survey and stool collection kit. Biweekly surveys included validated measures of the disease course, psychological functioning, health comorbidities, and medication use. Intestinal inflammation was identified through fecal calprotectin (positive level >250 MUg/g stool). RESULTS: There were 155 participants enrolled with confirmed IBD, 66.5% (103/155) with Crohn disease and 33.5% (52/155) with ulcerative colitis, of whom 98.7% (153/155) completed the study. Over the 1-year period, 47.7% (74/155) participants experienced a symptom exacerbation. The results of analyses on risk factors for symptom exacerbations are pending. CONCLUSIONS: We recruited and retained a longitudinal IBD cohort that will allow the determination of risk factors for symptom exacerbation with and without inflammation. This will increase understanding of symptom exacerbations among persons with IBD. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/11317. PMID- 30425033 TI - National plan is needed to tackle early childhood trauma, say MPs. PMID- 30425032 TI - Barriers and Facilitators of Using Sensored Medication Adherence Devices in a Diverse Sample of Patients With Multiple Myeloma: Qualitative Study. AB - BACKGROUND: Many recently approved medications to manage multiple myeloma (MM) are oral, require supportive medications to prevent adverse effects, and are taken under complex schedules. Medication adherence is a concern; however, little attention has been directed toward understanding adherence in MM or associated barriers and facilitators. Advanced sensored medication devices (SMDs) offer opportunities to intervene; however, acceptability among patients with MM, particularly African American patients, is untested. OBJECTIVE: This study aimed to explore patients' (1) perceptions of their health before MM including experiences with chronic medications, (2) perceptions of adherence barriers and facilitators, and (3) attitudes toward using SMDs. METHODS: An in-person, semistructured, qualitative interview was conducted with a convenience sample of patients being treated for MM. Patients were recruited from within an urban, minority-serving, academic medical center that had an established cancer center. A standardized interview guide included questions targeting medication use, attitudes, adherence, barriers, and facilitators. Demographics included the use of cell phone technology. Patients were shown 2 different pill bottles with sensor technology-Medication Event Monitoring System and the SMRxT bottle. After receiving information on the transmission ability of the bottles, patients were asked to discuss their reactions and concerns with the idea of using such a device. Medical records were reviewed to capture information on medication and diagnoses. The interviews were audio-recorded and transcribed. Interviews were independently coded by 2 members of the team with a third member providing guidance. RESULTS: A total of 20 patients with a mean age of 56 years (median=59 years; range=29-71 years) participated in this study and 80% (16/20) were African American. In addition, 18 (90%, 18/20) owned a smartphone and 85% (17/20) were comfortable using the internet, text messaging, and cell phone apps. The average number of medications reported per patient was 13 medications (median=10; range=3 24). Moreover, 14 (70%, 14/20) patients reported missed doses for a range of reasons such as fatigue, feeling ill, a busy schedule, forgetting, or side effects. Interest in using an SMD ranged from great interest to complete lack of interest. Examples of concerns related to the SMDs included privacy issues, potential added cost, and the size of the bottle (ie, too large). Despite the concerns, 60% (12/20) of the patients expressed interest in trying a bottle in the future. CONCLUSIONS: Results identified numerous patient-reported barriers and facilitators to missed doses of oral anticancer therapy. Many appear to be potentially mutable if uncovered and addressed. SMDs may allow for capture of these data. Although patients expressed concerns with SMDs, most remained willing to use one. A feasibility trial with SMDs is planned. PMID- 30425034 TI - Researcher questions new study suggesting benefits of breast screening. PMID- 30425036 TI - How do I prepare a personal development plan? PMID- 30425035 TI - Mesh scandal: lessons from Wall Street ignored. PMID- 30425037 TI - BRCA Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma. AB - A key resistance mechanism to platinum-based chemotherapies and PARP inhibitors in BRCA-mutant cancers is the acquisition of BRCA reversion mutations that restore protein function. To estimate the prevalence of BRCA reversion mutations in high-grade ovarian carcinoma (HGOC), we performed targeted next-generation sequencing of circulating cell-free DNA (cfDNA) extracted from pretreatment and postprogression plasma in patients with deleterious germline or somatic BRCA mutations treated with the PARP inhibitor rucaparib. BRCA reversion mutations were identified in pretreatment cfDNA from 18% (2/11) of platinum-refractory and 13% (5/38) of platinum-resistant cancers, compared to 2% (1/48) of platinum sensitive cancers (P = 0.049). Patients without BRCA reversion mutations detected in pretreatment cfDNA had significantly longer rucaparib progression-free survival than those with reversion mutations (median, 9.0 vs. 1.8 months; HR, 0.12; P < 0.0001). To study acquired resistance, we sequenced 78 postprogression cfDNA, identifying eight additional patients with BRCA reversion mutations not found in pretreatment cfDNA. PMID- 30425038 TI - Brexit will damage health. PMID- 30425039 TI - Time to put place based rivalry to rest. PMID- 30425040 TI - NICE responds to surgical mesh article. PMID- 30425041 TI - NHS England tells CCGs to end postcode lottery over diabetes glucose devices. PMID- 30425042 TI - MRG-1/MRG15 Is a Barrier for Germ Cell to Neuron Reprogramming in Caenorhabditis elegans. AB - Chromatin regulators play important roles in the safeguarding of cell identities by opposing the induction of ectopic cell fates and, thereby, preventing forced conversion of cell identities by reprogramming approaches. Our knowledge of chromatin regulators acting as reprogramming barriers in living organisms needs improvement as most studies use tissue culture. We used C. elegans as an in vivo gene discovery model and automated solid-phase RNAi screening, by which we identified 10 chromatin-regulating factors that protect cells against ectopic fate induction. Specifically, the chromodomain protein MRG-1 safeguards germ cells against conversion into neurons. MRG-1 is the ortholog of mammalian MRG15 (MORF-related gene on chromosome 15) and is required during germline development in C. elegans However, MRG-1's function as a barrier for germ cell reprogramming has not been revealed previously. Here, we further provide protein-protein and genome interactions of MRG-1 to characterize its molecular functions. Conserved chromatin regulators may have similar functions in higher organisms and, therefore, understanding cell fate protection in C. elegans may also help to facilitate reprogramming of human cells. PMID- 30425043 TI - Pervasive Positive and Negative Feedback Regulation of Insulin-Like Signaling in Caenorhabditis elegans. AB - The C. elegans insulin-like signaling network supports homeostasis and developmental plasticity. The genome encodes 40 insulin-like peptides and one known receptor. Feedback regulation has been reported, but the extent of feedback and its effect on signaling dynamics in response to changes in nutrient availability has not been determined. We measured mRNA expression for each insulin-like peptide, the receptor daf-2, components of the PI3K pathway, and its transcriptional effectors daf-16/FoxO and skn-1/Nrf at high temporal resolution during transition from a starved, quiescent state to a fed, growing state in wild type and mutants affecting daf-2/InsR and daf-16/FoxO. We also analyzed the effect of temperature on insulin-like gene expression. We found that most PI3K pathway components and insulin-like peptides are affected by signaling activity, revealing pervasive positive and negative feedback regulation at intra- and inter cellular levels. Reporter gene analysis demonstrated that the daf-2/InsR agonist daf-28 positively regulates its own transcription and that the putative agonist ins-6 cross-regulates DAF-28 protein expression through feedback. Our results show that positive and negative feedback regulation of insulin-like signaling is widespread, giving rise to an organismal FoxO-to-FoxO signaling network that supports homeostasis during fluctuations in nutrient availability. PMID- 30425044 TI - MRI bone marrow oedema precedes lumbar bone stress injury diagnosis in junior elite cricket fast bowlers. AB - OBJECTIVES: Lumbar bone stress injury ('bone stress injury') is common in junior fast bowlers. The repetitive loading of cricket fast bowling may cause bone marrow oedema (BMO), detectable on MRI, before the bowler suffers from symptomatic bone stress injury. We investigated the temporal relationship between BMO, bone stress injury, along with bowling workload correlates, in elite junior fast bowlers throughout a cricket season. METHODS: 65 junior fast bowlers were prospectively monitored for one 8-month cricket season. For research purposes, participants had up to six MRI scans at set times in the season; findings were withheld from them and their clinicians. Standard practices for bowling workload monitoring and injury diagnosis were followed. RESULTS: 15 (23%) participants developed bone stress injury during the study. All 15 of these participants had BMO detected on at least one of the preceding MRI scans, including the scan immediately prior to diagnosis. The risk of BMO progressing to bone stress injury during the season was greatest for participants with BMO present 2 weeks prior to the national championship tournament (period of high load) (RR=18.9, OR=44.8). Both bone stress injury and BMO were associated with bowling a higher percentage of days in training and having a shorter bowling break during the season. The number of balls bowled and acute-to-chronic workload were not associated with imaging abnormalities or injury. CONCLUSION: The presence of BMO on MRI in asymptomatic junior cricket fast bowlers confers a very high risk for bone stress injury. The risk may be managed by MRI screening and monitoring bowling frequency. PMID- 30425045 TI - In pursuit of the 'Unbreakable' Athlete: what is the role of moderating factors and circular causation? PMID- 30425047 TI - Twenty-metre shuttle run: (mis)representation, (mis)interpretation and (mis)use. PMID- 30425046 TI - Sudden cardiac arrest in sports: a video analysis. AB - OBJECTIVES: Information about sudden cardiac arrest (SCA) in sports arises from registries, insurance claims and various reports. Analysing video footage of SCA during sports for scientific purposes has scarcely been done. The objective of this study was to examine videotaped SCA in athletes to better understand the mechanisms of SCA. METHODS: Publicly available online video databases were searched for videos displaying SCA in athletes. RESULTS: Thirty-five online videos (26 from professional and 9 from amateur sport; 34 male victims) were obtained. Twenty-one events resulted in survival and 14 in sudden cardiac death. Level of physical activity prior to SCA was assessable in 28 videos; 19 events occurred during low-intensity, 6 during moderate-intensity and 3 during high intensity activity. SCA predominately occurred during low-intensity compared with both moderate-intensity and high-intensity activities (p<0.01). In 26/35 videos, it was possible to observe if resuscitation was provided. Resuscitation was carried out in 20 cases; cardiopulmonary resuscitation (CPR) alone (8 cases), CPR+defibrillation (10), cardiac thump (1) or shock from an implantable cardioverter defibrillator (1). Thirteen of the 20 cases with resuscitation received an intervention within 1 min after collapse. Survival was high when intervention occurred within 1 min (12/13) compared with those who received delayed (3/5) or no intervention (1/6). Associated signs of SCA such as agonal respirations and seizure-like movements were observed in 66% of the cases. CONCLUSIONS: SCA during sport most often occurred during low-intensity activity. Prompt intervention within 1 min demonstrated a high survival rate and should be the standard expectation for witnessed SCA in athletes. PMID- 30425048 TI - CSF1R inhibitors exhibit anti-tumor activity in acute myeloid leukemia by blocking paracrine signals from support cells. AB - To identify new therapeutic targets in AML, we performed small-molecule and siRNA screens of primary AML patient samples. In 23% of samples, we found sensitivity to inhibition of CSF1R, a receptor tyrosine kinase responsible for survival, proliferation, and differentiation of myeloid-lineage cells. Sensitivity to the CSF1R inhibitor GW-2580 was found preferentially in de novo and favorable risk patients, and resistance to GW-2580 was associated with reduced overall survival. Using flow cytometry, we discovered that CSF1R is not expressed on the majority of leukemic blasts but instead on a subpopulation of supportive cells. Comparison of CSF1R-expressing cells in AML versus healthy donors by mass cytometry (CyTOF) revealed the expression of unique cell-surface markers. The quantity of CSF1R expressing cells correlated with GW-2580 sensitivity. Exposure of primary AML patient samples to a panel of recombinant cytokines revealed that CSF1R inhibitor sensitivity correlated with a growth response to CSF1R ligand, CSF1, and other cytokines, including HGF, an alternative growth factor. The addition of CSF1 increased the secretion of HGF and other cytokines in conditioned media from AML patient samples, while adding GW-2580 reduced their secretion. In untreated cells, HGF levels correlated significantly with GW-2580 sensitivity. Finally, recombinant HGF and HS-5-conditioned media rescued cell viability after GW-2580 treatment in AML patient samples. Our results suggest that CSF1R-expressing cells support the bulk leukemia population through the secretion of HGF and other cytokines. This study identifies CSF1R as a novel therapeutic target of AML and provides a mechanism of paracrine cytokine/growth factor signaling in this disease. PMID- 30425049 TI - The transmembrane protein disulfide isomerase TMX1 negatively regulates platelet responses. AB - Secreted platelet protein disulfide isomerases, PDI, ERp57, ERp5 and ERp72, have important roles as positive regulators of platelet function and thrombosis. Thioredoxin-related transmembrane protein 1 (TMX1) was the first described transmembrane member of the protein disulfide isomerase family of enzymes. Using a specific antibody, recombinant TMX1 protein (rTMX1), a knockout mouse model, and thiol-labeling approach, we examined the role of TMX1 in platelet function and thrombosis. Expression of TMX1 on the platelet surface increased with thrombin stimulation. The anti-TMX1 antibody increased platelet aggregation induced by convulxin and thrombin, and potentiated platelet ATP release. In contrast, rTMX1 inhibited platelet aggregation and ATP release. TMX1-deficient platelets had increased aggregation, ATP release, alphaIIbbeta3 activation, and P selectin expression, which were reversed by addition of rTMX1. TMX1-knockout mice had increased incorporation of platelets into a growing thrombus in a FeCl3 induced mesenteric arterial injury, and shortened tail-bleeding times. rTMX1 oxidized thiols in the alphaIIbbeta3 integrin and TMX1-deficient platelets had increased thiols in the beta3 subunit of alphaIIbbeta3, consistent with oxidase activity of rTMX1 against alphaIIbbeta3. Thus, TMX1 is the first identified extracellular inhibitor of platelet function and the first disulfide isomerase that negatively regulates platelet function. PMID- 30425050 TI - Hospice patients' participation in choice experiments to value supportive care outcomes. AB - BACKGROUND: Values used in economic evaluation are typically obtained from the general public, which is problematic when measures are to be used with people experiencing a life-course stage such as the end of life. OBJECTIVE: To assess the feasibility of obtaining values for the ICECAP-Supportive Care Measure (SCM) from patients receiving advanced supportive care through a hospice. METHODS: Participants completed eight best-worst scaling questions in a think-aloud interview to explain choices in different hypothetical end-of-life scenarios. Three independent raters identified errors in completion of the best-worst scaling task, and thematic analysis of associated qualitative data was undertaken to explore task difficulty and choices. RESULTS: Twelve hospice patients were recruited. Most were able to complete the task and prioritise aspects of supportive care with either no difficulty (n=50%) or difficulty in just one of the eight scenarios (n=25%). Two patients (n=17%) were unable to comprehend the hypothetical nature of the task. The qualitative data confirmed there was good engagement with the task and identified the importance the respondents attached to maintaining dignity. CONCLUSION: The findings suggest that people at the end of life will be able to complete a short, interviewer-administered, best-worst scaling task. To maximise engagement, it is recommended that the task is short and initiated with an example. Scenarios are best presented on show-cards in large print. A full evaluation of the ICECAP-SCM with those at the end of life is feasible. PMID- 30425051 TI - The informal curriculum: what do junior doctors learn from a palliative care rotation? AB - OBJECTIVES: Junior doctors learn from the formal and informal curriculum. In a palliative care rotation, the informal curriculum may be useful in teaching attitudes like empathy and compassion. Our study aims to explore how the informal curriculum augments the formal curriculum of a palliative care rotation in shaping the professional development of a doctor. METHODS: We conducted a qualitative study with seven focus group discussions involving 21 junior doctors (medical officers and residents) who spent at least 2 months in a palliative care setting in a tertiary hospital or an inpatient hospice. Data were analysed using qualitative thematic analysis to identify the themes related to the junior doctors' perceptions of how the informal curriculum impacted their humanistic and professional development, thereby augmenting the formal curriculum in a palliative care setting. RESULTS: Three main themes illustrated how the informal curriculum influenced the doctors: (1) reconceptualisation of control: shifting perspectives as they grappled with their envisioned control versus reality while caring for dying patients; (2) emergence of professionalism: adapting perspectives as they learnt how to bridge theory and reality while developing professionalism and (3) personal growth: forming new perspectives, as doctors reflected on life, death and their calling through a renewed lens. CONCLUSION: This study explored how the informal curriculum influenced doctors' perceptions about professionalism and personal growth, embodying the values of the profession. Observations and interpersonal interactions with healthcare professionals, patients and their caregivers encouraged the doctors to reflect upon their own calling into medicine. PMID- 30425052 TI - Community palliative medicine out-of-hours needs and the 7-day week: a service evaluation. AB - BACKGROUND: Evidence regarding out-of-hours (OOH) community palliative care provision is required to inform the need for a 7-day work. AIM: This paper seeks to provide evidence for this discussion by defining general practitioners' (GPs) OOH workload and patients' demographics, symptomology and interventions. By quantifying the challenges faced, we can understand current practice and focus on what provision is required. DESIGN: Using Shropshire Doctors Co-operative's recorded data, the authors have collated a representative picture of the OOH GP palliative care practice over a year from 161 OOH GP-patient interactions. SETTING: Primary care. RESULTS: Palliative care makes up 11.4% of the total OOH GP home visits (HV). Overall 56% of OOH GP HVs are for patients who are expected to die within 48 hours, with 80% of the symptoms being agitation, secretions and pain. Overall 5.7% of OOH GP palliative HVs resulted in hospital admission; however, this decreased to 0.6% adjusting for the last 48-hour prognosis. CONCLUSION: OOH Shropshire GPs deal with a wide variety of scenarios in a heterogeneous population. The greatest demand is from 17:00 to 00:00 (65% of the total shift) on weekdays, and from 09:00 to 00:00 on weekends (82% of the shift). These data begin to quantify the role being performed by OOH GPs, have implications for service provision and support 7-day work. PMID- 30425053 TI - Is "watch-and-wait" after chemoradiotherapy safe in patients with rectal cancer? PMID- 30425054 TI - The Transcriptional Regulator Hbx1 Affects the Expression of Thousands of Genes in the Aflatoxin-Producing Fungus Aspergillus flavus. AB - In filamentous fungi, homeobox proteins are conserved transcriptional regulators described to control conidiogenesis and fruiting body formation. Eight homeobox (hbx) genes are found in the genome of the aflatoxin-producing ascomycete, Aspergillus flavus While loss-of-function of seven of the eight genes had little to no effect on fungal growth and development, disruption of hbx1, resulted in aconidial colonies and lack of sclerotial production. Furthermore, the hbx1 mutant was unable to produce aflatoxins B1 and B2, cyclopiazonic acid and aflatrem. In the present study, hbx1 transcriptome analysis revealed that hbx1 has a broad effect on A. flavus gene expression, and the effect of hbx1 increases overtime, impacting more than five thousand protein-coding genes. Among the affected genes, those in the category of secondary metabolism (SM), followed by that of cellular transport, were the most affected. Specifically, regarding the effect of hbx1 on SM, we found that genes in 44 SM gene clusters where upregulated while 49 were downregulated in the absence of hbx1, including genes in the SM clusters responsible for the synthesis of asparasone, piperazine and aflavarin, all known to be associated with sclerotia. In addition, our study revealed that hbx1 affects the expression of other transcription factor genes involved in development, including the conidiation central regulatory pathway and flb genes. PMID- 30425055 TI - David Oliver: Is Matt Hancock really prioritising prevention over cure? PMID- 30425056 TI - Development and Evaluation of High-Value Pediatrics: A High-Value Care Pediatric Resident Curriculum. AB - Low-value health care is pervasive in the United States, and clinicians need to be trained to be stewards of health care resources. Despite a mandate by the Accreditation Council for Graduate Medical Education to educate trainee physicians on cost awareness, only 10% of pediatric residency programs have a high-value care (HVC) curriculum. To meet this need, we set out to develop and evaluate the impact of High-Value Pediatrics, an open-access HVC curriculum. High Value Pediatrics is a 3-part curriculum that includes 4 standardized didactics, monthly interactive morning reports, and an embedded HVC improvement project. Curriculum evaluation through an anonymous, voluntary survey revealed an improvement in the self-reported knowledge of health care costs, charges, reimbursement, and value (P < .05). Qualitative results revealed self-reported behavior changes, and HVC improvement projects resulted in higher-value patient care. The implementation of High-Value Pediatrics is feasible and reveals improved knowledge and attitudes about HVC. HVC improvement projects augmented curricular knowledge gains and revealed behavior changes. It is imperative that formal high-value education be taught to every pediatric trainee to lead the culture change that is necessary to turn the tide against low-value health care. In addition, simultaneous work on faculty education and attention to the hidden curriculum of low-value care is needed for sustained and long-term improvements. PMID- 30425057 TI - Aberrant activation of beta-catenin signaling drives glioma tumorigenesis via USP1-mediated stabilization of EZH2. AB - Aberrant activation of beta-catenin signaling is a critical driver for tumorigenesis, but the mechanism underlying this activation is not completely understood. In this study, we demonstrate a critical role of beta-catenin signaling in stabilization of Enhancer of Zeste Homolog 2 (EZH2) and control of EZH2-mediated gene repression in oncogenesis. beta-catenin/TCF4 activated transcription of the deubiquitinase USP1, which then interacted with and deubiquitinated EZH2 directly. USP1-mediated stabilization of EZH2 promoted its recruitment to the promoters of CDKN1B, RUNX3, and HOXA5, resulting in enhanced enrichment of histone H3K27me3 and repression of target gene expression. In human glioma specimens, expression levels of nuclear beta-catenin, USP1, and EZH2 correlated with one another. Depletion of beta-catenin/USP1/EZH2 repressed glioma cell proliferation in vitro and tumor formation in vivo. Our findings indicate that a beta-catenin-USP1-EZH2 axis orchestrates the interplay between dysregulated beta-catenin signaling and EZH2-mediated gene epigenetic silencing during glioma tumorigenesis. PMID- 30425059 TI - miR-146a controls immune response in the melanoma microenvironment. AB - Micro-RNAs (miR) are small non-coding RNAs that regulate gene expression, post transcription, and manipulate immune responses in different types of cancer. In this study, we identify miR-146a as a negative regulator of immune activation, comparable to immune checkpoint molecules. miR-146a levels were increased in melanoma microenvironmental tissue, and miR-146a-/- mice survived longer and developed less metastases in comparison to wild type melanoma-bearing mice. T cells isolated from miR-146a-/- mice revealed higher expression levels of the miR 146a target gene Stat1 and the Stat1-regulated cytokine Interferon-gamma (IFN gamma). Neutralization of IFN-gamma in miR-146a-/- mice decreased survival and increased melanoma metastasis patterns to those of wild-type mice. In vitro, IFN gamma reduced melanoma cell migration, cell cycle activity, and basal metabolic rate. Conversely, IFN-gamma also increased PD-L1 levels on the melanoma cells, which may counterbalance some of the beneficial effects increasing immune escape in vivo. Combined treatment with a miR-146a antagomiR and anti-PD-1 resulted in improved survival over isotype-control or anti-PD-1 treatment alone. In summary, these data show that miR-146a plays a central role within the STAT1/IFN-gamma axis in the melanoma microenvironment, affecting melanoma migration, proliferation, and mitochondrial fitness as well as PD-L1 levels. Additionally, combined inhibition of PD-1 and miR-146a could be a novel strategy to enhance anti-tumor immune response elicited by checkpoint therapy. PMID- 30425060 TI - "Examining How the MAFB Transcription Factor Affects Islet beta Cell Function Postnatally". AB - The sustained expression of the MAFB transcription factor in human islet beta cells represents a distinct difference to mouse. Moreover, mRNA expression of closely related and islet beta cell-enriched MAFA does not peak in humans until after nine years in age. Here we show that the MAFA protein is also weakly produced within the juvenile human islet beta cell population, and that MafB expression is postnatally restricted in mouse beta cells by de novo DNA methylation. To obtain insight into how MAFB affects human beta cells, we developed a mouse model to ectopically express MafB in adult mouse beta cells using MafA transcriptional control sequences. Co-expression of MafB with MafA had no overt impact on mouse beta cells, suggesting that the human adult beta cell MAFA/MAFB heterodimer is functionally equivalent to the mouse MafA homodimer. However, MafB alone was unable to rescue the islet beta cell defects in a mouse mutant lacking MafA in beta cells. Interestingly, transgenic production of MafB in beta cells elevated tryptophan hydroxylase 1 mRNA production during pregnancy, which drives serotonin biosynthesis critical for adaptive maternal beta cell responses. Together, these studies provide novel insight into the role of MAFB in human islet beta cells. PMID- 30425058 TI - A collaborative analysis of individual participant data from 19 prospective studies assesses circulating vitamin D and prostate cancer risk. AB - Previous prospective studies assessing the relationship between circulating concentrations of vitamin D and prostate cancer risk have shown inconclusive results, particularly for risk of aggressive disease. In this study, we examine the association between pre-diagnostic concentrations of 25-hydroxyvitamin D (25(OH)D) and 1,25(OH)2D and the risk of prostate cancer overall and by tumor characteristics. Principal investigators of 19 prospective studies provided individual participant data on circulating 25(OH)D and 1,25(OH)2D for up to 13,462 men with incident prostate cancer and 20,261 control participants. Odds ratios (OR) for prostate cancer by study-specific fifths of season-standardized vitamin D concentration were estimated using multivariable-adjusted conditional logistic regression. 25(OH)D concentration was positively associated with risk for total prostate cancer (multivariable-adjusted OR comparing highest versus lowest study-specific fifth was 1.22, 95% CI 1.13-1.31; P trend<0.001). However, this association varied by disease aggressiveness (Pheterogeneity=0.014); higher circulating 25(OH)D was associated with a higher risk of non-aggressive disease (OR per 80 percentile increase=1.24, 1.13-1.36) but not with aggressive disease (defined as stage 4, metastases, or prostate cancer death, 0.95, 0.78-1.15). 1,25(OH)2D concentration was not associated with risk for prostate cancer overall or by tumor characteristics. The absence of an association of vitamin D with aggressive disease does not support the hypothesis that vitamin D deficiency increases prostate cancer risk. Rather, the association of high circulating 25(OH)D concentration with a higher risk of non-aggressive prostate cancer may be influenced by detection bias. PMID- 30425061 TI - Targeting the CDA1/CDA1BP1 Axis Retards Renal Fibrosis in Experimental Diabetic Nephropathy. AB - Targeting Cell Division Autoantigen 1 (CDA1) is postulated to attenuate the profibrotic actions of transforming growth factor-beta in diabetic nephropathy. This study has identified a regulatory protein for CDA1 and has then used genetic and pharmacological approaches to test in vivo if strategies to target this pathway would lead to reduced renal injury. A novel protein, named CDA1BP1, was identified as critical in regulating the profibrotic activity of CDA1. Genetic deletion of CDA1BP1 attenuated key parameters of renal fibrosis in diabetic mice. Furthermore, a series of short synthetic CDA1BP1 peptides competitively inhibited CDA1-CDA1BP1 binding in vitro with a hybrid peptide, CHA-050, containing a 12mer CDA1BP1 peptide and a previously known "Cell Penetrating Peptide", dose dependently reducing expression of collagens I and III in HK-2 cells. In vivo, a D-amino acid retro-inverso peptide, CHA-061, significantly attenuated diabetes associated increases in renal expression of genes involved in fibrotic and pro inflammatory pathways. In a delayed intervention study, CHA-061 treatment reversed diabetes associated molecular and pathological changes within the kidney. Specifically, CHA-061 attenuated significantly renal extracellular matrix accumulation and glomerular injury. Taken together, targeting the CDA1/CDA1BP1 axis is a safe, efficacious and feasible approach to retard experimental diabetic nephropathy. PMID- 30425062 TI - WASH Regulates Glucose Homeostasis by Facilitating Glut2 Receptor Recycling in Pancreatic Beta Cells. AB - WASH is an endosomal protein belonging to the Wiskott-Aldrich syndrome protein superfamily that participates in endosomal receptor trafficking by facilitating tubule fission via activation of the ubiquitously expressed Arp2/3 complex. While several studies have begun to understand the functions of WASH in cells lines, the in vivo function of WASH has not been fully elucidated since total body deletion in mice leads to early embryonic lethality. To circumvent this problem, we have used a WASH conditional knockout mouse model to investigate the role of WASH in the pancreas. We find that pancreas-specific deletion of WASH leads to impaired blood glucose clearance and reduced insulin release upon glucose stimulation. Furthermore, WASH depletion results in impaired trafficking of Glut2 in pancreatic beta cells as a consequence of an intracellular accumulation of Glut2 and overall decreased levels of Glut2 protein. Taken together, these results indicate that WASH participates in pancreatic beta-cell glucose sensing and whole body glucose homeostasis. Thus patients harboring mutations in components of the WASH complex could be at risk for developing type II diabetes. PMID- 30425064 TI - The Familiality of Rapid Renal Decline in Diabetes. AB - Sustained and rapid loss of glomerular filtration rate (GFR) is the predominant clinical feature of diabetic kidney disease and a requisite for the development of end-stage renal disease. While GFR trajectories have been studied in several diabetic and non-diabetic cohorts, whether rapid renal decline clusters in diabetic families has not been examined. To determine this, we estimated GFR (eGFR) from serum creatinine measurements obtained from 15,612 patients with diabetes at the University of Utah Health Sciences Center and established their renal function trajectories. Patients with rapid renal decline (eGFR slope <-5 ml/min/1.73m2/year) were then mapped to pedigrees using extensive genealogical records from the Utah Population Database to identify high-risk rapid renal decline pedigrees. We identified 2,127 (13.6%) rapid decliners with a median eGFR slope of -8.0 mL/min/1.73m2/year and 51 high-risk pedigrees (ranging in size from 1,450-24,501 members) with excess clustering of rapid renal decline. Familial analysis showed that rapid renal decline aggregates in these families and is associated with its increased risk among first-degree relatives. Further study of these families is necessary to understand the magnitude of the influence of shared familial factors, including environmental and genetic factors, on rapid renal decline in diabetes. PMID- 30425063 TI - NLRP3 Promotes Diabetic Bladder Dysfunction and Changes in Symptom-Specific Bladder Innervation. AB - The NLRP3 inflammasome senses diabetic metabolites and initiates inflammation implicated in diabetic complications and neurodegeneration. No studies have investigated NLRP3 in diabetic bladder dysfunction (DBD), despite a high clinical prevalence. In vitro, we found that numerous diabetic metabolites activate NLRP3 in primary urothelial cells. In vivo we demonstrate NLRP3 is activated in urothelia from a genetic Type 1 diabetic mouse (Akita) by week 15. We then bred a NLRP3-/- genotype into these mice and found this blocked bladder inflammation and cystometric markers of DBD. Analysis of bladder innervation established an NLRP3 dependent decrease in overall nerve density and Adelta-fibers in the bladder wall along with an increase in C-fiber populations in the urothelia, which potentially explains the decreased sense of bladder fullness reported by patients and overactivity detected early in DBD. Together, the results demonstrate the role of NLRP3 in the genesis of DBD and suggest specific NLRP3-mediated neuronal changes can produce specific DBD symptoms. PMID- 30425065 TI - Silencing of HDAC6 as a therapeutic target in chronic lymphocytic leukemia. AB - Although the treatment paradigm for chronic lymphocytic leukemia (CLL) is rapidly changing, the disease remains incurable, except with allogeneic bone marrow transplantation, and resistance, relapsed disease, and partial responses persist as significant challenges. Recent studies have uncovered roles for epigenetic modification in the regulation of mechanisms contributing to malignant progression of CLL B cells. However, the extent to which epigenetic modifiers can be targeted for therapeutic benefit in CLL patients remains poorly explored. We report for the first time that expression of epigenetic modifier histone deacetylase 6 (HDAC6) is upregulated in CLL patient samples, cell lines, and euTCL1 transgenic mouse models compared with HDAC6 in normal controls. Genetic silencing of HDAC6 conferred survival benefit in euTCL1 mice. Administration of isoform-specific HDAC6 inhibitor ACY738 in the euTCL1 aging and adoptive transfer models deterred proliferation of CLL B cells, delayed disease onset via disruption of B-cell receptor signaling, and sensitized CLL B cells to apoptosis. Furthermore, coadministration of ACY738 and ibrutinib displayed synergistic cell kill against CLL cell lines and improved overall survival compared with either single agent in vivo. These results demonstrate for the first time the therapeutic efficacy of selective HDAC6 inhibition in preclinical CLL models and suggest a rationale for the clinical development of HDAC6 inhibitors for CLL treatment, either alone or in combination with Bruton tyrosine kinase inhibition. PMID- 30425066 TI - Venous thromboembolism in chronic lymphocytic leukemia: a Danish nationwide cohort study. AB - Venous thromboembolism (VTE) is associated with inferior survival in cancer patients. The risk of VTE and its effect on survival in chronic lymphocytic leukemia (CLL) patients remains unclear. The present study investigated the impact of patient-related factors, CLL prognostic markers, and CLL treatment on the risk of VTE and assessed overall survival relative to VTE. All patients in the Danish National CLL Registry (2008-2015) were followed from the date of CLL diagnosis to death, VTE, emigration, or administrative censoring. Hazard ratios (HRs) were estimated using Cox models, and second primary cancers and anticoagulation treatment were included as time-varying exposures. During a median follow-up of 2.6 years, 92 VTEs occurred among 3609 CLL patients, corresponding to a total incidence rate of 8.2 VTEs per 1000 person-years (95% confidence interval [CI], 6.7-10.1). A history of VTE or second primary cancer was associated with HRs of VTE of 5.09 (95% CI, 2.82-9.17) and 3.72 (95% CI, 2.15 6.34), respectively, while beta2-microglobulin >4 mg/L, unmutated immunoglobulin HV and unfavorable cytogenetics had lower HRs. CLL patients with VTE had marginally higher mortality, which was most pronounced among patients <60 years of age (HR, 7.74; 95% CI, 2.12-28.29). Our findings suggest that markers of unfavorable CLL prognosis contribute to an increased risk of VTE; however, previous VTE or a second primary cancer is more strongly associated with the risk of VTE than any CLL-specific marker. Focusing attention on this preventable complication may improve survival in young CLL patients. PMID- 30425068 TI - Timing of treatment of smoldering myeloma: early treatment. PMID- 30425067 TI - Prevalence of inherited blood disorders and associations with malaria and anemia in Malawian children. AB - In sub-Saharan Africa, inherited causes of anemia are common, but data are limited regarding the geographical prevalence and coinheritance of these conditions and their overall contributions to childhood anemia. To address these questions in Malawi, we performed a secondary analysis of the 2015-2016 Malawi Micronutrient Survey, a nationally and regionally representative survey that estimated the prevalence of micronutrient deficiencies and evaluated both inherited and noninherited determinants of anemia. Children age 6 to 59 months were sampled from 105 clusters within the 2015-2016 Malawi Demographic Health Survey. Hemoglobin, ferritin, retinol binding protein, malaria, and inflammatory biomarkers were measured from venous blood. Molecular studies were performed using dried blood spots to determine the presence of sickle cell disease or trait, alpha-thalassemia trait, and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Of 1279 eligible children, 1071 were included in the final analysis. Anemia, iron deficiency, and malaria were common, affecting 30.9%, 21.5%, and 27.8% of the participating children, respectively. alpha-Thalassemia trait was common (>40% of children demonstrating deletion of 1 [33.1%] or 2 [10.0%] alpha globin genes) and associated with higher prevalence of anemia (P < .001). Approximately 20% of males had G6PD deficiency, which was associated with a 1.0 g/dL protection in hemoglobin decline during malaria infection (P = .02). These data document that inherited blood disorders are common and likely play an important role in the prevalence of anemia and malaria in Malawian children. PMID- 30425069 TI - Timing of treatment of smoldering myeloma: delay until progression. PMID- 30425071 TI - Stem cell safe harbor: the hematopoietic stem cell niche in zebrafish. AB - Each stem cell resides in a highly specialized anatomic location known as the niche that protects and regulates stem cell function. The importance of the niche in hematopoiesis has long been appreciated in transplantation, but without methods to observe activity in vivo, the components and mechanisms of the hematopoietic niche have remained incompletely understood. Zebrafish have emerged over the past few decades as an answer to this. Use of zebrafish to study the hematopoietic niche has enabled discovery of novel cell-cell interactions, as well as chemical and genetic regulators of hematopoietic stem cells. Mastery of niche components may improve therapeutic efforts to direct differentiation of hematopoietic stem cells from pluripotent cells, sustain stem cells in culture, or improve stem cell transplant. PMID- 30425070 TI - Activity of eltrombopag in severe aplastic anemia. AB - Since the approval of horse antithymocyte globulin (ATG) decades ago, there was a long hiatus in therapies with activity in severe aplastic anemia (SAA). This scenario changed in 2014 when eltrombopag, a thrombopoietin receptor agonist, was approved for SAA after an insufficient response to initial immunosuppressive therapy (IST). The basis for this approval was the observation of single-agent activity of eltrombopag in this patient population, where 40% to 50% recovered blood counts at times involving >1 lineage. The achievement of transfusion independence confirmed the clinical benefit of this approach. Increase in marrow cellularity and CD34+ cells suggested a recovery to a more functioning bone marrow. Further in its development, eltrombopag was associated with standard horse ATG plus cyclosporine in first line, producing increases in overall (at about 90%) and complete response rates (at about 40%) and leading to transfusion independence and excellent survival. Interestingly, best results were observed when all drugs were started simultaneously. The cumulative incidence of clonal cytogenetic abnormalities to date has compared favorably with the vast experience with IST alone in SAA. Longer follow-up will help in define these long-term risks. In this review, the development of eltrombopag in SAA will be discussed. PMID- 30425072 TI - When to obtain genomic data in acute myeloid leukemia (AML) and which mutations matter. AB - Mutational profiling has fundamentally changed our approach to patients with acute myeloid leukemia (AML). Patients with AML are routinely profiled for the presence of mutations in FLT3, NPM1, CEBPA, and, more recently, TP53 In this chapter, we review the role of mutational profiling to help define disease biology in AML, particularly among patients with putatively intermediate-risk disease. We describe the body of evidence supporting the utility of mutational profiling when performed at the time of diagnosis (to identify prognostic and targetable mutations), at the time of complete remission (to assess minimal residual disease as a marker for relapse), and at the time of relapse (to identify therapeutic targets and eligibility for clinical trials). We further identify particular mutations that have been shown to affect prognosis across the established European LeukemiaNet risk categories and discuss which mutational events might be used to alter the approach to patient care at various time points during the disease course. We also review the evidence in support of molecular profiling for assessment of minimal/measurable residual disease and describe the current landscape of studies designed to validate this approach. PMID- 30425073 TI - Who should get long-term anticoagulant therapy for venous thromboembolism and with what? AB - After an initial 3 to 6 months of anticoagulation for venous thromboembolism (VTE), clinicians and patients face an important question: "Do we stop anticoagulants or continue them indefinitely?" The decision is easy in some scenarios (eg, stop in VTE provoked by major surgery). In most scenarios, which are faced on a day-to-day basis in routine practice, it is a challenging decision because of uncertainty in estimates in the long-term risks (principally major bleeding) and benefits (reducing recurrent VTE) and the tight trade-offs between them. Once the decision is made to continue, the next question to tackle is "Which anticoagulant?" Here again, it is a difficult decision because of the uncertainty with regard to estimates of efficacy and the safety of anticoagulant options and the tight trade-offs between choices. We conclude with the approach that we take in our clinical practice. PMID- 30425074 TI - TCF/LEF dependent and independent transcriptional regulation of Wnt/beta-catenin target genes. AB - During canonical Wnt signalling, the activity of nuclear beta-catenin is largely mediated by the TCF/LEF family of transcription factors. To challenge this view, we used the CRISPR/Cas9 genome editing approach to generate HEK 293T cell clones lacking all four TCF/LEF genes. By performing unbiased whole transcriptome sequencing analysis, we found that a subset of beta-catenin transcriptional targets did not require TCF/LEF factors for their regulation. Consistent with this finding, we observed in a genome-wide analysis that beta-catenin occupied specific genomic regions in the absence of TCF/LEF Finally, we revealed the existence of a transcriptional activity of beta-catenin that specifically appears when TCF/LEF factors are absent, and refer to this as beta-catenin-GHOST response. Collectively, this study uncovers a previously neglected modus operandi of beta-catenin that bypasses the TCF/LEF transcription factors. PMID- 30425076 TI - Haemorrhagic vesicles and varioliform scarring: consider photosensitivity. PMID- 30425075 TI - Early neonatal vitamin A supplementation and infant mortality: an individual participant data meta-analysis of randomised controlled trials. AB - BACKGROUND: Biannual vitamin A supplementation is a well-established survival tool for preschool children 6 months and older in vitamin A deficient populations but this schedule misses the opportunity to intervene on most young infant deaths. Randomised trials of neonatal vitamin A supplementation (NVAS) in the first few days of life to assess its impact on under 6-month mortality in low/middle-income countries have had varying results. METHODS: Investigators of 11 published randomised placebo-controlled NVAS trials (n=163 567 children) reanalysed their data according to an agreed plan and pooled the primary outcomes of mortality from supplementation through 6 and 12 months of age using random effects models and meta-regression. One investigator withdrew but allowed use of the data. FINDINGS: Overall there was no effect of NVAS on infant survival through 6 (risk ratio (RR) 0.97; 95% CI 0.89 to 1.06) or 12 months of age (RR 1.00; 95% CI 0.93 to 1.08) but results varied by study population characteristics.NVAS significantly reduced 6-month mortality among the trials conducted in Southern Asia (RR 0.87; 95% CI 0.77 to 0.98), in contexts with moderate or severe vitamin A deficiency (defined as 10% or higher proportion of women with serum retinol <0.7 umol/L or 5% or more women with night blindness) (RR 0.87; 95% CI 0.80 to 0.94), early infant mortality was 30 or more per 1000 live births (RR 0.91; 95% CI 0.85 to 0.98), 75% or more of infant mortality occurred in the first 6 months of life (RR 0.92; 95% CI 0.84 to 1.01), or where >32% mothers had no schooling (RR 0.88; 95% CI 0.80 to 0.96). NVAS did not reduce mortality in the first 6 months of life in trials conducted in Africa, in contexts characterised by a low prevalence of vitamin A deficiency, lower rates of infant mortality and where maternal education was more prevalent. There was a suggestion of increased infant mortality in trials conducted in Africa (RR 1.07; 95% CI 1.00 to 1.15).Individual-level characteristics such as sex, birth weight, gestational age and size, age at dosing, parity, time of breast feeding initiation, maternal education and maternal vitamin A supplementation did not modify the impact of NVAS. CONCLUSION: NVAS reduced infant mortality in South Asia, in contexts where the prevalence of maternal vitamin A deficiency is moderate to severe and early infant mortality is high; but it had no beneficial effect on infant survival in Africa, in contexts where the prevalence of maternal vitamin A deficiency is lower, early infant mortality is low. PMID- 30425077 TI - Clonidine exposures in children under 6 (2004-2017): a retrospective study. AB - OBJECTIVE: To describe trends in clonidine exposures in children under 6. Clonidine has become increasingly popular for management of paediatric behavioural disorders. Clonidine has a narrow therapeutic index, and toxicity can occur with inadvertent double dosing. Clonidine is not recommended for use in children under 6 years. DESIGN AND SETTING: A retrospective review of clonidine exposures in children under 6 reported to the New South Wales Poisons Information Centre (NSWPIC, Australia's largest poison centre), 2004-2017. This was compared with community clonidine utilisation using dispensing data from Australian Statistics on Medicines, 2004-2015. Australian trends were compared with clonidine exposure calls to US poison centres, 2006-2016. MAIN OUTCOME MEASURES: Trends in poisonings and dispensing; demographics, dose, exposure type, clonidine source, symptoms, disposition. RESULTS: There were 802 clonidine exposures in the NSWPIC database, increasing 4.9% per year, 2004-2017 (95% CI 3.1% to 6.7%, p<0.001), correlated with increased dispensing, r=0.846 (95% CI 0.529 to 0.956, p<0.001). 78.6% were hospitalised and medical toxicologists were consulted in 7.2%, indicating high risk and/or morbidity. Clonidine was prescribed for the patient in at least 27.8%, providing evidence for prescribing outside of recommendations. US data reveals 19 056 clonidine exposures, with 3.7% increase per year, 2006-2016 (95% CI 2.2% to 5.3%, p<0.001). CONCLUSIONS: Clonidine exposures in children under 6 are increasing, and this trend is not isolated to Australia. Exposures have a high hospital referral rate and high morbidity. Caution should be exercised when prescribing clonidine, and parent/carer education is important for safe storage and increased vigilance when dosing. PMID- 30425078 TI - Assessing cardiovascular risk in aviation: if only we had a crystal ball! PMID- 30425079 TI - Beyond a 'wing and a prayer': building the evidence base for aviation cardiology. PMID- 30425080 TI - An introduction to aviation cardiology. AB - The management of cardiovascular disease (CVD) has evolved significantly in the last 20 years; however, the last major publication to address a consensus on the management of CVD in aircrew was published in 1999, following the second European Society of Cardiology conference of aviation cardiology experts. This article outlines an introduction to aviation cardiology and focuses on the broad aviation medicine considerations that are required to manage aircrew appropriately and optimally (both pilots and non-pilot aviation professionals). This and the other articles in this series are born out of a 3 year collaborative working group between international military aviation cardiologists and aviation medicine specialists, many of whom also work with and advise civil aviation authorities, as part of a North Atlantic Treaty Organization (NATO) led initiative to address the occupational ramifications of CVD in aircrew (HFM-251). This article describes the types of aircrew employed in the civil and military aviation profession in the 21st century; the types of aircraft and aviation environment that must be understood when managing aircrew with CVD; the regulatory bodies involved in aircrew licensing and the risk assessment processes that are used in aviation medicine to determine the suitability of aircrew to fly with medical (and specifically cardiovascular) disease; and the ethical, occupational and clinical tensions that exist when managing patients with CVD who are also professional aircrew. PMID- 30425081 TI - Assessing aeromedical risk: a three-dimensional risk matrix approach. AB - Early aeromedical risk i was based on aeromedical standards designed to eliminate individuals ii from air operations with any identifiable medical risk, and led to frequent medical disqualification. The concept of considering aeromedical risk as part of the spectrum of risks that could lead to aircraft accidents (including mechanical risks and human factors) was first proposed in the 1980s and led to the development of the 1% rule which defines the maximum acceptable risk for an incapacitating medical event as 1% per year (or 1 in 100 person-years) to align with acceptable overall risk in aviation operations. Risk management has subsequently evolved as a formal discipline, incorporating risk assessment as an integral part of the process. Risk assessment is often visualised as a risk matrix, with the level of risk, urgency or action required defined for each cell, and colour-coded as red, amber or green depending on the overall combination of risk and consequence. This manuscript describes an approach to aeromedical risk management which incorporates risk matrices and how they can be used in aeromedical decision-making, while highlighting some of their shortcomings. PMID- 30425082 TI - The challenge of asymptomatic coronary artery disease in aircrew; detecting plaque before the accident. AB - Coronary events remain a major cause of sudden incapacitation, including death, in both the general population and among aviation personnel, and are an ongoing threat to flight safety and operations. The presentation is often unheralded, especially in younger adults, and is often due to rupture of a previously non obstructive coronary atheromatous plaque. The challenge for aeromedical practitioners is to identify individuals at increased risk for such events. This paper presents the NATO Cardiology Working Group (HFM 251) consensus approach for screening and investigation of aircrew for asymptomatic coronary disease.A three phased approach to coronary artery disease (CAD) risk assessment is recommended, beginning with initial risk-stratification using a population-appropriate risk calculator and resting ECG. For aircrew identified as being at increased risk, enhanced screening is recommended by means of Coronary Artery Calcium Score alone or combined with a CT coronary angiography investigation. Additional screening may include exercise testing, and vascular ultrasound imaging. Aircrew identified as being at high risk based on enhanced screening require secondary investigations, which may include functional ischaemia, and potentially invasive coronary angiography. Functional stress testing as a stand-alone investigation for significant CAD is not recommended in aircrew. Aircrew identified with coronary disease require further clinical and aeromedical evaluation before being reconsidered for flying status. PMID- 30425083 TI - Management of established coronary artery disease in aircrew without myocardial infarction or revascularisation. AB - This paper is part of a series of expert consensus documents covering all aspects of aviation cardiology. In this manuscript, we focus on the broad aviation medicine considerations that are required to optimally manage aircrew with established coronary artery disease in those without myocardial infarction or revascularisation (both pilots and non-pilot aviation professionals). We present expert consensus opinion and associated recommendations. It is recommended that in aircrew with non-obstructive coronary artery disease or obstructive coronary artery disease not deemed haemodynamically significant, nor meeting the criteria for excessive burden (based on plaque morphology and aggregate stenosis), a return to flying duties may be possible, although with restrictions. It is recommended that aircrew with haemodynamically significant coronary artery disease (defined by a decrease in fractional flow reserve) or a total burden of disease that exceeds an aggregated stenosis of 120% are grounded. With aggressive cardiac risk factor modification and, at a minimum, annual follow-up with routine non-invasive cardiac evaluation, the majority of aircrew with coronary artery disease can safely return to flight duties. PMID- 30425084 TI - Management of established coronary artery disease in aircrew with previous myocardial infarction or revascularisation. AB - This manuscript focuses on the broad aviation medicine considerations that are required to optimally manage aircrew with established coronary artery disease (CAD) without myocardial infarction (MI) or revascularisation (both pilots and non-pilot aviation professionals). It presents expert consensus opinion and associated recommendations and is part of a series of expert consensus documents covering all aspects of aviation cardiology.Aircrew may present with MI (both ST elevation MI (STEMI) and non-ST elevation MI (NSTEMI)) as the initial presenting symptom of obstructive CAD requiring revascularisation. Management of these individuals should be conducted according to published guidelines, ideally with consultation between the cardiologist, surgeon and aviation medical examiner. Return to restricted flight duties is possible in the majority of aircrew; however, they must have normal cardiac function, acceptable residual disease burden and no residual ischaemia. They must also be treated with aggressive cardiac risk factor modification. Aircrew should be restricted to dual pilot operations in non-high-performance aircraft, with return to flying no sooner than 6 months after the event. At minimum, annual follow-up with routine non-invasive cardiac evaluation is recommended. PMID- 30425085 TI - Management of cardiac conduction abnormalities and arrhythmia in aircrew. AB - Cardiovascular diseases i are the most common cause of loss of flying licence globally, and cardiac arrhythmia is the main disqualifier in a substantial proportion of aircrew. Aircrew ii often operate within a demanding physiological environment, that potentially includes exposure to sustained acceleration (usually resulting in a positive gravitational force, from head to feet (+Gz)) in high performance aircraft. Aeromedical assessment is complicated further when trying to discriminate between benign and potentially significant rhythm abnormalities in aircrew, many of whom are young and fit, have a resultant high vagal tone, and among whom underlying cardiac disease has a low prevalence. In cases where a significant underlying aetiology is plausible, extensive investigation is often required and where appropriate should include review by an electrophysiologist. The decision regarding restriction of flying activity will be dependent on several factors including the underlying arrhythmia, associated pathology, risk of incapacitation and/or distraction, the type of aircraft operated, and the specific flight or mission criticality of the role performed by the individual aircrew. PMID- 30425086 TI - Heart muscle disease management in aircrew. AB - This manuscript focuses on the broad aviation medicine considerations that are required to optimally manage aircrew with suspected or confirmed heart muscle disease (both pilots and non-pilot aviation professionals). ECG abnormalities on aircrew periodic medical examination or presentation of a family member with a confirmed cardiomyopathy are the most common reason for investigation of heart muscle disease in aircrew. Holter monitoring and imaging, including cardiac MRI is recommended to confirm or exclude the presence of heart muscle disease and, if confirmed, management should be led by a subspecialist. Confirmed heart muscle disease often requires restriction toflying duties due to concerns regarding arrhythmia. Pericarditis and myocarditis usually require temporary restriction and return to flying duties is usually dependent on a lack of recurrent symptoms and acceptable imaging and electrophysiological investigations. PMID- 30425087 TI - Contemporaneous management of valvular heart disease and aortopathy in aircrew. AB - Valvular heart disease (VHD) is highly relevant in the aircrew population as it may limit appropriate augmentation of cardiac output in high-performance flying and predispose to arrhythmia. Aircrew with VHD require careful long-term follow up to ensure that they can fly if it is safe and appropriate for them to do so. Anything greater than mild stenotic valve disease and/or moderate or greater regurgitation is usually associated with flight restrictions. Associated features of arrhythmia, systolic dysfunction, thromboembolism and chamber dilatation indicate additional risk and will usually require more stringent restrictions. The use of appropriate cardiac imaging, along with routine ambulatory cardiac monitoring, is mandatory in aircrew with VHD.Aortopathy in aircrew may be found in isolation or, more commonly, associated with bicuspid aortic valve disease. Progression rates are unpredictable, but as the diameter of the vessel increases, the associated risk of dissection also increases. Restrictions on aircrew duties, particularly in the context of high-performance or solo flying, are usually required in those with progressive dilation of the aorta. PMID- 30425088 TI - Congenital heart disease in aircrew. AB - This article focuses i on the broad aviation medicine considerations that are required to optimally manage aircrew ii with suspected or confirmed congenital heart disease (both pilots and non-pilot aviation professionals). It presents expert consensus opinion and associated recommendations and is part of a series of expert consensus documents covering all aspects of aviation cardiology. This expert opinion was born out of a 3 year collaborative working group between international military aviation cardiologists and aviation medicine specialists, as part of a North Atlantic Treaty Organization (NATO) led initiative to address the occupational ramifications of cardiovascular disease in aircrew (HFM-251) many of whom also work with and advise civil aviation authorities. PMID- 30425089 TI - Non-coronary cardiac surgery and percutaneous cardiology procedures in aircrew. AB - This manuscript focuses on the broad aviation medicine considerations that are required to optimally manage aircrew following non-coronary surgery or percutaneous cardiology interventions (both pilots and non-pilot aviation professionals). Aircrew may have pathology identified earlier than non-aircrew due to occupational cardiovascular screening and while aircrew should be treated using international guidelines, if several interventional approaches exist, surgeons/interventional cardiologists should consider which alternative is most appropriate for the aircrew role being undertaken; liaison with the aircrew medical examiner is strongly recommended prior to intervention to fully understand this. This is especially important in aircrew of high-performance aircraft or in aircrew who undertake aerobatics. Many postoperative aircrew can return to restricted flying duties, although aircrew should normally not return to flying for a minimum period of 6 months to allow for appropriate postoperative recuperation and assessment of cardiac function and electrophysiology. PMID- 30425090 TI - Phase 1 Study of AMG 337, a Highly Selective Small-Molecule MET Inhibitor, in Patients With Advanced Solid Tumors. AB - PURPOSE: This first-in-human, open-label phase 1 study evaluated AMG 337, an oral, highly selective small-molecule inhibitor of MET in advanced solid tumors. EXPERIMENTAL DESIGN: Patients enrolled into dose-escalation cohorts received AMG 337 up to 400 mg once daily (QD) or up to 250 mg twice daily (BID), following a modified 3+3+3 design. Dose expansion was conducted in MET-amplified patients at the maximum tolerated dose (MTD). Primary endpoints included assessment of adverse events (AEs), establishment of the MTD, and pharmacokinetics; clinical response was a secondary endpoint. RESULTS: The safety analysis set included 111 patients who received >=1 dose of AMG 337. Thirteen patients had >=1 AE qualifying as dose-limiting toxicity. The MTD was determined to be 300 mg QD; the MTD for BID dosing was not reached. Most frequent treatment-related AEs were headache (63%) and nausea (31%). Grade >=3 treatment-related AEs occurred in 23 patients (21%), most commonly headache (n=6) and fatigue (n=5). Maximum plasma concentration occurred at 3.0 hours following 300-mg QD dosing, indicating AMG 337 absorption soon after treatment. Objective response rate was 9.9% (11/111; 95% CI, 5.1%-17.0%) in all patients and 29.6% (8/27; 95% CI, 13.8%-50.2%) in MET amplified patients; median (range) duration of response was 202 (51-1430+) days in all patients and 197 (64-1430+) days in MET-amplified patients. CONCLUSIONS: Oral AMG 337 was tolerated with manageable toxicities, with an MTD and recommended phase 2 dose of 300 mg QD. The promising response rate observed in patients with heavily pretreated MET-amplified tumors warrants further investigation. PMID- 30425091 TI - Prognostic value of RANKL/OPG serum levels and disseminated tumor cells in non metastatic breast cancer. AB - BACKGROUND: We assessed serum concentrations of the receptor activator of nuclear factor kappa-B ligand (RANKL) and its decoy receptor osteoprotegerin (OPG), two proteins implicated in the development and progression of breast cancer (BC), in 509 patients with primary, non-metastatic BC. Then the results were evaluated with regards to the occurrence of bone metastases, the presence of disseminated tumor cells (DTC) in the bone marrow, survival and risk of developing metastatic disease. PATIENTS AND METHODS: Before surgery, two bone marrow aspirates were analyzed for DTC using density centrifugation followed by immunocytochemistry (pan-cytokeratin antibody A45-B/B3). RANKL and OPG levels in the serum were measured by ELISA. RESULTS: RANKL levels were significantly lower in women >60 years (p<0.0001) and RANKL/OPG ratios higher in lymph node-positive patients (p<0.05). High OPG serum levels were associated with a higher risk of death from BC (HR 1.94 95%CI 1.23-3.07; p=0.005) and OPG was an independent prognostic marker for BC specific survival (multivariate analyses, p=0.035). RANKL levels were 33% higher (p<0.0001) in DTCpos patients (41%) whereas high levels were associated with a significantly better BC specific survival in DTCneg patients as compared to low levels (HR 0.524; 95%CI 0.30-0.95; p=0.04). RANKL serum levels were significantly increased in patients who developed bone metastases (p=0.01) and patients within the highest quartile of RANKL had a significantly increased risk of developing bone metastases compared to those in the lowest (HR 4.62, 95%CI 1.49-14.34, p=0.03). CONCLUSION: These findings warrant further investigation as they provide a rationale for novel diagnostic or therapeutic approaches. PMID- 30425092 TI - Preventing Lck activation in CAR T cells confers Treg resistance but requires 4 1BB signaling for them to persist and treat solid tumors in non-lymphodepleted hosts. AB - PURPOSE: CAR T cells have shown promise against solid tumors, but their efficacy has been limited, due in part, to immunosuppression by CD4+FoxP3+ regulatory T cells (Tregs). Although lymphodepletion is commonly used to deplete Tregs, these regimens are non-specific, toxic, and provide only a narrow window before Tregs repopulate hosts. Importantly, CARs have also been shown to inadvertently potentiate Tregs by providing a source of IL-2 for Treg consumption. We explored whether disruption of the IL-2 axis would confer efficacy against solid tumors without the need for lymphodepletion. EXPERIMENTAL DESIGN: We developed second- (CD28z) and third- (CD28-4-1BBz) generation CARs targeting EGFRvIII. To eliminate secretion of IL-2, two amino acid substitutions were introduced in the PYAP Lck binding-motif of the CD28 domain (DCD28). We evaluated CARs against B16 melanomas expressing EGFRvIII. RESULTS: CD28z CARs failed to engraft in vivo Although 4-1BB addition improved expansion, CD28-4-1BBz CARs required lymphodepletion to treat solid tumors. CARs deficient in Lck signaling, however, significantly retarded tumor growth without a need for lymphodepletion and this was dependent on inclusion of 4-1BB. To evaluate CAR vulnerability to Tregs, we lymphodepleted mice and transferred CARs alone or with purified Tregs. Co-transfer with Tregs abrogated the efficacy of CD28-4-1BBz CARs, whereas the efficacy of DCD28-4-1BBz CARs remained unperturbed. CONCLUSIONS: In the absence of lymphodepletion, CARs targeting solid tumors are hindered by Treg immunosuppression and poor persistence. Here, CARs were modified to circumvent Treg suppression and to simultaneously improve in vivo engraftment. Modified CARs treated solid tumors without a need for lymphodepletion. PMID- 30425093 TI - Rare, pathogenic germline variants in Fanconi Anemia genes increase risk for squamous lung cancer. AB - PURPOSE: Lung cancer is the leading cause of cancer deaths worldwide, with substantial better prognosis in early stage as opposed to late state disease. Identifying genetic factors for lung squamous carcinoma (SqCC) risk will enable their use in risk stratification, and personalized intensive surveillance, early detection, and prevention strategies for high-risk individuals. EXPERIMENTAL DESIGN: We analyzed whole-exome sequencing datasets of 318 cases and 814 controls (discovery cohort) and then validated our findings in an independent cohort of 444 patients and 3,479 controls (validation cohort), all of European descent, totaling a combined cohort of 765 cases and 4,344 controls. We focused on rare pathogenic variants found in the ClinVar database and used penalized logistic regression to identify genes in which such variants are enriched in cases. All statistical tests were two-sided. RESULTS: We observed an overall enrichment of rare, deleterious germline variants in Fanconi Anemia genes in cases with SqCC (joint analysis OR=3.08, p=1.4e-09, 95% confidence interval [CI]=2.2-4.3). Consistent with previous studies, BRCA2 in particular exhibited an increased overall burden of rare, deleterious variants (joint OR=3.2, p=8.7e-08, 95% CI=2.1 4.7). More importantly, rare deleterious germline variants were enriched in Fanconi Anemia genes even without the BRCA2 rs11571833 variant that is strongly enriched in lung SqCC cases (joint OR=2.76, p=7.0e-04, 95% CI=1.6-4.7). CONCLUSIONS: These findings can be used towards the development of a genetic diagnostic test in the clinic to identify SqCC high-risk individuals, who can benefit from personalized programs, improving prognosis. PMID- 30425095 TI - Hypoglycemia and Incident Cognitive Dysfunction: A Post Hoc Analysis From the ORIGIN Trial. AB - OBJECTIVE: Epidemiological studies have reported a relationship between severe hypoglycemia, cognitive dysfunction, and dementia in middle-aged and older people with type 2 diabetes. However, whether severe or nonsevere hypoglycemia precedes cognitive dysfunction is unclear. Thus, the aim of this study was to analyze the relationship between hypoglycemia and incident cognitive dysfunction in a group of carefully followed patients using prospectively collected data in the Outcome Reduction with Initial Glargine Intervention (ORIGIN trial). RESEARCH DESIGN AND METHODS: This prospective cohort analysis of data from a randomized controlled trial included individuals with dysglycemia who had additional cardiovascular risk factors and a Mini-Mental State Examination (MMSE) score >=24 (N = 11,495). Severe and nonsevere hypoglycemic events were collected prospectively during a median follow-up time of 6.2 years. Incident cognitive dysfunction was defined as either reported dementia or an MMSE score of <24. The hazard of at least one episode of severe or nonsevere hypoglycemia for incident cognitive dysfunction (i.e., the dependent variable) from the time of randomization was estimated using a Cox proportional hazard model after adjusting for baseline cardiovascular disease, diabetes status, treatment allocation, and a propensity score for either form of hypoglycemia. RESULTS: This analysis did not demonstrate an association between severe hypoglycemia and incident cognitive impairment either before (HR 1.16; 95% CI 0.89, 1.52) or after (HR 1.00; 95% CI 0.76, 1.31) adjusting for the severe hypoglycemia propensities. Conversely, nonsevere hypoglycemia was inversely related to incident cognitive impairment both before (HR 0.59; 95% CI 0.52, 0.68) and after (HR 0.58; 95% CI 0.51, 0.67) adjustment. CONCLUSIONS: Hypoglycemia did not increase the risk of incident cognitive dysfunction in 11,495 middle-aged individuals with dysglycemia. PMID- 30425094 TI - Evaluation and Management of Youth-Onset Type 2 Diabetes: A Position Statement by the American Diabetes Association. PMID- 30425096 TI - Inorganic polyphosphate, a multifunctional polyanionic protein scaffold. AB - Polyphosphate (polyP) consists of a linear arrangement of inorganic phosphates and defies its structural simplicity with an astounding number of different activities in the cell. Already well known for its ability to partake in phosphate, calcium, and energy metabolism, polyP recently gained a new functional dimension with the discovery that it serves as a stabilizing scaffold for protein folding intermediates. In this review, we summarize and discuss the recent studies that have identified polyP not only as a potent protein-like chaperone that protects cells against stress-induced protein aggregation, but also as a robust modifier of amyloidogenic processes that shields neuronal cells from amyloid toxicity. We consider some of the most pressing questions in the field, the obstacles faced, and the potential avenues to take to provide a complete picture about the working mechanism and physiological relevance of this intriguing biopolymer. PMID- 30425097 TI - N-terminal acetylation and the N-end rule pathway control degradation of the lipid droplet protein PLIN2. AB - Perilipin 2 (PLIN2) is a major lipid droplet (LD)-associated protein that regulates intracellular lipid homeostasis and LD formation. Under lipid-deprived conditions, the LD-unbound (free) form of PLIN2 is eliminated in the cytosol by an as yet unknown ubiquitin (Ub)-proteasome pathway that is associated with the N terminal or near N-terminal residues of the protein. Here, using HeLa, HEK293T and HepG2 human cell lines, cycloheximide chase, in vivo ubiquitylation, split-Ub yeast two hybrid and chemical crosslinking-based reciprocal co immunoprecipitation assays, we found that TEB4 (MARCH6), an E3 Ub ligase and recognition component of the Ac/N-end rule pathway, directly targets the N terminal acetyl moiety of Nalpha-terminally acetylated PLIN2 for its polyubiquitylation and degradation by the 26S proteasome. We also show that the TEB4-mediated Ac/N-end rule pathway reduces intracellular LD accumulation by degrading PLIN2. Collectively, these findings identify PLIN2 as a substrate of the Ac/N-end rule pathway and indicate a previously unappreciated role of the Ac/N-end rule pathway in LD metabolism. PMID- 30425098 TI - Desensitizing plant EPSP synthase to glyphosate: Optimized global sequence context accommodates a glycine-to-alanine change in the active site. AB - 5-Enolpyruvylshikimate-3-phosphate synthase (EPSPS) catalyzes the transfer of a carboxyvinyl group from phosphoenolpyruvate (PEP) to shikimate-3-phosphate and in plants is the target of the herbicide glyphosate. EPSPSs with high catalytic efficiency and insensitivity to glyphosate are of microbial origin, including the enzyme from Agrobacterium strain CP4, in which insensitivity is conferred by an active site alanine. In the sequence context of plant EPSPSs, alanine in place of glycine at the equivalent position interferes with the binding of both glyphosate and PEP. We show here that iterative optimization of maize EPSPS containing the G101A substitution yielded variants on par with CP4 in terms of catalytic activity in the presence of glyphosate. The improvement relative to G101A alone was entirely due to reduction in Km for PEP from 333 MUM to 18 MUM, versus 9.5 MUM for native maize EPSPS. A large portion of the reduction in Km was conferred by two down-sizing substitutions (L97C and V332A) within 8 A of glyphosate, which together reduced Km for PEP to 43 MUM. Though the original optimization was conducted with maize EPSPS, contextually homologous substitutions conferred similar properties to the EPSPSs of other crops. We also discovered a variant having the known glyphosate-desensitizing substitution P106L plus three additional ones that reduced the Km for PEP from 47 MUM, observed with P106L alone, to 10.3 MUM. The improvements obtained with both Ala-101 and Leu-106 have implications regarding glyphosate-tolerant crops and weeds. PMID- 30425100 TI - Exploring the quinone/inhibitor-binding pocket in mitochondrial respiratory complex I by chemical biology approaches. AB - NADH-quinone oxidoreductase (respiratory complex I) couples NADH-to-quinone electron transfer to the translocation of protons across the membrane. Even though the architectures of the quinone-access channel in the enzyme have been modeled by X-ray crystallography and cryo-EM, conflicting findings raise the question whether the models fully reflect physiologically relevant states present throughout the catalytic cycle. To gain further insights into the structural features of the binding pocket for quinone/inhibitor, we performed chemical biology experiments using bovine heart sub-mitochondrial particles. We synthesized ubiquinones that are oversized (SF-UQs) or lipid-like (PC-UQs) and are highly unlikely to enter and transit the predicted narrow channel. We found that SF-UQs and PC-UQs can be catalytically reduced by complex I, albeit only at moderate or low rates. Moreover, quinone-site inhibitors completely blocked the catalytic reduction and the membrane potential formation coupled to this reduction. Photoaffinity-labeling experiments revealed that amiloride-type inhibitors bind to the interfacial domain of multiple core subunits (49 kDa, ND1, and PSST) and 39 kDa supernumerary subunit, although the latter does not make up the channel cavity in the current models. The binding of amilorides to the multiple target subunits was remarkably suppressed by other quinone-site inhibitors and SF-UQs. Taken together, the present results are difficult to reconcile with the current channel models. On the basis of comprehensive interpretations of the present results and of previous findings, we discuss the physiological relevance of these models. PMID- 30425099 TI - Structural analysis reveals a "molecular calipers" mechanism for a LATERAL ORGAN BOUNDARIES DOMAIN transcription factor protein from wheat. AB - LATERAL ORGAN BOUNDARIES DOMAIN (LBD) proteins, a family of plant-specific transcription factors harboring a conserved LOB domain, are regulators of plant organ development. Recent studies have unraveled additional pivotal roles of the LBD protein family beyond defining lateral organ boundaries, such as pollen development and nitrogen metabolism. The structural basis for the molecular network of LBD-dependent processes remains to be deciphered. Here, we solved the first structure of the homodimeric LOB domain of Ramosa2 from wheat (TtRa2LD) to 1.9 A resolution. Our crystal structure reveals structural features shared with other zinc-finger transcriptional factors, as well as some features unique to LBD proteins. Formation of the TtRa2LD homodimer relied on hydrophobic interactions of its coiled-coil motifs. Several specific motifs/domains of the LBD protein were also involved in maintaining its overall conformation. The intricate assembly within and between the monomers determined the precise spatial configuration of the two zinc fingers that recognize palindromic DNA sequences. Biochemical, molecular modeling, and small-angle X-ray scattering (SAXS) experiments indicated that dimerization is important for cooperative DNA binding and discrimination of palindromic DNA through a molecular calipers mechanism. Along with previously published data, this study enables us to establish an atomic-scale mechanistic model for LBD proteins as transcriptional regulators in plants. PMID- 30425101 TI - Transglutaminase inhibition stimulates hematopoiesis and reduces aggressive behavior of crayfish, Pacifastacus leniusculus. AB - Transglutaminase (TGase) is a Ca2+-dependent cross-linking enzyme, which has both enzymatic and non-enzymatic properties. TGase is involved in several cellular activities, including adhesion, migration, survival, apoptosis, and extracellular matrix (ECM) organization. In this study, we focused on the role of the TGase enzyme in controlling hematopoiesis in the crayfish Pacifastacus leniusculus. We hypothesized that a high TGase activity could mediate an interaction of progenitor cells with the ECM to maintain cells in an undifferentiated stage in the hematopoietic tissue (HPT). We found here that the reversible inhibitor cystamine decreases the enzymatic activity of TGase from crayfish HPT as well as from guinea pig in a concentration-dependent manner. Cystamine injection could decrease TGase activity in HPT without affecting production of reactive oxygen species (ROS). Moreover the decrease in TGase activity in the HPT increased the number of circulating hemocytes. Interestingly the cystamine-mediated TGase inhibition reduced aggressive behavior and movement in crayfish. In conclusion, we show that cystamine-mediated TGase inhibition directly releases HPT progenitor cells from the HPT into the peripheral circulation in the hemolymph and strongly reduces aggressive behavior in crayfish. PMID- 30425102 TI - Structure of human cortisol-producing cytochrome P450 11B1 bound to the breast cancer drug fadrozole provides insights for drug design. AB - Human cytochrome P450 11B1 (CYP11B1) is responsible for the final step generating the steroid hormone cortisol, which controls stress and immune responses and glucose homeostasis. CYP11B1 is a promising drug target to manage Cushing's disease, a disorder arising from excessive cortisol production. However, the design of selective inhibitors has been hampered because structural information for CYP11B1 is unavailable and the enzyme has high amino acid sequence identity (93%) to a closely related enzyme, the aldosterone-producing CYP11B2. Here we report the X-ray crystal structure of human CYP11B1 (at 2.1 A resolution) in complex with fadrozole, a racemic compound normally used to treat breast cancer by inhibiting estrogen-producing CYP19A1. Comparison of fadrozole-bound CYP11B1 with fadrozole-bound CYP11B2 revealed that despite conservation of the active site residues, overall structures and active sites had structural rearrangements consistent with distinct protein functions and inhibition. While fadrozole binds to both CYP11B enzymes by coordinating the heme iron, CYP11B2 binds to the R enantiomer of fadrozole, whereas CYP11B1 binds to the S enantiomer, each with distinct orientations and interactions. These results provide insights into the cross-reactivity of drugs across multiple steroidogenic cytochrome P450 enzymes, provide a structural basis for understanding human steroidogenesis, and pave the way for the design of more selective inhibitors of both human CYP11B enzymes. PMID- 30425103 TI - Clinical Pharmacology of Antihypertensive Therapy for the Treatment of Hypertension in Chronic Kidney Disease. AB - CKD is common and frequently complicated with hypertension both predialysis and in ESKD. As a major modifiable risk factor for cardiovascular disease in this high-risk population, treatment of hypertension in CKD is important. We review the mechanisms and indications for the major classes of antihypertensive drugs, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-adrenergic blocking agents, dihydropyridine calcium channel blockers, thiazide diuretics, loop diuretics, mineralocorticoid receptor blockers, direct vasodilators, and centrally acting alpha-agonists. Recent evidence suggests that beta-adrenergic blocking agents may have a greater role in patients on dialysis and that thiazide diuretics may have a greater role in patients with advanced CKD. We conclude with sharing our general prescribing algorithm for both patients with predialysis CKD and patients with ESKD on dialysis. PMID- 30425104 TI - PTH, FGF23, and Intensive Blood Pressure Lowering in Chronic Kidney Disease Participants in SPRINT. AB - BACKGROUND AND OBJECTIVES: The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that intensive BP lowering reduced the risk of cardiovascular disease, but increased eGFR decline. Serum parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23) concentrations are elevated in CKD and are associated with cardiovascular disease. We evaluated whether intact PTH or intact FGF23 concentrations modify the effects of intensive BP control on cardiovascular events, heart failure, and all-cause mortality in SPRINT participants with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We measured PTH and FGF23 in 2486 SPRINT participants with eGFR<60 ml/min per 1.73 m2 at baseline. Cox models were used to evaluate whether serum PTH and FGF23 concentrations were associated with cardiovascular events, heart failure, and all cause mortality, and whether PTH and FGF23 modified the effects of intensive BP control. RESULTS: The mean age of this subcohort was 73 years, 60% were men, and mean eGFR was 46+/-11 ml/min per 1.73 m2. Median PTH was 48 (interquartile range [IQR], 35-67) pg/ml and FGF23 was 66 (IQR, 52-88) pg/ml. There were 261 composite cardiovascular events, 102 heart failure events, and 179 deaths within the subcohort. The adjusted hazard ratio (HR) per doubling of PTH concentration for cardiovascular events, heart failure, and all-cause mortality were 1.29 (95% confidence interval [95% CI], 1.06 to 1.57), 1.32 (95% CI, 0.96 to 1.83), and 1.04 (95% CI, 0.82 to 1.31), respectively. There were significant interactions between PTH and BP arm for both the cardiovascular (P-interaction=0.01) and heart failure (P-interaction=0.004) end points. Participants with a PTH above the median experienced attenuated benefits of intensive BP control on cardiovascular events (adjusted HR, 1.02; 95% CI, 0.72 to 1.42) compared with participants with a PTH below the median (adjusted HR, 0.67; 95% CI, 0.45 to 1.00). FGF23 was not independently associated with any outcome and did not modify the effects of the intervention. CONCLUSIONS: SPRINT participants with CKD and a high serum PTH received less cardiovascular protection from intensive BP therapy than participants with a lower serum PTH. PMID- 30425106 TI - High-throughput stability screening of neoantigen/HLA complexes improves immunogenicity predictions. AB - Mutated peptides (neoantigens) from a patient's cancer genome can serve as targets for T-cell immunity, but identifying which peptides can be presented by an MHC molecule and elicit T cells has been difficult. Although algorithms that predict MHC binding exist, they are not yet able to distinguish experimental differences in half-lives of the complexes (an immunologically relevant parameter, referred to here as kinetic stability). Improvement in determining actual neoantigen peptide/MHC stability could be important, as only a small fraction of peptides in most current vaccines are capable of eliciting CD8+ T cell responses. Here, we used a rapid, high-throughput method to experimentally determine peptide/HLA thermal stability on a scale that will be necessary for analysis of neoantigens from thousands of patients. The method combined the use of UV-cleavable peptide/HLA class I complexes and differential scanning fluorimetry (DSF) to determine the Tm values of neoantigen complexes. Measured Tm values were accurate and reproducible and were directly proportional to the half lives of the complexes. Analysis of known HLA-A2-restricted immunogenic peptides showed that Tm values better correlated with immunogenicity than algorithm predicted binding affinities. We propose that temperature stability information can be used as a guide for the selection of neoantigens in cancer vaccines in order to focus attention on those mutated peptides with the highest probability of being expressed on the cell surface. PMID- 30425105 TI - Peripheral blood TCR repertoire profiling may facilitate patient stratification for immunotherapy against melanoma. AB - Many metastatic melanoma patients experience durable responses to anti-PD1 and/or anti-CTLA4, however, a significant proportion (over 50%) do not benefit from the therapies. In this study, we sought to assess pretreatment liquid biopsies for biomarkers that may correlate with response to checkpoint blockade. We measured the combinatorial diversity evenness of the T-cell receptor (TCR) repertoire (the DE50, with low values corresponding to more clonality and lack of TCR diversity) in pretreatment liquid biopsies from melanoma patients treated with anti-CTLA4 (n = 42) or anti-PD1 (n = 38) using a multi-N-plex PCR assay on genomic DNA (gDNA). A ROC curve determined the optimal threshold for a dichotomized analysis according to objective responses as defined by RECIST1.1. Correlations between treatment outcome, clinical variables, and DE50 were assessed in multivariate regression models and confirmed with Fisher exact tests. In samples obtained prior to treatment initiation, we showed that low DE50 values were predictive of a longer progression-free survival and good responses to PD-1 blockade, but on the other hand predicted a poor responses to CTLA4 inhibition. Multivariate logistic regression models identified DE50 as the only independent predictive factor for response to anti-CTLA4 therapy (P = 0.03) and anti-PD1 therapy (P = 0.001). Fisher exact tests confirmed the association of low DE50 with response in the anti-CTLA4 (P = 0.041) and the anti-PD1 cohort (P = 0.0016). Thus, the evaluation of basal TCR repertoire diversity in peripheral blood, using a PCR based method, could help predict responses to anti-PD1 and anti-CTLA4 therapies. PMID- 30425107 TI - Autoantibody development under treatment with immune checkpoint inhibitors. AB - Immune checkpoint inhibitors (ICIs) activate the immune system to assault cancer cells in a manner that is not antigen specific. We hypothesized that tolerance may also be broken to autoantigens, resulting in autoantibody formation, which could be associated with immune-related adverse events (irAEs) and antitumor efficacy. Twenty-three common clinical autoantibodies in pre- and post-treatment sera from 133 ipilimumab-treated melanoma patients were determined, and their development linked to the occurrence of irAEs, best overall response, and survival. Autoantibodies developed in 19.2% (19/99) of patients who were autoantibody-negative pre-treatment. A non-significant association was observed between development of any autoantibodies and any irAEs (OR: 2.92 [95% CI: 0.85 to 10.01]). Patients with anti-thyroid antibodies after ipilimumab had significantly more thyroid dysfunction under subsequent anti-PD-1 therapy: 7/11 (54.6%) patients with anti-thyroid antibodies after ipilimumab developed thyroid dysfunction under anti-PD1 versus 7/49 (14.3%) patients without antibodies (OR: 9.96 [95% CI: 1.94 to 51.1]). Patients who developed autoantibodies showed a trend for better survival (HR for all-cause death: 0.66 [95% CI: 0.34 to 1.26]) and therapy response (OR: 2.64 [95% CI: 0.85 to 8.16]). We conclude that autoantibodies develop under ipilimumab treatment and could be a potential marker of ICI toxicity and efficacy. PMID- 30425108 TI - Mapping the MHC class I spliced immunopeptidome of cancer cells. AB - Anti-cancer immunotherapies demand optimal epitope targets, which could include proteasome-generated spliced peptides if tumor cells were to present them. Here, we show that spliced peptides are widely presented by MHC class I molecules of colon and breast carcinoma cell lines. The peptides derive from hot spots within antigens and enlarge the antigen coverage. Spliced peptides also represent a large number of antigens that would otherwise be neglected by patrolling T cells. These antigens tend to be long, hydrophobic, and basic. Thus, spliced peptides can be a key to identifying targets in an enlarged pool of antigens associated with cancer. PMID- 30425109 TI - Evolution and multiple origins of zona pellucida genes in vertebrates. AB - Animal egg coats are composed of different glycoproteins collectively named zona pellucida (ZP) proteins. The characterized vertebrate genes encoding ZP proteins have been classified into six subfamilies, and exhibit low similarity to the ZP genes characterized in certain invertebrates. The origin and evolution of the vertebrate ZP genes remain obscure. A search against 97 representative metazoan species revealed various numbers (ranging from three to 33) of different putative egg-coat ZP genes in all 47 vertebrates and several ZP genes in five invertebrate species, but no putative ZP gene was found in the other 45 species. Based on phylogenetic and synteny analyses, all vertebrate egg-coat ZP genes were classified into eight ZP gene subfamilies. Lineage- and species-specific gene duplications and gene losses occurred frequently and represented the main causes of the patchy distribution of the eight ZP gene subfamilies in vertebrates. Thorough phylogenetic analyses revealed that the vertebrate ZP genes could be traced to three independent origins but were not orthologues of the characterized invertebrate ZP genes. Our results suggested that vertebrate egg-coat ZP genes should be classified into eight subfamilies, and a putative evolutionary map is proposed. These findings would aid the functional and evolutionary analyses of these reproductive genes in vertebrates. PMID- 30425110 TI - Challenges and opportunities for antibiotic stewardship among preterm infants. AB - Antibiotic stewardship programmes aim to optimise antimicrobial use to prevent the emergence of resistance species and protect patients from the side effects of unnecessary medication. The high incidence of systemic infection and associated mortality from these infections leads neonatal providers to frequently initiate antibiotic therapy and make empiric antibiotic courses one of the main contributors of antibiotic use in the neonatal units. Yet, premature infants are also at risk for acute life-threatening complications associated with antibiotic use such as necrotising enterocolitis and for long-term morbidities such as asthma. In this review, we discuss specific aspects of antibiotic use in the very low birthweight preterm infants, with a focus on empiric use, that provide opportunities for stewardship practice. We discuss strategies to risk-stratify antibiotic initiation for the risk of early-onset sepsis, optimise empiric therapy duration and antibiotic choice in late-onset sepsis, and standardise decisions for stopping empiric therapy. Lastly, review the evolving role of biomarkers in antibiotic stewardship. PMID- 30425111 TI - Continuous glucose monitoring in the neonatal intensive care unit: not quite ready for 'plug and play'. PMID- 30425112 TI - Epidemiology and healthcare factors associated with neonatal enterococcal infections. AB - OBJECTIVE: To investigate the epidemiology and healthcare factors associated with late-onset neonatal enterococcal infections. DESIGN: Multicentre, multinational retrospective cohort study using prospectively collected infection data from a neonatal infection surveillance network between 2004 and 2016; this was supplemented with healthcare data from a questionnaire distributed to participating neonatal units. SETTING: Sixty neonatal units across Europe (UK, Greece, Estonia) and Australia. PATIENTS: Infants admitted to participating neonatal units who had a positive culture of blood, cerebrospinal fluid or urine after 48 hours of life. RESULTS: In total, 414 episodes of invasive Enterococcus spp infection were reported in 388 infants (10.1% of a total 4083 episodes in 3602 infants). Enterococcus spp were the second most common cause of late-onset infection after coagulase-negative Staphylococcus spp and were strongly associated with necrotising enterocolitis (NEC) (adjusted OR 1.44, 95% CI 1.02 to 2.03, p=0.038), total parenteral nutrition (TPN) (adjusted OR 1.34, 95% CI 1.06 to 1.70, p=0.016), increasing postnatal age (per 1-week increase: adjusted OR 1.04, 95% CI 1.02 to 1.06, p<0.001) and decreasing birth weight (per 1 kg increase: adjusted OR 0.85, 95% CI 0.74 to 0.97, p=0.017). There was no evidence that inadequate nurse to patient staffing ratios in high-dependency units were associated with a higher risk of enterococcal infections. CONCLUSIONS: Enterococcus spp were the second most frequent cause of late-onset infections. The association between enterococcal infections, NEC and TPN may inform empiric antimicrobial regimens in these contexts and provide insights into reducing these infections. PMID- 30425114 TI - Randomised study comparing heart rate measurement in newly born infants using a monitor incorporating electrocardiogram and pulse oximeter versus pulse oximeter alone. AB - AIM: To determine whether IntelliVue (ECG plus Masimo pulse oximeter (PO)) measures heart rate (HR) in low-risk newborns more quickly than Nellcor PO (PO alone). METHODS: Unmasked parallel group randomised (1:1) study. RESULTS: We studied 100 infants, 47 randomised to IntelliVue, 53 to Nellcor. Time to first HR was shorter with IntelliVue ECG than Nellcor (median (IQR) 24 (19, 39) vs 48 (36, 69) s, p<0.001). There was no difference in time to display both HR and SpO2 (52 (47, 76) vs 48 (36, 69) s, p=0.507). IntelliVue PO displayed initial bradycardia more often than the Nellcor (55% vs 6%). Infants monitored with IntelliVue were handled more frequently and for longer. CONCLUSIONS: IntelliVue ECG displayed HR more quickly than Nellcor PO. IntelliVue PO often displayed initial bradycardia. Infants monitored with IntelliVue were handled more often. Study of ECG in high risk infants is warranted. PMID- 30425113 TI - Therapeutic hypothermia initiated within 6 hours of birth is associated with reduced brain injury on MR biomarkers in mild hypoxic-ischaemic encephalopathy: a non-randomised cohort study. AB - OBJECTIVE: To examine the effect of therapeutic hypothermia on MR biomarkers and neurodevelopmental outcomes in babies with mild hypoxic-ischaemic encephalopathy (HIE). DESIGN: Non-randomised cohort study. SETTING: Eight tertiary neonatal units in the UK and the USA. PATIENTS: 47 babies with mild HIE on NICHD neurological examination performed within 6 hours after birth. INTERVENTIONS: Whole-body cooling for 72 hours (n=32) or usual care (n=15; of these 5 were cooled for <12 hours). MAIN OUTCOME MEASURES: MRI and MR spectroscopy (MRS) within 2 weeks after birth, and a neurodevelopmental outcome assessment at 2 years. RESULTS: The baseline characteristics in both groups were similar except for lower 10 min Apgar scores (p=0.02) in the cooled babies. Despite this, the mean (SD) thalamic NAA/Cr (1.4 (0.1) vs 1.6 (0.2); p<0.001) and NAA/Cho (0.67 (0.08) vs 0.89 (0.11); p<0.001) ratios from MRS were significantly higher in the cooled group. Cooled babies had lower white matter injury scores than non-cooled babies (p=0.02). Four (27%) non-cooled babies with mild HIE developed seizures after 6 hours of age, while none of the cooled babies developed seizures (p=0.008). Neurodevelopmental outcomes at 2 years were available in 40 (85%) of the babies. Adverse outcomes were seen in 2 (14.3%) non-cooled babies, and none of the cooled babies (p=0.09). CONCLUSIONS: Therapeutic hypothermia may have a neuroprotective effect in babies with mild HIE, as demonstrated by improved MRS biomarkers and reduced white matter injury on MRI. This may warrant further evaluation in adequately powered randomised controlled trials. PMID- 30425115 TI - Network meta-analysis explained. PMID- 30425116 TI - Premature small for gestational age infants fed an exclusive human milk-based diet achieve catch-up growth without metabolic consequences at 2 years of age. AB - OBJECTIVE: To compare postdischarge growth, adiposity and metabolic outcomes of appropriate for gestational age (AGA) versus small for gestational age (SGA) premature infants fed an exclusive human milk (HM)-based diet in the neonatal intensive care unit. DESIGN: Premature infants (birth weight <=1250 g) fed an exclusive HM-based diet were examined at 12-15 months corrected gestational age (CGA) (visit 1) for anthropometrics, serum glucose and non-fasting insulin, and at 18-22 months CGA (visit 2) for body composition by dual-energy X-ray absorptiometry. RESULTS: Of 51 children, 33 were AGA and 18 were SGA at birth. The SGA group had weight gain (g/day) equal to AGA group during the follow-up period. SGA had a significantly greater body mass index (BMI) z-score gain from visit 1 to visit 2 (0.25+/-1.10 vs -0.21+/-0.84, p=0.02) reflecting catch-up growth. There were no significant differences in total fat mass (FM) and trunk FM between groups. SGA had significantly lower insulin level (5.0+/-3.7vs17.3+/-15.1 uU/mL, p=0.02) and homeostatic model of assessment-insulin resistance (1.1+/ 0.9vs4.3+/-4.1, p=0.02). Although regional trunk FM correlated with insulin levels in SGA (r=0.893, p=0.04), they had lower insulin level compared with AGA and no difference in adiposity. CONCLUSIONS: SGA premature infants who received an exclusive HM-based diet exhibited greater catch-up growth without increased adiposity or elevated insulin resistance compared with AGA at 2 years of age. An exclusive HM-based diet may improve long-term body composition and metabolic outcomes of premature infants with <=1250 g birth weight, specifically SGA. PMID- 30425117 TI - 'This place is not for children like her': disability, ambiguous belonging and the claiming of disadvantage in postapartheid South Africa. AB - This paper presents an exploration of my experiences and unique positioning as a blind, White South African woman. It explores the complex intersections of multiple axes of identity in my own experience to do with disability, race, class and language and, in so doing, presents some ideas about the ways in which disability complicates and disturbs simplistic identity categories. It draws, in particular, on the experience of my first year of formal schooling which took place in 1994 as South Africa held its first democratic election, bringing a politico-legal, if not actual, end to decades of racial segregation. Using this experience, I explore the ways in which, against the sociopolitical backdrop of apartheid's racial segregation, ideas about race and disability, that is, Blackness and blindness, became entangled and how this entanglement impacted my ability to claim a place as either blind or sighted. Through this critical engagement I hope to be able to offer a perspective, not only on how the apartheid system operated, forcing the projection of negative characteristics onto Black people, but also on how this legacy continues to impact those of us who occupy unstable positions, at the intersection of privilege and marginality. Central to the argument is the position that the wholesale binding up of social disadvantage with race in the South African context prohibits and manages the status that persons with disabilities are able, or not able, to claim. PMID- 30425118 TI - Bulky DNA adducts, microRNA profiles, and lipid biomarkers in Norwegian tunnel finishing workers occupationally exposed to diesel exhaust. AB - OBJECTIVES: This study aimed to assess the biological impact of occupational exposure to diesel exhaust (DE) including DE particles (DEP) from heavy-duty diesel-powered equipment in Norwegian tunnel finishing workers (TFW). METHODS: TFW (n=69) and referents (n=69) were investigated for bulky DNA adducts (by 32P postlabelling) and expression of microRNAs (miRNAs) (by small RNA sequencing) in peripheral blood mononuclear cells (PBMC), as well as circulating free arachidonic acid (AA) and eicosanoid profiles in plasma (by liquid chromatography tandem mass spectrometry). RESULTS: PBMC from TFW showed significantly higher levels of DNA adducts compared with referents. Levels of DNA adducts were also related to smoking habits. Seventeen miRNAs were significantly deregulated in TFW. Several of these miRNAs are related to carcinogenesis, apoptosis and antioxidant effects. Analysis of putative miRNA-gene targets revealed deregulation of pathways associated with cancer, alterations in lipid molecules, steroid biosynthesis and cell cycle. Plasma profiles showed higher levels of free AA and 15-hydroxyeicosatetraenoic acid, and lower levels of prostaglandin D2 and 9-hydroxyoctadecadienoic acid in TFW compared with referents. CONCLUSION: Occupational exposure to DE/DEP is associated with biological alterations in TFW potentially affecting lung homoeostasis, carcinogenesis, inflammation status and the cardiovascular system. Of particular importance is the finding that tunnel finishing work is associated with an increased level of DNA adducts formation in PBMC. PMID- 30425119 TI - The Transcriptional Regulator SnoN Promotes the Proliferation of Cerebellar Granule Neuron Precursors in the Postnatal Mouse Brain. AB - Control of neuronal precursor cell proliferation is essential for normal brain development, and deregulation of this fundamental developmental event contributes to brain diseases. Typically, neuronal precursor cell proliferation extends over long periods of time during brain development. However, how neuronal precursor proliferation is regulated in a temporally specific manner remains to be elucidated. Here, we report that conditional knockout of the transcriptional regulator SnoN in cerebellar granule neuron precursors robustly inhibits the proliferation of these cells and promotes their cell cycle exit at later stages of cerebellar development in the postnatal male and female mouse brain. In laser capture microdissection followed by RNA-Seq, designed to profile gene expression specifically in the external granule layer (EGL) of the cerebellum, we find that SnoN promotes the expression of cell proliferation genes and concomitantly represses differentiation genes in granule neuron precursors in vivo Remarkably, bioinformatics analyses reveal that SnoN-regulated genes contain binding sites for the transcription factors N-myc and Pax6, which promote the proliferation and differentiation of granule neuron precursors, respectively. Accordingly, we uncover novel physical interactions of SnoN with N-myc and Pax6 in cells. In behavior analyses, conditional knockout of SnoN impairs cerebellar-dependent learning in a delayed eye-blink conditioning paradigm, suggesting that SnoN regulation of granule neuron precursor proliferation bears functional consequences at the organismal level. Our findings define a novel function and mechanism for the major transcriptional regulator SnoN in the control of granule neuron precursor proliferation in the mammalian brain.SIGNIFICANCE STATEMENTThis study reports the discovery that the transcriptional regulator SnoN plays a crucial role in the proliferation of cerebellar granule neuron precursors in the postnatal mouse brain. Conditional knockout of SnoN in granule neuron precursors robustly inhibits the proliferation of these cells and promotes their cycle exit specifically at later stages of cerebellar development, with biological consequences of impaired cerebellar-dependent learning. Genomics and bioinformatics analyses reveal that SnoN promotes the expression of cell proliferation genes and concomitantly represses cell differentiation genes in vivo Although SnoN has been implicated in distinct aspects of the development of postmitotic neurons, this study identifies a novel function for SnoN in neuronal precursors in the mammalian brain. PMID- 30425121 TI - Apocrine lesions of the breast: part 2 of a two-part review. Invasive apocrine carcinoma, the molecular apocrine signature and utility of immunohistochemistry in the diagnosis of apocrine lesions of the breast. AB - Pure apocrine carcinoma of the breast is rare and has been defined by using a combination of morphologic (apocrine morphology in >90% of tumour cells) and immunohistochemical criteria (oestrogen receptor (ER) and progesterone receptor (PR) negative and androgen receptor (AR) positive). Recent advances in the molecular classification of breast tumours have uncovered a subset of breast tumours associated with high expression of androgen receptor mRNA including the so-called 'luminal androgen receptor (LAR) tumours' and 'molecular apocrine tumours' (MATs). Recognition of these tumour subsets has opened potential avenues for therapies exploiting the AR pathway in triple negative breast carcinoma (TNBC). In this second part of our two-part review, we focus on the definition of pure apocrine carcinoma, recent advances in understanding the molecular apocrine signature in breast carcinoma, its relationship to pure apocrine carcinoma defined at the level of light microscopy and immunohistochemistry (IHC) and the therapeutic implications of androgen expression in TNBC. We complete the article with a summary of the utility of IHC in stratifying apocrine lesions of the breast. PMID- 30425120 TI - Endothelial cells act as gatekeepers for LTbetaR-dependent thymocyte emigration. AB - The emigration of mature thymocytes from the thymus is critical for establishing peripheral T cell compartments. However, the pathways controlling this process and the timing of egress in relation to postselection developmental stages are poorly defined. Here, we reexamine thymocyte egress and test current and opposing models in relation to the requirement for LTbetaR, a regulator of thymic microenvironments and thymocyte emigration. Using cell-specific gene targeting, we show that the requirement for LTbetaR in thymocyte egress is distinct from its control of thymic epithelium and instead maps to expression by endothelial cells. By separating emigration into sequential phases of perivascular space (PVS) entry and transendothelial migration, we reveal a developmentally ordered program of egress where LTbetaR operates to rate limit access to the PVS. Collectively, we show the process of thymic emigration ensures only the most mature thymocytes leave the thymus and demonstrate a role for LTbetaR in the initiation of thymus emigration that segregates from its control of medulla organization. PMID- 30425122 TI - RAS genes in colorectal carcinoma: pathogenesis, testing guidelines and treatment implications. AB - The RAS family is among the most commonly mutated genes in all human malignancies including colon cancer. In normal cells, RAS proteins act as a link in the intracellular signal transduction initiated by binding of growth factors to cell membrane receptors mediating cell survival. RAS isoproteins have great morphological similarities, but despite that, they are thought to have different functions in different tissues. RAS mutations, as supported by several studies including animal models, have a role in the development and progression of colorectal cancer. The detection of RAS mutations in patients with colorectal carcinoma, specifically KRAS and NRAS, has significant clinical implications. It is currently recommended that patients with colon cancer who are considered for antiepidermal growth factor receptor monoclonal antibodies, get RAS mutation testing since only those with wildtype-RAS genes benefit from such treatment. Despite decades of research, there is currently no effective and safe treatment that directly targets RAS-mutated neoplasms. Multiple therapeutic approaches directed against RAS mutations are currently experimental, including a promising immunotherapy study using T-cells in patients with metastatic colon cancer. PMID- 30425123 TI - Gene2vec: Gene Subsequence Embedding for Prediction of Mammalian N6 Methyladenosine Sites from mRNA. AB - N6-methyladenosine (m6A) refers to methylation modification of the adenosine nucleotide acid at the nitrogen-6 position. Many conventional computational methods for identifying N6-methyladenosine sites are limited by the small amount of data available. Taking advantage of the thousands of m6A sites detected by high-throughput sequencing, it is now possible to discover the characteristics of m6A sequences using deep learning techniques. To the best of our knowledge, our work is the first attempt to use word embedding and deep neural networks for m6A prediction from mRNA sequences. Using four deep neural networks, we developed a model inferred from a larger sequence shifting window that can predict m6A accurately and robustly. Four prediction schemes were built with various RNA sequence representations and optimized convolutional neural networks. The soft voting results from the four deep networks were shown to outperform all of the state-of-art methods. We evaluated these predictors mentioned above on a rigorous independent test dataset and proved that our proposed method outperforms the state-of-the-art predictors. The training, independent, and cross-species testing datasets are much larger than in previous studies, which could help to avoid the problem of overfitting. Furthermore, an online prediction webserver implementing the four proposed predictors has been built and is available at http://server.malab.cn/Gene2vec/. PMID- 30425124 TI - The hERG potassium channel intrinsic ligand regulates N- and C-terminal interactions and channel closure. AB - Human ether-a-go-go-related gene (hERG, KCNH2) voltage-activated potassium channels are critical for cardiac excitability. hERG channels have characteristic slow closing (deactivation), which is auto-regulated by a direct interaction between the N-terminal Per-Arnt-Sim (PAS) domain and the C-terminal cyclic nucleotide binding homology domain (CNBHD). hERG channels are not activated by the binding of extrinsic cyclic nucleotide ligands, but rather bind an "intrinsic ligand" that is composed of residues 860-862 within the CNBHD and mimics a cyclic nucleotide. The intrinsic ligand is located at the PAS-CNBHD interface, but its mechanism of action in hERG is not well understood. Here we use whole-cell patch clamp electrophysiology and FRET spectroscopy to examine how the intrinsic ligand regulates gating. To carry out this work, we coexpress PAS (a PAS domain fused to cyan fluorescent protein) in trans with hERG "core" channels (channels with a deletion of the PAS domain fused to citrine fluorescent protein). The PAS domain in trans with hERG core channels has slow (regulated) deactivation, like that of WT hERG channels, as well as robust FRET, which indicates there is a direct functional and structural interaction of the PAS domain with the channel core. In contrast, PAS in trans with hERG F860A core channels has intermediate deactivation and intermediate FRET, indicating perturbation of the PAS domain interaction with the CNBHD. Furthermore, PAS in trans with hERG L862A core channels, or PAS in trans with hERG F860G,L862G core channels, has fast (nonregulated) deactivation and no measurable FRET, indicating abolition of the PAS and CNBHD interaction. These results indicate that the intrinsic ligand is necessary for the functional and structural interaction between the PAS domain and the CNBHD, which regulates the characteristic slow deactivation gating in hERG channels. PMID- 30425125 TI - Alternative article-level metrics: The use of alternative metrics in research evaluation. PMID- 30425126 TI - Clinicopathological case: rapid cognitive decline and myoclonus associated with fever, arthropathy and scleritis. AB - A 65-year-old man presented with transient neurological symptoms, followed by rapid cognitive decline, myoclonus and fevers. He had evidence of scleritis and an arthropathy. This paper reports the clinicopathological conference discussed at the Association of British Neurologists Annual Meeting 2017. PMID- 30425127 TI - Interpreting CT perfusion in stroke. AB - CT perfusion images can be rapidly obtained on all modern CT scanners and easily incorporated into an acute stroke imaging protocol. Here we discuss the technique of CT perfusion imaging, how to interpret the data and how it can contribute to the diagnosis of acute stroke and selection of patients for treatment. Many patients with acute stroke are excluded from reperfusion therapy if the onset time is not known or if they present outside of traditional treatment time windows. There is a growing body of evidence supporting the use of perfusion imaging in these patients to identify patterns of brain perfusion that are favourable for recanalisation therapy. PMID- 30425128 TI - Malingering and factitious disorder. AB - Although exaggeration or amplification of symptoms is common in all illness, deliberate deception is rare. In settings associated with litigation/disability evaluation, the rate of malingering may be as high as 30%, but its frequency in clinical practice is not known. We describe the main characteristics of deliberate deception (factitious disorders and malingering) and ways that neurologists might detect symptom exaggeration. The key to establishing that the extent or severity of reported symptoms does not truly represent their severity is to elicit inconsistencies in different domains, but it is not possible to determine whether the reports are intentionally inaccurate. Neurological disorders where difficulty in determining the degree of willed exaggeration is most likely include functional weakness and movement disorders, post-concussional syndrome (or mild traumatic brain injury), psychogenic non-epileptic attacks and complex regional pain syndrome type 1 (especially when there is an associated functional movement disorder). Symptom amplification or even fabrication are more likely if the patient might gain benefit of some sort, not necessarily financial. Techniques to detect deception in medicolegal settings include covert surveillance and review of social media accounts. We also briefly describe specialised psychological tests designed to elicit effort from the patient. PMID- 30425129 TI - Omission of Lumbar Puncture From Evaluation of Source of Fever in Young Infants. PMID- 30425130 TI - Risk Stratification of Febrile Infants <=60 Days Old Without Routine Lumbar Puncture. AB - : : media-1vid110.1542/5840460609001PEDS-VA_2018-1879Video Abstract OBJECTIVES: To evaluate the Rochester and modified Philadelphia criteria for the risk stratification of febrile infants with invasive bacterial infection (IBI) who do not appear ill without routine cerebrospinal fluid (CSF) testing. METHODS: We performed a case-control study of febrile infants <=60 days old presenting to 1 of 9 emergency departments from 2011 to 2016. For each infant with IBI (defined as a blood [bacteremia] and/or CSF [bacterial meningitis] culture with growth of a pathogen), controls without IBI were matched by site and date of visit. Infants were excluded if they appeared ill or had a complex chronic condition or if data for any component of the Rochester or modified Philadelphia criteria were missing. RESULTS: Overall, 135 infants with IBI (118 [87.4%] with bacteremia without meningitis and 17 [12.6%] with bacterial meningitis) and 249 controls were included. The sensitivity of the modified Philadelphia criteria was higher than that of the Rochester criteria (91.9% vs 81.5%; P = .01), but the specificity was lower (34.5% vs 59.8%; P < .001). Among 67 infants >28 days old with IBI, the sensitivity of both criteria was 83.6%; none of the 11 low-risk infants had bacterial meningitis. Of 68 infants <=28 days old with IBI, 14 (20.6%) were low risk per the Rochester criteria, and 2 had meningitis. CONCLUSIONS: The modified Philadelphia criteria had high sensitivity for IBI without routine CSF testing, and all infants >28 days old with bacterial meningitis were classified as high risk. Because some infants with bacteremia were classified as low risk, infants discharged from the emergency department without CSF testing require close follow-up. PMID- 30425131 TI - MTORC1/2 inhibition as a therapeutic strategy for PIK3CA mutant cancers. AB - PIK3CA mutations are common in clinical molecular profiling, yet an effective means to target these cancers has yet to be developed. MTORC1 inhibitors are often used off-label for patients with PIK3CA mutant cancers with only limited data to support this approach. Here we describe a cohort of patients treated with cancers possessing mutations activating the PI3K signaling cascade with minimal benefit to treatment with the MTORC1 inhibitor everolimus. Previously, we demonstrated that dual PI3K/mTOR inhibition could decrease proliferation, induce differentiation, and result in a treatment response in APC and PIK3CA mutant colorectal cancer (CRC). However, reactivation of AKT was identified, indicating that the majority of the benefit may be secondary to MTORC1/2 inhibition. TAK 228, an MTORC1/2 inhibitor, was compared to dual PI3K/mTOR inhibition using BEZ235 in murine CRC spheroids. A reduction in spheroid size was observed with TAK-228 and BEZ235 (-13% and -14%, respectively) compared to an increase of >200% in control (p < 0.001). These spheroids were resistant to MTORC1 inhibition. In transgenic mice possessing Pik3ca and Apc mutations, BEZ235 and TAK-228 resulted in a median reduction in colon tumor size of 19% and 20%, respectively, with control tumors having a median increase of 18% (p = 0.02 and 0.004, respectively). This response correlated with a decrease in the phosphorylation of 4EBP1 and RPS6. MTORC1/2 inhibition is sufficient to overcome resistance to everolimus and induce a treatment response in PIK3CA mutant CRCs and deserves investigation in clinical trials and in future combination regimens. PMID- 30425132 TI - The T197A knock-in model of Cdkn1b gene to study the effects of p27 restoration in vivo. AB - The CDK inhibitor, p27kip1, encoded by the Cdkn1b gene can negatively modulate cell proliferation. The control of p27 activity during the cell cycle is regulated at multiple levels including transcription, translation and protein stability. The last residue of p27 (threonine 198 in human, threonine 197 in mouse) is involved in the control of protein stability. We have generated a murine knock-in model (Cdkn1bT197A) in which threonine 197 is replaced by alanine, which renders p27 protein highly unstable due to a high rate of proteasomal degradation. Expectedly, Cdkn1bT197A/T197A mice present increased body size and weight, organomegaly and multiple organ hyperplasia, similar to what observed in Cdkn1bKO/KO mice. We investigated the effects exerted by the restoration of normal levels of p27 protein in the tissue of Cdkn1bT197A/T197A mice. We found that proteasome inhibition with Bortezomib rescues the hyperplasia induced by the lack of p27 expression in Cdkn1bT197A/T197A but not in Cdkn1bKO/KO mice. However, BAY 11-7082, a proteasome inhibitor that stabilizes IkB but not p27, fails to rescue hyperplasia in Cdkn1bT197A/T197A mice. Bortezomib increases p27 half-life and reduces the proliferation in MEFs derived from Cdkn1bT197A/T197A but not from Cdkn1bWT/WT mice whereas BAY 11-7082 had no effect on the protein levels of p27 and on the proliferation rate of Cdkn1bT197A/T197A MEFs. The results presented here demonstrate that Cdkn1bT197A/T197A mice represent an attractive in vivo model to investigate whether the targeting of p27 degradation machinery might prove beneficial in the treatment of a variety of human proliferative disorders caused by increased turnover of p27 protein. PMID- 30425133 TI - Empowering junior doctors: a qualitative study of a QI programme in South West England. AB - AIM: To explore how the South-West Foundation Doctor Quality Improvement programme affected foundation year 1 (F1) doctors' attitudes and ability to implement change in healthcare. METHODS: Twenty-two qualitative interviews were carried out with two cohorts of doctors. The first F1 group before and after their participation in the QI programme; the second group comprised those who had completed the programme between 1 and 5 years earlier. Qualitative data were analysed using thematic analysis techniques. RESULTS : Prior to taking part in the QI programme, junior doctors' attitudes towards QI were mixed. Although there was agreement on the importance of QI in terms of patient safety, not all shared enthusiasm for engaging in QI, while some were sceptical that they could bring about any change. Following participation in the programme, attitudes towards QI and the ability to effect change were significantly transformed. Whether their projects were considered a success or not, all juniors reported that they valued the skills learnt and the overall experience they gained through carrying out QI projects. Participants reported feeling more empowered in their role as junior doctors, with several describing how they felt 'listened to' and able to 'have a voice', that they were beginning to see things 'at systems level' and learning to 'engage more critically' in their working environment. CONCLUSIONS : Junior doctors are ideally placed to engage in QI. Training in QI at the start of their medical careers may enable a new generation of doctors to acquire the skills necessary to improve patient safety and quality of care. PMID- 30425134 TI - Severe sleep disordered breathing in head and neck cancer survivor. PMID- 30425135 TI - Case of a tracheal diverticulum causing airway obstruction. PMID- 30425136 TI - Utility of trichoscopy in tinea capitis. PMID- 30425137 TI - Combining two-stage surgery and denosumab treatment in a patient with giant cell tumour of the lumbar spine with intraperitoneal growth. PMID- 30425138 TI - Marking the centenary of the Fellowship of Postgraduate Medicine. PMID- 30425139 TI - Immune checkpoint inhibitors in the management of malignancies in transplant recipients. AB - Cancer immunotherapy, an area of active research, has thus far yielded several exciting breakthroughs in cancer treatment strategies. So far, immune checkpoint inhibitors have been the most promising method of cancer immunotherapy. CTLA-4, PD-1 and PD-L1 are the immune checkpoint molecules against which monoclonal antibodies act against and revolutionised the treatment of several malignancies. However, it is still unclear whether using these monoclonal antibodies in patients with malignancy and a history of transplant is as beneficial as in patients without a history of transplantation. The reason being, with the therapeutic benefit, also comes the inherent disadvantage of transplant rejection because of the activation of T-cells against donor antigens. So, transplant related complications limit the usage of the checkpoint blockade therapy to treat malignancies. Here, we review the data published in this context and suggest optimal approaches to using the currently available repertoire of immunotherapies. PMID- 30425140 TI - Normal range: it is not normal and it is not a range. AB - The NHS 'Choose Wisely' campaign places greater emphasis on the clinician-patient dialogue. Patients are often in receipt of their laboratory data and want to know whether they are normal. But what is meant by normal? Comparator data, to a measured value, are colloquially known as the 'normal range'. It is often assumed that a result outside this limit signals disease and a result within health. However, this range is correctly termed the 'reference interval'. The clinical risk from a measured value is continuous, not binary. The reference interval provides a point of reference against which to interpret an individual's results rather than defining normality itself. This article discusses the theory of normality-and describes that it is relative and situational. The concept of normality being not an absolute state influenced the development of the reference interval. We conclude with suggestions to optimise the use and interpretation of the reference interval, thereby facilitating greater patient understanding. PMID- 30425141 TI - Confidentiality in medicine: how far should doctors prioritise the confidentiality of the individual they are treating? AB - There is a premium placed on the maintenance of our privacy and confidentiality as individuals in society. For a productive and functional doctor-patient relationship, there needs to be a belief that details divulged in confidence to the doctor will be kept confidential and not disclosed to the wider public. However, where the information disclosed to the doctor could have implications for the safety of the wider public, for example disclosures with potential criminal implications, or have serious consequences for another individual, as is the case in genetic medicine, should doctors feel confident about breaching confidentiality? This essay firstly explores the legal rulings regarding cases in which confidentiality has been breached where there was risk of significant harm to others following the patient's disclosure, and secondly, focusing on the evolving legal position with regard to confidentiality in contexts where information sharing would be beneficial to others, for example the evolving case of the implications of genetic diagnosis on families (eg, ABC v St George's Healthcare NHS Trust; 2017). PMID- 30425142 TI - Hypothesis: a Plastically Produced Phenotype Predicts Host Specialization and Can Precede Subsequent Mutations in Bacteriophage. AB - The role of phenotypic plasticity in the evolution of new traits is controversial due to a lack of direct evidence. Phage host range becomes plastic in the presence of restriction-modification (R-M) systems in their hosts. I modeled the evolution of phage host range in the presence of R-M systems. The model makes two main predictions. The first prediction is that the offspring of the first phage to gain a new methylation pattern by infecting a new host make up a disproportionate fraction of the subsequent specialist population, indicating that the plastically produced phenotype is highly predictive of evolutionary outcome. The second prediction is that the first phage to gain this pattern is not always genetically distinct from other phages in the population. Taken together, these results suggest that plasticity could play a causal role on par with mutation during the evolution of phage host range. This uniquely tractable system could enable the first direct test of "plasticity first" evolution. PMID- 30425143 TI - Suppression of Drug Resistance Reveals a Genetic Mechanism of Metabolic Plasticity in Malaria Parasites. AB - In the malaria parasite Plasmodium falciparum, synthesis of isoprenoids from glycolytic intermediates is essential for survival. The antimalarial fosmidomycin (FSM) inhibits isoprenoid synthesis. In P. falciparum, we identified a loss-of function mutation in HAD2 (P. falciparum 3D7_1226300 [PF3D7_1226300]) as necessary for FSM resistance. Enzymatic characterization revealed that HAD2, a member of the haloacid dehalogenase-like hydrolase (HAD) superfamily, is a phosphatase. Harnessing a growth defect in resistant parasites, we selected for suppression of HAD2-mediated FSM resistance and uncovered hypomorphic suppressor mutations in the locus encoding the glycolytic enzyme phosphofructokinase 9 (PFK9). Metabolic profiling demonstrated that FSM resistance is achieved via increased steady-state levels of methylerythritol phosphate (MEP) pathway and glycolytic intermediates and confirmed reduced PFK9 function in the suppressed strains. We identified HAD2 as a novel regulator of malaria parasite metabolism and drug sensitivity and uncovered PFK9 as a novel site of genetic metabolic plasticity in the parasite. Our report informs the biological functions of an evolutionarily conserved family of metabolic regulators and reveals a previously undescribed strategy by which malaria parasites adapt to cellular metabolic dysregulation.IMPORTANCE Unique and essential aspects of parasite metabolism are excellent targets for development of new antimalarials. An improved understanding of parasite metabolism and drug resistance mechanisms is urgently needed. The antibiotic fosmidomycin targets the synthesis of essential isoprenoid compounds from glucose and is a candidate for antimalarial development. Our report identifies a novel mechanism of drug resistance and further describes a family of metabolic regulators in the parasite. Using a novel forward genetic approach, we also uncovered mutations that suppress drug resistance in the glycolytic enzyme PFK9. Thus, we identify an unexpected genetic mechanism of adaptation to metabolic insult that influences parasite fitness and tolerance of antimalarials. PMID- 30425144 TI - The Structure of the Human Respiratory Syncytial Virus M2-1 Protein Bound to the Interaction Domain of the Phosphoprotein P Defines the Orientation of the Complex. AB - Human respiratory syncytial virus (HRSV) is a negative-stranded RNA virus that causes a globally prevalent respiratory infection, which can cause life threatening illness, particularly in the young, elderly, and immunocompromised. HRSV multiplication depends on replication and transcription of the HRSV genes by the virus-encoded RNA-dependent RNA polymerase (RdRp). For replication, this complex comprises the phosphoprotein (P) and the large protein (L), whereas for transcription, the M2-1 protein is also required. M2-1 is recruited to the RdRp by interaction with P and also interacts with RNA at overlapping binding sites on the M2-1 surface, such that binding of these partners is mutually exclusive. The molecular basis for the transcriptional requirement of M2-1 is unclear, as is the consequence of competition between P and RNA for M2-1 binding, which is likely a critical step in the transcription mechanism. Here, we report the crystal structure at 2.4 A of M2-1 bound to the P interaction domain, which comprises P residues 90 to 110. The P90-110 peptide is alpha helical, and its position on the surface of M2-1 defines the orientation of the three transcriptase components within the complex. The M2-1/P interface includes ionic, hydrophobic, and hydrogen bond interactions, and the critical contribution of these contacts to complex formation was assessed using a minigenome assay. The affinity of M2-1 for RNA and P ligands was quantified using fluorescence anisotropy, which showed high affinity RNAs could outcompete P. This has important implications for the mechanism of transcription, particularly the events surrounding transcription termination and synthesis of poly(A) sequences.IMPORTANCE Human respiratory syncytial virus (HRSV) is a leading cause of respiratory illness, particularly in the young, elderly, and immunocompromised, and has also been linked to the development of asthma. HRSV replication depends on P and L, whereas transcription also requires M2-1. M2-1 interacts with P and RNA at overlapping binding sites; while these interactions are necessary for transcriptional activity, the mechanism of M2-1 action is unclear. To better understand HRSV transcription, we solved the crystal structure of M2-1 in complex with the minimal P interaction domain, revealing molecular details of the M2-1/P interface and defining the orientation of M2-1 within the tripartite complex. The M2-1/P interaction is relatively weak, suggesting high-affinity RNAs may displace M2-1 from the complex, providing the basis for a new model describing the role of M2-1 in transcription. Recently, the small molecules quercetin and cyclopamine have been used to validate M2-1 as a drug target. PMID- 30425145 TI - Author Correction for Jones et al., "Identification of the I38T PA Substitution as a Resistance Marker for Next-Generation Influenza Virus Endonuclease Inhibitors". PMID- 30425147 TI - Identifying and Predicting Novelty in Microbiome Studies. AB - With the expansion of microbiome sequencing globally, a key challenge is to relate new microbiome samples to the existing space of microbiome samples. Here, we present Microbiome Search Engine (MSE), which enables the rapid search of query microbiome samples against a large, well-curated reference microbiome database organized by taxonomic similarity at the whole-microbiome level. Tracking the microbiome novelty score (MNS) over 8 years of microbiome depositions based on searching in more than 100,000 global 16S rRNA gene amplicon samples, we detected that the structural novelty of human microbiomes is approaching saturation and likely bounded, whereas that in environmental habitats remains 5 times higher. Via the microbiome focus index (MFI), which is derived from the MNS and microbiome attention score (MAS), we objectively track and compare the structural-novelty and attracted-attention scores of individual microbiome samples and projects, and we predict future trends in the field. For example, marine and indoor environments and mother-baby interactions are likely to receive disproportionate additional attention based on recent trends. Therefore, MNS, MAS, and MFI are proposed "alt-metrics" for evaluating a microbiome project or prospective developments in the microbiome field, both of which are done in the context of existing microbiome big data.IMPORTANCE We introduce two concepts to quantify the novelty of a microbiome. The first, the microbiome novelty score (MNS), allows identification of microbiomes that are especially different from what is already sequenced. The second, the microbiome attention score (MAS), allows identification of microbiomes that have many close neighbors, implying that considerable scientific attention is devoted to their study. By computing a microbiome focus index based on the MNS and MAS, we objectively track and compare the novelty and attention scores of individual microbiome samples and projects over time and predict future trends in the field; i.e., we work toward yielding fundamentally new microbiomes rather than filling in the details. Therefore, MNS, MAS, and MFI can serve as "alt-metrics" for evaluating a microbiome project or prospective developments in the microbiome field, both of which are done in the context of existing microbiome big data. PMID- 30425148 TI - A Small Regulatory RNA Controls Cell Wall Biosynthesis and Antibiotic Resistance. AB - Small regulatory RNAs play an important role in the adaptation to changing conditions. Here, we describe a differentially expressed small regulatory RNA (sRNA) that affects various cellular processes in the plant pathogen Agrobacterium tumefaciens Using a combination of bioinformatic predictions and comparative proteomics, we identified nine targets, most of which are positively regulated by the sRNA. According to these targets, we named the sRNA PmaR for peptidoglycan biosynthesis, motility, and ampicillin resistance regulator. Agrobacterium spp. are long known to be naturally resistant to high ampicillin concentrations, and we can now explain this phenotype by the positive PmaR mediated regulation of the beta-lactamase gene ampC Structure probing revealed a spoon-like structure of the sRNA, with a single-stranded loop that is engaged in target interaction in vivo and in vitro Several riboregulators have been implicated in antibiotic resistance mechanisms, such as uptake and efflux transporters, but PmaR represents the first example of an sRNA that directly controls the expression of an antibiotic resistance gene.IMPORTANCE The alphaproteobacterium Agrobacterium tumefaciens is able to infect various eudicots causing crown gall tumor formation. Based on its unique ability of interkingdom gene transfer, Agrobacterium serves as a crucial biotechnological tool for genetic manipulation of plant cells. The presence of hundreds of putative sRNAs in this organism suggests a considerable impact of riboregulation on A. tumefaciens physiology. Here, we characterized the biological function of the sRNA PmaR that controls various processes crucial for growth, motility, and virulence. Among the genes directly targeted by PmaR is ampC coding for a beta lactamase that confers ampicillin resistance, suggesting that the sRNA is crucial for fitness in the competitive microbial composition of the rhizosphere. PMID- 30425146 TI - High-Affinity Chemotaxis to Histamine Mediated by the TlpQ Chemoreceptor of the Human Pathogen Pseudomonas aeruginosa. AB - Histamine is a key biological signaling molecule. It acts as a neurotransmitter in the central and peripheral nervous systems and coordinates local inflammatory responses by modulating the activity of different immune cells. During inflammatory processes, including bacterial infections, neutrophils stimulate the production and release of histamine. Here, we report that the opportunistic human pathogen Pseudomonas aeruginosa exhibits chemotaxis toward histamine. This chemotactic response is mediated by the concerted action of the TlpQ, PctA, and PctC chemoreceptors, which display differing sensitivities to histamine. Low concentrations of histamine were sufficient to activate TlpQ, which binds histamine with an affinity of 639 nM. To explore this binding, we resolved the high-resolution structure of the TlpQ ligand binding domain in complex with histamine. It has an unusually large dCACHE domain and binds histamine through a highly negatively charged pocket at its membrane distal module. Chemotaxis to histamine may play a role in the virulence of P. aeruginosa by recruiting cells at the infection site and consequently modulating the expression of quorum sensing-dependent virulence genes. TlpQ is the first bacterial histamine receptor to be described and greatly differs from human histamine receptors, indicating that eukaryotes and bacteria have pursued different strategies for histamine recognition.IMPORTANCE Genome analyses indicate that many bacteria possess an elevated number of chemoreceptors, suggesting that these species are able to perform chemotaxis to a wide variety of compounds. The scientific community is now only beginning to explore this diversity and to elucidate the corresponding physiological relevance. The discovery of histamine chemotaxis in the human pathogen Pseudomonas aeruginosa provides insight into tactic movements that occur within the host. Since histamine is released in response to bacterial pathogens, histamine chemotaxis may permit bacterial migration and accumulation at infection sites, potentially modulating, in turn, quorum-sensing-mediated processes and the expression of virulence genes. As a consequence, the modulation of histamine chemotaxis by signal analogues may result in alterations of the bacterial virulence. As the first report of bacterial histamine chemotaxis, this study lays the foundation for the exploration of the physiological relevance of histamine chemotaxis and its role in pathogenicity. PMID- 30425149 TI - Changes in Endosymbiont Complexity Drive Host-Level Compensatory Adaptations in Cicadas. AB - For insects that depend on one or more bacterial endosymbionts for survival, it is critical that these bacteria are faithfully transmitted between insect generations. Cicadas harbor two essential bacterial endosymbionts, "Candidatus Sulcia muelleri" and "Candidatus Hodgkinia cicadicola." In some cicada species, Hodgkinia has fragmented into multiple distinct but interdependent cellular and genomic lineages that can differ in abundance by more than two orders of magnitude. This complexity presents a potential problem for the host cicada, because low-abundance but essential Hodgkinia lineages risk being lost during the symbiont transmission bottleneck from mother to egg. Here we show that all cicada eggs seem to receive the full complement of Hodgkinia lineages, and that in cicadas with more complex Hodgkinia this outcome is achieved by increasing the number of Hodgkinia cells transmitted by up to 6-fold. We further show that cicada species with varying Hodgkinia complexity do not visibly alter their transmission mechanism at the resolution of cell biological structures. Together these data suggest that a major cicada adaptation to changes in endosymbiont complexity is an increase in the number of Hodgkinia cells transmitted to each egg. We hypothesize that the requirement to increase the symbiont titer is one of the costs associated with Hodgkinia fragmentation.IMPORTANCE Sap-feeding insects critically rely on one or more bacteria or fungi to provide essential nutrients that are not available at sufficient levels in their diets. These microbes are passed between insect generations when the mother places a small packet of microbes into each of her eggs before it is laid. We have previously described an unusual lineage fragmentation process in a nutritional endosymbiotic bacterium of cicadas called Hodgkinia In some cicadas, a single Hodgkinia lineage has split into numerous related lineages, each performing a subset of original function and therefore each required for normal host function. Here we test how this splitting process affects symbiont transmission to eggs. We find that cicadas dramatically increase the titer of Hodgkinia cells passed to each egg in response to lineage fragmentation, and we hypothesize that this increase in bacterial cell count is one of the major costs associated with endosymbiont fragmentation. PMID- 30425150 TI - Salmonella enterica Serovar Typhi in Bangladesh: Exploration of Genomic Diversity and Antimicrobial Resistance. AB - Typhoid fever, caused by Salmonella enterica serovar Typhi, is a global public health concern due to increasing antimicrobial resistance (AMR). Characterization of S Typhi genomes for AMR and the evolution of different lineages, especially in countries where typhoid fever is endemic such as Bangladesh, will help public health professionals to better design and implement appropriate preventive measures. We studied whole-genome sequences (WGS) of 536 S Typhi isolates collected in Bangladesh during 1999 to 2013 and compared those sequences with data from a recent outbreak in Pakistan reported previously by E. J. Klemm, S. Shakoor, A. J. Page, F. N. Qamar, et al. (mBio 9:e00105-18, 2018, https://doi.org/10.1128/mBio.00105-18), and a laboratory surveillance in Nepal reported previously by C. D. Britto, Z. A. Dyson, S. Duchene, M. J. Carter, et al. [PLoS Negl. Trop. Dis. 12(4):e0006408, 2018, https://doi.org/10.1371/journal.pntd.0006408]. WGS had high sensitivity and specificity for prediction of ampicillin, chloramphenicol, co-trimoxazole, and ceftriaxone AMR phenotypes but needs further improvement for prediction of ciprofloxacin resistance. We detected a new local lineage of genotype 4.3.1 (named lineage Bd) which recently diverged into a sublineage (named Bdq) containing qnr genes associated with high-level ciprofloxacin resistance. We found a ceftriaxone-resistant isolate with the bla CTX-M-15 gene and a genotype distinct from the genotypes of extensively drug-resistant (XDR) isolates from Pakistan. This result suggests a different source and geographical origin of AMR. Genotype 4.3.1 was dominant in all three countries but formed country-specific clusters in the maximum likelihood phylogenetic tree. Thus, multiple independent genetic events leading to ciprofloxacin and ceftriaxone resistance took place in these neighboring regions of Pakistan, Nepal, and Bangladesh. These independent mutational events may enhance the risk of global spread of these highly resistant clones. A short-term global intervention plan is urgently needed.IMPORTANCE Typhoid fever, caused by Salmonella enterica serovar Typhi, is responsible for an estimated burden of approximately 17 million new episodes per year worldwide. Adequate and timely antimicrobial treatment invariably cures typhoid fever. The increasing antimicrobial resistance (AMR) of S Typhi severely limits the treatment options. We studied whole-genome sequences (WGS) of 536 S Typhi isolates collected in Bangladesh between 1999 and 2013 and compared those sequences with data from a recent outbreak in Pakistan and a laboratory surveillance in Nepal. The analysis suggests that multiple ancestral origins of resistance against ciprofloxacin and ceftriaxone are present in three countries. Such independent genetic events and subsequent dissemination could enhance the risk of a rapid global spread of these highly resistant clones. Given the current treatment challenges, vaccination seems to be the most appropriate short-term intervention to reduce the disease burden of typhoid fever at a time of increasing AMR. PMID- 30425152 TI - Drivers and Dynamics of Methicillin-Resistant Livestock-Associated Staphylococcus aureus CC398 in Pigs and Humans in Denmark. AB - The spread of livestock-associated methicillin-resistant Staphylococcus aureus clonal complex 398 (LA-MRSA CC398) within the Danish pig production system has been linked to an increased number of human infections. Yet, the population structure and transmission dynamics of this important pathogen remain poorly understood. In this study, whole-genome sequences from 371 LA-MRSA CC398 isolates collected between 2004 and 2015 were subjected to bioinformatic analyses. The isolates originated from Danish pig farms (n = 209) and people having livestock contact (n = 79). In addition, whole-genome sequence data from 82 isolates representing an international reference collection and 83 isolates from Danish patients were included in the analysis. The results demonstrated that the increasing prevalence of LA-MRSA CC398 in Danish pigs and patients was caused by clonal expansion of three dominant lineages. The results also showed that these lineages were enriched for the tetracycline resistance gene tet(K) and other determinants conferring resistance to some of the most frequently used antimicrobials in Danish pigs. The association between pig movements and the spread of LA-MRSA CC398 was assessed in a Poisson regression analysis of 17,009 pig movements into 273 farms with known LA-MRSA CC398 status. The results demonstrated that animal movements have played a critical role in the dissemination of LA-MRSA CC398 within the Danish pig production system, although other transmission routes may also have contributed. Consistent with this scenario, the genetic relatedness of isolates from different farms was positively correlated with the number of animal movements between the farms.IMPORTANCE Livestock-associated methicillin-resistant Staphylococcus aureus clonal complex CC398 (LA-MRSA CC398) is resistant to nearly all beta-lactams and several non beta-lactam antimicrobials. Over the last decade, it has become widespread in pig farms across Europe and is now an important cause of human infections in countries with previously low levels of MRSA, such as the Netherlands and Denmark. The hitherto uncontrolled spread of LA-MRSA CC398 underscores an urgent need to understand its epidemiology in order to develop evidence-based interventions. This study demonstrates that pig movements between farms in combination with increased bacterial resistance to specific antibiotics and heavy metals were important drivers of the rapid spread of LA-MRSA CC398 in the Danish pig production system. These findings should be taken into consideration when researchers and policy makers evaluate and decide on actions and policies to limit the spread of LA-MRSA CC398 and other pathogens in food animals. PMID- 30425151 TI - PAS Domain Protein Pas3 Interacts with the Chromatin Modifier Bre1 in Regulating Cryptococcal Morphogenesis. AB - Switching between different morphotypes is an adaptive cellular response in many microbes. In Cryptococcus neoformans, the yeast-to-hypha transition confers resistance to microbial predation in the soil and is an integral part of its life cycle. Morphogenesis is also known to be associated with virulence, with the filamentous form being immune-stimulatory and protective in mammalian models of cryptococcosis. Previous studies identified the transcription factor Znf2 as a master regulator of cryptococcal filamentation. However, the upstream regulators of Znf2 remain largely unknown. PAS domain proteins have long been recognized as transducers of diverse environmental signals. Here, we identified a PAS domain protein Pas3 as an upstream regulator of Znf2. Surprisingly, this small Pas3 protein lacks a nuclear localization signal but is enriched in the nucleus where it regulates the transcript level of ZNF2 and its prominent downstream targets. We discovered that the PAS domain is essential for Pas3's nuclear enrichment and function. Intriguingly, Pas3 interacts with Bre1, which is required for Cryptococcus histone H2B monoubiquitination (H2Bub1) and H3 lysine 4 dimethylation (H3K4me2), two histone modifications known to be associated with active gene transcription. Indeed, Bre1 functions together with Pas3 in regulating cryptococcal filamentation based on loss-of-function, epistasis, and transcriptome analysis. These findings provide the first evidence of a signaling regulator acting with a chromatin modifier to control cryptococcal filamentation.IMPORTANCE For the ubiquitous environmental pathogen Cryptococcus neoformans, the morphological transition from yeast to filament confers resistance to natural predators like soil amoeba and is an integral differentiation event to produce infectious spores. Interestingly, filamentation is immuno-stimulatory and attenuates cryptococcal virulence in a mammalian host. Consistently, the morphogenesis transcription factor Znf2 profoundly shapes cryptococcal interaction with various hosts. Identifying the signaling pathways activating filamentation is thus, conductive to a better understanding of cryptococcal biology. In this study, we identified a PAS domain protein Pas3 that functions upstream of Znf2 in regulating cryptococcal filamentation. Interestingly, Pas3 interacts with the chromatin modifier Bre1 in the nucleus to regulate the transcript level of Znf2 and its prominent downstream targets. This is the first example of a PAS domain signaling regulator interacting with a chromatin modifier to control filamentation through their impact on cryptococcal transcriptome. PMID- 30425155 TI - Plant Physiology Introduces New Editorial and News Formats for Reader Contributions and Discussion. PMID- 30425153 TI - Posttranscriptional Regulation of HIV-1 Gene Expression during Replication and Reactivation from Latency by Nuclear Matrix Protein MATR3. AB - Posttranscriptional regulation of HIV-1 replication is finely controlled by viral and host factors. Among the former, Rev controls the export of partially spliced and unspliced viral RNAs from the nucleus and their translation in the cytoplasm or incorporation into new virions as genomic viral RNA. To investigate the functional role of the Rev cofactor MATR3 in the context of HIV infection, we modulated its expression in Jurkat cells and primary peripheral blood lymphocytes (PBLs). We confirmed that MATR3 is a positive regulator of HIV-1 acting at a posttranscriptional level. By applying the same approach to J-lat cells, a well established model for the study of HIV-1 latency, we observed that MATR3 depletion did not affect transcriptional reactivation of the integrated provirus, but caused a reduction of Gag production. Following these observations, we hypothesized that MATR3 could be involved in the establishment of HIV-1 posttranscriptional latency. Indeed, mechanisms acting at the posttranscriptional level have been greatly overlooked in favor of transcriptional pathways. MATR3 was almost undetectable in resting PBLs, but could be promptly upregulated upon cellular stimulation with PHA. However, HIV latency-reversing agents were poor inducers of MATR3 levels, providing a rationale for their inability to fully reactivate the virus. These data have been confirmed ex vivo in cells derived from patients under suppressive ART. Finally, in the context of MATR3-depleted J lat cells, impaired reactivation by SAHA could be fully rescued by MATR3 reconstitution, demonstrating a direct role of MATR3 in the posttranscriptional regulation of HIV-1 latency.IMPORTANCE The life cycle of HIV-1 requires integration of a DNA copy into the genome of the host cell. Transcription of the viral genes generates RNAs that are exported to the cytoplasm with the contribution of viral and cellular factors to get translated or incorporated in the newly synthesized virions. It has been observed that highly effective antiretroviral therapy, which is able to reduce circulating virus to undetectable levels, cannot fully eradicate the virus from cellular reservoirs that harbor a transcriptionally latent provirus. Thus, persistence of latently infected cells is the major barrier to a cure for HIV-1 infection. In order to purge these reservoirs of latently infected cells, it has been proposed to activate transcription to stimulate the virus to complete its life cycle. This strategy is believed to unmask these reservoirs, making them vulnerable to the immune system. However, limited successes of this approach may indicate additional posttranscriptional restrictions that need to be overcome for full virus reactivation. In this work we identify the cellular protein MATR3 as an essential cofactor of viral RNA processing. Reactivation of HIV-1 transcription per se is not sufficient to allow completion of a full life cycle of the virus if MATR3 is depleted. Furthermore, MATR3 is poorly expressed in quiescent CD4+ T lymphocytes that are the major reservoir of latent HIV-1. Cells derived from aviremic HIV-1 patients under antiretroviral therapy didn't express MATR3, and most importantly, latency-reversing agents proposed for the rescue of latent provirus were ineffective for MATR3 upregulation. To conclude, our work identifies a cellular factor required for full HIV-1 reactivation and points to the revision of the current strategies for purging viral reservoirs that focus only on transcription. PMID- 30425154 TI - Temperature, by Controlling Growth Rate, Regulates CRISPR-Cas Activity in Pseudomonas aeruginosa. AB - Clustered regularly interspaced short palindromic repeat (CRISPR)-associated (CRISPR-Cas) systems are adaptive defense systems that protect bacteria and archaea from invading genetic elements. In Pseudomonas aeruginosa, quorum sensing (QS) induces the CRISPR-Cas defense system at high cell density when the risk of bacteriophage infection is high. Here, we show that another cue, temperature, modulates P. aeruginosa CRISPR-Cas. Increased CRISPR adaptation occurs at environmental (i.e., low) temperatures compared to that at body (i.e., high) temperature. This increase is a consequence of the accumulation of CRISPR-Cas complexes, coupled with reduced P. aeruginosa growth rate at the lower temperature, the latter of which provides additional time prior to cell division for CRISPR-Cas to patrol the cell and successfully eliminate and/or acquire immunity to foreign DNA. Analyses of a QS mutant and synthetic QS compounds show that the QS and temperature cues act synergistically. The diversity and level of phage encountered by P. aeruginosa in the environment exceed that in the human body, presumably warranting increased reliance on CRISPR-Cas at environmental temperatures.IMPORTANCE P. aeruginosa is a soil dwelling bacterium and a plant pathogen, and it also causes life-threatening infections in humans. Thus, P. aeruginosa thrives in diverse environments and over a broad range of temperatures. Some P. aeruginosa strains rely on the CRISPR-Cas adaptive immune system as a phage defense mechanism. Our discovery that low temperatures increase CRISPR adaptation suggests that the rarely occurring but crucial naive adaptation events may take place predominantly under conditions of slow growth, e.g., during the bacterium's soil dwelling existence and during slow growth in biofilms. PMID- 30425156 TI - What Is the Minimal Optimal Sample Size for Plant Ecophysiological Studies? PMID- 30425157 TI - Setting and Diffusing the Cyanide Bomb in Plant Defense. PMID- 30425158 TI - Autophagy and Chloroplast Quality Control: Fatty Acid Synthesis Counts. PMID- 30425159 TI - CORRECTION: Vol. 160: 379-395, 2012. PMID- 30425160 TI - CORRECTION: Vol. 177: 1303-1318, 2018. PMID- 30425162 TI - Distinct control of PERIOD2 degradation and circadian rhythms by the oncoprotein and ubiquitin ligase MDM2. AB - The circadian clock relies on posttranslational modifications to set the timing for degradation of core regulatory components, which drives clock progression. Ubiquitin-modifying enzymes that target clock components for degradation mainly recognize phosphorylated substrates. Degradation of the circadian clock component PERIOD 2 (PER2) is mediated by its phospho-specific recognition by beta transducin repeat-containing proteins (beta-TrCPs), which are F-box-containing proteins that function as substrate recognition subunits of the SCFbeta-TRCP ubiquitin ligase complex. However, this mode of regulating PER2 stability falls short of explaining the persistent oscillatory phenotypes reported in biological systems lacking functional elements of the phospho-dependent PER2 degradation machinery. We identified PER2 as a previously uncharacterized substrate for the ubiquitin ligase mouse double minute 2 homolog (MDM2) and found that MDM2 targeted PER2 for degradation in a manner independent of PER2 phosphorylation. Deregulation of MDM2 plays a major role in oncogenesis by contributing to the accumulation of genomic and epigenomic alterations that favor tumor development. MDM2-mediated PER2 turnover was important for defining the circadian period length in mammalian cells, a finding that emphasizes the connection between the circadian clock and cancer. Our results not only broaden the range of specific substrates of MDM2 beyond the cell cycle to include circadian components but also identify a previously unknown regulator of the clock as a druggable node that is often found to be deregulated during tumorigenesis. PMID- 30425163 TI - A cytoskeletal anchor connects ischemic mitochondrial fission to myocardial senescence. AB - The interplay between the actin cytoskeleton and mitochondria has been implicated in cell and tissue homeostasis and physiological function. In this issue of Science Signaling, Nishimura et al. demonstrate that inhibiting the interaction of filamin A, an actin cytoskeleton regulator, with Drp1, a modulator of mitochondrial dynamics, attenuates mitochondrial hyperfission and cardiomyocyte senescence after myocardial infarction. PMID- 30425161 TI - Impact of infarct location on functional outcome following endovascular therapy for stroke. AB - OBJECTIVES: The relationship between stroke topography (ie, the regions damaged by the infarct) and functional outcome can aid clinicians in their decision making at the acute and later stages. However, the side (left or right) of the stroke may also influence the identification of clinically relevant regions. We sought to determine which brain regions are associated with good functional outcome at 3 months in patients with left-sided and right-sided stroke treated by endovascular treatment using the diffusion-weighted imaging-Alberta Stroke Program Early CT Score (DWI-ASPECTS). METHODS: Patients with ischaemic stroke (n = 405) were included from the ASTER trial and Pitie-Salpetriere registry. Blinded readers rated ASPECTS on day 1 DWI. Stepwise logistic regression analyses were performed to identify the regions related to 3-month outcome in left (n = 190) and right (n = 215) sided strokes with the modified Rankin scale (0-2) as a binary independent variable and with the 10 regions-of-interest of the DWI ASPECTS as independent variables. RESULTS: Median National Institute of Health Stroke Scale (NIHSS) at baseline was 17 (IQR: 12-20), median age was 70 years (IQR: 58-80) and median day-one NIHSS 9 (IQR: 4-18). Not all brain regions have the same weight in predicting good outcome at 3 months; moreover, these regions depend on the affected hemisphere. In left-sided strokes, the multivariate analysis revealed that preservation of the caudate nucleus, the internal capsule and the cortical M5 region were independent predictors of good outcome. In right sided strokes, the cortical M3 and M6 regions were found to be clinically relevant. CONCLUSION: Cortical non-motors areas related to outcome differed between left-sided and right-sided strokes. This difference might reflect the specialisation of the dominant and non-dominant hemispheres for language and attention, respectively. These results may influence decision-making at the acute and later stages. TRIAL REGISTRATION NUMBER: NCT02523261. PMID- 30425164 TI - The transmembrane adaptor protein NTAL limits mast cell chemotaxis toward prostaglandin E2. AB - Chemotaxis of mast cells is one of the crucial steps in their development and function. Non-T cell activation linker (NTAL) is a transmembrane adaptor protein that inhibits the activation of mast cells and B cells in a phosphorylation dependent manner. Here, we studied the role of NTAL in the migration of mouse mast cells stimulated by prostaglandin E2 (PGE2). Although PGE2 does not induce the tyrosine phosphorylation of NTAL, unlike IgE immune complex antigens, we found that loss of NTAL increased the chemotaxis of mast cells toward PGE2 Stimulation of mast cells that lacked NTAL with PGE2 enhanced the phosphorylation of AKT and the production of phosphatidylinositol 3,4,5-trisphosphate. In resting NTAL-deficient mast cells, phosphorylation of an inhibitory threonine in ERM family proteins accompanied increased activation of beta1-containing integrins, which are features often associated with increased invasiveness in tumors. Rescue experiments indicated that only full-length, wild-type NTAL restored the chemotaxis of NTAL-deficient cells toward PGE2 Together, these data suggest that NTAL is a key inhibitor of mast cell chemotaxis toward PGE2, which may act through the RHOA/ERM/beta1-integrin and PI3K/AKT axes. PMID- 30425165 TI - Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission-associated myocardial senescence. AB - Defective mitochondrial dynamics through aberrant interactions between mitochondria and actin cytoskeleton is increasingly recognized as a key determinant of cardiac fragility after myocardial infarction (MI). Dynamin related protein 1 (Drp1), a mitochondrial fission-accelerating factor, is activated locally at the fission site through interactions with actin. Here, we report that the actin-binding protein filamin A acted as a guanine nucleotide exchange factor for Drp1 and mediated mitochondrial fission-associated myocardial senescence in mice after MI. In peri-infarct regions characterized by mitochondrial hyperfission and associated with myocardial senescence, filamin A colocalized with Drp1 around mitochondria. Hypoxic stress induced the interaction of filamin A with the GTPase domain of Drp1 and increased Drp1 activity in an actin-binding-dependent manner in rat cardiomyocytes. Expression of the A1545T filamin mutant, which potentiates actin aggregation, promoted mitochondrial hyperfission under normoxia. Furthermore, pharmacological perturbation of the Drp1-filamin A interaction by cilnidipine suppressed mitochondrial hyperfission associated myocardial senescence and heart failure after MI. Together, these data demonstrate that Drp1 association with filamin and the actin cytoskeleton contributes to cardiac fragility after MI and suggests a potential repurposing of cilnidipine, as well as provides a starting point for innovative Drp1 inhibitor development. PMID- 30425166 TI - Comparison of Two Cough-Augmentation Techniques Delivered by Home Ventilator in Subjects With Neuromuscular Disease. AB - BACKGROUND: Breath-stacking, which consists of taking 2 or more consecutive ventilator insufflations without exhaling, is a noninvasive and inexpensive cough assistance technique for patients with neuromuscular disease. Volumetric cough mode (VCM) is a recently introduced ventilator mode consisting of a programmable intermittent deep breath equal to a set percentage of the baseline tidal volume. Here, our objective was to compare VCM to breath-stacking during volume-control continuous mandatory ventilation in subjects on long-term noninvasive mechanical ventilation at home. METHODS: We included 20 subjects with neuromuscular disease causing severe respiratory muscle dysfunction with a cough peak flow (CPF) < 270 L/min or maximum expiratory pressure < 45 cm H2O. Each subject tested breath stacking and VCM in random order. RESULTS: CPF increased with both techniques but was higher with VCM than with breath-stacking in 16 subjects. In 17 subjects, CPF was highest with the technique that produced the greatest inspiratory capacity. CONCLUSION: Our results indicate that both breath-stacking and VCM are useful cough-augmentation techniques. Displaying insufflated volumes on the ventilator screen is a simple and accessible method for selecting the most efficient cough augmentation technique delivered by a home ventilator. PMID- 30425167 TI - A High Degree of Dyspnea Is Associated With a Poor Maximum Exercise Capacity in Subjects With COPD With the Same Severity of Air-Flow Obstruction. AB - BACKGROUND: In patients with COPD, limited data have been reported concerning the association between dyspnea perception and exercise tests. Moreover, the perception of dyspnea has not been analyzed in patients with the same severity of air-flow obstruction. The aim of our study was to evaluate the relationship between the degree of dyspnea and exercise capacity in subjects with COPD who had the same severity of air-flow obstruction. METHODS: We assessed dyspnea perception and maximum exercise capacity by using the modified Medical Research Council dyspnea scale (mMRC) questionnaire and by using the symptom-limited incremental cardiopulmonary exercise test, respectively. A propensity score matching was used to obtain the balance between the subjects with COPD and with an mMRC questionnaire score <2 and >=2 (mMRC score) according to the severity of air-flow obstruction. RESULTS: A total of 249 ambulatory adult patients with stable COPD (mean age, 68 y) were considered in the full cohort. After propensity score analysis, 160 subjects (65% men; mean +/- SD FEV1, 47.5 +/- 12.8% of predicted) were included in our study cohort. The subjects with an mMRC questionnaire score >=2 in comparison with those with an mMRC questionnaire score <2 showed lower values in oxygen uptake at peak (VO2 max) (P = .002) and in maximum work load (P < .001). In the regression models, the mMRC questionnaire score was able to predict oxygen uptake at peak (P < .001) and at maximum work load (P < .001). CONCLUSIONS: In subjects with COPD and with the same severity of air-flow obstruction, a high score in dyspnea was related to a poor maximum exercise capacity. Our results support the view that, in COPD, the severity of air-flow obstruction was less informative than symptoms in the combined assessment of the disease. PMID- 30425168 TI - The Risk of Latent Tuberculosis Infection in Respiratory Therapists in a Country with Intermediate Incidence. AB - BACKGROUND: Respiratory therapists (RTs) are exposed to aerosols more frequently than other health care workers (HCWs) and might bear a higher risk for tuberculosis (TB) infection. The QuantiFERON-TB Gold (QFTG) test was used to evaluate the risk for TB infection in Taiwan, a country with intermediate TB incidence. METHODS: A cross-sectional screening of HCWs, including RTs and other HCWs, with the QFTG test was conducted in Taiwan between October 2008 and December 2011. Those with initially negative QFTG results accepted repeated QFTG testing 1 y later. The positive rates of QFTG in RTs and other HCWs were compared. The risk factors for positive QFTG and QFTG conversion, including occupational group, age, duration of employment, and gender, were analyzed. RESULTS: A total of 274 HCWs were enrolled, including 43 RTs, 163 nurses, and 68 other HCWs. The positive rates of QFTG were 14.0% in RTs, 6.1% in nurses, and 8.8% in other HCWs, which were not significantly different among the 3 groups. Multivariate analysis demonstrated that the risk for positive QFTG positively correlated with increased age and the duration of employment, but did not relate to gender or occupational group. Of 81 HCWs with initially negative QFTG results, 4 (4.9%) had positive conversion on repeat QFTG testing 1 y later. The risk for QFTG conversion in HCWs was not related to occupational group, gender, age, or duration of employment. CONCLUSION: RTs had no higher risk for latent TB infection than other HCWs in a country with intermediate TB incidence. PMID- 30425169 TI - Urinary angiotensinogen as a biomarker for acute to chronic kidney injury transition - prognostic and mechanistic implications. AB - Accurate biomarkers that both predict the progression to, and detect the early stages of chronic kidney disease (CKD) are lacking, resulting in difficulty in identifying individuals who could potentially benefit from targeted intervention. In a recent issue [Clinical Science (2018) 132, 2121-2133], Cui et al. examine the ability of urinary angiotensinogen (uAGT) to predict the progression of acute kidney injury (AKI) to CKD. They principally employ a murine ischaemia reperfusion injury model to study this and provide data from a small prospective study of patients with biopsy proven acute tubular necrosis. The authors suggest that uAGT is a dynamic marker of renal injury that could be used to predict the likelihood of structural recovery following AKI. Here we comment on their findings, exploring the clinical utility of uAGT as a biomarker to predict AKI to CKD transition and perhaps more controversially, to discuss whether the early renin-angiotensin system blockade following AKI represents a therapeutic target. PMID- 30425170 TI - Double dissociation of single-interval and rhythmic temporal prediction in cerebellar degeneration and Parkinson's disease. AB - Predicting the timing of upcoming events is critical for successful interaction in a dynamic world, and is recognized as a key computation for attentional orienting. Temporal predictions can be formed when recent events define a rhythmic structure, as well as in aperiodic streams or even in isolation, when a specified interval is known from previous exposure. However, whether predictions in these two contexts are mediated by a common mechanism, or by distinct, context dependent mechanisms, is highly controversial. Moreover, although the basal ganglia and cerebellum have been linked to temporal processing, the role of these subcortical structures in temporal orienting of attention is unclear. To address these issues, we tested individuals with cerebellar degeneration or Parkinson's disease, with the latter serving as a model of basal ganglia dysfunction, on temporal prediction tasks in the subsecond range. The participants performed a visual detection task in which the onset of the target was predictable, based on either a rhythmic stream of stimuli, or a single interval, specified by two events that occurred within an aperiodic stream. Patients with cerebellar degeneration showed no benefit from single-interval cuing but preserved benefit from rhythm cuing, whereas patients with Parkinson's disease showed no benefit from rhythm cuing but preserved benefit from single-interval cuing. This double dissociation provides causal evidence for functionally nonoverlapping mechanisms of rhythm- and interval-based temporal prediction for attentional orienting, and establishes the separable contributions of the cerebellum and basal ganglia to these functions, suggesting a mechanistic specialization across timing domains. PMID- 30425171 TI - Nonmutational mechanism of inheritance in the Archaeon Sulfolobus solfataricus. AB - Epigenetic phenomena have not yet been reported in archaea, which are presumed to use a classical genetic process of heritability. Here, analysis of independent lineages of Sulfolobus solfataricus evolved for enhanced fitness implicated a non Mendelian basis for trait inheritance. The evolved strains, called super acid resistant Crenarchaeota (SARC), acquired traits of extreme acid resistance and genome stability relative to their wild-type parental lines. Acid resistance was heritable because it was retained regardless of extensive passage without selection. Despite the hereditary pattern, in one strain, it was impossible for these SARC traits to result from mutation because its resequenced genome had no mutation. All strains also had conserved, heritable transcriptomes implicated in acid resistance. In addition, they had improved genome stability with absent or greatly decreased mutation and transposition relative to a passaged control. A mechanism that would confer these traits without DNA sequence alteration could involve posttranslationally modified archaeal chromatin proteins. To test this idea, homologous recombination with isogenic DNA was used to perturb native chromatin structure. Recombination at up-regulated loci from the heritable SARC transcriptome reduced acid resistance and gene expression in the majority of recombinants. In contrast, recombination at a control locus that was not part of the heritable transcriptome changed neither acid resistance nor gene expression. Variation in the amount of phenotypic and expression changes across individuals was consistent with Rad54-dependent chromatin remodeling that dictated crossover location and branch migration. These data support an epigenetic model implicating chromatin structure as a contributor to heritable traits. PMID- 30425173 TI - Reply to O'Sullivan: Wicked problems demand sophisticated understandings of complexity and feedbacks, not focus on a single variable. PMID- 30425172 TI - Monomerization of far-red fluorescent proteins. AB - Anthozoa-class red fluorescent proteins (RFPs) are frequently used as biological markers, with far-red (lambdaem ~ 600-700 nm) emitting variants sought for whole animal imaging because biological tissues are more permeable to light in this range. A barrier to the use of naturally occurring RFP variants as molecular markers is that all are tetrameric, which is not ideal for cell biological applications. Efforts to engineer monomeric RFPs have typically produced dimmer and blue-shifted variants because the chromophore is sensitive to small structural perturbations. In fact, despite much effort, only four native RFPs have been successfully monomerized, leaving the majority of RFP biodiversity untapped in biomarker development. Here we report the generation of monomeric variants of HcRed and mCardinal, both far-red dimers, and describe a comprehensive methodology for the monomerization of red-shifted oligomeric RFPs. Among the resultant variants is mKelly1 (emission maximum, lambdaem = 656 nm), which, along with the recently reported mGarnet2 [Matela G, et al. (2017) Chem Commun (Camb) 53:979-982], forms a class of bright, monomeric, far-red FPs. PMID- 30425174 TI - Is failure to develop due to fundamentally different economic pathways or simply too much population growth? PMID- 30425175 TI - Reply to Charra et al.: Global longitudinal assessment of 2019 changes in defined daily doses. PMID- 30425176 TI - Penicillins' defined daily doses must be changed. PMID- 30425177 TI - Reply to Novembre and Iannetti: Conceptual and methodological issues. PMID- 30425178 TI - Tagging the musical beat: Neural entrainment or event-related potentials? PMID- 30425179 TI - How Does a Supervised Exercise Program Improve Quality of Life in Patients with Cancer? A Concept Mapping Study Examining Patients' Perspectives. AB - BACKGROUND: Previous systematic reviews and meta-analyses demonstrated beneficial effects of exercise during or following cancer treatment on quality of life (QoL). Aiming to understand how exercise contributes to a patient's QoL, we examined patients' perspectives via a process called concept mapping. This unique method provides structure and objectivity to rich qualitative data. METHODS: Patients with cancer who were participating in an exercise program were invited to enroll. Eleven meetings with 3-10 patients were organized in which patients generated ideas in response to the question "How has participating in a supervised exercise program contributed positively to your QoL?" Next, patients individually clustered (based on similarity) and rated (based on importance) the ideas online. The online assessments were combined, and one concept map was created, visualizing clusters of ideas of how patients perceive that participating in a supervised exercise program improved their QoL. The research team labelled the clusters of ideas, and physiotherapists reflected on the clusters during semistructured interviews. RESULTS: Sixty patients attended the meetings; of these, one patient was not able to generate an idea in response to the statement. Forty-four patients completed the online clustering and rating of ideas. The resulting concept map yielded six clusters: personalized care, coaching by a physiotherapist, social environment, self-concept, coping, and physical fitness and health. Personalized care was rated as most important. Overall, physiotherapists recognized these clusters in practice. CONCLUSION: Patients with cancer reported that participating in a supervised exercise program improved their physical fitness and influenced social, mental, and cognitive factors, resulting in improvements in QoL. These results can be used to increase the awareness of the importance of supervised exercise programs for the QoL of patients with cancer. IMPLICATIONS FOR PRACTICE: According to patients, a supervised exercise program contributes positively to their quality of life by improving physical fitness and health and providing personalized care, coaching by a physiotherapist, and improved social environment, self-concept, and coping. This knowledge could help to increase physicians' and patients' awareness of the importance of an exercise program during or following cancer treatment, possibly improving referral, participation, and adherence rates to these programs. Furthermore, patients' perspectives may be used to improve supervised exercise programs, taking into account the importance of personalized care, the supervision of a physiotherapist, the social environment, self-concept, and coping. PMID- 30425181 TI - Opinion: Soil carbon sequestration is an elusive climate mitigation tool. PMID- 30425184 TI - 31st Annual Scientific Meeting of The Hong Kong Neurological Society. PMID- 30425183 TI - Hong Kong domestic health spending: financial years 1989/90 to 2014/15. PMID- 30425180 TI - aCGH Analysis of Predictive Biomarkers for Response to Bevacizumab plus Oxaliplatin- or Irinotecan-Based Chemotherapy in Patients with Metastatic Colorectal Cancer. AB - BACKGROUND: The randomized phase III study (WJOG4407G) showed equivalent efficacy between FOLFOX and FOLFIRI in combination with bevacizumab as the first-line treatment for metastatic colorectal cancer (mCRC). We studied whole genome copy number profiles using array-based comparative genomic hybridization (aCGH) analysis of tumor tissue samples obtained in this study. The aim of this study was to identify gene copy number alterations that could aid in selecting either FOLFOX or FOLFIRI in combination with bevacizumab for patients with mCRC. MATERIALS AND METHODS: DNA was purified from 154 pretreatment formalin-fixed paraffin-embedded tissue samples (75 from the FOLFOX arm and 79 from the FOLFIRI arm) of 395 patients enrolled in the WJOG4407G trial and analyzed by aCGH. Genomic regions greater than 1.2-fold were regarded as copy number gain (CNG). RESULTS: Patient characteristics between the treatment arms were well balanced except for tumor laterality (left side; 64% in FOLFOX arm and 80% in FOLFIRI arm, p = .07). FOLFIRI showed a trend toward better response rate (RR), progression free survival (PFS) and overall survival (OS) than FOLFOX in the patients with CNG of chromosome 8q24.1 (Fisher's exact test, p = .134 for RR; interaction test, p = .102 for PFS and p = .003 for OS) and 8q24.2 (Fisher's exact test, p = .179 for RR; interaction test, p = .144 for PFS and p = .002 for OS). CONCLUSION: Chromosome 8q24.1-q24.2 may contain genes that could potentially serve as predictive markers for selecting either FOLFOX or FOLFIRI in combination with bevacizumab for treatment of patients with mCRC. IMPLICATIONS FOR PRACTICE: Bevacizumab has been used as a standard first-line treatment for patients with metastatic colorectal cancer (mCRC) in combination with either oxaliplatin-based or irinotecan-based chemotherapy. Until now, there has been no predictive marker to choose between the two combination chemotherapies. This array-based comparative genomic hybridization analysis revealed that the difference in therapeutic effect between the two combination chemotherapies is prominent in patients with mCRC with gene copy number gain in chromosome 8p24.1-p24.2. Such patients showed more favorable response and survival when treated with irinotecan based combination chemotherapy. Overlapping genes commonly found in this region may be predictive biomarkers of the efficacy of the combination chemotherapy with bevacizumab. PMID- 30425185 TI - Aging clocks: disrupted circadian rhythms. PMID- 30425186 TI - Uncoupling protein 4 (UCP4) gene variability in neurodegenerative disorders: further evidence of association in Frontotemporal dementia. AB - Ongoing research suggests that mitochondrial dysfunction is a common hallmark in neurodegenerative diseases, pointing to mitochondrial uncoupling process as a critical player. We recently reported that rs9472817-C/G, an intronic variant of neuronal mitochondrial uncoupling protein-4 (UCP4/SLC25A27) gene affects the risk of late onset Alzheimer's disease (LOAD), and that the variant's effect is strongly dependent on APOE-epsilon4 status. Here, we extended our analysis to a cohort of 751 subjects including late-onset familial and sporadic cases of frontotemporal dementia (FTD; 213), Parkinson disease (PD;96), and 442 healthy controls. In all subgroups, carriers of APOE-epsilon4 allele were at higher risk of disease. Regarding the rs9472817, no association was detected in familial FTD and both subgroups of PD patients. In sporadic FTD, as in LOAD, we found that the C allele increased the risk of disease of about 1.51-fold in a dose-dependent manner (p=0.013) independently from that conferred by APOE-epsilon4. Expression quantitative trait loci (eQTL) data of different brain regions suggest that rs9472817 likely exerts its effect by a cis-regulatory mechanism involving modulation of UCP4. If validated, the involvement of UCP4 in both FTD and LOAD might indicate interesting shared etiological factors which might give future therapeutic clues. PMID- 30425187 TI - APP signaling in Alzheimer's disease. PMID- 30425188 TI - Aging and drug discovery. AB - Multiple interventions in the aging process have been discovered to extend the healthspan of model organisms. Both industry and academia are therefore exploring possible transformative molecules that target aging and age-associated diseases. In this overview, we summarize the presented talks and discussion points of the 5th Annual Aging and Drug Discovery Forum 2018 in Basel, Switzerland. Here academia and industry came together, to discuss the latest progress and issues in aging research. The meeting covered talks about the mechanistic cause of aging, how longevity signatures may be highly conserved, emerging biomarkers of aging, possible interventions in the aging process and the use of artificial intelligence for aging research and drug discovery. Importantly, a consensus is emerging both in industry and academia, that molecules able to intervene in the aging process may contain the potential to transform both societies and healthcare. PMID- 30425189 TI - Methanolic extract of Tamarix Gallica attenuates hyperhomocysteinemia induced AD like pathology and cognitive impairments in rats. AB - Although few drugs are available today for the management of Alzheimer's disease (AD) and many plants and their extracts are extensively employed in animals' studies and AD patients, yet no drug or plant extract is able to reverse AD symptoms adequately. In the present study, Tamarix gallica (TG), a naturally occurring plant known for its strong antioxidative, anti-inflammatory and anti amyloidogenic properties, was evaluated on homocysteine (Hcy) induced AD-like pathology and cognitive impairments in rats. We found that TG attenuated Hcy induced oxidative stress and memory deficits. TG also improved neurodegeneration and neuroinflammation by upregulating synaptic proteins such as PSD95 and synapsin 1 and downregulating inflammatory markers including CD68 and GFAP with concomitant decrease in proinflammatory mediators interlukin-1beta (IL1beta) and tumor necrosis factor alpha (TNFalpha). TG attenuated tau hyperphosphorylation at multiple AD-related sites through decreasing some kinases and increasing phosphatase activities. Moreover, TG rescued amyloid-beta (Abeta) pathology through downregulating BACE1. Our data for the first time provide evidence that TG attenuates Hcy-induced AD-like pathological changes and cognitive impairments, making TG a promising candidate for the treatment of AD-associated pathological changes. PMID- 30425190 TI - Big Data Research in Chronic Kidney Disease. PMID- 30425191 TI - Predictive Score Model for Delayed Graft Function Based on Hypothermic Machine Perfusion Variables in Kidney Transplantation. AB - Background: Hypothermic machine perfusion (HMP) is being used more often in cardiac death kidney transplantation; however, the significance of assessing organ quality and predicting delayed graft function (DGF) by HMP parameters is still controversial. Therefore, we used a readily available HMP variable to design a scoring model that can identify the highest risk of DGF and provide the guidance and advice for organ allocation and DCD kidney assessment. Methods: From September 1, 2012 to August 31, 2016, 366 qualified kidneys were randomly assigned to the development and validation cohorts in a 2:1 distribution. The HMP variables of the development cohort served as candidate univariate predictors for DGF. The independent predictors of DGF were identified by multivariate logistic regression analysis with a P < 0.05. According to the odds ratios (ORs) value, each HMP variable was assigned a weighted integer, and the sum of the integers indicated the total risk score for each kidney. The validation cohort was used to verify the accuracy and reliability of the scoring model. Results: HMP duration (OR = 1.165, 95% confidence interval [CI]: 1.008-1.360, P = 0.043), resistance (OR = 2.190, 95% CI: 1.032-10.20, P < 0.001), and flow rate (OR = 0.931, 95% CI: 0.894-0.967, P = 0.011) were the independent predictors of identified DGF. The HMP predictive score ranged from 0 to 14, and there was a clear increase in the incidence of DGF, from the low predictive score group to the very high predictive score group. We formed four increasingly serious risk categories (scores 0-3, 4 7, 8-11, and 12-14) according to the frequency associated with the different risk scores of DGF. The HMP predictive score indicates good discriminative power with a c-statistic of 0.706 in the validation cohort, and it had significantly better prediction value for DGF compared to both terminal flow (P = 0.012) and resistance (P = 0.006). Conclusion: The HMP predictive score is a good noninvasive tool for assessing the quality of DCD kidneys, and it is potentially useful for physicians in making optimal decisions about the organs donated. PMID- 30425192 TI - Renoprotection Provided by Dipeptidyl Peptidase-4 Inhibitors in Combination with Angiotensin Receptor Blockers in Patients with Type 2 Diabetic Nephropathy. AB - Background: Treatment with the dipeptidyl peptidase-4 inhibitors (DPP4i) and angiotensin receptor blockers (ARBs) in patients with type 2 diabetic nephropathy (DN) has not been well characterized. This study aimed to assess the renoprotection of this combined treatment in DN patients. Methods: A total of 159 type 2 DN patients from 2013 to 2015 were enrolled retrospectively from a prospective DN cohort at the National Clinical Research Center of Kidney Diseases, Jinling Hospital (China). Fifty-seven patients received DPP4i and ARB treatment, and 102 patients were treated with ARBs alone. All patients were followed up for at least 12 months. Statistical analyses were performed using Stata version 12.0. Results: There were no significant differences at baseline for age, sex, body mass index, duration of diabetes, fasting blood glucose (FBG), hemoglobin A1c (HbA1c), and estimated glomerular filtration rate (eGFR) between the two groups. Antihypertensive and antidiabetic medication use was similar in each group except calcium channel antagonists (P = 0.032). No significant changes in FBG and HbA1c were observed in the two groups after treatment. The eGFR decreased slower in the DPP4i + ARB group than in the ARB group at 12 months (Delta12 months: -2.48 +/- 13.86 vs. -6.81 +/- 12.52 ml.min-1.1.73m-2, P = 0.044). In addition, proteinuria was decreased further in the DPP4i + ARB group than in the ARB group after 24 months of treatment (Delta24 months: -0.18 [-1.00, 0.17] vs. 0.32 [-0.35, 0.88], P = 0.031). There were 36 patients with an eGFR decrease of more than 30% over 24 months. After adjusting for FBG, HbA1c, and other risk factors, DPP4i + ARB treatment was still associated with a reduced incidence of an eGFR decrease of 20% or 30%. Conclusions: The combined treatment of DPP4i and ARBs is superior to ARBs alone, as evidenced by the greater proteinuria reduction and lower eGFR decline. In addition, the renoprotection of DPP4i combined with ARBs was independent of glycemic control. PMID- 30425193 TI - New Mutation of Coenzyme Q10 Monooxygenase 6 Causing Podocyte Injury in a Focal Segmental Glomerulosclerosis Patient. AB - Background: Focal segmental glomerulosclerosis (FSGS) is a kidney disease that is commonly associated with proteinuria and the progressive loss of renal function, which is characterized by podocyte injury and the depletion and collapse of glomerular capillary segments. The pathogenesis of FSGS has not been completely elucidated; however, recent advances in molecular genetics have provided increasing evidence that podocyte structural and functional disruption is central to FSGS pathogenesis. Here, we identified a patient with FSGS and aimed to characterize the pathogenic gene and verify its mechanism. Methods: Using next generation sequencing and Sanger sequencing, we screened the causative gene that was linked to FSGS in this study. The patient's total blood RNA was extracted to validate the messenger RNA (mRNA) expression of coenzyme Q10 monooxygenase 6 (COQ6) and validated it by immunohistochemistry. COQ6 knockdown in podocytes was performed in vitro with small interfering RNA, and then, F-actin was determined using immunofluorescence staining. Cell apoptosis was evaluated by flow cytometry, the expression of active caspase-3 was determined by Western blot, and mitochondrial function was detected by MitoSOX. Results: Using whole-exome sequencing and Sanger sequencing, we screened a new causative gene, COQ6, NM_182480: exon1: c.G41A: p.W14X. The mRNA expression of COQ6 in the proband showed decreased. Moreover, the expression of COQ6, which was validated by immunohistochemistry, also had the same change in the proband. Finally, we focused on the COQ6 gene to clarify the mechanism of podocyte injury. Flow cytometry showed significantly increased in apoptotic podocytes, and Western blotting showed increases in active caspase-3 in si-COQ6 podocytes. Meanwhile, reactive oxygen species (ROS) levels were increased and F-actin immunofluorescence was irregularly distributed in the si-COQ6 group. Conclusions: This study reported a possible mechanism for FSGS and suggested that a new mutation in COQ6, which could cause respiratory chain defect, increase the generation of ROS, destroy the podocyte cytoskeleton, and induce apoptosis. It provides basic theoretical basis for the screening of FSGS in the future. PMID- 30425194 TI - Beneficial Effect of Moderately Increasing Hypothermic Machine Perfusion Pressure on Donor after Cardiac Death Renal Transplantation. AB - Background: Vascular resistance and flow rate during hypothermic machine perfusion (HMP) of kidneys is correlated with graft function. We aimed to determine the effects of increasing HMP pressure versus maintaining the initial pressure on kidney transplantation outcomes. Methods: We retrospectively reviewed the data of 76 primary transplantation patients who received HMP-preserved kidneys from 48 donors after cardiac death between September 1, 2013, and August 31, 2015. HMP pressure was increased from 30 to 40 mmHg (1 mmHg = 0.133 kPa) in kidneys with poor flow and/or vascular resistance (increased pressure [IP] group; 36 patients); otherwise, the initial pressure was maintained (constant pressure group; 40 patients). Finally, the clinical characteristics and transplantation outcomes in both groups were assessed. Results: Delayed graft function (DGF) incidence, 1-year allograft, patient survival, kidney function recovery time, and serum creatinine level on day 30 were similar in both groups, with improved flow and resistance in the IP group. Among patients with DGF, kidney function recovery time and DGF duration were ameliorated in the IP group. Multivariate logistic regression analysis revealed that donor hypertension (odds ratio [OR]: 1.43, 95% confidence interval [CI]: 1.02-2.06, P = 0.035), donor terminal serum creatinine (OR: 1.27, 95% CI: 1.06-1.62, P = 0.023), warm ischemic time (OR: 3.45, 95% CI: 1.97-6.37, P = 0.002), and terminal resistance (OR: 3.12, 95% CI: 1.76-6.09, P = 0.012) were independent predictors of DGF. Cox proportional hazards analysis showed that terminal resistance (hazard ratio: 2.06, 95% CI: 1.32-5.16, P = 0.032) significantly affected graft survival. Conclusion: Increased HMP pressure improves graft perfusion but does not affect DGF incidence or 1-year graft survival. PMID- 30425195 TI - Efficacy and Safety of Tofacitinib in Chinese Patients with Rheumatoid Arthritis. AB - Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This study assessed the efficacy and safety of tofacitinib in Chinese patients with RA enrolled in Phase 3 and long-term extension (LTE) studies. Methods: ORAL Sync was a 1-year, randomized, placebo controlled, Phase 3 trial. Patients received tofacitinib 5 or 10 mg twice daily (BID) or placebo advanced to tofacitinib 5 or 10 mg BID at 3 or 6 months. All patients remained on >=1 background conventional synthetic disease-modifying antirheumatic drug. ORAL Sequel is an open-label LTE study (data-cut: March 2015; data collection and analyses were ongoing, and study database was not locked at the time of analysis; study was closed in 2017). Efficacy outcomes: American College of Rheumatology (ACR) 20/50/70 response rates and Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-4 [ESR]). Patient- and physician-reported outcomes: Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient and Physician Global Assessment of Arthritis, and pain (visual analog scale). Safety was assessed throughout. Results: ORAL Sync included 218 patients; 192 were subsequently enrolled into ORAL Sequel. In ORAL Sync, more patients achieved ACR20 (tofacitinib 5 mg BID, 67.4%; 10 mg BID, 70.6%; placebo, 34.1%) and DAS28-4 (ESR) <2.6 (tofacitinib 5 mg BID, 7.1%; 10 mg BID, 13.1%; placebo, 2.3%) with tofacitinib versus placebo at Month 6. Mean changes from baseline in HAQ-DI were greater with tofacitinib versus placebo at Month 6. In ORAL Sequel, efficacy was consistent to Month 48. Incidence rates for adverse events of special interest in tofacitinib-treated patients were similar to the global population. Conclusions: Tofacitinib significantly reduced signs/symptoms and improved physical function and quality of life in Chinese patients with moderate-to-severely active RA up to Month 48. The safety profile was consistent with the global population. Clinical Trial Identifier: NCT00856544 and NCT00413699. PMID- 30425196 TI - Validation of Predictive Value of Patterns of Nonadherence to Antiplatelet Regimen in Stented Patients Thrombotic Risk Score in Chinese Population Undergoing Percutaneous Coronary Intervention: A Prospective Observational Study. AB - Background: The patterns of nonadherence to antiplatelet regimen in stented patients (PARIS) thrombotic risk score are a novel score for predicting the risk of coronary thrombotic events (CTEs) after percutaneous coronary intervention (PCI) with drug-eluting stents. However, the prognostic value of this score has not been fully evaluated in non-Euro-American PCI populations. Methods: We performed a prospective, observational study of 10,724 patients who underwent PCI in Fuwai hospital, China and evaluated the PARIS thrombotic risk score's predictive value of CTEs in the PCI population. The area under the receiver operating characteristic curve (AUROC) was used to assess the predictive value of the PARIS score for CTE. Results: Among 9782 patients without in-hospital events, a total of 95 CTEs occurred during the 2-year follow-up. The PARIS score was significantly higher in patients with CTEs (3.38 +/- 2.04) compared with patients without events (2.53 +/- 1.70, P < 0.001). According to the risk stratification of the PARIS thrombotic score, the risk of CTEs in the high-risk group was 3.14 times higher than that in the low-risk group (hazard ratio [HR], 3.14; 95% confidence interval [CI], 1.92-5.13; P < 0.001). However, the risk of CTEs in the intermediate-risk and low-risk groups was not significant (HR, 1.39; 95% CI, [0.86-2.24]; P = 0.184). The PARIS score showed prognostic value in evaluating CTEs in the overall population (AUROC, 0.621; 95% CI, 0.561-0.681), the acute coronary syndrome (ACS) population (AUROC, 0.617; 95% CI, 0.534-0.700; P = 0.003), and the non-ACS population (AUROC, 0.647; 95% CI, 0.558-0.736; P = 0.001). Conclusions: In a real-world Chinese population, the PARIS thrombotic risk score shows a modest prognostic value for CTEs in patients after PCI. This score also has a predictive value for CTEs in the ACS and non-ACS subgroup populations. PMID- 30425197 TI - Clinical, Neuroimaging, and Pathological Analyses of 13 Chinese Leigh Syndrome Patients with Mitochondrial DNA Mutations. AB - Background: Leigh syndrome (LS) is a rare disease caused by mitochondrial defects and has high phenotypic and genotypic heterogeneity. We analyzed the clinical symptoms, neuroimaging, muscular histopathology, and genotypes of 13 Chinese LS patients with mitochondrial DNA (mtDNA) mutations. Methods: Mutations in mtDNA were identified by targeted sequencing. The brain imaging features on magnetic resonance imaging (MRI) were analyzed. The levels of lactate in fasting blood and cerebrospinal fluid (CSF) were routinely tested. The levels of urinary organic acids, plasma amino acids, and acylcarnitines were examined with gas chromatography-mass spectrometry and tandem mass spectrometry. The histopathological traits of skeletal muscles were analyzed under microscope. Results: Among 13 patients, mutations of MT-NDs (n = 8) and MT-ATP6 (n = 4) genes were most common. Strabismus (8/13), muscle weakness (8/13), and ataxia (5/13) were also common, especially for the patients with late-onset age after 2 years old. However, respiratory distress was common in patients with early-onset age before 2 years old. The most frequently affected brain area in these patients was the brain stem (12/13), particularly the dorsal part of midbrain, followed by basal ganglia (6/13), thalamus (6/13), cerebellum (5/13), and supratentorial white matter (2/13). Besides, the elevated lactate levels in CSF (6/6) were more common than those in serum (7/13). However, the analysis of abnormal plasma amino acid and urinary organic acid showed limited results (0/3 and 1/4, respectively). Muscular histopathology showed mitochondrial myopathy in the three late-onset patients but not in the early-onset ones. Conclusions: Noninvasive genetic screening is recommended for mtDNA mutations in MT-NDs and MT-ATP6 genes in patients with ophthalmoplegia, muscle weakness, ataxia, and respiratory disorder. Furthermore, the lactate detection in CSF and the brain MRI scanning are suggested as the diagnosis methods for LS patients with mtDNA mutations. PMID- 30425198 TI - Purinergic 2X7 Receptor is Involved in the Podocyte Damage of Obesity-Related Glomerulopathy via Activating Nucleotide-Binding and Oligomerization Domain-Like Receptor Protein 3 Inflammasome. AB - Background: The nucleotide-binding and oligomerization domain-like receptor protein 3 (NLRP3) inflammasome composed of NLRP3, apoptosis-associated speck-like protein containing CARD (ASC), and caspase-1 is engaged in the inflammatory response of many kidney diseases and can be activated by purinergic 2X7 receptor (P2X7R). This study was conducted to explore whether P2X7R plays a pathogenic role in the podocyte damage of obesity-related glomerulopathy (ORG) and whether this role is mediated by the activation of NLRP3 inflammasome. Methods: A mouse model of ORG was established by high-fat diet feeding. The conditionally immortalized mouse podocytes were cultured with leptin or with leptin and P2X7R antagonist (KN-62 or A438079). The mRNA and protein expression of the P2X7R and NLRP3 inflammasome components including NLRP3, ASC, and caspase-1, as well as the podocyte-associated molecules including nephrin, podocin, and desmin in mouse renal cortex or cultured mouse podocytes were tested by real-time-polymerase chain reaction and Western blot analysis, respectively. Results: The significantly upregulated expression of P2X7R and NLRP3 inflammasome components and the NLRP3 inflammasome activation were observed in the renal cortex (in fact their location in podocytes was proved by confocal microscopy) of ORG mice in vivo, which were accompanied with the morphological changes of podocyte damage and the expression changes of podocyte-associated molecules. Similar changes in the expression of P2X7R and NLRP3 inflammasome components as well as in the expression of podocyte-associated molecules were also observed in the cultured podocyte studies treated by leptin in vitro, and all of the above changes were significantly attenuated by the P2X7R antagonist KN-62 or A438079. Conclusions: P2X7R could trigger the activation of NLRP3 inflammasome, and the activated P2X7R/NLRP3 inflammasome in podocytes might be involved in the podocyte damage of ORG. PMID- 30425199 TI - Effect of Endothelial Microparticles Induced by Hypoxia on Migration and Angiogenesis of Human Umbilical Vein Endothelial Cells by Delivering MicroRNA 19b. AB - Background: Microparticles (MPs) are small extracellular plasma membrane particles shed by activated and apoptotic cells, which are involved in the development of atherosclerosis. Our previous study found that microRNA (miR)-19b encapsulated within endothelial MPs (EMPs) may contribute to the upregulation of circulating miR-19b in unstable angina patients. Hypoxia is involved in atherosclerosis as a critical pathological stimulus. However, it still remains unclear whether the increase of miR-19b levels in EMPs is related to hypoxia and if the effect of miR-19b - wrapped within EMPs - stimulates hypoxia on vascular endothelial cells. This study aimed to explore the changes of miR-19b in EMPs induced by hypoxia as well as their effects on endothelial cells. Methods: Human umbilical vein endothelial cells (HUVECs) were cultured in vitro and arranged to harvest EMPs in two parts: the first part consisted of EMPcontrol and EMPhypoxia and the second part included EMPvehicle, EMPNC mimic, and EMPmiR-19b mimic. Cell migration was detected by scratch migration and transwell chamber migration. Angiogenesis was assessed by tube formation assays. Furthermore, we predicted the target gene of miR-19b by bioinformatics analysis, and luciferase assay was used to verify the targeted gene of miR-19b. Data were analyzed by one-way analysis of variance. Student's t-test was used when two groups were compared. Results: Compared with EMPcontrol- and EMPhypoxia-inhibited migration of cells by scratch migration assay (80.77 +/- 1.10 vs. 28.37 +/- 1.40, P < 0. 001) and transwell chamber migration assay (83.00 +/- 3.46 vs. 235.00 +/- 16.52, P < 0.01), the number of tube formations was markedly reduced by 70% in the EMPhypoxia group (P < 0.001) in vitro analysis of HUVECs. Meanwhile, a strong inhibition of migration and tube formation of HUVECs in the presence of miR-19b-enriched EMPmiR-19b mimic was observed. This effect might be due to the delivery of miR-19b in EMPs. Transforming growth factor-beta2 (TGFbeta2) was predicted to be one of the target genes of miR-19b, and we further confirmed that TGFbeta2 was a direct target gene of miR-19b using the luciferase assay. The expression of TGFbeta2 in HUVECs was inhibited by treatment with EMPhypoxia and EMPmiR-19b mimic. Conclusions: MiR-19b in EMPs induced by hypoxia could reduce endothelial cell migration and angiogenesis by downregulating TGFbeta2 expression, which may have inhibited the progression of atherosclerosis. PMID- 30425200 TI - Helicobacter pylori Infection is Associated with Occurrence of Proteinuria in Type 2 Diabetes Patients: A Systemic Review and Meta-Analysis. AB - Background: Type 2 diabetes (T2DM) patients are susceptible to Helicobacter pylori (HP), and it has been reported that the occurrence of proteinuria is associated with HP infection in T2DM patients; however, this view remains controversial. This meta-analysis aimed to explore the association between HP infection and the occurrence of proteinuria in T2DM patients. In addition, we hope to provide some recommendations to readers in clinical or related fields. Methods: Our meta-analysis was conducted with the methodology of the Cochrane Collaboration. Search strategies were formulated by relevant professionals. Case control studies that compared the occurrence of proteinuria in T2DM patients with and without HP infection were involved in our meta-analysis. Relevant English or Chinese studies were searched on online databases before 2018, including PubMed, the Cochrane library, Medline, Google Scholar, the China National Infrastructure, and Wanfang database. The search strategies were "diabetic proteinuria, diabetic microalbuminuria, diabetic albuminuria, diabetic kidney disease, diabetic renal dysfunction, diabetic renal disease, diabetic nephropathy, diabetic complications, and diabetic mellitus, combined with HP." The quality of these involved articles was separately assessed by two investigators using the Newcastle-Ottawa Scale (NOS). Odds ratios (ORs) and associated 95% confidence intervals (CIs) were extracted and pooled using fixed-effects models. Results: Seven studies involving 1029 participants were included. The quality of these seven articles was all above five stars as assessed by NOS, and there was no significant publication bias in our meta-analysis. We found that T2DM patients with HP infection had a 2.00 times higher risk of the occurrence of proteinuria than patients without HP infection (OR: 2.00, 95% CI: 1.48-2.69). Conclusions: Our analysis showed that HP infection was associated with the occurrence of proteinuria in T2DM patients. HP radical surgery might be a therapeutic option for protecting kidney function in patients with T2DM. PMID- 30425201 TI - Statistical Prediction in Pathological Types of Chronic Kidney Disease. PMID- 30425202 TI - Serum Metabolic Profiling in a Mouse Model of Adriamycin-Induced Focal Segmental Glomerulosclerosis. PMID- 30425203 TI - A Case of Podocytic Infolding Glomerulopathy with Primary Sjogren's Syndrome and Hashimoto's Thyroiditis. PMID- 30425205 TI - Mining and Correlation Analysis of Association Rules between Properties and Therapeutic Efficacy of Chinese Materia Medica Based on Strategy Pattern. PMID- 30425204 TI - Prevalence of Chronic Kidney Disease-Mineral Bone Disorder in Hemodialysis Patients in Hebei, China. PMID- 30425206 TI - A Rare Cause of Recurrent Fatal Hemoptysis: Dieulafoy's Disease of the Bronchus. PMID- 30425207 TI - Cardiac Resynchronization Therapy-Pacemaker Implantation Guided by Three Dimensional Electroanatomic Mapping for a Chinese Young Man with Danon Disease. PMID- 30425208 TI - Evaluation of the Spasticity after Botulinum Toxin Injection Using Paired-Pulse Transcranial Magnetic Stimulation. PMID- 30425209 TI - Severe Lymphopenia and Related T-cell Immunity in an Avian Influenza A (H7N9) Infected Patient. PMID- 30425210 TI - Stenting for Aorto-Ostial In-Stent Restenosis via Side Strut of an Excessively Protruding Stent Guided by Intracoronary Imaging. PMID- 30425211 TI - Renal Fibrosis and Mitochondrial Damage. PMID- 30425212 TI - Evidence-based global cardiovascular disease control priority interventions. PMID- 30425213 TI - Ketogenic diets: Boon or bane? PMID- 30425214 TI - Pancreatic ductal adenocarcinoma: Role of chemotherapy & future perspectives. PMID- 30425215 TI - Department of Health Research-Health Technology Assessment (DHR-HTA) database: National prospective register of studies under HTAIn. PMID- 30425216 TI - A fascinating story of the discovery & development of biologicals for use in clinical medicine. AB - A young physician starting a fresh career in medicine in this millennium would hardly stop to think about the genesis of a particular biological drug that he/she will be prescribing for a patient evaluated in the morning outpatient department. For him/her, this is now routine, and the question of 'Who', 'How' and 'When' about these biologicals would be the last thing on their mind. However, for those who came to the medical profession in the 1950s, 1960s and 1970s, these targeted drugs are nothing short of 'miracles'. It would be a fascinating story for the young doctor to learn about the long journey that the dedicated biomedical scientists of yesteryears took to reach the final destination of producing such wonder drugs. The story is much like an interesting novel, full of twists and turns, heart-breaking failures and glorious successes. The biologicals acting as 'targeted therapy' have not only changed the natural history of a large number of incurable/uncontrollable diseases but have also transformed the whole approach towards drug development. From the classical empirical process, there is now a complete shift towards understanding the disease pathobiology focusing on the dysregulated molecule(s), targeting them with greater precision and aiming for better results. Seminal advances in understanding the disease mechanism, development of remarkably effective new technologies, greater knowledge of the human genome and genetic medicine have all made it possible to reach the stage where artificially developed 'targeted' drugs are now therapeutically used in routine clinical medicine. PMID- 30425217 TI - National ethical guidelines for biomedical & health research involving human participants, 2017: A commentary. AB - The Indian Council of Medical Research (ICMR) has been at the forefront in setting up the ethical guidance for the conduct of biomedical and health research in India. The latest version of National Guidelines for Biomedical and Health Research Involving Human Participants, 2017 was planned in order to provide a more detailed guidance to the existing topics in view of emerging ethical concerns and to add a number of newer areas in which guidance was lacking. The scope of the guidelines has been expanded to include socio-behavioural research related to health and research involving biological material and datasets. The guidelines have 12 sections which cover a wide range of topics and areas of research. The first six sections are more generic, applying to all types of biomedical and health research, while the next six sections are more subject specific. The guidelines have been revised in consultation with a large number of experts and stakeholders and went through an exhaustive process stretching over a period of two years in its drafting, review, consultation and finalisation. This commentary seeks to explain the process and key components of the Guidelines. PMID- 30425218 TI - Experience with non-cremophor-based paclitaxel-gemcitabine regimen in advanced pancreatic cancer: Results from a single tertiary cancer centre. AB - Background & objectives: Gemcitabine combined with non-cremophor-based paclitaxel is one of the standards of care in advanced inoperable pancreatic cancer. This study was undertaken to retrospectively evaluate real world non-trial outcomes with this combination. Methods: Patients with histologically proven advanced inoperable pancreatic adenocarcinoma (PDAC), treated with non-cremophor-based paclitaxel-gemcitabine combination (PG) (gemcitabine-nanoxel or gemcitabine abraxane) between January 2012 and June 2015, were retrospectively analyzed. Response assessment was done every 8-12 wk with computed tomography scan and responses were measured as per the Response Evaluation Criteria in Solid Tumours 1.1 criteria where feasible. Toxicity was recorded as per the Common Terminology Criteria for Adverse Events (CTCAE) v4 criteria. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Results: A total of 78 patients with PDAC were treated with the combination. Of these, 83.3 per cent of patients had metastatic disease. The median number of chemotherapy cycles administered was three. The objective response rate for the whole group was 30.8 per cent. Grade III/IV toxicities were seen in 35.9 per cent of patients. Median PFS was 5.6 months and median OS was 11.6 months. Interpretation & conclusions: Non-cremophor-based paclitaxel in combination with gemcitabine appeared efficacious for advanced pancreatic cancers in routine clinical practice. Within the confines of a single-centre retrospective analysis, gemcitabine-nanoxel and gemcitabine-abraxane appeared to have similar efficacy and toxicity in advanced pancreatic cancers. PMID- 30425219 TI - Prevalence, clinical & biochemical correlates of non-alcoholic fatty liver disease in overweight adolescents. AB - Background & objectives: Non-alcoholic fatty liver disease (NAFLD) characterized by excessive accumulation of fat in the liver, which can progress to inflammation, and cirrhosis, has emerged as an important complication of obesity in adults as well as children. This study was undertaken to assess the prevalence of NAFLD and its correlation with clinical and biochemical parameters in overweight Indian adolescents. Methods: In this cross-sectional study, 218 overweight adolescents aged 10 to 16 yr and their parents were included. Measurements included anthropometry, ultrasonography to diagnose NAFLD, fasting glucose, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lipids for adolescents and parents, and additional parameters of blood pressure, body fat percentage (BF%), fasting insulin, apolipoprotein C3, tumour necrosis factor-alpha and adiponectin for adolescents. The variables were compared between adolescents with and without NAFLD, and logistic regression analysis was performed. Results: Mean age and body mass index (BMI)SD score (SDS) were 11.9+/ 1.6 yr and 2.3+/-1.1, respectively. NAFLD was seen in 62.5 per cent of the adolescents. The prevalence of NAFLD in the parents was similar among the adolescents with and without NAFLD, while BMI and waist circumference SDS, BF per cent, blood pressure (BP), ALT, AST, insulin and homeostatic model assessment of insulin resistance (HOMA-IR) were significantly higher in the adolescents with NAFLD. On multiple logistic regression, abdominal obesity, HOMA-IR and BF per cent were independently associated with NAFLD with odds ratios (95% confidence interval) of 2.77 (1.40-5.47), 2.21 (1.16-4.21) and 2.17 (1.12-4.22), respectively. Interpretation & conclusions: NAFLD was noted among nearly two thirds of the overweight adolescents. An independent association was observed between abdominal obesity, HOMA-IR and body fat percentage and NAFLD in overweight adolescents. PMID- 30425220 TI - Addition of power Doppler to grey scale transvaginal ultrasonography for improving the prediction of endometrial pathology in perimenopausal women with abnormal uterine bleeding. AB - Background & objectives: Transvaginal ultrasonography (TVS) is a non-invasive procedure and can be used as a screening tool among women with abnormal uterine bleeding (AUB). Power Doppler is useful in depicting the vascular architecture better than the conventional Doppler. Hence, this study was conducted to evaluate whether addition of power Doppler to grey scale TVS can replace invasive hysteroscopy for the prediction of endometrial pathology in perimenopausal women with AUB. Methods: One hundred women (>45 yr) with perimenopausal AUB underwent evaluation with TVS, power Doppler and hysteroscopy-guided biopsy after a detailed history and examination. Histopathology was considered as gold standard and other tools such as grey scale TVS with power Doppler and hysteroscopy were compared with it. Results: Fifty six per cent women had no vascularity on power Doppler. Among those who had vascularity, the vascular patterns noted were single vessel in 18 per cent, scattered-vessel in 15 per cent and multiple-vessel in 11 per cent. The sensitivity, specificity, positive predictive value and negative predictive value of TVS-endometrial thickness with power Doppler in detecting hyperplasia were 50, 86.5, 13.3 and 97.6 per cent, respectively, whereas the same for hysteroscopy were 100, 97.6, 88.1 and 100 per cent, respectively. Interpretation & conclusions: Addition of power Doppler to grey scale TVS improved the specificity and negative predictive value almost comparable to hysteroscopy for evaluation of AUB, but sensitivity and positive predictive value remained poor. PMID- 30425221 TI - Labour & delivery monitoring patterns in facility births across five districts of India: A cross-sectional observational study. AB - Background & objectives: India has recorded a marked increase in facility births due to government's conditional cash benefit scheme initiated in 2005. However, concerns have been raised regarding the need for improvement in the quality of care at facilities. Here we report the monitoring patterns during labour and delivery documented by direct observation in reference to the government's evidence-based guidelines on skilled birth attendance in five districts of India. Methods: A cross-sectional study design with multistage sampling was used for observation of labour and delivery processes of low-risk women with singleton pregnancy in five districts of the country. Trained research staff recorded the findings on pre-tested case record sheets. Results: A total of 1479 women were observed during active first stage of labour and delivery in 55 facilities. The overall frequency of monitoring of temperature, pulse and blood pressure was low at all facilities. The frequency of monitoring uterine contractions and foetal heart sounds was less than the expected norm, while the frequency of vaginal examinations was high at all levels of facilities. Partograph plotting was done in only 15.8 per cent deliveries, and labour was augmented in about half of the cases. Interpretation & conclusions: The findings of our study point towards a need for improvement in monitoring of maternal and foetal parameters during labour and delivery in facility births and to improve adherence to government guidelines for skilled birth attendance. PMID- 30425222 TI - Association of reduced count of interleukin-13-producing cells in breast milk with atopic dermatitis in infancy. AB - Background & objectives: Atopic dermatitis (AD) is one of the most common pathologic conditions of skin in children. The effect of breastfeeding on the risk of AD remains controversial. The aim of this study was to determine the counts of cytokine-producing cells in the mothers' breast milk of infants with and without AD to assess association, if any. Methods: Breast milk samples (10 ml) were obtained from mothers of 25 infants with AD and of 26 healthy infants as a control group. The number of cytokine-producing cells including interferon gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), interleukin-13 (IL 13) and IL-4 in the milk samples was determined using an enzyme-linked immunospot assay technique. Results: The mean of IL-13-producing cells in milk was significantly lower in mothers of AD-affected infants in comparison with mothers of normal infants (324.91+/-255.45 vs. 538.93+/-465.39, P<0.05). There were no significant differences between mothers of infants with and without AD regarding milk count of IFN-gamma-, TNF-alpha- and IL-4-producing cells. Interpretation & conclusions: Our results showed lower number of IL-13-producing cells in milk of mothers of infants with AD. Therefore, lower count of IL-13-producing cells in mothers' milk may confer a susceptibility to AD. Further studies with a large number of samples need to be done to confirm our findings. PMID- 30425223 TI - High frequency of HPV16 European variant E350G among Mexican women from Sinaloa. AB - Background & objectives: Human papillomavirus (HPV) infections play a crucial role in the aetiology of cervical cancer (CC), and HPV16 is the primary viral genotype associated with CC. A number of variants of the HPV16 E6 gene are involved in the progression of CC, differing in their prevalence and biological and biochemical properties. This study was designed to determine the frequency of HPV types 16/18 and to identify the presence of HPV16 E6-variants in asymptomatic Mexican women. Methods: A total of 189 cervical Pap smears were collected from women attending public health services in three different cities in Sinaloa, Mexico. Viral DNA was identified by amplification of E6 viral gene fragments using polymerase chain reaction (PCR). Identification of variants was done by sequencing a DNA fragment (321bp) of the HPV16 E6 gene. Results: More than half of the women tested were HPV-positive (52.38%), with HPV16 being the most frequent genotype (21.16%), followed by HPV18 (8.99%). Sequence analysis of the E6-HPV16 PCR products showed that in all cases, the viruses corresponded to European variants. It was further observed that the E350G intra-variant was the most common (>76%). Interpretation & conclusions: This study showed a predominance of European lineage variants of HPV16 among asymptomatic women from Sinaloa, Mexico, predominantly with of the E350G variant. This variant has been shown to be associated with an increased risk of early development of CC. The use of molecular identification of carcinogenic HPV and Pap test screening may be a good strategy for monitoring women to prevent CC. PMID- 30425224 TI - Respiratory viruses in returning Hajj & Umrah pilgrims with acute respiratory illness in 2014-2015. AB - Background & objectives: Respiratory tract infections are common among Hajj and Umrah pilgrims which pose a public health risk of spread of respiratory infections. Influenza has been reported from Indian Hajj and Umrah returning pilgrims, but data on other respiratory pathogens are sparse in India. Here we report the presence of common respiratory viral pathogens in returning Hajj and Umrah pilgrims suffering from acute respiratory illness (ARI) in 2014-2015. Methods: Respiratory specimens (nasopharyngeal and throat swabs) were collected from 300 consenting pilgrims with ARI in the past one week and tested for influenza and Middle East Respiratory Syndrome coronavirus (MERS-CoV) and other respiratory viruses using in-house standardized quantitative real-time reverse transcription polymerase chain reaction. Clinical features among the pathogen positive and negative patients were compared. The patients received symptomatic treatment and antivirals where appropriate and were followed telephonically to collect data on illness outcome. Results: Ninety seven (32.3%) of the 300 participants were tested positive for any virus, most common being influenza viruses (n=33, 11%). Other respiratory viruses that were detected included human coronaviruses [n=26, 8.7%; OC43 (n=19, 6.3%) and C229E (n=7, 2.3%)], rhinovirus (n=20, 6%), adenoviruses (n=8, 2.6%), parainfluenza viruses (n=7, 2.3%), respiratory syncytial virus (n=3, 1%) and bocaviruses (n=2, 0.6%). Clinical features observed in pathogen positive and pathogen negative patients did not differ significantly. Eighteen influenza positive patients were treated with oseltamivir. Interpretation & conclusions: Pilgrims returning from mass gatherings are often afflicted with respiratory pathogens with a potential to facilitate transmission of respiratory pathogens across international borders. The study reinforces the need for better infection prevention and control measures such as vaccination, health education on cough etiquette and hand hygiene. PMID- 30425226 TI - Do the clonally different Escherichia coli isolates causing different infections in a HIV positive patient affect the selection of antibiotics for their treatment? PMID- 30425227 TI - Reduction in prevalence of anaemia in pregnant women. PMID- 30425225 TI - Courtship activity, copulation & insemination success in a mosquito vector fed a herbal aphrodisiac: Implications for sterile insect technology. AB - Background & objectives: In sterile insect technology (SIT), mating competitiveness is a pre-condition for the reduction of target pest populations and a crucial parameter for judging efficacy. Still, current SIT trials are being hindered by decreased effectiveness due to reduced sexual performance of released males. Here, we explored the possible role of a herbal aphrodisiac in boosting the mating activity of Aedes aegypti. Methods: Males were fed one of two diets in this study: experimental extract of Eurycoma longifolia (MSAs) and sugar only (MSOs). Differences in life span, courtship latency, copulation activity and mating success were examined between the two groups. Results: No deaths occurred among MSA and MSO males. Life span of MSOs was similar to that of MSAs. The courtship latency of MSAs was shorter than that of MSOs (P<0.01). MSAs had greater copulation success than MSOs (P<0.001). In all female treatments, MSAs mated more than MSOs, but the differences in rate were significant only in the highest female density (P<0.05). In MSAs, mating success varied significantly with female density (P<0.01), with the 20-female group (P<0.01) having the lowest rate. Single MSA had better mating success at the two lowest female densities. In MSOs, there were no significant differences in mating success rate between the different female densities. Interpretation & conclusions: Our results suggested that the herbal aphrodisiac, E. longifolia, stimulated the sexual activity of Ae. aegypti and may be useful for improving the mating competitiveness of sterile males, thus improving SIT programmes. PMID- 30425228 TI - Authors' Response. PMID- 30425229 TI - Procalcitonin-guided antibiotic usage - addressing heterogeneity in meta analysis. PMID- 30425230 TI - Authors' Response. PMID- 30425231 TI - Langerhans cell histiocytosis. PMID- 30425232 TI - Chronic ulcer with rejected skin graft in a female: Pentazocine-induced skin ulcers revisited. PMID- 30425233 TI - Solitary Metastatic Lesion of the Tibia from Clear Cell Renal Carcinoma: A Case Report of Segmental Skeletal Resection, Intercalary Allograft Over Reamed Nailing and Soleus Flap Interposition. AB - BACKGROUND Renal cell carcinoma (RCC) is the most common malignancy of the kidney, with clear cell (ccRCC) subtype identified in 85% of the cases; one-third of these patients experience synchronous metastatic disease, while 20-30% of the remaining patients develop metachronous metastatic RCC. The axial skeleton (pelvis and sacrum) is the second most common location (following the lungs), with a reported incidence of 35%. Diaphysis of the long bones is rarely involved, with the tibia being an even rarer site of metastasis. CASE REPORT We present a rare case of solitary diaphyseal tibial metachronous metastasis from RCC in a 54 year-old male that appeared 8 years after nephrectomy without any previous evidence of disease. He underwent segmental skeletal resection, intercalary allograft over locked reamed intramedullary nailing, and soleus flap coverage. Thirty months later he presented with hardware failure and nonunion at the distal part of the allograft site. He was successfully treated with exchange nailing, fibular osteotomy, and bone grafting, showing excellent clinical and radiological outcome without any evidence of recurrence 5 years after the index operation. CONCLUSIONS Wide resection and biological reconstruction using intramedullary nailing and incorporated allograft is a good option for metachronous solitary RCC tumors. PMID- 30425234 TI - Role of Pyk2 in Human Cancers. AB - Proline-rich tyrosine kinase 2 (Pyk2) plays essential roles in tumorigenesis and tumor progression. Pyk2 serves as a non-receptor tyrosine kinase regulating tumor cell survival, proliferation, migration, invasion, metastasis, and chemo resistance, and is associated with poor prognosis and shortened survival in various cancer types. Thus, Pyk2 has been traditionally regarded as an oncogene and potential therapeutic target for cancers. However, a few studies have also demonstrated that Pyk2 exerts tumor-suppressive effects in some cancers, and anti cancer treatment of Pyk2 inhibitors may only achieve marginal benefits in these cancers. Therefore, more detailed knowledge of the contradictory functions of Pyk2 is needed. In this review, we summarized the tissue distribution, expression, interactive molecules of Pyk2 in the signaling pathway, and roles of Pyk2 in cancers, and focused on regulation of the interconnectivity between Pyk2 and its downstream targets. The potential use of inhibitors of Pyk2 and its related pathways in cancer therapy is also discussed. PMID- 30425235 TI - Correction: Guanylate-binding protein 2 regulates Drp1-mediated mitochondrial fission to suppress breast cancer cell invasion. AB - The work was supported by the Natural Science Foundation of China (NSFC) 81773188, 81760557, 81703081, and Program for New Century Excellent Talents in University (NCET)-12-0381. And we would like to appreciate the help given to the work by the lab of Prof. Fuyu Yang's from Institute of Biophysics and Prof. Yaping Tu from Creighton University in USA. PMID- 30425236 TI - Ribosomal protein S27-like regulates autophagy via the beta-TrCP-DEPTOR-mTORC1 axis. AB - RPS27L (Ribosomal protein S27-like), an evolutionarily conserved ribosomal protein, is a p53 target and a physiological p53 regulator. We previously reported that Rps27l disruption enhanced lymphomagenesis in Trp53+/- mice by triggering genome instability and sensitized Trp53+/- mice to radiation by blocking DNA damage response. Whether and how RPS27L modulates autophagy is totally unknown. Here we report that RPS27L silencing significantly induced autophagy in breast cancer MB231 and SK-BR3 cells harboring mutant p53. Mechanistically, RPS27L silencing remarkably inactivated mTORC1, a major negative autophagy regulator, but not mTORC2. Autophagy induction and mTORC1 inactivation was also observed in MEFs with Rps27l deletion. More specifically, RPS27L silencing shortened the protein half-life of beta-TrCP, a substrate receptor of Skp1-Cullin 1-F-box (SCF) ubiquitin ligase, which is responsible for DEPTOR degradation, leading to DEPTOR accumulation to inhibit mTORC1 activity. Furthermore, RPS27L silencing-induced autophagy and mTORC1 inactivation can be partially rescued by simultaneous DEPTOR silencing, suggesting a causal role of DEPTOR. Biologically, autophagy inhibitor, chloroquine (CQ), or Bafilomycin A1 (BAF A1), significantly induced apoptosis in RPS27L silenced cells, indicating that autophagy is a cellular survival mechanism in response to RPS27L loss. Finally, RPS27L levels were reduced in human breast cancers, as compared to adjacent normal tissues. Collectively, our study suggests that RPS27L reduction might play a promoting role during breast tumorigenesis by autophagy induction via the beta-TrCP-DEPTOR-mTORC1 axis. PMID- 30425238 TI - Broad neutralizing activity of a human monoclonal antibody against H7N9 strains from 2013 to 2017. AB - H7N9 influenza virus has been circulating among humans for five epidemic waves since it was first isolated in 2013 in China. The recent increase in H7N9 infections during the fifth outbreak in China has caused concerns of a possible pandemic. In this study, we describe a previously characterized human monoclonal antibody, HNIgGA6, obtained by isolating rearranged heavy-chain and light-chain genes from patients who had recovered from H7N9 infections. HNIgGA6 recognized multiple HAs and neutralized the infectivity of 11 out of the 12 H7N9 strains tested, as well as three emerging HPAI H7N9 isolates. The only resistant strain was A/Shanghai/1/2013 (H7N9-SH1), which carries the avian receptor alleles 186V and 226Q in the sialic acid-binding pocket. The mAb broadly neutralized divergent H7N9 strains from 2013 to 2017 and represents a potential alternative treatment for H7N9 interventions. PMID- 30425237 TI - Renal tubular epithelial cells: the neglected mediator of tubulointerstitial fibrosis after injury. AB - Renal fibrosis, especially tubulointerstitial fibrosis, is the inevitable outcome of all progressive chronic kidney diseases (CKDs) and exerts a great health burden worldwide. For a long time, interests in renal fibrosis have been concentrated on fibroblasts and myofibroblasts. However, in recent years, growing numbers of studies have focused on the role of tubular epithelial cells (TECs). TECs, rather than a victim or bystander, are probably a neglected mediator in renal fibrosis, responding to a variety of injuries. The maladaptive repair mechanisms of TECs may be the key point in this process. In this review, we will focus on the role of TECs in tubulointerstitial fibrosis. We will follow the fate of a tubular cell and depict the intracellular changes after injury. We will then discuss how the repair mechanism of tubular cells becomes maladaptive, and we will finally discuss the intercellular crosstalk in the interstitium that ultimately proceeds tubulointerstitial fibrosis. PMID- 30425239 TI - Nitric oxide triggers the assembly of "type II" stress granules linked to decreased cell viability. AB - We show that 3-morpholinosydnonimine (SIN-1)-induced nitric oxide (NO) triggers the formation of SGs. Whereas the composition of NO-induced SGs is initially similar to sodium arsenite (SA)-induced type I (cytoprotective) SGs, the progressive loss of eIF3 over time converts them into pro-death (type II) SGs. NO induced SG assembly requires the phosphorylation of eIF2alpha, but the transition to type II SGs is temporally linked to the mTOR-regulated displacement of eIF4F complexes from the m7 guanine cap. Whereas SA does not affect mitochondrial morphology or function, NO alters mitochondrial integrity and function, resulting in increased ROS production, decreased cytoplasmic ATP, and plasma membrane permeabilization, all of which are supported by type II SG assembly. Thus, cellular energy balance is linked to the composition and function of NO-induced SGs in ways that determine whether cells live or die. PMID- 30425240 TI - Participation of xCT in melanoma cell proliferation in vitro and tumorigenesis in vivo. AB - Our research group demonstrated that riluzole, an inhibitor of glutamatergic signaling reduced melanoma cell proliferation in vitro and tumor progression in vivo. The underlying mechanisms of riluzole are largely unknown. Microarray analyses on two human melanoma cell lines revealed that riluzole stimulates expression of the cystine-glutamate amino acid antiporter, xCT (SLC7A11). Western immunoblot analysis from cultured human melanoma or normal melanocytic cells showed that xCT was significantly overexpressed in most melanomas, but not normal cells. Studies using human tumor biopsy samples demonstrated that overexpression of xCT was correlated with cancer stage and progression. To further investigate if xCT is involved in melanoma cell growth, we derived several stable clones through transfection of exogenous xCT to melanoma cells that originally showed very low expression of xCT. The elevated xCT expression promoted cell proliferation in vitro and inversely, these melanoma clones showed a dose dependent decrease in cell proliferation in response to riluzole treatment. Xenograft studies showed that these clones formed very aggressive tumors at a higher rate compared to vector controls. Conversely, treatment of xenograft bearing animals with riluzole down-regulated xCT expression suggesting that xCT is a molecular target of riluzole. Furthermore, protein lysates from tumor biopsies of patients that participated in a riluzole monotherapy phase II clinical trial showed a reduction in xCT levels in post-treatment specimens from patients with stable disease. Taken together, our results show that xCT may be utilized as a marker to monitor patients undergoing riluzole-based chemotherapies. PMID- 30425241 TI - TGFbeta1 signaling sustains aryl hydrocarbon receptor (AHR) expression and restrains the pathogenic potential of TH17 cells by an AHR-independent mechanism. AB - The aryl hydrocarbon receptor (AHR) is a transcription factor activated by ligand highly expressed on TH17 cells, and AHR-deficient CD4+ T cells have impaired production of IL-17A and IL-22. Although AHR activation can exacerbate in vivo TH17 cell-mediated autoimmunity, accumulating data indicate that AHR is a nonpathogenic TH17 marker. Thus it remains unclear how AHR activation is regulated and impacts on the generation of TH17 subsets. Here we demonstrated that AHR pathway is activated during in vitro pathogenic TH17 polarization, but it is quickly downregulated. Under these conditions, additional AHR activation promoted IL-22 but not IL-17A. Interestingly, AHR high sustained expression and IL-17A promotion were only achieved when TGFbeta1 was present in the culture. In addition to the effect on AHR regulation, TGFbeta1 presented a dual role by simultaneously suppressing the TH17 pathogenic phenotype acquisition. This latter effect was independent of AHR stimulation, since its activation did not confer a TH17 anti-inflammatory profile and Ahr-/- cells did not upregulate any TH17 pathogenic marker. Through the use of EAE model, we demonstrated that AHR is still functional in encephalitogenic CD4+ T cells and the adoptive transfer of Ahr-/- TH17 cells to recipient mice resulted in milder EAE development when compared to their WT counterparts. Altogether, our data demonstrated that although AHR is highly expressed on in vitro-generated nonpathogenic TH17 cells, its ligation does not shift TH17 cells to an anti-inflammatory phenotype. Further studies investigating the role of AHR beyond TH17 differentiation may provide a useful understanding of the physiopathology of autoimmune diseases. PMID- 30425242 TI - Hypoxia-mediated mitochondria apoptosis inhibition induces temozolomide treatment resistance through miR-26a/Bad/Bax axis. AB - Glioblastoma multiforme (GBM) is one of the most hypoxic tumors of the central nervous system. Although temozolomide (TMZ) is an effective clinical agent in the GBM therapy, the hypoxic microenvironment remains a major barrier in glioma chemotherapy resistance, and the underlying mechanisms are poorly understood. Here, we find hypoxia can induce the protective response to mitochondrion via HIF 1alpha-mediated miR-26a upregulation which is associated with TMZ resistance in vitro and in vivo. Further, we demonstrated that HIF-1alpha/miR-26a axis strengthened the acquisition of TMZ resistance through prevention of Bax and Bad in mitochondria dysfunction in GBM. In addition, miR-26a expression levels negatively correlate with Bax, Bad levels, and GBM progression; but highly correlate with HIF-1alpha levels in clinical cancer tissues. These findings provide a new link in the mechanistic understanding of TMZ resistance under glioma hypoxia microenvironment, and consequently HIF-1alpha/miR-26a/Bax/Bad signaling pathway as a promising adjuvant therapy for GBM with TMZ. PMID- 30425243 TI - Emergence of a novel recombinant Seneca Valley virus in Central China, 2018. PMID- 30425245 TI - Author Correction: A sulfotransferase dosage-dependently regulates mouthpart polyphenism in the nematode Pristionchus pacificus. AB - The original version of this Article contained errors in Figure 4. In panel a, the x axis labels of bars 6-11 were incorrect, as depicted in the associated Author Correction. These errors have been corrected in both the PDF and HTML versions of the Article. PMID- 30425244 TI - Unmasking GluN1/GluN3A excitatory glycine NMDA receptors. AB - GluN3A and GluN3B are glycine-binding subunits belonging to the NMDA receptor (NMDAR) family that can assemble with the GluN1 subunit to form unconventional receptors activated by glycine alone. Functional characterization of GluN1/GluN3 NMDARs has been difficult. Here, we uncover two modalities that have transformative properties on GluN1/GluN3A receptors. First, we identify a compound, CGP-78608, which greatly enhances GluN1/GluN3A responses, converting small and rapidly desensitizing currents into large and stable responses. Second, we show that an endogenous GluN3A disulfide bond endows GluN1/GluN3A receptors with distinct redox modulation, profoundly affecting agonist sensitivity and gating kinetics. Under reducing conditions, ambient glycine is sufficient to generate tonic receptor activation. Finally, using CGP-78608 on P8-P12 mouse hippocampal slices, we demonstrate that excitatory glycine GluN1/GluN3A NMDARs are functionally expressed in native neurons, at least in the juvenile brain. Our work opens new perspectives on the exploration of excitatory glycine receptors in brain function and development. PMID- 30425246 TI - Author Correction: Division of labour between Myc and G1 cyclins in cell cycle commitment and pace control. AB - This Article contains errors in Supplementary Table 3, which are described in the Author Correction associated with this Article. The simulation results in the Article were based on the correct formula and thus the results are not affected by this correction. The errors have not been fixed in the original Article. PMID- 30425248 TI - Experimental heatwaves compromise sperm function and cause transgenerational damage in a model insect. AB - Climate change is affecting biodiversity, but proximate drivers remain poorly understood. Here, we examine how experimental heatwaves impact on reproduction in an insect system. Male sensitivity to heat is recognised in endotherms, but ectotherms have received limited attention, despite comprising most of biodiversity and being more influenced by temperature variation. Using a flour beetle model system, we find that heatwave conditions (5 to 7 degrees C above optimum for 5 days) damaged male, but not female, reproduction. Heatwaves reduce male fertility and sperm competitiveness, and successive heatwaves almost sterilise males. Heatwaves reduce sperm production, viability, and migration through the female. Inseminated sperm in female storage are also damaged by heatwaves. Finally, we discover transgenerational impacts, with reduced reproductive potential and lifespan of offspring when fathered by males, or sperm, that had experienced heatwaves. This male reproductive damage under heatwave conditions provides one potential driver behind biodiversity declines and contractions through global warming. PMID- 30425247 TI - A low-gluten diet induces changes in the intestinal microbiome of healthy Danish adults. AB - Adherence to a low-gluten diet has become increasingly common in parts of the general population. However, the effects of reducing gluten-rich food items including wheat, barley and rye cereals in healthy adults are unclear. Here, we undertook a randomised, controlled, cross-over trial involving 60 middle-aged Danish adults without known disorders with two 8-week interventions comparing a low-gluten diet (2 g gluten per day) and a high-gluten diet (18 g gluten per day), separated by a washout period of at least six weeks with habitual diet (12 g gluten per day). We find that, in comparison with a high-gluten diet, a low gluten diet induces moderate changes in the intestinal microbiome, reduces fasting and postprandial hydrogen exhalation, and leads to improvements in self reported bloating. These observations suggest that most of the effects of a low gluten diet in non-coeliac adults may be driven by qualitative changes in dietary fibres. PMID- 30425249 TI - A web server for comparative analysis of single-cell RNA-seq data. AB - Single cell RNA-Seq (scRNA-seq) studies profile thousands of cells in heterogeneous environments. Current methods for characterizing cells perform unsupervised analysis followed by assignment using a small set of known marker genes. Such approaches are limited to a few, well characterized cell types. We developed an automated pipeline to download, process, and annotate publicly available scRNA-seq datasets to enable large scale supervised characterization. We extend supervised neural networks to obtain efficient and accurate representations for scRNA-seq data. We apply our pipeline to analyze data from over 500 different studies with over 300 unique cell types and show that supervised methods outperform unsupervised methods for cell type identification. A case study highlights the usefulness of these methods for comparing cell type distributions in healthy and diseased mice. Finally, we present scQuery, a web server which uses our neural networks and fast matching methods to determine cell types, key genes, and more. PMID- 30425250 TI - Proteome-wide analysis of USP14 substrates revealed its role in hepatosteatosis via stabilization of FASN. AB - Ubiquitin-specific protease 14 (USP14) is one of the major proteasome-associated deubiquitinating enzymes critical for proteome homeostasis. However, substrates of USP14 remain largely unknown, hindering the understanding of its functional roles. Here we conduct a comprehensive proteome, ubiquitinome and interactome analysis for USP14 substrate screening. Bioinformatics analysis reveals broad new potential roles of USP14, especially in lipid and carbohydrate metabolism. Among the potential substrates identified, we show that fatty acid synthase (FASN), a key enzyme involved in hepatic lipogenesis, is a bona fide substrate of USP14. USP14 directly interacts with and increases FASN stability. As a result, overexpression of USP14 promotes liver triglyceride accumulation in C57BL/6 mice, whereas genetic ablation or pharmacological inhibition of USP14 ameliorates hepatosteatosis, hyperglycemia and insulin resistance in obese mice. In conclusion, our findings reveal for the first time an indispensable role of USP14 in hepatosteatosis through FASN stabilization. PMID- 30425251 TI - Author Correction: Integrated molecular subtyping defines a curable oligometastatic state in colorectal liver metastasis. AB - In the originally published version of this Article, the affiliation details for Kevin P. White inadvertently omitted 'Tempus Labs, Chicago, IL, 60654, USA'. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 30425252 TI - An ultra-compact integrated system for brain activity recording and stimulation validated over cortical slow oscillations in vivo and in vitro. AB - The understanding of brain processing requires monitoring and exogenous modulation of neuronal ensembles. To this end, it is critical to implement equipment that ideally provides highly accurate, low latency recording and stimulation capabilities, that is functional for different experimental preparations and that is highly compact and mobile. To address these requirements, we designed a small ultra-flexible multielectrode array and combined it with an ultra-compact electronic system. The device consists of a polyimide microelectrode array (8 um thick and with electrodes measuring as low as 10 um in diameter) connected to a miniaturized electronic board capable of amplifying, filtering and digitalizing neural signals and, in addition, of stimulating brain tissue. To evaluate the system, we recorded slow oscillations generated in the cerebral cortex network both from in vitro slices and from in vivo anesthetized animals, and we modulated the oscillatory pattern by means of electrical and visual stimulation. Finally, we established a preliminary closed loop algorithm in vitro that exploits the low latency of the electronics (<0.5 ms), thus allowing monitoring and modulating emergent cortical activity in real time to a desired target oscillatory frequency. PMID- 30425254 TI - Author Correction: Predictive Value of Serum Gamma-glutamyltranspeptidase for Future Cardiometabolic Dysregulation in Adolescents- a 10-year longitudinal study. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30425253 TI - Mobilisation Mechanism of Pathogenicity Islands by Endogenous Phages in Staphylococcus aureus clinical strains. AB - Staphylococcus aureus pathogenicity islands (SaPIs) are a type of mobile genetic element that play a significant role in the pathogenesis and virulence of this microorganism. SaPIs are integrated in the chromosome under the control of the master repressor Stl, but they can be horizontally transferred at a high frequency due to certain bacteriophages. Thus, a phage protein can bind to the SaPI Stl and induce the SaPI cycle, spreading the SaPI virulence factors to other bacterial populations. We report the dissemination mechanism of SaPIs mediated by endogenous prophages in S. aureus clinical strains. We reveal the induction of SaPIs by a co-resident prophage in seven clinically relevant strains, and we further study this mechanism in MW2, a community-acquired methicillin-resistant S. aureus strain that contains two bacteriophages (phiSa2mw and phiSa3mw) and one SaPI (SaPImw2) encoding for three enterotoxins (sec, sel and ear). phiSa2mw was identified as responsible for SaPImw2 induction, and the specific phage derepressor protein DUF3113 was determined. The Stl-DUF3113 protein interaction was demonstrated, along with the existence of variants of this protein in S. aureus phages with different abilities to induce SaPI. Both Stl and DUF3113 are present in other Staphylococcus species, which indicates that this is a generalised mechanism. PMID- 30425255 TI - Assessing bone mineral changes in response to vitamin D supplementation using natural variability in stable isotopes of Calcium in Urine. AB - Osteoporosis is a chronic disease of public health importance, particularly in low and middle income countries. Measuring the bone mineral balance (BMB) in a non-invasive manner, and its response to different interventions, is critical to the definition of optimal strategies for its prevention and management. In this study, we demonstrate the usefulness of natural variability in calcium isotopes (delta44/40Ca) of urine and the derived BMB estimates as a biomarker of bone health and its responsiveness to interventions. Vitamin D3 is commonly used as a supplement for the prevention and treatment of osteoporosis, along with calcium supplements. We studied the effect of a short term vitamin D3 supplementation on changes in urine delta44/40Ca and the derived BMB. delta44/40Ca before and after the vitamin D3 supplementation yielded a statistically significant change (p = 0.050) with a positive delta44/40Ca enrichment. The mean derived BMB was net positive (0.04 +/- 0.05) in comparison to a net negative value for the control group (-0.03 +/- 0.01). These results indicate the potential usefulness of urinary natural delta44/40Ca and the derived BMB, which, along with bone mineral density could be used as a sensitive marker for precision in the prevention and treatment of osteoporosis. PMID- 30425256 TI - DNA based diagnostic for the quantification of sugarcane root DNA in the field. AB - Plant root systems play many key roles including nutrient and water uptake, interface with soil microorganisms and resistance to lodging. As for other crops, large and systematic studies of sugarcane root systems have always been hampered by the opaque and solid nature of the soil. In recent years, methods for efficient extraction of DNA from soil and for species-specific DNA amplification have been developed. Such tools could have potential to greatly improve root phenotyping and health diagnostic capability in sugarcane. In this paper, we present a fast, specific and efficient method for the quantification of sugarcane live root cells in soil samples. Previous studies were typically based on mass and length, so we established a calibration to convert root DNA quantity to live root mass. This diagnostic was validated on field samples and used to investigate the fate of the root system after harvest prior to regrowth of the ratoon crop. Two weeks after harvest, the sugarcane roots from the previous crop were still viable. This raises the question of the role that the root system of the harvested crop plays in the performance of the next crop and demonstrates how this test can be used to answer research questions. PMID- 30425257 TI - Association of Serum Aluminum Levels with Mortality in Patients on Chronic Hemodialysis. AB - Despite reported evidence on the relationship between higher serum aluminum levels and poor outcomes in patients on chronic hemodialysis (CHD), the acceptable cutoff value of serum aluminum for mortality remains unclear. A retrospective observational cohort study with 636 Taiwanese patients on CHD was conducted to investigate the impact of serum aluminum levels on mortality. The predictors were bivariate serum aluminum level (<6 and >=6 ng/mL) and the Outcomes were all-cause and cardiovascular (CV) mortality. During the mean follow up of 5.3 +/- 2.9 years, 253 all-cause and 173 CV deaths occurred. Crude analysis showed that a serum aluminum level of >=6 ng/mL was a significant predictor of all-cause [hazard ratio (HR), 1.80; 95% confidence interval (CI), 1.40-2.23] and CV (HR, 1.84; 95% CI, 1.36-2.50) mortality. After multivariable adjustment, the serum aluminum level of >=6 ng/mL remained a significant predictor of all-cause mortality (HR, 1.37, 95% CI, 1.05-1.81) but became insignificant for CV mortality (HR, 1.29; 95% CI, 0.92-1.81). Therefore, our study revealed that a serum aluminum level of >=6 ng/mL was independently associated with all-cause death in patients on CHD, suggesting that early intervention for aluminum level in patients on CHD might be beneficial even in the absence of overt aluminum toxicity. PMID- 30425258 TI - MicroRNA-182 Alleviates Neuropathic Pain by Regulating Nav1.7 Following Spared Nerve Injury in Rats. AB - The sodium channel 1.7 (Nav1.7), which is encoded by SCN9A gene, is involved in neuropathic pain. As crucial regulators of gene expression, many miRNAs have already gained importance in neuropathic pain, including miR-182, which is predicted to regulate the SCN9A gene. Nav1.7 expression in L4-L6 dorsal root ganglions (DRGs) can be up regulated by spared nerve injury (SNI), while miR-182 expression was down regulated following SNI model. Exploring the connection between Nav1.7 and miR-182 may facilitate the development of a better-targeted therapy. In the current study, direct pairing of miR-182 with the SCN9A gene was verified using a luciferase assay in vitro. Over-expression of miR-182 via microinjection of miR-182 agomir reversed the abnormal increase of Nav1.7 at both mRNA and protein level in L4-6 DRGs of SNI rats, and significantly attenuated the hypersensitivity to mechanical stimulus in the rats. In contrast, administration of miR-182 antagomir enhanced the Nav1.7 expression at both mRNA and protein level in L4-6 DRGs, companied with the generation of mechanical hypersensitivity in naive rats. Collectively, we concluded that miR-182 can alleviate SNI- induced neuropathic pain through regulating Nav1.7 in rats. PMID- 30425259 TI - Efficient immunoaffinity chromatography of lymphocytes directly from whole blood. AB - We show that defined lymphocytes can be rapidly purified by immunoaffinity chromatography starting directly from whole blood. The method relies on low affinity Fab-fragments attached to a column-matrix combined with the reversible Strep-tag technology. Compared to established cell enrichment protocols, the Strep-tag affinity chromatography of cells is independent of erythrocyte lysis or centrifugation steps, allowing for simple cell-enrichment with good yields, high purities, and excellent functionality of purified cells. PMID- 30425260 TI - Electrospun nerve guide conduits have the potential to bridge peripheral nerve injuries in vivo. AB - Electrospinning can be used to mimic the architecture of an acellular nerve graft, combining microfibers for guidance, and pores for cellular infiltration. We made electrospun nerve guides, from polycaprolactone (PCL) or poly-L-lactic acid (PLLA), with aligned fibers along the insides of the channels and random fibers around them. We bridged a 10 mm rat sciatic nerve defect with the guides, and, in selected groups, added a cell transplant derived from autologous stromal vascular fraction (SVF). For control, we compared to hollow silicone tubes; or autologous nerve grafts. PCL nerve guides had a high degree of autotomy (8/43 rats), a negative indicator with respect to future usefulness, while PLLA supported axonal regeneration, but did not outperform autologous nerve grafts. Transplanted cells survived in the PLLA nerve guides, but axonal regeneration was not enhanced as compared to nerve guides alone. The inflammatory response was partially enhanced by the transplanted cells in PLLA nerve grafts; Schwann cells were poorly distributed compared to nerve guide without cells. Tailor-made electrospun nerve guides support axonal regeneration in vivo, and can act as vehicles for co-transplanted cells. Our results motivate further studies exploring novel nerve guides and the effect of stromal cell-derived factors on nerve generation. PMID- 30425262 TI - Single-Crystal MoO3 Micrometer and Millimeter Belts Prepared from Discarded Molybdenum Disilicide Heating Elements. AB - Single-crystal MoO3 micrometer to millimeter even centimeter belts were prepared via a novel route of oxidizing a discarded molybdenum disilicide heating element at 1000 degrees C for 3 h. The morphology and structure features, and growth mechanism of the products were evidently investigated by X-ray diffraction, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, scanning electron microscopy, and transmission electron microscopy. The results indicated that the powdery and fibrous products were typical alpha-MoO3 belt-like structures which size could develop from micrometer to several millimeter even centimeter in length and up to 0.5 mm in width. It should be formed preferentially along the [001] direction via layer by layer growth to form 1-D single MoO3 belts by vapor-solid mechanism. Thermal and luminescence properties of the products were revealed by thermogravimetric analysis and differential thermal analysis and photoluminescence spectra that the resultant alpha-MoO3 belts had good thermal stability and characteristics of luminescence with a central peak at 481 nm. The MoO3 belts are of good potential being applied to luminescent and high temperature devices. PMID- 30425261 TI - Small Molecule Antagonists of NAADP-Induced Ca2+ Release in T-Lymphocytes Suggest Potential Therapeutic Agents for Autoimmune Disease. AB - Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca2+ releasing second messenger known to date, but the precise NAADP/Ca2+ signalling mechanisms are still controversial. We report the synthesis of small-molecule inhibitors of NAADP-induced Ca2+ release based upon the nicotinic acid motif. Alkylation of nicotinic acid with a series of bromoacetamides generated a diverse compound library. However, many members were only weakly active or had poor physicochemical properties. Structural optimisation produced the best inhibitors that interact specifically with the NAADP/Ca2+ release mechanism, having no effect on Ca2+ mobilized by the other well-known second messengers D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] or cyclic adenosine 5'-diphospho-ribose (cADPR). Lead compound (2) was an efficient antagonist of NAADP-evoked Ca2+ release in vitro in intact T lymphocytes and ameliorated clinical disease in vivo in a rat experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. Compound (3) (also known as BZ194) was synthesized as its bromide salt, confirmed by crystallography, and was more membrane permeant than 2. The corresponding zwitterion (3a), was also prepared and studied by crystallography, but 3 had more desirable physicochemical properties. 3 Is potent in vitro and in vivo and has found widespread use as a tool to modulate NAADP effects in autoimmunity and cardiovascular applications. Taken together, data suggest that the NAADP/Ca2+ signalling mechanism may serve as a potential target for T cell- or cardiomyocyte-related diseases such as multiple sclerosis or arrhythmia. Further modification of these lead compounds may potentially result in drug candidates of clinical use. PMID- 30425264 TI - Patterns and drivers of movement for a coastal benthopelagic fish, Pseudocaranx georgianus, on Australia's southeast coast. AB - Knowledge of connectivity and population structure is integral to the sustainable management of fished populations, yet such information is unavailable for many species over scales relevant to their exploitation. We examined broad-scale patterns and drivers of adult movement for a putatively mobile carangid (Pseudocaranx georgianus) on Australia's southeast coast using an angler tag recapture dataset. More than 6300 individuals were tagged and released across 1007 km of coastline, with anglers recapturing 157 (2.48%) individuals during a 14-year period. Median distance moved was 5 km and a substantial proportion of individuals (19%) were recaptured at their release location. Recapture latitude was also strongly predicted by release latitude (r2 = 0.87). However, a broad range of movements were observed (0-508 km), with 6% of individuals moving further than 100 km. Most individuals recaptured in areas now designated as Marine Protected Areas (MPAs) were originally released in the same area (79.2%). Larger body size, longer periods at liberty, and releases during Spring all positively influenced distance moved. Results support restricted movement over an intermediate scale, punctuated by occasional large movements. Our findings suggest adult movement of P. georgianus in southeastern Australia primarily occurs over smaller distances than the current spatial scale of management. PMID- 30425263 TI - DNA methylation and associated gene expression in blood prior to lung cancer diagnosis in the Norwegian Women and Cancer cohort. AB - The majority of lung cancer is caused by tobacco smoking, and lung cancer relevant epigenetic markers have been identified in relation to smoking exposure. Still, smoking-related markers appear to mediate little of the effect of smoking on lung cancer. Thus in order to identify disease-relevant markers and enhance our understanding of pathways, a wide search is warranted. Through an epigenome wide search within a case-control study (131 cases, 129 controls) nested in a Norwegian prospective cohort of women, we found 25 CpG sites associated with lung cancer. Twenty-three were classified as associated with smoking (LC-AwS), and two were classified as unassociated with smoking (LC-non-AwS), as they remained associated with lung cancer after stringent adjustment for smoking exposure using the comprehensive smoking index (CSI): cg10151248 (PC, CSI-adjusted odds ratio (OR) = 0.34 [0.23-0.52] per standard deviation change in methylation) and cg13482620 (B3GNTL1, CSI-adjusted OR = 0.33 [0.22-0.50]). Analysis among never smokers and a cohort of smoking-discordant twins confirmed the classification of the two LC-non-AwS CpG sites. Gene expression profiles demonstrated that the LC AwS CpG sites had different enriched pathways than LC-non-AwS sites. In conclusion, using blood-derived DNA methylation and gene expression profiles from a prospective lung cancer case-control study in women, we identified 25 CpG lung cancer markers prior to diagnosis, two of which were LC-non-AwS markers and related to distinct pathways. PMID- 30425266 TI - Development of novel antibodies for detection of mobile colistin-resistant bacteria contaminated in meats. AB - The recent discovery and rapid spread of mobile colistin-resistant gene, mcr-1, among bacteria isolated from a broad range of sources is undermining our ability to treat bacterial infections and threatening human health and safety. To prevent further transfer of colistin resistance, practical and reliable methods for mcr-1 containing bacteria are need. In this study, standards and novel polyclonal and monoclonal antibodies (mAbs) against MCR-1 were developed. Among nine mAbs, three were MCR-1 specific and six cross-reacted with both MCR-1 and MCR-2. A sandwich enzyme-linked immunosorbent assay (ELISA) was established using the polyclonal antibody as a capturer and the mAb MCR-1-7 as a detector. The assay had a limit of detection of 0.01 ng/mL for MCR-1 and 0.1 ng/mL for MCR-2 in buffer with coefficients of variation (CV) less than 15%. When applied to ground beef, chicken and pork, this ELISA identified samples inoculated with less than 0.4 cfu/g of meat, demonstrating its strong tolerance to complex food matrices. To our knowledge, this is the first immunoassay developed for MCR-1 and MCR-2. It should be useful for prompt and reliable screening of meat samples contaminated with plasmid-borne colistin-resistant bacteria, thus reducing human risk of foodborne infections with possibly no antibiotic treatment options. PMID- 30425267 TI - Characterization of coumarin-6 polycrystalline films growth from vacuum deposition at various substrate temperatures. AB - Coumarin-6 polycrystalline films were fabricated from vacuum deposition at various substrate temperatures Tsub from 106 to 178 degrees C with a fixed source temperature of 185 degrees C. Because of its slenderer and more asymmetric structure, the adhered coumarin-6 molecule on top of the growing interface encounters a larger steric energetic barrier of 0.92 eV as estimated from the Arrhenius plot of growth rate versus 1/Tsub. From top-view SEM pictures, the as-deposited coumarin-6 thin films exhibit a twisted pattern and a kinematic roughness for Tsub < 150 degrees C; while clear facets emerge for Tsub >= 150 degrees C due to the increase of surface diffusion energy of the adhered molecules. From XRD analysis, besides the confirmation of the triclinic structure two anomalous peaks observed at 2theta ~ 9.007 degrees and 7.260 degrees are explained due to the co-existence of N- and S-coumarin-6-isomers within the crystalline grains. Furthermore, for coumarin-6 polycrystalline films deposited at Tsub = 150 degrees C with high crystallinity of the constituent grains, the bandgap determined from optical transmission is around 2.392 eV; and from photoluminescence spectra, the fitted four emission components are assigned to the Frenkel and charge transfer excitons recombination with participation of molecular vibrational states. PMID- 30425265 TI - Chemically modified hCFTR mRNAs recuperate lung function in a mouse model of cystic fibrosis. AB - Gene therapy has always been a promising therapeutic approach for Cystic Fibrosis (CF). However, numerous trials using DNA or viral vectors encoding the correct protein resulted in a general low efficacy. In the last years, chemically modified messenger RNA (cmRNA) has been proven to be a highly potent, pulmonary drug. Consequently, we first explored the expression, function and immunogenicity of human (h)CFTR encoded by cmRNAhCFTR in vitro and ex vivo, quantified the expression by flow cytometry, determined its function using a YFP based assay and checked the immune response in human whole blood. Similarly, we examined the function of cmRNAhCFTR in vivo after intratracheal (i.t.) or intravenous (i.v.) injection of the assembled cmRNAhCFTR together with Chitosan-coated PLGA (poly-D, L-lactide-co-glycolide 75:25 (Resomer RG 752 H)) nanoparticles (NPs) by FlexiVent. The amount of expression of human hCFTR encoded by cmRNAhCFTR was quantified by hCFTR ELISA, and cmRNAhCFTR values were assessed by RT-qPCR. Thereby, we observed a significant improvement of lung function, especially in regards to FEV0.1, suggesting NP-cmRNAhCFTR as promising therapeutic option for CF patients independent of their CFTR genotype. PMID- 30425268 TI - Serum Golgi protein 73 is a marker comparable to APRI for diagnosing significant fibrosis in children with liver disease. AB - Serum Golgi protein 73 (GP73) is a promising marker for significant fibrosis in adults. However, current diagnostic value of serum GP73 for liver fibrosis in children is unknown. To investigate the relationship between levels of serum GP73 and liver fibrosis in children, we measured serum GP73 in 86 healthy controls and 183 patients with liver diseases using commercially available double-antibody sandwich enzyme-linked immunosorbent assay (ELISA) kit. The value of serum GP73 in fibrosis stage assessment was compared with aspartate transaminase to platelet ratio index (APRI). We found that serum GP73 was decreasing with age in healthy controls, while it was increasing with the extent of inflammation and fibrosis in patients with liver diseases. Though area under the receiver operating curve (AUROC) of serum GP73 for diagnosing significant fibrosis was nearly equal to APRI (0.62 vs 0.64) in patients aged 3 years or older, AUROC for serum GP73 was superior to APRI (0.76 vs 0.67) in patients aged below 3 years, indicating that serum GP73 is comparable to APRI for diagnosing significant fibrosis in children. PMID- 30425269 TI - Prospective diagnostic and prognostic study of copeptin in suspected acute aortic syndromes. AB - Acute aortic syndromes (AAS) are cardiovascular emergencies with unmet diagnostic needs. Copeptin is released upon stress conditions and is approved for rule-out of myocardial infarction (MI). As MI and AAS share presenting symptoms, stress mechanisms and necessity for rapid diagnosis, copeptin appears as an attractive biomarker also for AAS. We thus performed a diagnostic and observational study in Emergency Department (ED) outpatients. Inclusion criteria were chest/abdominal/back pain, syncope and/or perfusion deficit, plus AAS in differential diagnosis. Blood samples were obtained in the ED. 313 patients were analyzed and 105 (33.5%) were diagnosed with AAS. Median copeptin was 38.91 pmol/L (interquartile range, IQR, 16.33-173.4) in AAS and 7.51 pmol/L (IQR 3.58 15.08) in alternative diagnoses (P < 0.001). Copeptin (>=10 pmol/L) had a sensitivity of 80.8% (95% confidence interval, CI, 72.2-87.2) and a specificity of 63.6% (CI 56.9-69.9) for AAS. Within 6 hours, the sensitivity and specificity were 88.7% (CI 79.3-94.2) and 52.4% (CI 42.9-61.8) respectively. Combination with D-dimer did not increase the diagnostic yield. Furthermore, copeptin >=25 pmol/L predicted mortality in patients with alternative diagnoses but not with AAS. In conclusion, copeptin increases in most patients with AAS within the first hours, but the accuracy of copeptin for diagnosis AAS is suboptimal. PMID- 30425270 TI - Co-extinctions annihilate planetary life during extreme environmental change. AB - Climate change and human activity are dooming species at an unprecedented rate via a plethora of direct and indirect, often synergic, mechanisms. Among these, primary extinctions driven by environmental change could be just the tip of an enormous extinction iceberg. As our understanding of the importance of ecological interactions in shaping ecosystem identity advances, it is becoming clearer how the disappearance of consumers following the depletion of their resources - a process known as 'co-extinction' - is more likely the major driver of biodiversity loss. Although the general relevance of co-extinctions is supported by a sound and robust theoretical background, the challenges in obtaining empirical information about ongoing (and past) co-extinction events complicate the assessment of their relative contributions to the rapid decline of species diversity even in well-known systems, let alone at the global scale. By subjecting a large set of virtual Earths to different trajectories of extreme environmental change (global heating and cooling), and by tracking species loss up to the complete annihilation of all life either accounting or not for co extinction processes, we show how ecological dependencies amplify the direct effects of environmental change on the collapse of planetary diversity by up to ten times. PMID- 30425272 TI - Optimized cloaks made of near-zero materials for different-sized concealed targets. AB - The optimized cloaking design for conducting cylinders of different sizes is studied based on the Mie scattering theory. We construct a concentric multi layered cloak made of alternating materials with isotropic dielectrics and epsilon-near-zero (ENZ) material, the thickness of which can be determined through genetic algorithm. As the radius of the conducting cylinder increases, high order scattering contributions are becoming evident, and more layers are needed. The scattering cross sections of three different radii of PEC cylinders are minimized by utilizing different numbers of multi-layers respectively. We find that eight or less optimized layers can cancel most of the scattering from a conducting cylinder with its dimension compared to wavelength, and more effectively when taking the ENZ material as the inner starting shell. The frequency dependence of total scattering is also studied, leading to the result that the bandwidth decreases as the size of concealed PEC cylinder increases. Furthermore, it is shown that the cloaking efficiency is less sensitive to the permittivity and thickness of the ENZ material, due to the small phase variation in the ENZ material. The multi-layered cloak designed for a PEC target can also be used to evidently reduce the scattering of a dielectric core and design a multi-layered elliptical cloak. PMID- 30425271 TI - Serum selenoprotein P, but not selenium, predicts future hyperglycemia in a general Japanese population. AB - We aimed to test the hypothesis that selenoprotein P (SELENOP), a hepatokine involved in the development of both insulin resistance and impaired insulin production in mice, is related to future onset of hyperglycemia in humans. 76 healthy non-pregnant human subjects without diabetes underwent oral glucose tolerance test (OGTT) at baseline and 4-years follow-up. Nine subjects developed either impaired glucose tolerance or type 2 diabetes at follow-up. At baseline, SELENOP concentrations correlated negatively with insulinogenic index, but not with homeostasis model assessment-estimated insulin resistance (HOMA-IR). Multivariate analysis showed that baseline SELENOP predicted fasting plasma glucose at follow-up independently of the other parameters. The receiver operating characteristic (ROC) curve analysis showed that baseline concentrations of serum SELENOP, but not of selenium, were a reliable test to predict future onset of glucose intolerance. In conclusion, elevation of circulating SELENOP, but not of circulating selenium, was positively and independently associated with future onset of glucose intolerance in a general Japanese population. PMID- 30425273 TI - IL-17A expression in the adenoid tissue from children with sleep disordered breathing and its association with pneumococcal carriage. AB - Tonsil and adenoid-tissue hypertrophy (AH) is the most common cause of pediatric sleep-disordered breathing (SDB), with AH possibly initiated by repeated exposure to infectious agents or allergens. Here, we evaluated IL-17A activity in adenoid tissue from children with SDB and its association with AH and pneumococcal carriage. Thirty-five children (aged 3-12 years) with SDB and receiving adenoidectomy and tonsillectomy were enrolled. During surgery, nasopharyngeal carriage was determined by bacterial culture and multiplex PCR via nasopharyngeal swab, and adenoid samples were collected. IL-17A and associated cytokine expression was evaluated by real-time PCR and western blotting. The mRNA analysis showed that IL-17A level, IL-17A:IL-10 ratio, and RAR-related orphan receptor gammat:forkhead box P3 ratio were significantly higher in adenoid tissues with AH, as were IL-17A level and IL-17A:IL-10 ratio in adenoid tissues with pneumococcal carriage. Additionally, pneumococcal carriage was more common in nasopharyngeal adenoids from patients without AH than those with AH. IL-17A was upregulated in adenoid tissues from patients with AH and with pneumococcal carriage. These results suggested that pneumococcal carriage initiates an IL-17A mediated immune response in nasopharyngeal adenoids, which might be associated with AH in patients with SDB. PMID- 30425275 TI - Overlooked Trends in Observed Global Annual Precipitation Reveal Underestimated Risks. AB - Numerous human and environmental systems are sensitive to the spatial and temporal distribution of precipitation, including agriculture, water supply, and ecosystems. Trends in observed precipitation form an important line of evidence to understand how changes may increase system vulnerabilities. Linear trends reported in US and global climate assessments reflect changes in mean annual precipitation. Mean trends may not reflect changes across other quantiles in the precipitation probability distribution, including the tails (very high and low precipitation levels), leading to systematic mischaracterization of climate risk. Here we reanalyze global annual precipitation using quantile regression to reveal overlooked trends. We find trends in the tails inconsistent with the mean in 44.4% of land area and 40.7% of rainfed agricultural regions. Previously undetected trends offer a more accurate view of the changing climate. This work enables reappraisals of risk aggregated over thresholds in human and environmental systems, enabling revaluation of threats and identification of appropriate adaptation strategies. PMID- 30425276 TI - Systematic Review and Meta-analysis of Alarm versus Desmopressin Therapy for Pediatric Monosymptomatic Enuresis. AB - This study is to compare the efficacy of enuresis alarm and desmopressin therapy in managing pediatric monosymptomatic enuresis. We performed systematic literature searches on different databases from inception until April 2017 without language restriction. All randomized control trials comparing an enuresis alarm and desmopressin in managing children with monosymptomatic enuresis were included. A total of 15 studies with 1502 participants (aged 5 to 16 years) were included for pooled analysis. Overall, an enuresis alarm outperformed desmopressin in achieving at least a partial response (>50% reduction in wet nights) in per-protocol analysis (OR: 1.53, 95% CI 1.05 to 2.23) but not in intention-to-treat analysis (OR: 0.97, 95% CI 0.73 to 1.30) as the alarm was hampered by a high dropout rate (OR: 2.20, 95% CI 3.41 to 4.29). However, alarm therapy yielded a better sustained response (OR: 2.89, 95% CI 1.38 to 6.04) and lower relapse rate (OR: 0.25, 95% CI 0.12 to 0.50). In the intention to treat analysis, the results revealed that alarm and desmopressin therapy are comparable in efficacy with regards to achieving >50% reduction in baseline wet nights in enuretic children. However, enuresis alarms offer a superior treatment response and a lower relapse rate in well-motivated children. PMID- 30425274 TI - Detection of Activation Sequences in Spiking-Bursting Neurons by means of the Recognition of Intraburst Neural Signatures. AB - Bursting activity is present in many cells of different nervous systems playing important roles in neural information processing. Multiple assemblies of bursting neurons act cooperatively to produce coordinated spatio-temporal patterns of sequential activity. A major goal in neuroscience is unveiling the mechanisms underlying neural information processing based on this sequential dynamics. Experimental findings have revealed the presence of precise cell-type-specific intraburst firing patterns in the activity of some bursting neurons. This characteristic neural signature coexists with the information encoded in other aspects of the spiking-bursting signals, and its functional meaning is still unknown. We investigate the ability of a neuron conductance-based model to detect specific presynaptic activation sequences taking advantage of intraburst fingerprints identifying the source of the signals building up a sequential pattern of activity. Our simulations point out that a reader neuron could use this information to contextualize incoming signals and accordingly compute a characteristic response by relying on precise phase relationships among the activity of different emitters. This would provide individual neurons enhanced capabilities to control and negotiate sequential dynamics. In this regard, we discuss the possible implications of the proposed contextualization mechanism for neural information processing. PMID- 30425277 TI - Empirical Dynamic Modelling Identifies different Responses of Aedes Polynesiensis Subpopulations to Natural Environmental Variables. AB - To control mosquito populations for managing vector-borne diseases, a critical need is to identify and predict their response to causal environmental variables. However, most existing attempts rely on linear approaches based on correlation, which cannot apply in complex, nonlinear natural systems, because correlation is neither a necessary nor sufficient condition for causation. Applying empirical dynamic modelling that acknowledges nonlinear dynamics on nine subpopulations of tiger mosquitos from three neighbouring reef islets of the Raiatea atoll, we identified temperature, precipitation, dew point, air pressure, and mean tide level as causal environmental variables. Interestingly, responses of subpopulations in close proximity (100-500 m) differed with respect to their causal environmental variables and the time delay of effect, highlighting complexity in mosquito-environment causality network. Moreover, we demonstrated how to explore the effects of changing environmental variables on number and strength of mosquito outbreaks, providing a new framework for pest control and disease vector ecology. PMID- 30425278 TI - Nonsense mutation in PMEL is associated with yellowish plumage colour phenotype in Japanese quail. AB - The L strain of Japanese quail exhibits a plumage phenotype that is light yellowish in colour. In this study, we identified a nonsense mutation in the premelanosome protein (PMEL) gene showing complete concordance with the yellowish plumage within a pedigree as well as across strains by genetic linkage analysis of an F2 intercross population using approximately 2,000 single nucleotide polymorphisms (SNPs) that were detected by double digest restriction site associated DNA sequencing (ddRAD-seq). The yellowish plumage was inherited in an autosomal recessive manner, and the causative mutation was located within an 810 kb genomic region of the LGE22C19W28_E50C23 linkage group (LGE22). This region contained the PMEL gene that is required for the normal melanosome morphogenesis and eumelanin deposition. A nonsense mutation that leads to a marked truncation of the deduced protein was found in PMEL of the mutant. The gene expression level of PMEL decreased substantially in the mutant. Genotypes at the site of the nonsense mutation were fully concordant with plumage colour phenotypes in 196 F2 offspring. The nonsense mutation was not found in several quail strains with non yellowish plumage. Thus, the yellowish plumage may be caused by the reduced eumelanin content in feathers because of the loss of PMEL function. PMID- 30425279 TI - A machine learning approach for reliable prediction of amino acid interactions and its application in the directed evolution of enantioselective enzymes. AB - Directed evolution is an important research activity in synthetic biology and biotechnology. Numerous reports describe the application of tedious mutation/screening cycles for the improvement of proteins. Recently, knowledge based approaches have facilitated the prediction of protein properties and the identification of improved mutants. However, epistatic phenomena constitute an obstacle which can impair the predictions in protein engineering. We present an innovative sequence-activity relationship (innov'SAR) methodology based on digital signal processing combining wet-lab experimentation and computational protein design. In our machine learning approach, a predictive model is developed to find the resulting property of the protein when the n single point mutations are permuted (2n combinations). The originality of our approach is that only sequence information and the fitness of mutants measured in the wet-lab are needed to build models. We illustrate the application of the approach in the case of improving the enantioselectivity of an epoxide hydrolase from Aspergillus niger. n = 9 single point mutants of the enzyme were experimentally assessed for their enantioselectivity and used as a learning dataset to build a model. Based on combinations of the 9 single point mutations (29), the enantioselectivity of these 512 variants were predicted, and candidates were experimentally checked: better mutants with higher enantioselectivity were indeed found. PMID- 30425280 TI - Modulating Fundamental Resonance in Capacitive Coupled Asymmetric Terahertz Metamaterials. AB - In this work, we experimentally investigate near-field capacitive coupling between a pair of single-gap split ring resonators (SRRs) in a terahertz metamaterial. The unit cell of our design comprises of two coupled SRRs with the split gaps facing each other. The coupling between two SRRs is examined by changing the gap of one resonator with respect to the other for several inter resonator separations. When split gap size of one resonator is increased for a fixed inter-resonator distance, we observe a split in the fundamental resonance mode. This split ultimately results in the excitation of narrow band low frequency resonance mode along with a higher frequency mode which gets blue shifted when the split gap increases. We attribute resonance split to the excitation of symmetric and asymmetric modes due to strong capacitive or electric interaction between the near-field coupled resonators, however blue shift of the higher frequency mode occurs mainly due to the reduced capacitance. The ability of near-field capacitive coupled terahertz metamaterials to excite split resonances could be significant in the construction of modulator and sensing devices beside other potential applications for terahertz domain. PMID- 30425281 TI - Efficient silica synthesis from tetra(glycerol)orthosilicate with cathepsin- and silicatein-like proteins. AB - Silicateins play a key role in biosynthesis of spicules in marine sponges; they are also capable to catalyze formation of amorphous silica in vitro. Silicateins are highly homologous to cathepsins L - a family of cysteine proteases. Molecular mechanisms of silicatein activity remain controversial. Here site-directed mutagenesis was used to clarify significance of selected residues in silica polymerization. A number of mutations were introduced into two sponge proteins - silicatein A1 and cathepsin L from Latrunculia oparinae, as well as into human cathepsin L. First direction was alanine scanning of the proposed catalytic residues. Also, reciprocal mutations were introduced at selected positions that differ between cathepsins L and silicateins. Surprisingly, all the wild type and mutant proteins were capable to catalyze amorphous silica formation with a water soluble silica precursor tetra(glycerol)orthosilicate. Some mutants possessed several-fold enhanced silica-forming activity and can potentially be useful for nanomaterial synthesis applications. Our findings contradict to the previously suggested mechanisms of silicatein action via a catalytic triad analogous to that in cathepsins L. Instead, a surface-templated biosilification by silicateins and related proteins can be proposed. PMID- 30425283 TI - Testing bio-efficacy of insecticide-treated nets with fewer mosquitoes for enhanced malaria control. AB - Malaria control programs implementing Long-Lasting Insecticidal Nets (LLINs) are encouraged to conduct field monitoring of nets' survival, fabric integrity and insecticidal bio-efficacy. The reference method for testing the insecticide activity of LLINs needs 100 two-to-five-day-old female mosquitoes per net, which is highly resource-intensive. We aimed at identifying an alternative protocol, using fewer mosquitos, while ensuring a precision in the main indicator of +/-5 percentage points (pp). We compared different laboratory methods against the probability of the LLIN to fail the test as determined by a hierarchical Bayesian model. When using 50 mosquitoes per LLIN and considering mortality only instead of mortality or knock-down as validity criteria, the average error in the measure of the proportion of nets considered as valid was 0.40 pp. The 95% confidence interval of this value never exceed 5 pp when the number of LLIN tested was >=40. This method slightly outperforms the current recommendations. As a conclusion, testing the bio-efficacy of LLINs with half as many mosquitoes provides a valid evaluation of the proportion of valid LLINs. This approach could increase entomology labs' testing capacity and decrease costs, with no impact in the decision process for public health purposes. PMID- 30425282 TI - Compound heterozygous splice site variants in the SCLT1 gene highlight an additional candidate locus for Senior-Loken syndrome. AB - Senior Loken syndrome (SLS) is a heterogeneous disorder characterized by severe retinal degenerations and juvenile-onset nephronophthisis. Genetic variants in ten different genes have been reported as the causes of SLS. Clinical evaluation of a patient with SLS and her unaffected parents revealed that the patient had infantile-onset retinal dystrophy and juvenile-onset nephronophthisis. Other systemic abnormalities included hepatic dysfunction, megacystis, mild learning disability, autism, obesity, and hyperinsulinemia. Whole-exome sequencing identified compound heterozygous SCLT1 variants (c.1218 + 3insT and c.1631A > G) in the patient. The unaffected parents were heterozygous for each variant. Transcript analysis using reverse transcription PCR demonstrated that the c.1218 + 3insT variant leads to exon 14 skipping (p.V383_M406del), while the other variant (c.1631A > G) primarily leads to exon 17 skipping (p.D480EfsX11) as well as minor amounts of two transcripts (6 bps deletion in the last of exon 17 [p.V543_K544del] and exons 17 and 18 skipping [p.D480E, S481_K610del]). Immunohistochemical analysis demonstrated that the Sclt1 protein was localized to the distal appendage of the photoreceptor basal body, indicating a ciliary protein. In conclusion, we identified compound heterozygous splice site variants of SCLT1 in a patient with a new form of ciliopathies that exhibits clinical features of SLS. PMID- 30425284 TI - Somatic alterations compromised molecular diagnosis of DOCK8 hyper-IgE syndrome caused by a novel intronic splice site mutation. AB - In hyper-IgE syndromes (HIES), a group of primary immunodeficiencies clinically overlapping with atopic dermatitis, early diagnosis is crucial to initiate appropriate therapy and prevent irreversible complications. Identification of underlying gene defects such as in DOCK8 and STAT3 and corresponding molecular testing has improved diagnosis. Yet, in a child and her newborn sibling with HIES phenotype molecular diagnosis was misleading. Extensive analyses driven by the clinical phenotype identified an intronic homozygous DOCK8 variant c.4626 + 76 A > G creating a novel splice site as disease-causing. While the affected newborn carrying the homozygous variant had no expression of DOCK8 protein, in the index patient molecular diagnosis was compromised due to expression of altered and wildtype DOCK8 transcripts and DOCK8 protein as well as defective STAT3 signaling. Sanger sequencing of lymphocyte subsets revealed that somatic alterations and reversions revoked the predominance of the novel over the canonical splice site in the index patient explaining DOCK8 protein expression, whereas defective STAT3 responses in the index patient were explained by a T cell phenotype skewed towards central and effector memory T cells. Hence, somatic alterations and skewed immune cell phenotypes due to selective pressure may compromise molecular diagnosis and need to be considered with unexpected clinical and molecular findings. PMID- 30425285 TI - The effect of cell penetrating peptide-conjugated coactivator-associated arginine methyltransferase 1 (CPP-CARM1) on the cloned mouse embryonic development. AB - Abnormalities in gene expression that negatively affect embryonic development are frequently observed in cloned embryos generated by somatic cell nuclear transfer (SCNT). In the present study, we successfully produced a cell-penetrating peptide (CPP)-conjugated with coactivator-associated arginine methyltransferase 1 (CARM1) protein from mammalian cells and confirmed introduction into donor somatic cells and cloned 8-cell embryos within 3 hours after addition to culture medium. In addition, H3R17 dimethylation and embryonic development up to the blastocyst stage were increased in the group treated with exogenous CPP-CARM1 protein compared with the untreated group (control). Interestingly, the number of total cells and trophectoderm in blastocysts as well as implantation rate were significantly increased in the CPP-CARM1 protein-treated group. However, the cell number of inner cell mass (ICM) was not changed compared with the control group; similarly, expression of pluripotency-related genes Oct4 and Nanog (ICM markers) was not significantly different between groups. On the other hand, expression of the implantation-related gene Cdx2 (trophectoderm marker) was transiently increased after treatment with CPP-CARM1 protein. On the basis of these results, we conclude that supplementation with exogenous CPP-CARM1 protein improves embryonic development of cloned embryos through regulation of histone methylation and gene expression. In addition, our results suggest that CPP-CARM1 protein may be a useful tool for strengthening implantation of mammalian embryos. PMID- 30425286 TI - Proteomics reveals ablation of PlGF increases antioxidant and neuroprotective proteins in the diabetic mouse retina. AB - Placental growth factor (PlGF or PGF), a member of the vascular endothelial growth factor (VEGF) sub-family, plays a crucial role in pathological angiogenesis and inflammation. However, the underlying molecular mechanisms that PlGF mediates regarding the complications of non-proliferative diabetic retinopathy (DR) remain elusive. Using an LC-MS/MS-based label-free quantification proteomic approach we characterized the alterations in protein expression caused by PlGF ablation in the retinas obtained from C57BL6, Akita, PlGF-/- and Akita.PlGF-/- mice. After extraction and enzymatic digestion with Trypsin/LysC, the retinal proteins were analyzed by Q-Exactive hybrid Quadrupole Orbitrap mass spectrometry. Differentially expressed proteins (DEPs) were identified in four comparisons based on Z-score normalization and reproducibility by Pearson's correlation coefficient. The gene ontology (GO), functional pathways, and protein-protein network interaction analysis suggested that several proteins involved in insulin resistance pathways (Gnb1, Gnb2, Gnb4, Gnai2, Gnao1, Snap2, and Gngt1) were significantly down-regulated in PlGF ablated Akita diabetic mice (Akita.PlGF-/- vs. Akita) but up-regulated in Akita vs. C57 and PlGF-/- vs. C57 conditions. Two proteins involved in the antioxidant activity and neural protection pathways, Prdx6 and Map2 respectively, were up-regulated in the Akita.PlGF-/- vs. Akita condition. Overall, we predict that down-regulation of proteins essential for insulin resistance, together with the up-regulation of antioxidant and neuroprotection proteins highlight and epitomize the potential mechanisms important for future anti-PlGF therapies in the treatment of DR. PMID- 30425288 TI - A novel adiposity index as an integrated predictor of cardiometabolic disease morbidity and mortality. AB - We propose a new anthropometric index, weight-adjusted-waist index (WWI), to assess adiposity by standardizing waist circumference (WC) for weight. WWI, calculated as WC (cm) divided by the square root of weight (kg) (cm/?kg), was measured from 465,629 subjects in the Korean nationwide cohort (2008-2013). Cox regression analysis was used to compare WWI with BMI, WC, waist-to-height ratio (WHtR), and a body shape index (ABSI) for cardiometabolic morbidity and mortality risk in diagnostic and prognostic prediction models. For incident hypertension, type 2 diabetes and cardiovascular disease (CVD), BMI had the strongest predictive power, followed by WWI and WC. However, WWI showed the best predictive performance for CVD mortality. Also, a linear positive association between adiposity indices and cardiovascular and all-cause mortality was only shown in WWI and ABSI, not BMI, WC and WHtR which showed inverse J-shaped patterns. In the test of joint effects of each index, WWI combined with BMI was the strongest in both diagnostic and prognostic models. WWI is a unique adiposity index that shows linear positive association with both cardiometabolic morbidity and mortality. It also predicts incident cardiometabolic disease, cardiovascular and all-cause mortality risk with excellence in predictive power, especially when combined with BMI. PMID- 30425287 TI - High Oxygen Exchange to Music Indicates Auditory Distractibility in Acquired Brain Injury: An fNIRS Study with a Vector-Based Phase Analysis. AB - Attention deficits due to auditory distractibility are pervasive among patients with acquired brain injury (ABI). It remains unclear, however, whether attention deficits following ABI specific to auditory modality are associated with altered haemodynamic responses. Here, we examined cerebral haemodynamic changes using functional near-infrared spectroscopy combined with a topological vector-based analysis method. A total of thirty-seven participants (22 healthy adults, 15 patients with ABI) performed a melodic contour identification task (CIT) that simulates auditory distractibility. Findings demonstrated that the melodic CIT was able to detect auditory distractibility in patients with ABI. The rate corrected score showed that the ABI group performed significantly worse than the non-ABI group in both CIT1 (target contour identification against environmental sounds) and CIT2 (target contour identification against target-like distraction). Phase-associated response intensity during the CITs was greater in the ABI group than in the non-ABI group. Moreover, there existed a significant interaction effect in the left dorsolateral prefrontal cortex (DLPFC) during CIT1 and CIT2. These findings indicated that stronger hemodynamic responses involving oxygen exchange in the left DLPFC can serve as a biomarker for evaluating and monitoring auditory distractibility, which could potentially lead to the discovery of the underlying mechanism that causes auditory attention deficits in patients with ABI. PMID- 30425289 TI - Haematological analysis of Japanese macaques (Macaca fuscata) in the area affected by the Fukushima Daiichi Nuclear Power Plant accident. AB - Several populations of wild Japanese macaques (Macaca fuscata) inhabit the area around Fukushima Daiichi Nuclear Power Plant (FNPP). To measure and control the size of these populations, macaques are captured annually. Between May 2013 and December 2014, we performed a haematological analysis of Japanese macaques captured within a 40-km radius of FNPP, the location of a nuclear disaster two years post-accident. The dose-rate of radiocaesium was estimated using the ERICA Tool. The median internal dose-rate was 7.6 MUGy/day (ranging from 1.8 to 219 MUGy/day) and the external dose-rate was 13.9 MUGy/day (ranging from 6.7 to 35.1 MUGy/day). We performed multiple regression analyses to estimate the dose-rate effects on haematological values in peripheral blood and bone marrow. The white blood cell and platelet counts showed an inverse correlation with the internal dose-rate in mature macaques. Furthermore, the myeloid cell, megakaryocyte, and haematopoietic cell counts were inversely correlated and the occupancy of adipose tissue was positively correlated with internal dose-rate in femoral bone marrow of mature macaques. These relationships suggest that persistent whole body exposure to low-dose-rate radiation affects haematopoiesis in Japanese macaques. PMID- 30425290 TI - The anti-tumor diterpene oridonin is a direct inhibitor of Nucleolin in cancer cells. AB - The bioactive plant diterpene oridonin displays important pharmacological activities and is widely used in traditional Chinese medicine; however, its molecular mechanism of action is still incompletely described. In vitro and in vivo data have demonstrated anti-tumor activity of oridonin and its ability to interfere with several cell pathways; however, presently only the molecular chaperone HSP70 has been identified as a direct potential target of this compound. Here, using a combination of different proteomic approaches, innovative Cellular Thermal Shift Assay (CETSA) experiments, and classical biochemical methods, we demonstrate that oridonin interacts with Nucleolin, effectively modulating the activity of this multifunctional protein. The ability of oridonin to target Nucleolin and/or HSP70 could account for the bioactivity profile of this plant diterpene. Recently, Nucleolin has attracted attention as a druggable target, as its diverse functions are implicated in pathological processes such as cancer, inflammation, and viral infection. However, up to now, no small molecule as Nucleolin binders has been reported, thus our finding represents the first evidence of Nucleolin modulation by a small inhibitor. PMID- 30425291 TI - Structural basis for dimerization of the death effector domain of the F122A mutant of Caspase-8. AB - Caspase-8 is an apoptotic protease that is activated by a proximity-induced dimerization mechanism within the death-inducing signaling complex (DISC). The death effector domain (DED) of caspase-8 is involved in protein-protein interactions and is essential for the activation. Here, we report two crystal structures of the dimeric DEDs of the F122A mutant of caspase-8, both of which illustrate a novel domain-swapped dimerization, while differ in the relative orientation of the two subunits and the solvent exposure of the conserved hydrophobic patch Phe122/Leu123. We demonstrate that mutations disrupting the dimerization of the DEDs abrogate the formation of cellular death effector filaments (DEFs) and the induced apoptosis by overexpressed DEDs. Furthermore, such dimerization-disrupting mutations also impair the activation of the full length caspase-8 and the downstream apoptosis cascade. The structures provide new insights into understanding the mechanism underlying the activation of procaspase 8 within the DISC and DEFs. PMID- 30425292 TI - Establishment of a Regional Interdisciplinary Medical System for Managing Patients with Tuberous Sclerosis Complex (TSC). AB - Tuberous sclerosis complex (TSC) is an autosomal dominant inherited disease characterized by lesions that involve multiple organs. Interdisciplinary management at individual facilities needs to be coordinated to treat multiple organ systems. We hypothesized that the number of patients, opportunities for patients to undergo examinations, and opportunities for patients to be treated would increase after establishment of a TSC board (TB) in our hospital. From August 1979 to August 2017, 76 patients were studied. We established the TB in our hospital in 2014. We divided the patients into the pre-TB group and post-TB group. Patients consisted of 33 females and 43 males (mean age, 18.7 years; median age, 15 years). The follow-up period was 2 to 457 months (mean, 51.6 months; median, 24.5 months). Twenty-four patients were in the pre-TB group, and 52 were in the post-TB group. Regular follow-up (p < 0.001), younger age (p = 0.002), opportunities for patients to undergo examinations, opportunities for patients to receive neurological treatment (p < 0.001), and mammalian target of rapamycin (mTOR) inhibitor usage (p = 0.041) were significantly higher in the post-TB group. The radial relationship around the axis of TSC coordinators may be the key to interdisciplinary management of TSC. PMID- 30425293 TI - Highly Improved Solar Energy Harvesting for Fuel Production from CO2 by a Newly Designed Graphene Film Photocatalyst. AB - Our growing energy demands must be met by a sustainable supply with reduced carbon intensity. One of the most exciting prospects to realize this goal is the photocatalyst-biocatalyst integrated artificial photosynthesis system which affords solar fuel/chemicals in high selectivity from CO2. Graphene based photocatalysts are highly suitable for the system, but their industrial scale use requires immobilization for improved separation and recovery of the photocatalyst. Therefore for practical purposes, design and fabrication of film type graphene photocatalyst with higher solar energy conversion efficiency is an absolute necessity. As a means to achieve this, we report herein the successful development of a new type of flexible graphene film photocatalyst that leads to >225% rise in visible light harvesting efficiency of the resultant photocatalyst biocatalyst integrated artificial photosynthesis system for highly selective solar fuel production from CO2 compared to conventional spin coated graphene film photocatalyst. It is an important step towards the design of a new pool of graphene film based photocatalysts for artificial photosynthesis of solar fuels from CO2. PMID- 30425294 TI - Molecular Simulation of MoS2 Exfoliation. AB - A wide variety of two-dimensional layered materials are synthesized by liquid phase exfoliation. Here we examine exfoliation of MoS2 into nanosheets in a mixture of water and isopropanol (IPA) containing cavitation bubbles. Using force fields optimized with experimental data on interfacial energies between MoS2 and the solvent, multimillion-atom molecular dynamics simulations are performed in conjunction with experiments to examine shock-induced collapse of cavitation bubbles and the resulting exfoliation of MoS2. The collapse of cavitation bubbles generates high-speed nanojets and shock waves in the solvent. Large shear stresses due to the nanojet impact on MoS2 surfaces initiate exfoliation, and shock waves reflected from MoS2 surfaces enhance exfoliation. Structural correlations in the solvent indicate that shock induces an ice VII like motif in the first solvation shell of water. PMID- 30425295 TI - Development of local strontium ranelate delivery systems and long term in vitro drug release studies in osteogenic medium. AB - It has been recognized that the operative stabilization of osteoporotic fractures should be followed up with an appropriate osteoporosis treatment in order to decrease the risk of repeated fractures. Despite the good clinical results of strontium ranelate (SrRan) towards the osteoporosis treatment, high drug doses and long treatment period cause an increased risk of serious side effects. Novel local SrRan/poly(lactic acid) (SrRan/PLA) delivery systems containing from 3.57 +/- 0.28 wt% to 24.39 +/- 0.91 wt% of active substance were developed. In order to resemble the naturally occurring processes, osteogenic media (OM) was used as a release medium for long term (121 days) in vitro drug release studies and UV/VIS method for the determination of SrRan content in OM was developed and validated. Biomimetic calcium phosphate precipitates were found on the surface and in the pores of prepared delivery system after microcapsule exposure to OM for 121 days as well as SrRan particles, indicating that the release of the drug have not been completed within 121 days. In vitro cell viability evaluation approved no cytotoxic effects of microcapsule suspensions and extracts. PMID- 30425297 TI - Author Correction: High-altitude wind resources in the Middle East. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30425296 TI - AP endonuclease EXO-3 deficiency causes developmental delay and abnormal vulval organogenesis, Pvl, through DNA glycosylase-initiated checkpoint activation in Caenorhabditis elegans. AB - AP endonuclease deficiency causes cell death and embryonic lethality in mammals. However, the physiological roles of AP endonucleases in multicellular organisms remain unclear, especially after embryogenesis. Here, we report novel physiological roles of the AP endonuclease EXO-3 from larval to adult stages in Caenorhabditis elegans, and elucidated the mechanism of the observed phenotypes due to EXO-3 deficiency. The exo-3 mutants exhibited developmental delay, whereas the apn-1 mutants did not. The delay depended on the DNA glycosylase NTH-1 and checkpoint kinase CHK-2. The exo-3 mutants had further developmental delay when treated with AP site-generating agents such as methyl methane sulfonate and sodium bisulfite. The further delay due to sodium bisulfite was dependent on the DNA glycosylase UNG-1. The exo-3 mutants also demonstrated an increase in dut-1 (RNAi)-induced abnormal vulval organogenesis protruding vulva (Pvl), whereas the apn-1 mutants did not. The increase in Pvl was dependent on UNG-1 and CHK-2. Methyl viologen, ndx-1 (RNAi) and ndx-2 (RNAi) enhanced the incidence of Pvl among exo-3 mutants only when combined with dut-1 (RNAi). This further increase in Pvl incidence was independent of NTH-1. These results indicate that EXO-3 prevents developmental delay and Pvl in C. elegans, which are induced via DNA glycosylase-initiated checkpoint activation. PMID- 30425298 TI - The Core Eudicot Boom Registered in Myanmar Amber. AB - A perfect flower in a mid-Cretaceous (early Cenomanian) Myanmar amber is described as Lijinganthus revoluta gen. et sp. nov. The fossil flower is actinomorphic and pentamerous, including calyx, corolla, stamens, and gynoecium. The sepals are tiny, while the petals are large and revolute. The stamens are dorsifixed, filamentous, and each has a longitudinally dehiscing bisporangiate anther. The gynoecium is in the centre of the flower, composed of three fused carpels with a stout style. Lijinganthus revoluta gen. et sp. nov. demonstrates a great resemblance to the flowers of Pentapetalae (Eudicots), adding new information to the enigmatic early evolutionary history of Pentapetalae and Eudicots. PMID- 30425300 TI - Genetics in Medicine at Twenty. PMID- 30425301 TI - Deficiency of the human cysteine protease inhibitor cystatin M/E causes hypotrichosis and dry skin. AB - PURPOSE: We aimed to assess the biological and clinical significance of the human cysteine protease inhibitor cystatin M/E, encoded by the CTS6 gene, in diseases of human hair and skin. METHODS: Exome and Sanger sequencing was performed to reveal the genetic cause in two related patients with hypotrichosis. Immunohistochemical, biophysical, and biochemical measurements were performed on patient skin and 3D-reconstructed skin from patient-derived keratinocytes. RESULTS: We identified a homozygous variant c.361C>T (p.Gln121*), resulting in a premature stop codon in exon 2 of CST6 associated with hypotrichosis, eczema, blepharitis, photophobia and impaired sweating. Enzyme assays using recombinant mutant cystatin M/E protein, generated by site-directed mutagenesis, revealed that this p.Gln121* variant was unable to inhibit any of its three target proteases (legumain and cathepsins L and V). Three-dimensional protein structure prediction confirmed the disturbance of the protease/inhibitor binding sites of legumain and cathepsins L and V in the p.Gln121* variant. CONCLUSION: The herein characterized autosomal recessive hypotrichosis syndrome indicates an important role of human cystatin M/E in epidermal homeostasis and hair follicle morphogenesis. PMID- 30425299 TI - CETP genetic variant rs1800777 (allele A) is associated with abnormally low HDL-C levels and increased risk of AKI during sepsis. AB - High-density cholesterol (HDL-C) levels are influenced by genetic variation in several genes. Low levels of HDL-C have been associated with increased risk of acute kidney injury (AKI). We investigated whether genetic polymorphisms in ten genes known to regulate HDL-C levels are associated with both HDL-C levels and AKI development during sepsis. Two cohorts were retrospectively analyzed: Derivation Cohort (202 patients with sepsis enrolled at the Emergency Department from 2011 to 2014 in Vancouver, Canada); Validation Cohort (604 septic shock patients enrolled into the Vasopressin in Septic Shock Trial (VASST)). Associations between HDL-related genetic polymorphisms and both HDL-C levels, and risk for clinically significant sepsis-associated AKI (AKI KDIGO stages 2 and 3) were evaluated. In the Derivation Cohort, one genetic variant in the Cholesteryl Ester Transfer Protein (CETP) gene, rs1800777 (allele A), was strongly associated with lower HDL-C levels (17.4 mg/dL vs. 32.9 mg/dL, P = 0.002), greater CETP mass (3.43 ug/mL vs. 1.32 ug/mL, P = 0.034), and increased risk of clinically significant sepsis-associated AKI (OR: 8.28, p = 0.013). Moreover, the same allele was a predictor of sepsis-associated AKI in the Validation Cohort (OR: 2.38, p = 0.020). Our findings suggest that CETP modulates HDL-C levels in sepsis. CETP genotype may identify patients at high-risk of sepsis-associated AKI. PMID- 30425302 TI - Author Correction: Probing spermiogenesis: a digital strategy for mouse acrosome classification. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30425304 TI - Effect of fenofibrate on uric acid level in patients with gout. AB - Gout is a chronic disease associated with deposition of monosodium urate crystals and accompanied by diabetes, hypertension, and dyslipidemia. Hypertriglyceridemia is common among patients with gout, and fenofibrate is usually used to reduce triglyceride levels. The aim of this study is to determine the effect of uric acid reduction by fenofibrate in patients with gout administered uric acid lowering agents (viz., the xanthine oxidase inhibitors allopurinol and febuxostat). Data from 863 patients with gout were collected from electronic medical records comprising information on underlying diseases, laboratory findings, and drug histories. Among all the patients, 70 (8.11%) took fenofibrate with allopurinol or febuxostat. Male and young patients took fenofibrate more frequently, and hypertension was less frequent in patients administered xanthine oxidase inhibitors and fenofibrate than in those administered only xanthine oxidase inhibitors. After the treatment, serum uric acid levels more significantly decreased (-1.81 +/- 2.41 vs. -2.40 +/- 2.28 mg/dL, p = 0.043) in patients with fenofibrate cotreatment, than in those administered allopurinol or febuxostat alone. The effect of uric acid reduction was larger (b = -1.098, p < 0.001) in patients taking glucocorticoids than in those administered other treatments. There was no difference in the levels of creatinine, blood urea nitrogen, and aminotransferases between patients treated with and without fenofibrate. Fenofibrate additionally reduced uric acid levels without showing any change in the results of renal or liver function tests, suggesting that the addition of fenofibrate is a reasonable option for treating gout in patients having high triglyceride levels. PMID- 30425305 TI - Calpain-10 regulates actin dynamics by proteolysis of microtubule-associated protein 1B. AB - Calpain-10 (CAPN10) is the calpain family protease identified as the first candidate susceptibility gene for type 2 diabetes mellitus (T2DM). However, the detailed molecular mechanism has not yet been elucidated. Here we report that CAPN10 processes microtubule associated protein 1 (MAP1) family proteins into heavy and light chains and regulates their binding activities to microtubules and actin filaments. Immunofluorescent analysis of Capn10-/- mouse embryonic fibroblasts shows that MAP1B, a member of the MAP1 family of proteins, is localized at actin filaments rather than at microtubules. Furthermore, fluorescence recovery after photo-bleaching analysis shows that calpain-10 regulates actin dynamics via MAP1B cleavage. Moreover, in pancreatic islets from CAPN10 knockout mice, insulin secretion was significantly increased both at the high and low glucose levels. These findings indicate that deficiency of calpain 10 expression may affect insulin secretion by abnormal actin reorganization, coordination and dynamics through MAP1 family processing. PMID- 30425303 TI - Calpain-mediated tau fragmentation is altered in Alzheimer's disease progression. AB - The aggregation of intracellular tau protein is a major hallmark of Alzheimer's disease (AD). The extent and the stereotypical spread of tau pathology in the AD brain are correlated with cognitive decline during disease progression. Here we present an in-depth analysis of endogenous tau fragmentation in a well characterized cohort of AD and age-matched control subjects. Using protein mass spectrometry and Edman degradation to interrogate endogenous tau fragments in the human brain, we identified two novel proteolytic sites, G323 and G326, as major tau cleavage events in both normal and AD cortex. These sites are located within the sequence recently identified as the structural core of tau protofilaments, suggesting an inhibitory mechanism of fibril formation. In contrast, a different set of novel cleavages showed a distinct increase in late stage AD. These disease associated sites are located outside of the protofilament core sequence. We demonstrate that calpain 1 specifically cleaves at both the normal and diseased sites in vitro, and the site selection is conformation-dependent. Monomeric tau is predominantly cleaved at G323/G326 (normal sites), whereas oligomerization increases cleavages at the late-AD-associated sites. The fragmentation patterns specific to disease and healthy states suggest novel regulatory mechanisms of tau aggregation in the human brain. PMID- 30425306 TI - Comparative study of catalytic activities among transition metal-doped IrO2 nanoparticles. AB - Catalytic activities of transition metal-doped IrO2 nanoparticles (TM-IrO2 NPs; TM = Cr, Mn, Fe, Co, or Ni) are compared for various oxidation reactions such as electrochemical oxygen evolution reaction (OER), gas-phase photo-oxidation of thiol function group, and CO oxidative conversion. Here, we discovered a series of TM-IrO2 catalysts have a common activity trend for these oxidation reactions, and their activities are closely related with modified electronic states of IrO2, strongly affected by the types of the transition metal across the periodic table. For all oxidation reactions, Cr- and Mn-IrO2 achieved the highest oxidation catalytic activity, and sequentially decreased activities were obtained with Fe, Co, and Ni doped IrO2. For instance, the highest OER activity was achieved by Cr or Mn doping exhibiting the smallest overpotential eta = 275~230 mV at 10 mA/cm2, while Ni-IrO2 showed rather larger overpotential (eta = 347 mV) even compared with non-doped IrO2 (eta = 314 mV). Scanning transmission X-ray microscopy and high-resolution photoemission spectra of TM-IrO2 indicated dopant metals modified the Ir-O interaction and thus increasing oxygen vacancy defects in IrO2. Strongly positive correlation was observed between the catalytic activities and vacancy states. The amount of defect related signals was observed the most for Cr- or Mn IrO2, less so for Fe- or Co-IrO2, and unnoted for Ni-IrO2 compared with bare IrO2. Based on these catalytic activities and surface spectroscopic analysis results, vacancy defects induced by doping in TM-IrO2 NPs are proposed to contribute to enhance the oxidation activities. PMID- 30425307 TI - Luminescence lifetime encoding in time-domain flow cytometry. AB - Time-resolved flow cytometry represents an alternative to commonly applied spectral or intensity multiplexing in bioanalytics. At present, the vast majority of the reports on this topic focuses on phase-domain techniques and specific applications. In this report, we present a flow cytometry platform with time resolved detection based on a compact setup and straightforward time-domain measurements utilizing lifetime-encoded beads with lifetimes in the nanosecond range. We provide general assessment of time-domain flow cytometry and discuss the concept of this platform to address achievable resolution limits, data analysis, and requirements on suitable encoding dyes. Experimental data are complemented by numerical calculations on photon count numbers and impact of noise and measurement time on the obtained lifetime values. PMID- 30425308 TI - Pulsed interleaved excitation-based line-scanning spatial correlation spectroscopy (PIE-lsSCS). AB - We report pulsed interleaved excitation (PIE) based line-scanning spatial correlation spectroscopy (PIE-lsSCS), a quantitative fluorescence microscopy method for the study of dynamics in free-standing lipid bilayer membranes. Using a confocal microscope, we scan multiple lines perpendicularly through the membrane, each one laterally displaced from the previous one by several ten nanometers. Scanning through the membrane enables us to eliminate intensity fluctuations due to membrane displacements with respect to the observation volume. The diffusion of fluorescent molecules within the membrane is quantified by spatial correlation analysis, based on the fixed lag times between successive line scans. PIE affords dual-color excitation within a single line scan and avoids channel crosstalk. PIE-lsSCS data are acquired from a larger membrane region so that sampling is more efficient. Moreover, the local photon flux is reduced compared with single-point experiments, resulting in a smaller fraction of photobleached molecules for identical exposure times. This is helpful for precise measurements on live cells and tissues. We have evaluated the method with experiments on fluorescently labeled giant unilamellar vesicles (GUVs) and membrane-stained live cells. PMID- 30425311 TI - SUICIDE: A PATIENT'S WISH TO KILL OFF "BAD" INTROJECTS AND THUS ACHIEVE REBIRTH. AB - Benedict came for treatment because he experienced severe self-deprecating feelings that tortured him. He felt commanded-by what he characterized as internal demons-to kill himself. When he did not do so, he felt humiliated for having been a coward. Simultaneously, he reckoned that if he died his demons would be killed off, but that he would arise brand new. Because Benedict had already "killed off" several earlier therapists, he needed someone who could feel his pain, but would neither die from his emotional storms, nor give up on him. With considerable mutual work, he began to identify with my dogged determination to both survive his fierce attacks and to locate the source of the introjected demons that viciously attacked him (and others). When his emotionally-driven storms finally ebbed, he combined forces with me and began the ordeal of overcoming his fears and relinquishing his delusional system. PMID- 30425309 TI - Comprehensive molecular and cellular studies suggest avian scutate scales are secondarily derived from feathers, and more distant from reptilian scales. AB - Amniote skin appendages such as feathers, hairs and scales, provide thermoregulation, physical protection and display different color patterns to attract a mate or frighten an adversary. A long-standing question is whether "reptile scale" and "avian leg scales" are of the same origin. Understanding the relation between avian feathers, avian scales and reptilian scales will enhance our understanding of skin appendage evolution. We compared the molecular and cellular profiles in chicken feather, chicken scales and alligator scales and found that chicken scutate scales are similar to chicken feathers in morphogenesis at the early placode stage. When we compared the expression of the recently identified feather-specific genes and scale-specific genes in these skin appendages, we found that at the molecular level alligator scales are significantly different from both chicken feathers and chicken scales. Furthermore, we identified a similarly diffuse putative stem cell niche in morphologically similar chicken and alligator scales. These putative stem cells participate in alligator scale regeneration. In contrast, avian feathers have a more condensed stem cell niche, which may be responsible for cycling. Thus, our results suggest that chicken and alligator scales formed independently through convergent evolution. PMID- 30425310 TI - ME1 promotes basal-like breast cancer progression and associates with poor prognosis. AB - Basal-like breast cancer (BLBC) is associated with a poor clinical outcome due to the few treatment options and absence of effective targeted agents. Here, we show that malic enzyme 1 (ME1) is dramatically upregulated in BLBC due to ME1 copy number amplification. ME1 expression increases glucose uptake and lactate production, and reduces oxygen consumption, leading to aerobic glycolysis. ME1 expression promotes, whereas knockdown of ME1 expression suppresses tumorigenicity. In breast cancer patients, ME1 expression is positively correlated with large tumor size, high grade, poor survival, and chemotherapy resistance. Our study not only contributes to a new understanding of how metabolic reprogramming contributes to BLBC progression, but also provides a potential prognostic marker and therapeutic target for this challenging disease. PMID- 30425312 TI - Development of ultra-low volume, multi-bio fluid, cortisol sensing platform. AB - The development of a non-faradaic electrochemical sensor for screening across multiple bio-fluids that demonstrate the expression of cortisol using a gold microelectrode-based sensor is reported in this paper. Room temperature ionic liquid (RTIL), BMIM[BF4] was used as the buffer to modulate the electrical double layer (EDL) to enhance the electrochemical signal response of the sensor. The sensor design and the surface chemistry was optimized using COMSOL Multiphysics software simulations and FTIR respectively. The sensor was designed so that it uses ultra-low volumes between 3-5 uL of bio-fluid for detection. Cortisol detection was achieved in the physiologically relevant ranges when tested in serum, blood, sweat, and, saliva using non-faradaic Electrochemical Impedance Spectroscopy (EIS) and performance parameters of the sensor were determined. Sensor's response was tested against the only commercially available salivary cortisol point-of-care kit using regression analysis. Cross-reactive studies using prednisone indicated that the sensor is specific for cortisol. The sensor displayed a correlation value i.e. R2 > 0.95 between the signal response and the concentration of cortisol present in the system. Dynamic range of the sensor was across the physiologically relevant range of cortisol i.e. 50-200 ng/ml for serum/blood, 1-40 ng/ml for saliva, and 10-150 ng/ml for sweat. Limit of detection for serum and sweat was 10 ng/ml and 1 ng/ml for saliva. PMID- 30425313 TI - Risk factors for the presence of dental black plaque. AB - In order to evaluate risk factors related to the presence of extrinsic dental black stain, a total of 94 orally healthy volunteers (47 individuals with dental black stain and 47 individuals without dental black stain) were recruited from ten different dental clinics in Valencia and Castellon (Spain). Data regarding their oral hygiene, dietary habits, and oral health status were gathered by questionnaire. Samples of dental plaque, saliva and drinking water were collected for chemical analysis. Three factors were found to be statistically significantly associated with dental black stain, (i) consuming water with high iron content, (ii) consuming water with high pH, and (iii) having a high salivary pH. Other factors such as smoking, taking iron supplements or consuming caffeinated drinks were not found to be risk factors for the presence of black stain. A multivariate logistic regression analysis showed that drinking tap or osmosis-purified water and lower levels of salivary iron increase the risk of having dental black stain. Overall, several risk factors for the presence of dental black stain have been identified. The main modifiable risk factor identified in this study was the consumption of tap or osmosis drinking water. PMID- 30425314 TI - Hepatokine alpha1-Microglobulin Signaling Exacerbates Inflammation and Disturbs Fibrotic Repair in Mouse Myocardial Infarction. AB - Acute cardiac rupture and adverse left ventricular (LV) remodeling causing heart failure are serious complications of acute myocardial infarction (MI). While cardio-hepatic interactions have been recognized, their role in MI remains unknown. We treated cultured cardiomyocytes with conditioned media from various cell types and analyzed the media by mass spectrometry to identify alpha1 microglobulin (AM) as an Akt-activating hepatokine. In mouse MI model, AM protein transiently distributed in the infarct and border zones during the acute phase, reflecting infiltration of AM-bound macrophages. AM stimulation activated Akt, NFkappaB, and ERK signaling and enhanced inflammation as well as macrophage migration and polarization, while inhibited fibrogenesis-related mRNA expression in cultured macrophages and cardiac fibroblasts. Intramyocardial AM administration exacerbated macrophage infiltration, inflammation, and matrix metalloproteinase 9 mRNA expression in the infarct and border zones, whereas disturbed fibrotic repair, then provoked acute cardiac rupture in MI. Shotgun proteomics and lipid pull-down analysis found that AM partly binds to phosphatidic acid (PA) for its signaling and function. Furthermore, systemic delivery of a selective inhibitor of diacylglycerol kinase alpha-mediated PA synthesis notably reduced macrophage infiltration, inflammation, matrix metalloproteinase activity, and adverse LV remodeling in MI. Therefore, targeting AM signaling could be a novel pharmacological option to mitigate adverse LV remodeling in MI. PMID- 30425315 TI - Tensilely Strained Ge Films on Si Substrates Created by Physical Vapor Deposition of Solid Sources. AB - The development of Si-compatible active photonic devices is a high priority in computer and modern electronics industry. Ge is compatible with Si and is a promising light emission material. Nearly all Ge-on-Si materials reported so far were grown using toxic precursor gases. Here we demonstrate the creation of Ge films on Si substrates through physical vapor deposition of toxin-free solid Ge sources. Structural characterization indicates that a high tensile strain is introduced in the Ge film during the deposition process. We attribute the presence of such a tensile strain to the difference in thermal expansion coefficient between Si and Ge. A Ge peak, centered at ~2100 nm, is evident in the photoluminescence spectra of these materials, which might result from direct band gap photoluminescence alone, or from superposition of direct band gap and indirect band gap photoluminescence. These Ge-on-Si materials are therefore promising in light emission applications. PMID- 30425316 TI - Subwavelength Metamaterial Unit Cell for Low-Frequency Electromagnetic Absorber Applications. AB - In this paper, we propose a subwavelength metamaterial unit cell for low frequency electromagnetic absorber applications. To realize a periodic array for a metamaterial absorber, the footprint size and thickness of a unit cell must be miniaturized to a subwavelength. We achieved the electrical size of the unit cell as 0.027lambda * 0.027lambda * 0.043lambda at 2.4 GHz by introducing the inductive lump elements to a symmetric square-loop resonator. The performance of the proposed absorber was demonstrated by full-wave simulations and measurements. An inductance tolerance of 2% yielded errors of 1.2% and 1.25% in the absorptivity and absorption frequency, respectively. A prototype with 13 * 27 unit cells was fabricated and its absorptivity was measured to be 99.6% at 2.4 GHz. PMID- 30425317 TI - Real-time particle monitoring of pesticide drift from an axial fan airblast orchard sprayer. AB - In Washington State, a majority of reported pesticide-related illnesses and application-related complaints involve drift. We employed real-time particle monitors (Dylos) during a series of experimental spray events investigating drift. Sections of an orchard block were randomly sprayed by an axial fan airblast sprayer, while monitors sampled particulate matter above and below the canopy at various downwind locations. We found elevated particle mass concentrations (PMC) at all distances (16-74 m). The 75th percentile PMC while spraying was significantly greater than the control periods by 107 (95% CI 94 121) MUg/m3, after adjusting for sampler height and wind speed. The 75th percentile PMC below the canopy was significantly greater than above the canopy by 9.4 (95% CI 5.2-12) MUg/m3, after adjusting for spraying and wind speed. In a restricted analysis of the spray events, the 75th percentile PMC significantly decreased by 2.6 (95% CI -3.2 to -1.7) MUg/m3 for every additional meter away from the edge of the spray quadrant, after adjusting for canopy height and wind speed. Our results were consistent with a larger study that performed passive sampling during the same spray events, suggesting that real-time monitoring can be used as a screening tool for pesticide drift. Compared with traditional methods of drift sampling, real-time monitoring is overall an easily employed, affordable sampling technique, and it can provide minute-by-minute measurements that can be coupled with meteorological measurements to better understand how changes in wind speed and direction affect drift. PMID- 30425318 TI - Structure and oligomerization of the periplasmic domain of GspL from the type II secretion system of Pseudomonas aeruginosa. AB - The ability of bacteria to infect a host relies in part on the secretion of molecular virulence factors across the cell envelope. Pseudomonas aeruginosa, a ubiquitous environmental bacterium causing opportunistic infections in humans, employs the type II secretion system (T2SS) to transport effector proteins across its cellular envelope as part of a diverse array of virulence strategies. General secretory pathway protein L (GspL) is an essential inner-membrane component of the T2SS apparatus, and is thought to facilitate transduction of the energy from ATP hydrolysis in the cytoplasm to the periplasmic components of the system. However, our incomplete understanding of the assembly principles of the T2SS machinery prevents the mechanistic deconvolution of T2SS-mediated protein secretion. Here we show via two crystal structures that the periplasmic ferredoxin-like domain of GspL (GspLfld) is a dimer stabilized by hydrophobic interactions, and that this interface may allow significant interdomain plasticity. The general dimerization mode of GspLfld is shared with GspL from Vibrio parahaemolyticus suggesting a conserved oligomerization mode across the GspL family. Furthermore, we identified a tetrameric form of the complete periplasmic segment of GspL (GspLperi) which indicates that GspL may be able to adopt multiple oligomeric states as part of its dynamic role in the T2SS apparatus. PMID- 30425320 TI - Radon emission from soil gases in the active fault zones in the Capital of China and its environmental effects. AB - The release of radon in active fault zones is a sustained radioactive pollution source of the atmospheric environment. The species, concentration and flux of radon emitted in soil gas in active fault zones in the Capital of China were investigated by in-situ field measurements. Two main species of radon discharging from soil gas in active fault zones were identified, including radon diffused and dispersed from permeable soil, and upwelling from faults. Higher concentrations and flux of radon from faults were observed in the Bohai Bay Basin due to the accumulated uranium in the sandstone reservoirs and higher permeability of the strata and bed rocks. Increased radon released by strong earthquakes persists, with the max flux of 334.56 mBq m-2 s-1 observed in FN (Fengnan district) located at the epicenter of the 28 July, 1976 Tangshan MS 7.8 earthquake. The level of radon released in 8 of 22 locations within the Basin and Range Province (to the west of Taihangshan piedmont fault Zone) reached level 2, and 13 of 14 locations within the Bohai Bay Basin reached levels 2-4, according to the Chinese Code (GB 50325-2001, 2006). Corresponding protective and safety measures should be in place to protect the health of nearby residents, due to their exposure to radon emitted from the faults. Also, the concentration of radon in active fault zones should be investigated to assess the possible risk, before land-use is planned. PMID- 30425319 TI - Quadratic relationships between group size and foraging efficiency in a herbivorous primate. AB - The effect of feeding competition on foraging efficiency is an important link between ecological factors and the social organization of gregarious species. We examined the effects of group size on daily travel distances, activity budgets, and energy intake of mountain gorillas in Rwanda. We measured daily travel distances of five groups, activity budgets of 79 gorillas in nine groups, and energy intake data for 23 adult females in three groups over a 16-month period. Travel distances and the proportion of time spent traveling increased with size for most groups, which would be expected if their foraging efficiency is limited by intragroup feeding competition. However, travel distances and times decreased for the largest group, which also had higher energy intake rates than intermediate sized groups. The improved foraging efficiency of the largest group may be explained by advantages in intergroup contest competition. The largest group had much lower home range overlap than the other study groups which may be due to groups avoiding one another as a result of male mating competition. Collectively, our results indicate that intermediate sized groups had the lowest foraging efficiency and provide a new twist on the growing evidence of non-linear relationships between group size and foraging efficiency in primates. PMID- 30425322 TI - Plant HP1 protein ADCP1 links multivalent H3K9 methylation readout to heterochromatin formation. AB - Heterochromatin Protein 1 (HP1) recognizes histone H3 lysine 9 methylation (H3K9me) through its conserved chromodomain and maintains heterochromatin from fission yeast to mammals. However, in Arabidopsis, Like Heterochromatin Protein 1 (LHP1) recognizes and colocalizes genome-wide with H3K27me3, and is the functional homolog of Polycomb protein. This raises the question whether genuine HP1 homologs exist in plants. Here, we report on the discovery of ADCP1, a plant specific triple tandem Agenet protein, as a multivalent H3K9me reader in Arabidopsis, and establish that ADCP1 is essential for heterochromatin formation and transposon silencing through modulating H3K9 and DNA methylation levels. Structural studies revealed the molecular basis underlying H3K9me-specific recognition by tandem Agenet of ADCP1. Similar to human HP1alpha and fly HP1a, ADCP1 mediates heterochromatin phase separation. Our results demonstrate that despite its distinct domain compositions, ADCP1 convergently evolves as an HP1 equivalent protein in plants to regulate heterochromatin formation. PMID- 30425323 TI - 150 years of Darwin's theory of intercellular flow of hereditary information. AB - Charles Darwin's Pangenesis theory, which proposed an intercellular mechanism for the flow of hereditary information, is gaining new ground. PMID- 30425321 TI - Structural insights into Cas13b-guided CRISPR RNA maturation and recognition. PMID- 30425324 TI - Functions and mechanisms of epigenetic inheritance in animals. AB - The idea that epigenetic determinants such as DNA methylation, histone modifications or RNA can be passed to the next generation through meiotic products (gametes) is long standing. Such meiotic epigenetic inheritance (MEI) is fairly common in yeast, plants and nematodes, but its extent in mammals has been much debated. Advances in genomics techniques are now driving the profiling of germline and zygotic epigenomes, thereby improving our understanding of MEI in diverse species. Whereas the role of DNA methylation in MEI remains unclear, insights from genome-wide studies suggest that a previously underappreciated fraction of mammalian genomes bypass epigenetic reprogramming during development. Notably, intergenerational inheritance of histone modifications, tRNA fragments and microRNAs can affect gene regulation in the offspring. It is important to note that MEI in mammals rarely constitutes transgenerational epigenetic inheritance (TEI), which spans multiple generations. In this Review, we discuss the examples of MEI in mammals, including mammalian epigenome reprogramming, and the molecular mechanisms of MEI in vertebrates in general. We also discuss the implications of the inheritance of histone modifications and small RNA for embryogenesis in metazoans, with a particular focus on insights gained from genome-wide studies. PMID- 30425326 TI - Benefits of mindfulness meditation in reducing blood pressure and stress in patients with arterial hypertension. AB - The objective of this randomized controlled trial is to evaluate the benefits of mindfulness meditation in controlling ambulatory blood pressure (BP) and the impact of the intervention on anxiety, stress and depression levels in a Mediterranean population. Twenty-four and 18 patients [n = 42; mean age 56.5 (7.7) years; similar men and women proportions] with high-normal BP or grade I hypertension were enrolled to an intervention and a control group, respectively. For 2 h/week over 8 weeks, the intervention group received mindfulness training and the control group attended health education talks. The patients attended pre intervention, week 4, week 8 and week 20 follow-up visits. 61.9% of the patients had anxiety, 21.4% depression, 19.0% were smokers and 14.2% were diabetic (no significant differences between the 2 groups). At baseline, the intervention group had non-significant higher clinically measured BP values, whereas both groups had similar ambulatory BP monitoring (ABPM) values. At week 8, the intervention group had statistically significant lower ABPM scores than the control group (124/77 mmHg vs 126/80 mmHg (p < 0.05) and 108/65 mmHg vs 114/69 mmHg (p < 0.05) for 24-h and night-time systolic BP (SBP), respectively) and also had lower clinically measured SBP values (130 mmHg vs 133 mmHg; p = 0.02). At week 20 (follow-up), means were lower in the intervention group (although not statistically significant). Improvements were observed in the intervention group in terms of being less judgemental, more accepting and less depressed. In conclusion, by week 8 the mindfulness group had lower clinically measured SBP, 24 h SBP, at-rest SBP and diastolic BP values. PMID- 30425325 TI - Multifunctional self-assembled monolayers via microcontact printing and degas driven flow guided patterning. AB - Soft lithography-based patterning techniques have been developed to investigate biological and chemical phenomena. Until now, micropatterning with various materials required multiple procedural steps such as repeating layer-by-layer patterning, aligning of stamps, and incubating printed inks. Herein, we describe a facile micropatterning method for producing chemically well-defined surface architectures by combining microcontact (uCP) and microfluidic vacuum-assisted degas-driven flow guided patterning (DFGP) with a poly(dimethylsiloxane) (PDMS) stamp. To demonstrate our concept, we fabricated a bi-composite micropatterned surface with different functional molecular inks such as fluorescein isothiocyanate labelled bovine serum albumin (FITC-BSA) and polyethylene glycol (PEG)-silane for a biomolecule array, and 3-aminopropyltriethoxysilane (APTES) and PEG-silane pattern for a self-assembled colloid gold nanoparticle monolayer. With a certain composition of molecular inks for the patterning, bi-composite surface patterns could be produced by this uCP-DFGP approach without any supplementary process. This patterning approach can be used in microfabrication and highly applicable to biomolecules and nanoparticles that spread as a monolayer. PMID- 30425327 TI - Central-to-brachial blood pressure amplification in type 2 diabetes: a systematic review and meta-analysis. AB - Due to systolic blood pressure (SBP) amplification, brachial SBP may not accurately reflect central SBP, the pressure the organs are exposed to. Patients with type 2 diabetes (T2D) have vascular irregularities that may affect blood pressure (BP) amplification and central BP indices (i.e. augmentation index [AIx] and augmentation pressure [AP]). By systematic review and meta-analysis, this study aimed firstly to determine the magnitude of central-to-brachial SBP and pulse pressure (PP) amplification in T2D compared to healthy controls and secondly, the difference in AIx and AP between the groups. Online databases were searched for published studies reporting invasive or non-invasive central and brachial SBP in T2D and healthy controls up to the 20th of February 2018. Random effects meta-analyses and meta-regression were used to analyze the studies. Eighteen studies (all non-invasive: 17 radial tonometry, 1 carotid tonometry, 2 brachial oscillometry) with a total of 2758 patients with T2D and 10,561 healthy controls were identified. There was no significant difference in SBP amplification between groups (T2D = 9.9 +/- 4.7, healthy controls = 9.6 +/- 4.5 mmHg, p = 0.84; pooled difference = 0.64 mmHg, 95%CI -0.27 1.54, p = 0.17) or PP amplification ratio (p = 0.16). However, among these studies, central BP indices (AIx corrected for heart rate and AP) were significantly higher in T2D (p < 0.05 for both). Despite a similar magnitude of central-to-brachial SBP amplification, patients with T2D have increased central systolic loading (AIx and AP) that cannot be discerned from brachial BP alone. PMID- 30425328 TI - IgG1 variant promotes autoimmunity. PMID- 30425329 TI - A new antisense oligonucleotide therapy? PMID- 30425330 TI - Close to the bone - in search of the skeletal stem cell. PMID- 30425331 TI - Unravelling the pharmacogenomics of TNF inhibition. PMID- 30425332 TI - Gasdermin D opens the way for NETs. PMID- 30425333 TI - Author Correction: Clade-specific diversification dynamics of marine diatoms since the Jurassic. AB - In the version of this Article originally published, the authors did not give credit to David G. Mann for the four microscopic images used in Fig. 1a. This has now been amended in all versions of the Article. PMID- 30425334 TI - Amphiregulin in intestinal acute graft-versus-host disease: a possible diagnostic and prognostic aid. AB - Amphiregulin, a weak epidermal growth factor receptor agonist, is elevated, while epidermal growth factor, a strong epidermal growth factor receptor agonist, is low in the blood of patients with severe acute graft-versus-host disease. However, the tissue expression and function of these epidermal growth factor receptor ligands in acute graft-versus-host disease target organs is unknown. We compared by immunohistochemistry expression of amphiregulin and epidermal growth factor in archived, formalin-fixed, paraffin-embedded intestinal tissues of 48 patients with biopsy-proven gastrointestinal acute graft-versus-host disease to 3 groups: (1) 10 non-hematopoietic cell transplant normal controls, (2) 11 patients with newly diagnosed ulcerative colitis (ulcerative colitis), (3) 8 patients with a clinical diagnosis of acute graft-versus-host disease despite pathologically non-diagnostic biopsies, (4) and 10 cases of cytomegalovirus colitis. We used a semi-quantitative score of 0 (absent) through 3 (strong) to describe the intensity of immunohistochemical staining. We correlated serum and tissue amphiregulin and epidermal growth factor in patients with acute graft-versus-host disease. Gastrointestinal amphiregulin was significantly lower in acute graft versus-host disease biopsies (median score 1), ulcerative colitis (median score 1.5), and cytomegalovirus colitis (median score 1) than in normal colon (median score 2, p = 0.004, p = 0.03, p = 0.009 respectively). Amphiregulin expression in was low in 74% of acute graft-versus-host disease cases with or without significant apoptosis. Patients with acute graft-versus-host disease exhibiting the pattern of high gastrointestinal amphiregulin but low serum amphiregulin (n = 14) had the best 1-year survival at 71%, but patients with high serum amphiregulin had poorer survival (<30%) regardless of gastrointestinal amphiregulin expression. Overall, our results lead to the hypothesis that amphiregulin is released into the circulation from damaged intestinal epithelium and stroma, although contributions from other cellular sources are likely. Low gastrointestinal amphiregulin expression by immunohistochemistry may be further studied for its utility in the pathologic acute graft-versus-host disease diagnosis without classic apoptotic changes. PMID- 30425335 TI - RHOA mutations and CLDN18-ARHGAP fusions in intestinal-type adenocarcinoma with anastomosing glands of the stomach. AB - A subtype of intestinal-type adenocarcinoma of the stomach, characterized by low grade cytological atypia and anastomosing glands, has been described in several reports under different names. One of the remarkable features of these lesions, herein referred to as intestinal-type adenocarcinoma with anastomosing glands, is the frequent association of poorly differentiated adenocarcinoma components. Here we analyzed 44 intestinal-type adenocarcinomas with anastomosing glands focusing on the molecular abnormalities that are common in diffuse-type gastric cancers. Next-generation sequencing identified RHOA and CDH1 mutations in 22 (50%) and one lesion (2%), respectively. Reverse transcription-PCR detected CLDN18-ARHGAP fusions in three lesions (7%). Immunohistochemically, none of the lesions showed abnormal p53 expression patterns whereas focal and diffuse loss of ARID1A was observed in four and one lesion, respectively. Examination of 37 lesions of dysplasia and 26 usual-type intramucosal adenocarcinomas identified one RHOA mutation in adenocarcinoma and no CLDN18-ARHGAP fusions, indicating that these genetic alterations are highly specific to intestinal-type adenocarcinomas with anastomosing glands among differentiated-type intramucosal neoplasms. The present study showed that intestinal-type adenocarcinoma with anastomosing glands represents a genetically distinct group of tumors with the frequent presence of RHOA mutations and CLDN18-ARHGAP fusions, which are thought to be specific to diffuse-type gastric cancers. PMID- 30425336 TI - mTOR signalling and cellular metabolism are mutual determinants in cancer. AB - Oncogenic signalling and metabolic alterations are interrelated in cancer cells. mTOR, which is frequently activated in cancer, controls cell growth and metabolism. mTOR signalling regulates amino acid, glucose, nucleotide, fatty acid and lipid metabolism. Conversely, metabolic inputs, such as amino acids, activate mTOR. In this Review, we discuss how mTOR signalling rewires cancer cell metabolism and delineate how changes in metabolism, in turn, sustain mTOR signalling and tumorigenicity. Several drugs are being developed to perturb cancer cell metabolism. However, their efficacy as stand-alone therapies, similar to mTOR inhibitors, is limited. Here, we discuss how the interdependence of mTOR signalling and metabolism can be exploited for cancer therapy. PMID- 30425337 TI - Lowest PaCO2 on the first day of life predicts mortality and morbidity among infants with congenital diaphragmatic hernia. AB - OBJECTIVE: To evaluate the association between hypercarbia in the first 24 h of life and clinical outcomes in infants with congenital diaphragmatic hernia (CDH). STUDY DESIGN: Retrospective review of patients entered into the CDHSG registry between 2007-2014. Half of the identified patients were analyzed to identify the PaCO2 value most predictive of mortality. Prediction models for outcomes of death, ECMO, and respiratory support at 30 days of life (DOL) were developed using PaCO2. Remaining half of data was used for validation of study findings. RESULTS: 1878 and 1875 patients were analyzed in the testing and validation groups. Lowest PaCO2>=60 mmHg in the first DOL is highly predictive of death prior to discharge. Prediction models including this variable demonstrate good discrimination for outcomes of death, ECMO, and respiratory support (AUC 0.8808, 0.8279, 0.8065). CONCLUSION: Lowest PaCO2 in the first DOL is an independent risk factor of mortality and morbidity in CDH. PMID- 30425338 TI - Planned home deliveries in Finland, 1996-2013. AB - OBJECTIVE: To evaluate trends and perinatal outcomes of planned home deliveries in Finland. STUDY DESIGN: All infants born in 1996-2013, excluding those born preterm, by operative delivery, and without information on birth mode or gestational age, were studied. The study group included 170 infants born at home as planned, 720,047 infants born at hospital were controls. RESULT: The rate of planned home deliveries increased from 8.3 to 39.4 per 100,000. In the study group 63%, containing two perinatal deaths, were not low-risk pregnancies according to national guidelines. The rate of hypothermia, asphyxia, and need of invasive ventilation was increased in low-risk home deliveries. One infant had a major congenital malformation. Maternal outcomes were favorable. CONCLUSION: The rate of planned home deliveries increased. Guidelines for low-risk deliveries were not followed in a majority of cases, including two perinatal deaths. Even in low-risk home deliveries, the neonatal morbidity appeared to be increased. PMID- 30425340 TI - Microbiota drives sex-specific differences. PMID- 30425339 TI - Neonatal bloodspot DNA methylation patterns are associated with childhood weight status in the Healthy Families Project. AB - BACKGROUND: This study measured longitudinal DNA methylation dynamics at growth related genes during childhood, and then tested whether DNA methylation at various stages of childhood was associated with obesity status. METHODS: Using neonatal bloodspot (n = 132) and matched childhood blood samples (n = 65), DNA methylation was quantified at a repetitive element (long interspersed nuclear element-1 (LINE-1)), two imprinted genes (IGF2, H19), and four non-imprinted genes (LEP, PPARA, ESR1, SREBF1) related to growth and adiposity. Logistic regression was used to test whether neonatal bloodspot DNA methylation at target genes was associated with log odds of obesity (Y/N) in children recruited from three age groups-12-24 months old (n = 40), 3-5 years of age (n = 40), and 10-12 years of age (n = 52). RESULTS: In 3-5 year olds, neonatal bloodspot LINE-1 methylation was negatively associated with obesity (log odds = -0.40, p = 0.04). Across childhood age group in matched blood samples, DNA methylation levels in blood decreased (p < 0.05) at LINE-1, PPARA, ESR1, SREBF1, IGF2, and H19, and increased (p < 0.05) at LEP. CONCLUSIONS: Our results suggest that age-related epigenetic changes occur at growth-related genes in the first decade of life, and that gene-specific neonatal bloodspot DNA methylation may be a useful biomarker of obesity likelihood during childhood. PMID- 30425341 TI - New pathways in development of liver cancer. PMID- 30425344 TI - Erenumab succeeds in alleviating migraine where other treatments fail. PMID- 30425343 TI - eCoin device stops patients from spending a penny. PMID- 30425342 TI - Author Correction: Rock fluidization during peak-ring formation of large impact structures. AB - In this Article, the middle initial of author Kosei E. Yamaguchi (of the IODP ICDP Expedition 364 Science Party) was missing and his affiliation is to Toho University (not Tohu University). These errors have been corrected online. PMID- 30425346 TI - Tame or inflame: gut reactions to pro- and antibiotics. PMID- 30425345 TI - Blocking drug activation as a therapeutic strategy to attenuate acute toxicity and physiological effects of heroin. AB - Heroin is a growing national crisis in America. There is an increasing frequency of heroin overdoses. All of the currently used therapeutic approaches to treatment of heroin abuse and other opioid drugs of abuse focus on antagonizing a brain receptor (particularly u-opiate receptors). However, it has been known that the therapeutic use of certain u-opiate receptor antagonist may actually increase heroin overdose. Once overdosed, heroin addicts may continue to get overdosed again and again until fatal. Here we report our design and validation of a novel therapeutic strategy targeting heroin activation based on our analysis of the chemical transformation and functional change of heroin in the body. An effective blocker of heroin activation, such as ethopropazine tested in this study, may be used as a standalone therapy or in combination with a currently available, traditional medications targeting u-opiate receptors (e.g. naltrexone or its extended-release formulation Vivitrol). The combination therapy would be ideal for heroin abuse treatment as the effects of two therapeutic agents targeting two independent mechanisms are cooperative. PMID- 30425348 TI - Prognostic impact of CDX2 in stage II colon cancer: results from two nationwide cohorts. AB - BACKGROUND: The aim of the present study was to validate the prognostic impact of CDX2 in patients with stage II colon cancer. METHODS: Two unbiased population based cohorts representing all patients operated for stage II colon cancer in Denmark in 2002 and 2003. The CDX2 expression was evaluated by immunohistochemistry on whole tumour sections. Patients were classified into three groups, CDX2-positive, -moderate, and -negative, for comparison with the clinical data. RESULTS: A total of 1157 patients were included. We found a significant relationship between loss of CDX2 expression and poor disease-free survival in both cohorts, p = 0.0267 and 0.0118, respectively. Five-year disease free survival rates were 66%, 72% and 74% in the first cohort and 62%, 65%, and 75% in the second cohort for the negative, moderate, and positive CDX2 expression groups, respectively. Multiple Cox regression analysis performed on the combined cohorts confirmed an independent prognostic impact of CDX2 on disease-free survival, hazard ratio 1.543 (95% confidence interval 1.129-2.108), p = 0.0065. CONCLUSIONS: This retrospective study provides validation regarding the prognostic impact of CDX2 in patients with stage II colon cancer. The results justify prospective validation clarifying its clinical impact. PMID- 30425347 TI - Fibroblast growth factor 21 as a circulating biomarker at various stages of colorectal carcinogenesis. AB - BACKGROUND: Despite evidence that inflammation and metabolism play a crucial role in colorectal carcinogenesis, there have been few studies on the association of inflammatory and metabolic protein biomarkers in various stages of colorectal carcinogenesis. METHODS: Ninety-two inflammatory and metabolic biomarkers were measured in plasma samples of participants of screening colonoscopy. Markers identified to be significantly associated with the presence of advanced colorectal neoplasia (ACN) in a discovery set (n = 204) were validated in an independent replication set (n = 422). Adjusted associations with the presence of non-advanced adenomas (NAA), advanced precancerous lesions (APL) and colorectal cancer (CRC) were quantified by multiple logistic regression. RESULTS: Out of the 92 inflammatory proteins, 72 markers were evaluable and 8 showed statistically significant associations with the odds of ACN after full adjustment for potential risk factors for CRC in the discovery set. One of these, fibroblast growth factor 21 (FGF-21), could be validated in the replication set. The multivariable adjusted odds ratio (OR) reached 2.65 (95% CI, 1.50-4.81) for individuals with FGF-21 levels within the highest tertile, compared to those within the lowest tertile (Ptrend across tertiles = 0.001). Separate models revealed fully adjusted ORs for NAA, APL and CRC of 2.99 (95% CI, 1.45-6.58, Ptrend = 0.005), 2.24 (95% CI, 1.18-4.44, Ptrend = 0.021) and 3.92 (95% CI, 1.51-12.18, Ptrend = 0.003), respectively. CONCLUSIONS: Circulating FGF-21 level is associated with increased risk of early and late stages of colorectal carcinogenesis, supporting a role of inflammation and metabolism at all stages of colorectal carcinogenesis, and suggesting potential use of this biomarker for risk stratification in CRC screening. PMID- 30425349 TI - A phase Ib dose-escalation and expansion study of the oral MEK inhibitor pimasertib and PI3K/MTOR inhibitor voxtalisib in patients with advanced solid tumours. AB - BACKGROUND: This phase Ib study evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of pimasertib (MSC1936369B), a MEK1/2 inhibitor, in combination with voxtalisib (SAR245409), a pan-PI3K and mTORC1/mTORC2 inhibitor, in patients with advanced solid tumours. METHODS: This study included a dose escalation and expansion in patients with select tumour types and alterations in the MAPK or PI3K pathways. A 3 + 3 design was used to determine MTD. Patients were evaluated for adverse events and tumour response. RESULTS: 146 patients were treated, including 63 in dose escalation and 83 in expansion. The MTD was pimasertib 90 mg and voxtalisib 70 mg daily. Based on the safety profile, the recommended phase 2 dose (RP2D) was pimasertib 60 mg and voxtalisib 70 mg. The most frequent treatment-emergent adverse events (TEAEs) were diarrhoea (75%), fatigue (57%), and nausea (50%). Responses included a complete response in one patient (1%), partial response in five (5%), and stable disease in 51 (46%). At the RP2D, 74 patients required dose interruption (73%), 20 required dose reduction (20%), and 26 discontinued treatment due to TEAEs (26%). CONCLUSIONS: The combination of pimasertib and voxtalisib showed poor long term tolerability and limited anti-tumour activity in patients with advanced solid tumours. PMID- 30425350 TI - North American population-based validation of the National Comprehensive Cancer Network Practice Guideline Recommendations for locoregional lymph node and bone imaging in prostate cancer patients. AB - BACKGROUND: The National Comprehensive Cancer Network (NCCN) guidelines provide recommendations for staging of prostate cancer patients in the objective regarding presence of locoregional lymph node metastases (LNM) and bone metastases. We tested the performance characteristics of these recommendations in a community setting. METHODS: Within the Surveillance, Epidemiology, and End Results database (2004-2014), we identified patients with available Gleason, clinical stage and prostatic specific antigen. Performance characteristics endpoints consisted of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NVP), overall accuracy and the number needed to image (NNI). RESULTS: Totally, 191,308 patients were assessable for the validation of the LNM staging recommendations. Sensitivity ranged from 80.6 to 86.3%, specificity from 74.7 to 79.3%, PPV from 7.8 to 8.0%, overall accuracy from 75.0 to 79.3% and NPV was 99.5%. The respective NNI values were 12.5 and 12.8. 197,408 patients were assessable for the validation of bone scan recommendations. These recommendations resulted in 90.8% sensitivity, 76.3% specificity, PPV of 5.7%, NPV of 99.8% and overall accuracy of 76.5%. The NNI was 17.5. CONCLUSION: The NCCN recommendations for locoregional LNM miss few patients with clinical LNM (0.3-0.4%) and provide a virtually perfect NPV of 99.5%. Also, the recommendations for bone scan miss a marginal number of patients with established bone metastases (0.14%) and yield a virtually perfect NPV of 99.8%. PMID- 30425351 TI - Effect of home-based specialised palliative care and dyadic psychological intervention on caregiver anxiety and depression: a randomised controlled trial. AB - BACKGROUND: Specialised palliative care trials often fail to address intervention effects on caregiver anxiety and depression, particularly in bereavement. We evaluate effects of specialised palliative care and dyadic psychological intervention on caregiver anxiety and depression in a randomised controlled trial (RCT). METHODS: Patients with incurable cancer and limited antineoplastic treatment options and their caregivers, recruited from a university hospital oncology department, were randomised (1:1) to care as usual or accelerated transition from oncological treatment to home-based specialised palliative care. We assessed caregivers' symptoms of anxiety and depression with the Symptom Checklist-92 up to six months after randomisation and 19 months into bereavement, and estimated intervention effects in mixed effects models. RESULTS: The 'Domus' trial enrolled 258 caregivers. The intervention significantly attenuated increases in caregivers' symptoms of anxiety overall (estimated difference, 0.12; 95% confidence interval, -0.22 to -0.01, p = 0.0266), and symptoms of depression at eight weeks (-0.17; -0.33 to -0.02; p = 0.0314), six months (-0.27; -0.49 to -0.05; p = 0.0165), and in bereavement at two weeks (-0.28; -0.52 to 0.03; p = 0.0295) and two months (-0.24; -0.48 to -0.01; p = 0.0448). CONCLUSIONS: This first RCT evaluating specialised palliative care with dyadic psychological support significantly attenuated caregiver anxiety and depression before and during bereavement. (Clinicaltrials.gov: NCT01885637). PMID- 30425352 TI - Long-term treatment with the PARP inhibitor niraparib does not increase the mutation load in cell line models and tumour xenografts. AB - BACKGROUND: Poly-ADP ribose polymerase (PARP) inhibitor-based cancer therapy selectively targets cells with deficient homologous recombination repair. Considering their long-term use in maintenance treatment, any potential mutagenic effect of PARP inhibitor treatment could accelerate the development of resistance or harm non-malignant somatic cells. METHODS: We tested the mutagenicity of long term treatment with the PARP inhibitor niraparib using whole-genome sequencing of cultured cell clones and whole-exome sequencing of patient-derived breast cancer xenografts. RESULTS: We observed no significant increase in the number and alteration in the spectrum of base substitutions, short insertions and deletions and genomic rearrangements upon niraparib treatment of human DLD-1 colon adenocarcinoma cells, wild-type and BRCA1 mutant chicken DT40 lymphoblastoma cells and BRCA1-defective SUM149PT breast carcinoma cells, except for a minor increase in specific deletion classes. We also did not detect any contribution of in vivo niraparib treatment to subclonal mutations arising in breast cancer derived xenografts. CONCLUSIONS: The results suggest that long-term inhibition of DNA repair with PARP inhibitors has no or only limited mutagenic effect. Mutagenesis due to prolonged use of PARP inhibitors in cancer treatment is therefore not expected to contribute to the genetic evolution of resistance, generate significant immunogenic neoepitopes or induce secondary malignancies. PMID- 30425354 TI - Combination treatment prevents HIV re-emergence in monkeys. PMID- 30425355 TI - Increased synthesis of a coenzyme linked to longevity can combat disease. PMID- 30425356 TI - Gut microbes alter the walking activity of fruit flies. PMID- 30425357 TI - How Mongolia's milk-based empire got its start. PMID- 30425358 TI - Warming trend spoils Europe's winter wonderlands. PMID- 30425359 TI - Thar she blows! Whales seen exhaling from space. PMID- 30425353 TI - Publisher Correction: Allele-defined genome of the autopolyploid sugarcane Saccharum spontaneum L. AB - In the version of this article originally published, the accession codes listed in the data availability section were incorrect and the section was incomplete. The text for this section should have read "The genome assembly and gene annotation have been deposited in the NCBI database under accession number QVOL00000000, BioProject number PRJNA483885 and BioSample number SAMN09753102. The data can also be downloaded from the following link: http://www.life.illinois.edu/ming/downloads/Spontaneum_genome/ ." The errors have been corrected in the HTML and PDF versions of the article. PMID- 30425360 TI - 'Mining' Bitcoin takes more energy than mining gold. PMID- 30425361 TI - Science candidates prevail in US midterm elections. PMID- 30425362 TI - Sanger whistle-blowers dispute findings that cleared management of bullying. PMID- 30425363 TI - Ancient genomics is recasting the story of the Americas' first residents. PMID- 30425364 TI - Heart-in-a-dish dances to the beat. PMID- 30425365 TI - Oil foils corrosion in high-capacity batteries. PMID- 30425366 TI - A massive atom morphs with record-setting speed. PMID- 30425368 TI - Ethics at the cutting edge, beastly movers and shakers, and teeth as time machines: Books in brief. PMID- 30425367 TI - 'Invisible' mice reveal anatomical secrets. PMID- 30425369 TI - Be open about drug failures to speed up research. PMID- 30425370 TI - How a simple 'thank you' could improve clinical trials. PMID- 30425371 TI - If you can't build well, then build nothing at all. PMID- 30425372 TI - How Facebook and Twitter could be the next disruptive force in clinical trials. PMID- 30425373 TI - China's crackdown on genetics breaches could deter data sharing. PMID- 30425374 TI - Italy's olive crisis intensifies as deadly tree disease spreads. PMID- 30425375 TI - US elections signal a welcome change for science. PMID- 30425376 TI - [Implementation of echography in hospital emergency services of Catalonia (ECURCAT study)]. PMID- 30425377 TI - [Defensive Medicine: meaning vs. measurement]. PMID- 30425378 TI - [Do not do: from recommendations to action]. PMID- 30425379 TI - [Characteristics and statistical methods used in original articles published in Public Health journals in Spain]. AB - BACKGROUND: To describe the characteristics and statistical methods used in the original articles published in Gaceta Sanitaria, Revista Espanola de Salud Publica y Anales del Sistema Sanitario de Navarra, the Spanish public health journals in Spain indexed in the 2016 JRC. METHODS: All articles published in these journals in 2007, 2012 and 2017 were reviewed. For each article, general aspects (year, journal, language, area) and statistical characteristics (design, purpose, method and software) were recorded. RESULTS: A total of 310 articles were reviewed, 73% of them were cross-sectional studies. Evaluation and health services (24%) and chronic diseases were the most frequent areas. During the 2007 2017 period there was an increase in both the number of works written in English (4 vs 20%, p<0.001) and by women as the main (46 vs 62%, p=0.028) or senior authors (27 vs 36%, p=0.029). Significant changes concerning type of analysis were not detected (p=0.933). CONCLUSIONS: The characteristics and statistical methods used in scientific publications have not been modified in recent years. However, publications written in English have increased and women are playing a more relevant role in authorship. KEYWORDS: Authorship. STATISTICAL ANALYSIS: Scientific research. Public Health. Spain. PMID- 30425380 TI - [Tension-type headache. Narrative review of physiotherapy treatment]. AB - INTRODUCTION: Headache is a very common phenomenon with a high economic and psychosocial impact. Tension-type headache (TTH) is the most prevalent (40%), especially amongst adult western women. The aim was to evaluate the existing evidence on the effectiveness of physiotherapy techniques in treating TTH. METHODS: Literature review of randomised clinical trials (RCT) and systematic reviews, published over the last five years, on the physiotherapy techniques most used in treating TTH: therapeutic exercise, suboccipital inhibition, cervical manip-ulation, massage, joint mobilisation and puncture. RESULTS: Twenty-six articles (seven reviews) met the criteria for inclusion. The reviews found evidence of the effectiveness of therapeutic exercise on the intensity, frequency and duration of pain. Improvement was also achieved by manual therapy in a similar way to medicines (although with contradictory long-term results), by the combination of dry puncture and physiotherapy on the VAS score, and by the combination of mobilisation techniques with stretching and muscular massage, but not separately. Amongst other results, the RCT showed that massage achieved less pain and frequency, as well as better quality of life, perceived clinical sensation and range of movement; pain improved with suboccipital inhibition and aerobic exercises; and the range of movement with cervical manipulation, massage of soft tissues and mobilisation. CONCLUSION: The published clinical evidence endorses physiotherapy as an effective treatment in managing patients with TTH, although additional studies with a better quality methodology are required. PMID- 30425381 TI - [Cavernous hemangioma of the nasal bones: a case report]. AB - Cavernous hemangiomas represent less than 1% of all bone tumours, with the vertebrae and the skull being the most common locations. These tumours are extremely rare in the bones of the nose, with very few cases published in the medical literature, where they have been reported in turbinates, vomer, nasal bones or perpendicular lamina of the ethmoid. They usually present as a tumour lesion that grows over time, involving the bone and even the soft tissues, which can cause complications such as nasal obstruction, bleeding, ulcerations and infection. We present the case of a 37 year-old patient with a cavernous hemangioma located in the bones of the nose, reviewing the most notable aspects of this rare tumour. Keywords. Cavernous Hemangioma. Bone hemangioma. Nasal tumor. Nasal bones. Surgical treatment. PMID- 30425382 TI - [Implementation of echography in hospital emergency services]. PMID- 30425383 TI - [Defensive Medicine: meaning vs measurement]. PMID- 30425384 TI - [Drug-related mortality among inpatients admitted in Internal Medicine]. AB - BACKGROUND: To analyze the mortality associated with prescriptions, the drugs most frequently involved and the associated risk factors in patients admitted to Internal Medicine. METHODS: A retrospective, observational study. The clinical records of adult patients who died consecutively in the department of Internal Medicine in a Spanish tertiary hospital over twenty-two months were reviewed. The main variable was the prevalence of hospital death suspected of being related to the medications administered during admission. RESULTS: Out of the 455 deaths analyzed, 22.2% were related to the medications received; in 55 cases (12.1%) the drugs were suspected of being the cause of death and in 46 cases (10.1%) of contributing to it. The most frequent diagnoses in cases of death associated with drugs were cardiac arrhythmia (23.7%), severe hemorrhage (19.8%) and aspiration pneumonia (12.8%). The drugs with the highest prevalence in deaths related to pharmacological treatment were an-tithrombotic drugs (23.7%), digoxin (21.7%), antipsychotics (17.8%) and benzodiazepines (14.8%). The only independent risk factor for mortality associated with treatment was the number of medications administered (OR=1.25, 95%CI: 1.14-1.37). No significant association was found with age, sex, number of pathologies or duration of hospital stay. CONCLUSION: A high percentage of deaths of patients admitted to Internal Medicine were considered related to the medications received. Antithrombotic drugs, digoxin and psychotropic drugs were the agents most frequently implicated. This mortality is independently and significantly associated with the number of medications administered. PMID- 30425385 TI - [Michaelis-Manz syndrome. A case report]. AB - Michaelis-Manz syndrome is an autosomal recessive hereditary tubulopathy associated with mutations in the tight-junction proteins claudin-16 and claudin 19, which are present in the distal convoluted tubule and the loop of Henle in the kidney. Claudin-19 is also expressed in the retinal pigmentary epithelium. The clinical picture causes hypomagnesemia, hyper-calciuria and nephrocalcinosis that can lead to renal failure, which is the condition that marks the prognosis of the disease. Ophthalmologically patients can present macular coloboma, myopic staphyloma and nystagmus. We present the case report of an 18-year-old man suffering from hereditary hypomagnesemia, hypercalciuria and nephrocalcinosis, or Mich-aelis-Manz syndrome, with macular coloboma and stable visual acuities. Keywords. Hypomagnesemia. Hypercalciuria. Nephrocalcinosis. Macular coloboma. PMID- 30425387 TI - ? PMID- 30425386 TI - [Excessive daytime sleepiness and sleep hygiene of working adults in Spain]. AB - BACKGROUND: To calculate the prevalence of excessive daytime sleepiness (EDS) (through the Epworth Sleepiness Scale, ESE) and to identify the personal and working variables predicting the risk of EDS. METHODS: Cross-sectional study performed on 476 civil servants from Murcia (October 2013 - February 2016). Prevalence of EDS and bad sleep hygiene (LSH) were determined from scores on the Epworth Sleepiness Scale and Sleep Hygiene Scale (SHS), respectively, and their association with different variables was obtained from a self-administered questionnaire. Independent predictors of EDS were identified by multivariate logistic regression. RESULTS: EDS was less prevalent (16.7%) than LSH (23.4%). Women scored higher in ESE (7.5 vs 6.3; p=0,001) and suffered twice the EDS of men (23.0 vs 10.7%, p<0.001). Workers with EDS scored higher on SHS (34.3 vs 32.7; p=0.044) and had LSH more frequently (38.7 vs 24.9%, p=0.014). Smokers were predominantly women (57.0%; p=0.087) with LSH (50.0 vs 25.8 and 18.9% amongst ex smokers and non-smokers, p<0.001). Being a woman OR=2.5, 95%IC: 1.4-4.3; p<0.001) and having bad sleep hygiene (OR=1.8 95%IC: 1.0-3.2, p=0.032) were predictive factors irrespective of suffering from EDS. CONCLUSIONS: EDS was present in civil servants in the region of Murcia, and was higher in women than men. Excessive daytime sleepiness is strongly associated with bad sleep hygiene and became a woman. PMID- 30425388 TI - [70th Anniversary of the Framingham Heart Study. Cardiovascular epidemiology from the past to the future]. PMID- 30425389 TI - [Heart transplantation: from the pioneering era to future prospects]. PMID- 30425390 TI - [What are the main novelties in the recent US and European guidelines for the management of hypertension?] PMID- 30425391 TI - [Influenza infection and risk of myocardial infarction: the protective effect of influenza vaccination. One more reason to vaccinate]. AB - Influenza infection, although considered a relatively benign pathology, is associated with a high number of hospital admissions and significant mortality, especially for the most vulnerable subjects. There is a great deal of evidence regarding the existence of an association between influenza and occurrence of cardiovascular events. Influenza vaccination by reducing the transmission of infection aims to reduce its complications, including cardiovascular events. The available studies have confirmed the safety of influenza vaccination in patients at high cardiovascular risk, even if performed during acute coronary syndrome hospitalization, and its efficacy in reducing coronary events. The cardiac benefit of influenza vaccination has been acknowledged by the cardiological scientific societies in the drafting of guidelines for both stable coronary artery disease and heart failure. PMID- 30425392 TI - [Bleeding risk in patients with acute coronary syndromes treated with antiplatelet agents: incidence, prognosis and clinical evaluation. From research to clinical practice]. AB - Dual antiplatelet therapy (DAPT) including aspirin and a P2Y12 inhibitor is the cornerstone for the treatment of patients with acute coronary syndrome (ACS). The introduction of more potent drugs significantly reduced ischemic events, but with an associated increased risk of bleeding. Although appropriate estimation of bleeding risk by comparing the single drugs is challenging, mainly because of differences in definitions, it has been consistently shown that bleeding events are associated with an adverse outcome, both at short and long-term follow up.Current guidelines recommend a short DAPT in patients at high bleeding risk, making appropriate risk estimation of crucial importance. Several numerical scores have been proposed for use in daily clinical practice. Although an objective risk assessment provides superior risk discrimination compared to physician's estimation, none of these scores appear free from limitations, nor have been obtained from cohorts of patients on short-tern treatment with prasugrel or ticagrelor. In the present review, we report the rates of major bleeding observed in the main randomized clinical trials and registries, their association with mortality, differences in definitions when used as safety endpoint, and finally the scores currently used for evaluation in daily clinical practice. PMID- 30425393 TI - [Therapeutic strategies in elderly patients with acute coronary syndromes]. AB - Because of the aging of the population, the proportion of elderly patients admitted to the coronary care unit for an acute coronary syndrome (ACS) is increasing. Until a decade ago, treatment of elderly patients was based on poor scientific evidence, as older patients were commonly excluded from randomized controlled trials. In the last years, real-world registries and randomized controlled trials specifically addressing the older population have been published and provided clear evidence. Primary percutaneous angioplasty has become the standard of care for the treatment of ST-elevation myocardial infarction also in the elderly population, whereas the Italian Elderly ACS and the After Eighty randomized trials have demonstrated the superiority of an invasive strategy over an initial conservative strategy also in elderly patients affected by non-ST-elevation myocardial infarction. Moreover, real-world registries have shown that an increased use of early revascularization was associated with a progressive reduction in mortality after ACS: these findings have been confirmed also in a clinical context characterized by high mortality rates such as that of cardiogenic shock. As 80% of deaths after an ACS have been shown to be due to cardiovascular causes also in the elderly, the focus has been shifted to secondary prevention. Data regarding the use of both ticagrelor or low dose prasugrel, as compared to clopidogrel, showed that a reduction of ischemic events was counterbalanced by an increase in bleeding events. In perspective, it might be interesting to explore the superiority of a strategy that limits the duration of dual antiplatelet therapy to a short period after an ACS (when the ischemic event rate is higher) in elderly patients, and to explore other endpoints such as mid-term quality of life outcome after ACS in elderly patients. PMID- 30425394 TI - [Inverse association between mortality and estimated functional capacity in hypertensive male outpatients with established coronary artery disease]. AB - BACKGROUND: Exercise capacity has been inversely associated with the incidence and severity of hypertension and cardiovascular disease. Cardiopulmonary exercise testing (CPET) is the gold standard for the determination of exercise capacity (i.e. peak oxygen consumption [VO2peak]). However, CPET is not always readily available in clinical settings. A moderate 1-km treadmill walking test (1k-TWT) has been demonstrated to be a valid and simple tool for the assessment of exercise capacity in outpatients with cardiovascular disease. The aim of this study was to examine the association between VO2peak estimated during a 1k-TWT and all-cause mortality in patients with hypertension and stable coronary artery disease. METHODS: A total of 597 patients aged 63 +/- 9 years underwent the 1k TWT, and were followed up for all-cause mortality. The 1k-TWT was individualized at a moderate perceptually-regulated exercise intensity (11-13 on the 6-20 Borg scale). Age, body mass index, heart rate, and time to complete the 1k-TWT were entered into the equations originally validated for VO2peak estimation. Subjects were stratified into quartiles according to baseline VO2peak, and mortality risks were calculated. RESULTS: During a median follow-up of 7.7 years, 79 deaths from any cause occurred, and resulted 36, 28, 10 and 5 for the first, second, third, and fourth quartile respectively. Compared to the lowest quartile (average VO2peak 18.1 ml/kg/min, n=149), the full-adjusted hazard ratios were 0.80 (p=0.49), 0.31 (p=0.02), and 0.13 (p=0.005) for the second (average VO2peak 21.8 ml/kg/min, n=150), third (average VO2peak 24.4 ml/kg/min, n=149), and fourth quartile (average VO2peak 28.7 ml/kg/min, n=149), respectively. CONCLUSIONS: VO2peak estimated by the 1k-TWT is a strong and independent predictor of all cause mortality in patients with hypertension and coronary artery disease. Assessing VO2peak by the 1k-TWT can be a useful, simple and low-cost tool to stratify and follow up hypertensive patients with cardiovascular disease through cardiac rehabilitation and secondary prevention programs. PMID- 30425396 TI - [Prof. Eligio Piccolo]. PMID- 30425395 TI - [Hypokinetic cardiac arrest and hypereosinophilia: a case of Kounis or Churg Strauss syndrome?] AB - Ischemic heart disease can be caused by multiple factors. However, epidemiological studies have evidenced an association between hypereosinophilia and acute coronary syndrome, most frequently observed in the Kounis and Churg Strauss syndromes. We here report the case of a 37-year-old man, who was admitted to our hospital for acute coronary syndrome, complicated by hypokinetic cardiac arrest with severe hypereosinophilia. PMID- 30425397 TI - Training Students to Address Vaccine Hesitancy and/or Refusal. AB - Objective. To determine the impact of a vaccine hesitancy learning unit on student knowledge, attitudes, and ability to address vaccine hesitancy and/or refusal. Methods. The learning unit consisted of two standardized patient simulation encounters performed one week apart. A 13-item attitudes survey was administered prior to the simulations to determine student confidence and knowledge regarding vaccine hesitancy. Students then participated in an encounter with a simulated patient who assessed the students' abilities using a 16-item grading rubric related to the art of the rhetoric, communication skills, and social, emotional competence. Post-simulation, students received feedback, completed a self-reflection exercise, and received formal coursework on addressing vaccine hesitancy. The following week, students participated in a second simulated patient encounter and thereafter completed the same attitudes and satisfaction surveys. Results. There were 203 students who went through the learning unit, with 180 (88.6% response rate) completing all the survey tools. The results showed significant improvements in all 16 items of the assessment rubric. On the pre/post attitudes questions, 9 out of 13 items showed significant improvement. Gains were largest for knowledge on the use of thimerosal as a preservative, speaking about how vaccines will not overwhelm a child's immune system, and knowledge about vaccinations not overwhelming a child's immune system. Overall, 94% of students were satisfied with the learning unit. Conclusion. This learning unit was effective in improving student confidence and ability to address vaccine hesitancy. PMID- 30425398 TI - An Effective Approach to Teaching Pharmacogenomics in the First Year of Pharmacy Curriculum. AB - Objective. To develop an effective method in teaching pharmacogenomics as a part of a new course, Biopharmaceutics and Pharmacogenomics. Methods. Teaching effectiveness was measured by quizzes, retrospective pre- and post-surveys, team activities, and journal reflections. Four team activities were included in the course: genomic disease, patient case, genetic counselor and a debate about personalized medicine. Outcomes and course impact were evaluated at the end of the course. The evaluation methods included the assessment of knowledge, students' perceptions regarding the utility of team activities, the impact of the course on students' confidence to discuss pharmacogenomics with health care providers or patients, and long-term knowledge retention, measured in the following P2 semester. Results. Seventy-six students were enrolled in the course. Multiple assessments during the course demonstrated that students' knowledge of pharmacogenomics improved. The team activities had a positive impact on student learning, and the course improved their confidence level to discuss pharmacogenomics with another health care provider or a patient. While 86% of the students considered themselves "unconfident," "somewhat unconfident" or "neither confident nor unconfident" at the beginning of the course, 91% reported being "confident" or "somewhat confident" by the end of the course. This increase in confidence was statistically significant. Furthermore, students showed knowledge retention six months after taking the course. Conclusion. Implementation of a new course in pharmacogenomics was effective and well received by the students. It also prepared students for system-based therapeutics courses later in the curriculum. PMID- 30425399 TI - Stress, Satisfaction, and Competency of Hospital Pharmacy Preceptors under the New Pharmacy Program in South Korea. AB - Objective. To evaluate hospital pharmacy preceptors' views of preceptorship and to explore the factors that might influence their stress and satisfaction after joining the newly implemented six-year pharmacy program in South Korea. Methods. A nationwide, cross-sectional, self-administered 47-item online survey was conducted for preceptors at hospital pharmacy practice sites in 2015. Results. Among 601 preceptors, 395 responded to the survey. They reported high stress and moderate role satisfaction and likelihood of continuing preceptorship. Workload was a major cause of stress and a barrier for continuing preceptorship, whereas improvement of professional knowledge and performance ability was considered the most important benefit and motivation of preceptorship. Monetary rewards were the most valuable incentive. Extra work hours used for precepting were a significant positive covariate for stress, while willingness to engage in preceptorship was a negative covariate for stress and positive covariate for satisfaction. Self perceived assessments of preceptors' competencies showed moderate performance. Following an Importance-Performance Analysis (IPA), passion for teaching students and being a professional role model were identified as items in need of improvement. Conclusion. This study investigated relevant issues associated with hospital pharmacy preceptors in South Korea under the country's new experiential education program. The findings will help to enhance the quality of hospital pharmacy experiential education in countries that have implemented or are planning to implement a new pharmacy program. PMID- 30425400 TI - Use of a Modified Delphi Process to Determine Course Objectives for a Model Global Health Course in a Pharmacy Curriculum. AB - Objective. To define course objectives for a model global health course in a pharmacy curriculum. Methods. A modified Delphi process was used to determine a consensus among proposed course objectives. A three-round email panel was sent to members of three special interest groups (SIGs) within the American Association of Colleges of Pharmacy (Public Health, Global Pharmacy Education, and Health Disparities and Cultural Competence) to recruit educators broadly interested or engaged in this area of education. An initial list of 80 potential course objectives across 11 domains was proposed for inclusion. Objectives that were cumulatively rated as either "extremely important" or "very important" by at least 75%, 80%, and 85% of respondents in each of the three rounds, respectively, were moved forward (first and second rounds) or accepted (third round). Results. Responses were received from 87, 73, and 70 faculty panel members in the three consecutive rounds. The initial list of proposed objectives was narrowed to 65 objectives (19% reduction), and 38 objectives (53%) after the first and second rounds, respectively. The final list was composed of 20 objectives from seven domains. Global burden of disease and social/environmental determinants of health contained the most objectives selected by consensus. Conclusion. The process identified a consensus for course objectives for a model global health education course. These objectives can be used by pharmacy faculty to align global health education in the profession. PMID- 30425401 TI - Identification of Key Business and Management Skills Needed for Pharmacy Graduates. AB - Objective. To identify key business, management, and human resources skills needed by pharmacy graduates. Methods. Pharmacy preceptors were recruited for inclusion in one of four focus groups. At each focus group, participants were asked to complete a demographic questionnaire and to identify key skills that new graduates need but do not have. Each focus group was audio-recorded, transcribed, de-identified, and categorized using a data dictionary. Results. Twenty-seven preceptors participated in the focus groups. Fourteen participants had a Doctor of Pharmacy degree. Participants were involved in management positions for a median of 10.5 years (range 5-21 years) and 50% (median) of their time was devoted to management responsibilities (range 20%-80%). Seven themes were identified as being most critical: communication, business skills, decision making and time management, conflict resolution, leadership and professionalism, personnel management, and computer software techniques. Conclusion. Communication was the most prominent skill identified, followed by decision-making and business knowledge. These skills should be addressed in pharmacy curricula. Future research should focus on how to best teach these skills. PMID- 30425402 TI - Learning Activities to Build Population Health Management Skills for Pharmacy Students. AB - Objective. To describe the implementation and evaluation of population health management learning activities in a second-year Doctor of Pharmacy (PharmD) course. Methods. Population health learning sessions were implemented in a step wise manner: population needs assessment activity to identify priority programs for implementation given a specific patient population; didactic materials to introduce program evaluation foundational knowledge; program evaluation design activity to evaluate implemented programs using the Centers for Disease Control and Prevention's Program Evaluation Framework; and evaluation of program outcome data. Students' self-rated abilities (grouped into Bloom's Taxonomy classifications) and perceptions before and after program evaluation activities were assessed. Qualitative analyses evaluated student feedback on learning sessions. Results. Students' self-rated abilities for all Bloom's classifications increased after the learning sessions. Student perceptions on importance of program evaluation also improved (from 71% reporting "agree" or "strongly agree" pre-activities to 79% post-activities). Students found the application to case scenarios and the opportunity to integrate each component of program evaluation into a complete process useful. Conclusion. Step-wise population health management learning sessions were implemented, culminating in skill-based program evaluation activities. The activities improved students' self-rated abilities and perceptions regarding program evaluation. Areas for improvement for the learning sessions were also identified and will inform future instructional design. PMID- 30425403 TI - Personalized Learning in an Online Drugs and US Health Care System Controversies Course. AB - Objective. To examine if personalized learning objectives influenced student engagement and if achievement of objectives could be measured from course assignments. Methods. Learners created personalized learning objectives that correlated with their own goals within the context of the course. Using a mixed methods analysis approach, the influence of these objectives on engagement and evidence of achievement of objectives were examined. Results. Students reported a positive influence of personalized learning objectives on engagement. Additionally, measurement of student progression or achievement of objectives was possible from analysis of the course assignments. Conclusion. Personalized learning is an important educational design for future pharmacists and health care professionals. Creating personalized learning objectives that build on centralized course objectives and connect to a broader context is one way to achieve the goal of an engaged and expanded learning experience. PMID- 30425404 TI - Predictors of Publication Rates for Abstracts Presented at the American Association of Colleges of Pharmacy Annual Meetings. AB - Objective. To examine trends in manuscript publication rates for abstracts presented at the 2000, 2005, 2010, and 2015 American Association of Colleges of Pharmacy (AACP) annual meetings. Methods. A systematic search of PubMed, Scopus, and Google Scholar was performed. "New" colleges and schools of pharmacy were defined as receiving accreditation after 1996. Contingency tables and t-tests were applied. Results. There were 1382 abstracts evaluated. The overall publication rate was 20% and there was no difference in publication rates over 15 years. The median time to publication for years 2000, 2005, and 2010 was 15 months. The most frequent journal for publication was the American Journal of Pharmaceutical Education. The primary analysis identified several predictors for publication, including collaboration, presence of a PhD pharmaceutical program or academic medical center, and use of inferential statistics. There was no difference in manuscript publication when comparing "new" and legacy schools. Conclusion. The publication rate of AACP abstracts has remained steady despite the increase in pharmacy schools and colleges and faculty. Collaboration among institutions was the strongest predictor for publication, highlighting its importance. The low publication rate observed may be attributed to a lack of training for junior faculty, insufficient forums to publish work, or misaligned motivations for scholarship among faculty. These barriers should be examined further. PMID- 30425406 TI - Providing an Academic APPE Elective via Videoconference Between Off-campus Faculty and Students. AB - Objective. To describe students' experiences and learning outcomes of an academic advanced pharmacy practice experience (APPE) elective provided via videoconference. Faculty preceptor and experiential administration's perspectives also are described. Methods. This 5-week APPE was developed using backward design and delivered starting in 2015 via videoconferencing, with the faculty preceptor and students physically located in different locations throughout the state. After the APPE, students completed a retrospective survey comparing their perspectives and learning outcomes before and after the rotation. They also provided feedback on the experience. Students completed the standard APPE evaluation. Faculty preceptor's self-reflections and experiential administration's perspectives were documented. Results. Six students completed this unique APPE over three academic years. After the rotation, five students (83%) stated that their interest in a full-time academic career increased, while one student's (17%) interest stayed the same. All students stated there was "no hindrance" with this rotation being conducted via videoconference or with the geographical distance between the faculty preceptor and them. Student ratings of nine learning outcomes increased after completing the APPE, demonstrating their perception of their knowledge improved in all topic areas. Conclusion. Students, the faculty preceptor, and experiential administration deemed this videoconference academic APPE effective and successful. This experience affords students, without regard for physical location, the opportunity to pursue interests in academia, adds to the variety of APPEs offered by the school, and allows students to learn about careers in academic pharmacy, an area of growing need in the pharmacy profession. PMID- 30425405 TI - Use of Simulations to Improve Pharmacy Students' Knowledge, Skills, and Attitudes About Medication Errors and Patient Safety. AB - Objective. To design and evaluate the use of simulations in preparing students to identify and reduce medication errors and promote patient safety. Methods. Third year pharmacy students used methods of root cause analysis (RCA) to determine the cause of a medication error in three simulated pharmacy settings. Before and after the activity, students completed an anonymous survey. They also completed a modified Healthcare Professionals Patient Safety Assessment instrument to measure changes in their knowledge, skills, and attitudes. Results. Ninety out of 165 students submitted complete data sets for analysis. Students demonstrated significant changes in knowledge, skills, and attitudes regarding medication errors. They felt they could find the cause of an error, identify factors leading to an error, and work with a team to prevent error recurrence. They also demonstrated an increase in knowledge about medication-related errors and the root cause analysis process. Conclusion. Students used RCA methods to discover medication errors in three simulated pharmacy settings. Students improved their knowledge, skills, and attitudes regarding medication errors through this process. PMID- 30425407 TI - Incorporating an Entrepreneurial Certificate into the Pharmacy Curriculum. AB - Objective. To describe the implementation and assessment of an entrepreneurial certificate program within an elective. Methods. An entrepreneurial certificate program through the Kauffman Foundation was integrated within an entrepreneurial elective to provide students at Presbyterian College School of Pharmacy with more in-depth training regarding entrepreneurial skills. A pre-/post-survey was administered to assess knowledge and skills obtained. Results. Thirty-three students completed the survey. By completing the entrepreneurial certificate, 67% of students increased their knowledge and skills in entrepreneurism. Conclusion. Incorporating an entrepreneurial certificate program into the pharmacy curriculum increases student confidence in entrepreneurial principles and skills. PMID- 30425408 TI - Implementation and Evaluation of Near-Peer Facilitated Journal Club Activities in a Required MLE Course Series. AB - Objective. To describe and evaluate the implementation of multiple, content integrated journal club activities into a large, required medical literature evaluation (MLE) two-semester course series using near-peer student facilitators. Methods. Using near-peer, third-year (P3) students as a significant source of instructional personnel, 10 journal club activities were incorporated annually into the second-year (P2) MLE series. Activities included preparation, quiz, journal club, and debriefing. Each activity divided the P2s into groups of 8-12 students. In the fall semester, journal clubs were facilitated by faculty members and near-peers as P2s participated. In spring, P2s also facilitated, while faculty members' and near-peers' roles shifted to providing rubric-facilitated feedback and mentoring. Near-peers and P2s provided feedback on the experiences. Results. Over four years, two course faculty members and 62 near-peers facilitated (fall) or provided feedback/mentoring (spring) for 346 P2 MLE I/II students in 419 individual journal clubs. Course faculty members covered 80 journal clubs, while near-peers covered 339. Faculty and near-peer ratings of P2 facilitators demonstrated good P2 preparation. P2 facilitators were best at facilitating discussion of implications and results, while being most challenged by introduction and methods. P2 survey responses highly favored the addition of journal club activities and the use of P3 near-peer facilitators. Conclusion. The use of near-peers in the implementation of integrated journal club activities in a large, required MLE course series was successful. Future study will include refining formative feedback processes, exploring benefit to near-peers, and exploring near-peer use in other didactic settings. PMID- 30425409 TI - What Can Be Done to Help the Pharmacy Profession Advance Globally? PMID- 30425410 TI - P&T and Me. AB - Very few occasions bring more stress to a faculty member than the promotion and/or tenure (P&T) process. In this commentary, two recent chairs of P&T committees give their advice to future petitioners. Subtopics of the editorial discuss knowing the expectations, finding mentors to guide you, understanding the role of peer reviewers and preparing your dossier. PMID- 30425411 TI - Student and School-level Predictors of Pharmacy Residency Attainment. PMID- 30425412 TI - Instead of Casting Stones, Develop Empathy for Our Students. PMID- 30425413 TI - Response to Student and School-level Predictors of Pharmacy Residency Attainment. PMID- 30425414 TI - Doing Things Differently: EVP Report to the 2018 House of Delegates, July 25, 2018. PMID- 30425415 TI - Duplications and losses of genes encoding known elements of the stress defence system of the Aspergilli contribute to the evolution of these filamentous fungi but do not directly influence their environmental stress tolerance. AB - The contribution of stress protein duplication and deletion events to the evolution of the Aspergilli was studied. We performed a large-scale homology analysis of stress proteins and generated and analysed three stress defence system models based on Saccharomyces cerevisiae, Schizosaccharomyces pombe and Aspergillus nidulans. Although both yeast-based and A. nidulans-based models were suitable to trace evolutionary changes, the A. nidulans-based model performed better in mapping stress protein radiations. The strong Mantel correlation found between the positions of species in the phylogenetic tree on the one hand and either in the A. nidulans-based or S. cerevisiae-based models on the other hand demonstrated that stress protein expansions and reductions contributed significantly to the evolution of the Aspergilli. Interestingly, stress tolerance attributes correlated well with the number of orthologs only for a few stress proteins. Notable examples are Ftr1 iron permease and Fet3 ferro-O2 oxidoreductase, elements of the reductive iron assimilation pathway, in the S. cerevisiae-based model, as well as MpkC, a HogA-like mitogen activated protein kinase in the A. nidulans-based model. In the case of the iron assimilation proteins, the number of orthologs showed a positive correlation with H2O2-induced stress tolerance while the number of MpkC orthologs correlated positively with Congo Red induced cell wall stress, sorbitol induced osmotic stress and H2O2 induced oxidative stress tolerances. For most stress proteins, changes in the number of orthologs did not correlate well with any stress tolerance attributes. As a consequence, stress tolerance patterns of the studied Aspergilli did not correlate with either the sets of stress response proteins in general or with the phylogeny of the species studied. These observations suggest that stress protein duplication and deletion events significantly contributed to the evolution of stress tolerance attributes of Aspergilli. In contrast, there are other processes, which may counterbalance the effects of stress gene duplications or deletions including (i) alterations in the structures of stress proteins leading to changes in their biological activities, (ii) varying biosynthesis of stress proteins, (iii) rewiring stress response regulatory networks or even (iv) acquiring new stress response genes by horizontal gene transfer. All these multilevel changes are indispensable for the successful adaptation of filamentous fungi to altering environmental conditions, especially when these organisms are entering new ecological niches. PMID- 30425416 TI - Evolution of asexual and sexual reproduction in the aspergilli. AB - Aspergillus nidulans has long-been used as a model organism to gain insights into the genetic basis of asexual and sexual developmental processes both in other members of the genus Aspergillus, and filamentous fungi in general. Paradigms have been established concerning the regulatory mechanisms of conidial development. However, recent studies have shown considerable genome divergence in the fungal kingdom, questioning the general applicability of findings from Aspergillus, and certain longstanding evolutionary theories have been questioned. The phylogenetic distribution of key regulatory elements of asexual reproduction in A. nidulans was investigated in a broad taxonomic range of fungi. This revealed that some proteins were well conserved in the Pezizomycotina (e.g. AbaA, FlbA, FluG, NsdD, MedA, and some velvet proteins), suggesting similar developmental roles. However, other elements (e.g. BrlA) had a more restricted distribution solely in the Eurotiomycetes, and it appears that the genetic control of sporulation seems to be more complex in the aspergilli than in some other taxonomic groups of the Pezizomycotina. The evolution of the velvet protein family is discussed based on the history of expansion and contraction events in the early divergent fungi. Heterologous expression of the A. nidulans abaA gene in Monascus ruber failed to induce development of complete conidiophores as seen in the aspergilli, but did result in increased conidial production. The absence of many components of the asexual developmental pathway from members of the Saccharomycotina supports the hypothesis that differences in the complexity of their spore formation is due in part to the increased diversity of the sporulation machinery evident in the Pezizomycotina. Investigations were also made into the evolution of sex and sexuality in the aspergilli. MAT loci were identified from the heterothallic Aspergillus (Emericella) heterothallicus and Aspergillus (Neosartorya) fennelliae and the homothallic Aspergillus pseudoglaucus (=Eurotium repens). A consistent architecture of the MAT locus was seen in these and other heterothallic aspergilli whereas much variation was seen in the arrangement of MAT loci in homothallic aspergilli. This suggested that it is most likely that the common ancestor of the aspergilli exhibited a heterothallic breeding system. Finally, the supposed prevalence of asexuality in the aspergilli was examined. Investigations were made using A. clavatus as a representative 'asexual' species. It was possible to induce a sexual cycle in A. clavatus given the correct MAT1-1 and MAT1-2 partners and environmental conditions, with recombination confirmed utilising molecular markers. This indicated that sexual reproduction might be possible in many supposedly asexual aspergilli and beyond, providing general insights into the nature of asexuality in fungi. PMID- 30425417 TI - The gold-standard genome of Aspergillus niger NRRL 3 enables a detailed view of the diversity of sugar catabolism in fungi. AB - The fungal kingdom is too large to be discovered exclusively by classical genetics. The access to omics data opens a new opportunity to study the diversity within the fungal kingdom and how adaptation to new environments shapes fungal metabolism. Genomes are the foundation of modern science but their quality is crucial when analysing omics data. In this study, we demonstrate how one gold standard genome can improve functional prediction across closely related species to be able to identify key enzymes, reactions and pathways with the focus on primary carbon metabolism. Based on this approach we identified alternative genes encoding various steps of the different sugar catabolic pathways, and as such provided leads for functional studies into this topic. We also revealed significant diversity with respect to genome content, although this did not always correlate to the ability of the species to use the corresponding sugar as a carbon source. PMID- 30425418 TI - Exogenous nitric oxide donor and arginine provide protection against short-term drought stress in wheat seedlings. AB - Nitric oxide (NO) is an important plant signaling molecule that has a vital role in abiotic stress tolerance. In the present study, we assessed drought-induced (15 and 30% PEG, polyethylene glycol) damage in wheat (Triticum aestivum L. cv. Prodip) seedlings and mitigation by the synergistic effect of exogenous Arg (0.5 mM l-Arginine) and an NO donor (0.5 mM sodium nitroprusside, SNP). Drought stress sharply decreased the leaf relative water content (RWC) but markedly increased the proline (Pro) content in wheat seedlings. Drought stress caused overproduction of reactive oxygen species (ROS) and methylglyoxal (MG) due to the inefficiency of antioxidant enzymes, the glyoxalase system, and the ascorbate glutathione pool. However, supplementation with the NO donor and Arg enhanced the antioxidant defense system (both non-enzymatic and enzymatic components) in drought-stressed seedlings. Application of the NO donor and Arg also enhanced the glyoxalase system and reduced the MG content by increasing the activities of the glyoxalase system enzymes (Gly I and Gly II), which restored the leaf RWC and further increased the Pro content under drought stress conditions. Exogenous NO donor and Arg application enhanced the endogenous NO content, which positively regulated the antioxidant system and reduced ROS production. Thus, the present study reveals the crucial roles of Arg and NO in enhancing drought stress tolerance in wheat seedlings by upgrading their water status and reducing oxidative stress and MG toxicity. PMID- 30425419 TI - Evaluation of antioxidant bioindicators and growth responses in Malva parviflora L. exposed to cadmium. AB - In this study, the effect of cadmium (Cd) uptake and concentration on some growth and biochemical responses were investigated in Malva parviflora under Cd treatments including 0, 10, 50 and 100 uM. The shoots and roots were able to accumulate Cd. However, increased Cd dose led to a considerable Cd content in the roots. Cd stress decreased growth, increased lipid peroxidation and also enhanced proline and ascorbic acid contents in both shoots and roots. Chlorophyll and carotenoid contents decreased in the plants with the increasing Cd concentration. While the activities of catalase (CAT) and superoxide dismutase (SOD) increased in the shoots under different Cd doses, these activities decreased in the roots as compared to the control. Both shoots and roots demonstrated a significant increase in guaiacol peroxidase activity in response to Cd stress. Contrary to the aboveground parts, the roots subjected to Cd doses showed a rise in protein content. Despite higher Cd content in the roots, it seems that CAT and SOD do not play a key role in detoxification of Cd-induced oxidative stress. These findings confirm that reduced biomass and growth under Cd stress can be due to an increase in oxidative stress and a decrease in photosynthetic pigment content. The present study clearly indicates that the shoots and roots exploit different tolerance behaviors to alleviate Cd-induced oxidative stress in M. parviflora. PMID- 30425420 TI - Effect of salinity on osmotic adjustment, proline accumulation and possible role of ornithine-delta-aminotransferase in proline biosynthesis in Cakile maritima. AB - The short time response to salt stress was studied in Cakile maritima. Plants were exposed to different salt concentrations (0, 100, 200 and 400 mM NaCl) and harvested after 4, 24, 72 and 168 h of treatment. Before harvesting plants, tissue hydration, osmotic potential, inorganic and organic solute contents, and ornithine-delta-aminotransferase activity were measured. Plants of C. maritima maintained turgor and tissue hydration at low osmotic potential mainly at 400 mM NaCl. The results showed that, in leaves and stems, Na+ content increased significantly after the first 4 h of treatment. However, in roots, the increase of Na+ content remained relatively unchanged with increasing salt. The K+ content decreased sharply at 200 and 400 mM NaCl with treatment duration. This decrease was more pronounced in roots. The content of proline and amino acids increased with increasing salinity and treatment duration. These results indicated that the accumulation of inorganic and organic compounds was a central adaptive mechanism by which C. maritima maintained intracellular ionic balance under saline conditions. However, their percentage contribution to total osmotic adjustment varies from organ to organ; for example, Na+ accumulation mainly contributes in osmotic adjustment of stem tissue (60%). Proline contribution to osmotic adjustment reached 36% in roots. In all organs, proline as well as delta-OAT activity increased with salt concentration and treatment duration. Under normal growth conditions, delta-OAT is mainly involved in the mobilization of nitrogen required for plant growth. However, the highly significant positive correlation between proline and delta-OAT activity under salt-stress conditions suggests that ornithine pathway contributed to proline synthesis. PMID- 30425421 TI - Physiological characterization and allelic diversity of selected drought tolerant traditional rice (Oryza sativa L.) landraces of Koraput, India. AB - Water-deficit stress tolerance in rice is important for maintaining stable yield, especially under rain-fed ecosystem. After a thorough drought-tolerance screening of more than 130 rice genotypes from various regions of Koraput in our previous study, six rice landraces were selected for drought tolerance capacity. These six rice landraces were further used for detailed physiological and molecular assessment under control and simulated drought stress conditions. After imposing various levels of drought stress, leaf photosynthetic rate (PN), photochemical efficiency of photosystem II (Fv/Fm), SPAD chlorophyll index, membrane stability index and relative water content were found comparable with the drought-tolerant check variety (N22). Compared to the drought-susceptible variety IR64, significant positive attributes and varietal differences were observed for all the above physiological parameters in drought-tolerant landraces. Genetic diversity among the studied rice landraces was assessed using 19 previously reported drought tolerance trait linked SSR markers. A total of 50 alleles with an average of 2.6 per locus were detected at the loci of the 19 markers across studied rice genotypes. The Nei's genetic diversity (He) and the polymorphism information content (PIC) ranged from 0.0 to 0.767 and 0.0 to 0.718, respectively. Seven SSR loci, such as RM324, RM19367, RM72, RM246, RM3549, RM566 and RM515, showed the highest PIC values and are thus, useful in assessing the genetic diversity of studied rice lines for drought tolerance. Based on the result, two rice landraces (Pandkagura and Mugudi) showed the highest similarity index with tolerant check variety. However, three rice landraces (Kalajeera, Machhakanta and Haldichudi) are more diverse and showed highest genetic distance with N22. These landraces can be considered as the potential genetic resources for drought breeding program. PMID- 30425422 TI - Novel screening protocol for precise phenotyping of salt-tolerance at reproductive stage in rice. AB - The present study reports an unequivocal and improved protocol for efficient screening of salt tolerance at flowering stage in rice, which can aid phenotyping of population for subsequent identification of QTLs associated with salinity stress, particularly at reproductive stage. To validate the new method, the selection criteria, level and time of imposition of stress; plant growth medium were standardized using three rice genotypes. The setup was established with a piezometer placed in a perforated pot for continuous monitoring of soil EC and pH throughout the period of study. Further, fertilizer enriched soil was partially substituted by gravels for stabilization and maintaining the uniformity of soil EC in pots without hindering its buffering capacity. The protocol including modified medium (Soil:Stone, 4:1) at 8 dS m-1 salinity level was validated using seven different genotypes possessing differential salt sensitivity. Based on the important selection traits such as high stability index for plant yield, harvest index and number of grains/panicle and also high K+ concentration and low Na+- K+ ratio in flag leaf at grain filling stage were validated and employed in the evaluation of a mapping population in the modified screening medium. The method was found significantly efficient for easy maintenance of desired level of soil salinity and identification of genotypes tolerant to salinity at reproductive stage. PMID- 30425423 TI - Physiological, biochemical and morphoagronomic characterization of drought tolerant and drought-sensitive bean genotypes under water stress. AB - Water deficit is one of the main factors that reduce grain yield. A better understanding of the mechanisms related to this abiotic stress is a key aspect to design and act upon drought tolerance improvement in crop plants. Therefore, the major objective of this study was to investigate four common bean genotypes for drought tolerance and to establish their tolerance mechanisms. The experiment was carried out in a greenhouse, using the completely randomized design in a factorial arrangement (2 * 4), composed by 2 water conditions (well-watered and water deficit) and 4 cultivars, with six replicates per treatment. The four cultivars, two drought-sensitive (IAC Tybata and BRS Pontal) and two drought tolerant (IAPAR 81 and BAT 477), were evaluated for some physiological, biochemical and morphoagronomic traits. Drought promoted physiological and metabolic changes in the plants, reflecting on the morphoagronomic traits. Under water deficit, the genotype IAPAR 81 stood out from the others in terms of physiological characters, however, it presented a low efficiency concerning biochemical activities and a significant reduction in the morphoagronomic characters. The cultivar BAT 477 demonstrated to be drought-adapted presenting more efficient biochemical and morphoagronomic adaptions and the genotype BRS Pontal obtained morphoagronomic values similar to BAT 477, thus it may be classified as moderately tolerant to drought. PMID- 30425424 TI - RNAi-mediated silencing of spermidine synthase gene results in reduced reproductive potential in tobacco. AB - Spermidine belongs to a class of polycationic compounds known as polyamines. Polyamines are known to be involved in a wide range of biological processes but the exact role and contribution of different polyamines to these processes are still not clear. In the present study, we have tried to understand the contribution of triamine spermidine to the growth and development of tobacco by downregulating spermidine synthase gene (SPDS) using RNA interference. Down regulatioin of SPDS gene resulted in decreased spermidine levels and a slight increase in the levels of its precursor, the diamine putrescine and the molecule downstream of Spd, the tetraamine spermine. While the vegetative growth of the transgenics remained largely unaffected, SPDS down-regulation resulted in smaller size of flowers, decreased pollen viability and seed setting, and a reduced and delayed seed germination. When subjected to abiotic stress, the transgenics showed an increased tolerance to salinity and drought conditions owing to a steady intracellular pool of putrescine and spermine. The results not only highlight the importance of spermidine in determining reproductive potential in plants but have also help delineate its function from that of putrescine and spermine. PMID- 30425425 TI - Ascorbate-glutathione cycle confers salt tolerance in Egyptian lentil cultivars. AB - In order to investigate the salt tolerance mechanism in Egyptian lentils, five cultivars were grown under different salinity levels. The results indicated that Giza 9 is salt-tolerant, while Giza 4 is a salt-sensitive lentil cultivar, as Giza 9 showed the highest germination percentage and relative water content, the lowest decline in root and shoot length, and the highest proline content. Relative gene expression of ADH, CYS3, APX, SOD, and GR was significantly upregulated in Giza 9 roots after 24 h of high salt treatment (250 mM), while CAT transcripts level was non-significantly reduced (0.5-fold) relative to control. However, in Giza 4, only CAT gene was significantly upregulated in both root (2.3 fold) and shoot (8.5-fold) tissues. Investigation of ascorbate-glutathione enzymatic activities revealed significantly higher ascorbate peroxidase and glutathione reductase activities in Giza 9 roots compared to its shoots. Moreover, endogenous reduced glutathione (GSH) content as well as reduced ascorbate content were significantly high in the roots of Giza 9 compared to Giza 4. These results strongly indicate the involvement of ascorbate-glutathione cycle in the tolerance mechanism of Giza 9. Furthermore, exogenous application of 350 MUM of GSH assisted Giza 4 seedlings to tolerate salinity stress. As far as we know, this is the first work reporting the involvement of ascorbate-glutathione cycle in salt tolerance of lentil. PMID- 30425426 TI - Influence of salinity and Fusarium oxysporum as the stress factors on morpho physiological and yield attributes in onion. AB - Occurrence of salt stress with the soil borne fungus Fusarium oxysporum f. sp. cepa (FOC) are potential threat to the crop yield. This investigation reports effect of the concurrent stresses (salinity and FOC) on morpho-physiological and yield attributes in onion. In vitro growth tests revealed proliferation of FOC biomass at different levels of salinity (2-8 dS m-1). A greenhouse pot experiment with the proposed levels of salinity (2.5, 3.5 and 4.5 dS m-1) in combination with FOC inoculation showed more drastic effect of combined stress on disease severity, plant growth and bulb as compared to the individual stress. In general, osmotic potential, total chlorophyll content, membrane stability index and total protein content of the leaf were decreased, while total phenolics were increased due to the given stress/s. Total sugar content decreased due to effect of the individual stress of FOC, while it increased under the individual stress of salinity and in combination with FOC. FOC infection did not change activity of polyphenol oxidase (PPO), while it improved peroxidase (POX) and phenylalanine ammonia lyase (PAL) and decreased catalase (CAT) activity. Activities of POX and PPO increased, however PAL and CAT declined under individual as well as simultaneous stress of salinity and FOC. The research work concluded that FOC will be a more severe disease threat for onion cultivation in saline soils. PMID- 30425427 TI - Silicon influences growth and mycorrhizal responsiveness in strawberry plants. AB - Effect of silicon (Si) on the response of strawberry (Fragaria * ananassa var. Parus) plants to arbuscular mycorrhizal fungus (AMF) was studied under growth chamber conditions. Plants were grown in perlite irrigated with nutrient solution without (- Si) or with (+ Si) 3 mmol L-1 Si (~ 84 mg L-1 Si as Na2SiO3) in the absence (- AMF) or presence (+ AMF) of fungus. Dry matter production, root colonization rate, photosynthesis rate and water relation parameters were all improved by both Si and AMF, and the highest amounts were achieved by + Si + AMF treatment. Mycorrhizal effectiveness increased by Si treatment associated with higher Si concentration in the + AMF plants. Leaf concentrations of total soluble and cell wall-bound phenolics were increased by Si accompanied by the enhanced activity of phenylalanine ammonia lyase, but not polyphenol oxidase. Profile of phenolics compound revealed that gallic acid, caffeic acid, epicatechin, chlorogenic acid, ellagic acid and kaempferol increased by both Si and AMF treatments, while p-coumaric acid decreased. In addition to vegetative growth, both treatments improved fruit yield and its quality parameters. Our results showed that Si and AMF acted in a synergistic manner and improved growth and biochemical parameters in strawberry plants. However, the mechanism for Si mediated increase of mycorrhizal effectiveness is not known, thereby needing further elucidation. PMID- 30425429 TI - Adenine type and diphenyl urea derived cytokinins improve the postharvest performance of Iris germanica L. cut scapes. AB - An experiment was designed to evaluate the effect of various adenine derived cytokinins (kinetin and 6-benzylaminopurine) and diphenyl urea cytokinin (thidiazuron) on the postharvest performance of cut scapes of Iris germanica. Flower scapes were harvested with the oldest bud at '1 day before anthesis stage', brought to laboratory under water, cut to a uniform length of 35 cm, divided into three sets viz., kinetin (KIN), 6-benzyl aminopurine (BAP) and thidiazuron (TDZ). Each set of scapes was treated with a particular cytokinin alone or in combination with 0.1 M sucrose. TDZ was effective than KIN and BAP in improving the postharvest life of the I. germanica scapes by 5.4 days as compared to the control (untreated scapes held in distilled water). This was because of the minimum percentage of bud abortion by TDZ application. Cytokinin application resulted in increased antioxidant activity, higher protein and phenolic content, besides a decrease in specific protease activity and alpha-amino acids in the tepal tissues. Application of TDZ resulted in the maximum increase in the superoxide dismutase, catalase and ascorbate peroxidase activity in the tepal tissues. The scapes treated with BAP and KIN maintained higher carbohydrate content in the tissue samples as compared to control and TDZ treated scapes. TDZ and BAP application resulted in increased membrane stability because of the decreased lipoxygenase activity which prevented membrane lipid peroxidation. Among the cytokinins tested, TDZ proved to be the promising cytokinin in improving the postharvest performance of beautiful flowers of I. germanica scapes. PMID- 30425428 TI - Concentration of some metals in soil and plant organs and their biochemical profiles in Tulipa luanica, T. kosovarica and T. albanica native plant species. AB - The purpose of this study was to determine the concentration of some metals (Al, Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, Zn, Ca and Mg) in soil of serpentine and limestone sites, their bioaccumulation and impact on some biochemical parameters in T. luanica, T. kosovarica and T. albanica plants. T. kosovarica and T. albanica grows in serpentine soil, while T. luanica grow in limestone soil. The research showed that concentrations of Cd, Co, Cr, Fe, Mn and Ni were significantly higher at serpentine soil sites in comparison with limestone sites, while concentrations of Pb, Cd, Co and Cr in bulbs, leaves and seeds were under the limit of detection. The concentration of Ni in plant samples of T. kosovarica was significantly higher in comparison with its concentration in T. albanica, but it was under the limit of detection in T. luanica. Moreover, concentrations of Al and Fe in leaves of T. kosovarica and T. albanica were higher in comparison with T. luanica. The concentration of Mg was significantly higher in T. kosovarica and T. albanica than in T. luanica. The delta-aminolevulinic acid dehydratase activity, malondialdehyde and glutathione contents in leaves of T. luanica were higher in comparison with T. kosovarica and T. albanica. In addition, the amounts of total chlorophyll and delta-aminolevulinic acid (ALA) in leaves of T. albanica were higher in comparison with T. kosovarica and T. luanica. Our findings show that target organs of metal accumulation in three Tulip species appears to be leaves > seeds > bulbs, while the biochemical parameters show that limestone sites represent a less stressful habitat for growing these plant species in comparison with serpentine sites. PMID- 30425430 TI - Comparative analysis of photosynthetic and respiratory parameters in the psychrophilic unicellular green alga Koliella antarctica, cultured in indoor and outdoor photo-bioreactors. AB - Effect of temperatures and illumination of temperate winter on photosynthesis and respiration was studied in the psychrophilic microalgae, Koliella antarctica (Trebouxiophyceae). Outdoor and indoor algal cultures were compared. Photosynthetic as well as respiration rates increased as light and temperature increased, until 35 degrees C, more in outdoor than in indoor cells, in agreement with the calculated Q 10 values. K. antarctica showed important strategy mechanisms of adaption to the several temperature and light conditions. These significant photo-acclimation and thermo-acclimation abilities make it possible to cultivate Koliella for different uses, under less expensive outdoor conditions. Therefore, K. antarctica shows important strategy mechanisms of adaption to various temperature and light conditions; moreover, by varying the culture conditions, it is possible to modulate and optimize the growth and accordingly the biomass production. This is a very interesting point since it has been proved that this microalga is a promising potential source of functional ingredients, such as polyunsaturated fatty acids and carotenoids, suitable for industrial purposes. PMID- 30425431 TI - Characterization of backcross introgression lines derived from Oryza nivara accessions for photosynthesis and yield. AB - Improvement of photosynthetic traits is a promising strategy to break the yield potential barrier of major food crops. Leaf photosynthetic traits were evaluated in a set of high yielding Oryza sativa, cv. Swarna * Oryza nivara backcross introgression lines (BILs) along with recurrent parent Swarna, both in wet (Kharif) and dry (Rabi) seasons in normal irrigated field conditions. Net photosynthesis (P N) ranged from 15.37 to 23.25 umol (CO2) m-2 s-1 in the BILs. Significant difference in P N was observed across the seasons and genotypes. Six BILs showed high photosynthesis compared with recurrent parent in both seasons. Chlorophyll content showed minimum variation across the seasons for any specific BIL but significant variation was observed among BILs. Significant positive association between photosynthetic traits and yield traits was observed, but this association was not consistent across seasons mainly due to contrasting weather parameters in both seasons. BILs 166s and 248s with high and consistent photosynthetic rate exhibited stable high yield levels in both the seasons compared to the recurrent parent Swarna. There is scope to exploit photosynthetic efficiency of wild and weedy rice to identify genes for improvement of photosynthetic rate in cultivars. PMID- 30425432 TI - Biochemical diversity evaluation in chickpea accessions employing mini-core collection. AB - The seeds of chickpea provide an exceptional source of dietary proteins and is one of the important legumes in both developed and developing countries over the world. The available germplasm of cultivated chickpea is deficient in desired biochemical signatures. To identify new sources of variations for breeding, reduced subsets of germplasm such as mini-core collection can be explored as an effective resource. In the present investigation, mini-core collections consisting of 215 accessions of chickpea were extensively evaluated for tapping biochemical diversity. Analysis included ten biochemical parameters comprising total protein, total free amino acids, phytic acid, tannin, total phenolics, total flavonoids, lectin, DPPH radical scavenging activity, in vitro digestibility of protein and starch. The spectrum of diversity was documented for total protein (4.60-33.90%), total free amino acids (0.092-9.33 mg/g), phytic acid (0.009-4.06 mg/g), tannin (0.232-189.63 mg/g), total phenolics (0.15-0.81 mg/g), total flavonoids (0.04-1.57 mg/g), lectin (0.07-330.32 HU/mg), DPPH radical scavenging activity (26.74-49.11%), in vitro protein digestibility (59.45 76.22%) and in vitro starch digestibility (45.63-298.39 mg of maltose/g). The principal component analysis revealed association of chickpea higher protein content to the lower level of total phenolics and flavonoid contents. The dendrogram obtained by unweighted pair group method using arithmetic average cluster analysis grouped the chickpea accessions into two major clusters. This is the first comprehensive report on biochemical diversity analysed in the mini-core chickpea accessions. The ultimate purpose of conducting such studies was to deliver information on nutritional characteristics for effective breeding programmes. Depending on the objectives of the breeding aforesaid accessions could be employed as a parent. PMID- 30425433 TI - Cytotoxic effect of Semialarium mexicanum (Miers) Mennega root bark extracts and fractions against breast cancer cells. AB - The root bark of Semialarium mexicanum (Miers) Mennega (cancerina) is traditionally used in Mexico to treat cancer. However, there are no studies supporting its use. We evaluated whether S. mexicanum root bark induces cytotoxicity in breast cancer cells to determine if it has potential applications in the treatment of this disease. Extracts of S. mexicanum root bark in petroleum ether, ethanol, and water were obtained by ultrasound-assisted extraction. MTT and WST-1 assays were used to evaluate the cytotoxicity of the extracts toward breast cancer cells (MDA-MB-231 and MCF7), non-tumorigenic breast-derived cells (MCF 10A), and peripheral blood mononuclear cells (PBMCs). For the extract with greatest cytotoxicity, induction of apoptosis and oxidative stress were determined using flow cytometry. The extract was fractionated, and the cytotoxicity of its fractions was evaluated with the four cell types. The fractions were also analyzed by HPLC. Only the petroleum ether extract was cytotoxic for all cell types (MDA-MB-231 > MCF 10A/MCF7 > PBMCs). Cell death occurred by apoptosis, which could be associated with the induction of oxidative stress. Two fractions that were highly cytotoxic for breast cancer cells were obtained from this extract (IC50 <= 4.15 ug/mL for the most active fraction at 72 h). The MCF 10A cells were less affected, while PBMCs were not affected after 72 h of treatment. Pristimerin was identified in both fractions and may be partially responsible for the cytotoxic effect. These results suggest that S. mexicanum root bark has a potential application in breast cancer treatment. PMID- 30425434 TI - In vitro assessment of antimicrobial activity of aqueous and alcoholic extracts of moss Atrichum undulatum (Hedw.) P. Beauv. AB - Bryophytes, the shade loving plants, have tremendous medicinal properties. The aqueous and alcoholic extracts of Atrichum undulatum (Hedw.) P. Beauv. were analysed for antimicrobial properties against the fungi Aspergillus fumigatus and Fusarium oxysporum and the bacteria Escherichia coli, Bacillus mycoides, Proteus mirabilis, Staphylococcus aureus and Salmonella typhi. The study is an attempt to investigate the medicinal properties of Atrichum undulatum (Hedw.) P. Beauv. using disc-diffusion method. No inhibition was observed against A. fumigatus and P. mirabilis. For bacteria S. typhi and E. coli (20 and 15 mm), aqueous and alcoholic extracts of Atrichum showed significant inhibition. However, alcoholic extract was found remarkably effective against bacteria rather than aqueous extract. PMID- 30425435 TI - Solvent based optimization for extraction and stability of thymoquinone from Nigella sativa Linn. and its quantification using RP-HPLC. AB - The Nigella sativa pharmacological properties are mainly ascribed to its volatile oil, of which thymoquinone is an important bioactive component. Surprisingly, till date, no standard formulation or thymoquinone rich N. sativa extract is under clinical use probably due to its poor extraction and lesser stability in the already used solvents. In the present investigation solubility, extraction, percent composition and total antioxidant activity from the seeds of N. sativa was explored using five solvents. An HPLC method was standardized in an isocratic system (C-18 column, flow rate of 1.0 ml/min, mobile phase-water:methanol: 30:70, detection wavelength-254 nm, retention time-8.77 min) for quantification of thymoquinone. To further confirm the presence of thymoquinone in the respective extracts absorbance spectra analysis has been carried out and compared with pure thymoquinone. Additionally total antioxidant activity of Nigella sativa extracts has been evaluated using ascorbic acid as standard. Our results showed maximum percentage yield in aqueous extract while methanol having the least yield and the ethanol, benzene and hexane extracts exhibited moderate yields. A linear standard calibration curve of thymoquinone showed R2 as 0.999 and % RSD as 7.166. The HPLC analysis revealed maximum percentage composition of thymoquinone in the benzene extract, whereas in the hexane and methanol extracts the content was less. Aqueous and ethanol extracts displayed insignificant thymoquinone content. Absorbance spectra analysis confirms the presence of thymoquinone peak in the benzene, hexane and methanol extracts while aqueous and ethanol extracts showed minimal absorbance. Maximum total antioxidant activity was observed in the aqueous extract while minimum was observed in the methanolic extract. Weak positive (+ 0.3676) correlation was established between percent composition of thymoquinone and antioxidant activity among different extracts indicating that thymoquinone may not be the only factor for antioxidant activity, but other phytochemicals might also contribute. However, we for the first time demonstrated that the benzene extract of N. sativa has better solubility and percent composition of thymoquinone as compared to other solvents. It can be concluded that the solubility, differential composition of bioactive components among these extracts may have diverse effects on the total antiradical activity. Thus, our study provides insights on optimization and standardization of bioactive rich formulation of N. sativa. PMID- 30425436 TI - Characterization of hawthorn (Crataegus spp.) genotypes by SSR markers. AB - Hawthorn (Crataegus spp.) is an edible wild fruit that is used in traditional medicine, landscape studies, and food and beverage industries in many countries. It is an important wild plant species in Turkey and is numerous in the Yozgat Province. Genetic and breeding studies on hawthorn are very limited. Therefore, we aimed to characterize 91 hawthorn genotypes using simple sequence repeat (SSR) markers. The SSRs were developed from apple and pear and were screened in hawthorn for amplification and polymorphisms. A total of 265 alleles were detected from thirty-two SSR primer pairs, and those were used to identify genetic relationships. The number of alleles ranged from 2 to 21 alleles per locus with a mean value of 8.28. The Hi05b09 locus showed the highest allele number (Na = 21). The polymorphism information content (PIC) values ranged from 0.16 (CH03d10) to 0.89 (C6554) with a mean value of 0.60. An Unweighted Pair Group Method with Arithmetic Average method was used to cluster the genotypes, and four major clusters were obtained from the amplification of the SSRs. STRUCTURE software identified four populations (DeltaK = 4) and eight sub populations (DeltaK = 8), and four major clusters similar results to UPGMA analysis. Our study showed that the SSR markers could be utilized as a reliable tool for the determination of genetic variations and relationships of hawthorn genotypes. A basic molecular analysis on the hawthorn genotypes identified in this study will promote the collection of germplasm collection and the selection of parents' in future cross-breeding studies. PMID- 30425437 TI - Mapping QTLs for physiological and biochemical traits related to grain yield under control and terminal heat stress conditions in bread wheat (Triticum aestivum L.). AB - In order to detect genomic regions with different effects for some of the physiological and biochemical traits of wheat, four experiments were conducted at Research Farm of Agricultural and Natural Resources Research Center of Zabol in 2015-2016 and 2016-2017 growing seasons. The experiments were carried out using four alpha lattice designs with two replications under non-stress and terminal heat stress conditions. Plant materials used in this study included 167 recombinant inbred lines and their parents ('SeriM82' and 'Babax'). Six traits including grain yield (GY), proline content (PRO), water soluble carbohydrates (WSC), maximum efficiency of photosystem II (Fv/Fm), cytoplasmic membrane stability (CMS) and chlorophyll content (CHL) were evaluated. Genetic linkage map consisted of 211 AFLP marker, 120 SSR marker and 144 DArT markers with 1864 cm length and 4.4 cm mean distance. QTL analysis was carried out using a mixed-model based composite interval mapping (MCIM) method. By the combined analysis of normal phenotypic values, 27 additive QTLs and five pairs of epistatic effects were identified for studied traits, among which two additive and one epistatic QTL showed significant QTL * environment interactions. By the combined analysis of stress phenotypic values, a total of 26 QTLs with additive effects and 5 epistatic QTLs were detected, among which one additive and one epistatic QTL showed QTL * environment interactions. Six QTLs with major effects (QGY-2B, QGY 2D, QPro-5B, QWSC-4A, QFv/Fm-6A and QCMS-4B), which were common between two conditions could be useful for marker-assisted selection (MAS) in order to develop heat tolerant and high-performance wheat varieties. PMID- 30425438 TI - Validation of QTLs for plant ideotype, earliness and growth habit traits in pigeonpea (Cajanus cajan Millsp.). AB - Pigeonpea productivity is greatly constrained by poor plant ideotype of existing Indian cultivars. Enhancing pigeonpea yield demands a renewed focus on restructuring the ideal plant type by using more efficient approaches like genomic tools. Therefore, the present study aims to identify and validate a set of QTLs/gene(s) presumably associated with various plant ideotype traits in pigeonpea. A total of 133 pigeonpea germplasms were evaluated along with four checks in the augmented design for various ideotype traits i.e. initiation of flowering (IF), days to 50% flowering (DFF), days to maturity (DM), plant height (PH), primary branches (PB), seeds per pod (SP) and pod length (PL). We observed significant genetic diversity in the germplasm lines for these traits. The genetic control of IF, DFF, DM and PH renders these traits suitable for detection of marker trait associations. By using residual maximum likelihood algorithm, we obtained appropriate variance-covariance structures for modeling heterogeneity, correlation of genetic effects and non-genetic residual effects. The estimates of genetic correlations indicated a strong association among earliness traits. The best linear unbiased prediction values were calculated for individual traits, and association analysis was performed in a panel of 95 diverse genotypes with 19 genic SSRs. Out of five QTL-flanking SSRs used here for validation, only ASSR295 could show significant association with FDR and Bonferroni corrections, and accounted for 15.4% IF, 14.2% DFF and 16.2% DM of phenotypic variance (PV). Remaining SSR markers (ASSR1486, ASSR206 and ASSR408) could not qualify false discovery rate (FDR) and Bonferroni criteria, hence declared as false positives. Additionally, we identified two highly significant SSR markers, ASSR8 and ASSR390 on LG 1 and LG 2, respectively. The SSR marker ASSR8 explained up to 22 and 11% PV for earliness traits and PB respectively, whereas ASSR390 controlled up to 17% PV for earliness traits. The validation and identification of new QTLs in pigeonpea across diverse genetic backgrounds brightens the prospects for marker assisted selection to improve yield gains in pigeonpea. PMID- 30425439 TI - Molecular diversity assessment of a world collection of safflower genotypes by SRAP and SCoT molecular markers. AB - Safflower (Carthamus tinctorius L.) is considered as an oil crop that is rich in medicinal and industrial properties. In this study, the genetic diversity of safflower was assessed using 12 polymorphic sequence-related amplified polymorphism (SRAPs) and 11 polymorphic start codon targeted (SCoT) markers in 100 genotypes of safflower gathered from different geographical regions of the world. The 23 primers generated a total of 227 polymorphism fragments with a mean of 68.2% within the range of 3 (SCoT 31 and SCoT 35) to 13 (SCoT 35) bands per primer. Polymorphism per primer ranged between 100% (in Me4-Em1) and 18.1% (in SCoT19), with an average of 36.76%. The polymorphism information contents of the SRAP and SCoT markers were 0.35 and 0.30, respectively, indicating that SRAP markers were more effective than SCoT markers for assessing the degree of genetic diversity of the safflower. The results of the analysis of molecular variance showed a significant difference across cultivated safflower genotypes possessing a high intra-population variation. The examined accessions were categorized into five clusters based on similarity centers: the Middle East containing Iran, Iraq, Turkey, and Tajikistan; the Far East, including India, Pakistan, and Korea; Europe; the American continent; and Africa, including Egypt, Sudan and Libya. The present study shows the effectiveness of employing the mixture of SRAP and SCoT markers in the identification of safflower genetic diversity that would be useful for conservation and population genetics of safflower improvement in further studies. PMID- 30425440 TI - An improved micropropagation and ex vitro rooting of a commercially important crop Henna (Lawsonia inermis L.). AB - An improved micropropagation protocol has been developed for a cosmetically important, dye yielding crop, henna (Lawsonia inermis). Quality of henna product is governed by naphthoquinone based pigment lawsone, thus in vitro multiplication of superior healthy plant to achieve enhanced productivity in terms of dye content and biomass deserve due attention. In the present study, nodal explants collected from an elite plant screened on the basis of superiority in lawsone content was cultured on MS medium supplemented with 0.5 MUM benzyl adenine (BA) gave significantly (p < 0.05) high number of shoots (24.33). The explants placed on MS medium augmented with 0.5 MUM BA and 2-isopentenyladenine (2-iP) resulted in the formation of maximum number of shoots (43.67) and was elongated (12.57 cm) within 4 weeks of culture period. Enhanced axillary bud proliferation and production of mass number of micro shoots was achieved by the continuous subculture in MS medium containing 0.5 MUM BA and 2-iP. In vitro raised micro shoots were dipped in 0.44 mM NAA for 5 min followed by planting in polyethylene pots containing a soil: vermiculite (1:1 v/v) mixture produced rooted plantlets (100%). Different auxin types and its concentrations had significant role rooting of L. inermis. Rooting response of various size shoots of L. inermis treated with 0.44 mM NAA showed 100% rooting in 4.1-5 cm size class shoots. After two months of potting, survived (95%) plants were successfully transferred to medicinal plant garden of the Department. The lawsone content of one-year-old micropropagated plants (23.04 mg/g dw) growing in normal environmental conditions and elite mother plant (22.84 mg/g dw) was almost similar. Through the present study, efficient cloning of superior germplasm of L. inermis was established. PMID- 30425441 TI - In vitro propagation of some old Persian cypress accessions (Cupressus sempervirens L.) by embryo culture. AB - In order to study in vitro propagation of some old Persian cypress genotypes (Cupressus sempervirens L.), embryos of twenty old cypress accessions were cultured on MS and SH media containing 100 and 200 mg L-1 myo-inositol. Germination percentage and growth parameters of produced plantlets and their hardening off were evaluated. Results showed that the highest germination percentage and germination rate was obtained with MS medium containing 100 mg L-1 myo-inositol, although no significant difference was observed with MS containing 200 mg L-1 myo-inositol and SH containing 100 mg L-1 myo-inositol. Furthermore, based on the results, the highest root length was gained with SH medium containing 200 mg L-1 myo-inositol. Germination percentage of isolated embryos and shoot length of produced plantlets were affected by genotype, so that the highest germination percentage and shoot length was obtained with KB and KT genotypes, respectively. The oldest genotype which was 4000 years old (Abarkuh cypress) showed no significant difference with other genotypes in terms of shoot and root length. In hardening-off step, first all genotypes were initially established but after 2 weeks, KJ2, KK, KSHN, KD1, KB genotypes died. PMID- 30425442 TI - Physical state of the culture medium triggers shift in morphogenetic pattern from shoot bud formation to somatic embryo in Solanum khasianum. AB - Solanum khasianum is a rich source of steroidal alkaloids that are important secondary metabolites with enormous pharmaceutical uses. Development of plantlets from somatic tissues, under in vitro conditions, takes place both through adventitious shoot bud differentiation or somatic embryogenesis (SE) pathway. We observed that the physical state of medium, solid or liquid, determined the regenerant differentiation patterns from root segment explants in S. khasianum. In the solidified medium, the root segments developed adventitious shoot buds whereas somatic embryos were regenerated in the liquid medium. Varying gradients from liquid to solid medium were further used to confirm the effect of solidified condition on regeneration pathway. Histological analysis of developing shoot buds and somatic embryos was also performed to confirm their development and differentiation patterns. In order to further confirm the developmental pathways, qRT-PCR analysis of the marker genes of SE and shoot regeneration was also performed. While SOMATIC EMBRYOGENESIS RECEPTOR KINASE1 (SkSERK1) expression was significantly up-regulated during the early embryogenic stage, the LATE EMBRYOGENESIS ABUNDANT (SkLEA) protein was found to be highly expressed in the mature embryos. Expression of the HISTONE DEACETYLASE (HDA6), a repressor of SE related genes, was highly decreased during embryogenesis in the liquid culture. Furthermore, expression of the ENHANCER OF SHOOT REGENERATION (ESR) gene was comparatively increased during shoot regeneration in the culture using solid medium. Our results point out that the physical state of the medium in S. khasianum plays a decisive role in differentiation pattern which was independent of hormonal supplements. PMID- 30425443 TI - Exogenous melatonin trigger biomass accumulation and production of stress enzymes during callogenesis in medicinally important Prunella vulgaris L. (Selfheal). AB - The objective of the current study was to monitor the variations caused by the application of exogenous melatonin on growth kinetics and production of stress enzymes in Prunella vulgaris. Leaf and petiole explants were used for callogenesis. These explants were inoculated on Murashige and Skoog media containing various concentrations of melatonin alone or in combination with 2.0 mg/l naphthalene acetic acid. Herein, a maximum of 3.18-g/100 ml fresh biomass accumulation was observed on day 35 during log phase of growth kinetics at 1.0 mg/l melatonin concentration from leaf explants. While 0.5 and 1.0 mg/l melatonin enhanced the biomass accumulation from petiole explants. Moreover, the synergistic combination of melatonin and naphthalene acetic acid also promoted growth from leaf and petiole explants. Leaf derived callus cultures treated with 1.0 mg/l melatonin induced the production of total protein content (90.47 MUg BSAE/mg FW) and protease activity (4.77 U/g FW). While the calli obtained from petiole explants have shown highest content of total protein (160.8 MUg BSAE/mg FW) and protease activity (5.35 U/g FW) on media containing 0.5 mg/l melatonin. Similarly, 0.5 mg/l melatonin enhanced superoxide dismutase (3.011 nM/min/mg FW) and peroxidase (1.73 nM/min/mg FW) enzymes from leaf derived callus cultures. The combination of 1.0 and 1.5 mg/l naphthalene acetic acid enhanced content of total protein and protease activity in leaf and petiole derived cultures. These results suggested that the application of melatonin play a positive role in biomass accumulation and production of stress enzymes in P. vulgaris. PMID- 30425444 TI - Optimization of in vitro regeneration of Haloxylon salicornicum: a keystone species of extreme arid regions. AB - Haloxylon salicornicum is an economically important perennial woody shrub of family Amaranthaceae and is a good source of food additives, fodder, fuel and nutrients in Indian Thar Desert. In vitro regeneration of H. salicornicum through nodal shoot segments is achieved in present investigation. Young green shoots in horizontal orientation were found to be more responsive than vertical orientation. Axillary shoot buds were activated on MS medium containing 10 uM BAP. Adventitious roots with intense root hairs were induced on horizontally placed shoots on half strength MS medium containing 2 uM NOA + 100 mg L-1 activated charcoal. This is a first report on micropropagation of H. salicornicum. This protocol can be a useful means for in vitro characterization, mass propagation and conservation of the plant for future prospects. PMID- 30425445 TI - Endoscopic Ultrasound Elastography for Evaluation of Lymph Nodes: A Single Center Experience. AB - Background and Aim: The differentiation between malignant and benign lymph nodes (LNs) is important for tumor staging, for detection of prognosis, and for selection of the best treatment strategy in many cancers. On B-mode EUS, there are some known criteria that suggest the malignant nature of LNs; these criteria may be found in benign LNs. The aim of the work is to evaluate the effectiveness of elasticity score and SR to differentiate between benign and malignant LNs. Patients and Methods: The study was designed as a retrospective study that included 40 patients with abdominal or mediastinal LNs, either associated with primary masses or isolated, referred for EUS evaluation. Elasticity scores and SR were determined during the examination and finally, EUS-FNA was done at the end of the procedure. Results: In this 2-years study, 40 patients were enrolled (24 malignant; 16 benign). There were 23 males and 17 females. Their mean age was 52.5 years (range: 28-77). ES alone had a specificity of 87.5%, sensitivity of 41.7%, PPV of 83.3%, NPV of 50%, and accuracy of 60%. Based on the ROC curve analysis results, the best cut-off level of SR to obtain the maximum area under the curve (AUC) was 6.7 with a specificity of 99.9%, sensitivity of 57.1%, PPV of 99.9%, NPV of 64%, and accuracy of 77.5%. Conclusion: The use of elasticity score and SR increases the reliability of differentiation between benign and malignant LNs and can decrease the number of unnecessary biopsies. PMID- 30425446 TI - Binocular coordination and reading performance during smartphone reading in intermittent exotropia. AB - Purpose: This study aimed to evaluate binocular coordination using video oculography during smartphone reading in patients with intermittent exotropia compared to individuals with normal vision. Patients and methods: Eleven youth and adult patients with intermittent exotropia (21.9+/-9.3 years) and 15 control subjects (26.6+/-4.3 years) were examined. Eye movements were recorded during smartphone reading at 50, 30, and 20 cm using video-oculography. The loss of binocular coordination was tentatively defined as a horizontal disparity greater than 2 degrees . The proportion of monocular viewing was the percentage of time for which binocularity was lost during smartphone reading. The proportion of monocular viewing, the reading speed, and the correlation between proportion of monocular viewing and reading speed were analyzed. Results: The proportion of monocular viewing during smartphone reading was significantly higher in the intermittent exotropia group than in the control group (P<0.001). It was significantly more frequent at 20 cm than at 50 cm in the intermittent exotropia group (P<0.05). The reading speed was significantly negatively correlated with the proportion of monocular viewing at 30 and 20 cm in the intermittent exotropia group (P<0.05). Conclusion: A significant increase in the proportion of monocular viewing in the intermittent exotropia group suggests that an appropriate viewing distance should be advised so that users can maintain binocular coordination when viewing a smartphone. PMID- 30425447 TI - Safety and efficacy of lifitegrast 5% ophthalmic solution in contact lens discomfort. AB - Purpose: The aim of this study was to evaluate the safety and efficacy of lifitegrast 5% ophthalmic solution in improving contact lens discomfort (CLD) in patients wearing a low-modulus, nonionic, monthly replacement silicone hydrogel contact lenses (SHCLs). Patients and methods: A single center, prospective, open label study was undertaken on patients wearing monthly replacement, low modulus silicone hydrogel contact lenses. Best-corrected visual acuity (BVA), lissamine staining (LS) and eight item contact lens dry eye questionnaire (CLDEQ-8) scores were assessed at baseline and after 8-week therapy of twice-a-day lifitegrast 5% ophthalmic solution use. Pre- and Posttreatment data were analyzed for statistical significance. Results: Twenty-one subjects (15 female and six male) with the mean age of 31.7 (+/-5.29) years completed the study. No reduction or statistically significant change in monocular BVA or LS scores was observed. Data showed a statistically significant (P<0.05) reduction in total CLDEQ-8 score, questions 1A, 1B, 2A and 2B scores and nonstatistically significant reduction in questions 3A, 3B, 4 and 5 scores. Fifteen (n=15, 71.4%) study subjects found the therapy positive for their contact lens wear. Conclusion: Data suggest the use of topical lifitegrast 5% ophthalmic solution twice a day may be a safe and effective therapeutic intervention for managing patients with CLD in SHCL users; however further research is indicated. PMID- 30425448 TI - A clinical assessment of visual performance of combining the TECNIS(r) Symfony Extended Range of Vision IOL (ZXR00) with the +3.25 D TECNIS Multifocal 1-piece IOL (ZLB00) in subjects undergoing bilateral cataract extraction. AB - Purpose: To combine the increased depth of focus of the TECNIS(r) Symfony intraocular lens (IOL) with a TECNIS Multifocal (MF) low-add IOL (+3.25) to enable a patient to be less dependent on corrective lenses. Setting: Clinic in Canada. Design: Single-center, prospective, open-label. Materials and methods: Fifty patients were enrolled for bilateral surgery. Patients were implanted with TECNIS Symfony Extended Range of Focus lens in the dominant eye, and TECNIS low add +3.25 MF IOL in the non-dominant eye. Patients were >=18 years of age and had best-corrected visual acuity >20/30 in both eyes, pupil size >3.5 mm, and <1.5 D of corneal astigmatism. Patients were evaluated preoperatively, operatively, and postoperatively on Day 1, Day 7, Month 1, and Month 3. Postoperative evaluations at Month 3 were completed by 32 of 50 patients enrolled, and included distance, intermediate and near visual acuity (VA), and subjective outcomes. Results: Three months postoperatively, binocular results without correction revealed 97% (29/30) of patients had distance VA of 20/20 or better, 97% (29/30) had intermediate VA of 20/25 or better, and 94% (28/30) had near VA of 20/25 or better. At Month 3, the majority of patients reported "none" for visual symptoms of glare (30/30, 100%), halo (29/30, 96.6%), starbursts (29/30), or other - blur (30/30, 100%). Conclusion: Three months postoperatively, the combination of the increased depth of focus of the TECNIS Symfony IOL with a TECNIS MF low-add (+3.25) IOL may provide excellent uncorrected VA at near, intermediate, and far distances with minimal ocular symptoms. PMID- 30425449 TI - Clinical outcomes of 4-point scleral fixated 1-piece hydrophobic acrylic equiconvex intraocular lens using polytetrafluoroethylene suture. AB - Purpose: To report the visual outcomes and complications of scleral fixated intraocular lenses (IOLs) using Gore-Tex suture. Methods: The current study is a retrospective noncomparative case series including patients who underwent scleral fixation of IOL (Akreos AO60) using Gore-Tex suture from August 2015 to March 2017 at a university teaching center. Primary outcome measures were visual acuity and complications at last follow-up. Results: The current study included 49 eyes of 48 patients. Mean follow-up duration postsurgery was 6.9 months (range: 0.9 29.4 months). The indications for secondary IOL surgery were dislocated IOL in 16/49 (33%), subluxed IOL in 9/49 (18%), dislocated or subluxed crystalline lens in 9/49 (18%), traumatic cataract in 8/49 (16%), and complicated cataract surgery in 7/49 (14%). Mean best-corrected logMAR visual acuity improved from 1+/-0.7 (20/200 Snellen equivalent) preoperatively to 0.5+/-0.5 (20/63 Snellen equivalent) at last follow-up. There were no intraoperative complications noted. Early postoperative complications included significant persistent corneal edema (longer than 1 week) in 4/49 (8.2%), ocular hypertension (intraocular pressure >=25 mmHg) in 8/49 (16.3%), hypotony (intraocular pressure <=5 mmHg) in 6/49 (12.2%), cystoid macular edema 3/21 (6.1%), IOL tilt 2/49 (4.1%), hyphema in 2/49 (4.1%), and vitreous hemorrhage in 5/49 (4.8%). There was one case of recurrent retinal detachment. One patient presented with an erosion of the Gore-Tex suture through the conjunctiva resulting in a purulent scleritis 6 months after the initial surgery, and was managed with removal of the IOL, debridement, and cryotherapy. Forty-one of 49 patients completed 3-month follow-up, among which visual acuity improved, deteriorated, or remained same compared to baseline in 27/49 (55.1%), 8/49 (16.3%), and 6/49 (12.2%) eyes, respectively. Conclusion: In the current study, visual acuity outcomes were generally favorable. The complications were largely transient. Significant complications included a suture related infection, which required removal of the IOL, and a recurrence of a retinal detachment. PMID- 30425450 TI - Viscodilation of Schlemm's canal for the reduction of IOP via an ab-interno approach. AB - Purpose: The aim of this study was to compare the 1-year efficacy and safety profile of ab-interno canaloplasty (ABiC) when performed as a stand-alone procedure or as an adjunct to cataract extraction in reducing IOP and glaucoma medication dependence. Patients and methods: This retrospective, comparative, consecutive case series included patients with uncontrolled primary open-angle glaucoma (POAG) who underwent ABiC as a stand-alone procedure or in conjunction with cataract extraction. Data were collected over a 12-month period. Primary outcome measures were mean lower IOP and mean number of glaucoma medications. Secondary endpoints included surgical and postsurgical complications and secondary interventions. Results: The study included 75 eyes of 68 patients (mean age: 73.7+/-9.9 years) with a mean baseline IOP of 20.4+/-4.7 mmHg on 2.8+/-0.9 medications, which reduced to 13.3+/-1.9 mmHg (n=73) on 1.1+/-1.1 medications at 12 months postoperative (both P<0.0001). At 12 months, 40% of eyes were medication free. In the ABiC/phacoemulsification subgroup (n=34 eyes), the mean IOP and medication use decreased from 19.4+/-3.7 mmHg on 2.6+/-1.0 medications preoperatively to 13.0+/-1.8 mmHg on 0.8+/-0.2 medications at 12 months (both P<0.001). In the stand-alone ABiC subgroup (n=41), the mean IOP and medication use decreased from 21.2+/-5.3 mmHg on 3.0+/-0.7 medications preoperatively to 13.7+/-1.9 mmHg on 1.3+/-1.1 medications at 12 months (P=0.001 and <0.001, respectively). No serious adverse events were recorded. Conclusion: These data demonstrate that ABiC was effective at reducing IOP and medication use in eyes with uncontrolled POAG with or without cataract surgery. PMID- 30425452 TI - Enhanced oral bioavailability of fluvastatin by using nanosuspensions containing cyclodextrin. AB - Background: In this study, fluvastatin (FVT) nanosuspensions containing cyclodextrin were developed to improve oral bioavailability. Methods: FVT nanosuspensions containing cyclodextrin were prepared by a high pressure homogenization technique. The nanosuspensions system was then characterized by transmission electron microscopy (TEM), particle size, differential scanning calorimetry (DSC) and powder X-ray diffractometry (PXRD). In addition, in vitro drug release properties, pharmacokinetics and pharmacodynamics were also investigated in detail. Results: After lyophilization, the nanosuspensions could be redispersed gently and with a narrow particle size distribution, but the particle size has no obvious change. The powder X-ray diffraction and differential scanning calorimetry of FVT nanosuspensions showed that FVT existed in amorphous form in nanosuspensions. In vitro release, FVT nanosuspensions have sustained-release properties. Meanwhile, FVT nanosuspensions could significantly modify the pharmacokinetic profile and increase the bioavailability of FVT by more than 2.4-fold in comparison with the FVT capsules group. In vivo irritation test showed that there was almost no evidence of hemorrhagic mucosal erosion and intestinal villus destruction in rat gastric mucosa. Conclusion: The combination of nanocrystallization and cyclodextrin complexation techniques is a new attempt to formulate poorly water-soluble FVT. PMID- 30425451 TI - Comparison of variation of intraocular pressure in noncontact tonometry in patients subjected to phacoemulsification and trabeculectomy with phacoemulsification. AB - Objective: Evaluate the pattern of intraocular pressure (IOP) variations through the pneumatic tonometer, between two specific surgical techniques, and the possible variables that may influence the behavior of this pressure. Methods: Retrospective cross-sectional study carried out through the review of electronic medical records of a private ophthalmological reference hospital in the city of Goiania, Goias, Brazil, from 2012 to 2016, comprising of a sample of 550 eyes. The analyzed variables were, age, gender, IOP, axis, pachymetry, anterior chamber depth, and axial length. Results: In the end, the study consisted of 231 eyes, represented by 179 patients. Of these, 182 eyes were operated on by isolated cataract surgery, with a mean age of 72.0+/-9.5 years. The combined surgery represented a total of 49 eyes, 34 patients with a mean age of 71.9+/-8.14 years. There was statistical significance (P<0.05) in correlating the pre- and postoperative IOP values in the 24-hour, 7-, 15-day, and 12-month postoperative periods. Conclusion: A standard of variation of IOP was found through the pneumatic tonometer in both surgical techniques, but a more significant reduction was observed in combined surgery than in isolated cataract surgery, and further studies with a greater epidemiological impact are required for confirmation of this conclusion. PMID- 30425453 TI - Combination of Ginsenoside Rg1 and Astragaloside IV reduces oxidative stress and inhibits TGF-beta1/Smads signaling cascade on renal fibrosis in rats with diabetic nephropathy. AB - Introduction: Anti-oxidative stress and inhibition of TGF-beta1/Smads signaling cascade are essential therapeutic strategies for diabetic nephropathy (DN). In this study, we aimed to explore the effect of combination of Ginsenoside Rg1 and Astragaloside IV on oxidative stress and TGF-beta1/Smads signaling in DN rats. Materials and methods: Wistar rats were divided into five groups: N group, M group (streptozotocin [STZ], intraperitoneally), G group (STZ rats with Ginsenoside Rg1, intragastrically [ig]), A group (STZ rats with Astragaloside IV, ig) and C group (STZ rats with Ginsenoside Rg1 and Astragaloside IV, ig). The levels of methane dicarboxylic aldehyde (MDA), catalase (CAT), glutathione peroxidase (GSH-PX), total anti-oxidative capacity (T-AOC), blood urea nitrogen (BUN), beta2-microglobulin (beta2-MG), serum creatinine (SCr) and urinary creatinine (UCr) were detected in all the groups. The left kidneys of the rats were harvested to detect the expression of TGF-beta1, Smad2/3, Smad7 and CTGF by immunohistochemical staining, while the right kidneys were used to detect the mRNA expression of TGF-beta1, Smad7 and CTGF by real-time PCR. Results: Rats in G group, A group and C group had lower level of MDA but higher levels of CAT, GSH PX and T-AOC compared with rats in M group. Rats in C group showed the best anti oxidative stress level. G group, A group and C group treatments significantly decreased the levels of BUN, SCr, beta2-MG and UCr. In addition, C group treatment showed the best kidney protective effect. G group, A group and C group treatments significantly diminish ED both factor and mRNA overexpression of TGF beta1 and CTGF but increase Smad7 expression in kidney tissue. Conclusion: The combination of Ginsenoside Rg1 and Astragaloside IV may potentially protect against DN by reducing oxidative stress and inhibiting TGF-beta1/Smads signaling cascade. PMID- 30425454 TI - Antioxidative stress effects of vitamins C, E, and B12, and their combination can protect the liver against acetaminophen-induced hepatotoxicity in rats. AB - Background: Several vitamins, including C, E, and B12, have been recognized as antioxidants and have shown hepatoprotective effects against the hepatotoxicity caused by acetaminophen (APAP) overdose. The current investigation aims to study the effect of these vitamins and their combination in protecting the liver from APAP hepatotoxicity in rats. Materials and methods: An in vitro model of freshly isolated rat hepatocytes was utilized for assessing hepatocyte mitochondrial activity conducted by cell proliferation assay (MTT). The isolated hepatocytes were treated with vitamin C, vitamin E, vitamin B12 and their combination, with and without further addition of toxic concentrations of APAP. In addition, an in vivo experiment was carried out on Sprague Dawley rats treated intraperitoneally for 8 days with emulsions of the vitamins or their combination prior to injecting them with APAP. Results: In vitro results showed that vitamins C and B and the combination preparation significantly increased the percentage of hepatocyte mitochondrial activity, both with and without the addition of APAP (P<0.01). The mitochondrial activity in the isolated cultured hepatocytes was further enhanced with APAP addition. In vivo, the vitamins and their combination effectively reduced APAP-induced serum liver enzymes levels, namely ALT, AST, and ALP, and also attenuated oxidative stress and lipids peroxidation confirmed by the results of glutathione, superoxide dismutase, and maloondialdehyde. Conclusion: Pretreatment with vitamins C, E, B12, or their combination was found to be beneficial in preventing in vivo hepatic oxidative stress induced by APAP overdose. Vitamin C on its own showed superior protection against APAP-induced liver injury in rats compared to the other vitamins. The proliferation of APAP intoxicated liver cells in vitro was highest when protected with the vitamins' combination. PMID- 30425457 TI - Dry eye disease also might influence psychological status and quality of life in patients with primary Sjogren's syndrome. PMID- 30425455 TI - Glutathione S-transferase pi: a potential role in antitumor therapy. AB - Glutathione S-transferase pi (GSTpi) is a Phase II metabolic enzyme that is an important facilitator of cellular detoxification. Traditional dogma asserts that GSTpi functions to catalyze glutathione (GSH)-substrate conjunction to preserve the macromolecule upon exposure to oxidative stress, thus defending cells against various toxic compounds. Over the past 20 years, abnormal GSTpi expression has been linked to the occurrence of tumor resistance to chemotherapy drugs, demonstrating that this enzyme possesses functions beyond metabolism. This revelation reveals exciting possibilities in the realm of drug discovery, as GSTpi inhibitors and its prodrugs offer a feasible strategy in designing anticancer drugs with the primary purpose of reversing tumor resistance. In connection with the authors' current research, we provide a review on the biological function of GSTpi and current developments in GSTpi-targeting drugs, as well as the prospects of future strategies. PMID- 30425458 TI - Erratum: Patterns and predictors of long-term retention of inflammatory bowel or rheumatoid disease patients on innovator infliximab: an analysis of a Canadian prescriptions claims database [Erratum]. AB - [This corrects the article on p. 1805 in vol. 12, PMID: 30271124.]. PMID- 30425456 TI - Entrectinib and other ALK/TRK inhibitors for the treatment of neuroblastoma. AB - RTK plays important roles in many cellular signaling processes involved in cancer growth and development. ALK, TRKA, TRKB, TRKC, and ROS1 are RTKs involved in several canonical pathways related to oncogenesis. These proteins can be genetically altered in malignancies, leading to receptor activation and constitutive signaling through their respective downstream pathways. Neuroblastoma (NB) is the most common extracranial solid tumor in childhood, and despite intensive therapy, there is a high mortality rate in cases with a high risk disease. Alterations of ALK and differential expression of TRK proteins are reported in a proportion of NB. Several inhibitors of ALK or TRKA/B/C have been evaluated both preclinically and clinically in the treatment of NB. These agents have had variable success and are not routinely used in the treatment of NB. Entrectinib (RXDX-101) is a pan-ALK, TRKA, TRKB, TRKC, and ROS1 inhibitor with activity against tumors with ALK, NTRK1, NTRK2, NTRK3, and ROS1 alterations in Phase I clinical trials in adults. Entrectinib's activity against both ALK and TRK proteins suggests a possible role in NB treatment, and it is currently under investigation in both pediatric and adult oncology patients. PMID- 30425459 TI - Trajectory of thirst intensity and distress from admission to 4-weeks follow up at home in patients with heart failure. AB - Background: Patients with heart failure (HF) can suffer from increased thirst intensity and distress. Trajectories of thirst intensity and distress from hospital to home are unclear. The aim of this study was to describe thirst intensity and distress trajectories in patients from the time of hospital admission to 4 weeks after discharge, and describe trajectories of thirst intensity and distress by patients' characteristics (gender, age, body mass index [BMI], plasma urea, anxiety, and depression). Patients and methods: In this observational study, data were collected from patients with HF (n=30) at hospital admission, discharge, and at 2 and 4 weeks after discharge. Thirst intensity (visual analog scale, 100 mm) and distress (Thirst Distress Scale-HF, score 9-45) were used. Trajectories were examined using growth modeling. Results: Trajectory of the thirst intensity was significantly different, for patients with low and high thirst intensity levels (median cut-off 39 mm), from admission to 4 weeks follow up (thirst increased and decreased, respectively). Patients with high level of thirst distress (median score >22) at admission, having fluid restriction and women continued to have higher thirst distress over time. Patients feeling depressed had higher thirst intensity over time. There were no differences in the trajectories of thirst intensity and distress by age, BMI, plasma urea, and anxiety. Conclusion: Intensity and distress of thirst, having fluid restriction, and feeling depressed at the admission were critical in predicting the trajectory of thirst intensity and distress after discharge to home in patients with HF. Effective intervention relieving thirst should be provided before their discharge to home. PMID- 30425460 TI - Cognitive function and 3-year mortality in the very elderly Chinese population with chronic kidney disease. AB - Background: Cognitive function has been suggested to be correlated with mortality, while studies regarding the association among the very elderly population with chronic kidney disease (CKD) are extremely limited. Aim: To explore the association between cognitive function and mortality among the very elderly Chinese population with CKD. Methods: This prospective study included 163 Chinese participants aged 80 years or older with CKD. CKD was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2. Cognitive function was evaluated using the mini-mental state examination (MMSE) at baseline. Participants were divided into three groups based on the MMSE score. Cox proportional hazard models were used to assess the contribution of cognitive function to mortality. Results: During a median follow-up of 28 months, 24 (14.7%) participants died, and 14 of the events were cardiovascular death. After making adjustment for potential confounders, every 1-point increase of MMSE score was associated with 29% decreased risk of all-cause mortality (adjusted hazards ratio [HR], 0.71; 95% CI, 0.58-0.87) and 39% decreased risk of cardiovascular mortality (adjusted HR, 0.61; 95% CI, 0.44-0.83). Compared with participants with top category of MMSE score, the adjusted HRs for all-cause mortality and cardiovascular mortality among those with bottom category of MMSE score were 8.18 (95% CI, 2.05-32.54) and 14.72 (95% CI, 1.65-131.16). Conclusion: Cognitive function was associated with all-cause mortality and cardiovascular mortality among the very elderly population with CKD. PMID- 30425462 TI - Effect of sun exposure on cognitive function among elderly individuals in Northeast China. AB - Background: Previous findings on the relationship between serum 25-hydroxyvitamin D [25(OH)D] level and cognitive impairment have been inconsistent. One reason is that serum 25(OH)D has a relatively short half-life, but the development of cognitive impairment is a long-term process. Skin exposure to solar ultraviolet radiation is the primary source of vitamin D synthesis. For this study, we hypothesized that people with different sun exposure behaviors would have different cognitive functions. Methods: This study included 1,192 rural-dwelling elders in People's Republic of China whose sun exposure behaviors, including the duration of outdoor activities, use of sun protection, and time of day participants engaged in outdoor activities, were collected. Their global cognitive function was assessed by Mini-Mental State Examination (MMSE). Partitioning cluster analysis was used to classify participants into groups based on their sun exposure behaviors. Ordinal logistic regression analysis was used to examine the association between sun exposure and cognitive function. Results: The participants were divided into high-, medium-, and low-sun-exposure groups by cluster analysis. The participants in the high-sun-exposure group had the longest sun exposure time, reported the least sun-protective behaviors, and usually spent time outdoors in the morning (8:00-11:00) and afternoon (13:00-16:00). The participants in the low-sun-exposure group had the shortest sun exposure time, had the most positive sun-protective behaviors, and mainly spent time outdoors in the early morning (6:00-8:00) and late afternoon (16:00-18:00). After adjusting for potential confounders, participants with habitually high sun exposure were more likely to have higher MMSE score (25.4) than those with habitually low sun exposure (MMSE score =24.4). Conclusion: Long-term high sun exposure is positively related with better cognitive functioning. PMID- 30425461 TI - Identification of the optimal cognitive drugs among Alzheimer's disease: a Bayesian meta-analytic review. AB - Purpose: The increasing prevalence of Alzheimer's disease (AD) demands more effective drugs, which are still unclear. The aim of this study is to compare the effectiveness of six drugs, such as donepezil, rivastigmine, galantamine, memantine, huperzine-A, and tacrine, in senior AD patients and identify the most effective one to improve patients' cognitive function. Methods: A system of search strategies was used to identify relevant studies including randomized controlled trials and clinical controlled trials evaluating the efficacy of six drugs in patients with AD. We updated relevant studies that were published before March 2018 as full-text articles. Using Bayesian network meta-analysis (NMA), we ranked cognitive ability objectively based on Mini-Mental State Examination (MMSE). Pairwise and NMAs were sequentially performed for the efficacy of drugs compared to each drug or control group through the trials included. Results: Among the 35 trials included, no obvious heterogeneity (I 2=0.0%, P=0.583) was revealed according to the pooled data for cognition in NMA and the mean difference (MD) of memantine (MD=1.7, 95% CI: 0.73, 2.8) showed that the memantine was significantly efficacious in the treatment group in terms of MMSE. Followed by galantamine, huperzine-A, rivastigmine, tacrine, and donepezil. Conclusion: As the first NMA comparing the major drugs in market for AD, our study suggests that memantine might have a more significant benefit on cognition than other five drugs available. PMID- 30425463 TI - Merging current health care trends: innovative perspective in aging care. AB - Current trends in health care delivery and management such as predictive and personalized health care incorporating information and communication technologies, home-based care, health prevention and promotion through patients' empowerment, care coordination, community health networks and governance represent exciting possibilities to dramatically improve health care. However, as a whole, current health care trends involve a fragmented and scattered array of practices and uncoordinated pilot projects. The present paper describes an innovative and integrated model incorporating and "assembling" best practices and projects of new innovations into an overarching health care system that can effectively address the multidimensional health care challenges related to aging patient especially with chronic health issues. The main goal of the proposed model is to address the emerging health care challenges of an aging population and stimulate improved cost-efficiency, effectiveness, and patients' well-being. The proposed home-based and community-centered Integrated Healthcare Management System may facilitate reaching the persons in their natural context, improving early detection, and preventing illnesses. The system allows simplifying the health care institutional structures through interorganizational coordination, increasing inclusiveness and extensiveness of health care delivery. As a consequence of such coordination and integration, future merging efforts of current health care approaches may provide feasible solutions that result in improved cost-efficiency of health care services and simultaneously increase the quality of life, in particular, by switching the center of gravity of health delivery to a close relationship of individuals in their communities, making best use of their personal and social resources, especially effective in health delivery for aging persons with complex chronic illnesses. PMID- 30425464 TI - Low skeletal muscle mass as a risk factor for postoperative delirium in elderly patients undergoing colorectal cancer surgery. AB - Background: Both low skeletal muscle mass (LSMM) and delirium are frequently seen in elderly patients. This study aimed to investigate the association between preoperative LSMM and postoperative delirium (POD) in elderly patients undergoing colorectal cancer (CRC) surgery and to design a model to predict POD. Patients and methods: This is a retrospective observational cohort study. Patients aged 70 years or older undergoing CRC surgery from January 2013 to October 2015 were included in this study. The cross-sectional skeletal muscle area at the level of the third lumbar vertebra using computed tomography was adjusted for patients' height, resulting in the skeletal muscle index. The lowest quartile per sex was defined as LSMM. Short Nutritional Assessment Questionnaire for Residential Care and KATZ-Activities of Daily Living were used to define malnourishment and physical dependency, respectively. POD was diagnosed using the Delirium Observational Screening Scale and geriatricians' notes. Results: Median age of the 251 included patients was 76 years (IQR, 73-80 years), of whom 56% of patients were males, 24% malnourished, and 15% physically impaired. LSMM and POD were diagnosed in 65 and 33 (13%) patients, respectively. POD occurred significantly more in patients with LSMM (25%) compared with patients without LSMM (10%), P=0.006. In the multivariate analysis, age, history of delirium, and LSMM were significantly associated with POD. In addition, this effect increased in patients with LSMM and malnourishment (P=0.019) or physical dependency (P=0.017). Conclusion: Age, history of delirium, LSMM, and malnourishment or physical dependency were independently associated with POD. Our nomogram could be used to identify patients at an increased risk for delirium. These patients may benefit from intensive monitoring to prevent POD. PMID- 30425465 TI - Development of a tool for monitoring the prescribing of antipsychotic medications to people with dementia in general practice: a modified eDelphi consensus study. AB - Background: Despite their adverse effects, antipsychotics are frequently used to manage behavioral and psychological symptoms of dementia. Regular monitoring of antipsychotic prescribing has been shown to improve the appropriateness of prescribing. However, there is currently no consensus on what the components of such a monitoring tool would be. Aim: The aim of this study was to use an expert consensus process to identify the key components of an antipsychotic repeat prescribing tool for use with people with dementia in a general practice setting. Methods: A modified eDelphi technique was employed. We invited multidisciplinary experts in antipsychotic prescribing to people with dementia to participate. These experts included general practitioners (GPs), geriatricians and old age psychiatrists. The list of statements for round 1 was developed through a review of existing monitoring tools and international best practice guidelines. In the second round of the Delphi, any statement that had not reached consensus in the first round was presented for re-rating, with personalized feedback on the group and the individual's response to the specific statement. The final round consisted of a face-to-face expert meeting to resolve any uncertainties from round 2. Results: A total of 23 items were rated over two eDelphi rounds and one face-to-face consensus meeting to yield a total of 18 endorsed items and five rejected items. The endorsed statements informed the development of a structured, repeat prescribing tool for monitoring antipsychotics in people with dementia in primary care. Conclusion: The development of repeat prescribing tool provides GPs with practical advice that is lacking in current guidelines and will help to support GPs by providing a structured format to use when reviewing antipsychotic prescriptions for people with dementia, ultimately improving patient care. The feasibility and acceptability of the tool now need to be evaluated in clinical practice. PMID- 30425466 TI - Transcutaneous electrical acupoint stimulation for prevention of postoperative delirium in geriatric patients with silent lacunar infarction: a preliminary study. AB - Purpose: This study aims to investigate the effect of transcutaneous electrical acupoint stimulation (TEAS) on postoperative delirium (POD) in elderly patients with silent lacunar infarct and preliminarily to determine the relationship among TEAS, blood-brain barrier (BBB), neuroinflammation, and POD. Patients and methods: Sixty-four-old patients with silent lacunar infarct were randomly divided into two groups: group TEAS and control group (group C). Patients in the group TEAS received TEAS (disperse-dense waves; frequency, 2/100 Hz) on acupoints Hegu and Neiguan of both sides starting from 30 minutes before induction of anesthesia until the end of surgery, and the intensity was the maximum current that could be tolerated. In group C, electrodes were placed on the same acupoints before anesthesia induction, but no current was given. At 0 minute before the treatment of TEAS, 30 minutes after skin incision, and after completion of surgery (T1-3), blood samples were extracted to detect the concentration of serum tumor necrosis factor (TNF)-alpha, interleukin-6 (IL-6), matrix metalloproteinase 9 (MMP-9), and S100beta. We assessed patients for delirium and coma twice daily in the first 3 postoperative days using the Confusion Assessment Method for the intensive care unit and the Richmond Agitation-Sedation Scale. Results: This study preliminarily suggests that TEAS can reduce the development of POD in elderly patients with silent lacunar infarction (6.3% vs 25.0%; P=0.039). Compared with the baseline value at T1, the serum concentrations of IL-6, TNF alpha, MMP-9, and S100beta were significantly increased at T2-3 in both the groups (P<0.05). Compared with group TEAS, serum levels of TNF-alpha and IL-6 were higher at T2-3 and serum levels of MMP-9 and S100beta were higher at T3 in group C (P<0.05). The intraoperative anesthetic consumptions were less in group TEAS than group C. Conclusion: TEAS can alleviate POD in older patients with silent lacunar infarction and may be related to reduce the neuroinflammation by lowering the permeability of BBB. PMID- 30425467 TI - How whole-body vibration can help our COPD patients. Physiological changes at different vibration frequencies. AB - Objective: Evaluate cardiac, metabolic, and ventilatory changes during a training session with whole-body vibration training (WBVT) with 3 different frequencies in patients with chronic obstructive pulmonary disease (COPD). Methods: This was a prospective, interventional trial in outpatients with severe COPD. Participants performed 3 vertical WBVT sessions once a week using frequencies of 35, 25 Hz and no vibration in squatting position (isometric). Cardiac, metabolic, and ventilator parameters were monitored during the sessions using an ergospirometer. Changes in oxygen pulse response (VO2/HR) at the different frequencies were the primary outcome of the study. Results: Thirty-two male patients with a mean forced expiratory volume in 1 second of 39.7% completed the study. Compared to the reference of 35 Hz, VO2/HR at no vibration was 10.7% lower (P=0.005); however, no statistically significant differences were observed on comparing the frequencies of 35 and 25 Hz. The median oxygen uptake (VO2) at 25 Hz and no vibration was 9.43% and 13.9% lower, respectively, compared to that obtained at 35 Hz (both comparisons P<0.0001). The median expiratory volume without vibration was 9.43% lower than the VO2 at the end of the assessment at 35 Hz vibration (P=0.002). Conclusion: Vertical WBVT training sessions show greater cardiac, metabolic, and respiratory responses compared with the squat position. On comparing the 2 frequencies used, we observed that the frequency of 35 Hz provides higher cardiorespiratory adaptation. PMID- 30425468 TI - Difference in systemic inflammation and predictors of acute exacerbation between smoking-associated COPD and tuberculosis-associated COPD. AB - Purpose: Tuberculosis-associated COPD (T-COPD) has clinical characteristics similar to those of smoking-associated COPD (S-COPD), such as dyspnea, sputum production, and acute exacerbation (AE). However, the degree of systemic inflammation and prognosis might be different because of difference in the pathophysiology. The aim of this study was to compare the lung function, systemic inflammatory markers, and their impacts on AE in patients with S-COPD and T-COPD. Patients and methods: We performed a multicenter cross-sectional cohort study. We evaluated clinical characteristics, pulmonary function tests, levels of inflammatory markers, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and IL-6, and the association of these markers with AE in patients with S-COPD and T-COPD. Results: Patients with T-COPD included more women and had lesser smoking history and higher St George Respiratory Questionnaire score than did patients with S-COPD. Although the FEV1 of both groups was similar, FVC, vital capacity, total lung capacity, and functional residual capacity were lower in patients with T-COPD than in those with S-COPD. CRP, ESR, and IL-6 levels were significantly higher in patients with T-COPD compared to patients with S-COPD. According to a multivariate logistic regression analysis, FEV1 was a significant factor predicting AE in S-COPD, and IL-6 was a significant factor predicting AE in T-COPD. IL-6 level greater than 2.04 pg/mL was a cutoff for predicting exacerbation of T-COPD (sensitivity 84.8%, specificity 59.3%, P<0.001). Conclusion: Patients with T-COPD have higher levels of inflammatory markers, and IL-6 has a predictive value for AE in T-COPD. PMID- 30425469 TI - Safety, tolerability, and pharmacokinetics of single and repeat ascending doses of CHF6001, a novel inhaled phosphodiesterase-4 inhibitor: two randomized trials in healthy volunteers. AB - Purpose: The purpose of this study was to evaluate safety, tolerability, and pharmacokinetics (PK) of CHF6001, an inhaled phosphodiesterase-4 inhibitor. Materials and methods: Two healthy volunteer, randomized, double-blind, placebo controlled studies were conducted. In each, Part 1 evaluated single ascending doses, with PK sampling up to 48 hours post-dose; Part 2 evaluated multiple ascending doses (Study 1, 7 days; Study 2, 14 days), with PK sampling up to 24 hours post-dose on first and last day of each period. In Study 1, treatments were administered via single-dose dry-powder inhaler (SDDPI; Aerolizer): Part 1, 20, 100, 200, 400, 800, 1,600, and 2,000 ug or placebo; Part 2, 100, 300, 600, 1,200, and 1,600 ug or placebo once daily (OD). In Study 2, treatments were administered via multi-dose dry-powder inhaler (MDDPI; NEXThaler): Part 1, 2,400, 4,000, and 4,800 ug or placebo; Part 2, 1,200, 2,000, or 2,400 ug twice daily (BID) or placebo. Modeling and simulation then compared OD and BID dosing via MDDPI. Results: There was a clear correlation between CHF6001 dose and plasma concentration, following single and multiple doses and using SDDPI and MDDPI. CHF6001 plasma concentration area under the curve (AUC) was dose proportional, with steady state slopes of the fitted line of 0.95 (90% CI: 0.86, 1.04) for AUC0 24 h in Study 1, and 0.85 (90% CI: 0.38, 1.32) for AUC0-12 h in Study 2. Bioavailability was30% higher with MDDPI than SDDPI. The PK simulation confirmed dose proportionality; the same total daily dose OD or BID via MDDPI resulted in similar 24 hours exposure, with BID dosing providing smaller fluctuation and lower maximum concentration. CHF6001 was well tolerated with no relationship between dose and adverse events. Conclusion: CHF6001 demonstrated a good safety profile. There was a clear dose proportionality for systemic exposure, with higher bioavailability via MDDPI, suggesting that the MDDPI provides better pulmonary drug deposition. BID dosing was associated with a better exposure profile. PMID- 30425470 TI - Decreased serum club cell secretory protein in asthma and chronic obstructive pulmonary disease overlap: a pilot study. AB - Purpose: Improvement in the diagnosis of asthma and chronic obstructive pulmonary disease (COPD) overlap (ACO), and identification of biomarkers for phenotype recognition will encourage good patient care by providing optimal therapy. We investigated club cell secretory protein (CC-16), a protective and anti inflammatory mediator, as a new candidate biomarker for diagnosing ACO. Patients and methods: We performed a multicenter cohort study. A total of 107 patients were divided into three groups - asthma, COPD, and ACO - according to the Spanish guidelines algorithm, and enrolled into the study. Serum CC-16 levels were measured using commercial ELISA kits. Results: Serum CC-16 levels were the lowest in patients with ACO. Low serum CC-16 levels were a significant marker for the ACO even after adjustment for age, sex, and smoking intensity. Serum CC-16 levels were positively correlated with forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), forced expiratory flow at 25%-75% of FVC, FEV1/FVC, vital capacity, and diffusing capacity of the lung for carbon monoxide, and were negatively correlated with smoking amount (pack-years), bronchodilator response, fractional residual capacity, residual volume, and number of exacerbations per year. FEV1 and serum CC-16 levels were significantly lower in patients with frequent exacerbations. Conclusion: Serum CC-16 has the potential to be a biomarker for ACO diagnosis and also treat frequent exacerbations in patients with chronic inflammatory airway diseases. PMID- 30425472 TI - Validation of the GOLD 2017 and new 16 subgroups (1A-4D) classifications in predicting exacerbation and mortality in COPD patients. AB - Background and objective: A multidimensional assessment of COPD was recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) in 2013 and revised in 2017. We examined the ability of the GOLD 2017 and the new 16 subgroup (1A-4D) classifications to predict clinical outcomes, including exacerbation and mortality, and compared them with the GOLD 2013 classifications. Methods: Patients with COPD were recruited from January 2006 to December 2017. The predictive abilities of grades 1-4 and groups A-D were examined through a logistic regression analysis with receiver operating curve estimations and area under the curve (AUC). Results: A total of 553 subjects with COPD were analyzed. The mortality rate was 48.6% during a median follow-up period of 5.2 years. Both the GOLD 2017 and the 2013 group A-D classifications had good predictive ability for total and severe exacerbations, for which the AUCs were 0.79 vs 0.77 and 0.79 vs 0.78, respectively. The AUCs for the GOLD 2017 groups A-D, grades 1-4, and the GOLD 2013 group A-D classifications were 0.70, 0.66, and 0.70 for all-cause mortality and 0.73, 0.71, and 0.74 for respiratory cause mortality, respectively. Combining the spirometric staging with the grouping for the GOLD 2017 subgroups (1A-4D), the all-cause mortality rate for group B and D patients was significantly increased from subgroups 1B-4B (27.7%, 50.6%, 53.3%, and 69.2%, respectively) and groups 1D-4D (55.0%, 68.8%, 82.1%, and 90.5%, respectively). The AUCs of subgroups (1A-4D) were 0.73 and 0.77 for all-cause and respiratory mortality, respectively; the new classification was determined more accurate than the GOLD 2017 for predicting mortality (P<0.0001). Conclusion: The GOLD 2017 classification performed well by identifying individuals at risk of exacerbation, but its predictive ability for mortality was poor among COPD patients. Combining the spirometric staging with the grouping increased the predictive ability for all-cause and respiratory mortality. Summary at a glance: We validate the ability of the GOLD 2017 and 16 subgroup (1A-4D) classifications to predict clinical outcome for COPD patients. The GOLD 2017 classification performed well by identifying individuals at risk of exacerbation, but its predictive ability for mortality was poor. The new 16 subgroup (1A-4D) classification combining the spirometric 1-4 staging and the A-D grouping increased the predictive ability for mortality and was better than the GOLD 2017 for predicting all-cause and respiratory mortality among COPD patients. PMID- 30425471 TI - Toward effective prescription of inhaled corticosteroids in chronic airway disease. PMID- 30425473 TI - Is COPD associated with periodontal disease? A population-based study in Spain. AB - Background: Periodontal disease is more prevalent and more severe among men and women suffering from chronic obstructive pulmonary disease (COPD) compared with healthy adults. The objectives of this paper were to assess the association between periodontal disease and COPD, controlling the effect of sociodemographic characteristics, oral health status, lifestyle variables, and comorbidities. Second, we identified which of the variables analyzed were independently associated with periodontal disease among COPD sufferers. Methods: This descriptive study was done with data from the National/European Health Interview Surveys, conducted in years 2006, 2011/12, and 2014 in Spain. We included subjects >=40 years of age. COPD status was self-reported. One non-COPD patient was matched by age, gender, and the year of survey for each COPD case. The presence of periodontal disease was defined using the answers "my teeth bleed spontaneously or while brushing" or/and "my teeth move" to the question: "Do you suffer of any of these dental and oral disorders or diseases?" Independent variables included demographic, socioeconomic, and health care-related variables, oral health status, and presence of comorbidities. Results: The prevalence of periodontal disease was higher among COPD patients than their matched non-COPD controls (26.5% vs 22.2%; P<0.001). Adjusted odds ratio (AOR) of periodontal disease for subjects with COPD was 1.21 (95% CI: 1.12-1.30). Suffering mental disorders (AOR: 1.61; 95% CI: 1.32-1.97) was positively associated with higher risk of periodontal disease. Older age, having a private dental health insurance, and university education were variables associated with lower rates of periodontal disease. Conclusion: Prevalence of periodontal disease was higher among those with COPD compared to non-COPD controls. Dentists and physicians should increase their awareness with their COPD patients, especially those who are younger, with lower education, and suffer depression and/or anxiety. PMID- 30425474 TI - Intra- and inter-rater reproducibility of the 6-minute walk test and the 30 second sit-to-stand test in patients with severe and very severe COPD. AB - Background: In patients with COPD, the 6-minute walk test (6MWT) and the 30 second sit-to-stand test (30sec-STS) are widely used as clinical outcome measures of walking capacity, lower limb muscle strength, and functional ability. Due to a documented learning effect, at least two trials are recommended for assessment. The aim of our study was to investigate the intra- and inter-rater reliability and agreement of the two tests in patients with severe and very severe COPD (FEV1 <50%). Patients and methods: Fifty patients (22 females; mean [SD]: age 67 [9] years, FEV1 predicted 32 [9]%) were assessed with the 6MWT and the 30sec-STS twice by the same assessor on test-day 1 (T1) and by another assessor 7-10 days later on test-day 2 (T2). Results: The 6MWT intra- and inter-rater reliability (intraclass correlation coefficient, ICC1.1) was 0.98 (lower limit 95% CI: 0.94) and 0.96 (lower limit 95% CI: 0.94), respectively, and agreement (standard error of the measurement, SEM) was 14.8 and 20.5 m, respectively. The 30sec-STS intra- and inter-rater reliability and agreement results were, respectively, ICC1.1 0.94 (lower limit 95% CI: 0.90) and 0.92 (lower limit 95% CI: 0.86), with SEM of 0.97 and 1.14 repetitions. There was no difference (95% CI: -5.3; 8.1) between the 6MWT distances on T1, while the mean walking distance improved 7.9 m (0.0 m; 15.8 m) from T1 to T2. Improvement on the same test date was less likely (OR: 3.6 [95% CI: 1.1; 11.8], Fisher's exact test, P=0.047) in patients who walked less than 350 m in the 6MWT. We found no clinically relevant learning effect in the 30sec STS. Conclusion: In patients with severe and very severe COPD the 6MWT and the 30sec-STS showed excellent intra- and inter-rater reliability and acceptable agreement. No learning effect was documented for the tests when performed on the same day. Our data suggest that in clinical practice using different assessors is acceptable, and that a single test trial may be sufficient to assess patients with severe and very severe COPD. PMID- 30425476 TI - Self-nanoemulsifying drug-delivery systems for potentiated anti-inflammatory activity of diacerein. AB - Background: Effective treatment of osteoarthritis necessitates both symptomatic relief and hindrance of joint degeneration progression. Non-steroidal anti inflammatory drugs permit symptomatic relief only and can cause mucosal injury in the gut. Before absorption, diacerein (Dcn) is converted into rhein that counteracts cartilage degeneration without affecting prostaglandin production. Yet, low solubility and laxative action of unabsorbed rhein in the colon hindered its use. Thus, enhanced Dcn dissolution would allow absorption at the upper gut improving its bioavailability and possibly abolishing the laxative action. Methods: Therefore, self-nanoemulsifying drug delivery systems (SNEDDSs) with each of gelucire 44/14 (Glc) and d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) at different drug:carrier weight ratios of 1:1, 1:2, 1:4, 1:6, 1:8 and 1:10 were prepared by melt method and filled into hard gelatin capsules. The optimized binary systems were selected based on solid state characterization, scanning electron microscopy (SEM) and in vitro evaluation of the prepared SNEDDSs in comparison with their corresponding physical mixtures (PMs) and Dcn. The optimized systems were further examined with respect to their morphology, size distribution and zeta-potential. Moreover, the anti-inflammatory activity of the optimized systems against carrageenan-induced paw edema in rats was assessed through estimation of edema and edema inhibition percentages as well as histopathological examination and immunohistochemical localization of tumor necrosis factor-alpha (TNF-alpha) and caspase-3. Results: Significantly (P<0.05) enhanced in vitro drug release was recorded for SNEDDSs with either carrier when compared to Dcn and the corresponding PMs. SNEDDSs based on 1:10 Dcn:Glc and 1:8 Dcn:TPGS showed significantly (P<0.05) reduced edema and inflammation as well as expression of TNF-alpha and caspase-3 relative to positive control and Dcn pretreated groups. Conclusion: These SNEDDSs can be represented as potential oral drug delivery systems of Dcn for enhanced dissolution and anti-inflammatory activity against carrageenan-induced paw edema. PMID- 30425475 TI - Hypoxia-activated prodrugs and redox-responsive nanocarriers. AB - Hypoxia is one of the marked features of malignant tumors, which is associated with several adaptation changes in the microenvironment of tumor cells. Therefore, targeting tumor hypoxia is a research hotspot for cancer therapy. In this review, we summarize the developing chemotherapeutic drugs for targeting hypoxia, including quinones, nitroaromatic/nitroimidazole, N-oxides, and transition metal complexes. In addition, redox-responsive bonds, such as nitroimidazole groups, azogroups, and disulfide bonds, are frequently used in drug delivery systems for targeting the redox environment of tumors. Both hypoxia activated prodrugs and redox-responsive drug delivery nanocarriers have significant effects on targeting tumor hypoxia for cancer therapy. Hypoxia activated prodrugs are commonly used in clinical trials with favorable prospects, while redox-responsive nanocarriers are currently at the experimental stage. PMID- 30425477 TI - Highly efficient siRNA transfection in macrophages using apoptotic body-mimic Ca PS lipopolyplex. AB - Background: The discovery and development of RNA interference has made a tremendous contribution to the biochemical and biomedical field. However, liposomal transfection protocols to deliver siRNAs to certain types of cells, eg, immune cells, are not viable due to exceedingly low transfection efficiency. While viral delivery and electroporation are two widely adopted approaches to transfect immune cells, they are associated with certain drawbacks such as complexity of preparation, biosafety issues, and high cytotoxicity. We believe amendments can be made to liposomal formulas and protocols to achieve a highly efficient knockdown of genes by liposome-loaded siRNAs. Aim: The aim of this study was to use the apoptotic-mimic Ca-PS lipopolyplex to achieve highly efficient siRNA knockdown of genes in the hard-to-transfect macrophages with reduced cytotoxicity and more efficient cellular uptake. Results: We devised an anionic liposomal formula containing phosphatidylserine to mimic the apoptotic body, the Ca-PS lipopolyplex. Ca-PS lipopolyplex was proven to be capable of delivering and effecting efficient gene knockdown in multiple cell lines at lowered cytotoxicity. Among the two types of macrophages, namely Ana-1 and bone marrow derived macrophages, Ca-PS lipopolyplex showed an improvement in knockdown efficiency, as high as 157%, over Lipo2000. Further investigations revealed that Ca-PS promotes increased cellular uptake, lysosomal escape and localization of siRNAs to the perinuclear regions in macrophages. Lastly, transfection by Ca-PS lipopolyplex did not induce spontaneous polarization of macrophages. Conclusion: The apoptotic body-mimic Ca-PS lipopolyplex is a stable, non-cytotoxic liposomal delivery system for siRNAs featuring vastly improved potency for macrophages and lowered cytotoxicity. It is speculated that Ca-PS lipopolyplex can be applied to other immune cells such as T cells and DC cells, but further research efforts are required to explore its promising potentials. PMID- 30425479 TI - Protein nanoparticles with ligand-binding and enzymatic activities. AB - Purpose: To develop a general method for NP fabrication from various proteins with maintenance of biological activity. Methods: A novel general approach for producing protein nanoparticles (NP) by nanoprecipitation of the protein solutions in 1,1,1,3,3,3-hexafluoroisopropanol is described. Protein NP sizes and shapes were analyzed by dynamic light scattering, scanning electron and atomic force microscopy (SEM and AFM). Chemical composition of the NP was confirmed using ultraviolet (UV) spectroscopy, energy-dispersive X-ray spectroscopy (EDX) and circular dichroism (CD). Biological properties of the NP were analyzed in ELISA, immunofluorescent analysis and lysozyme activity assay. Results: Water insoluble NP were constructed from globular (bovine serum albumin (BSA), lysozyme, immunoglobulins), fibrillar (fibrinogen) proteins and linear polylysines by means of nanoprecipitation of protein solutions in fluoroalcohols. AFM and SEM revealed NP sizes of 20-250 nm. The NP chemical structure was confirmed by UV spectroscopy, protease digestion and EDX spectroscopy. CD spectra revealed a stable secondary structure of proteins in NP. The UV spectra, microscopy and SDS-PAA gel electrophoresis (PAGE) proved the NP stability at +4 degrees C for 7 months. Co-precipitation of proteins with fluorophores or nanoprecipitation of pre-labeled BSA resulted in fluorescent NP that retained antigenic structures as shown by their binding with specific antibodies. Moreover, NP from monoclonal antibodies could bind with the hepatitis B virus antigen S. Besides that, lysozyme NP could digest bacterial cellular walls. Conclusion: Thus, the water-insoluble, stable protein NP were produced by nanoprecipitation without cross-linking and retained ligand-binding and enzymatic activities. PMID- 30425478 TI - Evaluation of the internal fixation effect of nano-calcium-deficient hydroxyapatite/poly-amino acid composite screws for intraarticular fractures in rabbits. AB - Objective: To evaluate the internal fixation effect of nano-calcium-deficient hydroxyapatite/poly-amino acid (n-CDHA/PAA) composite screws in the intraarticular fracture model. Materials and methods: A total of 35 New Zealand White rabbits were used in a bilateral femoral intercondylar fracture model and randomly divided into two groups. n-CDHA/PAA screws were used in the experimental group, and medical metal screws were used in the control group. The fracture condition, range of motion, and the screw push-out strength were assessed, and an arthroscopic examination of knee joint was performed at 4, 8, and 12 weeks after surgery. The biodegradation of the n-CDHA/PAA screws in vivo was tested through weighing, and changes in screw structure were assessed by X-ray diffraction at 12 weeks after surgery. Results: The general situation of all animals was good and showed no incision infection and dehiscence after surgery. X-ray scanning showed that significant callus growth was present in both groups at 4 weeks after surgery, and there was no significant difference (P>0.05) in the Lane-Sandhu score between the experimental and control groups at all time points after surgery. There were no statistically significant differences (P>0.05) in the range of motion and Oswestry Arthroscopy Score of arthroscopic examination of the knee joints between the two groups. The screw push-out strength of the control group was stronger than that of the experimental group at 4 weeks after surgery (P<0.05), but after that, there was no significant difference between the groups (P>0.05). The degradation tests showed that the n-CDHA/PAA screws degraded gradually after implantation, and the weight loss rate was approximately 16% at 12 weeks after surgery. The X-ray diffraction results showed that the crystal structure of the outer surface of the n-CDHA/PAA screw has changed at 12 weeks after surgery. Conclusion: The n-CDHA/PAA screw is an effective and safe implant as a potential internal fixation device for an intercondylar fracture of the femur, and its internal fixation effect was similar to that of medical metal screw. PMID- 30425480 TI - Artificially controlled degradable nanoparticles for contrast switch MRI and programmed cancer therapy. AB - Background: Utilizing the permeability enhancement and irreversible biomolecule denaturation caused by hyperthermia, photothermal-chemo synergistic therapy has shown great potential in clinical cancer treatment. Purpose: The objective of this study was to provide a novel controlled drug release method to improve the efficiency of photothermal-chemo synergistic therapy. Patients and methods: HCT116 tumor-bearing mice were selected as modal for the study of cancer theranostics efficiency. The T2 to T1 magnetic resonance imaging contrast switch was studied in vivo. Analyses of the tumor growth of mice were carried out to evaluate the tumor therapy efficiency. Results: We developed novel artificially controlled degradable Co3O4 nanoparticles and explored their potential in drug delivery/release. In the presence of ascorbic acid (AA), the designed nanomaterials can be degraded via a redox process and hence release the loaded drugs. Importantly, the AA, in the lack of l-gulonolactone oxidase, cannot be synthesized in the body of typical mammal including human, which suggested that the degradation process can be controlled artificially. Moreover, the obtained nanoparticles have outstanding photothermal conversion efficiency and their degradation can also result in an magnetic resonance imaging contrast enhancement switch from T2 to T1, which benefits the cancer theranostics. Conclusion: Our results illustrated that the artificially controlled degradable nanoparticles can serve as an alternative candidate for controllable drug release as well as a platform for highly efficient photothermal-chemo synergistic cancer theranostics.